{"pmid":"27751224","title":"An analysis of clinical characteristics and gene mutation in two patients with medium- and short-chain acyl-CoA dehydrogenase deficiency","abstract":"Medium- and short-chain acyl-CoA dehydrogenase deficiency is a disorder of fatty acid β-oxidation. Gene mutation prevents medium- and short-chain fatty acids from entry into mitochondria for oxidation, which leads to multiple organ dysfunction. In this study, serum acylcarnitines and the organic acid profile in urea were analyzed in two children whose clinical symptoms were hypoglycemia and metabolic acidosis. Moreover, gene mutations in the two children and their parents were evaluated. One of the patients was a 3-day-old male who was admitted to the hospital due to neonatal asphyxia, sucking weakness, and sleepiness. The serum acylcarnitine profile showed increases in medium-chain acylcarnitines (C6-C10), particularly in C8, which showed a concentration of 3.52 μmol/L (reference value: 0.02-0.2 μmol/L). The analysis of organic acids in urea gave a normal result. Sanger sequencing revealed a reported c.580A>G (p.Asn194Asp) homozygous mutation at exon 7 of the ACADM gene. The other patient was a 3-month-old female who was admitted to the hospital due to cough and recurrent fever for around 10 days. The serum acylcarnitine profile showed an increase in serum C4 level, which was 1.66 μmol/L (reference value: 0.06-0.6 μmol/L). The analysis of organic acids in urea showed an increase in the level of ethyl malonic acid, which was 55.9 (reference value: 0-6.2). Sanger sequencing revealed a reported c.625G>A (p.Gly209Ser) homozygous mutation in the ACADS gene. This study indicates that screening tests for genetic metabolic diseases are recommended for children who have unexplained metabolic acidosis and hypoglycemia. Genetic analyses of the ACADM and ACADS genes are helpful for the diagnosis of medium- and short-chain acyl-CoA dehydrogenase deficiency.","variants":[{"Name":"NM_000016.6(ACADM):c.580A>G (p.Asn194Asp)","Chromosome":"1","Start":"75740091","Stop":"75740091","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":227886,"rule_based_match":true,"evidence_text":"c.580A>G (p.Asn194Asp)","llm_judgment":"PRESENT","evidence":"c.580A>G (p.Asn194Asp)","abstract_start":915,"abstract_end":937}]}
{"pmid":"22876138","title":"A novel mutation in GJA3 associated with congenital Coppock-like cataract in a large Chinese family.","abstract":"PURPOSE: To identify the potential pathogenic mutation over five generations of a Chinese family with congenital Coppock-like cataracts (CCL).\nMETHODS: We investigated five generations of a Chinese family affected with CCL. The family resides in a relatively isolated region of northern China. Peripheral blood samples were collected from all of the family members, and genomic DNA was then extracted from the blood samples. A genome-wide linkage scan was performed using about 400 microsatellite markers. Two-point LOD (linkage odd disequilibrium) scores (Z) were calculated using the LINKAGE programs (ver. 5.1). Cyrillic software processed the resulting haplotypes. Mutation detection was performed in the candidate gene by direct sequencing.\nRESULTS: The maximum LOD score was obtained at marker D13S175 (lod score [Z(max)]=5.90; recombination fraction [θ]=0.0). Haplotype analysis traced the disease gene to a 6.99-cM interval bounded by D13S1316 and D13S1275 on chromosome 13q12.11. Direct sequencing of the candidate gene GJA3 (gap junction protein alpha-3) revealed a c.427G>A transition in exon 2 of GJA3 that co-segregated with the cataract in the family members and was not observed in 100 control patients. This single-nucleotide change resulted in the substitution of a highly conserved glycine by arginine (G143R).\nCONCLUSIONS: The present study identified a novel mutation in GJA3 that causes CCL. As the first report to relate p.G143R mutation in GJA3, it expands the mutation spectrum of GJA3. Our report is the first in identification of the mutation of GJA3 in the cytoplasmic-loop domain. This mutation is associated with multiple members of a five-generation family with congenital CCL.","variants":[{"Name":"NM_021954.4(GJA3):c.427G>A (p.Gly143Arg)","Chromosome":"13","Start":"20142862","Stop":"20142862","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":65608,"rule_based_match":true,"evidence_text":"c.427G>A","llm_judgment":"PRESENT","evidence":"c.427G>A","abstract_start":1076,"abstract_end":1084}]}
{"pmid":"30635863","title":"Type 1 Sialidosis Patient With a Novel Deletion Mutation in the NEU1 Gene: Case Report and Literature Review.","abstract":"Recent advances in next-generation sequencing technologies have uncovered the genetic backgrounds of various diseases. Type 1 sialidosis (OMIM#256550) is a rare autosomal recessive lysosomal storage disease caused by a mutation in the NEU1 (OMIM * 608272) gene. In this study, we aimed to review the previous reports of type 1 sialidosis and compare those with the first case of type 1 sialidosis in Korea. A 36-year-old woman presented with progressive ataxia, myoclonus, and seizure since the age of 12. Whole-exome sequencing revealed a pathogenic missense variant c.928G > A (p.D310N) and novel c.15_16del (p.P6Qfs*21) of the NEU1 gene as final causal candidate as compound heterozygotes. We reviewed the literature and selected the clinical reports of genetically confirmed type 1 sialidosis patients. A total of 45 patients in 17 reports were identified. Cherry-red spot, myoclonus, ataxia, and seizure were reported in 51.2%, 100.0%, 87.8%, and 73.7% of patients, respectively. Abnormalities of cognitive function, EEG, and brain MRI and visual symptoms were reported in 22.2%, 40.7%, 66.7%, and 70.2% of patients, respectively. Overall, our patient showed similar clinical features to previous type 1 sialidosis patients, but she did not complain of visual symptoms despite having cherry-red spots. We summarize the clinical features of type 1 sialidosis and report the first case of type 1 sialidosis with novel deletion variant in the NEU1 gene in the Korean population. Our study suggests the importance of ophthalmologic examinations in patients with myoclonus, ataxia, and seizure who do not complain of visual symptoms.","variants":[{"Name":"NM_000434.4(NEU1):c.928G>A (p.Asp310Asn)","Chromosome":"6","Start":"31860135","Stop":"31860135","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3073039,"rule_based_match":true,"evidence_text":"c.928G > A (p.D310N)","llm_judgment":"PRESENT","evidence":"c.928G > A (p.D310N)","abstract_start":568,"abstract_end":588}]}
{"pmid":"27049303","title":"Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families.","abstract":"Tooth development is controlled by the same processes that regulate formation of other ectodermal structures. Mutations in the genes underlying these processes may cause ectodermal dysplasia, including severe absence of primary or permanent teeth. Four consanguineous Palestinian families presented with oligodontia and hair and skin features of ectodermal dysplasia. Appearance of ectodermal dysplasia was consistent with autosomal recessive inheritance. Exome sequencing followed by genotyping of 56 informative relatives in the 4 families suggests that the phenotype is due to homozygosity for KREMEN1 p.F209S (c.626 T>C) on chromosome 22 at g.29,521,399 (hg19). The variant occurs in the highly conserved extracellular WSC domain of KREMEN1, which is known to be a high affinity receptor of Dickkopf-1, a component of the Dickkopf-Kremen-LRP6 complex, and a potent regulator of Wnt signaling. The Wnt signaling pathway is critical to development of ectodermal structures. Mutations in WNT10A, LRP6, EDA, and other genes in this pathway lead to tooth agenesis with or without other ectodermal anomalies. Our results implicate KREMEN1 for the first time in a human disorder and provide additional details on the role of the Wnt signaling in ectodermal and dental development.","variants":[{"Name":"NM_001039570.3(KREMEN1):c.626T>C (p.Phe209Ser)","Chromosome":"22","Start":"29125411","Stop":"29125411","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":380291,"rule_based_match":true,"evidence_text":"KREMEN1 p.F209S (c.626 T>C)","llm_judgment":"PRESENT","evidence":"KREMEN1 p.F209S (c.626 T>C)","abstract_start":597,"abstract_end":624}]}
{"pmid":"30300539","title":"The RET C611Y mutation causes MEN 2A and associated cutaneous","abstract":"Background: Cutaneous lichen amyloidosis (CLA) has been reported in some multiple endocrine neoplasia type 2A (MEN 2A) families affected by specific germline RET mutations C634F/G/R/W/Y or V804M, as a characteristic of the clinical manifestation in ‘MEN 2A with CLA’, one of four variants of MEN 2A, which was strictly located in the scapular region of the upper back.\nPatient Findings: This study reports a large south-eastern Chinese pedigree with 17 individuals carrying the MEN 2A-harboring germline C611Y (c.1832G>A) RET mutation by Sanger sequencing. One individual presented MEN 2A-related clinical features, including typical CLA in the interscapular region; another individual exhibited neurological pruritus and scratching in the upper back but lacked CLA skin lesions. Both subjects presented with CLA or pruritic symptoms several years before the onset of medullary thyroid carcinoma (MTC) and/or pheochromocytoma. The remaining 15 RET mutation carriers did not exhibit CLA; of these, one presented with MTC and pheochromocytoma, nine with MTC only, two with elevated serum calcitonin and three younger subjects with normal serum calcitonin levels. This family’s clinical data revealed a later diagnosis of MTC (mean age, 45.9 (range: 23–73) years), a lower penetrance of pheochromocytoma (2/17, 11.8%) and CLA (1/17, 5.9%). However, no hyperparathyroidism and Hirschsprung disease were reported in this family.\nSummary and Conclusions: This is the first description of a family with MEN 2A-related CLA due to a germline RET C611Y mutation, which might exhibit a novel and diversified genotype–phenotype spectrum in MEN 2A.","variants":[{"Name":"NM_020975.6(RET):c.1832G>A (p.Cys611Tyr)","Chromosome":"10","Start":"43113628","Stop":"43113628","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":36239,"rule_based_match":true,"evidence_text":"c.1832G>A","llm_judgment":"PRESENT","evidence":"c.1832G>A","abstract_start":511,"abstract_end":520}]}
{"pmid":"22959829","title":"Clinical picture of S-adenosylhomocysteine hydrolase deficiency resembles phosphomannomutase 2 deficiency.","abstract":"We report on the seventh known patient with S-adenosylhomocysteine hydrolase (SAHH) deficiency presenting at birth with features resembling phosphomannomutase 2 (PMM2-CDG Ia) deficiency. Plasma methionine and total homocysteine levels were normal at 2 months and increased only after the 8th month of age. SAHH deficiency was confirmed at 4.5 years of age by showing decreased SAHH activity (11% in both erythrocytes and fibroblasts), and compound heterozygosity for a known mutation c.145C>T (p.R49C) and a novel variant c.211G>A (p.G71S) in the AHCY gene. Retrospective analysis of clinical features revealed striking similarities between SAHH deficiency and the PMM2-CDG Ia.","variants":[{"Name":"NM_000687.4(AHCY):c.145C>T (p.Arg49Cys)","Chromosome":"20","Start":"34295469","Stop":"34295469","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":974190,"rule_based_match":true,"evidence_text":"c.145C>T (p.R49C)","llm_judgment":"PRESENT","evidence":"c.145C>T (p.R49C)","abstract_start":484,"abstract_end":501}]}
{"pmid":"29313432","title":"Hb Hornchurch [β43(CD2)Glu→Lys; HBB: c.130G>A] Compromises the Molecular Diagnosis of β-Thalassemia in a Chinese Family.","abstract":"The combination of β-thalassemia (β-thal) and a hemoglobin (Hb) variant is not uncommon in regions with a high prevalence of thalassemia. Although most of the β-globin chain variants will not aggravate the β-thal, some can compromise the accurate molecular diagnosis. In this study, we present a rare case of coinheritance of β-thal and Hb Hornchurch [β43(CD2)Glu→Lys; HBB: c.130G>A], that compromises the molecular diagnosis of homozygous β-thal.","variants":[{"Name":"NM_000518.5(HBB):c.130G>A (p.Glu44Lys)","Chromosome":"11","Start":"5226762","Stop":"5226762","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3731017,"rule_based_match":true,"evidence_text":"HBB: c.130G>A","llm_judgment":"PRESENT","evidence":"HBB: c.130G>A","abstract_start":369,"abstract_end":382}]}
{"pmid":"26516448","title":"Congenital Cutis Laxa Type 2 Associated With Recurrent Aspiration Pneumonia and Growth Delay: Case Report.","abstract":"Cutis laxa is a connective tissue disorder caused by deficiency of fibro elastic plexus, which can involve multiple organs. It is inherited in autosomal dominant, autosomal recessive, and X-linked. Autosomal recessive cutis laxa type 2, which appears to compromise a spectrum of disorders, starts with severe wrinkly skin syndrome and leads to more severe diseases related to growth and developmental delays and skeletal anomalies. The clinical manifestations in some of cases of Cutis laxa consist of redundant loose skin, pre-and post-natal growth deficiency, mental retardation, large fontanels, and dislocation of the hips. The authors present the case of a female patient with involved internal organ disorder and delay in growth in addition to skin laxity in which gene sequence analysis of PYCR1 indicated C.797G>A mutation.","variants":[{"Name":"NM_006907.4(PYCR1):c.797G>A (p.Arg266Gln)","Chromosome":"17","Start":"81934326","Stop":"81934326","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28229,"rule_based_match":true,"evidence_text":"C.797G>A","llm_judgment":"PRESENT","evidence":"C.797G>A","abstract_start":813,"abstract_end":821}]}
{"pmid":"27243668","title":"A Novel Interferon Regulatory Factor 6 Mutation in an Asian Family With Van der Woude Syndrome.","abstract":"Van der Woude syndrome (VWS) is a rare autosomal dominant genetic disorder characterized by orofacial clefting and lip pits. Mutations in the transcription factor interferon regulatory factor 6 gene (IRF6) have been identified in individuals with VWS. We performed direct sequencing of the gene for molecular investigation of a proband with Bangladeshi-Malay ancestry. A novel transition mutation (c.113T>C), which resulted in an amino acid substitution (p.Ile38Thr) in the deoxyribonucleic acid-binding domain was detected. Testing of family members showed that the mutation segregated with the VWS phenotype for members of her immediate family. Although there is some phenotypic variability, all of the affected members are of the female gender.","variants":[{"Name":"NM_006147.4(IRF6):c.113T>C (p.Ile38Thr)","Chromosome":"1","Start":"209801301","Stop":"209801301","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":384611,"rule_based_match":true,"evidence_text":"c.113T>C (p.Ile38Thr)","llm_judgment":"PRESENT","evidence":"p.Ile38Thr","abstract_start":455,"abstract_end":465}]}
{"pmid":"22605915","title":"A new mutation in the RP1L1 gene in a patient with occult macular dystrophy associated with a depolarizing pattern of focal macular electroretinograms.","abstract":"PURPOSE: To determine whether a mutation in the RP1-like protein 1 (RP1L1) gene is present in a Japanese patient with sporadic occult macular dystrophy (OMD) and to examine the characteristics of focal macular electroretinograms (ERGs) of the patient with genetically identified OMD.\nMETHODS: An individual with OMD underwent detailed ophthalmic clinical evaluations including focal macular ERGs. Mutation screening of all coding regions and flanking intron sequences of the RP1L1 gene were performed with DNA sequencing analysis in this case with OMD.\nRESULTS: A new RP1L1 mutation (c.3596 C>G in exon 4) was identified. The variant c.3596 C>G in exon 4 resulted in the substitution of cysteine for serine at amino acid position 1199. The serine at position 1199 is well conserved among the RP1L1 family in other species. Four out of five computational assessment tools predicted that this mutation is damaging to the protein function. This mutation was not present in 294 control alleles. The waveform of focal macular ERGs recorded from the patient with OMD had a depolarizing pattern, simulating the ERG waveforms observed after the hyperpolarizing bipolar cell activity is blocked.\nCONCLUSIONS: We have demonstrated in a Japanese patient the possibility that sporadic OMD may also be caused by an RP1L1 mutation. The waveform of focal macular ERGs elicited from the OMD patient with the RP1L1 mutation showed a depolarizing pattern. This characteristic is the same as reported for the focal macular ERGs of OMD.","variants":[{"Name":"NM_178857.6(RP1L1):c.3596C>G (p.Ser1199Cys)","Chromosome":"8","Start":"10610502","Stop":"10610502","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":214808,"rule_based_match":true,"evidence_text":"c.3596 C>G in exon 4","llm_judgment":"PRESENT","evidence":"c.3596 C>G in exon 4","abstract_start":584,"abstract_end":604}]}
{"pmid":"23613326","title":"ACTA2 mutation with childhood cardiovascular, autonomic and brain anomalies and severe outcome.","abstract":"Thoracic aortic aneurysm and dissection (TAAD) are associated with connective tissue disorders like Marfan syndrome and Loeys-Dietz syndrome, caused by mutations in the fibrillin-1, the TGFβ-receptor 1- and -2 genes, the SMAD3 and TGFβ2 genes, but have also been ascribed to ACTA2 gene mutations in adults, spread throughout the gene. We report on a novel de novo c.535C>T in exon 6 leading to p.R179C aminoacid substitution in ACTA2 in a toddler girl with primary pulmonary hypertension, persistent ductus arteriosus, extensive cerebral white matter lesions, fixed dilated pupils, intestinal malrotation, and hypotonic bladder. Recently, de novo ACTA2 R179H substitutions have been associated with a similar phenotype and additional cerebral developmental defects including underdeveloped corpus callosum and vermis hypoplasia in a single patient. The patient here shows previously undescribed abnormal lobulation of the frontal lobes and position of the gyrus cinguli and rostral dysplasis of the corpus callosum; she died at the age of 3 years during surgery due to vascular fragility and rupture of the ductus arteriosus. Altogether these observations support a role of ACTA2 in brain development, especially related to the arginine at position 179. Although all previously reported patients with R179H substitution successfully underwent the same surgery at younger ages, the severe outcome of our patient warns against the devastating effects of the R179C substitution on vasculature.","variants":[{"Name":"NM_001613.4(ACTA2):c.535C>T (p.Arg179Cys)","Chromosome":"10","Start":"88941310","Stop":"88941310","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":259943,"rule_based_match":true,"evidence_text":"c.535C>T","llm_judgment":"PRESENT","evidence":"c.535C>T","abstract_start":364,"abstract_end":372}]}
{"pmid":"30210231","title":"Novel homozygous splicing mutations in","abstract":"Purpose: Mutations in <i>ARL2BP,</i> encoding ADP-ribosylation factor-like 2 binding protein, have recently been implicated as a cause of autosomal recessive retinitis pigmentosa (arRP), with three homozygous variants identified to date. In this study, we performed next-generation sequencing to reveal additional arRP cases associated with <i>ARL2BP</i> variants.\nMethods: Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in 1,051 unrelated individuals recruited for the UK Inherited Retinal Disease Consortium and NIHR-BioResource Rare Diseases research studies. Sanger sequencing was used to validate the next-generation sequencing data, and reverse transcriptase (RT)-PCR analysis was performed on RNA extracted from blood from affected individuals to test for altered splicing of <i>ARL2BP</i>. Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography.\nResults: Homozygous variants in <i>ARL2BP</i> (NM_012106.3) were identified in two unrelated individuals with RP. The variants, c.207+1G>A and c.390+5G>A, at conserved splice donor sites for intron 3 and intron 5, respectively, were predicted to alter the pre-mRNA splicing of <i>ARL2BP</i>. RT-PCR spanning the affected introns revealed that both variants caused abnormal splicing of <i>ARL2BP</i> in samples from affected individuals.\nConclusions: This study identified two homozygous variants in <i>ARL2BP</i> as a rare cause of arRP. Further studies are required to define the underlying disease mechanism causing retinal degeneration as a result of mutations in <i>ARL2BP</i> and any phenotype-genotype correlation associated with residual levels of the wild-type transcript.","variants":[{"Name":"NM_012106.4(ARL2BP):c.207+1G>A","Chromosome":"16","Start":"57248644","Stop":"57248644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":431790,"rule_based_match":true,"evidence_text":"c.207+1G>A","llm_judgment":"PRESENT","evidence":"c.207+1G>A","abstract_start":1146,"abstract_end":1156}]}
{"pmid":"32246227","title":"Four novel mutations of FAM20A in amelogenesis imperfecta type IG and review of literature for its genotype and phenotype spectra.","abstract":"Amelogenesis imperfecta type IG (AI1G) is caused by mutations in FAM20A. Genotypic and phenotypic features of AI1G are diverse and their full spectra remain to be characterized. The aim of this study was to identify and summarize variants in FAM20A in a broad population of patients with AI1G. We identified a Thai female (Pt-1) and a Saudi male (Pt-2) affected with AI1G. Both had hypoplastic enamel, gingival hyperplasia, and intrapulpal calcification. Pt-1 also had rapidly progressive embedding of unerupted teeth, early eruption of permanent teeth, and spontaneous dental infection. Uniquely, Pt-2 had all permanent teeth erupted which was uncommon in AI1G patients. Whole exome sequencing (WES) identified that Pt-1 was heterozygous for FAM20A, c.758A > G (p.Tyr253Cys), inherited from her father. The mutation on maternal allele was not detected by WES. Pt-2 possessed compound heterozygous mutations, c.1248dupG (p.Phe417Valfs*7); c.1081C > T (p.Arg361Cys) in FAM20A. Array comparative genomic hybridization (aCGH), cDNA sequencing, and whole genome sequencing successfully identified 7531 bp deletion on Pt-1's maternal allele. This was the largest FAM20A deletion ever found. A review of all 70 patients from 50 independent families with AI1G (including two families in this study) showed that the penetrance of hypoplastic enamel and gingival hyperplasia was complete. Unerupted permanent teeth were found in all 70 patients except Pt-2. Exons 1 and 11 were mutation-prone. Most mutations were frameshift. Certain variants showed founder effect. To conclude, this study reviews and expands phenotypic and genotypic spectra of AI1G. A large deletion missed by WES can be detected by WGS. Hypoplastic enamel, gingival hyperplasia, and unerupted permanent teeth prompt genetic testing of FAM20A. Screening of nephrocalcinosis, early removal of embedded teeth, and monitoring of dental infection are recommended.","variants":[{"Name":"NM_017565.4(FAM20A):c.758A>G (p.Tyr253Cys)","Chromosome":"17","Start":"68543683","Stop":"68543683","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1684280,"rule_based_match":true,"evidence_text":"c.758A > G (p.Tyr253Cys)","llm_judgment":"PRESENT","evidence":"c.758A > G (p.Tyr253Cys)","abstract_start":751,"abstract_end":775}]}
{"pmid":"38369462","title":"","abstract":"PURPOSE: This study aims to evaluate the ABCA4 variants in patients diagnosed with Stargardt disease.\nMETHODS: This is a retrospective study designed to investigate variants in the ABCA4 in Stargardt disease and the clinical findings of the cases. Sex, age, age of onset of symptoms, best-corrected visual acuity, color fundus photography, optical coherence tomography, and visual field test of the patients were recorded. Genetic analyses were screened, and patients with at least two variants in the ABCA4 were included in this study.\nRESULTS: Twenty-seven patients diagnosed with Stargardt disease with the ABCA4 variants were included in this study. Twelve of them (44.4%) were female and fifteen (55.5%) were male. The mean age of the cases was 27.44 years (ranging from 8 to 56 years). Thirty different variants were detected in 54 ABCA4 alleles of 27 patients. The two most common pathogenic variants were c.5882 G>A p.(Gly1961Glu) and c.52C>T p.(Arg18Trp) in this cohort. Two novel variants were identified (c.3855_3856dup, c.1554 + 3_1554 + 4del) and the patient with the c.1554 + 3_1554 + 4del variant additionally had a different ABCA4 variant in trans. The other novel variant was homozygous.\nCONCLUSIONS: In this study, two novel variants were described in a Turkish cohort with Stargardt disease. The variant c.52C>T p.(Arg18Trp) was the most common disease-causing variant besides the c.5882 G>A p.(Gly1961Glu) which was identified frequently in the previous studies. A larger sample size is necessary for describing different pathogenic variants and understanding the phenotype-genotype correlations.","variants":[{"Name":"NM_000350.3(ABCA4):c.52C>T (p.Arg18Trp)","Chromosome":"1","Start":"94120994","Stop":"94120994","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22938,"rule_based_match":true,"evidence_text":"c.52C>T p.(Arg18Trp)","llm_judgment":"PRESENT","evidence":"c.52C>T p.(Arg18Trp)","abstract_start":943,"abstract_end":963}]}
{"pmid":"34248956","title":"A Novel Mutation in the NBD Domain of","abstract":"Background: NOD-like receptor family CARD-containing 4 protein (NLRC4) is a cytosolic protein that forms an inflammasome in response to flagellin and type 3 secretion system (T3SS) proteins from invading Gram-negative bacteria. <i>NLRC4</i> mutations have been recently identified in early-onset severe autoinflammatory disorders. In this study, we reported a novel mutation in <i>NLRC4</i> in two Chinese patients, who manifested with recurrent urticaria and arthralgia.\nMethods: We summarized the clinical data of the two patients. Gene mutations were identified by whole-exome sequencing (WES). Swiss-PdbViewer was used to predict the pathogenicity of the identified mutations. Cytokine levels and caspase-1 activation were detected in the patient PBMCs with lipopolysaccharide (LPS) stimulation. All previously published cases with <i>NLRC4</i> mutations were reviewed.\nResults: We identified a missense heterozygous mutation (c.514G>A, p.Gly172Ser), which was located in the highly conserved residue of nucleotide-binding domain (NBD) of NLRC4. The mutation did not alter the expression of NLRC4 protein, but induced considerably much higher production of IL-1β and IL-6 in patient PBMCs than in healthy controls after LPS stimulation. Four NLRC4 inflammasomopathy phenotypes have been described, with severe inflammatory diseases including macrophage activation syndrome, enterocolitis and NOMID in patients with mutations in the NBD and HD1 domains, whereas a mild clinical phenotype was associated with two mutations in the WHD domain of NLRC4.\nConclusion: We identified a novel mutation in the NBD domain, and the patients just presented with a mild inflammatory phenotype. Thus, our findings reinforce the diversity of <i>NLRC4</i> mutations and expand the clinical spectrum of associated diseases.","variants":[{"Name":"NM_001199138.2(NLRC4):c.514G>A (p.Gly172Ser)","Chromosome":"2","Start":"32251350","Stop":"32251350","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":795231,"rule_based_match":true,"evidence_text":"c.514G>A, p.Gly172Ser","llm_judgment":"PRESENT","evidence":"c.514G>A, p.Gly172Ser","abstract_start":931,"abstract_end":952}]}
{"pmid":"25529926","title":"Lipoid proteinosis: phenotypic heterogeneity in Iranian families with c.507delT mutation in ECM1.","abstract":"Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis caused by loss-of-function mutations in the ECM1 gene, and previous studies have noted phenotypic variability. In this study, we examined 12 patients representing three Iranian families for clinical manifestations and genotyped them for mutations in ECM1. LP was diagnosed with characteristic mucocutaneous and neurologic manifestations. Five patients were also subjected to magnetic resonance imaging (MRI)/computed tomography (CT) scan of the central nervous system. DNA was isolated from peripheral blood from patients and their clinically unaffected relatives, and mutations in ECM1 were sought by PCR-based amplification of all exons and flanking intronic sequences, followed by bidirectional Sanger sequencing. Significant phenotypic variability in this multisystem disorder, including presence of convulsions and epilepsy in about half of the patients was noted. In most cases, this was associated with calcifications in the brain detected by MRI/CT scans. Genotyping of the affected individuals in three families from the central region of Iran revealed presence of homozygous c.507delT mutation in ECM1, reflecting the observed consanguinity in these families. This large cohort revealed extensive phenotypic variability in individuals with the same mutation in ECM1. This observation suggests a role for genetic and epigenetic as well as environmental modulation of the phenotype. Identification of mutations allows screening of unaffected individuals for presence or absence of this mutation in extended LP families, with implications for genetic counseling.","variants":[{"Name":"NM_004425.4(ECM1):c.507del (p.Arg171fs)","Chromosome":"1","Start":"150510997","Stop":"150510997","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":224660,"rule_based_match":true,"evidence_text":"c.507delT","llm_judgment":"PRESENT","evidence":"c.507delT","abstract_start":1154,"abstract_end":1163}]}
{"pmid":"20453710","title":"Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy.","abstract":"This patient presented on the first day of life with pronounced lactic acidosis with an elevated lactate/pyruvate ratio. Urine organic acids showed Krebs cycle metabolites and mildly elevated methylmalonate and methylcitrate. The acylcarnitine profile showed elevated propionylcarnitine and succinylcarnitine. Amino acids showed elevated glutamic acid, glutamine, proline, and alanine. From the age 2 of mo on, she had elevated transaminases and intermittent episodes of liver failure. Liver biopsy showed steatosis and a decrease of mitochondrial DNA to 50% of control. She had bilateral sensorineural hearing loss. Over the course of the first 2 y of life, she developed a progressively severe myopathy with pronounced muscle weakness eventually leading to respiratory failure, Leigh disease, and recurrent hepatic failure. The hepatic symptoms and the metabolic parameters temporarily improved on treatment with aspartate, but neither muscle symptoms nor brain lesions improved. Laboratory testing revealed a deficiency of succinyl-CoA ligase enzyme activity and protein in fibroblasts because of a novel homozygous mutation in the SUCLG1 gene: c.40A>T (p.M14L). Functional analysis suggests that this methionine is more likely to function as the translation initiator methionine, explaining the pathogenic nature of the mutation. Succinyl-CoA ligase deficiency due to an SUCLG1 mutation is a new cause for mitochondrial hepatoencephalomyopathy.","variants":[{"Name":"NM_003849.4(SUCLG1):c.40A>T (p.Met14Leu)","Chromosome":"2","Start":"84459230","Stop":"84459230","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":552068,"rule_based_match":true,"evidence_text":"c.40A>T (p.M14L)","llm_judgment":"PRESENT","evidence":"c.40A>T (p.M14L)","abstract_start":1148,"abstract_end":1164}]}
{"pmid":"21503673","title":"Prevalence of the most frequent BRCA1 mutations in Polish population.","abstract":"The purpose of our study was to establish the frequency and distribution of the four most common BRCA1 mutations in Polish general population and in a series of breast cancer patients. Analysis of the population frequency of 5382insC (c.5266dupC), 300T >G (p.181T >G), 185delAG (c.68_69delAG) and 3819del5 (c.3700_3704del5) mutations of the BRCA1 gene were performed on a group of respectively 16,849, 13,462, 12,485 and 3923 anonymous samples collected at birth in seven Polish provinces. The patient group consisted of 1845 consecutive female breast cancer cases. The most frequent BRCA1 mutation in the general population was 5382insC found in 29 out of 16,849 samples (0.17%). 300T >G and 3819del5 mutations were found in respectively 11 of 13,462 (0.08%) and four of 3923 (0.1%) samples. The population prevalence for combined Polish founder 5382insC and 300T >G mutations was 0.25% (1/400). The frequencies of 5382insC and 300T >G carriers among consecutive breast cancer cases were, respectively, 1.9% (35/1845) and 1.2% (18/1486). Comparing these data with the population frequency, we calculated the relative risk of breast cancer for 5382insC mutation at OR = 17 and for 300T >G mutation at OR = 26. Our results, based on large population studies, show high frequencies of founder 5382insC and 300T >G BRCA1 mutations in Polish general population. Carriage of one of these mutations is connected with a very high relative risk of breast cancer.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"c.5266dup","llm_judgment":"PRESENT","evidence":"c.5266dup","abstract_start":235,"abstract_end":244}]}
{"pmid":"32000930","title":"Omenn Syndrome Identified by Newborn Screening.","abstract":"Severe combined immunodeficiency (SCID) encompasses a group of genetic defects. T cell development is universally affected and has alteration of B and/or NK cells. We present the case of a 5-day-old boy with combined heterozygous frame shift (c.256_257del, p.(Lys86Valfs*33)) and missense (c.1186C>T, p.(Arg396Cys)) variations in the RAG1 gene. He was admitted to our institution because of 0 TREC on Newborn Screen and worsening rash. Initially thought to have Omenn syndrome versus maternal engraftment with graft versus host disease, DNA analysis identified the noted mutations and he subsequently received a bone marrow transplant from a matched sibling.","variants":[{"Name":"NM_000448.3(RAG1):c.1186C>T (p.Arg396Cys)","Chromosome":"11","Start":"36574490","Stop":"36574490","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28183,"rule_based_match":true,"evidence_text":"c.1186C>T (p.Arg396Cys)","llm_judgment":"PRESENT","evidence":"c.1186C>T","abstract_start":290,"abstract_end":299}]}
{"pmid":"23704329","title":"Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome.","abstract":"The sulfated polysaccharide dermatan sulfate (DS) forms proteoglycans with a number of distinct core proteins. Iduronic acid-containing domains in DS have a key role in mediating the functions of DS proteoglycans. Two tissue-specific DS epimerases, encoded by DSE and DSEL, and a GalNAc-4-O-sulfotransferase encoded by CHST14 are necessary for the formation of these domains. CHST14 mutations were previously identified for patients with the musculocontractural type of Ehlers-Danlos syndrome (MCEDS). We now identified a homozygous DSE missense mutation (c.803C>T, p.S268L) by the positional candidate approach in a male child with MCEDS, who was born to consanguineous parents. Heterologous expression of mutant full-length and soluble recombinant DSE proteins showed a loss of activity towards partially desulfated DS. Patient-derived fibroblasts also showed a significant reduction in epimerase activity. The amount of DS disaccharides was markedly decreased in the conditioned medium and the cell fraction from cultured fibroblasts of the patient when compared with a healthy control subject, whereas no apparent difference was observed in the chondroitin sulfate (CS) chains from the conditioned media. However, the total amount of CS disaccharides in the cell fraction from the patient was increased ∼1.5-fold, indicating an increased synthesis or a reduced conversion of CS chains in the cell fraction. Stable transfection of patient fibroblasts with a DSE expression vector increased the amount of secreted DS disaccharides. DSE deficiency represents a specific defect of DS biosynthesis. We demonstrate locus heterogeneity in MCEDS and provide evidence for the importance of DS in human development and extracellular matrix maintenance.","variants":[{"Name":"NM_013352.4(DSE):c.803C>T (p.Ser268Leu)","Chromosome":"6","Start":"116431086","Stop":"116431086","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":94417,"rule_based_match":true,"evidence_text":"c.803C>T, p.S268L","llm_judgment":"PRESENT","evidence":"c.803C>T, p.S268L","abstract_start":556,"abstract_end":573}]}
{"pmid":"34686677","title":"A novel deep intronic variant strongly associates with Alkaptonuria.","abstract":"Alkaptonuria is a rare autosomal recessive inherited disorder of tyrosine metabolism, which causes ochronosis, arthropathy, cardiac valvular calcification, and urolithiasis. The epidemiology of alkaptonuria in East Asia is not clear. In this study, patients diagnosed with alkaptonuria from January 2010 to June 2020 were reviewed. Their clinical and molecular features were further compared with those of patients from other countries. Three patients were found to have alkaptonuria. Mutation analyses of the homogentisate 1,2-dioxygenase gene (HGD) showed four novel variants c.16-2063 A > C, p.(Thr196Ile), p.(Gly344AspfsTer25), and p.(Gly362Arg) in six mutated alleles (83.3%). RNA sequencing revealed that c.16-2063 A > C activates a cryptic exon, causing protein truncation p.(Tyr5_Ile6insValTer17). A literature search identified another 6 patients with alkaptonuria in East Asia; including our cases, 13 of the 18 mutated alleles have not been reported elsewhere in the world. Alkaptonuria is rare in Taiwan and East Asia, with HGD variants being mostly novel and private.","variants":[{"Name":"NM_000187.4(HGD):c.16-2063A>C","Chromosome":"3","Start":"120677926","Stop":"120677926","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1254248,"rule_based_match":true,"evidence_text":"c.16-2063 A > C","llm_judgment":"PRESENT","evidence":"c.16-2063 A > C","abstract_start":578,"abstract_end":593}]}
{"pmid":"34904211","title":"Spinal cord injury-related thermoregulatory impairment masks a fatal malignant hyperthermia crisis: a case report.","abstract":"PURPOSE: Malignant hyperthermia (MH) is a hypermetabolic disorder that can occur in genetically susceptible individuals exposed to halogenated anesthetics and succinylcholine. Spinal cord injury (SCI) above the sixth thoracic vertebra is associated with dysfunction of the sympathetic/parasympathetic nervous pathways, including thermoregulatory dysfunction, presenting as hypothermia in cold environments because of vasodilation and heat loss. This effect could mitigate or obscure an MH episode. Here, we describe development of a fatal MH crisis in a patient with SCI.\nCLINICAL FEATURES: A 27-yr-old male patient with an SCI after fracture of the sixth cervical vertebra was admitted for spinal arthrodesis. Anesthetic medications included remifentanil, propofol, succinylcholine, rocuronium, and isoflurane. After the start of the surgery, muscular contractures resembling myoclonus were noted, which resolved with pancuronium administration. Four hours after the start of anesthesia, the patient presented with hyperthermia, hypercarbia, hypotension, muscle rigidity, arrhythmia, and cardiogenic shock, with metabolic/respiratory acidosis. Malignant hyperthermia was suspected and the treatment was started, but he developed cardiopulmonary arrest and died an hour and a half after the first cardiac arrest. Both parents were investigated and were found to have normal creatine kinase levels and positive in vitro contracture tests. His mother carried a variant in the ryanodine receptor type 1 (RYR1) gene (c.14918C>T), which is associated with MH.\nCONCLUSION: Spinal cord injury-induced thermoregulatory dysfunction may obscure the early diagnosis of MH and lead to fatal outcome.","variants":[{"Name":"NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu)","Chromosome":"19","Start":"38586140","Stop":"38586140","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":136845,"rule_based_match":true,"evidence_text":"c.14918C>T","llm_judgment":"PRESENT","evidence":"c.14918C>T","abstract_start":1513,"abstract_end":1523}]}
{"pmid":"23691375","title":"Trichorhinophalangeal Syndrome Type I: A Patient with Two Novel and Different Mutations in the TRPS1 Gene.","abstract":"Background. Trichorhinophalangeal syndrome (TRPS) is an autosomal dominant skeletal dysplasia caused by defects involving the TRPS1 gene. Three types (TRPSs I, II, and III) have been described, exhibiting the common triad of hair, craniofacial, and skeletal abnormalities. TRPS II includes the additional characteristics of mental retardation and multiple exostoses. Case Report. We describe a sporadic case of TRPS type I in a child with two novel nonsense pathogenic mutations in the TRPS1 gene, both in heterozygosity-c.1198C>T (p. Gln400X) and c.2086C>T (p.Arg696X). None of these mutations were found in her parents. Clinical presentation included typical hair and facial features, as well as slight skeletal abnormalities. Discussion. There is a wide variability in clinical expression of TRPS I. Manifestations of the disease can be subtle, yet skeletal anomalies imply that TRPS I is more than an esthetic problem. Clinical and genetic diagnosis allows adequate followup and timely therapeutic procedures. When a single mutation was sufficient for the onset of the disease, our patient presented two different ones.","variants":[{"Name":"NM_014112.5(TRPS1):c.2086C>T (p.Arg696Ter)","Chromosome":"8","Start":"115603883","Stop":"115603883","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":561897,"rule_based_match":true,"evidence_text":"c.2086C>T (p.Arg696X)","llm_judgment":"PRESENT","evidence":"c.2086C>T (p.Arg696X)","abstract_start":548,"abstract_end":569}]}
{"pmid":"24080738","title":"Cosegregation of focal segmental glomerulosclerosis in a family with familial partial lipodystrophy due to a mutation in LMNA.","abstract":"BACKGROUND AND AIM: Focal segmental glomerulosclerosis (FSGS) is a common cause of idiopathic nephrotic syndrome in adults (35%). A number of genetic and familial forms of FSGS have been recognized. Here, we report a large pedigree with a pathogenic mutation in LMNA (R349W) in which four members were found to have biopsy-proven FSGS. The LMNA gene codes for lamins A and C, major components of the nuclear lamina which function in nuclear architecture, integrity and the regulation of gene expression.\nMETHODS: Pedigree screening and mutation analysis of LMNA gene in all family members. Renal biopsies were performed in proteinuric patients. A molecular 3D model of the familial LMNA mutation was constructed.\nRESULTS: There were a total of 16 affected members from four generations, 12 of whom were found to carry the germline LMNA mutation. All affected adults had clinical features of familial partial lipodystrophy (FPLD) of the non-Dunnigan variety. Four patients within the same generation presented with a variable degree of renal impairment and proteinuria. Renal biopsies from all four revealed FSGS. The familial mutation is a missense change (R349W) in exon 6 of LMNA (c.1045C>T).\nCONCLUSIONS: We report a genetic link between LMNA and biopsy-proven FSGS in a large pedigree with FPLD. This unexpected association extends the disease spectrum of LMNA to the kidney and suggests that the physiological role of LMNA could be relevant to the maintenance of glomerular structure and function.","variants":[{"Name":"NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)","Chromosome":"1","Start":"156136009","Stop":"156136009","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77659,"rule_based_match":true,"evidence_text":"c.1045C>T","llm_judgment":"PRESENT","evidence":"c.1045C>T","abstract_start":1183,"abstract_end":1192}]}
{"pmid":"33190188","title":"Two Cases of Female Chinese Adult-Onset Krabbe Disease with One Novel Mutation and a Review of Literature.","abstract":"This study presented two Chinese adult female patients who were diagnosed with adult-onset Krabbe disease (KD) and reviewed this disease in Chinese patients. Two young female adults in their 20s were enrolled in this study. Clinical data, including symptoms, magnetic resonance imaging (MRI) scanning, and laboratory studies were collected. Sequence alignment and structural modeling were carried out to analyze the pathogenesis of the disease. Both patients were adult-onset and both had a mild clinical course, presented with spastic weakness. The MRI study showed demyelination confined to the corticospinal tracts and parieto-occipital white matter. The β-galactocerebrosidase (GALC) activity was obviously decreased in both patients. Gene test of GALC showed that both patients were compound heterozygotes; proband I was a carrier of p.L634S (c.1901 T > C) and p.I250T (c.749 T > C), while proband II was a carrier of p.L634S (c.1901 T > C) and a new variant of c.283_284del. Molecular analysis revealed the variants may influence the function of GALC. We provided two Chinese adult-onset KD, and the clinical and genetic characteristics of proband II was especially rare due to asymmetric symptoms, spinal cord involvement, and the identification of a new point mutation c.283_284del in the GALC gene. Variant c.749 T > C can present mild syndromes except for severe cases. c.283_284del is a new variant that may occur in adult-onset type.","variants":[{"Name":"NM_000153.4(GALC):c.283_284del (p.Leu95fs)","Chromosome":"14","Start":"87988188","Stop":"87988189","ReferenceAlleleVCF":"CAA","AlternateAlleleVCF":"C","allel_id":1425878,"rule_based_match":true,"evidence_text":"c.283_284del","llm_judgment":"PRESENT","evidence":"c.283_284del","abstract_start":967,"abstract_end":979}]}
{"pmid":"38660671","title":"Two missense","abstract":"BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11 (<i>STK11</i>/<i>LKB1</i>) gene mutations. Preimplantation genetic testing can protect a patient's offspring from mutated genes; however, some variations in this gene have been interpreted as variants of uncertain significance (VUS), which complicate reproductive decision-making in genetic counseling.\nAIM: To identify the pathogenicity of two missense variants and provide clinical guidance.\nMETHODS: Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya. Software was employed to predict the protein structure, conservation, and pathogenicity of the two missense variation sites in patients with PJS. Additionally, plasmids were constructed and transfected into HeLa cells to observe cell growth. The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry. Statistical analysis was performed using one-way analysis of variance. <i>P <</i> 0.05 was considered statistically significant.\nRESULTS: We identified two missense <i>STK11</i> gene VUS [c.889A>G (p.Arg297Gly) and c.733C>T (p.Leu245Phe)] in 9 unrelated PJS families who were seeking reproductive assistance. The two missense VUS were located in the catalytic domain of serine/threonine kinase, which is a key structure of the liver kinase B1 (LKB1) protein. <i>In vitro</i> experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells. In addition, the two missense <i>STK11</i> variants promoted the proliferation of HeLa cells. Subsequent immunohistochemical analysis showed that phosphorylated-AMPK (Thr172) expression was significantly lower in gastric, colonic, and uterine polyps from PJS patients with missense variations than in non-PJS patients. Our findings indicate that these two missense <i>STK11</i> variants are likely pathogenic and inactivate the <i>STK11</i> gene, causing it to lose its function of regulating downstream phosphorylated-AMPK (Thr172), which may lead to the development of PJS. The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance.\nCONCLUSION: These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients. These findings not only offer insights for clinical decision-making, but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.","variants":[{"Name":"NM_000455.5(STK11):c.733C>T (p.Leu245Phe)","Chromosome":"19","Start":"1220716","Stop":"1220716","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3416580,"rule_based_match":true,"evidence_text":"c.733C>T (p.Leu245Phe)","llm_judgment":"PRESENT","evidence":"c.733C>T (p.Leu245Phe)","abstract_start":1323,"abstract_end":1345}]}
{"pmid":"27830356","title":"Successful treatment of a patient with ethylmalonic encephalopathy by intravenous N-acetylcysteine.","abstract":"Ethylmalonic encephalopathy (EE) is an autosomal recessive devastating metabolic disorder affecting the brain, gastrointestinal tract, peripheral vessels and rarely the other vascular organs. We report a 10-month-old girl who presented as a meningococcemia clinic but later diagnosed ethylmalonic encephalopathy. Molecular analyses revealed a homozygous c.554 T > G; p. L185R mutation in ETHE1 gene. She was only partially benefited from riboflavine, coenzyme Q10, metronidazole, N-acetylcysteine and symptomatic treatment and discharged from hospital with the sequela of oxygene dependance and developmental delay. We observed N-acetylcysteine 100 mg/kg/day intravenous infusion theraphy may be the most important drug especially in comatous EE patients.","variants":[{"Name":"NM_014297.5(ETHE1):c.554T>G (p.Leu185Arg)","Chromosome":"19","Start":"43508816","Stop":"43508816","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":39682,"rule_based_match":true,"evidence_text":"c.554 T > G; p. L185R","llm_judgment":"PRESENT","evidence":"c.554 T > G; p. L185R","abstract_start":354,"abstract_end":375}]}
{"pmid":"31815888","title":"Metachronous Wilms Tumor, Glioblastoma, and T-cell Leukemia in an Child With Constitutional Mismatch Repair Deficiency syndrome due to Novel Mutation in MSH6 (c.2590G>T).","abstract":"Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer predisposition syndrome results from biallelic germline mutations affecting the key DNA mismatch repair gene: MLH1, MSH2, MSH6, or PMS2. CMMRD is associated with a high risk of developing early onset of central nervous system tumors, hematologic, and intestinal tract tumors. Clinical manifestations, genetic screening, and cancer prevention strategies are limited. In this report we present a patient with metachronous Wilms tumor, glioblastoma, and acute T-cell lymphoblastic leukemia. He had cutaneous features of neurofibromatosis type 1 (NF1). Molecular testing revealed a novel homozygous mutation in MSH6 (c.2590G>T; p.G864*) that has not been reported previously. CMMRD should be considered in patients with cutaneous features similar to NF1 if tumor is found other than expected tumors in NF, early onset cancer, and strong family history of cancer.","variants":[{"Name":"NM_000179.3(MSH6):c.2590G>T (p.Gly864Ter)","Chromosome":"2","Start":"47800573","Stop":"47800573","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1845647,"rule_based_match":true,"evidence_text":"c.2590G>T (p.G864*)","llm_judgment":"PRESENT","evidence":"c.2590G>T","abstract_start":718,"abstract_end":727}]}
{"pmid":"31968260","title":"Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants.","abstract":"Increased calpain activity is linked to neuroinflammation including a heritable retinal disease caused by hyper-activating mutations in the calcium-activated calpain-5 (CAPN5) protease. Although structures for classical calpains are known, the structure of CAPN5, a non-classical calpain, remains undetermined. Here we report the 2.8 Å crystal structure of the human CAPN5 protease core (CAPN5-PC). Compared to classical calpains, CAPN5-PC requires high calcium concentrations for maximal activity. Structure-based phylogenetic analysis and multiple sequence alignment reveal that CAPN5-PC contains three elongated flexible loops compared to its classical counterparts. The presence of a disease-causing mutation (c.799G>A, p.Gly267Ser) on the unique PC2L2 loop reveals a function in this region for regulating enzymatic activity. This mechanism could be transferred to distant calpains, using synthetic calpain hybrids, suggesting an evolutionary mechanism for fine-tuning calpain function by modifying flexible loops. Further, the open (inactive) conformation of CAPN5-PC provides structural insight into CAPN5-specific residues that can guide inhibitor design.","variants":[{"Name":"NM_004055.5(CAPN5):c.799G>A (p.Gly267Ser)","Chromosome":"11","Start":"77115494","Stop":"77115494","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":947668,"rule_based_match":true,"evidence_text":"c.799G>A, p.Gly267Ser","llm_judgment":"PRESENT","evidence":"c.799G>A, p.Gly267Ser","abstract_start":714,"abstract_end":735}]}
{"pmid":"25695920","title":"A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype.","abstract":"SPG10 is an autosomal dominant hereditary spastic paraplegia (HSP) caused by mutations in the gene KIF5A encoding the heavy chain of kinesin, a motor protein implied in motility functions within cells. Most of the KIF5A mutations are clustered in 2 areas of motor domain of the protein, the switch regions I and II, that are necessary for microtubules interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging from pure HSP to isolated peripheral nerve involvement (Charcot-Marie-Tooth phenotype) or complicated HSP phenotypes. We here describe a patient presenting with progressive walking difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed axonal damage of peripheral nerves at lower limbs. We identified the novel variant c.967C>T in the KIF5A gene resulting in the R323W change, which is located at the C-terminus of the motor domain of the KIF5A protein, just upstream the linker region but out of the switch regions. Our findings confirm that the \"mixed\" central-peripheral involvement is the most frequent clinical picture related to KIF5A motor domain mutations and that motor domain \"in toto,\" even outside of the switch regions, is a hot spot for pathogenic mutations. We stress the concept that detection of a peripheral axonal neuropathy in an autosomal dominant HSP patient should be regarded as an important diagnostic tool and should guide clinicians to seek, first of all, KIF5A mutations.","variants":[{"Name":"NM_004984.4(KIF5A):c.967C>T (p.Arg323Trp)","Chromosome":"12","Start":"57569403","Stop":"57569403","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":399176,"rule_based_match":true,"evidence_text":"c.967C>T","llm_judgment":"PRESENT","evidence":"c.967C>T","abstract_start":1004,"abstract_end":1012}]}
{"pmid":"33262786","title":"Targeted Next-Generation Sequencing in the Diagnosis of Facial Dysostoses.","abstract":"BACKGROUND: Defects in the development of the first and second pharyngeal arches and their derivatives result in abnormal formation of the craniofacial complex, consequently giving rise to facial dysostoses (FDs). FDs represent a group of rare and highly heterogeneous disease entities that encompass mandibulofacial dysostoses (MFDs) with normal extremities and acrofacial dysostoses (AFDs) with limb anomalies in addition to craniofacial defects.\nMETHODS: We examined 11 families with variable clinical symptoms of FDs, in most of which only one member was affected. We applied two custom gene panels-first comprising 37 genes related to the genetic disorders of craniofacial development such as FDs (On-Demand AmpliSeq Thermo Fisher Scientific gene panel with two primer pools) and second composed of 61 genes and 11 single nucleotide variants (SNVs) known to be involved in the development of skull malformations, mainly in the form of craniosynostoses (SureSelect Agilent Technologies). Targeted next-generation sequencing (NGS) was performed using the Ion Torrent S5 platform. To confirm the presence of each detected variant, we have analyzed a genomic region of interest using Sanger sequencing.\nRESULTS: In this paper, we summarized the results of custom targeted gene panel sequencing in the cohort of sixteen patients from 11 consecutive families affected by distinct forms of FDs. We have found three novel pathogenic variants in the <i>TCOF1</i> gene-c.2145_2148dupAAAG p.(Ser717Lys<i>fs</i> <sup>∗</sup>42), c.4370delA p.(Lys1457Arg<i>fs</i> <sup>∗</sup>118), c.83G>C p.(Arg28Pro) causing Treacher Collins syndrome type 1, two novel missense variants in the <i>EFTUD2</i> gene-c.491A>G p.(Asp164Gly) and c.779T>A p.(Ile260Asn) in two female patients affected by acrofacial dysostosis Guion-Almeida type, one previously reported-c.403C>T (p.Arg135Cys), as well as one novel missense variant-c.128C>T p.(Pro43Leu) in the <i>DHODH</i> gene in the male patient with Miller syndrome and finally one known pathogenic variant c.574G>T p.(Glu192<sup>∗</sup>) in the <i>SF3B4</i> gene in the patient with Nager syndrome.\nCONCLUSION: Our study confirms the efficiency and clinical utility of the targeted gene panel sequencing and shows that this strategy is suitable and efficient in the molecular screening of variable forms of FDs.","variants":[{"Name":"NM_001361.5(DHODH):c.403C>T (p.Arg135Cys)","Chromosome":"16","Start":"72014641","Stop":"72014641","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31840,"rule_based_match":true,"evidence_text":"c.403C>T (p.Arg135Cys)","llm_judgment":"PRESENT","evidence":"c.403C>T (p.Arg135Cys)","abstract_start":1842,"abstract_end":1864}]}
{"pmid":"25100374","title":"Childhood hypophosphatasia with homozygous mutation of ALPL.","abstract":"OBJECTIVE: To describe an unusual phenotype of a case with rare homozygous ALPL gene mutation that results in mild form of hypophosphatasia.\nMETHODS: Case presentation, description of biochemical profiles, genetic testing and a brief review of literature are presented.\nRESULTS: A 13-year-old male presented with chronic left knee pain. Radiogram of the left knee indicated two oval radiolucent lesions in the femoral metaphysis. Serum alkaline phosphatase activity (17 U/L) was markedly below normal (42 to 362 U/L). Serum pyridoxal 5' phosphate (258 μg/L) was above normal (5 to 50 μg/L). Sequence analysis of ALPL gene indicated a homozygous missense mutation c.1077 C>G (p. I359M). The mutation was previously identified in a case of perinatal hypophosphatasia with severe skeletal abnormalities in contrast to the mild phenotype of the patient we present.\nCONCLUSION: The case of homozygous mutation of ALPL gene but mild form of hypophosphatasia suggests that functions of the mutated protein may be modified by other factors.","variants":[{"Name":"NM_000478.6(ALPL):c.1077C>G (p.Ile359Met)","Chromosome":"1","Start":"21575812","Stop":"21575812","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":930290,"rule_based_match":true,"evidence_text":"c.1077 C>G (p. I359M)","llm_judgment":"PRESENT","evidence":"c.1077 C>G (p. I359M)","abstract_start":663,"abstract_end":684}]}
{"pmid":"22166512","title":"A rare splicing mutation in the PROS1 gene of a Korean patient with type I hereditary protein S deficiency.","abstract":"Hereditary protein S (PS) deficiency (Gene ID: 5627; MIM # 176880) is a notable risk factor for recurrent venous thrombosis, inherited as an autosomal-dominant trait, either homozygous or heterozygous. It may be caused by point mutations in the gene (PROS1) encoding PS, which contains 15 exons on the chromosome 3q11.2. Only a few point mutations associated with the PROS1 gene in patients with hereditary PS deficiency have been reported. A 60-year-old woman was admitted for deep vein thrombosis (DVT) of the right lower extremity. Upon coagulation examination, both the free PS antigen level and the total PS antigen level were decreased, so the DNA-PCR products of all 15 exons, including the exon-intron boundaries of the PROS1, gene were directly sequenced. A substitution from guanine to adenine at position +5 of the donor splice site of intron 10 (c.1155+5G>A) was identified. Further familial study was performed, and the patient's older sister was revealed to have the same mutation; she was already taking warfarin due to diagnosed pulmonary thromboembolism. Here we report a G to A transition at position +5 of intron 10 from the splice donor site as a rare case of a patient with type I hereditary PS deficiency in Korea.","variants":[{"Name":"NM_000313.4(PROS1):c.1155+5G>A","Chromosome":"3","Start":"93892928","Stop":"93892928","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":615722,"rule_based_match":true,"evidence_text":"c.1155+5G>A","llm_judgment":"PRESENT","evidence":"c.1155+5G>A","abstract_start":858,"abstract_end":869}]}
{"pmid":"22572734","title":"Selective haploinsufficiency of longer isoforms of PTCH1 protein can cause nevoid basal cell carcinoma syndrome.","abstract":"Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. The PTCH1 gene has five alternatively used first exons resulting in the translation of three isoforms of the PTCH1 protein; that is, PTCHL, PTCHM and PTCHS. However, the biological significance of each isoform is unclear. Here we show an individual with NBCCS carrying a nonsense mutation in PTCH1 exon2, c.387G>A (p.W129X). As the mutation lay upstream of the ATG codon used for PTCHS translation, the mutant allele still expressed RNA isoforms that encode PTCHS. These results clearly demonstrate that a selective haploinsufficiency of longer isoforms of the PTCH1 protein, PTCHL and PTCHM, but not PTCHS is sufficient to cause NBCCS. Although mice selectively deficient in PTCHS isoforms are currently unavailable, this study sheds light on the complex in vivo roles of PTCH1 isoforms.","variants":[{"Name":"NM_000264.5(PTCH1):c.387G>A (p.Trp129Ter)","Chromosome":"9","Start":"95506414","Stop":"95506414","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45752,"rule_based_match":true,"evidence_text":"c.387G>A (p.W129X)","llm_judgment":"PRESENT","evidence":"c.387G>A (p.W129X)","abstract_start":483,"abstract_end":501}]}
{"pmid":"25919556","title":"SLC2A2 gene analysis in three Chinese children with Fanconi-Bickel syndrome","abstract":"Fanconi-Bickel syndrome (FBS, OMIM 227810), a rare autosomal recessive disorder of carbohydrate metabolism, is caused by SLC2A2 (GLUT2) mutations. The study reported 3 cases of FBS who were confirmly diagnosed by SLC2A2 gene analysis. The three patients showed typical features like glycogen storage disease and proximal renal tubular nephropathy. Homozygous splice-site mutation IVS8+5G>C (c.1068+5 G>C) was found in patient A and homozygous nonsense mutation c.1194T>A (p.Tyr398X) in patient B. Patient C harboured a missense mutation c.380C>A (p.Ala127Asp) and a de novo insertion c.970dupT (p.324TyrfsX392) which was not inherited from her parents. Four mutations were identified in the 3 Chinese FBS patients. Except IVS8+5G>C mutation, the other 3 mutations were novel in Chinese population. To the best of our knowledge, patient C may be the first FBS case worldwide with de novo mutation.","variants":[{"Name":"NM_000340.2(SLC2A2):c.970dup (p.Tyr324fs)","Chromosome":"3","Start":"171002673","Stop":"171002674","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":561258,"rule_based_match":true,"evidence_text":"c.970dupT (p.324TyrfsX392)","llm_judgment":"PRESENT","evidence":"c.970dupT (p.324TyrfsX392)","abstract_start":584,"abstract_end":610}]}
{"pmid":"33030311","title":"Separation in genetic pathogenesis of mutations in FBN1-TB5 region between autosomal dominant acromelic dysplasia and Marfan syndrome.","abstract":"Mutations in the transforming growth factor β-binding protein-like domain 5 (TB5) region of FBN1 can lead to autosomal acromelic dysplasia and Marfan syndrome, which are two diseases with apparently opposite phenotypes. We identified six patients with acromelic dysplasia carrying either the previously reported mutations c.5284G > A (p.Gly1762Ser) and c.5096A > G (p.Tyr1699Cys) or the novel mutation c.5260G > A (p.Gly1754Ser). A systematic review of patients with mutations in the FBN1-TB5 region showed that acromelic dysplasia is caused only by in-frame amino acid substitutions. In contrast, truncating mutations in the FBN1-TB5 have been reported only in Marfan syndrome. Acromelic dysplasia subtypes that share symptoms with Marfan syndrome are associated with FBN1-TB5 disulfide disruptions, which are also commonly found in Marfan syndrome. These results suggest that the type and location of mutations in the FBN1-TB5 region determine the clinical spectrum of fibrillinopathy.","variants":[{"Name":"NM_000138.5(FBN1):c.5284G>A (p.Gly1762Ser)","Chromosome":"15","Start":"48460258","Stop":"48460258","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38652,"rule_based_match":true,"evidence_text":"c.5284G > A (p.Gly1762Ser)","llm_judgment":"PRESENT","evidence":"c.5284G > A (p.Gly1762Ser)","abstract_start":322,"abstract_end":348}]}
{"pmid":"22528600","title":"Extensive abdominal lipomatosis in a patient with Noonan/LEOPARD syndrome (Noonan syndrome-Multiple Lentigines).","abstract":"Noonan syndrome (NS) is a tumor predisposing disorder. Leukemia is observed in 1-3% of patients with NS, with rare occurrences of solid tumors. It also appears to predispose to non-malignant tumors. We report on a 26-year-old female with features of Noonan syndrome-Multiple Lentigines and a heterozygous mutation: c.1517A > C-p.Gln506Pro in the PTPN11 gene. The patient developed an unusual extensive lipomatosis and we discuss possible relationship between her lipomatosis and NS.","variants":[{"Name":"NM_002834.5(PTPN11):c.1517A>C (p.Gln506Pro)","Chromosome":"12","Start":"112489093","Stop":"112489093","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":49033,"rule_based_match":true,"evidence_text":"c.1517A > C-p.Gln506Pro","llm_judgment":"PRESENT","evidence":"c.1517A > C-p.Gln506Pro","abstract_start":315,"abstract_end":338}]}
{"pmid":"38066485","title":"Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions.","abstract":"BACKGROUND: TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations.\nMETHODS: In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity.\nRESULTS: We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability.\nCONCLUSIONS: This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.","variants":[{"Name":"NM_138691.3(TMC1):c.1256T>C (p.Phe419Ser)","Chromosome":"9","Start":"72791917","Stop":"72791917","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1952219,"rule_based_match":true,"evidence_text":"c.1256T > C:p.Phe419Ser","llm_judgment":"PRESENT","evidence":"c.1256T > C:p.Phe419Ser","abstract_start":1155,"abstract_end":1178}]}
{"pmid":"31114672","title":"Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models.","abstract":"BACKGROUND: Congenital chloride diarrhea (CCD) in a newborn is a rare autosomal recessive disorder with life-threatening complications, requiring early diagnostics and treatment to prevent severe dehydration and infant mortality. SLC26A3 rs386833481 (c.392C>G; p.P131R) gene polymorphism is an important genetic determinant of CCD. Here, we report the influence of the non-synonymous SLC26A3 variant rs386833481 gene polymorphism on the function of the epithelial barrier and the potential mechanisms of these effects.\nRESULTS: We found that P131R-SLC26A3 increased dysfunction of the epithelial barrier compared with wild type SLC26A3 in human colonic Caco-2 and mouse colonic CMT-93 cells. When P131R-SLC26A3 was subsequently reverted to wild type, the epithelial barrier function was restored similar to wild type cells. Further study demonstrated that variant P131R-SLC26A3 disrupts function of epithelial barrier through two distinct molecular mechanisms: (a) decreasing SLC26A3 expression through a ubiquitination pathway and (b) disrupting a key interaction with its partner ZO-1/CFTR, thereby increasing the epithelial permeability.\nCONCLUSION: Our study provides an important insight of SLC26A3 SNPs in the regulation of the epithelial permeability and indicates that SLC26A3 rs386833481 is likely a causative mutation in the dysfunction of epithelial barrier of CCD, and correction of this SNP or increasing SLC26A3 function could be therapeutically beneficial for chronic diarrhea diseases.","variants":[{"Name":"NM_000111.3(SLC26A3):c.392C>G (p.Pro131Arg)","Chromosome":"7","Start":"107791226","Stop":"107791226","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":70638,"rule_based_match":true,"evidence_text":"c.392C>G (p.P131R)","llm_judgment":"PRESENT","evidence":"c.392C>G","abstract_start":251,"abstract_end":259}]}
{"pmid":"32278775","title":"Acute liver failure due to DGUOK deficiency-is liver transplantation justified?","abstract":"BACKGROUND: Deoxyguanosine kinase (DGUOK) deficiency is one of the causes of the hepatocerebral form of mitochondrial depletion syndrome (MDS). It is characterized by an early onset of liver failure with concomitant neurological deterioration. In the current literature, there are only few reports regarding long-term observation of children with DGUOK deficiency. Liver transplantation (LTx) is controversial due to extrahepatic involvement and unpredictable outcome.\nMETHODS: Five patients (2 boys) from 4 different families with hepatocerebral MDS associated with DGUOK mutations diagnosed with liver failure were treated in our hospital between 2010-2019.\nRESULTS: In all children clinical symptoms developed within the first days of live and hypoglycemia (hypoketotic), conjugated hyperbilirubinemia (cholestasis), severe lactic acidosis, and coagulopathy were observed. Two neonates had low birth-weight for gestational age and failed to thrive. Mild neurological involvement as hypotonia was observed in all children. Three children died at the age of 2, 6 months and 6,5 months of age, respectively, due to end-stage liver failure. In one case, LTx was not considered, in two patients (sisters) parents did not agree to this procedure. LTx was subsequently performed in two patients at the age of 6 and 7 months, respectively, one from deceased, and one from living related donor, in both before the final confirmation of DGUOK mutations. One boy died 2 months after LTx due to post-LTx procedure-related complications; one is still alive with 3years of follow-up, with good liver function and mild neurological disturbances. The diagnosis of DGUOK deficiency was confirmed by biallelic DGUOK mutations detection. Equally, patients were compound heterozygotes (three cases) and homozygotes (two cases). Three known molecular variants, including regulatory substitutions (c.1A>G, c.3G>A) and in-frame insertion (c.813_814insTTT) were identified.\nCONCLUSIONS: Prognosis in patients with DGUOK deficiency is generally poor. Based on a review of the literature and our experience liver transplantation in selected patients with DGUOK mutation does not appear to be contraindicated, especially in those without or with minimal neurologic abnormalities.","variants":[{"Name":"NM_080916.3(DGUOK):c.1A>G (p.Met1Val)","Chromosome":"2","Start":"73926911","Stop":"73926911","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1925332,"rule_based_match":true,"evidence_text":"c.1A>G","llm_judgment":"PRESENT","evidence":"c.1A>G","abstract_start":1879,"abstract_end":1885}]}
{"pmid":"22554020","title":"Whole exome sequencing identifies a novel mutation in the transglutaminase 6 gene for spinocerebellar ataxia in a Chinese family.","abstract":"Autosomal dominant spinocerebellar ataxias (SCA) constitute a heterogeneous group of inherited disorders. The transglutaminase 6 (TGM6) gene was recently suggested as a SCA causative gene in Chinese SCA families. In this study, two affected members of a three-generation Chinese family with SCA characterized by progressive cerebellar ataxia and lower limb pyramidal signs were subjected to whole exome sequencing. Through bioinformatics analysis of the sequence variants in these two individuals, we identified a novel mutation in the TGM6 gene (c.1528G>C) which showed perfect co-segregation with disease phenotype in all nine members of this family. This finding confirms that mutations in TGM6 gene represent an important cause of SCA in Chinese. This study also shows that whole exome sequencing of a small number of affected individuals, leveraged on bioinformatics analysis, can be an efficient strategy for identifying causative mutations in rare Mendelian disorders.","variants":[{"Name":"NM_198994.3(TGM6):c.1528G>C (p.Asp510His)","Chromosome":"20","Start":"2417423","Stop":"2417423","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":51191,"rule_based_match":true,"evidence_text":"c.1528G>C","llm_judgment":"PRESENT","evidence":"c.1528G>C","abstract_start":547,"abstract_end":556}]}
{"pmid":"30816434","title":"Novel compound heterozygous mutations in the SPTA1 gene, causing hereditary spherocytosis in a neonate with Coombs‑negative hemolytic jaundice.","abstract":"Hereditary spherocytosis (HS) is a common heterogeneous type of inherited hemolytic anemia characterized by jaundice and splenomegaly. Diagnosis of HS in neonates is considered unreliable, and is generally based on positive family history, spherocytes in peripheral smears, increased osmotic fragility, and jaundice. In the present study, routine laboratory tests, next‑generation sequencing, and Sanger sequencing were applied to diagnose a neonatal patient with Coombs‑negative hemolytic jaundice. The neonate had no family history of HS; however, spherocytes were observed in peripheral smears, and the patient exhibited Coombs‑negative and severe hemolytic jaundice, normal mean corpuscular hemoglobin concentration (MCHC) and mean corpuscular volume (MCV), normal glucose‑6‑phosphate dehydrogenase activity, negative thalassemia genetic mutation screening results, and negative autoimmune antibody tests. Novel compound heterozygous mutations in the spectrin‑α, erythrocytic 1 (SPTA1) gene (c.3897‑1G>C and c.5029G>A) were identified. The SPTA1 c.3897‑1G>C mutation in intron 27‑1, which disrupted the consensus splice site, was inherited from his asymptomatic mother, and the SPTA1 c.5029G>A (p.Gly1677Arg) mutation in trans with the SPTA1 c.3897‑1G>C mutation was inherited from his asymptomatic father. Sanger sequencing of mRNA reverse transcribed into cDNA identified a deletion of the first 10 nucleotides of exon 28, confirming the splicing mutation. In conclusion, the present study reports a rare case of autosomal‑recessive HS with a severe clinical phenotype, but normal MCHC and MCV.","variants":[{"Name":"NM_003126.4(SPTA1):c.5029G>A (p.Gly1677Arg)","Chromosome":"1","Start":"158638193","Stop":"158638193","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":552282,"rule_based_match":true,"evidence_text":"c.5029G>A (p.Gly1677Arg)","llm_judgment":"PRESENT","evidence":"c.5029G>A (p.Gly1677Arg)","abstract_start":1188,"abstract_end":1212}]}
{"pmid":"24055421","title":"A splice donor site mutation in HOXD13 underlies synpolydactyly with cortical bone thinning.","abstract":"Synpolydactyly 1(SPD1) is a dominantly inherited distal limb anomaly that is characterized by incomplete digit separation and increased number of digits. SPD1 is most commonly caused by polyalanine repeat expansions and mutations in the homeodomain of the HOXD13. We report a splice donor site mutation in HOXD13 associated in most cases with cortical bone thinning. In vitro study of transcripts and truncated protein analysis indicated that c.781+1G>A mutation results in truncated HOXD13 protein p.G190fsX4. Luciferase assay indicated that the truncated HOXD13 protein failed to bind to DNA. The mechanism for this phenotype was truncated protein loss of function.","variants":[{"Name":"NM_000523.4(HOXD13):c.781+1G>A","Chromosome":"2","Start":"176093672","Stop":"176093672","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227489,"rule_based_match":true,"evidence_text":"c.781+1G>A","llm_judgment":"PRESENT","evidence":"c.781+1G>A","abstract_start":443,"abstract_end":453}]}
{"pmid":"31155284","title":"Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification.","abstract":"Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl<sup>-</sup>/H<sup>+</sup> exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.","variants":[{"Name":"NM_001287.6(CLCN7):c.2144A>G (p.Tyr715Cys)","Chromosome":"16","Start":"1447498","Stop":"1447498","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":360150,"rule_based_match":true,"evidence_text":"c.2144A>G","llm_judgment":"PRESENT","evidence":"c.2144A>G","abstract_start":569,"abstract_end":578}]}
{"pmid":"29300972","title":"A recurrent de novo missense mutation in UBTF causes developmental neuroregression.","abstract":"UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10: g.42290219C > T, NM_014233.3: c.628G > A) resulting in the same amino acid change in both UBTF1 and UBTF2 (p.Glu210Lys [p.E210K]). Disease onset in our cohort was at 2.5 to 3 years and characterized by slow progression of global motor, cognitive and behavioral dysfunction. Notable early features included hypotonia with a floppy gait, high-pitched dysarthria and hyperactivity. Later features included aphasia, dystonia, and spasticity. Speech and ambulatory ability were lost by the early teens. Magnetic resonance imaging showed progressive generalized cerebral atrophy (supratentorial > infratentorial) with involvement of both gray and white matter. Patient fibroblasts showed normal levels of UBTF transcripts, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF1 in Drosophila neurons was lethal. Although no loss-of-function variants are reported in the Exome Aggregation Consortium (ExAC) database and Ubtf-/- is early embryonic lethal in mice, Ubtf+/- mice displayed only mild motor and behavioral dysfunction in adulthood. Our data underscore the importance of including UBTF E210K in the differential diagnosis of neuroregression and suggest that mainly gain-of-function mechanisms contribute to the pathogenesis of the UBTF E210K neuroregression syndrome.","variants":[{"Name":"NM_014233.4(UBTF):c.628G>A (p.Glu210Lys)","Chromosome":"17","Start":"44212851","Stop":"44212851","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":431537,"rule_based_match":true,"evidence_text":"NM_014233.3: c.628G > A","llm_judgment":"PRESENT","evidence":"NM_014233.3: c.628G > A","abstract_start":354,"abstract_end":377}]}
{"pmid":"33949097","title":"Novel GUCY2C variant causing familial diarrhea in a Mennonite kindred and a potential therapeutic approach.","abstract":"Guanylate cyclase 2C (GC-C), encoded by the GUCY2C gene, is implicated in hereditary early onset chronic diarrhea. Several families with chronic diarrhea symptoms have been identified with autosomal dominant, gain-of-function mutations in GUCY2C. We have identified a Mennonite patient with a novel GUCY2C variant (c.2381A > T; p.Asp794Val) with chronic diarrhea and an extensive maternal family history of chronic diarrhea and bowel dilatation. Functional studies including co-segregation analysis showed that all family members who were heterozygous for this variant had GI-related symptoms. HEK-293 T cells expressing the Asp794Val GC-C variant showed increased cGMP production when stimulated with Escherichia coli heat-stable enterotoxin STp (HST), which was reversed when 5-(3-Bromophenyl)-5,11-dihydro-1,3-dimethyl-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (BPIPP; a GC-C inhibitor) was used. In addition, cystic fibrosis transmembrane conductance regulator (CFTR) activity measured with SPQ fluorescence assay was increased in these cells after treatment with HST, indicating a crucial role for CFTR activity in the pathogenesis of this disorder. These results support pathogenicity of the GC-C Asp794Val variant as a cause of chronic diarrhea in this family. Furthermore, this work identifies potential candidate drug, GC-C inhibitor BPIPP, to treat diarrhea caused by this syndrome.","variants":[{"Name":"NM_004963.4(GUCY2C):c.2381A>T (p.Asp794Val)","Chromosome":"12","Start":"14625784","Stop":"14625784","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1030824,"rule_based_match":true,"evidence_text":"c.2381A > T; p.Asp794Val","llm_judgment":"PRESENT","evidence":"c.2381A > T; p.Asp794Val","abstract_start":315,"abstract_end":339}]}
{"pmid":"28620495","title":"Familial partial lipodystrophy and proteinuric renal disease due to a missense c.1045C > T","abstract":"Proteinuric renal disease is prevalent in congenital or acquired forms of generalized lipodystrophy. In contrast, an association between familial partial lipodystrophy (FPLD) and renal disease has been documented in very few cases. A 22-year-old female patient presented with impaired glucose tolerance, hyperinsulinemia, hirsutism and oligomenorrhea. On examination, there was partial loss of subcutaneous adipose tissue in the face, upper and lower limbs, bird-like facies with micrognathia and low set ears and mild acanthosis nigricans. Laboratory investigations revealed hyperandrogenism, hyperlipidemia, elevated serum creatine kinase and mild proteinuria. A clinical diagnosis of FPLD of the non-Dunnigan variety was made; genetic testing revealed a heterozygous c.1045C > T mutation in exon 6 of the <i>LMNA</i> gene, predicted to result in an abnormal LMNA protein (p.R349W). Electromyography and muscle biopsy were suggestive of non-specific myopathy. Treatment with metformin and later with pioglitazone was initiated. Due to worsening proteinuria, a renal biopsy was performed; histological findings were consistent with mild focal glomerular mesangioproliferative changes, and the patient was started on angiotensin-converting enzyme inhibitor therapy. This is the fourth report of FPLD associated with the c.1045C > T missense <i>LMNA</i> mutation and the second with co-existent proteinuric renal disease. Patients carrying this specific mutation may exhibit a phenotype that includes partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.\nLEARNING POINTS: Lipodystrophy is a rare disorder characterized by the complete or partial loss of subcutaneous adipose tissue, insulin resistance, diabetes mellitus and hyperlipidemia.Proteinuric renal disease is a prevalent feature of generalized lipodystrophy but rare in familial partial lipodystrophy.Patients carrying the c.1045C > T missense <i>LMNA</i> mutation (p.R349W) may present with familial partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.","variants":[{"Name":"NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)","Chromosome":"1","Start":"156136009","Stop":"156136009","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77659,"rule_based_match":true,"evidence_text":"c.1045C > T","llm_judgment":"PRESENT","evidence":"c.1045C > T","abstract_start":770,"abstract_end":781}]}
{"pmid":"20604683","title":"Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population: human gene therapy initiated in Israel.","abstract":"The history of the North African Jewish community is ancient and complicated with a number of immigration waves and persecutions dramatically affecting its population size. A decade-long process in Israel of clinical-molecular screening of North African Jews with incurable autosomal recessive blindness led to the identification of a homozygous splicing mutation (c.95-2A > T; IVS2-2A > T) in RPE65, the gene encoding the isomerase that catalyzes a key step in the retinoid-visual cycle, in patients from 10 unrelated families. A total of 33 patients (four now deceased) had the severe childhood blindness known as Leber congenital amaurosis (LCA), making it the most common cause of retinal degeneration in this population. Haplotype analysis in seven of the patients revealed a shared homozygous region, indicating a population-specific founder mutation. The age of the RPE65 founder mutation was estimated to have emerged 100-230 (mean, 153) generations ago, suggesting it originated before the establishment of the Jewish community in North Africa. Individuals with this RPE65 mutation were characterized with retinal studies to determine if they were candidates for gene replacement, the recent and only therapy to date for this otherwise incurable blindness. The step from molecular anthropological studies to application of genetic medicine was then taken, and a representative of this patient subgroup was treated with subretinal rAAV2-RPE65 gene therapy. An increase in vision was present in the treated area as early as 15 days after the intervention. This process of genetically analyzing affected isolated populations as a screen for gene-based therapy suggests a new paradigm for disease diagnosis and treatment.","variants":[{"Name":"NM_000329.3(RPE65):c.95-2A>T","Chromosome":"1","Start":"68446862","Stop":"68446862","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":104789,"rule_based_match":true,"evidence_text":"c.95-2A > T; IVS2-2A > T","llm_judgment":"PRESENT","evidence":"c.95-2A > T; IVS2-2A > T","abstract_start":365,"abstract_end":389}]}
{"pmid":"22781092","title":"A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.","abstract":"Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy resulting from mutations in >30 genes expressed in either the Schwann cells or the axon of peripheral nerves. The disease is classified into demyelinating (CMT1), axonal (CMT2) or intermediate (CMTI) based on electrophysiological and pathological findings. Our study focused on the identification of a novel disease mutation in a large Sardinian family with CMT2 of autosomal dominant (AD) inheritance. All available family members were clinically evaluated and samples were collected from consenting individuals. Initially, we excluded known CMT2 genes/loci in this family. We then conducted a genome-wide linkage analysis and mapped the gene to chromosome 9q33-q34. Refined linkage and haplotype analyses defined an 11.6-Mb candidate region with a maximum LOD score of 8.06. Following exclusion of several candidate genes from the region, we targeted the LRSAM1 (leucine-rich repeat and sterile alpha motif-containing 1) gene, very recently found to be associated with autosomal recessive CMT2 in one family. For a more efficient investigation of this large gene, already available proband RNA (cDNA) was initially analyzed. Targeted DNA analysis then confirmed a novel LRSAM1 splice-site (c.2047-1G>A) mutation, causing a frameshift that introduces a stop codon three amino acids further down the new reading frame (p.Ala683ProfsX3). This mutation is located in the C-terminal RING finger motif of the encoded protein and leads to premature truncation of the protein. In the course of our work, a second LRSAM1 mutation dominantly transmitted was identified by another group. Our data further confirms that LRSAM1 mutations are associated with CMT2 of AD inheritance.","variants":[{"Name":"NM_001005373.4(LRSAM1):c.2047-1G>A","Chromosome":"9","Start":"127502773","Stop":"127502773","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":49853,"rule_based_match":true,"evidence_text":"c.2047-1G>A","llm_judgment":"PRESENT","evidence":"c.2047-1G>A","abstract_start":1267,"abstract_end":1278}]}
{"pmid":"27142677","title":"Enrichment of rare variants in population isolates: single AICDA mutation responsible for hyper-IgM syndrome type 2 in Finland.","abstract":"Antibody class-switch recombination and somatic hypermutation critically depend on the function of activation-induced cytidine deaminase (AID). Rare variants in its gene AICDA have been reported to cause autosomal recessive AID deficiency (autosomal recessive hyper-IgM syndrome type 2 (HIGM2)). Exome sequencing of a multicase Finnish family with an HIGM2 phenotype identified a rare, homozygous, variant (c.416T>C, p.(Met139Thr)) in the AICDA gene, found to be significantly enriched in the Finnish population compared with other populations of European origin (38.56-fold, P<0.001). The population history of Finland, characterized by a restricted number of founders, isolation and several population bottlenecks, has caused enrichment of certain rare disease-causing variants and losses of others, as part of a phenomenon called the Finnish Disease Heritage. Accordingly, rare founder mutations cause the majority of observed Finnish cases in these mostly autosomal recessive disorders that consequently are more frequent in Finland than elsewhere. Screening of all currently known Finnish patients with an HIGM2 phenotype showed them to be homozygous for p.(Met139Thr). All the Finnish p.(Met139Thr) carriers with available data on their geographic descent originated from the eastern and northeastern parts of Finland. They were observed to share more of their genome identity by descent (IBD) than Finns in general (P<0.001), and they all carried a 207.5-kb ancestral haplotype containing the variant. In conclusion, the identified p.(Met139Thr) variant is significantly enriched in Finns and explains all thus far found AID deficiencies in Finland.","variants":[{"Name":"NM_020661.4(AICDA):c.416T>C (p.Met139Thr)","Chromosome":"12","Start":"8605226","Stop":"8605226","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":624464,"rule_based_match":true,"evidence_text":"c.416T>C, p.(Met139Thr)","llm_judgment":"PRESENT","evidence":"c.416T>C, p.(Met139Thr)","abstract_start":407,"abstract_end":430}]}
{"pmid":"22441121","title":"Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation.","abstract":"Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event.","variants":[{"Name":"NM_000520.6(HEXA):c.459+5G>A","Chromosome":"15","Start":"72353686","Stop":"72353686","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":361391,"rule_based_match":true,"evidence_text":"c.459+5G>A","llm_judgment":"PRESENT","evidence":"c.459+5G>A","abstract_start":787,"abstract_end":797}]}
{"pmid":"33169910","title":"Aberrant COL11A1 splicing causes prelingual autosomal dominant nonsyndromic hearing loss in the DFNA37 locus.","abstract":"Alpha-chain collagen molecules encoded by genes that include COL11A1 are essential for skeletal, ocular, and auditory function. COL11A1 variants have been reported in syndromes involving these organ systems. However, a description of the complete clinical spectrum is lacking, as evidenced by a recent association of autosomal dominant nonsyndromic hearing loss due to a splice-altering variant in COL11A1, mapping the DFNA37 locus. Here, we describe two German families presenting prelingual autosomal dominant nonsyndromic hearing loss with novel COL11A1 heterozygous splice-altering variants (c.652-1G>C and c.4338+2T>C) that were molecularly characterized. Interestingly, the c.652-1G>C variant affects the same intron 4 canonical splice site originally reported in the DFNA37 family (c.652-2A>C) but elicits a different splicing outcome. Furthermore, the c.4338+2T>C variant originated de novo. We provide clinical and molecular genetic evidence to unambiguously confirm that COL11A1 splice-altering variants cause DFNA37 hearing loss and affirm that COL11A1 be included in the genetic testing of patients with nonsyndromic deafness.","variants":[{"Name":"NM_001854.4(COL11A1):c.652-1G>C","Chromosome":"1","Start":"103031245","Stop":"103031245","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":413241,"rule_based_match":true,"evidence_text":"c.652-1G>C","llm_judgment":"PRESENT","evidence":"c.652-1G>C","abstract_start":596,"abstract_end":606}]}
{"pmid":"24446915","title":"Clinical and molecular findings of chronic granulomatous disease in Oman: family studies.","abstract":"Chronic granulomatous disease (CGD), a rare inherited disorder of the innate immune system, results from mutations in any one of the five genes encoding the subunits of the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase enzyme, and is characterized by recurrent life-threatening bacterial and fungal infections. Molecular analysis of 14 Omani CGD patients from 10 families, diagnosed to have CGD on clinical (recurrent infections) and biochemical grounds (positive for both the nitroblue tetrazolium (NBT) test and the dihydrorhodamine (DHR-1,2,3 assay), revealed that only one patient had X-linked CGD, with a large deletion involving both the gp91-phox gene (CYBB) and the McLeod gene (XK). The remaining 13 patients were all homozygotes from a previously described c.579G>A (p.Trp193X) mutation in the NCF1 gene on chromosome 7, responsible for autosomal recessive CGD (AR-CGD). Although X-linked CGD is the most common type of CGD disorder in most population groups, AR-CGD is the most prevalent type in Oman.","variants":[{"Name":"NM_000265.7(NCF1):c.579G>A (p.Trp193Ter)","Chromosome":"7","Start":"74783529","Stop":"74783529","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":415113,"rule_based_match":true,"evidence_text":"c.579G>A (p.Trp193X)","llm_judgment":"PRESENT","evidence":"c.579G>A (p.Trp193X)","abstract_start":789,"abstract_end":809}]}
{"pmid":"20036593","title":"Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State.","abstract":"INTRODUCTION: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome.\nMETHOD: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms.\nRESULTS: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 micromol/L in the asymptomatic vs. 19.1 micromol/L in the symptomatic, p<0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p<0.012). Four infants had initial C8 level >30 micromol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from \"SIDS\", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians.\nDISCUSSION: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.","variants":[{"Name":"NM_000016.6(ACADM):c.985A>G (p.Lys329Glu)","Chromosome":"1","Start":"75761161","Stop":"75761161","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18625,"rule_based_match":true,"evidence_text":"c.985A>G","llm_judgment":"PRESENT","evidence":"c.985A>G","abstract_start":2034,"abstract_end":2042}]}
{"pmid":"24045841","title":"A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain.","abstract":"Mucolipidosis (ML) II and ML IIIα/β are allelic autosomal recessive metabolic disorders due to mutations in GNPTAB. The gene encodes the enzyme UDP-GlcNAc-1-phosphotransferase (GNPT), which is critical to proper trafficking of lysosomal acid hydrolases. The ML phenotypic spectrum is dichotomous. Criteria set for defining ML II and ML IIIα/β are inclusive for all but the few patients with phenotypes that span the archetypes. Clinical and biochemical findings of the 'intermediate' ML in eight patients with the c.10A>C missense mutation in GNPTAB are presented to define this intermediate ML and provide a broader insight into ML pathogenesis. Extensive clinical information, including radiographic examinations at various ages, was obtained from a detailed study of all patients. GNPTAB was sequenced in probands and parents. GNPT activity was measured and cathepsin D sorting assays were performed in fibroblasts. Intermediate ML patients who share the c.10A>C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIα/β in psychomotor development and life expectancy. GNPT activity is reduced to 7-12% but the majority of newly synthesized cathepsin D remains intracellular. The GNPTAB c.10A>C/p.K4Q missense allele results in an intermediate ML II/III with distinct clinical and biochemical characteristics. This delineation strengthens the utility of the discontinuous genotype-phenotype correlation in ML II and ML IIIα/β and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML.","variants":[{"Name":"NM_024312.5(GNPTAB):c.10A>C (p.Lys4Gln)","Chromosome":"12","Start":"101830666","Stop":"101830666","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":17813,"rule_based_match":true,"evidence_text":"c.10A>C/p.K4Q","llm_judgment":"PRESENT","evidence":"c.10A>C/p.K4Q","abstract_start":958,"abstract_end":971}]}
{"pmid":"25012701","title":"GJB2 c.-23+1G>A mutation is second most common mutation among Iranian individuals with autosomal recessive hearing loss.","abstract":"GJB2 mutation analysis is used routinely as a first step in genetic testing for autosomal recessive non-syndromic sensorineural hearing loss. Although most GJB2 mutations can be detected by sequencing of the exon 2 of this gene, a prevalent splice mutation, c.-23+1G>A (IVS1+1G>A), is not usually included in the analyzed region. In this study, we have developed an ARMS-PCR strategy for detection of this mutation among Iranian deaf individuals. A total of 418 Iranian individuals with hearing loss consistent with autosomal recessive non-syndromic sensorineural hearing loss based on audiological test result, medical history, physical examination and pedigree of the family, were included in this study. c.35delG and c.-23+1G>A mutations were detected by using ARMS-PCR. Direct sequencing of the exon 2 of the GJB2 gene was performed for mutation analysis of the coding region of this gene. Among 418 investigated cases, a total of 81 patients (~19.4 %) with biallelic pathogenic mutations in the GJB2 gene and 13 cases with only one pathogenic mutant allele were identified. The total allele frequencies of the two most frequent mutations, c.35delG and c.-23+1G>A, among mutated alleles were found to be around 59 and 15.7 %, respectively. High frequency of the c.35delG and c.-23+1G>A mutations among Iranian deaf individuals shows the importance of developing rapid and cost-effective methods for primary mutation screening methods before performing direct sequencing.","variants":[{"Name":"NM_004004.6(GJB2):c.-23+1G>A","Chromosome":"13","Start":"20192782","Stop":"20192782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32068,"rule_based_match":true,"evidence_text":"c.-23+1G>A","llm_judgment":"PRESENT","evidence":"c.-23+1G>A","abstract_start":258,"abstract_end":268}]}
{"pmid":"29850289","title":"A Novel RET D898Y Germline Mutation in a Patient with Pheochromocytoma.","abstract":"Pheochromocytoma and paraganglioma are tumors of neuroectoderm origin. Up to 40% of patients with these tumors have germline mutations in known susceptibility genes. We report a novel <i>RET</i> germline mutation (exon 15; c.2692G>T (D898Y)) in a pheochromocytoma patient, as well as in her two asymptomatic sons and older sister. A 49-year-old female came to our clinic presenting with a right adrenal gland mass detected during a healthcare examination. Her mother and two sisters had previously undergone thyroidectomy for papillary thyroid carcinomas. The levels of vanillylmandelic acid and other catecholamines were elevated in 24-hour urine, and an imaging study revealed a right adrenal mass. She underwent laparoscopic adrenalectomy and the final pathologic diagnosis was pheochromocytoma. Mutation screening detected a <i>RET</i> p.D898Y mutation, both in the patient and in the patient's two sons and older sister. This is the first description of a <i>RET</i> D898Y mutation in a pheochromocytoma patient and her family. The mutation should be categorized as a variant of unknown significance because no RET gene related disorders were detected in this family. Long term follow-up will be required to determine the clinical significance of the <i>RET</i> D898Y mutation.","variants":[{"Name":"NM_020975.6(RET):c.2692G>T (p.Asp898Tyr)","Chromosome":"10","Start":"43120165","Stop":"43120165","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":139824,"rule_based_match":true,"evidence_text":"c.2692G>T (D898Y)","llm_judgment":"PRESENT","evidence":"c.2692G>T (D898Y)","abstract_start":223,"abstract_end":240}]}
{"pmid":"25074465","title":"Identification of previously unrecognized FAP in children with Gardner fibroma.","abstract":"Fibromatous soft tissue lesions, namely desmoid-type fibromatosis and Gardner fibroma, may occur sporadically or as a result of inherited predisposition (as part of familial adenomatous polyposis, FAP). Whereas desmoid-type fibromatosis often present β-catenin overexpression (by activating CTNNB1 somatic variants or APC biallelic inactivation), the pathogenetic mechanisms in Gardner fibroma are unknown. We characterized in detail Gardner fibromas diagnosed in two infants to evaluate their role as sentinel lesions of previously unrecognized FAP. In the first infant we found a 5q deletion including APC in the tumor and the novel APC variant c.4687dup in constitutional DNA. In the second infant we found the c.5826_5829del and c.1678A>T APC variants in constitutional and tumor DNA, respectively. None of the constitutional APC variants occurred de novo and both tumors showed nuclear staining for β-catenin and no CTNNB1 variants. We present the first comprehensive characterization of the pathogenetic mechanisms of Gardner fibroma, which may be a sentinel lesion of previously unrecognized FAP families.","variants":[{"Name":"NM_000038.6(APC):c.5826_5829del (p.Asp1942fs)","Chromosome":"5","Start":"112841416","Stop":"112841419","ReferenceAlleleVCF":"CCAGA","AlternateAlleleVCF":"C","allel_id":221526,"rule_based_match":true,"evidence_text":"c.5826_5829del","llm_judgment":"PRESENT","evidence":"c.5826_5829del","abstract_start":714,"abstract_end":728}]}
{"pmid":"16479318","title":"The p.T191M mutation of the CBS gene is highly prevalent among homocystinuric patients from Spain, Portugal and South America.","abstract":"Classical homocystinuria is due to cystathionine beta-synthase (CBS) deficiency. More than 130 mutations, which differ in prevalence and severity, have been described at the CBS gene. Mutation p.I278T is very prevalent, has been found in all European countries where it has been looked for with the exception of the Iberian peninsula, and is known to respond to vitamin B6. On the other hand, mutation p.T191M is prevalent in Spain and Portugal and does not respond to B6. We analysed 30 pedigrees from Spain, Portugal, Colombia and Argentina, segregating for homocystinuria. The p.T191M mutation was detected in patients from all four countries and was particularly prevalent in Colombia. The number of p.T191M alleles described in this study, together with those previously published, is 71. The prevalence of p.T191M among CBS mutant alleles in the different countries was: 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina and 0.14 in Brazil. Haplotype analyses suggested a double origin for this mutation. No genotype-phenotype correlation other than the B6-nonresponsiveness could be established for the p.T191M mutation. Additionally, three new mutations, p.M173V, p.I429del and c.69_70+8del10, were found. The p.M173V was associated with a mild, B6-responsive, phenotype.","variants":[{"Name":"NM_000071.3(CBS):c.572C>T (p.Thr191Met)","Chromosome":"21","Start":"43065481","Stop":"43065481","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15171,"rule_based_match":false,"evidence_text":"p.T191M","llm_judgment":"PRESENT","evidence":"p.T191M","abstract_start":402,"abstract_end":409}]}
{"pmid":"22883144","title":"The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement.","abstract":"Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal-dominant neurodegenerative disorder characterized by widespread fasciculations, proximal-predominant muscle weakness, and atrophy followed by distal sensory involvement. To date, large families affected by HMSN-P have been reported from two different regions in Japan. Linkage and haplotype analyses of two previously reported families and two new families with the use of high-density SNP arrays further defined the minimum candidate region of 3.3 Mb in chromosomal region 3q12. Exome sequencing showed an identical c.854C>T (p.Pro285Leu) mutation in the TRK-fused gene (TFG) in the four families. Detailed haplotype analysis suggested two independent origins of the mutation. Pathological studies of an autopsied patient revealed TFG- and ubiquitin-immunopositive cytoplasmic inclusions in the spinal and cortical motor neurons. Fragmentation of the Golgi apparatus, a frequent finding in amyotrophic lateral sclerosis, was also observed in the motor neurons with inclusion bodies. Moreover, TAR DNA-binding protein 43 kDa (TDP-43)-positive cytoplasmic inclusions were also demonstrated. In cultured cells expressing mutant TFG, cytoplasmic aggregation of TDP-43 was demonstrated. These findings indicate that formation of TFG-containing cytoplasmic inclusions and concomitant mislocalization of TDP-43 underlie motor neuron degeneration in HMSN-P. Pathological overlap of proteinopathies involving TFG and TDP-43 highlights a new pathway leading to motor neuron degeneration.","variants":[{"Name":"NM_006070.6(TFG):c.854C>T (p.Pro285Leu)","Chromosome":"3","Start":"100748182","Stop":"100748182","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45764,"rule_based_match":true,"evidence_text":"c.854C>T (p.Pro285Leu)","llm_judgment":"PRESENT","evidence":"c.854C>T (p.Pro285Leu)","abstract_start":617,"abstract_end":639}]}
{"pmid":"29771303","title":"Visual impairment and progressive phthisis bulbi caused by recessive pathogenic variant in MARK3.","abstract":"Developmental eye defects often severely reduce vision. Despite extensive efforts, for a substantial fraction of these cases the molecular causes are unknown. Recessive eye disorders are frequent in consanguineous populations and such large families with multiple affected individuals provide an opportunity to identify recessive causative genes. We studied a Pakistani consanguineous family with three affected individuals with congenital vision loss and progressive eye degeneration. The family was analyzed by exome sequencing of one affected individual and genotyping of all family members. We have identified a non-synonymous homozygous variant (NM_001128918.2: c.1708C > G: p.Arg570Gly) in the MARK3 gene as the likely cause of the phenotype. Given that MARK3 is highly conserved in flies (I: 55%; S: 67%) we knocked down the MARK3 homologue, par-1, in the eye during development. This leads to a significant reduction in eye size, a severe loss of photoreceptors and loss of vision based on electroretinogram (ERG) recordings. Expression of the par-1 p.Arg792Gly mutation (equivalent to the MARK3 variant found in patients) in developing fly eyes also induces loss of eye tissue and reduces the ERG signals. The data in flies and human indicate that the MARK3 variant corresponds to a loss of function. We conclude that the identified mutation in MARK3 establishes a new gene-disease link, since it likely causes structural abnormalities during eye development and visual impairment in humans, and that the function of MARK3/par-1 is evolutionarily conserved in eye development.","variants":[{"Name":"NM_001128918.3(MARK3):c.1708C>G (p.Arg570Gly)","Chromosome":"14","Start":"103491898","Stop":"103491898","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":590746,"rule_based_match":true,"evidence_text":"NM_001128918.2: c.1708C > G: p.Arg570Gly","llm_judgment":"PRESENT","evidence":"NM_001128918.2: c.1708C > G: p.Arg570Gly","abstract_start":651,"abstract_end":691}]}
{"pmid":"16023832","title":"Association analysis of the Arg220His variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy.","abstract":"PURPOSE: Mutation analysis of the gene encoding the GABA delta subunit (GABRD) identified a common missense variation (c.659G>A; Arg220His) of which the His220 allele displayed decreased GABA(A) alpha(1)beta(2)delta receptor current amplitudes. The present association study tested whether the functional GABRD His220 allele confers susceptibility to common syndromes of idiopathic generalized epilepsy (IGE).\nMETHODS: Five hundred and sixty two unrelated German IGE patients and 664 healthy population controls were genotyped for the c.659G>A polymorphism in exon 6 of the GABRD gene.\nRESULTS: His220 allele frequencies did not differ significantly between IGE patients (2.3%) and the controls (2.8%; P=0.46). Likewise, no evidence for an allelic association was found with juvenile myoclonic epilepsy (n=218; 2.8%; P=0.97) or idiopathic absence epilepsy (n=260; 2.3%; P=0.56).\nCONCLUSION: Our results provide no evidence that the functional GABRD His220 allele mediates a substantial susceptibility effect to common IGE syndromes in the German population.","variants":[{"Name":"NM_000815.5(GABRD):c.659G>A (p.Arg220His)","Chromosome":"1","Start":"2028260","Stop":"2028260","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31252,"rule_based_match":true,"evidence_text":"c.659G>A","llm_judgment":"PRESENT","evidence":"c.659G>A","abstract_start":119,"abstract_end":127}]}
{"pmid":"22633639","title":"Two novel missense mutations observed in nonketotic hyperglycinemia.","abstract":"Nonketotic hyperglycinemia, also known as glycine encephalopathy, is an autosomal recessive disorder of an inborn error of the glycine metabolism, caused by deficiency in the mitochondrial glycine cleavage enzyme. The majority of cases are caused by mutations in P-protein, one of the four components of the glycine cleavage enzyme, glycine decarboxylase. We describe a male neonate with hypotonia, hiccups, and persistent apnea, but without seizures. The patient's glycine level in cerebrospinal fluid and plasma was 328.3 nmol/mL (reference value, 2.2-14.2 nmol/mL) and 1439 nmol/mL (reference value, 232-740 nmol/mL), respectively. The cerebrospinal fluid/plasma ratio of 0.228 represented an increase (normal range, <0.04). Two novel heterozygous missense mutations (c.1130C>T (p.A377V) and c.2081_2088del (p.A694DfsX11) in exons 8 and 18) in the glycine decarboxylase gene confirmed the diagnosis of nonketotic hyperglycinemia.","variants":[{"Name":"NM_000170.3(GLDC):c.2081_2088del (p.Ala694fs)","Chromosome":"9","Start":"6556267","Stop":"6556274","ReferenceAlleleVCF":"TCATGATAG","AlternateAlleleVCF":"T","allel_id":545569,"rule_based_match":true,"evidence_text":"c.2081_2088del (p.A694DfsX11)","llm_judgment":"PRESENT","evidence":"c.2081_2088del (p.A694DfsX11)","abstract_start":795,"abstract_end":824}]}
{"pmid":"19900589","title":"A novel c.592-4_c.592-3delTT mutation in DGUOK gene causes exon skipping.","abstract":"Deoxyguanosine kinase (DGUOK) catalyzes the first step of the mitochondrial deoxypurine salvage pathway, the phosphorylation of purine deoxyribonucleosides. Mutations in the DGUOK gene have been linked to inherited mtDNA depletion syndromes, neonatal liver failure, nystagmus, and hypotonia. Previously, we reported the first case of a heterozygous unclassified c.592-4_c.592-3delTT alteration in a patient with DGUOK deficiency without the demonstration of its pathogenicity (Dimmock et al., 2008). This alteration was predicted to cause aberrant splicing based upon two computer algorithms. We now report a homozygous c.592-4_c.592-3delTT mutation found in two affected siblings of asymptomatic consanguineous parents. The proband presented with symptoms of idiopathic hepatitis, liver dysfunction, nystagmus, and retinal blindness. This individual died at 6months of age due to liver failure. This individual's affected sibling presented similarly and has remarkable elevations of tyrosine, methionine, and alanine. Many organic acids were elevated in urine, including lactic acid, Krebs cycle intermediates, and para-hydroxy compounds; ketone bodies were also present. RNA studies support aberrant splicing. Sequencing of cDNA detected exon 5 skipping in the two affected siblings, but not in the normal control. These results indicate that the homozygous c.592-4_c.592-3delTT is deleterious and responsible for the DGUOK deficiency. The parents were subsequently confirmed to be carriers of this mutation. In summary, we have demonstrated that c.592-4_c.592-3delTT is a pathogenic splice acceptor site mutation leading to DGUOK deficiency.","variants":[{"Name":"NM_080916.3(DGUOK):c.592-4_592-3del","Chromosome":"2","Start":"73957119","Stop":"73957120","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":2739153,"rule_based_match":false,"evidence_text":"c.592-4_c.592-3delTT","llm_judgment":"PRESENT","evidence":"c.592-4_c.592-3delTT","abstract_start":362,"abstract_end":382}]}
{"pmid":"25712082","title":"Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family.","abstract":"Noonan syndrome (NS) is a genetic condition characterized by congenital heart defects, short stature and characteristic facial features. We here present the case of a girl with moderate learning disabilities, delayed language development, craniofacial features and skin anomalies reminiscent of NS. After a mutation screening of the known NS genes PTPN11, SOS1, RAF1, KRAS, GRB2, BRAF and SHOC2 we found the heterozygous c.755T>C variant in SOS1 causing the p.I252T amino-acid substitution, which was considered possibly pathogenetic by bioinformatic predictions. The same variant was present in the proband's mother, displaying some NS features, and maternal grandfather showing no NS traits, but also by a healthy subject in 1000 genomes project database without phenotype informations. The functional analysis revealed that SOS1 c.755C activated the RAS-ERK intracellular pathway, whereas no effects on RAC-JNK cascade have been detected. After a comparison between the sequence of SOS1 cDNA from peripheral blood and SOS1 genomic DNA, we showed for the first time a differential allelic expression of the SOS1 gene in healthy individuals, thus occurring as a physiologic condition. Interestingly, we found that the mutated allele C was 50% more expressed than the wild-type allele T in all familial carriers. The comparable amount of SOS1 mRNA between mutated individuals and the controls indicates that the variant does not affect SOS1 expression. The present study provides a first evidence of allelic imbalance of SOS1 and pinpoints this condition as a possible mechanism underlying a different penetrance of some SOS1-mutated alleles in unrelated carriers.","variants":[{"Name":"NM_005633.4(SOS1):c.755T>C (p.Ile252Thr)","Chromosome":"2","Start":"39051253","Stop":"39051253","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":486897,"rule_based_match":true,"evidence_text":"c.755T>C","llm_judgment":"PRESENT","evidence":"c.755T>C","abstract_start":421,"abstract_end":429}]}
{"pmid":"29531775","title":"An unclassified variant of","abstract":"CHARGE syndrome is a rare autosomal dominant disease that is typically caused by heterozygous <i>CHD7</i> mutations. A <i>de novo</i> variant in a <i>CHD7</i> splicing acceptor site (NM_017780.3:c.7165-4A>G) was identified in a Japanese boy with CHARGE syndrome. This variant has been considered to be an \"unclassified variant\" due to its position outside the consensus splicing sites. In this study, abnormal splicing derived from this known variant was confirmed by cDNA sequencing.","variants":[{"Name":"NM_017780.4(CHD7):c.7165-4A>G","Chromosome":"8","Start":"60856441","Stop":"60856441","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":438510,"rule_based_match":true,"evidence_text":"NM_017780.3:c.7165-4A>G","llm_judgment":"PRESENT","evidence":"NM_017780.3:c.7165-4A>G","abstract_start":183,"abstract_end":206}]}
{"pmid":"33085104","title":"Progressive Myoclonus Epilepsy Caused by a Homozygous Splicing Variant of SLC7A6OS.","abstract":"Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss-of-function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021;89:402-407.","variants":[{"Name":"NM_032178.3(SLC7A6OS):c.191A>G (p.Gln64Arg)","Chromosome":"16","Start":"68310736","Stop":"68310736","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":961746,"rule_based_match":true,"evidence_text":"c.191A > G","llm_judgment":"PRESENT","evidence":"c.191A > G","abstract_start":158,"abstract_end":168}]}
{"pmid":"19194555","title":"Two Korean infants with genetically confirmed congenital nephrotic syndrome of Finnish type.","abstract":"Congenital nephrotic syndrome is defined as nephrotic syndrome which manifests in utero or during the first 3 months of life. The prototype of congenital nephrotic syndrome is congenital nephrotic syndrome of Finnish type (CNF, OMIM #602716), which is caused by loss-of-function mutations of the nephrin gene (NPHS1). There have been few clinical case reports of CNF in Korea, but none of which was confirmed by genetic study. Here, we report two children with congenital nephrotic syndrome. Genetic analysis of the NPHS1 gene revealed compound heterozygous frame-shifting mutations (c.2156_2163 delTGCACTGC causing p.L719DfsX4 and c.3250_3251insG causing p.V1084GfsX12) in one patient and a missense mutation (c.1381G>A causing p.R460Q) and a nonsense mutation (c.2442C>G causing p.Y814X) in the other patient. The nonsense mutation was novel. The clinical courses of the patients were typical of CNF. This is the first report of genetically confirmed CNF in Korea to date. The early genetic diagnosis of CNF is important for proper clinical management of the patients and precise genetic counseling of the families.","variants":[{"Name":"NM_004646.4(NPHS1):c.2442C>G (p.Tyr814Ter)","Chromosome":"19","Start":"35842443","Stop":"35842443","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":71113,"rule_based_match":true,"evidence_text":"c.2442C>G (p.Y814X)","llm_judgment":"PRESENT","evidence":"c.2442C>G","abstract_start":763,"abstract_end":772},{"Name":"NM_004646.4(NPHS1):c.2156_2163del (p.Leu719fs)","Chromosome":"19","Start":"35844152","Stop":"35844159","ReferenceAlleleVCF":"GGCAGTGCA","AlternateAlleleVCF":"G","allel_id":71102,"rule_based_match":true,"evidence_text":"c.2156_2163 delTGCACTGC","llm_judgment":"PRESENT","evidence":"c.2156_2163 delTGCACTGC","abstract_start":584,"abstract_end":607}]}
{"pmid":"27753269","title":"Spondyloepiphyseal dysplasia Omani type: CHST3 mutation spectrum and phenotypes in three Indian families.","abstract":"We describe three consanguineous Indian families with a distinct form of spondyloepiphyseal dysplasia (SED Omani type). It is an autosomal recessive disorder due to mutation in CHST3 gene. CHST3 gene encodes the enzyme chondroitin 6-O-sulfotransferase-1 (C6ST-1) which mediates the sulfation of proteoglycans, (chondroitin sulfate), in the extracellular matrix of cartilage. CHST3 gene was sequenced in probands from three different families with SED. In two families missense mutations (c.904G>C predicting the substitution D302H) and c.491C>T (P164L) were identified. A frameshift (insertion) mutation (c.533_534ins G predicting the substitution A179Rfs*) was found in the third family. SNP micrarray in the family 2 helped to localize the common areas of homozygosity and identified the candidate gene. The confirmation by molecular diagnosis will be useful in the management and in the counseling of affected patients and their families. The presence of sclerosis of cranial sutures adds to the phenotypic spectrum of the disorder. Severe cardiac valvular disease in a case and triangular epiphyses of knees are other features which are highlighted in this report. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_004273.5(CHST3):c.904G>C (p.Asp302His)","Chromosome":"10","Start":"72007935","Stop":"72007935","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":472248,"rule_based_match":true,"evidence_text":"c.904G>C","llm_judgment":"PRESENT","evidence":"c.904G>C","abstract_start":488,"abstract_end":496},{"Name":"NM_004273.5(CHST3):c.491C>T (p.Pro164Leu)","Chromosome":"10","Start":"72007522","Stop":"72007522","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":472249,"rule_based_match":true,"evidence_text":"c.491C>T (P164L)","llm_judgment":"PRESENT","evidence":"c.491C>T (P164L)","abstract_start":536,"abstract_end":552}]}
{"pmid":"26252088","title":"Mutation analysis of the TRAPPC2 gene in a Chinese family with X-linked spondyloepiphyseal dysplasia tarda","abstract":"OBJECTIVE: To identify potential mutation of TRAPPC2 gene in a Chinese family affected with X-linked spondyloepiphyseal dysplasia tarda (X-SEDL), and explore its underlying molecular mechanism.\nMETHODS: Peripheral blood samples were collected from 32 members of the family and 50 healthy adults to extract genomic DNA. DNA sequences of exons 3 to 6 and their exon/intron boundaries were amplified with PCR amplification. Direct bi-directional sequencing analysis was performed on the PCR products. The sequences were aligned to the reference sequences from the GenBank to determine mutation site and type.\nRESULTS: A nucleotide substitution of the splice-donor in TRAPPC2 intron 3, c.93+5G>A, was detected in the proband, but no sequence change was detected in TRAPPC2 exons 3 to 6. All of the 6 male patients and 8 female carriers from the family were detected to have carried this mutation. The same mutation was not found in the remaining 18 family members with a normal phenotype and 50 healthy controls.\nCONCLUSION: We have detected a c.93+5G>A mutation in the TRAPPC2 gene in a Chinese family affected with X-SEDL. Our results have expanded the spectrum of TRAPPC2 mutations and is helpful for presymptomatic and prenatal diagnoses of this disease.","variants":[{"Name":"NM_001011658.4(TRAPPC2):c.93+5G>A","Chromosome":"X","Start":"13719866","Stop":"13719866","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26551,"rule_based_match":true,"evidence_text":"c.93+5G>A","llm_judgment":"PRESENT","evidence":"c.93+5G>A","abstract_start":682,"abstract_end":691}]}
{"pmid":"35855989","title":"Application of whole exome sequencing in fetal cases with skeletal abnormalities.","abstract":"Objectives: To investigate the role of whole exome sequencing (WES) technology in fetuses with skeletal abnormalities (SKA) for establishing an appropriate clinical diagnosis and treatment path.\nMethods: From April 2019 to August 2020, eight special families were enrolled into the study. Their fetuses showed abnormal SKA by ultrasonic testing during pregnancy, but it is inconsistent with the normal results identified by chromosomal microarray analysis (CMA) of amniotic fluid or abortion. For further diagnosis, WES was performed to detect the causative genes mutations followed by Sanger sequencing.\nResults: Among of these eight fetuses with SKA, we found more than half of pathogenic mutations were in <i>COL1A1/2</i> gene, except for a known hotspot mutation in <i>FGFR3</i> gene (c.1138G>A). Three heterozygous mutations of <i>COL1A1</i> gene, c.2885G>A p (Gly962Asp), c.994G>A p (Gly332Arg) and c.1002 + 5G>T, were <i>de novo</i> mutations. The c.1002 + 5G>T mutation in <i>COL1A1</i> was firstly reported. In addition, one fetus carried a novel heterozygous mutation of <i>COL1A1</i> c.644G>A p (Gly215Asp), which was inherited from the mother. Another novel heterozygous mutation c.2482G>T p (Val828Phe) in the <i>COL1A2</i> gene was identified in another fetus and was inherited from the father. Among of these <i>COL1A1</i> mutations, these results might involve in two novel splicing mutations.\nConclusion: Our study reported several novel heterozygous mutations which expands the <i>COL1A1/2</i> mutation spectrum for prenatal diagnosis of SKA. Most importantly, WES technology is necessary as a routine step of the SKA diagnosis before or during pregnancy, combining with the detection of chromosome level.","variants":[{"Name":"NM_000089.4(COL1A2):c.2482G>T (p.Val828Phe)","Chromosome":"7","Start":"94423035","Stop":"94423035","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3095332,"rule_based_match":true,"evidence_text":"c.2482G>T p (Val828Phe)","llm_judgment":"PRESENT","evidence":"c.2482G>T p (Val828Phe)","abstract_start":1192,"abstract_end":1215}]}
{"pmid":"21947752","title":"The BRCA2 c.9004G>A (E2002K) [corrected] variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent.","abstract":"Specific BRCA1 and BRCA2 mutations recur in French Canadian breast and/or ovarian cancer families because of common ancestors, facilitating carrier detection in this population. We recently reported a BRCA2 c.9004G>A variant of unknown clinical significance in two French Canadian breast cancer families. It confers a E3002K alteration in the conserved C-terminus domain of BRCA2, and has been reported in non-French Canadian cancer families. Seven variant positive French Canadian families have since been identified by mutation screening of referrals to hereditary cancer clinics. In this article, we describe the cancer phenotypes of these families and further assess the contribution of this variant in the French Canadian population. We screened index breast cancer cases from 58 cancer families with at least three confirmed cases of breast and/or ovarian cancer and 960 breast cancer cases (48 years mean age) not selected for family history of cancer that were previously found not to carry the most common BRCA1 and BRCA2 mutations reported in this population. The index variant-positive cases from each family had breast cancer between the ages of 35-55 years (43 years mean age); and reported close relatives with breast cancer diagnoses between the ages of 28-84 years (57 years mean age). Three families had ovarian or peritoneal cancers. BRCA2-associated cancers, such as bladder, esophagus, pancreas, prostate, and thyroid cancers also occurred in these families. One c.9004G>A carrier also harbored the PALB2 c.2323C>T (Q775X) mutation found to recur in French Canadian breast cancer cases. No new BRCA2 variant carriers were identified in mutation screens. The absence of BRCA2 c.9004G>A carriers in the breast cancer cases not selected for family history contrasts with familial cases, supporting a pathogenic status for this variant and addition to the existing common BRCA1 and BRCA2 mutation-screening panel for French Canadian breast and/or ovarian cancer families.","variants":[{"Name":"NM_000059.4(BRCA2):c.9004G>A (p.Glu3002Lys)","Chromosome":"13","Start":"32379800","Stop":"32379800","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46757,"rule_based_match":true,"evidence_text":"BRCA2 c.9004G>A","llm_judgment":"PRESENT","evidence":"BRCA2 c.9004G>A","abstract_start":201,"abstract_end":216},{"Name":"NM_024675.4(PALB2):c.2323C>T (p.Gln775Ter)","Chromosome":"16","Start":"23629831","Stop":"23629831","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132156,"rule_based_match":true,"evidence_text":"c.2323C>T (Q775X)","llm_judgment":"PRESENT","evidence":"c.2323C>T (Q775X)","abstract_start":1525,"abstract_end":1542}]}
{"pmid":"19449407","title":"Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome.","abstract":"Neurofibromatosis-Noonan syndrome (NFNS), an entity which combines both features of Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), was etiologically unresolved until recent reports demonstrated NF1 mutations in the majority of patients with NFNS. The phenotypic overlap was explained by the involvement of the Ras pathway in both disorders, and, accordingly, clustering of the NF1 mutations in the GTPase-activating protein (GAP) domain of neurofibromin was observed in individuals with NFNS. We report on an 18-month-old girl with typical findings suggestive of NS in combination with multiple café-au-lait spots and bilateral optic gliomas suggestive of NF1. The patient was found to carry a de novo PTPN11 mutation p.T2I as well as the maternally inherited NF1 mutation c.4661+1G>C. Her otherwise healthy mother and brother, who also had the NF1 mutation, showed few café-au-lait spots as the only sign of neurofibromatosis. Since our patient's unique NF1 mutation results in skipping of exon 27a and thus involves the same region, Gap-related domain, that had been shown to be associated with NFNS, her phenotype could have been misleadingly attributed to the NF1 mutation only. Contrarily, absence of both cutaneous neurofibromas and NS features in her relatives with the same NF1 mutation, suggests that the index patient's typical NFNS phenotype is caused by an additive effect of mutations in both NF1 and PTPN11. In contrast to previous findings, we speculate that absence of cutaneous neurofibromas is not solely associated with the recurrent 3-bp in-frame deletion in exon 17.","variants":[{"Name":"NM_002834.5(PTPN11):c.5C>T (p.Thr2Ile)","Chromosome":"12","Start":"112419116","Stop":"112419116","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28388,"rule_based_match":false,"evidence_text":"c.5C>T (p.Thr2Ile)","llm_judgment":"PRESENT","evidence":"T2I","abstract_start":730,"abstract_end":733}]}
{"pmid":"35071497","title":"Clinical manifestations and acid alpha-glucosidase mutation characterisation of a cohort of patients with late-onset Pompe disease in eastern China.","abstract":"BACKGROUND: Pompe disease is a rare, progressive, and life-threatening autosomal recessive disorder. In its late-onset form, the disease is primarily characterised by mild progressive proximal limb and respiratory muscle weakness. Mutations in the acid alpha-glucosidase (<i>GAA</i>) gene cause lysosomal enzyme GAA to be significantly reduced or missing altogether, for which supplementation can be given through enzyme replacement therapy.\nMETHODS: Fourteen patients diagnosed with late-onset Pompe disease (LOPD) in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2021 were enrolled. GAA activity was measured based on enzymatic activity in dried blood spots, and next-generation sequencing was used to detect mutations in the <i>GAA</i> gene. The impacts of novel missense variants were determined by five different prediction algorithms. The structural figures of novel variants and their wide types were processed with PyMOL.\nRESULTS: The study included 14 patients with LOPD (male-to-female ratio, 1:1) from eastern China. The median age at symptom onset and diagnosis was 15.0 years (7-36 years) and 21.5 years (8-47 years), respectively. The median diagnostic delay from onset was 3.0 years (0-22 years). Proximal muscle weakness was the first prominent symptom in 8 patients, while the other 6 patients experienced respiratory failure, chest congestion and asthma, and scoliosis. The most frequent mutation of the GAA gene was c.2238G>C (p.W746C), which was observed at an allele frequency of 14.3% (4/28) and in 28.6% of patients (4/14). Four novel variants potentially related to the pathogenicity of LOPD were found: c.1299G>C (p.Q433H), c.1409A>G (p.N470S), c.2242delG (p.E748Rfs*16), and c.2832delA (p.E945Sfs*78).\nCONCLUSIONS: The c.2238G>C (p.W746C) mutation was the most common mutation in 14 patients with LOPD from eastern China. This study has identified four novel variants in patients with LOPD. Predicting the pathogenicity of these novel variants may increase the understanding of the genetic mutation spectrum in LOPD. Our findings may also improve recognition of the characteristics of Chinese patients with LOPD.","variants":[{"Name":"NM_000152.5(GAA):c.2238G>C (p.Trp746Cys)","Chromosome":"17","Start":"80117016","Stop":"80117016","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":260196,"rule_based_match":true,"evidence_text":"c.2238G>C (p.W746C)","llm_judgment":"PRESENT","evidence":"c.2238G>C (p.W746C)","abstract_start":1462,"abstract_end":1481}]}
{"pmid":"21466533","title":"Junctional epidermolysis bullosa of late onset explained by mutations in COL17A1.","abstract":"BACKGROUND:   Junctional epidermolysis bullosa of late onset (JEB-lo) is a rare disease characterized by blistering of primarily the hands and feet starting in childhood. The pathogenesis remains unclear.\nOBJECTIVES: To clarify the pathogenesis of JEB-lo.\nMETHODS: Two patients with JEB-lo, a brother and a sister, were examined using electron microscopy (EM), immunofluorescence (IF) antigen mapping and molecular analysis.\nRESULTS: We found subtle changes in IF antigen mapping and EM. The most remarkable changes were loss of the apical-lateral staining of monoclonal antibodies (mAbs) against type XVII collagen (Col17), and a broadened distribution of mAb staining against the ectodomain of Col17, laminin-332 and type VII collagen. Mutation analysis of COL17A1, encoding Col17, showed a compound heterozygosity for a novel mutation c.1992_1995delGGGT and the known mutation c.3908G>A in both patients. The deletion c.1992_1995delGGGT results in a premature termination codon and mRNA decay, leaving the patients functionally hemizygous for the missense mutation c.3908G>A (p.R1303Q) in the noncollagenous 4 domain of Col17.\nCONCLUSIONS: JEB-lo is an autosomal recessive disorder caused by mutations in COL17A1, and subtle aberrations in EM and IF antigen mapping are clues to diagnosis.","variants":[{"Name":"NM_000494.4(COL17A1):c.3908G>A (p.Arg1303Gln)","Chromosome":"10","Start":"104034193","Stop":"104034193","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32689,"rule_based_match":true,"evidence_text":"c.3908G>A (p.R1303Q)","llm_judgment":"PRESENT","evidence":"c.3908G>A (p.R1303Q)","abstract_start":1068,"abstract_end":1088}]}
{"pmid":"29858533","title":"De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy.","abstract":"Mutations in FLNC for a long time are known in connection to neuromuscular disorders and only recently were described in association with various cardiomyopathies. Here, we report a new clinical phenotype of filaminopathy in four unrelated patients with early-onset restrictive cardiomyopathy (RCM) in combination with congenital myopathy due to FLNC mutations (NM_001458.4:c.3557C>T, p.A1186V, rs1114167361 in three probands and c.[3547G>C; 3548C>T], p.A1183L, rs1131692185 in one proband). In all cases, concurrent myopathy was confirmed by neurological examination, electromyography, and morphological studies. Three of the patients also presented with arthrogryposis. The pathogenicity of the described missense variants was verified by cellular and morphological studies and by in vivo modeling in zebrafish. Combination of in silico and experimental approaches revealed that FLNC missense variants localized in Ig-loop segments often lead to development of RCM. The described FLNC mutations associated with early-onset RCMP extend cardiac spectrum of filaminopathies and facilitate the differential diagnosis of restrictive cardiac phenotype associated with neuromuscular involvement in children.","variants":[{"Name":"NM_001458.5(FLNC):c.3557C>T (p.Ala1186Val)","Chromosome":"7","Start":"128845022","Stop":"128845022","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":419002,"rule_based_match":true,"evidence_text":"NM_001458.4:c.3557C>T, p.A1186V","llm_judgment":"PRESENT","evidence":"NM_001458.4:c.3557C>T, p.A1186V","abstract_start":362,"abstract_end":393}]}
{"pmid":"20385946","title":"Ophthalmological features associated with COL4A1 mutations.","abstract":"OBJECTIVE: To investigate the wide variability of ocular manifestations associated with mutations in the COL4A1 gene that encodes collagen IValpha1.\nMETHODS: We clinically evaluated 7 patients from 2 unrelated families in whom ocular features segregated with COL4A1 mutations that were identified by direct sequencing.\nRESULTS: The G2159A transition (c.2159G>A) that leads to the missense mutation p.Gly720Asp was identified in family A. An ocular phenotype of variable severity was observed in all affected relatives. The missense mutation c.2263G>A, p.Gly755Arg was identified in family B. One patient from family B also displayed notable ocular features.\nCONCLUSIONS: The COL4A1 mutations may be associated with various ophthalmologic developmental anomalies of anterior segment dysgenesis type, which are reminiscent of Axenfeld-Rieger anomalies (ARA). Cerebrovascular disorders should be added to the list of signs potentially associated with ARA.\nCLINICAL RELEVANCE: These data suggest that cerebral magnetic resonance imaging may be recommended in the clinical treatment of patients with apparently isolated ARA, even when neurological symptoms or signs are lacking.","variants":[{"Name":"NM_001845.6(COL4A1):c.2263G>A (p.Gly755Arg)","Chromosome":"13","Start":"110179352","Stop":"110179352","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171696,"rule_based_match":true,"evidence_text":"c.2263G>A, p.Gly755Arg","llm_judgment":"PRESENT","evidence":"c.2263G>A, p.Gly755Arg","abstract_start":541,"abstract_end":563}]}
{"pmid":"21174529","title":"A novel nonsense mutation in rhodopsin gene in two Indonesian families with autosomal recessive retinitis pigmentosa.","abstract":"PURPOSE: To report a novel, identical nonsense mutation in the rhodopsin (RHO) gene in two Indonesian families with autosomal recessive retinitis pigmentosa (arRP).\nMETHODS: Mutation screening for the RHO gene was performed in 38 unrelated patients with retinitis pigmentosa (RP) by direct sequencing. Clinical features were also characterized, through complete ophthalmologic examination. Family members of RP patients testing positive for the RHO gene were subjected to genetic and clinical examination. To assess the founder effect in the two families, haplotype analysis also was performed.\nRESULTS: A novel homozygous nonsense mutation was detected in two patients by a G to A transition at nucleotide position 482 in exon 2 of the RHO gene, resulting in substitution of a tryptophan-to-stop at codon 161 (c.482G>A, p.W161X). Examination of family members of these 2 patients showed that the affected members were homozygous and unaffected carriers were heterozygous for the p.W161X mutation. Haplotype analysis revealed that members of the two families carried the same disease-associated variants in markers (IVS1 RHO and D3S2322). No p.W161X mutations were detected in 45 normal Indonesian subjects, nor were any mutations detected in exons 1-5 of the RHO gene in the remaining 36 RP patients.\nCONCLUSION: We detected a novel, recessive nonsense mutation (p.W161X) in the RHO gene of two families through mutation screening of RHO in 38 Indonesian RP patients. Haplotype analysis suggested that p.W161X was the founder mutation.","variants":[{"Name":"NM_000539.3(RHO):c.482G>A (p.Trp161Ter)","Chromosome":"3","Start":"129530996","Stop":"129530996","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38830,"rule_based_match":true,"evidence_text":"c.482G>A, p.W161X","llm_judgment":"PRESENT","evidence":"c.482G>A, p.W161X","abstract_start":811,"abstract_end":828}]}
{"pmid":"27729122","title":"Compound heterozygous MYO7A mutations segregating Usher syndrome type 2 in a Han family.","abstract":"OBJECTIVE: Identification of rare deafness genes for inherited congenital sensorineural hearing impairment remains difficult, because a large variety of genes are implicated. In this study we applied targeted capture and next-generation sequencing to uncover the underlying gene in a three-generation Han family segregating recessive inherited hearing loss and retinitis pigmentosa.\nMETHODS: After excluding mutations in common deafness genes GJB2, SLC26A4 and the mitochondrial gene, genomic DNA of the proband of a Han family was subjected to targeted next-generation sequencing. The candidate mutations were confirmed by Sanger sequencing and subsequently analyzed with in silico tools.\nRESULTS: An unreported splice site mutation c.3924+1G > C compound with c.6028G > A in the MYO7A gene were detected to cosegregate with the phenotype in this pedigree. Both mutations, located in the evolutionarily conserved FERM domain in myosin VIIA, were predicted to be pathogenic. In this family, profound sensorineural hearing impairment and retinitis pigmentosa without vestibular disorder, constituted the typical Usher syndrome type 2.\nCONCLUSION: Identification of novel mutation in compound heterozygosity in MYO7A gene revealed the genetic origin of Usher syndrome type 2 in this Han family.","variants":[{"Name":"NM_000260.4(MYO7A):c.3924+1G>C","Chromosome":"11","Start":"77190871","Stop":"77190871","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":547038,"rule_based_match":true,"evidence_text":"c.3924+1G > C","llm_judgment":"PRESENT","evidence":"c.3924+1G > C","abstract_start":734,"abstract_end":747},{"Name":"NM_000260.4(MYO7A):c.6028G>A (p.Asp2010Asn)","Chromosome":"11","Start":"77208780","Stop":"77208780","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":547079,"rule_based_match":true,"evidence_text":"c.6028G > A","llm_judgment":"PRESENT","evidence":"c.6028G > A","abstract_start":762,"abstract_end":773}]}
{"pmid":"28285342","title":"Prevalence of two BRCA1 mutations, 5382insC and 300T > G, in ovarian cancer patients from Ukraine.","abstract":"Ovarian cancer is the seventh most common cancer in women worldwide and the leading cause of gynecological malignant diseases-related deaths in women. The most significant risk factor for ovarian cancer is an inherited genetic mutation in one of two genes: breast cancer gene 1 (BRCA1) or breast cancer gene 2 (BRCA2). The germline mutation c.5266dupC (also known as 5382insC or 5385insC) is the most common mutation among Slavic patients with breast and/or ovarian cancer. Missense mutation c.181T > G (also known as 300T > G or p.C61G) is regarded as the founder change in many Central European countries. We screened 306 ovarian cancer patients diagnosed at different ages by mutagenically separated polymerase chain reaction (PCR) and real-time PCR. A total of 25 BRCA1 mutations were detected (18 cases of 5382insC and 7 cases of 300 T > G). The frequency of the BRCA1 5382insC mutation is similar in breast and ovarian cancer patients from Ukraine, but the frequency of 300T > G was estimated in Ukraine at first time.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"c.5266dup","llm_judgment":"PRESENT","evidence":"c.5266dup","abstract_start":341,"abstract_end":350},{"Name":"NM_007294.4(BRCA1):c.181T>G (p.Cys61Gly)","Chromosome":"17","Start":"43106487","Stop":"43106487","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":32700,"rule_based_match":true,"evidence_text":"c.181T>G (also known as 300T>G or p.C61G)","llm_judgment":"PRESENT","evidence":"c.181T > G (also known as 300T > G or p.C61G)","abstract_start":492,"abstract_end":537}]}
{"pmid":"31625632","title":"Novel SPEG variant cause centronuclear myopathy in China.","abstract":"BACKGROUND: Centronuclear myopathy (CNM), a subtype of congenital myopathy (CM), is a group of clinical and genetically heterogeneous muscle disorders. Centronuclear myopathy is a kind of disease difficult to diagnose due to its genetic diversity. Since the discovery of the SPEG gene and disease-causing variants, only a few additional patients have been reported.\nMETHODS: A radiograph test, ultrasonic test, and biochemical tests were applied to clinical diagnosis of CNM. We performed trio medical exome sequencing of the family and conservation analysis to identify variants.\nRESULTS: We report a pair of severe CNM twins with the same novel homozygous SPEG variant c. 8710A>G (p.Thr2904Ala) identified by clinical trio medical exome sequencing of the family and conservation analysis. The twins showed clinical symptoms of facial weakness, hypotonia, arthrogryposis, strephenopodia, patent ductus arteriosus, and pulmonary arterial hypertension.\nCONCLUSIONS: Our report expands the clinical and molecular repertoire of CNM and enriches the variant spectrum of the SPEG gene in the Chinese population and helps us further understand the pathogenesis of CNM.","variants":[{"Name":"NM_005876.5(SPEG):c.8710A>G (p.Thr2904Ala)","Chromosome":"2","Start":"219489728","Stop":"219489728","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1515600,"rule_based_match":true,"evidence_text":"c. 8710A>G (p.Thr2904Ala)","llm_judgment":"PRESENT","evidence":"c. 8710A>G (p.Thr2904Ala)","abstract_start":671,"abstract_end":696}]}
{"pmid":"18362318","title":"DLX3 mutation in a new family and its phenotypic variations.","abstract":"Tricho-dento-osseous syndrome (TDO) is an autosomal-dominant disease characterized by curly hair at birth, enamel hypoplasia, taurodontism, and a thick cortical bone. A common DLX3 gene mutation (c.571_574delGGGG) has been identified in multiple families with variable clinical phenotypes. Recently, another DLX3 gene mutation (c.561_562delCT) was reported to cause amelogenesis imperfecta with taurodontism (AIHHT). We identified a Korean family with overlapping phenotypes of TDO and AIHHT. We performed mutational analysis to discover its genetic etiology. The identified mutation was c.561_562delCT mutation in the DLX3 gene. The enamel was hypomature and hypoplastic. The characteristic taurodontic features were not identified. Increased bone density or thickness could not be revealed by cephalometric, hand-wrist, and panoramic radiographs. Affected individuals reported that their nails were brittle, and they had curly hair at birth. This study clearly showed that the c.561_562delCT mutation had not only enamel defects, but also other clinical phenotypes resembling those of TDO syndrome.","variants":[{"Name":"NM_005220.3(DLX3):c.561_562del (p.Tyr188fs)","Chromosome":"17","Start":"49991819","Stop":"49991820","ReferenceAlleleVCF":"TAG","AlternateAlleleVCF":"T","allel_id":24112,"rule_based_match":true,"evidence_text":"c.561_562delCT","llm_judgment":"PRESENT","evidence":"c.561_562delCT","abstract_start":328,"abstract_end":342}]}
{"pmid":"21668430","title":"Analysis of TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 in autosomal recessive congenital ichthyosis from Galicia (NW Spain): evidence of founder effects.","abstract":"BACKGROUND:   Mutations in six genes have been identified in autosomal recessive congenital ichthyosis (ARCI). To date, few studies have analysed the spectrum of these mutations in specific populations.\nOBJECTIVES: We have studied the characteristics of patients with ARCI in Galicia (NW Spain). Methods  We recruited patients by contacting all dermatology departments of Galicia and the Spanish patient organization for ichthyosis. TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 were analysed in the patients and their relatives.\nRESULTS: We identified 23 patients with ARCI and estimated a prevalence of 1 : 122 000. Twenty of the patients were studied. Seventeen of them were clinically categorized as having lamellar ichthyosis (LI) and three as having congenital ichthyosiform erythroderma (CIE). TGM1 and ALOXE3 mutations were identified in 12/16 (75%) probands whereas no ALOX12B, NIPAL4 and CYP4F22 mutations were found. TGM1 mutations were found in 11/13 (85%) of LI probands. ALOXE3 mutations were identified in a single patient with CIE. Remarkably, mutations p.Arg760X, p.Asp408ValfsX21 and c.984+1G>A of TGM1 were present in six, four and two families, accounting for 41%, 23% and 14% of all TGM1 mutant alleles, respectively.\nCONCLUSIONS: The high percentage of patients with the same TGM1 mutations, together with the high number of homozygous probands (64%), indicates the existence of a strong founder effect in our population.","variants":[{"Name":"NM_000359.3(TGM1):c.984+1G>A","Chromosome":"14","Start":"24259703","Stop":"24259703","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1324010,"rule_based_match":true,"evidence_text":"c.984+1G>A","llm_judgment":"PRESENT","evidence":"c.984+1G>A","abstract_start":1098,"abstract_end":1108}]}
{"pmid":"31634165","title":"Whole-exome sequencing in a consanguineous Pakistani family identifies a mutational hotspot in the COL7A1 gene, causing recessive dystrophic epidermolysis bullosa.","abstract":"Dystrophic epidermolysis bullosa is a major form of epidermolysis bullosa and may be inherited as an autosomal dominant or recessive trait, with associated mutations in the COL7A1 gene. Here, we describe a consanguineous Pakistani family with four affected individuals suffering from recessive dystrophic epidermolysis bullosa. Exome sequencing of the proband's DNA revealed a homozygous missense variant (c.8038G>A:p.Gly2680Ser) in COL7A1 which cosegregated with disease in the family. The emergence of this particular glycine substitution in patients from diverse ethnic backgrounds such as China, United Kingdom, Poland, Iran, and Pakistan indicates that this variant most likely constitutes a recurrent mutational hotspot in the COL7A1 gene, rather than a germline mutation present at low levels in the general population.","variants":[{"Name":"NM_000094.4(COL7A1):c.8038G>A (p.Gly2680Ser)","Chromosome":"3","Start":"48567582","Stop":"48567582","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1059813,"rule_based_match":true,"evidence_text":"c.8038G>A:p.Gly2680Ser","llm_judgment":"PRESENT","evidence":"c.8038G>A:p.Gly2680Ser","abstract_start":406,"abstract_end":428}]}
{"pmid":"20044043","title":"Craniosynostosis: A rare complication of pycnodysostosis.","abstract":"Uncommon features of rare genetic disorders are often poorly known, as the likelihood of having them reported is low. We describe a 7-year-old boy with clinical and radiological diagnosis of pycnodysostosis, and c.436G>C (p.G146R) mutation in CSTK). He developed intracranial hypertension that required surgical decompression. Despite patent fontanels, the cause of the intracranial hypertension was identified to be a combination of coronal and metopic craniosynostoses. Intracranial hypertension and craniosynostosis have only been reported once in pycnodysostosis, which is on the contrary characterized by delayed closure of the sutures and persistence of open fontanels. Our observation confirms that intracranial hypertension represents a rare but life-threatening complication of pycnodysostosis. We strongly suggest including systematic examination of fundus oculi and monitoring of OFC in the systematic clinical follow-up of these patients.","variants":[{"Name":"NM_000396.4(CTSK):c.436G>C (p.Gly146Arg)","Chromosome":"1","Start":"150804203","Stop":"150804203","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":23460,"rule_based_match":true,"evidence_text":"c.436G>C (p.G146R)","llm_judgment":"PRESENT","evidence":"c.436G>C (p.G146R)","abstract_start":212,"abstract_end":230}]}
{"pmid":"31135626","title":"Adult Diagnosis of Type 1 Fiber Predominance Myopathy Caused by Novel Mutations in the RYR1 Gene.","abstract":"We describe a 57-year-old patient with mild diffuse weakness that was incidentally detected when he was evaluated for restless leg syndrome. An electromyography confirmed the presence of a myopathy without suggestion of inflammatory myopathy. A muscle biopsy demonstrated type 1 fiber predominance with minimal inflammatory features suggesting a genetic myopathy. Exome sequencing revealed c.10648C > T variant (p.R3550W), and a novel variant, c.10749_10753delGGAGG (E3584Rfs*3), in the ryanodine receptor 1 (RYR1) gene transmitted through his asymptomatic father indicating these mutations are in trans. Prompted by these results, a 47-year-old sister presented for evaluation. Her examination showed mild proximal muscle weakness, and an electromyography confirmed a noninflammatory myopathy. Her genotype was identical to her affected brother confirming that in these siblings, the RYR1 mutations, transmitted in an autosomal recessive pattern, are the cause of their myopathy. The adult age at diagnosis of these affected siblings likely reflects the mild and minimally progressive nature of the myopathy.","variants":[{"Name":"NM_000540.3(RYR1):c.10749_10753del (p.Glu3584fs)","Chromosome":"19","Start":"38527709","Stop":"38527713","ReferenceAlleleVCF":"AGGAGG","AlternateAlleleVCF":"A","allel_id":514761,"rule_based_match":true,"evidence_text":"c.10749_10753delGGAGG (E3584Rfs*3)","llm_judgment":"PRESENT","evidence":"c.10749_10753delGGAGG (E3584Rfs*3)","abstract_start":444,"abstract_end":478},{"Name":"NM_000540.3(RYR1):c.10648C>T (p.Arg3550Trp)","Chromosome":"19","Start":"38527014","Stop":"38527014","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":265716,"rule_based_match":true,"evidence_text":"c.10648C > T variant (p.R3550W)","llm_judgment":"PRESENT","evidence":"c.10648C > T variant (p.R3550W)","abstract_start":390,"abstract_end":421}]}
{"pmid":"37814107","title":"Novel GPR156 variants confirm its role in moderate sensorineural hearing loss.","abstract":"Hereditary hearing loss (HL) is a genetically heterogeneous disorder affecting people worldwide. The implementation of advanced sequencing technologies has significantly contributed to the identification of novel genes involved in HL. In this study, probands of two Turkish families with non-syndromic moderate HL were subjected to exome sequencing. The data analysis identified the c.600G > A (p.Thr200Thr) and c.1863dupG (p.His622fs) variants in GPR156, which co-segregated with the phenotype as an autosomal recessive trait in the respective families. The in silico predictions and a minigene assay showed that the c.600G > A variant disrupts mRNA splicing. This gene belongs to the family of G protein-coupled receptors whose function is not well established in the inner ear. GPR156 variants have very recently been reported to cause HL in three families. Our study from a different ethnic background confirms GPR156 as a bona fide gene involved in HL in humans. Further investigation towards the understanding of the role of GPCRs in the inner ear is warranted.","variants":[{"Name":"NM_153002.3(GPR156):c.600G>A (p.Thr200=)","Chromosome":"3","Start":"120186658","Stop":"120186658","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2739497,"rule_based_match":true,"evidence_text":"c.600G > A (p.Thr200Thr)","llm_judgment":"PRESENT","evidence":"c.600G > A (p.Thr200Thr)","abstract_start":383,"abstract_end":407},{"Name":"NM_153002.3(GPR156):c.1863dup (p.His622fs)","Chromosome":"3","Start":"120167613","Stop":"120167614","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":2739498,"rule_based_match":true,"evidence_text":"c.1863dupG (p.His622fs)","llm_judgment":"PRESENT","evidence":"c.1863dupG (p.His622fs)","abstract_start":412,"abstract_end":435}]}
{"pmid":"22449147","title":"Prevalent founder mutation c.736T>A of LIPH in autosomal recessive woolly hair of Japanese leads to variable severity of hypotrichosis in adulthood.","abstract":"BACKGROUND: Mutations in LIPH are a cause of autosomal recessive woolly hair (ARWH). Homozygous c.736T>A (p.Cys246Ser), and compound heterozygous c.736T>A and c.742C>A (p.His248Asn) have been reported in 5 and 7 Japanese children with ARWH respectively. The severity of hypotrichosis is known to be able to change in the clinical course, and the mutation patterns of LIPH do not always correlate with the severity of hypotrichosis in ARWH caused by other mutation sites of LIPH. However, all 12 Japanese children previously reported to have ARWH have shown similar severity of hypotrichosis.\nOBJECTIVE: In this study, we investigated the clinical features and molecular basis of ARWH in patients including three adults (three adults and two children) from five non-related Japanese families.\nMETHODS: Five families of Japanese origin that presented with woolly hair were studied. The phenotype was confirmed by clinical examination. Direct automated DNA sequencing of the LIPH gene was performed to identify the mutations in our probands.\nRESULTS: All patients had had woolly hair since birth. Homozygous c.736T>A mutations were found in four patients, including three adult cases, and compound heterozygous c.736T>A and c.742C>A mutations were found in one child patient. The two adults and two children had only sparse scalp hair, although one adult woman had mild hypotrichosis with long hairs.\nCONCLUSION: Some patients with homozygous c.736T>A can have a mild hypotrichosis phenotype with long hairs in adulthood.","variants":[{"Name":"NM_139248.3(LIPH):c.736T>A (p.Cys246Ser)","Chromosome":"3","Start":"185519292","Stop":"185519292","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":227256,"rule_based_match":true,"evidence_text":"c.736T>A (p.Cys246Ser)","llm_judgment":"PRESENT","evidence":"c.736T>A (p.Cys246Ser)","abstract_start":96,"abstract_end":118}]}
{"pmid":"20938048","title":"Novel WDR72 mutation and cytoplasmic localization.","abstract":"The proven candidate genes for amelogenesis imperfecta (AI) are AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72. We performed mutation analyses on seven families with hypomaturation AI. A novel WDR72 dinucleotide deletion mutation (g.57,426_57,427delAT; c.1467_ 1468delAT; p.V491fsX497) was identified in both alleles of probands from Mexico and Turkey. Haplotype analyses showed that the mutations arose independently in the two families. The disease perfectly segregated with the genotype. Only persons with both copies of the mutant allele were affected. Their hypomineralized enamel suffered attrition and orange-brown staining following eruption. Expression of WDR72 fused to green fluorescent protein showed a cytoplasmic localization exclusively and was absent from the nucleus. We conclude that WDR72 is a cytoplasmic protein that is critical for dental enamel formation.","variants":[{"Name":"NM_182758.4(WDR72):c.1467_1468del (p.Val491fs)","Chromosome":"15","Start":"53702235","Stop":"53702236","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":171258,"rule_based_match":true,"evidence_text":"c.1467_ 1468delAT","llm_judgment":"PRESENT","evidence":"c.1467_ 1468delAT","abstract_start":250,"abstract_end":267}]}
{"pmid":"20544538","title":"Determination of adenosine deaminase activity in dried blood spots by a nonradiochemical assay using reversed-phase high-performance liquid chromatography.","abstract":"Adenosine deaminase (ADA) deficiency is a rare metabolic disease causing severe combined immunodeficiency (SCID). An assay to determine ADA activity in dried blood spots was developed using reversed-phase HPLC. The assay was linear with reaction times up to at least 4 hours, and protein concentrations up to at least 2.2 mg/ml. The intra-assay CV and the inter-assay CV for the complete assay was 3.5 and 8.4%, respectively. The ADA activity in a control blood spot, stored at 4 degrees C, remained stable for at least one year. Only a slightly decreased ADA activity (35 +/- 13 nmol/mg/h, n = 4) was observed in heterozygotes for a c.704G > A mutation in the ADA gene when compared to that observed in controls (41 +/- 13 nmol/mg/h, n = 108). In addition, increased ADA activity as found in a rare form of congenital anemia can be assessed, as observed in a bloodspot from a patient diagnosed with Diamond Blackfan anemia (ADA activity 150 nmol/mg/h).","variants":[{"Name":"NM_000022.4(ADA):c.704G>A (p.Arg235Gln)","Chromosome":"20","Start":"44622905","Stop":"44622905","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":231104,"rule_based_match":true,"evidence_text":"c.704G > A","llm_judgment":"PRESENT","evidence":"c.704G > A","abstract_start":634,"abstract_end":644}]}
{"pmid":"31143303","title":"Diagnostic mRNA splicing assay for variants in","abstract":"BACKGROUND: Pathogenic variants in <i>BRCA1</i> and <i>BRCA2</i> cause hereditary breast and ovarian cancer. Screening of these genes has become easily accessible in diagnostic laboratories. Sequencing and copy number analyses are used to detect pathogenic variants, but also lead to identification of variants of unknown clinical significance (VUS). If the effect of a VUS can be clarified, it has direct consequence for the clinical management of the patient and family members. A splicing assay is one of several tools that might help in the classification of VUS. We therefore established mRNA analyses for <i>BRCA1</i> and <i>BRCA2</i> in the diagnostic laboratory in 2015. We hereby report the results of mRNA analysis variants in <i>BRCA1</i> and <i>BRCA2</i> after three years.\nMETHODS: Variants predicted to alter splicing and variants within the canonical splice sites were selected for splicing analyses. Splicing assays were performed by reverse transcription-PCR of patient RNA. A biallalic expression analysis was carried out whenever possible.\nRESULTS: Twenty-five variants in <i>BRCA1</i> and <i>BRCA2</i> were analyzed by splicing assays; nine showed altered transcripts and 16 showed normal splicing patterns. The two novel pathogenic variants in <i>BRCA1</i> c.4484 + 3 A > C and c.5407-10G > A were characterized.\nCONCLUSIONS: We conclude that mRNA analyses are useful in characterization of variants that may affect splicing. The results can guide classification of variants from unknown clinical significance to pathogenic or benign in a diagnostic laboratory, and thus be of direct clinical importance.","variants":[{"Name":"NM_007294.4(BRCA1):c.4484+3A>C","Chromosome":"17","Start":"43076485","Stop":"43076485","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":789696,"rule_based_match":true,"evidence_text":"c.4484 + 3 A > C","llm_judgment":"PRESENT","evidence":"c.4484 + 3 A > C","abstract_start":1278,"abstract_end":1294},{"Name":"NM_007294.4(BRCA1):c.5407-10G>A","Chromosome":"17","Start":"43047713","Stop":"43047713","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":102853,"rule_based_match":true,"evidence_text":"c.5407-10G>A","llm_judgment":"PRESENT","evidence":"c.5407-10G > A","abstract_start":1299,"abstract_end":1313}]}
{"pmid":"31674169","title":"Severe or Profound Sensorineural Hearing Loss Caused by Novel USH2A Variants in Korea: Potential Genotype-Phenotype Correlation.","abstract":"OBJECTIVES: We, herein, report two novel USH2A variants from two unrelated Korean families and their clinical phenotypes, with attention to severe or more than severe sensorineural hearing loss (SNHL).\nMETHODS: Two postlingually deafened subjects (SB237-461, M/46 and SB354-692, F/34) with more than severe SNHL and also with suspicion of Usher syndrome type II (USH2) were enrolled. A comprehensive audiological and ophthalmological assessments were evaluated. We conducted the whole exome sequencing and subsequent pathogenicity prediction analysis.\nRESULTS: We identified the following variants of USH2A from the two probands manifesting more than severe SNHL and retinitis pigmentosa (RP): compound heterozygosity for a nonsense (c.8176C>T: p.R2723X) and a missense variant (c.1823G>A: p.C608Y) in SB237, and compound heterozygosity for two frameshift variants (c.14835delT: p.S4945fs & c.13112_13115delAAAT: p.G4371fs) in SB354. Based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, two novel variants, c.1823G>A: p.C608Y and c.14835delT: p.Ser4945fs, can be classified as \"uncertain significance\" and \"pathogenic,\" respectively. The audiogram exhibited more than severe SNHL and a down-sloping configuration, necessitating cochlear implantation. The ophthalmic examinations revealed typical features of RP. Interestingly, one proband (SB 354-692) carrying two truncating compound heterozygous variants exhibited more severe hearing loss than the other proband (SB 237-461), carrying one truncation with one missense variant.\nCONCLUSION: Our results provide insight on the expansion of audiological spectrum encompassing more than severe SNHL in Korean subjects harboring USH2A variants, suggesting that USH2A should also be included in the candidate gene of cochlear implantation. A specific combination of USH2A variants causing truncating proteins in both alleles could demonstrate more severe audiological phenotype than that of USH2A variants carrying one truncating mutation and one missense mutation, suggesting a possible genotype-phenotype correlation. The understanding of audiological complexity associated with USH2A will be helpful for genetic counseling and treatment starategy.","variants":[{"Name":"NM_206933.4(USH2A):c.13112_13115del (p.Gln4371fs)","Chromosome":"1","Start":"215674796","Stop":"215674799","ReferenceAlleleVCF":"CATTT","AlternateAlleleVCF":"C","allel_id":540772,"rule_based_match":true,"evidence_text":"c.13112_13115delAAAT: p.G4371fs","llm_judgment":"PRESENT","evidence":"c.13112_13115delAAAT: p.G4371fs","abstract_start":891,"abstract_end":922}]}
{"pmid":"32759540","title":"Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia.","abstract":"AIM: Familial hypercholesterolemia (FH) is the most commonly encountered genetic condition that predisposes individuals to severe autosomal dominant lipid metabolism dysfunction. Although more than 75% of the European population has been scrutinized for FH-causing mutations, the genetic diagnosis proportion among Chinese people remains very low (less than 0.5%). The aim of this study was to identify genetic mutations and help make a precise diagnosis in Chinese FH patients.\nMETHODS: We designed a gene panel containing 20 genes responsible for FH and tested 208 unrelated Chinese possible/probable or definite FH probands. In addition, we called LDLR copy number variation (CNVs) with the panel data by panelcn.MOPS, and multiple ligation-dependent probe amplification (MLPA) was used to search for CNVs in LDLR, APOB, and PCSK9.\nRESULTS: A total of 79 probands (38.0%) tested positive for a (likely) pathogenic mutation, most of which were LDLR mutations, and three LDLR CNVs called from the panel data were all successfully confirmed by MLPA analysis. In total, 48 different mutations were identified, including 45 LDLR mutations, 1 APOB mutation, 1 ABCG5 mutation, and 1 APOE mutation. Among them, the five most frequent mutations (LDLR c.1879G＞A, c.1747C＞T, c.313＋1G＞A, c.400T＞C, and APOB c.10579C＞T) were detected. Moreover, we also found that patients with LDLR variants of CNVs and splicing and nonsense had increased low-density lipoprotein cholesterol levels when compared with those who carried missense variants.\nCONCLUSIONS: The spectrum of FH-causing mutations in the Chinese population is refined and expanded. Analyses of FH causal genes have been a great help in clinical diagnosis and have deep implications in disease treatment. These data can serve as a considerable dataset for next-generation sequencing analysis of the Chinese population with FH and contribute to the genetic diagnosis and counseling of FH patients.","variants":[{"Name":"NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)","Chromosome":"19","Start":"11116900","Stop":"11116900","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":198015,"rule_based_match":false,"evidence_text":"c.1747C＞T","llm_judgment":"PRESENT","evidence":"c.1747C＞T","abstract_start":1256,"abstract_end":1265}]}
{"pmid":"32515140","title":"Identification of novel mutations in BCKDHB and DBT genes in Vietnamese patients with maple sirup urine disease.","abstract":"BACKGROUND: Maple sirup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder. The disease-causing mutations can affect the BCKDHA, BCKDHB, and DBT genes encoding for the E1α, E1β, and E2 subunits of the multienzyme branched-chain α-keto acid dehydrogenase (BCKDH) complex. In the present study, novel pathogenic variants in BCKDHB and DBT genes were identified in three Vietnamese families with MSUD.\nMETHODS: Three newborn patients from three unrelated Vietnamese families were diagnosed with MSUD at the Metabolic Clinic, National Hospital of Pediatrics. Blood samples of 11 relatives from two generations of the three families diagnosed with MSUD were analyzed using exome and Sanger sequencing analyses.\nRESULTS: Novel pathogenic variants in BCKDHB (c.1103C>T, c.989A>G, and c.704G>A), and DBT (c.263_265delAAG) genes were identified in three pediatric patients with MSUD.\nCONCLUSIONS: We have identified novel pathogenic variants in the MSUD-related genes in the pedigree of the three patient's families. Our findings expand the mutational spectrum of MSUD and provide the scientific basis for genetic counseling for the patient's families.","variants":[{"Name":"NM_183050.4(BCKDHB):c.704G>A (p.Cys235Tyr)","Chromosome":"6","Start":"80171352","Stop":"80171352","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1687591,"rule_based_match":true,"evidence_text":"c.704G>A","llm_judgment":"PRESENT","evidence":"c.704G>A","abstract_start":802,"abstract_end":810}]}
{"pmid":"36958120","title":"Novel WFS1 mutations in patients with low-to-middle frequency hearing loss.","abstract":"BACKGROUND: Hearing loss (HL) is the most common sensorineural disorder in human. It is estimated that genetic factors contribute to over 50% of prelingual hearing loss. Most of dominant HHL patients manifest postlingual progressive hearing loss that mainly affect high frequencies. However, mutations in a few dominant HL genes, such as WFS1, TECTA and DIAPH1, cause distinct audiogram that primarily affects the low and middle frequencies.\nMETHODS: We recruited twelve independent HL families with worse low or middle frequency audiograms. Each proband of these families was excluded for pathogenic mutations in GJB2, SLC26A4, and MT-RNR1 genes. Mutation screening was performed by whole exome sequencing. Next, candidate variants were validated in each family by sanger sequencing.\nRESULTS: Six heterozygous WFS1 variants were identified in six families, including three novel mutations (c.2519T > G, p.F840C; c.2048T > G, p.M683R and c.2419A > C, p.S807R) and three previously reported variants (c.2005T > C, p.Y669H; c.2590G > A, p.E864K and c.G2389A, p.D797 N). All the novel mutations were absent in 100 ethnically matched controls and were predicted to be deleterious by multiple algorithms.\nCONCLUSIONS: We identified three novel and three previously reported WFS1 mutations in six unrelated Chinese families. Our findings enriched the genotype-phenotype spectrum of WFS1 related NSHL. Additional genotype-phenotype correlation study will clarify the detailed phenotypic range caused by WFS1 mutations.","variants":[{"Name":"NM_006005.3(WFS1):c.2389G>A (p.Asp797Asn)","Chromosome":"4","Start":"6302184","Stop":"6302184","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":496379,"rule_based_match":false,"evidence_text":"c.G2389A, p.D797 N","llm_judgment":"PRESENT","evidence":"c.G2389A, p.D797 N","abstract_start":1047,"abstract_end":1065}]}
{"pmid":"24449676","title":"A patient with an apparently sporadic pheochromocytoma with a rearranged during transfection codon 635 variant: a mild form of multiple endocrine neoplasia type 2?","abstract":"OBJECTIVE: Multiple endocrine neoplasia 2 (MEN2) is an autosomal dominant disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism, with mutations at codon 634 in exon 11 of the RET (REarranged during Transfection) proto-oncogene identified as the most common genetic defect.\nMETHODS: We present a patient diagnosed with a left adrenal pheochromocytoma at a young age in whom we identified a mutation at codon 635 of the RET gene. No MTC has been clinically detected during a 6-year follow-up.\nRESULTS: The C-to-T point mutation at nucleotide c.1903 results in an additional cysteine in the cysteine-rich domain due to the replacement of arginine with cysteine. One of the patient's 2 children has the same sequence variant in the RET proto-oncogene and has remained unaffected during follow-up.\nCONCLUSIONS: The majority of mutations in this disorder affect cysteine residues in the cysteine-rich region of the extracellular domain of the RET protein, disrupting normal cysteine pairing. Consequently, we consider that this variant is likely of pathogenic significance, but this has not been unequivocally confirmed.","variants":[{"Name":"NM_020975.6(RET):c.1903C>T (p.Arg635Cys)","Chromosome":"10","Start":"43114503","Stop":"43114503","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":459845,"rule_based_match":false,"evidence_text":"C-to-T point mutation at nucleotide c.1903","llm_judgment":"PRESENT","evidence":"C-to-T point mutation at nucleotide c.1903","abstract_start":553,"abstract_end":595}]}
{"pmid":"24898045","title":"IL36RN mutation causing generalized pustular psoriasis in a Palestinian patient.","abstract":"Deficiency of interleukin-36 (IL-36) receptor antagonist (DITRA; OMIM 614204) is a rare autoinflammatory disorder characterized by periodic fever associated with a generalized erythematous and pustular skin rash. A 6-year-old Arab-Palestinian boy presented with a history of periodic fever and unremitting, erythematous, scaly skin rash accompanied by widespread pustules that had been present since the age of one month. The patient's skin lesions were compatible with generalized pustular psoriasis. Sequence analysis revealed a homozygous nonsense mutation, c.28C>T (p.Arg10X) in the IL36RN gene. The patient improved with oral methotrexate in combination with oral and topical corticosteroids. The molecular basis for DITRA has only recently been identified, and the mutation spectrum for this disorder in many populations is still obscure. This paper reports the presence of the c.28C>T mutation in an Arab-Palestinian patient and thus represents the first description of this mutation in a non-Japanese subject.","variants":[{"Name":"NM_012275.3(IL36RN):c.28C>T (p.Arg10Ter)","Chromosome":"2","Start":"113059466","Stop":"113059466","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48520,"rule_based_match":true,"evidence_text":"c.28C>T (p.Arg10X)","llm_judgment":"PRESENT","evidence":"c.28C>T (p.Arg10X)","abstract_start":561,"abstract_end":579}]}
{"pmid":"25342276","title":"A TULP1 founder mutation, p.Gln301*, underlies a recognisable congenital rod-cone dystrophy phenotype on the Arabian Peninsula.","abstract":"BACKGROUND: In Arabian children referred with retinal dystrophy, we have observed that a specific biallelic nonsense mutation in the gene encoding tubby-like protein 1 (TULP1, c.901C>T (p.Gln301*)) is recurrent. This makes the mutation and its associated childhood retinopathy particularly interesting for genetic diagnostic and, potentially, gene therapy approaches. We characterise the ophthalmic phenotype associated with recessive p.Gln301* mutation in TULP1 and assess the mutation for single founder effect.\nMETHODS: Retrospective consecutive case series (2011-2014) of 10 Arabian children (8 families) homozygous for the p.Gln301* mutation (detected after next-generation sequencing) and 12 ethnically matched controls. TULP1 haplotypes were constructed by analysis of TULP1 intragenic single nucleotide polymorphisms from next-generation sequencing data and genotyping of gene-flanking polymorphic microsatellite markers.\nRESULTS: All 10 children (2-8 years old; mean 5.2, median 6) had nystagmus since soon after birth, a grossly normal posterior pole other than arteriolar attenuation, peripheral mottling with apparent evolution to bone spicules, and hyperopia. Rod function was non-recordable while cone function was present (albeit depressed and delayed); however, repeat electroretinogram years later in two children revealed loss of recordable cone function. Autofluorescence showed a hyper-fluorescent ring around the fovea while central optical coherence tomography was within normal limits. A specific haplotype was associated with p.Gln301* and was not present in controls.\nCONCLUSIONS: The TULP1 allele p.Gln301* represents a founder mutation on the Arabian Peninsula and is associated with a recognisable congenital recessive rod-cone dystrophy phenotype in the homozygous state.","variants":[{"Name":"NM_003322.6(TULP1):c.901C>T (p.Gln301Ter)","Chromosome":"6","Start":"35506101","Stop":"35506101","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":816462,"rule_based_match":true,"evidence_text":"c.901C>T (p.Gln301*)","llm_judgment":"PRESENT","evidence":"c.901C>T (p.Gln301*)","abstract_start":176,"abstract_end":196}]}
{"pmid":"21850189","title":"Mutation spectrum of PAX6 in Chinese patients with aniridia.","abstract":"PURPOSE: To identify mutations in the paired box 6 (PAX6) gene of 33 probands with aniridia and to reveal the mutational spectrum in the Chinese population.\nMETHODS: Unrelated probands with aniridia from 27 newly selected families and six previously analyzed families participated in this study. The coding regions of PAX6 in the 27 new families were analyzed using cycle sequencing. Families that lacked detectable variations based on sequencing (14 new and six previously analyzed) were further analyzed using multiplex ligation-dependent probe amplification (MLPA).\nRESULTS: Fifteen mutations were identified in 16 of the 33 families: c.[65_94del30; 99_105dup7], c.101_102insA, c.177delG, c.238_239insGCGA, c.1033-42_1033-26del17insG, c.1A>G, c.120C>A, c.718C>T, c.949C>T, c.1062C>A, c.1183G>A, c.1268A>T, and three gross deletions involving exons 1-14, exons 8-14, and exons 9-14. The first five mutations were novel and the c.1268A>T mutation was present in two families. Phenotypic variations were observed between families and between different affected patients within the families.\nCONCLUSIONS: The PAX6 mutation spectrum in Chinese aniridia patients is comparable to that reported in other ethnic groups. Further studies of the 17 families with no detected mutations may provide additional information to improve the understanding of the molecular genetics of aniridia.","variants":[{"Name":"NM_001368894.2(PAX6):c.120C>A (p.Cys40Ter)","Chromosome":"11","Start":"31802725","Stop":"31802725","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":461056,"rule_based_match":true,"evidence_text":"c.120C>A","llm_judgment":"PRESENT","evidence":"c.120C>A","abstract_start":746,"abstract_end":754}]}
{"pmid":"34404380","title":"Unique three-site compound heterozygous mutation in the WFS1 gene in Wolfram syndrome.","abstract":"BACKGROUND: Wolfram syndrome (WFS) is a rare autosomal recessive genetic disease whose main cause is mutations in the WFS1 and CISD2 genes. Its characteristic clinical manifestations are diabetes insipidus, diabetes mellitus, optic atrophy and deafness.\nMETHODS: In this study, two patients from this particular family underwent complete routine biochemical and ophthalmic tests. Blood, urine, routine stool test, visual acuity (VA) examination, visual field assessment, funduscope, optical coherence tomography and periorbital magnetic resonance imaging (MRI) scans were performed for each patient to evaluate whether the nerve fiber layer around the optic nerve head was atrophied and next-generation sequencing of target genes was performed in two patients.\nRESULTS: When the patients were diagnosed with Wolfram syndrome, their genetic analyses suggested unique three-site compound heterozygous mutations (c.2314C > T + c.2194C > T + c.2171C > T) in exon 8 of both patients' chromosome 4. One mutation (c.2314C > T) was a novel mutation in the known reports of Wolfram syndrome. As a degenerative genetic disease, the types of gene mutations in the Chinese population are generally homozygous mutations at the unit point or compound heterozygous mutations at two nucleotide change sites. However, the two patients reported in this study are the first known cases of compound heterozygous mutations with three mutation sites coexisting on the WFS1 gene in China or even globally.\nCONCLUSIONS: This study expands the phenotypic spectrum of Wolfram syndrome and may reveal a novel mutation pattern of pathogenesis of Wolfram syndrome. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with WFS1.","variants":[{"Name":"NM_006005.3(WFS1):c.2314C>T (p.Arg772Cys)","Chromosome":"4","Start":"6302109","Stop":"6302109","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1501442,"rule_based_match":true,"evidence_text":"c.2314C > T","llm_judgment":"PRESENT","evidence":"c.2314C > T","abstract_start":910,"abstract_end":921},{"Name":"NM_006005.3(WFS1):c.2194C>T (p.Arg732Cys)","Chromosome":"4","Start":"6301989","Stop":"6301989","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":211074,"rule_based_match":true,"evidence_text":"c.2194C > T","llm_judgment":"PRESENT","evidence":"c.2194C > T","abstract_start":924,"abstract_end":935}]}
{"pmid":"24315539","title":"Folinic acid responsive epilepsy in Ohtahara syndrome caused by STXBP1 mutation.","abstract":"BACKGROUND: Ohtahara syndrome is a severe condition with early onset of recurrent unprovoked seizures associated with abnormal electroencephalography and global developmental delay. Folinic acid-responsive seizures are treatable causes of Ohtahara syndrome, which is thought to be due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin.\nMETHOD: Here we report a girl with Ohtahara syndrome who exhibited transient folinic acid responsiveness but without evidence of antiquitin dysfunction.\nRESULTS: She was later found to have a known missense mutation (c.1439 C > T, p.P480 L) in exon 16 of the STXBP1 gene.\nCONCLUSION: For infants presenting with Ohtahara syndrome with responsiveness to folinic acid and negative antiquitin deficiency analyses, genetic testing for other possible causative genes such as STXBP1 mutation is recommended.","variants":[{"Name":"NM_001032221.6(STXBP1):c.1439C>T (p.Pro480Leu)","Chromosome":"9","Start":"127678510","Stop":"127678510","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":202320,"rule_based_match":true,"evidence_text":"c.1439 C > T, p.P480 L","llm_judgment":"PRESENT","evidence":"c.1439 C > T, p.P480 L","abstract_start":585,"abstract_end":607}]}
{"pmid":"31313512","title":"PAPSS2-related brachyolmia: Clinical and radiological phenotype in 18 new cases.","abstract":"Brachyolmia is a skeletal dysplasia characterized by short spine-short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their short-spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over-faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi-parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under-recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester.","variants":[{"Name":"NM_001015880.2(PAPSS2):c.809G>A (p.Gly270Asp)","Chromosome":"10","Start":"87715787","Stop":"87715787","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":271833,"rule_based_match":true,"evidence_text":"c.809G>A","llm_judgment":"PRESENT","evidence":"c.809G>A","abstract_start":1070,"abstract_end":1078}]}
{"pmid":"23279345","title":"Two novel mutations of GARS in Korean families with distal hereditary motor neuropathy type V.","abstract":"Glycyl-tRNA synthetase (GARS), which encodes the enzyme responsible for charging tRNA(Gly) with glycine in both the cytoplasm and mitochondria, is implicated to Charcot-Marie-Tooth disease 2D (CMT2D) and distal hereditary motor neuropathy type V (dHMN-V). We performed whole exome sequencing (WES) to identify the genetic defects in the two dHMN families. WES revealed several decades of non-synonymous variants in the CMT and aminoacyl-tRNA synthetase genes. The subsequent capillary sequencing for family members and controls revealed two novel causative mutations, c.598G>A (D200N) and c.794C>T (S265F), in the GARS gene in each dHMN family. Both mutations were cosegregated with affected individuals in each family, and were not found in the 200 controls. The mutation sites were well conserved between the different species and in silico analysis predicted that both mutations may affect protein function. Therefore, we believe that these two novel GARS mutations are the underlying causes of the dHMN phenotype.","variants":[{"Name":"NM_002047.4(GARS1):c.598G>A (p.Asp200Asn)","Chromosome":"7","Start":"30603062","Stop":"30603062","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625140,"rule_based_match":true,"evidence_text":"c.598G>A (D200N)","llm_judgment":"PRESENT","evidence":"c.598G>A (D200N)","abstract_start":568,"abstract_end":584},{"Name":"NM_002047.4(GARS1):c.794C>T (p.Ser265Phe)","Chromosome":"7","Start":"30609643","Stop":"30609643","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":457766,"rule_based_match":true,"evidence_text":"c.794C>T (S265F)","llm_judgment":"PRESENT","evidence":"c.794C>T (S265F)","abstract_start":589,"abstract_end":605}]}
{"pmid":"33335874","title":"Phenotypic Characterization of Intellectual Disability Caused by","abstract":"A homozygous in-frame deletion (c. 758_778del; p. Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (<i>MBOAT7)</i>, also known as lysophosphatidylinositol acyltransferase (LPIAT1), was previously reported to be the genetic cause of intellectual disability (ID) in consanguineous families from Pakistan. Here, we identified two additional Pakistani consanguineous families with severe ID individuals sharing the same homozygous variant. Thus, we provide further evidence to support this <i>MBOAT7</i> mutation as a potential founder variant. To understand the genotype-phenotype relationships of the in-frame deletion in the <i>MBOAT7</i> gene, we located the variant in the fifth transmembrane domain of the protein and determined that it causes steric hindrance to the formation of an α-helix and hydrogen bond, possibly influencing its effectiveness as a functional transmembrane protein. Moreover, extensive neuropsychological observations, clinical interviews and genetic analysis were performed on 6 patients from the 2 families. We characterized the phenotype of the patients and noted the serious outcome of severe paraplegia. Thus, optimal management for symptom alleviation and appropriate screening in these patients are crucial.","variants":[{"Name":"NM_024298.5(MBOAT7):c.758_778del (p.Glu253_Ala259del)","Chromosome":"19","Start":"54180849","Stop":"54180869","ReferenceAlleleVCF":"CCGGCGGCAATGCAGCCGCACT","AlternateAlleleVCF":"C","allel_id":263638,"rule_based_match":true,"evidence_text":"c. 758_778del; p. Glu253_Ala259del","llm_judgment":"PRESENT","evidence":"c. 758_778del; p. Glu253_Ala259del","abstract_start":32,"abstract_end":66}]}
{"pmid":"19099731","title":"Diagnosis, treatment and gene mutation analysis of the first case with dihydropteridine reductase deficiency in the mainland of China","abstract":"OBJECTIVE: The 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is the most common type of tetrahydrobiopterin (BH4) deficiency. The reported patients with BH4 deficiency are all PTPS deficient found in the mainland of China previously. The activity of dihydropteridine reductase in BH4 metabolism has been determined for 902 patients with hyperphenylalaninemia in the authors' laboratory since 2003. The purposes of this study were to characterize the first case with DHPR deficiency who was diagnosed in June, 2007, to investigate the clinical manifestation, the differential diagnostic criteria, the effect of treatment as well as gene mutation of DHPR deficiency.\nMETHODS: (1) A male patient presented with poor hand control, seizure, hypotonia and mental retardation since five-month after birth. His phenylalanine (Phe) level was 600 micromol/L and he was diagnosed as hyperphenylalaninemia at the age of one year and six-month. (2) This patient was subjected to combined Phe (100 mg/kg) and BH4 (20 mg/kg) loading test, to evaluate the degree of Phe level response to BH4. Urinary neopterin and biopterin analysis as well as the determination of DHPR activity in dried blood spot were also performed. (3) The blood DNA samples of the patient and his parents were collected to amplify the seven exons of QDPR gene using related primers, and the amplified products were directly sequenced for mutation analysis. (4) The patient was treated with BH4 or with a combined small amount of Phe-free special milk, neurotransmitter precursors and folic acid after the diagnosis and was followed up for clinical effects of treatment.\nRESULTS: (1) The basic Phe level was 476 micromol/L, then it increased to 1355 micromol/L at 3 h after taking Phe and slowly decreased to 610 micromol/L at 24h after taking BH4. (2) The basic urinary neopterin and biopterin were 2.92 mmol/mol Cr (normally < 2.61 mmol/mol Cr) and 7.44 mmol/molCr (normally < 2.67 mmol/mol Cr) respectively, and biopterin percentage was 71.79% (normally 42.7% - 75.9%). The patient had higher biopterin level. (3) The DHPR activity of this patient was (0.27 - 0.51) nmol/(min.5 mm disc) which were 6.11% - 10.6% of normal control, so he was diagnosed as DHPR deficiency. (4) The analysis of QDPR gene mutation showed that the patient carries missense mutation c.515C > T (P172L) from his father and nonsense mutation c.661C > T (R221X) from his mother. The c.515C > T is not reported before, we also did not find this mutation in 50 normal children. (5) The patient started to be treated with large dosage of BH4 (10 - 20) mg/(kg.d) or BH4 combined with small amounts of Phe-free milk, neurotransmitter precursors L-dopa (3 - 5) mg/(kg.d) plus carbidopa, 5-hydroxytryptophan (3 - 5) mg/(kg.d), and folic acid 15 mg/d as well at the age of one year and six-month after the diagnosis. The seizure has disappeared, the symptoms such as hypotonia have been obviously improved and the Phe level was 60 micromol/L at the six months after the treatment in this patient.\nCONCLUSION: (1) The patient with DHPR deficiency has common symptoms of BH4 deficiency (such as fair hair, hypotonia, mental retardation), and there is metabolic disturbance of folic acid in DHPR deficiency. (2) The higher Phe levels slowly decreased after BH4 loading test, the urinary biopterin level was very high and the DHPR activity was very low in the patient with DHPR deficiency. (3) The c.515C > T may be a new mutation of QDPR gene. (4) The DHPR deficient patient must be treated with higher dose of BH4 (8 - 20) mg/(kg.d), neurotransmitter precursors and folic acid as well.","variants":[{"Name":"NM_000320.3(QDPR):c.515C>T (p.Pro172Leu)","Chromosome":"4","Start":"17492262","Stop":"17492262","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2894677,"rule_based_match":true,"evidence_text":"c.515C > T (P172L)","llm_judgment":"PRESENT","evidence":"c.515C > T (P172L)","abstract_start":2328,"abstract_end":2346},{"Name":"NM_000320.3(QDPR):c.661C>T (p.Arg221Ter)","Chromosome":"4","Start":"17487205","Stop":"17487205","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":790458,"rule_based_match":true,"evidence_text":"c.661C > T (R221X)","llm_judgment":"PRESENT","evidence":"c.661C > T (R221X)","abstract_start":2385,"abstract_end":2403}]}
{"pmid":"31749211","title":"Molecular, biochemical, and clinical analyses of five patients with carbamoyl phosphate synthetase 1 deficiency.","abstract":"BACKGROUND: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare urea cycle disorder. The aim of this study was to present the clinical findings, management, biochemical data, molecular genetic analysis, and short-term prognosis of five children with CPS1D.\nMETHODS: The information of five CPS1D patients was retrospectively studied. We used targeted next-generation sequencing to identify carbamoyl phosphate synthetase 1 (CPS1) variants in patients suspected to have CPS1D. Candidate mutations were validated by Sanger sequencing. In silico and structure analyses were processed for the pathogenicity predictions of the identified mutations.\nRESULTS: The patients had typically clinical manifestations and biochemical data of CPS1D. Genetic analysis revealed nine mutations in the CPS1 gene, including recurrence of c.1145C > T, five of which were firstly reported. Seven mutations were missense changes, while the remaining two were predicted to create premature stop codons. In silico and structure analyses showed that these genetic lesions were predicted to affect the function or stability of the enzyme.\nCONCLUSION: We reported five cases of CPS1D. Five novel mutations of CPS1 gene were found. Mutations of CPS1 have private nature, and most of them are missense compound heterozygous. The mutation affecting residue predicted to interfere the catalytic sites, the internal tunnel, or the regulatory domain results in severe phenotype.","variants":[{"Name":"NM_001875.5(CPS1):c.1145C>T (p.Pro382Leu)","Chromosome":"2","Start":"210592937","Stop":"210592937","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":541787,"rule_based_match":true,"evidence_text":"c.1145C > T","llm_judgment":"PRESENT","evidence":"c.1145C > T","abstract_start":828,"abstract_end":839}]}
{"pmid":"27690257","title":"Hb Midnapore [β53(D4)Ala→Val; HBB: c.161C>T]: A Novel Hemoglobin Variant with a Structural Abnormality Associated with IVS-I-5 (G>C) (HBB: c.92+5G>C) Found in a Bengali Indian Family.","abstract":"We describe a novel C>T substitution at codon 53 of the HBB gene (HBB: c.161C>T). The proband was a transfusion-dependent β-thalassemia major (β-TM) patient. DNA was extracted and subsequently, DNA sequencing was done to detect the mutations on the HBB gene. Capillary zone electrophoresis (CZE) revealed the presence of an unknown peak. She inherited this mutation from her grandmother through her mother. This mutation exists in cis with the common β<sup>0</sup> mutation IVS-I-5 (G>C) (HBB: c.92+5G>C). The proband is homozygous for HBB: c.92+5G>C and needs monthly transfusions. On the other hand, her grandmother, mother and sister all possess this novel mutation cis with the heterozygous HBB: c.92+5G>C. They are carriers not thalassemic. This mutation produces the substitution β53(D4)Ala→Val; HBB: c.161C>T, a new structural hemoglobin (Hb) variant. As this variant was identified in a Bengali family from Paschim Midnapore district of West Bengal, India, it has been designated as Hb Midnapore. This variant has now been reported to the HbVar database.","variants":[{"Name":"NM_000518.5(HBB):c.161C>T (p.Ala54Val)","Chromosome":"11","Start":"5226731","Stop":"5226731","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3495281,"rule_based_match":true,"evidence_text":"HBB: c.161C>T","llm_judgment":"PRESENT","evidence":"HBB: c.161C>T","abstract_start":66,"abstract_end":79},{"Name":"NM_000518.5(HBB):c.92+5G>C","Chromosome":"11","Start":"5226925","Stop":"5226925","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":30486,"rule_based_match":true,"evidence_text":"IVS-I-5 (G>C) (HBB: c.92+5G>C)","llm_judgment":"PRESENT","evidence":"IVS-I-5 (G>C) (HBB: c.92+5G>C)","abstract_start":474,"abstract_end":504}]}
{"pmid":"29903538","title":"ATP13A2 novel mutations causing a rare form of juvenile-onset Parkinson disease.","abstract":"Parkinson disease is a common neurodegenerative disease that typically starts around the age of 60 years; however, juvenile-onset disease can occur rarely. Although Parkinson disease is typically sporadic; in rare occasions, it can be caused by a single gene defect that is inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Herein, we describe a 10-year-old child who had juvenile-onset parkinsonism with rigidity, bradykinesia, dystonia, gait disturbance, and cognitive impairment. Whole exome sequencing showed compound heterozygosity for two previously unreported novel mutations in ATP13A2 (PARK9): a paternally inherited c.1321A>T (p.I441F) and a maternally inherited c.3205G>A (p.A1069T). ATP13A2 mutations are rare cause of autosomal recessive juvenile-onset Parkinson disease. Family co-segregation study and the clinical phenotype support that p.I441F and p.A1069T are indeed disease-causing mutations.","variants":[{"Name":"NM_022089.4(ATP13A2):c.1321A>T (p.Ile441Phe)","Chromosome":"1","Start":"16996286","Stop":"16996286","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":952139,"rule_based_match":true,"evidence_text":"c.1321A>T (p.I441F)","llm_judgment":"PRESENT","evidence":"c.1321A>T (p.I441F)","abstract_start":653,"abstract_end":672},{"Name":"NM_022089.4(ATP13A2):c.3205G>A (p.Ala1069Thr)","Chromosome":"1","Start":"16986835","Stop":"16986835","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":696253,"rule_based_match":true,"evidence_text":"c.3205G>A (p.A1069T)","llm_judgment":"PRESENT","evidence":"c.3205G>A (p.A1069T)","abstract_start":700,"abstract_end":720}]}
{"pmid":"21301859","title":"Genetic analysis of two Japanese families with progressive external ophthalmoplegia and parkinsonism.","abstract":"Mutations in the progressive external ophthalmoplegia 1 (PEO1), adenine nucleotide translocator 1 (ANT1) and DNA polymerase gamma (POLG) genes were reported in patients with progressive external ophthalmoplegia and parkinsonism. However, the genotype-phenotype correlation and pathophysiology of these syndromes are still unknown. In order to define the molecular basis of progressive external ophthalmoplegia and parkinsonism, we screened for mutations in PEO1, ANT1, POLG genes and the whole mitochondrial genome in two families. In results, we identified a compound heterozygous POLG substitutions, c.830A>T (p.H277L) and c.2827C>T (p.R943C) in one of the families. These two mutations in the coding region of POLG alter conserved amino acids in the exonuclease and polymerase domains, respectively, of the POLG protein. Neither of these substitutions was found in the 100 chromosomes of ethnically matched control subjects. In the other family, no mutations were detected in any of the three genes and the whole mitochondrial genome in the blood sample, although mitochondrial DNA deletions were observed in the muscle biopsy sample. Progressive external ophthalmoplegia and parkinsonism are genetically heterogenous disorders, and part of this syndrome may be caused by mutations in other, unknown genes.","variants":[{"Name":"NM_002693.3(POLG):c.2827C>T (p.Arg943Cys)","Chromosome":"15","Start":"89320920","Stop":"89320920","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":610737,"rule_based_match":true,"evidence_text":"c.2827C>T (p.R943C)","llm_judgment":"PRESENT","evidence":"c.2827C>T (p.R943C)","abstract_start":625,"abstract_end":644},{"Name":"NM_002693.3(POLG):c.830A>T (p.His277Leu)","Chromosome":"15","Start":"89330106","Stop":"89330106","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":203034,"rule_based_match":true,"evidence_text":"c.830A>T (p.H277L)","llm_judgment":"PRESENT","evidence":"c.830A>T (p.H277L)","abstract_start":602,"abstract_end":620}]}
{"pmid":"32238352","title":"Clinical and genetical features of probands and affected family members with familial exudative vitreoretinopathy in a large Chinese cohort.","abstract":"AIMS: To explore the clinical and genetical features of families with strictly confirmed familial exudative vitreoretinopathy (FEVR) in a large Chinese cohort.\nMETHODS: A retrospective chart review study was conducted on the FEVR families diagnosed by both angiography and targeted next-generation sequencing in six FEVR known genes (<i>FZD4</i>, <i>LRP5</i>, <i>TSPAN12</i>, <i>NDP</i>, <i>KIF11, ZNF408</i>) in the probands and at least one first-degree family member. Variation in expressivity and severity was evaluated in different gene groups.\nRESULTS: 105 FEVR families (223 FEVR affected subjects with 434 eyes) met the inclusion criteria. There were 105 probands with mean age of 3.8 years old and 118 affected family members of 32.7 years old averagely. Mutations in <i>FZD4</i> were most prevalent (33.33%), followed by <i>LRP5</i> (29.52%), <i>TSPAN12</i> (22.86%), <i>NDP</i> (5.71%), <i>KIF11</i> (1.9%) and <i>ZNF408</i> (0.95%). 81% of the probands were classified as stage 4 or worse which most prevalently contributed to <i>FZD4</i> mutations. All of the three affected family members with stage 4 or worse carried <i>FZD4</i> variants. More than half (51.43%) of the probands in <i>FZD4</i> group showed asymmetry. Unilateral FEVR was detected in 11 (10.5%) families consisting of six probands and six affected relatives, and <i>FZD4</i> mutations accounted for 63.64% of all the cases with variant (c.1282_1285del, p. D428fs) identified in three families.\nCONCLUSIONS: Genotype-phenotype correlation in FEVR was complex with family dependent. Mutations in <i>FZD4</i> might initiate the most diverse and asymmetric phenotypes.","variants":[{"Name":"NM_012193.4(FZD4):c.1282_1285del (p.Asp428fs)","Chromosome":"11","Start":"86951471","Stop":"86951474","ReferenceAlleleVCF":"TTGTC","AlternateAlleleVCF":"T","allel_id":226403,"rule_based_match":true,"evidence_text":"c.1282_1285del, p. D428fs","llm_judgment":"PRESENT","evidence":"c.1282_1285del, p. D428fs","abstract_start":1419,"abstract_end":1444}]}
{"pmid":"29484903","title":"Complex Interaction of Hb Q-Thailand (HBA1: c.223G>C) with β-Thalassemia/Hb E (HBB: c.79G>A) Disease.","abstract":"Hb Q-Thailand [α74(EF3)Asp→His (α1), GAC>CAC, HBA1: c.223G>C] is an abnormal hemoglobin (Hb) frequently found in Thailand and Southeast Asian countries. The association of the α<sup>Q-Thailand</sup> allele with other globin gene disorders has important implications in diagnosis. Here, we report how to diagnose the coinheritance of Hb Q-Thailand with β-thalassemia (β-thal)/Hb E disease in four Thai samples from high performance liquid chromatography (HPLC) and capillary electrophoresis (CE) testing results. Understanding of the HPLC chromatogram and CE electropherogram patterns of this complex mutation is important for interpretation of testing results and providing genetic counseling.","variants":[{"Name":"NM_000558.5(HBA1):c.223G>C (p.Asp75His)","Chromosome":"16","Start":"177056","Stop":"177056","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":30772,"rule_based_match":true,"evidence_text":"HBA1: c.223G>C","llm_judgment":"PRESENT","evidence":"HBA1: c.223G>C","abstract_start":46,"abstract_end":60}]}
{"pmid":"23243084","title":"Riboflavin transporter 3 involvement in infantile Brown-Vialetto-Van Laere disease: two novel mutations.","abstract":"BACKGROUND: Brown-Vialetto-Van Laere (BVVL) syndrome is a rare disorder characterised by progressive pontobulbar palsy and sensorineural deafness. Causative mutations in genes encoding human riboflavin transporter 2 (hRFT2) and 3 (hRFT3) have been identified in BVVL patients.\nMETHODS AND RESULTS: We report the clinical and molecular features of a severe BVVL patient in whom screening of SLC52A3/hRFT2 was negative. Sequence analysis identified two novel compound heterozygous mutations in SLC52A2/hRFT3, namely c.155C>T and c.1255G>A, leading to the amino acid changes p.S52F and p.G419S, respectively. Functional studies show that these defects impair the gene expression of the corresponding transporter, resulting in a significant reduction of riboflavin transport.\nCONCLUSIONS: These findings support the pathogenetic role of SLC52A2/hRFT3 in BVVL with important clinical and therapeutic implications.","variants":[{"Name":"NM_001363118.2(SLC52A2):c.155C>T (p.Ser52Phe)","Chromosome":"8","Start":"144359647","Stop":"144359647","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48717,"rule_based_match":true,"evidence_text":"c.155C>T","llm_judgment":"PRESENT","evidence":"c.155C>T","abstract_start":514,"abstract_end":522},{"Name":"NM_001363118.2(SLC52A2):c.1255G>A (p.Gly419Ser)","Chromosome":"8","Start":"144360932","Stop":"144360932","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48718,"rule_based_match":true,"evidence_text":"c.1255G>A","llm_judgment":"PRESENT","evidence":"c.1255G>A","abstract_start":527,"abstract_end":536}]}
{"pmid":"22718341","title":"Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix.","abstract":"Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with ≈10% over-modification. Normal chain incorporation, helix folding, and collagen T(m) support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix.","variants":[{"Name":"NM_021939.4(FKBP10):c.1271_1272delinsA (p.Ala424fs)","Chromosome":"17","Start":"41820961","Stop":"41820962","ReferenceAlleleVCF":"CC","AlternateAlleleVCF":"A","allel_id":49863,"rule_based_match":false,"evidence_text":"c.1271_1272delCCinsA","llm_judgment":"PRESENT","evidence":"c.1271_1272delCCinsA","abstract_start":583,"abstract_end":603}]}
{"pmid":"28150585","title":"The first Slovak Legius syndrome patient carrying the SPRED1 gene mutation.","abstract":"Autosomal dominant disorder Legius syndrome (NF1- like syndrome) shows phenotype features that overlap with neurofibromatosis type 1 (NF1), such as CALMs, freckling, macrocephaly and learning disability. Mutation analysis provides an important tool in order to distinguish two entities that have different clinical implications. We analyzed SPRED1 gene by cDNA and/or gDNA sequencing in a cohort of 46 Slovak patients in whom previously NF1 mutation was excluded. In one case we identified a nonsense mutation c.46C>T (p.Arg16*) in exon 2 of SPRED1 gene, confirming diagnosis of Legius syndrome. This mutation was reported previously.","variants":[{"Name":"NM_152594.3(SPRED1):c.46C>T (p.Arg16Ter)","Chromosome":"15","Start":"38299386","Stop":"38299386","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360244,"rule_based_match":true,"evidence_text":"c.46C>T (p.Arg16*)","llm_judgment":"PRESENT","evidence":"c.46C>T (p.Arg16*)","abstract_start":510,"abstract_end":528}]}
{"pmid":"30450742","title":"Next generation sequencing-based molecular diagnosis in familial congenital cataract expands the mutational spectrum in known congenital cataract genes.","abstract":"Congenital cataract (CC) is a significant cause of childhood blindness worldwide. CC is a genetically heterogeneous disease because mutations in over 40 genes have been demonstrated to cause the disorder and up to 40% of cases arise from single-gene mutations. Hence, next generation sequencing (NGS) of deoxyribonucleic acid is a suitable approach for CC molecular diagnosis. In this study, we used commercially available inherited disease NGS panels including 50 CC genes for the genetic diagnosis of 11 probands with hereditary CC. Causal variants were recognized in six families. A novel CRYGC variant, p.(Phe6Ser), was identified in two apparently unrelated families. Two additional novel variants in the crystallin genes CRYBB2 (p.[Gly149Asp]) and CRYGA (p.[Arg48Cys]) were also identified. One family carried the novel p.[Gly8_Leu11del] variant in GJA8, while another family exhibited the previously reported c.2826-9G>A pathogenic change in EPHA2. Our results illustrate the utility of NGS for diagnosing CC in our population, and our results contribute to expand the mutational spectrum with four novel pathogenic variants in known CC genes.","variants":[{"Name":"NM_004431.5(EPHA2):c.2826-9G>A","Chromosome":"1","Start":"16125329","Stop":"16125329","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":263955,"rule_based_match":true,"evidence_text":"c.2826-9G>A","llm_judgment":"PRESENT","evidence":"c.2826-9G>A","abstract_start":916,"abstract_end":927},{"Name":"NM_005267.5(GJA8):c.23_34del (p.Gly8_Leu11del)","Chromosome":"1","Start":"147907975","Stop":"147907986","ReferenceAlleleVCF":"CTGGGGAACATCT","AlternateAlleleVCF":"C","allel_id":3412495,"rule_based_match":false,"evidence_text":"p.[Gly8_Leu11del]","llm_judgment":"PRESENT","evidence":"p.[Gly8_Leu11del]","abstract_start":826,"abstract_end":843}]}
{"pmid":"27103379","title":"PHKA2 mutation spectrum in Korean patients with glycogen storage disease type IX: prevalence of deletion mutations.","abstract":"BACKGROUND: Molecular diagnosis of glycogen storage diseases (GSDs) is important to enable accurate diagnoses and make appropriate therapeutic plans. The aim of this study was to evaluate the PHKA2 mutation spectrum in Korean patients with GSD type IX.\nMETHODS: Thirteen Korean patients were tested for PHKA2 mutations using direct sequencing and a multiplex polymerase chain reaction method. A comprehensive review of the literature on previously reported PHKA2 mutations in other ethnic populations was conducted for comparison.\nRESULTS: Among 13 patients tested, six unrelated male patients with GSD IX aged 2 to 6 years at the first diagnostic work-up for hepatomegaly with elevated aspartate transaminase (AST) and alanine transaminase (ALT) were found to have PHKA2 mutations. These patients had different PHKA2 mutations: five were known mutations (c.537 + 5G > A, c.884G > A [p.Arg295His], c.3210_3212delGAG [p.Arg1072del], exon 8 deletion, and exons 27-33 deletion) and one was a novel mutation (exons 18-33 deletion). Notably, the most common type of mutation was gross deletion, in contrast to other ethnic populations in which the most common mutation type was sequence variant.\nCONCLUSIONS: This study expands our knowledge of the PHKA2 mutation spectrum of GSD IX. Considering the PHKA2 mutation spectrum in Korean patients with GSD IX, molecular diagnostic methods for deletions should be conducted in conjunction with direct sequence analysis to enable accurate molecular diagnosis of this disease in the Korean population.","variants":[{"Name":"NM_000292.3(PHKA2):c.884G>A (p.Arg295His)","Chromosome":"X","Start":"18940029","Stop":"18940029","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":205340,"rule_based_match":true,"evidence_text":"c.884G > A [p.Arg295His]","llm_judgment":"PRESENT","evidence":"c.884G > A [p.Arg295His]","abstract_start":872,"abstract_end":896},{"Name":"NM_000292.3(PHKA2):c.3210_3212del (p.Arg1072del)","Chromosome":"X","Start":"18897233","Stop":"18897235","ReferenceAlleleVCF":"TCTC","AlternateAlleleVCF":"T","allel_id":492524,"rule_based_match":true,"evidence_text":"c.3210_3212delGAG [p.Arg1072del]","llm_judgment":"PRESENT","evidence":"c.3210_3212delGAG [p.Arg1072del]","abstract_start":898,"abstract_end":930}]}
{"pmid":"28451379","title":"Retrospective analysis in oculocutaneous albinism patients for the 2.7 kb deletion in the","abstract":"BACKGROUND: Oculocutaneous albinism (OCA) is an autosomal recessive disorder. A significant portion of OCA patients has been found with a single pathogenic variant either in the <i>TYR</i> or the <i>OCA2</i> gene. Diagnostic sequencing of the <i>TYR</i> and <i>OCA2</i> genes is routinely used for molecular diagnosis of OCA subtypes. To study the possibility that genomic abnormalities with single or multiple exon involvement may account for a portion of the potential missing pathogenic variants (the second), we retrospectively analyzed the <i>TYR</i> gene by long range PCR and analyzed the target 2.7 kb deletion in the <i>OCA2</i> gene spanning exon 7 in OCA patients with a single pathogenic variant in the target genes.\nRESULTS: In the 108 patients analyzed, we found that one patient was heterozygous for the 2.7 kb <i>OCA2</i> gene deletion and this patient was positive with one pathogenic variant and one possibly pathogenic variant [c.1103C>T (p.Ala368Val) + c.913C>T (p.R305W)]. Further analysis of maternal DNA, and two additional OCA DNA homozygous for the 2.7 kb deletion, revealed that the phenotypically normal mother is heterozygous of the 2.7 kb deletion and homozygous of the p.R305W. The two previously reported patients with homozygous of the 2.7 kb deletion are also homozygous of p.R305W.\nCONCLUSIONS: Among the reported pathogenic variants, the pathogenicity of the p.R305W has been discussed intensively in literature. Our results indicate that p.R305W is unlikely a pathogenic variant. The possibility of linkage disequilibrium between p.R305W with the 2.7 kb deletion in <i>OCA2</i> gene is also suggested.","variants":[{"Name":"NM_000275.3(OCA2):c.1103C>T (p.Ala368Val)","Chromosome":"15","Start":"27990589","Stop":"27990589","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":190737,"rule_based_match":true,"evidence_text":"c.1103C>T (p.Ala368Val)","llm_judgment":"PRESENT","evidence":"c.1103C>T (p.Ala368Val)","abstract_start":947,"abstract_end":970}]}
{"pmid":"32453731","title":"Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.","abstract":"Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain variants (p.E22*, p.K62*, p.E97*) that result in loss of the EF domains are stably expressed but show impaired localization. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither the MYL2-fs nor the MYL2:p.Gly162Arg variant supports normal cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants in infantile HCM and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathy.","variants":[{"Name":"NM_000432.4(MYL2):c.431_432del (p.Pro144fs)","Chromosome":"12","Start":"110911146","Stop":"110911147","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":615035,"rule_based_match":true,"evidence_text":"MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57","llm_judgment":"PRESENT","evidence":"MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57","abstract_start":482,"abstract_end":531},{"Name":"NM_000432.4(MYL2):c.484G>A (p.Gly162Arg)","Chromosome":"12","Start":"110911094","Stop":"110911094","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":136725,"rule_based_match":false,"evidence_text":"MYL2:p.Gly162Arg","llm_judgment":"PRESENT","evidence":"MYL2:p.Gly162Arg","abstract_start":1278,"abstract_end":1294}]}
{"pmid":"27307693","title":"Loss of function mutations in RP1 are responsible for retinitis pigmentosa in consanguineous familial cases.","abstract":"PURPOSE: This study was undertaken to identify causal mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous families.\nMETHODS: Large consanguineous families were ascertained from the Punjab province of Pakistan. An ophthalmic examination consisting of a fundus evaluation and electroretinography (ERG) was completed, and small aliquots of blood were collected from all participating individuals. Genomic DNA was extracted from white blood cells, and a genome-wide linkage or a locus-specific exclusion analysis was completed with polymorphic short tandem repeats (STRs). Two-point logarithm of odds (LOD) scores were calculated, and all coding exons and exon-intron boundaries of RP1 were sequenced to identify the causal mutation.\nRESULTS: The ophthalmic examination showed that affected individuals in all families manifest cardinal symptoms of RP. Genome-wide scans localized the disease phenotype to chromosome 8q, a region harboring RP1, a gene previously implicated in the pathogenesis of RP. Sanger sequencing identified a homozygous single base deletion in exon 4: c.3697delT (p.S1233Pfs22*), a single base substitution in intron 3: c.787+1G>A (p.I263Nfs8*), a 2 bp duplication in exon 2: c.551_552dupTA (p.Q185Yfs4*) and an 11,117 bp deletion that removes all three coding exons of RP1. These variations segregated with the disease phenotype within the respective families and were not present in ethnically matched control samples.\nCONCLUSIONS: These results strongly suggest that these mutations in RP1 are responsible for the retinal phenotype in affected individuals of all four consanguineous families.","variants":[{"Name":"NM_006269.2(RP1):c.787+1G>A","Chromosome":"8","Start":"54622289","Stop":"54622289","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3407568,"rule_based_match":true,"evidence_text":"c.787+1G>A (p.I263Nfs8*)","llm_judgment":"PRESENT","evidence":"c.787+1G>A (p.I263Nfs8*)","abstract_start":1179,"abstract_end":1203}]}
{"pmid":"12872266","title":"Neurofibromatosis type 1 (NF1): Identification of eight unreported mutations in NF1 gene in Italian patients [corrected].","abstract":"In the present study the entire NF1 coding region was analyzed for mutations in 132 unrelated Italian NF1 patients. Using PTT, SSCP, and DNA sequencing, we found 8 novel mutations. Clinical diagnosis of NF1 was established according to the NIH consensus criteria. We detected 59 truncated fragments, and 46 of them were characterized by SSCP and direct sequencing. Eight mutations represent novel changes that contribute to the germline mutational spectrum of the NF1 gene. In two patients, premature termination was due to substitutions at nucleotide c.3982C>T (Q1298X) and c.7411C>T (Q2471X), respectively. Two other mutations were caused by the deletions (1756delA, 4699delA), and two by the insertions (c.5266_5267insT, c.7464_7465insTCCA) of a small number of nucleotides. Lastly, we found 2 splice-site mutations (c.2252-2A>C, c.2251+1G>A).","variants":[{"Name":"NM_001042492.3(NF1):c.2251+1G>A","Chromosome":"17","Start":"31226685","Stop":"31226685","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":485770,"rule_based_match":true,"evidence_text":"c.2251+1G>A","llm_judgment":"PRESENT","evidence":"c.2251+1G>A","abstract_start":833,"abstract_end":844},{"Name":"NM_001042492.3(NF1):c.2252-2A>C","Chromosome":"17","Start":"31227216","Stop":"31227216","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":538143,"rule_based_match":true,"evidence_text":"c.2252-2A>C","llm_judgment":"PRESENT","evidence":"c.2252-2A>C","abstract_start":820,"abstract_end":831}]}
{"pmid":"16374432","title":"Heterogeneous mutations in the SLC3A1 and SLC7A9 genes in Chinese patients with cystinuria.","abstract":"Cystinuria is a recessively inherited aminoaciduria that leads to recurrent urolithiasis. It is caused by the defective transport of cystine and dibasic amino acids in the proximal renal tubules and intestinal epithelium. Two genes responsible for this, SLC3A1 and SLC7A9, are known. Patients with two SLC3A1 mutations are classified as type A cystinuria, whereas patients with two SLC7A9 mutations are classified as type B cystinuria. Few clinical and molecular data have been reported for Asian cystinuria patients. In this study, we determined the molecular basis of cystinuria in eight unrelated Chinese subjects. Coding exons and flanking introns of the SLC3A1 and SLC7A9 genes were directly sequenced after amplification by polymerase chain reaction. Five different SLC3A1 mutations were found. Two missense mutations, D210G and S547L, were novel. The other three SLC3A1 mutations (IVS6+2T>C, R181Q and R365W) have been described previously. In addition, four novel SLC7A9 mutations, C137R, c.730delG, IVS10+2_3delTG and IVS12+3insT, together with two previously reported mutations (A70V and G195R) were found. All patients except one carried compound heterozygous mutations. IVS12+3insT was detected in patients from two families. This is the first molecular genetic study on Chinese cystinuria patients. Three patients with type A cystinuria, two with type B cystinuria, and three carriers of type B cystinuria were identified. Our results suggest that the molecular basis of cystinuria is heterogeneous in our local population.","variants":[{"Name":"NM_014270.5(SLC7A9):c.730del (p.Glu244fs)","Chromosome":"19","Start":"32860625","Stop":"32860625","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":1679726,"rule_based_match":true,"evidence_text":"c.730delG","llm_judgment":"PRESENT","evidence":"c.730delG","abstract_start":997,"abstract_end":1006}]}
{"pmid":"33650182","title":"Establishing intellectual disability as the key feature of patients with biallelic RNPC3 variants.","abstract":"Some mammalian genes contain both major and minor introns, the splicing of which require distinctive major and minor spliceosomes, respectively; these genes are referred to as minor intron containing-genes. RNPC3 (RNA-binding domain-containing protein 3) is one of the proteins that are unique to the minor spliceosome U11/U12 di-snRNP. Only two families with biallelic pathogenic variants in the RNPC3 gene encoding the protein have been reported so far, and the affected members in both families had proportional short stature. While the affected members of the originally identified family did not have intellectual disability, the patients from the other family exhibited intellectual disability. Here, we report on a patient with severe primordial microcephalic dwarfism and intellectual disability who carried compound heterozygous variants in RNPC3 (NM_017619.3): c.261dup, p.Leu88Thrfs*11 and c.1228T>G, p.Phe410Val. The single nucleotide substitution c.1228T>G had a very high predictive score for pathogenicity: the p.Phe410 residue is highly conserved down to fish. Based on ACMG (American College of Medical Genetics and Genomics) guideline, this non-synonymous variant was scored as likely pathogenic. This documentation of yet another patient with biallelic RNPC3 variants exhibiting intellectual disability lends further support to the notion that intellectual disability is a key feature of the spectrum of RNPC3-related disorders.","variants":[{"Name":"NM_017619.4(RNPC3):c.261dup (p.Leu88fs)","Chromosome":"1","Start":"103533757","Stop":"103533758","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":1310248,"rule_based_match":true,"evidence_text":"c.261dup","llm_judgment":"PRESENT","evidence":"c.261dup","abstract_start":871,"abstract_end":879},{"Name":"NM_017619.4(RNPC3):c.1228T>G (p.Phe410Val)","Chromosome":"1","Start":"103546268","Stop":"103546268","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1310249,"rule_based_match":true,"evidence_text":"c.1228T>G, p.Phe410Val","llm_judgment":"PRESENT","evidence":"c.1228T>G, p.Phe410Val","abstract_start":901,"abstract_end":923}]}
{"pmid":"31969346","title":"The tale of two genes: from next-generation sequencing to phenotype.","abstract":"An 18-yr-old man with a history of intellectual disability, craniofacial dysmorphism, seizure disorder, and obesity was identified to carry a de novo, pathogenic variant in <i>ASXL1</i> (c.4198G>T; p.E1400X) associated with the diagnosis of Bohring-Opitz syndrome based on exome sequencing. In addition, he was identified to carry a maternally inherited and likely pathogenic variant in <i>MC4R</i> (c.817C>T; p.Q273X) associated with monogenic obesity. Dual genetic diagnosis occurs in 4%-6% of patients and results in unique clinical phenotypes that are a function of tissue-specific gene expression, involved pathways, clinical expressivity, and penetrance. This case highlights the utility of next-generation sequencing in patients with an unusual combination of clinical presentations for several pillars of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources.","variants":[{"Name":"NM_015338.6(ASXL1):c.4198G>T (p.Glu1400Ter)","Chromosome":"20","Start":"32436910","Stop":"32436910","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":446217,"rule_based_match":true,"evidence_text":"c.4198G>T; p.E1400X","llm_judgment":"PRESENT","evidence":"c.4198G>T; p.E1400X","abstract_start":187,"abstract_end":206},{"Name":"NM_005912.3(MC4R):c.817C>T (p.Gln273Ter)","Chromosome":"18","Start":"60371533","Stop":"60371533","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":445994,"rule_based_match":true,"evidence_text":"c.817C>T (p.Q273X)","llm_judgment":"PRESENT","evidence":"c.817C>T","abstract_start":400,"abstract_end":408}]}
{"pmid":"19901218","title":"Mutational hot spot potential of a novel base pair mutation of the CSPG2 gene in a family with Wagner syndrome.","abstract":"OBJECTIVE: To report a 3-generation white family clinically diagnosed variably with Wagner, Stickler, and Jansen syndromes and screened for sequence variants in the COL2A1 and CSPG2 genes. Wagner syndrome is an autosomal dominant vitreoretinopathy with a predisposition to retinal detachment and cataracts. It has significant phenotypic overlap with allelic Jansen syndrome and ocular Stickler syndrome type 1. Sticker syndrome type 1 maps to chromosome 12q13.11-q13.2, with associated COL2A1 gene mutations. Wagner syndrome maps to chromosome 5q13-q14 and is associated with mutations in CSPG2 encoding versican, a proteoglycan present in human vitreous.\nMETHODS: Genomic DNA samples derived from venous blood were collected from all family members. Complete sequencing of COL2A1 was performed on a proband. Primers for polymerase chain reaction and sequencing were designed to cover all exon and intron-exon boundaries. Direct sequencing of CSPG2 was performed on all family member samples.\nRESULTS: No detectable COL2A1 mutations were noted, making the diagnosis of ocular Stickler syndrome highly unlikely for this family. A unique base pair substitution (c.9265 + 1G>T) in intron 8 of the CSPG2 gene cosegregating with disease status was identified. This mutation occurred in a highly conserved previously reported splice site with a similar base pair substitution (G>A). Direct sequencing of this splice site mutation in 107 unrelated external controls revealed no variants, supporting the rarity of this base pair change and its causation in Wagner syndrome. This novel base pair substitution is thought to cause the deletion of exon 8 and formation of a truncated protein product.\nCONCLUSION: Mutation screening of CSPG2 in autosomal dominant vitreoretinopathy families is important for accurate diagnosis.\nCLINICAL RELEVANCE: This study underscores the importance of obtaining extensive pedigree information and comparative ophthalmologic clinical information, as the phenotypic findings may vary greatly among independent family members. The study also affirms the paradigm shift from diagnosis assignment based on eponyms to that based on gene mutation type.","variants":[{"Name":"NM_004385.5(VCAN):c.9265+1G>T","Chromosome":"5","Start":"83542269","Stop":"83542269","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":216063,"rule_based_match":true,"evidence_text":"c.9265 + 1G>T","llm_judgment":"PRESENT","evidence":"c.9265 + 1G>T","abstract_start":1160,"abstract_end":1173}]}
{"pmid":"21601224","title":"Clinical, electrophysiological and pathological findings of a patient with CMT2 due to the p.Ala738Val mitofusin 2 mutation.","abstract":"Mutations in the gene encoding mitofusin 2 (MFN2) are responsible of about 20% of Charcot-Marie-Tooth disease type 2 (CMT2) case. A great variability exists among CMT2A concerning severity and associated clinical features. Generally patients with an early onset CMT2A disclose a severe phenotype while the cases with a late onset present a more benign clinical course. We describe clinical, electrophysiological and pathological findings of a patient with a mild CMT2A due to the c.2213C>T, p.Ala738Val MFN2 mutation. This mutation has been already described to be only associated with an early onset and moderately severe CMT2A phenotype.","variants":[{"Name":"NM_014874.4(MFN2):c.2213C>T (p.Ala738Val)","Chromosome":"1","Start":"12011504","Stop":"12011504","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":624963,"rule_based_match":true,"evidence_text":"c.2213C>T, p.Ala738Val MFN2 mutation","llm_judgment":"PRESENT","evidence":"c.2213C>T, p.Ala738Val MFN2 mutation","abstract_start":480,"abstract_end":516}]}
{"pmid":"28371217","title":"Inherited germline ATRX mutation in two brothers with ATR-X syndrome and osteosarcoma.","abstract":"We report a family in which two brothers had an undiagnosed genetic disorder comprised of dysmorphic features, microcephaly, severe intellectual disability (non-verbal), mild anemia, and cryptorchidism. Both developed osteosarcoma. Trio exome sequencing (using blood samples from the younger brother and both parents) was performed and a nonsense NM_000489.4:c.7156C>T (p.Arg2386*) mutation in the ATRX gene was identified in the proband (hemizygous) and in the mother's peripheral blood DNA (heterozygous). The mother is healthy, does not exhibit any clinical manifestations of ATR-X syndrome and there was no family history of cancer. The same hemizygous pathogenic variant was confirmed in the affected older brother's skin tissue by subsequent Sanger sequencing. Chromosomal microarray studies of both brothers' osteosarcomas revealed complex copy number alterations consistent with the clinical diagnosis of osteosarcoma. Recently, somatic mutations in the ATRX gene have been observed as recurrent alterations in both osteosarcoma and brain tumors. However, it is unclear if there is any association between osteosarcoma and germline ATRX mutations, specifically in patients with constitutional ATR-X syndrome. This is the first report of osteosarcoma diagnosed in two males with ATR-X syndrome, suggesting a potential increased risk for cancer in patients with this disorder.","variants":[{"Name":"NM_000489.6(ATRX):c.7156C>T (p.Arg2386Ter)","Chromosome":"X","Start":"77520832","Stop":"77520832","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26767,"rule_based_match":true,"evidence_text":"NM_000489.4:c.7156C>T (p.Arg2386*)","llm_judgment":"PRESENT","evidence":"NM_000489.4:c.7156C>T (p.Arg2386*)","abstract_start":347,"abstract_end":381}]}
{"pmid":"18766993","title":"Bardet-biedl syndrome: an atypical phenotype in brothers with a proven BBS1 mutation.","abstract":"BACKGROUND: To report the clinical findings in two brothers presenting with a pigmentary retinopathy and post-axial polydactyly, who were found to have a mutation in the BBS1 gene, confirming a diagnosis of Bardet-Biedl syndrome (BBS).\nMATERIALS AND METHODS: Documentation of the clinical history, electrophysiological investigations, clinical examination and ocular findings of two brothers born to non-consanguineous white parents, with careful delineation of their clinical phenotypes. Screening of the BBS 1 gene on chromosome 11q13 by PCR-amplified exon alterations followed by direct sequencing was carried out to identify pathogenic mutations.\nRESULTS: Although both probands had polydactyly and the characteristic ocular signs of BBS on both ophthalmological examination and electro-retinography, neither of them had dysmorphic facial features, obesity, hypogonadism, cognitive impairment, or renal anomalies. The first proband did have mild learning difficulties, although this did not restrict him in activities of daily living. Both probands were homozygous positive for the presence of a c.1169T > G (p.Met390Arg) mutation in BBS1.\nCONCLUSION: Although neither proband fulfilled the typical criteria for BBS, this diagnosis was confirmed on mutation analysis. These cases serve to highlight the degree of clinical variability observed in BBS which may be under-diagnosed in patients with milder phenotypes.","variants":[{"Name":"NM_024649.5(BBS1):c.1169T>G (p.Met390Arg)","Chromosome":"11","Start":"66526181","Stop":"66526181","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":27182,"rule_based_match":true,"evidence_text":"c.1169T > G (p.Met390Arg)","llm_judgment":"PRESENT","evidence":"c.1169T > G (p.Met390Arg)","abstract_start":1100,"abstract_end":1125}]}
{"pmid":"28095071","title":"Mevalonate kinase deficiency associated with ataxia and retinitis pigmentosa in two brothers with MVK gene mutations.","abstract":"PURPOSE: To report the clinical and molecular genetic findings in two brothers with retinitis pigmentosa (RP) and mevalonate kinase deficiency (MKD).\nMETHODS: The brothers were examined clinically and with fundus autofluorescence, near-infrared autofluorescence, and spectral domain optical coherence tomography. Targeted resequencing was done with a custom designed gene panel containing 78 genes associated with RP. Mutations were confirmed by direct Sanger sequencing.\nRESULTS: Both brothers, aged 46 and 47 years, were found to carry compound heterozygous mutations in the MVK gene (c.59A>C, c.1000G>A) encoding mevalonate kinase. They presented with severe ataxia, pseudophakia due to early onset cataract, and progressed retinitis pigmentosa. In one brother with cystoid macular edema, treatment with dorzolamide was beneficial. Serum IgD levels were markedly increased in both brothers and mevalonic acid blood and urine levels were markedly increased in the one brother who could be examined. The disease severity differed between the brothers-one had more severe ataxia and less severe visual deficiency compared to the other.\nCONCLUSION: MKD can be associated with RP and early onset cataract. Most MKD patients developing RP carry the (p.Ala334Thr) mutation. Macular edema can be treated using local dorzolamide.","variants":[{"Name":"NM_000431.4(MVK):c.1000G>A (p.Ala334Thr)","Chromosome":"12","Start":"109595142","Stop":"109595142","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26969,"rule_based_match":true,"evidence_text":"c.1000G>A","llm_judgment":"PRESENT","evidence":"c.1000G>A","abstract_start":596,"abstract_end":605}]}
{"pmid":"21070677","title":"Female heterozygotes for the hypomorphic R40H mutation can have ornithine transcarbamylase deficiency and present in early adolescence: a case report and review of the literature.","abstract":"INTRODUCTION: Ornithine transcarbamylase deficiency is the most common hereditary urea cycle defect. It is inherited in an X-linked manner and classically presents in neonates with encephalopathy and hyperammonemia in males. Females and males with hypomorphic mutations present later, sometimes in adulthood, with episodes that are frequently fatal.\nCASE PRESENTATION: A 13-year-old Caucasian girl presented with progressive encephalopathy, hyperammonemic coma and lactic acidosis. She had a history of intermittent regular episodes of nausea and vomiting from seven years of age, previously diagnosed as abdominal migraines. At presentation she was hyperammonemic (ammonia 477 μmol/L) with no other biochemical indicators of hepatic dysfunction or damage and had grossly elevated urinary orotate (orotate/creatinine ratio 1.866 μmol/mmol creatinine, reference range <500 μmol/mmol creatinine) highly suggestive of ornithine transcarbamylase deficiency. She was treated with intravenous sodium benzoate and arginine and made a rapid full recovery. She was discharged on a protein-restricted diet. She has not required ongoing treatment with arginine, and baseline ammonia and serum amino acid concentrations are within normal ranges. She has had one further episode of hyperammonemia associated with intercurrent infection after one year of follow up. An R40H (c.119G>A) mutation was identified in the ornithine transcarbamylase gene (OTC) in our patient confirming the first symptomatic female shown heterozygous for the R40H mutation. A review of the literature and correspondence with authors of patients with the R40H mutation identified one other symptomatic female patient who died of hyperammonemic coma in her late teens.\nCONCLUSIONS: This report expands the clinical spectrum of presentation of ornithine transcarbamylase deficiency to female heterozygotes for the hypomorphic R40H OTC mutation. Although this mutation is usually associated with a mild phenotype, females with this mutation can present with acute decompensation, which can be fatal. Ornithine transcarbamylase deficiency should be considered in the differential diagnosis of unexplained acute confusion, even without a suggestive family history.","variants":[{"Name":"NM_000531.6(OTC):c.119G>A (p.Arg40His)","Chromosome":"X","Start":"38367332","Stop":"38367332","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26053,"rule_based_match":true,"evidence_text":"R40H (c.119G>A)","llm_judgment":"PRESENT","evidence":"R40H (c.119G>A)","abstract_start":1355,"abstract_end":1370}]}
{"pmid":"23703728","title":"Whole-exome sequencing identified a homozygous FNBP4 mutation in a family with a condition similar to microphthalmia with limb anomalies.","abstract":"Microphthalmia with limb anomalies (MLA), also known as Waardenburg anophthalmia syndrome or ophthalmoacromelic syndrome, is a rare autosomal recessive disorder. Recently, we and others successfully identified SMOC1 as the causative gene for MLA. However, there are several MLA families without SMOC1 abnormality, suggesting locus heterogeneity in MLA. We aimed to identify a pathogenic mutation in one Lebanese family having an MLA-like condition without SMOC1 mutation by whole-exome sequencing (WES) combined with homozygosity mapping. A c.683C>T (p.Thr228Met) in FNBP4 was found as a primary candidate, drawing the attention that FNBP4 and SMOC1 may potentially modulate BMP signaling.","variants":[{"Name":"NM_015308.5(FNBP4):c.683C>T (p.Thr228Met)","Chromosome":"11","Start":"47751245","Stop":"47751245","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":262316,"rule_based_match":true,"evidence_text":"c.683C>T (p.Thr228Met)","llm_judgment":"PRESENT","evidence":"c.683C>T (p.Thr228Met)","abstract_start":541,"abstract_end":563}]}
{"pmid":"23190448","title":"Novel PRRT2 mutations in paroxysmal dyskinesia patients with variant inheritance and phenotypes.","abstract":"Paroxysmal dyskinesias (PDs) are a group of episodic movement disorders with marked variability in clinical manifestation and potential association with epilepsy. PRRT2 has been identified as a causative gene for PDs, but the phenotypes and inheritance patterns of PRRT2 mutations need further clarification. In this study, 10 familial and 21 sporadic cases with PDs and PDs-related phenotypes were collected. Genomic DNA was screened for PRRT2 mutations by direct sequencing. Seven PRRT2 mutations were identified in nine (90.0%) familial cases and in six (28.6%) sporadic cases. Five mutations are novel: two missense mutations (c.647C>G/p.Pro216Arg and c.872C>T/p.Ala291Val) and three truncating mutations (c.117delA/p.Val41TyrfsX49, c.510dupT/p.Leu171SerfsX3 and c.579dupA/p.Glu194ArgfsX6). Autosomal dominant inheritance with incomplete penetrance was observed in most of the familial cases. In the sporadic cases, inheritance was heterogeneous including recessive inheritance with compound heterozygous mutations, inherited mutations with incomplete parental penetrance and de novo mutation. Variant phenotypes associated with PRRT2 mutations, found in 36.0% of the affected cases, included febrile convulsions, epilepsy, infantile non-convulsive seizures (INCS) and nocturnal convulsions (NC). All patients with INCS or NC, not reported previously, displayed abnormalities on electroencephalogram (EEG). No EEG abnormalities were recorded in patients with classical infantile convulsions and paroxysmal choreoathetosis (ICCA)/paroxysmal kinesigenic dyskinesia (PKD). Our study further confirms that PRRT2 mutations are the most common cause of familial PDs, displaying both dominant and recessive inheritance. Epilepsy may occasionally occur in ICCA/PKD patients with PRRT2 mutations. Variant phenotypes INCS or NC differ from classical ICCA/PKD clinically and electroencephalographically. They have some similarities with, but not identical to epilepsy, possibly represent an overlap between ICCA/PKD and epilepsy.","variants":[{"Name":"NM_145239.3(PRRT2):c.579dup (p.Glu194fs)","Chromosome":"16","Start":"29813631","Stop":"29813632","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":949363,"rule_based_match":true,"evidence_text":"c.579dupA/p.Glu194ArgfsX6","llm_judgment":"PRESENT","evidence":"c.579dupA/p.Glu194ArgfsX6","abstract_start":767,"abstract_end":792},{"Name":"NM_145239.3(PRRT2):c.647C>G (p.Pro216Arg)","Chromosome":"16","Start":"29813701","Stop":"29813701","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":76665,"rule_based_match":true,"evidence_text":"c.647C>G/p.Pro216Arg","llm_judgment":"PRESENT","evidence":"c.647C>G/p.Pro216Arg","abstract_start":631,"abstract_end":651}]}
{"pmid":"31939038","title":"Juvenile Onset Splenomegaly and Oculopathy Due to Germline Mutation in ALPK1.","abstract":"ROSAH syndrome was recently identified as an autosomal dominant systemic disorder due to mutations in ALPK1. It was characterized by retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. We collected and summarized the clinical data of two patients with juvenile onset splenomegaly and oculopathy. Whole exome sequencing (WES) was adapted for genetic analysis. Mutations in ALPK1 were confirmed by Sanger sequencing. Besides juvenile oculopathy and splenomegaly, both patients had intermittent fever and anhidrosis. Patient 2 also experienced recurrent upper respiratory infections in her infancy and developed dental and nail problems in childhood. Elevated TNF-α was their prominent laboratory features. Both patients were found to have a previously reported mutation, c.710C>T, p. T237M (NM_001102406) in ALPK1. Anti-TNF treatment of adalimumab was applied to patient 1, after which her optic disc edema in the left eye continued and the visual acuity deteriorated further. Patient 1 underwent elective splenectomy due to concern for spontaneous rupture of the spleen. Up to date, 18 patients of ROSAH syndrome have been reported. The clinical manifestations were relatively homogeneous, prominently presenting with juvenile onset oculopathy and splenomegaly. As it mainly involves ocular fundus, severe oculopathy deeply affects the quality of life and prognosis of ROSAH patients. Now little has been known about its treatment. As a newly recognized inherited systemic disorder, ROSAH syndrome needs to be paid more attention to, especially for those with juvenile onset splenomegaly and oculopathy.","variants":[{"Name":"NM_025144.4(ALPK1):c.710C>T (p.Thr237Met)","Chromosome":"4","Start":"112427580","Stop":"112427580","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":610429,"rule_based_match":true,"evidence_text":"c.710C>T, p. T237M (NM_001102406)","llm_judgment":"PRESENT","evidence":"c.710C>T, p. T237M (NM_001102406)","abstract_start":804,"abstract_end":837}]}
{"pmid":"33060515","title":"Diagnosis of Hyper IgM syndrome in a Previously Healthy Adolescent Boy Presented with Cutaneous and Cerebral Cryptococcosis.","abstract":"X-linked hyper IgM (X-HIGM) syndrome is a combined immunodeficiency disease caused by mutations in the CD40LG gene, leading to a defect in immunoglobulin (Ig) class switching recombination and effector T-cell responses. X-HIGM patients usually present in early life with pyogenic bacterial and opportunistic infections. Herein, we report a previously healthy 13-year-old Thai boy who first presented with cutaneous and meningoencephalitis cryptococcosis. Whole-exome sequencing revealed that he was hemizygous for a missense c.514T>C (p.Tyr172His) in CD40LG, confirming a diagnosis of X-HIGM. This report demonstrates that X-HIGM could have an age of onset in teens and systemic cryptococcosis could be its presenting symptoms.","variants":[{"Name":"NM_000074.3(CD40LG):c.514T>C (p.Tyr172His)","Chromosome":"X","Start":"136659143","Stop":"136659143","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":849681,"rule_based_match":true,"evidence_text":"c.514T>C (p.Tyr172His)","llm_judgment":"PRESENT","evidence":"c.514T>C (p.Tyr172His)","abstract_start":525,"abstract_end":547}]}
{"pmid":"20129749","title":"Two novel missense mutations in the aspartoacylase gene in a Chinese patient with congenital Canavan disease.","abstract":"We herein describe the first Chinese case of Canavan disease diagnosed by biochemical analysis and confirmed by DNA studies. We report two novel mutations: c.2T>C/M1T, an initiation codon mutation, and c.209A>G/N70S, which is located at the enzyme-substrate binding site. The combination of these two mutations resulted in a congenital form of Canavan disease.","variants":[{"Name":"NM_000049.4(ASPA):c.209A>G (p.Asn70Ser)","Chromosome":"17","Start":"3476368","Stop":"3476368","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2895081,"rule_based_match":true,"evidence_text":"c.209A>G/N70S","llm_judgment":"PRESENT","evidence":"c.209A>G/N70S","abstract_start":202,"abstract_end":215},{"Name":"NM_000049.4(ASPA):c.2T>C (p.Met1Thr)","Chromosome":"17","Start":"3476161","Stop":"3476161","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":358411,"rule_based_match":true,"evidence_text":"c.2T>C/M1T","llm_judgment":"PRESENT","evidence":"c.2T>C/M1T","abstract_start":156,"abstract_end":166}]}
{"pmid":"31515523","title":"SPTAN1 variants as a potential cause for autosomal recessive hereditary spastic paraplegia.","abstract":"More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10<sup>-15</sup>). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.","variants":[{"Name":"NM_001130438.3(SPTAN1):c.2572G>T (p.Ala858Ser)","Chromosome":"9","Start":"128585759","Stop":"128585759","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":524017,"rule_based_match":true,"evidence_text":"c.2572G>T p.(Ala858Ser)","llm_judgment":"PRESENT","evidence":"c.2572G>T p.(Ala858Ser)","abstract_start":471,"abstract_end":494},{"Name":"NM_001130438.3(SPTAN1):c.4283C>G (p.Ala1428Gly)","Chromosome":"9","Start":"128607988","Stop":"128607988","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":194022,"rule_based_match":true,"evidence_text":"c.4283C>G p.(Ala1428Gly)","llm_judgment":"PRESENT","evidence":"c.4283C>G p.(Ala1428Gly)","abstract_start":499,"abstract_end":523}]}
{"pmid":"26251176","title":"Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion.","abstract":"BACKGROUND: Short-chain enoyl-CoA hydratase-ECHS1-catalyses many metabolic pathways, including mitochondrial short-chain fatty acid β-oxidation and branched-chain amino acid catabolic pathways; however, the metabolic products essential for the diagnosis of ECHS1 deficiency have not yet been determined. The objective of this report is to characterise ECHS1 and a mild form of its deficiency biochemically, and to determine the candidate metabolic product that can be efficiently used for neonatal diagnosis.\nMETHODS: We conducted a detailed clinical, molecular genetics, biochemical and metabolic analysis of sibling patients with ECHS1 deficiency. Moreover, we purified human ECHS1, and determined the substrate specificity of ECHS1 for five substrates via different metabolic pathways.\nRESULTS: Human ECHS1 catalyses the hydration of five substrates via different metabolic pathways, with the highest specificity for crotonyl-CoA and the lowest specificity for tiglyl-CoA. The patients had relatively high (∼7%) residual ECHS1 enzyme activity for crotonyl-CoA and methacrylyl-CoA caused by the compound heterozygous mutations (c.176A>G, (p.N59S) and c.413C>T, (p.A138V)) with normal mitochondrial complex I-IV activities. Affected patients excrete large amounts of N-acetyl-S-(2-carboxypropyl)cysteine, a metabolite of methacrylyl-CoA.\nCONCLUSIONS: Laboratory data and clinical features demonstrated that the patients have a mild form of ECHS1 deficiency harbouring defective valine catabolic and β-oxidation pathways. N-Acetyl-S-(2-carboxypropyl) cysteine level was markedly high in the urine of the patients, and therefore, N-acetyl-S-(2-carboxypropyl)cysteine was regarded as a candidate metabolite for the diagnosis of ECHS1 deficiency. This metabolite is not part of current routine metabolic screening protocols, and its inclusion, therefore, holds immense potential in accurate diagnosis.","variants":[{"Name":"NM_004092.4(ECHS1):c.176A>G (p.Asn59Ser)","Chromosome":"10","Start":"133370670","Stop":"133370670","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":215649,"rule_based_match":true,"evidence_text":"c.176A>G, (p.N59S)","llm_judgment":"PRESENT","evidence":"c.176A>G, (p.N59S)","abstract_start":1130,"abstract_end":1148},{"Name":"NM_004092.4(ECHS1):c.413C>T (p.Ala138Val)","Chromosome":"10","Start":"133369905","Stop":"133369905","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":215650,"rule_based_match":true,"evidence_text":"c.413C>T, (p.A138V)","llm_judgment":"PRESENT","evidence":"c.413C>T, (p.A138V)","abstract_start":1153,"abstract_end":1172}]}
{"pmid":"25620204","title":"A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.","abstract":"Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutières syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. In vitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals' blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption.","variants":[{"Name":"NM_022168.4(IFIH1):c.2465G>A (p.Arg822Gln)","Chromosome":"2","Start":"162272377","Stop":"162272377","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187227,"rule_based_match":true,"evidence_text":"c.2465G>A (p.Arg822Gln)","llm_judgment":"PRESENT","evidence":"c.2465G>A (p.Arg822Gln)","abstract_start":421,"abstract_end":444}]}
{"pmid":"31877759","title":"Exploring the Genetic Landscape of Retinal Diseases in North-Western Pakistan Reveals a High Degree of Autozygosity and a Prevalent Founder Mutation in","abstract":"Variants in more than 271 different genes have been linked to hereditary retinal diseases, making comprehensive genomic approaches mandatory for accurate diagnosis. We explored the genetic landscape of retinal disorders in consanguineous families from North-Western Pakistan, harboring a population of approximately 35 million inhabitants that remains relatively isolated and highly inbred (~50% consanguinity). We leveraged on the high degree of consanguinity by applying genome-wide high-density single-nucleotide polymorphism (SNP) genotyping followed by targeted Sanger sequencing of candidate gene(s) lying inside autozygous intervals. In addition, we performed whole-exome sequencing (WES) on at least one proband per family. We identified 7 known and 4 novel variants in a total of 10 genes (<i>ABCA4</i>, <i>BBS2</i>, <i>CNGA1</i>, <i>CNGA3</i>, <i>CNGB3</i>, <i>MKKS</i>, <i>NMNAT1</i>, <i>PDE6B</i>, <i>RPE65</i>, and <i>TULP1</i>) previously known to cause inherited retinal diseases. In spite of all families being consanguineous, compound heterozygosity was detected in one family. All homozygous pathogenic variants resided in autozygous intervals ≥2.0 Mb in size. Putative founder variants were observed in the <i>ABCA4</i> (NM_000350.2:c.214G>A; p.Gly72Arg; ten families) and <i>NMNAT1</i> genes (NM_022787.3:c.25G>A; p.Val9Met; two families). We conclude that geographic isolation and sociocultural tradition of intrafamilial mating in North-Western Pakistan favor both the clinical manifestation of rare \"generic\" variants and the prevalence of founder mutations.","variants":[{"Name":"NM_022787.4(NMNAT1):c.25G>A (p.Val9Met)","Chromosome":"1","Start":"9972098","Stop":"9972098","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45801,"rule_based_match":true,"evidence_text":"NM_022787.3:c.25G>A; p.Val9Met","llm_judgment":"PRESENT","evidence":"NM_022787.3:c.25G>A; p.Val9Met","abstract_start":1313,"abstract_end":1343},{"Name":"NM_000350.3(ABCA4):c.214G>A (p.Gly72Arg)","Chromosome":"1","Start":"94111526","Stop":"94111526","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105009,"rule_based_match":true,"evidence_text":"NM_000350.2:c.214G>A; p.Gly72Arg","llm_judgment":"PRESENT","evidence":"NM_000350.2:c.214G>A; p.Gly72Arg","abstract_start":1240,"abstract_end":1272}]}
{"pmid":"36529819","title":"Two unrelated cases with biallelic CHEK2 variants:a novel condition with constitutional chromosomal instability?","abstract":"Constitutional heterozygous mutations in CHEK2 gene have been associated with hereditary cancer risk. To date, only a few homozygous CHEK2 mutations have been reported in families with cancer susceptibility. Here, we report two unrelated individuals with a personal and familial cancer history in whom biallelic CHEK2 alterations were identified. The first case resulted homozygous for the CHEK2 c.793-1 G > A (p.Asp265Thrfs*10) variant, and the second one was found to be compound heterozygous for the c.1100delC (p.Thr367Metfs*15) and the c.1312 G > T (p.Asp438Tyr) variants. Multiple cytogenetic anomalies were demonstrated on peripheral lymphocytes of both patients. A literature revision showed that a single other CHEK2 homozygous variant was previously associated to a constitutional randomly occurring multi-translocation karyotype from peripheral blood in humans. We hypothesize that, at least some biallelic CHEK2 mutations might be associated with a novel disorder, further expanding the group of chromosome instability syndromes. Additional studies on larger cohorts are needed to confirm if chromosomal instability could represent a marker for CHEK2 constitutionally mutated recessive genotypes, and to investigate the cancer risk and the occurrence of other anomalies typically observed in chromosome instability syndromes.","variants":[{"Name":"NM_007194.4(CHEK2):c.793-1G>A","Chromosome":"22","Start":"28710060","Stop":"28710060","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":181107,"rule_based_match":true,"evidence_text":"c.793-1 G > A (p.Asp265Thrfs*10)","llm_judgment":"PRESENT","evidence":"c.793-1 G > A (p.Asp265Thrfs*10)","abstract_start":396,"abstract_end":428}]}
{"pmid":"24498607","title":"A homozygous double mutation in SMN1: a complicated genetic diagnosis of SMA.","abstract":"Spinal muscular atrophy (SMA), the most common autosomal recessive cause of infant death, is typically diagnosed by determination of SMN1 copy number. Approximately 3-5% of patients with SMA retain at least one copy of the SMN1 gene carrying pathogenic insertions, deletions, or point mutations. We report a patient with SMA who is homozygous for two mutations carried in cis: an 8 bp duplication (c.48_55dupGGATTCCG; p.Val19fs*24) and a point mutation (c.662C>T; p.Pro221Leu). The consanguineous parents carry the same two mutations within one SMN1 gene copy. We demonstrate that a more accurate diagnosis of the disease is obtained through a novel diagnostic assay and development of a capillary electrophoresis method to determine the copy number of their mutant alleles. This illustrates the complexity of SMN mutations and suggests additional testing (gene sequencing) may be appropriate when based on family lines.","variants":[{"Name":"NM_000344.4(SMN1):c.662C>T (p.Pro221Leu)","Chromosome":"5","Start":"70944692","Stop":"70944692","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":622780,"rule_based_match":true,"evidence_text":"c.662C>T (p.Pro221Leu)","llm_judgment":"PRESENT","evidence":"p.Pro221Leu","abstract_start":464,"abstract_end":475},{"Name":"NM_000344.4(SMN1):c.48_55dup (p.Val19fs)","Chromosome":"5","Start":"70925150","Stop":"70925151","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AGGATTCCG","allel_id":622772,"rule_based_match":true,"evidence_text":"c.48_55dupGGATTCCG","llm_judgment":"PRESENT","evidence":"c.48_55dupGGATTCCG","abstract_start":398,"abstract_end":416}]}
{"pmid":"23424595","title":"X-linked agammaglobulinemia presenting with secondary hemophagocytic syndrome: a case report.","abstract":"Introduction. Coincidence of X-linked agammaglobulinemia (XLA) and secondary hemophagocytic syndrome (sHS) is atypical. Both diseases are rare and pathogenesis of the latter one is not clearly known. Case Presentation. A 5-year-old boy was diagnosed both with XLA and sHS. However, in his history, he did not have severe and recurrent infections. Bruton tyrosine kinase (BTK) gene mutation was present (c.1581_1584delTTTG). To the best of the authors' knowledge, coincidence of XLA and sHS had not been reported in the literature before. Conclusion. Patients with XLA are extremely vulnerable to recurrent bacterial infections. The diagnosis of XLA with sHS at any time of life is both an interesting and challenging situation without history of recurrent bacterial infections.","variants":[{"Name":"NM_000061.3(BTK):c.1581_1584del (p.Cys527fs)","Chromosome":"X","Start":"101354677","Stop":"101354680","ReferenceAlleleVCF":"CCAAA","AlternateAlleleVCF":"C","allel_id":485801,"rule_based_match":true,"evidence_text":"c.1581_1584delTTTG","llm_judgment":"PRESENT","evidence":"c.1581_1584delTTTG","abstract_start":403,"abstract_end":421}]}
{"pmid":"22847149","title":"A DYNC1H1 mutation causes a dominant spinal muscular atrophy with lower extremity predominance.","abstract":"Whole-exome sequencing of two affected sibs and their mother who showed a unique quadriceps-dominant form of neurogenic muscular atrophy disclosed a heterozygous DYNC1H1 mutation [p.H306R (c.917A>G)]. The identical mutation was recently reported in a pedigree with the axonal form of Charcot-Marie-Tooth disease. Three other missense mutations in DYNC1H1 were also identified in families with dominant spinal muscular atrophy with lower extremity predominance. Their clinical features were consistent with those of our family. Our study has demonstrated that the same DYNC1H1 mutation could cause spinal muscular atrophy as well as distal neuropathy, indicating pleotropic effects of the mutation.","variants":[{"Name":"NM_001376.5(DYNC1H1):c.917A>G (p.His306Arg)","Chromosome":"14","Start":"101980506","Stop":"101980506","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":38984,"rule_based_match":true,"evidence_text":"p.H306R (c.917A>G)","llm_judgment":"PRESENT","evidence":"p.H306R (c.917A>G)","abstract_start":180,"abstract_end":198}]}
{"pmid":"32655291","title":"Identification of Two Novel Mutations in the","abstract":"BACKGROUND: Ataxia telangiectasia (AT) is one of the most common autosomal recessive hereditary ataxia presenting in childhood. The responsible gene for AT designated ATM (AT, mutated) encodes a protein which is involved in cell cycle checkpoints and other responses to genotoxicity. We describe two novel disease-causing mutations in two unrelated Iranian families with Ataxia-telangiectasia.\nMETHODS: The probands including a 6-year-old female and an 18-year-old boy were diagnosed with Ataxia-telangiectasia among two different Iranian families. In this study, Whole-Exome Sequencing (WES) was employed for the detection of genetic changes in probands. The analysis of the co-segregation of the variants with the disease in families was conducted using PCR direct sequencing.\nRESULTS: Two novel frameshift mutations, (c.4236_4236del p. Pro1412fs) and (c.8907T>G p. Tyr2969Ter) in the ataxia telangiectasia mutated ATM gene were detected using Whole-Exome Sequencing (WES) in the probands. These mutations were observed in two separate A-T families.\nCONCLUSION: Next-generation sequencing successfully identified the causative mutation in families with ataxia-telangiectasia. These novel mutations in the ATM gene reported in the present study could assist genetic counseling, Preimplantation Genetic Diagnosis (PGD) and prenatal diagnosis (PND) of AT.","variants":[{"Name":"NM_000051.4(ATM):c.8907T>G (p.Tyr2969Ter)","Chromosome":"11","Start":"108365138","Stop":"108365138","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2672004,"rule_based_match":true,"evidence_text":"c.8907T>G p. Tyr2969Ter","llm_judgment":"PRESENT","evidence":"c.8907T>G p. Tyr2969Ter","abstract_start":855,"abstract_end":878}]}
{"pmid":"29282712","title":"Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas.","abstract":"Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane-protein-127 (TMEM127) is one of the PCC/PGL-susceptibility genes with an autosomal dominant inheritance pattern. Here, we report 2 patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year-old mentally retarded patient, the homozygous c.410-2A > G mutation was discovered during an update of DNA analysis. A 26-year-old mentally retarded patient was found to have a homozygous c.3G > A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127 mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC-susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127 mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrine concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127 mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information.","variants":[{"Name":"NM_017849.4(TMEM127):c.410-2A>G","Chromosome":"2","Start":"96254117","Stop":"96254117","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":443319,"rule_based_match":true,"evidence_text":"c.410-2A > G","llm_judgment":"PRESENT","evidence":"c.410-2A > G","abstract_start":423,"abstract_end":435},{"Name":"NM_017849.4(TMEM127):c.3G>A (p.Met1Ile)","Chromosome":"2","Start":"96265379","Stop":"96265379","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":518780,"rule_based_match":true,"evidence_text":"c.3G > A","llm_judgment":"PRESENT","evidence":"c.3G > A","abstract_start":565,"abstract_end":573}]}
{"pmid":"27374786","title":"Phenotypic expansion of TBX4 mutations to include acinar dysplasia of the lungs.","abstract":"Mutations in the T-box transcription factor TBX4 gene have been reported in patients with Ischiocoxopodopatellar syndrome (MIM# 147891) and childhood-onset pulmonary arterial hypertension. Whole exome sequencing of DNA from a 1 day old deceased newborn, with severe diffuse developmental lung disorder exhibiting features of acinar dysplasia, and her unaffected parents identified a de novo TBX4 missense mutation p.E86Q (c.256G>C) in the DNA-binding T-box domain. We propose phenotypic expansion of the TBX4-related clinical disease spectrum to include acinar dysplasia of the lungs. The reported mutation is the first identified genetic variant causative for acinar dysplasia. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_001321120.2(TBX4):c.256G>C (p.Glu86Gln)","Chromosome":"17","Start":"61457606","Stop":"61457606","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":622043,"rule_based_match":true,"evidence_text":"c.256G>C","llm_judgment":"PRESENT","evidence":"c.256G>C","abstract_start":422,"abstract_end":430}]}
{"pmid":"30461320","title":"Screening of","abstract":"<b><i>Aims:</i></b> Aryl hydrocarbon receptor-interacting protein (<i>AIP</i>) gene mutations have long been associated with apparently sporadic pituitary adenomas (PAs) with a prevalence range of 0-12%. The aim of this study was to evaluate the frequency of germline <i>AIP</i> variations in a large cohort of apparently sporadic PAs diagnosed before the age of 40 years, who did not exhibit hypercalcemia and/or MEN1 syndrome components during long-term follow-up. <b><i>Materials and Methods:</i></b> A total of 97 patients, diagnosed with functional PAs ≤40 years old, composed of somatotropinoma (<i>n</i> = 55), prolactinoma (<i>n</i> = 25), and corticotrophinoma (<i>n</i> = 17), were recruited for this study. Fifty-one of these patients [somatotropinoma (<i>n</i> = 30), prolactinoma (<i>n</i> = 15), and corticotrophinoma (<i>n</i> = 11)] were previously reported as <i>AIP</i> mutation-negative by Sanger sequencing. The entire coding sequence of the <i>AIP</i> gene, along with exon/intron boundaries and the untranslated regions of 41 newly recruited patients, were sequenced for germline variations. In addition, all patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in the <i>AIP</i> gene. <b><i>Results:</i></b> The <i>AIP</i> c.911G>A: p.Arg304Gln (rs104894190) variant was detected in only two patients with functional PA: one with somatotropinoma [in 1/55 (1.8%)] and one with prolactinoma [in 1/25 (4%)]. None of the corticotrophinomas revealed <i>AIP</i> gene alterations. Thus, the overall prevalence of <i>AIP</i> variation was 2.1% in our cohort. <b><i>Conclusions:</i></b> Germline <i>AIP</i> gene variations among Turkish patients with apparently sporadic PAs are relatively rare among patients ≤40 years old. None of the patients in our cohort revealed any obviously pathogenic <i>AIP</i> variants.","variants":[{"Name":"NM_003977.4(AIP):c.911G>A (p.Arg304Gln)","Chromosome":"11","Start":"67490911","Stop":"67490911","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19932,"rule_based_match":true,"evidence_text":"AIP c.911G>A: p.Arg304Gln (rs104894190)","llm_judgment":"PRESENT","evidence":"AIP</i> c.911G>A: p.Arg304Gln (rs104894190)","abstract_start":1294,"abstract_end":1337}]}
{"pmid":"19190165","title":"Rad50 c.687delT does not contribute significantly to familial breast cancer in a French population.","abstract":"Mutations in DNA repair genes are known for their association with hereditary breast cancer. BRCA1 and BRCA2 are the major genes for high-penetrance familial breast and ovarian cancer, whereas mutations in ATM or Chek2 confer more modest cancer risk. Additional genes involved in DNA double-strand break repair have more recently been associated with breast cancer risk: heterozygosity for deleterious mutations in components of the Rad50-Mre11-Nbs1 complex seems to predispose to breast cancer. In particular, the c.687delT mutation in Rad50 conferred an odds ratio of 4.3 for the risk of breast cancer in a study of Finnish breast cancer families. To explore the contribution of this mutation to breast cancer in French families for which no BRCA mutation could be found, we analyzed the relevant exon in 618 familial breast cancer cases and 513 controls with no personal or familial history of breast cancer. Rad50 was analyzed in its entirety for 231 familial cases, with no clearly deleterious mutations detected. These data together suggest that although founder mutations may make Rad50 a significant breast cancer risk factor in certain populations, it is not a factor in others.","variants":[{"Name":"NM_005732.4(RAD50):c.687del (p.Ser229fs)","Chromosome":"5","Start":"132579997","Stop":"132579997","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":182523,"rule_based_match":true,"evidence_text":"c.687delT","llm_judgment":"PRESENT","evidence":"c.687delT","abstract_start":515,"abstract_end":524}]}
{"pmid":"35290602","title":"A BRCA1 Splice Site Variant Responsible for Familial Ovarian Cancer in a Han-Chinese Family.","abstract":"OBJECTIVE: Ovarian cancer (OC) is one of the most common and most lethal gynecological malignancies. OC has an age-dependent incidence and occurs more commonly in females older than 50 years old. Most OC patients are diagnosed at an advanced stage and have a poor prognosis. Germline mutations in the BRCA1 DNA repair associated gene (BRCA1) and the BRCA2 DNA repair associated gene (BRCA2) account for 20%-25% of epithelial ovarian cancer (EOC). BRCA1 germline mutations are more common in Chinese EOC patients.\nMETHODS: This study reported a three-generation Han-Chinese family containing four EOC patients and a rectal adenocarcinoma patient. Whole-exome sequencing was performed on two EOC patients and an unaffected individual. Variant validation was also performed in all available members by Sanger sequencing.\nRESULTS: A heterozygous splice site variant, c.4358-2A>G in the BRCA1 gene, was identified. Bioinformatic analysis showed that the variant may change the splicing machinery.\nCONCLUSION: The BRCA1 splice site variant, c.4358-2A>G was identified as the likely genetic cause for EOC, and may also be associated with the increased risk of rectal adenocarcinoma in the family. The findings were beneficial for genetic counseling, helpful for cancer prevention in other family members, and may facilitate therapy decision-making in the future to reduce cancer lethality.","variants":[{"Name":"NM_007294.4(BRCA1):c.4358-2A>G","Chromosome":"17","Start":"43076616","Stop":"43076616","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":432900,"rule_based_match":true,"evidence_text":"c.4358-2A>G","llm_judgment":"PRESENT","evidence":"c.4358-2A>G","abstract_start":863,"abstract_end":874}]}
{"pmid":"29115605","title":"Genetic variations in Bestrophin‑1 and associated clinical findings in two Chinese patients with juvenile‑onset and adult‑onset best vitelliform macular dystrophy.","abstract":"Best vitelliform macular dystrophy (BVMD) is a hereditary retinal disease characterized by the bilateral accumulation of large egg yolk‑like lesions in the sub‑retinal and sub‑retinal pigment epithelium spaces. Macular degeneration in BVMD can begin in childhood or adulthood. The variation in the age of onset is not clearly understood. The present study characterized the clinical characteristics of two Chinese patients with either juvenile‑onset BVMD or adult‑onset BVMD and investigated the underlying genetic variations. A 16‑year‑old male (Patient 1) was diagnosed with juvenile‑onset BVMD and a 43‑year‑old female (Patient 2) was diagnosed with adult‑onset BVMD. Comprehensive ophthalmic examinations were performed, including best‑corrected visual acuity, intraocular pressure, slit‑lamp examination, fundus photography, optical coherence tomography, fundus fluorescein angiography imaging and Espion electrophysiology. Genomic DNA was extracted from peripheral blood leukocytes collected from these patients, their family members, and 200 unrelated subjects within in the same population. The 11 exons of the bestrophin‑1 (BEST1) gene were amplified by polymerase chain reaction and directly sequenced. Both patients presented lesions in the macular area. In Patient 1, a heterozygous mutation c.903T>G (p.D301E) in exon 8 of the BEST1 gene was identified. This mutation was not present in any of the unaffected family members or the normal controls. Polymorphism phenotyping and the sorting intolerant from tolerant algorithm predicted that the amino acid substitution D301E in bestrophin‑1 protein was damaging. In Patient 2, a single nucleotide polymorphism c.1608C>T (p.T536T) in exon 10 of the BEST1 gene was identified. These findings expand the spectrum of BEST1 genetic variation and will be valuable for genetic counseling and the development of therapeutic interventions for patients with BVMD.","variants":[{"Name":"NM_004183.4(BEST1):c.903T>G (p.Asp301Glu)","Chromosome":"11","Start":"61959533","Stop":"61959533","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":105662,"rule_based_match":true,"evidence_text":"c.903T>G (p.D301E)","llm_judgment":"PRESENT","evidence":"c.903T>G (p.D301E)","abstract_start":1304,"abstract_end":1322}]}
{"pmid":"29075935","title":"Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits.","abstract":"Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case. Both patients presented similarly in early childhood with global developmental delay, raised CSF lactate and abnormalities on cranial MRI. Sanger sequencing of familial samples confirmed the segregation of bi-allelic GFM2 variants with disease, while investigations into steady-state mitochondrial protein levels revealed respiratory chain subunit defects and loss of mtEFG2 protein in muscle. These data demonstrate the effects of defective mtEFG2 function, caused by previously unreported variants, confirming pathogenicity and expanding the clinical phenotypes associated with GFM2 variants.","variants":[{"Name":"NM_032380.5(GFM2):c.636del (p.Glu213fs)","Chromosome":"5","Start":"74746138","Stop":"74746138","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":434403,"rule_based_match":true,"evidence_text":"c.636delA, p.(Glu213Argfs*3)","llm_judgment":"PRESENT","evidence":"c.636delA, p.(Glu213Argfs*3)","abstract_start":395,"abstract_end":423},{"Name":"NM_032380.5(GFM2):c.275A>C (p.Tyr92Ser)","Chromosome":"5","Start":"74758878","Stop":"74758878","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":434404,"rule_based_match":true,"evidence_text":"c.275A>C, p.(Tyr92Ser)","llm_judgment":"PRESENT","evidence":"c.275A>C, p.(Tyr92Ser)","abstract_start":441,"abstract_end":463},{"Name":"NM_032380.5(GFM2):c.569G>A (p.Arg190Gln)","Chromosome":"5","Start":"74747731","Stop":"74747731","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":211189,"rule_based_match":true,"evidence_text":"c.569G>A, p.(Arg190Gln)","llm_judgment":"PRESENT","evidence":"c.569G>A, p.(Arg190Gln)","abstract_start":370,"abstract_end":393}]}
{"pmid":"23588064","title":"Molecular analysis of the dystrophin gene in 407 Chinese patients with Duchenne/Becker muscular dystrophy by the combination of multiplex ligation-dependent probe amplification and Sanger sequencing.","abstract":"BACKGROUND: Progressive muscular dystrophy is a leading neuromuscular disorder without any effective treatments and a common genetic cause of mortality among teenagers. A challenge exists in the screening of subtle mutations in 79 exons and little is known about the genotype-phenotype correlation.\nMETHODS: Here we adopted multiplex ligation-dependent probe amplification and Sanger sequencing to detect the dystrophin gene in 407 patients and 76 mothers.\nRESULTS: Sixty-three percent (257/407) of the patients harbored a deletion or duplication mutation, with a de novo mutation frequency of 39.5% in 76 affected patients, and approximately 43.7% of the deletions occurred from exon 45 to 52. To those patients suspected with single exon deletion, combined with Sanger sequencing, five subtle mutations were identified: c.8608C>T, c.2302C>T, c.7148dupT, c.10855C>T and c.2071-2093del AGGGAACAGATCCTGGTAAAGCA; the last three mutations were novel. Furthermore, after genotype-phenotype analysis, the severity of DMD/BMD was associated with the frame shift mutation but not with the deletion, the duplication or the number of deleted exons.\nCONCLUSION: The majority of patients have a deletion/duplication mutation in the dystrophin gene, with a hot deletion mutation region from exon 45 to 52. Combined with Sanger sequencing, multiplex ligation-dependent probe amplification is capable of detecting part of subtle mutations.","variants":[{"Name":"NM_004006.3(DMD):c.10855C>T (p.Gln3619Ter)","Chromosome":"X","Start":"31146357","Stop":"31146357","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1464503,"rule_based_match":true,"evidence_text":"c.10855C>T","llm_judgment":"PRESENT","evidence":"c.10855C>T","abstract_start":856,"abstract_end":866},{"Name":"NM_004006.3(DMD):c.8608C>T (p.Arg2870Ter)","Chromosome":"X","Start":"31479043","Stop":"31479043","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":100710,"rule_based_match":true,"evidence_text":"c.8608C>T","llm_judgment":"PRESENT","evidence":"c.8608C>T","abstract_start":822,"abstract_end":831}]}
{"pmid":"25666907","title":"Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: scapuloperoneal and respiratory weakness with dilated cardiomyopathy.","abstract":"Myosin storage myopathy (MSM) is a protein aggregate myopathy caused by the accumulation of myosin in muscle fibres and results from MYH7 mutation. Although MYH7 mutation is also an established cause of variable cardiomyopathy with or without skeletal myopathy, cardiomyopathy with MSM is a rare combination. Here, we update the clinical findings in the two brothers that we previously reported as having recessively inherited MSM characterized by scapuloperoneal distribution of weakness and typical hyaline-like bodies in type 1 muscle fibres. One of the patients, weak from childhood but not severely symptomatic until 28 years of age, had an unusual combination of MSM, severe dilated cardiomyopathy, and respiratory impairment at the age of 44 years. We identified homozygous missense mutation c.5458C>T (p.R1820W) in exon 37 in these patients as the second recessive MYH7 mutation reported to date.","variants":[{"Name":"NM_000257.4(MYH7):c.5458C>T (p.Arg1820Trp)","Chromosome":"14","Start":"23415096","Stop":"23415096","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":179477,"rule_based_match":true,"evidence_text":"c.5458C>T (p.R1820W)","llm_judgment":"PRESENT","evidence":"c.5458C>T (p.R1820W)","abstract_start":799,"abstract_end":819}]}
{"pmid":"25953249","title":"A case report and literature review of Fanconi Anemia (FA) diagnosed by genetic testing.","abstract":"Fanconi anemia (FA) is a genetically heterogeneous rare autosomal recessive disorder characterized by congenital malformations, hematological problems and predisposition to malignancies. The genes that have been found to be mutated in FA patients are called FANC. To date 16 distinct FANC genes have been reported. Among these, mutations in FANCA are the most frequent among FA patients worldwide which account for 60- 65%. In this study, a nine years old male child was brought to our hospital one year ago for opinion and advice. He was the third child born to consanguineous parents. The mutation analyses were performed for proband, parents, elder sibling and the relatives [maternal aunt and maternal aunt's son (cousin)]. Molecular genetic testing [targeted next-generation sequencing (MiSeq, Illumina method)] was performed by mutation analysis in 15 genes involved. Entire coding exons and their flanking regions of the genes were analysed. Sanger sequencing [(ABI 3730 analyzer by Applied Biosystems)] was performed using primers specific for 43 coding exons of the FANCA gene. A novel splice site mutation, c.3066 + 1G > T, (IVS31 + 1G > T), homozygote was detected by sequencing in the patient. The above sequence variant was identified in heterozygous state in his parents. Further, the above sequence variant was not identified in other family members (elder sibling, maternal aunt and cousin). It is concluded that genetic study should be done if possible in all the cases of suspected FA, including siblings, parents and close blood relatives. It will help us to plan appropriate treatment and also to select suitable donor for hematopoietic stem cell transplantation and to plan for genetic counseling. In addition to the case report, the main focus of this manuscript was to review literature on role of FANCA gene in FA since large number of FANCA mutations and polymorphisms have been identified.","variants":[{"Name":"NM_000135.4(FANCA):c.3066+1G>T","Chromosome":"16","Start":"89752137","Stop":"89752137","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":166180,"rule_based_match":true,"evidence_text":"c.3066+1G>T","llm_judgment":"PRESENT","evidence":"c.3066 + 1G > T","abstract_start":1117,"abstract_end":1132}]}
{"pmid":"32572202","title":"Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features.","abstract":"Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2A cause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2A variants (NG_053084.1, NM_032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750_753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386_1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM_032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM_032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2A deficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.","variants":[{"Name":"NM_032793.5(MFSD2A):c.1386_1435del (p.Gln462fs)","Chromosome":"1","Start":"39968600","Stop":"39968649","ReferenceAlleleVCF":"GCAGCCGGAACGTGTCAAGTTTACACTGAACATGCTCGTGACCATGGCTCC","AlternateAlleleVCF":"G","allel_id":1692970,"rule_based_match":true,"evidence_text":"c.1386_1435del; p.(Gln462HisfsTer17)","llm_judgment":"PRESENT","evidence":"c.1386_1435del; p.(Gln462HisfsTer17)","abstract_start":1215,"abstract_end":1251},{"Name":"NM_032793.5(MFSD2A):c.750_753del (p.Cys251fs)","Chromosome":"1","Start":"39966633","Stop":"39966636","ReferenceAlleleVCF":"TTGTC","AlternateAlleleVCF":"T","allel_id":1692971,"rule_based_match":true,"evidence_text":"c.750_753del; p.(Cys251SerfsTer3)","llm_judgment":"PRESENT","evidence":"c.750_753del; p.(Cys251SerfsTer3)","abstract_start":1155,"abstract_end":1188},{"Name":"NM_032793.5(MFSD2A):c.556+1G>A","Chromosome":"1","Start":"39965550","Stop":"39965550","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1692972,"rule_based_match":true,"evidence_text":"c.556+1G>A","llm_judgment":"PRESENT","evidence":"c.556+1G>A","abstract_start":1118,"abstract_end":1128}]}
{"pmid":"33190975","title":"Novel de novo mutation substantiates ATP6V0C as a gene causing epilepsy with intellectual disability.","abstract":"BACKGROUND: In approximately half of patients with epilepsy and intellectual disability (ID), the cause is unidentified and could be a mutation in a new disease gene.\nPATIENT DESCRIPTION: To determine the discovery of disease-causing mutation in a female patient with epilepsy and ID, we performed trio whole-exome sequencing, reverse transcription polymerase chain reaction (RT-PCR) followed by Sanger sequencing.\nRESULTS: Trio whole-exome sequencing was performed and revealed a novel de novo heterozygous stop-loss c.467A > T (p.*156Leuext*35) mutation in the ATP6V0C gene. Using RNA from leukocytes, RT-PCR followed by Sanger sequencing showed the existence of the mutant RNA, and real-time PCR demonstrated that the patient's ATP6V0C RNA level was approximately half of that in her parents, suggesting haploinsufficiency as a pathomechanism.\nCONCLUSION: These findings, along with previous reports of individuals with similar phenotypes and variants in the same gene, substantiate ATP6V0C as a gene causing epilepsy with ID.","variants":[{"Name":"NM_001694.4(ATP6V0C):c.467A>T (p.Ter156Leu)","Chromosome":"16","Start":"2519744","Stop":"2519744","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":805143,"rule_based_match":true,"evidence_text":"c.467A>T (p.*156Leuext*35)","llm_judgment":"PRESENT","evidence":"c.467A > T (p.*156Leuext*35)","abstract_start":518,"abstract_end":546}]}
{"pmid":"23099197","title":"Identification of a novel mutation in UDP-glucuronosyltransferase (UGT1A1) gene in a child with neonatal unconjugated hyperbilirubinemia.","abstract":"Genetic alterations of the UGT1A1 gene result in Crigler-Najjar (CNS) and Gilbert's (GS)-Syndromes, two autosomal recessive conditions characterized by non-hemolytic unconjugated hyperbilirubinemia. While GS is characterized by mild hyperbilirubinemia, CNS is classified as follows: type I (CNS-I), often associated with irreversible neurological damage due to total deficiency of the UGT1A1 enzyme activity, and type II (CNS-II) where a minimal level of UGT1A1 enzyme activity is maintained. In this context, differential diagnosis of CNS forms needs to be supported by clinical molecular laboratory, in order to correlate biochemical findings to specific genetic mutations. Our paper describes in detail the peculiar clinical feature found in a child with severe neonatal unconjugated hyperbilirubinemia, where DNA analysis showed a new compound heterozygosis determined by two mutations, a known (c.508_510delTTC) and a novel mutation (c.1099C>T) giving a genotype compatible with clinical picture of CNS-II. This novel genotype extends the spectrum of known UGT1A1 mutations, which, in our opinion, could be higher than that currently reported in the literature. Finally, genetic analysis may also be helpful for patients' management.","variants":[{"Name":"NM_000463.3(UGT1A1):c.1099C>T (p.Arg367Cys)","Chromosome":"2","Start":"233768234","Stop":"233768234","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":272335,"rule_based_match":true,"evidence_text":"c.1099C>T","llm_judgment":"PRESENT","evidence":"c.1099C>T","abstract_start":939,"abstract_end":948}]}
{"pmid":"26059211","title":"Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects.","abstract":"Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare, X-linked syndrome classically characterized by distal limb anomalies, pigmented skin defects of the face, and recurrent digital fibromas. X-inactivation plays a major role in determining the range of phenotypic expression. Thus, patients can demonstrate a wide spectrum of disease severity, making accurate diagnosis more challenging. Recent studies have identified a FLNA c.5217G>A mutation as the cause of TODPD, allowing for diagnostic genetic testing. We present a case of molecularly confirmed TODPD in a girl with the 47,XXX chromosomal complement and deformities of the hands and feet, craniofacial abnormalities, and discolored, linear facial lesions. Skin biopsy of the patient's facial lesion revealed absent papillary dermal elastic fibers, consistent with anetoderma, which contrasts with the dermal hypoplasia described in the only other such facial biopsy reported in the literature. The finding of absent elastic fibers in the skin lesions suggests that mutated filamin A, in part, exerts its effects through dysregulated elastin biology, which may explain the nature of many connective tissue pleotropic effects in FLNA-related disorders.","variants":[{"Name":"NM_001110556.2(FLNA):c.5217G>A (p.Thr1739=)","Chromosome":"X","Start":"154354825","Stop":"154354825","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26814,"rule_based_match":true,"evidence_text":"FLNA c.5217G>A","llm_judgment":"PRESENT","evidence":"FLNA c.5217G>A","abstract_start":438,"abstract_end":452}]}
{"pmid":"21750962","title":"Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility.","abstract":"RAD51C, a RAD51 paralogue involved in homologous recombination, is a recently established Fanconi anemia and breast cancer predisposing factor. In the initial report, RAD51C mutations were shown to confer a high risk for both breast and ovarian tumors, but most of the replication studies published so far have failed to identify any additional susceptibility alleles. Here, we report a full mutation screening of the RAD51C gene in 147 Finnish familial breast cancer cases and in 232 unselected ovarian cancer cases originating from Finland and Sweden. In addition, in order to resolve whether common RAD51C SNPs are risk factors for breast cancer, we genotyped five tagging single nucleotide polymorphisms, rs12946522, rs304270, rs304283, rs17222691, and rs28363312, all located within the gene, from 993 Finnish breast cancer cases and 871 controls for cancer associated variants. Whereas, none of the studied common SNPs associated with breast cancer susceptibility, mutation analysis revealed two clearly pathogenic alterations. RAD51C c.-13_14del27 was observed in one familial breast cancer case and c.774delT in one unselected ovarian cancer case, thus confirming that RAD51C mutations are implicated in breast and ovarian cancer predisposition, although their overall frequency seems to be low. Independent identification of the very recently reported RAD51C c.774delT mutation in yet another patient originating from Sweden suggests that it might be a recurrent mutation in that population and should be studied further. The reliable estimation of the clinical implications of carrying a defective RAD51C allele still requires the identification of additional mutation positive families.","variants":[{"Name":"NM_058216.3(RAD51C):c.774del (p.Thr259fs)","Chromosome":"17","Start":"58709927","Stop":"58709927","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":410106,"rule_based_match":true,"evidence_text":"RAD51C c.774delT","llm_judgment":"PRESENT","evidence":"RAD51C c.774delT","abstract_start":1361,"abstract_end":1377}]}
{"pmid":"25893793","title":"Skeletal dysplasia in a consanguineous clan from the island of Nias/Indonesia is caused by a novel mutation in B3GAT3.","abstract":"We describe a large family with disproportionate short stature and bone dysplasia from Nias in which we observed differences in severity when comparing the phenotypes of affected individuals from two remote branches. We conducted a linkage scan in the more severely affected family branch and determined a critical interval of 4.7 cM on chromosome 11. Sequencing of the primary candidate gene TBX10 did not reveal a disease-causing variant. When performing whole exome sequencing we noticed a homozygous missense variant in B3GAT3, c.419C>T [p.(Pro140Leu)]. B3GAT3 encodes β-1,3-glucuronyltransferase-I (GlcAT-I). GlcAT-I catalyzes an initial step of proteoglycan synthesis and the mutation p. (Pro140Leu) lies within the donor substrate-binding subdomain of the catalytic domain. In contrast to the previously published mutation in B3GAT3, c.830G>A [p.(Arg277Gln)], no heart phenotype could be detected in our family. Functional studies revealed a markedly reduced GlcAT-I activity in lymphoblastoid cells from patients when compared to matched controls. Moreover, relative numbers of glycosaminoglycan (GAG) side chains were decreased in patient cells. We found that Pro140Leu-mutant GlcAT-I cannot efficiently transfer GlcA to the linker region trisaccharide. This failure results in a partial deficiency of both chondroitin sulfate and heparan sulfate chains. Since the phenotype of the Nias patients differs from the Larsen-like syndrome described for patients with mutation p.(Arg277Gln), we suggest mutation B3GAT3:p.(Pro140Leu) to cause a different type of GAG linkeropathy showing no involvement of the heart.","variants":[{"Name":"NM_012200.4(B3GAT3):c.419C>T (p.Pro140Leu)","Chromosome":"11","Start":"62617186","Stop":"62617186","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227579,"rule_based_match":true,"evidence_text":"c.419C>T [p.(Pro140Leu)]","llm_judgment":"PRESENT","evidence":"c.419C>T [p.(Pro140Leu)]","abstract_start":532,"abstract_end":556}]}
{"pmid":"15769978","title":"A new case of congenital goiter with hypothyroidism caused by a homozygous p.R277X mutation in the exon 7 of the thyroglobulin gene: a mutational hot spot could explain the recurrence of this mutation.","abstract":"Identification of thyroglobulin (TG) gene mutations may provide insight into the structure-function relationship. In this study, we have performed molecular studies in a patient with congenital goiter, hypothyroidism, and impairment of TG synthesis. Genomic DNA sequencing revealed a homozygous c.886C-->T mutation in exon 7, resulting in a premature stop codon at amino acid 277 (p.R277X). The same nonsense mutation had been reported previously in two Brazilian families with multiple occurrence of congenital hypothyroidism with goiter. We compared the insertion/deletion polymorphism in intron 18, microsatellites (Tgm1, Tgm2, TGrI29, and TGrI30), and exonic single-nucleotide polymorphism haplotypes identified in the patient with a member of the previously reported family, who also carry the mutation as a compound heterozygous mutation. The single-nucleotide polymorphism and microsatellite analysis revealed that the two affected individuals do not share a common TG allele. This suggests that the p.R277X mutation is a mutational hot spot. No difference in either splicing or abundance of the amplified product was detected by RT-PCR, excluding that an alternative splicing mechanism, by skipping of exon 7, would restore the normal reading frame. In conclusion, we report a new case of congenital goiter and hypothyroidism caused by a p.R277X mutation in the TG gene. Moreover, we show that nucleotide 886 is a mutational hot spot that explains the recurrence of this mutation.","variants":[{"Name":"NM_003235.5(TG):c.886C>T (p.Arg296Ter)","Chromosome":"8","Start":"132882609","Stop":"132882609","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27734,"rule_based_match":false,"evidence_text":"c.886C-->T","llm_judgment":"PRESENT","evidence":"c.886C-->T","abstract_start":295,"abstract_end":305}]}
{"pmid":"34449519","title":"Early Diagnosis of Classic Homocystinuria in Kuwait through Newborn Screening: A 6-Year Experience.","abstract":"Kuwait is a small Arabian Gulf country with a high rate of consanguinity and where a national newborn screening program was expanded in October 2014 to include a wide range of endocrine and metabolic disorders. A retrospective study conducted between January 2015 and December 2020 revealed a total of 304,086 newborns have been screened in Kuwait. Six newborns were diagnosed with classic homocystinuria with an incidence of 1:50,000, which is not as high as in Qatar but higher than the global incidence. Molecular testing for five of them has revealed three previously reported pathogenic variants in the <i>CBS</i> gene, c.969G>A, p.(Trp323Ter); c.982G>A, p.(Asp328Asn); and the Qatari founder variant c.1006C>T, p.(Arg336Cys). This is the first study to review the screening of newborns in Kuwait for classic homocystinuria, starting with the detection of elevated blood methionine and providing a follow-up strategy for positive results, including plasma total homocysteine and amino acid analyses. Further, we have demonstrated an increase in the specificity of the current newborn screening test for classic homocystinuria by including the methionine to phenylalanine ratio along with the elevated methionine blood levels in first-tier testing. Here, we provide evidence that the newborn screening in Kuwait has led to the early detection of classic homocystinuria cases and enabled the affected individuals to lead active and productive lives.","variants":[{"Name":"NM_000071.3(CBS):c.982G>A (p.Asp328Asn)","Chromosome":"21","Start":"43062368","Stop":"43062368","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":549051,"rule_based_match":true,"evidence_text":"c.982G>A, p.(Asp328Asn)","llm_judgment":"PRESENT","evidence":"c.982G>A, p.(Asp328Asn)","abstract_start":650,"abstract_end":673}]}
{"pmid":"27116386","title":"A Novel Homozygous SLC2A9 Mutation Associated with Renal-Induced Hypouricemia.","abstract":"BACKGROUND: Hereditary renal hypouricemia (RHUC) is a genetically heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA; acute kidney injury (AKI) and nephrolithiasis are recognized complications. Type 1 (RHUC1) is caused by mutations in the SLC22A12 gene, whereas RHUC2 is caused by mutations in the SLC2A9 gene. Patient ethnicity is diverse but only few Caucasian families with an SLC2A9 mutation have been reported.\nMETHODS: The current report describes the clinical history, biochemical and molecular genetics findings of a native Austrian family with RHUC2. The propositus presented with 2 episodes of exercise-induced AKI and exhibited profound hypouricemia. Mutational screening of the SLC22A12 and SLC2A9 genes was performed.\nRESULTS: The molecular analyses revealed the homozygous c.512G>A transition that leads to the p.Arg171His missense substitution in SLC2A9, confirming the diagnosis of RHUC2. Segregation study of the causal mutation revealed that the mother and elder sister were heterozygous carriers, whereas the younger sister was found to be homozygous.\nCONCLUSION: We report the identification of a novel mutation in SLC2A9 as the cause of RHUC2 in a native Austrian family. We show that glucose transporter 9 mutations cause severe hypouricemia in homozygous individuals and confirm the high risk of AKI in male individuals harbouring these mutations. In our literature review, we provide an overview of the putative underlying pathophysiology, potential renal complications, findings on kidney biopsy as well as potential long-time renal sequelae.","variants":[{"Name":"NM_020041.3(SLC2A9):c.512G>A (p.Arg171His)","Chromosome":"4","Start":"9985692","Stop":"9985692","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":620177,"rule_based_match":true,"evidence_text":"c.512G>A","llm_judgment":"PRESENT","evidence":"c.512G>A","abstract_start":880,"abstract_end":888}]}
{"pmid":"29316097","title":"Splicing analysis of rare/novel synonymous or intronic variants identified in ABCB11 heterozygotes presenting as progressive intrahepatic cholestasis with low γ-glutamyltransferase.","abstract":"AIM: The aim of this study was to analyze the pathogenicity of rare/novel synonymous or intronic variants identified in ABCB11 heterozygotes presenting as progressive intrahepatic cholestasis with low γ-glutamyltransferase.\nMETHODS: The enrolled variants were identified in ABCB11 between October 2009 and June 2016. The effects on pre-RNA splicing were analyzed by in silico tools and minigene splicing assay.\nRESULTS: There were three intronic (c.908 + 5G > A, c.2815-8A > G, and c.612-15_-6del10bp) and two synonymous (c.1809G > A, p.K603 K and c.2418C > T, p.G806G) variants with unknown significance identified in ABCB11 of five ABCB11 heterozygotes. Parental studies were carried out for four patients, and revealed that the variants with unknown significance were compound heterozygous with other pathogenic variants. The five variants with unknown significance had minor allele frequency <0.1% or were absent from controls, and had positive prediction results by in silico tools. The effects on pre-RNA splicing were further confirmed by minigene splicing assay. c.908 + 5A caused abnormal splicing in at least 78.5 ± 3.8% of products using a cryptic splice site (ss) 22 nucleotides (nt) upstream of the wild-type (WT) 5'ss. Seven nucleotides of intron 22 upstream of the WT 3'ss was retained for all products from c.2815-8G. c.612-15_-6del caused exon 8 skipping in 24.8 ± 7.7% of products, and 55 nt of exon 8 downstream of the WT 3'ss removal in remaining products. c.1809A led to exon 15 skipping. c.2418 T removed exon 20 and 62 nt of exon 21 downstream of the WT 3'ss by using a cryptic ss.\nCONCLUSIONS: We successfully identified five pathogenic synonymous or intronic variants with some common features. These features might help to choose the right variant for further functional assay.","variants":[{"Name":"NM_003742.4(ABCB11):c.2418C>T (p.Gly806=)","Chromosome":"2","Start":"168944887","Stop":"168944887","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2838688,"rule_based_match":true,"evidence_text":"c.2418C>T (p.G806G)","llm_judgment":"PRESENT","evidence":"c.2418C > T","abstract_start":548,"abstract_end":559}]}
{"pmid":"24387994","title":"Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86.","abstract":"Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.","variants":[{"Name":"NM_001199107.2(TBC1D24):c.208G>T (p.Asp70Tyr)","Chromosome":"16","Start":"2496356","Stop":"2496356","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":106549,"rule_based_match":true,"evidence_text":"c.208G>T (p.Asp70Tyr)","llm_judgment":"PRESENT","evidence":"c.208G>T (p.Asp70Tyr)","abstract_start":413,"abstract_end":434},{"Name":"NM_001199107.2(TBC1D24):c.878G>C (p.Arg293Pro)","Chromosome":"16","Start":"2497026","Stop":"2497026","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":106550,"rule_based_match":true,"evidence_text":"c.878G>C (p.Arg293Pro)","llm_judgment":"PRESENT","evidence":"c.878G>C (p.Arg293Pro)","abstract_start":438,"abstract_end":460}]}
{"pmid":"29764441","title":"Case Report: Identification of an HNF1B p.Arg527Gln mutation in a Maltese patient with atypical early onset diabetes and diabetic nephropathy.","abstract":"BACKGROUND: The diagnosis of atypical non-autoimmune forms of diabetes mellitus, such as maturity onset diabetes of the young (MODY) presents several challenges, in view of the extensive clinical and genetic heterogeneity of the disease. In this report we describe a case of atypical non autoimmune diabetes associated with a damaging HNF1β mutation. This is distinguished by a number of uncharacteristic clinical features, including early-onset obesity, the absence of renal cysts and diabetic nephropathy. HNF1β-MODY (MODY5) is an uncommon form of monogenic diabetes that is often complicated by a wide array of congenital morphological anomalies of the urinary tract, including renal cysts. This report expands on the clinical phenotypes that have been described in the context of HNF1β mutations, and is relevant as only isolated cases of diabetic nephropathy in the setting of MODY5 have been reported.\nCASE PRESENTATION: An obese Maltese female with non-autoimmune diabetes, microalbuminuria, glomerular hyperfiltration, fatty liver and no renal cysts was studied by whole exome sequencing to investigate potential genes responsible for the proband's phenotype. A rare missense mutation at a highly conserved site in exon 8 of HNF1β was identified (c.1580G > A, NM_000458.3, p.Arg527Gln), with multiple in-silico predictions consistent with pathogenicity. This mutation has not been previously characterised. Additionally, several common susceptibility variants associated with early-onset obesity, polygenic type 2 diabetes and nephropathy were identified in the proband that could impose additional effects on the phenotype, its severity or its clinical course.\nCONCLUSION: This report highlights several atypical features in a proband with atypical diabetes associated with an HNF1β missense mutation. It also reinforces the concept that monogenic causes of diabetes could be significant contributors to disease burden in obese individuals with atypical diabetes.","variants":[{"Name":"NM_000458.4(HNF1B):c.1580G>A (p.Arg527Gln)","Chromosome":"17","Start":"37699149","Stop":"37699149","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":586328,"rule_based_match":true,"evidence_text":"c.1580G > A, NM_000458.3, p.Arg527Gln","llm_judgment":"PRESENT","evidence":"c.1580G > A, NM_000458.3, p.Arg527Gln","abstract_start":1255,"abstract_end":1292}]}
{"pmid":"34954454","title":"Generation of three iPSC lines from dilated cardiomyopathy patients carrying a pathogenic LMNA variant.","abstract":"LMNA-related dilated cardiomyopathy (DCM) is caused by pathogenic variants in LMNA and is characterized by left ventricular enlargement, reduced systolic function, and arrhythmia. Here, we generated three human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of three DCM patients carrying the same single heterozygous mutation, c.1129C > T, in LMNA. All lines expressed normal iPSC morphology, high levels of pluripotent markers, normal karyotypes, and could differentiate into the three germ layers. These iPSC lines can serve as invaluable tools to model pathological mechanisms of DCM in vitro caused by LMNA mutations.","variants":[{"Name":"NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys)","Chromosome":"1","Start":"156136093","Stop":"156136093","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":57195,"rule_based_match":true,"evidence_text":"c.1129C > T","llm_judgment":"PRESENT","evidence":"c.1129C > T","abstract_start":372,"abstract_end":383}]}
{"pmid":"34722561","title":"Broadening the Mutation Spectrum in","abstract":"<b>Purpose:</b> To broaden the mutation and phenotype spectrum of the <i>GJA8</i> and <i>CHMP4B</i> genes and to reveal genotype-phenotype correlations in a cohort of Chinese patients with congenital cataracts (CCs). <b>Methods:</b> Six Chinese Han families with CCs inherited in an autosomal dominant (AD) pattern were recruited for this study. All patients underwent full ocular examinations. Genomic DNA was extracted from the leukocytes of peripheral blood collected from all available patients and their unaffected family members. Whole-exome sequencing (WES) was performed on all probands and at least one of their parents. Candidate variants were further confirmed by Sanger sequencing. Bioinformatic analysis with several computational predictive programs was performed to assess the impacts of the candidate variants on the structure and function of the proteins. <b>Results:</b> Four heterozygous candidate variants in three different genes (<i>CRYBB2, GJA8</i>, and <i>CHMP4B</i>) were identified in affected individuals from the six families, including two novel missense variants (<i>GJA8</i>: c.64G > C/p. G22R, and <i>CHMP4B</i>: c.587C > G/p. S196C), one missense mutation (<i>CRYBB2</i>: c.562C > T/p. R188C), and one small deletion (<i>GJA8</i>: c.426_440delGCTGGAGGGGACCCT/p.143_147delLEGTL). The three missense mutations were predicted as deleterious in all four computational prediction programs. In the homologous model, the <i>GJA8</i>: p.143_147delLEGTL mutation showed a sequence deletion of five amino acids at the cytoplasmic loop of the Cx50 protein, close to the third transmembrane domain. Patients carrying mutations in the same gene showed similar cataract phenotypes at a young age, including total cataracts, Y-sutural with fetal nuclear cataracts, and subcapsular cataracts. <b>Conclusion:</b> This study further expands the mutation spectrum and genotype-phenotype correlation of <i>CRYBB2, GJA8</i>, and <i>CHMP4B</i> underlying CCs. This study sheds light on the importance of comparing congenital cataract phenotypes in patients at the same age stage. It offers clues for the pathogenesis of CCs and allows for an early prenatal diagnosis for families carrying these genetic variants.","variants":[{"Name":"NM_005267.5(GJA8):c.64G>C (p.Gly22Arg)","Chromosome":"1","Start":"147908019","Stop":"147908019","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3412497,"rule_based_match":true,"evidence_text":"c.64G > C/p. G22R","llm_judgment":"PRESENT","evidence":"c.64G > C/p. G22R","abstract_start":1107,"abstract_end":1124}]}
{"pmid":"16965330","title":"Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence.","abstract":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal-recessive autoimmune disease caused by autoimmune regulator gene mutations. The aim of this study was to examine the mutation profile of Polish APECED patients, determine the carrier rate of the most frequent mutation(s) and estimate disease prevalence. While studying 14 unrelated patients, we identified three novel mutations (c.1A>T, affecting the start codon; [IVS1 + 1G>C; IVS1 + 5delG], a complex mutation affecting splice site; c. 908G>C, p.R303P, a missense mutation in plant homeodomain (PHD) and three previously reported mutations (c.769C>T, p.R257X; c.967_979del13bp, C322fsX372; c.931delT, p.C311fsX376). Eleven patients had mutations on both chromosomes, whereas in three patients only a single alteration with proven or likely pathogenic effect was detected. The most frequent was the p.R257X mutation (71% of chromosomes); its carriage rate was assessed in the background population. Analysis of 2008 samples showed eight heterozygotes, indicating the frequency of 0.40% (1:250) and the disease prevalence - 1:129,000 (95% confidence interval: 1:555,000 to 1:30,000). Comparison with an epidemiological estimate (1:619,000, derived for women) suggested that in Poland, APECED is underdiagnosed. Among the patients, no genotype/phenotype correlations were found, but we noted that women had earlier onset of hypoparathyroidism (p < 0.02) and were younger at diagnosis (p < 0.05) than men.","variants":[{"Name":"NM_000383.4(AIRE):c.769C>T (p.Arg257Ter)","Chromosome":"21","Start":"44289773","Stop":"44289773","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18346,"rule_based_match":true,"evidence_text":"c.769C>T, p.R257X","llm_judgment":"PRESENT","evidence":"c.769C>T, p.R257X","abstract_start":631,"abstract_end":648},{"Name":"NM_000383.4(AIRE):c.967_979del (p.Leu323fs)","Chromosome":"21","Start":"44291180","Stop":"44291192","ReferenceAlleleVCF":"TGCCTGTCCCCTCC","AlternateAlleleVCF":"T","allel_id":18348,"rule_based_match":true,"evidence_text":"c.967_979del13bp","llm_judgment":"PRESENT","evidence":"c.967_979del13bp","abstract_start":650,"abstract_end":666},{"Name":"NM_000383.4(AIRE):c.1A>T (p.Met1Leu)","Chromosome":"21","Start":"44286007","Stop":"44286007","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":18353,"rule_based_match":true,"evidence_text":"c.1A>T","llm_judgment":"PRESENT","evidence":"c.1A>T","abstract_start":417,"abstract_end":423}]}
{"pmid":"14757438","title":"Expression and functional characterization of mutated glucocerebrosidase alleles causing Gaucher disease in Spanish patients.","abstract":"BACKGROUND: Gaucher disease (GD) is a heterogeneous disease characterized by an impaired activity of the lysosomal glucocerebrosidase. This heterogeneity is attributed in part to the existence of a large number of mutations in the corresponding gene.\nSUBJECTS AND METHODS: To establish genotype-phenotype relationships, we analyzed the residual enzyme activities of six naturally occurring mutations found in Spanish population in the glucocerebrosidase gene [c.160G > A (V15M), c.485T>C (M123T), c.914C>T (P266L), c.1124T>C (L336P), c.1207A>C (S364R) and c.1510-1512delTCT (S465del)]. The mutated genes were subcloned into the mammalian expression vector pCR 3.1 and expressed by transient transfection in COS cells. The enzymatic activity of the expressed protein were measured and compared with the wild-type human glucocerebrosidase cDNA. Also, two previously alleles, c.1226A>G (N370S) and c.1448T>C (L444P), were used for comparative purposes.\nRESULTS: The residual activity of the expressed proteins using the synthetic substrate (4-methylumbelliferyl-beta-D-glucopyranoside, 4MU-Glu) ranged from 5.5% (for the 3-bp deletion) to 42.7% (for S364R mutation) of the activity of the wild-type enzyme.\nCONCLUSION: The present analyses may help to better understand the molecular basis and the pathogenesis of Gaucher disease. However, results of expression of mutated enzymes are necessary but not sufficient to explain the ultimate clinical outcome of Gaucher disease.","variants":[{"Name":"NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)","Chromosome":"1","Start":"155235843","Stop":"155235843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":19329,"rule_based_match":true,"evidence_text":"c.1226A>G (N370S)","llm_judgment":"PRESENT","evidence":"c.1226A>G (N370S)","abstract_start":873,"abstract_end":890},{"Name":"NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)","Chromosome":"1","Start":"155235252","Stop":"155235252","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19327,"rule_based_match":true,"evidence_text":"c.1448T>C (L444P)","llm_judgment":"PRESENT","evidence":"c.1448T>C (L444P)","abstract_start":895,"abstract_end":912}]}
{"pmid":"34689181","title":"Genotypic spectrum and phenotype correlations of EYS-associated disease in a Chinese cohort.","abstract":"BACKGROUND: To date, certain efforts have been made to investigate the clinical and genetic characteristics of patients with EYS mutations. However, data for Chinese patients are limited.\nOBJECTIVES: To perform a detailed phenotyping and genetic characterization of 55 Chinese patients with EYS-RD, and to identify risk factors for these clinical data.\nMETHODS: A total of 55 patients with EYS-RD were recruited. Best-corrected visual acuity (BCVA), patient age, age at symptom onset, disease duration, and genetic information were collected.\nRESULTS: Thirty-six novel variants, three hot mutations of EYS (30.3%, c.6416G>A, c.6557G>A, c.7492G>C) and one hot region (49.06%, Laminin G domains) were identified. In all, 36.84% of the mutations occurred at base G site, and majority of mutations (56.56%) were missense. Late-truncating mutations are significantly more prevalent (41.30%). The mean age of onset was 15.65 ± 14.67 years old; it had no significant correlation with genotype. The average BCVA was 0.73 ± 0.93 LogMAR, and 61.8% of eyes had a BCVA better than 0.52 logMAR. BCVA was positively correlated with disease duration time. The mean MD was 23.18 ± 7.34 dB, MD showed a significant correlation with genotype and age. Cataract was present in 56.45% of patients, and 42.59% of patients showed an absence of pigmentation in the retina. Cataract and hyperpigmentation both showed a significant correlation with age.\nCONCLUSIONS: EYS-RD is associated with a moderate phenotype with onset around adolescence, but great variability. Our study largely enhances the current knowledge of phenotypic and genotypic characteristics of EYS-RD, which could pave the way for better management of these patients.","variants":[{"Name":"NM_001142800.2(EYS):c.7492G>C (p.Ala2498Pro)","Chromosome":"6","Start":"63789144","Stop":"63789144","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":954810,"rule_based_match":true,"evidence_text":"c.7492G>C","llm_judgment":"PRESENT","evidence":"c.7492G>C","abstract_start":636,"abstract_end":645}]}
{"pmid":"33134517","title":"Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by","abstract":"OBJECTIVE: To expand the clinical phenotype of <i>POLR3A</i> mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.\nMETHODS: We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [<sup>1</sup>H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.\nRESULTS: The patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in <i>POLR3A</i>, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant.\nCONCLUSIONS: Mutations in the <i>POLR3A</i> gene cause <i>POLR3A</i>-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of <i>POLR3A</i>-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.","variants":[{"Name":"NM_007055.4(POLR3A):c.1771-6C>G","Chromosome":"10","Start":"78009681","Stop":"78009681","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":964843,"rule_based_match":true,"evidence_text":"c.1771-6C>G","llm_judgment":"PRESENT","evidence":"c.1771-6C>G","abstract_start":799,"abstract_end":810}]}
{"pmid":"38173341","title":"A Mosaic Variant in CTNNB1/β-catenin as a Novel Cause for Osteopathia Striata With Cranial Sclerosis.","abstract":"CONTEXT: Osteopathia striata with cranial sclerosis (OSCS) is a rare bone disorder with X-linked dominant inheritance, characterized by a generalized hyperostosis in the skull and long bones and typical metaphyseal striations in the long bones. So far, loss-of-function variants in AMER1 (also known as WTX or FAM123B), encoding the APC membrane recruitment protein 1 (AMER1), have been described as the only molecular cause for OSCS. AMER1 promotes the degradation of β-catenin via AXIN stabilization, acting as a negative regulator of the WNT/β-catenin signaling pathway, a central pathway in bone formation.\nOBJECTIVE: In this study, we describe a Dutch adult woman with an OSCS-like phenotype, namely, generalized high bone mass and characteristic metaphyseal striations, but no genetic variant affecting AMER1.\nRESULTS: Whole exome sequencing led to the identification of a mosaic missense variant (c.876A > C; p.Lys292Asn) in CTNNB1, coding for β-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the β-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the β-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn β-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn β-catenin.\nCONCLUSION: In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata.","variants":[{"Name":"NM_001904.4(CTNNB1):c.876A>C (p.Lys292Asn)","Chromosome":"3","Start":"41225801","Stop":"41225801","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3222258,"rule_based_match":true,"evidence_text":"c.876A > C; p.Lys292Asn","llm_judgment":"PRESENT","evidence":"c.876A > C; p.Lys292Asn","abstract_start":904,"abstract_end":927}]}
{"pmid":"29062245","title":"Research of genetic bases of hereditary non-syndromic hearing loss.","abstract":"AIM: Hearing loss is the most common sensory disorder that affects approximately one per 1000 live births. With this project, we aimed to identify gene variants that were common causes of hearing loss in Turkey to contribute to the planning of genetic screening programs for hearing loss, as well as to improve genetic counseling to affected families.\nMATERIAL AND METHODS: Twenty-one families with at least two affected individuals and parental consanguinity who presented with non-syndromic severe-to-profound sensorineural hearing loss were included in this study. We first screened for mutations in GJB2 and mitochondrial DNA 12S RNA genes. Subsequently, we genotyped the TMIE c.250C>T and SNP markers flanking the <i>SLC26A4, MYO7A, MYO15A, OTOF, CDH23, TMIE, TECTA, PCDH15, TMC1, TMPRSS3, TMHS</i> genes in the remaining twelve families without mutations in GJB2.\nRESULTS: Screening for mutations in GJB2 gene showed c.[35delG];[35delG] mutation in four families, c.[35delG];[507C>A] mutation in two families, c.[35delG];[-23+1G>A] mutation in one family, and c.457G>A heterozygous mutation in one family. Genotyping SNP markers showed the c.[250C>T];[250C>T] mutation in TMIE in one family. A homozygous region with SNP genotypes was detected with the <i>OTOF</i> gene in one family, the <i>TMPRSS3</i> gene in another family, and also a homozygous region was detected with <i>TMHS, OTOF</i>, and <i>TMPRSS3</i> genes in another family.\nCONCLUSIONS: Further research will be required to determine the genetic bases of hearing loss in families with non-syndromic hearing loss.","variants":[{"Name":"NM_004004.6(GJB2):c.457G>A (p.Val153Ile)","Chromosome":"13","Start":"20189125","Stop":"20189125","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":53921,"rule_based_match":true,"evidence_text":"c.457G>A heterozygous mutation","llm_judgment":"PRESENT","evidence":"c.457G>A heterozygous mutation","abstract_start":1066,"abstract_end":1096}]}
{"pmid":"26722329","title":"Heterozygous p.I171V mutation of the","abstract":"The <i>NBN</i> gene, also known as <i>NBS1</i>, is located on the chromosome band 8q21.3, and encodes a 754-amino acid-long protein named nibrin. This protein is a member of the MRE1-RAD50-NBN nuclear complex, and is involved in numerous <i>cell</i> processes essential for maintaining genomic stability. Heterozygous variants in the <i>NBN</i> gene, including p.I171V, c.657del5 and p.R215W, have been described as risk factors for the development of several malignancies. However, there is no report regarding the association of these mutations with lung cancer thus far. Therefore, the present study aimed to evaluate whether there is an association between the heterozygous p.I171V, c.657del5 and p.R215W variants of the <i>NBN</i> gene and the risk of developing lung cancer. The frequency of these variants was estimated in a group of 453 adults diagnosed with non-small cell lung cancer (NSCLC) and in healthy controls (2,400 for p.I171V, 2,090 for c.657del5 and 498 for p.R215W). The p.I171V variant was assessed by restriction <i>fragment</i> length polymorphism analysis of polymerase chain reaction (PCR) products, using <i>Mun</i>I (<i>Mfe</i>I) restriction enzyme, whereas the c.657del5 and p.R215W variants were assessed by the <i>PCR s</i>ingle-strand conformation polymorphism method. A significantly increased risk of developing lung cancer was observed for the p.I171V variant, which was present in 17 (3.75%) of the 453 cases of lung cancer and in 12 (0.5%) of the 2,400 healthy individuals (odds ratio, 7.759; P<0.0001). The results obtained indicated an association between the p.I171V mutation and the development of lung cancer. Therefore, this variant may be considered a risk factor for NSCLC. Prospective studies with larger groups of patients may reveal the potential impact of the p.I171V variant in the occurrence of lung cancer.","variants":[{"Name":"NM_002485.5(NBN):c.511A>G (p.Ile171Val)","Chromosome":"8","Start":"89978293","Stop":"89978293","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":21985,"rule_based_match":false,"evidence_text":"p.I171V","llm_judgment":"PRESENT","evidence":"p.I171V","abstract_start":361,"abstract_end":368}]}
{"pmid":"28044000","title":"Painful locking of the wrist in a patient with pseudoachondroplasia confirmed by COMP mutation.","abstract":"We report the case of a 40-year-old woman with pseudoachondroplasia (PSACH), with a heterozygous mutation (c.806A > G, p.Asp269Gly) located in the Type 3 repeats domain of the cartilage oligomeric matrix protein gene, who complained of the unusual symptom of painful locking of the wrist. Her condition was caused by a non-traumatic enlargement of the extensor carpi radialis longus (ECRL) and brevis (ECRB) tendons along with bulbous swelling of the synoviums around them. Surgical treatment resolved these unusual tendon-related symptoms. Repetitive mechanical loading of the wrist in daily activities, including distal intersection tenosynovitis between the extensor pollicis longus tendon and ECRL and ECRB tendons, may have contributed to changes in the structural integrity of the tendons. We should pay more attention to tendon-related symptoms in patients with PSACH.","variants":[{"Name":"NM_000095.3(COMP):c.806A>G (p.Asp269Gly)","Chromosome":"19","Start":"18788471","Stop":"18788471","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1405488,"rule_based_match":true,"evidence_text":"c.806A > G, p.Asp269Gly","llm_judgment":"PRESENT","evidence":"c.806A > G, p.Asp269Gly","abstract_start":107,"abstract_end":130}]}
{"pmid":"23232253","title":"Mucopolysaccharidosis type II in a female carrying a heterozygous stop mutation of the iduronate-2-sulfatase gene and showing a skewed X chromosome inactivation.","abstract":"We report a Mexican girl showing the full blown clinical picture of mucopolysaccharidosis type II (MPSII). Iduronate-2-sulfatase (IDS) activity was low and she carried a heterozygous de novo c.1327C>T transition in exon 9, that changes codon 443 for a premature stop (TGA; p.Arg443(*)). Analysis of X-chromosome inactivation in androgen receptor (AR) locus showed a highly skewed ratio of 92:8 suggesting a functional hemizygosity with dominant expression of the mutant IDS and explaining the disease manifestation. This is one of the rare cases of females affected by MPSII due to the combined effect of a skewed X-chromosome inactivation and a de novo IDS mutation. We recommend that clinicians should consider the diagnosis of MPSII even in a girl without positive family history for this condition.","variants":[{"Name":"NM_000202.8(IDS):c.1327C>T (p.Arg443Ter)","Chromosome":"X","Start":"149483072","Stop":"149483072","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25525,"rule_based_match":true,"evidence_text":"c.1327C>T","llm_judgment":"PRESENT","evidence":"c.1327C>T","abstract_start":191,"abstract_end":200}]}
{"pmid":"26358778","title":"CDC174, a novel component of the exon junction complex whose mutation underlies a syndrome of hypotonia and psychomotor developmental delay.","abstract":"Siblings of non-consanguineous Jewish-Ethiopian ancestry presented with congenital axial hypotonia, weakness of the abducens nerve, psychomotor developmental delay with brain ventriculomegaly, variable thinning of corpus callosum and cardiac septal defects. Homozygosity mapping identified a single disease-associated locus of 3.5 Mb on chromosome 3. Studies of a Bedouin consanguineous kindred affected with a similar recessive phenotype identified a single disease-associated 18 Mb homozygosity locus encompassing the entire 3.5 Mb locus. Whole exome sequencing demonstrated only two homozygous mutations within a shared identical haplotype of 0.6 Mb, common to both Bedouin and Ethiopian affected individuals, suggesting an ancient common founder. Only one of the mutations segregated as expected in both kindreds and was not found in Bedouin and Jewish-Ethiopian controls: c.1404A>G, p.[*468Trpext*6] in CCDC174. We showed that CCDC174 is ubiquitous, restricted to the cell nucleus and co-localized with EIF4A3. In fact, yeast-two-hybrid assay demonstrated interaction of CCDC174 with EIF4A3, a component of exon junction complex. Knockdown of the CCDC174 ortholog in Xenopus laevis embryos resulted in poor neural fold closure at the neurula stage with later embryonic lethality. Knockdown embryos exhibited a sharp reduction in expression of n-tubulin, a marker for differentiating primary neurons, and of hindbrain markers krox20 and hoxb3. The Xenopus phenotype could be rescued by the human normal, yet not the mutant CCDC174 transcripts. Moreover, overexpression of mutant but not normal CCDC174 in neuroblastoma cells caused rapid apoptosis. In line with the hypotonia phenotype, the CCDC174 mutation caused depletion of RYR1 and marked myopathic changes in skeletal muscle of affected individuals.","variants":[{"Name":"NM_016474.5(CCDC174):c.1404A>G (p.Ter468Trp)","Chromosome":"3","Start":"14671194","Stop":"14671194","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":223779,"rule_based_match":true,"evidence_text":"c.1404A>G, p.[*468Trpext*6]","llm_judgment":"PRESENT","evidence":"c.1404A>G, p.[*468Trpext*6]","abstract_start":877,"abstract_end":904}]}
{"pmid":"33631708","title":"Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes - A recognizable clinical phenotype.","abstract":"Three unrelated girls, all born to consanguineous parents had respiratory distress, severe hypotonia at birth along with prominent fatigable muscle weakness and characteristic myopathic facies. In addition, patient 1 had fatigable ptosis, ophthalmoparesis and profound bulbar weakness and required nasogastric feeding from birth. A feeding gastrostomy was inserted at 9 months of age. She continued to have severe bulbar and limb weakness with dropped head at 5 years of age. Patient 2 and 3 did not have ocular signs at the time of initial presentation during infancy and at 2 years of age respectively. None of the patients attained independent walking. Patient 3, currently aged 16 years continues to be wheelchair bound and has only mild non-progressive bulbar weakness with normal cognitive development. Muscle biopsy in patient 1 and 3 showed predominant myopathic features admixed with small sized (atrophic/hypoplastic) fibres. Next generation sequencing confirmed the presence of a homozygous loss of function VAMP1 mutations in all three patients: A single nucleotide deletion resulting in frameshift: c.66delT (p.Gly23AlafsTer6) in patient 1 and nonsense mutations c.202C>T (pArg68Ter) and c.97C>T (p.Arg33Ter) in patient 2 and 3 respectively. Minimal but definite improvement in muscle power with pyridostigmine was reported in patients 1 and 2. This is the first report of VAMP1 mutations causing CMS from the Indian subcontinent, describing a clinically recognizable severe form of VAMP1-related CMS and highlighting the need for a strong index of suspicion for early genetic diagnosis of potentially treatable CMS phenotypes.","variants":[{"Name":"NM_014231.5(VAMP1):c.66del (p.Gly23fs)","Chromosome":"12","Start":"6466288","Stop":"6466288","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1863957,"rule_based_match":true,"evidence_text":"c.66delT (p.Gly23AlafsTer6)","llm_judgment":"PRESENT","evidence":"c.66delT (p.Gly23AlafsTer6)","abstract_start":1112,"abstract_end":1139}]}
{"pmid":"25099136","title":"Positive effects of an angiotensin II type 1 receptor antagonist in Camurati-Engelmann disease: a single case observation.","abstract":"Camurati-Engelmann disease is characterized by hyperostosis of the long bones and the skull, muscle atrophy, severe limb pain, and progressive joint contractures in some patients. It is caused by heterozygous mutations in the transforming growth factor β1 (TGFβ1) believed to result in improper folding of the latency-associated peptide domain of TGFβ1 and thus in increased or deregulated bioactivity. Losartan, an angiotensin II type 1 receptor antagonist, has been found to downregulate the expression of TGFβ type 1 and 2 receptors. Clinical trials with losartan have shown a benefit in Marfan syndrome, while trials are underway for Duchenne muscular dystrophy and other myopathies associated with TGFβ1 signaling. We hypothesized that due to its anti-TGFβ1 activity, losartan might be beneficial in Camurati-Engelmann disease. This report concerns a boy who presented at age 13 years with severe limb pain and difficulty in walking. Clinical and radiographic evaluation results were compatible with Camurati-Engelmann disease and the diagnosis was confirmed by mutation analysis (c.652C > T [p.Arg218Cys]). The boy underwent an experimental treatment with losartan at a dosage of 50 mg/day, orally. During the treatment period of 18 months, the intensity and frequency of limb pain decreased significantly (as shown by a pain diary), and muscle strength improved, allowing the boy to resume walking and climbing stairs. No obvious side effects were observed. We cautiously conclude that TGFβ1 inhibition with losartan deserves further evaluation in the clinical management of Camurati-Engelmann disease.","variants":[{"Name":"NM_000660.7(TGFB1):c.652C>T (p.Arg218Cys)","Chromosome":"19","Start":"41342230","Stop":"41342230","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27570,"rule_based_match":true,"evidence_text":"c.652C > T [p.Arg218Cys]","llm_judgment":"PRESENT","evidence":"c.652C > T [p.Arg218Cys]","abstract_start":1086,"abstract_end":1110}]}
{"pmid":"25818823","title":"Hemoglobin D-Punjab: origin, distribution and laboratory diagnosis.","abstract":"This review discusses hemoglobin D-Punjab, also known as hemoglobin D-Los Angeles, one of the most common hemoglobin variants worldwide. It is derived from a point mutation in the beta-globin gene (HBB: c.364G>C; rs33946267) prevalent in the Punjab region, Northwestern Indian. Hemoglobin D-Punjab can be inherited in heterozygosis with hemoglobin A causing no clinical or hematological alterations, or in homozygosis, the rarest form of inheritance, a condition that is commonly not related to clinical symptomatology. Moreover, this variant can exist in association with other hemoglobinopathies, such as thalassemias; the most noticeable clinical alterations occur when hemoglobin D-Punjab is associated to hemoglobin S. The clinical manifestations of this association can be similar to homozygosis for hemoglobin S. Although hemoglobin D-Punjab is a common variant globally with clinical importance especially in cases of double heterozygosis, hemoglobin S/D-Punjab is still understudied. In Brazil, for example, hemoglobin D-Punjab is the third most common hemoglobin variant. Thus, this paper summarizes information about the origin, geographic distribution, characterization and occurrence of hemoglobin D-Punjab haplotypes to try to improve our knowledge of this variant. Moreover, a list of the main techniques used in its identification is provided emphasizing the importance of complementary molecular analysis for accurate diagnosis.","variants":[{"Name":"NM_000518.4(HBB):c.364G>C (p.Glu122Gln)","Chromosome":"11","Start":"5225678","Stop":"5225678","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":30191,"rule_based_match":true,"evidence_text":"HBB: c.364G>C","llm_judgment":"PRESENT","evidence":"HBB: c.364G>C","abstract_start":198,"abstract_end":211}]}
{"pmid":"31683985","title":"The","abstract":"Mutations in <i>BRCA1</i> result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is <i>BRCA1</i> c.4096+3A>G, which affects production of the full-length <i>BRCA1</i> transcript, while augmenting transcripts lacking most or all of exon 11. Nonetheless, homozygosity of this variant has been reported in a healthy woman. We saw this variant cosegregate with breast and ovarian cancer in several family branches of four Icelandic pedigrees, with instances of phenocopies and a homozygous woman with lung cancer. We found eight heterozygous carriers (0.44%) in 1820 unselected breast cancer cases, and three (0.15%) in 1968 controls (<i>p</i> = 0.13). Seeking conclusive evidence, we studied tumors from carriers in the pedigrees for wild-type-loss of heterozygosity (wtLOH) and <i>BRCA1</i>-characteristic prevalence of estrogen receptor (ER) negativity. Of 15 breast and six ovarian tumors, wtLOH occurred in nine breast and all six ovarian tumours, and six of the nine breast tumors with wtLOH were ER-negative. These data accord with a pathogenic <i>BRCA1</i>-mutation. Our findings add to the current knowledge of <i>BRCA1</i><i>,</i> and the role of its exon 11 in cancer pathogenicity, and will be of use in clinical genetic counselling.","variants":[{"Name":"NM_007294.4(BRCA1):c.4096+3A>G","Chromosome":"17","Start":"43091432","Stop":"43091432","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":46122,"rule_based_match":true,"evidence_text":"c.4096+3A>G","llm_judgment":"PRESENT","evidence":"c.4096+3A>G","abstract_start":165,"abstract_end":176}]}
{"pmid":"30498755","title":"Clinical and Mutation Analysis of Patients with Best Vitelliform Macular Dystrophy or Autosomal Recessive Bestrophinopathy in Chinese Population.","abstract":"Mutations in the gene <i>BEST1</i> usually cause bestrophinopathies, such as the rare progressive diseases Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB). This study aimed to investigate the clinical characteristics of patients with BVMD or ARB carrying <i>BEST1</i> mutations. A total of 12 probands including 9 patients with a clinical diagnosis of BVMD and 3 patients with a clinical diagnosis of ARB were recruited for genetics analysis. All patients underwent detailed ophthalmic examination. All coding exons of the <i>BEST1</i> gene were screened by PCR-based DNA sequencing. Programs of PolyPhen-2, SIFT, and MutationTaster were used to analyze the potential pathogenicity of the mutations in <i>BEST1</i>. In the 9 unrelated patients with BVMD, one heterozygous <i>BEST1</i> mutation was revealed in 8 patients and two compound heterozygous mutations in 1 patient. In the 3 unrelated patients with ARB, two compound heterozygous mutations were revealed in 2 patients and three compound heterozygous mutations in 1 patient. Molecular analyses identified a total of 15 mutations, including 3 novel mutations (c.424A>G p.S142G, c.436G>A p.A146T, and c.155T>C p.L52P). Antivascular endothelial growth factor (VEGF) drugs were given to two affected eyes, especially those also exhibiting choroidal neovascularization (CNV), and no serious adverse events occurred. Our study indicates that there is wide genotypic and phenotypic variability in patients with BVMD or ARB in China. The screening of <i>BEST1</i> gene is significant for the precise diagnosis of BVMD and ARB.","variants":[{"Name":"NM_004183.4(BEST1):c.436G>A (p.Ala146Thr)","Chromosome":"11","Start":"61955906","Stop":"61955906","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1431810,"rule_based_match":true,"evidence_text":"c.436G>A p.A146T","llm_judgment":"PRESENT","evidence":"c.436G>A p.A146T","abstract_start":1176,"abstract_end":1192}]}
{"pmid":"32588437","title":"Telethonin variants found in Brugada syndrome, J-wave pattern ECG, and ARVC reduce peak Na","abstract":"BACKGROUND: Telethonin (TCAP) is a Z-disk protein that maintains cytoskeletal integrity and various signaling pathways in cardiomyocytes. TCAP is shown to modulate α-subunit of the human cardiac sodium channel (hNa<sub>v</sub> 1.5) by direct interactions. Several TCAP variants are found in cardiomyopathies. We sought to investigate whether TCAP variants are associated with arrhythmia syndromes.\nMETHODS: Mutational analyses for TCAP were performed in 303 Japanese patients with Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, and J-wave pattern ECG. Using patch-clamp techniques, electrophysiological characteristics of hNa<sub>v</sub> 1.5 were studied in HEK-293 cells stably expressing hNa<sub>v</sub> 1.5 and transiently transfected with wild-type (WT) or variant TCAP.\nRESULTS: We identified two TCAP variants, c.145G>A:p.E49K and c.458G>A:p.R153H, in four individuals. p.E49K was found in two patients with ARVC or BrS. p.R153H was found in two patients with BrS or J-wave pattern ECG. No patient had variant hNa<sub>v</sub> 1.5. Patch-clamp experiments demonstrated that peak sodium currents were significantly reduced in cells expressing p.R153H and p.E49K compared with WT-TCAP (66%, p.R153H; 72%, p.E49K). Voltage dependency of peak IV curve was rightward-shifted by 5 mV in cells expressing p.E49K compared with WT-TCAP. Voltage dependency of activation was not leftward-shifted by p.R153H, while voltage dependency of steady-state inactivation was leftward-shifted by p.E49K.\nCONCLUSIONS: We found two TCAP variants in the patients with BrS, J-wave pattern ECG, and ARVC that can cause loss-of-function of the hNa<sub>v</sub> 1.5 in heterologous expression systems. Our observation suggests that these variants might impair I<sub>Na</sub> and be associated with the patients' electrophysiological phenotypes. Further studies linking our experimental data to clinical phenotypes are warranted.","variants":[{"Name":"NM_003673.4(TCAP):c.145G>A (p.Glu49Lys)","Chromosome":"17","Start":"39665750","Stop":"39665750","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":645830,"rule_based_match":true,"evidence_text":"c.145G>A:p.E49K","llm_judgment":"PRESENT","evidence":"c.145G>A:p.E49K","abstract_start":837,"abstract_end":852}]}
{"pmid":"29449721","title":"Bi-allelic inactivating variants in the COCH gene cause autosomal recessive prelingual hearing impairment.","abstract":"Pathogenic variant in COCH are a known cause of DFNA9 autosomal dominant progressive hearing loss and vestibular dysfunction with adult onset. Hitherto, only dominant nonsynonymous variants and in-frame deletions with a presumed dominant negative or gain-of-function effect have been described. Here, we describe two brothers with congenital prelingual deafness and a homozygous nonsense c.292C>T(p.Arg98*) COCH variant, suggesting a loss-of-function effect. Vestibular dysfunction starting in the first decade was observed in the older patient. The heterozygous parents and sibling have normal hearing and vestibular function, except for the mother, who shows vestibular hyporeflexia and abnormal smooth pursuit tests, most likely due to concomitant disease. This is the first report of autosomal recessive inheritance of cochlea-vestibular dysfunction caused by a pathogenic variant in the COCH gene. An earlier onset of hearing impairment and vestibular dysfunction compared to the dominant hearing loss causing COCH variants is observed.","variants":[{"Name":"NM_004086.3(COCH):c.292C>T (p.Arg98Ter)","Chromosome":"14","Start":"30878863","Stop":"30878863","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":424972,"rule_based_match":true,"evidence_text":"c.292C>T(p.Arg98*)","llm_judgment":"PRESENT","evidence":"c.292C>T(p.Arg98*)","abstract_start":388,"abstract_end":406}]}
{"pmid":"29478779","title":"Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children.","abstract":"Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs<sup>∗</sup>75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs<sup>∗</sup>77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 × 10<sup>-8</sup>). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human \"pro-ovary\" and \"anti-testis\" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology.","variants":[{"Name":"NM_021005.4(NR2F2):c.97_103del (p.Pro33fs)","Chromosome":"15","Start":"96332197","Stop":"96332203","ReferenceAlleleVCF":"GGCCCGCC","AlternateAlleleVCF":"G","allel_id":904258,"rule_based_match":true,"evidence_text":"c.97_103delCCGCCCG (p.Pro33Alafs<sup>∗</sup>77)","llm_judgment":"PRESENT","evidence":"c.97_103delCCGCCCG (p.Pro33Alafs<sup>∗</sup>77)","abstract_start":787,"abstract_end":834},{"Name":"NM_021005.4(NR2F2):c.103_109del (p.Gly35fs)","Chromosome":"15","Start":"96332203","Stop":"96332209","ReferenceAlleleVCF":"CCGCCCGG","AlternateAlleleVCF":"C","allel_id":904262,"rule_based_match":true,"evidence_text":"c.103_109delGGCGCCC (p.Gly35Argfs<sup>∗</sup>75)","llm_judgment":"PRESENT","evidence":"c.103_109delGGCGCCC (p.Gly35Argfs<sup>∗</sup>75)","abstract_start":701,"abstract_end":749}]}
{"pmid":"30208423","title":"Confirmation of the Role of DHX38 in the Etiology of Early-Onset Retinitis Pigmentosa.","abstract":"Purpose: Retinitis pigmentosa (RP) is a genetically heterogeneous trait with autosomal-recessive (ar) inheritance underlying 50% of genetic disease cases. Sixty-one arRP genes have been identified, and recently, DHX38 has been reported as a potential candidate gene for arRP with only a single family reported with a variant of unknown significance. We identified a missense variant in DHX38 that co-segregates with the arRP phenotype in two Pakistani families confirming the involvement of DHX38 in the etiology of early-onset RP.\nMethods: Exome sequencing was performed using two DNA samples from affected members of Pakistani families (MA88 and MA157) with early onset arRP. Sanger sequencing of DNA samples from all family members confirmed the segregation of candidate variant within both families.\nResults: A novel missense DHX38 variant c.971G>A; p.(Arg324Gln) was identified which segregates with the arRP phenotype and yielded a logarithm of the odds (LOD) score of 5.0 and 4.3 for families MA88 and MA157, respectively. This variant is predicted to be conserved and deleterious by several bioinformatics tools.\nConclusions: We identified a second deleterious DHX38 variant that segregates with arRP in two families, providing additional evidence that DHX38 is involved in RP etiology. DHX38 encodes for pre-mRNA splicing factor PRP16, which is important in catalyzing pre-mRNA splicing.","variants":[{"Name":"NM_014003.4(DHX38):c.971G>A (p.Arg324Gln)","Chromosome":"16","Start":"72099742","Stop":"72099742","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":583166,"rule_based_match":true,"evidence_text":"DHX38 variant c.971G>A; p.(Arg324Gln)","llm_judgment":"PRESENT","evidence":"DHX38 variant c.971G>A; p.(Arg324Gln)","abstract_start":830,"abstract_end":867}]}
{"pmid":"23638917","title":"Leber's congenital amaurosis as the retinal degenerative phenotype in thiamine responsive megaloblastic anemia: a case report.","abstract":"BACKGROUND: Thiamine responsive megaloblastic anemia syndrome (TRMA), an autosomal recessive disorder is caused by mutations in the SLC19A2 gene which encodes for thiamine transporter 1 (THTR1) protein. TRMA presents with a triad of clinical features that includes diabetes mellitus, megaloblastic anemia and sensorineural hearing loss. Apart from the triad, reported ophthalmic features include cone rod dystrophy, optic atropy and retinitis pigmentosa.\nMATERIALS AND METHODS: A female child presented with Leber's congenital amaurosis at 10 months of age, later diagnosed with hearing impairment at 1 year, diabetes mellitus and megaloblastic anemia at 3 and a half years of age and hence as a case of thiamine responsive megaloblastic anemia. Six exons of the candidate gene SLC19A2 were screened by PCR and direct sequencing. SIFT and PolyPhen analysis was done to predict the probable effect of the mutation.\nRESULTS: Sequence analysis of the SLC19A2 coding region revealed a novel missense mutation in exon 2; c.314 G > A (p.G105E). Segregation analysis revealed parents heterozygous for the mutation and unaffected sib homozygous for wild type. SIFT and PolyPhen analyses predicted the mutation to be \"damaging\" (score-0.02) and \"probably damaging\" (score-0.994), respectively.\nCONCLUSIONS: SLC19A2, the high-affinity thiamine transporter, is the only gene known to be associated with TRMA. Here we describe for the first time Leber's congenital amaurosis as the retinal phenotype and also report a novel point mutation in the SLC19A2 gene that co-segregated with the disease in a TRMA patient.","variants":[{"Name":"NM_006996.3(SLC19A2):c.314G>A (p.Gly105Glu)","Chromosome":"1","Start":"169477648","Stop":"169477648","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2753141,"rule_based_match":true,"evidence_text":"c.314 G > A (p.G105E)","llm_judgment":"PRESENT","evidence":"c.314 G > A (p.G105E)","abstract_start":1016,"abstract_end":1037}]}
{"pmid":"19820980","title":"Frequency of the FKRP mutation c.826C>A in isolated hyperCKemia and in limb girdle muscular dystrophy type 2 in German patients.","abstract":"","variants":[{"Name":"NM_024301.5(FKRP):c.826C>A (p.Leu276Ile)","Chromosome":"19","Start":"46756276","Stop":"46756276","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":19260,"rule_based_match":true,"evidence_text":"c.826C>A","llm_judgment":"PRESENT","evidence":"c.826C>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"19936428","title":"A novel mutation in ARG1 gene is responsible for arginase deficiency in an Asian family.","abstract":"Argininemia is a rare autosomal recessive metabolic disorder caused by a deficiency in the arginase enzyme, which is the final enzyme in the urea cycle and responsible for the hydrolysis of arginine to urea and ornithine. The disease becomes symptomatic during childhood and is characterized by progressive spastic quadriplegia, progressive mental impairment, growth retardation, and periodic episodes of hyperammonemia. At least 19 distinct mutations in the ARG1 gene have been identified indicating the molecular heterogeneity of this condition. We report a homozygous novel mutation (c.93 delG) in the ARG1 gene from 3 affected children of a Pakistani family living in the United Arab Emirates. The mutation is expected to lead to a frame shift after the thirtieth residue and a stop codon at residue 44 (p.T30fsX14). Therefore, this mutation is expected to result in complete loss-of-function of the arginase enzyme and therefore is the mostly likely cause of argininemia in this family.","variants":[{"Name":"NM_000045.4(ARG1):c.93del (p.Arg32fs)","Chromosome":"6","Start":"131576698","Stop":"131576698","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":1060607,"rule_based_match":true,"evidence_text":"c.93 delG","llm_judgment":"PRESENT","evidence":"c.93 delG","abstract_start":587,"abstract_end":596}]}
{"pmid":"31621862","title":"CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report.","abstract":"The use of high-throughput sequencing techniques has allowed the identification of numerous mutations in genes responsible for severe astheno-teratozoospermia due to multiple morphological abnormalities of the sperm flagella (MMAF). However, more than half of the analysed cases remain unresolved suggesting that many yet uncharacterised gene defects account for this phenotype. Based on whole-exome sequencing data from a large cohort of 167 MMAF-affected subjects, we identified two unrelated affected individuals carrying a homozygous deleterious mutation in CFAP70, a gene not previously linked to the MMAF phenotype. One patient had a homozygous splice variant c.1723-1G>T, altering a consensus splice acceptor site of CFAP70 exon 16, and one had a likely deleterious missense variant in exon 3 (p.Phe60Ile). The CFAP70 gene encodes a regulator protein of the outer dynein arms (ODA) strongly expressed in the human testis. In the sperm cells from the patient carrying the splice variant, immunofluorescence (IF) experiments confirmed the absence of the protein in the sperm flagellum. Moreover, IF analysis showed the absence of markers for the ODAs and the central pair complex of the axoneme. Interestingly, whereas CFAP70 staining was present in sperm cells from patients with mutations in the three other MMAF-related genes ARMC2, FSIP2 and CFAP43, we observed an absence of staining in sperm cells from patients mutated in the WDR66 gene, suggesting a possible interaction between two different axonemal components. In conclusion, this work provides the first evidence that loss of CFAP70 function causes MMAF and that ODA-related proteins may be crucial for the assembly and/or stability of the flagellum axoneme in addition to its motility.","variants":[{"Name":"NM_001367801.1(CFAP70):c.1723-1G>T","Chromosome":"10","Start":"73297174","Stop":"73297174","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":682657,"rule_based_match":true,"evidence_text":"c.1723-1G>T","llm_judgment":"PRESENT","evidence":"c.1723-1G>T","abstract_start":666,"abstract_end":677}]}
{"pmid":"32738225","title":"De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.","abstract":"Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.","variants":[{"Name":"NM_004539.4(NARS1):c.1633C>T (p.Arg545Cys)","Chromosome":"18","Start":"57601666","Stop":"57601666","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":974447,"rule_based_match":true,"evidence_text":"c.1633C>T (p.Arg545Cys)","llm_judgment":"PRESENT","evidence":"c.1633C>T (p.Arg545Cys)","abstract_start":620,"abstract_end":643}]}
{"pmid":"25666562","title":"Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss.","abstract":"Pathogenic mutations of MARVELD2, encoding tricellulin, a tricelluar tight junction protein, cause autosomal recessive non-syndromic hearing loss (DFNB49) in families of Pakistan and Czech Roma origin. In fact, they are a significant cause of prelingual hearing loss in the Czech Roma, second only to GJB2 variants. Previously, we reported that mice homozygous for p.Arg497* variant of Marveld2 had a broad phenotypic spectrum, where defects were observed in the inner ear, heart, mandibular salivary gland, thyroid gland and olfactory epithelium. The current study describes the types and frequencies of MARVELD2 alleles and clinically reexamines members of DFNB49 families. We found that MARVELD2 variants are responsible for about 1.5 % (95 % CI 0.8-2.6) of non-syndromic hearing loss in our cohort of 800 Pakistani families. The c.1331+2T>C allele is recurrent. In addition, we identified a novel large deletion in a single family, which appears to have resulted from non-allelic homologous recombination between two similar Alu short interspersed elements. Finally, we observed no other clinical manifestations co-segregating with hearing loss in DFNB49 human families, and hypothesize that the additional abnormalities in the Marveld2 mutant mouse indicates a critical non-redundant function for tricellulin in other organ systems.","variants":[{"Name":"NM_001038603.3(MARVELD2):c.1331+2T>C","Chromosome":"5","Start":"69432677","Stop":"69432677","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":859444,"rule_based_match":true,"evidence_text":"c.1331+2T>C","llm_judgment":"PRESENT","evidence":"c.1331+2T>C","abstract_start":833,"abstract_end":844}]}
{"pmid":"30475797","title":"Mutations in Kinesin family member 6 reveal specific role in ependymal cell ciliogenesis and human neurological development.","abstract":"Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Member 6 (KIF6) gene in a child displaying neurodevelopmental defects and intellectual disability. To test the pathogenicity of this novel human KIF6 mutation we engineered an analogous C-terminal truncating mutation in mouse. These mutant mice display severe, postnatal-onset hydrocephalus. We generated a Kif6-LacZ transgenic mouse strain and report expression specifically and uniquely within the ependymal cells (ECs) of the brain, without labeling other multiciliated mouse tissues. Analysis of Kif6 mutant mice with scanning electron microscopy (SEM) and immunofluorescence (IF) revealed specific defects in the formation of EC cilia, without obvious effect of cilia of other multiciliated tissues. Dilation of the ventricular system and defects in the formation of EC cilia were also observed in adult kif6 mutant zebrafish. Finally, we report Kif6-GFP localization at the axoneme and basal bodies of multi-ciliated cells (MCCs) of the mucociliary Xenopus epidermis. Overall, this work describes the first clinically-defined KIF6 homozygous null mutation in human and defines KIF6 as a conserved mediator of neurological development with a specific role for EC ciliogenesis in vertebrates.","variants":[{"Name":"NM_145027.6(KIF6):c.1193del (p.Leu398fs)","Chromosome":"6","Start":"39545677","Stop":"39545677","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"T","allel_id":610415,"rule_based_match":true,"evidence_text":"c.1193delT (p.Leu398Glnfs*2)","llm_judgment":"PRESENT","evidence":"c.1193delT (p.Leu398Glnfs*2)","abstract_start":263,"abstract_end":291}]}
{"pmid":"33843396","title":"Hb Hezhou [β64(E8)Gly→Ser;","abstract":"We report a novel mutation on the β-globin gene, Hb Hezhou [β64(E8)Gly→Ser; <i>HBB</i>: c.193G>A] that was detected in two unrelated Chinese individuals. Patient 1 also carried an α<sup>+</sup>-thalassemia (α<sup>+</sup>-thal) -α<sup>4.2</sup> (leftward) deletion, but hematological analyses showed no clinical consequences. Patient 2 was heterozygous for Hb Hezhou. Hemoglobin (Hb) analysis was performed using capillary electrophoresis (CE) and high performance liquid chromatography (HPLC). The Hb variant remained undetected using HPLC, while an additional peak was detected by CE. The finding of Hb Hezhou indicates that the possibilities of rare Hb variants should be alerted in the thalassemia screening program and precisely diagnosed depending on the Hb separation technique used.","variants":[{"Name":"NM_000518.5(HBB):c.193G>A (p.Gly65Ser)","Chromosome":"11","Start":"5226699","Stop":"5226699","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2843014,"rule_based_match":true,"evidence_text":"HBB: c.193G>A","llm_judgment":"PRESENT","evidence":"c.193G>A","abstract_start":88,"abstract_end":96}]}
{"pmid":"31358886","title":"An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort.","abstract":"The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.1750G > A; p.Gly584Ser variant within the coding sequence of the KCNH2 gene implicated in Long QT Syndrome (LQTS), which occurred once in 500 whole genome sequences from this population, was investigated. Targeted sequencing of the KCNH2 gene in family members of the initial participant confirmed the presence of the sequence variant and identified two further members of the same family pedigree who shared the variant. Investigation of these three related participants for whom single nucleotide polymorphism (SNP) array genotypes were available allowed a unique shared haplotype of 1.22 Mb to be defined around this locus. Searching across the full cohort for this haplotype uncovered two additional apparently unrelated individuals with no known genealogical connection to the original kindred. All five participants with the defined haplotype were shown to share the rare variant by targeted Sanger sequencing. If this result were verified in a healthcare setting, it would be considered clinically actionable, and has been actioned in relatives ascertained independently through clinical presentation. The General Practitioners of four study participants with the rare variant were alerted to the research findings by letters outlining the phenotype (prolonged electrocardiographic QTc interval). A lack of detectable haplotype sharing between c.1750G > A; p.Gly584Ser chromosomes from previously reported individuals from Finland and those in this study from Shetland suggests that this mutation has arisen more than once in human history. This study showcases the potential value of isolate population-based research resources for genomic medicine. It also illustrates some challenges around communication of actionable findings in research participants in this context.","variants":[{"Name":"NM_000238.4(KCNH2):c.1750G>A (p.Gly584Ser)","Chromosome":"7","Start":"150951643","Stop":"150951643","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":78157,"rule_based_match":true,"evidence_text":"c.1750G > A; p.Gly584Ser","llm_judgment":"PRESENT","evidence":"c.1750G > A; p.Gly584Ser","abstract_start":373,"abstract_end":397}]}
{"pmid":"21993463","title":"A novel mutation of the decorin gene identified in a Korean family with congenital hereditary stromal dystrophy.","abstract":"PURPOSE: To identify mutations in the decorin (DCN) gene in family members with congenital hereditary stromal dystrophy (CHSD).\nMETHODS: Bilateral deep anterior lamellar keratoplasties using a big-bubble technique and a 60-kHz femtosecond laser (IntraLase; Abbott Medical Optics, Irvine, CA) for zig-zag incisions were performed for the patients with CHSD. Medical records were reviewed for the proband's daughter with the same corneal manifestation who had bilateral penetrating keratoplasty 8 years before. After obtaining informed consent from the pediatric patients and their guardians, we sampled the peripheral blood of 2 patients and the proband's son who had no clinical manifestation of CHSD. Genomic DNA was extracted from white blood cells. Eight exons and exon-intron boundaries of the DCN gene were amplified by polymerase chain reaction using specific primers for each exon. The polymerase chain reaction products were subsequently analyzed using the direct DNA sequencing method.\nRESULTS: The proband and her daughter showed typical pathological findings of CHSD, such as lamellae of normal collagen fibrils separated by layers of abnormal collagen filaments, as seen on electron microscopic examination. A novel mutation c.947delG (p.Gly316AspfsX12) was identified in the exon 8 of the DCN gene, which might lead to an abnormal truncation of the C-terminal in the decorin protein. However, the proband's son who was without any sign of CHSD showed a normal sequence of the DCN gene.\nCONCLUSIONS: We report a novel frameshift mutation of the DCN gene in a Korean family with CHSD.","variants":[{"Name":"NM_001920.5(DCN):c.947del (p.Gly316fs)","Chromosome":"12","Start":"91146191","Stop":"91146191","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":76571,"rule_based_match":true,"evidence_text":"c.947delG (p.Gly316AspfsX12)","llm_judgment":"PRESENT","evidence":"c.947delG (p.Gly316AspfsX12)","abstract_start":1237,"abstract_end":1265}]}
{"pmid":"25802884","title":"Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population.","abstract":"Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder that results from functional and ultrastructural abnormalities of motile cilia. Patients with PCD have diverse clinical phenotypes that include chronic upper and lower respiratory tract infections, situs inversus, heterotaxy with or without congenital heart disease, and male infertility, among others. In this report, the carrier frequencies for eleven mutations in eight PCD-associated genes (DNAI1, DNAI2, DNAH5, DNAH11, CCDC114, CCDC40, CCDC65, and C21orf59) that had been found in individuals of Ashkenazi Jewish descent were investigated in order to advise on including them in existing clinical mutation panels for this population. Results showed relatively high carrier frequencies for the DNAH5 c.7502G>C mutation (0.58%), the DNAI2 c.1304G>A mutation (0.50%), and the C21orf59 c.735C>G mutation (0.48%), as well as lower frequencies for mutations in DNAI1, CCDC65, CCDC114, and DNAH11 (0.10-0.29%). These results suggest that several of these genes should be considered for inclusion in carrier screening panels in the Ashkenazi Jewish population.","variants":[{"Name":"NM_001369.3(DNAH5):c.7502G>C (p.Arg2501Pro)","Chromosome":"5","Start":"13810166","Stop":"13810166","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":173691,"rule_based_match":true,"evidence_text":"DNAH5 c.7502G>C","llm_judgment":"PRESENT","evidence":"DNAH5 c.7502G>C","abstract_start":792,"abstract_end":807},{"Name":"NM_023036.6(DNAI2):c.1304G>A (p.Trp435Ter)","Chromosome":"17","Start":"74309345","Stop":"74309345","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":230781,"rule_based_match":true,"evidence_text":"the DNAI2 c.1304G>A mutation","llm_judgment":"PRESENT","evidence":"the DNAI2 c.1304G>A mutation","abstract_start":826,"abstract_end":854}]}
{"pmid":"25913853","title":"Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient.","abstract":"Cleft lip/palate-ectodermal dysplasia syndrome is a rare, autosomal recessive disorder caused by homozygous loss-of-function mutations of the poliovirus receptor-like 1 (PVRL1) gene encoding nectin-1. Nectin-1 is a cell-cell adhesion molecule that is important for the initial step in the formation of adherens junctions and tight junctions; it is expressed in keratinocytes, neurons, and the developing face and palate. Clinical manifestations comprise a unique facial appearance with cleft lip/palate, ectodermal dysplasia, cutaneous syndactyly of the fingers and/or toes, and in some cases, mental retardation. We present the first report, to our knowledge, of an Asian individual with cleft lip/palate-ectodermal dysplasia syndrome with a novel PVRL1 mutation. A 7-year-old Japanese boy, the first child of a consanguineous marriage, showed hypohidrotic ectodermal dysplasia with sparse, brittle, fine, dry hair and hypodontia, the unique facial appearance with cleft lip/palate, cutaneous syndactyly of the fingers and mild mental retardation. Scanning electron microscopic examination of the hair demonstrated pili torti and pili trianguli et canaliculi. Mutation analysis of exon 2 of PVRL1 revealed a novel homozygous nonsense mutation, c.400C>T (p.Arg134*). His parents were heterozygous for the mutant alleles. All four PVRL1 mutations identified in cleft lip/palate-ectodermal dysplasia syndrome to date, including this study, resulted in truncated proteins that lack the transmembrane domain and intracellular domain of nectin-1, which is necessary to initiate the cell-cell adhesion process.","variants":[{"Name":"NM_002855.5(NECTIN1):c.400C>T (p.Arg134Ter)","Chromosome":"11","Start":"119678445","Stop":"119678445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1689626,"rule_based_match":true,"evidence_text":"c.400C>T (p.Arg134*)","llm_judgment":"PRESENT","evidence":"c.400C>T (p.Arg134*)","abstract_start":1245,"abstract_end":1265}]}
{"pmid":"36999477","title":"Börjeson","abstract":"Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked intellectual disability. The main features of the patients include intellectual disability/global developmental delay, characteristic face, anomalies of fingers and toes, hypogonadism, linear skin hyperpigmentation, and tooth abnormalities in female patients, and obesity in male patients. A case of BFLS caused by a novel mutation of <i>PHF6</i> gene who was treated in the Department of Pediatrics, Xiangya Hospital, Central South University was reported. The 11 months old girl presented the following symptons: Global developmental delay, characteristic face, sparse hair, ocular hypertelorism, flat nasal bridge, hairy anterior to the tragus, thin upper lip, dental anomalies, ankyloglossia, simian line, tapering fingers, camptodactylia, and linear skin hyperpigmentation. The gene results of the second-generation sequencing technology showed that there was a novel heterozygous mutation site c.346C>T (p.Arg116*) of the <i>PHF6</i> (NM032458.3), variation rating as pathogenic variation. During the follow-up, the patient developed astigmatism, strabismus, awake bruxism, and stereotyped behavior, and the linear skin hyperpigmentation became gradually more evident. The disease is lack of effective therapy so far.","variants":[{"Name":"NM_001015877.2(PHF6):c.346C>T (p.Arg116Ter)","Chromosome":"X","Start":"134393606","Stop":"134393606","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2923423,"rule_based_match":true,"evidence_text":"c.346C>T (p.Arg116*)","llm_judgment":"PRESENT","evidence":"c.346C>T (p.Arg116*)","abstract_start":961,"abstract_end":981}]}
{"pmid":"33907643","title":"Fabry Disease p.M290I Mutation is Related to Organ Involvement: A Case Report.","abstract":"Fabry disease (FD) is an X-linked hereditary disease. It results from mutations in the GLA gene, leading to deficient activity of the enzyme alpha-galactosidase A (α-Gal A) and progressive accumulation of undegraded glycosphingolipids in cell lysosomes. Enzyme replacement therapy (ERT) can improve the natural course of this disease, but an early diagnosis is crucial for a successful treatment. We describe the case of a female diagnosed with chronic proteinuric kidney disease in the postpartum period. Despite receiving optimal medical treatment, the disease progressed and she started renal replacement therapy (RRT) with peritoneal dialysis (PD). Five years later, she was enrolled in a pilot screening study for FD, and the heterozygous mutation c.870G>C (p.Met290Ile; M290I) in exon six of the GLA gene was found. The family screening revealed the presence of this mutation in the patient's father and daughter. The proband did not meet the criteria for a definitive FD diagnosis, but she remained under follow-up at our nephrology metabolic diseases consultation, as the mutation was described as pathogenic and associated with a classic FD phenotype. Later that same year, reassessment exams revealed a worsening left ventricle mass index (LVMi), a new ischemic cerebral lesion, and a substantial increase in serum globotriaosylsphingosine (LysoGb3) levels. These clinical changes led to a decision to initiate ERT. p.M290I is a previously known but poorly described GLA mutation. To our knowledge, this is the first report of p.M290I mutation-associated disease activity that offers strong evidence of its pathogenicity.","variants":[{"Name":"NM_000169.3(GLA):c.870G>C (p.Met290Ile)","Chromosome":"X","Start":"101398499","Stop":"101398499","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":223884,"rule_based_match":true,"evidence_text":"c.870G>C (p.Met290Ile; M290I)","llm_judgment":"PRESENT","evidence":"c.870G>C (p.Met290Ile; M290I)","abstract_start":753,"abstract_end":782}]}
{"pmid":"17998451","title":"Choreoacanthocytosis in a Mexican family.","abstract":"BACKGROUND: Choreoacanthocytosis (CHAC) (Online Mendelian Inheritance in Man accession No. 200150) is a hereditary neurodegenerative syndrome characterized by movement disorders, cognitive decline, myopathy, behavioral changes, and acanthocytosis and is caused by mutations in the VPS13A gene.\nOBJECTIVE: To describe the cases of 2 Mexican women with clinical and molecular characteristics compatible with CHAC.\nDESIGN: Case reports. Patients Choreoacanthocytosis was identified in 2 Mexican mestizo sisters with healthy consanguineous parents. Clinical manifestations began at different ages.\nRESULTS: The onset of signs and symptoms of CHAC in the proband was at age 32 years and was characterized by balancing problems followed by chorea, compulsive lip and tongue biting with buccolingual self-mutilation, dysarthria, dysphagia, and weight loss. The first clinical manifestations in the proband's sister occurred at age 45 years and included multiple motor and verbal tics, with coprolalia, followed by lip and tongue biting, self-mutilation, and chorea. The clinical findings in both sisters were remarkable for acanthocytosis that developed late, when neurologic changes were already evident. Mutation screening of the VPS13A gene revealed homozygosity for the frameshift mutation c.3556_3557dupAC in exon 33. Currently, the proband's sister, in whom neurologic defects developed 13 years after onset of CHAC in the proband, is the least affected.\nCONCLUSIONS: The same mutation of the VPS13A gene can be expressed differently in the same family. This observation confirms the notion that there is considerable heterogeneity in the clinical manifestation of CHAC.","variants":[{"Name":"NM_033305.3(VPS13A):c.3556_3557dup (p.Val1187fs)","Chromosome":"9","Start":"77295589","Stop":"77295590","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AAC","allel_id":638388,"rule_based_match":true,"evidence_text":"c.3556_3557dupAC","llm_judgment":"PRESENT","evidence":"c.3556_3557dupAC","abstract_start":1287,"abstract_end":1303}]}
{"pmid":"23394911","title":"Variants of anterior segment dysgenesis and cerebral involvement in a large family with a novel COL4A1 mutation.","abstract":"PURPOSE: To investigate the diverse ocular manifestations and identify the causative mutation in a large family with autosomal dominant anterior segment dysgenesis accompanied in some individuals by cerebral vascular disease.\nDESIGN: Retrospective observational case series and laboratory investigation.\nMETHODS: Forty-five family members from 4 generations underwent ophthalmic examination. Molecular genetic investigation included analysis with single nucleotide polymorphism (SNP) markers and DNA sequencing. Whole exome sequencing was performed in 1 individual.\nRESULTS: A broad range of ocular manifestations was observed. Typical cases presented with corneal clouding, anterior synechiae, and iris hypoplasia. Posterior embryotoxon, corectopia, and early cataract development were also seen. One obligate carrier and several other family members had minor ocular anomalies, thus confounding the scoring of affected and unaffected individuals. Cerebral hemorrhages had occurred in 4 individuals, in 3 at birth or during the first year of life. Seven patients with corneal clouding were considered \"definitely affected\" for linkage studies. Haplotype mapping revealed that they shared a 14 cM region in the terminal part of chromosome 13q that included the locus for COL4A1. The affected family members were heterozygous for a novel COL4A1 sequence variant c.4881C>G (p.Asn1627Lys) predicted to be damaging and not found among 185 local blood donors. Exome sequencing showed that this variant was the only one in the candidate region not found in dbSNP.\nCONCLUSION: Among the family members shown to carry the novel COL4A1 mutation, heterogenous presentations of anterior segment dysgenesis was seen. Testing family members for this mutation also made a definite diagnosis possible in patients with a clinical presentation difficult to classify. In families where anterior segment dysgenesis occurs together with cerebral hemorrhages, genetic analysis of COL4A1 should be considered.","variants":[{"Name":"NM_001845.6(COL4A1):c.4881C>G (p.Asn1627Lys)","Chromosome":"13","Start":"110152381","Stop":"110152381","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":171698,"rule_based_match":true,"evidence_text":"c.4881C>G (p.Asn1627Lys)","llm_judgment":"PRESENT","evidence":"c.4881C>G (p.Asn1627Lys)","abstract_start":1361,"abstract_end":1385}]}
{"pmid":"23368878","title":"Hb Plasencia [α125(H8)Leu→Arg (α2)] is a frequent cause of α+-thalassemia in the Portuguese population.","abstract":"Hb Plasencia is a thalassemic hemoglobin (Hb) mutation caused by a leucine to arginine replacement at residue 125 of the α2-globin chain (HBA2:c.377T>G). This variant was first described in the heterozygous state in association with a very mild α-thalassemic phenotype in three members of a Spanish family from Plasencia, Western Spain. Reviewing the molecular characterization of 308 Portuguese individual suspected of having α-thalassemia (α-thal) we found Hb Plasencia to be the second most frequent mutation after the -α(3.7) deletion.","variants":[{"Name":"NM_000517.6(HBA2):c.377T>G (p.Leu126Arg)","Chromosome":"16","Start":"173548","Stop":"173548","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":30729,"rule_based_match":true,"evidence_text":"HBA2:c.377T>G","llm_judgment":"PRESENT","evidence":"HBA2:c.377T>G","abstract_start":138,"abstract_end":151}]}
{"pmid":"32203204","title":"Co-existence of ABCB11 and DCDC2 disease: Infantile cholestasis requires both next-generation sequencing and clinical-histopathologic correlation.","abstract":"A boy exhibiting conjugated hyperbilirubinemia from birth, with elevated serum gamma-glutamyl transpeptidase activity (GGT), developed liver failure unusually early (7mo); GGT concomitantly normalized. ABCB4 disease was suspected, but no ABCB4 lesion was found. The boy was instead homozygous for ABCB11 variant c.1213 T>C (p.(Cys405Arg)), which is predicted to affect protein function. Both ABCB4 and ABCB11 were normally expressed in the explanted liver, with intralobular cholestasis; however, large-duct sclerosing cholangiopathy and ductal-plate malformation also were present. The primary-cilium constituent doublecortin domain containing 2 (DCDC2) was not expressed. Co-existence of ABCB11 disease and DCDC2 disease was proposed. Further testing identified homozygosity for the canonical-receptor splice-site variant c.294-2A>G (p.?) in DCDC2. Our report emphasizes the need to integrate clinical, histological, and genetic data in patients with neonatal cholestasis.","variants":[{"Name":"NM_003742.4(ABCB11):c.1213T>C (p.Cys405Arg)","Chromosome":"2","Start":"168976672","Stop":"168976672","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2843572,"rule_based_match":true,"evidence_text":"c.1213 T>C (p.(Cys405Arg))","llm_judgment":"PRESENT","evidence":"c.1213 T>C (p.(Cys405Arg))","abstract_start":312,"abstract_end":338}]}
{"pmid":"37798908","title":"Refining the phenotypic spectrum of CCDC88A-related PEHO-like syndrome.","abstract":"Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and PEHO-like syndromes are very rare infantile disorders characterized by profound intellectual disability, hypotonia, convulsions, optic, and progressive brain atrophy. Many causative genes for PEHO and PEHO-like syndromes have been identified including CCDC88A. So far, only five patients from two unrelated families with biallelic CCDC88A variants have been reported in the literature. Herein, we describe a new family from Egypt with a lethal epileptic encephalopathy. Our patient was the youngest child born to a highly consanguineous couple and had a family history of five deceased sibs with the same condition. She presented with postnatal microcephaly, poor visual responsiveness, and epilepsy. Her brain MRI showed abnormal cortical gyration with failure of opercularization of the insula, hypogenesis of corpus callosum, colpocephaly, reduced white matter, hypoplastic vermis, and brain stem. Whole exome sequencing identified a new homozygous frameshift variant in CCDC88A gene (c.1795_1798delACAA, p.Thr599ValfsTer4). Our study presents the third reported family with this extremely rare disorder. We also reviewed all described cases to better refine the phenotypic spectrum associated with biallelic loss of function variants in the CCDC88A gene.","variants":[{"Name":"NM_001365480.1(CCDC88A):c.1795_1798del (p.Thr599fs)","Chromosome":"2","Start":"55335023","Stop":"55335026","ReferenceAlleleVCF":"CTTGT","AlternateAlleleVCF":"C","allel_id":3535685,"rule_based_match":true,"evidence_text":"c.1795_1798delACAA, p.Thr599ValfsTer4","llm_judgment":"PRESENT","evidence":"c.1795_1798delACAA, p.Thr599ValfsTer4","abstract_start":1072,"abstract_end":1109}]}
{"pmid":"32367058","title":"Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.","abstract":"Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.","variants":[{"Name":"NM_003104.6(SORD):c.757del (p.Ala253fs)","Chromosome":"15","Start":"45069019","Stop":"45069019","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":917579,"rule_based_match":true,"evidence_text":"c.757delG (p.Ala253GlnfsTer27)","llm_judgment":"PRESENT","evidence":"c.757delG (p.Ala253GlnfsTer27)","abstract_start":234,"abstract_end":264}]}
{"pmid":"33329693","title":"Preimplantation Genetic Testing for a Chinese Family With X-Linked Lymphoproliferative Syndrome Type 1.","abstract":"BACKGROUND: X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency disorder. We performed experiments based on two strategies of preimplantation genetic testing (PGT) for a family with XLP caused by a mutation in <i>SH2D1A</i> (c.191G > A).\nMETHODS: First, a single-cell polymerase chain reaction (PCR) protocol was established using single lymphocytes. A nested PCR experiment was performed with direct sequencing after whole genome amplification of single cells to assess the accuracy of the genetic diagnosis. Embryos obtained after intracytoplasmic sperm injection were biopsied on day 3 and detected using the established single-cell PCR protocol. In the second PGT cycle, targeted next generation sequencing (NGS) was performed and the single nucleotide polymorphism (SNP) markers flanking <i>SH2D1A</i> were selected to determine the disease-carrying haplotype phase in each embryo.\nRESULT: In the first PGT cycle, six embryos were biopsied. Discounting an embryo from a single failed PCR experiment, five embryos were identified, including three unaffected and two hemizygous. After PCR, one normal embryo was transferred when it was developing into an early blastocyst. Although the ultrasound images indicated a viable singleton pregnancy, the implantation was on the cesarean scar. Therefore, an artificial abortion was performed. In the haplotyping cycle, six embryos were identified to have inherited a haplotype without pathogenic mutations. After the embryo implantation process failed twice, a successful singleton pregnancy was established, and subsequently, a healthy female child was born.\nCONCLUSION: Targeted NGS with haplotyping analysis circumvents the laborious process of multiplex PCR and is more likely to ensure diagnostic accuracy. However, when a genetic recombination occurs close to the site of mutation, confirmed identification using selected SNP markers can be challenging.","variants":[{"Name":"NM_002351.5(SH2D1A):c.191G>A (p.Trp64Ter)","Chromosome":"X","Start":"124365814","Stop":"124365814","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1491324,"rule_based_match":true,"evidence_text":"c.191G > A","llm_judgment":"PRESENT","evidence":"c.191G > A","abstract_start":251,"abstract_end":261}]}
{"pmid":"32783137","title":"A whole-genome sequencing-based novel preimplantation genetic testing method for de novo mutations combined with chromosomal balanced translocations.","abstract":"PURPOSE: To explore a new preimplantation genetic testing (PGT) method for de novo mutations (DNMs) combined with chromosomal balanced translocations by whole-genome sequencing (WGS) using the MGISEQ-2000 sequencer.\nMETHODS: Two families, one with maternal Olmsted syndrome caused by DNM (c.1246C>T) in TRPV3 and a paternal Robertsonian translocation and one with paternal Marfan syndrome caused by DNM (c.4952_4955delAATG) in FBN1 and a maternal reciprocal translocation, underwent PGT for monogenetic disease (PGT-M), chromosomal aneuploidy, and structural rearrangement. WGS of embryos and family members were performed. Bioinformatics analysis based on gradient sequencing depth was performed, and parent-embryo haplotyping was conducted for DNM diagnosis. Sanger sequencing, karyotyping, and chromosomal microarray analysis were performed using an amniotic fluid sample to confirm the PGT results.\nRESULTS: After 1 PGT cycle, WGS of 2 embryos from the Olmsted syndrome family revealed euploid embryos without DNMs; after 2 cycles, the 11 embryos from the Marfan syndrome family showed only 1 normal embryo without DNM, copy number variations (CNVs), or aneuploidy. Moreover, 1 blastocyst from the Marfan syndrome family was transferred back to the uterus; the amniocentesis test results were confirmed by PGT and a healthy infant was born.\nCONCLUSIONS: WGS based on parent-embryo haplotypes was an effective strategy for PGT of DNMs combined with a chromosomal balanced translocation. Our results indicate this is a reliable and effective diagnostic method that is useful for clinical application in PGT of patients with DNMs.","variants":[{"Name":"NM_145068.4(TRPV3):c.1246C>T (p.Arg416Trp)","Chromosome":"17","Start":"3528992","Stop":"3528992","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2142371,"rule_based_match":true,"evidence_text":"c.1246C>T","llm_judgment":"PRESENT","evidence":"c.1246C>T","abstract_start":289,"abstract_end":298}]}
{"pmid":"29518248","title":"Defective mitochondrial protease LonP1 can cause classical mitochondrial disease.","abstract":"LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T > C predicting p.(Tyr565His) and c.2197G > A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense [p.(Glu733Lys)] variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild-type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically relevant tissues.","variants":[{"Name":"NM_004793.4(LONP1):c.2197G>A (p.Glu733Lys)","Chromosome":"19","Start":"5694510","Stop":"5694510","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1359441,"rule_based_match":true,"evidence_text":"c.2197G > A predicting p.(Glu733Lys)","llm_judgment":"PRESENT","evidence":"c.2197G > A predicting p.(Glu733Lys)","abstract_start":934,"abstract_end":970}]}
{"pmid":"36425069","title":"Case report: Familial glycogen storage disease type IV caused by novel compound heterozygous mutations in a glycogen branching enzyme 1 gene.","abstract":"Glycogen storage disease type IV (GSD IV), caused by a mutation in the glycogen branching enzyme 1 (GBE1) gene, is a rare metabolic disorder with an autosomal recessive inheritance that involves the liver, neuromuscular, and cardiac systems. Here, we reported a case of familial GSD IV induced by novel compound heterozygous mutations in GBE1. The proband (at age 1) and her younger brother (at age 10 months) manifested hepatosplenomegaly, liver dysfunction, and growth retardation at onset, followed by progressive disease deterioration to liver cirrhosis with liver failure. During the disease course, the proband presented rare intractable asymptomatic hypoglycemia. The liver pathology was in line with GSD IV. Both cases carried pathogenic compound heterozygous mutations in GBE1 mutations, i.e., a missense mutation (c.271T>A, <i>p</i>. W91R) in exon 2 and a deletion mutation in partial exons 3-7. Both mutations are first reported. The internationally pioneered split-liver transplantation was performed during progression to end-stage liver disease, and the patients had normal liver function and blood glucose after. This study broadens the mutation spectrum of the GBE1 gene and the phenotypic spectrum of GSD IV.","variants":[{"Name":"NM_000158.4(GBE1):c.271T>A (p.Trp91Arg)","Chromosome":"3","Start":"81705486","Stop":"81705486","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":3525529,"rule_based_match":true,"evidence_text":"c.271T>A","llm_judgment":"PRESENT","evidence":"c.271T>A","abstract_start":824,"abstract_end":832}]}
{"pmid":"24915262","title":"Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.","abstract":"IMPORTANCE: Latino populations have one of the highest prevalences of type 2 diabetes worldwide.\nOBJECTIVES: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships.\nDESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays.\nMAIN OUTCOME AND MEASURES: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function.\nRESULTS: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19).\nCONCLUSIONS AND RELEVANCE: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.","variants":[{"Name":"NM_000545.8(HNF1A):c.1522G>A (p.Glu508Lys)","Chromosome":"12","Start":"120999288","Stop":"120999288","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":139383,"rule_based_match":true,"evidence_text":"c.1522G>A [p.E508K]","llm_judgment":"PRESENT","evidence":"c.1522G>A [p.E508K]","abstract_start":933,"abstract_end":952}]}
{"pmid":"31217084","title":"Analysis of dementia-related gene variants in APOE ε4 noncarrying Korean patients with early-onset Alzheimer's disease.","abstract":"There is a genetic overlap among various neurodegenerative diseases that cause dementia. We analyzed dementia-related gene variants in 60 apolipoprotein E ε4 non-carrying Korean patients with early-onset Alzheimer's disease. Thirty-one dementia-related genes were screened by exome sequencing. Among the 60 patients, three likely pathogenic variants (LPVs) and 1 variant of uncertain significance (VUS) were identified in PSEN1. In addition, two LPVs in TYROBP (c.141del) and PINK1 (c.1220G>A) and 17 VUS were found in other dementia-causing genes. Two variants in SORL1 and TREM2 were identified that were associated with Alzheimer's disease. In this study, we identified 5 (8.3%) LPVs and 18 (30%) VUSs in known dementia-related genes in apolipoprotein E ε4 noncarrying Korean patients with early-onset Alzheimer's disease.","variants":[{"Name":"NM_032409.3(PINK1):c.1220G>A (p.Arg407Gln)","Chromosome":"1","Start":"20648601","Stop":"20648601","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":952221,"rule_based_match":true,"evidence_text":"PINK1 (c.1220G>A)","llm_judgment":"PRESENT","evidence":"PINK1 (c.1220G>A)","abstract_start":476,"abstract_end":493}]}
{"pmid":"26608784","title":"RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans.","abstract":"Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration.","variants":[{"Name":"NM_173630.4(RTTN):c.2885+8A>G","Chromosome":"18","Start":"70135176","Stop":"70135176","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":217212,"rule_based_match":true,"evidence_text":"c.2885+8A>G [p.Ser963(∗)]","llm_judgment":"PRESENT","evidence":"c.2885+8A>G [p.Ser963(∗)]","abstract_start":782,"abstract_end":807}]}
{"pmid":"22623405","title":"PRRT2 mutations are the major cause of benign familial infantile seizures.","abstract":"Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late-onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC","llm_judgment":"PRESENT","evidence":"c.649dupC","abstract_start":420,"abstract_end":429}]}
{"pmid":"30763665","title":"Characterization of a mutation in the zona pellucida module of Endoglin that causes Hereditary Hemorrhagic Telangiectasia.","abstract":"Hereditary hemorrhagic telangiectasia (HHT) is a vascular rare disease characterized by nose and gastrointestinal bleeding, skin and mucosa telangiectasias, and arteriovenous malformations in internal organs. HHT shows an autosomal dominant inheritance and a worldwide prevalence of approximately 1:5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG (HHT1) or ACVRL1 (HHT2) genes, which code for the membrane proteins Endoglin and Activin A Receptor Type II-Like Kinase 1 (ALK1), respectively, both belonging to the TGF-β/BMP signaling pathway. In this work, we describe a novel mutation in exon 9 of ENG (c.1145 G > A) found in five affected members of a family, all of them with characteristic symptoms of HHT. This mutation involves Cys382 residue of the Endoglin protein (p.Cys382 > Tyr) in the zona pellucida (ZP) module of its extracellular region. This is a critical residue involved in a conserved intrachain disulphide bond and in the correct folding of the protein. In fact, transfection studies in human cells using Endoglin expression vectors demonstrated that the p.Cys382 > Tyr mutation results in a marked reduction in the levels of the Endoglin protein. These results demonstrate the pathogenic role for this variant in HHT1 and confirm the key function of Cys382 in Endoglin expression.","variants":[{"Name":"NM_001114753.3(ENG):c.1145G>A (p.Cys382Tyr)","Chromosome":"9","Start":"127820027","Stop":"127820027","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":421702,"rule_based_match":true,"evidence_text":"c.1145 G > A","llm_judgment":"PRESENT","evidence":"c.1145 G > A","abstract_start":635,"abstract_end":647}]}
{"pmid":"33811063","title":"A description of novel variants and review of phenotypic spectrum in","abstract":"Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in <i>UBA5</i>, a gene involved in a ubiquitin-like post-translational modification system called UFMylation. Here we report five children from four families with biallelic pathogenic variants in <i>UBA5</i> All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Affected individuals in all four families have compound heterozygous pathogenic variants in <i>UBA5</i> All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in <i>trans</i> with a second <i>UBA5</i> variant. One patient has the previously described c.562C > T (p. Arg188*) variant, two other unrelated patients have a novel missense variant, c.907T > C (p.Cys303Arg), and the two siblings have a novel missense variant, c.761T > C (p.Leu254Pro). Functional analyses demonstrate that both the p.Cys303Arg variant and the p.Leu254Pro variants result in a significant decrease in protein function. We also review the phenotypes and genotypes of all 15 previously reported families with biallelic <i>UBA5</i> variants, of which two families have presented with distinct phenotypes, and we describe evidence for some limited genotype-phenotype correlation. The overlap of motor and developmental phenotypes noted in our cohort and literature review adds to the increasing understanding of genetic syndromes with movement disorders-epilepsy.","variants":[{"Name":"NM_024818.6(UBA5):c.1111G>A (p.Ala371Thr)","Chromosome":"3","Start":"132675903","Stop":"132675903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260377,"rule_based_match":true,"evidence_text":"c.1111G > A (p.Ala371Thr)","llm_judgment":"PRESENT","evidence":"c.1111G > A (p.Ala371Thr)","abstract_start":642,"abstract_end":667},{"Name":"NM_024818.6(UBA5):c.907T>C (p.Cys303Arg)","Chromosome":"3","Start":"132675342","Stop":"132675342","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":513414,"rule_based_match":true,"evidence_text":"c.907T > C (p.Cys303Arg)","llm_judgment":"PRESENT","evidence":"c.907T > C (p.Cys303Arg)","abstract_start":861,"abstract_end":885},{"Name":"NM_024818.6(UBA5):c.761T>C (p.Leu254Pro)","Chromosome":"3","Start":"132672126","Stop":"132672126","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1036439,"rule_based_match":true,"evidence_text":"c.761T > C (p.Leu254Pro)","llm_judgment":"PRESENT","evidence":"c.761T > C (p.Leu254Pro)","abstract_start":939,"abstract_end":963}]}
{"pmid":"31404531","title":"Thiamine phosphokinase deficiency and mutation in TPK1 presenting as biotin responsive basal ganglia disease.","abstract":"The product of thiamine phosphokinase is the cofactor for many enzymes, including the dehydrogenases of pyruvate, 2-ketoglutarate and branched chain ketoacids. Its deficiency has recently been described in a small number of patients, some of whom had a Leigh syndrome phenotype. The patient who also had a Leigh phenotype was initially found to have a low concentration of biotin in plasma and massive urinary excretion of biotin. Despite treatment with biotin and thiamine, her disease was progressive. Mutations c.311delG and c.426G > C were found in the TPK1 gene.","variants":[{"Name":"NM_022445.4(TPK1):c.426G>C (p.Leu142Phe)","Chromosome":"7","Start":"144591498","Stop":"144591498","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":259853,"rule_based_match":true,"evidence_text":"c.426G > C","llm_judgment":"PRESENT","evidence":"c.426G > C","abstract_start":528,"abstract_end":538}]}
{"pmid":"25125611","title":"ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism.","abstract":"Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.","variants":[{"Name":"NM_004092.4(ECHS1):c.414+3G>C","Chromosome":"10","Start":"133369901","Stop":"133369901","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":185752,"rule_based_match":true,"evidence_text":"c.414+3G>C","llm_judgment":"PRESENT","evidence":"c.414+3G>C","abstract_start":819,"abstract_end":829},{"Name":"NM_004092.4(ECHS1):c.473C>A (p.Ala158Asp)","Chromosome":"10","Start":"133368964","Stop":"133368964","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":185751,"rule_based_match":true,"evidence_text":"c.473C > A (p.A158D)","llm_judgment":"PRESENT","evidence":"c.473C > A (p.A158D)","abstract_start":774,"abstract_end":794}]}
{"pmid":"16470590","title":"Functional analysis of splicing mutations and of an exon 2 polymorphic variant of SERPING1/C1NH.","abstract":"Several sequence changes have been reported in hereditary angioedema patients in intron 2 of the SERPING1/C1NH gene, but their consequences on splicing have not been determined. We examined in cell transfection assays the consequences at the mRNA level of splicing mutations affecting either the +3 or the +5 donor site positions, or the conserved canonical splicing signals of exon 2, using mutant C1 inhibitor minigene constructs. Both intron 2 mutations, c.51+3A>G and c.51+5G>A, resulted in marked exon 2 skipping in these assays, but also yielded a large fraction of normal transcripts. We show that the c.51+3A>G mutation cosegregates with low C1 inhibitor protein levels in one family. Moreover, the second base of exon 2 of the SERPING1/C1NH gene is the site of a polymorphic variant, which has been proposed as a modifier of disease severity. We found that the c.-21C allele at this position yields low but significant levels of exon 2 skipping in transfected Hep G2 or Hep 3B cells, suggesting that this allele may contribute, at the RNA level, to more severe forms of angioedema. Furthermore, we describe a previously not detected alternative splicing of exon 3, found in peripheral blood cell mRNA but not in the liver or in hepatoma cell lines and we show that, in cultured monocytes of a patient carrying the c.51+3A>G mutation, this alternative splicing is shifted from exon 3 exclusion to skipping of both exons 2 and 3. The latter finding suggests that mutations affecting splicing of exon 2 of the SERPING1/C1NH gene may have different consequences in monocytes versus other cell types.","variants":[{"Name":"NM_000062.3(SERPING1):c.51+3A>G","Chromosome":"11","Start":"57598324","Stop":"57598324","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1802406,"rule_based_match":true,"evidence_text":"c.51+3A>G","llm_judgment":"PRESENT","evidence":"c.51+3A>G","abstract_start":458,"abstract_end":467}]}
{"pmid":"24501277","title":"New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.","abstract":"Germline mutations in DNA polymerase ɛ (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays. POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.","variants":[{"Name":"NM_006231.4(POLE):c.1270C>G (p.Leu424Val)","Chromosome":"12","Start":"132673664","Stop":"132673664","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":48560,"rule_based_match":true,"evidence_text":"POLE c.1270C>G (p.Leu424Val)","llm_judgment":"PRESENT","evidence":"POLE c.1270C>G (p.Leu424Val)","abstract_start":192,"abstract_end":220},{"Name":"NM_002691.4(POLD1):c.1421T>C (p.Leu474Pro)","Chromosome":"19","Start":"50406444","Stop":"50406444","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":153734,"rule_based_match":true,"evidence_text":"POLD1 c.1421T>C (p.Leu474Pro)","llm_judgment":"PRESENT","evidence":"POLD1 c.1421T>C (p.Leu474Pro)","abstract_start":1062,"abstract_end":1091}]}
{"pmid":"19014451","title":"A novel HSF4 gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan.","abstract":"BACKGROUND: Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can also be inherited in an autosomal recessive or X-linked fashion. To date, 12 loci for autosomal recessive cataracts have been mapped including a locus on chromosome 16q22 containing the disease-causing gene HSF4 (Genbank accession number NM_001040667). Here, we describe a family from Pakistan with the first nonsense mutation in HSF4 thus expanding the mutational spectrum of this heat shock transcription factor gene.\nMETHODS: A large consanguineous Pakistani family with autosomal recessive cataracts was collected from Quetta. Genetic linkage analysis was performed for the common known autosomal recessive cataracts loci and linkage to a locus containing HSF4 (OMIM 602438) was found. All exons and adjacent splice sites of the heat shock transcription factor 4 gene (HSF4) were sequenced. A mutation-specific restriction enzyme digest (HphI) was performed for all family members and unrelated controls.\nRESULTS: The disease phenotype perfectly co-segregated with markers flanking the known cataract gene HSF4, whereas other autosomal recessive loci were excluded. A maximum two-point LOD score with a Zmax=5.6 at theta=0 was obtained for D16S421. Direct sequencing of HSF4 revealed the nucleotide exchange c.1213C>T in this family predicting an arginine to stop codon exchange (p.R405X).\nCONCLUSION: We identified the first nonsense mutation (p.R405X) in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract.","variants":[{"Name":"NM_001374675.1(HSF4):c.1213C>T (p.Arg405Ter)","Chromosome":"16","Start":"67169060","Stop":"67169060","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3535930,"rule_based_match":true,"evidence_text":"c.1213C>T","llm_judgment":"PRESENT","evidence":"c.1213C>T","abstract_start":1313,"abstract_end":1322}]}
{"pmid":"17132287","title":"A mild case of abetalipoproteinaemia in association with subclinical hypothyroidism.","abstract":"Abetalipoproteinaemia (ABL), an extremely rare recessive disorder, is characterized by exceptionally low or undetectable concentrations of apolipoprotein (apo) B-containing lipoproteins. ABL results from mutations in the gene encoding microsomal triglyceride transfer protein (MTP), a chaperone that facilitates the transfer of lipids onto apoB. Patients with ABL often present in childhood with a range of symptoms including fat malabsorption and manifestations of fat-soluble vitamin deficiencies. We describe a patient with sub-clinical hypothyroidism and ABL found to be compound heterozygous for a novel splice site mutation of intron 1 (c.61 + 2T > C) and a single adenine insertion in MTP exon 4 (c.419-420insA) that results in a frameshift and a protein truncated at 140 amino acids.","variants":[{"Name":"NM_001386140.1(MTTP):c.61+2T>C","Chromosome":"4","Start":"99574972","Stop":"99574972","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3536278,"rule_based_match":true,"evidence_text":"c.61 + 2T > C","llm_judgment":"PRESENT","evidence":"c.61 + 2T > C","abstract_start":643,"abstract_end":656}]}
{"pmid":"22995099","title":"Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation.","abstract":"Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM #607721) has been recently related to the invariant c.4A > G missense change in SHOC2. It is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated to growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We compare in two patients with molecularly confirmed NS/LAH diagnosis, the clinical phenotype and pathogenetic mechanism underlying short stature. In particular, while both the patients exhibited a severe short stature, GH/IGFI axis functional evaluation revealed a different pathogenetic alteration, suggesting in one patient an upstream alteration (typical GHD) and in the other one a peripheral GH insensitivity.","variants":[{"Name":"NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly)","Chromosome":"10","Start":"110964362","Stop":"110964362","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":21860,"rule_based_match":true,"evidence_text":"c.4A>G","llm_judgment":"PRESENT","evidence":"c.4A > G","abstract_start":110,"abstract_end":118}]}
{"pmid":"35280287","title":"Case Report: Thymidine Kinase 2 (TK2) Deficiency: A Novel Mutation Associated With Childhood-Onset Mitochondrial Myopathy and Atypical Progression.","abstract":"The nuclear gene <i>TK2</i> encodes the mitochondrial thymidine kinase, an enzyme involved in the phosphorylation of deoxycytidine and deoxythymidine nucleosides. Biallelic <i>TK2</i> mutations are associated with a spectrum of clinical presentations mainly affecting skeletal muscle and featuring muscle mitochondrial DNA (mtDNA) instability. Current classification includes infantile- ( ≤ 1 year), childhood- (1-12 years), and late-onset (≥12 years) forms. In addition to age at onset, these forms differ for progression, life expectancy, and signs of mtDNA instability (mtDNA depletion vs. accumulation of multiple mtDNA deletions). Childhood-onset TK2 deficiency typically causes a rapidly progressive proximal myopathy, which leads to wheelchair-bound status within 10 years of disease onset, and severe respiratory impairment. Muscle biopsy usually reveals a combination of mitochondrial myopathy and dystrophic features with reduced mtDNA content. Here we report the case of an Italian patient presenting childhood-onset, slowly progressive mitochondrial myopathy, ptosis, hypoacusis, dysphonia, and dysphagia, harboring the <i>TK2</i> variants c.278A>G and c.543del, the latter unreported so far. Compared to other childhood-onset <i>TK2</i>-patients, our case displays atypical features, including slowly progressive muscle weakness and absence of respiratory failure, which are usually observed in late-onset forms. This report extends the genetic background of TK2-related myopathy, highlighting the clinical overlap among different forms.","variants":[{"Name":"NM_004614.5(TK2):c.278A>G (p.Asn93Ser)","Chromosome":"16","Start":"66536971","Stop":"66536971","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":47586,"rule_based_match":true,"evidence_text":"c.278A>G","llm_judgment":"PRESENT","evidence":"c.278A>G","abstract_start":1152,"abstract_end":1160}]}
{"pmid":"29720200","title":"Splice-site mutation causing partial retention of intron in the FLCN gene in Birt-Hogg-Dubé syndrome: a case report.","abstract":"BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). Nearly 150 pathogenic mutations have been identified in FLCN. The most frequent pattern is a frameshift mutation within a coding exon. In addition, splice-site mutations have been reported, and previous studies have confirmed exon skipping in several cases. However, it is poorly understood whether there are any splice-site mutations that cause translation of intron regions in FLCN.\nCASE PRESENTATION: A 59-year-old Japanese patient with multiple pulmonary cysts and pneumothorax was hospitalized due to dyspnea. BHD was suspected and genetic testing was performed. The patient exhibited the splice-site mutation of FLCN in the 5' end of intron 9 (c.1062 + 1G > A). Total mRNA was extracted from pulmonary cysts, and RT-PCR assessment and sequence analyses were done. Two distinct bands were generated; one was wild-type and the other was a larger-sized mutant. Sequence analysis of the latter transcript revealed the insertion of 130 base pairs of intron 9 from the beginning of the splice-site between exons 9 and 10.\nCONCLUSION: To our knowledge, this is the first report of distinct intron insertion using a BHD patient's diseased tissue-derived mRNA. The present case suggests that a splice-site mutation can lead to exon skipping as well as intron reading mRNA. The splicing process may be dependent in part on whether the donor or acceptor site is affected.","variants":[{"Name":"NM_144997.7(FLCN):c.1062+1G>A","Chromosome":"17","Start":"17219018","Stop":"17219018","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":420616,"rule_based_match":true,"evidence_text":"c.1062 + 1G > A","llm_judgment":"PRESENT","evidence":"c.1062 + 1G > A","abstract_start":786,"abstract_end":801}]}
{"pmid":"28236508","title":"Phenotypical features of a new dominant GDAP1 pathogenic variant (p.R226del) in axonal Charcot-Marie-Tooth disease.","abstract":"There are few reports on axonal CMT due to dominant GDAP1 mutations. We describe two unrelated Spanish families with a dominant axonal CMT. A novel in frame GAA deletion in exon 5 of the GDAP1 gene (c.677_679del; p.R226del) was identified in both families. Disease onset varied from early childhood to adulthood. Affected family members complained of distal lower limb weakness, cramps and foot deformities with variable CMTNS score in both families. Several individuals were asymptomatic or had paraesthesia only, however neurological examination and nerve conduction studies demonstrated neuropathic signs. Transfection of HeLa cells with the p.R226del mutation led to an increased mitochondrial aggregation. We report an AD-CMT2K with large phenotypic variability due to a novel dominant GDAP1 variant. This is the second founder GDAP1 pathogenic variant reported in Spain.","variants":[{"Name":"NM_018972.4(GDAP1):c.674GAA[1] (p.Arg226del)","Chromosome":"8","Start":"74363031","Stop":"74363033","ReferenceAlleleVCF":"AAAG","AlternateAlleleVCF":"A","allel_id":790815,"rule_based_match":false,"evidence_text":"c.677_679del; p.R226del","llm_judgment":"PRESENT","evidence":"c.677_679del; p.R226del","abstract_start":199,"abstract_end":222}]}
{"pmid":"31858365","title":"Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency.","abstract":"BACKGROUND: Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)-like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition.\nMETHODS: A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA.\nRESULTS: Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4<sup>+</sup> T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy.\nCONCLUSIONS: ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.","variants":[{"Name":"NM_012092.4(ICOS):c.356T>C (p.Phe119Ser)","Chromosome":"2","Start":"203955933","Stop":"203955933","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":815894,"rule_based_match":true,"evidence_text":"c.356T>C","llm_judgment":"PRESENT","evidence":"c.356T>C","abstract_start":1035,"abstract_end":1043}]}
{"pmid":"28669926","title":"Identification of four novel XPC mutations in two xeroderma pigmentosum complementation group C patients and functional study of XPC Q320X mutant.","abstract":"Xeroderma pigmentosum (XP) is a rare, recessive hereditary disease characterized by sunlight hypersensitivity and high incidence of skin cancer with clinical and genetic heterogeneity. We collected two unrelated Chinese patients showing typical symptoms of XPC without neurologic symptoms. Direct sequencing of XPC gene revealed that patient 1 carried IVS1+1G>A and c.958 C>T mutations, and patient 2 carried c.545_546delTA and c.2257_2258insC mutations. All these four mutations introduced premature terminal codons (PTCs) in XPC gene. The nonsense mutation c.958 C>T yielded truncated mutant Q320X, and we studied its function for global genome repair kinetics. Overexpressed Q320X mutant can localize to site of DNA damage, but it is defective in CPD and 6-4PP repair. Readthrough of PTCs is a new approach to treatment of genetic diseases. We found that aminoglycosides could significantly increase the full length protein expression of Q320X mutant, but NER defects were not rescued in vitro.","variants":[{"Name":"NM_004628.5(XPC):c.958C>T (p.Gln320Ter)","Chromosome":"3","Start":"14159773","Stop":"14159773","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":543064,"rule_based_match":true,"evidence_text":"c.958 C>T","llm_judgment":"PRESENT","evidence":"c.958 C>T","abstract_start":366,"abstract_end":375}]}
{"pmid":"31838784","title":"Novel mutation in optineurin causing aggressive ALS+/-frontotemporal dementia.","abstract":"OBJECTIVE: Mutations in optineurin (OPTN) have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). We screened a cohort of Chinese patients for mutations in optineurin. We also performed an extensive literatures review of all mutations in optineurin identified previously to detect genotype-phenotype associations.\nMETHODS: All 16 exons of the OPTN gene in a cohort of 15 familial ALS indexes and 275 sporadic ALS patients of Chinese origin were sequenced by targeted next generation sequencing.\nRESULTS: Two known heterozygous missense mutations in the OPTN, c.1481T> G (p.L494W), and c.1546G> C (p.E516Q), as well as one novel heterozygous missense mutation c.1690G> C (p.D564H) were each detected in one sporadic ALS patient. The patient carrying the p.E516Q mutation developed clinical features of ALS-frontotemporal dementia (FTD) and the patient carrying the p.D564H mutation showed a phenotype of ALS. They both had an aggressive course, with a survival of 18 and 14 months respectively. Literature review showed that the clinical phenotypes in OPTN mutated ALS were not homogeneous, although some individuals showed a relatively slow progression and a long duration, some mutations carriers developed an aggressive progression and a short survival.\nINTERPRETATION: OPTN mutations contribute to ALS in Chinese population and account for 0.8% of sporadic ALS patients and 1.5% of familial ALS in the pooled Chinese ALS cohorts. Mutations in optineurin can cause aggressive ALS+/-FTD.","variants":[{"Name":"NM_001008212.2(OPTN):c.1546G>C (p.Glu516Gln)","Chromosome":"10","Start":"13133515","Stop":"13133515","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":980496,"rule_based_match":true,"evidence_text":"c.1546G> C (p.E516Q)","llm_judgment":"PRESENT","evidence":"c.1546G> C (p.E516Q)","abstract_start":612,"abstract_end":632}]}
{"pmid":"35861300","title":"Expanding the phenotype of DNAJC30-associated Leigh syndrome.","abstract":"Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30-associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9-year-old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9-year-old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement.","variants":[{"Name":"NM_032317.3(DNAJC30):c.152A>G (p.Tyr51Cys)","Chromosome":"7","Start":"73683272","Stop":"73683272","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":964835,"rule_based_match":true,"evidence_text":"c.152A>G, p.(Tyr51Cys)","llm_judgment":"PRESENT","evidence":"c.152A>G, p.(Tyr51Cys)","abstract_start":698,"abstract_end":720},{"Name":"NM_032317.3(DNAJC30):c.130_131del (p.Ser44fs)","Chromosome":"7","Start":"73683293","Stop":"73683294","ReferenceAlleleVCF":"CGA","AlternateAlleleVCF":"C","allel_id":2795519,"rule_based_match":true,"evidence_text":"c.130_131del, p.(Ser44ValfsTer8)","llm_judgment":"PRESENT","evidence":"c.130_131del, p.(Ser44ValfsTer8)","abstract_start":824,"abstract_end":856}]}
{"pmid":"38514665","title":"Identification of a novel LDLR p.Glu179Met variant in Thai families with familial hypercholesterolemia and response to treatment with PCSK9 inhibitor.","abstract":"Familial hypercholesterolemia (FH) is a genetic disease characterized by elevated LDL-C levels. In this study, two FH probands and 9 family members from two families from northeastern Thailand were tested for LDLR, APOB, and PCSK9 variants by whole-exome sequencing, PCR-HRM, and Sanger sequencing. In silico analysis of LDLR was performed to analyse its structure‒function relationship. A novel variant of LDLR (c.535_536delinsAT, p.Glu179Met) was detected in proband 1 and proband 2 in homozygous and heterozygous forms, respectively. A total of 6 of 9 family members were heterozygous for LDLR p.Glu179Met variant. Compared with proband 2, proband 1 had higher baseline TC and LDL-C levels and a poorer response to lipid-lowering therapy combined with a PCSK9 inhibitor. Multiple sequence alignment showed that LDLR p.Glu179Met was located in a fully conserved region. Homology modelling demonstrated that LDLR p.Glu179Met variant lost one H-bond and a negative charge. In conclusion, a novel LDLR p.Glu179Met variant was identified for the first time in Thai FH patients. This was also the first report of homozygous FH patient in Thailand. Our findings may expand the knowledge of FH-causing variants in Thai population, which is beneficial for cascade screening, genetic counselling, and FH management to prevent coronary artery disease.","variants":[{"Name":"NM_000527.5(LDLR):c.535_536delinsAT (p.Glu179Met)","Chromosome":"19","Start":"11105441","Stop":"11105442","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"AT","allel_id":2839822,"rule_based_match":true,"evidence_text":"c.535_536delinsAT, p.Glu179Met","llm_judgment":"PRESENT","evidence":"c.535_536delinsAT, p.Glu179Met","abstract_start":413,"abstract_end":443}]}
{"pmid":"34513758","title":"Case Report: A Pediatric Case of Lipoprotein Glomerulopathy in China and Literature Review.","abstract":"<b>Background:</b> Lipoprotein glomerulopathy is a rare kidney disease characterized by lipoprotein thrombi in the glomerulus. Here, we report a case of lipoprotein glomerulopathy in a Chinese pediatric patient. Furthermore, we summarized the clinical features and genetic characteristics of lipoprotein glomerulopathy in China. <b>Case Presentation:</b> An 11-year-old Chinese girl presented with nephrotic syndrome with anemia (98 g/L). After excluding secondary causes, primary nephrotic syndrome was considered. Treatment with prednisone (60 mg/day) did not improve her condition. Renal biopsy showed marked dilation of the capillary lumen with lipoprotein thrombi and positive oil red O staining. Genetic testing revealed the genetic variant c.127C > T (p.R43C), known as the Kyoto mutation of the APOE gene. These findings are consistent with the diagnosis of lipoprotein glomerulopathy. Prednisone was gradually tapered and captopril was initiated. A 2-year follow-up revealed elevated urine protein and serum creatinine levels. We also reviewed 17 pediatric and 156 adult cases of lipoprotein glomerulopathy reported in China from the year of creation to 2021. The most common clinical features were edema, hematuria, hypertriglyceridemia, and increased serum apoE levels. Extra-renal manifestations included anemia, splenomegaly, and cardiac lipoprotein deposition. <b>Conclusion:</b> APOE Kyoto is the most common mutation in patients with lipoprotein glomerulopathy. In China, homozygosity for E3 (E3/3) is the most common isoform.","variants":[{"Name":"NM_000041.4(APOE):c.127C>T (p.Arg43Cys)","Chromosome":"19","Start":"44907843","Stop":"44907843","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32919,"rule_based_match":true,"evidence_text":"c.127C > T (p.R43C)","llm_judgment":"PRESENT","evidence":"c.127C > T (p.R43C)","abstract_start":747,"abstract_end":766}]}
{"pmid":"34218547","title":"Mild phenotype in two siblings with a missense GHR variant.","abstract":"OBJECTIVES:  Laron syndrome (LS) is a disease caused by growth hormone receptor (GHR) defects. It is characterized by severe postnatal growth retardation and distinctive facial features.\nCASE PRESENTATION: In this case report, we describe the clinical and biochemical characteristics of two siblings with LS, a sister and a brother, and identify a homozygous c.344A> C (p.Asn115Thr) variant in GHR. The sister was 11 years 9 months old with a height of 127.5 cm (-3.86 SDS), and the brother was 14 years 10 months old with a height of 139 cm (-4.27 SDS). Their phenotype did not have features suggesting classical LS.\nCONCLUSION: In the current literature, there are three cases with the same missense variant. Our cases differ from them in clinical (higher height SDS, mild dysmorphism including a broad forehead, malar hypoplasia, prominent columella and chin, thick lips) and biochemical characteristics. Here, we present the variable expressivity in the two siblings.","variants":[{"Name":"NM_000163.5(GHR):c.344A>C (p.Asn115Thr)","Chromosome":"5","Start":"42694994","Stop":"42694994","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":798561,"rule_based_match":true,"evidence_text":"c.344A> C (p.Asn115Thr)","llm_judgment":"PRESENT","evidence":"c.344A> C (p.Asn115Thr)","abstract_start":359,"abstract_end":382}]}
{"pmid":"37091781","title":"Genetic variations in the","abstract":"<b>Background and aims:</b> Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) represents a type of severe fetal skeletal dysplasia (SD) characterized by shortened limbs, narrow thorax with or without polydactyly, which is caused by the homozygous or compound heterozygous mutations in the <i>DYNC2H1</i> gene. SRTD3 is a recessive disorder, identification of the responsible genetic variation would be beneficial to an accurate prenatal diagnosis and well-grounded counseling for the affected families. <b>Material and methods:</b> Two families having experienced recurrent fetal SDs were recruited and submitted to a multiplatform genetic investigation. Whole-exome sequencing (WES) was performed with samples collected from the probands. Sanger sequencing and fluorescent quantitative PCR (qPCR) were conducted as validation assays for suspected variations. <b>Results:</b> WES identified two compound heterozygous variations in the <i>DYNC</i>2H1(NM_001080463.2) gene, namely c.2386C>T (p.Arg796Trp) and c.7289T>C (p.Ile2430Thr) for one; and exon (64-83)del and c.8190G>T (p.Leu2730Phe) for the other, respectively. One variant in them, exon (64-83)del, was novelly identified. <b>Conclusion:</b> The study detected two compound heterozygous variation in <i>DYNC2H1</i> including one novel deletion: exon (64-83) del. Our findings clarified the cause of fetal skeletal dysplasia in the subject families, provided guidance for their future pregnancies, and highlighted the value of WES in diagnosis of skeletal dysplasia with unclear prenatal indications.","variants":[{"Name":"NM_001377.3(DYNC2H1):c.8190G>T (p.Leu2730Phe)","Chromosome":"11","Start":"103200147","Stop":"103200147","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":798631,"rule_based_match":true,"evidence_text":"c.8190G>T (p.Leu2730Phe)","llm_judgment":"PRESENT","evidence":"c.8190G>T (p.Leu2730Phe)","abstract_start":1082,"abstract_end":1106}]}
{"pmid":"29620684","title":"Neutropenia and Increased Mean Corpuscular Volume (MCV) With Abnormal Neurologic Findings: A Case of Cobalamin D Deficiency.","abstract":"BACKGROUND: Disorders of intracellular cobalamin (Cbl) metabolism are classified from A to J according to biochemical phenotype, and genetic and complementation analyses. CblD-deficient patients present with developmental, hematologic, neurologic, and metabolic findings.\nCLINICAL OBSERVATION: An 11-year-old boy presented with neutropenia, increased mean corpuscular volume, psychomotor retardation, and seizures. His plasma total homocysteine and urinary methylmalonic acid levels were elevated, and a homozygous nonsense mutation [p. R250X (c.748C>T] leading to premature termination of translation was identified in the MMADHC gene, which was compatible with CblD defect.\nCONCLUSION: In the presence of increased mean corpuscular volume and other hematologic manifestations, such as leukopenia, thrombocytopenia, and megaloblastic anemia, with severe nonspecific or mild neurologic symptoms, Cbl synthesis defects should be considered.","variants":[{"Name":"NM_015702.3(MMADHC):c.748C>T (p.Arg250Ter)","Chromosome":"2","Start":"149570117","Stop":"149570117","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15806,"rule_based_match":true,"evidence_text":"c.748C>T","llm_judgment":"PRESENT","evidence":"c.748C>T","abstract_start":544,"abstract_end":552}]}
{"pmid":"34652576","title":"TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.","abstract":"Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.","variants":[{"Name":"NM_006086.4(TUBB3):c.785G>A (p.Arg262His)","Chromosome":"16","Start":"89935236","Stop":"89935236","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":217280,"rule_based_match":true,"evidence_text":"NM_006086.4 (TUBB3):c.785G>A (p.Arg262His)","llm_judgment":"PRESENT","evidence":"NM_006086.4 (TUBB3):c.785G>A (p.Arg262His)","abstract_start":585,"abstract_end":627}]}
{"pmid":"34528292","title":"Identification of a compound heterozygous missense mutation in LAMA2 gene from a patient with merosin-deficient congenital muscular dystrophy type 1A.","abstract":"BACKGROUND: Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is occurred by mutations in LAMA2 gene that encodes the laminin α2 chain (merosin). MDC1A is a predominant subtype of congenital muscular dystrophy. Herein, we identified two missense mutations in LAMA2 gene in compound heterozygous status in an Iranian patient with MDC1A using whole-exome sequencing (WES).\nMETHODS: In the present study, we evaluated genetic alterations in an Iranian 35-month-old boy with MDC1A and his healthy family using WES method. The identified mutations further confirmed by Sanger sequencing method. Finally, in silico analysis was conducted to further evaluation of molecular function of the identified genetic variants.\nRESULTS: We identified two potentially pathogenic missense mutations in compound heterozygous state (c.7681G>A p.Gly2561Ser and c.4840A>G p.Asn1614Asp) in LAMA2 gene as contributing to the MDC1A phenotype. The healthy parents of our proband are single heterozygous for identified mutations. These variants were found to be pathogenic by in silico analysis.\nCONCLUSIONS: In general, we successfully identified LAMA2 gene mutations in an Iranian patient with MDC1A using WES. The identified mutations in LAMA2 gene can be useful in genetic counseling, prenatal diagnosis, and predicting prognosis of MDC1A.","variants":[{"Name":"NM_000426.4(LAMA2):c.4840A>G (p.Asn1614Asp)","Chromosome":"6","Start":"129366341","Stop":"129366341","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1410741,"rule_based_match":true,"evidence_text":"c.4840A>G p.Asn1614Asp","llm_judgment":"PRESENT","evidence":"c.4840A>G p.Asn1614Asp","abstract_start":854,"abstract_end":876},{"Name":"NM_000426.4(LAMA2):c.7681G>A (p.Gly2561Ser)","Chromosome":"6","Start":"129481371","Stop":"129481371","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":634606,"rule_based_match":true,"evidence_text":"c.7681G>A p.Gly2561Ser","llm_judgment":"PRESENT","evidence":"c.7681G>A p.Gly2561Ser","abstract_start":827,"abstract_end":849}]}
{"pmid":"28747464","title":"Lethal digenic mutations in the K","abstract":"A 2-yr-old boy presented profound developmental delay, failure to thrive, ataxia, hypotonia, and tonic-clonic seizures that caused the death of the patient. Targeted and whole exome sequencing revealed two heterozygous missense variants: a novel mutation in the <i>KCNJ10</i> gene that encodes for the inward-rectifying K<sup>+</sup> channel Kir4.1 and another previously characterized mutation in <i>KCNT1</i> that encodes for the Na<sup>+</sup>-activated K<sup>+</sup> channel known as Slo2.2 or SLACK. The objectives of this study were to perform the clinical and genetic characterization of the proband and his family and to examine the functional consequence of the Kir4.1 mutation. The mutant and wild-type <i>KCNJ10</i> constructs were generated and heterologously expressed in <i>Xenopus laevis</i> oocytes, and whole cell K<sup>+</sup> currents were measured using the two-electrode voltage-clamp technique. The <i>KCNJ10</i> mutation c.652C>T resulted in a p.L218F substitution at a highly conserved residue site. Wild-type <i>KCNJ10</i> expression yielded robust Kir current, whereas currents from oocytes expressing the mutation were reduced, remarkably. Western Blot analysis revealed reduced protein expression by the mutation. Kir5.1 subunits display selective heteromultimerization with Kir4.1 constituting channels with unique kinetics. The effect of the mutation on Kir4.1/5.1 channel activity was twofold: a reduction in current amplitudes and an increase in the pH-dependent inhibition. We thus report a novel loss-of-function mutation in Kir4.1 found in a patient with a coexisting mutation in SLACK channels that results in a fatal disease.<b>NEW & NOTEWORTHY</b> We present and characterize a novel mutation in <i>KCNJ10</i> Unlike previously reported EAST/SeSAME patients, our patient was heterozygous, and contrary to previous studies, mimicking the heterozygous state by coexpression resulted in loss of channel function. We report in the same patient co-occurrence of a <i>KCNT1</i> mutation resulting in a more severe phenotype. This study provides new insights into the phenotypic spectrum and to the genotype-phenotype correlations associated with EAST/SeSAME and MMFSI.","variants":[{"Name":"NM_002241.5(KCNJ10):c.652C>T (p.Leu218Phe)","Chromosome":"1","Start":"160041881","Stop":"160041881","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":201055,"rule_based_match":true,"evidence_text":"c.652C>T","llm_judgment":"PRESENT","evidence":"c.652C>T","abstract_start":944,"abstract_end":952}]}
{"pmid":"33375403","title":"The Effect of Synonymous Single-Nucleotide Polymorphisms on an Atypical Cystic Fibrosis Clinical Presentation.","abstract":"Synonymous single nucleotide polymorphisms (sSNPs), which change a nucleotide, but not the encoded amino acid, are perceived as neutral to protein function and thus, classified as benign. We report a patient who was diagnosed with cystic fibrosis (CF) at an advanced age and presented very mild CF symptoms. The sequencing of the whole cystic fibrosis transmembrane conductance regulator (<i>CFTR</i>) gene locus revealed that the patient lacks known CF-causing mutations. We found a homozygous sSNP (c.1584G>A) at the end of exon 11 in the <i>CFTR</i> gene. Using sensitive molecular methods, we report that the c.1584G>A sSNP causes cognate exon skipping and retention of a sequence from the downstream intron, both of which, however, occur at a relatively low frequency. In addition, we found two other sSNPs (c.2562T>G (p.Thr854=) and c.4389G>A (p.Gln1463=)), for which the patient is also homozygous. These two sSNPs stabilize the CFTR protein expression, compensating, at least in part, for the c.1584G>A-triggered inefficient splicing. Our data highlight the importance of considering sSNPs when assessing the effect(s) of complex CFTR alleles. sSNPs may epistatically modulate mRNA and protein expression levels and consequently influence disease phenotype and progression.","variants":[{"Name":"NM_000492.4(CFTR):c.1584G>A (p.Glu528=)","Chromosome":"7","Start":"117559655","Stop":"117559655","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":52745,"rule_based_match":true,"evidence_text":"c.1584G>A","llm_judgment":"PRESENT","evidence":"c.1584G>A","abstract_start":501,"abstract_end":510}]}
{"pmid":"23731542","title":"Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis.","abstract":"Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.","variants":[{"Name":"NM_000435.3(NOTCH3):c.4556T>C (p.Leu1519Pro)","Chromosome":"19","Start":"15174248","Stop":"15174248","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":70504,"rule_based_match":true,"evidence_text":"c.4556T>C (p.Leu1519Pro)","llm_judgment":"PRESENT","evidence":"c.4556T>C (p.Leu1519Pro)","abstract_start":777,"abstract_end":801},{"Name":"NM_002609.4(PDGFRB):c.1681C>T (p.Arg561Cys)","Chromosome":"5","Start":"150125571","Stop":"150125571","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70502,"rule_based_match":true,"evidence_text":"c.1681C>T (p.Arg561Cys)","llm_judgment":"PRESENT","evidence":"c.1681C>T (p.Arg561Cys)","abstract_start":635,"abstract_end":658},{"Name":"NM_002609.4(PDGFRB):c.1978C>A (p.Pro660Thr)","Chromosome":"5","Start":"150124295","Stop":"150124295","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":70503,"rule_based_match":true,"evidence_text":"c.1978C>A (p.Pro660Thr)","llm_judgment":"PRESENT","evidence":"c.1978C>A (p.Pro660Thr)","abstract_start":607,"abstract_end":630}]}
{"pmid":"33966551","title":"Molecular Spectrum of β-Thalassemia Mutations in Central to Eastern Thailand.","abstract":"The aim of this study was to determine the molecular spectrum of β-thalassemia (β-thal) mutations in eastern Thailand. We identified β-thal mutations using allele specific-polymerase chain reaction (ASPCR) and direct DNA sequencing. We found 18 different β-thal mutations in a total of 191 unrelated subjects. Six common β-thal mutations comprised 86.91% of all the mutations, including codons 41/42 (-TTCT) (<i>HBB</i>: c.126_129delCTTT) (35.60%), codon 17 (A>T) (<i>HBB</i>: c.52A>T) (18.85%), -28 (A>G) (<i>HBB</i>: c.-78A>G) (15.71%), IVS-II-654 (C>T) (<i>HBB</i>: c.316-197C>T) (6.28%), IVS-I-1 (G>T) (<i>HBB</i>: c.92+1G>T) (5.76%) and codon 19 (A>G) (<i>HBB</i>:(c.59A>G) (4.71%). In addition, a novel 60 kb deletion in two unrelated cases was characterized and initially suspected to originate from eastern Thailand. Moreover, we demonstrated the molecular spectrum of recent β-thal mutations in Thailand, and data from this study were compared with five reference laboratory centers in Thailand. This study is the first to identify the comprehensive molecular spectrum of β-thal mutations in eastern Thailand, information that may be essential for screening, genetic counseling and prenatal diagnosis (PND) in this region.","variants":[{"Name":"NM_000518.5(HBB):c.59A>G (p.Asn20Ser)","Chromosome":"11","Start":"5226963","Stop":"5226963","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":30297,"rule_based_match":true,"evidence_text":"(c.59A>G)","llm_judgment":"PRESENT","evidence":"(c.59A>G)","abstract_start":669,"abstract_end":678}]}
{"pmid":"21941004","title":"Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.","abstract":"OBJECTIVE: To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer.\nDESIGN: A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing.\nRESULTS: Of the 53 UM patients studied, a single patient was identified with a germline BAP1 truncating mutation, c. 799 C→T (p.Q267X), which segregated in several family members and was associated with UM and other cancers. Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation. Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients.\nCONCLUSION: This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers. The results indicate that BAP1 is the candidate gene in only a small subset of hereditary UM, suggesting the contribution of other candidate genes.","variants":[{"Name":"NM_004656.4(BAP1):c.799C>T (p.Gln267Ter)","Chromosome":"3","Start":"52405897","Stop":"52405897","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39261,"rule_based_match":false,"evidence_text":"c. 799 C→T (p.Q267X)","llm_judgment":"PRESENT","evidence":"c. 799 C→T (p.Q267X)","abstract_start":504,"abstract_end":524}]}
{"pmid":"25534848","title":"A complement C5 gene mutation, c.754G>A:p.A252T, is common in the Western Cape, South Africa and found to be homozygous in seven percent of Black African meningococcal disease cases.","abstract":"Patients with genetically determined deficiency of complement component 5 are usually diagnosed because of recurrent invasive Neisseria meningitidis infections. Approximately 40 individual cases have been diagnosed worldwide. Nevertheless, reports of the responsible genetic defects have been sporadic, and we know of no previous reports of C5 deficiency being associated with a number of independent meningococcal disease cases in particular communities. Here we describe C5 deficiency in seven unrelated Western Cape, South African families. Three different C5 mutations c.55C>T:p.Q19X, c.754G>A:p.A252T and c.4426C>T:p.R1476X were diagnosed in index cases from two families who had both presented with recurrent meningococcal disease. p.Q19X and p.R1476X have already been described in North American Black families and more recently p.Q19X in a Saudi family. However, p.A252T was only reported in SNP databases and was not associated with disease until the present study was undertaken in the Western Cape, South Africa. We tested for p.A252T in 140 patients presenting with meningococcal disease in the Cape Town area, and found seven individuals in five families who were homozygous for the mutation p.A252T. Very low serum C5 protein levels (0.1-4%) and correspondingly low in vitro functional activity were found in all homozygous individuals. Allele frequencies of p.A252T in the Black African and Cape Coloured communities were 3% and 0.66% and estimated homozygosities are 1/1100 and 1/22,500 respectively. In 2012 we reported association between p.A252T and meningococcal disease. Molecular modelling of p.A252T has indicated an area of molecular stress in the C5 molecule which may provide a mechanism for the very low level in the circulation. This report includes seven affected families indicating that C5D is not rare in South Africa.","variants":[{"Name":"NM_001735.3(C5):c.55C>T (p.Gln19Ter)","Chromosome":"9","Start":"121050192","Stop":"121050192","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32089,"rule_based_match":true,"evidence_text":"c.55C>T:p.Q19X","llm_judgment":"PRESENT","evidence":"c.55C>T:p.Q19X","abstract_start":573,"abstract_end":587},{"Name":"NM_001735.3(C5):c.754G>A (p.Ala252Thr)","Chromosome":"9","Start":"121030401","Stop":"121030401","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":993109,"rule_based_match":true,"evidence_text":"c.754G>A:p.A252T","llm_judgment":"PRESENT","evidence":"c.754G>A:p.A252T","abstract_start":589,"abstract_end":605}]}
{"pmid":"25546334","title":"Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype.","abstract":"Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.1738C>T (p.Arg580Ter)","Chromosome":"12","Start":"21222355","Stop":"21222355","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39394,"rule_based_match":true,"evidence_text":"c.1738C>T","llm_judgment":"PRESENT","evidence":"c.1738C>T","abstract_start":628,"abstract_end":637}]}
{"pmid":"31821646","title":"The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype.","abstract":"RHOA is a member of the Rho family of GTPases that are involved in fundamental cellular processes including cell adhesion, migration, and proliferation. RHOA can stimulate the formation of stress fibers and focal adhesions and is a key regulator of actomyosin dynamics in various tissues. In a Genematcher-facilitated collaboration, we were able to identify four unrelated individuals with a specific phenotype characterized by hypopigmented areas of the skin, dental anomalies, body asymmetry, and limb length discrepancy due to hemihypotrophy of one half of the body, as well as brain magnetic resonance imaging (MRI) anomalies. Using whole-exome and ultra-deep amplicon sequencing and comparing genomic data of affected and unaffected areas of the skin, we discovered that all four individuals carried the identical RHOA missense variant, c.139G>A; p.Glu47Lys, in a postzygotic state. Molecular modeling and in silico analysis of the affected p.Glu47Lys residue in RHOA indicated that this exchange is predicted to specifically alter the interaction of RHOA with its downstream effectors containing a PKN-type binding domain and thereby disrupts its ability to activate signaling. Our findings indicate that the recurrent postzygotic RHOA missense variant p.Glu47Lys causes a specific mosaic disorder in humans.","variants":[{"Name":"NM_001664.4(RHOA):c.139G>A (p.Glu47Lys)","Chromosome":"3","Start":"49375451","Stop":"49375451","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":683186,"rule_based_match":true,"evidence_text":"c.139G>A; p.Glu47Lys","llm_judgment":"PRESENT","evidence":"c.139G>A; p.Glu47Lys","abstract_start":842,"abstract_end":862}]}
{"pmid":"31575858","title":"ABCC9-related Intellectual disability Myopathy Syndrome is a K","abstract":"Mutations in genes encoding K<sub>ATP</sub> channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of K<sub>ATP</sub> channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional K<sub>ATP</sub> channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing K<sub>ATP</sub> channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of K<sub>ATP</sub> loss- versus gain-of-function.","variants":[{"Name":"NM_020297.4(ABCC9):c.1320+1G>A","Chromosome":"12","Start":"21910156","Stop":"21910156","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":258727,"rule_based_match":true,"evidence_text":"c.1320+1G>A","llm_judgment":"PRESENT","evidence":"c.1320+1G>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"28854412","title":"Wide-spread cone-shaped epiphyses in two Saudi siblings with Ellis-van Creveld syndrome.","abstract":"INTRODUCTION: Ellis-van Creveld (EVC) syndrome is one of the rarest ciliopathy syndromes. It is caused by mutations of the EVC and EVC2 genes which encode the EVC proteins present in the basal body of the primary cilium.\nPRESENTATION OF CASES: We report on a Saudi family with two affected children. Gene analysis revealed a homozygous c.2T >A in exon 1 of the EVC gene. The most interesting finding in our patients was the wide - spread cone-shaped epiphyses in the hands and feet.\nDISCUSSION: Although cone-shaped epiphyses is a known feature of EVC syndrome, it usually limited to the middle or proximal phalanges. The wide-spread cone-shaped epiphyses seen in our patients have not been previously reported.\nCONCLUSION: EVC syndrome is very rare in the Middle East. We report on the first Saudi family with EVC syndrome confirmed by gene analysis. The most unique finding in our patients was the wide-spread cone-shaped epiphyses in the hands and feet. The abnormality is probably related to abnormal Indian hedgehog signaling in the primary cilium.","variants":[{"Name":"NM_153717.3(EVC):c.2T>A (p.Met1Lys)","Chromosome":"4","Start":"5711382","Stop":"5711382","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":543534,"rule_based_match":true,"evidence_text":"c.2T >A","llm_judgment":"PRESENT","evidence":"c.2T >A","abstract_start":336,"abstract_end":343}]}
{"pmid":"15300850","title":"TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA.","abstract":"Human malignant infantile osteopetrosis (arOP) is a genetically heterogeneous autosomal recessive disorder of bone metabolism. The TCIRG1 gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, is responsible for more than one-half of the arOP patients. We performed genetic analysis of TCIRG1 in 55 arOP patients including 25 new cases and identified nine novel mutations. The two most frequent mutations, c.1674-1G>A (aberrant splicing: r.1674_1884del) and c.2005C>T (protein variation: p.Arg669X), found in 17 and 16 alleles, respectively, constituted 30% of all TCIRG1 abnormalities. They both originated in Northern Europe, p.Arg669X quite recently from West Flanders, Belgium. As substitutions in splicing regulatory sequences represented a large portion (40%; 44 alleles) of the TCIRG1 variations, we developed a functional splicing assay to distinguish between polymorphic variants and disease-causing mutations. Three intronic nucleotide substitutions flanking the splice sites (c.117+4A>T; c.1673+5G>A; and c.504-8G>A) were studied using hybrid minigenes and an abnormal processing of the transcripts was demonstrated in all cases. Cotransfection experiments with complementary U1 snRNAs performed in c.117+4A>T and c.1673+5G>A mutations showed that only in the first case was the defect at the 5' splice site corrected, indicating that mutations near the invariant GT donor sites are mechanistically different. These findings indicate the feasibility of the hybrid minigene approach to detect splicing defects, particularly in patients in whom the RNA is not available. In addition, the present results suggest that modified U1 snRNAs may represent a new therapeutic strategy for arOP patients with a U1 snRNP-dependent splicing defect.","variants":[{"Name":"NM_006019.4(TCIRG1):c.1674-1G>A","Chromosome":"11","Start":"68049080","Stop":"68049080","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187118,"rule_based_match":true,"evidence_text":"c.1674-1G>A","llm_judgment":"PRESENT","evidence":"c.1674-1G>A","abstract_start":477,"abstract_end":488}]}
{"pmid":"22315194","title":"Phenotypic variability in hyperphosphatasia with seizures and neurologic deficit (Mabry syndrome).","abstract":"Hyperphosphatasia with neurologic deficit (Mabry syndrome) was first described in a single family (OMIM#239300) by Mabry et al. [1970]. Although considered rare at the time, more than 20 individuals with the triad of developmental disability, seizures, and hyperphosphatasia have been identified world-wide. The 1-6 mannosyltransferase 2, phosphatidylinositol glycan V (PIGV) gene has been found to be disrupted in some patients with the additional feature of brachytelephalangy. In the present report we identify three patients compound homozygous for PIGV mutations. Two siblings were found to be compound heterozygotes for c.467G > A and c.494C > A in exon 3 of PIGV (the c.494C > A PIGV variant is novel). A third patient with similar phenotype, was a compound heterozygote for the known c.1022C > A/c.1022C > T (p.Ala341Glu/p.Ala341Val) mutation. This patient was also noted to have lysosomal storage in cultured fibroblasts. In contrast, the fourth patient who had no apparent hand abnormality, was found to be heterozygous for a previously unclassified c.1369C > T mutation in exon 4 of the PIGV gene, resulting in a p.Leu457Phe substitution in the catalytic domain of the enzyme. Unless this variant has a dominant negative effect, however, it seems likely that another GPI biosynthesis gene variant may contribute to the disorder, possibly through digenic inheritance. Since slightly fewer than half of the nine cases presented in this report and our previous report [Thompson et al., 2010] have PIGV mutations, we suggest that other genes critical to GPI anchor biosynthesis are likely to be disrupted in some patients.","variants":[{"Name":"NM_017837.4(PIGV):c.467G>A (p.Cys156Tyr)","Chromosome":"1","Start":"26794501","Stop":"26794501","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39778,"rule_based_match":true,"evidence_text":"c.467G > A","llm_judgment":"PRESENT","evidence":"c.467G > A","abstract_start":626,"abstract_end":636},{"Name":"NM_017837.4(PIGV):c.1022C>A (p.Ala341Glu)","Chromosome":"1","Start":"26795056","Stop":"26795056","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":16323,"rule_based_match":true,"evidence_text":"c.1022C > A","llm_judgment":"PRESENT","evidence":"c.1022C > A","abstract_start":792,"abstract_end":803},{"Name":"NM_017837.4(PIGV):c.1369C>T (p.Leu457Phe)","Chromosome":"1","Start":"26797731","Stop":"26797731","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":414791,"rule_based_match":true,"evidence_text":"c.1369C > T","llm_judgment":"PRESENT","evidence":"c.1369C > T","abstract_start":1060,"abstract_end":1071},{"Name":"NM_017837.4(PIGV):c.494C>A (p.Ala165Glu)","Chromosome":"1","Start":"26794528","Stop":"26794528","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":139380,"rule_based_match":true,"evidence_text":"c.494C > A","llm_judgment":"PRESENT","evidence":"c.494C > A","abstract_start":641,"abstract_end":651}]}
{"pmid":"23077016","title":"PRRT2 mutations cause hemiplegic migraine.","abstract":"OBJECTIVE: Hemiplegic migraine (HM) is a rare subtype of migraine with aura that occurs as a familial or sporadic condition. The 3 culprit genes identified so far do not account for all familial forms of HM. PRRT2 mutations have recently been shown to cause various childhood-onset episodic syndromes including paroxysmal kinesigenic dyskinesia, infantile convulsions with choreoathetosis syndrome, and benign familial infantile epilepsy. Our objective was to test the possible implication of PRRT2 in HM, another episodic disorder with early onset in most cases.\nMETHODS: The whole genomic coding region of PRRT2 was sequenced in 101 index cases with HM that started before age 20 years and for whom no mutation was found in the 3 known HM genes. Affected relatives of mutated patients were analyzed when available.\nRESULTS: PRRT2 mutations were identified in 4 patients: the previously reported c.649dupC mutation was found in 2 cases, and a novel mutation, c.649delC, was found in the other 2. One patient with mutation subsequently developed paroxysmal dyskinesia, as well as generalized epileptic seizures.\nCONCLUSIONS: PRRT2 mutations can occasionally cause HM. This underscores the complexity of the phenotypic consequences of PRRT2 mutations.","variants":[{"Name":"NM_145239.3(PRRT2):c.649del (p.Arg217fs)","Chromosome":"16","Start":"29813695","Stop":"29813695","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":48351,"rule_based_match":true,"evidence_text":"c.649delC","llm_judgment":"PRESENT","evidence":"c.649delC","abstract_start":960,"abstract_end":969}]}
{"pmid":"26350383","title":"Identification of two novel mutations in CDHR1 in consanguineous Spanish families with autosomal recessive retinal dystrophy.","abstract":"Inherited retinal dystrophies present extensive phenotypic and genetic heterogeneity, posing a challenge for patients' molecular and clinical diagnoses. In this study, we wanted to clinically characterize and investigate the molecular etiology of an atypical form of autosomal recessive retinal dystrophy in two consanguineous Spanish families. Affected members of the respective families exhibited an array of clinical features including reduced visual acuity, photophobia, defective color vision, reduced or absent ERG responses, macular atrophy and pigmentary deposits in the peripheral retina. Genetic investigation included autozygosity mapping coupled with exome sequencing in the first family, whereas autozygome-guided candidate gene screening was performed by means of Sanger DNA sequencing in the second family. Our approach revealed nucleotide changes in CDHR1; a homozygous missense variant (c.1720C>G, p.P574A) and a homozygous single base transition (c.1485+2T>C) affecting the canonical 5' splice site of intron 13, respectively. Both changes co-segregated with the disease and were absent among cohorts of unrelated control individuals. To date, only five mutations in CDHR1 have been identified, all resulting in premature stop codons leading to mRNA nonsense mediated decay. Our work reports two previously unidentified homozygous mutations in CDHR1 further expanding the mutational spectrum of this gene.","variants":[{"Name":"NM_033100.4(CDHR1):c.1485+2T>C","Chromosome":"10","Start":"84211167","Stop":"84211167","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":852268,"rule_based_match":true,"evidence_text":"c.1485+2T>C","llm_judgment":"PRESENT","evidence":"c.1485+2T>C","abstract_start":965,"abstract_end":976},{"Name":"NM_033100.4(CDHR1):c.1720C>G (p.Pro574Ala)","Chromosome":"10","Start":"84212345","Stop":"84212345","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1454838,"rule_based_match":true,"evidence_text":"c.1720C>G, p.P574A","llm_judgment":"PRESENT","evidence":"c.1720C>G, p.P574A","abstract_start":904,"abstract_end":922}]}
{"pmid":"29442027","title":"The effect of","abstract":"The pharmacokinetics of statins show substantial inter-subject variability. Increasing systemic exposure of statins may lead to adverse drug reactions such as myopathy. The variation in statin pharmacokinetics is partly explained by genetic factors. OATP1B1, coded by SLCO1B1 transports a large number of therapeutic drugs, such as atorvastatin. Here we investigated the effect of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and its metabolites. Two pharmacokinetic studies were conducted in Chinese Han volunteers and 132 volunteers were enrolled in our study as 72 in trial 1 and 60 in trial 2. A LC-MS/MS method was developed for the identification and quantification of atorvastatin acid and its metabolites. S LCO1B1 c.521T>C (rs4149056) was identified by the MALDI-TOF MS and Sequenom MassARRAY system. The distribution frequencies of SLCO1B1 c.521T>C were in agreement with Hardy-Weinberg equilibrium both in trial 1 and trial 2. In subjects with 521C allele the mean Cmax, AUC0-24h and AUC0-∞ of atorvastatin acid and 2-hydroxyatorvastatin acid were significantly higher than subjects with 521TT genotype, while the mean CL was lower. In conclusion, our results suggested that SLCO1B1 c.521T>C had an effect on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in Chinese Han population. Subjects with 521C allele have an increased risk of toxic effects caused by atorvastatin.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":true,"evidence_text":"SLCO1B1 c.521T>C","llm_judgment":"PRESENT","evidence":"SLCO1B1 c.521T>C","abstract_start":858,"abstract_end":874}]}
{"pmid":"33825116","title":"A rare triad of morning glory disc anomaly, moyamoya vasculopathy, and transsphenoidal cephalocele: pathophysiological considerations and surgical management.","abstract":"Morning glory disc anomaly is a congenital abnormality of the optic disc and peripapillary retina reported as an isolated condition or associated with various anomalies, including basal encephaloceles and moyamoya vasculopathy. However, the co-occurrence of these three entities is extremely rare and the pathogenesis is still poorly understood. Moreover, data on the surgical management and long-term follow-up of the intracranial anomalies are scarce. Here, we describe the case of a 11-year-old boy with morning glory disc anomaly, transsphenoidal cephalocele, and moyamoya vasculopathy, who underwent bilateral indirect revascularization with encephalo-duro-myo-arterio-pericranio-synangiosis at the age of 2 years, and endoscopic repair of the transsphenoidal cephalocele at the age of 6 years. A rare missense variant (c.1081T>C,p.Tyr361His) was found in OFD1, a gene responsible for a X-linked ciliopathy, the oral-facial-digital syndrome type 1 (OFD1; OMIM 311200). This case expands the complex phenotype of OFD1 syndrome and suggests a possible involvement of OFD1 gene and Shh pathway in the pathogenesis of these anomalies.","variants":[{"Name":"NM_003611.3(OFD1):c.1081T>C (p.Tyr361His)","Chromosome":"X","Start":"13753393","Stop":"13753393","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1442996,"rule_based_match":true,"evidence_text":"c.1081T>C,p.Tyr361His","llm_judgment":"PRESENT","evidence":"c.1081T>C,p.Tyr361His","abstract_start":825,"abstract_end":846}]}
{"pmid":"36814108","title":"A novel variant of","abstract":"Pediatric cardiomyopathies (CM) are rare and challenging to diagnose due to the complex and mixed phenotypes. With the advent of next-generation sequencing (NGS), variants in several genes associated with CM have been identified, such as Troponin C (TnC), encoded by the <i>TNNC1</i> gene. <i>De novo</i> variants in <i>TNNC1</i> have been associated with different types of CM, including dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The American College of Medical Genetics and Genomics recently added <i>TNNC1</i> to their recommended list of genes for reporting secondary findings. In this study, we report a de novo variant, c.100G>C (p.Gly34Arg) in the <i>TNNC1</i> gene identified in three siblings with a diagnosis of severe DCM causing infant death for one of the siblings and stillbirth in the other two pregnancies. The identification of the same <i>de novo</i> variant in all affected siblings is suggestive of germline mosaicism in this family.","variants":[{"Name":"NM_003280.3(TNNC1):c.100G>C (p.Gly34Arg)","Chromosome":"3","Start":"52452208","Stop":"52452208","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2738066,"rule_based_match":true,"evidence_text":"c.100G>C (p.Gly34Arg)","llm_judgment":"PRESENT","evidence":"c.100G>C (p.Gly34Arg)","abstract_start":652,"abstract_end":673}]}
{"pmid":"35620871","title":"Hereditary hemorrhagic telangiectasia: First demonstration of a founder effect in Italy; the ACVRL1 c.289_294del variant originated in the country of Bergamo 200 years ago.","abstract":"BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder, affecting 1:5000 individuals worldwide. All the genes associated to the disease (ENG, ACVRL1, SMAD4, GDF2) belong to the TGF-β/BMPs signaling pathway. We found 19 HHT unrelated families, coming from a Northern Italy region and sharing the ACVRL1 in-frame deletion c.289_294del (p.H97_N98).\nMETHODS: To test the hypothesis of a founder effect, we analyzed 88 subjects from 19 families (66 variant carriers, showing clinical signs of HHT, and 22 non-carriers, unaffected) using eight microsatellite markers within 3.7 Mb around the ACVRL1 locus. After the haplotype reconstruction, age estimation of the variant was carried out.\nRESULTS: We observed a common disease haplotype in 16/19 families, while three families showed evidence of recombination around the ACVRL1 locus. The subsequent age estimation analyses suggested that the mutation occurred about 8 generations ago, corresponding to about 200 years ago. We also present novel in silico and modeling data supporting the variant pathogenicity: the deletion alters the protein stability and removes the unique extracellular glycosylation site.\nCONCLUSION: We have demonstrated, for the first time, a \"founder effect\" for a HHT pathogenic variant in Italy.","variants":[{"Name":"NM_000020.3(ACVRL1):c.289_294del (p.His97_Asn98del)","Chromosome":"12","Start":"51913322","Stop":"51913327","ReferenceAlleleVCF":"GCAACCA","AlternateAlleleVCF":"G","allel_id":2671553,"rule_based_match":true,"evidence_text":"ACVRL1 in-frame deletion c.289_294del (p.H97_N98)","llm_judgment":"PRESENT","evidence":"ACVRL1 in-frame deletion c.289_294del (p.H97_N98)","abstract_start":339,"abstract_end":388}]}
{"pmid":"20179009","title":"Novel compound mutations of SMARCAL1 associated with severe Schimke immuno-osseous dysplasia in a Chinese patient.","abstract":"BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive pleiotropic disease caused by mutations in the SMARCAL1 gene. To date there have been no data from the Chinese population. Here, we report the first SIOD case in the Chinese population. No case with gross carpal bone age retardation has been reported previously.\nMETHODS: The index patient was diagnosed by clinical and laboratory investigations. Mutations analysis of the SMARCAL1 gene and haplotype analysis were performed in the family. Structural predictions of the wild-type and mutant proteins were conducted.\nRESULTS: Severe SIOD was diagnosed in an 8-year-old boy, who exhibited growth failure, recurrent infection, neutropaenia, spondyloepiphyseal dysplasia, focal segmental glomerulosclerosis, T cell immunodeficiency and facial dysmorphism. Marked carpal bone age retardation was also observed. Sequence analysis of the SMARCAL1 gene revealed two novel mutations: c.3G>A (p.Met1?) and c.1682G>A (p.Arg561His) in the boy. Haplotype analysis and mutation detection showed that the father is the carrier of c.3G>A (p.Met1?) and the mother is the carrier of c.1682G>A (p.Arg561His). The paternal mutation, c.3G>A (p.Met1?), is predicted to introduce a new open reading frame, resulting in truncation of 103 amino acids at the N-terminus. The maternal mutation occurred in the SNF2-related domain involved in ATP hydrolyzation and DNA binding and is predicted to alter the local spatial structure of the protein.\nCONCLUSION: We report the first SIOD patient from China, who exhibited gross carpal bone age retardation and carried two novel mutations, c.3G>A (p.Met1?) and c.1682G>A (p.Arg561His), in the SMARCAL1 gene.","variants":[{"Name":"NM_014140.4(SMARCAL1):c.1682G>A (p.Arg561His)","Chromosome":"2","Start":"216438457","Stop":"216438457","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1928193,"rule_based_match":true,"evidence_text":"c.1682G>A (p.Arg561His)","llm_judgment":"PRESENT","evidence":"c.1682G>A (p.Arg561His)","abstract_start":978,"abstract_end":1001}]}
{"pmid":"18518985","title":"A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings.","abstract":"BACKGROUND: Low frequency sensorineural hearing loss (LFSNHL) is an uncommon clinical finding. Mutations within three different identified genes (DIAPH1, MYO7A, and WFS1) are known to cause LFSNHL. The majority of hereditary LFSNHL is associated with heterozygous mutations in the WFS1 gene (wolframin protein). The goal of this study was to use genetic analysis to determine if a small American family's hereditary LFSNHL is linked to a mutation in the WFS1 gene and to use VEMP and EcochG testing to further characterize the family's audiovestibular phenotype.\nMETHODS: The clinical phenotype of the American family was characterized by audiologic testing, vestibular evoked myogenic potentials (VEMP), and electrocochleography (EcochG) evaluation. Genetic characterization was performed by microsatellite analysis and direct sequencing of WFS1 for mutation detection.\nRESULTS: Sequence analysis of the WFS1 gene revealed a novel heterozygous mutation at c.2054G>C predicting a p.R685P amino acid substitution in wolframin. The c.2054G>C mutation segregates faithfully with hearing loss in the family and is absent in 230 control chromosomes. The p.R685 residue is located within the hydrophilic C-terminus of wolframin and is conserved across species. The VEMP and EcochG findings were normal in individuals segregating the WFS1 c.2054G>C mutation.\nCONCLUSION: We discovered a novel heterozygous missense mutation in exon 8 of WFS1 predicting a p.R685P amino acid substitution that is likely to underlie the LFSNHL phenotype in the American family. For the first time, we describe VEMP and EcochG findings for individuals segregating a heterozygous WFS1 mutation.","variants":[{"Name":"NM_006005.3(WFS1):c.2054G>C (p.Arg685Pro)","Chromosome":"4","Start":"6301849","Stop":"6301849","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":54613,"rule_based_match":true,"evidence_text":"c.2054G>C","llm_judgment":"PRESENT","evidence":"c.2054G>C","abstract_start":957,"abstract_end":966}]}
{"pmid":"37467895","title":"Hemophagocytic lymphohistiocytosis with a hemizygous PRF1 c.674G>A mutation.","abstract":"Hemophagocytic lymphohistiocytosis(HLH) is a rare highly-fatal disease presenting with fever, hepatosplenomegaly, and pancytopenia and has a poor prognosis. Homozygous or semi-zygous or complex heterozygous variants can cause familial HLH and heterozygous carriers are frequently seen in secondary HLH. A 42-year-old male patient was admitted to the hospital for persistent fever, fatigue, and splenomegaly. Investigations revealed hypertriglyceridemia, hyperlactatemia dehydrogenaseemia, hyperferritinemia, and elevated levels of soluble cluster of differentiation 25. We found a heterozygous mutation of PRF1: c.674G>A (p.R225Q) through next-generation sequencing technology of hemophagocytic-lymphohistiocytosis-related genes. After a brief remission with dexamethasone and etoposide-based therapy, the disease relapsed quickly, and an allogeneic hematopoietic stem cell transplant was performed to achieve complete remission. To date, the patient's condition was in complete remission. Our study detected a rare missense mutation in the PRF1 gene in a patient with HLH disease and the c.674G>A mutation may be rated as a possible pathogenic variant.","variants":[{"Name":"NM_001083116.3(PRF1):c.674G>A (p.Arg225Gln)","Chromosome":"10","Start":"70599047","Stop":"70599047","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":639111,"rule_based_match":true,"evidence_text":"c.674G>A (p.R225Q)","llm_judgment":"PRESENT","evidence":"c.674G>A (p.R225Q)","abstract_start":612,"abstract_end":630}]}
{"pmid":"29237407","title":"Identification and in silico characterization of a novel p.P208PfsX1 mutation in V-ATPase a3 subunit associated with autosomal recessive osteopetrosis in a Pakistani family.","abstract":"BACKGROUND: Osteopetrosis is a rare inherited bone disorder mainly described as an increased bone density caused by defective osteoclastic bone resorption. To date, genetic variants of eleven genes have been reported so far to be associated with different types of osteopetrosis. However, malignant infantile osteopetrosis, a lethal form of the disease, is mostly (50%) caused by mutation(s) in TCIRG1 gene. In this study, we investigated a consanguineous Pakistani family clinically and genetically to elucidate underlying molecular basis of the infantile osteopetrosis.\nMETHODS: DNA samples from five family members were subjected to SNP-array based whole genome homozygosity mapping. Data was analyzed and potentially pathogenic mutation was identified by Sanger sequencing of two affected as well as three phenotypically healthy individuals in the family. The significance of identified pathogenic variation and its impact on protein structure and function was studied using various bioinformatics tools.\nRESULTS: DNA samples from five family members were subjected to genome-wide SNP array genotyping and homozygosity mapping which identified ~4 Mb region on chr11 harboring the TCIRG1 gene. Sanger sequencing unveiled a novel homozygous deletion c. 624delC in exon 6 of the TCIRG1 gene encodes a3 subunit of V-ATPase complex. The identified deletion resulted in a frame shift producing a truncated protein of 208 aa. In silico analysis of premature termination of the a3 subunit of V-ATPase complex revealed deleterious effects on the protein structure, predicting impaired or complete loss of V-ATPase function causing infantile osteopetrosis.\nCONCLUSIONS: Since a3 subunit of V-ATPase complex plays a crucial role in bone resorption process, structurally abnormal a3 subunit might have adversely affected bone resorption process, leading to infantile osteopetrosis in Pakistani family. Therefore, the present study not only expands the genotypic spectrum of osteopetrosis but also improve understandings of the role of V-ATPase a3 subunit in bone resorption process. Moreover, our findings should help in genetic counseling and provide further insight into the disease pathogenesis and potential targeted therapy.","variants":[{"Name":"NM_006019.4(TCIRG1):c.624del (p.Pro208_Val209insTer)","Chromosome":"11","Start":"68043488","Stop":"68043488","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":3856863,"rule_based_match":true,"evidence_text":"c. 624delC","llm_judgment":"PRESENT","evidence":"c. 624delC","abstract_start":1252,"abstract_end":1262}]}
{"pmid":"32109208","title":"Variant analysis of HPD genes from two families showing elevated tyrosine upon newborn screening by tandem mass spectrometry (MS/MS).","abstract":"Background Alterations in the structure and activity of 4-hydroxyphenylpyruvate dioxygenase (HPD) are causally related to two different metabolic disorders: recessively inherited tyrosinemia type III and dominantly inherited hawkinsinuria. The aim of this study was to provide a new perspective for the clinical understanding of the pathogenesis of tyrosinemia type III or hawkinsinuria. Case presentation A full-term newborn baby born after a safe pregnancy and childbirth with a birth weight of 3200 g and another full-term baby born after a safe pregnancy and childbirth with a birth weight of 2800 g are reported and analysed. DNA extraction, next-generation sequencing, bioinformatics analysis, Sanger sequencing and biochemical analysis were performed. One patient with a heterozygous HPD gene (NM_002150.2) c.460G > A mutation and one patient with a heterozygous HPD gene (NM_002150.2) c.248delG mutation showing elevated tyrosine levels upon newborn screening by tandem mass spectrometry (MS/MS) are reported. Conclusions The HPD gene may not be a strictly autosomal recessive pathogenic gene, which provides a new perspective for the clinical understanding of the pathogenesis of tyrosinemia type III or hawkinsinuria.","variants":[{"Name":"NM_002150.3(HPD):c.460G>A (p.Gly154Ser)","Chromosome":"12","Start":"121849745","Stop":"121849745","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2843604,"rule_based_match":true,"evidence_text":"c.460G > A","llm_judgment":"PRESENT","evidence":"c.460G > A","abstract_start":814,"abstract_end":824},{"Name":"NM_002150.3(HPD):c.248del (p.Gly83fs)","Chromosome":"12","Start":"121856400","Stop":"121856400","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":2402620,"rule_based_match":true,"evidence_text":"c.248delG","llm_judgment":"PRESENT","evidence":"c.248delG","abstract_start":893,"abstract_end":902}]}
{"pmid":"25403292","title":"Multi-physiopathological consequences of the c.1392G>T CFTR mutation revealed by clinical and cellular investigations.","abstract":"This study combines a clinical approach and multiple level cellular analyses to determine the physiopathological consequences of the c.1392G>T (p.Lys464Asn) CFTR exon 10 mutation, detected in a CF patient with a frameshift deletion in trans and a TG(11)T(5) in cis. Minigene experiment, with different TG(m)T(n) alleles, and nasal cell mRNA extracts were used to study the impact of c.1392G>T on splicing in both in cellulo and in vivo studies. The processing and localization of p.Lys464Asn protein were evaluated, in cellulo, by western blotting analyses and confocal microscopy. Clinical and channel exploration tests were performed on the patient to determine the exact CF phenotype profile and the CFTR chloride transport activity. c.1392G>T affects exon 10 splicing by inducing its complete deletion and encoding a frameshift transcript. The polymorphism TG(11)T(5) aggravates the effects of this mutation on aberrant splicing. Analysis of mRNA obtained from parental airway epithelial cells confirmed these in cellulo results. At the protein level the p.Lys464Asn protein showed neither maturated form nor membrane localization. Furthermore, the in vivo channel tests confirmed the absence of CFTR activity. Thus, the c.1392G>T mutation alone or in association with the TG repeats and the poly T tract revealed obvious impacts on splicing and CFTR protein processing and functionality. The c.[T(5); 1392G>T] complex allele contributes to the CF phenotype by affecting splicing and inducing a severe misprocessing defect. These results demonstrate that the classical CFTR mutations classification is not sufficient: in vivo and in cellulo studies of a possible complex allele in a patient are required to provide correct CFTR mutation classification, adequate medical counseling, and adapted therapeutic strategies.","variants":[{"Name":"NM_000492.4(CFTR):c.1392G>T (p.Lys464Asn)","Chromosome":"7","Start":"117548823","Stop":"117548823","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":67908,"rule_based_match":true,"evidence_text":"c.1392G>T (p.Lys464Asn)","llm_judgment":"PRESENT","evidence":"c.1392G>T (p.Lys464Asn)","abstract_start":133,"abstract_end":156}]}
{"pmid":"29376577","title":"p.Val452Ile mutation of the SLC25A13 gene in a Turkish patient with citrin deficiency.","abstract":"Şeker-Yılmaz B, Kör D, Tümgör G, Ceylaner S, Önenli-Mungan N. p.Val452Ile mutation of the SLC25A13 gene in a Turkish patient with citrin deficiency. Turk J Pediatr 2017; 59: 311-314. Citrin deficiency is an autosomal recessive metabolic disorder, which is caused by pathogenic mutations in the SLC25A13 gene on chromosome 7q21.3, as the causative gene that encodes the liver type aspartate/glutamate carrier isoform 2 (AGC2). One of the main clinical presentations is neonatal intrahepatic cholestatic hepatitis caused by citrin deficiency. We report a Turkish child presented with prolonged neonatal jaundice associated with elevated plasma citrulline and galactosuria. NICCD was suspected at this point and mutation study of SLC25A13 showed that she was homozygous for the missense NM_014251.2:c.1354G > A (NP_055066.1:p.Val452Ile) (dbSNP: rs143877538) mutation. Dramatic response was observed to the dietary treatment with medium-chain triglycerides containing formula, ursodeoxycholic acid and fat-soluble vitamin supplementation. The minor allele frequency of this variant was given as nearly as 0.01 in the South Asian population; it seems like a disease causing variant. This is the first report of this variant in the Turkish and European population.","variants":[{"Name":"NM_014251.3(SLC25A13):c.1354G>A (p.Val452Ile)","Chromosome":"7","Start":"96146654","Stop":"96146654","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":587153,"rule_based_match":true,"evidence_text":"NM_014251.2:c.1354G > A (NP_055066.1:p.Val452Ile)","llm_judgment":"PRESENT","evidence":"NM_014251.2:c.1354G > A (NP_055066.1:p.Val452Ile)","abstract_start":784,"abstract_end":833}]}
{"pmid":"34487536","title":"Clinical feature and genetic analysis of a fetus with autosomal recessive polycystic kidney disease","abstract":"OBJECTIVE: To explore the genetic etiology of a fetus with autosomal recessive polycystic kidney disease (ARPKD).\nMETHODS: Prenatal ultrasonography has revealed oligohydramnios and abnormal structure of fetal kidneys. After careful counseling, the couple opted induced abortion. With informed consent, genomic DNA was extracted from the muscle sample of the abortus and peripheral blood samples of the couple. High throughput whole exome sequencing was carried out to detect potential variants in relation with the disease. Suspected variants were verified by Sanger sequencing.\nRESULTS: Prenatal ultrasound revealed increased size of fetal kidneys, with multiple hyperechos from the right kidney, and multiple hyperechos with anechoic masses within the left kidney. DNA sequencing revealed that the fetus has carried heterozygous variants of the PKHD1 gene, including c.7994T>C inherited from its father, and two heterozygous variants of the PKHD1 gene c.5681G>A from its mother.\nCONCLUSION: The compound heterozygous c.7994T>C and c.5681G>A variants of the PKHD1 gene probably underlay the pathogenesis of ARPKD in this fetus. Above results can provide guidance for subsequent pregnancies of the couple.","variants":[{"Name":"NM_138694.4(PKHD1):c.7994T>C (p.Leu2665Pro)","Chromosome":"6","Start":"51847888","Stop":"51847888","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1892091,"rule_based_match":true,"evidence_text":"c.7994T>C","llm_judgment":"PRESENT","evidence":"c.7994T>C","abstract_start":869,"abstract_end":878},{"Name":"NM_138694.4(PKHD1):c.5681G>A (p.Cys1894Tyr)","Chromosome":"6","Start":"52010379","Stop":"52010379","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3392756,"rule_based_match":true,"evidence_text":"c.5681G>A","llm_judgment":"PRESENT","evidence":"c.5681G>A","abstract_start":954,"abstract_end":963}]}
{"pmid":"25480383","title":"Development of a practical NF1 genetic testing method through the pilot analysis of five Japanese families with neurofibromatosis type 1.","abstract":"OBJECTIVE: Mutation analysis of NF1, the responsible gene for neurofibromatosis type 1 (NF1), is still difficult due to its large size, lack of mutational hotspots, the presence of many pseudogenes, and its wide spectrum of mutations. To develop a simple and inexpensive NF1 genetic testing for clinical use, we analyzed five Japanese families with NF1 as a pilot study.\nMETHODS: Our original method, CEL endonuclease mediated heteroduplex incision with polyacrylamide gel electrophoresis and silver staining (CHIPS) was optimized for NF1 mutation screening, and reverse transcription polymerase chain reaction (RT-PCR) was performed to determine the effect of transcription. Also, we employed DNA microarray analysis to evaluate the break points of the large deletion.\nRESULTS: A new nonsense mutation, p.Gln209(∗), was detected in family 1 and the splicing donor site mutation, c.2850+1G>T, was detected in family 2. In family 3, c.4402A>G was detected in exon 34 and the p.Ser1468Gly missense mutation was predicted. However mRNA analysis revealed that this substitution created an aberrant splicing acceptor site, thereby causing the p.Phe1457(∗) nonsense mutation. In the other two families, type-1 and unique NF1 microdeletions were detected by DNA microarray analysis.\nCONCLUSIONS: Our results show that the combination of CHIPS and RT-PCR effectively screen and characterize NF1 point mutations, and both DNA and RNA level analysis are required to understand the nature of the NF1 mutation. Our results also suggest the possibility of a higher incidence and unique profile of NF1 large deletions in the Japanese population as compared to previous studies performed in Europe.","variants":[{"Name":"NM_001042492.3(NF1):c.2850+1G>T","Chromosome":"17","Start":"31229466","Stop":"31229466","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":420790,"rule_based_match":true,"evidence_text":"c.2850+1G>T","llm_judgment":"PRESENT","evidence":"c.2850+1G>T","abstract_start":880,"abstract_end":891}]}
{"pmid":"28228640","title":"Autosomal dominant cutis laxa with progeroid features due to a novel, de novo mutation in ALDH18A1.","abstract":"De novo dominant mutations in the aldehyde dehydrogenase 18 family member A1 (ALDH18A1) gene have recently been shown to cause autosomal dominant cutis laxa with progeroid features (MIM 616603). To date, all de novo dominant mutations have been found in a single highly conserved amino acid residue at position p.Arg138. We report an 8-year-old male with a clinical diagnosis of autosomal dominant cutis laxa (ADCL) with progeroid features and a novel de novo missense mutation in ALDH18A1 (NM_002860.3: c.377G>A (p.Arg126His)). This is the first report of an individual with ALDH18A1-ADCL due to a substitution at a residue other than p.Arg138. Knowledge of the complete spectrum of dominant-acting mutations that cause this rare syndrome will have implications for molecular diagnosis and genetic counselling of these families.","variants":[{"Name":"NM_002860.4(ALDH18A1):c.377G>A (p.Arg126His)","Chromosome":"10","Start":"95637363","Stop":"95637363","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2405433,"rule_based_match":true,"evidence_text":"NM_002860.3: c.377G>A (p.Arg126His)","llm_judgment":"PRESENT","evidence":"NM_002860.3: c.377G>A (p.Arg126His)","abstract_start":491,"abstract_end":526}]}
{"pmid":"33621656","title":"Alkaptonuria in Russia: mutational spectrum and novel variants.","abstract":"Alkaptonuria is a rare genetic disease caused by mutations in HGD gene. Here we report the results of genetic and biochemical analysis of 49 Russian patients with alkaptonuria. One of the common variants c.481G > A; p.(Gly161Arg) comprising 72.4% of identified alleles was found in 45 of 49 patients in our cohort, which is probably the highest frequency of this variant worldwide. 9 novel variants were found: 6 missense, 2 splicing and 1 loss of start-codon. For missense variants we performed bioinformatic analysis, protein 3D-modeling and molecular dynamics simulations, which strongly suggest their pathogenic effect. For the rare synonymous variant c.753C > T; p.(Gly251Gly), which was found in 3 cases and predicted to activate cryptic splice site, we performed the detailed functional analysis on patient's cDNA and minigene assay and confirmed its pathogenicity.","variants":[{"Name":"NM_000187.4(HGD):c.753C>T (p.Gly251=)","Chromosome":"3","Start":"120644340","Stop":"120644340","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":857330,"rule_based_match":true,"evidence_text":"c.753C>T; p.(Gly251Gly)","llm_judgment":"PRESENT","evidence":"c.753C > T; p.(Gly251Gly)","abstract_start":656,"abstract_end":681}]}
{"pmid":"12754704","title":"Single base substitutions at the initiator codon in the mitochondrial acetoacetyl-CoA thiolase (ACAT1/T2) gene result in production of varying amounts of wild-type T2 polypeptide.","abstract":"Initiator codon mutations are relatively uncommon and less well characterized compared to other types of mutations. We identified a novel initiator codon mutation (c.2T>C) heterozygously in a Japanese patient (Patient GK30) with mitochondrial acetoacetyl-CoA thiolase (T2) gene deficiency (ACAT1 deficiency); c.149delC was on the other allele. We examined translation efficiencies of nine mutant T2 cDNAs harboring one-base substitutions at the initiator methionine codon using in vivo transient expression analysis. We found that all the mutants produced wild-type T2 polypeptide, to various degrees (wild type (100%) > c.1A>C (66%) > c.2T>C, c.3G>C, c.3G>T (22%) > c3G>A, c.1A>G (11%) > c.2T>A, c.2T>G, c.1A>T (7.4%)). T2 mRNA expression levels in Patient GK08 (a homozygote of c.2T>A) and Patient GK30 fibroblasts, respectively, were almost the same as in control fibroblasts, when examined using semiquantitative PCR. This means that initiator codon mutations did not affect T2 mRNA levels. We propose that all one-base substitutions at the initiator methionine codon in the T2 gene could be mutations, which retain some residual T2 activity.","variants":[{"Name":"NM_000019.4(ACAT1):c.2T>C (p.Met1Thr)","Chromosome":"11","Start":"108121608","Stop":"108121608","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":654020,"rule_based_match":true,"evidence_text":"c.2T>C","llm_judgment":"PRESENT","evidence":"c.2T>C","abstract_start":164,"abstract_end":170}]}
{"pmid":"27667277","title":"Pedigree survey in a family with hereditary protein S deficiency","abstract":"<b>Objective:</b> To observe the clinical feature of familiar hereditary protein S deficiency(HPSD), and to explore the related gene mutations. <b>Methods:</b> A total of seven family members were enrolled in this study and examined during the June to September 2015. Medical histories of the families were analyzed to detect HPSD according to the diagnostic criteria. PROS1 genes of the proband and her family were analyzed. DNA was extracted from peripheral blood. The 15 exons and their intron-exon boundaries of PROS1 were amplified with PCR, and the PCR products were sequenced and analyzed to identify potential mutations. Medical histories from the family members died prior this study were also obtained. <b>Results:</b> Four out of 7 family members of 2 generations were diagnosed as HPSD. The proband suffered from pulmonary embolism, her elder brother suffered from cerebral infarction and her niece suffered from deep vein thrombosis. A missense mutation at the 1063 bp of cDNA(c.1063C>T)was detected in the exon 10 of PROS1, which resulted in arginine 355 to cysteine replacement in the first ball domain of laminin of the protein S(p.R355C). <b>Conclusion:</b> HPSD is an autosomal dominant genetic disease, patients often suffer from recurring vein thrombosis and pulmonary embolism. A missense mutation(c.1063C>T, p. R355C)of PROS1 was discovered in this Chinese family with HPSD, thus, this mutation might be the genetic basis responsible for these family members with HPSD .","variants":[{"Name":"NM_000313.4(PROS1):c.1063C>T (p.Arg355Cys)","Chromosome":"3","Start":"93893025","Stop":"93893025","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38801,"rule_based_match":true,"evidence_text":"c.1063C>T","llm_judgment":"PRESENT","evidence":"c.1063C>T","abstract_start":990,"abstract_end":999}]}
{"pmid":"25627829","title":"Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation.","abstract":"PURPOSE: A male infant developed generalized rash, intestinal inflammation and severe infections including persistent cytomegalovirus. Family history was negative, T cell receptor excision circles were normal, and engraftment of maternal cells was absent. No defects were found in multiple genes associated with severe combined immunodeficiency. A 9/10 HLA matched unrelated hematopoietic cell transplant (HCT) led to mixed chimerism with clinical resolution. We sought an underlying cause for this patient's immune deficiency and dysregulation.\nMETHODS: Clinical and laboratory features were reviewed. Whole exome sequencing and analysis of genomic DNA from the patient, parents and 2 unaffected siblings was performed, revealing 2 MALT1 variants. With a host-specific HLA-C antibody, we assessed MALT1 expression and function in the patient's post-HCT autologous and donor lymphocytes. Wild type MALT1 cDNA was added to transformed autologous patient B cells to assess functional correction.\nRESULTS: The patient had compound heterozygous DNA variants affecting exon 10 of MALT1 (isoform a, NM_006785.3), a maternally inherited splice acceptor c.1019-2A > G, and a de novo deletion of c.1059C leading to a frameshift and premature termination. Autologous lymphocytes failed to express MALT1 and lacked NF-κB signaling dependent upon the CARMA1, BCL-10 and MALT1 signalosome. Transduction with wild type MALT1 cDNA corrected the observed defects.\nCONCLUSIONS: Our nonconsanguineous patient with early onset profound combined immunodeficiency and immune dysregulation due to compound heterozygous MALT1 mutations extends the clinical and immunologic phenotype reported in 2 prior families. Clinical cure was achieved with mixed chimerism after nonmyeloablative conditioning and HCT.","variants":[{"Name":"NM_006785.4(MALT1):c.1019-2A>G","Chromosome":"18","Start":"58723046","Stop":"58723046","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":187140,"rule_based_match":true,"evidence_text":"c.1019-2A > G","llm_judgment":"PRESENT","evidence":"c.1019-2A > G","abstract_start":1146,"abstract_end":1159}]}
{"pmid":"31030436","title":"Clinical and genetic analysis of a patient with tyrosinemia type I but without elevated succinylacetone","abstract":"OBJECTIVE: To analyze the clinical manifestation and genetic mutation of a child with tyrosinemia type I but without elevated succinylacetone.\nMETHODS: Clinical data of the patient was collected. Tandem mass spectrometry and gas chromatography mass spectrometry were used to analyze the blood amino acid and urine organic acid component of the proband. DNA was extracted from the child and his parents and used for mutation analysis.\nRESULTS: The proband was of acute type, with features including hepatomegaly, jaundice, anemia and tendency of bleeding. Serum levels of Tyrosine, Methionine and Phenylalanine were 397.12 μmol/L, 896.16 μmol/L and 292.52 μmol/L, respectively, which all distinctly exceeded the normal levels. The level of phenyllactic acid and 4-hydroxyphenyl-lactic acid of proband's urine were 17.4 μmol/L and 417.0 μmol/L, respectively, which also exceeded the normal levels, but the level of succinylacetone was within the normal range. Compound heterozygous mutations of the FAH gene, namely c.634delT (p.L212Wfs*20) and c.455G>A (p.W152X), were detected in the proband, which were both predicted to be pathogenic and were inherited from her father and mother, respectively.\nCONCLUSION: For children with tyrosinemia type I, detection of urine succinylacetone by gas phase mass spectrometry can be negative. The diagnosis of tyrosinemia type I must rely on genetic testing and/or enzymatic assaying.","variants":[{"Name":"NM_000137.4(FAH):c.455G>A (p.Trp152Ter)","Chromosome":"15","Start":"80162336","Stop":"80162336","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":358330,"rule_based_match":true,"evidence_text":"c.455G>A (p.W152X)","llm_judgment":"PRESENT","evidence":"c.455G>A (p.W152X)","abstract_start":1043,"abstract_end":1061}]}
{"pmid":"33960148","title":"Progressive cerebellar atrophy in a patient with complex II and III deficiency and a novel deleterious variant in SDHA: A Counseling Conundrum.","abstract":"BACKGROUND: Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma-pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh-like syndromes.\nMETHODS AND RESULTS: Here, we describe a case of a 9-year-old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA, a known pathogenic variant (c.91C>T (p.R31*)), and a variant of unknown significance (c.454G>A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder.\nCONCLUSION: We, therefore, consider whether c.454G>A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant.","variants":[{"Name":"NM_004168.4(SDHA):c.454G>A (p.Glu152Lys)","Chromosome":"5","Start":"225560","Stop":"225560","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":454905,"rule_based_match":true,"evidence_text":"c.454G>A (p.E152K)","llm_judgment":"PRESENT","evidence":"c.454G>A (p.E152K)","abstract_start":851,"abstract_end":869},{"Name":"NM_004168.4(SDHA):c.91C>T (p.Arg31Ter)","Chromosome":"5","Start":"223509","Stop":"223509","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152315,"rule_based_match":true,"evidence_text":"c.91C>T (p.R31*)","llm_judgment":"PRESENT","evidence":"c.91C>T (p.R31*)","abstract_start":793,"abstract_end":809}]}
{"pmid":"23559858","title":"Exome sequencing identifies a novel and a recurrent BBS1 mutation in Pakistani families with Bardet-Biedl syndrome.","abstract":"PURPOSE: To determine the genetic cause of Bardet-Biedl syndrome (BBS) in two consanguineous Pakistani families.\nMETHODS: Clinical characterization of the affected individuals in both families was performed with ophthalmic examination, electroretinography, electrocardiography, and liver and renal profiling. Seventeen genes are known to be associated with BBS, so exome sequencing was preferred over candidate gene sequencing. One affected individual from both families was selected for exome sequencing. Segregation of the identified variants was confirmed with Sanger sequencing.\nRESULTS: Retinitis pigmentosa, obesity, and learning difficulties were present in the affected individuals in both families. In family A, a sixth finger (polydactyly) of the proband's sister was removed by a surgical operation leaving a scar on the little finger. Polydactyly was also present in both affected individuals from family B. All diagnostic symptoms were characteristic of BBS in both families. In both affected individuals from family A, exome sequencing identified a novel homozygous mutation (c.47+1G>T) in BBS1 that inactivates the splice donor site at the end of exon 1. In family B, a previously reported mutation, c.442G>A; p.(Asp148Asn), was detected.\nCONCLUSIONS: Exome sequencing is an efficient and cost-effective technique for identifying mutations in genetically heterogeneous diseases. In addition, intrafamilial phenotypic variability in family A argues for the modifying effect of other still unknown modifier alleles.","variants":[{"Name":"NM_024649.5(BBS1):c.442G>A (p.Asp148Asn)","Chromosome":"11","Start":"66515549","Stop":"66515549","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":640363,"rule_based_match":true,"evidence_text":"c.442G>A; p.(Asp148Asn)","llm_judgment":"PRESENT","evidence":"c.442G>A; p.(Asp148Asn)","abstract_start":1215,"abstract_end":1238},{"Name":"NM_024649.5(BBS1):c.47+1G>T","Chromosome":"11","Start":"66510707","Stop":"66510707","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1314565,"rule_based_match":true,"evidence_text":"c.47+1G>T","llm_judgment":"PRESENT","evidence":"c.47+1G>T","abstract_start":1090,"abstract_end":1099}]}
{"pmid":"22847544","title":"Autosomal-dominant chronic mucocutaneous candidiasis with STAT1-mutation can be complicated with chronic active hepatitis and hypothyroidism.","abstract":"PURPOSE: To describe a case of autosomal-dominant (AD)-chronic mucocutaneous candidiasis (CMC) with a signal transducer and activator of transcription (STAT) 1 gene mutation, and some of the important complications of this disease such as chronic hepatitis.\nMETHODS: We present a 23-year-old woman with CMC, chronic active hepatitis, and hypothyroidism. Her father also had CMC. We performed several immunological analyses of blood and liver samples, and searched for gene mutations for CMC in the patient and her father.\nRESULTS: We identified the heterozygous substitution c.821 G > A (p.Arg274Gln) in the STAT1 gene of both the patient and her father. The level of β-glucan induced interferon (IFN)-γ in her blood cells was significantly low. Immunoblot analysis detected serum anti-interleukin (IL)-17 F autoantibody. She was found to have increased (low-titer) antibodies related to her hypothyroidism and hepatitis. Her serum IL-18 levels fluctuated with her AST and ALT levels. Liver biopsy revealed CD68-positive cell infiltration and IL-18 expression in the sinusoidal regions. These results suggest that the chronic active hepatitis in this patient may be exacerbated by the excessive IL-18 accumulation caused by recurrent mucocutaneous fungal infection, and decreased IFN-γ production.\nCONCLUSIONS: AD-CMC is known to be caused by a gain-of-function mutation of the STAT1 gene. Chronic active hepatitis is a rare complication of AD-CMC, with currently unknown pathogenesis. It seems that the clinical phenotype in this patient is modified by autoimmune mechanisms and cytokine dysregulation. AD-CMC can be complicated by various immune disorders including autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.","variants":[{"Name":"NM_007315.4(STAT1):c.821G>A (p.Arg274Gln)","Chromosome":"2","Start":"190995184","Stop":"190995184","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39040,"rule_based_match":true,"evidence_text":"c.821 G > A (p.Arg274Gln)","llm_judgment":"PRESENT","evidence":"c.821 G > A (p.Arg274Gln)","abstract_start":575,"abstract_end":600}]}
{"pmid":"33058507","title":"Novel NUDT2 variant causes intellectual disability and polyneuropathy.","abstract":"Exome or genome sequencing was performed to identify the genetic etiology for the clinical presentation of global developmental delay, intellectual disability, and sensorimotor neuropathy with associated distal weakness in two unrelated families. A homozygous frameshift variant c.186delA (p.A63Qfs*3) in the NUDT2 gene was identified in cases 1 and 2 from one family and a third case from another family. Variants in NUDT2 were previously shown to cause intellectual disability, but here we expand the phenotype by demonstrating its association with distal upper and lower extremity weakness due to a sensorimotor polyneuropathy with demyelinating and/or axonal features.","variants":[{"Name":"NM_001161.5(NUDT2):c.186del (p.Ala63fs)","Chromosome":"9","Start":"34343181","Stop":"34343181","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":677336,"rule_based_match":true,"evidence_text":"c.186delA (p.A63Qfs*3)","llm_judgment":"PRESENT","evidence":"c.186delA (p.A63Qfs*3)","abstract_start":279,"abstract_end":301}]}
{"pmid":"23574375","title":"Regional differences in the frequency of the c.985A>G ACADM mutation: findings from a meta-regression of genotyping and screening studies.","abstract":"Several countries include medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, a rare autosomal recessive disease, in their newborn screening programmes despite prevalence uncertainty. We estimated the frequency of its most common mutation, c.985A>G, tested for regional differences and compared screening and genotype frequencies. We identified 43 studies reporting the frequency of c.985A>G over 10 million individuals, and pooled frequency data using a novel Bayesian approach. We found significant variation in the frequency of the mutation across regions supporting a reported founder effect. The proportion of c.985A>G homozygotes was highest in Western Europe with 4.1 (95%CI: 2.8-5.6) per 100,000 individuals, then the New World (3.2, 95%CI: 2.0-4.7), Southern (1.2, 95%CI: 0.6-2.0) and Eastern European regions (0.9, 95%CI: 0.5-1.7). No cases with the mutation were identified in Asian and Middle Eastern regions. Significant differences were found in some countries between the genotype and screening allele frequency of c.985A>G. Our predictions could inform the frequency of the mutation by region and our approach could apply to other genetic conditions.","variants":[{"Name":"NM_000016.6(ACADM):c.985A>G (p.Lys329Glu)","Chromosome":"1","Start":"75761161","Stop":"75761161","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18625,"rule_based_match":true,"evidence_text":"c.985A>G","llm_judgment":"PRESENT","evidence":"c.985A>G","abstract_start":243,"abstract_end":251}]}
{"pmid":"31455392","title":"Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders.","abstract":"BACKGROUND: Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations.\nMETHODS: Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene.\nRESULTS: Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern.\nCONCLUSIONS: Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.","variants":[{"Name":"NM_021830.5(TWNK):c.85C>T (p.Arg29Ter)","Chromosome":"10","Start":"100988295","Stop":"100988295","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1877927,"rule_based_match":true,"evidence_text":"c.85C>T (p.Arg29*)","llm_judgment":"PRESENT","evidence":"c.85C>T (p.Arg29*)","abstract_start":1532,"abstract_end":1550}]}
{"pmid":"21503806","title":"Search for genetic variants in the ryanodine receptor 1 gene in patients with symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage.","abstract":"BACKGROUND: Cerebral vasospasm is one of the most serious complications after subarachnoid hemorrhage (SAH). The cerebral artery diameter is regulated by complex physiological mechanisms. Among them the regulation of intracellular calcium homeostasis seems to play a crucial role. Recent data suggest that ryanodine receptors (RYRs) are involved in regulating the luminal calcium concentration in vascular smooth muscle cells. In this gene association investigation, we studied the question as to whether variants in the gene for the ryanodine receptors subtype 1 (RYR1) are associated with symptomatic cerebral vasospasm following SAH.\nMETHODS: After informed consent genomic DNA analysis was performed from a whole blood sample in 46 patients suffering from aneurysmal SAH. 16 Patients were affected by symptomatic vasospasm. The RYR1 gene was screened for possible genetic variants by means of direct sequencing. The association of these variants was correlated to the development of symptomatic vasospasm, which was confirmed by clinical examination combined with cerebral angiography, transcranial doppler sonography, or CT scan.\nRESULTS: Three different genetic RYR1 variants (c.5360C>T, c.6178G>T, and c.7244G>A) were identified in the study. The G/T genotype of RYR1 c.6178G>T was associated with an increased risk for development of symptomatic vasospasm (odds ratio 6.4; 95% CI 1.1-37.8; P = 0.04).\nCONCLUSION: Our pilot study suggests that RYRs are involved in the complex pathophysiology of vasospasm development following SAH. The potential role of RYR1 as a biomarker for prediction of cerebral vasospasm after SAH has to be confirmed in a larger clinical trial.","variants":[{"Name":"NM_000540.3(RYR1):c.5360C>T (p.Pro1787Leu)","Chromosome":"19","Start":"38486015","Stop":"38486015","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":136896,"rule_based_match":true,"evidence_text":"c.5360C>T","llm_judgment":"PRESENT","evidence":"c.5360C>T","abstract_start":1183,"abstract_end":1192}]}
{"pmid":"24224009","title":"Novel mutations of ABCB6 associated with autosomal dominant dyschromatosis universalis hereditaria.","abstract":"OBJECTIVE: Dyschromatosis universalis hereditaria (DUH) is a rare heterogeneous pigmentary genodermatosis, which was first described in 1933. The genetic cause has recently been discovered by the discovery of mutations in ABCB6. Here we investigated a Chinese family with typical features of autosomal dominant DUH and 3 unrelated patients with sporadic DUH.\nMETHODS: Skin tissues were obtained from the proband, of this family and the 3 sporadic patients. Histopathological examination and immunohistochemical analysis of ABCB6 were performed. Peripheral blood DNA samples were obtained from 21 affected, 14 unaffected, 11 spouses in the family and the 3 sporadic patients. A genome-wide linkage scan for the family was carried out to localize the causative gene. Exome sequencing was performed from 3 affected and 1 unaffected in the family. Sanger sequencing of ABCB6 was further used to identify the causative gene for all samples obtained from available family members, the 3 sporadic patients and a panel of 455 ethnically-matched normal Chinese individuals.\nRESULTS: Histopathological analysis showed melanocytes in normal control's skin tissue and the hyperpigmented area contained more melanized, mature melanosomes than those within the hypopigmented areas. Empty immature melanosomes were found in the hypopigmented melanocytes. Parametric multipoint linkage analysis produced a HLOD score of 4.68, with markers on chromosome 2q35-q37.2. A missense mutation (c.1663 C>A, p.Gln555Lys) in ABCB6 was identified in this family by exome and Sanger sequencing. The mutation perfectly cosegregated with the skin phenotype. An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient. No mutation in ABCB6 was discovered in the other two sporadic patients. Neither of the two mutations was present in the 455 controls. Melanocytes showed positive immunoreactivity to ABCB6.\nCONCLUSION: Our data add new variants to the repertoire of ABCB6 mutations with DUH.","variants":[{"Name":"NM_005689.4(ABCB6):c.1663C>A (p.Gln555Lys)","Chromosome":"2","Start":"219213495","Stop":"219213495","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":204484,"rule_based_match":true,"evidence_text":"c.1663 C>A, p.Gln555Lys","llm_judgment":"PRESENT","evidence":"c.1663 C>A, p.Gln555Lys","abstract_start":1470,"abstract_end":1493}]}
{"pmid":"38514665","title":"Identification of a novel LDLR p.Glu179Met variant in Thai families with familial hypercholesterolemia and response to treatment with PCSK9 inhibitor.","abstract":"Familial hypercholesterolemia (FH) is a genetic disease characterized by elevated LDL-C levels. In this study, two FH probands and 9 family members from two families from northeastern Thailand were tested for LDLR, APOB, and PCSK9 variants by whole-exome sequencing, PCR-HRM, and Sanger sequencing. In silico analysis of LDLR was performed to analyse its structure‒function relationship. A novel variant of LDLR (c.535_536delinsAT, p.Glu179Met) was detected in proband 1 and proband 2 in homozygous and heterozygous forms, respectively. A total of 6 of 9 family members were heterozygous for LDLR p.Glu179Met variant. Compared with proband 2, proband 1 had higher baseline TC and LDL-C levels and a poorer response to lipid-lowering therapy combined with a PCSK9 inhibitor. Multiple sequence alignment showed that LDLR p.Glu179Met was located in a fully conserved region. Homology modelling demonstrated that LDLR p.Glu179Met variant lost one H-bond and a negative charge. In conclusion, a novel LDLR p.Glu179Met variant was identified for the first time in Thai FH patients. This was also the first report of homozygous FH patient in Thailand. Our findings may expand the knowledge of FH-causing variants in Thai population, which is beneficial for cascade screening, genetic counselling, and FH management to prevent coronary artery disease.","variants":[{"Name":"NM_000527.5(LDLR):c.535_536delinsAT (p.Glu179Met)","Chromosome":"19","Start":"11105441","Stop":"11105442","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"AT","allel_id":2839822,"rule_based_match":true,"evidence_text":"c.535_536delinsAT, p.Glu179Met","llm_judgment":"PRESENT","evidence":"c.535_536delinsAT, p.Glu179Met","abstract_start":413,"abstract_end":443}]}
{"pmid":"32534219","title":"A missense variant, p.(Ile269Asn), in MC4R as a secondary finding in a child with BCL11A-related intellectual disability.","abstract":"We describe a three year old female who underwent clinical exome sequencing and was diagnosed with BCL11A-related intellectual disability/Dias-Logan syndrome due to a de novo, heterozygous variant in the BCL11A gene, NM_018014.3:c.148C > T; p.(Gln50*). A missense variant in MC4R, NM_005912.3:c.806T > A; p.(Ile269Asn), was also reported as a secondary finding. In her family, her father, paternal aunt, and paternal uncle were all reported to have height and weight measurements suggestive of Class 3 obesity with BMI>40 kg/m<sup>2</sup>. The MC4R gene is not currently listed among those recommended for reporting of secondary findings by the American College of Medical Genetics and Genomics (ACMG). The identification of genetic risk factors for obesity is an emerging field without established guidelines for the care of patients who are found to have a predisposing genetic variant for obesity as a secondary finding. Management suggestions include interventions for weight-management, early screening for obesity-related co-morbidities, such as diabetes and dyslipidemia, and targeted therapies, such as MC4R agonists.","variants":[{"Name":"NM_005912.3(MC4R):c.806T>A (p.Ile269Asn)","Chromosome":"18","Start":"60371544","Stop":"60371544","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":45148,"rule_based_match":true,"evidence_text":"NM_005912.3:c.806T > A; p.(Ile269Asn)","llm_judgment":"PRESENT","evidence":"NM_005912.3:c.806T > A; p.(Ile269Asn)","abstract_start":281,"abstract_end":318}]}
{"pmid":"33486620","title":"Neuronal ceroid lipofuscinosis: genetic and phenotypic spectrum of 14 patients from Turkey.","abstract":"INTRODUCTION AND PURPOSE: Neuronal ceroid lipofuscinoses (NCLs) is a group of congenital metabolic diseases where the neurodegenerative process with the accumulation of ceroid and lipofuscin autofluorescent storage materials is at the forefront. According to the age of presentation, NCLs are classified as congenital, infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult (ANCL) NCLs. In our study, it was aimed to discuss the clinical and molecular characteristics of our patients diagnosed with NCL.\nMATERIAL AND METHOD: This is a descriptive cross-sectional study which was conducted in 14 patients from 10 unrelated families who were diagnosed with different types of NCL based on clinical presentation, neuroimaging, biochemical measurements, and molecular analyses, at the department of pediatric metabolism between June 2015 and June 2020.\nRESULTS: A total of 14 patients were diagnosed with different types of NCL. Of those, 4 patients were diagnosed with NCL7 (4/14; 30%), 3/14 (23%) with NCL1, 3/14 (23%) with NCL2, 2/14 (14.2%) with NCL13, and 1/14 (7.1%) with NCL10. Eleven pathogenic variants were detected, 5 of which are novel (c.721G>T [p.Gly241Ter] and c.301G>C [p.Ala146Pro] in MFDS8 gene; c.316C>T [p.Gln106Ter] in PPT1 gene; c.341C>T [p.Ala114Val] in TPP1 gene; c.686A>T [p.Glu229Val] in CTSD gene) CONCLUSION: This study is one of the pioneer comprehensive researches from Turkey that provides information about disease-causing variants and clinical presentation of different and rare types of NCLs. The identification of novel variants and phenotypic expansion is important for genetic counselling in Turkey and expected to improve understanding of NCLs.","variants":[{"Name":"NM_000310.4(PPT1):c.316C>T (p.Gln106Ter)","Chromosome":"1","Start":"40092091","Stop":"40092091","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2947156,"rule_based_match":true,"evidence_text":"c.316C>T [p.Gln106Ter] in PPT1 gene","llm_judgment":"PRESENT","evidence":"c.316C>T [p.Gln106Ter] in PPT1 gene","abstract_start":1224,"abstract_end":1259}]}
{"pmid":"32425876","title":"PCDH19-Related Epilepsy in Early Onset of Chinese Male Patient: Case Report and Literature Review.","abstract":"Mutations in <i>PCDH19</i> are associated with epilepsy, intellectual disability and behavioral disturbances, mostly related to females. The unique X-linked pattern of inheritance affects females predominantly, while usually is transmitted through asymptomatic males. Recently, new research has demonstrated that males with a mosaic pattern of inheritance could also be affected. As yet, <i>PCDH19</i> mutations have been reported in hundreds of females; however, only 15 mosaic males were reported to exhibit epileptic seizures with the onset ranges between 6 and 31 months. These patients were usually reported to carry various mutations in the <i>PCDH19</i>. Here we describe a non-sense variant at the <i>PCDH19</i> (c.498C>G; p.Y166<sup>*</sup>) in the Chinese male that exhibited early developmental delay and frequent seizures starting from the age of 5 months. We aim that this case report, focusing on studying clinical seizures, therapeutic approaches, and the patient's prognosis, will contribute to the cumulative knowledge of this rare and complex genetic disorder.","variants":[{"Name":"NM_001184880.2(PCDH19):c.498C>G (p.Tyr166Ter)","Chromosome":"X","Start":"100408100","Stop":"100408100","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":203940,"rule_based_match":true,"evidence_text":"c.498C>G","llm_judgment":"PRESENT","evidence":"c.498C>G","abstract_start":721,"abstract_end":729}]}
{"pmid":"18728072","title":"Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations.","abstract":"OBJECTIVE: We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to five previously described patients with TUBA1A mutations.\nRESULTS: We detected de novo TUBA1A mutations in six patients and highlight the existence of a prominent form of TUBA1A related lissencephaly. In four patients, the mutations identified, c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R), have not been reported before and in two others, the mutation corresponds to a recurrent missense mutation, c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific to TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia/tetraplegia.\nCONCLUSIONS: Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A related lissencephalies from those related to LIS1, DCX and ARX genes.","variants":[{"Name":"NM_006009.4(TUBA1A):c.1190T>C (p.Leu397Pro)","Chromosome":"12","Start":"49185176","Stop":"49185176","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":22114,"rule_based_match":true,"evidence_text":"c.1190T>C (p.L397P)","llm_judgment":"PRESENT","evidence":"c.1190T>C (p.L397P)","abstract_start":624,"abstract_end":643},{"Name":"NM_006009.4(TUBA1A):c.1264C>T (p.Arg422Cys)","Chromosome":"12","Start":"49185102","Stop":"49185102","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22115,"rule_based_match":true,"evidence_text":"c.1264C>T (p.R422C)","llm_judgment":"PRESENT","evidence":"c.1264C>T (p.R422C)","abstract_start":666,"abstract_end":685},{"Name":"NM_006009.4(TUBA1A):c.1265G>A (p.Arg422His)","Chromosome":"12","Start":"49185101","Stop":"49185101","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22116,"rule_based_match":true,"evidence_text":"c.1265G>A (p.R422H)","llm_judgment":"PRESENT","evidence":"c.1265G>A (p.R422H)","abstract_start":645,"abstract_end":664},{"Name":"NM_006009.4(TUBA1A):c.790C>T (p.Arg264Cys)","Chromosome":"12","Start":"49185576","Stop":"49185576","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22109,"rule_based_match":true,"evidence_text":"c.790C>T (p.R264C)","llm_judgment":"PRESENT","evidence":"c.790C>T (p.R264C)","abstract_start":816,"abstract_end":834}]}
{"pmid":"30528907","title":"Severe aortic valve stenosis in a 14-year-old boy with sitosterolemia.","abstract":"We report a 14-year-old boy finally diagnosed with sitosterolemia, presenting with severe aortic valve stenosis. Genetic analysis revealed homozygous null mutation c.1336 C > T (p.R446X) in ABCG5 gene. His cardiac ultrasound presented aortic valve stenosis and moderate aortic regurgitation. His whole aorta computed tomography angiogram scan revealed aortic stenosis superior to the aortic valve, followed by ascending aorta dilation, whereas his coronary and peripheral arteries appeared normal. His maximum total cholesterol and low-density lipoprotein-cholesterol levels dropped dramatically after diet control, and ezetimibe was prescribed for treatment. The current case indicated that sitosterolemia may be a heterogeneous disease in clinical phenotype.","variants":[{"Name":"NM_022436.3(ABCG5):c.1336C>T (p.Arg446Ter)","Chromosome":"2","Start":"43822924","Stop":"43822924","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39442,"rule_based_match":true,"evidence_text":"c.1336 C > T (p.R446X)","llm_judgment":"PRESENT","evidence":"c.1336 C > T (p.R446X)","abstract_start":164,"abstract_end":186}]}
{"pmid":"26855056","title":"Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia.","abstract":"Neonatal severe hyperparathyroidism (NSHPT) is a rare, life-threatening condition that presents with severe hypercalcemia, hyperparathyroidism, and osteopenia in the newborn period. Treatment of NSHPT traditionally includes hydration and bisphosphonates; however newer calcimimetic agents, such as cinacalcet, are now being utilized to prevent or delay parathyroidectomy which is technically difficult in the newborn. Medical treatment success is related to calcium sensing receptor (CaSR) genotype. We report a 4-day-old infant who presented with hyperbilirubinemia, poor feeding, weight loss, severe hypotonia and was ultimately diagnosed with NSHPT. The patient's total serum calcium level of 36.8 mg/dL (reference range: 8.5-10.4 mg/dL) is, to our knowledge, the highest ever documented in this setting. Exome data previously obtained on the infant's parents was re-analyzed demonstrating bi-parental heterozygosity for a mutation of the CASR gene: c.206G > A, and Sanger sequencing data confirmed the patient was a homozygote for the same mutation. Though a patient with the same CaSR gene mutation described here has responded to cinacalcet, our patient did not respond and required parathyroidectomy. Though this case has previously been published as a surgical case report, a full report of the medical management and underlying genetic etiology is warranted; this case underscores the importance of disclosing bi-parental heterozygosity for a gene causing severe neonatal disease particularly when treatment is available and illustrates the need for further in vitro studies of this CaSR mutation.","variants":[{"Name":"NM_000388.4(CASR):c.206G>A (p.Arg69His)","Chromosome":"3","Start":"122257101","Stop":"122257101","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44451,"rule_based_match":true,"evidence_text":"c.206G > A","llm_judgment":"PRESENT","evidence":"c.206G > A","abstract_start":953,"abstract_end":963}]}
{"pmid":"22629021","title":"Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome.","abstract":"BACKGROUND: Long QT syndrome (LQTS) is characterized by QT prolongation, syncope and sudden death. This study aims to explore the causes, clinical manifestations and therapeutic outcomes of Jervell and Lange-Nielsen syndrome (JLNS), a rare form of LQTS with congenital sensorineural deafness, in Chinese individuals.\nMATERIALS AND METHODS: Three JLNS kindreds from the Chinese National LQTS Registry were investigated. Mutational screening of KCNQ1 and KCNE1 genes was performed by polymerase chain reaction and direct DNA sequence analysis. LQTS phenotype and therapeutic outcomes were evaluated for all probands and family members.\nRESULTS: We identified 7 KCNQ1 mutations. c.1032_1117dup (p.Ser373TrpfsX10) and c.1319delT (p.Val440AlafsX26) were novel, causing JLNS in a 16-year-old boy with a QTc (QT interval corrected for heart rate) of 620 ms and recurrent syncope. c.605-2A>G and c.815G>A (p.Gly272Asp) caused JLNS in a 12-year-old girl and her 5-year-old brother, showing QTc of 590 to 600 ms and recurrent syncope. The fourth JLNS case, a 46-year-old man carrying c.1032G>A (p.Ala344Alasp) and c.569G>A (p.Arg190Gln) and with QTc of 460 ms, has been syncope-free since age 30. His 16-year-old daughter carries novel missense mutation c.574C>T (p.Arg192Cys) and c.1032G>A(p.Ala344Alasp) and displayed a severe phenotype of Romano-Ward syndrome (RWS) characterized by a QTc of 530 ms and recurrent syncope with normal hearing. Both the father and daughter also carried c.253G>A (p.Asp85Asn; rs1805128), a rare single nucleotide polymorphism (SNP) on KCNE1. Bizarre T waves were seen in 3/4 JLNS patients. Symptoms were improved and T wave abnormalities became less abnormal after appropriate treatment.\nCONCLUSION: This study broadens the mutation and phenotype spectrums of JLNS. Compound heterozygous KCNQ1 mutations can result in both JLNS and severe forms of RWS in Chinese individuals.","variants":[{"Name":"NM_000218.3(KCNQ1):c.815G>A (p.Gly272Asp)","Chromosome":"11","Start":"2572880","Stop":"2572880","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67777,"rule_based_match":true,"evidence_text":"c.815G>A (p.Gly272Asp)","llm_judgment":"PRESENT","evidence":"c.815G>A (p.Gly272Asp)","abstract_start":888,"abstract_end":910},{"Name":"NM_000218.3(KCNQ1):c.605-2A>G","Chromosome":"11","Start":"2571323","Stop":"2571323","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1334283,"rule_based_match":true,"evidence_text":"c.605-2A>G","llm_judgment":"PRESENT","evidence":"c.605-2A>G","abstract_start":873,"abstract_end":883},{"Name":"NM_000218.3(KCNQ1):c.569G>A (p.Arg190Gln)","Chromosome":"11","Start":"2570719","Stop":"2570719","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18156,"rule_based_match":true,"evidence_text":"c.569G>A (p.Arg190Gln)","llm_judgment":"PRESENT","evidence":"c.569G>A (p.Arg190Gln)","abstract_start":1104,"abstract_end":1126},{"Name":"NM_000218.3(KCNQ1):c.574C>T (p.Arg192Cys)","Chromosome":"11","Start":"2570724","Stop":"2570724","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":567156,"rule_based_match":true,"evidence_text":"c.574C>T (p.Arg192Cys)","llm_judgment":"PRESENT","evidence":"c.574C>T (p.Arg192Cys)","abstract_start":1244,"abstract_end":1266}]}
{"pmid":"25107857","title":"A case of familial paroxysmal nonkinesigenic dyskinesia due to mutation of the PNKD gene in Chinese Mainland.","abstract":"BACKGROUND: Paroxysmal dyskinesia is a rare neurological disorder characterized by paroxysmal movement disorders. Paroxysmal movement disorders include kinesigenic choreoathetosis, nonkinesigenic choreoathetosis or dyskinesia (PNKD), exercise-induced choreoathetosis, and hypnogenic paroxysmal dystonia. There have been some sporadic reports of PNKD occurrences in Chinese Mainland, but none has been reported on familial PNKD. Proband and methods A 32 years old male admitted to the First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China in 2009 with recurrent limb involuntary movements spanning over 30 years was diagnosed with PNKD. Family history was collected to identify if it was a case of familial or sporadic PNKD. Mutation and linkage analysis were performed to identify the pathogenic gene and the localization of the same.\nRESULTS: There were five generations of 26 patients, out of which 3 of these patients died. Follow-up was conducted on 17 out of the 23 patients alive and 9 normal family members. The pedigree showed autosomal dominant inheritance, whom could be divided into light, moderate, and severe group according to clinical signs, spontaneous attack and response to drugs. All patients harbored c.20C>T (p.A7V) mutation in exon 1 of the PNKD/MR-1 gene. Preliminary linkage analyses using phenocopy rates of 0.0001 and 0.1 suggested that linkage signal localizes between D2S126 and D2S377. The functional consequence of the mutation in the disease pathogenesis is pending investigation. Conclusions We report the first case of familial paroxysmal non-kinesigenic dyskinesia (PNKD) in Chinese Mainland, which coincidentally is also the largest case of familial PNKD ever reported. This article is part of a Special Issue entitled Brain and Memory.","variants":[{"Name":"NM_015488.5(PNKD):c.20C>T (p.Ala7Val)","Chromosome":"2","Start":"218270555","Stop":"218270555","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16932,"rule_based_match":true,"evidence_text":"c.20C>T (p.A7V)","llm_judgment":"PRESENT","evidence":"c.20C>T (p.A7V)","abstract_start":1241,"abstract_end":1256}]}
{"pmid":"28075532","title":"Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism.","abstract":"Essentials Prothrombin Belgrade mutation leads to antithrombin resistance. Clinical and biochemical phenotypes in a large family with this mutation were investigated. In carriers, we detected decreased factor II activity and increased endogenous thrombin potential. Prothrombin Belgrade mutation represents a strong prothrombotic risk factor.\nSUMMARY: Background The recently reported c.1787G>A mutation in the prothrombin gene leads to Arg596Gln replacement in the protein molecule (prothrombin Belgrade). This substitution impairs binding of antithrombin to thrombin and results in inherited thrombophilia, known as antithrombin resistance. Objectives We aimed to elucidate the clinical and biochemical characteristics of thrombophilia associated with antithrombin resistance in a large Serbian family with the prothrombin Belgrade mutation. Patients and methods Nineteen family members were investigated, among whom 10 were carriers of the c.1787G>A mutation. In all subjects the clinical phenotype was determined and laboratory investigations of hemostatic parameters were performed. Results Six out of the 10 mutation carriers developed thromboembolic events, mainly deep venous and mesenteric vein thrombosis. The median age of the first thrombotic event was 26.5 (12-41) years, whereas the incidence rate of first thrombosis was 2.2% per year. In all mutation carriers prothrombin activity was significantly decreased in comparison with non-carriers, clearly distinguishing each group. However, the presence of the mutation did not affect the prothrombin antigen level in plasma. The endogenous thrombin potential was significantly increased in all carriers in comparison with non-carriers, indicating the presence of blood hypercoagulability. Interestingly, levels of D-dimer and the F1+2 fragment were similar in both groups. Conclusions Although rare, the prothrombin Belgrade mutation represents strong thrombophilia with early onset of thrombosis in the investigated family. According to our results, decreased prothrombin activity may be a simple screening test for detection of this mutation in thrombotic patients.","variants":[{"Name":"NM_000506.5(F2):c.1787G>A (p.Arg596Gln)","Chromosome":"11","Start":"46739326","Stop":"46739326","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":679780,"rule_based_match":true,"evidence_text":"c.1787G>A","llm_judgment":"PRESENT","evidence":"c.1787G>A","abstract_start":385,"abstract_end":394}]}
{"pmid":"33414089","title":"Cholestasis as a dominating symptom of patients with CYP27A1 mutations: An analysis of 17 Chinese infants.","abstract":"BACKGROUND: CYP27A1 is the disease-causing gene of cerebrotendinous xanthomatosis (CTX). As a treatable lipid storage disease, early treatment can improve the prognosis. However, CTX patients reported in the literature are mostly adult patients; the phenotype spectrum of CTX in the infantile population remains elusive.\nOBJECTIVE: We aimed to investigate the phenotype spectrum of infants who carried pathogenic or likely pathogenic variants in the CYP27A1 gene and were suspected of having CTX.\nMETHODS: From June 2014 to May 2020, infants with pathogenic or likely pathogenic variants in CYP27A1 gene were enrolled, who underwent next-generation sequencing or Sanger sequencing in Children's Hospital of Fudan University. Patient characteristics, clinical treatments and outcomes were extracted from electronic medical records.\nRESULTS: A total of 17 patients with an average onset age of 8 (1-42) days were found. The average diagnosis age was ten months. Cholestasis was the dominant symptom of these infants. Thirteen variants were detected, of which c.379C > T was a hotspot variant (26.5% alleles, 9/34). Cholestatic CTX is usually underestimated, but it could be severe or even fatal in infancy. For outcomes, 5 suffered from liver failure (36%, 5/14), 1 still showed cholestasis (7%, 1/14), 7 were asymptomatic (50%, 7/14), and 1 presented seizure and developmental delay in later childhood (7%, 1/14).\nCONCLUSION: Based on this infantile cohort, we concluded that it is necessary to consider the possibility of CTX caused by CYP27A1 gene variants for infants with cholestasis.","variants":[{"Name":"NM_000784.4(CYP27A1):c.379C>T (p.Arg127Trp)","Chromosome":"2","Start":"218809700","Stop":"218809700","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76773,"rule_based_match":true,"evidence_text":"c.379C > T","llm_judgment":"PRESENT","evidence":"c.379C > T","abstract_start":1057,"abstract_end":1067}]}
{"pmid":"36973888","title":"X-linked myotubular myopathy: a clinical report and a review of the mild phenotype.","abstract":"INTRODUCTION: X-linked myotubular myopathy is a rare centronuclear myopathy that affects approximately 1 in 50,000 male newborns caused by pathogenic variants in the myotubularin 1 gene (MTM1). The clinical severity varies, however the need for ventilatory support occurs almost invariably.\nCASE REPORT: We report the case of a 4-year-old boy presenting mild muscle hypotonia at 12 months-old, expressive language disorder, global developmental delay, and a sensory processing disorder. Clinical exome sequencing identified the hemizygous variant c.722G>A p.(Arg241His) in exon 9 of the myotubularin 1 gene (NM_000252.2). The mother is a heterozygous carrier of the same variant. A diagnosis of a mild form of maternal inherited X-linked myotubular myopathy was established. The child presented significant improvement with speech, occupational, and physical therapies, with no respiratory intercurrences or ventilator dependency.\nCONCLUSION: The presentation of a mild form of this myotubular myopathy, being less commonly reported, added challenge to the diagnosis. The combination of mild hypotonia, feeding difficulties and expressive language disorder should raise suspicion of a neuromuscular disease. There is a lack of verified motor or developmental scores specific to this myopathy to further determine prognosis and need of other therapies. While currently the severity myotubular myopathy is classified according to ventilator dependency, this may be insufficient and unapplicable to milder cases. There is an evident need for a grading system for mild and moderate cases assessing muscle weakness and fatigue, daily life limitations, motor developmental delay, early phenotypical scores, or recurrent respiratory infections.","variants":[{"Name":"NM_000252.3(MTM1):c.722G>A (p.Arg241His)","Chromosome":"X","Start":"150645726","Stop":"150645726","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3494671,"rule_based_match":true,"evidence_text":"c.722G>A p.(Arg241His)","llm_judgment":"PRESENT","evidence":"c.722G>A p.(Arg241His)","abstract_start":547,"abstract_end":569}]}
{"pmid":"21108397","title":"Familial Ohtahara syndrome due to a novel ARX gene mutation.","abstract":"Recently, it has been reported that longer expansions of the polyalanine tract of the ARX gene could cause an early infantile encephalopathy with suppression burst pattern and that the length of this repeat region could be related to the severity of the electroclinical picture. We describe the history of two male individuals, born from monozygotic twin sisters, with Ohtahara syndrome (OS) that evolved into West syndrome phenotype and epileptic encephalopathy. In both children, we have found a previously unreported missense mutation in exon 5 of ARX gene (c.1604T>A) resulting in the substitution of a leucine with a glutamine in the aminoacid sequence. The two mothers and the maternal grandmother carry the same mutation which segregates with the disease phenotype in the family. This study confirms that ARX is involved in the pathogenesis of cryptogenic early onset epileptic encephalopathy, such as OS, and suggests that the severity of the electroclinical picture is likely to not exclusively correlate with the extent of expansions of the polyalanine tracts, but rather with the functional effect of different pathogenetic mutations.","variants":[{"Name":"NM_139058.3(ARX):c.1604T>A (p.Leu535Gln)","Chromosome":"X","Start":"25004755","Stop":"25004755","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":38920,"rule_based_match":true,"evidence_text":"c.1604T>A","llm_judgment":"PRESENT","evidence":"c.1604T>A","abstract_start":561,"abstract_end":570}]}
{"pmid":"20442745","title":"Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population.","abstract":"Screening for carriers of spinal muscular atrophy (SMA) is necessary for effective clinical/prenatal diagnosis and genetic counseling. However, a population-based study of SMA prevalence in mainland China has not yet been conducted. In this study, the copy number of survival motor neuron (SMN) genes was determined in 1712 newborn cord blood samples collected from southern China and from 25 core families, which included 26 SMA patients and 44 parents, to identify SMA carriers. The results presented 13 groups with different SMN1/SMN2 ratios among 1712 newborn individuals, which corresponded to 1535 subjects with two copies of SMN1, 119 with three copies of SMN1, 17 with four copies of SMN1, and 41 with a heterozygous deletion of SMN1 exon 7. Simultaneously, two '2+0' genotypes and two point mutations were found among the 44 obligate carriers in the core families, including a novel SMN1 splice-site mutation that was identified in the junction between intron 6 and exon 7 (c. 835-1G>A). These results indicated that the carrier frequency is 1/42 in the general Chinese population and that duplicated SMN1 alleles and de novo deletion mutations are present in a small number of SMA carriers. In addition, we developed and validated a new alternative screening method using a reverse dot blot assay for rapid genotyping of deletional SMA. Our research elucidated the genetic load and SMN gene variants that are present in the Chinese population, and could serve as the basis for a nationwide program of genetic counseling and clinical/prenatal diagnosis to prevent SMA in China.","variants":[{"Name":"NM_000344.4(SMN1):c.835-1G>A","Chromosome":"5","Start":"70951940","Stop":"70951940","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":621745,"rule_based_match":true,"evidence_text":"c. 835-1G>A","llm_judgment":"PRESENT","evidence":"c. 835-1G>A","abstract_start":983,"abstract_end":994}]}
{"pmid":"31848916","title":"HINT1 gene pathogenic variants: the most common cause of recessive hereditary motor and sensory neuropathies in Russian patients.","abstract":"Pathogenic variants in the HINT1 gene lead to hereditary axonopathy with neuromyotonia. However, many studies show that neuromyotonia may remain undiagnosed, while axonopathy is the major clinical finding. The most common cause of neuromyotonia and axonopathy, especially in patients of Slavic origin, is a c.110G>C (p.Arg37Pro) pathogenic variant in homozygous or compound heterozygous state. In this study, we analyzed a peripheral neuropathy caused by pathogenic variants in the HINT1 gene and evaluated its contribution to the hereditary neuropathy structure. The studied group included 1596 non-related families diagnosed with hereditary motor and sensory neuropathy (HMSN). The results show that HINT1 gene pathogenic variants make a significant contribution to the hereditary neuropathy epidemiology in Russian patients. They account for at least 1.9% of all HMSN cases and 9% of axonopathy cases. The most common HINT1 pathogenic variant in Russian patients is the c.110G>C (p.Arg37Pro) substitution. Its allelic frequency is 0.2% (95% CI 0.19-0.21%), carrier frequency is 1 in 250 people in Russian Federation, and the estimated disease incidence is 1 in 234,000 individuals. It was determined that the cause of this pathogenic variant's prevalence is the founder effect.","variants":[{"Name":"NM_005340.7(HINT1):c.110G>C (p.Arg37Pro)","Chromosome":"5","Start":"131165096","Stop":"131165096","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":45887,"rule_based_match":true,"evidence_text":"c.110G>C (p.Arg37Pro)","llm_judgment":"PRESENT","evidence":"c.110G>C (p.Arg37Pro)","abstract_start":307,"abstract_end":328}]}
{"pmid":"23418033","title":"Novel CYP2B6 enzyme variants in a Rwandese population: functional characterization and assessment of in silico prediction tools.","abstract":"Cytochrome P450 CYP2B6 is a highly polymorphic enzyme that metabolizes numerous drugs, pesticides, and environmental toxins. Sequence analysis of a Rwandese population identified eight functionally uncharacterized nonsynonymous variants c.329G>T (p.G110V), c.341T>C (p.I114T), c.444G>T (p.E148D), c.548T>G (p.V183G), c.637T>C (p.F213L), c.758G>A (p.R253H), c.835G>C (p.A279P), and c.1459C>A (p.R487S), and five novel alleles termed CYP2B6*33 to CYP2B6*37 were assigned. Recombinant expression in COS-1 cells and functional characterization using the antidepressant bupropion and the antiretroviral efavirenz (EFV) as substrates demonstrated complete or almost complete loss-of-function for variants p.G110V, p.I114T, p.V183G, and p.F213L, whereas p.E148D, p.R253H, p.A279P, and p.R487S variants were functional. The data were used to assess the predictive power of eight online available functional prediction programs for amino-acid changes. Although none of the programs correctly predicted the functionality of all variants, substrate docking simulation analyses indicated similar conformational changes by all four deleterious mutations within the enzyme's active site, thus explaining lack of enzymatic function for both substrates. Because low-activity alleles of CYP2B6 are associated with impaired EFV metabolism and adverse drug response, these results are of potential utility for personalized treatment strategies in HIV/AIDS therapy.","variants":[{"Name":"NM_000767.5(CYP2B6):c.329G>T (p.Gly110Val)","Chromosome":"19","Start":"41004158","Stop":"41004158","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":125780,"rule_based_match":true,"evidence_text":"c.329G>T (p.G110V)","llm_judgment":"PRESENT","evidence":"c.329G>T (p.G110V)","abstract_start":237,"abstract_end":255},{"Name":"NM_000767.5(CYP2B6):c.341T>C (p.Ile114Thr)","Chromosome":"19","Start":"41004303","Stop":"41004303","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":125781,"rule_based_match":true,"evidence_text":"c.341T>C (p.I114T)","llm_judgment":"PRESENT","evidence":"c.341T>C (p.I114T)","abstract_start":257,"abstract_end":275},{"Name":"NM_000767.5(CYP2B6):c.548T>G (p.Val183Gly)","Chromosome":"19","Start":"41006968","Stop":"41006968","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":125782,"rule_based_match":true,"evidence_text":"c.548T>G (p.V183G)","llm_judgment":"PRESENT","evidence":"c.548T>G (p.V183G)","abstract_start":297,"abstract_end":315},{"Name":"NM_000767.5(CYP2B6):c.637T>C (p.Phe213Leu)","Chromosome":"19","Start":"41007057","Stop":"41007057","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":125783,"rule_based_match":true,"evidence_text":"c.637T>C (p.F213L)","llm_judgment":"PRESENT","evidence":"c.637T>C (p.F213L)","abstract_start":317,"abstract_end":335}]}
{"pmid":"24464670","title":"Prevention of metabolic decompensation in an infant with mutase deficient methylmalonic aciduria undergoing cardiopulmonary bypass.","abstract":"BACKGROUND: Effects of circulatory arrest upon an inborn error of metabolism patient are unknown.\nMETHODS: A retrospective chart review was performed of outcome and biochemical parameters obtained during palliative cardiac surgery for a mutase-deficient methylmalonic aciduria patient with Ebstein's cardiac anomaly was performed.\nRESULTS: The levels of ammonia, methylmalonic acid, free carnitine, and propionylcarnitine of the patient were improved. The patient survived surgery following institution of four metabolic treatment principles: 1) restriction of toxic substrate; 2) promotion of anabolism via administration of carbohydrate and lipid calories; 3) administration of detoxifying levocarnitine and sodium benzoate; and 4) cobalamin enzymatic co-factor administration. The patient died from post-operative dysrhythmia and was posthumously determined to have compound heterozygosity for mutations predicting severe, cobalamin non-responsive disease: c.322C>T/c.1233del3 (p.R108C/p.ΔI412).\nCONCLUSION: Metabolic decompensation is preventable during cardiopulmonary bypass and cardioplegia using four principles of metabolic treatment.","variants":[{"Name":"NM_000255.4(MMUT):c.322C>T (p.Arg108Cys)","Chromosome":"6","Start":"49459145","Stop":"49459145","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16926,"rule_based_match":true,"evidence_text":"c.322C>T (p.R108C/p.ΔI412)","llm_judgment":"PRESENT","evidence":"c.322C>T","abstract_start":960,"abstract_end":968}]}
{"pmid":"36338977","title":"Case report: A late-onset cobalamin C defect first presenting as a depression in a teenager.","abstract":"<b>Background:</b> The cobalamin C (cblC) defect, a common inborn disorder of cobalamin metabolism due to a genetic mutation in <i>MMACHC</i>, can cause combined methylmalonic acid and homocysteine accumulation in blood, urine, or both. In this article, a late-onset case was reported, and the patient first presented with depression identified with the <i>MMACHC</i> gene. We summarized the clinical features of the cblC defect, the relationship between genotype and phenotype, and the clinical experience concerning the diagnosis and treatment of the cblC defect. <b>Case presentation:</b> Initially presented with depression, the 16-year-old female patient showed progressive abnormal gait and bilateral lower limb weakness after 3 months. Blood routine examination suggested severe hyperhomocysteinemia, and screening for urine organic acids found elevated methylmalonic acid. Family gene sequencing showed mutations detected in <i>MMACHC</i>. She had a compound heterozygous mutation, while the c.271dupA (p.R91Kfs∗14) was only detected in her father and the c.482 G>A (p.R161Q) was only detected in her mother. Hence, she was diagnosed with a cblC defect and treated with B vitamin supplements. The muscle strength of both lower limbs improved notably. <b>Conclusion:</b> This case indicated that depression could be a presenting sign of cblC-type methylmalonic aciduria and homocysteinemia, and enhanced the genotype-phenotype relationship of the cblC defect, which will contribute to further understanding of this emerging disease.","variants":[{"Name":"NM_015506.3(MMACHC):c.271dup (p.Arg91fs)","Chromosome":"1","Start":"45507544","Stop":"45507545","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":16460,"rule_based_match":true,"evidence_text":"c.271dupA (p.R91Kfs∗14)","llm_judgment":"PRESENT","evidence":"c.271dupA (p.R91Kfs∗14)","abstract_start":1000,"abstract_end":1023}]}
{"pmid":"16791840","title":"Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.","abstract":"Ten years ago, the groundwork for the discovery of the genetic basis of chronic pancreatitis was laid by linkage analyses of large kindreds with autosomal dominant hereditary chronic pancreatitis. Subsequent candidate gene sequencing of the 7q35 chromosome region revealed a strong association of the c.365G > A (p.R122 H) mutation of the PRSS1 gene encoding cationic trypsinogen with hereditary pancreatitis. In the following years, further mutations of this gene were discovered in patients with hereditary or idiopathic chronic pancreatitis. In vitro the mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation in vivo. The clinical presentation is highly variable, but most affected mutation carriers have relatively mild disease. In this review, we summarize the current knowledge on trypsinogen mutations and their role in pancreatic diseases.","variants":[{"Name":"NM_002769.5(PRSS1):c.365G>A (p.Arg122His)","Chromosome":"7","Start":"142751938","Stop":"142751938","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26915,"rule_based_match":true,"evidence_text":"c.365G > A (p.R122 H)","llm_judgment":"PRESENT","evidence":"c.365G > A (p.R122 H)","abstract_start":301,"abstract_end":322}]}
{"pmid":"35247231","title":"Genome sequencing reveals novel noncoding variants in PLA2G6 and LMNB1 causing progressive neurologic disease.","abstract":"Neurodegenerative disorders and leukodystrophies are progressive neurologic conditions that can occur following the disruption of intricately coordinated patterns of gene expression. Exome sequencing has been adopted as an effective diagnostic tool for determining the underlying genetic etiology of Mendelian neurologic disorders, however genome sequencing offer advantages in its ability to identify and characterize copy number, structural, and sequence variants in noncoding regions. Genome sequencing from peripheral leukocytes was performed on two patients with progressive neurologic disease of unknown etiology following negative genetic investigations including exome sequencing. RNA sequencing from peripheral blood was performed to determine gene expression patterns in one of the patients. Potential causative variants were matched to the patients' clinical presentation. The first proband was found to be heterozygous for a likely pathogenic missense variant in PLA2G6 (c.386T>C; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6 (c.2035-926G>A). RNA sequencing indicated this latter variant created a splice acceptor site leading to the incorporation of a pseudo-exon introducing a premature termination codon. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. Previous reports of copy number variants spanning this region of cis-acting regulatory elements corroborated its pathogenicity. When combined with clinical presentations, these findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult-onset demyelinating leukodystrophy, respectively. In patients with progressive neurologic disease of unknown etiology, genome sequencing with the addition of RNA analysis where appropriate should be considered for the identification of causative noncoding pathogenic variants.","variants":[{"Name":"NM_003560.4(PLA2G6):c.386T>C (p.Leu129Pro)","Chromosome":"22","Start":"38145477","Stop":"38145477","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":169816,"rule_based_match":true,"evidence_text":"c.386T>C; p.Leu129Pro","llm_judgment":"PRESENT","evidence":"c.386T>C; p.Leu129Pro","abstract_start":983,"abstract_end":1004},{"Name":"NM_003560.4(PLA2G6):c.2035-926G>A","Chromosome":"22","Start":"38114580","Stop":"38114580","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1709968,"rule_based_match":true,"evidence_text":"c.2035-926G>A","llm_judgment":"PRESENT","evidence":"c.2035-926G>A","abstract_start":1062,"abstract_end":1075}]}
{"pmid":"30599486","title":"A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets.","abstract":"X-linked hypophosphatemic rickets is caused by loss-of-function mutations in PHEX, which encodes a phosphate-regulating endopeptidase homolog. We report a 26-year-old man with X-linked hypophosphatemic rickets who showed decreased serum phosphate accompanied by bilateral genu valgum and short stature. He had received medical treatment with vitamin D (alfacalcidol) and phosphate from the age of 3 to 20 years. He underwent surgery due to valgus deformity at the age of 14 and 15. Targeted gene panel sequencing for Mendelian genes identified a nonsense mutation in PHEX (c.589C&gt;T; p.Gln197Ter) and a mosaic pattern where only 38% of sequence reads showed the variant allele. This mutation was not found in his mother, who had a normal phenotype. This is a case of a sporadic nonsense mutation in PHEX and up to date, this is the first case of a mosaic mutation in PHEX in Korea.","variants":[{"Name":"NM_000444.6(PHEX):c.589C>T (p.Gln197Ter)","Chromosome":"X","Start":"22077628","Stop":"22077628","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3074078,"rule_based_match":false,"evidence_text":"c.589C>T (p.Gln197Ter)","llm_judgment":"PRESENT","evidence":"p.Gln197Ter","abstract_start":586,"abstract_end":597}]}
{"pmid":"10767182","title":"An unexpected affected female patient in a classical Lesch-Nyhan family.","abstract":"Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classical phenotype, which includes spasticity, involuntary movements, developmental disability, and self-injurious behavior, occurs exclusively in males, while heterozygous, carrier females are clinically normal. We analyzed an Argentine family in which there were male and female siblings with clinically identical classic features of Lesch-Nyhan disease. The mother and an older daughter were carriers and had normal phenotypes. We identified the HPRT mutation in the family. It is a C --> T transition at position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169) to the TGA stop codon (R169X). The female patient was karyotypically normal and heterozygous for the mutation. She inherited the HPRT mutation from her mother, but she also had unexpected nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene. This additional genetic alteration is the cause of the clinical expression of disease in this female patient.","variants":[{"Name":"NM_000194.3(HPRT1):c.508C>T (p.Arg170Ter)","Chromosome":"X","Start":"134498412","Stop":"134498412","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25102,"rule_based_match":false,"evidence_text":"c.508 C --> T","llm_judgment":"PRESENT","evidence":"c.508 C --> T","abstract_start":795,"abstract_end":808}]}
{"pmid":"17366579","title":"Familial neonatal Marfan syndrome due to parental mosaicism of a missense mutation in the FBN1 gene.","abstract":"We present a family in which three siblings were born with neonatal Marfan syndrome (MFS) to unaffected parents. The clinical findings included joint contractures, large ears, loose skin, ectopia lentis, muscular hypoplasia, aortic root dilatation, mitral and tricuspid valve insufficiency, and pulmonary emphysema. All three siblings died due to cardiorespiratory insufficiency by 2-4 months of age. Screening of the FBN1 gene showed the heterozygous c.3257G > A (p.Cys1086Tyr) mutation in the proband. Mosaicism of the mutation was demonstrated in the somatic cells and in the germ line of the father. Although three examples of parental mosaicism for classical MFS were demonstrated previously, this is the first report of familial occurrence of neonatal MFS due to a heterozygous mutation in FBN1. In conclusion, the p.Cys1086Tyr mutation in FBN1 is consistently associated with neonatal MFS. Parental mosaicism should always be kept in mind when counseling families with MFS.","variants":[{"Name":"NM_000138.5(FBN1):c.3257G>A (p.Cys1086Tyr)","Chromosome":"15","Start":"48488193","Stop":"48488193","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31504,"rule_based_match":true,"evidence_text":"c.3257G > A (p.Cys1086Tyr)","llm_judgment":"PRESENT","evidence":"c.3257G > A (p.Cys1086Tyr)","abstract_start":452,"abstract_end":478}]}
{"pmid":"29458334","title":"Identification of novel L2HGDH mutation in a large consanguineous Pakistani family- a case report.","abstract":"BACKGROUND: L-2-hydroxyglutaric aciduria (L2HGA) is a progressive neurometabolic disease of brain caused by mutations of in L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. Cardinal clinical features include cerebellar ataxia, epilepsy, neurodevelopmental delay, intellectual disability, and other clinical neurological deficits.\nCASE PRESENTATION: We describe an index case of the family presented with generalised tonic-clonic seizure, developmental delay, intellectual disability, and ataxia. Initially, the differential diagnosis was difficult to be established and a SNP genome wide scan identified the candidate region on chromosome 14q22.1. DNA sequencing showed a novel homozygous mutation in the candidate gene L2HGDH (NM_024884.2: c.178G > A; p.Gly60Arg). The mutation p.Gly60Arg lies in the highly conserved FAD/NAD(P)-binding domain of this mitochondrial enzyme, predicted to disturb enzymatic function.\nCONCLUSIONS: The combination of homozygosity mapping and DNA sequencing identified a novel mutation in Pakistani family with variable clinical features. This is second report of a mutation in L2HGDH gene from Pakistan and the largest family with L2HGA reported to date.","variants":[{"Name":"NM_024884.3(L2HGDH):c.178G>A (p.Gly60Arg)","Chromosome":"14","Start":"50302980","Stop":"50302980","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1892278,"rule_based_match":true,"evidence_text":"NM_024884.2: c.178G > A; p.Gly60Arg","llm_judgment":"PRESENT","evidence":"NM_024884.2: c.178G > A; p.Gly60Arg","abstract_start":729,"abstract_end":764}]}
{"pmid":"16950801","title":"Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.","abstract":"Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.","variants":[{"Name":"NM_002087.4(GRN):c.1477C>T (p.Arg493Ter)","Chromosome":"17","Start":"44352404","Stop":"44352404","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31053,"rule_based_match":true,"evidence_text":"c.1477C>T (p.Arg493X)","llm_judgment":"PRESENT","evidence":"c.1477C>T (p.Arg493X)","abstract_start":1225,"abstract_end":1246}]}
{"pmid":"12124998","title":"Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia.","abstract":"Phytosterolemia or Sitosterolemia is a rare autosomal recessive disorder characterized by highly elevated plasma levels of plant sterols and cholesterol as a consequence of hyperabsorption and impaired biliary secretion of sterols. The disease is caused by mutations in two half size ATP-binding cassette transporters, ABCG5 and ABCG8. We have analyzed the genomic sequence of ABCG5 and ABCG8 in five well-characterized patients with Sitosterolemia. In the first patient we found a heterozygous mutation in exon 8 of the ABCG5 gene leading to a premature termination of the protein (Arg408Ter). This German patient is the first European showing a mutation of the ABCG5 gene. In a second patient we found a novel heterozygous mutation in exon 5 of ABCG8 (c.584T>A; Leu195Gln). Both patients were heterozygous for the identified mutation, but no mutation could be identified on the other chromosome. In three further analyzed patients we found mutations in exons 7, 9 and 11 of the ABCG8 gene, respectively, of which two result in a premature termination signal for translation products. One of these patients was compound heterozygous (Trp361Ter and Arg412Ter), the other was homozygous for Trp361Ter. The third patient was homozygous for an amino acid exchange (Gly574Arg). In conclusion this report describes one novel mutation affecting a highly conserved amino acid and two previously identified mutations in the ABCG8 gene. In addition, we identified for the first time a mutation in the ABCG5 gene of a European Sitosterolemia patient.","variants":[{"Name":"NM_022437.3(ABCG8):c.584T>A (p.Leu195Gln)","Chromosome":"2","Start":"43852376","Stop":"43852376","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1925286,"rule_based_match":true,"evidence_text":"c.584T>A (Leu195Gln)","llm_judgment":"PRESENT","evidence":"c.584T>A","abstract_start":754,"abstract_end":762}]}
{"pmid":"26443266","title":"A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.","abstract":"PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.","variants":[{"Name":"NM_000314.8(PTEN):c.545T>C (p.Leu182Ser)","Chromosome":"10","Start":"87952170","Stop":"87952170","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":185731,"rule_based_match":true,"evidence_text":"NM_000314.4; c.545T>C; p.Leu182Ser","llm_judgment":"PRESENT","evidence":"NM_000314.4; c.545T>C; p.Leu182Ser","abstract_start":393,"abstract_end":427}]}
{"pmid":"35178478","title":"Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene.","abstract":"Malignant hyperthermia (MH) is an autosomal dominant genetic condition of the skeletal muscle triggered by inhaled general anesthetic agents or succinylcholine and associated with a hypermetabolic state and skeletal muscle rigidity. Tachycardia, increased carbon dioxide production, hypercarbia, hyperthermia, acidosis, hyperkalemia, cardiac arrhythmias, muscle rigidity, and rhabdomyolysis are common symptoms of MH. As the progression of the syndrome could be rapid or less evident, even experienced physicians have difficulty in diagnosing MH, which can lead to delays in treatment and increased mortality. We report a rare case of a 36-year-old man, who underwent open reduction and internal fixation of the left clavicle after inhaled anesthetics. The patient developed dyspnea, hypotension, unremitting hyperthermia, tachycardia, and elevated serum myoglobin, and finally died of pyemia and disseminated intravascular coagulation. We reviewed the process of disease development, summarized the steps of diagnosis, and improved genetic testing. Exome sequencing revealed a new mutation c.8519G>A (p.arg2840 GLN) in the RYR1 gene that could be associated with MH. The gene mutation was also found in his daughter's genetic test. This case emphasized the importance of the awareness of MH and its atypical clinical symptoms. The presence of dyspnea, hypotension, unremitting hyperthermia, tachycardia, and raised myoglobin in serum might further strengthen the clinical diagnosis of suspected MH.","variants":[{"Name":"NM_000540.3(RYR1):c.8519G>A (p.Arg2840Gln)","Chromosome":"19","Start":"38505924","Stop":"38505924","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":919859,"rule_based_match":true,"evidence_text":"c.8519G>A (p.arg2840 GLN)","llm_judgment":"PRESENT","evidence":"c.8519G>A (p.arg2840 GLN)","abstract_start":1091,"abstract_end":1116}]}
{"pmid":"16166444","title":"Molecular alterations in tumors and response to combination chemotherapy with gefitinib for advanced colorectal cancer.","abstract":"PURPOSE: Recently, activating mutations of the epidermal growth factor receptor (EGFR) gene were discovered in non-small cell lung cancers sensitive to gefitinib (ZD1839, an EGFR tyrosine kinase inhibitor) but not in gefitinib-resistant cancers. Abnormalities of EGFR and related pathways may have an effect on responsiveness of advanced colorectal cancer to combination chemotherapy with gefitinib.\nEXPERIMENTAL DESIGN: We examined patients with previously untreated metastatic colorectal cancer, who were enrolled into two phase I/II trials of combination chemotherapy (irinotecan, leucovorin, and 5-fluorouracil) and daily oral gefitinib. We obtained paraffin tissue blocks of primary tumors from 31 patients, sequenced the EGFR, KRAS, and BRAF genes, and did immunohistochemistry for EGFR, phosphorylated AKT1, p53, p21, and p27.\nRESULTS: Twelve (39%) of the 31 patients experienced a partial objective response to the therapy. A novel EGFR mutation in exon 18 (c.2170G>A, p.Gly724Ser) was identified in only one patient who did not experience an objective tumor response. EGFR immunohistochemistry was not predictive of responsiveness. In contrast, loss of p21 was associated with a higher response rate to therapy (P = 0.05). Moreover, the response rate among patients whose tumors maintained p21 expression and possessed a mutation in p53 was only 9% (1 of 11, P = 0.005). Overexpression of phosphorylated AKT1 also seemed to predict a trend towards resistance to the therapy.\nCONCLUSIONS: p21 expression in colorectal cancer, especially in combination with p53 mutation, is a predictor of resistance to the combination chemotherapy with gefitinib. Activating EGFR mutations are rare in colorectal cancer and do not seem to confer sensitivity to gefitinib and chemotherapy.","variants":[{"Name":"NM_005228.5(EGFR):c.2170G>A (p.Gly724Ser)","Chromosome":"7","Start":"55174029","Stop":"55174029","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":363239,"rule_based_match":true,"evidence_text":"c.2170G>A, p.Gly724Ser","llm_judgment":"PRESENT","evidence":"c.2170G>A, p.Gly724Ser","abstract_start":966,"abstract_end":988}]}
{"pmid":"26553470","title":"Correction of a Cystic Fibrosis Splicing Mutation by Antisense Oligonucleotides.","abstract":"Cystic fibrosis (CF), the most common life-threatening genetic disease in Caucasians, is caused by ∼2,000 different mutations in the CF transmembrane conductance regulator (CFTR) gene. A significant fraction of these (∼13%) affect pre-mRNA splicing for which novel therapies have been somewhat neglected. We have previously described the effect of the CFTR splicing mutation c.2657+5G>A in IVS16, showing that it originates transcripts lacking exon 16 as well as wild-type transcripts. Here, we tested an RNA-based antisense oligonucleotide (AON) strategy to correct the aberrant splicing caused by this mutation. Two AONs (AON1/2) complementary to the pre-mRNA IVS16 mutant region were designed and their effect on splicing was assessed at the RNA and protein levels, on intracellular protein localization and function. To this end, we used the 2657+5G>A mutant CFTR minigene stably expressed in HEK293 Flp-In cells that express a single copy of the transgene. RNA data from AON1-treated mutant cells show that exon 16 inclusion was almost completely restored (to 95%), also resulting in increased levels of correctly localized CFTR protein at the plasma membrane (PM) and with increased function. A novel two-color CFTR splicing reporter minigene developed here allowed the quantitative monitoring of splicing by automated microscopy localization of CFTR at the PM. The AON strategy is thus a promising therapeutic approach for the specific correction of alternative splicing.","variants":[{"Name":"NM_000492.4(CFTR):c.2657+5G>A","Chromosome":"7","Start":"117602868","Stop":"117602868","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":47062,"rule_based_match":true,"evidence_text":"c.2657+5G>A","llm_judgment":"PRESENT","evidence":"c.2657+5G>A","abstract_start":375,"abstract_end":386}]}
{"pmid":"36407031","title":"RET T244I Germline Variant Mutation in a Patient with Pancreatic Paraganglioma and Primary Hyperparathyroidism.","abstract":"Introduction: Paragangliomas are rare neuroendocrine tumors that arise from chromaffin cells. Often termed extra-adrenal pheochromocytomas, these tumors vary with regards to their functionality, location, and malignant potential. Mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia syndrome type 2 (MEN-2) and paragangliomas. The phenotypes of the individual mutations are documented to help determine prognosis.\nCase Presentation: We report a case of a 64-year-old man with a history of parathyroid adenoma who developed a pancreatic retroperitoneal paraganglioma. Despite having laboratory evidence of excess circulating catecholamines, the patient's only presenting symptom was hip pain. The patient underwent resection, and histologic findings were consistent with paraganglioma with lymph node metastasis. Genetic testing revealed a variant of uncertain significance within the RET gene [c.731C>T (p.T244I)].\nConclusions: Paragangliomas are rare extra-adrenal neuroendocrine tumors that can be associated with germline mutations. Our patient was diagnosed with a pancreatic paraganglioma associated with a RET T244I mutation. Identifying patients with germline mutations is important for documenting phenotypic presentations of RET gene variants of uncertain significance, which will allow physicians to provide proper management and surveillance of paragangliomas and other associated tumors.","variants":[{"Name":"NM_020975.6(RET):c.731C>T (p.Thr244Ile)","Chromosome":"10","Start":"43105057","Stop":"43105057","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":460009,"rule_based_match":true,"evidence_text":"c.731C>T (p.T244I)","llm_judgment":"PRESENT","evidence":"c.731C>T (p.T244I)","abstract_start":926,"abstract_end":944}]}
{"pmid":"38775840","title":"A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.","abstract":"RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4<sup>+</sup> T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOH<sup>C82Y</sup>, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.","variants":[{"Name":"NM_004310.5(RHOH):c.245G>A (p.Cys82Tyr)","Chromosome":"4","Start":"40243631","Stop":"40243631","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3543312,"rule_based_match":true,"evidence_text":"NM_004310.5(RHOH):c.245G>A (p.Cys82Tyr)","llm_judgment":"PRESENT","evidence":"p.Cys82Tyr","abstract_start":303,"abstract_end":313}]}
{"pmid":"28477317","title":"TP53 germline and somatic mutations in a patient with fibrolamellar hepatocellular carcinoma.","abstract":"Li-Fraumeni syndrome is a rare hereditary cancer predisposition syndrome associated with germline pathogenic variants in TP53 gene. The phenotype may vary from classical to variant forms, known as Li-Fraumeni-like phenotypes. We searched for pathogenic variants in TP53 in a 14 year-old female diagnosed with fibrolamellar hepatocellular carcinoma, a rare subtype of hepatocellular carcinoma. The proband is a heterozygote carrier of the TP53 c.467G>A (p.Arg156His) in exon 5, and her mother is an asymptomatic carrier. Analysis of tumor DNA disclosed an additional somatic mutation in TP53, c.461G>A; p.Gly154Asp. The TP53 germline and somatic pathogenic variants may have acted as possible driver mutations, resulting in genomic instability and tumor development. The fibrolamellar subtype of hepatocellular carcinoma may be part of the broad spectrum of tumors associated with Li-Fraumeni phenotype.","variants":[{"Name":"NM_000546.6(TP53):c.467G>A (p.Arg156His)","Chromosome":"17","Start":"7675145","Stop":"7675145","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":133268,"rule_based_match":true,"evidence_text":"TP53 c.467G>A (p.Arg156His)","llm_judgment":"PRESENT","evidence":"TP53 c.467G>A (p.Arg156His)","abstract_start":438,"abstract_end":465}]}
{"pmid":"32660024","title":"","abstract":"Over 175 pathogenic mutations in the Peripherin-2 (<i>PRPH2)</i> gene are linked to various retinal diseases. We report the phenotype and genotype of eight families (24 patients) with retinal diseases associated with seven distinct <i>PRPH2</i> gene mutations. We identified a new mutation, c.824_828+3delinsCATTTGGGCTCCTCATTTGG, in a patient with adult-onset vitelliform macular dystrophy (AVMD). One family with the p.Arg46Ter mutation presented with the already described AVMD phenotype, but another family presented with the same mutation and two heterozygous pathogenic mutations (p.Leu2027Phe and p.Gly1977Ser) in the ATP Binding Cassette Subfamily A Member 4 (<i>ABCA4</i>) gene that cause extensive chorioretinal atrophy (ECA), which could be a blended phenotype. The p.Lys154del <i>PRPH2</i> gene mutation associated with the p.Arg2030Glu mutation in the <i>ABCA4</i> gene was found in a patient with multifocal pattern dystrophy simulating fundus flavimaculatus (PDsFF), for whom we considered <i>ABCA4</i> as a possible modifying gene. The mutation p.Gly167Ser was already known to cause pattern dystrophy, but we also found ECA, PDsFF, and autosomal-dominant retinitis pigmentosa (ADRP) as possible phenotypes. Finally, we identified the mutation p.Arg195Leu in a large family with common ancestry, which previously was described to cause central areolar choroidal dystrophy (CACD), but we also found ADRP and observed that it caused ECA more frequently than CACD in this family.","variants":[{"Name":"NM_000322.5(PRPH2):c.824_828+3delinsCATTTGGGCTCCTCATTTGG","Chromosome":"6","Start":"42704362","Stop":"42704369","ReferenceAlleleVCF":"TACCTCGA","AlternateAlleleVCF":"CCAAATGAGGAGCCCAAATG","allel_id":1164663,"rule_based_match":true,"evidence_text":"c.824_828+3delinsCATTTGGGCTCCTCATTTGG","llm_judgment":"PRESENT","evidence":"c.824_828+3delinsCATTTGGGCTCCTCATTTGG","abstract_start":291,"abstract_end":328}]}
{"pmid":"21652691","title":"CDC73-related hereditary hyperparathyroidism: five new mutations and the clinical spectrum.","abstract":"OBJECTIVE: Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is a rare autosomal dominant cause of benign and malignant parathyroid tumours, ossifying jaw tumours, various cystic and neoplastic renal abnormalities and benign and malignant uterine tumours. Disease-causing mutations have been localised in the tumour suppressor gene CDC73. There is limited information available on the mutations, and resulting phenotypes and long-term follow-up data are especially scarce.\nDESIGN: We analysed the clinical data from 16 patients (including three families) carrying mutations in the CDC73 gene. We describe five new mutations/gene variants, the corresponding phenotypes of these carriers and the long-term follow-up.\nMETHODS: The 16 patients were evaluated at an endocrine outpatient clinic and at a surgical department. DNA samples were obtained for sequence analysis of the CDC73 gene.\nRESULTS: Clinical features of HPT-JT syndrome were detected in 13 of the 15 carriers with germline CDC73 mutations. The major features were benign (n=7; 47%) or cancerous (n=3; 20%) HPT-JT was present in eight cases (53%). Most patients had severe hypercalcaemia, and median serum calcium levels were 3.36 mmol/l. A patient with non-secretory parathyroid carcinoma was included. HPT was diagnosed at a median age of 28.5 years. Mutational analysis of the CDC73 gene identified eight sequence changes, three of them have been reported previously, whereas five are novel: c.1346delG, c.88_94delTTCTCCT, the non-coding variants, c.307+5G>T and c.424-5T>C and c.*12C>A of unknown significance.\nCONCLUSIONS: This study significantly increases the information available on the mutations and phenotypes of HPT-JT syndrome.","variants":[{"Name":"NM_024529.5(CDC73):c.307+5G>T","Chromosome":"1","Start":"193130248","Stop":"193130248","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1436170,"rule_based_match":true,"evidence_text":"c.307+5G>T","llm_judgment":"PRESENT","evidence":"c.307+5G>T","abstract_start":1511,"abstract_end":1521}]}
{"pmid":"28664505","title":"SSADH deficiency in an Italian family: a novel ALDH5A1 gene mutation affecting the succinic semialdehyde substrate binding site.","abstract":"SSADH deficiency (SSADHD) is a rare autosomal recessively inherited metabolic disorder. It is associated with mutations of ALDH5A1 gene, coding for the homotetrameric enzyme SSADH. This enzyme is involved in γ-aminobutyric acid (GABA) catabolism, since it oxidizes succinic semialdehyde (SSA) to succinate. Mutations in ALDH5A1 gene result in the abnormal accumulation of γ-hydroxybutyrate (GHB), which is pathognomonic of SSADHD. In the present report, diagnosis of SSADHD in a three-month-old female was achieved by detection of high levels of GHB in urine. Sequence analysis of ALDH5A1 gene showed that the patient was a compound heterozygote for c.1226G > A (p.G409D) and the novel missense mutation, c.1498G > C (p.V500 L). By ALDH5A1 gene expression in transiently transfected HEK293 cells and enzyme activity assays, we demonstrate that the p.V500 L mutation, despite being conservative, produces complete loss of enzyme activity. In silico protein modelling analysis and evaluation of tetramer destabilizing energies suggest that structural impairment and partial occlusion of the access channel to the active site affect enzyme activity. These findings add further knowledge on the missense mutations associated with SSADHD and the molecular mechanisms underlying the loss of the enzyme activity.","variants":[{"Name":"NM_001080.3(ALDH5A1):c.1498G>C (p.Val500Leu)","Chromosome":"6","Start":"24533602","Stop":"24533602","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1483901,"rule_based_match":true,"evidence_text":"c.1498G > C (p.V500 L)","llm_judgment":"PRESENT","evidence":"c.1498G > C (p.V500 L)","abstract_start":705,"abstract_end":727},{"Name":"NM_001080.3(ALDH5A1):c.1226G>A (p.Gly409Asp)","Chromosome":"6","Start":"24528049","Stop":"24528049","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16398,"rule_based_match":true,"evidence_text":"c.1226G > A (p.G409D)","llm_judgment":"PRESENT","evidence":"c.1226G > A (p.G409D)","abstract_start":650,"abstract_end":671}]}
{"pmid":"18671782","title":"A newly identified splice site mutation in ZMPSTE24 causes restrictive dermopathy in the Middle East.","abstract":"Restrictive dermopathy (RD) is a severe neonatal inherited skin syndrome of which children die shortly after birth. Clinical features include intrauterine growth retardation, taut translucent and easily eroded skin, multiple joint ankylosis and distinct facial features. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24, predicted to cause loss of function of the encoded zinc metalloproteinase STE24. ZMPSTE24 is essential for the processing of the nuclear intermediate filament protein prelamin A. We report two distantly related children from the United Arab Emirates with RD. Remarkably, they lived up to 2 months, suggesting some residual function of the mutant protein. We sought to confirm the diagnosis by thorough microscopic analysis of patient skin, to identify the causative mutation and to study its functional consequences. A skin biopsy was obtained and processed for light and electron microscopy. Peripheral blood leucocytes were used for DNA and RNA isolation, and detection of prelamin A by immunofluorescence. Analysis of the skin confirmed the earlier reported densely packed collagen bundles and lack of elastin fibres. In both patients a homozygous splice site mutation c.627+1G>C in ZMPSTE24 was identified. Analysis of the ZMPSTE24 mRNA revealed an in-frame exon 5 skipping. Accumulation of prelamin A could be detected at the nuclear envelope of patient blood lymphocytes. We thus report the first splice site mutation in ZMPSTE24, which is likely to be a founder mutation in the United Arab Emirates. The accumulation of prelamin A at the nuclear periphery is consistent with defective ZMPSTE24 function. Interestingly, a regular blood sample can be used to investigate prelamin A accumulation.","variants":[{"Name":"NM_005857.5(ZMPSTE24):c.627+1G>C","Chromosome":"1","Start":"40270128","Stop":"40270128","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":150210,"rule_based_match":true,"evidence_text":"c.627+1G>C","llm_judgment":"PRESENT","evidence":"c.627+1G>C","abstract_start":1226,"abstract_end":1236}]}
{"pmid":"26957854","title":"Novel Mutations in Two Saudi Patients with Congenital Retinal Dystrophy.","abstract":"UNLABELLED: To report novel mutations in two Saudi children with clinical features of Leber congenital amaurosis (LCA) and Alström syndrome.\nCASE REPORTS: Case 1 was a child with phenotypic features of LCA including oculodigital sign, bilateral enophthalmos, nystagmus, pale disc, and retinal changes. Direct sequencing of the coding sequence of GUCY2D revealed a missense mutation affecting highly conserved position (c. 743C > T; p.S248 L). Case 2 describes a girl with marked nystagmus, photophobia, and retinal changes in both eyes with short and stubby fingers tapering at the distal phalanges. The electroretinograms were nonrecordable in each eye. She had a hearing aid in the left ear, mid-facial hypoplasia, bilateral enophthalmos, and insulin dependent diabetes. Mutation screening of candidates genes revealed a pathogenic mutation in ALMS1 gene (c. 8441C > A, p.S2814). Two novel mutations causing phenotypic LCA and Alström syndrome in Saudi patients from consanguineous families expand the genotypic spectrum of congenital retinal dystrophies.","variants":[{"Name":"NM_000180.4(GUCY2D):c.743C>T (p.Ser248Leu)","Chromosome":"17","Start":"8003873","Stop":"8003873","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":962932,"rule_based_match":true,"evidence_text":"c. 743C > T; p.S248 L","llm_judgment":"PRESENT","evidence":"c. 743C > T; p.S248 L","abstract_start":419,"abstract_end":440}]}
{"pmid":"25954033","title":"DLX4 is associated with orofacial clefting and abnormal jaw development.","abstract":"Cleft lip and/or palate (CL/P) are common structural birth defects in humans. We used exome sequencing to study a patient with bilateral CL/P and identified a single nucleotide deletion in the patient and her similarly affected son—c.546_546delG, predicting p.Gln183Argfs*57 in the Distal-less 4 (DLX4) gene. The sequence variant was absent from databases, predicted to be deleterious and was verified by Sanger sequencing. In mammals, there are three Dlx homeobox clusters with closely located gene pairs (Dlx1/Dlx2, Dlx3/Dlx4, Dlx5/Dlx6). In situ hybridization showed that Dlx4 was expressed in the mesenchyme of the murine palatal shelves at E12.5, prior to palate closure. Wild-type human DLX4, but not mutant DLX4_c.546delG, could activate two murine Dlx conserved regulatory elements, implying that the mutation caused haploinsufficiency. We showed that reduced DLX4 expression after short interfering RNA treatment in a human cell line resulted in significant up-regulation of DLX3, DLX5 and DLX6, with reduced expression of DLX2 and significant up-regulation of BMP4, although the increased BMP4 expression was demonstrated only in HeLa cells. We used antisense morpholino oligonucleotides to target the orthologous Danio rerio gene, dlx4b, and found reduced cranial size and abnormal cartilaginous elements. We sequenced DLX4 in 155 patients with non-syndromic CL/P and CP, but observed no sequence variants. From the published literature, Dlx1/Dlx2 double homozygous null mice and Dlx5 homozygous null mice both have clefts of the secondary palate. This first finding of a DLX4 mutation in a family with CL/P establishes DLX4 as a potential cause of human clefts.","variants":[{"Name":"NM_138281.3(DLX4):c.546del (p.Gln183fs)","Chromosome":"17","Start":"49973761","Stop":"49973761","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":223017,"rule_based_match":true,"evidence_text":"c.546_546delG","llm_judgment":"PRESENT","evidence":"c.546_546delG","abstract_start":232,"abstract_end":245}]}
{"pmid":"26794436","title":"Identification of a rhodopsin gene mutation in a large family with autosomal dominant retinitis pigmentosa.","abstract":"Retinitis pigmentosa (RP) is a genetically highly heterogeneous retinal disease and one of the leading causes of blindness in the world. Next-generation sequencing technology has enormous potential for determining the genetic etiology of RP. We sought to identify the underlying genetic defect in a 35-year-old male from an autosomal-dominant RP family with 14 affected individuals. By capturing next-generation sequencing (CNGS) of 144 genes associated with retinal diseases, we identified eight novel DNA variants; however, none of them cosegregated for all the members of the family. Further analysis of the CNGS data led to identification of a recurrent missense mutation (c.403C > T, p.R135W) in the rhodopsin (RHO) gene, which cosegregated with all affected individuals in the family and was not observed in any of the unaffected family members. The p.R135W mutation has a reference single nucleotide polymorphism (SNP) ID (rs104893775), and it appears to be responsible for the disease in this large family. This study highlights the importance of examining NGS data with reference SNP IDs. Thus, our study is important for data analysis of NGS-based clinical genetic diagnoses.","variants":[{"Name":"NM_000539.3(RHO):c.403C>T (p.Arg135Trp)","Chromosome":"3","Start":"129530917","Stop":"129530917","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28067,"rule_based_match":true,"evidence_text":"c.403C > T, p.R135W","llm_judgment":"PRESENT","evidence":"c.403C > T, p.R135W","abstract_start":677,"abstract_end":696}]}
{"pmid":"34120093","title":"A hereditary ovarian cancer family with rare pathogenic splicing mutation: Implications for variant interpretation.","abstract":"The BRCA1/2 gene is important for assessing the risk of familial/hereditary ovarian cancer (OC). This case is a patient with OC, and two of her immediate family members are cancer patients. We sequenced the coding and splicing regions of 42 OC susceptibility genes, and found a rare pathogenic splicing mutation BRCA1:c.132C > T (p.cys44 =) in 2 patients. Although the mutation is synonymous, software prediction and functional verification have shown that it affects alternative splicing and leads to frameshift mutations (c.131_134del). Chromosome microarray analysis of the tissue samples revealed the presence of a BRCA1 gene deletion with a fragment size of 1.42 Mb and an HRD score of 71. In addition, the proband showed a sensitive response to platinum treatment. This case suggests the clinical significance of OC susceptibility genes sequencing and HRD scoring in screening hereditary OC families.","variants":[{"Name":"NM_007294.4(BRCA1):c.132C>T (p.Cys44=)","Chromosome":"17","Start":"43115728","Stop":"43115728","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":236178,"rule_based_match":true,"evidence_text":"BRCA1:c.132C > T (p.cys44 =)","llm_judgment":"PRESENT","evidence":"BRCA1:c.132C > T (p.cys44 =)","abstract_start":312,"abstract_end":340}]}
{"pmid":"22619057","title":"ZASPopathy with childhood-onset distal myopathy.","abstract":"We report on a German family presenting with a predominantly distal myopathy primarily affecting anterior compartments of lower legs in childhood. Proximal lower limb and hip girdle weakness developed later in early adulthood in the female index patient and likewise in her mother. Consecutive muscle biopsy findings were first attributed to a mild congenital myopathy and later on interpreted as neurogenic changes without clear signs of a myopathy. Molecular genetic analysis was performed because of the clinical impression of a distal myopathy combined with dominant inheritance. The heterozygous mutation c.349G>A (p.D117N) in the ZASP gene could be found. This mutation had been previously associated with an adult-onset, isolated, dilated left ventricular non-compaction cardiomyopathy (OMIM*605906.0007), which was not present in our patients. Our data show that this mutation can be associated with an isolated skeletal muscle phenotype. Second, mutation analysis of the ZASP gene is suggested for distal myopathies of any age, even in cases of uncharacteristic muscle biopsy findings on routine analysis.","variants":[{"Name":"NM_001368067.1(LDB3):c.349G>A (p.Asp117Asn)","Chromosome":"10","Start":"86687073","Stop":"86687073","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19772,"rule_based_match":true,"evidence_text":"c.349G>A (p.D117N)","llm_judgment":"PRESENT","evidence":"c.349G>A (p.D117N)","abstract_start":610,"abstract_end":628}]}
{"pmid":"25913727","title":"Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability.","abstract":"In some cases Neu-Laxova syndrome (NLS) is linked to serine deficiency due to mutations in the phosphoglycerate dehydrogenase (PHGDH) gene. We describe the prenatal and postnatal findings in a fetus with one of the most severe NLS phenotypes described so far, caused by a homozygous nonsense mutation of PHGDH. Serial ultrasound (US) and pre- and postnatal magnetic resonance imaging (MRI) evaluations were performed. Prenatally, serial US evaluations suggested symmetric growth restriction, microcephaly, hypoplasia of the cerebellar vermis, micrognathia, hydrops, shortened limbs, arthrogryposis, and talipes equinovarus. The prenatal MRI confirmed these findings prompting a diagnosis of NLS. After birth, radiological imaging did not detect any gross bone abnormalities. DNA was extracted from fetal and parental peripheral blood, all coding exons of PHGDH were PCR-amplified and subjected to Sanger sequencing. Sequencing of PHGDH identified a homozygous premature stop codon mutation (c.1297C>T; p.Gln433*) in fetal DNA, both parents (first-cousins) being heterozygotes. Based on previous associations of mutations in this gene with a milder NLS phenotype, as well as cases of serine deficiency, these observations lend further support to a genotype-phenotype correlation between the degree of PHGDH inactivation and disease severity.","variants":[{"Name":"NM_006623.4(PHGDH):c.1297C>T (p.Gln433Ter)","Chromosome":"1","Start":"119742894","Stop":"119742894","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1928484,"rule_based_match":true,"evidence_text":"c.1297C>T (p.Gln433*)","llm_judgment":"PRESENT","evidence":"c.1297C>T","abstract_start":991,"abstract_end":1000}]}
{"pmid":"30369353","title":"Clinical, pathological and genetic studies of two cases of childhood-onset nemaline myopathy","abstract":"This article reports two cases of childhood-onset nemaline myopathy diagnosed by muscle pathology and genetic diagnosis. The two patients had onset in early childhood, with muscle weakness as the first manifestation, as well as long disease duration and slow progression. Gomori staining and hematoxylin-eosin staining showed red-stained rods in the sarcoplasmic cytoplasm and sarcolemma under a light microscope. Electron microscopy showed that the dense nemaline rods were located under the muscle fiber sarcolemma and parallel to the long axis of the muscle fibers, and some muscle fiber myofilaments were dissolved and necrotic. Gene testing found that one of the two patients had heterozygous mutation (c.1013A>C) in the ACTA1 gene, and the other had compound heterozygous mutation (c.18676C>T and c.9812C>A) in the NEB gene. The two mutations were more common in nemaline myopathy. Nemaline myopathy is a recessive or dominant inheritance myopathy, in which the nemaline rod in the cytoplasm of myocytes is a characteristic muscle pathological change. Pathological and genetic diagnosis is the gold standard for diagnosis of nemaline myopathy.","variants":[{"Name":"NM_001164508.2(NEB):c.18676C>T (p.Gln6226Ter)","Chromosome":"2","Start":"151563623","Stop":"151563623","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":541640,"rule_based_match":true,"evidence_text":"c.18676C>T","llm_judgment":"PRESENT","evidence":"c.18676C>T","abstract_start":788,"abstract_end":798}]}
{"pmid":"32519820","title":"A novel missense variant in MYO3A is associated with autosomal dominant high-frequency hearing loss in a German family.","abstract":"BACKGROUND: MYO3A, encoding the myosin IIIA protein, is associated with autosomal recessive and autosomal dominant nonsyndromic hearing loss. To date, only two missense variants located in the motor-head domain of MYO3A have been described in autosomal dominant families with progressive, mild-to-profound sensorineural hearing loss. These variants alter the ATPase activity of myosin IIIA.\nMETHODS: Exome sequencing of a proband from a three-generation German family with prelingual, moderate-to-profound, high-frequency hearing loss was performed. Segregation analysis confirmed a dominant inheritance pattern. Regression analysis of mean hearing level thresholds per individual and ear was performed at high-, mid-, and low-frequencies.\nRESULTS: A novel heterozygous missense variant c.716T>C, p.(Leu239Pro) in the kinase domain of MYO3A was identified that is predicted in silico as disease causing. High-frequency, progressive hearing loss was identified.\nCONCLUSION: Correlation analysis of pure-tone hearing thresholds revealed progressive hearing loss, especially in the high-frequencies. In the present study, we report the first dominant likely pathogenic variant in MYO3A in a European family and further support MYO3A as an autosomal dominant hearing loss gene.","variants":[{"Name":"NM_017433.5(MYO3A):c.716T>C (p.Leu239Pro)","Chromosome":"10","Start":"26021633","Stop":"26021633","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3081758,"rule_based_match":true,"evidence_text":"c.716T>C, p.(Leu239Pro)","llm_judgment":"PRESENT","evidence":"c.716T>C, p.(Leu239Pro)","abstract_start":787,"abstract_end":810}]}
{"pmid":"21791690","title":"Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma.","abstract":"CONTEXT: Barrett esophagus (BE) occurs in 1% to 10% of the general population and is believed to be the precursor of esophageal adenocarcinoma (EAC). The incidence of EAC has increased 350% in the last 3 decades without clear etiology. Finding predisposition genes may improve premorbid risk assessment, genetic counseling, and management. Genome-wide multiplatform approaches may lead to the identification of genes important in BE/EAC development.\nOBJECTIVE: To identify risk alleles or mutated genes associated with BE/EAC.\nDESIGN, SETTING, AND PATIENTS: Model-free linkage analyses of 21 concordant-affected sibling pairs with BE/EAC and 11 discordant sibling pairs (2005-2006). Significant germline genomic regions in independent prospectively accrued series of 176 white patients with BE/EAC and 200 ancestry-matched controls (2007-2010) were validated and fine mapped. Integrating data from these significant genomic regions with somatic gene expression data from 19 BE/EAC tissues yielded 12 \"priority\" candidate genes for mutation analysis (2010). Genes that showed mutations in cases but not in controls were further screened in an independent prospectively accrued validation series of 58 cases (2010).\nMAIN OUTCOME MEASURES: Identification of germline mutations in genes associated with BE/EAC cases. Functional interrogation of the most commonly mutated gene.\nRESULTS: Three major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/EAC (all P < .001). In addition, 13 patients (11.2%) with BE/EAC carried germline mutations in MSR1, ASCC1, or CTHRC1. MSR1 was the most frequently mutated, with 8 of 116 (proportion, 0.069; 95% confidence interval [CI], 0.030-0.130; P < .001) cases with c.877C>T (p.R293X). An independent validation series confirmed germline MSR1 mutations in 2 of 58 cases (proportion, 0.035; 95% CI, 0.004-0.120; P = .09). MSR1 mutation resulted in CCND1 up-regulation in peripheral-protein lysate. Immunohistochemistry of BE tissues in MSR1-mutation carriers showed increased nuclear expression of CCND1.\nCONCLUSION: MSR1 was significantly associated with the presence of BE/EAC in derivation and validation samples, although it was only present in a small percentage of the cases.","variants":[{"Name":"NM_138715.3(MSR1):c.877C>T (p.Arg293Ter)","Chromosome":"8","Start":"16155085","Stop":"16155085","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29396,"rule_based_match":true,"evidence_text":"c.877C>T (p.R293X)","llm_judgment":"PRESENT","evidence":"c.877C>T (p.R293X)","abstract_start":1704,"abstract_end":1722}]}
{"pmid":"17059986","title":"A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension.","abstract":"We report a case of Gitelman syndrome (GS) in a dizygotic twin who presented at 12 years of age with growth delay, metabolic alkalosis, hypomagnesemia and hypokalemia with inappropriate kaliuresis, and idiopathic intracranial hypertension with bilateral papilledema (pseudotumor cerebri). The patient, her twin sister, and her mother also presented with cerebral cavernous malformations. Based on the early onset and normocalciuria, Bartter syndrome was diagnosed first. However, mutation analysis showed that the proband is a compound heterozygote for 2 mutations in SLC12A3: a substitution of serine by leucine at amino acid position 555 (p.Ser555Leu) and a novel guanine to cytosine transition at the 5' splice site of intron 22 (c.2633+1G>C), providing the molecular diagnosis of GS. These mutations were not detected in 200 normal chromosomes and cosegregated within the family. Analysis of complementary DNA showed that the heterozygous nucleotide change c.2633+1G>C caused the appearance of 2 RNA molecules, 1 normal transcript and 1 skipping the entire exon 22 (r.2521_2634del). Supplementation with potassium and magnesium improved clinical symptoms and resulted in catch-up growth, but vision remained impaired. Three similar associations of Bartter syndrome/GS with pseudotumor cerebri were found in the literature, suggesting that electrolyte abnormalities and secondary aldosteronism may have a role in idiopathic intracranial hypertension. This study provides further evidence for the phenotypical heterogeneity of GS and its association with severe manifestations in children. It also shows the independent segregation of familial cavernomatosis and GS.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1664C>T (p.Ser555Leu)","Chromosome":"16","Start":"56882492","Stop":"56882492","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":644775,"rule_based_match":false,"evidence_text":"p.Ser555Leu","llm_judgment":"PRESENT","evidence":"p.Ser555Leu","abstract_start":641,"abstract_end":652}]}
{"pmid":"21850171","title":"Molecular screening of the CYP4V2 gene in Bietti crystalline dystrophy that is associated with choroidal neovascularization.","abstract":"PURPOSE: Bietti crystalline dystrophy (BCD) is an autosomal recessive disease characterized by intraretinal deposits of multiple small crystals, with or without associated crystal deposits in the cornea. The disease is caused by mutation in the cytochrome p450, family 4, subfamily v, polypeptide 2 (CYP4V2) gene. Choroidal neovascularization (CNV) is a rare event in BCD. We report two cases of BCD associated with CNV. CYP4V2 and exon 5 of tissue inhibitor of metalloproteinase 3 (TIMP3) were screened in both cases. A patient with BCD, but without CNV, was also screened to identify pathogenic variations.\nMETHODS: Three BCD families of Asian Indian origin were recruited after a comprehensive ophthalmic examination. Genomic DNA was isolated from blood leukocytes, and coding exons and flanking introns of CYP4V2 and exon 5 of TIMP3 were amplified via polymerase chain reaction (PCR) and were sequenced. Family segregation, control screening, and bioinformatics tools were used to assess the pathogenicity of the novel variations.\nRESULTS: Of the three BCD patients, two had parafoveal CNV. The patient with BCD, but without CNV had novel single base-pair duplication (c.1062_1063dupA). This mutation results in a structurally defective and unstable protein with impaired protein function. Four novel benign variations (three in exons and one in an intron) were observed in the cohort. Screening of exon 5 of TIMP3 did not reveal any variation in these families.\nCONCLUSIONS: A novel mutation was found in a patient with BCD but without CNV, while patients with BCD and CNV did not show any pathogenic variation. The modifier role of TIMP3 in the pathogenesis of CNV in BCD was partly ruled out, as no variation was observed in exon 5 of the gene. A larger BCD cohort with CNV needs to be studied and screened to understand the genetics of CNV in BCD.","variants":[{"Name":"NM_207352.4(CYP4V2):c.1062dup (p.Val355fs)","Chromosome":"4","Start":"186205268","Stop":"186205269","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":1468071,"rule_based_match":false,"evidence_text":"c.1062_1063dupA","llm_judgment":"PRESENT","evidence":"c.1062_1063dupA","abstract_start":1173,"abstract_end":1188}]}
{"pmid":"27212590","title":"Parathyroid carcinoma and atypical parathyroid neoplasms in MEN1 patients; A clinico-pathologic challenge. The MD Anderson case series and review of the literature.","abstract":"BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a genetic disorder characterized by usually benign tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary. Hyperparathyroidism (HPT) occurs in 90% of MEN1 patients. In rare cases, it is associated with parathyroid carcinoma (PC) or atypical parathyroid neoplasm (APN). We present a cohort of 3 such patients.\nMETHODS: We performed a retrospective review of our institution's MEN1 database to identify patients who underwent operations for HPT and had a histopathologic diagnosis of PC or APN. Clinical features, genetics, and outcomes were summarized.\nRESULTS: Of 291 MEN1 patients, 242 had HPT (83.2%). Two of the 242 patients (0.8%) had a histopathologic diagnosis of PC, and 1 (0.4%) had a diagnosis of APN. The patients with PC were male, ages 62 and 56 years at the time of surgery; the patient with APN was female, age 32 years. All patients also had a pancreatic endocrine tumor. The observed genetic mutations in the PC patients were c.703G > A (p.E235K) in exon 4 and c.1378C > T (p.R460X) in exon 10. All 3 patients had recurrence of hypercalcemia, and 2 patients underwent reoperation; pathologic analysis revealed the presence of a hyperplastic gland, not tumor recurrence. No cases had distant metastasis.\nCONCLUSIONS: This is the first report of APN in an MEN1 patient. Although rare, the presence of PC or APN in MEN1 is noteworthy because it affects the management if hypercalcemia recurs, possibly requiring an open approach rather than the minimally invasive techniques used in the reoperative setting for benign disease.","variants":[{"Name":"NM_001370259.2(MEN1):c.703G>A (p.Glu235Lys)","Chromosome":"11","Start":"64807632","Stop":"64807632","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":419833,"rule_based_match":true,"evidence_text":"c.703G > A (p.E235K)","llm_judgment":"PRESENT","evidence":"c.703G > A (p.E235K)","abstract_start":1026,"abstract_end":1046}]}
{"pmid":"37057673","title":"De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.","abstract":"PURPOSE: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene.\nMETHODS: Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences.\nRESULTS: We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model.\nCONCLUSION: The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.","variants":[{"Name":"NM_022157.4(RRAGC):c.343T>C (p.Trp115Arg)","Chromosome":"1","Start":"38856977","Stop":"38856977","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2403833,"rule_based_match":true,"evidence_text":"c.343T>C, p.(Trp115Arg)","llm_judgment":"PRESENT","evidence":"c.343T>C, p.(Trp115Arg)","abstract_start":808,"abstract_end":831},{"Name":"NM_022157.4(RRAGC):c.353C>T (p.Pro118Leu)","Chromosome":"1","Start":"38856967","Stop":"38856967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2831322,"rule_based_match":true,"evidence_text":"c.353C>T, p.(Pro118Leu)","llm_judgment":"PRESENT","evidence":"c.353C>T, p.(Pro118Leu)","abstract_start":779,"abstract_end":802},{"Name":"NM_022157.4(RRAGC):c.269C>A (p.Thr90Asn)","Chromosome":"1","Start":"38857051","Stop":"38857051","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2831321,"rule_based_match":true,"evidence_text":"c.269C>A, p.(Thr90Asn)","llm_judgment":"PRESENT","evidence":"c.269C>A, p.(Thr90Asn)","abstract_start":755,"abstract_end":777}]}
{"pmid":"29769320","title":"","abstract":"It is estimated that ∼1% of the world's population has intellectual disability, with males affected more often than females. <i>OGT</i> is an X-linked gene encoding for the enzyme <i>O-</i>GlcNAc transferase (OGT), which carries out the reversible addition of <i>N</i>-acetylglucosamine (GlcNAc) to Ser/Thr residues of its intracellular substrates. Three missense mutations in the tetratricopeptide (TPR) repeats of OGT have recently been reported to cause X-linked intellectual disability (XLID). Here, we report the discovery of two additional novel missense mutations (c.775 G>A, p.A259T, and c.1016 A>G, p.E339G) in the TPR domain of OGT that segregate with XLID in affected families. Characterization of all five of these XLID missense variants of OGT demonstrates modest declines in thermodynamic stability and/or activities of the variants. We engineered each of the mutations into a male human embryonic stem cell line using CRISPR/Cas9. Investigation of the global <i>O-</i>GlcNAc profile as well as OGT and <i>O-</i>GlcNAc hydrolase levels by Western blotting showed no gross changes in steady-state levels in the engineered lines. However, analyses of the differential transcriptomes of the OGT variant-expressing stem cells revealed shared deregulation of genes involved in cell fate determination and liver X receptor/retinoid X receptor signaling, which has been implicated in neuronal development. Thus, here we reveal two additional mutations encoding residues in the TPR regions of OGT that appear causal for XLID and provide evidence that the relatively stable and active TPR variants may share a common, unelucidated mechanism of altering gene expression profiles in human embryonic stem cells.","variants":[{"Name":"NM_181672.3(OGT):c.775G>A (p.Ala259Thr)","Chromosome":"X","Start":"71555236","Stop":"71555236","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205352,"rule_based_match":true,"evidence_text":"c.775 G>A, p.A259T","llm_judgment":"PRESENT","evidence":"c.775 G>A, p.A259T","abstract_start":572,"abstract_end":590},{"Name":"NM_181672.3(OGT):c.1016A>G (p.Glu339Gly)","Chromosome":"X","Start":"71556045","Stop":"71556045","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":792640,"rule_based_match":true,"evidence_text":"c.1016 A>G, p.E339G","llm_judgment":"PRESENT","evidence":"c.1016 A>G, p.E339G","abstract_start":596,"abstract_end":615}]}
{"pmid":"20085885","title":"Two novel mutations of FBN1 gene in the patients with MFS among Han population","abstract":"To detect the mutations of fibrillin-1 (FBN1) gene in the patients with Marfan syndrome (MFS), polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) were conducted to screen for the mutations in FBN1 gene. Sequence analyses were carried out when the DNA amplification fragments of the DHPLC elution profiles showed difference from the corresponding normal elution profile. Two novel mutations were detected in two families with MFS, respectively. One was a multiplex mutation in exon 55 containing a deletion mutation c.6862_6871delGGCTGTGTAG (p.Gly2288MetfsX109), a synonymous mutation (c.6861A>G) and an intronic mutation c.[6871+1_6871+11delGTAAGAGGATC; 6871+34dupCATCAGAAGTGACAGTGGACA], and the other was a missense mutation in exon 20 c.2462G>A (p.Cys821Tyr). The results indicated that the deletion mutation c.[6862_6871delGGCTGT GTAG; 6871+1_6871+11delGTAAGAGGATC] (p.Gly2288MetfsX109) and the missense mutation c.2462G>A (p.Cys821Tyr) of FBN1 gene may cause the two family patients with MFS respectively.","variants":[{"Name":"NM_000138.5(FBN1):c.2462G>A (p.Cys821Tyr)","Chromosome":"15","Start":"48495546","Stop":"48495546","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":948933,"rule_based_match":true,"evidence_text":"c.2462G>A (p.Cys821Tyr)","llm_judgment":"PRESENT","evidence":"c.2462G>A (p.Cys821Tyr)","abstract_start":780,"abstract_end":803}]}
{"pmid":"25337068","title":"Clinical and Molecular Findings of Tunisian Patients with RASopathies.","abstract":"Noonan syndrome (NS) and related disorders, which are now summarized under the term RASopathies, are caused by germline mutations in genes encoding protein components of the Ras/mitogen-activated protein kinase pathway. In this study, we evaluated the clinical and molecular spectrum of 21 Tunisian patients, recruited by a cardiology unit, for whom RASopathy diagnosis was suspected by clinical geneticists. Overall, 19 patients had a clinical diagnosis of NS and 2 were classified as having Cardiofaciocutaneous (CFC) syndrome. In 52% (n = 11) of patients, a RASopathy has been molecularly confirmed. Mutations in PTPN11 and SOS1 genes were found in patients with diagnosis of NS and BRAF gene mutations in patients with CFC syndrome. As reported from other cohorts, mutations in exons 3 and 8 of the PTPN11 gene predominated in Tunisian NS patients. A very uncommon PTPN11 mutation c.5C>T (p.T2I), the functional consequences of which have so far remained unclear, was identified in one patient. As biased by the mode of recruitment, all patients included in this study had a congenital heart defect, with pulmonary valve stenosis being the most frequent one. Short stature and developmental abnormalities were present in mutation-positive cases. This is the first molecular study in patients from southern Tunisia with RASopathy diagnosis.","variants":[{"Name":"NM_002834.5(PTPN11):c.5C>T (p.Thr2Ile)","Chromosome":"12","Start":"112419116","Stop":"112419116","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28388,"rule_based_match":true,"evidence_text":"PTPN11 mutation c.5C>T (p.T2I)","llm_judgment":"PRESENT","evidence":"PTPN11 mutation c.5C>T (p.T2I)","abstract_start":869,"abstract_end":899}]}
{"pmid":"34059105","title":"Characterization of genotype-phenotype correlation with MORC2 mutated Axonal Charcot-Marie-Tooth disease in a cohort of Chinese patients.","abstract":"BACKGROUND: Charcot-Marie-Tooth (CMT) disease is an exciting field of study, with a growing number of causal genes and an expanding phenotypic spectrum. The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of CMT2Z in 2016. We aimed to describe the phenotypic-genetic spectrum of MORC2-related diseases in the Chinese population.\nMETHODS: With the use of Sanger sequencing and Next Generation Sequencing (NGS) technologies, we screened a cohort of 284 unrelated Chinese CMT2 families. Pathogenicity assessments of MORC2 variants were interpreted according to the ACMG guidelines. Potential pathogenic variants were confirmed by Sanger sequencing.\nRESULTS: We identified 4 different heterozygous MORC2 mutations in four unrelated families, accounting for 1.4% (4/284). A novel mutation c.1397A>G p. D466G was detected in family 1 and all affected patients presented with later onset axonal CMT with hyperCKemia. The patient in family 2 showed a spinal muscular atrophy (SMA)-like disease with cerebellar hypoplasia and mental retardation, with a hot spot de novo mutation c.260C>T p. S87L. The twin sisters in family 3 were identified as having the most common mutation c.754C>T p. R252W and suffered from axonal motor neuropathy with high variability in disease severity and duration. The patient in family 4 developed an early onset axonal motor and sensory neuropathy, with a reported mutation c.1220G>A p.C407Y. All identified mutations associated with MORC2-related neuropathies are localized in the N-terminal ATPase module.\nCONCLUSIONS: Our study confirmed that MORC2-related neuropathies exist in the Chinese population at a relatively high mutation rate. We revealed a complex genotype-phenotype correlation with MORC2 mutations. This report adds a new piece to the puzzle of the genetics of CMT and contributes to a better understanding of the disease mechanisms.","variants":[{"Name":"NM_001303256.3(MORC2):c.260C>T (p.Ser87Leu)","Chromosome":"22","Start":"30949809","Stop":"30949809","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":215004,"rule_based_match":true,"evidence_text":"c.260C>T p. S87L","llm_judgment":"PRESENT","evidence":"c.260C>T p. S87L","abstract_start":1118,"abstract_end":1134}]}
{"pmid":"14635104","title":"Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF).","abstract":"Inherited hearing impairment affects one in 2,000 newborns. Nonsyndromic prelingual forms are inherited mainly as autosomal recessive traits, for which 16 genes are currently known. Mutations in the genes encoding connexins 26 and 30 account for up to 50% of these cases. However, the individual contribution of the remaining genes to the whole remains undetermined. In addition, for most of the genes there is a need for studies on genotype-phenotype correlations, to identify distinctive clinical features which may direct the molecular diagnosis to specific genes. Here we present a mutation analysis and a genotype-phenotype correlation study on the gene encoding otoferlin (OTOF), responsible for the DFNB9 subtype of prelingual hearing impairment. Four novel mutations were identified: c.2122C>T (p.Arg708Ter), c.4275G>A (p.Trp1425Ter), c.4362+2T>G, and c.5860_5862delATC (p.Ile1954del). A total of 37 subjects with mutations in OTOF were studied clinically. They were phenotypically homogeneous, having profound hearing impairment with very early onset, as shown by pure-tone audiometry and auditory brainstem responses. Magnetic resonance imaging and computed tomography did not reveal any inner ear malformation. Unexpectedly, transient evoked otoacoustic emissions (TEOAEs) were present, either bilaterally or unilaterally in 11 subjects. Altogether, clinical data of these subjects met the diagnostic criteria of auditory neuropathy. A total of 10 subjects had been successfully provided with cochlear implants. The results of our study indicate that genetic diagnosis of subjects with auditory neuropathy and profound hearing impairment should be directed to the otoferlin gene. Our data are of concern to universal screening programs which use TEOAEs as the first detection test for hearing impairment in newborns, since this technique may overlook a nonnegligible proportion of cases.","variants":[{"Name":"NM_194248.3(OTOF):c.4275G>A (p.Trp1425Ter)","Chromosome":"2","Start":"26467186","Stop":"26467186","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34701,"rule_based_match":true,"evidence_text":"c.4275G>A (p.Trp1425Ter)","llm_judgment":"PRESENT","evidence":"c.4275G>A (p.Trp1425Ter)","abstract_start":817,"abstract_end":841},{"Name":"NM_194248.3(OTOF):c.2122C>T (p.Arg708Ter)","Chromosome":"2","Start":"26479356","Stop":"26479356","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34683,"rule_based_match":true,"evidence_text":"c.2122C>T (p.Arg708Ter)","llm_judgment":"PRESENT","evidence":"c.2122C>T (p.Arg708Ter)","abstract_start":792,"abstract_end":815}]}
{"pmid":"33276791","title":"The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy.","abstract":"BACKGROUND: Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants.\nMETHODS: In our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature.\nRESULTS: A novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years.\nCONCLUSIONS: Here we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.","variants":[{"Name":"NM_001042424.3(NSD2):c.1577dup (p.Asn527fs)","Chromosome":"4","Start":"1935164","Stop":"1935165","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":1323953,"rule_based_match":true,"evidence_text":"c.1577dupG (p.Asn527Lysfs*14)","llm_judgment":"PRESENT","evidence":"c.1577dupG (p.Asn527Lysfs*14)","abstract_start":813,"abstract_end":842}]}
{"pmid":"29137068","title":"Carnitine-acylcarnitine translocase deficiency with c.199-10 T>G and novel c.1A>G mutation: Two case reports and brief literature review.","abstract":"RATIONALE: Carnitine-acylcarnitine translocate deficiency (CACTD) is a rare and life-threatening, autosomal recessive disorder of fatty acid β-oxidation characterized by hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, liver dysfunction, and muscle weakness; culminating in early death. To date, CACTD cases screened from the Chinese mainland population, especially patient with compound heterozygote with c.199-10T>G and a novel c.1A>G mutation in the SLC25A20 gene has never been described.\nPATIENT CONCERNS: Herein, we report 2 neonatal cases of CACTD identified from the mainland China. These 2 patients were presented with severe metabolic crisis and their clinical conditions deteriorate rapidly and both died of cardiorespiratory collapse in the first week of life. We present the clinical and biochemical features of 2 probands and a brief literature review of previously reported CACTD cases with the c.199-10T>G mutation.\nDIAGNOSES: The acylcarnitine profiles by tandem-mass-spectrometry and the mutation analysis of SLC25A20 gene confirmed the diagnosis of CACTD in both patients. Mutation analysis demonstrated that patient No. 1 was homozygous for c.199-10T>G mutation, while patient No. 2 was a compound heterozygote for 2 mutations, a maternally-inherited c.199-10T>G and a paternally-inherited, novel c.1A>G mutation.\nINTERVENTIONS: Both patients were treated with an aggressive treatment regimen include high glucose and arginine infusion, respiratory, and circulatory support.\nOUTCOMES: The first proband died 3 days after delivery due to sudden cardiac arrest. The second patient's clinical condition, at one time, was improved by high glucose infusion, intravenous arginine, and circulatory support. However, the patient failed to wean from mechanical ventilation. Unfortunately, her parents refused further treatment due to fear of financial burdens. The patient died of congestive heart failure in the 6th day of life.\nLESSONS: We report the first 2 cases of CACTD identified from the mainland China. Apart from a founder mutation c.199-10T>G, we identified a novel c.1A>G mutation. Patients with CACTD with a genotype of c.199-10T>G mutation usually presents with a severe clinical phenotype. Early recognition and appropriate treatment is crucial in this highly lethal disorder. This case series highlights the importance of screening for metabolic diseases including CACTD in cases of sudden infant death and unexplained abrupt clinical deterioration in the early neonatal period.","variants":[{"Name":"NM_000387.6(SLC25A20):c.1A>G (p.Met1Val)","Chromosome":"3","Start":"48898794","Stop":"48898794","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2889687,"rule_based_match":true,"evidence_text":"c.1A>G","llm_judgment":"PRESENT","evidence":"c.1A>G","abstract_start":439,"abstract_end":445}]}
{"pmid":"26995144","title":"Genetic analysis of consanguineous families presenting with congenital ocular defects.","abstract":"Anophthalmia and microphthalmia (A/M) are a group of rare developmental disorders that affect the size of the ocular globe. A/M may present as the sole clinical feature, but are also frequently found in a variety of syndromes. A/M is genetically heterogeneous and can be caused by chromosomal aberrations, copy number variations and single gene mutations. To date, A/M has been caused by mutations in at least 20 genes that show different modes of inheritance. In this study, we enrolled eight consanguineous families with A/M, including seven from Pakistan and one from India. Sanger and exome sequencing of DNA samples from these families identified three novel mutations including two mutations in the Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3) gene, [c.1310_1311delAT; p.(Tyr437Trpfs*44) and c.964G > A; p.(Val322Met)] and a single missense mutation in Forkhead Box E3 (FOXE3) gene, [c.289A > G p.(Ile97Val)]. Additionally two previously reported mutations were identified in FOXE3 and in Visual System Homeobox 2 (VSX2). This is the first comprehensive study on families with A/M from the Indian subcontinent which provides further evidence for the involvement of known genes with novel and recurrent mutations.","variants":[{"Name":"NM_000693.4(ALDH1A3):c.964G>A (p.Val322Met)","Chromosome":"15","Start":"100900655","Stop":"100900655","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":642983,"rule_based_match":true,"evidence_text":"c.964G > A; p.(Val322Met)","llm_judgment":"PRESENT","evidence":"c.964G > A; p.(Val322Met)","abstract_start":805,"abstract_end":830},{"Name":"NM_012186.3(FOXE3):c.289A>G (p.Ile97Val)","Chromosome":"1","Start":"47416604","Stop":"47416604","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":971542,"rule_based_match":true,"evidence_text":"c.289A > G p.(Ile97Val)","llm_judgment":"PRESENT","evidence":"c.289A > G p.(Ile97Val)","abstract_start":897,"abstract_end":920}]}
{"pmid":"28506345","title":"Infantile hypophosphatasia caused by a novel compound heterozygous mutation: a case report and pedigree analysis","abstract":"This article reported the clinical features of one child with infantile hypophosphatasia (HPP) and his pedigree information. The proband was a 5-month-old boy with multiple skeletal dysplasia (koilosternia, bending deformity of both radii, and knock-knee deformity of both knees), feeding difficulty, reduction in body weight, developmental delay, recurrent pneumonia and respiratory failure, and a significant reduction in blood alkaline phosphatase. Among his parents, sister, uncle, and aunt (other family members did not cooperate with us in the examination), his parents and aunt had a slight reduction in alkaline phosphatase and his aunt had scoliosis; there were no other clinical phenotypes or abnormal laboratory testing results. His ALPL gene mutation came from c.228delG mutation in his mother and c.407G>A compound heterozygous mutation in his father. His aunt carried c.228delG mutation. The c.407G>A mutation had been reported as the pathogenic mutation of HPP, and c.228delG mutation was a novel pathogenic mutation. Hypophosphatasia is caused by ALPL gene mutation, and ALPL gene detection is an effective diagnostic method. This study expands the mutation spectrum of ALPL gene and provides a theoretical basis for genetic diagnosis of this disease.","variants":[{"Name":"NM_000478.6(ALPL):c.407G>A (p.Arg136His)","Chromosome":"1","Start":"21563219","Stop":"21563219","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28714,"rule_based_match":true,"evidence_text":"c.407G>A","llm_judgment":"PRESENT","evidence":"c.407G>A","abstract_start":810,"abstract_end":818}]}
{"pmid":"27302843","title":"Spectrum of PEX1 and PEX6 variants in Heimler syndrome.","abstract":"Heimler syndrome (HS) consists of recessively inherited sensorineural hearing loss, amelogenesis imperfecta (AI) and nail abnormalities, with or without visual defects. Recently HS was shown to result from hypomorphic mutations in PEX1 or PEX6, both previously implicated in Zellweger Syndrome Spectrum Disorders (ZSSD). ZSSD are a group of conditions consisting of craniofacial and neurological abnormalities, sensory defects and multi-organ dysfunction. The finding of HS-causing mutations in PEX1 and PEX6 shows that HS represents the mild end of the ZSSD spectrum, though these conditions were previously thought to be distinct nosological entities. Here, we present six further HS families, five with PEX6 variants and one with PEX1 variants, and show the patterns of Pex1, Pex14 and Pex6 immunoreactivity in the mouse retina. While Ratbi et al. found more HS-causing mutations in PEX1 than in PEX6, as is the case for ZSSD, in this cohort PEX6 variants predominate, suggesting both genes play a significant role in HS. The PEX6 variant c.1802G>A, p.(R601Q), reported previously in compound heterozygous state in one HS and three ZSSD cases, was found in compound heterozygous state in three HS families. Haplotype analysis suggests a common founder variant. All families segregated at least one missense variant, consistent with the hypothesis that HS results from genotypes including milder hypomorphic alleles. The clinical overlap of HS with the more common Usher syndrome and lack of peroxisomal abnormalities on plasma screening suggest that HS may be under-diagnosed. Recognition of AI is key to the accurate diagnosis of HS.","variants":[{"Name":"NM_000287.4(PEX6):c.1802G>A (p.Arg601Gln)","Chromosome":"6","Start":"42967450","Stop":"42967450","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":195870,"rule_based_match":true,"evidence_text":"c.1802G>A","llm_judgment":"PRESENT","evidence":"c.1802G>A","abstract_start":1042,"abstract_end":1051}]}
{"pmid":"37713976","title":"Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease.","abstract":"BACKGROUND: Biallelic pathogenic variants in SLC17A5 cause three forms of free sialic acid storage disease categorized based on severity from least to most severe: Salla disease, intermediate-severe Salla disease, and infantile free sialic acid storage disease. Intermediate-severe Salla disease is the most recently described form. Here, we report a longitudinal characterization of intermediate-severe Salla disease progression in two sisters carrying the following biallelic variants in SLC17A5: c.406A>G (p.Lys136Glu) and c.819+1G>A.\nMETHODS: A retrospective review of medical records was performed. A developmental questionnaire was completed to obtain further clinical information. For functional characterization of the predicted splice site variant, RNA was extracted from patient blood samples and sequenced.\nRESULTS: Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood. After this, both patients began a slow and progressive neurological regression in adolescence. Functional studies confirmed the pathogenicity of the c.819+1G>A variant, resulting in a frameshift and deletion of exon 6.\nCONCLUSIONS: We present a detailed study describing the clinical course of intermediate-severe Salla disease with over 15 to 20 years of evolution and demonstrate the pathogenicity of the c.819+1G>A splice site variant.","variants":[{"Name":"NM_012434.5(SLC17A5):c.406A>G (p.Lys136Glu)","Chromosome":"6","Start":"73641810","Stop":"73641810","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":34345,"rule_based_match":true,"evidence_text":"c.406A>G (p.Lys136Glu)","llm_judgment":"PRESENT","evidence":"c.406A>G (p.Lys136Glu)","abstract_start":499,"abstract_end":521}]}
{"pmid":"29419865","title":"Screening of genetic mutations in a Chinese pedigree affected with hypokalemic periodic paralysis","abstract":"OBJECTIVE To screen for mutations in a Chinese pedigree affected with hypokalemic periodic paralysis. METHODS The proband and nine family members were enrolled for the analysis of CACNA1S and SCN4A gene mutations. Genomic DNA was extracted from peripheral blood samples. The coding regions of the two genes were amplified with PCR and subjected to Sanger sequencing. Potential impact of suspected mutations was predicted with Bioinformatics software. The mutations were also verified among 100 healthy controls. RESULTS The proband and 5 family members (including 5 males and 1 female) had presented with episodes of flaccid paralysis accompanied by low serum potassium. Genetic testing has identified a c.664C>T (p.Arg222Trp) mutation in the proband, which has been reported previously. The same mutation was identified in other 5 affected members from the family. No mutation of the CACNA1S gene was detected. CONCLUSION The c.664C>T mutation of the SCN4A gene probably underlies the hypokalemic periodic paralysis in this family. All patients from the family have shown a complete penetrance of the disease.","variants":[{"Name":"NM_000334.4(SCN4A):c.664C>T (p.Arg222Trp)","Chromosome":"17","Start":"63971201","Stop":"63971201","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152917,"rule_based_match":true,"evidence_text":"c.664C>T (p.Arg222Trp)","llm_judgment":"PRESENT","evidence":"c.664C>T (p.Arg222Trp)","abstract_start":704,"abstract_end":726}]}
{"pmid":"28289593","title":"Is c.1431-12G>A A common European mutation of","abstract":"Netherton Syndrome (NS) is a very rare genetic skin disease resulting from defects in the <i>SPINK5</i> gene (encoding the protease inhibitor lympho-epithelial Kazal type inhibitor 1, LEKTI1). In this report, we provide a detailed clinical description of a Polish patient with two <i>SPINK5</i> mutations, the novel c.1816_1820+21delinsCT and possibly recurrent c.1431-12G>A. A detailed pathogenesis of Netherton Syndrome, on the basis of literature review, is discussed in the view of current knowledge about the LEKT1 molecular processing and activity.","variants":[{"Name":"NM_006846.4(SPINK5):c.1431-12G>A","Chromosome":"5","Start":"148104940","Stop":"148104940","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":359552,"rule_based_match":true,"evidence_text":"c.1431-12G>A","llm_judgment":"PRESENT","evidence":"c.1431-12G>A","abstract_start":362,"abstract_end":374},{"Name":"NM_006846.4(SPINK5):c.1816_1820+21delinsCT","Chromosome":"5","Start":"148111891","Stop":"148111916","ReferenceAlleleVCF":"TTCTTGTGAGTGGGCGGCAGCCACTG","AlternateAlleleVCF":"CT","allel_id":613509,"rule_based_match":true,"evidence_text":"c.1816_1820+21delinsCT","llm_judgment":"PRESENT","evidence":"c.1816_1820+21delinsCT","abstract_start":316,"abstract_end":338}]}
{"pmid":"23302420","title":"A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series.","abstract":"UNLABELLED: \nINTRODUCTION: Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood.\nCASE PRESENTATION: Case 1 is the 12-year-old daughter (index patient) of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1), whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (CGG>TGG) located in exon 15 (c.1225C>T) of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T).Case 2 is the 16-year-old son (brother of the index patient) of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride channel 7 gene in this patient (Case 2). The missense mutation (CGG>TGG) located in exon 15 (c.1225C>T) of the Chloride channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T).In addition to the clinical diagnosis of both cases, the missense mutation we identified in one allele of the Chloride channel 7 gene could be linked to autosomal dominant osteopetrosis-II because the symptoms appear in late childhood or adolescence.\nCONCLUSION: In this family, the molecular diagnosis was confirmed after identification of the same mutation in the older son (sibling). Furthermore, we detected that the father and his brother (the uncle) are carriers of the same mutation, whereas the mother and her sister (the aunt) do not carry any mutation of the Chloride channel 7 gene. Thus, the disease penetrance is at least 60% in the family. The mother and father are cousins and a further consanguineous marriage between the aunt and the uncle is not recommended because the dominant allele of the Chloride channel 7 gene will be transferred to the progeny. However, a similar risk is also expected following a marriage between the uncle and an unrelated woman. The p.R409W mutation in the Chloride channel 7 gene has not yet been described in the literature and it possibly has a dominant-negative impact on the protein.","variants":[{"Name":"NM_001287.6(CLCN7):c.1225C>T (p.Arg409Trp)","Chromosome":"16","Start":"1452883","Stop":"1452883","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1421829,"rule_based_match":true,"evidence_text":"c.1225C>T","llm_judgment":"PRESENT","evidence":"c.1225C>T","abstract_start":1630,"abstract_end":1639}]}
{"pmid":"35091571","title":"Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder.","abstract":"TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug-resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597-1340A>G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice-switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients' cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility.","variants":[{"Name":"NM_016589.4(TIMMDC1):c.597-1340A>G","Chromosome":"3","Start":"119515865","Stop":"119515865","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":420976,"rule_based_match":true,"evidence_text":"TIMMDC1 c.597-1340A>G","llm_judgment":"PRESENT","evidence":"TIMMDC1 c.597-1340A>G","abstract_start":482,"abstract_end":503}]}
{"pmid":"34587972","title":"Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4.","abstract":"BACKGROUND: Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and progressive polyneuropathy with the onset of fever of unknown origin. The limited number of reported cases and lack of functional annotation of related gene variants continue to limit diagnosis.\nRESULTS: We report three cases of encephalopathy from two unrelated pedigrees with basal ganglia signal changes after fever of unknown origin. To distinguish this from other types of encephalopathy, such as acute necrotizing encephalopathy, exome sequencing was performed, and four novel heterozygous variations, namely, c.169G>A (p.Ala57Thr), c.383C>T (p.Ala128Val), c.76G>A (p.Gly26Arg), and c.745T>A (p.Phe249Ile), were identified in SLC25A19. All variants were confirmed using Sanger sequencing. To determine the pathogenicity of these variants, functional studies were performed. We found that mitochondrial TPP levels were significantly decreased in the presence of SLC25A19 variants, indicating that TPP transport activities of mutated SLC25A19 proteins were impaired. Thus, combining clinical phenotype, genetic analysis, and functional studies, these variants were deemed as likely pathogenic.\nCONCLUSIONS: Exome sequencing analysis enables molecular diagnosis as well as provides potential etiology. Further studies will enable the elucidation of SLC25A19 protein function. Our investigation supplied key molecular evidence for the precise diagnosis of and clinical decision-making for a rare disease.","variants":[{"Name":"NM_001126121.2(SLC25A19):c.76G>A (p.Gly26Arg)","Chromosome":"17","Start":"75286689","Stop":"75286689","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1687768,"rule_based_match":true,"evidence_text":"c.76G>A (p.Gly26Arg)","llm_judgment":"PRESENT","evidence":"c.76G>A (p.Gly26Arg)","abstract_start":863,"abstract_end":883},{"Name":"NM_001126121.2(SLC25A19):c.745T>A (p.Phe249Ile)","Chromosome":"17","Start":"75277382","Stop":"75277382","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1687767,"rule_based_match":true,"evidence_text":"c.745T>A (p.Phe249Ile)","llm_judgment":"PRESENT","evidence":"c.745T>A (p.Phe249Ile)","abstract_start":889,"abstract_end":911}]}
{"pmid":"20727754","title":"Clinical and neuropathological findings in patients with TACO1 mutations.","abstract":"We have recently identified mutations in the translation activator of cytochrome c oxidase 1 (TACO1) gene, leading to cytochrome c oxidase (COX) deficiency. Here, we report the clinical and neuroimaging findings of five members of a big consanguinous family homozygous for c.472insC in TACO1. All 5 patients had an uneventful early childhood and a subtle onset, slowly progressive cognitive dysfunction, dystonia or visual impairment between ages 4 and 16years. Affected girls had a milder phenotype and preserved ambulation into the late twenties. Brain MRI revealed bilateral, symmetric lesions of the basal ganglia in all affected family members, but less prominent in girls. TACO1 analysis showed no mutations in 17 patients with juvenile-onset Leigh syndrome and isolated COX or combined respiratory chain deficiency, indicating that TACO1 mutations are a rare cause of Leigh syndrome.","variants":[{"Name":"NM_016360.4(TACO1):c.472dup (p.His158fs)","Chromosome":"17","Start":"63606395","Stop":"63606396","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":15450,"rule_based_match":false,"evidence_text":"c.472insC","llm_judgment":"PRESENT","evidence":"c.472insC","abstract_start":273,"abstract_end":282}]}
{"pmid":"22365152","title":"De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP.","abstract":"Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.","variants":[{"Name":"NM_001330260.2(SCN8A):c.5302A>G (p.Asn1768Asp)","Chromosome":"12","Start":"51806788","Stop":"51806788","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":39079,"rule_based_match":true,"evidence_text":"c.5302A>G [p.Asn1768Asp]","llm_judgment":"PRESENT","evidence":"c.5302A>G [p.Asn1768Asp]","abstract_start":727,"abstract_end":751}]}
{"pmid":"30520551","title":"Epidermolytic ichthyosis due to a de novo missense mutation c.1307T> C; p.Leu436Pro in KRT10.","abstract":"","variants":[{"Name":"NM_000421.5(KRT10):c.1307T>C (p.Leu436Pro)","Chromosome":"17","Start":"40819583","Stop":"40819583","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3536451,"rule_based_match":true,"evidence_text":"c.1307T> C; p.Leu436Pro","llm_judgment":"PRESENT","evidence":"c.1307T> C; p.Leu436Pro","abstract_start":null,"abstract_end":null}]}
{"pmid":"21813566","title":"Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband.","abstract":"OBJECTIVE: An infant was investigated because of megaloblastic anaemia, atypical hemolytic uraemic syndrome, severe combined immune deficiency, elevated blood levels of homocysteine and methylmalonic acid, and a selective decreased synthesis of methylcobalamin in cultured fibroblasts.\nMETHODS: Exome sequencing was performed on patient genomic DNA.\nRESULTS: Two mutations were identified in the MTHFD1 gene, which encodes a protein that catalyses three reactions involved in cellular folate metabolism. This protein is essential for the generation of formyltetrahydrofolate and methylenetetrahydrofolate and important for nucleotide and homocysteine metabolism. One mutation (c.727+1G>A) affects the splice acceptor site of intron 8. The second mutation, c.517C>T (p.R173C), changes a critical arginine residue in the NADP-binding site of the protein. Mutations affecting this arginine have previously been shown to affect enzyme activity. Both parents carry a single mutation and an unaffected sibling carries neither mutation. The combination of two mutations in the MTHFRD1 gene, predicted to have severe consequences, in the patient and their absence in the unaffected sibling, supports causality.\nCONCLUSION: This patient represents the first case of an inborn error of folate metabolism affecting the trifunctional MTHFD1 protein. This report reinforces the power of exome capture and sequencing for the discovery of novel genes, even when only a single proband is available for study.","variants":[{"Name":"NM_005956.4(MTHFD1):c.727+1G>A","Chromosome":"14","Start":"64419926","Stop":"64419926","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":439706,"rule_based_match":true,"evidence_text":"c.727+1G>A","llm_judgment":"PRESENT","evidence":"c.727+1G>A","abstract_start":677,"abstract_end":687},{"Name":"NM_005956.4(MTHFD1):c.517C>T (p.Arg173Cys)","Chromosome":"14","Start":"64417926","Stop":"64417926","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439707,"rule_based_match":true,"evidence_text":"c.517C>T (p.R173C)","llm_judgment":"PRESENT","evidence":"c.517C>T (p.R173C)","abstract_start":756,"abstract_end":774}]}
{"pmid":"25606403","title":"The first family with Tay-Sachs disease in Cyprus: Genetic analysis reveals a nonsense (c.78G>A) and a silent (c.1305C>T) mutation and allows preimplantation genetic diagnosis.","abstract":"Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder caused by mutations in the HEXA gene resulting in β-hexosaminidase A (HEX A) deficiency and neuronal accumulation of GM2 ganglioside. We describe the first patient with Tay-Sachs disease in the Cypriot population, a juvenile case which presented with developmental regression at the age of five. The diagnosis was confirmed by measurement of HEXA activity in plasma, peripheral leucocytes and fibroblasts. Sequencing the HEXA gene resulted in the identification of two previously described mutations: the nonsense mutation c.78G>A (p.Trp26X) and the silent mutation c.1305C>T (p.=). The silent mutation was reported once before in a juvenile TSD patient of West Indian origin with an unusually mild phenotype. The presence of this mutation in another juvenile TSD patient provides further evidence that it is a disease-causing mutation. Successful preimplantation genetic diagnosis (PGD) and prenatal follow-up were provided to the couple.","variants":[{"Name":"NM_000520.6(HEXA):c.1305C>T (p.Tyr435=)","Chromosome":"15","Start":"72346552","Stop":"72346552","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":106594,"rule_based_match":true,"evidence_text":"c.1305C>T (p.=)","llm_judgment":"PRESENT","evidence":"c.1305C>T (p.=)","abstract_start":644,"abstract_end":659},{"Name":"NM_000520.6(HEXA):c.78G>A (p.Trp26Ter)","Chromosome":"15","Start":"72375895","Stop":"72375895","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18950,"rule_based_match":true,"evidence_text":"c.78G>A (p.Trp26X)","llm_judgment":"PRESENT","evidence":"c.78G>A (p.Trp26X)","abstract_start":601,"abstract_end":619}]}
{"pmid":"22170724","title":"Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH?","abstract":"BACKGROUND: Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD).\nAIM: Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma.\nPATIENTS AND METHODS: A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298_301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors.\nCONCLUSION: We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.","variants":[{"Name":"NM_003002.4(SDHD):c.298_301del (p.Thr100fs)","Chromosome":"11","Start":"112088992","Stop":"112088995","ReferenceAlleleVCF":"CCTCA","AlternateAlleleVCF":"C","allel_id":183478,"rule_based_match":true,"evidence_text":"c.298_301delACTC","llm_judgment":"PRESENT","evidence":"c.298_301delACTC","abstract_start":875,"abstract_end":891}]}
{"pmid":"37819013","title":"Identification of c.104T > G, p.Met35Arg (NM_00314.8) variant in heterozygosity in exon 2 of the PTEN gene as the Causative Factor for Cowden Syndrome: A Medical Case Study.","abstract":"Cowden syndrome (CS) is a genodermatosis caused by autosomal dominant pattern mutations in the tumor suppressor gene PTEN. It is part of the PTEN spectrum, which includes Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos syndrome, and SOLAMEN syndrome (Segmental Overgrowth, Lipomatosis, Arteriovenous Malformation and Epidermal Nevus). Identical mutations can lead to different clinical presentations within the same family. Phenotypically, CS is characterized by cutaneous lesions such as trichilemmomas, intraoral papillomatosis, and acral keratosis, among others. It is essential to recognize its association with internal tumors, including those of the thyroid, breast, endometrium, and colorectum. In addition to symptomatic treatment, sirolimus has emerged as a potential therapeutic option in recent years. We present a characteristic clinical case of CS, highlighting its etiopathogenic, clinical, and therapeutic aspects. Early recognition of CS is crucial for every dermatologist. Cutaneous lesions are often the first diagnostic sign and allow for diagnosis before the appearance of internal neoplasms.","variants":[{"Name":"NM_000314.8(PTEN):c.104T>G (p.Met35Arg)","Chromosome":"10","Start":"87894049","Stop":"87894049","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":22864,"rule_based_match":true,"evidence_text":"c.104T > G, p.Met35Arg (NM_00314.8)","llm_judgment":"PRESENT","evidence":"c.104T > G, p.Met35Arg (NM_00314.8)","abstract_start":null,"abstract_end":null}]}
{"pmid":"18029453","title":"Pseudodominant inheritance of goitrous congenital hypothyroidism caused by TPO mutations: molecular and in silico studies.","abstract":"CONTEXT AND OBJECTIVE: Most cases of goitrous congenital hypothyroidism (CH) from thyroid dyshormonogenesis 1) follow a recessive mode of inheritance and 2) are due to mutations in the thyroid peroxidase gene (TPO). We report the genetic mechanism underlying the apparently dominant inheritance of goitrous CH in a nonconsanguineous family of French Canadian origin.\nDESIGN, SETTING, AND PARTICIPANTS: Two brothers identified by newborn TSH screening had severe hypothyroidism and a goiter with increased (99m)Tc uptake. The mother was euthyroid, but the father and two paternal uncles had also been diagnosed with goitrous CH. After having excluded PAX8 gene mutations, we hypothesized that the underlying defect could be TPO mutations.\nRESULTS: Both compound heterozygous siblings had inherited a mutant TPO allele carried by their mother (c.1496delC; p.Pro499Argfs2X), and from their father, one brother had inherited a missense mutation (c.1978C-->G; p.Gln660Glu) and the other an insertion (c.1955insT; p.Phe653Valfs15X). The thyroid gland of one uncle who is a compound heterozygote for TPO mutations (p.Phe653Valfs15X/p.Gln660Glu) was removed because of concurrent multiple endocrine neoplasia type 2A. Immunohistochemistry revealed normal TPO staining, implying that Gln660Glu TPO is expressed properly. Modeling of this mutant in silico suggests that its three-dimensional structure is conserved, whereas the electrostatic binding energy between the Gln660Glu TPO and its heme group becomes repulsive.\nCONCLUSION: We report a pedigree presenting with pseudodominant goitrous CH due to segregation of three different TPO mutations. Although goitrous CH generally follows a recessive mode of inheritance, the high frequency of TPO mutations carriers may lead to pseudodominant inheritance.","variants":[{"Name":"NM_001206744.2(TPO):c.1496del (p.Pro499fs)","Chromosome":"2","Start":"1484751","Stop":"1484751","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":19091,"rule_based_match":true,"evidence_text":"c.1496delC","llm_judgment":"PRESENT","evidence":"c.1496delC","abstract_start":842,"abstract_end":852},{"Name":"NM_001206744.2(TPO):c.1978C>G (p.Gln660Glu)","Chromosome":"2","Start":"1494011","Stop":"1494011","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":19092,"rule_based_match":false,"evidence_text":"c.1978C-->G (p.Gln660Glu)","llm_judgment":"PRESENT","evidence":"p.Gln660Glu","abstract_start":955,"abstract_end":966}]}
{"pmid":"17492760","title":"New founder germline mutations of CDKN2A in melanoma-prone families and multiple primary melanoma development in a patient receiving levodopa treatment.","abstract":"Germline mutations in the CDKN2A gene have been shown to predispose individuals to cutaneous malignant melanoma. Here, we describe three melanoma-prone families and one isolated patient affected by multiple melanoma who carried a tandem germline mutation of CDKN2A at the nucleotide level, [c.339G>C;c.340C>T], [p.Leu113Leu;p.Pro114Ser]. We also describe three other melanoma-prone families that carried a missense germline CDKN2A mutation, c.167G>T, p.Ser56Ile. All these families and patients resided in southeast France. We analyzed six 9p21 markers where the CDKN2A gene is located and found that carrier haplotypes for both mutations were consistent with two respective common founder ancestors. In one family, we identified two fourth-degree relatives homozygous for the Ser56Ile mutation, indicating a possible consanguinity. Furthermore, we observed that a carrier of the founder CDKN2A [p.Leu113Leu;p.Pro114Ser] mutation as well as two MC1R moderate-risk variants, [p.Arg151Cys(+)p.Arg163Gln] developed 22 primary melanomas in the three years that followed initiation of levodopa therapy for Parkinson's disease. This observation suggests that there is a need for reconsideration of the hypothesis that levodopa may play a role in melanoma development, at least when in the context of a high-risk genetic background.","variants":[{"Name":"NM_000077.5(CDKN2A):c.340C>T (p.Pro114Ser)","Chromosome":"9","Start":"21971019","Stop":"21971019","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1493193,"rule_based_match":true,"evidence_text":"c.340C>T","llm_judgment":"PRESENT","evidence":"c.340C>T","abstract_start":300,"abstract_end":308},{"Name":"NM_000077.5(CDKN2A):c.167G>T (p.Ser56Ile)","Chromosome":"9","Start":"21971192","Stop":"21971192","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":24464,"rule_based_match":true,"evidence_text":"c.167G>T, p.Ser56Ile","llm_judgment":"PRESENT","evidence":"c.167G>T, p.Ser56Ile","abstract_start":441,"abstract_end":461}]}
{"pmid":"31548836","title":"Identification of","abstract":"BACKGROUND: Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder mainly characterized by hypoplastic or absent clavicles, delayed closure of the fontanelles, multiple dental abnormalities, and short stature. Runt-related transcription factor 2 (<i>RUNX2</i>) gene variants can cause CCD, but are not identified in all CCD patients.\nMETHODS: In this study, we detected genetic variants in seven unrelated children with CCD by targeted high-throughput DNA sequencing or Sanger sequencing.\nRESULTS: All patients carried a <i>RUNX2</i> variant, totally including three novel pathogenic variants (c.722_725delTGTT, p.Leu241Serfs*8; c.231_232delTG, Ala78Glyfs*82; c.909C > G, p.Tyr303*), three reported pathogenic variants (c.577C > T, p.Arg193*; c.574G > A, p.Gly192Arg; c.673 C > T, p.Arg225Trp), one likely pathogenic variant (c.668G > T, p.Gly223Val). The analysis of the variant source showed that all variants were de novo except the two variants (c.909C > G, p.Tyr303*; c.668G > T, p.Gly223Val) inherited from the patient's father and mother with CCD respectively. Further bioinformatics analysis indicated that these variants could influence the structure of RUNX2 protein by changing the number of H-bonds or amino acids. The experimental result showed that the Gly223Val mutation made RUNX2 protein unable to quantitatively accumulate in the nucleus.\nCONCLUSIONS: The present study expands the pathogenic variant spectrum of <i>RUNX2</i> gene, which will contribute to the diagnosis of CCD and better genetic counseling in the future.","variants":[{"Name":"NM_001024630.4(RUNX2):c.909C>G (p.Tyr303Ter)","Chromosome":"6","Start":"45512295","Stop":"45512295","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1977804,"rule_based_match":true,"evidence_text":"c.909C > G, p.Tyr303*","llm_judgment":"PRESENT","evidence":"c.909C > G, p.Tyr303*","abstract_start":673,"abstract_end":694},{"Name":"NM_001024630.4(RUNX2):c.673C>T (p.Arg225Trp)","Chromosome":"6","Start":"45438039","Stop":"45438039","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":24342,"rule_based_match":true,"evidence_text":"c.673 C > T, p.Arg225Trp","llm_judgment":"PRESENT","evidence":"c.673 C > T, p.Arg225Trp","abstract_start":781,"abstract_end":805}]}
{"pmid":"27283035","title":"Analysis of FOXL2 detects three novel mutations and an atypical phenotype of blepharophimosis-ptosis-epicanthus inversus syndrome.","abstract":"BACKGROUND: Mutations in FOXL2 are known to cause autosomal dominant blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), variably associated with premature ovarian failure. In this study, we report results of mutational screening in a Czech and Slovak patient population with BPES.\nDESIGN: Case series.\nPARTICIPANTS: Thirteen probands of Czech and one proband of Slovak origin with BPES and their available family members.\nMETHODS: Sanger sequencing and multiplex ligation-dependent probe amplification in 14 probands with BPES. Targeted mutational screening in first-degree relatives.\nMAIN OUTCOME MEASURES: Genetic characterization and phenotype evaluation in Czech and Slovak individuals with BPES and their family members.\nRESULTS: Eight different mutations were detected including three novel ones: c.5T>G; p.(Met2Arg), c.197C>A; p.(Ala66Glu) and c.701_702insTGCAGCCGCAGCGGCTGCAGCAGCTGCGGCTGCAGCCGC; p.(Ala222_Ala234dup). In one family, the molecular genetic cause of disease was not identified by the methodology used. In 13 pedigrees, a negative family history suggested a de novo origin, which could be confirmed by targeted mutational screening in four families. One 62-year-old female with the c.663_692dup30 mutation had an atypical phenotype presenting as moderate ptosis compensated by frontalis muscle contraction, no epicanthus inversus and no premature ovarian failure.\nCONCLUSIONS: The de novo mutation rate in FOXL2 is exceptionally high compared with other dominant disorders manifesting with an ocular phenotype. In cases reporting a negative family history, careful examination of both parents is important to exclude mild features of the BPES phenotype.","variants":[{"Name":"NM_023067.4(FOXL2):c.197C>A (p.Ala66Glu)","Chromosome":"3","Start":"138946526","Stop":"138946526","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2894606,"rule_based_match":true,"evidence_text":"c.197C>A; p.(Ala66Glu)","llm_judgment":"PRESENT","evidence":"c.197C>A; p.(Ala66Glu)","abstract_start":834,"abstract_end":856}]}
{"pmid":"24743232","title":"A gain of function mutation in TNFRSF11B encoding osteoprotegerin causes osteoarthritis with chondrocalcinosis.","abstract":"OBJECTIVE: To identify pathogenic mutations that reveal underlying biological mechanisms driving osteoarthritis (OA).\nMETHODS: Exome sequencing was applied to two distant family members with dominantly inherited early onset primary OA at multiple joint sites with chondrocalcinosis (familial generalised osteoarthritis, FOA). Confirmation of mutations occurred by genotyping and linkage analyses across the extended family. The functional effect of the mutation was investigated by means of a cell-based assay. To explore generalisability, mRNA expression analysis of the relevant genes in the discovered pathway was explored in preserved and osteoarthritic articular cartilage of independent patients undergoing joint replacement surgery.\nRESULTS: We identified a heterozygous, probably damaging, read-through mutation (c.1205A=>T; p.Stop402Leu) in TNFRSF11B encoding osteoprotegerin that is likely causal to the OA phenotype in the extended family. In a bone resorption assay, the mutant form of osteoprotegerin showed enhanced capacity to inhibit osteoclastogenesis and bone resorption. Expression analyses in preserved and affected articular cartilage of independent OA patients showed that upregulation of TNFRSF11B is a general phenomenon in the pathophysiological process.\nCONCLUSIONS: Albeit that the role of the molecular pathway of osteoprotegerin has been studied in OA, we are the first to demonstrate that enhanced osteoprotegerin function could be a directly underlying cause. We advocate that agents counteracting the function of osteoprotegerin could comply with new therapeutic interventions of OA.","variants":[{"Name":"NM_002546.4(TNFRSF11B):c.1205A>T (p.Ter402Leu)","Chromosome":"8","Start":"118924375","Stop":"118924375","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1445094,"rule_based_match":false,"evidence_text":"c.1205A=>T; p.Stop402Leu","llm_judgment":"PRESENT","evidence":"c.1205A=>T; p.Stop402Leu","abstract_start":821,"abstract_end":845}]}
{"pmid":"38184646","title":"Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease.","abstract":"BACKGROUND: 5' untranslated regions (5'UTRs) are essential modulators of protein translation. Predicting the impact of 5'UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5'UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs).\nMETHODS: We performed an isoform-level re-analysis of retinal RNA-seq data to identify the protein-coding transcripts of 378 IRD genes with highest expression in retina. We evaluated the coverage of their 5'UTRs by different whole exome sequencing (WES) kits. The selected 5'UTRs were analyzed in whole genome sequencing (WGS) and WES data from IRD sub-cohorts from the 100,000 Genomes Project (n = 2397 WGS) and an in-house database (n = 1682 WES), respectively. Identified variants were annotated for 5'UTR-relevant features and classified into seven categories based on their predicted functional consequence. We developed a variant prioritization strategy by integrating population frequency, specific criteria for each category, and family and phenotypic data. A selection of candidate variants underwent functional validation using diverse approaches.\nRESULTS: Isoform-level re-quantification of retinal gene expression revealed 76 IRD genes with a non-canonical retina-enriched isoform, of which 20 display a fully distinct 5'UTR compared to that of their canonical isoform. Depending on the probe design, 3-20% of IRD genes have 5'UTRs fully captured by WES. After analyzing these regions in both cohorts, we prioritized 11 (likely) pathogenic variants in 10 genes (ARL3, MERTK, NDP, NMNAT1, NPHP4, PAX6, PRPF31, PRPF4, RDH12, RD3), of which 7 were novel. Functional analyses further supported the pathogenicity of three variants. Mis-splicing was demonstrated for the PRPF31:c.-9+1G>T variant. The MERTK:c.-125G>A variant, overlapping a transcriptional start site, was shown to significantly reduce both luciferase mRNA levels and activity. The RDH12:c.-123C>T variant was found in cis with the hypomorphic RDH12:c.701G>A (p.Arg234His) variant in 11 patients. This 5'UTR variant, predicted to introduce an upstream open reading frame, was shown to result in reduced RDH12 protein but unaltered mRNA levels.\nCONCLUSIONS: This study demonstrates the importance of 5'UTR variants implicated in IRDs and provides a systematic approach for 5'UTR annotation and validation that is applicable to other inherited diseases.","variants":[{"Name":"NM_152443.3(RDH12):c.-123C>T","Chromosome":"14","Start":"67722520","Stop":"67722520","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":872095,"rule_based_match":true,"evidence_text":"RDH12:c.-123C>T","llm_judgment":"PRESENT","evidence":"RDH12:c.-123C>T","abstract_start":2051,"abstract_end":2066}]}
{"pmid":"26504826","title":"SAMHD1 Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis.","abstract":"BACKGROUND: To investigate whether one or more SAMHD1 gene mutations are associated with cerebrovascular disease in the general population using a Chinese stroke cohort.\nMETHODS: Patients with a Chinese Han background (N = 300) diagnosed with either cerebral large-artery atherosclerosis (LAA, n = 100), cerebral small vessel disease (SVD, n = 100), or other stroke-free neurological disorders (control, n = 100) were recruited. Genomic DNA from the whole blood of each patient was isolated, and direct sequencing of the SAMHD1 gene was performed. Both wild type and mutant SAMHD1 proteins identified from the patients were expressed in E. coli and purified; then their dNTPase activities and ability to form stable tetramers were analysed in vitro.\nRESULTS: Three heterozygous mutations, including two missense mutations c.64C>T (P22S) and c.841G>A (p.E281K) and one splice site mutation c.696+2T>A, were identified in the LAA group with a prevalence of 3%. No mutations were found in the patients with SVD or the controls (p = 0.05). The mutant SAMHD1 proteins were functionally impaired in terms of their catalytic activity as a dNTPase and ability to assemble stable tetramers.\nCONCLUSIONS: Heterozygous SAMHD1 gene mutations might cause genetic predispositions that interact with other risk factors, resulting in increased vulnerability to stroke.","variants":[{"Name":"NM_015474.4(SAMHD1):c.841G>A (p.Glu281Lys)","Chromosome":"20","Start":"36919375","Stop":"36919375","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1319727,"rule_based_match":true,"evidence_text":"c.841G>A (p.E281K)","llm_judgment":"PRESENT","evidence":"c.841G>A (p.E281K)","abstract_start":841,"abstract_end":859}]}
{"pmid":"35731190","title":"CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related.","abstract":"The investigated intronic CAPN3 variant NM_000070.3:c.1746-20C>G occurs in the Central and Eastern Europe with a frequency of >1% and there are conflicting interpretations on its pathogenicity. We collected data on 14 patients carrying the CAPN3 c.1746-20C>G variant in trans position with another CAPN3 pathogenic/likely pathogenic variant. The patients compound heterozygous for the CAPN3 c.1746-20C>G variant presented a phenotype consistent with calpainopathy of mild/medium severity. This variant is most frequent in the North/West regions of Russia and may originate from that area. Molecular studies revealed that different splicing isoforms are produced in the muscle. We hypothesize that c.1746-20C>G is a hypomorphic variant with a reduction of RNA and protein expression and only individuals having a higher ratio of abnormal isoforms are affected. Reclassification of the CAPN3 variant c.1746-20C>G from variant with a conflicting interpretation of pathogenicity to hypomorphic variant explains many unidentified cases of limb girdle muscular dystrophy R1 calpain 3-related in Eastern and Central Europe.","variants":[{"Name":"NM_000070.3(CAPN3):c.1746-20C>G","Chromosome":"15","Start":"42403721","Stop":"42403721","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":98319,"rule_based_match":true,"evidence_text":"NM_000070.3:c.1746-20C>G","llm_judgment":"PRESENT","evidence":"NM_000070.3:c.1746-20C>G","abstract_start":40,"abstract_end":64}]}
{"pmid":"25182139","title":"The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy.","abstract":"Next-generation sequencing is currently the technology of choice for gene/mutation discovery in genetically-heterogeneous disorders, such as inherited sensorineural hearing loss (HL). Whole-exome sequencing of a single Italian proband affected by non-syndromic HL identified a novel missense variant within the PRPS1 gene (NM_002764.3:c.337G>T (p.A113S)) segregating with post-lingual, bilateral, progressive deafness in the proband's family. Defects in this gene, encoding the phosphoribosyl pyrophosphate synthetase 1 (PRS-I) enzyme, determine either X-linked syndromic conditions associated with hearing impairment (eg, Arts syndrome and Charcot-Marie-Tooth neuropathy type X-5) or non-syndromic HL (DFNX1). A subsequent screening of the entire PRPS1 gene in 16 unrelated probands from X-linked deaf families led to the discovery of two additional missense variants (c.343A>G (p.M115V) and c.925G>T (p.V309F)) segregating with hearing impairment, and associated with mildly-symptomatic peripheral neuropathy. All three variants result in a marked reduction (>60%) of the PRS-I activity in the patients' erythrocytes, with c.343A>G (p.M115V) and c.925G>T (p.V309F) affecting more severely the enzyme function. Our data significantly expand the current spectrum of pathogenic variants in PRPS1, confirming that they are associated with a continuum disease spectrum, thus stressing the importance of functional studies and detailed clinical investigations for genotype-phenotype correlation.","variants":[{"Name":"NM_002764.4(PRPS1):c.343A>G (p.Met115Val)","Chromosome":"X","Start":"107640938","Stop":"107640938","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":150246,"rule_based_match":true,"evidence_text":"c.343A>G (p.M115V)","llm_judgment":"PRESENT","evidence":"c.343A>G (p.M115V)","abstract_start":870,"abstract_end":888},{"Name":"NM_002764.4(PRPS1):c.337G>T (p.Ala113Ser)","Chromosome":"X","Start":"107640932","Stop":"107640932","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":150245,"rule_based_match":true,"evidence_text":"NM_002764.3:c.337G>T (p.A113S)","llm_judgment":"PRESENT","evidence":"NM_002764.3:c.337G>T (p.A113S)","abstract_start":323,"abstract_end":353},{"Name":"NM_002764.4(PRPS1):c.925G>T (p.Val309Phe)","Chromosome":"X","Start":"107650000","Stop":"107650000","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":150247,"rule_based_match":true,"evidence_text":"c.925G>T (p.V309F)","llm_judgment":"PRESENT","evidence":"c.925G>T (p.V309F)","abstract_start":893,"abstract_end":911}]}
{"pmid":"35186387","title":"Autosomal Recessive Congenital Ichthyosis and Steroid-Resistant Nephrotic Syndrome due to Homozygous Mutation in the","abstract":"Nephrotic syndrome (NS) associated with autosomal recessive congenital ichthyosis (ARCI) is a rare association. In this article, we described a 4-year-old boy with steroid-resistant NS (SRNS) who had a history of ichthyotic skin lesions since birth. Renal biopsy revealed focal segmental glomerulosclerosis (tip variant). The skin biopsy was consistent with the findings of ichthyosis. Next-generation sequencing revealed a homozygous pathogenic variant (c.1625_1626del) in the exon 12 of the <i>ALOX12B</i> gene, confirming the diagnosis of ARCI2. The <i>ALOX12B</i> gene belongs to the lipoxygenase family and has a pivotal role in the formation of lipid layers in the epidermis. Leukotrienes have a counter-regulatory effect within the inflamed glomeruli, which influences the vascular tone and glomerular basement membrane permeability, that can be implicated in the pathogenesis of the NS. This child is currently in remission, on tacrolimus and low-dose prednisolone, with emollients and is on regular follow-up. SRNS associated with congenital ichthyosis secondary to a mutation in the <i>ALOX12B</i> gene has never been reported so far. The knowledge regarding this novel association will help the treating physicians in diagnosing this condition early, which will enable proper genetic counseling and prognostication of the disease to the family.","variants":[{"Name":"NM_001139.3(ALOX12B):c.1625_1626del (p.Lys542fs)","Chromosome":"17","Start":"8075623","Stop":"8075624","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":1517452,"rule_based_match":true,"evidence_text":"c.1625_1626del","llm_judgment":"PRESENT","evidence":"c.1625_1626del","abstract_start":455,"abstract_end":469}]}
{"pmid":"30105122","title":"Report of the Third Family with Multiple Mitochondrial Dysfunctions Syndrome 5 Caused by the Founder Variant p.(Glu87Lys) in","abstract":"Iron-sulfur cluster assembly 1 (ISCA1) is one of the essential proteins operating in the mitochondrial iron-sulfur (Fe-S) cluster biogenesis pathway. We reported the variant c.259G > A [p.(Glu87Lys)] in homozygous state in exon 4 of the <i>ISCA1</i> gene as the likely cause of multiple mitochondrial dysfunction syndrome 5 in a previous publication. We now report the third patient with the same phenotype and variant, further supporting the possibility of a founder event. Our observation confirms the clinical presentation associated with a probable founder variant in this condition.","variants":[{"Name":"NM_030940.4(ISCA1):c.259G>A (p.Glu87Lys)","Chromosome":"9","Start":"86266174","Stop":"86266174","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":362182,"rule_based_match":true,"evidence_text":"c.259G > A [p.(Glu87Lys)]","llm_judgment":"PRESENT","evidence":"c.259G > A [p.(Glu87Lys)]","abstract_start":174,"abstract_end":199}]}
{"pmid":"14523376","title":"Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis.","abstract":"A predominance of de novo mutations in the paternal germ line has been reported for several disorders; however, in familial adenomatous polyposis (FAP), the parental origin of APC mutations has been scarcely analysed so far. Among 563 unrelated FAP families with known family history, we identified 58 patients with a suspected de novo mutation in the APC gene. A germline mutation was detected in 52 of them; in 38 patients, the mutation could be excluded in both parents. The five base pair deletion at codon 1309 (c.3927_3931delAAAGA) was over-represented in the group of patients with suspected de novo mutations (17/58=29%), when compared to the group of familial cases (26/505=5%); thus, the high frequency of this mutation is not due to a founder effect but rather due to de novo mutation events. Parental origin of de novo mutations could be traced in 16 families, including three families with large chromosomal deletions. Four mutations were of maternal and 12 of paternal origin, pointing to a moderate preponderance towards paternal origin. Sex-related differences of mutation types could be observed: large deletions and single-base substitutions were exclusively of paternal origin, whereas the small deletions were equally distributed (maternal/paternal ratio 4:4).","variants":[{"Name":"NM_000038.6(APC):c.3927_3931del (p.Glu1309fs)","Chromosome":"5","Start":"112839515","Stop":"112839519","ReferenceAlleleVCF":"TAAAAG","AlternateAlleleVCF":"T","allel_id":15855,"rule_based_match":true,"evidence_text":"c.3927_3931delAAAGA","llm_judgment":"PRESENT","evidence":"c.3927_3931delAAAGA","abstract_start":517,"abstract_end":536}]}
{"pmid":"20652410","title":"Dihydrolipoamide dehydrogenase (DLD) deficiency in a Spanish patient with myopathic presentation due to a new mutation in the interface domain.","abstract":"We present a 32-year-old patient who, from age 7 months, developed photophobia, left-eye ptosis and progressive muscular weakness. At age 7 years, she showed normal psychomotor development, bilateral ptosis and exercise-induced weakness with severe acidosis. Basal blood and urine lactate were normal, increasing dramatically after effort. PDHc deficiency was demonstrated in muscle and fibroblasts without detectable PDHA1 mutations. Ketogenic diet was ineffective, however thiamine gave good response although bilateral ptosis and weakness with acidosis on exercise persisted. Recently, DLD gene analysis revealed a homozygous missense mutation, c.1440 A>G (p.I480M), in the interface domain. Both parents are heterozygous and DLD activity in the patient's fibroblasts is undetectable. The five patients that have been reported with DLD-interface mutations suffered fatal deteriorations. Our patient's disease is milder, only myopathic, more similar to that due to mutation p.G229C in the NAD(+)-binding domain. Two of the five patients presented mutations (p.D479V and p.R482G) very close to the present case (p.I480M). Despite differing degrees of clinical severity, all three had minimal clues to DLD deficiency, with occasional minor increases in α-ketoglutarate and branched-chain amino acids. In the two other patients, hypertrophic cardiomyopathy was a significant feature that has been attributed to moonlighting proteolytic activity of monomeric DLD, which can degrade other mitochondrial proteins, such as frataxin. Our patient does not have cardiomyopathy, suggesting that p.I480M may not affect the DLD ability to dimerize to the same extent as p.D479V and p.R482G. Our patient, with a novel mutation in the DLD interface and mild clinical symptoms, further broadens the spectrum of this enzyme defect.","variants":[{"Name":"NM_000108.5(DLD):c.1440A>G (p.Ile480Met)","Chromosome":"7","Start":"107919075","Stop":"107919075","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":544107,"rule_based_match":true,"evidence_text":"c.1440 A>G (p.I480M)","llm_judgment":"PRESENT","evidence":"c.1440 A>G (p.I480M)","abstract_start":648,"abstract_end":668}]}
{"pmid":"16389551","title":"Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment.","abstract":"To date, 37 genes have been identified for nonsyndromic hearing impairment (NSHI). Identifying the functional sequence variants within these genes and knowing their population-specific frequencies is of public health value, in particular for genetic screening for NSHI. To determine putatively functional sequence variants in the transmembrane inner ear (TMIE) gene in Pakistani and Jordanian families with autosomal recessive (AR) NSHI, four Jordanian and 168 Pakistani families with ARNSHI that is not due to GJB2 (CX26) were submitted to a genome scan. Two-point and multipoint parametric linkage analyses were performed, and families with logarithmic odds (LOD) scores of 1.0 or greater within the TMIE region underwent further DNA sequencing. The evolutionary conservation and location in predicted protein domains of amino acid residues where sequence variants occurred were studied to elucidate the possible effects of these sequence variants on function. Of seven families that were screened for TMIE, putatively functional sequence variants were found to segregate with hearing impairment in four families but were not seen in not less than 110 ethnically matched control chromosomes. The previously reported c.241C>T (p.R81C) variant was observed in two Pakistani families. Two novel variants, c.92A>G (p.E31G) and the splice site mutation c.212 -2A>C, were identified in one Pakistani and one Jordanian family, respectively. The c.92A>G (p.E31G) variant occurred at a residue that is conserved in the mouse and is predicted to be extracellular. Conservation and potential functionality of previously published mutations were also examined. The prevalence of functional TMIE variants in Pakistani families is 1.7% [95% confidence interval (CI) 0.3-4.8]. Further studies on the spectrum, prevalence rates, and functional effect of sequence variants in the TMIE gene in other populations should demonstrate the true importance of this gene as a cause of hearing impairment.","variants":[{"Name":"NM_147196.3(TMIE):c.92A>G (p.Glu31Gly)","Chromosome":"3","Start":"46701579","Stop":"46701579","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":359531,"rule_based_match":true,"evidence_text":"c.92A>G (p.E31G)","llm_judgment":"PRESENT","evidence":"c.92A>G (p.E31G)","abstract_start":1304,"abstract_end":1320}]}
{"pmid":"26689116","title":"Novel mutation in C10orf2 associated with multiple mtDNA deletions, chronic progressive external ophthalmoplegia and premature aging.","abstract":"Chronic progressive external ophthalmoplegia (CPEO) is caused by defects in both mitochondrial and nuclear genes, however, the causal genetic factors in large number of patients remains undetermined. Therefore, our aim was to screen 12 unrelated patients with CPEO for mutation/multiple deletions in mtDNA and mutations in the coding regions of C10orf2, which is essential for mtDNA replication. Histopathological study of muscle biopsy revealed cytochrome c oxidase-deficient fibers and ragged blue fibers in all the patients. Long-range PCR of DNA from skeletal muscle revealed multiple mtDNA deletions in all the 12 patients. Further, sequencing coding regions of C10orf2 revealed three variants in three different patients, of which two were novel (c.1964G>A/p.G655D; c.204G>A/p.G68G) variants and one was reported (c.1052A>G/p. N351S). Sequencing of other nuclear genes that are associated with CPEO and multiple mtDNA deletions, such as; POLG1, POLG2, TK2, ANT1, DGUOK, MPV17 and RRM2B did not reveal any pathogenic mutation in patients with C10orf2 mutation. Since in silico analyses revealed p.G655D could be a potentially pathogenic and it was absent in 200 healthy controls, p.G655D could be the causative factor for CPEO. Therefore, we suggest that C10orf2 gene should be screened in CPEO individuals with multiple mtDNA deletions, which might help in prognosis of this disease and appropriate genetic counseling.","variants":[{"Name":"NM_021830.5(TWNK):c.1052A>G (p.Asn351Ser)","Chromosome":"10","Start":"100989262","Stop":"100989262","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":414703,"rule_based_match":true,"evidence_text":"c.1052A>G/p. N351S","llm_judgment":"PRESENT","evidence":"c.1052A>G/p. N351S","abstract_start":820,"abstract_end":838}]}
{"pmid":"18337586","title":"Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease.","abstract":"OBJECTIVE: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C.\nMETHODS: We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis.\nRESULTS: The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30-79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation.\nCONCLUSIONS: The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.","variants":[{"Name":"NM_198578.4(LRRK2):c.4321C>T (p.Arg1441Cys)","Chromosome":"12","Start":"40310434","Stop":"40310434","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16977,"rule_based_match":true,"evidence_text":"LRRK2 c.4321C>T (p.R1441C)","llm_judgment":"PRESENT","evidence":"LRRK2 c.4321C>T (p.R1441C)","abstract_start":372,"abstract_end":398}]}
{"pmid":"24519355","title":"Sensory ataxia as a prominent clinical presentation in three families with mutations in CYP7B1.","abstract":"Pathogenic mutations in CYP7B1 account for SPG5, an autosomal recessive hereditary spastic paraplegia characterized by a complex phenotype including visual problems and cerebellar dysfunction. Sensory ataxia is not usually regarded as a typical clinical feature of SPG5. The purpose of this study was to describe six patients showing features of sensory ataxia as the prominent and/or initial symptoms of SPG5. Six patients from three distinct pedigrees (three women, three men; age 49.5 ± 18.2 years), all presenting gait unsteadiness and frequent falls since childhood, underwent clinical and molecular investigations. All showed marked sensory ataxic gait with positive Romberg's sign, as well as severely impaired position and vibration sense. Comparatively minor signs of pyramidal involvement were also detected. In four of the patients, brain MRI showed white matter hyperintensities on T2-weighted images. An already reported homozygous c.889A>G (p.T297A) mutation in SPG5/CYP7B1 was found in five patients from two families, whereas the remaining case harbored the novel c.250_251delC/p.L84Ffs*6 and c.266A>C/p.Y89S variants. Marked and enduring sensory ataxia can be a pivotal sign in SPG5, and expands the phenotypic spectrum associated with mutations in CYP7B1.","variants":[{"Name":"NM_004820.5(CYP7B1):c.889A>G (p.Thr297Ala)","Chromosome":"8","Start":"64615194","Stop":"64615194","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":125787,"rule_based_match":true,"evidence_text":"c.889A>G (p.T297A)","llm_judgment":"PRESENT","evidence":"c.889A>G (p.T297A)","abstract_start":945,"abstract_end":963}]}
{"pmid":"15542400","title":"Glycogen storage disease type Ia in Argentina: two novel glucose-6-phosphatase mutations affecting protein stability.","abstract":"Glycogen storage disease type Ia (GSD-Ia) is caused by deleterious mutations in the glucose-6-phosphatase gene (G6PC). A molecular study of this gene was carried out in 11 Argentinean patients from 8 unrelated families. Four missense (p.Gln54Pro, p.Arg83Cys, p.Thr16Arg, and p.Tyr209Cys) and one deletion (c.79delC) mutations have been identified. Two novel mutations, p.Thr16Arg (c.47C>G) located within the amino-terminal domain and p.Tyr209Cys (c.626A>G) situated in the sixth transmembrane helix, were uncovered in this study. Site-directed mutagenesis and transient expression assays demonstrated that both p.Thr16Arg and p.Tyr209Cys mutations abolished enzymatic activity as well as reduced G6Pase stability.","variants":[{"Name":"NM_000151.4(G6PC1):c.626A>G (p.Tyr209Cys)","Chromosome":"17","Start":"42910978","Stop":"42910978","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":845356,"rule_based_match":true,"evidence_text":"c.626A>G (p.Tyr209Cys)","llm_judgment":"PRESENT","evidence":"p.Tyr209Cys","abstract_start":275,"abstract_end":286},{"Name":"NM_000151.4(G6PC1):c.47C>G (p.Thr16Arg)","Chromosome":"17","Start":"42900923","Stop":"42900923","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":548508,"rule_based_match":true,"evidence_text":"c.47C>G (p.Thr16Arg)","llm_judgment":"PRESENT","evidence":"p.Thr16Arg","abstract_start":259,"abstract_end":269}]}
{"pmid":"16088929","title":"Molecular analysis of the HEXA gene in Italian patients with infantile and late onset Tay-Sachs disease: detection of fourteen novel alleles.","abstract":"Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the hexosaminidase A deficiency. We report the molecular characterization performed on 31 Italian patients, 22 with the infantile, acute form of TSD and nine patients with the subacute juvenile form, biochemically classified as B1 Variant. Of the 29 different alleles identified, fourteen were due to 15 novel mutations, two being in-cis on a new complex allele. The new alleles caused four frameshifts, three premature stop codons, three amino acid changes, two amino acid deletions and two splicing alterations. As previously reported, the c.533G>A (p.R178H) mutation was present either in homozygosity or as compound heterozygote, in all the patients with the late onset TSD form (B1 Variant); the allele frequency in this group is discussed by comparison with that found in infantile TSD.","variants":[{"Name":"NM_000520.6(HEXA):c.533G>A (p.Arg178His)","Chromosome":"15","Start":"72353105","Stop":"72353105","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18935,"rule_based_match":true,"evidence_text":"c.533G>A (p.R178H)","llm_judgment":"PRESENT","evidence":"c.533G>A (p.R178H)","abstract_start":612,"abstract_end":630}]}
{"pmid":"33682124","title":"Congenital ataxia due to novel variant in ATP8A2.","abstract":"Congenital ataxias are a heterogeneous group of disorders characterized by congenital or early-onset ataxia. Here, we describe two siblings with congenital ataxia, who acquired independent gait by age 4 years. After 16 years of follow-up they presented near normal cognition, cerebellar ataxia, mild pyramidal signs, and dystonia. On exome sequencing, a novel homozygous variant (c.1580-18C > G - intron 17) in ATP8A2 was identified. A new acceptor splice site was predicted by bioinformatics tools, and functionally characterized through a minigene assay. Minigene constructs were generated by PCR-amplification of genomic sequences surrounding the variant of interest and cloning into the pCMVdi vector. Altered splicing was evaluated by expressing these constructs in HEK293T cells. The construct with the c.1580-18C > G homozygous variant produced an aberrant transcript, leading to retention of 17 bp of intron 17, by the use of an alternative acceptor splice site, resulting in a premature stop codon by insertion of four amino acids. These results allowed us to establish this as a disease-causing variant and expand ATP8A2-related disorders to include less severe forms of congenital ataxia.","variants":[{"Name":"NM_016529.6(ATP8A2):c.1580-18C>G","Chromosome":"13","Start":"25571592","Stop":"25571592","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2795820,"rule_based_match":true,"evidence_text":"c.1580-18C > G","llm_judgment":"PRESENT","evidence":"c.1580-18C > G","abstract_start":380,"abstract_end":394}]}
{"pmid":"35384599","title":"Post-acute cardiac complications following SARS-CoV-2 infection in partial lipodystrophy due to LMNA gene p.R349W mutation.","abstract":"PURPOSE: SARS-CoV-2 infection may cause varying degrees of cardiac injury and the presence of underlying cardiovascular morbidities contributes to the frequency and severity of occurrence of this complication. Lipodystrophy syndromes are frequently characterized by severe metabolic derangements that represent relevant cardiovascular risk factors. Besides causing lipodystrophy, mutations in the lamin A/C (LMNA) gene can lead to a wide spectrum of tissue-specific disorders including cardiac involvement.\nMETHODS AND RESULTS: We herein examine the case of two patients affected by atypical progeroid syndrome and partial lipodystrophy due to a heterozygous missense LMNA mutation c.1045 C > T (p.R349W) who presented initially with mild COVID-19 and developed severe cardiovascular complications within few weeks of SARS-CoV-2 infection. Before being infected with SARS-CoV-2, our patients had cardiovascular morbidities (mild mitral regurgitation in one patient, ischemic heart disease with bifascicular block in the other patient) in adjunct to cardiovascular risk factors, but the SARS-CoV-2 infection contributed to quickly and significantly decompensate their balance.\nCONCLUSION: These findings warn that patients affected by LMNA p.R349W mutation and likely other LMNA mutations associated with cardiovascular morbidity should be considered at extremely elevated risk of post-acute cardiological manifestations and should therefore undergo a vigilant follow-up after SARS-CoV-2 infection. Both patients developed COVID-19 before the specific vaccination was available to them and this unfortunate situation should remark the importance of vaccination coverage against SARS-CoV-2 infection for all patients affected by lipodystrophy, especially those with underlying comorbidities.","variants":[{"Name":"NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)","Chromosome":"1","Start":"156136009","Stop":"156136009","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77659,"rule_based_match":true,"evidence_text":"c.1045 C > T (p.R349W)","llm_judgment":"PRESENT","evidence":"c.1045 C > T (p.R349W)","abstract_start":682,"abstract_end":704}]}
{"pmid":"21189962","title":"An atypical phenotype of hypokalemic periodic paralysis caused by a mutation in the sodium channel gene SCN4A.","abstract":"Familial hypokalemic periodic paralysis is an autosomal-dominant channelopathy characterized by episodic muscle weakness with hypokalemia. The respiratory and cardiac muscles typically remain unaffected, but we report an atypical case of a family with hypokalemic periodic paralysis in which the affected members presented with frequent respiratory insufficiency during severe attacks. Molecular analysis revealed a heterozygous c.664 C>T transition in the sodium channel gene SCN4A, leading to an Arg222Trp mutation in the channel protein. The patients described here presented unusual clinical characteristics that included a severe respiratory phenotype, an incomplete penetrance in female carriers, and a different response to medications.","variants":[{"Name":"NM_000334.4(SCN4A):c.664C>T (p.Arg222Trp)","Chromosome":"17","Start":"63971201","Stop":"63971201","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152917,"rule_based_match":true,"evidence_text":"c.664 C>T","llm_judgment":"PRESENT","evidence":"c.664 C>T","abstract_start":429,"abstract_end":438}]}
{"pmid":"25636364","title":"Relationship between CFTR and CTRC variants and the clinical phenotype in late-onset cystic fibrosis disease with chronic pancreatitis.","abstract":"Cystic fibrosis (CF), the most common autosomal recessive disease in whites, is caused by mutations in the CF transmembrane conductance regulator (CFTR). So far, >1900 mutations have been described, most of which are nonsense, missense, and frameshift, and can lead to severe phenotypes, reducing the level of function of the CFTR protein. Synonymous variations are usually considered silent without pathogenic effects. However, synonymous mutations exhibiting exon skipping as a consequence of aberrant splicing of pre-mRNA differ. Herein, we describe the effect of the aberrant splicing of the c.273G>C (G91G) synonymous variation found in a 9-year-old white (ΔF508) patient affected by CF and pancreatitis associated with a variant in chymotrypsin C (CTRC). Magnetic resonance imaging showed an atrophic pancreatic gland with substitution of the pancreatic parenchyma with three cysts. Genetic examination revealed compound heterozygosity for the c.1521_1523delCTT (ΔF508) pathogenic variant and the c.273G>C (G91G) variant in CFTR. Sweat test results confirmed the diagnosis of CF. We have thus identified a synonymous variation (G91G) causing the skipping of exon 3 in a CF patient carrying the ΔF508 mutation. However, the clinical phenotype with pancreatic symptoms encouraged us to investigate a panel of pancreas-related genes, which resulted in finding a known sequence variation inside CTRC. We further discuss the role of these variants and their possible interactions in determining the current phenotype.","variants":[{"Name":"NM_000492.3(CFTR):c.1521_1523del (p.Phe508del)","Chromosome":"7","Start":"117559591","Stop":"117559593","ReferenceAlleleVCF":"ATCT","AlternateAlleleVCF":"A","allel_id":22144,"rule_based_match":true,"evidence_text":"c.1521_1523delCTT (ΔF508)","llm_judgment":"PRESENT","evidence":"c.1521_1523delCTT (ΔF508)","abstract_start":950,"abstract_end":975},{"Name":"NM_000492.4(CFTR):c.273G>C (p.Gly91=)","Chromosome":"7","Start":"117509142","Stop":"117509142","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":487236,"rule_based_match":true,"evidence_text":"c.273G>C (G91G)","llm_judgment":"PRESENT","evidence":"c.273G>C (G91G)","abstract_start":596,"abstract_end":611}]}
{"pmid":"24259288","title":"A novel germline PIGA mutation in Ferro-Cerebro-Cutaneous syndrome: a neurodegenerative X-linked epileptic encephalopathy with systemic iron-overload.","abstract":"Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3-Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism.","variants":[{"Name":"NM_002641.4(PIGA):c.1030_1032del (p.Leu344del)","Chromosome":"X","Start":"15324821","Stop":"15324823","ReferenceAlleleVCF":"TAAG","AlternateAlleleVCF":"T","allel_id":136567,"rule_based_match":true,"evidence_text":"c.1030_1032delCTT, p.Leu344del","llm_judgment":"PRESENT","evidence":"c.1030_1032delCTT, p.Leu344del","abstract_start":445,"abstract_end":475}]}
{"pmid":"27634470","title":"De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis.","abstract":"BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder that manifests recurrent attacks of hemiplegia, oculogyric, and choreoathetotic involuntary movements. De novo mutations in ATP1A3 cause three types of neurological diseases: AHC; rapid-onset dystonia-Parkinsonism (RDP); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndromes. It remains to be determined whether or not a rare mutation in ATP1A3 may cause atypical phenotypes.\nCASE PRESENTATION: A 7-year-old boy presented with recurrent symptoms of generalized paralysis since 1 year and 5 months of age. Hypotonia, dystonia, and choreoathetosis persisted with exacerbation under febrile conditions, but no cerebellar ataxia had ever evolved in 6 years. Whole-exome sequencing (WES) was performed to determine his genetic background, and mutations were validated by the Sanger method. Crude protein extracts were prepared from the cultured cells, and expression of the wild-type or mutant ATP1A3 proteins were analyzed by Western blotting. WES identified a de novo pathogenic mutation in ATP1A3 (c.2266C > T:p.R756C) for this patient. A literature overview of two reported cases with p.R756C and p.R756H mutations showed both overlapping and distinct phenotypes when compared with those of the present case. The expression of the mutant form (R756C) of ATP1A3 did not differ markedly from that of the wild-type and D801N proteins.\nCONCLUSIONS: This study confirmed that p.R756C mutation of ATP1A3 cause atypical forms of AHC-associated disorders. The wide spectra of neurological phenotypes in AHC are linked to as-yet-unknown deficits in the functions of mutant ATP1A3.","variants":[{"Name":"NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)","Chromosome":"19","Start":"41970540","Stop":"41970540","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":413523,"rule_based_match":true,"evidence_text":"c.2266C > T:p.R756C","llm_judgment":"PRESENT","evidence":"c.2266C > T:p.R756C","abstract_start":1137,"abstract_end":1156}]}
{"pmid":"33749153","title":"PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder.","abstract":"Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.","variants":[{"Name":"NM_025179.4(PLXNA2):c.614G>A (p.Arg205Gln)","Chromosome":"1","Start":"208217309","Stop":"208217309","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1375583,"rule_based_match":true,"evidence_text":"c.614G>A (p.Arg205Gln)","llm_judgment":"PRESENT","evidence":"c.614G>A (p.Arg205Gln)","abstract_start":767,"abstract_end":789}]}
{"pmid":"31513438","title":"Whole-Exome Sequencing Analysis Identified Novel Mutations in the","abstract":"<b><i>Background:</i></b> Familial exudative vitreoretinopathy (FEVR, OMIM 133780), characterized by incomplete retinal vascular development and pathological neovascularization, is a severe inherited retinal disorder. Mutations in 10 genes have been reported to be associated with FEVR, but this still leaves ∼50% of FEVR cases to be genetically explained. <b><i>Purpose:</i></b> The purpose of this study was to identify novel FEVR-causing mutations and explore the causative mutations in Chinese FEVR families. <b><i>Methods:</i></b> Whole-exome sequencing was performed to analyze the genomic DNA of the probands from 121 Chinese FEVR families. Sanger sequencing was carried out to verify all identified mutations. Luciferase assays were used to test the activity of a mutant protein in the Norrin-β-catenin signaling pathway. <b><i>Results:</i></b> Four novel heterozygous <i>TSPAN12</i> (Tetraspanin 12) mutations, including two single-base substitution mutations and two small-deletion mutations, were identified in these FEVR families: c.1A>G (p.0), c.614G>A (p.G205D), c.695delT (p.V232Gfs*7), and c.833_842del (p.L278Qfs*25). <b><i>Conclusion:</i></b> This study revealed the causative mutations in four Chinese FEVR families and identified four novel FEVR-causing mutations, thus expanding the mutation spectrum of FEVR in the Chinese population.","variants":[{"Name":"NM_012338.4(TSPAN12):c.614G>A (p.Gly205Asp)","Chromosome":"7","Start":"120788896","Stop":"120788896","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1007140,"rule_based_match":true,"evidence_text":"c.614G>A (p.G205D)","llm_judgment":"PRESENT","evidence":"c.614G>A (p.G205D)","abstract_start":1057,"abstract_end":1075}]}
{"pmid":"19371217","title":"RNA analysis of consensus sequence splicing mutations: implications for the diagnosis of Wilson disease.","abstract":"Wilson disease (WD) is an autosomal recessive disorder caused by a defective function of the copper-transporting ATP7B protein. This results in progressive copper overload and consequent liver, brain, and kidney damage. Approximately 300 WD-causing mutations have been described to date. Missense mutations are largely prevalent, while splice-site mutations are rarer. Of these, only a minority are detected in splicing consensus sequences. Further, few splicing mutations have been studied at the RNA level. In this study we report the RNA molecular characterization of three consensus splice-site mutations identified by DNA analysis in WD patients. One of them, c.51 + 4 A --> T, resides in the consensus sequence of the donor splice site of intron 1; the second, c. 2121 + 3 A --> G, occurred in position + 3 of intron 7; and the c.2447 + 5 G --> A is localized in the consensus sequence of the donor splice site of intron 9. Analysis revealed predominantly abnormal splicing in the samples carrying mutations compared to the normal controls. These results strongly suggest that consensus sequence splice-site mutations result in disease by interfering with the production of the normal WD protein. Our data contribute to understanding the mutational spectrum that affect splicing and improve our capability in WD diagnosis.","variants":[{"Name":"NM_000053.4(ATP7B):c.51+4A>T","Chromosome":"13","Start":"52011283","Stop":"52011283","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":328547,"rule_based_match":false,"evidence_text":"c.51 + 4 A --> T","llm_judgment":"PRESENT","evidence":"c.51 + 4 A --> T","abstract_start":665,"abstract_end":681},{"Name":"NM_000053.4(ATP7B):c.2121+3A>G","Chromosome":"13","Start":"51960145","Stop":"51960145","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":547701,"rule_based_match":false,"evidence_text":"c. 2121 + 3 A --> G","llm_judgment":"PRESENT","evidence":"c. 2121 + 3 A --> G","abstract_start":767,"abstract_end":786}]}
{"pmid":"34837691","title":"Excluding embryos with two novel mutations in","abstract":"Fraser syndrome is a rare autosomal recessive malformation disorder. It is characterized by cryptophthalmos, syndactyly, urinary tract abnormalities and ambiguous genitalia. This condition is due to homozygous or heterozygous mutations in the <i>FRAS1</i>, <i>FREM1</i>, <i>FREM2</i>, and <i>GRIP1</i> genes<i>.</i> In the present study, we recruited a Chinese family with Fraser syndrome. Two novel mutations c.7542_7543insG and c.2689C>T in the <i>FREM2</i> gene were detected in this Fraser syndrome family by PCR-based sequencing. The next-generation sequencing-based single nucleotide polymorphism haplotyping method was applied to exclude these two mutations in 9 blastocysts obtained from the patient. After obtaining consent and informing the risk, the patient received <i>in vitro</i> fertilization and embryo transfer treatment with an embryo carrying a heterozygous mutation. Finally, she delivered a healthy baby without any complications on March 17, 2019. In conclusion, we first reported two novel mutations in the <i>FREM2</i> gene associated with the risk of Fraser syndrome. Moreover, we described a next-generation sequencing-based single nucleotide polymorphism haplotyping method to select the 'right' embryos from patients with Fraser syndrome for <i>in vitro</i> fertilization and embryo transfer treatment.","variants":[{"Name":"NM_207361.6(FREM2):c.2689C>T (p.Gln897Ter)","Chromosome":"13","Start":"38690033","Stop":"38690033","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2750662,"rule_based_match":true,"evidence_text":"c.2689C>T","llm_judgment":"PRESENT","evidence":"c.2689C>T","abstract_start":430,"abstract_end":439}]}
{"pmid":"36691871","title":"Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family.","abstract":"BACKGROUND: Germline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants.\nMETHODS: The proband was tested via a clinical testing, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). RT-PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach.\nRESULTS: We report a 56-year-old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein.\nCONCLUSION: Our results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.","variants":[{"Name":"NM_000179.3(MSH6):c.4001G>C (p.Arg1334Pro)","Chromosome":"2","Start":"47806651","Stop":"47806651","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":232853,"rule_based_match":true,"evidence_text":"MSH6 c.4001G > C","llm_judgment":"PRESENT","evidence":"MSH6 c.4001G > C","abstract_start":712,"abstract_end":728}]}
{"pmid":"33710525","title":"The p.Ala2430Val mutation in filamin C causes a \"hypertrophic myofibrillar cardiomyopathy\".","abstract":"Hypertrophic cardiomyopathy (HCM) often leads to heart failure. Mutations in sarcomeric proteins are most frequently the cause of HCM but in many patients the gene defect is not known. Here we report on a young man who was diagnosed with HCM shortly after birth. Whole exome sequencing revealed a mutation in the FLNC gene (c.7289C > T; p.Ala2430Val) that was previously shown to cause aggregation of the mutant protein in transfected cells. Myocardial tissue from patients with this mutation has not been analyzed before and thus, the underlying etiology is not well understood. Myocardial tissue of our patient obtained during myectomy at the age of 23 years was analyzed in detail by histochemistry, immunofluorescence staining, electron microscopy and western blot analysis. Cardiac histology showed a pathology typical for myofibrillar myopathy with myofibril disarray and abnormal protein aggregates containing BAG3, desmin, HSPB5 and filamin C. Analysis of sarcomeric and intercalated disc proteins showed focally reduced expression of the gap junction protein connexin43 and Xin-positive sarcomeric lesions in the cardiomyocytes of our patient. In addition, autophagy pathways were altered with upregulation of LC3-II, WIPI1 and HSPB5, 6, 7 and 8. We conclude that the p.Ala2430Val mutation in FLNC most probably is associated with HCM characterized by abnormal intercalated discs, disarray of myofibrils and aggregates containing Z-disc proteins similar to myofibrillar myopathy, which supports the pathological effect of the mutation.","variants":[{"Name":"NM_001458.5(FLNC):c.7289C>T (p.Ala2430Val)","Chromosome":"7","Start":"128856555","Stop":"128856555","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":194663,"rule_based_match":true,"evidence_text":"c.7289C > T; p.Ala2430Val","llm_judgment":"PRESENT","evidence":"c.7289C > T; p.Ala2430Val","abstract_start":324,"abstract_end":349}]}
{"pmid":"32743982","title":"Primary coenzyme Q10 deficiency due to COQ8A gene mutations.","abstract":"BACKGROUND: Primary deficiency of coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive cerebellar ataxia with mitochondrial respiratory chain disfunction. The main clinical manifestation involves early-onset exercise intolerance, progressive cerebellar ataxia, and movement disorders. COQ8A gene mutations are responsible for this disease. Here, we provide clinical, laboratory, and genetic findings of a patient with cerebellar ataxia caused by compound heterozygous mutations in COQ8A gene.\nMETHODS: A male patient from a non-consanguineous Chinese family underwent detailed physical and auxiliary examination. After exclusion of acquired causes of ataxia, Friedreich's Ataxia, and common types of spinocerebellar ataxia, the patient was subjected to whole exome sequencing (WES) followed by confirmation of sequence variants using Sanger sequencing. His asymptomatic parents, two brothers and one sister were genotyped for these variants.\nRESULTS: This patient showed early-onset exercise intolerance and progressive cerebellar ataxia, wide-based gait and tremor, accompanied by symptoms of dysautonomia. His serum lactate level was elevated and plasma total Coenzyme Q10 (CoQ10) was decreased. Brain MRI showed cerebellar atrophy, and X-ray of the spine revealed thoraco-lumbar scoliosis. Compound heterozygous mutations in the COQ8A gene were identified through WES: c.1844_1845insG, p.Ser616Leufs*114 and c.902G>A, p.Arg301Gln. After treatment with ubidecarenone, 40 mg three times per day for 2 years, the symptoms dramatically improved.\nCONCLUSIONS: We identified a patient with COQ10D4 caused by novel COQ8A mutations. Our findings widen the spectrum of COQ8A gene mutations and clinical manifestations.","variants":[{"Name":"NM_020247.5(COQ8A):c.1844dup (p.Ser616fs)","Chromosome":"1","Start":"226986631","Stop":"226986632","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":210644,"rule_based_match":false,"evidence_text":"c.1844_1845insG, p.Ser616Leufs*114","llm_judgment":"PRESENT","evidence":"c.1844_1845insG, p.Ser616Leufs*114","abstract_start":1381,"abstract_end":1415},{"Name":"NM_020247.5(COQ8A):c.902G>A (p.Arg301Gln)","Chromosome":"1","Start":"226982726","Stop":"226982726","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2409487,"rule_based_match":true,"evidence_text":"c.902G>A, p.Arg301Gln","llm_judgment":"PRESENT","evidence":"c.902G>A, p.Arg301Gln","abstract_start":1420,"abstract_end":1441}]}
{"pmid":"31707899","title":"Compound Heterozygous Mutations in","abstract":"BACKGROUND: Pathogenic variants within polynucleotide kinase 3'phosphatase (<i>PNKP</i>) gene cause microcephaly, seizures, and developmental delay (MCSZ) and ataxia-oculomotor apraxia type 4 (AOA4) disorders due to unrepaired DNA lesions.\nMETHODS: Whole exome sequencing was performed on a child with microcephaly, seizures, developmental delay, callosal dysgenesis on MRI, intellectual disability, speech disorder, hyperactivity, and ataxic gait.\nRESULTS: Two heterozygous mutations in the <i>PKNP</i> gene, a novel intronic frameshift variant c.1298 + 33_1299-24del and a previously reported duplication, c.1253_1269dup; p.Thr424Glyfs*49 in exon 14 were identified. Both of these mutations affect the DNA kinase domain of PKNP.\nCONCLUSIONS: Our finding along with previous studies provide more evidence of the clinical heterogeneity of diseases caused by mutations in <i>PNKP</i> which makes its clinical diagnosis difficult and highlights the importance of genetic testing to unravel the cause of these diseases.","variants":[{"Name":"NM_007254.4(PNKP):c.1253_1269dup (p.Thr424fs)","Chromosome":"19","Start":"49861800","Stop":"49861801","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGTTGTCGATGGCGACCC","allel_id":19886,"rule_based_match":true,"evidence_text":"c.1253_1269dup; p.Thr424Glyfs*49","llm_judgment":"PRESENT","evidence":"c.1253_1269dup; p.Thr424Glyfs*49","abstract_start":608,"abstract_end":640}]}
{"pmid":"29137435","title":"Recurrent mutations in a","abstract":"Despite the essential anticoagulant function of antithrombin and the high risk of thrombosis associated with its deficiency, the prevalence of antithrombin deficiency among patients with venous thromboembolism (VTE) is very low. However, increasing evidence suggests that antithrombin deficiency may be underestimated. The analysis of <i>SERPINC1</i>, the gene encoding antithrombin, in 1,304 consecutive Chinese VTE patients and 1,334 healthy controls revealed a hotspot involving residues 294 and 295 that severely increases the risk of VTE. We detected the c.883G>A (p.Val295Met) (rs201381904) mutation in 11 patients and just one control (OR = 13.6; 95% CI: 1.7-107.1); c.881G>T (p.Arg294Leu) (rs587776397) in six patients but no controls; and c.880C>T (p.Arg294Cys) (rs747142328) in two patients but no controls. In addition, c.881G>A (p.Arg294His) (rs587776397) was identified in one control. These mutations were absent in a Caucasian cohort. Carriers of these mutations had normal antithrombin levels and anticoagulant activity, consistent with results obtained in a recombinant model. However, mutation carriers had a significantly increased endogenous thrombin potential. Our results suggest the existence in the Chinese population of a hotspot in <i>SERPINC1</i> that significantly increases the risk of VTE by impairing the anticoagulant capacity of the hemostatic system. This effect is not revealed by current antigen or <i>in vitro</i> functional antithrombin assays.","variants":[{"Name":"NM_000488.4(SERPINC1):c.883G>A (p.Val295Met)","Chromosome":"1","Start":"173909822","Stop":"173909822","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1000166,"rule_based_match":true,"evidence_text":"c.883G>A (p.Val295Met) (rs201381904)","llm_judgment":"PRESENT","evidence":"c.883G>A (p.Val295Met) (rs201381904)","abstract_start":560,"abstract_end":596}]}
{"pmid":"31349084","title":"Co-inheritance of pathogenic variants in PKD1 and PKD2 genes presenting as severe antenatal phenotype of autosomal dominant polycystic kidney disease.","abstract":"Autosomal dominant polycystic kidney disease (ADPKD) is caused by pathogenic variants in either PKD1 or PKD2 genes. Disease severity is dependent on various factors including the presence of modifier genes. We describe a family with recurrent foetal presentation of ADPKD due to co-inheritance of pathogenic variants in both PKD1 [c.3860T > C; p.(Leu1287Pro)] and PKD2 [(c.1000C > A; p.(Pro334Thr)] genes. Familial segregation studies revealed the mother and the father to be heterozygous for the same variants in the PKD1 and PKD2 genes, respectively, as found in the foetus. Renal ultrasonography detected evidence of cystic disease in the mother and two of her family members. No cysts were detected in the father, however the paternal grandfather died of renal cystic disease. The absence of disease in the father can be explained by the phenomenon of incomplete penetrance, or Knudson's two-hit hypothesis of cystogenesis in the grandfather. This case underscores the importance of sequencing PKD2 gene even in the presence of a familial PKD1 variant, as well as genetic testing of the cysts for evidence of the second hit.","variants":[{"Name":"NM_001009944.3(PKD1):c.3860T>C (p.Leu1287Pro)","Chromosome":"16","Start":"2111307","Stop":"2111307","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2743102,"rule_based_match":true,"evidence_text":"c.3860T > C; p.(Leu1287Pro)","llm_judgment":"PRESENT","evidence":"c.3860T > C; p.(Leu1287Pro)","abstract_start":331,"abstract_end":358}]}
{"pmid":"28917829","title":"A chinese boy with geleophysic dysplasia caused by compound heterozygous mutations in ADAMTSL2.","abstract":"Geleophysic dysplasia, belonging to the group of acromelic dysplasia, is a rare genetic disease. Two genes, FBN1 and ADAMTSL2, were known to be linked to this disorder. The disorder presents as extreme short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness, toe walking, skin thickening, progressive cardiac valvular thickening and characteristic facial features, including a round face with full cheeks. Here, we report the first Chinese case with geleophysic dysplasia type 1 based on clinical and genetic features. The boy was admitted because of severe physical growth retardation and mild motor retardation. Comprehensive medical evaluations were performed including metabolic studies, endocrine function examination, bone X-rays and echocardiography. Much delayed bone age and geleophysic dysplasia were found. Targeted next-generation sequencing was used to detect genetic mutations associated with skeletal dysplasia. Sanger sequencing was used to confirm the mutations in the patient. PCR amplification, cloing, and sequencing was used to determine the de novo mutation origin. Two compound heterozygous mutations were confirmed in the ADAMTSL2 gene of the patient. The c.340G > A (p.Glu114Lys) mutation was a de novo heterozygous mutation, and our results suggested that it was located on the paternal allele. While the c.234-2A > G inherited from his mother was a novel pathogenic heterozygous splicing mutation. Growth hormone deficiency had been observed in the patient. His growth velocity was improved by growth hormone supplementation. In conclusion, we have identified a novel splicing mutation of ADAMTSL2 carried by a Chinese boy with geleophysic dysplasia type 1. The patient was treated effectively with growth hormone supplementation.","variants":[{"Name":"NM_014694.4(ADAMTSL2):c.340G>A (p.Glu114Lys)","Chromosome":"9","Start":"133539801","Stop":"133539801","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15734,"rule_based_match":true,"evidence_text":"c.340G > A (p.Glu114Lys)","llm_judgment":"PRESENT","evidence":"c.340G > A (p.Glu114Lys)","abstract_start":1215,"abstract_end":1239}]}
{"pmid":"32594361","title":"Spinocerebellar Ataxia-Like Presentation of the M233V PSEN1 Mutation.","abstract":"PSEN1 gene is considered to be the most common gene, which is responsible for the development of an autosomal dominant Alzheimer disease with early onset and sometimes broad phenotype. We present a patient with a spinocerebellar ataxia (SCA)-like phenotype who was found to carry an M233V mutation. General and neurological exam was carried out. Brain MRI as well as genetic testing for SCAs 1, 2, 3, 6, and 17 were performed. The patient was then referred for a next-generation sequencing-based gene panel test with 723 genes included. A 26-year-old man of an Azerbaijani origin presented with a progressive impairment of coordination followed by memory impairment. Family history was positive for a similar disorder suggesting autosomal dominant inheritance. Brain MRI showed bilateral hippocampal atrophy (more pronounced in the left), as well as mild atrophy of the left temporoparietal cortex. Tests for SCAs 1, 2, 3, 6, and 17 came negative. Gene panel test showed c.697A > G heterozygous variant in the PSEN1 gene leading to a M233V amino acid change, which was validated by a Sanger sequencing. So far, M233V mutation has not been associated with a combination of cerebellar and cognitive features at onset. Our case contributes to a better characterization of the PSEN1 mutations and expands the phenotype of the M233V carriers. We propose to consider PSEN1 mutations in patients presenting with an SCA-like phenotype but negative for common types of SCA.","variants":[{"Name":"NM_000021.4(PSEN1):c.697A>G (p.Met233Val)","Chromosome":"14","Start":"73192792","Stop":"73192792","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":33880,"rule_based_match":true,"evidence_text":"c.697A > G","llm_judgment":"PRESENT","evidence":"c.697A > G","abstract_start":971,"abstract_end":981}]}
{"pmid":"16336662","title":"C.35delG/ GJB2 and del(GJB6-D13S1830) mutations in Croatians with prelingual non-syndromic hearing impairment.","abstract":"BACKGROUND: C.35delG/GJB2 mutation is the most frequent genetic cause of deafness in Caucasians. Another frequent mutation in some Caucasian populations is del(GJB6-D13S1830). Both GJB2 and GJB6 genes belong to the same DFNB1 locus and when the two mutations are found in combination in a hearing-impaired person, a digenic pattern of inheritance is suggested.\nMETHODS: We examined 63 Croatian subjects (25 familial and 38 sporadic cases) with prelingual non-syndromic hearing impairment by polymerase chain reaction for the presence of the c.35delG/GJB2 and the del(GJB6-D13S1830) mutations.\nRESULTS: Of the 63 unrelated hearing-impaired subjects, the mutation c.35delG/GJB2 was found in 21 subjects (33.3%). In 5 of them the mutation was found in the heterozygous state, all of them being compound heterozygotes, as sequencing revealed a second mutation within the coding region of the gene in 3 subjects, and a splice site mutation in 2 subjects. The del(GJB6-D13S1830) mutation was not found in the investigated hearing-impaired Croatian subjects.\nCONCLUSION: Our results contribute to the knowledge of geographic distribution and population genetics of the GJB2 and GJB6 mutations in the Europeans.","variants":[{"Name":"NM_004004.6(GJB2):c.35del (p.Gly12fs)","Chromosome":"13","Start":"20189547","Stop":"20189547","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":32043,"rule_based_match":true,"evidence_text":"c.35delG/GJB2","llm_judgment":"PRESENT","evidence":"C.35delG/GJB2","abstract_start":12,"abstract_end":25}]}
{"pmid":"33263785","title":"Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients.","abstract":"INTRODUCTION: Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort.\nMETHODS: We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy.\nRESULTS: 70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient's perceived efficacy were mexiletine and lamotrigine.\nCONCLUSION: This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.","variants":[{"Name":"NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter)","Chromosome":"7","Start":"143351678","Stop":"143351678","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32584,"rule_based_match":true,"evidence_text":"c.2680C>T (p.Arg894*)","llm_judgment":"PRESENT","evidence":"c.2680C>T (p.Arg894*)","abstract_start":1194,"abstract_end":1215}]}
{"pmid":"34999423","title":"Heterozygous LMNA mutation-carrying iPSC lines from three cardiac laminopathy patients.","abstract":"LMNA-related dilated cardiomyopathy (LMNA-DCM) is caused by pathogenic variants in the LMNA gene and is characterized by left ventricular chamber enlargement, reduced systolic function, and arrhythmia. Here, we generated three human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of three DCM patients carrying the same single heterozygous mutation, c.398 G > A, in LMNA. All lines exhibited normal iPSC morphology, expressed high levels of pluripotency markers, showed normal karyotypes, and could differentiate into the three germ layers. These patient-specific iPSC lines can serve as invaluable tools to model in vitro pathological mechanisms of LMNA-DCM.","variants":[{"Name":"NM_170707.4(LMNA):c.398G>A (p.Arg133Gln)","Chromosome":"1","Start":"156130658","Stop":"156130658","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":196461,"rule_based_match":true,"evidence_text":"c.398 G > A","llm_judgment":"PRESENT","evidence":"c.398 G > A","abstract_start":394,"abstract_end":405}]}
{"pmid":"24081251","title":"Clinical presentation and molecular identification of four uncommon alpha globin variants in Thailand. Initiation codon mutation of α2-globin Gene (HBA2:c.1delA), donor splice site mutation of α1-globin gene (IVSI-1, HBA1:c.95 + 1G>A), hemoglobin Queens Park/Chao Pra Ya (HBA1:c.98T>A) and hemoglobin Westmead (HBA2:c.369C>G).","abstract":"Alpha thalassemia is the most common genetic disease in the world with the prevalence of carriers ranging from 5-50% in several populations. Coinheritance of two defective α-globin genes usually gives rise to a symptomatic condition, hemoglobin (Hb) H disease. Previously, it has been suggested from several studies in different populations that nondeletional Hb H disease (--/α(T)α or --/αα(T)) is generally more severe than the deletional type (--/-α). In this report, we describe four rare nondeletional α-thalassemia mutations in Thai individuals, including initiation codon mutation (HBA2:c.1delA), donor splice site mutation (IVSI-1, HBA1:c.95 + 1G>A), Hb Queens Park (HBA1:c.98T>A) [α32(B13)Met>Lys], and Hb Westmead (HBA2:c.369C>G) [α122(H5)His>Gln]. Interactions of the first three mutations with the α(0)-thalassemia resulted in nondeletional Hb H disease; however, their clinical presentations were rather mild and some were detected accidentally. This suggests that a genotype-phenotype correlation of α-thalassemia syndrome might be more heterogeneous and so the type of mutation does not simply imply the prediction of the resulting phenotype. Our data will be of use in future genetic counseling of such conditions that are increasingly identified thanks to the improvement of molecular analysis in routine laboratories.","variants":[{"Name":"NM_000517.6(HBA2):c.369C>G (p.His123Gln)","Chromosome":"16","Start":"173540","Stop":"173540","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":433152,"rule_based_match":true,"evidence_text":"Hb Westmead (HBA2:c.369C>G)","llm_judgment":"PRESENT","evidence":"Hb Westmead (HBA2:c.369C>G)","abstract_start":712,"abstract_end":739},{"Name":"NM_000558.5(HBA1):c.98T>A (p.Met33Lys)","Chromosome":"16","Start":"176931","Stop":"176931","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1321472,"rule_based_match":true,"evidence_text":"Hb Queens Park (HBA1:c.98T>A)","llm_judgment":"PRESENT","evidence":"Hb Queens Park (HBA1:c.98T>A)","abstract_start":659,"abstract_end":688},{"Name":"NM_000558.5(HBA1):c.95+1G>A","Chromosome":"16","Start":"176812","Stop":"176812","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1021418,"rule_based_match":true,"evidence_text":"HBA1:c.95 + 1G>A","llm_judgment":"PRESENT","evidence":"HBA1:c.95 + 1G>A","abstract_start":640,"abstract_end":656}]}
{"pmid":"34008001","title":"Characterization of PROM1 p.Arg373Cys Variant in a Cohort of Chinese Patients: Macular Dystrophy Plus Peripheral Bone-Spicule Degeneration.","abstract":"Purpose: The PROM1 p.Arg373Cys variant has been reported to cause dominant Stargardt disease, cone-rod dystrophy, and occasionally retinitis pigmentosa. This study aimed to evaluate the common phenotype associated with this variant in Chinese patients.\nMethods: Variants in PROM1 were collected from in-house exome data. Potential pathogenic variants were selected, verified, and then confirmed by Sanger sequencing and co-segregation analysis. Ocular phenotypes were reviewed and further clarified by ophthalmologic examinations.\nResults: The heterozygous c.1117C>T (p.Arg373Cys) variant was identified in four unrelated families, and biallelic variants were detected in three families. Of the 10 patients from four families with the p.Arg373Cys variant, six patients from three families who underwent full fundus examination demonstrated various degrees of macular dystrophy, as well as typical bone-spicule pigment deposits in the peripheral retina. The remaining four patients did not undergo a full dilated fundus examination. A relatively preserved zone was observed between the macular and peripheral lesions. Electroretinography results showed cone and rod involvement in three patients.\nConclusions: Unlike Stargardt disease alone, which was considered to be the main phenotype of the p.Arg373Cys variant, all patients with full-field fundus examination in our study presented with macular dystrophy plus peripheral retinopathy resembling retinitis pigmentosa. Different phenotypes associated with the p.Arg373Cys variant may actually reflect different stages of the same disease: a predominant central cone phenotype at an early stage and peripheral rod involvement as degeneration progresses. Evaluation of the full fundus, especially the peripheral region in additional patients, is expected to confirm our findings.","variants":[{"Name":"NM_006017.3(PROM1):c.1117C>T (p.Arg373Cys)","Chromosome":"4","Start":"16013299","Stop":"16013299","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20649,"rule_based_match":true,"evidence_text":"c.1117C>T (p.Arg373Cys)","llm_judgment":"PRESENT","evidence":"c.1117C>T (p.Arg373Cys)","abstract_start":557,"abstract_end":580}]}
{"pmid":"32150116","title":"NMNAT1-ASSOCIATED CONE-ROD DYSTROPHY: EVIDENCE FOR A SPECTRUM OF FOVEAL MALDEVELOPMENT.","abstract":"PURPOSE: To describe in detail the phenotype of two siblings with biallelic NMNAT1 mutations.\nMETHODS: A 4-year-old male patient (P1) and his 7-year-old sister (P2), product of a nonconsanguineous union of Egyptian ancestry, underwent a comprehensive ophthalmic examination, retinal imaging with spectral domain optical coherence tomography and near infrared (NIR) fundus autofluorescence (FAF), and full-field electroretinograms (ERG).\nRESULTS: Patients had blurred vision and nystagmus at ∼3 years of age. P2 was hyperopic (+6D). Visual acuity in P1 was 20/100 at age 3 and remained at ∼20/125 at age 4; P2 visual acuity was 20/70 at age 4 and declined to ∼20/200 at age 7. ERGs recorded in P1 showed relatively large rod-mediated responses but nearly undetectable cone signals. There was foveal/parafoveal depigmentation. Spectral domain optical coherence tomography showed hypoplastic foveas, a thin outer nuclear layer centrally but normal thickness beyond the vascular arcades. At the foveal center, cone outer segments were absent and the outer nuclear layer was further hyporreflective. The inner retina was mostly within normal limits. There was central depigmentation on near infrared fundus autofluorescence. Biallelic mutations were identified in NMNAT1: One was previously reported (c.769 G>A; pGlu257Lys), and the other one (c.245T>C; pVal82Ala) was novel.\nCONCLUSION: NMNAT1 mutations cause a consistent phenotype characterized by early-onset, progressive, cone>rod retinawide dysfunction and predominantly central abnormalities ranging from a hypoplastic to an atrophic fovea, supporting a critical role for NMNAT1 in central retinal development and maintenance. Relatively preserved inner retina and detectable photoreceptors may become therapeutic targets.","variants":[{"Name":"NM_022787.4(NMNAT1):c.245T>C (p.Val82Ala)","Chromosome":"1","Start":"9975721","Stop":"9975721","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1052585,"rule_based_match":true,"evidence_text":"c.245T>C (pVal82Ala)","llm_judgment":"PRESENT","evidence":"c.245T>C","abstract_start":1339,"abstract_end":1347},{"Name":"NM_022787.4(NMNAT1):c.769G>A (p.Glu257Lys)","Chromosome":"1","Start":"9982630","Stop":"9982630","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45795,"rule_based_match":true,"evidence_text":"c.769 G>A; pGlu257Lys","llm_judgment":"PRESENT","evidence":"c.769 G>A; pGlu257Lys","abstract_start":1296,"abstract_end":1317}]}
{"pmid":"28508289","title":"Somatic mosaicism with reversion to normality of a mutated transthyretin allele related to a familial amyloidotic polyneuropathy.","abstract":"Familial amyloidotic polyneuropathy (FAP) is a progressive neuropathy, with onset in adulthood and high mortality. It is related to an altered transthyretin (TTR) plasma protein, mainly produced by the liver and responsible for amyloid deposit in the peripheral nervous system. SNPs in the TTR gene were associated with FAP, and the G>C substitution (NM_000371.3:c.325G>C) in the 109th codon (GAG vs CAG; NP_362.1:p.E109Q) was previously described in Sicily (Italy). Here, we report on a Sicilian family with several patients affected by FAP related to the E109Q mutation, which displayed a somatic mosaicism with the reversion to normality of the c.325G>C mutation. After exclusion of isodisomy and allele deletion, this event seems to be due to a rare, post-zygotic interallelic gene conversion with the wild-type allele serving as a donor. Further investigations will be necessary to better understand the molecular basis of this phenomenon, and could help determine if this can be induced in a targeted manner in the context of natural gene therapy to treat TTR-related FAP patients, as previously proposed for other diseases. Moreover, our results confirm the need to perform DNA-based diagnostic tests with at least a second tissue when a suspected germline mutation in a candidate gene is not identified in the first tissue.","variants":[{"Name":"NM_000371.4(TTR):c.325G>C (p.Glu109Gln)","Chromosome":"18","Start":"31595244","Stop":"31595244","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":28481,"rule_based_match":true,"evidence_text":"NM_000371.3:c.325G>C","llm_judgment":"PRESENT","evidence":"NM_000371.3:c.325G>C","abstract_start":351,"abstract_end":371}]}
{"pmid":"8751852","title":"Succinyl CoA: 3-oxoacid CoA transferase (SCOT): human cDNA cloning, human chromosomal mapping to 5p13, and mutation detection in a SCOT-deficient patient.","abstract":"Succinyl CoA: 3-oxoacid CoA transferase (SCOT; E.C.2.8.3.5) mediates the rate-determining step of ketolysis in extrahepatic tissues, the esterification of acetoacetate to CoA for use in energy production. Hereditary SCOT deficiency in humans causes episodes of severe ketoacidosis. We obtained human-heart SCOT cDNA clones spanning the entire 1,560-nt coding sequence. Sequence alignment of the human SCOT peptides with other known CoA transferases revealed several conserved regions of potential functional importance. A single approximately 3.2-kb SCOT mRNA is present in human tissues (heart > leukocytes >> fibroblasts), but no signal is detectable in the human hepatoma cell line HepG2. We mapped the human SCOT locus (OXCT) to the cytogenetic band 5p13 by in situ hybridization. From fibroblasts of a patient with hereditary SCOT deficiency, we amplified and cloned cDNA fragments containing the entire SCOT coding sequence. We found a homozygous C-to-G transversion at nt 848, which changes the Ser 283 codon to a stop codon. This mutation (S283X) is incompatible with normal enzyme function and represents the first documentation of a pathogenic mutation in SCOT deficiency.","variants":[{"Name":"NM_000436.4(OXCT1):c.848C>G (p.Ser283Ter)","Chromosome":"5","Start":"41805674","Stop":"41805674","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":23202,"rule_based_match":false,"evidence_text":"homozygous C-to-G transversion at nt 848","llm_judgment":"PRESENT","evidence":"homozygous C-to-G transversion at nt 848","abstract_start":942,"abstract_end":982}]}
{"pmid":"23551045","title":"Testing new susceptibility genes in the cohort of apparently sporadic phaeochromocytoma/paraganglioma patients with clinical characteristics of hereditary syndromes.","abstract":"BACKGROUND: Phaeochromocytoma (PCC) and paraganglioma (PGL) can occur sporadically or as a part of familial cancer syndromes. Red flags of hereditary syndromes are young age and multifocal tumours. We hypothesized that such patients are candidates for further molecular diagnosis in case of normal results in 'classical' genes.\nMATERIAL AND METHODS: We selected patients with PCC/PGL under the age of 40 and/or with multiple tumours. First, we tested the genes RET, VHL, NF1, SDHB, SDHC and SDHD. Patients without mutations in these genes were tested for mutations in MAX, TMEM127 and SDHAF2.\nRESULTS: In 153 patients included, mutations were detected in the classical genes in 72 patients (47%) [RET-22 (14%), VHL-13 (9%), NF1-3 (2%), SDHB-13 (9%), SDHC-3 (2%), SDHD-16 (11%), SDHB large deletions- 2 (1%)]. One patient with MAXc.223C>T (p.R75X) mutation was detected. It was a male with bilateral, metachronous phaeochromocytomas diagnosed in 36 and 40 years of age. Remarkably, he showed in the period before the MAX gene was detected, a RET p. Y791F variant. During 10-year follow-up, we did not find any thyroid abnormalities. LOH examination of tumour tissue showed somatic loss of the wild-type allele of MAX.\nCONCLUSION: Analysis of the MAX gene should be performed in selected patients, especially those with bilateral adrenal phaeochromocytoma in whom mutations of the classical genes are absent. Our study provides with further support that Y791F RET is a polymorphism.","variants":[{"Name":"NM_002382.5(MAX):c.223C>T (p.Arg75Ter)","Chromosome":"14","Start":"65077985","Stop":"65077985","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38741,"rule_based_match":true,"evidence_text":"MAXc.223C>T (p.R75X)","llm_judgment":"PRESENT","evidence":"MAXc.223C>T (p.R75X)","abstract_start":826,"abstract_end":846}]}
{"pmid":"34801268","title":"Clinical and genetic analysis of children with hearing loss and bilateral enlarged vestibular aqueducts.","abstract":"OBJECTIVES: To evaluate the clinical and genetic features of children with hearing loss associated with one of the most common malformations of the inner ear: bilateral enlargement of vestibular aqueducts (EVA).\nMETHODS: Clinical and genetic features were investigated in 28 children with hearing loss diagnosed with bilateral EVA by computed tomography from January 2008 to September 2019.\nRESULTS: Fourteen subjects had undergone newborn hearing screening (NHS). Nine subjects (64.3%) were referred in both ears, 4 subjects (28.6%) were referred in one ear, and one subject (7.1%) passed in both ears. Nineteen of 26 subjects (73.1%) who were followed for more than 3 years had hearing fluctuations, while 17 (65.4%) had hearing loss progression. Eleven of 28 subjects (39.2%) had vertigo attacks. Pathogenic variants were identified in two alleles of the SLC26A4 gene in 24 of 27 subjects (88.9%) by sequencing of all exons and flanking introns, leading to genetic diagnosis of Pendred syndrome/DFNB4. Our results indicate that genetic screening for specific SLC26A4 variants using a commercial clinical laboratory test in Japan would have achieved genetic diagnoses in 13 of the 27 subjects (54.2%). Although there was no statistically significance in the frequency of hearing fluctuation or progression depending on the presence or absence of the gene variant, mean hearing level was severe in subjects with two pathogenic variants in SLC26A4 gene. The most common variant detected in our subjects was p.His723Arg (13 alleles, 27.1%), followed by c. 919-2A > G (four alleles, 8.3%). Two novel variants were detected in this study: c.1544+1G > T and c.1614+5G > A.\nCONCLUSIONS: Our data suggest that some subjects may present with bilateral EVA that cannot be detected by NHS. We estimated that genetic diagnosis for SLC264 gene would not have been made in almost half subjects with the commercial genetic screening approach used in the present study in Japan. Although there were some limitations in this study, the subjects with pathogenic variants in two alleles of the SLC26A4 gene could have more severe hearing loss.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1614+5G>A","Chromosome":"7","Start":"107698116","Stop":"107698116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2136616,"rule_based_match":true,"evidence_text":"c.1614+5G > A","llm_judgment":"PRESENT","evidence":"c.1614+5G > A","abstract_start":1654,"abstract_end":1667}]}
{"pmid":"32014857","title":"Mortality in a neonate with molybdenum cofactor deficiency illustrates the need for a comprehensive rapid precision medicine system.","abstract":"Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (<i>MOCS1</i> c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM.","variants":[{"Name":"NM_001358530.2(MOCS1):c.377G>A (p.Gly126Asp)","Chromosome":"6","Start":"39925719","Stop":"39925719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":679750,"rule_based_match":true,"evidence_text":"c.377G > A","llm_judgment":"PRESENT","evidence":"c.377G > A","abstract_start":497,"abstract_end":507}]}
{"pmid":"22903787","title":"Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis.","abstract":"Generalized pustular psoriasis (GPP) is a rare, potentially life threatening, and aggressive form of psoriasis, which is characterized by sudden onset with repeated episodic skin inflammation leading to pustule formation. Familial GPP is known to be caused by recessively inherited mutations in the IL36RN gene, which encodes interleukin 36 receptor antagonist (IL-36Ra). In this article, we performed mutation analysis of the IL36RN gene in 14 Japanese patients with GPP, and identified mutations in two of these patients analyzed. One patient was compound heterozygous for mutations c.115+6T>C and c.368C>G (p.Thr123Arg), whereas the other carried compound heterozygous mutations c.28C>T (p.Arg10*) and c.115+6T>C in the IL36RN gene. Expression studies using total RNA from the patients' skin revealed that the mutation c.115+6T>C resulted in skipping of exon 3, leading to a frameshift and a premature termination codon (p.Arg10Argfs*1). The protein structure analysis suggested that the missense mutation p.Thr123Arg caused misfolding and instability of IL-36Ra protein. In vitro studies in cultured cells showed impaired expression of the p.Thr123Arg mutant IL-36Ra protein, which failed to antagonize the IL-36 signaling pathway. Our data further underscore the critical role of IL36RN in pathogenesis of GPP.","variants":[{"Name":"NM_012275.3(IL36RN):c.28C>T (p.Arg10Ter)","Chromosome":"2","Start":"113059466","Stop":"113059466","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48520,"rule_based_match":true,"evidence_text":"c.28C>T (p.Arg10*)","llm_judgment":"PRESENT","evidence":"c.28C>T (p.Arg10*)","abstract_start":682,"abstract_end":700},{"Name":"NM_012275.3(IL36RN):c.115+6T>C","Chromosome":"2","Start":"113060943","Stop":"113060943","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":48518,"rule_based_match":true,"evidence_text":"c.115+6T>C","llm_judgment":"PRESENT","evidence":"c.115+6T>C","abstract_start":585,"abstract_end":595},{"Name":"NM_012275.3(IL36RN):c.368C>G (p.Thr123Arg)","Chromosome":"2","Start":"113062577","Stop":"113062577","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":48519,"rule_based_match":true,"evidence_text":"c.368C>G (p.Thr123Arg)","llm_judgment":"PRESENT","evidence":"c.368C>G (p.Thr123Arg)","abstract_start":600,"abstract_end":622}]}
{"pmid":"35110381","title":"De Novo","abstract":"<i>ATP1A1</i> encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by <i>ATP1A2</i> or <i>ATP1A3</i>, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic <i>ATP1A1</i> variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous <i>ATP1A1</i> variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity <i>in silico</i> prediction scores. In HEK cells transfected with ouabain-insensitive <i>ATP1A1</i> constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of <i>ATP1A1</i>.","variants":[{"Name":"NM_000701.8(ATP1A1):c.2152G>A (p.Gly718Ser)","Chromosome":"1","Start":"116398648","Stop":"116398648","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2741689,"rule_based_match":true,"evidence_text":"c.2152G>A;p.Gly718Ser","llm_judgment":"PRESENT","evidence":"c.2152G>A;p.Gly718Ser","abstract_start":715,"abstract_end":736}]}
{"pmid":"20729108","title":"Clinical and genetic characteristics of Korean patients with Gaucher disease.","abstract":"Gaucher disease (GD) is an autosomal recessive glycolipid lysosomal storage disease caused by a deficiency of the β-glucocerebrosidase enzyme (GBA). Allelic heterogeneity in GD has been well described. To date, more than 270 different GBA mutations have been reported. In order to determine the GBA mutation spectrum in Korean GD patients, we performed GBA mutation analysis of Korean patients and identified 72 GBA mutant alleles from 36 unrelated patients (100% identification), including 60 single-nucleotide substitutions, 6 single-nucleotide deletions, 4 recombinants, 1 splicing error, and 1 complex allele. N370S, the most common GBA mutation, was not detected, and most of the Korean GBA mutations were previously known to be rare, with the exception of L444P (~21%). Three mutations, P201H, F347L+L444P, and c.630delC, are novel. Examination of the GBA mutant alleles found in 6 ethnic groups revealed that the prevalences of GBA mutant alleles in Korean patients are very different from those seen in Jewish, non-Jewish Caucasian, and Italian patients, but similar to those seen in Japanese and Chinese patients. Our data may provide greater understanding of GBA allelic heterogeneity and an Asian perspective(1) on correlations between genotypes and phenotypes, which may help further the development of better management strategies for patients with GD.","variants":[{"Name":"NM_000157.4(GBA1):c.630del (p.Val211fs)","Chromosome":"1","Start":"155238265","Stop":"155238265","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":486844,"rule_based_match":true,"evidence_text":"c.630delC","llm_judgment":"PRESENT","evidence":"c.630delC","abstract_start":817,"abstract_end":826}]}
{"pmid":"32827848","title":"A homozygous variant in the Lamin B receptor gene LBR results in a non-lethal skeletal dysplasia without Pelger-Huët anomaly.","abstract":"Lamin B receptor, a member of the sterol reductase family, is an inner nuclear membrane protein which binds lamin B proteins and is involved in the organization of heterochromatin. Mutations in LBR have been associated with a variety of disorders, such as Pelger-Huët anomaly, a benign abnormality affecting neutrophils, and Greenberg Dysplasia, a lethal condition in the perinatal period. We identified a homozygous LBR missense mutation (NM_002296.4: c.1366C > G, p.(Leu456Val)) in two adult sisters with a Lamin B receptor-related disorder associated with a skeletal dysplasia milder than Greenberg Dysplasia. Individual 1 has short stature with short limbs (mostly rhizomelic for the upper extremities, and mesomelic for the lower extremities), limited elbow extension. She required Achilles tenotomy, and does not have facial dysmorphisms. Individual 2 has similar skeletal features, but also has bowed femurs, osteopenia, spastic paraplegia of the lower limbs, equinovarus feet, a single kidney, neurogenic bladder, obstructive hydronephrosis, scoliosis and syndactyly of the toes. This report provides additional evidence of variability for Lamin B receptor-related disorders associated with a non-lethal skeletal dysplasia without Pelger-Huët anomaly. We describe a novel pathogenic variant that has not been previously associated with disease and demonstrate the effect of this variant on sterol C14-reductase activity.","variants":[{"Name":"NM_002296.4(LBR):c.1366C>G (p.Leu456Val)","Chromosome":"1","Start":"225406781","Stop":"225406781","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":414768,"rule_based_match":true,"evidence_text":"NM_002296.4: c.1366C > G, p.(Leu456Val)","llm_judgment":"PRESENT","evidence":"NM_002296.4: c.1366C > G, p.(Leu456Val)","abstract_start":440,"abstract_end":479}]}
{"pmid":"28503590","title":"Clinical Phenotype of De Novo","abstract":"Mutations in the guanine nucleotide-binding protein (G protein), α activating activity polypeptide O (<i>GNAO1</i>) gene have recently been described in 6 patients with early infantile epileptic encephalopathies. In the present study, we report the phenotype and the clinical course of a 4-year-old female with an epileptic encephalopathy (Ohtahara syndrome) and profound intellectual disability due to a de novo <i>GNAO1</i> mutation (c.692A>G; p.Tyr231Cys). Ohtahara syndrome is a devastating early infantile epileptic encephalopathy that can be caused by mutations in different genes, now also including <i>GNAO1</i>. The mutation was found using a targeted next generation sequencing gene panel and demonstrates targeted sequencing as a powerful tool for identifying mutations in genes where only a few de novo mutations have been identified.","variants":[{"Name":"NM_020988.3(GNAO1):c.692A>G (p.Tyr231Cys)","Chromosome":"16","Start":"56336829","Stop":"56336829","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":361222,"rule_based_match":true,"evidence_text":"c.692A>G; p.Tyr231Cys","llm_judgment":"PRESENT","evidence":"c.692A>G; p.Tyr231Cys","abstract_start":436,"abstract_end":457}]}
{"pmid":"23659550","title":"Cerebrotendinous xanthomatosis with the c.379C>T (p.R127W) mutation in the CYP27A1 gene associated with premature age-associated limbic tauopathy.","abstract":"","variants":[{"Name":"NM_000784.4(CYP27A1):c.379C>T (p.Arg127Trp)","Chromosome":"2","Start":"218809700","Stop":"218809700","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76773,"rule_based_match":true,"evidence_text":"c.379C>T (p.R127W)","llm_judgment":"PRESENT","evidence":"c.379C>T (p.R127W)","abstract_start":null,"abstract_end":null}]}
{"pmid":"28604959","title":"Analysis of TCIRG1 gene mutation in a Chinese family affected with infantile malignant osteopetrosis","abstract":"OBJECTIVE: To detect potential mutation of the TCIRG1 gene in a boy with infantile malignant osteopetrosis.\nMETHODS: Target sequence capture and next-generation sequencing were applied for the proband and his parents to identify the causative mutation, and Sanger sequencing was used to verify the suspected mutation.\nRESULTS: The proband manifested at 4 months of age with symptoms including anemia, thrombocytopenia, hepatosplenomegaly, and cephalus quadratus. X-ray revealed generalized increased bone density. A novel compound heterozygous mutation, c.796G to T (p.E266X) and c.1372G to A (p.G458S), were identified in the boy. His father and grandmother also carried the c.796G to T (p.E266X) mutation, and his mother carried the c.1372G to A (p.G458S) mutation. Neither mutation was found in the PubMed and ClinVar databases.\nCONCLUSION: The novel compound heterozygous mutation c.796G to T (p.E266X) and c.1372G to A (p.G458S) probably underlies the disease in the proband. Above results may enrich the mutation spectrum of the TCIRG1 gene and provide new evidence for the molecular basis of infantile malignant osteopetrosis.","variants":[{"Name":"NM_006019.4(TCIRG1):c.1372G>A (p.Gly458Ser)","Chromosome":"11","Start":"68047713","Stop":"68047713","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":546253,"rule_based_match":false,"evidence_text":"c.1372G to A (p.G458S)","llm_judgment":"PRESENT","evidence":"c.1372G to A (p.G458S)","abstract_start":580,"abstract_end":602}]}
{"pmid":"35148715","title":"Novel SOX2 mutation in autosomal dominant cataract-microcornea syndrome.","abstract":"BACKGROUND: Congenital cataract-microcornea syndrome (CCMC) is characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although several causative genes have been reported in patients with CCMC, the genetic etiology of CCMC is yet to be clearly understood.\nPURPOSE: To unravel the genetic cause of autosomal dominant family with CCMC.\nMETHODS: All patients and available family members underwent a comprehensive ophthalmologic clinical examination in the hospital by expert ophthalmologists and carried out to clinically diagnosis. All the patients were screened by whole-exome sequencing and then validated using co-segregation by Sanger sequencing.\nRESULTS: Four CCMC patients from a Chinese family and five unaffected family members were enrolled in this study. Using whole-exome sequencing, a missense mutation c.295G > T (p.A99S, NM_003106.4) in the SOX2 gene was identified and validated by segregation analysis. In addition, this missense mutation was predicted to be damaging by multiple predictive tools. Variant p.Ala99Ser was located in a conservation high mobility group (HMG)-box domain in SOX2 protein, with a potential pathogenic impact of p.Ala99Ser on protein level.\nCONCLUSIONS: A novel missense mutation (c.295G > T, p.Ala99Ser) in the SOX2 gene was found in this Han Chinese family with congenital cataract and microcornea. Our study determined that mutations in SOX2 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder. This result expands the mutation spectrum of SOX2 and provides useful information to study the molecular pathogenesis of CCMC.","variants":[{"Name":"NM_003106.4(SOX2):c.295G>T (p.Ala99Ser)","Chromosome":"3","Start":"181712655","Stop":"181712655","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3414881,"rule_based_match":true,"evidence_text":"c.295G > T (p.A99S, NM_003106.4)","llm_judgment":"PRESENT","evidence":"c.295G > T (p.A99S, NM_003106.4)","abstract_start":881,"abstract_end":913}]}
{"pmid":"20603584","title":"Diamond-Blackfan anemia confirmed by RPS19 gene mutation analysis: a case study and literature review of Korean patients","abstract":"Diamond-Blackfan anemia (DBA) is a rare congenital erythroid hypoplastic anemia that usually presents early in infancy and is inherited in up to 45% of cases. It is characterized by red cell aplasia, congenital anomalies, and a predisposition to cancer. Corticosteroids and red blood cell transfusions are the mainstays of therapy. We describe a case of 3-month-old infant who presented with severe anemia, elevated levels of HbF and adenosine deaminase and bilateral hydronephrosis, who was later confirmed as DBA by mutation analysis using the direct sequencing method. Direct sequencing analysis of RPS19 gene was performed with both cDNA and genomic DNA extracted from peripheral blood and a c.3G>A point mutation of exon 2 resulting in p.Met1Ile was identified in this patient. The patient showed an inadequate response to steroid therapy and a partial response to RBC transfusion with a follow-up Hb level of 8.3 g/dL on her last visit to the outpatient clinic. DBA is a genetically and phenotypically heterogeneous disease, and we have reviewed the clinical characteristics of 25 Korean patients thus far reported in the literature. To our knowledge, this is the first case of DBA confirmed by mutation analysis in Korea, and mutation identification using molecular method is recommended for confirmation of this genetically and phenotypically heterogeneous disease.","variants":[{"Name":"NM_001022.4(RPS19):c.3G>A (p.Met1Ile)","Chromosome":"19","Start":"41860777","Stop":"41860777","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":847728,"rule_based_match":true,"evidence_text":"c.3G>A point mutation of exon 2 resulting in p.Met1Ile","llm_judgment":"PRESENT","evidence":"c.3G>A point mutation of exon 2 resulting in p.Met1Ile","abstract_start":696,"abstract_end":750}]}
{"pmid":"30512145","title":"Screening of LDLR gene mutations in nine patients with familial hypercholesterolemia","abstract":"OBJECTIVE: To screen for LDLR gene mutations in 9 patients with familial hypercholesterolemia (FH).\nMETHODS: All exons of the LDLR gene and flanking intronic sequences were amplified by PCR and subjected to automatic DNA sequencing. For patients with homozygous or compound heterozygous mutations, parental DNA sequencing or T cloning sequencing was carried out to determine the parental origin of the mutant alleles.\nRESULTS: Direct sequencing of PCR products revealed 8 LDLR variants in 7 patients, which included c.259T>G, c.513delC, c.530C>T, c.682G>T, c.763C>T, c.1187-10G>A, c.1948delG, and c.1730G>A, among which c.1948delG was novel. Four patients have carried heterozygous mutations, two carried homozygous mutations, and one carried compound heterozygous mutations. The patients with biallelic mutations presented with a more severe phenotype compared those carrying heterozygous mutations.\nCONCLUSION: LDLR mutations were identified in 7 out of 9 patients with FH. Among the 8 identified LDLR mutations, c.1948delG was firstly reported. Above findings have expanded the mutation spectrum of LDLR gene.","variants":[{"Name":"NM_000527.5(LDLR):c.1187-10G>A","Chromosome":"19","Start":"11113268","Stop":"11113268","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":228162,"rule_based_match":true,"evidence_text":"c.1187-10G>A","llm_judgment":"PRESENT","evidence":"c.1187-10G>A","abstract_start":567,"abstract_end":579},{"Name":"NM_000527.5(LDLR):c.682G>T (p.Glu228Ter)","Chromosome":"19","Start":"11105588","Stop":"11105588","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":228146,"rule_based_match":true,"evidence_text":"c.682G>T","llm_judgment":"PRESENT","evidence":"c.682G>T","abstract_start":547,"abstract_end":555},{"Name":"NM_000527.5(LDLR):c.259T>G (p.Trp87Gly)","Chromosome":"19","Start":"11102732","Stop":"11102732","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18724,"rule_based_match":true,"evidence_text":"c.259T>G","llm_judgment":"PRESENT","evidence":"c.259T>G","abstract_start":516,"abstract_end":524},{"Name":"NM_000527.5(LDLR):c.530C>T (p.Ser177Leu)","Chromosome":"19","Start":"11105436","Stop":"11105436","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18725,"rule_based_match":true,"evidence_text":"c.530C>T","llm_judgment":"PRESENT","evidence":"c.530C>T","abstract_start":537,"abstract_end":545}]}
{"pmid":"27174565","title":"Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia.","abstract":"Dystonia is a neurological movement disorder that is clinically and genetically heterogeneous. Herein, we report the identification a novel homozygous missense mutation, c.156 C > A in VPS16, co-segregating with disease status in a Chinese consanguineous family with adolescent-onset primary dystonia by whole exome sequencing and homozygosity mapping. To assess the biological role of c.156 C > A homozygous mutation of VPS16, we generated mice with targeted mutation site of Vps16 through CRISPR-Cas9 genome-editing approach. Vps16 c.156 C > A homozygous mutant mice exhibited significantly impaired motor function, suggesting that VPS16 is a new causative gene for adolescent-onset primary dystonia.","variants":[{"Name":"NM_022575.4(VPS16):c.156C>A (p.Asn52Lys)","Chromosome":"20","Start":"2860067","Stop":"2860067","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1053719,"rule_based_match":true,"evidence_text":"c.156 C > A","llm_judgment":"PRESENT","evidence":"c.156 C > A","abstract_start":170,"abstract_end":181}]}
{"pmid":"31796088","title":"Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report.","abstract":"BACKGROUND: Pathogenic variants in KIF1A (kinesin family member 1A) gene have been associated with hereditary spastic paraplegia (HSP) type 30 (SPG30), encopassing autosomal dominant and recessive, pure and complicated forms.\nCASE PRESENTATION: We report the long-term follow-up of a 19 years-old boy first evaluated at 18 months of age because of toe walking and unstable gait with frequent falls. He developed speech delay, mild intellectual disability, a slowly progressive pyramidal syndrome, microcephaly, bilateral optic subatrophy and a sensory axonal polyneuropathy. Brain MRI showed cerebellar atrophy, stable along serial evaluations (last performed at 18 years of age). Targeted NGS sequencing disclosed the de novo c.914C > T missense, likely pathogenic variant on KIF1A gene.\nCONCLUSIONS: We report on a previously unpublished de novo heterozygous likely pathogenic KIF1A variant associated with slowly progressive complicated SPG30 and stable cerebellar atrophy on long-term follow-up, adding to current knowledge on this HSP subtype.","variants":[{"Name":"NM_001244008.2(KIF1A):c.914C>T (p.Pro305Leu)","Chromosome":"2","Start":"240775895","Stop":"240775895","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":420290,"rule_based_match":true,"evidence_text":"c.914C > T","llm_judgment":"PRESENT","evidence":"c.914C > T","abstract_start":727,"abstract_end":737}]}
{"pmid":"25557462","title":"Delayed diagnosis of congenital myasthenia due to associated mitochondrial enzyme defect.","abstract":"Clinical phenotypes of congenital myasthenic syndromes and primary mitochondrial disorders share significant overlap in their clinical presentations, leading to challenges in making the correct diagnosis. Next generation sequencing is transforming molecular diagnosis of inherited neuromuscular disorders by identifying novel disease genes and by identifying previously known genes in undiagnosed patients. This is evident in two patients who were initially suspected to have a mitochondrial myopathy, but in whom a clear diagnosis of congenital myasthenic syndromes was made through whole exome sequencing. In patient 1, whole exome sequencing revealed compound heterozygous mutations c.1228C > T (p.Arg410Trp) and c.679C > T (p.Arg227*) in collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). In patient 2, in whom a deletion of exon 52 in Dystrophin gene was previously detected by multiplex ligation-dependent probe amplification, Sanger sequencing revealed an additional homozygous mutation c.1511_1513delCTT (p.Pro504Argfs*183) in docking protein7 (DOK7). These case reports highlight the need for careful diagnosis of clinically heterogeneous syndromes like congenital myasthenic syndromes, which are treatable, and for which delayed diagnosis is likely to have implications for patient health. The report also demonstrates that whole exome sequencing is an effective diagnostic tool in providing molecular diagnosis in patients with complex phenotypes.","variants":[{"Name":"NM_005677.4(COLQ):c.1228C>T (p.Arg410Trp)","Chromosome":"3","Start":"15453899","Stop":"15453899","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":367241,"rule_based_match":true,"evidence_text":"c.1228C > T (p.Arg410Trp)","llm_judgment":"PRESENT","evidence":"c.1228C > T (p.Arg410Trp)","abstract_start":686,"abstract_end":711}]}
{"pmid":"21412940","title":"A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy.","abstract":"The cellular quality control systems enable surveillance and selective degradation of nonsense, nonstop, and no-go mRNAs. In the case of nonstop mRNA, different mechanisms of nonstop-mediated decay (NSD) have been described for bacteria, yeast and mammals, but the molecular consequences of nonstop mutations have been examined in only few cases of human disease. We describe a novel homozygous nonstop mRNA mutation (c.1416delC) in the TYMP gene encoding thymidine phosphorylase, in a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In contrast to previous reports showing selective decay of pathogenic nonstop mRNAs, quantitative real-time PCR and 3'-RACE-RFLP analysis revealed unreduced nonstop mRNA levels in our patient and 2 heterozygous carriers of the mutation. The absence of thymidine phosphorylase protein in the homozygous patient, together with the partial decrease in levels of this protein in 2 carriers suggest that the main control system in this case resides at the translational or post-translational levels rather than through NSD. This is the first report showing an absence of NSD in a human disease, revealing that this surveillance mechanism has exceptions in vivo.","variants":[{"Name":"NM_001953.5(TYMP):c.1416del (p.Phe473fs)","Chromosome":"22","Start":"50525803","Stop":"50525803","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":806134,"rule_based_match":true,"evidence_text":"c.1416delC","llm_judgment":"PRESENT","evidence":"c.1416delC","abstract_start":418,"abstract_end":428}]}
{"pmid":"25727044","title":"Novel patched 1 mutations in patients with nevoid basal cell carcinoma syndrome--case report.","abstract":"Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is a rare autosomal dominant disorder characterized by numerous basal cell carcinomas, keratocystic odontogenic tumors of the jaws, and diverse developmental defects. This disorder is associated with mutations in tumor suppressor gene Patched 1 (PTCH1). We present two patients with Gorlin syndrome, one sporadic and one familial. Clinical examination, radiological and CT imaging, and mutation screening of PTCH1 gene were performed. Family members, as well as eleven healthy controls were included in the study. Both patients fulfilled the specific criteria for diagnosis of Gorlin syndrome. Molecular analysis of the first patient showed a novel frameshift mutation in exon 6 of PTCH1gene (c.903delT). Additionally, a somatic frameshift mutation in exon 21 (c.3524delT) along with germline mutation in exon 6 was detected in tumor-derived tissue sample of this patient. Analysis of the second patient, as well as two affected family members, revealed a novel nonsense germline mutation in exon 8 (c.1148 C>A).","variants":[{"Name":"NM_000264.5(PTCH1):c.1148C>A (p.Ser383Ter)","Chromosome":"9","Start":"95479067","Stop":"95479067","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1877800,"rule_based_match":true,"evidence_text":"c.1148 C>A","llm_judgment":"PRESENT","evidence":"c.1148 C>A","abstract_start":1055,"abstract_end":1065}]}
{"pmid":"16410054","title":"Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria.","abstract":"Methylmalonic aciduria, cblB type (OMIM 251110) is an inborn error of vitamin B(12) metabolism that occurs due to mutations in the MMAB gene. MMAB encodes the enzyme ATP:cobalamin adenosyltransferase, which catalyzes the synthesis of the coenzyme adenosylcobalamin required for the activity of the mitochondrial enzyme methylmalonyl CoA mutase (MCM). MCM catalyzes the isomerization of methylmalonyl CoA to succinyl CoA. Deficient MCM activity results in methylmalonic aciduria and a susceptibility to life-threatening acidotic crises. The MMAB gene was sequenced from genomic DNA from a panel of 35 cblB patients, including five patients previously investigated. Nineteen MMAB mutations were identified, including 13 previously unknown mutations. These included 11 missense mutations, two duplications, one deletion, four splice-site mutations, and one nonsense mutation. None of these mutations was identified in 100 control alleles. Most of the missense mutations (9/11) were clustered in exon 7; many of these affected amino acid residues that are part of the probable active site of the enzyme. One previously described mutation, c.556C >T (p.R186W), was particularly common, accounting for 33% of pathogenic alleles. It was seen almost exclusively in patients of European background and was typically associated with presentation in the first year of life.","variants":[{"Name":"NM_052845.4(MMAB):c.556C>T (p.Arg186Trp)","Chromosome":"12","Start":"109561068","Stop":"109561068","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18134,"rule_based_match":true,"evidence_text":"c.556C >T (p.R186W)","llm_judgment":"PRESENT","evidence":"c.556C >T (p.R186W)","abstract_start":1135,"abstract_end":1154}]}
{"pmid":"18693280","title":"Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs.","abstract":"A large number of sequence variants identified in BRCA1 and BRCA2 cannot be distinguished as either disease-causing mutations or neutral variants. These so-called unclassified variants (UVs) include variants that are located in the intronic sequences of BRCA1 and BRCA2. The purpose of this study was to assess the use of splice-site prediction programs (SSPPs) to select intronic variants in BRCA1 and BRCA2 that are likely to affect RNA splicing. We performed in vitro molecular characterization of RNA of six intronic variants in BRCA1 and BRCA2. In four cases (BRCA1, c.81-6T>A and c.4986+5G>T; BRCA2, c.7617+2T>G and c.8754+5G>A) a deleterious effect on RNA splicing was seen, whereas the c.135-15_-12del variant in BRCA1 showed no effect on RNA splicing. In the case of the BRCA2 c.68-7T>A variant, RNA analysis was not sufficient to establish the clinical significance. Six SSPPs were used to predict whether an effect on RNA splicing was expected for these six variants as well as for 23 intronic variants in BRCA1 for which the effect on RNA splicing has been published. Out of a total of 174 predictions, 161 (93%) were informative (i.e., the wild-type splice-site was recognized). No false-negative predictions were observed; an effect on RNA splicing was always predicted by these programs. In four cases (2.5%) a false-positive prediction was observed. For DNA diagnostic laboratories, these programs are therefore very useful to select intronic variants that are likely to affect RNA splicing for further analysis.","variants":[{"Name":"NM_007294.4(BRCA1):c.81-6T>A","Chromosome":"17","Start":"43115785","Stop":"43115785","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":70385,"rule_based_match":true,"evidence_text":"BRCA1, c.81-6T>A","llm_judgment":"PRESENT","evidence":"BRCA1, c.81-6T>A","abstract_start":565,"abstract_end":581},{"Name":"NM_000059.4(BRCA2):c.8754+5G>A","Chromosome":"13","Start":"32376796","Stop":"32376796","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46738,"rule_based_match":true,"evidence_text":"BRCA2, c.8754+5G>A","llm_judgment":"PRESENT","evidence":"c.8754+5G>A","abstract_start":622,"abstract_end":633},{"Name":"NM_000059.4(BRCA2):c.7617+2T>G","Chromosome":"13","Start":"32356611","Stop":"32356611","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":67032,"rule_based_match":true,"evidence_text":"BRCA2, c.7617+2T>G","llm_judgment":"PRESENT","evidence":"BRCA2, c.7617+2T>G","abstract_start":599,"abstract_end":617},{"Name":"NM_007294.4(BRCA1):c.4986+5G>T","Chromosome":"17","Start":"43070923","Stop":"43070923","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":70010,"rule_based_match":true,"evidence_text":"c.4986+5G>T","llm_judgment":"PRESENT","evidence":"c.4986+5G>T","abstract_start":586,"abstract_end":597}]}
{"pmid":"30586141","title":"Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma.","abstract":"Importance: The protection of telomeres 1 protein (POT1) is a critical component of the shelterin complex, a multiple-protein machine that regulates telomere length and protects telomere ends. Germline variants in POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of cancers including cutaneous T-cell lymphoma (CTCL).\nObjective: To characterize pathogenic variation in POT1 in families with melanoma to inform clinical management.\nDesign, Setting, and Participants: In this case study and pedigree evaluation, analysis of the pedigree of 1 patient with melanoma revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) that was subsequently found in 2 other pedigrees obtained from the GenoMEL Consortium.\nMain Outcomes and Measures: (1) Identification of the POT1 p.I78T variant; (2) evaluation of the clinical features and characteristics of patients with this variant; (3) analysis of 3 pedigrees; (4) genomewide single-nucleotide polymorphism genotyping of germline DNA; and (5) a somatic genetic analysis of available nevi and 1 melanoma lesion.\nResults: The POT1 p.I78T variant was found in 3 melanoma pedigrees, all of persons who self-reported as being of Jewish descent, and was shown to disrupt POT1-telomere binding. A UV mutation signature was associated with nevus and melanoma formation in POT1 variant carriers, and somatic mutations in driver genes such as BRAF, NRAS, and KIT were associated with lesion development in these patients.\nConclusions and Relevance: POT1 p.I78T is a newly identified, likely pathogenic, variant meriting screening for in families with melanoma after more common predisposition genes such as CDKN2A have been excluded. It could also be included as part of gene panel testing.","variants":[{"Name":"NM_015450.3(POT1):c.233T>C (p.Ile78Thr)","Chromosome":"7","Start":"124870933","Stop":"124870933","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":456457,"rule_based_match":true,"evidence_text":"p.I78T, c.233T>C","llm_judgment":"PRESENT","evidence":"p.I78T, c.233T>C","abstract_start":647,"abstract_end":663}]}
{"pmid":"29996803","title":"Mild clinical features of isolated methylmalonic acidemia associated with a novel variant in the MMAA gene in two Chinese siblings.","abstract":"BACKGROUND: Methylmalonic acidemia (MMA) is an autosomal recessive inherited disorder caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut- enzymatic subtype, respectively); a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA); or deficiency of the enzyme methylmalonyl-CoA epimerase. The cblA type of MMA is very rare in China. This study aimed to describe the biochemical, clinical, and genetic characteristics of two siblings in a Chinese family, suspected of having the cblA-type of MMA.\nMETHODS: The Chinese family of Han ethnicity of two siblings with the cblA-type of MMA, was enrolled. Target-exome sequencing was performed for a panel of MMA-related genes to detect causative mutations. The influence of an identified missense variant on the protein's structure and function was analysed using SIFT, PolyPhen-2, PROVEAN, and MutationTaster software. Moreover, homology modelling of the human wild-type and mutant proteins was performed using SWISSMODEL to evaluate the variant.\nRESULTS: The proband was identified via newborn screening (NBS); whereas, her elder brother, who had not undergone expanded NBS, was diagnosed later through genetic family screening. The younger sibling exhibited abnormal biochemical manifestations, and the clinical performance was relatively good after treatment, while the older brother had a mild biochemical and clinical phenotype, mainly featuring poor academic performance. A novel, homozygous missense c.365T>C variant in exon 2 of their MMAA genes was identified using next-generation sequencing and validated by Sanger sequencing. Several different types of bioinformatics software predicted that the novel variant c.365T>C (p.L122P) was deleterious. Furthermore, three-dimensional crystal structure analysis revealed that replacement of Leu122 with Pro122 led to the loss of two intramolecular hydrogen bonds between the residue at position 122 and Leu188 and Ala119, resulting in instability of the MMAA protein structure.\nCONCLUSIONS: The two siblings suspected of having the cblA-type of MMA showed mild phenotypes during follow-up, and a novel, homozygous missense variant in their MMAA genes was identified. We believe that the clinical features of the two siblings were associated with the MMAA c.365T>C variant; however, further functional studies are warranted to confirm the variant's pathogenicity.","variants":[{"Name":"NM_172250.3(MMAA):c.365T>C (p.Leu122Pro)","Chromosome":"4","Start":"145639504","Stop":"145639504","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1441587,"rule_based_match":true,"evidence_text":"c.365T>C (p.L122P)","llm_judgment":"PRESENT","evidence":"c.365T>C (p.L122P)","abstract_start":1768,"abstract_end":1786}]}
{"pmid":"28383812","title":"Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets.","abstract":"CONTEXT: Hypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3.\nOBJECTIVE: To investigate underlying genetic defects in patients with hypophosphataemic rickets.\nMETHODS: We analysed genomic DNA from nine unrelated families for mutations in the entire coding region of PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3 by PCR sequencing and copy number analysis.\nRESULTS: A total of 14 patients were studied. PHEX mutations were identified in 12 patients from seven families. Five of them were novel mutations present in eight patients: c.154G>T (p.E52*), c.401_402insGCCAAA (p.Q134_K135insPK), c.1600C>T (p.P534S), g.22016715_22056805del (40-kb deletion including promoter and exons 1-3) and c.2242_2243delCT (p.L748 fs*48). Four patients had previously reported mutations: c.1768+1G>A and c.1807G>A (p.W602*). Novel CLCN5 (c.1205G>A, p.W402*) and FGF23 (c.526C>G, p.R176G) mutations were found in two patients from the remaining two families. Many of the mutations were de novo: c.154G>T and c.2242_2243delCT in PHEX and c.526C>G in FGF23. Furthermore, we characterized the breakpoint of the novel PHEX g.22016715_22056805del and the c.2242_2243delCT, which is 6 bp from the stop codon, resulting in a frameshift and extension of the reading frame by 42 amino acids.\nCONCLUSIONS: Novel and de novo mutations are frequent and PHEX mutations are still the most common genetic defects in the Turkish population. Gene copy number analysis should be considered in patients with negative results by conventional PCR-based sequencing analysis. The current study further expands the mutation spectrum underlying HR.","variants":[{"Name":"NM_000444.6(PHEX):c.1768+1G>A","Chromosome":"X","Start":"22219104","Stop":"22219104","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432176,"rule_based_match":true,"evidence_text":"c.1768+1G>A","llm_judgment":"PRESENT","evidence":"c.1768+1G>A","abstract_start":874,"abstract_end":885}]}
{"pmid":"28965491","title":"Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.","abstract":"BACKGROUND: Epileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease.\nCASE PRESENTATION: We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease.\nCONCLUSIONS: We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease.","variants":[{"Name":"NM_024818.6(UBA5):c.1111G>A (p.Ala371Thr)","Chromosome":"3","Start":"132675903","Stop":"132675903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260377,"rule_based_match":false,"evidence_text":"p.Ala371Thr","llm_judgment":"PRESENT","evidence":"p.Ala371Thr","abstract_start":1468,"abstract_end":1479}]}
{"pmid":"34720973","title":"Two Novel Disease-Causing Variants in the PDE6C Gene Underlying Achromatopsia.","abstract":"We report the clinical phenotype and genetic findings of two variants in PDE6C underlying achromatopsia (ACHM). Four patients with the variant c.1670G>A in exon 13 of the PDE6C gene were identified. Additionally, one had compound heterozygous genotype, with two variants in the <i>PDE6C</i> gene, a variant of c.2192G>A in exon 18 and c.1670G>A in exon 13. All patients presented the symptomatic triad of decreased visual acuity, severe photophobia, and colour vision disturbances. SD-OCT showed an absence of the ellipsoid zone, creating an optically empty cavity at the fovea in three patients. The patient with the compound heterozygous genotype presented a more severe subfoveal outer retina atrophy. ERG recordings showed extinguished responses under photopic and 30-Hz flicker stimulation, with a normal rod response. We identified two new variants in the <i>PDE6C</i> gene that leads to ACHM.","variants":[{"Name":"NM_006204.4(PDE6C):c.1670G>A (p.Arg557Gln)","Chromosome":"10","Start":"93640490","Stop":"93640490","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2108347,"rule_based_match":true,"evidence_text":"c.1670G>A","llm_judgment":"PRESENT","evidence":"c.1670G>A","abstract_start":143,"abstract_end":152}]}
{"pmid":"18625862","title":"A novel loss-of-function LGI1 mutation linked to autosomal dominant lateral temporal epilepsy.","abstract":"BACKGROUND: Mutations responsible for autosomal dominant lateral temporal epilepsy have been found in the leucine-rich, glioma-inactivated 1 (LGI1) gene.\nOBJECTIVES: To describe the clinical and genetic findings in a family with autosomal dominant lateral temporal epilepsy and to determine the functional effects of a novel LGI1 mutation in culture cells.\nDESIGN: Clinical, genetic, and functional investigations.\nSETTING: University hospital and laboratory.\nPATIENTS: An Italian family with autosomal dominant lateral temporal epilepsy.\nMAIN OUTCOME MEASURE: Mutation analysis.\nRESULTS: A novel LGI1 mutation, c.365T>A (Ile122Lys), segregating with the disease was identified. The mutant Lgi1 protein was not secreted by culture cells.\nCONCLUSION: Our data provide further evidence that mutations in LGI1 hamper secretion of the Lgi1 protein, thereby precluding its normal function.","variants":[{"Name":"NM_005097.4(LGI1):c.365T>A (p.Ile122Lys)","Chromosome":"10","Start":"93777551","Stop":"93777551","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":20478,"rule_based_match":true,"evidence_text":"c.365T>A (Ile122Lys)","llm_judgment":"PRESENT","evidence":"c.365T>A (Ile122Lys)","abstract_start":612,"abstract_end":632}]}
{"pmid":"26493165","title":"GREM1 and POLE variants in hereditary colorectal cancer syndromes.","abstract":"Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high-penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy-number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease-causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease-causing mutations in hereditary CRC syndromes.","variants":[{"Name":"NM_006231.4(POLE):c.1274A>G (p.Lys425Arg)","Chromosome":"12","Start":"132673660","Stop":"132673660","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":226348,"rule_based_match":true,"evidence_text":"c.1274A>G, p.Lys425Arg","llm_judgment":"PRESENT","evidence":"c.1274A>G, p.Lys425Arg","abstract_start":1156,"abstract_end":1178}]}
{"pmid":"34765396","title":"HSD10 disease in a female: A case report and review of literature.","abstract":"HSD10 disease is a rare X-linked mitochondrial disorder caused by pathogenic variants in the <i>HSD17B10</i> gene. The phenotype results from impaired 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10) protein structure and function. HSD10 is a multifunctional protein involved in enzymatic degradation of isoleucine and branched-chain fatty acids, the metabolism of sex hormones and neurosteroids, as well as in regulating mitochondrial RNA maturation. HSD10 disease is characterised by progressive neurologic impairment. Disease onset is varied and includes neonatal-onset, infantile-onset and late-onset in males. Females can also be affected. Our index case is a 45-month-old female, who initially presented at 11 months of age with global developmental delay. She subsequently began to lose previously acquired cognitive and motor skills starting around 29 months of age. Brain MRI showed abnormalities in the basal ganglia indicative of possible mitochondrial disease. Urine organic acid analysis revealed elevations of 2-methyl-3-hydroxybutyric acid and tiglyglycine. <i>HSD17B10</i> gene sequencing revealed a likely pathogenic variant, NM_001037811.2:c.439C>T (p.Arg147Cys) inherited from her mother, expected to be causative of HSD10 disease. Her X-chromosome inactivation study is consistent with a skewed X-inactivation pattern. We report a female patient with HSD10 disease caused by a missense pathogenic variant, Arg147Cys in the <i>HSD17B10</i> gene. The patient is the fifth severely affected female with this disease. This case adds to the small number of known affected families with this highly variable disease in the literature. These findings support the possibility of X-inactivation patterns influencing the penetrance of HSD10 disease in females.","variants":[{"Name":"NM_004493.3(HSD17B10):c.439C>T (p.Arg147Cys)","Chromosome":"X","Start":"53432035","Stop":"53432035","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":411425,"rule_based_match":true,"evidence_text":"NM_001037811.2:c.439C>T (p.Arg147Cys)","llm_judgment":"PRESENT","evidence":"NM_001037811.2:c.439C>T (p.Arg147Cys)","abstract_start":1142,"abstract_end":1179}]}
{"pmid":"29953972","title":"Resistant Paediatric Somatotropinomas due to AIP Mutations: Role of Pegvisomant.","abstract":"BACKGROUND: Somatotropinomas are rare in childhood and frequently associated with genetic mutations. AIP mutations are found in 20-25% cases and cause aggressive somatotropinomas, often resistant to somatostatin analogues.\nAIMS: To assess responses to multimodal therapy including pegvisomant in 2 children with sporadic somatotropinomas due to AIP mutations.\nCASE DESCRIPTION: We report 2 children, a boy aged 13 and a girl aged 10, with rapid growth, visual impairment, and growth hormone hypersecretion. Magnetic resonance imaging confirmed a pituitary macroadenoma with parasellar extension in both. Despite multiple surgical attempts to debulk tumour mass, residual tumour persisted. Genetic analysis showed two different AIP mutations (patient 1: c.562delC [p.Arg188Glyfs*8]; patient 2: c.140_ 163del24 [p.Gly47_Arg54del8]). They were initially treated with a long-acting somatostatin analogue (octreotide LAR 30 mg/month) and cabergoline as a dopamine agonist, with the later addition of pegvisomant titrated up to 20 mg/day and with radiotherapy for long-term control. Somatostatin analogue was ceased due to patient intolerance and lack of control. Patient 1 had normalization of insulin-like growth factor-1 (IGF-1) after 5 months of combined therapy with pegvisomant and cabergoline. For patient 2, normalization of IGF-1 was achieved after 2 months of cabergoline and pegvisomant.\nCONCLUSION: AIP-associated tumours can be resistant to management with somatostatin analogues. Pegvisomant can safely be used, to normalize IGF-1 levels and help control disease.","variants":[{"Name":"NM_003977.4(AIP):c.140_163del (p.Gly47_Arg54del)","Chromosome":"11","Start":"67487044","Stop":"67487067","ReferenceAlleleVCF":"AGGGCACCGTGCTGGACGACAGCCG","AlternateAlleleVCF":"A","allel_id":49585,"rule_based_match":true,"evidence_text":"c.140_ 163del24 [p.Gly47_Arg54del8]","llm_judgment":"PRESENT","evidence":"c.140_ 163del24 [p.Gly47_Arg54del8]","abstract_start":793,"abstract_end":828}]}
{"pmid":"38631813","title":"Novel genetic variant in hereditary spastic paraparesis.","abstract":"A man in his 30s was referred to neurology with right-sided paraesthesia, tremors, chest pain and lower urinary tract and erectile dysfunction. He had a medical history of left acetabular dysplasia, and subjective memory impairment, the latter being in the context of depression and chronic pain with opioid use. There was no notable family history. On examination, he had a spastic paraparesis. Imaging revealed atrophy of the thoracic spine. Lumbar puncture demonstrated a raised protein but other constituents were normal, including no presence of oligoclonal bands. Genetic testing revealed a novel heterozygous likely pathogenic SPAST variant c. 1643A>T p.(Asp548Val), confirming the diagnosis of hereditary spastic paraparesis. Symptomatic treatment with physiotherapy and antispasmodic therapy was initiated. This is the first study reporting a patient with this SPAST variant. Ensembl variant effect predictor was used, with the application of computational variant prediction tools providing support that the variant we have identified is likely deleterious and damaging. Our variant CADD score was high, indicating that our identified variant was a highly deleterious substitution.","variants":[{"Name":"NM_014946.4(SPAST):c.1643A>T (p.Asp548Val)","Chromosome":"2","Start":"32144963","Stop":"32144963","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":3779239,"rule_based_match":true,"evidence_text":"c. 1643A>T p.(Asp548Val)","llm_judgment":"PRESENT","evidence":"c. 1643A>T p.(Asp548Val)","abstract_start":648,"abstract_end":672}]}
{"pmid":"27172833","title":"Activation-resistant homozygous protein C R229W mutation causing familial perinatal intracranial hemorrhage and delayed onset of thrombosis.","abstract":"INTRODUCTION: We describe a family with two first-degree cousins who presented with similar phenotypes characterized by neonatal intracranial hemorrhage and subsequent onset of thrombosis.\nPATIENTS/METHODS: We enrolled the two affected patients, five unaffected family members and fifty-five normal controls. Clinical, laboratory, and radiological characteristics of patients were obtained. Exome sequencing was performed for the older affected child. PROC c.811 C>T was genotyped by PCR in patients, family members, and controls. Protein C amidolytic activity and antigen were measured using the STACHROM® protein C kit and ELISAs. To define functional abnormalities caused by the patients' mutation, recombinant wildtype protein C and its mutants R229W, R229Q and R229A were studied.\nRESULTS: For the two cousins, protein C amidolytic activity was 61% and 59% and antigen was 57% and 73% (nl 70-140%), respectively. Exome sequencing revealed a homozygous variant in exon 9 of the protein C (PROC) gene c.811 C>T (R229W). The R229W mutation is located in the calcium binding loop of protein C's protease domain that mediates thrombomodulin interactions. Recombinant R229W-protein C mutant was strikingly defective in rate of activation by thrombin: thrombomodulin, suggesting an in vivo deficit in these children for generation of activated protein C.\nCONCLUSIONS: These cases emphasize that protein C and activated protein C are important in maintaining the integrity of the brain vascular endothelium in humans. Moreover, routine protein C assays utilizing snake venom protease fail to detect protein C mutants that are resistant to thrombin:thrombomodulin activation.","variants":[{"Name":"NM_000312.4(PROC):c.811C>T (p.Arg271Trp)","Chromosome":"2","Start":"127428371","Stop":"127428371","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":516415,"rule_based_match":true,"evidence_text":"PROC c.811 C>T","llm_judgment":"PRESENT","evidence":"PROC c.811 C>T","abstract_start":452,"abstract_end":466}]}
{"pmid":"22075048","title":"New novel mutation of the ATP7B gene in a family with Wilson disease.","abstract":"Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The WD gene codes for a copper transporting P-type ATPase (ATP7B) are located on chromosome 13q14.3. Mutation of this gene disrupts copper homeostasis, resulting in the accumulation of copper in the liver, brain, kidneys and corneas and copper toxication at these sites. Since the detection of the WD gene in 1993, approximately 300 disease-specific muations have been identified. We recently evaluated a Korean family with WD. The proband, a 17-year-old boy, visited our hospital due to abnormal behaviors including generalized slow movement, dysphagia, drooling and ataxia. Laboratory results revealed decreases in serum copper and ceruloplasmin and an increase in urinary excretion of copper. He had liver cirrhosis, brain lesions and Kayser-Fleischer corenal rings. Molecular genetic analysis of the ATP7B gene demonstrated that he was heterozygous for deletion mutation c.2697_2723del27 in exon 11. Further study of family members revealed that his father and younger brother had the same mutation. The c.2697_2723del27 deletion mutation in exon 11 has not yet been reported as a causative muation of WD and is an in-frame deletion not expected to lead to a frame shift. Therefore, we report a novel mutation of the ATP7B gene in a family with WD.","variants":[{"Name":"NM_000053.4(ATP7B):c.2697_2723del (p.Ile899_Gln907del)","Chromosome":"13","Start":"51950014","Stop":"51950040","ReferenceAlleleVCF":"CATCTGAGCCTCTTCCACCAGTTTCACA","AlternateAlleleVCF":"C","allel_id":1314241,"rule_based_match":true,"evidence_text":"c.2697_2723del","llm_judgment":"PRESENT","evidence":"c.2697_2723del","abstract_start":952,"abstract_end":966}]}
{"pmid":"26463574","title":"Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures.","abstract":"Exome sequencing identified homozygous loss-of-function variants in DIAPH1 (c.2769delT; p.F923fs and c.3145C>T; p.R1049X) in four affected individuals from two unrelated consanguineous families. The affected individuals in our report were diagnosed with postnatal microcephaly, early-onset epilepsy, severe vision impairment, and pulmonary symptoms including bronchiectasis and recurrent respiratory infections. A heterozygous DIAPH1 mutation was originally reported in one family with autosomal dominant deafness. Recently, however, a homozygous nonsense DIAPH1 mutation (c.2332C4T; p.Q778X) was reported in five siblings in a single family affected by microcephaly, blindness, early onset seizures, developmental delay, and bronchiectasis. The role of DIAPH1 was supported using parametric linkage analysis, RNA and protein studies in their patients' cell lines and further studies in human neural progenitors cells and a diap1 knockout mouse. In this report, the proband was initially brought to medical attention for profound metopic synostosis. Additional concerns arose when his head circumference did not increase after surgical release at 5 months of age and he was diagnosed with microcephaly and epilepsy at 6 months of age. Clinical exome analysis identified a homozygous DIAPH1 mutation. Another homozygous DIAPH1 mutation was identified in the research exome analysis of a second family with three siblings presenting with a similar phenotype. Importantly, no hearing impairment is reported in the homozygous affected individuals or in the heterozygous carrier parents in any of the families demonstrating the autosomal recessive microcephaly phenotype. These additional families provide further evidence of the likely causal relationship between DIAPH1 mutations and a neurodevelopmental disorder.","variants":[{"Name":"NM_005219.5(DIAPH1):c.2769del (p.Phe923fs)","Chromosome":"5","Start":"141529181","Stop":"141529181","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":214405,"rule_based_match":true,"evidence_text":"c.2769delT","llm_judgment":"PRESENT","evidence":"c.2769delT","abstract_start":76,"abstract_end":86},{"Name":"NM_005219.5(DIAPH1):c.3145C>T (p.Arg1049Ter)","Chromosome":"5","Start":"141528456","Stop":"141528456","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":214406,"rule_based_match":true,"evidence_text":"c.3145C>T; p.R1049X","llm_judgment":"PRESENT","evidence":"c.3145C>T; p.R1049X","abstract_start":101,"abstract_end":120}]}
{"pmid":"29866057","title":"Chinese cases of early infantile epileptic encephalopathy: a novel mutation in the PCDH19 gene was proved in a mosaic male- case report.","abstract":"BACKGROUND: The link between the protocadherin-19 (PCDH19) gene and epilepsy suggests that an unusual form of X-linked inheritance affects females but is transmitted through asymptomatic males. Individuals with epilepsy associated with mutations in the PCDH19 gene display generalized or focal seizures with or without fever sensitivity. The clinical manifestation of the condition ranges from mild to severe, resulting in intellectual disability and behavioural disturbance. In the present study, we assessed mutations in the PCDH19 gene and the clinical features of a group of Chinese patients with early infantile epileptic encephalopathy and aimed to provide further insight into the understanding of epilepsy and mental retardation limited to females (EFMR; MIM 300088).\nCASE PRESENTATION: We described three variations in the PCDH19 gene in Chinese patients with epilepsy who developed generalized seizures occurring in clusters with or without triggering by fever. Candidate genes were screened for mutations that cause epilepsy and related paroxysmal or nervous system diseases in the coding exons and intron-exon boundaries using polymerase chain reaction (PCR) of genomic deoxyribonucleic acid (DNA) followed by sequencing. The variations were sequenced using next-generation sequencing technology and verified with first-generation sequencing. Exome sequencing of a multigene epilepsy panel revealed three mutations in the PCDH19 gene in a mosaic male and two unrelated females. These included a frameshift mutation c.1508_1509insT (p.Thr504HisfsTer19), a missense mutation c.1681C > T (p.Pro561Ser) and a nonsense mutation c.918C > G (p.Tyr306Ter). Of the three mutations in the PCDH19 gene associated with early infantile epileptic encephalopathy, the frameshift variation in a mosaic male is novel and de novo, the missense variation is de novo and is the second ever reported in females, and the nonsense variation was inherited from the paternal line and is the first example discovered in a female.\nCONCLUSIONS: The results from our current study provide new insight into and perspectives for the molecular genetic link between epilepsy and PCDH19 alterations. Moreover, our new findings of the male mosaic variant broaden the spectrum of PCDH19-related epilepsy and provide a new understanding of this complex genetic disorder.","variants":[{"Name":"NM_001184880.2(PCDH19):c.918C>G (p.Tyr306Ter)","Chromosome":"X","Start":"100407680","Stop":"100407680","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":575311,"rule_based_match":true,"evidence_text":"c.918C > G (p.Tyr306Ter)","llm_judgment":"PRESENT","evidence":"c.918C > G (p.Tyr306Ter)","abstract_start":1635,"abstract_end":1659}]}
{"pmid":"27681349","title":"Peripheral nerve involvement in classic homocystinuria: an unusual association.","abstract":"Classic homocystinuria is one of the most common causes of hereditary hyperhomocysteinemia. It is an autosomal recessive and multisystemic disorder due to cystathionine β-synthase deficiency. We described a case of an 18-year-old Portuguese man with an ischaemic stroke, who was subsequently diagnosed with classic homocystinuria [Thr191Met (c.572C>T) CBS mutation] associated with a sensorimotor neuropathy. The patient had a good clinical and metabolic response to pyridoxine plus methionine-restricted diet after 12 months of treatment. Neurophysiological re-evaluation with nerve conduction studies disclosed an improvement on the peripheral nerve lesion. Central nervous system manifestations in classic homocystinuria have been well documented, but this is to the best of our knowledge the first report of an association with peripheral neuropathy, which improved after hyperhomocysteinemia treatment.","variants":[{"Name":"NM_000071.3(CBS):c.572C>T (p.Thr191Met)","Chromosome":"21","Start":"43065481","Stop":"43065481","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15171,"rule_based_match":true,"evidence_text":"Thr191Met (c.572C>T) CBS mutation","llm_judgment":"PRESENT","evidence":"Thr191Met (c.572C>T) CBS mutation","abstract_start":331,"abstract_end":364}]}
{"pmid":"19373884","title":"Danon disease: further clinical and molecular heterogeneity.","abstract":"Two families of Greek patients with subclinical to severe cardiomyopathy are presented. The diagnosis of Danon disease was supported by a total lack of LAMP2 immunostaining in cultured skin fibroblasts and muscle biopsies. The LAMP2 mutation carried by one patient (c.928G>A) has already been reported but with different symptoms. The second patient had a novel point deletion. This has not been described previously, but it could be detected easily by restriction analysis. This mutation was also found in the patient's brother, and it was associated with severe cardiomyopathy leading to heart failure. Surprisingly, the proband also had partial reduction of alpha-galactosidase A activity, despite the absence of characteristic clinical features of Fabry disease. A substitution in the GLA gene (c.937G>T) was found, and its involvement in the cardiac disease is discussed.","variants":[{"Name":"NM_000169.3(GLA):c.937G>T (p.Asp313Tyr)","Chromosome":"X","Start":"101398432","Stop":"101398432","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":25777,"rule_based_match":true,"evidence_text":"c.937G>T","llm_judgment":"PRESENT","evidence":"c.937G>T","abstract_start":799,"abstract_end":807},{"Name":"NM_002294.3(LAMP2):c.928G>A (p.Val310Ile)","Chromosome":"X","Start":"120442599","Stop":"120442599","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25021,"rule_based_match":true,"evidence_text":"c.928G>A","llm_judgment":"PRESENT","evidence":"c.928G>A","abstract_start":266,"abstract_end":274}]}
{"pmid":"24026677","title":"The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family.","abstract":"Inherited retinal diseases are a group of clinically and genetically heterogeneous disorders for which a significant number of cases remain genetically unresolved. Increasing knowledge on underlying pathogenic mechanisms with precise phenotype-genotype correlation is, however, critical for establishing novel therapeutic interventions for these yet incurable neurodegenerative conditions. We report phenotypic and genetic characterization of a large family presenting an unusual autosomal dominant retinal dystrophy. Phenotypic characterization revealed a retinopathy dominated by inner retinal dysfunction and ganglion cell abnormalities. Whole-exome sequencing identified a missense variant (c.782A>C, p.Glu261Ala) in ITM2B coding for Integral Membrane Protein 2B, which co-segregates with the disease in this large family and lies within the 24.6 Mb interval identified by microsatellite haplotyping. The physiological role of ITM2B remains unclear and has never been investigated in the retina. RNA in situ hybridization reveals Itm2b mRNA in inner nuclear and ganglion cell layers within the retina, with immunostaining demonstrating the presence of the corresponding protein in the same layers. Furthermore, ITM2B in the retina co-localizes with its known interacting partner in cerebral tissue, the amyloid β precursor protein, critical in Alzheimer disease physiopathology. Interestingly, two distinct ITM2B mutations, both resulting in a longer protein product, had already been reported in two large autosomal dominant families with Alzheimer-like dementia but never in subjects with isolated retinal diseases. These findings should better define pathogenic mechanism(s) associated with ITM2B mutations underlying dementia or retinal disease and add a new candidate to the list of genes involved in inherited retinal dystrophies.","variants":[{"Name":"NM_021999.5(ITM2B):c.782A>C (p.Glu261Ala)","Chromosome":"13","Start":"48261205","Stop":"48261205","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":167466,"rule_based_match":true,"evidence_text":"c.782A>C (p.Glu261Ala)","llm_judgment":"PRESENT","evidence":"p.Glu261Ala","abstract_start":705,"abstract_end":716}]}
{"pmid":"22233338","title":"Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report.","abstract":"BACKGROUND: Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb. BDE may occur as an isolated trait or as part of a syndrome. Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved. Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous missense mutations in the homeodomain of the HOXD13 gene. Since the initial manuscript, one further HOXD13 mutation has been reported only in a single family manifesting isolated BDE.\nCASE PRESENTATION: In this paper, we report on a Polish family exhibiting isolated BDE caused by a novel nonsense heterozygous HOXD13 mutation. We investigated a Polish female proband and her father, both affected by isolated BDE, in whom we identified a nonsense heterozygous mutation c.820C > T(p.R274X) in the HOXD13 gene. So far, only two missense HOXD13 substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE. Both missense changes were supposed to alter DNA binding affinity of the protein.\nCONCLUSION: The variant p.R274X identified in our proband is the fourth HOXD13 mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE. We refer our clinical and molecular findings to the previously described HOXD13 associated phenotypes and mutations.","variants":[{"Name":"NM_000523.4(HOXD13):c.820C>T (p.Arg274Ter)","Chromosome":"2","Start":"176094518","Stop":"176094518","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360827,"rule_based_match":true,"evidence_text":"c.820C > T(p.R274X)","llm_judgment":"PRESENT","evidence":"c.820C > T(p.R274X)","abstract_start":955,"abstract_end":974}]}
{"pmid":"28670945","title":"Coinheritance of Hb Bristol-Alesha [β67(E11)Val→Met; HBB: c.202G>A] and the α212 Patchwork Allele in a Brazilian Child with Severe Congenital Hemolytic Anemia.","abstract":"Hb Bristol-Alesha [HBB: c.202G>A; β 67 Val>Met] is a rare structural variant of hemoglobin (Hb) resulting from a GTG>ATG substitution at codon 67 of the β-globin gene that leads to the replacement of valine by methionine in the corresponding position of the β-globin chain. The methionine residue is subsequently modified to aspartic acid [β67(E11)Val-Met→Asp], possibly by autoxidation mechanisms. This substitution prevents normal non-polar binding of Val67 to the heme group, resulting in molecular instability and severe hemolysis. We identified Hb Bristol-Alesha (in the heterozygous state), as the cause of severe congenital hemolytic anemia in an 11-month-old girl of mixed (native Indian and European) ethnic origin from the Midwestern region of Brazil, whose parents were clinically and hematologically normal. The mutation on the β-globin gene was found to have been coinherited with the α212 patchwork allele.","variants":[{"Name":"NM_000518.4(HBB):c.202G>A (p.Val68Met)","Chromosome":"11","Start":"5226690","Stop":"5226690","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30575,"rule_based_match":true,"evidence_text":"HBB: c.202G>A","llm_judgment":"PRESENT","evidence":"HBB: c.202G>A","abstract_start":19,"abstract_end":32}]}
{"pmid":"38279137","title":"Genetic and clinical characterization of a novel FH founder mutation in families with hereditary leiomyomatosis and renal cell cancer syndrome.","abstract":"BACKGROUND: Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH(NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype.\nRESULTS: Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61-0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH_c.1118A > G variant is a Spanish founder mutation that originated 12-26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome.\nCONCLUSIONS: In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing.","variants":[{"Name":"NM_000143.4(FH):c.1118A>G (p.Asn373Ser)","Chromosome":"1","Start":"241502561","Stop":"241502561","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":380451,"rule_based_match":true,"evidence_text":"FH(NM_000143.4):c.1118A > G p.(Asn373Ser)","llm_judgment":"PRESENT","evidence":"FH(NM_000143.4):c.1118A > G p.(Asn373Ser)","abstract_start":259,"abstract_end":300}]}
{"pmid":"24824479","title":"Spastin mutation screening in Chinese patients with pure hereditary spastic paraplegia.","abstract":"BACKGROUND: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative diseases. Mutations in the spastin (SPAST) gene are the most common cause of pure HSP. However, few data are available regarding the clinical and genetic spectrum of HSP among Chinese patients.\nMETHODS: Clinical data were collected at diagnosis and follow-up of 42 Chinese patients with pure HSP. All seventeen exons of the SPAST gene were directly sequenced. Additionally, we used a multiplex ligation dependent probe amplification (MLPA) assay targeting the SPAST gene to evaluate large exon deletion or insertion mutations in patients without SPAST point mutations.\nRESULTS: The age of disease onset of our patients was 19.6 ± 14.4 years. Six novel variations were found, including three missense mutations (p. L363P, p. D441V, and p. S595R), one insertion (c.1511dupT (p. Y505Ifs*7)), and two larger deletions (exons 5-17 and exons 10-17). Four previously reported mutations, including p. S399L, c.1215_c.1219delTATAA (p. N405Kfs*36), exon 1 deletion, and exon 16 deletion, were detected. The SPAST mutation rate was 40% (4/10) in Chinese familial patients and 33.33% (7/21) in Chinese sporadic pure HSP patients. The frequency of large deletions was high in both AD-HSP (20%, 2/10) and sporadic HSP (14.28%, 3/21).\nCONCLUSION: SPAST mutations are common in Chinese patients with pure HSP. Large exon deletions are an important cause of AD-HSP and sporadic pure HSP in Chinese patients. Large fragment tests should be performed to explore large SPAST mutations in familial and sporadic HSP patients without SPAST point mutations.","variants":[{"Name":"NM_014946.4(SPAST):c.1196C>T (p.Ser399Leu)","Chromosome":"2","Start":"32128430","Stop":"32128430","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":440709,"rule_based_match":false,"evidence_text":"c.1196C>T (p.Ser399Leu)","llm_judgment":"PRESENT","evidence":"S399L","abstract_start":1014,"abstract_end":1019},{"Name":"NM_014946.4(SPAST):c.1322A>T (p.Asp441Val)","Chromosome":"2","Start":"32136877","Stop":"32136877","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":942904,"rule_based_match":false,"evidence_text":"p. D441V","llm_judgment":"PRESENT","evidence":"p. D441V","abstract_start":842,"abstract_end":850}]}
{"pmid":"34367815","title":"Iatrogenic Iron Overload Causing Porphyria Cutanea Tarda in a Patient With a Rare Nonsense Heterozygous UROD Gene Mutation.","abstract":"Porphyria cutanea tarda (PCT) is a rare dermatologic condition characterized by blistering of sun-exposed surfaces and elevated hepatic enzymes. It may infrequently occur as the primary presentation of underlying hemochromatosis. A 61-year-old female with anemia caused by chronic kidney disease and end-stage renal disease on hemodialysis presented with a bullous rash on her hands with associated pruritus. The rash worsened despite conservative treatment. An initial biopsy demonstrated a pauci-inflammatory cell-poor subepidermal cleft. Subsequent workup revealed elevated serum and urine porphyrins, confirming a diagnosis of PCT. Additionally, her skin was darkened and ferritin was elevated. MRI of the liver demonstrated iron overload with genetic testing negative for <i>C282Y</i> or <i>H63D</i> mutations, supporting a diagnosis of secondary hemochromatosis. Further genetic testing revealed that the patient had a rare heterozygous nonsense mutation of the <i>uroporphyrinogen decarboxylase</i> (<i>UROD</i>) gene, for a sequence variant designated c.616C>T, which is predicted to result in premature protein termination (p.Gln206*). PCT occurs due to decreased function of <i>UROD</i>, leading to accumulation of porphyrins causing dermatologic manifestations and liver injury. <i>UROD</i> is inactivated in an iron-dependent process, explaining the mechanistic link between hemochromatosis and PCT.","variants":[{"Name":"NM_000374.5(UROD):c.616C>T (p.Gln206Ter)","Chromosome":"1","Start":"45014050","Stop":"45014050","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1393280,"rule_based_match":true,"evidence_text":"c.616C>T","llm_judgment":"PRESENT","evidence":"c.616C>T","abstract_start":1060,"abstract_end":1068}]}
{"pmid":"30853829","title":"An Autopsy Proven Case of CSF1R-mutant Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) with Premature Ovarian Failure.","abstract":"Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a progressive degenerative white matter disorder caused by mutations in the tyrosine kinase domain of the <i>CSF1R</i> gene. ALSP is often misdiagnosed as other diseases due to its rarity and various clinical presentations such as Parkinsonism, pyramidal signs, cognitive impairment and/or psychiatric symptoms. We describe an autopsy case of ALSP with a <i>CSF1R</i> mutation. A 61-year-old woman presented insidious-onset gait difficulty for 12 years since her age of 49, and premature ovarian failure since her age of 35. At initial hospital visit, brain magnetic resonance imaging revealed hydrocephalus. Initially, Parkinson's syndrome was diagnosed, and she was prescribed L-dopa/carbidopa because of spasticity and rigidity of extremities, which had worsened. Subsequently, severe neuropsychiatric symptoms and cognitive impairment developed and radiologically, features of leukoencephalopathy or leukodystrophy were detected. She showed a down-hill course and died, 12 years after initial diagnosis. At autopsy, the brain showed severe symmetric atrophy of bilateral white matter, paper-thin corpus callosum, thin internal capsule, and marked hydrocephalus. Microscopically, diffuse loss of white matter, relatively preserved subcortical U-fibers, and many eosinophilic bulbous neuroaxonal spheroids were noted, but there was no calcification. Pigmented glia with brown cytoplasmic pigmentation were readily found in the white matter, which were positive for Periodic acid-Schiff, p62, and CD163 stains, but almost negative for CD68. Whole-exome and Sanger sequencing revealed a <i>CSF1R</i> mutation (c.2539G>A, p.Glu847Lys) which was reported in prior one ALSP case. This example demonstrates that ALSP could be associated with premature ovarian failure.","variants":[{"Name":"NM_001288705.3(CSF1R):c.2539G>A (p.Glu847Lys)","Chromosome":"5","Start":"150056041","Stop":"150056041","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1467987,"rule_based_match":true,"evidence_text":"c.2539G>A, p.Glu847Lys","llm_judgment":"PRESENT","evidence":"c.2539G>A, p.Glu847Lys","abstract_start":1693,"abstract_end":1715}]}
{"pmid":"32022391","title":"A phenotypically severe, biochemically \"silent\" case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing.","abstract":"3-Hydroxyisobutyryl-CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome-like phenotype, mitochondrial dysfunction, and increased C4-OH. We report the most severe case to date in a full-term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow-up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.","variants":[{"Name":"NM_014362.4(HIBCH):c.488G>T (p.Cys163Phe)","Chromosome":"2","Start":"190261185","Stop":"190261185","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":421352,"rule_based_match":true,"evidence_text":"c.488G>T (p.C163F)","llm_judgment":"PRESENT","evidence":"c.488G>T","abstract_start":881,"abstract_end":889},{"Name":"NM_014362.4(HIBCH):c.852del (p.Leu284fs)","Chromosome":"2","Start":"190244926","Stop":"190244926","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":421351,"rule_based_match":true,"evidence_text":"c.852delA","llm_judgment":"PRESENT","evidence":"c.852delA","abstract_start":814,"abstract_end":823}]}
{"pmid":"33731098","title":"Clinical analysis and long-term treatment monitoring of 3 patients with glycogen storage disease type Ib.","abstract":"BACKGROUND: To investigate the clinical and genetic characteristics of patients with glycogen storage disease type Ib (GSD Ib).\nCASE PRESENTATION: This report retrospectively analyzed the clinical data of 3 patients with GSD Ib admitted into our hospital, and summarized their onset characteristics, clinical manifestations, related examinations and treatment as well as mutational spectrum. After gene sequencing, the diagnosis of GSD Ib was confirmed in all 3 patients. Five variants of SLC37A4 gene were detected, of which c. 572C > T was the common variant and c. 680G > A was a novel variant. The 3 cases of GSD Ib were mainly affected by liver enlargement, growth retardation, etc., and all had a history of repeated infections. At the onset, patients mainly manifested as mildly elevated alanine-aminotransferase (ALT), accompanied by decreased absolute neutrophil count (ANC), hypertriglyceridemia, and metabolic disorders (hypoglycemia, hyperlactic acidemia, metabolic acidosis, etc.). After long-term treatment by oral uncooked cornstarch, the abnormal liver enzymes gradually returned to normal, and metabolic abnormalities were basically controlled most of the time. With increasing age, ANC of 2 patients decreased progressively, whereas the times of infections was reduced.\nCONCLUSIONS: We reported 3 cases with GSD Ib and a novel SLC37A4 variant. The possibility of GSD type Ib should be kept on alert when a patient suffers recurrent infections, accompanied by hepatomegaly, elevated liver enzymes, hypoglycemia, dyslipidemia, and metabolic disorders.","variants":[{"Name":"NM_001164277.2(SLC37A4):c.572C>T (p.Pro191Leu)","Chromosome":"11","Start":"119027681","Stop":"119027681","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":79176,"rule_based_match":true,"evidence_text":"c. 572C > T","llm_judgment":"PRESENT","evidence":"c. 572C > T","abstract_start":526,"abstract_end":537}]}
{"pmid":"33300499","title":"Functional significance of germline EPAS1 variants.","abstract":"Mosaic or somatic EPAS1 mutations are associated with a range of phenotypes including pheochromocytoma and/or paraganglioma (PPGL), polycythemia and somatostatinoma. The pathogenic potential of germline EPAS1 variants however is not well understood. We report a number of germline EPAS1 variants occurring in patients with PPGL, including a novel variant c.739C>A (p.Arg247Ser); a previously described variant c.1121T>A (p.Phe374Tyr); several rare variants, c.581A>G (p.His194Arg), c.2353C>A (p.Pro785Thr) and c.2365A>G (p.Ile789Val); a common variant c.2296A>C (p.Thr766Pro). We performed detailed functional studies to understand their pathogenic role in PPGL. In transient transfection studies, EPAS1/HIF-2α p.Arg247Ser, p.Phe374Tyr and p.Pro785Thr were all stable in normoxia. In co-immunoprecipitation assays, only the novel variant p.Arg247Ser showed diminished interaction with pVHL. A direct interaction between HIF-2α Arg247 and pVHL was confirmed in structural models. Transactivation was assessed by means of a HRE-containing reporter gene in transiently transfected cells, and significantly higher reporter activity was only observed with EPAS1/HIF-2α p.Phe374Tyr and p.Pro785Thr. In conclusion, three germline EPAS1 variants (c.739C>A (p.Arg247Ser), c.1121T>A (p.Phe374Tyr) and c.2353C>A (p.Pro785Thr)) all have some functional features in common with somatic activating mutations. Our findings suggest that these three germline variants are hypermorphic alleles that may act as modifiers to the expression of PPGLs.","variants":[{"Name":"NM_001430.5(EPAS1):c.581A>G (p.His194Arg)","Chromosome":"2","Start":"46360892","Stop":"46360892","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3801938,"rule_based_match":true,"evidence_text":"c.581A>G (p.His194Arg)","llm_judgment":"PRESENT","evidence":"c.581A>G (p.His194Arg)","abstract_start":458,"abstract_end":480}]}
{"pmid":"28794131","title":"Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability.","abstract":"BACKGROUND: Autosomal recessive mutations in <i>DNAJC12</i>, encoding a cochaperone of HSP70 with hitherto unknown function, were recently described to lead to hyperphenylalaninemia, central monoamine neurotransmitter (dopamine and serotonin) deficiency, dystonia and intellectual disability in six subjects affected by homozygous variants.\nOBJECTIVE: Patients exhibiting hyperphenylalaninemia in whom deficiencies in hepatic phenylalanine hydroxylase and tetrahydrobiopterin cofactor metabolism had been excluded were subsequently analysed for <i>DNAJC12</i> variants.\nMETHODS: To analyse DNAJC12, genomic DNA from peripheral blood (Sanger sequencing), as well as quantitative messenger RNA (Real Time Quantitative Polymerase Chain Reaction (RT-qPCR)) and protein expression (Western blot) from primary skin fibroblasts were performed.\nRESULTS: We describe five additional patients from three unrelated families with homozygosity/compound heterozygosity in <i>DNAJC12</i> with three novel variants: c.85delC/p.Gln29Lysfs*38, c.596G>T/p.*199Leuext*42 and c.214C>T/p.(Arg72*). In contrast to previously reported DNAJC12-deficient patients, all five cases showed a very mild neurological phenotype. In two subjects, cerebrospinal fluid and primary skin fibroblasts were analysed showing similarly low 5-hydroxyindolacetic acid and homovanillic acid concentrations but more reduced expressions of mRNA and DNAJC12 compared with previously described patients. All patients responded to tetrahydrobiopterin challenge by lowering blood phenylalanine levels.\nCONCLUSIONS: DNAJC12 deficiency appears to result in a more heterogeneous neurological phenotype than originally described. While early identification and institution of treatment with tetrahydrobiopterin and neurotransmitter precursors is crucial to ensure optimal neurological outcome in DNAJC12-deficient patients with a severe phenotype, optimal treatment for patients with a milder phenotype remains to be defined.","variants":[{"Name":"NM_021800.3(DNAJC12):c.214C>T (p.Arg72Ter)","Chromosome":"10","Start":"67811607","Stop":"67811607","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":681920,"rule_based_match":true,"evidence_text":"c.214C>T/p.(Arg72*)","llm_judgment":"PRESENT","evidence":"c.214C>T/p.(Arg72*)","abstract_start":1055,"abstract_end":1074},{"Name":"NM_021800.3(DNAJC12):c.85del (p.Gln29fs)","Chromosome":"10","Start":"67823386","Stop":"67823386","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":681918,"rule_based_match":true,"evidence_text":"c.85delC/p.Gln29Lysfs*38","llm_judgment":"PRESENT","evidence":"c.85delC/p.Gln29Lysfs*38","abstract_start":1000,"abstract_end":1024},{"Name":"NM_021800.3(DNAJC12):c.596G>T (p.Ter199Leu)","Chromosome":"10","Start":"67797117","Stop":"67797117","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":681919,"rule_based_match":true,"evidence_text":"c.596G>T/p.*199Leuext*42","llm_judgment":"PRESENT","evidence":"c.596G>T/p.*199Leuext*42","abstract_start":1026,"abstract_end":1050}]}
{"pmid":"25563136","title":"Moyamoya syndrome in a patient with Noonan-like syndrome with loose anagen hair.","abstract":"BACKGROUND: Noonan-like syndrome with loose anagen hair is one of the RASopathies characterized by Noonan syndrome-like features with unique ectodermal abnormalities. This syndrome is caused by mutations in the SHOC2 gene. We encountered a patient with moyamoya syndrome associated with Noonan-like syndrome with loose anagen hair presenting with transient ischemic attacks.\nPATIENT DESCRIPTION: A 6-year-old girl was diagnosed with Noonan-like syndrome with loose anagen hair because of profound short stature and ectodermal anomalies such as sparse and easily pluckable hair. A heterozygous mutation of c.4A>G (p.S2G) in the SHOC2 gene was identified, and recombinant human growth hormone therapy was initiated at 8 years of age. At age 10, she manifested recurrent left hemiplegia. Moreover, cerebrovascular imaging revealed occlusion or narrowing of both internal carotid arteries and both middle cerebral arteries with distal moyamoya-like vessels. She is treated with aspirin and calcium channel blocker.\nCONCLUSIONS: We describe the first case of Noonan-like syndrome with loose anagen hair associated with moyamoya syndrome, although it has been reported to be associated with a few cases of other RASopathies, including Noonan, cardiofaciocutaneous, and Costello syndromes. This report emphasizes the associations between cerebrovascular anomalies and Noonan-like syndrome with loose anagen hair.","variants":[{"Name":"NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly)","Chromosome":"10","Start":"110964362","Stop":"110964362","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":21860,"rule_based_match":true,"evidence_text":"c.4A>G (p.S2G)","llm_judgment":"PRESENT","evidence":"c.4A>G (p.S2G)","abstract_start":605,"abstract_end":619}]}
{"pmid":"24297685","title":"Detection of a novel mutation in exon 20 of the BRCA1 gene.","abstract":"Hereditary breast cancer constitutes 5-10% of all breast cancer cases. Inherited mutations in the BRCA1 and BRCA2 tumor-suppressor genes account for the majority of hereditary breast cancer cases. The BRCA1 C-terminal region (BRCT) has a functional duplicated globular domain, which helps with DNA damage repair and cell cycle checkpoint protein control. More than 100 distinct BRCA1 missense variants with structural and functional effects have been documented within the BRCT domain. Interpreting the results of mutation screening of tumor-suppressor genes that can have high-risk susceptibility mutations is increasingly important in clinical practice. This study includes a novel mutation, p.His1746 Pro (c.5237A>C), which was found in BRCA1 exon 20 of a breast cancer patient. In silico analysis suggests that this mutation could alter the stability and orientation of the BRCT domain and the differential binding of the BACH1 substrate.","variants":[{"Name":"NM_007294.4(BRCA1):c.5237A>C (p.His1746Pro)","Chromosome":"17","Start":"43057092","Stop":"43057092","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":235937,"rule_based_match":true,"evidence_text":"c.5237A>C","llm_judgment":"PRESENT","evidence":"c.5237A>C","abstract_start":709,"abstract_end":718}]}
{"pmid":"22042873","title":"Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria.","abstract":"Pentosuria is one of four conditions hypothesized by Archibald Garrod in 1908 to be inborn errors of metabolism. Mutations responsible for the other three conditions (albinism, alkaptonuria, and cystinuria) have been identified, but the mutations responsible for pentosuria remained unknown. Pentosuria, which affects almost exclusively individuals of Ashkenazi Jewish ancestry, is characterized by high levels of the pentose sugar L-xylulose in blood and urine and deficiency of the enzyme L-xylulose reductase. The condition is autosomal-recessive and completely clinically benign, but in the early and mid-20th century attracted attention because it was often confused with diabetes mellitus and inappropriately treated with insulin. Persons with pentosuria were identified from records of Margaret Lasker, who studied the condition in the 1930s to 1960s. In the DCXR gene encoding L-xylulose reductase, we identified two mutations, DCXR c.583ΔC and DCXR c.52(+1)G > A, each predicted to lead to loss of enzyme activity. Of nine unrelated living pentosuric subjects, six were homozygous for DCXR c.583ΔC, one was homozygous for DCXR c.52(+1)G > A, and two were compound heterozygous for the two mutant alleles. L-xylulose reductase was not detectable in protein lysates from subjects' cells and high levels of xylulose were detected in their sera, confirming the relationship between the DCXR genotypes and the pentosuric phenotype. The combined frequency of the two mutant DCXR alleles in 1,067 Ashkenazi Jewish controls was 0.0173, suggesting a pentosuria frequency of approximately one in 3,300 in this population. Haplotype analysis indicated that the DCXR c.52(+1)G > A mutation arose more recently than the DCXR c.583ΔC mutation.","variants":[{"Name":"NM_016286.4(DCXR):c.583del (p.His195fs)","Chromosome":"17","Start":"82036239","Stop":"82036239","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":106818,"rule_based_match":false,"evidence_text":"DCXR c.583ΔC","llm_judgment":"PRESENT","evidence":"DCXR c.583ΔC","abstract_start":936,"abstract_end":948},{"Name":"NM_016286.4(DCXR):c.52+1G>A","Chromosome":"17","Start":"82037630","Stop":"82037630","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":106819,"rule_based_match":false,"evidence_text":"DCXR c.52(+1)G > A","llm_judgment":"PRESENT","evidence":"DCXR c.52(+1)G > A","abstract_start":953,"abstract_end":971}]}
{"pmid":"23400408","title":"Jervell and Lange-Nielsen syndrome: homozygous missense mutation of KCNQ1 in a Turkish family.","abstract":"Long QT syndrome is one of the most common cardiac ion channel diseases, but its morbidity and mortality rate can be lessened with an early diagnosis and proper treatment. This cardiac ventricular repolarization abnormality is characterized by a prolonged QT interval and a propensity for ventricular tachycardia (VT) of the torsades de pointes type. The long QT syndrome represents a high risk for presyncope, syncope, cardiac arrest, and sudden death. Jervell and Lange-Nielsen syndrome (JLNS) is a recessively inherited form of long QT syndrome characterized by profound sensorineural deafness and prolongation of the QT interval. Findings have shown that JLNS occurs due to homozygous and compound heterozygous pathogenic variants in KCNQ1 or KCNE1. A 3.5-year-old girl presented to the hospital with recurrent syncope, seizures, and congenital sensorineural deafness. Her electrocardiogram showed a markedly prolonged QT interval, and she had a diagnosis of JLNS. The sequence analysis of the proband showed the presence of a pathogenic homozygous missense variant (c.728G>A, p.Arg243His). Heterozygous mutations of KCNQ1 were identified in her mother, father, and sister, demonstrating true homozygosity. Even with high-dose beta-blocker therapy, the patient had two VT attacks, so an implantable cardioverter defibrillator was fitted. The authors suggest early genetic diagnosis for proper management of the disease in the proband and genetic counseling for both the proband and the girl's extended family.","variants":[{"Name":"NM_000218.3(KCNQ1):c.728G>A (p.Arg243His)","Chromosome":"11","Start":"2572057","Stop":"2572057","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67760,"rule_based_match":true,"evidence_text":"c.728G>A, p.Arg243His","llm_judgment":"PRESENT","evidence":"c.728G>A, p.Arg243His","abstract_start":1071,"abstract_end":1092}]}
{"pmid":"24013081","title":"GJB2-associated hearing loss undetected by hearing screening of newborns.","abstract":"The hearing loss caused by GJB2 mutations is usually congenital in onset, moderate to profound in degree, and non-progressive. The objective of this study was to study genotype/phenotype correlations and to document 14 children with biallelic GJB2 mutations who passed newborn hearing screening (NHS). Genetic testing for GJB2 mutations by direct sequencing was performed on 924 individuals (810 families) with hearing loss, and 204 patients (175 families) were found to carry biallelic GJB2 mutations. NHS results were obtained through medical records. A total of 18 pathological mutations were identified, which were subclassified as eight inactivating and 10 non-inactivating mutations. p.I128M and p.H73Y were identified as novel missense GJB2 mutations. Of the 14 children with biallelic GJB2 mutations who passed NHS, eight were compound heterozygotes and 3 were homozygous for the c.235delC mutation in GJB2, and the other three combinations of non-c.235delC mutations identified were p.Y136X-p.G45E/p.V37I heterozygous, c.512ins4/p.R143W heterozygous, and p.V37I/p.R143W heterozygous. These 14 cases demonstrate that the current NHS does not identify all infants with biallelic GJB2 mutations. They suggest that the frequency of non-penetrance at birth is approximately 6.9% or higher in DFNB1 patients and provide further evidence that GJB2 hearing loss may not always be congenital in onset.","variants":[{"Name":"NM_004004.6(GJB2):c.235del (p.Leu79fs)","Chromosome":"13","Start":"20189347","Stop":"20189347","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":32053,"rule_based_match":true,"evidence_text":"c.235delC","llm_judgment":"PRESENT","evidence":"c.235delC","abstract_start":888,"abstract_end":897}]}
{"pmid":"23734086","title":"Mutation analysis of paired box 6 gene in inherited aniridia in northern China.","abstract":"PURPOSE: Aniridia is phenotypically and genetically heterogeneous. This study is to summarize the phenotypes and identify the underlying genetic cause of the paired box 6 (PAX6) gene responsible for aniridia in two three-generation Chinese families in northern China.\nMETHODS: A detailed family history and clinical data were collected from patients during an ophthalmologic examination. All exons and flanking intronic sequences of the PAX6 gene were amplified with PCR and screened for mutation with direct DNA sequencing. Haplotyping was used to confirm the mutation sequence. Real-time PCR was used to determine the PAX6 messenger ribonucleic acid(mRNA) level in patients with aniridia and in unaffected family members.\nRESULTS: The probands and other patients in the two families were affected with aniridia accompanied with or without congenital cataract. A heterozygous PAX6 mutation in exon 5 (c.112delC, p.Arg38GlyfsX16) was identified in FAMILY-1, which was predicted to generate a frameshift and created a premature termination codon. A heterozygous PAX6 mutation in exon 7 (c.362C>T, p.Ser121Leu) was identified in FAMILY-2. Each mutation cosegregated with the affected individuals in the family and did not exist in unaffected family members and 200 unrelated normal controls. The PAX6 messenger ribonucleic acid level was about 50% lower in patients with aniridia than in unaffected family members in FAMILY-1.\nCONCLUSIONS: The deletion mutation (c.112delC) in the PAX6 gene was first identified in a Chinese family with aniridia, congenital progressive cataract, developmental delay, or the absence of ulna. The mutation (c.362C>T, p.Ser121Leu) in the PAX6 gene was first identified in a patient with aniridia with congenital ptosis. We summarized the variable phenotypes among the patients, which expanded the phenotypic spectrum of aniridia in a different ethnic background.","variants":[{"Name":"NM_001368894.2(PAX6):c.112del (p.Arg38fs)","Chromosome":"11","Start":"31802733","Stop":"31802733","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":639955,"rule_based_match":true,"evidence_text":"c.112delC","llm_judgment":"PRESENT","evidence":"c.112delC","abstract_start":902,"abstract_end":911}]}
{"pmid":"24001973","title":"Molecular diagnosis of infantile onset inflammatory bowel disease by exome sequencing.","abstract":"Pediatric-onset inflammatory bowel disease (IBD) is known to be associated with severe disease, poor response to therapy, and increased morbidity and mortality. We conducted exome sequencing of two brothers from a non-consanguineous relationship who presented before the age of one with severe infantile-onset IBD, failure to thrive, skin rash, and perirectal abscesses refractory to medical management. We examined the variants discovered in all known IBD-associated and primary immunodeficiency genes in both siblings. The siblings were identified to harbor compound heterozygous mutations in IL10RA (c.784C>T, p.Arg262Cys; c.349C>T, p.Arg117Cys). Upon molecular diagnosis, the proband underwent successful hematopoietic stem cell transplantation and demonstrated marked clinical improvement of all IBD-associated clinical symptoms. Exome sequencing can be an effective tool to aid in the molecular diagnosis of pediatric-onset IBD. We provide additional evidence of the safety and benefit of HSCT for patients with IBD due to mutations in the IL10RA gene.","variants":[{"Name":"NM_001558.4(IL10RA):c.349C>T (p.Arg117Cys)","Chromosome":"11","Start":"117989602","Stop":"117989602","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2919415,"rule_based_match":true,"evidence_text":"c.349C>T (p.Arg117Cys)","llm_judgment":"PRESENT","evidence":"p.Arg117Cys","abstract_start":636,"abstract_end":647},{"Name":"NM_001558.4(IL10RA):c.784C>T (p.Arg262Cys)","Chromosome":"11","Start":"117995684","Stop":"117995684","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48029,"rule_based_match":true,"evidence_text":"c.784C>T, p.Arg262Cys","llm_judgment":"PRESENT","evidence":"c.784C>T, p.Arg262Cys","abstract_start":603,"abstract_end":624}]}
{"pmid":"24677493","title":"Autosomal dominant brachyolmia in a large Swedish family: phenotypic spectrum and natural course.","abstract":"Autosomal dominant brachyolmia (Type 3, OMIM #113500) belongs to a group of skeletal dysplasias caused by mutations in the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) gene, encoding a Ca++-permeable, non-selective cation channel. The disorder is characterized by disproportionate short stature with short trunk, scoliosis and platyspondyly. The phenotypic variability and long-term natural course remain inadequately characterized. The purpose of this study was to describe a large Swedish family with brachyolmia type 3 due to a heterozygous TRPV4 mutation c.1847G>A (p.R616Q) in 11 individuals. The mutation has previously been detected in another family with autosomal dominant brachyolmia [Rock et al., 2008]. Review of hospital records and patient assessments indicated that clinical symptoms of brachyolmia became evident by school age with chronic pain in the spine and hips; radiographic changes were evident earlier. Growth was not affected during early childhood but deteriorated with age in some patients due to increasing spinal involvement. Affected individuals had a wide range of subjective symptoms with chronic pain in the extremities and the spine, and paresthesias. Our findings indicate that autosomal dominant brachyolmia may be associated with significant long-term morbidity, as seen in this family.","variants":[{"Name":"NM_021625.5(TRPV4):c.1847G>A (p.Arg616Gln)","Chromosome":"12","Start":"109792407","Stop":"109792407","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20031,"rule_based_match":true,"evidence_text":"c.1847G>A (p.R616Q)","llm_judgment":"PRESENT","evidence":"c.1847G>A (p.R616Q)","abstract_start":589,"abstract_end":608}]}
{"pmid":"22718341","title":"Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix.","abstract":"Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with ≈10% over-modification. Normal chain incorporation, helix folding, and collagen T(m) support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix.","variants":[{"Name":"NM_021939.4(FKBP10):c.1271_1272delinsA (p.Ala424fs)","Chromosome":"17","Start":"41820961","Stop":"41820962","ReferenceAlleleVCF":"CC","AlternateAlleleVCF":"A","allel_id":49863,"rule_based_match":false,"evidence_text":"c.1271_1272delCCinsA","llm_judgment":"PRESENT","evidence":"c.1271_1272delCCinsA","abstract_start":583,"abstract_end":603}]}
{"pmid":"28069055","title":"Novel germline mutations in FLCN gene identified in two Chinese patients with Birt-Hogg-Dubé syndrome.","abstract":"Birt-Hogg-Dubé (BHD) syndrome, a hereditary renal cancer syndrome caused by mutations in the folliculin (FLCN) gene, is characterized by the presence of fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cell carcinoma (RCC). Few BHD syndrome cases have been reported in Asian countries, and cutaneous presentations are relatively rare in Asian patients. Asian BHD patients may be misdiagnosed due to their atypical manifestations. Here, we report two Chinese BHD patients with novel FLCN mutations (c.946-947delAG in exon 9 and c.770-772delCCT in exon 7). Both of them had RCC and spontaneous pneumothorax without fibrofolliculomas. In patients with RCC and pulmonary cysts but without cutaneous lesions, screening for mutations in the FLCN gene should be performed, especially for those with a family history of RCC or pulmonary cysts (pneumothorax).","variants":[{"Name":"NM_144997.7(FLCN):c.946_947del (p.Ser316fs)","Chromosome":"17","Start":"17219134","Stop":"17219135","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":645372,"rule_based_match":false,"evidence_text":"c.946-947delAG","llm_judgment":"PRESENT","evidence":"c.946-947delAG","abstract_start":521,"abstract_end":535}]}
{"pmid":"31076878","title":"Amyotrophy, cerebellar impairment and psychiatric disease are the main symptoms in a cohort of 14 Czech patients with the late-onset form of Tay-Sachs disease.","abstract":"BACKGROUND: Tay-Sachs disease (TSD) is an inherited neurodegenerative disorder caused by a lysosomal β-hexosaminidase A deficiency due to mutations in the HEXA gene. The late-onset form of disease (LOTS) is considered rare, and only a limited number of cases have been reported. The clinical course of LOTS differs substantially from classic infantile TSD.\nMETHODS: Comprehensive data from 14 Czech patients with LOTS were collated, including results of enzyme assays and genetic analyses.\nRESULTS: 14 patients (9 females, 5 males) with LOTS were diagnosed between 2002 and 2018 in the Czech Republic (a calculated birth prevalence of 1 per 325,175 live births). The median age of first symptoms was 21 years (range 10-33 years), and the median diagnostic delay was 10.5 years (range 0-29 years). The main clinical symptoms at the time of manifestation were stammering or slurred speech, proximal weakness of the lower extremities due to anterior horn cell neuronopathy, signs of neo- and paleocerebellar dysfunction and/or psychiatric disorders. Cerebellar atrophy detected through brain MRI was a common finding. Residual enzyme activity was 1.8-4.1% of controls. All patients carried the typical LOTS-associated c.805G>A (p.Gly269Ser) mutation on at least one allele, while a novel point mutation, c.754C>T (p.Arg252Cys) was found in two siblings.\nCONCLUSION: LOTS seems to be an underdiagnosed cause of progressive distal motor neuron disease, with variably expressed cerebellar impairment and psychiatric symptomatology in our group of adolescent and adult patients. The enzyme assay of β-hexosaminidase A in serum/plasma is a rapid and reliable tool to verify clinical suspicions.","variants":[{"Name":"NM_000520.6(HEXA):c.754C>T (p.Arg252Cys)","Chromosome":"15","Start":"72350569","Stop":"72350569","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":513352,"rule_based_match":true,"evidence_text":"c.754C>T (p.Arg252Cys)","llm_judgment":"PRESENT","evidence":"c.754C>T (p.Arg252Cys)","abstract_start":1301,"abstract_end":1323},{"Name":"NM_000520.6(HEXA):c.805G>A (p.Gly269Ser)","Chromosome":"15","Start":"72350518","Stop":"72350518","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18937,"rule_based_match":true,"evidence_text":"c.805G>A (p.Gly269Ser)","llm_judgment":"PRESENT","evidence":"c.805G>A (p.Gly269Ser)","abstract_start":1215,"abstract_end":1237}]}
{"pmid":"33688152","title":"Clinical and genetic findings in Italian patients with sector retinitis pigmentosa.","abstract":"Purpose: To describe clinical and genetic features in a series of Italian patients with sector retinitis pigmentosa (sector RP).\nMethods: Fifteen patients with sector RP were selected from the database of Hereditary Retinal Degenerations Referring Center of Careggi Hospital (Florence, Italy). Eleven patients from five independent pedigrees underwent genetic analysis with next-generation sequencing (NGS) confirmed with Sanger sequencing. The diagnosis of sector RP was based on the detection of topographically limited retinal abnormalities consistent with corresponding sectorial visual field defects. Best-corrected visual acuity (BCVA), fundus color pictures as well as fundus autofluorescence (FAF), spectral domain-optical coherence tomography (SD-OCT), full-field electroretinography (ERG), and 30-2 Humphrey visual field (VF) data were retrospectively collected and analyzed.\nResults: For the 30 eyes, the mean BCVA was 0.05 ± 0.13 logMAR, and the mean refractive error was -0.52 ± 1.89 D. The inferior retina was the most affected sector (86.7%), and the VF defect corresponded to the affected sector. FAF showed a demarcation line of increased autofluorescence between the healthy and affected retina, corresponding on SD-OCT to an interruption of the ellipsoid zone (EZ) band in the diseased retina. Dark-adapted ERG amplitudes were decreased in comparison to normative values. In five unrelated families, the sector RP phenotype was associated with sequence variants in the <i>RHO</i> gene. The same mutation c.568G>A p.(Asp190Asn) was found in nine patients of four families.\nConclusions: Typical sector RP is a mild form of RP characterized by preserved visual acuity with limited retinal involvement and, generally, a more favorable prognosis than other forms of RP.","variants":[{"Name":"NM_000539.3(RHO):c.568G>A (p.Asp190Asn)","Chromosome":"3","Start":"129532288","Stop":"129532288","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28062,"rule_based_match":true,"evidence_text":"c.568G>A p.(Asp190Asn)","llm_judgment":"PRESENT","evidence":"c.568G>A p.(Asp190Asn)","abstract_start":1523,"abstract_end":1545}]}
{"pmid":"26662178","title":"Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline.","abstract":"Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes.","variants":[{"Name":"NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)","Chromosome":"11","Start":"108329202","Stop":"108329202","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18062,"rule_based_match":true,"evidence_text":"ATM c.7271T>G","llm_judgment":"PRESENT","evidence":"ATM c.7271T>G","abstract_start":1094,"abstract_end":1107}]}
{"pmid":"26260218","title":"A novel SLC12A3 gene homozygous mutation of Gitelman syndrome in an Asian pedigree and literature review.","abstract":"OBJECTIVES: Gitelman syndrome (GS) is an autosomal recessive disease characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and hypocalciuria which is caused by mutations in the SLC12A3 gene. In this study, we reported a case of GS pedigree and reviewed pertinent literature so as to explore the relationship between clinical characteristics and genotype meanwhile provide recommendations for the diagnosis and treatment of GS.\nDESIGN AND METHODS: This is a pedigree-based genetic study of GS and 11 members from one family were included. We summarized their clinical features, analyzed laboratory parameters related to GS and SLC12A3 gene.\nRESULTS: The proband experienced intermittent severe symptoms of weakness accompanied by significant hypokalemia, hypomagnesemia and hypocalciuria in laboratory test with poor treatments. His mother had more slight symptoms of weakness than him with mild hypokalemia and hypocalciuria. Mild hypomagnesemia was also observed in his sister with occasional weakness. All other pedigree members had normal laboratory test with no GS-related symptoms. A homozygous mutation of SLC12A3 gene (c.488C > T) was detected by genetic testing in three members, and six were carriers of this mutation.\nCONCLUSIONS: Genotype and phenotype vary significantly among GS patients. Male patients tend to experience more severe symptoms and poor treatment effect. Further large-scale population, animal, and molecular biology experiments are required to investigate the complexity of GS and to find a better treatment regimen for this disease.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.488C>T (p.Thr163Met)","Chromosome":"16","Start":"56868355","Stop":"56868355","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23635,"rule_based_match":true,"evidence_text":"c.488C>T","llm_judgment":"PRESENT","evidence":"c.488C > T","abstract_start":1168,"abstract_end":1178}]}
{"pmid":"23612258","title":"Mild clinical presentation and prolonged survival of a patient with fumarase deficiency due to the combination of a known and a novel mutation in FH gene.","abstract":"Mutations in the FH gene cause the deficiency of the enzyme fumarase (fumarate hydratase, EC 4.2.1.2) which result in autosomal recessive fumaric aciduria in early childhood with failure to thrive, seizures, developmental delay, mental retardation, hypotonia and sometimes with polycythemia, leukopenia, and neutropenia. Many children with fumarate hydratase deficiency do not survive infancy or childhood; those surviving beyond childhood have severe psychomotor retardation. Recently, FH gene was also identified as a \"non-classical\" tumor suppressor gene and heterozygous mutations were shown to cause multiple cutaneous and uterine leiomyomas as well as hereditary leiomyomatosis and renal cell cancer. A male patient who was referred to investigate the etiology of psychomotor retardation was later diagnosed to have fumaric aciduria due to the combination of a previously known (c.1431_1433dupAAA) and a novel (c.782G>T) mutation. The patient had an unusually mild clinical course without acidotic attacks. Interestingly his father who was heterozygous for the c.1431_1433dupAAA mutation in the FH gene had cutaneous leiomyoma.","variants":[{"Name":"NM_000143.4(FH):c.782G>T (p.Arg261Ile)","Chromosome":"1","Start":"241506125","Stop":"241506125","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":472305,"rule_based_match":true,"evidence_text":"c.782G>T","llm_judgment":"PRESENT","evidence":"c.782G>T","abstract_start":917,"abstract_end":925},{"Name":"NM_000143.4(FH):c.1431_1433dup (p.Lys477dup)","Chromosome":"1","Start":"241497927","Stop":"241497928","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ATTT","allel_id":51261,"rule_based_match":true,"evidence_text":"c.1431_1433dupAAA","llm_judgment":"PRESENT","evidence":"c.1431_1433dupAAA","abstract_start":885,"abstract_end":902}]}
{"pmid":"25416039","title":"Functional characterization of a CDKN1B mutation in a Sardinian kindred with multiple endocrine neoplasia type 4 (MEN4).","abstract":"Inactivating germline mutations of the CDKN1B gene, encoding for the nuclear cyclin-dependent kinase inhibitor p27kip1 protein, have been reported in patients with multiple endocrine neoplasia type 4 (MEN4), a MEN1-like phenotype without MEN1 mutations. The aim of this study was to in vitro characterize the germline CDKN1B mutation c.374_375delCT (S125X) we detected in a patient with MEN4. The proband was affected by multiglandular primary hyperparathyroidism and gastro-entero-pancreatic tumors. We carried out subcellular localization experiments transfecting into eukaryotic HeLa and GH3 cell lines plasmid vectors expressing the CDKN1B wild type (wt) or mutant cDNA. Western blot studies showed that fusion proteins were expressed at equal levels. The mutated protein was shorter compared to the wt protein and lacked the highly conserved C-terminal domain, which includes the bipartite nuclear localization signal at amino acids 152/153 and 166/168. In HeLa and GH3 cells wt p27 localized in the nucleus whereas the p27_S125X protein was retained in the cytoplasm predicting the loss of tumor suppressive function. The proband's tumoral parathyroid tissue did not show allelic loss, since wt and mutant alleles were both present by sequencing the somatic DNA. Immunohistochemistry showed a complete loss of nuclear p27 expression in the parathyroid adenoma removed by the patient at the second surgery. In conclusion, our study confirms the pathogenic role of the c.374_375delCT CDKN1B germline mutation in a patient with MEN4.","variants":[{"Name":"NM_004064.5(CDKN1B):c.374_375del (p.Asn124_Ser125insTer)","Chromosome":"12","Start":"12718211","Stop":"12718212","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":181499,"rule_based_match":true,"evidence_text":"c.374_375delCT","llm_judgment":"PRESENT","evidence":"c.374_375delCT","abstract_start":334,"abstract_end":348}]}
{"pmid":"25154303","title":"Whole-exome sequencing in an extended family with myocardial infarction unmasks familial hypercholesterolemia.","abstract":"BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal-dominant disease leading to markedly elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature myocardial infarction (MI). Mutation carriers display variable LDL cholesterol levels, which may obscure the diagnosis. We examined by whole-exome sequencing a family in which multiple myocardial infarctions occurred at a young age with unclear etiology.\nMETHODS: Whole-exome sequencing of three affected family members, validation of the identified variant with Sanger-sequencing, and subsequent co-segregation analysis in the family.\nRESULTS: The index patient (LDL cholesterol 188 mg/dL) was referred for molecular-genetic investigations. He had coronary artery bypass graft (CABG) at the age of 59 years; 12 out of 15 1st, 2nd and 3rd degree relatives were affected with coronary artery disease (CAD) and/or premature myocardial infarction (MI). We sequenced the whole-exome of the patient and two cousins with premature MI. After filtering, we were left with a potentially disease causing variant in the LDL receptor (LDLR) gene, which we validated by Sanger-sequencing (nucleotide substitution in the acceptor splice-site of exon 10, c.1359-1G > A). Sequencing of all family members available for genetic analysis revealed co-segregation of the variant with CAD (LOD 3.0) and increased LDLC (>190 mg/dL), following correction for statin treatment (LOD 4.3). Interestingly, mutation carriers presented with highly variable corrected (183-354 mg/dL) and on-treatment LDL levels (116-274 mg/dL) such that the diagnosis of FH in this family was made only after the molecular-genetic analysis.\nCONCLUSION: Even in families with unusual clustering of CAD FH remains to be underdiagnosed, which underscores the need for implementation of systematic screening programs. Whole-exome sequencing may facilitate identification of disease-causing variants in families with unclear etiology of MI and enable preventive treatment of mutation carriers in a more timely fashion.","variants":[{"Name":"NM_000527.5(LDLR):c.1359-1G>A","Chromosome":"19","Start":"11113534","Stop":"11113534","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":172183,"rule_based_match":true,"evidence_text":"c.1359-1G > A","llm_judgment":"PRESENT","evidence":"c.1359-1G > A","abstract_start":1231,"abstract_end":1244}]}
{"pmid":"38358893","title":"Clinical, immunohistochemical, and genetic characterization of splice-altering biallelic DES variants: Therapeutic implications.","abstract":"Pathogenic variants in the DES gene clinically manifest as progressive skeletal muscle weakness, cardiomyopathy with associated severe arrhythmias, and respiratory insufficiency, and are collectively known as desminopathies. While most DES pathogenic variants act via a dominant mechanism, recessively acting variants have also been reported. Currently, there are no effective therapeutic interventions for desminopathies of any type. Here, we report an affected individual with rapidly progressive dilated cardiomyopathy, requiring heart transplantation at age 13 years, in the setting of childhood-onset skeletal muscle weakness. We identified biallelic DES variants (c.640-13 T>A and c.1288+1 G>A) and show aberrant DES gene splicing in the affected individual's muscle. Through the generation of an inducible lentiviral system, we transdifferentiated fibroblast cultures derived from the affected individual into myoblasts and validated this system using RNA sequencing. We tested rationally designed, custom antisense oligonucleotides to screen for splice correction in these transdifferentiated cells and a functional minigene splicing assay. However, rather than correctly redirecting splicing, we found them to induce undesired exon skipping. Our results indicate that, while an individual precision-based molecular therapeutic approach to splice-altering pathogenic variants is promising, careful preclinical testing is imperative for each novel variant to test the feasibility of this type of approach for translation.","variants":[{"Name":"NM_001927.4(DES):c.1288+1G>A","Chromosome":"2","Start":"219423821","Stop":"219423821","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":650939,"rule_based_match":true,"evidence_text":"c.1288+1 G>A","llm_judgment":"PRESENT","evidence":"c.1288+1 G>A","abstract_start":687,"abstract_end":699}]}
{"pmid":"32303603","title":"Homozygous variants in","abstract":"BACKGROUND: The genetic causes of the majority of cases of female infertility caused by premature ovarian insufficiency (POI) are unknown.\nOBJECTIVE: To identify the genetic causes of POI in 110 patients.\nMETHODS: Whole-exome sequencing was performed on 110 patients with POI, and putative disease-causative variants were validated by Sanger sequencing. Bioinformatic and in vitro functional analyses were performed for functional characterisation of the identified candidate disease-causative variants.\nRESULTS: We identified two homozygous variants (NM_001040274: c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in <i>SYCP2L</i> in two patients, which had co-segregated with POI in these families. Bioinformatic analysis predicted that the two variants are deleterious, and in vitro functional analysis showed that mutant SYCP2L proteins exhibited mislocalisation and loss of function.\nCONCLUSIONS: <i>SYCP2L</i> is a novel gene found to be responsible for human POI. Our findings provide a potential molecular marker for POI and improve the understanding of the genetic basis of female infertility.","variants":[{"Name":"NM_001040274.3(SYCP2L):c.999A>G (p.Ile333Met)","Chromosome":"6","Start":"10912753","Stop":"10912753","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3396276,"rule_based_match":true,"evidence_text":"c.999A>G (p.Ile333Met)","llm_judgment":"PRESENT","evidence":"c.999A>G (p.Ile333Met)","abstract_start":597,"abstract_end":619}]}
{"pmid":"28834584","title":"A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder.","abstract":"Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system. We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder (ASD), spastic paraplegia and axonal neuropathy. The presence of ASD distinguishes this case from previously reported patients with de novo dominant mutations in KIF1A.","variants":[{"Name":"NM_001244008.2(KIF1A):c.38G>A (p.Arg13His)","Chromosome":"2","Start":"240797715","Stop":"240797715","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":205730,"rule_based_match":true,"evidence_text":"c.38G>A, p.R13H","llm_judgment":"PRESENT","evidence":"c.38G>A, p.R13H","abstract_start":416,"abstract_end":431}]}
{"pmid":"34643235","title":"Urine Organic Acid Analysis: Key Diagnostic Test for Fumaric Aciduria in a Sri Lankan Child.","abstract":"Fumaric aciduria resulting from fumarate hydratase deficiency is a rare inherited disorder of the Krebs tricarboxylic acid cycle that is characterized by neurologic manifestations, a spectrum of brain abnormalities, and the excretion of fumaric acid in urine. We describe a 3 year old Sri Lankan boy who was referred at age 10 months with poor weight gain and hypotonia for further laboratory investigations. In addition to global developmental delay, there were noticeable dysmorphic features with a prominent forehead, low-set ears, micrognathia, and hypertelorism with persistent neutropenia. Urine organic acid assay revealed a massive elevation of fumaric acid on 2 occasions. Molecular analysis revealed a homozygous likely pathogenic missense variant, NM000143.3:c.1048C>T p. (Arg350Trp), in the FH gene, confirming the biochemical diagnosis. Our patient was the first patient in Sri Lanka molecularly diagnosed with fumaric aciduria. This case study highlights the importance of performing organic acid assays in children presenting with neurologic manifestations especially when these are suspected to have a metabolic basis.","variants":[{"Name":"NM_000143.4(FH):c.1048C>T (p.Arg350Trp)","Chromosome":"1","Start":"241504102","Stop":"241504102","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":210673,"rule_based_match":true,"evidence_text":"NM000143.3:c.1048C>T p. (Arg350Trp)","llm_judgment":"PRESENT","evidence":"NM000143.3:c.1048C>T p. (Arg350Trp)","abstract_start":759,"abstract_end":794}]}
{"pmid":"29718797","title":"CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.","abstract":"BACKGROUND: CEP250 encodes the C-Nap1 protein which belongs to the CEP family of proteins. C-Nap1 has been reported to be expressed in the photoreceptor cilia and is known to interact with other ciliary proteins. Mutations of CEP250 cause atypical Usher syndrome which is characterized by early-onset sensorineural hearing loss (SNHL) and a relatively mild retinitis pigmentosa. This study tested the hypothesis that the mild cone-rod dystrophy (CRD) and SNHL in a non-consanguineous Japanese family was caused by CEP250 mutations.\nMETHODS: Detailed ophthalmic and auditory examinations were performed on the proband and her family members. Whole exome sequencing (WES) was used on the DNA obtained from the proband.\nRESULTS: Electrophysiological analysis revealed a mild CRD in two family members. Adaptive optics (AO) imaging showed reduced cone density around the fovea. Auditory examinations showed a slight SNHL in both patients. WES of the proband identified compound heterozygous variants c.361C>T, p.R121*, and c.562C>T, p.R188* in CEP250. The variants were found to co-segregate with the disease in five members of the family.\nCONCLUSIONS: The variants of CEP250 are both null variants and according to American College of Medical Genetics and Genomics (ACMG) standards and guideline, these variants are classified into the very strong category (PVS1). The criteria for both alleles will be pathogenic. Our data indicate that mutations of CEP250 can cause mild CRD and SNHL in Japanese patients. Because the ophthalmological phenotypes were very mild, high-resolution retinal imaging analysis, such as AO, will be helpful in diagnosing CEP250-associated disease.","variants":[{"Name":"NM_007186.6(CEP250):c.361C>T (p.Arg121Ter)","Chromosome":"20","Start":"35466073","Stop":"35466073","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":612045,"rule_based_match":true,"evidence_text":"c.361C>T, p.R121*","llm_judgment":"PRESENT","evidence":"c.361C>T, p.R121*","abstract_start":996,"abstract_end":1013},{"Name":"NM_007186.6(CEP250):c.562C>T (p.Arg188Ter)","Chromosome":"20","Start":"35467035","Stop":"35467035","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":612046,"rule_based_match":true,"evidence_text":"c.562C>T, p.R188*","llm_judgment":"PRESENT","evidence":"c.562C>T, p.R188*","abstract_start":1019,"abstract_end":1036}]}
{"pmid":"26428751","title":"Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia.","abstract":"BACKGROUND: Beukes hip dysplasia (BHD) is an autosomal dominant disorder of variable penetrance that was originally identified in a large South African family of European origin. BHD is characterised by bilateral dysmorphism of the proximal femur, which results in severe degenerative osteoarthropathy. Previous studies mapped the disorder to a 3.34 Mb region on chromosome 4q35.\nOBJECTIVE: To fine-map the BHD locus and identify the disease-causing mutation by direct sequencing.\nRESULTS: The linked BHD allele was refined to 1.33 Mb, reducing the number of candidate genes from 25 to 16. Analysis of protein coding and invariant splice-site sequences in three distantly related individuals identified a single-candidate disease-causing variant c.868T>C within exon 8 of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 gene, UFSP2. The presence of this unique mutation was confirmed in all 17 affected members of the BHD family who were genotyped. The mutation segregated with the BHD phenotype in the extended family with a two-point (single marker) LOD score of 10.4 (θ=0.0 and 80% penetrance). The mutation predicts the substitution of a highly conserved amino acid, p.Tyr290His, in the encoded protein. In vitro functional assays performed using purified recombinant wild-type and mutant UFSP2 protein demonstrated that the BHD mutation abolishes UFSP2-mediated C-terminal cleavage of its substrate, Ufm1.\nCONCLUSION: We report a unique UFSP2 mutation that segregates with the BHD phenotype. The predicted amino acid substitution inactivates UFSP2 proteolytic function, thus implicating the ubiquitin-fold modifier 1 cascade in this form of severe hip osteoarthropathy. The facile polymerase chain reaction-based assay we describe could be used to confirm the diagnosis of BHD, or for presymptomatic testing of members of the extended BHD family.","variants":[{"Name":"NM_018359.5(UFSP2):c.868T>C (p.Tyr290His)","Chromosome":"4","Start":"185408399","Stop":"185408399","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":201007,"rule_based_match":true,"evidence_text":"c.868T>C","llm_judgment":"PRESENT","evidence":"c.868T>C","abstract_start":746,"abstract_end":754}]}
{"pmid":"33691324","title":"Atypical Clinical Presentation of Persistent Müllerian Duct Syndrome in Siblings.","abstract":"Persistent Müllerian duct syndrome (PMDS) is a rare autosomal recessive disorder characterized by the lack of regression of the derivatives of the Müllerian ducts in males. Boys with this condition usually present with unilateral or bilateral cryptorchidism, inguinal hernias, and reproductive disorders with normal male genitalia. Variants in the AMH or AMHR2 genes are responsible for the development of this syndrome. The genetic diagnosis and surgery in PMDS is challenging for both the endocrinologist and the urologist. Here, we describe the management of 2 siblings from 1 family who presented with bilateral cryptorchidism and hypospadias at birth. One child had testis located in the pelvis in the position of normal ovaries, while the other child had testis which were located in the inguinal canals (bilateral inguinal cryptorchidism). Exome sequencing revealed a compound heterozygous variant in the AMHR2 gene c.1388G>A, p.R463H and c.1412G>A p.R471H. To our knowledge, hypospadias has not been described in association with PMDS.","variants":[{"Name":"NM_020547.3(AMHR2):c.1412G>A (p.Arg471His)","Chromosome":"12","Start":"53430269","Stop":"53430269","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3043352,"rule_based_match":true,"evidence_text":"c.1412G>A p.R471H","llm_judgment":"PRESENT","evidence":"c.1412G>A p.R471H","abstract_start":946,"abstract_end":963}]}
{"pmid":"38204953","title":"A novel nonsense mutation in the fumarate hydratase gene in a Chinese patient with recurrent leiomyomas.","abstract":"Objective: To describe a novel nonsense mutation in the fumarate hydratase (FH) gene in a Chinese patient with recurrent multiple leiomyomas.\nDesign: Case report.\nSetting: Medical school-affiliated tertiary hospital.\nPatients: A nulligravida patient aged 30 years with large uterine leiomyomas (ULMs) and severe anemia.\nInterventions: Clinical evaluation, abdominal myomectomy, targeted next-generation sequencing.\nMain outcome measures: Fumarate hydratase gene mutation in ULMs.\nResults: A novel nonsense mutation (c.771T>G) in the <i>FH</i> gene was identified in this patient. This mutation is located in exon 6, which encodes the N-terminal fumarate lyase domain. It leads to a predicted truncated protein with loss of the majority of the lyase domain, resulting in FH deficiency.\nConclusions: Because of the recurrent multiple leiomyomas, this patient received 2 myomectomies within 5 years. On immunostaining the leiomyoma, FH deficiency was detected, and targeted next-generation sequencing revealed a novel mutation of the <i>FH</i> gene. This patient was at risk for early disease relapse and developing renal cancer, and close disease monitoring is recommended. Meanwhile, the expanded mutation database should benefit patients in diagnosing <i>FH</i> gene-associated ULMs.","variants":[{"Name":"NM_000143.4(FH):c.771T>G (p.Tyr257Ter)","Chromosome":"1","Start":"241506136","Stop":"241506136","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2979428,"rule_based_match":true,"evidence_text":"c.771T>G","llm_judgment":"PRESENT","evidence":"c.771T>G","abstract_start":516,"abstract_end":524}]}
{"pmid":"28257693","title":"Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly.","abstract":"In two independent consanguineous families each with two children affected by mild intellectual disability and microcephaly, we identified two homozygous missense variants (c.119T>A [p.Met40Lys] and c.92T>A [p.Leu31His]) in TATA-box-binding-protein-associated factor 13 (TAF13). Molecular modeling suggested a pathogenic effect of both variants through disruption of the interaction between TAF13 and TAF11. These two proteins form a histone-like heterodimer that is essential for their recruitment into the general RNA polymerase II transcription factor IID (TFIID) complex. Co-immunoprecipitation in HeLa cells transfected with plasmids encoding TAF11 and TAF13 revealed that both variants indeed impaired formation of the TAF13-TAF11 heterodimer, thus confirming the protein modeling analysis. To further understand the functional role of TAF13, we performed RNA sequencing of neuroblastoma cell lines upon TAF13 knockdown. The transcriptional profile showed significant deregulation of gene expression patterns with an emphasis on genes related to neuronal and skeletal functions and those containing E-box motives in their promoters. Here, we expand the spectrum of TAF-associated phenotypes and highlight the importance of TAF13 in neuronal functions.","variants":[{"Name":"NM_005645.4(TAF13):c.119T>A (p.Met40Lys)","Chromosome":"1","Start":"109066220","Stop":"109066220","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":362616,"rule_based_match":true,"evidence_text":"c.119T>A [p.Met40Lys]","llm_judgment":"PRESENT","evidence":"c.119T>A [p.Met40Lys]","abstract_start":173,"abstract_end":194},{"Name":"NM_005645.4(TAF13):c.92T>A (p.Leu31His)","Chromosome":"1","Start":"109075001","Stop":"109075001","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":362617,"rule_based_match":true,"evidence_text":"c.92T>A (p.Leu31His)","llm_judgment":"PRESENT","evidence":"p.Leu31His","abstract_start":208,"abstract_end":218}]}
{"pmid":"31320686","title":"Identification of a missense variant in CLDN2 in obstructive azoospermia.","abstract":"Obstructive azoospermia (OA), defined as an obstruction in any region of the male genital tract, accounts for 40% of all azoospermia cases. Of all OA cases, ~30% are thought to have a genetic origin, however, hitherto, the underlying genetic etiology of the majority of these cases remain unknown. To address this, we took a family-based whole-exome sequencing approach to identify causal variants of OA in a multiplex family with epidydimal obstruction. A novel gain-of-function missense variant in CLDN2 (c.481G>C; p.Gly161Arg) was found to co-segregate with the phenotype, consistent with the X-linked inheritance pattern observed in the pedigree. To assess the pathogenicity of this variant, the wild and mutant protein structures were modeled and their potential for strand formation in multimeric form was assessed and compared. The results showed that dimeric and tetrameric arrangements of Claudin-2 were not only reduced, but were also significantly altered by this single residue change. We, therefore, envisage that this amino acid change likely forms a polymeric discontinuous strand, which may lead to the disruption of tight junctions among epithelial cells. This missense variant is thus likely to be responsible for the disruption of the blood-epididymis barrier, causing dislodged epithelial cells to clog the genital tract, hence causing OA. This study not only sheds light on the underlying pathobiology of OA, but also provides a basis for more efficient diagnosis in the clinical setting.","variants":[{"Name":"NM_020384.4(CLDN2):c.481G>C (p.Gly161Arg)","Chromosome":"X","Start":"106928709","Stop":"106928709","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":481525,"rule_based_match":true,"evidence_text":"c.481G>C; p.Gly161Arg","llm_judgment":"PRESENT","evidence":"c.481G>C; p.Gly161Arg","abstract_start":507,"abstract_end":528}]}
{"pmid":"36302598","title":"Long-Read Sequencing Identifies Novel Pathogenic Intronic Variants in Gitelman Syndrome.","abstract":"BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3 , which encodes the Na + -Cl - cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield.\nMETHODS: Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants.\nRESULTS: A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C>T variant and intronic candidate variants demonstrated aberrant splicing patterns.\nCONCLUSION: Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1670-191C>T","Chromosome":"16","Start":"56883858","Stop":"56883858","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":652576,"rule_based_match":true,"evidence_text":"c.1670-191C>T","llm_judgment":"PRESENT","evidence":"c.1670-191C>T","abstract_start":1377,"abstract_end":1390}]}
{"pmid":"16498234","title":"A PTPN11 gene mutation (Y63C) causing Noonan syndrome is not associated with short stature in general population.","abstract":"Human growth is a highly complicated process, but it is obviously influenced by a genetic factor. Recent genome-wide linkage analyses suggested some genetic regions underlying stature variations. However, any specific genes underlying stature variations have not been identified. Noonan syndrome (NS) is an autosomal dominant disorder clinically characterized by short stature, minor facial anomalies, and congenital heart defects. Recently, PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) has been identified as a major responsible gene for NS, causing about half of the affected individuals. We herein report a large family demonstrating NS caused by one of the common PTPN11 mutations, c.188 A > G (Y63C). In this family, the patients were apparently healthy, but heterozygosity of the c.188 A > G (Y63C) mutation was related to growth impairment. This finding suggested that PTPN11 genetic variants contribute to adult height in the general population. However, c.188 A > G (Y63C) was not identified in 96 short individuals from the general population of 2,281 healthy adults. Thus, it is unlikely that PTPN11 is one of the genes underlying stature variations in the general population.","variants":[{"Name":"NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)","Chromosome":"12","Start":"112450368","Stop":"112450368","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28372,"rule_based_match":true,"evidence_text":"c.188 A > G (Y63C)","llm_judgment":"PRESENT","evidence":"c.188 A > G (Y63C)","abstract_start":700,"abstract_end":718}]}
{"pmid":"21360064","title":"Identification of de novo germline mutations in the HRPT2 gene in two apparently sporadic cases with challenging parathyroid tumor diagnoses.","abstract":"The diagnosis of parathyroid carcinomas is often difficult. HRPT2 mutations have been identified in familial [hyperparathyroidism-jaw tumor (HPT-JT) syndrome] and sporadic parathyroid carcinomas, supporting that HRPT2 mutations may confer a malignant potential to parathyroid tumors. In this study, we report the clinical, histopathological, and genetic investigation of two unrelated cases, whom had apparently sporadic malignant parathyroid tumors, initially diagnosed as adenomas. In one case, the differential diagnosis was complicated by cervical seeding of parathyroid tumor cells. Genetic studies identified de novo HRPT2 germline mutations in cases 1 (c.518_521delTGTC [p.Ser174LysfsX27]) and 2 (c.226 C > T [p.Arg76X]), unveiling the hereditary HPT-JT syndrome in both patients. Furthermore, the identification of somatic mutations in the patients‟ parathyroid tumors provided evidence for complete inactivation of the HRPT2 gene, which was consistent with the tumor malignant features. The sensitivity of parafibromin immunostaining to detect HRPT2 mutations was limited. The present data suggests that patients with apparently sporadic parathyroid carcinomas, or parathyroid tumors with atypical histological features, should undergo molecular genetic testing, as it may detect germline HRPT2 mutations. Establishing the diagnosis of hereditary HPT-JT syndrome is relevant for clinical counseling and management of the carriers and their relatives.","variants":[{"Name":"NM_024529.5(CDC73):c.226C>T (p.Arg76Ter)","Chromosome":"1","Start":"193125206","Stop":"193125206","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":263993,"rule_based_match":true,"evidence_text":"c.226 C > T [p.Arg76X]","llm_judgment":"PRESENT","evidence":"c.226 C > T [p.Arg76X]","abstract_start":704,"abstract_end":726}]}
{"pmid":"37827496","title":"Biochemical and biophysical properties of a rare TTRA81V mutation causing mild transthyretin amyloid cardiomyopathy.","abstract":"AIMS: We conducted a presentation on an 84-year-old male patient who has been diagnosed with TTRA81V (p. TTRA101V) hereditary transthyretin cardiac amyloidosis (hATTR-CM). In order to establish its pathogenicity, we extensively investigated the biochemical and biophysical properties of the condition.\nMETHODS AND RESULTS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly acknowledged progressive infiltrative cardiomyopathy that leads to heart failure and potentially fatal arrhythmias. Gaining a comprehensive understanding of the biochemical and biophysical characteristics of genetically mutated TTR proteins serves as the fundamental cornerstone for delivering precise medical care to individuals affected by ATTR. Laboratory assessments indicated a brain natriuretic peptide of 200.12 ng/L (normal range: 0-100 ng/L) and high-sensitivity cardiac troponin I of 0.189 μg/L (normal range: 0-0.1 μg/L). Echocardiography identified left atrial enlargement, symmetrical left ventricular hypertrophy (16 mm septal and 16 mm posterior wall), and a left ventricular ejection fraction of 56%. Cardiac-enhanced magnetic resonance imaging revealed subendocardial late gadolinium enhancement. Tc-99m-PYP nuclear scintigraphy confirmed grade 3 myocardial uptake, showing an increased heart-to-contralateral ratio (H/CL = 2.33). Genetic testing revealed a heterozygous missense mutation in the TTR gene (c.302C>T), resulting in an alanine-to-valine residue change (p. Ala81Val, following the first 20 residues of signal sequence nomenclature). Biochemical analysis of this variant displayed compromised kinetic stability in both the TTRA81V:WT (wild-type) heterozygote protein (half-life, t<sub>1/2</sub>  = 21 h) and the TTRA81V homozygote protein (t<sub>1/2</sub>  = 17.5 h). The kinetic stability fell between that of the TTRWT (t<sub>1/2</sub>  = 42 h) and the early-onset TTRL55P mutation (t<sub>1/2</sub>  = 4.4 h), indicating the patient's late-onset condition. Kinetic stabilizers (Tafamidis, Diflunisal, and AG10) all exhibited the capacity to inhibit TTRA81V acid- and mechanical force-induced fibril formation, albeit less effectively than with TTRWT. Chromatographic assessment of the patient's serum TTR tetramers indicated a slightly lower concentration (3.0 μM) before oral administration of Tafamidis compared with the normal range (3.6-7.2 μM).\nCONCLUSIONS: We identified a patient with hATTR-CM who possesses a rare TTRA81V mutation solely associated with cardiac complications. The slightly reduced kinetic stability of this mutation indicates its late-onset nature and contributes to the gradual progression of the disease.","variants":[{"Name":"NM_000371.4(TTR):c.302C>T (p.Ala101Val)","Chromosome":"18","Start":"31595221","Stop":"31595221","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":488022,"rule_based_match":true,"evidence_text":"c.302C>T","llm_judgment":"PRESENT","evidence":"c.302C>T","abstract_start":1412,"abstract_end":1420}]}
{"pmid":"30669781","title":"Study on spectrum of UGT1A1 mutations in connection with inherited non-hemolytic unconjugated hyperbilirubinemia","abstract":"<b>Objective:</b> To compare and analyze patient's general condition, changes in laboratory parameters, and the spectrum of UGT1A1 mutations in patients with inherited non-hemolytic unconjugated hyperbilirubinemia. <b>Methods:</b> A retrospective study was conducted at Nanjing Second Hospital from January 2015 to July 2018 and patients' demographic characteristics, liver function test, and UGT1A1 gene were analyzed. The categorical variable data were compared by <i>χ</i> (2) test. The normal distribution continuous variable data were compared by t-test and the non-normal distribution continuous variable data were compared using Mann-Whitney U test. <b>Results:</b> Of the 51 patients with inherited non-hemolytic unconjugated hyperbilirubinemia, 44 (86.3%) were Gilbert's syndrome (GS) and seven (13.7%) were Crigler-Najjar syndrome type II (CNS- II). The male to female ratio was 2.9:1 and the average age was 36.11 ± 13.17 years. Six variant types were detected: C. -40_-39insTA, C. -3279T > G, c.211G > A (p.G71R), c.686C > A (p.P229Q), c.1091C > T (p.P364L), c.1456T > G (P.Y486D). Among them, c.211G > A accounted for 58.82% (30/51), c.-40_-39insTA accounted for 27.5% (14/51), and c.1456T > G accounted for 25.5% (13/51). The total bilirubin(TB) and unconjugated bilirubin (UCB) in CNS-II patients were significantly higher than GS patients[155.91 (130 ~ 207) vs. 38.25(29 ~ 52.15) μmol/L, <i>U</i> = 0, <i>P</i> < 0.01; 144.13 (120.8 ~ 197) vs. 30.00 (21.7 ~ 46.75) μmol/L, <i>U</i> = 0.00, <i>P</i> < 0.01, respectively]. Exon mutations of c.1091C > T and c.1456T > G were statistically significant(<i>P</i> < 0.01).There were no differences in age, TB, UCB, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) between the c.211G > A homozygous variants and heterozygous variants (<i>P</i> > 0.05). <b>Conclusion:</b> The common pathogenic mutations of UGT1A1 gene were c.211G > A, c.-40_-39insTA, c.1456T > G. c.211G > A. The mutation has little effect on the level of total bilirubin, but c.1091C > T, c.1456T > G mutations has great influence on the level of total bilirubin.","variants":[{"Name":"NM_000463.3(UGT1A1):c.1091C>T (p.Pro364Leu)","Chromosome":"2","Start":"233768226","Stop":"233768226","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":206952,"rule_based_match":true,"evidence_text":"c.1091C > T (p.P364L)","llm_judgment":"PRESENT","evidence":"c.1091C > T (p.P364L)","abstract_start":1048,"abstract_end":1069}]}
{"pmid":"36156392","title":"Newborn screening for Fabry disease in Oregon: Approaching the iceberg of A143T and variants of uncertain significance.","abstract":"Fabry disease newborn screening (NBS) has been ongoing in Oregon for over 41 months by first-tier enzyme quantitation and second-tier DNA testing. During that period the majority of abnormal referrals received (34/60) were for the presence of the controversial c.427G > A (p.Ala143Thr) aka A143T and the majority of non-A143T referrals were for other variants of uncertain significance (17/60) resulting in at least 32 infants with an inconclusive case outcome even after clinical evaluation and/or diagnostic testing. To date there has been no significant family history or onset of symptoms in individuals with an inconclusive outcome. Based on our experience, we have developed a framework for approaching A143T and other variants of uncertain clinical significance in an attempt to balance sensitivity with the unnecessary medicalization of healthy infants.","variants":[{"Name":"NM_000169.3(GLA):c.427G>A (p.Ala143Thr)","Chromosome":"X","Start":"101401752","Stop":"101401752","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25787,"rule_based_match":true,"evidence_text":"c.427G > A (p.Ala143Thr)","llm_judgment":"PRESENT","evidence":"c.427G > A (p.Ala143Thr)","abstract_start":261,"abstract_end":285}]}
{"pmid":"28216420","title":"Evaluation of RAG1 mutations in an adult with combined immunodeficiency and progressive multifocal leukoencephalopathy.","abstract":"Here we describe novel mutations in recombination activation gene 1 (RAG1) in a compound heterozygous male patient with combined T and B cell immunodeficiency (CID). Clinical manifestations besides antibody deficiency included airway infections, granulomatosis and autoimmune features. He died at the age of 37 due to PML caused by JC virus infection. By targeted next-generation sequencing we detected post mortem in this patient three mutations in RAG1. One allele harbored two novel mutations (c.1123C>G, p.H375D and c.1430delC, p.F478Sfs*14), namely a missense variant and a frameshift deletion, of which the latter leads to a truncated RAG1 protein. The other allele revealed a previously described missense mutation (c.1420C>T, p.R474C, rs199474678). Functional analysis of the p.R474C variant in an in vitro V(D)J recombination assay exhibited reduced recombination activity compared to a wild-type control. Our findings suggest that mutations in RAG1, specifically the p.R474C variant, can be associated with relatively mild clinical symptoms or delayed occurrence of T cell and B cell deficiencies but may predispose to PML.","variants":[{"Name":"NM_000448.3(RAG1):c.1123C>G (p.His375Asp)","Chromosome":"11","Start":"36574427","Stop":"36574427","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1437993,"rule_based_match":true,"evidence_text":"c.1123C>G, p.H375D","llm_judgment":"PRESENT","evidence":"c.1123C>G, p.H375D","abstract_start":497,"abstract_end":515},{"Name":"NM_000448.3(RAG1):c.1420C>T (p.Arg474Cys)","Chromosome":"11","Start":"36574724","Stop":"36574724","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":79575,"rule_based_match":true,"evidence_text":"c.1420C>T (p.R474C, rs199474678)","llm_judgment":"PRESENT","evidence":"c.1420C>T","abstract_start":723,"abstract_end":732}]}
{"pmid":"31934343","title":"Normal early development in siblings with novel compound heterozygous variants in","abstract":"Autosomal recessive primary microcephaly 5 (MCPH5) is caused by pathogenic variants in <i>ASPM</i>. Using whole-exome sequencing, we diagnosed two siblings with MCPH5. A known pathogenic variant (NM_018136.4: c.9697C > T, p.(Arg3233*)) and a novel pathogenic variant (c.1402_1406del, p.(Asn468Serfs*2)) of <i>ASPM</i> were identified in affected siblings with normal intelligence. Their pathogenic variants were not located in the critical regions of <i>ASPM</i>, but the relationship between the genotypes and their normal intelligence was unclear.","variants":[{"Name":"NM_018136.5(ASPM):c.9697C>T (p.Arg3233Ter)","Chromosome":"1","Start":"197090328","Stop":"197090328","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34486,"rule_based_match":true,"evidence_text":"NM_018136.4: c.9697C > T, p.(Arg3233*)","llm_judgment":"PRESENT","evidence":"NM_018136.4: c.9697C > T, p.(Arg3233*)","abstract_start":196,"abstract_end":234}]}
{"pmid":"30892814","title":"Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP.","abstract":"CREBBP loss-of function variants cause Rubinstein-Taybi syndrome (RTS). There have been two separate reports of patients with missense variants in exon 30 or 31 of CREBBP in individuals lacking the characteristic facial and limb dysmorphism associated with RTS. Frequent features in this condition include variable intellectual disability, short stature, autistic behavior, microcephaly, feeding problems, epilepsy, recurrent upper airway infections, and mild hearing impairment. We report three further patients with de novo exon 31 CREBBP missense variants. The first individual has a c.5357G>A p. (Arg1786His) variant affecting the same codon as one of the previously described patients. Both these patients could be recognized by clinicians as mild RTS. Our second patient has a c.5602C>T p.(Arg1868Trp) variant that has been described in five other individuals who all share a strikingly similar phenotype. The third individual has a novel c.5354G>A p.(Cys1785Try) variant. Our reports expand the clinical spectrum to include ventriculomegaly, absent corpus callosum, staphyloma, cochlear malformations, and exomphalos. These additional cases also help to establish genotype-phenotype correlations in this disorder. After the first and last authors of the previous two reports, we propose to call this disorder \"Menke-Hennekam syndrome\" to establish it as a clinical entity distinct from RTS and to provide a satisfactory name for adoption by parents and professionals, thus facilitating appropriate clinical management and research.","variants":[{"Name":"NM_004380.3(CREBBP):c.5602C>T (p.Arg1868Trp)","Chromosome":"16","Start":"3729445","Stop":"3729445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260116,"rule_based_match":true,"evidence_text":"c.5602C>T p.(Arg1868Trp)","llm_judgment":"PRESENT","evidence":"c.5602C>T p.(Arg1868Trp)","abstract_start":783,"abstract_end":807}]}
{"pmid":"27014572","title":"Successful therapy for protein-losing enteropathy caused by chronic neuronopathic Gaucher disease.","abstract":"Gaucher disease (OMIM #230800) is caused by β-glucosidase deficiency and primarily involves the mononuclear phagocyte system (also called Reticuloendothelial System or Macrophage System). The disease is classified into three main phenotypes based on the presence or absence of neurological manifestations: non-neuronopathic (type 1), acute neuronopathic (type 2) and chronic neuronopathic (type 3). Typical manifestations include hepatosplenomegaly, skeletal deformities, hematological abnormalities, interstitial lung fibrosis and neurodegeneration in neuronopathic cases. Mesenteric lymphadenopathy with resultant protein losing enteropathy (PLE) has only been rarely described. Mesenteric lymphadenopathy may lead to intestinal lymphatic obstruction and secondary lymphangiectasia resulting in chronic diarrhea, abdominal pain and weight loss. Fecal protein loss with secondary hypoalbuminemia can be significant. We report a male with Chronic Neuronopathic Gaucher disease (GD) (homozygous for c.1448T > C (NM_000157.3) GBA mutation) who at 16 years of age developed intractable abdominal pain, diarrhea and weight loss. This was caused by PLE secondary to intestinal lymphangiectasia caused by calcified mesenteric lymphadenopathy despite prior long term enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). His older similarly affected sister who had been receiving treatment with ERT and/or SRT remains stable on these treatments with no evidence of mesenteric lymphadenopathy. Medical management with total parenteral nutrition, daily medium chain triglyceride-oil (MCT) supplementation, low dose oral budesonide, continued oral SRT and an increased dose of parenteral ERT has stabilized his condition with resolution of the gastrointestinal symptoms and appropriate weight gain.","variants":[{"Name":"NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)","Chromosome":"1","Start":"155235252","Stop":"155235252","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19327,"rule_based_match":true,"evidence_text":"c.1448T > C (NM_000157.3)","llm_judgment":"PRESENT","evidence":"c.1448T > C (NM_000157.3)","abstract_start":998,"abstract_end":1023}]}
{"pmid":"26372199","title":"Hereditary Persistence of Fetal Hemoglobin Caused by Single Nucleotide Promoter Mutations in Sickle Cell Trait and Hb SC Disease.","abstract":"Hereditary persistence of fetal hemoglobin (HPFH) can be caused by point mutations in the γ-globin gene promoters. We report three rare cases: a child compound heterozygous for Hb S (HBB: c.20A > T) and HPFH with a novel point mutation in the (A)γ-globin gene promoter who had 42.0% Hb S, 17.0% Hb A and 38.0% Hb F; a man with Hb SC (HBB: c.19G > A) disease and a point mutation in the (G)γ-globin gene promoter who had 54.0% Hb S, 18.0% Hb C and 25.0% Hb F; a child heterozygous for Hb S and HPFH due to mutations in both the (A)γ- and (G)γ-globin gene promoters in cis [(G)γ(A)γ(β(+)) HPFH], with 67.0% Hb A, 6.5% Hb S and 25.0% Hb F.","variants":[{"Name":"NM_000518.5(HBB):c.20A>T (p.Glu7Val)","Chromosome":"11","Start":"5227002","Stop":"5227002","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":30372,"rule_based_match":true,"evidence_text":"HBB: c.20A > T","llm_judgment":"PRESENT","evidence":"HBB: c.20A > T","abstract_start":183,"abstract_end":197},{"Name":"NM_000518.4(HBB):c.19G>A (p.Glu7Lys)","Chromosome":"11","Start":"5227003","Stop":"5227003","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30165,"rule_based_match":true,"evidence_text":"HBB: c.19G > A","llm_judgment":"PRESENT","evidence":"HBB: c.19G > A","abstract_start":334,"abstract_end":348}]}
{"pmid":"36984475","title":"Association of Homozygous","abstract":"<i>Background and Objectives</i>: Combined pituitary hormone deficiency (CPHD) is a rare heterogeneous disease. It is characterized by the deficiency of growth hormone (GH) and shortage of at least one or more other hormones of the pituitary gland including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin. Rare pathogenic variants in nearly 30 genes have been identified as an underlying cause of CPHD pathogenicity. Among these genes, paired-like homeobox 1 (<i>PROP1</i>) has been reported to be the most common cause of CPHD. <i>Materials and Methods</i>: In the present study, we investigated a large family of Saudi origin with three adult sisters suffering from short stature in combination of secondary amenorrhea. <i>Results</i>: Whole-exome sequencing followed by Sanger sequencing shows a homozygous missense variant (NM_006261.5; c.211C > T; p.R71C) in the <i>PROP1</i> gene segregating with the disease phenotype within the family. In silico analysis studies show that this variant is highly conserved among several orthologues and is predicted as likely pathogenic using various bioinformatics tools. <i>Conclusions</i>: Our finding presents the first Saudi familial case of autosomal recessive form of CPHD caused by the <i>PROP1</i> variant.","variants":[{"Name":"NM_006261.5(PROP1):c.211C>T (p.Arg71Cys)","Chromosome":"5","Start":"177994237","Stop":"177994237","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2835215,"rule_based_match":true,"evidence_text":"NM_006261.5; c.211C > T; p.R71C","llm_judgment":"PRESENT","evidence":"NM_006261.5; c.211C > T; p.R71C","abstract_start":892,"abstract_end":923}]}
{"pmid":"23509889","title":"Acute lymphoblastic leukemia in early childhood as the presenting sign of ataxia-telangiectasia variant.","abstract":"Ataxia-telangiectasia (A-T), an autosomal recessive disorder is characterized by progressive neurodegeneration, immunodeficiency, sensitivity to ionizing radiation, and predisposition to cancer, especially to lymphoid malignancies. A-T variant is characterized by a milder clinical phenotype and is caused by missense or leaky splice site mutations that produce residual ataxia telangiectasia mutated (ATM) kinase activity. Lymphoid malignancy can precede the diagnosis of A-T, particularly in young children with mild neurological symptoms. We studied a consanguineous family with four A-T variant patients, three of them developed T-ALL at a young age before the diagnosis of A-T was established. ATM mutation analysis detected two new missense mutations both within exon 12: c.1514T>C and c.1547T>C. All four patients are homozygous for the two mutations, while their parents are heterozygous for the mutations. ATM protein level was low in all patients and the response to the radiomimetic agent, neocarzinostatin, was reduced. Leukemic presentation in a young age in three members of consanguineous family led to the identification of a new missense mutation in the ATM gene. The diagnosis of A-T or A-T variant should be considered in children with neurological abnormalities who develop T-ALL at a young age.","variants":[{"Name":"NM_000051.4(ATM):c.1514T>C (p.Phe505Ser)","Chromosome":"11","Start":"108250979","Stop":"108250979","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":810251,"rule_based_match":true,"evidence_text":"c.1514T>C","llm_judgment":"PRESENT","evidence":"c.1514T>C","abstract_start":778,"abstract_end":787},{"Name":"NM_000051.4(ATM):c.1547T>C (p.Leu516Ser)","Chromosome":"11","Start":"108251012","Stop":"108251012","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":183150,"rule_based_match":true,"evidence_text":"c.1547T>C","llm_judgment":"PRESENT","evidence":"c.1547T>C","abstract_start":792,"abstract_end":801}]}
{"pmid":"29230161","title":"A Homozygous Missense Variant in","abstract":"Joubert syndrome and related disorders (JSRD; ORPHA 140874) is a complex set of neurodevelopmental disorders with multiple organ involvement. JSRD is a type of ciliopathy which is caused by the presence of defective primary cilia in an individual. JSRD is commonly inherited in an autosomal recessive pattern, and more than 23 genes are known to be associated with JSRD. We report a novel homozygous mutation identified in the <i>INPP5E</i> gene, c.1303C>T, which leads to a change of an amino acid from arginine to tryptophan at residue 435 in the protein chain. In silico analysis indicates that p.Arg435Trp substitution affects the functionality of the protein product of the gene. Our result adds to the growing body of evidences that underlines the clinical utility of next-generation sequencing in the diagnosis of a genetic disorder when clinical features are inconclusive.","variants":[{"Name":"NM_019892.6(INPP5E):c.1303C>T (p.Arg435Trp)","Chromosome":"9","Start":"136432563","Stop":"136432563","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":362277,"rule_based_match":true,"evidence_text":"c.1303C>T","llm_judgment":"PRESENT","evidence":"c.1303C>T","abstract_start":447,"abstract_end":456}]}
{"pmid":"25884655","title":"PTPN11 mutation manifesting as LEOPARD syndrome associated with hypertrophic plexi and neuropathic pain.","abstract":"BACKGROUND: LEOPARD syndrome (LS) belongs to the family of neuro-cardio-facio-cutaneous syndromes, which include Neurofibromatosis-1 (NF1), Noonan syndrome, Costello Syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair and Legius syndrome. These conditions are caused by mutations in genes encoding proteins involved in the RAS-MAPK cellular pathway. Clinical heterogeneity and phenotype overlaps across those different syndromes is already recognized.\nCASE PRESENTATION: We hereby report a heterozygous de novo mutation in the PTPN11 gene (c.1403C > T) manifesting with a clinical picture of LS during childhood, and later development of neuropathic pain with hypertrophic plexi, which are typically observed in NF1 but have not been reported in LS.\nCONCLUSION: LS caused by PTPN11 mutations may be associated with hypertrophic roots and plexi. Consequently, clinicians should be aware of the possible development of neuropathic pain and consider specific diagnostic work-up and management.","variants":[{"Name":"NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met)","Chromosome":"12","Start":"112488466","Stop":"112488466","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28370,"rule_based_match":true,"evidence_text":"c.1403C > T","llm_judgment":"PRESENT","evidence":"c.1403C > T","abstract_start":575,"abstract_end":586}]}
{"pmid":"33413275","title":"Polyglucosan body myopathy 1 may cause cognitive impairment: a case report from China.","abstract":"BACKGROUND: Polyglucosan body myopathy 1 (PGBM1) is a type of glycogen storage disease that can cause skeletal muscle myopathy and cardiomyopathy with or without immunodeficiency due to a pathogenic mutation in the RBCK1 gene. PGBM1 has been reported in only 14 European and American families, and no cognitive impairment phenotype was reported. Its prevalence in Asia is unknown.\nCASE PRESENTATION: We report a Chinese boy with teenage onset of skeletal muscle myopathy and mild cognitive impairment. Whole-exome sequencing analysis identified a homozygous missense mutation in RBCK1 (c.1411G > A:p.Glu471Lys). A muscle biopsy indicated the accumulation of periodic acid-Schiff-positive material, which could be ubiquitinated by immunohistochemistry with an anti-ubiquitin antibody. In skeletal muscle tissue, HOIL-1 and HOIP protein levels were lower than those in the control, confirming the phenotype of an RBCK1 mutation. MRI revealed abnormal cerebral white matter signals. Immune system and cardiac examination found no abnormalities. The patient was diagnosed with PGBM1 with no effective treatment.\nCONCLUSIONS: This case from China with a novel homozygous missense mutation in RBCK1 extends the phenotypic spectrum and geographical distribution of PGBM 1, which may cause cerebral white matter changes and cognitive impairment.","variants":[{"Name":"NM_031229.4(RBCK1):c.1411G>A (p.Glu471Lys)","Chromosome":"20","Start":"429053","Stop":"429053","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":792583,"rule_based_match":true,"evidence_text":"c.1411G > A:p.Glu471Lys","llm_judgment":"PRESENT","evidence":"c.1411G > A:p.Glu471Lys","abstract_start":586,"abstract_end":609}]}
{"pmid":"27862672","title":"Clinical and genetic spectra of Charcot-Marie-Tooth disease in Chinese Han patients.","abstract":"Charcot-Marie-Tooth disease (CMT) is a common hereditary motor and sensory neuropathy. Epidemiological data for Chinese CMT patients are few. This study aimed to analyze the electrophysiological and genetic characteristics of Chinese Han patients. A total of 106 unrelated patients with the clinical diagnosis of CMT were included. Clinical examination, nerve conduction studies (NCS), next-generation sequencing (NGS), and bioinformatic analyses were performed. Genetic testing was performed for 82 patients; 27 (33%) patients carried known CMT-associated gene mutations. PMP22 duplication was detected in 10 (12%) patients and GJB1 mutations in 9 (11%) patients. The mutation rate was higher in patients with a positive family history than in the sporadic cases (50% vs. 27%, p < 0.05). Six novel CMT-associated gene mutations including BSCL2 (c.461C>T), LITAF (c.32C>G), MFN2 (c.497C>T), GARS (c.794C>T), NEFL (c.280C>T), and MPZ (c.440T>C) were discovered. All except the LITAF (c.32C>G) mutation were identified as \"disease causing\" via bioinformatic analyses. In this Chinese Han population, the frequency of PMP22 gene duplication in those with CMT1 was slightly (50% vs. 70%-80%) less than in Western/Caucasian populations. The novel CMT-associated gene mutations broaden the mutation diversity of CMT1. NGS should be considered for genetic analyses in CMT patients.","variants":[{"Name":"NM_014874.4(MFN2):c.497C>T (p.Ala166Val)","Chromosome":"1","Start":"11997319","Stop":"11997319","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":556900,"rule_based_match":true,"evidence_text":"MFN2 (c.497C>T)","llm_judgment":"PRESENT","evidence":"MFN2 (c.497C>T)","abstract_start":874,"abstract_end":889},{"Name":"NM_002047.4(GARS1):c.794C>T (p.Ser265Phe)","Chromosome":"7","Start":"30609643","Stop":"30609643","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":457766,"rule_based_match":true,"evidence_text":"c.794C>T","llm_judgment":"PRESENT","evidence":"c.794C>T","abstract_start":897,"abstract_end":905},{"Name":"NM_001122955.4(BSCL2):c.461C>T (p.Ser154Leu)","Chromosome":"11","Start":"62702493","Stop":"62702493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19583,"rule_based_match":true,"evidence_text":"BSCL2 (c.461C>T)","llm_judgment":"PRESENT","evidence":"BSCL2 (c.461C>T)","abstract_start":839,"abstract_end":855}]}
{"pmid":"18252212","title":"Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways.","abstract":"Developmental ocular malformations, including anophthalmia-microphthalmia (AM), are heterogeneous disorders with frequent sporadic or non-Mendelian inheritance. Recurrent interstitial deletions of 14q22-q23 have been associated with AM, sometimes with poly/syndactyly and hypopituitarism. We identify two further cases of AM (one with associated pituitary anomalies) with a 14q22-q23 deletion. Using a positional candidate gene approach, we analyzed the BMP4 (Bone Morphogenetic Protein-4) gene and identified a frameshift mutation (c.226del2, p.S76fs104X) that segregated with AM, retinal dystrophy, myopia, brain anomalies, and polydactyly in a family and a nonconservative missense mutation (c.278A-->G, p.E93G) in a highly conserved base in another family. MR imaging and tractography in the c.226del2 proband revealed a primary brain developmental disorder affecting thalamostriatal and callosal pathways, also present in the affected grandmother. Using in situ hybridization in human embryos, we demonstrate expression of BMP4 in optic vesicle, developing retina and lens, pituitary region, and digits strongly supporting BMP4 as a causative gene for AM, pituitary, and poly/syndactyly. Because BMP4 interacts with HH signaling genes in animals, we evaluated gene expression in human embryos and demonstrate cotemporal and cospatial expression of BMP4 and HH signaling genes. We also identified four cases, some of whom had retinal dystrophy, with \"low-penetrant\" mutations in both BMP4 and HH signaling genes: SHH (Sonic Hedgehog) or PTCH1 (Patched). We propose that BMP4 is a major gene for AM and/or retinal dystrophy and brain anomalies and may be a candidate gene for myopia and poly/syndactyly. Our finding of low-penetrant variants in BMP4 and HH signaling partners is suggestive of an interaction between the two pathways in humans.","variants":[{"Name":"NM_001202.6(BMP4):c.278A>G (p.Glu93Gly)","Chromosome":"14","Start":"53951945","Stop":"53951945","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":32740,"rule_based_match":false,"evidence_text":"c.278A-->G, p.E93G","llm_judgment":"PRESENT","evidence":"c.278A-->G, p.E93G","abstract_start":695,"abstract_end":713}]}
{"pmid":"33644825","title":"Mass spectrometry glycophenotype characterization of ALG2-CDG in Argentinean patients with a new genetic variant in homozygosis.","abstract":"Human ALG2 encodes an α 1,3mannosyltransferase that catalyzes the first steps in the synthesis of N-glycans in the endoplasmic reticulum. Variants in ALG2cause a congenital disorder of glycosylation (CDG) known as ALG2-CDG. Up to date, nine ALG2-CDG patients have been reported worldwide. ALG2-CDG is a rare autosomal recessive inherited disorder characterized by neurological involvement, convulsive syndrome of unknown origin, axial hypotonia, and mental and motor regression. In this study, we used MALDI-TOF MS to define both total serum protein and transferrin (Tf) N-glycan phenotypes in three ALG2-CDG patients carrying a c.752G > T, p.Arg251Leu ALG2 missense variant in homozygous state, as determined by exome sequencing. Comparing it to control samples, we have observed Tf under-occupancy of glycosylation site(s) typical of a defective N-glycan assembly and the occurrence of oligomannose and hybrid type N-glycans. Moreover, we have observed a slight oligomannose accumulation in total serum glyco-profiles. The increased heterogeneity of serum N-glycome in the studied patients suggests a marginal disarrangement of the glycan processing in ALG2-CDG. Previous studies reported on slightly increased concentrations of abnormal serum N-glycans in CDG-I due to defects in the mannosylation steps of dolichol-linked oligosaccharide biosynthesis. This preliminary work aims at considering serum N-glycan accumulation of high mannosylated glycoforms, such as oligomannose and hybrid type N-glycans, as potential diagnostic signals for ALG2-CDG patients.","variants":[{"Name":"NM_033087.4(ALG2):c.752G>T (p.Arg251Leu)","Chromosome":"9","Start":"99218433","Stop":"99218433","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1667578,"rule_based_match":true,"evidence_text":"c.752G > T, p.Arg251Leu","llm_judgment":"PRESENT","evidence":"c.752G > T, p.Arg251Leu","abstract_start":629,"abstract_end":652}]}
{"pmid":"16712870","title":"First report of two Taiwanese siblings with sialidosis type I: a 10-year follow-up study.","abstract":"We report the clinical features, electrophysiological findings and genetic characteristics of the first two Taiwanese siblings ever reported with sialidosis type I. We also provide a 10-year follow-up result. Enzymological analysis revealed a primary sialidase deficit. The back-averaged electroencephalography demonstrated myoclonic jerk-related cortical activities and the somatosensory evoked potential studies revealed giant cortical components. During the 10-year follow-up, the brain magnetic resonance images of the younger brother remained normal, whereas they showed mild cerebellar atrophy in the older sister. Macular cherry red spots were absent in both siblings. However, visual evoked potential revealed progressively prolonged latencies of P100 bilaterally, which was consistent with progressive deterioration of the siblings' visions. DNA analysis showed that the siblings had a homozygous missense point mutation c.544A-->G (Ser182Gly) in the exon 3 of the alpha-N-acetyl-neuraminidase (NEU1) gene. The mutation is predicted to cause a decreased sialidase activity but the mutant sialidase can still be targeted to the lysosomes, which may correlate with the mild clinical phenotypes and absent cherry red spots in the siblings.","variants":[{"Name":"NM_000434.4(NEU1):c.544A>G (p.Ser182Gly)","Chromosome":"6","Start":"31861259","Stop":"31861259","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":421584,"rule_based_match":false,"evidence_text":"c.544A-->G (Ser182Gly)","llm_judgment":"PRESENT","evidence":"c.544A-->G (Ser182Gly)","abstract_start":930,"abstract_end":952}]}
{"pmid":"24965226","title":"Bartter syndrome type 3 in an elderly complicated with adrenocorticotropin-deficiency.","abstract":"Bartter syndrome (BS) is a disorder with normotensive hypokalemic alkalosis and hyperreninemic hyperaldosteronemia. BS affects infants or early childhood. Patients with BS type 3 harbor mutation in CLCNKB, Cl channel Kb. Gitelman syndrome (GS) is a disorder in childhood, with mutation in SLC12A3. Isolated adrenocorticotropin deficiency (IAD) causes secondary adrenal insufficiency. Neither elderly cases, nor cases with IAD were previously reported in BS. A 72-year-old man was admitted with acute adrenal crisis. He had been treated for IAD for 19 years. He had no trouble during perinatal period, delivery, and growth. After the recovery from adrenal crisis, laboratory tests revealed hypokalemia; 3.0 mEq/L (normal: 3.5-4.5), impaired renal function: eGFR; 37.6 mL/min/1.73 m2, normomagnesemia; 2.1 mg/dL (1.7-2.3), hyperreninemia; 59.4 ng/mL/h (0.2-2.7), hyperaldosteronemia; 23.5 ng/dL (3.0-15.9), and normal urinary ratio of calcium/creatinine. In diuretic tests, he showed a fine response to furosemide, and a mild response to thiazide. In genetic tests, no mutation of SLC12A3 was found and homozygous mutation: c.1830 G > A in CLCNKB was shown. Thus he was diagnosed as BS type 3. Current case presented with unusual features as BS type 3, 1) his late and mild clinical manifestation suggested GS rather than BS, 2) laboratory data and diuretics tests did not show typical features as BS, and 3) IAD and chronic renal failure altered electrolyte metabolism. In conclusion, current case implies that BS type 3 should be considered even in elderly cases with normotensive hypokalemia, and highlights importance of endocrinological and genetic examinations.","variants":[{"Name":"NM_000085.5(CLCNKB):c.1830G>A (p.Trp610Ter)","Chromosome":"1","Start":"16055508","Stop":"16055508","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22638,"rule_based_match":true,"evidence_text":"c.1830 G > A","llm_judgment":"PRESENT","evidence":"c.1830 G > A","abstract_start":1122,"abstract_end":1134}]}
{"pmid":"25741866","title":"Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia.","abstract":"PURPOSE: High myopia is one of the leading causes of blindness worldwide, with high heritability. However, only a few causative genes have been identified, and the pathogenesis is still unclear. Our aim was to identify a novel causative gene in a family with autosomal-dominant, nonsyndromic high myopia.\nMETHODS: Whole-genome linkage and whole-exome sequencing were conducted on the family. Real-time quantitative polymerase chain reaction and immunoblotting were applied to test the functional consequence of the candidate mutation. Sanger sequencing was performed to screen for the candidate gene in other families or sporadic cases.\nRESULTS: A heterozygous missense mutation, c.871G>A (p.Glu291Lys), within P4HA2 was cosegregating with the phenotype in the family. The segregating mutation caused premature degradation of unstable messenger RNA. Subsequent screening for P4HA2 in 186 cases identified an additional four mutations in 5 cases, including the frameshift mutation c.1349_1350delGT (p.Arg451Glyfs*8), the nonsense mutation c.1327A>G (p.Lys443*), and two deleterious missense mutations, c.419A>G (p.Gln140Arg) and c.448A>G (p.Ile150Val). The missense mutation c.419A>G (p.Gln140Arg) was recurrently identified in a sporadic case and was segregating in a three-generation family.\nCONCLUSION: P4HA2 was identified as a novel causative gene for nonsyndromic high myopia. This study also indicated that the disruption of posttranslational modifications of collagen is an important factor in the pathogenesis of high myopia.","variants":[{"Name":"NM_001017974.2(P4HA2):c.871G>A (p.Glu291Lys)","Chromosome":"5","Start":"132209170","Stop":"132209170","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359070,"rule_based_match":true,"evidence_text":"c.871G>A (p.Glu291Lys)","llm_judgment":"PRESENT","evidence":"c.871G>A (p.Glu291Lys)","abstract_start":680,"abstract_end":702},{"Name":"NM_001017974.2(P4HA2):c.419A>G (p.Gln140Arg)","Chromosome":"5","Start":"132213966","Stop":"132213966","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":359071,"rule_based_match":true,"evidence_text":"c.419A>G (p.Gln140Arg)","llm_judgment":"PRESENT","evidence":"c.419A>G (p.Gln140Arg)","abstract_start":1101,"abstract_end":1123}]}
{"pmid":"34111619","title":"Further Delineation of the Clinical and Pathologic Features of HIKESHI-Related Hypomyelinating Leukodystrophy.","abstract":"BACKGROUND: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study.\nMETHODS: Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case.\nRESULTS: Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia.\nCONCLUSIONS: We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.","variants":[{"Name":"NM_016401.4(HIKESHI):c.160G>C (p.Val54Leu)","Chromosome":"11","Start":"86306374","Stop":"86306374","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":226737,"rule_based_match":true,"evidence_text":"c.160G>C;p.(Val54Leu)","llm_judgment":"PRESENT","evidence":"c.160G>C;p.(Val54Leu)","abstract_start":53,"abstract_end":74}]}
{"pmid":"30298486","title":"Analysis of PHEX gene mutations in three pedigrees affected with hypophosphatemic rickets","abstract":"OBJECTIVE: To explore the molecular basis for three pedigrees affected with hypophosphatemia vitamin D resistant rickets (X-linked hypophosphatemia, XLH).\nMETHODS: Peripheral blood samples from the three pedigrees were collected. Following DNA extraction, the 11 exons and flanking regions of the PHEX gene were subjected to PCR amplification and direct sequencing. Pathogenicity of identified mutations was evaluated through genotype-phenotype correlation.\nRESULTS: For pedigrees 1 and 2, pathogenic mutations were respectively identified in exon 8 (c.871C>T, p.R291X) and exon 15 (c.1601C>T, p.P534L) of the PHEX gene. For pedigree 3, a novel mutation (c.1234delA, p.S412Vfs*12) was found in exon 11 of the PHEX gene, which caused shift the reading frame and premature termination of protein translation.\nCONCLUSION: The three mutations probably account for the XLH in the affected pedigrees. The discovery of novel mutations has enriched the spectrum of PHEX gene mutations.","variants":[{"Name":"NM_000444.6(PHEX):c.871C>T (p.Arg291Ter)","Chromosome":"X","Start":"22096976","Stop":"22096976","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360620,"rule_based_match":true,"evidence_text":"c.871C>T","llm_judgment":"PRESENT","evidence":"c.871C>T","abstract_start":551,"abstract_end":559}]}
{"pmid":"31240153","title":"Genotype and phenotype classification of 29 patients affected by Krabbe disease.","abstract":"Krabbe disease is a rare neurodegenerative lysosomal storage disorder caused by mutations in the galactocerebrosidase gene, <i>GALC</i>. Krabbe disease usually affects infants, but has also been reported in older children and adults. Different phenotypes are described based on age at onset. The gene encoding the galactocerebrosidase enzyme was cloned and expressed in 1993, and up until today 117 mutations have been described. In a patient population of Northern European origin, a 30-kb deletion and two missense mutations, c.1586C>T; p.T529M and c.1700A>C; p.Y567S, are expected to account for 50%-60% of pathogenic alleles. In this study, we present information on genetic variation, enzyme activity, and phenotypes of 29 patients affected by Krabbe disease. Patient data were collected from patient files at the Department of Clinical Genetics, Rigshospitalet. Ten previously unreported mutations were identified, including four missense mutations; c.1142C>T; p.T381I, c.596G>T; p.R199M, c.443G>A; p.G148E, c.1858G>A; p.G620R, two nonsense mutations; c.863G>A; p.W288*, c.1214c>G; p.S405*, one splice site mutation; c.442+1G>A, one insertion; c.293insT and two deletions; c.1003_1004del, c.887delA. For all of the new mutations, we were able to classify them in phenotype groups. Furthermore, we present a combined allele frequency of the three frequent mutations p.T529M, p.Y567S, and the 30-kb deletion of 62%, and we describe a broadening of the phenotypes associated with the mutations p.T529M and p.Y567S.","variants":[{"Name":"NM_000153.4(GALC):c.1700A>C (p.Tyr567Ser)","Chromosome":"14","Start":"87941529","Stop":"87941529","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":186914,"rule_based_match":true,"evidence_text":"c.1700A>C; p.Y567S","llm_judgment":"PRESENT","evidence":"c.1700A>C; p.Y567S","abstract_start":551,"abstract_end":569},{"Name":"NM_000153.4(GALC):c.443G>A (p.Gly148Glu)","Chromosome":"14","Start":"87984533","Stop":"87984533","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3392947,"rule_based_match":true,"evidence_text":"c.443G>A; p.G148E","llm_judgment":"PRESENT","evidence":"c.443G>A; p.G148E","abstract_start":995,"abstract_end":1012},{"Name":"NM_000153.4(GALC):c.863G>A (p.Trp288Ter)","Chromosome":"14","Start":"87968380","Stop":"87968380","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":936757,"rule_based_match":true,"evidence_text":"c.863G>A; p.W288*","llm_judgment":"PRESENT","evidence":"c.863G>A; p.W288*","abstract_start":1058,"abstract_end":1075}]}
{"pmid":"24684806","title":"Novel missense mutation in the FH gene in familial renal cell cancer patients lacking cutaneous leiomyomas.","abstract":"BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare tumor predisposition syndrome characterized by cutaneous and uterine leiomyomas and papillary type 2 renal cell cancer. Germline mutation of the fumarate hydratase (FH) gene is known to be associated with HLRCC.\nCASE PRESENTATION: We describe a 64-year-old father and his 39-year-old son with HLRCC who developed papillary type 2 RCCs lacking cutaneous leiomyomas at any site. A common missense mutation in the FH gene, (c.1021G > A, p.D341N) in exon 7, was detected in the 2 cases. Functional prediction with the bioinformatics programs, SIFT and Polyphen-2, reported \"damaging (SIFT score 0.00)\" and \"probably damaging (PSIC score 1.621)\" values, respectively. In 162 healthy individuals, there were no cases of a G transition to any base. Finally, (c.1021G > A) in exon 7, was identified as a point mutation.\nCONCLUSION: We report a family with HLRCC in which a novel missense mutation was detected. A familial papillary type 2 renal cancer should be considered HLRCC unless typical cutaneous leiomyomas do not occur.","variants":[{"Name":"NM_000143.4(FH):c.1021G>A (p.Asp341Asn)","Chromosome":"1","Start":"241504129","Stop":"241504129","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":391128,"rule_based_match":true,"evidence_text":"c.1021G > A, p.D341N","llm_judgment":"PRESENT","evidence":"c.1021G > A, p.D341N","abstract_start":499,"abstract_end":519}]}
{"pmid":"31604776","title":"Novel biallelic variants in","abstract":"Mitochondrial disorders are caused by nuclear and mitochondrial pathogenic variants leading to defects in mitochondrial function and cellular respiration. Recently, the nuclear-encoded mitochondrial fusion gene <i>MSTO1</i> (Misato 1) has been implicated in mitochondrial myopathy and ataxia. Here we report on a 30-yr-old man presenting with a maternally inherited NM_018116.3:c.651C>G, p.F217L missense variant as well as a paternally inherited arr[GRCh37] 1q22(155581773_155706887) × 1 deletion encompassing exons 7-14 of <i>MSTO1</i> His phenotype included muscle weakness, hypotonia, early motor developmental delay, pectus excavatum, and scoliosis. Testing revealed elevated plasma creatine kinase, and electromyogram results were consistent with longstanding generalized myopathy. These phenotypic features overlap well with previously reported patients harboring biallelic <i>MSTO1</i> variants. Additionally, our patient presents with dysphagia and restrictive lung disease, not previously reported for <i>MSTO1</i>-associated disorders. The majority of patients with disease-associated variants in <i>MSTO1</i> present with biallelic variants suggesting autosomal recessive inheritance; however, one family has been reported with a single variant and presumed autosomal dominant inheritance. The pattern of inheritance we observed is consistent with the majority of previous reports suggesting an autosomal recessive disorder. We add to our knowledge of the syndrome caused by variants in <i>MSTO1</i> and provide additional evidence supporting autosomal recessive inheritance. We also describe phenotypic features not reported in previous cases, although further research is needed to confirm they are associated with defects in MSTO1.","variants":[{"Name":"NM_018116.4(MSTO1):c.651C>G (p.Phe217Leu)","Chromosome":"1","Start":"155612073","Stop":"155612073","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":672003,"rule_based_match":true,"evidence_text":"NM_018116.3:c.651C>G, p.F217L","llm_judgment":"PRESENT","evidence":"NM_018116.3:c.651C>G, p.F217L","abstract_start":366,"abstract_end":395}]}
{"pmid":"30918256","title":"Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions.","abstract":"Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O<sub>2,</sub> facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T (p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O<sub>2</sub> binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.","variants":[{"Name":"NM_005368.3(MB):c.292C>T (p.His98Tyr)","Chromosome":"22","Start":"35610910","Stop":"35610910","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":609034,"rule_based_match":true,"evidence_text":"c.292C>T (p.His98Tyr)","llm_judgment":"PRESENT","evidence":"c.292C>T (p.His98Tyr)","abstract_start":314,"abstract_end":335}]}
{"pmid":"32293802","title":"Identification of Novel EXT Mutations in Patients with Hereditary Multiple Exostoses Using Whole-Exome Sequencing.","abstract":"OBJECTIVE: To find novel potential gene mutations other than EXT1 and EXT2 mutations, to expand the mutational spectrum of EXT and to explore the correlation between clinical outcome and genotype in patients with hereditary multiple exostoses (HME).\nMETHODS: The study recruited seven families diagnosed with multiple osteochondromas (MO). Family histories and clinical information were collected in detail through comprehensive physical and image examination. Patients with deformities and functional limitations were classified as \"severe\" and the remaining without functional limitations were classified as \"mild,\" in accordance with previous study. Whole-exome sequencing (WES) was performed on a total of 13 affected individuals, 1 available unaffected relative, and 10 healthy unrelated individuals. Sanger sequencing was used to validate the screened mutations. Finally, the structural change in protein caused by pathogenic mutations was analyzed using information from the relevant database online and we attempted to correlate clinical phenotype with genotype in patients with HME.\nRESULTS: Other than EXT1 and EXT2, no novel potential gene mutations were found through WES. We identified nine heterozygous mutations in EXT1 or EXT2. Of these mutations, four have not been reported previously. These are c.996delT in exon 2 of EXT1 (family 1), c.544C > T in exon 3 of EXT2 (family 2), c.1171C > T in exon 7 of EXT2 (family 5), and c.823<sub>-</sub> 824delAA in exon 5 of EXT1 (family 7). The other five mutations have already been reported in previous works. It was surprising that we found two mutation sites, in exon 2 and exon 5, respectively, of EXT1 in 1 patient diagnosed with MO, when his father had two mutation sites, in exon 6 and exon 5, respectively, of EXT1 and EXT2 (family 4). In addition, 1 patient showed degeneration, while his father only exhibited slight symptoms (family 7). In our study, among 51 affected patients in seven families, the sex ratio (male vs female) was 58.9% (n = 30) vs 41.2% (n = 21). Male patients seemed to show more severe symptoms compared to females, but because the sample was small, we did not obtain statistically significance results.\nCONCLUSION: Whole-exome sequencing to screen pathogenic gene mutations was applied successfully. Although no third-gene mutation associated with HME was found, a total of nine mutations across EXT1 and EXT2 were identified, four of which are novel. Our results expand the mutational spectrum of EXT and can be used in genetic counseling and prenatal diagnosis for patients with MO.","variants":[{"Name":"NM_207122.2(EXT2):c.1171C>T (p.Gln391Ter)","Chromosome":"11","Start":"44130136","Stop":"44130136","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":973794,"rule_based_match":true,"evidence_text":"c.1171C > T in exon 7 of EXT2","llm_judgment":"PRESENT","evidence":"c.1171C > T in exon 7 of EXT2","abstract_start":1395,"abstract_end":1424}]}
{"pmid":"30898877","title":"Leukodystrophy-associated","abstract":"RNA polymerase III (Pol III) is an essential enzyme responsible for the synthesis of several small noncoding RNAs, a number of which are involved in mRNA translation. Recessive mutations in <i>POLR3A</i>, encoding the largest subunit of Pol III, cause POLR3-related hypomyelinating leukodystrophy (POLR3-HLD), characterized by deficient central nervous system myelination. Identification of the downstream effectors of pathogenic POLR3A mutations has so far been elusive. Here, we used CRISPR-Cas9 to introduce the <i>POLR3A</i> mutation c.2554A→G (p.M852V) into human cell lines and assessed its impact on Pol III biogenesis, nuclear import, DNA occupancy, transcription, and protein levels. Transcriptomic profiling uncovered a subset of transcripts vulnerable to Pol III hypofunction, including a global reduction in tRNA levels. The brain cytoplasmic BC200 RNA (<i>BCYRN1</i>), involved in translation regulation, was consistently affected in all our cellular models, including patient-derived fibroblasts. Genomic <i>BC200</i> deletion in an oligodendroglial cell line led to major transcriptomic and proteomic changes, having a larger impact than those of <i>POLR3A</i> mutations. Upon differentiation, mRNA levels of the <i>MBP</i> gene, encoding myelin basic protein, were significantly decreased in <i>POLR3A</i>-mutant cells. Our findings provide the first evidence for impaired Pol III transcription in cellular models of POLR3-HLD and identify several candidate effectors, including BC200 RNA, having a potential role in oligodendrocyte biology and involvement in the disease.","variants":[{"Name":"NM_007055.4(POLR3A):c.2554A>G (p.Met852Val)","Chromosome":"10","Start":"78000043","Stop":"78000043","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40102,"rule_based_match":false,"evidence_text":"c.2554A→G (p.M852V)","llm_judgment":"PRESENT","evidence":"c.2554A→G (p.M852V)","abstract_start":538,"abstract_end":557}]}
{"pmid":"23935836","title":"Analysis of PALB2 gene in BRCA1/BRCA2 negative Spanish hereditary breast/ovarian cancer families with pancreatic cancer cases.","abstract":"BACKGROUND: The PALB2 gene, also known as FANCN, forms a bond and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer and 3-4% of familial pancreatic cancer. The goal of this study was to determine the prevalence of PALB2 mutations in a population of BRCA1/BRCA2 negative breast cancer patients selected from either a personal or family history of pancreatic cancer.\nMETHODS: 132 non-BRCA1/BRCA2 breast/ovarian cancer families with at least one pancreatic cancer case were included in the study. PALB2 mutational analysis was performed by direct sequencing of all coding exons and intron/exon boundaries, as well as multiplex ligation-dependent probe amplification.\nRESULTS: Two PALB2 truncating mutations, the c.1653T>A (p.Tyr551Stop) previously reported, and c.3362del (p.Gly1121ValfsX3) which is a novel frameshift mutation, were identified. Moreover, several PALB2 variants were detected; some of them were predicted as pathological by bioinformatic analysis. Considering truncating mutations, the prevalence rate of our population of BRCA1/2-negative breast cancer patients with pancreatic cancer is 1.5%.\nCONCLUSIONS: The prevalence rate of PALB2 mutations in non-BRCA1/BRCA2 breast/ovarian cancer families, selected from either a personal or family pancreatic cancer history, is similar to that previously described for unselected breast/ovarian cancer families. Future research directed towards identifying other gene(s) involved in the development of breast/pancreatic cancer families is required.","variants":[{"Name":"NM_024675.4(PALB2):c.3362del (p.Gly1121fs)","Chromosome":"16","Start":"23603658","Stop":"23603658","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":132249,"rule_based_match":true,"evidence_text":"c.3362del (p.Gly1121ValfsX3)","llm_judgment":"PRESENT","evidence":"c.3362del (p.Gly1121ValfsX3)","abstract_start":843,"abstract_end":871},{"Name":"NM_024675.4(PALB2):c.1653T>A (p.Tyr551Ter)","Chromosome":"16","Start":"23634893","Stop":"23634893","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":16282,"rule_based_match":true,"evidence_text":"c.1653T>A (p.Tyr551Stop)","llm_judgment":"PRESENT","evidence":"c.1653T>A (p.Tyr551Stop)","abstract_start":793,"abstract_end":817}]}
{"pmid":"24728566","title":"Identification of a novel mutation of the gene for gap junction protein α3 (GJA3) in a Chinese family with congenital cataract.","abstract":"Cataract, defined as any opacity of the crystallin lens, can be divided into early onset (congenital or infantile) and age-related. It is the leading cause of visual disability in children, and mutations in many genes have currently been linked with this disorder. In the present study, we identified a genetic defect in a Chinese family with congenital cataract. Genomic DNA was extracted from the venous blood of the family and 100 normal controls. To screen for the disease-causing mutation, we sequenced eight candidate genes, and to predict the functional consequences of the mutation, a structural model of the protein was developed using the Protein Data Bank and PyMOL 1.1r1. We found a novel variant (c.163 A > G transition) in the gene for gap junction protein α3, or the connexin46 gene. This mutation resulted in the substitution of a highly conserved asparagine at codon 55 by aspartic acid (p.N55D). There were no nucleotide polymorphisms in the other candidate genes sequenced.","variants":[{"Name":"NM_021954.4(GJA3):c.163A>G (p.Asn55Asp)","Chromosome":"13","Start":"20143126","Stop":"20143126","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3412474,"rule_based_match":true,"evidence_text":"c.163 A > G","llm_judgment":"PRESENT","evidence":"c.163 A > G","abstract_start":710,"abstract_end":721}]}
{"pmid":"25986071","title":"Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.","abstract":"BACKGROUND: Auditory neuropathy spectrum disorder (ANSD) is a form of hearing loss in which auditory signal transmission from the inner ear to the auditory nerve and brain stem is distorted, giving rise to speech perception difficulties beyond that expected for the observed degree of hearing loss. For many cases of ANSD, the underlying molecular pathology and the site of lesion remain unclear. The X-linked form of the condition, AUNX1, has been mapped to Xq23-q27.3, although the causative gene has yet to be identified.\nMETHODS: We performed whole-exome sequencing on DNA samples from the AUNX1 family and another small phenotypically similar but unrelated ANSD family.\nRESULTS: We identified two missense mutations in AIFM1 in these families: c.1352G>A (p.R451Q) in the AUNX1 family and c.1030C>T (p.L344F) in the second ANSD family. Mutation screening in a large cohort of 3 additional unrelated families and 93 sporadic cases with ANSD identified 9 more missense mutations in AIFM1. Bioinformatics analysis and expression studies support this gene as being causative of ANSD.\nCONCLUSIONS: Variants in AIFM1 gene are a common cause of familial and sporadic ANSD and provide insight into the expanded spectrum of AIFM1-associated diseases. The finding of cochlear nerve hypoplasia in some patients was AIFM1-related ANSD implies that MRI may be of value in localising the site of lesion and suggests that cochlea implantation in these patients may have limited success.","variants":[{"Name":"NM_004208.4(AIFM1):c.1352G>A (p.Arg451Gln)","Chromosome":"X","Start":"130133409","Stop":"130133409","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":214763,"rule_based_match":true,"evidence_text":"c.1352G>A (p.R451Q)","llm_judgment":"PRESENT","evidence":"c.1352G>A (p.R451Q)","abstract_start":749,"abstract_end":768},{"Name":"NM_004208.4(AIFM1):c.1030C>T (p.Leu344Phe)","Chromosome":"X","Start":"130137123","Stop":"130137123","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":172155,"rule_based_match":true,"evidence_text":"c.1030C>T (p.L344F)","llm_judgment":"PRESENT","evidence":"c.1030C>T (p.L344F)","abstract_start":793,"abstract_end":812}]}
{"pmid":"25809233","title":"Muscle magnetic resonance imaging abnormalities in X-linked myopathy with excessive autophagy.","abstract":"INTRODUCTION: X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recently reported mutations in the VMA21 gene.\nMETHODS: Four men from 2 separate families were studied. The clinical presentation, genetic data, muscle biopsy, and muscle MRI were analyzed.\nRESULTS: A known VMA21 mutation, c.163+4A>G, and a new mutation, c.163+3A>G, respectively, were found in the 2 families. The clinical course was characterized by onset in childhood and progressive muscle weakness with a limb-girdle pattern. Muscle biopsy revealed a mild myopathy with an increased number of giant autophagic vacuoles. Whole-body muscle MRI showed that pelvic girdle and proximal thighs were the most and earliest affected territories, with sparing of rectus femoris muscles. Muscle changes essentially consisted of degenerative fatty replacement.\nCONCLUSIONS: This study highlights a distinctive MRI pattern of muscle involvement, which can be helpful for diagnosis of XMEA, even before muscle biopsy or genetic analysis.","variants":[{"Name":"NM_001017980.4(VMA21):c.163+4A>G","Chromosome":"X","Start":"151403744","Stop":"151403744","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":205332,"rule_based_match":true,"evidence_text":"c.163+4A>G","llm_judgment":"PRESENT","evidence":"c.163+4A>G","abstract_start":328,"abstract_end":338}]}
{"pmid":"37057673","title":"De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.","abstract":"PURPOSE: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene.\nMETHODS: Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences.\nRESULTS: We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model.\nCONCLUSION: The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.","variants":[{"Name":"NM_022157.4(RRAGC):c.343T>C (p.Trp115Arg)","Chromosome":"1","Start":"38856977","Stop":"38856977","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2403833,"rule_based_match":true,"evidence_text":"c.343T>C, p.(Trp115Arg)","llm_judgment":"PRESENT","evidence":"c.343T>C, p.(Trp115Arg)","abstract_start":808,"abstract_end":831},{"Name":"NM_022157.4(RRAGC):c.353C>T (p.Pro118Leu)","Chromosome":"1","Start":"38856967","Stop":"38856967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2831322,"rule_based_match":true,"evidence_text":"c.353C>T, p.(Pro118Leu)","llm_judgment":"PRESENT","evidence":"c.353C>T, p.(Pro118Leu)","abstract_start":779,"abstract_end":802},{"Name":"NM_022157.4(RRAGC):c.269C>A (p.Thr90Asn)","Chromosome":"1","Start":"38857051","Stop":"38857051","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2831321,"rule_based_match":true,"evidence_text":"c.269C>A, p.(Thr90Asn)","llm_judgment":"PRESENT","evidence":"c.269C>A, p.(Thr90Asn)","abstract_start":755,"abstract_end":777}]}
{"pmid":"28175301","title":"Mutations in MSH5 in primary ovarian insufficiency.","abstract":"Primary ovarian insufficiency (POI) is a genetically heterogeneous disorder that occurs in familial or sporadic fashion. Through whole exome sequencing in a Chinese pedigree with POI, we identified a novel homozygous missense mutation (ENST00000375755: c.1459G > T, p.D487Y) in the MSH5 gene in two sisters with POI. The homologous mutation in mice resulted in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. From sanger sequencing of MSH5 in 200 sporadic POI patients, we identified three heterozygous mutations (ENST00000375755: c.1057C > A, p.L353M; c.1459G > T, p.D487Y and c.2107 A > G, p.I703V). Considering the heterozygous p.D487Y carrier in the POI pedigree was fertile, the causality of the three heterozygous mutations in POI need more evidence. Our studies confirmed that perturbation of genes involved in DNA damage repair could lead to non-syndromic POI. The underlying mechanism-inability to repair DNA damage-will receive increasing attention with respect to POI.","variants":[{"Name":"NM_172166.4(MSH5):c.1459G>T (p.Asp487Tyr)","Chromosome":"6","Start":"31759476","Stop":"31759476","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":404856,"rule_based_match":true,"evidence_text":"c.1459G>T (p.D487Y)","llm_judgment":"PRESENT","evidence":"c.1459G > T","abstract_start":253,"abstract_end":264}]}
{"pmid":"23703872","title":"Novel CLCNKB mutations causing Bartter syndrome affect channel surface expression.","abstract":"Mutations in the CLCNKB gene encoding the ClC-Kb Cl(-) channel cause Bartter syndrome, which is a salt-losing renal tubulopathy. Here, we investigate the functional consequences of seven mutations. When expressed in Xenopus laevis oocytes, four mutants carried no current (c.736G>C, p.Gly246Arg; c.1271G>A, p.Gly424Glu; c.1313G>A, p.Arg438His; c.1316T>C, p.Leu439Pro), whereas others displayed a 30%-60% reduction in conductance as compared with wild-type ClC-Kb (c.242T>C, p.Leu81Pro; c.274C>T, p.Arg92Trp; c.1052G>C, p.Arg351Pro). Anion selectivity and sensitivity to external Ca(2+) and H(+), typical of the ClC-Kb channel, were not modified in the partially active mutants. In oocytes, we found that all the mutations reduced surface expression with a profile similar to that observed for currents. In HEK293 cells, the currents in the mutants had similar profiles to those obtained in oocytes, except for p.Leu81Pro, which produced no current. Furthermore, p.Arg92Trp and p.Arg351Pro mutations did not modify the unit-conductance of closely related ClC-K1. Western blot analysis in HEK293 cells showed that ClC-Kb protein abundance was lower for the nonconducting mutants but similar to wild-type for other mutants. Overall, two classes of mutants can be distinguished: nonconducting mutants associated with low total protein expression, and partially conducting mutants with unaltered channel properties and ClC-Kb protein abundance.","variants":[{"Name":"NM_000085.5(CLCNKB):c.1313G>A (p.Arg438His)","Chromosome":"1","Start":"16051725","Stop":"16051725","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2116053,"rule_based_match":true,"evidence_text":"c.1313G>A, p.Arg438His","llm_judgment":"PRESENT","evidence":"c.1313G>A, p.Arg438His","abstract_start":320,"abstract_end":342},{"Name":"NM_000085.5(CLCNKB):c.1316T>C (p.Leu439Pro)","Chromosome":"1","Start":"16051728","Stop":"16051728","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2898167,"rule_based_match":true,"evidence_text":"c.1316T>C, p.Leu439Pro","llm_judgment":"PRESENT","evidence":"c.1316T>C, p.Leu439Pro","abstract_start":344,"abstract_end":366}]}
{"pmid":"27984190","title":"Mutation screening of PDGFB gene in Chinese population with primary familial brain calcification.","abstract":"BACKGROUND: Until recently, primary familial brain calcification (PFBC) has been determined by four genes, SLC20A2, PDGFRB, PDGFB and XPR1. No studies have been carried out to analyze the gene mutation of PDGFB in Chinese population.\nOBJECTIVE: To screen mutations of PDGFB gene in a large cohort of Chinese PFBC patients with no SLC20A2 mutations.\nMETHODS: We recruited 192 PFBC patients, including 21 index cases and 171 sporadic cases, in our study. Peripheral venous blood samples of all included participants were collected for genomic DNA extraction. The coding sequence of PDGFB was amplified by polymerase chain reaction (PCR) followed by direct sequencing. The potential effects of the identified variants on protein function were assessed by bioinformatics analysis.\nRESULTS: Three missense variants (c.35G>T, c.232C>T, and c.610C>A) and one nonsense variant (c.220G>T) of PDGFB were identified in five sporadic PFBC patients. The variant c.35G>T was found in 2 healthy controls from the same ethnic background, whereas c.220G>T, c.232C>T and c.610C>A were absent from 500 controls. c.220G>T (p.E74*) produced a stop codon in the place of the glutamicacid residue number 74. c.232C>T (p.R78C) occurred at highly conserved regions and were predicted as damaging by at least two computational predictive programs, suggesting that this variant were likely to have a causal role in PFBC. Although variant c.610C>A (p.P204T) also occurred at a highly conserved region, it was predicted to be most likely benign by two computational predictive programs, suggesting an uncertain role of this variant on PFBC.\nCONCLUSIONS: The present study identified one likely pathogenic variant (p.E74*) and two variants of uncertain significance (p.R78C and p.P204T) in PDGFB. Further studies of PDGF-B functional expression for these variants are still required to confirm the pathogenic effect.","variants":[{"Name":"NM_002608.4(PDGFB):c.232C>T (p.Arg78Cys)","Chromosome":"22","Start":"39233453","Stop":"39233453","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3860799,"rule_based_match":true,"evidence_text":"c.232C>T (p.R78C)","llm_judgment":"PRESENT","evidence":"c.232C>T (p.R78C)","abstract_start":1185,"abstract_end":1202}]}
{"pmid":"21921978","title":"Autosomal dominant Best disease with an unusual electrooculographic light rise and risk of angle-closure glaucoma: a clinical and molecular genetic study.","abstract":"PURPOSE: To describe the clinical and molecular characteristics of two families with autosomal dominant Best disease and atypical electrooculography (EOG).\nMETHODS: Four affected individuals from two families were ascertained. Detailed ophthalmic examinations, refraction, and biometry (anterior chamber depth [ACD] and axial length [AL]), gonioscopy, optical coherence tomography of the anterior segment and retina, retinal imaging, and electrophysiological assessment were performed. Arden ratios from EOG testing were calculated by direct measurement of the light peak to dark trough amplitudes. Mutations in bestrophin 1 (BEST1) were identified by bidirectional Sanger sequencing. In family 1, segregation of BEST1 alleles was performed by assaying four microsatellite markers (D11S935, D11S4102, D11S987, and D11S4162) that flank BEST1.\nRESULTS: The proband from family 1 (three of four siblings affected with Best disease) was 42 years old with bilateral macular vitelliform lesions, advanced angle closure glaucoma (ACG), a normal electroretinogram, and no EOG light rise. Her 44-year-old brother had similar fundus appearances and an EOG light rise of 170%. Their 48-year-old sister had a normal left fundus, whereas the right fundus showed a vitelliform lesion and subretinal thickening. There was no EOG light rise detectable from either eye. Mutation analysis of BEST1 showed all affected siblings to be heterozygous for a missense mutation, c.914T>C, p.Phe305Ser. Their unaffected sister had an EOG light rise of 200%, a normal fundus appearance, and did not harbor the BEST1 mutation. Haplotype analysis of family 1 showed that the affected brother with the 170% EOG light rise had inherited the same nondiseased parental BEST1 allele as his unaffected sister. The other two affected sisters with undetectable EOG light rises shared a different nondiseased parental BEST1 allele. An unrelated 53-year-old female carrying the same c.914T>C, p.Phe305Ser mutation showed typical features of Best disease and an EOG light rise of 180%. All four siblings from family 1 had shorter axial biometry (ACD range 2.06-2.74 mm; AL range 20.46-22.60 mm) than the normal population, contributing to their risk of ACG development. Proband 2 had deeper ACDs (2.83 mm OD and 2.85 mm OS), but similar ALs (21.52 mm OD and 21.42 mm OS) compared to family 1. She had no gonioscopic evidence of angle closure.\nCONCLUSIONS: A near normal EOG light rise is uncommon in molecularly confirmed Best disease, and in the present report is associated with the same mutation in two families, suggesting a specific role for this amino acid in the retinal pigment epithelium dysfunction associated with this disorder. Haplotype analysis in family 1 was consistent with an effect of the nondisease allele in mediating the presence of an EOG light rise. Clinical assessment of ACG risk is recommended for BEST1 mutation carriers and their first degree relatives.","variants":[{"Name":"NM_004183.4(BEST1):c.914T>C (p.Phe305Ser)","Chromosome":"11","Start":"61959544","Stop":"61959544","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":105667,"rule_based_match":true,"evidence_text":"c.914T>C, p.Phe305Ser","llm_judgment":"PRESENT","evidence":"c.914T>C, p.Phe305Ser","abstract_start":1453,"abstract_end":1474}]}
{"pmid":"26283294","title":"Sporadic paraganglioma caused by de novo SDHB mutations in a 6-year-old girl.","abstract":"Germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene (SDHB) cause susceptibility to paragangliomas and pheochromocytomas; however, it is exceedingly rare in childhood and especially in sporadic cases. We report the first Japanese pediatric case of paraganglioma with a de novo mutation in the SDHB gene. A 6-year-old girl with convulsions and hypertension was found to have a paravertebral abdominal tumor. Urinary and blood examinations revealed markedly elevated levels of norepinephrine. Following treatment for hypertension, the tumor was removed completely and histological findings were consistent with paraganglioma. Immunohistochemistry studies demonstrated the absence of SDHB protein expression, indicating an underlying SDH mutation with high probability. Germline mutation analysis of the SDHB gene revealed a heterozygous splice site mutation in intron 4 (C.423 + 1G > A). Subsequently, a second somatic genetic change was confirmed by multiplex ligation-dependent probe amplification (MLPA) analysis, showing that deletion of the wild-type allele resulted in loss of function of SDHB. No germline mutations in SDHB were detected in her parents.\nCONCLUSION: Genetic testing should be considered for pediatric patients with paragangliomas, even in the absence of familial history, as closer lifelong screening to detect the development of malignancy will be required for patients with SDHB mutations.\nWHAT IS KNOWN: Most sporadic cases of paraganglioma with SDHB mutations occur between adolescence and adulthood. Screening methods for carriers of SDHB mutations assessing recurrence and detecting developing metastases are yet to be standardized.\nWHAT IS NEW: The current case of an extra-adrenal paraganglioma with a de novo SDHB mutation had an onset at 6 years. We suggest much closer periodical observation for these high-risk children.","variants":[{"Name":"NM_003000.3(SDHB):c.423+1G>A","Chromosome":"1","Start":"17028599","Stop":"17028599","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38851,"rule_based_match":true,"evidence_text":"C.423 + 1G > A","llm_judgment":"PRESENT","evidence":"C.423 + 1G > A","abstract_start":896,"abstract_end":910}]}
{"pmid":"21220647","title":"Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene.","abstract":"OBJECTIVE: To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)-related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.\nDESIGN: Population-based, prospective cohort study.\nPATIENTS: A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.\nINTERVENTION: Patients underwent mutational analysis for SOD1, FUS, and TARDBP.\nRESULTS: Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G>A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94-single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.\nCONCLUSIONS: The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.","variants":[{"Name":"NM_007375.4(TARDBP):c.1144G>A (p.Ala382Thr)","Chromosome":"1","Start":"11022553","Stop":"11022553","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34326,"rule_based_match":true,"evidence_text":"c.1144G>A (p.A382T)","llm_judgment":"PRESENT","evidence":"c.1144G>A (p.A382T)","abstract_start":609,"abstract_end":628}]}
{"pmid":"27224056","title":"Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic).","abstract":"Pathogenic variants in the GJB2 gene, encoding connexin 26, are known to be a major cause of hearing impairment (HI). More than 300 allelic variants have been identified in the GJB2 gene. Spectrum and allelic frequencies of the GJB2 gene vary significantly among different ethnic groups worldwide. Until now, the spectrum and frequency of the pathogenic variants in exon 1, exon 2 and the flanking intronic regions of the GJB2 gene have not been described thoroughly in the Sakha Republic (Yakutia), which is located in a subarctic region in Russia. The complete sequencing of the non-coding and coding regions of the GJB2 gene was performed in 393 patients with HI (Yakuts-296, Russians-51, mixed and other ethnicities-46) and in 187 normal hearing individuals of Yakut (n = 107) and Russian (n = 80) populations. In the total sample (n = 580), we revealed 12 allelic variants of the GJB2 gene, 8 of which were recessive pathogenic variants. Ten genotypes with biallelic recessive pathogenic variants in the GJB2 gene (in a homozygous or a compound heterozygous state) were found in 192 out of 393 patients (48.85%). We found that the most frequent GJB2 pathogenic variant in the Yakut patients was c.-23+1G>A (51.82%) and that the second most frequent was c.109G>A (2.37%), followed by c.35delG (1.64%). Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were found to be the most frequent among the Russian patients. The carrier frequencies of the c.-23+1G>A and с.109G>A pathogenic variants in the Yakut control group were 10.20% and 2.80%, respectively. The carrier frequencies of с.35delG and c.101T>C were identical (2.5%) in the Russian control group. We found that the contribution of the GJB2 gene pathogenic variants in HI in the population of the Sakha Republic (48.85%) was the highest among all of the previously studied regions of Asia. We suggest that extensive accumulation of the c.-23+1G>A pathogenic variant in the indigenous Yakut population (92.20% of all mutant chromosomes in patients) and an extremely high (10.20%) carrier frequency in the control group may indicate a possible selective advantage for the c.-23+1G>A carriers living in subarctic climate.","variants":[{"Name":"NM_004004.6(GJB2):c.-23+1G>A","Chromosome":"13","Start":"20192782","Stop":"20192782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32068,"rule_based_match":true,"evidence_text":"c.-23+1G>A","llm_judgment":"PRESENT","evidence":"c.-23+1G>A","abstract_start":1200,"abstract_end":1210}]}
{"pmid":"33193564","title":"Germline","abstract":"<i>PALB2</i> is an important BRCAx candidate for familial breast cancers (FBC). <i>PALB2</i> pathogenic variants (PVs) may not to conform to \"two hit\" paradigm. However, a recent study demonstrates that in the majority <i>PALB2</i> germline mutant breast cancers, the loss of heterozygosity (LOH) and somatic point mutations are the \"second hit.\" This study aimed to investigate the second hits in germline <i>PALB2</i> mutations in breast cancers. We screened out 28 germline <i>PALB2-</i>mutation carriers among 480 familial cancer patients (including 143 FBC patients) in Geneplus database pool. Of the 143 patients with FBC, 10 had mono-allelic <i>PALB2</i> germline mutations. All these germline <i>PALB2</i> mutations were high-risk stop-gain, frameshift, or splicing mutations that concentrated in EX5-EX9 and might led to truncated proteins, severe functional defects and malignant phenotype. The hotspots were c.1057A[3 > 2] and c.3114-1G > A. Other mutations included c.389delA, c.2068C > T, c.2167_2168delAT, c.2629delT and c.2968G > T. Only one FBC patient has <i>PALB2</i> somatic mutation and two patients had LOH of <i>PALB2</i>. All germline <i>PALB2</i> mutations were high-risk mutations, whereas the somatic <i>PALB2</i> mutations were moderate-risk missense mutations. We also distinguished PALB2 \"novel mutations\" from \"reported mutations.\" In conclusion, germline <i>PALB2</i> mutation should be put into the context of future screening.","variants":[{"Name":"NM_024675.4(PALB2):c.3114-1G>A","Chromosome":"16","Start":"23614092","Stop":"23614092","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":260096,"rule_based_match":true,"evidence_text":"c.3114-1G > A","llm_judgment":"PRESENT","evidence":"c.3114-1G > A","abstract_start":938,"abstract_end":951},{"Name":"NM_024675.4(PALB2):c.2968G>T (p.Glu990Ter)","Chromosome":"16","Start":"23622997","Stop":"23622997","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":235190,"rule_based_match":true,"evidence_text":"c.2968G>T","llm_judgment":"PRESENT","evidence":"c.2968G > T","abstract_start":1035,"abstract_end":1046}]}
{"pmid":"33919865","title":"Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study.","abstract":"Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in <i>NF1</i> and characterized by a heterogeneous phenotypic presentation. Relevant genotype-phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype-phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (<i>p</i> = 0.005). Skeletal abnormalities were associated with whole gene deletions (<i>p</i> = 0.05) and frameshift variants (<i>p</i> = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (<i>p</i> = 0.031), whereas Lisch nodules (<i>p</i> = 0.05) and endocrinological disorders (<i>p</i> = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype-phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.","variants":[{"Name":"NM_001042492.3(NF1):c.3721C>T (p.Arg1241Ter)","Chromosome":"17","Start":"31235623","Stop":"31235623","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15400,"rule_based_match":true,"evidence_text":"c.3721C>T; p.(R1241*)","llm_judgment":"PRESENT","evidence":"c.3721C>T; p.(R1241*)","abstract_start":1198,"abstract_end":1219}]}
{"pmid":"24296660","title":"A novel GHR intronic variant, c.266+83G>T , activates a cryptic 5' splice site causing severe GHR deficiency and classical GH insensitivity syndrome.","abstract":"BACKGROUND/AIMS: Mutations in the human growth hormone receptor gene (GHR) are the most common cause of growth hormone insensitivity (GHI) syndrome and insulin-like growth factor (IGF-1) deficiency. The extracellular domain of GHR (encoded by exons 2-7 of the GHR gene) can be proteolytically cleaved to circulate as GH-binding protein (GHBP).\nMETHODS: We evaluated the cause of classical GHI (Laron) phenotypes in 3 siblings.\nRESULTS: Two brothers (aged 16.5 and 14.9 years) and their half-brother (aged 11.3 years) presented with extreme short stature (height standard deviation score, SDS, of -7.05, -6.34 and -8.02, respectively). The parents were consanguineous and of normal stature. Serum GHBP levels of probands were undetectable and circulating IGF-1 and IGF-binding protein-3 were abnormally low, but GH concentrations were elevated. Molecular analysis of the GHR gene revealed homozygous deletion of exon 3, a common polymorphism, and a novel c.266+83G>T variant within intron 4 which generated a 5' donor splice site. Splicing events from this cryptic 5' donor site resulted in retention of 81 intronic nucleotides in the GHR mRNA. Long-term rhIGF-1 therapy combined with leuprolide depot increased height by +2 to +3 SDS.\nCONCLUSION: The c.266+83G>T is the second intronic GHR mutation identified that activates a cryptic 5' donor splice site. The abnormal splicing event led to early protein termination and undetectable serum GHBP concentrations. © 2013 S. Karger AG, Basel.","variants":[{"Name":"NM_000163.5(GHR):c.266+83G>T","Chromosome":"5","Start":"42689102","Stop":"42689102","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1934934,"rule_based_match":true,"evidence_text":"c.266+83G>T","llm_judgment":"PRESENT","evidence":"c.266+83G>T","abstract_start":954,"abstract_end":965}]}
{"pmid":"27588307","title":"Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.","abstract":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous <i>AIRE</i> mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common <i>AIRE</i> mutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic <i>AIRE</i> mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4<sup>+</sup> T cells and CD21<sup>lo</sup>CD38<sup>lo</sup> B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.","variants":[{"Name":"NM_000383.4(AIRE):c.967_979del (p.Leu323fs)","Chromosome":"21","Start":"44291180","Stop":"44291192","ReferenceAlleleVCF":"TGCCTGTCCCCTCC","AlternateAlleleVCF":"T","allel_id":18348,"rule_based_match":true,"evidence_text":"c.967_979del13","llm_judgment":"PRESENT","evidence":"c.967_979del13","abstract_start":906,"abstract_end":920}]}
{"pmid":"25755106","title":"Familial periventricular nodular heterotopia, epilepsy and Melnick-Needles Syndrome caused by a single FLNA mutation with combined gain-of-function and loss-of-function effects.","abstract":"BACKGROUND: Loss-of-function mutations of the FLNA gene cause a neuronal migration disorder defined as X-linked periventricular nodular heterotopia (PNH); gain-of-function mutations are associated with a group of X-linked skeletal dysplasias designed as otopalatodigital (OPD) spectrum. We describe a family in which a woman and her three daughters exhibited a complex phenotype combining PNH, epilepsy and Melnick-Needles syndrome (MNS), a skeletal disorder assigned to the OPD spectrum. All four individuals harboured a novel non-conservative missense mutation in FLNA exon 3.\nMETHODS: In all affected family members, we performed mutation analysis of the FLNA gene, RT-PCR, ultradeep sequencing analysis in FLNA cDNAs and western blot in lymphocyte cells to further characterise the mutation. We also assessed the effects on RT-PCR products of treatment of patients' lymphocytes with cycloheximide, a nonsense mediated mRNA decay (NMD) inhibitor.\nRESULTS: We identified a novel c.622G>C change in FLNA exon 3, leading to the substitution of a highly conserved aminoacid (p.Gly208Arg). Gel electrophoresis and ultradeep sequencing revealed the missense mutation as well as retention of intron 3. Cycloheximide treatment demonstrated that the aberrant mRNA transcript-retaining intron 3 is subjected to NMD. Western blot analysis confirmed reduced FLNA levels in lymphocyte cells.\nCONCLUSIONS: The novel c.622G>C substitution leads to two aberrant FLNA transcripts, one of which carries the missense mutation, plus a longer transcript resulting from intron 3 retention. We propose that the exceptional co-occurrence of PNH and MNS, two otherwise mutually exclusive allelic phenotypes, is the consequence of a single mutational event resulting in co-occurring gain-of-function and loss-of-function effects.","variants":[{"Name":"NM_001110556.2(FLNA):c.622G>C (p.Gly208Arg)","Chromosome":"X","Start":"154367842","Stop":"154367842","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":205664,"rule_based_match":true,"evidence_text":"c.622G>C","llm_judgment":"PRESENT","evidence":"c.622G>C","abstract_start":981,"abstract_end":989}]}
{"pmid":"29663722","title":"Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy.","abstract":"Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium with variable expressivity and penetrance. Occasionally, homozygous sarcomere genetic variants emerge while genotyping HCM patients. In these cases, a more severe HCM phenotype is generally seen. Here, we report a case of HCM that was diagnosed clinically at 39 years of age. Initial symptoms were shortness of breath during exertion. Successively, he developed a wide array of severe clinical manifestations, which progressed to an ominous end-stage heart failure that resulted in heart transplantation. Genotype analysis revealed a missense MYBPC3 variant NM_000256.3:c.2618C>A,p.(Pro873His) that presented in the homozygous form. Conflicting interpretations of pathogenicity have been reported for the Pro873His MYBPC3 variant described here. Our patient, presenting with two copies of the variant and devoid of a normal allele, progressed to end-stage heart failure, which supports the notion of a deleterious effect of this variant in the homozygous form.","variants":[{"Name":"NM_000256.3(MYBPC3):c.2618C>A (p.Pro873His)","Chromosome":"11","Start":"47335996","Stop":"47335996","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39099,"rule_based_match":true,"evidence_text":"NM_000256.3:c.2618C>A,p.(Pro873His)","llm_judgment":"PRESENT","evidence":"NM_000256.3:c.2618C>A,p.(Pro873His)","abstract_start":651,"abstract_end":686}]}
{"pmid":"27014650","title":"Autosomal Recessive Nonsyndromic Hearing Loss: A Case Report with a Mutation in TRIOBP Gene.","abstract":"Hearing loss (HL) is the most common sensory defect. Various genetic as well as environmental factors have been shown to contribute in it. More than 100 loci have been recognized to cause autosomal recessive nonsyndromic hearing loss (ARNSHL). Here, we report a 6-year old female patient with bilateral pre-lingual HL in whom a mutation has been identified in TRIOBP gene (c.6362C>T, S2121L). In silico analysis has shown that this variant is possibly pathogenic. Although several mutations have been detected in this gene in various populations, this is the first report identifying TRIOBP mutation in Iranian population. Consequently, the results of the present study may be of importance in genetic counseling.","variants":[{"Name":"NM_001039141.3(TRIOBP):c.6362C>T (p.Ser2121Leu)","Chromosome":"22","Start":"37765707","Stop":"37765707","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":176426,"rule_based_match":true,"evidence_text":"c.6362C>T","llm_judgment":"PRESENT","evidence":"c.6362C>T","abstract_start":373,"abstract_end":382}]}
{"pmid":"19330033","title":"Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients.","abstract":"Fibrodysplasia Ossificans Progressiva (FOP) is a rare, heritable condition typified by progression of extensive ossification within skeletal muscle, ligament and tendon together with defects in skeletal development. The condition is easily diagnosed by the presence of shortened great toes and there is severe advancement of disability with age. FOP has been shown to result from a point mutation (c.617G>A) in the ACVR1 gene in almost all patients reported. Very recently two other mutations have been described in three FOP patients. We present here evidence for two further unique mutations (c.605G>T and c.983G>A) in this gene in two FOP patients with some atypical digit abnormalities and other clinical features. The observation of disparate missense mutations mapped to the GS and kinase domains of the protein supports the disease model of mild kinase activation and provides a potential rationale for phenotypic variation.","variants":[{"Name":"NM_001111067.4(ACVR1):c.983G>A (p.Gly328Glu)","Chromosome":"2","Start":"157766004","Stop":"157766004","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38549,"rule_based_match":true,"evidence_text":"c.983G>A","llm_judgment":"PRESENT","evidence":"c.983G>A","abstract_start":608,"abstract_end":616},{"Name":"NM_001111067.4(ACVR1):c.605G>T (p.Arg202Ile)","Chromosome":"2","Start":"157774126","Stop":"157774126","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":38551,"rule_based_match":true,"evidence_text":"c.605G>T","llm_judgment":"PRESENT","evidence":"c.605G>T","abstract_start":595,"abstract_end":603}]}
{"pmid":"26113502","title":"Diverse clinical phenotypes associated with a nonsense mutation in FAM161A.","abstract":"PURPOSE: Mutations in the FAM161A gene have been reported in association with autosomal recessive retinitis pigmentosa (arRP) in several ethnic populations. This study aimed to assess the prevalence of FAM161A-related retinopathy in a British cohort and to characterise the phenotype associated with mutations in this gene.\nMETHODS: The FAM161A coding region and intron-exon boundaries were screened by Sanger sequencing in 120 retinitis pigmentosa (RP) patients (with likely autosomal recessive inheritance) in whom mutations in other known major RP genes have been ruled out by commercially available testing. Homozygosity mapping was performed in one consanguineous family, and high-throughput sequencing of candidate genes was performed to identify disease-associated changes. Clinical assessment of affected individuals included perimetry testing, fundus autofluorescence imaging, and optical coherence tomography.\nRESULTS: Two patients of British origin with a homozygous mutation in FAM161A (c.1309A>T, p.Arg437*) were identified by Sanger sequencing. Homozygosity mapping and subsequent high-throughput sequencing analysis identified a further family of Pakistani origin with the same genotype. Clinical examination of affected members of these families revealed that this mutation was associated with a diverse clinical phenotype, ranging from mild disease with preservation of central acuity to severe visual impairment.\nCONCLUSIONS: Homozygosity for the c.1309A>T, p.Arg437* variant in FAM161A is a relatively common cause of arRP. The mutation occurs in diverse ethnic populations, associated with typical retinitis pigmentosa with disease onset usually in the second or third decade of life.","variants":[{"Name":"NM_001201543.2(FAM161A):c.1309A>T (p.Arg437Ter)","Chromosome":"2","Start":"61839695","Stop":"61839695","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":15075,"rule_based_match":true,"evidence_text":"c.1309A>T, p.Arg437*","llm_judgment":"PRESENT","evidence":"c.1309A>T, p.Arg437*","abstract_start":999,"abstract_end":1019}]}
{"pmid":"30726305","title":"Rapid and easy detection of the five most common mutations in BRCA1 and BRCA2 genes in the Polish population using CAPS and ACRS-PCR methods.","abstract":"In this publication we present a fast method of diagnosing the most common polymorphisms of BRCA1 and BRCA2 genes in Poland - C61G [c.300T>G], C64R [c.190T>C], 4153delA [c.4035delA], 3819del5 [c.3700_3704delGTAAA], and C5972T [c.5744C>T]. Our procedure is based on the use of the cleaved amplified polymorphic sequences (CAPS) and artificially created restriction site (ACRS) PCR techniques. The precise selection of appropriate primer sequences and restriction enzymes enabled specific cuts of DNA fragments. The final quantity and size of the obtained products depend on the presence or the absence of the mutations. The obtained results are unambiguous and do not have to be confirmed by sequencing. The methods of detection of the C61G, C64R, 4153delA, 3819del5, and C5972T mutations in the BRCA1 and BRCA2 genes described by us do not require a sequencing process, which is more expensive, time-consuming and associated with numerous errors. The technique developed by us enables the use of simple electrophoresis for accurate detection of the presence or absence of a specific mutation. Our procedures are fast, precise and unambiguous.","variants":[{"Name":"NM_007294.4(BRCA1):c.190T>C (p.Cys64Arg)","Chromosome":"17","Start":"43106478","Stop":"43106478","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":69061,"rule_based_match":true,"evidence_text":"C64R [c.190T>C]","llm_judgment":"PRESENT","evidence":"C64R [c.190T>C]","abstract_start":143,"abstract_end":158}]}
{"pmid":"38050059","title":"Clinical and functional analysis of the germline","abstract":"<i>TP53</i> plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline <i>TP53</i> p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify <i>TP53</i> p.K164E as a likely pathogenic variant.","variants":[{"Name":"NM_000546.6(TP53):c.490A>G (p.Lys164Glu)","Chromosome":"17","Start":"7675122","Stop":"7675122","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":245075,"rule_based_match":true,"evidence_text":"NM_000546.5: c.490A>G","llm_judgment":"PRESENT","evidence":"NM_000546.5: c.490A>G","abstract_start":397,"abstract_end":418}]}
{"pmid":"25308559","title":"Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor (GIF) Deficiency: A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario.","abstract":"Intrinsic factor deficiency (OMIM #261000, IFD) is a rare inherited disorder of vitamin B12 metabolism due to mutations in the gastric intrinsic factor (GIF) gene.We report three individuals from an Old Order Mennonite community who presented with B12 deficiency. Two cases are siblings born to consanguineous parents and the third case is not known to be closely related. The older male sib presented at 4 years with gastrointestinal symptoms, listlessness, and pallor. He had pancytopenia with megaloblastic anemia. Serum B12 was 61 (198-615 pmol/L). Methylmalonic aciduria was present. C3 was elevated on acylcarnitine profile. Homocysteine was high at 16.7 (5.0-12.0 umol/L). His asymptomatic female sibling was also found to have B12 deficiency. Genetic testing for methylmalonic aciduria (MMAA), transcobalamin deficiency (TCN2), and Imerslund-Gräsbeck syndrome (AMN) showed no mutation in both siblings. The third patient, a 34-year-old woman, had presented in infancy with a diagnosis of pernicious anemia. Mutation analysis of GIF revealed compound heterozygosity for a c.79+1G>A substitution and a c.973delG deletion in all three individuals. Oral or parenteral vitamin B12 has led to complete recovery of clinical parameters and vitamin B12 levels. Newborn screening samples on the siblings revealed normal methylcitrate, C3, and C3/C2 ratios thus indicating no disruption of propionic or methylmalonic acid metabolism.A high index of suspicion should be maintained if children present with megaloblastic anemia since GIF deficiency is a treatable disorder and newborn screening may not be able to detect this condition.","variants":[{"Name":"NM_005142.3(CBLIF):c.79+1G>A","Chromosome":"11","Start":"59845374","Stop":"59845374","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":433589,"rule_based_match":true,"evidence_text":"c.79+1G>A","llm_judgment":"PRESENT","evidence":"c.79+1G>A","abstract_start":1079,"abstract_end":1088}]}
{"pmid":"26123486","title":"POLG2 disease variants: analyses reveal a dominant negative heterodimer, altered mitochondrial localization and impaired respiratory capacity.","abstract":"Human mitochondrial DNA (mtDNA) is replicated and repaired by the mtDNA polymerase gamma, polγ. Polγ is composed of three subunits encoded by two nuclear genes: (1) POLG codes for the 140-kilodalton (kDa) catalytic subunit, p140 and (2) POLG2 encodes the ∼110-kDa homodimeric accessory subunit, p55. Specific mutations are associated with POLG- or POLG2-related disorders. During DNA replication the p55 accessory subunit binds to p140 and increases processivity by preventing polγ's dissociation from the template. To date, studies have demonstrated that homodimeric p55 disease variants are deficient in the ability to stimulate p140; however, all patients currently identified with POLG2-related disorders are heterozygotes. In these patients, we expect p55 to occur as 25% wild-type (WT) homodimers, 25% variant homodimers and 50% heterodimers. We report the development of a tandem affinity strategy to isolate p55 heterodimers. The WT/G451E p55 heterodimer impairs polγ function in vitro, demonstrating that the POLG2 c.1352G>A/p.G451E mutation encodes a dominant negative protein. To analyze the subcellular consequence of disease mutations in HEK293 cells, we designed plasmids encoding p55 disease variants tagged with green fluorescent protein (GFP). P205R and L475DfsX2 p55 variants exhibit irregular diffuse mitochondrial fluorescence and unlike WT p55, they fail to form distinct puncta associated with mtDNA nucleoids. Furthermore, homogenous preparations of P205R and L475DfsX2 p55 form aberrant reducible multimers. We predict that abnormal protein folding or aggregation or both contribute to the pathophysiology of these disorders. Examination of mitochondrial bioenergetics in stable cell lines overexpressing GFP-tagged p55 variants revealed impaired mitochondrial reserve capacity.","variants":[{"Name":"NM_007215.4(POLG2):c.1352G>A (p.Gly451Glu)","Chromosome":"17","Start":"64477929","Stop":"64477929","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20315,"rule_based_match":true,"evidence_text":"c.1352G>A/p.G451E","llm_judgment":"PRESENT","evidence":"c.1352G>A/p.G451E","abstract_start":1024,"abstract_end":1041}]}
{"pmid":"30777047","title":"Hb Knossos (HBB: c.82G > T), β-globin CD 5 (-CT) (HBB: c.17_18delCT) and δ-globin CD 59 (-a) (HBD: c.179delA) mutations in a Syrian patient with β-thalassemia intermedia.","abstract":"BACKGROUND: Beta thalassemia (β-thal) is an inherited hemoglobin disorder characterized by reduced synthesis of the hemoglobin that results in microcytic hypochromic anemia. β-Thalassemia intermedia (TI) is a clinical term of intermediate gravity between the carrier state and β-thalassemia major (β -TM).\nCASE PRESENTATION: We describe a 12-year-old male proband originating from Al-Quneitra province - southwest Syria. Hematological investigations revealed, pallor and anemia (Hb 9 g/dl). The mean cell volume (MCV) 64 fL; mean cell hemoglobin (MCH) 21.8 pg. Capillary electrophoresis (CE) electropherogram revealed low level of Hb A1 (36.2%), high level of Hb F (62.2%) and low level of Hb A2 (1.6%). The proband requires blood transfusion occasionally. Direct DNA sequencing and Polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP) for mutations detection were used. The molecular analysis revealed the presence of rare β<sup>+</sup> Hb Knossos codon 27 (G > T) (HBB: c.82G > T) variant associated with β<sup>0</sup> codon 5 [-CT] (HBB: c.17_18delCT) mutation in beta-globin (β-globin) gene and δ<sup>0</sup> codon 59 [-A] (HBD: c.179delA) mutation in delta-globin (δ-globin) gene. The proband tested negative for the common deletional forms of alpha thalassemia (α-thal). Polymorphism of the Xmn-I locus (HBG2: c.-211C > T) revealed that the proband had a homozygous [TT] for Xmn-1 locus.\nCONCLUSIONS: To our knowledge, this is the first report of beta thalassemia intermedia due to combination of Hb Knossos /codon 5 [-CT] associated with δ<sup>0</sup> codon 59 [-A] in Syrian patient. On the other hand, in Syria, β-thal carriers who have low level of Hb A2 due to decreased δ-chain production, different δ-thal gene mutations must be screened to avoid the failure diagnosis of β-thal disease.","variants":[{"Name":"NM_000518.5(HBB):c.82G>T (p.Ala28Ser)","Chromosome":"11","Start":"5226940","Stop":"5226940","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":30278,"rule_based_match":true,"evidence_text":"HBB: c.82G > T","llm_judgment":"PRESENT","evidence":"HBB: c.82G > T","abstract_start":992,"abstract_end":1006}]}
{"pmid":"16972078","title":"The fatty acid amide hydrolase 385 A/A (P129T) variant: haplotype analysis of an ancient missense mutation and validation of risk for drug addiction.","abstract":"The human fatty acid amide hydrolase (FAAH) missense mutation c.385 C-->A, which results in conversion of a conserved proline residue to threonine (P129T), has been associated with street drug use and problem drug abuse. Although a link between the FAAH P129T variant and human drug abuse has been reported, the extent of risk and specific types of substance addiction vulnerability remain to be determined. Here, we investigated the relationship of the FAAH P129T variant to a number of linked single nucleotide polymorphisms to establish a haplotyping system, calculate the estimated age and origin of the FAAH 385 C-->A mutation and evaluate its association with clinically significant drug addiction in a case control study. The results showed a significant over-representation of the FAAH P129T homozygotes in 249 subjects with documented multiple different drug addictions compared to drug free individuals of the same ethnic backgrounds (P = 0.05) using logistic regression analysis controlling for ethnicity. To increase the logistic regression analysis power by increasing the sample size, the data from our previous study (Sipe et al. in Proc Natl Acad Sci USA 99:8394-8399, 2002) were pooled with the present cohort which increased the significance to P = 0.00003. Investigation of the FAAH chromosomal backgrounds of the P129T variant in both multiple different drug addicted and control subjects revealed a common ancestral haplotype, marked population differences in haplotype genetic diversity and an estimated P129T mutation age of 114,425-177,525 years. Collectively, these results show that the P129T mutation is the only common mutation in the FAAH gene and is significantly associated with addictive traits. Moreover, this mutation appears to have arisen early in human evolution and this study validates the previous link between the FAAH P129T variant and vulnerability to addiction of multiple different drugs.","variants":[{"Name":"NM_001441.3(FAAH):c.385C>A (p.Pro129Thr)","Chromosome":"1","Start":"46405089","Stop":"46405089","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":21763,"rule_based_match":false,"evidence_text":"c.385 C-->A","llm_judgment":"PRESENT","evidence":"c.385 C-->A","abstract_start":62,"abstract_end":73}]}
{"pmid":"34224960","title":"Phenotypic dento-osseous characterization of a Brazilian family with Familial Adenomatous Polyposis.","abstract":"OBJECTIVE: To perform a phenotypic characterization of the dento-osseous anomalies in a Brazilian family with Familial Adenomatous Polyposis (FAP) and to investigate the adenomatous polyposis coli (APC) causative variant.\nDESIGN: The study included a family of 14 individuals (Group A: affected; Group B: non-affected). The frequency of radiographic findings in both groups was evaluated according to the Dental Panoramic Radiograph Score (DPRS) diagnostic method. The accuracy and reproducibility of DPRS were tested. The DNA was isolated from the index patient's saliva and submitted to whole-exome and Sanger sequencing approach.\nRESULTS: DPRS ≥ 7 was observed in 80 % of Group A but in none of Group B. The most common findings in Group A were dense bone islands (60 %), hazy sclerosis (40 %), osteomas (40 %), and supernumerary tooth (20 %). DPRS has proved to be a reliable method while DPRS ≥ 5 and DPRS ≥ 7 were taken as positive for FAP, and reproducible diagnosis test considering that the evaluators correctly identified the affected patients (Kappa agreement>0.8, p = 0.002). A nonsense heterozygous mutation in the APC gene (c.1370C > G; p.Ser457*) of the index case was detected.\nCONCLUSION: FAP patients have a higher frequency of dento-osseous anomalies (p = 0.005). Bone abnormalities were more prevalent than dental anomalies (p = 0.001). Thus, FAP patients should be referred for dental examination and genetic counseling to perform early diagnosis of dento-osseous anomalies and evaluate the implications of the molecular findings in each particular family.","variants":[{"Name":"NM_000038.6(APC):c.1370C>G (p.Ser457Ter)","Chromosome":"5","Start":"112821953","Stop":"112821953","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":394439,"rule_based_match":true,"evidence_text":"c.1370C > G; p.Ser457*","llm_judgment":"PRESENT","evidence":"c.1370C > G; p.Ser457*","abstract_start":1138,"abstract_end":1160}]}
{"pmid":"32135595","title":"A case report of BCL11B mutation induced neurodevelopmental disorder and literature review","abstract":"<b>Objective:</b> To analyze the clinical , immunological and genetic features of a child with BCL11B mutation induced neurodevelopmental disorder. <b>Methods:</b> The clinical data and genetic test of a child with BCL11B mutation hospitalized in the Department of Rheumatology and Immunology in Children's Hospital of Chongqing Medical University in December 2018 were extracted and analyzed. The literature was searched with \"BCL11B mutation\" and \"immunodeficiency 49\" as key words in Chinese databases and Pubmed until January 2019 was reviewed. <b>Results:</b> A male patient aged 3 years and 11 months with facial dysmorphisms and delayed language and motor development was admitted due to neurodevelopmental retardation over two years. Laboratory tests showed normal human immunoglobulin (IgG 12.90 g/L, IgA 1.02 g/L, IgM 1.15 g/L, IgE 532 000 U/L), Trec (228) and proliferation of T and B cells. The lymphocyte subsets revealeda reduced percentage of B cells (0.108) but normal absolute numbers (0.574×10(-3)/L), and an increased percentage (0.828) as well as absolute numbers (4.415×10(-3)/L) of T cells. A heterozygous BCL11B mutation was detected by sanger sequencing, showing a de novo frameshift mutation c.1887_c.1893delCGGCGGG in exon 4. Two papers were found which were all in English, with total of 14 patients(13 patients with complete information). Thirteen mutations were reposed, including 7 frameshift, 2 nonsense, 2 missense, and 2 chromosomal rearrangements; Thirteen patients had heterozygous mutations. All patients had delayed language and motor development and facial dysplasia which were mainly hypertelorism, thin eyebrows and small palpebral fissures. Some patients had dental anomalies, ametropia and allergy, and a few were combined with immune impairment, but without overt signs of immunodeficiency. Only one patient had multisystem anomalies and profound immune deficiency. <b>Conclusions:</b> BCL11B is essential for development of the nervous and the immune system. In this study, the de novo mutation of BCL11B gene resulted in neurodevelopmental and immunological disorders.","variants":[{"Name":"NM_138576.4(BCL11B):c.1887_1893del (p.Gly630fs)","Chromosome":"14","Start":"99174943","Stop":"99174949","ReferenceAlleleVCF":"CCCCGCCG","AlternateAlleleVCF":"C","allel_id":1265643,"rule_based_match":false,"evidence_text":"c.1887_c.1893delCGGCGGG","llm_judgment":"PRESENT","evidence":"c.1887_c.1893delCGGCGGG","abstract_start":1217,"abstract_end":1240}]}
{"pmid":"21793738","title":"A mosaic activating mutation in AKT1 associated with the Proteus syndrome.","abstract":"BACKGROUND: The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state.\nMETHODS: We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots.\nRESULTS: Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation.\nCONCLUSIONS: The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.).","variants":[{"Name":"NM_001382430.1(AKT1):c.49G>A (p.Glu17Lys)","Chromosome":"14","Start":"104780214","Stop":"104780214","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29022,"rule_based_match":false,"evidence_text":"c.49G→A, p.Glu17Lys","llm_judgment":"PRESENT","evidence":"c.49G→A, p.Glu17Lys","abstract_start":857,"abstract_end":876}]}
{"pmid":"29074860","title":"Steroid hormone profiling in obese and nonobese women with polycystic ovary syndrome.","abstract":"The study explored differences in the steroidogenic pathway between obese and nonobese women with polycystic ovary syndrome (PCOS) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). 1044 women with PCOS (including 350 lean, 312 overweight and 382 obese) and 366 control women without PCOS (including 203 lean, 32 overweight and 131 obese) were enrolled. The differences in steroid hormones were amplified in lean PCOS versus lean controls compared with obese PCOS versus obese controls. Compared with obese PCOS, lean PCOS demonstrated increased dehydroepiandrosterone sulfate (P = 0.015), 17-hydropregnenolone (P = 0.003), 17-hydroprogesterone (17-OHP) (P < 0.001), progesterone (P < 0.001) and estrone (P < 0.001) levels. Enzyme activity evaluation showed that lean PCOS had increased activity of P450c17 (17-hydropregnenolone/pregnenolone, P < 0.001), P450aro (P < 0.001), 3βHSD2 (progesterone/ pregnenolone and 17-OHP/17-hydropregnenolone, both P < 0.001) and decreased activity of P450c21(11-deoxycorticorsterone/progesterone and 11-deoxycortisol/17-OHP, P < 0.001). Moreover, we found higher frequencies of CYP21A2- (encoding P450c21) c.552 C > G (p. D184E) in lean PCOS compared with obese PCOS patients (P = 0.006). In conclusion, this study demonstrated for the first time that the adrenal-specific enzyme P450c21 showed decreased activity in lean PCOS patients, and that the adrenal androgen excess may play different roles in lean and obese PCOS patients, which represents as different enzyme activity in the steroidogenic pathway.","variants":[{"Name":"NM_000500.9(CYP21A2):c.552C>G (p.Asp184Glu)","Chromosome":"6","Start":"32039548","Stop":"32039548","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":76517,"rule_based_match":true,"evidence_text":"c.552 C > G (p. D184E)","llm_judgment":"PRESENT","evidence":"c.552 C > G (p. D184E)","abstract_start":1155,"abstract_end":1177}]}
{"pmid":"27122014","title":"Homozygous mutation in the APOA1BP is associated with a lethal infantile leukoencephalopathy.","abstract":"Febrile-induced neurodegenerative diseases are a heterogeneous group of genetic disorders most commonly inborn errors of metabolism that result in irreversible damage involving the central nervous system. Here, we report on five siblings of consanguineous family who developed normally for the first 6-12 months of life then presented with a severe leukoencephalopathy following a trivial febrile illness. Using homozygosity mapping followed by whole exome sequencing, we identified a homozygous c. 281C>A mutation in the APOA1BP gene resulting in substitution of a highly conserved alanine residue with aspartic acid (p.Ala94Asp). APOA1BP encodes for epimerase that catalyzes the R to S epimerization of NAD(P)XH, a crucial step in the dehydration of these toxic metabolites accumulating during cellular metabolism. This is the first report of a defect in the nicotinamide nucleotide repair system in humans.","variants":[{"Name":"NM_144772.3(NAXE):c.281C>A (p.Ala94Asp)","Chromosome":"1","Start":"156592199","Stop":"156592199","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":247557,"rule_based_match":true,"evidence_text":"c. 281C>A","llm_judgment":"PRESENT","evidence":"c. 281C>A","abstract_start":496,"abstract_end":505}]}
{"pmid":"33838017","title":"Immune cytopenias as a continuum in inborn errors of immunity: An in-depth clinical and immunological exploration.","abstract":"BACKGROUND: Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune-mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms.\nOBJECTIVE: Aim of this study is to provide clinical-immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation.\nMETHODS: We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0-18 years at onset of immune cytopenias and/or immune-dysregulation. The cohort was divided into two groups (IEI+ and IEI-), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19).\nRESULTS: IEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p < .05) specific characteristics, namely T/B lymphopenia, decrease in naїve T-cells%, switched memory B-cells%, plasmablasts%, and/or immunoglobulins, increase in effector/central memory T-cells% and CD21low B-cells%. Except for DiGeorge and three ALPS patients, only 2/9 CVID patients had a molecular diagnosis for IEI: one carrying the pathogenic variant CR2:c.826delT, the likely pathogenic variant PRF1:c.272C> and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn.\nCONCLUSION: The synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI-related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted-gene variants responsible for IEI phenotype.","variants":[{"Name":"NM_012452.3(TNFRSF13B):c.260T>A (p.Ile87Asn)","Chromosome":"17","Start":"16948923","Stop":"16948923","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":610057,"rule_based_match":false,"evidence_text":"TNFRSF13B:p.Ile87Asn","llm_judgment":"PRESENT","evidence":"TNFRSF13B:p.Ile87Asn","abstract_start":1948,"abstract_end":1968}]}
{"pmid":"23125284","title":"A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia.","abstract":"The mitochondrial respiratory chain complex IV (cytochrome c oxidase) is a multi-subunit enzyme that transfers electrons from cytochrome c to molecular oxygen, yielding water. Its biogenesis requires concerted expression of mitochondria- and nuclear-encoded subunits and assembly factors. In this report, we describe a homozygous missense mutation in FAM36A from a patient who displays ataxia and muscle hypotonia. The FAM36A gene is a remote, putative ortholog of the fungal complex IV assembly factor COX20. Messenger RNA (mRNA) and protein co-expression analyses support the involvement of FAM36A in complex IV function in mammals. The c.154A>C mutation in the FAM36A gene, a mutation that is absent in sequenced exomes, leads to a reduced activity and lower levels of complex IV and its protein subunits. The FAM36A protein is nearly absent in patient's fibroblasts. Cells affected by the mutation accumulate subassemblies of complex IV that contain COX1 but are almost devoid of COX2 protein. We observe co-purification of FAM36A and COX2 proteins, supporting that the FAM36A defect hampers the early step of complex IV assembly at the incorporation of the COX2 subunit. Lentiviral complementation of patient's fibroblasts with wild-type FAM36A increases the complex IV activity as well as the amount of holocomplex IV and of individual subunits. These results establish the function of the human gene FAM36A/COX20 in complex IV assembly and support a causal role of the gene in complex IV deficiency.","variants":[{"Name":"NM_198076.6(COX20):c.154A>C (p.Thr52Pro)","Chromosome":"1","Start":"244842055","Stop":"244842055","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":70537,"rule_based_match":true,"evidence_text":"c.154A>C","llm_judgment":"PRESENT","evidence":"c.154A>C","abstract_start":639,"abstract_end":647}]}
{"pmid":"24459464","title":"An N-Terminal Missense Mutation in STX11 Causative of FHL4 Abrogates Syntaxin-11 Binding to Munc18-2.","abstract":"Familial hemophagocytic lymphohistiocytosis (FHL) is an often-fatal hyperinflammatory disorder caused by autosomal recessive mutations in PRF1, UNC13D, STX11, and STXBP2. We identified a homozygous STX11 mutation, c.173T > C (p.L58P), in three patients presenting clinically with hemophagocytic lymphohistiocytosis from unrelated Pakistani families. The mutation yields an amino acid substitution in the N-terminal Habc domain of syntaxin-11 and resulted in defective natural killer cell degranulation. Notably, syntaxin-11 expression was decreased in patient cells. However, in an ectopic expression system, syntaxin-11 L58P was expressed at levels comparable to wild-type syntaxin-11, but did not bind Munc18-2. Moreover, another N-terminal syntaxin-11 mutant, R4A, also did not bind Munc18-2. Thus, we have identified a novel missense STX11 mutation causative of FHL type 4. The syntaxin-11 R4A and L58P mutations reveal that both the N-terminus and Habc domain of syntaxin-11 are required for binding to Munc18-2, implying similarity to the dynamic binary binding of neuronal syntaxin-1 to Munc18-1.","variants":[{"Name":"NM_003764.4(STX11):c.173T>C (p.Leu58Pro)","Chromosome":"6","Start":"144186800","Stop":"144186800","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":102897,"rule_based_match":true,"evidence_text":"c.173T > C (p.L58P)","llm_judgment":"PRESENT","evidence":"c.173T > C (p.L58P)","abstract_start":214,"abstract_end":233}]}
{"pmid":"31448411","title":"The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies.","abstract":"Signal Transducer and Activator of Transcription 1 (STAT1) is a DNA-binding signal transducer that regulates transcription of specific genes in response to IFNγ and IFNα/β stimulation. Loss-of-function mutations impairing STAT1 activity are known to confer susceptibility to intracellular bacterial and viral diseases. Conversely, the few known activating mutations of STAT1 allow predisposition to chronic mucocutaneous candidiasis disease, and occur in patients with combined immunodeficiency and defective Th1 and Th17 responses. Here, we report on a de novo gain-of-function (GoF) STAT1 mutation (c.1398C>G, p.Ser466Arg) identified by exome sequencing in an individual with brain calcification, arthritis, recurrent pericarditis, leukopenia, thrombocytopenia and low C3 levels, a phenotype resembling an interferonopathy. The Ser466Arg change affects a highly conserved residue located in the DNA binding domain of the protein and the amino acid substitution was documented to have an activating role both in vitro and in vivo. Altogether, clinical features and functional studies are compatible with hyperactivation of the Interferon pathways, highlighting a role of STAT1 GoF mutation in clinical phenotypes fitting interferonopathies.","variants":[{"Name":"NM_007315.4(STAT1):c.1398C>G (p.Ser466Arg)","Chromosome":"2","Start":"190983690","Stop":"190983690","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1698855,"rule_based_match":true,"evidence_text":"c.1398C>G, p.Ser466Arg","llm_judgment":"PRESENT","evidence":"c.1398C>G, p.Ser466Arg","abstract_start":601,"abstract_end":623}]}
{"pmid":"29288010","title":"Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia.","abstract":"BACKGROUND AND AIMS: Type I hyperlipoproteinemia, also known as familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disorder caused by variants in LPL, APOC2, APOA5, LMF1 or GPIHBP1 genes. The aim of this study was to identify novel variants in the LPL gene causing lipoprotein lipase deficiency and to understand the molecular mechanisms.\nMETHODS AND RESULTS: A total of 3 individuals with severe hypertriglyceridemia and recurrent pancreatitis were selected from the Lipid Clinic at Sahlgrenska University Hospital and LPL was sequenced. In vitro experiments were performed in human embryonic kidney 293T/17 (HEK293T/17) cells transiently transfected with wild type or mutant LPL plasmids. Cell lysates and media were used to analyze LPL synthesis and secretion. Media were used to measure LPL activity. Patient 1 was compound heterozygous for three known variants: c.337T > C (W113R), c.644G > A (G215E) and c.1211T > G (M404R); patient 2 was heterozygous for the known variant c.658A > C (S220R) while patient 3 was homozygous for a novel variant in the exon 5 c.679G > T (V227F). All the LPL variants identified were loss-of-function variants and resulted in a substantial reduction in the secretion of LPL protein.\nCONCLUSION: We characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic.","variants":[{"Name":"NM_000237.3(LPL):c.644G>A (p.Gly215Glu)","Chromosome":"8","Start":"19954222","Stop":"19954222","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16561,"rule_based_match":true,"evidence_text":"c.644G > A (G215E)","llm_judgment":"PRESENT","evidence":"c.644G > A (G215E)","abstract_start":907,"abstract_end":925}]}
{"pmid":"34513534","title":"Primary Ciliary Dyskinesia: Ancestral Haplotypes Analysis of the RSPH4A Founder Mutation in Puerto Rico.","abstract":"Genetic mutations in >50 genes, including <i>RSPH4A,</i> can lead to primary ciliary dyskinesia (PCD). <i>RSPH4A</i> mutations affect radial spokes, which alter the configuration of the ciliary ultrastructure and lead to chronic oto-sinopulmonary disease. The <i>RSPH4A</i> [c.921+3_6delAAGT] founder mutation was described as one cause of PCD without laterality defects in Puerto Rico. The average Puerto Rican genetic composition includes 64% European, 21% African ancestral, and 15% Native-American or Taino, a native tribe in the Caribbean at the start of the European colonization, genes. Due to the relatively elevated Taino ancestry on the island, it might have contributed to the endemicity of the <i>RSPH4A</i> [c.921+3_6delAAGT] splice site mutation. However, the ancestry of this mutation is still not confirmed. This article describes the two pediatric PCD cases with the Puerto Rican foundermutationand reports an ancestral haplotype analysis of the <i>RSPH4A</i> [c.921+3_6delAAGT] splice site mutation. A median-joining haplotype network was constructed with the genome sequence data from 104 Puerto Rican subjects in the 1000 Genomes Project (1000GP). This study found that the <i>RSPH4A</i> [c.921+3_6delAAGT] splice site mutation was carried to Puerto Rico from Europe by conquistadors or shortly after the conquest and that it gained frequency on the island through genetic drift fueled by a subsequent population expansion.","variants":[{"Name":"NM_001010892.3(RSPH4A):c.921+3_921+6del","Chromosome":"6","Start":"116623002","Stop":"116623005","ReferenceAlleleVCF":"TAGTA","AlternateAlleleVCF":"T","allel_id":94432,"rule_based_match":false,"evidence_text":"c.921+3_6delAAGT","llm_judgment":"PRESENT","evidence":"c.921+3_6delAAGT","abstract_start":275,"abstract_end":291}]}
{"pmid":"30730599","title":"Revealing the functions of novel mutations in RAB3GAP1 in Martsolf and Warburg micro syndromes.","abstract":"PURPOSE: Martsolf (MS) and Warburg micro syndromes (WARBM) are rare autosomal recessive inherited allelic disorders, which share similar clinical features including microcephaly, intellectual disability, brain malformations, ocular abnormalities, and spasticity. Here, we revealed the functions of novel mutations in RAB3GAP1 in a Turkish female patient with MS and two siblings with WARBM. We also present a review of MS patients as well as all reported RAB3GAP1 pathogenic mutations in the literature.\nMETHODS: We present a female with MS phenotype and two siblings with WARBM having more severe phenotypes. We utilized whole-exome sequencing to identify the molecular basis of these syndromes and confirmed suspected variants by Sanger sequencing. Quantitative (q) RT-PCR analysis was carried out to reveal the functions of novel splice site mutation detected in MS patient.\nRESULTS: We found a novel homozygous c.2607-1G>C splice site mutation in intron 22 of RAB3GAP1 in MS patient and a novel homozygous c.2187_2188delinsCT, p.(Met729_Lys730delinsIleTer) mutation in exon 19 of RAB3GAP1 in the WARBM patients. We showed exon skipping in MS patient by Sanger sequencing and gel electrophoresis. qRT-PCR analysis demonstrated the reduced expression of RAB3GAP1 in the patient with the c.2607-1G>C splice site mutation compared to a healthy control individual.\nCONCLUSION: Here, we have studied two novel RAB3GAP1 mutations in two different phenotypes; a MS associated novel splice site mutation, and a WARBM1 associated novel deletion-insertion mutation. Our findings suggest that this splice site mutation is responsible for milder phenotype and the deletion-insertion mutation presented here is associated with severe phenotype.","variants":[{"Name":"NM_012233.3(RAB3GAP1):c.2607-1G>C","Chromosome":"2","Start":"135164593","Stop":"135164593","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1166547,"rule_based_match":true,"evidence_text":"c.2607-1G>C","llm_judgment":"PRESENT","evidence":"c.2607-1G>C","abstract_start":915,"abstract_end":926},{"Name":"NM_012233.3(RAB3GAP1):c.2187_2188delinsCT (p.Met729_Lys730delinsIleTer)","Chromosome":"2","Start":"135153774","Stop":"135153775","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"CT","allel_id":1166548,"rule_based_match":true,"evidence_text":"c.2187_2188delinsCT, p.(Met729_Lys730delinsIleTer)","llm_judgment":"PRESENT","evidence":"c.2187_2188delinsCT, p.(Met729_Lys730delinsIleTer)","abstract_start":1010,"abstract_end":1060}]}
{"pmid":"25601412","title":"Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic features in French patients.","abstract":"Fructose-1,6-bisphosphatase (FBPase) deficiency is a very rare autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase gene(FBP1). Disease is mainly revealed by hypoglycemia and lactic acidosis, both symptoms being characteristic for an enzymatic block in the last steps of the gluconeogenesis. Twelve patients with FBPase deficiency were diagnosed in France in the 2001-2013 period, using a diagnostic system based on a single blood sample which allows simultaneous enzyme activity measurement on mononuclear white blood cells and molecular analysis. Sequencing of exons and intron-exon junctions of FBP1 gene was completed in unsolved cases by a gene dosage assay developed for each exon. For most patients, first metabolic decompensation occurred before two years of age with a similar sequence: the triggering factors were fever, fasting, or decrease of food intake. However, diagnosis was made late at a mean age of 3 years, as mitochondrial defects or glycogen storage diseases were firstly suspected. Enzyme activity in leukocytes was dramatically decreased (<10%). Twelve different mutations were identified in 22 alleles among them seven were novels: one missense mutation c.472C > T, one point deletion c.48del, one point duplication c.865dupA, one deletion-insertion, and two splice mutations (c.427-1del and c.825 + 1G > A). We described the first intragenic deletion in FBP1 (g.97,364,754_97,382,011del) in homozygous state. Our report also confirms that this very rare disease is misdiagnosed, as other energetic defects are firstly suspected.","variants":[{"Name":"NM_000507.4(FBP1):c.472C>T (p.Arg158Trp)","Chromosome":"9","Start":"94610016","Stop":"94610016","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":553128,"rule_based_match":true,"evidence_text":"c.472C > T","llm_judgment":"PRESENT","evidence":"c.472C > T","abstract_start":1211,"abstract_end":1221},{"Name":"NM_000507.4(FBP1):c.825+1G>A","Chromosome":"9","Start":"94605456","Stop":"94605456","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":390676,"rule_based_match":true,"evidence_text":"c.825 + 1G > A","llm_judgment":"PRESENT","evidence":"c.825 + 1G > A","abstract_start":1349,"abstract_end":1363}]}
{"pmid":"23810505","title":"Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California.","abstract":"California uses a unique method to screen newborns for cystic fibrosis (CF) that includes gene scanning and DNA sequencing after only one California-40 cystic fibrosis transmembrane conductance regulator (CFTR) panel mutation has been identified in hypertrypsinogenemic specimens. Newborns found by sequencing to have one or more additional mutations or variants (including novel variants) in the CFTR gene are systematically followed, allowing for prospective assessment of the pathogenic potential of these variants. During the first 3 years of screening, 55 novel variants were identified. Six of these novel variants were discovered in five screen-negative participants and three were identified in multiple unrelated participants. Ten novel variants (c.2554_2555insT, p.F1107L, c.-152G>C, p.L323P, p.L32M, c.2883_2886dupGTCA, c.2349_2350insT, p.K114del, c.-602A>T, and c.2822delT) were associated with a CF phenotype (42% of participants were diagnosed at 4 to 25 months of age), whereas 26 were associated with CFTR-related metabolic syndrome to date. Associations with the remaining novel variants were confounded by the presence of other diseases or other mutations in cis or by inadequate follow-up. These findings have implications for how CF newborn screening and follow-up is conducted and will help guide which genotypes should, and which should not, be considered screen positive for CF in California and elsewhere.","variants":[{"Name":"NM_000492.4(CFTR):c.2822del (p.Leu941fs)","Chromosome":"7","Start":"117603696","Stop":"117603696","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":544191,"rule_based_match":true,"evidence_text":"c.2822delT","llm_judgment":"PRESENT","evidence":"c.2822delT","abstract_start":874,"abstract_end":884}]}
{"pmid":"22475618","title":"Hereditary motor neuron disease in a large Norwegian family with a \"H46R\" substitution in the superoxide dismutase 1 gene.","abstract":"Mutant genes associated with Charcot Marie Tooth type 2, distal hereditary motor neuropathy and familial amyotrophic lateral sclerosis may cause overlapping clinical phenotypes. We performed whole genome linkage analysis, haplotype analysis, sequencing and detailed clinical and neurophysiological investigations in a large Norwegian kindred with a condition that clinically had been classified as Charcot Marie Tooth type 2. The mutation c.140A>G, p.His47Arg (alias p.His46Arg or H46R) in the superoxide dismutase 1 gene (SOD1) segregated with the disease. The patients present a hereditary motor neuropathy-like clinical picture and long survival (mean 29years). To our knowledge, this is the first extensive report describing a large non-Japanese kindred. The prognostic implications of the condition seen in this family have little in common with what is normally associated with sporadic amyotrophic lateral sclerosis and illustrates the complexity of the genetic etiology of lower motor neuron disease.","variants":[{"Name":"NM_000454.5(SOD1):c.140A>G (p.His47Arg)","Chromosome":"21","Start":"31663857","Stop":"31663857","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":29803,"rule_based_match":true,"evidence_text":"c.140A>G, p.His47Arg","llm_judgment":"PRESENT","evidence":"c.140A>G, p.His47Arg","abstract_start":439,"abstract_end":459}]}
{"pmid":"22257947","title":"Non-bullous congentital ichthyosiform erythroderma associated with homozygosity for a novel missense mutation in an ATP binding domain of ABCA12.","abstract":"A Mutations in the gene encoding the ABCA12 protein are associated with different subtypes of autosomal recessive congenital ichthyosis (ARCI), including Harlequin ichthyosis (HI), lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE). Disruption of ABCA12 lead to perturbed lipid transport in lamellar granules and a defective intercellular lipid layer of the stratum corneum. We have identified a large consanguineous Pakistani family affected by NCIE. Autozygosity mapping showed that affected individuals are homozygous for the ABCA12 gene region. Subsequent mutation screening revealed a homozygous c.4676G>T transition in all five affected family members. The mutation results in a novel p.G1559V substitution within the first nucleotide binding domain of ABCA12. The combined results support that an ABCA12 missense mutation, despite its location in a functional domain, may be associated with a mild ichthyosis phenotype. Furthermore, our findings increase the mutational spectrum in ABCA12 associated with ARCI of diagnostic and prognostic importance.","variants":[{"Name":"NM_173076.3(ABCA12):c.4676G>T (p.Gly1559Val)","Chromosome":"2","Start":"214980547","Stop":"214980547","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1517627,"rule_based_match":true,"evidence_text":"c.4676G>T","llm_judgment":"PRESENT","evidence":"c.4676G>T","abstract_start":636,"abstract_end":645}]}
{"pmid":"24697219","title":"De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability, autistic behaviors and epilepsy.","abstract":"Eukaryotic elongation factor 1, alpha-2 (eEF1A2) protein is involved in protein synthesis, suppression of apoptosis, and regulation of actin function and cytoskeletal structure. EEF1A2 gene is highly expressed in the central nervous system and Eef1a2 knockout mice show the neuronal degeneration. Until now, only one missense mutation (c.208G > A, p.Gly70Ser) in EEF1A2 has been reported in two independent patients with neurological disease. In this report, we described two patients with de novo mutations (c.754G > C, p.Asp252His and c.364G > A, p.Glu122Lys) in EEF1A2 found by whole-exome sequencing. Common clinical features are shared by all four individuals: severe intellectual disability, autistic behavior, absent speech, neonatal hypotonia, epilepsy and progressive microcephaly. Furthermore, the two patients share the similar characteristic facial features including a depressed nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth. These data strongly indicate that a new recognizable disorder is caused by EEF1A2 mutations.","variants":[{"Name":"NM_001958.5(EEF1A2):c.754G>C (p.Asp252His)","Chromosome":"20","Start":"63493155","Stop":"63493155","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":190048,"rule_based_match":true,"evidence_text":"c.754G > C, p.Asp252His","llm_judgment":"PRESENT","evidence":"c.754G > C, p.Asp252His","abstract_start":509,"abstract_end":532},{"Name":"NM_001958.5(EEF1A2):c.364G>A (p.Glu122Lys)","Chromosome":"20","Start":"63495062","Stop":"63495062","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":190049,"rule_based_match":true,"evidence_text":"c.364G>A (p.Glu122Lys)","llm_judgment":"PRESENT","evidence":"p.Glu122Lys","abstract_start":549,"abstract_end":560}]}
{"pmid":"33949776","title":"Childhood onset nexilin dilated cardiomyopathy: A heterozygous and a homozygous case.","abstract":"Pathogenic heterozygous NEXN variants are associated with progressive dilated cardiomyopathy (DCM) usually presenting around 50 years of age. We describe an asymptomatic boy who had transient DCM at 3 months of age, that resolved by 4 months. Presently, at 11 years of age, he has normal cardiac function with signs of mild DCM on cardiac MRI. Genetic diagnostics revealed a paternally derived, heterozygous 1949_1951del class 4 variant in NEXN. His father had mild DCM with mildly reduced systolic function. The second patient presented with fetal hydrops at 33 weeks gestation requiring emergency caesarian delivery. Postnatally she required ventilation and continuous inotropic support for left ventricle systolic dysfunction. She died after 2 weeks when therapy was withdrawn. Homozygous c.1174C > T,p.(R392*) class 4 variants in the NEXN gene were found via WES. Microscopic investigation showed endomyocardial fibroelastosis. Her parents, both heterozygous carriers, had normal cardiac function and the family history was normal. These patients show a new clinical spectrum of pediatric cardiac disease seen in heterozygous and homozygous NEXN variants, ranging from mild, transient DCM to a severe, fatal neonatal DCM. These patients support the inclusion of the NEXN gene in the investigation of pediatric patients with DCM, even in cases with transient DCM.","variants":[{"Name":"NM_144573.4(NEXN):c.1174C>T (p.Arg392Ter)","Chromosome":"1","Start":"77933402","Stop":"77933402","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":228518,"rule_based_match":true,"evidence_text":"c.1174C > T,p.(R392*)","llm_judgment":"PRESENT","evidence":"c.1174C > T,p.(R392*)","abstract_start":792,"abstract_end":813}]}
{"pmid":"33672558","title":"Pancytopenia, Recurrent Infection, Poor Wound Healing, Heterotopia of the Brain Probably Associated with A Candidate Novel de Novo","abstract":"CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the <i>CDC42</i> gene in mammalian physiology remains largely unclear. Here, we report the genetic and functional characterization of a non-consanguineous Saudi family with a single affected individual. Clinical examinations revealed poor wound healing, heterotopia of the brain, pancytopenia, and recurrent infections. Whole exome sequencing revealed a de novo missense variant (c.101C > A, p.Pro34Gln) in the <i>CDC42</i> gene. The functional assays revealed a substantial reduction in the growth and motility of the patient cells as compared to the normal cells control. Homology three-dimensional (3-D) modeling of CDC42 revealed that the Pro34 is important for the proper protein secondary structure. In conclusion, we report a candidate disease-causing variant, which requires further confirmation for the etiology of <i>CDC42</i> pathogenesis. This represents the first case from the Saudi population. The current study adds to the spectrum of mutations in the <i>CDC42</i> gene that might help in genetic counseling and contributes to the CDC42-related genetic and functional characterization. However, further studies into the molecular mechanisms that are involved are needed in order to determine the role of the <i>CDC42</i> gene associated with aberrant cell migration and immune response.","variants":[{"Name":"NM_001791.4(CDC42):c.101C>A (p.Pro34Gln)","Chromosome":"1","Start":"22078579","Stop":"22078579","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1000184,"rule_based_match":true,"evidence_text":"c.101C > A, p.Pro34Gln","llm_judgment":"PRESENT","evidence":"c.101C > A, p.Pro34Gln","abstract_start":647,"abstract_end":669}]}
{"pmid":"32498547","title":"A novel","abstract":"PURPOSE: This study aimed to examine pathogenic mutation within one Chinese family of five-generations suffering from autosomal dominant cataract.\nMETHODS: Next-generation sequencing and Sanger sequencing were used to find the pathogenic variants.\nRESULTS: A rare mutation, c.563G > A, in <i>CRYBB2</i> gene was found in the proband that showed symptom of non-syndromic congenital autosomal dominant cataract. This mutation had been found in all affected individuals and in one healthy infant, but it did not exist between two individuals who did not develop such disease in that family, as well as in 100 healthy subjects who showed no relation with that family. Cataracts in this family varied with different severity of lens opacities and elongation of axial length.\nCONCLUSION: One missense mutation c.563G > A is reported in the <i>CRYBB2</i> gene among one Chinese family suffering from early-onset cataract, and associated novel phenotypes are the elongation of axial length and the types of cataract. Our results expand the spectrum of associated phenotypes of <i>CRYBB2</i> mutation.","variants":[{"Name":"NM_000496.3(CRYBB2):c.563G>A (p.Arg188His)","Chromosome":"22","Start":"25231717","Stop":"25231717","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":264987,"rule_based_match":true,"evidence_text":"c.563G > A","llm_judgment":"PRESENT","evidence":"c.563G > A","abstract_start":274,"abstract_end":284}]}
{"pmid":"31056671","title":"Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies.","abstract":"We performed next generation sequencing on 1696 patients with epilepsy and intellectual disability using a gene panel with 480 epilepsy-related genes including all GABAA receptor subunit genes (GABRs), and we identified six de novo GABR mutations, two novel GABRA5 mutations (c.880G>T, p.V294F and c.1238C>T, p.S413F), two novel GABRA1 mutations (c.778C>T, p.P260S and c.887T>C, p.L296S/c.944G>T, p.W315L) and two known GABRA1 mutations (c.335G>A, p.R112Q and c.343A>G, p.N115D) in six patients with intractable early onset epileptic encephalopathy. The α5(V294F and S413F) and α1(P260S and L296S/W315L) subunit residue substitutions were all in transmembrane domains, while the α1(R112Q and N115R) subunit residue substitutions were in the N-terminal GABA binding domain. Using multidisciplinary approaches, we compared effects of mutant GABAA receptor α5 and α1 subunits on the properties of recombinant α5β3γ2 and α1β3γ2 GABAA receptors in both neuronal and non-neuronal cells and characterized their effects on receptor clustering, biogenesis and channel function. GABAA receptors containing mutant α5 and α1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABAA receptor function and decreased GABA binding potency. Our study identified GABRA5 as a causative gene for early onset epileptic encephalopathy and expands the mutant GABRA1 phenotypic spectrum, supporting growing evidence that defects in GABAergic neurotransmission contribute to early onset epileptic encephalopathy phenotypes.","variants":[{"Name":"NM_000810.4(GABRA5):c.880G>T (p.Val294Phe)","Chromosome":"15","Start":"26943217","Stop":"26943217","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":676984,"rule_based_match":true,"evidence_text":"c.880G>T, p.V294F","llm_judgment":"PRESENT","evidence":"c.880G>T, p.V294F","abstract_start":276,"abstract_end":293},{"Name":"NM_000810.4(GABRA5):c.1238C>T (p.Ser413Phe)","Chromosome":"15","Start":"26948082","Stop":"26948082","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":676985,"rule_based_match":true,"evidence_text":"c.1238C>T, p.S413F","llm_judgment":"PRESENT","evidence":"c.1238C>T, p.S413F","abstract_start":298,"abstract_end":316}]}
{"pmid":"36168867","title":"Two heterozygous mutations in the calcium/calmodulin-dependent serine protein kinase gene (CASK) in cases with developmental disorders.","abstract":"BACKGROUND: The calcium/calmodulin-dependent serine protein kinase gene (CASK) is an essential gene in mammals, critical for neurodevelopment. The purpose of this study is to expand the understanding of the diagnosis of CASK-linked disorders.\nMATERIALS/METHODS: From clinical and genetic mutational analyses, relevant data in 2 Han Chinese patients were collected and analyzed. Real-time quantitative PCR (RT-qPCR) was performed to investigate the CASK expression levels in the patients. The X-chromosome inactivation (XCI) patterns of the patients and their nuclear families were tested by quantitation of methylation of the polymorphic human androgen receptor (HUMARA) locus.\nRESULTS: Two Han Chinese patients both presented with intellectual disability (ID), microcephaly with pontine and cerebellar hypoplasia (MICPCH). Two de novo mutations of c.82C>T (p.Arg28*) and c.846C>G (p.Tyr282*) in CASK have been investigated and predicted to be deleterious, which have produced truncated proteins. The functional protein association network of STRING (http://string-db.org) generated three-dimensional (3D) atomic models based on protein sequences in CASK and two Arg28 and Tyr282 residues were marked. RT-qPCR showed lower copy numbers of CASK expression in the patients than in their parents, as well as the sex- and age- matched control groups. Patient 1 showed a skewed XCI pattern, while no related changes noted in patient 2.\nCONCLUSIONS: Patients carrying different nonsense variants may have different degrees of different clinical phenotypes. This study expands the spectrum of genotype and phenotype correlations of CASK-linked disorders in the Han Chinese ethnicity and provides new insights into the molecular mechanism.","variants":[{"Name":"NM_001367721.1(CASK):c.846C>G (p.Tyr282Ter)","Chromosome":"X","Start":"41636647","Stop":"41636647","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":430790,"rule_based_match":true,"evidence_text":"c.846C>G (p.Tyr282*)","llm_judgment":"PRESENT","evidence":"c.846C>G (p.Tyr282*)","abstract_start":872,"abstract_end":892}]}
{"pmid":"30213762","title":"Further evidence of a causal association between AGO1, a critical regulator of microRNA formation, and intellectual disability/autism spectrum disorder.","abstract":"Among the many regulators of microRNA formation, Argonaute 1 (AGO1) plays critical roles in RNA interference, which controls a wide range of biological activities. Recent large-scale genomic studies have identified at least five patients with intellectual disability/autism spectrum disorder who had de novo mutations in AGO1, but detailed clinical information was not available. The recognizable clinical features that are associated with AGO1 mutations remain to be determined. The proposita was a 15-year-old girl with diffuse hypotonia, infrequent seizures, and intellectual disability with an intelligence quotient of 41. She had characteristic facial features consisting of telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures. Serial computed tomography scans showed progressive calcification in the globus pallidus that became evident during childhood. A whole exome analysis in trio revealed a de novo heterozygous mutation in AGO1, i.e., c.595G > A p.(Gly199Ser). The distinctive facial features, i.e., telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures, closely resembled previously reported patients who had a chromosomal microdeletion encompassing AGO1 locus. The combinatory phenotype of such characteristic facial features and radiographic features, i.e. progressive calcification in the globus pallidus, in the presently reported patient suggest that AGO1 mutations lead to a syndromic form of intellectual disability/autism spectrum disorder. Distinctive facial features with early and progressive calcification in the globus pallidus may be suggestive of the presence of AGO1 mutations.","variants":[{"Name":"NM_012199.5(AGO1):c.595G>A (p.Gly199Ser)","Chromosome":"1","Start":"35893756","Stop":"35893756","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1289816,"rule_based_match":true,"evidence_text":"c.595G > A p.(Gly199Ser)","llm_judgment":"PRESENT","evidence":"c.595G > A p.(Gly199Ser)","abstract_start":1003,"abstract_end":1027}]}
{"pmid":"28649545","title":"","abstract":"Patient samples play an important role in the study of inherited metabolic disorders. Open-access biorepositories distribute such samples. Unfortunately, not all clinically-characterized samples come with reliable genotype information. During studies directed toward population frequency assessments of cystinosis, a rare heritable disorder, we sequenced the <i>CTNS</i> gene from 14 cystinosis-related samples obtained from the Coriell Cell Repository. As a result, the disease genotypes of 7 samples were determined for the first time. The reported disease genotypes of 2 additional samples were found to be incorrect. Furthermore, we identified and experimentally confirmed a novel mutation, c.225 + 5G > A, which causes skipping of the 5th exon and is associated with infantile nephropathic cystinosis.","variants":[{"Name":"NM_004937.3(CTNS):c.225+5G>A","Chromosome":"17","Start":"3648936","Stop":"3648936","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3092942,"rule_based_match":true,"evidence_text":"c.225 + 5G > A","llm_judgment":"PRESENT","evidence":"c.225 + 5G > A","abstract_start":695,"abstract_end":709}]}
{"pmid":"31723423","title":"A Hong Kong Chinese kindred with familial hypocalciuric hypercalcaemia caused by","abstract":"Familial hypocalciuric hypercalcaemia (FHH) is a genetic disorder of altered calcium homeostasis. Mutations in the <i>CASR</i>, <i>GNA11</i> and <i>AP2S1</i> genes have been reported to cause FHH. We report a Hong Kong Chinese kindred with FHH type 3 (FHH3) caused by mutations in <i>AP2S1</i>. The proband, a 51-year-old woman with hypercalcaemia, was initially diagnosed to have primary hyperparathyroidism but repeated parathyroidectomy failed to normalize her plasma calcium concentrations. Later, FHH was suspected and yet no mutations were identified in the <i>CASR</i> gene which causes FHH type 1 (FHH1), the most common form of FHH. Genetic testing of <i>AP2S1</i> revealed a heterozygous c.43C>T (p.Arg15Cys) mutation, confirming the diagnosis of FHH3. The elder brother and niece of the proband, who both have hypercalcaemia, were found to harbour the same mutation. To our knowledge, this is the first Chinese kindred of FHH3 reported in the English literature.","variants":[{"Name":"NM_004069.6(AP2S1):c.43C>T (p.Arg15Cys)","Chromosome":"19","Start":"46846103","Stop":"46846103","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48023,"rule_based_match":true,"evidence_text":"c.43C>T (p.Arg15Cys)","llm_judgment":"PRESENT","evidence":"c.43C>T (p.Arg15Cys)","abstract_start":698,"abstract_end":718}]}
{"pmid":"32934261","title":"Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients.","abstract":"Pulmonary Arterial Hypertension (PAH) is a rare and fatal disease where knowledge about its genetic basis continues to increase. In this study, we used targeted panel sequencing in a cohort of 624 adult and pediatric patients from the Spanish PAH registry. We identified 11 rare variants in the ATP-binding Cassette subfamily C member 8 (ABCC8) gene, most of them with splicing alteration predictions. One patient also carried another variant in SMAD1 gene (c.27delinsGTAAAG). We performed an ABCC8 in vitro biochemical analyses using hybrid minigenes to confirm the correct mRNA processing of 3 missense variants (c.211C > T p.His71Tyr, c.298G > A p.Glu100Lys and c.1429G > A p.Val477Met) and the skipping of exon 27 in the novel splicing variant c.3394G > A. Finally, we used structural protein information to further assess the pathogenicity of the variants. The results showed 11 novel changes in ABCC8 and 1 in SMAD1 present in PAH patients. After in silico and in vitro biochemical analyses, we classified 2 as pathogenic (c.3288_3289del and c.3394G > A), 6 as likely pathogenic (c.211C > T, c.1429G > A, c.1643C > T, c.2422C > A, c.2694 + 1G > A, c.3976G > A and SMAD1 c.27delinsGTAAAG) and 3 as Variants of Uncertain Significance (c.298G > A, c.2176G > A and c.3238G > A). In all, we show that coupling in silico tools with in vitro biochemical studies can improve the classification of genetic variants.","variants":[{"Name":"NM_000352.6(ABCC8):c.1429G>A (p.Val477Met)","Chromosome":"11","Start":"17443216","Stop":"17443216","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3720058,"rule_based_match":true,"evidence_text":"c.1429G>A p.Val477Met","llm_judgment":"PRESENT","evidence":"c.1429G > A p.Val477Met","abstract_start":665,"abstract_end":688}]}
{"pmid":"37803361","title":"Genetic insights into PHARC syndrome: identification of a novel frameshift mutation in ABHD12.","abstract":"BACKGROUND: Mutations in ABHD12 (OMIM: 613,599) are associated with polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) syndrome (OMIM: 612674), which is a rare autosomal recessive neurodegenerative disease. PHARC syndrome is easily misdiagnosed as other neurologic disorders, such as retinitis pigmentosa, Charcot-Marie-Tooth disease, and Refsum disease, due to phenotype variability and slow progression. This paper presents a novel mutation in ABHD12 in two affected siblings with PHARC syndrome phenotypes. In addition, we summarize genotype-phenotype information of the previously reported patients with ABHD12 mutation.\nMETHODS: Following a thorough medical evaluation, whole-exome sequencing was done on the proband to look for potential genetic causes. This was followed by confirmation of identified variant in the proband and segregation analysis in the family by Sanger sequencing. The variants were interpreted based on the American College of Medical Genetics and Genomics (ACMG) guidelines.\nRESULTS: A novel pathogenic homozygous frameshift variant, NM_001042472.3:c.601dup, p.(Val201GlyfsTer4), was identified in exon 6 of ABHD12 (ACMG criteria: PVS1 and PM2, PM1, PM4, PP3, and PP4). Through Sanger sequencing, we showed that this variant is co-segregated with the disease in the family. Further medical evaluations confirmed the compatibility of the patients' phenotype with PHARC syndrome.\nCONCLUSIONS: Our findings expand the spectrum of mutations in the ABHD12 and emphasize the significance of multidisciplinary diagnostic collaboration among clinicians and geneticists to solve the differential diagnosis of related disorders. Moreover, a summary based on mutations found so far in the ABHD12 gene did not suggest a clear genotype-phenotype correlation for PHARC syndrome.","variants":[{"Name":"NM_001042472.3(ABHD12):c.601dup (p.Val201fs)","Chromosome":"20","Start":"25314942","Stop":"25314943","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":1784724,"rule_based_match":true,"evidence_text":"NM_001042472.3:c.601dup, p.(Val201GlyfsTer4)","llm_judgment":"PRESENT","evidence":"NM_001042472.3:c.601dup, p.(Val201GlyfsTer4)","abstract_start":1093,"abstract_end":1137}]}
{"pmid":"35170849","title":"Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS.","abstract":"Autoinflammatory diseases are a heterogenous group of disorders defined by fever and systemic inflammation suggesting involvement of genes regulating innate immune responses. Patients with homozygous loss-of-function variants in the OTU-deubiquitinase OTULIN suffer from neonatal-onset OTULIN-related autoinflammatory syndrome (ORAS) characterized by fever, panniculitis, diarrhea, and arthritis. Here, we describe an atypical form of ORAS with distinct clinical manifestation of the disease caused by two new compound heterozygous variants (c.258G>A (p.M86I)/c.500G>C (p.W167S)) in the OTULIN gene in a 7-year-old affected by a life-threatening autoinflammatory episode with sterile abscess formation. On the molecular level, we find binding of OTULIN to linear ubiquitin to be compromised by both variants; however, protein stability and catalytic activity is most affected by OTULIN variant p.W167S. These molecular changes together lead to increased levels of linear ubiquitin linkages in patient-derived cells triggering the disease. Our data indicate that the spectrum of ORAS patients is more diverse than previously thought and, thus, supposedly asymptomatic individuals might also be affected. Based on our results, we propose to subdivide the ORAS into classical and atypical entities.","variants":[{"Name":"NM_138348.6(OTULIN):c.258G>A (p.Met86Ile)","Chromosome":"5","Start":"14678709","Stop":"14678709","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1704893,"rule_based_match":true,"evidence_text":"c.258G>A (p.M86I)","llm_judgment":"PRESENT","evidence":"c.258G>A (p.M86I)","abstract_start":542,"abstract_end":559},{"Name":"NM_138348.6(OTULIN):c.500G>C (p.Trp167Ser)","Chromosome":"5","Start":"14687552","Stop":"14687552","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1704894,"rule_based_match":true,"evidence_text":"c.500G>C (p.W167S)","llm_judgment":"PRESENT","evidence":"c.500G>C (p.W167S)","abstract_start":560,"abstract_end":578}]}
{"pmid":"26670336","title":"Enhanced SRSF5 Protein Expression Reinforces Lamin A mRNA Production in HeLa Cells and Fibroblasts of Progeria Patients.","abstract":"The Hutchinson Gilford Progeria Syndrome (HGPS) is a rare genetic disease leading to accelerated aging. Three mutations of the LMNA gene leading to HGPS were identified. The more frequent ones, c.1824C>T and c.1822G>A, enhance the use of the intron 11 progerin 5'splice site (5'SS) instead of the LMNA 5'SS, leading to the production of the truncated dominant negative progerin. The less frequent c.1868C>G mutation creates a novel 5'SS (LAΔ35 5'SS), inducing the production of another truncated LMNA protein (LAΔ35). Our data show that the progerin 5'SS is used at low yield in the absence of HGPS mutation, whereas utilization of the LAΔ35 5'SS is dependent upon the presence of the c.1868C>G mutation. In the perspective to correct HGPS splicing defects, we investigated whether SR proteins can modify the relative yields of utilization of intron 11 5'SSs. By in cellulo and in vitro assays, we identified SRSF5 as a direct key regulator increasing the utilization of the LMNA 5'SS in the presence of the HGPS mutations. Enhanced SRSF5 expression in dermal fibroblasts of HGPS patients as well as PDGF-BB stimulation of these cells decreased the utilization of the progerin 5'SS, and improves nuclear morphology, opening new therapeutic perspectives for premature aging.","variants":[{"Name":"NM_170707.4(LMNA):c.1824C>T (p.Gly608=)","Chromosome":"1","Start":"156138613","Stop":"156138613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29539,"rule_based_match":true,"evidence_text":"c.1824C>T","llm_judgment":"PRESENT","evidence":"c.1824C>T","abstract_start":194,"abstract_end":203}]}
{"pmid":"24035930","title":"Molecular genetic assay of mucopolysaccharidosis IVA in South China.","abstract":"Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Molecular mutational analysis was performed by PCR product sequencing for fourteen exons and exon-intron boundaries of GALNS gene in 21 patients from 19 unrelated families with severe MPS IVA in South China. We identified fifteen different mutations, including 10 reported mutations (p.P125L, p.G290S, p.M318R, p.G340D, p.L366P, p.R386C, p.A392V, c.1243-1G>C, p.L440RfsX54 and p.X523E) and five novel mutations (p.N177S, p.G290R, p.F306S, p.W403_T404delinsCS, p.W520X). All five novel mutations were inherited from parents of the patients and not found in 100 normal control alleles. Three mutations, p.M318R, p.L366P and p.R386C were common, accounting for 36.8% of mutant alleles investigated. One patient homozygous of p.A392V and the other two unrelated patients homozygous of p.L366P presented classical disease course. The results show that the GALNS gene has a different mutational spectrum in South China as compared to other regions. The p.A392V and p.L366P mutations were associated with severe phenotype of MPS IVA.","variants":[{"Name":"NM_000512.5(GALNS):c.868G>C (p.Gly290Arg)","Chromosome":"16","Start":"88835243","Stop":"88835243","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1036248,"rule_based_match":false,"evidence_text":"c.868G>C (p.Gly290Arg)","llm_judgment":"PRESENT","evidence":"G290R","abstract_start":591,"abstract_end":596},{"Name":"NM_000512.5(GALNS):c.953T>G (p.Met318Arg)","Chromosome":"16","Start":"88832047","Stop":"88832047","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":196191,"rule_based_match":false,"evidence_text":"c.953T>G (p.Met318Arg)","llm_judgment":"PRESENT","evidence":"M318R","abstract_start":472,"abstract_end":477},{"Name":"NM_000512.5(GALNS):c.374C>T (p.Pro125Leu)","Chromosome":"16","Start":"88841040","Stop":"88841040","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":861281,"rule_based_match":false,"evidence_text":"c.374C>T (p.Pro125Leu)","llm_judgment":"PRESENT","evidence":"P125L","abstract_start":454,"abstract_end":459},{"Name":"NM_000512.5(GALNS):c.1243-1G>C","Chromosome":"16","Start":"88822711","Stop":"88822711","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1036159,"rule_based_match":true,"evidence_text":"c.1243-1G>C","llm_judgment":"PRESENT","evidence":"c.1243-1G>C","abstract_start":515,"abstract_end":526}]}
{"pmid":"24989646","title":"SNaPshot reveals high mutation and carrier frequencies of 15 common hearing loss mutants in a Chinese newborn cohort.","abstract":"Genetic causes account for more than half of congenital hearing loss cases. The most frequent mutations found in non-syndromic hearing loss patients occur in GJB2 and SLC26A4. Mitochondrial genome mutations are also prevalent. However, the frequency of common hearing loss mutations in the Chinese population has not yet been well estimated. Here, we implemented the SNaPshot genotyping method to investigate the carrier frequency of 15 commonly reported hearing loss mutations in GJB2, SLC26A4 and the mitochondrial genome based on a cohort of 5800 neonates in China. Up to 15.9% (923/5800) of the newborns carry at least one mutant allele. The top three were GJB2-c.109G>A, GJB2-c.235delC, and SLC26A4-c.919A>G, with notably high carrier frequencies of 1/10, 1/53 and 1/62 respectively, and mt-7444G>A with 1/141 was the most frequent allele in the mitochondrial genome. In this cohort, 0.48% (28/5800) of neonates were genetically diagnosed with hearing loss, from which seven cases failed an OAE test. This is the first epidemiological study of non-syndromic hearing loss in Chinese newborns indicating a notably high carrier frequency (1 per 6.3 newborns) among these 15 mutant alleles. Our carrier frequency data also aid in effective risk assessment and genetic counseling for hearing loss patients in the Chinese population.","variants":[{"Name":"NM_000441.2(SLC26A4):c.919A>G (p.Thr307Ala)","Chromosome":"7","Start":"107683455","Stop":"107683455","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":679196,"rule_based_match":true,"evidence_text":"SLC26A4-c.919A>G","llm_judgment":"PRESENT","evidence":"SLC26A4-c.919A>G","abstract_start":696,"abstract_end":712}]}
{"pmid":"23851939","title":"A hypofunctional PAX1 mutation causes autosomal recessively inherited otofaciocervical syndrome.","abstract":"Otofaciocervical syndrome (OFCS) is an autosomal recessively inherited disorder characterized by facial dysmorphism, external ear anomalies with preauricular pits and hearing impairment, branchial cysts or fistulas, anomalies of the vertebrae and the shoulder girdle, and mild intellectual disability. In a large consanguineous family with OFCS from Turkey, we performed whole-exome sequencing (WES) of a single pooled DNA sample of four affected individuals. Filtering for variants with a percentage of alternate reads ≥ 90 % and a coverage of at least five reads identified only a single novel homozygous variant, c.497G>T, located in PAX1 that co-segregated with the disease in the family. PAX1 encodes a transcription factor with a critical role in pattern formation during embryogenesis in vertebrates. The mutation is predicted to substitute the glycine at position 166 to valine (p.G166V) within the highly conserved paired-box domain of the PAX1 protein. We performed a dual luciferase reporter assay to examine the transactivation of a regulatory sequence in the Nkx3-2 promoter region, which is a direct target of mouse Pax1 transcriptional regulation. We observed a significantly reduced transactivation in HEK293T cells overexpressing Pax1(G157V) in comparison to Pax1(WT) expressing cells, indicating a reduced DNA-binding affinity of the mutant protein. Taken together, our results show that the strategy of pooling DNA is a powerful, cost-effective application for WES in consanguineous families and establish PAX1 as a new disease-causing gene for OFCS and as part of the EYA-DACH-SIX-PAX network, important in early embryogenesis.","variants":[{"Name":"NM_001257096.2(PAX1):c.497G>T (p.Gly166Val)","Chromosome":"20","Start":"21706648","Stop":"21706648","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":94572,"rule_based_match":true,"evidence_text":"c.497G>T","llm_judgment":"PRESENT","evidence":"c.497G>T","abstract_start":616,"abstract_end":624}]}
{"pmid":"32442430","title":"Late-onset Pseudoxanthoma Elasticum Associated with a Hypomorphic ABCC6 Variant.","abstract":"PURPOSE: To describe patients with late-onset pseudoxanthoma elasticum (PXE) associated with a likely hypomorphic ABCC6 variant.\nDESIGN: Retrospective observational case series.\nMETHODS: Clinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling.\nRESULTS: Three patients, in whom vision symptoms first arose at 80 years of age or later, showed age-related macular degeneration (AMD)-like fundus changes. However, features characteristic of PXE, including discrete angioid streaks and reduced fluorescence on late-phase indocyanine green angiography, prompted genetic testing which revealed the c.1171A>G variant in combination with a large deletion in the ABCC6 gene in each case. None of the patients had obvious skin changes or cardiovascular disease atypical for their age. Comparative molecular modeling supported the hypothesis that the c.1171A>G<sub>ABCC6</sub> variant acted as a hypomorphic variant.\nCONCLUSIONS: Late-onset PXE extends the spectrum of ectopic calcification disorders caused by mutations in ABCC6 and may clinically be limited to the eye, mimicking AMD. Patients may be identified based on specific ocular changes, whereas skin and cardiovascular changes may remain ambiguous. The study provides evidence for a role for hypomorphic ABCC6 variants in the pathogenesis of PXE.","variants":[{"Name":"NM_001171.6(ABCC6):c.1171A>G (p.Arg391Gly)","Chromosome":"16","Start":"16202006","Stop":"16202006","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":260088,"rule_based_match":true,"evidence_text":"c.1171A>G","llm_judgment":"PRESENT","evidence":"c.1171A>G","abstract_start":624,"abstract_end":633}]}
{"pmid":"30820150","title":"Identities and frequencies of variants in","abstract":"Purpose: Primary congenital glaucoma (PCG) is a clinically and genetically heterogeneous disease. The present study was undertaken to find the genetic causes of PCG segregating in 36 large consanguineous Pakistani families.\nMethods: Ophthalmic examination including fundoscopy, or slit-lamp microscopy was performed to clinically characterize the PCG phenotype. Genomic nucleotide sequences of the <i>CYP1B1</i> and <i>LTBP2</i> genes were analyzed with either Sanger or whole exome sequencing. In silico prediction programs were used to assess the pathogenicity of identified alleles. ClustalW alignments were performed to determine evolutionary conservation, and three-dimensional (3D) modeling was performed using HOPE and Phyre2 software.\nResults: Among the known loci, mutations in <i>CYP1B1</i> and <i>LTBP2</i> are the common causes of PCG. Therefore, we analyzed the genomic nucleotide sequences of <i>CYP1B1</i> and <i>LTBP2</i>, and detected probable pathogenic variants cosegregating with PCG in 14 families. These included the three novel (c.542T>A, c.1436A>G, and c.1325delC) and five known (c.868dupC, c.1168C>T, c.1169G>A, c.1209InsTCATGCCACC, and c.1310C>T) variants in <i>CYP1B1</i>. Two of the novel variants are missense substitutions [p.(Leu181Gln), p.(Gln479Arg)], which replaced evolutionary conserved amino acids, and are predicted to be pathogenic by various in silico programs, while the third variant (c.1325delC) is predicted to cause reading frameshift and premature truncation of the protein. A single mutation, p.(Arg390His), causes PCG in six (~43%) of the 14 <i>CYP1B1</i> mutations harboring families, and thus, is the most common variant in this cohort. Surprisingly, we did not find any <i>LTBP2</i> pathogenic variants in the families, which further supports the genetic heterogeneity of PCG in the Pakistani population.\nConclusions: In conclusion, results of the present study enhance our understanding of the genetic basis of PCG, support the notion of a genetic modifier of <i>CYP1B1</i>, and contribute to the development of genetic testing protocols and genetic counseling for PCG in Pakistani families.","variants":[{"Name":"NM_000104.4(CYP1B1):c.868dup (p.Arg290fs)","Chromosome":"2","Start":"38074520","Stop":"38074521","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":79360,"rule_based_match":true,"evidence_text":"c.868dupC","llm_judgment":"PRESENT","evidence":"c.868dupC","abstract_start":1105,"abstract_end":1114}]}
{"pmid":"19208379","title":"The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism.","abstract":"Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.","variants":[{"Name":"NM_000372.5(TYR):c.1205G>A (p.Arg402Gln)","Chromosome":"11","Start":"89284793","Stop":"89284793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18818,"rule_based_match":true,"evidence_text":"c.1205G > A","llm_judgment":"PRESENT","evidence":"c.1205G > A","abstract_start":194,"abstract_end":205}]}
{"pmid":"30939602","title":"A De Novo Dominant Negative Mutation in DNM1L Causes Sudden Onset Status Epilepticus with Subsequent Epileptic Encephalopathy.","abstract":"Mitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity. <i>DNM1L</i> encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for proper mitochondrial fission. The clinical phenotype of <i>DNM1L</i> mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in <i>DNM1L</i> (c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in <i>DNM1L</i>.","variants":[{"Name":"NM_012062.5(DNM1L):c.1207C>T (p.Arg403Cys)","Chromosome":"12","Start":"32731362","Stop":"32731362","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":211619,"rule_based_match":true,"evidence_text":"c.1207C > T, p.R403C","llm_judgment":"PRESENT","evidence":"c.1207C > T, p.R403C","abstract_start":810,"abstract_end":830}]}
{"pmid":"29600799","title":"Whole exome sequencing in a multi-generation family from India reveals a genetic variation c.10C>T (p.Gln4Ter) in keratin 5 gene associated with Dowling-Degos disease.","abstract":"","variants":[{"Name":"NM_000424.4(KRT5):c.10C>T (p.Gln4Ter)","Chromosome":"12","Start":"52520287","Stop":"52520287","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":77096,"rule_based_match":true,"evidence_text":"c.10C>T (p.Gln4Ter)","llm_judgment":"PRESENT","evidence":"c.10C>T (p.Gln4Ter)","abstract_start":null,"abstract_end":null}]}
{"pmid":"26791926","title":"Clinical and molecular analysis of two Chinese siblings with Cockayne syndrome","abstract":"OBJECTIVE: Cockayne syndrome is a rare disease and difficult to be recognized. This study aimed to expand the knowledge of the clinical and molecular characteristics of the children with Cockayne syndrome (CS).\nMETHOD: Clinical data of two siblings with classic CS of Guangzhou Women and Children's Medical Center from July 2013 to November 2014 were obtained and analyzed. The whole DNA of peripheral blood was collected from two CS siblings and their parents. Amplification of all exons and adjacent introns for ERCC6 gene was conducted using PCR, and measurement of reaction product was performed to find mutation sites by two-way sequencing.\nRESULT: Two affected siblings were males, and came from unconsanguineous parents, 7 years and 5 months old and 4 years and 8 months old, respectively. They were in treatment because of developmental and mental retardation for years. When they were younger than one year of age, their heights and weight were within normal limits. However, poor growth of height and weight and psychomotor retardation appeared after one and a half years of age, as well as skin and eye sensitivity to sunshine, hearing impairment, optic nerve atrophy, microcephaly, and deep-set eyes. The proband's height was 90.8 cm, and weight 9.1 kg, head circumference 41 cm, and chest circumference 44 cm when he was taken to hospital. The elder brother of the proband had a height of 92 cm, weight 11.2 kg, head circumference 41 cm, and chest circumference 44 cm when he was taken to hospital. When the proband was four and a half years old, ventricular enlargement, hypomyelination, and brain atrophy were detected for his elder brother at 7 years of age by cranial MRI. MRS imaging indicated that damages occurred at the left and right sides of dorsal thalamus, lobus insularis, along with the left half circle of central neurons. Symmetrical calcification on bilateral basal ganglia was found on the brain CT scan. Pathogenic compound heterozygous c. 1357C > T (p.Arg453Ter) and c. 1607T > G (p.Leu536Trp) mutations of ERCC6 gene were identified in the two siblings which were separately inherited from their unaffected parents.\nCONCLUSION: CS children are usually normal at birth, however, they have severe clinical characteristics such as poor growth, psychomotor retardation, cerebral injury, microcephalus, deep-set eyes, and skin sensitivity to sunshine. ERCC6 gene mutation usually occurs, and it is easy to misdiagnose CS as cerebral palsy, primary microcephaly, and so on.","variants":[{"Name":"NM_000124.4(ERCC6):c.1607T>G (p.Leu536Trp)","Chromosome":"10","Start":"49500616","Stop":"49500616","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":836915,"rule_based_match":true,"evidence_text":"c. 1607T > G (p.Leu536Trp)","llm_judgment":"PRESENT","evidence":"c. 1607T > G (p.Leu536Trp)","abstract_start":2000,"abstract_end":2026}]}
{"pmid":"38649918","title":"A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts.","abstract":"BACKGROUND: This report presents a clinical case of syndromic rod-cone dystrophy due to a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts. The presence of renal agenesis and cryptorchidism expands the clinical manifestations due to ARL2BP variants. The detailed, long-term follow-up contributes valuable insights into disease progression, aiding clinical diagnosis and patient management.\nCASE PRESENTATION: The male patient complained of photophobia as the first symptom when he was 20 years old followed by nyctalopia, loss of central visual acuity and peripheral visual field ten years later. Genetic analysis identified a likely pathogenic homozygous variant (c.294-1G > C) involving the splicing acceptor site of intron 4. Reported symptoms together with full-field stimulus threshold testing, electroretinogram and advanced multimodal imaging allowed us to recognize the typical characteristics of a mixed retinal dystrophy. Despite the end-stage retinal disease, this patient still retained a useful residual vision at 63 years and had a slow disease progression during the last 5 years of evaluation.\nDISCUSSION AND CONCLUSIONS: Our findings underscore the variable clinical presentation of ARL2BP variants, emphasizing the importance of a nuanced approach in diagnosing and managing patients. The presence of renal cysts warrants consideration of a differential diagnosis, particularly with Senior-Loken (SLS), Bardet-Biedl (BBS) and Joubert syndromes (JS) but also with Short Rib Thoracic Dysplasia 9, highlighting the need for careful phenotypic evaluation in these cases.","variants":[{"Name":"NM_012106.4(ARL2BP):c.294-1G>C","Chromosome":"16","Start":"57250410","Stop":"57250410","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3496830,"rule_based_match":true,"evidence_text":"c.294-1G > C","llm_judgment":"PRESENT","evidence":"c.294-1G > C","abstract_start":739,"abstract_end":751}]}
{"pmid":"20485507","title":"A male with unilateral microphthalmia reveals a role for TMX3 in eye development.","abstract":"Anophthalmia and microphthalmia are important birth defects, but their pathogenesis remains incompletely understood. We studied a patient with severe unilateral microphthalmia who had a 2.7 Mb deletion at chromosome 18q22.1 that was inherited from his mother. In-situ hybridization showed that one of the deleted genes, TMX3, was expressed in the retinal neuroepithelium and lens epithelium in the developing murine eye. We re-sequenced TMX3 in 162 patients with anophthalmia or microphthalmia, and found two missense substitutions in unrelated patients: c.116G>A, predicting p.Arg39Gln, in a male with unilateral microphthalmia and retinal coloboma, and c.322G>A, predicting p.Asp108Asn, in a female with unilateral microphthalmia and severe micrognathia. We used two antisense morpholinos targeted against the zebrafish TMX3 orthologue, zgc:110025, to examine the effects of reduced gene expression in eye development. We noted that the morphant larvae resulting from both morpholinos had significantly smaller eye sizes and reduced labeling with islet-1 antibody directed against retinal ganglion cells at 2 days post fertilization. Co-injection of human wild type TMX3 mRNA rescued the small eye phenotype obtained with both morpholinos, whereas co-injection of human TMX3(p.Arg39Gln) mutant mRNA, analogous to the mutation in the patient with microphthalmia and coloboma, did not rescue the small eye phenotype. Our results show that haploinsufficiency for TMX3 results in a small eye phenotype and represents a novel genetic cause of microphthalmia and coloboma. Future experiments to determine if other thioredoxins are important in eye morphogenesis and to clarify the mechanism of function of TMX3 in eye development are warranted.","variants":[{"Name":"NM_019022.5(TMX3):c.116G>A (p.Arg39Gln)","Chromosome":"18","Start":"68711389","Stop":"68711389","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171701,"rule_based_match":true,"evidence_text":"c.116G>A","llm_judgment":"PRESENT","evidence":"c.116G>A","abstract_start":555,"abstract_end":563}]}
{"pmid":"26782016","title":"Proximal myopathy with focal depletion of mitochondria and megaconial congenital muscular dystrophy are allelic conditions caused by mutations in CHKB.","abstract":"We recently evaluated two of the original three patients (siblings) diagnosed with Proximal Myopathy with Focal Depletion of Mitochondria. The condition was named for the distinctive pattern of enlarged mitochondria around the periphery of muscle fibres with a complete absence in the middle. These siblings, aged 37 and 40, are cognitively normal with mild non-progressive muscle weakness and a susceptibility to rhabdomyolysis. Both were shown to be compound heterozygotes for novel mutations (c.263C>T + c.950T>A) in CHKB, the gene currently associated with Megaconial Congenital Muscular Dystrophy. Individuals with this condition have early-onset muscle weakness and profound intellectual disability but share the same unique pattern on muscle biopsy as was noted in Proximal Myopathy with Focal Depletion of Mitochondria; focal depletion of mitochondria was surrounded by abnormally large \"megaconial\" mitochondria. Thus the phenotypic spectrum of CHKB mutations ranges from a congenital muscular dystrophy with intellectual disability to a later-onset non-progressive muscular weakness with normal cognition.","variants":[{"Name":"NM_005198.5(CHKB):c.263C>T (p.Pro88Leu)","Chromosome":"22","Start":"50582319","Stop":"50582319","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":442355,"rule_based_match":true,"evidence_text":"c.263C>T","llm_judgment":"PRESENT","evidence":"c.263C>T","abstract_start":496,"abstract_end":504}]}
{"pmid":"18513683","title":"Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome--an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13.","abstract":"We present clinical, radiological, biochemical, and genetic findings on six patients from two consanguineous families that show EDS-like features and radiological findings of a mild skeletal dysplasia. The EDS-like findings comprise hyperelastic, thin, and bruisable skin, hypermobility of the small joints with a tendency to contractures, protuberant eyes with bluish sclerae, hands with finely wrinkled palms, atrophy of the thenar muscles, and tapering fingers. The skeletal dysplasia comprises platyspondyly with moderate short stature, osteopenia, and widened metaphyses. Patients have an increased ratio of total urinary pyridinolines, lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP), of approximately 1 as opposed to approximately 6 in EDS VI or approximately 0.2 in controls. Lysyl and prolyl residues of collagens were underhydroxylated despite normal lysyl hydroxylase and prolyl 4-hydroxylase activities; underhydroxylation was a generalized process as shown by mass spectrometry of the alpha1(I)- and alpha2(I)-chain-derived peptides of collagen type I and involved at least collagen types I and II. A genome-wide SNP scan and sequence analyses identified in all patients a homozygous c.483_491 del9 SLC39A13 mutation that encodes for a membrane-bound zinc transporter SLC39A13. We hypothesize that an increased Zn(2+) content inside the endoplasmic reticulum competes with Fe(2+), a cofactor that is necessary for hydroxylation of lysyl and prolyl residues, and thus explains the biochemical findings. These data suggest an entity that we have designated \"spondylocheiro dysplastic form of EDS (SCD-EDS)\" to indicate a generalized skeletal dysplasia involving mainly the spine (spondylo) and striking clinical abnormalities of the hands (cheiro) in addition to the EDS-like features.","variants":[{"Name":"NM_001128225.3(SLC39A13):c.483_491del (p.Phe162_Ala164del)","Chromosome":"11","Start":"47412412","Stop":"47412420","ReferenceAlleleVCF":"ACCTTCCTGG","AlternateAlleleVCF":"A","allel_id":17171,"rule_based_match":true,"evidence_text":"c.483_491 del9 SLC39A13","llm_judgment":"PRESENT","evidence":"c.483_491 del9 SLC39A13","abstract_start":1202,"abstract_end":1225}]}
{"pmid":"26721323","title":"An Ashkenazi founder mutation in the PKHD1 gene.","abstract":"Autosomal recessive polycystic kidney disease (ARPKD) is usually detected late in pregnancies in embryos with large echogenic kidneys accompanied by oligohydramnios. Hundreds of private pathogenic variants have been identified in the large PKHD1 gene in various populations. Yet, because of the large size of the gene, segregation analysis of microsatellite polymorphic markers residing in the PKDH1 locus has commonly been utilized for prenatal diagnosis. Keeping in mind the limitations of this strategy, we utilized it for testing 7 families with affected fetuses or newborns, of which in 5 at least one parent was Ashkenazi, and identified that the same haplotype was shared by the majority of the Ashkenazi parents (7/9). This led us to suspect that they carry the same founder mutation. Whole Exome analysis of DNA from a fetus of one of the families detected an already known pathogenic variant c.3761_3762delCCinsG, an indel variant resulting in frameshift (p.Ala1254GlyfsX49). This variant was detected in 9 parents (5 families), of them 7 individuals were Ashkenazi and one Moroccan Jew who shared the same haplotype, and one Ashkenazi, who carried the same variant on a recombinant haplotype. Screening for this variant in 364 Ashkenazi individuals detected 2 carriers. These findings suggest that although c.3761_3762delCCinsG is considered one of the frequent variants detected in unrelated individuals, and was thought to have occurred independently on various haplotypes, it is in fact a founder mutation in the Ashkenazi population.","variants":[{"Name":"NM_138694.4(PKHD1):c.3761_3762delinsG (p.Ala1254fs)","Chromosome":"6","Start":"52026048","Stop":"52026049","ReferenceAlleleVCF":"GG","AlternateAlleleVCF":"C","allel_id":102292,"rule_based_match":false,"evidence_text":"c.3761_3762delCCinsG","llm_judgment":"PRESENT","evidence":"c.3761_3762delCCinsG","abstract_start":902,"abstract_end":922}]}
{"pmid":"30920170","title":"Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.","abstract":"BACKGROUND: Mutations in mitochondrial aminoacyl tRNA synthetases form a subgroup of mitochondrial disorders often only perturbing brain function by affecting mitochondrial translation. Here we report two siblings with mitochondrial disease, due to compound heterozygous mutations in the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, presenting with severe neurological symptoms but normal mitochondrial function in skeletal muscle biopsies and cultured skin fibroblasts.\nMETHODS: Whole exome sequencing on genomic DNA samples from both subjects and their parents identified two compound heterozygous variants c.833T>G (p.Val278Gly) and c.938A>T (p.Lys313Met) in the WARS2 gene as potential disease-causing variants. We generated patient-derived neuroepithelial stem cells and modeled the disease in yeast and Drosophila melanogaster to confirm pathogenicity.\nRESULTS: Biochemical analysis of patient-derived neuroepithelial stem cells revealed a mild combined complex I and IV defect, while modeling the disease in yeast demonstrated that the reported aminoacylation defect severely affects respiration and viability. Furthermore, silencing of wild type WARS2 in Drosophila melanogaster showed that a partial defect in aminoacylation is enough to cause lethality.\nCONCLUSIONS: Our results establish the identified WARS2 variants as disease-causing and highlight the benefit of including human neuronal models, when investigating mutations specifically affecting the nervous system.","variants":[{"Name":"NM_015836.4(WARS2):c.938A>T (p.Lys313Met)","Chromosome":"1","Start":"119033056","Stop":"119033056","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":434545,"rule_based_match":true,"evidence_text":"c.938A>T (p.Lys313Met)","llm_judgment":"PRESENT","evidence":"c.938A>T (p.Lys313Met)","abstract_start":648,"abstract_end":670},{"Name":"NM_015836.4(WARS2):c.833T>G (p.Val278Gly)","Chromosome":"1","Start":"119033161","Stop":"119033161","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1333201,"rule_based_match":true,"evidence_text":"c.833T>G (p.Val278Gly)","llm_judgment":"PRESENT","evidence":"c.833T>G (p.Val278Gly)","abstract_start":621,"abstract_end":643}]}
{"pmid":"31706999","title":"Novel splice site and nonsense variants in INVS cause infantile nephronophthisis.","abstract":"Nephronophthisis is an autosomal recessive disease characterized by cystic kidney disease with progression to end-stage kidney disease in children and adolescents with or without extra-renal involvement. It is caused by biallelic pathogenic variants in 19 genes including INVS that encodes a ciliary protein essential for renal development and left-right axis establishment. We report a child with bilateral enlarged, echogenic, polycystic kidneys with end-stage renal disease, anemia and metabolic acidosis caused by biallelic novel pathogenic variants, c.796 + 5G > A and c.1789C > T in INVS. We show that the variant, c.796 + 5G > A disrupts the canonical splicing and nonsense variant, c.1789C > T results in nonsense mediated decay.","variants":[{"Name":"NM_014425.5(INVS):c.796+5G>A","Chromosome":"9","Start":"100240245","Stop":"100240245","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1323434,"rule_based_match":true,"evidence_text":"c.796 + 5G > A","llm_judgment":"PRESENT","evidence":"c.796 + 5G > A","abstract_start":555,"abstract_end":569},{"Name":"NM_014425.5(INVS):c.1789C>T (p.Arg597Ter)","Chromosome":"9","Start":"100284324","Stop":"100284324","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":678068,"rule_based_match":true,"evidence_text":"c.1789C>T","llm_judgment":"PRESENT","evidence":"c.1789C > T","abstract_start":574,"abstract_end":585}]}
{"pmid":"32920683","title":"Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature.","abstract":"Autosomal recessive hypophosphatemic rickets type 1 (ARHR1) was reported to be caused by homozygous mutation of dentin matrix protein 1 (DMP1). To date, very few cases have been reported. Here, we summarized clinical, laboratory and imaging findings of ARHR1 patients in our hospital. Literature review was performed to analyze genotype-phenotype correlation. Five Chinese patients from three unrelated pedigrees presented with lower extremity deformity and short stature. Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found. X-ray uncovered coexistence of osteomalacia and osteosclerosis. Although areal bone mineral density (aBMD) of axial bone measured by dual-energy X-ray absorptiometry was relatively high in all patients, volumetric BMD (vBMD) and microstructure of one adult patient's peripheral bone detected by HR-pQCT were damaged. Mutation analyses of DMP1 revealed three homozygous mutations including two novel mutations, c.54 + 1G > C and c.94C > A (p.E32X), and a reported mutation c.184-1G > A. Genotype-phenotype correlation analysis including 30 cases (25 from literature review and 5 from our study) revealed that patients harboring mutations affecting C-terminal fragment of DMP1 presented with shorter stature (Z score of height = - 3.4 ± 1.6 vs - 1.0 ± 1.6, p = 0.001) and lower serum phosphate level (0.70 ± 0.15 vs 0.84 ± 0.16, p = 0.03) than those harboring mutations only affecting N-terminal fragment. In summary, we reported five Chinese ARHR1 patients and identified two novel DMP1 mutations. High aBMD and local osteosclerosis in axial bone with low vBMD and damaged microstructure in peripheral bone were featured. Genotype-phenotype correlation analysis confirmed the important role of C-terminal fragment of DMP1.","variants":[{"Name":"NM_004407.4(DMP1):c.184-1G>A","Chromosome":"4","Start":"87661961","Stop":"87661961","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2894684,"rule_based_match":true,"evidence_text":"c.184-1G>A","llm_judgment":"PRESENT","evidence":"c.184-1G > A","abstract_start":1061,"abstract_end":1073}]}
{"pmid":"30039856","title":"Exome sequencing revealed a novel deletion in the ERCC8 gene in an Iranian family with Cockayne syndrome.","abstract":"Cockayne syndrome (CS) is one the rare DNA-repair deficiency disorders with autosomal recessive inheritance. Failure to thrive and microcephaly are the major criteria of diagnosis. Owing to genetic heterogeneity of CS, whole exome sequencing is promising way to determine the genetic basis of the disease. Here, we present c.1053delT in ERCC8 gene in an Iranian family with symptom of CS using whole exome sequencing. The deletion was novel and was not previously reported elsewhere.","variants":[{"Name":"NM_000082.4(ERCC8):c.1053del (p.Ser351fs)","Chromosome":"5","Start":"60887509","Stop":"60887509","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":830905,"rule_based_match":true,"evidence_text":"c.1053delT","llm_judgment":"PRESENT","evidence":"c.1053delT","abstract_start":323,"abstract_end":333}]}
{"pmid":"33209960","title":"A Generic Assay to Detect Aberrant","abstract":"Identification and characterization of disease-associated variants in monogenic disorders is an important aspect of diagnosis, genetic counseling, prediction of disease severity, and development of therapy. However, the effects of disease-associated variants on pre-mRNA splicing and mRNA degradation are difficult to predict and often missed. Here we present a generic assay for unbiased identification and quantification of arylsulfatase B (<i>ARSB</i>) mRNA for molecular diagnosis of patients with mucopolysaccharidosis VI (MPS VI). We found that healthy control individuals have inefficient <i>ARSB</i> splicing because of natural skipping of exon 5 and inclusion of two pseudoexons in introns 5 and 6. Analyses of 12 MPS VI patients with 10 different genotypes resulted in identification of a 151-bp intron inclusion caused by the c.1142+2T>C variant and detection of low <i>ARSB</i> expression from alleles with the c.629A>G variant. A special case showed skipping of exon 4 and low <i>ARSB</i> expression. Although no disease-associated DNA variant could be identified in this patient, the molecular diagnosis could be made based on RNA. These results highlight the relevance of RNA-based analyses to establish a molecular diagnosis of MPS VI. We speculate that inefficient natural splicing of <i>ARSB</i> may be a target for therapy based on promotion of canonical splicing.","variants":[{"Name":"NM_000046.5(ARSB):c.1142+2T>C","Chromosome":"5","Start":"78885582","Stop":"78885582","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":550431,"rule_based_match":true,"evidence_text":"c.1142+2T>C","llm_judgment":"PRESENT","evidence":"c.1142+2T>C","abstract_start":837,"abstract_end":848}]}
{"pmid":"22652533","title":"A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer.","abstract":"BACKGROUND: RAD51D and RAD54L are involved in homologous recombination, and rare mutations in RAD51D were recently found in breast-ovarian cancer families. This study investigated RAD51D and RAD54L for mutations in breast and ovarian cancer patients in the Finnish population.\nMETHODS: The study sequenced the RAD51D and RAD54L genes in 95 breast and/or ovarian cancer families and genotyped the identified mutation in an additional 2200 breast and 553 ovarian cancer patients and 2102 population controls. To investigate the role of the mutation in other common cancers, 1094 prostate and 980 colorectal cancer patients were genotyped.\nRESULTS: In the screening of RAD51D, one deleterious founder mutation c.576+1G>A was identified in two breast-ovarian cancer families. No mutations were found in RAD54L. Altogether, the c.576+1G>A mutation was detected in 5/707 patients with a personal or family history of ovarian cancer (OR 9.16, 95% CI 1.07 to 78.56; p=0.024), with the highest frequency among breast-ovarian cancer families (3/105 vs 1/1287 controls, OR 37.82, 95% CI 3.90 to 366.91; p=0.0016), but no elevated frequency among breast cancer patients/families (2/2105, p=1). The mutation was not found among prostate or colorectal cancer patients.\nCONCLUSIONS: The results of this study on familial and unselected breast, ovarian, colorectal, and prostate cancer patients suggest that RAD51D is primarily a moderate penetrance susceptibility gene for ovarian cancer, with clinical significance for the carriers.","variants":[{"Name":"NM_002878.4(RAD51D):c.576+1G>A","Chromosome":"17","Start":"35106385","Stop":"35106385","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":358920,"rule_based_match":true,"evidence_text":"c.576+1G>A","llm_judgment":"PRESENT","evidence":"c.576+1G>A","abstract_start":707,"abstract_end":717}]}
{"pmid":"24423689","title":"Novel deoxyguanosine kinase gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome.","abstract":"Deoxyguanosine kinase (DGUOK) gene mutations have been identified in the hepatocerebral form of mitochondrial DNA depletion syndromes. We report here clinical and laboratory features of 3 infants with novel DGUOK gene mutations, c.130G>A (Glu44Lys), c.493G>A (Glu165Lys), and c.707+3_6delTAAG.","variants":[{"Name":"NM_080916.3(DGUOK):c.130G>A (p.Glu44Lys)","Chromosome":"2","Start":"73927040","Stop":"73927040","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247477,"rule_based_match":true,"evidence_text":"c.130G>A (Glu44Lys)","llm_judgment":"PRESENT","evidence":"c.130G>A (Glu44Lys)","abstract_start":229,"abstract_end":248}]}
{"pmid":"15945244","title":"The first molecular analysis of a Hungarian HNPCC family: a novel MSH2 germline mutation","abstract":"BACKGROUND: Hereditary nonpolyposis colorectal cancer is an inherited disease characterized by onset at an early age, an excess of synchronous and metachronous large bowel tumors and a variety of extracolorectal malignancies. Basal and squamous cell carcinomas of the skin are not customarily included in the tumor spectrum of the syndrome. The disease is caused by a germline mutation in one of the DNA mismatch repair genes, most commonly MSH2 or MLH1, and typically presents with microsatellite instability and frequent loss of mismatch repair protein expression in the tumor tissue.\nPATIENT: The case of a 62-year old woman who had a history of colon cancer at the age of 46 years, endometrial cancer at the age of 56 years, baso-squamous, and squamous cell cancer of the face at the ages of 53, 54, 62 and 58 years, respectively, and rectal cancer at 60 is reported. Her family fulfills the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer. The baso-squamous cell, the squamous cell, the endometrial and the rectal cancers were assessed for the microsatellite instability status and the expression of the MSH2 and MLH1 mismatch repair proteins, and the p53 tumor suppressor protein by immunohistochemistry. Mutational screening using an automated capillary DNA sequencer was performed by the direct genomic sequencing of 17 fragments of the MSH2 gene, which covers promoter, all exons and flanking intronic regions.\nRESULTS: All cancers displayed microsatellite instability and were positive for the p53 protein. The immunohistochemical staining in the baso-squamous cell, the squamous cell, the rectal and endometrial cancers were negative for MSH2 and positive for MLH1 proteins. DNA sequencing analysis revealed a mutation c.2292G > A in exon 14 of the MSH2 gene, which is altering the 764. amino acid, the tryptophan to STOP codon (p.W764X). Thus the MSH2 protein is presumably truncated by 171 aminoacids.\nCONCLUSION: To the best of authors' knowledge, this is the first molecular characterization of a Hungarian hereditary nonpolyposis colorectal cancer family. According to the Human Mutation Database and International Collaborative Group of HNPCC Database, this mutation is novel, has not been reported previously. Cutaneous baso-squamous and squamous cell cancers may present as part of the HNPCC phenotype. Detection of the loss of mismatch repair protein expression and mismatch repair gene mutation mapping, represents a significant improvement of the diagnosis of this syndrome in Hungary. These examinations identify the mutation carriers who are at an increased risk of developing cancers.","variants":[{"Name":"NM_000251.3(MSH2):c.2292G>A (p.Trp764Ter)","Chromosome":"2","Start":"47478353","Stop":"47478353","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":96424,"rule_based_match":true,"evidence_text":"c.2292G > A","llm_judgment":"PRESENT","evidence":"c.2292G > A","abstract_start":1764,"abstract_end":1775}]}
{"pmid":"18257781","title":"Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease.","abstract":"BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians.\nMATERIALS AND METHODS: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing.\nRESULTS: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls.\nCONCLUSIONS: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.","variants":[{"Name":"NM_000297.4(PKD2):c.1445T>G (p.Phe482Cys)","Chromosome":"4","Start":"88046767","Stop":"88046767","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":221477,"rule_based_match":true,"evidence_text":"c.1445T > G","llm_judgment":"PRESENT","evidence":"c.1445T > G","abstract_start":426,"abstract_end":437}]}
{"pmid":"31031081","title":"Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency.","abstract":"BACKGROUND: Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is a disorder of fatty acid oxidation included in the recommended uniform newborn screening (NBS) panel in the USA. It can have variable clinical severity and there is limited information on the natural history of this condition, clinical presentation according to genotype and effectiveness of newborn screening.\nMETHODS: Retrospective data (growth parameters, morbidity, biochemical and genetic testing results) were collected from patients with VLCAD deficiency, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate continuous variables.\nRESULTS: VLCAD deficiency (screened by measuring elevated levels of C14:1-carnitine in blood spots) was more frequent in Utah than the national average (1:27,617 versus 1:63,481) in the first ten years of screening. Twenty-six patients had a confirmed diagnosis of VLCAD deficiency using DNA testing or functional studies. The c.848T>C (p.V283A) variant in the ACADVL gene was the most frequent in our population. Novel variants (c.623-21A>G (IVS7-21A>G); c.1052C>T (p.T351I); c.1183-7A>G (IVS11-7A>G); c.1281G>C (p.W427C); c.1923G>C (p.L641F); c.1924G>A (p.V642M)) were identified in this study, with their pathogenicity remaining unclear in most cases. C14:1-carnitine levels decreased with age and significantly correlated with CK levels as index of muscle involvement. There were no cases of HELLP syndrome nor liver disease during pregnancies in the mothers of VLCAD patients. None of our patients developed cardiac involvement after birth and all patients had normal growth parameters while on treatment. Clinical manifestations were related to concomitant infections and altered biochemical parameters.\nDISCUSSION: VLCAD deficiency can be identified by neonatal screening. Most patients compliant with therapy normalized biochemical parameters and had no major clinical manifestations. Complications were completely prevented with a relatively low number of pre-emptive ER visits or hospital admissions. It remains unclear whether neonatal screening is now identifying less severely affected patient or if complications will arise as subjects become older. Observation beyond puberty is necessary to fully understand the impact of VLCAD deficiency on morbidity in patients with VLCAD deficiency.","variants":[{"Name":"NM_000018.4(ACADVL):c.1183-7A>G","Chromosome":"17","Start":"7223637","Stop":"7223637","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":571574,"rule_based_match":true,"evidence_text":"c.1183-7A>G (IVS11-7A>G)","llm_judgment":"PRESENT","evidence":"c.1183-7A>G (IVS11-7A>G)","abstract_start":1196,"abstract_end":1220},{"Name":"NM_000018.4(ACADVL):c.1924G>A (p.Val642Met)","Chromosome":"17","Start":"7225053","Stop":"7225053","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1941318,"rule_based_match":true,"evidence_text":"c.1924G>A (p.V642M)","llm_judgment":"PRESENT","evidence":"c.1924G>A (p.V642M)","abstract_start":1264,"abstract_end":1283},{"Name":"NM_000018.4(ACADVL):c.848T>C (p.Val283Ala)","Chromosome":"17","Start":"7222272","Stop":"7222272","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":33877,"rule_based_match":true,"evidence_text":"c.848T>C (p.V283A)","llm_judgment":"PRESENT","evidence":"c.848T>C (p.V283A)","abstract_start":1046,"abstract_end":1064},{"Name":"NM_000018.4(ACADVL):c.1923G>C (p.Leu641Phe)","Chromosome":"17","Start":"7225052","Stop":"7225052","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":548323,"rule_based_match":true,"evidence_text":"c.1923G>C (p.L641F)","llm_judgment":"PRESENT","evidence":"c.1923G>C (p.L641F)","abstract_start":1243,"abstract_end":1262}]}
{"pmid":"23193493","title":"Residual NADPH oxidase activity and isolated lung involvement in x-linked chronic granulomatous disease.","abstract":"Chronic granulomatous disease (CGD) is characterized by inherited immune defects resulting from mutations in the NADPH oxidase complex genes. The X-linked type of CGD is caused by defects in the CYBB gene that encodes gp91-phox, a fundamental component of the NADPH oxidase complex. This mutation originates the most common and severe form of CGD, which typically has absence of NADPH oxidase function and aggressive multisystemic infections. We present the case of a 9-year-old child with a rare CYBB mutation that preserves some NADPH oxidase activity, resulting in an atypical mild form of X-linked CGD with isolated lung involvement. Although the clinical picture and partially preserved oxidase function suggested an autosomal recessive form of CGD, genetic testing demonstrated a mutation in the exon 3 of CYBB gene (c.252 G>A, p.Ala84Ala), an uncommon X-linked CGD variant that affects splicing. Atypical presentation and diagnostic difficulties are discussed. This case highlights that the diagnosis of mild forms of X-linked CGD caused by rare CYBB mutations and partially preserved NADPH function should be considered early in the evaluation of atypical and recurrent lung infections.","variants":[{"Name":"NM_000397.4(CYBB):c.252G>A (p.Ala84=)","Chromosome":"X","Start":"37783600","Stop":"37783600","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25972,"rule_based_match":true,"evidence_text":"c.252 G>A, p.Ala84Ala","llm_judgment":"PRESENT","evidence":"c.252 G>A, p.Ala84Ala","abstract_start":823,"abstract_end":844}]}
{"pmid":"31741144","title":"Childhood-onset autosomal recessive ataxias: a cross-sectional study from Turkey.","abstract":"Autosomal recessive ataxias (ARAs) are a heterogeneous group of inherited neurodegenerative disorders that affect the cerebellum, the spinocerebellar tract, and/or the sensory tracts of the spinal cord. This study is aimed at establishing molecular classification and phenotypic correlation of childhood-onset ARAs in Southeast Anatolia of Turkey. Sixty-five children (aged 0 to 18) from 40 unrelated families who were analyzed through hereditary ataxia NGS panel between the years of 2015-2018 were selected for the study. Seventeen different, clinically significant ARA-related pathogenic variants were detected in 33 of 40 families (82.5%), 12 of which were noted to be unreported variants. Among these 33 families, 24 had ATM-related (72.72%), four had SACS-related (12.12%), three had COQ8A-related (9.09%), and two had APTX-related (6.06%) pathogenic variants. The c.3576G>A (p.K1192=) was the most common homozygous pathogenic ATM variant (33.33%) that was associated with milder phenotype of ataxia telangiectasia (AT) with the onset of age of 3. Patients with SACS variants demonstrated developmental delay and progressive ataxia before the age of 3. Slowly progressive ataxia and intellectual disability were the common clinical manifestations of the patients with homozygous c.1396delG (p. E466Rfs*11) pathogenic variant in COQ8A. Homozygous APTX c.689T>G (p.V230G) pathogenic variant was identified in two patients who had chief complaint of ataxic gait onset after puberty. The most common types of ARAs in this region are AT- and Charlevoix-Saguenay-type spastic ataxia. ATM gene analysis should be performed foremost on children presenting early-onset ataxia from Southeastern Anatolia. If there is a concomitant peripheral neuron involvement, SACS gene analysis should be preferred. This valuable data will be a guide for the first step molecular diagnostic approach before requesting the NGS panel for ARA.","variants":[{"Name":"NM_000051.4(ATM):c.3576G>A (p.Lys1192=)","Chromosome":"11","Start":"108281168","Stop":"108281168","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18074,"rule_based_match":true,"evidence_text":"c.3576G>A (p.K1192=)","llm_judgment":"PRESENT","evidence":"c.3576G>A (p.K1192=)","abstract_start":871,"abstract_end":891}]}
{"pmid":"20625965","title":"Familial partial lipodystrophy associated with the heterozygous LMNA mutation 1445G>A (Arg482Gln) in a Polish family.","abstract":"Familial partial lipodystrophy (FPLD) belongs to the family of laminopathies - disorders associated with mutation in the lamin A/C gene (LMNA). FPLD is characterized by loss of subcutaneous adipose tissue from the limbs, trunk and buttocks, with its concomitant accumulation on the face, neck and intra-abdominal region, and by metabolic disorders. We present the first Polish family with FPLD confirmed genetically. A 34-year-old woman admitted with myalgia and cushingoid appearance was found to have a round face with double chin, neck bump, and loss of fat on extremities. Diagnostic tests revealed impaired glucose tolerance and increased levels of liver enzymes, and ultrasonography revealed hepatic steatosis. Her 9-year-old daughter presented a similar phenotype, but no fat loss. A genetic test revealed the presence of a heterozygous LMNA gene mutation: c.1445G>A, consistent with the \"hot spot\" for FPLD. Treatment with metformin to improve insulin resistance and address the diabetes proved successful.","variants":[{"Name":"NM_170707.4(LMNA):c.1445G>A (p.Arg482Gln)","Chromosome":"1","Start":"156136985","Stop":"156136985","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29525,"rule_based_match":true,"evidence_text":"c.1445G>A","llm_judgment":"PRESENT","evidence":"c.1445G>A","abstract_start":864,"abstract_end":873}]}
{"pmid":"29465609","title":"Novel Myelin Protein Zero Mutation in 3 Generations of Vermonters With Demyelinating Charcot-Marie-Tooth Disease.","abstract":"OBJECTIVES: We report the clinical phenotype in 3 consecutive generations with demyelinating Charcot-Marie-Tooth disease that possess a novel sequence variant of myelin protein zero (MPZ).\nMETHODS: Family members from 3 consecutive generations were interviewed, examined, and studied with electrodiagnostic testing. Commercially available next-generation sequencing was performed for the proband. Single-gene analysis was performed for the remaining family members.\nRESULTS: All patients demonstrated symmetric distal weakness; symmetric distal sensory loss; and diminished deep tendon reflexes. Electrodiagnostic testing was consistent with primary distal demyelination with secondary axon loss. Genetic testing identified a novel base-pair substitution of MPZ (c.314C>T), resulting in a missense variant (p.Pro105Leu).\nCONCLUSIONS: The novel MPZ base-pair substitution in this family is associated with inherited distal demyelinating neuropathy and should be reclassified as pathogenic for Charcot-Marie-Tooth.","variants":[{"Name":"NM_000530.8(MPZ):c.314C>T (p.Pro105Leu)","Chromosome":"1","Start":"161306842","Stop":"161306842","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":185951,"rule_based_match":true,"evidence_text":"c.314C>T","llm_judgment":"PRESENT","evidence":"c.314C>T","abstract_start":763,"abstract_end":771}]}
{"pmid":"28483234","title":"Identification of a novel missence mutation in FGFR3 gene in an Iranian family with LADD syndrome by Next-Generation Sequencing.","abstract":"Lacrimo-auriculo-dento-digital syndrome (LADD) is a multiple congenital anomaly and a genetically heterogeneous disorder. The aim of this study was to identify the pathogenic gene in an Iranian family with LADD syndrome and review the literature on reported mutations that involved in pathogenesis of LADD syndrome. One novel variant, c.1882 G > A, in fibroblast growth factor receptor 3 (FGFR3) was identified by next generation sequencing and Sanger sequencing. The heterozygous FGFR3 c.1882 G > A variant results in substitution of aspartic acid with asparagine at amino acid 628 (p.D628N) and co-segregated with the phenotype in the LADD family. Our findings suggest that the heterozygous FGFR3 c.1882 G > A variant might be the pathogenic mutation, because this amino acid is conserved in several species. Our data extend the mutation spectrum of the FGFR3 gene and have important implications for genetic counseling for the families. This is the second report of FGFR3 involvement in syndromic deafness in humans, and confirms the gene's positive role in inner ear development. In addition, this is the first FGFR3 mutation recognized in the Iranian LADD family.","variants":[{"Name":"NM_000142.5(FGFR3):c.1882G>A (p.Asp628Asn)","Chromosome":"4","Start":"1806096","Stop":"1806096","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":535686,"rule_based_match":true,"evidence_text":"c.1882 G > A","llm_judgment":"PRESENT","evidence":"c.1882 G > A","abstract_start":335,"abstract_end":347}]}
{"pmid":"19224587","title":"High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis.","abstract":"Recent studies identified rare missense mutations in amyotrophic lateral sclerosis (ALS) patients in the TARDBP gene encoding TAR DNA binding protein (TDP)-43, the major protein of the ubiquitinated inclusions (UBIs) found in affected motor neurons (MNs). The aim of this study was to further define the spectrum of TARDBP mutations in a large cohort of 666 Italian ALS patients (125 familial and 541 sporadic cases). The entire coding region was sequenced in 281 patients, while in the remaining 385 cases only exon 6 was sequenced. In 18 patients, of which six are familial, we identified 12 different heterozygous missense mutations (nine novel) all locating to exon 6, which were absent in 771 matched controls. The c.1144G>A (p.A382T) variation was observed in seven patients, thus representing the most frequent TARDBP mutation in ALS. Analysis of microsatellites surrounding the TARDBP gene indicated that p.A382T was inherited from a common ancestor in 5 of the 7 patients. Altogether, the frequency of TARDBP gene mutations appears to be particularly high in Italian ALS patients compared to individuals of mainly Northern European origin (2.7% vs. 1%). Western blot analysis of lymphocyte extracts from two patients carrying the p.A382T and p.S393L TARDBP mutations showed the presence of lower molecular weight TDP-43 bands, which were more abundant than observed in healthy controls and patients negative for TARDBP mutations. In conclusion, this report contributes to the demonstration of the causative role of the TARDBP gene in ALS pathogenesis and indicates that mutations may affect the stability of the protein even in nonneuronal tissues.","variants":[{"Name":"NM_007375.4(TARDBP):c.1144G>A (p.Ala382Thr)","Chromosome":"1","Start":"11022553","Stop":"11022553","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34326,"rule_based_match":true,"evidence_text":"c.1144G>A (p.A382T)","llm_judgment":"PRESENT","evidence":"c.1144G>A (p.A382T)","abstract_start":720,"abstract_end":739}]}
{"pmid":"30327238","title":"Lethal NARS2-Related Disorder Associated With Rapidly Progressive Intractable Epilepsy and Global Brain Atrophy.","abstract":"BACKGROUND: Infantile epileptic encephalopathy is a heterogeneous condition that has been associated with variants in more than 200 genes. The variability in findings and prognosis creates challenges to making the correct diagnosis and initiating the appropriate therapy. Biallelic variants in NARS2, a mitochondrial aminoacyl-tRNA synthetase gene, were recently associated with neurodegenerative disorders that include epilepsy.\nMETHODS: We describe two infant brothers who presented with focal status epilepticus that progressed to lethal epileptic encephalopathy. We compared the cost of diagnostic laboratory evaluation for each child. Detailed NARS2 protein analysis was performed using a sequence-to-structure-to-function workflow, merging multiple homologous structures, to suggest biologic impact of the NARS2 variants.\nRESULTS: Brain magnetic resonance imaging showed rapid progression to generalized atrophy. Extensive metabolic, infectious, chromosomal and genetic testing of the first infant failed to reach a specific diagnosis. The younger brother presented similarly. Rapid whole exome sequencing was performed revealing novel biallelic variants in NARS2. The variants c.167A>G (p.Gln56Arg) and c.631T>A (p.Phe211Ile) were confirmed in a reserved sample from the older brother. Management was then redirected toward palliative care and the child died at age nine months.\nCONCLUSIONS: NARS2-related disorder should be considered in infants presenting with refractory seizures and rapid brain atrophy. Metabolic screening tests may be normal or yield nonspecific findings. Rapid whole exome sequencing in children with fulminant onset intractable epilepsy may minimize extensive diagnostic evaluation and aid in prognosis and medical management.","variants":[{"Name":"NM_024678.6(NARS2):c.631T>A (p.Phe211Ile)","Chromosome":"11","Start":"78528900","Stop":"78528900","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":408483,"rule_based_match":true,"evidence_text":"c.631T>A (p.Phe211Ile)","llm_judgment":"PRESENT","evidence":"c.631T>A (p.Phe211Ile)","abstract_start":1210,"abstract_end":1232},{"Name":"NM_024678.6(NARS2):c.167A>G (p.Gln56Arg)","Chromosome":"11","Start":"78571419","Stop":"78571419","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":408484,"rule_based_match":true,"evidence_text":"c.167A>G (p.Gln56Arg)","llm_judgment":"PRESENT","evidence":"c.167A>G (p.Gln56Arg)","abstract_start":1184,"abstract_end":1205}]}
{"pmid":"24940037","title":"Novel mutation in FBN1 causes ectopia lentis and varicose great saphenous vein in one Chinese autosomal dominant family.","abstract":"PURPOSE: To identify genetic defects in a Chinese family with ectopia lentis (EL) and varicose great saphenous vein (GSV) and to analyze the correlations between phenotype and genotype.\nMETHODS: Twenty-two (12 affected subjects and ten unaffected subjects) among 53 members of a Chinese family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from the leukocytes in the subjects' peripheral blood. A minimum interval was achieved with linkage study and haplotype analysis. All 65 exons and the flanking intronic regions of fibrillin-1 (FBN1) were amplified with PCR and screened for mutations with direct Sanger sequencing. Molecular modeling was analyzed in an in silico study.\nRESULTS: The linkage study showed a strong cosegregation signal on chromosome 15. The non-parametric linkage analysis yielded a maximum score of 29.1(p<0.00001), and the parametric logarithm of the odds (LOD) score was 3.6. The minimum interval of the shared haplotype was rs1565863-rs877228. The best candidate gene in this region was FBN1. A novel mutation, c.3928G>A, p.1310G>S in exon 31, was identified in FBN1 and cosegregated well in the family. We applied molecular modeling to show the effect of this mutation on the fibrillin-1 structure. The mutation significantly distorts the calcium coordination, decreases the binding of the calcium ion in that motif, and affects the local calcium-binding epidermal growth factor (cbEGF) interface that depends on Ca binding.\nCONCLUSIONS: FBN1-associated fibrillinopathies are a group of diseases with dynamic phenotype changes. Novel mutation p.1310G>S was first reported to cause Marfan syndrome (MFS). Our results expand the mutation spectrum in FBN1 and enhance our knowledge of genotype-phenotype correlations underlying FBN1 mutations.","variants":[{"Name":"NM_000138.5(FBN1):c.3928G>A (p.Gly1310Ser)","Chromosome":"15","Start":"48481691","Stop":"48481691","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3086438,"rule_based_match":true,"evidence_text":"c.3928G>A, p.1310G>S","llm_judgment":"PRESENT","evidence":"c.3928G>A, p.1310G>S","abstract_start":1090,"abstract_end":1110}]}
{"pmid":"35144002","title":"Anterior megalophthalmos in sisters with Witteveen-Kolk syndrome.","abstract":"Anterior megalophthalmos is a form of anterior segment dysgenesis characterized by megalocornea (>12.5 mm) coupled with an enlarged lens-iris diaphragm and ciliary body ring. Importantly, intraocular pressure (IOP) is normal, and in contrast to buphthalmos, the ratio of anterior segment to vitreous cavity measurements is increased. Anterior megalophthalmos may be an isolated ocular finding, or it may be associated with syndromes such as albinism, Down syndrome, Frank-Ter-Haar, Marfan, Neuhauser, mucolipidosis type 2, and osteogenesis imperfecta. We report anterior megalophthalmos in 2 sisters with genetically confirmed (SIN3A, c.1657C>T, p.R553∗) Witteveen-Kolk syndrome (OMIM #613406).","variants":[{"Name":"NM_001145358.2(SIN3A):c.1657C>T (p.Arg553Ter)","Chromosome":"15","Start":"75400810","Stop":"75400810","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":512154,"rule_based_match":true,"evidence_text":"SIN3A, c.1657C>T, p.R553∗","llm_judgment":"PRESENT","evidence":"SIN3A, c.1657C>T, p.R553∗","abstract_start":628,"abstract_end":653}]}
{"pmid":"32619608","title":"Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants.","abstract":"PURPOSE: To define genotype-phenotype correlations in the largest cohort study worldwide of patients with biallelic ABCA4 variants, including 434 patients with Stargardt disease (STGD1) and 72 with cone-rod dystrophy (CRD).\nDESIGN: Cohort study.\nMETHODS: We characterized 506 patients with ABCA4 variants using conventional genetic tools and next-generation sequencing technologies. Medical history and ophthalmologic data were obtained from 372 patients. Genotype-phenotype correlation studies were carried out for the following variables: variant type, age at symptom onset (AO), and clinical phenotype.\nRESULTS: A total of 228 different pathogenic variants were identified in 506 ABCA4 patients, 50 of which were novel. Genotype-phenotype correlations showed that most of the patients with biallelic truncating variants presented with CRD and that these cases had a significantly earlier AO than patients with STGD1. Three missense variants are associated with CRD for the first time (c.1804C>T; p.[Arg602Trp], c.3056C>T; p.[Thr1019Met], and c.6320G>C; p.[Arg2107Pro]). Analysis of the most prevalent ABCA4 variant in Spain, c.3386G>T; p.(Arg1129Leu), revealed that is correlated to STGD1, later AO, and foveal sparing.\nCONCLUSIONS: Our study, conducted in the largest ABCA4-associated disease cohort reported to date, updates the genotype-phenotype model established for ABCA4 variants and broadens the mutational spectrum of the gene. According to our observations, patients with ABCA4 presenting with 2 truncating variants may first present features of STGD1 but eventually develop rod dysfunction, and specific missense variants may be associated with a different phenotype, underscoring the importance of an accurate genetic diagnosis. Also, it is a prerequisite for enrollment in clinical trials, and to date, no other treatment has been approved for STGD1.","variants":[{"Name":"NM_000350.3(ABCA4):c.1804C>T (p.Arg602Trp)","Chromosome":"1","Start":"94062710","Stop":"94062710","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":104973,"rule_based_match":true,"evidence_text":"c.1804C>T; p.[Arg602Trp]","llm_judgment":"PRESENT","evidence":"c.1804C>T; p.[Arg602Trp]","abstract_start":988,"abstract_end":1012},{"Name":"NM_000350.3(ABCA4):c.3056C>T (p.Thr1019Met)","Chromosome":"1","Start":"94043470","Stop":"94043470","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":273547,"rule_based_match":true,"evidence_text":"c.3056C>T; p.[Thr1019Met]","llm_judgment":"PRESENT","evidence":"c.3056C>T; p.[Thr1019Met]","abstract_start":1014,"abstract_end":1039},{"Name":"NM_000350.3(ABCA4):c.3386G>T (p.Arg1129Leu)","Chromosome":"1","Start":"94041345","Stop":"94041345","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":105113,"rule_based_match":true,"evidence_text":"c.3386G>T; p.(Arg1129Leu)","llm_judgment":"PRESENT","evidence":"c.3386G>T; p.(Arg1129Leu)","abstract_start":1128,"abstract_end":1153}]}
{"pmid":"25477324","title":"A homozygous missense mutation in NEUROD1 is associated with nonsyndromic autosomal recessive retinitis pigmentosa.","abstract":"PURPOSE: Mutations in the same gene can lead to different clinical phenotypes. In this study, we aim to identify novel genotype-phenotype correlations and novel disease genes by analyzing an unsolved autosomal recessive retinitis pigmentosa (ARRP) Han Chinese family.\nMETHODS: Whole exome sequencing was performed for one proband from the consanguineous ARRP family. Stringent variants filtering and prioritizations were applied to identify the causative mutation.\nRESULTS: A homozygous missense variant, c.724G>A; p.V242I, in NEUROD1 was identified as the most likely cause of disease. This allele perfectly segregates in the family and affects an amino acid, which is highly conserved among mammals. A previous study showed that a homozygous null allele in NEUROD1 causes severe syndromic disease with neonatal diabetes, systematic neurological abnormalities, and early-onset retinal dystrophy. Consistent with these results, our patients who are homozygous for a less severe missense allele presented only late-onset retinal degeneration without any syndromic symptoms.\nCONCLUSIONS: We identified a potential novel genotype-phenotype correlation between NEUROD1 and nonsyndromic ARRP. Our study supports the idea that NEUROD1 is important for maintenance of the retina function and partial loss-of-function mutation in NEUROD1 is likely a rare cause of nonsyndromic ARRP.","variants":[{"Name":"NM_002500.5(NEUROD1):c.724G>A (p.Val242Ile)","Chromosome":"2","Start":"181678137","Stop":"181678137","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187939,"rule_based_match":true,"evidence_text":"c.724G>A; p.V242I","llm_judgment":"PRESENT","evidence":"c.724G>A; p.V242I","abstract_start":505,"abstract_end":522}]}
{"pmid":"24727571","title":"Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.","abstract":"Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis.","variants":[{"Name":"NM_003119.4(SPG7):c.1067C>T (p.Thr356Met)","Chromosome":"16","Start":"89531983","Stop":"89531983","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":530706,"rule_based_match":true,"evidence_text":"c.1067C>T; p.(Thr356Met)","llm_judgment":"PRESENT","evidence":"c.1067C>T; p.(Thr356Met)","abstract_start":1097,"abstract_end":1121},{"Name":"NM_003119.4(SPG7):c.861dup (p.Asn288Ter)","Chromosome":"16","Start":"89529575","Stop":"89529576","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":208318,"rule_based_match":true,"evidence_text":"c.861dupT; p.Asn288*","llm_judgment":"PRESENT","evidence":"c.861dupT; p.Asn288*","abstract_start":849,"abstract_end":869}]}
{"pmid":"32014857","title":"Mortality in a neonate with molybdenum cofactor deficiency illustrates the need for a comprehensive rapid precision medicine system.","abstract":"Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (<i>MOCS1</i> c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM.","variants":[{"Name":"NM_001358530.2(MOCS1):c.377G>A (p.Gly126Asp)","Chromosome":"6","Start":"39925719","Stop":"39925719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":679750,"rule_based_match":true,"evidence_text":"c.377G > A","llm_judgment":"PRESENT","evidence":"c.377G > A","abstract_start":497,"abstract_end":507}]}
{"pmid":"17434307","title":"Cap disease caused by heterozygous deletion of the beta-tropomyosin gene TPM2.","abstract":"\"Cap myopathy\" or \"cap disease\" is a congenital myopathy characterised by cap-like structures at the periphery of muscle fibres, consisting of disarranged thin filaments with enlarged Z discs. Here we report a deletion in the beta-tropomyosin (TPM2) gene causing cap disease in a 36-year-old male patient with congenital muscle weakness, myopathic facies and respiratory insufficiency. The mutation identified in this patient is an in-frame deletion (c.415_417delGAG) of one codon in exon 4 of TPM2 removing a single glutamate residue (p.Glu139del) from the beta-tropomyosin protein. This is expected to disrupt the seven-amino acid repeat essential for making a coiled coil, and thus to impair tropomyosin-actin interaction. Missense mutations in TPM2 have previously been found to cause rare cases of nemaline myopathy and distal arthrogryposis. This mutation is one not previously described and the first genetic cause identified for cap disease.","variants":[{"Name":"NM_003289.4(TPM2):c.412GAG[1] (p.Glu139del)","Chromosome":"9","Start":"35685509","Stop":"35685511","ReferenceAlleleVCF":"TCTC","AlternateAlleleVCF":"T","allel_id":27504,"rule_based_match":false,"evidence_text":"c.415_417delGAG (p.Glu139del)","llm_judgment":"PRESENT","evidence":"c.415_417delGAG","abstract_start":451,"abstract_end":466}]}
{"pmid":"30374066","title":"Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome.","abstract":"Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival<sup>1,2</sup>. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH-SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH-SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.","variants":[{"Name":"NM_032782.5(HAVCR2):c.245A>G (p.Tyr82Cys)","Chromosome":"5","Start":"157106776","Stop":"157106776","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":614546,"rule_based_match":true,"evidence_text":"c.245A>G (p.Tyr82Cys)","llm_judgment":"PRESENT","evidence":"c.245A>G (p.Tyr82Cys)","abstract_start":481,"abstract_end":502}]}
{"pmid":"26639818","title":"Mutation spectra of the ITGB2 gene in Iranian families with leukocyte adhesion deficiency type 1.","abstract":"Leukocyte adhesion deficiency type 1 (LAD1) is an autosomal recessive disorder clinically characterized by severe, recurrent bacterial infections, impaired pus formation and wound healing. It is caused by mutation in the ITGB2 gene, encoding the β2 integrin subunit of the leukocyte adhesion cell molecule. This study aimed to identify disease causing mutations in 19 consanguineous families diagnosed with LAD1. Blood samples were collected after informed and written consent was obtained. Genomic DNA was extracted from peripheral blood of patients and their parents. PCR amplification of the ITGB2 gene was done using specific primers followed by sequencing for mutation detection. A total number of 14 alterations scattered throughout the ITGB2 gene were ascertained in which 10 mutations were previously reported, including c.329-6C>A, c.382G>T, c.715G>A, c.843delC, c.897+1G>A, c.1062A>T, c.1143delC, c.1877+2T>C, c.1907delA and c.2147G>C. Four novel likely pathogenic mutations consisting of c.576dupC (Asn193GlnfsX72), c.706G>A (Gly236Arg), c.897+1G>T and c.1030G>T (Glu344(∗)), were identified. The majority of these mutations were located in exon six, suggesting this exon as a hotspot region probably. This study emphasis on allelic heterogeneity of the ITGB2 gene in Iranian patients diagnosed with LAD1. Our results suggest that every population should develop a mutation database for rare genetic disorders to take advantage in genetic counseling clinic as well as genetic testing for rapid diagnostic purposes.","variants":[{"Name":"NM_000211.5(ITGB2):c.706G>A (p.Gly236Arg)","Chromosome":"21","Start":"44901527","Stop":"44901527","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":106624,"rule_based_match":true,"evidence_text":"c.706G>A (Gly236Arg)","llm_judgment":"PRESENT","evidence":"c.706G>A (Gly236Arg)","abstract_start":1027,"abstract_end":1047},{"Name":"NM_000211.5(ITGB2):c.715G>A (p.Ala239Thr)","Chromosome":"21","Start":"44901518","Stop":"44901518","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":79107,"rule_based_match":true,"evidence_text":"c.715G>A","llm_judgment":"PRESENT","evidence":"c.715G>A","abstract_start":851,"abstract_end":859},{"Name":"NM_000211.5(ITGB2):c.897+1G>A","Chromosome":"21","Start":"44900319","Stop":"44900319","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":106628,"rule_based_match":true,"evidence_text":"c.897+1G>A","llm_judgment":"PRESENT","evidence":"c.897+1G>A","abstract_start":872,"abstract_end":882}]}
{"pmid":"28395541","title":"Hb Presbyterian (HBB: c.327C>G) in a Nicaraguan Family.","abstract":"Hemoglobin (Hb) is the protein responsible for oxygen transportation. It is a tetrameric protein comprising two α- and two β-globin subunits. In the literature, a large number of mutations in the α- and β-globin genes have been documented. Among these mutations, Hb Presbyterian (HBB: c.327 C>G), is a naturally occurring mutant exerting low oxygen affinity. The C to G exchange (AAC>AAG) at codon 108 of the β-globin gene results in the substitution of asparagine by lysine. Here, we document the identification of HBB: c.327 C>G in a 6-year-old female patient and her father from Nicaragua and Cuba, respectively. The presence of the abnormal Hb was confirmed by cellulose acetate electrophoresis, high performance liquid chromatography (HPLC) and genomic DNA sequencing. The β-globin gene sequences for both, father and daughter, disclosed the heterozygous mutation at codon 108 to be Hb Presbyterian or HBB: c.327 C>G. The mutant Hb was previously reported in four families from North America, Germany, Japan and Spain, respectively. This is the fifth family carrying HBB: c.327 C>G described to date and the first report from Latin America.","variants":[{"Name":"NM_000518.5(HBB):c.327C>G (p.Asn109Lys)","Chromosome":"11","Start":"5225715","Stop":"5225715","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3494966,"rule_based_match":true,"evidence_text":"HBB: c.327 C>G","llm_judgment":"PRESENT","evidence":"HBB: c.327 C>G","abstract_start":280,"abstract_end":294}]}
{"pmid":"22829014","title":"Heterozygote FANCD2 mutations associated with childhood T Cell ALL and testicular seminoma.","abstract":"Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities characterised by cellular cross linker hypersensitivity. FA is caused by mutations in any of so far 15 identified FANC genes, which encode proteins that interact in a common DNA damage response (DDR) pathway. Individuals with FA have a high risk of developing acute myeloid leukaemia (AML) and squamous cell carcinoma. An increased cancer risk has been firmly established for carriers of mutations in FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, RAD51C/FANCO and link the FA pathway to inherited breast and ovarian cancer. We describe a pedigree with FANCD2 mutations c.458T > C (p.Leu153Ser) and c.2715 + 1G > A (p.Glu906LeufsX4) with mild phenotype FA in the index case, T cell ALL in the Leu153Ser heterozygous brother and testicular seminoma in the p.Glu906LeufsX4 heterozygous father. Both FANCD2 alleles were present in the T Cell ALL and the seminoma. This links specific FANCD2 mutations to T cell ALL and seminoma without evidence of allelic loss in the tumour tissue.","variants":[{"Name":"NM_001018115.3(FANCD2):c.458T>C (p.Leu153Ser)","Chromosome":"3","Start":"10036306","Stop":"10036306","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3048505,"rule_based_match":true,"evidence_text":"c.458T > C (p.Leu153Ser)","llm_judgment":"PRESENT","evidence":"c.458T > C (p.Leu153Ser)","abstract_start":656,"abstract_end":680}]}
{"pmid":"17256792","title":"IVIC syndrome is caused by a c.2607delA mutation in the SALL4 locus.","abstract":"The IVIC syndrome described in 1980 in a large Venezuelan family, is an autosomal dominant condition characterized by upper limbs anomalies (radial ray defects, carpal bones fusion), extraocular motor disturbances, congenital bilateral non-progressive mixed hearing loss; other less consistent malformations include heart involvement, mild thrombocytopenia and leukocytosis (before age 50), shoulder girdle hypoplasia, imperforate anus, kidney malrotation or rectovaginal fistula. Since 2002, mutations in the SALL4 locus have been reported producing phenotypic features quite similar to those in IVIC syndrome; this gene was thus proposed as a candidate for the condition. A segregation analysis of four SNPs in exon 2 (c.1520T > G, c.1860A > G, c.2037C > T, and c.2392A > C) was carried out in 14 affected and in 15 normal family members. Haplotype T;A;C;A was found to always segregate with the disease. Sequencing the whole coding regions revealed one heterozygous base deletion in exon 3 (c.2607delA) causing a premature stop signal 44 codons downstream (p.Q869fsX44) which segregates with the phenotype, being absent in controls. The large number of affected individuals presumably carrying the same mutation (n = 26) with quite different degrees of involvement allowed a discussion about possible mechanisms for the SALL4 action. The finding of a SALL4 mutation in a family with such a wide pleiotropic spectrum proves that at least Okihiro, acro-renal-ocular and IVIC syndromes are allelic entities.","variants":[{"Name":"NM_020436.5(SALL4):c.2607del (p.Gln869fs)","Chromosome":"20","Start":"51788996","Stop":"51788996","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":18369,"rule_based_match":true,"evidence_text":"c.2607delA","llm_judgment":"PRESENT","evidence":"c.2607delA","abstract_start":994,"abstract_end":1004}]}
{"pmid":"27834068","title":"First Report of Familial Dysalbuminemic Hyperthyroxinemia With an ALB Variant.","abstract":"Familial dysalbuminemic hyperthyroxinemia (FDH) is an inherited disease characterized by increased circulating total thyroxine (T4) levels and normal physiological thyroid function. Heterozygous albumin gene (ALB) variants have been reported to be the underlying cause of FDH. To our knowledge, there have been no confirmed FDH cases in Korea. We recently observed a female patient with mild T4 elevation (1.2 to 1.4-fold) and variable levels of free T4 according to different assay methods. Upon Sanger sequencing of her ALB, a heterozygous c.725G>A (p.Arg242His) variant was identified. The patient's father and eldest son had similar thyroid function test results and were confirmed to have the same variant. Although the prevalence of FDH might be very low in the Korean population, clinical suspicion is important to avoid unnecessary evaluation and treatment.","variants":[{"Name":"NM_000477.7(ALB):c.725G>A (p.Arg242His)","Chromosome":"4","Start":"73412007","Stop":"73412007","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":33264,"rule_based_match":true,"evidence_text":"c.725G>A (p.Arg242His)","llm_judgment":"PRESENT","evidence":"c.725G>A (p.Arg242His)","abstract_start":542,"abstract_end":564}]}
{"pmid":"31251474","title":"Identification of a novel splice site mutation in the SERAC1 gene responsible for the MEGDHEL syndrome.","abstract":"BACKGROUND: MEGDHEL is an autosomal recessive syndrome defined as 3-MEthylGlutaconic aciduria (3-MGA) with Deafness, Hepatopathy, Encephalopathy, and Leigh-like syndrome on magnetic resonance imaging, due to mutations in the SERAC1 (Serine Active Site Containing 1) gene, which plays a role in the mitochondrial cardiolipin metabolism.\nMETHODS: We report the case of a young patient who presented with a convulsive encephalopathy, 3-methylglutaconic aciduria, deafness, and bilateral T2 hypersignals of the putamen and the thalami, who passed away at 8 years of age.\nRESULTS: Analysis of nuclear genes using an ampliSeq<sup>™</sup> targeted custom panel disclosed two compound heterozygous variants in the SERAC1 gene: a nonsense substitution in exon 4, c.202C>T, resulting in a premature stop codon (p.Arg68*), and a novel variant at a canonical splicing site upstream exon 4 (c.129-1G>C). mRNAs sequencing from the fibroblasts of the patient showed that the splice site variant resulted in exon 3 skipping without frameshift while Western blot experiments showed the absence of SERAC1 expression compared to controls and abnormal filipin staining.\nCONCLUSION: We showed that the loss of the putative transmembrane domain of SERAC1, due to a novel splice site variant, impairs the protein expression and is responsible for the MEGDHEL syndrome.","variants":[{"Name":"NM_032861.4(SERAC1):c.202C>T (p.Arg68Ter)","Chromosome":"6","Start":"158150516","Stop":"158150516","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":125792,"rule_based_match":true,"evidence_text":"c.202C>T","llm_judgment":"PRESENT","evidence":"c.202C>T","abstract_start":754,"abstract_end":762}]}
{"pmid":"30670881","title":"ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.","abstract":"PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability.\nMETHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4.\nRESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells.\nCONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.","variants":[{"Name":"NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)","Chromosome":"1","Start":"94010911","Stop":"94010911","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":105279,"rule_based_match":true,"evidence_text":"c.5603A>T p.(Asn1868Ile)","llm_judgment":"PRESENT","evidence":"c.5603A>T p.(Asn1868Ile)","abstract_start":815,"abstract_end":839}]}
{"pmid":"28379183","title":"Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing.","abstract":"Charcot-Marie-Tooth disease (CMT) is a common inherited peripheral neuropathy affecting up to 1 in 1214 of the general population with more than 60 nuclear genes implicated in its pathogenesis. Traditional molecular diagnostic pathways based on relative prevalence and clinical phenotyping are limited by long turnaround time, population-specific prevalence of causative variants and inability to assess multiple co-existing variants. In this study, a CMT gene panel comprising 27 genes was used to uncover the pathogenic mutations in two index patients. The first patient is a 15-year-old boy, born of consanguineous parents, who has had frequent trips and falls since infancy, and was later found to have inverted champagne bottle appearance of bilateral legs and foot drop. His elder sister is similarly affected. The second patient is a 37-year-old woman referred for pre-pregnancy genetic diagnosis. During early adulthood, she developed progressive lower limb weakness, difficulties in tip-toe walking and thinning of calf muscles. Both patients are clinically compatible with CMT, have undergone multiple genetic testings and have not previously received a definitive genetic diagnosis. Patients 1 and 2 were found to have pathogenic homozygous <i>HSPB1</i>:NM_001540:c.250G>A (p.G84R) variant and heterozygous <i>GDAP1</i>:NM_018972:c.358C>T (p.R120W) variant, respectively. Advantages and limitations of the current approach are discussed.","variants":[{"Name":"NM_001540.5(HSPB1):c.250G>A (p.Gly84Arg)","Chromosome":"7","Start":"76302962","Stop":"76302962","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620269,"rule_based_match":true,"evidence_text":"NM_001540:c.250G>A (p.G84R)","llm_judgment":"PRESENT","evidence":"NM_001540:c.250G>A (p.G84R)","abstract_start":1265,"abstract_end":1292},{"Name":"NM_018972.4(GDAP1):c.358C>T (p.Arg120Trp)","Chromosome":"8","Start":"74360184","Stop":"74360184","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19237,"rule_based_match":true,"evidence_text":"NM_018972:c.358C>T (p.R120W)","llm_judgment":"PRESENT","evidence":"NM_018972:c.358C>T (p.R120W)","abstract_start":1331,"abstract_end":1359}]}
{"pmid":"28686329","title":"Juvenile-onset generalized lipodystrophy due to a novel heterozygous missense LMNA mutation affecting lamin C.","abstract":"The LMNA gene contains 12 exons and encodes lamins A and C by alternative splicing within exon 10. While mutations in lamin A specific residues cause several diseases including lipodystrophy, progeria, muscular dystrophy, neuropathy, and cardiomyopathy, only three families with mutations in lamin C-specific residues are reported with cardiomyopathy, neuropathy, and muscular dystrophy so far. We now report two brothers with juvenile-onset generalized lipodystrophy due to a lamin C-specific mutation. The proband, a 23-year-old Caucasian male was reported to have generalized lipodystrophy at 3 weeks of age, developed diabetes, hypertriglyceridemia, hypertension and liver problems and died with complications of cirrhosis, and kidney failure. His younger brother, a 37-year-old Caucasian male developed generalized lipodystrophy around 2 years of age and was diagnosed with diabetes, hypertriglyceridemia, fatty liver, and hypertension at 36 years of age. Their father also died of end stage renal disease at age 52 years. Exome sequencing of the proband revealed an extremely rare missense heterozygous variant c.1711_1712CG>TC; p.(Arg571Ser) in LMNA which was confirmed by Sanger sequencing in both the patients. Interestingly, the mutation had no effect on mRNA splicing or relative expression of lamin A or C mRNA and protein in the lymphoblasts. Our observations suggest that mutant lamin C disrupts its interaction with other cellular proteins resulting in generalized lipodystrophy due to defective development and maintenance of adipose tissue.","variants":[{"Name":"NM_005572.4(LMNA):c.1711_1712delinsTC (p.Arg571Ser)","Chromosome":"1","Start":"156137756","Stop":"156137757","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"TC","allel_id":196485,"rule_based_match":false,"evidence_text":"c.1711_1712CG>TC; p.(Arg571Ser)","llm_judgment":"PRESENT","evidence":"c.1711_1712CG>TC; p.(Arg571Ser)","abstract_start":1117,"abstract_end":1148}]}
{"pmid":"24351118","title":"Severe α-thalassemia intermedia due to a compound heterozygosity for the highly unstable Hb Adana (HBA2: c.179G>A) and a novel codon 24 (HBA2: c.75T>A) mutation.","abstract":"We report a novel mutation at codon 24 of the α2-globin gene (HBA2: c.75T > A) found in a Sundanese family. This novel mutation was detected during prenatal diagnosis. The couple already had a 7-year-old boy who exhibited clinically severe α-thalassemia intermedia (α-TI), and he was found to be a compound heterozygote for the novel mutation at codon 24 and the previously described Hb Adana (HBA2: c.179G > A) at codon 59 of the α2-globin gene. The father was a carrier of the novel point mutation and showed normal hemoglobin (Hb) and a low mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) value.","variants":[{"Name":"NM_000517.6(HBA2):c.179G>A (p.Gly60Asp)","Chromosome":"16","Start":"173208","Stop":"173208","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432850,"rule_based_match":true,"evidence_text":"HBA2: c.179G > A","llm_judgment":"PRESENT","evidence":"HBA2: c.179G > A","abstract_start":394,"abstract_end":410}]}
{"pmid":"26909334","title":"Molecular findings of Colombian patients with type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome).","abstract":"INTRODUCTION: Maroteaux-Lamy syndrome, or mucopolysaccharidosis (MPS) type VI, is an autosomal recessive lysosomal storage disease caused by a deficient activity of the enzyme arylsulfatase B (ARSB), required to degrade dermatan sulfate. The onset and progression of the disease vary, producing a spectrum of clinical presentation. So far, 133 mutations have been reported. The aim of this study is to determine the mutations in the ARSB gene that are responsible for this disease in Colombian patients.\nRESULTS: Fourteen patients with clinical manifestations and biochemical diagnosis of MPS VI were studied, including two siblings. The 8 exons of the gene were directly sequenced from patients' DNA, and 14 mutations were found. 57% of these mutations had not been previously reported (p.H111P, p.C121R, p.G446S, p.*534W, p.S334I, p.H147P, c.900T > G, and c.1531_1553del) and 43% had been previously reported (p.G144R, p.W322*, p.G302R, p.C447F, p.L128del, and c.1143-1G > C). Of the previously reported mutations, 80% have been associated with severe phenotypes and 20% with intermediate-severe phenotypes. Bioinformatic predictions indicate that the new mutations reported in this paper are also highly deleterious.\nCONCLUSIONS: Most of the Colombian patients in this study had private mutations.","variants":[{"Name":"NM_000046.5(ARSB):c.1001G>T (p.Ser334Ile)","Chromosome":"5","Start":"78885725","Stop":"78885725","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":550445,"rule_based_match":false,"evidence_text":"p.S334I","llm_judgment":"PRESENT","evidence":"p.S334I","abstract_start":824,"abstract_end":831}]}
{"pmid":"27066562","title":"Turkish families with juvenile motor neuron disease broaden the phenotypic spectrum of SPG11.","abstract":"OBJECTIVE: Identification of causative mutations in 3 consanguineous families (with 4 affected members) referred to our center with young-onset motor neuron disease and overlapping phenotypes resembling autosomal recessive juvenile amyotrophic lateral sclerosis (ARJALS) and autosomal recessive hereditary spastic paraplegia (ARHSP).\nMETHODS: Patients have a slowly progressive motor neuron disease with upper and lower motor neuron dysfunction. There is distal muscle weakness and atrophy associated with pyramidal signs. Whole-exome sequencing was performed on the patients and the unaffected parent samples to identify disease-causing mutations. Variants were prioritized according to their predicted pathogenicity and their relevance to the clinical phenotypes.\nRESULTS: Five distinct homozygous mutations within the SPG11 gene were identified, 3 of which were novel and truncating: c.7155T>G/p.Tyr2385Ter, c.2250delT/p.Phe750Leufs*3, and c.1966_1967delAA/p.Lys656Valfs*11. The copresence of 2 distinct homozygous missense variations was observed in 2 families: c.6224A>G/p.Asn2075Ser and c.7132T>C/p.Phe2378Leu. The segregation of these variations in the family members was validated by Sanger sequencing.\nCONCLUSIONS: Four patients with juvenile-onset motor neuron disease with consanguineous parents were found to carry homozygous mutations in the SPG11 gene. Our findings confirm the overlapping phenotypes of SPG11-based ARJALS and ARHSP, indicating that these 2 entities may be the extreme phenotypes of the same disease continuum with many common features. This, in turn, confirms the difficult differential diagnosis of these 2 diseases in the clinic.","variants":[{"Name":"NM_025137.4(SPG11):c.6224A>G (p.Asn2075Ser)","Chromosome":"15","Start":"44572802","Stop":"44572802","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":186200,"rule_based_match":true,"evidence_text":"c.6224A>G/p.Asn2075Ser","llm_judgment":"PRESENT","evidence":"c.6224A>G/p.Asn2075Ser","abstract_start":1066,"abstract_end":1088},{"Name":"NM_025137.4(SPG11):c.7155T>G (p.Tyr2385Ter)","Chromosome":"15","Start":"44563298","Stop":"44563298","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":374516,"rule_based_match":true,"evidence_text":"c.7155T>G/p.Tyr2385Ter","llm_judgment":"PRESENT","evidence":"c.7155T>G/p.Tyr2385Ter","abstract_start":887,"abstract_end":909},{"Name":"NM_025137.4(SPG11):c.7132T>C (p.Phe2378Leu)","Chromosome":"15","Start":"44564566","Stop":"44564566","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":213128,"rule_based_match":true,"evidence_text":"c.7132T>C (p.Phe2378Leu)","llm_judgment":"PRESENT","evidence":"p.Phe2378Leu","abstract_start":1103,"abstract_end":1115},{"Name":"NM_025137.4(SPG11):c.1966_1967del (p.Lys656fs)","Chromosome":"15","Start":"44628769","Stop":"44628770","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":861399,"rule_based_match":true,"evidence_text":"c.1966_1967delAA/p.Lys656Valfs*11","llm_judgment":"PRESENT","evidence":"c.1966_1967delAA/p.Lys656Valfs*11","abstract_start":943,"abstract_end":976}]}
{"pmid":"22353391","title":"Homocystinuria in Taiwan: an inordinately high prevalence in an Austronesian aboriginal tribe, Tao.","abstract":"The newborn screening of homocystinuria in Taiwan has never been formally reported before. Since 1984, out of 5 million newborns screened, only 3 newborns (Han Taiwanese) suffering from homocystinuria were detected in this newborn screening program. Four mutations (p.R121L [c.362G>T], p.E176K [c.526G>A], p.V320G [c.959T>G] and p.G259D [c.776G>A]) were identified in these 3 patients. Unexpectedly, we recently found 8 patients presenting with homocystinuria in an Austronesian Taiwanese Tao tribe. Out of them, three patients participated in the newborn screening program but were unidentified by the current newborn homocystinuria (using methionine as a marker) screening. All the Tao patients are homozygous for a new p.D47E (c.141T>A) mutation. Among the 428 adult islanders screened for the D47E mutation, approximately 1 in 7.78 is a carrier of the mutation, and an estimated 1 in 240 islanders suffered from homocystinuria. This is the highest known prevalence of homocystinuria worldwide. The result of expression studies of all the mutations identified in Taiwan revealed that, except for p.D47E mutation, all mutations were severely limited in their ability to form functional tetramers. The clinical manifestations of the Tao patients varied widely, despite sharing the same mutation and very similar genetic and environmental backgrounds. Comparisons of clinical and biochemical phenotypes of these patients were presented in this report.","variants":[{"Name":"NM_000071.3(CBS):c.776G>A (p.Gly259Asp)","Chromosome":"21","Start":"43063952","Stop":"43063952","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2901696,"rule_based_match":true,"evidence_text":"c.776G>A","llm_judgment":"PRESENT","evidence":"c.776G>A","abstract_start":338,"abstract_end":346},{"Name":"NM_000071.3(CBS):c.362G>T (p.Arg121Leu)","Chromosome":"21","Start":"43066332","Stop":"43066332","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":204459,"rule_based_match":true,"evidence_text":"c.362G>T","llm_judgment":"PRESENT","evidence":"c.362G>T","abstract_start":275,"abstract_end":283}]}
{"pmid":"32750061","title":"Identification of APTX disease-causing mutation in two unrelated Jordanian families with cerebellar ataxia and sensitivity to DNA damaging agents.","abstract":"BACKGROUND: Ataxia with oculomotor apraxia type 1 (AOA1) is a rare autosomal recessive cerebellar ataxia, caused by mutations in the APTX gene. The disease is characterized by early-onset cerebellar ataxia, oculomotor apraxia and severe axonal polyneuropathy. The aim of this study was to detect the disease-causing variants in two unrelated consanguineous Jordanian families with cerebellar ataxia using whole exome sequencing (WES), and to correlate the identified mutation(s) with the clinical and cellular phenotypes.\nMETHODS: WES was performed in three affected individuals and segregation analysis of p.W279* APTX candidate variant was performed. Expression levels of APTX were measured in patients' skin fibroblasts and peripheral blood mononuclear cells, followed by western blot analysis in skin fibroblasts. Genotoxicity assay was performed to detect the sensitivity of APTX mutated cells to H2O2, MMC, MMS and etoposide.\nRESULTS: A recurrent homozygous nonsense variant in APTX gene (c.837G>A, p.W279*) was revealed in all affected individuals. qRT-PCR showed normal APTX levels in peripheral blood and lower levels in fibroblast cells. However, western blot showed the absence of APTX protein in patients' skin fibroblasts. Significant hypersensitivity to H2O2, MMC and etoposide and lack of sensitivity to MMS were noted.\nCONCLUSIONS: This is the first study to report the identification of a nonsense variant in the APTX gene (c.837G>A; p.W279*) in AOA1 patients within the Jordanian population. This study confirmed the need of WES to assist in the diagnosis of cerebellar ataxia and it emphasizes the importance of studying the pathophysiology of the APTX gene.","variants":[{"Name":"NM_001195248.2(APTX):c.837G>A (p.Trp279Ter)","Chromosome":"9","Start":"32974495","Stop":"32974495","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19470,"rule_based_match":true,"evidence_text":"c.837G>A (p.W279*)","llm_judgment":"PRESENT","evidence":"c.837G>A","abstract_start":995,"abstract_end":1003}]}
{"pmid":"29806606","title":"Screening for mutation hotspots in Bardet-Biedl syndrome patients from India.","abstract":"BACKGROUND & OBJECTIVES: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by multiple organ defects involving retina, kidney, liver and brain. Disease-causing mutations in BBS genes narrowed down by homozygosity mapping in small consanguineous and non-consanguineous pedigrees were reported in 80 per cent of the study population. This study was aimed to screen these genes (BBS3, BBS10) and specific exons of BBS genes (BBS1, BBS5, MKKS, BBS9, BBS11 and BBS12) for recurrent mutations in a selected sample of BBS patients.\nMETHODS: The recurrent mutations in BBS genes were screened in the BBS affected individuals by PCR based direct sequencing. The pathogenicity of the observed mutations were confirmed by co-segregation analysis, screening of healthy unrelated controls and in silico analysis.\nRESULTS: In the 64 BBS patients (44 males, 20 females) were studied, mutations were predominant in BBS10 and ARL6 genes; the c.272T>C; p.(I91T) mutation in ARL6 gene was a recurrent mutation. One novel non-sense mutation c.425T>G; p(L142<sup>FNx01</sup>) was obtained in BBS5 gene (family BSI-31).\nINTERPRETATION & CONCLUSIONS: BBS10 gene mutations clustered in exon 2 of the gene suggesting the exon as a probable hotspot for mutations in Indian population. A cost- and time-effective strategy for the molecular diagnosis of BBS was designed based on these results.","variants":[{"Name":"NM_152384.3(BBS5):c.425T>G (p.Leu142Ter)","Chromosome":"2","Start":"169492912","Stop":"169492912","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1199882,"rule_based_match":true,"evidence_text":"c.425T>G; p(L142<sup>FNx01</sup>)","llm_judgment":"PRESENT","evidence":"c.425T>G; p(L142<sup>FNx01</sup>)","abstract_start":1073,"abstract_end":1106},{"Name":"NM_001278293.3(ARL6):c.272T>C (p.Ile91Thr)","Chromosome":"3","Start":"97784972","Stop":"97784972","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":78955,"rule_based_match":true,"evidence_text":"c.272T>C; p.(I91T)","llm_judgment":"PRESENT","evidence":"c.272T>C; p.(I91T)","abstract_start":977,"abstract_end":995}]}
{"pmid":"18325042","title":"Three novel mutations in the PORCN gene underlying focal dermal hypoplasia.","abstract":"Focal dermal hypoplasia (FDH) is an X-linked dominant disorder characterized by patchy dermal hypoplasia with digital, ocular and dental abnormalities. Very recently, mutations in the PORCN gene were demonstrated to cause FDH. Here, we described three unrelated Thai girls who were sporadic cases of FDH. One of them had unilateral athelia, which has never been described in FDH. Mutation analysis by polymerase chain reaction sequencing the entire coding regions of PORCN successfully revealed three potentially pathogenic mutations, c.373+1G>A, c.737_738insA and c.1094G>A (p.R365Q). One was found in each of three patients. In addition, another sequence variant c.682C>T (p.R228C) with an inconclusive role was found in one patient and her unaffected mother. The two missense mutations were not detected in at least 100 ethnic-matched control chromosomes, and all four mutations had never been previously described. X chromosome inactivation studies showed random patterns in all of them. This study demonstrates that PORCN is the gene responsible for FDH across different populations and extends the total number of confirmed mutations to 26.","variants":[{"Name":"NM_203475.3(PORCN):c.1094G>A (p.Arg365Gln)","Chromosome":"X","Start":"48516067","Stop":"48516067","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":975661,"rule_based_match":true,"evidence_text":"c.1094G>A (p.R365Q)","llm_judgment":"PRESENT","evidence":"c.1094G>A (p.R365Q)","abstract_start":565,"abstract_end":584}]}
{"pmid":"31230978","title":"The novel synonymous variant in LIPA gene affects splicing and causes lysosomal acid lipase deficiency.","abstract":"Lysosomal acid lipase deficiency (LALD; MIM#278000) is a continuum of autosomal recessive diseases caused by defects in the gene LIPA and historically divided into two phenotypes: severe infantile-onset form called Wolman disease (WD) and childhood/adult-onset form known as cholesteryl ester storage disease (CESD). We report a novel synonymous homozygous variant c.600G > A in LIPA of a patient with LALD. Functional analysis of the patient cDNA and minigene assay revealed this variant as the cause of exonic cryptic splice site activation and 63 b.p. deletion in exon 6. To investigate the impact of this in-frame deletion on protein function, we performed 3D modeling of the human lysosomal acid lipase and showed the alteration of highly conservative region in close proximity to protein active site, which may completely eliminate the enzymatic activity. Using transcript specific real-time quantitative PCR method, we evaluated the relative ratio of the patient's wild type transcript isoform which is significantly reduced and correlates with severe childhood-onset variant of LALD.","variants":[{"Name":"NM_000235.4(LIPA):c.600G>A (p.Leu200=)","Chromosome":"10","Start":"89225167","Stop":"89225167","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":857331,"rule_based_match":true,"evidence_text":"c.600G > A","llm_judgment":"PRESENT","evidence":"c.600G > A","abstract_start":365,"abstract_end":375}]}
{"pmid":"34161864","title":"A case of digenic maturity onset diabetes of the young with heterozygous variants in both HNF1Α and HNF1Β genes.","abstract":"BACKGROUND: Maturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now.\nCASE REPORT: A female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant.\nCONCLUSION: Digenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.","variants":[{"Name":"NM_000545.8(HNF1A):c.685C>T (p.Arg229Ter)","Chromosome":"12","Start":"120993678","Stop":"120993678","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":408541,"rule_based_match":true,"evidence_text":"c.685C > T; (p.Arg229Ter)","llm_judgment":"PRESENT","evidence":"c.685C > T; (p.Arg229Ter)","abstract_start":603,"abstract_end":628}]}
{"pmid":"23814038","title":"Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes.","abstract":"Iron-sulfur clusters (ISCs) are important prosthetic groups that define the functions of many proteins. Proteins with ISCs (called iron-sulfur or Fe-S proteins) are present in mitochondria, the cytosol, the endoplasmic reticulum and the nucleus. They participate in various biological pathways including oxidative phosphorylation (OXPHOS), the citric acid cycle, iron homeostasis, heme biosynthesis and DNA repair. Here, we report a homozygous mutation in LYRM4 in two patients with combined OXPHOS deficiency. LYRM4 encodes the ISD11 protein, which forms a complex with, and stabilizes, the sulfur donor NFS1. The homozygous mutation (c.203G>T, p.R68L) was identified via massively parallel sequencing of >1000 mitochondrial genes (MitoExome sequencing) in a patient with deficiency of complexes I, II and III in muscle and liver. These three complexes contain ISCs. Sanger sequencing identified the same mutation in his similarly affected cousin, who had a more severe phenotype and died while a neonate. Complex IV was also deficient in her skeletal muscle. Several other Fe-S proteins were also affected in both patients, including the aconitases and ferrochelatase. Mutant ISD11 only partially complemented for an ISD11 deletion in yeast. Our in vitro studies showed that the l-cysteine desulfurase activity of NFS1 was barely present when co-expressed with mutant ISD11. Our findings are consistent with a defect in the early step of ISC assembly affecting a broad variety of Fe-S proteins. The differences in biochemical and clinical features between the two patients may relate to limited availability of cysteine in the newborn period and suggest a potential approach to therapy.","variants":[{"Name":"NM_020408.6(LYRM4):c.203G>T (p.Arg68Leu)","Chromosome":"6","Start":"5216622","Stop":"5216622","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":108192,"rule_based_match":true,"evidence_text":"c.203G>T, p.R68L","llm_judgment":"PRESENT","evidence":"c.203G>T, p.R68L","abstract_start":636,"abstract_end":652}]}
{"pmid":"30929736","title":"Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas.","abstract":"Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and <sup>13</sup>C<sub>5</sub>-glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals (∼7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.","variants":[{"Name":"NM_001933.5(DLST):c.1121G>A (p.Gly374Glu)","Chromosome":"14","Start":"74901127","Stop":"74901127","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":622968,"rule_based_match":true,"evidence_text":"c.1121G>A (p.Gly374Glu)","llm_judgment":"PRESENT","evidence":"c.1121G>A (p.Gly374Glu)","abstract_start":1129,"abstract_end":1152}]}
{"pmid":"17979987","title":"Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay.","abstract":"Mutations in the gene encoding calpain-3 (CAPN3) cause autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) and idiopathic eosinophilic myositis. Accurate diagnosis and genetic counselling are based on the identification of disease-causing mutations on both alleles of CAPN3 in the patients. In the present study, we used transcriptional analysis as a complementary approach for patients suspected of being affected with LGMD2A, in whom initial denaturing high-performance liquid chromatography genomic mutation screening evidenced no or only one CAPN3 mutation obviously considered as disease causing. This allowed to identify and characterize cDNA deletions. Further genomic analysis allowed to determine the origin of these deletions, either as splicing defects caused by intronic mutations or as an internal multi-exonic deletion. In particular, we report two novel CAPN3 mutations (c.1745 + 4_1745 + 7delAGTG in IVS13 and c.2185-16A>G in IVS20) and a recurrent large-sized genomic deletion including exons 2-8 for which genomic breakpoints have been characterized. In addition, our results indicate nonsense-mediated messenger RNA decay as a mechanism for under-expression of CAPN3 associated to some specific variations.","variants":[{"Name":"NM_000070.3(CAPN3):c.2185-16A>G","Chromosome":"15","Start":"42410572","Stop":"42410572","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1056221,"rule_based_match":true,"evidence_text":"c.2185-16A>G in IVS20","llm_judgment":"PRESENT","evidence":"c.2185-16A>G in IVS20","abstract_start":942,"abstract_end":963}]}
{"pmid":"22310900","title":"Mutation identification of the DSPP in a Chinese family with DGI-II and an up-to-date bioinformatic analysis.","abstract":"In this study, through linkage analysis of a four-generation Chinese family with multiple members afflicted with DGI (type II), we identified a novel missense mutation in DSPP. The mutation was located in exon 2 at the second nucleotide position of the last codon and resulted in a substitution of a proline with a leucine residue (c.50C>T, p.P17L, g.50C>T). To assess the potential effects of this novel mutation, we utilized various bioinformatics analysis programs. The results indicate that the mutation likely affects protein cleavage/trafficking. We also analyzed previously reported mutations of DSPP. In summary, our finding supports that the genomic sequence that corresponds to the P17 residue of DSPP is a mutational hotspot and P17 may be critical for the function of DSPP.","variants":[{"Name":"NM_014208.3(DSPP):c.50C>T (p.Pro17Leu)","Chromosome":"4","Start":"87610958","Stop":"87610958","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2894683,"rule_based_match":true,"evidence_text":"c.50C>T, p.P17L, g.50C>T","llm_judgment":"PRESENT","evidence":"c.50C>T, p.P17L, g.50C>T","abstract_start":332,"abstract_end":356}]}
{"pmid":"24515575","title":"AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate.","abstract":"BACKGROUND: Whole exome sequencing (WES) offers a powerful diagnostic tool to rapidly and efficiently sequence all coding genes in individuals presenting for consideration of phenotypically and genetically heterogeneous disorders such as suspected mitochondrial disease. Here, we report results of WES and functional validation in a consanguineous Indian kindred where two siblings presented with profound developmental delay, congenital hypotonia, refractory epilepsy, abnormal myelination, fluctuating basal ganglia changes, cerebral atrophy, and reduced N-acetylaspartate (NAA).\nMETHODS: Whole blood DNA from one affected and one unaffected sibling was captured by Agilent SureSelect Human All Exon kit and sequenced on the Illumina HiSeq2000. Mutations were validated by Sanger sequencing in all family members. Protein from wild-type and mutant fibroblasts was isolated to assess mutation effects on protein expression and enzyme activity.\nRESULTS: A novel SLC25A12 homozygous missense mutation, c.1058G>A; p.Arg353Gln, segregated with disease in this kindred. SLC25A12 encodes the neuronal aspartate-glutamate carrier 1 (AGC1) protein, an essential component of the neuronal malate/aspartate shuttle that transfers NADH and H(+) reducing equivalents from the cytosol to mitochondria. AGC1 activity enables neuronal export of aspartate, the glial substrate necessary for proper neuronal myelination. Recombinant mutant p.Arg353Gln AGC1 activity was reduced to 15% of wild type. One prior reported SLC25A12 mutation caused complete loss of AGC1 activity in a child with epilepsy, hypotonia, hypomyelination, and reduced brain NAA.\nCONCLUSIONS: These data strongly suggest that SLC25A12 disease impairs neuronal AGC1 activity. SLC25A12 sequencing should be considered in children with infantile epilepsy, congenital hypotonia, global delay, abnormal myelination, and reduced brain NAA.","variants":[{"Name":"NM_003705.5(SLC25A12):c.1058G>A (p.Arg353Gln)","Chromosome":"2","Start":"171813452","Stop":"171813452","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":247548,"rule_based_match":true,"evidence_text":"c.1058G>A; p.Arg353Gln","llm_judgment":"PRESENT","evidence":"c.1058G>A; p.Arg353Gln","abstract_start":1001,"abstract_end":1023}]}
{"pmid":"29143313","title":"Polyglucosan myopathy and functional characterization of a novel GYG1 mutation.","abstract":"OBJECTIVES: Disorders of glycogen metabolism include rare hereditary muscle glycogen storage diseases with polyglucosan, which are characterized by storage of abnormally structured glycogen in muscle in addition to exercise intolerance or muscle weakness. In this study, we investigated the etiology and pathogenesis of a late-onset myopathy associated with glycogenin-1 deficiency.\nMATERIALS AND METHODS: A family with two affected siblings, 64- and 66-year-olds, was studied. Clinical examination and whole-body MRI revealed weakness and wasting in the hip girdle and proximal leg muscles affecting ambulation in the brother. The sister had weakness and atrophy of hands and slight foot dorsiflexion difficulties. Muscle biopsy and whole-exome sequencing were performed in both cases to identify and characterize the pathogenesis including the functional effects of identified mutations.\nRESULTS: Both siblings demonstrated storage of glycogen that was partly resistant to alpha-amylase digestion. Both were heterozygous for two mutations in GYG1, one truncating 1-base deletion (c.484delG; p.Asp163Thrfs*5) and one novel missense mutation (c.403G>A; p.Gly135Arg). The mutations caused reduced expression of glycogenin-1 protein, and the missense mutation abolished the enzymatic function as analyzed by an in vitro autoglucosylation assay.\nCONCLUSION: We present functional evidence for the pathogenicity of a novel GYG1 missense mutation located in the substrate binding domain. Our results also demonstrate that glycogenin-1 deficiency may present with highly variable distribution of weakness and wasting also in the same family.","variants":[{"Name":"NM_004130.4(GYG1):c.403G>A (p.Gly135Arg)","Chromosome":"3","Start":"148996826","Stop":"148996826","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1496602,"rule_based_match":true,"evidence_text":"c.403G>A (p.Gly135Arg)","llm_judgment":"PRESENT","evidence":"p.Gly135Arg","abstract_start":1153,"abstract_end":1164}]}
{"pmid":"34761252","title":"A novel Lynch syndrome pedigree bearing germ-line MSH2 missense mutation c.1808A>T (Asp603Val).","abstract":"We report the first pedigree of Lynch syndrome bearing a germ-line MSH2 missense mutation c.1808A>T (Asp603Val). Until now, this missense mutation, in exon 12 of MSH2, was identified as a variant of unknown significance in the International Society for Gastrointestinal Hereditary Tumours database. In vitro induction mutagenesis experiments indicated that the MSH2 mutant protein (Asp603Val) is easily degraded in embryonic stem cells, albeit there is no clinical information concerning this mutant. Our pedigree includes four patients with Lynch syndrome-associated malignancies and clinically matches the Amsterdam II criteria. The proband, a female, first had an endometrial cancer at the age of 49 and then mantle cell lymphoma, colonic and gastric adenocarcinomas and neuroendocrine carcinoma, successively. Her mother also had Lynch syndrome-associated malignancies, including colonic, uterine and gastric cancers, and her elder son had rectal cancer. In the germline of the proband and her son, an MSH2 missense mutation c.1808A>T was discovered. Immunohistochemical analyses indicated that the expression of the MSH2 protein was decreased in the tumors, such as gastric cancer and neuroendocrine carcinoma, due to the missense mutation c.1808A>T. This study showed that the MSH2 missense mutation c.1808A>T (Asp603Val) is a likely pathogenic mutation and is responsible for typical Lynch syndrome-associated malignancies, including neuroendocrine carcinoma.","variants":[{"Name":"NM_000251.3(MSH2):c.1808A>T (p.Asp603Val)","Chromosome":"2","Start":"47475073","Stop":"47475073","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":472937,"rule_based_match":true,"evidence_text":"c.1808A>T (Asp603Val)","llm_judgment":"PRESENT","evidence":"c.1808A>T (Asp603Val)","abstract_start":90,"abstract_end":111}]}
{"pmid":"17637804","title":"Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses.","abstract":"The branchio-oto-renal (BOR) syndrome is an autosomal-dominant disorder characterized by hearing loss, branchial and renal anomalies. BOR is genetically heterogeneous and caused by mutations in EYA1 (8q13.3), SIX1 (14q23.1), SIX5 (19q13.3) and in an unidentified gene on 1q31. We examined six Danish families with BOR syndrome by assessing linkage to BOR loci, by performing EYA1 multiplex ligation-dependent probe amplification (MLPA) analysis for deletions and duplications and by sequencing of EYA1, SIX1 and SIX5. We identified four EYA1 mutations (c.920delG, IVS10-1G>A, IVS12+4A>G and p.Y591X) and one SIX1 mutation (p.W122R), providing a molecular diagnosis in five out of the six families (83%). The present, yet preliminary, observation that renal and temporal bone malformations are less frequent in SIX1-related disease suggests a slightly different clinical profile compared to EYA1-related disease. Unidentified mutations impairing mRNA expression or further genetic heterogeneity may explain the lack of mutation finding in one family despite LOD score indications of EYA1 involvement.","variants":[{"Name":"NM_005982.4(SIX1):c.364T>A (p.Trp122Arg)","Chromosome":"14","Start":"60648826","Stop":"60648826","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":23350,"rule_based_match":false,"evidence_text":"p.W122R","llm_judgment":"PRESENT","evidence":"p.W122R","abstract_start":623,"abstract_end":630}]}
{"pmid":"25793145","title":"Myoclonus in ataxia-telangiectasia.","abstract":"BACKGROUND: Various movement disorders can be found in ataxia-telangiectasia (AT), including ataxia, dystonia, chorea, and myoclonus, but myoclonus has rarely been described as the predominant feature in AT.\nCASE REPORT: We report two AT patients with prominent myoclonus, illustrating an unusual presentation of this disorder. Sequencing of the ATM gene in the first patient revealed a homozygous truncating mutation, c.5908C>T (p.Q1970*) in exon 38 of the ATM gene, which has been previously reported as a founder mutation in the Costa Rican population.\nDISCUSSION: Myoclonus can be a predominant or presenting feature in AT, even without dystonia.","variants":[{"Name":"NM_000051.4(ATM):c.5908C>T (p.Gln1970Ter)","Chromosome":"11","Start":"108310305","Stop":"108310305","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":151118,"rule_based_match":true,"evidence_text":"c.5908C>T (p.Q1970*)","llm_judgment":"PRESENT","evidence":"c.5908C>T (p.Q1970*)","abstract_start":419,"abstract_end":439}]}
{"pmid":"17438221","title":"Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation.","abstract":"A 10-year-old boy developed corticosteroid-responsive relapsing neurologic signs, including nystagmus and ataxia. MRI revealed multifocal T2 white matter hyperintensities; several were gadolinium-enhancing. CSF contained oligoclonal bands. Although the patient met criteria for multiple sclerosis (MS), the proteolipid protein-1 gene (PLP1) contained a mutation in exon 3B (c.409C>T), predicting a tryptophan-for-arginine substitution. This case raises questions about the role of inflammation in PLP1-related disorders and, conversely, PLP1 mutations in MS.","variants":[{"Name":"NM_000533.5(PLP1):c.409C>T (p.Arg137Trp)","Chromosome":"X","Start":"103786682","Stop":"103786682","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26137,"rule_based_match":true,"evidence_text":"c.409C>T","llm_judgment":"PRESENT","evidence":"c.409C>T","abstract_start":374,"abstract_end":382}]}
{"pmid":"21165770","title":"PALB2 mutations in German and Russian patients with bilateral breast cancer.","abstract":"Since germline mutations in the PALB2 (Partner and Localizer of BRCA2) gene have been identified as breast cancer (BC) susceptibility alleles, the geographical spread and risks associated with PALB2 mutations are subject of intense investigation. Patients with bilateral breast cancer constitute a valuable group for genetic studies. We have thus scanned the whole coding region of PALB2 in a total of 203 German or Russian bilateral breast cancer patients using an approach based on high-resolution melting analysis and direct sequencing of genomic DNA samples. Truncating PALB2 mutations were identified in 4/203 (2%) breast cancer patients with bilateral disease. The two nonsense mutations, p.E545X and p.Q921X, have not been previously described whereas the two other mutations, p.R414X and c.509_510delGA, are recurrent. Our results indicate that PALB2 germline mutations account for a small, but not negligible, proportion of bilateral breast carcinomas in German and Russian populations.","variants":[{"Name":"NM_024675.4(PALB2):c.509_510del (p.Arg170fs)","Chromosome":"16","Start":"23636036","Stop":"23636037","ReferenceAlleleVCF":"ATC","AlternateAlleleVCF":"A","allel_id":132267,"rule_based_match":true,"evidence_text":"c.509_510delGA","llm_judgment":"PRESENT","evidence":"c.509_510delGA","abstract_start":796,"abstract_end":810}]}
{"pmid":"25707956","title":"Multi-systemic involvement in NGLY1-related disorder caused by two novel mutations.","abstract":"NGLY1-related disorder is a newly described autosomal recessive condition characterized by neurological, hepatic, ophthalmological findings and associated with dysmorphic features, constipation and scoliosis. It is caused by mutations in NGLY1, which encodes an enzyme, N-glycanase 1, involved in deglycosylation of glycoproteins, an essential step in the endoplasmic reticulum-associated degradation (ERAD) pathway. The disorder has been described in eight patients. We investigated the molecular basis and phenotype of NGLY1-related disorder in an additional patient. The proband is a 14-year-old who presented in early infancy with profound hypotonia and elevated transaminases. Liver biopsy showed lipid accumulation with dilated endoplasmic reticulum. He exhibited global developmental delay, acquired microcephaly, seizures, involuntary body movements, muscle atrophy, absent reflexes, and poor growth. He had multiple procedures for lacrimal duct stenosis and strabismus and had intractable blepharitis. He had severe osteopenia and persistent hypocholesterolemia. Whole exome sequencing revealed two novel variants in NGLY1: a truncating mutation, c.347C > G (p.S116X), and a splicing mutation, c.881 + 5G (p.IVS5 + 5G>T), predicted to abolish the splice donor site of exon 5. This study, along with previously reported cases, suggests that mutations in NGLY1 cause a recognizable phenotype and targeted sequencing should be considered in patients with typical presentation. This study expands the molecular spectrum of NGLY1-related condition and suggests that osteopenia and hypocholesterolemia may be part of the phenotype.","variants":[{"Name":"NM_018297.4(NGLY1):c.881+5G>T","Chromosome":"3","Start":"25739572","Stop":"25739572","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":223313,"rule_based_match":false,"evidence_text":"c.881 + 5G (p.IVS5 + 5G>T)","llm_judgment":"PRESENT","evidence":"c.881 + 5G (p.IVS5 + 5G>T)","abstract_start":1203,"abstract_end":1229},{"Name":"NM_018297.4(NGLY1):c.347C>G (p.Ser116Ter)","Chromosome":"3","Start":"25764211","Stop":"25764211","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":223316,"rule_based_match":true,"evidence_text":"c.347C > G (p.S116X)","llm_judgment":"PRESENT","evidence":"c.347C > G (p.S116X)","abstract_start":1156,"abstract_end":1176}]}
{"pmid":"29797630","title":"Histopathological analysis of aggressive renal cell carcinoma harboring a unique germline mutation in fumarate hydratase.","abstract":"Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis with RCC. This disorder is caused by a germline mutation in the fumarate hydratase (FH) gene, which encodes an important enzyme of the tricarboxylic acid (TCA) cycle. This mutation distinguishes HLRCC from sporadic RCCs. Herein, we investigated a case of HLRCC in a 32-year-old man who underwent nephrectomy for treatment of a solid-cystic tumor in the left kidney. Histopathology demonstrated a variegated architecture of papillary, tubulocystic and cribriform patterns composed of high-grade tumor cells with enlarged nuclei and eosinophilic nucleoli. Immunostaining and western blotting revealed no FH expression in the tumor. Genomic DNA sequencing identified a heterozygous mutation involving deletion of the 3' end of exon 2 and intron 2 of the FH gene (c.251_267+7delTGACAGAACGCATGCCAGTAAGTG), and RT-PCR confirmed exon 2 skipping in FH mRNA. The somatic FH gene status of the tumor showed only the mutated allele, indicating loss of heterozygosity as the \"second hit\" of tumor suppressor gene inactivation. These data support that an FH mutation involving the splice site causes exon skipping, changing the conformation of the protein and accelerating carcinogenic cascades under impaired FH functioning in the TCA cycle.","variants":[{"Name":"NM_000143.4(FH):c.251_267+7del","Chromosome":"1","Start":"241517175","Stop":"241517198","ReferenceAlleleVCF":"CCACTTACTGGCATGCGTTCTGTCA","AlternateAlleleVCF":"C","allel_id":3494700,"rule_based_match":true,"evidence_text":"c.251_267+7delTGACAGAACGCATGCCAGTAAGTG","llm_judgment":"PRESENT","evidence":"c.251_267+7delTGACAGAACGCATGCCAGTAAGTG","abstract_start":897,"abstract_end":935}]}
{"pmid":"28283652","title":"","abstract":"Breast cancer risks conferred by many germline missense variants in the <i>BRCA1</i> and <i>BRCA2</i> genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; <i>P</i> = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; <i>P</i> = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; <i>P</i> = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; <i>P</i> = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. <i>Cancer Res; 77(11); 2789-99. ©2017 AACR</i>.","variants":[{"Name":"NM_000059.4(BRCA2):c.9104A>C (p.Tyr3035Ser)","Chromosome":"13","Start":"32379900","Stop":"32379900","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":46767,"rule_based_match":true,"evidence_text":"BRCA2 c.9104A>C, p.Tyr3035Ser","llm_judgment":"PRESENT","evidence":"BRCA2 c.9104A>C, p.Tyr3035Ser","abstract_start":553,"abstract_end":582},{"Name":"NM_000059.4(BRCA2):c.7522G>A (p.Gly2508Ser)","Chromosome":"13","Start":"32356514","Stop":"32356514","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67015,"rule_based_match":true,"evidence_text":"BRCA2 c.7522G>A, p.Gly2508Ser","llm_judgment":"PRESENT","evidence":"BRCA2 c.7522G>A, p.Gly2508Ser","abstract_start":775,"abstract_end":804},{"Name":"NM_000059.4(BRCA2):c.8187G>T (p.Lys2729Asn)","Chromosome":"13","Start":"32363389","Stop":"32363389","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":46698,"rule_based_match":true,"evidence_text":"c.8187G>T, p.Lys2729Asn","llm_judgment":"PRESENT","evidence":"c.8187G>T, p.Lys2729Asn","abstract_start":840,"abstract_end":863},{"Name":"NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln)","Chromosome":"17","Start":"43063930","Stop":"43063930","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46192,"rule_based_match":true,"evidence_text":"BRCA1 c.5096G>A, p.Arg1699Gln","llm_judgment":"PRESENT","evidence":"BRCA1 c.5096G>A, p.Arg1699Gln","abstract_start":617,"abstract_end":646}]}
{"pmid":"23398055","title":"Normal Hb A2 β-thalassemia trait: frameshift mutation (HBB: c.187_251dup) in cis with the Hb A2' δ-globin gene missense mutation (HBD: c.49G>C).","abstract":"We report the case of a father and daughter who are heterozygous for a duplication of 65 bp within exon 2 of the β-globin gene, resulting in an altered and truncated β-globin chain that is predicted to be non functional. The β-globin gene mutation is in cis with the common Hb A2 ' missense mutation of the δ-globin gene (HBD: c.49G>C), resulting in β-thalassemia (β-thal) trait with normal levels of Hb A2. This is the second report of this β(0)-thal mutation, and both families were associated with the Hb A2 ' variant and normal levels of Hb A2. Laboratories should be aware of the rare occurrence of β-thal trait with normal levels of Hb A2.","variants":[{"Name":"NM_000518.5(HBB):c.187_251dup (p.Thr85fs)","Chromosome":"11","Start":"5226640","Stop":"5226641","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCCCTTGAGGTTGTCCAGGTGAGCCAGGCCATCACTAAAGGCACCGAGCACTTTCTTGCCATGAGC","allel_id":857568,"rule_based_match":true,"evidence_text":"HBB: c.187_251dup","llm_judgment":"PRESENT","evidence":"HBB: c.187_251dup","abstract_start":null,"abstract_end":null}]}
{"pmid":"23362850","title":"Report of a novel mutation in CRB1 in a Lebanese family presenting retinal dystrophy.","abstract":"PURPOSE: To identify the genetic basis of a recessive inheritance form of retinal dystrophy (RD) in a Lebanese family.\nMATERIALS AND METHODS: Clinical data were recorded for five patients of the 14 family members. Genetic linkage was carried out using Affymetrix 250 K Nspl SNP array followed by sequencing.\nRESULTS: The patients showed variable phenotypes ranging from Leber Congenital Amaurosis (LCA) to progressive forms of Retinitis Pigmentosa (RP). A 46.1 Mb chromosomal region at chromosome 1q23.3-32.2 was identified by homozygosity mapping. This region contained the Crumbs homologue-1, CRB1, a gene responsible for recessive retinal dystrophies. CRB1 is required for photoreceptor morphogenesis, and it has been associated with RP and LCA. Sequencing of CRB1 revealed two mutations: a novel deletion in exon 6 (c.1772_1775delGCAT; p.C591Sfs*28) and a missense mutation in exon 7 (c.2234C > T; p.T745M).\nCONCLUSION: We report a novel CRB1 mutation in inherited RD in a Lebanese family, and confirm the considerable phenotype heterogeneity that may exist between individuals sharing the same mutations.","variants":[{"Name":"NM_201253.3(CRB1):c.1772_1775del (p.Cys591fs)","Chromosome":"1","Start":"197421598","Stop":"197421601","ReferenceAlleleVCF":"AATGC","AlternateAlleleVCF":"A","allel_id":855876,"rule_based_match":true,"evidence_text":"c.1772_1775delGCAT","llm_judgment":"PRESENT","evidence":"c.1772_1775delGCAT","abstract_start":820,"abstract_end":838}]}
{"pmid":"23662636","title":"Collapse of the keratin filament network through the expression of mutant keratin 6c observed in a case of focal plantar keratoderma.","abstract":"Focal palmoplantar keratoderma (PPK) with severe pain is a hallmark of pachyonychia congenita, a rare autosomal dominant disorder involving PPK and hypertrophic nail dystrophy. Some families present focal PPK with either minimal or no nail changes. Dominant-negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16 or KRT17, lead to pachyonychia congenita. However, the majority of families with focal PPK showing minimal or no nail changes do not harbor mutations in these genes. Recently, mutations of KRT6C were identified in families with focal PPK alone. Here, we report a 26-year-old Japanese man with focal plantar hyperkeratosis that developed at approximately 10 years of age with no palmar involvement and no nail alterations. We identified a missense KRT6C mutation c.1414G>A resulting in an p.Glu472Lys substitution, as reported in other Japanese patients. When the mutant keratin 6c protein is exogenously expressed in human HaCaT cells, a collapse of the keratin filament network is observed in a dose-dependent manner, suggesting the mutation has a dominant-negative effect on keratin filament network formation. The mutated residue is located at the helix termination motif of keratin 6c. The peptide sequence around this residue is highly conserved among type II, III and IV intermediate filament proteins. Glu to Lys mutations of the equivalent residue have been reported in a variety of inherited diseases, including neurodegenerative diseases, corneal dystrophy and skin disorders, suggesting that this residue is vital to keratin function.","variants":[{"Name":"NM_173086.5(KRT6C):c.1414G>A (p.Glu472Lys)","Chromosome":"12","Start":"52469680","Stop":"52469680","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":132051,"rule_based_match":true,"evidence_text":"c.1414G>A","llm_judgment":"PRESENT","evidence":"c.1414G>A","abstract_start":804,"abstract_end":813}]}
{"pmid":"28892560","title":"Mutations of KIF14 cause primary microcephaly by impairing cytokinesis.","abstract":"OBJECTIVE: Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (citron rho-interacting kinase)-a component of the central spindle matrix-were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis.\nMETHODS: Linkage analysis and whole exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on the cellular level using immunofluorescence and microscopy.\nRESULTS: We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG; p.Val827del, and c.4071G>A;p.Gln1357=) as the likely cause in 3 MCPH families. Furthermore, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Furthermore, we observed a large number of binucleated and apoptotic cells-signs of failed cytokinesis that we also observed in experimentally KIF14-depleted cells.\nINTERPRETATION: Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations. Ann Neurol 2017;82:562-577.","variants":[{"Name":"NM_014875.3(KIF14):c.2545C>G (p.His849Asp)","Chromosome":"1","Start":"200598241","Stop":"200598241","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":495008,"rule_based_match":true,"evidence_text":"NM_014875.2;c.2545C>G;p.His849Asp","llm_judgment":"PRESENT","evidence":"NM_014875.2;c.2545C>G;p.His849Asp","abstract_start":1090,"abstract_end":1123},{"Name":"NM_014875.3(KIF14):c.3662G>T (p.Gly1221Val)","Chromosome":"1","Start":"200565669","Stop":"200565669","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":495009,"rule_based_match":true,"evidence_text":"NM_014875.2;c.3662G>T;p.Gly1221Val","llm_judgment":"PRESENT","evidence":"p.Gly1221Val","abstract_start":1138,"abstract_end":1150},{"Name":"NM_014875.3(KIF14):c.263T>A (p.Leu88Ter)","Chromosome":"1","Start":"200618461","Stop":"200618461","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":495005,"rule_based_match":true,"evidence_text":"NM_014875.2;c.263T>A;pLeu88*","llm_judgment":"PRESENT","evidence":"NM_014875.2;c.263T>A;pLeu88*","abstract_start":798,"abstract_end":826},{"Name":"NM_014875.3(KIF14):c.2480_2482del (p.Val827del)","Chromosome":"1","Start":"200598304","Stop":"200598306","ReferenceAlleleVCF":"CCAA","AlternateAlleleVCF":"C","allel_id":495006,"rule_based_match":true,"evidence_text":"c.2480_2482delTTG; p.Val827del","llm_judgment":"PRESENT","evidence":"c.2480_2482delTTG; p.Val827del","abstract_start":828,"abstract_end":858},{"Name":"NM_014875.3(KIF14):c.4071G>A (p.Gln1357=)","Chromosome":"1","Start":"200565069","Stop":"200565069","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":495007,"rule_based_match":true,"evidence_text":"c.4071G>A;p.Gln1357=","llm_judgment":"PRESENT","evidence":"c.4071G>A;p.Gln1357=","abstract_start":864,"abstract_end":884}]}
{"pmid":"22847164","title":"Molecular diagnosis for a fatal case of very long-chain acyl-CoA dehydrogenase deficiency in Hong Kong Chinese with a novel mutation: a preventable death by newborn screening.","abstract":"Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is one of the most common fatty acid oxidation defects that cause sudden unexpected deaths in infants. The death attributed to VLCAD deficiency can be prevented by early diagnosis with expanded newborn screening using tandem mass spectrometry. A favorable outcome can be achieved with early diagnosis and prompt treatment. However, such newborn screening has not yet been available in Hong Kong. We report a 2-month-old boy who succumbed 5 hours after admission with the diagnosis of VLCAD deficiency confirmed by genetic analysis performed after death. The patient was compound heterozygous for a novel splicing mutation ACADVL NM_000018.2:c.277+2T>G; NC_000017.10:g.7123997T>G and a known disease-causing mutation ACADVL NM_000018.2:c.388_390del; NP_000009.1: p.Glu130del. Family screening was performed for at-risk siblings. The rapid downhill course of the patient clearly illustrates the need of newborn screening for early diagnosis. Our patient was asymptomatic before metabolic decompensation. However, once metabolic decompensation occurred, rapid deterioration and death followed, which obviated the opportunity to diagnose and treat. The only way to save these patients' lives and improve their outcome is early diagnosis and appropriate treatment. Therefore, we strongly urge the implementation of newborn screening using tandem mass spectrometry for VLCAD deficiency and other highly treatable inborn errors of metabolism in Hong Kong.","variants":[{"Name":"NM_000018.4(ACADVL):c.277+2T>G","Chromosome":"17","Start":"7220678","Stop":"7220678","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":548628,"rule_based_match":true,"evidence_text":"ACADVL NM_000018.2:c.277+2T>G","llm_judgment":"PRESENT","evidence":"ACADVL NM_000018.2:c.277+2T>G","abstract_start":680,"abstract_end":709}]}
{"pmid":"29998006","title":"Germline pharmacogenomics of DPYD*9A (c.85T>C) variant in patients with gastrointestinal malignancies treated with fluoropyrimidines.","abstract":"BACKGROUND: The correlation between DPYD*9A (c.85T>C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency clinical phenotype is controversial. Reference laboratories either did not perform DPYD*9A genotyping or have stopped DPYD*9A genotyping and limited genotyping to high-risk variants (DPYD*2A, DPYD*13 and DPYD*9B) only. This study explored DPYD*9A genotype and clinical phenotype correlation in patients with gastrointestinal (GI) malignancies treated with fluoropyrimidines.\nMETHODS: Between 2011 and 2017, 67 patients with GI malignancies were genotyped for DPYD variants. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Fisher's exact test was used for statistical analysis.\nRESULTS: DPYD variants were identified in 17 out of 67 (25%) patients. One patient was homozygous for DPYD*9A variant and one patient was double heterozygous for DPYD*9A and DPYD*9B variants. In patients with identified DPYD variants, 13/17 (76%) patients had DPYD*9A variant, 3/17 (18%) patients had DPYD*2A variant and 2/17 (12%) patient had DPYD*9B variant. Only patients genotyped prior to 2015 were genotyped for DPYD*9A variant (N=28). Of those, 13/28 patients (46%) had DPYD*9A variant. Grade 3-4 diarrhea was associated with DPYD*9A variant in patients treated with full dose fluoropyrimidines (P=0.0055).\nCONCLUSIONS: In our cohort, DPYD*9A variant was the most common diagnosed variant. The correlation between DPYD*9A genotype and DPD deficiency in clinical phenotype was noticeable in patients who received full dose fluoropyrimidines as they all experienced grade 3-4 toxicities (diarrhea).","variants":[{"Name":"NM_000110.4(DPYD):c.85T>C (p.Cys29Arg)","Chromosome":"1","Start":"97883329","Stop":"97883329","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15474,"rule_based_match":true,"evidence_text":"DPYD*9A (c.85T>C)","llm_judgment":"PRESENT","evidence":"DPYD*9A (c.85T>C)","abstract_start":36,"abstract_end":53}]}
{"pmid":"38128568","title":"Biallelic BORCS8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics.","abstract":"BLOC-one-related complex (BORC) is a multiprotein complex composed of eight subunits named BORCS1-8. BORC associates with the cytosolic face of lysosomes, where it sequentially recruits the small GTPase ARL8 and kinesin-1 and -3 microtubule motors to promote anterograde transport of lysosomes toward the peripheral cytoplasm in non-neuronal cells and the distal axon in neurons. The physiological and pathological importance of BORC in humans, however, remains to be determined. Here, we report the identification of compound heterozygous variants [missense c.85T>C (p.Ser29Pro) and frameshift c.71-75dupTGGCC (p.Asn26Trpfs*51)] and homozygous variants [missense c.196A>C (p.Thr66Pro) and c.124T>C (p.Ser42Pro)] in BORCS8 in five children with a severe early-infantile neurodegenerative disorder from three unrelated families. The children exhibit global developmental delay, severe-to-profound intellectual disability, hypotonia, limb spasticity, muscle wasting, dysmorphic facies, optic atrophy, leuko-axonopathy with hypomyelination, and neurodegenerative features with prevalent supratentorial involvement. Cellular studies using a heterologous transfection system show that the BORCS8 missense variants p.Ser29Pro, p.Ser42Pro and p.Thr66Pro are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution toward the cell periphery. The BORCS8 frameshift variant p.Asn26Trpfs*51, on the other hand, is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution toward the cell periphery. Therefore, all the BORCS8 variants are partial or total loss-of-function alleles and are thus likely pathogenic. Knockout of the orthologous borcs8 in zebrafish causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease. These findings thus identify BORCS8 as a novel genetic locus for an early-infantile neurodegenerative disorder and highlight the critical importance of BORC and lysosome dynamics for the development and function of the central nervous system.","variants":[{"Name":"NM_001145784.2(BORCS8):c.85T>C (p.Ser29Pro)","Chromosome":"19","Start":"19186958","Stop":"19186958","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2401041,"rule_based_match":true,"evidence_text":"c.85T>C (p.Ser29Pro)","llm_judgment":"PRESENT","evidence":"c.85T>C (p.Ser29Pro)","abstract_start":559,"abstract_end":579}]}
{"pmid":"26969503","title":"The p.Phe174Ser mutation is associated with mild forms of Smith Lemli Opitz Syndrome.","abstract":"BACKGROUND: Smith Lemli Opitz syndrome (SLOS; OMIM #270400) is an autosomal recessive metabolic disorder caused by mutations in the DHCR7 gene. SLOS is characterized by a plethora of abnormalities involving mainly the brain and the genitalia but also the cardiac, skeletal and gastroenteric system, typical dysmorphic facial features, and variable degrees of developmental delay and intellectual disability (ID). SLOS has a broad phenotypic spectrum, ranging from multiple congenital malformation syndrome, to mild developmental delay and minor malformations. A large number of mutations have been described in the DHCR7 gene, with few common mutations accounting for the majority of mutated alleles found in patients and a large number of very rare or even private variants. Due to the wide variety of clinical presentations, diagnosis can be difficult, especially in the milder forms of the disorder. Furthermore, establishing a molecular diagnosis can be complicated by finding variants of unknown clinical significance in such cases.\nCASE PRESENTATION: We report a case of SLOS at the mild end of the clinical spectrum, presenting with bilateral pelvis ectasia, mild dysmorphic features and mild intellectual disability. The case is compound heterozygous for a known pathogenic mutation (c.724C > T, p.Arg242Cys) and a mutation that has only been reported once in a Portuguese patient (c.521 T > C, p.Phe174Ser) whose pathogenicity has not been yet assessed. We compared the two patients carrying the p.Phe174Ser variant and concluded that this variant is associated with mild forms of SLOS.\nCONCLUSION: We report a patient with a mild case of SLOS, highlighting the importance of recognizing subtle anomalies of the genitourinary system, associated with mild dysmorphic features and mild intellectual disability in establishing the diagnosis of mild forms of SLOS. With this report, we confirm the pathogenicity of the p.Phe174Ser variant and we also provide evidence of its association with mild forms of SLOS. This finding further facilitates the establishment of a genotype-phenotype correlation for SLOS. This helps in counselling for this disorder and in predicting therapeutic responses.","variants":[{"Name":"NM_001360.3(DHCR7):c.724C>T (p.Arg242Cys)","Chromosome":"11","Start":"71438986","Stop":"71438986","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34127,"rule_based_match":true,"evidence_text":"c.724C > T, p.Arg242Cys","llm_judgment":"PRESENT","evidence":"c.724C > T, p.Arg242Cys","abstract_start":1292,"abstract_end":1315},{"Name":"NM_001360.3(DHCR7):c.521T>C (p.Phe174Ser)","Chromosome":"11","Start":"71441332","Stop":"71441332","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":546357,"rule_based_match":true,"evidence_text":"c.521 T > C, p.Phe174Ser","llm_judgment":"PRESENT","evidence":"c.521 T > C, p.Phe174Ser","abstract_start":1390,"abstract_end":1414}]}
{"pmid":"34097983","title":"Novel mutations of the CYP17A1 gene in four Chinese 46,XX cases with partial 17a-hydroxylase/17,20-lyase deficiency.","abstract":"The condition 17a-Hydroxylase/17,20-lyase deficiency (17-OHD) is a rare kind of congenital adrenal hyperplasia (CAH) characterized by failure to synthetize cortisol, adrenal androgens and gonadal steroids. Partial deficiency is much rarer, presenting with subtler symptoms. In this study, we summarized the clinical characteristics and identified the underlying gene mutation in four Chinese 46,XX patients with partial 17-OHD. Mutational analysis of the CYP17A1 gene was performed by polymerase chain reaction (PCR) and Sanger sequencing. Clinical and hormonal findings in these patients were consistent with typical manifestations of partial 17-OHD. All patients were found to have a compound heterozygous mutation of the CYP17A1 gene, with five mutations identified. Among them, c.887 T > C(p. I296T), c.1019G > A(p. R340H) and c.1346G > A(p. R449H) were novel missense mutations. In conclusion, we identified three novel missense mutations of the CYP17A1 gene from four patients with partial 17-OHD deficiency. Genotype-phenotype correlation analysis revealed that these novel mutations can lead to partial 17-OHD. Our findings thus provide novel insight into the clinical evaluations and molecular basis of 17-OHD.","variants":[{"Name":"NM_000102.4(CYP17A1):c.887T>C (p.Ile296Thr)","Chromosome":"10","Start":"102833075","Stop":"102833075","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2837363,"rule_based_match":true,"evidence_text":"c.887 T > C(p. I296T)","llm_judgment":"PRESENT","evidence":"c.887 T > C(p. I296T)","abstract_start":782,"abstract_end":803},{"Name":"NM_000102.4(CYP17A1):c.1346G>A (p.Arg449His)","Chromosome":"10","Start":"102830883","Stop":"102830883","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2040911,"rule_based_match":true,"evidence_text":"c.1346G > A(p. R449H)","llm_judgment":"PRESENT","evidence":"c.1346G > A(p. R449H)","abstract_start":831,"abstract_end":852}]}
{"pmid":"15781192","title":"Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants.","abstract":"Isolated methylmalonic aciduria (MMA) is an inborn error of metabolism due to the impaired isomerization of l-methylmalonyl-CoA to succinyl-CoA. This reaction is catalyzed by the mitochondrial protein methylmalonyl-CoA mutase (MCM, EC 5.4.99.2), an adenosylcobalamin-dependent enzyme. Four different forms of isolated MMA have been described: mut MMA associated with defects in the MCM apoenzyme, and phenotypically divided into two subtypes mut- and mut0 MMA, and three different defects involved in the synthesis of the active form of the cofactor adenosylcobalamin, termed cbl MMA, and classified into three different complementation groups cblA, cblB, and cblH associated with defects in the MMAA and MMAB genes and with an unidentified protein, respectively. In this work we describe the genetic analysis of 25 MMA patients, mainly from Spain. Using biochemical and cellular approaches our patients have been classified, identifying 13 mut MMA, 7 cblA, 2 cblB, and 3 noncblA, noncblB deficient patients. cDNA and genomic DNA sequence analysis of the MUT, MMAA, and MMAB genes have allowed us to identify 27 different changes, 21 novel ones. Among the missense mutations identified in the MUT gene only one, the c.970G>A (p.A324T) variant located in the substrate binding domain is likely a mut- mutation. The remaining missense mutations c.326A>G (p.Q109R), c.983T>C (p.L328P), c.1846C>T (p.R616C), and c.1850T>G (p.L617R) are probably mut0. In the MMAA patients analyzed, frameshift mutations are prevalent. We have explored the genotype-phenotype correlation for this clinically heterogeneous disease.","variants":[{"Name":"NM_000255.4(MMUT):c.1850T>G (p.Leu617Arg)","Chromosome":"6","Start":"49440312","Stop":"49440312","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":543997,"rule_based_match":true,"evidence_text":"c.1850T>G (p.L617R)","llm_judgment":"PRESENT","evidence":"c.1850T>G (p.L617R)","abstract_start":1408,"abstract_end":1427},{"Name":"NM_000255.4(MMUT):c.1846C>T (p.Arg616Cys)","Chromosome":"6","Start":"49440316","Stop":"49440316","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544018,"rule_based_match":true,"evidence_text":"c.1846C>T (p.R616C)","llm_judgment":"PRESENT","evidence":"c.1846C>T (p.R616C)","abstract_start":1383,"abstract_end":1402},{"Name":"NM_000255.4(MMUT):c.970G>A (p.Ala324Thr)","Chromosome":"6","Start":"49453698","Stop":"49453698","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":544049,"rule_based_match":true,"evidence_text":"c.970G>A (p.A324T)","llm_judgment":"PRESENT","evidence":"c.970G>A (p.A324T)","abstract_start":1216,"abstract_end":1234},{"Name":"NM_000255.4(MMUT):c.983T>C (p.Leu328Pro)","Chromosome":"6","Start":"49453685","Stop":"49453685","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":544145,"rule_based_match":true,"evidence_text":"c.983T>C (p.L328P)","llm_judgment":"PRESENT","evidence":"c.983T>C (p.L328P)","abstract_start":1363,"abstract_end":1381}]}
{"pmid":"23840593","title":"Autosomal recessive transmission of MYBPC3 mutation results in malignant phenotype of hypertrophic cardiomyopathy.","abstract":"BACKGROUND: Hypertrophic cardiomyopathy (HCM) due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved.\nMETHODS: A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls.\nRESULTS: A novel missense mutation (c.1469G>T, p.Gly490Val) in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM.\nCONCLUSIONS: Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.","variants":[{"Name":"NM_000256.3(MYBPC3):c.1469G>T (p.Gly490Val)","Chromosome":"11","Start":"47342733","Stop":"47342733","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":75580,"rule_based_match":true,"evidence_text":"c.1469G>T (p.Gly490Val)","llm_judgment":"PRESENT","evidence":"p.Gly490Val","abstract_start":678,"abstract_end":689}]}
{"pmid":"27734841","title":"A novel founder MYO15A frameshift duplication is the major cause of genetic hearing loss in Oman.","abstract":"The increased risk for autosomal recessive disorders is one of the most well-known medical implications of consanguinity. In the Sultanate of Oman, a country characterized by one of the highest rates of consanguineous marriages worldwide, prevalence of genetic hearing loss (GHL) is estimated to be 6/10 000. Families of GHL patients have higher consanguinity rates than the general Omani population, indicating a major role for recessive forms. Mutations in GJB2, the most commonly mutated GHL gene, have been sporadically described. We collected 97 DNA samples of GHL probands, affected/unaffected siblings and parents from 26 Omani consanguineous families. Analyzing a first family by whole-exome sequencing, we identified a novel homozygous frameshift duplication (c.1171_1177dupGCCATCT) in MYO15A, the gene linked to the deafness locus DFNB3. This duplication was then found in a total of 8/26 (28%) families, within a 849 kb founder haplotype. Reconstruction of haplotype structure at MYO15A surrounding genomic regions indicated that the founder haplotype branched out in the past two to three centuries from a haplotype present worldwide. The MYO15A duplication emerges as the major cause of GHL in Oman. These findings have major implications for the design of GHL diagnosis and prevention policies in Oman.","variants":[{"Name":"NM_016239.4(MYO15A):c.1171_1177dup (p.Tyr393fs)","Chromosome":"17","Start":"18119970","Stop":"18119971","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGCCATCT","allel_id":612316,"rule_based_match":true,"evidence_text":"c.1171_1177dupGCCATCT","llm_judgment":"PRESENT","evidence":"c.1171_1177dupGCCATCT","abstract_start":769,"abstract_end":790}]}
{"pmid":"22408144","title":"Lissencephaly and band heterotopia: LIS1, TUBA1A, and DCX mutations in Hungary.","abstract":"The spectrum of lissencephaly ranges from absent (agyria) or decreased (pachygyria) convolutions to less severe malformation known as subcortical band heterotopia. Mutations involving LIS1 and TUBA1A result in the classic form of lissencephaly, whereas mutations of the DCX gene cause lissencephaly in males and subcortical band heterotopia in females. This report describes the clinical manifestations and imaging and genetic findings in 2 boys with lissencephaly and a girl with subcortical band heterotopia. An ovel mutation (c.83_84delAT, p.Tyr28Phefs*31) was identified in LIS1 in 1 of the boys with lissencephaly and another novel mutation (c.200delG, p.Ile68Leufs*87) was found in DCX in the girl with subcortical band heterotopia. The mutations appeared in the first half of the genes and are predicted to result in truncated proteins. A mutation was found in the TUBA1A gene (c.1205G>A, p.Arg402His) in the other boy. This mutation affects the folding of tubulin heterodimers, changing the interactions with proteins that bind microtubules.","variants":[{"Name":"NM_006009.4(TUBA1A):c.1205G>A (p.Arg402His)","Chromosome":"12","Start":"49185161","Stop":"49185161","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22110,"rule_based_match":true,"evidence_text":"c.1205G>A (p.Arg402His)","llm_judgment":"PRESENT","evidence":"p.Arg402His","abstract_start":896,"abstract_end":907}]}
{"pmid":"33879184","title":"Management strategy and novel ophthalmological findings in neonatal severe hypertriglyceridemia: a case report and literature review.","abstract":"BACKGROUND: Neonatal severe hypertriglyceridemia is rarely reported in the literature and there is no consensus for hypertriglyceridemia management at this age group.\nMETHODS: The index case is a 4-week-old male infant with severe hypertriglyceridemia accidentally discovered during a circumcision surgery. His clinical and genetic characteristics and his successful management strategy are described. Furthermore, a detailed ophthalmological examination of the proband was conducted at 3 and 6 months of age using Fourier-domain-optical coherence tomography.\nRESULTS: Triglycerides level at presentation was extremely high 33,727 mg/dL (380.8 mmol/L). Two sessions of exchange blood transfusion on two consecutive days successfully reduced triglycerides to 382 mg/dL (4.3 mmol/L) with no adverse effects. The infant was discharged 3 days later. At discharge, the mother was advised to continue breastfeeding together with a medium-chain triglycerides formula. Satisfactory growth parameters and lipid profile values were obtained for a follow-up duration of 5 months with no reported attacks of acute pancreatitis. Lipoprotein lipase deficiency was confirmed by the detection of the LPL homozygous pathogenic variant c.805G > A; p.(Glu269Lys). Early corneal and macular lesions were detected and persisted on follow-up despite relatively good lipemic control.\nCONCLUSION: This case highlights the importance of the early discovery of severe hypertriglyceridemia during the neonatal period, which is needed for prompt management and prevention of severe complications. Rationalized breastfeeding can be tolerated within the diet plan of the disease with satisfactory outcomes. To our knowledge, it is the first study reporting early corneal and macular affection by severe hypertriglyceridemia in a neonate. Prolonged follow-up is needed to determine the extent of ophthalmological lesions.","variants":[{"Name":"NM_000237.3(LPL):c.805G>A (p.Glu269Lys)","Chromosome":"8","Start":"19955870","Stop":"19955870","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1055722,"rule_based_match":true,"evidence_text":"c.805G > A; p.(Glu269Lys)","llm_judgment":"PRESENT","evidence":"c.805G > A; p.(Glu269Lys)","abstract_start":1218,"abstract_end":1243}]}
{"pmid":"26836830","title":"A Novel Mutation in DMD (c.10797+5G>A) Causes Becker Muscular Dystrophy Associated with Intellectual Disability.","abstract":"BACKGROUND: Severe intellectual disability has been reported in a subgroup of patients with Duchenne muscular dystrophy but is not typically associated with Becker muscular dystrophy.\nPATIENT: The authors report a 13-year-old boy, with severe intellectual disability (Wechsler Intelligence Scales for Children-IV, Full Scale IQ < 0.1 percentile), attention-deficit hyperactivity disorder, and mild muscle weakness. He had elevated serum creatine kinase and dystrophic changes on muscle biopsy. Dystrophin immunohistochemistry revealed decreased staining with the C-terminal and mid-rod antibodies and essentially absent staining of the N-terminal immunostain. Sequencing of muscle mRNA revealed aberrant splicing due to a c.10797+5G > A mutation in DMD.\nCONCLUSION: Dystrophinopathy may be associated with predominantly cognitive impairment and neurobehavioral disorder, and should be considered in the differential diagnosis of unexplained cognitive or psychiatric disturbance in males.","variants":[{"Name":"NM_004006.3(DMD):c.10797+5G>A","Chromosome":"X","Start":"31147270","Stop":"31147270","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":100347,"rule_based_match":true,"evidence_text":"c.10797+5G > A","llm_judgment":"PRESENT","evidence":"c.10797+5G > A","abstract_start":722,"abstract_end":736}]}
{"pmid":"34750995","title":"Pseudoachondroplasia: Phenotype and genotype in 11 Indian patients.","abstract":"Pseudoachondroplasia (PSACH) is an autosomal dominant disorder characterized by rhizomelic short-limbed skeletal dysplasia. The primary clinical and radiographic features include disproportionate dwarfism, joint laxity and hyperextensibility, exaggerated lumbar lordosis, and late ossification of the epiphyses. Identification of disease-causing variants in heterozygous state in COMP establishes the molecular diagnosis of PSACH. We examined 11 families with clinical features suggestive of PSACH. In nine families, we used Sanger sequencing of exons 8-19 of COMP (NM_000095.2) and in two families exome sequencing was used for confirming the diagnosis. We identified 10 de novo variants, including five known variants (c.925G>A, c.976G>A, c.1201G>T, c.1417_1419del, and c.1511G>A) and five variants (c.874T>C, c.1201G>C, c.1309G>A, c.1416_1421delCGACAA, and c.1445A>T) which are not reported outside Indian ethnicity. We hereby report the largest series of individuals with molecular diagnosis of PSACH from India and reiterate the well-known genotype-phenotype corelation in PSACH.","variants":[{"Name":"NM_000095.3(COMP):c.1201G>A (p.Asp401Asn)","Chromosome":"19","Start":"18786585","Stop":"18786585","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":976442,"rule_based_match":false,"evidence_text":"c.1201G>A","llm_judgment":"PRESENT","evidence":"c.1201G>A","abstract_start":null,"abstract_end":null},{"Name":"NM_000095.3(COMP):c.925G>A (p.Gly309Arg)","Chromosome":"19","Start":"18788262","Stop":"18788262","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1323549,"rule_based_match":true,"evidence_text":"c.925G>A","llm_judgment":"PRESENT","evidence":"c.925G>A","abstract_start":721,"abstract_end":729}]}
{"pmid":"20734096","title":"A FOXG1 mutation in a boy with congenital variant of Rett syndrome.","abstract":"Mutations in the FOXG1 gene have been shown to cause congenital variant of Rett syndrome. To date, point mutations have been reported only in female patients. We screened the entire coding region of the gene for mutations in 50 boys with congenital encephalopathy, postnatal microcephaly, and complex movement disorders, a clinical picture very similar to that described in girls with FOXG1 mutations. We found one boy carrying the de novo c.256_257dupC frameshift mutation. He presented the association of postnatal microcephaly, severe axial dystonia with severe feeding difficulties with protruding tongue movements during the first year of life that subsequently evolved into dyskinetic movement disorders with hand stereotypies. In contrast to his severe motor impairment, he developed nonverbal communication skills and relative good eye contact. Brain MRI showed frontal gyral simplification with dramatic myelination delay most prominent in both frontal lobes. Altogether the presentation in this male patient is highly reminiscent of that observed in FOXG1-mutated females with the congenital variant of Rett syndrome. This new case confirms the prediction that congenital variant of Rett syndrome should be found also in males, with the characteristic hallmarks consisting of postnatal microcephaly, dyskinetic movement disorder with Rett-like features, i.e., hand stereotypies, and frontal gyral simplification with myelination delay. FOXG1 screening should be considered in individuals with these clinical features.","variants":[{"Name":"NM_005249.5(FOXG1):c.256dup (p.Gln86fs)","Chromosome":"14","Start":"28767528","Stop":"28767529","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":187402,"rule_based_match":false,"evidence_text":"c.256_257dupC","llm_judgment":"PRESENT","evidence":"c.256_257dupC","abstract_start":440,"abstract_end":453}]}
{"pmid":"21932610","title":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) due to AIRET16M mutation in a consanguineous Greek girl.","abstract":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) or autoimmune polyendocrine syndrome type 1 (APS-1) is a rare autosomal recessive disease caused by mutations of the AutoImmune REgulator (AIRE) gene, an important mediator of tolerance to self-antigens. It is characterized by two out of three major components: chronic mucocutaneous candidiasis, hypoparathyroidism and Addison's disease. We present an 11-year-old girl suffering from recurrent episodes of mucocutaneous candidiasis and onychomycosis from 1 to 6 years of age, and transient alopecia at the age of 4 years. Hypoparathyroidism and dental enamel hypoplasia were diagnosed at 8 years. Autoantibodies to thyroid and adrenal glands were not detected and all other endocrine functions have remained normal. Genetic analysis revealed that the patient was homozygous for the mutation T16M in exon 1 of the AIRE gene (p.T16M, c.47C>T). This is the first APECED case reported for carrying this mutation in homozygous form. Parents were third cousins and heterozygous carriers of this mutation.","variants":[{"Name":"NM_000383.4(AIRE):c.47C>T (p.Thr16Met)","Chromosome":"21","Start":"44286053","Stop":"44286053","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":79118,"rule_based_match":true,"evidence_text":"c.47C>T","llm_judgment":"PRESENT","evidence":"c.47C>T","abstract_start":914,"abstract_end":921}]}
{"pmid":"19701946","title":"RFT1 deficiency in three novel CDG patients.","abstract":"The medical significance of N-glycosylation is underlined by a group of inherited human disorders called Congenital Disorders of Glycosylation (CDG). One key step in the biosynthesis of the Glc(3)Man(9)GlcNAc(2)-PP-dolichol precursor, essential for N-glycosylation, is the translocation of Man(5)GlcNAc(2)-PP-dolichol across the endoplasmic reticulum membrane. This step is facilitated by the RFT1 protein. Recently, the first RFT1-deficient CDG (RFT1-CDG) patient was identified and presented a severe N-glycosylation disorder. In the present study, we describe three novel CDG patients with an RFT1 deficiency. The first patient was homozygous for the earlier reported RFT1 missense mutation (c.199C>T; p.R67C), whereas the two other patients were homozygous for the missense mutation c.454A>G (p.K152E) and c.892G>A (p.E298 K), respectively. The pathogenic character of the novel mutations was illustrated by the accumulation of Man(5)GlcNAc(2)-PP-dolichol and by reduced recombinant DNase 1 secretion. Both the glycosylation pattern and recombinant DNase 1 secretion could be normalized by expression of normal RFT1 cDNA in the patients' fibroblasts. The clinical phenotype of these patients comprised typical CDG symptoms in addition to sensorineural deafness, rarely reported in CDG patients. The identification of additional RFT1-deficient patients allowed to delineate the main clinical picture of RFT1-CDG and confirmed the crucial role of RFT1 in Man(5)GlcNAc(2)-PP-dolichol translocation.","variants":[{"Name":"NM_052859.4(RFT1):c.199C>T (p.Arg67Cys)","Chromosome":"3","Start":"53123791","Stop":"53123791","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15824,"rule_based_match":true,"evidence_text":"c.199C>T (p.R67C)","llm_judgment":"PRESENT","evidence":"c.199C>T","abstract_start":695,"abstract_end":703},{"Name":"NM_052859.4(RFT1):c.454A>G (p.Lys152Glu)","Chromosome":"3","Start":"53122376","Stop":"53122376","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":204228,"rule_based_match":true,"evidence_text":"c.454A>G (p.K152E)","llm_judgment":"PRESENT","evidence":"c.454A>G (p.K152E)","abstract_start":787,"abstract_end":805},{"Name":"NM_052859.4(RFT1):c.892G>A (p.Glu298Lys)","Chromosome":"3","Start":"53105738","Stop":"53105738","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":204229,"rule_based_match":true,"evidence_text":"c.892G>A (p.E298 K)","llm_judgment":"PRESENT","evidence":"c.892G>A (p.E298 K)","abstract_start":810,"abstract_end":829}]}
{"pmid":"33367756","title":"Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?","abstract":"CONTEXT: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors.\nOBJECTIVE: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors.\nMETHODS: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants.\nRESULTS: Family A has multiple individuals with PC (including bilateral and metastatic disease) and 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (IGF-1). A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss of heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss of function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified.\nCONCLUSION: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.","variants":[{"Name":"NM_002382.5(MAX):c.200C>A (p.Ala67Asp)","Chromosome":"14","Start":"65078008","Stop":"65078008","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":184110,"rule_based_match":true,"evidence_text":"c.200C>A, p.Ala67Asp","llm_judgment":"PRESENT","evidence":"c.200C>A, p.Ala67Asp","abstract_start":1147,"abstract_end":1167}]}
{"pmid":"20200614","title":"Recurrent and founder mutations in the Netherlands: Extensive clinical variability in Marfan syndrome patients with a single novel recurrent fibrillin-1 missense mutation.","abstract":"Background/Methods. Marfan syndrome (MFS) is a heritable connective tissue disorder usually caused by a mutation in the fibrillin 1 (FBN1) gene. Typical characteristics of MFS that have been described include dolichostenomelia, ectopia lentis and aortic root dilatation. However, there is great clinical variability in the expression of the syndrome's manifestations, both between and within families. Here we discuss the clinical variability of MFS by describing a large fourgeneration Dutch family with MFS.Results. Nineteen individuals of one family with a single missense FBN1 mutation (c.7916A>G) were identified. The same mutation was found in one unrelated person. Clinical variability was extensive and not all mutation carriers fulfilled the diagnostic criteria for MFS. Some patients only expressed mild skeletal abnormalities, whereas aortic root dilation was present in eight patients, an acute type A aortic dissection was recorded in two other patients, and a mitral valve prolapse was present in eight patients. In some patients cardiac features were not present on initial screening, but did however develop over time.Conclusion. MFS is a clinically highly variable syndrome, which means a meticulous evaluation of suspected cases is crucial. Mutation carriers should be re-evaluated regularly as cardiovascular symptoms may develop over time. (Neth Heart J 2010;18:85-9.).","variants":[{"Name":"NM_000138.5(FBN1):c.7916A>G (p.Tyr2639Cys)","Chromosome":"15","Start":"48415671","Stop":"48415671","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":197590,"rule_based_match":true,"evidence_text":"c.7916A>G","llm_judgment":"PRESENT","evidence":"c.7916A>G","abstract_start":591,"abstract_end":600}]}
{"pmid":"26462740","title":"Diagnostic Exome Sequencing Identifies a Novel Gene, EMILIN1, Associated with Autosomal-Dominant Hereditary Connective Tissue Disease.","abstract":"Heritable connective tissue diseases are a highly heterogeneous family of over 200 disorders that affect the extracellular matrix. While the genetic basis of several disorders is established, the etiology has not been discovered for a large portion of patients, likely due to rare yet undiscovered disease genes. By performing trio-exome sequencing of a 55-year-old male proband presenting with multiple symptoms indicative of a connective disorder, we identified a heterozygous missense alteration in exon 1 of the Elastin Microfibril Interfacer 1 (EMILIN1) gene, c.64G>A (p.A22T). The proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Sanger sequencing confirmed that the EMILIN1 alteration, which maps around the signal peptide cleavage site, segregated with disease in the affected proband, mother, and son. The impaired secretion of EMILIN-1 in cells transfected with the mutant p.A22T coincided with abnormal protein accumulation within the endoplasmic reticulum. In skin biopsy of the proband, we detected less EMILIN-1 with disorganized and abnormal coarse fibrils, aggregated deposits underneath the epidermis basal lamina, and dermal cells apoptosis. These findings collectively suggest that EMILIN1 may represent a new disease gene associated with an autosomal-dominant connective tissue disorder.","variants":[{"Name":"NM_007046.4(EMILIN1):c.64G>A (p.Ala22Thr)","Chromosome":"2","Start":"27079129","Stop":"27079129","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205234,"rule_based_match":true,"evidence_text":"c.64G>A (p.A22T)","llm_judgment":"PRESENT","evidence":"c.64G>A (p.A22T)","abstract_start":565,"abstract_end":581}]}
{"pmid":"18583217","title":"Small mutations of the DMD gene in Taiwanese families.","abstract":"BACKGROUND/PURPOSE: Duchenne/Becker muscular dystrophies are X-linked recessive disorders caused by mutations in the Duchenne muscular dystrophy (DMD) gene. We aimed to demonstrate the small mutation patterns of the DMD gene in Taiwanese subjects.\nMETHODS: We sequenced all 79 exons of the DMD gene in 33 unrelated Taiwanese families in which large-scale deletions and duplications had been excluded by multiplex ligation-dependent probe amplification.\nRESULTS: Direct sequencing detected 23 different mutations from 26 families, including 15 novel mutations and eight previously reported ones. The 15 novel mutations consisted of seven substitutions (c.1238C>G [p.S413X], c.2971G>T [p.E991X], c.3172C>T [p.Q1058X], c.7402G>T [p.E2468X], c.8022C>G [p.S2605X], c.10018T>C [p.C3340R], c.10546G>T [p.E3516X]), six small deletions (c.2202delG [p.A668fsX676], c.2268delC [p.F756fsX759], c.4611delT [p.N1537fsX1545], c.4856_4857delAA [p.K1619fsX1621], c.6638delT [p.L2213fsX2220], c.9457delT [p.C3153fsX3154]), and two small insertions (c.4351insA [p.L1451fsX1468], c.10493_10495insAAT [p.L3498X]). Twenty-two of the 23 pathologic changes disrupted the translational reading frame (13 nonsense, 7 frameshift, 2 splice-site change), whereas only one was a missense variant with known pathogenic nature. Two previously reported mutations, c.8038C>T [p.R2680X] and c.10108C>T [p.R3370X] were detected in two and three unrelated families, respectively.\nCONCLUSION: Most identified mutations either led to a predictable premature stop codon or resulted in splicing defects, which caused defective function of dystrophin. Our findings extend the mutation spectrum of the DMD gene. Molecular characterization of the affected families is important for genetic counseling and prenatal diagnosis.","variants":[{"Name":"NM_004006.3(DMD):c.10546G>T (p.Glu3516Ter)","Chromosome":"X","Start":"31169450","Stop":"31169450","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":577955,"rule_based_match":true,"evidence_text":"c.10546G>T [p.E3516X]","llm_judgment":"PRESENT","evidence":"c.10546G>T [p.E3516X]","abstract_start":783,"abstract_end":804},{"Name":"NM_004006.3(DMD):c.3172C>T (p.Gln1058Ter)","Chromosome":"X","Start":"32464690","Stop":"32464690","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1312839,"rule_based_match":true,"evidence_text":"c.3172C>T [p.Q1058X]","llm_judgment":"PRESENT","evidence":"c.3172C>T [p.Q1058X]","abstract_start":694,"abstract_end":714},{"Name":"NM_004006.3(DMD):c.2971G>T (p.Glu991Ter)","Chromosome":"X","Start":"32468689","Stop":"32468689","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1312986,"rule_based_match":true,"evidence_text":"c.2971G>T [p.E991X]","llm_judgment":"PRESENT","evidence":"c.2971G>T [p.E991X]","abstract_start":673,"abstract_end":692},{"Name":"NM_004006.3(DMD):c.10108C>T (p.Arg3370Ter)","Chromosome":"X","Start":"31178784","Stop":"31178784","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26252,"rule_based_match":true,"evidence_text":"c.10108C>T [p.R3370X]","llm_judgment":"PRESENT","evidence":"c.10108C>T [p.R3370X]","abstract_start":1356,"abstract_end":1377},{"Name":"NM_004006.3(DMD):c.4351_4352insA (p.Leu1451fs)","Chromosome":"X","Start":"32389667","Stop":"32389668","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AT","allel_id":969201,"rule_based_match":false,"evidence_text":"c.4351insA [p.L1451fsX1468]","llm_judgment":"PRESENT","evidence":"c.4351insA [p.L1451fsX1468]","abstract_start":1031,"abstract_end":1058},{"Name":"NM_004006.3(DMD):c.9457del (p.Cys3153fs)","Chromosome":"X","Start":"31209604","Stop":"31209604","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1065333,"rule_based_match":true,"evidence_text":"c.9457delT [p.C3153fsX3154]","llm_judgment":"PRESENT","evidence":"c.9457delT [p.C3153fsX3154]","abstract_start":975,"abstract_end":1002},{"Name":"NM_004006.3(DMD):c.8038C>T (p.Arg2680Ter)","Chromosome":"X","Start":"31627852","Stop":"31627852","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":213850,"rule_based_match":true,"evidence_text":"c.8038C>T [p.R2680X]","llm_judgment":"PRESENT","evidence":"c.8038C>T [p.R2680X]","abstract_start":1331,"abstract_end":1351}]}
{"pmid":"26549536","title":"Pitfall in the Diagnosis of Fructose-1,6-Bisphosphatase Deficiency: Difficulty in Detecting Glycerol-3-Phosphate with Solvent Extraction in Urinary GC/MS Analysis.","abstract":"Fructose-1,6-bisphosphatase (FBPase), an enzyme involved in gluconeogenesis, catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate. FBPase deficiency is an autosomal recessive inherited disorder, characterized by episodic attacks of hypoglycemia, ketosis, and lactic acidosis during fasting. In general, urinary organic acid analysis using gas chromatography-mass spectrometry (GC/MS) is very useful for the diagnosis of FBPase deficiency, because the appearance of glycerol or glycerol-3-phosphate in the urine is characteristic of this disease. Here, we report a case of FBPase deficiency in a girl with a history of several severe lactic acidosis events, both as a neonate and after the age of 12 months. The patient was identified as a compound heterozygote with two mutations in the FBPase 1 gene: c.841G>A (p.Glu281Lys) and c.960_961insG (p.Ser321fs). The c.841G>A is a newly identified pathogenic mutation. An abnormal level of glycerol-3-phosphate was not detected in the conventional urinary organic acid analysis using GC/MS after solvent extraction. This method, which is a widely used diagnostic standard, could not detect increased levels of glycerol or glycerol-3-phosphate in the patient's urine, which was sampled during the episode. However, glycerol and glycerol-3-phosphate were detected in the same sample, when it was analyzed using GC/MS with the urease pretreatment non-extraction method. Patients with FBPase deficiency have good glycemic control after correct treatment. Therefore, accurate and early diagnosis is essential for a good prognosis. Accordingly, when a patient presents with hypoglycemia and lactic acidosis, it is important to select the appropriate method of urinalysis for organic acids by GC/MS.","variants":[{"Name":"NM_000507.4(FBP1):c.841G>A (p.Glu281Lys)","Chromosome":"9","Start":"94603557","Stop":"94603557","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":370993,"rule_based_match":true,"evidence_text":"c.841G>A (p.Glu281Lys)","llm_judgment":"PRESENT","evidence":"c.841G>A (p.Glu281Lys)","abstract_start":851,"abstract_end":873},{"Name":"NM_000507.4(FBP1):c.960_961insG (p.Ser321fs)","Chromosome":"9","Start":"94603437","Stop":"94603438","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":15906,"rule_based_match":true,"evidence_text":"c.960_961insG (p.Ser321fs)","llm_judgment":"PRESENT","evidence":"c.960_961insG (p.Ser321fs)","abstract_start":878,"abstract_end":904}]}
{"pmid":"35170189","title":"Prenatally detected encephalocele associated with a novel pathogenic TCTN3 variant: A case report and literature review.","abstract":"Primary cilia are a component of almost all vertebrate cells with a crucial role in sensing and transducing environmental signals during tissue development. Their dysfunction is known as ciliopathies and can manifest with a wide spectrum of clinical disorders. Overlapping features and molecular heterogeneity of ciliopathies make diagnoses distinctly challenging. In this group of diseases, tectonic genes, and their mutations play an important role. We present a first-trimester fetus with occipital encephalocele and OFD type IV caused by TCTN3 compound heterozygous pathogenic variants: c.1423_1429del (p.Arg475Serfs*10) and c.3G>A (initiator codon). A severe arm anomaly was described in our case, with two fingers along the atrophic forearm and polydactyly on other limbs. This could be a new phenotypic characteristic contributing to further understanding of TCTN3-related disorders as well as other tectonic proteins in ciliopathy spectrum diseases.","variants":[{"Name":"NM_015631.6(TCTN3):c.3G>A (p.Met1Ile)","Chromosome":"10","Start":"95693897","Stop":"95693897","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":214308,"rule_based_match":true,"evidence_text":"c.3G>A (initiator codon)","llm_judgment":"PRESENT","evidence":"c.3G>A (initiator codon)","abstract_start":629,"abstract_end":653}]}
{"pmid":"15221796","title":"Novel MC1R variants in Ligurian melanoma patients and controls.","abstract":"Several variant forms of the melanocortin-1 receptor gene (MC1R) have been associated with red hair, fair skin and an increased risk for melanoma. Their involvement in melanoma susceptibility is apparently linked both to skin sensitivity and to non-pigmentary pathways. We investigated the frequency of the MC1R variants in the Italian region of Liguria, where the occurrence and penetrance of melanoma are low and primary susceptibility is characterized by prevalence of the CDKN2A c.301G>T [p.G101W] founder mutation. Additionally, we attempted to establish the frequency of the red hair/fair skin phenotype in our region. As predicted by anecdotal evidence, the frequency of red hair/phototype I was very low (0.7%). Screening of 17 red-haired individuals and their red-haired relatives, 207 controls and 214 melanoma patients unselected for hair color but all of Ligurian descent, led to the detection of 8 novel substitutions (c.133T>C [p.F45L], c.248C>T [p.S83L], c.332C>T [p. A111V], c.479G>A [p.R160Q], c.637C>T [p.R213W], c.793G>A [p. V265I], c.923C>T [p. T308M], c.943T>C [p.C315R]), 1 novel deletion (c.520_523delGTC [p.V174del]) and 3 novel synonymous variants (c.366G>C [p. V122V], c.684G>A [p. Q228Q], c.726C>T [p.T241T]). Preliminary genotype/phenotype correlation seems to indicate that other genes involved in the regulation of human pigmentation may mask the recessive action of high-penetrance MC1R alleles, thus determining the low frequency of at-risk phototypes and of incidence and/or penetrance of melanoma in Liguria.","variants":[{"Name":"NM_002386.4(MC1R):c.637C>T (p.Arg213Trp)","Chromosome":"16","Start":"89919895","Stop":"89919895","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":343073,"rule_based_match":true,"evidence_text":"c.637C>T [p.R213W]","llm_judgment":"PRESENT","evidence":"c.637C>T [p.R213W]","abstract_start":1011,"abstract_end":1029},{"Name":"NM_002386.4(MC1R):c.133T>C (p.Phe45Leu)","Chromosome":"16","Start":"89919391","Stop":"89919391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":467239,"rule_based_match":true,"evidence_text":"c.133T>C [p.F45L]","llm_judgment":"PRESENT","evidence":"c.133T>C [p.F45L]","abstract_start":932,"abstract_end":949},{"Name":"NM_002386.4(MC1R):c.248C>T (p.Ser83Leu)","Chromosome":"16","Start":"89919506","Stop":"89919506","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":467240,"rule_based_match":true,"evidence_text":"c.248C>T [p.S83L]","llm_judgment":"PRESENT","evidence":"c.248C>T [p.S83L]","abstract_start":951,"abstract_end":968},{"Name":"NM_002386.4(MC1R):c.923C>T (p.Thr308Met)","Chromosome":"16","Start":"89920181","Stop":"89920181","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":844623,"rule_based_match":true,"evidence_text":"c.923C>T (p. T308M)","llm_judgment":"PRESENT","evidence":"c.923C>T","abstract_start":1052,"abstract_end":1060},{"Name":"NM_002386.4(MC1R):c.332C>T (p.Ala111Val)","Chromosome":"16","Start":"89919590","Stop":"89919590","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":467249,"rule_based_match":true,"evidence_text":"c.332C>T [p. A111V]","llm_judgment":"PRESENT","evidence":"c.332C>T [p. A111V]","abstract_start":970,"abstract_end":989}]}
{"pmid":"24884697","title":"EDAR-induced hypohidrotic ectodermal dysplasia: a clinical study on signs and symptoms in individuals with a heterozygous c.1072C > T mutation.","abstract":"BACKGROUND: Mutations in the EDAR-gene cause hypohidrotic ectodermal dysplasia, however, the oral phenotype has been described in a limited number of cases. The aim of the present study was to clinically describe individuals with the c.1072C > T mutation (p. Arg358X) in the EDAR gene with respect to dental signs and saliva secretion, symptoms from other ectodermal structures and to assess orofacial function.\nMETHODS: Individuals in three families living in Sweden, where some members had a known c.1072C > T mutation in the EDAR gene with an autosomal dominant inheritance (AD), were included in a clinical investigation on oral signs and symptoms and self-reported symptoms from other ectodermal structures (n = 37). Confirmation of the c.1072C > T mutation in the EDAR gene were performed by genomic sequencing. Orofacial function was evaluated with NOT-S.\nRESULTS: The mutation was identified in 17 of 37 family members. The mean number of missing teeth due to agenesis was 10.3 ± 4.1, (range 4-17) in the mutation group and 0.1 ± 0.3, (range 0-1) in the non-mutation group (p < 0.01). All individuals with the mutation were missing the maxillary lateral incisors and one or more of the mandibular incisors; and 81.3% were missing all four. Stimulated saliva secretion was 0.9 ± 0.5 ml/min in the mutation group vs 1.7 ± 0.6 ml/min in the non-mutation group (p < 0.01). Reduced ability to sweat was reported by 82% in the mutation group and by 20% in the non-mutation group (p < 0.01). The mean NOT-S score was 3.0 ± 1.9 (range 0-6) in the mutation group and 1.5 ± 1.1 (range 0-5) in the non-mutation group (p < 0.01). Lisping was present in 56% of individuals in the mutation group.\nCONCLUSIONS: Individuals with a c.1072C > T mutation in the EDAR-gene displayed a typical pattern of congenitally missing teeth in the frontal area with functional consequences. They therefore have a need for special attention in dental care, both with reference to tooth agenesis and low salivary secretion with an increased risk for caries. Sweating problems were the most frequently reported symptom from other ectodermal structures.","variants":[{"Name":"NM_022336.4(EDAR):c.1072C>T (p.Arg358Ter)","Chromosome":"2","Start":"108897182","Stop":"108897182","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20891,"rule_based_match":true,"evidence_text":"c.1072C>T","llm_judgment":"PRESENT","evidence":"c.1072C > T","abstract_start":234,"abstract_end":245}]}
{"pmid":"25390358","title":"Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype.","abstract":"Genotype phenotype correlations in Wilson disease (WD) are best established in homozygous patients or in compound heterozygous patients carrying the same set of mutations. We determined the clinical phenotype of patients with WD carrying the c.2298_2299insC in Exon 8 (c.2299insC) or the p. Ala1003Thr missense substitution in Exon 13 mutations in the homozygous or compound heterozygous state. We investigated 76 members of a single large Lebanese family. Their genotypes were determined, and clinical assessments were carried out for affected subjects. We also performed a literature search retrieving the phenotypes of patients carrying the same mutations of our patients in the homozygous or compound heterozygous state. There were 7 consanguineous marriages in this family and the prevalence of WD was 8.9% and of carriers of ATP7B mutation 44.7%. WD was confirmed in 9 out of 76 subjects. All 9 had the c.2299insC mutation, 5 homozygous and 4-compound heterozygous with p. Ala1003Thr. Six of our patients had hepatic, 2 had neurologic and 1 had asymptomatic phenotype. Based on our data and a literature review, clear phenotypes were reported for 38 patients worldwide carrying the c.2299insC mutation. About 53% of those have hepatic and 29% have neurologic phenotype. Furthermore, there were 10 compound heterozygous patients carrying the p. Ala1003Thr mutation. Among those, 80% having c.2299insC as the second mutation had hepatic phenotype, and all others had neurologic phenotype. We hereby report an association between the c.2299insC mutation and hepatic phenotype and between the p. Ala1003Thr mutation and neurologic phenotype.","variants":[{"Name":"NM_000053.4(ATP7B):c.3007G>A (p.Ala1003Thr)","Chromosome":"13","Start":"51946337","Stop":"51946337","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186890,"rule_based_match":false,"evidence_text":"p. Ala1003Thr","llm_judgment":"PRESENT","evidence":"p. Ala1003Thr","abstract_start":288,"abstract_end":301}]}
{"pmid":"24357517","title":"Early frameshift mutation in PIGA identified in a large XLID family without neonatal lethality.","abstract":"The phosphatidylinositol glycan class A (PIGA) protein is a member of the glycosylphosphatidylinositol anchor pathway. Germline mutations in PIGA located at Xp22.2 are thought to be lethal in males. However, a nonsense mutation in the last coding exon was recently described in two brothers with multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) who survived through birth likely because of the hypomorphic nature of the truncated protein, but died in their first weeks of life. Here, we report on a frameshift mutation early in the PIGA cDNA (c.76dupT; p.Y26Lfs*3) that cosegregates with the disease in a large family diagnosed with a severe syndromic form of X-linked intellectual disability. Unexpectedly, CD59 surface expression suggested the production of a shorter PIGA protein with residual functionality. We provide evidence that the second methionine at position 37 may be used for the translation of a 36 amino acids shorter PIGA. Complementation assays confirmed that this shorter PIGA cDNA was able to partially rescue the surface expression of CD59 in a PIGA-null cell line. Taken together, our data strongly suggest that the early frameshift mutation in PIGA produces a truncated hypomorph, which is sufficient to rescue the lethality in males but not the MCAHS2-like phenotype.","variants":[{"Name":"NM_002641.4(PIGA):c.76dup (p.Tyr26fs)","Chromosome":"X","Start":"15331854","Stop":"15331855","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":136564,"rule_based_match":true,"evidence_text":"c.76dupT; p.Y26Lfs*3","llm_judgment":"PRESENT","evidence":"c.76dupT; p.Y26Lfs*3","abstract_start":563,"abstract_end":583}]}
{"pmid":"22848035","title":"Case report: Noonan syndrome with multiple giant cell lesions and review of the literature.","abstract":"Noonan syndrome with multiple giant cell lesions (NS/MGCL) was recently shown to be a phenotypic variation within the syndromes of the Ras/MAPK pathway and not an independent entity as previously thought. Here we report on a 13-year-old boy with a typical phenotype of NS including atrial septal defect, pulmonic stenosis, short stature, and combined pectus carinatum/excavatum, pronounced MGCL of both jaws, and a de novo mutation in PTPN11, c.236A>G (which predicts p.Q79R). Mutations in PTPN11 are the most frequent cause of NS and p.Q79R is a recurrent mutation in exon 3. Including this patient, 24 patients with molecularly confirmed NS, LEOPARD, or CFC/MGCL syndrome have been reported to date, of these 21 patients have PTPN11, SOS1, or RAF1 mutations and three have BRAF or MAP2K1 mutations, confirming that MGCL is a rare complication of the deregulated RAS/MAPK pathway. In all patients, the lesions of the mandible and to a lesser extent of the maxilla were first noted between ages 2 and 19 years (median 11 years), and were combined with enlargement of the jaws in 11/24 patients (46%). In this case and, with one exception (mutation not reported), all previous cases the NS/MGCL was caused by known mutations in the PTPN11, SOS1, RAF1, BRAF1, and MAP2K1 genes that were previously reported with RASopathies without MGCL.","variants":[{"Name":"NM_002834.5(PTPN11):c.236A>G (p.Gln79Arg)","Chromosome":"12","Start":"112450416","Stop":"112450416","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28379,"rule_based_match":true,"evidence_text":"c.236A>G (which predicts p.Q79R)","llm_judgment":"PRESENT","evidence":"c.236A>G (which predicts p.Q79R)","abstract_start":443,"abstract_end":475}]}
{"pmid":"20507642","title":"Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts.","abstract":"BACKGROUND: Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2. Evaluation of such unclassified variants may be assisted by web-based bioinformatic prediction tools, although accurate prediction of aberrant splicing by unclassified variants affecting exonic splice enhancers (ESEs) remains a challenge.\nMETHODS: This study used a combination of RT-PCR analysis and splicing reporter minigene assays to assess five unclassified variants in the BRCA2 gene that we had previously predicted to disrupt an ESE using bioinformatic approaches.\nRESULTS: Analysis of BRCA2 c.8308 G > A (p.Ala2770Thr) by mRNA analysis, and BRCA2 c.8962A > G (p.Ser2988Gly), BRCA2 c.8972G > A (p.Arg2991His), BRCA2 c.9172A > G (p.Ser3058Gly), and BRCA2 c.9213G > T (p.Glu3071Asp) by a minigene assay, revealed no evidence for aberrant splicing.\nCONCLUSIONS: These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.","variants":[{"Name":"NM_000059.4(BRCA2):c.8972G>A (p.Arg2991His)","Chromosome":"13","Start":"32379768","Stop":"32379768","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46756,"rule_based_match":true,"evidence_text":"BRCA2 c.8972G > A (p.Arg2991His)","llm_judgment":"PRESENT","evidence":"BRCA2 c.8972G > A (p.Arg2991His)","abstract_start":789,"abstract_end":821},{"Name":"NM_000059.4(BRCA2):c.9213G>T (p.Glu3071Asp)","Chromosome":"13","Start":"32380102","Stop":"32380102","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":67445,"rule_based_match":true,"evidence_text":"BRCA2 c.9213G > T (p.Glu3071Asp)","llm_judgment":"PRESENT","evidence":"BRCA2 c.9213G > T (p.Glu3071Asp)","abstract_start":861,"abstract_end":893}]}
{"pmid":"32933640","title":"Hereditary hemorrhagic telangiectasia: a report of two cases","abstract":"This article reports two children with hereditary hemorrhagic telangiectasia (HHT). Patient 1 was a boy aged 12 years and was admitted due to intermittent cough and wheezing for more than 10 years. This boy and his mother and grandmother had a history of epistaxis. The boy had a history of the rupture of cerebral arteriovenous malformations. Gene detection showed a heterozygous mutation, c.277C>T(p.Arg93*), in the ENG gene. Patient 2 was a girl aged 13 years and was admitted due to cyanosis of lips for more than 1 year. The girl had a history of recurrent epistaxis and the manifestations of severe decline in pulmonary diffuse function, pulmonary hypertension, dilation of blood vessels at the distal end of lungs, and small arteriovenous communications in both lungs. Children with HHT often lack typical respiratory symptoms, which may lead to missed diagnosis and misdiagnosis in the early stage. Pulmonary computed tomography or right cardiac acoustic contrast can help with the diagnosis of HHT, and gene detection can improve the early diagnostic rate of this disease.","variants":[{"Name":"NM_001114753.3(ENG):c.277C>T (p.Arg93Ter)","Chromosome":"9","Start":"127829770","Stop":"127829770","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":259914,"rule_based_match":true,"evidence_text":"c.277C>T(p.Arg93*)","llm_judgment":"PRESENT","evidence":"c.277C>T(p.Arg93*)","abstract_start":391,"abstract_end":409}]}
{"pmid":"21255007","title":"Clinical, biochemical and molecular characterization of cystinuria in a cohort of 12 patients.","abstract":"Cystinuria is a rare autosomal inherited disorder characterized by impaired transport of cystine and dibasic aminoacids in the proximal renal tubule. Classically, cystinuria is classified as type I (silent heterozygotes) and non-type I (heterozygotes with urinary hyperexcretion of cystine). Molecularly, cystinuria is classified as type A (mutations on SLC3A1 gene) and type B (mutations on SLC7A9 gene). The goal of this study is to provide a comprehensive clinical, biochemical and molecular characterization of a cohort of 12 Portuguese patients affected with cystinuria in order to provide insight into genotype-phenotype correlations. We describe seven type I and five non-type I patients. Regarding the molecular classification, seven patients were type A and five were type B. In SLC3A1 gene, two large genomic rearrangements and 13 sequence variants, including four new variants c.611-2A>C; c.1136+44G>A; c.1597T (p.Y533N); c.*70A>G, were found. One large genomic rearrangement was found in SLC7A9 gene as well as 24 sequence variants including 3 novel variants: c.216C>T (p.C72C), c.1119G>A (p.S373S) and c.*82C>T. In our cohort the most frequent pathogenic mutations were: large rearrangements (33.3% of mutant alleles) and a missense mutation c.1400T>C (p.M467T) (11.1%). This report expands the spectrum of SLC3A1 and SLC7A9 mutations and provides guidance in the clinical implementation of molecular assays in routine genetic counseling of Portuguese patients affected with cystinuria.","variants":[{"Name":"NM_000341.4(SLC3A1):c.1400T>C (p.Met467Thr)","Chromosome":"2","Start":"44312653","Stop":"44312653","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":33154,"rule_based_match":true,"evidence_text":"c.1400T>C (p.M467T)","llm_judgment":"PRESENT","evidence":"c.1400T>C (p.M467T)","abstract_start":1255,"abstract_end":1274}]}
{"pmid":"16583127","title":"A novel missense mutation of the EDA gene in a Mongolian family with congenital hypodontia.","abstract":"X-linked hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by the hypoplasia or absence of eccrine glands, dry skin, scant hair, and dental abnormalities. Here, we report a Mongolian family with congenital absence of teeth inherited in an X-linked fashion. The affected members of the family did not show other HED characteristics, except hypodontia. We successfully mapped the affected locus to chromosome Xq12-q13.1, and then found a novel missense mutation, c.193C>G, in the ectodysplasin A (EDA) gene in all affected males and carrier females. The mutation causes arginine to be replaced by glycine in codon 65 (R65G) in the juxtamembrane region of EDA. In addition, 33% (3/9) of female carriers have a skewed X-chromosome inactivation pattern. Our result strongly suggests that the c.193C>G mutation is the disease-causing mutation in this family.","variants":[{"Name":"NM_001399.5(EDA):c.193C>G (p.Arg65Gly)","Chromosome":"X","Start":"69616501","Stop":"69616501","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":26083,"rule_based_match":true,"evidence_text":"c.193C>G","llm_judgment":"PRESENT","evidence":"c.193C>G","abstract_start":483,"abstract_end":491}]}
{"pmid":"33393008","title":"Clinical and molecular findings in a Turkish family with an ultra-rare condition, ELP2-related neurodevelopmental disorder.","abstract":"Elongator is a multi-subunit protein complex bearing six different protein subunits, Elp1 to -6, that are highly conserved among eukaryotes. Elp2 is the second major subunit of Elongator and, together with Elp1 and Elp3, form the catalytic core of this essential complex. Pathogenic variants that affect the structure and function of the Elongator complex may cause neurodevelopmental disorders. Here, we report on a new family with three children affected with a severe form of intellectual disability along with spastic tetraparesis, choreoathetosis, and self injury. Molecular genetic analyses reveal a homozygous missense variant in the ELP2 gene (NM_018255.4 (ELP2): c.1385G > A (p.Arg462Gln)), while in silico studies suggest a loss of electrostatic interactions that may contribute to the overall stability of the encoded protein. We also include a comparison of the patients with ELP2-related neurodevelopmental disorder to those previously reported in the literature. Apart from being affected with intellectual disability, we have extremely limited clinical knowledge about patients harboring ELP2 variants. Besides providing support to the causal role of p.Arg462Gln in ELP2-related neurodevelopmental disorder, we add self-injurious behavior to the clinical phenotypic repertoire of the disease.","variants":[{"Name":"NM_018255.4(ELP2):c.1385G>A (p.Arg462Gln)","Chromosome":"18","Start":"36156575","Stop":"36156575","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":858578,"rule_based_match":true,"evidence_text":"NM_018255.4 (ELP2): c.1385G > A (p.Arg462Gln)","llm_judgment":"PRESENT","evidence":"NM_018255.4 (ELP2): c.1385G > A (p.Arg462Gln)","abstract_start":652,"abstract_end":697}]}
{"pmid":"27571996","title":"Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features.","abstract":"Mitochondrial translation defects are important causes of early onset mitochondrial disease. Although the biochemical (combined respiratory chain deficiency) signature and neuroimaging are usually distinctive, they are not diagnostic as the genetic origin of mitochondrial translation defects is heterogeneous. We report a female child, born at term to non-consanguineous parents, who exhibited global hypotonia, failure to thrive, persistent and progressive hyperlactacidaemia with lactic acidosis, liver dysfunction and encephalopathy and died at the age of 5 months. Brain MRI revealed hypogenesis of the corpus callosum, T2 signal abnormalities in the medulla oblongata, pons, midbrain, thalami, cerebellar white matter, and a lactate peak on MRS. Muscle histochemistry showed cytochrome c oxidase (COX)-deficient and ragged-red fibres, while muscle biochemical studies showed decreased activities of mitochondrial respiratory chain complexes I and IV. Whole exome sequencing (WES) identified biallelic EARS2 (NM_001083614) variants, a previously reported start-loss (c.1>G, p.Met1?) variant and a novel missense (c.184A>T, p.Ile62Phe) variant. Patient fibroblasts and muscle homogenate displayed markedly decreased EARS2 protein levels, although decreased steady-state levels of complex I (NDUFB8) and complex IV (MT-CO1 and MT-CO2) subunits were only observed in muscle. Pathogenic variants in EARS2, encoding mitochondrial glutamyl-tRNA synthetase (mtGluR), are associated with Leukoencephalopathy involving the Thalamus and Brainstem with high Lactate (LTBL), a mitochondrial disorder characterised by a distinctive brain MRI pattern and a biphasic clinical course. We further outline the unique phenotypic spectrum of LTBL and review the neuroradiological features reported in all patients documented in the literature.","variants":[{"Name":"NM_001083614.2(EARS2):c.184A>T (p.Ile62Phe)","Chromosome":"16","Start":"23552260","Stop":"23552260","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1871407,"rule_based_match":true,"evidence_text":"c.184A>T (p.Ile62Phe)","llm_judgment":"PRESENT","evidence":"p.Ile62Phe","abstract_start":1128,"abstract_end":1138}]}
{"pmid":"24313005","title":"Sibling cases of severe infantile form of nemaline myopathy with ACTA1-gene mutation","abstract":"Severe infantile form of nemaline myopathy is clinically characterized by marked muscle hypotonia and weakness with respiratory and feeding difficulties since infancy. Recently, mutations in the skeletal muscle alpha-actine gene (ACTA1) have been identified in many patients with the nemaline myopathy. We experienced two cases of severe infantile form of nemaline myopathy with ACTA1 mutation (missence heterozygous mutation;c.553C>T, p.R185C) in siblings presenting with different clinical symptoms and courses. The elder brother was a typical \"floppy infant\" at birth. Because he could not suck and swallow at all, he was fed completely through a nasogastric tube. At 2 months of age, he developed respiratory insufficiency and was placed on a respirator all day. He was diagnosed with having nemaline myopathy from his muscle biopsy, which revealed marked variation in muscle fiber size with large numbers of nemaline bodies on Gomori-trichrome stain. In contrast, the younger brother presented with mild muscular hypotonia and feeding difficulty during the neonatal stage;therefore, he was partly fed through a nasogastric tube. At 2 months of age, he was admitted to our hospital because of respiratory distress, and he required nasal continuous positive airway pressure with oxygen followed by noninvasive positive pressure ventilation intermittently, mainly at night. He was followed at his home by parents with no serious problems;however he unexpectedly died at the age of 15 months. Although most cases of severe infantile form of nemaline myopathy caused by ACTA1 mutations are sporadic and have no family history, we emphasize that clinical symptoms are variable in siblings with the same mutation.","variants":[{"Name":"NM_001100.4(ACTA1):c.553C>T (p.Arg185Cys)","Chromosome":"1","Start":"229432333","Stop":"229432333","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":447521,"rule_based_match":true,"evidence_text":"c.553C>T, p.R185C","llm_judgment":"PRESENT","evidence":"c.553C>T, p.R185C","abstract_start":426,"abstract_end":443}]}
{"pmid":"33178108","title":"Pathogenic Variants in","abstract":"<b>Background:</b> Krabbe disease is an autosomal recessive demyelinating disorder resulting from deficiency of the lysosomal enzyme galactocerebrosidase. While blindness is often described as a characteristic finding of the disease, it is more common in the infantile phenotype, where vision loss typically arises in the late stages of disease. In comparison, reports of vision loss in late onset phenotypes are less well-described and may be subject to variation between genotypes. <b>Methods:</b> Charts of Krabbe patients with a confirmed diagnosis, who presented with substantial visual impairment, were retrospectively reviewed from a larger group of 199 Krabbe patients. Assessment of clinical status was obtained through review of neurological evaluations, neurodevelopmental assessments, ophthalmological evaluations, visual evoked potentials (VEP), electroretinogram (ERG), nerve conduction velocity (NCV) studies, auditory brainstem responses (ABR), and brain magnetic resonance imaging. <b>Results:</b> Five late onset patients with Krabbe disease (four juvenile and one late-infantile) were included. Three patients were homozygous for c.956A>G_p.Y319C, one was compound heterozygous for c.296+1G>T and c.956A>G_p.Y319C, and one was compound heterozygous for c.1186C>T_p.R396W and c.1901T>C_p.L634S. All patients were of Asian descent and presented initially with vision impairment. Notably, the patients did not present with marked appendicular spasticity or axial hypotonia and all five reached developmental milestones within the normal time frame. For neurophysiological testing, no patient showed abnormalities in NCV or ABR. However, abnormalities in VEP or ERG were seen in all patients. The one patient who underwent transplantation stabilized following treatment. <b>Conclusions:</b> Depending on their genotype, patients with late onset Krabbe disease may initially present with vision loss. Furthermore, patients with p.L634S and p.Y319C should be closely monitored for changes in vision and VEP. This knowledge will become increasingly important as physicians may otherwise overlook these signs and symptoms when monitoring children identified through newborn screening who have the variants described in this report.","variants":[{"Name":"NM_000153.4(GALC):c.1901T>C (p.Leu634Ser)","Chromosome":"14","Start":"87939915","Stop":"87939915","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":227363,"rule_based_match":true,"evidence_text":"c.1901T>C_p.L634S","llm_judgment":"PRESENT","evidence":"c.1901T>C_p.L634S","abstract_start":1294,"abstract_end":1311},{"Name":"NM_000153.4(GALC):c.956A>G (p.Tyr319Cys)","Chromosome":"14","Start":"87965582","Stop":"87965582","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":260059,"rule_based_match":true,"evidence_text":"c.956A>G_p.Y319C","llm_judgment":"PRESENT","evidence":"c.956A>G_p.Y319C","abstract_start":1149,"abstract_end":1165}]}
{"pmid":"31925597","title":"Identification and characterization of novel mutations in MOGS in a Chinese patient with infantile spams.","abstract":"Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of disorders caused by the defects in the synthesis and processing of glycoproteins. CDG is caused by mannosyl-oligosaccharide glucosidase (MOGS) deficiency, and is an extremely rare type, and only six patients have been reported. Here, we report a patient from China with facial dysmorphism, infantile spams, developmental delay, low vison, and abnormal liver function and low immunoglobulin. Brain MRI showed hypoplasia of the corpus callosum and slightly wide sulci at bilateral frontal parietal lobes. Compound heterozygous mutations of (c.1694G>A: R565Q and c.1619G>A: R540H) in exon 4 of MOGS gene (NM_006302.2) were identified by whole exome sequencing. Further investigation showed that the gene expression of MOGS in patients' peripheral blood was decreased. We observed that two mutations were associated with lower protein expression of MOGS, cell growth, and cell cycle in transiently transfected Hela cells. We also noticed that cell cycle-related proteins, β-catenin, cyclin D1, and C-myc, were decreased in mutant cells. In conclusion, our study suggested whole exome sequencing, and genes associated with CDGs should be analyzed in patients with infantile spams and multiple system involvement, and mutant MOGS-impaired cell cycle progression. Our work broadens the mutation spectrum of MOGS gene.","variants":[{"Name":"NM_006302.3(MOGS):c.1619G>A (p.Arg540His)","Chromosome":"2","Start":"74462170","Stop":"74462170","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1977732,"rule_based_match":true,"evidence_text":"c.1619G>A: R540H","llm_judgment":"PRESENT","evidence":"c.1619G>A: R540H","abstract_start":646,"abstract_end":662}]}
{"pmid":"30643219","title":"Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides.","abstract":"PURPOSE: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability.\nMETHODS: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.\nRESULTS: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.\nCONCLUSION: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.","variants":[{"Name":"NM_000350.3(ABCA4):c.4253+43G>A","Chromosome":"1","Start":"94030953","Stop":"94030953","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105154,"rule_based_match":true,"evidence_text":"c.4253+43G>A","llm_judgment":"PRESENT","evidence":"c.4253+43G>A","abstract_start":1020,"abstract_end":1032},{"Name":"NM_000350.3(ABCA4):c.769-784C>T","Chromosome":"1","Start":"94084225","Stop":"94084225","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2743578,"rule_based_match":true,"evidence_text":"c.769-784C>T","llm_judgment":"PRESENT","evidence":"c.769-784C>T","abstract_start":855,"abstract_end":867},{"Name":"NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)","Chromosome":"1","Start":"94010911","Stop":"94010911","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":105279,"rule_based_match":true,"evidence_text":"c.5603A>T (p.Asn1868Ile)","llm_judgment":"PRESENT","evidence":"c.5603A>T (p.Asn1868Ile)","abstract_start":935,"abstract_end":959}]}
{"pmid":"35583673","title":"Prenatal trio-based whole exome sequencing in fetuses with abnormalities of the skeletal system.","abstract":"Whole exome sequencing (WES) could yield diagnostic significance in the prenatal diagnosis of skeletal abnormalities. But the phenotypes of fetuses with skeletal abnormalities are heterogenous, and the clinical information we could obtain from an ongoing pregnancy is limited, making the prenatal diagnosis complicated. Therefore, the following interpretation and genetic counseling remain a challenge for clinicians. The aim of this study is to present and investigate the utility of trio-based WES in five fetuses with skeletal anomalies. Five trios with fetal ultrasonic skeletal anomalies were recruited in our study. Fetal specimens and parental peripheral blood were subjected to WES. The fetal skeletal abnormalities were presented through ultrasound scanning images. Fetal WES results showed variants in the PPIB, CHST3, COL1A1, and FGFR3 genes in the five trios. Inherited variants were found in two of the trios, while de novo variants were observed in three of them. Two novel compound heterozygous variants (c.437C > A and c.1044C > G) in CHST3 were identified. We presented five trios with fetal skeletal anomalies, found two novel variants and broadened the spectrum of variants associated with skeletal abnormalities, which would help the establishment of genotype-phenotype relationship in the prenatal setting. Trio-based WES could assist the prenatal diagnosis and genetic counseling of fetuses with skeletal abnormalities.","variants":[{"Name":"NM_004273.5(CHST3):c.1044C>G (p.Ile348Met)","Chromosome":"10","Start":"72008075","Stop":"72008075","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":866188,"rule_based_match":true,"evidence_text":"c.1044C > G","llm_judgment":"PRESENT","evidence":"c.1044C > G","abstract_start":1035,"abstract_end":1046}]}
{"pmid":"28197878","title":"Two homozygous mutations in the exon 5 of BCKDHB gene that may cause the classic form of maple syrup urine disease.","abstract":"Maple syrup urine disease (MSUD) is a rare autosomal recessive genetic disorder caused by defects in the catabolism of the branched-chain amino acids (BCAAs). Classic form of MSUD (CMSUD) is caused by mutations in BCKDHA, BCKDHB, DBT genes mostly. In this study, we analyzed the clinical and genetic characteristics of two patients with CMSUD. Two homozygous mutations, c.517G > T (p.Asp173Tyr) and c.503G > A (p.Arg168His), both in the exon 5 of BCKDHB were detected respectively. The novel mutation p.Asp173Tyr of patient A, inherited from his parents, is predicted to affect conformation of protein by computer analysis. The reported mutation p.Arg168His observed in patient B seemed to occur in a maternal uniparental disomy inheritance manner. Review of related literature revealed that most missense mutations in exon 5 of BCKDHB in homozygous genotype often result in CMSUD because of its incorrect conformation, and exon 5 of BCKDHB might be a susceptible region. Thus the novel homozygous mutation p.Asp173Tyr and the founder homozygous mutation p.Arg168His may be responsible for the clinical presentation of the two CMSUD patients, facilitating the future genetic counselling and prenatal diagnosis.","variants":[{"Name":"NM_183050.4(BCKDHB):c.517G>T (p.Asp173Tyr)","Chromosome":"6","Start":"80168914","Stop":"80168914","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":544268,"rule_based_match":true,"evidence_text":"c.517G > T (p.Asp173Tyr)","llm_judgment":"PRESENT","evidence":"c.517G > T (p.Asp173Tyr)","abstract_start":370,"abstract_end":394},{"Name":"NM_183050.4(BCKDHB):c.503G>A (p.Arg168His)","Chromosome":"6","Start":"80168900","Stop":"80168900","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":456437,"rule_based_match":true,"evidence_text":"c.503G > A (p.Arg168His)","llm_judgment":"PRESENT","evidence":"c.503G > A (p.Arg168His)","abstract_start":399,"abstract_end":423}]}
{"pmid":"38459354","title":"PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss.","abstract":"Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.","variants":[{"Name":"NM_177531.6(PKHD1L1):c.385G>A (p.Gly129Ser)","Chromosome":"8","Start":"109382539","Stop":"109382539","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3380118,"rule_based_match":false,"evidence_text":"p.[(Gly129Ser)]","llm_judgment":"PRESENT","evidence":"p.[(Gly129Ser)]","abstract_start":610,"abstract_end":625},{"Name":"NM_177531.6(PKHD1L1):c.1813G>A (p.Gly605Arg)","Chromosome":"8","Start":"109406478","Stop":"109406478","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3380122,"rule_based_match":true,"evidence_text":"c.1813G>A p.(Gly605Arg)","llm_judgment":"PRESENT","evidence":"c.1813G>A p.(Gly605Arg)","abstract_start":1644,"abstract_end":1667}]}
{"pmid":"18665195","title":"An USH2A founder mutation is the major cause of Usher syndrome type 2 in Canadians of French origin and confirms common roots of Quebecois and Acadians.","abstract":"Congenital hearing loss affects approximately one child in 1000. About 10% of the deaf population have Usher syndrome (USH). In USH, hearing loss is complicated by retinal degeneration with onset in the first (USH1) or second (USH2) decade. In most populations, diagnostic testing is hampered by a multitude of mutations in nine genes. We have recently shown that in French Canadians from Quebec, USH1 largely results from a single USH1C founder mutation, c.216G>A ('Acadian allele'). The genetic basis of USH2 in Canadians of French descent, however, has remained elusive. Here, we have investigated nine USH2 families from Quebec and New Brunswick (the former Acadia) by haplotype analyses of the USH2A locus and sequencing of the three known USH2 genes. Seven USH2A mutations were identified in eight patients. One of them, c.4338_4339delCT, accounts for 10 out of 18 disease alleles (55.6%). This mutation has previously been reported in an Acadian USH2 family, and it was found in homozygous state in the three Acadians of our sample. As in the case of c.216G>A (USH1C), a common haplotype is associated with c.4338_4339delCT. With a limited number of molecular tests, it will now be possible in these populations to estimate whether children with congenital hearing impairment of different degrees will develop retinal disease - with important clinical and therapeutic implications. USH2 is the second example that reveals a significant genetic overlap between Quebecois and Acadians: in contrast to current understanding, other genetic disorders present in both populations are likely based on common founder mutations as well.","variants":[{"Name":"NM_206933.4(USH2A):c.4338_4339del (p.Cys1447fs)","Chromosome":"1","Start":"216190280","Stop":"216190281","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":17392,"rule_based_match":true,"evidence_text":"c.4338_4339delCT","llm_judgment":"PRESENT","evidence":"c.4338_4339delCT","abstract_start":827,"abstract_end":843}]}
{"pmid":"24624349","title":"Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing.","abstract":"BACKGROUND: Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows. AO-I is caused by mutations in the filamin B (FLNB) gene; however, several other genes can cause AO-like lethal skeletal dysplasias.\nMETHODS: In order to screen all possible genes associated with AO-like lethal skeletal dysplasias simultaneously, we performed whole-exome sequencing in a female newborn having clinical features of AO-I.\nRESULTS: Exome sequencing identified a novel missense variant (c.517G>A; p.Ala173Thr) in exon 2 of the FLNB gene in the patient. Sanger sequencing validated this variant, and genetic analysis of the patient's parents suggested a de novo occurrence of the variant.\nCONCLUSIONS: This study shows that exome sequencing can be a useful tool for the identification of causative mutations in lethal skeletal dysplasia patients.","variants":[{"Name":"NM_001457.4(FLNB):c.517G>A (p.Ala173Thr)","Chromosome":"3","Start":"58077270","Stop":"58077270","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":131909,"rule_based_match":true,"evidence_text":"c.517G>A; p.Ala173Thr","llm_judgment":"PRESENT","evidence":"c.517G>A; p.Ala173Thr","abstract_start":575,"abstract_end":596}]}
{"pmid":"24616084","title":"Mutations in riboflavin transporter present with severe sensory loss and deafness in childhood.","abstract":"INTRODUCTION: We have identified a large consanguineous Lebanese family with 5 individuals with severe childhood-onset recessive sensory loss associated with deafness and variable optic atrophy.\nMETHODS: Autozygosity mapping was performed in all affected individuals, followed by whole-exome sequencing (WES) in 2 individuals.\nRESULTS: WES identified a homozygous missense mutation (c.916G>A, p.G306R) in the cerebral riboflavin transporter SLC52A2, recently shown to cause Brown-Vialetto-Van-Laere syndrome (BVVLS), which is considered primarily a motor neuronopathy. Our patients have a phenotype distinct from BVVLS, characterized by severe progressive sensory loss mainly affecting vibration and proprioception that evolves to include sensorineural hearing loss in childhood, variable degrees of optic atrophy, and marked upper extremity weakness and atrophy. Treatment of 3 patients with 400 mg/day riboflavin over 3 months produced definite clinical improvement.\nCONCLUSIONS: Mutations in SLC52A2 result in a recognizable phenotype distinct from BVVLS. Early recognition of this disorder is critical, given its potential treatability.","variants":[{"Name":"NM_001363118.2(SLC52A2):c.916G>A (p.Gly306Arg)","Chromosome":"8","Start":"144360408","Stop":"144360408","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44139,"rule_based_match":true,"evidence_text":"c.916G>A, p.G306R","llm_judgment":"PRESENT","evidence":"c.916G>A, p.G306R","abstract_start":383,"abstract_end":400}]}
{"pmid":"19370759","title":"Molecular neonatal screening for homocystinuria in the Qatari population.","abstract":"We report the results of molecular neonatal screening for homocystinuria (cystathionine beta-synthase deficiency) in neonates of Qatari origin, developed in conjunction with a novel biochemical screening approach. DNA was extracted from dried blood spots (DBS); the prevalent Qatari CBS gene mutation p.R336C (c.1006C>T) and a second mutation were tested with specific TaqMan assays. Over a period of 2 years we screened 12,603 neonates and identified six affected neonates homozygous for p.R336C. There were 225 heterozygous carriers for p.R336C. One additional child with homocystinuria detected through biochemical screening was homozygous for a mutation not previously identified in Qatar. Homocystinuria in the Qatari population has an incidence of 1:1,800, the highest in the world and even higher than previously estimated. Allele frequency of the mutation p.R336C is approximately 1%, displaying a significant deviation from Hardy Weinberg equilibrium. In conclusion, first-line molecular neonatal screening is technically feasible and may be developed as an option for presymptomatic identification of genetic disorders caused by specific mutations or a limited number of prevalent mutations. However, sensitivity for the diagnosis of disorders caused by various mutations is limited even in a homogeneous population such as Qatar.","variants":[{"Name":"NM_000071.3(CBS):c.1006C>T (p.Arg336Cys)","Chromosome":"21","Start":"43062344","Stop":"43062344","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":98334,"rule_based_match":true,"evidence_text":"c.1006C>T","llm_judgment":"PRESENT","evidence":"c.1006C>T","abstract_start":310,"abstract_end":319}]}
{"pmid":"30381368","title":"Heterozygous","abstract":"OBJECTIVE: To describe a new spinocerebellar ataxia (SCA48) characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA.\nMETHODS: This is a descriptive study of a family that has been followed for more than a decade with periodic neurologic and neuropsychological examinations, MRI, brain SPECT perfusion, and genetic analysis. Whole exome sequencing was performed in 3 affected and 1 unaffected family member and subsequently validated by linkage analysis of chromosome 16p13.3.\nRESULTS: Six patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with vermian and hemispheric cerebellar atrophy, suggesting a continuum from a dysexecutive syndrome slowly evolving to a complete and severe CCAS with late truncal ataxia. Three presymptomatic patients showed focal cerebellar atrophy in the vermian, paravermian, and the medial part of cerebellar lobes VI and VII, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum. Among the candidate variants, only the frameshift heterozygous c.823_824delCT <i>STUB1</i> (p.L275Dfs*16) pathogenic variant cosegregated with the disease. The p.L275Dfs*16 heterozygous <i>STUB1</i> pathogenic variant leads to neurodegeneration and atrophy in cognition- and emotion-related cerebellar areas and reinforces the importance of <i>STUB1</i> in maintaining cognitive cerebellar function.\nCONCLUSIONS: We report a heterozygous <i>STUB1</i> pathogenic genetic variant causing dominant cerebellar ataxia. Since recessive mutations in <i>STUB1</i> gene have been previously associated with SCAR16, these findings suggest a previously undescribed SCA locus (SCA48; MIM# 618093).","variants":[{"Name":"NM_005861.4(STUB1):c.823_824del (p.Leu275fs)","Chromosome":"16","Start":"682400","Stop":"682401","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":581213,"rule_based_match":true,"evidence_text":"c.823_824delCT <i>STUB1</i> (p.L275Dfs*16)","llm_judgment":"PRESENT","evidence":"c.823_824delCT <i>STUB1</i> (p.L275Dfs*16)","abstract_start":1185,"abstract_end":1227}]}
{"pmid":"28877251","title":"Identification of a novel GJA3 mutation in a large Chinese family with congenital cataract using targeted exome sequencing.","abstract":"Autosomal dominant congenital cataract (ADCC) is a clinically and genetically heterogeneous ocular disease in children that results in serious visual impairments or even blindness. Targeted exome sequencing (TES) is an efficient method used for genetic diagnoses of inherited diseases. In the present study, we used a custom-made TES panel to identify the genetic defect of a four-generation Chinese family with bilateral pulverulent nuclear cataracts. A novel heterozygous missense mutation c.443C>T (p. T148I) in GJA3 was identified. The results of the bioinformatic analysis showed that the mutation was deleterious to the structure and hemichannel function of Cx46 encoded by GJA3. Plasmids expressing wild-type and mutant human Cx46 were constructed and ectopically expressed in human lens epithelial cells (HLECs) or human embryonic kidney (HEK-293) cells. Fluorescent images indicated aggregated signals of mutant protein in the cytoplasm, and a higher protein level was also detected in T148I stable cell lines. In summary, we identified a novel mutation in GJA3 for ADCC, which provided molecular insights into the pathogenic mechanism of ADCC.","variants":[{"Name":"NM_021954.4(GJA3):c.443C>T (p.Thr148Ile)","Chromosome":"13","Start":"20142846","Stop":"20142846","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":527510,"rule_based_match":true,"evidence_text":"c.443C>T (p. T148I)","llm_judgment":"PRESENT","evidence":"c.443C>T (p. T148I)","abstract_start":492,"abstract_end":511}]}
{"pmid":"31748968","title":"Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD).","abstract":"Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, and absence of the splenium of corpus callosum. Exome sequencing in the trio revealed novel compound heterozygous pathogenic mutations in SNAP29 (p.Leu119AlafsX15, c.354DupG and p.0?, c.2T > C). Quantitative analysis of the patient's blood cells through RNA sequencing identified a significant decrease in SNAP29 mRNA expression, while western blot analysis on fibroblast cells revealed a lack of protein expression compared to parental and control cells. Mutations in SNAP29 have previously been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. Typical skin features described in CEDNIK syndrome, such as generalized ichthyosis and keratoderma, were absent in our patient. Moreover, the early onset nystagmus and leukodystrophy were consistent with a PMLD diagnosis. These findings suggest that loss of SNAP29 function, which was previously associated with CEDNIK syndrome, is also associated with PMLD. Overall, our study expands the genetic spectrum of PMLD.","variants":[{"Name":"NM_004782.4(SNAP29):c.354dup (p.Leu119fs)","Chromosome":"22","Start":"20870447","Stop":"20870448","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":264778,"rule_based_match":true,"evidence_text":"c.354DupG","llm_judgment":"PRESENT","evidence":"c.354DupG","abstract_start":785,"abstract_end":794},{"Name":"NM_004782.4(SNAP29):c.2T>C (p.Met1Thr)","Chromosome":"22","Start":"20859112","Stop":"20859112","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":264773,"rule_based_match":true,"evidence_text":"c.2T>C","llm_judgment":"PRESENT","evidence":"c.2T > C","abstract_start":805,"abstract_end":813}]}
{"pmid":"26220699","title":"Rare FOXC1 variants in congenital glaucoma: identification of translation regulatory sequences.","abstract":"Primary congenital glaucoma (PCG) is the cause of a significant proportion of inherited visual loss in children, but the underlying mechanism is poorly understood. In this study, we assessed the relationship between PCG and FOXC1 variants by Sanger sequencing the proximal promoter and transcribed sequence of FOXC1 from a cohort of 133 PCG families with no known CYP1B1 or MYOC mutations. The pathogenicity of the identified variants was evaluated by functional analyses. Ten patients (7.5%) with no family history of glaucoma carried five different rare heterozygous FOXC1 variants with both increased (rs77888940:C>G, c.-429C>G, rs730882054:c.1134_144del(CGGCGGCGCGG), p.(G380Rfs*144) and rs35717904:A>T, c.*734A>T) and decreased (rs185790394: C>T, c.-244C>T and rs79691946:C>T, p.(P297S)) transactivation, ranging from 50 to 180% of the wild-type activity. The five variants did not show monogenic segregation, and four of them were absent in a control group (n=233). To the best of our knowledge, one of these variants (p.(G380Rfs*144)) has not previously been described. One of the FOXC1 variant carriers (p.(P297S)) also coinherited a functionally altered rare PITX2 heterozygous variant (rs6533526:C>T, c.*454C>T). Bioinformatics and functional analyses provided novel information on three of these variants. c.-429C>G potentially disrupts a consensus sequence for a terminal oligopyrimidine tract, whereas c.-244C>T may alter the RNA secondary structure in the 5'-untranslated region (UTR) that affects mRNA translation. In addition, p.(G380Rfs*144) led to increased protein stability. In summary, these data reveal the presence of translation regulatory sequences in the UTRs of FOXC1 and provide evidence for a possible role of rare FOXC1 variants as modifying factors of goniodysgenesis in PCG.","variants":[{"Name":"NM_000325.6(PITX2):c.*454C>T","Chromosome":"4","Start":"110617671","Stop":"110617671","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":181382,"rule_based_match":true,"evidence_text":"rs6533526:C>T, c.*454C>T","llm_judgment":"PRESENT","evidence":"rs6533526:C>T, c.*454C>T","abstract_start":1196,"abstract_end":1220}]}
{"pmid":"21529752","title":"The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.","abstract":"We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10% of expected size (≤10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination (microlissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment.","variants":[{"Name":"NM_017668.3(NDE1):c.684_685del (p.Pro229fs)","Chromosome":"16","Start":"15691300","Stop":"15691301","ReferenceAlleleVCF":"AAC","AlternateAlleleVCF":"A","allel_id":39744,"rule_based_match":true,"evidence_text":"c.684_685del (p.Pro229TrpfsX85)","llm_judgment":"PRESENT","evidence":"c.684_685del (p.Pro229TrpfsX85)","abstract_start":570,"abstract_end":601},{"Name":"NM_017668.3(NDE1):c.83+1G>T","Chromosome":"16","Start":"15664862","Stop":"15664862","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":429772,"rule_based_match":true,"evidence_text":"c.83+1G>T (p.Ala29GlnfsX114)","llm_judgment":"PRESENT","evidence":"c.83+1G>T (p.Ala29GlnfsX114)","abstract_start":517,"abstract_end":545}]}
{"pmid":"30135305","title":"Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice.","abstract":"Ion channel-controlled cell volume regulation is of fundamental significance to the physiological function of sperm. In addition to volume regulation, LRRC8A-dependent volume-regulated anion channel (VRAC) activity is involved in cell cycle progression, insulin signaling, and cisplatin resistance. Nevertheless, the contribution of LRRC8A and its dependent VRAC activity in the germ cell lineage remain unknown. By utilizing a spontaneous Lrrc8a mouse mutation (c.1325delTG, p.F443*) and genetically engineered mouse models, we demonstrate that LRRC8A-dependent VRAC activity is essential for male germ cell development and fertility. Lrrc8a-null male germ cells undergo progressive degeneration independent of the apoptotic pathway during postnatal testicular development. Lrrc8a-deficient mouse sperm exhibit multiple morphological abnormalities of the flagella (MMAF), a feature commonly observed in the sperm of infertile human patients. Importantly, we identified a human patient with a rare LRRC8A hypomorphic mutation (c.1634G>A, p.Arg545His) possibly linked to Sertoli cell-only syndrome (SCOS), a male sterility disorder characterized by the loss of germ cells. Thus, LRRC8A is a critical factor required for germ cell development and volume regulation in the mouse, and it might serve as a novel diagnostic and therapeutic target for SCOS patients.","variants":[{"Name":"NM_019594.4(LRRC8A):c.1634G>A (p.Arg545His)","Chromosome":"9","Start":"128908798","Stop":"128908798","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3144371,"rule_based_match":true,"evidence_text":"c.1634G>A (p.Arg545His)","llm_judgment":"PRESENT","evidence":"p.Arg545His","abstract_start":1038,"abstract_end":1049}]}
{"pmid":"20019893","title":"A novel GJA8 mutation (p.I31T) causing autosomal dominant congenital cataract in a Chinese family.","abstract":"PURPOSE: To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family.\nMETHODS: Family history and clinical data were recorded. The genomic DNA was extracted from peripheral blood leukocytes. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point logarithm of odds (LOD) scores were calculated by using the Linkage software after genotyping. Mutations were detected by DNA sequence analysis of the candidate genes. Effects of amino acid changes on the structure and function of proteins were predicted by bioinformatics analysis.\nRESULTS: Evidence of a linkage was obtained at markers D1S514 (LOD score [Z]=3.48, recombination fraction [theta]=0.0) and D1S1595 (Z=2.49, theta=0.0). Haplotype analysis indicated that the cataract gene was close to these two markers. Sequencing of the connexin 50 (GJA8) gene revealed a T>C transition at nucleotide position c.92. This nucleotide change resulted in the substitution of highly conserved isoleucine by threonine at codon 31(I31T). This mutation co-segregated with all affected individuals and was not observed in unaffected or 110 normal unrelated individuals. Bioinformatics analysis showed that a highly conserved region was located at Ile31, and the mutation was predicted to affect the function and secondary structure of the GJA8 protein.\nCONCLUSION: A novel mutation in GJA8 was detected in a Chinese family with autosomal dominant congenital nuclear cataract, providing clear evidence of a relationship between the genotype and the corresponding cataract phenotype.","variants":[{"Name":"NM_005267.5(GJA8):c.92T>C (p.Ile31Thr)","Chromosome":"1","Start":"147908047","Stop":"147908047","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3412498,"rule_based_match":false,"evidence_text":"c.92T>C (p.Ile31Thr)","llm_judgment":"PRESENT","evidence":"I31T","abstract_start":1090,"abstract_end":1094}]}
{"pmid":"33078099","title":"A novel mutation of","abstract":"AIM: To identify mutations in the genes of a four-generation Chinese family with congenital membranous cataracts and investigate the morphologic changes and possible functional damage underlying the role of the mutant gene.\nMETHODS: Whole exome analysis of thirteen members of a four-generation pedigree affected with congenital membranous cataracts was performed; co-segregation analysis of identified variants was validated by Sanger sequencing. All members underwent detailed physical and complete eye examinations. The physical changes caused by the mutation were analyzed in silico through homology modeling. The lens fiber block from a patient was observed under a scanning electron microscope (SEM). Cell membrane proteins and cytoplasmic proteins from the human lenses donated by one patient with cataract in this family and from the dislocated lens resulted from the penetrating ocular trauma of a patient unrelated with this family were extracted, and the expression and localization of MP20 and Cx46 were detected by Western blot (WB) assay in these proteins.\nRESULTS: A novel <i>LIM2</i> heterozygous mutation (c.388C>T, p.R130C) was identified with congenital membranous cataracts inherited by an autosomal dominant (AD) pattern. Nystagmus and amblyopia were observed in all patients of this family, and exotropia and long axial length were observed in most patients. A/B ultrasound scan and ultrasound biomicroscopy revealed obvious thin crystalline lenses from 1.7 to 2.7 mm in central thickness in all cataract eyes. The bioinformatic analysis showed that the mutation was deleterious to the physiological function of <i>LIM2</i>-encoded MP20. Furthermore, by SEM, ultrastructure of the cataract nucleus showed that lens fiber cells (LFCs) remained morphologic characteristics of immature fiber cells, including flap cell surface with straight edges and lacking normal ball-and-socket joint boundaries, which implied that the differentiation of LFCs might be inhibited. Accumulation of MP20 and Cx46 in the cytoplasm was observed in the cytoplasm of the LFCs in human cataract lens.\nCONCLUSION: We identify a novel heterozygous <i>LIM2</i> (c.388C>T, p.R130C) mutation inherited by an AD pattern. This <i>LIM2</i> mutation causes the abnormal sub-localization of MP20 and Cx46 in LFCs resulting in membranous cataracts.","variants":[{"Name":"NM_001161748.2(LIM2):c.388C>T (p.Arg130Cys)","Chromosome":"19","Start":"51380577","Stop":"51380577","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":613458,"rule_based_match":true,"evidence_text":"c.388C>T, p.R130C","llm_judgment":"PRESENT","evidence":"c.388C>T, p.R130C","abstract_start":1123,"abstract_end":1140}]}
{"pmid":"29211946","title":"A rare ANOS1 variant in siblings with Kallmann syndrome identified by whole exome sequencing.","abstract":"Kallmann syndrome is a rare genetic condition causing congenital hypogonadotropic hypogonadism. It presents with delayed puberty, anosmia, and infertility. Here, we set out to identify a causative DNA variant for Kallmann syndrome in two affected brothers of Hispanic ancestry. The male siblings presented with a clinical diagnosis of Kallmann syndrome (anosmia, delayed puberty, azoospermia, and undetectable luteinizing hormone and follicle stimulating hormone levels). Genetic variations were investigated by whole exome sequencing. Potentially pathogenic variants were filtered and prioritized followed by validation by Sanger sequencing in the two brothers and their mother. A pathogenic variant was identified in the ANOS1 gene on the X chromosome: c.1267C>T; both brothers were hemizygous, and their mother was heterozygous for the variant. The variant is a single nucleotide change that introduces a stop codon in exon 9 (p.R423*), likely producing a truncated variant of the protein. This variant has only been reported twice in the literature, in the setting of finding genetic causes for other conditions. This result supports the clinical value of whole exome sequencing for identification of genetic pathogenic variants. Genetic diagnosis is the essential first step for genetic counseling, preimplantation diagnosis, and research for a potential treatment.","variants":[{"Name":"NM_000216.4(ANOS1):c.1267C>T (p.Arg423Ter)","Chromosome":"X","Start":"8554039","Stop":"8554039","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":482267,"rule_based_match":true,"evidence_text":"c.1267C>T","llm_judgment":"PRESENT","evidence":"c.1267C>T","abstract_start":755,"abstract_end":764}]}
{"pmid":"26956854","title":"Correlation between Pituitary Stalk Interruption Syndrome and Prokineticin Receptor 2 and Prokineticin 2 Mutations.","abstract":"OBJECTIVE: To analyze the correlation between pituitary stalk interruption syndrome (PSIS) and prokineticin receptor 2 (PROKR2) and prokineticin 2 (RROK2) mutations.\nMETHODS: PROKR2 and RROK2 genotypes were identified by multiplex polymerase chain reaction analysis with exon-flanking primers and by automated sequencing techniques with peripheral blood DNA samples from 59 patients with PSIS.\nRESULTS: Of these 59 PSIS patients, 6 showed intragenic deletions at the PROKR2 locus. Of them, 5 patients exhibited intragenic subsititution of exon 2 (c.991G>A), and the remaining one patient exhibited intragenic subsititution of exon 2 (c.1057C>T). No PROK2 mutation was found in these PSIS patients.\nCONCLUSION: PROKR2 may be the susceptibility gene of PSIS.","variants":[{"Name":"NM_144773.4(PROKR2):c.1057C>T (p.Arg353Cys)","Chromosome":"20","Start":"5302138","Stop":"5302138","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3860514,"rule_based_match":true,"evidence_text":"c.1057C>T","llm_judgment":"PRESENT","evidence":"c.1057C>T","abstract_start":634,"abstract_end":643}]}
{"pmid":"16098014","title":"Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations.","abstract":"To better characterize Niemann-Pick type C (NPC) in Spain and improve genetic counselling, molecular analyses were carried out in 40 unrelated Spanish patients. The search identified 70/80 alleles (88%) involving 38 different NPC1 mutations, 26 of which are described for the first time. No patient with NPC2 mutations was identified. The novel NPC1 mutations include 14 amino acid substitutions [R372W (c.1114C>T), P434L (c.1301C>T), C479Y (c.1436G>A), K576R (c.1727G>A), V727F (c.2179G>T), M754K (c.2261T>A), S865L (c.2594C>T), A926T (c.2776G>A), D948H (c.2842G>C), V959E (c.2876T>A), T1036K (c.3107C>A), T1066N (c.3197C>A), N1156I (c.3467A>T) and F1224L (c.3672C>G)], four stop codon [W260X (c.780G>A), S425X (c.1274C>A), C645X (c.1935T>A) and R1059X (c.3175C>T)], two donor splice-site mutations [IVS7+1G>A (g.31432G>A) and IVS21+2insG (g.51871insG)], one in-frame mutation [N961_F966delinsS (c.2882del16bpins1bp)] and five frameshift mutations [V299fsX8 (c.895insT), A558fsX11 (c.1673insG), C778fsX10 (c.2334insT), G993fsX3 (c.2973_78delG) and F1221fsX20 (c.3662delT)]. We also identified three novel changes [V562V (c.1686G>A), A580A (c.1740C>G) and A1187A (c.3561G>T)] in three independent NPC patients and five polymorphisms that have been described previously. The combination of these polymorphisms gave rise to the establishment of different haplotypes. Linkage disequilibrium was detected between mutations C177Y and G993fsX3 and specific haplotypes, suggesting a unique origin for these mutations. In contrast, I1061T mutation showed at least two different origins. The most prevalent mutations in Spanish patients were I1061T, Q775P, C177Y and P1007A (10, 7, 7 and 5% of alleles, respectively). Our data in homozygous patients indicate that the Q775P mutation correlates with a severe infantile neurological form and the C177Y mutation with a late infantile clinical phenotype.","variants":[{"Name":"NM_000271.5(NPC1):c.3175C>T (p.Arg1059Ter)","Chromosome":"18","Start":"23536743","Stop":"23536743","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187023,"rule_based_match":true,"evidence_text":"c.3175C>T","llm_judgment":"PRESENT","evidence":"c.3175C>T","abstract_start":755,"abstract_end":764},{"Name":"NM_000271.5(NPC1):c.2776G>A (p.Ala926Thr)","Chromosome":"18","Start":"23539830","Stop":"23539830","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":974116,"rule_based_match":true,"evidence_text":"c.2776G>A","llm_judgment":"PRESENT","evidence":"c.2776G>A","abstract_start":537,"abstract_end":546},{"Name":"NM_000271.5(NPC1):c.1436G>A (p.Cys479Tyr)","Chromosome":"18","Start":"23554875","Stop":"23554875","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":532264,"rule_based_match":true,"evidence_text":"C479Y (c.1436G>A)","llm_judgment":"PRESENT","evidence":"C479Y (c.1436G>A)","abstract_start":435,"abstract_end":452},{"Name":"NM_000271.5(NPC1):c.2594C>T (p.Ser865Leu)","Chromosome":"18","Start":"23540458","Stop":"23540458","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":791852,"rule_based_match":true,"evidence_text":"c.2594C>T","llm_judgment":"PRESENT","evidence":"c.2594C>T","abstract_start":518,"abstract_end":527},{"Name":"NM_000271.5(NPC1):c.1686G>A (p.Val562=)","Chromosome":"18","Start":"23548077","Stop":"23548077","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":548914,"rule_based_match":true,"evidence_text":"c.1686G>A","llm_judgment":"PRESENT","evidence":"c.1686G>A","abstract_start":1122,"abstract_end":1131},{"Name":"NM_000271.5(NPC1):c.3561G>T (p.Ala1187=)","Chromosome":"18","Start":"23534476","Stop":"23534476","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":208444,"rule_based_match":true,"evidence_text":"c.3561G>T","llm_judgment":"PRESENT","evidence":"c.3561G>T","abstract_start":1164,"abstract_end":1173},{"Name":"NM_000271.5(NPC1):c.1301C>T (p.Pro434Leu)","Chromosome":"18","Start":"23556268","Stop":"23556268","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":422213,"rule_based_match":true,"evidence_text":"c.1301C>T","llm_judgment":"PRESENT","evidence":"c.1301C>T","abstract_start":423,"abstract_end":432},{"Name":"NM_000271.5(NPC1):c.3019C>G (p.Pro1007Ala)","Chromosome":"18","Start":"23538564","Stop":"23538564","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":18005,"rule_based_match":false,"evidence_text":"P1007A","llm_judgment":"PRESENT","evidence":"P1007A","abstract_start":1658,"abstract_end":1664},{"Name":"NM_000271.5(NPC1):c.3182T>C (p.Ile1061Thr)","Chromosome":"18","Start":"23536736","Stop":"23536736","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18006,"rule_based_match":false,"evidence_text":"I1061T","llm_judgment":"PRESENT","evidence":"I1061T","abstract_start":1524,"abstract_end":1530},{"Name":"NM_000271.5(NPC1):c.1114C>T (p.Arg372Trp)","Chromosome":"18","Start":"23556455","Stop":"23556455","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1056489,"rule_based_match":true,"evidence_text":"c.1114C>T","llm_judgment":"PRESENT","evidence":"c.1114C>T","abstract_start":404,"abstract_end":413},{"Name":"NM_000271.5(NPC1):c.3467A>T (p.Asn1156Ile)","Chromosome":"18","Start":"23535479","Stop":"23535479","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":549234,"rule_based_match":true,"evidence_text":"c.3467A>T","llm_judgment":"PRESENT","evidence":"c.3467A>T","abstract_start":635,"abstract_end":644},{"Name":"NM_000271.5(NPC1):c.3197C>A (p.Thr1066Asn)","Chromosome":"18","Start":"23536721","Stop":"23536721","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1356923,"rule_based_match":true,"evidence_text":"c.3197C>A","llm_judgment":"PRESENT","evidence":"c.3197C>A","abstract_start":615,"abstract_end":624}]}
{"pmid":"34719423","title":"D-bifunctional protein deficiency caused by","abstract":"A 15-day-old boy was admitted to the hospital due to repeated convulsions for 14 days. The main clinical manifestations were uncontrolled seizures, hypoergia, feeding difficulties, limb hypotonia, and bilateral hearing impairment. Clinical neurophysiology showed reduced brainstem auditory evoked potential on both sides and burst-suppression pattern on electroencephalogram. Measurement of very-long-chain fatty acids in serum showed that C26:0 was significantly increased. Genetic testing showed a pathogenic compound heterozygous mutation, c.101C>T(p.Ala34Val) and c.1448_1460del(p.Ala483Aspfs*37), in the <i>HSD17B4</i> gene. This article reports a case of D-bifunctional protein deficiency caused by <i>HSD17B4</i> gene mutation and summarizes the epidemiological and clinical features, diagnosis, and treatment of this disease, with a focus on the differential diagnosis of this disease from Ohtahara syndrome.","variants":[{"Name":"NM_000414.4(HSD17B4):c.101C>T (p.Ala34Val)","Chromosome":"5","Start":"119456357","Stop":"119456357","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":141319,"rule_based_match":true,"evidence_text":"c.101C>T(p.Ala34Val)","llm_judgment":"PRESENT","evidence":"c.101C>T(p.Ala34Val)","abstract_start":543,"abstract_end":563}]}
{"pmid":"38230957","title":"Floating-Harbor Syndrome in a Korean Patient with Short Stature and Early Puberty: A Case Report.","abstract":"Floating-Harbor syndrome (FHS) is a rare autosomal dominant genetic disorder characterized by proportionately short stature, lack of expressive language, and distinctive facial features, including a large nose, long eyelashes, deeply set eyes, and a triangular face. We present a case of an 11-year-old Korean girl who was initially suspected of having Noonan-like syndrome but was later diagnosed with Floating-Harbor syndrome. The patient exhibited short stature, developmental language delay, dysmorphic facial features, and early puberty. Targeted exome sequencing revealed a heterozygous mutation, c.7303C>T (p.Arg2435Ter), in the SRCAP gene, confirming a diagnosis of Floating-Harbor syndrome. She responded well to human recombinant growth hormone and gonadotropin-releasing hormone (GnRH) agonist, effectively suppressing bone maturation and improving her height SDS from -4.6 to -2.4.","variants":[{"Name":"NM_006662.3(SRCAP):c.7303C>T (p.Arg2435Ter)","Chromosome":"16","Start":"30737343","Stop":"30737343","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39866,"rule_based_match":true,"evidence_text":"c.7303C>T (p.Arg2435Ter)","llm_judgment":"PRESENT","evidence":"c.7303C>T (p.Arg2435Ter)","abstract_start":603,"abstract_end":627}]}
{"pmid":"30334930","title":"Clinical and Genetic Study of Children With Peutz-Jeghers Syndrome Identifies a High Frequency of STK11 De Novo Mutation.","abstract":"OBJECTIVES: The present study aims to identify the genotype-phenotype correlation in children with Peutz-Jeghers Syndrome (PJS) through the analysis of STK11 gene mutations in the context of clinical and pathological characteristics.\nMETHOD: In this observational cohort study, the clinical characteristics of 18 families diagnosed with pediatric PJS were collected. Genomic DNA from the peripheral blood of affected children and their family members was collected. The coding region of STK11 was amplified by PCR and screened for mutation by Sanger sequencing. The families that were negative for STK11 mutation were further assessed by multiplex ligation-dependent probe amplification (MLPA).\nRESULT: Initial presentation in affected children was at 1.6 to 14.2 years and included anemia in 8 patients whereas 6 presented for screening by virtue of family history. All patients underwent endoscopy, colonoscopy, and polypectomy. Polyps were distributed throughout the gastrointestinal (GI) tract, including the small intestine, stomach, colon, and rectum.In the 18 pediatric PJS families, STK11 mutations were detected in 8 families by Sanger sequencing, and large deletions were detected in 3 by MLPA, respectively. Nine of the 11 STK11 mutations were de novo, 3 were novel (c.419T>C:p.L140P, c.314T>G:p.L105X), and (c.488_489insACGG p.L164fs).\nCONCLUSIONS: Although the main clinical features of pediatric PJS were similar to those of PJS cases in adults, a high frequency of STK11 de novo mutations were encountered in our population of patients with PJS.","variants":[{"Name":"NM_000455.5(STK11):c.419T>C (p.Leu140Pro)","Chromosome":"19","Start":"1219368","Stop":"1219368","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":532680,"rule_based_match":true,"evidence_text":"c.419T>C:p.L140P","llm_judgment":"PRESENT","evidence":"c.419T>C:p.L140P","abstract_start":1278,"abstract_end":1294}]}
{"pmid":"21255762","title":"Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42.","abstract":"By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31-q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment.","variants":[{"Name":"NM_001199799.2(ILDR1):c.1135G>T (p.Glu379Ter)","Chromosome":"3","Start":"121993614","Stop":"121993614","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":39753,"rule_based_match":true,"evidence_text":"c.1135G>T [p.Glu379X]","llm_judgment":"PRESENT","evidence":"c.1135G>T [p.Glu379X]","abstract_start":289,"abstract_end":310}]}
{"pmid":"30084681","title":"A NOVEL COMPOUND HETEROZYGOUS VARIANT OF SLC12A3 GENE IN A PEDIGREE WITH GITELMAN SYNDROME CO-EXISTENT WITH THYROID DYSFUNCTION.","abstract":"OBJECTIVE: Gitelman syndrome (GS) is an autosomal recessive disorder characterized by salt wasting and hypokalemia resulting from mutations in the SLC12A3 (solute carrier family 12 member 3) gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. To date, more than 488 mutations of the SLC12A3 gene have been discovered in patients with GS. In this study, we reported a GS pedigree complicated by thyroid diseases or thyroid dysfunction.\nMETHODS: Sanger sequencing and next-generation sequencing analysis were performed to determine the SLC12A3 gene mutations in a GS pedigree including the 16-year old male patient with GS and his family members within 3 generations. Chemiluminescence immunoassays were used to detect thyroid hormone and antibody concentrations.\nRESULTS: Genetic analysis of the SLC12A3 gene identified 2 mutations in the 16-year old male patient with GS concomitant with Graves disease (GD) and his younger sister accompanied by abnormal thyroid function. Additionally, one mutation site (c.1456G>A) in SLC12A3 gene was found in his father, paternal uncle and elder female cousin, who were complicated by subclinical hypothyroidism or autoantibody against thyroid. The other mutation site (c.2102_2107 delACAAGA) in SLC12A3 gene, a novel mutated variant of SLC12A3 gene, was carried by his mother and maternal grandfather.\nCONCLUSION: Two mutation sites were documented in the pedigree with GS, and one has not been reported before. Moreover, we found a mutation at nucleotide c.1456 G>A in the SLC12A3 gene that may affect thyroid function. However, further studies are needed to explore the underlying molecular mechanisms.\nABBREVIATIONS: FT3 = free triiodothyronine; FT4 = free tetraiodothyronine; GD = Graves disease; GS = Gitelman syndrome; SLC12A3 = solute carrier family 12 member 3; TGAb = thyroglobulin antibody; TPOAb = thyroid peroxidase antibody; TSH = thyroid-stimulating hormone; TT3 = total triiodothyronine; TT4 = total tetraiodothyronine.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1456G>A (p.Asp486Asn)","Chromosome":"16","Start":"56880142","Stop":"56880142","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":644774,"rule_based_match":true,"evidence_text":"c.1456G>A","llm_judgment":"PRESENT","evidence":"c.1456G>A","abstract_start":1028,"abstract_end":1037}]}
{"pmid":"34536092","title":"The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype.","abstract":"Pathogenic variants in aminoacyl-tRNA synthetases (ARS1) cause a diverse spectrum of autosomal recessive disorders. Tyrosyl tRNA synthetase (TyrRS) is encoded by YARS1 (cytosolic, OMIM*603,623) and is responsible of coupling tyrosine to its specific tRNA. Next to the enzymatic domain, TyrRS has two additional functional domains (N-Terminal TyrRS<sup>Mini</sup> and C-terminal EMAP-II-like domain) which confer cytokine-like functions. Mutations in YARS1 have been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) neuropathy type C and a heterogenous group of autosomal recessive, multisystem diseases. We identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) (NM_003680.3) in YARS1. This variant causes a multisystem disorder with developmental delay, microcephaly, failure to thrive, short stature, muscular hypotonia, ataxia, brain anomalies, microcytic anemia, hepatomegaly, and hypothyroidism. In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain. The phenotype associated with p.(Arg367Trp) is distinct from the other biallelic pathogenic variants that reside in different functional domains of TyrRS which all show some common, but also divergent clinical signs [(e.g., p.(Phe269Ser)-retinal anomalies, p.(Pro213Leu)/p.(Gly525Arg)-mild ID, p.(Pro167Thr)-high fatality)]. The diverse clinical spectrum of ARS1-associated disorders is related to mutations affecting the various non-canonical domains of ARS1, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders. KEY MESSAGES: The missense variant p.(Arg367Trp) in YARS1 causes a distinct multisystem disorder. p.(Arg367Trp) affects a non-canonical domain with cytokine-like functions. Phenotypic heterogeneity associates with the different affected YARS1 domains. Impaired protein translation is likely not the exclusive mechanism of ARS1-associated disorders.","variants":[{"Name":"NM_003680.4(YARS1):c.1099C>T (p.Arg367Trp)","Chromosome":"1","Start":"32781089","Stop":"32781089","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":557027,"rule_based_match":true,"evidence_text":"c.1099C > T;p.(Arg367Trp) (NM_003680.3)","llm_judgment":"PRESENT","evidence":"c.1099C > T;p.(Arg367Trp) (NM_003680.3)","abstract_start":708,"abstract_end":747}]}
{"pmid":"21381113","title":"Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa-responsive Parkinsonism.","abstract":"BACKGROUND: Autosomal recessive hereditary spastic paraplegia with thin corpus callosum is a neurodegenerative disorder characterized by spastic paraparesis, cognitive impairment, and peripheral neuropathy. The neuroradiologic hallmarks are thin corpus callosum and periventricular white matter changes. Mutations in the SPG11 gene have been identified to be a major cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and recently also proven to be responsible for juvenile parkinsonism associated with spastic paraplegia.\nMETHODS: We describe one Italian autosomal recessive hereditary spastic paraplegia with thin corpus callosum patient who unusually presented at onset, 16 years, with parkinsonism-like features, responsive to dopaminergic therapy. Then the clinical picture evolved and became more complex. A brain magnetic resonance imaging scan showed thin corpus callosum and hyperintense T(2)-weighted lesions in periventricular regions, and the (123)I-ioflupane single-photon emission coupled tomography was abnormal.\nRESULTS: Genetic analysis detected two novel mutations, a c.3664insT variant in compound heterozygosity with a c.6331insG mutation, in SPG11.\nDISCUSSION: This case confirms the high genetic and clinical heterogeneity associated with SPG11 mutations. It also offers further evidence that parkinsonism may initiate autosomal recessive hereditary spastic paraplegia with thin corpus callosum and that parkinsonian symptoms can have variable dopaminergic response in these patients.","variants":[{"Name":"NM_025137.4(SPG11):c.3664_3665insT (p.Lys1222fs)","Chromosome":"15","Start":"44600488","Stop":"44600489","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":49733,"rule_based_match":false,"evidence_text":"c.3664insT","llm_judgment":"PRESENT","evidence":"c.3664insT","abstract_start":1120,"abstract_end":1130}]}
{"pmid":"38279137","title":"Genetic and clinical characterization of a novel FH founder mutation in families with hereditary leiomyomatosis and renal cell cancer syndrome.","abstract":"BACKGROUND: Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH(NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype.\nRESULTS: Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61-0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH_c.1118A > G variant is a Spanish founder mutation that originated 12-26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome.\nCONCLUSIONS: In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing.","variants":[{"Name":"NM_000143.4(FH):c.1118A>G (p.Asn373Ser)","Chromosome":"1","Start":"241502561","Stop":"241502561","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":380451,"rule_based_match":true,"evidence_text":"FH(NM_000143.4):c.1118A > G p.(Asn373Ser)","llm_judgment":"PRESENT","evidence":"FH(NM_000143.4):c.1118A > G p.(Asn373Ser)","abstract_start":259,"abstract_end":300}]}
{"pmid":"21147909","title":"Molecular diagnosis for heterogeneous genetic diseases with targeted high-throughput DNA sequencing applied to retinitis pigmentosa.","abstract":"BACKGROUND: The genetic heterogeneity of many Mendelian disorders, such as retinitis pigmentosa which results from mutations in over 40 genes, is a major obstacle to obtaining a molecular diagnosis in clinical practice. Targeted high-throughput DNA sequencing offers a potential solution and was used to develop a molecular diagnostic screen for patients with retinitis pigmentosa.\nMETHODS: A custom sequence capture array was designed to target the coding regions of all known retinitis pigmentosa genes and used to enrich these sequences from DNA samples of five patients. Enriched DNA was subjected to high-throughput sequencing singly or in pools, and sequence variants were identified by alignment of up to 10 million reads per sample to the normal reference sequence. Potential pathogenicity was assessed by functional predictions and frequency in controls.\nRESULTS AND CONCLUSIONS: Known homozygous PDE6B and compound heterozygous CRB1 mutations were detected in two patients. A novel homozygous missense mutation (c.2957A→T; p.N986I) in the cyclic nucleotide gated channel β1 (CNGB1) gene predicted to have a deleterious effect and absent in 720 control chromosomes was detected in one case in which conventional genetic screening had failed to detect mutations. The detection of known and novel retinitis pigmentosa mutations in this study establishes high-throughput DNA sequencing with DNA pooling as an effective diagnostic tool for heterogeneous genetic diseases.","variants":[{"Name":"NM_001297.5(CNGB1):c.2957A>T (p.Asn986Ile)","Chromosome":"16","Start":"57901371","Stop":"57901371","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":177287,"rule_based_match":false,"evidence_text":"c.2957A→T; p.N986I","llm_judgment":"PRESENT","evidence":"c.2957A→T; p.N986I","abstract_start":1022,"abstract_end":1040}]}
{"pmid":"30298599","title":"MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy.","abstract":"MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early-onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile-onset peripheral sensorimotor neuropathy associated with an MVP17 c.122G>A (p.Arg41Gln) variant have been reported. Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants. Patients of the first family carried the known c.122G>A variant and affected individuals of the second family had a novel c.376-9T>G near-splice variant, which was shown to result in an in-frame deletion of 11 amino acids. This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy.","variants":[{"Name":"NM_002437.5(MPV17):c.376-9T>G","Chromosome":"2","Start":"27312255","Stop":"27312255","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":584407,"rule_based_match":true,"evidence_text":"c.376-9T>G","llm_judgment":"PRESENT","evidence":"c.376-9T>G","abstract_start":860,"abstract_end":870},{"Name":"NM_002437.5(MPV17):c.122G>A (p.Arg41Gln)","Chromosome":"2","Start":"27313058","Stop":"27313058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":614556,"rule_based_match":true,"evidence_text":"c.122G>A (p.Arg41Gln)","llm_judgment":"PRESENT","evidence":"c.122G>A (p.Arg41Gln)","abstract_start":511,"abstract_end":532}]}
{"pmid":"34625929","title":"Analysis of genetic variant in a child with autosomal recessive Alport syndrome","abstract":"OBJECTIVE: To explore the genetic basis for a pedigree affected with Alport syndrome.\nMETHODS: Next generation sequencing and Sanger sequencing was applied to detect potential variants of the COL4A3, COL4A4 and COL4A5 genes among members from the pedigree and 100 unrelated healthy controls.\nRESULTS: The proband and his twin brother were found to carry two novel variants, namely c.4953G>A and c.4623C>A, of the COL4A4 gene, which were respectively inherited from her father and mother. The same variants were not detected among the 100 healthy controls and medical literature. Based on the guidelines of the American College of Medical Genetics and Genomics, both the c.4953G>A and c.4623C>A variants were predicted to be pathogenic (PVS1+PM2_supporting+PP1).\nCONCLUSION: The c.4953G>A and c.4623C>A variants of the COLA4A gene probably underlay the Alport syndrome in this pedigree. Above finding has enriched the spectrum of COLA4A gene variants.","variants":[{"Name":"NM_000092.5(COL4A4):c.4953G>A (p.Trp1651Ter)","Chromosome":"2","Start":"227007445","Stop":"227007445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1059209,"rule_based_match":true,"evidence_text":"c.4953G>A","llm_judgment":"PRESENT","evidence":"c.4953G>A","abstract_start":381,"abstract_end":390}]}
{"pmid":"26573920","title":"The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy.","abstract":"Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme's substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.547C>T, p.(Arg183Trp). The variant changed a conserved amino acid and was not found in public variant databases. All patients had a relatively mild progressive distal sensory impairment, with onset after age 50. Small fibers were affected early, leading to abnormalities on quantitative sensory testing. Sural biopsy revealed a severe chronic axonal neuropathy with subtotal loss of myelinated axons, relatively preserved number of non-myelinated fibers and no signs for regeneration. Skin biopsy with PGP9.5 labeling showed lack of intraepidermal nerve endings early in the disease. Motor manifestations developed later in the disease course, but there was no evidence of autonomic involvement. Patients had elevated serum 1-deoxysphingolipids, and the variant protein produced elevated amounts of 1-deoxysphingolipids in vitro, which proved the pathogenicity of the variant. Our results expand the genetic spectrum of HSAN1C and provide further detail about the clinical characteristics. Sequencing of SPTLC2 should be considered in all patients presenting with mild late-onset sensory-predominant small or large fiber neuropathy.","variants":[{"Name":"NM_004863.4(SPTLC2):c.547C>T (p.Arg183Trp)","Chromosome":"14","Start":"77576851","Stop":"77576851","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":463539,"rule_based_match":true,"evidence_text":"c.547C>T, p.(Arg183Trp)","llm_judgment":"PRESENT","evidence":"c.547C>T, p.(Arg183Trp)","abstract_start":405,"abstract_end":428}]}
{"pmid":"32534991","title":"Ligase IV syndrome can present with microcephaly and radial ray anomalies similar to Fanconi anaemia plus fatal kidney malformations.","abstract":"Ligase IV (LIG4) syndrome is a rare disorder of DNA damage repair caused by biallelic, pathogenic variants in LIG4. This is a phenotypically heterogeneous condition with clinical presentation varying from lymphoreticular malignancies in developmentally normal individuals to significant microcephaly, primordial dwarfism, radiation hypersensitivity, severe combined immunodeficiency and early mortality. Renal defects have only rarely been described as part of the ligase IV disease spectrum. We identified a consanguineous family where three siblings presenting with antenatal growth retardation, microcephaly, severe renal anomalies and skeletal abnormalities, including radial ray defects. Autozygosity mapping and exome sequencing identified a novel homozygous frameshift variant in LIG4, c.597_600delTCAG, p.(Gln200LysfsTer33), which segregated in the family. LIG4 is encoded by a single exon and so this frameshift variant is predicted to result in a protein truncated by 678 amino acids. This is the shortest predicted LIG4 protein product reported and correlates with the most severe clinical phenotype described to date. We note the clinical overlap with Fanconi anemia and suggest that LIG4 syndrome is considered in the differential diagnosis of this severe developmental disorder.","variants":[{"Name":"NM_206937.2(LIG4):c.597_600del (p.Gln200fs)","Chromosome":"13","Start":"108210669","Stop":"108210672","ReferenceAlleleVCF":"GCTGA","AlternateAlleleVCF":"G","allel_id":1352461,"rule_based_match":true,"evidence_text":"c.597_600delTCAG, p.(Gln200LysfsTer33)","llm_judgment":"PRESENT","evidence":"c.597_600delTCAG, p.(Gln200LysfsTer33)","abstract_start":793,"abstract_end":831}]}
{"pmid":"23084198","title":"Screening of the RET gene of Vietnamese Hirschsprung patients identifies 2 novel missense mutations.","abstract":"BACKGROUND/PURPOSE: Hirschsprung disease (HSCR; megacolon, congenital aganglionosis) is a congenital disorder characterized by the absence of ganglion cells along variable segments of the gut. Both rare (RV) and common variants of the RET gene are associated with HSCR. The aim of this study is to assess, for the first time, the variation in the RET gene of Vietnamese HSCR patients.\nMETHODS: We used Sanger sequencing to screen the coding sequence of the RET gene of 97 Vietnamese HSCR patients of Southern Chinese ancestry. The healthy population consisted of 250 Southern Chinese individuals with no diagnosis of HSCR.\nRESULTS: We detected 8 heterozygous RVs distributed among 13 patients (13.40%) and that were not present in healthy individuals. Among those variants, there were 2 novel and deleterious (R133C [c.397 C>T]; R144C [c.430 C>T]) missense amino acid substitutions, 2 novel silent variants (P667P [c.2001 A>T]; Y809Y [c.2427 C>T]), and 4 previously described missense substitutions (R114H [c.341 G>A]; V292M [c.874 G>A]; G533S [c.1597 G>A]; R982C [c.2944 C>T]). As expected, the common RET coding sequence variants rs1800858 (A45A [c.135 G>A]) and rs1800861 (L769L [c.2307 T>G]) were highly associated with the disease.\nCONCLUSIONS: The identification of novel deleterious variants together with the fact RET RVs are virtually unique to HSCR patients indicates that the RET gene is a target for mutations among Hirschsprung patients of any population.","variants":[{"Name":"NM_020975.6(RET):c.1597G>A (p.Gly533Ser)","Chromosome":"10","Start":"43112173","Stop":"43112173","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":36228,"rule_based_match":true,"evidence_text":"c.1597 G>A","llm_judgment":"PRESENT","evidence":"c.1597 G>A","abstract_start":1045,"abstract_end":1055},{"Name":"NM_020975.6(RET):c.2001A>T (p.Pro667=)","Chromosome":"10","Start":"43114601","Stop":"43114601","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":139818,"rule_based_match":true,"evidence_text":"P667P [c.2001 A>T]","llm_judgment":"PRESENT","evidence":"P667P [c.2001 A>T]","abstract_start":908,"abstract_end":926},{"Name":"NM_020975.6(RET):c.2944C>T (p.Arg982Cys)","Chromosome":"10","Start":"43124887","Stop":"43124887","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28977,"rule_based_match":true,"evidence_text":"R982C [c.2944 C>T]","llm_judgment":"PRESENT","evidence":"R982C [c.2944 C>T]","abstract_start":1058,"abstract_end":1076},{"Name":"NM_020975.6(RET):c.397C>T (p.Arg133Cys)","Chromosome":"10","Start":"43102401","Stop":"43102401","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":566263,"rule_based_match":true,"evidence_text":"c.397 C>T","llm_judgment":"PRESENT","evidence":"c.397 C>T","abstract_start":817,"abstract_end":826},{"Name":"NM_020975.6(RET):c.430C>T (p.Arg144Cys)","Chromosome":"10","Start":"43102434","Stop":"43102434","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":809886,"rule_based_match":true,"evidence_text":"R144C [c.430 C>T]","llm_judgment":"PRESENT","evidence":"R144C [c.430 C>T]","abstract_start":829,"abstract_end":846},{"Name":"NM_020975.6(RET):c.341G>A (p.Arg114His)","Chromosome":"10","Start":"43102345","Stop":"43102345","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28986,"rule_based_match":true,"evidence_text":"c.341 G>A","llm_judgment":"PRESENT","evidence":"c.341 G>A","abstract_start":1007,"abstract_end":1016},{"Name":"NM_020975.6(RET):c.874G>A (p.Val292Met)","Chromosome":"10","Start":"43106382","Stop":"43106382","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":36221,"rule_based_match":true,"evidence_text":"V292M [c.874 G>A]","llm_judgment":"PRESENT","evidence":"V292M [c.874 G>A]","abstract_start":1019,"abstract_end":1036}]}
{"pmid":"22178352","title":"Morquio A syndrome due to maternal uniparental isodisomy of the telomeric end of chromosome 16.","abstract":"Morquio A syndrome (MPS IVA) is a recessive lysosomal storage disorder (LSD) caused by mutations in the GALNS gene leading to the deficiency of lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Patients show a broad spectrum of phenotypes ranging from classical severe type to mild forms. Classical forms are characterized by severe bone dysplasia and usually normal intelligence. So far, more than 170 unique mutations have been identified in the GALNS gene of MPS IVA patients. We report on a Morquio A patient with a classical phenotype who was found to be homozygous for a missense mutation (c.236 G>A; p.Cys79Tyr) in the GALNS gene. This alteration affects the highly conserved p.Cys79 that is transformed into formylglycine, the catalytic residue of the active site. The mutation was present in the proband's mother, but not in the father, whose paternity was confirmed by microsatellite analysis. In order to test the hypothesis of maternal uniparental disomy (UPD), we investigated the segregation of sixteen microsatellite markers from chromosome 16. The results showed a condition of maternal UPD due to an error in meiosis I. Maternal isodisomy of the 16q24 region led to homozygosity for the GALNS mutant allele, causing the patient's disease. These findings allow to add for the first time the LSD Morquio A syndrome to the list of conditions that can be caused by UPD. The possibility of UPD is relevant when giving genetic counseling to couples since the recurrent risk in future pregnancies is dramatically reduced.","variants":[{"Name":"NM_000512.5(GALNS):c.236G>A (p.Cys79Tyr)","Chromosome":"16","Start":"88842714","Stop":"88842714","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1036391,"rule_based_match":true,"evidence_text":"c.236 G>A; p.Cys79Tyr","llm_judgment":"PRESENT","evidence":"c.236 G>A; p.Cys79Tyr","abstract_start":614,"abstract_end":635}]}
{"pmid":"25910686","title":"Molecular characterization of piebaldism in a Tunisian family.","abstract":"OBJECTIVE: The present study is aimed at performing the molecular characterization of a Tunisian family with piebaldism.\nMETHODS: As the proband and her mother showed a severe phenotype, we first chose to screen exons 10, 11, 12, 13, 16, 17 and 18 of the KIT proto-oncogene by direct sequencing.\nRESULTS: Direct sequencing analysis showed a C to T substitution at 1939 in exon 13 (c.1939C>T) in heterozygous state in the patient and her mother. The mutation was not found in their unaffected family members or normal controls.\nCONCLUSION: Our results provide additional support that mutations in the tyrosine kinase domain of the KIT gene are responsible for the severe form of piebaldism.","variants":[{"Name":"NM_000222.3(KIT):c.1939C>T (p.Leu647Phe)","Chromosome":"4","Start":"54728070","Stop":"54728070","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3859978,"rule_based_match":true,"evidence_text":"c.1939C>T","llm_judgment":"PRESENT","evidence":"c.1939C>T","abstract_start":381,"abstract_end":390}]}
{"pmid":"24484558","title":"Clinical characterization and mutation identification for multiple sulfatase deficiency patients in China","abstract":"OBJECTIVE: Multiple sulfatase deficiency is a rare autosomal recessively inherited lysosomal storage disorder characterized by the accumulation of sulfated lipids and acid mucopolysaccharides. The aim of this study was to explore the clinical manifestations, enzyme activities and SUMF1 gene mutations in two Chinese patients with multiple sulfatase deficiency.\nMETHOD: One boy and one girl from two families were studied. Both patients presented with mental retardation, mild coarse facial features, a neurodegenerative course of disease with loss of sensory and motor function after 2 years of age, ichthyosis and skeletal abnormalities (kyphosis or/and scoliosis). Clinical characteristics indicate multiple sulfatase deficiency.Sulfatases activities in blood leucocytes, plasma or cultured fibroblast of the patients were measured.Genomic DNAs were extracted from peripheral blood leukocytes from the patients and their parents. All SUMF1 gene exons and intron-exon boundaries were amplified by PCR and subjected for direct sequencing.\nRESULT: In case 1, five sulfatases activities of blood leucocytes and four sulfatases of cultured skin-fibroblasts were analyzed.In case 2, three sulfatases activities of blood leucocytes were tested.Significantly decreased sulfatases activities confirmed the diagnosis of multiple sulfatase deficiency.On SUMF1 gene, c.793_794 insATG (p. P265X)/ c.1045C>T (p.R349W) in case 1 and c.451A>G (p.K151E)/ c.1046G>C (p.R349Q) in case 2 were detected, respectively. Three novel mutations c.793_794insAGT, c.1046G>C and c.451A>G were identified.\nCONCLUSIONS: Multiple sulfatase deficiency usually results in multi-organ damage, especially neurologic, skeletal and skin.Sulfatases assay and SUMF1 gene analysis are necessary for the diagnosis. Two Chinese cases with multiple sulfatase deficiency were firstly reported. Three novel mutations were found.It should be considered that the mutation profile of SUMF1 gene in Chinese patients is different from other populations.","variants":[{"Name":"NM_182760.4(SUMF1):c.451A>G (p.Lys151Glu)","Chromosome":"3","Start":"4449334","Stop":"4449334","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1403998,"rule_based_match":true,"evidence_text":"c.451A>G (p.K151E)","llm_judgment":"PRESENT","evidence":"c.451A>G (p.K151E)","abstract_start":1421,"abstract_end":1439}]}
{"pmid":"18477710","title":"Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1).","abstract":"BACKGROUND: The three-nucleotide deletion, triangle upGAG (within the gene TOR1A), is the only proven cause of childhood-onset dystonia (DYT1). A potentially pathogenic role of additional sequence changes within TOR1A has not been conclusively shown.\nMETHODS: DNA sequencing of exon 5 of TOR1A in a patient with DYT1.\nRESULTS: Detection of sequence change c.863G>A in exon 5 of TOR1A in the patient. The G>A transition results in an exchange of an arginine for glutamine (p.Arg288Gln) in subdomain alpha5 of TOR1A. Several findings point to a potentially pathogenic role of the sequence change in the patient: The base change is absent in 1000 control chromosomes; an Arg at position 288 of TOR1A has been conserved throughout vertebrate evolution, indicating an important role of Arg288 in TOR1A function; functional studies demonstrate enlarged perinuclear space in HEK293 cells overexpressing TOR1A with the p.Arg288Gln mutation. The same morphological changes are observed in cells overexpressing the common triangle upGAG TOR1A mutation but not in cells overexpressing wild-type TOR1A.\nCONCLUSIONS: The sequence change described here may be a novel pathogenic mutation of TOR1A in DYT1.","variants":[{"Name":"NM_000113.3(TOR1A):c.863G>A (p.Arg288Gln)","Chromosome":"9","Start":"129814108","Stop":"129814108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":172165,"rule_based_match":true,"evidence_text":"c.863G>A","llm_judgment":"PRESENT","evidence":"c.863G>A","abstract_start":356,"abstract_end":364}]}
{"pmid":"30078639","title":"Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.","abstract":"BACKGROUND: Mutations in PEX16 cause peroxisome biogenesis disorder (PBD). Zellweger syndrome characterized by neurological dysfunction, dysmorphic features, liver disease and early death represents the severe end of this clinical spectrum. Here we discuss the diagnostic challenge of atypical PEX16 related PBD in 3 patients from highly inbred kindred and describe the role of specific metabolites analyses, fibroblasts studies, whole-exome sequencing (WES) and metabolomics profiling to establish the diagnosis.\nMETHODS AND PATIENTS: The proband is a 12-year-old male born to consanguineous parents. Despite normal development in the first year, regression and progressive spastic diplegia, poor coordination and dysarthria occurred thereafter. Patient 2 (3-year old female) and Patient 3 (19-month old female) shared similar clinical course with the proband. Biochemical studies on plasma and fibroblasts, WES and global metabolomics analyses were performed.\nRESULTS: Very-long-chain fatty acids analysis showed subtle elevations in C26 and C26/C22. Global Metabolomics-Assisted Pathway profiling was not remarkable. Immunocytochemical investigations on fibroblasts revealed fewer catalase and PMP70-containing particles indicating aberrant peroxisomal assembly. Complementation studies were inconclusive. WES revealed a novel homozygous variant in PEX16 (c.859C>T). The biochemical profiles of Patient 2 and Patient 3 were similar to the proband and the same genotype was confirmed.\nCONCLUSION: This paper highlights the diagnostic challenge of PEX16 patients due to the widely variable clinical and biochemical phenotypes. It also emphasizes the important roles of combined biochemical assays with next generation sequencing techniques in reaching diagnosis in the context of atypical clinical presentations, subtle biomarker abnormalities and consanguinity.","variants":[{"Name":"NM_004813.4(PEX16):c.859C>T (p.Arg287Cys)","Chromosome":"11","Start":"45913847","Stop":"45913847","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":552151,"rule_based_match":true,"evidence_text":"c.859C>T","llm_judgment":"PRESENT","evidence":"c.859C>T","abstract_start":1359,"abstract_end":1367}]}
{"pmid":"38459354","title":"PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss.","abstract":"Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.","variants":[{"Name":"NM_177531.6(PKHD1L1):c.385G>A (p.Gly129Ser)","Chromosome":"8","Start":"109382539","Stop":"109382539","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3380118,"rule_based_match":false,"evidence_text":"p.[(Gly129Ser)]","llm_judgment":"PRESENT","evidence":"p.[(Gly129Ser)]","abstract_start":610,"abstract_end":625},{"Name":"NM_177531.6(PKHD1L1):c.1813G>A (p.Gly605Arg)","Chromosome":"8","Start":"109406478","Stop":"109406478","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3380122,"rule_based_match":true,"evidence_text":"c.1813G>A p.(Gly605Arg)","llm_judgment":"PRESENT","evidence":"c.1813G>A p.(Gly605Arg)","abstract_start":1644,"abstract_end":1667}]}
{"pmid":"18616530","title":"Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and DFNB7/11.","abstract":"Hearing loss is the most frequent sensorineural disorder affecting 1 in 1000 newborns. In more than half of these babies, the hearing loss is inherited. Hereditary hearing loss is a very heterogeneous trait with about 100 gene localizations and 44 gene identifications for non-syndromic hearing loss. Transmembrane channel-like gene 1 (TMC1) has been identified as the disease-causing gene for autosomal dominant and autosomal recessive non-syndromic hearing loss at the DFNA36 and DFNB7/11 loci, respectively. To date, 2 dominant and 18 recessive TMC1 mutations have been reported as the cause of hearing loss in 34 families. In this report, we describe linkage to DFNA36 and DFNB7/11 in 1 family with dominant and 10 families with recessive non-syndromic sensorineural hearing loss. In addition, mutation analysis of TMC1 was performed in 51 familial Turkish patients with autosomal recessive hearing loss. TMC1 mutations were identified in seven of the families segregating recessive hearing loss. The pathogenic variants we found included two known mutations, c.100C>T and c.1165C>T, and four new mutations, c.2350C>T, c.776+1G>A, c.767delT and c.1166G>A. The absence of TMC1 mutations in the remaining six linked families implies the presence of mutations outside the coding region of this gene or alternatively at least one additional deafness-causing gene in this region. The analysis of copy number variations in TMC1 as well as DNA sequencing of 15 additional candidate genes did not reveal any proven pathogenic changes, leaving both hypotheses open.","variants":[{"Name":"NM_138691.3(TMC1):c.1165C>T (p.Arg389Ter)","Chromosome":"9","Start":"72789258","Stop":"72789258","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":57020,"rule_based_match":true,"evidence_text":"c.1165C>T","llm_judgment":"PRESENT","evidence":"c.1165C>T","abstract_start":1077,"abstract_end":1086},{"Name":"NM_138691.3(TMC1):c.1166G>A (p.Arg389Gln)","Chromosome":"9","Start":"72789259","Stop":"72789259","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2901309,"rule_based_match":true,"evidence_text":"c.1166G>A","llm_judgment":"PRESENT","evidence":"c.1166G>A","abstract_start":1149,"abstract_end":1158}]}
{"pmid":"27789399","title":"Generation of Mucopolysaccharidosis type II (MPS II) human induced pluripotent stem cell (iPSC) line from a 1-year-old male with pathogenic IDS mutation.","abstract":"Peripheral blood was collected from a 1-year-old male patient with an X-linked recessive mutation of Iduronate 2-sulfatase (IDS) gene (NM_000202.7(IDS):c.85C>T) causing MPS II (OMIM 309900). Peripheral blood mononuclear cells (PBMCs) were reprogrammed by lentiviral delivery of a self-silencing hOKSM polycistronic vector. The pluripotency of the iPSC line was confirmed by the expression of pluripotency-associated markers and in vitro spontaneous differentiation towards the 3 germ layers. The iPSC line showed normal karyotype. The cell line offers a good platform to study MPS II pathophysiology, for drug testing, early biomarker discovery and gene therapy studies.","variants":[{"Name":"NM_000202.8(IDS):c.85C>T (p.Gln29Ter)","Chromosome":"X","Start":"149505053","Stop":"149505053","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3414453,"rule_based_match":true,"evidence_text":"NM_000202.7(IDS):c.85C>T","llm_judgment":"PRESENT","evidence":"NM_000202.7(IDS):c.85C>T","abstract_start":135,"abstract_end":159}]}
{"pmid":"28644047","title":"Mutational analysis of GALT gene in Greek patients with galactosaemia: identification of two novel mutations and clinical evaluation.","abstract":"Classical galactosaemia is an inborn error of metabolism due to the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). The aim of the study was to identify the underlying mutations in Greek patients with GALT deficiency and evaluate their psychomotor and speech development. Patients with GALT deficiency (n = 17) were picked up through neonatal screening. Mutational analysis was conducted via Sanger sequencing, while in silico analysis was used in the cases of novel missense mutations. Psychomotor speech development tests were utilized for the clinical evaluation of the patients. Eleven different mutations in the GALT gene were detected in the patient cohort, including two novel ones. The most frequent mutation was p.Q188R (c.563 A > G). As for the novel mutations, p.M298I (c.894 G > A) was identified in four out of 32 independent alleles, while p.P115S (c.343 C > T) was identified once. Psychomotor evaluation revealed that most of the patients were found in the borderline area (Peabody test), while only two had speech delay problems. The WISK test revealed three patients at borderline limits and two were at lower than normal limits. The mutational spectrum of the GALT gene in Greek patients is presented for the first time. The mutation p.Q188R is the most frequent among Greek patients. Two novel mutations were identified and their potential pathogenicity was estimated. Regarding the phenotypic characteristics, psychomotor disturbances and speech delay were mainly observed among GALT-deficient patients.","variants":[{"Name":"NM_000155.4(GALT):c.894G>A (p.Met298Ile)","Chromosome":"9","Start":"34649071","Stop":"34649071","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1471671,"rule_based_match":true,"evidence_text":"c.894 G > A","llm_judgment":"PRESENT","evidence":"c.894 G > A","abstract_start":808,"abstract_end":819}]}
{"pmid":"28371533","title":"Preliminary screening of mutations in the glucokinase gene of Chinese patients with gestational diabetes.","abstract":"AIMS/INTRODUCTION: Mutations in the glucokinase gene (GCK) are a pathogenetic cause of maturity-onset diabetes of the young. Studies have found that female patients with GCK maturity-onset diabetes of the young often present with gestational diabetes during pregnancy. Our aim was to preliminarily assess the prevalence of mutations in the glucokinase gene in Chinese women with gestational diabetes.\nMATERIALS AND METHODS: Chinese gestational diabetes patients who underwent a 100-g oral glucose tolerance test in Peking Union Medical College Hospital from July 2005 to May 2008 were retrospectively analyzed. Participants were selected for direct sequencing of the GCK gene if they met the following criteria: (i) fasting plasma glucose between 5.5 and 10.0 mmol/L; and (ii) a small increment (<4.6 mmol/L) during a 2-h oral glucose tolerance test.\nRESULTS: Of the 501 participants with gestational diabetes, there were 38 participants who met the criteria for GCK analysis. In the 29 participants whose deoxyribonucleic acid samples were available, two mutations in coding regions were detected, c.626 C>T (p.T209M, NP_000153.1) mutation in exon 6 and c.824 G>A (p.R275H, NP_000153.1; rs767565869) mutation in exon 7. According to our results, the minimum prevalence of GCK mutations in Chinese women with gestational diabetes was estimated to be 0.4%, and the minimum prevalence of GCK maturity-onset diabetes of the young in the Chinese population might be one in 2,000.\nCONCLUSIONS: Our screening criteria allowed for the identification of glucokinase-deficient patients who were diagnosed with gestational diabetes, and these mutations in the GCK gene were not common in Chinese women with gestational diabetes.","variants":[{"Name":"NM_000162.5(GCK):c.824G>A (p.Arg275His)","Chromosome":"7","Start":"44147689","Stop":"44147689","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":425755,"rule_based_match":true,"evidence_text":"c.824 G>A (p.R275H, NP_000153.1; rs767565869)","llm_judgment":"PRESENT","evidence":"c.824 G>A (p.R275H, NP_000153.1; rs767565869)","abstract_start":1155,"abstract_end":1200},{"Name":"NM_000162.5(GCK):c.626C>T (p.Thr209Met)","Chromosome":"7","Start":"44149813","Stop":"44149813","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":793235,"rule_based_match":true,"evidence_text":"c.626 C>T (p.T209M, NP_000153.1)","llm_judgment":"PRESENT","evidence":"c.626 C>T (p.T209M, NP_000153.1)","abstract_start":1099,"abstract_end":1131}]}
{"pmid":"30617623","title":"A Novel Missense LIG4 Mutation in a Patient With a Phenotype Mimicking Behçet's Disease.","abstract":"DNA ligase IV (LIG4) syndrome is a rare autosomal recessive disorder, manifesting with variable immune deficiency, growth failure, predisposition to malignancy, and cellular sensitivity to ionizing radiation. The facial features are subtle and variable, as well. Herein, we described an 18-year-old boy, the first child of consanguineous parents who presented with Behçet's disease (BD)-like phenotype, developmental delay, and dysembryoplastic neuroepithelial tumor (DNET). Whole-exome sequencing revealed a homozygous p.Arg871His (c.2612G > A) mutation in LIG4. To date, 35 cases have been reported with LIG4 syndrome. Peripheral blood mononuclear cells of the patient displayed notable sensitivity to ionizing radiation. Flow cytometric annexin V-propidium iodide (PI) and eFluor670 proliferation assays showed accelerated radiation-induced apoptosis and diminished proliferation, respectively. To our knowledge, this is the first case presenting with a BD-like phenotype. This case provides further evidence that rare monogenic defects could be the underlying cause of atypical presentations of some well-described disorders. Moreover, this clinical report further expands the phenotypical spectrum of LIG4 deficiency.","variants":[{"Name":"NM_206937.2(LIG4):c.2612G>A (p.Arg871His)","Chromosome":"13","Start":"108208657","Stop":"108208657","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2805084,"rule_based_match":true,"evidence_text":"c.2612G > A","llm_judgment":"PRESENT","evidence":"c.2612G > A","abstract_start":533,"abstract_end":544}]}
{"pmid":"27129361","title":"NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects.","abstract":"OBJECTIVE: Nicotinamide nucleotide transhydrogenase (NNT), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify NNT mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages.\nMETHODS: Sanger or massive parallel sequencing of NNT and patient monitoring.\nRESULTS: Homozygous or compound heterozygous NNT mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G>A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8-18 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed.\nCONCLUSIONS: NNT should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.","variants":[{"Name":"NM_182977.3(NNT):c.385C>T (p.Arg129Ter)","Chromosome":"5","Start":"43615851","Stop":"43615851","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":260550,"rule_based_match":false,"evidence_text":"c.385C>T (p.Arg129Ter)","llm_judgment":"PRESENT","evidence":"c.385C>T (p.Arg129Ter)","abstract_start":null,"abstract_end":null}]}
{"pmid":"24263182","title":"The SLCO1B1 c.521T>C polymorphism is associated with dose decrease or switching during statin therapy in the Rotterdam Study.","abstract":"OBJECTIVE: The SLCO1B1 c.521T>C polymorphism is associated with statin plasma levels and simvastatin-induced adverse drug reactions. We studied whether the c.521T>C polymorphism is associated with dose decreases or switches to other cholesterol-lowering drugs during simvastatin and atorvastatin therapy, because these events are indicators of adverse drug reactions.\nMATERIALS AND METHODS: We identified 1939 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations were studied using Cox proportional hazards analysis. Meta-analysis was performed with data from the Utrecht Cardiovascular Pharmacogenetics study.\nRESULTS: Simvastatin users with the c.521 CC genotype had a significantly higher risk of a dose decrease or switch than users with the TT genotype [hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.05-2.88]. Female sex, age below 70 years, and low starting dose were risk factors. In atorvastatin users with starting dose of more than 20 mg, the risk of a dose decrease or switch was higher in users carrying a C allele than in users with the TT genotype (HR 3.26, 95% CI 1.47-7.25). In the meta-analysis the association in simvastatin users remained, with a significantly higher risk of a dose decrease or switch in simvastatin users with two minor alleles (HR 1.69, 95% CI 1.05-2.73). For atorvastatin users no significant association was found.\nCONCLUSION: In simvastatin users in the Rotterdam Study, we demonstrated an association between the c.521T>C polymorphism and dose decrease or switching, as indicators of adverse drug reactions, and provided risk factors for this association. For atorvastatin, an association was found in users with a starting dose of more than 20 mg.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":true,"evidence_text":"c.521T>C","llm_judgment":"PRESENT","evidence":"c.521T>C","abstract_start":23,"abstract_end":31}]}
{"pmid":"28735299","title":"Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix.","abstract":"BACKGROUND: The laminin alpha 5 gene (<i>LAMA5</i>) plays a master role in the maintenance and function of the extracellular matrix (ECM) in mammalian tissues, which is critical in developmental patterning, stem cell niches, cancer and genetic diseases. Its mutations have never been reported in human disease so far. The aim of this study was to associate the first mutation in <i>LAMA5</i> gene to a novel multisystem syndrome.\nMETHODS: A detailed characterisation of a three-generation family, including clinical, biochemical, instrumental and morphological analysis, together with genetics and expression (WES and RNAseq) studies, was performed.\nRESULTS: The heterozygous <i>LAMA5</i> mutation c.9418G>A (p.V3140M) was associated with skin anomalies, impaired scarring, night blindness, muscle weakness, osteoarthritis, joint and internal organs ligaments laxity, malabsorption syndrome and hypothyroidism. We demonstrated that the mutation alters the amount of LAMA5 peptides likely derived from protein cleavage and perturbs the activation of the epithelial-mesenchymal signalling, producing an unbalanced expression of Sonic hedgehog and <i>GLI1</i>, which are upregulated in cells from affected individuals, and of ECM proteins (COL1A1, MMP1 and MMP3), which are strongly inhibited. Studies carried out using human skin biopsies showed alteration of dermal papilla with a reduction of the germinative layer and an early arrest of hair follicle downgrowth. The knock-in mouse model, generated in our laboratory, shows similar changes in the tissues studied so far.\nCONCLUSIONS: This is the first report of a disease phenotype associated with <i>LAMA5</i> mutation in humans.","variants":[{"Name":"NM_005560.6(LAMA5):c.9418G>A (p.Val3140Met)","Chromosome":"20","Start":"62312259","Stop":"62312259","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":610997,"rule_based_match":true,"evidence_text":"c.9418G>A (p.V3140M)","llm_judgment":"PRESENT","evidence":"c.9418G>A (p.V3140M)","abstract_start":698,"abstract_end":718}]}
{"pmid":"20549516","title":"An ancient autosomal haplotype bearing a rare achromatopsia-causing founder mutation is shared among Arab Muslims and Oriental Jews.","abstract":"Numerous cultural aspects, mainly based on historical records, suggest a common origin of the Middle-Eastern Arab Muslim and Jewish populations. This is supported, to some extent, by Y-chromosome haplogroup analysis of Middle-Eastern and European samples. Up to date, no genomic regions that are shared among Arab Muslim and Jewish chromosomes and are unique to these populations have been reported. Here, we report of a rare achromatopsia-causing CNGA3 mutation (c.1585G>A) presents in both Arab Muslim and Oriental Jewish patients. A haplotype analysis of c.1585G>A-bearing chromosomes from Middle Eastern and European origins revealed a shared Muslim-Jewish haplotype, which is different from those detected in European patients, indicating a recurrent mutation stratified by a Jewish-Muslim founder effect. Comprehensive whole-genome haplotype analysis using 250 K single nucleotide polymorphism arrays revealed a large homozygous region of ~11 Mbp shared by both Arab Muslim and Oriental Jewish chromosomes. A subsequent microsatellite analysis of a 21.5 cM interval including CNGA3 and the adjacent chromosome 2 centromere revealed a unique and extremely rare haplotype associated with the c.1585G>A mutation. The age of the shared c.1585G>A mutation was calculated using the microsatellite genotyping data to be about 200 generations ago. A similar analysis of mutation age based on the Arab Muslim data alone showed that the mutation was unlikely to be the product of a recent gene flow event. The data present here demonstrate a large (11 Mbp) genomic region that is likely to originate from an ancient common ancestor of Middle-Eastern Arab Muslims and Jews who lived approximately 5,000 years ago.","variants":[{"Name":"NM_001298.3(CNGA3):c.1585G>A (p.Val529Met)","Chromosome":"2","Start":"98396755","Stop":"98396755","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24519,"rule_based_match":true,"evidence_text":"c.1585G>A","llm_judgment":"PRESENT","evidence":"c.1585G>A","abstract_start":464,"abstract_end":473}]}
{"pmid":"26825529","title":"Rare Variants in the Complement Factor H-Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy.","abstract":"A recent genome-wide association study of IgA nephropathy (IgAN) identified 1q32, which contains multiple complement regulatory genes, including the complement factor H (CFH) gene and the complement factor H-related (CFHRs) genes, as an IgAN susceptibility locus. Abnormal complement activation caused by a mutation in CFHR5 was shown to cause CFHR5 nephropathy, which shares many characteristics with IgAN. To explore the genetic effect of variants in CFHR5 on IgAN susceptibility, we recruited 500 patients with IgAN and 576 healthy controls for genetic analysis. We sequenced all exons and their intronic flanking regions as well as the untranslated regions of CFHR5 and compared the frequencies of identified variants using the sequence kernel association test. We identified 32 variants in CFHR5, including 28 rare and four common variants. The distribution of rare variants in CFHR5 in patients with IgAN differed significantly from that in controls (P=0.002). Among the rare variants, in silico programs predicted nine as potential functional variants, which we then assessed in functional assays. Compared with wild-type CFHR5, three recombinant CFHR5 proteins, CFHR5-M (c.508G>A/p.Val170Met), CFHR5-S (c.533A>G/p.Asn178Ser), and CFHR5-D (c.822A>T/p.Glu274Asp), showed significantly higher C3b binding capacity (CFHR5-M: 109.67%±3.54%; P=0.02; CFHR5-S: 174.27%±9.78%; P<0.001; CFHR5-D: 127.25%±1.75%; P<0.001), whereas another recombinant CFHR5 (c.776T>A/p.Leu259Termination) showed less C3b binding (56.89%±0.57%; P<0.001). Our study found that rare variants in CFHR5 may contribute to the genetic susceptibility to IgAN, which suggests that CFHR5 is an IgAN susceptibility gene.","variants":[{"Name":"NM_030787.4(CFHR5):c.508G>A (p.Val170Met)","Chromosome":"1","Start":"196994157","Stop":"196994157","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":863133,"rule_based_match":true,"evidence_text":"c.508G>A/p.Val170Met","llm_judgment":"PRESENT","evidence":"c.508G>A/p.Val170Met","abstract_start":1179,"abstract_end":1199}]}
{"pmid":"20830524","title":"Long-term follow-up results in enzyme replacement therapy for Pompe disease: a case report.","abstract":"Pompe disease (PD) is a metabolic myopathy caused by a deficiency of acid-alpha glucosidase (GAA), a lysosomal enzyme that cleaves glycogen. The classic infantile-onset form is characterised by severe hypotonia and cardiomyopathy. Untreated patients usually die within the first year of life due to cardiorespiratory failure. Several studies involving patients with infantile-onset PD have shown that enzyme replacement therapy (ERT) with alglucosidase alfa, recombinant human GAA (rhGAA), significantly prolongs survival, decreases cardiomegaly, and improves cardiac function and conduction abnormalities. However, the efficacy on motor, cognitive and social milestones appears to be more related to the condition of the patient before the start of treatment. To date, the sample of early diagnosed and treated patients is small and the length of follow-up is still limited. We report the results of a long-term follow-up of one patient presenting severe bradycardia and cardiomyopathy at birth, diagnosed in the third day of life and successfully treated by ERT. Serum muscle enzymes at diagnosis were AST 200 U/L, ALT 99 U/L and CPK 731 U/L (n.v. 0-295); the molecular study identified the homozygous missense mutation c.1933 G> A p.Asp645Asn (GAA exon 14). Left Ventricular Mass Index (LVMI) at baseline was 171 g/m(2) (Z-score = 4.3) and decreased to normal values since the 3-month follow-up. A muscle biopsy performed at 18 months after the start of therapy, showed only a low degree of muscle involvement. To our knowledge, this is the longest ERT treatment follow-up in a symptomatic neonatal patient with Pompe disease.","variants":[{"Name":"NM_000152.5(GAA):c.1933G>A (p.Asp645Asn)","Chromosome":"17","Start":"80112920","Stop":"80112920","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187010,"rule_based_match":true,"evidence_text":"c.1933 G> A p.Asp645Asn","llm_judgment":"PRESENT","evidence":"c.1933 G> A p.Asp645Asn","abstract_start":1222,"abstract_end":1245}]}
{"pmid":"16897190","title":"Functional analysis of PKHD1 splicing in autosomal recessive polycystic kidney disease.","abstract":"Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene on chromosome 6p12. The longest continuous open reading frame comprises 66 exons encoding a novel 4,074 aa multidomain integral membrane protein (polyductin/fibrocystin) of unknown function. Various alternatively spliced transcripts may additionally result in different isoproteins. Overall, the large size of PKHD1, its complex pattern of splicing, multiple allelism and lack of knowledge of the encoded protein's/proteins' functions pose significant challenges to DNA-based diagnostic testing. Nucleotide substitutions, particularly if residing in regulatory elements or introns outside the splice consensus sites, are often difficult to assess without further functional analyses and cannot be unambiguously classified as disease-associated. Investigations on the transcript level, however, are hampered as PKHD1 is not widely expressed in blood lymphocytes. We thus determined the functional significance of the novel splice site mutation c.53-3C>A in intron 2 by RNA analyses by minigene-construction. The mutant allele was shown to cause skipping of exon 3. Thus, given the minigene results together with 400 control chromosomes negative for this change, segregation of the mutation with the phenotype, and a significant lowering of the strength of the splice site by bioinformatics, the mutant allele is most likely pathogenic. To the best of our knowledge, this is the first study that defines the consequences of a PKHD1 splice mutation and underlines the relevance of functional analyses in determining the pathogenicity of changes of unknown significance.","variants":[{"Name":"NM_138694.4(PKHD1):c.53-3C>A","Chromosome":"6","Start":"52083258","Stop":"52083258","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2904819,"rule_based_match":true,"evidence_text":"c.53-3C>A","llm_judgment":"PRESENT","evidence":"c.53-3C>A","abstract_start":1080,"abstract_end":1089}]}
{"pmid":"34399712","title":"A novel mutation in the PRPH2 gene in a Chinese pedigree with retinitis pigmentosa and angle-closure glaucoma.","abstract":"BACKGROUND: Retinitis pigmentosa (RP) is a rare, progressive, and hereditary disorder that leads to the progressive loss of vision and visual field, and in some cases blindness. The specific relationship between RP and glaucoma has been debated for decades.\nMETHODS: In this study, we examined a Han RP family with concomitant angle-closure glaucoma (ACG), performed an inductive analysis of their clinical features and assistant results, and applied whole-exome sequencing (WES) technology for a molecular diagnosis.\nRESULTS: A novel transversion mutation (c.626 T > A) was identified in the peripherin-2 (PRPH2) gene in the proband, resulting in the substitution of Valine to aspartic acid in codon 209. A full ophthalmic examination showed that the proband with the c.626 T > A mutation had a typical RP manifestation, with close angles; however, the proband's elder brother, who lacked the novel mutation, had a normal fundus and open angles.\nCONCLUSION: Our results extend the genetic mutation spectrum of PRPH2 in RP, and provide evidence to support a genetic correlation between RP and ACG.","variants":[{"Name":"NM_000322.5(PRPH2):c.626T>A (p.Val209Asp)","Chromosome":"6","Start":"42704567","Stop":"42704567","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1055592,"rule_based_match":true,"evidence_text":"c.626 T > A","llm_judgment":"PRESENT","evidence":"c.626 T > A","abstract_start":558,"abstract_end":569}]}
{"pmid":"27203561","title":"LEBER CONGENITAL AMAUROSIS WITH LARGE RETINAL PIGMENT CLUMPS CAUSED BY COMPOUND HETEROZYGOUS MUTATIONS IN KCNJ13.","abstract":"PURPOSE: To describe a patient with mutations in KCNJ13 presenting particular clinical features.\nMETHODS: Standard ophthalmic examination, fundus autofluorescence, spectral domain optical coherence tomography, full-field electroretinography. The 3 exons of KCNJ13 were polymerase chain reaction amplified and Sanger sequenced.\nPATIENTS: A 31-year-old man with Leber congenital amaurosis.\nRESULTS: Patient had nystagmus since childhood, best-corrected visual acuity limited to 20/400 OD and 20/200 OS, and had cataracts extracted in both eyes. There were clumpy pigment deposits mostly in macular area, causing an uneven line of retinal pigment epithelium on spectral domain optical coherence tomography. In retinal parts devoid of pigment deposits around the optic disk and in periphery, retinal thickness was increased and hyperreflective formations were present either in the inner nuclear layer or in the outer nuclear layer. The patient was compound heterozygous for new mutations in KCNJ13 which encodes the Kir 7.1 potassium channel, c.314G>T (p.Ser105Ile) in exon 2 and c.655C>T (p.Gln219*) in exon 3. Both mutations were absent from databases.\nCONCLUSION: KCNJ13 mutations are responsible for early-onset retinal dystrophy, featuring remarkable clumpy pigment deposits at the level of the retinal pigment epithelium, suggesting dysfunction and disorganization of this tissue. Parts of the retina remain relatively preserved anatomically but are increased in thickness. This distinct fundus appearance should help in identifying the \"KCNJ13 retinal dystrophy\" to orient the molecular diagnosis.","variants":[{"Name":"NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter)","Chromosome":"2","Start":"232768619","Stop":"232768619","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":966579,"rule_based_match":true,"evidence_text":"c.655C>T (p.Gln219*)","llm_judgment":"PRESENT","evidence":"c.655C>T (p.Gln219*)","abstract_start":1077,"abstract_end":1097},{"Name":"NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile)","Chromosome":"2","Start":"232771049","Stop":"232771049","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":966581,"rule_based_match":true,"evidence_text":"c.314G>T (p.Ser105Ile)","llm_judgment":"PRESENT","evidence":"c.314G>T (p.Ser105Ile)","abstract_start":1040,"abstract_end":1062}]}
{"pmid":"17454734","title":"Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients.","abstract":"Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an inborn error of purine metabolism responsible for Lesch-Nyhan Disease (LND) and its partial phenotypes, HPRT-related hyperuricemia with neurologic dysfunction (HRND) and hyperuricemia alone. We report here the recognition of six Argentine patients, two with LND and four with HRND. All patients presented elevated excretion of uric acid, hypoxanthine, and xanthine and decreased HPRT enzyme activities <1 nmol/h/mg Hb. The molecular analysis demonstrated in the two LND patients a novel inherited transition mutation, c.203T >C (L68P), in one subject and a germline transition mutation, c.209G >A (G70E), in the other. In the HRND patients a novel transversion mutation, c.584 A >C (Y195S), was found in three related patients and an inherited transition mutation, c.143G >A (R48H), in the fourth subject.","variants":[{"Name":"NM_000194.2(HPRT1):c.209G>A (p.Gly70Glu)","Chromosome":"X","Start":"134475255","Stop":"134475255","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25083,"rule_based_match":true,"evidence_text":"c.209G >A (G70E)","llm_judgment":"PRESENT","evidence":"c.209G >A (G70E)","abstract_start":658,"abstract_end":674},{"Name":"NM_000194.3(HPRT1):c.143G>A (p.Arg48His)","Chromosome":"X","Start":"134475189","Stop":"134475189","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38940,"rule_based_match":true,"evidence_text":"c.143G >A (R48H)","llm_judgment":"PRESENT","evidence":"c.143G >A (R48H)","abstract_start":836,"abstract_end":852}]}
{"pmid":"26235987","title":"Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development.","abstract":"Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.","variants":[{"Name":"NM_001080508.3(TBX18):c.1010del (p.Gly337fs)","Chromosome":"6","Start":"84738586","Stop":"84738586","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":205045,"rule_based_match":true,"evidence_text":"c.1010delG","llm_judgment":"PRESENT","evidence":"c.1010delG","abstract_start":525,"abstract_end":535},{"Name":"NM_001080508.3(TBX18):c.1570C>T (p.His524Tyr)","Chromosome":"6","Start":"84736939","Stop":"84736939","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205046,"rule_based_match":true,"evidence_text":"c.1570C>T","llm_judgment":"PRESENT","evidence":"c.1570C>T","abstract_start":739,"abstract_end":748},{"Name":"NM_001080508.3(TBX18):c.487A>G (p.Lys163Glu)","Chromosome":"6","Start":"84762554","Stop":"84762554","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":205047,"rule_based_match":true,"evidence_text":"c.487A>G","llm_judgment":"PRESENT","evidence":"c.487A>G","abstract_start":753,"abstract_end":761}]}
{"pmid":"23562786","title":"A novel COMP mutation in a Chinese patient with pseudoachondroplasia.","abstract":"A 2.75-year-old Chinese boy presented with typical clinical features of pseudoachondroplasia, including disproportionate short-limb short stature, brachydactyly, genu varus and waddling gait. Radiologically, tubular bones were short with widened metaphyses, irregular and small epiphyses; anterior tonguing or beaking of vertebral bodies were characteristic. DNA sequencing analysis of the COMP gene revealed a heterozygous mutation (c.1511G>A, p.Cys504Tyr) in the patient but his parents were unaffected without this genetic change. The missense mutation (c.1511G>A) was not found in 100 healthy controls and has not been reported previously. Our findings expand the spectrum of known mutations in COMP leading to pseudoachondroplasia.","variants":[{"Name":"NM_000095.3(COMP):c.1511G>A (p.Cys504Tyr)","Chromosome":"19","Start":"18785830","Stop":"18785830","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1868415,"rule_based_match":true,"evidence_text":"c.1511G>A (p.Cys504Tyr)","llm_judgment":"PRESENT","evidence":"p.Cys504Tyr","abstract_start":445,"abstract_end":456}]}
{"pmid":"30402232","title":"Ataxia-telangiectasia with a novel ATM gene mutation and Burkitt leukemia: A case report.","abstract":"Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive disorder that involves multiple systems and is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent respiratory infections, and a tendency to develop lymphoid malignancies. A-T is caused by mutations in the ATM gene, with >1,000 mutations reported to date and gradually increasing in number. Patients with A-T have an increased incidence of cancers. The aim of the present study was to retrospectively review the case of a patient who presented at the age of 5 years with cerebellar ataxia without telangiectasia, and was diagnosed with Burkitt leukemia by bone marrow biopsy and molecular testing at the age of 7 years at the Xiangya Hospital of Central South University (Changsha, China). The patient received chemotherapy with the pediatric CCCG-BNHL-2015 regimen (R4 group) and achieved a complete remission after 2 courses. However, recurrent respiratory infections and thrombosis occurred during chemotherapy. The diagnosis of A-T was confirmed by uncovering two variants of the ATM gene, including c.742C>T (p.R248X; rs730881336) in exon 7 and c.6067-c.6068 ins GAGGGAAGAT in exon 41 by whole-exome sequencing. Unfortunately, the patient's parents refused follow-up treatment and he succumbed to recurrent severe infections 4 months after the diagnosis of Burkitt leukemia. The diagnosis of A-T may be challenging, as its phenotype can be incomplete early in the course of the disease. Detailed medical history, characteristic clinical manifestations and increasingly developed exome sequencing techniques may be helpful in diagnosing this rare disease. Management should be based on multidisciplinary guidance and other treatment options must be investigated in the future.","variants":[{"Name":"NM_000051.4(ATM):c.742C>T (p.Arg248Ter)","Chromosome":"11","Start":"108244867","Stop":"108244867","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":180391,"rule_based_match":true,"evidence_text":"c.742C>T (p.R248X; rs730881336)","llm_judgment":"PRESENT","evidence":"c.742C>T (p.R248X; rs730881336)","abstract_start":1148,"abstract_end":1179}]}
{"pmid":"32943488","title":"Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.","abstract":"OBJECTIVE: To analyze the clinical characteristics of patients with hydrocephalus secondary to cobalamin C (cblC) deficiency and to discuss the optimal strategies for assessing and treating such patients by performing clinical and laboratory studies in 70 patients.\nMETHODS: A total of 1,211 patients were clinically diagnosed with methylmalonic acidemia (MMA) from 1998 to 2019. Among them, cblC deficiency was confirmed in 70 patients with hydrocephalus by brain imaging and biochemical and genetic analysis.\nRESULTS: Of the 70 patients, 67 (95.7%) had early-onset MMA and homocystinuria. The patients typically had high blood propionylcarnitine and total homocysteine, low methionine, and methylmalonic aciduria. Signs of intracranial hypertension were relatively rare. We measured ventricular dilatation early in the disease by cranial ultrasound and MRI and/or CT. Eighteen different <i>MMACHC</i> mutations, including 4 novel mutations (c.427C>T, c.568insT, c.599G>A, and c.615C>A), were identified biallelically in all 70 patients. c.609G>A was the most frequent mutation, followed by c.658_660del, c.217C>T, and c.567dupT. Three cases were diagnosed by postmortem study. Metabolic therapy, including cobalamin injections supplemented with oral l-carnitine and betaine, was administered in the remaining 67 cases. A ventriculoperitoneal shunt was performed in 36 cases. During the follow-up, psychomotor development, nystagmus, impaired vision, and sunset eyes improved gradually.\nCONCLUSION: Hydrocephalus is a severe condition with several different causes. In this study, ventriculomegaly was found in 70 patients with cblC deficiency. Early diagnosis, etiologic treatment, and prompt surgical intervention are crucial to improve the prognosis of patients.","variants":[{"Name":"NM_015506.3(MMACHC):c.658_660del (p.Lys220del)","Chromosome":"1","Start":"45509022","Stop":"45509024","ReferenceAlleleVCF":"CAGA","AlternateAlleleVCF":"C","allel_id":101604,"rule_based_match":true,"evidence_text":"c.658_660del","llm_judgment":"PRESENT","evidence":"c.658_660del","abstract_start":1092,"abstract_end":1104},{"Name":"NM_015506.3(MMACHC):c.609G>A (p.Trp203Ter)","Chromosome":"1","Start":"45508975","Stop":"45508975","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39757,"rule_based_match":true,"evidence_text":"c.609G>A","llm_judgment":"PRESENT","evidence":"c.609G>A","abstract_start":1039,"abstract_end":1047}]}
{"pmid":"38193604","title":"Expanding the phenotypic spectrum for CDK8-related disease: A case report.","abstract":"BACKGROUND: Cyclin-dependent kinase 8 (CDK8) is part of a regulatory kinase module that regulates the activity of the Mediator complex. The Mediator, a large conformationally flexible protein complex, goes on to regulate RNA polymerase II activity, consequently affecting transcriptional regulation. Thus, inactivating mutations of the genes within the kinase module cause aberrant transcriptional regulation and disease, namely, CDK8-related intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA).\nCASE PRESENTATION: We describe, for the first time, a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother. The clinical presentation of the child and mother is within the described clinical spectrum for IDDHBA; however, undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child. This phenotype was not found in the mother, highlighting a heterogenous presentation for the same variant within the same family. Furthermore, the described clinical presentation may further support the notion of a module- or Mediator-related syndrome with varying clinical presentation.\nCONCLUSION: This case report documents the first inherited case of IDDHBA and expands the phenotypic spectrum for CDK8-related disease to include undocumented progressive contractures of the hips and knees as well as scoliosis, which may support the notion of a module- or Mediator-related syndrome with varying clinical presentation.","variants":[{"Name":"NM_001260.3(CDK8):c.599G>A (p.Arg200Gln)","Chromosome":"13","Start":"26385295","Stop":"26385295","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":860055,"rule_based_match":true,"evidence_text":"CDK8 variant c.599G>A, p.(Arg200Gln)","llm_judgment":"PRESENT","evidence":"CDK8 variant c.599G>A, p.(Arg200Gln)","abstract_start":618,"abstract_end":654}]}
{"pmid":"27856190","title":"Screening of MCAD deficiency in Japan: 16years' experience of enzymatic and genetic evaluation.","abstract":"BACKGROUND: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a representative disorder of fatty acid oxidation and is one of the most prevalent inborn errors of metabolism among Caucasian populations. In Japan, however, it was as late as 2000 when the first patient was found, and enzymatic and genetic evaluation of MCAD deficiency began.\nMETHODS: We measured octanoyl-CoA dehydrogenase activity in lymphocytes of symptomatic children and newborn screening (NBS)-positive subjects who showed elevated levels of C8-acylcarnitine in blood. The results were further confirmed by direct sequencing of the ACADM gene.\nRESULTS: The disease was diagnosed in 9 out of 18 symptomatic children. The affected patients showed residual activities from 0% to 3% of the normal average value, except for one patient with 10% activity. Concerning 50 NBS-positive subjects, 18 with enzymatic activities around 10% or lower and 14 with activities ranging from 13% to 30% were judged to be affected patients, and biallelic variants were detected in most of the cases tested. Newborns with higher enzymatic activities were estimated to be heterozygous carriers or healthy subjects, though biallelic variants were detected in 5 of them. Genetic analysis detected 22 kinds of variant alleles. The most prevalent was c.449_452delCTGA (p.T150Rfs), which was followed by c.50G>A (p.R17H), c.1085G>A (p.G362E), c.157C>T (p.R53C), and c.843A>T (p.R281S); these five variants accounted for approximately 60% of all the alleles examined.\nCONCLUSION: Our study has revealed the unique genetic backgrounds of MCAD deficiency among Japanese, based on the largest series of non-Caucasian cases. A continuous spectrum of severity was also observed in our series of NBS-positive cases, suggesting that it is essential for every nation and ethnic group to accumulate its own information on gene variants, together with their enzymatic evaluation, in order to establish an efficient NBS system for MCAD deficiency.","variants":[{"Name":"NM_000016.6(ACADM):c.1085G>A (p.Gly362Glu)","Chromosome":"1","Start":"75761261","Stop":"75761261","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":824418,"rule_based_match":true,"evidence_text":"c.1085G>A (p.G362E)","llm_judgment":"PRESENT","evidence":"c.1085G>A (p.G362E)","abstract_start":1372,"abstract_end":1391},{"Name":"NM_000016.6(ACADM):c.449_452del (p.Thr150fs)","Chromosome":"1","Start":"75734849","Stop":"75734852","ReferenceAlleleVCF":"ATGAC","AlternateAlleleVCF":"A","allel_id":186630,"rule_based_match":true,"evidence_text":"c.449_452delCTGA (p.T150Rfs)","llm_judgment":"PRESENT","evidence":"c.449_452delCTGA (p.T150Rfs)","abstract_start":1302,"abstract_end":1330},{"Name":"NM_000016.6(ACADM):c.50G>A (p.Arg17His)","Chromosome":"1","Start":"75728420","Stop":"75728420","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227859,"rule_based_match":true,"evidence_text":"c.50G>A (p.R17H)","llm_judgment":"PRESENT","evidence":"c.50G>A (p.R17H)","abstract_start":1354,"abstract_end":1370}]}
{"pmid":"29192808","title":"A splice-site variant in FLVCR1 produces retinitis pigmentosa without posterior column ataxia.","abstract":"FLVCR1 (feline leukemia virus subgroup c receptor 1) is a transmembrane protein involved in the trafficking of intracellular heme. Homozygous variants in FLVCR1 have been described in association with a clinical syndrome of posterior column ataxia with retinitis pigmentosa (PCARP). Here, we describe a patient with non-syndromic retinitis pigmentosa homozygous for a splice-site variant in FLVCR1 (c.1092 + 5G>A) without evidence of posterior column ataxia or cerebellar degeneration. We suggest an association between intronic splice-site variants in FLVCR1 and the absence of posterior column degeneration and suggest a hypothesis to explain this observation. Should this association be proven, it would provide valuable prognostic information for patients. Retinal degeneration appears to be the sole clinical manifestation of this FLVCR1 variant; gene therapy approaches using an adeno-associated viral vector with sub-retinal delivery may therefore represent a therapeutic approach to halting retinal degeneration in this patient group.","variants":[{"Name":"NM_014053.4(FLVCR1):c.1092+5G>A","Chromosome":"1","Start":"212883443","Stop":"212883443","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":361654,"rule_based_match":true,"evidence_text":"c.1092+5G>A","llm_judgment":"PRESENT","evidence":"c.1092 + 5G>A","abstract_start":399,"abstract_end":412}]}
{"pmid":"34839509","title":"Phenotype and genotype analysis of a pedigree affected with Joubert syndrome due to variant of TMEM237 gene","abstract":"OBJECTIVE: To explore the pathogenesis of two siblings (including a fetus) from a pedigree affected with Joubert syndrome.\nMETHODS: Peripheral blood samples of the proband and his parents as well as amniotic fluid and abortion tissues of the fetus were collected. Part of the samples were used for the extraction of DNA, and whole exome sequencing (WES) was carried out to screen potential variants in the proband and his parents. Suspected variants were subjected to bioinformatics analysis with consideration of the clinical phenotype, and were verified by Sanger sequencing of the proband, fetus and their parents.The remainders were used for the extraction of RNA, and the mechanism of splicing variant was validated by reverse transcription-PCR (RT-PCR).\nRESULTS: WES showed that both patients have carried c.175C>T (p.R59X) and c.553+1G>A compound heterozygous variants of the TMEM237 gene. Among these, c.175C>T was a nonsense mutation inherited from the asymptomatic mother, while c.553+1G>A was an alternative splicing mutation inherited from the asymptomatic father. RT-PCR showed that this variant has resulted in aberrant splicing by exon skipping.\nCONCLUSION: The compound heterozygous variants of the TMEM237 gene probably underlay the etiology of Joubert syndrome in this pedigree. Above finding has enriched the phenotype and variant spectrum of the TMEM237 gene, and facilitated genetic counseling and prenatal diagnosis for the family.","variants":[{"Name":"NM_001044385.3(TMEM237):c.553+1G>A","Chromosome":"2","Start":"201632050","Stop":"201632050","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":851143,"rule_based_match":true,"evidence_text":"c.553+1G>A","llm_judgment":"PRESENT","evidence":"c.553+1G>A","abstract_start":834,"abstract_end":844}]}
{"pmid":"30661771","title":"Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder.","abstract":"Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2. Biosynthesis of hypusine is a two-step reaction involving the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). eIF5A is highly conserved throughout eukaryotic evolution and plays a role in mRNA translation, cellular proliferation, cellular differentiation, and inflammation. DHPS is also highly conserved and is essential for life, as Dhps-null mice are embryonic lethal. Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families. These individuals have similar neurodevelopmental features that include global developmental delay and seizures. Two of four affected females have short stature. All five affected individuals share a recurrent missense variant (c.518A>G [p.Asn173Ser]) in trans with a likely gene disrupting variant (c.1014+1G>A, c.912_917delTTACAT [p.Tyr305_Ile306del], or c.1A>G [p.Met1?]). cDNA studies demonstrated that the c.1014+1G>A variant causes aberrant splicing. Recombinant DHPS enzyme harboring either the p.Asn173Ser or p.Tyr305_Ile306del variant showed reduced (20%) or absent in vitro activity, respectively. We co-transfected constructs overexpressing HA-tagged DHPS (wild-type or mutant) and GFP-tagged eIF5A into HEK293T cells to determine the effect of these variants on hypusine biosynthesis and observed that the p.Tyr305_Ile306del and p.Asn173Ser variants resulted in reduced hypusination of eIF5A compared to wild-type DHPS enzyme. Our data suggest that rare biallelic variants in DHPS result in reduced enzyme activity that limits the hypusination of eIF5A and are associated with a neurodevelopmental disorder.","variants":[{"Name":"NM_001930.4(DHPS):c.912_917del (p.Tyr305_Ile306del)","Chromosome":"19","Start":"12676114","Stop":"12676119","ReferenceAlleleVCF":"GATGTAA","AlternateAlleleVCF":"G","allel_id":551248,"rule_based_match":true,"evidence_text":"c.912_917delTTACAT [p.Tyr305_Ile306del]","llm_judgment":"PRESENT","evidence":"c.912_917delTTACAT [p.Tyr305_Ile306del]","abstract_start":1078,"abstract_end":1117},{"Name":"NM_001930.4(DHPS):c.518A>G (p.Asn173Ser)","Chromosome":"19","Start":"12679696","Stop":"12679696","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":551249,"rule_based_match":true,"evidence_text":"c.518A>G [p.Asn173Ser]","llm_judgment":"PRESENT","evidence":"c.518A>G [p.Asn173Ser]","abstract_start":993,"abstract_end":1015},{"Name":"NM_001930.4(DHPS):c.1A>G (p.Met1Val)","Chromosome":"19","Start":"12681766","Stop":"12681766","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":551250,"rule_based_match":true,"evidence_text":"c.1A>G (p.Met1?)","llm_judgment":"PRESENT","evidence":"c.1A>G","abstract_start":1122,"abstract_end":1128},{"Name":"NM_001930.4(DHPS):c.1014+1G>A","Chromosome":"19","Start":"12676016","Stop":"12676016","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":551247,"rule_based_match":true,"evidence_text":"c.1014+1G>A","llm_judgment":"PRESENT","evidence":"c.1014+1G>A","abstract_start":1065,"abstract_end":1076}]}
{"pmid":"19398212","title":"Hermansky-Pudlak syndrome type 1 in patients of Indian descent.","abstract":"Hermansky-Pudlak syndrome (HPS) develops from defects in the biogenesis and/or function of lysosome-related organelles essential to membrane and protein trafficking. Of the eight known human subtypes, only HPS-1 and HPS-4 develop pulmonary fibrosis in addition to the general clinical manifestations of oculocutaneous albinism and bleeding diathesis. We identified HPS-1 in three unrelated patients from different regions of India, who presented with iris transillumination, pale fundi, hypopigmentation, nystagmus, decreased visual acuity, and a bleeding diathesis. Two of these patients carried the homozygous mutation c.398+5G>A (IVS5+5G>A) in HPS1, resulting in skipping of exon 5 in HPS1 mRNA. The third patient carried a novel homozygous c.988-1G>T mutation that resulted in in-frame skipping of HPS1 exon 12 and removes 56 amino acids from the HPS1 protein. Given the discovery of HPS-1 in an ethnic group where oculocutaneous albinism (OCA) is highly prevalent, it is possible that HPS in India is under-diagnosed. We recommend that unconfirmed OCA patients in this ethic group be considered for mutational screening of known HPS genes, in particular c.398+5G>A and c.980-1G>T, to ensure that patients can be monitored and treated for clinical complications unique to HPS.","variants":[{"Name":"NM_000195.5(HPS1):c.988-1G>T","Chromosome":"10","Start":"98425986","Stop":"98425986","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1062059,"rule_based_match":true,"evidence_text":"c.988-1G>T","llm_judgment":"PRESENT","evidence":"c.988-1G>T","abstract_start":744,"abstract_end":754}]}
{"pmid":"15926618","title":"Spectrum of germ-line MLH1 and MSH2 mutations in Austrian patients with hereditary nonpolyposis colorectal cancer.","abstract":"BACKGROUND: Germ-line mutations in mismatch repair genes are associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, which is characterized by susceptibility to cancer of the colon, endometrium, small bowel or urothelium at an unusually young age and with a high degree of penetration in all generations.\nMATERIAL AND METHODS: One hundred and nine individuals from 46 Austrian families who fulfilled the Amsterdam criteria (n = 29) or at least one of the Bethesda guidelines (n = 17) were analyzed for mutations in MLH1 and MSH2. Microsatellite instability was determined in the tumors of index persons and affected relatives.\nRESULTS AND CONCLUSION: High-grade instability was present in 60.6% of the tumor samples from index patients. Twenty-three germ-line DNA sequence variants in 24/46 families and four somatic mutations in three tumors were detected in MLH1 and MSH2. Fifteen mutations are novel. None of the newly identified germ-line variants was found in 100 alleles of healthy control individuals. We were able to characterize two intronic variants (MLH1 c.589-10T>A; MSH2 c.367-1G>A) with regard to their effect on mRNA. Both created new splice sites that replaced the regular ones. Germ-line mutations occurred in 44.8% of the families fulfilling the Amsterdam criteria and in 35.3% of the Bethesda patients. The detection of a pathogenic mutation was strongly correlated with microsatellite instability in the tumor DNA (p=0.007). This study is the first comprehensive report of mutations in mismatch repair genes in Austrian patients with HNPCC.","variants":[{"Name":"NM_000251.3(MSH2):c.367-1G>A","Chromosome":"2","Start":"47410093","Stop":"47410093","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":96550,"rule_based_match":true,"evidence_text":"MSH2 c.367-1G>A","llm_judgment":"PRESENT","evidence":"MSH2 c.367-1G>A","abstract_start":1103,"abstract_end":1118}]}
{"pmid":"30882689","title":"Identification of a PRKAR1A mutation (c.491_492delTG) in familial cardiac myxoma: A case report.","abstract":"RATIONALE: Cardiac myxoma is the most common cardiac neoplasm. Currently, there are not many reports on familial cardiac myxoma. Herein, we reported 2 first-degree relatives with left atrial myxoma.\nPATIENT CONCERNS: A 20-year-old female was admitted in our hospital for lapsing into a coma for 24 hours, and was diagnosed with recurrent left atrial cardiac myxoma. The patient's father also had a history of cardiac myxoma.\nDIAGNOSIS: The patient was diagnosed with left atrial myxoma using transthoracic echocardiography (TTE). Whole exome sequencing (WES) identified a p.Val164Aspfs (c.491-492delTG) mutation in the cAMP-dependent protein kinase A (PKA) regulatory (R) subunit 1 (PRKAR1A) gene for both the proband and her father, but not in her uncle and brother, who had not shown manifestation of cardiac myxoma by the time of this report.\nINTERVENTIONS: The myxoma resection was performed following the standard procedure of open chest surgery.\nOUTCOMES: The tumor was successfully removed along with the tuberculum. The patient recovered well and was discharged home. No recurrence occurred during 1-year follow-up.\nLESSONS: Our findings suggest that PRKAR1A mutation (c.491_492delTG) may be associated with cardiac myxoma, and genetic counseling and specific locus mutation tests may contribute to assessing the risk of cardiac myxoma.","variants":[{"Name":"NM_002734.5(PRKAR1A):c.491_492del (p.Val164fs)","Chromosome":"17","Start":"68524064","Stop":"68524065","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":27701,"rule_based_match":true,"evidence_text":"c.491_492delTG","llm_judgment":"PRESENT","evidence":"c.491_492delTG","abstract_start":1177,"abstract_end":1191}]}
{"pmid":"28832386","title":"Marfanoid habitus is a nonspecific feature of Perrault syndrome.","abstract":"The objective of this study was to report the clinical and biological characteristics of two Perrault syndrome cases in a Moroccan family with homozygous variant c.1565C>A in the LARS2 gene and to establish genotype-phenotype correlation of patients with the same mutation by review of the literature. Whole-exome sequencing was performed. Data analysis was carried out and confirmed by Sanger sequencing and segregation. The affected siblings were diagnosed as having Perrault syndrome with sensorineural hearing loss at low frequencies; the female proband had primary amenorrhea and ovarian dysgenesis. Both affected individuals had a marfanoid habitus and no neurological features. Both patients carried the homozygous variant c.1565C>A; p.Thr522Asn in exon 13 of the LARS2 gene. This variant has already been reported as a homozygous variant in three other Perrault syndrome families. Both affected siblings of a Moroccan consanguineous family with LARS2 variants had low-frequency sensorineural hearing loss, marfanoid habitus, and primary ovarian insufficiency in the affected girl. According to the literature, this variant, c.1565C>A; p.Thr522Asn, can be correlated with low-frequency hearing loss. However, marfanoid habitus was been considered a nonspecific feature in Perrault syndrome, but we believe that it may be more specific than considered previously. This diagnosis allowed us to provide appropriate management to the patients and to provide more accurate genetic counseling to this family.","variants":[{"Name":"NM_015340.4(LARS2):c.1565C>A (p.Thr522Asn)","Chromosome":"3","Start":"45496316","Stop":"45496316","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":70522,"rule_based_match":true,"evidence_text":"c.1565C>A; p.Thr522Asn","llm_judgment":"PRESENT","evidence":"c.1565C>A; p.Thr522Asn","abstract_start":730,"abstract_end":752}]}
{"pmid":"38050059","title":"Clinical and functional analysis of the germline","abstract":"<i>TP53</i> plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline <i>TP53</i> p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify <i>TP53</i> p.K164E as a likely pathogenic variant.","variants":[{"Name":"NM_000546.6(TP53):c.490A>G (p.Lys164Glu)","Chromosome":"17","Start":"7675122","Stop":"7675122","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":245075,"rule_based_match":true,"evidence_text":"p.K164E (NM_000546.5: c.490A>G)","llm_judgment":"PRESENT","evidence":"p.K164E (NM_000546.5: c.490A>G)","abstract_start":388,"abstract_end":419}]}
{"pmid":"35152178","title":"Induced pluripotent stem cell line ICGi038-A, obtained by reprogramming peripheral blood mononuclear cells from a patient with familial hypercholesterolemia due to compound heterozygous c.1246C > T/c.940 + 3_940 + 6del mutations in LDLR.","abstract":"The development of cellular models for familial hypercholesterolemia (FH) is an important direction for creating new approaches to atherosclerosis treatment. Pathogenic mutations in the LDLR gene are the main FH source. We generated an iPSC line from peripheral blood mononuclear cells of the patient with compound heterozygous c.1246C > T/c.940 + 3_940 + 6del LDLR mutation. The resulting iPSC line with confirmed patient-specific mutations maintains a normal karyotype and a typical undifferentiated state, including morphology, pluripotent gene expression, and in vitro differentiation potential. This iPSC line can be further differentiated toward relevant cells to better understand FH pathogenesis.","variants":[{"Name":"NM_000527.5(LDLR):c.940+3_940+6del","Chromosome":"19","Start":"11107515","Stop":"11107518","ReferenceAlleleVCF":"GGTGA","AlternateAlleleVCF":"G","allel_id":857609,"rule_based_match":true,"evidence_text":"c.940+3_940+6del","llm_judgment":"PRESENT","evidence":"c.940 + 3_940 + 6del","abstract_start":340,"abstract_end":360}]}
{"pmid":"31350873","title":"TASP1 mutation in a female with craniofacial anomalies, anterior segment dysgenesis, congenital immunodeficiency and macrocytic anemia.","abstract":"BACKGROUND: Threonine Aspartase 1 (Taspase 1) is a highly conserved site-specific protease whose substrates are broad-acting nuclear transcription factors that govern diverse biological programs, such as organogenesis, oncogenesis, and tumor progression. To date, no single base pair mutations in Taspase 1 have been implicated in human disease.\nMETHODS: A female infant with a new pattern of diagnostic abnormalities was identified, including severe craniofacial anomalies, anterior and posterior segment dysgenesis, immunodeficiency, and macrocytic anemia. Trio-based whole exome sequencing was performed to identify disease-causing variants.\nRESULTS: Whole exome sequencing revealed a normal female karyotype (46,XX) without increased regions of homozygosity. The proband was heterozygous for a de novo missense variant, c.1027G>A predicting p.(Val343Met), in the TASP1 gene (NM_017714.2). This variant has not been observed in population databases and is predicted to be deleterious.\nCONCLUSION: One human patient has been reported previously with a large TASP1 deletion and substantial evidence exists regarding the role of several known Taspase 1 substrates in human craniofacial and hematopoietic disorders. Moreover, Taspase 1 deficiency in mice results in craniofacial, ophthalmological and structural brain defects. Taken together, there exists substantial evidence to conclude that the TASP1 variant, p.(Val343Met), is pathogenic in this patient.","variants":[{"Name":"NM_017714.3(TASP1):c.1027G>A (p.Val343Met)","Chromosome":"20","Start":"13435113","Stop":"13435113","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":962272,"rule_based_match":true,"evidence_text":"c.1027G>A predicting p.(Val343Met)","llm_judgment":"PRESENT","evidence":"c.1027G>A predicting p.(Val343Met)","abstract_start":824,"abstract_end":858}]}
{"pmid":"32341788","title":"Hypertrophic cardiomyopathy in myosin-binding protein C (","abstract":"Objective: The myosin-binding protein C (<i>MYBPC3</i>) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation.\nMethods: We studied 60 probands with HCM caused by <i>MYBPC3</i> c.927-2A>G and 225 first-degree relatives. All participants underwent comprehensive clinical evaluation and relatives were genotyped.\nResults: Genetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH-) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH- subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives.\nConclusions: Phenotypic expression of the Icelandic <i>MYBPC3</i> founder mutation varies by age, sex and proband status. Men are more likely to have LVH at a younger age, and disease manifestations were more prominent in probands than in relatives identified via family screening. G+/LVH- individuals had subtle clinical differences from unaffected relatives well into adulthood, indicating subclinical phenotypic expression of the pathogenic mutation.","variants":[{"Name":"NM_000256.3(MYBPC3):c.927-2A>G","Chromosome":"11","Start":"47346372","Stop":"47346372","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":51976,"rule_based_match":true,"evidence_text":"c.927-2A>G","llm_judgment":"PRESENT","evidence":"c.927-2A>G","abstract_start":56,"abstract_end":66}]}
{"pmid":"37188672","title":"A novel compound heterozygous of β-thalassemia with HbG-Coushatta: case report of Iran.","abstract":"A 30-year-old male couple from Ardabil city, Iran, were admitted for premarital screening. An abnormal band in HbS/D regions with high levels of HbF and HbA 2 led us to suspect the possibility of a compound heterozygous state of β-thalassemia in our affected proband. Therefore, beta globin chain sequencing of proband discovered a heterozygote combination of the Hb G-Coushatta [b22 (B4) Glu>Ala, HBB: c.68A>C) with HBB: IVS-II-1 (G>A) mutation as a compound heterozygote.","variants":[{"Name":"NM_000518.4(HBB):c.68A>C (p.Glu23Ala)","Chromosome":"11","Start":"5226954","Stop":"5226954","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":30210,"rule_based_match":true,"evidence_text":"HBB: c.68A>C","llm_judgment":"PRESENT","evidence":"HBB: c.68A>C","abstract_start":398,"abstract_end":410}]}
{"pmid":"26849169","title":"Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene.","abstract":"OBJECTIVE: PDZD7 was identified in 2009 in a family with apparent nonsyndromic sensorineural hearing loss. However, subsequent clinical reports have associated PDZD7 with digenic Usher syndrome, the most common cause of deaf-blindness, or as a modifier of retinal disease. No further reports have validated this gene for nonsyndromic hearing loss, intuitively calling correct genotype-phenotype association into question. This report describes a validating second case for biallelic mutations in PDZD7 causing nonsyndromic mild to severe sensorineural hearing loss. It also provides detailed audiometric and ophthalmologic data excluding Usher syndrome in both the present proband (proband 1) and the first proband described in 2009 (proband 2).\nDESIGN: Proband 1 was sequenced using a custom-designed next generation sequencing panel consisting of 151 deafness genes. Bioinformatics analysis and filtering disclosed two PDZD7 sequence variants (c.1648C>T, p.Q550* and c.2107del, p.S703Vfs*20). Segregation testing followed in the family. For both probands, audiograms were collected and analyzed for progressive hearing loss and detailed ophthalmic evaluations were performed including electroretinography.\nRESULTS: Proband 1 demonstrated a prelingual, nonsyndromic, sensorineural hearing loss that progressed in the higher frequencies between 4 and 9 years old. PDZD7 segregation analysis confirmed biallelic inheritance (compound heterozygosity). Mutation analysis determined the c.1648C>T mutation as novel and reported the c.2107del deletion as rs397516633 with a calculated minor allele frequency of 0.000018. Clinical evaluation spanning well over a decade in proband 2 disclosed bilateral, nonprogressive hearing loss. Both probands showed healthy retinas, excluding Usher syndrome-like changes in the eye.\nCONCLUSIONS: PDZD7 is confirmed as a bona fide autosomal recessive nonsyndromic hearing loss gene. In both probands, there was no evidence of impaired vision or ophthalmic pathology. As the current understanding of PDZD7 mutations bridge Mendelian and complex phenotypes, the authors recommend careful variant interpretation, since PDZD7 is one of many genes associated with both Usher syndrome and autosomal recessive nonsyndromic hearing loss. Additional reports are required for understanding the complete phenotypic spectrum of this gene, including the possibility of high-frequency progression, as well as noise-induced hearing loss susceptibility in adult carriers. This report rules out all forms of Usher syndrome with an onset before 12 and 15 years old in probands 1 and 2, respectively. However, due to the young ages of the probands, this report is uninformative regarding older patients.","variants":[{"Name":"NM_001195263.2(PDZD7):c.2107del (p.Ser703fs)","Chromosome":"10","Start":"101010782","Stop":"101010782","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":53289,"rule_based_match":true,"evidence_text":"c.2107del","llm_judgment":"PRESENT","evidence":"c.2107del","abstract_start":969,"abstract_end":978},{"Name":"NM_001195263.2(PDZD7):c.1648C>T (p.Gln550Ter)","Chromosome":"10","Start":"101015737","Stop":"101015737","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":535668,"rule_based_match":true,"evidence_text":"c.1648C>T","llm_judgment":"PRESENT","evidence":"c.1648C>T","abstract_start":946,"abstract_end":955}]}
{"pmid":"27789106","title":"Reversible Dilated Cardiomyopathy Caused by a High Burden of Ventricular Arrhythmias in Andersen-Tawil Syndrome.","abstract":"Andersen-Tawil syndrome (ATS) is caused by mutations in KCNJ2 (Kir2.1). It remains unclear whether dilated cardiomyopathy (DCM) is a primary feature of ATS. We studied a proband with typical physical features of ATS plus DCM and moderate to severe left ventricular dysfunction (left ventricular ejection fraction = 30.5%). Genetic screening revealed a novel mutation in Kir2.1 (c.665T>C, p.L222S). Functional studies showed that this mutation reduced ionic currents in a dominant-negative manner. Suppression of ventricular arrhythmias with bisoprolol led to normalization of left ventricular size and function. We conclude that DCM is likely a secondary phenotype in ATS and is caused by high ventricular arrhythmia burden.","variants":[{"Name":"NM_000891.3(KCNJ2):c.665T>C (p.Leu222Ser)","Chromosome":"17","Start":"70175704","Stop":"70175704","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":536956,"rule_based_match":true,"evidence_text":"c.665T>C","llm_judgment":"PRESENT","evidence":"c.665T>C","abstract_start":378,"abstract_end":386}]}
{"pmid":"36302598","title":"Long-Read Sequencing Identifies Novel Pathogenic Intronic Variants in Gitelman Syndrome.","abstract":"BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3 , which encodes the Na + -Cl - cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield.\nMETHODS: Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants.\nRESULTS: A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C>T variant and intronic candidate variants demonstrated aberrant splicing patterns.\nCONCLUSION: Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1670-191C>T","Chromosome":"16","Start":"56883858","Stop":"56883858","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":652576,"rule_based_match":true,"evidence_text":"c.1670-191C>T","llm_judgment":"PRESENT","evidence":"c.1670-191C>T","abstract_start":1377,"abstract_end":1390}]}
{"pmid":"25948108","title":"Three cases with L1 syndrome and two novel mutations in the L1CAM gene.","abstract":"UNLABELLED: Mutations in the L1CAM gene have been identified in the following various X-linked neurological disorders: congenital hydrocephalus; mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome; spastic paraplegia; and agenesis of the corpus callosum. These conditions are currently considered different phenotypes of a single entity known as L1 syndrome. We present three families with L1 syndrome. Sequencing of the L1CAM gene allowed the identification of the following mutations involved: a known splicing mutation (c.3531-12G>A) and two novel ones: a missense mutation (c.1754A>C; p.Asp585Ala) and a nonsense mutation (c.3478C>T; p.Gln1160Stop). The number of affected males and carrier females identified in a relatively small population suggests that L1 syndrome may be under-diagnosed.\nCONCLUSION: L1 syndrome should be considered in the differential diagnosis of intellectual disability or mental retardation in children, especially when other signs such as hydrocephalus or adducted thumbs are present.","variants":[{"Name":"NM_001278116.2(L1CAM):c.3531-12G>A","Chromosome":"X","Start":"153863391","Stop":"153863391","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1203666,"rule_based_match":true,"evidence_text":"c.3531-12G>A","llm_judgment":"PRESENT","evidence":"c.3531-12G>A","abstract_start":552,"abstract_end":564}]}
{"pmid":"18306170","title":"Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy.","abstract":"Influenza-associated encephalopathy (IAE) is characterized by persistent high fever, febrile convulsions, severe brain edema, and high mortality in otherwise apparently healthy individuals. We have reported that a large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylcarnitine during high fever, exhibit a thermolabile phenotype of compound homo-/heterozygous variants of carnitine palmitoyltransferase II (CPT II, gene symbol CPT2). We characterized the enzymatic properties of five single and three compound CPT II variants in patients with IAE. The kinetic characteristics of WT and variant CPT IIs, expressed in COS-7 cells, indicated that the variants exert a dominant-negative effect on the homotetrameric protein of the enzyme. Among the variants, three compound variations found in patients with severe encephalopathy; [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile)], [c.1511C>T (p.Pro504Leu); c.1813G>C (p.Val605Leu)], and [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile); c.1813G>C (p.Val605Leu)], showed reduced activities, thermal instability, and short half-lives compared with the WT. Like other disease-causing mutant proteins, these variant proteins were poly-ubiquitinated and rapidly degraded by a lactacystin-sensitive proteasome pathway. COS-7 cells transfected with the compound variants had their fatty acid beta-oxidation decreased to 30-59% and intracellular ATP levels to 48-79%, and a marked reduction of mitochondrial membrane potential at 41 degrees C, compared with control cells transfected with WT at 37 degrees C. The unstable CPT II variants with decreased enzymatic activities may bring mitochondrial fuel utilization below the phenotypic threshold during high fever, and thus may play an important etiopathological role in the development of brain edema of IAE.","variants":[{"Name":"NM_000098.3(CPT2):c.1055T>G (p.Phe352Cys)","Chromosome":"1","Start":"53210729","Stop":"53210729","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":39073,"rule_based_match":true,"evidence_text":"c.1055T>G (p.Phe352Cys)","llm_judgment":"PRESENT","evidence":"c.1055T>G (p.Phe352Cys)","abstract_start":879,"abstract_end":902},{"Name":"NM_000098.3(CPT2):c.1102G>A (p.Val368Ile)","Chromosome":"1","Start":"53210776","Stop":"53210776","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39074,"rule_based_match":true,"evidence_text":"c.1102G>A (p.Val368Ile)","llm_judgment":"PRESENT","evidence":"c.1102G>A (p.Val368Ile)","abstract_start":904,"abstract_end":927},{"Name":"NM_000098.3(CPT2):c.1511C>T (p.Pro504Leu)","Chromosome":"1","Start":"53211185","Stop":"53211185","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":199964,"rule_based_match":true,"evidence_text":"c.1511C>T (p.Pro504Leu)","llm_judgment":"PRESENT","evidence":"c.1511C>T (p.Pro504Leu)","abstract_start":931,"abstract_end":954}]}
{"pmid":"35262690","title":"CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.","abstract":"The transmembrane domain recognition complex (TRC) pathway is required for the insertion of C-terminal tail-anchored (TA) proteins into the lipid bilayer of specific intracellular organelles such as the endoplasmic reticulum (ER) membrane. In order to facilitate correct insertion, the recognition complex (consisting of BAG6, GET4 and UBL4A) must first bind to TA proteins and then to GET3 (TRC40, ASNA1), which chaperones the protein to the ER membrane. Subsequently, GET1 (WRB) and CAML form a receptor that enables integration of the TA protein within the lipid bilayer. We report an individual with the homozygous c.633 + 4A>G splice variant in CAMLG, encoding CAML. This variant leads to aberrant splicing and lack of functional protein in patient-derived fibroblasts. The patient displays a predominantly neurological phenotype with psychomotor disability, hypotonia, epilepsy and structural brain abnormalities. Biochemically, a combined O-linked and type II N-linked glycosylation defect was found. Mislocalization of syntaxin-5 in patient fibroblasts and in siCAMLG deleted Hela cells confirms this as a consistent cellular marker of TRC dysfunction. Interestingly, the level of the v-SNARE Bet1L is also drastically reduced in both of these models, indicating a fundamental role of the TRC complex in the assembly of Golgi SNARE complexes. It also points towards a possible mechanism behind the hyposialylation of N and O-glycans. This is the first reported patient with pathogenic variants in CAMLG. CAMLG-CDG is the third disorder, after GET4 and GET3 deficiencies, caused by pathogenic variants in a member of the TRC pathway, further expanding this novel group of disorders.","variants":[{"Name":"NM_001745.4(CAMLG):c.633+4A>G","Chromosome":"5","Start":"134741527","Stop":"134741527","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2417526,"rule_based_match":true,"evidence_text":"c.633 + 4A>G","llm_judgment":"PRESENT","evidence":"c.633 + 4A>G","abstract_start":619,"abstract_end":631}]}
{"pmid":"30125677","title":"A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature.","abstract":"Cornelia de Lange syndrome (CdLS) is a heterogeneous developmental disorder where 70% of clinically diagnosed patients harbor a variant in one of five CdLS associated cohesin proteins. Around 500 variants have been identified to cause CdLS, however only eight different alterations have been identified in the RAD21 gene, encoding the RAD21 cohesin complex component protein that constitute the link between SMC1A and SMC3 within the cohesin ring. We report a 15-month-old boy presenting with developmental delay, distinct CdLS-like facial features, gastrointestinal reflux in early infancy, testis retention, prominent digit pads and diaphragmatic hernia. Exome sequencing revealed a novel RAD21 variant, c.1774_1776del, p.(Gln592del), suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo and bioinformatic analysis predicted the variant as disease-causing. Assessment by in silico structural model predicted that the p.Gln592del variant results in a discontinued contact between RAD21-Lys591 and the SMC1A residues Glu1191 and Glu1192, causing changes in the RAD21-SMC1A interface. In conclusion, we report a patient that expands the clinical description of CdLS type 4 and presents with a novel RAD21 p.(Glu592del) variant that causes a disturbed RAD21-SMC1A interface according to in silco structural modeling.","variants":[{"Name":"NM_006265.3(RAD21):c.1774_1776del (p.Gln592del)","Chromosome":"8","Start":"116847620","Stop":"116847622","ReferenceAlleleVCF":"CTTG","AlternateAlleleVCF":"C","allel_id":535385,"rule_based_match":true,"evidence_text":"c.1774_1776del, p.(Gln592del)","llm_judgment":"PRESENT","evidence":"c.1774_1776del, p.(Gln592del)","abstract_start":706,"abstract_end":735}]}
{"pmid":"31438897","title":"Adult-onset vanishing white matter disease with the EIF2B2 gene mutation presenting as menometrorrhagia.","abstract":"BACKGROUND: Vanishing white matter disease (VWMD) is one of the most prevalent inherited leukoencephalopathies, which generally presents in childhood as a progressive disorder while less beginning in adulthood. The present report describes the clinical, neuroimaging, and genetic findings of a female patient with adult-onset VWMD. In addition, to provide a clearer delineation of the clinical and genetic characteristics of female adult-onset VWMD patients, 32 genetically confirmed female adult-onset EIF2B-mutated cases are summarized.\nCASE PRESENTATION: The patient described here suffered from long-term menometrorrhagia prior to manifesting progressive neurological impairments that included tremors, bilateral pyramidal tract injury, cerebellar ataxia, and dementia. To the best of our knowledge, this is the first female patient with adult-onset VWMD suffering from long-term menometrorrhagia attributed to the c.254 T > A and c.496A > G mutations in the EIF2B2 gene; the c.496A > G mutation has not been reported in previous studies. The patient also exhibited metabolic dysfunction. The present findings widen the spectrum of phenotypic heterogeneity observed in VWMD patients.\nCONCLUSIONS: The present report summarizes 33 female patients with adult-onset VWMD to provide an overview of the clinical and genetic characteristics of this disorder and ovarioleukodystrophy. The mean age of clinical onset in female patients with adult-onset VWMD was 36.8 years and the neurological symptoms primarily included motor and cognitive dysfunction such as paraparesis, cerebellar ataxia, and executive deficits. In addition, ovarian failure occurred in all of these female patients and usually preceded the neurological symptoms. Furthermore, several patients also suffered from metabolic dysfunction. All 33 patients had mutations on EIF2B1-5, and of these, the c.338 G > A mutation in the EIF2B5 gene (p.Arg113His) was the most common. These findings suggest that clinicians should be aware of adult-onset forms of VWMD as well as its typical magnetic resonance imaging (MRI) and clinical characteristics although this pathology is usually recognized as a pediatric disorder. No curative treatment is presently available, and thus early recognition is important to prevent triggering events and to allow for genetic counseling.","variants":[{"Name":"NM_014239.4(EIF2B2):c.496A>G (p.Met166Val)","Chromosome":"14","Start":"75004799","Stop":"75004799","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3525669,"rule_based_match":true,"evidence_text":"c.496A > G","llm_judgment":"PRESENT","evidence":"c.496A > G","abstract_start":935,"abstract_end":945},{"Name":"NM_014239.4(EIF2B2):c.254T>A (p.Val85Glu)","Chromosome":"14","Start":"75003365","Stop":"75003365","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":48677,"rule_based_match":true,"evidence_text":"c.254 T > A","llm_judgment":"PRESENT","evidence":"c.254 T > A","abstract_start":919,"abstract_end":930}]}
{"pmid":"22016685","title":"A novel missense mutation Asp506Gly in Exon 13 of the F11 gene in an asymptomatic Korean woman with mild factor XI deficiency.","abstract":"Factor XI (FXI) deficiency is a rare autosomal recessive coagulation disorder most commonly found in Ashkenazi and Iraqi Jews, but it is also found in other ethnic groups. It is a trauma or surgery-related bleeding disorder, but spontaneous bleeding is rarely seen. The clinical manifestation of bleeding in FXI deficiency cases is variable and seems to poorly correlate with plasma FXI levels. The molecular pathology of FXI deficiency is mutation in the F11 gene on the chromosome band 4q35. We report a novel mutation of the F11 gene in an 18-year-old asymptomatic Korean woman with mild FXI deficiency. Pre-operative laboratory screen tests for lipoma on her back revealed slightly prolonged activated partial thromboplastin time (45.2 sec; reference range, 23.2-39.4 sec). Her FXI activity (35%) was slightly lower than the normal FXI activity (reference range, 50-150%). Direct sequence analysis of the F11 gene revealed a heterozygous A to G substitution in nucleotide 1517 (c.1517A>G) of exon 13, resulting in the substitution of aspartic acid with glycine in codon 506 (p.Asp506Gly). To the best of our knowledge, the Asp506Gly is a novel missense mutation, and this is the first genetically confirmed case of mild FXI deficiency in Korea.","variants":[{"Name":"NM_000128.4(F11):c.1517A>G (p.Asp506Gly)","Chromosome":"4","Start":"186286451","Stop":"186286451","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":79070,"rule_based_match":true,"evidence_text":"c.1517A>G (p.Asp506Gly)","llm_judgment":"PRESENT","evidence":"p.Asp506Gly","abstract_start":1079,"abstract_end":1090}]}
{"pmid":"28719906","title":"A Common Ancestral Asn242Ser Mutation in TMEM67 Identified in Multiple Iranian Families with Joubert Syndrome.","abstract":"BACKGROUND: Joubert syndrome (JS) is a clinically and genetically heterogeneous group of rare neurodevelopmental disorder characterised by peculiar midbrain-hindbrain malformation, known as the \"molar tooth\" sign. JS can manifest a broad range of signs and symptoms. The most common features of JS are hypotonia, ataxia, developmental delay/intellectual disability, abnormal eye movements, and neonatal breathing abnormalities. To date, 29 genes have been shown to cause JS.\nMETHODS: We employed whole-genome single nucleotide polymorphism genotyping in a group of Iranian families with JS and Sanger sequencing of a known mutation associated with JS located in a single homozygous regions shared by affected members of the families.\nRESULTS: Homozygosity mapping uncovered a shared ∼2.2-Mb run of homozygosity on chromosome 8q21.3-q22.1 encompassing the known JS-causing TMEM67 gene. Sanger sequencing of a known mutation (NM_153704.5: c.725A>G; p.Asn242Ser) in TMEM67 identified from studying another Iranian family using whole-exome sequencing confirmed the presence of the homozygous mutation in 22 affected members of 12 nuclear families. \"Molar tooth\" sign of brain magnetic resonance imaging, moderate-to-severe neurodevelopmental delay, and abnormal eye movements were the most common features of affected individuals. In addition, liver disease, seizure, behavioural abnormalities, failure to thrive, and kidney disease were observed variably in some of the patients.\nCONCLUSION: We propose that Asn242Ser is a founder mutation in the Iranian population, which might explain a significant proportion of JS cases from eastern Iran. Therefore, screening for this variant should be considered for genetic testing in Iranian patients with JS. In addition, this finding is important for developing population-specific genetic testing in Iran.","variants":[{"Name":"NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)","Chromosome":"8","Start":"93780603","Stop":"93780603","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":212652,"rule_based_match":true,"evidence_text":"NM_153704.5: c.725A>G; p.Asn242Ser","llm_judgment":"PRESENT","evidence":"NM_153704.5: c.725A>G; p.Asn242Ser","abstract_start":924,"abstract_end":958}]}
{"pmid":"32772503","title":"Genotypic and clinical analysis of 49 Chinese children with hepatic glycogen storage diseases.","abstract":"BACKGROUND: Glycogen storage disease (GSD) is a relatively rare inborn metabolic disorder, our study aims to investigate the genotypic and clinical feature of hepatic GSDs in China.\nMETHODS: The clinical and genotypic data of 49 patients with hepatic GSDs were collected retrospectively and analyzed.\nRESULTS: After gene sequencing, 49 patients were diagnosed as GSDs, including GSD Ia (24 cases), GSD IIIa (11 cases), GSD IXa (8 cases), GSD VI (3 cases) and GSD Ib (3 cases). About 45 gene variants of G6PC, AGL, PHKA2, PYGL, and SLC37A4 were detected; among which, 22 variants were unreported previously. c.648G>T (p. Leu216Leu) of G6PC exon 5 is the most common variant for GSD Ia patients (20/24,83.33%）, splice variant c.1735+1G>T of AGL exon 13 is relatively common among GSD IIIa, while novel variant accounts for the majority of GSD IXa and GSD VI patients. As for clinical features, there was no significant difference in the onset age among group GSD Ia, GSD IIIa, and GSD IXa, but the age at diagnosis and average disease duration from diagnosis of GSD Ia were significantly higher than GSD IIIa and GSD IXa. Body weight of GSD patients was basically normal, but growth retardation was relatively common among them, especially for GSD Ia patients; and renomegaly was only found in GSD Ia. Besides, serum cholesterol, triglyceride, lactic acid, and uric acid in GSD Ia were significantly higher than those with GSD IIIa and IXa (p < 0.05); but ALT, AST, CK, and LDH of GSD III and GSD IXa were significantly higher when compared to GSD Ia (p < 0.05).\nCONCLUSIONS: All hepatic GSDs patients share similarity in clinical and biochemical spectrum, but delayed diagnosis and biochemical metabolic abnormalities were common in GSD Ia. For family with GSD proband, pedigree analysis and genetic testing is strongly recommended.","variants":[{"Name":"NM_000642.3(AGL):c.1735+1G>T","Chromosome":"1","Start":"99880047","Stop":"99880047","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":16139,"rule_based_match":true,"evidence_text":"c.1735+1G>T","llm_judgment":"PRESENT","evidence":"c.1735+1G>T","abstract_start":724,"abstract_end":735}]}
{"pmid":"28503627","title":"Two Novel","abstract":"Benign familial neonatal convulsion is a rare autosomal dominant inherited epilepsy syndrome characterized by unprovoked seizures in the first few days of life, normal psychomotor development, and a positive intergenerational family history of neonatal seizures. Over 90% of the affected individuals have inherited causal mutations in <i>KCNQ2</i>, which encodes for the potassium voltage-gated channel subfamily Q, member 2. Mutations in <i>KCNQ2</i> are also associated with a severe neonatal encephalopathy phenotype associated with poor seizure control and neurodevelopmental deficits. The authors report the clinical presentations, response to medication, and intrafamilial phenotypic variability in 2 families with benign familial neonatal convulsions, carrying previously unreported heterozygous missense mutations, c.1066C>G (p.Leu356Val) and c.1721G<b><</b>A (p.Gly574Asp), in <i>KCNQ2</i>. The cases reported herein suggest that inherited missense mutations in <i>KCNQ2</i> can be associated with an intermediate phenotype and illustrate the challenges associated with prognosis and counselling for individuals with inherited missense mutations in <i>KCNQ2</i>.","variants":[{"Name":"NM_172107.4(KCNQ2):c.1721G>A (p.Gly574Asp)","Chromosome":"20","Start":"63413492","Stop":"63413492","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":203723,"rule_based_match":false,"evidence_text":"c.1721G<b><</b>A (p.Gly574Asp)","llm_judgment":"PRESENT","evidence":"c.1721G<b><</b>A (p.Gly574Asp)","abstract_start":851,"abstract_end":881}]}
{"pmid":"34177781","title":"A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood.","abstract":"<b>Background:</b> Bilateral striatal necrosis (BSN) is characterized by symmetrical degeneration, predominantly of the caudate and putamen nucleus, in the basal ganglia. It is associated with numerous acquired and hereditary neuro-developmental and motor dysfunction-related pathological conditions. BSN results in high morbidity and mortality among infants and children, and its diagnosis is clinically challenging due to several overlapping disease phenotypes. Therefore, a precise genetic diagnosis is urgently needed for accurate genetic counseling and improved prognostic outcomes as well. <b>Objective:</b> To identify novel missense mutations in the <i>NDUFAF5</i> gene as a cause of childhood BSN in members of a Chinese family and summarize the clinical characteristics of patients with the <i>NDUFAF5</i> gene mutations. <b>Methods:</b> This study included a large family living in a remote northwestern area of China. Three siblings developed a neurological disorder characterized by generalized dystonia within the first decade of their lives. Cerebral computed tomography (CT) and magnetic resonance imaging (MRI) showed bilateral lesions of the putamen. Biochemical and genetic approaches were used to identify the cause of BSN. <b>Results:</b> Sequence analysis showed no pathogenic variation in <i>PANK2, SLC25A19, SLC19A3</i>, and <i>NUP62</i> genes and in the entire mitochondrial genome as well. Whole-exome sequencing revealed compound heterozygous mutations consisting of <i>NDUFAF5</i>:c.425A > C(p.E142A) and c.836T > G (p.M279R). The father, a healthy sister, and a healthy brother of the affected siblings carried the c.836T > G mutation, and the mother carried the c.425A > C mutation. These variants were absent in 100 ethnically matched non-BSN controls. <i>In silico</i> analysis demonstrated that the E142A and M279R mutations in NDUFAF5 protein significantly perturbed the normal conformation of the protein due to alterations in the hydrogen bonding patterns around the evolutionarily conserved catalytic domains, leading to its loss of function in the early stage of mitochondrial complex I assembly. <b>Conclusions:</b> We identified a novel compound heterozygous mutation (c.425A > C and c.836T > G) in the <i>NDUFAF5</i> gene as the potential cause of autosomal recessive childhood BSN, which extended the pathogenic variation spectrum of the <i>NDUFAF5</i> gene. This study provides substantial evidence for further improvement of genetic counseling and better clinical management of BSN affected individuals.","variants":[{"Name":"NM_024120.5(NDUFAF5):c.836T>G (p.Met279Arg)","Chromosome":"20","Start":"13816520","Stop":"13816520","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":226977,"rule_based_match":true,"evidence_text":"c.836T > G (p.M279R)","llm_judgment":"PRESENT","evidence":"c.836T > G (p.M279R)","abstract_start":1533,"abstract_end":1553},{"Name":"NM_024120.5(NDUFAF5):c.425A>C (p.Glu142Ala)","Chromosome":"20","Start":"13794887","Stop":"13794887","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3534103,"rule_based_match":true,"evidence_text":"c.425A > C(p.E142A)","llm_judgment":"PRESENT","evidence":"c.425A > C(p.E142A)","abstract_start":1509,"abstract_end":1528}]}
{"pmid":"27196898","title":"Clinical and Molecular Characterization of Patients with Mucopolysaccharidosis Type I in an Algerian Series.","abstract":"Mucopolysaccharidoses (MPS's) represent a subgroup of lysosomal storage diseases related to a deficiency of enzymes that catalyze glycosaminoglycans degradation. Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by a deficiency of α-l-iduronidase encoded by the IDUA gene. Partially degraded heparan sulfate and dermatan sulfate accumulate progressively and lead to multiorgan dysfunction and damage. The aim of this study is to describe the clinical, biochemical, and molecular characteristics of 13 Algerian patients from 11 distinct families. MPS I diagnosis was confirmed by molecular study of the patients' IDUA gene. Clinical features at the diagnosis and during the follow-up are reported. Eighty-four percent of the studied patients presented with a mild clinical phenotype. Molecular study of the IDUA gene allowed the characterization of four pathological variations at the homozygous or compound heterozygote status: IDUA NM_00203.4:c.1598C>G-p.(Pro533Arg) in 21/26 alleles, IDUA NM_00203.4:c.532G>A-p.(Glu178Lys) in 2/26 alleles, IDUA NM_00203.4:c.501C>G-p.(Tyr167*) in 2/26 alleles, and IDUA NM_00203. 4: c.1743C>G-p.(Tyr581*) in 1/26 alleles. This molecular study unveils the predominance of p.(Pro533Arg) variation in our MPS I patients. In this series, the occurrence of some clinical features linked to the Scheie syndrome is consistent with the literature, such as systematic valvulopathies, corneal opacity, and umbilical hernia; however, storage signs, facial dysmorphic features, and hepatomegaly were more frequent in our series. Screening measures for these debilitating diseases in highly consanguineous at-risk populations must be considered a priority health problem.","variants":[{"Name":"NM_000203.5(IDUA):c.532G>A (p.Glu178Lys)","Chromosome":"4","Start":"1001506","Stop":"1001506","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1934785,"rule_based_match":true,"evidence_text":"IDUA NM_00203.4:c.532G>A-p.(Glu178Lys)","llm_judgment":"PRESENT","evidence":"IDUA NM_00203.4:c.532G>A-p.(Glu178Lys)","abstract_start":1019,"abstract_end":1057},{"Name":"NM_000203.5(IDUA):c.1598C>G (p.Pro533Arg)","Chromosome":"4","Start":"1003418","Stop":"1003418","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":26949,"rule_based_match":true,"evidence_text":"IDUA NM_00203.4:c.1598C>G-p.(Pro533Arg)","llm_judgment":"PRESENT","evidence":"IDUA NM_00203.4:c.1598C>G-p.(Pro533Arg)","abstract_start":961,"abstract_end":1000},{"Name":"NM_000203.5(IDUA):c.1743C>G (p.Tyr581Ter)","Chromosome":"4","Start":"1004027","Stop":"1004027","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":543319,"rule_based_match":true,"evidence_text":"IDUA NM_00203. 4: c.1743C>G-p.(Tyr581*)","llm_judgment":"PRESENT","evidence":"IDUA NM_00203. 4: c.1743C>G-p.(Tyr581*)","abstract_start":1133,"abstract_end":1172}]}
{"pmid":"37203213","title":"A novel KCNC1 gain-of-function variant causing developmental and epileptic encephalopathy: \"Precision medicine\" approach with fluoxetine.","abstract":"Variable phenotypes, including developmental encephalopathy with (DEE) or without seizures and myoclonic epilepsy and ataxia due to potassium channel mutation, are caused by pathogenetic variants in KCNC1, encoding for Kv3.1 channel subunits. In vitro, channels carrying most KCNC1 pathogenic variants display loss-of-function features. Here, we describe a child affected by DEE with fever-triggered seizures, caused by a novel de novo heterozygous missense KCNC1 variant (c.1273G>A; V425M). Patch-clamp recordings in transiently transfected CHO cells revealed that, compared to wild-type, Kv3.1 V425M currents (1) were larger, with membrane potentials between -40 and +40 mV; (2) displayed a hyperpolarizing shift in activation gating; (3) failed to inactivate; and (4) had slower activation and deactivation kinetics, consistent with a mixed functional pattern with prevalent gain-of-function effects. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant Kv3.1 channels. Treatment of the proband with fluoxetine led to a rapid and prolonged clinical amelioration, with the disappearance of seizures and an improvement in balance, gross motor skills, and oculomotor coordination. These results suggest that drug repurposing based on the specific genetic defect may provide an effective personalized treatment for KCNC1-related DEEs.","variants":[{"Name":"NM_001112741.2(KCNC1):c.1273G>A (p.Val425Met)","Chromosome":"11","Start":"17772367","Stop":"17772367","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":415258,"rule_based_match":true,"evidence_text":"c.1273G>A; V425M","llm_judgment":"PRESENT","evidence":"c.1273G>A; V425M","abstract_start":473,"abstract_end":489}]}
{"pmid":"28777933","title":"Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.","abstract":"Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.","variants":[{"Name":"NM_014233.4(UBTF):c.628G>A (p.Glu210Lys)","Chromosome":"17","Start":"44212851","Stop":"44212851","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":431537,"rule_based_match":true,"evidence_text":"c.628G>A","llm_judgment":"PRESENT","evidence":"c.628G>A","abstract_start":599,"abstract_end":607}]}
{"pmid":"25224241","title":"Tyrosine hydroxylase deficiency: a case of autosomal recessive dopa-responsive dystonia","abstract":"OBJECTIVE: To analyze the clinical characteristics of the patient with tyrosine hydroxylase deficiency, and investigate it's molecular mechanism.\nMETHOD: The clinical characteristics of a patient with tyrosine hydroxylase deficiency were summarized and analyzed, his and his family's peripheral blood specimens were collected after informed consent was signed. All exons and the intron-exon boundaries of guanosine triphosphate hydroxylase I gene, tyrosine hydroxylase gene and sepiapterin reductase gene were examined by DNA-PCR, bi-directional sequencing.\nRESULT: The patient was a 3-year-old boy, presented with unexplained dystonia for 3 years, without significant impairment of intelligence. Physical examination showed limb muscle strength grade V, rigidity of extremities, hypertonicity, brisk deep tendon reflexes in limbs, without obvious abnormalities in auxiliary examination, such as brain MRI, hepatic biochemical panel, creatine kinase, and ceruloplasmin. He dramatically responded to small doses of levodopa in the follow-up for half a year. A homozygous missense change in exon 5 of TH gene, c.605G > A (p.R202H), which was a known pathogenic mutation, was found in the patient. His parents were heterozygous for the R202H mutation.\nCONCLUSION: The age of onset in tyrosine hydroxylase deficiency patients is usually within the first year of life. Unexplained dystonia and hypokinesia were the main clinical features of tyrosine hydroxylase deficiency. The dopa-responsive effects for some patients are so obvious that we should strengthen awareness of the disease. TH gene c.605G > A (p.R202H) may be a common type of causative mutations for the mild form at home and abroad.","variants":[{"Name":"NM_000360.4(TH):c.605G>A (p.Arg202His)","Chromosome":"11","Start":"2167905","Stop":"2167905","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27366,"rule_based_match":true,"evidence_text":"c.605G > A (p.R202H)","llm_judgment":"PRESENT","evidence":"c.605G > A (p.R202H)","abstract_start":1108,"abstract_end":1128}]}
{"pmid":"30675866","title":"Clinical features and ABCC2 genotypic analysis of an infant with Dubin-Johnson syndrome","abstract":"Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder resulting from biallelic mutations of ABCC2 gene, with long-term or intermittent conjugated hyperbilirubinemia being the main clinical manifestation. This paper aims to report the clinical features and ABCC2 genotypes of an infant with DJS. A 9.5-month-old male infant was referred to the hospital due to abnormal liver function discovered over 9 months. The major clinical presentation was prolonged jaundice since neonatal period. A series of biochemistry analysis revealed markedly elevated total bilirubin, conjugated bilirubin and total bile acids. The patient had been managed in different hospitals, but the therapeutic effects were unsatisfactory due to undetermined etiology. Physical examination revealed jaundiced skin and sclera, and a palpable liver 3 cm below the right subcostal margin with medium texture. The spleen was not enlarged. Genetic analysis revealed a splice-site variant c.3988-2A>T and a nonsense variant c.3825C>G (p.Y1275X) in the ABCC2 gene of the infant, which were inherited from his mother and father respectively. The former had not been previously reported. Then ursodeoxycholic acid and phenobarbital were given orally. Half a month later, as a result, his jaundice disappeared and the biochemistry indices improved. However, the long-term outcome needs to be observed. Literature review revealed that neonates/infants with DJS presented with cholestatic jaundice soon after birth as the major clinical feature, and the ABCC2 variants exhibited marked heterogeneity.","variants":[{"Name":"NM_000392.5(ABCC2):c.3825C>G (p.Tyr1275Ter)","Chromosome":"10","Start":"99843882","Stop":"99843882","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2901492,"rule_based_match":true,"evidence_text":"c.3825C>G (p.Y1275X)","llm_judgment":"PRESENT","evidence":"c.3825C>G (p.Y1275X)","abstract_start":998,"abstract_end":1018}]}
{"pmid":"17937443","title":"Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa.","abstract":"Mutations involving elastic tissue proteins result in a broad spectrum of phenotypes affecting skin, skeleton, ocular and vascular structures, including tortuous blood vessels and cutis laxa. Here we report on a female newborn with apparently long fingers, aortic aneurysm, tortuous pulmonary arteries and mild generalized lax skin. She died at 27 days of age due to severe respiratory distress and inoperable systemic vascular abnormalities. Skin biopsy showed marked paucity and fragmentation of elastic fibers and autopsy revealed occlusion of the pulmonary artery. DNA analysis identified compound heterozygous mutations ((c.835C > T (p.R279C)/c.1070_1073dupCCGC) in fibulin-4, a recently recognized elastic fiber associated protein. Analyses of dermal fibroblasts from the patient indicated that fibulin-4 mRNAs with the 4-bp duplication transcribed from one allele are probably subject to nonsense-mediated decay, whereas synthesis and secretion of the missense R279C fibulin-4 protein from the other allele is severely impaired. Immunostaining demonstrated a total absence of fibulin-4 fibers in the extracellular matrix deposited by the patient's fibroblasts. Our studies provide evidence that deficiency in fibulin-4 leads to a perinatal lethal condition associated with elastic tissue abnormalities.","variants":[{"Name":"NM_016938.5(EFEMP2):c.835C>T (p.Arg279Cys)","Chromosome":"11","Start":"65868522","Stop":"65868522","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20463,"rule_based_match":true,"evidence_text":"c.835C > T (p.R279C)","llm_judgment":"PRESENT","evidence":"c.835C > T (p.R279C)","abstract_start":627,"abstract_end":647},{"Name":"NM_016938.5(EFEMP2):c.1070_1073dup (p.Asp359fs)","Chromosome":"11","Start":"65867957","Stop":"65867958","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AGCGG","allel_id":20464,"rule_based_match":true,"evidence_text":"c.1070_1073dupCCGC","llm_judgment":"PRESENT","evidence":"c.1070_1073dupCCGC","abstract_start":648,"abstract_end":666}]}
{"pmid":"26901124","title":"Identification of six novel mutations in Iranian patients with maple syrup urine disease and their in silico analysis.","abstract":"Maple syrup urine disease (MSUD) is a rare inborn error of branched-chain amino acid metabolism. The disease prevalence is higher in populations with elevated rate of consanguineous marriages such as Iran. Different types of disease causing mutations have been previously reported in BCKDHA, BCKDHB, DBT and DLD genes known to be responsible for MSUD phenotype. In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above genes were used to aid in homozygosity mapping in order to find probable pathogenic change(s) in the studied families. The families who showed homozygote haplotype for the BCKDHA gene were subsequently sequenced. Our findings showed that exons 2, 4 and 6 contain most of the mutations which are novel. The changes include two single nucleotide deletion (i.e. c. 143delT and c.702delT), one gross deletion covering the whole exon four c.(375+1_376-1)_(8849+1_885-1), two splice site changes (c.1167+1G>T, c. 288+1G>A), and one point mutation (c.731G>A). Computational approaches were used to analyze these two novel mutations in terms of their impact on protein structure. Computational structural modeling indicated that these mutations might affect structural stability and multimeric assembly of branched-chain α-keto acid dehydrogenase complex (BCKDC).","variants":[{"Name":"NM_000709.4(BCKDHA):c.288+1G>A","Chromosome":"19","Start":"41410817","Stop":"41410817","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":99258,"rule_based_match":true,"evidence_text":"c. 288+1G>A","llm_judgment":"PRESENT","evidence":"c. 288+1G>A","abstract_start":969,"abstract_end":980},{"Name":"NM_000709.4(BCKDHA):c.143del (p.Leu48fs)","Chromosome":"19","Start":"41410671","Stop":"41410671","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":513375,"rule_based_match":true,"evidence_text":"c. 143delT","llm_judgment":"PRESENT","evidence":"c. 143delT","abstract_start":824,"abstract_end":834}]}
{"pmid":"23281106","title":"Molecular basis of two-exon skipping (exons 12 and 13) by c.1248+5g>a in OXCT1 gene: study on intermediates of OXCT1 transcripts in fibroblasts.","abstract":"The molecular basis of simultaneous two-exon skipping induced by a splice-site mutation has yet to be completely explained. The splice donor site mutation c.1248+5g>a (IVS13) of the OXCT1 gene resulted predominantly in skipping of exons 12 and 13 in fibroblasts from a patient (GS23) with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. We compared heteronuclear RNA (hnRNA) intermediates between controls' and GS23's fibroblasts. Our strategy was to use RT-PCR of hnRNA to detect the presence or absence of spliced exon clusters in RNA intermediates (SECRIs) comprising sequential exons. Our initial hypothesis was that a SECRI comprising exons 12 and 13 was formed first followed by skipping of this SECRI in GS23 cells. However, such a pathway was revealed to be not a major one. Hence, we compared the intron removal of SCOT transcript between controls and GS23. In controls, intron 11 was the last intron to be spliced and the removal of intron 12 was also rather slow and occurred after the removal of intron 13 in a major pathway. However, the mutation in GS23 cells resulted in retention of intron 13, thus causing the retention of introns 12 and 11. This \"splicing paralysis\" may be solved by skipping the whole intron 11-exon 12-intron 12-exon 13-mutated intron 13, resulting in skipping of exons 12 and 13.","variants":[{"Name":"NM_000436.4(OXCT1):c.1248+5G>A","Chromosome":"5","Start":"41793998","Stop":"41793998","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49933,"rule_based_match":true,"evidence_text":"c.1248+5g>a","llm_judgment":"PRESENT","evidence":"c.1248+5g>a","abstract_start":155,"abstract_end":166}]}
{"pmid":"19292878","title":"Acute intermittent porphyria--impact of mutations found in the hydroxymethylbilane synthase gene on biochemical and enzymatic protein properties.","abstract":"Acute intermittent porphyria is an autosomal dominantly inherited disorder, classified as acute hepatic porphyria, caused by a deficiency of hydroxymethylbilane synthase (EC 2.5.1.61, EC 4.3.1.8, also known as porphobilinogen deaminase, uroporphyrinogen I synthase), the third enzyme in heme biosynthesis. Clinical features include autonomous, central, motor or sensory symptoms, but the most common clinical presentation is abdominal pain caused by neurovisceral crises. A diagnosis of acute intermittent porphyria is crucial to prevent life-threatening acute attacks. Detection of DNA variations by molecular techniques allows a diagnosis of acute intermittent porphyria in situations where the measurement of porphyrins and precursors in urine and faeces and erythrocyte hydroxymethylbilane synthase activity is inconclusive. In the present study, we identified gene defects in six Czech patients with acute intermittent porphyria, as diagnosed based on biochemical findings, and members of their families to confirm the diagnosis at the molecular level and/or to provide genetic counselling. Molecular analyses of the hydroxymethylbilane synthase gene revealed seven mutations. Four were previously reported: c.76C>T, c.77G>A, c.518G>A, c.771 + 1G>T (p.Arg26Cys, p.Arg26His, p.Arg173Gln). Three were novel mutations: c.610C>A, c.675delA, c.750A>T (p.Gln204Lys, p.Ala226ProfsX28, p.Glu250Asp). Of particular interest, one patient had two mutations (c.518G>A; c.610C>A), both located in exon 10 of the same allele. To establish the effects of the mutations on enzyme function, biochemical characterization of the expressed normal recombinant and mutated proteins was performed. Prokaryotic expression of the mutant alleles of the hydroxymethylbilane synthase gene revealed that, with the exception of the p.Gln204Lys mutation, all mutations resulted in little, if any, enzymatic activity. Moreover, the 3D structure of the Escherichia coli and human protein was used to interpret structure-function relationships for the mutations in the human isoform.","variants":[{"Name":"NM_000190.4(HMBS):c.77G>A (p.Arg26His)","Chromosome":"11","Start":"119088298","Stop":"119088298","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16482,"rule_based_match":true,"evidence_text":"c.77G>A (p.Arg26His)","llm_judgment":"PRESENT","evidence":"p.Arg26His","abstract_start":1267,"abstract_end":1277},{"Name":"NM_000190.4(HMBS):c.76C>T (p.Arg26Cys)","Chromosome":"11","Start":"119088297","Stop":"119088297","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":639774,"rule_based_match":true,"evidence_text":"c.76C>T","llm_judgment":"PRESENT","evidence":"c.76C>T","abstract_start":1213,"abstract_end":1220}]}
{"pmid":"11462243","title":"Four novel mutations in the RPE65 gene in patients with Leber congenital amaurosis.","abstract":"Leber congenital amaurosis (LCArpar; is a heterogeneous disorder representing the congenital forms of retinitis pigmentosa accounting for about 5% of all retinal dystrophies. The RPE65 gene product is required for regeneration of the visual pigment for phototransduction. Defects in the RPE65 gene have so far been shown to account for approximately 10 % of known cases of LCA. Here we describe four additional novel mutations in the RPE65 gene (c.889delA, c.131G>A, c.1249G>C, c.430T>G) and several novel polymorphisms in a large series of LCA patients. Hum Mutat 18:164, 2001.","variants":[{"Name":"NM_000329.3(RPE65):c.1249G>C (p.Glu417Gln)","Chromosome":"1","Start":"68431371","Stop":"68431371","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":104725,"rule_based_match":true,"evidence_text":"c.1249G>C","llm_judgment":"PRESENT","evidence":"c.1249G>C","abstract_start":467,"abstract_end":476},{"Name":"NM_000329.3(RPE65):c.430T>G (p.Tyr144Asp)","Chromosome":"1","Start":"68444596","Stop":"68444596","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":104758,"rule_based_match":true,"evidence_text":"c.430T>G","llm_judgment":"PRESENT","evidence":"c.430T>G","abstract_start":478,"abstract_end":486},{"Name":"NM_000329.3(RPE65):c.131G>A (p.Arg44Gln)","Chromosome":"1","Start":"68446824","Stop":"68446824","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":104730,"rule_based_match":true,"evidence_text":"c.131G>A","llm_judgment":"PRESENT","evidence":"c.131G>A","abstract_start":457,"abstract_end":465}]}
{"pmid":"26298607","title":"Autosomal recessive axonal polyneuropathy in a sibling pair due to a novel homozygous mutation in IGHMBP2.","abstract":"Charcot-Marie-Tooth disease is a group of genetically heterogeneous disorders characterized by a sensorimotor polyneuropathy with subsequent muscle atrophy, areflexia, and sensory loss. More than 60 genes have been linked to Charcot-Marie-Tooth phenotypes, including IGHMBP2. Until recently, mutations in IGHMBP2 were exclusively associated with spinal muscular atrophy with respiratory distress (SMARD1). We present a sibling pair with a novel homozygous truncating mutation in IGHMBP2. The patients presented with childhood-onset distal weakness, wasting in the upper and lower limbs, areflexia and decreased sensation, but no respiratory involvement. Exome sequencing was performed and a homozygous variant was identified (c.2601_2604del; p.Lys868Profs*109). Sanger sequencing confirmed the presence of this variant in a homozygous state in the two affected siblings, while both parents were heterozygous. Further analyses showed decreased mRNA and IGHMBP2 protein in a lymphoblast cell line derived from one of the siblings. We demonstrate the utility of next-generation sequencing in reaching a molecular diagnosis for a heterogeneous condition such as Charcot-Marie-Tooth. Taken together, our data and that from the literature suggest that the spectrum of clinical presentations associated with mutations in IGHMBP2 may be secondary, at least in part, to the amount of residual protein.","variants":[{"Name":"NM_002180.3(IGHMBP2):c.2601_2604del (p.Lys868fs)","Chromosome":"11","Start":"68937079","Stop":"68937082","ReferenceAlleleVCF":"GAAAA","AlternateAlleleVCF":"G","allel_id":3086367,"rule_based_match":true,"evidence_text":"c.2601_2604del","llm_judgment":"PRESENT","evidence":"c.2601_2604del","abstract_start":726,"abstract_end":740}]}
{"pmid":"24243779","title":"Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases.","abstract":"The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.","variants":[{"Name":"NM_004656.4(BAP1):c.1182C>G (p.Tyr394Ter)","Chromosome":"3","Start":"52404521","Stop":"52404521","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1436331,"rule_based_match":true,"evidence_text":"c.1182C>G, p.Tyr394*","llm_judgment":"PRESENT","evidence":"c.1182C>G, p.Tyr394*","abstract_start":656,"abstract_end":676},{"Name":"NM_004656.4(BAP1):c.1882_1885del (p.Ser628fs)","Chromosome":"3","Start":"52403143","Stop":"52403146","ReferenceAlleleVCF":"GGTGA","AlternateAlleleVCF":"G","allel_id":616952,"rule_based_match":true,"evidence_text":"c.1882_1885delTCAC, p. Ser628Profs*8","llm_judgment":"PRESENT","evidence":"c.1882_1885delTCAC, p. Ser628Profs*8","abstract_start":682,"abstract_end":718},{"Name":"NM_004656.4(BAP1):c.2050C>T (p.Gln684Ter)","Chromosome":"3","Start":"52402608","Stop":"52402608","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39258,"rule_based_match":true,"evidence_text":"c.2050 C>T","llm_judgment":"PRESENT","evidence":"c.2050 C>T","abstract_start":634,"abstract_end":644}]}
{"pmid":"32637358","title":"A Novel Splice-Site Mutation in","abstract":"Lynch syndrome (LS) is an inherited autosomal dominant disorder caused by germline mutations of mismatch repair (MMR) genes, including <i>MSH2, MSH6, PMS2</i>, and <i>MLH1</i>. This study aimed to analyze the molecular defects and clinical manifestations of an affected family and propose appropriate individual prevention strategies for all mutation carriers. A novel splicing mutation (c.1661+2 T>G) was identified in the <i>MSH2</i> gene, which was found to co-segregate among affected family members by Whole exome sequencing (WES). RT-PCR analysis confirmed that c.1661+2 T>G could produce 3 transcripts, including 1 normal transcript and 2 aberrant transcripts. The 2 aberrant transcripts resulted in premature termination at the 6th nucleotide codon of <i>MSH2</i> exon 11, so that the predicted products of the mutant <i>MSH2</i> mRNAs were truncated proteins of 505 amino acids (with all of exon 10 deleted) and 528 amino acids (with a deletion of 82-nucleotides in exon 10), resulting in the loss of the interaction domain, the ATP domain and post-translationally modified residues. Quantitative RT-PCR (qRT-PCR) analysis showed that <i>MSH2</i> mRNA levels in all patients were reduced to only 1/4 of the control levels. Our study reveals that a novel splicing mutation (c.1661+2 T>G) in the <i>MSH2</i> gene causes LS and reaffirms the importance of genetic testing for LS.","variants":[{"Name":"NM_000251.3(MSH2):c.1661+2T>G","Chromosome":"2","Start":"47466810","Stop":"47466810","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1984280,"rule_based_match":true,"evidence_text":"c.1661+2 T>G","llm_judgment":"PRESENT","evidence":"c.1661+2 T>G","abstract_start":388,"abstract_end":400}]}
{"pmid":"31053111","title":"A novel small deletion of LMX1B in a large Chinese family with nail-patella syndrome.","abstract":"BACKGROUND: Nail-patella syndrome (NPS) is an autosomal dominant developmental disorder most commonly characterized by dyplasia of nail or patella, the radial head or the humeral head hypoplasia, and, frequently ocular abnormalities and renal disease. It is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes LIM homeodomain transcription factor and is essential for regulating the dorsal limb fate.\nMETHODS: A five generation pedigree was recruited. Genomic DNA was extracted from the peripheral blood samples. Mutation detection was performed by Sanger sequencing the LMX1B gene. In silico functional annotation of the variant was performed using the in silico predictors SIFT, PolyPhen-2 and Mutation Taster.\nRESULTS: A novel heterozygous small deletion within exon 4 of LMX1B, c.712_714delTTC, was identified in a rare five-generation NPS pedigree. The mutation resulted in a deletion of the conserved amino acid phenylalanine at codon 238 (p.Phe238del), which located in the homeodomain of LMX1B may abolish DNA binding with the molecule. Conformational prediction showed that the variation could transform the helical structure comprising p.Phe234, p.Lys235, p.Ala236, and p.Ser237.\nCONCLUSION: We identified a novel NPS-causing LMX1B mutation and expanded the spectrum of mutations in the LMX1B gene. The c.712_714delTTC mutation may affect the quaternary structure of LMX1B, which is essential for the specification of dorsal limb fate at both zeugopodal and autopodal levels, leading to typical NPS.","variants":[{"Name":"NM_001174147.2(LMX1B):c.712_714del (p.Phe238del)","Chromosome":"9","Start":"126693293","Stop":"126693295","ReferenceAlleleVCF":"CCTT","AlternateAlleleVCF":"C","allel_id":511781,"rule_based_match":true,"evidence_text":"c.712_714delTTC","llm_judgment":"PRESENT","evidence":"c.712_714delTTC","abstract_start":813,"abstract_end":828}]}
{"pmid":"31353855","title":"Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations.","abstract":"OBJECTIVE: To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy-causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype-phenotype-physiological correlations.\nMETHODS: Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole-exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the K<sub>v</sub> 3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two-electrode voltage clamping were used.\nRESULTS: Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole-cell current, but no dominant-negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole-cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance.\nINTERPRETATION: These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.","variants":[{"Name":"NM_001112741.2(KCNC1):c.1538C>T (p.Ala513Val)","Chromosome":"11","Start":"17779489","Stop":"17779489","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":935451,"rule_based_match":true,"evidence_text":"c.1538C > T","llm_judgment":"PRESENT","evidence":"c.1538C > T","abstract_start":1198,"abstract_end":1209},{"Name":"NM_001112741.2(KCNC1):c.1262C>T (p.Ala421Val)","Chromosome":"11","Start":"17772356","Stop":"17772356","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":481404,"rule_based_match":true,"evidence_text":"c.1262C > T","llm_judgment":"PRESENT","evidence":"c.1262C > T","abstract_start":803,"abstract_end":814}]}
{"pmid":"31196892","title":"Neonatal diabetes mellitus due to a novel variant in the","abstract":"Neonatal diabetes mellitus (NDM) is a rare condition that presents with diabetes in the first few months of life. The treatment of NDM may differ depending on the genetic etiology, with numerous studies showing the benefit of sulfonylurea therapy in cases caused by mutations in <i>KCNJ11</i> or <i>ABCC8</i> Mutations in the insulin gene (<i>INS</i>) have also been identified as causes of NDM; these cases are generally best treated with insulin alone. We report a case of a female infant born small for gestational age (SGA) at late preterm diagnosed with NDM at 7 wk of life who was found by rapid whole-genome sequencing to harbor a novel de novo c.26C>G (p.Pro9Arg) variant in the <i>INS</i> gene. She presented with diabetic ketoacidosis, which responded to insulin therapy. She did not respond to empiric trial of sulfonylurea therapy early in her hospital course, and it was discontinued once a genetic diagnosis was made. Early genetic evaluation in patients presenting with NDM is essential to optimize therapeutic decision-making.","variants":[{"Name":"NM_000207.3(INS):c.26C>G (p.Pro9Arg)","Chromosome":"11","Start":"2160946","Stop":"2160946","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":614519,"rule_based_match":true,"evidence_text":"c.26C>G (p.Pro9Arg)","llm_judgment":"PRESENT","evidence":"c.26C>G (p.Pro9Arg)","abstract_start":652,"abstract_end":671}]}
{"pmid":"33175337","title":"Identification of a novel missense c.386G > A variant in a boy with the POMGNT1-related muscular dystrophy-dystroglycanopathy.","abstract":"Muscular dystrophy-dystroglycanopathies are autosomal recessive neurologic disorders, caused by homozygous or compound heterozygous mutations in the POMGNT1 gene-encoding protein O-mannose beta-1,2-N-acetylglucosaminyl transferase. This type of muscular dystrophy is characterized by early-onset muscle weakness, gait ataxia, microcephaly, and developmental delay.We performed whole-exome sequencing to detect the disease-causing variants in a 4 year-old boy. Afterwards, Sanger sequencing was performed to confirm the detected variant in the patient and his family. We evaluated a 4 year-old Iranian boy presented with delayed speech and language development, gait ataxia, global developmental delay, motor delay, neurodevelopmental delay, postnatal microcephaly and strabismus. His parents were first cousins, and the mother had a history of spontaneous abortion. In this study, we report a novel missense c.386G > A; p.(Arg129Gln) variant in the POMGNT1 gene which was confirmed by Sanger sequencing in the patient and segregated with the disease in the family.","variants":[{"Name":"NM_017739.4(POMGNT1):c.386G>A (p.Arg129Gln)","Chromosome":"1","Start":"46196046","Stop":"46196046","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":448216,"rule_based_match":true,"evidence_text":"c.386G > A; p.(Arg129Gln)","llm_judgment":"PRESENT","evidence":"c.386G > A; p.(Arg129Gln)","abstract_start":908,"abstract_end":933}]}
{"pmid":"21840485","title":"Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5'UTR.","abstract":"Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem; c.-27C > A located near the transcription initiation site and c.85G > T. The c.-27C > A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation.","variants":[{"Name":"NM_000249.4(MLH1):c.-27C>A","Chromosome":"3","Start":"36993521","Stop":"36993521","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":95063,"rule_based_match":true,"evidence_text":"c.-27C > A","llm_judgment":"PRESENT","evidence":"c.-27C > A","abstract_start":718,"abstract_end":728}]}
{"pmid":"32297714","title":"Hutchinson-Gilford Progeria syndrome: Report of the first Togolese case.","abstract":"The aim of this article is to describe the first case of Hutchinson-Gilford Progeria Syndrome (HGPS) in Togo and review all Africans cases. Our patient was a 12.8-year-old Togolese boy followed in our unit till he was 15-year-old for HGPS. He was the only child of non-consanguineous parents. The phenotypic findings were craniofacial dysmorphy, dwarfism, lipodystrophy, diffusely scattered hyperpigmented foci, pyriform thorax, nail dystrophy, decreased joint mobility, and camptodactyly. He had characteristic facies with prominent forehead, prominent eyes, absent ear lobule, thin nasal skin, convex nasal profile, micrognathia, and crowded teeth. Radiologicals findings were bilateral coxa valga, pyriform thorax, and acro-osteolysis. We sequenced the entire coding region of LMNA gene, and mutation analysis revealed a heterozygous mutation c.1824C>T (p.Gly608Gly). Our patient is therefore the fifth African and the fourth with classical mutation, first of Western Africa, and second of (sub-Saharan) African black race. The recurrence of HGPS is low like the cause is neomutation or germinal mosaicism.","variants":[{"Name":"NM_170707.4(LMNA):c.1824C>T (p.Gly608=)","Chromosome":"1","Start":"156138613","Stop":"156138613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29539,"rule_based_match":true,"evidence_text":"c.1824C>T (p.Gly608Gly)","llm_judgment":"PRESENT","evidence":"c.1824C>T (p.Gly608Gly)","abstract_start":846,"abstract_end":869}]}
{"pmid":"28204496","title":"The glycan-specific sulfotransferase (R77W)GalNAc-4-ST1 putatively responsible for peeling skin syndrome has normal properties consistent with a simple sequence polymorphisim.","abstract":"Expanded access to DNA sequencing now fosters ready detection of site-specific human genome alterations whose actual significance requires in-depth functional study to rule in or out disease-causing mutations. This is a particular concern for genomic sequence differences in glycosyltransferases, whose implications are often difficult to assess. A recent whole-exome sequencing study identifies (c.229 C > T) in the GalNAc-4-ST1 glycosyltransferase (CHST8) as a disease-causing missense R77W mutation yielding the genodermatosis peeling skin syndrome (PSS) when homozygous. Cabral et al. (Genomics. 2012;99:202-208) cite this sequence change as reducing keratinocyte GalNAc-4-ST1 activity, thus decreasing glycosaminoglycan sulfation, as the mechanism for this blistering disorder. Such an identification could point toward potential clinical and/or prenatal diagnosis of a harmful medical condition. However, GalNAc-4-ST1 has minimal activity toward glycosaminoglycans, instead modifying terminal β1,4-linked GalNAc on N- and O-linked oligosaccharides on specific glycoproteins. We find expression, processing and catalytic activity of GalNAc-4-ST1 completely equivalent between wild type and (R77W) sulfotransferases. Moreover, keratinocytes have little or no GalNAc-4-ST1 mRNA, indicating that they do not express GalNAc-4-ST1. In addition, loss-of-function of GalNAc-4-ST1 primarily presents as reproductive system aberrations rather than skin effects. These findings, an allele frequency of 0.004357, and a 10-fold difference in prevalence of CHST8 (c.299 C > T, R77W) across different ethnic groups, suggest that this sequence represents a \"passenger\" distributed polymorphism, a simple sequence variant form of the enzyme having normal activity, rather than a \"driver\" disease-causing mutation that accounts for PSS. This study presents an example for guiding biomedical research initiatives, as well as medical and personal/family perspectives, regarding newly-identified genomic sequence differences.","variants":[{"Name":"NM_001127895.2(CHST8):c.229C>T (p.Arg77Trp)","Chromosome":"19","Start":"33772017","Stop":"33772017","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":181559,"rule_based_match":true,"evidence_text":"c.229 C > T","llm_judgment":"PRESENT","evidence":"c.229 C > T","abstract_start":397,"abstract_end":408}]}
{"pmid":"18249525","title":"A novel mutation of KCNQ3 gene in a Chinese family with benign familial neonatal convulsions.","abstract":"Benign familial neonatal convulsions (BFNC, also named benign familial neonatal seizures, BFNS) is a rare autosomal dominant inherited epilepsy syndrome with clinical and genetic heterogeneity. Two voltage-gated potassium channel subunit genes, KCNQ2 and KCNQ3, have been identified to cause BFNC1 and BFNC2, respectively. To date, only three mutations of KCNQ3, all located within exon 5, have been reported. By limited linkage analysis and mutation analysis of KCNQ3 in a Chinese family with BFNC, we identified a novel missense mutation of KCNQ3, c.988C>T located within exon 6. c.988C>T led to the substitution Cys for Arg in amino acid position 330 (p.R330C) in KCNQ3 potassium channel, which possibly impaired the neuronal M-current and altered neuronal excitability. Seizures of all BFNC patients started from day 2 to 3 after birth and remitted during 1 month, and no recurrence was found. One family member who displayed fever-associated seizures for two times at age 5 years and was diagnosed as febrile seizures, however, did not carry this mutation, which suggests that febrile seizures and BFNC have different pathogenesis. To our knowledge, this is the first report of KCNQ3 mutation in Chinese family with BFNC.","variants":[{"Name":"NM_004519.4(KCNQ3):c.988C>T (p.Arg330Cys)","Chromosome":"8","Start":"132174295","Stop":"132174295","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34269,"rule_based_match":true,"evidence_text":"c.988C>T","llm_judgment":"PRESENT","evidence":"c.988C>T","abstract_start":550,"abstract_end":558}]}
{"pmid":"33963797","title":"The genotypic and phenotypic spectrum of pycnodysostosis in Saudi Arabia: Novel variants and clinical findings.","abstract":"Pycnodysostosis is characterized by short stature, osteosclerosis, acro-osteolysis, increased tendency of fractures, and distinctive dysmorphic features. It is a rare autosomal recessive disease caused by biallelic CTSK mutations. The clinical details of 18 patients from Saudi Arabia were reviewed. Short stature, osteopetrosis, acro-osteolysis, and distinctive facial dysmorphism were documented in all cases. Our results highlight the significant complications associated with this disease. The large anterior fontanelle is one of the cardinal signs of this disease; however, half of our patients had small fontanelles and a quarter had craniosynostosis, which caused optic nerve compression. Sleep apnea was of the major complications in three patients. Bone fracture can be a presenting symptom, and in our patients it mainly occurred after the age of 3 years. Bone marrow suppression was seen in a single patient of our cohort who was misdiagnosed initially with malignant osteopetrosis. In this study, we also describe two novel (c.5G > A [p.Trp2Ter], c.538G > A [p.Gly180Ser]) and two reported (c.244-29 A > G, c.830C > T [p.Ala277Val]) CTSK mutations. Our results indicate that the recurrent intronic variant, c.244-29 A > G is likely to be a founder mutation, as it was found in 78% (14/18 patients) of our cohort belonging to the same tribe.","variants":[{"Name":"NM_000396.4(CTSK):c.244-29A>G","Chromosome":"1","Start":"150806045","Stop":"150806045","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":970194,"rule_based_match":true,"evidence_text":"c.244-29 A > G","llm_judgment":"PRESENT","evidence":"c.244-29 A > G","abstract_start":1103,"abstract_end":1117}]}
{"pmid":"26748608","title":"The c.65-2A>G splice site mutation is associated with a mild phenotype in Danon disease due to the transcription of normal LAMP2 mRNA.","abstract":"Danon disease (DD) is a rare X-linked multisystem disorder caused by mutations of the LAMP2 gene and characterized by intellectual disability, skeletal myopathy and cardiomyopathy. The survival time is severely reduced. Contrasting with the usual disease course, we report on a family with an exceptionally mild phenotype of DD despite having two potentially damaging LAMP2 mutations. Using RNA-Seq analysis, we showed that a c.65-2A>G splice site mutation results in the tissue-specific production of four different transcripts including the full-length mRNA in muscle tissue but not in leukocytes. We confirmed our results by immunohistochemistry and immunoblotting, showing the detection of LAMP2 protein only in muscle. The second mutation (c.586A>T, p.T196S) has been reported before to have an uncertain clinical significance. In our patients, however, neither of the two mutations seem to have a high enough functional impact to cause a severe phenotype. Overall, our study reveals that alternative splicing is a potential mechanism in DD with underlying splice site mutations of the LAMP2 gene in order to rescue the full-length mRNA. Moreover, our report of a mild phenotype complements the DD spectrum, which is of great importance for a rare disease suspected to be underdiagnosed.","variants":[{"Name":"NM_002294.3(LAMP2):c.586A>T (p.Thr196Ser)","Chromosome":"X","Start":"120447996","Stop":"120447996","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":53599,"rule_based_match":true,"evidence_text":"c.586A>T, p.T196S","llm_judgment":"PRESENT","evidence":"c.586A>T, p.T196S","abstract_start":745,"abstract_end":762}]}
{"pmid":"24358150","title":"A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy.","abstract":"Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental.","variants":[{"Name":"NM_006030.4(CACNA2D2):c.1295del (p.Asn432fs)","Chromosome":"3","Start":"50378959","Stop":"50378959","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":106650,"rule_based_match":true,"evidence_text":"c.1295delA (p.Asn432fs)","llm_judgment":"PRESENT","evidence":"c.1295delA (p.Asn432fs)","abstract_start":763,"abstract_end":786}]}
{"pmid":"27600236","title":"SNP Analysis and Whole Exome Sequencing: Their Application in the Analysis of a Consanguineous Pedigree Segregating Ataxia.","abstract":"Autosomal recessive cerebellar ataxia encompasses a large and heterogeneous group of neurodegenerative disorders. We employed single nucleotide polymorphism (SNP) analysis and whole exome sequencing to investigate a consanguineous Maori pedigree segregating ataxia. We identified a novel mutation in exon 10 of the SACS gene: c.7962T>G p.(Tyr2654*), establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Our findings expand both the genetic and phenotypic spectrum of this rare disorder, and highlight the value of high-density SNP analysis and whole exome sequencing as powerful and cost-effective tools in the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias.","variants":[{"Name":"NM_014363.6(SACS):c.7962T>G (p.Tyr2654Ter)","Chromosome":"13","Start":"23335914","Stop":"23335914","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1874593,"rule_based_match":true,"evidence_text":"c.7962T>G p.(Tyr2654*)","llm_judgment":"PRESENT","evidence":"c.7962T>G p.(Tyr2654*)","abstract_start":326,"abstract_end":348}]}
{"pmid":"35899201","title":"Case Report: Identification of Two Variants of","abstract":"<b>Background:</b> Genetic causes in most affected children with intellectual disability and/or development delay remain unknown. <b>Methods:</b> To identify potential variants responsible for these disorders, we recruited 161 affected families and performed whole-exome sequencing and associated bioinformatics analysis. <b>Results:</b> In the present study, we report the identification of variants in the <i>ALG13</i> gene in two of the families. In family 1, a known pathogenic missense variant (c.23T > C; p.V8A) of <i>ALG13</i> was identified in a boy and his mother. In family 2, a novel missense variant (c.862C > G; p.L288V) of the same gene was identified in the affected boy and his phenotypically normal mother. Genotype-phenotype correlation analysis by comparing reported 28 different variants (HGMD) showed that three major phenotypes, including various seizures/epilepsy, intellectual disability, and development delay (such as growth, speech, motor, etc.), are present in most affected individuals. However, other phenotypes, such as strabismus and absence of seizure in our second patient, are not reported if any, which may represent a unique case of X-linked recessive nonsyndromic disorder caused by a mutation in <i>ALG13</i>. <b>Conclusion:</b> We identified two missense variants in <i>ALG13</i> in a cohort of 161 families with affected individuals diagnosed as intellectual disability and/or development delay. A novel c.862C > G mutation may represent a case of X-linked recessive.","variants":[{"Name":"NM_001099922.3(ALG13):c.862C>G (p.Leu288Val)","Chromosome":"X","Start":"111711702","Stop":"111711702","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2984698,"rule_based_match":true,"evidence_text":"c.862C > G (p.L288V)","llm_judgment":"PRESENT","evidence":"c.862C > G","abstract_start":613,"abstract_end":623}]}
{"pmid":"29981851","title":"A novel insertion (c.1098dupT) in the albumin gene causes analbuminemia in a consanguineous family.","abstract":"Congenital analbuminemia (OMIM # 616000) is an extremely rare autosomal recessive disorder, caused by variations in the albumin gene (ALB), which is generally thought to be a relatively benign condition in adulthood, but seems to be potentially life threatening in the pre- and peri-natal period. The subject of our study was a consanguineous family, in which we identified two analbuminemic individuals. Mutation analysis of ALB revealed that both are homozygous for a previously unreported insertion in exon 9 (c.1098dupT), causing a subsequent frame-shift with the generation of a premature stop codon, and an aberrant truncated putative protein product, p.Val367fsTer12. This variation is present in heterozygous condition in several other members of the family. The phenotype and the molecular genetics of CAA are discussed.","variants":[{"Name":"NM_000477.7(ALB):c.1098dup (p.Val367fs)","Chromosome":"4","Start":"73415073","Stop":"73415074","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":624071,"rule_based_match":true,"evidence_text":"c.1098dupT","llm_judgment":"PRESENT","evidence":"c.1098dupT","abstract_start":513,"abstract_end":523}]}
{"pmid":"32284662","title":"BRCA1 and BRCA2 mutations in a sample of breast and ovarian cancer families from the Colombian pacific.","abstract":"INTRODUCTION: Breast cancer is the most common neoplasia of women from all over the world especially women from Colombia. 5%-10% of all cases are caused by hereditary factors, 25% of those cases have mutations in the <i>BRCA1/BRCA2</i> genes.\nOBJECTIVE: The purpose of this study was to identify the mutations associated with the risk of familial breast and/or ovarian cancer in a population of Colombian pacific.\nMETHODS: 58 high-risk breast and/or ovarian cancer families and 20 controls were screened for germline mutations in <i>BRCA1</i> and <i>BRCA2</i>, by Single Strand Conformation Polymorphism (SSCP) and sequencing.\nRESULTS: Four families (6.9%) were found to carry <i>BRCA1</i> mutations and eight families (13.8%) had mutations in <i>BRCA2.</i> In <i>BRCA1</i>, we found three Variants of Uncertain Significance (VUS), of which we concluded, using <i>in silico</i> tools, that c.81-12C>G and c.3119G>A (p.Ser1040Asn) are probably deleterious, and c.3083G>A (p.Arg1028His) is probably neutral. In <i>BRCA2</i>, we found three variants of uncertain significance: two were previously described and one novel mutation. Using <i>in silico</i> analysis, we concluded that c.865A>G (p.Asn289Asp) and c.6427T>C (p.Ser2143Pro) are probably deleterious and c.125A>G (p.Tyr42Cys) is probably neutral. Only one of them has previously been reported in Colombia. We also identified 13 polymorphisms (4 in <i>BRCA1</i> and 9 in <i>BRCA2</i>), two of them are associated with a moderate increase in breast cancer risk (<i>BRCA2</i> c.1114A>C and c.8755-66T>C).\nCONCLUSION: According to our results, the Colombian pacific population presents diverse mutational spectrum for BRCA genes that differs from the findings in other regions in the country.","variants":[{"Name":"NM_000059.4(BRCA2):c.865A>G (p.Asn289Asp)","Chromosome":"13","Start":"32332343","Stop":"32332343","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":46732,"rule_based_match":true,"evidence_text":"c.865A>G (p.Asn289Asp)","llm_judgment":"PRESENT","evidence":"c.865A>G (p.Asn289Asp)","abstract_start":1179,"abstract_end":1201}]}
{"pmid":"31268865","title":"First description of the molecular and clinical characterization of hereditary factor V deficiency in Saudi Arabia: report of four novel mutations.","abstract":"Coagulation factor V plays a significant role in the blood coagulation cascade as part of the prothrombinase complex. Factor V deficiency (FVD) is a rare autosomal recessive bleeding disorder with a variable phenotypic expression which varies from being asymptomatic-to-severe bleeding episodes. The aim of this study was to perform molecular and clinical characterization of FVD in patients originating from Saudi Arabia. Eleven patients (two males and nine females) with confirmed FVD were recruited in the study with ages ranging between 5 and 53 years. A next-generation sequencing-based hematology panel encompassing 393 known genes was used. A total of six sequence variations in F5 gene were identified, including four missense mutations (p.Pro189Leu, p.Trp2004Arg, p.Met2148Thr, p. Arg2202Cys), a deletion (p.Arg872Lysfs*12) and a splicing variant (c.1118+5G>T). Four variants were identified for the first time in this study. Three patients were homozygous for their respective mutations and seven patients were heterozygous. We were not able to identify a pathogenic variant in one patient of the cohort. In-silico and three-dimensional structural analyses were performed to predict the possible impact and functional consequences of the identified variants. To our knowledge, this is the first study addressing factor V mutations in patients with Arab ancestry. Results have helped in providing a definitive diagnosis to the patients and carrier detection in extended family members. Overall, the hematology panel assay was an efficient platform, demonstrating a formidable approach for the molecular diagnosis of other suspected bleeding disorders.","variants":[{"Name":"NM_000130.5(F5):c.6604C>T (p.Arg2202Cys)","Chromosome":"1","Start":"169514384","Stop":"169514384","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3498723,"rule_based_match":false,"evidence_text":"p. Arg2202Cys","llm_judgment":"PRESENT","evidence":"p. Arg2202Cys","abstract_start":787,"abstract_end":800}]}
{"pmid":"23064905","title":"Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia.","abstract":"Patients with fibromuscular dysplasia (FMD) may have clinical features consistent with Mendelian vascular connective tissue disorders. The yield of genetic testing for these disorders among patients with FMD has not been determined. A total of 216 consecutive patients with FMD were identified. Clinical characteristics were collected and genetic test results reviewed for abnormalities in the following genes: transforming growth factor-β receptor 1 and 2 (TGFβR1 and TGFβR2), collagen 3A1, fibrillin-1, smooth muscle α-actin 2, and SMAD3. A total of 63 patients (63/216; 29.2%) were referred for genetic counseling with testing performed in 35 (35/63; 55.6%). The percentage of patients with a history of arterial or aortic dissection, history of aortic aneurysm, systemic features of a connective tissue disorder, and a family history of sudden death was significantly larger in the group that underwent genetic testing (62.9% vs 18.2%, p < 0.001; 8.6% vs 1.7%, p = 0.02; 51.4% vs 17.1%, p < 0.001; and 42.9% vs 22.7%, p = 0.04, respectively). Two patients were found to have distinct variants in the TGFβR1 gene (c.611 C>T, p.Thr204lle and c.1285 T>C, p.Tyr429His). The yield of genetic testing for vascular connective tissue disorders was low in a high-risk subset of FMD patients. However, two patients with a similar phenotype had novel and distinct variants in the TGFβR1 gene, a finding which merits further investigation.","variants":[{"Name":"NM_004612.4(TGFBR1):c.1285T>C (p.Tyr429His)","Chromosome":"9","Start":"99147683","Stop":"99147683","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":612873,"rule_based_match":true,"evidence_text":"c.1285 T>C, p.Tyr429His","llm_judgment":"PRESENT","evidence":"c.1285 T>C, p.Tyr429His","abstract_start":1144,"abstract_end":1167},{"Name":"NM_004612.4(TGFBR1):c.611C>T (p.Thr204Ile)","Chromosome":"9","Start":"99137895","Stop":"99137895","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":258613,"rule_based_match":true,"evidence_text":"c.611 C>T, p.Thr204lle","llm_judgment":"PRESENT","evidence":"c.611 C>T, p.Thr204lle","abstract_start":1117,"abstract_end":1139}]}
{"pmid":"29938792","title":"Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation.","abstract":"The HNRNPH2-associated disease (mental retardation, X-linked, syndromic, Bain type [MRXSB, MIM #300986]) is caused by de novo mutations in the X-linked HNRNPH2 gene. MRXSB has been described in six female patients with dysmorphy, developmental delay, intellectual disability, autism, hypotonia and seizures. The reported HNRNPH2 mutations were clustered in the small domain encoding nuclear localization signal; in particular, the p.Arg206Trp was found in four independent de novo events. HNRNPH1 is a conserved autosomal paralogue of HNRNPH2 with a similar function in regulation of pre-mRNAs splicing but so far it has not been associated with human disease. We describe a boy with a disease similar to MRXSB in whom a novel de novo mutation c.616C>T (p.Arg206Trp) in HNRNPH1 was found (ie, the exact paralogue of the recurrent HNRNPH2 mutation). We propose that defective function of HNRNPH2 and HNRNPH1 nuclear localization signal has similar clinical consequences. An important difference between the two diseases is that the HNRNPH1-associated syndrome may occur in boys (as in the case of our proband) which is well explained by the autosomal (chr5q35.3) rather than X-linked localization of the HNRNPH2 gene.","variants":[{"Name":"NM_001257293.2(HNRNPH1):c.616C>T (p.Arg206Trp)","Chromosome":"5","Start":"179618244","Stop":"179618244","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":973480,"rule_based_match":true,"evidence_text":"c.616C>T (p.Arg206Trp)","llm_judgment":"PRESENT","evidence":"c.616C>T (p.Arg206Trp)","abstract_start":744,"abstract_end":766}]}
{"pmid":"27799408","title":"Congenital valvular defects associated with deleterious mutations in the","abstract":"BACKGROUND: The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families.\nMETHODS: Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves. The significance of the findings was assessed by studying sporulation of yeast carrying a homologous Phospholipase D (<i>PLD1</i>) mutation, in situ hybridisation in chick embryo and echocardiography and histological examination of hearts of <i>PLD1</i> knockout mice.\nRESULTS: Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the <i>PLD1</i> gene. The mutations affected highly conserved sites in the PLD1 protein and the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain. Here we show that in chick embryos <i>PLD1</i> expression is confined to the forming heart (E2-E8) and homogeneously expressed all over the heart during days E2-E3. Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract. This pattern of expression follows the known dynamic patterning of apoptosis in the developing heart, consistent with the known role of PLD1 in the promotion of apoptosis. In hearts of <i>PLD1</i> knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve.\nCONCLUSIONS: The findings support a role for PLD1 in normal heart valvulogenesis.","variants":[{"Name":"NM_002662.5(PLD1):c.1325A>C (p.His442Pro)","Chromosome":"3","Start":"171692345","Stop":"171692345","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":414648,"rule_based_match":false,"evidence_text":"p.His442Pro","llm_judgment":"PRESENT","evidence":"p.His442Pro","abstract_start":710,"abstract_end":721},{"Name":"NM_002662.5(PLD1):c.2882+2T>C","Chromosome":"3","Start":"171612277","Stop":"171612277","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":414650,"rule_based_match":true,"evidence_text":"c.2882+2T>C","llm_judgment":"PRESENT","evidence":"c.2882+2T>C","abstract_start":741,"abstract_end":752}]}
{"pmid":"30690819","title":"Splicing analysis of 26 F8 nucleotide variations using a minigene assay.","abstract":"BACKGROUND: Classically, the study of splicing impact of variation located near the splice site is performed by both in silico and mRNA analysis. However, RNA sample was rarely available.\nOBJECTIVE: To characterize a panel of putative haemophilia A splicing variations.\nMATERIALS AND METHODS: Twenty-six F8 variations identified from a cohort of 2075 haemophilia A families were studied using both bioinformatic tools and in vitro minigene assays in HeLa and Huh7 cells.\nRESULTS: An aberrant splicing was demonstrated for 21/26 tested sequence variations. A good correlation between in silico and in vitro analysis was obtained for variations affecting donor splice site (12/14) and for the synonymous variations located inside an exon (6/6). Conversely, no concordant results were observed for the six variations affecting acceptor splice sites. The variations resulted more frequently in exon skipping (n = 13) than in activation of nearby cryptic splice sites (n = 5), in use of a de novo splice site (n = 2) or in insertion of large intronic sequences (n = 1). This study allowed to reclassify 5 synonymous substitutions c.1167A>G (p.Gln389Gln), c.1569G>T (p.Leu523Leu), c.1752G>A (p.Gln584Gln), c.5586G>A (p.Leu1862Leu) and c.6066C>T (p.Gly2022Gly) as splicing variations. The pathological significance of five variations remained unclear (c.222G>A [p.Thr74Thr], c.237C>T [p.Asn79Asn], c.240C>T [p.Ile80Ile], c.2113+5_2113+8del and c.2113+5G>A).\nDISCUSSION: The minigene assay herein gave additional evidences for the clinical significance of 21/26 F8 putative splice site mutations. Such investigation should be performed for each F8 putative splice site variation for which no mRNA sample is available, notably to greatly improve the genetic counselling given to female carriers.","variants":[{"Name":"NM_000132.4(F8):c.6066C>T (p.Gly2022=)","Chromosome":"X","Start":"154902100","Stop":"154902100","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3081373,"rule_based_match":true,"evidence_text":"c.6066C>T (p.Gly2022Gly)","llm_judgment":"PRESENT","evidence":"c.6066C>T (p.Gly2022Gly)","abstract_start":1229,"abstract_end":1253}]}
{"pmid":"28267090","title":"A Rare Cause of Neonatal Hemolytic Anemia: Glutathione Synthetase Deficiency.","abstract":"BACKGROUND: Isolated hemolysis or hemolytic anemia and 5-oxoprolinuria are 2 distinct medical conditions in the clinical spectrum associated with glutathione synthetase deficiency.\nCLINICAL OBSERVATION: A 1-day-old female baby presented with anemia and respiratory distress. Her hemoglobin level was 9.5 g/dL and the total serum bilirubin level was 5.6 mg/dL. Metabolic acidosis was detected in her blood gas analysis. Metabolic acidosis recurred despite treatment and further investigation was required. Her 5-oxoproline level was 3815 mmol/mol creatinine in urine organic acid analysis, and a homozygous mutation [p.R125H (c.374G>A)] was found in the glutathione synthetase gene.\nCONCLUSIONS: GSD has been observed in very few patients and is rarely considered in the differential diagnosis of hemolytic anemia in newborns.","variants":[{"Name":"NM_000178.4(GSS):c.374G>A (p.Arg125His)","Chromosome":"20","Start":"34942605","Stop":"34942605","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2905532,"rule_based_match":true,"evidence_text":"p.R125H (c.374G>A)","llm_judgment":"PRESENT","evidence":"p.R125H (c.374G>A)","abstract_start":616,"abstract_end":634}]}
{"pmid":"19338683","title":"The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype.","abstract":"BACKGROUND: CHEK2 has previously been excluded as a major cause of Li-Fraumeni syndrome (LFS). One particular CHEK2 germline mutation, c.1100delC, has been shown to be associated with elevated breast cancer risk. The prevalence of CHEK2*1100delC differs between populations and has been found to be relatively high in the Netherlands. The question remains nevertheless whether CHEK2 germline mutations contribute to the Li-Fraumeni phenotype.\nMETHODS: We have screened 65 Dutch TP53-negative LFS/LFL candidate patients for CHEK2 germline mutations to determine their contribution to the LFS/LFL phenotype.\nRESULTS: We identified six index patients with a CHEK2 sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del.\nCONCLUSION: Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population. However, CHEK2 might be a factor contributing to individual tumour development in TP53-negative cancer-prone families.","variants":[{"Name":"NM_007194.4(CHEK2):c.1100del (p.Thr367fs)","Chromosome":"22","Start":"28695869","Stop":"28695869","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":133499,"rule_based_match":true,"evidence_text":"c.1100delC","llm_judgment":"PRESENT","evidence":"c.1100delC","abstract_start":135,"abstract_end":145}]}
{"pmid":"31015583","title":"Molecular assay for an intronic variant in NUP93 that causes steroid resistant nephrotic syndrome.","abstract":"Advances in molecular genetics have revealed that approximately 30% of cases with steroid-resistant nephrotic syndrome (SRNS) are caused by single-gene mutations. More than 50 genes are responsible for SRNS. One such gene is the nucleoporin, 93-KD (NUP93). Thus far, few studies have reported mutations of NUP93 in SRNS. Here, we describe an NUP93 biallelic mutation in a 9-year-old boy with focal segmental glomerular sclerosis (FSGS). Notably, one mutation comprised an intronic variant; we conducted in vivo and in vitro analysis to characterize this variant. We found two heterozygous mutations in NUP93: c.2137-18G>A in intron 19 and a novel nonsense mutation c.727A>T (p.Lys243*) in exon 8. We conducted RNA sequencing and in vitro splicing assays by using minigene construction, combined with protein expression analysis to determine the pathogenicity of the intronic variant. Both RNA sequencing and in vitro splicing assay showed exon 20-skipping by the intronic variant. In protein expression analysis, aberrant subcellular localization with small punctate vesicles in the cytoplasm was observed for the intronic variant. Taken together, we concluded that c.2137-18G>A was linked to pathogenicity due to aberrant splicing. NUP93 variants are quite rare; however, we have shown that even intronic variants in NUP93 can cause SRNS. This study provides a fundamental approach to validate the intronic variant, as well as new insights regarding the clinical spectrum of SRNS caused by rare gene variants.","variants":[{"Name":"NM_014669.5(NUP93):c.2137-18G>A","Chromosome":"16","Start":"56839503","Stop":"56839503","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":904618,"rule_based_match":true,"evidence_text":"c.2137-18G>A","llm_judgment":"PRESENT","evidence":"c.2137-18G>A","abstract_start":609,"abstract_end":621}]}
{"pmid":"31456457","title":"Double Heterozygosity for Hb Durham-N.C. (","abstract":"The evaluation of a 10-month-old girl of Sicilian origin with a clinical phenotype of severe thalassemia led to the identification of two β-globin gene defects, a β-thalassemia (β-thal), mutation at IVS-I-110 (<i>HBB</i>: c.93-21G>A) and a variant hemoglobin (Hb) mutation at codon 114 (<i>HBB</i>: c.344T>C) on the other allele, reported as Hb Durham-N.C. (also known as Hb Brescia) [β114(G16)Leu→Pro] in the HbVar database. A very low Hb level (Hb 3.5 g/dL), microcytosis [mean corpuscular volume (MCV) 63.2 fL] and hypocromia [mean corpuscular Hb (MCH) 19.6 pg], increased red blood cell (RBC) distribution width (RDW) (36.0%), higher reticulocytes (6.2%), anisocytosis, poikilocytosis, hypocromia, basophilic stippling and inclusion body formation, were present in the affected subject. Analysis of other family components showed the presence of <i>HBB</i>: c.93-21G>A defect in the mother and in her brother, while Hb Durham-N.C. was absent in all other relatives, thus, this mutation has arisen as a <i>de novo</i> defect. This is the first case described as a severe thalassemic phenotype in a compound heterozygote carrier of this unstable Hb and a common β-thalassemic allele. The important information gained from this case is that a rare dominant or recessive mutation may arise in every individual, even if this is a very rare event.","variants":[{"Name":"NM_000518.5(HBB):c.93-21G>A","Chromosome":"11","Start":"5226820","Stop":"5226820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30493,"rule_based_match":true,"evidence_text":"HBB: c.93-21G>A","llm_judgment":"PRESENT","evidence":"c.93-21G>A","abstract_start":222,"abstract_end":232}]}
{"pmid":"33360097","title":"Generation of three induced pluripotent stem cell lines from a patient with Usher syndrome caused by biallelic c.949C > A and c.1256G > T mutations in the USH2A gene.","abstract":"Mutations in the USH2A gene are the most common cause of Usher syndrome and autosomal recessive non-syndromic retinitis pigmentosa. Here, we describe the generation of three induced pluripotent stem cell lines from dermal fibroblasts derived from a patient carrying biallelic c.949C > A and c.1256G > T variants in the USH2A gene, using episomal reprogramming plasmids expressing OCT4, SOX2, KLF4, MYCL, LIN28, mir302/367 and shRNA targeting TP53. All three lines expressed pluripotency markers, displayed unaltered karyotypes as well as trilineage differentiation potential, and were negative for reprogramming episomes and mycoplasma.","variants":[{"Name":"NM_206933.4(USH2A):c.949C>A (p.Arg317=)","Chromosome":"1","Start":"216325499","Stop":"216325499","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":17397,"rule_based_match":true,"evidence_text":"c.949C > A","llm_judgment":"PRESENT","evidence":"c.949C > A","abstract_start":276,"abstract_end":286},{"Name":"NM_206933.4(USH2A):c.1256G>T (p.Cys419Phe)","Chromosome":"1","Start":"216324240","Stop":"216324240","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":17398,"rule_based_match":true,"evidence_text":"c.1256G>T","llm_judgment":"PRESENT","evidence":"c.1256G > T","abstract_start":291,"abstract_end":302}]}
{"pmid":"15954104","title":"Mutation analysis of the GJB2 (connexin 26) gene in Egypt.","abstract":"Fifty to eighty percent of autosomal recessive deafness is due to mutations in the GJB2 gene encoding connexin 26. Among Caucasians, the c.35delG mutation in this gene accounts for up to 30 to 70% of all cases with early childhood deafness. In this study, we present the analysis of the GJB2 gene in 159 Egyptians from 111 families with non-syndromic mild to profound hearing impairment. An additional family with Vohwinkel syndrome, a combination of hearing impairment and palmoplantar keratoderma with constriction of the digits, was also included. We used direct sequencing analysis to detect all possible coding GJB2 variants in this population. The presence of the g.1777179_2085947del mutation (hereafter called del(GJB6-D13S1830)) was also investigated as it was shown to be the second most common mutation causing non-syndromic prelingual hearing impairment in Spain. Sequencing analysis of one randomly chosen individual per family revealed that the c.35delG mutation was present in 24 out of 222 chromosomes (10.8%), making it the most frequent mutation in the GJB2 gene in Egypt. Five other mutations were already described previously [p.Thr8Met, p.Val37Ile, p.Val153Ile, c.333_334delAA, c.1-3172G>A (commonly designated as IVS1+1G>A)]. This study also revealed three other novel gene variants resulting in amino acid substitutions (p.Phe142del, p.Asp117His, p.Ala148Pro). In contrast with most populations, the del(GJB6-D13S1830) mutation upstream of the GJB2 gene was not present in this Egyptian population. A dominant mutation at a highly conserved residue, p.Gly130Val, was found in the family with Vohwinkel syndrome.","variants":[{"Name":"NM_004004.6(GJB2):c.389G>T (p.Gly130Val)","Chromosome":"13","Start":"20189193","Stop":"20189193","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3853576,"rule_based_match":false,"evidence_text":"p.Gly130Val","llm_judgment":"PRESENT","evidence":"p.Gly130Val","abstract_start":1573,"abstract_end":1584},{"Name":"NM_004004.6(GJB2):c.35del (p.Gly12fs)","Chromosome":"13","Start":"20189547","Stop":"20189547","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":32043,"rule_based_match":true,"evidence_text":"c.35delG","llm_judgment":"PRESENT","evidence":"c.35delG","abstract_start":137,"abstract_end":145},{"Name":"NM_004004.6(GJB2):c.421TTC[1] (p.Phe142del)","Chromosome":"13","Start":"20189156","Stop":"20189158","ReferenceAlleleVCF":"GGAA","AlternateAlleleVCF":"G","allel_id":1874584,"rule_based_match":false,"evidence_text":"p.Phe142del","llm_judgment":"PRESENT","evidence":"p.Phe142del","abstract_start":1344,"abstract_end":1355},{"Name":"NM_004004.6(GJB2):c.109G>A (p.Val37Ile)","Chromosome":"13","Start":"20189473","Stop":"20189473","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32062,"rule_based_match":false,"evidence_text":"p.Val37Ile","llm_judgment":"PRESENT","evidence":"p.Val37Ile","abstract_start":1158,"abstract_end":1168}]}
{"pmid":"30967997","title":"Deleterious Mutations in DNA Repair Gene","abstract":"<b>Introduction:</b> <i>FANCC</i> is reported as a novel susceptibility gene for breast cancer, however, its mutation remains unclear in Chinese population. We aimed to identify the germline mutations of <i>FANCC</i> in high-risk breast cancer patients in China. <b>Methods:</b> 255 <i>BRCA1/2</i>-negative Chinese familial breast and/or ovarian cancer (FBOC) patients were recruited for <i>FANCC</i> germline mutations screen. For whom 90 patients were detected by PCR-sequencing assay, and another 165 patients were detected by a 98-gene panel sequencing assay. The 98-gene panel sequencing assay was also used to screen other possible gene mutations for the patients with <i>FANCC</i> mutations detected by PCR-sequencing assay. Two hundred and fifty sporadic breast cancer (SBC) patients and 248 female non-cancer controls (FNCCs) were recruited for the genotyping analysis. Immunohistochemistry (IHC) analysis was used to evaluate the FANCC expression in patients with <i>FANCC</i> mutation. <b>Results:</b> We found one rare <i>FANCC</i> deleterious mutation (c.339G>A, p.W113X, 0.4%) and two novel non-synonymous variants (c.51G>C, p.Q17H, 0.4% and c.758C>A, p.A253E, 0.4%) in FBOC patients, whereas none of above mutations was identified in SBC patients or FNCCs. We also found that one novel synonymous variant (c.903A>G, p.A301A) existed in one FBOC patient. Additionally, two non-synonymous SNPs rs201407189 (c.973G>A, p.A325T) and rs1800367 (c.1345G>A, p.V449M), and two synonymous SNPs rs55719336 (c.816C>T, p.I272I) and rs79722116 (c.1407G>A, p.T469T) were identified in FBOC patients. <b>Conclusion:</b> <i>FANCC</i> deleterious mutations exist in Chinese FBOC patients and investigations on the penetrance and spectrum of <i>FANCC</i> mutations need to be further conducted.","variants":[{"Name":"NM_000136.3(FANCC):c.973G>A (p.Ala325Thr)","Chromosome":"9","Start":"95125109","Stop":"95125109","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":133007,"rule_based_match":true,"evidence_text":"c.973G>A (p.A325T)","llm_judgment":"PRESENT","evidence":"c.973G>A","abstract_start":1420,"abstract_end":1428}]}
{"pmid":"19725132","title":"Multiple genomic aberrations in a patient with mental retardation and hypogonadism: 45,X/46,X,psu dic(Y) karyotype, thyroid hormone receptor beta (THRB) mutation and heterozygosity for Wilson disease.","abstract":"We report on multiple genomic aberrations in a patient with mental retardation. In addition, he had hypogonadism, elevated thyroid hormone levels, hearing loss, delayed speech development and mild dysmorphic features. First, we identified a mosaic karyotype, 45,X/46,X,psu dic(Y). The pseudo-dicentric Y chromosome has three short arm segments. Second, we found a germline mutation (Pro453Thr) of the thyroid hormone receptor beta (THRB) which is associated with resistance to thyroid hormone. Third, he was found to be a carrier of a heterozygous ATP7B mutation (c.2575 + 5G > C), the Wilson disease gene. Even though an array-CGH (with a density of approximately 1 Mb) did not reveal any further genomic gains or losses, we cannot exclude that all contributing factors have been identified. However, this case report shows that with increasing technological possibilities we can find more than one cause for developmental problems in a single patient. The identification of multiple causes in a single patient may complicate explaining the disorder and genetic counseling.","variants":[{"Name":"NM_000053.4(ATP7B):c.2575+5G>C","Chromosome":"13","Start":"51950267","Stop":"51950267","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":547340,"rule_based_match":true,"evidence_text":"c.2575 + 5G > C","llm_judgment":"PRESENT","evidence":"c.2575 + 5G > C","abstract_start":564,"abstract_end":579}]}
{"pmid":"27885891","title":"Wiskott-Aldrich syndrome in a child presenting with macrothrombocytopenia.","abstract":"Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease resulting from variants in the WAS gene, characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Despite the fact that WAS is traditionally differentiated from immune thrombocytopenia (ITP) by small size of WAS platelets, in practice, microthrombocytopenia may occasionally not be present, and in certain cases, WAS patients exhibit some parallelism to ITP patients. We characterized one patient presenting with the classic form of the disease but increased mean platelet volume. Molecular studies revealed a novel hemizygous 1-bp deletion in WAS gene, c.802delC, leading to a frameshift and stop codon at amino acid 308 (p.Arg268Glyfs*40). Next-generation sequencing of a total of 70 additional genes known to harbor variants implicated in inherited platelet disorders did not identify additional defects. The pathogenesis of macrothrombocytopenia in this case is not known, but probably the coexistence of a still unidentified additional genetic variant might be involved.","variants":[{"Name":"NM_000377.3(WAS):c.802del (p.Arg268fs)","Chromosome":"X","Start":"48688324","Stop":"48688324","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1676335,"rule_based_match":true,"evidence_text":"c.802delC","llm_judgment":"PRESENT","evidence":"c.802delC","abstract_start":641,"abstract_end":650}]}
{"pmid":"33177553","title":"Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients.","abstract":"Due to the genotype-phenotype heterogeneity in retinitis pigmentosa (RP), molecular diagnoses and prediction of disease progression is difficult. This study aimed to report ocular and genetic data from Korean patients with PDE6B-associated RP (PDE6B-RP), and establish genotype-phenotype correlations to predict the clinical course. We retrospectively reviewed targeted next-generation sequencing or whole exome sequencing data for 305 patients with RP, and identified PDE6B-RP in 15 patients (median age, 40.0 years). Amongst these patients, ten previously reported PDE6B variants (c.1280G > A, c.1488del, c.1547T > C, c.1604T > A, c.1669C > T, c.1712C > T, c.2395C > T, c.2492C > T, c.592G > A, and c.815G > A) and one novel variant (c.712del) were identified. Thirteen patients (86.7%) experienced night blindness as the first symptom at a median age of 10.0 years. Median age at diagnosis was 21.0 years and median visual acuity (VA) was 0.20 LogMAR at the time of genetic analysis. Nonlinear mixed models were developed and analysis revealed that VA exponentially decreased over time, while optical coherence tomography parameters linearly decreased, and this was related with visual field constriction. A high proportion of patients with the c.1669C > T variant (7/9, 77.8%) had cystoid macular edema; despite this, patients with this variant did not show a higher rate of functional or structural progression. This study will help clinicians predict functional and structural progression in patients with PDE6B-RP.","variants":[{"Name":"NM_000283.4(PDE6B):c.815G>A (p.Arg272Gln)","Chromosome":"4","Start":"653955","Stop":"653955","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1399418,"rule_based_match":true,"evidence_text":"c.815G > A","llm_judgment":"PRESENT","evidence":"c.815G > A","abstract_start":701,"abstract_end":711},{"Name":"NM_000283.4(PDE6B):c.2492C>T (p.Ala831Val)","Chromosome":"4","Start":"667995","Stop":"667995","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1941475,"rule_based_match":true,"evidence_text":"c.2492C > T","llm_judgment":"PRESENT","evidence":"c.2492C > T","abstract_start":672,"abstract_end":683},{"Name":"NM_000283.4(PDE6B):c.592G>A (p.Gly198Ser)","Chromosome":"4","Start":"634800","Stop":"634800","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":944108,"rule_based_match":true,"evidence_text":"c.592G > A","llm_judgment":"PRESENT","evidence":"c.592G > A","abstract_start":685,"abstract_end":695}]}
{"pmid":"33066778","title":"Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares.","abstract":"BACKGROUND: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited.\nCASE PRESENTATION: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells.\nCONCLUSIONS: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.","variants":[{"Name":"NM_002133.3(HMOX1):c.636+2T>A","Chromosome":"22","Start":"35387178","Stop":"35387178","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1174777,"rule_based_match":true,"evidence_text":"HMOX1 (c.636 + 2 T > A)","llm_judgment":"PRESENT","evidence":"HMOX1 (c.636 + 2 T > A)","abstract_start":1250,"abstract_end":1273}]}
{"pmid":"28888044","title":"Novel mutations in Thai patients with glanzmann thrombasthenia.","abstract":"OBJECTIVES: Glanzmann thrombasthenia (GT) is an autosomal recessive platelet disorder, caused by defects of the platelet integrin αIIbβ3 (GPIIb/IIIa) resulting from pathogenic mutations in either ITGA2B or ITGB3. It is characterized by spontaneous mucocutaneous bleeding. The molecular features of GT in Thailand have not been identified. This study aimed to determine the clinical and molecular features of unrelated Thai patients with GT.\nMETHODS: Four patients with clinically suspected GT were recruited at the Division of Pediatric Hematology/Oncology, King Chulalongkorn Memorial Hospital. The diagnosis was based on clinical and hematological parameters as well as genetic analysis. Whole exome sequencing (WES) was performed in all cases.\nRESULTS: Of the four patients studied, the median age at first suspicion of GT was 2.5 years. All presented with severe bleeding symptoms (WHO bleeding scale 3). Flow cytometry to assess the surface GPIIb/IIIa complex showed reduced expression. By WES, we successfully identified seven mutant alleles in ITGA2B. One alteration, the c.2915dup (p.Leu973Alafs*63), was detected in two unrelated families. One patient was homozygous for the c.617T>A (p.Val206Asp). Of the five different mutations, three have never been previously described. These include a missense, c.617T>A (p.Val206Asp), a deletion, c.1524_1533del (p.Gln508Hisfs*3), and a nonsense, c.2344C>T (p.Arg782Ter).\nCONCLUSION: This study reported three novel mutations expanding the genotypic spectrum of ITGA2B causing GT.","variants":[{"Name":"NM_000419.5(ITGA2B):c.2915dup (p.Leu973fs)","Chromosome":"17","Start":"44374686","Stop":"44374687","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":959441,"rule_based_match":true,"evidence_text":"c.2915dup (p.Leu973Alafs*63)","llm_judgment":"PRESENT","evidence":"c.2915dup (p.Leu973Alafs*63)","abstract_start":1079,"abstract_end":1107},{"Name":"NM_000419.5(ITGA2B):c.2344C>T (p.Arg782Ter)","Chromosome":"17","Start":"44376312","Stop":"44376312","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":615573,"rule_based_match":true,"evidence_text":"c.2344C>T (p.Arg782Ter)","llm_judgment":"PRESENT","evidence":"c.2344C>T (p.Arg782Ter)","abstract_start":1397,"abstract_end":1420}]}
{"pmid":"26100117","title":"Functional Analysis of GLRX5 Mutants Reveals Distinct Functionalities of GLRX5 Protein.","abstract":"Glutaredoxin 5 (GLRX5) is a 156 amino acid mitochondrial protein that plays an essential role in mitochondrial iron-sulfur cluster transfer. Mutations in this protein were reported to result in sideroblastic anemia and variant nonketotic hyperglycinemia in human. Recently, we have characterized a Chinese congenital sideroblastic anemia patient who has two compound heterozygous missense mutations (c. 301 A>C and c. 443 T>C) in his GLRX5 gene. Herein, we developed a GLRX5 knockout K562 cell line and studied the biochemical functions of the identified pathogenic mutations and other conserved amino acids with predicted essential functions. We observed that the K101Q mutation (due to c. 301 A>C mutation) may prevent the binding of [Fe-S] to GLRX5 protein, while L148S (due to c. 443 T>C mutation) may interfere with [Fe-S] transfer from GLRX5 to iron regulatory protein 1 (IRP1), mitochondrial aconitase (m-aconitase) and ferrochelatase. We also demonstrated that L148S is functionally complementary to the K51del mutant with respect to Fe/S-ferrochelatase, Fe/S-IRP1, Fe/S-succinate dehydrogenase, and Fe/S-m-aconitase biosynthesis and lipoylation of pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex. Furthermore, we demonstrated that the mutations of highly conserved amino acid residues in GLRX5 protein can have different effects on downstream Fe/S proteins. Collectively, our current work demonstrates that GLRX5 protein is multifunctional in [Fe-S] protein synthesis and maturation and defects of the different amino acids of the protein will lead to distinct effects on downstream Fe/S biosynthesis.","variants":[{"Name":"NM_016417.3(GLRX5):c.301A>C (p.Lys101Gln)","Chromosome":"14","Start":"95543952","Stop":"95543952","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":226288,"rule_based_match":true,"evidence_text":"c. 301 A>C","llm_judgment":"PRESENT","evidence":"c. 301 A>C","abstract_start":400,"abstract_end":410}]}
{"pmid":"30665703","title":"Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.","abstract":"More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as \"clinically relevant\" variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.","variants":[{"Name":"NM_175914.5(HNF4A):c.340C>T (p.Arg114Trp)","Chromosome":"20","Start":"44413714","Stop":"44413714","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":24251,"rule_based_match":true,"evidence_text":"HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4)","llm_judgment":"PRESENT","evidence":"HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4)","abstract_start":1180,"abstract_end":1231}]}
{"pmid":"27860360","title":"Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy.","abstract":"Pyrroline-5-carboxylate reductase 2, encoded by PYCR2, is one of the three homologous enzymes that catalyze the last step of proline synthesis. Homozygous variants in PYCR2 have been reported in patients from multiple consanguineous families with hypomyelinating leukodystrophy 10 (HLD10) (MIM: 616420). Here, we report five additional patients from three families with homozygous nonsense or missense variants in PYCR2, identified through clinical exome sequencing. All patients presented with postnatally acquired microcephaly, moderate to profound global developmental delay, and failure to thrive. Brain MRI in these patients showed thin corpus callosum, delayed myelination, and generalized white-matter volume loss. Additional phenotypes that were less consistent among patients included seizures or seizure-like movements, spasticity and ataxic gait, recurrent vomiting, cortical blindness, dysmorphic features, joint contractures, and irritability. Exome sequencing identified homozygous variants in PYCR2 in the proband from each family: c.28C>T (p.(Glu10Ter)), c.796C>T (p.(Arg266Ter)), and c.577G>A (p.(Val193Met)). Subsequent targeted analyses demonstrated co-segregation of the disease with the variant in the family. Despite the metabolic role of PYCR2, routine serum metabolic test in these patients were normal. To further understand the disease etiology and functions of PYCR2, small molecule metabolomics profiling was performed in plasma from three severely affected patients. No significant changes were identified in proline biosynthesis pathway or related metabolites. Studying the clinical features and the metabolic profiles of the PYCR2-deficient patients provides a more comprehensive picture for this newly identified disorder and facilitates further research on the gene function and disease etiology. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_013328.4(PYCR2):c.577G>A (p.Val193Met)","Chromosome":"1","Start":"225921608","Stop":"225921608","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2843520,"rule_based_match":true,"evidence_text":"c.577G>A (p.(Val193Met))","llm_judgment":"PRESENT","evidence":"c.577G>A (p.(Val193Met))","abstract_start":1101,"abstract_end":1125},{"Name":"NM_013328.4(PYCR2):c.796C>T (p.Arg266Ter)","Chromosome":"1","Start":"225921209","Stop":"225921209","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":248761,"rule_based_match":true,"evidence_text":"c.796C>T (p.(Arg266Ter))","llm_judgment":"PRESENT","evidence":"c.796C>T (p.(Arg266Ter))","abstract_start":1071,"abstract_end":1095}]}
{"pmid":"30256902","title":"De novo PHACTR1 mutations in West syndrome and their pathophysiological effects.","abstract":"Trio-based whole exome sequencing identified two de novo heterozygous missense mutations [c.1449T > C/p.(Leu500Pro) and c.1436A > T/p.(Asn479Ile)] in PHACTR1, encoding a molecule critical for the regulation of protein phosphatase 1 (PP1) and the actin cytoskeleton, in unrelated Japanese individuals with West syndrome (infantile spasms with intellectual disability). We then examined the role of Phactr1 in the development of mouse cerebral cortex and the pathophysiological significance of these two mutations and others [c.1561C > T/p.(Arg521Cys) and c.1553T > A/p.(Ile518Asn)], which had been reported in undiagnosed patients with intellectual disability. Immunoprecipitation analyses revealed that actin-binding activity of PHACTR1 was impaired by the p.Leu500Pro, p.Asn479Ile and p.Ile518Asn mutations while the p.Arg521Cys mutation exhibited impaired binding to PP1. Acute knockdown of mouse Phactr1 using in utero electroporation caused defects in cortical neuron migration during corticogenesis, which were rescued by an RNAi-resistant PHACTR1 but not by the four mutants. Experiments using knockdown combined with expression mutants, aimed to mimic the effects of the heterozygous mutations under conditions of haploinsufficiency, suggested a dominant negative effect of the mutant allele. As for dendritic development in vivo, only the p.Arg521Cys mutant was determined to have dominant negative effects, because the three other mutants appeared to be degraded with these experimental conditions. Electrophysiological analyses revealed abnormal synaptic properties in Phactr1-deficient excitatory cortical neurons. Our data show that the PHACTR1 mutations may cause morphological and functional defects in cortical neurons during brain development, which is likely to be related to the pathophysiology of West syndrome and other neurodevelopmental disorders.","variants":[{"Name":"NM_030948.6(PHACTR1):c.1561C>T (p.Arg521Cys)","Chromosome":"6","Start":"13283473","Stop":"13283473","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":608857,"rule_based_match":true,"evidence_text":"c.1561C > T/p.(Arg521Cys)","llm_judgment":"PRESENT","evidence":"c.1561C > T/p.(Arg521Cys)","abstract_start":524,"abstract_end":549},{"Name":"NM_030948.6(PHACTR1):c.1436A>T (p.Asn479Ile)","Chromosome":"6","Start":"13272904","Stop":"13272904","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":608859,"rule_based_match":true,"evidence_text":"c.1436A > T/p.(Asn479Ile)","llm_judgment":"PRESENT","evidence":"c.1436A > T/p.(Asn479Ile)","abstract_start":120,"abstract_end":145}]}
{"pmid":"16181148","title":"A novel mutation in the cardiac myosin-binding protein C gene is responsible for hypertrophic cardiomyopathy with severe ventricular hypertrophy and sudden death.","abstract":"It has been demonstrated previously that clinical phenotypes of HCM (hypertrophic cardiomyopathy) caused by mutations in the cardiac MyBP-C (myosin-binding protein C) gene show late onset, low penetrance and favourable clinical course. However, we have encountered severe phenotypes in several carriers of the MyBP-C gene mutations. The aim of the present study was to screen novel MyBP-C gene mutations in patients with HCM and to investigate the genetic differences in affected subjects with severe phenotypes. The MyBP-C gene was screened in 292 Japanese probands with HCM, and a novel c.2067+1G-->A mutation was present in 15 subjects in five families. Clinical phenotypes of carriers of the c.2067+1G-->A mutation were compared with those of a previously identified Arg820Gln (Arg820-->Gln) mutation in the MyBP-C gene. The disease penetrance in subjects aged > or =30 years was 90% in carriers of the c.2067+1G-->A mutation and 61% in carriers of the Arg820Gln mutation. Sudden death occurred in four subjects from three families with the c.2067+1G-->A mutation and in two subjects from one family with the Arg820Gln mutation. Two carriers of the c.2067+1G-->A mutation had substantial hypertrophy (maximal wall thickness > or =30 mm). In contrast, two carriers of the Arg820Gln mutation had end-stage HCM. In conclusion, the c.2067+1G-->A mutation is associated with HCM with substantial hypertrophy and moderate incidence of sudden death, whereas the Arg820Gln mutation is associated with end-stage HCM. These observations may provide important prognostic information regarding the clinical practice of HCM.","variants":[{"Name":"NM_000256.3(MYBPC3):c.2067+1G>A","Chromosome":"11","Start":"47339650","Stop":"47339650","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":444818,"rule_based_match":false,"evidence_text":"c.2067+1G-->A","llm_judgment":"PRESENT","evidence":"c.2067+1G-->A","abstract_start":589,"abstract_end":602}]}
{"pmid":"27662472","title":"Mutation Analysis of 16 Mucolipidosis II and III Alpha/Beta Chinese Children Revealed Genotype-Phenotype Correlations.","abstract":"Mucolipidosis II and III alpha/beta are autosomal recessive diseases caused by mutations in the GNPTAB gene which encodes the α and β subunits of the N-acetylglucosamine-1-phosphotransferase. Clinically, mucolipidosis II (MLII) is characterized by severe developmental delay, coarse facial features, skeletal deformities, and other systemic involvement. In contrast, MLIII alpha/beta is a much milder disorder, the symptoms of which include progressive joint stiffness, short stature, and scoliosis. To study the relationship between the genotypes and phenotypes of the MLII and MLIII alpha/beta patients, we analyzed the GNPTAB gene in 16 Chinese MLII and MLIII alpha/beta patients. We collected and analyzed the patients' available clinical data and all showed clinical features typical of MLII or MLIII alpha/beta. Moreover, the activity of several lysosomal enzymes was measured in the plasma and finally the GNPTAB gene was sequenced. We detected 30 mutant alleles out of 32 alleles in our patients. These include 10 new mutations (c.99delC, c.118-1G>A, c.523_524delAAinsG, c.1212C>G, c.2213C>A, c.2345C>T, c.2356C>T, c.2455G>T, c.2821dupA, and c.3136-2A>G) and 5 previously reported mutations (c.1071G>A, c.1090C>T, c.2715+1G>A, c.2550_2554delGAAA, and c.3613C>T). The most frequent mutation was the splicing mutation c.2715+1G>A, which accounted for 28% of the mutations. The majority of the mutations reported in the Chinese patients (57%) were located on exon 13 or in its intronic flanking regions.","variants":[{"Name":"NM_024312.5(GNPTAB):c.1212C>G (p.Tyr404Ter)","Chromosome":"12","Start":"101770093","Stop":"101770093","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1874528,"rule_based_match":true,"evidence_text":"c.1212C>G","llm_judgment":"PRESENT","evidence":"c.1212C>G","abstract_start":1079,"abstract_end":1088},{"Name":"NM_024312.5(GNPTAB):c.118-1G>A","Chromosome":"12","Start":"101796763","Stop":"101796763","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1062565,"rule_based_match":true,"evidence_text":"c.118-1G>A","llm_judgment":"PRESENT","evidence":"c.118-1G>A","abstract_start":1047,"abstract_end":1057},{"Name":"NM_024312.5(GNPTAB):c.1090C>T (p.Arg364Ter)","Chromosome":"12","Start":"101770429","Stop":"101770429","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":47624,"rule_based_match":true,"evidence_text":"c.1090C>T","llm_judgment":"PRESENT","evidence":"c.1090C>T","abstract_start":1211,"abstract_end":1220},{"Name":"NM_024312.5(GNPTAB):c.1071G>A (p.Trp357Ter)","Chromosome":"12","Start":"101770448","Stop":"101770448","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1393469,"rule_based_match":true,"evidence_text":"c.1071G>A","llm_judgment":"PRESENT","evidence":"c.1071G>A","abstract_start":1200,"abstract_end":1209},{"Name":"NM_024312.5(GNPTAB):c.2715+1G>A","Chromosome":"12","Start":"101764201","Stop":"101764201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17807,"rule_based_match":true,"evidence_text":"c.2715+1G>A","llm_judgment":"PRESENT","evidence":"c.2715+1G>A","abstract_start":1222,"abstract_end":1233},{"Name":"NM_024312.5(GNPTAB):c.2213C>A (p.Ser738Ter)","Chromosome":"12","Start":"101764704","Stop":"101764704","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1432191,"rule_based_match":true,"evidence_text":"c.2213C>A","llm_judgment":"PRESENT","evidence":"c.2213C>A","abstract_start":1090,"abstract_end":1099}]}
{"pmid":"30115503","title":"GLUT-1 deficiency presenting with seizures and reversible leukoencephalopathy on MRI imaging.","abstract":"Glucose transporter type 1 (GLUT1) deficiency syndrome is a well recognised genetic neurometabolic disorder typically presenting with progressive encephalopathy, acquired microcephaly and drug-resistant epilepsy. Imaging is normal in the majority. Here we describe a 5-month-old boy who presented with motor delay, myoclonic jerks and tonic-clonic seizures. His MRI brain scan revealed confluent symmetrical T2 hyperintense signal abnormality in both anterior frontal lobes and delayed myelination. Neurometabolic screen revealed low CSF glucose and lactate levels. A pathogenic de novo heterozygous mutation in SLC2A1 (c.275+1G > A) confirmed the diagnosis of GLUT1 deficiency. Ketogenic diet resulted in a dramatic termination of his seizures at 72 h. At 15 months, he continued to be seizure free with marked developmental catch up. Repeat imaging revealed a significant resolution of the previously seen changes. This case suggests that GLUT1 deficiency should be considered in the differential diagnosis of infants with suspected genetic leukoencephalopathies with important treatment implications.","variants":[{"Name":"NM_006516.4(SLC2A1):c.275+1G>A","Chromosome":"1","Start":"42931045","Stop":"42931045","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1347343,"rule_based_match":true,"evidence_text":"c.275+1G > A","llm_judgment":"PRESENT","evidence":"c.275+1G > A","abstract_start":620,"abstract_end":632}]}
{"pmid":"26635043","title":"Ten Years of Routine α- and β-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations.","abstract":"We review and report here the genotypes and phenotypes of 60 novel thalassemia and abnormal hemoglobin (Hb) mutations discovered following the adoption of routine DNA sequencing of both α- and β-globin genes for all UK hemoglobinopathy samples referred for molecular investigation. This screening strategy over the last 10 years has revealed a total of 11 new β chain variants, 15 α chain variants, 19 β-thalassemia (β-thal) mutations and 15 α(+)-thalassemia (α(+)-thal) mutations. The large number of new thalassemia alleles confirms the wide racial heterogeneity of mutations in the UK immigrant population. Eleven of the new variants ran with Hb A on high performance liquid chromatography (HPLC), demonstrating the value of routine sequencing of both α- and β-globin genes for all hemoglobinopathy investigations. The new β chain variants are: Hb Bury [β22(B4)Glu  →  Asp (HBB: c.69A > T)], Hb Fulwood [β35(C1)Tyr → His (HBB: c.106T > C)], Hb Little Venice [β42(CD1)Phe → Cys (HBB: c.128T > G)], Hb Cork [β57(E1)Asn → Ser (HBB: c.173A > G), Hb Basingstoke [β118(GH1)Phe → Ser (HBB: c.356T > C)], Hb Howden [β20(B2)Val → Ala (HBB: c.62T > C)], Hb Wilton [β41(C7)Phe → Leu (HBB: c.126C > A)], Hb Belsize Park [β120(GH3)Lys → Asn (HBB: c.363A > T)], Hb Hampstead Heath [β2(NA2)His → Gln;β26(B8)Glu → Lys (HBB: c.[6C > G;79G > A])], Hb Grantham [β85(F1)Phe → Cys (HBB: c.257T > G)] and Hb Calgary [β64(E8)Gly → Val (HBB: c.194G > T). The new α chain variants are: Hb Edinburgh [α70(E19)Val → Gly (HBA2: c.212T > G)], Hb Walsgrave [α116(GH4)Glu → Val (HBA2: c.350A > T)], Hb Wexham [α117(GH5) and 118(H1) insertion Ser (HBA1: c.354-355insTCA)], Hb Coombe Park [α127(H10)Lys → Glu (HBA2: c.382A > G)], Hb Oxford [α17(A15)Val → Asp (HBA2: c.53T > A)], Hb Bridlington [α32(B13)Met → Thr (HBA1: c.98T > C), Hb Wolverhampton [α81(F2)Ser → Tyr (HBA2: c.9245C > A)], Hb Little Waltham [α13(A11)Ala → Asp (HBA2: c.41C > A)], Hb Derby [α61(E10)Lys → Arg (HBA1: c.185A > G)], Hb Uttoxter [α74(EF3)Tyr → Asp (HBA2: c.223G > T)], Hb Harehills [α124(H7)Ser → Cys (HBA1: c.374C > G)], Hb Hekinan II [α27(B8)Glu → Asp (HBA1: c.84G > T)], Hb Manitoba IV [α102(G9)Ser → Arg (HBA1: c.307A > C), Hb Witham [α139(HC1)Lys → Arg (HBA2: c.419A > G) and Hb Farnborough [α9(A7)Asn → Asp (HBA1: c.28A > G). In addition, 10 more paralogous α-globin chain variants have been discovered. The novel β-thal alleles are: HBB: c.-138C > G, HBB: c.-121C > T, HBB: c.-80T > G, HBB: c.18_19delTG, HBB: c.219_220insT, HBB: c.315 + 2_315 + 13delTGAGTCTATGGG, HBB: c.316-70C > G, HBB: c.345_346insTGTGCTG, HBB: c.354delC, HBB: c.376-381delCCAGTG, HBB: c.393T > A, HBB: c.394_395insA, HBB: c.375_376insA, HBB: c.*+95_*+107delTGGATTCTinsC, HBB: c.* + 111_*+112delAA, HBB: c.*+112A > T, HBB: c.394C > T, HBB: c.271delG and HBB: c.316-3C > T. The novel α (+ )-thal alleles are: HBA1: c.95+1G > C, HBA1: c.315C > G [Hb Donnington, α104(G11)Cys → Trp], HBA1: c.327delC, HBA1: c.333_345del, HBA1: c.*+96G > A, HBA2: c.2T > G, HBA2: c.112delC, HBA2: c.143delA, HBA2: c.143_146delACCT, HBA2: c.156_157insG, HBA2: c.220_223delGTGG, HBA2: c.305T > C [Hb Bishopstown, α101(G8)Leu → His], HBA2: c.169_170delAA, HBA2: c.1A > T and HBA2: c.-3delA.","variants":[{"Name":"NM_000518.5(HBB):c.-121C>T","Chromosome":"11","Start":"5227142","Stop":"5227142","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":789685,"rule_based_match":true,"evidence_text":"HBB: c.-121C > T","llm_judgment":"PRESENT","evidence":"HBB: c.-121C > T","abstract_start":2406,"abstract_end":2422},{"Name":"NM_000518.5(HBB):c.316-70C>G","Chromosome":"11","Start":"5225796","Stop":"5225796","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":44984,"rule_based_match":true,"evidence_text":"HBB: c.316-70C>G","llm_judgment":"PRESENT","evidence":"HBB: c.316-70C > G","abstract_start":2520,"abstract_end":2538},{"Name":"NM_000518.4(HBB):c.-138C>G","Chromosome":"11","Start":"5227159","Stop":"5227159","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":857539,"rule_based_match":true,"evidence_text":"HBB: c.-138C > G","llm_judgment":"PRESENT","evidence":"HBB: c.-138C > G","abstract_start":2388,"abstract_end":2404},{"Name":"NM_000518.5(HBB):c.394C>T (p.Gln132Ter)","Chromosome":"11","Start":"5225648","Stop":"5225648","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":857437,"rule_based_match":true,"evidence_text":"HBB: c.394C > T","llm_judgment":"PRESENT","evidence":"HBB: c.394C > T","abstract_start":2744,"abstract_end":2759},{"Name":"NM_000518.5(HBB):c.354del (p.Phe119fs)","Chromosome":"11","Start":"5225688","Stop":"5225688","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":857440,"rule_based_match":true,"evidence_text":"HBB: c.354delC","llm_judgment":"PRESENT","evidence":"HBB: c.354delC","abstract_start":2566,"abstract_end":2580},{"Name":"NM_000518.5(HBB):c.393T>A (p.Tyr131Ter)","Chromosome":"11","Start":"5225649","Stop":"5225649","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":789496,"rule_based_match":true,"evidence_text":"HBB: c.393T > A","llm_judgment":"PRESENT","evidence":"HBB: c.393T > A","abstract_start":2607,"abstract_end":2622},{"Name":"NM_000518.5(HBB):c.316-3C>T","Chromosome":"11","Start":"5225729","Stop":"5225729","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1320703,"rule_based_match":true,"evidence_text":"HBB: c.316-3C > T","llm_judgment":"PRESENT","evidence":"HBB: c.316-3C > T","abstract_start":2780,"abstract_end":2797}]}
{"pmid":"20505798","title":"Founder mutations in hypertrophic cardiomyopathy patients in the Netherlands.","abstract":"In this part of a series on cardiogenetic founder mutations in the Netherlands, we review the Dutch founder mutations in hypertrophic cardiomyopathy (HCM) patients. HCM is a common autosomal dominant genetic disease affecting at least one in 500 persons in the general population. Worldwide, most mutations in HCM patients are identified in genes encoding sarcomeric proteins, mainly in the myosin-binding protein C gene (MYBPC3, OMIM #600958) and the beta myosin heavy chain gene (MYH7, OMIM #160760). In the Netherlands, the great majority of mutations occur in the MYBPC3, involving mainly three Dutch founder mutations in the MYBPC3 gene, the c.2373_2374insG, the c.2864_2865delCT and the c.2827C>T mutation. In this review, we describe the genetics of HCM, the genotype-phenotype relation of Dutch founder MYBPC3 gene mutations, the prevalence and the geographic distribution of the Dutch founder mutations, and the consequences for genetic counselling and testing. (Neth Heart J 2010;18:248-54.).","variants":[{"Name":"NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)","Chromosome":"11","Start":"47335120","Stop":"47335120","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45725,"rule_based_match":true,"evidence_text":"c.2827C>T","llm_judgment":"PRESENT","evidence":"c.2827C>T","abstract_start":693,"abstract_end":702}]}
{"pmid":"38311799","title":"Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.","abstract":"OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.\nMETHODS: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant.\nRESULTS: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing.\nINTERPRETATION: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.","variants":[{"Name":"NM_001103.4(ACTN2):c.1516A>G (p.Arg506Gly)","Chromosome":"1","Start":"236749124","Stop":"236749124","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":198055,"rule_based_match":true,"evidence_text":"c.1516A>G (p.Arg506Gly)","llm_judgment":"PRESENT","evidence":"c.1516A>G (p.Arg506Gly)","abstract_start":710,"abstract_end":733}]}
{"pmid":"31273614","title":"New germline BRCA2 gene variant in the Tuvinian Mongol breast cancer patients.","abstract":"To date, there are a limited number of reports on inherited gene mutations associated with breast cancer (BC) among Mongoloid indigenous people in Russia. The present study aimed at identifying the BC-associated genes in 26 Russian Mongoloid BC patients (Buryats, Tuvinians and others). The median age of the patients at the time of breast cancer diagnosis was 41 years (range 25-51 years). Genomic DNA isolated from blood samples was used to prepare libraries using a capture-based target enrichment kit (Hereditary Cancer Solution™, SOPHiA GENETICS, Switzerland) covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). Next-generation sequencing (NGS) was performed on an Illumina NextSeq 500 System (Illumina, USA). In our study, we found 1 Indel and 11 SNPs that passed filters during variant calling. We identified a highly pathogenic germline rs483353122 (c.8208_8209insAG, p.Leu2737Serfs*2) in the BRCA2 gene in six unrelated Tuvinian Mongol BC patients. We also identified a likely damaging germline rs35352891 in the MUTYH gene (c.1118C>T, p.Ala373Val) in one Buryat Mongol BC patient. Other SNPs were classified as variants of uncertain significance. To the best of our knowledge, this report is the first to describe the highly pathogenic variant in the BRCA2 gene (rs483353122) and the likely damaging germline variant in the MUTYH gene (rs35352891) in Russian Mongoloid BC patients with young-onset and/or bilateral and/or familial BC. Further studies are therefore necessary to evaluate the contributions of novel sequence variants to hereditary BC.","variants":[{"Name":"NM_000059.4(BRCA2):c.8208_8209insAG (p.Leu2737fs)","Chromosome":"13","Start":"32363410","Stop":"32363411","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CAG","allel_id":131707,"rule_based_match":true,"evidence_text":"c.8208_8209insAG","llm_judgment":"PRESENT","evidence":"c.8208_8209insAG","abstract_start":1012,"abstract_end":1028}]}
{"pmid":"25943428","title":"Homozygosity mapping reveals novel and known mutations in Pakistani families with inherited retinal dystrophies.","abstract":"Inherited retinal dystrophies are phenotypically and genetically heterogeneous. This extensive heterogeneity poses a challenge when performing molecular diagnosis of patients, especially in developing countries. In this study, we applied homozygosity mapping as a tool to reduce the complexity given by genetic heterogeneity and identify disease-causing variants in consanguineous Pakistani pedigrees. DNA samples from eight families with autosomal recessive retinal dystrophies were subjected to genome wide homozygosity mapping (seven by SNP arrays and one by STR markers) and genes comprised within the detected homozygous regions were analyzed by Sanger sequencing. All families displayed consistent autozygous genomic regions. Sequence analysis of candidate genes identified four previously-reported mutations in CNGB3, CNGA3, RHO, and PDE6A, as well as three novel mutations: c.2656C > T (p.L886F) in RPGRIP1, c.991G > C (p.G331R) in CNGA3, and c.413-1G > A (IVS6-1G > A) in CNGB1. This latter mutation impacted pre-mRNA splicing of CNGB1 by creating a -1 frameshift leading to a premature termination codon. In addition to better delineating the genetic landscape of inherited retinal dystrophies in Pakistan, our data confirm that combining homozygosity mapping and candidate gene sequencing is a powerful approach for mutation identification in populations where consanguineous unions are common.","variants":[{"Name":"NM_001297.5(CNGB1):c.413-1G>A","Chromosome":"16","Start":"57962611","Stop":"57962611","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":431798,"rule_based_match":true,"evidence_text":"c.413-1G > A (IVS6-1G > A) in CNGB1","llm_judgment":"PRESENT","evidence":"c.413-1G > A (IVS6-1G > A) in CNGB1","abstract_start":951,"abstract_end":986}]}
{"pmid":"26799614","title":"An overlapping phenotype of Osteogenesis imperfecta and Ehlers-Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing.","abstract":"Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype.","variants":[{"Name":"NM_000088.4(COL1A1):c.4006-1G>A","Chromosome":"17","Start":"50186021","Stop":"50186021","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1706797,"rule_based_match":true,"evidence_text":"c.4006-1G > A","llm_judgment":"PRESENT","evidence":"c.4006-1G > A","abstract_start":415,"abstract_end":428}]}
{"pmid":"26915297","title":"Effects of genetic correction on the differentiation of hair cell-like cells from iPSCs with MYO15A mutation.","abstract":"Deafness or hearing loss is a major issue in human health. Inner ear hair cells are the main sensory receptors responsible for hearing. Defects in hair cells are one of the major causes of deafness. A combination of induced pluripotent stem cell (iPSC) technology with genome-editing technology may provide an attractive cell-based strategy to regenerate hair cells and treat hereditary deafness in humans. Here, we report the generation of iPSCs from members of a Chinese family carrying MYO15A c.4642G>A and c.8374G>A mutations and the induction of hair cell-like cells from those iPSCs. The compound heterozygous MYO15A mutations resulted in abnormal morphology and dysfunction of the derived hair cell-like cells. We used a CRISPR/Cas9 approach to genetically correct the MYO15A mutation in the iPSCs and rescued the morphology and function of the derived hair cell-like cells. Our data demonstrate the feasibility of generating inner ear hair cells from human iPSCs and the functional rescue of gene mutation-based deafness by using genetic correction.","variants":[{"Name":"NM_016239.4(MYO15A):c.4642G>A (p.Ala1548Thr)","Chromosome":"17","Start":"18136462","Stop":"18136462","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":230716,"rule_based_match":true,"evidence_text":"MYO15A c.4642G>A","llm_judgment":"PRESENT","evidence":"MYO15A c.4642G>A","abstract_start":489,"abstract_end":505}]}
{"pmid":"34114358","title":"CD40LG mutations in Vietnamese patients with X-linked hyper-IgM syndrome; catastrophic anti-phospholipid syndrome as a new complication.","abstract":"BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects.\nMETHODS: We identified three patients with XHIGM in Ho Chi Minh City, Vietnam. Whole-exome sequencing, immunological analyses and western blot were performed to investigate phenotypic and genotypic features.\nRESULTS: Despite showing symptoms typical of XHIGM, including recurrent sinopulmonary infections, oral ulcers and otitis media, the diagnosis was significantly delayed. One patient developed anti-phospholipid syndrome, which has been documented for the first time in XHIGM syndrome. Two patients had elevated IgM levels and all of them had low IgG levels. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non-frameshift deletion c.436_438delTAC, stop-gain c.654C>A). Due to these mutations, the CD40 ligand was not expressed in any of the three patients, as demonstrated by western blot analysis.\nCONCLUSION: This is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy.","variants":[{"Name":"NM_000074.3(CD40LG):c.654C>A (p.Cys218Ter)","Chromosome":"X","Start":"136659283","Stop":"136659283","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2405123,"rule_based_match":true,"evidence_text":"c.654C>A","llm_judgment":"PRESENT","evidence":"c.654C>A","abstract_start":868,"abstract_end":876}]}
{"pmid":"24016645","title":"Juvenile Pompe disease: retrospective clinical study","abstract":"INTRODUCTION: Pompe disease or glycogen storage disease type II is an autosomal recessive disorder due to acid maltase deficiency. It is a rare disease with a prevalence of 1/40.000 in the dutch and african-american populations and 1/46000 in the australian population. There are three forms of clinical presentation (infantile-onset, childhood-onset and adult-onset), although the disease presents as a continuum of clinical phenotypes. Enzyme replacement therapy is available in Portugal since 2006.\nMATERIALS AND METHODS: The clinical files of four patients (two sisters) were analyzed retrospectively.\nRESULTS: In all, disease presented in the second year of life and the time to diagnosis ranged from two to eleven years. At diagnosis, all presented myopathic features with a delay in motor skills achievement and two had myocardium hypertrophy. Clinical suspicion arose as the result of respiratory failure during infection in two patients. Plasma creatine kinase and aminotransferases levels were increased in all. All patients progressed to pulmonary restrictive syndrome with chronic respiratory failure. The diagnosis was based on reduced activity of acid maltase in fibroblasts: 0 to 1.5% of the lower normal value. Muscle biopsy, performed in three patients, showed lysosomal glycogen accumulation. A c.1064T > C mutation in exon 6 of GAA (glucosidase-alpha-acid) gene was found in all patients, in homozygosity in one. In the sisters, it was associated to c.1666A > G and c.2065G > A mutations in exons 12 and 15, respectively and in the youngest patient, to c.380G > T mutation in exon 2. All patients started enzyme replacement therapy as soon as it became available, with good tolerance. The youngest patient died. The surviving patients maintain ventilatory support measures and physiotherapy. The oldest patient is wheelchair ridden and her sister keeps independent walking. The youngest uses a walking aid.\nCONCLUSIONS: Our cases are clinically included in the juvenile form of Pompe Disease. Pompe disease should be suspected in progressive myopathies at any age, especially those involving limb-girdle and respiratory muscles and in small infants with cardiomyopathy. High creatine kinase is a sensitive, although nonspecific, marker. Given the great variability of the genetic findings, demonstration of reduced activity of acid maltase (in leukocytes or other tissues) remains the diagnosis cornerstone of this rare disorder.","variants":[{"Name":"NM_000152.5(GAA):c.1064T>C (p.Leu355Pro)","Chromosome":"17","Start":"80108398","Stop":"80108398","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":268330,"rule_based_match":true,"evidence_text":"c.1064T > C","llm_judgment":"PRESENT","evidence":"c.1064T > C","abstract_start":1313,"abstract_end":1324}]}
{"pmid":"27446417","title":"First application of next-generation sequencing in Moroccan breast/ovarian cancer families and report of a novel frameshift mutation of the","abstract":"At present, breast cancer is the most common type of cancer in females. The majority of cases are sporadic, but 5-10% are due to an inherited predisposition to develop breast and ovarian cancers, which are transmitted as an autosomal dominant form with incomplete penetrance. The beneficial effects of clinical genetic testing, including next generation sequencing (NGS) for <i>BRCA1/2</i> mutations, is major; in particular, it benefits the care of patients and the counseling of relatives that are at risk of breast cancer, in order to reduce breast cancer mortality. <i>BRCA</i> genetic testing was performed in 15 patients with breast cancer and a family with positivity for the heterozygous c.6428C>A mutation of the <i>BRCA2</i> gene. Informed consent was obtained from all the subjects. Genomic DNAs were extracted and the NGS for genes was performed using the Ion Torrent Personal Genome Machine (PGM) with a 316 chip. The reads were aligned with the human reference HG19 genome to elucidate variants in the <i>BRCA1</i> and <i>BRCA2</i> genes. Mutations detected by the PGM platform were confirmed by target direct Sanger sequencing on a second patient DNA sample. In total, 4 <i>BRCA</i> variants were identified in 6 families by NGS. Of these, 3 mutations had been previously reported: c.2126insA of <i>BRCA1</i>, and c.1310_1313delAAGA and c.7235insG of <i>BRCA2</i>. The fourth variant, c.3453delT in <i>BRCA1</i>, has, to the best of our knowledge, never been previously reported. The present study is the first to apply NGS of the <i>BRCA1</i> and <i>BRCA2</i> genes to a Moroccan population, prompting additional investigation into local founder mutations and variant characteristics in the region. The variants with no clear clinical significance may present a diagnostic challenge when performing targeted resequencing. These results confirm that an NGS approach based on Ampliseq libraries and PGM sequencing is a highly efficient, speedy and high-throughput mutation detection method, which may be preferable in lower income countries.","variants":[{"Name":"NM_000059.4(BRCA2):c.1310_1313del (p.Lys437fs)","Chromosome":"13","Start":"32332779","Stop":"32332782","ReferenceAlleleVCF":"AAAAG","AlternateAlleleVCF":"A","allel_id":46293,"rule_based_match":true,"evidence_text":"c.1310_1313delAAGA","llm_judgment":"PRESENT","evidence":"c.1310_1313delAAGA","abstract_start":1329,"abstract_end":1347}]}
{"pmid":"32212377","title":"Human RAD50 deficiency: Confirmation of a distinctive phenotype.","abstract":"DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)-like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS-like disorder. Here, we report a long-term follow-up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient-derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the patient-derived fibroblasts and provided evidence for a markedly reduced radiation-induced AT-mutated signaling. Comparison with the previously reported case and with patients presenting with NBS confirms that RAD50 mutations lead to a similar, but distinctive phenotype.","variants":[{"Name":"NM_005732.4(RAD50):c.2524G>A (p.Val842Ile)","Chromosome":"5","Start":"132604046","Stop":"132604046","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1052778,"rule_based_match":true,"evidence_text":"c.2524G > A","llm_judgment":"PRESENT","evidence":"c.2524G > A","abstract_start":1007,"abstract_end":1018}]}
{"pmid":"20358311","title":"Mutation studies in X-linked myotubular myopathy in three Indian families.","abstract":"Congenital myopathies are a group of genetic disorders characterized by generalised muscle hypotonia and weakness of varying severity. They are distinct entities and do not include muscular dystrophies, metabolic myopathies and mitochondrial disorders. Myotubular myopathy is a rare sub type within this group of disorders. Clinical differentiation of the various types is difficult and requires muscle biopsy with histopathological and immunohistochemical studies for specific diagnosis. Gene studies are a prerequisite for genetic counseling adn prenatal diagnosis. Here presented three cases of X-linked myotubular myopathy in three Indian families where the diagnosis was established by mutation analysis in the MTM1 gene in all, and supported his histopathology in two. All three families had history of previous male neonatal deaths with similar complaints. Molecular analysis revealed hemizygous mutations in the MTM1 gene including c.1261-10A>G in case, 1, c.70C>T (R24X) in case 2, and a previously unreported mutation, c.924_926delCTT(p. F308del), in case 3. Genetic counseling was performed regarding the X-linked inheritance, their 50% risk of recurrence in boys in subsequent pregnancies, and a feasibility of prenatal diagnosis. This is the first report of cases of X-linked myotubular myopathy from India.","variants":[{"Name":"NM_000252.3(MTM1):c.1261-10A>G","Chromosome":"X","Start":"150659654","Stop":"150659654","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":26097,"rule_based_match":true,"evidence_text":"c.1261-10A>G","llm_judgment":"PRESENT","evidence":"c.1261-10A>G","abstract_start":940,"abstract_end":952},{"Name":"NM_000252.3(MTM1):c.70C>T (p.Arg24Ter)","Chromosome":"X","Start":"150596504","Stop":"150596504","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":98585,"rule_based_match":true,"evidence_text":"c.70C>T (R24X)","llm_judgment":"PRESENT","evidence":"c.70C>T (R24X)","abstract_start":965,"abstract_end":979}]}
{"pmid":"29355282","title":"Malignant Hyperthermia and Ryanodine Receptor Type 1 Gene (RyR1) Mutation in a Family in Singapore.","abstract":"INTRODUCTION: Sporadic clinical episodes of malignant hyperthermia (MH) that develop during general anaesthesia (GA) have been reported in Singapore. However, there is no published local report of a confirmed case of MH susceptibility (MHS) by skeletal muscle contracture tests and/or molecular tests.\nMATERIALS AND METHODS: We report 2 patients from an extended family who developed signs of clinical MH while under GA. The MH episodes were successfully treated with intravenous dantrolene sodium. Sequence analysis of the entire <i>Ryanodine Receptor Type 1 (RyR1)</i> coding gene was carried out in an index patient.\nRESULTS: The index patient was found to carry a c.7373G>A (p.Arg2458His) mutation in exon 46. This particular mutation satisfies the criteria for a MHS causative mutation. Hence, the index patient was considered to be MHS and did not need to undergo further muscle contracture testing. The same mutation was also found in 3 other members of his extended family.\nCONCLUSION: This is the first report of a Singaporean family with at least 4 members carrying a MH-causative mutation in <i>RyR1</i> gene. This report serves to highlight the existence of the putative gene for MH in Singapore, and the need for clinical vigilance during anaesthesia involving the use of triggering agents.","variants":[{"Name":"NM_000540.3(RYR1):c.7373G>A (p.Arg2458His)","Chromosome":"19","Start":"38500655","Stop":"38500655","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28011,"rule_based_match":true,"evidence_text":"c.7373G>A (p.Arg2458His)","llm_judgment":"PRESENT","evidence":"c.7373G>A (p.Arg2458His)","abstract_start":668,"abstract_end":692}]}
{"pmid":"25402387","title":"Precocious presentation of autoimmune polyglandular syndrome type 2 associated with an AIRE mutation.","abstract":"Autoimmune polyglandular syndrome type 2 (type 2 APS), or Schmidt's syndrome, is defined by the presence of Addison's disease in combination with type 1 diabetes and/or autoimmune thyroid disease. The estimated prevalence of this syndrome is 1.4-4.5 per 100,000 inhabitants and it is more frequent in middle-aged females, whilst it is quite rare in children. Type 2 APS, which shows a pattern of autosomal dominant inheritance with low penetrance, has been associated with HLA specific DR3/DQ2 and DR4/DQ8 haplotypes. However, it has been hypothesized that genetic variability in the AIRE gene, which causing type 1 APS, may play a role in more common organ-specific autoimmune conditions like type 1 diabetes, Hashimoto's disease and type 2 APS, among others. Here we present the case of an 8-year-old girl, with a past medical history of type 1 diabetes diagnosed at the age of 3. She was taken to the Emergency Department because she complained of abdominal pain, nausea and vomiting, and her blood analysis revealed a severe hyponatremia. She also had seizures as a consequence of the hyponatremia and frequent hypoglycemia. She was ultimately found to be suffering from autoimmune primary adrenal insufficiency. The combination of both mentioned conditions, type 1 diabetes and Addison's disease, in the absence of chronic mucocutaneous candidiasis, made a diagnosis of type 2 APS plausible in this girl. The genetic study showed two heterozygous variants: NM_000383.2:C.1411C>T (p. Arg471Cys) in exon 12 and IVS9+6G>A in intron 9 of the AIRE gene. The description of an uncommon case of type 2 APS with precocious presentation associated with an AIRE mutation in a very young girl could help to clarify the role of AIRE in the development of autoimmune diseases.","variants":[{"Name":"NM_000383.4(AIRE):c.1411C>T (p.Arg471Cys)","Chromosome":"21","Start":"44294411","Stop":"44294411","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":133781,"rule_based_match":true,"evidence_text":"NM_000383.2:C.1411C>T (p. Arg471Cys)","llm_judgment":"PRESENT","evidence":"NM_000383.2:C.1411C>T (p. Arg471Cys)","abstract_start":1462,"abstract_end":1498}]}
{"pmid":"32531461","title":"Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation.","abstract":"Mutations in the TRIM8 gene have been described in patients with severe developmental delay, intellectual disability and epilepsy. Only six patients have been described to date. All the previous mutations were truncating variants clustered in the C-terminus of the protein. A previous patient with TRIM8-related epileptic encephalopathy was reported to have nephrotic syndrome. Here we describe the clinical, radiological and histological features of an 8-year-old male patient with a TRIM8 mutation who, in contrast to previous patients, had only mild intellectual disability and well-controlled epilepsy. The patient was found to have proteinuria at 2 years of age. Renal biopsy findings were suggestive of focal segmental glomerulosclerosis. His kidney function declined and peritoneal dialysis was started at 5 years of age. He underwent renal transplant at 7 years of age. Trio-based whole genome sequencing identified a novel de novo heterozygous frameshift mutation in TRIM8 (NM_030912.2) c.1198_1220del, p.(Tyr400ArgfsTer2). This patient is further evidence that TRIM8 mutations cause a syndrome with both neurological and renal features. Our findings suggest the spectrum of TRIM8-related disease may be wider than previously thought with the possibility of milder neurodevelopmental problems and/or a more severe, progressive renal phenotype. We highlight the need for proteinuria screening in patients with TRIM8 mutations.","variants":[{"Name":"NM_030912.3(TRIM8):c.1198_1220del (p.Tyr400fs)","Chromosome":"10","Start":"102656891","Stop":"102656913","ReferenceAlleleVCF":"GGCCAGTACGGGGCGGCGGGCACA","AlternateAlleleVCF":"G","allel_id":1182181,"rule_based_match":true,"evidence_text":"c.1198_1220del, p.(Tyr400ArgfsTer2)","llm_judgment":"PRESENT","evidence":"c.1198_1220del, p.(Tyr400ArgfsTer2)","abstract_start":996,"abstract_end":1031}]}
{"pmid":"35670744","title":"Biallelic variants in MOS cause large polar body in oocyte and human female infertility.","abstract":"STUDY QUESTION: What is the genetic basis of female infertility involving abnormal oocyte morphology with the production of a large first polar body (PB1)?\nSUMMARY ANSWER: The homozygous missense variant (c.791C>G) and compound missense variants (c.596A>T and c.875C>T) in MOS proto-oncogene, serine/threonine kinase (MOS) (Online Mendelian Inheritance in Man (OMIM) reference: 190060; NM_005372.1) are responsible for abnormal oocyte morphology with the production of a large PB1 to cause infertility in women.\nWHAT IS KNOWN ALREADY: MOS, an oocyte-specific gene, encodes a serine/threonine-protein kinase that directly phosphorylates mitogen-activated protein kinase (MAPK) kinase (MEK) to activate MAPK (also called extracellular-signal-regulated kinase (ERK)) signal cascade in the oocyte. Female mice lacking Mos remained viable, but infertile because of oocyte symmetric division, spontaneous parthenogenetic activation and early embryonic arrest. Recently, two independent studies demonstrated that female infertility with early embryonic arrest and fragmentation can be caused by biallelic mutations in MOS. However, so far, MOS variants have not been associated with the phenotype of large PB1 extrusion in human oocytes to contribute to female infertility.\nSTUDY DESIGN, SIZE, DURATION: Two independent infertile families characterized by the presence of large PB1 in oocytes were recruited between December 2020 and February 2022.\nPARTICIPANTS/MATERIALS, SETTING, METHODS: Genomic DNA was extracted from the peripheral blood samples of the subjects for whole-exome sequencing. Pedigree analysis was validated by Sanger sequencing. Then, the pathogenic effects of the MOS variants on MOS protein properties and ERK1/2 activation were determined in HEK293 cells and mouse oocytes.\nMAIN RESULTS AND THE ROLE OF CHANCE: We identified three rare missense variants in MOS, including a homozygous missense variant (c.791C>G) from Patient 1 in Family 1 and two compound missense variants (c.596A>T and c.875C>T) from twin sisters in Family 2. The MOS variants followed a recessive inheritance pattern in infertile patients. All three patients displayed a high percentage of large PB1 extrusion in the oocytes. The three MOS variants could not activate MEK1/2 and ERK1/2 in oocytes and HEK293 cells. In addition, when compared with wild-type MOS, the MOS variants decreased the MOS protein level and attenuated the binding capacity with MEK1. Microinjection of wild-type human MOS complementary RNAs (cRNAs) reversed the symmetric division of oocytes after siMos treatment. In contrast, the three MOS variants demonstrated no rescuing ability.\nLARGE SCALE DATA: N/A.\nLIMITATIONS, REASONS FOR CAUTION: Owing to the scarcity of human oocyte samples and the associated ethical restrictions, we could not perform the rescue attempt for the study patients.\nWIDER IMPLICATIONS OF THE FINDINGS: Our findings expand the genetic and phenotypic spectrum of MOS variants in causing female infertility. Our study findings facilitate the early genetic diagnosis of abnormal oocyte morphology characterized as large PB1 that eventually causes infertility in women.\nSTUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (82071640 and 82001633), Natural Science Foundation of Zhejiang Province (LD22C060001), the Key Projects Jointly Constructed by the Ministry and the Province of Zhejiang Medical and Health Science and Technology Project (WKJ-ZJ-2005), China Postdoctoral Science Foundation (2020M682575 and 2021T140198), the Changsha Municipal Natural Science Foundation (kq2007022) and Hunan Provincial Grant for Innovative Province Construction (2019SK4012). None of the authors declare any competing interests.\nTRIAL REGISTRATION NUMBER: N/A.","variants":[{"Name":"NM_005372.1(MOS):c.596A>T (p.His199Leu)","Chromosome":"8","Start":"56113387","Stop":"56113387","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2543816,"rule_based_match":true,"evidence_text":"c.596A>T","llm_judgment":"PRESENT","evidence":"c.596A>T","abstract_start":247,"abstract_end":255},{"Name":"NM_005372.1(MOS):c.875C>T (p.Ala292Val)","Chromosome":"8","Start":"56113108","Stop":"56113108","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2543811,"rule_based_match":true,"evidence_text":"c.875C>T","llm_judgment":"PRESENT","evidence":"c.875C>T","abstract_start":260,"abstract_end":268},{"Name":"NM_005372.1(MOS):c.791C>G (p.Ser264Cys)","Chromosome":"8","Start":"56113192","Stop":"56113192","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2543815,"rule_based_match":true,"evidence_text":"c.791C>G","llm_judgment":"PRESENT","evidence":"c.791C>G","abstract_start":205,"abstract_end":213}]}
{"pmid":"20352457","title":"Analysis of CTNS gene transcripts in nephropathic cystinosis.","abstract":"Nephropathic cystinosis (NC) is an autosomal recessive disorder caused by mutations of the CTNS gene that encodes for a cystine transmembrane transporter. Several mutations have been described in the coding and promoter regions of the CTNS gene in affected individuals. We selected three patients with NC from two unrelated families, in whom sequence analysis of the CTNS gene detected only one or no mutations. Total RNA was isolated from peripheral blood mononuclear cells or fibroblasts and CTNS transcripts were analyzed. We observed a skipping of exon 5 (85 bp) in two siblings and an intron 9 retention of 75 bp associated with partial replication of exon 9 in the third patient. Genomic DNA analysis of intron regions surrounding exon 5 showed a point mutation in the hypothetical lariat branch site of intron 4 at position -24 (c.141-24 T > C) in the first two patients and a duplication of 266 bp including a part of exon and intron 9 in the third patient. Analysis of CTNS gene transcripts allowed identification of mutations in patients in whom CTNS mutations could not be detected by traditional DNA sequencing. These results support the hypothesis that cystinosis is a monogenic disorder.","variants":[{"Name":"NM_004937.3(CTNS):c.141-24T>C","Chromosome":"17","Start":"3648823","Stop":"3648823","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1932729,"rule_based_match":true,"evidence_text":"c.141-24 T > C","llm_judgment":"PRESENT","evidence":"c.141-24 T > C","abstract_start":836,"abstract_end":850}]}
{"pmid":"23707711","title":"Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.","abstract":"3-Methylglutaconic aciduria (3-MGA-uria) is a heterogeneous group of syndromes characterized by an increased excretion of 3-methylglutaconic and 3-methylglutaric acids. Five types of 3-MGA-uria (I to V) with different clinical presentations have been described. Causative mutations in TAZ, OPA3, DNAJC19, ATP12, ATP5E, and TMEM70 have been identified. After excluding the known genetic causes of 3-MGA-uria we used exome sequencing to investigate a patient with Leigh syndrome and 3-MGA-uria. We identified a homozygous variant in SERAC1 (c.202C>T; p.Arg68*), that generates a premature stop codon at position 68 of SERAC1 protein. Western blot analysis in patient's fibroblasts showed a complete absence of SERAC1 that was consistent with the prediction of a truncated protein and supports the pathogenic role of the mutation. During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. In addition, our patient developed microcephaly and optic atrophy, two features not previously reported in MEGDEL syndrome. We highlight the usefulness of exome sequencing to reveal the genetic bases of human rare diseases even if only one affected individual is available.","variants":[{"Name":"NM_032861.4(SERAC1):c.202C>T (p.Arg68Ter)","Chromosome":"6","Start":"158150516","Stop":"158150516","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":125792,"rule_based_match":true,"evidence_text":"c.202C>T; p.Arg68*","llm_judgment":"PRESENT","evidence":"c.202C>T; p.Arg68*","abstract_start":539,"abstract_end":557}]}
{"pmid":"29858860","title":"Two rare forms of congenital adrenal hyperplasia, 11β hydroxylase deficiency and 17-hydroxylase/17,20-lyase deficiency, presenting with novel mutations.","abstract":"BACKGROUND: Congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder caused by deficiency of various enzymes responsible for adrenal steroidogenesis. 11-Beta-hydroxylase deficiency (11βOHD) and 17-hydroxylase/17,20-lyase deficiency (17OHD) are rare causes of CAH.\nMETHODS/RESULTS: We hereby present a 65-year-old man with 11βOHD and a 33-year-old woman with 17OHD. The man with 11βOHD presented with peripheral precocious puberty and hypertension at age 15 years, fathered two children but developed complications of chronic glucocorticoid therapy on long-term follow-up. Interestingly, his younger sister had been diagnosed with the same condition at age 19 and had later given birth to four children while on glucocorticoids. Exome sequencing of the CYP11B1 gene detected the previously reported pathogenic mutation T318T (c.954G > A [p.Thr318Thr]) on one of the alleles and a novel mutation, R123G (c.367C > G [p.Arg123Gly]), on the other in a highly conserved region of the CYP11B1 gene. The woman with 17OHD presented with severe hypokalemia at age 22 years against a background of primary amenorrhea and lack of development of secondary sexual characteristics. She was heterozygous for a previously recognized mutation, R125Q (c.374G > A [p.Arg125Gln]), and a novel single base-pair deletion, G337fs (c.1010delG [p.Gly337Valfs*82]), which creates a frameshift with a new stop codon in the last exon of the gene, making it a likely pathogenic variant.\nCONCLUSION: Recognition of novel mutations is clinically significant and will contribute to the understanding of the phenotype-genotype relationship of these rare disorders in the future. It also highlights successful fertility outcomes in 11βOHD which have not been well documented in the literature so far.","variants":[{"Name":"NM_000102.4(CYP17A1):c.374G>A (p.Arg125Gln)","Chromosome":"10","Start":"102835316","Stop":"102835316","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16842,"rule_based_match":true,"evidence_text":"c.374G>A (p.Arg125Gln)","llm_judgment":"PRESENT","evidence":"p.Arg125Gln","abstract_start":1264,"abstract_end":1275},{"Name":"NM_000497.4(CYP11B1):c.367C>G (p.Arg123Gly)","Chromosome":"8","Start":"142879060","Stop":"142879060","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3512908,"rule_based_match":true,"evidence_text":"c.367C > G [p.Arg123Gly]","llm_judgment":"PRESENT","evidence":"c.367C > G [p.Arg123Gly]","abstract_start":921,"abstract_end":945},{"Name":"NM_000497.4(CYP11B1):c.954G>A (p.Thr318=)","Chromosome":"8","Start":"142876241","Stop":"142876241","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":441178,"rule_based_match":true,"evidence_text":"c.954G>A (p.Thr318Thr)","llm_judgment":"PRESENT","evidence":"p.Thr318Thr","abstract_start":856,"abstract_end":867}]}
{"pmid":"35532199","title":"Classic infantile-onset Pompe disease with histopathological neurologic findings linked to a novel GAA gene 4 bp deletion: A case study.","abstract":"Pompe disease (PD) is an autosomal recessive disorder by a deficiency of acid α-glucosidase (GAA) with intralysosomal glycogen accumulation in multiple tissues. We present the case of a 5-month-old male with hypertrophic cardiomyopathy, hypotony, feeding difficulties, and oxygen requirement since birth. At 3 months of age, he develops heart failure, respiratory impairment, and neurological deterioration. The echocardiogram revealed concentric hypertrophic cardiomyopathy with left-diastolic dysfunction. We found increased creatine-phosphokinase, lactate dehydrogenase, and urinary glucose tetrasaccharide levels, 50% of PAS-positive vacuolated lymphocytes in the peripheral blood smear, and low GAA activity. Sequencing of coding exons and flanking intronic sequences revealed a novel homozygous 4 bp deletion in exon 15 of the GAA gene (c.2066_2069delAGCC/p.Glu689Glyfs*6). IOPD was diagnosed. At 5 months old, we started enzyme replacement therapy with an alpha-alglucosidase of 20 mg/kg weekly and immunomodulation with intravenous immunoglobulin. He developed two cardiorespiratory arrests with subsequent neurologic deterioration, convulsive crisis, and respiratory failure and died at 9 months old. We found the usual PD hallmarks in the heart, striated muscle, and liver but also we found neuronal lesions characterized by cytoplasm vacuolization with PAS-positive granules in the central nervous system and myenteric plexus. We describe a novel GAA gene pathogenic variant with a particular phenotype characterized by classic IOPD and neurologic histopathological findings. Enhancing the knowledge of lysosomal diseases is critical to improving the diagnosis and treatment of these patients.","variants":[{"Name":"NM_000152.5(GAA):c.2066_2069del (p.Glu689fs)","Chromosome":"17","Start":"80113243","Stop":"80113246","ReferenceAlleleVCF":"GAGCC","AlternateAlleleVCF":"G","allel_id":2523941,"rule_based_match":true,"evidence_text":"c.2066_2069delAGCC/p.Glu689Glyfs*6","llm_judgment":"PRESENT","evidence":"c.2066_2069delAGCC/p.Glu689Glyfs*6","abstract_start":843,"abstract_end":877}]}
{"pmid":"32250532","title":"Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence.","abstract":"Defects in the gene encoding synaptotagmin 2 (SYT2) have been linked to a presynaptic congenital myasthenic syndrome (CMS) and motor neuropathies. However, to date only dominant forms of the disease have been described. We report here a consanguineous patient with a severe recessive form of presynaptic CMS and denervation atrophy caused by the homozygous mutation c.1191delG, p.Arg397Serfs*37 in SYT2. The affected 2-year-old girl had profound weakness and areflexia with moderate bulbar deficit. Repetitive nerve stimulation revealed an extreme reduction of compound muscle action potential amplitudes at rest, with a striking facilitation followed by a progressive decline at fast stimulation rates. These findings were reminiscent, but not identical to those seen in the Lambert-Eaton myasthenic syndrome. 3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective. Modeling of the mutation using the rat Syt1 C2B x-ray structure revealed that Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom face of the C2B domain not directly involved in calcium binding, but crucial for synaptotagmin-SNARE interaction and exocytosis. Thus, this report describes a recessive form of synaptotagmin 2-CMS and highlights the importance of the synaptotagmin C-terminal on synaptic vesicle fusion and exocytosis.","variants":[{"Name":"NM_177402.5(SYT2):c.1191del (p.Arg397fs)","Chromosome":"1","Start":"202596826","Stop":"202596826","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1182324,"rule_based_match":true,"evidence_text":"c.1191delG, p.Arg397Serfs*37","llm_judgment":"PRESENT","evidence":"c.1191delG, p.Arg397Serfs*37","abstract_start":366,"abstract_end":394}]}
{"pmid":"27395053","title":"Identification of Novel Compound Mutations in PLA2G6-Associated Neurodegeneration Patient with Characteristic MRI Imaging.","abstract":"Neurodegeneration with brain iron accumulation comprises a heterogeneous group of disorders characterized clinically by progressive motor dysfunction. Accurate identification of de novo and rare inherited mutations is important for determining causative genes of undiagnosed neurological diseases. In the present study, we report a unique case with cerebellar ataxia symptoms and social communication difficulties in an intermarriage family. MRI showed a marked cerebellar atrophy and the \"eye-of-the-tiger\"-like sign in the medial globus pallidus. Potential genetic defects were screened by whole-exome sequencing (WES) for the patient and four additional family members. A previously undescribed de novo missense mutation (c.1634A>G, p.K545R) in the exon 12 of the PLA2G6 gene was identified. A second rare variant c.1077G>A at the end of exon 7 was also identified, which was inherited from the mother, and resulted in a frame-shift mutation (c.1074_1077del.GTCG) due to an alternative splicing. In conclusion, the identification of the \"eye-of-the-tiger\"-like sign in the globus pallidus of the patient expands the phenotypic spectrum of PLA2G6-associated disorders and reveals its value in differential diagnosis of PLA2G6-associated disorders.","variants":[{"Name":"NM_003560.4(PLA2G6):c.1634A>G (p.Lys545Arg)","Chromosome":"22","Start":"38120867","Stop":"38120867","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":169786,"rule_based_match":true,"evidence_text":"c.1634A>G, p.K545R","llm_judgment":"PRESENT","evidence":"c.1634A>G, p.K545R","abstract_start":725,"abstract_end":743}]}
{"pmid":"21598003","title":"A novel pathogenic germline mutation in the adenomatous polyposis coli gene in a Tunisian family with FAP.","abstract":"Familial adenomatous polyposis (FAP) is an autosomal dominant disorder which typically presents with colorectal cancer in early adult life, secondary to extensive adenomatous polyps of the colon. In addition to the colonic manifestations, the syndrome presents several extracolonic features including, congenital hypertrophy of the retinal pigment, osteomata and desmoid tumors. In this study, we aimed to investigate the clinical and genetic features in a Tunisian family with FAP. Sequence of the APC gene (Adenomatous Polyposis Coli) revealed a novel mutation (c.2016-2017 del TA) in exon 15, present in all affected individuals in an heterozygous state. The frameshift mutation generates a premature stop codon at amino acid 677 of the APC protein (p. H672Qfs X5). The unaffected family members did not harbor this mutation, however, a first degree relative of the patient aged of 32-year-old was phenotypically normal but carries the c.2016-2017 del TA mutation. This discrepancy can be explained by the effect of modifier gene which can affect the expressivity of the disease.","variants":[{"Name":"NM_000038.6(APC):c.2016_2017del (p.His672fs)","Chromosome":"5","Start":"112837609","Stop":"112837610","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":1467928,"rule_based_match":false,"evidence_text":"c.2016-2017 del TA","llm_judgment":"PRESENT","evidence":"c.2016-2017 del TA","abstract_start":564,"abstract_end":582}]}
{"pmid":"19862333","title":"Sequence variations of GRM6 in patients with high myopia.","abstract":"PURPOSE: Mutations in the glutamate receptor metabotropic 6 gene (GRM6) have been identified in patients with congenital stationary night blindness (CSNB1B). High myopia is usually observed in CSNB1B patients. This study tested if any mutations in GRM6 were solely responsible for high myopia.\nMETHODS: DNA was prepared from the venous leukocytes of 96 Chinese patients with high myopia (refraction of spherical equivalent of at least -6.00 diopters [D]) and 96 controls (refraction of spherical equivalent between -0.50 D and +2.00 D with normal visual acuity). The coding regions and adjacent intronic sequence of GRM6 were amplified by a polymerase chain reaction (PCR) and then analyzed by cycle sequencing. Detected variations were evaluated in normal controls by heteroduplex-single-strand-conformation (SSCP) polymorphism analysis or restriction fragment polymorphism (RFLP).\nRESULTS: Four novel variations predicted to have potential functional changes were identified: c.67-82delCAGGCGGGCCTGGCGCinsT (p.Gln23_Arg28delinsCys), c.858-5a>g (r.spl?), c.1172G>A (p.Arg391Gln), and c.1537G>A (p.Val513Met). Except for c.1172G>A, the other three were not detected in the 96 controls. In addition, five rare variations-(c.72G>A, c.504+10g>t, c.726-50g>c, c.1359C>T, and c.1383C>T)-and one common variation (c.2437-6g>a) without predicted functional consequences and nine known single nucleotide polymorphisms (SNPs) were also detected.\nCONCLUSION: Three novel variations with potential functional consequences were identified in the GRM6 of patients with high myopia, suggesting a potential role in the development of myopia in rare cases.","variants":[{"Name":"NM_000843.4(GRM6):c.1537G>A (p.Val513Met)","Chromosome":"5","Start":"178986717","Stop":"178986717","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227285,"rule_based_match":true,"evidence_text":"c.1537G>A (p.Val513Met)","llm_judgment":"PRESENT","evidence":"c.1537G>A (p.Val513Met)","abstract_start":1085,"abstract_end":1108}]}
{"pmid":"30260545","title":"The mutation-dependent pathogenicity of NPHS2 p.R229Q: A guide for clinical assessment.","abstract":"NPHS2, encoding podocin, is the major gene implicated in steroid-resistant nephrotic syndrome. Its c.686G>A, p.R229Q variant is the first human variant with a mutation-dependent pathogenicity; it is only pathogenic when trans-associated to specific mutations. Secondary to its high allele frequency in the European, South Asian, African, and Latino populations, its benign trans-associations can be accidentally identified in affected patients. Distinguishing pathogenic and benign p.R229Q associations can be challenging. In this paper, we present the currently known pathogenic and benign associations, and show that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; it affects the 270-351 residues and alters but does not disrupt the oligomerization, its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:10<sup>6</sup> ). We show that >15% of the p.R229Q associations identified so far in patients are benign.","variants":[{"Name":"NM_014625.4(NPHS2):c.686G>A (p.Arg229Gln)","Chromosome":"1","Start":"179557079","Stop":"179557079","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20409,"rule_based_match":true,"evidence_text":"c.686G>A, p.R229Q","llm_judgment":"PRESENT","evidence":"c.686G>A, p.R229Q","abstract_start":99,"abstract_end":116}]}
{"pmid":"34210262","title":"Two novel mutations in TCIRG1 induced infantile malignant osteopetrosis: a case report.","abstract":"BACKGROUND: Infantile malignant osteopetrosis (IMO) is a rare autosomal recessive disease characterized by a higher bone density in bone marrow caused by the dysfunction of bone resorption. Clinically, IMO can be diagnosed with medical examination, bone mineral density test and whole genome sequencing.\nCASE PRESENTATION: We present the case of a 4-month-old male infant with abnormal skull development, hypocalcemia and premature closure of the cranial sutures. Due to the hyper bone density showed by his radiographic examination, which are characteristic patterns of IMO, we speculated that he might be an IMO patient. In order to confirm this diagnosis, a high-precision whole exome sequencing of the infant and his parents was performed. The analysis of high-precision whole exome sequencing results lead to the identification of two novel heterozygous mutations c.504-1G > C (a splicing site mutation) and c.1371delC (p.G458Afs*70, a frameshift mutation) in gene TCIRG1 derived from his parents. Therefore, we propose that there is a close association between these two mutations and the onset of IMO.\nCONCLUSIONS: To date, these two novel mutations in gene TCIRG1 have not been reported in the reference gene database of Chinese population. These variants have likewise not been reported outside of China in the Genome Aggregation Database (gnomAD). Our case suggests that the use of whole exome sequencing to detect these two mutations will improve the identification and early diagnosis of IMO, and more specifically, the identification of homozygous individuals with TCIRG1 gene mutation. We propose that these mutations in gene TCIRG1 could be a novel therapeutic target for the IMO in the future.","variants":[{"Name":"NM_006019.4(TCIRG1):c.504-1G>C","Chromosome":"11","Start":"68043370","Stop":"68043370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2943958,"rule_based_match":true,"evidence_text":"c.504-1G > C","llm_judgment":"PRESENT","evidence":"c.504-1G > C","abstract_start":869,"abstract_end":881}]}
{"pmid":"37397863","title":"Identification of an","abstract":"BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant hereditary disease. Its early diagnosis and intervention significantly improve the patient's quality of life. However, there are few types of research on the FH pathogenic genes in China.\nMETHODS: In this study, we recruited a family diagnosed with FH and used whole exome sequencing (WES) to analyze the proband variants. Intracellular cholesterol level, reactive oxygen species (ROS) level, and the expression of pyroptosis-related genes were detected after overexpression of wild-type or variant <i>LDLR</i> in L02 cells.\nRESULTS: A heterozygous missense variant predicted to be deleterious to <i>LDLR</i> (c.1879G > A, p.Ala627Thr) was identified in the proband. Mechanistically, intracellular cholesterol level, ROS level, and the expression of pyroptosis-related genes, nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome and components (caspase 1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and NLRP3), gasdermin D (GSDMD), interleukin (IL) -18, IL-1β was elevated in the variant <i>LDLR</i> group, which was attenuated by inhibition of ROS.\nCONCLUSIONS: FH is associated with a variant (c.1879G>A, p.Ala627Thr) in the <i>LDLR</i> gene. Regarding the mechanism, the ROS/NLRP3-mediated pyroptosis in hepatic cells may contribute to the pathogenesis of the <i>LDLR</i> variant.","variants":[{"Name":"NM_000527.5(LDLR):c.1879G>A (p.Ala627Thr)","Chromosome":"19","Start":"11120125","Stop":"11120125","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":246397,"rule_based_match":true,"evidence_text":"c.1879G > A, p.Ala627Thr","llm_judgment":"PRESENT","evidence":"c.1879G > A, p.Ala627Thr","abstract_start":688,"abstract_end":712}]}
{"pmid":"26184463","title":"Exome sequencing identifies a novel heterozygous TGFB3 mutation in a disorder overlapping with Marfan and Loeys-Dietz syndrome.","abstract":"Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are clinically related autosomal dominant systemic connective tissue disorders. Although mutations in several genes of the TGF-beta signalling and related pathways have been identified in the past (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2), there are still many individuals with \"marfanoid\" phenotypes in whom no causative mutations are identified. We performed whole exome sequencing in two of three affected individuals from a family with phenotypic features overlapping MFS and LDS. The two affected children and their affected father had tall stature, arachnodactyly, hyperextensible joints, hypertelorism, bifid uvula, but no cardiac involvement, aortic dilation or eye involvement. We detected a novel heterozygous mutation in TGFB3, c.898C>G, predicting the missense substitution p.Arg300Gly. Sanger sequencing confirmed the mutation and its segregation with the phenotype. The first two TGFB3 mutations were reported previously in two unrelated individuals with marfanoid features: one individual with growth retardation carried a heterozygous loss-of-function mutation (c.1226G>A; p.Cys409Tyr; Rienhoff et al., 2013), whereas a child with overgrowth carried a mutation in the same codon as the mutation identified in the three affected individuals reported here (c.899G>A; p.Arg300Gln; Matyas et al., 2014). The mutations at codon Arg300 presumably lead to increased TGF-beta signalling, suggesting that the short or tall stature seen in patients with TGFB3 mutations may result from opposing effects of mutations on TGF-beta signalling. Thus, we add a novel human TGFB3 mutation, contribute to the clinical delineation of the emerging connective tissue disorder tentatively called Rienhoff syndrome and compare the data with a very recent report (Bertoli-Avella et al., 2015) on TGFB3 mutations associated with aortic aneurysms or dissections.","variants":[{"Name":"NM_003239.5(TGFB3):c.899G>A (p.Arg300Gln)","Chromosome":"14","Start":"75963343","Stop":"75963343","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":153683,"rule_based_match":true,"evidence_text":"c.899G>A (p.Arg300Gln)","llm_judgment":"PRESENT","evidence":"p.Arg300Gln","abstract_start":1334,"abstract_end":1345}]}
{"pmid":"35047275","title":"A Rare Cause of Recurrent Febrile Encephalopathy in a Child: The Expanding Spectrum of ATP1A3 Mutations.","abstract":"ATP1A3 mutations have been recognized in infants and children presenting with a diverse group of neurological phenotypes, including rapid-onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. A new phenotype of fever-induced paroxysmal muscle weakness and encephalopathy (FIPWE) in patients with ATP1A3 mutations at c.2267G>A p residue 756H has been described most recently in few cases. Here, we report an additional case with an ATP1A3 mutation at c.2267G>A p residue 756H presenting with fever-induced paroxysmal muscle weakness and encephalopathy. To the best of our knowledge, this is the first reported case from the Middle East. This 18-month-old boy presented with recurrent, reversible fever-induced episodes of seizures, central hypotonia, areflexia, and developmental regression. The mainstay management for patients with ATP1A3 related diseases is symptomatic treatment as there is no specific proposed treatment. Aggressive management of febrile illness may be helpful in alleviating the symptoms.","variants":[{"Name":"NM_152296.5(ATP1A3):c.2267G>A (p.Arg756His)","Chromosome":"19","Start":"41970539","Stop":"41970539","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":170985,"rule_based_match":true,"evidence_text":"c.2267G>A","llm_judgment":"PRESENT","evidence":"c.2267G>A","abstract_start":449,"abstract_end":458}]}
{"pmid":"30376817","title":"Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation.","abstract":"BACKGROUND: MEF2C (Myocyte-specific enhancer factor 2C) has been associated with neurodevelopmental disorders. This study aimed at delineating the clinical profiles of MEF2C gene mutations.\nMETHODS: In total, 112 Chinese patients with intellectual disability (ID) were recruited, including 44 patients presented with Rett syndrome (RTT) or RTT-like syndrome, and 68 patients with non-syndromic ID. Targeted next-generation sequencing (NGS) was performed. Detailed clinical information was collected.\nRESULTS: Five heterozygous MEF2C gene mutations were identified, of which three were novel. The MEF2C mutant rate was 4.5% (5/112) in total, and 6.8% (3/44) in the RTT (-like) cohort. All patients with MEF2C gene mutation presented with cognitive impairment, gross motor delay, speech disorder and autistic features. Four patients had epilepsy, which responded well to antiepileptic drugs. One female was diagnosed with classical RTT, two females with RTT-like syndrome, and two males with non-syndromic ID. Generally, the phenotype of two males with relatively downstream mutations (c.565C > T, p.Arg 189*; c.766C > T, p.Arg 256*) was milder than that of three females with upstream mutations (c.48C > G, p.Asn16Lys; c.334G > T, p.Glu112* and c.403-1G > T).\nCONCLUSIONS: Our findings expanded the current understanding of the consequences of MEF2C dysfunctions, especially MEF2C point mutations. MEF2C mutations are associated with a broad clinical spectrum, ranged from classical RTT to non-syndromic ID. Through our study, it can be inferred that there is correlation between the phenotype and MEF2C-genotype, the mutation site. Overall, the MEF2C gene mutational analysis should be performed in ID cohort, especially in patients with features overlapped with RTT.","variants":[{"Name":"NM_002397.5(MEF2C):c.48C>G (p.Asn16Lys)","Chromosome":"5","Start":"88823741","Stop":"88823741","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3839136,"rule_based_match":true,"evidence_text":"c.48C > G, p.Asn16Lys","llm_judgment":"PRESENT","evidence":"c.48C > G, p.Asn16Lys","abstract_start":1195,"abstract_end":1216},{"Name":"NM_002397.5(MEF2C):c.766C>T (p.Arg256Ter)","Chromosome":"5","Start":"88731773","Stop":"88731773","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":201908,"rule_based_match":true,"evidence_text":"c.766C > T, p.Arg 256*","llm_judgment":"PRESENT","evidence":"c.766C > T, p.Arg 256*","abstract_start":1108,"abstract_end":1130},{"Name":"NM_002397.5(MEF2C):c.565C>T (p.Arg189Ter)","Chromosome":"5","Start":"88751881","Stop":"88751881","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":168543,"rule_based_match":true,"evidence_text":"c.565C > T, p.Arg 189*","llm_judgment":"PRESENT","evidence":"c.565C > T, p.Arg 189*","abstract_start":1084,"abstract_end":1106}]}
{"pmid":"27595995","title":"PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.","abstract":"BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.\nMETHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.\nRESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10<sup>-5</sup>), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10<sup>-8</sup>) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.\nCONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.","variants":[{"Name":"NM_007194.4(CHEK2):c.1036C>T (p.Arg346Cys)","Chromosome":"22","Start":"28696960","Stop":"28696960","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":151936,"rule_based_match":true,"evidence_text":"c.1036C>T","llm_judgment":"PRESENT","evidence":"c.1036C>T","abstract_start":602,"abstract_end":611},{"Name":"NM_007194.4(CHEK2):c.1312G>T (p.Asp438Tyr)","Chromosome":"22","Start":"28695190","Stop":"28695190","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":133513,"rule_based_match":true,"evidence_text":"CHEK2 c.1312G>T","llm_judgment":"PRESENT","evidence":"CHEK2 c.1312G>T","abstract_start":1527,"abstract_end":1542},{"Name":"NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)","Chromosome":"11","Start":"108329202","Stop":"108329202","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18062,"rule_based_match":true,"evidence_text":"ATM c.7271T>G","llm_judgment":"PRESENT","evidence":"ATM c.7271T>G","abstract_start":642,"abstract_end":655},{"Name":"NM_024675.4(PALB2):c.1592del (p.Leu531fs)","Chromosome":"16","Start":"23634954","Stop":"23634954","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":132119,"rule_based_match":true,"evidence_text":"PALB2 c.1592delT","llm_judgment":"PRESENT","evidence":"PALB2 c.1592delT","abstract_start":523,"abstract_end":539},{"Name":"NM_007194.4(CHEK2):c.349A>G (p.Arg117Gly)","Chromosome":"22","Start":"28725338","Stop":"28725338","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":133528,"rule_based_match":true,"evidence_text":"CHEK2 c.349A>G","llm_judgment":"PRESENT","evidence":"CHEK2 c.349A>G","abstract_start":566,"abstract_end":580},{"Name":"NM_007194.4(CHEK2):c.1343T>G (p.Ile448Ser)","Chromosome":"22","Start":"28695159","Stop":"28695159","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":137631,"rule_based_match":true,"evidence_text":"CHEK2 c.1343T>G","llm_judgment":"PRESENT","evidence":"CHEK2 c.1343T>G","abstract_start":1451,"abstract_end":1466},{"Name":"NM_007194.4(CHEK2):c.715G>A (p.Glu239Lys)","Chromosome":"22","Start":"28711986","Stop":"28711986","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20639,"rule_based_match":true,"evidence_text":"CHEK2 c.715G>A","llm_judgment":"PRESENT","evidence":"c.715G>A","abstract_start":592,"abstract_end":600},{"Name":"NM_007194.4(CHEK2):c.538C>T (p.Arg180Cys)","Chromosome":"22","Start":"28725031","Stop":"28725031","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133538,"rule_based_match":true,"evidence_text":"c.538C>T","llm_judgment":"PRESENT","evidence":"c.538C>T","abstract_start":582,"abstract_end":590},{"Name":"NM_024675.4(PALB2):c.2816T>G (p.Leu939Trp)","Chromosome":"16","Start":"23624027","Stop":"23624027","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":132193,"rule_based_match":true,"evidence_text":"PALB2 c.2816T>G","llm_judgment":"PRESENT","evidence":"c.2816T>G","abstract_start":541,"abstract_end":550},{"Name":"NM_024675.4(PALB2):c.3113G>A (p.Trp1038Ter)","Chromosome":"16","Start":"23621362","Stop":"23621362","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":132221,"rule_based_match":true,"evidence_text":"PALB2 c.3113G>A","llm_judgment":"PRESENT","evidence":"PALB2 c.3113G>A","abstract_start":1047,"abstract_end":1062}]}
{"pmid":"15472169","title":"Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy.","abstract":"Congenital leptin deficiency is a rare, but treatable, cause of severe early-onset obesity. To date, two United Kingdom families of Pakistani origin carrying a frameshift/premature stop mutation, c.398delG (Delta133G), and one Turkish family carrying a missense mutation, c.313C>T (Arg(105)Trp), have been described. Affected subjects are homozygotes and manifest severe obesity and hyperphagia accompanied by metabolic, neuroendocrine, and immune dysfunction. The effects of recombinant leptin therapy have been reported in three children with the Delta133G mutation, and in all cases this has led to a dramatic resolution of clinical and biochemical abnormalities. We now report a Canadian child, of Pakistani origin but unrelated to the previously reported subjects, presenting with severe hyperphagia and obesity, who was found to be homozygous for the Delta133G mutation. In this child, 4 yr of therapy with sc injections of recombinant leptin provided additional evidence for the sustained beneficial effects of leptin replacement on fat mass, hyperinsulinemia, and hyperlipidemia. In addition, leptin administration corrected abnormal thyroid biochemistry and allowed the withdrawal of T(4) treatment, providing additional support for the role of leptin in the regulation of the human hypothalamic-pituitary-thyroid axis.","variants":[{"Name":"NM_000230.3(LEP):c.398del (p.Gly133fs)","Chromosome":"7","Start":"128254652","Stop":"128254652","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":29025,"rule_based_match":true,"evidence_text":"c.398del (Delta133G)","llm_judgment":"PRESENT","evidence":"c.398del","abstract_start":196,"abstract_end":204}]}
{"pmid":"35586824","title":"Analysis of Clinical and Genetic Characterization of Three Ataxia-Telangiectasia Pedigrees With Novel","abstract":"Objective: The clinical manifestations of ataxia-telangiectasia (AT) are very complex and are easily misdiagnosed and missed. The purpose of this study was to explore the clinical characteristics and genetic features of five pediatric patients with AT from three pedigrees in china.\nMethods: Retrospectively collected and analyzed the clinical data and genetic testing results of five AT patients diagnosed by the Whole-exome sequencing followed by Sanger sequencing. The five patients with AT were from three pedigrees, including two female patients (case 1 and case 2) in pedigree I, one male patient (case 3) in pedigree II, and two male patients (case 4 and case 5) in pedigree III. According to the United Kingdom Association for Clinical Genomic Science Best Practice Guidelines for Variants Classification in Rare Disease 2020 to grade the genetic variants.\nResults: Five patients had mainly clinical presentations including unsteady gait, dysarthria, bulbar conjunctive telangiectasia, cerebellar atrophy, intellectual disability, stunted growth, increase of alpha-fetoprotein in serum, lymphopenia. Notably, one patient with classical AT presented dystonia as the first symptom. One patient had recurrent infections, five patients had serum Immunoglobulin (Ig) A deficiency, and two patients had IgG deficiency. In three pedigrees, we observed five pathogenic variants of the <i>ATM</i> gene, which were c.1339C>T (p.Arg447Ter), c.7141_7151delAATGGAAAAAT (p.Asn2381GlufsTer18), c.437_440delTCAA (p.Leu146GlnfsTer6), c.2482A>T (p.Lys828Ter), and c.5495_5496+2delAAGT (p.Glu1832GlyfsTer4). Moreover, the c.437_440delTCAA, c.2482A>T, and c.5495_5496+2delAAGT were previously unreported variants.\nConclusions: Pediatric patients with classical AT may present dystonia as the main manifestation, or even a first symptom, besides typical cerebellar ataxia, bulbar conjunctive telangiectasia, etc. Crucially, we also found three novel pathogenic <i>ATM</i> gene variants (c.437_440delTCAA, c.2482A>T, and c.5495_5496+2delAAGT), expanding the <i>ATM</i> pathogenic gene mutation spectrum.","variants":[{"Name":"NM_000051.4(ATM):c.2482A>T (p.Lys828Ter)","Chromosome":"11","Start":"108267186","Stop":"108267186","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":3787693,"rule_based_match":true,"evidence_text":"c.2482A>T (p.Lys828Ter)","llm_judgment":"PRESENT","evidence":"c.2482A>T (p.Lys828Ter)","abstract_start":1525,"abstract_end":1548}]}
{"pmid":"12872264","title":"Four novel mutations in APOB causing heterozygous and homozygous familial hypobetalipoproteinemia.","abstract":"Familial hypobetalipoproteinemia (FHBL) is a rare codominant disorder of lipoprotein metabolism characterized by low levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B. Heterozygotes for FHBL have less-than-half normal LDL-cholesterol and apoB concentrations, whereas homozygotes have extremely low or undetectable LDL-cholesterol and apoB levels. These reductions in LDL-cholesterol and apoB have been suggested to provide FHBL subjects with resistance to atherosclerosis. FHBL can be caused by mutations in the APOB gene on chromosome 2. We present four novel mutations and one previously described mutation in APOB causing FHBL in five families. Immunoblotting and DNA sequencing were used to characterize the novel mutation apoB-40.3 (c.5564_5565insC) and the previously reported mutation apoB-80.5 (c.11040T>G). The apoB-6.9 (c.1018_1025del) and apoB-25.8 (c.3600T>A) mutations were identified by DNA sequence analysis, as variants shorter than apoB-31 are not detectable in plasma. A fifth mutation, the splice variant c.82+1G>A, was identified by sequencing and was found in a homozygous subject. In approximately 50% of the FHBL subjects, plasma alanine aminotransferase concentrations were mildly increased, suggestive of fatty liver. All affected FHBL subjects had low to low-normal serum vitamin E concentrations, highlighting the important and recognized relationship between lipid and vitamin E concentrations.","variants":[{"Name":"NM_000384.3(APOB):c.11040T>G (p.Tyr3680Ter)","Chromosome":"2","Start":"21005828","Stop":"21005828","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1313611,"rule_based_match":true,"evidence_text":"c.11040T>G","llm_judgment":"PRESENT","evidence":"c.11040T>G","abstract_start":832,"abstract_end":842},{"Name":"NM_000384.3(APOB):c.3600T>A (p.Tyr1200Ter)","Chromosome":"2","Start":"21015169","Stop":"21015169","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":32940,"rule_based_match":true,"evidence_text":"c.3600T>A","llm_judgment":"PRESENT","evidence":"c.3600T>A","abstract_start":890,"abstract_end":899}]}
{"pmid":"26834045","title":"Identification of a syndrome comprising microcephaly and intellectual disability but not white matter disease associated with a homozygous c.676C>T p.R226W DEAF1 mutation.","abstract":"We evaluated a 13-year-old East Pakistani male affected with microcephaly, apparent intellectual disability, hypotonia, and brisk reflexes without spasticity. His parents were first cousins. The patient also had a brother who was similarly affected and died at 10 years due to an accident. Previous SNP array testing showed a 1.63 Mb duplication at 16p13.11 of uncertain significance along with regions of homozygosity. Exome sequencing identified a known pathogenic homozygous alteration in DEAF1, c.676C>T (p.R226W), in this patient. The alteration had been reported in two individuals from a consanguineous Saudi Arabian family. Both individuals had microcephaly, intellectual disability, hypotonia, feeding difficulties, and poor growth. The patient reported here did not have evidence of white matter disease, as had been reported with prior patients. We conclude that this DEAF1 gene alteration caused this patient's symptoms and that white matter disease should not be considered a obligate feature of this syndrome.","variants":[{"Name":"NM_021008.4(DEAF1):c.676C>T (p.Arg226Trp)","Chromosome":"11","Start":"686986","Stop":"686986","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":153719,"rule_based_match":true,"evidence_text":"c.676C>T (p.R226W)","llm_judgment":"PRESENT","evidence":"c.676C>T (p.R226W)","abstract_start":499,"abstract_end":517}]}
{"pmid":"29207168","title":"Targeted next‑generation sequencing reveals two novel mutations of NBAS in a patient with infantile liver failure syndrome‑2.","abstract":"Mutations in neuroblastoma amplified sequence (NBAS) cause infantile liver failure syndrome-2 (ILFS2). NBAS is a protein involved in Golgi‑to‑endoplasmic reticulum retrograde transport. Exon capture in combination with high‑throughput sequencing was used to detect NBAS mutations. Via targeted sequencing, two causative mutations were identified from 358 selected genes associated with growth and development diseases; one was a missense mutation, c.3596G>A (p.C1199Y), detected in the coding region of NBAS (NM_015909.3), and the other a splice site mutation, c.209+1G>A. Both of these were heterozygous. The SEC39 structure of the wild‑type NBAS protein was compared with a model of the mutated protein. The overall structure of the SEC39 after mutation did not change; however, steric hindrance did increase. In conclusion, two novel NBAS mutations were identified in a 4‑year‑old Chinese girl with ILFS2.","variants":[{"Name":"NM_015909.4(NBAS):c.209+1G>A","Chromosome":"2","Start":"15556782","Stop":"15556782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1892003,"rule_based_match":true,"evidence_text":"c.209+1G>A","llm_judgment":"PRESENT","evidence":"c.209+1G>A","abstract_start":561,"abstract_end":571}]}
{"pmid":"18579543","title":"Novel mutations in the folliculin gene associated with spontaneous pneumothorax.","abstract":"Spontaneous pneumothorax is mostly sporadic but may also occur in families with genetic disorders, such as Birt-Hogg-Dubé syndrome, which is caused by mutations in the folliculin (FLCN) gene. The aim of the present study was to investigate the presence and type of mutation in a Swiss pedigree and in a sporadic case. Clinical examination, lung function tests and high-resolution computed tomography were performed. All coding exons and flanking intronic regions of FLCN were amplified by PCR and directly sequenced. The amount of FLCN transcripts was determined by quantitative real-time RT-PCR. Two novel mutations in FLCN were identified. Three investigated family members with a history of at least one spontaneous pneumothorax were heterozygous for a single nucleotide substitution (c.779G>A) that leads to a premature stop codon (p.W260X). Quantitative real-time RT-PCR revealed a reduction of FLCN transcripts from the patient compared with an unaffected family member. DNA from the sporadic case carried a heterozygous missense mutation (c.394G>A). Lung function of this patient was normal and computed tomography showed similar bilateral cysts, as observed in the two members of the unrelated Swiss family. Mutations in the folliculin gene are associated with cystic lung lesions in an otherwise morphological normal lung and predispose to spontaneous pneumothorax.","variants":[{"Name":"NM_144997.7(FLCN):c.779G>A (p.Trp260Ter)","Chromosome":"17","Start":"17222501","Stop":"17222501","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171188,"rule_based_match":true,"evidence_text":"c.779G>A","llm_judgment":"PRESENT","evidence":"c.779G>A","abstract_start":788,"abstract_end":796}]}
{"pmid":"28133914","title":"Molecular basis of pyruvate kinase deficiency among Tunisians: description of new mutations affecting coding and noncoding regions in the PKLR gene.","abstract":"INTRODUCTION: Pyruvate kinase (PK) deficiency is one of the most common hereditary nonspherocytic hemolytic anemias worldwide with clinical manifestations ranging from mild to severe hemolysis. However, investigation of this enzymopathy is lacking in Tunisia. We report here a pioneer investigation of PK deficiency among Tunisian cases referred to our laboratory for biological analysis of unknown cause of hemolytic anemia.\nMETHODS: Two hundred and fifty-three patients with unknown cause of hemolytic anemia have been addressed to our laboratory in order to investigate for red blood cells genetic disorders. Red cell enzyme activities were measured by standard methods, and molecular analysis was performed by DNA sequencing. The interpretation of mutation effect and the molecular modeling were performed by using specific software.\nRESULTS: Six different PKLR mutations were found (c.966-1G>T; c.965+1G>A; c.721G>T; c.1163C>A; c.1456C>T; c.1537T>A), among which four are described for the first time. Genotype-phenotype correlations for the novel missense mutations were investigated by three-dimensional structure analysis.\nCONCLUSION: This study provides important data of PK deficiency among Tunisians. It might be followed by a large neonatal screening to determine the spectrum of PK mutations and identify potential deficient patients for an early medical follow-up.","variants":[{"Name":"NM_000298.6(PKLR):c.1456C>T (p.Arg486Trp)","Chromosome":"1","Start":"155291918","Stop":"155291918","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16552,"rule_based_match":true,"evidence_text":"c.1456C>T","llm_judgment":"PRESENT","evidence":"c.1456C>T","abstract_start":933,"abstract_end":942},{"Name":"NM_000298.6(PKLR):c.721G>T (p.Glu241Ter)","Chromosome":"1","Start":"155294726","Stop":"155294726","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":263974,"rule_based_match":true,"evidence_text":"c.721G>T","llm_judgment":"PRESENT","evidence":"c.721G>T","abstract_start":912,"abstract_end":920}]}
{"pmid":"37895203","title":"Potential Founder Variants in COL4A4 Identified in Bukharian Jews Linked to Autosomal Dominant and Autosomal Recessive Alport Syndrome.","abstract":"BACKGROUND: Alport syndrome is a hereditary disorder caused by pathogenic variants in the COL4A gene, which can be inherited in an autosomal recessive, dominant, or X-linked pattern. In the Bukharian Jewish population, no founder pathogenic variant has been reported in COL4A4.\nMETHODS: The cohort included 38 patients from 22 Bukharian Jewish families with suspected Alport syndrome who were referred the nephrogenetics clinic between 2012 and 2022. The study collected demographic, clinical, and genetic data from electronic medical records, which were used to evaluate the molecular basis of the disease using Sanger sequencing, and next-generation sequencing.\nRESULTS: Molecular diagnosis was confirmed in 20/38 patients, with each patient having at least one of the three disease-causing COL4A4 variants detected: c.338G<A (p.Gly113Asp), c.3022G>A (p.Gly1008Arg), and c.871-6T>C. In addition, two patients were obligate carriers. Overall, there were 17 heterozygotes, 2 compound heterozygotes, and 3 homozygotes. Each variant was detected in more than one unrelated family. All patients had hematuria with/without proteinuria at referral, and the youngest patient with proteinuria (age 5 years) was homozygous for the c.338G>A variant. End-stage renal disease was diagnosed in two patients at the age of 38 years, a compound heterozygote for c.338G>A and c.871-6T>C. Hearing deterioration was detected in three patients, the youngest aged 40 years, all of whom were heterozygous for c.338G>A.\nCONCLUSION: This study unveils three novel disease-causing variants, c.3022G>A, c.871-6T>C, and c.338G>A, in the COL4A4 gene that are recurrent among Jews of Bukharian ancestry, and cause Alport syndrome in both dominant and recessive autosomal inheritance patterns.","variants":[{"Name":"NM_000092.5(COL4A4):c.3022G>A (p.Gly1008Arg)","Chromosome":"2","Start":"227051105","Stop":"227051105","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":542036,"rule_based_match":true,"evidence_text":"c.3022G>A (p.Gly1008Arg)","llm_judgment":"PRESENT","evidence":"c.3022G>A (p.Gly1008Arg)","abstract_start":843,"abstract_end":867},{"Name":"NM_000092.5(COL4A4):c.871-6T>C","Chromosome":"2","Start":"227102854","Stop":"227102854","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":988405,"rule_based_match":true,"evidence_text":"c.871-6T>C","llm_judgment":"PRESENT","evidence":"c.871-6T>C","abstract_start":873,"abstract_end":883}]}
{"pmid":"22488877","title":"Adult presentation of arterial tortuosity syndrome in a 51-year-old woman with a novel homozygous c.1411+1G>A mutation in the SLC2A10 gene.","abstract":"Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and elongation of the large- and medium-sized arteries with predisposition to stenoses and aneurysms. ATS is caused by mutations in the SLC2A10 gene, encoding for the facilitative glucose transporter 10 (GLUT10) and is described typically in pediatric patients. We report on a 51-year-old woman, originally ascertained because of unexplained widespread chronic pain and positive family history of aortic malformation. The main findings included aged appearance, congenital joint hypermobility, joint instability complications, chronic fatigue syndrome, progressive painful joint stiffness, abdominal hernias, pelvic prolapses, multiple cardiac valve prolapses, varicose veins, easy bruising, and gingival recession. Vascular imaging revealed kinking and anomalous origin of the aortic arch branches, marked tortuosity of the aorta, pulmonary and most middle arteries, and a small aneurysm of the splenic artery. SLC2A10 analysis disclosed homozygosity for the novel c.1411+1G>A splice mutation, leading to a 41 amino acids GLUT10 internal deletion. Expression study by immunofluorescence using healthy control cells showed lack of membrane internalization of GLUT10 in patient's skin fibroblasts. This report describes the first splice-site SLC2A10 mutation and increases to 19 the repertoire of known mutations in this gene. Comparison with the few previously published adult patients with ATS contributes to the natural history of this condition, which is probably under diagnosed within the expanding family of inherited connective tissue disorders.","variants":[{"Name":"NM_030777.4(SLC2A10):c.1411+1G>A","Chromosome":"20","Start":"46726987","Stop":"46726987","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":170951,"rule_based_match":true,"evidence_text":"c.1411+1G>A","llm_judgment":"PRESENT","evidence":"c.1411+1G>A","abstract_start":1090,"abstract_end":1101}]}
{"pmid":"33736665","title":"EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum.","abstract":"BACKGROUND: An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients.\nRESULTS: 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation.\nCONCLUSIONS: Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.","variants":[{"Name":"NM_003754.3(EIF3F):c.694T>G (p.Phe232Val)","Chromosome":"11","Start":"7994466","Stop":"7994466","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":608837,"rule_based_match":true,"evidence_text":"c.694T>G/p.(Phe232Val)","llm_judgment":"PRESENT","evidence":"c.694T>G/p.(Phe232Val)","abstract_start":523,"abstract_end":545}]}
{"pmid":"27612597","title":"Phosphoglycerate mutase deficiency (glycogen storage disease X) caused by a novel variant in PGAM-M.","abstract":"Phosphoglycerate mutase enzyme deficiency in muscle causes a metabolic myopathy (glycogen storage disease X) characterized by exertional muscle contractures, weakness, hyperCKemia, and myoglobinuria. Six different autosomal recessive variants in PGAM-M have been described thus far (Salameh et al., 2013). In this case report, we report a novel disease-causing variant. A 52-year-old African-American woman presented with exertional muscle contractures, myalgias, and weakness since childhood including an episode of rhabdomyolysis. Neurologic examination and EMG were normal. CK was mildly elevated at rest and over 20,000 U/L during her episode of rhabdomyolysis. Muscle biopsy revealed subsarcolemmal collections suggestive of tubular aggregates. Phosphoglycerate mutase activity was 8% of the reference value. PGAM-M sequencing showed compound heterozygous variants: c.233G>A, which has been found only in African-Americans with this disease, and a novel variant, c.278G>A. This case expands the genetic spectrum of phosphoglycerate mutase deficiency.","variants":[{"Name":"NM_000290.4(PGAM2):c.233G>A (p.Trp78Ter)","Chromosome":"7","Start":"44065297","Stop":"44065297","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15457,"rule_based_match":true,"evidence_text":"c.233G>A","llm_judgment":"PRESENT","evidence":"c.233G>A","abstract_start":871,"abstract_end":879}]}
{"pmid":"16738945","title":"X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology.","abstract":"Mutations in the creatine transporter gene, SLC6A8 (MIM 30036), located in Xq28, have been found in families with X-linked mental retardation (XLMR) as well as in males with idiopathic mental retardation (MR). In order to estimate the frequency of such mutations in the MR population, a screening of 478 males with MR of unknown cause was undertaken. All 13 exons of SLC6A8 were sequenced using genomic DNA. Six novel potentially pathogenic mutations were identified that were not encountered in at least 588 male control chromosomes: two deletions (p.Asn336del, p.Ile347del) and a splice site alteration (c.1016+2C>T) are considered pathogenic based on the nature of the variant. A mutation (p.Arg391Trp) should be considered pathogenic owing to its localization in a highly conserved region. Two other missense variants (p.Lys4Arg, p.Gly26Arg) are not conserved but were not observed in over 300 male control chromosomes. Their pathogenicity is uncertain. A missense variant (p.Val182Met), was classified as a polymorphism based on a normal creatine/creatinine (Cr:Crn) ratio and cerebral creatine signal in proton magnetic resonance spectroscopy (H-MRS) in the patient. Furthermore, we found 14 novel intronic and neutral variants that were not encountered in at least 280 male control chromosomes and should be considered as unclassified variants. Our findings of a minimum of four pathogenic mutations and two potentially pathogenic mutations indicate that about 1% of males with MR of unknown etiology might have a SLC6A8 mutation. Thus, DNA sequence analysis and/or a Cr:Crn urine screen is warranted in any male with MR of unknown cause.","variants":[{"Name":"NM_005629.4(SLC6A8):c.1171C>T (p.Arg391Trp)","Chromosome":"X","Start":"153693934","Stop":"153693934","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":472081,"rule_based_match":false,"evidence_text":"p.Arg391Trp","llm_judgment":"PRESENT","evidence":"p.Arg391Trp","abstract_start":693,"abstract_end":704},{"Name":"NM_005629.4(SLC6A8):c.1000AAC[2] (p.Asn336del)","Chromosome":"X","Start":"153693349","Stop":"153693351","ReferenceAlleleVCF":"TCAA","AlternateAlleleVCF":"T","allel_id":260285,"rule_based_match":false,"evidence_text":"p.Asn336del","llm_judgment":"PRESENT","evidence":"p.Asn336del","abstract_start":550,"abstract_end":561}]}
{"pmid":"30895400","title":"Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil.","abstract":"INTRODUCTION: The contribution of CDH1 germline variants to gastric cancer burden among young adults is unknown in Brazil. We aimed to evaluate the frequency of CDH1 germline variants and the diet/lifestyle habits in early age onset gastric cancer (EOGC, ≤ 55 years old) patients.\nMETHODOLOGY: From 2013 to 2015, a total of 88 unrelated and consecutive patients diagnosed with EOGC were enrolled. All CDH1 exons and intronic boundaries were sequenced, and large genomic rearrangements were screened by MLPA. CDH1 transcription analysis was performed for variants that could potentially induce an effect on splicing. The diet and lifestyle habits of EOGC patients were compared to Brazilian population diet and lifestyle, obtained from governmental databases.\nRESULTS: Of 88 patients, the mean age at EOGC diagnosis was 39 years and 55% fulfilled the criteria for hereditary diffuse gastric cancer. The majority of the tumors were diffuse (74%) and poorly differentiated (80%). In total, 4 novel missense variants of uncertain significance (VUS) were identified: c.313T>A, c.387G>T, c.1676G>A, and c.1806C>A. The MLPA results revealed no rearrangements and CDH1 transcription analysis for variants of interest were inconclusive. EOGC patients had a higher red (OR:2.6, 95%CI:1.4-4.9) and processed (OR:3.1, 95%CI:1.6-6.0) meat intake and higher fruit consumption (OR:0.4, 95%IC:0.3-0.7) compared to eating habits of the Brazilian population.\nCONCLUSIONS: No unequivocal pathogenic germline CDH1 variants were identified in Brazilian EOGC patients. Dietary habits may be associated with the EOGC development.","variants":[{"Name":"NM_004360.5(CDH1):c.1676G>A (p.Ser559Asn)","Chromosome":"16","Start":"68819390","Stop":"68819390","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":812952,"rule_based_match":true,"evidence_text":"c.1676G>A","llm_judgment":"PRESENT","evidence":"c.1676G>A","abstract_start":1082,"abstract_end":1091},{"Name":"NM_004360.5(CDH1):c.387G>T (p.Gln129His)","Chromosome":"16","Start":"68801893","Stop":"68801893","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":812882,"rule_based_match":true,"evidence_text":"c.387G>T","llm_judgment":"PRESENT","evidence":"c.387G>T","abstract_start":1072,"abstract_end":1080},{"Name":"NM_004360.5(CDH1):c.313T>A (p.Ser105Thr)","Chromosome":"16","Start":"68801819","Stop":"68801819","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":530126,"rule_based_match":true,"evidence_text":"c.313T>A","llm_judgment":"PRESENT","evidence":"c.313T>A","abstract_start":1062,"abstract_end":1070}]}
{"pmid":"22901038","title":"Case of dominant dystrophic epidermolysis bullosa pruriginosa with a c.7868G>A (G2623D) mutation in type VII collagen.","abstract":"","variants":[{"Name":"NM_000094.4(COL7A1):c.7868G>A (p.Gly2623Asp)","Chromosome":"3","Start":"48568097","Stop":"48568097","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1925574,"rule_based_match":true,"evidence_text":"c.7868G>A (G2623D)","llm_judgment":"PRESENT","evidence":"c.7868G>A (G2623D)","abstract_start":null,"abstract_end":null}]}
{"pmid":"35994252","title":"Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy.","abstract":"Purpose: The purpose of this study was to elucidate the genetic basis of 2 distinct phenotypes associated with biallelic variants in RDH12.\nMethods: Patients with biallelic variants in RDH12 were recruited from our genetic eye clinic. Ocular phenotypes were evaluated. Genotype-phenotype correlations were further clarified using in-house and existing databases.\nResults: In total, 22 biallelic RDH12 variants, including 5 novel variants, were identified in 29 patients from 27 families. Two distinct phenotypes were observed: early-onset and generalized retinal dystrophy with severe impairment of rods and cones in 24 patients (82.8%, 24/29), and late-onset cone-rod dystrophy (CORD) with central macular atrophy in 5 patients from 5 unrelated families (17.2%, 5/29), in which a hypomorphic allele (c.806C>G/p.Ala269Gly) was shared by all 5 patients. During follow-up, patients with late-onset CORD were relatively stable and did not progress to the severe form, which was considered to be an independent manifestation of RDH12-associated retinopathy caused by specific genotypes.\nConclusions: The hypomorphic allele is responsible for the unique late-onset CORD in 5 families with recessive RDH12-associated retinopathy, in contrast to the well-known severe and generalized retinopathy. Determining the therapeutic value of interventions may depend on understanding the molecular mechanisms underlying manifestation of this hypomorphic variant only in the central macular region, with relative preservation of the peripheral retina.","variants":[{"Name":"NM_152443.3(RDH12):c.806C>G (p.Ala269Gly)","Chromosome":"14","Start":"67729338","Stop":"67729338","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":702961,"rule_based_match":true,"evidence_text":"c.806C>G/p.Ala269Gly","llm_judgment":"PRESENT","evidence":"c.806C>G/p.Ala269Gly","abstract_start":801,"abstract_end":821}]}
{"pmid":"26197441","title":"A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment.","abstract":"Nonsyndromic hearing impairment (NSHI) is a highly heterogeneous condition with more than eighty known causative genes. However, in the clinical setting, a large number of NSHI families have unexplained etiology, suggesting that there are many more genes to be identified. In this study we used SNP-based linkage analysis and follow up microsatellite markers to identify a novel locus (DFNA66) on chromosome 6q15-21 (LOD 5.1) in a large Danish family with dominantly inherited NSHI. By locus specific capture and next-generation sequencing, we identified a c.574C>T heterozygous nonsense mutation (p.R192*) in CD164. This gene encodes a 197 amino acid transmembrane sialomucin (known as endolyn, MUC-24 or CD164), which is widely expressed and involved in cell adhesion and migration. The mutation segregated with the phenotype and was absent in 1200 Danish control individuals and in databases with whole-genome and exome sequence data. The predicted effect of the mutation was a truncation of the last six C-terminal residues of the cytoplasmic tail of CD164, including a highly conserved canonical sorting motif (YXXФ). In whole blood from an affected individual, we found by RT-PCR both the wild-type and the mutated transcript suggesting that the mutant transcript escapes nonsense mediated decay. Functional studies in HEK cells demonstrated that the truncated protein was almost completely retained on the plasma cell membrane in contrast to the wild-type protein, which targeted primarily to the endo-lysosomal compartments, implicating failed endocytosis as a possible disease mechanism. In the mouse ear, we found CD164 expressed in the inner and outer hair cells of the organ of Corti, as well as in other locations in the cochlear duct. In conclusion, we have identified a new DFNA locus located on chromosome 6q15-21 and implicated CD164 as a novel gene for hearing impairment.","variants":[{"Name":"NM_006016.6(CD164):c.574C>T (p.Arg192Ter)","Chromosome":"6","Start":"109368871","Stop":"109368871","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":236864,"rule_based_match":true,"evidence_text":"c.574C>T","llm_judgment":"PRESENT","evidence":"c.574C>T","abstract_start":557,"abstract_end":565}]}
{"pmid":"25319849","title":"Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly.","abstract":"Homozygous frameshift BRAT1 mutations were found in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498). Here, we report on two siblings with compound heterozygous mutations in BRAT1. They had intractable seizures from neonatal period, dysmorphic features and hypertonia. Progressive microcephaly was also observed. Initial electroencephalogram showed a suppression-burst pattern, leading to a diagnosis of Ohtahara syndrome. They both died from pneumonia at 1 year and 3 months, respectively. Whole-exome sequencing of one patient revealed a compound heterozygous BRAT1 mutations (c.176T>C (p.Leu59Pro) and c.962_963del (p.Leu321Profs*81)). We are unable to obtain DNA from another patient. The p.Leu59Pro mutation occurred at an evolutionarily conserved amino acid in a CIDE-N (N-terminal of an cell death-inducing DFF45-like effector) domain, which has a regulatory role in the DNA fragmentation pathway of apoptosis. Our results further support that mutations of BRAT1 could lead to epileptic encephalopathy.","variants":[{"Name":"NM_152743.4(BRAT1):c.176T>C (p.Leu59Pro)","Chromosome":"7","Start":"2547430","Stop":"2547430","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":178318,"rule_based_match":true,"evidence_text":"c.176T>C (p.Leu59Pro)","llm_judgment":"PRESENT","evidence":"c.176T>C (p.Leu59Pro)","abstract_start":615,"abstract_end":636},{"Name":"NM_152743.4(BRAT1):c.962_963del (p.Leu321fs)","Chromosome":"7","Start":"2542172","Stop":"2542173","ReferenceAlleleVCF":"GGA","AlternateAlleleVCF":"G","allel_id":178319,"rule_based_match":true,"evidence_text":"c.962_963del (p.Leu321Profs*81)","llm_judgment":"PRESENT","evidence":"c.962_963del (p.Leu321Profs*81)","abstract_start":641,"abstract_end":672}]}
{"pmid":"28695016","title":"Identification of","abstract":"Hereditary hearing loss is characterized by a high degree of genetic heterogeneity. Mutations in the <i>TMPRSS3</i> (transmembrane protease, serine 3) gene cause prelingual (DFNB10) or postlingual (DFNB8) deafness. In our previous study, three pathogenic mutations in <i>TMPRSS3</i> were identified in one Chinese family. To evaluate the importance of <i>TMPRSS3</i> mutations in recessive deafness among the Chinese, we screened 150 autosomal recessive nonsyndromic hearing loss (ARNSHL) families and identified 6 that carried seven causative <i>TMPRSS3</i> mutations, including five novel mutations (c.809T>A, c.1151T>G, c.1204G>A, c.1244T>C, and c.1250G>A) and two previously reported mutations (c.323-6G>A and c.916G>A). Each of the five novel mutations was classified as severe, by both age of onset and severity of hearing loss. Together with our previous study, six families were found to share one pathogenic mutation (c.916G>A, p.Ala306Thr). To determine whether this mutation arose from a common ancestor, we analyzed six short tandem repeat (STR) markers spanning the <i>TMPRSS3</i> gene. In four families, we observed linkage disequilibrium between p.Ala306Thr and STR markers. Our results indicate that mutations in <i>TMPRSS3</i> account for about 4.6% (7/151) of Chinese ARNSHL cases lacking mutations in <i>SLC26A4</i> or <i>GJB2</i> and that the recurrent <i>TMPRSS3</i> mutation p.Ala306Thr is likely to be a founder mutation.","variants":[{"Name":"NM_001256317.3(TMPRSS3):c.916G>A (p.Ala306Thr)","Chromosome":"21","Start":"42382101","Stop":"42382101","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":55296,"rule_based_match":true,"evidence_text":"c.916G>A (p.Ala306Thr)","llm_judgment":"PRESENT","evidence":"p.Ala306Thr","abstract_start":937,"abstract_end":948}]}
{"pmid":"28642161","title":"Digenic inheritance of mutations in the cardiac troponin (TNNT2) and cardiac beta myosin heavy chain (MYH7) as the cause of severe dilated cardiomyopathy.","abstract":"Familial dilated cardiomyopathy (DCM) is characterized by ventricular dilation and depressed myocardial performance. It is a genetically heterogeneous disorder associated with mutations in over 60 genes. We carried out whole exome sequencing in combination with cardiomyopathy-related gene-filtering on two affected family members to identify the possible causative mutation in a consanguineous Iranian family with DCM. Two novel variants in cardiomyopathy-related genes were identified: c.247 A > C; p.N83H in the Troponin T Type 2 gene (TNNT2) and c.2863G > A; p.D955N in the Myosin Heavy Polypeptide 7 gene (MYH7). Sanger sequencing and co-segregation analysis in the remaining family members supported the coexistence of these digenic mutations in affected members of the family. Carriers of either variant alone were asymptomatic. In summary, we find that digenic inheritance of two novel variants in DCM related genes is associated with a severe form of DCM. Exome sequencing has been shown to be very useful in identifying pathogenic mutations in cardiomyopathy families, and this report emphasizes the importance of comprehensive screening of DCM related genes, even after the identification of a single disease-causing mutation.","variants":[{"Name":"NM_000257.4(MYH7):c.2863G>A (p.Asp955Asn)","Chromosome":"14","Start":"23423966","Stop":"23423966","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":258804,"rule_based_match":true,"evidence_text":"c.2863G > A; p.D955N","llm_judgment":"PRESENT","evidence":"c.2863G > A; p.D955N","abstract_start":550,"abstract_end":570}]}
{"pmid":"23161826","title":"Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency.","abstract":"De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP-activating protein, cause nonsyndromic intellectual disability (NSID). All disease-causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R], c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5], c.2212_2213del [p.S738X], and (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild-type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity-dependent phosphorylated extracellular signal-regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.","variants":[{"Name":"NM_006772.3(SYNGAP1):c.1084T>C (p.Trp362Arg)","Chromosome":"6","Start":"33437989","Stop":"33437989","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":49897,"rule_based_match":true,"evidence_text":"c.1084T>C [p.W362R]","llm_judgment":"PRESENT","evidence":"c.1084T>C [p.W362R]","abstract_start":377,"abstract_end":396},{"Name":"NM_006772.3(SYNGAP1):c.1685C>T (p.Pro562Leu)","Chromosome":"6","Start":"33440737","Stop":"33440737","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49898,"rule_based_match":true,"evidence_text":"c.1685C>T [p.P562L]","llm_judgment":"PRESENT","evidence":"c.1685C>T [p.P562L]","abstract_start":398,"abstract_end":417}]}
{"pmid":"26800689","title":"c.3623G > A mutation encodes a CFTR protein with impaired channel function.","abstract":"BACKGROUND: The aims of this study were to characterize clinical features of a pediatric African-American cystic fibrosis (CF) patient heterozygous for F508del and a novel c.3623G > A mutation, and to identify the molecular defect(s) associated with c.3623G > A mutation.\nMETHODS: The medical record of this patient was analyzed retrospectively. Western blotting and iodide efflux assay were used to study mutant CFTR protein expression level, maturation status, channel function, and the effects of CFTR modulation on these characteristics.\nRESULTS: The encoding protein of c.3623G > A mutation, G1208D-CFTR, has a moderate processing defect and exhibits impaired channel function, which were partially rescued by using VX-809 or exposed to low temperature (28 °C). The patient has mild CF disease manifestations.\nCONCLUSIONS: Our biochemical findings correlate with the clinical phenotype and suggest that c.3623G > A is a CF-causing mutation. The study helps expand our knowledge of rare CFTR mutations in a minority population and may have important clinical implications for personalized therapeutic intervention.","variants":[{"Name":"NM_000492.4(CFTR):c.3623G>A (p.Gly1208Asp)","Chromosome":"7","Start":"117627676","Stop":"117627676","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544215,"rule_based_match":true,"evidence_text":"c.3623G > A","llm_judgment":"PRESENT","evidence":"c.3623G > A","abstract_start":172,"abstract_end":183}]}
{"pmid":"35066879","title":"Functional loss of ubiquitin-specific protease 14 may lead to a novel distal arthrogryposis phenotype.","abstract":"Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features.","variants":[{"Name":"NM_005151.4(USP14):c.233_236del (p.Leu78fs)","Chromosome":"18","Start":"178969","Stop":"178972","ReferenceAlleleVCF":"TCTTC","AlternateAlleleVCF":"T","allel_id":1052983,"rule_based_match":true,"evidence_text":"c.233_236delTTCC; p.Leu78Glnfs*11","llm_judgment":"PRESENT","evidence":"c.233_236delTTCC; p.Leu78Glnfs*11","abstract_start":1146,"abstract_end":1179}]}
{"pmid":"28541266","title":"RETINOCHOROIDAL ANASTOMOSIS ASSOCIATED WITH ENHANCED S-CONE SYNDROME.","abstract":"PURPOSE: To describe the phenotype and genotype of a 10-year-old boy affected with enhanced S-cone syndrome associated with neovascularization.\nMETHODS: Fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, full-field electroretinogram and NR2E3 molecular testing were performed.\nRESULTS: Best-corrected visual acuity was measured as 20/32, right eye and 20/20, left eye. Fluorescein and indocyanine green angiographies showed unilateral macular retinochoroidal anastomosis on his right eye, and spectral domain optical coherence tomography showed typical signs of subretinal exudation and foveolar pseudoschisis consistent with the diagnosis of enhanced S-cone syndrome. Genetic analysis revealed biparental transmission of mutations in the enhanced S-cone syndrome-causing gene, NR2E3, namely, c.194_202del (p.Asn65_Cys67del), and c.932 G>A (p.Arg311Gln), supporting an autosomal recessive inheritance. The patient received three intravitreal injections of anti-VEGF agents.\nCONCLUSION: Evidence of retinochoroidal anastomosis in an individual affected with enhanced S-cone syndrome supports the view that neovascularization can occur early in the course of the disease, and raises the question to know whether it might be responsible for previously described enhanced S-cone syndrome-associated hemorrhage-induced fibrosis.","variants":[{"Name":"NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln)","Chromosome":"15","Start":"71813573","Stop":"71813573","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20571,"rule_based_match":true,"evidence_text":"c.932 G>A (p.Arg311Gln)","llm_judgment":"PRESENT","evidence":"c.932 G>A (p.Arg311Gln)","abstract_start":906,"abstract_end":929},{"Name":"NM_014249.4(NR2E3):c.194_202del (p.Asn65_Cys67del)","Chromosome":"15","Start":"71811553","Stop":"71811561","ReferenceAlleleVCF":"CCTGCAACGG","AlternateAlleleVCF":"C","allel_id":547531,"rule_based_match":true,"evidence_text":"c.194_202del (p.Asn65_Cys67del)","llm_judgment":"PRESENT","evidence":"c.194_202del (p.Asn65_Cys67del)","abstract_start":869,"abstract_end":900}]}
{"pmid":"28176280","title":"Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia.","abstract":"PURPOSE: Patients with familial hyperparathyroidism and low urinary calcium excretion may have familial hypocalciuric hypercalcemia (FHH) with mutations in one of three genes: the calcium-sensing receptor (CaSR) defining FHH-type 1, the adaptor-related protein complex 2 (AP2S1) related to FHH-type 3 or the G-protein subunit alpha11 (GNA11) associated with FHH-type 2. We aimed to evaluate the presence of mutations in these genes and to identify phenotypic specificities and differences in these patients.\nSUBJECTS AND METHODS: Selected patients were recruited for genetic evaluation. After informed consent was signed, blood for DNA extraction was obtained and genetic sequencing of CaSR was done. In negative cases, we further performed sequencing of AP2S1 and GNA11.\nRESULTS: A total of 10 index cases were recruited. CaSR sequencing yielded three missense heterozygous mutations (30%): c.554G > A (p.I32V) previously characterized by our team, c.1394 G > A (p.R465Q) and a novel expected disease-causing mutation c.2479 A > C (p.S827R). We identified 2 additional patients (20%) carrying the deleterious recurrent mutation c.44G > T (p.R15L) in the AP2S1 gene. No GNA11 mutation was found. Clinically, patients with AP2S1 mutations had significant cognitive and behavioral disorders, and higher blood calcium and magnesium levels than patients with FHH1.\nCONCLUSION: CaSR and AP2S1 sequencing is worthwhile in patients with familial hyperparathyroidism and phenotype suggesting FHH as it can diagnose up to 50% of cases. GNA11 mutations seem much rarer. Learning disabilities in these patients, associated with higher serum calcium and magnesium levels may suggest the presence of AP2S1 rather than CaSR mutation and may guide the first step in the genetic evaluation.","variants":[{"Name":"NM_000388.4(CASR):c.1394G>A (p.Arg465Gln)","Chromosome":"3","Start":"122275828","Stop":"122275828","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23391,"rule_based_match":true,"evidence_text":"c.1394 G > A (p.R465Q)","llm_judgment":"PRESENT","evidence":"c.1394 G > A (p.R465Q)","abstract_start":950,"abstract_end":972}]}
{"pmid":"25740612","title":"New splicing mutation in the choline kinase beta (CHKB) gene causing a muscular dystrophy detected by whole-exome sequencing.","abstract":"Muscular dystrophies (MDs) are a group of hereditary muscle disorders that include two particularly heterogeneous subgroups: limb-girdle MD and congenital MD, linked to 52 different genes (seven common to both subgroups). Massive parallel sequencing technology may avoid the usual stepwise gene-by-gene analysis. We report the whole-exome sequencing (WES) analysis of a patient with childhood-onset progressive MD, also presenting mental retardation and dilated cardiomyopathy. Conventional sequencing had excluded eight candidate genes. WES of the trio (patient and parents) was performed using the ion proton sequencing system. Data analysis resorted to filtering steps using the GEMINI software revealed a novel silent variant in the choline kinase beta (CHKB) gene. Inspection of sequence alignments ultimately identified the causal variant (CHKB:c.1031+3G>C). This splice site mutation was confirmed using Sanger sequencing and its effect was further evaluated with gene expression analysis. On reassessment of the muscle biopsy, typical abnormal mitochondrial oxidative changes were observed. Mutations in CHKB have been shown to cause phosphatidylcholine deficiency in myofibers, causing a rare form of CMD (only 21 patients reported). Notwithstanding interpretative difficulties that need to be overcome before the integration of WES in the diagnostic workflow, this work corroborates its utility in solving cases from highly heterogeneous groups of diseases, in which conventional diagnostic approaches fail to provide a definitive diagnosis.","variants":[{"Name":"NM_005198.5(CHKB):c.1031+3G>C","Chromosome":"22","Start":"50579724","Stop":"50579724","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":552235,"rule_based_match":true,"evidence_text":"CHKB:c.1031+3G>C","llm_judgment":"PRESENT","evidence":"CHKB:c.1031+3G>C","abstract_start":846,"abstract_end":862}]}
{"pmid":"21455010","title":"Congenital ichthyosis in severe type II Gaucher disease with a homozygous null mutation.","abstract":"This paper describes a neonate with type II Gaucher disease. The phenotype was unusually severe with congenital ichthyosis, hepatosplenomegaly, muscular hypotonia, myoclonus and respiratory failure. Electron microscopy of the skin revealed lamellar body contents in the stratum corneum interstices, appearances considered to be typical of type II Gaucher disease. The baby died from respiratory failure 1 month postpartum having made no neurological progress. Molecular analysis identified a previously not reported homozygous null mutation, c.1505G→A of the β-glucocerebrosidase gene.","variants":[{"Name":"NM_000157.4(GBA1):c.1505G>A (p.Arg502His)","Chromosome":"1","Start":"155235195","Stop":"155235195","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33922,"rule_based_match":false,"evidence_text":"c.1505G→A","llm_judgment":"PRESENT","evidence":"c.1505G→A","abstract_start":542,"abstract_end":551}]}
{"pmid":"36131268","title":"Prenatal diagnosis identifies compound heterozygous variants in RYR1 that causes ultrasound abnormalities in a fetus.","abstract":"OBJECTIVE: We presented a non-consanguineous healthy Chinese couple with five pregnancies, three early miscarriages, the fetus II-2 and II-5 with similar abnormal phenotypes of fetal hydrops, scoliosis, fetal akinesia and polyhydramnios. This study aimed to uncover the molecular etiology of this family with a history of multiple adverse pregnancies.\nMATERIALS AND METHODS: DNA extracted from the fifth fetal umbilical cord and parents' peripheral blood were subjected to SNP-array and whole exome sequencing. The result was verified by Sanger sequencing. Functional characterization of the c.2682G > C (p.Ile860_Pro894del) variant was completed by minigene splicing assay.\nRESULTS: Trio whole-exome sequencing has identified compound heterozygous variants in RYR1 (c.2682G > C; p.Ile860_Pro894del and c.12572G > A; p.Arg4191His) in fetus II-5. The variant c.2682G > C (p.Ile860_Pro894del) comes from the father and the c.12572G > A (p.Arg4191His) comes from the mother. The c.2682G > C (p.Ile860_Pro894del) affects the splice site resulting in exon 21 skipping, therefore is classified as likely pathogenic. The c.12572G > A (p.Arg4191His) locates in the C-terminal hot spots region of the RYR1, classified as of uncertain significance.\nCONCLUSIONS: We report the first prenatal case of RYR1-related disorders in Chinese population, expanding the variant spectrum of RYR1 in fetuses.","variants":[{"Name":"NM_000540.3(RYR1):c.12572G>A (p.Arg4191His)","Chromosome":"19","Start":"38561402","Stop":"38561402","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":581626,"rule_based_match":true,"evidence_text":"c.12572G > A (p.Arg4191His)","llm_judgment":"PRESENT","evidence":"c.12572G > A (p.Arg4191His)","abstract_start":921,"abstract_end":948}]}
{"pmid":"29742505","title":"The COL4A3 and COL4A4 Digenic Mutations in cis Result in Benign Familial Hematuria in a Large Chinese Family.","abstract":"Mutations in the COL4A5 gene result in X-linked Alport syndrome, homozygous or compound heterozygous mutations in COL4A3 or COL4A4 are responsible for autosomal recessive Alport syndrome, and heterozygous mutations in COL4A3 or COL4A4 cause autosomal dominant Alport syndrome or benign familial hematuria. Recently, the existence of a digenic inheritance in Alport syndrome has been demonstrated. We here report heterozygous COL4A3 and COL4A4 digenic mutations in cis responsible for benign familial hematuria. Using bioinformatics analyses and pedigree verification, we showed that COL4A4 c.1471C>T and COL4A3 c.3418 + 1G>T variants in cis are pathogenic and co-segregate with the benign familial hematuria. This result suggests that COL4A3 and COL4A4 digenic mutations in cis mimicking an autosomal dominant inheritance should be considered as a novel inheritance pattern of benign familial hematuria, although the disease-causing mechanism remains unknown.","variants":[{"Name":"NM_000091.5(COL4A3):c.3418+1G>T","Chromosome":"2","Start":"227294571","Stop":"227294571","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3075456,"rule_based_match":true,"evidence_text":"COL4A3 c.3418 + 1G>T","llm_judgment":"PRESENT","evidence":"COL4A3 c.3418 + 1G>T","abstract_start":604,"abstract_end":624}]}
{"pmid":"23430864","title":"Efficacy of vigabatrin intervention in a mild phenotypic expression of succinic semialdehyde dehydrogenase deficiency.","abstract":"We report a patient with succinic semialdehyde dehydrogenase deficiency who presented a mild phenotype including developmental language delay, in association with the typical elevations of 4-hydroxybutyric acid (GHB) in biological fluids and MRI alterations. Two pathogenic mutations were identified one transversion (c.278 G>T) in exon 1 and another (c.1557 T>G) in exon 10. Both parents are carriers of one of the mutations, confirming compound-heterozygosity in their affected child. To reduce the GHB levels in body fluids, a treatment with vigabatrin at low dose (25 mg/kg per day) was started, monitoring its efficacy by clinical and neurochemical follow-up. After 9 months of therapy with vigabatrin, a significant reduction of GHB concentrations in urine and CSF was observed; after 36 months, a significant improvement of communicative skills, not previously reported, was referred. These results support the hypothesis that the clinical improvement is correlated to the reduction in the GHB levels and the importance of considering the SSADH deficiency in the differential diagnosis of patients with mental retardation and language delay.","variants":[{"Name":"NM_001080.3(ALDH5A1):c.278G>T (p.Cys93Phe)","Chromosome":"6","Start":"24495274","Stop":"24495274","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":443937,"rule_based_match":true,"evidence_text":"c.278 G>T","llm_judgment":"PRESENT","evidence":"c.278 G>T","abstract_start":318,"abstract_end":327},{"Name":"NM_001080.3(ALDH5A1):c.1557T>G (p.Tyr519Ter)","Chromosome":"6","Start":"24533661","Stop":"24533661","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1935257,"rule_based_match":true,"evidence_text":"c.1557 T>G","llm_judgment":"PRESENT","evidence":"c.1557 T>G","abstract_start":352,"abstract_end":362}]}
{"pmid":"32307445","title":"Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.","abstract":"PURPOSE: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands.\nMETHODS: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays.\nRESULTS: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband.\nCONCLUSION: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.","variants":[{"Name":"NM_000350.3(ABCA4):c.1938-621G>A","Chromosome":"1","Start":"94061380","Stop":"94061380","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3408814,"rule_based_match":true,"evidence_text":"c.1938-621G>A","llm_judgment":"PRESENT","evidence":"c.1938-621G>A","abstract_start":789,"abstract_end":802}]}
{"pmid":"24791901","title":"Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy.","abstract":"In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with \"cone-first\" retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumed loss-of-function variants: c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs(∗)2];[Glu529Valfs(∗)2], and c.[401delT(;)3354G>A], p.[Leu134Argfs(∗)45(;)Trp1118(∗)]. We then inspected previously collected exome sequence data from individuals with related phenotypes and found two siblings with homozygous nonsense variant c.1627G>T (p.Glu543(∗)) in TTLL5. Subsequently, we tested a panel of 55 probands with retinal dystrophy for TTLL5 mutations; one proband had a homozygous missense change (c.1627G>A [p.Glu543Lys]). The retinal phenotype was highly similar in three of four families; the sibling pair had a more severe, early-onset disease. In human and murine retinae, TTLL5 localized to the centrioles at the base of the connecting cilium. TTLL5 has been previously reported to be essential for the correct function of sperm flagella in mice and play a role in polyglutamylation of primary cilia in vitro. Notably, genes involved in the polyglutamylation and deglutamylation of tubulin have been associated with photoreceptor degeneration in mice. The electrophysiological and fundus autofluorescence imaging presented here should facilitate the molecular diagnosis in further families.","variants":[{"Name":"NM_015072.5(TTLL5):c.1586_1589del (p.Glu529fs)","Chromosome":"14","Start":"75764648","Stop":"75764651","ReferenceAlleleVCF":"TAGAG","AlternateAlleleVCF":"T","allel_id":143158,"rule_based_match":false,"evidence_text":"c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs(∗)2];[Glu529Valfs(∗)2]","llm_judgment":"PRESENT","evidence":"c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs(∗)2];[Glu529Valfs(∗)2]","abstract_start":710,"abstract_end":788},{"Name":"NM_015072.5(TTLL5):c.1627G>T (p.Glu543Ter)","Chromosome":"14","Start":"75764691","Stop":"75764691","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":143161,"rule_based_match":true,"evidence_text":"c.1627G>T (p.Glu543(∗))","llm_judgment":"PRESENT","evidence":"c.1627G>T (p.Glu543(∗))","abstract_start":1008,"abstract_end":1031},{"Name":"NM_015072.5(TTLL5):c.1627G>A (p.Glu543Lys)","Chromosome":"14","Start":"75764691","Stop":"75764691","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":143162,"rule_based_match":true,"evidence_text":"c.1627G>A [p.Glu543Lys]","llm_judgment":"PRESENT","evidence":"c.1627G>A [p.Glu543Lys]","abstract_start":1179,"abstract_end":1202}]}
{"pmid":"35094236","title":"Characterization of the CYP21A2 Gene Mutations in Children with Classic Congenital Adrenal Hyperplasia.","abstract":"OBJECTIVE: To characterize the CYP21A2 gene mutations in children with classic congenital adrenal hyperplasia (CAH).\nMETHODS: A prospective, cross-sectional study was conducted on 24 children with classic CAH. Molecular characterization of the CYP21A2 gene was carried out by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or clinical exome sequencing. Another 21 previously mutation-proven CAH patients were also included and a combined result was drawn.\nRESULTS: Out of 45 children, pathogenic variants in the CYP21A2 gene were identified in 43 patients (95.5%). Homozygous, probable compound heterozygous, and heterozygous variants were seen in 69%, 22%, and 18% of patients, respectively. The most common variant was c.293-13C/A>G (33%), followed by deletion/duplication (24%), and c.955C>T (p.Gln319Ter) (21%), similar to previous Indian studies. Allelic frequencies of c.332_339del and c.518 T>A (p.Ile173Asn) were 9% and 4%, respectively. Less common variants were c.923dupT (p.Leu308PhefsTer6), c.92C>T (p.Pro31Leu), c.1069C>T (p.Arg357Trp), c.1267G>C (p.Gly423Arg), and c.710_719delins (p.Ile237_Met240delinsAsnGluGluLys). A good genotype-phenotype correlation was observed; only p.Pro31Leu and p.Ile173Asn variants showed discordance. The diagnostic yield of Sanger sequencing alone, Sanger sequencing with MLPA, and clinical exome alone was 85%, 100%, and 100%, respectively.\nCONCLUSIONS: All children, except two, diagnosed clinically as classic CAH, showed pathogenic variants in the CYP21A2 gene; the most common variant was c.293-13 C/A>G. The results suggest a broad mutation spectrum in the authors' single-center cohort of children with CAH. Clinical exome sequencing is the preferred stand-alone method for molecular diagnosis of CAH.","variants":[{"Name":"NM_000500.9(CYP21A2):c.710_719delinsACGAGGAGAA (p.Ile237_Met240delinsAsnGluGluLys)","Chromosome":"6","Start":"32039807","Stop":"32039816","ReferenceAlleleVCF":"TCGTGGAGAT","AlternateAlleleVCF":"ACGAGGAGAA","allel_id":186703,"rule_based_match":false,"evidence_text":"c.710_719delins (p.Ile237_Met240delinsAsnGluGluLys)","llm_judgment":"PRESENT","evidence":"c.710_719delins (p.Ile237_Met240delinsAsnGluGluLys)","abstract_start":1108,"abstract_end":1159},{"Name":"NM_000500.9(CYP21A2):c.923dup (p.Leu308fs)","Chromosome":"6","Start":"32040182","Stop":"32040183","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":76519,"rule_based_match":true,"evidence_text":"c.923dupT (p.Leu308PhefsTer6)","llm_judgment":"PRESENT","evidence":"c.923dupT (p.Leu308PhefsTer6)","abstract_start":1001,"abstract_end":1030}]}
{"pmid":"36950719","title":"A Case Report of Congenital Afibrinogenemia and Literature Review of Management of Post-circumcision Bleeding.","abstract":"We present a case of bleeding from circumcision in a full-term newborn male resulting from a rare coagulopathy, congenital afibrinogenemia, and a review of the literature regarding the management of bleeding after circumcision. Bleeding was managed with silver nitrate, suturing, thrombin powder, Arista<sup>TM</sup> AH (absorbable hemostatic particles; Becton, Dickinson and Company, Franklin Lakes, USA), FFP (fresh frozen plasma), and cryoprecipitate. The Fibrinogen level was less than 30 mg/dl (ref 150-430 mg/dl). The diagnosis of congenital afibrinogenemia was confirmed by a gene test. The baby was found to have a heterozygous pathogenic variant (c.510+1G>T) and a heterozygous likely pathogenic variant (c.1037del) in the <i>FGA</i> gene.","variants":[{"Name":"NM_021871.4(FGA):c.1037del (p.Asn346fs)","Chromosome":"4","Start":"154586392","Stop":"154586392","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":3540160,"rule_based_match":true,"evidence_text":"c.1037del","llm_judgment":"PRESENT","evidence":"c.1037del","abstract_start":714,"abstract_end":723},{"Name":"NM_021871.4(FGA):c.510+1G>T","Chromosome":"4","Start":"154587511","Stop":"154587511","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":31454,"rule_based_match":true,"evidence_text":"c.510+1G>T","llm_judgment":"PRESENT","evidence":"c.510+1G>T","abstract_start":656,"abstract_end":666}]}
{"pmid":"27271812","title":"Predominant Neurologic Manifestations Seen in a Patient With a Biallelic Perforin1 Mutation (PRF1; p.R225W).","abstract":"Neurological manifestations in familial hemophagocytic lymphohistiocytosis (FHL) are common, seen in up to 73% of patients in their course of disease. However, in majority of the cases central nervous system manifestations are associated with other clinical and laboratory parameters of hemophagocytic lymphohistiocytosis. We report here a case with FHL2 in whom hemophagocytic lymphohistiocytosis was a presenting manifestation which responded to specific therapy, however, there was isolated central nervous system relapse while patient was in remission and off therapy. FHL2 was confirmed on the basis of reduced perforin expression and homozygous mutation in PRF1at codon 637 in exon 3 (c.673C>T p.Arg225Trp).","variants":[{"Name":"NM_001083116.3(PRF1):c.673C>T (p.Arg225Trp)","Chromosome":"10","Start":"70599048","Stop":"70599048","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28750,"rule_based_match":true,"evidence_text":"c.673C>T p.Arg225Trp","llm_judgment":"PRESENT","evidence":"c.673C>T p.Arg225Trp","abstract_start":691,"abstract_end":711}]}
{"pmid":"35296306","title":"Evaluating the variety of GNAS inactivation disorders and their clinical manifestations in 11 Chinese children.","abstract":"BACKGROUND: The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis.\nMETHODS: We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations.\nRESULTS: Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright's hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH.\nCONCLUSIONS: Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician's ability to distinguish between heterotopic ossification in the POH and AHO phenotype.","variants":[{"Name":"NM_000516.7(GNAS):c.308T>C (p.Ile103Thr)","Chromosome":"20","Start":"58903581","Stop":"58903581","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1868513,"rule_based_match":true,"evidence_text":"c.308 T>C","llm_judgment":"PRESENT","evidence":"c.308 T > C","abstract_start":1183,"abstract_end":1194}]}
{"pmid":"16834925","title":"Identification of four novel mutations in the HNF-1A gene in Chinese early-onset and/or multiplex diabetes pedigrees.","abstract":"BACKGROUND: Mutations in the hepatocyte nuclear factor-1A gene cause the type 3 form of maturity-onset diabetes of the young (MODY3). This study was undertaken to determine mutations and sequence variations of the HNF-1A gene in Chinese with familial early-onset and/or multiplex diabetes mellitus.\nMETHODS: We screened all ten exons of the HNF-1A gene, including exon/intron junctions, by direct sequencing in 272 unrelated Chinese, including 80 healthy controls and 192 probands of early-onset and/or multiplex diabetes pedigrees.\nRESULTS: In addition to one silent mutation of c.864 G > C [p.G288G] in exon4 at codon 288, which had been reported previously, a total of four novel mutations including two missense mutations (c.245C > T [p.T82M] and c. 390 G > T [p.Q130H]) and one frameshift mutation P353fsdelACGGGCCTGGAGC and one silent mutation c.759 G > T [p.G253G] were identified. Moreover, eleven substitutions were identified in 192 probands. Of these, three variants (-8 G > A, -128 T > G and IVS2 + 21 G > A) were not observed in 80 healthy controls and one of them (-8 G > A) was not reported previously and the two promoter variants co-segregated with diabetes. The genotype and allele frequencies of the other eight variants in the diabetic patients were not significantly different from those in the healthy controls. No significant relationships were observed between the eight variants of the HNF-1A gene and clinical variables (plasma glucose, insulin, C-peptide and fasting lipid profile).\nCONCLUSION: The prevalence of structural mutations in the HNF-1A gene responsible for familial early-onset and/or multiplex diabetes appears to be rare among Chinese patients.","variants":[{"Name":"NM_000545.8(HNF1A):c.245C>T (p.Thr82Met)","Chromosome":"12","Start":"120979013","Stop":"120979013","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1108907,"rule_based_match":true,"evidence_text":"c.245C > T [p.T82M]","llm_judgment":"PRESENT","evidence":"c.245C > T [p.T82M]","abstract_start":727,"abstract_end":746}]}
{"pmid":"30145633","title":"BAG3 mutation in a patient with atypical phenotypes of myofibrillar myopathy and Charcot-Marie-Tooth disease.","abstract":"Bcl2-associated athanogene 3 (BAG3) mutations have been reported to cause the myofibrillar myopathy (MFM) which shows progressive limb muscle weakness, respiratory failure, and cardiomyopathy. Myopathy patients with BAG3 mutation are very rare. We described a patient showing atypical phenotypes. We aimed to find the genetic cause of Korean patients with sensory motor polyneuropathy, myopathy and rigid spine. We performed whole exome sequencing (WES) with 423 patients with sensory motor polyneuropathy. We found BAG3 mutation in one patient with neuropathy, myopathy and rigid spine syndrome, and performed electrophysiological study, whole body MRI and muscle biopsy on the patient. A de novo heterozygous p.Pro209Leu (c.626C>T) mutation in BAG3 was identified in a female myopathy. She first noticed a gait disturbance and spinal rigidity at the age of 11, and serum creatine kinase levels were elevated ninefolds than normal. She showed an axonal sensory-motor polyneuropathy like Charcot-Marie-Tooth disease (CMT), myopathy, rigid spine and respiratory dysfunction; however, she did not show any cardiomyopathy, which is a common symptom in BAG3 mutation. Lower limb MRI and whole spine MRI showed bilateral symmetric fatty atrophy of muscles at the lower limb and paraspinal muscles. When we track traceable MRI 1 year later, the muscle damage progressed slowly. As far as our knowledge, this is the first Korean patient with BAG3 mutation. We described a BAG3 mutation patient with atypical phenotype of CMT and myopathy, and those are expected to broaden the clinical spectrum of the disease and help to diagnose it.","variants":[{"Name":"NM_004281.4(BAG3):c.626C>T (p.Pro209Leu)","Chromosome":"10","Start":"119672373","Stop":"119672373","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21020,"rule_based_match":true,"evidence_text":"p.Pro209Leu (c.626C>T)","llm_judgment":"PRESENT","evidence":"p.Pro209Leu (c.626C>T)","abstract_start":711,"abstract_end":733}]}
{"pmid":"31857675","title":"Association of ALPL variants with serum alkaline phosphatase and bone traits in the general Japanese population: The Nagahama Study.","abstract":"Although alkaline phosphatase (ALP) activity is relatively low in carriers of recessive type hypophosphatasia (HPP), most are asymptomatic and therefore do not undergo medical evaluations. We analyzed the association of ALP-encoding ALPL variants with serum ALP and bone traits in the general Japanese population. Study participants (n = 9671) were from the Nagahama Study, which was a longitudinal cohort study of an apparently healthy general Japanese population. ALPL variants were analyzed by whole-genome sequencing or TaqMan probe assays using DNA extracted from peripheral blood samples. The speed of sound in calcaneal bone was assessed by quantitative ultrasound (QUS) and used as surrogate measures of bone mineral density. We identified 13 ALPL variants. Minor allele frequencies of three variants were higher than expected. Variant c.529G > A has been reported as a possible pathogenic variant for adult type HPP. Variants c.979C > T and c.1559delT are reported as pathogenic variants for perinatal severe HPP or infantile HPP. The allele frequencies of c.529G > A, c.979C > T, and c.1559delT were 0.0107, 0.0040, and 0.0014, respectively. Serum ALP activity was significantly lower and differed among the three variants (P < 0.001), as well as between individuals with and without any of the three variants (P < 0.001). Serum ALP activity was inversely associated with QUS values, although no direct association was observed between the ALPL variants and QUS values. An association between serum ALP activity and QUS was confirmed; however, we failed to detect an association between ALPL variants and bone traits in the general Japanese population.","variants":[{"Name":"NM_000478.6(ALPL):c.529G>A (p.Ala177Thr)","Chromosome":"1","Start":"21564097","Stop":"21564097","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":540880,"rule_based_match":true,"evidence_text":"c.529G > A","llm_judgment":"PRESENT","evidence":"c.529G > A","abstract_start":844,"abstract_end":854}]}
{"pmid":"20405026","title":"Nonsense mutation in TMEM126A causing autosomal recessive optic atrophy and auditory neuropathy.","abstract":"PURPOSE: To define the phenotype and elucidate the molecular basis for an autosomal recessively inherited optic atrophy and auditory neuropathy in a consanguineous family with two affected children.\nMETHODS: Family members underwent detailed ophthalmologic, electrophysiological, and audiological assessments. An autozygosity mapping strategy using high-density single nucleotide polymorphism microarrays and microsatellite markers was used to detect regions of genome homozygosity that might contain the disease gene. Candidate genes were then screened for mutations by direct sequencing.\nRESULTS: Both affected subjects had poor vision from birth and complained of progressive visual loss over time. Current visual acuity ranged from 6/60 to 6/120. Fundus examination revealed bilateral temporal optic nerve pallor in both patients with otherwise normal retinal findings. International-standard full-field electroretinograms were normal in both individuals, with no evidence of generalized retinal dysfunction. Pattern cortical visual evoked potentials were grossly abnormal bilaterally in both cases. The pattern electroretinogram N95:P50 ratio was subnormal, and the P50 was of shortened peak time bilaterally in both patients. The electrophysiological findings were consistent with bilateral retinal ganglion cell/optic nerve dysfunction. Audiological investigation in both siblings revealed abnormalities falling within the auditory neuropathy/dysynchrony spectrum. There were no auditory symptoms and good outer hair cell function (as demonstrated by transient evoked otoacoustic emissions) but impaired inner hair cell/neural function with abnormal stapedial reflex thresholds and abnormal or absent auditory brainstem-evoked responses. The single nucleotide polymorphism microarray data demonstrated a 24.17 Mb region of homozygosity at 11q14.1-11q22.3, which was confirmed by microsatellite marker analysis. The candidate target region contained the transmembrane protein 126A (TMEM126A) gene, and direct sequencing identified a previously described nonsense mutation (c.163C>T; p.Arg55X).\nCONCLUSIONS: We describe the first detailed phenotyping of patients with autosomal recessive TMEM126A-associated optic atrophy and auditory neuropathy. These findings will facilitate the identification of individuals with this recently described disorder.","variants":[{"Name":"NM_032273.4(TMEM126A):c.163C>T (p.Arg55Ter)","Chromosome":"11","Start":"85654139","Stop":"85654139","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15449,"rule_based_match":true,"evidence_text":"c.163C>T; p.Arg55X","llm_judgment":"PRESENT","evidence":"c.163C>T; p.Arg55X","abstract_start":2079,"abstract_end":2097}]}
{"pmid":"18330718","title":"Genetic analysis of hereditary multiple exostoses in Tunisian families: a novel frame-shift mutation in the EXT1 gene.","abstract":"Hereditary multiple exostoses (HME) is an autosomal dominant orthopaedic disorder most frequently caused by mutations in the EXT1 gene. The aim of the present study is to determine the underlying molecular defect of HME in two multigenerational Tunisian families with 21 affected members and to examine the degree of intrafamilial variability. Linkage analysis was performed using three microsatellite markers encompassing the EXT1 locus and mutation screening was carried out by direct sequencing. In family 1, evidence for linkage to EXT1 was obtained on the basis of a maximum LOD score of 4.26 at theta = 0.00 with D8S1694 marker. Sequencing of the EXT1 revealed a heterozygous G > T transversion (c.1019G>T) in exon 2, leading to a missense mutation at the codon 340 (p.Arg340Leu). In family 2 we identified a novel heterozygous 1 bp deletion in the exon 1 (c.529_531delA) leading to a premature codon stop and truncated EXT1 protein expression (p.Lys177LysfsX15). This mutation was associated with the evidence of an intrafamilial clinical variability and considered to be a novel disease-causing mutation in the EXT1 gene. These findings provide additional support for the involvement of EXT1 gene in the HME disease.","variants":[{"Name":"NM_000127.3(EXT1):c.1019G>T (p.Arg340Leu)","Chromosome":"8","Start":"117837145","Stop":"117837145","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":17534,"rule_based_match":true,"evidence_text":"c.1019G>T","llm_judgment":"PRESENT","evidence":"c.1019G>T","abstract_start":702,"abstract_end":711}]}
{"pmid":"22185575","title":"Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome.","abstract":"About 5-10% of breast and ovarian carcinomas are hereditary and most of these result from germline mutations in the BRCA1 and BRCA2 genes. In women of Ashkenazi Jewish ascendance, up to 30% of breast and ovarian carcinomas may be attributable to mutations in these genes, where 3 founder mutations, c.68_69del (185delAG) and c.5266dup (5382insC) in BRCA1 and c.5946del (6174delT) in BRCA2, are commonly encountered. It has been suggested by some authors that screening for founder mutations should be undertaken in all Brazilian women with breast cancer. Thus, the goal of this study was to determine the prevalence of three founder mutations, commonly identified in Ashkenazi individuals in a sample of non-Ashkenazi cancer-affected Brazilian women with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. Among 137 unrelated Brazilian women from HBOC families, the BRCA1c.5266dup mutation was identified in seven individuals (5%). This prevalence is similar to that encountered in non-Ashkenazi HBOC families in other populations. However, among patients with bilateral breast cancer, the frequency of c.5266dup was significantly higher when compared to patients with unilateral breast tumors (12.1% vs 1.2%, p = 0.023). The BRCA1 c.68_69del and BRCA2 c.5946del mutations did not occur in this sample. We conclude that screening non-Ashkenazi breast cancer-affected women from the ethnically heterogeneous Brazilian populations for the BRCA1 c.68_69del and BRCA2 c.5946del is not justified, and that screening for BRCA1c.5266dup should be considered in high risk patients, given its prevalence as a single mutation. In high-risk patients, a negative screening result should always be followed by comprehensive BRCA gene testing. The finding of a significantly higher frequency of BRCA1 c.5266dup in women with bilateral breast cancer, as well as existence of other as yet unidentified founder mutations in this population, should be further assessed in a larger well characterized high-risk cohort.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"BRCA1c.5266dup","llm_judgment":"PRESENT","evidence":"BRCA1c.5266dup","abstract_start":902,"abstract_end":916}]}
{"pmid":"15013869","title":"Novel mutations in the carbohydrate sulfotransferase gene (CHST6) in American patients with macular corneal dystrophy.","abstract":"PURPOSE: To further characterize the mutations within the CHST6 gene responsible for causing macular corneal dystrophy in a cohort of affected patients from the United States.\nDESIGN: Experimental study.\nMETHODS: Genomic DNA was extracted from buccal epithelium of 16 affected patients (14 families), 17 unaffected relatives, and 127 controls, followed by polymerase chain reaction amplification and direct sequencing of the CHST6 coding region. Subtyping of affected patients into type I and II macular corneal dystrophy was performed by measuring antigenic keratan sulfate (AgKS) serum levels. Haplotype analysis was performed in families that demonstrated common mutations.\nRESULTS: CHST6 coding region analysis in 10 patients identified as having type I macular corneal dystrophy revealed 10 sequence changes: eight missense mutations, four of which are novel (Met104Val, Tyr110Cys, Gln122Pro, and Leu276Pro) and four of which have been reported previously (Ser51Leu, Pro72Ser, Cys102Gly, and Leu200Arg); one novel homozygous nonsense mutation in two patients from a single family (c. 1683C>T, Gln331X); and one frameshift mutation in a heterozygous state in a single patient (c.1744_1751dupGTGCGCTG). Mutation analysis in the four patients identified as having type II macular corneal dystrophy (serum samples were not obtained from two affected patients) revealed three patients heterozygous for either the c.923G>C, c.969C>A, or c.1519T>C sequence changes. The fourth patient was compound heterozygous for c.969C>A and c.1291T>G. None of these changes was observed in 127 control individuals. Haplotype analysis using microsatellite markers flanking the CHST6 gene did not reveal a common founder for the Leu200Arg (1291T>G) missense mutation, present in five families, identifying this position as a mutation hot-spot.\nCONCLUSIONS: A variety of previously unreported mutations in the coding region of the CHST6 gene are associated with type I macular corneal dystrophy in a cohort of patients from the United States.","variants":[{"Name":"NM_021615.5(CHST6):c.365A>C (p.Gln122Pro)","Chromosome":"16","Start":"75479464","Stop":"75479464","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3498733,"rule_based_match":false,"evidence_text":"Gln122Pro","llm_judgment":"PRESENT","evidence":"Gln122Pro","abstract_start":887,"abstract_end":896},{"Name":"NM_021615.5(CHST6):c.329A>G (p.Tyr110Cys)","Chromosome":"16","Start":"75479500","Stop":"75479500","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":20116,"rule_based_match":false,"evidence_text":"Tyr110Cys","llm_judgment":"PRESENT","evidence":"Tyr110Cys","abstract_start":876,"abstract_end":885},{"Name":"NM_021615.5(CHST6):c.827T>C (p.Leu276Pro)","Chromosome":"16","Start":"75479002","Stop":"75479002","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":20117,"rule_based_match":false,"evidence_text":"Leu276Pro","llm_judgment":"PRESENT","evidence":"Leu276Pro","abstract_start":902,"abstract_end":911}]}
{"pmid":"36996441","title":"Management of a unique case of Coats'-like X-linked retinitis pigmentosa associated with a RPGR variant in the era of anti-VEGF.","abstract":"PURPOSE: To describe a unique case of X-linked Coats-like Retinitis Pigmentosa (CLRP), a form of exudative Retinitis Pigmentosa, in association with a RPGR variant, and its management with intravitreal anti-Vascular Endothelium Growth Factor drugs (anti-VEGFs), along with a peculiar OCT finding observed in a late stage of disease.\nMETHODS: Case report.\nRESULTS: A 33-year-old man previously treated with anti-VEGFs for macular edema came to our clinic for bilateral visual loss. A hemizygous RPGR variant (c.2442_2445del) was found and a diagnosis of CLRP was made. He was initially treated with carbonic anhydrase inhibitors; when efficacy wore off, he was switched to anti-VEGF injections in both eyes with improvement. After a year without treatment, visual acuity drastically worsened in both eyes; optical coherence tomography displayed disruption and increased hyperreflectivity of the inner retinal layers in the right eye.\nCONCLUSION: The c.2442_2445del variant is added to the number of known ORF 15 RPGR mutations associated with CLRP. Anti-VEGF treatment was successful in blocking visual loss in our patient and withholding treatment had a negative impact on his visual outcome.","variants":[{"Name":"NM_001034853.2(RPGR):c.2442_2445del (p.Gly817fs)","Chromosome":"X","Start":"38286554","Stop":"38286557","ReferenceAlleleVCF":"CCTCT","AlternateAlleleVCF":"C","allel_id":611983,"rule_based_match":true,"evidence_text":"c.2442_2445del","llm_judgment":"PRESENT","evidence":"c.2442_2445del","abstract_start":508,"abstract_end":522}]}
{"pmid":"20079539","title":"Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy.","abstract":"OBJECTIVE: To investigate whether the major achromatopsia genes (CNGA3 and CNGB3) play a role in the cause of progressive cone dystrophy (CD).\nDESIGN: Prospective multicenter study.\nPARTICIPANTS: Probands (N = 60) with autosomal recessive (ar) CD from various ophthalmogenetic clinics in The Netherlands.\nMETHODS: All available ophthalmologic data from the arCD probands were registered from medical charts and updated by an additional ophthalmologic examination. Mutations in the CNGA3 and CNGB3 genes were analyzed by direct sequencing.\nMAIN OUTCOME MEASURES: CNGA3 and CNGB3 mutations and clinical course in arCD probands.\nRESULTS: In 3 arCD probands (3/60; 5%) we found 2 mutations in the CNGB3 gene. Two of these probands had compound heterozygous mutations (p.R296YfsX9/p.R274VfsX12 and p.R296YfsX9/c.991-3T>g). The third proband revealed homozygous missense mutations (p.R403Q) with 2 additional variants in the CNGA3 gene (p.E228K and p.V266M). These probands did not have a congenital nystagmus, but had a progressive deterioration of visual acuity, color vision, and photopic electroretinogram, with onset in the second decade. In 6 other unrelated probands, we found 6 different heterozygous amino acid changes in the CNGA3 (N = 4) and CNGB3 (N = 2) gene.\nCONCLUSIONS: The CNGB3 gene accounts for a small fraction of the later onset progressive form of cone photoreceptor disorders, and CNGA3 may have an additive causative effect. Our data indicate that these genes are involved in a broader spectrum of cone dysfunction, and it remains intriguing why initial cone function can be spared despite similar gene defects.\nFINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.","variants":[{"Name":"NM_019098.5(CNGB3):c.991-3T>G","Chromosome":"8","Start":"86644689","Stop":"86644689","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":186767,"rule_based_match":true,"evidence_text":"c.991-3T>g","llm_judgment":"PRESENT","evidence":"c.991-3T>g","abstract_start":805,"abstract_end":815}]}
{"pmid":"37868241","title":"Demyelinating Peripheral Neuropathy Caused by the p.R160H Mutation in the","abstract":"We report a 62-year-old woman who presented with complaints of numbness and tingling in her feet without a family history suggestive of neuropathy. Neurological examination and electromyogram testing confirmed the presence of a demyelinating neuropathy with a mild phenotype. Extensive testing revealed no etiology and she was diagnosed and treated unsuccessfully for chronic inflammatory demyelinating polyneuropathy. Ultimately, with the availability of next-generation sequencing, genetic testing revealed a heterozygous variant, chr16:11643500C > T, c.479 G > A, p.R160H, in the <i>lipopolysaccharide-induced tumor necrosis factor (LITAF )</i> gene. Further analysis of this variant employing protein modeling suggests that this is a disease producing mutation causing Charcot Marie Tooth disease type 1C (CMT1C). Our study demonstrates the power of next-generation sequencing to diagnose patients with idiopathic neuropathy. This is important as it avoids unnecessary and expensive treatments for the patient and furthermore, allows genetic counseling for family members.","variants":[{"Name":"NM_001136472.2(LITAF):c.479G>A (p.Arg160His)","Chromosome":"16","Start":"11549644","Stop":"11549644","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":222442,"rule_based_match":true,"evidence_text":"c.479 G > A, p.R160H","llm_judgment":"PRESENT","evidence":"c.479 G > A, p.R160H","abstract_start":554,"abstract_end":574}]}
{"pmid":"27834932","title":"Functional Studies and In Silico Analyses to Evaluate Non-Coding Variants in Inherited Cardiomyopathies.","abstract":"Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis of intronic variants can reveal their impact on the splicing process, but the consequence of a given substitution is generally not predictable. The aim of this study was to functionally test five intronic variants (<i>MYBPC3</i>-c.506-2A>C, <i>MYBPC3</i>-c.906-7G>T, <i>MYBPC3</i>-c.2308+3G>C, <i>SCN5A</i>-c.393-5C>A, and <i>ACTC1</i>-c.617-7T>C) found in five patients affected by inherited cardiomyopathies in the attempt to verify their pathogenic role. Analysis of the <i>MYBPC3</i>-c.506-2A>C mutation in mRNA from the peripheral blood of one of the patients affected by hypertrophic cardiac myopathy revealed the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (<i>MYBPC3</i>-G169AfsX14). In the other four patients, we generated minigene constructs and transfected them in HEK-293 cells. This minigene approach showed that <i>MYBPC3</i>-c.2308+3G>C and <i>SCN5A</i>-c.393-5C>A altered pre-mRNA processing, thus resulting in the skipping of one exon. No alterations were found in either <i>MYBPC3</i>-c.906-7G>T or <i>ACTC1</i>-c.617-7T>C. In conclusion, functional in vitro analysis of the effects of potential splicing mutations can confirm or otherwise the putative pathogenicity of non-coding mutations, and thus help to guide the patient's clinical management and improve genetic counseling in affected families.","variants":[{"Name":"NM_000335.5(SCN5A):c.393-5C>A","Chromosome":"3","Start":"38622494","Stop":"38622494","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":178526,"rule_based_match":true,"evidence_text":"<i>SCN5A</i>-c.393-5C>A","llm_judgment":"PRESENT","evidence":"<i>SCN5A</i>-c.393-5C>A","abstract_start":578,"abstract_end":601},{"Name":"NM_000256.3(MYBPC3):c.506-2A>C","Chromosome":"11","Start":"47349924","Stop":"47349924","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":51935,"rule_based_match":true,"evidence_text":"MYBPC3-c.506-2A>C","llm_judgment":"PRESENT","evidence":"c.506-2A>C","abstract_start":513,"abstract_end":523}]}
{"pmid":"18955168","title":"XPC initiation codon mutation in xeroderma pigmentosum patients with and without neurological symptoms.","abstract":"Two unrelated xeroderma pigmentosum (XP) patients, with and without neurological abnormalities, respectively, had identical defects in the XPC DNA nucleotide excision repair (NER) gene. Patient XP21BE, a 27-year-old woman, had developmental delay and early onset of sensorineural hearing loss. In contrast, patient XP329BE, a 13-year-old boy, had a normal neurological examination. Both patients had marked lentiginous hyperpigmentation and multiple skin cancers at an early age. Their cultured fibroblasts showed similar hypersensitivity to killing by UV and reduced repair of DNA photoproducts. Cells from both patients had a homozygous c.2T>G mutation in the XPC gene which changed the ATG initiation codon to arginine (AGG). Both had low levels of XPC message and no detectable XPC protein on Western blotting. There was no functional XPC activity in both as revealed by the failure of localization of XPC and other NER proteins at the sites of UV-induced DNA damage in a sensitive in vivo immunofluorescence assay. XPC cDNA containing the initiation codon mutation was functionally inactive in a post-UV host cell reactivation (HCR) assay. Microsatellite markers flanking the XPC gene showed only a small region of identity ( approximately 30kBP), indicating that the patients were not closely related. Thus, the initiation codon mutation resulted in DNA repair deficiency in cells from both patients and greatly increased cancer susceptibility. The neurological abnormalities in patient XP21BE may be related to close consanguinity and simultaneous inheritance of other recessive genes or other gene modifying effects rather than the influence of XPC gene itself.","variants":[{"Name":"NM_004628.5(XPC):c.2T>G (p.Met1Arg)","Chromosome":"3","Start":"14178567","Stop":"14178567","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1055301,"rule_based_match":true,"evidence_text":"c.2T>G","llm_judgment":"PRESENT","evidence":"c.2T>G","abstract_start":639,"abstract_end":645}]}
{"pmid":"29178646","title":"Novel autosomal dominant TNNT1 mutation causing nemaline myopathy.","abstract":"BACKGROUND: Nemaline myopathy (NEM) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 (TNNT1) is 1 of 10 genes known to cause NEM. To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT1 gene have been identified in NEM. This extended family is of historical importance as some members were reported in the 1960s as initial evidence that NEM is a hereditary disorder.\nMETHODS: Proband and extended family underwent Sanger sequencing for TNNT1. We performed RT-PCR and immunoblot on muscle to assess TNNT1 RNA expression and protein levels in proband and father.\nRESULTS: We report a novel heterozygous missense mutation of TNNT1 c.311A>T (p.E104V) that segregated in an autosomal dominant fashion in a large family residing in the United States. Extensive sequencing of the other known genes for NEM failed to identify any other mutant alleles. Muscle biopsies revealed a characteristic pattern of nemaline rods and severe myofiber hypotrophy that was almost entirely restricted to the type 1 fiber population.\nCONCLUSION: This novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM, but that this novel mutation likely acts via a dominant negative mechanism.","variants":[{"Name":"NM_003283.6(TNNT1):c.311A>T (p.Glu104Val)","Chromosome":"19","Start":"55140959","Stop":"55140959","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":938854,"rule_based_match":true,"evidence_text":"TNNT1 c.311A>T (p.E104V)","llm_judgment":"PRESENT","evidence":"TNNT1 c.311A>T (p.E104V)","abstract_start":866,"abstract_end":890}]}
{"pmid":"32499600","title":"The novel duplication HRAS c.186_206dup p.(Glu62_Arg68dup): clinical and functional aspects.","abstract":"Specific activating missense HRAS variants cause Costello syndrome (CS), a RASopathy with recognizable facial features. The majority of these dominant disease causing variants affect the glycine residues in position 12 or 13. A clinically suspected CS diagnosis can be confirmed through identification of a dominant pathogenic HRAS variant. A novel HRAS variant predicting p.(Glu62_Arg68dup) was identified in an individual with hypertrophic cardiomyopathy, Chiari 1 malformation and ectodermal findings consistent with a RASopathy. Functional studies showed that the p.Glu62_Arg68dup alteration affects HRAS interaction with effector protein PIK3CA (catalytic subunit of phosphoinositide 3-kinase) and the regulator neurofibromin 1 (NF1) GTPase-activating protein (GAP). HRAS<sup>Glu62_Arg68dup</sup> binding with effectors rapidly accelerated fibrosarcoma (RAF1), RAL guanine nucleotide dissociation stimulator (RALGDS) and phospholipase C1 (PLCE1) was enhanced. Accordingly, p.Glu62_Arg68dup increased steady-state phosphorylation of MEK1/2 and ERK1/2 downstream of RAF1, whereas AKT phosphorylation downstream of PI3K was not significantly affected. Growth factor stimulation revealed that expression of HRAS<sup>Glu62_Arg68dup</sup> abolished the HRAS' capacity to modulate downstream signaling. Our data underscore that different qualities of dysregulated HRAS-dependent signaling dynamics determine the clinical severity in CS.","variants":[{"Name":"NM_005343.4(HRAS):c.186_206dup (p.Glu62_Arg68dup)","Chromosome":"11","Start":"533849","Stop":"533850","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GTCCCGCATGGCGCTGTACTCC","allel_id":461391,"rule_based_match":true,"evidence_text":"c.186_206dup p.(Glu62_Arg68dup)","llm_judgment":"PRESENT","evidence":"c.186_206dup p.(Glu62_Arg68dup)","abstract_start":null,"abstract_end":null}]}
{"pmid":"22413764","title":"Variants of the lamin A/C (LMNA) gene in non-valvular atrial fibrillation patients: a possible pathogenic role of the Thr528Met mutation.","abstract":"BACKGROUND AND OBJECTIVE: Lamin A/C (LMNA) gene mutations cause dilated cardiomyopathy, often accompanied by conduction disturbances. Our aim was to search for LMNA mutations in individuals with atrial fibrillation.\nMETHODS: A cohort of Polish subjects (N = 103) with non-valvular atrial fibrillation with a high (48.5%) prevalence of conduction system disturbances was screened for LMNA variants by direct DNA sequencing.\nRESULTS: We found a single non-synonymous variant (Thr528Met) in a 72-year-old patient with normal left ventricular function and episodes of advanced atrioventricular block. One of his two mutation-carrying daughters had episodes of type I second-degree atrioventricular block on a 24-hour Holter ECG and peak exercise arrhythmia. Interpretation of cardiac anomalies observed in the other daughter was complicated by thyroid insufficiency. A Thr528Met weak pathogenic effect was supported by transient transfections of C2C12 mouse myoblasts and computationally. Another interesting variant was Ile26Ile (c.78C>T), found in a New York Heart Association class III patient with a depressed left ventricular ejection fraction (30%), left bundle branch block, and a family history of heart disease. Ile26Ile was absent in 246 healthy individuals and was computationally predicted to interfere with splicing.\nCONCLUSION: LMNA mutations are not a frequent cause of atrial fibrillation even when conduction disease is present. Unlike the majority of LMNA mutations clearly associated with a severe clinical phenotype and a poor prognosis, Thr528Met results in a more subtle pathogenic effect, while Ile26Ile should be considered as a variant of unknown significance.","variants":[{"Name":"NM_170707.4(LMNA):c.1583C>T (p.Thr528Met)","Chromosome":"1","Start":"156137207","Stop":"156137207","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77748,"rule_based_match":false,"evidence_text":"Thr528Met","llm_judgment":"PRESENT","evidence":"Thr528Met","abstract_start":474,"abstract_end":483}]}
{"pmid":"19372260","title":"A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3.","abstract":"Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) failed to reveal a causative homozygous or compound heterozygous VWF genotype in 5 cases. Subsequent analysis of VWF mRNA led to the discovery of a deletion (c.221-977_532 + 7059del [p.Asp75_Gly178del]) of VWF in 7 of 12 white type 3 VWD patients from 6 unrelated families. This deletion of VWF exons 4 and 5 was absent in 9 patients of Asian origin. We developed a genomic DNA-based assay for the deletion, which also revealed its presence in 2 of 34 type 1 VWD families, segregating with VWD in an autosomal dominant fashion. The deletion was associated with a specific VWF haplotype, indicating a possible founder origin. Expression studies indicated markedly decreased secretion and defective multimerization of the mutant VWF protein. Further studies have found the mutation in additional type 1 VWD patients and in a family expressing both type 3 and type 1 VWD. The c.221-977_532 + 7059del mutation represents a previously unreported cause of both types 1 and 3 VWD. Screening for this mutation in other type 1 and type 3 VWD patient populations is required to elucidate further its overall contribution to VWD arising from quantitative deficiencies of VWF.","variants":[{"Name":"NM_000552.5(VWF):c.221-977_532+7059del","Chromosome":"12","Start":"6103315","Stop":"6111945","ReferenceAlleleVCF":"GAGACTCCGTCTCAAAAAATATATATATATATGTGTGTATATATACATATATATGTGTGTGTGTGTATACACGTGTGTGTATACACGTGTGTGTATACACACGTGTGTGTATACACACGTGTGTATATACATACACATATATGTGTATATACACATATGTGTGTATATACATATATGTGTATACACACACGTATATATATACACACATATGTGTATATACACATATATGTATACACACACACACACACACACACACACACACACACACACAGATCAATGGAATAGAATAGACACCCAGAGATAGAGCCAGTTGATATTTGACAAAGCTGACAAGAATATATACTAGGGAAAGGACACCCTCTTCAACAAATGTTGCTGGGAAAACTGGATTGCCATATGCAGAAGAATGAAACTGGACCCCTATCTCTCACCATATACAAAAAAAAATCAACTCAAGATGTATTAAAGACTTGAATGTAAGGTCTGAAACTATAAAAATCCTAGAAAAAAACCTTGGGAAAACTGTACTGGACATTGGCCTAGGCAAGGAATTTCTGACTAAGACTTCAAAAACACAGGCAACAAAAACAAAAATAGATAAATGAGACTTCATTAAACTAAAAATCTTCTGCACAGCAAAAGAAATCATCAACAGAGTGAAGAGACAGCTTGCAGAATGGAAGAAAATATTTGCAAACTTTTTCATCCAGCAAGAGACTAGTATCCAGAATACACAAGGAACTCAAACAACTCAACAACAATGAAAAATAACAAATAATATCAGCAAGAAGTGGGCAAAGGACATGAGTAGACATTTTTCAAAGGAAGACATACAAATATCTGACAGGAATGTGAAAAAAATGGTCAACATAACTTGTCATGAGAGAAATGCAAATTAAAACCACAATGAGATATCATCTTACCCTAGTCACAACGGTTATTATTAAAAAGACAGAAAATAACAGATGTTGGCAAGGATGAGGAAAAAGGGGAACTCTTACACACTGTTGGTGGGAATGTAAATGAGTACAACCTCTATGGAAAACAGTATGCAGATTTTTCAAAGAACTTTAAAAAAAAAAAAAATAGGACTGCCAGGCGCGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCTGAGGCGGGCGTATCACGAGGTCAGGAGTTTGAGACCAGCCTGGCCAACATGGTGAAACCCCGCCTCTACTAAAAAAATACAAAAGAAAAAAAAATGAGCCGGACGTGGTGACATGCGCCTGTAGTCCCAGCTACTCAGGAGTCTGAGGCAGGAGAATTGCTTGAACCCGGGAACTGGAGGTTGCAGTGAGCTGAGATCAGGCCACTGCACTCCAGCCTGGGCAACAGAGTGAGACTCTGTCTCGGAAAAAAAAAAAATATATAGGACTACCATTCAATCCAGCAATCCCACTACTGGATATCTACCCAAAGGAAAAGAAATCAATATATCAAAAATATACCTGCACTAGTATATTTATTGTGCATTATTCACAATAGCAAAGACATGGTATGAACCTAAATGCCCATCAACAGATGATTAGATGAAGAAAATGTGGTACATATACACAATGGAAGACTATTTGGCCATAAGAATGAAATCGCATCTTTTGCAGCAACATGGGTGGGATTGGAGGTCATTATGTTAAGTGAAACAAACCACATAAAGTCAAATATGACATGTTCTCACCAAAAAGTGGTTACTAAAAGATGTGTACACACAGACAGAAAGAGTAGAATGATAGATATTGGAGACTCAGAAAGGTGAGAGAGAGTGGGAGTGGGGCAGATGATGAGAAATTACTTAATGGGTACAAAGTATATTGTACCCTAAAAGTCCTGACTTGACCACTACACAATCTGTGCATGTAACAAAATTGCGCTTGTACCCCATAAATTTATACAATTTTTTTTTTGAGACAGAGTCTCGCTTTGTCACCCAGGCTAGAGTGCAGTGGGGCGATCTCGGCTCATTGCAACCTCCGTCCCCTGGGTTCAAGCAACTCTCCTGCCTCAGCCTCCCTAGTAGCTAGGATTACAGGCATGTGCTACCACCCCCAGCTAATTTTTATATTTTTAGTAGAGATGGGGTTTCACATGTTGGCCAGGCTGGTCTTGAACTTCTGACCTCAAATGATCCATCCACCTCGGCCTCCTGAAGTGCTGGGATTACAGGATTACAGGCGTGGGCCACCACGCCCGGCCTTATACAAATTTTTAAAAAGAAAAAATTTAAAAAATGTTTAAGAAGAAATTGCATATCAAATTTTTCTCCTTTTAAGTAAAGAGAAATAGATATTGTAAAAGGAATATTTTAAAATTTCACATACCTGAAAAATAAATCATGAAATATATGAAGAAAATAGAATTGCCATTAGAAATCATCCAGGAATTCTGCCTCTGGGAATATACTCAAAAGAATTGAGCCGGACGCGGTGGTTCATGCCTGTAATCCCAGCACTCTGGGAGGCCAAGGTGGGCAGATCAAGAGGTCAAGAGATGGAGACCCTCCTGGCCAACATGGTGAAACCCCATCTCTACTAAAAATACAAAAAAAAAAAAATTAGCTGTGCGTGGTGGCATGCGCCTGTAGTCCCAGCTACTCAGGAGGCTGAGGCAGGAGAATCACTTGAACCCGGGAGGTGGAGGTTGCAGTAAGCCGAGATCAGGCCACTGCACTTCAGCCTGGCGACAGAGGGAAACTCCATCTCAAAAAAAATAAAGAAGAATTGAAAGCAGGGTTTTAAAGAGTTATTTGTACACCTATACTCATAGCAGCTTTATTCACTATAGGCAAAACGTGGAAGCAATCTAAGTGTCTACTGATGGATAAATGGATAAGCAAAGTACGTACGGTCTGTATGCACAATGAAATTTTTTTTCTTTTCCTCAAATTCCTCTGATACAATGGAATATTATTCATCCTTAAAAAGGAAGAAAATTCTGACATACACCACAACATGAATGAACCTTGAGGACATTATGCAAAGTGAAATAAGCCAGCCACAAAAAGACAAATGCTGTATGATTCCACTTATATGAGATACTTAGAGTAGTCAAAATCATAGACAGAAAGTAAAATGATGGTTTCCAGGAGCCCAGAGGGAAGAATGGGAAGTTATTGTGTAATGAATATAAAGTTTCAGTTCTGCAAGATGAAAAGAGTTCTGGAGATGGATGGTGGTGATGGTTGTACAACTACATGAATGTACCTGATACCACTGAACTATATACATAAAAATGGTTAAGATAATAAATTTTGGCCAGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCTAAGCGGAGGCGGATCACCTGAGGTCAGGAGTTCAAGAGCAGCCTGGCCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGACATAGTAGCGGACACCTGTAATCCCAGCTACTAGGGAAGCTGAGACTGGAGAATTGCTTCAGCCCGGGAGGCGGAGGTTGGAGTGAGCTGAGATCACACCATTGCACTGCAGCCTGGGCAACAAGAGTGAAACTCCGACTCAAAAAAAAAAAAAAAAAAAAAAAAGATAGTAAATTTTATGTTACATGTATCATAGCACAATAAAAAATGCGGCGGGGTGTAGAAATCTATACACAAATGTTTACACTGGCTTTGTTCATAATTTTCCATAATTGGAAACAACAAAGCATCCTTCAACTGGTGAATGGGTAAACAAATTGTGGTAACTACTCCTTAGCAATAAATAGGAACAAACTACTGATACATGCACCAATATGGATTAACCTCTCACGGACCATGTTAAATGAAAGAAGCCAGACTTACAAGACTAAATACTGCAAATAGGGTATGATTACAGTCATATGAATTTTGGAAATATCAAGACTACAGAAACAGATAAAAGATCAGTGGCCACCAGGAGCTAGGAGTTGGGGGAAGATTTGACTACAAAGGAGCATGGTGATTTTGAGGGTGACAAAACTGTTCTATAGTTTGATTGTGGTGGTTACATGACTCTACGCTTTTGCGAAAACTCAGAGAACTGTATGTGAAAGGGTGAATTTTACTGTCTGTAAATTAACCTCAATAAATCTGACTTTTGAAAGAACAATAATAAAATAGAGCCATGTGGTGCTTCCATGACACACATCTGAAACAAAATCACATAGAAAGGTTGAAAGAATGGAAAAAGATACATCAAACAAACACTAACCAAAAGAAAGGTGGAATAGCTATACTAATATCAGACAGATTGAAGGCAAAAAGCACTGGTAAAAATGAGAGTCATTACATTAAAGGAACAATTCCCTAGAAAGATTCAATATATATATATATATATTTTTTGAGACGGAGTCTCACTCTGTCGCCCAGGCTGGAGTGCAGTGGTGCGATTTCAGCTCACTGCAAGCTCCGCCTCCAAGGTTCATGCCATTCTCCTGCCTCAGCTTCCCGAGTAGCTGGGACTACAGGCACCTGCCACCACACCTGGCTCATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCGTGGTAGCCAGGATAGTCTCCATCTCCTGACCTCATGATCCGCCCACTTCGGCCTCCCAAAGTGCTGGGATGACAGGCTTGAGCCACCGCACCCAGCCGAAAGATTCAGTATTTCTAAACACTAATAACAAAGGCTCAAGATATACAAAGCAGGCCAGGCACGGTGACTCACGCCTGTAATCCCAGCACTTTGGGAGGCAGAGGCGGAGAGATCACTTGAGGTCAGGAGTTCAAGACTAGCCTGGCCAACATGCTGAAACCTCATCTCTACTAAAAATACAAAAATTAGCCAGGCGTGGTGACACCTGGATGTAGTCCCAGCTACTCAGGAGGCTGAGGTAGAAGAATCGCTTGAATCTGGGAGGTGGAGGCTGTAGTGAGCTGAGATCTCACCACTGCAATCCGGCCTGGGTGACAGAGCAAGACTCTGTCTTTAAAAAAAAAAAAAAAGAAAGAAAGAAAGAAAGAAATATATACACACACACACACACACACACACACACACACAAAGCAAAATTTGACAGAATTACATGAAGAAAGTGACAAATTCACCACCATTATAGAAAAATTTAGCTCTTTTAGTAATGGGTCATTAATAAGCAGACAAGAAGTAGTACACATACAGAAGATCTGGAAAACACAATTAAAAAGCTTAATTCAAGAAGTATAGGTAGAGTCCTGCACCAATCAGAGAATACATTATTTTTGGGCATACATAGAACACTTGTAAAAAAAAAAAAAAAGGCTGCAAACAAGTCTACAATTTTTTAACTAGGCCACAATTTTTTAACCAAATTTAGAAATCAATTTAGTTACAAATAGGTAACTTTAAAAACTTCAGGCCAGGTACAGTGGCTCACACCTGTAAGCCCAGCACTTTGGGAGGCCGAGGGGGGCAGATCACGAGGTCAGGAGTTGGAGACCACCCTGGCTAACACAGTGAAACCCTGTCTCTACTAAAAATACAAAAAATTAGCCAGGCATGGTGGCGGGTGCCTGTAGTCCCAGCTACTCGGAAGGCTGAGGCAGGAGAATGGCGTGAACCCAGGAGGCAGAGCTTGCAGTGAGCCGAGATCGCGCCACTGCACTCCAGCCTGGGTGACAGAGCGAGACTCCGTCTCAAAAAAAAAAAAAAAAAAATTCAAACTTTTGAATTTGTAAATGTATATAGGTTCAGAAAGAGCTCAAAATGGAAGTTAGAAAATTTAAAACATGAAATATGTTACATATCAAAATTGGTACAGCTGGGCACAGTAACACACACCTATAATTCCACTAGGAAGGCTGAGGCAAGAGGATTCCTTGAGCCCAAGAGTTCAAGATCAGTTTGGGCAACTTAGCAAGACCTTATCTCTAAATACACACACACAGAGACACACAGACACACACACACACGTGTATATATATACATATATATACACACACATATATAATTACATATATACACACATATACAGTATATATACATATTTACACAAACACACACACATATATAGAGTGCAACTAAAGTGATATTTAGAGGGAAATTTATAGCCCTAAATGTACATATCAGACAATAAAATCAGTGCTGGAGAAAACCAAAAAATAAACTATCATGCTATTTTCCAATATGGTACATTCCAATGAAAGGAAGAGTCAATTGTTTCTCTGCATGTTTACTCTCTAATCAGAAAGTGGTTGGGTCATAAGGAAGAAAGATAACATATGTAAGTGTTTAGCTTTGGCAAGGGAACATCACTAATTGAATGTTTATGTAATTGAAATTAAAGAAGATTGAAATATTCATCTTTAGTGTTTTCTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGAAGCGGCACGATCACTGCTCACTGCAAGTTCTCCCTCCCGGGTTCACGCCATTCTCCTGTCTCAGCCTCCCAAGTAGCTGGAACTACAGGCACCCGCCACCACGCCTGGCTAATTTTCTGTATTTTTAGTAGAGACATGGTTTCACCATGTTAGCCAGGATGGTCTCAATCTCCTGACCTCATGATCCGCCTGCCTCGGCCTCCCAAAATGCTGGGATTACAGGGGTAAGCCACTGCGCCCAGCCTAGTGTTTTCACATTATCCATATTACTTTCTATTGCTCGTGAACACACACATGCACACACACATAAACTGGCCTTTTTGGATGGTGTGGAGGACCGACCACTCCATAGATTTTATCCACTCCACTGTAGTGGGCTGAGGAGGATCGACTCAAACTACCCAGCATTGACCAACCATCTGCCACGTGCAAGTTGCTACAGAGAATTCAAAGTTGAACGAAGTCAGCTTTGAGGAGCTCTAAGACCTGGTTTCACTAGAGGTCTAGGCATTGGAATGGAATGCAAAGAGATAAGGTTGGCAACATAAATTGAGGTGAGGTCACAGTGAGGCTTGAATGCCAGGGAAGGCATGTTAGTGAAGGTTTATGAGCAAGGAAATAAAAAGCATGGCCACACTTTAGGGAAATGGTATCCCAGAACATCTTACCTTCTTGGGTCATAAAGTCATCTTCAGCAAAGATGTTAAAGTTGCCACACAGCCCGCAGGTCTTGTTGAAGTATCTGTCTGACAGCAGGACTTGAAAGTTGCCGCTGCCATCGATCCTGGCCACAAAGCCATAGGCCTCACCGGACAGCTTGTAGTACCCAGCCTCAGTTTCTAGATACAGCCCTTTGGAGGCATAGGGCATGGAGACTCTGGAGGGCAAAGGCTAAGTTCAGAAGTGGGCTTCTTGTGCATTTTCTGGATGTCTCTCCCACCTTCTAACCCCAACCCCATGTTGTAGGGTTCAGAACATGGTGCAAAGTGGCTGAGGACCTAGATCAGCAATCGGGAGAGCTGGCTCTCACCCAGCCCTGCTACTCACTTCCTTGGAACATTTGCTTCCATTCTCTGGGCCCCAGCTTCCTCATCTAAAAATGAGGGGGTTGTGTCAGGGGATCCCTAGGGTCCTTTCTAACTCAGACATTGTTGGCTTACCTTTGGTCCCCCTGTGTCACGGTACCATTGACAAACAAATGGATGTCAAAAAATTCCCCAAGATACACGGAGAGGCTCACTCTCTTGCCATTCTGGAAGTCCCCTGAAAGAGAAAAAAGTCAATAGTAGTGATTATTACTCCTCTCAAAAAATGAATACATTGATTAAGAATCATTATCTACGTAACCTTTTCTCAGCAGAAAACGCCCCAAAAAGTCTTTACAAGCGAGCAACAAAAATCTCCCTAAAAATCTCATTTTCTCACCCATTTTTCCATTCATCTAAAAATAATTATTGAGTGACTTCTGGATACATTGCCCTCAGGTAGGCTCTCAAACATCACAAAAGAAAAATCTAAAAGCATGATCTTTTGCTTCTGGGAGTTTACAACCTGCGTATAAATAGAAGACAAACATGCGACAATTGAGTATATTGTAAGGCAGCAAACAAAAAGGCAACACTGTGAGTTACTGGTAACAGGTGCTCTAGGAGAGTGTTATTTATTCATTCATTCATTCACTTATTGAGACAGGGTTGTGCTCTGTTGCCCAGGTTGGGGTGCAGTGATGTGAACATGGCTCGCTGCAGTTTCTGCCTCCTGGGCCCAGGTTATCCTCCCACCTCAGCCTCCAGGGTAACTGGGATCACAAGTATGTACCACCACATCCAGCTAATTTTTTTTTTCTTTTTGTAGAGACAAGATCTCACCGTGTCGCCCAGGCTGGTCTTGAGCTCCTTGGTGCGAGTAATTACAGGCATGAGCCACCCCGCTCTGGCCTAGCAGTGCTATTTAAAATGGTATCGGTCGAGTGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCTGAGGCGGGTGGATCACGAGGTCAGGAGATCGAGACCATCCTGGCTAACACGGTGAAACCCCGTCTCTACTAAAAATATGAAGAAAAAAAAAATTAGCCAGGCGAGGTGGCTGGCGTCTGTGGTCCCAGTTCTTTGGGAGGCTGAGGCAGAAGAACGGCGTGAACCCAGGAGGCGGAGCTTGCAGTGAGCGGAGATCGCGCCACTGCACTCCAGCCTGGGTGACAGAGCA","AlternateAlleleVCF":"G","allel_id":166109,"rule_based_match":true,"evidence_text":"c.221-977_532 + 7059del","llm_judgment":"PRESENT","evidence":"c.221-977_532 + 7059del","abstract_start":251,"abstract_end":274}]}
{"pmid":"30796655","title":"Germline TP53 mutation spectrum in Sudanese premenopausal breast cancer patients: correlations with reproductive factors.","abstract":"PURPOSE: The role of non-genetic factors as modifiers of TP53-related hereditary breast cancer (BC) risk is debated. In this regard, little is known about the impact of germline TP53 mutations on BC in sub-Saharan Africa, where the disease often presents in non-contraceptive multiparous premenopausal women with extended history of breastfeeding. Herein, we report the germline TP53 mutations found in a series of 92 Sudanese premenopausal BC patients characterized for reproductive history.\nMETHODS: The entire TP53 coding sequence, including intron-exon boundaries and UTRs, was analyzed via DHPLC and direct sequencing, and the association of TP53 genotypes with BC risk and with individual lifetime exposures to reproductive factors was investigated with statistical tools.\nRESULTS: The germline TP53 mutation spectrum comprised 20 variants, 15 in the non-coding and 5 in the coding region. The latter included a deleterious missense mutation, c.817C>T (p.Arg273Cys), in a unique patient, and the common and functionally relevant coding polymorphism at amino acid 72 [Pro72Arg (rs1042522)]. The non-coding mutations included c.919+1G>A, a known deleterious splice site mutation, also in a unique patient. Notably, the 2 carriers of deleterious TP53 mutations clustered in the subset of cases with stronger reproductive history relative to childbearing age. When analyzed in comparison to population controls, the codon 72 polymorphism did not reveal associations with BC.\nCONCLUSIONS: Our study suggests that the codon 72 Arg>Pro polymorphism is not implicated in premenopausal BC susceptibility, whereas multiparity and breastfeeding might be BC risk factors for carriers of deleterious TP53 mutations.","variants":[{"Name":"NM_000546.6(TP53):c.919+1G>A","Chromosome":"17","Start":"7673700","Stop":"7673700","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":622038,"rule_based_match":true,"evidence_text":"c.919+1G>A","llm_judgment":"PRESENT","evidence":"c.919+1G>A","abstract_start":1130,"abstract_end":1140}]}
{"pmid":"31637490","title":"POLR3A-related spastic ataxia: new mutations and a look into the phenotype.","abstract":"Adolescent-onset spastic ataxia is a proposed novel phenotype in compound heterozygous carriers of an intronic mutation (c.1909 + 22G > A) in the POLR3A gene. Here, we present ten new cases of POLR3A-related spastic ataxia and discuss the genetic, clinical and imaging findings. Patients belonged to six pedigrees with hereditary spastic paraplegia or cerebellar ataxia of unknown origin. All affected subjects presented with compound heterozygous variants, comprising c.1909 + 22G > A in combination in each pedigree with one of the following novel mutations (Thr596Met, Tyr665LeufsTer11, Glu198Ter, c.646-687_1185 + 844del). The new mutations segregated with the phenotype in all families. The phenotype combined variable cerebellar ataxia, gait and lower limb spasticity, involvement of central sensory tracts and in some cases also intention tremor. The reportedly characteristic hyperintensity along the superior cerebellar peduncle on MRI was observed in ~ 80% of the cases. Our study extends the clinical and molecular phenotype further supporting the pathogenic role of the c.1909 + 22G4A intronic mutation and identifying four novel causative mutations in POLR3A-related spastic ataxia. Certain characteristic MRI features may be useful to guide genetic diagnosis.","variants":[{"Name":"NM_007055.4(POLR3A):c.1909+22G>A","Chromosome":"10","Start":"78009515","Stop":"78009515","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439194,"rule_based_match":true,"evidence_text":"c.1909+22G>A","llm_judgment":"PRESENT","evidence":"c.1909 + 22G > A","abstract_start":121,"abstract_end":137}]}
{"pmid":"38009286","title":"Clinical and genetic analysis of infants with pontocerebellar hypoplasia type 6 caused by RARS2 variations.","abstract":"OBJECTIVE: Defects in RARS2 cause cerebellopontine hypoplasia type 6 (pontocerebellar hypoplasia type 6, PCH6, OMIM: #611523), a rare autosomal recessive inherited mitochondrial disease. Here, we report two male patients and their respective family histories.\nMETHODS: We describe the clinical presentation and magnetic resonance imaging (MRI) findings of these patients. Whole-exome sequencing was used to identify the genetic mutations.\nRESULTS: One patient showed hypoglycemia, high lactic acid levels (fluctuating from 6.7 to 14.1 mmol/L), and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and pons. The other patient presented with early infantile developmental and epileptic encephalopathies (EIDEEs) with an initial developmental delay followed by infantile epileptic spasm syndrome (IESS) at 5 months old, with no imaging changes. Whole-exome sequencing identified compound heterozygous RARS2 variants c.25A>G (p.I9V) with c.1261C>T (p.Q421*) and c.1A>G (p.M1V) with c.122A>G (p.D41G) in these two patients. Of these loci, c.1261C>T and c.122A>G have not been previously reported.\nSIGNIFICANCE: Our findings have expanded the RARS2 gene variant spectrum and present EIDEEs and IESS as phenotypes which deepened the association between PCH6 and RARS2.\nPLAIN LANGUAGE SUMMARY: Defects in RARS2 cause cerebellopontine hypoplasia type 6, a rare autosomal recessive inherited mitochondrial disease. Two patients with RARS2 variants were reported in this article. One patient showed hypoglycemia, high lactic acid levels, and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and Page 3 of 21 Epilepsia OpenFor Review Only pons. The other patient presented with an initial developmental delay followed by refractory epilepsy at 5 months old, with no imaging changes. Our findings deepened the association between PCH6 and RARS2.","variants":[{"Name":"NM_020320.5(RARS2):c.1A>G (p.Met1Val)","Chromosome":"6","Start":"87589957","Stop":"87589957","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":226903,"rule_based_match":true,"evidence_text":"c.1A>G (p.M1V)","llm_judgment":"PRESENT","evidence":"c.1A>G (p.M1V)","abstract_start":994,"abstract_end":1008}]}
{"pmid":"23810382","title":"Mutations in PIK3R1 cause SHORT syndrome.","abstract":"SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs*18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657*]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.","variants":[{"Name":"NM_181523.3(PIK3R1):c.1945C>T (p.Arg649Trp)","Chromosome":"5","Start":"68296301","Stop":"68296301","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75301,"rule_based_match":true,"evidence_text":"c.1945C>T (p.Arg649Trp)","llm_judgment":"PRESENT","evidence":"c.1945C>T (p.Arg649Trp)","abstract_start":777,"abstract_end":800},{"Name":"NM_181523.3(PIK3R1):c.1906_1907insC (p.Asn636fs)","Chromosome":"5","Start":"68296262","Stop":"68296263","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":75303,"rule_based_match":true,"evidence_text":"c.1906_1907insC (p.Asn636Thrfs*18)","llm_judgment":"PRESENT","evidence":"c.1906_1907insC (p.Asn636Thrfs*18)","abstract_start":527,"abstract_end":561}]}
{"pmid":"31598604","title":"Dramatic Response of Familial Majeed Syndrome to Interleukin-1 Antagonist Therapy: Case report.","abstract":"Majeed syndrome (MS) is a rare, autosomal recessive, autoinflammatory disease characterized by recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and inflammatory dermatome. In this article, we report the cases of two siblings with MS. Genetic studies of both siblings were obtained and revealed mutations in LPIN2 gene by means of a homozygous single-base pair change in the donor splice site of exon 17 (c.2327+1G>C). Both patients underwent different modalities of treatment for MS which involved immune-suppressive and biologic therapies. We observed a significant clinical response to biologic anti-interleukin-1 (IL-1) therapy in our patients. This impressive clinical response indicates the pivotal role of IL-1 in MS pathogenesis. There are limited data on the use of anti-IL-1 therapy in treating MS due to the rarity of the condition. Anti-IL-1 therapy should be considered as a promising treatment for this disease.","variants":[{"Name":"NM_001375808.2(LPIN2):c.2327+1G>C","Chromosome":"18","Start":"2922046","Stop":"2922046","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":34371,"rule_based_match":true,"evidence_text":"c.2327+1G>C","llm_judgment":"PRESENT","evidence":"c.2327+1G>C","abstract_start":428,"abstract_end":439}]}
{"pmid":"33209585","title":"Fatal outcome after heart surgery in PMM2-CDG due to a rare homozygous gene variant with double effects.","abstract":"Variants in Phosphomannomutase 2 (PMM2) lead to PMM2-CDG, the most frequent congenital disorder of glycosylation (CDG). We here describe the disease course of a ten-month old patient who presented with the classical PMM2-CDG symptoms as cerebellar hypoplasia, retinitis pigmentosa, seizures, short stature, hepato- and splenomegaly, anaemia, recurrent vomiting and inverted mamillae. A severe form of tetralogy of Fallot was diagnosed and corrective surgery was performed at the age of 10 months. At the end of the cardiopulmonary bypass, a sudden oedematous reaction of the myocardium accompanied by biventricular pump failure was observed immediately after heparin antagonization with protamine sulfate. The patient died seven days after surgery, since myocardial function did not recover on ECMO support. We here describe the first patient carrying the homozygous variant g.18313A > T in the <i>PMM2</i> gene (NG_009209.1) that either can lead to c.394A > T (p.I132F) or even loss of 100 bp due to exon 5 skipping (c.348_447del; p.G117Rfs*4) which is comparable to a null allele. Proliferation and doubling time of the patient's fibroblasts were affected. In addition, we show that the induction of cellular stress by elevating the cell culture temperature to 40 °C led to a decrease of the patients' <i>PMM2</i> transcript as well as PMM2 protein levels and subsequently to a significant loss of residual activity. We assume that metabolic stressful processes occurring after cardiac surgery led to the drop of the patient's PMM activity below a life-sustaining niveau which paved the way for the fatal outcome.","variants":[{"Name":"NM_000303.3(PMM2):c.394A>T (p.Ile132Phe)","Chromosome":"16","Start":"8811125","Stop":"8811125","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":806409,"rule_based_match":true,"evidence_text":"c.394A > T (p.I132F)","llm_judgment":"PRESENT","evidence":"c.394A > T (p.I132F)","abstract_start":950,"abstract_end":970}]}
{"pmid":"28973348","title":"PLK1-mediated phosphorylation of WDR62/MCPH2 ensures proper mitotic spindle orientation.","abstract":"Primary microcephaly (MCPH) is an autosomal recessive disorder characterized by congenital reduction of head circumference. Here, we identified compound heterozygous mutations c.731 C > T (p.Ser 244 Leu) and c.2413 G > T (p.Glu 805 X) in the WDR62/MCPH2 gene, which encodes the mitotic centrosomal protein WDR62, in two siblings in a Japanese family with microcephaly using whole-exome sequencing. However, the molecular and cellular pathology of microcephaly caused by WDR62/MCPH2 mutation remains unclear. To clarify the physiological role of WDR62, we used the CRISPR/Cas9 system and single-stranded oligonucleotides as a point-mutation-targeting donor to generate human cell lines with knock-in of WDR62/MCPH2 c.731 C > T (p.Ser 244 Leu) missense mutation. In normal metaphase, the mitotic spindle forms parallel to the substratum to ensure symmetric cell division, while WDR62/MCPH2-mutated cells exhibited a randomized spindle orientation caused by the impaired astral microtubule assembly. It was shown that a mitotic kinase, Polo-like kinase 1 (PLK1), is required for the maintenance of spindle orientation through astral microtubule development. In this study, we demonstrated that WDR62 is a PLK1 substrate that is phosphorylated at Ser 897, and that this phosphorylation at the spindle poles promotes astral microtubule assembly to stabilize spindle orientation. Our findings provide insights into the role of the PLK1-WDR62 pathway in the maintenance of proper spindle orientation.","variants":[{"Name":"NM_001083961.2(WDR62):c.731C>T (p.Ser244Leu)","Chromosome":"19","Start":"36067859","Stop":"36067859","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1454576,"rule_based_match":true,"evidence_text":"c.731 C > T (p.Ser 244 Leu)","llm_judgment":"PRESENT","evidence":"c.731 C > T (p.Ser 244 Leu)","abstract_start":176,"abstract_end":203}]}
{"pmid":"23551631","title":"A novel mutation of the ornithine transcarbamylase gene leading to fatal hyperammonemia in a liver transplant recipient.","abstract":"Ornithine transcarbamylase (OTC) deficiency (OTCD) is an X-linked urea cycle disorder. Being an X-linked disease, the onset and severity of the disease may vary among female carriers. Some of them start to develop the disease early in life, whereas others remain asymptomatic throughout their lives. Our patient was a 42-year-old man who developed severe hyperammonemia and fatal brain edema after receiving a right lobe graft from an asymptomatic female living donor with unrecognized OTCD. The donor developed hyperammonemia and disturbed level of consciousness that was managed successfully by hemodialysis. Molecular testing of the OTC gene in the donor revealed a heterozygous nonsense mutation (c.429T>A) in exon 5.","variants":[{"Name":"NM_000531.6(OTC):c.429T>A (p.Tyr143Ter)","Chromosome":"X","Start":"38401317","Stop":"38401317","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1065406,"rule_based_match":true,"evidence_text":"c.429T>A","llm_judgment":"PRESENT","evidence":"c.429T>A","abstract_start":701,"abstract_end":709}]}
{"pmid":"32925086","title":"Phenotypic Spectrum of Myopathies with Recessive Anoctamin-5 Mutations.","abstract":"BACKGROUND: Biallelic variants in Anoctamin 5 (ANO5) gene are causative of limb-girdle muscular dystrophy (LGMD) R12 anoctamin5-related, non-dysferlin Miyoshi-like distal myopathy (MMD3), and asymptomatic hyperCKemia.\nOBJECTIVE: To describe clinic, histologic, genetic and imaging features, of ANO5 mutated patients.\nMETHODS: Five patients, four from France (P1, P2, P3 and P4) and one from Mexico (P5), from four families were included. P1 and P2, belonging to group 1, had normal muscle strength; Group 2, P3, P4 and P5, presented with muscular weakness. Muscle strength was measured by manual muscle testing, Medical Research Council (MRC) grades 1/5 to 5/5. Laboratory exams included serum CK levels, nerve conduction studies (NCS)/needle electromyography (EMG), pulmonary function tests, EKG and cardiac ultrasound. ANO5 molecular screening was performed with different approaches.\nRESULTS: Group 1 patients showed myalgias with hyperCKemia or isolated hyperCKemia. Group 2 patients presented with limb-girdle or proximo-distal muscular weakness. Serum CK levels ranged from 897 to 5000 UI/L. Muscle biopsy analysis in P4 and P5 showed subsarcolemmal mitochondrial aggregates. Electron microscopy confirmed mitochondrial proliferation and revealed discontinuity of the sarcolemmal membrane. Muscle MRI showed asymmetrical fibro-fatty substitution predominant in the lower limbs.P1 and P2 were compound heterozygous for c.191dupA (p.Asn64Lysfs*15) and c.1898 + G>A; P3 was homozygous for the c.692G>T. (p.Gly231Val); P4 harbored a novel biallelic homozygous exons 1-7 ANO5 gene deletion, and P5 was homozygous for a c.172 C > T (p.(Arg 58 Trp)) ANO5 pathogenic variant.\nCONCLUSIONS: Our cohort confirms the wide clinical variability and enlarge the genetic spectrum of ANO5-related myopathies.","variants":[{"Name":"NM_213599.3(ANO5):c.172C>T (p.Arg58Trp)","Chromosome":"11","Start":"22218279","Stop":"22218279","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":194563,"rule_based_match":true,"evidence_text":"c.172 C > T (p.(Arg 58 Trp))","llm_judgment":"PRESENT","evidence":"c.172 C > T (p.(Arg 58 Trp))","abstract_start":1620,"abstract_end":1648},{"Name":"NM_213599.3(ANO5):c.692G>T (p.Gly231Val)","Chromosome":"11","Start":"22236206","Stop":"22236206","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":17204,"rule_based_match":true,"evidence_text":"c.692G>T (p.Gly231Val)","llm_judgment":"PRESENT","evidence":"p.Gly231Val","abstract_start":1507,"abstract_end":1518}]}
{"pmid":"17189986","title":"Two germline alterations in mismatch repair genes found in a HNPCC patient with poor family history.","abstract":"The Bethesda guidelines may offer more useful criteria in patients' selection for germline mismatch repair gene mutation analysis than guidelines merely based on family background. An early onset double primary colorectal cancer patient with poor family history with MSI-H status was investigated for MLH1 promoter methylation, expression of the MLH1 and MSH2 gene by immunohistochemistry and mutations in the MLH1 and MSH2 genes. The index patient carried two germline alterations, the p.Val716Met in MLH1 and the c.2210+1G>C in MSH2 genes, and both tumors failed to express MLH1 and MSH2 proteins. After subsequent analysis of the whole family of the index patient, the p.Val716Met variant can be defined as a rare polymorphism with the possible contribution of pathogenicity to tumor formation and c.2210+1G>C as a true pathogenic mutation causing an out-of-frame deletion of exon 13.","variants":[{"Name":"NM_000251.3(MSH2):c.2210+1G>C","Chromosome":"2","Start":"47476572","Stop":"47476572","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":96397,"rule_based_match":true,"evidence_text":"c.2210+1G>C","llm_judgment":"PRESENT","evidence":"c.2210+1G>C","abstract_start":515,"abstract_end":526}]}
{"pmid":"29490685","title":"A novel single variant in the MEFV gene causing Mediterranean fever and Behçet's disease: a case report.","abstract":"BACKGROUND: Familial Mediterranean fever is an autoinflammatory disease of unknown etiology, characterized clinically by recurrent attacks of sudden-onset fever with arthralgia and/or thoracoabdominal pain and pathogenetically by autosomal recessive inheritance due to a mutation in the MEFV gene. Behçet's disease is an inflammatory disease characterized by recurrent oral and genital aphthous ulcerations, uveitis, and skin lesions. Preliminarily, our literature review suggested that patients with familial Mediterranean fever who also have Behçet's disease have only a single mutated familial Mediterranean fever gene. The MEFV gene mutation responsible for familial Mediterranean fever is probably a susceptibility factor for Behçet's disease, particularly for patients with vascular involvement, and both disorders can occur concurrently in a patient, as in the present case.\nCASE PRESENTATION: A 10-year-old girl of Moroccan origin presented to our institution for genetic consultation for genetic testing of the MEFV gene. She had fever associated with abdominal and diffuse joint pain in addition to headache. These symptoms have oriented pediatricians to familial Mediterranean fever. The evolution was marked by Behçet's syndrome symptoms. Sanger sequencing followed by complete exome sequencing analysis of the MEFV gene for the proband mutation revealed a novel variant. We conclude that the novel single variant c.2078 T > A (p.Met693Lys) could be responsible for the association of familial Mediterranean fever and Behçet's disease.\nCONCLUSION: To the best of our knowledge, this is the first report of a new variant in exon 10 of the MEFV gene in a Moroccan family. This novel variant should be listed in the MEFV sequence variant databases.","variants":[{"Name":"NM_000243.3(MEFV):c.2078T>A (p.Met693Lys)","Chromosome":"16","Start":"3243409","Stop":"3243409","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1291599,"rule_based_match":true,"evidence_text":"c.2078 T > A (p.Met693Lys)","llm_judgment":"PRESENT","evidence":"c.2078 T > A (p.Met693Lys)","abstract_start":1426,"abstract_end":1452}]}
{"pmid":"27440999","title":"Genetic analysis of Tunisian families with Usher syndrome type 1: toward improving early molecular diagnosis.","abstract":"PURPOSE: Usher syndrome accounts for about 50% of all hereditary deaf-blindness cases. The most severe form of this syndrome, Usher syndrome type I (USH1), is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. Six USH1 genes have been identified, MYO7A, CDH23, PCDH15, USH1C, SANS, and CIB2, encoding myosin VIIA, cadherin-23, protocadherin-15, harmonin, scaffold protein containing ankyrin repeats and a sterile alpha motif (SAM) domain, and calcium- and integrin-binding member 2, respectively.\nMETHODS: In the present study, we recruited four Tunisian families with a diagnosis of USH1, together with healthy unrelated controls. Affected members underwent detailed audiologic and ocular examinations. We used the North African Deafness (NADf) chip to search for known North African mutations associated with USH. Then, we selected microsatellite markers covering USH1 known loci to genotype the DNA samples. Finally, we performed DNA sequencing of three known USH1 genes: MYO7A, PCDH15, and USH1C.\nRESULTS: Four biallelic mutations, all single base changes, were found in the MYO7A, USH1C, and PCDH15 genes. These mutations consist of a previously reported splicing defect c.470+1G>A in MYO7A, three novel variants, including two nonsense (p.Arg3X and p.Arg134X) in USH1C and PCDH15, respectively, and one frameshift (p.Lys615Asnfs*6) in MYO7A.\nCONCLUSIONS: We found a remarkable genetic heterogeneity in the studied families with USH1 with a variety of mutations, among which three were novel. These novel mutations will be included in the NADf mutation screening chip that will allow a higher diagnosis efficiency of this extremely genetically heterogeneous disease. Ultimately, efficient molecular diagnosis of USH in a patient's early childhood is of utmost importance, allowing better educational and therapeutic management.","variants":[{"Name":"NM_000260.4(MYO7A):c.470+1G>A","Chromosome":"11","Start":"77156092","Stop":"77156092","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":178183,"rule_based_match":true,"evidence_text":"c.470+1G>A","llm_judgment":"PRESENT","evidence":"c.470+1G>A","abstract_start":1236,"abstract_end":1246}]}
{"pmid":"26208274","title":"Distribution of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutations in a Cohort of Patients Residing in Palestine.","abstract":"Cystic fibrosis (CF) is an autosomal recessive inherited life-threatening disorder that causes severe damage to the lungs and the digestive system. In Palestine, mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) that contributes to the clinical presentation of CF are ill defined. A cohort of thirty three clinically diagnosed CF patients from twenty one different Palestinian families residing in the central and southern part of Palestine were incorporated in this study. Sweat chloride testing was performed using the Sweat Chek Conductivity Analyzer (ELITECH Group, France) to confirm the clinical diagnosis of CF. In addition, nucleic acid from the patients' blood samples was extracted and the CFTR mutation profiles were assessed by direct sequencing of the CFTR 27 exons and the intron-exon boundaries. For patient's DNA samples where no homozygous or two heterozygous CFTR mutations were identified by exon sequencing, DNA samples were tested for deletions or duplications using SALSA MLPA probemix P091-D1 CFTR assay. Sweat chloride testing confirmed the clinical diagnosis of CF in those patients. All patients had NaCl conductivity >60 mmol/l. In addition, nine different CFTR mutations were identified in all 21 different families evaluated. These mutations were c.1393-1G>A, F508del, W1282X, G85E, c.313delA, N1303K, deletion exons 17a-17b-18, deletion exons 17a-17b and Q1100P. c.1393-1G>A was shown to be the most frequent occurring mutation among tested families. We have profiled the underling mutations in the CFTR gene of a cohort of 21 different families affected by CF. Unlike other studies from the Arab countries where F508del was reported to be the most common mutation, in southern/central Palestine, the c.1393-1G>A appeared to be the most common. Further studies are needed per sample size and geographic distribution to account for other possible CFTR genetic alterations and their frequencies. Genotype/phenotype assessments are also recommended and finally carrier frequency should be ascertained.","variants":[{"Name":"NM_000492.4(CFTR):c.1393-1G>A","Chromosome":"7","Start":"117559463","Stop":"117559463","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67910,"rule_based_match":true,"evidence_text":"c.1393-1G>A","llm_judgment":"PRESENT","evidence":"c.1393-1G>A","abstract_start":1307,"abstract_end":1318}]}
{"pmid":"19286384","title":"The neurofilament light chain gene (NEFL) mutation Pro22Ser can be associated with mixed axonal and demyelinating neuropathy.","abstract":"We report the detailed clinical, electrophysiological and molecular analysis of a patient with Charcot-Marie-Tooth (CMT) disease. DNA sequencing of the coding sequences of the neurofilament light chain polypeptide (NEFL) gene revealed a c.64C>T heterozygous, missense mutation resulting in a Pro22Ser amino acid substitution. Clinical and electrophysiological studies revealed a mixed axonal and demyelinating neuropathy, with widespread demyelination involving both proximal and distal nerve segments. Mutations at this site in the NEFL gene have been previously linked to an axonal neuropathy or distal nerve demyelination. Our results emphasize the complexity of genotype-phenotype correlations in CMT and underline the possible importance of host factors and gene interactions in the development of clinical phenotypes.","variants":[{"Name":"NM_006158.5(NEFL):c.64C>T (p.Pro22Ser)","Chromosome":"8","Start":"24956452","Stop":"24956452","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29068,"rule_based_match":true,"evidence_text":"c.64C>T","llm_judgment":"PRESENT","evidence":"c.64C>T","abstract_start":237,"abstract_end":244}]}
{"pmid":"24498631","title":"Exome sequencing identifies NFS1 deficiency in a novel Fe-S cluster disease, infantile mitochondrial complex II/III deficiency.","abstract":"Iron-sulfur (Fe-S) clusters are a class of highly conserved and ubiquitous prosthetic groups with unique chemical properties that allow the proteins that contain them, Fe-S proteins, to assist in various key biochemical pathways. Mutations in Fe-S proteins often disrupt Fe-S cluster assembly leading to a spectrum of severe disorders such as Friedreich's ataxia or iron-sulfur cluster assembly enzyme (ISCU) myopathy. Herein, we describe infantile mitochondrial complex II/III deficiency, a novel autosomal recessive mitochondrial disease characterized by lactic acidemia, hypotonia, respiratory chain complex II and III deficiency, multisystem organ failure and abnormal mitochondria. Through autozygosity mapping, exome sequencing, in silico analyses, population studies and functional tests, we identified c.215G>A, p.Arg72Gln in NFS1 as the likely causative mutation. We describe the first disease in man likely caused by deficiency in NFS1, a cysteine desulfurase that is implicated in respiratory chain function and iron maintenance by initiating Fe-S cluster biosynthesis. Our results further demonstrate the importance of sufficient NFS1 expression in human physiology.","variants":[{"Name":"NM_021100.5(NFS1):c.215G>A (p.Arg72Gln)","Chromosome":"20","Start":"35697793","Stop":"35697793","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1161574,"rule_based_match":true,"evidence_text":"c.215G>A, p.Arg72Gln","llm_judgment":"PRESENT","evidence":"c.215G>A, p.Arg72Gln","abstract_start":810,"abstract_end":830}]}
{"pmid":"32881472","title":"Phenotype Driven Analysis of Whole Genome Sequencing Identifies Deep Intronic Variants that Cause Retinal Dystrophies by Aberrant Exonization.","abstract":"Purpose: To demonstrate the effectiveness of combining retinal phenotyping and focused variant filtering from genome sequencing (GS) in identifying deep intronic disease causing variants in inherited retinal dystrophies.\nMethods: Affected members from three pedigrees with classical enhanced S-cone syndrome (ESCS; Pedigree 1), congenital stationary night blindness (CSNB; Pedigree 2), and achromatopsia (ACHM; Pedigree 3), respectively, underwent detailed ophthalmologic evaluation, optical coherence tomography, and electroretinography. The probands underwent panel-based genetic testing followed by GS analysis. Minigene constructs (NR2E3, GPR179 and CNGB3) and patient-derived cDNA experiments (NR2E3 and GPR179) were performed to assess the functional effect of the deep intronic variants.\nResults: The electrophysiological findings confirmed the clinical diagnosis of ESCS, CSNB, and ACHM in the respective pedigrees. Panel-based testing revealed heterozygous pathogenic variants in NR2E3 (NM_014249.3; c.119-2A>C; Pedigree 1) and CNGB3 (NM_019098.4; c.1148delC/p.Thr383Ilefs*13; Pedigree 3). The GS revealed heterozygous deep intronic variants in Pedigrees 1 (NR2E3; c.1100+1124G>A) and 3 (CNGB3; c.852+4751A>T), and a homozygous GPR179 variant in Pedigree 2 (NM_001004334.3; c.903+343G>A). The identified variants segregated with the phenotype in all pedigrees. All deep intronic variants were predicted to generate a splice acceptor gain causing aberrant exonization in NR2E3 [89 base pairs (bp)], GPR179 (197 bp), and CNGB3 (73 bp); splicing defects were validated through patient-derived cDNA experiments and/or minigene constructs and rescued by antisense oligonucleotide treatment.\nConclusions: Deep intronic mutations contribute to missing heritability in retinal dystrophies. Combining results from phenotype-directed gene panel testing, GS, and in silico splice prediction tools can help identify these difficult-to-detect pathogenic deep intronic variants.","variants":[{"Name":"NM_014249.4(NR2E3):c.1100+1124G>A","Chromosome":"15","Start":"71815241","Stop":"71815241","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3149048,"rule_based_match":true,"evidence_text":"NR2E3; c.1100+1124G>A","llm_judgment":"PRESENT","evidence":"NR2E3; c.1100+1124G>A","abstract_start":1167,"abstract_end":1188}]}
{"pmid":"30512148","title":"Clinical and variation analysis of three Chinese families affected with glutaric acidemia type 1","abstract":"OBJECTIVE: To detect potential variation in glutaryl-CoA dehydrogenase (GCDH) gene among three Chinese families affected with glutaric acidemia type Ⅰ(GA-1) and correlate the genotypes with phenotypes.\nMETHODS: Genomic DNA was extracted from peripheral blood samples derived from three patients with GA-1 and their family members. The coding regions of the GCDH gene were amplified with PCR and subjected to Sanger sequencing.\nRESULTS: The clinical manifestation of the patients varied from macrocephaly to severe encephalopathy, with notable phenotypic difference between siblings carrying the same variation. In pedigrees 1 and 2, the probands have carried compound heterozygous variations c.1133C>T(p.Ala378Val) and c.1244-2A>C, which were derived their fathers and mothers, respectively. In pedigree 3, the proband has carried compound heterozygous variation c.339delT (p.Tyr113) and c.406G>T (p.Gly136Cys). Among these, variations c.339delT and c.1133C>T were verified as novel by retrieval of dsSNP, HGMD and 1000 genome database. Bioinformatic analysis suggested that above variations can affect protein function and are probably pathogenic.\nCONCLUSION: Above discovery has expanded the mutation spectrum of the GCDH gene. No correlation was found between the clinical phenotype and genotype of GA-1 patients.","variants":[{"Name":"NM_000159.4(GCDH):c.1133C>T (p.Ala378Val)","Chromosome":"19","Start":"12897753","Stop":"12897753","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":847321,"rule_based_match":true,"evidence_text":"c.1133C>T(p.Ala378Val)","llm_judgment":"PRESENT","evidence":"c.1133C>T(p.Ala378Val)","abstract_start":692,"abstract_end":714}]}
{"pmid":"23431752","title":"Analysis of the genes encoding neuroligins NLGN3 and NLGN4 in Bulgarian patients with autism.","abstract":"Many studies have supported a genetic aetiology for autism. Neuroligins are postsynaptically located cell-adhesion molecules. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have been implicated in pathogenesis of autism. In order to confirm these causative mutations in our autistic population and to determine their frequency we screened 20 individuals affected with autism. We identified one patient with a point mutation in NLGN4 gene that substituted a Met for Thr 787 - c.2360C > T, p.(Thr787Met) and three patients with identical polymorphisms in the same gene: c.933C > T, p.(Thr311Thr) in combination with c.[1777C > T+1779C > G, p.(Leu593Leu)]. All patients tested for NLGN3 mutations were negative. These results indicate that mutations in these genes are responsible for at most a small fraction of autism cases.","variants":[{"Name":"NM_181332.3(NLGN4X):c.2360C>T (p.Thr787Met)","Chromosome":"X","Start":"5892908","Stop":"5892908","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":209137,"rule_based_match":true,"evidence_text":"c.2360C > T, p.(Thr787Met)","llm_judgment":"PRESENT","evidence":"c.2360C > T, p.(Thr787Met)","abstract_start":489,"abstract_end":515}]}
{"pmid":"25548624","title":"Skinfold over toenail is pathognomonic for the popliteal pterygium syndrome in a Congolese family with large intrafamilial variability.","abstract":"KEY CLINICAL MESSAGE: We report on three related Congolese popliteal pterygium syndrome (PPS) patients concordant only for the skinfold over the toenail. Mutation analysis revealed that the three affected individuals carried a heterozygous missense mutation in the Exon 4, NM_006147.2:c.250C>T; p.Arg84Cys. This is the first molecularly confirmed PPS family from central Africa.","variants":[{"Name":"NM_006147.4(IRF6):c.250C>T (p.Arg84Cys)","Chromosome":"1","Start":"209796477","Stop":"209796477","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18453,"rule_based_match":true,"evidence_text":"NM_006147.2:c.250C>T; p.Arg84Cys","llm_judgment":"PRESENT","evidence":"NM_006147.2:c.250C>T; p.Arg84Cys","abstract_start":273,"abstract_end":305}]}
{"pmid":"18618993","title":"Tumoral calcinosis due to GALNT3 C.516-2A >T mutation in a black African family.","abstract":"Familial Tumoral Calcinosis (FTC) is a rare autosomal recessive disorder of the phosphocalcic metabolism caused by mutations in the FGF23 or GALNT3 genes. We have identified a Beninese family in which two brothers present FTC caused by a homozygous A>T transversion at the acceptor splice site in intron 1 of GALNT3 gene. We report on the clinical, biochemical, histopathological and molecular spectrum of the disorder in this family. The particularly severe phenotype, the amelogenesis imperfecta, and the carbapatite deposit observed in these patients, seem to be characteristic of our observations.","variants":[{"Name":"NM_004482.4(GALNT3):c.516-2A>T","Chromosome":"2","Start":"165765058","Stop":"165765058","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":22833,"rule_based_match":true,"evidence_text":"C.516-2A >T","llm_judgment":"PRESENT","evidence":"C.516-2A >T","abstract_start":null,"abstract_end":null}]}
{"pmid":"22541562","title":"Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability.","abstract":"Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease-causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32-p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development.","variants":[{"Name":"NM_017755.6(NSUN2):c.2035G>A (p.Gly679Arg)","Chromosome":"5","Start":"6600195","Stop":"6600195","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40340,"rule_based_match":true,"evidence_text":"c.2035G>A (p.Gly679Arg)","llm_judgment":"PRESENT","evidence":"c.2035G>A (p.Gly679Arg)","abstract_start":684,"abstract_end":707}]}
{"pmid":"32767280","title":"Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients.","abstract":"BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive genetic disease due to mutations in the AIRE (AutoImmune REgulator) gene. The clinical diagnosis is classically based on the presence of at least two of the three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Patients often suffer from other endocrine or non-endocrine autoimmune conditions throughout life. APECED etiopathogenesis is mediated by T lymphocytes. Autoantibodies against proteins of the affected organs are found in the serum of APECED patients as well as neutralizing antibodies against cytokines. We report here the clinical and genetic characteristics of 45 Indian APECED patients in comparison to Finnish, Sardinian, Turkish and North/South American cohorts from their published results. We also report a new case of APECED of Indian origin, a 2-year old child suffering from chronic mucocutaneous candidiasis since the age of 8 months, with confirmatory AIRE homozygous mutation c.274C > T (p.R92W).\nCONCLUSION: With the inherent limitations of a retrospective study, analysis of Indian APECED patients suggested that compared to classic criteria, application of Ferre/Lionakis criteria validated in North/South American patients could help in earlier diagnosis in 3 of 8 (37.5%) patients for whom adequate information for evaluation was available.","variants":[{"Name":"NM_000383.4(AIRE):c.274C>T (p.Arg92Trp)","Chromosome":"21","Start":"44286698","Stop":"44286698","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":378471,"rule_based_match":true,"evidence_text":"c.274C > T (p.R92W)","llm_judgment":"PRESENT","evidence":"c.274C > T (p.R92W)","abstract_start":1124,"abstract_end":1143}]}
{"pmid":"29936235","title":"A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability.","abstract":"The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C > G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.","variants":[{"Name":"NM_021072.4(HCN1):c.469C>G (p.Leu157Val)","Chromosome":"5","Start":"45645565","Stop":"45645565","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":623027,"rule_based_match":true,"evidence_text":"c.469C > G","llm_judgment":"PRESENT","evidence":"c.469C > G","abstract_start":600,"abstract_end":610}]}
{"pmid":"25808193","title":"Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations.","abstract":"Oculoectodermal syndrome (OES) is a rare disease characterized by a combination of congenital scalp lesions and ocular dermoids, with additional manifestations including non-ossifying fibromas and giant cell granulomas of the jaw occurring during the first decade of life. To identify the genetic etiology of OES, we conducted whole-genome sequencing of several tissues in an affected individual. Comparison of DNA from a non-ossifying fibroma to blood-derived DNA allowed identification of a somatic missense alteration in KRAS NM_033360.3(KRAS):c.38G>A, resulting in p.Gly13Asp. This alteration was also observed in the patient's other affected tissues including the skin and muscle. Targeted sequencing in a second, unrelated OES patient identified an NM_033360.3(KRAS):c.57G>C, p.Leu19Phe alteration. Allelic frequencies fell below 40% in all tissues examined in both patients, suggesting that OES is a mosaic RAS-related disorder, or RASopathy. The characteristic findings in OES, including scalp lesions, ocular dermoids, and benign tumors, are found in other mosaic and germline RASopathies. This discovery also broadens our understanding of the spectrum of phenotypes resulting from KRAS alterations. Future research into disease progression with regard to malignancy risk and investigation of RAS-targeted therapies in OES is warranted. KRAS sequencing is clinically available and may also now improve OES diagnostic criteria.","variants":[{"Name":"NM_004985.5(KRAS):c.38G>A (p.Gly13Asp)","Chromosome":"12","Start":"25245347","Stop":"25245347","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27619,"rule_based_match":true,"evidence_text":"NM_033360.3(KRAS):c.38G>A","llm_judgment":"PRESENT","evidence":"NM_033360.3(KRAS):c.38G>A","abstract_start":529,"abstract_end":554},{"Name":"NM_004985.5(KRAS):c.57G>C (p.Leu19Phe)","Chromosome":"12","Start":"25245328","Stop":"25245328","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":214479,"rule_based_match":true,"evidence_text":"NM_033360.3(KRAS):c.57G>C, p.Leu19Phe","llm_judgment":"PRESENT","evidence":"NM_033360.3(KRAS):c.57G>C, p.Leu19Phe","abstract_start":755,"abstract_end":792}]}
{"pmid":"35323613","title":"Further Evidence of Autosomal Recessive Inheritance of","abstract":"Neonatal dilated cardiomyopathy (DCM) is rare with high etiologic heterogeneity. Recently, biallelic, autosomal recessive, pathogenic variants in RPL3L (ribosomal protein L3-like) have been reported in the literature with severe early-onset DCM. In the present brief report, we identified two pathogenic RPL3L variants, each harbored in unaffected heterozygous parents: mother (RPL3L c.1076_1080delCCGTG (p.Ala359Glyfs*4)) and father (RPL3L c.80G > A (p.Gly27Asp)). Pathogenic variants were segregated as autosomal recessive to two offspring born with compound heterozygous RPL3L variants and affected by neonatal DCM. This is the second report in the literature to the best of our knowledge and our findings support the pathogenicity of biallelic RPL3L pathologic variants associated with rapidly progressive neonatal DCM and heart failure with a poor prognosis.","variants":[{"Name":"NM_005061.3(RPL3L):c.80G>A (p.Gly27Asp)","Chromosome":"16","Start":"1954072","Stop":"1954072","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1151148,"rule_based_match":true,"evidence_text":"RPL3L c.80G > A (p.Gly27Asp)","llm_judgment":"PRESENT","evidence":"RPL3L c.80G > A (p.Gly27Asp)","abstract_start":435,"abstract_end":463}]}
{"pmid":"32908489","title":"Targeted Next-Generation Sequencing Identifies Separate Causes of Hearing Loss in One Deaf Family and Variable Clinical Manifestations for the p.R161C Mutation in","abstract":"Hearing loss is the most common sensory deficit in humans. Identifying the genetic cause and genotype-phenotype correlation of hearing loss is sometimes challenging due to extensive clinical and genetic heterogeneity. In this study, we applied targeted next-generation sequencing (NGS) to resolve the genetic etiology of hearing loss in a Chinese Han family with multiple affected family members. Targeted sequencing of 415 deafness-related genes identified the heterozygous c.481C>T (p.R161C) mutation in <i>SOX10</i> and the homozygous c.235delC (p.L79Cfs∗3) mutation in <i>GJB2</i> as separate pathogenic mutations in distinct affected family members. The <i>SOX10</i> c.481C>T (p.R161C) mutation has been previously reported in a Caucasian patient with Kallmann syndrome that features congenital hypogonadotropic hypogonadism with anosmia. In contrast, family members carrying the same p.R161C mutation in this study had variable Waardenburg syndrome-associated phenotypes (hearing loss and/or hair hypopigmentation) without olfactory or reproductive anomalies. Our results highlight the importance of applying comprehensive diagnostic approaches such as NGS in molecular diagnosis of hearing loss and show that the p.R161C mutation in <i>SOX10</i> may be associated with a wide range of variable clinical manifestations.","variants":[{"Name":"NM_006941.4(SOX10):c.481C>T (p.Arg161Cys)","Chromosome":"22","Start":"37978083","Stop":"37978083","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1506530,"rule_based_match":true,"evidence_text":"c.481C>T (p.R161C)","llm_judgment":"PRESENT","evidence":"c.481C>T (p.R161C)","abstract_start":475,"abstract_end":493}]}
{"pmid":"27183861","title":"A recessive syndrome of intellectual disability, moderate overgrowth, and renal dysplasia predisposing to Wilms tumor is caused by a mutation in FIBP gene.","abstract":"Clinical classification of overgrowth syndromes represents a challenge since a wide spectrum of disorders result in marked overgrowth. Therefore, there is a continuous effort to identify the genetic basis of these disorders that will eventually facilitate their molecular classification. Here, we have identified the genetic etiology and the pathogenetic mechanism underlying a rare autosomal recessive overgrowth syndrome in three affected siblings. The overgrowth phenotype in the patients was accompanied by developmental delay, learning disabilities, and variable congenital abnormalities. To elucidate the genetic etiology of the disorder, whole-genome genotyping and whole-exome sequencing were used. The disease was mapped to 3p21.1-p14.2 and 11q13.1-q13.4, where an in-frame insertion (c.175_176insTAA) in FIBP gene was revealed. The resulting indel (p.H59LN) was predicted to change the protein conformation with likely deleterious effect on its function as one of the fibroblast growth factor signaling mediators. In vitro cellular proliferation assay and in situ hypridization in vivo were then performed to understand the pathophysiology of the disease. The patients' skin fibroblasts showed an increased proliferation capacity compared to the controls' explaining the observed overgrowth phenotype. In addition, we detected Fibp expression most notably in the brains of mice embryos suggesting a possible effect on cognitive functions early in development. To date, only one patient has been reported with a homozygous nonsense mutation in FIBP exhibiting an overgrowth syndrome with multiple congenital abnormalities. Taken all together, these findings provide convincing evidence implicating FIBP aberrations in the newly recognized overgrowth syndrome and expand the associated phenotypes to include possible Wilms tumor predisposition. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_004214.5(FIBP):c.175_176insTAA (p.His59delinsLeuAsn)","Chromosome":"11","Start":"65888042","Stop":"65888043","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TTTA","allel_id":248750,"rule_based_match":true,"evidence_text":"c.175_176insTAA","llm_judgment":"PRESENT","evidence":"c.175_176insTAA","abstract_start":794,"abstract_end":809}]}
{"pmid":"27472364","title":"Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan.","abstract":"We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan.","variants":[{"Name":"NM_001162498.3(LPAR6):c.188A>T (p.Asp63Val)","Chromosome":"13","Start":"48412236","Stop":"48412236","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":214140,"rule_based_match":true,"evidence_text":"LPAR6:c.188A>T (p.Asp63Val)","llm_judgment":"PRESENT","evidence":"LPAR6:c.188A>T (p.Asp63Val)","abstract_start":917,"abstract_end":944},{"Name":"NM_006205.3(PDE6H):c.35C>G (p.Ser12Ter)","Chromosome":"12","Start":"14978047","Stop":"14978047","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":45838,"rule_based_match":true,"evidence_text":"PDE6H:c.35C>G (p.Ser12*)","llm_judgment":"PRESENT","evidence":"PDE6H:c.35C>G (p.Ser12*)","abstract_start":463,"abstract_end":487}]}
{"pmid":"28095294","title":"A novel SLC12A1 gene mutation associated with hyperparathyroidism, hypercalcemia, nephrogenic diabetes insipidus, and nephrocalcinosis in four patients.","abstract":"Solute Carrier Family 12 member 1 (SLC12A1) gene encodes the sodium-potassium-chloride co-transporter (NKCC2) at the apical membrane of the thick ascending loop of Henle (TAL). Bartter's syndrome (BS) type I is a rare, autosomal recessive, renal tubular disorder associated with mutation of the SLC12A1 gene. Presenting features include: hypokalemic metabolic alkalosis, hypercalciuria and nephrocalcinosis. The many allelic variants reported present with a spectrum of phenotypes, biochemical abnormalities and clinical severities. However, to date, only two reports have described hyperparathyroidism and hypercalcemia in patients with SLC12A1 gene mutations. We describe 4 patients with 4 novel mutation variants in the SLC12A1 gene (c.735C>G, c.1137del, c.2498-2499del, and c.1833delT) presenting with variable degrees of hyperparathyroidism, hypercalcemia, hypokalemic metabolic alkalosis, nephrocalcinosis, and nephrogenic diabetes insipidus. The link between calcium and parathyroid hormone abnormalities in patients with SLC12A1 mutations is unclear; the cases described suggest an association between primary hyperparathyroidism and loss of function mutation of SLC12A1, which may result in an aberrant threshold of the calcium sensing receptor at the level of the kidney.","variants":[{"Name":"NM_000338.3(SLC12A1):c.1137del (p.Phe380fs)","Chromosome":"15","Start":"48234926","Stop":"48234926","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":380138,"rule_based_match":true,"evidence_text":"c.1137del","llm_judgment":"PRESENT","evidence":"c.1137del","abstract_start":747,"abstract_end":756},{"Name":"NM_000338.3(SLC12A1):c.1833del (p.Phe611fs)","Chromosome":"15","Start":"48251657","Stop":"48251657","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":380142,"rule_based_match":true,"evidence_text":"c.1833delT","llm_judgment":"PRESENT","evidence":"c.1833delT","abstract_start":778,"abstract_end":788}]}
{"pmid":"30231930","title":"Clinical pitfalls in the diagnosis of segmental overgrowth syndromes: a child with the c.2740G > A mutation in PIK3CA gene.","abstract":"BACKGROUND: Overgrowth syndromes are known as a heterogeneous group of conditions characterized by a generalized or segmental, symmetric or asymmetric, overgrowth that may involve several tissues. These disorders, which present a wide range of phenotypic variability, are often caused by mosaic somatic mutations in the genes associated with the PI3K/AKT/mTOR cellular pathway, a signaling cascade that plays a key role in cellular growth. Overgrowth syndromes are frequently misdiagnosed. Given that they are also associated to an increased oncologic risk, it is important to distinguish the clinical characteristic of these disorders since the first months of life.\nCASE PRESENTATION: We report the case of a seven-year-old male child with macrocephaly and right lateralized overgrowth, reported from birth. The patient arrived to our attention after an initial diagnosis of isolated benign macrocephaly was formulated at the age of 12 months. Afterwards, the child presented a moderate intellectual disability and pain episodes at right lower limb. We repeated a brain Magnetic Resonance Imaging that revealed ventriculomegaly, cerebellar tonsillar ectopia, a markedly thick corpus callosum, and white matter abnormalities. The diagnosis of segmental overgrowth syndrome was formulated according to the clinical presentation and confirmed by the finding of the variant c.2740G > A in the gene PIK3CA presented in somatic mosaicism.\nCONCLUSIONS: Our patient is the first children with the c.2740G > A variant in PIK3CA gene reported in Italy. We underline the importance of the genotype-phenotype correlation in the diagnostic process of overgrowth syndromes and emphasize the strict correlation between the mutation c.2740G > A in the PIK3CA gene and the Megalencephaly-Capillary Malformation syndrome phenotype.","variants":[{"Name":"NM_006218.4(PIK3CA):c.2740G>A (p.Gly914Arg)","Chromosome":"3","Start":"179230077","Stop":"179230077","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48302,"rule_based_match":true,"evidence_text":"c.2740G > A","llm_judgment":"PRESENT","evidence":"c.2740G > A","abstract_start":1372,"abstract_end":1383}]}
{"pmid":"38050059","title":"Clinical and functional analysis of the germline","abstract":"<i>TP53</i> plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline <i>TP53</i> p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify <i>TP53</i> p.K164E as a likely pathogenic variant.","variants":[{"Name":"NM_000546.6(TP53):c.490A>G (p.Lys164Glu)","Chromosome":"17","Start":"7675122","Stop":"7675122","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":245075,"rule_based_match":true,"evidence_text":"NM_000546.5: c.490A>G","llm_judgment":"PRESENT","evidence":"NM_000546.5: c.490A>G","abstract_start":397,"abstract_end":418}]}
{"pmid":"19924139","title":"Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities.","abstract":"Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 14 years from undiagnosed cardiomyopathy. The skin showed hyperplasia and acantholysis in the mid- and lower epidermal layers, whereas the heart showed extensive fibrosis and fibrofatty replacement in both ventricles. Immunofluorescence microscopy showed a reduction in the C-terminal domain of DP in the skin and oral mucosa. Sequencing of the DP gene showed undescribed mutations in the maternal and paternal alleles. Both mutations affected exon 24 encoding the C-terminal domain. The paternal mutation, c.6310delA, leads to a premature stop codon. The maternal mutation, c.7964 C to A, results in a substitution of an aspartic acid for a conserved alanine residue at amino acid 2655 (A2655D). Structural modeling indicated that this mutation changes the electrostatic potential of the mutated region of DP, possibly altering functions that depend on intermolecular interactions. To conclude, we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth. This patient case emphasizes the importance of heart examination of patients with desmosomal genodermatoses.","variants":[{"Name":"NM_004415.4(DSP):c.6310del (p.Thr2104fs)","Chromosome":"6","Start":"7583572","Stop":"7583572","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":178567,"rule_based_match":true,"evidence_text":"c.6310delA","llm_judgment":"PRESENT","evidence":"c.6310delA","abstract_start":856,"abstract_end":866}]}
{"pmid":"30787879","title":"Two Novel","abstract":"Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder characterized by a defect in the liver-specific peroxisomal enzyme alanine-glyoxylate and serine-pyruvate aminotransferase (AGT). This disorder results in hyperoxaluria, recurrent urolithiasis, and nephrocalcinosis. Three forms of PH1 have been reported. Data on the infantile form of PH1 are currently limited in literature. Despite the fact that China is the most populated country in the world, only a few <i>AGXT</i> mutations have been reported in several Chinese PH1 patients. In the present study, we investigated a Chinese family in which two siblings are affected by the infantile form of PH1. Sanger sequencing was carried out on the proband, but the results were misleading. Two novel missense mutations (c.517T > C/p.Cys173Arg and c.667A > C/p.Ser223Arg) of the <i>AGXT</i> gene were successfully detected through whole-exome sequencing. These two mutations occurred in the highly conserved residues of the AGT. Four software programs predicted both mutations as the cause of the disease. A postmortem examination was performed and revealed the occurrence of global nephrocalcinosis on both kidneys. The crystals were collected and analyzed as calcium oxalate monohydrate. This study extends the knowledge on the clinical phenotype-genotype correlation of the <i>AGXT</i> mutation. That is, (i) two novel missense mutations were identified for the infantile form of PH1 and (ii) the same <i>AGXT</i> genotype caused the same infantile form of PH1 within the family.","variants":[{"Name":"NM_000030.3(AGXT):c.667A>C (p.Ser223Arg)","Chromosome":"2","Start":"240874049","Stop":"240874049","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2842229,"rule_based_match":true,"evidence_text":"c.667A > C/p.Ser223Arg","llm_judgment":"PRESENT","evidence":"c.667A > C/p.Ser223Arg","abstract_start":807,"abstract_end":829},{"Name":"NM_000030.3(AGXT):c.517T>C (p.Cys173Arg)","Chromosome":"2","Start":"240871442","Stop":"240871442","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1314147,"rule_based_match":true,"evidence_text":"c.517T > C/p.Cys173Arg","llm_judgment":"PRESENT","evidence":"c.517T > C/p.Cys173Arg","abstract_start":780,"abstract_end":802}]}
{"pmid":"27180337","title":"A novel splice site mutation in the GNPTAB gene in an Iranian patient with mucolipidosis II α/β.","abstract":"Mucolipidosis type II α/β (ML II α/β) and mucolipidosis type III α/β (ML III α/β) have been shown to be caused by an absence or reduced level of uridine diphosphate (UDP)-N-acetylglucosamine-1-phosphotransferase enzyme (EC 2.7.8.17) activity, respectively. Both disorders are caused by mutations in the GNPTAB gene and are inherited in an autosomal recessive manner. Here we report a 2-year-old female patient being diagnosed as a case of ML II α/β due to coarse face, severe developmental delay, multiple dysostosis, noticeable increase of multiple lysosomal enzymes activity in plasma and normal acid mucopolysaccharides in urine. Mutational analysis of the GNPTAB gene has revealed a novel homozygous mutation in the patient (c.3250-2A>G) with both parents being heterozygote. Transcript analyses showed that this novel splice site mutation leads to exon 17 skipping and a frameshift afterwards (p.P1084_R1112del F1113Vfs*1). Consequently, we confirmed the association of this mutation with ML II α/β. Our finding expands the number of reported cases of this rare metabolic disorder and adds to the GNPTAB mutation database.","variants":[{"Name":"NM_024312.5(GNPTAB):c.3250-2A>G","Chromosome":"12","Start":"101757659","Stop":"101757659","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":228217,"rule_based_match":true,"evidence_text":"c.3250-2A>G","llm_judgment":"PRESENT","evidence":"c.3250-2A>G","abstract_start":729,"abstract_end":740}]}
{"pmid":"36001086","title":"A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.","abstract":"PURPOSE: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families.\nMETHODS: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9.\nRESULTS: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes.\nCONCLUSION: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration.","variants":[{"Name":"NM_001001683.4(MED11):c.325C>T (p.Arg109Ter)","Chromosome":"17","Start":"4733158","Stop":"4733158","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2477483,"rule_based_match":true,"evidence_text":"MED11 (c.325C>T; p.Arg109Ter)","llm_judgment":"PRESENT","evidence":"MED11 (c.325C>T; p.Arg109Ter)","abstract_start":273,"abstract_end":302}]}
{"pmid":"31061749","title":"Classic Ehlers-Danlos Syndrome in a Son and Father with a Heart Transplant Performed in the Father.","abstract":"We report a 13-year-old male patient with severe orthopedic problems including features of a connective tissue disorder and a heterozygous c.305T > A variant found within exon 3 of the autosomal dominant collagen ( <i>COL5A1</i> ) gene causing the classic Ehlers-Danlos syndrome. This variant has not been reported previously and identified as having an unknown clinical significance but classified as trending damaging per in silico prediction with high conservation among species. Our patient's father had the same gene variant and similar features of stretchable skin, easy bruising, and multiple joint dislocations. The father had unexplained heart failure requiring cardiac transplantation at 43 years of age.","variants":[{"Name":"NM_000093.5(COL5A1):c.305T>A (p.Ile102Asn)","Chromosome":"9","Start":"134699936","Stop":"134699936","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3744538,"rule_based_match":true,"evidence_text":"c.305T > A","llm_judgment":"PRESENT","evidence":"c.305T > A","abstract_start":139,"abstract_end":149}]}
{"pmid":"29678143","title":"Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population.","abstract":"BACKGROUND: DNA damage repair is a complex process, which can trigger the development of cancer if disturbed. In this study, we hypothesize a role of variants in the ATM, H2AFX and MRE11 genes in determining breast cancer (BC) susceptibility.\nMETHODS: We examined the whole sequence of the ATM kinase domain and estimated the frequency of founder mutations in the ATM gene (c.5932G > T, c.6095G > A, and c.7630-2A > C) and single nucleotide polymorphisms (SNPs) in H2AFX (rs643788, rs8551, rs7759, and rs2509049) and MRE11 (rs1061956 and rs2155209) among 315 breast cancer patients and 515 controls. The analysis was performed using high-resolution melting for new variants and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for recurrent ATM mutations. H2AFX and MRE11 polymorphisms were analyzed using TaqMan assays. The cumulative genetic risk scores (CGRS) were calculated using unweighted and weighted approaches.\nRESULTS: We identified four mutations (c.6067G > A, c.8314G > A, c.8187A > T, and c.6095G > A) in the ATM gene in three BC cases and two control subjects. We observed a statistically significant association of H2AFX variants with BC. Risk alleles (the G of rs7759 and the T of rs8551 and rs2509049) were observed more frequently in BC cases compared to the control group, with P values, odds ratios (OR) and 95% confidence intervals (CIs) of 0.0018, 1.47 (1.19 to 1.82); 0.018, 1.33 (1.09 to 1.64); and 0.024, 1.3 (1.06 to 1.59), respectively. Haplotype-based tests identified a significant association of the H2AFX CACT haplotype with BC (P <  0.0001, OR = 27.29, 95% CI 3.56 to 209.5). The risk of BC increased with the growing number of risk alleles. The OR (95% CI) for carriers of ≥ four risk alleles was 1.71 (1.11 to 2.62) for the CGRS.\nCONCLUSIONS: This study confirms that H2AFX variants are associated with an increased risk of BC. The above-reported sequence variants of MRE11 genes may not constitute a risk factor of breast cancer in the Polish population. The contribution of mutations detected in the ATM gene to the development of breast cancer needs further detailed study.","variants":[{"Name":"NM_000051.4(ATM):c.8187A>T (p.Gln2729His)","Chromosome":"11","Start":"108335880","Stop":"108335880","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":180513,"rule_based_match":true,"evidence_text":"c.8187A > T","llm_judgment":"PRESENT","evidence":"c.8187A > T","abstract_start":1026,"abstract_end":1037},{"Name":"NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys)","Chromosome":"11","Start":"108315911","Stop":"108315911","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":180483,"rule_based_match":true,"evidence_text":"c.6095G>A","llm_judgment":"PRESENT","evidence":"c.6095G > A","abstract_start":387,"abstract_end":398},{"Name":"NM_000051.4(ATM):c.6067G>A (p.Gly2023Arg)","Chromosome":"11","Start":"108315883","Stop":"108315883","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132873,"rule_based_match":true,"evidence_text":"c.6067G > A","llm_judgment":"PRESENT","evidence":"c.6067G > A","abstract_start":1000,"abstract_end":1011},{"Name":"NM_000051.4(ATM):c.8314G>A (p.Gly2772Arg)","Chromosome":"11","Start":"108343267","Stop":"108343267","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":408242,"rule_based_match":true,"evidence_text":"c.8314G > A","llm_judgment":"PRESENT","evidence":"c.8314G > A","abstract_start":1013,"abstract_end":1024}]}
{"pmid":"23028790","title":"Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants.","abstract":"Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (OMIM 201450) is the most common inherited disorder of fatty acid metabolism presenting with hypoglycaemia, hepatopathy and Reye-like symptoms during catabolism. In the past, the majority of patients carried the prevalent c.985A>G mutation in the ACADM gene. Since the introduction of newborn screening many other mutations with unknown clinical relevance have been identified in asymptomatic newborns. In order to identify functional effects of these mutant genotypes we correlated residual MCAD (OMIM 607008) activities as measured by octanoyl-CoA oxidation in lymphocytes with both genotype and relevant medical reports in 65 newborns harbouring mutant alleles. We identified true disease-causing mutations with residual activities of 0 to 20%. In individuals carrying the c.199T>C or c.127G>A mutation on one allele, residual activities were much higher and in the range of heterozygotes (31%-60%). Therefore, both mutations cannot clearly be associated with a clinical phenotype. This demonstrates a correlation between the octanoyl-CoA oxidation rate in lymphocytes and the clinical outcome. With newborn screening, the natural course of disease is difficult to assess. The octanoyl-CoA oxidation rate, therefore, allows a risk assessment at birth and the identification of new ACADM genotypes associated with asymptomatic disease variants.","variants":[{"Name":"NM_000016.6(ACADM):c.985A>G (p.Lys329Glu)","Chromosome":"1","Start":"75761161","Stop":"75761161","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18625,"rule_based_match":true,"evidence_text":"c.985A>G","llm_judgment":"PRESENT","evidence":"c.985A>G","abstract_start":276,"abstract_end":284}]}
{"pmid":"29472286","title":"A novel de novo","abstract":"Mutations that activate the protease calpain-5 (<i>CAPN5)</i> cause a nonsyndromic adult-onset autoinflammatory eye disease characterized by uveitis, altered synaptic signaling, retinal degeneration, neovascularization, and intraocular fibrosis. We describe a pediatric patient with severe inflammatory vitreoretinopathy accompanied by hearing loss and developmental delay associated with a novel, de novo <i>CAPN5</i> missense mutation (c.865C>T, p.Arg289Trp) that shows greater hyperactivation of the calpain protease, indicating a genotype-phenotype correlation that links mutation severity to proteolytic activity and the possibility of earlier onset syndromic disease with auditory and neurological abnormalities.","variants":[{"Name":"NM_004055.5(CAPN5):c.865C>T (p.Arg289Trp)","Chromosome":"11","Start":"77115560","Stop":"77115560","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":264453,"rule_based_match":true,"evidence_text":"c.865C>T, p.Arg289Trp","llm_judgment":"PRESENT","evidence":"c.865C>T, p.Arg289Trp","abstract_start":438,"abstract_end":459}]}
{"pmid":"23255472","title":"Novel XPG (ERCC5) mutations affect DNA repair and cell survival after ultraviolet but not oxidative stress.","abstract":"Nucleotide excision repair (NER) is the most flexible of all known DNA-repair mechanisms, and XPG is a 3'-endonuclease that participates in NER. Mutations in this gene (ERCC5) may result in the human syndrome xeroderma pigmentosum (XP) and, in some cases, in the complex phenotype of Cockayne syndrome (CS). Two Brazilian XP siblings, who were mildly affected, were investigated and classified into the XP-G group. The cells from these patients were highly ultraviolet (UV) sensitive but not sensitive to photosensitized methylene blue, an agent that causes oxidative stress. This phenotype is in contrast to XP-G/CS cells, which are highly sensitive to this oxidative agent. Sequencing revealed a compound heterozygous genotype with two novel missense mutations: c.83C>A (p.Ala28Asp) and c.2904G>C (p.Trp968Cys). The first mutation maps to the catalytic site of the XPG protein, whereas the second may compromise binding to DNA. Functional assays indicated that the mutated alleles were unable to perform the complete repair of UV-irradiated plasmids; however, full correction was observed for oxidatively damaged plasmids. Therefore, the XP phenotype of these patients is caused by novel missense mutations that specifically affect DNA repair for UV- but not oxidative-stress-induced DNA damage, and implications for XP versus XP/CS phenotype are discussed.","variants":[{"Name":"NM_000123.4(ERCC5):c.83C>A (p.Ala28Asp)","Chromosome":"13","Start":"102846349","Stop":"102846349","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":49931,"rule_based_match":true,"evidence_text":"c.83C>A (p.Ala28Asp)","llm_judgment":"PRESENT","evidence":"c.83C>A (p.Ala28Asp)","abstract_start":764,"abstract_end":784},{"Name":"NM_000123.4(ERCC5):c.2904G>C (p.Trp968Cys)","Chromosome":"13","Start":"102873283","Stop":"102873283","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":49932,"rule_based_match":true,"evidence_text":"c.2904G>C (p.Trp968Cys)","llm_judgment":"PRESENT","evidence":"c.2904G>C (p.Trp968Cys)","abstract_start":789,"abstract_end":812}]}
{"pmid":"31556760","title":"Retinal dystrophy associated with a Kizuna (","abstract":"<b>Introduction</b>: Mutations in Kizuna (<i>KIZ)</i>, a gene involved in ciliary function, have been previously associated with rod-cone dystrophy with relative macular sparing and a number of other systemic abnormalities.<b>Purpose</b>: We present a patient with a phenotype dominated by retinal dystrophy and macular cysts as a result of a homozygous nonsense mutation in <i>KIZ.</i><b>Methods</b>: A 32-year-old female of Ashkenazi Jewish ancestry presented with progressive central vision loss and peripheral visual field loss following decades of night-blindness. She was noted to have a bull's-eye pattern of macular hyper-autofluorescence, intraretinal cystoid macular changes and outer retinal atrophy in both eyes. Visual fields were constricted to <10 degrees centrally with inferior preserved islands of vision. Genetic testing revealed a homozygous <i>KIZ</i> c.226 C > T (p.Arg76*) nonsense mutation. The patient was treated with topical dorzolamide and showed significant improvement in the degree of macular cysts.<b>Conclusion</b>: Mutations in <i>KIZ</i> can present with a predominantly macular phenotype and develop cystoid macular changes responsive to carbonic anhydrase inhibitor treatment. Because of the importance of KIZ in cilia function, it is critical to look for associated systemic manifestations to ensure best patient care.","variants":[{"Name":"NM_018474.6(KIZ):c.226C>T (p.Arg76Ter)","Chromosome":"20","Start":"21136463","Stop":"21136463","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":133696,"rule_based_match":true,"evidence_text":"homozygous KIZ c.226 C > T (p.Arg76*) nonsense mutation","llm_judgment":"PRESENT","evidence":"homozygous <i>KIZ</i> c.226 C > T (p.Arg76*) nonsense mutation","abstract_start":851,"abstract_end":913}]}
{"pmid":"28730136","title":"Early Diagnosis of","abstract":"PURPOSE: The goal of this study was the early diagnosis of <i>ABCB11</i> spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis.\nMETHODS: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or <i>ABCB11</i> spectrum liver disorders. Two families with proven <i>ABCB11</i> spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members.\nRESULTS: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of <i>ABCB11</i> c.11C>G (p.Ser4<sup>*</sup>) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of <i>ABCB11</i> c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of <i>ABCB11</i> spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis.\nCONCLUSION: <i>ABCB11</i> spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.","variants":[{"Name":"NM_003742.4(ABCB11):c.1543A>G (p.Asn515Asp)","Chromosome":"2","Start":"168971942","Stop":"168971942","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2898657,"rule_based_match":true,"evidence_text":"c.1543A>G (p.Asn515Asp)","llm_judgment":"PRESENT","evidence":"c.1543A>G (p.Asn515Asp)","abstract_start":1153,"abstract_end":1176}]}
{"pmid":"33216760","title":"No association between SCN9A and monogenic human epilepsy disorders.","abstract":"Many studies have demonstrated the clinical utility and importance of epilepsy gene panel testing to confirm the specific aetiology of disease, enable appropriate therapeutic interventions, and inform accurate family counselling. Previously, SCN9A gene variants, in particular a c.1921A>T p.(Asn641Tyr) substitution, have been identified as a likely autosomal dominant cause of febrile seizures/febrile seizures plus and other monogenic seizure phenotypes indistinguishable from those associated with SCN1A, leading to inclusion of SCN9A on epilepsy gene testing panels. Here we present serendipitous findings of genetic studies that identify the SCN9A c.1921A>T p.(Asn641Tyr) variant at high frequency in the Amish community in the absence of such seizure phenotypes. Together with findings in UK Biobank these data refute an association of SCN9A with epilepsy, which has important clinical diagnostic implications.","variants":[{"Name":"NM_001365536.1(SCN9A):c.1921A>T (p.Asn641Tyr)","Chromosome":"2","Start":"166284506","Stop":"166284506","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":21405,"rule_based_match":true,"evidence_text":"c.1921A>T p.(Asn641Tyr)","llm_judgment":"PRESENT","evidence":"c.1921A>T p.(Asn641Tyr)","abstract_start":279,"abstract_end":302}]}
{"pmid":"34977057","title":"Mosaic","abstract":"Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal cystic disease caused mainly by the polycystic kidney and hepatic disease 1 (<i>PKHD1)</i>. However, the genetic cause, pathologic features, and mechanism of action of ARPKD are not well known. Here, we identified a family with ARPKD. Two siblings harbored biallelic variants in <i>PKHD1</i> (c.7205G>A, c.7973T>A). We determined that the \"<i>de novo</i>\" variant, c.7205G>A, arose from the mosaicism of the father and had a 7.4% level. Pathologic characterization, using biopsy analysis, was evidenced with predominant cystic dilation in proximal tubules, slight ectasia of collecting ducts, defective ciliogenesis, and impaired cell-cell junctions in renal tubules and collecting ducts. Exosome proteomics in the urine from patients with ARPKD were markedly different from those of controls, with the most significant alterations occurring in mitochondrial and lysosomal proteins. Expression of the proteins of OXPHOS was downregulated sharply, in parallel with upregulated expression of the proteins involved in glycolysis in patients with ARPKD. Several lysosomal proteins associated with renal lesions were more abundant in the exosome of the patient than in controls. Moreover, the lysosomal enzyme sulfamidase, which is produced by the <i>SGSH</i> gene, was abrupt uniquely in the exosome of the patient. Consistently, swollen mitochondria and abundant lysosomes were visualized in the mutant tubular epithelial cells of patients with mutant <i>PKHD1</i>. Collectively, these findings provide new insights on the pathophysiology of the polycystic kidney due to PKHD1 deficiency. <i>PKHD1</i> mosaicism should be considered in genetic testing of ARPKD patients.","variants":[{"Name":"NM_138694.4(PKHD1):c.7205G>A (p.Gly2402Asp)","Chromosome":"6","Start":"51885877","Stop":"51885877","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2671060,"rule_based_match":true,"evidence_text":"c.7205G>A","llm_judgment":"PRESENT","evidence":"c.7205G>A","abstract_start":365,"abstract_end":374}]}
{"pmid":"21690267","title":"Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism.","abstract":"Activating mutations of RET, a gene encoding two isoforms of a tyrosine kinase receptor physiologically expressed in several neural crest-derived cell lineages, are associated with the inherited forms of medullary thyroid carcinoma (MTC). The identification and characterization of novel RET mutations involved in MTC is valuable, as RET gene testing plays a crucial role in the management of these patients. In an MTC patient, we have identified a germline c.1996A>G transition in heterozygosis leading to K666E substitution. In addition, the conservative S904S (c.2712C>G) and the non-conservative functional G691S (c.2071G>A) polymorphisms have been identified. Through functional studies, we demonstrate for the first time that K666E is a gain-of-function mutation with oncogenic potential, based on its ability to transform NIH3T3 cells. It was not possible to define whether K666E is a de novo or inherited RET variant in the patient, as the family history was negative for MTC, and the carrier status of family members could not be tested. Our results, together with a recent report of co-segregation of the mutation in three MTC families, suggest that K666E is a causative MTC mutation. As we have shown that the same patient allele carries both K666E and G691S variants, the latter known to increase downstream RET signaling, a possible role for the G691S polymorphism has also been investigated. We have demonstrated that, although RET-G691S is not oncogenic per se, it enhances the transforming activity of the RET-K666E mutant, thus suggesting a modifier role for this functional polymorphism.","variants":[{"Name":"NM_020975.6(RET):c.1996A>G (p.Lys666Glu)","Chromosome":"10","Start":"43114596","Stop":"43114596","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":36272,"rule_based_match":true,"evidence_text":"c.1996A>G","llm_judgment":"PRESENT","evidence":"c.1996A>G","abstract_start":458,"abstract_end":467}]}
{"pmid":"25599739","title":"Cystinuria in a patient with a novel mutation in SLC7A9 gene.","abstract":"Cystinuria, one of the first inborn errors of metabolism, is characterized by hyperexcretion of cystine, arginine, lysine, and ornithine into urine. Cystinuria is genetically classified into types A and B. Mutations in the SLC3A1 gene lead to type A, and type B is caused by mutations in the SLC7A9 gene. We described a 19-year-old woman that had early onset of cystine calculus formation at the age of 3 years. After DNA extraction and polymerase chain reaction, direct sequencing was performed. By these methods, a novel nucleotide substitution c.177G>A in exon 3 of the SLC7A9 gene was found, which had not been reported elsewhere previously. This nucleotide substitution occurs in the extracellular domain of the SLC7A9 gene. In addition, a previously described intron variant c.1136+2/3delT (intron 6 of SLC3A1) in homozygosity status was detected in the patient. To our knowledge, this is the first report of novel nucleotide substitution c.177G>A in exon 3 of the SLC7A9 gene.","variants":[{"Name":"NM_014270.5(SLC7A9):c.177G>A (p.Thr59=)","Chromosome":"19","Start":"32864687","Stop":"32864687","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":880269,"rule_based_match":true,"evidence_text":"c.177G>A","llm_judgment":"PRESENT","evidence":"c.177G>A","abstract_start":547,"abstract_end":555}]}
{"pmid":"34863162","title":"Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report.","abstract":"BACKGROUND: Autosomal recessive limb-girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis.\nCASE PRESENTATION: In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband's cDNA sample. The results revealed that this splicing variant disrupts the original 3' splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)).\nCONCLUSIONS: Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease.","variants":[{"Name":"NM_000070.3(CAPN3):c.1746-20C>G","Chromosome":"15","Start":"42403721","Stop":"42403721","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":98319,"rule_based_match":true,"evidence_text":"NG_008660.1(NM_000070.3):c.1746-20C > G","llm_judgment":"PRESENT","evidence":"NG_008660.1(NM_000070.3):c.1746-20C > G","abstract_start":385,"abstract_end":424}]}
{"pmid":"27861123","title":"TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT.","abstract":"Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL Analysis of intracellular calcium ([Ca<sup>2+</sup>]<sub>i</sub>) dynamics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from this individual (TECRL<sub>H</sub><sub>om</sub>-hiPSCs), his heterozygous but clinically asymptomatic father (TECRL<sub>H</sub><sub>et</sub>-hiPSCs), and a healthy individual (CTRL-hiPSCs) from the same Sudanese family, revealed smaller [Ca<sup>2+</sup>]<sub>i</sub> transient amplitudes as well as elevated diastolic [Ca<sup>2+</sup>]<sub>i</sub> in TECRL<sub>H</sub><sub>om</sub>-hiPSC-CMs compared with CTRL-hiPSC-CMs. The [Ca<sup>2+</sup>]<sub>i</sub> transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca<sup>2+</sup>]<sub>i</sub> transients. In addition, the decay phase of the [Ca<sup>2+</sup>]<sub>i</sub> transient was slower in TECRL<sub>H</sub><sub>om</sub>-hiPSC-CMs due to decreased SERCA and NCX activities. Furthermore, TECRL<sub>H</sub><sub>om</sub>-hiPSC-CMs showed prolonged action potentials (APs) compared with CTRL-hiPSC-CMs. TECRL knockdown in control human embryonic stem cell-derived CMs (hESC-CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRL<sub>H</sub><sub>om</sub>-hiPSC-CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT Patient-specific hiPSC-CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.","variants":[{"Name":"NM_001010874.5(TECRL):c.331+1G>A","Chromosome":"4","Start":"64328511","Stop":"64328511","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359191,"rule_based_match":true,"evidence_text":"c.331+1G>A","llm_judgment":"PRESENT","evidence":"c.331+1G>A","abstract_start":728,"abstract_end":738},{"Name":"NM_001010874.5(TECRL):c.587G>A (p.Arg196Gln)","Chromosome":"4","Start":"64309896","Stop":"64309896","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359192,"rule_based_match":false,"evidence_text":"p.Arg196Gln","llm_judgment":"PRESENT","evidence":"p.Arg196Gln","abstract_start":351,"abstract_end":362}]}
{"pmid":"26733286","title":"Distal acroosteolysis, poikiloderma and joint stiffness: a novel laminopathy?","abstract":"LMNA encodes lamin A and lamin C, two major components of the nuclear lamina, and its pathogenic variants lead to a dozen distinct clinical entities collectively known as laminopathies. Most LMNA-related laminopathies are autosomal dominant but four are autosomal recessive; furthermore, some of the dominant variants have been associated with distinct phenotypes when inherited recessively, further complicating the ability to correlate genotype with phenotype. We report a consanguineous family in which the index presented with an apparently unique constellation of poikiloderma, joint motion restriction and distal acroosteolysis but lacks features of muscle weakness, lipodystrophy, or cardiac or craniofacial involvement. Molecular analysis revealed the presence of a novel homozygous LMNA missense variant (NM_170707.3:c.1774G>A; p.(Gly592Arg)) within an area of autozygome that is not shared by his unaffected siblings. The proposed causal link is further supported by in silico analysis of this variant. Our case suggests an expansion of LMNA allelic disorders to include distal acroosteolysis, poikiloderma and joint stiffness (DAPJ).","variants":[{"Name":"NM_170707.4(LMNA):c.1774G>A (p.Gly592Arg)","Chromosome":"1","Start":"156138563","Stop":"156138563","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188793,"rule_based_match":true,"evidence_text":"NM_170707.3:c.1774G>A; p.(Gly592Arg)","llm_judgment":"PRESENT","evidence":"NM_170707.3:c.1774G>A; p.(Gly592Arg)","abstract_start":814,"abstract_end":850}]}
{"pmid":"27168869","title":"An unusual case of Cowden syndrome associated with ganglioneuromatous polyposis.","abstract":"BACKGROUND: Ganglioneuromatous polyposis (GP) is a very rare disorder which may be associated with other clinical manifestations and syndromes, such as Cowden syndrome, multiple endocrine neoplasia (MEN) type II and neurofibromatosis (NF) 1. The risk for malignant transformation of ganglioneuromas is unknown, and the combination of GP with colon cancer has been only very seldom reported.\nMETHODS AND RESULTS: We report the case of a 60-year old male patient with adenocarcinoma, adenomas and lipomas of the colon and multiple gastroduodenal lesions combined with generalised lipomatosis and macrocephaly. Based on the initial endoscopic and histological findings, a (restorative) proctocolectomy was recommended but declined by the patient. Instead, a colectomy was performed. The histological examination revealed an unforeseen GP in addition to the colon cancer. Extensive molecular diagnostics allowed for the differential diagnosis of the causes of the clinical manifestations, and the clinical suspicion of Cowden syndrome could not be confirmed using Sanger Sequencing and MLPA for the analysis of PTEN. Finally, a pathogenic germline mutation in PTEN (heterozygous stop mutation in exon 2: NM_000314 (PTEN):c.138C > A; p.Tyr46*) could be detected by next-generation sequencing (NGS), confirming an unusual presentation of Cowden syndrome with GP.\nCONCLUSIONS: Cowden syndrome should be considered in cases of GP with extracolonic manifestation and verified by combined clinical and molecular diagnostics. Because GP may represent a premalignant condition, a surgical-oncological prophylactic procedure should be considered. Based on our experience, we recommend early implementation of Panel NGS rather than classical Sanger sequencing for genetic diagnostics, especially if various diagnoses are considered.","variants":[{"Name":"NM_000314.8(PTEN):c.138C>A (p.Tyr46Ter)","Chromosome":"10","Start":"87894083","Stop":"87894083","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":419700,"rule_based_match":true,"evidence_text":"NM_000314 (PTEN):c.138C > A; p.Tyr46*","llm_judgment":"PRESENT","evidence":"NM_000314 (PTEN):c.138C > A; p.Tyr46*","abstract_start":1200,"abstract_end":1237}]}
{"pmid":"29454663","title":"Novel PLA2G6 mutations and clinical heterogeneity in Chinese cases with phospholipase A2-associated neurodegeneration.","abstract":"INTRODUCTION: Phospholipase A2-associated neurodegeneration (PLAN) is an autosomal recessive movement disorder with abnormal iron deposition in basal ganglia, substantial nigra and adjacent areas, and cerebellar atrophy. It is caused by PLA2G6 mutations and comprises three phenotypes. We aimed to investigate genetic mutations in patients with predominantly extrapyramidal symptoms.\nMETHODS: Eighteen Chinese patients with early onset of extrapyramidal symptoms were identified and underwent targeted next-generation sequencing, followed by Sanger sequencing. Detailed clinical and radiological features are presented. Prediction software was used to evaluate the pathogenicity of the identified variants.\nRESULTS: We identified 7 PLA2G6 variants including five known variants (c.668C > T, c.991G > T, c.1117G > A, c.1982C > T, and c.2218G > A) and two novel variants (c.1511C > T, and c.1915G > A) in four index cases. Among them, three cases had initial symptoms of difficulty walking or gait disturbance around the age of 30, and one case and his sibling developed mental handicap at age 7. Two cases exhibited a phenotype of \"early parkinsonism\" and the other two cases mimicked a phenotype of \"hereditary spastic paraplegia (HSP)\". Iron deposition in globus pallidus and substantia nigra was seen in three cases. Cerebellar atrophy was present in all four cases.\nCONCLUSIONS: Our study expands the mutation spectrum of the PLA2G6 gene and further supports the hypothesis that PLA2G6 mutations are associated with a continuous clinical spectrum from PLAN to HSP.","variants":[{"Name":"NM_003560.4(PLA2G6):c.1511C>T (p.Ser504Leu)","Chromosome":"22","Start":"38123175","Stop":"38123175","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1779896,"rule_based_match":true,"evidence_text":"c.1511C > T","llm_judgment":"PRESENT","evidence":"c.1511C > T","abstract_start":870,"abstract_end":881},{"Name":"NM_003560.4(PLA2G6):c.668C>T (p.Pro223Leu)","Chromosome":"22","Start":"38140111","Stop":"38140111","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1693830,"rule_based_match":true,"evidence_text":"c.668C > T","llm_judgment":"PRESENT","evidence":"c.668C > T","abstract_start":779,"abstract_end":789},{"Name":"NM_003560.4(PLA2G6):c.1117G>A (p.Gly373Arg)","Chromosome":"22","Start":"38129523","Stop":"38129523","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":169799,"rule_based_match":true,"evidence_text":"c.1117G > A","llm_judgment":"PRESENT","evidence":"c.1117G > A","abstract_start":803,"abstract_end":814}]}
{"pmid":"28831785","title":"Clinical, Pathologic, and Genetic Features of Collagen VI-Related Myopathy in Korea.","abstract":"BACKGROUND AND PURPOSE: Mutations in collagen VI-related genes (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). These were previously believed to be separate disease entities, but they are now both classified as collagen VI-related myopathies, which cover a broad clinical spectrum. We aimed to analyze the clinical, pathologic, and genetic characteristics of patients with collagen VI-related myopathy in Korea.\nMETHODS: We reviewed the clinical, pathologic, and genetic features in 22 patients with collagen VI-related myopathy from 13 families, as confirmed by genetic analysis of collagen VI-related genes.\nRESULTS: The mean ages of the 22 patients at first symptom presentation and diagnosis were 4.5 and 24.9 years, respectively. Four patients in 4 families showed the phenotype of intermediate collagen VI-related myopathies (IM), 16 patients in 7 families had the BM phenotype, and 2 patients in 2 families presented with the typical UCMD phenotype. Based on genetic analysis, five patients (five families) comprising four with IM and one with typical UCMD had missense mutations in the triple-helical domain of COL6A1, and ten patients (four families) with BM showed exon-14-skipping mutations. Additionally, we found two novel mutations: c.956A>G (p.K319R) in COL6A1 and c.6221G>T (p.G2074V) in COL6A3.\nCONCLUSIONS: Missense mutations in the triple-helical domain of COL6A1 are the most common mutations related to collagen VI-related myopathy in Korea. Patients with these mutations have a tendency toward an earlier disease onset and more severe progression compared to patients with other mutations.","variants":[{"Name":"NM_001848.3(COL6A1):c.956A>G (p.Lys319Arg)","Chromosome":"21","Start":"45990283","Stop":"45990283","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":191202,"rule_based_match":true,"evidence_text":"c.956A>G (p.K319R)","llm_judgment":"PRESENT","evidence":"c.956A>G (p.K319R)","abstract_start":1306,"abstract_end":1324}]}
{"pmid":"35651951","title":"Novel Missense and Splice Site Mutations in","abstract":"The purpose of this study was to expand the mutation spectrum by searching the causative mutations in nine Lebanese families with Usher syndrome (USH) using whole-exome sequencing. The pathogenicity of candidate mutations was first evaluated according to their frequency, conservation, and <i>in silico</i> prediction tools. Then, it was confirmed <i>via</i> Sanger sequencing, followed by segregation analysis. Finally, a meta-analysis was conducted to calculate the prevalence of USH genes in the Lebanese population. Three missense mutations, two splice site mutations, and one insertion/deletion were detected in eight of the families. Four of these variants were novel: c.5535C > A; p.(Asn1845Lys) in exon 41 of <i>CDH23</i>, c.7130G > A; p.(Arg2377Gln) in exon 32 of <i>ADGRV1</i>, c.11390-1G > A in <i>USH2A</i>, and c.3999-6A > G in <i>PCDH15</i>. All the identified mutations were shown to be likely disease-causing through our bioinformatics analysis and co-segregated with the USH phenotype. The mutations were classified according to the ACMG standards. Finally, our meta-analysis showed that the mutations in <i>ADGRV1</i>, <i>USH2A</i>, and <i>CLRN1</i> are the most prevalent and responsible for approximately 75% of USH cases in Lebanon. Of note, the frequency USH type 3 showed a relatively high incidence (23%) compared to the worldwide prevalence, which is around 2-4%. In conclusion, our study has broadened the mutational spectrum of USH and showed a high heterogeneity of this disease in the Lebanese population.","variants":[{"Name":"NM_206933.4(USH2A):c.11390-1G>A","Chromosome":"1","Start":"215743336","Stop":"215743336","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1054794,"rule_based_match":true,"evidence_text":"c.11390-1G > A","llm_judgment":"PRESENT","evidence":"c.11390-1G > A","abstract_start":788,"abstract_end":802}]}
{"pmid":"33833410","title":"Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain.","abstract":"PURPOSE: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).\nMETHODS: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.\nRESULTS: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.\nCONCLUSION: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.","variants":[{"Name":"NM_001164760.2(PRKAR1B):c.1003C>T (p.Arg335Trp)","Chromosome":"7","Start":"550573","Stop":"550573","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1161645,"rule_based_match":true,"evidence_text":"c.1003C>T (p.Arg335Trp; NM_001164760)","llm_judgment":"PRESENT","evidence":"c.1003C>T (p.Arg335Trp; NM_001164760)","abstract_start":912,"abstract_end":949}]}
{"pmid":"24473461","title":"Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.","abstract":"Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for ∼80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.","variants":[{"Name":"NM_015915.5(ATL1):c.353G>A (p.Arg118Gln)","Chromosome":"14","Start":"50591011","Stop":"50591011","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":167412,"rule_based_match":true,"evidence_text":"c.353G>A, p.(Arg118Gln)","llm_judgment":"PRESENT","evidence":"c.353G>A, p.(Arg118Gln)","abstract_start":573,"abstract_end":596}]}
{"pmid":"29021971","title":"Evaluation of relative quantification of alternatively spliced transcripts using droplet digital PCR.","abstract":"INTRODUCTION: For the relative quantification of isoform expression, RT-qPCR has been the gold standard for over a decade. More recently, digital PCR is becoming widely implemented, as it is promised to be more accurate, sensitive and less affected by inhibitors, without the need for standard curves. In this study we evaluated RT-qPCR versus RT-droplet digital PCR (ddPCR) for the relative quantification of isoforms in controls and carriers of the splice site mutation <i>BRCA1</i> c.212+3A>G, associated with increased expression of several isoforms.\nMATERIALS AND METHODS: RNA was extracted from EBV cell lines of controls and heterozygous <i>BRCA1</i> c.212+3A>G carriers. Transcript-specific plasmids were available to determine the efficiency, precision, reproducibility and accuracy of each method.\nRESULTS: Both ddPCR and RT-qPCR were able to accurately quantify all targets and showed the same LOB, LOD and LOQ; also precision and reproducibility were similar. Both techniques have the same dynamic range and linearity at biologically relevant template concentrations. However, a significantly higher cost and workload was required for ddPCR experiments.\nCONCLUSIONS: Our study recognizes the potential and validity of digital PCR but shows the value of a highly optimized qPCR for the relative quantification of isoforms. Cost efficiency and simplicity turned out to be better for RT-qPCR.","variants":[{"Name":"NM_007294.4(BRCA1):c.212+3A>G","Chromosome":"17","Start":"43106453","Stop":"43106453","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":69134,"rule_based_match":true,"evidence_text":"c.212+3A>G","llm_judgment":"PRESENT","evidence":"c.212+3A>G","abstract_start":485,"abstract_end":495}]}
{"pmid":"31068150","title":"UMOD gene mutations in Chinese patients with autosomal dominant tubulointerstitial kidney disease: a pediatric case report and literature review.","abstract":"BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by UMOD gene mutation (ADTKD-UMOD) is rare in children, characterized by hyperuricemia, gout, and progressive chronic kidney disease. It usually leads to end-stage renal failure at fiftieth decades. Here, we report a 3-year-old Chinese boy in an ADTKD family caused by a novel UMOD gene mutation.\nCASE PRESENTATION: A 3-year-old boy was admitted to our hospital because of persistent hematuria. Urinalysis showed BLD 2+ without proteinuria. The serum levels of uric acid, creatinine and electrolytes were normal. No renal cyst or calculus was found by ultrasonography. Renal biopsy was performed and focal and segmental glomerulosclerosis was found in 4 glomeruli among 35 glomeruli examined. His father was found with end-stage renal disease (ESRD) at the age of 29, and renal ultrasound showed several cysts in both kidneys. A novel heterozygous mutation (c.1648G > A,p.V550I) in exon 8 of UMOD gene was identified by whole exome sequencing in the family. SCBC Genome Browser alignment showed that V550 were highly conserved in uromodulin among different species. Software predicted that the mutation is suspected to be harmful. By literature review, there are 12 mutations of UMOD gene in 14 Chinese families including only one pediatric case(a 16-year-old girl).\nCONCLUSIONS: A novel heterozygous mutation (c.1648G > A,p.V550I) in exon 8 of UMOD gene was found in in a Chinese child case with ADTKD-UMOD, which extends our understanding of UMOD gene mutation spectrum and phenotype of ADTKD-UMOD in children.","variants":[{"Name":"NM_003361.4(UMOD):c.1648G>A (p.Val550Ile)","Chromosome":"16","Start":"20337383","Stop":"20337383","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75408,"rule_based_match":true,"evidence_text":"c.1648G > A,p.V550I","llm_judgment":"PRESENT","evidence":"c.1648G > A,p.V550I","abstract_start":938,"abstract_end":957}]}
{"pmid":"29242796","title":"Bilateral Femoral Neck Fractures in Cerebrotendinous Xanthomatosis Treated by Hip Arthroplasties: The First Case Report and Literature Review.","abstract":"INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by mutations of the CYP27A1 gene and deficiency of the sterol-27-hydroxylase enzyme in bile acid biosynthesis. It is characterized by the accumulation of cholestanol and bile alcohols in plasma, the formation of xanthomatous lesions in various tissues, and organ degeneration. This disorder is also associated with osteoporosis and increased risk of fracture. To date, only two CTX patients with femoral neck fractures have been reported. Neither was treated by arthroplasties, and the operative outcomes are lacking.\nCASE REPORT: We report the case of a 46-year-old Thai female who presented with consecutive bilateral femoral neck fractures following minor trauma within a 3-year period and received cementless bipolar hemiarthroplasties. Her phenotypic expression included Achilles tendon masses, childhood-onset cataracts, intellectual disability, and cerebellar ataxia. A brain computed tomography showed non-enhancing hypodense lesions in the bilateral cerebellar hemispheres with mild brain atrophy. Histopathology from an Achilles tendon biopsy revealed tendinous xanthoma and molecular analysis confirmed a homozygous nonsense mutation, c.1072C>T (p.Gln358Ter), in exon 6 of the CYP27A1 gene. The intra-operative crack of a calcar femorale was a major complication during both prosthetic insertion surgeries and warranted cerclage wiring. At the 7-month follow-up of the right hip and the 41-month follow-up of the left hip, postoperative radiographs showed well-fixed and well-aligned prostheses. Independent household ambulation could be resumed with Harris hip scores of 81 points equally.\nCONCLUSION: CTX is associated with osteoporosis, and middle-aged patients could present with femoral neck fracture following minor trauma. Cementless bipolar hemiarthroplasty for a totally displaced fracture is justified for a patient who has cognitive impairment. Intra-operative fracture is a major complication during prosthetic insertion and warrants cerclage wiring to achieve predictable bone healing and a satisfactory result.","variants":[{"Name":"NM_000784.4(CYP27A1):c.1072C>T (p.Gln358Ter)","Chromosome":"2","Start":"218814075","Stop":"218814075","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":541940,"rule_based_match":true,"evidence_text":"c.1072C>T (p.Gln358Ter)","llm_judgment":"PRESENT","evidence":"c.1072C>T (p.Gln358Ter)","abstract_start":1256,"abstract_end":1279}]}
{"pmid":"30155607","title":"Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study.","abstract":"Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.","variants":[{"Name":"NM_000152.5(GAA):c.655G>A (p.Gly219Arg)","Chromosome":"17","Start":"80105857","Stop":"80105857","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186993,"rule_based_match":true,"evidence_text":"c.655G>A (p.Gly219Arg)","llm_judgment":"PRESENT","evidence":"c.655G>A (p.Gly219Arg)","abstract_start":1211,"abstract_end":1233},{"Name":"NM_000152.5(GAA):c.1927G>A (p.Gly643Arg)","Chromosome":"17","Start":"80112914","Stop":"80112914","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19062,"rule_based_match":true,"evidence_text":"c.1927G>A (p.Gly643Arg)","llm_judgment":"PRESENT","evidence":"c.1927G>A (p.Gly643Arg)","abstract_start":1183,"abstract_end":1206}]}
{"pmid":"19306278","title":"Monozygotic female twins discordant for phenotype of Wilson's disease.","abstract":"Wilson's disease (WD) is an autosomal recessive disorder characterized by the functional disruption of the copper-transporting protein adenosine triphosphatase 7B (ATP-ase 7B). The disease is caused by mutations in ATP7B gene. It seems that the type of mutation in ATP7B only to some degree determines phenotypic manifestation of WD. We examined two pairs of monozygotic twins discordant for WD phenotype. The first set of twins were ATP7B compound heterozygotes c.3207C>A (p.H1069Q)/c.1211_1212insA (p.N404Kfs). The index case developed severe liver failure followed by depressive symptoms, dysarthria, and tremor at the age of 36. Her sister remained presymptomatic at diagnosis at the age of 39. The second twins were ATP7B c.3207C.A (p.H1069Q) homozygotes. The index case presented with dysarthria and tremor at the age of 26. Her sister remained clinically presymptomatic at diagnosis at the age of 28. We concluded that the phenotypic characteristics of WD are possibly attributable to epigenetic/environmental factors.","variants":[{"Name":"NM_000053.4(ATP7B):c.3207C>A (p.His1069Gln)","Chromosome":"13","Start":"51944145","Stop":"51944145","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":18887,"rule_based_match":true,"evidence_text":"c.3207C>A (p.H1069Q)","llm_judgment":"PRESENT","evidence":"c.3207C>A (p.H1069Q)","abstract_start":463,"abstract_end":483}]}
{"pmid":"23386947","title":"Infantile systemic hyalinosis: a case report with a novel mutation.","abstract":"Infantile Systemic Hyalinosis (ISH) (OMIM 236490) is a rare, progressive and fatal autosomal recessive disorder characterized by multiple subcutaneous skin nodules, gingival hypertrophy, osteopenia, joint contractures, failure to thrive, diarrhea with protein losing enteropathy, and frequent infections. There is diffuse deposition of hyaline material in the skin, gastrointestinal tract, muscle and endocrine glands. It is caused by mutations in the ANTXR2 (also known as CMG2) gene, which encodes a trans-membranous protein involved in endothelial development and basement membrane-extracellular matrix assembly. We describe a child with classical features of ISH presenting in infancy with severe chronic debilitating pain and progressive joint contractures. The diagnosis was confirmed by molecular DNA sequencing of ANTXR2 gene which revealed a novel homozygous mutation not previously reported; 79 bp deletion of the entire exon 11 (c.867_945del, p.E289DfsX22). Although this is the first reported case of ISH in Oman, we believe that the disease is under-diagnosed since children affected with this lethal disease pass away early in infancy prior to establishing a final diagnosis.","variants":[{"Name":"NM_058172.6(ANTXR2):c.867_945del (p.Glu289fs)","Chromosome":"4","Start":"80018898","Stop":"80018976","ReferenceAlleleVCF":"CACATTCTGTGGCTGTGACAATTAATGATCCTGAAATGACAGATTTTCCTCCATTAAAGCTCACTGAAACATCAAGAGTT","AlternateAlleleVCF":"C","allel_id":612351,"rule_based_match":true,"evidence_text":"c.867_945del","llm_judgment":"PRESENT","evidence":"c.867_945del","abstract_start":940,"abstract_end":952}]}
{"pmid":"23269703","title":"Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer.","abstract":"UNLABELLED: BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi anemia and predisposition to cancers, whereas biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations and have implications for the interpretation of genetic test results.\nSIGNIFICANCE: Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the fi rst validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy.","variants":[{"Name":"NM_007294.4(BRCA1):c.2457del (p.Asp821fs)","Chromosome":"17","Start":"43093074","Stop":"43093074","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":46027,"rule_based_match":true,"evidence_text":"c.2457delC (p.Asp821Ilefs*25)","llm_judgment":"PRESENT","evidence":"c.2457delC (p.Asp821Ilefs*25)","abstract_start":478,"abstract_end":507},{"Name":"NM_007294.4(BRCA1):c.5207T>C (p.Val1736Ala)","Chromosome":"17","Start":"43057122","Stop":"43057122","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":46204,"rule_based_match":true,"evidence_text":"c.5207T>C (p.Val1736Ala)","llm_judgment":"PRESENT","evidence":"c.5207T>C (p.Val1736Ala)","abstract_start":578,"abstract_end":602}]}
{"pmid":"28794131","title":"Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability.","abstract":"BACKGROUND: Autosomal recessive mutations in <i>DNAJC12</i>, encoding a cochaperone of HSP70 with hitherto unknown function, were recently described to lead to hyperphenylalaninemia, central monoamine neurotransmitter (dopamine and serotonin) deficiency, dystonia and intellectual disability in six subjects affected by homozygous variants.\nOBJECTIVE: Patients exhibiting hyperphenylalaninemia in whom deficiencies in hepatic phenylalanine hydroxylase and tetrahydrobiopterin cofactor metabolism had been excluded were subsequently analysed for <i>DNAJC12</i> variants.\nMETHODS: To analyse DNAJC12, genomic DNA from peripheral blood (Sanger sequencing), as well as quantitative messenger RNA (Real Time Quantitative Polymerase Chain Reaction (RT-qPCR)) and protein expression (Western blot) from primary skin fibroblasts were performed.\nRESULTS: We describe five additional patients from three unrelated families with homozygosity/compound heterozygosity in <i>DNAJC12</i> with three novel variants: c.85delC/p.Gln29Lysfs*38, c.596G>T/p.*199Leuext*42 and c.214C>T/p.(Arg72*). In contrast to previously reported DNAJC12-deficient patients, all five cases showed a very mild neurological phenotype. In two subjects, cerebrospinal fluid and primary skin fibroblasts were analysed showing similarly low 5-hydroxyindolacetic acid and homovanillic acid concentrations but more reduced expressions of mRNA and DNAJC12 compared with previously described patients. All patients responded to tetrahydrobiopterin challenge by lowering blood phenylalanine levels.\nCONCLUSIONS: DNAJC12 deficiency appears to result in a more heterogeneous neurological phenotype than originally described. While early identification and institution of treatment with tetrahydrobiopterin and neurotransmitter precursors is crucial to ensure optimal neurological outcome in DNAJC12-deficient patients with a severe phenotype, optimal treatment for patients with a milder phenotype remains to be defined.","variants":[{"Name":"NM_021800.3(DNAJC12):c.214C>T (p.Arg72Ter)","Chromosome":"10","Start":"67811607","Stop":"67811607","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":681920,"rule_based_match":true,"evidence_text":"c.214C>T/p.(Arg72*)","llm_judgment":"PRESENT","evidence":"c.214C>T/p.(Arg72*)","abstract_start":1055,"abstract_end":1074},{"Name":"NM_021800.3(DNAJC12):c.85del (p.Gln29fs)","Chromosome":"10","Start":"67823386","Stop":"67823386","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":681918,"rule_based_match":true,"evidence_text":"c.85delC/p.Gln29Lysfs*38","llm_judgment":"PRESENT","evidence":"c.85delC/p.Gln29Lysfs*38","abstract_start":1000,"abstract_end":1024},{"Name":"NM_021800.3(DNAJC12):c.596G>T (p.Ter199Leu)","Chromosome":"10","Start":"67797117","Stop":"67797117","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":681919,"rule_based_match":true,"evidence_text":"c.596G>T/p.*199Leuext*42","llm_judgment":"PRESENT","evidence":"c.596G>T/p.*199Leuext*42","abstract_start":1026,"abstract_end":1050}]}
{"pmid":"22226083","title":"Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1.","abstract":"The molecular basis for primary hereditary hypertriglyceridemia has been identified in fewer than 5% of cases. Investigation of monogenic dyslipidemias has the potential to expose key metabolic pathways. We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition. We performed SNP array-based homozygosity mapping and found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that are listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. We performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in GPD1, which encodes glycerol-3-phosphate dehydrogenase 1. Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals. This mutation is predicted to result in a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition. Functional consequences of the mutation were evaluated by measuring intracellular concentrations of cholesterol and triglyceride as well as triglyceride secretion in HepG2 (hepatocellular carcinoma) human cells lines overexpressing normal and mutant GPD1 cDNA. Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01). This finding supports the pathogenicity of the identified mutation.","variants":[{"Name":"NM_005276.4(GPD1):c.361-1G>C","Chromosome":"12","Start":"50106287","Stop":"50106287","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":38696,"rule_based_match":true,"evidence_text":"c.361-1G>C","llm_judgment":"PRESENT","evidence":"c.361-1G>C","abstract_start":1021,"abstract_end":1031}]}
{"pmid":"23431748","title":"EEC syndrome with a de novo mutation (c.953g > a) on exon 7 of P63 gene: a case report.","abstract":"EEC syndrome is characterized by ectodermal dysplasia, ectrodactyly and cleft lip and/or palate and associated anomalies such as lacrimal duct obstruction, urinary tract anomaly, and hearing loss. This syndrome is a rare autosomal dominant disorder caused by heterozygous mutations in the p63 gene. Herein, a newborn infant with EEC syndrome with secundum atrial septal defect who had a de novo mutation (c.953G > A) on exon 7 of p63 gene is presented.","variants":[{"Name":"NM_003722.5(TP63):c.953G>A (p.Arg318His)","Chromosome":"3","Start":"189867903","Stop":"189867903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21572,"rule_based_match":true,"evidence_text":"c.953G > A","llm_judgment":"PRESENT","evidence":"c.953G > A","abstract_start":405,"abstract_end":415}]}
{"pmid":"36115851","title":"Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model.","abstract":"Retinitis pigmentosa is a group of progressive inherited retinal dystrophies that may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. In an Indian family suffering from retinitis pigmentosa, we identified a missense variation in CNGA1 affecting the cyclic nucleotide binding domain (CNBD) and characterized a mouse model developed with mutated CNBD. A gene panel analysis comprising 105 known RP genes was used to analyze a family with autosomal-recessive retinitis pigmentosa (arRP) and revealed that CNGA1 was affected. From sperm samples of ENU mutagenesis derived F<sub>1</sub> mice, we re-derived a mutant with a Cnga1 mutation. Homozygous mutant mice, developing retinal degeneration, were examined for morphological and functional consequences of the mutation. In the family, we identified a rare CNGA1 variant (NM_001379270.1) c.1525 G > A; (p.Gly509Arg), which co-segregated among the affected family members. Homozygous Cnga1 mice harboring a (ENSMUST00000087213.12) c.1526 A > G (p.Tyr509Cys) mutation showed progressive degeneration in the retinal photoreceptors from 8 weeks on. This study supports a role for CNGA1 as a disease gene for arRP and provides new insights on the pathobiology of cGMP-binding domain mutations in CNGA1-RP.","variants":[{"Name":"NM_001379270.1(CNGA1):c.1525G>A (p.Gly509Arg)","Chromosome":"4","Start":"47936957","Stop":"47936957","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1060035,"rule_based_match":true,"evidence_text":"NM_001379270.1) c.1525 G > A; (p.Gly509Arg)","llm_judgment":"PRESENT","evidence":"NM_001379270.1) c.1525 G > A; (p.Gly509Arg)","abstract_start":868,"abstract_end":911}]}
{"pmid":"27843125","title":"Recessive Mutations in ACPT, Encoding Testicular Acid Phosphatase, Cause Hypoplastic Amelogenesis Imperfecta.","abstract":"Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders affecting tooth enamel. The affected enamel can be hypoplastic and/or hypomineralized. In this study, we identified ACPT (testicular acid phosphatase) biallelic mutations causing non-syndromic, generalized hypoplastic autosomal-recessive amelogenesis imperfecta (AI) in individuals from six apparently unrelated Turkish families. Families 1, 4, and 5 were affected by the homozygous ACPT mutation c.713C>T (p.Ser238Leu), family 2 by the homozygous ACPT mutation c.331C>T (p.Arg111Cys), family 3 by the homozygous ACPT mutation c.226C>T (p.Arg76Cys), and family 6 by the compound heterozygous ACPT mutations c.382G>C (p.Ala128Pro) and 397G>A (p.Glu133Lys). Analysis of the ACPT crystal structure suggests that these mutations damaged the activity of ACPT by altering the sizes and charges of key amino acid side chains, limiting accessibility of the catalytic core, and interfering with homodimerization. Immunohistochemical analysis confirmed localization of ACPT in secretory-stage ameloblasts. The study results provide evidence for the crucial function of ACPT during amelogenesis.","variants":[{"Name":"NM_033068.3(ACP4):c.713C>T (p.Ser238Leu)","Chromosome":"19","Start":"50793751","Stop":"50793751","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":361767,"rule_based_match":true,"evidence_text":"c.713C>T (p.Ser238Leu)","llm_judgment":"PRESENT","evidence":"c.713C>T (p.Ser238Leu)","abstract_start":472,"abstract_end":494},{"Name":"NM_033068.3(ACP4):c.331C>T (p.Arg111Cys)","Chromosome":"19","Start":"50791683","Stop":"50791683","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":361768,"rule_based_match":true,"evidence_text":"c.331C>T (p.Arg111Cys)","llm_judgment":"PRESENT","evidence":"c.331C>T (p.Arg111Cys)","abstract_start":537,"abstract_end":559},{"Name":"NM_033068.3(ACP4):c.226C>T (p.Arg76Cys)","Chromosome":"19","Start":"50790783","Stop":"50790783","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":361769,"rule_based_match":true,"evidence_text":"c.226C>T (p.Arg76Cys)","llm_judgment":"PRESENT","evidence":"c.226C>T (p.Arg76Cys)","abstract_start":602,"abstract_end":623},{"Name":"NM_033068.3(ACP4):c.382G>C (p.Ala128Pro)","Chromosome":"19","Start":"50791734","Stop":"50791734","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":361770,"rule_based_match":true,"evidence_text":"c.382G>C (p.Ala128Pro)","llm_judgment":"PRESENT","evidence":"c.382G>C (p.Ala128Pro)","abstract_start":682,"abstract_end":704},{"Name":"NM_033068.3(ACP4):c.397G>A (p.Glu133Lys)","Chromosome":"19","Start":"50791749","Stop":"50791749","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":361771,"rule_based_match":false,"evidence_text":"c.397G>A (p.Glu133Lys)","llm_judgment":"PRESENT","evidence":"p.Glu133Lys","abstract_start":717,"abstract_end":728}]}
{"pmid":"23582645","title":"Missense mutations in SLC26A8, encoding a sperm-specific activator of CFTR, are associated with human asthenozoospermia.","abstract":"The cystic fibrosis transmembrane conductance regulator (CFTR) is present in mature sperm and is required for sperm motility and capacitation. Both these processes are controlled by ions fluxes and are essential for fertilization. We have shown that SLC26A8, a sperm-specific member of the SLC26 family of anion exchangers, associates with the CFTR channel and strongly stimulates its activity. This suggests that the two proteins cooperate to regulate the anion fluxes required for correct sperm motility and capacitation. Here, we report on three heterozygous SLC26A8 missense mutations identified in a cohort of 146 men presenting with asthenozoospermia: c.260G>A (p.Arg87Gln), c.2434G>A (p.Glu812Lys), and c.2860C>T (p.Arg954Cys). These mutations were not present in 121 controls matched for ethnicity, and statistical analysis on a control population of 8,600 individuals (from dbSNP and 1000 Genomes) showed them to be associated with asthenozoospermia with a power > 95%. By cotransfecting Chinese hamster ovary (CHO)-K1 cells with SLC26A8 variants and CFTR, we showed that the physical interaction between the two proteins was partly conserved but that the capacity to activate CFTR-dependent anion transport was completely abolished for all mutants. Biochemical studies revealed the presence of much smaller amounts of protein for all variants, but these amounts were restored to wild-type levels upon treatment with the proteasome inhibitor MG132. Immunocytochemistry also showed the amounts of SLC26A8 in sperm to be abnormally small in individuals carrying the mutations. These mutations might therefore impair formation of the SLC26A8-CFTR complex, principally by affecting SLC26A8 stability, consistent with an impairment of CFTR-dependent sperm-activation events in affected individuals.","variants":[{"Name":"NM_052961.4(SLC26A8):c.260G>A (p.Arg87Gln)","Chromosome":"6","Start":"36012301","Stop":"36012301","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":65571,"rule_based_match":true,"evidence_text":"c.260G>A (p.Arg87Gln)","llm_judgment":"PRESENT","evidence":"c.260G>A (p.Arg87Gln)","abstract_start":658,"abstract_end":679},{"Name":"NM_052961.4(SLC26A8):c.2434G>A (p.Glu812Lys)","Chromosome":"6","Start":"35951201","Stop":"35951201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":65572,"rule_based_match":true,"evidence_text":"c.2434G>A (p.Glu812Lys)","llm_judgment":"PRESENT","evidence":"c.2434G>A (p.Glu812Lys)","abstract_start":681,"abstract_end":704},{"Name":"NM_052961.4(SLC26A8):c.2860C>T (p.Arg954Cys)","Chromosome":"6","Start":"35943953","Stop":"35943953","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":65573,"rule_based_match":true,"evidence_text":"c.2860C>T (p.Arg954Cys)","llm_judgment":"PRESENT","evidence":"c.2860C>T (p.Arg954Cys)","abstract_start":710,"abstract_end":733}]}
{"pmid":"36585007","title":"Clinical report and genetic analysis of a child with Aicardi-Goutières syndrome type 3 due to compound heterozygous variants of RNASEH2C gene","abstract":"OBJECTIVE: To explore the clinical characteristics and genetic etiology of a child with Aicardi-Goutières syndrome 3 (AGS3).\nMETHODS: Trio whole exome sequencing was carried out for the child and his parents, and candidate variants were verified by Sanger sequencing. To further clarify their pathogenicity, the crystal structure of the variants was simulated and analyzed, and the plasmid of variants was expressed in vitro. A literature search was also carried out to summarize the phenotypic and genetic characteristics of AGS3.\nRESULTS: The child was found to harbor novel compound heterozygous variants of the RNASEH2C gene, namely c.434G>T (p.Arg145Leu) and c.494G>C (p.Ter165Ser), which were inherited from his mother and father, respectively. Analysis of protein crystal structure suggested that the c.434G>T (p.Arg145Leu) variant may affect the stability of local structure, and in vitro experiments showed that this variant can lead to protein degradation. The c.494G>C (p.Ter165Ser) variant has destroyed the stop codon, resulting in prolonged variant.\nCONCLUSION: The novel compound heterozygous variants of the RNASEH2C gene probably underlay the AGS3 in this child, which has enriched the phenotypic and mutational spectrum of this disorder.","variants":[{"Name":"NM_032193.4(RNASEH2C):c.434G>T (p.Arg145Leu)","Chromosome":"11","Start":"65720079","Stop":"65720079","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":640326,"rule_based_match":true,"evidence_text":"c.434G>T (p.Arg145Leu)","llm_judgment":"PRESENT","evidence":"c.434G>T (p.Arg145Leu)","abstract_start":637,"abstract_end":659}]}
{"pmid":"23716654","title":"ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature.","abstract":"Familial exudative vitreoretinopathy (FEVR) is a genetically heterogeneous disorder characterized by abnormal vascularization of the peripheral retina, which can result in retinal detachment and severe visual impairment. In a large Dutch FEVR family, we performed linkage analysis, exome sequencing, and segregation analysis of DNA variants. We identified putative disease-causing DNA variants in proline-alanine-rich ste20-related kinase (c.791dup; p.Ser265ValfsX64) and zinc finger protein 408 (ZNF408) (c.1363C>T; p.His455Tyr), the latter of which was also present in an additional Dutch FEVR family that subsequently appeared to share a common ancestor with the original family. Sequence analysis of ZNF408 in 132 additional individuals with FEVR revealed another potentially pathogenic missense variant, p.Ser126Asn, in a Japanese family. Immunolocalization studies in COS-1 cells transfected with constructs encoding the WT and mutant ZNF408 proteins, revealed that the WT and the p.Ser126Asn mutant protein show complete nuclear localization, whereas the p.His455Tyr mutant protein was localized almost exclusively in the cytoplasm. Moreover, in a cotransfection assay, the p.His455Tyr mutant protein retains the WT ZNF408 protein in the cytoplasm, suggesting that this mutation acts in a dominant-negative fashion. Finally, morpholino-induced knockdown of znf408 in zebrafish revealed defects in developing retinal and trunk vasculature, that could be rescued by coinjection of RNA encoding human WT ZNF408 but not p.His455Tyr mutant ZNF408. Together, our data strongly suggest that mutant ZNF408 results in abnormal retinal vasculogenesis in humans and is associated with FEVR.","variants":[{"Name":"NM_024741.3(ZNF408):c.1363C>T (p.His455Tyr)","Chromosome":"11","Start":"46705063","Stop":"46705063","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":200708,"rule_based_match":true,"evidence_text":"c.1363C>T; p.His455Tyr","llm_judgment":"PRESENT","evidence":"c.1363C>T; p.His455Tyr","abstract_start":506,"abstract_end":528}]}
{"pmid":"17979197","title":"Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.Lys117Arg mutation.","abstract":"Costello syndrome is a mental retardation syndrome characterized by high birth weight, postnatal growth retardation, coarse face, loose skin, cardiovascular problems, and tumor predisposition. De novo heterozygous missense mutations in HRAS codon 12 and 13 disturbing the intrinsic GTP hydrolysis cause Costello syndrome. We report a patient with typical Costello syndrome and a novel heterozygous missense mutation in codon 117 (c.350A>G, p.Lys117Arg) of the HRAS gene, resulting in constitutive activation of the RAS/MAPK pathway similar to the typical p.Gly12Ser and p.Gly12Ala mutations. Recombinant HRAS p.Lys117Arg demonstrates normal intrinsic GTP hydrolysis and responsiveness to GTPase-activating proteins, but the nucleotide dissociation rate is increased 80-fold. Consistent with the biochemical data, the crystal structure of the p.Lys117Arg mutant indicates an altered interaction pattern of the side chain that is associated with unfavorable nucleotide binding properties. Together, these data show that a RAS mutation that only perturbs guanine nucleotide binding has similar functional consequences as mutations that impair GTP hydrolysis and causes human disease.","variants":[{"Name":"NM_005343.4(HRAS):c.350A>G (p.Lys117Arg)","Chromosome":"11","Start":"533553","Stop":"533553","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":27644,"rule_based_match":true,"evidence_text":"c.350A>G, p.Lys117Arg","llm_judgment":"PRESENT","evidence":"c.350A>G, p.Lys117Arg","abstract_start":430,"abstract_end":451}]}
{"pmid":"24721225","title":"X-exome sequencing in Finnish families with intellectual disability--four novel mutations and two novel syndromic phenotypes.","abstract":"BACKGROUND: X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis.\nMETHODS & OBJECTIVES: Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause.\nRESULTS: We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype.\nCONCLUSIONS: All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations and the challenges of interpreting the results. Further functional studies are required to confirm the cause of the syndromic phenotypes associated with ZMYM3 and SYP in this study.","variants":[{"Name":"NM_201599.3(ZMYM3):c.1321C>T (p.Arg441Trp)","Chromosome":"X","Start":"71249610","Stop":"71249610","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132676,"rule_based_match":true,"evidence_text":"c.1321C > T","llm_judgment":"PRESENT","evidence":"c.1321C > T","abstract_start":1088,"abstract_end":1099},{"Name":"NM_021120.4(DLG3):c.357+1G>C","Chromosome":"X","Start":"70445559","Stop":"70445559","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":132677,"rule_based_match":true,"evidence_text":"c.357 + 1G > C","llm_judgment":"PRESENT","evidence":"c.357 + 1G > C","abstract_start":996,"abstract_end":1010},{"Name":"NM_021120.4(DLG3):c.985+1G>C","Chromosome":"X","Start":"70450784","Stop":"70450784","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":132678,"rule_based_match":true,"evidence_text":"c.985 + 1G > C","llm_judgment":"PRESENT","evidence":"c.985 + 1G > C","abstract_start":1015,"abstract_end":1029},{"Name":"NM_007325.5(GRIA3):c.1888G>C (p.Gly630Arg)","Chromosome":"X","Start":"123427951","Stop":"123427951","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":132679,"rule_based_match":true,"evidence_text":"c.1888G > C","llm_judgment":"PRESENT","evidence":"c.1888G > C","abstract_start":921,"abstract_end":932},{"Name":"NM_006517.5(SLC16A2):c.1111C>T (p.Arg371Cys)","Chromosome":"X","Start":"74525834","Stop":"74525834","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":170184,"rule_based_match":true,"evidence_text":"c.1111C > T","llm_judgment":"PRESENT","evidence":"c.1111C > T","abstract_start":726,"abstract_end":737}]}
{"pmid":"24787270","title":"Hypoxic ischemic encephalopathy in a case of intranuclear rod myopathy without any prenatal sentinel event.","abstract":"Intranuclear rod myopathy (IRM), a variant of nemaline myopathy, is characterized by the presence of nemaline bodies in myonuclei. We report a case of IRM presenting with hypoxic ischemic encephalopathy (HIE). There were no prenatal complications caused by fetal brain injury. Although no nemaline bodies were observed in the cytoplasm, intranuclear rods were observed in some fibers under light and electron microscopy. Molecular analysis identified a heterozygous variant, c.449C>T (p.Thr150Ile), in ACTA1. On magnetic resonance imaging at 9days of age, injuries to the basal ganglia, thalamus, and brainstem consistent with perinatal HIE were seen. Respiratory insufficiency at birth was strongly suspected to be the cause of HIE. Our case highlights that a patient with a congenital neuromuscular disorder who presents with severe respiratory dysfunction requiring substantial resuscitative efforts at birth can be complicated by HIE without any prenatal sentinel event. Prenatal detection of neuromuscular disorders, careful management of delivery, and neonatal resuscitation and adequate respiratory management are important in preventing irreversible brain injury in these patients.","variants":[{"Name":"NM_001100.4(ACTA1):c.449C>T (p.Thr150Ile)","Chromosome":"1","Start":"229432561","Stop":"229432561","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2750382,"rule_based_match":true,"evidence_text":"c.449C>T (p.Thr150Ile)","llm_judgment":"PRESENT","evidence":"c.449C>T (p.Thr150Ile)","abstract_start":475,"abstract_end":497}]}
{"pmid":"21763484","title":"Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability.","abstract":"We have used genome-wide genotyping to identify an overlapping homozygosity-by-descent locus on chromosome 9q34.3 (MRT15) in four consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability (NS-ARID) and one in which the patients show additional clinical features. Four of the families are from Pakistan, and one is from Iran. Using a combination of next-generation sequencing and Sanger sequencing, we have identified mutations in the gene MAN1B1, encoding a mannosyl oligosaccharide, alpha 1,2-mannosidase. In one Pakistani family, MR43, a homozygous nonsense mutation (RefSeq number NM_016219.3: c.1418G>A [p.Trp473*]), segregated with intellectual disability and additional dysmorphic features. We also identified the missense mutation c. 1189G>A (p.Glu397Lys; RefSeq number NM_016219.3), which segregates with NS-ARID in three families who come from the same village and probably have shared inheritance. In the Iranian family, the missense mutation c.1000C>T (p.Arg334Cys; RefSeq number NM_016219.3) also segregates with NS-ARID. Both missense mutations are at amino acid residues that are conserved across the animal kingdom, and they either reduce k(cat) by ∼1300-fold or disrupt stable protein expression in mammalian cells. MAN1B1 is one of the few NS-ARID genes with an elevated mutation frequency in patients with NS-ARID from different populations.","variants":[{"Name":"NM_016219.5(MAN1B1):c.1189G>A (p.Glu397Lys)","Chromosome":"9","Start":"137101607","Stop":"137101607","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39370,"rule_based_match":true,"evidence_text":"c. 1189G>A (p.Glu397Lys; RefSeq number NM_016219.3)","llm_judgment":"PRESENT","evidence":"c. 1189G>A (p.Glu397Lys; RefSeq number NM_016219.3)","abstract_start":773,"abstract_end":824},{"Name":"NM_016219.5(MAN1B1):c.1418G>A (p.Trp473Ter)","Chromosome":"9","Start":"137106288","Stop":"137106288","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39371,"rule_based_match":true,"evidence_text":"c.1418G>A (p.Trp473*)","llm_judgment":"PRESENT","evidence":"c.1418G>A","abstract_start":632,"abstract_end":641},{"Name":"NM_016219.5(MAN1B1):c.1000C>T (p.Arg334Cys)","Chromosome":"9","Start":"137101088","Stop":"137101088","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39372,"rule_based_match":true,"evidence_text":"c.1000C>T (p.Arg334Cys; RefSeq number NM_016219.3)","llm_judgment":"PRESENT","evidence":"c.1000C>T (p.Arg334Cys; RefSeq number NM_016219.3)","abstract_start":988,"abstract_end":1038}]}
{"pmid":"34842280","title":"Mitochondrial developmental encephalopathy with bilateral optic neuropathy related to homozygous variants in IMMT gene.","abstract":"IMMT gene codes for mitofilin, a mitochondrial inner membrane protein that regulates the morphology of mitochondrial cristae. The phenotype associated with mutations in this gene has not been yet established, but functional studies carried out show that its loss causes a mitochondrial alteration, both in the morphology of the mitochondrial crests and in their function. We present two cousins from an extended highly consanguineous family with developmental encephalopathy, hypotonia, nystagmus due to optic neuropathy. The likely pathogenic homozygous c.895A>G (p.Lys299Glu) variant in the IMMT gene co-segregates with the disease and associates altered mitochondrial cristae observed by electron microscopy.","variants":[{"Name":"NM_006839.3(IMMT):c.895A>G (p.Lys299Glu)","Chromosome":"2","Start":"86161977","Stop":"86161977","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2422018,"rule_based_match":true,"evidence_text":"c.895A>G (p.Lys299Glu)","llm_judgment":"PRESENT","evidence":"c.895A>G (p.Lys299Glu)","abstract_start":555,"abstract_end":577}]}
{"pmid":"23315978","title":"A homozygous frameshift mutation in the HOXC13 gene underlies pure hair and nail ectodermal dysplasia in a Syrian family.","abstract":"Pure hair and nail ectodermal dysplasia (PHNED) is a rare genetic disorder characterized by hypotrichosis or complete alopecia, as well as nail dystrophy. Mutations in the type II hair keratin gene KRT85 and the HOXC13 gene on chromosome 12q have recently been identified in families with autosomal-recessive PHNED. In the present study, we have analyzed a consanguineous Syrian family with an affected girl having complete alopecia and nail dystrophy since birth. The family clearly showed linkage to chromosome 12q13.13-12q14.3, which excluded the KRT85 gene. Sequencing of another candidate gene HOXC13 within the linkage interval identified a homozygous frameshift mutation (c.355delC; p.Leu119Trpfs*20). Expression studies in cultured cells revealed that the mutant HOXC13 protein mislocalized within the cytoplasm, and failed to upregulate the promoter activities of its target genes. Our results strongly suggest crucial roles of the HOXC13 gene in the development of hair and nails in humans.","variants":[{"Name":"NM_017410.3(HOXC13):c.355del (p.Leu119fs)","Chromosome":"12","Start":"53939259","Stop":"53939259","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":59678,"rule_based_match":true,"evidence_text":"c.355delC","llm_judgment":"PRESENT","evidence":"c.355delC","abstract_start":679,"abstract_end":688}]}
{"pmid":"26310427","title":"GMPPB-Associated Dystroglycanopathy: Emerging Common Variants with Phenotype Correlation.","abstract":"Mutations in GDP-mannose pyrophosphorylase B (GMPPB), a catalyst for the formation of the sugar donor GDP-mannose, were recently identified as a cause of muscular dystrophy resulting from abnormal glycosylation of α-dystroglycan. In this series, we report nine unrelated individuals with GMPPB-associated dystroglycanopathy. The most mildly affected subject has normal strength at 25 years, whereas three severely affected children presented in infancy with intellectual disability and epilepsy. Muscle biopsies of all subjects are dystrophic with abnormal immunostaining for glycosylated α-dystroglycan. This cohort, together with previously published cases, allows preliminary genotype-phenotype correlations to be made for the emerging GMPPB common variants c.79G>C (p.D27H) and c.860G>A (p.R287Q). We observe that c.79G>C (p.D27H) is associated with a mild limb-girdle muscular dystrophy phenotype, whereas c.860G>A (p.R287Q) is associated with a relatively severe congenital muscular dystrophy typically involving brain development. Sixty-six percent of GMPPB families to date have one of these common variants.","variants":[{"Name":"NM_021971.4(GMPPB):c.860G>A (p.Arg287Gln)","Chromosome":"3","Start":"49722056","Stop":"49722056","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75126,"rule_based_match":true,"evidence_text":"c.860G>A (p.R287Q)","llm_judgment":"PRESENT","evidence":"c.860G>A (p.R287Q)","abstract_start":782,"abstract_end":800},{"Name":"NM_021971.4(GMPPB):c.79G>C (p.Asp27His)","Chromosome":"3","Start":"49723648","Stop":"49723648","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":75127,"rule_based_match":true,"evidence_text":"c.79G>C (p.D27H)","llm_judgment":"PRESENT","evidence":"c.79G>C (p.D27H)","abstract_start":761,"abstract_end":777}]}
{"pmid":"28709814","title":"The therapeutic implication of a novel SCN2A mutation associated early-onset epileptic encephalopathy with Rett-like features.","abstract":"Epileptic encephalopathies are highly heterogeneous and phenotypical disorders with different underlying genetic defects. Mutations in the SCN2A gene cause different epilepsy syndromes, including epilepsy of infancy with migrating focal seizures, Ohtahara syndrome, and West syndrome. We utilized a targeted next generation sequencing (NGS) approach on a girl with early-onset seizures and Rett-like features, including autistic behavior, limited hand function with chorea, and profound intellectual disability, to identify novel missense mutation (c.1270G>A; p.V424M) in the SCN2A gene, which encodes the αII-subunit of the voltage-gated Na<sup>+</sup> channel (Na<sub>v</sub>1.2). The identified SCN2A mutation responsible for the development of the disease is confirmed to be de novo for the proband. Our findings broaden the clinical spectrum of SCN2A mutations, which resembles clinical phenotypes of SCN1A mutations by manifesting as fever sensitive seizures, and highlights that SCN2A mutations are an important cause of early-onset epileptic encephalopathies with movement disorders. In addition, the use of levetiracetam to treat SCN2A epileptic encephalopathy, when Na<sup>+</sup> channel-blocking anticonvulsants are ineffective, is also recommended.","variants":[{"Name":"NM_001040142.2(SCN2A):c.1270G>A (p.Val424Met)","Chromosome":"2","Start":"165313995","Stop":"165313995","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":628774,"rule_based_match":true,"evidence_text":"c.1270G>A; p.V424M","llm_judgment":"PRESENT","evidence":"c.1270G>A; p.V424M","abstract_start":549,"abstract_end":567}]}
{"pmid":"21070211","title":"Krabbe leukodystrophy in a selected population with high rate of late onset forms: longer survival linked to c.121G>A (p.Gly41Ser) mutation.","abstract":"Krabbe leukodystrophy (KD) is a neurodegenerative lysosomal disorder caused by mutations in the galactocerebrosidase (GALC) gene. Different clinical forms are described based on the age at onset. In reported series, the early infantile form (EIKD) accounts for more than 90% of the cases. The rarer late onset forms (LOKD) become manifest later than 6 months up to the adult age. We report clinical, imaging, mutational analysis and geographic data in a large cohort of individuals with Krabbe disease examined over a 30-year period. Retrospective analyses of disease onset and long-term follow-up were conducted in 26 KD patients. Molecular analysis was performed in 12 patients and their families. Nine cases had EIKD, and 17 LOKD, accounting for two thirds of our series. No correlation was found between enzymatic activity, onset age and disease progression. Despite common geographical origin, only in a few cases could parental consanguinity be proven. The p.Gly41Ser mutation was associated with longer survival. A wide spectrum of LOKD is found despite similar genotype. Although current knowledge about onset age, residual enzyme activity and molecular analysis still fail to allow the identification of patient candidates for treatment, this information is valuable for long-term outcome prediction and could lead to reconsideration of inclusion criteria for bone marrow transplant (BMT) or other future therapeutic approaches.","variants":[{"Name":"NM_000153.4(GALC):c.121G>A (p.Gly41Ser)","Chromosome":"14","Start":"87993044","Stop":"87993044","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39578,"rule_based_match":true,"evidence_text":"c.121G>A (p.Gly41Ser)","llm_judgment":"PRESENT","evidence":"p.Gly41Ser","abstract_start":963,"abstract_end":973}]}
{"pmid":"22753417","title":"A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2.","abstract":"Hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, producing hypertonia and apnea episodes. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Dominant and recessive mutations in the human glycine receptor (GlyR) α1 gene (GLRA1) are the major cause of this disorder. However, recessive mutations in the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease. In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation: pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom. Curiously, individuals harboring this mutation show significant variation in clinical presentation. In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. We functionally characterized this mutation using molecular modeling, electrophysiology, [(3)H]glycine transport, cell surface expression, and cysteine labeling assays. We found that the introduced cysteine interacts with the cysteine pair Cys-311-Cys-320 in the second external loop of GlyT2. This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function. Additionally, Y705C presents altered H(+) and Zn(2+) dependence of glycine transport that may affect the function of glycinergic neurotransmission in vivo.","variants":[{"Name":"NM_004211.5(SLC6A5):c.2114A>G (p.Tyr705Cys)","Chromosome":"11","Start":"20652332","Stop":"20652332","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":791122,"rule_based_match":false,"evidence_text":"c.2114A→G","llm_judgment":"PRESENT","evidence":"c.2114A→G","abstract_start":662,"abstract_end":671}]}
{"pmid":"27038293","title":"Mucolipidosis III GNPTG Missense Mutations Cause Misfolding of the γ Subunit of GlcNAc-1-Phosphotransferase.","abstract":"The lysosomal storage disorder ML III γ is caused by defects in the γ subunit of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, the enzyme that tags lysosomal enzymes with the mannose 6-phosphate lysosomal targeting signal. In patients with this disorder, most of the newly synthesized lysosomal enzymes are secreted rather than being sorted to lysosomes, resulting in increased levels of these enzymes in the plasma. Several missense mutations in GNPTG, the gene encoding the γ subunit, have been reported in mucolipidosis III γ patients. However, in most cases, the impact of these mutations on γ subunit function has remained unclear. Here, we report that the variants c.316G>A (p.G106S), c.376G>A (p.G126S), and c.425G>A (p.C142Y) cause misfolding of the γ subunit, whereas another variant, c.857C>T (p.T286M), does not appear to alter γ subunit function. The misfolded γ subunits were retained in the ER and failed to rescue the lysosomal targeting of lysosomal acid glycosidases.","variants":[{"Name":"NM_032520.5(GNPTG):c.857C>T (p.Thr286Met)","Chromosome":"16","Start":"1363030","Stop":"1363030","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34576,"rule_based_match":true,"evidence_text":"c.857C>T (p.T286M)","llm_judgment":"PRESENT","evidence":"c.857C>T (p.T286M)","abstract_start":818,"abstract_end":836},{"Name":"NM_032520.5(GNPTG):c.376G>A (p.Gly126Ser)","Chromosome":"16","Start":"1362096","Stop":"1362096","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":843080,"rule_based_match":true,"evidence_text":"c.376G>A (p.G126S)","llm_judgment":"PRESENT","evidence":"c.376G>A (p.G126S)","abstract_start":715,"abstract_end":733},{"Name":"NM_032520.5(GNPTG):c.316G>A (p.Gly106Ser)","Chromosome":"16","Start":"1361954","Stop":"1361954","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17838,"rule_based_match":true,"evidence_text":"c.316G>A (p.G106S)","llm_judgment":"PRESENT","evidence":"c.316G>A (p.G106S)","abstract_start":695,"abstract_end":713}]}
{"pmid":"24451227","title":"p.Arg75Gln, a CFTR variant involved in the risk of CFTR-related disorders?","abstract":"c.224G>A, p.Arg75Gln (R75Q) presumably leads to an amino-acid change from arginine to glutamine in the membrane-spanning domain of the CFTR protein. Initially reported as a benign sequence variation, p.Arg75Gln was shown to be associated with a high risk of pancreatitis, a risk that was strikingly higher when p.Arg75Gln was combined with a SPINK1 variant. In addition, it was shown that p.Arg75Gln alters bicarbonate but not chloride conductance and that the mutation also induces exon 3 skipping. To investigate the role of p.Arg75Gln in idiopathic chronic pancreatitis (ICP), we performed genotyping of the CFTR gene in 880 patients with ICP, 198 patients with idiopathic bronchiectasis (IB), 74 patients with classical cystic fibrosis (CF), 48 patients with congenital bilateral absence of the vas deferens (CBAVD) and 148 healthy controls. p.Arg75Gln variant was identified in 3.3% (29/880) of patients with ICP, 3.3% (9/272) patients with a pulmonary disease, 2.1% (1/48) of patients with CBAVD and 4.7% (7/148) of healthy controls. It was frequently associated with the c.[1210-12T[7];1408A>G] (T7-p.Val470) allele and this CFTR genetic background could not explain the putative pathogenicity of this variant. To assess whether CFTR and SPINK1 mutations are co-inherited in pancreatitis, we sequenced SPINK1 gene exon 3 in the 46 patients who were previously identified to be heterozygous for p.Arg75Gln. Two SPINK1 pancreatitis-associated variants, p.Asn34Ser and p.Pro55Ser, were found in 6 patients: 4 of 29 (13.8%) patients with ICP (3 p.Asn34Ser and 1 p.Pro55Ser), 1 of 7 (14.3%) healthy controls (p.Asn34Ser) and 1 of 9 (11.1%) patients with IB (p.Pro55Ser). Our study does not confirm that the CFTR p.Arg75Gln mutation confers a significant risk of pancreatitis both when considered individually and with a concurrent SPINK1 mutation, suggesting the role of other genetic and environmental factors.","variants":[{"Name":"NM_000492.4(CFTR):c.224G>A (p.Arg75Gln)","Chromosome":"7","Start":"117509093","Stop":"117509093","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44503,"rule_based_match":true,"evidence_text":"c.224G>A, p.Arg75Gln (R75Q)","llm_judgment":"PRESENT","evidence":"c.224G>A, p.Arg75Gln (R75Q)","abstract_start":0,"abstract_end":27}]}
{"pmid":"30912300","title":"Biallelic novel missense HHAT variant causes syndromic microcephaly and cerebellar-vermis hypoplasia.","abstract":"We report two siblings with microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia, in whom whole exome sequencing revealed a novel homozygous missense (c.770T>C, p.[Leu257Pro]) variant in the hedgehog acyl-transferase gene (HHAT), encoding an enzyme required for the attachment of palmitoyl residues that are critical for multimerization and long and short range hedgehog signaling. There is a report of one family with Nivelon-Nivelon-Mabille syndrome in which HHAT was proposed as the likely candidate gene. The phenotypic overlap with the family we report herein provides further evidence implicating HHAT in cerebellar development and the pathogenesis of this rare spectrum.","variants":[{"Name":"NM_018194.6(HHAT):c.770T>C (p.Leu257Pro)","Chromosome":"1","Start":"210418239","Stop":"210418239","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":975900,"rule_based_match":true,"evidence_text":"c.770T>C, p.[Leu257Pro]","llm_judgment":"PRESENT","evidence":"c.770T>C, p.[Leu257Pro]","abstract_start":177,"abstract_end":200}]}
{"pmid":"23317988","title":"Delayed diagnosis of transthyretin amyloidosis with a novel mutation (c.210T>A) in the transthyretin gene.","abstract":"","variants":[{"Name":"NM_000371.4(TTR):c.210T>A (p.Ser70Arg)","Chromosome":"18","Start":"31595129","Stop":"31595129","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":45551,"rule_based_match":true,"evidence_text":"c.210T>A","llm_judgment":"PRESENT","evidence":"c.210T>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"36237225","title":"Case report of Loeys-Dietz syndrome presenting with coronary artery aneurysm.","abstract":"Background: Loeys-Dietz syndrome (LDS) is a heritable disorder that presents with thoracic aortic aneurysm and/or dissection caused by a mutation in one of the transforming growth factor-B receptor or ligand genes. It is associated with widespread familial arterial aneurysm and rupture.\nCase summary: We present a case of a 70-year-old male with a family history of heritable thoracic aortic aneurysm disease who presented to the emergency department with chest pain. His presenting electrocardiogram was significant for ST elevation in the inferior leads with complete heart block. Computed tomography-angiography was done to rule out aortic dissection, which was negative for aortic dissection but did reveal 3.9 cm infrarenal abdominal aortic aneurysm and 2.7 cm bilateral iliac artery aneurysms. He was then taken for invasive angiography and was found to have aneurysmal dilation of the entire right coronary artery measuring up to 6 mm with 100% occlusion secondary to thrombus in the distal segment. He was found to have obstructive disease in the left anterior descending artery and first and second obtuse marginals (OMs). Genetic testing performed confirmed a pathogenic mutation in the <i>TGFBRI</i> gene (<i>TGFBRI</i> c.934G > A p.Gly312Ser) consistent with the diagnosis of LDS.\nDiscussion: Although LDS is known to cause arterial aneurysms throughout the arterial tree, there have been no other cases of primary coronary aneurysms reported in this patient population. This case represents the first description of a patient with genetically confirmed LDS presenting with coronary artery aneurysm.","variants":[{"Name":"NM_004612.4(TGFBR1):c.934G>A (p.Gly312Ser)","Chromosome":"9","Start":"99142664","Stop":"99142664","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":210182,"rule_based_match":true,"evidence_text":"TGFBRI c.934G > A p.Gly312Ser","llm_judgment":"PRESENT","evidence":"TGFBRI</i> c.934G > A p.Gly312Ser","abstract_start":1221,"abstract_end":1254}]}
{"pmid":"23424026","title":"Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups.","abstract":"UNLABELLED: Cholesteryl ester storage disease (CESD) and Wolman disease are autosomal recessive later-onset and severe infantile disorders, respectively, which result from the deficient activity of lysosomal acid lipase (LAL). LAL is encoded by LIPA (10q23.31) and the most common mutation associated with CESD is an exon 8 splice junction mutation (c.894G>A; E8SJM), which expresses only ∼3%-5% of normally spliced LAL. However, the frequency of c.894G>A is unknown in most populations. To estimate the prevalence of CESD in different populations, the frequencies of the c.894G>A mutation were determined in 10,000 LIPA alleles from healthy African-American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals from the greater New York metropolitan area and 6,578 LIPA alleles from African-American, Caucasian, and Hispanic subjects enrolled in the Dallas Heart Study. The combined c.894G>A allele frequencies from the two cohorts ranged from 0.0005 (Asian) to 0.0017 (Caucasian and Hispanic), which translated to carrier frequencies of 1 in 1,000 to ∼1 in 300, respectively. No African-American heterozygotes were detected. Additionally, by surveying the available literature, c.894G>A was estimated to account for 60% (95% confidence interval [CI]: 51%-69%) of reported mutations among multiethnic CESD patients. Using this estimate, the predicted prevalence of CESD in the Caucasian and Hispanic populations is ∼0.8 per 100,000 (∼1 in 130,000; 95% CI: ∼1 in 90,000 to 1 in 170,000).\nCONCLUSION: These data indicate that CESD may be underdiagnosed in the general Caucasian and Hispanic populations, which is important since clinical trials of enzyme replacement therapy for LAL deficiency are currently being developed. Moreover, future studies on CESD prevalence in African and Asian populations may require full-gene LIPA sequencing to determine heterozygote frequencies, since c.894G>A is not common in these racial groups.","variants":[{"Name":"NM_000235.4(LIPA):c.894G>A (p.Gln298=)","Chromosome":"10","Start":"89222511","Stop":"89222511","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":199794,"rule_based_match":true,"evidence_text":"c.894G>A","llm_judgment":"PRESENT","evidence":"c.894G>A","abstract_start":350,"abstract_end":358}]}
{"pmid":"15943552","title":"The Arg482His mutation in the beta-galactosidase gene is responsible for a high frequency of GM1 gangliosidosis carriers in a Cypriot village.","abstract":"GM1 gangliosidosis is a lysosomal storage disorder caused by deficiency of beta-galactosidase. It is mainly characterized by progressive neurodegeneration, and in its most severe infantile form, it leads to death before the age of 4. The GLB1 gene gives rise to two alternatively spliced mRNAs that encode the beta-galactosidase and the elastin binding protein (EBP). The diagnosis of two patients with the infantile form of GM1 gangliosidosis and 11 carriers in a small mountainous village in Cyprus prompted us to carry out a study in order to establish the frequency of carriers in the village and identify the mutations involved. Carrier detection was initially based on the measurement of beta-galactosidase activity in leucocytes. Among 85 random samples from the village, 10 were classified as carriers. Sequencing of the GLB1 gene in a Cypriot patient identified the missense mutation c.1445G>A (p.Arg482His) in the homozygous state. Seven of the 10 carriers identified using the enzyme assay were found to carry the same mutation by NspI restriction enzyme analysis. The three individuals who were negative for the c.1445G>A had borderline enzyme results and were probably wrongly classified as carriers. The frequency of GM1 gangliosidosis carriers in this village is approximately 8% (1:12). Western blot analysis showed a marked decrease of the 64-kDa mature form of the enzyme protein and a similar reduction of the 67-kDa EBP. Our results indicate that the c.1445G>A mutation, which appears to be responsible for all GM1 gangliosidosis alleles in this Cypriot village, affects protein conformation.","variants":[{"Name":"NM_000404.4(GLB1):c.1445G>A (p.Arg482His)","Chromosome":"3","Start":"33016743","Stop":"33016743","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15971,"rule_based_match":true,"evidence_text":"c.1445G>A (p.Arg482His)","llm_judgment":"PRESENT","evidence":"c.1445G>A (p.Arg482His)","abstract_start":893,"abstract_end":916}]}
{"pmid":"20685671","title":"The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K.","abstract":"BACKGROUND: Mutations in GDAP1 associate with demyelinating (CMT4A) and axonal (CMT2K) forms of CMT. While CMT4A shows recessive inheritance, CMT2K can present with either recessive (AR-CMT2K) or dominant segregation pattern (AD-CMT2K), the latter being characterised by milder phenotypes and later onset. The majority of the GDAP1 mutations are associated with CMT4A and AR-CMT2K, with only four heterozygous mutations identified in AD-CMT2K.\nMETHODS: We screened GDAP1 gene in a series of 43 index patients, 39 with CMT2 and 4 with intermediate CMT, with sporadic and familial occurrence of the disease.\nRESULTS: Three novel mutations were identified in three families with dominant segregation of the disease: two missense changes, p.Arg226Ser and p.Ser34Cys, affecting the GST domain of the GDAP1 protein and a novel deletion (c.23delAG) leading to early truncation of the protein upstream the GST domain. Wide variability in clinical presentation is shared by all three families mostly in terms of age at onset and disease severity. A rare variant p.Gly269Arg, located within the GST domain, apparently acts as phenotype modulator in the family carrying the deletion.\nCONCLUSION: The results obtained reveal a GDAP1 mutation frequency of 27% in the dominant families analysed, a figure still unreported for this gene, thus suggesting that GDAP1 involvement in dominant CMT2 might be higher than expected.","variants":[{"Name":"NM_018972.4(GDAP1):c.805G>A (p.Gly269Arg)","Chromosome":"8","Start":"74364095","Stop":"74364095","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1045668,"rule_based_match":false,"evidence_text":"p.Gly269Arg","llm_judgment":"PRESENT","evidence":"p.Gly269Arg","abstract_start":1053,"abstract_end":1064},{"Name":"NM_018972.4(GDAP1):c.101C>G (p.Ser34Cys)","Chromosome":"8","Start":"74350562","Stop":"74350562","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":625158,"rule_based_match":false,"evidence_text":"p.Ser34Cys","llm_judgment":"PRESENT","evidence":"p.Ser34Cys","abstract_start":751,"abstract_end":761},{"Name":"NM_018972.4(GDAP1):c.678A>T (p.Arg226Ser)","Chromosome":"8","Start":"74363037","Stop":"74363037","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":19243,"rule_based_match":false,"evidence_text":"p.Arg226Ser","llm_judgment":"PRESENT","evidence":"p.Arg226Ser","abstract_start":735,"abstract_end":746}]}
{"pmid":"21955071","title":"Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix.","abstract":"Deficiency of any component of the ER-resident collagen prolyl 3-hydroxylation complex causes recessive osteogenesis imperfecta (OI). The complex modifies the α1(I)Pro986 residue and contains cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1) and cyclophilin B (CyPB). Fibroblasts normally secrete about 10% of CRTAP. Most CRTAP mutations cause a null allele and lethal type VII OI. We identified a 7-year-old Egyptian boy with non-lethal type VII OI and investigated the effects of his null CRTAP mutation on collagen biochemistry, the prolyl 3-hydroxylation complex, and collagen in extracellular matrix. The proband is homozygous for an insertion/deletion in CRTAP (c.118_133del16insTACCC). His dermal fibroblasts synthesize fully overmodified type I collagen, and 3-hydroxylate only 5% of α1(I)Pro986. CRTAP transcripts are 10% of control. CRTAP protein is absent from proband cells, with residual P3H1 and normal CyPB levels. Dermal collagen fibril diameters are significantly increased. By immunofluorescence of long-term cultures, we identified a severe deficiency (10-15% of control) of collagen deposited in extracellular matrix, with disorganization of the minimal fibrillar network. Quantitative pulse-chase experiments corroborate deficiency of matrix deposition, rather than increased matrix turnover. We conclude that defects of extracellular matrix, as well as intracellular defects in collagen modification, contribute to the pathology of type VII OI.","variants":[{"Name":"NM_006371.5(CRTAP):c.118_133delinsTACCC (p.Glu40fs)","Chromosome":"3","Start":"33114195","Stop":"33114210","ReferenceAlleleVCF":"GAGCTGATGCCGCTCG","AlternateAlleleVCF":"TACCC","allel_id":51090,"rule_based_match":false,"evidence_text":"c.118_133del16insTACCC","llm_judgment":"PRESENT","evidence":"c.118_133del16insTACCC","abstract_start":686,"abstract_end":708}]}
{"pmid":"21844578","title":"Two novel PEX1 mutations in a patient with Zellweger syndrome: the first Korean case confirmed by biochemical, and molecular evidence.","abstract":"Peroxisome biogenesis disorders (PBD) represent a spectrum of genetic disorders characterized by impaired peroxisome assembly. Zellweger syndrome (ZS) is the most severe form of PBD and is characterized by craniofacial abnormalities, severe hypotonia, neonatal seizures, ocular abnormalities, psychomotor retardation, hepatomegaly and increased levels of very long chain fatty acids (VLCFA). The most common mutation associated with the PBD is PEX1. Here, the first Korean patient with ZS confirmed by clinical, biochemical, and molecular findings is reported. Two novel mutations of the PEX1 gene were identified in the patient with ZS. The patient was a compound heterozygote for c.2034_2035delCA and c.2845C>T mutations of the PEX1 gene. Both mutations are novel findings and were inherited from the patient's parents. In summary, here the first Korean case of ZS is reported that was confirmed by two novel mutations of the PEX1 gene.","variants":[{"Name":"NM_000466.3(PEX1):c.2034_2035del (p.His678fs)","Chromosome":"7","Start":"92504768","Stop":"92504769","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":357601,"rule_based_match":true,"evidence_text":"c.2034_2035delCA","llm_judgment":"PRESENT","evidence":"c.2034_2035delCA","abstract_start":682,"abstract_end":698},{"Name":"NM_000466.3(PEX1):c.2845C>T (p.Arg949Trp)","Chromosome":"7","Start":"92494568","Stop":"92494568","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":561815,"rule_based_match":true,"evidence_text":"c.2845C>T","llm_judgment":"PRESENT","evidence":"c.2845C>T","abstract_start":703,"abstract_end":712}]}
{"pmid":"22577899","title":"Recurrent and founder mutations in the PMS2 gene.","abstract":"Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However, some mutations are observed repeatedly across individuals not known to be related due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here, we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations and one (c.903G>T) a probable founder. One (c.1A>G) could not be evaluated for founder mutation status. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2.","variants":[{"Name":"NM_000535.7(PMS2):c.1A>G (p.Met1Val)","Chromosome":"7","Start":"6009019","Stop":"6009019","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":96798,"rule_based_match":true,"evidence_text":"c.1A>G","llm_judgment":"PRESENT","evidence":"c.1A>G","abstract_start":1174,"abstract_end":1180},{"Name":"NM_000535.7(PMS2):c.903G>T (p.Lys301Asn)","Chromosome":"7","Start":"5995534","Stop":"5995534","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":96852,"rule_based_match":true,"evidence_text":"c.903G>T","llm_judgment":"PRESENT","evidence":"c.903G>T","abstract_start":1139,"abstract_end":1147},{"Name":"NM_000535.7(PMS2):c.137G>T (p.Ser46Ile)","Chromosome":"7","Start":"6005918","Stop":"6005918","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":24284,"rule_based_match":true,"evidence_text":"c.137G>T","llm_judgment":"PRESENT","evidence":"c.137G>T","abstract_start":1075,"abstract_end":1083}]}
{"pmid":"37348440","title":"Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): A challenging diagnosis and a rare multiple sclerosis mimic.","abstract":"Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an extremely rare hereditary cerebral small vessel disease caused by homozygous or compound heterozygous mutations in the gene coding for high-temperature requirement A serine peptidase 1 (HtrA1). Given the rare nature of the disease, delays in diagnosis and misdiagnosis are not uncommon. In this article, we reported the first case of CARASIL from Saudi Arabia with a novel homozygous variant c.1156C>T in exon 7 of the HTRA1 gene. The patient was initially misdiagnosed with primary progressive multiple sclerosis and treated with rituximab. CARASIL should be considered in the differential diagnosis of patients with suspected atypical progressive multiple sclerosis who have additional signs such as premature scalp alopecia and low back pain with diffuse white matter lesions in brain MRI. Genetic testing is important to confirm the diagnosis.","variants":[{"Name":"NM_002775.5(HTRA1):c.1156C>T (p.Arg386Ter)","Chromosome":"10","Start":"122510131","Stop":"122510131","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3209684,"rule_based_match":true,"evidence_text":"c.1156C>T","llm_judgment":"PRESENT","evidence":"c.1156C>T","abstract_start":500,"abstract_end":509}]}
{"pmid":"31619740","title":"A systematic review of predicted pathogenic PALB2 variants: an analysis of mutational overlap between epithelial cancers.","abstract":"Partner and localiser of BRCA2 forms part of a macromolecular complex with BRCA1 and BRCA2, which is critical for the repair of double-strand DNA breaks by homologous DNA recombination. Germline loss-of-function variants in the PALB2 gene may confer an increased lifetime risk of breast, pancreatic, ovarian and other cancers. However, the complete spectrum of predicted pathogenic PALB2 variants associated with each tissue type of cancer remains unknown. A systematic review is performed with the aim of cataloguing predicted pathogenic PALB2 variants in breast, ovary and pancreas cancers. All catalogued predicted pathogenic variants are analysed to assess for overlap and mutational \"hotspots\" within gene exons. Our results showed that 911 (92.5%) cases were described in breast cancer patients, 49 (5.0%) cases were described in ovarian cancer patients, and 24 (2.4%) cases were described in pancreatic cancer patients. The top five most frequently reported predicted pathogenic PALB2 variants were c.509_510delGA, c.3113G > A, c.1592delT, c.172_175delTTGT, and c.1240C > T, accounting for 57.3% of all cases. Breast and pancreatic cancers share five variants while breast and ovarian cancers share 12 variants. Breast, ovarian and pancreatic cancers share eight common variants. Exons with the highest mutation rates were exons 2 (6.7%), 1 (6.3%) and 3 (5.8%). This systematic review provides a quantitative catalogue of predicted pathogenic PALB2 variants described in cancers. This comprehensive analysis of the PALB2 mutational spectrum represents a useful resource for clinicians overseeing PALB2-related cancer surveillance and provides a valuable resource for future PALB2-specific research.","variants":[{"Name":"NM_024675.4(PALB2):c.1240C>T (p.Arg414Ter)","Chromosome":"16","Start":"23635306","Stop":"23635306","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133574,"rule_based_match":true,"evidence_text":"c.1240C > T","llm_judgment":"PRESENT","evidence":"c.1240C > T","abstract_start":1069,"abstract_end":1080}]}
{"pmid":"23430526","title":"Questioning the Pathogenic Role of the GLA p.Ala143Thr \"Mutation\" in Fabry Disease: Implications for Screening Studies and ERT.","abstract":"Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.","variants":[{"Name":"NM_000169.3(GLA):c.427G>A (p.Ala143Thr)","Chromosome":"X","Start":"101401752","Stop":"101401752","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25787,"rule_based_match":true,"evidence_text":"c.427G>A","llm_judgment":"PRESENT","evidence":"c.427G>A","abstract_start":492,"abstract_end":500}]}
{"pmid":"25060679","title":"Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors.","abstract":"Lynch syndrome (LS) is an autosomal dominant cancer-susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico-pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS-associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non-pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C-terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.","variants":[{"Name":"NM_000249.4(MLH1):c.121G>C (p.Asp41His)","Chromosome":"3","Start":"36996623","Stop":"36996623","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":95156,"rule_based_match":true,"evidence_text":"c.121G > C (p.D41H)","llm_judgment":"PRESENT","evidence":"c.121G > C (p.D41H)","abstract_start":348,"abstract_end":367}]}
{"pmid":"25839108","title":"Mutations of SCN4A gene cause different diseases: 2 case reports and literature review.","abstract":"SCN4A encodes the Nav1.4 channel and mutations in SCN4A lead to different ionic channelopathies. In this study, one sporadic individual of periodic paralysis, one paramyotonia family and 200 normal healthy controls are enrolled. Genomic DNA was extracted from peripheral blood leukocytes, followed by polymerase chain reaction and DNA sequencing of candidate genes, including SCN4A and CACNA1S. As a result, heterozygous mutations c.2024G>A (R675Q) and c.1333G>A (V445M) of gene SCN4A were identified in the hypokalemic periodic paralysis patient and the paramyotonia congenita family respectively. Both mutations were not detected in healthy controls. Compared with reported cases, patients with mutation R675Q usually do not present hypokalemic periodic paralysis but hyperkalemic or normokalemic periodic paralysis. The mutation V445M was first reported in Chinese patients with nondystrophic myotonias. In addition, we carried out literature review by summarizing clinical features of the 2 mutations and establish the genotype-phenotype correlations to provide guidance for diagnosis.","variants":[{"Name":"NM_000334.4(SCN4A):c.1333G>A (p.Val445Met)","Chromosome":"17","Start":"63964587","Stop":"63964587","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20949,"rule_based_match":true,"evidence_text":"c.1333G>A (V445M)","llm_judgment":"PRESENT","evidence":"c.1333G>A (V445M)","abstract_start":453,"abstract_end":470},{"Name":"NM_000334.4(SCN4A):c.2024G>A (p.Arg675Gln)","Chromosome":"17","Start":"63957514","Stop":"63957514","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20958,"rule_based_match":true,"evidence_text":"c.2024G>A (R675Q)","llm_judgment":"PRESENT","evidence":"c.2024G>A (R675Q)","abstract_start":431,"abstract_end":448}]}
{"pmid":"21667091","title":"Bacterial expression of mutant argininosuccinate lyase reveals imperfect correlation of in-vitro enzyme activity with clinical phenotype in argininosuccinic aciduria.","abstract":"BACKGROUND: The urea cycle defect argininosuccinate lyase (ASL) deficiency has a large spectrum of presentations from highly severe to asymptomatic. Enzyme activity assays in red blood cells or fibroblasts, although diagnostic of the deficiency, fail to discriminate between severe, mild or asymptomatic cases. Mutation/phenotype correlation studies are needed to characterize the effects of individual mutations on the activity of the enzyme.\nMETHODS: Bacterial in-vitro expression studies allowed the enzyme analysis of purified mutant ASL proteins p.I100T (c.299 T > C), p.V178M (c.532 G > A), p.E189G (c.566A > G), p.Q286R (c.857A > G), p.K315E (c.943A > G), p.R379C (c.1135 C > T) and p.R385C (c.1153 C > T) in comparison to the wildtype protein.\nRESULTS: In the bacterial in-vitro expression system, ASL wild-type protein was successfully expressed. The known classical p.Q286R, the novel classical p.K315E and the known mutations p.I100T, p.E189G and p.R385C, which all have been linked to a mild phenotype, showed no significant residual activity. There was some enzyme activity detected with the p.V178M (5 % of wild-type) and p.R379C (10 % of wild-type) mutations in which K(m) values for argininosuccinic acid differed significantly from the wild-type ASL protein.\nCONCLUSION: The bacterially expressed enzymes proved that the mutations found in patients and studied here indeed are detrimental. However, as in the case of red cell ASL activity assays, some mutations found in genetically homozygous patients with mild presentations resulted in virtual loss of enzyme activity in the bacterial system, suggesting a more protective environment for the mutant enzyme in the liver than in the heterologous expression system and/or in the highly dilute assays utilized here.","variants":[{"Name":"NM_000048.4(ASL):c.1153C>T (p.Arg385Cys)","Chromosome":"7","Start":"66092566","Stop":"66092566","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17440,"rule_based_match":true,"evidence_text":"c.1153 C > T","llm_judgment":"PRESENT","evidence":"c.1153 C > T","abstract_start":699,"abstract_end":711},{"Name":"NM_000048.4(ASL):c.532G>A (p.Val178Met)","Chromosome":"7","Start":"66086751","Stop":"66086751","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17441,"rule_based_match":true,"evidence_text":"c.532 G>A","llm_judgment":"PRESENT","evidence":"c.532 G > A","abstract_start":583,"abstract_end":594},{"Name":"NM_000048.4(ASL):c.1135C>T (p.Arg379Cys)","Chromosome":"7","Start":"66092078","Stop":"66092078","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17442,"rule_based_match":true,"evidence_text":"c.1135 C > T","llm_judgment":"PRESENT","evidence":"c.1135 C > T","abstract_start":672,"abstract_end":684},{"Name":"NM_000048.4(ASL):c.566A>G (p.Glu189Gly)","Chromosome":"7","Start":"66086785","Stop":"66086785","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":544640,"rule_based_match":true,"evidence_text":"c.566A>G","llm_judgment":"PRESENT","evidence":"c.566A > G","abstract_start":606,"abstract_end":616},{"Name":"NM_000048.4(ASL):c.857A>G (p.Gln286Arg)","Chromosome":"7","Start":"66089114","Stop":"66089114","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":17438,"rule_based_match":true,"evidence_text":"c.857A>G","llm_judgment":"PRESENT","evidence":"c.857A > G","abstract_start":628,"abstract_end":638},{"Name":"NM_000048.4(ASL):c.299T>C (p.Ile100Thr)","Chromosome":"7","Start":"66082887","Stop":"66082887","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":487358,"rule_based_match":true,"evidence_text":"c.299 T>C","llm_judgment":"PRESENT","evidence":"c.299 T > C","abstract_start":560,"abstract_end":571}]}
{"pmid":"35782386","title":"Expanding the Phenotypic and Genotypic Spectrum of","abstract":"Mono-allelic loss-of-function variants in <i>ARFGEF1</i> have recently caused a developmental delay, intellectual disability, and epilepsy, with varying clinical expressivity. However, given the clinical heterogeneity and low-penetrance mutations of <i>ARFGEF1</i>-related neurodevelopmental disorder, the robustness of the gene-disease association requires additional evidence. In this study, five novel heterozygous <i>ARFGEF1</i> variants were identified in five unrelated pediatric patients with neurodevelopmental disorders, including one missense change (c.3539T>G), two canonical splice site variants (c.917-1G>T, c.2850+2T>A), and two frameshift (c.2923_c.2924delCT, c.4951delG) mutations resulting in truncation of ARFGEF1. The pathogenic/likely pathogenic variants presented here will be highly beneficial to patients undergoing genetic testing in the future by providing an expanded reference list of disease-causing variants.","variants":[{"Name":"NM_006421.5(ARFGEF1):c.3539T>G (p.Ile1180Arg)","Chromosome":"8","Start":"67228015","Stop":"67228015","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3731922,"rule_based_match":true,"evidence_text":"c.3539T>G","llm_judgment":"PRESENT","evidence":"c.3539T>G","abstract_start":561,"abstract_end":570}]}
{"pmid":"33062891","title":"Intragenic variants in the","abstract":"OBJECTIVE: The aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (<i>SMN1</i>) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in <i>SMN1</i> and with the <i>SMN2</i> copy number.\nMETHODS: Four hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the <i>SMN2</i> copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in <i>SMN1</i> by next-generation sequencing.\nRESULTS: Four hundred two patients (89.3%) presented homozygous exon 7-<i>SMN1</i> deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with <i>SMN2</i> copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the <i>SMN2</i> copies.\nCONCLUSIONS: Patients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the <i>SMN2</i> copy number did not correlate with disease severity in this group.","variants":[{"Name":"NM_000344.4(SMN1):c.5C>G (p.Ala2Gly)","Chromosome":"5","Start":"70925108","Stop":"70925108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":24207,"rule_based_match":true,"evidence_text":"c.5C>G","llm_judgment":"PRESENT","evidence":"c.5C>G","abstract_start":1091,"abstract_end":1097}]}
{"pmid":"32335878","title":"Newborn screening and variant analysis for methionine adenosyltransferase I/III deficiency","abstract":"OBJECTIVE: To summarize newborn screening for methionine adenosyltransferase I/III (MAT I/III) deficiency in Quanzhou region of Fujian Province.\nMETHODS: A total of 364 545 neonates were screened for inherited metabolic diseases by tandem mass spectrometry. High-throughput next generation sequencing combined with Sanger sequencing was used to detect potential variants in newborns with MAT I/III deficiency. Pathogenicity of suspected variants was predicted by using MutationTaster and HSF software.\nRESULTS: Three newborns were identified with MAT I/III deficiency by newborn screening, which yielded an incidence rate of 1 in 121 515. Amino acid and acylcarnitine analysis suggested that the serum methionine of the three patients have increased to various extents. All patients showed normal growth and development during follow-up, and were found to carry MAT1A gene variants including two missense variants [c.776C>T (p.Ala259Val) and c.791G>A (p.Arg264His)] and a synonymous variant [c.360C>T (p.Cys120Cys)]. Among these, c.776C>T (p.Ala259Val) and c.791G>A (p.Arg264His) were known to be pathogenic, whereas c.360C>T (p.Cys120Cys) was a novel variant. Bioinformatics analysis suggested that this variant may alter RNA splicing and affect the structure and function of the MAT1A protein.\nCONCLUSION: A systematic review of newborn screening for MAT I/III deficiency was provided. Discovery of the novel variant has enriched the variant profile of the MAT1A gene and provided a basis for the diagnosis of this disease.","variants":[{"Name":"NM_000429.3(MAT1A):c.360C>T (p.Cys120=)","Chromosome":"10","Start":"80280725","Stop":"80280725","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1972024,"rule_based_match":true,"evidence_text":"c.360C>T (p.Cys120Cys)","llm_judgment":"PRESENT","evidence":"c.360C>T (p.Cys120Cys)","abstract_start":992,"abstract_end":1014}]}
{"pmid":"28870973","title":"Primary hyperparathyroidism in young patients in Russia: high frequency of hyperparathyroidism-jaw tumor syndrome.","abstract":"BACKGROUND: Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial.\nOBJECTIVE: To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age.\nDESIGN: We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had <i>MEN1</i> mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome.\nMETHODS: The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (<i>MEN1</i>, <i>CASR</i>, <i>CDC73</i>, <i>CDKN1A</i>, <i>CDKN1B</i>, <i>CDKN1C</i>, <i>CDKN2A</i>, <i>CDKN2C</i>, <i>CDKN2D</i>). In cases suspicious for gross <i>CDC73</i> deletions multiplex ligation-dependent probe amplification was performed.\nRESULTS: NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in <i>CDC73</i> c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in <i>CASR</i> c.3145G>T (p.Glu1049*) and one in <i>MEN1</i> c.784-9G>A. In two patients, MLPA confirmed gross <i>CDC73</i> deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom <i>CDC73</i> mutations were found in 5/8.\nCONCLUSIONS: Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with <i>CDC73</i> mutations.","variants":[{"Name":"NM_001370259.2(MEN1):c.784-9G>A","Chromosome":"11","Start":"64807228","Stop":"64807228","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":197538,"rule_based_match":true,"evidence_text":"c.784-9G>A","llm_judgment":"PRESENT","evidence":"c.784-9G>A","abstract_start":1250,"abstract_end":1260},{"Name":"NM_024529.5(CDC73):c.685A>T (p.Arg229Ter)","Chromosome":"1","Start":"193142022","Stop":"193142022","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2753332,"rule_based_match":true,"evidence_text":"c.685A>T (p.Arg229*)","llm_judgment":"PRESENT","evidence":"c.685A>T (p.Arg229*)","abstract_start":1136,"abstract_end":1156},{"Name":"NM_000388.4(CASR):c.3145G>T (p.Glu1049Ter)","Chromosome":"3","Start":"122285099","Stop":"122285099","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1041913,"rule_based_match":true,"evidence_text":"c.3145G>T (p.Glu1049*)","llm_judgment":"PRESENT","evidence":"c.3145G>T (p.Glu1049*)","abstract_start":1204,"abstract_end":1226},{"Name":"NM_024529.5(CDC73):c.787C>T (p.Arg263Cys)","Chromosome":"1","Start":"193147924","Stop":"193147924","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":238202,"rule_based_match":true,"evidence_text":"c.787C>T (p.Arg263Cys)","llm_judgment":"PRESENT","evidence":"c.787C>T (p.Arg263Cys)","abstract_start":1161,"abstract_end":1183},{"Name":"NM_024529.5(CDC73):c.496C>T (p.Gln166Ter)","Chromosome":"1","Start":"193138157","Stop":"193138157","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1471391,"rule_based_match":true,"evidence_text":"c.496C>T (p.Gln166*)","llm_judgment":"PRESENT","evidence":"c.496C>T (p.Gln166*)","abstract_start":1114,"abstract_end":1134}]}
{"pmid":"23728841","title":"Novel DICER1 mutation as cause of multinodular goiter in children.","abstract":"BACKGROUND: The aim of this report was to present a rare case of an adolescent with multinodular goiter (MNG) found to have a DICER1 mutation.\nMETHODS AND RESULTS: The methodology includes a presentation and discussion of a chart review including endocrine hormone tests, thyroid ultrasound, and genetic testing for DICER1. A 12-year-old girl presented with a diffusely enlarged thyroid gland. Family history revealed an older sister with a history of bilateral ovarian Sertoli-Leydig cell tumors and MNG. Thyroid function tests were normal. Serial thyroid ultrasounds showed enlarging multiple bilateral nodules. Fine-needle aspiration suggested MNG. Genetic testing revealed a novel heterozygous premature termination mutation (c.1525C>T p.R509X) in the DICER1 gene.\nCONCLUSIONS: Thyroid nodules are rare in children but carry a higher risk for malignancy. It is essential to inquire about family history and refer for genetic evaluation with a family history of MNG. In patients with DICER1 mutations, tumor surveillance is critical due to the increased risk of multiple tumors, including ovarian tumors and pleuropulmonary blastoma.","variants":[{"Name":"NM_177438.3(DICER1):c.1525C>T (p.Arg509Ter)","Chromosome":"14","Start":"95116680","Stop":"95116680","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":248876,"rule_based_match":true,"evidence_text":"c.1525C>T p.R509X","llm_judgment":"PRESENT","evidence":"c.1525C>T p.R509X","abstract_start":730,"abstract_end":747}]}
{"pmid":"32161077","title":"Adult-onset methylenetetrahydrofolate reductase deficiency.","abstract":"Severe hyperhomocysteinemia (>100 µmol/L) is often associated with inborn errors of homocysteine metabolism. It manifests typically in neonatal period with developmental delay, hypotonia, feeding problems or failure to thrive. Adult-onset forms are rare and include less severe manifestations. Early diagnosis is crucial because effective treatment is available. A 23-year-old man presented with a 3-week history of speech and gait impairment, and numbness in lower limbs. Neurological examination revealed dysarthria, decreased vibratory sensation in both legs and appendicular and gait ataxia. Brain MRI revealed T2-hyperintense symmetric white matter lesions and cortical atrophy. He had folate and vitamin B<sub>12</sub> deficiency, a markedly elevated serum homocysteine and low methionine. Despite vitamin supplementation homocysteine levels remained elevated. Molecular studies of 5,10-methylenetetrahydrofolate reductase (<i>MTHFR</i>) gene revealed a new pathogenic mutation (c.1003C>T (p.Arg335Cys)) and a polymorphism (C677T (p.Ala222Val)) associated with hyperhomocysteinemia, both in homozygosity. The patient started betaine with clinical and biochemical improvement.","variants":[{"Name":"NM_005957.5(MTHFR):c.1003C>T (p.Arg335Cys)","Chromosome":"1","Start":"11795126","Stop":"11795126","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2108913,"rule_based_match":true,"evidence_text":"c.1003C>T (p.Arg335Cys)","llm_judgment":"PRESENT","evidence":"c.1003C>T (p.Arg335Cys)","abstract_start":985,"abstract_end":1008}]}
{"pmid":"31600781","title":"The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.","abstract":"In this study, we investigated the sequence of (Structural Maintenance of Chromosomes flexible Hinge Domain containing 1) SMCHD1 gene in a cohort of clinically defined FSHD (facioscapulohumeral muscular dystrophy) patients in order to assess the distribution of SMCHD1 variants, considering the D4Z4 fragment size in terms of repeated units (RUs; short fragment: 1-7 RU, borderline: 8-10RU and normal fragment: >11RU). The analysis of SMCHD1 revealed the presence of 82 variants scattered throughout the introns, exons and 3'untranslated region (3'UTR) of the gene. Among them, 64 were classified as benign polymorphisms and 6 as VUS (variants of uncertain significance). Interestingly, seven pathogenic/likely pathogenic variants were identified in patients carrying a borderline or normal D4Z4 fragment size, namely c.182_183dupGT (p.Q62Vfs*48), c.2129dupC (p.A711Cfs*11), c.3469G>T (p.G1157*), c.5150_5151delAA (p.K1717Rfs*16) and c.1131+2_1131+5delTAAG, c.3010A>T (p.K1004*), c.853G>C (p.G285R). All of them were predicted to disrupt the structure and conformation of SMCHD1, resulting in the loss of GHKL-ATPase and SMC hinge essential domains. These results are consistent with the FSHD symptomatology and the Clinical Severity Score (CSS) of patients. In addition, five variants (c.*1376A>C, rs7238459; c.*1579G>A, rs559994; c.*1397A>G, rs150573037; c.*1631C>T, rs193227855; c.*1889G>C, rs149259359) were identified in the 3'UTR region of SMCHD1, suggesting a possible miRNA-dependent regulatory effect on FSHD-related pathways. The present study highlights the clinical utility of next-generation sequencing (NGS) platforms for the molecular diagnosis of FSHD and the importance of integrating molecular findings and clinical data in order to improve the accuracy of genotype-phenotype correlations.","variants":[{"Name":"NM_015295.3(SMCHD1):c.182_183dup (p.Gln62fs)","Chromosome":"18","Start":"2656248","Stop":"2656249","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CGT","allel_id":999987,"rule_based_match":true,"evidence_text":"c.182_183dupGT (p.Q62Vfs*48)","llm_judgment":"PRESENT","evidence":"c.182_183dupGT (p.Q62Vfs*48)","abstract_start":818,"abstract_end":846},{"Name":"NM_015295.3(SMCHD1):c.3469G>T (p.Gly1157Ter)","Chromosome":"18","Start":"2739475","Stop":"2739475","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":999988,"rule_based_match":true,"evidence_text":"c.3469G>T (p.G1157*)","llm_judgment":"PRESENT","evidence":"c.3469G>T (p.G1157*)","abstract_start":875,"abstract_end":895},{"Name":"NM_015295.3(SMCHD1):c.5150_5151del (p.Lys1717fs)","Chromosome":"18","Start":"2772346","Stop":"2772347","ReferenceAlleleVCF":"TAA","AlternateAlleleVCF":"T","allel_id":999989,"rule_based_match":true,"evidence_text":"c.5150_5151delAA (p.K1717Rfs*16)","llm_judgment":"PRESENT","evidence":"c.5150_5151delAA (p.K1717Rfs*16)","abstract_start":897,"abstract_end":929},{"Name":"NM_015295.3(SMCHD1):c.2129dup (p.Ala711fs)","Chromosome":"18","Start":"2707626","Stop":"2707627","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":999990,"rule_based_match":true,"evidence_text":"c.2129dupC (p.A711Cfs*11)","llm_judgment":"PRESENT","evidence":"c.2129dupC (p.A711Cfs*11)","abstract_start":848,"abstract_end":873}]}
{"pmid":"27683825","title":"COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.","abstract":"BACKGROUND: Assembly of cytochrome c oxidase (COX, complex IV, cIV), the terminal component of the mitochondrial respiratory chain, is assisted by several factors, most of which are conserved from yeast to humans. However, some of them, including COA7, are found in humans but not in yeast. COA7 is a 231aa-long mitochondrial protein present in animals, containing five Sel1-like tetratricopeptide repeat sequences, which are likely to interact with partner proteins.\nMETHODS: Whole exome sequencing was carried out on a 19 year old woman, affected by early onset, progressive severe ataxia and peripheral neuropathy, mild cognitive impairment and a cavitating leukodystrophy of the brain with spinal cord hypotrophy. Biochemical analysis of the mitochondrial respiratory chain revealed the presence of isolated deficiency of cytochrome c oxidase (COX) activity in skin fibroblasts and skeletal muscle. Mitochondrial localization studies were carried out in isolated mitochondria and mitoplasts from immortalized control human fibroblasts.\nRESULTS: We found compound heterozygous mutations in COA7: a paternal c.410A>G, p.Y137C, and a maternal c.287+1G>T variants. Lentiviral-mediated expression of recombinant wild-type COA7 cDNA in the patient fibroblasts led to the recovery of the defect in COX activity and restoration of normal COX amount. In mitochondrial localization experiments, COA7 behaved as the soluble matrix protein Citrate Synthase.\nCONCLUSIONS: We report here the first patient carrying pathogenic mutations of COA7, causative of isolated COX deficiency and progressive neurological impairment. We also show that COA7 is a soluble protein localized to the matrix, rather than in the intermembrane space as previously suggested.","variants":[{"Name":"NM_023077.3(COA7):c.410A>G (p.Tyr137Cys)","Chromosome":"1","Start":"52688006","Stop":"52688006","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":431981,"rule_based_match":true,"evidence_text":"c.410A>G, p.Y137C","llm_judgment":"PRESENT","evidence":"c.410A>G, p.Y137C","abstract_start":1110,"abstract_end":1127}]}
{"pmid":"32532510","title":"Reduction in Filamin C transcript is associated with arrhythmogenic cardiomyopathy in Ashkenazi Jews.","abstract":"BACKGROUND: Filamin C is a cytoskeletal protein expressed in cardiac cells. Nonsense variations in the filamin C gene (FLNC) were associated with dilated and arrhythmogenic cardiomyopathies.\nMETHODS AND RESULTS: We identified an intronic variation in FLNC gene (c.3791-1G > C) in three unrelated Ashkenazi Jewish families with variable expression of arrhythmia and cardiomyopathy. cDNA was prepared from a mutation carrier's cultured skin fibroblasts. Quantitative PCR demonstrated a reduction in total FLNC transcript, and no other FLNC splice variants were found. Single-nucleotide polymorphism (SNP) analysis revealed heterozygous variations in the genomic DNA that were not expressed in the messenger RNA. Immunohistochemical analysis of cardiac sections detected a normal distribution of filamin C protein in the heart ventricles.\nCONCLUSION: The transcript that included the FLNC variant was degraded. Haploinsufficiency in filamin C underlies arrhythmogenic cardiomyopathy with variable symptoms.","variants":[{"Name":"NM_001458.5(FLNC):c.3791-1G>C","Chromosome":"7","Start":"128845989","Stop":"128845989","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":406971,"rule_based_match":true,"evidence_text":"c.3791-1G > C","llm_judgment":"PRESENT","evidence":"c.3791-1G > C","abstract_start":262,"abstract_end":275}]}
{"pmid":"33457206","title":"A recurring","abstract":"Iron‑sulfur clusters (FeSCs) are vital components of a variety of essential proteins, most prominently within mitochondrial respiratory chain complexes I-III; Fe-S assembly and distribution is performed <i>via</i> multi-step pathways. Variants affecting several proteins in these pathways have been described in genetic disorders, including severe mitochondrial disease. Here we describe a Christian Arab kindred with two infants that died due to mitochondrial disorder involving Fe-S containing respiratory chain complexes and a third sibling who survived the initial crisis. A homozygous missense variant in <i>NFS1</i>: c.215G>A; p.Arg72Gln was detected by whole exome sequencing. The <i>NFS1</i> gene encodes a cysteine desulfurase, which, in complex with ISD11 and ACP, initiates the first step of Fe-S formation. Arginine at position 72 plays a role in NFS1-ISD11 complex formation; therefore, its substitution with glutamine is expected to affect complex stability and function. Interestingly, this is the only pathogenic variant ever reported in the <i>NFS1</i> gene, previously described once in an Old Order Mennonite family presenting a similar phenotype with intra-familial variability in patient outcomes. Analysis of datasets from both populations did not show a common haplotype, suggesting this variant is a recurrent <i>de novo</i> variant. Our report of the second case of NFS1-related mitochondrial disease corroborates the pathogenicity of this recurring variant and implicates it as a hot-spot variant. While the genetic resolution allows for prenatal diagnosis for the family, it also raises critical clinical questions regarding follow-up and possible treatment options of severely affected and healthy homozygous individuals with mitochondrial co-factor therapy or cysteine supplementation.","variants":[{"Name":"NM_021100.5(NFS1):c.215G>A (p.Arg72Gln)","Chromosome":"20","Start":"35697793","Stop":"35697793","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1161574,"rule_based_match":true,"evidence_text":"c.215G>A; p.Arg72Gln","llm_judgment":"PRESENT","evidence":"c.215G>A; p.Arg72Gln","abstract_start":623,"abstract_end":643}]}
{"pmid":"16830052","title":"Novel and recurrent germline alterations in the MLH1 and MSH2 genes identified in hereditary nonpolyposis colorectal cancer patients in Slovakia.","abstract":"Hereditary non-polyposis colorectal cancer (HNPCC) is associated with germline mutations in DNA mismatch repair genes, predominantly MSH2 and MLH1. Mutation carriers develop cancers in the colorectum, endometrium, ovary, stomach, small intestine and the upper urinary tract. We describe here the results of a mutational analysis of 11 unrelated HNPCC patients by direct genomic sequencing of MLH1 and MSH2. The alterations found include 7 novel changes and 4 different pathogenic mutations described previously in Poland, Moldavia, Finland, Germany, France and USA. Four novel pathogenic mutations in the MLH1 gene include two frameshift mutations (c.1150delG and c.1210_1211delCT), one missense mutation (c.793C>A) and one intron-exon border mutation (c.546- 2A>C). The last change resulted in the skipping of exon 7, as shown by sequencing of RT-PCR products. The only novel MSH2 pathogenic change was a nonsense mutation c.1129C>T. The novel intronic change c.381-41A>G in MLH1 was found in a patient carrying a previously-described mutation in the MSH2 gene. Interestingly, two unrelated patients carried also a novel change in the promoter region of MLH1 in one of the CpG islands (c.-269C>G). However, this alteration does not abrogate transcription, as shown by RT-PCR analysis. In summary, most (approximately 80%) pathogenic germline mutations detected in the studied group of patients by direct genomic sequencing of MLH1 and MSH2 were located in the MLH1 gene. These and previous data indicate that the majority of germline point mutations and small deletions/insertions in HNPCC families in Slovakia affect the MLH1 locus.","variants":[{"Name":"NM_000249.4(MLH1):c.1210_1211del (p.Leu404fs)","Chromosome":"3","Start":"37025808","Stop":"37025809","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":95152,"rule_based_match":true,"evidence_text":"c.1210_1211delCT","llm_judgment":"PRESENT","evidence":"c.1210_1211delCT","abstract_start":664,"abstract_end":680},{"Name":"NM_000251.3(MSH2):c.1129C>T (p.Gln377Ter)","Chromosome":"2","Start":"47429794","Stop":"47429794","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":96025,"rule_based_match":true,"evidence_text":"c.1129C>T","llm_judgment":"PRESENT","evidence":"c.1129C>T","abstract_start":924,"abstract_end":933},{"Name":"NM_000249.4(MLH1):c.546-2A>C","Chromosome":"3","Start":"37011818","Stop":"37011818","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":95740,"rule_based_match":true,"evidence_text":"c.546- 2A>C","llm_judgment":"PRESENT","evidence":"c.546- 2A>C","abstract_start":753,"abstract_end":764}]}
{"pmid":"34267460","title":"Next-Generation Sequencing Based Approach to Identify Underlying Genetic Defects of Glanzmann Thrombasthenia.","abstract":"Glanzmann thrombasthenia (GT) is an autosomal recessive platelet function disorder characterized by mucocutaneous bleeding as the most common clinical phenotype. Patients with GT have normal platelet counts, platelet morphology but reduced platelet aggregation in response to various agonists. Homozygosity or compound heterozygosity for variants in the <i>ITGA2B/ITGB3</i> genes is the genetic basis for GT. Establishing a molecular diagnosis is definitive and is important for predictive testing. Using multi-gene panels is an accurate, faster, and cost-effective mode as compared to Sanger sequencing in large genes. We used a targeted resequencing based approach to identify pathogenic variants in eight cases in seven families. These variants were validated using Sanger sequencing in patients as well as family members and were predicted probably pathogenic using <i>in-silico</i> prediction tools. The variants include three missense (3/7 = 43%) (<i>ITGA2B:</i>c.1028 T > C, <i>ITGA2B:</i>c.1186G > A, <i>ITGB3:</i>c.1388G > C), two deletions (<i>ITGA2B:</i>c.559delG, <i>ITGA2B:</i>c.3092delT), one duplication (<i>ITGA2B:</i>c.1424_1427dupAGGT) and nonsense variant (<i>ITGA2B:</i>c.2578C > T, p.Gln860Ter). Except for one case which was compound heterozygous, the rest of the cases were homozygous. We found two novel variants that are reported for the first time in GT. The targeted resequencing based approach revealed varied genetic variants in North Indian patients, including two novels ones. The high yield of our panel indicates its suitability for usage in larger cohorts for the genetic diagnosis of GT patients. This approach is cost-effective and less cumbersome as compared to Sanger sequencing for these large size genes with multiple exons. The information so obtained is helpful in prenatal testing, carrier analysis, and genetic counseling.","variants":[{"Name":"NM_000419.5(ITGA2B):c.3092del (p.Leu1031fs)","Chromosome":"17","Start":"44372392","Stop":"44372392","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1683967,"rule_based_match":true,"evidence_text":"ITGA2B:c.3092delT","llm_judgment":"PRESENT","evidence":"c.3092delT","abstract_start":1090,"abstract_end":1100}]}
{"pmid":"29207047","title":"Clinical and next-generation sequencing findings in a Chinese family exhibiting severe familial exudative vitreoretinopathy.","abstract":"Familial exudative vitreoretinopathy (FEVR) is a rare hereditary retinal disorder characterized by the premature arrest of vascularization in the peripheral retina. The aim of the present study was to characterize the clinical presentations of a Chinese family affected by bilateral severe FEVR, and to identify the underlying genetic variations. One family that presented with bilateral FEVR was recruited for this study. Comprehensive ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus photography, fundus fluorescein angiography imaging and electroretinogram were performed. Genomic DNA was extracted from leukocytes of the peripheral blood collected from the affected and unaffected family members, as well as 200 unrelated control subjects from the same population. Next‑generation sequencing of the candidate genes associated with ocular diseases was performed, and the identified mutations were validated by conventional polymerase chain reaction‑based sequencing. The functional effects of the mutations were analyzed by polymorphism phenotyping (PolyPhen) and sorting intolerant from tolerant (SIFT). One heterozygous ATP binding cassette subfamily A member 4 (ABCA4) c.5693G>A (p.R1898H) mutation in exon 40 and one heterozygous LDL receptor related protein 5 (LRP5) c.260T>G (p.I87S) mutation in exon 2 were identified in this family. To the best of our knowledge, the ABCA4 c.5693G>A (p.R1898H) mutation has not been reported in FEVR, and the LRP5 c.260T>G (p.I87S) mutation is a novel mutation. PolyPhen and SIFT predicted that the amino acid substitution R1898H in protein ABCA4 is benign, whereas the amino acid substitution I87S in protein LRP5 is damaging. A single nucleotide polymorphism c.266A>G (p.Q89R, rs41494349) was identified in exon 2 of LRP5. These findings expand the mutation spectrums of ABCA4 and LRP5, and will be valuable for genetic counseling and development of therapeutic interventions for patients with FEVR.","variants":[{"Name":"NM_000350.3(ABCA4):c.5693G>A (p.Arg1898His)","Chromosome":"1","Start":"94010821","Stop":"94010821","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105287,"rule_based_match":true,"evidence_text":"ABCA4 c.5693G>A (p.R1898H)","llm_judgment":"PRESENT","evidence":"ABCA4 c.5693G>A (p.R1898H)","abstract_start":1424,"abstract_end":1450}]}
{"pmid":"20381179","title":"What can be done when asymptomatic patients discover they have Brugada syndrome? A case report of Brugada syndrome.","abstract":"Brugada syndrome is an inherited cardiac disorder associated with a specific electrocardiographic pattern, involving ST segment elevation in leads V1 to V3. When not spontaneously terminated, it can lead to ventricular fibrillation and sudden death. We present a case report of a young male whose brother suffered a sudden cardiac arrest while playing soccer. A novel mutation c.2678G>A was detected on the gene SCN5A through molecular diagnosis. The mutation was shown to be present in the individual, his daughter and his other brother. For patients with previous ventricular fibrillation and/or syncope, implantable cardiac device (ICD) is recommended. However, how can patients without symptoms but with a clear diagnosis prevent cardiac arrest?","variants":[{"Name":"NM_000335.5(SCN5A):c.2678G>A (p.Arg893His)","Chromosome":"3","Start":"38585800","Stop":"38585800","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":78644,"rule_based_match":true,"evidence_text":"c.2678G>A","llm_judgment":"PRESENT","evidence":"c.2678G>A","abstract_start":377,"abstract_end":386}]}
{"pmid":"23368983","title":"HPA-5 typing discrepancy reveals an Ile503Leu substitution in platelet GPIa (α2 integrin).","abstract":"BACKGROUND AND OBJECTIVES: In fetal/neonatal thrombocytopenia, maternal alloimmunization is diagnosed by the identification of the maternal alloantibody and the offending paternal antigen inherited by the foetus/neonate. Today, for practical reasons, most laboratories perform platelet genotyping instead of phenotyping. Here, we report the case of a human platelet antigen (HPA)-5 genotype/phenotype discrepancy observed in a mother who delivered a mildly thrombocytopenic newborn.\nMATERIALS AND METHODS: Platelet antibody detection and platelet phenotyping were performed using the MAIPA assay; platelet genotypes were determined using BeadChip technology (BioArray), PCR-SSP, PCR-RFLP and sequencing.\nRESULTS: Serological investigations revealed the presence of maternal anti-GPIIbIIIa autoantibodies. No alloantibodies were detected. No feto-maternal platelet incompatibility was observed for HPA-1 to -21. The mother and newborn were genotyped as HPA-5aa using BeadChips, but as HPA-5a (weak b) with PCR-SSP and HPA-5ab with PCR-RFLP. Mother's platelets were phenotyped as HPA-5b(+). GPIa exon 13 sequencing confirmed the HPA-5ab genotype of the mother and newborn, and revealed an NM_002203.3:c.1594A>C mutation near the HPA-5 polymorphism (5' side), leading to an I503L amino acid change.\nCONCLUSION: Feto-maternal alloimmunization was ruled out: the neonatal thrombocytopenia probably resulted from maternal anti-GPIIbIIIa autoantibodies. This case highlights that platelet typing should be performed using two different methods to avoid false diagnosis.","variants":[{"Name":"NM_002203.4(ITGA2):c.1594A>C (p.Ile532Leu)","Chromosome":"5","Start":"53062921","Stop":"53062921","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":304422,"rule_based_match":true,"evidence_text":"NM_002203.3:c.1594A>C","llm_judgment":"PRESENT","evidence":"NM_002203.3:c.1594A>C","abstract_start":1187,"abstract_end":1208}]}
{"pmid":"24430573","title":"A novel homozygous YARS2 mutation causes severe myopathy, lactic acidosis, and sideroblastic anemia 2.","abstract":"Mitochondrial diseases are associated with defects of adenosine triphosphate production and energy supply to organs as a result of dysfunctions of the mitochondrial respiratory chain. Biallelic mutations in the YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase cause myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2), a type of mitochondrial disease. Here, we report a consanguineous Turkish family with two siblings showing severe metabolic decompensation including recurrent hypoglycemia, lactic acidosis, and transfusion-dependent anemia. Using whole-exome sequencing of the proband and his parents, we identified a novel YARS2 mutation (c.1303A>G, p.Ser435Gly) that was homozygous in the patient and heterozygous in his parents. This mutation is located at the ribosomal protein S4-like domain of the gene, while other reported YARS2 mutations are all within the catalytic domain. Interestingly, the proband showed more severe symptoms and an earlier onset than previously reported patients, suggesting the functional importance of the S4-like domain in tyrosyl-tRNA synthetase.","variants":[{"Name":"NM_001040436.3(YARS2):c.1303A>G (p.Ser435Gly)","Chromosome":"12","Start":"32747335","Stop":"32747335","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":108178,"rule_based_match":true,"evidence_text":"c.1303A>G (p.Ser435Gly)","llm_judgment":"PRESENT","evidence":"p.Ser435Gly","abstract_start":673,"abstract_end":684}]}
{"pmid":"32662074","title":"Generalized bullae in a young girl with KRT6A-related pachyonychia congenita.","abstract":"Pachyonychia congenita (PC) is a rare genodermatosis showing heterogeneity with five causative keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). Clinically, PC is characterized by hypertrophic onychodystrophy, painful palmoplantar keratoderma, oral leukokeratosis, and follicular hyperkeratosis. We describe an atypical case of PC in a young Chinese girl presenting with generalized bullae and identified a recurrent heterozygous missense mutation c.1406T > C (p.Leu469Pro) in KRT6A. This suggests that bullae may represent an important feature of KRT6A-related PC.","variants":[{"Name":"NM_005554.4(KRT6A):c.1406T>C (p.Leu469Pro)","Chromosome":"12","Start":"52488346","Stop":"52488346","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":77473,"rule_based_match":true,"evidence_text":"c.1406T > C (p.Leu469Pro)","llm_judgment":"PRESENT","evidence":"c.1406T > C (p.Leu469Pro)","abstract_start":452,"abstract_end":477}]}
{"pmid":"35991577","title":"Case report: FOXP1 syndrome caused by a","abstract":"FOXP1 syndrome is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, and language delay, with or without autistic features. Several splicing variants have been reported for this condition, but most of them lack functional evidence, and the actual effects of the sequence changes are still unknown. In this study, a <i>de novo</i> splicing variant (c.1652 + 5 G>A) of the <i>FOXP1</i> gene was identified in a patient with global developmental delay, mild intellectual disability, speech delay, and autistic features. Assessed by TA-cloning, the variant promoted the skipping of exon 18 and a premature stop codon (p.Asn511*), resulting in a predicted truncated protein. This variant, that is lacking the forkhead-box DNA-binding domain and nuclear localization signal 2, may disrupt the protein function and thus cause FOXP1 syndrome-related symptoms. Our study extends the phenotypic and allelic spectra of the FOXP1 syndrome.","variants":[{"Name":"NM_001349338.3(FOXP1):c.1652+5G>A","Chromosome":"3","Start":"70972550","Stop":"70972550","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":192059,"rule_based_match":true,"evidence_text":"c.1652 + 5 G>A","llm_judgment":"PRESENT","evidence":"c.1652 + 5 G>A","abstract_start":402,"abstract_end":416}]}
{"pmid":"34790634","title":"Myotonia Congenita: Clinical Characteristic and Mutation Spectrum of CLCN1 in Chinese Patients.","abstract":"<b>Background:</b> <i>CLCN1</i>-related myotonia congenita (MC) is one of the most common forms of non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. However, there is limited data of clinical and molecular spectrum of MC patients in China. <b>Patients and Methods:</b> Five patients with myotonia congenita due to mutations in <i>CLCN1</i> gene were enrolled, which were identified through trio-whole-exome sequencing or panel-based next-generation sequencing test. The clinical presentation, laboratory data, electrophysiological tests, muscular pathology feature, and genetic results were collected and reviewed. We also searched all previously reported cases of MC patients with genetic diagnosis in Chinese populations, and their data were reviewed. <b>Results:</b> The median onset age of five patients was 3.0 years old, ranging from 1.0 to 5.0 years old, while the median age of admit was 5.0 years old, ranging from 3.5 to 8.8 years old. Five patients complained of muscle stiffness when rising from chairs or starting to climb stairs (5/5, 100.0%), four patients complained of delayed relaxation of their hands after forceful grip (4/5, 80.0%), all of which improved with exercise (warm-up phenomenon) (5/5, 100%). Electromyogram was conducted in five patients, which all revealed myotonic change (100%). Genetic tests revealed nine potential disease-causing variants in <i>CLCN1</i> gene, including two novel variants: c.962T>A (p.V321E) and c.1250A>T (p.E417V). Literature review showed that 43 MC Chinese patients with genetic diagnosis have been reported till now (including our five patients). Forty-seven variants in <i>CLCN1</i> gene were found, which consisted of 33 missense variants, 6 nonsense variants, 5 frame-shift variants, and 3 splicing variants. Variants in exon 8, 15, 12, and 16 were most prevalent, while the most common variants were c.892G>A (p.A298T) (<i>n</i> = 9), c.139C>T (p.R47W) (<i>n</i> = 3), c.1205C>T(p.A402V) (<i>n</i> = 3), c.1657A>T (p.I553F) (<i>n</i> = 3), c.1679T>C (p.M560T) (<i>n</i> = 3), c.350A>G (p.D117G) (<i>n</i> = 2), c.762C>G (p.C254W) (<i>n</i> = 2), c.782A>G (P.Y261C) (<i>n</i> = 2), and c.1277C>A (p.T426N) (<i>n</i> = 2). <b>Conclusion:</b> Our results reported five <i>CLCN1</i>-related MC patients, which expanded the clinical and genetic spectrum of MC patients in China. Based on literature review, 43MC Chinese patients with genetic diagnosis have been reported till now, and variants in exon eight were most prevalent in Chinese MC patients while c.892G>A (p.A298T) was probably a founder mutation.","variants":[{"Name":"NM_000083.3(CLCN1):c.762C>G (p.Cys254Trp)","Chromosome":"7","Start":"143323374","Stop":"143323374","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":635817,"rule_based_match":true,"evidence_text":"c.762C>G (p.C254W)","llm_judgment":"PRESENT","evidence":"c.762C>G (p.C254W)","abstract_start":2128,"abstract_end":2146},{"Name":"NM_000083.3(CLCN1):c.962T>A (p.Val321Glu)","Chromosome":"7","Start":"143330880","Stop":"143330880","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":635827,"rule_based_match":true,"evidence_text":"c.962T>A (p.V321E)","llm_judgment":"PRESENT","evidence":"c.962T>A (p.V321E)","abstract_start":1481,"abstract_end":1499},{"Name":"NM_000083.3(CLCN1):c.892G>A (p.Ala298Thr)","Chromosome":"7","Start":"143330810","Stop":"143330810","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":523094,"rule_based_match":true,"evidence_text":"c.892G>A (p.A298T)","llm_judgment":"PRESENT","evidence":"c.892G>A (p.A298T)","abstract_start":1917,"abstract_end":1935}]}
{"pmid":"31118044","title":"Next-generation sequencing for identifying a novel/de novo pathogenic variant in a Mexican patient with cystic fibrosis: a case report.","abstract":"BACKGROUND: Mexico is among the countries showing the highest heterogeneity of CFTR variants. However, no de novo variants have previously been reported in Mexican patients with cystic fibrosis (CF).\nCASE PRESENTATION: Here, we report the first case of a novel/de novo variant in a Mexican patient with CF. Our patient was an 8-year-old male who had exhibited the clinical onset of CF at one month of age, with steatorrhea, malabsorption, poor weight gain, anemia, and recurrent respiratory tract infections. Complete sequencing of the CFTR gene by next generation sequencing (NGS) revealed two different variants in trans, including the previously reported CF-causing variant c.3266G > A (p.Trp1089*, W1089*), that was inherited from the mother, and the novel/de novo CFTR variant c.1762G > T (p.Glu588*).\nCONCLUSION: Our results demonstrate the efficiency of targeted NGS for making a rapid and precise diagnosis in patients with clinically suspected CF. This method can enable the provision of accurate genetic counselling, and improve our understanding of the molecular basis of genetic diseases.","variants":[{"Name":"NM_000492.4(CFTR):c.3266G>A (p.Trp1089Ter)","Chromosome":"7","Start":"117611707","Stop":"117611707","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22233,"rule_based_match":true,"evidence_text":"c.3266G > A (p.Trp1089*, W1089*)","llm_judgment":"PRESENT","evidence":"c.3266G > A (p.Trp1089*, W1089*)","abstract_start":677,"abstract_end":709}]}
{"pmid":"21722858","title":"Disruption of PTPRO causes childhood-onset nephrotic syndrome.","abstract":"Idiopathic nephrotic syndrome (INS) is a genetically heterogeneous group of disorders characterized by proteinuria, hypoalbuminemia, and edema. Because it typically results in end-stage kidney disease, the steroid-resistant subtype (SRNS) of INS is especially important when it occurs in children. The present study included 29 affected and 22 normal individuals from 17 SRNS families; genome-wide analysis was performed with Affymetrix 250K SNP arrays followed by homozygosity mapping. A large homozygous stretch on chromosomal region 12p12 was identified in one consanguineous family with two affected siblings. Direct sequencing of protein tyrosine phosphatase receptor type O (PTPRO; also known as glomerular epithelial protein-1 [GLEPP1]) showed homozygous c.2627+1G>T donor splice-site mutation. This mutation causes skipping of the evolutionarily conserved exon 16 (p.Glu854_Trp876del) at the RNA level. Immunohistochemistry with GLEPP1 antibody showed a similar staining pattern in the podocytes of the diseased and control kidney tissues. We used a highly polymorphic intragenic DNA marker-D12S1303-to search for homozygosity in 120 Turkish and 13 non-Turkish individuals in the PodoNet registry. This analysis yielded 17 candidate families, and a distinct homozygous c.2745+1G>A donor splice-site mutation in PTPRO was further identified via DNA sequencing in a second Turkish family. This mutation causes skipping of exon 19, and this introduces a premature stop codon at the very beginning of exon 20 (p.Asn888Lysfs*3) and causes degradation of mRNA via nonsense-mediated decay. Immunohistochemical analysis showed complete absence of immunoreactive PTPRO. Ultrastructural alterations, such as diffuse foot process fusion and extensive microvillus transformation of podocytes, were observed via electron microscopy in both families. The present study introduces mutations in PTPRO as another cause of autosomal-recessive nephrotic syndrome.","variants":[{"Name":"NM_030667.3(PTPRO):c.2627+1G>T","Chromosome":"12","Start":"15557524","Stop":"15557524","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39065,"rule_based_match":true,"evidence_text":"c.2627+1G>T","llm_judgment":"PRESENT","evidence":"c.2627+1G>T","abstract_start":762,"abstract_end":773}]}
{"pmid":"34993563","title":"Genetic and phenotypic variability in adult patients with Niemann Pick type C from Serbia: single-center experience.","abstract":"BACKGROUND: Niemann Pick type C is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 and NPC2 genes. It is a neuro-visceral disease with a heterogeneous phenotype. Clinical features depend on the age at onset. Visceral manifestations are more prominent in the early onset (infantile) form, while neuro-psychiatric symptoms are more prominent in the late disease onset (juvenile and adult forms).\nMETHODS: A total number of 150 patients have been screened for changes in NPC1 and NPC2 gene at the Neurology Clinic, University Clinical Centre of Serbia in the period 2012-2020. Clinical data were extracted for patients with biallelic mutations.\nRESULTS: Fifteen patients carried biallelic mutations in the NPC1. Out of eight different reported NPC1 variants, four are novel (c.1204_1205TT>GC, p.F402A; c.2486T>G, p.L829R; c.2795+5 G>C; c.3722T>A, p.L1241*). The mean age at the disease onset was 20.3 ± 11.9 years with the average diagnostic delay of 7.7 ± 4.3 years. Movement disorders and psychiatric or cognitive disturbances were the most common initial symptoms (in 33% and 28% patients, respectively). The average age at the first neurological manifestation was 21 ± 12.0 years. At the last examination, eye movement abnormalities (vertical slow saccades or vertical supranuclear gaze palsy), and ataxia were present in all patients, while dystonia was common (in 78.6% of patients). Presence of c.2861C>T, p.S954L mutation in homozygous state was associated with older age at the neurological symptom onset.\nCONCLUSIONS: Clinical findings were in line with the expected, but the diagnostic delay was common. We hypothesize that the presence of c.2861C>T, p.S954L mutation may contribute to the phenotype attenuation.","variants":[{"Name":"NM_000271.5(NPC1):c.1204_1205delinsGC (p.Phe402Ala)","Chromosome":"18","Start":"23556364","Stop":"23556365","ReferenceAlleleVCF":"AA","AlternateAlleleVCF":"GC","allel_id":3410328,"rule_based_match":false,"evidence_text":"c.1204_1205TT>GC, p.F402A","llm_judgment":"PRESENT","evidence":"c.1204_1205TT>GC, p.F402A","abstract_start":802,"abstract_end":827}]}
{"pmid":"29582136","title":"Unexplained cardiac arrest: a tale of conflicting interpretations of KCNQ1 genetic test results.","abstract":"OBJECTIVE: Unexplained cardiac arrest (UCA) is often the first manifestation of an inherited arrhythmogenic disease. Genetic testing in UCA is challenging due to the complexities of variant interpretation in the absence of supporting cardiac phenotype. We aimed to investigate if a KCNQ1 variant [p.(Pro64_Pro70del)], previously reported as pathogenic, contributes to the long-QT syndrome phenotype, co-segregates with disease or affects KCNQ1 function in vitro.\nMETHODS: DNA was extracted from peripheral blood of a 22-year-old male after resuscitation from UCA. Targeted exome sequencing was performed using the TruSight-One Sequencing Panel (Illumina). Variants in 190 clinically relevant cardiac genes with minor allele frequency < 1% were analyzed according to the guidelines of the American College of Medical Genetics. Functional characterization was performed using site-directed mutagenesis, expression in Xenopus laevis oocytes using the two-electrode voltage-clamp technique.\nRESULTS: The 12-lead ECG, transthoracic echocardiography and coronary angiography after resuscitation showed no specific abnormalities. Two variants were identified: c.190_210del in-frame deletion in KCNQ1 (p.Pro64_Pro70del), reported previously as pathogenic and c.2431C > A in PKP2 (p.Arg811Ser), classified as likely benign. Two asymptomatic family members with no evident phenotype hosted the KCNQ1 variant. Functional studies showed that the wild-type and mutant channels have no significant differences in current levels, conductance-voltage relationships, as well as activation and deactivation kinetics, in the absence and presence of the auxiliary subunit KCNE1.\nCONCLUSIONS: Based on our data and previous reports, available evidence is insufficient to consider the variant KCNQ1:c.190_210del as pathogenic. Our findings call for cautious interpretation of genetic tests in UCA in the absence of a clinical phenotype.","variants":[{"Name":"NM_000218.3(KCNQ1):c.190_210del (p.Pro64_Pro70del)","Chromosome":"11","Start":"2445280","Stop":"2445300","ReferenceAlleleVCF":"CCCGCGCCCCCTGCGTCCCCGG","AlternateAlleleVCF":"C","allel_id":994444,"rule_based_match":true,"evidence_text":"c.190_210del in-frame deletion in KCNQ1 (p.Pro64_Pro70del)","llm_judgment":"PRESENT","evidence":"c.190_210del in-frame deletion in KCNQ1 (p.Pro64_Pro70del)","abstract_start":1153,"abstract_end":1211}]}
{"pmid":"29255276","title":"CHARGE syndrome: a recurrent hotspot of mutations in CHD7 IVS25 analyzed by bioinformatic tools and minigene assays.","abstract":"CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3' splice site, of which the existence was confirmed using pSpliceExpress, an easy-to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis.","variants":[{"Name":"NM_017780.4(CHD7):c.5405-18C>A","Chromosome":"8","Start":"60850475","Stop":"60850475","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":420428,"rule_based_match":true,"evidence_text":"c.5405-18C > A","llm_judgment":"PRESENT","evidence":"c.5405-18C > A","abstract_start":223,"abstract_end":237},{"Name":"NM_017780.4(CHD7):c.5405-13G>A","Chromosome":"8","Start":"60850480","Stop":"60850480","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":420429,"rule_based_match":true,"evidence_text":"c.5405-13G > A","llm_judgment":"PRESENT","evidence":"c.5405-13G > A","abstract_start":188,"abstract_end":202},{"Name":"NM_017780.4(CHD7):c.5405-17G>A","Chromosome":"8","Start":"60850476","Stop":"60850476","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":193139,"rule_based_match":true,"evidence_text":"c.5405-17G>A","llm_judgment":"PRESENT","evidence":"c.5405-17G > A","abstract_start":204,"abstract_end":218},{"Name":"NM_017780.4(CHD7):c.5405-7G>A","Chromosome":"8","Start":"60850486","Stop":"60850486","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":101692,"rule_based_match":true,"evidence_text":"c.5405-7G > A","llm_judgment":"PRESENT","evidence":"c.5405-7G > A","abstract_start":173,"abstract_end":186}]}
{"pmid":"24266705","title":"Ocular and craniofacial phenotypes in a large Brazilian family with congenital aniridia.","abstract":"Congenital aniridia is a rare genetic disorder characterized by varying degrees of iris hypoplasia that are associated with additional ocular abnormalities. More than 90% of the causal mutations identified are found in the PAX6 gene, a transcription factor of critical importance in the process of neurogenesis and ocular development. Here, we investigate clinical, molecular, and craniofacial features of a large Brazilian family with congenital aniridia. Among the 56 eyes evaluated, phenotype variation encompassed bilateral total aniridia to mild iris defects with extensive variation between eyes of the same individual. PAX6 molecular screening indicated a heterozygous splice mutation (c.141 + 1G>A). Thus, we hypothesize that this splicing event may cause variation in the expression of the wild-type transcript, which may lead to the observed variation in phenotype. Affected individuals were more brachycephalic, even though their face height and cephalic circumference were not significantly different when compared to those of non-affected relatives. From this, we infer that the head shape of affected subjects may also be a result of the PAX6 splice-site mutation. Our data summarize the clinical variability associated with the ocular phenotype in a large family with aniridia, and help shed light on the role of PAX6 in neurocranial development.","variants":[{"Name":"NM_001368894.2(PAX6):c.141+1G>A","Chromosome":"11","Start":"31802703","Stop":"31802703","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":495530,"rule_based_match":true,"evidence_text":"c.141 + 1G>A","llm_judgment":"PRESENT","evidence":"c.141 + 1G>A","abstract_start":693,"abstract_end":705}]}
{"pmid":"25936346","title":"Rare intracranial cholesterol deposition and a homozygous mutation of LDLR in a familial hypercholesterolemia patient.","abstract":"Familial hypercholesterolemia (FH MIM# 143890) is one of the most common autosomal inherited diseases. FH is characterized by elevated plasma levels of total cholesterol and low-density lipoprotein-cholesterol. Mutation in the LDLR gene, which encodes the LDL receptor protein, is responsible for most of the morbidity of FH. The incidence of heterozygous FH is about 1/500, whereas the incidence of homozygous FH is only 1/1,000,000 in Caucasian population. In this study, we report a homozygous LDLR mutation (c.298G>A) in a familial hypercholesterolemia patient, who exhibited intracranial cholesterol deposition, which is a rare addition to the common FH phenotypes. The proband's consanguineous parents have the same heterozygous mutation with elevated concentrations of LDL-C but no xanthoma.","variants":[{"Name":"NM_000527.5(LDLR):c.298G>A (p.Asp100Asn)","Chromosome":"19","Start":"11102771","Stop":"11102771","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":245464,"rule_based_match":true,"evidence_text":"c.298G>A","llm_judgment":"PRESENT","evidence":"c.298G>A","abstract_start":512,"abstract_end":520}]}
{"pmid":"21654728","title":"Desbuquois dysplasia type I and fetal hydrops due to novel mutations in the CANT1 gene.","abstract":"We report on three hydropic fetuses of 17, 22 and 25 gestational weeks from three distinct families presenting with Desbuquois dysplasia type 1. All fetuses showed brachymelia and characteristic dysmorphic features. X-ray studies revealed δ-shaped extraphalangeal bones and disease-specific prominence of the lesser trochanter, varying in severity with fetal age. Early lethal manifestation of the disorder was reflected in lung hypoplasia and in early death of similarly affected siblings in cases 1 and 2. All families were German Caucasians by descent. Sequence analysis of the CANT1 gene revealed two frameshift mutations, c.228_229insC and c.277_278delCT, in homozygous and compound heterozygous configuration, respectively, and a homozygously novel missense mutation, c.336C>A (p.D112E), located within a highly conserved region of exon 2. Haplotype analyses by high-resolution single-nucleotide polymorphism array showed that the haplotype associated with c.228_229insC may be traced to a single founder in the German population.","variants":[{"Name":"NM_001159773.2(CANT1):c.277_278del (p.Leu93fs)","Chromosome":"17","Start":"78997345","Stop":"78997346","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":39972,"rule_based_match":true,"evidence_text":"c.277_278delCT","llm_judgment":"PRESENT","evidence":"c.277_278delCT","abstract_start":645,"abstract_end":659},{"Name":"NM_001159773.2(CANT1):c.336C>A (p.Asp112Glu)","Chromosome":"17","Start":"78997287","Stop":"78997287","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1432598,"rule_based_match":true,"evidence_text":"c.336C>A (p.D112E)","llm_judgment":"PRESENT","evidence":"c.336C>A (p.D112E)","abstract_start":774,"abstract_end":792}]}
{"pmid":"36708031","title":"Bi-allelic human TEKT3 mutations cause male infertility with oligoasthenoteratozoospermia owing to acrosomal hypoplasia and reduced progressive motility.","abstract":"Oligoasthenoteratozoospermia (OAT) can result in male infertility owing to reduced sperm motility and abnormal spermatozoan morphology. The Tektins are a family of highly conserved filamentous proteins expressed in the axoneme and associated structures in many different metazoan species. Earlier studies on mice identified Tektin3 (Tekt3) as a testis-enriched gene, and knockout of Tekt3 resulted in asthenozoospermia in the mice. Here, whole-exome sequencing of 100 males with asthenozoospermia from unrelated families was performed, followed by Sanger sequencing, leading to the identification of TEKT3 as a candidate gene in two of these patients and their associated family members. In total, three mutations in the TEKT3 gene were identified in both these patients, including one homozygous deletion-insertion mutation (c.543_547delinsTTGAT: p.Glu182*) and one compound heterozygous mutation (c.[548G > A]; [752A > C], p.[Arg183Gln]; [Gln251Pro]). Both of these mutations resulted in the complete loss of TEKT3 expression. The patients were both found to produce sperm that, although those showed no apparent defects in the flagellar structure, had reduced progressive motility. In contrast to mice, most sperm from these two patients exhibited acrosomal hypoplasia, although this did not prevent the use of the sperm for in vitro fertilization through an ICSI approach. TEKT3 was found to bind to other TEKT proteins, suggesting that these proteins form a complex within human spermatozoa. Overall, these results suggest that a loss of TEKT3 function can contribute to OAT incidence in humans. TEKT3 deficiencies can reduce sperm motility and contribute to severe acrosomal hypoplasia in spermatozoa, compromising their normal function.","variants":[{"Name":"NM_031898.3(TEKT3):c.752A>C (p.Gln251Pro)","Chromosome":"17","Start":"15314213","Stop":"15314213","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2417712,"rule_based_match":false,"evidence_text":"c.752A>C (p.Gln251Pro)","llm_judgment":"PRESENT","evidence":"c.752A>C (p.Gln251Pro)","abstract_start":null,"abstract_end":null},{"Name":"NM_031898.3(TEKT3):c.548G>A (p.Arg183Gln)","Chromosome":"17","Start":"15331038","Stop":"15331038","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2417711,"rule_based_match":false,"evidence_text":"c.548G > A","llm_judgment":"PRESENT","evidence":"c.[548G > A","abstract_start":899,"abstract_end":910}]}
{"pmid":"32921582","title":"A new homozygous HERC1 gain-of-function variant in MDFPMR syndrome leads to mTORC1 hyperactivation and reduced autophagy during cell catabolism.","abstract":"The giant 532 kDa HERC1 protein is a ubiquitin ligase that interacts with tuberous sclerosis complex subunit 2 (TSC2), a negative upstream regulator of the mammalian target of rapamycin complex 1 (mTORC1). TSC2 regulates anabolic cell growth through its influence on protein synthesis, cell growth, proliferation, autophagy, and differentiation. TSC subunit 1 (TSC1) stabilizes TSC2 by inhibiting the interaction between TSC2 and HERC1, forming a TSC1-TSC2 complex that negatively regulates mTORC1. HERC1-TSC2 interaction destabilizes and degrades TSC2. Recessive mutations in HERC1 have been reported in patients with intellectual disability. Some patients exhibit epilepsy, macrocephaly, somatic overgrowth, and dysmorphic facial features as well. Here we describe two sisters from a consanguineous marriage with a novel homozygous missense variant in the C-terminal HECT domain of HERC1 [chr15:g63,907,989C>G GRCh37.p11 | c.14,072G>C NM_003922 | p.(Arg4,691Pro)]. Symptoms compris global developmental delay, macrocephaly, somatic overgrowth, intellectual disability, seizures, schizoaffective disorder, and pyramidal tract signs. We functionally assessed the HERC1 mutation by investigation of patient and control fibroblasts under normal and nutrient starving conditions. During catabolic state, mTORC1 activity remained high in patient fibroblasts, which stands in stark contrast to its downregulation in controls. This was corroborated by an abnormally high phosphorylation of S6K1-kinase, a direct downstream target of mTORC1, in patients. Moreover, autophagy, usually enhanced in catabolic states, was down-regulated in patient fibroblasts. These data confirm that the missense variant found in both patients results in a gain-of-function for the mutant HERC1 protein.","variants":[{"Name":"NM_003922.4(HERC1):c.14072G>C (p.Arg4691Pro)","Chromosome":"15","Start":"63615790","Stop":"63615790","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":973050,"rule_based_match":false,"evidence_text":"c.14,072G>C NM_003922 | p.(Arg4,691Pro)","llm_judgment":"PRESENT","evidence":"c.14,072G>C NM_003922 | p.(Arg4,691Pro)","abstract_start":925,"abstract_end":964}]}
{"pmid":"28656292","title":"Novel mutations of FRMD7 in Chinese patients with congenital motor nystagmus.","abstract":"The purpose of the current study was to identify novel mutations in the FRMD7 (FERM domain containing 7) gene and to characterize clinical features in Chinese patients with congenital motor nystagmus. For this purpose, 18 patients with congenital motor nystagmus were selected from the ocular genetic diseases bank of the Pediatric and Genetic Clinic of Zhongshan Ophthalmic Center (Guangdong, China). Direct sequencing was used to analyze the exons and adjacent introns of the FRMD7 gene. The heteroduplex‑single strand conformation polypeptide method was used to analyze 96 unrelated normal controls and gene‑screening positive patients. Slit lamp photography of the anterior segment, fundus photography, optical coherence tomography and electroretinogram were carried out to identify the clinical features of congenital motor nystagmus. The authors noted that in, 18 patients with congenital motor nystagmus, there were 7FRMD7 gene mutations (six new mutations). The screening rate was 38.89%, including c.41_43delAGA (p.13‑15delK); c.473T>A (p.I158N); c.605T>A (p.I202N); c.580G>T (p.A194S); c.811T>A (p.C271S); c.1493insA (p.Y498X); c.57+1G>A (slice mutation). There were no such mutations in the 96 normal controls. These results enriched the gene mutation spectrum of FRMD7. The authors systematically investigated the clinical phenotype of congenital motor nystagmus in a Chinese population. The study provides further evidence for clinical diagnosis and differential diagnosis and genetic counseling.","variants":[{"Name":"NM_194277.3(FRMD7):c.1493dup (p.Tyr498Ter)","Chromosome":"X","Start":"132078523","Stop":"132078524","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AT","allel_id":2902025,"rule_based_match":false,"evidence_text":"c.1493insA (p.Y498X)","llm_judgment":"PRESENT","evidence":"c.1493insA (p.Y498X)","abstract_start":1116,"abstract_end":1136}]}
{"pmid":"18348267","title":"A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.","abstract":"Type 4 Waardenburg syndrome represents a well define entity caused by neural crest derivatives anomalies (melanocytes, intrinsic ganglion cells, central, autonomous and peripheral nervous systems) leading, with variable expressivity, to pigmentary anomalies, deafness, mental retardation, peripheral neuropathy, and Hirschsprung disease. Autosomal dominant mode of inheritance is prevalent when Sox10 gene mutation is identified. We report the natural history of a child who presented with synophrys, vivid blue eye, deafness, bilateral complete semicircular canals agenesis with mental retardation, subtle signs for peripheral neuropathy and lack of Hirschsprung disease. SOX10 gene sequencing identified \"de novo\" splice site mutation (c.698-2A > C). The present phenotype and the genotype findings underline the wide spectrum of SOX10 gene implication in unusual type 4 Waardenburg syndrome patient.","variants":[{"Name":"NM_006941.4(SOX10):c.698-2A>C","Chromosome":"22","Start":"37974200","Stop":"37974200","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":22448,"rule_based_match":true,"evidence_text":"c.698-2A > C","llm_judgment":"PRESENT","evidence":"c.698-2A > C","abstract_start":738,"abstract_end":750}]}
{"pmid":"26561923","title":"Characteristics of patients with benign partial epilepsy in infancy without PRRT2 mutations.","abstract":"Mutations in the proline-rich transmembrane protein 2 gene (PRRT2) are known to cause clinical symptoms of paroxysmal kinesigenic dyskinesia (PKD), benign partial epilepsy in infancy (BPEI), and infantile convulsions with choreoathetosis (ICCA) syndrome; however, not all patients with BPEI have PRRT2 mutations, and the genetic backgrounds for such patients are still unknown. To characterize BPEI patients without PRRT2 mutations, we analyzed unrelated 63 patients with BPEI. Sanger sequencing identified PRRT2 mutations in 33 probands (52%). The most common insertion, c.649dup, was identified in 28 probands. Two novel truncation mutations, c.232dup and c.503_504del were identified independently. 16p11.2 microdeletion was not detected in patients without PRRT2 mutations. PRRT2 mutation detection rates were 21/31 (68%) and 12/32 (38%) in probands who were positive or negative for family history, respectively, indicating a significant difference between the two groups. In this study, 20 probands with BPEI were negative for family history of BPEI and negative for PRRT2 mutation. BPEI in these probands may be due to complex genetic predispositions. Because the possibility remains that a second gene contributes to BPEI, further studies are necessary in patients with BPEI but no PRRT2 mutation, especially in Asian people.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dup","llm_judgment":"PRESENT","evidence":"c.649dup","abstract_start":572,"abstract_end":580}]}
{"pmid":"35091116","title":"Recurrent missense variant in the nuclear export signal of FMR1 associated with FXS-like phenotype including intellectual disability, ASD, facial abnormalities.","abstract":"Fragile X syndrome (FXS; MIM 300624) is an X-linked genetic disorder characterized by physical abnormalities associated with intellectual disability and a wide spectrum of neurological and psychiatric impairments. FXS occurs more frequently in males, 1 in 5000 males and 1 in 8000 females accounting for 1-2% of overall intellectual disability (ID). In more than 99% of patients, FXS results from expansions of a CGG triplet repeat (>200 in male) of the FMR1 gene. In the last years an increasing number, albeit still limited, of FXS subjects carrying FMR1 mutations including deletions, splicing errors, missense, and nonsense variants was reported. Nevertheless, the studies concerning the functional consequences of mutations in the FMR1 gene are rare so far and, therefore, we do not have sufficient knowledge regarding the genotype/phenotype correlation. We report a child carrying a hemizygous missense FMR1 (NM_002024.5:c.1325G > A p.Arg442Gln) variant, maternally inherited, associated with facial abnormalities, developmental delay, and social and communication deficits assessed with formal neuropsychological tests. The study contributes to highlighting the clinical differences between the CGG triplet repeat dependent phenotype and FMR1variant dependent phenotype and it also confirms the pathogenicity of the variant being reported for the second time in the literature.","variants":[{"Name":"NM_002024.6(FMR1):c.1325G>A (p.Arg442Gln)","Chromosome":"X","Start":"147943180","Stop":"147943180","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1859622,"rule_based_match":true,"evidence_text":"NM_002024.5:c.1325G > A p.Arg442Gln","llm_judgment":"PRESENT","evidence":"NM_002024.5:c.1325G > A p.Arg442Gln","abstract_start":915,"abstract_end":950}]}
{"pmid":"36134573","title":"First report of tethered cord syndrome in a patient with Verheij syndrome.","abstract":"BACKGROUND: Verheij syndrome (VRJS) is a rare microdeletion syndrome of chromosome 8q24.3 that is characterized by severe growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, psychomotor retardation, cardiac and renal defects, and dysmorphic facial features. Pathogenic variants of PUF60 (Poly-U Binding Splicing Factor 60 kDa) have been found to cause VRJS. Here we present a Turkish patient with Verheij syndrome who has typical facial dysmorphic features and renal and cardiac abnormalities, scoliosis, tethered cord, and mild intellectual disability.\nMETHODS: This is a case report of a 11-year-old female child who presented with Verheij syndrome. Blood samples were collected from the patient and the family. We performed whole exome sequencing was used to identify potential genetic mutations. We also used 3-dimensional protein structure analysis to identify the effect of the mutation.\nRESULTS: A de-novo in-frame variant (c.449_457delCAAAGGGGG; p.Ala150_Phe152del) of the PUF60 gene was identified by whole exome sequencing. According to ACMG guidelines in 2015, the mutation is classified as pathogenic and it has been reported in the clinvar database. Results of in-silico prediction software tools predicted the mutation was pathogenic. Protein structure analysis showed that the three residues affected by the in-frame deletion form could lead to impaired stability and function of the PUF60 protein.\nCONCLUSIONS: To date, 25 patients have been reported with PUF60 mutations in the medical literature. In this article, we report a patient with VRJS who had the unusual findings of tethered cord syndrome and renal abnormalities. As far as we know, this is the first patient from Turkey who has been diagnosed with Verheij syndrome.","variants":[{"Name":"NM_078480.3(PUF60):c.449_457del (p.Ala150_Phe152del)","Chromosome":"8","Start":"143818426","Stop":"143818434","ReferenceAlleleVCF":"CCAAAGGGGG","AlternateAlleleVCF":"C","allel_id":424347,"rule_based_match":true,"evidence_text":"c.449_457delCAAAGGGGG; p.Ala150_Phe152del","llm_judgment":"PRESENT","evidence":"c.449_457delCAAAGGGGG; p.Ala150_Phe152del","abstract_start":960,"abstract_end":1001}]}
{"pmid":"26735160","title":"NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn's disease.","abstract":"PURPOSE: Thiopurine-induced leukopenia is a relatively common adverse event related to thiopurine medication in Korean pediatric Crohn's disease. In addition to the mutations of TPMT gene, the NUDT15 c.415C>T variant was recently identified to have a strong association with thiopurine-induced early leukopenia. We conducted this study to define the incidence of azathioprine (AZA)-related leukopenia and to determine the incidence and characteristics of their genetic variants in Korean pediatric Crohn's disease patients.\nPATIENTS AND METHODS: Patients diagnosed with pediatric Crohn's disease who had used AZA for more than 3 months were recruited. The dose and duration of medication and data regarding adverse events including leukopenia were collected. TPMT and NUDT15 gene sequencing was performed for patients who had experienced AZA-induced leukopenia.\nRESULTS: A total of 81 patients had used AZA as a maintenance therapy of Crohn's disease. The mean dose of AZA was 1.88±0.39 mg/kg/day. Nine patients (11.1%) experienced AZA-induced leukopenia, and eight patients (9.9%) experienced AZA-induced early leukopenia. Among the eight early leukopenia patients, six patients (75.0%) harbored the NUDT15 c.415C>T variant and one patient (12.5%) had the TPMT c.719A>G (TPMT*3C) variant. All the three patients with NUDT15 c.415C>T homozygous variant suffered from alopecia totalis, and two of them experienced severe systemic infection. Three patients with the NUDT15 heterozygous variant are currently treated with AZA at a dose of 0.76 mg/kg/day.\nCONCLUSION: Mutations of the NUDT15 and TPMT gene accounted for ∼88% of cases with thiopurine-induced early leukopenia. Extensive hair loss was a recognizable early symptom in patients with the homozygous NUDT15 c.415C>T variant. Sequencing of the NUDT15 genes can guide the clinicians before thiopurine medication. An alternative immunosuppressive medication is recommended for patients with homozygous NUDT15 c.415C>T variant. For those with the heterozygous variant, half the usual dose of AZA can achieve efficacy comparable to that for wild-type patients.","variants":[{"Name":"NM_018283.4(NUDT15):c.415C>T (p.Arg139Cys)","Chromosome":"13","Start":"48045719","Stop":"48045719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227129,"rule_based_match":true,"evidence_text":"NUDT15 c.415C>T","llm_judgment":"PRESENT","evidence":"NUDT15 c.415C>T","abstract_start":193,"abstract_end":208}]}
{"pmid":"30462810","title":"Congenital hyperinsulinism in two siblings with ABCC8 mutation: same genotype, different phenotypes.","abstract":"Congenital hyperinsulinism (CHI) is a heterogenous disease caused by insulin secretion regulatory defects, being ABCC8/KCNJ11 the most commonly affected genes. Therapeutic options include diazoxide, somatostatin analogues and surgery, which is curative in focal CHI. We report the case of two siblings (born two years apart) that presented themselves with hypoketotic hyperinsulinemic persistent hypoglycemias during neonatal period. The diagnosis of diffuse CHI due to an ABCC8 compound mutation (c.3576delG and c.742C>T) was concluded. They did not benefit from diazoxide therapy (or pancreatectomy performed in patient number 1) yet responded to somatostatin analogues. Patient number 1 developed various neurological deficits (including epilepsy), however patient number 2 experienced an entirely normal neurodevelopment. We believe this case shows how previous knowledge of the firstborn sibling's disease contributed to a better and timelier medical care in patient number 2, which could potentially explain her better neurological outcome despite their same genotype.","variants":[{"Name":"NM_000352.6(ABCC8):c.742C>T (p.Arg248Ter)","Chromosome":"11","Start":"17461663","Stop":"17461663","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":577184,"rule_based_match":true,"evidence_text":"c.742C>T","llm_judgment":"PRESENT","evidence":"c.742C>T","abstract_start":513,"abstract_end":521}]}
{"pmid":"31444830","title":"Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma.","abstract":"Fumarate hydratase (FH) mutations underpin the autosomal recessive syndrome. FH deficiency and the autosomal dominant syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH c.1431_1433dupAAA (p.Lys477dup) genomic alteration has been conclusively shown to contribute to FH deficiency when occurring with another FH germline alteration. However, a sufficiently large dataset has been lacking to conclusively determine its clinical significance to cancer predisposition in the heterozygous state. We reviewed a series of 7,571 patients with cancer who received germline results through MSK-IMPACT testing at the Memorial Sloan Kettering Cancer Center. The FH c.1431_1433dupAAA (p.Lys477dup) variant was detected in 24 individuals, none of whom was affected with renal cancer. Eleven of the 372 patients with renal cancer were identified to carried pathogenic FH variants associated with HLRCC. None of these 372 patients with renal cancer carried the FH c.1431_1433dupAAA variant. Our data indicate the FH c.1431_1433dupAAA is not associated with cancer including renal cell carcinoma.","variants":[{"Name":"NM_000143.4(FH):c.1431_1433dup (p.Lys477dup)","Chromosome":"1","Start":"241497927","Stop":"241497928","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ATTT","allel_id":51261,"rule_based_match":true,"evidence_text":"FH c.1431_1433dupAAA (p.Lys477dup)","llm_judgment":"PRESENT","evidence":"FH c.1431_1433dupAAA (p.Lys477dup)","abstract_start":191,"abstract_end":225}]}
{"pmid":"29953849","title":"Efficacy Outcome Measures for Clinical Trials of USH2A Caused by the Common c.2299delG Mutation.","abstract":"PURPOSE: To determine the change in vision and retinal structure in patients with the common c.2299delG mutation in the USH2A gene in anticipation of clinical trials of therapy.\nDESIGN: Retrospective observational case series.\nMETHODS: Eighteen patients, homozygotes or compound heterozygotes with the c.2299delG mutation in USH2A, were studied with regard to visual acuity, kinetic perimetry, dark- and light-adapted static perimetry, optical coherence tomography (OCT), and autofluorescence (AF) imaging. Serial data were available for at least half of the patients, depending on the parameter analyzed.\nRESULTS: The kinetics of disease progression in this specific molecular form of USH2A differed between the measured parameters. Visual acuity could remain normal for decades. Kinetic and light-adapted static perimetry across the entire visual field had similar rates of decline that were slower than those of rod-based perimetry. Horizontal OCT scans through the macula showed that inner segment/outer segment line width had a similar rate of constriction as co-localized AF imaging and cone-based light-adapted sensitivity extent. The rate of constriction of rod-based sensitivity extent across this same region was twice as rapid as that of cones.\nCONCLUSIONS: In patients with the c.2299delG mutation in USH2A, rod photoreceptors are the cells that express disease early and more aggressively than cones. Rod-based vision measurements in central or extracentral-peripheral retinal regions warrant monitoring in order to complete a clinical trial in a timely manner.","variants":[{"Name":"NM_206933.4(USH2A):c.2299del (p.Glu767fs)","Chromosome":"1","Start":"216247095","Stop":"216247095","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":17390,"rule_based_match":true,"evidence_text":"c.2299delG","llm_judgment":"PRESENT","evidence":"c.2299delG","abstract_start":93,"abstract_end":103}]}
{"pmid":"31096510","title":"Identification of pathogenic mutations in 6 Chinese families with multiple exostoses by whole-exome sequencing and multiplex ligation-dependent probe amplification: Case series.","abstract":"RATIONALE: Hereditary multiple exostoses (HMEs) is an autosomal dominant skeletal disorder.\nPATIENT CONCERNS: Six probands of the 6 unrelated Han Chinese families were identified as having HME. These patients had exostoses at multiple sites and significantly affected joints malformation and movement.\nDIAGNOSES: Hereditary multiple exostoses.\nINTERVENTIONS: To detect the genetic mechanism of HME in 6 unrelated Chinese families, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were used after genomic DNA was isolated from peripheral blood leucocytes. Point mutations identified by these methods were verified by Sanger sequencing after PCR amplification.\nOUTCOMES: Six mutations in the EXT1 and EXT2 genes were identified, including a heterozygous deletion mutation from exon 2 to exon 8 (Family 1), a c.448C>T, p.(Gln150X) heterozygous nonsense mutation (Family 4), a c.1057-2A>T heterozygous splicing substitution (Family 5), and a c.1468dupC, p.(Leu490fs519X) (Family 6) heterozygous duplication mutation in the EXT1 gene in addition to a heterozygous deletion mutation from exon 2 to exon 3 (Family 2) and a c.1197C>G, p.(Tyr399X) heterozygous nonsense mutation (Family 3) in the EXT2 gene.\nLESSONS: Overall, we identified 5 novel mutations and 1 recurrent mutation in the EXT1 and EXT2 genes in 6 Chinese families with HME. Our findings expand the mutational spectrum of the EXT1 and EXT2 genes and are useful for genetic counseling and prenatal diagnosis.","variants":[{"Name":"NM_000127.3(EXT1):c.1057-2A>T","Chromosome":"8","Start":"117835553","Stop":"117835553","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1471344,"rule_based_match":true,"evidence_text":"c.1057-2A>T","llm_judgment":"PRESENT","evidence":"c.1057-2A>T","abstract_start":913,"abstract_end":924},{"Name":"NM_207122.2(EXT2):c.1197C>G (p.Tyr399Ter)","Chromosome":"11","Start":"44171634","Stop":"44171634","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1941535,"rule_based_match":true,"evidence_text":"c.1197C>G, p.(Tyr399X)","llm_judgment":"PRESENT","evidence":"c.1197C>G, p.(Tyr399X)","abstract_start":1156,"abstract_end":1178}]}
{"pmid":"29068140","title":"A founder mutation in CERKL is a major cause of retinal dystrophy in Finland.","abstract":"PURPOSE: To study the genetic aetiology of retinal dystrophies (RD) in Finnish patients.\nMETHODS: A targeted next-generation sequencing (NGS) panel of 105 retinal dystrophy genes was used in a cohort of 55 RD patients.\nRESULTS: The overall diagnostic yield was 60% demonstrating the power of this approach. Interestingly, a missense mutation c.375C>G p.(Cys125Trp) in the CERKL gene was found in 18% of the patients in either a homozygous or compound heterozygous state. Data from Exome Aggregation Consortium (ExAC) Browser show that the CERKL c.375C>G p.(Cys125Trp) allele is enriched in the Finnish population and thus is a founder mutation. Furthermore, we report the clinical picture of 18 patients with mutations in the CERKL gene. CERKL mutations cause a macular-onset disease, in which symptoms first become apparent at the second decade. We also detected other novel founder mutations in the CERKL, EYS, RP1, ABCA4 and GUCY2D genes.\nCONCLUSION: Our report indicates that the first diagnostic test for Finnish patients with sporadic or autosomal recessive RD should be a targeted test for founder mutations in the CERKL, EYS, RP1, ABCA4 and GUCY2D genes. These results confirm the utility of NGS-based gene panels as a powerful method for mutation identification in RD, thus enabling improved genetic counselling for these families.","variants":[{"Name":"NM_201548.5(CERKL):c.375C>G (p.Cys125Trp)","Chromosome":"2","Start":"181603943","Stop":"181603943","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":856153,"rule_based_match":true,"evidence_text":"c.375C>G p.(Cys125Trp)","llm_judgment":"PRESENT","evidence":"c.375C>G p.(Cys125Trp)","abstract_start":342,"abstract_end":364}]}
{"pmid":"25361784","title":"Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome.","abstract":"OBJECTIVE: To elucidate the genetic cause of a rare recessive ataxia presented by 2 siblings from a consanguineous Turkish family with a nonprogressive, congenital ataxia with mental retardation of unknown etiology.\nMETHODS: Whole-exome sequencing was combined with homozygosity mapping, linkage, and expression analysis to identify candidate genes, confirmed by Sanger sequencing. Reverse transcription-PCR and immunoblotting were used to determine the functional consequences of the gene variant. A zebrafish model was developed using morpholino-mediated knockdown.\nRESULTS: We identified a homozygous mutation at the invariant +1 position (c.964+1G>A) in intron 9 of the CWF19L1 (complexed with cdc5 protein 19-like 1) gene. This mutation is absent in >6,500 European and African American individuals and 200 Turkish control DNAs. The mutation causes exon skipping, reduction in messenger RNA levels, and protein loss in cell lines of affected individuals. Morpholino-mediated knockdown in a zebrafish model demonstrates that loss of the evolutionarily highly conserved CWF19L1, whose normal biological function is unknown, alters cerebellar morphology and causes movement abnormalities.\nCONCLUSIONS: Our results suggest that CWF19L1 mutations may be a novel cause of recessive ataxia with developmental delay. Our research may help with diagnosis, especially in Turkey, identify causes of other ataxias, and may lead to novel therapies.","variants":[{"Name":"NM_018294.6(CWF19L1):c.964+1G>A","Chromosome":"10","Start":"100245798","Stop":"100245798","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":134329,"rule_based_match":true,"evidence_text":"c.964+1G>A","llm_judgment":"PRESENT","evidence":"c.964+1G>A","abstract_start":643,"abstract_end":653}]}
{"pmid":"35726044","title":"A Novel CEBPE Variant Causes Severe Infections and Profound Neutropenia.","abstract":"PURPOSE: Specific granule deficiency (SGD) is a rare inborn error of immunity resulting from loss-of-function variants in CEBPE gene (encoding for transcription factor C/EBPε). Although this genetic etiology has been known for over two decades, only a few patients with CEBPE variant-proven SGD (type I) have been reported. Herein, we describe two siblings with a novel homozygous CEBPE deletion who were noted to have profound neutropenia on initial evaluation. We aimed to evaluate the immunohematological consequences of this novel variant, including profound neutropenia.\nMETHODS: Light scatter characteristics of granulocytes were examined on various automated hematology analyzers. Phagocyte immunophenotype, reactive oxygen species generation, and Toll-like receptor (TLR) signaling were assessed using flow cytometry. Relative expression of genes encoding various granule proteins was studied using RT-PCR. Western blot analysis and luciferase reporter assay were performed to explore variant C/EBPε expression and function.\nRESULTS: Severe infections occurred in both siblings. Analysis of granulocyte light scatter plots revealed automated hematology analyzers can provide anomalously low neutrophil counts due to abnormal neutrophil morphology. Neutrophils displayed absence/marked reduction of CD15/CD16 expression and overexpression (in a subset) of CD14/CD64. Three distinct populations of phagocytes with different oxidase activities were observed. Impaired shedding of CD62-ligand was noted on stimulation with TLR-4, TLR-2/6, and TLR-7/8 agonists. We demonstrated the variant C/EBPε to be functionally deficient.\nCONCLUSION: Homozygous c.655_665del variant in CEBPE causes SGD. Anomalous automated neutrophil counts may be reported in patients with SGD type I. Aberrant TLR signaling might be an additional pathogenetic mechanism underlying immunodeficiency in SGD type I.","variants":[{"Name":"NM_001805.4(CEBPE):c.655_665del (p.Lys220fs)","Chromosome":"14","Start":"23117668","Stop":"23117678","ReferenceAlleleVCF":"TCGGCTCTTGCG","AlternateAlleleVCF":"T","allel_id":1704175,"rule_based_match":true,"evidence_text":"Homozygous c.655_665del variant in CEBPE","llm_judgment":"PRESENT","evidence":"Homozygous c.655_665del variant in CEBPE","abstract_start":1642,"abstract_end":1682}]}
{"pmid":"21407258","title":"Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG).","abstract":"Osteoporosis-pseudoglioma sydrome (OPPG) is an autosomal recessive disorder with early-onset severe osteoporosis and blindness, caused by biallelic loss-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Heterozygous carriers exhibit a milder bone phenotype. Only a few splice mutations in LRP5 have been published. We present clinical and genetic data for four patients with novel LRP5 mutations, three of which affect splicing. Patients were evaluated clinically and by radiography and bone densitometry. Genetic screening of LRP5 was performed on the basis of the clinical diagnosis of OPPG. Splice aberrances were confirmed by cDNA sequencing or exon trapping. The effect of one splice mutation on LRP5 protein function was studied. A novel splice-site mutation c.1584+4A>T abolished the donor splice site of exon 7 and activated a cryptic splice site, which led to an in-frame insertion of 21 amino acids (p.E528_V529ins21). Functional studies revealed severely impaired signal transduction presumably caused by defective intracellular transport of the mutated receptor. Exon trapping was used on two samples to confirm that splice-site mutations c.4112-2A>G and c.1015+1G>T caused splicing-out of exons 20 and 5, respectively. One patient carried a homozygous deletion of exon 4 causing the loss of exons 4 and 5, as demonstrated by cDNA analysis. Our results broaden the spectrum of mutations in LRP5 and provide the first functional data on splice aberrations.","variants":[{"Name":"NM_002335.4(LRP5):c.4112-2A>G","Chromosome":"11","Start":"68438444","Stop":"68438444","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1874311,"rule_based_match":true,"evidence_text":"c.4112-2A>G","llm_judgment":"PRESENT","evidence":"c.4112-2A>G","abstract_start":1194,"abstract_end":1205}]}
{"pmid":"32738225","title":"De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.","abstract":"Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.","variants":[{"Name":"NM_004539.4(NARS1):c.1633C>T (p.Arg545Cys)","Chromosome":"18","Start":"57601666","Stop":"57601666","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":974447,"rule_based_match":true,"evidence_text":"c.1633C>T (p.Arg545Cys)","llm_judgment":"PRESENT","evidence":"c.1633C>T (p.Arg545Cys)","abstract_start":620,"abstract_end":643}]}
{"pmid":"25491635","title":"Identification and functional study of novel PLP1 mutations in Chinese patients with Pelizaeus-Merzbacher disease.","abstract":"PURPOSE: Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive hypomyelination disorder characterized by nystagmus, ataxia, impaired motor development, and progressive spasticity. Identification of proteolipid protein 1 (PLP1) mutations in Chinese patients with Pelizaeus-Merzbacher disease (PMD) and confirmation of the biological impacts of the identified mutations are the aims of this study.\nMETHODS: An analysis of clinical materials and a follow-up study were conducted for the patients with PMD. Sequencing and immunofluorescence were applied for molecular analysis of the causative gene PLP1.\nRESULTS: We identified PLP1 mutations in seven male patients with PMD. Three novel missense mutations (c.353C>G, p.T118R; c.623G>T, p.G208V; c.709T>G, p.F237V) and three reported missense mutations (c.467C>T, p.T156I; c.517C>T, p.P173S; c.646C>T, p.P216S) of PLP1 were identified from seven Chinese PMD patients. The three mutations (F237V in patient 2, P216S in patient 5 and T156I in patient 6) were de novo. Mutant proteins were trapped in the lumen of endoplasmic reticulum.\nCONCLUSION: We have identified six pathogenic mutations, enriching the specific spectrum of missense mutations in the patients with PMD. The six PLP1 mutations are probably pathogenic. By reviewing the known PLP1 mutations, we have preliminarily revealed the position of missense mutation may be associated with the severity of PMD.","variants":[{"Name":"NM_000533.5(PLP1):c.709T>G (p.Phe237Val)","Chromosome":"X","Start":"103789345","Stop":"103789345","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":804833,"rule_based_match":true,"evidence_text":"c.709T>G, p.F237V","llm_judgment":"PRESENT","evidence":"c.709T>G, p.F237V","abstract_start":752,"abstract_end":769},{"Name":"NM_000533.5(PLP1):c.517C>T (p.Pro173Ser)","Chromosome":"X","Start":"103787861","Stop":"103787861","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3414198,"rule_based_match":true,"evidence_text":"c.517C>T, p.P173S","llm_judgment":"PRESENT","evidence":"c.517C>T, p.P173S","abstract_start":829,"abstract_end":846}]}
{"pmid":"33713692","title":"Characterization of a novel ABCC2 mutation in infantile Dubin Johnson syndrome.","abstract":"BACKGROUND AND AIMS: The Dubin Johnson Syndrome (DJS) occurs mostly in young adults but an early-onset of the disease has been reported in less common forms (Neonatal DJS and Infantile DJS). In this case, the clinical findings are of limit for the DJS diagnosis. Hence, the genetic testing remains the method of choice to provide an accurate diagnosis. In our study, we aimed to perform a genetic analysis for two siblings presented with an intrahepatic cholestasis before the age of 1 year to provide a molecular explanation for the developed phenotype.\nPATIENTS & METHODS: A Tunisian family, having two siblings, manifesting signs of a hepatopathy, was enrolled in our study. A molecular analysis was performed, using a panel-based next generation sequencing, supplying results that were the subject of computational analysis. Then, a clinical follow-up was carried out to assess the evolution of the disease.\nRESULTS: The genetic analysis revealed the presence of a novel missense c.4179G > T, (p.M1393I) mutation in ABCC2 gene associated with a substitution c.2789G > A (R930Q) in ATP8B1 gene. Predictive results consolidated the pathogenic effect of both variants. These results confirmed the DJS diagnosis in the studied patients. The clinical course of both patients fit well with the benign nature of DJS.\nCONCLUSION: We described here a novel ABCC2 mutation associated with a putative ATP8B1 modifier variant. This finding constituted the first report of a complex genotype in DJS. Hence, genetic analysis by a panel-based next generation sequencing permits an accurate diagnosis and the identification of putative variants that could influence the developed phenotype.","variants":[{"Name":"NM_000392.5(ABCC2):c.4179G>T (p.Met1393Ile)","Chromosome":"10","Start":"99846993","Stop":"99846993","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":193771,"rule_based_match":true,"evidence_text":"c.4179G > T, (p.M1393I)","llm_judgment":"PRESENT","evidence":"c.4179G > T, (p.M1393I)","abstract_start":984,"abstract_end":1007}]}
{"pmid":"22763723","title":"Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study.","abstract":"Wilson disease (WD), a disorder of copper metabolism is caused by mutations in the ATP7B gene, a copper transporting ATPase. In the present study we describe a novel mutation in exon 9 of the ATP7B gene. The ATP7B gene was analyzed for mutations by denaturing HPLC and direct sequencing. DNA from 100 healthy blood donors from the same geographic area was examined as control. Sixteen (7.4%) out of the 216 patients diagnosed with WD in Austria carried the newly identified R816S(c.2448G>T) point mutation in exon 9 (4 male, age: 19 (6-30) years, median (range)). One patient was homozygous for R816S(c.2448G>T). Thirteen patients were compound heterozygotes (p.H1069Q(c.3207C>A)/R816S(c.2448G>T) (N=6), P539L/R816S(c.2448G>T) (N=3), each one G710S/R816S(c.2448G>T), P767P(2299insC)/R816S(c.2448G>T), W779G/R816S(c.2448G>T), T1220M/R816S(c.2448G>T)). In two patients no second mutation was identified. Interestingly, all but three of the patients originated within a distinct geographical area in Austria. Eleven patients presented with hepatic disease, 3 patients with neurological disease and 2 were asymptomatic sisters of an index case. A liver biopsy was available in 14 patients. Three patients showed advanced liver disease with liver transplantation for acute hepatic failure in two. The remaining patients had only mild histological changes, most commonly steatosis. Chronic hepatitis was described in five patients. Kayser-Fleischer ring was present in five patients. None of the 100 healthy controls carried the mutation. We describe a novel mutation in the ATP7B gene, occurring in patients originated from a distinct geographical area in Austria associated with a variable course of the disease.","variants":[{"Name":"NM_000053.4(ATP7B):c.2448G>T (p.Arg816Ser)","Chromosome":"13","Start":"51950399","Stop":"51950399","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1380314,"rule_based_match":true,"evidence_text":"R816S(c.2448G>T)","llm_judgment":"PRESENT","evidence":"R816S(c.2448G>T)","abstract_start":474,"abstract_end":490}]}
{"pmid":"25434006","title":"MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections.","abstract":"Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome sequencing of affected members in a large TAAD-affected family, we identified the c.472C>T (p.Arg158(∗)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62G>T [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.","variants":[{"Name":"NM_003480.4(MFAP5):c.472C>T (p.Arg158Ter)","Chromosome":"12","Start":"8648141","Stop":"8648141","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171907,"rule_based_match":true,"evidence_text":"c.472C>T (p.Arg158(∗))","llm_judgment":"PRESENT","evidence":"c.472C>T (p.Arg158(∗))","abstract_start":417,"abstract_end":439},{"Name":"NM_003480.4(MFAP5):c.62G>T (p.Trp21Leu)","Chromosome":"12","Start":"8660895","Stop":"8660895","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":171908,"rule_based_match":true,"evidence_text":"c.62G>T (p.Trp21Leu)","llm_judgment":"PRESENT","evidence":"p.Trp21Leu","abstract_start":702,"abstract_end":712}]}
{"pmid":"20120036","title":"The deep intronic c.903+469T>C mutation in the MTRR gene creates an SF2/ASF binding exonic splicing enhancer, which leads to pseudoexon activation and causes the cblE type of homocystinuria.","abstract":"Deep intronic mutations are often ignored as possible causes of human diseases. A deep intronic mutation in the MTRR gene, c.903+469T>C, is the most frequent mutation causing the cblE type of homocystinuria. It is well known to be associated with pre-mRNA mis-splicing, resulting in pseudoexon inclusion; however, the pathological mechanism remains unknown. We used minigenes to demonstrate that this mutation is the direct cause of MTRR pseudoexon inclusion, and that the pseudoexon is normally not recognized due to a suboptimal 5' splice site. Within the pseudoexon we identified an exonic splicing enhancer (ESE), which is activated by the mutation. Cotransfection and siRNA experiments showed that pseudoexon inclusion depends on the cellular amounts of SF2/ASF and in vitro RNA-binding assays showed dramatically increased SF2/ASF binding to the mutant MTRR ESE. The mutant MTRR ESE sequence is identical to an ESE of the alternatively spliced MST1R proto-oncogene, which suggests that this ESE could be frequently involved in splicing regulation. Our study conclusively demonstrates that an intronic single nucleotide change is sufficient to cause pseudoexon activation via creation of a functional ESE, which binds a specific splicing factor. We suggest that this mechanism may cause genetic disease much more frequently than previously reported.","variants":[{"Name":"NM_002454.3(MTRR):c.903+469T>C","Chromosome":"5","Start":"7883746","Stop":"7883746","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":651340,"rule_based_match":true,"evidence_text":"c.903+469T>C","llm_judgment":"PRESENT","evidence":"c.903+469T>C","abstract_start":123,"abstract_end":135}]}
{"pmid":"22764886","title":"Fumarate hydratase gene mutation in two young patients with sporadic uterine fibroids.","abstract":"Fumarate hydratase (FH) is a key enzyme of the Krebs cycle. Germline mutations in the FH gene encoding fumarate hydratase cause autosomal dominant syndromes multiple cutaneous and uterine leiomyomata and hereditary leiomyomatosis and renal cell cancer (HLRCC). Few data have been published on the role of FH gene mutation in development of uterine fibroids outside the context of multiple cutaneous and uterine leiomyomata /HLRCC. We report two FH gene mutations, one novel and one previously described, in two young patients with sporadic uterine fibroids and decreased fumarate hydratase activity in lymphocytes. In patient 1, a novel heterozygous mutation c.892G>C was found. In patient 2 we detected heterozygous mutation c.584T>C. Both the patients had a negative family history for renal cancer and cutaneous leiomyomatosis. None of the relatives, however, underwent renal imaging at the time of writing. FH mutation carriers may be easily identified by analysis of fumarate hydratase activity in blood lymphocytes. We suggest performing fumarate hydratase activity or FH mutation screening in women with onset of uterine fibroids in their 20s and family history of uterine fibroids or other HLRCC-associated malignancies.","variants":[{"Name":"NM_000143.4(FH):c.892G>C (p.Ala298Pro)","Chromosome":"1","Start":"241506015","Stop":"241506015","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":195206,"rule_based_match":true,"evidence_text":"c.892G>C","llm_judgment":"PRESENT","evidence":"c.892G>C","abstract_start":659,"abstract_end":667},{"Name":"NM_000143.4(FH):c.584T>C (p.Met195Thr)","Chromosome":"1","Start":"241508757","Stop":"241508757","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":210695,"rule_based_match":true,"evidence_text":"c.584T>C","llm_judgment":"PRESENT","evidence":"c.584T>C","abstract_start":726,"abstract_end":734}]}
{"pmid":"30685992","title":"Targeted next-generation sequencing in Slovak cardiomyopathy patients.","abstract":"OBJECTIVES: For the first time we used targeted next-generation sequencing to detect candidate pathogenic variants in Slovak cardiomyopathy patients.\nBACKGROUND: Targeted next-generation sequencing is considered to be the best practice in genetic diagnostics of cardiomyopathies. However, in Slovakia, with high cardiomyopathies prevalence of 1/440, the current diagnostic tests are still based on Sanger sequencing of a few genes. Consequently, little is known about the exact contribution of pathogenic variants in known cardiomyopathy genes in Slovak patients.\nMETHODS: We used a panel of 46 known cardiomyopathy-associated genes to detect genetic variants in 16 Slovak cardiomyopathy patients (6 dilated, 8 hypertrophic, 2 non-compaction subtypes).\nRESULTS: We identified candidate pathogenic variants in 11 of 16 patients (69 %). Genes with higher count of candidate pathogenic variants were MYBPC3, MYH and TTN, each with 3 different variants. Seven variants ACTC1 (c.329C>T), ANKRD1 (c.683G>T), MYH7 (c.1025C>T), PKP2 (c.2003delA), TTN (c.51655C>T, c.84841G>T, c.101874_101881delAGAATTTG) have been detected for the first time and might represent Slovak-specific genetic cause.\nCONCLUSIONS: We have performed genetic testing of previously untested Slovak cardiomyopathy patients using next-generation sequencing cardiomyopathy gene panel. Given the high percentage of candidate pathogenic variants it should be recommended to implement this method into routine genetic diagnostic practice in Slovakia (Tab. 4, Ref. 39).","variants":[{"Name":"NM_000257.4(MYH7):c.1025C>T (p.Thr342Ile)","Chromosome":"14","Start":"23429888","Stop":"23429888","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2087015,"rule_based_match":true,"evidence_text":"MYH7 (c.1025C>T)","llm_judgment":"PRESENT","evidence":"MYH7 (c.1025C>T)","abstract_start":1002,"abstract_end":1018},{"Name":"NM_005159.5(ACTC1):c.329C>T (p.Ala110Val)","Chromosome":"15","Start":"34793370","Stop":"34793370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1871257,"rule_based_match":true,"evidence_text":"c.329C>T","llm_judgment":"PRESENT","evidence":"c.329C>T","abstract_start":972,"abstract_end":980}]}
{"pmid":"17437620","title":"Mitofusin 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A).","abstract":"Charcot-Marie-Tooth disease (CMT) has been classified into two types: demyelinating forms (CMT1) and axonal forms (CMT2). Mutations in the CMT2A locus have been linked to the KIF1B and the mitofusin 2 (MFN2) genes. Here, we report a German patient with CMT2 with an underlying spontaneous mutation (c.281G-->A) in the MFN2 gene. Clinically, the patient presented with early-onset CMT that was not associated with additional central nervous system pathology. The disease course was rapidly progressive in the first years and slowed afterwards. We also suggest that single patients with early-onset axonal polyneuropathies should be screened for MFN2 mutations.","variants":[{"Name":"NM_014874.4(MFN2):c.281G>A (p.Arg94Gln)","Chromosome":"1","Start":"11992660","Stop":"11992660","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17307,"rule_based_match":false,"evidence_text":"c.281G-->A","llm_judgment":"PRESENT","evidence":"c.281G-->A","abstract_start":299,"abstract_end":309}]}
{"pmid":"16116615","title":"Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase alpha/beta subunits in Korean patients with mucolipidosis type II or type IIIA.","abstract":"Mucolipidosis types II and III are autosomal recessive inherited diseases caused by a deficiency in the lysosomal enzyme N-acetylglucosamine-1 phosphotransferase (GlcNAc-phosphotransferase), which adds phosphate to function as a recognition marker for the uptake and transport of lysosomal enzymes. We investigated mutations in the GNPTA (MGC4170) gene, which codes for the alpha/beta subunits of phosphotransferase, and in the GNPTAG gene, which codes for its gamma subunits in five Korean patients with mucolipidosis type II or IIIA. We identified seven mutations in the GNPTA gene, but none in GNPTAG. The mutations in type II patients included p.Q104X (c.310C>T), p.R1189X (c.3565C>T), p.S1058X (c.3173C>G), p.W894X (c.2681G>A), and p.H1158fsX15 (c.3474_3475delTA), all of which are nonsense or frameshift mutations. However, a splicing site mutation, IVS13+1G>A (c.2715+1G>A) was detected along with a nonsense or a frameshift mutation (p.R1189X or p.E858fsX3 (c.2574_2575delGA)) in two mucolipidosis type IIIA patients. This report shows that mutations in the GNPTA gene coding for the alpha/beta subunits of phosphotransferase, and not mutations in the GNPTAG gene, account for most of the genetic mutations found in Korean patients with mucolipidosis type II or IIIA.","variants":[{"Name":"NM_024312.5(GNPTAB):c.310C>T (p.Gln104Ter)","Chromosome":"12","Start":"101789951","Stop":"101789951","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17802,"rule_based_match":true,"evidence_text":"c.310C>T","llm_judgment":"PRESENT","evidence":"c.310C>T","abstract_start":657,"abstract_end":665},{"Name":"NM_024312.5(GNPTAB):c.3565C>T (p.Arg1189Ter)","Chromosome":"12","Start":"101753409","Stop":"101753409","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17803,"rule_based_match":true,"evidence_text":"p.R1189X (c.3565C>T)","llm_judgment":"PRESENT","evidence":"p.R1189X (c.3565C>T)","abstract_start":668,"abstract_end":688},{"Name":"NM_024312.5(GNPTAB):c.3173C>G (p.Ser1058Ter)","Chromosome":"12","Start":"101760106","Stop":"101760106","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":17804,"rule_based_match":true,"evidence_text":"c.3173C>G","llm_judgment":"PRESENT","evidence":"c.3173C>G","abstract_start":700,"abstract_end":709},{"Name":"NM_024312.5(GNPTAB):c.3474_3475del (p.His1158fs)","Chromosome":"12","Start":"101753499","Stop":"101753500","ReferenceAlleleVCF":"TTA","AlternateAlleleVCF":"T","allel_id":17805,"rule_based_match":true,"evidence_text":"c.3474_3475delTA","llm_judgment":"PRESENT","evidence":"c.3474_3475delTA","abstract_start":751,"abstract_end":767},{"Name":"NM_024312.5(GNPTAB):c.2681G>A (p.Trp894Ter)","Chromosome":"12","Start":"101764236","Stop":"101764236","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17806,"rule_based_match":true,"evidence_text":"p.W894X (c.2681G>A)","llm_judgment":"PRESENT","evidence":"p.W894X (c.2681G>A)","abstract_start":712,"abstract_end":731},{"Name":"NM_024312.5(GNPTAB):c.2715+1G>A","Chromosome":"12","Start":"101764201","Stop":"101764201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17807,"rule_based_match":true,"evidence_text":"IVS13+1G>A (c.2715+1G>A)","llm_judgment":"PRESENT","evidence":"IVS13+1G>A (c.2715+1G>A)","abstract_start":856,"abstract_end":880}]}
{"pmid":"28242437","title":"Congenital hyperinsulinism and glycogenosis-like phenotype due to a novel HNF4A mutation.","abstract":"AIM: Congenital hyperinsulinism (CHI) and glycogen storage disease (glycogenosis) are both causing hypoglycemia during infancy, but with different additional clinical features and therapeutic approach. We aimed to identify a genetic cause in a child with an ambiguous phenotype.\nMETHODS AND RESULTS: We present a child with hyperinsulinemic hypoglycemia, physiological 3-OH butyrate, increased triglyceride serum levels, increased level of glycogen in erythrocytes, increased liver transaminases, and increased echogenicity on liver ultrasonography. As both parents of the proband were referred as healthy, we raised a clinical suspicion on glycogenosis with recessive inheritance. However, whole exome sequencing revealed no mutation in genes causing glycogenosis, but a novel heterozygous variant LRG_483t1: c.427-1G>A in the HNF4A gene was identified. Aberrant splicing resulting in in-frame deletion c.429_476del, p.(T144_I159del) was confirmed by sequencing of HNF4A transcripts reverse-transcribed from whole blood RNA. The same variant was found in five of eight tested family relatives (one of them already had diabetes, two had prediabetes). With regard to the results of DNA analysis, we added diazoxide to the therapy. Consequently, the frequency and severity of hypoglycemia in the proband decreased. We have also recommended sulfonylurea treatment after diabetes onset in adult mutation carriers.\nCONCLUSIONS: We have identified a novel HNF4A gene mutation in our patient with CHI and glycogenosis-like phenotype. The proband and her family members benefited from the genetic testing by WES method and consequently personalized therapy. Nevertheless, the HNF4A gene testing may be considered in selected CHI cases with glycogenosis-like phenotype prior WES analysis.","variants":[{"Name":"NM_175914.5(HNF4A):c.427-1G>A","Chromosome":"20","Start":"44414506","Stop":"44414506","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":578356,"rule_based_match":true,"evidence_text":"LRG_483t1: c.427-1G>A","llm_judgment":"PRESENT","evidence":"LRG_483t1: c.427-1G>A","abstract_start":799,"abstract_end":820}]}
{"pmid":"27412952","title":"The clinical, biochemical and genetic features associated with","abstract":"BACKGROUND: Mutations in the <i>RMND1</i> (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects.\nMETHODS: We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with <i>RMND1</i> mutations. In addition, we reviewed all the previously published cases to determine the genotype-phenotype correlates and performed survival analysis to identify prognostic factors.\nRESULTS: We identified 14 new cases from 11 pedigrees that harbour recessive <i>RMND1</i> mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, p.(Leu435Phe); c.830+1G>A and c.1317+1G>T. Together with all previously published cases (n=32), we show that congenital sensorineural deafness, hypotonia, developmental delay and lactic acidaemia are common clinical manifestations with disease onset under 2 years. Renal involvement is more prevalent than seizures (66% vs 44%). In addition, median survival time was longer in patients with renal involvement compared with those without renal disease (6 years vs 8 months, p=0.009). The neurological phenotype also appears milder in patients with renal involvement.\nCONCLUSIONS: The clinical phenotypes and prognosis associated with <i>RMND1</i> mutations are more heterogeneous than that were initially described. Regular monitoring of kidney function is imperative in the clinical practice in light of nephropathy being present in over 60% of cases. Furthermore, renal replacement therapy should be considered particularly in those patients with mild neurological manifestation as shown in our study that four recipients of kidney transplant demonstrate good clinical outcome to date.","variants":[{"Name":"NM_017909.4(RMND1):c.1317+1G>T","Chromosome":"6","Start":"151405719","Stop":"151405719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":227162,"rule_based_match":true,"evidence_text":"c.1317+1G>T","llm_judgment":"PRESENT","evidence":"c.1317+1G>T","abstract_start":810,"abstract_end":821},{"Name":"NM_017909.4(RMND1):c.1303C>T (p.Leu435Phe)","Chromosome":"6","Start":"151405734","Stop":"151405734","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227163,"rule_based_match":true,"evidence_text":"c.1303C>T, p.(Leu435Phe)","llm_judgment":"PRESENT","evidence":"c.1303C>T, p.(Leu435Phe)","abstract_start":769,"abstract_end":793},{"Name":"NM_017909.4(RMND1):c.830+1G>A","Chromosome":"6","Start":"151427481","Stop":"151427481","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227164,"rule_based_match":true,"evidence_text":"c.830+1G>A","llm_judgment":"PRESENT","evidence":"c.830+1G>A","abstract_start":795,"abstract_end":805},{"Name":"NM_017909.4(RMND1):c.631G>A (p.Val211Met)","Chromosome":"6","Start":"151433213","Stop":"151433213","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227165,"rule_based_match":true,"evidence_text":"c.631G>A, p.(Val211Met)","llm_judgment":"PRESENT","evidence":"c.631G>A, p.(Val211Met)","abstract_start":744,"abstract_end":767},{"Name":"NM_017909.4(RMND1):c.565C>T (p.Gln189Ter)","Chromosome":"6","Start":"151436494","Stop":"151436494","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227166,"rule_based_match":true,"evidence_text":"c.565C>T, p.(Gln189*)","llm_judgment":"PRESENT","evidence":"c.565C>T, p.(Gln189*)","abstract_start":721,"abstract_end":742},{"Name":"NM_017909.4(RMND1):c.533C>A (p.Thr178Lys)","Chromosome":"6","Start":"151436526","Stop":"151436526","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":227167,"rule_based_match":true,"evidence_text":"c.533C>A, p.(Thr178Lys)","llm_judgment":"PRESENT","evidence":"c.533C>A, p.(Thr178Lys)","abstract_start":696,"abstract_end":719}]}
{"pmid":"24152768","title":"Genetic risk transmission in a family affected by familial breast cancer.","abstract":"Breast Cancer is the most common malignancy among women. Family history is the strongest single predictor of breast cancer risk, and thus great attention has been focused on BRCA1 and BRCA2 genes whose mutations lead to a high risk of developing this disease. Today, only 25% of high- and moderate-risk genes are known, suggesting the importance of the discovery of new risk modifiers. Therefore, the investigation of new polygenic alterations is of great importance, especially if considered high- and moderate-risk variants. In this study, the transmission of BRCA1-2 polymorphisms in association with the transmission of polymorphisms in the genes NUMA1, CCND1, COX11, FGFR2, TNRC9 and SLC4A7 were examined in all members of a family with the BRCA2 c.6447_6448dup mutation. This is the first study about the transmission of high-risk polygenic variants in all members of a family with a strong history of breast cancer. The results about the possible polygenic variant associations that could increase and modify the risk suggested the importance to search new variants to better manage patients and their family members.","variants":[{"Name":"NM_000059.4(BRCA2):c.6447_6448dup (p.Lys2150fs)","Chromosome":"13","Start":"32340801","Stop":"32340802","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TTA","allel_id":66772,"rule_based_match":true,"evidence_text":"BRCA2 c.6447_6448dup","llm_judgment":"PRESENT","evidence":"BRCA2 c.6447_6448dup","abstract_start":746,"abstract_end":766}]}
{"pmid":"38337174","title":"Oculocutaneous albinism type 4: Novel compound heterozygous mutations in the SLC45A2 gene in a Chinese case.","abstract":"BACKGROUND: Oculocutaneous albinism type 4 (OCA4) is a rare autosomal recessive disorder characterized by a reduction of pigmentation in skin, hair, and eyes, and OCA4 is mainly seen in the SLC45A2 gene variants.\nOBJECTIVE: To report a Chinese patient suspected of oculocutaneous albinism and identify the causing mutation.\nMETHODS: Genomic DNA was extracted from the peripheral blood samples of the patient, his parents, and elder brother. Whole exome sequencing was performed in the family, and Sanger sequencing was then used to verify the mutations.\nRESULTS: Compound heterozygous variants, c.1304C>A (p.S435Y) and c.301C>G (p.R101G) in SLC45A2 gene, were detected in the proband, which were inherited from his father and mother respectively. Based on the ACMG guidelines, we can interpret the c.1304C>A (p.S435Y) variant as a suspected pathogenic variant and the c.301C>G (p.R101G) variant as a clinically significant unspecified variant. The diagnosis of OCA4 is confirmed.\nCONCLUSION: We firstly reported this case of OCA4 with the compound heterozygous variants in the SLC45A2 gene. Our findings further enrich the reservoir of SLC45A2 mutations in OCA4.","variants":[{"Name":"NM_016180.5(SLC45A2):c.1304C>A (p.Ser435Tyr)","Chromosome":"5","Start":"33947227","Stop":"33947227","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3222590,"rule_based_match":true,"evidence_text":"c.1304C>A (p.S435Y)","llm_judgment":"PRESENT","evidence":"c.1304C>A (p.S435Y)","abstract_start":595,"abstract_end":614},{"Name":"NM_016180.5(SLC45A2):c.301C>G (p.Arg101Gly)","Chromosome":"5","Start":"33984283","Stop":"33984283","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3222591,"rule_based_match":true,"evidence_text":"c.301C>G (p.R101G)","llm_judgment":"PRESENT","evidence":"c.301C>G (p.R101G)","abstract_start":619,"abstract_end":637}]}
{"pmid":"29606302","title":"Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome.","abstract":"AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1<sup>-/-</sup> mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581<sup>∗</sup>]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs<sup>∗</sup>3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.","variants":[{"Name":"NM_001129.5(AEBP1):c.1630+1G>A","Chromosome":"7","Start":"44111058","Stop":"44111058","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":535285,"rule_based_match":true,"evidence_text":"c.1630+1G>A","llm_judgment":"PRESENT","evidence":"c.1630+1G>A","abstract_start":1232,"abstract_end":1243},{"Name":"NM_001129.5(AEBP1):c.1743C>A (p.Cys581Ter)","Chromosome":"7","Start":"44111533","Stop":"44111533","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":535286,"rule_based_match":true,"evidence_text":"c.1743C>A (p.Cys581<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"c.1743C>A","abstract_start":1042,"abstract_end":1051}]}
{"pmid":"15365989","title":"Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7).","abstract":"Mutations in the parkin gene have been identified as a common cause of autosomal recessive inherited Parkinson disease (PD) associated with early disease manifestation. However, based on linkage data, mutations in other genes contribute to the genetic heterogeneity of early-onset PD (EOPD). Recently, two mutations in the DJ1 gene were described as a second cause of autosomal recessive EOPD (PARK7). Analyzing the PARK7/DJ1 gene in 104 EOPD patients, we identified a third mutation, c.192G>C (p.E64D), associated with EOPD in a patient of Turkish ancestry and characterized the functional significance of this amino acid substitution. In the patient, a substantial reduction of dopamine uptake transporter (DAT) binding was found in the striatum using [(18)F]FP-CIT and PET, indicating a serious loss of presynaptic dopaminergic afferents. His sister, homozygous for E64D, was clinically unaffected but showed reduced dopamine uptake when compared with a clinically unaffected brother, who is heterozygous for E64D. We demonstrate by crystallography that the E64D mutation does not alter the structure of the DJ1 protein, however we observe a tendency towards decreased levels of the mutant protein when overexpressed in HEK293 or COS7 cells. Using immunocytochemistry in contrast to the homogenous nuclear and cytoplasmic staining in HEK293 cells overexpressing wild-type DJ1, about 5% of the cells expressing E64D and up to 80% of the cells expressing the recently described L166P mutation displayed a predominant nuclear localization of the mutant DJ1 protein.","variants":[{"Name":"NM_007262.5(PARK7):c.192G>C (p.Glu64Asp)","Chromosome":"1","Start":"7965425","Stop":"7965425","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":22106,"rule_based_match":true,"evidence_text":"c.192G>C (p.E64D)","llm_judgment":"PRESENT","evidence":"c.192G>C (p.E64D)","abstract_start":485,"abstract_end":502}]}
{"pmid":"22481662","title":"Clinical variability in dystrophic epidermolysis bullosa and findings with scanning electron microscopy.","abstract":"In dystrophic epidermolysis bullosa, the genetic defect of anchoring fibrils leads to cleavage beneath the basement membrane and its consequent loss. A 46 year-old female patient presented blisters with a pretibial distribution associated with nail dystrophy. Her two children had hyponychia and anonychia, which affected all toe nails and the thumb, forefinger and middle finger. DNA sequencing identified in exon 75 of COL7A1 gene a pathologic mutation: c.6235G>A (p.Gly2079Arg). Immunomapping of a blister demonstrated collagen IV (basal membrane) in the blister roof and collagen VII in its floor, confirming dystrophic epidermolysis bullosa. Scanning electron microscopy of an inverted blister showed net-forming collagen attached to the blister roof . The variability found in this family has already been reported and confirms, on a clinical basis, the nail subtype as a dystrophic variant.","variants":[{"Name":"NM_000094.4(COL7A1):c.6235G>A (p.Gly2079Arg)","Chromosome":"3","Start":"48575108","Stop":"48575108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1202884,"rule_based_match":true,"evidence_text":"c.6235G>A (p.Gly2079Arg)","llm_judgment":"PRESENT","evidence":"c.6235G>A (p.Gly2079Arg)","abstract_start":456,"abstract_end":480}]}
{"pmid":"21638052","title":"Characterisation of unclassified variants in the BRCA1/2 genes with a putative effect on splicing.","abstract":"A subset of the unclassified variants (UVs) identified during genetic screening of BRCA1/2 genes may affect splicing. We assessed at RNA level the effect of four BRCA1 and ten BRCA2 UVs with a putative splice effect, as predicted in silico. The variants selected for this study were beyond the positions -1, -2 or +1, +2 from the exon, and were not previously described (n = 8) or their effect on splicing was not assessed previously (n = 6). Lymphocytes from UV carriers and healthy controls were cultured and treated with puromycin to prevent nonsense-mediated mRNA decay. The relative contribution of each allele to the various transcripts was assessed using combinations of allele-specific and transcript-specific primers. BRCA2 c.425G>T, c.7976+3_7976+4del and c.8754+3G>C give rise to aberrant transcripts BRCA2Δ4, BRCA2Δ17 and retention of 46nt of intron 21, respectively, and were considered pathogenic. BRCA1 c.4987-3C>G gives rise to BRCA1Δ17 that is likely pathogenic; however, residual expression of the full-length transcript from the variant allele could not be excluded. BRCA1 c.692C>T, c.693G>A and BRCA2 c.6935A>T, besides expressing the full-length transcript, increased expression of BRCA1Δ11 and BRCA2Δ12, respectively. As these are naturally occurring isoforms, also observed in controls, the clinical relevance is unclear. The seven remaining UVs did not affect splicing and three intronic variants were therefore classified as neutral. In conclusion, the RNA analysis results clarified the clinical relevance of 6 of the 14 studied UVs and thereby greatly improve the genetic counselling of high-risk breast/ovarian cancer patients carrying these classified variants.","variants":[{"Name":"NM_007294.4(BRCA1):c.692C>T (p.Thr231Met)","Chromosome":"17","Start":"43094839","Stop":"43094839","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70336,"rule_based_match":true,"evidence_text":"BRCA1 c.692C>T","llm_judgment":"PRESENT","evidence":"BRCA1 c.692C>T","abstract_start":1086,"abstract_end":1100},{"Name":"NM_007294.4(BRCA1):c.693G>A (p.Thr231=)","Chromosome":"17","Start":"43094838","Stop":"43094838","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70337,"rule_based_match":true,"evidence_text":"BRCA1 c.693G>A","llm_judgment":"PRESENT","evidence":"c.693G>A","abstract_start":1102,"abstract_end":1110},{"Name":"NM_000059.4(BRCA2):c.6935A>T (p.Asp2312Val)","Chromosome":"13","Start":"32344651","Stop":"32344651","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":66888,"rule_based_match":true,"evidence_text":"BRCA2 c.6935A>T","llm_judgment":"PRESENT","evidence":"BRCA2 c.6935A>T","abstract_start":1115,"abstract_end":1130},{"Name":"NM_000059.4(BRCA2):c.8754+3G>C","Chromosome":"13","Start":"32376794","Stop":"32376794","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":67336,"rule_based_match":true,"evidence_text":"BRCA2 c.8754+3G>C","llm_judgment":"PRESENT","evidence":"c.8754+3G>C","abstract_start":766,"abstract_end":777},{"Name":"NM_000059.4(BRCA2):c.425G>T (p.Ser142Ile)","Chromosome":"13","Start":"32325184","Stop":"32325184","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":66286,"rule_based_match":true,"evidence_text":"BRCA2 c.425G>T","llm_judgment":"PRESENT","evidence":"BRCA2 c.425G>T","abstract_start":727,"abstract_end":741},{"Name":"NM_007294.4(BRCA1):c.4987-3C>G","Chromosome":"17","Start":"43067698","Stop":"43067698","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":70013,"rule_based_match":true,"evidence_text":"BRCA1 c.4987-3C>G","llm_judgment":"PRESENT","evidence":"BRCA1 c.4987-3C>G","abstract_start":912,"abstract_end":929}]}
{"pmid":"33443672","title":"A novel Q93H missense mutation in DCTN1 caused distal hereditary motor neuropathy type 7B and Perry syndrome from a Chinese family.","abstract":"The Dynactin 1 (DCTN1) encodes the p150 subunit of dynactin, which engages retrograde axonal transport. Missense mutations in DCTN1 have been linked to a series of neurodegenerative diseases, including distal hereditary motor neuropathies (dHMN) and Perry syndrome. A few pathogenic DCTN1 mutations related with Perry syndrome have been described within, or adjacent to, the highly conserved N-terminal cytoskeleton-associated protein, glycine-rich (CAP-Gly) domain. But to our best knowledge, only the pathogenic G59S mutation in DCTN1 has been reported in dHMN7B families. Herein, we provided a novel heterozygous mutation in DCTN1 which caused both dHMN7B and Perry syndrome from a Chinese family. Whole exome sequencing (WES) was performed to identify the disease-associated genes. Single nucleotide variants (SNVs) and small insertions/deletions (INDELs) were further predicted with Mutation Taster, Polymorphism Phenotyping v2 (PolyPhen-2), and Sorting Intolerant From Tolerant (SIFT) and compared to the Single Nucleotide Polymorphism Database(dbSNP), Exome Aggregation Consortium (ExAC), and the 1000 Genomes Project. Furthermore, a novel missense mutation c.279G>C (Q93H) in DCTN1 was identified as the candidate loci. The mutation was confirmed with Sanger sequencing in the family members and cosegregated with various phenotypes. In silico analysis and molecular structural modeling, the mutation not only caused the loss of a hydrogen bond within the p150 protein but also affected the formation of hydrogen bonds between p150 and EB. Therefore, the new Q93H mutation in DCTN1 caused both familial dHMN7B and Perry syndrome. Our findings could expand the clinical and pathogenic spectrum and strengthen the clinical diagnostic role of the DCTN1 gene.","variants":[{"Name":"NM_004082.5(DCTN1):c.279G>C (p.Gln93His)","Chromosome":"2","Start":"74378000","Stop":"74378000","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2740766,"rule_based_match":true,"evidence_text":"c.279G>C (Q93H)","llm_judgment":"PRESENT","evidence":"c.279G>C (Q93H)","abstract_start":1165,"abstract_end":1180}]}
{"pmid":"16141001","title":"Genetic and clinical aspects of Zellweger spectrum patients with PEX1 mutations.","abstract":"OBJECTIVE: To analyse the PEX1 gene, the most common cause for peroxisome biogenesis disorders (PBD), in a consecutive series of patients with Zellweger spectrum.\nMETHODS: Mutations were detected by different methods including SSCP analyses as a screening technique on the basis of genomic or cDNA, followed by direct sequencing of PCR fragments with an abnormal electrophoresis pattern.\nRESULTS: 33 patients were studied. Two common mutations, c.2528G-->A, G843D and c.2098_2098insT, I700YfsX42, accounted for over 80% of all abnormal PEX1 alleles, emphasising their diagnostic relevance. Most PEX1 mutations were distributed over the two AAA cassettes with the two functional protein domains, D1 and D2, and the highly conserved Walker motifs. Phenotypic severity of Zellweger spectrum in CG1 depended on the effect of the mutation on the PEX1 protein, peroxin 1. PEX1 mutations could be divided into two classes of genotype-phenotype correlation: class I mutations led to residual PEX1 protein levels and function and a milder phenotype; class II mutations almost abolished PEX1 protein levels and function, resulting in a severe phenotype. Compound heterozygote patients for a class I and class II mutation had an intermediate phenotype.\nCONCLUSIONS: Molecular confirmation of the clinical and biochemical diagnosis will allow the prediction of the clinical course of disease in individual PBD cases.","variants":[{"Name":"NM_000466.3(PEX1):c.2528G>A (p.Gly843Asp)","Chromosome":"7","Start":"92501562","Stop":"92501562","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22555,"rule_based_match":false,"evidence_text":"c.2528G-->A, G843D","llm_judgment":"PRESENT","evidence":"c.2528G-->A, G843D","abstract_start":445,"abstract_end":463}]}
{"pmid":"23408450","title":"Genetic variation in the parasympathetic signaling pathway in patients with reflex syncope.","abstract":"Reflex syncope is defined by a self-terminating transient loss of consciousness associated with an exaggerated response of the vagal reflexes upon orthostatic challenges. A hereditary component has previously been suggested. We hypothesized that variations in genes encoding proteins mediating the vagal signaling in the heart may be involved in reflex syncope pathogenesis. We systematically resequenced the entire coding regions and flanking intron sequences in 5 genes in the cardiac post-synaptic parasympathetic signaling pathway [muscarinic acetylcholine receptor M2 (CHRM2); G-protein beta-1 subunit (GNB1); G-protein gamma-2 subunit (GNG2); potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3); and potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)] in 74 patients with well-characterized reflex syncope of either cardioinhibitory [Vasovagal Syncope International Study (VASIS-IIB), N = 38] or vasodepressor (VASIS-III, N = 36) type. We identified 2 novel genetic variants (CHRM2 c.1114C>G and GNG2 c.87+34G>A) and several known variants (GNB1: c.267+14G>A, c.267+19C>T, and c.738C>T; KCNJ3: c.119A>G, c.591C>T, c.1038T>C, and c.1494T>C; KCNJ5: c. 171T>C, c.810T>G, c.834T>C, c.844C>G, c.938+7C>T, and c.938-10G>A). The minor allele frequency of the KCNJ5 c.938+7C>T variant was significantly lower in patients than in the control group (0.014 versus 0.089, P = 0.001), and the frequency of heterozygosity and homozygosity was lower in cardioinhibitory patients compared to controls. Genetic variations in genes responsible for the vagal signaling in the heart, including CHRM2, GNB1, GNG2, KCNJ3, and KCNJ5, are not major contributors to the pathogenesis of reflex syncope of vasodepressor or cardioinhibitory types.","variants":[{"Name":"NM_001006630.2(CHRM2):c.1114C>G (p.Pro372Ala)","Chromosome":"7","Start":"137015979","Stop":"137015979","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":229559,"rule_based_match":true,"evidence_text":"CHRM2 c.1114C>G","llm_judgment":"PRESENT","evidence":"CHRM2 c.1114C>G","abstract_start":1017,"abstract_end":1032}]}
{"pmid":"28391974","title":"Generation of induced Pluripotent Stem Cells as disease modelling of NLSDM.","abstract":"Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare defect of triacylglycerol metabolism, characterized by the abnormal storage of neutral lipid in organelles known as lipid droplets (LDs). The main clinical features are progressive myopathy and cardiomyopathy. The onset of NLSDM is caused by autosomal recessive mutations in the PNPLA2 gene, which encodes adipose triglyceride lipase (ATGL). Despite its name, this enzyme is present in a wide variety of cell types and catalyzes the first step in triacylglycerol lipolysis and the release of fatty acids. Here, we report the derivation of NLSDM-induced pluripotent stem cells (NLSDM-iPSCs) from fibroblasts of two patients carrying different PNPLA2 mutations. The first patient was homozygous for the c.541delAC, while the second was homozygous for the c.662G>C mutation in the PNPLA2 gene. We verified that the two types of NLSDM-iPSCs possessed properties of embryonic-like stem cells and could differentiate into the three germ layers in vitro. Immunofluorescence analysis revealed that iPSCs had an abnormal accumulation of triglycerides in LDs, the hallmark of NLSDM. Furthermore, NLSDM-iPSCs were deficient in long chain fatty acid lipolysis, when subjected to a pulse chase experiment with oleic acid. Collectively, these results demonstrate that NLSDM-iPSCs are a promising in vitro model to investigate disease mechanisms and screen drug compounds for NLSDM, a rare disease with few therapeutic options.","variants":[{"Name":"NM_020376.4(PNPLA2):c.662G>C (p.Arg221Pro)","Chromosome":"11","Start":"822572","Stop":"822572","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":640483,"rule_based_match":true,"evidence_text":"c.662G>C","llm_judgment":"PRESENT","evidence":"c.662G>C","abstract_start":815,"abstract_end":823}]}
{"pmid":"21457052","title":"A novel pathogenic nonsense triple-nucleotide mutation in the low-density lipoprotein receptor gene and its clinical correlation with familial hypercholesterolemia.","abstract":"AIM: The aim of this study was to determine the genetic basis of familial hypercholesterolemia in a Pakistani family with a history of myocardial infarction and premature coronary artery disease.\nRESULTS: Direct sequencing of the low-density lipoprotein receptor gene resulted in the identification of a novel missense mutation c.264G>C (p.R88S) in exon 3 and a novel nonsense triple-nucleotide polymorphism (TNP) c.887-889GCA>AGC (p.C296X) in exon 6, the latter being probably the disease-causing mutation in this family. Both of these mutations were not present in the probands of 14 familial hypercholesterolemia families, 100 myocardial infarction patients, as well as 150 normolipidemic ethnically matched control individuals.\nCONCLUSIONS: The identification of the novel nonsense TNP is the first report of a nonsense pathogenic TNP in low-density lipoprotein receptor or any other gene and only the fourth report of a pathogenic TNP of any type, which emphasizes the importance of screening for TNPs in patients and in familial studies that might otherwise be missed if only analyzed on single-nucleotide polymorphism arrays.","variants":[{"Name":"NM_000527.5(LDLR):c.264G>C (p.Arg88Ser)","Chromosome":"19","Start":"11102737","Stop":"11102737","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":245444,"rule_based_match":true,"evidence_text":"c.264G>C (p.R88S)","llm_judgment":"PRESENT","evidence":"c.264G>C (p.R88S)","abstract_start":328,"abstract_end":345}]}
{"pmid":"35247231","title":"Genome sequencing reveals novel noncoding variants in PLA2G6 and LMNB1 causing progressive neurologic disease.","abstract":"Neurodegenerative disorders and leukodystrophies are progressive neurologic conditions that can occur following the disruption of intricately coordinated patterns of gene expression. Exome sequencing has been adopted as an effective diagnostic tool for determining the underlying genetic etiology of Mendelian neurologic disorders, however genome sequencing offer advantages in its ability to identify and characterize copy number, structural, and sequence variants in noncoding regions. Genome sequencing from peripheral leukocytes was performed on two patients with progressive neurologic disease of unknown etiology following negative genetic investigations including exome sequencing. RNA sequencing from peripheral blood was performed to determine gene expression patterns in one of the patients. Potential causative variants were matched to the patients' clinical presentation. The first proband was found to be heterozygous for a likely pathogenic missense variant in PLA2G6 (c.386T>C; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6 (c.2035-926G>A). RNA sequencing indicated this latter variant created a splice acceptor site leading to the incorporation of a pseudo-exon introducing a premature termination codon. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. Previous reports of copy number variants spanning this region of cis-acting regulatory elements corroborated its pathogenicity. When combined with clinical presentations, these findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult-onset demyelinating leukodystrophy, respectively. In patients with progressive neurologic disease of unknown etiology, genome sequencing with the addition of RNA analysis where appropriate should be considered for the identification of causative noncoding pathogenic variants.","variants":[{"Name":"NM_003560.4(PLA2G6):c.386T>C (p.Leu129Pro)","Chromosome":"22","Start":"38145477","Stop":"38145477","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":169816,"rule_based_match":true,"evidence_text":"c.386T>C; p.Leu129Pro","llm_judgment":"PRESENT","evidence":"c.386T>C; p.Leu129Pro","abstract_start":983,"abstract_end":1004},{"Name":"NM_003560.4(PLA2G6):c.2035-926G>A","Chromosome":"22","Start":"38114580","Stop":"38114580","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1709968,"rule_based_match":true,"evidence_text":"c.2035-926G>A","llm_judgment":"PRESENT","evidence":"c.2035-926G>A","abstract_start":1062,"abstract_end":1075}]}
{"pmid":"19478085","title":"Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication.","abstract":"Forty-five different point mutations in POLG, the gene encoding the catalytic subunit of the human mitochondrial DNA polymerase (pol gamma), cause the early onset mitochondrial DNA depletion disorder, Alpers syndrome. Sequence analysis of the C-terminal polymerase region of pol gamma revealed a cluster of four Alpers mutations at highly conserved residues in the thumb subdomain (G848S, c.2542g-->a; T851A, c.2551a-->g; R852C, c.2554c-->t; R853Q, c.2558g-->a) and two Alpers mutations at less conserved positions in the adjacent palm subdomain (Q879H, c.2637g-->t and T885S, c.2653a-->t). Biochemical characterization of purified, recombinant forms of pol gamma revealed that Alpers mutations in the thumb subdomain reduced polymerase activity more than 99% relative to the wild-type enzyme, whereas the palm subdomain mutations retained 50-70% wild-type polymerase activity. All six mutant enzymes retained physical and functional interaction with the pol gamma accessory subunit (p55), and none of the six mutants exhibited defects in misinsertion fidelity in vitro. However, differential DNA binding by these mutants suggests a possible orientation of the DNA with respect to the polymerase during catalysis. To our knowledge this study represents the first structure-function analysis of the thumb subdomain in pol gamma and examines the consequences of mitochondrial disease mutations in this region.","variants":[{"Name":"NM_002693.3(POLG):c.2558G>A (p.Arg853Gln)","Chromosome":"15","Start":"89321776","Stop":"89321776","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":202959,"rule_based_match":false,"evidence_text":"c.2558g-->a","llm_judgment":"PRESENT","evidence":"c.2558g-->a","abstract_start":449,"abstract_end":460},{"Name":"NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)","Chromosome":"15","Start":"89321780","Stop":"89321780","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":202960,"rule_based_match":false,"evidence_text":"c.2554c-->t","llm_judgment":"PRESENT","evidence":"c.2554c-->t","abstract_start":429,"abstract_end":440},{"Name":"NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)","Chromosome":"15","Start":"89321792","Stop":"89321792","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28541,"rule_based_match":false,"evidence_text":"c.2542g-->a","llm_judgment":"PRESENT","evidence":"c.2542g-->a","abstract_start":389,"abstract_end":400},{"Name":"NM_002693.3(POLG):c.2551A>G (p.Thr851Ala)","Chromosome":"15","Start":"89321783","Stop":"89321783","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":610751,"rule_based_match":false,"evidence_text":"c.2551a-->g","llm_judgment":"PRESENT","evidence":"c.2551a-->g","abstract_start":409,"abstract_end":420}]}
{"pmid":"27815843","title":"COXPD9 an Evolving Multisystem Disease; Congenital Lactic Acidosis, Sensorineural Hearing Loss, Hypertrophic Cardiomyopathy, Cirrhosis and Interstitial Nephritis.","abstract":"We present the second report of combined oxidative phosphorylation deficiency-9. The infant presented in the neonatal period with poor feeding, lactic acidosis and sensorineural hearing loss. He subsequently developed a lethal hypertrophic cardiomyopathy during infancy. Cirrhosis and interstitial nephritis were identified at autopsy. Exome sequencing has detected compound heterozygous mutations in the MRPL3 gene which encodes a large mitochondrial ribosome subunit protein. We identified a known heterozygous variant NM_007208 c.950>G (Pro317Arg) in the MRPL3 gene and a novel heterozygous mutation NM_007208 c.49delC p.(Arg17Aspfs*57). Mutations in MRPL3 have previously been shown to alter ribosome assembly and cause abnormal function of multiple respiratory chain complexes. Our case adds to the evolving knowledge of disorders of mitochondrial translation.","variants":[{"Name":"NM_007208.4(MRPL3):c.950C>G (p.Pro317Arg)","Chromosome":"3","Start":"131462820","Stop":"131462820","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":39600,"rule_based_match":false,"evidence_text":"NM_007208 c.950>G (Pro317Arg)","llm_judgment":"PRESENT","evidence":"NM_007208 c.950>G (Pro317Arg)","abstract_start":521,"abstract_end":550},{"Name":"NM_007208.4(MRPL3):c.49del (p.Arg17fs)","Chromosome":"3","Start":"131502773","Stop":"131502773","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":677003,"rule_based_match":true,"evidence_text":"NM_007208 c.49delC p.(Arg17Aspfs*57)","llm_judgment":"PRESENT","evidence":"NM_007208 c.49delC p.(Arg17Aspfs*57)","abstract_start":603,"abstract_end":639}]}
{"pmid":"17285242","title":"Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients.","abstract":"Megaloblastic anaemia 1 (MGA1) is a rare autosomal recessive condition characterized by selective intestinal vitamin B12 malabsorption and proteinuria. More than 200 MGA1 patients have been identified worldwide, but the disease is relatively prevalent in Finland, Norway and several Eastern Mediterranean regions. MGA1 is genetically heterogeneous and can be caused by mutations in either the cubilin (CUBN) or the amnionless (AMN) gene. In the present study we investigated the molecular defect underlying MGA1 in nine Tunisian patients belonging to six unrelated consanguineous families. Haplotype and linkage analyses, using microsatellite markers surrounding both CUBN and AMN genes, indicated that four out of the six families were likely to be linked to the CUBN gene. Patients from these families were screened for the Finnish, Mediterranean and Arabian mutations already published. None of the screened mutations could be detected in our population. One family showed a linkage to AMN gene. Direct screening of the AMN gene allowed the identification of the c.208-2A>G mutation, previously described in a Jewish Israeli patient of Tunisian origin and in Turkish patients. This suggests that the c.208-2A>G mutation may derive from a single Mediterranean founder ancestor. For the last family, haplotype analysis excluded both CUBN and AMN genes, suggesting the existence of a third locus that may cause MGA1.","variants":[{"Name":"NM_030943.4(AMN):c.208-2A>G","Chromosome":"14","Start":"102928424","Stop":"102928424","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":71390,"rule_based_match":true,"evidence_text":"c.208-2A>G","llm_judgment":"PRESENT","evidence":"c.208-2A>G","abstract_start":1066,"abstract_end":1076}]}
{"pmid":"35958417","title":"Case report: An unusual case of desmin myopathy associated with heart failure and arrhythmia.","abstract":"Introduction: Desmin myopathy is a novel desmin (DES) indel mutation that causes severe atypical cardiomyopathy as well as atrioventricular block and skeletal myopathy. The mutation of the gene of the nodal tail causes myocardial injury. Rarely does desmin myopathy cause bilateral ventricular changes.\nCase presentation: We present a case of a 48-year-old man admitted with dyspnea and edema of both lower extremities. Due to bilateral lower limb weakness and calf muscle atrophy, gene sequencing was performed. The results showed that there was a pure missense mutation in the 8th exon region of the DES gene (c.1366G>A), encoding amino acid p.G456R (glycine>arginine). Supplementary examination suggests a high possibility of heart failure, atrial flutter, and desmin myopathy. Atrial flutter was treated by radiofrequency ablation. The clinical symptoms were stable after oral administration of rivaroxaban, coenzyme Q10, and ARNI.\nConclusion: In our case, mutation results are the gold standard for the diagnosis of nodular myopathy. Cardiac magnetic resonance can define the extent and degree of cardiomyopathy and quantitatively evaluate cardiac function. At present, there is a lack of specific treatment for proteolytic myopathy. Therefore, the treatment for heart failure proves effective. Due to the multiple systems involved, early diagnosis and multidisciplinary management are critical to improving patient outcomes.","variants":[{"Name":"NM_001927.4(DES):c.1366G>A (p.Gly456Arg)","Chromosome":"2","Start":"219425740","Stop":"219425740","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":53418,"rule_based_match":true,"evidence_text":"c.1366G>A","llm_judgment":"PRESENT","evidence":"c.1366G>A","abstract_start":612,"abstract_end":621}]}
{"pmid":"22465514","title":"A case of primary selective hypoaldosteronism carrying three mutations in the aldosterone synthase (Cyp11b2) gene.","abstract":"An infant with a clinical phenotype of early onset hypoaldosteronism has been screened for mutation analysis of the Cyp11b2 gene encoding aldosterone synthase enzyme. We have described a novel nonsense mutation in exon 3 (c.508C>T) that gave rise to a shorter protein (Q170X) and two known concurrent missense mutations (c.594A>C in exon 3 and c.1157T>C in exon 7) that led to substitution of glutamic acid for aspartic acid at amino acid position 198 (E198D) and of valine for alanine at amino acid position 386 (V386A). The father, who carried E198D plus V386A mutations, showed a fractional sodium excretion of 1.25% that was unmodified by dietary salt restriction, suggesting a mild haploinsufficiency. We examined by in silico analysis the effect of the mutations on the secondary and tertiary structures of aldosterone synthase to explain the inefficient enzymatic activity. The Q170X mutation produced a truncated protein, which was consequently associated with a loss of catalytic activity. As predicted by JPred web system and Dock 6.3 software, the concurrent expression of E198D and V386A mutations induced a significant secondary structure rearrangement and a shift of the heme group and the 18-hydroxycorticosterone substrate from their optimal placement.","variants":[{"Name":"NM_000498.3(CYP11B2):c.1157T>C (p.Val386Ala)","Chromosome":"8","Start":"142912850","Stop":"142912850","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":31916,"rule_based_match":true,"evidence_text":"c.1157T>C","llm_judgment":"PRESENT","evidence":"c.1157T>C","abstract_start":344,"abstract_end":353},{"Name":"NM_000498.3(CYP11B2):c.594A>C (p.Glu198Asp)","Chromosome":"8","Start":"142915047","Stop":"142915047","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":38484,"rule_based_match":true,"evidence_text":"c.594A>C","llm_judgment":"PRESENT","evidence":"c.594A>C","abstract_start":321,"abstract_end":329},{"Name":"NM_000498.3(CYP11B2):c.508C>T (p.Gln170Ter)","Chromosome":"8","Start":"142915133","Stop":"142915133","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1868181,"rule_based_match":true,"evidence_text":"c.508C>T","llm_judgment":"PRESENT","evidence":"c.508C>T","abstract_start":222,"abstract_end":230}]}
{"pmid":"26016410","title":"Compound heterozygous GFM2 mutations with Leigh syndrome complicated by arthrogryposis multiplex congenita.","abstract":"Defects in the mitochondrial translation apparatus can impair energy production in affected tissues and organs. Most components of this apparatus are encoded by nuclear genes, including GFM2, which encodes a mitochondrial ribosome recycling factor. A few patients with mutations in some of these genes have been reported to date. Here, we present two female siblings with arthrogryposis multiplex congenita, optic atrophy and severe mental retardation. The younger sister had a progressive cerebellar atrophy and bilateral neuropathological findings in the brainstem. Although her cerebrospinal fluid (CSF) levels of lactate and pyruvate were not increased, brain magnetic resonance spectroscopy showed a lactate peak. Additionally, her CSF lactate/pyruvate and serum beta-hydroxybutyrate/acetoacetate ratios were high, and levels of oxidative phosphorylation in skin fibroblasts were reduced. We therefore diagnosed Leigh syndrome. Genomic investigation confirmed the presence of compound heterozygous GFM2 mutations (c.206+4A>G and c.2029-1G>A) in both siblings, causing aberrant splicing with premature stop codons (p.Gly50Glufs*4 and p.Ala677Leufs*2, respectively). These findings suggest that GFM2 mutations could be causative of a phenotype of Leigh syndrome with arthrogryposis multiplex congenita.","variants":[{"Name":"NM_032380.5(GFM2):c.206+4A>G","Chromosome":"5","Start":"74759365","Stop":"74759365","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":227133,"rule_based_match":true,"evidence_text":"c.206+4A>G","llm_judgment":"PRESENT","evidence":"c.206+4A>G","abstract_start":1019,"abstract_end":1029},{"Name":"NM_032380.5(GFM2):c.2029-1G>A","Chromosome":"5","Start":"74722562","Stop":"74722562","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227134,"rule_based_match":true,"evidence_text":"c.2029-1G>A","llm_judgment":"PRESENT","evidence":"c.2029-1G>A","abstract_start":1034,"abstract_end":1045}]}
{"pmid":"28489339","title":"De novo IGF2 mutation on the paternal allele in a patient with Silver-Russell syndrome and ectrodactyly.","abstract":"Although paternally expressed IGF2 is known to play a critical role in placental and body growth, only a single mutation has been found in IGF2. We identified, through whole-exome sequencing, a de novo IGF2 indel mutation leading to frameshift (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) in a patient with Silver-Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia. Furthermore, we demonstrated that the mutation resided on the paternal allele by sequencing the long PCR product harboring the mutation- and methylation-sensitive SmaI and SalI sites before and after SmaI/SalI digestion. The results, together with the previous findings in four cases from a single family with a paternally inherited IGF2 nonsense mutation and those in patients with variable H19 differentially methylated region epimutations leading to compromised IGF2 expression, suggest that the whole phenotype of this patient is explainable by the IGF2 mutation, and that phenotypic severity is primarily determined by the IGF2 expression level in target tissues.","variants":[{"Name":"NM_000612.6(IGF2):c.110_117delinsAGGTAA (p.Leu37fs)","Chromosome":"11","Start":"2135407","Stop":"2135414","ReferenceAlleleVCF":"GTCCACCA","AlternateAlleleVCF":"TTACCT","allel_id":905829,"rule_based_match":true,"evidence_text":"NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)","llm_judgment":"PRESENT","evidence":"NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)","abstract_start":245,"abstract_end":297}]}
{"pmid":"18164228","title":"Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type.","abstract":"Methylmalonic aciduria (MMA) and homocystinuria, cblC type (MIM 277400) is the most frequent inborn error of vitamin B(12). The recent identification of the disease gene, MMACHC, has permitted preliminary genotype-phenotype correlations. We studied 24 Italian and 17 Portuguese patients with cblC defect to illustrate the spectrum of mutations in a southern European population and discuss the impact that mutation identification has on routine diagnostic procedures. Since the metabolic defect raises the serum levels of homocysteine, we also tested if variants in MTHFR-playing a key role in homocysteine remethylation pathway-could act as genetic modifier in cblC defect. We found that the c.271dupA (accounting for 55% of the MMACH alleles in our cohort) followed by c.394C>T (16%) and c.331C>T (9%) were the most frequent mutations. In our study we also identified a novel mutation (c.544T>C). On the other hand, the MTHFR genotype did not appear to influence age at onset, the clinical phenotype and outcome of patients with cblC defect. This study shows that mutation screening for the most common MMACH mutations occurring in early-onset forms (c.271dupA and c.331C>T) seems to have a high diagnostic yield in a southern European population with cblC defect. Although the identification of the gene defect per se does not predict completely time and severity of disease appearance, our data corroborate the importance of a molecular testing to offer accurate prenatal diagnosis to couples at high risk of having affected children.","variants":[{"Name":"NM_015506.3(MMACHC):c.271dup (p.Arg91fs)","Chromosome":"1","Start":"45507544","Stop":"45507545","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":16460,"rule_based_match":true,"evidence_text":"c.271dupA","llm_judgment":"PRESENT","evidence":"c.271dupA","abstract_start":693,"abstract_end":702},{"Name":"NM_015506.3(MMACHC):c.544T>C (p.Cys182Arg)","Chromosome":"1","Start":"45508910","Stop":"45508910","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":541132,"rule_based_match":true,"evidence_text":"c.544T>C","llm_judgment":"PRESENT","evidence":"c.544T>C","abstract_start":888,"abstract_end":896},{"Name":"NM_015506.3(MMACHC):c.331C>T (p.Arg111Ter)","Chromosome":"1","Start":"45508266","Stop":"45508266","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16463,"rule_based_match":true,"evidence_text":"c.331C>T","llm_judgment":"PRESENT","evidence":"c.331C>T","abstract_start":790,"abstract_end":798}]}
{"pmid":"27739212","title":"Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA.","abstract":"Filamin A is an X-linked, ubiquitous actin-binding protein whose mutations are associated to multiple disorders with limited genotype-phenotype correlations. While gain-of-function mutations cause various bone dysplasias, loss-of-function variants are the most common cause of periventricular nodular heterotopias with variable soft connective tissue involvement, as well as X-linked cardiac valvular dystrophy (XCVD). The term \"Ehlers-Danlos syndrome (EDS) with periventricular heterotopias\" has been used in females with neurological, cardiovascular, integument and joint manifestations, but this nosology is still a matter of debate. We report the clinical and molecular update of an Italian family with an X-linked recessive soft connective tissue disorder and which was described, in 1975, as the first example of EDS type V of the Berlin nosology. The cutaneous phenotype of the index patient was close to classical EDS and all males died for a lethal cardiac valvular dystrophy. Whole exome sequencing identified the novel c.1829-1G>C splice variation in FLNA in two affected cousins. The nucleotide change was predicted to abolish the canonical splice acceptor site of exon 13 and to activate a cryptic acceptor site 15 bp downstream, leading to in frame deletion of five amino acid residues (p.Phe611_Gly615del). The predicted in frame deletion clusters with all the mutations previously identified in XCVD and falls within the N-terminus rod 1 domain of filamin A. Our findings expand the male-specific phenotype of FLNA mutations that now includes classical-like EDS with lethal cardiac valvular dystrophy, and offer further insights for the genotype-phenotype correlations within this spectrum. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_001110556.2(FLNA):c.1829-1G>C","Chromosome":"X","Start":"154364720","Stop":"154364720","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":623788,"rule_based_match":true,"evidence_text":"c.1829-1G>C","llm_judgment":"PRESENT","evidence":"c.1829-1G>C","abstract_start":1030,"abstract_end":1041}]}
{"pmid":"27530795","title":"Clinical feature and ATP8B1 mutation analysis of a patient with progressive familial intrahepatic cholestasis type I","abstract":"Progressive familial intrahepatic cholestasis type I (PFIC1) is an autosomal recessive disorder caused by biallelic mutations of ATP8B1 gene, with progressive cholestasis as the main clinical manifestation. This paper reports the clinical and genetic features of a PFIC1 patient definitely diagnosed by ATP8B1 genetic analysis. The patient, a boy aged 14 months, was referred to the hospital with the complaint of jaundiced skin and sclera over 10 months. The patient had been managed in different hospitals, but the therapeutic effects were unsatisfactory due to undetermined etiology. On physical examination, hepatosplenomegaly was discovered in addition to jaundice of the skin and sclera. The liver was palpable 4 cm below the right subcostal margin and 2 cm below the xiphoid while the spleen 2 cm below the left subcostal margin. The liver function test revealed elevated levels of serum total bile acids, bilirubin, and transaminases; however, the γ-glutamyl transferase level was normal. The diagnosis was genetic cholestasis of undetermined origin. At the age of 1 year and 8 months, a Roux-en-Y cholecystocolonic bypass operation was performed, and thereafter the jaundice disappeared. At 5 years and 1 month, via whole genome sequencing analysis and Sanger sequencing confirmation, the boy was found to be a homozygote of mutation c.2081T>A(p.I694N) of ATP8B1 gene, and thus PFIC1 was definitely diagnosed. The boy was followed up until he was 6 years, and jaundice did not recur, but the long-term outcome remains to be observed.","variants":[{"Name":"NM_001374385.1(ATP8B1):c.2081T>A (p.Ile694Asn)","Chromosome":"18","Start":"57669334","Stop":"57669334","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2833578,"rule_based_match":true,"evidence_text":"c.2081T>A(p.I694N)","llm_judgment":"PRESENT","evidence":"c.2081T>A(p.I694N)","abstract_start":1343,"abstract_end":1361}]}
{"pmid":"20924721","title":"p.R672C mutation of MYH3 gene in an Egyptian infant presented with Freeman-Sheldon syndrome.","abstract":"OBJECTIVE: To define the mutation type in a clinically suspected Egyptian child with Freeman-Sheldon syndrome (FSS); it involves certain skeletal malformations with some facial characteristics; skeletal malformations include camptodactyly with ulnar deviation, talipes equinovarus, while the facial characteristics include deep-sunken eyes with hypertelorism, long philtrum, small pinched nose and pursed mouth.\nMETHODS: Amplification of exon 17 of the embryonic myosin heavy chain (MYH3) gene was done using one forward and two different reverse primers, and then the cleaned PCR product was sequenced.\nRESULT: A de novo missense mutation (c.2014C>T with replacement C > Y) in MYH3 gene leading to change of arginine at position 672 by cytosine in protein sequence.\nCONCLUSION: Mutation analysis remains to be the standard way for definitive diagnosis in FSS. The authors currently report, for the first time in an Egyptian infant aged 16 months who presented with FSS, a c.2014C>T missense mutation of MYH3 gene, with no family history or consanguinity.","variants":[{"Name":"NM_002470.4(MYH3):c.2014C>T (p.Arg672Cys)","Chromosome":"17","Start":"10641318","Stop":"10641318","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29178,"rule_based_match":true,"evidence_text":"c.2014C>T","llm_judgment":"PRESENT","evidence":"c.2014C>T","abstract_start":641,"abstract_end":650}]}
{"pmid":"26852015","title":"Novel germline mutations and unclassified variants of BRCA1 and BRCA2 genes in Chinese women with familial breast/ovarian cancer.","abstract":"BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes greatly increase a woman's risk of developing breast and/or ovarian cancer. The prevalence and distribution of such mutations differ across races/ethnicities. Several studies have investigated Chinese women with high-risk breast cancer, but the full spectrum of the mutations in these two genes remains unclear.\nMETHODS: In this study, 133 unrelated Chinese women with familial breast/ovarian cancer living in Zhejiang, eastern China, were enrolled between the years 2008 and 2014. The complete coding regions and exon-intron boundaries of BRCA1 and BRCA2 were screened by PCR-sequencing assay. Haplotype analysis was performed to confirm BRCA1 and BRCA2 founder mutations. In silico predictions were performed to identify the non-synonymous amino acid changes that were likely to disrupt the functions of BRCA1 and BRCA2.\nRESULTS: A total of 23 deleterious mutations were detected in the two genes in 31 familial breast/ovarian cancer patients with a total mutation frequency of 23.3% (31/133). The highest frequency of 50.0% (8/16) was found in breast cancer patients with a history of ovarian cancer. The frequencies of BRCA1 and BRCA2 mutations were 13.5 % (18/133) and 9.8% (13/133), respectively. We identified five novel deleterious mutations (c.3295delC, c.3780_3781delAG, c.4063_4066delAATC, c.5161 > T and c.5173insA) in BRCA1 and seven (c.1-40delGA, c.4487delC, c.469_473delAAGTC, c.5495delC, c.6141T > A, c.6359C > G and c.7588C > T) in BRCA2, which accounted for 52.2% (12/23) of the total mutations. Six recurrent mutations were found, including four (c.3780_3781delAG, c.5154G > A, c.5468-1del8 and c.5470_5477del8) in BRCA1 and two (c.3109C > T and c.5682C > G) in BRCA2. Two recurrent BRCA1 mutations (c.5154G > A and c.5468-1del8) were identified as putative founder mutations. We also found 11 unclassified variants, and nine of these are novel. The possibility was that each of the non-synonymous amino acid changes would disrupt the function of BRCA1 and BRCA2 varied according to the different algorithms used.\nCONCLUSIONS: BRCA1 and BRCA2 mutations accounted for a considerable proportion of hereditary breast/ovarian cancer patients from eastern China and the spectrum of the mutations of these two genes exhibited some unique features. The two BRCA1 putative founder mutations may provide a cost-effective option to screen Chinese population, while founder effects of the two mutations should be investigated in a lager sample size of patients.","variants":[{"Name":"NM_000059.4(BRCA2):c.3109C>T (p.Gln1037Ter)","Chromosome":"13","Start":"32337464","Stop":"32337464","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46375,"rule_based_match":true,"evidence_text":"c.3109C > T","llm_judgment":"PRESENT","evidence":"c.3109C > T","abstract_start":1709,"abstract_end":1720},{"Name":"NM_000059.4(BRCA2):c.7588C>T (p.Gln2530Ter)","Chromosome":"13","Start":"32356580","Stop":"32356580","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1230194,"rule_based_match":true,"evidence_text":"c.7588C > T","llm_judgment":"PRESENT","evidence":"c.7588C > T","abstract_start":1493,"abstract_end":1504},{"Name":"NM_007294.4(BRCA1):c.5154G>A (p.Trp1718Ter)","Chromosome":"17","Start":"43063372","Stop":"43063372","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70101,"rule_based_match":true,"evidence_text":"c.5154G > A","llm_judgment":"PRESENT","evidence":"c.5154G > A","abstract_start":1644,"abstract_end":1655},{"Name":"NM_000059.4(BRCA2):c.6141T>A (p.Tyr2047Ter)","Chromosome":"13","Start":"32340496","Stop":"32340496","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":926879,"rule_based_match":true,"evidence_text":"c.6141T > A","llm_judgment":"PRESENT","evidence":"c.6141T > A","abstract_start":1464,"abstract_end":1475}]}
{"pmid":"23590336","title":"A deleterious mutation in the PEX2 gene causes Zellweger syndrome in individuals of Ashkenazi Jewish descent.","abstract":"Zellweger syndrome is known to be caused by numerous mutations that occur in at least 12 of the PEX genes. While phenotypes vary, many are severely debilitating, and death can result in affected newborns. Since the disease follows an autosomal recessive pattern of inheritance, carrier screening can be done for at-risk couples, but the number of potential mutations sites to screen can be daunting. Ethnicity-specific studies can help narrow this range by highlighting mutations that are present at higher percentages in certain populations. In this article, the carrier frequencies for two mutations causative of the severe Zellweger syndrome spectrum phenotype that occur in the PEX2 gene, c.355C>T and c.550del, were studied in individuals of Ashkenazi Jewish descent in order to advise on inclusion in existing carrier screening mutation panels for this population. The screening was performed for 2093 individuals through the use of TaqMan genotyping assays, real-time PCR, and allelic discrimination. Results indicated a carrier frequency of 0.813% (±0.385%) for the c.355C>T mutation and a carrier frequency of 0.00% (±0.00%) for the c.550del mutation. On the basis of these frequencies, we believe that the c.355C>T mutation should be considered for inclusion in carrier screening panels for the Ashkenazi population.","variants":[{"Name":"NM_000318.3(PEX2):c.355C>T (p.Arg119Ter)","Chromosome":"8","Start":"76983824","Stop":"76983824","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28743,"rule_based_match":true,"evidence_text":"c.355C>T","llm_judgment":"PRESENT","evidence":"c.355C>T","abstract_start":693,"abstract_end":701}]}
{"pmid":"27439424","title":"Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma.","abstract":"BACKGROUND: von Hippel-Lindau (VHL) disease is a rare hereditary tumor syndrome caused by VHL gene mutations that is characterized by heterogeneous phenotypes such as benign/malignant tumors of the central nervous system, retina, kidney, adrenal gland, and pancreas. The genotype-phenotype correlation has not been well characterized in the Korean population so far. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Korean VHL patients.\nMETHODS: Thirteen unrelated subjects with VHL mutations were included. Direct sequencing and multiplex ligation-dependent probe amplification were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated.\nRESULTS: We identified 10 different VHL mutations. The c.160_161delAT frameshift mutation was novel. Missense mutations clustered in 2 domains (α domain in exon 1; β domain in exon 3). The most frequently observed mutation was c.208G > A (p.Glu70Lys). Milder phenotypes were observed in subjects with de novo mutations. Age-specific risk for CNS hemangioblastoma was significantly higher in subjects carrying missense mutations within the HIF-α binding site (P < 0.05).\nCONCLUSIONS: This study provides insight into the genotype-phenotype correlation in that amino acid substitutions in the HIF-α binding site may predispose patients to age-related risks of CNS hemangioblastoma.","variants":[{"Name":"NM_000551.4(VHL):c.208G>A (p.Glu70Lys)","Chromosome":"3","Start":"10142055","Stop":"10142055","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":52767,"rule_based_match":true,"evidence_text":"c.208G > A (p.Glu70Lys)","llm_judgment":"PRESENT","evidence":"c.208G > A (p.Glu70Lys)","abstract_start":973,"abstract_end":996}]}
{"pmid":"32219828","title":"Clinical phenotype and variantal analysis of a pedigree affected with hereditary coagulation factor V deficiency","abstract":"OBJECTIVE: To explore the molecular basis for a pedigree affected with coagulation factor V (FV) deficiency.\nMETHODS: Clinical data of the patient and his family members was analyzed. Targeted capture and next-generation sequencing (NGS) and Sanger sequencing were carried out to detect potential variant of the FV gene.\nRESULTS: The patient presented with jaundice and prolonged prothrombin time (PT) and activated partial thromboplastic time (APTT). V factor activity measured only 0.1% of the normal level, though the patient had no sign of bleeding. A paternal heterozygous variant c.653T>C (p.F218S) and a maternal heterozygous variant c.3642_3643del (p.P1215Rfs*175) were identified in the FV gene of the patient. His elder brother was a heterozygous carrier of the c.653T>C (p.F218S) variant. c.653T>C(p.F218S) was a known pathogenic variant, while the c.3642_3643del (p.P1215Rfs*175) variant was unreported previously.\nCONCLUSION: Mutations of the FV gene probably underlie the hereditary coagulation factor V deficiency in this patient. NGS combined with Sanger sequencing has detected potential variant with efficiency and provided a reliable basis for clinical and prenatal diagnosis for this family.","variants":[{"Name":"NM_000130.5(F5):c.653T>C (p.Phe218Ser)","Chromosome":"1","Start":"169559230","Stop":"169559230","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2898358,"rule_based_match":true,"evidence_text":"c.653T>C (p.F218S)","llm_judgment":"PRESENT","evidence":"c.653T>C (p.F218S)","abstract_start":586,"abstract_end":604}]}
{"pmid":"27549011","title":"Clinical findings in a patient with FARS2 mutations and early-infantile-encephalopathy with epilepsy.","abstract":"The FARS2 gene encodes the mitochondrial phenylalanyl-tRNA synthetase and is implicated in autosomal recessive combined oxidative phosphorylation deficiency 14, a clinical condition characterized by infantile onset epilepsy and encephalopathy. Mutations in FARS2 have been reported in only few patients, but a detailed description of seizures, electroencephalographic patterns, magnetic resonance imaging findings, and long-term follow-up is still needed. We provide a clinical report of a child with FARS2-related disease manifesting drug-resistant infantile spasms associated with focal seizures. By comparative genomic hybridization analysis we identified a heterozygous microdeletion in the short arm of chromosome 6, inherited from the mother, that encompasses the first coding exon of FARS2. By sequencing of the FARS2 gene we identified a variant c.1156C>G; p.(R386G), inherited from the father. By using standard spectrophotometric techniques in skin fibroblasts, we found a combined abnormality of complexes I and IV of the mitochondrial respiratory chain. The main clinical features of the patient included axial hypotonia, mild distal hypertonia, and psychomotor delay. The magnetic resonance imaging showed microcephaly, frontal cerebral atrophy, and signal changes of dentate nuclei. At the age of 3 years and 6 months, the patient was still under treatment with vigabatrin and he has been seizure free for the last 23 months. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_006567.5(FARS2):c.1156C>G (p.Arg386Gly)","Chromosome":"6","Start":"5613259","Stop":"5613259","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":578633,"rule_based_match":true,"evidence_text":"c.1156C>G; p.(R386G)","llm_judgment":"PRESENT","evidence":"c.1156C>G; p.(R386G)","abstract_start":854,"abstract_end":874}]}
{"pmid":"15235904","title":"Qualitative and quantitative analysis of the effect of splicing mutations in propionic acidemia underlying non-severe phenotypes.","abstract":"In this work we analyze splicing mutations identified in propionic acidemia patients to clarify their functional effects and their involvement in the disease phenotype. Two mutations in the PCCA gene detected in homozygous patients and involving consensus splice sequences (IVS21+3del4 and IVS22-2A>G) were shown to produce some normal splicing in patients' cells, at very low levels, which were quantitated by real-time PCR methods, and which presumably are sufficient to moderate the phenotype. We have also analysed the effect of mutations c.653A>G and IVS10-11del6 in the PCCB gene present in heterozygous patients with mild phenotype. The c.653A>G mutation is located in the last codon of exon 6 and interferes with the correct spliceosomal assembly activating a cryptic splice site within exon 6, which leads to an in-frame six-nucleotide deletion (delV217-K218). Minigene analysis and sequence-specific hybridization probes using real-time PCR methods showed that no normally spliced transcript is detectable in the patients' fibroblasts. The IVS10-11del6 mutation shortens the polypyrimidine tract of the 3'-splice site of exon 11, resulting in exon skipping. Some normal transcript is detectable by allele-specific hybridization probes. These analyses suggest that, in some cases, the regulation of gene splicing can potentially play an important role in human disease influencing phenotypic parameters.","variants":[{"Name":"NM_000532.5(PCCB):c.653A>G (p.Lys218Arg)","Chromosome":"3","Start":"136283946","Stop":"136283946","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3495260,"rule_based_match":true,"evidence_text":"c.653A>G","llm_judgment":"PRESENT","evidence":"c.653A>G","abstract_start":543,"abstract_end":551}]}
{"pmid":"34090370","title":"ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings.","abstract":"BACKGROUND: ALG3-CDG is a rare autosomal recessive disease. It is characterized by deficiency of alpha-1,3-mannosyltransferase caused by pathogenic variants in the ALG3 gene. Patients manifest with severe neurologic, cardiac, musculoskeletal and ophthalmic phenotype in combination with dysmorphic features, and almost half of them die before or during the neonatal period.\nCASE PRESENTATION: A 23 months-old girl presented with severe developmental delay, epilepsy, cortical atrophy, cerebellar vermis hypoplasia and ocular impairment. Facial dysmorphism, clubfeet and multiple joint contractures were observed already at birth. Transferrin isoelectric focusing revealed a type 1 pattern. Funduscopy showed hypopigmentation and optic disc pallor. Profound retinal ganglion cell loss and inner retinal layer thinning was documented on spectral-domain optical coherence tomography imaging. The presence of optic nerve hypoplasia was also supported by magnetic resonance imaging. A gene panel based next-generation sequencing and subsequent Sanger sequencing identified compound heterozygosity for two novel variants c.116del p.(Pro39Argfs*40) and c.1060 C > T p.(Arg354Cys) in ALG3.\nCONCLUSIONS: Our study expands the spectrum of pathogenic variants identified in ALG3. Thirty-three variants in 43 subjects with ALG3-CDG have been reported. Literature review shows that visual impairment in ALG3-CDG is most commonly linked to optic nerve hypoplasia.","variants":[{"Name":"NM_005787.6(ALG3):c.1060C>T (p.Arg354Cys)","Chromosome":"3","Start":"184242907","Stop":"184242907","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2894630,"rule_based_match":true,"evidence_text":"c.1060 C > T p.(Arg354Cys)","llm_judgment":"PRESENT","evidence":"c.1060 C > T p.(Arg354Cys)","abstract_start":1146,"abstract_end":1172}]}
{"pmid":"31267164","title":"Hereditary methemoglobinemia caused by Hb M-Hyde Park (Hb M-Akita) (HBB:c.277C > T; p.His93Tyr).","abstract":"Healthy human blood contains only a trace amount of methemoglobin (Hb M), less than 1%. In Hb M iron is present in the oxidized ferric state (Fe<sup>3+</sup>) not in the reduced ferrous form (Fe<sup>2+</sup>) and this reduces the ability of hemoglobin to bind oxygen. The described rare hemoglobin variant Hb M‑Hyde Park (also known as Hb M-Akita) results from the substitution of amino acid tyrosine by histidine at position 93 of the beta-globin chain of hemoglobin. The rare Hb variant Hb M‑Hyde Park (Hb M‑Akita) is mainly inherited autosomal dominant and causes methemoglobinemia. Due to the low frequency of inherited Hb M variants, the diagnosis is challenging. Here, we here report on a family with Hb M‑Hyde Park (Hb M‑Akita) whose members demonstrated Hb M > 10%, but were, asymptomatic except for chronic cyanosis. Due to human mobility and migration other hemogobin variants, such as beta-thalassemia minor have spread to Austria . A genetic combination of two different hemoglobin variants may result in severe anemia. Genetic counseling for patients with hemoglobin variants, including Hb M‑Hyde Park (Hb M‑Akita) and beta-thalassemia minor, is essential.","variants":[{"Name":"NM_000518.4(HBB):c.277C>T (p.His93Tyr)","Chromosome":"11","Start":"5226615","Stop":"5226615","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":30294,"rule_based_match":true,"evidence_text":"HBB:c.277C > T; p.His93Tyr","llm_judgment":"PRESENT","evidence":"HBB:c.277C > T; p.His93Tyr","abstract_start":null,"abstract_end":null}]}
{"pmid":"34098919","title":"Lumbar Scheuermann's disease found in a patient with osteogenesis imperfecta (OI) caused by a heterozygous mutation in COL1A2 (c.4048G > A): a case report.","abstract":"BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder characterized by increased bone fragility and a series of extraskeletal manifestations. Approximately 90 % of OI cases are caused by type I collagen variants encoded by the collagen type I alpha 1 (COL1A1) or type I alpha 2 (COL1A2) gene. Lumbar Scheuermann's disease is an atypical type of Scheuermann's disease accompanied by Schmorl's nodes and irregular endplates but without pronounced kyphosis. Although the etiology of Scheuermann's disease is unclear, genetic and environmental factors are likely.\nCASE PRESENTATION: Here, we report a 32-year-old male patient who experienced multiple brittle fractures. Gene sequencing revealed a heterozygous mutation, c.4048G > A (p.G1350S), in the COL1A2 gene, and the patient was diagnosed with OI. Magnetic resonance imaging of his thoracolumbar spine revealed multiple Schmorl's nodes.\nCONCLUSIONS: This is the first reported case of OI coexisting with the spinal presentation of Scheuermann's disease. It is speculated that the COL1A2 gene mutation might be an underlying novel genetic cause of Scheuermann's disease. In conclusion, this case demonstrates the relationship between Scheuermann's disease and OI for the first time and enriches the genotype-phenotype spectrum of OI.","variants":[{"Name":"NM_000089.4(COL1A2):c.4048G>A (p.Gly1350Ser)","Chromosome":"7","Start":"94430340","Stop":"94430340","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44615,"rule_based_match":true,"evidence_text":"c.4048G > A (p.G1350S)","llm_judgment":"PRESENT","evidence":"c.4048G > A (p.G1350S)","abstract_start":749,"abstract_end":771}]}
{"pmid":"32165108","title":"A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy.","abstract":"Mutations in heat shock protein B8 were initially identified in inherited neuropathies and were more recently found to cause a predominantly distal myopathy with myofibrillar pathology and rimmed vacuoles. Rare patients also had proximal weakness. Only very few pathogenic variants have been identified in HSPB8. Disruption of the chaperone activity of heat shock protein B8 impairs chaperone-assisted selective autophagy and results in protein aggregation. We report a 23-year-old patient who presented with a 4-year history of predominantly proximal lower limb weakness due to a novel variant in HSPB8. The creatine kinase level was mildly elevated. Electrodiagnostic studies demonstrated a proximal-predominant myopathy without evidence of neuropathy, and muscle histopathology revealed rimmed vacuoles and myofibrillar protein aggregates. Whole exome sequencing identified a de novo frameshift variant in the C-terminal region of HSPB8 (c.577_580dupGTCA, p.Thr194Serfs*23). This case demonstrates that HSPB8-related disorders can present with early onset limb-girdle myopathy without associated neuropathy.","variants":[{"Name":"NM_014365.3(HSPB8):c.577_580dup (p.Thr194fs)","Chromosome":"12","Start":"119193842","Stop":"119193843","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AAGTC","allel_id":961303,"rule_based_match":true,"evidence_text":"c.577_580dupGTCA, p.Thr194Serfs*23","llm_judgment":"PRESENT","evidence":"c.577_580dupGTCA, p.Thr194Serfs*23","abstract_start":941,"abstract_end":975}]}
{"pmid":"29409816","title":"Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain).","abstract":"RAD51C and RAD51D have been defined as susceptibility genes for hereditary breast and ovarian cancer syndrome in several studies. In the present study, a mutation analysis of these genes was performed on non BRCA1/2 families. RAD51C and RAD51D genes were analyzed in 141 and 77 families, respectively. The analysis included direct sequencing and multiple ligation probe analysis. The RAD51C pathogenic variant c.404G > A was identified in a breast and ovarian cancer family (0.7%), while the RAD51D pathogenic variant c.694C > T was described in an ovarian cancer family (1.3%). Moreover, three unknown clinical significance variants were detected: c.307T > G in RAD51C, and c.413A > G and c.715C > T in RAD51D. No large genomic rearrangements (LGRs) were found. RAD51D carriers suffered from premenopausal ovarian tumors. These results increase our knowledge about the RAD51C and RAD51D mutation spectrum and support the notion that these genes should be included in the gene panel testing performed on patients with hereditary breast and ovarian cancer syndrome.","variants":[{"Name":"NM_058216.3(RAD51C):c.307T>G (p.Phe103Val)","Chromosome":"17","Start":"58695092","Stop":"58695092","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":418977,"rule_based_match":true,"evidence_text":"c.307T > G in RAD51C","llm_judgment":"PRESENT","evidence":"c.307T > G in RAD51C","abstract_start":649,"abstract_end":669},{"Name":"NM_002878.4(RAD51D):c.413A>G (p.Asn138Ser)","Chromosome":"17","Start":"35107055","Stop":"35107055","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":133346,"rule_based_match":true,"evidence_text":"c.413A>G","llm_judgment":"PRESENT","evidence":"c.413A > G","abstract_start":675,"abstract_end":685},{"Name":"NM_002878.4(RAD51D):c.694C>T (p.Arg232Ter)","Chromosome":"17","Start":"35103298","Stop":"35103298","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133350,"rule_based_match":true,"evidence_text":"RAD51D pathogenic variant c.694C > T","llm_judgment":"PRESENT","evidence":"RAD51D pathogenic variant c.694C > T","abstract_start":492,"abstract_end":528},{"Name":"NM_002878.4(RAD51D):c.715C>T (p.Arg239Trp)","Chromosome":"17","Start":"35103277","Stop":"35103277","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":184818,"rule_based_match":true,"evidence_text":"c.715C>T","llm_judgment":"PRESENT","evidence":"c.715C > T","abstract_start":690,"abstract_end":700},{"Name":"NM_058216.3(RAD51C):c.404G>A (p.Cys135Tyr)","Chromosome":"17","Start":"58695189","Stop":"58695189","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":236214,"rule_based_match":true,"evidence_text":"RAD51C pathogenic variant c.404G > A","llm_judgment":"PRESENT","evidence":"RAD51C pathogenic variant c.404G > A","abstract_start":384,"abstract_end":420}]}
{"pmid":"22592156","title":"A missense mutation within the helix initiation motif of the keratin K71 gene underlies autosomal dominant woolly hair/hypotrichosis.","abstract":"Woolly hair (WH) is an abnormal variant of tightly curled hair, which is frequently associated with hypotrichosis. Non-syndromic forms of WH can show either autosomal-dominant WH (ADWH) or autosomal-recessive WH (ARWH) inheritance patterns. ARWH has recently been shown to be caused by mutations in either the lysophosphatidic acid receptor 6 (LPAR6) or lipase H (LIPH) gene. More recently, a mutation in the keratin K74 (KRT74) gene has been reported to underlie ADWH. Importantly, all of these genes are abundantly expressed in the inner root sheath (IRS) of human hair follicles. Besides these findings, the molecular mechanisms underlying hereditary WH have not been fully disclosed. In this study, we identified a Japanese family with ADWH and associated hypotrichosis. After exclusion of known causative genes, we discovered the heterozygous mutation c.422T>G (p.Phe141Cys) within the helix initiation motif of the IRS-specific keratin K71 (KRT71) gene in affected family members. We demonstrated that the mutant K71 protein led to disruption of keratin intermediate filament formation in cultured cells. To our knowledge, it is previously unreported that the KRT71 mutation is associated with a hereditary hair disorder in humans. Our findings further underscore the crucial role of the IRS-specific keratins in hair follicle development and hair growth in humans.","variants":[{"Name":"NM_033448.3(KRT71):c.422T>G (p.Phe141Cys)","Chromosome":"12","Start":"52552656","Stop":"52552656","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":150144,"rule_based_match":true,"evidence_text":"c.422T>G (p.Phe141Cys)","llm_judgment":"PRESENT","evidence":"c.422T>G (p.Phe141Cys)","abstract_start":857,"abstract_end":879}]}
{"pmid":"20938162","title":"Mild clinical phenotype of Kindler syndrome associated with late diagnosis and skin cancer.","abstract":"Kindler syndrome (KS) is a heritable skin disorder with a complex phenotype consisting of congenital skin blistering, photosensitivity, progressive generalized poikiloderma and extensive skin atrophy. Here we describe 2 siblings with KS, who are, to the best of our knowledge, the oldest patients reported so far in the literature. The diagnosis was established in their seventh and eighth decades of life, and confirmed by mutation analysis. Both patients were homozygous for the recurrent FERMT1 mutation, c.328C→T, p.R110X. Because of a relatively mild course of the disease, mucosal membranes in the eyes and oesophagus being predominantly affected in recent years, they had been treated under other diagnoses, such as scleroderma. Cutaneous precancerous lesions and epithelial skin cancer arose in both siblings after the age of 50 years and were treated in an early stage. Taken together, we describe the natural course of KS, the morphological abnormalities occurring in the skin of older KS patients, we discuss the differential diagnosis and the association between KS and squamous cell carcinoma.","variants":[{"Name":"NM_017671.5(FERMT1):c.328C>T (p.Arg110Ter)","Chromosome":"20","Start":"6115868","Stop":"6115868","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1313192,"rule_based_match":false,"evidence_text":"c.328C→T, p.R110X","llm_judgment":"PRESENT","evidence":"c.328C→T, p.R110X","abstract_start":508,"abstract_end":525}]}
{"pmid":"24072241","title":"Acute lymphoblastic leukemia developing in a patient with Noonan syndrome harboring a PTPN11 germline mutation.","abstract":"Noonan syndrome (NS) is a congenital genetic disorder characterized by certain facial features, short stature, and congenital heart disease. The disorder is caused by genetic alterations in the RAS/MAPK signal pathway. NS patients show a predisposition to malignancy; however, acute lymphoblastic leukemia (ALL) is rarely reported. Here, we describe a NS patient with B-cell precursor ALL (BCP-ALL) harboring a hyperdiploid karyotype and a PTPN11 germline mutation (c.922A>G; p.N308D). We also discuss the relationship between the hyperdiploid karyotype and genetic alterations in the RAS/MAPK pathway in BCP-ALL.","variants":[{"Name":"NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp)","Chromosome":"12","Start":"112477719","Stop":"112477719","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28365,"rule_based_match":true,"evidence_text":"c.922A>G; p.N308D","llm_judgment":"PRESENT","evidence":"c.922A>G; p.N308D","abstract_start":466,"abstract_end":483}]}
{"pmid":"24489791","title":"Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation.","abstract":"Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1), nine were likely not pathogenic (Class 2), and one was uncertain (Class 3).These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.","variants":[{"Name":"NM_007294.4(BRCA1):c.4484G>C (p.Arg1495Thr)","Chromosome":"17","Start":"43076488","Stop":"43076488","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":245029,"rule_based_match":true,"evidence_text":"BRCA1:c.4484G> C(p.Arg1495Thr)","llm_judgment":"PRESENT","evidence":"BRCA1:c.4484G> C(p.Arg1495Thr)","abstract_start":459,"abstract_end":489},{"Name":"NM_007294.4(BRCA1):c.122A>G (p.His41Arg)","Chromosome":"17","Start":"43115738","Stop":"43115738","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":68833,"rule_based_match":true,"evidence_text":"BRCA1:c.122A>G(p.His41Arg)","llm_judgment":"PRESENT","evidence":"BRCA1:c.122A>G(p.His41Arg)","abstract_start":583,"abstract_end":609}]}
{"pmid":"32636080","title":"Autosomal recessive hypercholesterolemia in a kindred of Syrian ancestry.","abstract":"Autosomal recessive hypercholesterolemia is a rare genetic disorder due to homozygosity or compound heterozygosity for mutations in the low-density lipoprotein receptor adapter protein 1 gene (LDLRAP1), resulting in elevated low-density lipoprotein cholesterol (LDL-C) levels, large xanthomas, and increased cardiovascular risk. Here, we describe a Danish family of Syrian ancestry carrying a frameshift mutation in LDLRAP1, previously only described in Sardinia and Sicily in Italy and in Spain. In 2 children homozygous for this mutation, we evaluate the effect of long-term lipid-lowering treatment with atorvastatin as monotherapy or in combination with ezetimibe. At referral to the lipid clinic at Viborg Regional Hospital, 3 of 4 children had LDL-C levels of 468, 538, and 371 mg/dL, respectively, with 1 child already showing cutaneous xanthomas at 10 years of age. For comparison, the fourth child and the parents had LDL-C levels of 85, 116, and 124 mg/dL. Genetic testing revealed that all 3 children with severely elevated LDL-C were homozygous for a rare frameshift mutation in LDLRAP1, p.His144GlnfsTer27 (c.431dupA), whereas the fourth child and both parents were heterozygous for this mutation. Lipid-lowering treatment was started in the 2 oldest children (at 10 and 7 years of age). Atorvastatin (40 mg/d) combined with ezetimibe (10 mg/d) reduced LDL-C by 75% in the first child and resulted in near-complete regression of xanthomas. In the second child, atorvastatin (40 mg/d) as monotherapy reduced LDL-C by 61%. Both regimens were superior to treatment with pravastatin as monotherapy (20 mg/d) and to pravastatin in combination with cholestyramine (2 g twice daily). High-intensity statin therapy alone or in combination with ezetimibe resulted in marked reductions in LDL-C in 2 children homozygous for a rare frameshift mutation in LDLRAP1 and lead to regression of large xanthomas.","variants":[{"Name":"NM_015627.3(LDLRAP1):c.431dup (p.His144fs)","Chromosome":"1","Start":"25557238","Stop":"25557239","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":627723,"rule_based_match":true,"evidence_text":"c.431dupA","llm_judgment":"PRESENT","evidence":"c.431dupA","abstract_start":1120,"abstract_end":1129}]}
{"pmid":"28575107","title":"Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling.","abstract":"Retinoblastoma (RB) is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA) assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59) while only 42.4% (25/59) of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9%) of tumors screened. There were 3 cases (5.1%) in which no mutations could be detected and germline mutations were detected in 19.5% (8/41) of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59) of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and asymptomatic family members carrying low-penetrance, germline mosaicism or heritable unilateral mutational phenotypes.","variants":[{"Name":"NM_000321.3(RB1):c.607+1G>T","Chromosome":"13","Start":"48349024","Stop":"48349024","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":28132,"rule_based_match":true,"evidence_text":"c.607+1G>T","llm_judgment":"PRESENT","evidence":"c.607+1G>T","abstract_start":1421,"abstract_end":1431},{"Name":"NM_000321.3(RB1):c.1981C>T (p.Arg661Trp)","Chromosome":"13","Start":"48459708","Stop":"48459708","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28126,"rule_based_match":true,"evidence_text":"missense-c.1981C>T","llm_judgment":"PRESENT","evidence":"missense-c.1981C>T","abstract_start":1383,"abstract_end":1401}]}
{"pmid":"29436111","title":"A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis.","abstract":"Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.","variants":[{"Name":"NM_032208.3(ANTXR1):c.1312C>T (p.Arg438Cys)","Chromosome":"2","Start":"69182619","Stop":"69182619","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2200905,"rule_based_match":true,"evidence_text":"c.1312C>T","llm_judgment":"PRESENT","evidence":"c.1312C>T","abstract_start":566,"abstract_end":575}]}
{"pmid":"36743879","title":"Pulmonary Artery Intimal Sarcoma in a Patient with Lynch Syndrome: Response to an Immune Checkpoint Inhibitor.","abstract":"Intimal sarcoma is an extremely rare mesenchymal tumor arising in the great vessels. To date, intimal sarcoma has not been reported in patients with Lynch syndrome (LS), even though this syndrome lacks DNA mismatch repair ability genetically and is prone to various malignancies. This patient was diagnosed with LS by the Revised Amsterdam Criteria II, and she suffered from intimal sarcoma in the left pulmonary artery. She had a germline missense variant of <i>PMS2</i> (c.1399G>A, pV467I) which is classified as a variant of unknown significance. In her intimal sarcoma, PMS2 expression was decreased. Additionally, it exhibited microsatellite instability and a high tumor mutational burden (69 mutations/Mb) which are features of mismatch repair deficiency, although <i>PMS2</i> (c.1399G>A, pV467I) missense is a variant of unknown significance. The metastatic lesions of intimal sarcoma in this patient responded heterogeneously to pembrolizumab, an immune checkpoint inhibitor. Cytotoxic agents and radiation were also effective for some metastatic lesions, but some lesions, including her liver metastases, were resistant. The hypermutable nature of the LS genotype might acquire resistance to an immune checkpoint inhibitor and other cytotoxic agents such as occurred with her liver metastases.","variants":[{"Name":"NM_000535.7(PMS2):c.1399G>A (p.Val467Ile)","Chromosome":"7","Start":"5987366","Stop":"5987366","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152161,"rule_based_match":true,"evidence_text":"PMS2 (c.1399G>A, pV467I)","llm_judgment":"PRESENT","evidence":"PMS2</i> (c.1399G>A, pV467I)","abstract_start":463,"abstract_end":491}]}
{"pmid":"33369194","title":"ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders.","abstract":"Ehlers-Danlos syndrome (EDS) consists of a heterogeneous group of genetically inherited connective tissue disorders. A family with three affected members over two generations with features of Dermatosparaxic EDS (dEDS) autosomal dominant transmission was reported by Desai et al. and having a heterozygous nonsynonymous missense variant of ADAMTSL2 (c.1261G > A; p. Gly421Ser). Variation in this gene is also reported to cause autosomal recessive geleophysic dysplasia. We report five unrelated patients with the Gly421Ser variant identified from a large series of patients presenting with features of connective tissue disorders, each with a positive family history consistent with autosomal dominant transmission. Clinical features of a connective tissue disorder included generalized joint hypermobility and pain with fragility of internal and external tissues including of skin, dura, and arteries. Overall, our analyses including bioinformatics, protein modeling, and gene-protein interactions with the cases described would add evidence for the Gly421Ser variant in ADAMTSL2 as causative for variable expressivity of autosomal dominant connective tissue disorders.","variants":[{"Name":"NM_014694.4(ADAMTSL2):c.1261G>A (p.Gly421Ser)","Chromosome":"9","Start":"133554678","Stop":"133554678","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":901407,"rule_based_match":true,"evidence_text":"c.1261G > A; p. Gly421Ser","llm_judgment":"PRESENT","evidence":"c.1261G > A; p. Gly421Ser","abstract_start":350,"abstract_end":375}]}
{"pmid":"35104462","title":"CYB5R3 homozygous pathogenic variant as a rare cause of cyanosis in the newborn.","abstract":"Detailed below is a very illustrative case of a rare pathology of recessive congenital methemoglobinemia. The patient, a newborn female, was homozygous for c.535G > A, p.(Ala179Thr) a pathogenic variant in the CYB5R3 gene. The reported population frequency of the allele is 0.853%, demonstrating why it is remarkable to find both parents are heterozygous carriers without consanguinity. A brief review of previously published cases is also presented.","variants":[{"Name":"NM_000398.7(CYB5R3):c.535G>A (p.Ala179Thr)","Chromosome":"22","Start":"42627617","Stop":"42627617","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3860808,"rule_based_match":true,"evidence_text":"c.535G > A, p.(Ala179Thr)","llm_judgment":"PRESENT","evidence":"c.535G > A, p.(Ala179Thr)","abstract_start":156,"abstract_end":181}]}
{"pmid":"29473937","title":"Large deletion in PIGL: a common mutational mechanism in CHIME syndrome?","abstract":"CHIME syndrome is an extremely rare autosomal recessive multisystemic disorder caused by mutations in PIGL. PIGL is an endoplasmic reticulum localized enzyme that catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which plays a role in the anchorage of cell-surface proteins including receptors, enzymes, and adhesion molecules. Germline mutations in other members of GPI and Post GPI Attachment to Proteins (PGAP) family genes have been described and constitute a group of diseases within the congenital disorders of glycosylation. Patients in this group often present alkaline phosphatase serum levels abnormalities and neurological symptoms. We report a CHIME syndrome patient who harbors a missense mutation c.500T > C (p.Leu167Pro) and a large deletion involving the 5' untranslated region and part of exon 1 of PIGL. In CHIME syndrome, a recurrent missense mutation c.500T > C (p.Leu167Pro) is found in the majority of patients, associated with a null mutation in the other allele, including an overrepresentation of large deletions. The latter are not detected by the standard analysis in sequencing techniques, including next-generation sequencing. Thus, in individuals with a clinical diagnosis of CHIME syndrome in which only one mutation is found, an active search for a large deletion should be sought.","variants":[{"Name":"NM_004278.4(PIGL):c.500T>C (p.Leu167Pro)","Chromosome":"17","Start":"16316686","Stop":"16316686","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39501,"rule_based_match":true,"evidence_text":"c.500T > C (p.Leu167Pro)","llm_judgment":"PRESENT","evidence":"c.500T > C (p.Leu167Pro)","abstract_start":739,"abstract_end":763}]}
{"pmid":"32924381","title":"Effect of recombinant human insulin-like growth factor 1 therapy in a child with 3-M syndrome-1 with","abstract":"OBJECTIVE: 3-M syndrome is characterized by severe short stature, syndromic features, and characteristic radiographic findings. Growth hormone (GH) has been used with variable success. Recombinant human insulin like growth factor-1 (rhIGF-1) has never been utilized.\nCASE PRESENTATION: We describe a child with severe growth retardation, macrocephaly, and skeletal abnormalities with evidence of GH insensitivity subsequently treated with rhIGF-1. He developed morbid obesity and comorbidities including voracious appetite, acanthosis nigricans, tonsillar hypertrophy, and severe obstructive sleep apnea with minimal height improvement. Genetic testing done at 11.5 years revealed a compound heterozygous mutation (c.2112G>A(p.W704X) and c.2559delC) in the <i>CUL</i>7 gene consistent with 3-M syndrome-1. rhIGF-1 therapy was discontinued.\nCONCLUSIONS: This case highlights the novel use of rhIGF-1 therapy on a child with 3-M syndrome-1 with minimal height benefit but accelerated weight gain and serves as a reminder of the importance of re-evaluating therapy efficacy and side effect profile.","variants":[{"Name":"NM_014780.5(CUL7):c.2112G>A (p.Trp704Ter)","Chromosome":"6","Start":"43048205","Stop":"43048205","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":489513,"rule_based_match":true,"evidence_text":"c.2112G>A(p.W704X)","llm_judgment":"PRESENT","evidence":"c.2112G>A(p.W704X)","abstract_start":715,"abstract_end":733}]}
{"pmid":"21617276","title":"A novel hepatocyte nuclear factor-1β (MODY 5) gene mutation in a Romanian boy with pancreatic calcifications, renal and hepatic dysfunction.","abstract":"We report a 12-years-old Romanian boy with a diagnosis of diabetes and renal insufficiency. Mutations in homeodomain-containing transcription factor hepatocyte nuclear factor (HNF-1β) have been reported in association with maturity-onset diabetes of the young (MODY 5) and early maturity-onset diabetes, progressive non-diabetic renal dysfunction and bilateral renal cysts. We found a new heterozygous mutation in HFN-1β located in the exon 3 (c.715 G>C; p.239R) associated to pancreatic calcifications. The importance of molecular diagnosis of MODY patients is reinforced and the need for a careful follow-up is stressed in order to monitor the progression of clinical manifestations and its correlation with the gene mutation.","variants":[{"Name":"NM_000458.4(HNF1B):c.715G>C (p.Gly239Arg)","Chromosome":"17","Start":"37733651","Stop":"37733651","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":623480,"rule_based_match":true,"evidence_text":"c.715 G>C; p.239R","llm_judgment":"PRESENT","evidence":"c.715 G>C; p.239R","abstract_start":444,"abstract_end":461}]}
{"pmid":"33042249","title":"Delayed Diagnosis of Cobalamin E Defect in an Adolescent Patient.","abstract":"Cobalamin and its metabolites play a critical role in deoxyribonucleic acid synthesis. Disorders of cobalamin metabolism are rare and related with neurological and hematological problems. We report an adolescent patient with cobalamin E (CblE) defect presenting with megaloblastic anemia, mental retardation, cerebral atrophy, cortical visual impairment, white matter changes on brain magnetic resonance imaging, and hyperhomocysteinemia. Homozygous mutation at the c.245C>T in exon 3 of the <i>MTRR</i> gene was identified, which had been found to be related to CblE defect. He was treated with betaine, folic acid, vitamin B6, riboflavin, hydroxycobalamin (OH-B<sub>12</sub>), and carnitine. During treatment, homocysteine levels decreased over time.","variants":[{"Name":"NM_002454.3(MTRR):c.245C>T (p.Pro82Leu)","Chromosome":"5","Start":"7873488","Stop":"7873488","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2837876,"rule_based_match":true,"evidence_text":"c.245C>T","llm_judgment":"PRESENT","evidence":"c.245C>T","abstract_start":466,"abstract_end":474}]}
{"pmid":"28202424","title":"GNAO1-associated epileptic encephalopathy and movement disorders: c.607G>A variant represents a probable mutation hotspot with a distinct phenotype.","abstract":"We describe a case of GNAO1-associated epilepsy and chorea in a patient with a de novo pathogenic mutation. This patient is unique in being the first reported male with this phenotype, and we propose that this genetic variant may represent a mutation hotspot that characterizes a unique phenotype. This 5.2-years-old boy presented with seizures, chorea, and severe global developmental delay. Brain imaging showed progressive diffuse cerebral atrophy. EEG monitoring revealed multifocal and diffuse discharges, along with generalized-onset seizures. Genetic testing found a de novo pathogenic variant in the GNAO1 gene (c.607G>A; p.Gly203Arg). A review of the literature showed two other patients with similar phenotype and the same genetic variant. In contrast, other patients with neurological involvement had private mutations in the GNAO1 gene. The neurological phenotypes associated with GNAO1 mutations appear to lie on a spectrum, and it is possible that the c.607G>A (p.Gly203Arg) variant characterizes a phenotype with both severe epilepsy and chorea. [Published with video sequence on www.epilepticdisorders.com].","variants":[{"Name":"NM_020988.3(GNAO1):c.607G>A (p.Gly203Arg)","Chromosome":"16","Start":"56336744","Stop":"56336744","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":77012,"rule_based_match":true,"evidence_text":"c.607G>A (p.Gly203Arg)","llm_judgment":"PRESENT","evidence":"c.607G>A (p.Gly203Arg)","abstract_start":966,"abstract_end":988}]}
{"pmid":"33004071","title":"Clinical and genetic analysis of two Chinese families with vitamin D-dependent rickets type IA and follow-up.","abstract":"OBJECTIVE: Vitamin D-dependent rickets type IA (VDDR-IA) is a rare autosomal recessive disorder characterized by the early onset of severe rickets. The objectives of this study were twofold: (1) to analyze the clinical characteristics and therapy of two patients with VDDR-IA from two separate Chinese families, and (2) investigate the CYP27B1 gene mutations in two large pedigrees.\nMETHODS: Medical history, clinical manifestations, physical examination, radiological findings and laboratory data were analyzed from two patients with VDDR-IA. Serum 1, 25-dihydroxyvitamin D [1, 25-(OH)<sub>2</sub>D<sub>3</sub>] of the two patients and their respective families were measured by ELISA and blood samples from both families was obtained for CYP27B1 gene sequence.\nRESULTS: Two patients had typical manifestations and radiological evidence of rickets. Laboratory data showed hypocalcaemia and hypophosphataemia, along with high levels of serum alkaline phosphatase, parathyroid hormone and 25-hydroxyvitamin D<sub>3.</sub> However, serum 1,25-(OH)<sub>2</sub>D<sub>3</sub> level were low in the patients but normal in their family members. Genetic sequence identified two patients were homozygous for a duplication mutation in exon 8 of CYP27B1 gene (c.1319_1325dupCCCACCC, p.Phe443Profs * 24). After treating with calcitriol and calcium, there was biochemical improvement with normalization of serum calcium and phosphorus, and radiographic evidence of compensatory skeletal mineralization. One patient developed nephrocalcinosis during follow-up.\nCONCLUSIONS: This study identified a recurrent seven-nucleotide insertion of CYP27B1 in two large pedigrees, and compared the clinical characteristics and individual therapy of two affected patients. Additionally, our experience further supports the notion that nephrocalcinosis can occur even on standard doses of calcitriol and oral calcium, and normal level of serum calcium, phosphorus, PTH and 25-(OH)D<sub>3</sub>.","variants":[{"Name":"NM_000785.4(CYP27B1):c.1319_1325dup (p.Phe443fs)","Chromosome":"12","Start":"57763698","Stop":"57763699","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGGGTGGG","allel_id":264701,"rule_based_match":true,"evidence_text":"c.1319_1325dupCCCACCC, p.Phe443Profs * 24","llm_judgment":"PRESENT","evidence":"c.1319_1325dupCCCACCC, p.Phe443Profs * 24","abstract_start":1249,"abstract_end":1290}]}
{"pmid":"34654017","title":"Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation.","abstract":"DNAJC3, a co-chaperone of BiP, is a member of the heat shock protein family. These proteins are produced in the endoplasmic reticulum (ER) to counter cell stress resulting from healthy functional protein processing. Dysregulation of unfolded proteins within the ER is implicated as a mechanism of genetic disease. Examples include Marinesco-Sjogren and Wolcott-Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction. Recently, loss of function mutations in DNAJC3 was associated with syndromic diabetes mellitus in three families. The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism. A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia. Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of DNAJC3 [c.1367_1370delAGAA (p.Lys456SerfsTer85)] resulting in protein elongation predicted to abrogate the functional J domain. This report confirms DNAJC3 as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia. Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose DNAJC3 should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition.","variants":[{"Name":"NM_006260.5(DNAJC3):c.1367_1370del (p.Lys456fs)","Chromosome":"13","Start":"95790878","Stop":"95790881","ReferenceAlleleVCF":"GAGAA","AlternateAlleleVCF":"G","allel_id":1685920,"rule_based_match":true,"evidence_text":"c.1367_1370delAGAA (p.Lys456SerfsTer85)","llm_judgment":"PRESENT","evidence":"c.1367_1370delAGAA (p.Lys456SerfsTer85)","abstract_start":1034,"abstract_end":1073}]}
{"pmid":"31312277","title":"Allelic variants of breast cancer susceptibility genes","abstract":"BACKGROUND: Large-scale case control studies revealed a number of moderate risk - low frequency breast cancer alleles of the <i>PALB2</i> and <i>RECQL</i> genes. Some of these were reported as founder variants of Central and Eastern Europe. Based on highly similar founder variant spectra of the <i>BRCA1</i> in Poland and Latvia, we decided to test the frequency of other common variants of moderate breast cancer risk - c.509_510delGA (rs515726124) and c.172_175delTTGT (rs180177143) of the <i>PALB2</i> gene and c.1667_1667+3delAGTA variant of the <i>RECQL</i> gene in a breast cancer case-control series from Latvia to better understand the role of genes in susceptibility to breast cancer and their clinical significance.\nMETHODS: The case-control study was performed based on an unselected breast cancer case group of 2480 women and a control group, including 1240 voluntary, to our knowledge unrelated, female donors without reported oncological disease.\nRESULTS: The calculated frequency for c.509_510delGA of the <i>PALB2</i> gene in the case group is 0.35 and 0.00% in the control group, with respective relative risk (RR) 7.18 (CI 95% 0.37-138.75; <i>p</i> = 0.19). As for the <i>PALB2</i> c.172_175delTTGT variant, the frequency in the case group of our study is 0.04%. In the control group of our study all individuals were homozygous for the wild-type allele, which lead to calculated RR = 1.50 (CI 95% 0.06-36.83; <i>p</i>-value = 0.80). There were no carriers of the <i>RECQL</i> variant c.1667_1667+3delAGTA identified in our case group and 2 heterozygotes were identified in the control group. The calculated RR = 0.26 (CI 95% 0.01-5.33; <i>p</i>-value = 0.38).\nCONCLUSION: Results obtained for the <i>PALB2</i> gene variants are able to supplement evidence on the allele frequency in breast cancer patients from the region of Central and Eastern Europe. Based on our results we cannot confirm the contribution of the <i>RECQL</i> variant c.1667_1667+3delAGTA allele to breast cancer development.","variants":[{"Name":"NM_024675.4(PALB2):c.509_510del (p.Arg170fs)","Chromosome":"16","Start":"23636036","Stop":"23636037","ReferenceAlleleVCF":"ATC","AlternateAlleleVCF":"A","allel_id":132267,"rule_based_match":true,"evidence_text":"c.509_510delGA","llm_judgment":"PRESENT","evidence":"c.509_510delGA","abstract_start":422,"abstract_end":436},{"Name":"NM_024675.4(PALB2):c.172_175del (p.Gln60fs)","Chromosome":"16","Start":"23637886","Stop":"23637889","ReferenceAlleleVCF":"GACAA","AlternateAlleleVCF":"G","allel_id":132133,"rule_based_match":true,"evidence_text":"c.172_175delTTGT","llm_judgment":"PRESENT","evidence":"c.172_175delTTGT","abstract_start":455,"abstract_end":471},{"Name":"NM_002907.4(RECQL):c.1667_1667+3del","Chromosome":"12","Start":"21471425","Stop":"21471428","ReferenceAlleleVCF":"ATACT","AlternateAlleleVCF":"A","allel_id":851494,"rule_based_match":true,"evidence_text":"c.1667_1667+3delAGTA","llm_judgment":"PRESENT","evidence":"c.1667_1667+3delAGTA","abstract_start":515,"abstract_end":535}]}
{"pmid":"35222528","title":"A Novel Variant of the","abstract":"Pathogenic variants in <i>CHD2</i> have been reported to have a wide range of phenotypic variability in neurodevelopmental disorders, such as early-onset epileptic encephalopathy, developmental delay, and behavior problems. So far, there is no clear correlation between genotypes and phenotypes. This study reports a Chinese patient with a novel heterozygous <i>CHD2</i> mutation (c.4318C>T, pArg1440*). Her main clinical manifestations include developmental delay, myoclonic epilepsy, and hypothyroidism. Then, we reviewed a total of 144 individuals carrying <i>CHD2</i> variants with epileptic encephalopathy. In terms of clinical manifestations, these patients are usually described with variable epilepsy phenotypes, including idiopathic photosensitive occipital epilepsy, Dravet syndrome, Jeavons syndrome, Lennox-Gastaut syndrome, juvenile myoclonic epilepsy, and non-specific epileptic encephalopathy. Among them, myoclonic seizures and generalized tonic-clonic seizures are the main seizure types in all patients hosting <i>CHD2</i> single-nucleotide or indel variants (non-CNVs). At the molecular level, there are 102 types of <i>CHD2</i> non-CNVs in 126 patients, almost one mutational type corresponding to one person, and there is no difference in the incidence ratio of each position. Furthermore, we summarized that a small proportion of patients inherited <i>CHD2</i> variants, and not all patients with <i>CHD2</i> variants had seizures. Importantly, the phenotypes, especially seizures control and fever sensitivity, and genotypes had a relative association. These results enriched the database of CHD2-relative neurodevelopmental disorders and provided a theoretical foundation for researching the relationship between genotypes and phenotypes.","variants":[{"Name":"NM_001271.4(CHD2):c.4318C>T (p.Arg1440Ter)","Chromosome":"15","Start":"93004656","Stop":"93004656","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3075975,"rule_based_match":true,"evidence_text":"c.4318C>T, pArg1440*","llm_judgment":"PRESENT","evidence":"c.4318C>T, pArg1440*","abstract_start":381,"abstract_end":401}]}
{"pmid":"15806320","title":"Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population.","abstract":"We have identified 21 different alpha-galactosidase A gene (GLA) mutations in 22 unrelated Czech and Slovak families with Fabry disease. Eleven of these mutations were novel (point mutations D93N, A135V, D155H, G171R, Q280K, G360S, Q330X, splicing errors c.194ins14, c.801ins36 and deletions c.674_732del59, g.3405_6021del2617). Genotyping of family members for family-specific mutations revealed 55 heterozygotes that manifested clinical symptoms of different severity. To examine the contribution of X-inactivation skewing to disease manifestation in Fabry heterozygotes, we have adopted the Mainz severity scoring scheme and compared the score values with the X-inactivation status in 39 carriers in an age-dependent manner. The age-score trendline of Fabry females who had a predominantly inactivated X-chromosome bearing a wild-type GLA allele (10 of 38 females) was markedly steeper than in the rest of the cohort. One female carrier with an inactivated mutated allele had a low score value when compared to the other heterozygotes of the same age. These data suggest that X-inactivation is indeed a major factor determining the severity of clinical involvement in Fabry heterozygotes. There was a statistically significant difference between the severity score values of heterozygotes with random and non-random X-chromosome inactivation at the 5% level of significance. Further studies will show if the degree of the wildtype allele inactivation will be useful as a predictive marker of severity of phenotype in Fabry heterozygotes. Although the correlation between X-inactivation skewing and presentation of the disease in Fabry heterozygotes has previously been suggested in the literature, this report is among the first attempts to examine this relationship systematically.","variants":[{"Name":"NM_000169.3(GLA):c.277G>A (p.Asp93Asn)","Chromosome":"X","Start":"101403903","Stop":"101403903","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":224099,"rule_based_match":false,"evidence_text":"c.277G>A (p.Asp93Asn)","llm_judgment":"PRESENT","evidence":"D93N","abstract_start":191,"abstract_end":195}]}
{"pmid":"32244026","title":"Molecular diagnosis of glycogen storage disease type IX using a glycogen storage disease gene panel.","abstract":"Glycogen storage disease type IX (GSD IX) is caused by a deficiency of hepatic phosphorylase kinase. The aim of this study was to clarify the clinical features, long term outcomes, and genetic analysis of GSD IX in Korea. A GSD gene panel was created and hybridization capture-based next-generation sequencing was performed. We investigated clinical laboratory data, results of molecular genetic analysis, liver biopsy findings, and long-term outcomes. Ten children were diagnosed with GSD IX at Seoul National University Children's Hospital. Hypoglycemia, hyperlactacidemia, hypertriglyceridemia, hyperuricemia, liver fibrosis on liver biopsy, and short stature was found in 30%, 56%, 100%, 60%, 80% and 50% of the children, respectively. Seven PHKA2 variants were identified in eight children with GSD IXa-one nonsense (c.2268dupT; p.(Asp757Ter)), two splicing (c.918+1G > A, c.718-2A > G), one frameshift (c.405_419delinsTCCTGGCC; p.(Asp136ProfsTer11)), and three missense variants (c.3628G > A; p.(Gly1210Arg), c.1245G > T and c.2746C > T; p.(Arg916Trp)). Two variants of PHKG2 were identified in two children with GSD IXc-one frameshift (c.783delC; p.(Ser262AlafsTer6)) and one missense (c.661G > A; p.(Val221Met)). Elevated liver enzymes and hypertriglyceridemia in children with GSD IXa tended to improve with age. For the first time, we report hepatocellular carcinoma in a patient with GSD IXc. The GSD gene panel is a useful diagnostic tool to confirm GSD IX. The clinical phenotype of GSD IXc is severe and monitoring for the development of hepatocellular carcinoma should be implemented.","variants":[{"Name":"NM_000292.3(PHKA2):c.918+1G>A","Chromosome":"X","Start":"18939994","Stop":"18939994","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":682745,"rule_based_match":true,"evidence_text":"c.918+1G > A","llm_judgment":"PRESENT","evidence":"c.918+1G > A","abstract_start":864,"abstract_end":876}]}
{"pmid":"23637914","title":"Minor hypospadias: the \"tip of the iceberg\" of the partial androgen insensitivity syndrome.","abstract":"BACKGROUND: Androgens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS).\nOBJECTIVE: The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR.\nMATERIALS AND METHODS: Two hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1-8) was performed. In silico and luciferase functional assays were performed for unreported variants.\nRESULTS: Five missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient.\nCONCLUSION: AR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life.","variants":[{"Name":"NM_000044.6(AR):c.1424C>T (p.Ala475Val)","Chromosome":"X","Start":"67546570","Stop":"67546570","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":792489,"rule_based_match":true,"evidence_text":"p.A475V (c.1424C>T)","llm_judgment":"PRESENT","evidence":"p.A475V (c.1424C>T)","abstract_start":1137,"abstract_end":1156}]}
{"pmid":"27650626","title":"Creatine Deficiency Syndrome could be Missed Easily: A Case Report of Guanidinoacetate Methyltransferase Deficiency Presented with Neurodevelopmental Delay, Seizures, and Behavioral Changes, but Normal Structural MRI.","abstract":"A case with GAMT deficiency (homozygous c.64dupG mutation) presented with neurodevelopmental delay, rare seizures, behavioral disturbances, and mild hypotonia, posing diagnostic challenges. Metabolic investigations showed low creatinine in plasma and urine (guanidinoacetate couldn't be investigated) and slightly elevated lactate. MRI was normal. Correct diagnosis was possible only after MR spectroscopy was performed at age 5½ years. A homozygous c.64dupG mutation of the GAMT gene was identified in the proband. In conclusion, every case with neurodevelopmental delay or arrest, especially when accompanied by seizures, behavioral impairment, muscle hypotonia or extrapyramidal symptoms should undergo MRI with MR spectroscopy. Normal structural MRI doesn't exclude a creatine deficiency syndrome. Biochemical investigations of guanidinoacetate, creatine, and creatinine in body fluid should be done to diagnose cerebral creatine deficiency syndromes and to specify the deficient enzyme. Thus, a treatable disease will not be missed.","variants":[{"Name":"NM_000156.6(GAMT):c.64dup (p.Ala22fs)","Chromosome":"19","Start":"1401412","Stop":"1401413","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":1477189,"rule_based_match":true,"evidence_text":"c.64dupG","llm_judgment":"PRESENT","evidence":"c.64dupG","abstract_start":40,"abstract_end":48}]}
{"pmid":"35254204","title":"SPG11: clinical and genetic features of seven Czech patients and literature review.","abstract":"SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11. The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly. The speed of disease progression, and the severity of gait impairment, was fast in all patients but the phenotype varied from patient to patient. Thin corpus callosum was not observed in two patients. Two Czech SPG11 patients had unusual late onset of disease and both were compound heterozygotes for the c.5381T>C variant. Therefore, we looked for a potential ralationship between the type of variant in the SPG11 gene and the age of disease onset. By reviewing all described SPG11 patients carrying at least one missense pathogenic variant in the SPG11 gene we did not found any relationship between the age of onset and the type of variant. Together twelve pathogenic variants, including gross deletions, were found in the SPG11 gene the Czech SPG11 patients, the c.3454-2A>G variant is novel.","variants":[{"Name":"NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro)","Chromosome":"15","Start":"44584299","Stop":"44584299","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":360970,"rule_based_match":true,"evidence_text":"c.5381T>C","llm_judgment":"PRESENT","evidence":"c.5381T>C","abstract_start":676,"abstract_end":685}]}
{"pmid":"26542770","title":"Mutational and phenotypical spectrum of phenylalanine hydroxylase deficiency in Denmark.","abstract":"We describe the genotypes of the complete cohort, from 1967 to 2014, of phenylketonuria (PKU) patients in Denmark, in total 376 patients. A total of 752 independent alleles were investigated. Mutations were identified on 744 PKU alleles (98.9%). In total, 82 different mutations were present in the cohort. The most frequent mutation c.1315+1G>A (IVS12+1G>A) was found on 25.80% of the 744 alleles. Other very frequent mutations were c.1222C>T (p.R408W) (16.93%) and c.1241A>G (p.Y414C) (11.15%). Among the identified mutations, five mutations; c.532G>A (p.E178K), c.730C>T (p.P244S), c.925G>A (p.A309T), c.1228T>A (p.F410I), and c.1199+4A>G (IVS11+4A>G) have not been reported previously. The metabolic phenotypes of PKU are classified into four categories; 'classical PKU', 'moderate PKU', 'mild PKU' and 'mild hyperphenylalaninemia'. In this study, we assigned the phenotypic outcome of three of the five novel mutations and furthermore six not previously classified mutations to one of the four PKU categories.","variants":[{"Name":"NM_000277.3(PAH):c.1199+4A>G","Chromosome":"12","Start":"102843642","Stop":"102843642","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":975744,"rule_based_match":true,"evidence_text":"c.1199+4A>G (IVS11+4A>G)","llm_judgment":"PRESENT","evidence":"c.1199+4A>G (IVS11+4A>G)","abstract_start":630,"abstract_end":654},{"Name":"NM_000277.3(PAH):c.1241A>G (p.Tyr414Cys)","Chromosome":"12","Start":"102840474","Stop":"102840474","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":15632,"rule_based_match":true,"evidence_text":"c.1241A>G (p.Y414C)","llm_judgment":"PRESENT","evidence":"c.1241A>G (p.Y414C)","abstract_start":467,"abstract_end":486},{"Name":"NM_000277.3(PAH):c.730C>T (p.Pro244Ser)","Chromosome":"12","Start":"102852927","Stop":"102852927","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1318161,"rule_based_match":true,"evidence_text":"c.730C>T (p.P244S)","llm_judgment":"PRESENT","evidence":"c.730C>T (p.P244S)","abstract_start":565,"abstract_end":583},{"Name":"NM_000277.3(PAH):c.532G>A (p.Glu178Lys)","Chromosome":"12","Start":"102855310","Stop":"102855310","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":917099,"rule_based_match":true,"evidence_text":"c.532G>A (p.E178K)","llm_judgment":"PRESENT","evidence":"c.532G>A (p.E178K)","abstract_start":545,"abstract_end":563},{"Name":"NM_000277.3(PAH):c.1228T>A (p.Phe410Ile)","Chromosome":"12","Start":"102840487","Stop":"102840487","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":920561,"rule_based_match":true,"evidence_text":"c.1228T>A (p.F410I)","llm_judgment":"PRESENT","evidence":"c.1228T>A (p.F410I)","abstract_start":605,"abstract_end":624},{"Name":"NM_000277.3(PAH):c.1315+1G>A","Chromosome":"12","Start":"102840399","Stop":"102840399","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15615,"rule_based_match":true,"evidence_text":"c.1315+1G>A (IVS12+1G>A)","llm_judgment":"PRESENT","evidence":"c.1315+1G>A (IVS12+1G>A)","abstract_start":334,"abstract_end":358}]}
{"pmid":"34694653","title":"HINT1-related neuropathy in Greek patients with Charcot-Marie-Tooth disease.","abstract":"Autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) is a rare hereditary neuropathy within the Charcot-Marie-Tooth disease (CMT) spectrum, linked to mutations in the histidine triad nucleotide-binding protein 1 (HINT1) gene. HINT1-related neuropathy is particularly common in selected populations from Central and Eastern Europe but rare in Western European cohorts. It has not been investigated to date in the Greek population. We presently investigated the frequency of HINT1-neuropathy in a selected cohort of 42 Greek index patients with autosomal recessive or sporadic axonal hereditary neuropathy according to standard molecular genetics procedures. We identified 4 patients with biallelic mutations in HINT1, comprising 9.5% of all cases and 44.4% of cases also displaying neuromyotonia. The c.110G> C (p.Arg37Pro) HINT1 mutation was present in all cases (2 homozygous) and the c.250T> C (p.Cys84Arg) in 2 cases (compound heterozygous). HINT1-related neuropathy patients were characterized by early onset and neuromyotonia. Two patients had noteworthy clinical features, one case developing myoclonic epilepsy and the other displaying \"adducted thumbs.\" We conclude that HINT1-related neuropathy is common in selected Greek patients with hereditary neuropathy within the CMT spectrum, in accordance with some, but not all, European populations.","variants":[{"Name":"NM_005340.7(HINT1):c.250T>C (p.Cys84Arg)","Chromosome":"5","Start":"131159578","Stop":"131159578","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":45888,"rule_based_match":true,"evidence_text":"c.250T> C (p.Cys84Arg)","llm_judgment":"PRESENT","evidence":"c.250T> C (p.Cys84Arg)","abstract_start":900,"abstract_end":922},{"Name":"NM_005340.7(HINT1):c.110G>C (p.Arg37Pro)","Chromosome":"5","Start":"131165096","Stop":"131165096","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":45887,"rule_based_match":true,"evidence_text":"c.110G> C (p.Arg37Pro)","llm_judgment":"PRESENT","evidence":"c.110G> C (p.Arg37Pro)","abstract_start":814,"abstract_end":836}]}
{"pmid":"30384990","title":"A case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis.","abstract":"Dihydropyrimidinase deficiency is a rare autosomal recessive disease affecting the second step of pyrimidine degradation. It is caused by mutations in the DPYS gene. Only approximately 30 cases have been reported to date, with a phenotypical variability ranging from asymptomatic to severe neurological illness. We report a case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis. Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant elevations of dihydrouracil and dihydrothymine, which were subsequently confirmed by a quantitative analysis using liquid chromatography-tandem mass spectrometry. Genetic testing of the DPYS gene revealed two mutations: a novel mutation (c.175G > T) and a previously reported mutation (c.1469G > A). Dihydropyrimidinase deficiency is probably underdiagnosed, considering its wide phenotypical variability, nonspecific neurological presentations, and an estimated prevalence of 2/20,000. As severe 5-fluorouracil-associated toxicity has been reported in patients and carriers of congenital pyrimidine metabolic disorders, urinary pyrimidine analysis should be considered for those who will undergo 5-fluorouracil treatment.","variants":[{"Name":"NM_001385.3(DPYS):c.1469G>A (p.Arg490His)","Chromosome":"8","Start":"104381289","Stop":"104381289","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":898597,"rule_based_match":true,"evidence_text":"c.1469G > A","llm_judgment":"PRESENT","evidence":"c.1469G > A","abstract_start":788,"abstract_end":799},{"Name":"NM_001385.3(DPYS):c.175G>T (p.Val59Phe)","Chromosome":"8","Start":"104466746","Stop":"104466746","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":961062,"rule_based_match":true,"evidence_text":"c.175G > T","llm_judgment":"PRESENT","evidence":"c.175G > T","abstract_start":740,"abstract_end":750}]}
{"pmid":"24795062","title":"A Korean patient with glutaric aciduria type 1 with a novel mutation in the glutaryl CoA dehydrogenase gene.","abstract":"Mutations in the glutaryl-CoA dehydrogenase gene can result in Glutaric aciduria type 1(GA 1) by accumulation of glutaric acid, 3-hydroxyglutaric acid (3-OH-GA), and glutarylcarnitine (C5DC). GA 1 is characterized by macrocephaly, subdural hemorrhage (SDH), and dystonic movement disorder after acute encephalopathic crisis. We report a Korean patient with GA1 and a novel mutation. A 16-month-old boy presented with SDH, macrocephaly, and developmental delay. In the neurologic examination, the patient had mild axial hypotonia, but otherwise normal neurologic functions. The brain MRI showed large amounts of bilateral SDH and high signal intensity in both basal ganglia and thalamus. Metabolic screening tests detected highly elevated urinary GA levels but 3-OH-glutaric acid was normal. C5DC was 0.94 μM/L (reference range < 0.3 μM/L). The patient had compound heterozygous mutations of the GCDH gene: p.Arg257Gln (c.770G>A) and p.Cys308Arg (c.922T>C). p.Cys308Arg is a novel mutation; reports of p.Arg257Gln were also rare both in Caucasians and Asian populations. In summary, we hereby report one Korean patient with GA1 with clinical, biochemical, and radiologic characteristics confirmed by genetic analysis.","variants":[{"Name":"NM_000159.4(GCDH):c.770G>A (p.Arg257Gln)","Chromosome":"19","Start":"12896339","Stop":"12896339","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":533136,"rule_based_match":true,"evidence_text":"c.770G>A","llm_judgment":"PRESENT","evidence":"c.770G>A","abstract_start":919,"abstract_end":927}]}
{"pmid":"30706156","title":"Bethlem myopathy: a series of 16 patients and description of seven new associated mutations.","abstract":"BACKGROUND: Bethlem myopathy represents the milder phenotype of collagen type VI-related myopathies. However, clinical manifestations are highly variable among patients and no phenotype-genotype correlation has been described. We aim to analyse the clinical, pathological and genetic features of a series of patients with Bethlem myopathy, and we describe seven new mutations.\nMETHODS: A series of 16 patients with the diagnosis of Bethlem myopathy were analyzed retrospectively from their medical records for clinical, creatine kinase (CK), muscle biopsy, and muscle magnetic resonance (MRI) data. Genetic testing was performed through next-generation sequencing of custom amplicon-based targeted genes panel of myopathies. Mutations were confirmed by Sanger sequencing.\nRESULTS: The most frequent phenotype consisted of proximal limb weakness associated with interphalangeal and wrists contractures. However, cases with isolated contractures or isolated myopathy were found. CK levels did not correlate with severity of the disease. The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous or compound heterozygous presentation. Five new mutations were found in COL6A1 gene and other two in COL6A3 gene, all of them with a dominant heritability pattern. From these, a new COL6A1 mutation (c.1657G>A, p.Glu553Arg) was related to an oligosymptomatic phenotype with predominating contractures in the absence of weakness and a normal muscle MRI. Finally, the most common COL6A1 mutation reported to date that leads to an Ullrich phenotype (c. 868G>A, p.Gly290Arg), has been found here as Bethlem presentation.\nCONCLUSIONS: Manifestations of Bethlem myopathy are quite variable, so either contractures or weakness may be lacking, and no phenotype-genotype associations can be brought.","variants":[{"Name":"NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)","Chromosome":"2","Start":"237344571","Stop":"237344571","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":194138,"rule_based_match":true,"evidence_text":"c.7447A>G","llm_judgment":"PRESENT","evidence":"c.7447A>G","abstract_start":1085,"abstract_end":1094}]}
{"pmid":"30890586","title":"Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report.","abstract":"BACKGROUND: <i>PALB2</i> monoallelic <i>loss-of-function</i> germ-line variants confer a breast cancer risk comparable to the average <i>BRCA2</i> pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify <i>loss-of-function</i> variants in <i>PALB2-</i>without incurring overprediction-is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in <i>PALB2</i>, analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.\nMETHODS: Alternative splicing was characterised in RNAs extracted from blood, breast and <i>fimbriae</i>/ovary-related human specimens (n=112). RNAseq, RT-PCR/CE and CloneSeq experiments were performed by five contributing laboratories. Centralised revision/curation was performed to assure high-quality annotations. Additional splicing analyses were performed in <i>PALB2</i> c.212-1G>A, c.1684+1G>A, c.2748+2T>G, c.3113+5G>A, c.3350+1G>A, c.3350+4A>C and c.3350+5G>A carriers. The impact of the findings on PVS1 status was evaluated for truncating and splice site variant.\nRESULTS: We identified 88 naturally occurring alternative splicing events (81 newly described), including 4 in-frame events predicted relevant to evaluate PVS1 status of splice site variants. We did not identify tissue-specific alternate gene transcripts in breast or ovarian-related samples, supporting the clinical relevance of blood-based splicing studies.\nCONCLUSIONS: PVS1 is not necessarily warranted for splice site variants targeting four <i>PALB2</i> acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed <i>pathogenic</i>/<i>likely pathogenic</i> without further evidences. Our study puts a warning in up to five <i>PALB2</i> genetic variants that are currently reported as <i>pathogenic/likely pathogenic</i> in ClinVar.","variants":[{"Name":"NM_024675.4(PALB2):c.1684+1G>A","Chromosome":"16","Start":"23634861","Stop":"23634861","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":477590,"rule_based_match":true,"evidence_text":"c.1684+1G>A","llm_judgment":"PRESENT","evidence":"c.1684+1G>A","abstract_start":1106,"abstract_end":1117},{"Name":"NM_024675.4(PALB2):c.3113+5G>A","Chromosome":"16","Start":"23621357","Stop":"23621357","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":652718,"rule_based_match":true,"evidence_text":"c.3113+5G>A","llm_judgment":"PRESENT","evidence":"c.3113+5G>A","abstract_start":1132,"abstract_end":1143},{"Name":"NM_024675.4(PALB2):c.3350+4A>C","Chromosome":"16","Start":"23607860","Stop":"23607860","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":477542,"rule_based_match":true,"evidence_text":"c.3350+4A>C","llm_judgment":"PRESENT","evidence":"c.3350+4A>C","abstract_start":1158,"abstract_end":1169},{"Name":"NM_024675.4(PALB2):c.212-1G>A","Chromosome":"16","Start":"23636335","Stop":"23636335","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":915946,"rule_based_match":true,"evidence_text":"c.212-1G>A","llm_judgment":"PRESENT","evidence":"c.212-1G>A","abstract_start":1094,"abstract_end":1104},{"Name":"NM_024675.4(PALB2):c.3350+5G>A","Chromosome":"16","Start":"23607859","Stop":"23607859","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152300,"rule_based_match":true,"evidence_text":"c.3350+5G>A","llm_judgment":"PRESENT","evidence":"c.3350+5G>A","abstract_start":1174,"abstract_end":1185},{"Name":"NM_024675.4(PALB2):c.3350+1G>A","Chromosome":"16","Start":"23607863","Stop":"23607863","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":222455,"rule_based_match":true,"evidence_text":"c.3350+1G>A","llm_judgment":"PRESENT","evidence":"c.3350+1G>A","abstract_start":1145,"abstract_end":1156}]}
{"pmid":"22700598","title":"Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations.","abstract":"OBJECTIVE: Mutations in LMNA have been linked to diverse disorders called laminopathies, which display heterogeneous phenotypes and include diseases affecting muscles, axonal neurons, progeroid syndromes, and lipodystrophies. Among the lipodystrophies, LMNA mutations have been reported most frequently in patients with familial partial lipodystrophy (FPLD) of the Dunnigan variety; however, phenotypic heterogeneity in the pattern of body fat loss has been observed. In this study, we searched for LMNA mutations in patients with various forms of lipodystrophy.\nDESIGN AND METHODS: We studied 21 unrelated individuals with lipodystrophy. Subjects underwent a complete clinical evaluation and were classified as typical FPLD (n=12), atypical partial lipodystrophy (n=7), or generalized lipodystrophy (n=2). Molecular analysis of LMNA gene, analysis of body fat by dual-energy X-ray absorptiometry, and biochemical measurements were performed.\nRESULTS: ALL PATIENTS WITH TYPICAL FPLD WERE FOUND TO CARRY LMNA MUTATIONS: seven patients harbored the heterozygous p.R482W (c.1444C>T), two patients harbored the p.R482Q (c.1445G>A), and two individuals harbored the novel heterozygous variant p.N466D (c.1396A>G), all in exon 8. Also, a homozygous p.R584H (c.1751 G>A) mutation in exon 11 was found. Among patients with atypical partial lipodystrophy, two of them were found to have LMNA mutations: a novel heterozygous p.R582C variation (c.1744 C>T) in exon 11 and a heterozygous substitution p.R349W (c.1045C>T) in exon 6. Among patients with generalized lipodystrophy, only one harbored LMNA mutation, a heterozygous p.T10I (c.29C>T) in exon 1.\nCONCLUSIONS: We have identified LMNA mutations in phenotypically diverse lipodystrophies. Also, our study broadens the spectrum of LMNA mutations in lipodystrophy.","variants":[{"Name":"NM_170707.4(LMNA):c.1744C>T (p.Arg582Cys)","Chromosome":"1","Start":"156138533","Stop":"156138533","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":626929,"rule_based_match":true,"evidence_text":"c.1744 C>T","llm_judgment":"PRESENT","evidence":"c.1744 C>T","abstract_start":1434,"abstract_end":1444},{"Name":"NM_170707.4(LMNA):c.1445G>A (p.Arg482Gln)","Chromosome":"1","Start":"156136985","Stop":"156136985","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29525,"rule_based_match":true,"evidence_text":"c.1445G>A","llm_judgment":"PRESENT","evidence":"c.1445G>A","abstract_start":1116,"abstract_end":1125},{"Name":"NM_170707.4(LMNA):c.29C>T (p.Thr10Ile)","Chromosome":"1","Start":"156114947","Stop":"156114947","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77785,"rule_based_match":true,"evidence_text":"p.T10I (c.29C>T)","llm_judgment":"PRESENT","evidence":"p.T10I (c.29C>T)","abstract_start":1615,"abstract_end":1631},{"Name":"NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)","Chromosome":"1","Start":"156136009","Stop":"156136009","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77659,"rule_based_match":true,"evidence_text":"p.R349W (c.1045C>T)","llm_judgment":"PRESENT","evidence":"p.R349W (c.1045C>T)","abstract_start":1489,"abstract_end":1508},{"Name":"NM_170707.4(LMNA):c.1751G>A (p.Arg584His)","Chromosome":"1","Start":"156138540","Stop":"156138540","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":57213,"rule_based_match":true,"evidence_text":"a homozygous p.R584H (c.1751 G>A) mutation in exon 11","llm_judgment":"PRESENT","evidence":"a homozygous p.R584H (c.1751 G>A) mutation in exon 11","abstract_start":1230,"abstract_end":1283}]}
{"pmid":"32710830","title":"A Pathogenic Galactosidase A Mutation Coexisting With an MYBPC3 Mutation in a Female Patient With Hypertrophic Cardiomyopathy.","abstract":"The coexistence of GLA (Pro259Ser, c.775C>T) and MYBPC3 (c.1351+2T>C) mutations was found in a female patient with hypertrophic cardiomyopathy. Histology documented abundant vacuolisation with osmiophilic lamellar bodies and positive Gb3 immunohistochemistry. In the presence of a hypertrophic cardiomyopathy phenotype, the systematic search for unusual findings is mandatory to rule out a phenocopy.","variants":[{"Name":"NM_000256.3(MYBPC3):c.1351+2T>C","Chromosome":"11","Start":"47343019","Stop":"47343019","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":51695,"rule_based_match":true,"evidence_text":"c.1351+2T>C","llm_judgment":"PRESENT","evidence":"c.1351+2T>C","abstract_start":57,"abstract_end":68}]}
{"pmid":"24577744","title":"VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2).","abstract":"BACKGROUND: Progressive cerebello-cerebral atrophy (PCCA) leading to profound mental retardation, progressive microcephaly, spasticity and early onset epilepsy, was diagnosed in four non-consanguineous apparently unrelated families of Jewish Moroccan ancestry. Common founder mutation(s) were assumed.\nMETHODS: Genome-wide linkage analysis and whole exome sequencing were done, followed by realtime PCR and immunofluorescent microscopy.\nRESULTS: Genome-wide linkage analysis mapped the disease-associated gene to 0.5 Mb on chromosome 17p13.3. Whole exome sequencing identified only two mutations within this locus, which were common to the affected individuals: compound heterozygous mutations in VPS53, segregating as expected for autosomal recessive heredity within all four families, and common in Moroccan Jews (∼1:37 carrier rate). The Golgi-associated retrograde protein (GARP) complex is involved in the retrograde pathway recycling endocytic vesicles to Golgi; c.2084A>G and c.1556+5G>A VPS53 founder mutations are predicted to affect the C-terminal domain of VPS53, known to be critical to its role as part of this complex. Immunofluorescent microscopy demonstrated swollen and abnormally numerous CD63 positive vesicular bodies, likely intermediate recycling/late endosomes, in fibroblasts of affected individuals.\nCONCLUSIONS: Autosomal recessive PCCA type 2 is caused by VPS53 mutations.","variants":[{"Name":"NM_001128159.3(VPS53):c.2084A>G (p.Gln695Arg)","Chromosome":"17","Start":"532843","Stop":"532843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":143136,"rule_based_match":true,"evidence_text":"c.2084A>G","llm_judgment":"PRESENT","evidence":"c.2084A>G","abstract_start":969,"abstract_end":978},{"Name":"NM_001128159.3(VPS53):c.1556+5G>A","Chromosome":"17","Start":"562498","Stop":"562498","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":143137,"rule_based_match":true,"evidence_text":"c.1556+5G>A","llm_judgment":"PRESENT","evidence":"c.1556+5G>A","abstract_start":983,"abstract_end":994}]}
{"pmid":"28112372","title":"Identification of a missense mutation in the tyrosinase gene in a Chinese family with oculocutaneous albinism type 1.","abstract":"Oculocutaneous albinism (OCA) is a group of heterogeneous and autosomal recessive disorders characterized by a reduction or complete loss of melanin biosynthesis in melanocytes. OCA type 1 (OCA1) is the most severe and common form of OCA, and is caused by mutations in the tyrosinase gene (TYR). The present study aimed to identify the genetic cause of OCA1 in a four‑generation consanguineous Chinese Han family. Complete physical examinations were performed and blood samples were collected from five members of the family and 100 unrelated healthy controls. Exome sequencing was conducted in the proband, followed by verification in other family members, using Sanger sequencing. Patients in the family presented with typical OCA1 features, including hypopigmentation of the skin and hair, and distinctive ocular changes. A homozygous missense variant, c.896G>A (p.R299H), in the TYR gene was identified in two patients, which co‑segregated with disease in the family. This variant was not present in the 100 healthy controls. These results expand the number of mutations identified to be responsible for OCA1 in the Chinese Han population, and may have implications for genetic counseling and clinical management of the disease.","variants":[{"Name":"NM_000372.5(TYR):c.896G>A (p.Arg299His)","Chromosome":"11","Start":"89191278","Stop":"89191278","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18835,"rule_based_match":true,"evidence_text":"c.896G>A (p.R299H)","llm_judgment":"PRESENT","evidence":"c.896G>A (p.R299H)","abstract_start":856,"abstract_end":874}]}
{"pmid":"38075699","title":"Case report: Neonatal-onset inflammatory bowel disease due to novel compound heterozygous mutations in","abstract":"Very Early Onset Inflammatory Bowel Disease (VEO-IBD) is potentially associated with genetic disorders of the intestinal epithelial barrier or inborn errors of immunity (IEI). Dual oxidase 2 (DUOX2), an H<sub>2</sub>O<sub>2</sub>-producing NADPH oxidase expressed at apical enterocyte membranes, plays a crucial role in innate defense response. Biallelic <i>DUOX2</i> mutations have been described only in two patients with VEO-IBD to date. We report the case of a 1-month-old female infant who presented persistent high C-reactive protein (CRP) levels from birth and anemia. Positive occult blood and very high calprotectin in the stool were detected and abdominal ultrasound showed thickened last ileal loop. Full endoscopy evaluation revealed important colon stenosis with multiple pseudo-polyploidy formations that resulted refractory to steroid therapy, requiring a partial colic resection. Histological examination of biopsy samples showed morphological features of IBD. Whole Exome Sequencing (WES) disclosed compound heterozygous variants in the <i>DUOX2</i> gene: the pathogenic c.2524C>T; p.Arg842Ter and the variant of uncertain significance (VUS) c.3175C>T; p.Arg1059Cys. Molecular and functional studies showed the presence of mutant DUOX2 in the intestinal epithelium of the patient, albeit with at least 50% decreased catalytic activity. In conclusion, we describe the third patient to date with compound heterozygous variants of <i>DUOX2</i>, responsible for monogenic neonatal-IBD. This case expands the knowledge about Mendelian causes of VEO-IBD and DUOX2 deficiency. We suggest that DUOX2 should be part of the diagnostic evaluation of patients with suspected monogenic VEO-IBD.","variants":[{"Name":"NM_001363711.2(DUOX2):c.3175C>T (p.Arg1059Cys)","Chromosome":"15","Start":"45100059","Stop":"45100059","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1516358,"rule_based_match":true,"evidence_text":"c.3175C>T; p.Arg1059Cys","llm_judgment":"PRESENT","evidence":"c.3175C>T; p.Arg1059Cys","abstract_start":1159,"abstract_end":1182}]}
{"pmid":"26751395","title":"De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability.","abstract":"A rare syndromic form of intellectual disability with impaired speech was recently found associated with mutations in CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), the protein product of which is directly involved in microtubule-kinetochore attachment. Through whole-exome sequencing in six unrelated nonconsanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1: c.1880C>G p.(Ser627*), c.1489C>T; p.(Arg497*), c.1876_1877delAG; p.(Ser626Leufs*4), c.1043G>A; p.(Trp348*), c.1002G>A; p.(Trp334*), and c.958_959delCC; p.(Pro320*). Our clinical observations confirm the phenotypic homogeneity of the syndrome, which represents therefore a distinct clinical entity. Besides, our functional studies show that CHAMP1 protein variants are delocalized from chromatin and are unable to bind to two of its direct partners, POGZ and HP1. These data suggest a pathogenic mechanism of the CHAMP1-associated intellectual disability syndrome mediated by direct interacting partners of CHAMP1, several of which are involved in chromo/kinetochore-related disorders.","variants":[{"Name":"NM_032436.4(CHAMP1):c.1489C>T (p.Arg497Ter)","Chromosome":"13","Start":"114325331","Stop":"114325331","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":206662,"rule_based_match":true,"evidence_text":"c.1489C>T; p.(Arg497*)","llm_judgment":"PRESENT","evidence":"c.1489C>T; p.(Arg497*)","abstract_start":480,"abstract_end":502},{"Name":"NM_032436.4(CHAMP1):c.1043G>A (p.Trp348Ter)","Chromosome":"13","Start":"114324885","Stop":"114324885","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1678986,"rule_based_match":true,"evidence_text":"c.1043G>A; p.(Trp348*)","llm_judgment":"PRESENT","evidence":"c.1043G>A; p.(Trp348*)","abstract_start":541,"abstract_end":563},{"Name":"NM_032436.4(CHAMP1):c.1876_1877del (p.Ser626fs)","Chromosome":"13","Start":"114325714","Stop":"114325715","ReferenceAlleleVCF":"AAG","AlternateAlleleVCF":"A","allel_id":1678987,"rule_based_match":true,"evidence_text":"c.1876_1877delAG; p.(Ser626Leufs*4)","llm_judgment":"PRESENT","evidence":"c.1876_1877delAG; p.(Ser626Leufs*4)","abstract_start":504,"abstract_end":539}]}
{"pmid":"34925234","title":"Germline","abstract":"Activating variants in the receptor tyrosine kinase <i>RE</i>arranged during <i>T</i>ransfection (RET) cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer-susceptibility syndrome. The variant c.166C>A, p.Leu56Met in <i>RET</i> was recently reported in two patients with medullary thyroid cancer (MTC). The presence of a pheochromocytoma in one of the patients, suggested a possible pathogenic role of the variant in MEN 2A. Here, we present clinical follow up of a Danish <i>RET</i> Leu56Met cohort. Patients were evaluated for signs of MEN 2 according to a set of predefined criteria. None of the seven patients in our cohort exhibited evidence of MEN 2. Furthermore, we found the Leu56Met variant in our in-house diagnostic cohort with an allele frequency of 0.59%, suggesting that it is a common variant in the population. Additionally, none of the patients who harbored the allele were listed in the Danish MTC and MEN 2 registries. In conclusion, our findings do not support a pathogenic role of the Leu56Met variant in MEN 2.","variants":[{"Name":"NM_020975.6(RET):c.166C>A (p.Leu56Met)","Chromosome":"10","Start":"43100551","Stop":"43100551","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":45384,"rule_based_match":true,"evidence_text":"The variant c.166C>A, p.Leu56Met in <i>RET</i>","llm_judgment":"PRESENT","evidence":"The variant c.166C>A, p.Leu56Met in <i>RET</i>","abstract_start":220,"abstract_end":266}]}
{"pmid":"29082380","title":"Bilateral Breast Cancer with Neurofibromatosis Type 1 Patient: Case Report.","abstract":"Neurofibromatosis type 1 (NF1) is autosomal dominant and it is the most common hereditary disease. This case report is about a woman and her daughter. Both of them are NF1 and mother also has metachronous bilateral breast carcinoma. We analyzed expressions of 84 genes related with DNA Repair by Real Time PCR (AB Applied Biosystem 7000 Sequence Detection System; Thermo Fisher, Foster City, CA, USA). We also performed NF1 sequencing analyzing in exon 9 of the NF1 gene for mother. In Real Time PCR analysis of DNA Repair Genes, expression chances were predominant both in mother and daughter compared with control group. When the mother and daughter's expression profiles were compared, similar DNA repair array gene expression profiles were observed and the expression of DDB2, MGMT, MLH1, POLB UNG, XPA genes were high in both mother and daughter. In sequencing analysis, we obtained a mutation in c.1246 C>T. This mutation is reported to be common in NF1 cases with breast carcinoma. Our results indicate that the daughter with NF1 is probably prone to have malignancy in her future life. She should be carefully followed up for early diagnosis of a probable malignancy.","variants":[{"Name":"NM_001042492.3(NF1):c.1246C>T (p.Arg416Ter)","Chromosome":"17","Start":"31201471","Stop":"31201471","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":402141,"rule_based_match":true,"evidence_text":"c.1246 C>T","llm_judgment":"PRESENT","evidence":"c.1246 C>T","abstract_start":902,"abstract_end":912}]}
{"pmid":"30898715","title":"TCIRG1 and SNX10 gene mutations in the patients with autosomal recessive osteopetrosis.","abstract":"Autosomal recessive osteopetrosis (ARO) is a rare genetic bone disease characterized by dense and fragile bone, caused by a defect in osteoclasts responsible for the bone destruction. In this study, we aimed to investigate the mutations in TCIRG1 and SNX10 that are responsible for 50% and 4% of the cases, respectively. All amplicons were sequenced by Sanger sequencing following PCR amplification. As a result, six different mutations of the TCIRG1 gene were found in five of the twelve unrelated cases. These include two novel mutations, namely c.630 + 1G > T mutation and c.1778_1779delTG mutation of the gene which are identified as homozygous. A compound heterozygosity of known mutations c.649_674del26 and c.1372G > A and homozygous presence of the known c.2235 + 1G > A mutation were also observed in different patients. In addition, as a result of the prenatal testing in a family with osteopetrosis infant, the c.1674-1G > A mutation was detected as homozygous for the fetus. In TCIRG1, c.166C > T change, which is indicated as likely benign according to ClinVar database, was heterozygous. Several known polymorphisms; c.117 + 83 T > C, c.417 + 11A > G and c.714-19C > A in TCIRG1 gene; c.24 + 36 T > A and c.112-84G > A in SNX10 gene were also detected. In conclusion, our study revealed that five of the twelve cases carry at least one mutation of TCIRG1 gene. Further studies with more patients and other genes would help better understanding of genetic etiology of the disease.","variants":[{"Name":"NM_006019.4(TCIRG1):c.630+1G>T","Chromosome":"11","Start":"68043498","Stop":"68043498","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":546504,"rule_based_match":true,"evidence_text":"c.630 + 1G > T","llm_judgment":"PRESENT","evidence":"c.630 + 1G > T","abstract_start":548,"abstract_end":562},{"Name":"NM_006019.4(TCIRG1):c.1372G>A (p.Gly458Ser)","Chromosome":"11","Start":"68047713","Stop":"68047713","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":546253,"rule_based_match":true,"evidence_text":"c.1372G > A","llm_judgment":"PRESENT","evidence":"c.1372G > A","abstract_start":714,"abstract_end":725},{"Name":"NM_006019.4(TCIRG1):c.1674-1G>A","Chromosome":"11","Start":"68049080","Stop":"68049080","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187118,"rule_based_match":true,"evidence_text":"c.1674-1G > A","llm_judgment":"PRESENT","evidence":"c.1674-1G > A","abstract_start":922,"abstract_end":935}]}
{"pmid":"35012925","title":"Whole exome sequencing analysis of compound heterozygous variants of CDAN1 gene in a Chinese family with non-immune hydrops fetalis","abstract":"OBJECTIVE: To study the clinical characteristics and genetic variants in a family with non-immune hydrops fetalis.\nMETHODS: Peripheral blood samples were collected from a pregnant woman with suspected non-immune hydrops fetalis of the fetus for routine blood analysis, Rh typing and TORCH test. Amniotic fluid sample was collected for G-banded chromosomal karyotyping. The genomic DNA of the proband was extracted for analysis of chromosomal abnormalities using copy number variation sequencing. Whole-exome sequencing (Trios-WES) was performed on Illumina NovaSeq 6000 platform and exonic DNA was enriched using Agilent Sure Select XT Human All Exon V6. Sorting intolerant from tolerant (SIFT), I-mutant2, PolyPhen-2 and PROVEAN were used to predict the potential effects of amino acid substitution on protein function and splicing variation. The spatial structure of codanin-1 was modeled and visualized with Alpha Fold 2 and PyMOL 2.3 software, and the variants with potential clinical significance were confirmed by Sanger sequencing.\nRESULTS: Fetal ultrasound at 17 weeks of gestation showed extensive subcutaneous edema, ascites, pleural effusion, enlarged liver and spleen, thickened placenta and pericardium defect. NGS reveals that proband has carried c.2140C>T, p.R714W, and c.1264_1265delCT, p.L422* compound heterozygous variants of CDAN1 gene, which were found to be pathogenic and inherited from proband's father and mother respectively.\nCONCLUSION: We identified a novel heterozygous CDAN1 gene mutation causing fetal-onset congenital dyserythropoietic anemia type 1, which triggers non-immune hydrops fetalis.","variants":[{"Name":"NM_138477.4(CDAN1):c.2140C>T (p.Arg714Trp)","Chromosome":"15","Start":"42730632","Stop":"42730632","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34600,"rule_based_match":true,"evidence_text":"c.2140C>T, p.R714W","llm_judgment":"PRESENT","evidence":"c.2140C>T, p.R714W","abstract_start":1261,"abstract_end":1279}]}
{"pmid":"28673863","title":"MPV17 hepatocerebral mitochondrial DNA depletion syndrome presenting as acute flaccid paralysis - A case report.","abstract":"Mutations in human MPV17 have been reported in patients with severe mitochondrial DNA (mtDNA) depletion manifesting as early childhood onset failure to thrive, hypoglycemia, encephalopathy and progressive liver failure. We describe an 11 year old girl, born to consanguineous parents, who presented with rapidly progressive weakness of all 4 limbs with symmetrical proximal and distal weakness, gastrointestinal disease and leukoencephalopathy. Genetic analysis of the patient revealed a homozygous pathogenic mutation c.121C>T (p.R41W) in the MPV17 gene. Further, screening for this mutation in the parents revealed the presence of heterozygous mutation in both the parents, suggesting the recessive nature of the disease.","variants":[{"Name":"NM_002437.5(MPV17):c.121C>T (p.Arg41Trp)","Chromosome":"2","Start":"27313059","Stop":"27313059","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":210811,"rule_based_match":true,"evidence_text":"c.121C>T (p.R41W)","llm_judgment":"PRESENT","evidence":"c.121C>T (p.R41W)","abstract_start":519,"abstract_end":536}]}
{"pmid":"18285823","title":"Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients.","abstract":"Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by widespread arteriovenous malformations and caused by mutations in two major genes: ENG and ACVRL1. Two decades ago, a French epidemiological study pointed out that its prevalence was higher than previously thought and that its distribution varied greatly from one area to another, one of the highest concentrations of patients being found in the Haut-Jura mountains. Although germline mutations are usually family specific, some of them have been reported in unrelated patients, especially for ACVRL1. We performed haplotype analysis of 116 French and Italian patients carrying 13 ACVRL1 different mutations. For five of these mutations, we estimated the age of the most recent common ancestors (MRCAs) using the ESTIAGE program. Most mutations were related to both recurrent mutational events and founder effects with age estimates ranging from 100 to 550 years. The c.1112dupG mutation, which is likely to be responsible for the very high concentration of HHT patients found in the former epidemiological study, probably occurred in one inhabitant of the Haut-Jura Mountains more than three centuries ago. The p.Arg374Gln mutation occurred independently in at least two distinct geographical areas, including the area with the second highest prevalence in the epidemiological study and where the MRCA is rather recent (about 100 years ago). Partially shared haplotypes between French and Italian patients were found for three mutations. This suggests a common origin and a possible diffusion of these mutations from Italy to France.","variants":[{"Name":"NM_000020.3(ACVRL1):c.1121G>A (p.Arg374Gln)","Chromosome":"12","Start":"51916108","Stop":"51916108","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":399783,"rule_based_match":false,"evidence_text":"p.Arg374Gln","llm_judgment":"PRESENT","evidence":"p.Arg374Gln","abstract_start":1206,"abstract_end":1217}]}
{"pmid":"21594992","title":"Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3' end of the FBN1 gene.","abstract":"We report on a 20-year-old man who presented in infancy with severe generalized lipodystrophy with a progeroid appearance and some Marfanoid features. He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene. This analysis showed him to have a novel heterozygous, de novo, c.8156_8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene. His phenotype is similar to a patient described by Graul-Neumann et al. [2010] who was found to have a de novo, heterozygous, c.8155_8156del deletion in exon 64 of FBN1. Both mutations result in a truncated protein with an extremely charged C-terminus, containing two positive and four negative charges in the last eight amino acids. This most likely has a profound impact on protein–protein interactions, which are very important in the extracellular matrix. The similarities in the phenotypes, and overlapping molecular defects, provides further evidence that the phenotype with features of Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy is a distinct clinical entity due to frameshift mutations in exon 64 of the FBN1 gene.","variants":[{"Name":"NM_000138.5(FBN1):c.8156_8175del (p.Lys2719fs)","Chromosome":"15","Start":"48412620","Stop":"48412639","ReferenceAlleleVCF":"GTTTGGGGTAGCCATTGATCT","AlternateAlleleVCF":"G","allel_id":48728,"rule_based_match":true,"evidence_text":"c.8156_8175del","llm_judgment":"PRESENT","evidence":"c.8156_8175del","abstract_start":343,"abstract_end":357}]}
{"pmid":"24276437","title":"Clinical and genetic aspects of hypophosphatasia in Japanese patients.","abstract":"OBJECTIVE: We examined the clinical and genetic features of hypophosphatasia (HPP) in Japanese patients. HPP is a rare metabolic bone disorder of bone mineralisation caused by mutations in the liver/bone/kidney alkaline phosphatase (ALPL) gene, which encodes tissue-non-specific alkaline phosphatase isoenzyme. \nMETHODS: We retrospectively investigate the incidence and clinical features of 52 patients with paediatric HPP who were born between 1999 and 2010. Mutations of the ALPL gene were analysed in 31 patients.\nRESULTS: The annual incidence of perinatal lethal HPP (PLH) was estimated to be 2-3/1 000 000 births. The most frequent clinical type was PLH followed by prenatal benign. In addition to bone symptoms, cerebral manifestations were frequently observed including convulsion, mental retardation, deafness and short stature with growth hormone deficiency. Respiratory failure was the most significant predictor of a poor prognosis for PLH. The first and second most frequent mutations in the ALPL gene were c.1559delT and c.T979C (p.F327L), respectively. The c.1559delT homozygous mutation was lethal with respiratory failure. Patients with the p.F327L compound heterozygous mutation had the different non-lethal type with short stature and a gradual improvement in ALP level and bone mineralisation.\nCONCLUSIONS: The most frequent clinical type was the PLH type with prognosis related to respiratory failure, biochemical/radiological changes and ALPL mutations. Cerebral manifestations frequently occurred. Genotype-phenotype correlations were associated with specific outcomes in the PLH type, whereas different clinical features were associated with the same genotype in the non-lethal type.","variants":[{"Name":"NM_000478.6(ALPL):c.979T>C (p.Phe327Leu)","Chromosome":"1","Start":"21573781","Stop":"21573781","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":28712,"rule_based_match":false,"evidence_text":"c.T979C (p.F327L)","llm_judgment":"PRESENT","evidence":"c.T979C (p.F327L)","abstract_start":1034,"abstract_end":1051}]}
{"pmid":"21932012","title":"Efficacy and safety of 2-year etidronate treatment in a child with generalized arterial calcification of infancy.","abstract":"UNLABELLED: Generalized arterial calcification of infancy (GACI, MIM#208000) is a rare autosomal recessive disorder characterized by extensive calcifications in the media of large- and medium-sized muscular arteries. Most affected children die in early infancy because of cardiac failure. GACI is linked to mutations in the ENPP1 gene, which encodes for an enzyme that generates inorganic pyrophosphate (PP(i)), a potent inhibitor of hydroxyapatite crystal formation. Treatment with bisphosphonates, which are synthetic PP(i) analogues, has been proposed as a means of reducing arterial calcifications in GACI patients, but no formalized treatment approach exists. We report on the long-term survival of a severe case of GACI linked to a novel homozygous missense mutation c.583T/C in the ENPP1 gene, diagnosed prenatally, and treated with bisphosphonates. Intravenous disodium pamidronate (three infusions at days 8, 15, and 18 of 0.25, 0.50, and 0.50 mg/kg, respectively) was changed to oral disodium etidronate (starting dose of 20 mg/kg daily, 50 mg die) at 3 weeks of age. Although the etidronate dose was maintained at 50 mg daily in our patient (corresponding to a progressive decrease from 20 to 5 mg/kg daily), the progressive resolution of arterial calcifications seen by 3 months of age was maintained until 2 years of age. Throughout the 2-year follow-up, our patient developed mild hypophosphatemia, due to renal phosphate wasting, without clinical, biochemical, or radiological sign of rickets.\nCONCLUSION: High-dose bisphosphonate therapy may not be necessary for an extended period of time in children with GACI.","variants":[{"Name":"NM_006208.3(ENPP1):c.583T>C (p.Cys195Arg)","Chromosome":"6","Start":"131852201","Stop":"131852201","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2748218,"rule_based_match":false,"evidence_text":"c.583T/C","llm_judgment":"PRESENT","evidence":"c.583T/C","abstract_start":773,"abstract_end":781}]}
{"pmid":"34304999","title":"Genetic basis and hematologic manifestations of sitosterolemia in a group of Turkish patients.","abstract":"BACKGROUND: Sitosterolemia is a rare lipid disorder caused by mutations in adenosine triphosphate-binding cassette genes (ABCG) 5 and 8.\nOBJECTIVE: To evaluate the phenotypic/genotypic features of sitosterolemia in a group of Turkish patients.\nMETHODS: Seven probands with unexplained hematologic abnormalities and their 13 relatives were enrolled. Sterol levels were measured by gas chromatography and genetic studies were performed using Sanger sequencing. Individuals were diagnosed with sitosterolemia if they were found to have frankly elevated sitosterol level >15 μg/mL and/or pathogenic variants of the ABCG5/ABCG8.\nRESULTS: The seven probands and their six relatives  were diagnosed with frank sitosterolemia, and all these patients had hematologic abnormalities. The remaining seven relatives were asymptomatic heterozygous carriers. Three novel variants in the ABCG5 gene (c.161G>A, c.1375C>T, IVS10-1G>T), one novel variant in the ABCG8 gene (c.1762G>C) and one known variant in the ABCG5 gene (c.1336 C>T) were identified. No variant was identified in one case. The mean sitosterol level was significantly higher and mean platelet count was significantly lower in patients with homozygous variants compared to heterozygous variants (p<0.05, for all). Diets low in plant sterols were recommended for 13 symptomatic cases. Four homozygotes received ezetimibe, and their splenomegaly, anemia, and thrombocytopenia completely resolved except one.\nCONCLUSION: The five pathogenic variants identified in this study indicate the genetic heterogeneity of sitosterolemia in Turkish population. Patients with unexplained hematologic abnormalities (specifically macrothrombocytopenia) should have their sterol level measured as initial testing. Ezetimibe can be a good choice for sitosterolemia.","variants":[{"Name":"NM_022436.3(ABCG5):c.1336C>T (p.Arg446Ter)","Chromosome":"2","Start":"43822924","Stop":"43822924","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39442,"rule_based_match":true,"evidence_text":"c.1336 C>T","llm_judgment":"PRESENT","evidence":"c.1336 C>T","abstract_start":1007,"abstract_end":1017}]}
{"pmid":"28088608","title":"Gene analysis of six cases of congenital protein S deficiency and functional analysis of protein S mutations (A139V, C449F, R451Q, C475F, A525V and D599TfsTer13).","abstract":"Congenital deficiency of protein S (PS), an anticoagulant factor, leads to venous thrombosis, with onset predominantly beginning in adolescence. In the present study, gene analysis of six unrelated Japanese families diagnosed with congenital PS deficiency identified five missense mutations in the PROS1 gene - c.757C>T (Ala139Val; A139V), c.1346 G>T (Cys449Phe; C449F), c.1352G>A (Arg451Gln; R451Q), c.1424G>T (Cys475Phe; C475F) and c.1574C>T (Ala525Val; A525V) - and one frameshift mutation, c.2135delA (Asp599ThrfsTer13; D599TfsTer13). C449F, R451Q, A525V and D599TfsTer13 are novel mutations. Results from ELISA to measure PS antigen levels in culture supernatant showed that the A139V variant was similar to wild-type, but other variants showed reductions when compared with wild-type. Results from pulse-chase analysis confirmed that the A139V variant exhibited secretion equivalent to wild-type, but for the other variants, there was no extracellular secretion, and it had nearly all been degraded inside the cell within six hours. Results from pulse-chase analysis using proteasome inhibitors also showed that intracellular degradation of mutant protein was inhibited. Activity of the A139V variant was decreased to 71% of wild-type, and the phospholipid binding capacity fell to as low as 45%. These results suggest that although the A139V variant has normal secretion, it has abnormal phospholipid binding capacity, and therefore causes type II PS deficiency, in which PS activity is decreased. It is also thought that with the other variants, misfolding due to amino acid mutations causes nearly all PS to be degraded intracellularly, therefore leading to type I PS deficiency.","variants":[{"Name":"NM_000313.4(PROS1):c.1352G>A (p.Arg451Gln)","Chromosome":"3","Start":"93884868","Stop":"93884868","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2893227,"rule_based_match":true,"evidence_text":"c.1352G>A (Arg451Gln; R451Q)","llm_judgment":"PRESENT","evidence":"c.1352G>A (Arg451Gln; R451Q)","abstract_start":371,"abstract_end":399},{"Name":"NM_000313.4(PROS1):c.1424G>T (p.Cys475Phe)","Chromosome":"3","Start":"93884796","Stop":"93884796","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2894575,"rule_based_match":true,"evidence_text":"c.1424G>T (Cys475Phe; C475F)","llm_judgment":"PRESENT","evidence":"c.1424G>T (Cys475Phe; C475F)","abstract_start":401,"abstract_end":429}]}
{"pmid":"32032626","title":"The pathogenicity of SLC38A8 in five families with foveal hypoplasia and congenital nystagmus.","abstract":"PURPOSE: A recently described subtype of foveal hypoplasia with congenital nystagmus and optic-nerve-decussation defects was found to be associated with mutations in the SLC38A8 gene. The aim of this study is to advance the clinical and molecular knowledge of SLC38A8 gene mutations.\nMETHODS: Five Israeli families with congenital foveal hypoplasia were studied, two of Karait Jewish origins and three of Indian Jewish origins. Subjects underwent a comprehensive ophthalmic examination including retinal photography and ocular coherence tomography. Molecular analysis including whole exome sequencing and screening of the SLC38A8 gene for specific disease-causing variants was performed.\nRESULTS: Eight affected individuals were identified, all had congenital nystagmus and all but one had hypoplastic foveal pits. Anterior segment dysgenesis was observed in only one patient, one had evidence of developmental delay and another displayed early age-related macular degeneration (AMD). Molecular analysis revealed a recently described homozygous mutation, c.95T > G; p.Ile32Ser, in two families of Jewish Indian descent, and the same mutation in two families of Karaite Jewish descent. In a patient with only one pathogenic mutation (c.95T > G; p.Ile32Ser), a possible partial clinical expression of the disorder was seen. One patient of Jewish Indian descent was found to be compound heterozygous for c.95T > G; p.Ile32Ser and a novel mutation c.490_491delCT; p.L164Vfs*41.\nCONCLUSIONS: In five unrelated families with congenital nystagmus and foveal hypoplasia, mutations in the SLC38A8 gene were identified. Possible partial expression in a heterozygous patient was observed and novel potential disease-related phenotypes were identified including early-onset AMD and developmental delay. A novel mutation was also identified and a similar mutation in both Indian and Karaite Jewish ethnicities could be suggestive for common ancestry.","variants":[{"Name":"NM_001080442.3(SLC38A8):c.95T>G (p.Ile32Ser)","Chromosome":"16","Start":"84042063","Stop":"84042063","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":130980,"rule_based_match":true,"evidence_text":"c.95T>G; p.Ile32Ser","llm_judgment":"PRESENT","evidence":"c.95T > G; p.Ile32Ser","abstract_start":1055,"abstract_end":1076}]}
{"pmid":"37718511","title":"BRCA1 frameshift variants leading to extended incorrect protein C termini.","abstract":"Carriers of BRCA1 germline pathogenic variants are at substantially higher risk of developing breast and ovarian cancer than the general population. Accurate identification of at-risk individuals is crucial for risk stratification and the implementation of targeted preventive and therapeutic interventions. Despite significant progress in variant classification efforts, a sizable portion of reported BRCA1 variants remain as variants of uncertain clinical significance (VUSs). Variants leading to premature protein termination and loss of essential functional domains are typically classified as pathogenic. However, the impact of frameshift variants that result in an extended incorrect terminus is not clear. Using validated functional assays, we conducted a systematic functional assessment of 17 previously reported BRCA1 extended incorrect terminus variants (EITs) and concluded that 16 constitute loss-of-function variants. This suggests that most EITs are likely to be pathogenic. However, one variant, c.5578dup, displayed a protein expression level, affinity to known binding partners, and activity in transcription and homologous recombination assays comparable to the wild-type BRCA1 protein. Twenty-three additional carriers of c.5578dup were identified at a US clinical diagnostic lab and assessed using a family history likelihood model providing, in combination with the functional data, a likely benign interpretation. These results, consistent with family history data in the current study and available data from ClinVar, indicate that most, but not all, BRCA1 variants leading to an extended incorrect terminus constitute loss-of-function variants and underscore the need for comprehensive assessment of individual variants.","variants":[{"Name":"NM_007294.4(BRCA1):c.5578dup (p.His1860fs)","Chromosome":"17","Start":"43045691","Stop":"43045692","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":46239,"rule_based_match":true,"evidence_text":"c.5578dup","llm_judgment":"PRESENT","evidence":"c.5578dup","abstract_start":1012,"abstract_end":1021}]}
{"pmid":"28588666","title":"Molecular analysis of the novel","abstract":"Hunter syndrome (or mucopolysaccharidosis type II, MPS II) is an X-linked recessive disorder induced by a deficiency of the iduronate 2-sulfatase (IDS) enzyme, resulting in the accumulation of glycosaminoglycan substrates, heparan sulfate and dermatan sulfate, in the lysosomes. The progressive accumulation of undegraded metabolites induces cell and tissue dysfunction, leading to multi-systemic pathology. The heterogeneity of clinical phenotypes, ranging from mild to severe forms, results from different mutations in the <i>IDS</i> gene. To date, >550 MPS II causal mutations have been reported in the <i>IDS</i> gene, of which ~10% are nonsense mutations that lead to premature protein termination. In the present study, the IDS mutation causing MPS II in an extended Thai family was identified using IDS enzyme assay and IDS gene exon sequencing. Three family members were enzymatically confirmed to have MPS II and to carry the novel IDS nonsense allele c.928C>T (p.Gln310*). The IDS mRNA levels were evaluated by reverse transcription-quantitative polymerase chain reaction, which demonstrated that all patients exhibited a reduction of IDS mRNA, suggesting its degradation by nonsense-mediated mRNA decay. Expression of wild type and mutant IDS in COS-7 cells revealed that the IDS p.Gln310* mutant lacked IDS activity, consistent with production of a nonfunctional, prematurely truncated protein. Taken together, these results indicate that the IDS c.928C>T (p.Gln310*) mutation is a severe disease-causing mutation for MPS II.","variants":[{"Name":"NM_000202.8(IDS):c.928C>T (p.Gln310Ter)","Chromosome":"X","Start":"149490392","Stop":"149490392","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3414646,"rule_based_match":true,"evidence_text":"c.928C>T (p.Gln310*)","llm_judgment":"PRESENT","evidence":"c.928C>T (p.Gln310*)","abstract_start":961,"abstract_end":981}]}
{"pmid":"22311046","title":"Novel and recurrent LDLR gene mutations in Pakistani hypercholesterolemia patients.","abstract":"The majority of patients with the autosomal dominant disorder familial hypercholesterolemia (FH) carry novel mutations in the low density lipoprotein receptor (LDLR) that is involved in cholesterol regulation. In different populations the spectrum of mutations identified is quite different and to date there have been only a few reports of the spectrum of mutations in FH patients from Pakistan. In order to identify the causative LDLR variants the gene was sequenced in a Pakistani FH family, while high resolution melting analysis followed by sequencing was performed in a panel of 27 unrelated sporadic hypercholesterolemia patients. In the family a novel missense variant (c.1916T > G, p.(V639G)) in exon 13 of LDLR was identified in the proband. The segregation of the identified nucleotide change in the family and carrier status screening in a group of 100 healthy subjects was done using restriction fragment length polymorphism analysis. All affected members of the FH family carried the variant and none of the non-affected members nor any of the healthy subjects. In one of the sporadic cases, two sequence changes were detected in exon 9, one of these was a recurrent missense variant (c.1211C > T; p.T404I), while the other was a novel substitution mutation (c.1214 A > C; N405T). In order to define the allelic status of this double heterozygous individual, PCR amplified fragments were cloned and sequenced, which identified that both changes occurred on the same allele. In silico tools (PolyPhen and SIFT) were used to predict the effect of the variants on the protein structure, which predicted both of these variants to have deleterious effect. These findings support the view that there will be a novel spectrum of mutations causing FH in patients with hypercholesterolaemia from Pakistan.","variants":[{"Name":"NM_000527.5(LDLR):c.1916T>G (p.Val639Gly)","Chromosome":"19","Start":"11120162","Stop":"11120162","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":246408,"rule_based_match":true,"evidence_text":"c.1916T > G, p.(V639G)","llm_judgment":"PRESENT","evidence":"c.1916T > G, p.(V639G)","abstract_start":678,"abstract_end":700},{"Name":"NM_000527.5(LDLR):c.1211C>T (p.Thr404Ile)","Chromosome":"19","Start":"11113302","Stop":"11113302","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":246050,"rule_based_match":true,"evidence_text":"c.1211C > T; p.T404I","llm_judgment":"PRESENT","evidence":"c.1211C > T; p.T404I","abstract_start":1199,"abstract_end":1219},{"Name":"NM_000527.5(LDLR):c.1214A>C (p.Asn405Thr)","Chromosome":"19","Start":"11113305","Stop":"11113305","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":246051,"rule_based_match":true,"evidence_text":"c.1214 A > C; N405T","llm_judgment":"PRESENT","evidence":"c.1214 A > C; N405T","abstract_start":1273,"abstract_end":1292}]}
{"pmid":"31363008","title":"Segregation of two variants suggests the presence of autosomal dominant and recessive forms of","abstract":"BACKGROUND: <i>WFS1</i> was initially described as causative agent of autosomal recessive (AR) Wolfram syndrome, a childhood-onset disorder involving diabetes, optic atrophy, hearing loss and neurodegenerative features. However, the discovery of autosomal dominant (AD) disorders caused by this gene has resulted in clinical counselling and result interpretation challenges.\nOBJECTIVE: We seek to report a family that appears to segregate dominant and recessive forms of <i>WFS1</i>-related disease.\nMETHODS/RESULTS: A 19-year-old woman presented with progressive childhood sensorineural hearing loss and recent optic atrophy, with biallelic mutations in <i>WFS1</i>: c.2486T>C (likely pathogenic) and c.2470G>A (uncertain significance). Her A<sub>1</sub>C was normal. Her sister carried the same variants and had a similar phenotype. Their father carried c.2486T>C and was found to have mild-moderate hearing loss but no optic atrophy or neurological symptoms. The mother carried c.2470G>A and had a normal audiogram and ophthalmological exam. Providing anticipatory guidance for this family was difficult given the phenotypic variability of <i>WFS1</i>-related disorders and the uncertainty surrounding whether the inheritance pattern was AR or AD.\nCONCLUSION: The clinical correlation of the variants identified in this family suggests an AR Wolfram-like syndrome, without the typical diabetes mellitus or diabetes insipidus nor neurological decline. To our knowledge, this is a novel <i>WFS1</i>-related phenotype.","variants":[{"Name":"NM_006005.3(WFS1):c.2486T>C (p.Leu829Pro)","Chromosome":"4","Start":"6302281","Stop":"6302281","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":19560,"rule_based_match":true,"evidence_text":"c.2486T>C","llm_judgment":"PRESENT","evidence":"c.2486T>C","abstract_start":668,"abstract_end":677},{"Name":"NM_006005.3(WFS1):c.2470G>A (p.Glu824Lys)","Chromosome":"4","Start":"6302265","Stop":"6302265","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":173982,"rule_based_match":true,"evidence_text":"c.2470G>A","llm_judgment":"PRESENT","evidence":"c.2470G>A","abstract_start":702,"abstract_end":711}]}
{"pmid":"19621418","title":"Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in the SEC23B gene.","abstract":"Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease characterized by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypoglycosylation of some red blood cell (RBC) membrane proteins. Recent studies indicated that CDAII is caused by a defect disturbing Golgi processing in erythroblasts. A linkage analysis located a candidate region on chromosome 20, termed the CDAN2 locus, in the majority of CDAII patients but the aberrant gene has not so far been elucidated. We used a proteomic-genomic approach to identify SEC23B as the candidate gene for CDAII by matching the recently published data on the cytoplasmic proteome of human RBCs with the chromosomic localization of CDAN2 locus. Sequencing analysis of SEC23B gene in 13 CDAII patients from 10 families revealed 12 different mutations: six missense (c.40C>T, c.325G>A, c.1043A>C, c.1489C>T, c.1808C>T, and c.2101C>T), two frameshift (c.428_428delAinsCG and c.1821delT), one splicing (c.689+1G>A), and three nonsense (c.568C>T, c.649C>T, and c.1660C>T). Mutations c.40C>T and c.325G>A were detected in unrelated patients. SEC23B is a member of the Sec23/Sec24 family, a component of the COPII coat protein complex involved in protein transport through membrane vesicles. Abnormalities in this gene are likely to disturb endoplasmic reticulum (ER)-to-Golgi trafficking, affecting different glycosylation pathways and ultimately accounting for the cellular phenotype observed in CDAII.","variants":[{"Name":"NM_006363.6(SEC23B):c.325G>A (p.Glu109Lys)","Chromosome":"20","Start":"18515695","Stop":"18515695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16261,"rule_based_match":true,"evidence_text":"c.325G>A","llm_judgment":"PRESENT","evidence":"c.325G>A","abstract_start":883,"abstract_end":891},{"Name":"NM_006363.6(SEC23B):c.40C>T (p.Arg14Trp)","Chromosome":"20","Start":"18510875","Stop":"18510875","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16262,"rule_based_match":true,"evidence_text":"c.40C>T","llm_judgment":"PRESENT","evidence":"c.40C>T","abstract_start":874,"abstract_end":881},{"Name":"NM_006363.6(SEC23B):c.689+1G>A","Chromosome":"20","Start":"18525021","Stop":"18525021","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":101288,"rule_based_match":true,"evidence_text":"c.689+1G>A","llm_judgment":"PRESENT","evidence":"c.689+1G>A","abstract_start":1008,"abstract_end":1018},{"Name":"NM_006363.6(SEC23B):c.649C>T (p.Arg217Ter)","Chromosome":"20","Start":"18524980","Stop":"18524980","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16266,"rule_based_match":true,"evidence_text":"c.649C>T","llm_judgment":"PRESENT","evidence":"c.649C>T","abstract_start":1051,"abstract_end":1059},{"Name":"NM_006363.6(SEC23B):c.1660C>T (p.Arg554Ter)","Chromosome":"20","Start":"18543167","Stop":"18543167","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3111659,"rule_based_match":true,"evidence_text":"c.1660C>T","llm_judgment":"PRESENT","evidence":"c.1660C>T","abstract_start":1065,"abstract_end":1074},{"Name":"NM_006363.6(SEC23B):c.568C>T (p.Arg190Ter)","Chromosome":"20","Start":"18524634","Stop":"18524634","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3082641,"rule_based_match":true,"evidence_text":"c.568C>T","llm_judgment":"PRESENT","evidence":"c.568C>T","abstract_start":1041,"abstract_end":1049},{"Name":"NM_006363.6(SEC23B):c.1489C>T (p.Arg497Cys)","Chromosome":"20","Start":"18542380","Stop":"18542380","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":177431,"rule_based_match":true,"evidence_text":"c.1489C>T","llm_judgment":"PRESENT","evidence":"c.1489C>T","abstract_start":904,"abstract_end":913},{"Name":"NM_006363.6(SEC23B):c.2101C>T (p.Arg701Cys)","Chromosome":"20","Start":"18554343","Stop":"18554343","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1482334,"rule_based_match":true,"evidence_text":"c.2101C>T","llm_judgment":"PRESENT","evidence":"c.2101C>T","abstract_start":930,"abstract_end":939}]}
{"pmid":"25410674","title":"Haplotype analysis of CLDN19 single nucleotide polymorphisms in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.","abstract":"BACKGROUND: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disease caused by mutations in the CLDN16 or CLDN19 gene. Previous studies using microsatellite markers flanking the CLDN19 locus estimated that p.G20D (c.59G>A), a recurrent mutation in Spanish families, is a founder mutation. In the present study, we assessed the haplotype of Spanish patients using single nucleotide polymorphisms (SNPs).\nMETHODS: Twenty-seven FHHNC patients were included in this study. We analyzed four SNPs located in CLDN19 introns 3 and 4 by polymerase chain reaction amplification and DNA sequencing.\nRESULTS: Three new patients with homozygous p.G20D were identified. The SNP genotyping analysis showed that alleles carrying this mutation shared a common SNP haplotype.\nCONCLUSIONS: Our findings suggest the existence of a founder effect responsible for FHHNC in our cohort. Testing for the presence of mutation p.G20D should be the first genetic screening in Spanish patients.","variants":[{"Name":"NM_148960.3(CLDN19):c.59G>A (p.Gly20Asp)","Chromosome":"1","Start":"42740005","Stop":"42740005","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16400,"rule_based_match":true,"evidence_text":"c.59G>A","llm_judgment":"PRESENT","evidence":"c.59G>A","abstract_start":272,"abstract_end":279}]}
{"pmid":"20035706","title":"Preimplantation genetic diagnosis of beta-thalassemia using real-time polymerase chain reaction with fluorescence resonance energy transfer hybridization probes.","abstract":"Preimplantation genetic diagnosis (PGD) is employed increasingly to allow transfer of embryos to the uterus in assisted reproduction procedures. There are three stages of biopsy: polar bodies, one or two blastomeres from the cleavage-stage embryos, and trophectoderm cells ( approximately 5cells) from the blastocyst-stage embryos. Validation of polymerase chain reaction (PCR)-based assays are challenging because only limited genetic material can be obtained for PGD. In the current study, we modified a valid single-cell PCR protocol for PGD using real-time PCR assay with fluorescence resonance energy transfer (FRET) hybridization probes followed by melting curve analysis. We optimized and clinically applied the protocol, permitting molecular genetic analysis to amplify a specific region on the beta-globin (HBB) gene for a couple, carriers of two mutations: c.-78A>G and c.52A>T. Among a total of eight embryos obtained after ovarian stimulation, a single blastomere per embryo at the six- to eight-cell stage was biopsied. This PGD method showed that four embryos were unaffected, two embryos were selected for transfer, and one pregnancy was achieved. Finally, a healthy male baby was delivered at 38weeks' gestation. The results obtained using the new method, FRET hybridization probes, were compared with findings using an existing method, primer extension minisequencing.","variants":[{"Name":"NM_000518.5(HBB):c.-78A>G","Chromosome":"11","Start":"5227099","Stop":"5227099","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":30510,"rule_based_match":true,"evidence_text":"c.-78A>G","llm_judgment":"PRESENT","evidence":"c.-78A>G","abstract_start":867,"abstract_end":875}]}
{"pmid":"31698099","title":"Exome reports A de novo GNB2 variant associated with global developmental delay, intellectual disability, and dysmorphic features.","abstract":"Heterotrimeric G proteins are composed of α, β, and γ subunits and are involved in integrating signals between receptors and effector proteins. The 5 human Gβ proteins (encoded by GNB1, GNB2, GNB3, GNB4, and GNB5) are highly similar. Variants in GNB1 were identified as a genetic cause of developmental delay. De novo variant in GNB2 has recently been reported as a cause of sinus node dysfunction and atrioventricular block but not as a cause of developmental delay. Trio-based whole-exome sequencing was performed on an individual with global developmental delay, muscle hypotonia, multiple congenital joint contractures and dysmorphism such as brachycephalus, thick eyebrows, thin upper lip, micrognathia, prominent chin, and bilateral tapered fingers. We identified a de novo GNB2 variant c.229G>A, p.(Gly77Arg). Notably, pathogenic substitutions of the homologous Gly77 residue including an identical variant (p.Gly77Arg, p.Gly77Val, p.Gly77Ser, p.Gly77Ala) of GNB1, a paralog of GNB2, was reported in individuals with global developmental delay and hypotonia. Clinical features of our case overlap with those of GNB1 variants. Our study suggests that a GNB2 variant may be associated with syndromic global developmental delay.","variants":[{"Name":"NM_005273.4(GNB2):c.229G>A (p.Gly77Arg)","Chromosome":"7","Start":"100677377","Stop":"100677377","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":965878,"rule_based_match":true,"evidence_text":"c.229G>A, p.(Gly77Arg)","llm_judgment":"PRESENT","evidence":"c.229G>A, p.(Gly77Arg)","abstract_start":793,"abstract_end":815}]}
{"pmid":"23829229","title":"Novel c.191C>G (p.Pro64Arg) MPV17 mutation identified in two pairs of unrelated Polish siblings with mitochondrial hepatoencephalopathy.","abstract":"This study reports clinical, biochemical and histopathological findings associated with a novel homozygous MPV17 mutation in four patients with mitochondrial depletion syndrome. The severe course of the disease, which started in the first weeks of life, was dominated by a failure to thrive, hypotonia and liver dysfunction, with relatively mild neurological involvement. All affected infants died by 1 year of age. Laboratory findings included progressive liver failure (hypertransaminasaemia, icterus, and coagulopathy), recurrent hypoglycaemia, lactic acidaemia, hyperferritinaemia, and increased transferrin saturation. Histological and ultrastructural analyses uncovered significant lipid accumulation in hepatocytes and myocytes. A severe decrease in the mitochondrial/nuclear DNA (mtDNA/nDNA) ratio was found post-mortem in the livers (and in one muscle specimen) of both examined patients. Oxidative phosphorylation system (OXPHOS) Western blotting revealed low levels of complexes I, III and IV subunits. The highlights of our findings are as follows: (i) The novel p.Pro64Arg mutation is the second recurrent MPV17 mutation reported. The phenotype associated with the p.Pro64Arg mutation differs from the phenotype of the relatively common p.Arg50Gln mutation, suggesting the existence of a genotype-phenotype correlation. (ii) Tissues collected from patients during autopsy may be useful for both mtDNA/nDNA ratio assessment and OXPHOS Western blotting.","variants":[{"Name":"NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)","Chromosome":"2","Start":"27312768","Stop":"27312768","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":366592,"rule_based_match":true,"evidence_text":"NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)","llm_judgment":"PRESENT","evidence":"p.Pro64Arg","abstract_start":1075,"abstract_end":1085}]}
{"pmid":"33473208","title":"A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy.","abstract":"PURPOSE: Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation.\nMETHODS: Exome sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts.\nRESULTS: The variant (c.344T>A; p.V115E) is rare and alters a conserved residue in UFSP2. Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation. Reconstituting patient-derived fibroblasts with wild-type UFSP2 reduced UFMylation marks. Analysis of UFSP2's structure indicated that variants observed in skeletal disorders localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved in substrate binding.\nCONCLUSION: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.","variants":[{"Name":"NM_018359.5(UFSP2):c.344T>A (p.Val115Glu)","Chromosome":"4","Start":"185415857","Stop":"185415857","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":921245,"rule_based_match":true,"evidence_text":"c.344T>A; p.V115E","llm_judgment":"PRESENT","evidence":"c.344T>A; p.V115E","abstract_start":826,"abstract_end":843}]}
{"pmid":"29181157","title":"Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene.","abstract":"Autosomal dominant optic atrophy (DOA) is the most frequent form of hereditary optic atrophy, a disease presenting with considerable inter- and intra-familial clinical variability. Although a number of mutations in different genes are now known to cause DOA, many cases remain undiagnosed. In an attempt to identify the underlying genetic defect, whole exome sequencing was performed in a 19-year-old male that had been affected by isolated DOA since childhood. The exome sequencing revealed a pathogenic mutation (p.R468C, c.1402C>T) in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene, a gene known to be associated with spinocerebellar ataxia. The patient did not show any signs other than DOA. Thus, the result demonstrates the possibility that mutations in the AFG3L2 gene may be a cause of isolated autosomal DOA.","variants":[{"Name":"NM_006796.3(AFG3L2):c.1402C>T (p.Arg468Cys)","Chromosome":"18","Start":"12351330","Stop":"12351330","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":556459,"rule_based_match":true,"evidence_text":"c.1402C>T (p.Arg468Cys)","llm_judgment":"PRESENT","evidence":"c.1402C>T","abstract_start":524,"abstract_end":533}]}
{"pmid":"32851286","title":"Variant analysis of the chromodomain helicase DNA-binding protein 7 in pediatric disorders of sex development.","abstract":"IMPORTANCE: This study investigated the role of the chromodomain helicase DNA-binding protein 7 (<i>CHD7</i>) in disorders of sex development (DSD).\nOBJECTIVE: We aimed to present the potential pathogenicity of <i>CHD7</i> variants in pediatric patients with DSD.\nMETHODS: Choosing cases with <i>CHD7</i> variants from DSD patients in Beijing Children's Hospital to assess for the study. Prediction software tools were used to predict variant pathogenicity in these subjects.\nRESULTS: Among the 113 DSD patients, 22 cases had <i>CHD7</i> variants. Twenty-four different <i>CHD7</i> variants were identified in the 22 DSD patients. Prediction software combined with ClinVar database information and their clinical manifestations revealed that, of the 18 patients with 46, XY DSD, two had CHARGE syndrome and two had Kallmann syndrome. Seven of the variants were highly categorized as \"likely to be pathogenic\" and seven as \"suspected to be pathogenic\". Of the four patients with 46, XX DSD, three had ovotesticular DSD (c.305A>G, c.2788G>A, and c.3098G>A) and one had testicular DSD (c.2831G>A).\nINTERPRETATION: A high frequency of <i>CHD7</i> variants was found in the DSD patients, especially those with 46, XY DSD. Thus, the detection of a pathogenic <i>CHD7</i> variant could suggest a diagnosis of hypogonadotropic hypogonadism for 46, XY DSD patients, but pre-pubescent patients should be reassessed in adolescence to confirm this diagnosis. This study also suggests that DNA sequencing could help to identify pre-pubescent DSD patients. Further data are required to determine the connection between <i>CHD7</i> variants and sex-reversal in patients with 46, XX DSD, and the accumulation of these data is essential and necessary for DSD research.","variants":[{"Name":"NM_017780.4(CHD7):c.2831G>A (p.Arg944His)","Chromosome":"8","Start":"60821923","Stop":"60821923","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":240393,"rule_based_match":true,"evidence_text":"c.2831G>A","llm_judgment":"PRESENT","evidence":"c.2831G>A","abstract_start":1083,"abstract_end":1092}]}
{"pmid":"25856303","title":"Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.","abstract":"CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G>T, p.Lys250Asn) missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.","variants":[{"Name":"NM_004055.5(CAPN5):c.750G>T (p.Lys250Asn)","Chromosome":"11","Start":"77115445","Stop":"77115445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1047531,"rule_based_match":true,"evidence_text":"c.750G>T (p.Lys250Asn)","llm_judgment":"PRESENT","evidence":"p.Lys250Asn","abstract_start":731,"abstract_end":742}]}
{"pmid":"30744660","title":"The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy.","abstract":"BACKGROUND: The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.\nRESULTS: In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.\nCONCLUSIONS: With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.","variants":[{"Name":"NM_006009.4(TUBA1A):c.641G>A (p.Arg214His)","Chromosome":"12","Start":"49185725","Stop":"49185725","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359970,"rule_based_match":true,"evidence_text":"c.641G > A, p.(Arg214His)","llm_judgment":"PRESENT","evidence":"c.641G > A, p.(Arg214His)","abstract_start":510,"abstract_end":535},{"Name":"NM_006009.4(TUBA1A):c.1307G>A (p.Gly436Asp)","Chromosome":"12","Start":"49185059","Stop":"49185059","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":613777,"rule_based_match":true,"evidence_text":"c.1307G > A, p.(Gly436Asp)","llm_judgment":"PRESENT","evidence":"c.1307G > A, p.(Gly436Asp)","abstract_start":417,"abstract_end":443},{"Name":"NM_006009.4(TUBA1A):c.518C>T (p.Pro173Leu)","Chromosome":"12","Start":"49185848","Stop":"49185848","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":613801,"rule_based_match":true,"evidence_text":"c.518C > T, p.(Pro173Leu)","llm_judgment":"PRESENT","evidence":"c.518C > T, p.(Pro173Leu)","abstract_start":480,"abstract_end":505}]}
{"pmid":"23043934","title":"Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia.","abstract":"Monogenic hypobetalipoproteinemias include three disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) with recessive transmission and familial hypobetalipoproteinemia (FHBL) with dominant transmission. We investigated three unrelated Tunisian children born from consanguineous marriages, presenting hypobetalipoproteinemia associated with chronic diarrhea and retarded growth. Proband HBL-108 had a moderate hypobetalipoproteinemia, apparently transmitted as dominant trait, suggesting the diagnosis of FHBL. However, she had no mutations in FHBL candidate genes (APOB, PCSK9 and ANGPTL3). The analysis of MTTP gene was also negative, whereas SAR1B gene resequencing showed that the patient was homozygous for a novel mutation (c.184G>A), resulting in an amino acid substitution (p.Glu62Lys), located in a conserved region of Sar1b protein. In the HBL-103 and HBL-148 probands, the severity of hypobetalipoproteinemia and its recessive transmission suggested the diagnosis of ABL. The MTTP gene resequencing showed that probands HBL-103 and HBL-148 were homozygous for a nucleotide substitution in the donor splice site of intron 9 (c.1236+2T>G) and intron 16 (c.2342+1G>A) respectively. Both mutations were predicted in silico to abolish the function of the splice site. In vitro functional assay with splicing mutation reporter MTTP minigenes showed that the intron 9 mutation caused the skipping of exon 9, while the intron 16 mutation caused a partial retention of this intron in the mature mRNA. The predicted translation products of these mRNAs are non-functional truncated proteins. The diagnosis of ABL and CMRD should be considered in children born from consanguineous parents, presenting chronic diarrhea associated with hypobetalipoproteinemia.","variants":[{"Name":"NM_016103.4(SAR1B):c.184G>A (p.Glu62Lys)","Chromosome":"5","Start":"134612751","Stop":"134612751","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1483787,"rule_based_match":true,"evidence_text":"c.184G>A","llm_judgment":"PRESENT","evidence":"c.184G>A","abstract_start":754,"abstract_end":762},{"Name":"NM_001386140.1(MTTP):c.2342+1G>A","Chromosome":"4","Start":"99619099","Stop":"99619099","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2418819,"rule_based_match":true,"evidence_text":"c.2342+1G>A","llm_judgment":"PRESENT","evidence":"c.2342+1G>A","abstract_start":1187,"abstract_end":1198}]}
{"pmid":"21524769","title":"Hyperferritinemia, ferropenia and metabolic syndrome in a patient with a new mutation of gene TFR2 and another in gene FTL. A family study","abstract":"BACKGROUND AND OBJECTIVES: Hyperferritinemia is a common finding in clinical practice. This condition can be congenital or acquired, although it is not always associated with iron overload. Genetic hyperferritinemia is associated with iron overload, hereditary hemochromatosis, or cataracts that progress without iron overload (hereditary hyperferritinemia-cataract syndrome). Metabolic syndrome is associated with hyperferritinemia and mild iron overload, with no increase in transferrin saturation. We report a family with hyperferritinemia.\nPATIENTS AND METHODS: We present the study of a family with dual hyperferritinemia (congenital and acquired) and an analysis of the genes involved in iron metabolism.\nRESULTS: Patients with hereditary hyperferritinemia-cataract syndrome have the mutation c.-167C>T in the FTL gene; patients with metabolic syndrome present a new mutation in the TFR2 gene (c.1259G>A, p.Arg420His).\nCONCLUSIONS: The phenotypic and genotypic diversity of hyperferritinemia makes it a diagnostic challenge for clinicians. Basic research and clinical research should be combined to ensure better patient care.","variants":[{"Name":"NM_003227.4(TFR2):c.1259G>A (p.Arg420His)","Chromosome":"7","Start":"100630900","Stop":"100630900","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":897046,"rule_based_match":true,"evidence_text":"c.1259G>A, p.Arg420His","llm_judgment":"PRESENT","evidence":"c.1259G>A, p.Arg420His","abstract_start":900,"abstract_end":922}]}
{"pmid":"26098624","title":"Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.","abstract":"This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.","variants":[{"Name":"NM_170707.4(LMNA):c.91G>A (p.Glu31Lys)","Chromosome":"1","Start":"156115009","Stop":"156115009","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":556955,"rule_based_match":true,"evidence_text":"c.91G>A","llm_judgment":"PRESENT","evidence":"c.91G>A","abstract_start":970,"abstract_end":977},{"Name":"NM_170707.4(LMNA):c.1580G>C (p.Arg527Pro)","Chromosome":"1","Start":"156137204","Stop":"156137204","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":29520,"rule_based_match":true,"evidence_text":"c.1580G>C","llm_judgment":"PRESENT","evidence":"c.1580G>C","abstract_start":1028,"abstract_end":1037},{"Name":"NM_170707.4(LMNA):c.116A>G (p.Asn39Ser)","Chromosome":"1","Start":"156115034","Stop":"156115034","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":77688,"rule_based_match":true,"evidence_text":"c.116A>G","llm_judgment":"PRESENT","evidence":"c.116A>G","abstract_start":994,"abstract_end":1002},{"Name":"NM_170707.4(LMNA):c.745C>T (p.Arg249Trp)","Chromosome":"1","Start":"156134910","Stop":"156134910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29563,"rule_based_match":true,"evidence_text":"c.745C>T","llm_judgment":"PRESENT","evidence":"c.745C>T","abstract_start":1004,"abstract_end":1012}]}
{"pmid":"30633606","title":"Exon skipping in CYBB mRNA and skewed inactivation of X chromosome cause late-onset chronic granulomatous disease.","abstract":"Chronic granulomatous disease (CGD) is a hereditary immunodeficiency syndrome caused by a defect in the NADPH oxidase complex, which is essential for bactericidal function of phagocytes. Approximately 70% of patients with CGD have a mutation in the CYBB gene on the X chromosome, resulting in defective expression of gp91<sup>phox</sup>, one of the membrane-bound subunits of NADPH oxidase. Although most patients with X-linked CGD are males, owing to transmission of this disease as an X-linked recessive trait, there are female patients with X-linked CGD. Here, we report the case of a teenage girl with X-linked CGD associated with a heterozygous mutation in exon 5 of the CYBB gene (c.389G > C; R130P), which causes skipping of exon 5, resulting in a premature stop codon in exon 6 of CYBB. Accurate pro-mRNA splicing for mature mRNA formation is regulated by several splicing mechanisms that are essential for appropriate recognition of exonic sequences. The c.389G > C mutation disrupts exonic-splicing regulator sequences, thereby resulting in the aberrant skipping of exon 5 in the CYBB transcript of the patient. The patient showed an extremely skewed (≥96%) X inactivation pattern of the HUMARA locus; this inactivation is thought to be responsible for the development of CGD not only in neutrophils but also in monocytic, T-cell, and B-cell lineages and in CD34-positive immature hematopoietic cells. Our case and other reports indicate that the onset of X-linked CGD in female patients tends to occur later in life, and that the symptoms tend to be milder as compared to male patients.","variants":[{"Name":"NM_000397.4(CYBB):c.389G>C (p.Arg130Pro)","Chromosome":"X","Start":"37793716","Stop":"37793716","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":44636,"rule_based_match":true,"evidence_text":"c.389G > C","llm_judgment":"PRESENT","evidence":"c.389G > C","abstract_start":687,"abstract_end":697}]}
{"pmid":"21552498","title":"A novel mutation in the GJA3 (connexin46) gene is associated with autosomal dominant congenital nuclear cataract in a Chinese family.","abstract":"PURPOSE: Congenital cataract is both a clinically and genetically heterogeneous lens disorder. The purpose of this study is to map and identify the mutation in an autosomal dominant congenital nuclear cataract in a Chinese family.\nMETHODS: Patients were given physical examinations and their blood samples were collected for DNA extraction. Genotyping was performed by microsatellite markers and logarithm of odds (LOD) scores were calculated using the LINKAGE programs. Mutation detection was performed by direct sequencing.\nRESULTS: Linkage to the gap-junction protein α3 (GJA3) locus was verified. Sequencing of GJA3 revealed a G>A transition at nucleotide position c.139, which causes an Asn substitution for the conservative Asp at codon 47 (P.D47N).This mutation is identified in all affected individuals but is not found in 100 control chromosomes.\nCONCLUSIONS: Our results identify that the mutation (D47N) in GJA3 is responsible for this Chinese pedigree. It is further identified that GJA3 is responsible for congenital cataract. In our study, the novel mutation broadens the spectrum of GJA3 mutations.","variants":[{"Name":"NM_021954.4(GJA3):c.139G>A (p.Asp47Asn)","Chromosome":"13","Start":"20143150","Stop":"20143150","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3412471,"rule_based_match":false,"evidence_text":"c.139G>A (p.Asp47Asn)","llm_judgment":"PRESENT","evidence":"D47N","abstract_start":749,"abstract_end":753}]}
{"pmid":"30120606","title":"Candidate gene sequencing reveals mutations causing hypoplastic amelogenesis imperfecta.","abstract":"OBJECTIVE: Amelogenesis imperfecta (AI) is a rare hereditary disorder affecting the quality and quantity of the tooth enamel. The purpose of this study was to identify the genetic etiology of hypoplastic AI families based on the candidate gene approach.\nMATERIALS AND METHODS: We recruited three Turkish families with hypoplastic AI and performed a candidate gene screening based on the characteristic clinical feature to find the pathogenic genetic etiology.\nRESULTS: The candidate gene sequencing of the LAMB3 gene for family 1 revealed a heterozygous nonsense mutation in the last exon [c.3431C > A, p.(Ser1144*)]. FAM20A gene sequencing for families 2 and 3 identified a homozygous deletion [c.34_35delCT, p.(Leu12Alafs*67)] and a homozygous deletion-insertion (c.1109 + 3_1109 + 7delinsTGGTC) mutation, respectively.\nCONCLUSION: The candidate gene approach can be successfully used to identify the genetic etiology of the AI in some cases with characteristic clinical features.\nCLINICAL RELEVANCE: Identification of the genetic etiology of the AI will help both the family members and dentist understand the nature of the disorder. Characteristic clinical feature can suggest possible genetic causes.","variants":[{"Name":"NM_017565.4(FAM20A):c.1109+3_1109+7delinsTGGTC","Chromosome":"17","Start":"68541978","Stop":"68541982","ReferenceAlleleVCF":"AACTC","AlternateAlleleVCF":"GACCA","allel_id":1683901,"rule_based_match":true,"evidence_text":"c.1109 + 3_1109 + 7delinsTGGTC","llm_judgment":"PRESENT","evidence":"c.1109 + 3_1109 + 7delinsTGGTC","abstract_start":766,"abstract_end":796}]}
{"pmid":"28259707","title":"Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS.","abstract":"PURPOSE: Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder with ten reported genetic types; each type has defects in subunits of either Adaptor Protein-3 complex or Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2, or -3. Very few patients with BLOC-1 deficiency (HPS-7, -8, and -9 types) have been diagnosed. We report results of comprehensive clinical testing and molecular analyses of primary fibroblasts from a new case of HPS-7.\nRESULTS: A 6-year old Paraguayan male presented with hypopigmentation, ocular albinism, nystagmus, reduced visual acuity, and easy bruising. He also experienced delayed motor and language development as a very young child; head and chest trauma resulted in intracranial hemorrhage with subsequent right hemiparesis and lung scarring. There was no clinical evidence of immunodeficiency or colitis. Whole mount transmission electron microscopy revealed absent platelet delta granules; platelet aggregation testing was abnormal. Exome sequencing revealed a homozygous nonsense mutation in the Dystrobrevin binding protein 1 (DTNBP1) gene [NM_032122.4: c.307C>T; p.Gln103*], previously reported in a Portuguese adult. The gene encodes the dysbindin subunit of BLOC-1. Dysbindin protein expression was negligible in our patient's dermal fibroblasts, while his DTNBP1 mRNA level was similar to that of a normal control.\nCONCLUSIONS: Comprehensive clinical evaluation of the first pediatric case reported with HPS-7 reveals oculocutaneous albinism and platelet storage pool deficiency; his phenotype is consistent with findings in other patients with BLOC-1 disorders. This patient's markedly reduced Dysbindin protein expression in HPS-7 resulted from a mechanism other than nonsense mediated decay.","variants":[{"Name":"NM_032122.5(DTNBP1):c.307C>T (p.Gln103Ter)","Chromosome":"6","Start":"15627391","Stop":"15627391","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18471,"rule_based_match":true,"evidence_text":"NM_032122.4: c.307C>T; p.Gln103*","llm_judgment":"PRESENT","evidence":"NM_032122.4: c.307C>T; p.Gln103*","abstract_start":1095,"abstract_end":1127}]}
{"pmid":"32126153","title":"AG-exclusion zone revisited: Lessons to learn from 91 intronic NF1 3' splice site mutations outside the canonical AG-dinucleotides.","abstract":"Uncovering frequent motives of action by which variants impair 3' splice site (3'ss) recognition and selection is essential to improve our understanding of this complex process. Through several mini-gene experiments, we demonstrate that the pyrimidine (Y) to purine (R) transversion NM_000267.3(NF1):c.1722-11T>G, although expected to weaken the polypyrimidine tract, causes exon skipping primarily by introducing a novel AG in the AG-exclusion zone (AGEZ) between the authentic 3'ss AG and the branch point. Evaluation of 90 additional noncanonical intronic NF1 3'ss mutations confirmed that 63% of all mutations and 89% (49/55) of the single-nucleotide variants upstream of positions -3 interrupt the AGEZ. Of these AGEZ-interrupting mutations, 24/49 lead to exon skipping suggesting that absence of AG in this region is necessary for accurate 3'ss selection already in the initial steps of splicing. The analysis of 91 noncanonical NF1 3'ss mutations also shows that 90% either introduce a novel AG in the AGEZ, cause a Y>R transversion at position -3 or remove ≥2 Ys in the AGEZ. We confirm in a validation cohort that these three motives distinguish spliceogenic from splice-neutral variants with 85% accuracy and, therefore, are generally applicable to select among variants of unknown significance those likely to affect splicing.","variants":[{"Name":"NM_001042492.3(NF1):c.1722-11T>G","Chromosome":"17","Start":"31223433","Stop":"31223433","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":861165,"rule_based_match":true,"evidence_text":"NM_000267.3(NF1):c.1722-11T>G","llm_judgment":"PRESENT","evidence":"NM_000267.3(NF1):c.1722-11T>G","abstract_start":283,"abstract_end":312}]}
{"pmid":"35691949","title":"A novel nonsense PKD1L1 variant cause heterotaxy syndrome with congenital asplenia in a Han Chinese patient.","abstract":"Heterotaxy syndrome is a very rare congenital disease, which is caused by the disorder of left-right asymmetry during visceral development. However, pathogenic genetic lesions are found in less than 20% of HS patients. In this cohort study, whole-exome sequencing was performed for 110 patients with situs inversus or situs ambiguous. We identified a novel nonsense variant in PKD1L1(c.1387 C > T; p.463Gln*) in a Chinese patient with heterotaxy syndrome and congenital asplenia. This homozygous variant caused the domain of PKD1L1 complete absence. To our knowledge, this novel variant is the first phenotype of congenital asplenia found in patients with PKD1L1 variants, and the first PKD1L1 variant found in China. Our findings expand the spectrum of PKD1L1 variants and provide support for PKD1L1 variant and congenital asplenia, and the critical role of PKD1L1 during left-right patterning in the Han Chinese population.","variants":[{"Name":"NM_138295.5(PKD1L1):c.1387C>T (p.Gln463Ter)","Chromosome":"7","Start":"47908092","Stop":"47908092","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2524704,"rule_based_match":true,"evidence_text":"c.1387 C > T; p.463Gln*","llm_judgment":"PRESENT","evidence":"c.1387 C > T; p.463Gln*","abstract_start":384,"abstract_end":407}]}
{"pmid":"23709298","title":"A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma.","abstract":"UNLABELLED: Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene.\nIMPLICATIONS: BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.","variants":[{"Name":"NM_004656.4(BAP1):c.41T>A (p.Leu14His)","Chromosome":"3","Start":"52409740","Stop":"52409740","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1347692,"rule_based_match":true,"evidence_text":"c.41T>A; p.L14H","llm_judgment":"PRESENT","evidence":"c.41T>A; p.L14H","abstract_start":767,"abstract_end":782}]}
{"pmid":"28841907","title":"A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature.","abstract":"BACKGROUND: Stickler syndrome is a group of collagenopathies characterized by ophthalmic, skeletal, and orofacial abnormalities, with the degree of symptoms varying among patients. Mutations in the COL2A1, COL11A1, and COL11A2 procollagen genes cause Stickler syndrome. Marshall syndrome, caused by a COL11A1 mutation, has clinical overlap with Stickler syndrome.\nCASE PRESENTATION: A 2-year-old Japanese boy was presented to our hospital with short stature (79.1 cm, -2.52 standard deviation). His past medical history was significant for soft cleft palate and bilateral cataracts. He had a flat midface, micrognathia, and limitations in bilateral elbow flexion. Radiographs showed mild spondyloepiphyseal dysplasia. Initially, we suspected Marshall syndrome, but no mutation was identified in COL11A1. At 8 years old, his height was 116.2 cm (-1.89 standard deviation), and his orofacial characteristics appeared unremarkable. We analyzed the COL2A1 gene and found a novel heterozygous mutation (c.1142 G > A, p.Gly381Asp).\nCONCLUSIONS: In this case report, we identify a novel missense mutation in the COL2A1 gene in a patient with Stickler syndrome type 1, and we describe age-related changes in the clinical phenotype with regard to orofacial characteristics and height. Genetic analysis is helpful for the diagnosis of this clinically variable and genetically heterogeneous disorder.","variants":[{"Name":"NM_001844.5(COL2A1):c.1142G>A (p.Gly381Asp)","Chromosome":"12","Start":"47987690","Stop":"47987690","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1062638,"rule_based_match":true,"evidence_text":"c.1142 G > A, p.Gly381Asp","llm_judgment":"PRESENT","evidence":"c.1142 G > A, p.Gly381Asp","abstract_start":998,"abstract_end":1023}]}
{"pmid":"26359340","title":"The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy.","abstract":"BACKGROUND: Conorenal syndrome is a systemic skeletal ciliopathy characterised by skeletal and renal findings and caused by biallelic mutations in the gene intraflagellar transport 140 Chlamydomonas homologue (IFT140). Most studies have focused on syndromic features and are by non-ophthalmologists. We highlight the ophthalmic phenotype.\nMETHODS: Retrospective consecutive case series (2010-2014).\nRESULTS: Twelve subjects with confirmed homozygous mutations were identified (11 consanguineous families; 7 boys; assessed at age 10 months to 20 years, average and median age 6.5 and 4 years). All were homozygous for the same IFT140 mutation (c.1990G>A; p.Glu664Lys) except one who was homozygous for c.1541_1542delinsAA. All had poor vision and nystagmus since birth, with visual acuity after 5 years old of hand motions or light perception. In early childhood, nine were noted to stare at lights, four were noted to have a happy demeanour, high hyperopia was typical, and electroretinography was non-recordable. Fundus appearance was grossly normal before the age of 1 year but thereafter appeared dystrophic. Eight children had developmental delay, two had short stubby fingers, and one had renal disease, but four had no evident extraocular disease, including one aged 18 years who also had two older affected siblings in their twenties who remained non-syndromic and were excelling academically.\nCONCLUSIONS: Recessive IFT140 mutations cause a severe congenital retinal dystrophy with high hyperopia and often early photophilia. Developmental delay is common but not universal and not all patients have obvious extraocular findings. The c.1990G>A mutation represents a founder effect or mutational hotspot on the Arabian Peninsula.","variants":[{"Name":"NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys)","Chromosome":"16","Start":"1564074","Stop":"1564074","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40341,"rule_based_match":true,"evidence_text":"c.1990G>A; p.Glu664Lys","llm_judgment":"PRESENT","evidence":"c.1990G>A; p.Glu664Lys","abstract_start":643,"abstract_end":665}]}
{"pmid":"32549991","title":"Unusual context of","abstract":"Primary microcephaly (MCPH) is a genetically heterogeneous disorder showing an autosomal recessive mode of inheritance. Patients with MCPH present head circumference values two or three standard deviations (SDs) significantly below the mean for age- and sex-matched populations. MCPH is associated with a nonprogressive mild to severe intellectual disability, with normal brain structure in most patients, or with a small brain and gyri without visceral malformations. We present the case of an adult patient born from Argentinian nonconsanguineous healthy parents. He had a head circumference >5 SD below the mean, cerebral neuroimaging showing hypoplasia of the corpus callosum, bilateral migration disorder with heterotopia of the sylvian fissure and colpocephaly. The patient was compound heterozygous for pathogenic variants in the <i>CENPJ</i> gene (c.289dupA inherited from his mother and c.1132 C > T inherited from his father). Our patient represents an uncommon situation for the usual known context of <i>CENPJ</i> and MCPH, including family origin (Argentinian), pedigree (nonconsanguineous), and genotype (a compound heterozygous case with two variants predicting a truncated protein). Next-generation sequencing studies applied in a broader spectrum of clinical presentations of MCPH syndromes may discover additional similar patients and families.","variants":[{"Name":"NM_018451.5(CENPJ):c.1132C>T (p.Arg378Ter)","Chromosome":"13","Start":"24906906","Stop":"24906906","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":495314,"rule_based_match":true,"evidence_text":"c.1132 C > T","llm_judgment":"PRESENT","evidence":"c.1132 C > T","abstract_start":896,"abstract_end":908}]}
{"pmid":"34161333","title":"X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3.","abstract":"The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.","variants":[{"Name":"NM_007325.5(GRIA3):c.1979G>C (p.Arg660Thr)","Chromosome":"X","Start":"123428042","Stop":"123428042","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1289397,"rule_based_match":true,"evidence_text":"c.1979G>C; p. R660T","llm_judgment":"PRESENT","evidence":"c.1979G>C; p. R660T","abstract_start":284,"abstract_end":303}]}
{"pmid":"28791129","title":"A novel","abstract":"The tubulin beta-4A gene (<i>TUBB4A</i>) is associated with two different clinical conditions, dystonia type 4 (DYT4) and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). We identified a novel <i>TUBB4A</i> mutation, c.286G>A (p.G96R), in an adult male patient who suffered neurological symptoms beyond adolescence. This patient shows intermediate clinical features between DYT4 and H-ABC, suggesting that the <i>TUBB4A</i> disorder would constitute a spectrum disorder.","variants":[{"Name":"NM_006087.4(TUBB4A):c.286G>A (p.Gly96Arg)","Chromosome":"19","Start":"6496213","Stop":"6496213","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":422301,"rule_based_match":true,"evidence_text":"c.286G>A (p.G96R)","llm_judgment":"PRESENT","evidence":"c.286G>A (p.G96R)","abstract_start":242,"abstract_end":259}]}
{"pmid":"20861472","title":"Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavalpha1S-subunit.","abstract":"To identify the genetic locus responsible for malignant hyperthermia susceptibility (MHS) in an Italian family, we performed linkage analysis to recognized MHS loci. All MHS individuals showed cosegregation of informative markers close to the voltage-dependent Ca(2+) channel (Ca(V)) α(1S)-subunit gene (CACNA1S) with logarithm of odds (LOD)-score values that matched or approached the maximal possible value for this family. This is particularly interesting, because so far MHS was mapped to >178 different positions on the ryanodine receptor (RYR1) gene but only to two on CACNA1S. Sequence analysis of CACNA1S revealed a c.4060A>T transversion resulting in amino acid exchange T1354S in the IVS5-S6 extracellular pore-loop region of Ca(V)α(1S) in all MHS subjects of the family but not in 268 control subjects. To investigate the impact of mutation T1354S on the assembly and function of the excitation-contraction coupling apparatus, we expressed GFP-tagged α(1S)T1354S in dysgenic (α(1S)-null) myotubes. Whole cell patch-clamp analysis revealed that α(1S)T1354S produced significantly faster activation of L-type Ca(2+) currents upon 200-ms depolarizing test pulses compared with wild-type GFP-α(1S) (α(1S)WT). In addition, α(1S)T1354S-expressing myotubes showed a tendency to increased sensitivity for caffeine-induced Ca(2+) release and to larger action-potential-induced intracellular Ca(2+) transients under low (≤ 2 mM) caffeine concentrations compared with α(1S)WT. Thus our data suggest that an additional influx of Ca(2+) due to faster activation of the α(1S)T1354S L-type Ca(2+) current, in concert with higher caffeine sensitivity of Ca(2+) release, leads to elevated muscle contraction under pharmacological trigger, which might be sufficient to explain the MHS phenotype.","variants":[{"Name":"NM_000069.3(CACNA1S):c.4060A>T (p.Thr1354Ser)","Chromosome":"1","Start":"201051037","Stop":"201051037","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":171056,"rule_based_match":true,"evidence_text":"c.4060A>T","llm_judgment":"PRESENT","evidence":"c.4060A>T","abstract_start":624,"abstract_end":633}]}
{"pmid":"33836713","title":"Targeted next generation sequencing and family survey enable correct genetic diagnosis in CRX associated macular dystrophy - a case report.","abstract":"BACKGROUND: We present 3 members of a family with macular dystrophy, originally diagnosed as Stargardt disease, with a significantly variable age at onset, caused by a heterozygous mutation in CRX.\nCASE PRESENTATION: A 43-year-old female with bull's eye maculopathy, whose sister was diagnosed with Stargardt disease previously at another centre, was found to have a single ABCA4 variant. Further examination of the family revealed that the asymptomatic father was also affected, indicating a dominant pattern of inheritance. In addition, the ABCA4 variant was not identified in the sister originally diagnosed with Stargardt disease. Next generation sequencing identified a heterozygous c.121C > T, p.R41W missense mutation in CRX in all 3 affected members.\nCONCLUSIONS: We describe a common phenotype, but with variable age at onset, with autosomal dominant inheritance and reduced penetrance in a family found to have a pathogenic sequence variant in CRX. This illustrates the importance of panel based molecular genetic testing accompanied by family studies to establish a definitive diagnosis.","variants":[{"Name":"NM_000554.6(CRX):c.121C>T (p.Arg41Trp)","Chromosome":"19","Start":"47836263","Stop":"47836263","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22457,"rule_based_match":true,"evidence_text":"c.121C > T, p.R41W","llm_judgment":"PRESENT","evidence":"c.121C > T, p.R41W","abstract_start":688,"abstract_end":706}]}
{"pmid":"28339459","title":"Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18.","abstract":"Mutation screening of the breast cancer genes BRCA1 and BRCA2 identifies a large fraction of variants of uncertain clinical significance (VUS) whose functional and clinical interpretations pose a challenge for genomic medicine. Likewise, an increasing amount of evidence indicates that genetic variants can have deleterious effects on pre-mRNA splicing. Our goal was to investigate the impact on splicing of a set of reported variants of BRCA2 exons 17 and 18 to assess their role in hereditary breast cancer and to identify critical regulatory elements that may constitute hotspots for spliceogenic variants. A splicing reporter minigene with BRCA2 exons 14 to-20 (MGBR2_ex14-20) was constructed in the pSAD vector. Fifty-two candidate variants were selected with splicing prediction programs, introduced in MGBR2_ex14-20 by site-directed mutagenesis and assayed in triplicate in MCF-7 cells. Wild type MGBR2_ex14-20 produced a stable transcript of the expected size (1,806 nucleotides) and structure (V1-[BRCA2_exons_14-20]-V2). Functional mapping by microdeletions revealed essential sequences for exon recognition on the 3' end of exon 17 (c.7944-7973) and the 5' end of exon 18 (c.7979-7988, c.7999-8013). Thirty out of the 52 selected variants induced anomalous splicing in minigene assays with >16 different aberrant transcripts, where exon skipping was the most common event. A wide range of splicing motifs were affected including the canonical splice sites (15 variants), novel alternative sites (3 variants), the polypyrimidine tract (3 variants) and enhancers/silencers (9 variants). According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), 20 variants could be classified as pathogenic (c.7806-2A>G, c.7806-1G>A, c.7806-1G>T, c.7806-1_7806-2dup, c.7976+1G>A, c.7977-3_7978del, c.7977-2A>T, c.7977-1G>T, c.7977-1G>C, c.8009C>A, c.8331+1G>T and c.8331+2T>C) or likely pathogenic (c.7806-9T>G, c.7976G>C, c.7976G>A, c.7977-7C>G, c.7985C>G, c.8023A>G, c.8035G>T and c.8331G>A), accounting for 30.8% of all pathogenic/likely pathogenic variants of exons 17-18 at the BRCA Share database. The remaining 8 variants (c.7975A>G, c.7977-6T>G, c.7988A>T, c.7992T>A, c.8007A>G, c.8009C>T, c.8009C>G, and c.8072C>T) induced partial splicing anomalies with important ratios of the full-length transcript (≥70%), so that they remained classified as VUS. Aberrant splicing is therefore especially prevalent in BRCA2 exons 17 and 18 due to the presence of active ESEs involved in exon recognition. Splicing functional assays with minigenes are a valuable strategy for the initial characterization of the splicing outcomes and the subsequent clinical interpretation of variants of any disease-gene, although these results should be checked, whenever possible, against patient RNA.","variants":[{"Name":"NM_000059.4(BRCA2):c.7806-1G>T","Chromosome":"13","Start":"32362522","Stop":"32362522","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":67085,"rule_based_match":true,"evidence_text":"c.7806-1G>T","llm_judgment":"PRESENT","evidence":"c.7806-1G>T","abstract_start":1762,"abstract_end":1773},{"Name":"NM_000059.4(BRCA2):c.7806-2A>G","Chromosome":"13","Start":"32362521","Stop":"32362521","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":67086,"rule_based_match":true,"evidence_text":"c.7806-2A>G","llm_judgment":"PRESENT","evidence":"c.7806-2A>G","abstract_start":1736,"abstract_end":1747},{"Name":"NM_000059.4(BRCA2):c.7806-9T>G","Chromosome":"13","Start":"32362514","Stop":"32362514","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":67088,"rule_based_match":true,"evidence_text":"c.7806-9T>G","llm_judgment":"PRESENT","evidence":"c.7806-9T>G","abstract_start":1927,"abstract_end":1938},{"Name":"NM_000059.4(BRCA2):c.8331+1G>T","Chromosome":"13","Start":"32363534","Stop":"32363534","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":67218,"rule_based_match":true,"evidence_text":"c.8331+1G>T","llm_judgment":"PRESENT","evidence":"c.8331+1G>T","abstract_start":1876,"abstract_end":1887},{"Name":"NM_000059.4(BRCA2):c.8331G>A (p.Lys2777=)","Chromosome":"13","Start":"32363533","Stop":"32363533","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67220,"rule_based_match":true,"evidence_text":"c.8331G>A","llm_judgment":"PRESENT","evidence":"c.8331G>A","abstract_start":2011,"abstract_end":2020},{"Name":"NM_000059.4(BRCA2):c.7977-6T>G","Chromosome":"13","Start":"32363173","Stop":"32363173","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1506452,"rule_based_match":true,"evidence_text":"c.7977-6T>G","llm_judgment":"PRESENT","evidence":"c.7977-6T>G","abstract_start":2169,"abstract_end":2180},{"Name":"NM_000059.4(BRCA2):c.8009C>G (p.Ser2670Trp)","Chromosome":"13","Start":"32363211","Stop":"32363211","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":482844,"rule_based_match":true,"evidence_text":"c.8009C>G","llm_judgment":"PRESENT","evidence":"c.8009C>G","abstract_start":2226,"abstract_end":2235},{"Name":"NM_000059.4(BRCA2):c.7976+1G>A","Chromosome":"13","Start":"32362694","Stop":"32362694","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67120,"rule_based_match":true,"evidence_text":"c.7976+1G>A","llm_judgment":"PRESENT","evidence":"c.7976+1G>A","abstract_start":1795,"abstract_end":1806},{"Name":"NM_000059.4(BRCA2):c.7977-1G>A","Chromosome":"13","Start":"32363178","Stop":"32363178","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":262840,"rule_based_match":false,"evidence_text":"c.7977-1G>A","llm_judgment":"PRESENT","evidence":"c.7977-1G>A","abstract_start":null,"abstract_end":null},{"Name":"NM_000059.4(BRCA2):c.7988A>T (p.Glu2663Val)","Chromosome":"13","Start":"32363190","Stop":"32363190","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":67130,"rule_based_match":true,"evidence_text":"c.7988A>T","llm_judgment":"PRESENT","evidence":"c.7988A>T","abstract_start":2182,"abstract_end":2191},{"Name":"NM_000059.4(BRCA2):c.8331+2T>C","Chromosome":"13","Start":"32363535","Stop":"32363535","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":262841,"rule_based_match":true,"evidence_text":"c.8331+2T>C","llm_judgment":"PRESENT","evidence":"c.8331+2T>C","abstract_start":1892,"abstract_end":1903},{"Name":"NM_000059.4(BRCA2):c.7985C>G (p.Thr2662Arg)","Chromosome":"13","Start":"32363187","Stop":"32363187","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2899000,"rule_based_match":true,"evidence_text":"c.7985C>G","llm_judgment":"PRESENT","evidence":"c.7985C>G","abstract_start":1975,"abstract_end":1984},{"Name":"NM_000059.4(BRCA2):c.8009C>A (p.Ser2670Ter)","Chromosome":"13","Start":"32363211","Stop":"32363211","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":67138,"rule_based_match":true,"evidence_text":"c.8009C>A","llm_judgment":"PRESENT","evidence":"c.8009C>A","abstract_start":1865,"abstract_end":1874},{"Name":"NM_000059.4(BRCA2):c.8009C>T (p.Ser2670Leu)","Chromosome":"13","Start":"32363211","Stop":"32363211","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67139,"rule_based_match":true,"evidence_text":"c.8009C>T","llm_judgment":"PRESENT","evidence":"c.8009C>T","abstract_start":2215,"abstract_end":2224},{"Name":"NM_000059.4(BRCA2):c.8023A>G (p.Ile2675Val)","Chromosome":"13","Start":"32363225","Stop":"32363225","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":67143,"rule_based_match":true,"evidence_text":"c.8023A>G","llm_judgment":"PRESENT","evidence":"c.8023A>G","abstract_start":1986,"abstract_end":1995},{"Name":"NM_000059.4(BRCA2):c.8035G>T (p.Asp2679Tyr)","Chromosome":"13","Start":"32363237","Stop":"32363237","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":67148,"rule_based_match":true,"evidence_text":"c.8035G>T","llm_judgment":"PRESENT","evidence":"c.8035G>T","abstract_start":1997,"abstract_end":2006},{"Name":"NM_000059.4(BRCA2):c.8007A>G (p.Arg2669=)","Chromosome":"13","Start":"32363209","Stop":"32363209","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":186455,"rule_based_match":true,"evidence_text":"c.8007A>G","llm_judgment":"PRESENT","evidence":"c.8007A>G","abstract_start":2204,"abstract_end":2213},{"Name":"NM_000059.4(BRCA2):c.7975A>G (p.Arg2659Gly)","Chromosome":"13","Start":"32362692","Stop":"32362692","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":46686,"rule_based_match":true,"evidence_text":"c.7975A>G","llm_judgment":"PRESENT","evidence":"c.7975A>G","abstract_start":2158,"abstract_end":2167},{"Name":"NM_000059.4(BRCA2):c.7976G>A (p.Arg2659Lys)","Chromosome":"13","Start":"32362693","Stop":"32362693","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46687,"rule_based_match":true,"evidence_text":"c.7976G>A","llm_judgment":"PRESENT","evidence":"c.7976G>A","abstract_start":1951,"abstract_end":1960},{"Name":"NM_000059.4(BRCA2):c.7977-1G>C","Chromosome":"13","Start":"32363178","Stop":"32363178","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":46688,"rule_based_match":true,"evidence_text":"c.7977-1G>C","llm_judgment":"PRESENT","evidence":"c.7977-1G>C","abstract_start":1852,"abstract_end":1863},{"Name":"NM_000059.4(BRCA2):c.7977-1G>T","Chromosome":"13","Start":"32363178","Stop":"32363178","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":131701,"rule_based_match":true,"evidence_text":"c.7977-1G>T","llm_judgment":"PRESENT","evidence":"c.7977-1G>T","abstract_start":1839,"abstract_end":1850},{"Name":"NM_000059.4(BRCA2):c.7806-1G>A","Chromosome":"13","Start":"32362522","Stop":"32362522","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":611321,"rule_based_match":true,"evidence_text":"c.7806-1G>A","llm_judgment":"PRESENT","evidence":"c.7806-1G>A","abstract_start":1749,"abstract_end":1760}]}
{"pmid":"32936766","title":"A New Cause of Obesity Syndrome Associated with a Mutation in the Carboxypeptidase Gene Detected in Three Siblings with Obesity, Intellectual Disability and Hypogonadotropic Hypogonadism","abstract":"Objective: Carboxypeptidase E (CPE) plays a critical role in the biosynthesis of peptide hormones and neuropeptides in the endocrine system and central nervous system. <i>CPE</i> knockout mice models exhibit disorders such as diabetes, hyperproinsulinaemia, low bone mineral density and neurodevelopmental disorders. Only one patient is described with morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotropic hypogonadism, which was associated with a homozygous frameshift deletion in <i>CPE</i>.\nMethods: Herein are described three siblings with obesity, intellectual disability and hypogonadotropic hypogonadism. Whole exome sequencing (WES) was performed in the index case. Candidate variants were prioritised and segregation of the variant, consistent with the phenotype of the index case, was assessed by Sanger sequencing in affected siblings and parents.\nResults: WES analysis revealed a homozygous nonsense c.405C>A (p.Y135*) mutation in <i>CPE</i>. Validation and segregation analysis confirmed the homozygous mutation in the index case and his affected siblings. The parents were phenotypically normal heterozygous mutation carriers.\nConclusion: This study provides additional evidence of the association between a homozygous nonsense mutation in <i>CPE</i> and a clinical phenotype consisting of obesity, intellectual disability and hypogonadotropic hypogonadism, which may be considered as a new monogenic obesity syndrome.","variants":[{"Name":"NM_001873.4(CPE):c.405C>A (p.Tyr135Ter)","Chromosome":"4","Start":"165464487","Stop":"165464487","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1086966,"rule_based_match":true,"evidence_text":"c.405C>A (p.Y135*)","llm_judgment":"PRESENT","evidence":"c.405C>A (p.Y135*)","abstract_start":949,"abstract_end":967}]}
{"pmid":"23651435","title":"Mild β(+)-thalassemia associated with two linked sequence variants: IVS-II-839 (T>C) and IVS-II-844 (C>A).","abstract":"We report four unrelated families with a mild β(+)-thalassemia (β(+)-thal) allele consisting of two sequence variants at the 3' end of IVS-II: IVS-II-839 (T>C) (HBB: c.316-12T>C) and IVS-II-844 (C>A) (HBB: c.316-7C>A). These sequence variants alter the conserved polypyrimidine tract of the consensus splice acceptor sequence (Y11NYAG/G), which could reduce splicing efficiency. This may represent a common, yet under-diagnosed β(+)-thal allele in African populations.","variants":[{"Name":"NM_000518.5(HBB):c.316-7C>A","Chromosome":"11","Start":"5225733","Stop":"5225733","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":546448,"rule_based_match":true,"evidence_text":"HBB: c.316-7C>A","llm_judgment":"PRESENT","evidence":"HBB: c.316-7C>A","abstract_start":201,"abstract_end":216},{"Name":"NM_000518.5(HBB):c.316-12T>C","Chromosome":"11","Start":"5225738","Stop":"5225738","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":799648,"rule_based_match":true,"evidence_text":"HBB: c.316-12T>C","llm_judgment":"PRESENT","evidence":"HBB: c.316-12T>C","abstract_start":161,"abstract_end":177}]}
{"pmid":"16630165","title":"Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.","abstract":"Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene encoding methyl CpG binding protein 2 (MeCP2). Recently, a new isoform of MeCP2 including exon 1 was identified. This new isoform is more abundantly expressed in brain than the isoform including exons 2-4. Very little is known about the phenotypes associated with mutations in exon 1 of MECP2 since only a limited number of RTT patients carrying such mutations have been identified so far. In this study, we screened a cohort of 20 girls with RTT for exon 1 mutations by sequencing and multiplex ligation-dependent probe amplification (MLPA). We identified one girl with a novel exon 1 mutation (c.30delCinsGA) by sequencing and three with genomic rearrangements by MLPA. Comparison of the phenotypes showed that the girls carrying a mutation or rearrangement encompassing exon 1 were more severely affected than the girls with rearrangements not affecting exon 1.","variants":[{"Name":"NM_001110792.2(MECP2):c.30delinsGA (p.Ser10fs)","Chromosome":"X","Start":"154097636","Stop":"154097636","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"TC","allel_id":187567,"rule_based_match":false,"evidence_text":"c.30delCinsGA","llm_judgment":"PRESENT","evidence":"c.30delCinsGA","abstract_start":696,"abstract_end":709}]}
{"pmid":"31669644","title":"A tetranucleotide deletion in the ANK1 gene causes hereditary spherocytosis; a case of misdiagnosis.","abstract":"Hereditary spherocytosis is a congenital red blood cell disorder. Typical clinical manifestations include anemia, jaundice and splenomegaly, which overlap with the thalassemia phenotype. Therefore, in high prevalence thalassemia regions, hereditary spherocytosis cases are often misdiagnosed. Here, a case once diagnosed as thalassemia, based on preliminary clinical examinations, underwent genetic testing in our laboratory, where analysis of globin gene mutations proved negative. We conducted both clinical and genetic analyses on the patient and his family. We collected clinical data, performed erythrocyte membrane protein analysis by SDS-PAGE and sequenced the ANK1 gene. We also investigated pathogenic mechanisms through cDNA sequencing and literature studies. From patient clinical data, we diagnosed the patient with moderate to severe hereditary spherocytosis, rather than thalassemia. SDS-PAGE data showed that Ankyrin protein expression was reduced. Sequencing of genomic DNA identified a frameshift mutation (ANK1:c.2394_2397del CAGT). cDNA sequencing showed that the expression of a mutant allele was significantly decreased. Our study corrected a clinical misdiagnosis and confirmed the diagnosis of hereditary spherocytosis in this patient. Identification of such causative mutations is important for accurate downstream patient therapy and is critically important for the prevention/detection of another affected birth. Additionally, the disruption of mRNA transcribed from the mutant allele resulted in a significant reduction in Ankyrin expression and was speculatively considered the pathogenic mechanism behind this mutation.","variants":[{"Name":"NM_000037.4(ANK1):c.2394_2397del (p.Ser799fs)","Chromosome":"8","Start":"41701614","Stop":"41701617","ReferenceAlleleVCF":"CACTG","AlternateAlleleVCF":"C","allel_id":1313424,"rule_based_match":true,"evidence_text":"ANK1:c.2394_2397del CAGT","llm_judgment":"PRESENT","evidence":"ANK1:c.2394_2397del CAGT","abstract_start":1024,"abstract_end":1048}]}
{"pmid":"22753590","title":"BRCA2 deep intronic mutation causing activation of a cryptic exon: opening toward a new preventive therapeutic strategy.","abstract":"PURPOSE: Diagnostic screening of the BRCA1/2 genes in breast cancer families is mostly done on genomic DNA. For families with a very strong family history and no mutation identified in the coding sequences or the exon-intron boundaries, BRCA1/2 transcripts' analysis is an efficient approach to uncover gene inversion and pre-mRNA splicing defaults missed by conventional DNA-based protocols.\nEXPERIMENTAL DESIGN: We analyzed RNA from patients of negative BRCA families by reverse transcriptase PCR and identified an insertion in one family that we characterized by sequencing and by using a minigene splicing assay. More than 2,000 additional BRCA1/2 negative families were subsequently screened for this mutation using a dedicated PCR approach.\nRESULTS: Nine families were found to harbor a BRCA2 mutant transcript containing a 95-nucleotide cryptic exon between exons 12 and 13. This cryptic exon results from a new mutation located deep into intron 12, c.6937+594T > G, which reinforces the strength of a preexisting 5' splice site, turning it into a perfect consensus sequence. It is systematically included in transcripts produced by the mutant allele in cells from mutation carriers or produced by a mutant splicing reporter minigene. The inclusion of the cryptic exon was prevented when we cotransfected the minigene with antisense oligonucleotides complementary to the 3' or mutated 5' splice sites.\nCONCLUSION: This first deep intronic BRCA mutation emphasizes the importance of analyzing RNA to provide comprehensive BRCA1/2 diagnostic tests and opens the possibility of using antisense therapy in the future as an alternative strategy for cancer prevention.","variants":[{"Name":"NM_000059.4(BRCA2):c.6937+594T>G","Chromosome":"13","Start":"32345247","Stop":"32345247","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":94596,"rule_based_match":true,"evidence_text":"c.6937+594T > G","llm_judgment":"PRESENT","evidence":"c.6937+594T > G","abstract_start":957,"abstract_end":972}]}
{"pmid":"31488070","title":"BRCA mutations in a cohort of Iraqi patients presenting to a tertiary referral center.","abstract":"BACKGROUND: Unique pathogenic mutations in BRCA1 and 2 genes have been reported in different populations of patients originating from the Middle East region. Limited data are available for the Iraqi population. For many reasons a large number of Iraqi patients present to Lebanon for medical care. This is the first report of BRCA full gene sequencing conducted in a cohort of high-risk patients originating from Iraq.\nMETHODS: This is a retrospective review of Iraqi patients diagnosed with breast or ovarian cancer referred for BRCA mutation testing at the American University of Beirut from January 2012 to October 2018.\nRESULTS: Of the 42 Iraqi women who underwent genetic testing at our institution, 3 BRCA pathogenic variants were found. Two mutations in BRCA1 c.224_227delAAAG and c.5431C > T and one mutation in BRCA2 c.5576_5579delTTAA were identified. Three other patients had sequence changes considered as variants of undetermined significance.\nCONCLUSION: In this cohort of high-risk patients, one out of the three pathogenic BRCA variants detected has not previously been reported in the Middle Eastern population. Further studies are required to delineate the spectrum of BRCA mutations in the Iraqi population.","variants":[{"Name":"NM_007294.4(BRCA1):c.224_227del (p.Glu75fs)","Chromosome":"17","Start":"43104942","Stop":"43104945","ReferenceAlleleVCF":"ACTTT","AlternateAlleleVCF":"A","allel_id":69181,"rule_based_match":true,"evidence_text":"c.224_227delAAAG","llm_judgment":"PRESENT","evidence":"c.224_227delAAAG","abstract_start":767,"abstract_end":783}]}
{"pmid":"27659786","title":"Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination.","abstract":"Pathogenic mutations in genes (SASH1 and PTPN11) can cause a rare genetic disorder associated with pigmentation defects and the well-known LEOPARD syndrome, respectively. Both conditions presented with lentiginous phenotypes. The aim of this study was to arrive at definite diagnoses of three Chinese boys with clinically suspected lentigines-related syndromes. ADAR1, ABCB6, SASH1 and PTPN11 were candidate genes for mutational screening. Sanger sequencing was performed to identify the mutations, whereas bioinformatic analysis was used to predict the pathogenicity of novel missense mutations. Two novel mutations c.1537A>C (p.Ser513Arg) and 1527_1530dupAAGT (p.Leu511Lysfs*21) in SASH1 and a common p.Thr468Met mutation in PTPN11 were detected in three pediatric patients with lentiginous phenotypes, respectively. Comparisons between clinical presentations showed that SASH1-related phenotypes can exhibit hyper- and hypopigmentation on the trunk and extremities, similar to dyschromatosis, while scattered café au-lait spots usually appeared in PTPN11-related LEOPARD syndrome. Furthermore, the similarity in the clinical presentations of Peutz-Jeghers syndrome, Laugier-Hunziker syndrome, xeroderma pigmentosum, neurofibromatosis type I, suggesting that these conditions should be added into the differential diagnoses of lentiginous phenotypes.","variants":[{"Name":"NM_015278.5(SASH1):c.1537A>C (p.Ser513Arg)","Chromosome":"6","Start":"148531634","Stop":"148531634","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":613449,"rule_based_match":true,"evidence_text":"c.1537A>C (p.Ser513Arg)","llm_judgment":"PRESENT","evidence":"c.1537A>C (p.Ser513Arg)","abstract_start":617,"abstract_end":640},{"Name":"NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met)","Chromosome":"12","Start":"112488466","Stop":"112488466","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28370,"rule_based_match":false,"evidence_text":"p.Thr468Met","llm_judgment":"PRESENT","evidence":"p.Thr468Met","abstract_start":703,"abstract_end":714},{"Name":"NM_015278.5(SASH1):c.1527_1530dup (p.Leu511fs)","Chromosome":"6","Start":"148531623","Stop":"148531624","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AAAGT","allel_id":613450,"rule_based_match":false,"evidence_text":"1527_1530dupAAGT (p.Leu511Lysfs*21)","llm_judgment":"PRESENT","evidence":"1527_1530dupAAGT (p.Leu511Lysfs*21)","abstract_start":645,"abstract_end":680}]}
{"pmid":"23707712","title":"Molecular basis of acid ceramidase deficiency in a neonatal form of Farber disease: identification of the first large deletion in ASAH1 gene.","abstract":"Farber disease, also known as Farber's lipogranulomatosis, is a clinically heterogeneous autosomal recessive disease caused by mutations in the ASAH1 gene. This gene codes for acid ceramidase, a lysosomal heterodimeric enzyme that hydrolyzes ceramide into sphingosine and fatty acid. To date, less than 25 distinct mutations have been identified in Farber patients, but no large deletions have yet been reported. In this work, cultured fibroblasts from a Farber patient with the rare neonatal form of Farber disease were studied to elucidate the molecular basis of this extremely severe phenotype. Direct sequencing of ASAH1 genomic DNA revealed the causative heterozygous mutation in the donor splice site consensus sequence of intron 11, g.24491A > G (c.917 + 4A > G), that resulted in the absence of detectable mRNA. Subsequent analysis of ASAH1 mRNA showed total skipping of exons 3 to 5. Long-range PCR and sequencing led to the identification of a gross deletion of ASAH1 gene, g.8728_18197del (c.126-3941_382 + 1358del) predicting the synthesis of a truncated polypeptide, p.Tyr42_Leu127delinsArgfs*10. Accordingly, no molecular forms corresponding to precursor or proteolytically processed mature protein were observed. These findings indicate that any functionally active acid ceramidase is absent in patient cells, underscoring the severity of the clinical phenotype. Molecular findings in the non-consanguineous parents confirmed the compound heterozygous ASAH1 genotype identified in this Farber case. This work unravels for the first time the mutations underlying the neonatal form of Farber disease and represents the first report of a large deletion identified in the ASAH1 gene. Screening for gross deletions in other patients in whom the mutation present in the second allele had not yet been identified is required to elucidate further its overall contribution for the molecular pathogenesis of this devastating disease.","variants":[{"Name":"NM_177924.5(ASAH1):c.917+4A>G","Chromosome":"8","Start":"18059568","Stop":"18059568","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":70551,"rule_based_match":true,"evidence_text":"c.917 + 4A > G","llm_judgment":"PRESENT","evidence":"c.917 + 4A > G","abstract_start":754,"abstract_end":768}]}
{"pmid":"27511503","title":"Evaluation and identification of IDUA gene mutations in Turkishpatients with mucopolysaccharidosis type I.","abstract":"BACKGROUND/AIM: This study aimed to identify IDUA gene mutations in Turkish patients morphologically (phenotypic) diagnosed with MPS type I. It also sought to discuss the possible effects of detected mutations on alpha-L-iduronidase enzyme function based on current knowledge.\nMATERIALS AND METHODS: Genetic analysis was carried out in 15 patients using direct DNA sequencing. Moreover, segregation analysis was performed among family members to predict the pathogenic effect of novel mutations, and computational programs were used to predict their functional impact.\nRESULTS: Nine different mutations (c.494-1G>A, c.793-6C>G, c.793-5C>A, p.M1L, p.Y64X, p.A327P, p.W402X, p.P533L, and p.R628X) were identified. Computational analysis results supported the pathogenicity of novel mutations, suggesting improper splicing. Seven already-known polymorphisms were detected in the screened cohort as well.\nCONCLUSION: Our results revealed heterogeneity in the mutation spectrum of Turkish patients. Six of the mutations, including the novel ones, have never before been reported in the Turkish population. Moreover, 5 patients who were phenotypically diagnosed with MPS type I could not be confirmed by genetic analysis, indicating the importance of the molecular characterization of MPS subtypes.","variants":[{"Name":"NM_000203.5(IDUA):c.494-1G>A","Chromosome":"4","Start":"1001467","Stop":"1001467","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":543275,"rule_based_match":true,"evidence_text":"c.494-1G>A","llm_judgment":"PRESENT","evidence":"c.494-1G>A","abstract_start":604,"abstract_end":614},{"Name":"NM_000203.5(IDUA):c.1A>C (p.Met1Leu)","Chromosome":"4","Start":"987085","Stop":"987085","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":543531,"rule_based_match":false,"evidence_text":"p.M1L","llm_judgment":"PRESENT","evidence":"p.M1L","abstract_start":640,"abstract_end":645}]}
{"pmid":"23736036","title":"Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity.","abstract":"BACKGROUND: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity.\nMETHODS: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models.\nRESULTS: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻⁶, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively).\nCONCLUSION: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.","variants":[{"Name":"NM_000110.4(DPYD):c.2846A>T (p.Asp949Val)","Chromosome":"1","Start":"97082391","Stop":"97082391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":94529,"rule_based_match":true,"evidence_text":"c.2846A>T","llm_judgment":"PRESENT","evidence":"c.2846A>T","abstract_start":640,"abstract_end":649},{"Name":"NM_000110.4(DPYD):c.1679T>G (p.Ile560Ser)","Chromosome":"1","Start":"97515787","Stop":"97515787","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":94530,"rule_based_match":true,"evidence_text":"c.1679T>G","llm_judgment":"PRESENT","evidence":"c.1679T>G","abstract_start":665,"abstract_end":674},{"Name":"NM_000110.4(DPYD):c.1905+1G>A","Chromosome":"1","Start":"97450058","Stop":"97450058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15471,"rule_based_match":true,"evidence_text":"c.1905+1G>A","llm_judgment":"PRESENT","evidence":"c.1905+1G>A","abstract_start":627,"abstract_end":638},{"Name":"NM_000110.4(DPYD):c.1601G>A (p.Ser534Asn)","Chromosome":"1","Start":"97515865","Stop":"97515865","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105971,"rule_based_match":true,"evidence_text":"c.1601G>A","llm_judgment":"PRESENT","evidence":"c.1601G>A","abstract_start":651,"abstract_end":660}]}
{"pmid":"23824952","title":"Camurati-Engelmann disease with obesity in a newly identified family carrying a missense p.Arg156Cys mutation in the TGFB1 gene.","abstract":"We report on a family affected by Camurati-Engelmann disease, characterized by radiological signs limited to the tibia, and associated with overweight or obesity, which is not a known feature of this disorder. The affected patients were heterozygous for a c.466C > T mutation (which predicts p.Arg156Cys) in the latency associated protein (LAP)-coding domain of the TGFB1 gene. This mutation had previously been reported once in another family with a similar, atypical phenotype, which suggests a possible phenotype/genotype relationship.","variants":[{"Name":"NM_000660.7(TGFB1):c.466C>T (p.Arg156Cys)","Chromosome":"19","Start":"41348345","Stop":"41348345","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":47500,"rule_based_match":true,"evidence_text":"c.466C > T (which predicts p.Arg156Cys)","llm_judgment":"PRESENT","evidence":"p.Arg156Cys","abstract_start":292,"abstract_end":303}]}
{"pmid":"35206658","title":"An Atypical Case of Late-Onset Wolfram Syndrome 1 without Diabetes Insipidus.","abstract":"Wolfram syndrome 1, a rare autosomal recessive neurodegenerative disease, is caused by mutations in the <i>WFS1</i> gene. It is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD), and other clinical manifestations such as urological and neurological disorders. Here we described the case of a patient with an atypical late-onset Wolfram syndrome 1 without DI. Our WS1 patient was a c.1620_1622delGTG (p.Trp540del)/c.124 C > T (p.Arg42*) heterozygous compound. The p.Arg42* nonsense mutation was also found in heterozygosity in his sister and niece, both suffering from psychiatric disorders. The p.Arg42* nonsense mutation has never been found in WS1 and its pathogenicity is unclear so far. Our study underlined the need to study a greater number of WS1 cases in order to better understand the clinical significance of many <i>WFS1</i> variants.","variants":[{"Name":"NM_006005.3(WFS1):c.124C>T (p.Arg42Ter)","Chromosome":"4","Start":"6277579","Stop":"6277579","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187111,"rule_based_match":true,"evidence_text":"c.124 C > T (p.Arg42*)","llm_judgment":"PRESENT","evidence":"c.124 C > T (p.Arg42*)","abstract_start":457,"abstract_end":479}]}
{"pmid":"35432464","title":"Mutation Analysis of the RPGR Gene in a Chinese Cohort.","abstract":"<b>Purpose:</b> The purpose of this study was to investigate the clinical and genetic characteristics of the retinitis pigmentosa GTPase regulatory factor gene (<i>RPGR</i>) in a Chinese cohort. <b>Methods:</b> A retrospective analysis was performed on 80 subjects with <i>RPGR</i>-retinal dystrophy (<i>RPGR</i>-RD) for detailed genetic and clinical characterization. The panel-based next-generation sequencing of 792 causative genes involved in common genetic eye diseases was conducted in all individuals, followed by clinical variant interpretation. Information, including age, sex, geographic distribution, family history, consanguineous marriage, age at symptom onset, disease duration, best corrected visual acuity (BCVA), and complete ophthalmologic examination results, was collected. <b>Results:</b> This cohort (41 men and 39 women) included 26 families (26 probands and their available family members) and 13 sporadic cases. The average age of these participants was 36.35 ± 17.68 years, and the majority of the families were from eastern China (28 families, 71.79%). The average duration of disease in the probands was 22.68 ± 15.80 years. In addition, the average BCVA values of the right and left eyes in the probands were 0.96 ± 0.77 and 1.00 ± 0.77, respectively. A total of 34 <i>RPGR</i> variants were identified, including 6 reported variants and 28 novel variants. Among these variants, NM_001034853.1: c.2899_2902delGAAG and c.2744_2745ins24 were considered <i>de novo</i> variants. The majority of the <i>RPGR</i> variants were classified as likely pathogenic, accounting for 70.59% of the variants (24 variants). The most common nucleotide and amino acid changes identified in this study were deletions (16 variants, 45.06%) and frameshifts (17 variants, 50.00%), respectively. Genetic analysis revealed that these <i>RPGR</i> variants were distributed in 10 different subregions of <i>RPGR,</i> and 70.59% of the <i>RPGR</i> variants (24 variants) were located in exon 15. Four <i>RPGR</i> variants, NM_001034853.1: c.2405_2406delAG, c.1345C > T, c.2218G > T and c.2236_2237delGA, occurred at a very high frequency of 28.21% (11 families) among 39 unrelated families. <b>Conclusion:</b> This study expands the known mutational spectrum of <i>RPGR</i>, and we provide a new reference for the genetic diagnosis of <i>RPGR</i> variants.","variants":[{"Name":"NM_001034853.2(RPGR):c.2405_2406del (p.Glu802fs)","Chromosome":"X","Start":"38286593","Stop":"38286594","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":96865,"rule_based_match":true,"evidence_text":"NM_001034853.1: c.2405_2406delAG","llm_judgment":"PRESENT","evidence":"NM_001034853.1: c.2405_2406delAG","abstract_start":2025,"abstract_end":2057}]}
{"pmid":"16134148","title":"Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin.","abstract":"We studied 21 patients, from 18 families, with L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic disorder with a homogeneous presentation: progressive neurodegeneration with extrapyramidal and cerebellar signs, seizures, and subcortical leukoencephalopathy. Increased levels of L-2-hydroxyglutaric acid in body fluids proved the diagnosis of L-2-HGA in all 21 patients. We analyzed the L-2-HGA gene (L2HGDH), recently found to be mutated in consanguineous families with L-2-HGA, and identified seven novel mutations in 15 families. Three mutations appeared to be particularly prevalent in this Portuguese panel: a frameshift mutation (c.529delC) was detected in 12 out of 30 mutant alleles (40%), a nonsense mutation (c.208C>T; p.Arg70X) in 7/30 alleles (23%), and a missense mutation (c.293A>G; p.His98Arg) in four out of 30 mutant alleles (13%), suggesting that common origin may exist. Furthermore, two novel missense (c.169G>A; p.Gly57Arg, c.1301A>C; p.His434Pro) and two splice error (c.257-2A>G, c.907-2A>G) mutations were found. All the mutations presumably lead to loss-of-function with no relationship between clinical signs, progression of the disease, levels of L-2-HGA and site of the mutation. In the three remaining families, no pathogenic mutations in the L-2-HGA were found, which suggests either alterations in regulatory regions of the gene or of its intervening sequences, compound heterozygosity for large genomic deletion and, or further genetic heterogeneity.","variants":[{"Name":"NM_024884.3(L2HGDH):c.293A>G (p.His98Arg)","Chromosome":"14","Start":"50302132","Stop":"50302132","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":16651,"rule_based_match":true,"evidence_text":"c.293A>G; p.His98Arg","llm_judgment":"PRESENT","evidence":"c.293A>G; p.His98Arg","abstract_start":798,"abstract_end":818},{"Name":"NM_024884.3(L2HGDH):c.208C>T (p.Arg70Ter)","Chromosome":"14","Start":"50302950","Stop":"50302950","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":568936,"rule_based_match":true,"evidence_text":"c.208C>T; p.Arg70X","llm_judgment":"PRESENT","evidence":"c.208C>T; p.Arg70X","abstract_start":730,"abstract_end":748}]}
{"pmid":"23421333","title":"Clinical phenotype in ten unrelated Japanese patients with mutations in the EYS gene.","abstract":"BACKGROUND: To characterize the clinical phenotypes associated with previously-reported mutations of the eyes shut homolog (EYS) gene, including a truncating mutation, c.4957_4958insA, which is a major causative mutation for retinitis pigmentosa (RP) in Japan.\nMATERIALS AND METHODS: The study population comprised ten unrelated RP subjects with very likely pathogenic mutations in both alleles, four of them with a homozygous c.4957_4958insA mutation. The phenotype analysis was based on ophthalmic examination, Goldmann perimetry, and digital fundus photography.\nRESULTS: The study population included six men and four women aged 34-74 years. The average age at first visit was 31 years (range, 14-44 years), and the patients typically presented with night blindness as the initial symptom and subsequently developed progressive constriction of the visual field. Myopia was noted in 9/20 affected eyes. For most patients, central visual acuity was preserved relatively well up to their thirties, after which it deteriorated rapidly over the next two decades. The visual acuity of patients homozygous for the c.4957_4958insA mutation was uniform. Visual fields were constricted symmetrically, and the extent of constriction seemed to be better correlated with age than visual acuity. The fundus displayed bone spicules, which increased in density with age, and attenuated retinal vessels.\nCONCLUSIONS: Although additional studies with more patients with mutations of the EYS gene are required, it appears that patients share a relatively uniform phenotype with near-normal central visual function up to their twenties. The patients homozygous for the c.4957_4958insA mutation showed a uniform course of visual acuity changes.","variants":[{"Name":"NM_001142800.2(EYS):c.4957dup (p.Ser1653fs)","Chromosome":"6","Start":"64590909","Stop":"64590910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":152823,"rule_based_match":false,"evidence_text":"c.4957_4958insA","llm_judgment":"PRESENT","evidence":"c.4957_4958insA","abstract_start":168,"abstract_end":183}]}
{"pmid":"15793835","title":"Somatic and gonadal mosaicism in Hutchinson-Gilford progeria.","abstract":"We have studied a patient with Hutchinson-Gilford progeria (HGP). Sequence analysis of the LMNA gene demonstrated the presence of a c.1824 C > T (p.G608G) mutation, activating a cryptic splice donor site and leading to the formation of a truncated Lamin A protein. All molecularly characterized autosomal dominant HGP cases described so far result from de novo LMNA mutations, mostly originating on the paternal allele and are often linked with advanced paternal age. However, in our patient, the mutation was transmitted by the mother who showed somatic and germline mosaicism without HGP manifestations.","variants":[{"Name":"NM_170707.4(LMNA):c.1824C>T (p.Gly608=)","Chromosome":"1","Start":"156138613","Stop":"156138613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29539,"rule_based_match":true,"evidence_text":"c.1824 C > T (p.G608G)","llm_judgment":"PRESENT","evidence":"c.1824 C > T (p.G608G)","abstract_start":132,"abstract_end":154}]}
{"pmid":"34162253","title":"Two novel compound heterozygous","abstract":"BACKGROUND: Oguchi disease is a rare autosomal recessive retinal dystrophy, characterized by congenital stationary blindness and caused by pathogenic variants in <i>SAG</i> and <i>GRK1</i> genes. The present study aimed to report an Italian patient affected by Oguchi disease, evaluated by means of a multimodal retinal imaging study and harboring two novel heterozygous pathogenic variants in the <i>SAG</i> gene.\nMATERIALS AND METHODS: A 60-year-old female complaining congenital stationary night blindness was investigated through fundus photograph, optical coherence tomography (OCT), electroretinography (ERG), and genetic testing.\nRESULTS: Fundus examination showed a golden-grayish fundus aspect. The rod response of the scotopic ERG was undetectable and mixed rod-cone response was electronegative. Fundus photographs obtained in light and in prolonged dark-adapted conditions allowed to detect the Mizuo-Nakamura phenomenon. Light condition OCT over the abnormal retinal regions showed high-intensity areas in the outer photoreceptor segment layer, that reduced with prolonged dark adaption. Genetic testing identified two rare heterozygous sequence variants in the <i>SAG</i> gene: NM_000541.5:c.807delA p.(Glu270Lysfs*9) and NM_000541.5:c.1047-1G>C confirming the diagnosis of Oguchi disease.\nCONCLUSIONS: We identified the first Italian compound heterozygous patient harboring two novel alterations in the <i>SAG</i> gene (a frameshift deletion and a splicing variant). The involvement of the <i>SAG</i> gene in Oguchi disease is a common finding in Japanese population, but rarely identified in Caucasians. Clinical suspicion should prompt the molecular analysis of genes associated with this condition.","variants":[{"Name":"NM_000541.5(SAG):c.1047-1G>C","Chromosome":"2","Start":"233342270","Stop":"233342270","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3004203,"rule_based_match":true,"evidence_text":"NM_000541.5:c.1047-1G>C","llm_judgment":"PRESENT","evidence":"NM_000541.5:c.1047-1G>C","abstract_start":1236,"abstract_end":1259},{"Name":"NM_000541.5(SAG):c.807delA (p.Glu270fs)","Chromosome":"2","Start":"233334962","Stop":"233334962","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1957133,"rule_based_match":true,"evidence_text":"NM_000541.5:c.807delA p.(Glu270Lysfs*9)","llm_judgment":"PRESENT","evidence":"NM_000541.5:c.807delA p.(Glu270Lysfs*9)","abstract_start":1192,"abstract_end":1231}]}
{"pmid":"35245693","title":"Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance.","abstract":"INTRODUCTION: BRCA1 and BRCA2 are the two main genes causing hereditary breast and ovarian cancer (HBOC). However, thanks to the development of Next Generation Sequencing (NGS), other genes linked to this syndrome (CHEK2, BRIP1, ATM and PALB2 among others) can be analysed.\nMATERIAL AND METHODS: an analysis by multigene panel testing was performed in 138 index cases (ICs) from HBOC Spanish families with a previous non-informative result for BRCA1/2. The BRCA Hereditary Cancer Master™ Plus kit, including 26 actionable and candidate genes related to HBOC was employed. Once classified, an algorithm was employed to prioritized those variants of unknown significance with a higher risk of having a deleterious effect. Moreover, a mRNA splicing assay was performed for the prioritized VUS c.3402+3A > C in ATM, located at intron 23.\nRESULTS: A total of 82 variants were found: 70 VUS and 12 pathogenic or probably pathogenic variants. The diagnostic yield in actionable genes non-BRCA was 7.97% of the total tested ICs. Overall, 19 VUS were prioritized, which meant 27% of the 70 total VUS. RNA analysis of the variant 3402+3A > C confirmed a deleterious impact on splicing.\nDISCUSSION: The implementation of a multigene panel in HBOC studied families improved the diagnostic yield, concordant with results obtained in previous publications. Due to the important number of VUS obtained in NGS, the application of a prioritization algorithm is needed in order to select those variants in which it is necessary to conduct further studies.","variants":[{"Name":"NM_000051.4(ATM):c.3402+3A>C","Chromosome":"11","Start":"108279611","Stop":"108279611","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":815479,"rule_based_match":true,"evidence_text":"c.3402+3A>C","llm_judgment":"PRESENT","evidence":"c.3402+3A > C","abstract_start":790,"abstract_end":803}]}
{"pmid":"29127258","title":"Homozygous mutation in","abstract":"BACKGROUND: Bardet-Biedl syndrome (BBS) is a ciliopathy with extensive phenotypic variability and genetic heterogeneity. We aimed to discover the gene mutated in a consanguineous kindred with multiple cases of a BBS phenotype.\nMETHODS: SNP genotype data were used for linkage analysis and exome sequencing to identify mutations. Modelling and in silico analysis were performed to predict mutation severity.\nRESULTS: Patients had postaxial polydactyly plus variable other clinical features including rod-cone dystrophy, obesity, intellectual disability, renal malformation, developmental delay, dental anomalies, speech disorder and enlarged fatty liver. The 4.57 Mb disease locus harboured homozygous, truncating <i>CEP19</i> c.194_195insA (p.Tyr65*) mutation. We also found <i>glioma-associated oncogene homolog</i> 1(<i>GLI1</i>) c.820G>C (p.Gly274Arg) in the homozygous state in most patients. In silico modelling strongly suggests that it is damaging. Also, different combinations of four possible modifier alleles in BBS-related genes were detected. Two are known modifier alleles for BBS, splicing variant <i>CCDC28B</i> c.330C>T and missense <i>MKKS/BBS6</i> p.Ile339Val, and the others are <i>C8ORF37/BBS21</i> p.Ala178Val and <i>TMEM67</i>/<i>BBS14 modifier</i> p.Asp799Asp. Some patients carry all those five known/possible modifier alleles. Such variants are highly significantly more abundant in our patients than in a control group.\nCONCLUSION: <i>CEP19</i> encodes a centrosomal and ciliary protein, as all BBS genes do. Another truncating mutation p.Arg82* has been reported as responsible for morbid obesity in a family; however, in the family we present, not all homozygotes are obese, although some are severely obese. The variant in <i>GLI1</i>, encoding a transcription factor that localises to the primary cilium and nucleus and is a mediator of the sonic hedgehog pathway, possibly exacerbates disease severity when in the homozygous state.","variants":[{"Name":"NM_005269.3(GLI1):c.820G>C (p.Gly274Arg)","Chromosome":"12","Start":"57466297","Stop":"57466297","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":424187,"rule_based_match":true,"evidence_text":"GLI1 c.820G>C (p.Gly274Arg)","llm_judgment":"PRESENT","evidence":"p.Gly274Arg","abstract_start":842,"abstract_end":853}]}
{"pmid":"25153125","title":"In silico identification of new putative pathogenic variants in the NEU1 sialidase gene affecting enzyme function and subcellular localization.","abstract":"The NEU1 gene is the first identified member of the human sialidases, glycohydrolitic enzymes that remove the terminal sialic acid from oligosaccharide chains. Mutations in NEU1 gene are causative of sialidosis (MIM 256550), a severe lysosomal storage disorder showing autosomal recessive mode of inheritance. Sialidosis has been classified into two subtypes: sialidosis type I, a normomorphic, late-onset form, and sialidosis type II, a more severe neonatal or early-onset form. A total of 50 causative mutations are reported in HGMD database, most of which are missense variants. To further characterize the NEU1 gene and identify new functionally relevant protein isoforms, we decided to study its genetic variability in the human population using the data generated by two large sequencing projects: the 1000 Genomes Project (1000G) and the NHLBI GO Exome Sequencing Project (ESP). Together these two datasets comprise a cohort of 7595 sequenced individuals, making it possible to identify rare variants and dissect population specific ones. By integrating this approach with biochemical and cellular studies, we were able to identify new rare missense and frameshift alleles in NEU1 gene. Among the 9 candidate variants tested, only two resulted in significantly lower levels of sialidase activity (p<0.05), namely c.650T>C and c.700G>A. These two mutations give rise to the amino acid substitutions p.V217A and p.D234N, respectively. NEU1 variants including either of these two amino acid changes have 44% and 25% residual sialidase activity when compared to the wild-type enzyme, reduced protein levels and altered subcellular localization. Thus they may represent new, putative pathological mutations resulting in sialidosis type I. The in silico approach used in this study has enabled the identification of previously unknown NEU1 functional alleles that are widespread in the population and could be tested in future functional studies.","variants":[{"Name":"NM_000434.4(NEU1):c.700G>A (p.Asp234Asn)","Chromosome":"6","Start":"31860537","Stop":"31860537","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2236901,"rule_based_match":true,"evidence_text":"c.700G>A","llm_judgment":"PRESENT","evidence":"c.700G>A","abstract_start":1333,"abstract_end":1341}]}
{"pmid":"24805811","title":"Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X).","abstract":"Alpha-thalassemia intellectual disability, one of the recognizable X-linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X-inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c.109C>T (p.R37X) mutation segregates with a variable but overall milder phenotype. The distinctive facial appearance of alpha-thalassemia intellectual disability was present in only one of the 18 affected males evaluated beyond the age of puberty, although suggestive facial appearance was present in several during infancy or early childhood. Although the responsible genetic alteration is a nonsense mutation in exon 2 of ATRX, the phenotype appears to be partially rescued by the production of alternative transcripts and/or other molecular mechanisms.","variants":[{"Name":"NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)","Chromosome":"X","Start":"77717155","Stop":"77717155","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26781,"rule_based_match":true,"evidence_text":"c.109C>T (p.R37X)","llm_judgment":"PRESENT","evidence":"c.109C>T (p.R37X)","abstract_start":499,"abstract_end":516}]}
{"pmid":"26762690","title":"Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome.","abstract":"Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions.","variants":[{"Name":"NM_000202.8(IDS):c.1463del (p.Met488fs)","Chromosome":"X","Start":"149482936","Stop":"149482936","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":223658,"rule_based_match":true,"evidence_text":"c.1463del","llm_judgment":"PRESENT","evidence":"c.1463del","abstract_start":406,"abstract_end":415},{"Name":"NM_000202.8(IDS):c.1132_1133del (p.Phe378fs)","Chromosome":"X","Start":"149486972","Stop":"149486973","ReferenceAlleleVCF":"GAA","AlternateAlleleVCF":"G","allel_id":223659,"rule_based_match":true,"evidence_text":"c.1132_1133del","llm_judgment":"PRESENT","evidence":"c.1132_1133del","abstract_start":390,"abstract_end":404},{"Name":"NM_000202.8(IDS):c.1025A>C (p.His342Pro)","Chromosome":"X","Start":"149487080","Stop":"149487080","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":223660,"rule_based_match":true,"evidence_text":"c.1025A>C","llm_judgment":"PRESENT","evidence":"c.1025A>C","abstract_start":336,"abstract_end":345},{"Name":"NM_000202.8(IDS):c.1003C>T (p.His335Tyr)","Chromosome":"X","Start":"149490317","Stop":"149490317","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":223662,"rule_based_match":true,"evidence_text":"c.1003C>T","llm_judgment":"PRESENT","evidence":"c.1003C>T","abstract_start":325,"abstract_end":334},{"Name":"NM_000202.8(IDS):c.754_767del (p.Pro251_Asp252insTer)","Chromosome":"X","Start":"149496458","Stop":"149496471","ReferenceAlleleVCF":"AGGGACCTCGGGATC","AlternateAlleleVCF":"A","allel_id":223663,"rule_based_match":true,"evidence_text":"c.754_767del","llm_judgment":"PRESENT","evidence":"c.754_767del","abstract_start":376,"abstract_end":388},{"Name":"NM_000202.8(IDS):c.508-1G>C","Chromosome":"X","Start":"149498308","Stop":"149498308","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":223664,"rule_based_match":true,"evidence_text":"c.508-1G>C","llm_judgment":"PRESENT","evidence":"c.508-1G>C","abstract_start":417,"abstract_end":427},{"Name":"NM_000202.8(IDS):c.463_464delinsCCGTATAGCTGG (p.Phe155fs)","Chromosome":"X","Start":"149500992","Stop":"149500993","ReferenceAlleleVCF":"AA","AlternateAlleleVCF":"CCAGCTATACGG","allel_id":223665,"rule_based_match":true,"evidence_text":"c.463_464delinsCCGTATAGCTGG","llm_judgment":"PRESENT","evidence":"c.463_464delinsCCGTATAGCTGG","abstract_start":347,"abstract_end":374},{"Name":"NM_000202.8(IDS):c.133G>C (p.Asp45His)","Chromosome":"X","Start":"149504264","Stop":"149504264","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":223666,"rule_based_match":true,"evidence_text":"c.133G>C","llm_judgment":"PRESENT","evidence":"c.133G>C","abstract_start":315,"abstract_end":323}]}
{"pmid":"25085631","title":"Frequency and clinical pattern of vitelliform macular dystrophy caused by mutations of interphotoreceptor matrix IMPG1 and IMPG2 genes.","abstract":"PURPOSE: To assess the frequency of and to characterize the clinical spectrum and optical coherence tomography findings of vitelliform macular dystrophy linked to IMPG1 and IMPG2, 2 new causal genes expressed in the interphotoreceptor matrix.\nDESIGN: Retrospective epidemiologic, clinical, electrophysiologic, and molecular genetic study.\nPARTICIPANTS: The database of a national referral center specialized in genetic sensory diseases was screened for patients with a macular vitelliform dystrophy without identified mutation or small deletion or large rearrangement in BEST1 and PRPH2 genes. Forty-nine families were included.\nMETHODS: Clinical, imaging, and electro-oculogram findings were reviewed. Mutation screening of IMPG1 and IMPG2 genes were performed systematically.\nMAIN OUTCOME MEASURES: Frequency, inheritance, and clinical pattern of vitelliform dystrophy associated with IMPG1 and IMPG2 mutations were characterized.\nRESULTS: IMPG1 was the causal gene in 3 families (IMPG1 1-3, 11 patients) and IMPG2 in a fourth family (2 patients). With an autosomal dominant transmission, families 1 and 2 had the c.713T→G (p.Leu238Arg) mutation in IMPG1 and family 4 had the c.3230G→T (p.Cys1077Phe) mutation in IMPG2. Patients with IMPG1 or IMPG2 mutations had a late onset and moderate visual impairment (mean visual acuity, 20/40; mean age of onset, 42 years), even in the sporadic case of family 3 with a presumed recessive transmission (age at onset, 38 years; mean visual acuity, 20/50). Drusen-like lesions adjacent to the vitelliform deposits were observed in 9 of 13 patients. The vitelliform material was above the retinal pigment epithelium (RPE) at any stage of the macular dystrophy, and this epithelium was well preserved and maintained its classical reflectivity on spectral-domain optical coherence tomography (SD-OCT). Electro-oculogram results were normal or borderline in 9 cases.\nCONCLUSIONS: IMPG1 and IMPG2 are new causal genes in 8% of families negative for BEST1 and PRPH2 mutations. These genes should be screened in adult-onset vitelliform dystrophy with (1) moderate visual impairment, (2) drusen-like lesions, (3) normal reflectivity of the RPE line on SD-OCT, and (4) vitelliform deposits located between ellipsoid and interdigitation lines on SD-OCT. These clinical characteristics are not observed in the classical forms of BEST1 or PRPH2 vitelliform dystrophies.","variants":[{"Name":"NM_016247.4(IMPG2):c.3230G>T (p.Cys1077Phe)","Chromosome":"3","Start":"101232784","Stop":"101232784","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":171853,"rule_based_match":false,"evidence_text":"c.3230G→T (p.Cys1077Phe)","llm_judgment":"PRESENT","evidence":"c.3230G→T (p.Cys1077Phe)","abstract_start":1178,"abstract_end":1202}]}
{"pmid":"29097701","title":"Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis.","abstract":"Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.","variants":[{"Name":"NM_000218.3(KCNQ1):c.1106C>T (p.Pro369Leu)","Chromosome":"11","Start":"2585285","Stop":"2585285","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1330759,"rule_based_match":true,"evidence_text":"c.1106C>T p.(Pro369Leu)","llm_judgment":"PRESENT","evidence":"c.1106C>T p.(Pro369Leu)","abstract_start":384,"abstract_end":407}]}
{"pmid":"17010210","title":"A novel mutation in STK11 gene is associated with Peutz-Jeghers Syndrome in Indian patients.","abstract":"BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare multi-organ cancer syndrome and understanding its genetic basis may help comprehend the molecular mechanism of familial cancer. A number of germ line mutations in the STK11 gene, encoding a serine threonine kinase have been reported in these patients. However, STK11 mutations do not explain all PJS cases. An earlier study reported absence of STK11 mutations in two Indian families and suggested another potential locus on 19q13.4 in one of them.\nMETHODS: We sequenced the promoter and the coding region including the splice-site junctions of the STK11 gene in 16 affected members from ten well-characterized Indian PJS families with a positive family history.\nRESULTS: We did not observe any of the reported mutations in the STK11 gene in the index patients from these families. We identified a novel pathogenic mutation (c.790_793 delTTTG) in the STK11 gene in one index patient (10%) and three members of his family. The mutation resulted in a frame-shift leading to premature termination of the STK11 protein at 286th codon, disruption of kinase domain and complete loss of C-terminal regulatory domain. Based on these results, we could offer predictive genetic testing, prenatal diagnosis and genetic counselling to other members of the family.\nCONCLUSION: Ours is the first study reporting the presence of STK11 mutation in Indian PJS patients. It also suggests that reported mutations in the STK11 gene are not responsible for the disease and novel mutations also do not account for many Indian PJS patients. Large-scale genomic deletions in the STK11 gene or another locus may be associated with the PJS phenotype in India and are worth future investigation.","variants":[{"Name":"NM_000455.5(STK11):c.790_793del (p.Phe264fs)","Chromosome":"19","Start":"1221265","Stop":"1221268","ReferenceAlleleVCF":"GTTGT","AlternateAlleleVCF":"G","allel_id":360512,"rule_based_match":true,"evidence_text":"c.790_793 delTTTG","llm_judgment":"PRESENT","evidence":"c.790_793 delTTTG","abstract_start":875,"abstract_end":892}]}
{"pmid":"14695530","title":"Five novel mutations in the lysosomal sialidase gene (NEU1) in type II sialidosis patients and assessment of their impact on enzyme activity and intracellular targeting using adenovirus-mediated expression.","abstract":"Sialidosis is an autosomal recessive disease resulting from a deficiency of lysosomal sialidase. Type II sialidosis is a rare disease characterized clinically by hydrops fetalis, hepatosplenomegaly, and severe psychomotor retardation. Genomic DNA from four unrelated sialidosis patients was screened for mutations within the sialidase gene NEU1. Five novel mutations were identified. Four are missense and one is nonsense: c.674G>C (p.R225P), c.893C>T (p.A298V), c.3G>A (p.M1?), c.941C>G (p.R341G), and c.69G>A (p.W23X). We have used our findings and diagnostic tools to confirm the presence of a homozygous null allele in a neonate sibling. Recombinant adenoviruses expressing the mutant sialidase alleles in primary cell cultures were utilized to assess the impact of each mutation on enzyme activity and intracellular localization. None of the mutant alleles expressed significant enzymatic activity. The p.R341G mutation exerts its pathological effect by perturbing substrate binding, while the p.A298V and p.R225P mutations appear to impair the folding of the sialidase enzyme. Our findings point to mutation-sensitive amino acids involved in catalytic function or structural stability and indicate the potential utility of these mutations for molecular diagnosis of this rare disease.","variants":[{"Name":"NM_000434.4(NEU1):c.3G>A (p.Met1Ile)","Chromosome":"6","Start":"31862774","Stop":"31862774","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2904749,"rule_based_match":true,"evidence_text":"c.3G>A (p.M1?)","llm_judgment":"PRESENT","evidence":"c.3G>A (p.M1?)","abstract_start":463,"abstract_end":477},{"Name":"NM_000434.4(NEU1):c.674G>C (p.Arg225Pro)","Chromosome":"6","Start":"31860563","Stop":"31860563","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":17495,"rule_based_match":true,"evidence_text":"c.674G>C (p.R225P)","llm_judgment":"PRESENT","evidence":"c.674G>C (p.R225P)","abstract_start":423,"abstract_end":441},{"Name":"NM_000434.4(NEU1):c.893C>T (p.Ala298Val)","Chromosome":"6","Start":"31860170","Stop":"31860170","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17496,"rule_based_match":true,"evidence_text":"c.893C>T (p.A298V)","llm_judgment":"PRESENT","evidence":"c.893C>T (p.A298V)","abstract_start":443,"abstract_end":461},{"Name":"NM_000434.4(NEU1):c.69G>A (p.Trp23Ter)","Chromosome":"6","Start":"31862708","Stop":"31862708","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17497,"rule_based_match":true,"evidence_text":"c.69G>A (p.W23X)","llm_judgment":"PRESENT","evidence":"c.69G>A (p.W23X)","abstract_start":503,"abstract_end":519}]}
{"pmid":"35754802","title":"Oral Phenotype of Singleton-Merten Syndrome: A Systematic Review Illustrated With a Case Report.","abstract":"<b>Background:</b> Singleton-Merten syndrome type 1 (SGMRT1) is a rare autosomal dominant disorder caused by <i>IFIH1</i> variations with blood vessel calcifications, teeth anomalies, and bone defects. <b>Aim:</b> We aimed to summarize the oral findings in SGMRT1 through a systematic review of the literature and to describe the phenotype of a 10-year-old patient with SGMRT1 diagnosis. <b>Results:</b> A total of 20 patients were described in the literature, in nine articles. Eight <i>IFIH1</i> mutations were described in 11 families. Delayed eruption, short roots, and premature loss of permanent teeth were the most described features (100%). Impacted teeth (89%) and carious lesions (67%) were also described. Our patient, a 10-year-old male with Singleton-Merten syndrome, presented numerous carious lesions, severe teeth malposition, especially in the anterior arch, and an oral hygiene deficiency with a 100% plaque index. The panoramic X-ray did not show any dental agenesis but revealed very short roots and a decrease in the jaw alveolar bone height. The whole-genome sequencing analysis revealed a heterozygous <i>de novo</i> variant in <i>IFIH1</i> (NM_022168.4) c.2465G > A (p.Arg822Gln). <b>Conclusion:</b> Confused descriptions of oral features occurred in the literature between congenital findings and \"acquired\" pathology, especially carious lesions. The dental phenotype of these patients encompasses eruption anomalies (delayed eruption and impacted teeth) and lack of root edification, leading to premature loss of permanent teeth, and it may contribute to the diagnosis. An early diagnosis is essential to prevent teeth loss and to improve the quality of life of these patients. <b>Systematic Review Registration</b>: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022300025].","variants":[{"Name":"NM_022168.4(IFIH1):c.2465G>A (p.Arg822Gln)","Chromosome":"2","Start":"162272377","Stop":"162272377","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187227,"rule_based_match":true,"evidence_text":"c.2465G > A (p.Arg822Gln)","llm_judgment":"PRESENT","evidence":"c.2465G > A (p.Arg822Gln)","abstract_start":1178,"abstract_end":1203}]}
{"pmid":"30545545","title":"Mosaicism in carrier of Duchenne muscular dystrophy mutation - Implication for prenatal diagnosis.","abstract":"OBJECTIVE: Duchenne muscular dystrophy (DMD) is a severe disorder caused by mutation in the X-linked dystrophin gene, therefor carrier testing is required for all female family members. However, there are cases mutation analysis cannot detect any mutation due to a phenomenon called mosaicism. The case report describes a case of mosaicism in a DMD carrier and discusses the approach in diagnosis and counseling of familial disorder.\nCASE REPORT: The proband was diagnosed with DMD at age six. Sequencing of Dystrophin gene identified a 2-nucleotide deletion c.2032_2033delCA, p.Q678DfsX41. Family investigation suggested that the mother was an obligate carrier of Dystrophin mutation. Sequencing of DNA sample from the mother's peripheral blood did not reveal any mutation, there for we take sample from hair follicle for analysis. The result indicated that the mother was a carrier but was masked from initial analysis by mosaicsism.\nCONCLUSION: We suggested that more care need to be taken in identifying cases when no mutation was detected in probable or obligate carrier and prenatal diagnosis should remain an option.","variants":[{"Name":"NM_004006.3(DMD):c.2032_2033del (p.Gln678fs)","Chromosome":"X","Start":"32545294","Stop":"32545295","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":100390,"rule_based_match":true,"evidence_text":"c.2032_2033delCA","llm_judgment":"PRESENT","evidence":"c.2032_2033delCA","abstract_start":559,"abstract_end":575}]}
{"pmid":"18301443","title":"p.[G576S; E689K]: pathogenic combination or polymorphism in Pompe disease?","abstract":"We discuss four cases of acid alpha-glucosidase deficiency (EC, 3.2.1.3/20) without evident symptoms of Pompe disease (OMIM No 232300) in individuals of Asian descent. In three cases, the deficiency was associated with homozygosity for the sequence variant c.[1726G>A; 2065G>A] in the acid alpha-glucosidase gene (GAA) translating into p.[G576S; E689K]. One of these cases was a patient with profound muscular atrophy, another had cardio-myopathy and the third had no symptoms. The fourth case, the mother of a child with Pompe disease, was compound heterozygote for the GAA sequence variants c.[1726G>A; 2065G>A]/c.2338G>A (p.W746X) and had no symptoms either. Further investigations revealed that c.[1726A; 2065A] is a common GAA allele in the Japanese and Chinese populations. Our limited study predicts that approximately 4% of individuals in these populations are homozygote c.[1726A; 2065A]. The height of this figure in contrast to the rarity of Pompe disease in Asian populations and the clinical history of the cases described in this paper virtually exclude that homozygosity for c.[1726A; 2065A] causes Pompe disease. As c.[1726A; 2065A] homozygotes have been observed with similarly low acid alpha-glucosidase activity as some patients with Pompe disease, we caution they may present as false positives in newborn screening programs especially in Asian populations.","variants":[{"Name":"NM_000152.5(GAA):c.1726G>A (p.Gly576Ser)","Chromosome":"17","Start":"80112072","Stop":"80112072","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":98376,"rule_based_match":false,"evidence_text":"c.1726G>A","llm_judgment":"PRESENT","evidence":"c.[1726G>A","abstract_start":257,"abstract_end":267}]}
{"pmid":"28293831","title":"Isolated Hearing Impairment Caused by SPATA5 Mutations in a Family with Variable Phenotypic Expression.","abstract":"Biallelic mutations in the SPATA5 gene, encoding ATPase family protein, are an important cause of newly recognized epileptic encephalopathy classified as epilepsy, hearing loss, and mental retardation syndrome (EHLMRS, OMIM: 616577). Herein we describe a family in which two SPATA5 mutations with established pathogenicity (p.Thr330del and c.1714+1G>A) were found in the proband and her younger sister. The proband had a similar clinical picture to the previous descriptions of EHLMRS. In the sister, the only manifestation was an isolated sensorineural hearing loss. Our findings extend the phenotypic spectrum of SPATA5-associated diseases and indicate that SPATA5 defects may account for a fraction of isolated sensorineural hearing impairment cases.","variants":[{"Name":"NM_145207.3(AFG2A):c.1714+1G>A","Chromosome":"4","Start":"122947489","Stop":"122947489","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":204039,"rule_based_match":true,"evidence_text":"c.1714+1G>A","llm_judgment":"PRESENT","evidence":"c.1714+1G>A","abstract_start":340,"abstract_end":351}]}
{"pmid":"30798342","title":"Evaluating pathogenicity of SLC34A3-Ser192Leu, a frequent European missense variant in disorders of renal phosphate wasting.","abstract":"Loss-of-function mutations of SLC34A3 represent an established cause of a distinct renal phosphate wasting disorder termed hereditary hypophosphatemic rickets with hypercalciuria (HHRH). SLC34A3 encodes the renal phosphate transporter NaPi2c expressed at the apical brush border of proximal renal tubules. Substitution of p.Ser192Leu is one of the most frequent genetic changes among HHRH patients in Europe, but has never been systematically evaluated, clinically or on a cellular level. Identification of a 32-year-old female with a homozgyous c.575C>T, p.Ser192Leu substitution enabled a more comprehensive assessment of the impact of this missense variant. Clinically, the patient showed renal phosphate wasting and nephrocalcinosis without any bone abnormalities. Heterozygous carriers of deleterious SLC34A3 variants were previously described to harbor an increased risk of kidney stone formation and renal calcification. We hence examined the frequency of p.Ser192Leu variants in our adult kidney stone cohort and compared the results to clinical findings of previously published cases of both mono- and biallelic p.Ser192Leu changes. On a cellular level, p.Ser192Leu-mutated transporters localize to the plasma membrane in different cellular systems, but lead to significantly reduced transport activity of inorganic phosphate upon overexpression in Xenopus oocytes. Despite the reduced function in ectopic cellular systems, the clinical consequences of p.Ser192Leu may appear relatively mild, at least in our index patient, and can potentially be missed in clinical practice.","variants":[{"Name":"NM_001177316.2(SLC34A3):c.575C>T (p.Ser192Leu)","Chromosome":"9","Start":"137233223","Stop":"137233223","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":195771,"rule_based_match":true,"evidence_text":"c.575C>T, p.Ser192Leu","llm_judgment":"PRESENT","evidence":"c.575C>T, p.Ser192Leu","abstract_start":546,"abstract_end":567}]}
{"pmid":"35701104","title":"Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/β-catenin pathway.","abstract":"BACKGROUND: The SCN5A variant is a common cause of familial dilated cardiomyopathy (DCM). We previously reported a SCN5A variant (c.674G>A), located in the high-risk S4 segment of domain I (DI-S4) region in patients with idiopathic DCM and R225Q knockin (p.R225Q) mice carrying the c.674G>A variant exhibited prolonged baseline PR intervals without DCM phenotypes. In this study, we explored the association and mechanism between R225Q variant and DCM phenotype.\nMETHODS: Prevalence of DI-S4 variant was compared between patients with idiopathic DCM and the control participants. R225Q knockin and wild-type (WT) mice were subjected to doxorubicin (DOX), D-galactose (D-gal) or D-gal combined with DOX.\nRESULTS: Clinical data suggested that the prevalence of DI-S4 variant was higher in DCM group than in the control group (4/90 (4.4%) vs 3/1339 (0.2%), p<0.001). Cardiomyocytes from R225Q knockin mice treated with D-gal and DOX exhibited more significant hypertrophic phenotype and weaker contraction/dilation function and an increased level of apoptosis as compared with WT mice. Mechanistically, we found that R225Q variant could increase intracellular pH and further induce the activation of the WNT/β-catenin pathway as well as the overexpression of pro-hypertrophic and pro-apoptotic targets. WNT-C59 inhibitor improved cardiac function in the R225Q knockin mice treated with D-gal and DOX.\nCONCLUSION: Our results suggest that R225Q variant is associated with increased susceptibility to DCM. Ageing could enhance this process via activating WNT/β-catenin signaling in response to increased intracellular pH. Antagonising the WNT/β-catenin pathway might be a potential therapeutic strategy for mitigating R225Q variant-related DCM pathogenesis.","variants":[{"Name":"NM_000335.5(SCN5A):c.674G>A (p.Arg225Gln)","Chromosome":"3","Start":"38613772","Stop":"38613772","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":78925,"rule_based_match":true,"evidence_text":"c.674G>A","llm_judgment":"PRESENT","evidence":"c.674G>A","abstract_start":130,"abstract_end":138}]}
{"pmid":"27264673","title":"A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.","abstract":"Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen-activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears, and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_002709.3(PPP1CB):c.166G>C (p.Ala56Pro)","Chromosome":"2","Start":"28776964","Stop":"28776964","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":417069,"rule_based_match":true,"evidence_text":"c.166G>C, p.Ala56Pro","llm_judgment":"PRESENT","evidence":"c.166G>C, p.Ala56Pro","abstract_start":880,"abstract_end":900}]}
{"pmid":"27900361","title":"KBG syndrome involving a single-nucleotide duplication in","abstract":"KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis. Subsequent exome sequencing identified a novel de novo heterozygous single base pair duplication (c.6015dupA) in <i>ANKRD11,</i> which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in <i>ANKRD11,</i> thereby implicating it as contributing to the proband's symptoms and yielding a molecular diagnosis of KBG syndrome. Before molecular diagnosis, this syndrome was not recognized in the proband, as several key features of the disorder were mild and were not recognized by clinicians, further supporting the concept of variable expressivity in many disorders. Although a diagnosis of cerebral folate deficiency has also been given, its significance for the proband's condition remains uncertain.","variants":[{"Name":"NM_013275.6(ANKRD11):c.6015dup (p.Gly2006fs)","Chromosome":"16","Start":"89280526","Stop":"89280527","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":244063,"rule_based_match":true,"evidence_text":"c.6015dupA","llm_judgment":"PRESENT","evidence":"c.6015dupA","abstract_start":671,"abstract_end":681}]}
{"pmid":"27063057","title":"Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness.","abstract":"Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the β subunit of G protein heterotrimer (Gαβγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling.","variants":[{"Name":"NM_002075.4(GNB3):c.1017G>A (p.Trp339Ter)","Chromosome":"12","Start":"6846892","Stop":"6846892","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":244066,"rule_based_match":true,"evidence_text":"c.1017G>A (p.Trp339(∗))","llm_judgment":"PRESENT","evidence":"c.1017G>A","abstract_start":1227,"abstract_end":1236},{"Name":"NM_002075.4(GNB3):c.170_172del (p.Lys57del)","Chromosome":"12","Start":"6843042","Stop":"6843044","ReferenceAlleleVCF":"CAAG","AlternateAlleleVCF":"C","allel_id":244067,"rule_based_match":true,"evidence_text":"c.170_172delAGA [p.Lys57del]","llm_judgment":"PRESENT","evidence":"c.170_172delAGA [p.Lys57del]","abstract_start":1172,"abstract_end":1200},{"Name":"NM_002075.4(GNB3):c.200C>T (p.Ser67Phe)","Chromosome":"12","Start":"6843073","Stop":"6843073","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":244068,"rule_based_match":true,"evidence_text":"c.200C>T (p.Ser67Phe)","llm_judgment":"PRESENT","evidence":"p.Ser67Phe","abstract_start":1485,"abstract_end":1495}]}
{"pmid":"30235038","title":"Mutational Screening of GLI3, SHH, and SHH ZRS in 78 Chinese Children with Nonsyndromic Polydactyly.","abstract":"BACKGROUND: Polydactyly is one of the most common congenital limb abnormalities. Our objective was to identify the genetic causes of non-syndromic polydactyly in 78 Chinese children.\nMATERIALS AND METHODS: Genomic DNA was isolated from 78 independent nonsyndromic polydactyly patients, of whom 71 had preaxial polydactyly (PPD), six had postaxial polydactyly (PAP), and one showed combined PPD1 and PAP-A/B. The coding areas and exon/intron boundaries of the GLI3 and SHH genes and the genomic region of SHH ZRS were amplified by polymerase chain reaction and sequenced.\nRESULTS: The patient with combined PPD1 and PAP-A/B (subject DUO36) exhibited a heterozygous nonsense mutation in chr7: 42004164G>A (ENST00000395925, c.4507C>T, p.Gln1503Stop ) of the GLI3 gene that has not been previously recorded. We did not detect any mutations in GLI3, SHH, or SHH ZRS in the other 77 nonsyndromic polydactyly patients.\nCONCLUSION: The novel mutation in GLI3 c.4507C>T is likely one of the causes of the PAP and PPD1 of subject DUO36. This important finding should facilitate the optimization of genetic testing for nonsyndromic polydactyly.","variants":[{"Name":"NM_000168.6(GLI3):c.4507C>T (p.Gln1503Ter)","Chromosome":"7","Start":"41964566","Stop":"41964566","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1496504,"rule_based_match":true,"evidence_text":"c.4507C>T","llm_judgment":"PRESENT","evidence":"c.4507C>T","abstract_start":721,"abstract_end":730}]}
{"pmid":"32065797","title":"ErbB4 Mutation that Decreased NRG1-ErbB4 Signaling Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.","abstract":"BACKGROUND: Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) includes a large spectrum of neurodegenerative disorders.\nOBJECTIVE: To identify the relationship of ErbB4 mutation and ALS/FTD.\nMETHODS: Here, we report an atypical case of frontal variant behavioral abnormalities at the initial stage, a stable plateau stage of 5 years, and paralysis involving both upper and lower motor neurons followed by progressive cognitive dysfunction at the advanced stage. The clinical findings suggested a diagnosis of ALS/FTD, and genetic testing revealed erb-b2 receptor tyrosine kinase 4 (ErbB4) heterozygous mutation (c.2136 T>G, p.I712M), identified in an ALS pedigree previously. We modeled mutant ErbB4 protein through the SWISS-MODEL Server, and speculated on the structural change caused by the mutation. We also identified that ErbB4 (I712M) mutation led to reduced auto-phosphorylation of ErbB4 upon neuregulin-1 (NRG1) stimulation.\nRESULTS: A functional analysis of ErbB4 mutation demonstrated an obviously decreased auto-phosphorylation of ErbB4 involving in the pathogenesis of ALS/FTD.\nCONCLUSION: We firstly found ErbB4 mutation to be identified in ALS/FTD.","variants":[{"Name":"NM_005235.3(ERBB4):c.2136T>G (p.Ile712Met)","Chromosome":"2","Start":"211623988","Stop":"211623988","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1469465,"rule_based_match":true,"evidence_text":"c.2136 T>G, p.I712M","llm_judgment":"PRESENT","evidence":"c.2136 T>G, p.I712M","abstract_start":626,"abstract_end":645}]}
{"pmid":"31515790","title":"Analysis of a pedigree with autosomal dominant intermediate Charcot-Marie-Tooth disease type E and nephropathy","abstract":"OBJECTIVE: To explore phenotypic and mutational characteristics of a pedigree affected with autosomal dominant Charcot-Marie-Tooth disease (CMT) and nephropathy.\nMETHODS: Clinical data of the proband and his family members was collected. Electrophysiology, renal biopsy and next-generation sequencing were carried out for the proband.\nRESULTS: The proband presented with distal lower limb weakness and proteinuria in childhood. His mother and brother had similar symptoms. Electrophysiological test of the proband revealed demyelination and axonal changes in both motor and sensory nerves. Renal biopsy suggested focal segmental glomerulosclerosis. Genetic testing revealed a heterozygous c.341G>A (p.G114D) mutation in exon 2 of the INF2 gene.\nCONCLUSION: The phenotypic feature of the pedigree is autosomal dominant intermediate CMT and focal segmental glomerulosclerosis, which may be attributed to the c.341G>A mutation of the INF2 gene.","variants":[{"Name":"NM_022489.4(INF2):c.341G>A (p.Gly114Asp)","Chromosome":"14","Start":"104701706","Stop":"104701706","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625304,"rule_based_match":true,"evidence_text":"c.341G>A (p.G114D)","llm_judgment":"PRESENT","evidence":"c.341G>A (p.G114D)","abstract_start":689,"abstract_end":707}]}
{"pmid":"24772966","title":"Analysis of gene mutations among South Indian patients with maple syrup urine disease: identification of four novel mutations.","abstract":"Maple syrup urine disease (MSUD) is predominantly caused by mutations in the BCKDHA, BCKDHB and DBT genes, which encode for the E1alpha, E1beta and E2 subunits of the branched-chain alpha-keto acid dehydrogenase complex, respectively. Because disease causing mutations play a major role in the development of the disease, prenatal diagnosis at gestational level may have significance in making decisions by parents. Thus, this study was aimed to screen South Indian MSUD patients for mutations and assess the genotype-phenotype correlation. Thirteen patients diagnosed with MSUD by conventional biochemical screening such as urine analysis by DNPH test, thin layer chromatography for amino acids and blood amino acid quantification by HPLC were selected for mutation analysis. The entire coding regions of the BCKDHA, BCKDHB and DBT genes were analyzed for mutations by PCR-based direct DNA sequencing. BCKDHA and BCKDHB mutations were seen in 43% of the total ten patients, while disease-causing DBT gene mutation was observed only in 14%. Three patients displayed no mutations. Novel mutations were c.130C>T in BCKDHA gene, c. 599C>T and c.121_122delAC in BCKDHB gene and c.190G>A in DBT gene. Notably, patients harbouring these mutations were non-responsive to thiamine supplementation and other treatment regimens and might have a worse prognosis as compared to the patients not having such mutations. Thus, identification of these mutations may have a crucial role in the treatment as well as understanding the molecular mechanisms in MSUD.","variants":[{"Name":"NM_183050.4(BCKDHB):c.599C>T (p.Pro200Leu)","Chromosome":"6","Start":"80168996","Stop":"80168996","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":543978,"rule_based_match":true,"evidence_text":"c. 599C>T","llm_judgment":"PRESENT","evidence":"c. 599C>T","abstract_start":1126,"abstract_end":1135},{"Name":"NM_000709.4(BCKDHA):c.130C>T (p.Gln44Ter)","Chromosome":"19","Start":"41410658","Stop":"41410658","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1064719,"rule_based_match":true,"evidence_text":"c.130C>T","llm_judgment":"PRESENT","evidence":"c.130C>T","abstract_start":1101,"abstract_end":1109}]}
{"pmid":"28126021","title":"De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease.","abstract":"BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease of the gastrointestinal tract which includes ulcerative colitis and Crohn's disease. Genetic risk factors for IBD are not well understood.\nMETHODS: We performed a family-based whole exome sequencing (WES) analysis on a core family (Family A) to identify potential causal mutations and then analyzed exome data from a Caucasian pediatric cohort (136 patients and 106 controls) to validate the presence of mutations in the candidate gene, heat shock 70 kDa protein 1-like (HSPA1L). Biochemical assays of the de novo and rare (minor allele frequency, MAF < 0.01) mutation variant proteins further validated the predicted deleterious effects of the identified alleles.\nRESULTS: In the proband of Family A, we found a heterozygous de novo mutation (c.830C > T; p.Ser277Leu) in HSPA1L. Through analysis of WES data of 136 patients, we identified five additional rare HSPA1L mutations (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients. In contrast, rare HSPA1L mutations were not observed in controls, and were significantly enriched in patients (P = 0.02). Interestingly, we did not find non-synonymous rare mutations in the HSP70 isoforms HSPA1A and HSPA1B. Biochemical assays revealed that all six rare HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity.\nCONCLUSIONS: Our results indicate that de novo and rare mutations in HSPA1L are associated with IBD and provide insights into the pathogenesis of IBD, and also expand our understanding of the roles of HSP70s in human disease.","variants":[{"Name":"NM_005527.4(HSPA1L):c.515_517del (p.Leu172del)","Chromosome":"6","Start":"31811456","Stop":"31811458","ReferenceAlleleVCF":"CTTA","AlternateAlleleVCF":"C","allel_id":359041,"rule_based_match":false,"evidence_text":"c.515_517del (p.Leu172del)","llm_judgment":"PRESENT","evidence":"p.Leu172del","abstract_start":981,"abstract_end":992}]}
{"pmid":"26900323","title":"EPHA2 MUTATIONS CONTRIBUTE TO CONGENITAL CATARACT THROUGH DIVERSE MECHANISMS.","abstract":"PURPOSE: Congenital cataract is a leading cause of childhood blindness. Mutations in the EPHA2 gene are one of the causes of inherited congenital cataract. The EPHA2 gene encodes a membrane-bound tyrosine kinase receptor and is highly expressed in epithelial cells, including in the ocular lens. Signaling through the EPHA2 receptor plays a pivotal role in epithelial cell homeostasis. The aim of this study was to determine the effect of congenital cataract causing mutations in the EPHA2 gene on the encoded protein in epithelial cells.\nMETHODS: The effect of five disease-causing mutations, p.P584L (c.1751C>T), p.T940I (c.2819C>T), p.D942fsXC71 (c.2826-9G>A), p.A959T (c.2875G>A), and p.V972GfsX39 (c.2915_2916delTG), on localization of the protein was examined in two in vitro epithelial cell culture systems: Madin-Darby Canine Kidney (MDCK) and human colorectal adenocarcinoma (Caco-2) epithelial cells. Myc-tagged mutant constructs were generated by polymerase chain reaction (PCR)-based mutagenesis. The Myc-tagged wild-type construct was used as a control. The Myc-tagged wild-type and mutant proteins were ectopically expressed and detected by immunofluorescence labeling.\nRESULTS: Two of the mutations, p.T940I and p.D942fsXC71, located within the cytoplasmic sterile-α-motif (SAM) domain of EPHA2, led to mis-localization of the protein to the perinuclear space and co-localization with the cis-golgi apparatus, indicating sub-organellar/cellular retention of the mutant proteins. The mutant proteins carrying the remaining three mutations, similar to the wild-type EPHA2, localized to the cell membrane.\nCONCLUSIONS: Mis-localization of two of the mutant proteins in epithelial cells suggests that some disease-causing mutations in EPHA2 likely affect lens epithelial cell homeostasis and contribute to cataract. This study suggests that mutations in EPHA2 contribute to congenital cataract through diverse mechanisms.","variants":[{"Name":"NM_004431.5(EPHA2):c.2915_2916del (p.Val972fs)","Chromosome":"1","Start":"16125230","Stop":"16125231","ReferenceAlleleVCF":"CCA","AlternateAlleleVCF":"C","allel_id":822930,"rule_based_match":true,"evidence_text":"c.2915_2916delTG","llm_judgment":"PRESENT","evidence":"c.2915_2916delTG","abstract_start":703,"abstract_end":719}]}
{"pmid":"31997689","title":"Investigation of MYO15A and MYO7A Mutations in Iranian Patients with Nonsyndromic Hearing Loss.","abstract":"BACKGROUND: Hearing loss (HL) is the most common sensory disorder in humans, which affects individuals in both inherited and acquired forms. MYO15A and MYO7A gene mutations have a significant role in the development of deafness. In this study, we assessed the prevalence of MYO15A and MYO7A mutations in one hundred non-relative deaf Iranians. <b>Materials and methods:</b> The existence of MYO15A and MYO7A mutations were assessed using the tetra-primer ARMS-PCR method, High Resolution Melting (HRM) and sequencing method. <b>Results:</b> A heterozygote missense mutation, p.V2135L (c.6403G > T) in the MYO15A gene, was found in a patient using the sequencing method. <b>Conclusion:</b> These results explain the negligible prevalence of selected mutations among Iranian patients. Identifying common mutations in patients of an ethnic group can reduce the financial costs and time needed for identifying the causes of deafness.","variants":[{"Name":"NM_016239.4(MYO15A):c.6403G>T (p.Val2135Leu)","Chromosome":"17","Start":"18146001","Stop":"18146001","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":215532,"rule_based_match":true,"evidence_text":"c.6403G > T","llm_judgment":"PRESENT","evidence":"c.6403G > T","abstract_start":585,"abstract_end":596}]}
{"pmid":"24006930","title":"Hb Fulton-Georgia [α20(B1)His→Pro; HBA1: c.62A>C]: a new α-globin variant coinherited with α-thalassemia-2 (3.7 kb deletion) and Hb SC disease.","abstract":"We report a novel hemoglobin (Hb) variant that we named Hb Fulton-Georgia, caused by a point mutation in exon 1/codon 20 of the α-globin gene [α20(B1)His→Pro; HBA1: c.62A>C]. This α chain variant was identified in an adult African-American female with Hb SC disease who was also heterozygous for the α-thalassemia-2 (α-thal-2) (3.7 kb deletion or αα/-α(3.7)). The Hb Fulton-Georgia mutation was located on the intact α1-globin gene not involved by α-thal-2. Molecular models indicated that the α20 residue of Hb Fulton-Georgia was the first amino acid of the B helix, and was not involved in α1/β1 or α1/β2 contacts in Hb S [β6(A3)Glu→Val; HBB: c.20A>T] or Hb C [β6(A3)Glu→Lys; HBB: c.19G>A] tetramers. Furthermore, the histidine→proline substitution at α20 did not disrupt the helical structure. High performance liquid chromatography (HPLC) detected Hb Fulton-Georgia in 16.0% of total Hb, consistent with inheritance on the α1 gene. Coinheritance of Hb Fulton-Georgia, heterozygous α-thal-2 and Hb SC disease was associated with a mild phenotype, consisting of microcytosis and anisocytosis, but no anemia or other hematological abnormality.","variants":[{"Name":"NM_000558.5(HBA1):c.62A>C (p.His21Pro)","Chromosome":"16","Start":"176778","Stop":"176778","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1320817,"rule_based_match":true,"evidence_text":"HBA1: c.62A>C","llm_judgment":"PRESENT","evidence":"HBA1: c.62A>C","abstract_start":159,"abstract_end":172}]}
{"pmid":"28944232","title":"Mutational analysis of","abstract":"BACKGROUND: Breast cancer is one of the most prevalent malignancies in the world. In Peru, breast cancer is the second cause of death among women. Five to ten percent of patients present a high genetic predisposition due to <i>BRCA1</i> and <i>BRCA2</i> germline mutations.\nMETHODS: We performed a comprehensive analysis of <i>BRCA1</i> and <i>BRCA2</i> genes by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to detect large rearrangements in patients from 18 families, which met the criteria for hereditary breast cancer.\nRESULTS: In this series, we found four pathogenic mutations, three previously reported (<i>BRCA1</i>: c.302-1G>C and c.815_824dup10; <i>BRCA2</i>: c.5946delT) and a duplication of adenines in exon 15 in <i>BRCA1</i> gene (c.4647_4648dupAA, ClinVar SCV000256598.1). We also found two exonic and four intronic variants of unknown significance and 28 polymorphic variants.\nCONCLUSION: This is the first report to determine the spectrum of mutations in the <i>BRCA1/BRCA2</i> genes in Peruvian families selected by clinical and genetic criteria. The alteration rate in <i>BRCA1/BRCA2</i> with proven pathogenic mutation was 22.2% (4 out 18) and this finding could be influenced by the reduced sample size or clinical criteria. In addition, we found three known <i>BRCA1/BRCA2</i> mutations and a <i>BRCA1</i> c.4647_4648dupAA as a novel pathogenic mutation.","variants":[{"Name":"NM_007294.4(BRCA1):c.302-1G>C","Chromosome":"17","Start":"43104262","Stop":"43104262","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":69418,"rule_based_match":true,"evidence_text":"c.302-1G>C","llm_judgment":"PRESENT","evidence":"c.302-1G>C","abstract_start":657,"abstract_end":667},{"Name":"NM_000059.4(BRCA2):c.5946del (p.Ser1982fs)","Chromosome":"13","Start":"32340301","Stop":"32340301","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":24364,"rule_based_match":true,"evidence_text":"c.5946delT","llm_judgment":"PRESENT","evidence":"c.5946delT","abstract_start":702,"abstract_end":712},{"Name":"NM_007294.4(BRCA1):c.4647_4648dup (p.Thr1550fs)","Chromosome":"17","Start":"43074357","Stop":"43074358","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GTT","allel_id":224600,"rule_based_match":true,"evidence_text":"c.4647_4648dupAA","llm_judgment":"PRESENT","evidence":"c.4647_4648dupAA","abstract_start":777,"abstract_end":793}]}
{"pmid":"34747535","title":"Targeted massively parallel sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas: An analysis of 51 individuals in a single-center experience.","abstract":"Constitutional LZTR1 or SMARCB1 pathogenic variants (PVs) have been found in ∼86% of familial and ∼40% of sporadic schwannomatosis cases. Hence, we performed massively parallel sequencing of the entire LZTR1, SMARCB1, and NF2 genomic loci in 35 individuals with schwannomas negative for constitutional first-hit PVs in the LZTR1/SMARCB1/NF2 coding sequences; however, with 22q deletion and/or a different NF2 PV in each tumor, including six cases with only one tumor available. Furthermore, we verified whether any other LZTR1/SMARCB1/NF2 (likely) PVs could be found in 16 cases carrying a SMARCB1 constitutional variant in the 3'-untranslated region (3'-UTR) c.*17C>T, c.*70C>T, or c.*82C>T. As no additional variants were found, functional studies were performed to clarify the effect of these 3'-UTR variants on the transcript. The 3'-UTR variants c.*17C>T and c.*82C>T showed pathogenicity by negatively affecting the SMARCB1 transcript level. Two novel deep intronic SMARCB1 variants, c.500+883T>G and c.500+887G>A, resulting in out-of-frame missplicing of intron 4, were identified in two unrelated individuals. Further resequencing of the entire repeat-masked genomics sequences of chromosome 22q in individuals negative for PVs in the SMARCB1/LZTR1/NF2 coding- and noncoding regions revealed five potential schwannomatosis-predisposing candidate genes, that is, MYO18B, NEFH, SGSM1, SGSM3, and SBF1, pending further verification.","variants":[{"Name":"NM_003073.5(SMARCB1):c.*82C>T","Chromosome":"22","Start":"23834262","Stop":"23834262","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":243654,"rule_based_match":true,"evidence_text":"c.*82C>T","llm_judgment":"PRESENT","evidence":"c.*82C>T","abstract_start":683,"abstract_end":691}]}
{"pmid":"37308967","title":"Beyond germline genetic testing - heterozygous pathogenic variants in PMS2 in two children with Osteosarcoma and Ependymoma.","abstract":"BACKGROUND: Lynch syndrome (LS) is not considered part of childhood cancer predisposition syndromes.\nCASE PRESENTATION: Analysis of a pediatric osteosarcoma (OS) displayed hypermutation (16.8), alternative lengthening of telomeres (ALT), loss of PMS2 expression in tumor tissue (retained in non-neoplastic cells), PMS2 loss of heterozygosity (LOH), and high-degree of microsatellite instability (MSI) tested by PCR. A heterozygous duplication c.1076dup p.(Leu359Phefs*6) in exon 10 of NM_000535.6:PMS2 was detected by SNV analysis in peripheral blood, confirming diagnosis of LS in the patient. The tumor molecular features suggest LS-associated development of OS. In a second case, whole-genome sequencing identified a heterozygous SNV c.1 A > T p.? in exon 1 of PMS2 in tumor and germline material of a girl with ependymoma. Tumor analysis displayed evidence for ALT and low mutational burden (0.6), PMS2 expression was retained, MSI was low. Multiplex ligation-dependent probe amplification identified no additional PMS2 variant and germline MSI testing did not reveal increased gMSI ratios in the patient´s lymphocytes. Thus, CMMRD was most closely excluded and our data do not suggest that ependymoma was related to LS in the child.\nCONCLUSIONS: Our data suggest that the LS cancer spectrum may include childhood cancer. The importance of LS in pediatric cancers necessitates prospective data collection. Comprehensive molecular workup of tumor samples is necessary to explore the causal role of germline genetic variants.","variants":[{"Name":"NM_000535.7(PMS2):c.1076dup (p.Leu359fs)","Chromosome":"7","Start":"5989867","Stop":"5989868","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":96764,"rule_based_match":true,"evidence_text":"c.1076dup p.(Leu359Phefs*6)","llm_judgment":"PRESENT","evidence":"c.1076dup p.(Leu359Phefs*6)","abstract_start":443,"abstract_end":470}]}
{"pmid":"25394566","title":"Evaluation of genotype-phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome.","abstract":"DESIGN: Patients with Pendred syndrome have genotypic and phenotypic variability, leading to challenges in definitive diagnosis. Deaf children with enlarged vestibular aqueducts are often subjected to repeated investigations when tests for mutations in SLC26A4 are abnormal. This study provides genotype and phenotype information from patients with suspected Pendred syndrome referred to a single clinical endocrinology unit.\nMETHODS: A retrospective analysis of 50 patients with suspected Pendred syndrome to investigate the correlation between genetic, perchlorate discharge test (PDT) and endocrine status.\nRESULTS: Eight patients with monoallelic SLC26A4 mutations had normal PDT. Of the 33 patients with biallelic mutations, ten of 12 patients with >30% discharge developed hypothyroidism. In our cohort, c.626G>T and c.3-2A>G result in milder clinical presentations with lower median perchlorate discharge of 9.3% (interquartile range 4-15%) compared with 40% (interquartile range 21-60%) for the remaining mutations. Eight novel mutations were detected. All patients with PDT <30% remained euthyroid to date, although the majority are still under the age of 30. There was a significant correlation between PDT and goitre size (R=0.61, P=0.0009) and the age of onset of hypothyroidism (R=-0.62, P=0.0297). In our population, the hazard of becoming hypothyroid increased by 7% per percentage point increase in PDT (P<0.001).\nCONCLUSION: There is a correlation between SLC26A4 genotype and thyroid phenotype. If results hold true for larger patient numbers and longer follow-up, then for patients with monoallelic mutations, PDT could be unnecessary. Patients with biallelic mutations and PDT discharge >30% have a high risk of developing goitre and hypothyroidism, and should have lifelong monitoring.","variants":[{"Name":"NM_000441.2(SLC26A4):c.626G>T (p.Gly209Val)","Chromosome":"7","Start":"107674970","Stop":"107674970","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":19860,"rule_based_match":true,"evidence_text":"c.626G>T","llm_judgment":"PRESENT","evidence":"c.626G>T","abstract_start":810,"abstract_end":818}]}
{"pmid":"35048620","title":"Pedigree Analysis and Diagnosis of Congenital Dysfibrinogenemia: A Case Report","abstract":"OBJECTIVE: To improve the understanding and diagnosis and treatment of congenital dysfibrinogenemia (CD) through analyzing the clinical data of a pediatric patient and his pedigree.\nMETHODS: The clinical manifestations, laboratory findings and treatment of a case of CD diagnosed at West China Second University Hospital, Sichuan University and those of its pedigree members were analyzed, and genetic tracing and follow-up were conducted on the patient and its pedigree.\nRESULTS: The child has no clinical manifestations at the time of admission. Coagulation function examination showed normal prothrombin time (PT), normal activated partial thrombin time (APTT), significantly prolonged thrombin time (TT), fibrinogen activity (Fg: C<0.5 g/L) measured with the Clauss method, and fibrinogen antigen (Fg: Ag) measured at 2.8 g/L with PT algorithm. Gene sequencing results showed that heterozygous missense mutation c.901C>T (p.Arg301Cys) in exon 8 of <i>FGG</i> gene. Combined with the family history, the child was diagnosed with CD. During the follow-up of 4 <sup>+</sup> months, the patient did not present bleeding, abnormal coagulation or thrombosis, and the coagulation function did not show significant changes compared with the findings obtained on admission.\nCONCLUSION: The diagnosis of CD is confirmed mainly based on genetic testing and the treatment is characterized by the principle of precise individualized treatment. No special treatment is needed for patients presenting no clinical manifestations. However, it is important to provide thorough prenatal diagnosis and follow-up services for female patients planning for pregnancy so as to prevent miscarriage and complications caused by postpartum coagulation dysfunction.","variants":[{"Name":"NM_021870.2(FGG):c.901C>T (p.Arg301Cys)","Chromosome":"4","Start":"154606933","Stop":"154606933","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31400,"rule_based_match":true,"evidence_text":"c.901C>T (p.Arg301Cys)","llm_judgment":"PRESENT","evidence":"c.901C>T (p.Arg301Cys)","abstract_start":916,"abstract_end":938}]}
{"pmid":"33993910","title":"Genetic analysis of","abstract":"As the most frequent inherited tubulopathy, Gitelman syndrome (GS), has an incidence that has increased worldwide. The distribution of <i>SLC12A3</i> gene mutation hotspots deserves exploration. In addition, GS is not a benign syndrome; however, the diagnostic process of GS has not yet been completely detailed.\nMATERIALS AND METHODS: We report two cases of GS pedigrees involving two previously unreported mutations, c. 676G>A, p. A226T and c. 421G>A, p. G141R, in the <i>SLC12A3</i> gene and reviewed relevant literature. We searched the literature for nucleotide of <i>SLC12A3</i> in PubMed and other databases as of April 20, 2020.\nRESULTS: A total of 1,794 detected mutated alleles in 939 patients worldwide were included in this study. Splicing mutations and p. Gly741Arg were mutation hotspots in a European population. P. Leu858His and p. Thr60Met were mutation hotspots in an Asian population. P. Leu858His and p. Thr180Lys were considered mutation hotspots in the Japanese population, while p. Thr60Met and p. Asp486Asn were considered mutation hotspots in the Chinese population.\nCONCLUSION: Our results identified two novel mutation sites (c. 676G>A, p. A226T and c. 421G>A, p. G141R), if their pathogenicity was determined this could contribute to the enrichment of database resources on GS. Our study has compiled the most comprehensive <i>SLC12A3</i> gene mutation database in the world thus far to reveal that different regions have different mutation hotspots in SLC12A3. Moreover, the establishment of a diagnostic process for GS has important implications for confirmed cases.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.676G>A (p.Ala226Thr)","Chromosome":"16","Start":"56870170","Stop":"56870170","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1871428,"rule_based_match":true,"evidence_text":"c. 676G>A, p. A226T","llm_judgment":"PRESENT","evidence":"c. 676G>A, p. A226T","abstract_start":419,"abstract_end":438}]}
{"pmid":"33179225","title":"Clinical and genetic analysis of four patients with congenital neutropenia","abstract":"OBJECTIVE: To delineate the clinical feature and genetic basis of four patients with congenital neutropenia.\nMETHODS: All patients were subjected to whole exome sequencing (WES). Suspected variants were verified by Sanger sequencing.\nRESULTS: The patients (two boys and two girls), aged 7 to 15 months, suffered from neutropenia and recurrent infections. Bone marrow smears showed a significant decrease in the proportion of rod-shaped and lobulated granulocytes, which suggested impaired development and maturation of bone marrow neutrophils. WES has discovered heterozygous variants (c.496G>A, c.58C>G, c.391G>A and IVS1+5T>A) of the ELANE gene in the patients. Among these, c.58C>G and IVS1+5T>A were unreported previously. Follow up revealed patients 1 and 3 had periodic neutropenia, while patients 2 and 4 had severe congenital neutropenia. After attaining the definite diagnosis, the patients were treated symptomatically.\nCONCLUSION: The main clinical feature of congenital neutropenia is refractory recurrent bacterial infections, for which mutations of the ELANE gene are a common cause. Two novel pathogenic ELANE variants have been discovered in this study.","variants":[{"Name":"NM_001972.4(ELANE):c.496G>A (p.Ala166Thr)","Chromosome":"19","Start":"855693","Stop":"855693","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1945472,"rule_based_match":true,"evidence_text":"c.496G>A","llm_judgment":"PRESENT","evidence":"c.496G>A","abstract_start":586,"abstract_end":594},{"Name":"NM_001972.4(ELANE):c.391G>A (p.Ala131Thr)","Chromosome":"19","Start":"855588","Stop":"855588","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3088309,"rule_based_match":true,"evidence_text":"c.391G>A","llm_judgment":"PRESENT","evidence":"c.391G>A","abstract_start":605,"abstract_end":613}]}
{"pmid":"11901181","title":"Deficiency of UDP-galactose:N-acetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId.","abstract":"Deficiency of the Golgi enzyme UDP-Gal:N-acetylglucosamine beta-1,4-galactosyltransferase I (beta4GalT I) (E.C.2.4.1.38) causes a new congenital disorder of glycosylation (CDG), designated type IId (CDG-IId), a severe neurologic disease characterized by a hydrocephalus, myopathy, and blood-clotting defects. Analysis of oligosaccharides from serum transferrin by HPLC, mass spectrometry, and lectin binding revealed the loss of sialic acid and galactose residues. In skin fibroblasts and leukocytes, galactosyltransferase activity was reduced to 5% that of controls. In fibroblasts, a truncated polypeptide was detected that was about 12 kDa smaller in size than wild-type beta4GalT I and that failed to localize to the Golgi apparatus. Sequencing of the beta4GalT I cDNA and gene revealed an insertion of a single nucleotide (1031-1032insC) leading to premature translation stop and loss of the C-terminal 50 amino acids of the enzyme. The patient was homozygous and his parents heterozygous for this mutation. Expression of a corresponding mutant cDNA in COS-7 cells led to the synthesis of a truncated, inactive polypeptide, which localized to the endoplasmic reticulum.","variants":[{"Name":"NM_001497.4(B4GALT1):c.1031dup (p.Arg345fs)","Chromosome":"9","Start":"33113806","Stop":"33113807","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":31268,"rule_based_match":false,"evidence_text":"1031-1032insC","llm_judgment":"PRESENT","evidence":"1031-1032insC","abstract_start":828,"abstract_end":841}]}
{"pmid":"32222963","title":"Mutational and clinical spectrum in a cohort of Chinese patients with hereditary nemaline myopathy.","abstract":"Hereditary nemaline myopathy (NM) is one of the most common congenital myopathies with the histopathological findings of nemaline bodies. We used targeted next-generation sequencing to identify causative mutations in 48 NM patients with confirmed myopathological diagnosis, analyze the mutational spectrum and phenotypic features. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) was used to confirm the pathogenic effect of one nebulin (NEB) splicing variant. The results showed that variants were found in five NM-associated genes, including NEB, actin alpha 1 (ACTA1), troponin T1, Kelch repeat and BTB domain-containing 13, and cofilin-2, in 34 (73.9%), 7 (15.2%), 3 (6.5%), 1 (2.2%), and 1 (2.2%) patients, respectively, in a total of 46/48 (95.8%) NM patients. Of the total 64 variants identified, 51 were novel variants including 26 pathogenic, 1 probably pathogenic, and 24 variant of uncertain significance (VUS). Notably, one NEB splicing mutation, c.21417+3A>G causing exon 144 splicing (NM_001164508.1), as confirmed by RT-PCR, was found in 52.9% (18 patients) of NEB variant-carrying patients. Typical congenital NM, the most common clinical subtype (60.4%), was associated with five NM genes. We concluded that hereditary NM showed a highly variable genetic spectrum. NEB was the most frequent causative gene in this Chinese cohort, followed by ACTA1. We found a hotspot splicing mutation in NEB among Chinese cohort.","variants":[{"Name":"NM_001164508.2(NEB):c.21417+3A>G","Chromosome":"2","Start":"151533439","Stop":"151533439","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":421280,"rule_based_match":true,"evidence_text":"c.21417+3A>G","llm_judgment":"PRESENT","evidence":"c.21417+3A>G","abstract_start":980,"abstract_end":992}]}
{"pmid":"34567246","title":"Hereditary breast cancer and ancestry in the Madeira archipelago: an exploratory study.","abstract":"Access to genetic testing and counselling in remote areas such as the Madeira archipelago, in the Northern Atlantic Ocean, may be complex. Different counselling methods, including telegenetics, should be explored. In this study, we characterise the Hereditary Breast/Ovarian Cancer (HBOC) families with Madeira ancestry enrolled in our programme. Of a total of 3,566 index patients tested between January 2000 and June 2018, 68 had Madeira ancestry and 22 were diagnosed with a pathogenic germline variant (PV). As in the whole group, BRCA2 PV were more frequent in Madeira patients (68.4%: c.9382C>T (26.3%), c.658_659del (21%), c.156_157insAlu (10.5%), c.793+1G>A (5.3%) and c.298A>T (5.3%). However, the most frequently diagnosed PV in Madeira patients was the BRCA1 c.3331_3334del (31.6%). <i>BRCA1/2</i> detection rates were 27.9% and 10.5% for Madeira and the whole group, respectively. This study is the first characterisation of HBOC patients with Madeira ancestry. A distinct pattern of <i>BRCA1/2</i> variants was observed, and the geographic clustering of <i>BRCA1</i> c.3331_3334del variant may support the possibility of a founder mutation previously described in Northern Portugal. The high detection rate observed reinforces the need to reduce gaps in access to genetic testing in Madeira and other remote areas. According to current guidelines, timely identification of HBOC patients can contribute to their ongoing care and treatment.","variants":[{"Name":"NM_000059.4(BRCA2):c.9382C>T (p.Arg3128Ter)","Chromosome":"13","Start":"32394814","Stop":"32394814","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67494,"rule_based_match":true,"evidence_text":"c.9382C>T (26.3%)","llm_judgment":"PRESENT","evidence":"c.9382C>T (26.3%)","abstract_start":591,"abstract_end":608}]}
{"pmid":"33864784","title":"Novel TEAD1 gene variant in a Serbian family with Sveinsson's chorioretinal atrophy.","abstract":"Sveinsson's chorioretinal atrophy (SCRA) or helicoidal peripapillary chorioretinal degeneration (HPCD) as previously referred, is a rare ocular disease with autosomal dominant pattern of inheritance. The vast majority of reported cases were of Icelandic origin but the characteristic clinical picture of SCRA was also described in patients of non-Icelandic descent. Here, we report a novel disease-causing variant c.1261T>A, p.Tyr421Asn in TEAD1, detected in a Serbian family from Bosnia diagnosed with SCRA. The newly discovered change occurred at the same position as the \"Icelandic mutation\" (c.1261T>C, p.Tyr421His). According to our findings, this position in the exon 13 of the TEAD1 gene, at base pair 94, should be considered as a mutation hotspot and a starting point for future genetic analyses of patients with SCRA diagnosis.","variants":[{"Name":"NM_021961.6(TEAD1):c.1261T>A (p.Tyr421Asn)","Chromosome":"11","Start":"12937202","Stop":"12937202","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":972520,"rule_based_match":true,"evidence_text":"c.1261T>A, p.Tyr421Asn","llm_judgment":"PRESENT","evidence":"c.1261T>A, p.Tyr421Asn","abstract_start":414,"abstract_end":436}]}
{"pmid":"33565069","title":"Isovaleric acidemia due to compound heterozygous variants of IVD gene in a case","abstract":"OBJECTIVE: To analyze the clinical features, biochemical characteristics and molecular pathogenesis of a girl with isovaleric acidemia.\nMETHODS: Clinical features, blood spot amino acid profiles and urinary organic acid profiles of the patient were analyzed. Targeted capture, next generation sequencing and Sanger sequencing were carried out to detect potential variant of the IVD gene.\nRESULTS: The patient presented with poor weight gain, poor feeding, lethargy, and a \"sweaty feet\" odor 10 days after birth. Biochemical test suggested hyperammonemia. Blood spot amino acid profiles displayed a dramatic increase in isovalerylcarnitine (C5: 3. 044, reference range 0.04 - 0.4 μmol/L). Organic acid analysis of her urine sample revealed a high level of isovaleric glycine (669. 53, reference range 0 - 0.5). The child was ultimately diagnosed with isovaleric acidemia, and was found to harbor a paternally derived heterozygous variant c.149G>A (p.R50H) and a maternally derived heterozygous variant c.1123G>A (p.G375S) of the IVD gene. Her elder brother was a heterozygous carrier of c.1123G>A (p.G375S) variant. The c.149G>A (p.R50H) was a known pathogenic variant, while the c.1123G>A (p.G375S) variant was previously unreported.\nCONCLUSION: The pathogenesis of the patient was delineated from the perspective of genetics, which has provided a basis for clinical diagnosis, treatment as well as genetic counseling.","variants":[{"Name":"NM_002225.5(IVD):c.1123G>A (p.Gly375Ser)","Chromosome":"15","Start":"40416347","Stop":"40416347","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1322158,"rule_based_match":true,"evidence_text":"c.1123G>A (p.G375S)","llm_judgment":"PRESENT","evidence":"c.1123G>A (p.G375S)","abstract_start":1001,"abstract_end":1020}]}
{"pmid":"31852446","title":"Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families.","abstract":"BACKGROUND: Neurological disorders are a common cause of morbidity and mortality within Pakistani populations. It is one of the most important challenges in healthcare, with significant life-long socio-economic burden.\nMETHODS: We investigated the cause of disease in three Pakistani families in individuals with unexplained autosomal recessive neurological conditions, using both genome-wide SNP mapping and whole exome sequencing (WES) of affected individuals.\nRESULTS: We identified a homozygous splice site variant (NM_000521:c.445 + 1G > T) in the hexosaminidase B (HEXB) gene confirming a diagnosis of Sandhoff disease (SD; type II GM2-gangliosidosis), an autosomal recessive lysosomal storage disorder caused by deficiency of hexosaminidases in a single family. In two further unrelated families, we identified a homozygous frameshift variant (NM_024298.3:c.758_778del; p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) as the likely cause of disease. MBOAT7 gene variants have recently been identified as a cause of intellectual disability (ID), seizures and autistic features.\nCONCLUSIONS: We identified two metabolic disorders of lipid biosynthesis within three Pakistani families presenting with undiagnosed neurodevelopmental conditions. These findings enabled an accurate neurological disease diagnosis to be provided for these families, facilitating disease management and genetic counselling within this population. This study consolidates variation within MBOAT7 as a cause of neurodevelopmental disorder, broadens knowledge of the clinical outcomes associated with MBOAT7-related disorder, and confirms the likely presence of a regionally prevalent founder variant (c.758_778del; p.Glu253_Ala259del) in Pakistan.","variants":[{"Name":"NM_024298.5(MBOAT7):c.758_778del (p.Glu253_Ala259del)","Chromosome":"19","Start":"54180849","Stop":"54180869","ReferenceAlleleVCF":"CCGGCGGCAATGCAGCCGCACT","AlternateAlleleVCF":"C","allel_id":263638,"rule_based_match":true,"evidence_text":"NM_024298.3:c.758_778del; p.Glu253_Ala259del","llm_judgment":"PRESENT","evidence":"NM_024298.3:c.758_778del; p.Glu253_Ala259del","abstract_start":851,"abstract_end":895}]}
{"pmid":"27256227","title":"Blood 7-ketocholesterol level, clinical features and gene mutation analysis of 18 children with Niemann-Pick disease type C","abstract":"OBJECTIVE: To investigate 7-ketocholesterol (7-KC) level in the blood, clinical features and gene mutation of Niemann-Pick disease type C (NPC).\nMETHOD: Eighteen patients diagnosed as NPC in Shanghai Xinhua Hospital seen from February 2013 to October 2014 were enrolled in this study. They included 13 males and 5 females and aged from 5 months to 21 years. The plasma 7-KC concentrations, clinical features and gene mutations of NPC patients were reviewed retrospectively.\nRESULT: Fourteen NPC patients had neurological symptoms with the age of neurological onset from 1 year to 16 years. In seven cases the disease was early-infantile subtype, in 1 late-infantile subtype, in five juvenile subtype and in one adult subtype. The 7-KC value in the plasma of NPC patients was higher than the normal range, (348.5±168.7) μg/L in the early-infantile subtype, 150.6 μg/L in the late-infantile subtype, (145.0±46.3) μg/L in the juvenile subtype, and 32.0 μg/L in the adult subtype, respectively, additionally, four NPC patients had no observable neuropsychiatric disability when confirmed to be NPC by genetic testing, with the plasma 7-KC value (345.6±134.2) μg/L; 16 of 18 patients had splenomegaly or hepatosplenomegaly. Among 18 patients, 34 different mutations in the NPC1 gene were identified including 27 reported mutations, 1 novel small deletion 3609_3610delAC, five novel exonic point mutations, c. 3683T>C(M1228T), c. 3679A>T(R1227W), c. 1070C>T(S357L), c. 1456A>C(N486H) and c. 1142G>A(W381X) and 1 novel intronic mutation c. 881+ 3A>G.\nCONCLUSION: The 7-KC levels in the blood of patient was remarkably increased, and there was a tendency that 7-KC levels inversely correlated with the age of neurological onset. Most NPC patient had splenomegaly or hepatosplenomegaly. Among 18 patients, 34 different mutations in the NPC1 gene were identified including seven novel mutations, which enriched the gene mutation spectrum.","variants":[{"Name":"NM_000271.5(NPC1):c.1070C>T (p.Ser357Leu)","Chromosome":"18","Start":"23556499","Stop":"23556499","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":532171,"rule_based_match":true,"evidence_text":"c. 1070C>T(S357L)","llm_judgment":"PRESENT","evidence":"c. 1070C>T(S357L)","abstract_start":1441,"abstract_end":1458}]}
{"pmid":"35415221","title":"Camurati-Engelmann Disease Complicated by Hypopituitarism: Management Challenges and Literature Review of Outcomes With Bisphosphonates.","abstract":"Background: Camurati-Engelmann disease (CED) is a rare bone dysplasia characterized by diffuse diaphyseal osteosclerosis. Skull base involvement in CED can result in hypopituitarism but is seldom reported. Our objective was to report a patient with acquired hypopituitarism due to CED and assess the management challenges.\nCase Report: A 20-year-old boy presented with lower limb pain. He had walking difficulty in childhood, which was diagnosed as CED and managed with prednisolone. He later discontinued treatment and was lost to follow-up. Current re-evaluation showed short stature (-3.6 standard deviation), low weight (-4.3 standard deviation), and delayed puberty with delayed bone age (13 years). He was found to have secondary hypogonadism (luteinizing hormone level, 0.1 mIU/mL [1.7-8.6 mIU/mL]; follicle-stimulating hormone level, 1.0 mIU/mL [1.5-12.4 mIU/mL]; and testosterone level, 0.087 nmol/L [9-27 nmol/L]), growth hormone deficiency (low insulin-like growth factor I level, 120 ng/mL [226-903 ng/mL] and peak growth hormone level of 7 ng/mL on insulin-induced hypoglycemia), and secondary hypocortisolism (cortisol level, 105 nmol/L [170-550 nmol/L] and adrenocorticotropic hormone level, 6 pg/mL [5-65 pg/mL]). Serum prolactin level was normal (8.3 ng/mL [5-20 ng/mL]), and he was euthyroid on levothyroxine replacement. Magnetic resonance imaging revealed a partially empty sella. Sanger sequencing revealed a missense mutation (p.R218C/c.652C>T) in exon 4 of the <i>TGFβ1</i> gene. The patient was treated with zoledronate, losartan, and oral prednisolone and continued on levothyroxine and testosterone replacement, which resulted in symptomatic improvement.\nDiscussion: The index case manifested severe CED requiring multimodality therapy. Later, he developed combined pituitary hormone deficiencies, which were managed with thyroid and gonadal hormone replacement with the continuation of glucocorticoids. The partial efficacy of bisphosphonates in CED has been reported in the literature.\nConclusion: Skull base involvement in CED can lead to structural and functional hypopituitarism as a result of intracranial hypertension.","variants":[{"Name":"NM_000660.7(TGFB1):c.652C>T (p.Arg218Cys)","Chromosome":"19","Start":"41342230","Stop":"41342230","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27570,"rule_based_match":true,"evidence_text":"p.R218C/c.652C>T","llm_judgment":"PRESENT","evidence":"p.R218C/c.652C>T","abstract_start":1449,"abstract_end":1465}]}
{"pmid":"19335424","title":"A novel missense mutation in the SLC6A19 gene in a Chinese family with Hartnup disorder.","abstract":"BACKGROUND: Hartnup disease is a rare autosomal-recessive abnormality of renal and gastrointestinal neutral amino acid transport associated with neurologic, psychiatric, and dermatologic symptoms. Mutations in the SLC6A19 gene have been proposed to be responsible for the underlying changes in this disorder.\nAIM: To investigate a pedigree with Hartnup disorder and to search for the mutation in the SLC6A19 gene in this pedigree.\nMETHODS: The encoding exons of the SLC6A19 gene were amplified and sequenced from genomic DNA samples. Amino acids were determined in urine samples from the proband and her family members.\nRESULTS: The proband and her brother had a homozygous mutation of c.850G > A in the SLC6A19 gene, causing G284R in the transmembrane domain of the SLC6A19 transporter, inherited from their parents who were heterozygous carriers. Their urine samples showed increased values of eight neutral amino acids.\nCONCLUSION: We found a novel homozygous mutation of G284R in the transmembrane domain of the SLC6A19 transporter in the proband, with typical dermatologic and neurologic manifestations and increased levels of urinary neutral amino acids.","variants":[{"Name":"NM_001003841.3(SLC6A19):c.850G>A (p.Gly284Arg)","Chromosome":"5","Start":"1214028","Stop":"1214028","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1934893,"rule_based_match":true,"evidence_text":"c.850G > A","llm_judgment":"PRESENT","evidence":"c.850G > A","abstract_start":686,"abstract_end":696}]}
{"pmid":"20925952","title":"A novel mutation in the sterol 27-hydroxylase gene of a woman with autosomal recessive cerebrotendinous xanthomatosis.","abstract":"Mutations of the gene encoding the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1 gene) cause defects in the cholesterol pathway to bile acids that lead to the storage of cholestanol and cholesterol in tendons, lenses and the central nervous system. This disorder is the cause of a clinical syndrome known as cerebrotendinous xanthomatosis (CTX). Since 1991 several mutations of the CYP27A1 gene have been reported. We diagnosed the clinical features of CTX in a caucasian woman. Serum levels of cholestanol and 7α-hydroxycholesterol were elevated and the concentration of 27-hydroxycholesterol was reduced. Bile alcohols in the urine and faeces were increased. The analysis of the CYP27A1 gene showed that the patient was a compound heterozygote carrying two mutations both located in exon 8. One mutation is a novel four nucleotide deletion (c.1330-1333delTTCC) that results in a frameshift and the occurrence of a premature stop codon leading to the formation of a truncated protein of 448 amino acids. The other mutation, previously reported, is a C - > T transition (c. c.1381C > T) that converts the glutamine codon at position 461 into a termination codon (p.Q461X). These truncated proteins are expected to have no biological function being devoid of the cysteine residue at position 476 of the normal enzyme that is crucial for heme binding and enzyme activity.","variants":[{"Name":"NM_000784.4(CYP27A1):c.1330_1333del (p.Phe444fs)","Chromosome":"2","Start":"218814610","Stop":"218814613","ReferenceAlleleVCF":"GCTTC","AlternateAlleleVCF":"G","allel_id":2894432,"rule_based_match":false,"evidence_text":"c.1330-1333delTTCC","llm_judgment":"PRESENT","evidence":"c.1330-1333delTTCC","abstract_start":849,"abstract_end":867},{"Name":"NM_000784.4(CYP27A1):c.1381C>T (p.Gln461Ter)","Chromosome":"2","Start":"218814662","Stop":"218814662","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":588692,"rule_based_match":true,"evidence_text":"c.1381C > T","llm_judgment":"PRESENT","evidence":"c.1381C > T","abstract_start":1080,"abstract_end":1091}]}
{"pmid":"31475485","title":"Pathogenic effect of a TGFBR1 mutation in a family with Loeys-Dietz syndrome.","abstract":"BACKGROUND: Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD.\nMETHODS: Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation.\nRESULTS: The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for pathogenicity was found by the predicted damaging effect of this mutation and the co-segregation in the family. Functional analysis with myogenic transdifferentiation of dermal fibroblasts to smooth muscle-like cells, revealed increased myogenic differentiation in patient cells with the TGFBR1 mutation, shown by a higher expression of myogenic markers ACTA2, MYH11 and CNN1 compared to cells from healthy controls.\nCONCLUSION: Our findings confirm the pathogenic effect of the TGFBR1 mutation in causing TAAD in Loeys-Dietz syndrome and show increased myogenic differentiation of patient fibroblasts.","variants":[{"Name":"NM_004612.4(TGFBR1):c.1043G>A (p.Cys348Tyr)","Chromosome":"9","Start":"99144801","Stop":"99144801","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3136420,"rule_based_match":true,"evidence_text":"c.1043G>A","llm_judgment":"PRESENT","evidence":"c.1043G>A","abstract_start":339,"abstract_end":348}]}
{"pmid":"27380589","title":"Haemostatic patterns and bleeding scores of a genetically characterised Italian family with combined haemophilia A and type 1 von Willebrand disease.","abstract":": We report on the coinheritance of mild haemophilia A and type 1 von Willebrand disease (VWD) in a genetically characterized Italian family. The proband is a 56-year-old man carrying both the c.2167G>A mutation in the factor VIII (FVIII) gene (responsible for p.A723T substitution) and the c.4751A>G mutation (p.Y1584C) in the von Willebrand factor (VWF) gene. His FVIII and VWF levels were 9.8 and 43.2 IU/dl, respectively. His bleeding symptoms included mucocutaneous bleeding, haemarthrosis, and muscle haematomas. Using the bleeding assessment tool, a questionnaire currently employed in diagnosing VWD, the patient had a bleeding score of 27 as compared with the 10.2 ± 3.4 found in patients with mild-to-moderate haemophilia A, and 0-3 in normal men. One of the proband's two daughters (both obligate carriers of haemophilia A) also harboured the VWF p.Y1584C mutation. Her FVIII and VWF levels were 45.9 and 54 IU/dl, respectively, and her bleeding score was slightly higher than normal for women (6 vs. 0-5). The other daughter had a normal bleeding score, and so did the proband's father (with type 1 VWD) and mother (haemophilia A carrier). Discrepancies between haemostatic patterns and bleeding symptoms in cases of haemophilia A, as seen in our patient, suggest the need to search for other coagulation defects, especially involving VWF, which is the carrier of FVIII. Although the presence of a VWF mutation significantly exacerbates the haemorrhagic complications in patients with mild haemophilia A, it has only mild effects on haemophilia A carriers.","variants":[{"Name":"NM_000132.4(F8):c.2167G>A (p.Ala723Thr)","Chromosome":"X","Start":"154931623","Stop":"154931623","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25285,"rule_based_match":true,"evidence_text":"c.2167G>A","llm_judgment":"PRESENT","evidence":"c.2167G>A","abstract_start":193,"abstract_end":202},{"Name":"NM_000552.5(VWF):c.4751A>G (p.Tyr1584Cys)","Chromosome":"12","Start":"6018667","Stop":"6018667","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":15349,"rule_based_match":true,"evidence_text":"c.4751A>G mutation (p.Y1584C)","llm_judgment":"PRESENT","evidence":"c.4751A>G mutation (p.Y1584C)","abstract_start":291,"abstract_end":320}]}
{"pmid":"35327962","title":"Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive","abstract":"Osteogenesis imperfecta (OI) is a syndromic disorder of bone fragility with high variation in its clinical presentation. Equally variable is molecular aetiology; recessive forms are caused by approximately 20 different genes, many of which are directly implicated in collagen type I biosynthesis. Biallelic variants in prolyl 3-hydroxylase 1 (P3H1) are known to cause severe OI by affecting the competence of the prolyl 3-hydroxylation—cartilage associated protein—peptidyl-prolyl cis-trans isomerase B (P3H1-CRTAP-CyPB) complex, which acts on the Pro986 residue of collagen type I α 1 (COL1A1) and Pro707 collagen type I α 2 (COL1A2) chains. The investigation of an OI cohort of 146 patients in Vietnam identified 14 families with P3H1 variants. The c.1170+5G>C variant was found to be very prevalent (12/14) and accounted for 10.3% of the Vietnamese OI cohort. New P3H1 variants were also identified in this population. Interestingly, the c.1170+5G>C variants were found in families with the severe clinical Sillence types 2 and 3 but also the milder types 1 and 4. This is the first time that OI type 1 is reported in patients with P3H1 variants expanding the clinical spectrum. Patients with a homozygous c.1170+5G>C variant shared severe progressively deforming OI type 3: bowed long bones, deformities of ribcage, long phalanges and hands, bluish sclera, brachycephaly, and early intrauterine fractures. Although it remains unclear if the c.1170+5G>C variant constitutes a founder mutation in the Vietnamese population, its prevalence makes it valuable for the molecular diagnosis of OI in patients of the Kinh ethnicity. Our study provides insight into the clinical and genetic variation of P3H1-related OI in the Vietnamese population.","variants":[{"Name":"NM_022356.4(P3H1):c.1170+5G>C","Chromosome":"1","Start":"42755543","Stop":"42755543","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1040097,"rule_based_match":true,"evidence_text":"c.1170+5G>C","llm_judgment":"PRESENT","evidence":"c.1170+5G>C","abstract_start":751,"abstract_end":762}]}
{"pmid":"20864636","title":"A novel and rapid method of determining the effect of unclassified MLH1 genetic variants on differential allelic expression.","abstract":"Germline mutations in mismatch repair genes predispose patients to Lynch Syndrome and the majority of these mutations have been detected in two key genes, MLH1 and MSH2. In particular, about a third of the missense variants identified in MLH1 are of unknown clinical significance. Using the PeakPicker software program, we have conducted a proof-of-principle study to investigate whether missense variants in MLH1 lead to allelic imbalances. Lymphocyte RNA extracted from patients harboring known MLH1 variants was used to quantify the ratio of variant to wild-type transcript, while patient lymphocyte DNA was used to establish baseline allelic expression levels. Our analysis indicated that the missense variants c.350C>T, c.793C>T, and c.1852_1853AA>GC, as well as the truncating variant c.1528C>T were all associated with significantly unbalanced allelic expression. However, the variants c.55A>T and c.2246T>C did not demonstrate an allelic imbalance. These results illustrate a novel and efficient method to investigate the pathogenicity of unclassified genetic variants discovered in mismatch repair genes, as well as genes implicated in other inherited diseases. In addition, the PeakPicker methodology has the potential to be applied in the diagnostic setting, which, in conjunction with results from other assays, will help increase both the accuracy and efficiency of genetic testing of colorectal cancer, as well as other inherited diseases.","variants":[{"Name":"NM_000249.4(MLH1):c.1528C>T (p.Gln510Ter)","Chromosome":"3","Start":"37028902","Stop":"37028902","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":95235,"rule_based_match":true,"evidence_text":"c.1528C>T","llm_judgment":"PRESENT","evidence":"c.1528C>T","abstract_start":791,"abstract_end":800},{"Name":"NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)","Chromosome":"3","Start":"37017508","Stop":"37017508","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38609,"rule_based_match":true,"evidence_text":"c.793C>T","llm_judgment":"PRESENT","evidence":"c.793C>T","abstract_start":725,"abstract_end":733}]}
{"pmid":"27876694","title":"Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency.","abstract":"BACKGROUND: A high level of succinylacetone (SA) in blood is a sensitive, specific newborn screening marker for hepatorenal tyrosinemia type 1 (HT1, MIM 276700) caused by deficiency of fumarylacetoacetate hydrolase (FAH). Newborns with HT1 are usually clinically asymptomatic but show liver dysfunction with coagulation abnormalities (prolonged prothrombin time and/or high international normalised ratio). Early treatment with nitisinone (NTBC) plus dietary restriction of tyrosine and phenylalanine prevents the complications of severe liver disease and neurological crises.\nMETHODS AND RESULTS: Six newborns referred for hypersuccinylacetonaemia but who had normal coagulation testing on initial evaluation had sequence variants in the <i>GSTZ1</i> gene, encoding maleylacetoacetate isomerase (MAAI), the enzyme preceding FAH in tyrosine degradation. Initial plasma SA levels ranged from 233 to 1282 nmol/L, greater than normal (<24 nmol/L) but less than the initial values of patients with HT1 (16 944-74 377 nmol/L, n=15). Four individuals were homozygous for c.449C>T (p.Ala150Val). One was compound heterozygous for c.259C>T (p.Arg87Ter) and an intronic sequence variant. In one, a single heterozygous <i>GSTZ1</i> sequence variant was identified, c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met revealed low MAAI activity. The six individuals with mild hypersuccinylacetonaemia (MHSA) were not treated with diet or nitisinone. Their clinical course has been normal for up to 13 years.\nCONCLUSIONS: MHSA can be caused by sequence variants in <i>GSTZ1</i>. Such individuals have thus far remained asymptomatic despite receiving no specific treatment.","variants":[{"Name":"NM_145870.3(GSTZ1):c.449C>T (p.Ala150Val)","Chromosome":"14","Start":"77329782","Stop":"77329782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":424570,"rule_based_match":true,"evidence_text":"c.449C>T (p.Ala150Val)","llm_judgment":"PRESENT","evidence":"c.449C>T (p.Ala150Val)","abstract_start":1065,"abstract_end":1087},{"Name":"NM_145870.3(GSTZ1):c.259C>T (p.Arg87Ter)","Chromosome":"14","Start":"77327954","Stop":"77327954","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":424571,"rule_based_match":true,"evidence_text":"c.259C>T (p.Arg87Ter)","llm_judgment":"PRESENT","evidence":"c.259C>T (p.Arg87Ter)","abstract_start":1123,"abstract_end":1144},{"Name":"NM_145870.3(GSTZ1):c.295G>A (p.Val99Met)","Chromosome":"14","Start":"77327990","Stop":"77327990","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":424573,"rule_based_match":true,"evidence_text":"c.295G>A (p.Val99Met)","llm_judgment":"PRESENT","evidence":"c.295G>A (p.Val99Met)","abstract_start":1255,"abstract_end":1276}]}
{"pmid":"19744044","title":"22-year-old girl with status epilepticus and progressive neurological symptoms.","abstract":"A 22-year-old girl presented with convulsive status epilepticus and a previous history of recurrent seizures, myoclonus, ataxia and impaired cognitive functions. Neurological examination revealed rest and action-induced myoclonus, pyramidal signs and opposition hypertonia. Testing revealed severe metabolic acidosis, elevated transaminases and creatine kinase, and respiratory insufficiency. After intubation and ventilation, thiopental was introduced but the patient's condition worsened dramatically with death in a few hours. Autopsy showed profuse periodic acid-Schiff (PAS) positive intracellular inclusions in the CNS (Lafora bodies), most abundant in thalamus, cerebellum, and brainstem, as well as in other organs. Genetic testing revealed a homozygous missense mutation (c.205C > G, P69A) in the EPM2B (NHLRC1) gene, confirming the diagnosis of progressive myoclonic epilepsy Lafora-type.","variants":[{"Name":"NM_198586.3(NHLRC1):c.205C>G (p.Pro69Ala)","Chromosome":"6","Start":"18122402","Stop":"18122402","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":17626,"rule_based_match":true,"evidence_text":"c.205C > G, P69A","llm_judgment":"PRESENT","evidence":"c.205C > G, P69A","abstract_start":781,"abstract_end":797}]}
{"pmid":"24045990","title":"Functional analysis of HSF4 mutations found in patients with autosomal recessive congenital cataracts.","abstract":"PURPOSE: The goal of this study was to functionally evaluate three previously uncharacterized heat shock factor protein 4 (HSF4) mutations (c.595_599delGGGCC, c.1213C>T, c.1327+4A>G) encoding mutant HSF4 proteins (G199EfsX15, R405X, and M419GfsX29) with missing C-terminal ends. These HSF4 mutations were previously identified in families with congenital autosomal recessive cataracts.\nMETHODS: FLAG-tagged recombinant wild type (WT) and mutant HSF4 proteins were analyzed using the protein stability assay, cellular immunofluorescence, Western blotting, electrophoretic mobility shift assay (EMSA), and reporter activation.\nRESULTS: HSF4 mutant proteins did not differ in the protein turnover rate when compared with WT HSF4. Immunofluorescence revealed that WT and mutant HSF4 proteins were properly trafficked to the nucleus. EMSA analysis revealed that the G199EfsX15 and M419GfsX29 proteins exhibited decreased heat shock element (HSE)-mediated DNA binding, whereas the R405X mutant exhibited increased HSE-mediated DNA binding when compared with WT HSF4. All three HSF4 mutant proteins exhibited abolished HSE-mediated luciferase reporter activation. Detailed evaluation of the C-terminal region identified three novel domains: two activation domains and one repression domain.\nCONCLUSIONS: The three HSF4 autosomal recessive mutations evaluated here result in a loss of HSF4 function due to a loss of regulatory domains present at the C-terminal end. These findings collectively indicate that the transcriptional activation of HSF4 is mediated by interactions between activator and repressor domains within the C-terminal end.","variants":[{"Name":"NM_001374675.1(HSF4):c.1213C>T (p.Arg405Ter)","Chromosome":"16","Start":"67169060","Stop":"67169060","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3535930,"rule_based_match":true,"evidence_text":"c.1213C>T","llm_judgment":"PRESENT","evidence":"c.1213C>T","abstract_start":159,"abstract_end":168}]}
{"pmid":"29963054","title":"Deficiency of Adenosine Deaminase 2 in Adult Siblings: Many Years of a Misdiagnosed Disease With Severe Consequences.","abstract":"OBJECTIVE: Describe the clinical characteristics and histopathology findings in a family with two siblings affected with deficiency of adenosine deaminase 2 (DADA2). Both patients presented in childhood with polyarthritis and developed significant neurological and gastrointestinal features of DADA2 in ear, including variable degrees of immunologic and hematologic manifestations.\nMETHODS: Adenosine Deaminase 2 (ADA2; also known as <i>cat eye syndrome chromosome region, candidate 1 gene; CECR1)</i> exon sequencing and serum ADA2 levels were performed to confirm the diagnosis of DADA2. Comparison of serum adenosine deaminase 2 levels was made to DADA2 patients, carriers, and healthy controls in Patient 2. Autopsy specimens from brain and liver tissues were submitted for analysis.\nRESULTS: Both patients were found to carry a previously reported rare intronic missense mutation predicted to affect the transcript splicing (c.973-2A > G; rs139750129) and an unreported missense mutation p.Val458Asp (c.1373T > A; V458D). Both brothers started therapy with a tumor necrosis factor inhibitor following the molecular diagnosis of DADA2 with good response and were eventually tapered off prednisone. However, Patient 1 died 18 months later due to complications of end-stage liver disease. His autopsy showed evidence for nodular hyperplasia of the liver often seen in common variable immunodeficiency (CVID) and numerous small, old infarcts throughout the brain that had not been demonstrated on prior MRI/MRA imaging.\nCONCLUSION: These cases emphasize the importance of recognition of DADA2 in adults, compare CNS imaging modalities to pathologic findings and suggest similarities in liver pathology between DADA2 and CVID. MRI may not be most sensitive method to identify small subcortical infarcts in patients suspected to have DADA2.","variants":[{"Name":"NM_001282225.2(ADA2):c.1373T>A (p.Val458Asp)","Chromosome":"22","Start":"17181889","Stop":"17181889","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1018777,"rule_based_match":true,"evidence_text":"c.1373T > A; V458D","llm_judgment":"PRESENT","evidence":"c.1373T > A; V458D","abstract_start":1006,"abstract_end":1024},{"Name":"NM_001282225.2(ADA2):c.973-2A>G","Chromosome":"22","Start":"17188449","Stop":"17188449","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":534594,"rule_based_match":true,"evidence_text":"c.973-2A > G","llm_judgment":"PRESENT","evidence":"c.973-2A > G","abstract_start":930,"abstract_end":942}]}
{"pmid":"37164047","title":"Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant.","abstract":"BACKGROUND: Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype.\nOBJECTIVE: The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G.\nMETHODS: Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers. We used in silico predictors and functional studies with peripheral blood and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Isolated RNA was studied by reverse transcription polymerase chain reaction. iPSC-CMs were further characterized at baseline and after nonsense-mediated decay (NMD) inhibition, using quantitative polymerase chain reaction (qPCR), RNA-sequencing, and cellular electrophysiology. American College of Medical Genetics and Genomics (ACMG) criteria were used to adjudicate variant pathogenicity.\nRESULTS: Variant heterozygotes displayed a spectrum of disease phenotypes, spanning from mild ventricular dysfunction with palpitations to severe ventricular arrhythmias requiring device shocks or progressive cardiomyopathy requiring heart transplantation. Consistent with in silico predictors, the c.970-4A>G FLNC variant activated a cryptic splice acceptor site, introducing a 3-bp insertion containing a premature termination codon. NMD inhibition upregulated aberrantly spliced transcripts by qPCR and RNA-sequencing. Patch clamp studies revealed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current in proband-derived iPSC-CMs. These findings fulfilled multiple ACMG criteria for pathogenicity.\nCONCLUSION: Clinical, in silico, and functional evidence support the prediction that the intronic c.970-4A>G VUS disrupts splicing and drives ACM, enabling reclassification from VUS to pathogenic.","variants":[{"Name":"NM_001458.5(FLNC):c.970-4A>G","Chromosome":"7","Start":"128837983","Stop":"128837983","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":425723,"rule_based_match":true,"evidence_text":"c.970-4A>G","llm_judgment":"PRESENT","evidence":"c.970-4A>G","abstract_start":365,"abstract_end":375}]}
{"pmid":"31575858","title":"ABCC9-related Intellectual disability Myopathy Syndrome is a K","abstract":"Mutations in genes encoding K<sub>ATP</sub> channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of K<sub>ATP</sub> channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional K<sub>ATP</sub> channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing K<sub>ATP</sub> channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of K<sub>ATP</sub> loss- versus gain-of-function.","variants":[{"Name":"NM_020297.4(ABCC9):c.1320+1G>A","Chromosome":"12","Start":"21910156","Stop":"21910156","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":258727,"rule_based_match":true,"evidence_text":"c.1320+1G>A","llm_judgment":"PRESENT","evidence":"c.1320+1G>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"24168455","title":"EIF2AK3 mutations in South Indian children with permanent neonatal diabetes mellitus associated with Wolcott-Rallison syndrome.","abstract":"OBJECTIVE: This study describes the clinical and genetic evaluation of permanent neonatal diabetes due to Wolcott-Rallison syndrome (WRS) in south Indian consanguineous families. We aimed to evaluate the genetic basis of the disease in eight children with WRS from five South Indian families.\nPATIENTS AND METHODS: We studied eight children who presented with permanent neonatal diabetes from five South Indian families. Follow up clinical evaluation revealed features (like liver disease, skeletal dysplasia, and thyroid dysfunction) suggestive of WRS. All the coding exons along with splice sites of KCNJ11, ABCC8, INS, GCK and EIF2AK3 genes were sequenced in all the probands.\nRESULTS: Two novel homozygous mutations (Trp658Ser, c.3150+1G>T) and one known homozygous mutation (Arg1065*, c.3193C>T) in EIF2AK3 gene were identified in children with WRS. Mutation Arg1065*was identified in four children.\nCONCLUSIONS: Our results in these families show that the mutations in homozygous state are likely to be causative. We suggest the screening for EIF2AK3 gene mutations as WRS is now recognized as the most frequent cause of neonatal diabetes in children with consanguineous parents. As the mode of inheritance is recessive, screening for genetic mutations becomes important to aid in risk prediction and clinical management.","variants":[{"Name":"NM_004836.7(EIF2AK3):c.3193C>T (p.Arg1065Ter)","Chromosome":"2","Start":"88557894","Stop":"88557894","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2898571,"rule_based_match":true,"evidence_text":"c.3193C>T","llm_judgment":"PRESENT","evidence":"c.3193C>T","abstract_start":790,"abstract_end":799}]}
{"pmid":"31599855","title":"Constitutional Mismatch Repair Gene Defect Syndrome Presenting With Adenomatous Polyposis and Cafe au Lait Spots: A Case Report.","abstract":"INTRODUCTION: Adenomatous polyps in the gastrointestinal system rarely occur in childhood and are accompanied by syndromes such as Familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis, Gardner and Turcot syndrome, and also mismatch repair (MMR) gene defects. In this article, we want to present a rare patient who had adenomatous polyposis and in situ carcinoma and was detected biallelic MMR gene defect.\nCASE: A 16-year-old female patient admitted with painless rectal bleeding, chronic abdominal pain, and anorexia for 1 year. Her physical examination was notable for multiple cafe au lait spots. The colonoscopic and histopathologic examination revealed multiple adenomatous polyps that one of them contains low-high grade dysplasia and in situ carsinoma. Genetic analysis revealed a homozygous mutation in the PMS2 gene [c.1164delT (p.H388Qfs*10) (p.His388GInfsTer10)] and she was diagnosed with constitutional MMR gene defect syndrome. Polypectomy was performed 4 times in 2 years period. Then, the patient's last colonoscopic examination revealed a large broad polyp in the rectum and multiple polyps in the other colon segments, and she underwent colectomy because of high risk of colorectal cancer.\nCONCLUSIONS: Adenomatous polyps are very important in childhood because of rarity. In particular, the presence of cafe au lait spots and a history of malignancy detected in relatives at an early age must be considered for CMMRD.","variants":[{"Name":"NM_000535.7(PMS2):c.1164del (p.His388fs)","Chromosome":"7","Start":"5987601","Stop":"5987601","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":474621,"rule_based_match":true,"evidence_text":"c.1164delT (p.H388Qfs*10) (p.His388GInfsTer10)","llm_judgment":"PRESENT","evidence":"c.1164delT (p.H388Qfs*10) (p.His388GInfsTer10)","abstract_start":879,"abstract_end":925}]}
{"pmid":"25041374","title":"A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy.","abstract":"Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of malignant arrhythmia and sudden death particularly in young people. Although it is considered a desmosomal disease, mutations in non-desmosomal genes have also been identified. We report on a family where a mutation in LDB3 is associated with this condition. The index case and first and second degree relatives underwent a complete clinical evaluation: physical examination, electrocardiography (ECG), signal-averaged ECG, 2D echocardiogram, cardiac magnetic resonance and 24-h monitoring. After ruling out mutations in the five desmosomal genes, genetic testing by means of Next Generation Sequencing was carried out on the proband. A heterozygous missense mutation in LDB3 c.1051A>G was identified. This result was confirmed by subsequent Sanger DNA sequencing. Another six carriers were identified amongst her relatives. Three subjects fulfilled the criteria for a definitive diagnosis of ARVC and one reached a borderline diagnosis. In conclusion, this is the first family with ARVC where a mutation in LDB3 is associated with ARVC. Next generation sequencing arises as a particular useful tool to point to new causative genes in ARVC.","variants":[{"Name":"NM_007078.3(LDB3):c.1051A>G (p.Thr351Ala)","Chromosome":"10","Start":"86706685","Stop":"86706685","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":45599,"rule_based_match":true,"evidence_text":"c.1051A>G","llm_judgment":"PRESENT","evidence":"c.1051A>G","abstract_start":756,"abstract_end":765}]}
{"pmid":"32655480","title":"A Family With a Complex Phenotype Caused by Two Different Rare Metabolic Disorders: GLUT1 and Very-Long-Chain Fatty Acid Dehydrogenase (VLCAD) Deficiencies.","abstract":"GLUT1 Deficiency Syndrome (GLUT1-DS) is a rare and potentially treatable neurometabolic condition, caused by a reduced glucose transport into the brain and clinically characterized by an epileptic encephalopathy with movement disorders. A wide inter-intrafamilial phenotypic variability has been reported. Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of mitochondrial long-chain fatty acid oxidation (FAO) with also a variable age of onset and clinical presentation including cardiomyopathy, hypoketotic hypoglycemia, and liver disease. Sometimes, VLCAD manifests later with a prevalent muscle involvement characterized by exercise intolerance and recurrent rhabdomyolysis. We report a 40-year-old man with mild mental retardation and sporadic choreo-athetoid movements, who complained of recurrent episodes of rhabdomyolysis triggered by exercise or fasting since his twenties. His 15-year-old son had a psychomotor developmental delay with episodes of drowsiness mainly at fasting and exercise-induced choreo-athetoid movements but no history of pigmenturia. Clinical and laboratory findings in the son suggested a diagnosis of GLUT1-DS confirmed by <i>SCL2A1</i> genetic analysis that revealed a heterozygous mutation c.997C>T (p.R333W) that was also found in the proband. However, the presence in the latter of recurrent exercise-induced rhabdomyolysis, never reported in GLUT1-DS, implied a second metabolic disorder. Increased plasma C14:1-carnitine levels and the identification of two known heterozygous mutations c. 553G>A (p.G185S) and c.1153C>T (p.R385W) in <i>ACADVL</i> confirmed the additional diagnosis of VLCAD deficiency in the proband. Nowadays, there is an increasing evidence of \"double trouble\" cases of genetic origin. Consequently, when atypical features accompany a known phenotype, associated comorbidities should be considered.","variants":[{"Name":"NM_000018.4(ACADVL):c.1153C>T (p.Arg385Trp)","Chromosome":"17","Start":"7223208","Stop":"7223208","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":190949,"rule_based_match":true,"evidence_text":"c.1153C>T (p.R385W)","llm_judgment":"PRESENT","evidence":"c.1153C>T (p.R385W)","abstract_start":1594,"abstract_end":1613}]}
{"pmid":"23084290","title":"A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss.","abstract":"A subset of nuclear-encoded RNAs has to be imported into mitochondria for the proper replication and transcription of the mitochondrial genome and, hence, for proper mitochondrial function. Polynucleotide phosphorylase (PNPase or PNPT1) is one of the very few components known to be involved in this poorly characterized process in mammals. At the organismal level, however, the effect of PNPase dysfunction and impaired mitochondrial RNA import are unknown. By positional cloning, we identified a homozygous PNPT1 missense mutation (c.1424A>G predicting the protein substitution p.Glu475Gly) of a highly conserved PNPase residue within the second RNase-PH domain in a family affected by autosomal-recessive nonsyndromic hearing impairment. In vitro analyses in bacteria, yeast, and mammalian cells showed that the identified mutation results in a hypofunctional protein leading to disturbed PNPase trimerization and impaired mitochondrial RNA import. Immunohistochemistry revealed strong PNPase staining in the murine cochlea, including the sensory hair cells and the auditory ganglion neurons. In summary, we show that a component of the mitochondrial RNA-import machinery is specifically required for auditory function.","variants":[{"Name":"NM_033109.5(PNPT1):c.1424A>G (p.Glu475Gly)","Chromosome":"2","Start":"55656148","Stop":"55656148","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":48401,"rule_based_match":true,"evidence_text":"c.1424A>G (p.Glu475Gly)","llm_judgment":"PRESENT","evidence":"p.Glu475Gly","abstract_start":580,"abstract_end":591}]}
{"pmid":"24099628","title":"Distinctive mutation spectrum of the HBB gene in an urban eastern Indian population.","abstract":"ABSTRACT Hemoglobinopathies such as β-thalassemia (β-thal) and sickle cell anemia (or Hb S [β6(A3)Glu→Val]) impose a major health burden in the Indian population. To determine the frequencies of the HBB gene mutations in eastern Indian populations and to compare with the available data, a comprehensive molecular analysis of the HBB gene was done in the normal Odisha State population. Using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), amplification refractory mutation system (ARMS) and DNA sequencing techniques, β-thal and sickle cell anemia mutations were characterized in 267 healthy individuals. Entire HBB gene sequencing showed 63 different mutations including 11 new ones. The predominant mutation HBB: c.9T > C was observed at a high frequency (19.57%) in the normal population. In the urban population of Odisha State, India, carrier frequency of hemoglobinopathies was found to be 18.48%, and for β-thal, the carrier rate was 14.13%, which is very high indeed. In the absence of a complete cure by any expensive treatment and drug administration, this information would be helpful for planning a population screening program and establishing prenatal diagnosis of β-thal in order to reduce the burden of such a genetic disease.","variants":[{"Name":"NM_000518.5(HBB):c.9T>C (p.His3=)","Chromosome":"11","Start":"5227013","Stop":"5227013","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":190271,"rule_based_match":true,"evidence_text":"HBB: c.9T > C","llm_judgment":"PRESENT","evidence":"HBB: c.9T > C","abstract_start":746,"abstract_end":759}]}
{"pmid":"29091352","title":"Type 2 Gaucher disease in an infant despite a normal maternal glucocerebrosidase gene.","abstract":"Gaucher disease (GD) is a recessively inherited autosomal lysosomal storage disease, the most severe of which is type 2, an acute neuronopathic form. We report an affected infant who inherited one mutant allele, Arg257Gln (c.887G>A; p.Arg296Gln) from his father, while the second, Gly202Arg (c.721G>A; p.Gly241Arg) arose by either maternal germline mosaicism or as a de novo mutation. This is the first time mutation Gly202Arg has been reported to be inherited non-traditionally. This report is part of a growing literature suggesting that GD can be inherited via germline or de novo mutations, and emphasizes that it is critical for clinicians to consider such inheritance when making diagnostic decisions or providing genetic counseling.","variants":[{"Name":"NM_000157.4(GBA1):c.721G>A (p.Gly241Arg)","Chromosome":"1","Start":"155238174","Stop":"155238174","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":99364,"rule_based_match":true,"evidence_text":"c.721G>A (p.Gly241Arg)","llm_judgment":"PRESENT","evidence":"p.Gly241Arg","abstract_start":302,"abstract_end":313},{"Name":"NM_000157.4(GBA1):c.887G>A (p.Arg296Gln)","Chromosome":"1","Start":"155237453","Stop":"155237453","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19367,"rule_based_match":true,"evidence_text":"c.887G>A (p.Arg296Gln)","llm_judgment":"PRESENT","evidence":"p.Arg296Gln","abstract_start":233,"abstract_end":244}]}
{"pmid":"27264814","title":"Genetic analysis of a child affected with Crigler-Najjar syndrome type II","abstract":"OBJECTIVE: To detect potential mutation of the UGT1A1 gene in a child affected with Crigler-Najjar syndrome type II.\nMETHODS: Blood samples were collected from the patient and his parents for the extraction of genomic DNA. Potential mutation of the UGT1A1 gene was detected with polymerase chain reaction (PCR) and direct sequencing. The child was followed up until the age of 3 years and 6 months.\nRESULTS: The patient showed persistent unconjugated hyperbilirubinemia. Sequencing of the UGT1A1 gene has detected a rare heterozygous c.610 A>G (p.Met204Val) mutation in the exon 1, in addition with a heterozygous c.1091 C>T (p.Pro364Leu) mutation in exon 4. The two mutations were inherited from his father and mother, respectively. The patient was diagnosed with Crigler-Najjar syndrome type II and received oral phenobarbital treatment.\nCONCLUSION: The compound UGT1A1 gene mutation probably accounts for the disease in the patient manifesting persistent mild unconjugated hyperbilirubinemia. Genetic counseling and prenatal diagnosis should be provided for his family.","variants":[{"Name":"NM_000463.3(UGT1A1):c.1091C>T (p.Pro364Leu)","Chromosome":"2","Start":"233768226","Stop":"233768226","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":206952,"rule_based_match":true,"evidence_text":"c.1091 C>T (p.Pro364Leu)","llm_judgment":"PRESENT","evidence":"c.1091 C>T (p.Pro364Leu)","abstract_start":614,"abstract_end":638},{"Name":"NM_000463.3(UGT1A1):c.610A>G (p.Met204Val)","Chromosome":"2","Start":"233760897","Stop":"233760897","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3534480,"rule_based_match":true,"evidence_text":"c.610 A>G (p.Met204Val)","llm_judgment":"PRESENT","evidence":"c.610 A>G (p.Met204Val)","abstract_start":534,"abstract_end":557}]}
{"pmid":"24444136","title":"Segregation analysis in families with Charcot-Marie-Tooth disease allows reclassification of putative disease causing mutations.","abstract":"BACKGROUND: The identification of disease causing, or putative disease causing, mutations in index patients with Charcot-Marie-Tooth disease (CMT) allows for genetic testing of family members. Relevant variants identified in index patients are of either definite, likely or uncertain pathogenicity. The main objective of this study was to make an evaluation of the family investigations performed as part of the assessment of genetic variants of unknown clinical significance (VUS).\nMETHODS: Between 2004 and 2010 molecular genetic family investigations were requested for 87 family members from 41 families harbouring PMP22dup or genetic variants in GJB1, MPZ, MFN2 and NEFL. Relatives were tested for the family mutation and data from the requisitions were evaluated by means of statistical tools.\nRESULTS: The results within each indication category are presented and discussed in detail. Twenty-two relatives (9 affected) from eight families were included in the segregation analyses, which invoked reclassification of three MFN2 mutations, two of which were de novo substitutions (c.2146_2148dup, c.692C > T). One MFN2 substitution was downgraded due to non-segregation (c.1709 A > G), and a MPZ substitution (c.103 G > A) upgraded due to segregation with the phenotype in the family.\nCONCLUSIONS: The results allow for the evaluation of the patient phenotypes ascertained in families, as opposed to the phenotypic descriptions of index patients. They indicate that de novo MFN2 mutations are regularly found in patients with a classical CMT2 phenotype. They also demonstrate the importance of a precise clinical and neurophysiologic diagnosis of affected family members. This particularly applies for the examination of variants of uncertain clinical significance. Finally, the fact that 14,6% of affected relatives tested for (probable or certain) pathogenic mutations were mutation negative, demonstrates that clinical evaluation alone is not always sufficient in order to determine their diagnosis. We believe that the results will aid in the estimation and planning of resources required for the various aspects of family evaluations in CMT.","variants":[{"Name":"NM_000530.8(MPZ):c.103G>A (p.Asp35Asn)","Chromosome":"1","Start":"161307389","Stop":"161307389","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":447442,"rule_based_match":true,"evidence_text":"c.103 G > A","llm_judgment":"PRESENT","evidence":"c.103 G > A","abstract_start":1215,"abstract_end":1226},{"Name":"NM_014874.4(MFN2):c.692C>T (p.Ser231Phe)","Chromosome":"1","Start":"11998862","Stop":"11998862","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":624917,"rule_based_match":true,"evidence_text":"c.692C > T","llm_judgment":"PRESENT","evidence":"c.692C > T","abstract_start":1102,"abstract_end":1112},{"Name":"NM_014874.4(MFN2):c.1709A>G (p.Asn570Ser)","Chromosome":"1","Start":"12005924","Stop":"12005924","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":624950,"rule_based_match":true,"evidence_text":"c.1709 A > G","llm_judgment":"PRESENT","evidence":"c.1709 A > G","abstract_start":1176,"abstract_end":1188}]}
{"pmid":"21288719","title":"A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy.","abstract":"This study aimed to identify the genetic defect in a multigenerational family presenting an autosomal dominant myopathy with histological features of congenital fiber type disproportion. Linkage analysis and genetic sequencing identified, in all affected members of the family, the c.5807A>G heterozygous mutation in MYH7, which encodes the slow/β-cardiac myosin heavy chain. This mutation causes skeletal but not cardiac involvement. Myosin heavy chain expression pattern was also characterized by immunohistochemistry, western blot and q-PCR in muscle biopsies from two patients aged 25 and 62, respectively. While only congenital fiber type disproportion was observed in the younger patient, older patient's biopsy presented aggregates of slow myosin heavy chains, in fiber sub-sarcolemmal region. These clinico-pathologic findings suggest a novel phenotype within the emerging group of hereditary myosin myopathies, which in this family presents typical characteristics of congenital fiber type disproportion in early stages and later evolves to myosin storage myopathy.","variants":[{"Name":"NM_000257.4(MYH7):c.5807A>G (p.Ter1936Trp)","Chromosome":"14","Start":"23412855","Stop":"23412855","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":51263,"rule_based_match":true,"evidence_text":"c.5807A>G","llm_judgment":"PRESENT","evidence":"c.5807A>G","abstract_start":282,"abstract_end":291}]}
{"pmid":"25765181","title":"Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing.","abstract":"AIMS: To date, 13 genes causing maturity-onset diabetes of the young (MODY) have been identified. However, there is a big discrepancy in the genetic locus between Asian and Caucasian patients with MODY. Thus, we conducted whole-exome sequencing in Korean MODY families to identify causative gene variants.\nMETHODS: Six MODY probands and their family members were included. Variants in the dbSNP135 and TIARA databases for Koreans and the variants with minor allele frequencies >0.5% of the 1000 Genomes database were excluded. We selected only the functional variants (gain of stop codon, frameshifts and nonsynonymous single-nucleotide variants) and conducted a case-control comparison in the family members. The selected variants were scanned for the previously introduced gene set implicated in glucose metabolism.\nRESULTS: Three variants c.620C>T:p.Thr207Ile in PTPRD, c.559C>G:p.Gln187Glu in SYT9, and c.1526T>G:p.Val509Gly in WFS1 were respectively identified in 3 families. We could not find any disease-causative alleles of known MODY 1-13 genes. Based on the predictive program, Thr207Ile in PTPRD was considered pathogenic.\nCONCLUSIONS: Whole-exome sequencing is a valuable method for the genetic diagnosis of MODY. Further evaluation is necessary about the role of PTPRD, SYT9 and WFS1 in normal insulin release from pancreatic beta cells.","variants":[{"Name":"NM_006005.3(WFS1):c.1526T>G (p.Val509Gly)","Chromosome":"4","Start":"6301321","Stop":"6301321","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1934810,"rule_based_match":true,"evidence_text":"c.1526T>G:p.Val509Gly in WFS1","llm_judgment":"PRESENT","evidence":"c.1526T>G:p.Val509Gly in WFS1","abstract_start":907,"abstract_end":936}]}
{"pmid":"30989645","title":"Enantiospecific Pharmacogenomics of Fluvastatin.","abstract":"The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S-fluvastatin and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 × 10<sup>-9</sup> and P = 3.19 × 10<sup>-12</sup> ). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 × 10<sup>-8</sup> ). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single-nucleotide variations may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":true,"evidence_text":"SLCO1B1 c.521T>C","llm_judgment":"PRESENT","evidence":"SLCO1B1 c.521T>C","abstract_start":520,"abstract_end":536}]}
{"pmid":"22761713","title":"Glucokinase (GCK) mutations and their characterization in MODY2 children of southern Italy.","abstract":"Type 2 Maturity Onset Diabetes of the Young (MODY2) is a monogenic autosomal disease characterized by a primary defect in insulin secretion and hyperglycemia. It results from GCK gene mutations that impair enzyme activity. Between 2006 and 2010, we investigated GCK mutations in 66 diabetic children from southern Italy with suspected MODY2. Denaturing High Performance Liquid Chromatography (DHPLC) and sequence analysis revealed 19 GCK mutations in 28 children, six of which were novel: p.Glu40Asp, p.Val154Leu, p.Arg447Glyfs, p.Lys458_Cys461del, p.Glu395_Arg397del and c.580-2A>T. We evaluated the effect of these 19 mutations using bioinformatic tools such as Polymorphism Phenotyping (Polyphen), Sorting Intolerant From Tolerant (SIFT) and in silico modelling. We also conducted a functional study to evaluate the pathogenic significance of seven mutations that are among the most severe mutations found in our population, and have never been characterized: p.Glu70Asp, p.His137Asp, p.Phe150Tyr, p.Val154Leu, p.Gly162Asp, p.Arg303Trp and p.Arg392Ser. These seven mutations, by altering one or more kinetic parameters, reduced enzyme catalytic activity by >40%. All mutations except p.Glu70Asp displayed thermal-instability, indeed >50% of enzyme activity was lost at 50°C/30 min. Thus, these seven mutations play a pathogenic role in MODY2 insurgence. In conclusion, this report revealed six novel GCK mutations and sheds some light on the structure-function relationship of human GCK mutations and MODY2.","variants":[{"Name":"NM_000162.5(GCK):c.907C>T (p.Arg303Trp)","Chromosome":"7","Start":"44146575","Stop":"44146575","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44928,"rule_based_match":false,"evidence_text":"p.Arg303Trp","llm_judgment":"PRESENT","evidence":"p.Arg303Trp","abstract_start":1027,"abstract_end":1038},{"Name":"NM_000162.5(GCK):c.449T>A (p.Phe150Tyr)","Chromosome":"7","Start":"44150990","Stop":"44150990","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":134588,"rule_based_match":false,"evidence_text":"c.449T>A (p.Phe150Tyr)","llm_judgment":"PRESENT","evidence":"p.Phe150Tyr","abstract_start":988,"abstract_end":999}]}
{"pmid":"32351751","title":"Severe Generalized Epidermolysis Bullosa Simplex in Two Hong Kong Children due to","abstract":"We report two Hong Kong children with severe generalized epidermolysis bullosa simplex (EBS), the most severe form of EBS, without a family history of EBS. EBS is a rare genodermatosis usually inherited in an autosomal dominant fashion although rare autosomal recessive cases have been reported. Genetic studies in these patients showed that the first case was due to a novel <i>de novo</i> heterozygous variant, c.377T>G (NM_000526.5 (c.377T>G, p.Leu126Arg)) in the <i>KRT14</i> gene and the second case was due to a rare <i>de novo</i> heterozygous variant c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser) in the <i>KRT5</i> gene. To our knowledge, the c.377T>G variant in the <i>KRT14</i> gene has not been previously reported, and the c.527A>G variant in the <i>KRT5</i> gene is a rare cause of severe generalized EBS. In severe generalized EBS, infants exhibit severe symptoms at the onset; however, they tend to improve with time. A precise genetic diagnosis in these two cases aided in counseling the families concerning the prognosis in their affected children and the recurrence risk for future pregnancies.","variants":[{"Name":"NM_000424.4(KRT5):c.527A>G (p.Asn176Ser)","Chromosome":"12","Start":"52519770","Stop":"52519770","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":77150,"rule_based_match":true,"evidence_text":"c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser)","llm_judgment":"PRESENT","evidence":"c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser)","abstract_start":559,"abstract_end":604}]}
{"pmid":"31374327","title":"A novel mutation of the ITGB2 gene in a Chinese Zhuang minority patient with leukocyte adhesion deficiency type 1 and glucose-6-phosphate dehydrogenase deficiency.","abstract":"OBJECTIVES: To explore the clinical and molecular characteristics of a Chinese Zhuang minority patient with leukocyte adhesion deficiency type-1 (LAD-1) and glucose-6-phosphate dehydrogenase deficiency (G6PDD).\nMETHODS: Routine clinical and physical examinations were performed, and patient data was collected and analyzed. Protein expression levels of Itgb2 and glucose-6-phosphate dehydrogenase (G6pd) proteins were assessed by flow cytometry and the glucose-6-phosphate (G6P) substrate method, respectively. Whole exome sequencing was performed to investigate genetic variations of the patient and his parents.\nRESULTS: The patient had fester disease and delayed separation of the umbilical cord at birth. Staphylococcus was detected in the fluid secretion of the auditory meatus of the patient. He exhibited a recurrent cheek scab, swollen hand, and swollen gum. Hematological examination indicated dramatic elevation of leukocytes including lymphocytes, monocytes, neutrophils and eosinophils. A novel homozygous mutation was detected in the ITGB2 gene of the patient, which was determined to be a two nucleotide deletion at the site of c.1537-1538 (c.1537-1538delGT), causing a frameshift of 24 amino acids from p.513 and inducing a stop codon (p.V513Lfs*24). A base substitution mutation was identified at c.1466 (c.1466G>T) of G6PD on chromosome X of the patient, which resulted in an amino acid change from arginine to leucine at p.489 (p.R489L). The patient also showed deficient lymphocyte expression of CD18 (2.99%) and significant downregulation of the G6pd protein.\nCONCLUSIONS: The patient was diagnosed with G6PDD and moderate LAD-1. The combination of LAD-1 and G6PDD in this case may have been due to the high incidence of genetic disease in this minority ethnic population. Analyzing existing LAD-1 and G6PDD cases from different populations can facilitate disease diagnosis and treatment. Particularly, reporting pathogenic mutations of LAD-1 and G6PDD will be crucial for genetic testing and prenatal diagnosis in an effort to decrease the incidence of these diseases.","variants":[{"Name":"NM_000211.5(ITGB2):c.1537_1538del (p.Val513fs)","Chromosome":"21","Start":"44890097","Stop":"44890098","ReferenceAlleleVCF":"GAC","AlternateAlleleVCF":"G","allel_id":1451322,"rule_based_match":false,"evidence_text":"c.1537-1538 (c.1537-1538delGT)","llm_judgment":"PRESENT","evidence":"c.1537-1538 (c.1537-1538delGT)","abstract_start":1142,"abstract_end":1172}]}
{"pmid":"17420318","title":"Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism.","abstract":"OBJECTIVE: To define the molecular basis of the autosomal dominant progressive external ophthalmoplegia and parkinsonism in a large family with a dominantly transmitted multiple mitochondrial DNA deletion disorder.\nDESIGN: Microsatellite analysis and screening of the progressive external ophthalmoplegia 1 (PEO1), adenine nucleotide translocator 1 (ANT1), and polymerase gamma-1 (POLG1) genes.\nRESULTS: We identified 3 novel heterozygous POLG1 substitutions in the same family. Autosomal dominant progressive external ophthalmoplegia segregated with 1532G>A in exon 8 and an intronic variant c.2070 + 158G>A in cis. The one patient with parkinsonism had an additional heterozygous substitution in exon 7 in trans (1389G>T). Both coding region mutations were predicted to alter conserved amino acids in the linker region of polymerase gamma. None of the substitutions were found in 192 ethnically matched control chromosomes, 108 patients with progressive external ophthalmoplegia, nor 140 cases of sporadic idiopathic Parkinson disease.\nCONCLUSION: Both autosomal dominant progressive external ophthalmoplegia and parkinsonism can because caused by mutations that directly affect the polymerase domain of polymerase gamma.","variants":[{"Name":"NM_002693.3(POLG):c.1532G>A (p.Ser511Asn)","Chromosome":"15","Start":"89326965","Stop":"89326965","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28553,"rule_based_match":false,"evidence_text":"1532G>A","llm_judgment":"PRESENT","evidence":"1532G>A","abstract_start":551,"abstract_end":558}]}
{"pmid":"29150899","title":"p.Arg69Trp in RNASEH2C is a founder variant in three Indian families with Aicardi-Goutières syndrome.","abstract":"Aicardi-Goutières syndrome is an early-onset severe neurological disorder characterized by intracranial calcification, white matter abnormalities, hepatosplenomegaly, cerebrospinal fluid lymphocytosis, and elevated interferon-α levels, thus mimicking congenital viral infections. It is a genetically heterogeneous condition and autosomal recessive and autosomal dominant forms with variations in seven genes known till date. Variations in RNASEH2C cause an autosomal recessive form of AGS. Here we report three Indian families with variant, c.205C>T (NM_032193.3, p.Arg69Trp) in RNASEH2C gene identified by whole-exome sequencing and targeted molecular testing of the variant. Review of literature and our data suggest this is likely to be a founder variant in Asians and it would be a good initial variant to screen in patients with Aicardi-Goutières syndrome in Indians.","variants":[{"Name":"NM_032193.4(RNASEH2C):c.205C>T (p.Arg69Trp)","Chromosome":"11","Start":"65720385","Stop":"65720385","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16299,"rule_based_match":true,"evidence_text":"c.205C>T (NM_032193.3, p.Arg69Trp)","llm_judgment":"PRESENT","evidence":"c.205C>T (NM_032193.3, p.Arg69Trp)","abstract_start":541,"abstract_end":575}]}
{"pmid":"17646629","title":"A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation.","abstract":"BACKGROUND: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder characterized by progressive spastic paraparesis of the lower limbs.\nOBJECTIVE: To identify the genotype and characterize the phenotype in a family with a novel form of complicated autosomal recessive hereditary spastic paraparesis (ARHSP).\nMETHODS: Six subjects of a Turkish family were examined by clinical evaluation, detailed neuropsychological testing, neurophysiologic studies, MRI, diffusion tensor imaging (DTI), and mutation analysis of SPG7 gene.\nRESULTS: Three individuals were affected by a juvenile-onset form of complicated ARHSP due to the missense mutation c.2075G>C in exon 15 of the SPG7 gene in the homozygous state, substituting serine with threonine at codon 692. As additional clinical features, cerebellar syndrome, supranuclear palsy, and cognitive impairment, particularly disturbance of attention and executive functions, were found. MRI showed cerebellar atrophy and mild frontal cerebral atrophy. DTI revealed bilateral disturbance of white matter integrity in corticospinal tracts, frontal lobes, and the midbrain.\nCONCLUSIONS: The new SPG7 gene mutation leads to a novel complicated autosomal recessive hereditary spastic paraparesis phenotype that widens the spectrum of different brain systems that are optionally affected in hereditary spastic paraplegia (HSP). In this novel phenotype, spastic paraparesis is related to cerebral damage of corticospinal tracts. Impairment of attention and executive functions is due to white matter loss in frontal lobes. Furthermore, supranuclear palsy is caused by white matter damage in the midbrain. This multisystem affection, which was detected by the use of diffusion tensor imaging, may reflect a mitochondrial dysfunction that contributes to the underlying pathogenesis of SPG7-HSP.","variants":[{"Name":"NM_003119.4(SPG7):c.2075G>C (p.Ser692Thr)","Chromosome":"16","Start":"89553932","Stop":"89553932","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":21854,"rule_based_match":true,"evidence_text":"c.2075G>C","llm_judgment":"PRESENT","evidence":"c.2075G>C","abstract_start":694,"abstract_end":703}]}
{"pmid":"25451272","title":"Inherent lipid metabolic dysfunction in glycogen storage disease IIIa.","abstract":"We studied two patients from a nonconsanguineous family with life-long abnormal liver function, hepatomegaly and abnormal fatty acid profiles. Abnormal liver function, hypoglycemia and muscle weakness are observed in various genetic diseases, including medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and glycogen storage diseases. The proband showed increased free fatty acids, mainly C8 and C10, resembling fatty acid oxidation disorder. However, no mutation was found in ACADM and ACADL gene. Sequencing of theamylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) gene showed that both patients were compound heterozygotes for c.118C > T (p.Gln40X) and c.753_756 del CAGA (p.Asp251Glufsx29), whereas their parents were each heterozygous for one of these mutations. The AGL protein was undetectable in EBV-B cells from the two patients. Transcriptome analysis demonstrated a significant different pattern of gene expression in both of patients’ cells, including genes involving in the PPAR signaling pathway, fatty acid biosynthesis, lipid synthesis and visceral fat deposition and metabolic syndrome. This unique gene expression pattern is probably due to the absence of AGL, which potentially accounts for the observed clinical phenotypes of hyperlipidemia and hepatocyte steatosis in glycogen storage disease type IIIa.","variants":[{"Name":"NM_000642.3(AGL):c.753_756del (p.Asp251fs)","Chromosome":"1","Start":"99870485","Stop":"99870488","ReferenceAlleleVCF":"TAGAC","AlternateAlleleVCF":"T","allel_id":357199,"rule_based_match":true,"evidence_text":"c.753_756 del CAGA (p.Asp251Glufsx29)","llm_judgment":"PRESENT","evidence":"c.753_756 del CAGA (p.Asp251Glufsx29)","abstract_start":671,"abstract_end":708},{"Name":"NM_000642.3(AGL):c.118C>T (p.Gln40Ter)","Chromosome":"1","Start":"99861538","Stop":"99861538","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186639,"rule_based_match":true,"evidence_text":"c.118C > T (p.Gln40X)","llm_judgment":"PRESENT","evidence":"c.118C > T (p.Gln40X)","abstract_start":645,"abstract_end":666}]}
{"pmid":"19931173","title":"Novel de novo mutation in the KCNJ2 gene in a patient with Andersen-Tawil syndrome.","abstract":"Andersen-Tawil syndrome is a rare autosomal-dominant disease characterized by episodic muscle weakness, cardiac arrhythmias, and dysmorphic features. Mutations in the KCNJ2 gene (which encodes an inward-rectifying potassium channel protein, Kir2.1) have been reported to be responsible for this disorder. Reported here is a novel de novo mutation in the KCNJ2 gene in a patient with Andersen-Tawil syndrome. This mutation predicts the substitution of alanine for glycine at position 146 (Gly146Ala, c.437G > C) of Kir2.1 and is located at the extracellular pore loop region that serves as a principal ion-selective filter. The patient did not respond to acetazolamide, but experienced an improvement of the paralytic symptoms on treatment with a combination of spironolactone, amiloride, and potassium supplements.","variants":[{"Name":"NM_000891.3(KCNJ2):c.437G>C (p.Gly146Ala)","Chromosome":"17","Start":"70175476","Stop":"70175476","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":78474,"rule_based_match":true,"evidence_text":"c.437G > C","llm_judgment":"PRESENT","evidence":"c.437G > C","abstract_start":499,"abstract_end":509}]}
{"pmid":"26428316","title":"A survey of DICER1 hotspot mutations in ovarian and testicular sex cord-stromal tumors.","abstract":"Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations. In this study, we sought to define the association between DICER1 hotspot mutations and different morphologic subtypes of ovarian Sertoli-Leydig cell tumors. Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation. We subjected a series of ovarian Sertoli-Leydig cell tumors (n=32), Sertoli cell tumors (n=5) and gynandroblastomas (n=5), testicular sex cord-stromal tumors (n=15) and a diverse group of female genital tract tumors with rhabdomyosarcomatous morphology (n=10) to DICER1 hotspot mutation analysis using Sanger sequencing. We also tested two gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G). Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation. No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors. DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; P>0.1), and all mutated tumors harbored a p.E1705K mutation. DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma. No DICER1 mutations were detected in testicular sex cord-stromal tumors. Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components. In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli-Leydig cell tumors, and are unrelated to tumor differentiation. We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to occur, to include Sertoli cell tumors and gynandroblastomas. Our results suggest that DICER1 mutations may not have a role in testicular sex cord-stromal tumorigenesis.","variants":[{"Name":"NM_177438.3(DICER1):c.5113G>A (p.Glu1705Lys)","Chromosome":"14","Start":"95094139","Stop":"95094139","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":921320,"rule_based_match":false,"evidence_text":"p.E1705K","llm_judgment":"PRESENT","evidence":"p.E1705K","abstract_start":1011,"abstract_end":1019}]}
{"pmid":"32160317","title":"Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease.","abstract":"Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging. She died shortly after. Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.","variants":[{"Name":"NM_021199.4(SQOR):c.446del (p.Leu149fs)","Chromosome":"15","Start":"45669968","Stop":"45669968","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":999992,"rule_based_match":true,"evidence_text":"c.446delT","llm_judgment":"PRESENT","evidence":"c.446delT","abstract_start":1452,"abstract_end":1461},{"Name":"NM_021199.4(SQOR):c.637G>A (p.Glu213Lys)","Chromosome":"15","Start":"45673784","Stop":"45673784","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":999991,"rule_based_match":true,"evidence_text":"c.637G > A","llm_judgment":"PRESENT","evidence":"c.637G > A","abstract_start":1027,"abstract_end":1037}]}
{"pmid":"37619988","title":"Compound heterozygous variants in RAB34 in a rare skeletal ciliopathy syndrome.","abstract":"Skeletal ciliopathies are a heterogenous group of congenital disorders characterized by multiple internal abnormalities, and distinct radiographic presentation. Pathogenic variants in at least 30 cilia genes are known to cause skeletal ciliopathies. Here we report a fetus with an atypical skeletal ciliopathy phenotype and compound heterozygous variants in the RAB34 gene. The affected fetus had multiple malformations, including posterior neck edema, micrognathia, low-set and small ears, auricular hypoplasia, cleft lip and palate, short extremities, and a combination of rarely occurring pre- and postaxial polydactyly. Genome sequencing identified compound heterozygous variants in the RAB34 gene: maternal c.254T>C, p.(Ile85Thr), and paternal c.691C>T, p.(Arg231*) variants. Only the paternal variant was present in the unaffected sibling. Evidence in the literature indicated that Rab34<sup>-/-</sup> mice displayed a ciliopathy phenotype with cleft palate and polydactyly. These features were consistent with malformations detected in our patient supporting the pathogenicity of the identified RAB34 variants. Overall, this case report further expands genetic landscape of human ciliopathy syndromes and suggests RAB34 as a candidate gene for skeletal ciliopathies.","variants":[{"Name":"NM_031934.6(RAB34):c.254T>C (p.Ile85Thr)","Chromosome":"17","Start":"28715860","Stop":"28715860","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2671947,"rule_based_match":true,"evidence_text":"c.254T>C, p.(Ile85Thr)","llm_judgment":"PRESENT","evidence":"c.254T>C, p.(Ile85Thr)","abstract_start":712,"abstract_end":734},{"Name":"NM_031934.6(RAB34):c.691C>T (p.Arg231Ter)","Chromosome":"17","Start":"28714814","Stop":"28714814","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2671948,"rule_based_match":true,"evidence_text":"c.691C>T, p.(Arg231*)","llm_judgment":"PRESENT","evidence":"c.691C>T, p.(Arg231*)","abstract_start":749,"abstract_end":770}]}
{"pmid":"21800139","title":"THAP1/DYT6 sequence variants in non-DYT1 early-onset primary dystonia in China and their effects on RNA expression.","abstract":"Mutations in the THAP1 gene were recently identified as the cause of DYT6 primary dystonia. More than 40 mutations in this gene have been described in different populations. However, no previous report has identified sequence variations that affect the transcript process of the THAP1 gene. In addition, the mutation frequency in Chinese early-onset primary dystonia has not been well characterized. One hundred and two unrelated patients with non-DYT1 early-onset primary dystonia (age at onset <26 years), family members of participants with mutations, and 200 neurologically normal controls were screened for THAP1 gene mutations. The effects of the identified mutations on RNA expression were analyzed using semi-quantitative real-time PCR. Seven sequence variants (c.63_66del TTTC, c.161G>T, c.224A>T, c.267G>A, c.339T>C, c.449A>C, and c.539T>C) were identified in this group of patients (6.9%). In this cohort, 15 subjects (seven unrelated patients and eight family members) were detected to have THAP1 sequence variants. Among these 15 subjects, 11 were manifested (penetrance of DYT6 was 73.3%) and seven presented with craniocervical involvement (63.6%). However, one patient manifested paroxysmal headshake, and one presented with essential hand tremor. Semi-quantitative real-time PCR indicated that a novel silent mutation (c.267G>A) decreased the expression of THAP1 in human lymphocytes. Our findings indicated that THAP1 sequence variants are not common in non-DYT1 early-onset primary dystonia in China and that the clinical manifestation may vary. One silent mutation (c.267G>A) was shown to affect THAP1 expression.","variants":[{"Name":"NM_018105.3(THAP1):c.63_66del (p.Phe22fs)","Chromosome":"8","Start":"42843029","Stop":"42843032","ReferenceAlleleVCF":"GGAAA","AlternateAlleleVCF":"G","allel_id":3856621,"rule_based_match":true,"evidence_text":"c.63_66del TTTC","llm_judgment":"PRESENT","evidence":"c.63_66del TTTC","abstract_start":770,"abstract_end":785}]}
{"pmid":"21150893","title":"A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly.","abstract":"Anterior segment dysgenesis (ASD) is a spectrum of disorders that affect the anterior ocular chamber. Clinical studies on a Newfoundland family over the past 30 years show that 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly, segregating as an autosomal dominant trait. To determine the molecular etiology of the variable ASD in this family, we sequenced nine functional candidate genes and identified 44 variants. A point mutation in FOXE3, which codes for a transcription factor involved in the formation of the lens and surrounding structures, co-segregated with the variable ocular phenotype. This novel mutation (c.959G>T) substitutes the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Two recent reports have also identified non-stop mutations in FOXE3 in patients with variable ocular phenotypes and predict an extended protein. Although FOXE3 is a lens-specific gene, we successfully isolated complementary DNA from lymphoblasts of an affected family member, and our sequencing results show that the c.959T allele is absent, suggesting that it may be degraded at the RNA level. Though preliminary, our results challenge the notion that an extended FOXE3 protein causes ASD, and instead suggests a mechanism of haploinsufficiency in the case of non-stop mutations. This study adds to several reports that suggest that autosomal-dominant mutations within FOXE3 cause ASD and has important clinical utility, especially for the diagnosis of mildly affected patients.","variants":[{"Name":"NM_012186.3(FOXE3):c.959G>T (p.Ter320Leu)","Chromosome":"1","Start":"47417274","Stop":"47417274","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39113,"rule_based_match":true,"evidence_text":"c.959G>T","llm_judgment":"PRESENT","evidence":"c.959G>T","abstract_start":659,"abstract_end":667}]}
{"pmid":"33030641","title":"Bilateral Disease Common Among Slovenian CHEK2-Positive Breast Cancer Patients.","abstract":"BACKGROUND: Currently, data on pathogenic variants in the CHEK2 gene and their impact on cancer risk are lacking. This study aimed to explore the characteristics of breast cancer (BC) patients from families with CHEK2 pathogenic variants in Slovenia.\nMETHODS: In the years 2014 to 2019, CHEK2 pathogenic variants/likely pathogenic variants (PV/LPVs) were found in probands from 50 different families who underwent genetic counseling and testing using a multigene panel at the authors' institution. Altogether, the study enrolled 75 individuals from 50 CHEK2 families who were carriers of a CHEK2 PV/LPV. The clinical data on 41 BC patients with CHEK2 PV/LPV and other carriers of CHEK2 PV/LPV from Slovenia were collected and analyzed.\nRESULTS: Breast cancer was diagnosed in 41 of 75 CHEK2 PV/LPV carriers (40 females, 1 male). The mean age at BC diagnosis was 42.8 years (range, 21-63 years), and 27 (65.8%) of the 41 of patients with BC had a positive family history for BC. Contralateral BC (CBC) was observed in 8 (19.5%) of the 41 patients (mean age, 55.6 years). Of 12 patients with human epidermal growth factor receptor 2 (HER2)-positive tumor type, a c.444+1G > A PV/LPV was detected in 4 patients, c.349A > G in 3 patients, deletion of exons 9-10 in 3 patients, deletion of exon 8 in 1 patient, and c.1427C > T PV/LPV in 1 patient.\nCONCLUSION: Bilateral BC was diagnosed in as many as 19.5% of the Slovenian BC patients with CHEK2 PV/LPVs. Breast cancer associated with a germline CHEK2 PV/LPV occurs in younger patients compared with sporadic BC.","variants":[{"Name":"NM_007194.4(CHEK2):c.349A>G (p.Arg117Gly)","Chromosome":"22","Start":"28725338","Stop":"28725338","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":133528,"rule_based_match":true,"evidence_text":"c.349A > G","llm_judgment":"PRESENT","evidence":"c.349A > G","abstract_start":1209,"abstract_end":1219},{"Name":"NM_007194.4(CHEK2):c.444+1G>A","Chromosome":"22","Start":"28725242","Stop":"28725242","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":133532,"rule_based_match":true,"evidence_text":"c.444+1G > A","llm_judgment":"PRESENT","evidence":"c.444+1G > A","abstract_start":1161,"abstract_end":1173},{"Name":"NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)","Chromosome":"22","Start":"28694066","Stop":"28694066","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133517,"rule_based_match":true,"evidence_text":"c.1427C > T PV/LPV","llm_judgment":"PRESENT","evidence":"c.1427C > T PV/LPV","abstract_start":1310,"abstract_end":1328}]}
{"pmid":"23099647","title":"Exome sequencing identified a missense mutation of EPS8L3 in Marie Unna hereditary hypotrichosis.","abstract":"BACKGROUND: Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant disorder characterised by coarse, wiry, twisted hair developed in early childhood and subsequent progressive hair loss. MUHH is a genetically heterogeneous disorder. No gene in 1p21.1-1q21.3 region responsible for MUHH has been identified.\nMETHODS: Exome sequencing was performed on two affected subjects, who had normal vertex hair and modest alopecia, and one unaffected individual from a four-generation MUHH family of which our previous linkage study mapped the MUHH locus on chromosome 1p21.1-1q21.3.\nRESULTS: We identified a missense mutation in EPS8L3 (NM_024526.3: exon2: c.22G->A:p.Ala8Thr) within 1p21.1-1q21.3. Sanger sequencing confirmed the cosegregation of this mutation with the disease phenotype in the family by demonstrating the presence of the heterozygous mutation in all the eight affected and absence in all the seven unaffected individuals. This mutation was found to be absent in 676 unrelated healthy controls and 781 patients of other disease from another unpublished project of our group.\nCONCLUSIONS: Taken together, our results suggest that EPS8L3 is a causative gene for MUHH, which was helpful for advancing us on understanding of the pathogenesis of MUHH. Our study also has further demonstrated the effectiveness of combining exome sequencing with linkage information for identifying Mendelian disease genes.","variants":[{"Name":"NM_133181.4(EPS8L3):c.22G>A (p.Ala8Thr)","Chromosome":"1","Start":"109761728","Stop":"109761728","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":818634,"rule_based_match":false,"evidence_text":"NM_024526.3: exon2: c.22G->A:p.Ala8Thr","llm_judgment":"PRESENT","evidence":"NM_024526.3: exon2: c.22G->A:p.Ala8Thr","abstract_start":640,"abstract_end":678}]}
{"pmid":"21733974","title":"A new AURKC mutation causing macrozoospermia: implications for human spermatogenesis and clinical diagnosis.","abstract":"The presence of close to 100% large-headed multi-tailed spermatozoa in the ejaculate has been described as a rare phenotype of male infertility with a very poor prognosis. We demonstrated previously that most cases were caused by a homozygous mutation (c.144delC) in the Aurora Kinase C gene (AURKC) leading to the absence or the production of a non-functional protein. AURKC deficiency in these patients blocked meiosis and resulted in the production of tetraploid spermatozoa unsuitable for fertilization. We describe here the study of two brothers presenting with large-headed spermatozoa. Molecular analysis of the AURKC gene was carried out in two brothers presenting with a typical large-headed spermatozoa phenotype. Both affected brothers were heterozygous for the c.144delC mutation. After complete sequencing of the gene a new heterozygous variant, c.436-2A>G, was identified in both patients. This mutation is located in the acceptor consensus splice site of exon 5. AURKC transcripts were extracted from one of the patient's leukocytes and reverse transcription polymerase chain reaction could be realized showing the presence of a truncated transcript indicating that c.436-2A>G leads to the skipping of exon 5. These results indicate that AURKC molecular analysis of patients with large-headed spermatozoa should not be stopped in the absence of a homozygous recurrent mutation on exon 3 but complete sequence analysis should be performed. This diagnosis is important as the identification of AURKC mutations in patients indicates that all spermatozoa will be chromosomally abnormal and that ICSI should not be attempted.","variants":[{"Name":"NM_001015878.2(AURKC):c.436-2A>G","Chromosome":"19","Start":"57233458","Stop":"57233458","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":76990,"rule_based_match":true,"evidence_text":"c.436-2A>G","llm_judgment":"PRESENT","evidence":"c.436-2A>G","abstract_start":859,"abstract_end":869}]}
{"pmid":"22095910","title":"VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans.","abstract":"Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M). In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for A/M.","variants":[{"Name":"NM_001112704.2(VAX1):c.454C>A (p.Arg152Ser)","Chromosome":"10","Start":"117134559","Stop":"117134559","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":45612,"rule_based_match":true,"evidence_text":"c.454C>A","llm_judgment":"PRESENT","evidence":"c.454C>A","abstract_start":309,"abstract_end":317}]}
{"pmid":"30152191","title":"Functionally significant, novel GATA4 variants are frequently associated with Tetralogy of Fallot.","abstract":"Transcription factor GATA4 is known to play crucial role during heart development, regulating expression of several other key cardiogenic factors. Various GATA4 mutations are reported in familial as well as sporadic cases of congenital heart defects (CHDs). To estimate the prevalence and pathogenic potential of GATA4 variants in our CHD cohort, we have screened 285 CHD cases along with 200 controls by Sanger sequencing and identified 9 genetic variants (c.23C>A; p.Ala8Asp, c.25G>A; p.Ala9Thr, c.223G>T; p.Ala75Ser, c.383A>T; p.Glu128Val, c.397A>T; p.Ser133Cys, c.682T>A; p.Trp228Arg, c.1064C>G; p.Thr355Ser, c.1073G>C; p.Ser358Thr, and c.1220C>A; p.Pro407Gln) in 22 unrelated CHD probands (frequency:7.72%). Five of these are novel and located in the N-terminal transactivation domain (TAD) and first zinc finger domain. Majority C-terminal domain variants are polymorphic. Two of the TAD variants p.Glu128Val, p.Ser133Cys, and a first zinc finger variant p.Trp228Arg, impair combinatorial synergy of NKX2-5, SRF, and TBX5, suggesting potential role of these domains in GATA4 interactions with these factors. Decreased DNA-binding affinity with EMSA also supports this observation. Homology modeling and tertiary structure comparison show conformational changes in these variants. Interestingly, GATA4 variants are more frequently associated with ToF (45%; P = 0.0046) and PS (22.7%; P < 0.0001) in spite of abundance of septal defects in our study cohort.","variants":[{"Name":"NM_001308093.3(GATA4):c.25G>A (p.Ala9Thr)","Chromosome":"8","Start":"11708337","Stop":"11708337","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":217248,"rule_based_match":true,"evidence_text":"c.25G>A; p.Ala9Thr","llm_judgment":"PRESENT","evidence":"c.25G>A; p.Ala9Thr","abstract_start":478,"abstract_end":496}]}
{"pmid":"38184646","title":"Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease.","abstract":"BACKGROUND: 5' untranslated regions (5'UTRs) are essential modulators of protein translation. Predicting the impact of 5'UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5'UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs).\nMETHODS: We performed an isoform-level re-analysis of retinal RNA-seq data to identify the protein-coding transcripts of 378 IRD genes with highest expression in retina. We evaluated the coverage of their 5'UTRs by different whole exome sequencing (WES) kits. The selected 5'UTRs were analyzed in whole genome sequencing (WGS) and WES data from IRD sub-cohorts from the 100,000 Genomes Project (n = 2397 WGS) and an in-house database (n = 1682 WES), respectively. Identified variants were annotated for 5'UTR-relevant features and classified into seven categories based on their predicted functional consequence. We developed a variant prioritization strategy by integrating population frequency, specific criteria for each category, and family and phenotypic data. A selection of candidate variants underwent functional validation using diverse approaches.\nRESULTS: Isoform-level re-quantification of retinal gene expression revealed 76 IRD genes with a non-canonical retina-enriched isoform, of which 20 display a fully distinct 5'UTR compared to that of their canonical isoform. Depending on the probe design, 3-20% of IRD genes have 5'UTRs fully captured by WES. After analyzing these regions in both cohorts, we prioritized 11 (likely) pathogenic variants in 10 genes (ARL3, MERTK, NDP, NMNAT1, NPHP4, PAX6, PRPF31, PRPF4, RDH12, RD3), of which 7 were novel. Functional analyses further supported the pathogenicity of three variants. Mis-splicing was demonstrated for the PRPF31:c.-9+1G>T variant. The MERTK:c.-125G>A variant, overlapping a transcriptional start site, was shown to significantly reduce both luciferase mRNA levels and activity. The RDH12:c.-123C>T variant was found in cis with the hypomorphic RDH12:c.701G>A (p.Arg234His) variant in 11 patients. This 5'UTR variant, predicted to introduce an upstream open reading frame, was shown to result in reduced RDH12 protein but unaltered mRNA levels.\nCONCLUSIONS: This study demonstrates the importance of 5'UTR variants implicated in IRDs and provides a systematic approach for 5'UTR annotation and validation that is applicable to other inherited diseases.","variants":[{"Name":"NM_152443.3(RDH12):c.-123C>T","Chromosome":"14","Start":"67722520","Stop":"67722520","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":872095,"rule_based_match":true,"evidence_text":"RDH12:c.-123C>T","llm_judgment":"PRESENT","evidence":"RDH12:c.-123C>T","abstract_start":2051,"abstract_end":2066}]}
{"pmid":"30286154","title":"BRCA1/2 mutations are not a common cause of malignant melanoma in the Polish population.","abstract":"The association of BRCA1/2 mutations with melanoma is not completely determined; the interpretation of variants of unknown significance is also problematic. To evaluate these issues we explored the molecular basis of melanoma risk by performing whole-exome sequencing on a cohort of 96 unrelated Polish early-onset melanoma patients and targeted sequencing of BRCA1/2 genes on additional 30 melanoma patients with familial aggregation of breast and other cancers. Sequencing was performed on peripheral blood. We evaluated MutationTaster, Polyphen2, SIFT, PROVEAN algorithms, analyzed segregation with cancer disease (in both families with identified BRCA2 variants) and in one family performed LOH (based on 2 primary tumors). We found neither pathogenic mutations nor variants of unknown significance within BRCA1. We identified two BRCA2 variants of unknown significance: c.9334G>A and c.4534 C>T. Disease allele frequency was evaluated by genotyping of 1230 consecutive melanoma cases, 5000 breast cancer patients, 3500 prostate cancers and 9900 controls. Both variants were found to be absent among unselected cancer patients and healthy controls. The MutationTaster, Polyphen2 and SIFT algorithms indicate that c.9334G>A is a damaging variant. Due to lack of tumour tissue LOH analysis could not be performed for this variant. The variant segregated with the disease. The c.4534 C>T variant did not segregate with disease, there was no LOH of the variant. The c.9334G>A variant, classified as a rare variant of unknown significance, on current evidence may predisposes to cancers of the breast, prostate and melanoma. Functional studies to describe how the DNA change affects the protein function and a large multi-center study to evaluate its penetrance are required.","variants":[{"Name":"NM_000059.4(BRCA2):c.9334G>A (p.Asp3112Asn)","Chromosome":"13","Start":"32394766","Stop":"32394766","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":463231,"rule_based_match":true,"evidence_text":"c.9334G>A","llm_judgment":"PRESENT","evidence":"c.9334G>A","abstract_start":875,"abstract_end":884}]}
{"pmid":"25704634","title":"Genetic and Clinical Analysis in a Cohort of Patients with Wilson's Disease in Southwestern China.","abstract":"BACKGROUND AND AIMS: Wilson's disease (WD), characterized by a disorder of copper metabolism, is an inherited autosomal recessive disease caused by mutations in the ATP7B gene.\nMETHODS: To explore genotype-phenotype correlations in Chinese WD patients and to evaluate the frequency of the ATP7B mutations, we described 77 clinically and biochemically confirmed WD patients and detected mutations in ten WD families from southwestern China. Clinical features were presented and all the exons of the ATP7B gene were screened.\nRESULTS: The appearance of Kayser-Fleischer (K-F) rings was closely related to onset age, particularly before 10 years old. For those patients with predominantly neurological symptoms, MRI was the most sensitive and preferred examination. Eight mutations of the ATP7B gene were detected including seven reported mutations (c.2302dup, c.2304delC, c.2333 G>T, c.2621 C>T, c.2755 C>G, c.2975 C>T and c.1366 G>C) and four novel mutations (c.3446 G>A, c.3767insCA, c.3406 G>A and c.3700delG). c.2333 G>T was detected in 6/20 alleles (30%), accounting for the largest proportion, which could be regarded as a mutation hotspot in this region.\nCONCLUSIONS: Our study extends the mutation spectrum of ATP7B and analyzes the relationship between mutations in the ATP7B gene and clinical findings of WD.","variants":[{"Name":"NM_000053.4(ATP7B):c.2755C>G (p.Arg919Gly)","Chromosome":"13","Start":"51949772","Stop":"51949772","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":18896,"rule_based_match":true,"evidence_text":"c.2755 C>G","llm_judgment":"PRESENT","evidence":"c.2755 C>G","abstract_start":894,"abstract_end":904}]}
{"pmid":"26872964","title":"Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency.","abstract":"Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are \"private.\" The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.","variants":[{"Name":"NM_005957.5(MTHFR):c.1129C>T (p.Arg377Cys)","Chromosome":"1","Start":"11794766","Stop":"11794766","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18567,"rule_based_match":true,"evidence_text":"c.1129C>T (p.Arg377Cys)","llm_judgment":"PRESENT","evidence":"c.1129C>T (p.Arg377Cys)","abstract_start":753,"abstract_end":776}]}
{"pmid":"28475293","title":"Synonymous mutation in TP53 results in a cryptic splice site affecting its DNA-binding site in an adolescent with two primary sarcomas.","abstract":"Pathologic variants in TP53 are known risk factors for the development of cancer. We report a 17-year-old male who presented with two primary sarcomas. Germline sequencing revealed a novel TP53 c.672 G>A mutation. Sequencing revealed wild-type TP53 in the parents, and there was no history of cancer in first-degree relatives. This de novo synonymous germline mutation results in a 5' cryptic splice site that is bound by U1, resulting in a shift of the splice site by 5 base pairs. The frame shift results in a truncated protein at residue 246, which disrupts the DNA-binding domain of p53.","variants":[{"Name":"NM_000546.6(TP53):c.672G>A (p.Glu224=)","Chromosome":"17","Start":"7674859","Stop":"7674859","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":91600,"rule_based_match":true,"evidence_text":"c.672 G>A","llm_judgment":"PRESENT","evidence":"c.672 G>A","abstract_start":194,"abstract_end":203}]}
{"pmid":"28024295","title":"Characterization of two novel FANCG mutations in Indian Fanconi anemia patients.","abstract":"FA is a rare recessive genetic disorder with autosomal or X-linked mode of inheritance and is associated with 19 different FA complementation groups. We have studied three patients clinically diagnosed as FA. All three patients showed a high frequency chromosomal breakage in MMC induced blood cultures and FANCD2 non-monoubiquitination by western blotting. The molecular analysis using direct sequencing revealed two novel mutations in FANCG; 2 novel mutations c.1143+5G>C and c.883dupG, and a reported mutation c.1471_1473delAAAinsG. We have for the first time modeled FANCG protein with fold based template search using pGenthreader which revealed sequence fold identical to super helical TPR domain of O linked GLCNAC transferase and have studied the impact of mutations on the function and structure of FANCG. All three mutations are potential pathogenic molecular changes which can affect FANCG interactions required for FA pathway, homologous recombination repairs and unhooking step of the ICL repair process.","variants":[{"Name":"NM_004629.2(FANCG):c.1143+5G>C","Chromosome":"9","Start":"35075957","Stop":"35075957","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":918004,"rule_based_match":true,"evidence_text":"c.1143+5G>C","llm_judgment":"PRESENT","evidence":"c.1143+5G>C","abstract_start":462,"abstract_end":473}]}
{"pmid":"21199751","title":"Ellis-van Creveld syndrome: prenatal diagnosis, molecular analysis and genetic counseling.","abstract":"OBJECTIVE: To present the perinatal findings and molecular genetic analysis of two siblings with Ellis-van Creveld (EvC) syndrome.\nMATERIALS, METHODS AND RESULTS: A 33-year-old woman, gravida 3, para 1, was referred for genetic counseling at 18 gestational weeks because of recurrent fetal skeletal dysplasia. Two years previously, she had delivered a 1,316-g dead male baby at 28 gestational weeks with a karyotype of 46,XY, postaxial polydactyly of the hands, thoracic narrowness, endocardial cushion defects, transposition of the great arteries, shortening of the long bones, malposition of the toes, and hypoplastic nails. During this pregnancy, prenatal ultrasound at 18 gestational weeks revealed shortening of the long bones (equivalent to 15 weeks), postaxial polydactyly of both hands, thoracic narrowness, and endocardial cushion defects. The pregnancy was subsequently terminated, and a 236-g female fetus was delivered with a karyotype of 46,XX, postaxial polydactyly of the hands, thoracic dysplasia, endocardial cushion defects, shortening of the long bones, and malposition of the toes and hypoplastic nails. The phenotype of each of the two siblings was consistent with EVC syndrome. Molecular analysis of the EVC and EVC2 genes revealed heterozygous mutations in the EVC2 gene. A heterozygous deletion mutation of a 26-bp deletion of c.871-2_894del26 encompassing the junction between intron 7 and exon 8 of the EVC2 gene was found in the mother and two siblings, and a heterozygous nonsense mutation of c.1195C >T, p.R399X in exon 10 of the EVC2 gene was found in the father and two siblings.\nCONCLUSION: Prenatal sonographic identification of endocardial cushion defects in association with shortening of the long bones should alert clinicians to the possibility of EvC syndrome and prompt a careful search of hexadactyly of the hands. Molecular analysis of the EVC and EVC2 genes is helpful in genetic counseling in cases with prenatally detected postaxial polydactyly, thoracic narrowness, short limbs and endocardial cushion defects.","variants":[{"Name":"NM_147127.5(EVC2):c.1195C>T (p.Arg399Ter)","Chromosome":"4","Start":"5640789","Stop":"5640789","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18422,"rule_based_match":true,"evidence_text":"c.1195C >T, p.R399X","llm_judgment":"PRESENT","evidence":"c.1195C >T, p.R399X","abstract_start":1521,"abstract_end":1540}]}
{"pmid":"33411215","title":"Identification of MMACHC and PROKR2 mutations causing coexistent cobalamin C disease and Kallmann syndrome in a young woman.","abstract":"Cobalamin C (cblC) disease and Kallmann syndrome (KS) are rare hereditary diseases. To date, no report has described the coexistence of those two genetic disorders in the same patient, or an association between them. We report the case of a 23-year-old woman with cblC defect and KS. She first presented mild memory problems in puberty, which worsened in adulthood to progressive memory loss accompanied by slow and unsteady walking, slow response, inattention, cognitive impairment, insomnia, no sense of smell, and the lack of spontaneous puberty. Laboratory tests revealed gonadotropin deficiency, a low estrogen level, and remarkably elevated serum homocysteine and serum and urine organic acid levels. Whole-exome sequencing detected compound heterozygous variants in MMACHC [c.398_399del (p.Gln133Argfs*4) and c.482G > A (p.Arg161Gln)] and heterozygous variants in PROKR2 [c.337T > C (p.Tyr113His)]. Thus, clinical and genetic examinations confirmed the cblC disease and KS diagnoses. This report on coexisting cblC disease and KS caused by different pathogenic genes in a single patient enriches the clinical research on these two rare genetic diseases.","variants":[{"Name":"NM_015506.3(MMACHC):c.398_399del (p.Gln133fs)","Chromosome":"1","Start":"45508333","Stop":"45508334","ReferenceAlleleVCF":"CAA","AlternateAlleleVCF":"C","allel_id":541241,"rule_based_match":true,"evidence_text":"c.398_399del (p.Gln133Argfs*4)","llm_judgment":"PRESENT","evidence":"c.398_399del (p.Gln133Argfs*4)","abstract_start":781,"abstract_end":811},{"Name":"NM_144773.4(PROKR2):c.337T>C (p.Tyr113His)","Chromosome":"20","Start":"5314033","Stop":"5314033","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":345522,"rule_based_match":true,"evidence_text":"c.337T > C (p.Tyr113His)","llm_judgment":"PRESENT","evidence":"c.337T > C (p.Tyr113His)","abstract_start":879,"abstract_end":903}]}
{"pmid":"28394026","title":"Recurrent Hyperparathyroidism Due to a Novel CDC73 Splice Mutation.","abstract":"The recognition of hereditary causes of primary hyperparathyroidism (pHPT) is important because clinical care and surveillance differ significantly between sporadic and hereditary pHPT. In addition, the increasing number of genetic tests poses a challenge to classify mutations as benign or pathogenic. Functional work-up of variants remains a mainstay to provide evidence for pathogenicity. We describe a 52-year-old male patient with recurrent pHPT since age 35 years. Despite several neck surgeries with complete parathyroidectomy, he experienced persistent pHPT, necessitating repeated surgery for a forearm autotransplant, which finally resulted in unmeasurable parathyroid hormone (PTH) levels. Genetic testing revealed a new CDC73 variant (c.238-8G>A [IVS2-8G>A]), initially classified as a variant of uncertain significance. Parathyroid tissue from the initial surgeries showed loss of heterozygosity. Using an RT-PCR approach, we show that the mutation leads to the use of a cryptic splice site in peripheral mononuclear cells. In addition, a minigene approach confirms the use of the cryptic splice site in a heterologous cell system. The novel c.238-8G>A CDC73 variant activates a cryptic splice site, and the functional data provided justify the classification as a likely pathogenic variant. Our results underscore the importance of functional work-up for variant classification in the absence of other available data, such as presence in disease-specific databases, other syndromic clinical findings, or family history. In addition, the presented case exemplifies the importance to consider a hereditary condition in young patients with pHPT, particularly those with multi-gland involvement. © 2017 American Society for Bone and Mineral Research.","variants":[{"Name":"NM_024529.5(CDC73):c.238-8G>A","Chromosome":"1","Start":"193130166","Stop":"193130166","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1372446,"rule_based_match":true,"evidence_text":"c.238-8G>A [IVS2-8G>A]","llm_judgment":"PRESENT","evidence":"c.238-8G>A [IVS2-8G>A]","abstract_start":747,"abstract_end":769}]}
{"pmid":"34828371","title":"A Monoallelic Variant in","abstract":"Hearing impairment (HI) is a sensory disorder with a prevalence of 0.0055 live births in South Africa. DNA samples from a South African family presenting with progressive, autosomal dominant non-syndromic HI were subjected to whole-exome sequencing, and a novel monoallelic variant in <i>REST</i> [c.1244GC; p.(C415S)], was identified as the putative causative variant. The co-segregation of the variant was confirmed with Sanger Sequencing. The variant is absent from databases, 103 healthy South African controls, and 52 South African probands with isolated HI. In silico analysis indicates that the p.C415S variant in <i>REST</i> substitutes a conserved cysteine and results in changes to the surrounding secondary structure and the disulphide bonds, culminating in alteration of the tertiary structure of REST. Localization studies using ectopically expressed GFP-tagged Wild type (WT) and mutant <i>REST</i> in HEK-293 cells show that WT REST localizes exclusively to the nucleus; however, the mutant protein localizes throughout the cell. Additionally, mutant REST has an impaired ability to repress its known target <i>AF1q</i>. The data demonstrates that the identified mutation compromises the function of <i>REST</i> and support its implication in HI. This study is the second report, worldwide, to implicate <i>REST</i> in HI and suggests that it should be included in diagnostic HI panels.","variants":[{"Name":"NM_005612.5(REST):c.1244G>C (p.Cys415Ser)","Chromosome":"4","Start":"56930102","Stop":"56930102","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1678968,"rule_based_match":false,"evidence_text":"c.1244G>C (p.Cys415Ser)","llm_judgment":"PRESENT","evidence":"C415S","abstract_start":311,"abstract_end":316}]}
{"pmid":"32467599","title":"The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate.","abstract":"Stargardt disease (STGD1) is a form of inherited retinal dystrophy attributed to variants affecting function of the large ABCA4 gene and is arguably the most complex monogenic disease. Therapeutic trials in patients depend on identifying causal ABCA4 variants in trans, which is complicated by extreme allelic and clinical heterogeneity. We report the genetic architecture of STGD1 in the young genetically isolated population of Newfoundland, Canada. Population-based clinical recruitment over several decades yielded 29 STGD1 and STGD1-like families (15 multiplex, 14 singleton). Family interviews and public archival records reveal the vast majority of pedigree founders to be of English extraction. Full gene sequencing and haplotype analysis yielded a high solve rate (38/41 cases; 92.7%) for STGD1 and identified 16 causative STGD1 alleles, including a novel deletion (NM_000350.3: ABCA4 c.67-1delG). Several STGD1 alleles of European origin (including NM_000350.3: ABCA4 c.5714 + 5G>A and NM_000350.3: ABCA4 c.5461-10T>C) have drifted to a relatively high population frequency due to founder effect. We report on retinal disease progression in homozygous patients, providing valuable allele-specific insights. The least involved retinal disease is seen in patients homozygous for c.5714 + 5G>A variant, a so-called \"mild\" variant which is sufficient to precipitate a STGD1 phenotype in the absence of other pathogenic variants in the coding region and intron/exon boundaries of ABCA4. The most severe retinal disease is observed in cases with ABCA4 c.[5461-10T>C;5603A>T] complex allele. We discuss the advantages of determining genetic architecture in genetic isolates in order to begin to meet the grand challenge of human genetics.","variants":[{"Name":"NM_000350.3(ABCA4):c.5461-10T>C","Chromosome":"1","Start":"94011395","Stop":"94011395","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":98777,"rule_based_match":true,"evidence_text":"NM_000350.3: ABCA4 c.5461-10T>C","llm_judgment":"PRESENT","evidence":"NM_000350.3: ABCA4 c.5461-10T>C","abstract_start":996,"abstract_end":1027},{"Name":"NM_000350.3(ABCA4):c.5714+5G>A","Chromosome":"1","Start":"94010795","Stop":"94010795","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105292,"rule_based_match":true,"evidence_text":"NM_000350.3: ABCA4 c.5714 + 5G>A","llm_judgment":"PRESENT","evidence":"NM_000350.3: ABCA4 c.5714 + 5G>A","abstract_start":959,"abstract_end":991}]}
{"pmid":"29095867","title":"Role of GALNT12 in the genetic predisposition to attenuated adenomatous polyposis syndrome.","abstract":"The involvement of GALNT12 in colorectal carcinogenesis has been demonstrated but it is not clear to what extent it is implicated in familial CRC susceptibility. Partially inactivating variant, NM_024642.4:c.907G>A, p.(D303N), has been previously detected in familial CRC and proposed as the causative risk allele. Since phenotypes of the described carrier families showed not only CRC but also a polyp history, we hypothesized that GALNT12 could be involved in adenoma predisposition and consequently, in hereditary polyposis CRC syndromes. For that purpose, we have screened the GALNT12 gene in germline DNA from 183 unrelated attenuated polyposis patients. c.907G>A, p.(D303N) was detected in 4 cases (MAF = 1.1%) and no other candidate variants were found. After segregation studies, LOH analyses, glycosylation pattern tests and case-control studies, our results did not support the role of c.907G>A, p.(D303N) as a high-penetrance risk allele for polyposis CRC.","variants":[{"Name":"NM_024642.5(GALNT12):c.907G>A (p.Asp303Asn)","Chromosome":"9","Start":"98831947","Stop":"98831947","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":226331,"rule_based_match":true,"evidence_text":"NM_024642.4:c.907G>A, p.(D303N)","llm_judgment":"PRESENT","evidence":"NM_024642.4:c.907G>A, p.(D303N)","abstract_start":194,"abstract_end":225}]}
{"pmid":"35796944","title":"Transcript-Based Diagnosis and Expanded Phenotype of an Intronic Mutation in TPM3 Myopathy.","abstract":"INTRODUCTION: Congenital myopathies are a broad group of inborn muscle disorders caused by a multitude of genetic factors, often characterized by muscle atrophy and hypotonia.\nMETHODS: Clinical studies, imaging, histology, whole-exome sequencing (WES) and muscle tissue RNA studies.\nRESULTS: We describe a severe congenital myopathy manifesting at birth with bilateral clubfeet, delayed motor development and hypotonia, becoming evident by 4 months of age. At 3 years of age, the patient had tongue fasciculations, was bedridden, and was chronically ventilated via tracheostomy. Imaging studies demonstrated severe muscle atrophy and, surprisingly, cerebral atrophy; electromyography demonstrated a myasthenic pattern and histological evaluation did not facilitate a definitive diagnosis. Trio WES did not identify a causative variant, except for a non-canonical intronic TPM3 c.118-12G>A variant of uncertain significance. Transcript analysis of muscle tissue from the patient proved the pathogenicity of this homozygous variant, with a 97% reduction in the muscle-specific TPM3.12 transcript.\nDISCUSSION: This study broadens the phenotypic spectrum of recessive TPM3 disease, highlighting tongue fasciculations and bilateral clubfoot, as well as possibly-related cerebral atrophy. It also shows the importance of a broad approach to genetic analysis and the utility of RNA-based studies, demonstrating efficacy of early genome and transcriptome queries in facilitating rapid and cost-effective diagnosis of congenital myopathies.","variants":[{"Name":"NM_152263.4(TPM3):c.118-12G>A","Chromosome":"1","Start":"154191323","Stop":"154191323","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1517893,"rule_based_match":true,"evidence_text":"TPM3 c.118-12G>A","llm_judgment":"PRESENT","evidence":"TPM3 c.118-12G>A","abstract_start":872,"abstract_end":888}]}
{"pmid":"34078970","title":"Evident hypopigmentation without other ocular deficits in Dutch patients with oculocutaneous albinism type 4.","abstract":"To describe the phenotype of Dutch patients with oculocutaneous albinism type 4 (OCA4), we collected data on pigmentation (skin, hair, and eyes), visual acuity (VA), nystagmus, foveal hypoplasia, chiasmal misrouting, and molecular analyses of nine Dutch OCA4 patients from the Bartiméus Diagnostic Center for complex visual disorders. All patients had severely reduced pigmentation of skin, hair, and eyes with iris transillumination over 360 degrees. Three unrelated OCA4 patients had normal VA, no nystagmus, no foveal hypoplasia, and no misrouting of the visual pathways. Six patients had poor visual acuity (0.6 to 1.0 logMAR), nystagmus, severe foveal hypoplasia and misrouting. We found two novel variants in the SLC45A2 gene, c.310C > T; (p.Pro104Ser), and c.1368 + 3_1368 + 9del; (p.?). OCA4 patients of this Dutch cohort all had hypopigmentation of skin, hair, and iris translucency. However, patients were either severely affected with regard to visual acuity, foveal hypoplasia, and misrouting, or visually not affected at all. We describe for the first time OCA4 patients with an evident lack of pigmentation, but normal visual acuity, normal foveal development and absence of misrouting. This implies that absence of melanin does not invariably lead to foveal hypoplasia and abnormal routing of the visual pathways.","variants":[{"Name":"NM_016180.5(SLC45A2):c.310C>T (p.Pro104Ser)","Chromosome":"5","Start":"33984274","Stop":"33984274","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":894106,"rule_based_match":true,"evidence_text":"c.310C > T; (p.Pro104Ser)","llm_judgment":"PRESENT","evidence":"c.310C > T; (p.Pro104Ser)","abstract_start":733,"abstract_end":758}]}
{"pmid":"19233912","title":"Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies.","abstract":"BACKGROUND: Porphyria cutanea tarda (PCT) occurs in sporadic (sPCT) and familial (fPCT) forms, which are generally clinically indistinguishable and have traditionally been differentiated by erythrocyte uroporphyrinogen decarboxylase (UROD, EC 4.1.1.37) activity. We used UROD gene sequencing as the reference standard in assessing the diagnostic accuracy of UROD activity, evaluating the mutation spectrum of the UROD gene, determining the frequency and disease attributes of PCT and its subtypes in Norway, and developing diagnostic models that use clinical and laboratory characteristics for differentiating fPCT and sPCT.\nMETHODS: All consecutive patients with PCT diagnosed within a 6-year period were used for incidence calculations. UROD activity analysis, UROD gene sequencing, analysis of hemochromatosis mutations, and registration of clinical and laboratory data were carried out for 253 patients.\nRESULTS: Fifty-three percent of the patients had disease-relevant mutations, 74% of which were c.578G>C or c.636+1G>C. The UROD activity at the optimal cutoff had a likelihood ratio (LR) of 9.2 for fPCT, whereas a positive family history had an LR of 19. A logistic regression model indicated that low UROD activity, a high uroporphyrin-heptaporphyrin ratio, a young age at diagnosis, male sex, and low alcohol consumption were predictors of fPCT. The incidence of PCT was 1 in 100 000.\nCONCLUSIONS: Two commonly occurring mutations are responsible for the high frequency of fPCT in Norway. UROD activity has a high diagnostic accuracy for differentiating the 2 PCT types, and a model that takes into account both clinical information and laboratory test results can be used to predict fPCT.","variants":[{"Name":"NM_000374.5(UROD):c.636+1G>C","Chromosome":"1","Start":"45014071","Stop":"45014071","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":15106,"rule_based_match":true,"evidence_text":"c.636+1G>C","llm_judgment":"PRESENT","evidence":"c.636+1G>C","abstract_start":1015,"abstract_end":1025},{"Name":"NM_000374.5(UROD):c.578G>C (p.Arg193Pro)","Chromosome":"1","Start":"45014012","Stop":"45014012","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":248651,"rule_based_match":true,"evidence_text":"c.578G>C","llm_judgment":"PRESENT","evidence":"c.578G>C","abstract_start":1003,"abstract_end":1011}]}
{"pmid":"30620006","title":"Predicted Benign and Synonymous Variants in","abstract":"Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) in <i>CYP11A1</i> in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; <i>P</i> < 0.0001). Seventeen individuals harbored a second heterozygous rare disruptive variant in <i>CYP11A1</i> and two had very rare synonymous changes in <i>trans</i> (c.990G>A, Thr330 = ; c.1173C>T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an <i>Escherichia coli</i> assay system, <i>in silico</i> and <i>in vitro</i> studies revealed that the rs6161/c.940G>A variant, plus the c.990G>A and c.1173C>T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted \"benign\" variant in <i>CYP11A1</i> is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.","variants":[{"Name":"NM_000781.3(CYP11A1):c.940G>A (p.Glu314Lys)","Chromosome":"15","Start":"74343027","Stop":"74343027","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360206,"rule_based_match":true,"evidence_text":"c.940G>A (p.Glu314Lys)","llm_judgment":"PRESENT","evidence":"p.Glu314Lys","abstract_start":355,"abstract_end":366}]}
{"pmid":"31033143","title":"Medium-chain acyl-coenzyme A dehydrogenase deficiency: Six cases in the Chinese population.","abstract":"BACKGROUND: Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder that affects the degradation of medium-chain fatty acids. Few cases of MCADD have been documented to date in mainland China.\nMETHODS: Medium-chain acyl-coenzyme A dehydrogenase deficiency was diagnosed in six patients (three girls and three boys) from six unrelated Chinese families at ages ranging from 10 days to 3 years old. The diagnosis was confirmed by the identification of a primary biomarker of serum octanoyl-carnitine (C8) and genetic pathogenic mutations.\nRESULTS: Only two patients were admitted because of vomiting, diarrhea, myasthenia, and coma; the other four patients were diagnosed via the newborn screening process. Six mutations were found in acyl-CoA dehydrogenase medium chain (ACADM). One mutation (c.727C>T) was novel and the others (c.158G>A, c.387+1delG, c.449_452del, c.1045C>T, and c.1085G>A) have been previously reported.\nCONCLUSIONS: Six Chinese cases of MCADD were identified. One novel mutation was found. c.449_452del and c.1085G>A were common mutations in this study.","variants":[{"Name":"NM_000016.6(ACADM):c.158G>A (p.Arg53His)","Chromosome":"1","Start":"75732683","Stop":"75732683","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227865,"rule_based_match":true,"evidence_text":"c.158G>A","llm_judgment":"PRESENT","evidence":"c.158G>A","abstract_start":872,"abstract_end":880},{"Name":"NM_000016.6(ACADM):c.1045C>T (p.Arg349Ter)","Chromosome":"1","Start":"75761221","Stop":"75761221","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186634,"rule_based_match":true,"evidence_text":"c.1045C>T","llm_judgment":"PRESENT","evidence":"c.1045C>T","abstract_start":909,"abstract_end":918},{"Name":"NM_000016.6(ACADM):c.727C>T (p.Arg243Ter)","Chromosome":"1","Start":"75749437","Stop":"75749437","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1355342,"rule_based_match":true,"evidence_text":"c.727C>T","llm_judgment":"PRESENT","evidence":"c.727C>T","abstract_start":836,"abstract_end":844}]}
{"pmid":"34680898","title":"A Familial Form of Epidermolysis Bullosa Simplex Associated with a Pathogenic Variant in","abstract":"Epidermolysis bullosa simplex is a disease that belongs to a group of genodermatoses characterised by the formation of superficial bullous lesions caused by minor mechanical trauma to the skin. The skin fragility observed in the EBS is mainly caused by pathogenic variants in the <i>KRT5</i> and <i>KRT14</i> genes that compromise the mechanical stability of epithelial cells. By performing DNA sequencing in a female patient with EBS, we found the pathogenic variant c.967G>A (p.Val323Met) in the <i>KRT5</i> gene. This variant co-segregated with EBS in the family pedigree and was transmitted in an autosomal dominant inheritance manner. This is the first report showing a familial form of EBS due to this pathogenic variant.","variants":[{"Name":"NM_000424.4(KRT5):c.967G>A (p.Val323Met)","Chromosome":"12","Start":"52517715","Stop":"52517715","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1697497,"rule_based_match":true,"evidence_text":"c.967G>A (p.Val323Met)","llm_judgment":"PRESENT","evidence":"c.967G>A (p.Val323Met)","abstract_start":468,"abstract_end":490}]}
{"pmid":"31580392","title":"Utility of In Vitro Mutagenesis of RPE65 Protein for Verification of Mutational Pathogenicity Before Gene Therapy.","abstract":"Importance: Next-generation sequencing can detect variants of uncertain significance (VUSs), for some of which gene therapy would not be advantageous. Therefore, the pathogenicity of compound heterozygous or homozygous variants should be confirmed before bilateral vitrectomy and administration of voretigene neparvovec-rzyl.\nObjective: To describe an in vitro mutagenesis assay for assessing the pathogenicity of variants in the RPE65 gene.\nDesign, Setting, and Participants: This case series was conducted at 2 tertiary referral centers. Clinical history, imaging, and electrophysiologic testing results were reviewed from September 5, 2008, to December 31, 2019. Participants were 4 pediatric patients with Leber congenital amaurosis who were evaluated for or met the inclusion criteria for phase 1 to 3 clinical trials or were referred for voretigene neparvovec-rzyl treatment.\nMain Outcomes and Measures: A functional assay was used to confirm the pathogenicity of novel RPE65 VUSs in 4 patients with Leber congenital amaurosis.\nResults: Four patients with Leber congenital amaurosis had VUSs in RPE65. Patients 1 and 2 were siblings with the homozygous VUS c.311G>T p.(G104V). Patient 3 was a compound heterozygote with 1 known pathogenic allele, c.1202_1203insCTGG p.(Glu404AlafsTer4), and 1 VUS, c.311G>T p.(G104V), which segregated to separate alleles. Patient 4 was also a compound heterozygote with 1 pathogenic variant, c.11 + 5G>A, and 1 variant in trans, c.1399C>T p.(P467S). In vitro mutagenesis revealed that the G104V and P467S RPE65 proteins were catalytically inactive (0% isomerase activity). Patients 1 and 2 were excluded from participation in a phase 1 trial owing to high Adeno-associated virus 2 capsid-neutralizing antibodies. Patients 3 (G104V) and 4 (P467S) underwent successful surgical gene therapy with voretigene neparvovec-rzyl, and their response to lower white light intensity and visual field increased in fewer than 30 days after gene therapy intervention.\nConclusions and Relevance: Findings from this study suggest that, in patients with missense mutations in RPE65, functional assays of protein function can be performed to assess the pathogenicity of variants in both compound heterozygous and homozygous cases. Given the potential risks of gene therapy operations, in vitro RPE65 activity testing should be considered to avoid the possibility of treating a false genotype.","variants":[{"Name":"NM_000329.3(RPE65):c.1399C>T (p.Pro467Ser)","Chromosome":"1","Start":"68431116","Stop":"68431116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":551518,"rule_based_match":true,"evidence_text":"c.1399C>T p.(P467S)","llm_judgment":"PRESENT","evidence":"c.1399C>T p.(P467S)","abstract_start":1469,"abstract_end":1488}]}
{"pmid":"23340379","title":"Progressive hereditary hearing impairment caused by a MYO6 mutation resembles presbyacusis.","abstract":"Since deafness is the most common sensorineural disorder in humans, better understanding of the underlying causes is necessary to improve counseling and rehabilitation. A Dutch family with autosomal dominantly inherited sensorineural hearing loss was clinically and genetically assessed. The MYO6 gene was selected to be sequenced because of similarities with other, previously described DFNA22 phenotypes and a pathogenic c.3610C > T (p.R1204W) mutation was found to co-segregate with the disease. This missense mutation results in a flat configured audiogram with a mild hearing loss, which becomes severe to profound and gently to steeply downsloping later in life. The age-related typical audiograms (ARTA) constructed for this family resemble presbyacusis. Speech audiometry and results of loudness scaling support the hypothesis that the phenotype of this specific MYO6 mutation mimics presbyacusis.","variants":[{"Name":"NM_004999.4(MYO6):c.3610C>T (p.Arg1204Trp)","Chromosome":"6","Start":"75914233","Stop":"75914233","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":229529,"rule_based_match":true,"evidence_text":"c.3610C > T (p.R1204W)","llm_judgment":"PRESENT","evidence":"c.3610C > T (p.R1204W)","abstract_start":423,"abstract_end":445}]}
{"pmid":"30701076","title":"Activation of TGF-β signaling in an aortic aneurysm in a patient with Loeys-Dietz syndrome caused by a novel loss-of-function variant of","abstract":"Loeys-Dietz syndrome (LDS) is caused by variants of transforming growth factor-β (TGF-β)-related genes and is characterized by aortic aneurysm and dissection. We report an LDS patient with a de novo missense variant of <i>TGFBR1</i> [c.1126A>G, p.(Lys376Glu)] in which active TGF-β signaling was observed in the aorta, despite the in vitro demonstration that the loss-of-function mutation lies within the serine/threonine kinase domain. The mechanism underlying this TGF-β paradox in LDS aortopathy should be further investigated.","variants":[{"Name":"NM_004612.4(TGFBR1):c.1126A>G (p.Lys376Glu)","Chromosome":"9","Start":"99144884","Stop":"99144884","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1301199,"rule_based_match":true,"evidence_text":"c.1126A>G, p.(Lys376Glu)","llm_judgment":"PRESENT","evidence":"c.1126A>G, p.(Lys376Glu)","abstract_start":234,"abstract_end":258}]}
{"pmid":"26455428","title":"Reevaluation of the BRCA2 truncating allele c.9976A > T (p.Lys3326Ter) in a familial breast cancer context.","abstract":"The breast cancer predisposition gene, BRCA2, has a large number of genetic variants of unknown effect. The variant rs11571833, an A > T transversion in the final exon of the gene that leads to the creation of a stop codon 93 amino acids early (K3326*), is reported as a neutral polymorphism but there is some evidence to suggest an association with an increased risk of breast cancer. We assessed whether this variant was enriched in a cohort of breast cancer cases ascertained through familial cancer clinics compared to population-based non-cancer controls using a targeted sequencing approach. We identified the variant in 66/2634 (2.5%) cases and 33/1996 (1.65%) controls, indicating an enrichment in the breast cancer cases (p = 0.047, OR 1.53, 95% CI 1.00-2.34). This data is consistent with recent iCOGs data suggesting that this variant is not neutral with respect to breast cancer risk. rs11571833 may need to be included in SNP panels for evaluating breast cancer risk.","variants":[{"Name":"NM_000059.4(BRCA2):c.9976A>T (p.Lys3326Ter)","Chromosome":"13","Start":"32398489","Stop":"32398489","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":46822,"rule_based_match":true,"evidence_text":"c.9976A > T (p.Lys3326Ter)","llm_judgment":"PRESENT","evidence":"K3326*","abstract_start":245,"abstract_end":251}]}
{"pmid":"32477874","title":"Glycogenin-1 deficiency mimicking limb-girdle muscular dystrophy.","abstract":"Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (<i>GYG1</i>) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy (Polyglucosan body myopathy-2, PGBM2). Here we describe a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy (LGMD), and early onset exertional myalgia. Neurologic examination revealed a waddling gait with hyperlordosis, bilateral asymmetric scapular winging, mild asymmetric deltoid and biceps brachii weakness, and pelvic-girdle weakness involving the gluteal muscles and, to a lesser extent, the quadriceps. Serum creatine kinase levels were slightly elevated. Electrophysiological examination showed a myopathic pattern. There was no cardiac or respiratory involvement. Whole-body muscle MRI revealed atrophy and fat replacement of the tongue, biceps brachii, pelvic girdle and erector spinae. A deltoid muscle biopsy showed the presence of PAS-positive inclusions that remained non-digested with alpha-amylase treatment. Electron microscopy studies confirmed the presence of polyglucosan bodies. A diagnostic gene panel designed by the Genetic Diagnosis Laboratory of Strasbourg University Hospital (France) for 210 muscular disorders genes disclosed two heterozygous, pathogenic <i>GYG1</i> gene mutations (c.304G>C;p.(Asp102His) + c.164_165del). Considering the clinical heterogeneity found in the previously described 38 GYG-1 deficient patients, we suggest that <i>GYG1</i> should be systematically included in targeted NGS gene panels for LGMDs, distal myopathies, and metabolic myopathies.","variants":[{"Name":"NM_004130.4(GYG1):c.304G>C (p.Asp102His)","Chromosome":"3","Start":"148996462","Stop":"148996462","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":172317,"rule_based_match":true,"evidence_text":"c.304G>C;p.(Asp102His)","llm_judgment":"PRESENT","evidence":"c.304G>C;p.(Asp102His)","abstract_start":1355,"abstract_end":1377}]}
{"pmid":"31523618","title":"Cystic Fibrosis Mutation Spectrum in North Macedonia: A Step Toward Personalized Therapy.","abstract":"The most prevalent \"rare\" disease worldwide, cystic fibrosis (CF), is an autosomal recessive multisystem disease, caused by mutations in the <i>CFTR</i> gene. The knowledge of <i>CFTR</i> mutations present in certain population is important for designing a simple, fast and cost-effective genetic testing approach, also for better management of CF patients, including the administration of novel targeted therapies. Here, we present genetic results of 158 unrelated CF patients from the National CF Registry of the Republic of North Macedonia. Initially, patients were screened for the 11 most common CF mutations. Additional CF mutations and large deletions/duplications in the <i>CFTR</i> gene were analyzed using commercial kits. If the genotype was undetermined, all <i>CFTR</i> exons were analyzed using Sanger DNA sequencing or next generation sequencing (NGS) (since 2014). The most common CF mutation, c.l521_ 1523del (legacy name F508del), was found with an overall incidence of 75.9%. Additionally, 26 other pathogenic variants and three large deletions were identified in the <i>CFTR</i> gene as a genetic cause of CF. Two of these, c.1070 C>T (p.Ala357Val) and c.2779_2788dup CTTGCTATGG (p.Gly930AlafsTer48), were novel. According to the distribution and prevalence of the pathogenic variants detected in our patients, a fast and cost-effective method, based on a single base extension was designed as a first-line CF genetic test with a 90.0% detection rate within our population. Furthermore, the knowledge of <i>CFTR</i> mutation classes in our CF patients represents the first step toward personalized therapy for CF in our country.","variants":[{"Name":"NM_000492.3(CFTR):c.1521_1523del (p.Phe508del)","Chromosome":"7","Start":"117559591","Stop":"117559593","ReferenceAlleleVCF":"ATCT","AlternateAlleleVCF":"A","allel_id":22144,"rule_based_match":false,"evidence_text":"c.1521_1523del","llm_judgment":"PRESENT","evidence":"c.1521_1523del","abstract_start":null,"abstract_end":null},{"Name":"NM_000492.4(CFTR):c.1070C>T (p.Ala357Val)","Chromosome":"7","Start":"117540300","Stop":"117540300","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2738368,"rule_based_match":true,"evidence_text":"c.1070 C>T (p.Ala357Val)","llm_judgment":"PRESENT","evidence":"c.1070 C>T (p.Ala357Val)","abstract_start":1144,"abstract_end":1168}]}
{"pmid":"32383294","title":"A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease.","abstract":"2-Oxoglutarate dehydrogenase (OGDH) is a rate-limiting enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α-Ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Using whole exome sequencing, we identified two individuals carrying a homozygous missense variant c.959A>G (p.N320S) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Skin fibroblasts from subject # 2 showed a decrease in both OGDH protein and enzyme activity. Transfection of human OGDH cDNA in HEK293 cells carrying p.N320S also produced significantly lower protein levels compared to those with wild-type cDNA. Loss of Drosophila Ogdh (dOgdh) caused early developmental lethality, rescued by expressing wild-type dOgdh (dOgdh<sup>WT</sup> ) or human OGDH (OGDH<sup>WT</sup> ) cDNA. In contrast, expression to the mutant OGDH (OGDH<sup>N320S</sup> ) or dOgdh carrying homologous mutations to human OGDH p.N320S variant (dOgdh<sup>N324S</sup> ) failed to rescue lethality of dOgdh null mutants. Knockdown of dOgdh in the nervous system resulted in locomotion defects which were rescued by dOgdh<sup>WT</sup> expression but not by dOgdh<sup>N324S</sup> expression. Collectively, the results indicate that c.959A>G variant in OGDH leads to an amino acid change (p.N320S) causing a severe loss of OGDH protein function. Our study establishes in the first time a genetic link between an OGDH gene mutation and OGDH deficiency.","variants":[{"Name":"NM_002541.4(OGDH):c.959A>G (p.Asn320Ser)","Chromosome":"7","Start":"44675201","Stop":"44675201","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1322068,"rule_based_match":true,"evidence_text":"c.959A>G (p.N320S)","llm_judgment":"PRESENT","evidence":"c.959A>G (p.N320S)","abstract_start":427,"abstract_end":445}]}
{"pmid":"24641183","title":"Clinical and genetic analysis of Taiwanese patients with hereditary spastic paraplegia type 5.","abstract":"BACKGROUND AND PURPOSE: Spastic paraplegia type 5 (SPG5) is an autosomal recessive (AR) hereditary spastic paraplegia (HSP) associated with pure or complicated phenotypes. This study aimed to screen SPG5 in Taiwanese HSP patients.\nMETHODS: Sequencing of the SPG5 gene, CYP7B1, was performed in a cohort of 25 ethnic Han Taiwanese patients with AR or sporadic HSP. Clinical information and magnetic resonance imaging (MRI) were analyzed in confirmed SPG5 patients.\nRESULTS: One (33%) AR kindred and four (18%) sporadic cases had CYP7B1 mutations. All of the SPG5 cases carried the mutation c.334 C>T (R112X). Haplotype analysis suggested a 'founder effect' in ethnic Hans for this mutation. The phenotype was either pure or complicated by cerebellar ataxia. For the primary HSP phenotype, there were profound dorsal column sensory deficits in all patients. Spine MRI showed thoraco-lumbar cord atrophy in some patients.\nCONCLUSIONS: Spastic paraplegia type 5 is a common cause of AR and sporadic HSPs that has a higher frequency in Taiwanese than in other ethnic groups. It is associated with a CYP7B1 founder mutation and its phenotype is characterized by pronounced dorsal column sensory loss, with cerebellar ataxia in some patients.","variants":[{"Name":"NM_004820.5(CYP7B1):c.334C>T (p.Arg112Ter)","Chromosome":"8","Start":"64616207","Stop":"64616207","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":221765,"rule_based_match":true,"evidence_text":"c.334 C>T (R112X)","llm_judgment":"PRESENT","evidence":"c.334 C>T (R112X)","abstract_start":589,"abstract_end":606}]}
{"pmid":"34788392","title":"NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia.","abstract":"With more than 40 causative genes identified so far, autosomal dominant cerebellar ataxias exhibit a remarkable genetic heterogeneity. Yet, half the patients are lacking a molecular diagnosis. In a large family with nine sampled affected members, we performed exome sequencing combined with whole-genome linkage analysis. We identified a missense variant in NPTX1, NM_002522.3:c.1165G>A: p.G389R, segregating with the phenotype. Further investigations with whole-exome sequencing and an amplicon-based panel identified four additional unrelated families segregating the same variant, for whom a common founder effect could be excluded. A second missense variant, NM_002522.3:c.980A>G: p.E327G, was identified in a fifth familial case. The NPTX1-associated phenotype consists of a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging. NPTX1 encodes the neuronal pentraxin 1, a secreted protein with various cellular and synaptic functions. Both variants affect conserved amino acid residues and are extremely rare or absent from public databases. In COS7 cells, overexpression of both neuronal pentraxin 1 variants altered endoplasmic reticulum morphology and induced ATF6-mediated endoplasmic reticulum stress, associated with cytotoxicity. In addition, the p.E327G variant abolished neuronal pentraxin 1 secretion, as well as its capacity to form a high molecular weight complex with the wild-type protein. Co-immunoprecipitation experiments coupled with mass spectrometry analysis demonstrated abnormal interactions of this variant with the cytoskeleton. In agreement with these observations, in silico modelling of the neuronal pentraxin 1 complex evidenced a destabilizing effect for the p.E327G substitution, located at the interface between monomers. On the contrary, the p.G389 residue, located at the protein surface, had no predictable effect on the complex stability. Our results establish NPTX1 as a new causative gene in autosomal dominant cerebellar ataxias. We suggest that variants in NPTX1 can lead to cerebellar ataxia due to endoplasmic reticulum stress, mediated by ATF6, and associated to a destabilization of NP1 polymers in a dominant-negative manner for one of the variants.","variants":[{"Name":"NM_002522.4(NPTX1):c.1165G>A (p.Gly389Arg)","Chromosome":"17","Start":"80470947","Stop":"80470947","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1174864,"rule_based_match":true,"evidence_text":"NM_002522.3:c.1165G>A: p.G389R","llm_judgment":"PRESENT","evidence":"NM_002522.3:c.1165G>A: p.G389R","abstract_start":365,"abstract_end":395},{"Name":"NM_002522.4(NPTX1):c.980A>G (p.Glu327Gly)","Chromosome":"17","Start":"80471829","Stop":"80471829","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1863397,"rule_based_match":true,"evidence_text":"NM_002522.3:c.980A>G: p.E327G","llm_judgment":"PRESENT","evidence":"NM_002522.3:c.980A>G: p.E327G","abstract_start":663,"abstract_end":692}]}
{"pmid":"25012610","title":"A novel mutation in the CSF1R gene causes a variable leukoencephalopathy with spheroids.","abstract":"Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids is a neurodegenerative disease associated with mutations in the colony-stimulating factor 1 receptor gene (CSF1R). A 44-year-old woman with a 7-year history of depression presented with neurological signs and a recent cognitive decline. The diagnosis of hereditary diffuse leukoencephalopathy with neuroaxonal spheroids was suspected based on the findings of a predominant frontal leukoencephalopathy and neuroaxonal spheroids on brain biopsy. She shares with her mother a novel CSF1R exon 18 missense mutation (c.2350G > A; p.V784M). The mother has a long-standing bipolar disorder and mild multifocal white matter abnormalities in her 70s. This is the first report of hereditary diffuse leukoencephalopathy with neuroaxonal spheroids due to this novel CSF1R missense mutation. Our report suggests that either marked intrafamilial variability or incomplete penetrance can be associated with CSF1R mutations. The observation of a small bone cyst in our patient supports the hypothesis that hereditary diffuse leukoencephalopathy with neuroaxonal spheroids and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy may belong to a spectrum of overlapping phenotypes.","variants":[{"Name":"NM_001288705.3(CSF1R):c.2350G>A (p.Val784Met)","Chromosome":"5","Start":"150056311","Stop":"150056311","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171838,"rule_based_match":true,"evidence_text":"c.2350G > A; p.V784M","llm_judgment":"PRESENT","evidence":"c.2350G > A; p.V784M","abstract_start":578,"abstract_end":598}]}
{"pmid":"27558265","title":"Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes.","abstract":"Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis.","variants":[{"Name":"NM_000494.4(COL17A1):c.1873C>T (p.Arg625Ter)","Chromosome":"10","Start":"104053097","Stop":"104053097","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1345799,"rule_based_match":true,"evidence_text":"c.1873C>T, p.R625*","llm_judgment":"PRESENT","evidence":"c.1873C>T, p.R625*","abstract_start":432,"abstract_end":450}]}
{"pmid":"22678952","title":"Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships.","abstract":"Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed.","variants":[{"Name":"NM_001323289.2(CDKL5):c.119C>T (p.Ala40Val)","Chromosome":"X","Start":"18564496","Stop":"18564496","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26541,"rule_based_match":false,"evidence_text":"p.Ala40Val","llm_judgment":"PRESENT","evidence":"p.Ala40Val","abstract_start":1040,"abstract_end":1050}]}
{"pmid":"28877251","title":"Identification of a novel GJA3 mutation in a large Chinese family with congenital cataract using targeted exome sequencing.","abstract":"Autosomal dominant congenital cataract (ADCC) is a clinically and genetically heterogeneous ocular disease in children that results in serious visual impairments or even blindness. Targeted exome sequencing (TES) is an efficient method used for genetic diagnoses of inherited diseases. In the present study, we used a custom-made TES panel to identify the genetic defect of a four-generation Chinese family with bilateral pulverulent nuclear cataracts. A novel heterozygous missense mutation c.443C>T (p. T148I) in GJA3 was identified. The results of the bioinformatic analysis showed that the mutation was deleterious to the structure and hemichannel function of Cx46 encoded by GJA3. Plasmids expressing wild-type and mutant human Cx46 were constructed and ectopically expressed in human lens epithelial cells (HLECs) or human embryonic kidney (HEK-293) cells. Fluorescent images indicated aggregated signals of mutant protein in the cytoplasm, and a higher protein level was also detected in T148I stable cell lines. In summary, we identified a novel mutation in GJA3 for ADCC, which provided molecular insights into the pathogenic mechanism of ADCC.","variants":[{"Name":"NM_021954.4(GJA3):c.443C>T (p.Thr148Ile)","Chromosome":"13","Start":"20142846","Stop":"20142846","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":527510,"rule_based_match":true,"evidence_text":"c.443C>T (p. T148I)","llm_judgment":"PRESENT","evidence":"c.443C>T (p. T148I)","abstract_start":492,"abstract_end":511}]}
{"pmid":"38642139","title":"Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases.","abstract":"Leiomyoma is the most prevalent benign tumor of the female reproductive system. Benign metastasizing leiomyoma (BML) is a rare phenomenon that presents at distant sites, typically the lungs, exhibiting histopathological features similar to the primary uterine tumor in the absence of malignancy features in both. Fumarate hydratase-deficient uterine leiomyoma (FH-d UL) is an uncommon subtype among uterine smooth muscle tumors (0.5-2%), showing distinctive histomorphology and FH inactivation. The majority of FH-d ULs are sporadic, caused by somatic FH inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline FH inactivation. Metastasizing FH-d UL has not been well documented and might be under-reported. Here, we present two cases (21- and 34-year-old females) who presented with metastasizing FH-d UL after myomectomy/hysterectomy with histologically proven multiple lung metastases in both, in addition to multi-organ involvement in one case (cervical-thoracic lymph nodes, left kidney, perihepatic region, left zygomatic bone, and soft tissues). Pathological examination confirmed FH-d leiomyomas in the primary/recurrent uterine tumors, multiple lung lesions, and a renal mass. The minimal criteria for diagnosis of leiomyosarcoma were not fulfilled. Genetic testing revealed germline pathogenic FH variants in both cases (c.1256C > T; p.Ser419Leu in Case 1 and c.425A > G; p.Gln142Arg in Case 2). These novel cases highlight a rare but possibly under-recognized presentation of FH-d BML. Our study suggests that FH-d BML cases might be enriched for the HLRCC syndrome.","variants":[{"Name":"NM_000143.4(FH):c.1256C>T (p.Ser419Leu)","Chromosome":"1","Start":"241500571","Stop":"241500571","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":421002,"rule_based_match":true,"evidence_text":"c.1256C > T; p.Ser419Leu","llm_judgment":"PRESENT","evidence":"c.1256C > T; p.Ser419Leu","abstract_start":1430,"abstract_end":1454}]}
{"pmid":"25666743","title":"Analysis of PALB2 in a cohort of Italian breast cancer patients: identification of a novel PALB2 truncating mutation.","abstract":"PALB2 gene is mutated in about 1-2% of familial breast cancer as well as in 3-4% of familial pancreatic cancer cases. Few studies have reported mutations in Italian patients with breast or pancreatic cancer. We evaluate the occurrence of PALB2 mutations in Italian patients affected with hereditary breast and ovarian cancers and define the pathological significance of the putative allelic variants. We recruited 98 patients (F = 93, M = 5) affected with breast and/or ovarian cancer, negative for mutations in BRCA1 and BRCA2 (BRCAX). Genomic DNA was isolated from peripheral blood lymphocytes, PALB2 coding regions and adjacent intronic were sequenced; in silico predictions were carried out using prediction programs. Mutational analysis of PALB2 gene revealed the novel mutation c.1919C>A (p.S640X) in a 29 years old woman with breast cancer. The c.1919C>A (p.S640X) mutation causes the lack of C-terminus region inducing alteration of MORF4L1-PALB2 association and the lack of interaction of PALB2 with RAD51 and BRCA2. In addition, we identified two novel PALB2 variants, c.3047T>C (p.F1016S) and c.*146A>G. In silico analysis conducted for c.*146A>G indicates that this variant does not affect the splicing while c.3047T>C (p.F1016S) was predicted as damaging in three classifier algorithms. The proband carrier of c.3047T>C (p.F1016S) showed two breast cancer cases, two ovarian cancer cases and one pancreatic cancer in mother's family. c.3047T>C (p.F1016S) and c.*146A>G should be considered PALB2 UVs even though the genotype-phenotype correlation for these variants remains still unclear. Our findings indicate that the presence of PALB2 mutation should be routinely investigated in hereditary breast and ovarian cancers families since it could be of clinical relevance for clinical management.","variants":[{"Name":"NM_024675.4(PALB2):c.1919C>A (p.Ser640Ter)","Chromosome":"16","Start":"23630235","Stop":"23630235","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":235256,"rule_based_match":true,"evidence_text":"c.1919C>A (p.S640X)","llm_judgment":"PRESENT","evidence":"c.1919C>A (p.S640X)","abstract_start":784,"abstract_end":803},{"Name":"NM_024675.4(PALB2):c.3047T>C (p.Phe1016Ser)","Chromosome":"16","Start":"23621428","Stop":"23621428","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":409518,"rule_based_match":true,"evidence_text":"c.3047T>C (p.F1016S)","llm_judgment":"PRESENT","evidence":"c.3047T>C (p.F1016S)","abstract_start":1079,"abstract_end":1099}]}
{"pmid":"37382551","title":"Spondyloenchondrodysplasia with immune dysregulation related to ACP5. A report of 4 cases.","abstract":"Spondyloenchondrodysplasia with immune dysregulation related to ACP5 (SPENCDI, OMIM number 607944) is an uncommon immune-skeletal dysplasia with heterogeneous manifestations and variable severity. It is characterized by spondylar and metaphyseal lesions, immune dysfunction, and neurological involvement. Here we report the clinical, radiological and genetic aspects of 4 girls with SPENCDI treated at a children's hospital. They all had skeletal manifestations and 3 developed severe immune disease. In 3 patients, the likely pathogenic variant c.791T>A; p.Met264Lys (homozygous mutation) was observed, while 1 patient had variants c.791T>A; p.Met264Lys and c.632T>C; p.lle211Thr (variant of uncertain significance with pathogenic prediction based on bioinformatics algorithms) caused by a compound heterozygous mutation in ACP5. The repeated presence of variant c.791T>A suggests the possibility of a common ancestor in our population. The recognition and diagnosis of this disorder is important to achieve a timely approach, which should be multidisciplinary and aimed at preventing possible complications.","variants":[{"Name":"NM_001611.5(ACP5):c.791T>A (p.Met264Lys)","Chromosome":"19","Start":"11575197","Stop":"11575197","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":38786,"rule_based_match":true,"evidence_text":"c.791T>A; p.Met264Lys","llm_judgment":"PRESENT","evidence":"c.791T>A; p.Met264Lys","abstract_start":546,"abstract_end":567}]}
{"pmid":"29608813","title":"Identification of a PTEN mutation with reduced protein stability, phosphatase activity, and nuclear localization in Hong Kong patients with autistic features, neurodevelopmental delays, and macrocephaly.","abstract":"PTEN is a tumor suppressor gene inactivated in over 30% of human cancers. It encodes a lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase signaling pathway. Germline mutation frequently occurs in this gene in patients diagnosed with PTEN Hamartoma Tumor Syndrome (PHTS). PHTS individuals are characterized by macrocephaly, benign growth of multiple tissues and increased tumor risk. In addition, autistic phenotypes are found in 10-20% of individuals carrying the germline PTEN mutation with macrocephaly. In this report, 13 suspected PHTS patients were screened for mutation in the PTEN gene. A missense variant (c. 302T > C) substituting the isoleucine at codon 101 to a threonine, a single nucleotide insertion (c. 327-328insC) causing a frame shift mutation and termination at codon 109, and a nonsense variant (c. 1003C > T) truncated the protein at codon 335 were identified. The I101T mutation significantly reduced PTEN protein expression levels by 2.5- to 4.0-fold. Mechanistically, I101T reduced the protein half-life of PTEN possibly due to enhanced polyubiquitination at Lysine 13. However, the I101T mutant retained almost 30% of the lipid phosphatase activity of the wild-type protein. Finally, the I101T mutant has reduced phosphorylation at a PTEN auto-dephosphorylation site at Threonine 366 and a lowered ratio of nuclear to cytosolic protein level. These partial losses of multiple PTEN biochemical functions may contribute to the tissue overgrowth and autistic features of this PHTS patient. Autism Res 2018, 11: 1098-1109. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: The genetics of autism spectrum disorders is highly complex with individual risk influenced by both genetic and environmental factors. Mutation in the human PTEN gene confers a high risk of developing autistic behavior. This report revealed that PTEN mutations occurred in 23% of a selected group of Hong Kong patients harboring autistic features with gross overgrowth symptoms. Detailed characterization of a PTEN mutation revealed reduced protein stability as one of the underlying mechanisms responsible for reduced PTEN activity.","variants":[{"Name":"NM_000314.8(PTEN):c.302T>C (p.Ile101Thr)","Chromosome":"10","Start":"87933061","Stop":"87933061","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":810095,"rule_based_match":true,"evidence_text":"c. 302T > C","llm_judgment":"PRESENT","evidence":"c. 302T > C","abstract_start":642,"abstract_end":653}]}
{"pmid":"28955726","title":"De novo","abstract":"OBJECTIVE: To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.\nMETHODS: A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.\nRESULTS: After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous <i>CTBP1</i> missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.\nCONCLUSIONS: We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) <i>CTBP1</i> variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.","variants":[{"Name":"NM_001012614.2(CTBP1):c.991C>T (p.Arg331Trp)","Chromosome":"4","Start":"1213028","Stop":"1213028","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227573,"rule_based_match":true,"evidence_text":"c.991C>T (p.Arg331Trp)","llm_judgment":"PRESENT","evidence":"p.Arg331Trp","abstract_start":752,"abstract_end":763}]}
{"pmid":"23266810","title":"Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America.","abstract":"Tripeptidyl-peptidase 1 (TPP1) null or residual activity occurs in neuronal ceroid lipofuscinosis (NCL) with underlying TPP1/CLN2 mutations. A survey of 25 South American CLN2 affected individuals enabled the differentiation of two phenotypes: classical late-infantile and variant juvenile, each in approximately 50% of patients, with residual TPP1 activity occurring in approximately 32%. Each individual was assigned to one of three subgroups: (I) n=11, null TPP1 activity in leukocytes; (II) n=8, residual TPP1 activity of 0.60-15.85 nmol/h/mg (nr 110-476); (III) n=6, activity not measured in leukocytes. Curvilinear bodies (CB) appeared in almost all studied CLN2 subjects; the only exceptions occurred in cases of subgroup II: two individuals had combined CBs/fingerprints (FPs), and one case had pure FPs. There were 15 mutations (4 first published in this paper, 3 previously observed in South America by our group, and 8 previously observed by others). In subgroup I, mutations were either missense or nonsense; in subgroups II and III, mutations prevailed at the non-conserved intronic site, c.887-10A>G (intron 7), and to a lesser extent at c.89+5G>C (intron 2), in heterozygous combinations. Grouping phenotypically and genetically known individuals on the basis of TPP1 activity supported the concept that residual enzyme activity underlies a protracted disease course. The prevalence of intronic mutations at non-conserved sites in subgroup II individuals indicates that some alternative splicing might allow some residual TPP1 activity.","variants":[{"Name":"NM_000391.4(TPP1):c.89+5G>C","Chromosome":"11","Start":"6619191","Stop":"6619191","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":202604,"rule_based_match":true,"evidence_text":"c.89+5G>C (intron 2)","llm_judgment":"PRESENT","evidence":"c.89+5G>C (intron 2)","abstract_start":1152,"abstract_end":1172},{"Name":"NM_000391.4(TPP1):c.887-10A>G","Chromosome":"11","Start":"6616513","Stop":"6616513","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":17688,"rule_based_match":true,"evidence_text":"c.887-10A>G (intron 7)","llm_judgment":"PRESENT","evidence":"c.887-10A>G (intron 7)","abstract_start":1102,"abstract_end":1124}]}
{"pmid":"21031134","title":"Reinforcement of a minor alternative splicing event in MYO7A due to a missense mutation results in a mild form of retinopathy and deafness.","abstract":"PURPOSE: Recessive mutations of the myosin VIIA (MYO7A) gene are reported to be responsible for both a deaf-blindness syndrome (Usher type 1B [USH1B] and atypical Usher syndrome) and nonsyndromic hearing loss (HL; Deafness, Neurosensory, Autosomal Recessive 2 [DFNB2]). The existence of DFNB2 is controversial, and often there is no relationship between the type and location of the MYO7A mutations corresponding to the USH1B and DFNB2 phenotype. We investigated the molecular determinant of a mild form of retinopathy in association with a subtle splicing modulation of MYO7A mRNA.\nMETHODS: Affected members underwent detailed audiologic and ocular characterization. DNA samples from family members were genotyped with polymorphic microsatellite markers. Sequencing of MYO7A was performed. Endogenous lymphoid RNA analysis and a splicing minigene assay were used to study the effect of the c.1935G>A mutation.\nRESULTS: Funduscopy showed mild retinitis pigmentosa in adults with HL. Microsatellite analysis showed linkage to markers in the region on chromosome 11q13.5. Sequencing of MYO7A revealed a mutation in the last nucleotide of exon 16 (c.1935G>A), which corresponds to a substitution of a methionine to an isoleucine residue at amino acid 645 of the myosin VIIA. However, structural prediction of the molecular model of myosin VIIA shows that this amino acid replacement induces only minor structural changes in the immediate environment of the mutation and thus does not alter the overall native structure. We found that, although predominantly included in mature mRNA, exon 16 is in fact alternatively spliced in control cells and that the mutation at the very last position is associated with a switch toward a predominant exclusion of that exon. This observation was further supported using a splicing minigene transfection assay; the c.1935G>A mutation was found to trigger a partial impairment of the adjacent donor splice site, suggesting that the unique change at the last position of the exon is responsible for the enhanced exon exclusion in this family.\nCONCLUSIONS: This study shows how an exonic mutation that weakens the 5' splice site enhances a minor alternative splicing without abolishing a complete exclusion of the exon and therefore causes a less severe retinitis pigmentosa than the USH1B-associated alleles. It would be interesting to examine a possible correlation between intrafamilial phenotypic variability and the subtle variation in exon 16 inclusion, probably related to genetic background specificities.","variants":[{"Name":"NM_000260.4(MYO7A):c.1935G>A (p.Met645Ile)","Chromosome":"11","Start":"77172885","Stop":"77172885","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3853444,"rule_based_match":true,"evidence_text":"c.1935G>A","llm_judgment":"PRESENT","evidence":"c.1935G>A","abstract_start":891,"abstract_end":900}]}
{"pmid":"36572041","title":"Infantile-onset Pompe disease in seven Mexican children.","abstract":"INTRODUCTION: Pompe disease (PD) is a rare form of metabolic myopathy; the classic infantile presentation is severe, with death occurring before reaching one year of life, and the non-classical form is of slower progression and survival can exceed one year.\nOBJECTIVE: To describe the genotype and characteristics of Mexican patients with infantile-onset PD.\nMETHODS: Seven patients with PD confirmed by enzymatic activity determination and GAA gene molecular analysis were included. Mutations were reviewed in genomic databases.\nRESULTS: Median age at symptom onset was four months (1-12 months) and age at diagnosis was eight months (4-16 months). All patients had cardiomyopathy: four who died before one year of age had mutations that predicted severe disease (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) and were negative for cross-reactive immunologic material (CRIM). Three patients survived after one year of age with enzyme replacement therapy; one survived almost five years, another 18 months, and one girl was almost three years of age at the time of this report; their pathogenic variants predicted potentially less severe disease (c.1979G>A, c.655G>A, c.1447G>A) and they were positive for CRIM.\nCONCLUSION: There was a good correlation between genotype and phenotype in children with Pompe disease.","variants":[{"Name":"NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)","Chromosome":"17","Start":"80118271","Stop":"80118271","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19073,"rule_based_match":true,"evidence_text":"c.2560C>T","llm_judgment":"PRESENT","evidence":"c.2560C>T","abstract_start":776,"abstract_end":785}]}
{"pmid":"29917077","title":"USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis.","abstract":"Leigh syndrome is a frequent, heterogeneous pediatric presentation of mitochondrial oxidative phosphorylation (OXPHOS) disease, manifesting with psychomotor retardation and necrotizing lesions in brain deep gray matter. OXPHOS occurs at the inner mitochondrial membrane through the integrated activity of five protein complexes, of which complex V (CV) functions in a dimeric form to directly generate adenosine triphosphate (ATP). Mutations in several different structural CV subunits cause Leigh syndrome; however, dimerization defects have not been associated with human disease. We report four Leigh syndrome subjects from three unrelated Ashkenazi Jewish families harboring a homozygous splice-site mutation (c.87 + 1G>C) in a novel CV subunit disease gene, USMG5. The Ashkenazi population allele frequency is 0.57%. This mutation produces two USMG5 transcripts, wild-type and lacking exon 3. Fibroblasts from two Leigh syndrome probands had reduced wild-type USMG5 mRNA expression and undetectable protein. The mutation did not alter monomeric CV expression, but reduced both CV dimer expression and ATP synthesis rate. Rescue with wild-type USMG5 cDNA in proband fibroblasts restored USMG5 protein, increased CV dimerization and enhanced ATP production rate. These data demonstrate that a recurrent USMG5 splice-site founder mutation in the Ashkenazi Jewish population causes autosomal recessive Leigh syndrome by reduction of CV dimerization and ATP synthesis.","variants":[{"Name":"NM_001206427.2(ATP5MK):c.87+1G>C","Chromosome":"10","Start":"103392370","Stop":"103392370","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":682950,"rule_based_match":true,"evidence_text":"c.87+1G>C","llm_judgment":"PRESENT","evidence":"c.87 + 1G>C","abstract_start":714,"abstract_end":725}]}
{"pmid":"33960148","title":"Progressive cerebellar atrophy in a patient with complex II and III deficiency and a novel deleterious variant in SDHA: A Counseling Conundrum.","abstract":"BACKGROUND: Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma-pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh-like syndromes.\nMETHODS AND RESULTS: Here, we describe a case of a 9-year-old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA, a known pathogenic variant (c.91C>T (p.R31*)), and a variant of unknown significance (c.454G>A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder.\nCONCLUSION: We, therefore, consider whether c.454G>A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant.","variants":[{"Name":"NM_004168.4(SDHA):c.454G>A (p.Glu152Lys)","Chromosome":"5","Start":"225560","Stop":"225560","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":454905,"rule_based_match":true,"evidence_text":"c.454G>A (p.E152K)","llm_judgment":"PRESENT","evidence":"c.454G>A (p.E152K)","abstract_start":851,"abstract_end":869},{"Name":"NM_004168.4(SDHA):c.91C>T (p.Arg31Ter)","Chromosome":"5","Start":"223509","Stop":"223509","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152315,"rule_based_match":true,"evidence_text":"c.91C>T (p.R31*)","llm_judgment":"PRESENT","evidence":"c.91C>T (p.R31*)","abstract_start":793,"abstract_end":809}]}
{"pmid":"23000146","title":"Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer.","abstract":"Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles. To date, two different loci in chromosomal regions 15q22-15q24 and 8q24.13-8q24.21 have been reported. Pathogenic mutations, however, have yet to be identified. In order to elucidate the genetic cause of PPKP type Buschke-Fischer-Brauer (PPKP1), we performed exome sequencing in five affected individuals from three families, and we identified in chromosomal region 15q22.33-q23 two heterozygous nonsense mutations-c.370C>T (p.Arg124(∗)) and c.481C>T (p.Arg161(∗))-in AAGAB in all affected individuals. Using immunoblot analysis, we showed that both mutations result in premature termination of translation and truncated protein products. Analyses of mRNA of affected individuals revealed that the disease allele is either not detectable or only detectable at low levels. To assess the consequences of the mutations in skin, we performed immunofluorescence analyses. Notably, the amount of granular staining in the keratinocytes of affected individuals was lower in the cytoplasm but higher around the nucleus than it was in the keratinocytes of control individuals. AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone. The identification of mutations, along with the results from additional studies, defines the genetic basis of PPKP1 and provides evidence that AAGAB plays an important role in skin integrity.","variants":[{"Name":"NM_024666.5(AAGAB):c.481C>T (p.Arg161Ter)","Chromosome":"15","Start":"67231868","Stop":"67231868","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48331,"rule_based_match":true,"evidence_text":"c.481C>T (p.Arg161(∗))","llm_judgment":"PRESENT","evidence":"c.481C>T (p.Arg161(∗))","abstract_start":631,"abstract_end":653},{"Name":"NM_024666.5(AAGAB):c.370C>T (p.Arg124Ter)","Chromosome":"15","Start":"67236060","Stop":"67236060","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48332,"rule_based_match":true,"evidence_text":"c.370C>T (p.Arg124(∗))","llm_judgment":"PRESENT","evidence":"c.370C>T (p.Arg124(∗))","abstract_start":604,"abstract_end":626}]}
{"pmid":"21769658","title":"Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members.","abstract":"Mutations in BRCA1 and BRCA2 predispose carriers to early onset breast and ovarian cancer. A common problem in clinical genetic testing is interpretation of variants with unknown clinical significance. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different laboratories. Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood analysis, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c.8754+3G>C). Combined interpretation of splicing and multifactorial analysis classified an initiation codon variant (BRCA2 c.3G>A) as likely pathogenic, uncertain clinical significance for 7 variants, and indicated low clinical significance or unlikely pathogenicity for another 10 variants. Bioinformatic tools predicted disruption of consensus donor or acceptor sites with high sensitivity, but cryptic site usage was predicted with low specificity, supporting the value of RNA-based assays. The findings also provide further evidence that clinical RNA-based assays should be extended from analysis of invariant dinucleotides to routinely include all variants located within the donor and acceptor consensus splicing sites. Importantly, this study demonstrates the added value of collaboration between laboratories, and across disciplines, to collate and interpret information from clinical testing laboratories to consolidate patient management.","variants":[{"Name":"NM_000059.4(BRCA2):c.8754+3G>C","Chromosome":"13","Start":"32376794","Stop":"32376794","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":67336,"rule_based_match":true,"evidence_text":"BRCA2 c.8754+3G>C","llm_judgment":"PRESENT","evidence":"c.8754+3G>C","abstract_start":1206,"abstract_end":1217},{"Name":"NM_000059.4(BRCA2):c.316+5G>A","Chromosome":"13","Start":"32319330","Stop":"32319330","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":66077,"rule_based_match":true,"evidence_text":"BRCA2 c.316+5G>A","llm_judgment":"PRESENT","evidence":"BRCA2 c.316+5G>A","abstract_start":1184,"abstract_end":1200},{"Name":"NM_007294.4(BRCA1):c.4357+1G>A","Chromosome":"17","Start":"43082403","Stop":"43082403","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46140,"rule_based_match":true,"evidence_text":"BRCA1 c.4357+1G>A","llm_judgment":"PRESENT","evidence":"c.4357+1G>A","abstract_start":1147,"abstract_end":1158},{"Name":"NM_000059.4(BRCA2):c.3G>A (p.Met1Ile)","Chromosome":"13","Start":"32316463","Stop":"32316463","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":66247,"rule_based_match":true,"evidence_text":"BRCA2 c.3G>A","llm_judgment":"PRESENT","evidence":"BRCA2 c.3G>A","abstract_start":1324,"abstract_end":1336},{"Name":"NM_007294.4(BRCA1):c.441+2T>A","Chromosome":"17","Start":"43104120","Stop":"43104120","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":69863,"rule_based_match":true,"evidence_text":"BRCA1 c.441+2T>A","llm_judgment":"PRESENT","evidence":"BRCA1 c.441+2T>A","abstract_start":1111,"abstract_end":1127},{"Name":"NM_007294.4(BRCA1):c.5074G>C (p.Asp1692His)","Chromosome":"17","Start":"43067608","Stop":"43067608","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":46189,"rule_based_match":true,"evidence_text":"c.5074G>C","llm_judgment":"PRESENT","evidence":"c.5074G>C","abstract_start":1173,"abstract_end":1182},{"Name":"NM_007294.4(BRCA1):c.4987-2A>G","Chromosome":"17","Start":"43067697","Stop":"43067697","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":70012,"rule_based_match":true,"evidence_text":"BRCA1 c.4987-2A>G","llm_judgment":"PRESENT","evidence":"c.4987-2A>G","abstract_start":1160,"abstract_end":1171}]}
{"pmid":"21972112","title":"A novel mutation in CRYBB1 associated with congenital cataract-microcornea syndrome: the p.Ser129Arg mutation destabilizes the βB1/βA3-crystallin heteromer but not the βB1-crystallin homomer.","abstract":"Congenital cataract-microcornea syndrome (CCMC) is a clinically and genetically heterogeneous condition characterized by lens opacities and microcornea. It appears as a distinct phenotype of heritable congenital cataract. Here we report a large Chinese family with autosomal dominant congenital cataract and microcornea. Evidence for linkage was detected at marker D22S1167 (LOD score [Z]=4.49, recombination fraction [θ]=0.0), which closely flanks the â-crystallin gene cluster locus. Direct sequencing of the candidate âB1-crystallin gene (CRYBB1) revealed a c.387C>A transversion in exon 4, which cosegregated with the disease in the family and resulted in the substitution of serine by arginine at codon 129 (p.Ser129Arg). A comparison of the biophysical properties of the recombinant β-crystallins revealed that the mutation impaired the structures of both βB1-crystallin homomer and βB1/βA3-crystallin heteromer. More importantly, the mutation significantly decreased the thermal stability of βB1/βA3-crystallin but not βB1-crystallin. These findings highlight the importance of protein-protein interactions among β-crystallins in maintaining lens transparency, and provide a novel insight into the molecular mechanism underlying the pathogenesis of human CCMC.","variants":[{"Name":"NM_001887.4(CRYBB1):c.387C>A (p.Ser129Arg)","Chromosome":"22","Start":"26607934","Stop":"26607934","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":417543,"rule_based_match":true,"evidence_text":"c.387C>A (p.Ser129Arg)","llm_judgment":"PRESENT","evidence":"p.Ser129Arg","abstract_start":713,"abstract_end":724}]}
{"pmid":"17896316","title":"An unusual presentation of macular corneal dystrophy associated with uniparental isodisomy and a novel Leu173Pro mutation.","abstract":"PURPOSE: To report an unusual phenotype of macular corneal dystrophy (MCDC1) associated with a novel CHST6 mutation transmitted via maternal isodisomy.\nMETHODS: Slit lamp examination of the patient and his parents was performed. DNA was collected from each individual for amplification and sequencing of the CHST6 coding region, as well as exons 4 and 12 of TGFBI. Serum antigenic keratan sulfate (AgKS) levels were measured for confirmation of the diagnosis and subtyping of MCDC1. Quantitative real-time PCR (qPCR) was performed to differentiate between homozygous and hemizygous sequence variants. Genotyping at 12 single nucleotide polymorphisms (SNPs) within and surrounding CHST6 was performed to determine the pattern of inheritance of mutations identified in CHST6.\nRESULTS: Examination of the proband revealed bilateral, discrete, axially distributed, gray-white deposits at the level of Bowman's layer, with diffuse fine corneal stromal haze. Screening of TGFBI exons 4 and 12 in the proband did not reveal any allelic variants. However, screening of CHST6 in the proband demonstrated a novel homozygous missense mutation involving a highly conserved amino acid (c.518T > C; Leu173Pro) and undetectable serum AgKS levels in the proband confirmed the diagnosis of type I MCDC1. Quantitative PCR confirmed that both copies of CHST6 were present in the patient, excluding the possibility that the mutation was present in the hemizygous state. The results of genotyping were consistent with maternal isodisomy, as the patient was homozygous for an allele possessed by his mother at each SNP, two of which were informative and demonstrated nonpaternal inheritance.\nCONCLUSION: A phenotypically unusual variant of MCDC1 was found to be associated with the novel Leu173Pro mutation in CHST6, transmitted via uniparental isodisomy, a previously unreported pattern of inheritance in the corneal dystrophies.","variants":[{"Name":"NM_021615.5(CHST6):c.518T>C (p.Leu173Pro)","Chromosome":"16","Start":"75479311","Stop":"75479311","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1049857,"rule_based_match":true,"evidence_text":"c.518T > C; Leu173Pro","llm_judgment":"PRESENT","evidence":"c.518T > C; Leu173Pro","abstract_start":1173,"abstract_end":1194}]}
{"pmid":"18924225","title":"Clinicopathological analysis of the homozygous p.W1327X AGL mutation in glycogen storage disease type 3.","abstract":"We report on clinicopathological and whole body MRI analyses of the index patient of a large nonconsanguineous German-Ukraine family with homozygous and heterozygous AGL gene mutations at position p.W1327X (c.3980G > A). There are only limited reports on this phenotype with a homozygous genotype. The index patient, a 49-year-old woman presented with hepatomegaly, cardiomyopathy and moderate progressive proximal limb myopathy. Skeletal muscle showed severe vacuolar myopathy with storage of PAS-positive non-membrane-limited glycogen. An increase in glycogen content and completely decrease of debranching enzyme activity was measured in erythrocytes. Mutational analysis of the AGL gene showed a homozygous p.W1327X mutation. In the family, two brothers had been affected by severe infantile onset hepatomegaly and died within their first years of life by fatal liver cirrhosis. Furthermore, another sister severely affected by hepatomegaly, cardiomyopathy and proximal skeletal myopathy died at age 33. Three younger heterozygous sisters and a brother noticed exercise-induced myalgia and weakness since their teens. In sum, a homozygous p.W1327X mutation leads to a severe generalized glycogenosis types 3a and 3b within the same family. Even heterozygous p.W1327X mutation carriers may present with mild non-progressive neuromuscular symptoms, such as exercise-induced myalgia and fatigue.","variants":[{"Name":"NM_000642.3(AGL):c.3980G>A (p.Trp1327Ter)","Chromosome":"1","Start":"99913557","Stop":"99913557","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16147,"rule_based_match":true,"evidence_text":"c.3980G > A","llm_judgment":"PRESENT","evidence":"c.3980G > A","abstract_start":207,"abstract_end":218}]}
{"pmid":"18535392","title":"Molecular diagnosis and management of hereditary angioedema in a Greek family.","abstract":"BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent angioedema episodes caused by a quantitative or functional defect of the plasma protein C1 esterase inhibitor (C1-INH). Relapsing skin swellings, abdominal pain attacks and upper airway obstruction constitute the typical clinical manifestations. The incidence and severity of angioedema attacks are highly variable among HAE patients.\nCASES: We report on 4 patients with HAE type I, members of the same family, originating from a Greek island. The patients, 2 males and 2 females (aged 8-45 years) suffer from recurrent edema episodes (1-2 attacks/month). Skin swellings at the extremities and the face, abdominal episodes and laryngeal edema are the classical clinical triad, with significant variation in the severity and frequency of symptoms among our patients. The new missense mutation in exon 2 of the C1-INH gene, c.1A>G; p.Met-22Val (p.Met1Val), in a heterozygous form was detected in all our patients. Acute and severe attacks are successfully treated with administration of C1-INH concentrate.\nCONCLUSION: Variability of phenotypic expression of HAE was observed among the affected family members, despite carrying identical mutation of the C1-INH gene. Acute exacerbations of the disease are safely and effectively treated with C1-INH concentrate.","variants":[{"Name":"NM_000062.3(SERPING1):c.1A>G (p.Met1Val)","Chromosome":"11","Start":"57598271","Stop":"57598271","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":614680,"rule_based_match":true,"evidence_text":"c.1A>G; p.Met-22Val (p.Met1Val)","llm_judgment":"PRESENT","evidence":"c.1A>G; p.Met-22Val (p.Met1Val)","abstract_start":922,"abstract_end":953}]}
{"pmid":"33996489","title":"The perioperative transition of serum biomarkers of a 1.5-year-old boy with very-long-chain acyl-CoA dehydrogenase deficiency.","abstract":"Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD, OMIM 201475) is a congenital fatty acid oxidation disorder. Individuals with VLCADD should avoid catabolic states, including strenuous exercise and long-term fasting; however, such conditions are required when undergoing surgery. The perioperative management of VLCADD in infants has rarely been reported and details regarding the transition of serum biomarkers reflecting catabolic status have not been disclosed. Herein, we present the perioperative clinical and biological data of cryptorchidism in a 1.5-year-old boy with VLCADD. The patient was diagnosed through newborn screening and his clinical course was very stable. Genetic testing of <i>ACADVL</i> revealed compound heterozygous variants c.506 T > C (p.Met169Thr) and c.606-609delC (p.L216*). The enzyme activity of the patient with VLCAD was only 20% compared to that of healthy control. Left orchiopexy for the pediatric cryptorchidism was planned and performed at 1 and a half year of age. Induction anesthesia involved thiopental, fentanyl and rocuronium. The glucose infusion rate was maintained above 6.6 mg/kg/min starting the day before surgery until the operation was completed. Anesthesia was maintained with sevoflurane at approximately 2%. The serum concentration of tetradecenoylcarnitine were stable during the operation, ranging between 0.08 and 0.19 μM (cutoff <0.2 μM), and never deviated from the reference range. Concentration of other serum biomarkers including free fatty acid, 3-OH-butyrate, and creatine kinase, remained similarly unchanged. In this report, we describe the uneventful perioperative management of unilateral orchiopexy for left cryptorchidism in a 1.5-year-old boy with VLCADD using sufficient glucose infusion and volatile anesthesia.","variants":[{"Name":"NM_000018.4(ACADVL):c.506T>C (p.Met169Thr)","Chromosome":"17","Start":"7221566","Stop":"7221566","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":846144,"rule_based_match":true,"evidence_text":"c.506 T > C (p.Met169Thr)","llm_judgment":"PRESENT","evidence":"c.506 T > C (p.Met169Thr)","abstract_start":766,"abstract_end":791}]}
{"pmid":"20358596","title":"Three novel mutations in the ANK membrane protein cause craniometaphyseal dysplasia with variable conductive hearing loss.","abstract":"Craniometaphyseal dysplasia (CMD) is a rare, sclerosing skeletal disorder caused by mutations in ANKH, which encodes a putative pyrophosphate transporting membrane protein. Six distinct ANKH mutations have been described to date. We report here on three novel mutations in simplex patients with CMD. The c.1015T>C (p.Cys339Arg) mutation found in Patient A was associated with congenital facial palsy, early-onset conductive hearing loss, and a generalized undermodeling of the long bones. The c.1172T>C (p.Leu391Pro) mutation in Patient B was associated with facial palsy, progressive conductive hearing loss, and generalized undermodeling of tubular bones. A milder phenotype without cranial nerve affection was observed in Patient C, associated with a c.1001T>G (p.Leu334Arg) mutation. All affected residues lie in evolutionarily conserved sequence blocks. These additional cases and the associated mutations contribute to an improved appreciation of the variability of this rare skeletal dysplasia. (c) 2010 Wiley-Liss, Inc.","variants":[{"Name":"NM_054027.6(ANKH):c.1172T>C (p.Leu391Pro)","Chromosome":"5","Start":"14713637","Stop":"14713637","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":20240,"rule_based_match":true,"evidence_text":"c.1172T>C (p.Leu391Pro)","llm_judgment":"PRESENT","evidence":"c.1172T>C (p.Leu391Pro)","abstract_start":493,"abstract_end":516},{"Name":"NM_054027.6(ANKH):c.1001T>G (p.Leu334Arg)","Chromosome":"5","Start":"14741837","Stop":"14741837","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":20241,"rule_based_match":true,"evidence_text":"c.1001T>G (p.Leu334Arg)","llm_judgment":"PRESENT","evidence":"c.1001T>G (p.Leu334Arg)","abstract_start":754,"abstract_end":777},{"Name":"NM_054027.6(ANKH):c.1015T>C (p.Cys339Arg)","Chromosome":"5","Start":"14716832","Stop":"14716832","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":20239,"rule_based_match":true,"evidence_text":"c.1015T>C (p.Cys339Arg)","llm_judgment":"PRESENT","evidence":"c.1015T>C (p.Cys339Arg)","abstract_start":304,"abstract_end":327}]}
{"pmid":"26845227","title":"A rare case of familial multiple subcutaneous lipomatosis with novel PALB2 mutation and increased predilection to cancers.","abstract":"We describe the association of familial multiple subcutaneous lipomatosis with a PALB2 gene mutation (c.2716delT) and its increased predilection to cancers.","variants":[{"Name":"NM_024675.4(PALB2):c.2716del (p.Trp906fs)","Chromosome":"16","Start":"23626268","Stop":"23626268","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":843573,"rule_based_match":true,"evidence_text":"c.2716delT","llm_judgment":"PRESENT","evidence":"c.2716delT","abstract_start":102,"abstract_end":112}]}
{"pmid":"31958439","title":"Genetic Risk Factors for Spontaneous Pneumothorax in Birt-Hogg-Dubé Syndrome.","abstract":"BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, spontaneous pneumothorax, fibrofolliculomas, and renal cell cancer. Because of its rarity and clinical heterogeneity, much is still unknown regarding the course of the disease and individual risk assessment. Therefore, we studied nonenvironmental risk factors for pneumothorax in a large sample of patients with BHDS.\nMETHODS: Clinical data were available from 197 patients with BHDS (male patients, 103; female patients, 94) belonging to 63 unrelated families. The FLCN coding region including adjacent intronic sequences was analyzed by PCR and subsequent Sanger sequencing as well as by multiplex ligation-dependent probe amplification. Statistical analyses were performed, using adequate methods to account for familial clustering.\nRESULTS: Patients who had only a single spontaneous pneumothorax were significantly older at the time of occurrence than those with multiple pneumothoraces (mean, 38.93 vs 29.74 years; P value, .010). The risk for three or more pneumothoraces drastically increased after the second event. Significantly increased pneumothorax risks were found for mutations c.1300G>C (59%) and c.250-2A>G (77%), compared with FLCN hotspot mutation c.1285dup (37% risk) (P value, .02).\nCONCLUSIONS: We observed significant differences for the spontaneous pneumothorax risk regarding both age and sex in patients with BHDS. Furthermore, two FLCN mutations were identified that are associated with significantly increased pneumothorax risk. Thus, formerly unknown individual predictors have been identified that provide improved risk stratification for patients with BHDS.","variants":[{"Name":"NM_144997.7(FLCN):c.1285dup (p.His429fs)","Chromosome":"17","Start":"17216394","Stop":"17216395","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":18402,"rule_based_match":true,"evidence_text":"c.1285dup","llm_judgment":"PRESENT","evidence":"c.1285dup","abstract_start":1267,"abstract_end":1276},{"Name":"NM_144997.7(FLCN):c.250-2A>G","Chromosome":"17","Start":"17226324","Stop":"17226324","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":102375,"rule_based_match":true,"evidence_text":"c.250-2A>G","llm_judgment":"PRESENT","evidence":"c.250-2A>G","abstract_start":1213,"abstract_end":1223}]}
{"pmid":"21681551","title":"The identification and management of hereditary diffuse gastric cancer in a large Jordanian family.","abstract":"The management of families with hereditary diffuse gastric cancer is challenging as screening for cancer in CDH1 mutation carriers is insufficiently sensitive and the commonly recommended option, prophylactic total gastrectomy, is associated with certain morbidity and even potential mortality. We describe the particular challenges associated with the diagnosis and management of a large Jordanian family with hereditary diffuse gastric cancer. A preliminary pedigree enabled DNA testing for CDH1 mutation, denoted as c.1137G → A, on 4 family members; all were identified as mutation carriers. A family information service was then conducted in Amman, Jordan, where 40 family members gathered and we provided education and counseling. Signed permission enabled DNA collection for CDH1 germline mutation studies. Non-attendees were contacted and provided detailed information. Twenty-three family members have been tested for CDH1; 13 were positive and 10 were negative. The proband, a CDH1 mutation carrier, has undergone successful prophylactic total gastrectomy. We are hopeful that this model can be repeated throughout Jordan as well as other emerging countries where knowledge and action about hereditary cancer is lacking.","variants":[{"Name":"NM_004360.5(CDH1):c.1137G>A (p.Thr379=)","Chromosome":"16","Start":"68812263","Stop":"68812263","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":166264,"rule_based_match":false,"evidence_text":"c.1137G → A","llm_judgment":"PRESENT","evidence":"c.1137G → A","abstract_start":519,"abstract_end":530}]}
{"pmid":"29435075","title":"","abstract":"The present case report discusses a woman affected by chronic lymphatic leukemia and breast cancer with a familial history of breast cancer; suspected to be hereditary breast and ovarian cancer (HBOC) syndrome. The patient underwent <i>BRCA1</i> and <i>BRCA2</i> genetic testing. Sequencing of <i>BRCA1</i> revealed the presence of the variant of unknown significance (VUS) c.3082C>T (p.Arg1028Cys) at homozygous state, whereas no mutations were detected in <i>BRCA2</i>. Multiplex ligation-dependent probe amplification confirmed the presence of two alleles. Although consanguineity between her parents was reported, which therefore supported the molecular data, her clinical phenotype was not suggestive of typical Fanconi anemia (FA), particularly of a <i>BRCA1</i>-linked FA. In the two cases reported in the literature, carriers of biallelic <i>BRCA1</i> mutation present a severe and quite typical phenotype. For this reason, the patient was offered a diepoxybutane test, where neither complex rearrangements nor multiradial formation were detected. We were therefore inclined to consider that <i>BRCA1</i> VUS as of little clinical significance.","variants":[{"Name":"NM_007294.4(BRCA1):c.3082C>T (p.Arg1028Cys)","Chromosome":"17","Start":"43092449","Stop":"43092449","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46062,"rule_based_match":true,"evidence_text":"c.3082C>T (p.Arg1028Cys)","llm_judgment":"PRESENT","evidence":"c.3082C>T (p.Arg1028Cys)","abstract_start":374,"abstract_end":398}]}
{"pmid":"21746984","title":"Prolonged pursuit by optokinetic drum testing in asymptomatic female carriers of novel FRMD7 splice mutation c.1050 +5 G>A.","abstract":"OBJECTIVE: To determine the genotype underlying suspected X-linked infantile nystagmus in a family and to correlate genotype with clinical examination in potential female carriers.\nMETHODS: Ophthalmic examination (ophthalmic, orthoptic, optokinetic [OKN] drum, and electrophysiologic when possible) and candidate gene analysis.\nRESULTS: Two affected brothers had infantile nystagmus with no evidence of associated visual or neurological disease. The symptomatic maternal aunt had infantile nystagmus in addition to congenital fibrosis of the extraocular muscles (CFEOM) (bilateral hypotropia, exotropia, ptosis, almost complete ophthalmoplegia, and poorly reactive pupils). A sister, the mother, and the maternal grandmother-all 3 of whom were asymptomatic-had delayed corrective saccades (prolonged pursuit) during OKN drum testing.A brother and the father—both of whom were asymptomatic—had unremarkable examination findings [corrected]. A FRMD7 splice variant (c.1050 + 5 G>A) was identified in the 2 affected brothers and in the 3 asymptomatic women only. Allele sharing analysis further confirmed that the aunt's phenotype was not related to the FRMD7 variant, which was absent in 246 ethnic controls. Her phenotype was also not related to mutation in known CFEOM genes (KIF21A, PHOX2A, TUBB3).\nCONCLUSIONS: Prolonged pursuit responses during OKN drum testing in asymptomatic female carriers is consistent with the concept of infantile nystagmus being an abnormally increased pursuit oscillation. Further studies are required to determine the reproducibility of this potential female carrier sign. Rather than being FRMD7 related, nystagmus in the maternal aunt represented a second disease in this family, likely related to CFEOM.\nCLINICAL RELEVANCE: Clinicians can use the OKN drum to assess obligate female carriers in a family suspected of having X-linked nystagmus.","variants":[{"Name":"NM_194277.3(FRMD7):c.1050+5G>A","Chromosome":"X","Start":"132080001","Stop":"132080001","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38933,"rule_based_match":true,"evidence_text":"c.1050 + 5 G>A","llm_judgment":"PRESENT","evidence":"c.1050 + 5 G>A","abstract_start":964,"abstract_end":978}]}
{"pmid":"21562927","title":"Enhanced exon 2 skipping caused by c.910G>A variant and alternative splicing of MEFV genes in two independent cases of familial Mediterranean fever.","abstract":"Most reported cases of familial Mediterranean fever (FMF) involve missense mutations of MEFV concentrated within exon 10. We experienced two independent pedigrees of a unique variant in the MEFV gene that might cause excessive exon 2 skipping due to enhanced alternative splicing. In this study, we tried to elucidate the molecular mechanism of the MEFV variant as a cause of the FMF phenotype. Peripheral blood was obtained from volunteers and two patients with homozygous c.910G>A variant of the MEFV gene. MEFV messenger RNA (mRNA) expression patterns in mononuclear cells and granulocytes were compared using forward and reverse primers from exons 1 and 3, respectively. Expression profiles of pyrin were examined by transfecting wild-type and variant MEFV genes into HEK293T cells. Expression of normal-sized mRNA was extremely reduced in these patients, whereas that of aberrant short mRNA, deleting exon 2 (Δex2), was significantly increased. Immunohistochemical and immunoblotting analyses revealed a truncated immunoreactive pyrin protein in cells transfected with Δex2 cDNA. The MEFV gene c.910G>A variant results in accelerated aberrant splicing with abnormal protein size, presumably leading to anomalous pyrin function. This is the first report to show that an MEFV variant other than missense mutation is responsible for the FMF phenotype.","variants":[{"Name":"NM_000243.3(MEFV):c.910G>A (p.Gly304Arg)","Chromosome":"16","Start":"3254158","Stop":"3254158","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45175,"rule_based_match":true,"evidence_text":"c.910G>A","llm_judgment":"PRESENT","evidence":"c.910G>A","abstract_start":474,"abstract_end":482}]}
{"pmid":"26321508","title":"Whole exome sequencing identifies a novel frameshift mutation in GPC3 gene in a patient with overgrowth syndrome.","abstract":"Overgrowth syndromes are a heterogeneous group of diseases characterized by focal or generalized overgrowth. Many of the syndromes have overlapping clinical features and it is difficult to diagnose the condition based on clinical features alone. In the present study we report on a patient with overgrowth syndrome where extensive investigation did not reveal the cause of disease. Finally exome sequencing revealed a novel hemizygous single base pair deletion in exon 8 of GPC3 gene (chrX:132670203delA) resulting in a frameshift and creating a new stop codon at 62 amino acids downstream to codon 564 (c.1692delT; p.Leu565SerfsTer63) of the protein. The mutation was confirmed by Sanger sequencing. The mother was found to be heterozygous for the mutation. This variation is not reported in the 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC) and dbSNP databases and the region is conserved across primates. Exome sequencing was helpful in establishing diagnosis of Simpson-Golabi-Behmel syndrome type 1 (SGBS1) in a patient with unknown overgrowth syndrome.","variants":[{"Name":"NM_004484.4(GPC3):c.1692del (p.Leu565fs)","Chromosome":"X","Start":"133536175","Stop":"133536175","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":260942,"rule_based_match":true,"evidence_text":"c.1692delT; p.Leu565SerfsTer63","llm_judgment":"PRESENT","evidence":"c.1692delT; p.Leu565SerfsTer63","abstract_start":604,"abstract_end":634}]}
{"pmid":"28377545","title":"A novel WDR62 mutation causes primary microcephaly in a large consanguineous Saudi family.","abstract":"BACKGROUND: Primary microcephaly (MCPH) is a rare developmental defect characterized by impaired cognitive functions, retarded neurodevelopment and reduced brain size. It is genetically heterogeneous and more than 17 genes so far have been identified that are associated with this disease.\nOBJECTIVE: To study the genetic defect in a consanguineous Saudi family with primary microcephaly.\nDESIGN: Cross-sectional clinical genetics study of a Saudi family.\nSETTING: Medical genomics research center.\nPATIENTS AND METHODS: Blood samples collected from six members of a family of healthy consanguineous parents were analyzed by whole exome sequencing to identify the underlying pathogenic mutations in two members of the family (23-year-old female and 7-year-old male) who presented with primary microcephaly, intellectual disability, delayed psychomotor development and walking difficulty, speech impedi-ments and seizures.\nMAIN OUTCOME MEASURE(S): Detection of mutation in the WD repeat domain 62 (WDR62) gene in a family segregating autosomal recessive primary microcephaly.\nRESULTS: The exome variant analysis identified a novel missense mutation (c.3878C > A) in WDR62 gene in exon 30 resulting in amino acid change from alanine to aspartate (p.Ala1293Asp). Further validation in the affected patients and healthy members of family and 100 unrelated healthy persons as controls confirmed it to be pathogenic.\nCONCLUSIONS: Functional impairment of the WDR62 gene can lead to severe neurodevelopmental de-fects, brain malformations and reduced head size. A missense mutation of exon 30 changed alanine to aspartate in the WDR62 protein leading to the typical MCPH phenotype.\nLIMITATIONS: Mutation was identified in a single family.","variants":[{"Name":"NM_001083961.2(WDR62):c.3878C>A (p.Ala1293Asp)","Chromosome":"19","Start":"36103706","Stop":"36103706","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":620636,"rule_based_match":true,"evidence_text":"c.3878C > A","llm_judgment":"PRESENT","evidence":"c.3878C > A","abstract_start":1149,"abstract_end":1160}]}
{"pmid":"38631813","title":"Novel genetic variant in hereditary spastic paraparesis.","abstract":"A man in his 30s was referred to neurology with right-sided paraesthesia, tremors, chest pain and lower urinary tract and erectile dysfunction. He had a medical history of left acetabular dysplasia, and subjective memory impairment, the latter being in the context of depression and chronic pain with opioid use. There was no notable family history. On examination, he had a spastic paraparesis. Imaging revealed atrophy of the thoracic spine. Lumbar puncture demonstrated a raised protein but other constituents were normal, including no presence of oligoclonal bands. Genetic testing revealed a novel heterozygous likely pathogenic SPAST variant c. 1643A>T p.(Asp548Val), confirming the diagnosis of hereditary spastic paraparesis. Symptomatic treatment with physiotherapy and antispasmodic therapy was initiated. This is the first study reporting a patient with this SPAST variant. Ensembl variant effect predictor was used, with the application of computational variant prediction tools providing support that the variant we have identified is likely deleterious and damaging. Our variant CADD score was high, indicating that our identified variant was a highly deleterious substitution.","variants":[{"Name":"NM_014946.4(SPAST):c.1643A>T (p.Asp548Val)","Chromosome":"2","Start":"32144963","Stop":"32144963","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":3779239,"rule_based_match":true,"evidence_text":"c. 1643A>T p.(Asp548Val)","llm_judgment":"PRESENT","evidence":"c. 1643A>T p.(Asp548Val)","abstract_start":648,"abstract_end":672}]}
{"pmid":"26406231","title":"A Novel AXIN2 Missense Mutation Is Associated with Non-Syndromic Oligodontia.","abstract":"Oligodontia is defined as the congenital absence of six or more permanent teeth, excluding the third molars. Oligodontia may contribute to masticatory dysfunction, speech alteration, aesthetic problems and malocclusion. Numerous gene mutations have been association with oligodontia. In the present study, we identified a de novo AXIN2 missense mutation (c.314T>G) in a Chinese individual with non-syndromic oligodontia. This mutation results in the substitution of Val at residue 105 for Gly (p.Val105Gly); residue 105 is located in the highly conserved regulator of G protein signaling (RGS) domain of the AXIN2 protein. This is the first report indicating that a mutation in the RGS domain of AXIN2 is responsible for non-syndromic oligodontia. Our study supports the relationship between AXIN2 mutation and non-syndromic oligodontia and extends the mutation spectrum of the AXIN2 gene.","variants":[{"Name":"NM_004655.4(AXIN2):c.314T>G (p.Val105Gly)","Chromosome":"17","Start":"65558307","Stop":"65558307","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":214080,"rule_based_match":true,"evidence_text":"c.314T>G (p.Val105Gly)","llm_judgment":"PRESENT","evidence":"p.Val105Gly","abstract_start":494,"abstract_end":505}]}
{"pmid":"23897642","title":"Missense mutations in FBN1 exons 41 and 42 cause Weill-Marchesani syndrome with thoracic aortic disease and Marfan syndrome.","abstract":"Mutations in FBN1 cause a range of overlapping but distinct conditions including Marfan syndrome (MFS), Weill-Marchesani syndrome (WMS), familial thoracic aortic aneurysms/dissections (FTAAD), acromicric dysplasia (AD), and geleophysic dysplasia (GD). Two forms of acromelic dysplasia, AD and GD, characterized by short stature, brachydactyly, reduced joint mobility, and characteristic facies, result from heterozygous missense mutations occurring in exons 41 and 42 of FBN1; missense mutations in these exons have not been reported to cause MFS or other syndromes. Here we report on probands with MFS and WMS who have heterozygous FBN1 missense mutations in exons 41 and 42, respectively. The proband with WMS has ectopia lentis, short stature, thickened pinnae, tight skin, striae atrophicae, reduced extension of the elbows, contractures of the fingers and toes, and brachydactyly and has a missense mutation in exon 42 of FBN1 (c.5242T>C; p.C1748R). He also experienced a previously unreported complication of WMS, an acute thoracic aortic dissection. The second proband displays classic characteristics of MFS, including ectopia lentis, skeletal features, and aortic root dilatation, and has a missense mutation in exon 41 of FBN1 (c.5084G>A; p.C1695Y). These phenotypes provide evidence that missense mutations in exons 41 and 42 of FBN1 lead to MFS and WMS in addition to AD and GD and also suggest that all individuals with pathogenic FBN1 mutations in these exons should be assessed for thoracic aortic disease and ectopia lentis. Further studies are necessary to elucidate the factors responsible for the different phenotypes associated with missense mutations in these exons of FBN1.","variants":[{"Name":"NM_000138.5(FBN1):c.5242T>C (p.Cys1748Arg)","Chromosome":"15","Start":"48460300","Stop":"48460300","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1871299,"rule_based_match":true,"evidence_text":"c.5242T>C; p.C1748R","llm_judgment":"PRESENT","evidence":"c.5242T>C; p.C1748R","abstract_start":933,"abstract_end":952},{"Name":"NM_000138.5(FBN1):c.5084G>A (p.Cys1695Tyr)","Chromosome":"15","Start":"48463222","Stop":"48463222","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1871301,"rule_based_match":true,"evidence_text":"c.5084G>A (p.C1695Y)","llm_judgment":"PRESENT","evidence":"c.5084G>A","abstract_start":1238,"abstract_end":1247}]}
{"pmid":"32728620","title":"Olaparib for metastatic breast cancer in a patient with a germline","abstract":"There is a strong biologic rationale that poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors may benefit a broader range of metastatic breast cancer (MBC) patients than covered by current approvals, which require a germline <i>BRCA1/2</i> sequence variant affecting function. We report a patient with germline/somatic <i>BRCA1/2</i> wild-type MBC, who had a dramatic response to the PARP inhibitor olaparib of at least 8 months' duration. The patient is a 37-year-old woman with recurrent, hormone receptor-positive, HER2-negative MBC that had progressed despite hormonal therapy and palbociclib. Sensitivity to olaparib was likely conferred by a germline sequence variant affecting function in <i>PALB2</i> (exon 1, c.18G>T, p.(=)). This case documenting activity of olaparib monotherapy in germline/somatic <i>BRCA1/2</i> wild-type MBC illustrates that the clinical potential of PARP inhibition in MBC extends beyond currently approved indications to additional patients whose tumors have (epi)genetic changes affecting homologous recombination repair.","variants":[{"Name":"NM_024675.4(PALB2):c.18G>T (p.Gly6=)","Chromosome":"16","Start":"23641140","Stop":"23641140","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":152146,"rule_based_match":true,"evidence_text":"c.18G>T","llm_judgment":"PRESENT","evidence":"c.18G>T","abstract_start":730,"abstract_end":737}]}
{"pmid":"27466185","title":"Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6.","abstract":"The Acadian variant of Fanconi Syndrome refers to a specific condition characterized by generalized proximal tubular dysfunction from birth, slowly progressive chronic kidney disease and pulmonary interstitial fibrosis. This condition occurs only in Acadians, a founder population in Nova Scotia, Canada. The genetic and molecular basis of this disease is unknown. We carried out whole exome and genome sequencing and found that nine affected individuals were homozygous for the ultra-rare non-coding variant chr8:96046914 T > C; rs575462405, whereas 13 healthy siblings were either heterozygotes or lacked the mutant allele. This variant is located in intron 2 of NDUFAF6 (NM_152416.3; c.298-768 T > C), 37 base pairs upstream from an alternative splicing variant in NDUFAF6 chr8:96046951 A > G; rs74395342 (c.298-731 A > G). NDUFAF6 encodes NADH:ubiquinone oxidoreductase complex assembly factor 6, also known as C8ORF38. We found that rs575462405-either alone or in combination with rs74395342-affects splicing and synthesis of NDUFAF6 isoforms. Affected kidney and lung showed specific loss of the mitochondria-located NDUFAF6 isoform and ultrastructural characteristics of mitochondrial dysfunction. Accordingly, affected tissues had defects in mitochondrial respiration and complex I biogenesis that were corrected with NDUFAF6 cDNA transfection. Our results demonstrate that the Acadian variant of Fanconi Syndrome results from mitochondrial respiratory chain complex I deficiency. This information may be used in the diagnosis and prevention of this disease in individuals and families of Acadian descent and broadens the spectrum of the clinical presentation of mitochondrial diseases, respiratory chain defects and defects of complex I specifically.","variants":[{"Name":"NM_152416.4(NDUFAF6):c.298-768T>C","Chromosome":"8","Start":"95034686","Stop":"95034686","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":906219,"rule_based_match":true,"evidence_text":"NM_152416.3; c.298-768 T > C","llm_judgment":"PRESENT","evidence":"NM_152416.3; c.298-768 T > C","abstract_start":674,"abstract_end":702}]}
{"pmid":"35684947","title":"New phenotype of RTN2-related spectrum: Complicated form of spastic paraplegia-12.","abstract":"OBJECTIVE: Spastic paraplegia-12 (SPG12) is a subtype of hereditary spastic paraplegia caused by Reticulon-2 (RTN2) mutations. We described the clinical and genetic features of three SPG12 patients, functionally explored the potential pathogenic mechanism of RTN2 mutations, and reviewed RTN2-related cases worldwide.\nMETHODS: The three patients were 31, 36, and 50 years old, respectively, with chronic progressive lower limb spasticity and walking difficulty. Physical examination showed elevated muscle tone, hyperreflexia and Babinski signs in the lower limbs. Patients 1 and 3 additionally had visual, urinary, and/or coordination dysfunctions. Patient 2 also had epileptic seizures. RTN2 mutations were identified by whole-exome sequencing, followed by Sanger sequencing, segregation analysis, and phenotypic reevaluation. Functional examination of identified mutations was further explored.\nRESULTS: Three variants in RTN2 were identified in Patient 1 (c.103C>T, p.R35X), Patient 2 (c.230G>A, p.G77D), and Patient 3 (c.337C>A, p.P113T) with SPG, respectively. Western blotting revealed the p.R35X with smaller molecular weight than WT and other two missense mutants. Immunostaining showed the wild type colocalized with endoplasmic reticulum (ER) in vitro. p.R35X mutant diffusely distributes in the cytoplasm, losing colocalization with ER. p.G77D and p.P113T co-localized with ER, which was abnormally aggregated in clumps.\nINTERPRETATION: In this study, we identified three cases with complicated SPG12 due to three novel RTN2 mutations, respectively, presenting various phenotypes: classic SPG symptoms with (1) visual abnormalities and sphincter disturbances or (2) seizures. The phenotypic heterogeneity might arise from the abnormal subcellular localization of mutant Reticulon-2 and improper ER morphogenesis, revealing the RTN2-related spectrum is still expanding.","variants":[{"Name":"NM_005619.5(RTN2):c.337C>A (p.Pro113Thr)","Chromosome":"19","Start":"45494748","Stop":"45494748","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3739660,"rule_based_match":true,"evidence_text":"c.337C>A (p.P113T)","llm_judgment":"PRESENT","evidence":"c.337C>A","abstract_start":1024,"abstract_end":1032},{"Name":"NM_005619.5(RTN2):c.103C>T (p.Arg35Ter)","Chromosome":"19","Start":"45494982","Stop":"45494982","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3407446,"rule_based_match":true,"evidence_text":"c.103C>T, p.R35X","llm_judgment":"PRESENT","evidence":"c.103C>T, p.R35X","abstract_start":960,"abstract_end":976}]}
{"pmid":"30488450","title":"VCP myopathy: A family with unusual clinical manifestations.","abstract":"INTRODUCTION: Valosin-containing protein (VCP) variants that affect muscle, bone, and the nervous system are termed multisystem proteinopathy. VCP myopathy is manifested as limb-girdle weakness, distal weakness and scapuloperoneal weakness.\nMETHODS: We reviewed clinical, genetic, and muscle biopsy data from 6 members of a family with VCP myopathy.\nRESULTS: Clinical features of family members were complex and included dementia, myopathy, and hearing impairment. Ophthalmoplegia, ptosis, and dysphagia were present in 3 siblings. Rimmed vacuoles were observed in muscle biopsies, consistent with the pathological changes of VCP myopathy. A heterozygous VCP c.463C>A (p.R155S) that segregated in an autosomal-dominant pattern was identified by genetic analysis.\nCONCLUSIONS: VCP myopathy can cause unusual manifestations that include ophthalmoplegia, ptosis, and dysphagia. This study increased our understanding of the clinical manifestations of VCP myopathy. Muscle Nerve 59:365-369, 2019.","variants":[{"Name":"NM_007126.5(VCP):c.463C>A (p.Arg155Ser)","Chromosome":"9","Start":"35065364","Stop":"35065364","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1393321,"rule_based_match":true,"evidence_text":"VCP c.463C>A (p.R155S)","llm_judgment":"PRESENT","evidence":"VCP c.463C>A (p.R155S)","abstract_start":655,"abstract_end":677}]}
{"pmid":"21393332","title":"Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia.","abstract":"BACKGROUND: Congenital sideroblastic anemias are rare disorders with several genetic causes; they are characterized by erythroblast mitochondrial iron overload, differ greatly in severity and some occur within a syndrome. The most common cause of non-syndromic, microcytic sideroblastic anemia is a defect in the X-linked 5-aminolevulinate synthase 2 gene but this is not always present. Recently, variations in the gene for the mitochondrial carrier SLC25A38 were reported to cause a non-syndromic, severe type of autosomal-recessive sideroblastic anemia. Further evaluation of the importance of this gene was required to estimate the proportion of patients affected and to gain further insight into the range and types of variations involved.\nDESIGN AND METHODS: In three European diagnostic laboratories sequence analysis of SLC25A38 was performed on DNA from patients affected by congenital sideroblastic anemia of a non-syndromic nature not caused by variations in the 5-aminolevulinate synthase 2 gene.\nRESULTS: Eleven patients whose ancestral origins spread across several continents were homozygous or compound heterozygous for ten different SLC25A38 variations causing premature termination of translation (p.Arg117X, p.Tyr109LeufsX43), predicted splicing alteration (c.625G>C; p.Asp209His) or missense substitution (p.Gln56Lys, p.Arg134Cys, p.Ile147Asn, p.Arg187Gln, p.Pro190Arg, p.Gly228Val, p.Arg278Gly). Only three of these variations have been described previously (p.Arg117X, p.Tyr109LeufsX43 and p.Asp209His). All new variants reported here are missense and affect conserved amino acids. Structure modeling suggests that these variants may influence different aspects of transport as described for mutations in other mitochondrial carrier disorders.\nCONCLUSIONS: Mutations in the SLC25A38 gene cause severe, non-syndromic, microcytic/hypochromic sideroblastic anemia in many populations. Missense mutations are shown to be of importance as are mutations that affect protein production. Further investigation of these mutations should shed light on structure-function relationships in this protein.","variants":[{"Name":"NM_017875.4(SLC25A38):c.440T>A (p.Ile147Asn)","Chromosome":"3","Start":"39391604","Stop":"39391604","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1161601,"rule_based_match":false,"evidence_text":"p.Ile147Asn","llm_judgment":"PRESENT","evidence":"p.Ile147Asn","abstract_start":1351,"abstract_end":1362},{"Name":"NM_017875.4(SLC25A38):c.560G>A (p.Arg187Gln)","Chromosome":"3","Start":"39391956","Stop":"39391956","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1161606,"rule_based_match":false,"evidence_text":"p.Arg187Gln","llm_judgment":"PRESENT","evidence":"p.Arg187Gln","abstract_start":1364,"abstract_end":1375},{"Name":"NM_017875.4(SLC25A38):c.569C>G (p.Pro190Arg)","Chromosome":"3","Start":"39391965","Stop":"39391965","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1161608,"rule_based_match":false,"evidence_text":"p.Pro190Arg","llm_judgment":"PRESENT","evidence":"p.Pro190Arg","abstract_start":1377,"abstract_end":1388},{"Name":"NM_017875.4(SLC25A38):c.683G>T (p.Gly228Val)","Chromosome":"3","Start":"39394467","Stop":"39394467","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1161613,"rule_based_match":false,"evidence_text":"c.683G>T (p.Gly228Val)","llm_judgment":"PRESENT","evidence":"p.Gly228Val","abstract_start":1390,"abstract_end":1401},{"Name":"NM_017875.4(SLC25A38):c.166C>A (p.Gln56Lys)","Chromosome":"3","Start":"39389591","Stop":"39389591","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1161583,"rule_based_match":false,"evidence_text":"c.166C>A (p.Gln56Lys)","llm_judgment":"PRESENT","evidence":"p.Gln56Lys","abstract_start":1326,"abstract_end":1336},{"Name":"NM_017875.4(SLC25A38):c.832C>G (p.Arg278Gly)","Chromosome":"3","Start":"39396437","Stop":"39396437","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1161617,"rule_based_match":false,"evidence_text":"p.Arg278Gly","llm_judgment":"PRESENT","evidence":"p.Arg278Gly","abstract_start":1403,"abstract_end":1414},{"Name":"NM_017875.4(SLC25A38):c.400C>T (p.Arg134Cys)","Chromosome":"3","Start":"39391564","Stop":"39391564","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":620125,"rule_based_match":false,"evidence_text":"p.Arg134Cys","llm_judgment":"PRESENT","evidence":"p.Arg134Cys","abstract_start":1338,"abstract_end":1349},{"Name":"NM_017875.4(SLC25A38):c.625G>C (p.Asp209His)","Chromosome":"3","Start":"39392021","Stop":"39392021","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":620126,"rule_based_match":true,"evidence_text":"c.625G>C (p.Asp209His)","llm_judgment":"PRESENT","evidence":"p.Asp209His","abstract_start":1287,"abstract_end":1298}]}
{"pmid":"34247374","title":"Analysis of genetic variant in a fetus featuring pontocerebellar hypoplasia type 6","abstract":"OBJECTIVE: To explore the genetic basis for a fetus with cerebellar dysplasia and widened lateral ventricles.\nMETHODS: The couple have elected induced abortion after careful counseling. Skin tissue sample from the abortus and peripheral venous blood samples from both parents were collected for the extraction of genomic DNA, which was then subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing.\nRESULTS: Prenatal ultrasonography showed increased nuchal translucency (0.4 cm) and widened lateral ventricles. Magnetic resonance imaging revealed infratentorial brain dysplasia. By DNA sequencing, the fetus was found to carry compound heterozygous variants c.1A>G and c.1564G>A of the RARS2 gene, which were inherited from its father and mother, respectively. Among these, c.1A>G was known to be pathogenic, but the pathogenicity of c.1564G>A was unreported previously. Based on the American College of Medical Genetics and Genomics guidelines, the c.1564G>A variant of RARS2 gene was predicted to be likely pathogenic(PM2+PM3+PP3+PP4).\nCONCLUSION: The compound heterozygous variants c.1A>G and c.1564G>A of RARS2 gene contributed to the fetus suffering from pontocerebellar hypoplasia type 6, which expanded variant spectrum of RARS2 gene.","variants":[{"Name":"NM_020320.5(RARS2):c.1564G>A (p.Val522Ile)","Chromosome":"6","Start":"87516828","Stop":"87516828","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":857620,"rule_based_match":true,"evidence_text":"c.1564G>A","llm_judgment":"PRESENT","evidence":"c.1564G>A","abstract_start":701,"abstract_end":710},{"Name":"NM_020320.5(RARS2):c.1A>G (p.Met1Val)","Chromosome":"6","Start":"87589957","Stop":"87589957","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":226903,"rule_based_match":true,"evidence_text":"c.1A>G","llm_judgment":"PRESENT","evidence":"c.1A>G","abstract_start":690,"abstract_end":696}]}
{"pmid":"33804940","title":"Targeted Double-Stranded cDNA Sequencing-Based Phase Analysis to Identify Compound Heterozygous Mutations and Differential Allelic Expression.","abstract":"There are two combinations of heterozygous mutation, i.e., <i>in trans,</i> which carries mutations on different alleles, and <i>in cis,</i> which carries mutations on the same allele. Because only <i>in trans</i> compound heterozygous mutations have been implicated in autosomal recessive diseases, it is important to distinguish them for clinical diagnosis. However, conventional phase analysis is limited because of the large target size of genomic DNA. Here, we performed a genetic analysis on a patient with Wilson disease, and we detected two heterozygous mutations chr13:51958362;G>GG (NM_000053.4:c.2304dup r.2304dup p.Met769HisfsTer26) and chr13:51964900;C>T (NM_000053.4:c.1841G>A r.1841g>a p.Gly614Asp) in the causative gene <i>ATP7B</i>. The distance between the two mutations was 6.5 kb in genomic DNA but 464 bp in mRNA. Targeted double-stranded cDNA sequencing-based phase analysis was performed using direct adapter ligation library preparation and paired-end sequencing, and we elucidated they are <i>in trans</i> compound heterozygous mutations. Trio analysis showed that the mutation (chr13:51964900;C>T) derived from the father and the other mutation from the mother, validating that the mutations are <i>in trans</i> composition. Furthermore, targeted double-stranded cDNA sequencing-based phase analysis detected the differential allelic expression, suggesting that the mutation (chr13:51958362;G>GG) caused downregulation of expression by nonsense-mediated mRNA decay. Our results indicate that targeted double-stranded cDNA sequencing-based phase analysis is useful for determining compound heterozygous mutations and confers information on allelic expression.","variants":[{"Name":"NM_000053.4(ATP7B):c.2304dup (p.Met769fs)","Chromosome":"13","Start":"51958361","Stop":"51958362","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":463941,"rule_based_match":true,"evidence_text":"chr13:51958362;G>GG (NM_000053.4:c.2304dup r.2304dup p.Met769HisfsTer26)","llm_judgment":"PRESENT","evidence":"chr13:51958362;G>GG (NM_000053.4:c.2304dup r.2304dup p.Met769HisfsTer26)","abstract_start":572,"abstract_end":644}]}
{"pmid":"37658095","title":"Homogentisate 1,2-dioxygenase (HGD) gene variants in young Egyptian patients with alkaptonuria.","abstract":"Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the homogentisate 1,2-dioxygenase (HGD) gene. This leads to a deficient HGD enzyme with the consequent accumulation of homogentisic acid (HGA) in different tissues causing complications in various organs, particularly in joints, heart valves and kidneys. The genetic basis of AKU in Egypt is completely unknown. We evaluated the clinical and genetic spectrum of six pediatric and adolescents AKU patients from four unrelated Egyptian families. All probands had a high level of HGA in urine by qualitative GC/MS before genetic confirmation by Sanger sequencing. Recruited AKU patients were four females and two males (median age 13 years). We identified four different pathogenic missense variants within HGD gene. Detected variants included a novel variant c.1079G > T;p.(Gly360Val) and three recurrent variants; c.1078G > C;p.(Gly360Arg), c.808G > A;p.(Gly270Arg) and c.473C > T;p.(Pro158Leu). All identified variants were properly segregating in the four families consistent with autosomal recessive inheritance. In this study, we reported the phenotypic and genotypic spectrum of alkaptonuria for the first time in Egypt. We further enriched the HGD-variant database with another novel pathogenic variant. The recent availability of nitisinone may promote the need for genetic confirmation at younger ages to start therapy earlier and prevent serious complications.","variants":[{"Name":"NM_000187.4(HGD):c.1079G>T (p.Gly360Val)","Chromosome":"3","Start":"120633256","Stop":"120633256","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3544188,"rule_based_match":true,"evidence_text":"c.1079G > T;p.(Gly360Val)","llm_judgment":"PRESENT","evidence":"c.1079G > T;p.(Gly360Val)","abstract_start":858,"abstract_end":883}]}
{"pmid":"35220961","title":"Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China.","abstract":"BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race and geographical region. This study was aimed to provide a comprehensive analysis of ATP7B variants in China and to investigate a plausible role of common variants in WD manifestations.\nMETHODS: A total of 1366 patients (1302 index patients and 64 siblings) clinically diagnosed with WD (Leipzig score ≥ 4) were recruited. They underwent ATP7B gene sequencing and information of age and symptoms at onset was collected. The genotype-phenotype correlation was assessed in the index patients who were examined with two pathogenic variants and onset with hepatic (n = 276) or neurologic (n = 665) symptoms.\nRESULTS: We identified 294 potentially pathogenic ATP7B variants (112 truncating, 174 missense, 8 in-frame) in the 1302 index patients, including 116 novel variants. The most frequent variant was c.2333G>T (R778L, allele frequency: 28.96%), followed by c.2975C>T (P992L, 13.82%), c.2621C>T (A874V, 5.99%), c.2755C>G (R919G, 2.46%), and c.3646G>A (V1216M, 1.92%). In 1167 patients, both pathogentic variants were identified, of which 532 different variant combinations were found. By binary logistic regression analysis, the factor associated with neurological presentation was high age-at-onset, but not sex, protein-truncating variant (PTV), or the common missense variants (R778L, P992L, and A874V). In the neurological group, low age-at-onset was a factor associated with dystonia, gait abnormality, and salivation; high age-at-onset was a factor associated with tremor; and the sex, low age-at-onset and A874V were independent factors associated with dysarthria. In addition, PTV, R778L, and P992L were predominant in early-onset patients, whereas A874V was predominant in late-onset patients, and patients with R778L/A874V genotype displayed a higher age-at-onset than patients with R778L/R778L or R778L/P992L genotype.\nCONCLUSIONS: Our work expanded the ATP7B variant spectrum and highlighted the differences among patients with WD in age-at-onset and ATP7B variants, which may provide some valuable insights into the diagnosis, counseling, and treatment of patients with WD.","variants":[{"Name":"NM_000053.4(ATP7B):c.2333G>T (p.Arg778Leu)","Chromosome":"13","Start":"51958333","Stop":"51958333","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":18891,"rule_based_match":true,"evidence_text":"c.2333G>T (R778L","llm_judgment":"PRESENT","evidence":"c.2333G>T (R778L","abstract_start":1015,"abstract_end":1031},{"Name":"NM_000053.4(ATP7B):c.2755C>G (p.Arg919Gly)","Chromosome":"13","Start":"51949772","Stop":"51949772","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":18896,"rule_based_match":true,"evidence_text":"c.2755C>G (R919G, 2.46%)","llm_judgment":"PRESENT","evidence":"c.2755C>G (R919G, 2.46%)","abstract_start":1125,"abstract_end":1149}]}
{"pmid":"31319082","title":"Identification of two novel RHO mutations in Chinese retinitis pigmentosa patients.","abstract":"Retinitis pigmentosa (RP) is a group of genetically heterogeneous retinal diseases with more than 80 identified causative genes to date. Mutations in the RHO (rhodopsin, OMIM, 180380) are the most common cause of autosomal dominant RP (adRP) worldwide. RHO is also one of the few RP genes that can cause autosomal recessive RP (arRP). To explore the frequency of RP mutations in Chinese populations, panel-based NGS (next-generation sequencing) screening and Sanger sequencing validation were performed for RP patients from 72 unrelated Chinese families. Here we reported the identified mutations only in the RHO gene. Our results showed that 4 mutations in RHO were detected in 5 (6.94%) of the 72 RP families, including two known missense mutations, c.158C > G (p.P53R) and c.551A > C (p.Q184P), and two novel mutations, c.34delC (p.P12NA) and c.82C > T (p.Q28X). The c.34delC (p.P12NA) mutation was detected in heterozygous state in one patient with intermediate RP phenotype. The c.82C > T (p.Q28X) mutation was found in a homozygous state in one proband with advanced RP phenotype at the age of 32. Clinical examination of the heterozygous carriers of c.82C > T (p.Q28X) in that family showed that the father at the age of 60s experienced no symptoms of RP and normal fundus examinations but displayed reduced electroretinography (ERG) and abnormal visual field. The sister and brother at the age of 30s showed no typical aspects of RP phenotypes. Our results not only expand the mutation spectrum of the RHO gene, but also suggest that the 2 null mutations might play minor dominant effects, leading to less severe and slower retinal degeneration in heterozygous state and more severe phenotype in homozygous state.","variants":[{"Name":"NM_000539.3(RHO):c.158C>G (p.Pro53Arg)","Chromosome":"3","Start":"129528891","Stop":"129528891","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":28076,"rule_based_match":true,"evidence_text":"c.158C > G (p.P53R)","llm_judgment":"PRESENT","evidence":"c.158C > G (p.P53R)","abstract_start":752,"abstract_end":771}]}
{"pmid":"19474787","title":"ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin.","abstract":"The ABCG2 c.421C>A single-nucleotide polymorphism (SNP) was determined in 660 healthy Finnish volunteers, of whom 32 participated in a pharmacokinetic crossover study involving the administration of 20 mg atorvastatin and rosuvastatin. The frequency of the c.421A variant allele was 9.5% (95% confidence interval 8.1-11.3%). Subjects with the c.421AA genotype (n = 4) had a 72% larger mean area under the plasma atorvastatin concentration-time curve from time 0 to infinity (AUC(0-infinity)) than individuals with the c.421CC genotype had (n = 16; P = 0.049). In participants with the c.421AA genotype, the rosuvastatin AUC(0-infinity) was 100% greater than in those with c.421CA (n = 12) and 144% greater than in those with the c.421CC genotype. Also, those with the c.421AA genotype showed peak plasma rosuvastatin concentrations 108% higher than those in the c.421CA genotype group and 131% higher than those in the c.421CC genotype group (P < or = 0.01). In MDCKII-ABCG2 cells, atorvastatin transport was increased in the apical direction as compared with vector control cells (transport ratio 1.9 +/- 0.1 vs. 1.1 +/- 0.1). These results indicate that the ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and, even more so, of rosuvastatin-potentially affecting the efficacy and toxicity of statin therapy.","variants":[{"Name":"NM_004827.3(ABCG2):c.421C>A (p.Gln141Lys)","Chromosome":"4","Start":"88131171","Stop":"88131171","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39346,"rule_based_match":true,"evidence_text":"ABCG2 c.421C>A","llm_judgment":"PRESENT","evidence":"ABCG2 c.421C>A","abstract_start":4,"abstract_end":18}]}
{"pmid":"23850684","title":"A diagnostic gene chip for hereditary spastic paraplegias.","abstract":"Hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous monogenic neurodegenerative disorders. The gene screen of hereditary spastic paraplegias patients remains time consuming and costly because of their highly heterogeneous. As we know, there are some hot spots of mutation in many genes causing HSPs. Our aim was to develop a quick method for gene screen of HSP patients. The online mutation data banks of HSPs were searched and Chinese data for point mutations were mainly considered. Then mutations were comprehensively analyzed and ninety-six more common point mutations of HSPs disease genes were chose for the 96-plex GoldenGate assay diagnostic gene chip for HSPs. After that, we used this diagnostic gene chip to detect ninety-six clinically diagnosed HSP patients. For validation purpose, six previously Sanger sequenced cases with known point mutations were redetected on this array. The scores of all the ninety-six point mutations were between 0.601 and 0.993, and the call rate of the whole gene chip was 97.7% and its consistency was 99.0%. A patient suspected with a c.316G>C substitution in SPG6 was detected by the chip, which was further confirmed by polymerase chain reaction and sequencing. The high successful performance of this GoldenGate assay makes it a useful technique for preliminary genetic screening for HSP patients and it may be used in clinic in the future.","variants":[{"Name":"NM_144599.5(NIPA1):c.316G>C (p.Gly106Arg)","Chromosome":"15","Start":"22812252","Stop":"22812252","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":17560,"rule_based_match":true,"evidence_text":"c.316G>C","llm_judgment":"PRESENT","evidence":"c.316G>C","abstract_start":1122,"abstract_end":1130}]}
{"pmid":"24014202","title":"Mutations in the EPHA2 gene are a major contributor to inherited cataracts in South-Eastern Australia.","abstract":"Congenital cataract is the most common cause of treatable visual impairment in children worldwide. Mutations in many different genes lead to congenital cataract. Recently, mutations in the receptor tyrosine kinase gene, EPHA2, have been found to cause congenital cataract in six different families. Although these findings have established EPHA2 as a causative gene, the total contribution of mutations in this gene to congenital cataract is unknown. In this study, for the first time, a population-based approach was used to investigate the frequency of disease causing mutations in the EPHA2 gene in inherited cataract cases in South-Eastern Australia. A cohort of 84 familial congenital or juvenile cataract index cases was screened for mutations in the EPHA2 gene by direct sequencing. Novel changes were assessed for segregation with the disease within the family and in unrelated controls. Microsatellite marker analysis was performed to establish any relationship between families carrying the same mutation. We report a novel congenital cataract causing mutation c.1751C>T in the EPHA2 gene and the previously reported splice mutation c.2826-9G>A in two new families. Additionally, we report a rare variant rs139787163 potentially associated with increased susceptibility to cataract. Thus mutations in EPHA2 account for 4.7% of inherited cataract cases in South-Eastern Australia. Interestingly, the identified rare variant provides a link between congenital and age-related cataract.","variants":[{"Name":"NM_004431.5(EPHA2):c.2826-9G>A","Chromosome":"1","Start":"16125329","Stop":"16125329","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":263955,"rule_based_match":true,"evidence_text":"c.2826-9G>A","llm_judgment":"PRESENT","evidence":"c.2826-9G>A","abstract_start":1143,"abstract_end":1154}]}
{"pmid":"19632868","title":"A rare G6PD variant (c.383T>G; p.128Leu>Arg) with a molecular pathophysiological mechanism similar to that of G6PD A- (68Val>Met, 126Asn>Asp).","abstract":"We report the second documented observation of a rare class-III variant, we named G6PD Pyrgos, [c.383 T>G, p.128Leu>Arg] found in a Greek family. A 3-dimensional structure model for the enzyme shows that the region modified by the substitution is identical to that modified in G6PD A(-) (68Val>Met, 126Asn>Asp), suggesting a common underlying pathophysiological mechanism. Observation of this mutation in different Mediterranean regions suggests that it might be more widespread that initially supposed and, in the absence of molecular characterization, could be confused with other frequent variants.","variants":[{"Name":"NM_001360016.2(G6PD):c.383T>G (p.Leu128Arg)","Chromosome":"X","Start":"154535270","Stop":"154535270","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":959209,"rule_based_match":true,"evidence_text":"c.383T>G","llm_judgment":"PRESENT","evidence":"c.383T>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"22371648","title":"A case of Cowden syndrome diagnosed from multiple gastric polyposis.","abstract":"Cowden syndrome is a rare autosomal dominant disorder that is characterized by multiple hamartomas in a variety of tissues and this is associated with germline mutations in the phosphatase and tensin homologue (PTEN) gene, which is the tumor suppressor gene located on chromosome 10q23.3. It is characterized by multiple hamartomatous neoplasms of the skin, oral mucosa, gastrointestinal (GI) tract, bones, central nervous system, eyes, and genitourinary tract. Cowden syndrome does not have increased risk of GI malignancy; however, it has an increased risk of breast, thyroid and endometrial cancer development. Here the authors report a rare case of Cowden syndrome incidentally diagnosed from multiple gastric polyposis. A 29-year-old woman presented with multiple gastric polyps. The laboratory results were normal except for mild anemia, with a hemoglobin level of 11.9 g/dL. Esophagogastroduodenoscopy revealed multiple gastric, duodenal polyps and esophageal acanthosis. Colonoscopy revealed possible hamartomatous polyps in the rectum. Under the suspicion of Cowden syndrome, sonography of the thyroid and breasts was carried out, which revealed multiple thyroid masses. Subsequent fine-needle aspiration biopsy revealed the presence of clusters of follicular epithelial cells, and due to the possibility of malignancy, the patient underwent total thyroidectomy. The pathology was reported as invasive follicular carcinoma. A gene study by direct sequencing showed the presence of a PTEN mutation (c.633C > A /p.Cys211*).","variants":[{"Name":"NM_000314.8(PTEN):c.633C>A (p.Cys211Ter)","Chromosome":"10","Start":"87952258","Stop":"87952258","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":22875,"rule_based_match":true,"evidence_text":"c.633C > A /p.Cys211*","llm_judgment":"PRESENT","evidence":"c.633C > A /p.Cys211*","abstract_start":1507,"abstract_end":1528}]}
{"pmid":"26117665","title":"The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes.","abstract":"INTRODUCTION: Recent advances in molecular genetics have increased the identification of genes and mutations responsible for inherited forms of hearing loss (HL), enabling early detection of these cases. Approximately, 60% of early-onset HL cases are due to genetic causes, of which 70% are non-syndromic. Of these, 75-80% are inherited in an autosomal recessive pattern (DFNB). Mutations in GJB2 gene, coding for connexin 26 (Cx26), are the major cause of autosomal recessive hereditary HL, but some GJB2 mutations are yet of unclear or controversial significance.\nOBJECTIVES: The aim of the present study was to identify the etiology of hearing loss, and correlate genotype-phenotype, in two Portuguese siblings with profound and moderate non-syndromic sensorineural bilateral HL.\nMATERIAL AND METHODS: The affected subjects and their parents underwent audiological and genetic study. Molecular analysis of GJB2 gene was performed, searching for mutations in the coding region and receptor splicing site by automated sequencing.\nRESULTS: The onset and the degree of HL were different in the two affected subjects. However, the same GJB2 genotype [p.Met34Thr]+[p.Arg184Pro] was identified in both siblings. The c.551G>C (p.Arg184Pro) and c.101T>C (p.Met34Thr) missense variants were inherited from the father and mother, respectively, both heterozygous carriers of these variants.\nCONCLUSION: The clinical and genetic data here presented suggest that the non-syndromic sensorineural HL of these two Portuguese siblings might be due to the presence of p.Met34Thr and p.Arg184Pro variants in compound heterozygosity. If so, p.Met34Thr variant could have function as a hypomorphic allele that may cause HL depending on the opposing GJB2 allele. The observed phenotypic variability may not, however, be solely explained by variable expression of this genotype. A putative modifier gene or mutations in another HL-associated gene could probably be contributing to the severe HL in one of the siblings.","variants":[{"Name":"NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)","Chromosome":"13","Start":"20189031","Stop":"20189031","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":32046,"rule_based_match":true,"evidence_text":"c.551G>C (p.Arg184Pro)","llm_judgment":"PRESENT","evidence":"c.551G>C (p.Arg184Pro)","abstract_start":1212,"abstract_end":1234},{"Name":"NM_004004.6(GJB2):c.101T>C (p.Met34Thr)","Chromosome":"13","Start":"20189481","Stop":"20189481","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":32039,"rule_based_match":true,"evidence_text":"c.101T>C (p.Met34Thr)","llm_judgment":"PRESENT","evidence":"c.101T>C (p.Met34Thr)","abstract_start":1239,"abstract_end":1260}]}
{"pmid":"23664119","title":"Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance.","abstract":"The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by deleterious SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogeneous and largely remain to be elucidated. In a Bulgarian family affected by autosomal-dominant proximal SMA, we performed genome-wide linkage analysis and whole-exome sequencing and found a heterozygous de novo c.320C>T (p.Ser107Leu) mutation in bicaudal D homolog 2 (Drosophila) (BICD2). Further analysis of BICD2 in a cohort of 119 individuals with non-5q SMA identified a second de novo BICD2 mutation, c.2321A>G (p.Glu774Gly), in a simplex case. Detailed clinical and electrophysiological investigations revealed that both families are affected by a very similar disease course, characterized by early childhood onset, predominant involvement of lower extremities, and very slow disease progression. The amino acid substitutions are located in two interaction domains of BICD2, an adaptor protein linking the dynein molecular motor with its cargo. Our immunoprecipitation and localization experiments in HeLa and SH-SY5Y cells and affected individuals' lymphoblasts demonstrated that p.Ser107Leu causes increased dynein binding and thus leads to accumulation of BICD2 at the microtubule-organizing complex and Golgi fragmentation. In addition, the altered protein had a reduced colocalization with RAB6A, a regulator of vesicle trafficking between the Golgi and the endoplasmic reticulum. The interaction between p.Glu744Gly altered BICD2 and RAB6A was impaired, which also led to their reduced colocalization. Our study identifies BICD2 mutations as a cause of non-5q linked SMA and highlights the importance of dynein-mediated motility in motor neuron function in humans.","variants":[{"Name":"NM_001003800.2(BICD2):c.2321A>G (p.Glu774Gly)","Chromosome":"9","Start":"92715401","Stop":"92715401","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":70514,"rule_based_match":true,"evidence_text":"c.2321A>G (p.Glu774Gly)","llm_judgment":"PRESENT","evidence":"c.2321A>G (p.Glu774Gly)","abstract_start":593,"abstract_end":616},{"Name":"NM_001003800.2(BICD2):c.320C>T (p.Ser107Leu)","Chromosome":"9","Start":"92729157","Stop":"92729157","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70511,"rule_based_match":true,"evidence_text":"c.320C>T (p.Ser107Leu)","llm_judgment":"PRESENT","evidence":"c.320C>T (p.Ser107Leu)","abstract_start":398,"abstract_end":420}]}
{"pmid":"20358619","title":"Germline TGF-beta receptor mutations and skeletal fragility: a report on two patients with Loeys-Dietz syndrome.","abstract":"Loeys-Dietz syndrome (LDS, OMIM # 609192) caused by heterozygous mutations in TGFBR1 and TGFBR2 has recently been described as an important cause of familial aortic aneurysms. These patients have craniofacial and skeletal features that overlap with the Marfan syndrome (MFS), and more importantly, have significant vascular fragility as is seen in MFS and Ehlers-Danlos syndrome Type IV (EDS-IV). The skeletal phenotype with respect to low bone mineral density and skeletal fragility is not clear. We present two patients with LDS with significant skeletal fragility. The first is a 17-year-old male who had talipes equinovarus, diaphragmatic and inguinal and herniae, aortic root dilatation necessitating surgical repair, craniofacial and skeletal dysmorphism consistent with LDS, and a history of numerous fragility fractures leading to significant skeletal deformity. He was found to be heterozygous for a c.923T > C transition in exon 4 of TGFBR2. The second is a 26-year-old male with submucous cleft palate, talipes equinovarus, pectus excavatum requiring surgery, inguinal hernia, and aneurysms in the ascending aorta, abdominal aorta, carotid, subclavian, vertebral and brachial arteries requiring surgical repairs. He also had craniofacial and skeletal dysmorphism consistent with LDS, multiple fractures in childhood, low bone mineral density, and was found to be heterozygous for a c.1561 T > C transition in exon 7 of TGFBR2. These case studies highlight the importance of paying close attention to fractures and bone density in patients with LDS. Osteopenia or osteoporosis may become increasingly important issues as earlier detection and treatment of the vascular complications of LDS improves life expectancy in these patients.","variants":[{"Name":"NM_003242.6(TGFBR2):c.923T>C (p.Leu308Pro)","Chromosome":"3","Start":"30672106","Stop":"30672106","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":27544,"rule_based_match":true,"evidence_text":"c.923T > C","llm_judgment":"PRESENT","evidence":"c.923T > C","abstract_start":909,"abstract_end":919},{"Name":"NM_003242.6(TGFBR2):c.1561T>C (p.Trp521Arg)","Chromosome":"3","Start":"30691456","Stop":"30691456","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":799321,"rule_based_match":true,"evidence_text":"c.1561 T > C","llm_judgment":"PRESENT","evidence":"c.1561 T > C","abstract_start":1393,"abstract_end":1405}]}
{"pmid":"22570643","title":"Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies.","abstract":"Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the LMNA gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in LMNA and ZMPSTE24, respectively. ZMPSTE24 in addition to ICMT encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with LMNA mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes LMNA, ZMPSTE24 and ICMT in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C>T (p.R644C) in LMNA in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In ZMPSTE24 and ICMT, no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy.","variants":[{"Name":"NM_170707.4(LMNA):c.1930C>T (p.Arg644Cys)","Chromosome":"1","Start":"156138719","Stop":"156138719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29566,"rule_based_match":true,"evidence_text":"c.1930C>T (p.R644C)","llm_judgment":"PRESENT","evidence":"c.1930C>T (p.R644C)","abstract_start":1396,"abstract_end":1415}]}
{"pmid":"19515746","title":"RUNX2 mutations in Chinese patients with cleidocranial dysplasia.","abstract":"Cleidocranial dysplasia (CCD) is an autosomal dominant bone disease in humans caused by haploinsufficiency of the RUNX2 gene. The RUNX2 has two major isoforms derived from P1 and P2 promoters. Over 90 mutations of RUNX2 have been reported associated with CCD. In our study, DNA samples of nine individuals from three unrelated CCD families were collected and screened for all exons of RUNX2 and 2 kb of P1 and P2 promoters. We identified two point mutations in the RUNX2 gene in Case 1, including a nonsense mutation (c.577C>T) that has been reported previously and a silent substitution (c.240G>A). In vitro studies demonstrated that c.577C>T mutation led to truncated RUNX2 protein production and diminished stimulating effects on mouse osteocalcin promoter activity when compared with full-length Runx2-II and Runx2-I isoforms. These results confirm that loss of function RUNX2 mutation (c.577C>T) in Case 1 family is responsible for its CCD phenotype.","variants":[{"Name":"NM_001024630.4(RUNX2):c.577C>T (p.Arg193Ter)","Chromosome":"6","Start":"45432016","Stop":"45432016","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":818248,"rule_based_match":true,"evidence_text":"c.577C>T","llm_judgment":"PRESENT","evidence":"c.577C>T","abstract_start":518,"abstract_end":526}]}
{"pmid":"33976695","title":"Next-Generation Sequencing Identifies Pathogenic Variants in","abstract":"Background: Approximately 70% of congenital deafness is attributable to genetic causes. Incidence of congenital deafness is known to be higher in families with consanguineous marriage. In this study, we investigated the genetic causes in three consanguineous Pakistani families segregating with prelingual, severe-to-profound deafness.\nResults: Through targeted next-generation sequencing of 414 genes known to be associated with deafness, homozygous variants c.536del (p. Leu180Serfs∗20) in <i>TECTA</i>, c.3719 G>A (p. Arg1240Gln) in <i>MYO7A</i>, and c.482+1986_1988del in <i>HGF</i> were identified as the pathogenic causes of enrolled families. Interestingly, in one large consanguineous family, an additional c.706G>A (p. Glu236Lys) variant in the X-linked <i>POU3F4</i> gene was also identified in multiple affected family members causing deafness. Genotype-phenotype cosegregation was confirmed in all participating family members by Sanger sequencing.\nConclusions: Our results showed that the genetic causes of deafness are highly heterogeneous. Even within a single family, the affected members with apparently indistinguishable clinical phenotypes may have different pathogenic variants.","variants":[{"Name":"NM_000260.4(MYO7A):c.3719G>A (p.Arg1240Gln)","Chromosome":"11","Start":"77190108","Stop":"77190108","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":52388,"rule_based_match":true,"evidence_text":"c.3719 G>A (p. Arg1240Gln)","llm_judgment":"PRESENT","evidence":"c.3719 G>A (p. Arg1240Gln)","abstract_start":506,"abstract_end":532}]}
{"pmid":"28941186","title":"Three novel mutations in CYBA among 22 Iranians with Chronic granulomatous disease.","abstract":"Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defect in one of the components of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme. The enzyme is at least composed of membrane-bound subunits gp91-phox and p22-phox (also named cytochrome b<sub>558</sub> ), and cytosolic ones p40-phox, p47-phox and p67-phox. A defect in the enzyme activity leads to impaired intracellular killing of phagocytic cells. The CYBA gene encoding p22-phox is located on chromosome 16q24. In this study, new genetic changes of CYBA gene in 22 Iranian patients with autosomal recessive-CGD (AR-CGD) were identified. Twenty-two patients with CGD were referred to Immunology, Asthma and Allergy Research Institute (IAARI) and enrolled in this study based on defect in NADPH oxidase activity, demographic data and clinical histories. All patients had p22-phox deficiency based on Western blotting. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs), and PCR followed by direct sequencing was performed to find p22-phox mutations. Mutation analysis of CYBA revealed 12 different mutations, including three novel mutations: one was deletion of exon 1, and two were point mutations in exon 3 (c.136G>A (p.Gly46Ser)), and exon 6 (c.388C>T (p.Gln130X)). Three new mutations of CYBA gene in four of 22 Iranian patients with AR-CGD were found. These three novel mutations can partly complete the database of Human Gene Mutation Database (HGMD) and other related ones. It can also be helpful for further prenatal diagnosis in the affected families. Given that currently bone marrow transplantation is considered to be the curative treatment for patients with CGD, finding mutations will also be useful for timely decision-making in bone marrow transplantation.","variants":[{"Name":"NM_000101.4(CYBA):c.136G>A (p.Gly46Ser)","Chromosome":"16","Start":"88647168","Stop":"88647168","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1871466,"rule_based_match":true,"evidence_text":"c.136G>A (p.Gly46Ser)","llm_judgment":"PRESENT","evidence":"c.136G>A (p.Gly46Ser)","abstract_start":1237,"abstract_end":1258}]}
{"pmid":"26238251","title":"Transaldolase Deficiency: A New Case Expands the Phenotypic Spectrum.","abstract":"Transaldolase (TALDO) deficiency has various clinical manifestations including liver dysfunction, hepatosplenomegaly, anemia, thrombocytopenia, and dysmorphic features. We report a case presenting prenatally with hyperechogenic bowel and intrauterine growth restriction. The infant was born small for gestational age, with cutis laxa and hypertrichosis. Postnatally, meconium plug was identified, complicated with intestinal obstruction necessitating laparotomy, partial resection of the intestine, and ileostomy. Liver biopsy revealed cholangiolar proliferation and portal fibrosis. He also suffered from persistent congenital thrombocytopenia requiring platelet transfusions and severe hypothyroidism with normal anatomical and structural gland responding only to the combination of T3 and T4 treatment. Neurologically, severe hypotonia and anisocoria were noted at the age of 2 months. Brain MRI was normal. Shortly after the abdominal surgery, a rapid liver failure ensued, which eventually led to his death. Specific metabolic tests ruled out glycosylation disorders, yet urine analysis using 1H NMR showed accumulation of sedoheptulose which was previously described in patients with transaldolase deficiency. Sequencing of the gene-encoding transaldolase (TALDO1) revealed a homozygous stop mutation c.669C>G; p.Tyr223*. In conclusion, we present an infant with a novel homozygous mutation in TALDO1, causing TALDO deficiency, and extend the clinical characteristics of this rare syndrome.","variants":[{"Name":"NM_006755.2(TALDO1):c.669C>G (p.Tyr223Ter)","Chromosome":"11","Start":"763778","Stop":"763778","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":963068,"rule_based_match":true,"evidence_text":"c.669C>G; p.Tyr223*","llm_judgment":"PRESENT","evidence":"c.669C>G; p.Tyr223*","abstract_start":1307,"abstract_end":1326}]}
{"pmid":"21472225","title":"Novel ETHE1 mutation in a carrier couple having prior offspring affected with ethylmalonic encephalopathy: Genetic analysis, clinical management and reproductive outcome.","abstract":"Ethylmalonic encephalopathy (EE) is an autosomally recessive inherited disorder with a relentlessly progressive decline in neurological function, usually fatal by the age of ten. It is characterised by generalised hypotonia, psychomotor regression, spastic tetraparesis, dystonia, seizures and, eventually, global neurological failure. Approximately 50 reports have been published worldwide describing this devastating disease, most involving patients of Mediterranean or Arab origin. The fundamental defect in EE likely involves the impairment of a mitochondrial sulphur dioxygenase coded by the ETHE1 gene responsible for the catabolism of sulphide, which subsequently accumulates to toxic levels. A diagnosis of EE should initiate careful genetic evaluation and counselling, particularly if the parents intend to have additional offspring. The present report describes the diagnosis of EE in a reproductive endocrinology context, where both members of a non-consanguineous couple were confirmed to be carriers of an identical A↷G mutation. This previously unknown mutation at nucleotide position c.494 resulted in an amino acid substitution, p.Asp165Gly. Although consideration was given to in vitro fertilisation, embryo biopsy and single gene pre-implantation genetic diagnosis, the couple decided to first utilise a less aggressive therapeutic approach with donor sperm insemination. Pregnancy with a low risk of EE was indeed achieved; however, the infant was affected with a different anomaly (hypoplastic left heart). As this case demonstrates, prior to the initiation of fertility therapy, genetic analysis may be used to provide a confirmatory diagnosis when EE is suspected.","variants":[{"Name":"NM_014297.5(ETHE1):c.494A>G (p.Asp165Gly)","Chromosome":"19","Start":"43511448","Stop":"43511448","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":430239,"rule_based_match":false,"evidence_text":"c.494A>G (p.Asp165Gly)","llm_judgment":"PRESENT","evidence":"p.Asp165Gly","abstract_start":1145,"abstract_end":1156}]}
{"pmid":"28664756","title":"Late onset bipolar disorder and frontotemporal dementia with mutation in progranulin gene: a case report.","abstract":"Bipolar disorder is a chronic psychiatric illness characterised by fluctuation in mood state, with a relapsing and remitting course. Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous syndrome, with the most frequent phenotype being behavioural variant frontotemporal dementia (bvFTD). Here, we report the case of an Italian male presenting with late-onset bipolar disorder that developed into bvFTD over time, carrying a mutation in the GRN gene. Interestingly, the patient carried the c.1639 C > T variant in the GRN gene, resulting in a R547C substitution. Our case report further corroborates the notion that, in addition to FTD, progranulin may be involved in the neurobiology of bipolar disorder type 1, and suggests to screen patients with late-onset bipolar disorder for GRN mutations.","variants":[{"Name":"NM_002087.4(GRN):c.1639C>T (p.Arg547Cys)","Chromosome":"17","Start":"44352566","Stop":"44352566","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1868211,"rule_based_match":true,"evidence_text":"c.1639 C > T","llm_judgment":"PRESENT","evidence":"c.1639 C > T","abstract_start":512,"abstract_end":524}]}
{"pmid":"32942919","title":"Investigating the role of BEST1 and PRPH2 variants in the molecular aetiology of adult-onset vitelliform macular dystrophies.","abstract":"<b>Objective</b>: To determine the clinical relevance and frequency of BEST1 and PRPH2 mutations in a clinically diagnosed adult-onset vitelliform macular dystrophy (AVMD) group with Caucasian ethnicity. <b>Methods</b>: The study comprised 24 patients who had been diagnosed with AVMD via indirect fundus ophthalmoscopy and presented with a dome-shaped appearance between the retinal pigment epithelium and photoreceptors on their spectral-domain optical coherence tomography. They had lesion hyper- autofluorescence on their fundus autofluorescence images and were also investigated for BEST1 and PRPH2 mutations for a probable molecular aetiology. <b>Results</b>: No pathogenic or likely pathogenic mutation was detected in the BEST1 and PRPH2 genes of any of the clinically diagnosed AVDM patients. A heterozygous NM_000322.5:c.938C>T (p.Pro313Leu) variant of the PRPH2 gene was detected in 2 non-consanguineous patients. According to current guidelines, this variant was classified as a 'variant of uncertain significance'. <b>Conclusion</b>: In conclusion, AVMD is a genotypic and phenotypic heterogeneous disease. The genetic aetiology could not be explained by sequencing BEST1 and PRPH2 genes in the AVMD patients; however, the variant of PRPH2 could be a cause of predisposition relevant to the phenotype.","variants":[{"Name":"NM_000322.5(PRPH2):c.938C>T (p.Pro313Leu)","Chromosome":"6","Start":"42698398","Stop":"42698398","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":104611,"rule_based_match":true,"evidence_text":"NM_000322.5:c.938C>T (p.Pro313Leu)","llm_judgment":"PRESENT","evidence":"NM_000322.5:c.938C>T (p.Pro313Leu)","abstract_start":817,"abstract_end":851}]}
{"pmid":"37743782","title":"De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities.","abstract":"The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.","variants":[{"Name":"NM_145166.4(ZBTB47):c.2039A>G (p.Glu680Gly)","Chromosome":"3","Start":"42664393","Stop":"42664393","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2403696,"rule_based_match":true,"evidence_text":"c.2039A>G","llm_judgment":"PRESENT","evidence":"c.2039A>G","abstract_start":719,"abstract_end":728}]}
{"pmid":"24281370","title":"Genealogical analysis as a new approach for the investigation of drug intolerance heritability.","abstract":"Genealogical analysis has proven a useful method to understand the origins and frequencies of hereditary diseases in many populations. However, this type of analysis has not yet been used for the investigation of drug intolerance among patients suffering from inherited disorders. This study aims to do so, using data from familial hypercholesterolemia (FH) patients receiving high doses of statins. The objective is to measure and compare various genealogical parameters that could shed light on the origins and heritability of muscular intolerance to statins using FH as a model. Analysis was performed on 224 genealogies from 112 FH subjects carrying either the low-density lipoprotein receptor (LDLR) prom_e1 deletion>15 kb (n=28) or c.259T>G (p.Trp87Gly) (n=84) mutations and 112 non-FH controls. Number of ancestors, geographical origins and genetic contribution of founders, inbreeding and kinship coefficients were calculated using the S-Plus-based GENLIB software package. For both mutations, repeated occurrences of the same ancestors are more frequent among the carriers' genealogies than among the controls', but no difference was observed between tolerant and intolerant subjects. Founders who may have introduced both mutations in the population appear with approximately the same frequencies in all genealogies. Kinship coefficients are higher among carriers, with no difference according to statins tolerance. Inbreeding coefficients are slightly lower among >15-kb deletion carriers than among c.259 T>G carriers, but the differences between tolerants and intolerants are not significant. These findings suggest that although muscular intolerance to statins shows a family aggregation, it is not transmitted through the same Mendelian pattern as LDLR mutations.","variants":[{"Name":"NM_000527.5(LDLR):c.259T>G (p.Trp87Gly)","Chromosome":"19","Start":"11102732","Stop":"11102732","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18724,"rule_based_match":true,"evidence_text":"c.259T>G (p.Trp87Gly)","llm_judgment":"PRESENT","evidence":"c.259T>G (p.Trp87Gly)","abstract_start":738,"abstract_end":759}]}
{"pmid":"22573628","title":"Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy.","abstract":"OBJECTIVE: To identify a new genetic cause of distal hereditary motor neuropathy (dHMN), which is also known as a variant of Charcot-Marie-Tooth disease (CMT), in a Chinese family.\nMETHODS: We investigated a Chinese family with dHMN clinically, electrophysiologically, and genetically. We screened for the mutations of 28 CMT or related pathogenic genes using an originally designed microarray resequencing DNA chip.\nRESULTS: Investigation of the family history revealed an autosomal dominant transmission pattern. The clinical features of the family included mild weakness and wasting of the distal muscles of the lower limb and foot deformity, without clinical sensory involvement. Electrophysiologic studies revealed motor neuropathy. MRI of the lower limbs showed accentuated fatty infiltration of the gastrocnemius and vastus lateralis muscles. All 4 affected family members had a heterozygous missense mutation c.2677G>A (p.D893N) of alanyl-tRNA synthetase (AARS), which was not found in the 4 unaffected members and control subjects.\nCONCLUSION: An AARS mutation caused dHMN in a Chinese family. AARS mutations result in not only a CMT phenotype but also a dHMN phenotype.","variants":[{"Name":"NM_001605.3(AARS1):c.2677G>A (p.Asp893Asn)","Chromosome":"16","Start":"70253312","Stop":"70253312","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":188761,"rule_based_match":true,"evidence_text":"c.2677G>A (p.D893N)","llm_judgment":"PRESENT","evidence":"c.2677G>A (p.D893N)","abstract_start":917,"abstract_end":936}]}
{"pmid":"24516540","title":"Characterization of an Italian founder mutation in the RING-finger domain of BRCA1.","abstract":"The identification of founder mutations in cancer predisposing genes is important to improve risk assessment in geographically defined populations, since it may provide specific targets resulting in cost-effective genetic testing. Here, we report the characterization of the BRCA1 c.190T>C (p.Cys64Arg) mutation, mapped to the RING-finger domain coding region, that we detected in 43 hereditary breast/ovarian cancer (HBOC) families, for the large part originating from the province of Bergamo (Northern Italy). Haplotype analysis was performed in 21 families, and led to the identification of a shared haplotype extending over three BRCA1-associated marker loci (0.4 cM). Using the DMLE+2.2 software program and regional population demographic data, we were able to estimate the age of the mutation to vary between 3,100 and 3,350 years old. Functional characterization of the mutation was carried out at both transcript and protein level. Reverse transcriptase-PCR analysis on lymphoblastoid cells revealed expression of full length mRNA from the mutant allele. A green fluorescent protein (GFP)-fragment reassembly assay showed that the p.Cys64Arg substitution prevents the binding of the BRCA1 protein to the interacting protein BARD1, in a similar way as proven deleterious mutations in the RING-domain. Overall, 55 of 83 (66%) female mutation carriers had a diagnosis of breast and/or ovarian cancer. Our observations indicate that the BRCA1 c.190T>C is a pathogenic founder mutation present in the Italian population. Further analyses will evaluate whether screening for this mutation can be suggested as an effective strategy for the rapid identification of at-risk individuals in the Bergamo area.","variants":[{"Name":"NM_007294.4(BRCA1):c.190T>C (p.Cys64Arg)","Chromosome":"17","Start":"43106478","Stop":"43106478","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":69061,"rule_based_match":true,"evidence_text":"BRCA1 c.190T>C (p.Cys64Arg)","llm_judgment":"PRESENT","evidence":"BRCA1 c.190T>C (p.Cys64Arg)","abstract_start":275,"abstract_end":302}]}
{"pmid":"26220941","title":"A new knock-in mouse model of l-DOPA-responsive dystonia.","abstract":"Abnormal dopamine neurotransmission is associated with many different genetic and acquired dystonic disorders. For instance, mutations in genes critical for the synthesis of dopamine, including GCH1 and TH cause l-DOPA-responsive dystonia. Despite evidence that implicates abnormal dopamine neurotransmission in dystonia, the precise nature of the pre- and postsynaptic defects that result in dystonia are not known. To better understand these defects, we generated a knock-in mouse model of l-DOPA-responsive dystonia (DRD) mice that recapitulates the human p.381Q>K TH mutation (c.1141C>A). Mice homozygous for this mutation displayed the core features of the human disorder, including reduced TH activity, dystonia that worsened throughout the course of the active phase, and improvement in the dystonia in response to both l-DOPA and trihexyphenidyl. Although the gross anatomy of the nigrostriatal dopaminergic neurons was normal in DRD mice, the microstructure of striatal synapses was affected whereby the ratio of axo-spinous to axo-dendritic corticostriatal synaptic contacts was reduced. Microinjection of l-DOPA directly into the striatum ameliorated the dystonic movements but cerebellar microinjections of l-DOPA had no effect. Surprisingly, the striatal dopamine concentration was reduced to ∼1% of normal, a concentration more typically associated with akinesia, suggesting that (mal)adaptive postsynaptic responses may also play a role in the development of dystonia. Administration of D1- or D2-like dopamine receptor agonists to enhance dopamine signalling reduced the dystonic movements, whereas administration of D1- or D2-like dopamine receptor antagonists to further reduce dopamine signalling worsened the dystonia, suggesting that both receptors mediate the abnormal movements. Further, D1-dopamine receptors were supersensitive; adenylate cyclase activity, locomotor activity and stereotypy were exaggerated in DRD mice in response to the D1-dopamine receptor agonist SKF 81297. D2-dopamine receptors exhibited a change in the valence in DRD mice with an increase in adenylate cyclase activity and blunted behavioural responses after challenge with the D2-dopamine receptor agonist quinpirole. Together, our findings suggest that the development of dystonia may depend on a reduction in dopamine in combination with specific abnormal receptor responses.","variants":[{"Name":"NM_000360.4(TH):c.1141C>A (p.Gln381Lys)","Chromosome":"11","Start":"2165727","Stop":"2165727","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":27363,"rule_based_match":true,"evidence_text":"c.1141C>A","llm_judgment":"PRESENT","evidence":"c.1141C>A","abstract_start":581,"abstract_end":590}]}
{"pmid":"17601449","title":"Atypical mild enhanced S-cone syndrome with novel compound heterozygosity of the NR2E3 gene.","abstract":"PURPOSE: To report mild enhanced s-cone syndrome (ESCS) associated with a novel heterozygous mutation of the NR2E3 gene.\nDESIGN: Observational case report.\nMETHODS: Clinical examination, optical coherence tomography (OCT), electroretinography (ERG), genetic analysis, and protein homology modeling.\nRESULTS: Examination of a 9-year-old girl with acute visual loss of the left eye showed visual acuity of 20/30 in the right eye and 20/200 in the left eye; OCT revealed a choroidal neovascular membrane (CNVM) in the left fovea and cystic maculopathy in the right eye. Full-field ERG showed supranormal s-cone responses, reduced rod response, and characteristic ESCS waveform in photopic cone response but not in scotopic bright-flash response. Sequence analysis revealed heterozygous mutations in the NR2E3 gene, c.767C-->T yielding a substitution p.Ala256Val, and a mutation in the splice site before exon 2, c.119-2 A-->C.\nCONCLUSIONS: The p.Ala256Val mutation affects the ligand binding domain of the NR2E3 nuclear receptor only, resulting in modestly impaired ESCS ERG results.","variants":[{"Name":"NM_014249.4(NR2E3):c.767C>T (p.Ala256Val)","Chromosome":"15","Start":"71813408","Stop":"71813408","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":842650,"rule_based_match":false,"evidence_text":"c.767C-->T yielding a substitution p.Ala256Val","llm_judgment":"PRESENT","evidence":"c.767C-->T yielding a substitution p.Ala256Val","abstract_start":812,"abstract_end":858}]}
{"pmid":"36329109","title":"Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service.","abstract":"Several studies have demonstrated the cost-effectiveness of genetic testing for surveillance and treatment of carriers of germline pathogenic variants associated with hereditary breast/ovarian cancer syndrome (HBOC). In Brazil, seventy percent of the population is assisted by the public Unified Health System (SUS), where genetic testing is still unavailable. And few studies were performed regarding the prevalence of HBOC pathogenic variants in this context. Here, we estimated the prevalence of germline pathogenic variants in BRCA1, BRCA2 and TP53 genes in Brazilian patients suspected of HBOC and referred to public healthcare service. Predictive power of risk prediction models for detecting mutation carriers was also evaluated. We found that 41 out of 257 tested patients (15.9%) were carriers of pathogenic variants in the analyzed genes. Most frequent pathogenic variant was the founder Brazilian mutation TP53 c.1010G > A (p.Arg337His), adding to the accumulated evidence that supports inclusion of TP53 in routine testing of Brazilian HBOC patients. Surprisingly, BRCA1 c.5266dupC (p.Gln1756fs), a frequently reported pathogenic variant in Brazilian HBOC patients, was not observed. Regarding the use of predictive models, we found that familial history of cancer might be used to improve selection or prioritization of patients for genetic testing, especially in a context of limited resources.","variants":[{"Name":"NM_000546.6(TP53):c.1010G>A (p.Arg337His)","Chromosome":"17","Start":"7670699","Stop":"7670699","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27418,"rule_based_match":true,"evidence_text":"TP53 c.1010G > A (p.Arg337His)","llm_judgment":"PRESENT","evidence":"TP53 c.1010G > A (p.Arg337His)","abstract_start":917,"abstract_end":947}]}
{"pmid":"18818946","title":"A novel non-sense mutation in the SLC2A10 gene of an arterial tortuosity syndrome patient of Kurdish origin.","abstract":"Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder in which patients display tortuosity of arteries in addition to hyperextensible skin, joint laxity, and other connective tissue features. This syndrome is caused by mutations in the SLC2A10 gene. In this article we describe an ATS girl of Kurdish origin who, in addition to arterial tortuosity and connective tissue features, displays stomach displacement within the thorax and bilateral hip dislocation. Clinical details of this patient have been reported previously. Sequencing of the SLC2A10 gene identified a novel homozygous non-sense c.756C>A mutation in this patient's DNA. This mutation in the SLC2A10 gene replaces a cysteine encoding codon with a stop signal. This is believed to cause a premature truncation of GLUT10 protein in this patient. We conclude that patients of Kurdish origin who display arterial tortuosity associated with skin hyperextensibility, joint hypermobility, and characteristic facial features may carry mutations in the SLC2A10 gene.","variants":[{"Name":"NM_030777.4(SLC2A10):c.756C>A (p.Cys252Ter)","Chromosome":"20","Start":"46725792","Stop":"46725792","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":170947,"rule_based_match":true,"evidence_text":"c.756C>A","llm_judgment":"PRESENT","evidence":"c.756C>A","abstract_start":614,"abstract_end":622}]}
{"pmid":"34783940","title":"Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus.","abstract":"PURPOSE: NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis.\nMETHODS: Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1β/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal.\nRESULTS: A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1β therapy partially controlled symptoms. While on treatment, serum IL-1β and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1β/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778-3.644), P = 0.01305.\nCONCLUSION: NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.","variants":[{"Name":"NM_001199138.2(NLRC4):c.478G>A (p.Ala160Thr)","Chromosome":"2","Start":"32251386","Stop":"32251386","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":518328,"rule_based_match":true,"evidence_text":"c.478G > A, p.A160T","llm_judgment":"PRESENT","evidence":"c.478G > A, p.A160T","abstract_start":284,"abstract_end":303}]}
{"pmid":"22611636","title":"A mutation of aspartoacylase gene in a Turkish patient with Canavan disease.","abstract":"Canavan disease (CD) is an autosomal recessive inherited disorder characterized by spongy degeneration of the brain. The deficiency of aspartoacylase (ASPA), resulting in the accumulation of N-acetyl aspartic acid (NAA) in the brain, plays an important role in the pathogenesis of the disease. The cardinal features of this neurodegenerative disease are macrocephaly, mental retardation, and hypotonia. Magnetic resonance imaging (MRI) of the brain generally shows diffuse white matter degeneration and also elevated excretion of urinary NAA is usually seen. A large number of mutations were identified to date. We report here a 9 months old girl with Canavan Disease and a homozygous c.79G>A mutation in the ASPA gene, detected for the first time in Turkish population.","variants":[{"Name":"NM_000049.4(ASPA):c.79G>A (p.Gly27Arg)","Chromosome":"17","Start":"3476238","Stop":"3476238","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186962,"rule_based_match":true,"evidence_text":"c.79G>A","llm_judgment":"PRESENT","evidence":"c.79G>A","abstract_start":685,"abstract_end":692}]}
{"pmid":"20455026","title":"Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations.","abstract":"Mutations in the two breast cancer susceptibility genes BRCA1 and BRCA2 are associated with increased risk of breast and ovarian cancer. Patients with mutations in both genes are rarely reported and often involve Ashkenazi founder mutations. Here we report the first identification of a Danish breast and ovarian cancer family heterozygote for mutations in the BRCA1 and BRCA2 genes. The BRCA1 nucleotide 5215G > A/c.5096G > A mutation results in the missense mutation Arg1699Gln, while the BRCA2 nucleotide 859 + 4A > G/c.631 + 4A > G is novel. Exon trapping experiments and reverse transcriptase (RT)-PCR analysis revealed that the BRCA2 mutation results in skipping of exon 7, thereby introducing a frameshift and a premature stop codon. We therefore classify the mutation as disease causing. Since the BRCA1 Arg1699Gln mutation is also suggested to be disease-causing, we consider this family double heterozygote for BRCA1 and BRCA2 mutations.","variants":[{"Name":"NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln)","Chromosome":"17","Start":"43063930","Stop":"43063930","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46192,"rule_based_match":true,"evidence_text":"c.5096G > A","llm_judgment":"PRESENT","evidence":"c.5096G > A","abstract_start":415,"abstract_end":426},{"Name":"NM_000059.4(BRCA2):c.631+4A>G","Chromosome":"13","Start":"32326617","Stop":"32326617","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":66724,"rule_based_match":true,"evidence_text":"BRCA2 nucleotide 859 + 4A > G/c.631 + 4A > G","llm_judgment":"PRESENT","evidence":"BRCA2 nucleotide 859 + 4A > G/c.631 + 4A > G","abstract_start":491,"abstract_end":535}]}
{"pmid":"28806213","title":"MAINTENANCE OF GOOD VISUAL ACUITY IN BEST DISEASE ASSOCIATED WITH CHRONIC BILATERAL SEROUS MACULAR DETACHMENT.","abstract":"PURPOSE: We describe the long-term follow-up of a patient with multifocal Best disease with chronic bilateral serous macular detachment and unusual peripheral findings associated with a novel mutation in the BEST1 gene.\nMETHODS: Case report.\nRESULTS: A 59-year-old white woman was referred for an evaluation of her macular findings in 1992. There was a family history of Best disease in the patient's mother and a male sibling. Her medical history was unremarkable. Best-corrected visual acuity was 20/20 in her right eye and 20/25 in her left eye. The anterior segment examination was normal in both eyes. Funduscopic examination showed multifocal hyperautofluorescent vitelliform deposits with areas of subretinal fibrosis in both eyes. An electrooculogram showed Arden ratios of 1.32 in the right eye and 1.97 in the left eye. Ultra-widefield color and fundus autofluorescence imaging showed degenerative retinal changes in areas throughout the entire fundus in both eyes. Optical coherence tomography, including annual eye-tracked scans from 2005 to 2016, showed persistent bilateral serous macular detachments. Despite chronic foveal detachment, visual acuity was 20/25 in her right eye and 20/40 in her left eye, 24 years after initial presentation. Genetic testing showed a novel c.238T>A (p.Phe80Ile) missense mutation in the BEST1 gene.\nCONCLUSION: Some patients with Best disease associated with chronic serous macular detachment can maintain good visual acuity over an extended follow-up. To our knowledge, this is the first report of Best disease associated with this mutation in the BEST1 gene.","variants":[{"Name":"NM_004183.4(BEST1):c.238T>A (p.Phe80Ile)","Chromosome":"11","Start":"61955192","Stop":"61955192","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":408394,"rule_based_match":true,"evidence_text":"c.238T>A (p.Phe80Ile)","llm_judgment":"PRESENT","evidence":"c.238T>A (p.Phe80Ile)","abstract_start":1287,"abstract_end":1308}]}
{"pmid":"32333190","title":"Oguchi disease caused by a homozygous novel SAG splicing alteration associated with the multiple evanescent white dot syndrome: A 15-month follow-up.","abstract":"PURPOSE: We report a 15-month follow-up case on a Chinese patient with Oguchi disease associated with the multiple evanescent white dot syndrome (MEWDS).\nMETHODS: The patient's clinical presentation and follow-up visits were documented via decimal best-corrected visual acuity, fundus photography, fundus autofluorescence (FAF) imaging, near-infrared FAF, spectral domain optical coherence tomography, Humphrey's visual fields, microperimetry, and multifocal electroretinography. We also performed whole exome sequencing for screening variation in the patient and her relatives.\nRESULTS: The patient had typical clinical characteristic of Oguchi disease, including night blindness, the Mizuo-Nakamura phenomenon (a golden yellow discoloration of the fundus that disappears in the prolonged dark adaptation [DA]) and typical full-field electroretinogram changes (nearly undetected b-wave in 0.01 and 0.03 ERGs that can partially recover only after prolonged DA). Aside from Oguchi disease, the patient was also diagnosed with the MEWDS based on clinical detections, including suddenly reduced visual acuity, appeared white dots, blurred ellipsoid zone and disrupted interdigitation zone, enlarged blind spot, and reduced macular sensitivity. A series of investigations revealed that along with the 15-month follow-up after onset, the visual acuity enhanced, the numerous white dots disappeared, and the macular structure returned to normal. Moreover, the novel homozygous splicing alteration c.181 + 1G > A was identified in the SAG gene.\nCONCLUSIONS: This work is the first long-term case study of a patient with Oguchi disease associated with the MEWDS. The recovery period of symptoms caused by the MEWDS was much longer than that in typical patients with MEWDS. Molecular genetics demonstrate that this is the first case of Oguchi disease caused by splicing alterations in the SAG gene.","variants":[{"Name":"NM_000541.5(SAG):c.181+1G>A","Chromosome":"2","Start":"233318796","Stop":"233318796","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1967274,"rule_based_match":true,"evidence_text":"c.181 + 1G > A","llm_judgment":"PRESENT","evidence":"c.181 + 1G > A","abstract_start":1491,"abstract_end":1505}]}
{"pmid":"31453851","title":"Novel MFN2 Missense Mutation Induces Hereditary Axonal Motor and Sensory Neuropathy in a Saudi Arabian Family.","abstract":"Hereditary axonal motor and sensory neuropathy or Charcot-Marie-Tooth type 2 (CMT2) is a common inherited peripheral neuropathy. Major symptomatologic signs vary from minimal to significant weakness and loss of sensation, feet usually affected more than hands. It may also cause visual acuity impairment, hearing loss, and skeletal deformity. CMT2 classification is based on the clinical, electrophysiological, and genetic inheritance pattern. Dominant CMT2 is classified from CMT2A to CMT2N and recessive CMT2 into CMT2B1 and CMT2B2. CMT2A is the most frequent subtype of CMT2 and caused by mutations in the mitofusin 2 (MFN2) gene. We hereby report a Saudi Arabian CMT2A patient with a variant c.58C>T of the MFN2 gene mutation.","variants":[{"Name":"NM_014874.4(MFN2):c.58C>T (p.His20Tyr)","Chromosome":"1","Start":"11989226","Stop":"11989226","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":210581,"rule_based_match":true,"evidence_text":"c.58C>T","llm_judgment":"PRESENT","evidence":"c.58C>T","abstract_start":696,"abstract_end":703}]}
{"pmid":"21457405","title":"Three dominant-negative mutations in factor XI-deficient patients.","abstract":"Factor XI (FXI) deficiency results from genetic defects of the F11 gene and is generally considered to be inherited in an autosomal recessive manner. However, the homodimeric structure of FXI allows, in some cases, the dominant-negative transmission of the disease. The aim of this study was to characterize novel missense mutations in three unrelated patients and verify the dominant-negative effects of these mutations on the secretion of wild-type FXI protein by expression studies. The F11 gene was PCR amplified, from genomic DNA extracted from peripheral blood, and sequenced on an ABI 3100 Genetic Analyzer. Human wild-type FXI and FXI mutants were expressed in BHK570 cells using Lipofectamin transfection reagents. Conditioned media and cell lysates were collected for the measurement of luciferase activity, FXI antigen and Western blot analysis. DNA sequencing revealed three novel missense F11 mutations; c.127G>A in exon 3 (Ala43Thr), c.723C>G in exon 7 (Phe241Leu) and c.1207G>A in exon 11 (Val403Met). In vitro expression studies showed that the mutation Ala43Thr, Phe241Leu or Val403Met remarkably decreased the extracellular secretion of mutant FXI, rather than reducing synthesis of the mutant proteins. Cotransfection of wild-type FXI with mutant FXI constructs indicated that the mutation Ala43Thr, Phe241Leu or Val403Met reduced the secretion of wild-type FXI by 75.9%, 68.6% or 71.4%, respectively. Our study suggests that dominant-negative mutations in FXI-deficient patients of non-Ashkenazi Jewish origin may be more prevalent than thought, resulting from FXI's unique dimeric structure.","variants":[{"Name":"NM_000128.4(F11):c.1207G>A (p.Val403Met)","Chromosome":"4","Start":"186284163","Stop":"186284163","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":79064,"rule_based_match":true,"evidence_text":"c.1207G>A in exon 11 (Val403Met)","llm_judgment":"PRESENT","evidence":"c.1207G>A in exon 11 (Val403Met)","abstract_start":983,"abstract_end":1015},{"Name":"NM_000128.4(F11):c.127G>A (p.Ala43Thr)","Chromosome":"4","Start":"186271680","Stop":"186271680","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":79065,"rule_based_match":true,"evidence_text":"c.127G>A","llm_judgment":"PRESENT","evidence":"c.127G>A","abstract_start":917,"abstract_end":925},{"Name":"NM_000128.4(F11):c.723C>G (p.Phe241Leu)","Chromosome":"4","Start":"186276358","Stop":"186276358","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":79088,"rule_based_match":true,"evidence_text":"c.723C>G in exon 7 (Phe241Leu)","llm_judgment":"PRESENT","evidence":"c.723C>G in exon 7 (Phe241Leu)","abstract_start":948,"abstract_end":978}]}
{"pmid":"25497208","title":"Most frequent mutation c.3402delC (p.Ala1135GlnfsX13) among Wilson disease patients in Venezuela has a wide distribution and two old origins.","abstract":"Wilson disease is an infrequent autosomal recessive disorder caused by mutations in the ATP7B gene (13q14.3) producing pathologic phenotypes due to copper accumulation in critical tissues. The aim of the research was to probe Wilson disease genetic epidemiology in Venezuela, through the identification in diagnosed index cases, of ATP7B locus mutations, their geographic distribution, frequency, in-phase haplotypes and probable ethnic ancestry. During the last three decades 33 independent Wilson disease families from the country at large were ascertained and diagnosed through severely reduced ceruloplasmin activity, higher urinary copper excretion, and specific clinical signs. Molecular studies of the ATP7B gene were accomplished in 26 of the families. Disease prevalence was estimated as 1:94,000 families between 1985 and 2013, showing geographic aggregation in the state of Zulia with 1:27,000 families in it. DNA analysis in 26 families revealed 13 different mutations. The c.3402delC was the most frequent one (26.9%), presenting two independent in-phase haplotypes, both of likely European descent; which is followed by the not previously reported p.G691V (9.6%) and by the frequent European H1069Q (7.7%). Known mutations c.51 + 4A > T, c.1285 + 5G > T, M645R, T788I, V845SfsX28, T977M, L1088X, T1220M, R1319X and a novel P767L showed frequencies between 5.8 and 1.9%. Despite the ample mutation heterogeneity for Wilson disease in the country, the findings provide a diagnostic algorithm to ease mutation assessment in new patients; the predominant c.3402delC displayed wide geographic distribution and two genetic origins.","variants":[{"Name":"NM_000053.4(ATP7B):c.3402del (p.Ala1135fs)","Chromosome":"13","Start":"51942396","Stop":"51942396","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":94515,"rule_based_match":true,"evidence_text":"c.3402delC","llm_judgment":"PRESENT","evidence":"c.3402delC","abstract_start":986,"abstract_end":996}]}
{"pmid":"23562994","title":"Pontocerebellar hypoplasia type 2 and TSEN2: review of the literature and two novel mutations.","abstract":"Pontocerebellar hypoplasias (PCH) represent a heterogeneous group of autosomal recessive neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, variable cerebral involvement, microcephaly, severe delay in cognitive and motor development, and seizures. Seven different subtypes have been reported (PCH1-7) and mutations in three genes, TSEN2, TSEN34 and TSEN54 encoding three of four subunits of the tRNA splicing endonuclease complex have been found to underlie PCH2, PCH4 and PCH5. PCH2 is characterized by cerebellar hypoplasia affecting the hemispheres more severely than the vermis, progressive cerebral atrophy and microcephaly, dyskinesia, seizures, and death in early childhood. We describe a male patient with progressive microcephaly, severe hypotonia, and myoclonic-tonic seizures. Brain MRI confirmed microcephaly with simplified cortical gyration and revealed hypoplasia of the brainstem, cerebellum and cerebellar vermis. Sequencing of the TSEN2 gene detected the novel missense mutation c.934G > A (p.G312R) on one allele and the first nonsense mutation c.691C > T (p.Q231*) on the second allele. Although the cytosine-to-thymine transition results in introduction of a premature stop codon in the majority of annotated TSEN2 transcript variants, it could represent a splice site mutation (c.517-3C > T) in variant 4. However, by RT-PCR analysis we did not identify mRNAs representing TSEN2 transcript form 4 in leukocyte-derived RNA of the patient and healthy individuals. The clinical phenotype of the patient is comparable with PCH2. However, we noticed decreased cerebral volume with increased extra-axial cerebrospinal fluid spaces and wide-open Sylvian fissures indicating cerebral immaturity that might be associated with the TSEN2 null allele. We conclude that the severity of pontocerebellar hypoplasia in the patient fits PCH2, while the large involvement of the cerebrum better corresponds to PCH4 demonstrating the phenotypic spectrum of PCH2 and 4. To establish a possible genotype-phenotype correlation, more individuals with biallelic TSEN2 mutations need to be investigated.","variants":[{"Name":"NM_025265.4(TSEN2):c.934G>A (p.Gly312Arg)","Chromosome":"3","Start":"12516635","Stop":"12516635","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":178838,"rule_based_match":true,"evidence_text":"c.934G > A (p.G312R)","llm_judgment":"PRESENT","evidence":"c.934G > A (p.G312R)","abstract_start":1030,"abstract_end":1050},{"Name":"NM_025265.4(TSEN2):c.691C>T (p.Gln231Ter)","Chromosome":"3","Start":"12503644","Stop":"12503644","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":178839,"rule_based_match":true,"evidence_text":"c.691C > T (p.Q231*)","llm_judgment":"PRESENT","evidence":"c.691C > T (p.Q231*)","abstract_start":1097,"abstract_end":1117}]}
{"pmid":"33508266","title":"Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.","abstract":"BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disorder resulting in recurrent attacks of severe swelling. It may be associated with a genetic deficiency of functional C1 inhibitor or with normal C1 inhibitor (HAEnCI). In families with HAEnCI, HAE-linked mutations in the F12, PLG, KNG1, ANGPT1, or MYOF genes have been identified. In many families with HAEnCI the genetic cause of the disease is currently unknown.\nOBJECTIVE: The aim of this study was to identify a novel disease-linked mutation for HAEnCI.\nMETHODS: The study methods comprised whole exome sequencing, Sanger sequencing analysis, pedigree analysis, bioinformatic analysis of the mutation, and biochemical analysis of parameters of the kallikrein-kinin (contact) system.\nRESULTS: By performing whole exome sequencing on a multigenerational family with HAEnCI we were able to identify the heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6) mutation c.430A>T (p.Thr144Ser) in all 3 affected family members who were sequenced. This gene encodes HS-glucosamine 3-O-sulfotransferase 6 (3-OST-6), which is involved in the last step of HS biosynthesis. The p.Thr144Ser mutation is likely to affect the interaction between 2 β-sheets stabilizing the active center of the 3-OST-6 protein.\nCONCLUSIONS: We conclude that mutant 3-OST-6 fails to transfer sulfo groups to the 3-OH position of HS, resulting in incomplete HS biosynthesis. This likely affects cell surface interactions of key players in angioedema formation and is a novel mechanism for disease development.","variants":[{"Name":"NM_001009606.4(HS3ST6):c.430A>T (p.Thr144Ser)","Chromosome":"16","Start":"1912189","Stop":"1912189","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1151313,"rule_based_match":true,"evidence_text":"c.430A>T (p.Thr144Ser)","llm_judgment":"PRESENT","evidence":"c.430A>T (p.Thr144Ser)","abstract_start":945,"abstract_end":967}]}
{"pmid":"16571645","title":"Polymorphisms in the xylosyltransferase genes cause higher serum XT-I activity in patients with pseudoxanthoma elasticum (PXE) and are involved in a severe disease course.","abstract":"BACKGROUND: Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder caused by mutations in the ABCC6 gene. Fragmentation of elastic fibres and deposition of proteoglycans result in a highly variable clinical picture. The altered proteoglycan metabolism suggests that enzymes from this pathway function as genetic co-factors in the severity of PXE. Therefore, we propose the XYLT genes encoding xylosyltransferase I (XT-I) as the chain-initiating enzyme in the biosynthesis of proteoglycans and the highly homologous XT-II as potential candidate genes.\nMETHODS: We screened all XYLT exons in 65 German PXE patients using denaturing high performance liquid chromatography and analysed the influence of the variations on clinical characteristics.\nRESULTS: We identified 22 variations in the XYLT genes. The missense variation p.A115S (XT-I) is associated with higher serum XT activity (p = 0.005). The amino acid substitution p.T801R (XT-II; c.2402C>G) occurs with significantly higher frequency in patients under 30 years of age at diagnosis (43% v 26%; p = 0.04); all PXE patients with this variation suffer from skin lesions compared to only 75% of the wild type patients (p = 0.002). c.166G>A, c.1569C>T, and c.2402C>G in the XYLT-II gene were found to be more frequent in patients with higher organ involvement (p = 0.04, p = 0.01, and p = 0.02, respectively).\nCONCLUSIONS: Here we show for the first time that variations in the XYLT-II gene are genetic co-factors in the severity of PXE. Furthermore, the higher XT activity in patients with the exchange p.A115S (XT-I) indicates that this polymorphism is a potential marker for increased remodelling of the extracellular matrix.","variants":[{"Name":"NM_022167.4(XYLT2):c.2402C>G (p.Thr801Arg)","Chromosome":"17","Start":"50360095","Stop":"50360095","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":17572,"rule_based_match":true,"evidence_text":"c.2402C>G","llm_judgment":"PRESENT","evidence":"c.2402C>G","abstract_start":956,"abstract_end":965}]}
{"pmid":"26955893","title":"Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with diaphragmatic weakness: Case report and literature review.","abstract":"Pathogenic variants in the mitofusin 2 gene (MFN2) are the most common cause of autosomal dominant Charcot-Marie-Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7-month-old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next-generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2. A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2-related CMT2. Our patient with MFN2-related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_014874.4(MFN2):c.392A>G (p.Asn131Ser)","Chromosome":"1","Start":"11996236","Stop":"11996236","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":353954,"rule_based_match":true,"evidence_text":"c.392A>G","llm_judgment":"PRESENT","evidence":"c.392A>G","abstract_start":448,"abstract_end":456}]}
{"pmid":"22229330","title":"Conradi-Hünermann-Happle syndrome in males vs. MEND syndrome (male EBP disorder with neurological defects).","abstract":"BACKGROUND: There is confusion in the literature concerning disorders caused by EBP (emopamil-binding protein) mutations in males.\nOBJECTIVES: To study the clinical and genetic differences in males affected either with Conradi-Hünermann-Happle (CHH) syndrome (X-linked dominant chondrodysplasia punctata, CDPX2) or with a nonmosaic, X-linked recessive disorder for which we propose the acronymic term MEND syndrome (male EBP disorder with neurological defects).\nMETHODS: We report a 7-year-old boy with a history of transient scaly erythematous lesions on his limbs, trunk and scalp soon after birth. DNA was isolated from ethylenediamine tetraacetic acid-blood samples of the patient and the four coding exons of the EBP gene were amplified by polymerase chain reaction. We review all published cases of CHH syndrome in males in the literature and elaborate the clinical and genetic differences between CHH syndrome in males and MEND syndrome.\nRESULTS: We found at position 33 of the EBP gene the variant c.33C>A leading to the same nonsense mutation p.Y11X that had previously occurred de novo in a female with typical manifestations of CHH syndrome. When the known male cases with EBP mutations were reviewed, a striking nosological difference between the mosaic and nonmosaic phenotypes was evident. Clear-cut clinical criteria are elaborated to distinguish between CHH syndrome in males and MEND syndrome.\nCONCLUSIONS: Because the clinical outcome and prognosis are different it is important to distinguish between males with CHH syndrome that represents a mosaic phenotype, and those with MEND syndrome that is a nonmosaic trait.","variants":[{"Name":"NM_006579.3(EBP):c.33C>A (p.Tyr11Ter)","Chromosome":"X","Start":"48523804","Stop":"48523804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":205598,"rule_based_match":true,"evidence_text":"c.33C>A","llm_judgment":"PRESENT","evidence":"c.33C>A","abstract_start":1006,"abstract_end":1013}]}
{"pmid":"30078507","title":"BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls.","abstract":"OBJECTIVE: To investigate the BRCA status in Chinese patients with ovarian cancer (OC). Though there were two large prevalence studies in Chinese OC patients, this was the first time to observe it in healthy controls.\nMETHODS: We performed BRCA mutation screening using next-generation sequencing to determine the prevalence of BRCA germline deleterious mutations in an unselected cohort of Chinese OC patients (n = 1331) versus healthy controls (n = 1763) and describe the types and spectrum of BRCA deleterious variants.\nRESULTS: Among the 1331 patients with OC, 227 (17.1%) carried deleterious variants in BRCA1 and 70 (5.3%) carried deleterious variants in BRCA2. Of 1763 control subjects, 6 (0.3%) and 2 (0.1%) had deleterious variants in BRCA1 and BRCA2. No patient carried mutations in both BRCA1 and BRCA2 simultaneously. Sixty-three novel mutations were identified, and three Chinese specific hot-spot mutations were notified as BRCA1 c.5470_5477delATTGGGCA, BRCA1 c.981_982delAT, and BRCA1 c.3770_3771delAG. Interestingly, all these high-frequency recurrent mutations were distributed on exon 10, which may also be the Chinese OC BRCA mutations' distinct characteristics. In addition, in our study, the estimated odds ratio (OR) of OC associated with BRCA1 positive variants were approximately 34.6 (95% CI, 12.5-95.7) in age group under 40 and 42.4 (95% CI, 5.9-305.2) in group older than 50 in the Chinese population, respectively.\nCONCLUSIONS: We recommend BRCA testing to all Chinese OC patients and those general Chinese who have family members with hereditary breast and ovarian related cancer (HBOC)-related cancers. Variants carriers would not only benefit from early prevention of OC but also for the medical management.","variants":[{"Name":"NM_007294.4(BRCA1):c.3770_3771del (p.Glu1257fs)","Chromosome":"17","Start":"43091760","Stop":"43091761","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":46102,"rule_based_match":true,"evidence_text":"BRCA1 c.3770_3771delAG","llm_judgment":"PRESENT","evidence":"BRCA1 c.3770_3771delAG","abstract_start":994,"abstract_end":1016},{"Name":"NM_007294.4(BRCA1):c.981_982del (p.Thr327_Cys328insTer)","Chromosome":"17","Start":"43094549","Stop":"43094550","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":70439,"rule_based_match":true,"evidence_text":"BRCA1 c.981_982delAT","llm_judgment":"PRESENT","evidence":"BRCA1 c.981_982delAT","abstract_start":968,"abstract_end":988}]}
{"pmid":"22717650","title":"A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.","abstract":"BACKGROUND: Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis.\nMETHODS: The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish.\nRESULTS: The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study.\nCONCLUSIONS: The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.","variants":[{"Name":"NM_152415.3(VPS37A):c.1146A>T (p.Lys382Asn)","Chromosome":"8","Start":"17286379","Stop":"17286379","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":48340,"rule_based_match":true,"evidence_text":"c.1146A>T (p.K382N)","llm_judgment":"PRESENT","evidence":"c.1146A>T (p.K382N)","abstract_start":870,"abstract_end":889}]}
{"pmid":"22205354","title":"Bietti crystalline dystrophy: a morpho-functional evaluation.","abstract":"We report the clinical findings and macular function of a patient with Bietti crystalline dystrophy. A 39-year-old woman reported visual loss in both eyes and nyctalopia. A complete ophthalmological evaluation, retromode imaging, SD-OCT acquisition, MP1 microperimetry, and multifocal electroretinogram (mfERG) were performed. Microcrystalline deposits in the cornea and the retina with retinal pigment epithelial atrophy were observed. Retromode imaging revealed visualization of normal large choroidal vessels, cystoid macular edema, and small defined glistening lesions. SD-OCT showed changes in the outer retina with numerous microcrystalline deposits. Microperimetry showed an absolute scotoma involving the perimacular area but sparing of the fovea. In both eyes, mfERG analysis suggests a dysfunction of pre-ganglionic retinal elements detectable in the 20 central retinal degrees. The genetic characterization showed an homozygous mutation c.772C > T[p.Leu258Phe] in exon 6. Retromode imaging and SD-OCT were useful tools to determine the extent and the localization of the crystals. Microperimetry should allow evaluation of the progression of the macular changes.","variants":[{"Name":"NM_207352.4(CYP4V2):c.772C>T (p.Leu258Phe)","Chromosome":"4","Start":"186199054","Stop":"186199054","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1337010,"rule_based_match":true,"evidence_text":"c.772C > T[p.Leu258Phe]","llm_judgment":"PRESENT","evidence":"c.772C > T[p.Leu258Phe]","abstract_start":948,"abstract_end":971}]}
{"pmid":"28086997","title":"Enamel-renal syndrome in 2 patients with a mutation in FAM20 A and atypical hypertrichosis and hearing loss phenotypes.","abstract":"Enamel-renal syndrome (OMIM #204690) is an uncommon disorder characterized by amelogenesis imperfecta and nephrocalcinosis and is caused by mutations in FAM20 A. We report 2 patients with enamel-renal syndrome who exhibited the typical features of this syndrome and a homozygous nonsense mutation in the FAM20 A gene (c.406 C>T), genetically confirming the diagnosis. They also exhibited 2 undescribed clinical features, hypertrichosis and hearing loss. Alterations in genes frequently associated with nonsyndromic hearing loss in the Brazilian population, including connexin 26 (GJB2), connexin 30 (GJB6) and mitochondrial 12 S rRNA (m.A1555 G mutation), were not found. These results suggest a putative function of FAM20 A in the development of the inner ear and in the formation of hair. The presence of nephrocalcinosis is a risk factor for renal impairment, and it is important to perform regular renal monitoring in order to avoid renal failure.","variants":[{"Name":"NM_017565.4(FAM20A):c.406C>T (p.Arg136Ter)","Chromosome":"17","Start":"68555742","Stop":"68555742","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39836,"rule_based_match":true,"evidence_text":"c.406 C>T","llm_judgment":"PRESENT","evidence":"c.406 C>T","abstract_start":318,"abstract_end":327}]}
{"pmid":"33028743","title":"Hereditary Fructose Intolerance Diagnosed in Adulthood.","abstract":"Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a mutation in the aldolase B gene. HFI patients exhibit nausea, vomiting, abdominal pain, hypoglycemia, and elevated liver enzymes after dietary fructose exposure. Chronic exposure might lead to failure to thrive, liver failure, renal failure, and, eventually, death. HFI usually manifests in infants when they are being weaned off of breastmilk. Because HFI has an excellent prognosis when patients maintain a strict restrictive diet, some patients remain undiagnosed due to the voluntary avoidance of sweet foods. In the past, HFI was diagnosed using a fructose tolerance test, liver enzyme assays or intestinal biopsy specimens. Currently, HFI is diagnosed through the analysis of aldolase B mutations. Here, HFI was diagnosed in a 41-year-old woman who complained of sweating, nausea, and vomiting after consuming sweets. She had a compound heterozygous mutation in the aldolase B gene; gene analysis revealed pathogenic nonsense (c.178C>T, p.Arg60Ter) and frameshift (c.360_363delCAAA, p.Asn120LysfsTer32) variants. This is the first report of a Korean HFI patient diagnosed in adulthood.","variants":[{"Name":"NM_000035.4(ALDOB):c.360_363del (p.Asn120fs)","Chromosome":"9","Start":"101428485","Stop":"101428488","ReferenceAlleleVCF":"CTTTG","AlternateAlleleVCF":"C","allel_id":186778,"rule_based_match":true,"evidence_text":"c.360_363delCAAA, p.Asn120LysfsTer32","llm_judgment":"PRESENT","evidence":"c.360_363delCAAA, p.Asn120LysfsTer32","abstract_start":1056,"abstract_end":1092},{"Name":"NM_000035.4(ALDOB):c.178C>T (p.Arg60Ter)","Chromosome":"9","Start":"101429901","Stop":"101429901","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15511,"rule_based_match":true,"evidence_text":"c.178C>T, p.Arg60Ter","llm_judgment":"PRESENT","evidence":"c.178C>T, p.Arg60Ter","abstract_start":1018,"abstract_end":1038}]}
{"pmid":"32317190","title":"Exon skipping in Duchenne Muscle dystrophy due to a silent p.Ser443= mutation in the DMD gene.","abstract":"Duchenne Muscle dystrophy (DMD) is a X-linked inherited disease predominantly caused by severe mutations in DMD gene leading to absence of dystrophin protein. Here we report a 14-year-old Mongolian boy suffering from proximal muscle weakness, pseudohypertrophic deltoid and gastrocnemius muscles since early childhood. Lactate dehydrogenase (LDH) and creatine kinase (CK) levels were elevated. Mutation analysis including MLPA and sequencing of the DMD gene revealed a hemizygous silent variant, c.1329C>T (p.Ser443=) in exon 11. This silent mutation, listed in the SNP database (rs1060502631), was described as a variant of unknown significance (VUS) in ClinVar database. cDNA analysis demonstrated partial skipping of exon 11 due to this mutation. Although silent mutations are usually considered non-pathogenic, our case emphasizes that silent mutations can be potentially pathogenic. Hence, if silent variants are not annotated in database or not known to be benign, they should be analysed further at cDNA level.","variants":[{"Name":"NM_004006.3(DMD):c.1329C>T (p.Ser443=)","Chromosome":"X","Start":"32644134","Stop":"32644134","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":404558,"rule_based_match":true,"evidence_text":"c.1329C>T (p.Ser443=)","llm_judgment":"PRESENT","evidence":"c.1329C>T (p.Ser443=)","abstract_start":496,"abstract_end":517}]}
{"pmid":"31278392","title":"Expansion of B4GALT7 linkeropathy phenotype to include perinatal lethal skeletal dysplasia.","abstract":"Proteoglycans have a core polypeptide connected to glycosaminoglycans (GAGs) via a common tetrasaccharide linker region. Defects in enzymes that synthesize the linker result in a group of autosomal recessive conditions called \"linkeropathies\". Disease manifests with skeletal and connective tissue features, including short stature, hyperextensible skin, and joint hypermobility. We report a family with three affected pregnancies showing short limbs, cystic hygroma, and perinatal death. Two spontaneously aborted; one survived 1 day after term delivery, and had short limbs, bell-shaped thorax, 11 ribs, absent thumbs, and cleft palate. Exome sequencing of the proband and one affected fetus identified compound heterozygous missense variants, NM_007255.3: c.808C>T (p.(Arg270Cys)) and NM_007255.3: c.398A>G (p.(Gln133Arg)), in B4GALT7, a gene required for GAG linker biosynthesis. Homozygosity for p.(Arg270Cys), associated with partial loss of B4GALT7 function, causes Larsen of Reunion Island syndrome (LRS), however no previous studies have linked p.(Gln133Arg) to disease. The p.(Gln133Arg) and p.(Arg270Cys) variants were transfected into CHO pgsB-618 cells. High protein expression of p.(Gln133Arg) was found, with mislocalization, compared to p.(Arg270Cys) that had a normal Golgi-like pattern. The p.(Gln133Arg) had almost no enzyme activity and little production of heparan sulfate GAGs, while p.(Arg270Cys) only had 17% of wild-type activity. These findings expand the phenotype of B4GALT7-related linkeropathies to include lethal skeletal dysplasia due to more severe loss of function.","variants":[{"Name":"NM_007255.3(B4GALT7):c.398A>G (p.Gln133Arg)","Chromosome":"5","Start":"177604526","Stop":"177604526","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":620945,"rule_based_match":true,"evidence_text":"NM_007255.3: c.398A>G (p.(Gln133Arg))","llm_judgment":"PRESENT","evidence":"NM_007255.3: c.398A>G (p.(Gln133Arg))","abstract_start":788,"abstract_end":825},{"Name":"NM_007255.3(B4GALT7):c.808C>T (p.Arg270Cys)","Chromosome":"5","Start":"177608994","Stop":"177608994","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20652,"rule_based_match":true,"evidence_text":"NM_007255.3: c.808C>T (p.(Arg270Cys))","llm_judgment":"PRESENT","evidence":"NM_007255.3: c.808C>T (p.(Arg270Cys))","abstract_start":746,"abstract_end":783}]}
{"pmid":"30393977","title":"CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures.","abstract":"BACKGROUND: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 (CTC1) gene. The CTC1 forms the telomeric capping complex, CST, which functions in telomere homeostasis and replication.\nMETHODS: A Brazilian pedigree and an Australian pedigree were referred to the International Registry of Werner Syndrome (Seattle, WA, USA), with clinical features of accelerated aging and recurrent bone fractures. Whole exome sequencing was performed to identify the genetic causes.\nRESULTS: Whole exome sequencing of the Brazilian pedigree revealed compound heterozygous pathogenic variants in CTC1: a missense mutation (c.2959C>T, p.Arg987Trp) and a novel stop codon change (c.322C>T, p.Arg108*). The Australian patient carried two novel heterozygous CTC1 variants, c.2916G>T, p.Val972Gly and c.2926G>T, p.Val976Phe within the same allele. Both heterozygous variants were inherited from the unaffected father, excluding the diagnosis of CRMCC in this pedigree. Cell biological studies demonstrated accumulation of double strand break foci in lymphoblastoid cell lines derived from the patients. Increased DSB foci were extended to non-telomeric regions of the genome, in agreement with previous biochemical studies showing a preferential binding of CTC1 protein to GC-rich sequences.\nCONCLUSION: CTC1 pathogenic variants can present with unusual manifestations of progeria accompanied with recurrent bone fractures. Further studies are needed to elucidate the disease mechanism leading to the clinical presentation with intra-familial variations of CRMCC.","variants":[{"Name":"NM_025099.6(CTC1):c.322C>T (p.Arg108Ter)","Chromosome":"17","Start":"8238505","Stop":"8238505","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":846648,"rule_based_match":true,"evidence_text":"c.322C>T, p.Arg108*","llm_judgment":"PRESENT","evidence":"c.322C>T, p.Arg108*","abstract_start":794,"abstract_end":813},{"Name":"NM_025099.6(CTC1):c.2926G>T (p.Val976Phe)","Chromosome":"17","Start":"8230301","Stop":"8230301","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3764306,"rule_based_match":true,"evidence_text":"c.2926G>T, p.Val976Phe","llm_judgment":"PRESENT","evidence":"c.2926G>T, p.Val976Phe","abstract_start":912,"abstract_end":934}]}
{"pmid":"25703136","title":"Founder haplotype analysis of Fanconi anemia in the Korean population finds common ancestral haplotypes for a FANCG variant.","abstract":"A common ancestral haplotype is strongly suggested in the Korean and Japanese patients with Fanconi anemia (FA), because common mutations have been frequently found: c.2546delC and c.3720_3724delAAACA of FANCA; c.307+1G>C, c.1066C>T, and c.1589_1591delATA of FANCG. Our aim in this study was to investigate the origin of these common mutations of FANCA and FANCG. We genotyped 13 FA patients consisting of five FA-A patients and eight FA-G patients from the Korean FA population. Microsatellite markers used for haplotype analysis included four CA repeat markers which are closely linked with FANCA and eight CA repeat markers which are contiguous with FANCG. As a result, Korean FA-A patients carrying c.2546delC or c.3720_3724delAAACA did not share the same haplotypes. However, three unique haplotypes carrying c.307+1G>C, c.1066C > T, or c.1589_1591delATA, that consisted of eight polymorphic loci covering a flanking region were strongly associated with Korean FA-G, consistent with founder haplotypes reported previously in the Japanese FA-G population. Our finding confirmed the common ancestral haplotypes on the origins of the East Asian FA-G patients, which will improve our understanding of the molecular population genetics of FA-G. To the best of our knowledge, this is the first report on the association between disease-linked mutations and common ancestral haplotypes in the Korean FA population.","variants":[{"Name":"NM_004629.2(FANCG):c.1589_1591del (p.Asp530_Thr531delinsAla)","Chromosome":"9","Start":"35074972","Stop":"35074974","ReferenceAlleleVCF":"GTAT","AlternateAlleleVCF":"G","allel_id":1055828,"rule_based_match":true,"evidence_text":"c.1589_1591delATA","llm_judgment":"PRESENT","evidence":"c.1589_1591delATA","abstract_start":238,"abstract_end":255},{"Name":"NM_004629.2(FANCG):c.1066C>T (p.Gln356Ter)","Chromosome":"9","Start":"35076442","Stop":"35076442","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21754,"rule_based_match":true,"evidence_text":"c.1066C>T","llm_judgment":"PRESENT","evidence":"c.1066C>T","abstract_start":223,"abstract_end":232}]}
{"pmid":"26124219","title":"Novel MMP20 and KLK4 Mutations in Amelogenesis Imperfecta.","abstract":"In order to achieve highly mineralized tooth enamel, enamel proteinases serve the important function of removing the remaining organic matrix in the mineralization and maturation of the enamel matrix. Mutations in the kallikrein 4 (KLK4), enamelysin (MMP20), and WDR72 genes have been identified as causing hypomaturation enamel defects in an autosomal-recessive hereditary pattern. In this report, 2 consanguineous families with a hypomaturation-type enamel defect were recruited, and mutational analysis was performed to determine the molecular genetic etiology of the disease. Whole exome sequencing and autozygosity mapping identified novel homozygous mutations in the KLK4 (c.620_621delCT, p.Ser207Trpfs*38) and MMP20 (c.1054G>A, p.Glu352Lys) genes. Further analysis on the effect of the mutations on the translation, secretion, and function of KLK4 and MMP20 revealed that mutant KLK4 was degraded intracellularly and became inactive while mutant MMP20 was expressed at a normal level but secreted only minimally with proteolytic function.","variants":[{"Name":"NM_004917.5(KLK4):c.620_621del (p.Ser207fs)","Chromosome":"19","Start":"50907078","Stop":"50907079","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":1289213,"rule_based_match":true,"evidence_text":"c.620_621delCT","llm_judgment":"PRESENT","evidence":"c.620_621delCT","abstract_start":679,"abstract_end":693}]}
{"pmid":"30903322","title":"Celia's encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant.","abstract":"Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. Clinical characterization, biochemistry, and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification, and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. One with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy, and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene and is responsible for a variant of Celia's encephalopathy, with variable phenotypic expression.","variants":[{"Name":"NM_001122955.4(BSCL2):c.974dup (p.Ile326fs)","Chromosome":"11","Start":"62691310","Stop":"62691311","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":359020,"rule_based_match":true,"evidence_text":"c.974dupG","llm_judgment":"PRESENT","evidence":"c.974dupG","abstract_start":394,"abstract_end":403}]}
{"pmid":"30026549","title":"Arylsulphatase A Pseudodeficiency (ARSA-PD), hypertension and chronic renal disease in Aboriginal Australians.","abstract":"Chronic renal disease (CRD) associated with cardiovascular disease (CVD) and/or type 2 diabetes (T2D) is a significant problem in Aboriginal Australians. Whole exome sequencing data (N = 72) showed enrichment for ClinVar pathogenic variants in gene sets/pathways linking lipoprotein, lipid and glucose metabolism. The top Ingenuity Pathway Analysis canonical pathways were Farsenoid X Receptor and Retinoid Receptor (FXR/RXR; (P = 1.86 × 10<sup>-7</sup>), Liver X Receptor and Retinoid Receptor (LXR/RXR; P = 2.88 × 10<sup>-6</sup>), and atherosclerosis signalling (P = 3.80 × 10<sup>-6</sup>). Top pathways/processes identified using Enrichr included: Reactome 2016 chylomicron-mediated lipid transport (P = 3.55 × 10<sup>-7</sup>); Wiki 2016 statin (P = 8.29 × 10<sup>-8</sup>); GO Biological Processes 2017 chylomicron remodelling (P = 1.92 × 10<sup>-8</sup>). ClinVar arylsulfatase A pseudodeficiency (ARSA-PD) pathogenic variants were common, including the missense variant c.511 G > A (p.Asp171Asn; rs74315466; frequency 0.44) only reported in Polynesians. This variant is in cis with known ARSA-PD 3' regulatory c.*96 A > G (rs6151429; frequency 0.47) and missense c.1055 A > G (p.Asn352Ser; rs2071421; frequency 0.47) variants. These latter two variants are associated with T2D (risk haplotype GG; odds ratio 2.67; 95% CI 2.32-3.08; P = 2.43 × 10<sup>-4</sup>) in genome-wide association data (N = 402), but are more strongly associated with quantitative traits (DBP, SBP, ACR, eGFR) for hypertension and renal function in non-diabetic than diabetic subgroups. Traits associated with CVD, CRD and T2D in Aboriginal Australians provide novel insight into function of ARSA-PD variants.","variants":[{"Name":"NM_000487.6(ARSA):c.511G>A (p.Asp171Asn)","Chromosome":"22","Start":"50627007","Stop":"50627007","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18108,"rule_based_match":true,"evidence_text":"c.511 G > A (p.Asp171Asn; rs74315466)","llm_judgment":"PRESENT","evidence":"p.Asp171Asn","abstract_start":992,"abstract_end":1003}]}
{"pmid":"29422440","title":"GYG1 causing progressive limb girdle myopathy with onset during teenage years (polyglucosan body myopathy 2).","abstract":"An 84-year-old lady with slowly progressive limb and axial muscle weakness with onset in her teens was referred for genetic investigations. Targeted next generation sequencing (NGS) revealed a homozygous mutation GYG1 in exon5:c.487delG:p.D163fs, confirming the diagnosis of Polyglucosan Body Myopathy 2 (PGBM2). Retrospective review of muscle pathology revealed a florid vacuolar myopathy with histochemical and ultrastructural features consistent with a polyglucosan storage myopathy. No cardiac symptoms were reported. Our case is consistent with the core phenotype of GYG1-related PGBM2 apart from an early onset of weakness without cardiac symptoms. The presence of α-amylase resistant PAS-positive material in skeletal muscle biopsy of patients with slowly progressive limb girdle muscle weakness should prompt the search for GYG1 mutations. This case highlights the combined role of muscle pathology and NGS in the molecular resolution of patients with undiagnosed neuromuscular conditions.","variants":[{"Name":"NM_004130.4(GYG1):c.487del (p.Asp163fs)","Chromosome":"3","Start":"149009278","Stop":"149009278","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":172319,"rule_based_match":true,"evidence_text":"NM_004130.4(GYG1):c.487del (p.Asp163fs)","llm_judgment":"PRESENT","evidence":"c.487del","abstract_start":227,"abstract_end":235}]}
{"pmid":"20052365","title":"Novel CFTR mutations in a Korean infant with cystic fibrosis and pancreatic insufficiency.","abstract":"Cystic fibrosis (CF) is an autosomal recessive disease that is very rare in Asians: only a few cases have been reported in Korea. We treated a female infant with CF who had steatorrhea and failure to thrive. Her sweat chloride concentration was 102.0 mM/L. Genetic analysis identified two novel mutations including a splice site mutation (c.1766+2T >C) and a frameshift mutation (c.3908dupA; Asn1303LysfsX6). Pancreatic enzyme replacement and fat-soluble vitamin supplementation enabled the patient to get a catch-up growth. This is the first report of a Korean patient with CF demonstrating pancreatic insufficiency. CF should therefore be considered in the differential diagnosis of infants with steatorrhea and failure to thrive.","variants":[{"Name":"NM_000492.4(CFTR):c.3908dup (p.Asn1303fs)","Chromosome":"7","Start":"117652870","Stop":"117652871","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":68515,"rule_based_match":true,"evidence_text":"c.3908dupA; Asn1303LysfsX6","llm_judgment":"PRESENT","evidence":"c.3908dupA; Asn1303LysfsX6","abstract_start":380,"abstract_end":406},{"Name":"NM_000492.4(CFTR):c.1766+2T>C","Chromosome":"7","Start":"117590441","Stop":"117590441","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":544550,"rule_based_match":true,"evidence_text":"c.1766+2T >C","llm_judgment":"PRESENT","evidence":"c.1766+2T >C","abstract_start":339,"abstract_end":351}]}
{"pmid":"21356067","title":"Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals.","abstract":"INTRODUCTION: Two major high-penetrance breast cancer genes, BRCA1 and BRCA2, are responsible for approximately 20% of hereditary breast cancer (HBC) cases in Finland. Additionally, rare mutations in several other genes that interact with BRCA1 and BRCA2 increase the risk of HBC. Still, a majority of HBC cases remain unexplained which is challenging for genetic counseling. We aimed to analyze additional mutations in HBC-associated genes and to define the sensitivity of our current BRCA1/2 mutation analysis protocol used in genetic counseling.\nMETHODS: Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. In silico prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P).\nRESULTS: Three previously reported breast cancer-associated variants, BRCA1 c.5095C > T, CHEK2 c.470T > C, and CHEK2 c.1100delC, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had CHEK2 variants, c.470T > C and/or c.1100delC. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants, BRCA2 c.72A > T (Leu24Phe) was predicted to be likely pathogenic in silico. No large genomic rearrangements were detected in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA).\nCONCLUSIONS: In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk BRCA1/2-negative HBOC individuals. CHEK2 mutations, c.470T > C and c.1100delC, make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish BRCA1/2-founder mutations and protein truncation test (PTT) of the largest exons is sensitive enough for clinical use as a primary screening tool.","variants":[{"Name":"NM_007294.4(BRCA1):c.5095C>T (p.Arg1699Trp)","Chromosome":"17","Start":"43063931","Stop":"43063931","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70063,"rule_based_match":true,"evidence_text":"BRCA1 c.5095C > T","llm_judgment":"PRESENT","evidence":"BRCA1 c.5095C > T","abstract_start":1439,"abstract_end":1456},{"Name":"NM_000059.4(BRCA2):c.72A>T (p.Leu24Phe)","Chromosome":"13","Start":"32319081","Stop":"32319081","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":66971,"rule_based_match":true,"evidence_text":"BRCA2 c.72A > T (Leu24Phe)","llm_judgment":"PRESENT","evidence":"BRCA2 c.72A > T (Leu24Phe)","abstract_start":1769,"abstract_end":1795},{"Name":"NM_007194.4(CHEK2):c.470T>C (p.Ile157Thr)","Chromosome":"22","Start":"28725099","Stop":"28725099","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":20630,"rule_based_match":true,"evidence_text":"c.470T > C","llm_judgment":"PRESENT","evidence":"c.470T > C","abstract_start":1464,"abstract_end":1474}]}
{"pmid":"26887364","title":"The clinical analysis of plakophilin-2 gene mutation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia","abstract":"OBJECTIVE: The purpose of this study was to screen genetic variations in plakophilin-2 (PKP2) gene in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) and investigate the differences in clinical features between mutation and no-mutation groups.\nMETHODS: Thirty unrelated Chinese patients clinically diagnosed with ARVC/D and 50 healthy controls were included. Genomic DNA was isolated from peripheral blood samples. PCR and direct sequencing were used to detect variations in PKP2 gene.\nRESULTS: Eight PKP2 mutant variants were identified in 10 ARVC/D patients (8 men, 2 women). Among the eight mutation, three (c.2194C>T, c. 1170+ 1G>A and c. 810_813delGGTC) were novel mutation. Clinical features of the PKP2 mutation group were similar to those of the non-mutation group.\nCONCLUSIONS: The rate of PKP2 mutation is 33.3% (10/30) in ARVC/D patients. The penetrance of PKP2 mutation for ARVC/D tends to be higher in man patients. No significant differences could be detected in phenotype characteristics between patients with and without PKP2 mutation.","variants":[{"Name":"NM_001005242.3(PKP2):c.1170+1G>A","Chromosome":"12","Start":"32868926","Stop":"32868926","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186425,"rule_based_match":true,"evidence_text":"c. 1170+ 1G>A","llm_judgment":"PRESENT","evidence":"c. 1170+ 1G>A","abstract_start":655,"abstract_end":668}]}
{"pmid":"31045292","title":"Biallelic variants in DNA2 cause microcephalic primordial dwarfism.","abstract":"Microcephalic primordial dwarfism (MPD) is a group of rare single-gene disorders characterized by the extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD-associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report the identification of four MPD individuals with biallelic variants in DNA2, which encodes an adenosine triphosphate (ATP)-dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764-38_1764-37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally, we identify a missense variant (c.1963A>G), affecting a residue of the ATP-dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP (adenosine diphosphate) binding by DNA2. Our findings support the pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD disease gene.","variants":[{"Name":"NM_001080449.3(DNA2):c.1963A>G (p.Thr655Ala)","Chromosome":"10","Start":"68431882","Stop":"68431882","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3394250,"rule_based_match":true,"evidence_text":"c.1963A>G (p.Thr655Ala)","llm_judgment":"PRESENT","evidence":"p.Thr655Ala","abstract_start":876,"abstract_end":887},{"Name":"NM_001080449.3(DNA2):c.74+4A>C","Chromosome":"10","Start":"68471787","Stop":"68471787","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3062546,"rule_based_match":true,"evidence_text":"c.74+4A>C","llm_judgment":"PRESENT","evidence":"c.74+4A>C","abstract_start":592,"abstract_end":601}]}
{"pmid":"37701149","title":"Hypervitaminosis D Secondary to a","abstract":"Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The <i>CYP24A1</i> gene encodes for the 24-hydroxylase enzyme, which is responsible for the catabolism of 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D). Mutations in <i>CYP24A1</i> can result in elevated 1,25(OH)2D causing parathyroid hormone (PTH)-independent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. We present the cases of two siblings exhibiting hypercalcemia secondary to a <i>CYP24A1</i> loss-of-function mutation. Case 1 presented initially with PTH-dependent hypercalcemia, with localization of a left upper parathyroid adenoma on parathyroid technetium sestamibi (<sup>99m</sup>Tc-MIBI) uptake study. Despite parathyroidectomy (180 mg adenoma), hypercalcemia, hypercalciuria, and low normal PTH levels persisted. A repeat parathyroid <sup>99m</sup>Tc-MIBI uptake study localized a second adenoma and a right inferior parathyroidectomy was performed (170 mg adenoma). PTH subsequently became undetectable, however hypercalcemia and hypercalciuria persisted. A new presentation of PTH-independent hypercalcemia found to be secondary to a <i>CYP24A1</i> loss-of-function mutation in his sibling, Case 2, signaled the underlying cause. Cascade testing confirmed both siblings were homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W) of <i>CYP24A1</i> (NM_000782.5). In clinical practice <i>CYP24A1</i> loss-of-function mutations should be considered in patients presenting with PTH-independent hypercalcemia, hypercalciuria, and 1,25(OH)2D levels in the upper normal or elevated range. Although in our case assays of 24,25(OH)2D were not available, calculation of the 25(OH)D:24,25(OH)2D ratio can assist in the diagnostic process. Possible treatments to manage the risk of hypercalcemia in patients with a <i>CYP24A1</i> loss-of-function mutation include avoidance of vitamin D oversupplementation and excessive sun exposure. Hydration and bisphosphonate therapy can be useful in managing the hypercalcemia. Although not utilized in our cases, treatment with ketoconazole, fluconazole, and rifampicin have been described as potential therapeutic options. © 2023 The Authors. <i>JBMR Plus</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.","variants":[{"Name":"NM_000782.5(CYP24A1):c.1186C>T (p.Arg396Trp)","Chromosome":"20","Start":"54158136","Stop":"54158136","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38634,"rule_based_match":true,"evidence_text":"c.1186C>T, p.Arg396Trp (R396W)","llm_judgment":"PRESENT","evidence":"c.1186C>T, p.Arg396Trp (R396W)","abstract_start":1429,"abstract_end":1459}]}
{"pmid":"31753093","title":"Congenital deaf-mutism with pale complexion and anemia for 1 year in a school-aged girl","abstract":"An 11-year-old girl was found to have pale complexion and anemia with gradual aggravation for one year. She was weak in the past and developed pneumonia in the right middle lung 3-5 times per year, which was improved after anti-infective therapy. She and her mother had congenital deaf-mutism. Physical examination showed the appearance of anemia, without bleeding, jaundice, hepatosplenomegaly, or lymph node enlargement. Routine blood test results showed reductions in all three blood cell lines, normocytic anemia, and megaloblastoid change in granulocytic and erythroid cell lines in bone marrow, with no obvious increase in primitive cells or metastatic tumor cells. Whole exome sequencing indicated the presence of a known pathogenic mutation for Emberger syndrome (ES), c.1084C>T (p.Arg362*) in the GATA2 gene. The girl was finally diagnosed with ES, and myelodysplastic syndrome (MDS) progressed to acute myeloid leukemia during follow-up. ES is a rare type of MDS with autosomal dominant inheritance in clinical practice, and it is difficult to make a confirmed diagnosis. ES should be considered for children with unexplained lymphedema and congenital deafness, and gene detection should be performed to make a confirmed diagnosis.","variants":[{"Name":"NM_032638.5(GATA2):c.1084C>T (p.Arg362Ter)","Chromosome":"3","Start":"128481878","Stop":"128481878","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":428130,"rule_based_match":true,"evidence_text":"c.1084C>T (p.Arg362*)","llm_judgment":"PRESENT","evidence":"c.1084C>T (p.Arg362*)","abstract_start":777,"abstract_end":798}]}
{"pmid":"25505835","title":"Frequency of the allelic variant c.1150T > C in exon 10 of the fibroblast growth factor receptor 3 (FGFR3) gene is not increased in patients with pathogenic mutations and related chondrodysplasia phenotypes.","abstract":"Mutations in the FGFR3 gene cause the phenotypic spectrum of FGFR3 chondrodysplasias ranging from lethal forms to the milder phenotype seen in hypochondroplasia (Hch). The p.N540K mutation in the FGFR3 gene occurs in ∼70% of individuals with Hch, and nearly 30% of individuals with the Hch phenotype have no mutations in the FGFR3, which suggests genetic heterogeneity. The identification of a severe case of Hch associated with the typical mutation c.1620C > A and the occurrence of a c.1150T > C change that resulted in a p.F384L in exon 10, together with the suspicion that this second change could be a modulator of the phenotype, prompted us to investigate this hypothesis in a cohort of patients. An analysis of 48 patients with FGFR3 chondrodysplasia phenotypes and 330 healthy (control) individuals revealed no significant difference in the frequency of the C allele at the c.1150 position (p = 0.34). One patient carrying the combination `pathogenic mutation plus the allelic variant c.1150T > C' had a typical achondroplasia (Ach) phenotype. In addition, three other patients with atypical phenotypes showed no association with the allelic variant. Together, these results do not support the hypothesis of a modulatory role for the c.1150T > C change in the FGFR3 gene.","variants":[{"Name":"NM_000142.5(FGFR3):c.1150T>C (p.Phe384Leu)","Chromosome":"4","Start":"1804404","Stop":"1804404","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":138143,"rule_based_match":true,"evidence_text":"c.1150T > C","llm_judgment":"PRESENT","evidence":"c.1150T > C","abstract_start":486,"abstract_end":497}]}
{"pmid":"28967191","title":"Missense variants in the X-linked gene PRPS1 cause retinal degeneration in females.","abstract":"Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next-generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation.","variants":[{"Name":"NM_002764.4(PRPS1):c.47C>T (p.Ser16Phe)","Chromosome":"X","Start":"107628675","Stop":"107628675","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439508,"rule_based_match":true,"evidence_text":"c.47C > T, p.(Ser16Phe)","llm_judgment":"PRESENT","evidence":"c.47C > T, p.(Ser16Phe)","abstract_start":361,"abstract_end":384},{"Name":"NM_002764.4(PRPS1):c.586C>T (p.Arg196Trp)","Chromosome":"X","Start":"107645232","Stop":"107645232","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439509,"rule_based_match":true,"evidence_text":"c.586C > T, p.(Arg196Trp)","llm_judgment":"PRESENT","evidence":"c.586C > T, p.(Arg196Trp)","abstract_start":386,"abstract_end":411},{"Name":"NM_002764.4(PRPS1):c.640C>T (p.Arg214Trp)","Chromosome":"X","Start":"107645286","Stop":"107645286","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439510,"rule_based_match":true,"evidence_text":"c.640C > T, p.(Arg214Trp)","llm_judgment":"PRESENT","evidence":"c.640C > T, p.(Arg214Trp)","abstract_start":444,"abstract_end":469},{"Name":"NM_002764.4(PRPS1):c.641G>C (p.Arg214Pro)","Chromosome":"X","Start":"107645287","Stop":"107645287","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":439511,"rule_based_match":true,"evidence_text":"c.641G > C, p.(Arg214Pro)","llm_judgment":"PRESENT","evidence":"c.641G > C, p.(Arg214Pro)","abstract_start":413,"abstract_end":438}]}
{"pmid":"31104773","title":"A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.","abstract":"The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.","variants":[{"Name":"NM_004068.4(AP2M1):c.508C>T (p.Arg170Trp)","Chromosome":"3","Start":"184180927","Stop":"184180927","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":677400,"rule_based_match":true,"evidence_text":"c.508C>T (p.Arg170Trp)","llm_judgment":"PRESENT","evidence":"c.508C>T (p.Arg170Trp)","abstract_start":494,"abstract_end":516}]}
{"pmid":"22665975","title":"Ala344Pro mutation in the FGFR2 gene and related clinical findings in one Chinese family with Crouzon syndrome.","abstract":"PURPOSE: The purpose of this study was to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in three Chinese patients with Crouzon syndrome and to characterize the related clinical features.\nMETHODS: A single family underwent complete ophthalmic examinations, and three patients were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood collected from members of the family as well as from 100 unrelated control subjects from the same population. Exons 8 and 10 of FGFR 2 were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, Pentacam, Goldmann perimetry, and computed tomography (CT) of the skull.\nRESULTS: The three patients were affected with shallow orbits and ocular proptosis, accompanied by mid-face hypoplasia and craniosynostosis, but had clinically normal hands and feet. A heterozygous FGFR2 missense mutation c.1030G>C (Ala344Pro) in exon 10 was identified in the affected individuals, but not in any of the unaffected family members or the normal controls. The mutation we identified has not previously been reported, either in China or abroad.\nCONCLUSIONS: Although FGFR2 mutations and polymorphisms have been reported in various ethnic groups, especially in the area of osteology, we report, for the first time, the identification of one new FGFR2 gene mutation in Chinese patients with Crouzon syndrome.","variants":[{"Name":"NM_000141.5(FGFR2):c.1030G>C (p.Ala344Pro)","Chromosome":"10","Start":"121517373","Stop":"121517373","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1061868,"rule_based_match":true,"evidence_text":"c.1030G>C (Ala344Pro)","llm_judgment":"PRESENT","evidence":"c.1030G>C (Ala344Pro)","abstract_start":1019,"abstract_end":1040}]}
{"pmid":"24845513","title":"The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma.","abstract":"We report intracellular RET mutation in a Han Chinese pedigree with familial medullary thyroid carcinoma (FMTC). Direct sequencing of RET proto-oncogene identified a missense c.2671T greater than G (p.S891A) mutation in 6 of 14 family members. The single nucleotide polymorphisms c. 135A greater than G (p.A45A), IVS4 + 48A greater than G, c. 1296A greater than G (p.A432A), c. 2071G greater than A (p.G691S), c. 2307T greater than G (p.L769L) and a variant c. 833C greater than A (p.T278N) were also found in 6 carriers. Among 5 of the 6 carriers presented medullary thyroid carcinoma (MTC) as an isolated clinical phenotype, with elevated basal serum calcitonin (Ct). Two underwent non-normative thyroidectomy either two or four times without physician awareness or diagnosis of this disease at initial treatment, but with elevated Ct. One with elevated pre-Ct accepted total thyroidectomy (TT) with modified bilateral neck dissection (MBiND), and whose seventh posterior rib MTC metastases was confirmed 5 months after surgery. Moreover, results of two affected individuals with elevated Ct were reduced to normal after TT with MBiND or prophylactic VI compartmental dissection. However, only another carrier with the variant p.T278N had slightly elevated Ct rejected surgery and was strictly monitored. Given these case results, we suggest that screening of RET and pre-surgical Ct levels in the management of MTC patients is essential for earlier diagnosis and more normative initial treatment, that FMTC patients with cervical lymph nodes metastases may be cured by TT with MBiND, and that prophylactic VI compartmental dissection should be avoided when Ct levels are low.","variants":[{"Name":"NM_020975.6(RET):c.2671T>G (p.Ser891Ala)","Chromosome":"10","Start":"43120144","Stop":"43120144","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":28990,"rule_based_match":false,"evidence_text":"c.2671T greater than G (p.S891A)","llm_judgment":"PRESENT","evidence":"c.2671T greater than G (p.S891A)","abstract_start":175,"abstract_end":207}]}
{"pmid":"21567926","title":"Clinical and molecular description of a Wilms tumor in a patient with tuberous sclerosis complex.","abstract":"We report on a girl affected with tuberous sclerosis, carrying a germline de novo TSC2 mutation, c.4934-4935delTT, leading to a p.F1645CfsX7, who developed a unilateral Wilms tumor (WT). Molecular investigation of the tumor biopsy at diagnosis revealed the loss of the constitutional wild-type TSC2 allele, and loss of heterozygosity for the WT1 gene. Deletion of the WTX gene was also present, but it involved the functionally inactive X chromosome. No mutation affecting the remaining WT1 and WTX alleles, as well as the CTNNB1 gene was found. Pathological examination of the surgical specimen documented the presence of diffuse anaplasia and p53 immunoreactivity. To the best of our knowledge, this is the second report of a patient with tuberous sclerosis who developed a WT, and it represents the first case in which a detailed clinical and molecular description is provided.","variants":[{"Name":"NM_000548.5(TSC2):c.4934_4935del (p.Phe1645fs)","Chromosome":"16","Start":"2086815","Stop":"2086816","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":59143,"rule_based_match":false,"evidence_text":"c.4934-4935delTT","llm_judgment":"PRESENT","evidence":"c.4934-4935delTT","abstract_start":97,"abstract_end":113}]}
{"pmid":"24482635","title":"Detection of heterozygous c.1708C>T and c.1978C>G thyroid peroxidase (TPO) mutations in Iraqi patients with toxic and nontoxic goiter.","abstract":"Sixty-three Arabic patients (16 males and 47 females) with thyroid toxic and nontoxic goiter who attended the endocrinologist in Nuclear Medicine Hospital and Al Yarmok Nuclear Medicine Department in Baghdad, Iraq were examined for thyroid peroxidase (TPO) gene mutations. A total of ten heterozygous mutations have been identified in the human <i>TPO</i> gene associated with thyroid toxic and nontoxic goiter. These mutations involved transition or transversion of cysteine either by thymine or guanine at the position 1708 of the exon 10 (c.1708C>T) and the position 1978 of the exon 11 (c.1978C>G). From a total of ten detected mutations, two c.1978C>G mutations were detected in nontoxic goiter patients and eight (two c.1708C>T and six c.1978C>G mutations) were detected in toxic goiter. In conclusion, this study identified ten TPO mutations associated with toxic and nontoxic goiter that have not been yet reported in Iraq, and most of them are detected among females (90 %) and adults age between 30 and 50 years old (80 %).","variants":[{"Name":"NM_001206744.2(TPO):c.1978C>G (p.Gln660Glu)","Chromosome":"2","Start":"1494011","Stop":"1494011","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":19092,"rule_based_match":true,"evidence_text":"c.1978C>G","llm_judgment":"PRESENT","evidence":"c.1978C>G","abstract_start":591,"abstract_end":600}]}
{"pmid":"30401457","title":"FUT2 Variants Confer Susceptibility to Familial Otitis Media.","abstract":"Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154<sup>∗</sup>) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202<sup>∗</sup>) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10<sup>-5</sup>) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154<sup>∗</sup>) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10<sup>-7</sup>) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154<sup>∗</sup>, and p.Arg202<sup>∗</sup>-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.","variants":[{"Name":"NM_000511.6(FUT2):c.604C>T (p.Arg202Ter)","Chromosome":"19","Start":"48703560","Stop":"48703560","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227407,"rule_based_match":true,"evidence_text":"FUT2 c.604C>T (p.Arg202<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"FUT2 c.604C>T (p.Arg202<sup>∗</sup>)","abstract_start":499,"abstract_end":535},{"Name":"NM_000511.6(FUT2):c.461G>A (p.Trp154Ter)","Chromosome":"19","Start":"48703417","Stop":"48703417","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27984,"rule_based_match":true,"evidence_text":"c.461G>A (p.Trp154<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"c.461G>A (p.Trp154<sup>∗</sup>)","abstract_start":68,"abstract_end":99},{"Name":"NM_000511.6(FUT2):c.412C>T (p.Arg138Cys)","Chromosome":"19","Start":"48703368","Stop":"48703368","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":984436,"rule_based_match":true,"evidence_text":"c.412C>T (p.Arg138Cys)","llm_judgment":"PRESENT","evidence":"c.412C>T (p.Arg138Cys)","abstract_start":642,"abstract_end":664}]}
{"pmid":"33509806","title":"Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (","abstract":"Pathogenic variants (PVs) in <i>ATM</i> are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate <i>ATM</i> PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (<i>N</i> = 627,742). Cancer risks for <i>ATM</i> PV carriers (<i>N</i> = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24-5.47), prostate (OR, 2.58; 95% CI, 1.93-3.44), gastric (OR, 2.97; 95% CI, 1.66-5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89-2.19) cancers were estimated for <i>ATM</i> PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76-5.12) than other missense and truncating <i>ATM</i> PVs. Low-to-moderate risks were seen for ductal carcinoma <i>in situ</i> (OR, 1.80; 95% CI, 1.61-2.02), male breast cancer (OR, 1.72; 95% CI, 1.08-2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35-1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24-1.79), and melanoma (OR, 1.46; 95% CI, 1.18-1.81). <i>ATM</i> PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. PREVENTION RELEVANCE: This study estimated risks for multiple cancers associated with <i>ATM</i> pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of <i>ATM</i> pathogenic variants.","variants":[{"Name":"NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)","Chromosome":"11","Start":"108329202","Stop":"108329202","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18062,"rule_based_match":true,"evidence_text":"c.7271T>G","llm_judgment":"PRESENT","evidence":"c.7271T>G","abstract_start":537,"abstract_end":546}]}
{"pmid":"30628995","title":"Clinical Characteristics of Autosomal Dominant GJA1 Missense Mutation Linked to Oculodentodigital Dysplasia in a Korean Family.","abstract":"PURPOSE: We aimed to present a comprehensive assessment of the ophthalmic characteristics of genetically confirmed oculodentodigital dysplasia (ODDD) in 4 members of a single Korean family across 3 generations.\nPATIENTS AND METHODS: The characteristics of 4 affected ODDD patients were evaluated. Comprehensive ophthalmic and medical examinations were performed in 3 patients including the proband, together with genetic analysis, and retrospective chart review was conducted for an affected ancestor. For genetic analysis, targeted gene panel sequencing was conducted using genomic DNA extracted from peripheral blood.\nRESULTS: All affected individuals in this family showed shared ophthalmic abnormalities of microcornea, microphthalmia, elevated intraocular pressure, and shallow anterior chamber, all of which have been reported as typical ocular features of ODDD. Myopic refractive error despite short axial length and thick cornea were highlighted as new findings of ODDD. Facial abnormalities were common in all affected members, but their fingers were normal. Severity of glaucoma was different among the affected individuals and seemed to depend on elevation of intraocular pressure, which occurred in narrow, but open-angle. Genetic analysis revealed the presence of c.119C>T (p.Ala40Val) in GJA1, which is responsible for ODDD, but not found in the control population.\nCONCLUSIONS: This report describes detailed ocular characteristics in a genetically confirmed ODDD family, including unreported findings of thick cornea and myopic refractive error despite short axial length. The ocular features derived from the A40V mutation in GJA1 showed complete penetrance, suggesting a possible role of Cx43 in regulation of IOP and pathogenesis of glaucoma.","variants":[{"Name":"NM_000165.5(GJA1):c.119C>T (p.Ala40Val)","Chromosome":"6","Start":"121446966","Stop":"121446966","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":428500,"rule_based_match":true,"evidence_text":"c.119C>T (p.Ala40Val)","llm_judgment":"PRESENT","evidence":"c.119C>T (p.Ala40Val)","abstract_start":1277,"abstract_end":1298}]}
{"pmid":"31288420","title":"Utility of Whole Blood Thiamine Pyrophosphate Evaluation in","abstract":"<i>TPK1</i> mutations are a rare, but potentially treatable, cause of thiamine deficiency. Diagnosis is challenging given the phenotypic overlap that exists with other metabolic and neurological disorders. We report a case of <i>TPK1</i>-related disease presenting with Leigh-like syndrome and review the diagnostic utility of thiamine pyrophosphate (TPP) blood measurement. The proband, a 35-year-old male, presented at four months of age with recurrent episodes of post-infectious encephalopathy. He subsequently developed epilepsy, learning difficulties, sensorineural hearing loss, spasticity, and dysphagia. There was a positive family history for Leigh syndrome in an older brother. Plasma lactate was elevated (3.51 mmol/L) and brain MRI showed bilateral basal ganglia hyperintensities, indicative of Leigh syndrome. Histochemical and spectrophotometric analysis of mitochondrial respiratory chain complexes I, II+III, and IV was normal. Genetic analysis of muscle mitochondrial DNA was negative. Whole exome sequencing of the proband confirmed compound heterozygous variants in <i>TPK1</i>: c. 426G>C (p. Leu142Phe) and c. 258+1G>A (p.?). Blood TPP levels were reduced, providing functional evidence for the deleterious effects of the variants. We highlight the clinical and bioinformatics challenges to diagnosing rare genetic disorders and the continued utility of biochemical analyses, despite major advances in DNA sequencing technology, when investigating novel, potentially disease-causing, genetic variants. Blood TPP measurement represents a fast and cost-effective diagnostic tool in <i>TPK1</i>-related diseases.","variants":[{"Name":"NM_022445.4(TPK1):c.426G>C (p.Leu142Phe)","Chromosome":"7","Start":"144591498","Stop":"144591498","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":259853,"rule_based_match":true,"evidence_text":"c. 426G>C (p. Leu142Phe)","llm_judgment":"PRESENT","evidence":"c. 426G>C (p. Leu142Phe)","abstract_start":1099,"abstract_end":1123}]}
{"pmid":"35923690","title":"Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in","abstract":"<b>Introduction:</b> Diamond Blackfan anemia (DBA) is an autosomal dominant ribosomopathy caused predominantly by pathogenic germline variants in ribosomal protein genes. It is characterized by failure of red blood cell production, and common features include congenital malformations and cancer predisposition. Mainstays of treatment are corticosteroids, red blood cell transfusions, and hematologic stem cell transplantation (HSCT). Despite a better understanding of the genotype of DBA, the biological mechanism resulting in the clinical phenotype remains poorly understood, and wide heterogeneity can be seen even within a single family as depicted here. <b>Case Description:</b> Thirty family members enrolled in the National Cancer Institute inherited bone marrow failure syndromes study were evaluated with detailed medical questionnaires and physical examinations, including 22 in the family bloodline and eight unrelated partners. Eight participants had been previously told they had DBA by clinical criteria. Targeted germline <i>RPS19</i> testing was done on all family members. A pathogenic heterozygous missense mutation in <i>RPS19</i> (p.R62Q, c.185G > A) was detected in ten family members, including one person previously presumed unaffected. Eight family members presented with macrocytic anemia in infancy; all of whom were responsive to prednisone. Four family members became treatment independent; however, one individual became transfusion-dependent 36 years later following an episode of pneumonia. One prednisone responsive individual electively discontinued steroid treatment, and lives with severe anemia. One prednisone responsive individual died at age 28 from a stroke. Two family members developed colorectal cancer in their fifties; one had never required treatment for anemia. None had major congenital anomalies. <b>Discussion:</b> This large family with DBA demonstrates the heterogeneity of phenotypes that can be seen within the same genotype. Most family members presented with steroid-responsive anemia in infancy and subtle congenital malformations, findings consistent with recent genotype-phenotype studies of <i>RPS</i> DBA. However, two family members were relatively unaffected, underscoring the importance of further studies to assess modifier genes, and epigenetic and/or environmental factors which may result in normal erythropoiesis despite underlying ribosome dysfunction. This large, multigenerational family highlights the need for individualized treatment, the importance of early cancer surveillance even in individuals with clinically mild phenotypes, and the benefit of long-term follow-up to identify late complications.","variants":[{"Name":"NM_001022.4(RPS19):c.185G>A (p.Arg62Gln)","Chromosome":"19","Start":"41869043","Stop":"41869043","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":468836,"rule_based_match":true,"evidence_text":"c.185G > A","llm_judgment":"PRESENT","evidence":"c.185G > A","abstract_start":1159,"abstract_end":1169}]}
{"pmid":"18930476","title":"Phenotypic variability in a Spanish family with a Caveolin-3 mutation.","abstract":"UNLABELLED: We report a Spanish family affected from a late onset, hand-involved and autosomal dominant distal myopathy associated to Caveolin-3 mutation. Signs of muscle hyperexcitability and hyperckemia were observed in the youngest relatives but not motor symptoms.\nPATIENTS AND METHODS: Neurological examination was performed in all members of the family. Muscle biopsy sample was taken from the proband and DNA genomics was amplified for the two exons of Cav-3 by the polymerase chain reaction (PCR) in all the affected members and in three asymptomatic relatives.\nRESULTS: Signs of muscle hyperexcitability and hyperckemia were observed in the affected members from early ages. Cav-3 expression was greatly reduced in the sarcolemma of the proband's muscle. Genetic studies revealed a G --> A transition at nucleotide position 80 in exon 1 of the Cav-3 gene (c.80G>A), generating a Arg --> Gln change at codon 27 (p.R27Q) of the amino acid chain in heterozygous state, while no mutation was found in unaffected members.\nCONCLUSIONS: Signs of muscle hyperexcitability and hyperckemia at early ages may predict the development of a late onset autosomal dominant hand-involved myopathy associated to Cav-3 mutation in the family reported herein.","variants":[{"Name":"NM_033337.3(CAV3):c.80G>A (p.Arg27Gln)","Chromosome":"3","Start":"8733956","Stop":"8733956","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23322,"rule_based_match":true,"evidence_text":"c.80G>A","llm_judgment":"PRESENT","evidence":"c.80G>A","abstract_start":865,"abstract_end":872}]}
{"pmid":"36231052","title":"A Novel Missense Mutation in","abstract":"Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation <i>ERCC8</i>:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in <i>ERCC8</i> as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. <i>ERCC8</i> plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of <i>ERCC8</i> mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.","variants":[{"Name":"NM_000082.4(ERCC8):c.176T>C (p.Met59Thr)","Chromosome":"5","Start":"60922153","Stop":"60922153","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3499310,"rule_based_match":true,"evidence_text":"ERCC8:c.176T>C (p.M59T)","llm_judgment":"PRESENT","evidence":"c.176T>C","abstract_start":597,"abstract_end":605}]}
{"pmid":"31880392","title":"Biallelic c.1263dupC in DOK7 results in fetal akinesia deformation sequence.","abstract":"Fetal akinesia deformation sequence (FADS) is a clinically and genetically heterogeneous condition. Pathogenic variants in DOK7 are known to cause myasthenic syndrome, congenital, 10 (MIM#254300) and, rarely (reported in a single family) lethal FADS. Herein, we describe a biallelic variant c.1263dupC in DOK7, known to cause congenital myasthenic syndrome 10, causing lethal FADS in a consanguineous family. The present report illustrates wide phenotypic variability caused by biallelic pathogenic variants in DOK7. We also describe the second family with FADS due to pathogenic variants in DOK7.","variants":[{"Name":"NM_173660.5(DOK7):c.1263dup (p.Ser422fs)","Chromosome":"4","Start":"3493242","Stop":"3493243","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":16313,"rule_based_match":true,"evidence_text":"c.1263dupC","llm_judgment":"PRESENT","evidence":"c.1263dupC","abstract_start":291,"abstract_end":301}]}
{"pmid":"26729423","title":"A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2).","abstract":"Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), a G-protein coupled receptor that predominantly signals via G-protein subunit alpha-11 (Gα11 ) to regulate calcium homeostasis. FHH2 is the result of loss-of-function mutations in Gα11 , encoded by GNA11, and to date only two FHH2-associated Gα11 missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss-of-function mutations of the adaptor protein-2 σ-subunit (AP2σ), which plays a pivotal role in clathrin-mediated endocytosis. We describe a 65-year-old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα11 variant was assessed by homology modeling of the related Gαq protein and by measuring the CaSR-mediated intracellular calcium (Ca(2+) i ) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca(2+) o ) using flow cytometry. Three-dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα11 helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild-type and the mutant Gα11 in HEK293 cells stably expressing CaSR demonstrate that the Ca(2+) i responses after stimulation with Ca(2+) o of the mutant Met54 Gα11 led to a rightward shift of the concentration-response curve with a significantly (p < 0.01) increased mean half-maximal concentration (EC50 ) value of 3.88 mM (95% confidence interval [CI] 3.76-4.01 mM), when compared with the wild-type EC50 of 2.94 mM (95% CI 2.81-3.07 mM) consistent with a loss-of-function. Thus, our studies have identified a third Gα11 mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα11 interdomain interface in CaSR signaling and Ca(2+) o homeostasis. © 2016 American Society for Bone and Mineral Research.","variants":[{"Name":"NM_002067.5(GNA11):c.161C>T (p.Thr54Met)","Chromosome":"19","Start":"3110173","Stop":"3110173","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1275224,"rule_based_match":true,"evidence_text":"c.161C>T; p.Thr54Met","llm_judgment":"PRESENT","evidence":"c.161C>T; p.Thr54Met","abstract_start":1018,"abstract_end":1038}]}
{"pmid":"33470548","title":"A novel SLC4A1 splice variant (c.2655+2_2655+3 del) in hereditary spherocytosis.","abstract":"","variants":[{"Name":"NM_000342.4(SLC4A1):c.2655+2_2655+3del","Chromosome":"17","Start":"44251156","Stop":"44251157","ReferenceAlleleVCF":"TCA","AlternateAlleleVCF":"T","allel_id":1698898,"rule_based_match":true,"evidence_text":"c.2655+2_2655+3 del","llm_judgment":"PRESENT","evidence":"c.2655+2_2655+3 del","abstract_start":null,"abstract_end":null}]}
{"pmid":"27271331","title":"DNA studies are necessary for accurate patient diagnosis in compound heterozygosity for Hb Adana (HBA2:c.179>A) with deletional or nondeletional α-thalassaemia.","abstract":"Haemoglobin (Hb) Adana (HBA2:c.179>A) interacts with deletional and nondeletional α-thalassaemia mutations to produce HbH disorders with varying clinical manifestations from asymptomatic to severe anaemia with significant hepatosplenomegaly. Hb Adana carriers are generally asymptomatic and haemoglobin subtyping is unable to detect this highly unstable α-haemoglobin variant. This study identified 13 patients with compound heterozygosity for Hb Adana with either the 3.7 kb gene deletion (-α(3.7)), Hb Constant Spring (HbCS) (HBA2:c.427T>C) or Hb Paksé (HBA2:429A>T). Multiplex Amplification Refractory Mutation System was used for the detection of five deletional and six nondeletional α-thalassaemia mutations. Duplex-PCR was used to confirm Hb Paksé and HbCS. Results showed 84.6% of the Hb Adana patients were Malays. Using DNA studies, compound heterozygosity for Hb Adana and HbCS (α(codon 59)α/α(CS)α) was confirmed in 11 patients. A novel point in this investigation was that DNA studies confirmed Hb Paksé for the first time in a Malaysian patient (α(codon 59)α/α(Paksé)α) after nine years of being misdiagnosis with Hb Adana and HbCS (α(codon 59)α/α(CS)α). Thus, the reliance on haematology studies and Hb subtyping to detect Hb variants is inadequate in countries where thalassaemia is prevalent and caused by a wide spectrum of mutations.","variants":[{"Name":"NM_000517.4(HBA2):c.427T>C (p.Ter143Gln)","Chromosome":"16","Start":"173598","Stop":"173598","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":30663,"rule_based_match":true,"evidence_text":"Hb Constant Spring (HbCS) (HBA2:c.427T>C)","llm_judgment":"PRESENT","evidence":"Hb Constant Spring (HbCS) (HBA2:c.427T>C)","abstract_start":501,"abstract_end":542}]}
{"pmid":"31020813","title":"Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice-site and Charcot-Marie-Tooth phenotype with early onset symptoms.","abstract":"BACKGROUND: Rare variants (RV) in immunoglobulin mu-binding protein 2 (IGHMBP2) [OMIM 600502] can cause an autosomal recessive type of Charcot-Marie-Tooth (CMT) disease [OMIM 616155], an inherited peripheral neuropathy. Over 40 different genes are associated with CMT, with different possible inheritance patterns.\nMETHODS AND RESULTS: An 11-year-old female with motor delays was found to have distal atrophy, weakness, and areflexia without bulbar or sensory findings. Her clinical evaluation was unrevealing. Whole exome sequencing (WES) revealed a maternally inherited IGHMBP2 RV (c.1730T>C) predicted to be pathogenic, but no variant on the other allele was identified. Deletion and duplication analysis was negative. She was referred to the Undiagnosed Disease Network (UDN) for further evaluation. Whole genome sequencing (WGS) confirmed the previously identified IGHMBP2 RV and identified a paternally inherited non-coding IGHMBP2 RV. This was predicted to activate a cryptic splice site perturbing IGHMBP2 splicing. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was consistent with activation of the cryptic splice site. The abnormal transcript was shown to undergo nonsense-mediated decay (NMD), resulting in halpoinsufficiency.\nCONCLUSION: This case demonstrates the deficiencies of WES and traditional molecular analyses and highlights the advantages of utilization of WGS and functional studies.","variants":[{"Name":"NM_002180.3(IGHMBP2):c.1730T>C (p.Leu577Pro)","Chromosome":"11","Start":"68935396","Stop":"68935396","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":513441,"rule_based_match":true,"evidence_text":"c.1730T>C","llm_judgment":"PRESENT","evidence":"c.1730T>C","abstract_start":584,"abstract_end":593}]}
{"pmid":"26036859","title":"Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction.","abstract":"Familial hypercholesterolemia (FH) is an oligogenic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDLC) levels. Variants in four genes have been reported to cause the classical autosomal-dominant form of the disease. FH is largely under-diagnosed in European countries. As FH increases the risk for coronary artery disease (CAD) and myocardial infarction (MI), it might be specifically overlooked in the large number of such patients. Here, we systematically examined the frequency of potential FH-causing variants by exome sequencing in 255 German patients with premature MI and a positive family history for CAD. We further performed co-segregation analyses in an average of 5.5 family members per MI patient. In total, we identified 11 potential disease-causing variants that co-segregate within the families, that is, 5% of patients with premature MI and positive CAD family history had FH. Eight variants were previously reported as disease-causing and three are novel (LDLR.c.811G>A p.(V271I)), PCSK9.c.610G>A (p.(D204N)) and STAP1.c.139A>G (p.(T47A))). Co-segregation analyses identified multiple additional family members carrying one of these FH variants and the clinical phenotype of either FH (n=2) or FH and premature CAD (n=15). However, exome sequencing also revealed that some variants in FH genes, which have been reported to cause FH, do not co-segregate with FH. The data reveal that a large proportion of FH patients escape the diagnosis, even when they have premature MI. Hence, systematic molecular-genetic screening for FH in such patients may reveal a substantial number of cases and thereby allow a timely LDLC-lowering in both FH/MI patients as well as their variant-carrying family members.","variants":[{"Name":"NM_012108.4(STAP1):c.139A>G (p.Thr47Ala)","Chromosome":"4","Start":"67571102","Stop":"67571102","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":187192,"rule_based_match":true,"evidence_text":"STAP1.c.139A>G (p.(T47A))","llm_judgment":"PRESENT","evidence":"STAP1.c.139A>G (p.(T47A))","abstract_start":1067,"abstract_end":1092},{"Name":"NM_000527.5(LDLR):c.811G>A (p.Val271Ile)","Chromosome":"19","Start":"11106681","Stop":"11106681","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187194,"rule_based_match":true,"evidence_text":"LDLR.c.811G>A p.(V271I)","llm_judgment":"PRESENT","evidence":"LDLR.c.811G>A p.(V271I)","abstract_start":1010,"abstract_end":1033}]}
{"pmid":"18182741","title":"A novel SPINK1 gene mutation, c.206C>T, in a Thai patient with chronic alcoholic pancreatitis.","abstract":"CONTEXT: The exact mechanism of alcoholic pancreatitis has not yet been clarified. Recent studies suggest that alcohol represents only a risk factor for developing pancreatic inflammation in genetic or environmental susceptible subjects. In this regard, various genes involving an alcohol-metabolizing pathway or pancreatitis protecting factors have been extensively studied in order to identify genetic predisposition to alcoholic pancreatitis.\nCASE REPORT: A 43-year-old man with a history of heavy alcohol drinking presented with recurrent abdominal pain. Alcoholic pancreatitis was diagnosed and responded well to pancreatic stricture dilatation with stent insertion. Sequencing analysis revealed that he was heterozygous for a novel transition c.206C>T in exon 4 of the SPINK1 gene, resulting in the substitution of threonine for isoleucine at codon 69 (T69I). Evidence supporting its etiologic role includes the alteration of the polarity of the amino acid change, its revolutionary conservation among mammals and its absence in 100 ethnic-matched control alleles.\nCONCLUSIONS: We identified a novel SPINK1 mutation, c.206C>T (T69I), in a Thai patient with alcoholic pancreatitis. This extends the total number of confirmed SPINK1 mutations and polymorphisms to more than 30. It also supports a previous observation that the SPINK1 gene is a susceptibility locus for alcoholic pancreatitis.","variants":[{"Name":"NM_001379610.1(SPINK1):c.206C>T (p.Thr69Ile)","Chromosome":"5","Start":"147824695","Stop":"147824695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":433010,"rule_based_match":true,"evidence_text":"c.206C>T","llm_judgment":"PRESENT","evidence":"c.206C>T","abstract_start":749,"abstract_end":757}]}
{"pmid":"24762113","title":"Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations.","abstract":"CONTEXT: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common.\nOBJECTIVE: The aim was to identify underlying genetic causes of short stature with advanced bone age.\nSETTING AND DESIGN: We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation.\nRESULTS: Affected individuals presented with short stature [adult heights -2.3 to -4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS -1.9 to -3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c.2026+1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function.\nCONCLUSIONS: Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation.","variants":[{"Name":"NM_001369268.1(ACAN):c.2026+1G>A","Chromosome":"15","Start":"88849732","Stop":"88849732","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":434370,"rule_based_match":true,"evidence_text":"c.2026+1G>A","llm_judgment":"PRESENT","evidence":"c.2026+1G>A","abstract_start":1215,"abstract_end":1226}]}
{"pmid":"24700531","title":"A novel homozygous ERCC5 truncating mutation in a family with prenatal arthrogryposis--further evidence of genotype-phenotype correlation.","abstract":"We report on a family with five fetuses conceived to first cousin parents presenting with abnormal ultrasound findings including contractures and microcephaly. Cerebellar hypoplasia and ventriculomegaly were also present in two and fetal edema developed in the one fetus that survived beyond 24 weeks of gestation. Linkage studies of 15 members of the family, including four affecteds, were undertaken followed by exome sequencing of one affected individual and their parents. Analysis of exome data was restricted to the 9.3 Mb largest shared region of homozygosity identified by linkage; a single novel homozygous mutation in the proband that was heterozygous in the parents (ERCC5 c.2766dupA, p.Leu923ThrfsX7) was identified. This segregated with disease. ERCC5 is a component of the nucleotide excision repair machinery and biallelic mutations in the gene have previously been associated with xeroderma pigmentosum (group G), Cockayne syndrome and the more severe cerebrooculofacioskeletal syndrome. The phenotype in the family we report on is consistent with a severe manifestation of cerebrooculofacioskeletal syndrome. Our data broaden the reported clinical spectrum of ERCC5 mutations and provide further evidence of genotype-phenotype correlation with truncating mutations being associated with severe phenotypes. They also demonstrate the molecular diagnostic power of a combined approach of linkage studies and exome sequencing in families with rare, genetically heterogeneous disorders and a well described pedigree.","variants":[{"Name":"NM_000123.4(ERCC5):c.2766dup (p.Leu923fs)","Chromosome":"13","Start":"102872283","Stop":"102872284","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":206564,"rule_based_match":true,"evidence_text":"ERCC5 c.2766dupA, p.Leu923ThrfsX7","llm_judgment":"PRESENT","evidence":"ERCC5 c.2766dupA, p.Leu923ThrfsX7","abstract_start":678,"abstract_end":711}]}
{"pmid":"26709265","title":"Two Likely Pathogenic Variants of COL2A1 in Unrelated Korean Patients With Ocular-Only Variants of Stickler Syndrome: The First Molecular Diagnosis in Korea.","abstract":"Stickler syndrome is a genetically heterogeneous disorder that affects the ocular, auditory, and musculoskeletal systems. Ocular-only variant of Stickler syndrome type 1 (OSTL1) is characterized by high risk of retinal detachment without systemic involvement and is caused by alternatively spliced exon 2 mutation of COL2A1. We report the cases of two Korean families with OSTL1 carrying likely pathogenic variants of COL2A1. All patients presented with membranous vitreous anomaly, peripheral retinal degeneration, and/or rhegmatogenous retinal detachment, but no systemic manifestations. By genetic analysis, two likely pathogenic non-exon 2 variants, c.2678dupC (p.Ala895Serfs*49) and c.3327+ 1G>C, were identified in COL2A1. Our results demonstrate that COL2A1 defects in OSTL1 are not confined to mutations in exon 2. Together with molecular data, ophthalmologists should consider genetic diagnosis of Stickler syndrome in patients with vitreous anomaly to prevent blindness from retinal detachment. To our knowledge, this is the first report of genetically confirmed OSTL1 in Korea.","variants":[{"Name":"NM_001844.5(COL2A1):c.2678dup (p.Ala895fs)","Chromosome":"12","Start":"47980009","Stop":"47980010","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":956878,"rule_based_match":true,"evidence_text":"c.2678dupC (p.Ala895Serfs*49)","llm_judgment":"PRESENT","evidence":"c.2678dupC (p.Ala895Serfs*49)","abstract_start":654,"abstract_end":683}]}
{"pmid":"30220951","title":"A Case of Recurrent Pregnancy-Induced Adult Onset Familial Hemophagocytic Lymphohistiocytosis.","abstract":"Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal disease primarily of children, characterized by a severe hyperinflammatory state. We describe a case of adult onset familial HLH with a novel exon 19, c.1607G>T (p.Arg536Leu) heterozygous mutation of the <i>UNC13D</i> gene in a 40-year-old woman who developed HLH during her first and second pregnancies, both episodes occurring during the first trimester. Our patient was treated successfully both times with HLH-94 protocol following spontaneous abortions and is currently in the process of getting a bone marrow transplant. We also discuss pregnancy as a potential trigger for late onset familial HLH.","variants":[{"Name":"NM_199242.3(UNC13D):c.1607G>T (p.Arg536Leu)","Chromosome":"17","Start":"75835767","Stop":"75835767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":468851,"rule_based_match":true,"evidence_text":"c.1607G>T (p.Arg536Leu)","llm_judgment":"PRESENT","evidence":"c.1607G>T (p.Arg536Leu)","abstract_start":224,"abstract_end":247}]}
{"pmid":"34675999","title":"Whole-exome sequencing identifies an","abstract":"A notable behavioural feature of X-linked retinoschisis (XLRS) is extensive structural schisis (splitting) of the outer plexiform and inner nuclear layers of the neurosensory retina, which is partly combined with complications related to vitreous hemorrhage, macular holes and retinal detachment. The present study aimed to identify the pathogenic gene mutation in a three-generation Chinese family with XLRS by whole-exome sequencing (WES). The clinical information of a three-generation Chinese family with cases of XLRS was collected. WES was performed for the proband. A comparison with the human reference genome sequence (hg38) and bioinformatic analysis were performed to reveal putative variants and Sanger sequencing was applied to verify mutations in this family and healthy control participants. Intraretinal cystic spaces were detected by optical coherence tomography imaging. Structures of the wild-type and mutant retinoschisin 1 (RS1) protein were modelled by PyMol. Almost all patients had a history of vision loss and abnormal blue-purple colour vision; however, the phenotypes of the 4 patients were distinctly different. There was no linear correlation between phenotypic severity and age. A recurrent <i>RS1</i> (Xp22.2) mutation (NM_000330: c.559C>T) was detected, resulting in the p.Q187X variant. According to the protein model, this variant is likely pathogenic. The present study was the first to report that <i>RS1</i>:c.559C>T induces XLRS in a three-generation Chinese pedigree, with the mutation leading to premature termination of translation of the RS1 protein. WES was able to diagnose XLRS, which has the characteristics of clinical and genetic heterogeneity.","variants":[{"Name":"NM_000330.4(RS1):c.559C>T (p.Gln187Ter)","Chromosome":"X","Start":"18642120","Stop":"18642120","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3408574,"rule_based_match":true,"evidence_text":"NM_000330: c.559C>T","llm_judgment":"PRESENT","evidence":"NM_000330: c.559C>T","abstract_start":1251,"abstract_end":1270}]}
{"pmid":"24801240","title":"Congenital dyserythropoietic anemia, type II with SEC23B exon 12 c.1385 A → G mutation, and pseudo-Gaucher cells in two siblings.","abstract":"OBJECTIVE AND IMPORTANCE: Congenital dyserythropoietic anemia (CDA) represents a genotypically and phenotypically heterogeneous group of disorders. CDA type II, the most frequent variant, was recently shown to be caused by mutations in the gene encoding the secretory COPII component SEC23B. We report two siblings hailing from Punjab in northern India with classical CDA type II where this mutation was demonstrated.\nCLINICAL PRESENTATION: A 7-year-old girl presented with transfusion-dependent anemia, splenomegaly, and progressive growth failure since 1 year of age. Her 5-year-old brother was similarly afflicted, but there was no other family history. Extensive prior work-up for hemolytic anemia, storage and metabolic disorders, and infectious diseases was negative. Hemoglobin was 71 g/l with normal leukocyte, platelet, and corrected reticulocyte counts. Bone marrow examination revealed marked normoblastic erythroid hyperplasia with dyserythropoiesis (36%) and the presence of bi- and multinucleated erythroblasts with equal-sized nuclei. Many pseudo-Gaucher cells were also seen. Iron stores were increased although ring sideroblasts were absent. Hereditary erythrocyte multinuclearity with positive acidified serum (HEMPAS) test revealed lysis of the red cells in four out of five control sera.\nTECHNIQUE: Genomic DNA sequencing of the SEC23B exon 12 revealed homozygosity for c.1385 A → G; Y462C mutations in both siblings.\nCONCLUSION: CDA has traditionally been a difficult diagnosis to establish, since it requires exclusion of other causes of dyserythropoiesis and the performance of complex tests including HEMPAS and electron microscopy for confirmation. The availability of molecular genetic testing for SEC23B promises to streamline and hasten the diagnostic process for this rare and intriguing disease.","variants":[{"Name":"NM_006363.6(SEC23B):c.1385A>G (p.Tyr462Cys)","Chromosome":"20","Start":"18535723","Stop":"18535723","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1315305,"rule_based_match":false,"evidence_text":"c.1385 A → G; Y462C","llm_judgment":"PRESENT","evidence":"c.1385 A → G; Y462C","abstract_start":1390,"abstract_end":1409}]}
{"pmid":"24989076","title":"Finnish Fanconi anemia mutations and hereditary predisposition to breast and prostate cancer.","abstract":"Mutations in downstream Fanconi anemia (FA) pathway genes, BRCA2, PALB2, BRIP1 and RAD51C, explain part of the hereditary breast cancer susceptibility, but the contribution of other FA genes has remained questionable. Due to FA's rarity, the finding of recurrent deleterious FA mutations among breast cancer families is challenging. The use of founder populations, such as the Finns, could provide some advantage in this. Here, we have resolved complementation groups and causative mutations of five FA patients, representing the first mutation confirmed FA cases in Finland. These patients belonged to complementation groups FA-A (n = 3), FA-G (n = 1) and FA-I (n = 1). The prevalence of the six FA causing mutations was then studied in breast (n = 1840) and prostate (n = 565) cancer cohorts, and in matched controls (n = 1176 females, n = 469 males). All mutations were recurrent, but no significant association with cancer susceptibility was observed for any: the prevalence of FANCI c.2957_2969del and c.3041G>A mutations was even highest in healthy males (1.7%). This strengthens the exclusive role of downstream genes in cancer predisposition. From a clinical point of view, current results provide fundamental information of the mutations to be tested first in all suspected FA cases in Finland.","variants":[{"Name":"NM_001113378.2(FANCI):c.3041G>A (p.Cys1014Tyr)","Chromosome":"15","Start":"89303898","Stop":"89303898","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620531,"rule_based_match":true,"evidence_text":"c.3041G>A","llm_judgment":"PRESENT","evidence":"c.3041G>A","abstract_start":1007,"abstract_end":1016}]}
{"pmid":"25453094","title":"Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue.","abstract":"Jervell and Lange-Nielsen syndrome (JLNS) is one of the most severe life-threatening cardiac arrhythmias. Patients display delayed cardiac repolarization, associated high risk of sudden death due to ventricular tachycardia, and congenital bilateral deafness. In contrast to the autosomal dominant forms of long QT syndrome, JLNS is a recessive trait, resulting from homozygous (or compound heterozygous) mutations in KCNQ1 or KCNE1. These genes encode the α and β subunits, respectively, of the ion channel conducting the slow component of the delayed rectifier K(+) current, IKs. We used complementary approaches, reprogramming patient cells and genetic engineering, to generate human induced pluripotent stem cell (hiPSC) models of JLNS, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1. Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs) from homozygous JLNS, heterozygous, and wild-type lines recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of IKs. We show that this phenotype had distinct underlying molecular mechanisms in the two sets of cell lines: the previously unidentified c.478-2A>T mutation was amorphic and gave rise to a strictly recessive phenotype in JLNS-CMs, whereas the missense c.1781G>A lesion caused a gene dosage-dependent channel reduction at the cell membrane. Moreover, adrenergic stimulation caused action potential prolongation specifically in JLNS-CMs. Furthermore, sensitivity to proarrhythmic drugs was strongly enhanced in JLNS-CMs but could be pharmacologically corrected. Our data provide mechanistic insight into distinct classes of JLNS-causing mutations and demonstrate the potential of hiPSC-CMs in drug evaluation.","variants":[{"Name":"NM_000218.3(KCNQ1):c.1781G>A (p.Arg594Gln)","Chromosome":"11","Start":"2778024","Stop":"2778024","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67686,"rule_based_match":true,"evidence_text":"c.1781G>A","llm_judgment":"PRESENT","evidence":"c.1781G>A","abstract_start":788,"abstract_end":797}]}
{"pmid":"34755279","title":"Adult-onset vanishing white matter in a patient with EIF2B3 variants misdiagnosed as multiple sclerosis.","abstract":"BACKGROUND: Vanishing white matter (VWM) is an autosomal recessive disorder characterized by childhood ataxia with central hypomyelination. Adult-onset VWM should be considered as a differential diagnosis for suspected cases of multiple sclerosis (MS).\nMETHODS: Targeted region sequencing (TRS) and Sanger sequencing validation were performed to identify and validate the likely pathogenic mutations in a family with VWM.\nRESULTS: The main clinical manifestations of the proband included decreased vision and sleepiness accompanied by atrophy of the corpus callosum, affected inner rim of the corpus callosum, decreased apparent diffusion coefficient value or persistent hyperintensity-diffusion-weighted imaging, atrophied optic nerve, and no recordable visual evoked potentials. Due to the slow development and atypical VWM image features, MS was initially suspected. After prednisone was administered, the patient's condition did not improve significantly, and other diseases were considered. The TRS and Sanger sequencing identified compound heterozygous mutations of EIF2B3 in the proband; c.965C > G /p.Ala322Gly in exon 8 and c.130G > A/p.Glu44Lys in exon 2 were missense mutations inherited from the mother and father, respectively. The proband's oldest brother had the same compound heterozygous mutations but showed no symptoms.\nCONCLUSION: This is the first report of adult-onset VWM in a Chinese family. Initially, MS was suspected, and genetic testing confirmed the diagnosis of VWM. This study may further broaden the clinical spectrum of EIF2B3, thus providing a foundation for further research on the pathogenesis and genetic therapy for VWM.","variants":[{"Name":"NM_020365.5(EIF2B3):c.130G>A (p.Glu44Lys)","Chromosome":"1","Start":"44981039","Stop":"44981039","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":280656,"rule_based_match":true,"evidence_text":"c.130G > A/p.Glu44Lys","llm_judgment":"PRESENT","evidence":"c.130G > A/p.Glu44Lys","abstract_start":1133,"abstract_end":1154}]}
{"pmid":"28624958","title":"Whole-exome sequencing identified compound heterozygous variants in MMKS in a Chinese pedigree with Bardet-Biedl syndrome.","abstract":"Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. At least 21 candidate BBS-associated genes (BBS1-19, NPHP1, and IFT172) have previously been identified, and all of them play important roles in ciliary function. Here, we collected a BBS pedigree with four members and performed whole-exome sequencing on the proband. The variants were analyzed and evaluated to confirm their pathogenicity. We found compound heterozygous variants (c.1192C>T, p.Q398* and c.1175C>T, p.T392M) in MKKS in both the siblings, and these were likely to be pathogenic variants. We also found a missense variant (c.2029G>C, p.E677Q) in NPHP1 and a missense variant (c.2470C>T, p.R824C) in BBS9 in the proband only, which are variants of uncertain significance. The compound heterozygous variants were probably responsible for the BBS phenotype in this Chinese pedigree and the missense mutations in NPHP1 and BBS9 might contribute to the mutation load.","variants":[{"Name":"NM_170784.3(MKKS):c.1175C>T (p.Thr392Met)","Chromosome":"20","Start":"10407713","Stop":"10407713","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1400701,"rule_based_match":true,"evidence_text":"c.1175C>T, p.T392M","llm_judgment":"PRESENT","evidence":"c.1175C>T, p.T392M","abstract_start":571,"abstract_end":589}]}
{"pmid":"30745910","title":"Identification of a Novel","abstract":"Alport syndrome (AS) is a rare and inherited renal disorder with an autosomal recessive mode of inheritance. AS patients usually manifest with hematuria and progressive renal disorder also occasionally accompanied by hearing loss and ophthalmic disease. Germline variants in collagen type IV α-4 (<i>COL4A4</i>) gene lead to autosomal recessive Alport syndrome. In the present study, we investigated a Chinese family with Alport syndrome. The index patient is a 24-year-old Chinese woman who has been suffering from proteinuria. Renal biopsy and renal pathology were performed and found focal segmental glomerulosclerosis (FSGS) like lesion in the index patient. The index patient also presented with binocular edema and blurred vision. However, binocular edema dissipated gradually without any further treatment. Unlikely, the index patient was not diagnosed with hearing impairment. Index patient's parents are phenotypically normal. Targeted next generation sequencing and Sanger sequencing was performed. A novel heterozygous single nucleotide insertion, c.4760_4761insC and a previously reported likely pathogenic variant, c.1323_1340delTGGCTTGCCTGGAGCACC in the <i>COL4A4</i> gene were identified in the index patient. The novel heterozygous single nucleotide insertion (c.4760_4761insC) leads to a frameshift which eventually results in the formations of a truncated COL4A4 protein. In addition, the other heterozygous likely pathogenic variant, c.1323_1340delTGGCTTGCCTGGAGCACC, has been already identified with causing AS an autosomal recessive mode of inheritance. Sanger sequencing confirmed that these two variants were inherited in the index patient from her father and mother, respectively. These two variants were not found in 100 normal control individuals. In conclusion, our present finding emphasizes the significance of high throughput targeted next generation sequencing technology for rapid and cost-effective genetic screening which allows us easy and accurate clinical diagnosis of AS patients.","variants":[{"Name":"NM_000092.5(COL4A4):c.1323_1340del (p.Pro444_Leu449del)","Chromosome":"2","Start":"227094154","Stop":"227094171","ReferenceAlleleVCF":"TGGTGCTCCAGGCAAGCCA","AlternateAlleleVCF":"T","allel_id":541966,"rule_based_match":true,"evidence_text":"c.1323_1340delTGGCTTGCCTGGAGCACC","llm_judgment":"PRESENT","evidence":"c.1323_1340delTGGCTTGCCTGGAGCACC","abstract_start":1128,"abstract_end":1160}]}
{"pmid":"30157172","title":"Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa.","abstract":"We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.","variants":[{"Name":"NM_001377458.1(CLCC1):c.75C>A (p.Asp25Glu)","Chromosome":"1","Start":"108950363","Stop":"108950363","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":961063,"rule_based_match":true,"evidence_text":"c.75C>A (p.D25E)","llm_judgment":"PRESENT","evidence":"c.75C>A","abstract_start":48,"abstract_end":55}]}
{"pmid":"24501230","title":"Functional analysis of MSH2 unclassified variants found in suspected Lynch syndrome patients reveals pathogenicity due to attenuated mismatch repair.","abstract":"BACKGROUND: Lynch syndrome, an autosomal-dominant disorder characterised by high colorectal and endometrial cancer risks, is caused by inherited mutations in DNA mismatch repair (MMR) genes. Mutations fully abrogating gene function are unambiguously disease causing. However, missense mutations often have unknown functional implications, hampering genetic counselling. We have applied a novel approach to study three MSH2 unclassified variants (UVs) found in Dutch families with suspected Lynch syndrome.\nMETHODS: The three mutations were recreated in the endogenous Msh2 gene in mouse embryonic stem cells by oligonucleotide-directed gene modification. The effect of the UVs on MMR activity was then tested using a set of functional assays interrogating the main MMR functions.\nRESULTS: We recreated and functionally tested three MSH2 UVs: MSH2-Y165D (c.493T>G), MSH2-Q690E (c.2068C>G) and MSH2-M813V (c.2437A>G). We observed reduced levels of MSH2-Y165D and MSH2-Q690E but not MSH2-M813V proteins. MSH2-M813V was able to support all MMR functions similar to wild-type MSH2, whereas MSH2-Y165D and MSH2-Q690E showed partial defects.\nCONCLUSIONS: Based on the results from our functional assays, we conclude that the MSH2-M813V variant is not disease causing. The MSH2-Y165D and MSH2-Q690E variants affect MMR function and are therefore likely the underlying cause of familial cancer predisposition. Since the MMR defect is partial, these variants may represent low penetrance alleles.","variants":[{"Name":"NM_000251.3(MSH2):c.2437A>G (p.Met813Val)","Chromosome":"2","Start":"47478498","Stop":"47478498","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":96447,"rule_based_match":true,"evidence_text":"MSH2-M813V (c.2437A>G)","llm_judgment":"PRESENT","evidence":"MSH2-M813V (c.2437A>G)","abstract_start":892,"abstract_end":914},{"Name":"NM_000251.3(MSH2):c.493T>G (p.Tyr165Asp)","Chromosome":"2","Start":"47410220","Stop":"47410220","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":96586,"rule_based_match":true,"evidence_text":"c.493T>G","llm_judgment":"PRESENT","evidence":"c.493T>G","abstract_start":854,"abstract_end":862},{"Name":"NM_000251.3(MSH2):c.2068C>G (p.Gln690Glu)","Chromosome":"2","Start":"47476429","Stop":"47476429","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":96351,"rule_based_match":true,"evidence_text":"c.2068C>G","llm_judgment":"PRESENT","evidence":"c.2068C>G","abstract_start":877,"abstract_end":886}]}
{"pmid":"20530095","title":"Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia.","abstract":"BACKGROUND: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27(KIP1) encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors.\nMETHODS: Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated.\nRESULTS: Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49+/-18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families.\nCONCLUSION: AIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27(KIP1) is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.","variants":[{"Name":"NM_003977.4(AIP):c.911G>A (p.Arg304Gln)","Chromosome":"11","Start":"67490911","Stop":"67490911","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19932,"rule_based_match":true,"evidence_text":"c.911G>A","llm_judgment":"PRESENT","evidence":"c.911G>A","abstract_start":905,"abstract_end":913}]}
{"pmid":"23380547","title":"Mucopolysaccharidosis type IIIB mutations in Chinese patients: identification of two novel NAGLU mutations and analysis of two cases involving prenatal diagnosis.","abstract":"BACKGROUND: Mucopolysaccharidosis type IIIB (MPS IIIB) is a lysosomal storage disorder caused by over 130 mutations in NAGLU gene. However, there are not much mutations that have been reported in China. Here we studied five MPS IIIB patients from three unrelated Chinese families.\nMETHODS: Urine test and NAGLU activity assay were used to validate the patients' type of MPS. We performed DNA analyses by direct sequencing, PCR-DHPLC, and PCR-restriction enzyme techniques. In addition, prenatal gene diagnosis was performed to one couple with two pregnancies. Finally RT-PCR and bioinformatics analysis were used to identify mutations.\nRESULT: A total of six different mutations were found, including a novel deletion, c.867delC, and five missense mutations, c.1081T>C (p.W361R) (novel), c.700C>T (p.R234C), c.874G>A (p.G292R), c.1693C>T (p.R565W), and c.1694G>A (p.R565Q). Prenatal diagnosis revealed that the first fetus was a compound heterozygote carrying two mutations (p.R565W and p.R565Q), whereas the second fetus carried only p.R565Q mutation.\nCONCLUSIONS: Our research may enrich the mutation spectrum of the NAGLU gene in the Chinese population and help us further in understanding the pathogenesis of MPS IIIB.","variants":[{"Name":"NM_000263.4(NAGLU):c.700C>T (p.Arg234Cys)","Chromosome":"17","Start":"42538691","Stop":"42538691","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16611,"rule_based_match":true,"evidence_text":"c.700C>T (p.R234C)","llm_judgment":"PRESENT","evidence":"c.700C>T (p.R234C)","abstract_start":788,"abstract_end":806},{"Name":"NM_000263.4(NAGLU):c.1694G>A (p.Arg565Gln)","Chromosome":"17","Start":"42543700","Stop":"42543700","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39752,"rule_based_match":true,"evidence_text":"c.1694G>A (p.R565Q)","llm_judgment":"PRESENT","evidence":"c.1694G>A (p.R565Q)","abstract_start":853,"abstract_end":872},{"Name":"NM_000263.4(NAGLU):c.1081T>C (p.Trp361Arg)","Chromosome":"17","Start":"42543087","Stop":"42543087","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1056430,"rule_based_match":true,"evidence_text":"c.1081T>C (p.W361R) (novel)","llm_judgment":"PRESENT","evidence":"c.1081T>C (p.W361R) (novel)","abstract_start":759,"abstract_end":786},{"Name":"NM_000263.4(NAGLU):c.874G>A (p.Gly292Arg)","Chromosome":"17","Start":"42541059","Stop":"42541059","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":548441,"rule_based_match":true,"evidence_text":"c.874G>A (p.G292R)","llm_judgment":"PRESENT","evidence":"c.874G>A (p.G292R)","abstract_start":808,"abstract_end":826},{"Name":"NM_000263.4(NAGLU):c.1693C>T (p.Arg565Trp)","Chromosome":"17","Start":"42543699","Stop":"42543699","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16606,"rule_based_match":true,"evidence_text":"c.1693C>T (p.R565W)","llm_judgment":"PRESENT","evidence":"c.1693C>T (p.R565W)","abstract_start":828,"abstract_end":847}]}
{"pmid":"24927999","title":"Genetic analysis of ASS1, ASL and SLC25A13 in citrullinemia patients","abstract":"OBJECTIVE: To detect potential mutations of Y9ASS1, ASL and SLC25A13 genes in four patients manifesting citrullinemia.\nMETHODS: Genomic DNA was extracted from peripheral blood leukocytes. Exons and their flanking sequences of the three genes were amplified with polymerase chain reaction and subjected to direct DNA sequencing.\nRESULTS: Based on DNA sequence analysis, one case was diagnosed with argininosuccinate synthetase deficiency, and the mutation type (ASS1 gene) was c.236C>T (p.S79F) + c.431C>G (p.P144R). Two cases were diagnosed with argininosuccinic aciduria (ASL gene), and their gene mutations were c.434A>G (p.D145G) + c.1366C>T (p.R456W) and c.331C>T (p.R111W) + IVS8+2insT, respectively. A thirteen months boy who carried a heterozygous 851del4 mutation (SLC25A13 gene) was diagnosed with citrullinemia adult-onset type II.\nCONCLUSION: Through analysis of relevant pathogenic genes, four patients have been diagnosed.","variants":[{"Name":"NM_054012.4(ASS1):c.431C>G (p.Pro144Arg)","Chromosome":"9","Start":"130466735","Stop":"130466735","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2836641,"rule_based_match":true,"evidence_text":"c.431C>G (p.P144R)","llm_judgment":"PRESENT","evidence":"c.431C>G (p.P144R)","abstract_start":496,"abstract_end":514},{"Name":"NM_000048.4(ASL):c.434A>G (p.Asp145Gly)","Chromosome":"7","Start":"66083162","Stop":"66083162","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2748994,"rule_based_match":true,"evidence_text":"c.434A>G (p.D145G)","llm_judgment":"PRESENT","evidence":"c.434A>G (p.D145G)","abstract_start":614,"abstract_end":632},{"Name":"NM_000048.4(ASL):c.331C>T (p.Arg111Trp)","Chromosome":"7","Start":"66082919","Stop":"66082919","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1495084,"rule_based_match":true,"evidence_text":"c.331C>T (p.R111W)","llm_judgment":"PRESENT","evidence":"c.331C>T (p.R111W)","abstract_start":659,"abstract_end":677}]}
{"pmid":"26007199","title":"Clinical, Molecular, and Functional Characterization of CLCN1 Mutations in Three Families with Recessive Myotonia Congenita.","abstract":"Myotonia congenita (MC) is an inherited muscle disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. Both recessive (Becker's disease) or dominant (Thomsen's disease) MC are caused by mutations in the CLCN1 gene encoding the voltage-dependent chloride ClC-1 channel, which is quite exclusively expressed in skeletal muscle. More than 200 CLCN1 mutations have been associated with MC. We provide herein a detailed clinical, molecular, and functional evaluation of four patients with recessive MC belonging to three different families. Four CLCN1 variants were identified, three of which have never been characterized. The c.244A>G (p.T82A) and c.1357C>T (p.R453W) variants were each associated in compound heterozygosity with c.568GG>TC (p.G190S), for which pathogenicity is already known. The new c.809G>T (p.G270V) variant was found in the homozygous state. Patch-clamp studies of ClC-1 mutants expressed in tsA201 cells confirmed the pathogenicity of p.G270V, which greatly shifts the voltage dependence of channel activation toward positive potentials. Conversely, the mechanisms by which p.T82A and p.R453W cause the disease remained elusive, as the mutated channels behave similarly to WT. The results also suggest that p.G190S does not exert dominant-negative effects on other mutated ClC-1 subunits. Moreover, we performed a RT-PCR quantification of selected ion channels transcripts in muscle biopsies of two patients. The results suggest gene expression alteration of sodium and potassium channel subunits in myotonic muscles; if confirmed, such analysis may pave the way toward a better understanding of disease phenotype and a possible identification of new therapeutic options.","variants":[{"Name":"NM_000083.3(CLCN1):c.809G>T (p.Gly270Val)","Chromosome":"7","Start":"143324448","Stop":"143324448","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1868084,"rule_based_match":true,"evidence_text":"c.809G>T (p.G270V)","llm_judgment":"PRESENT","evidence":"c.809G>T (p.G270V)","abstract_start":845,"abstract_end":863}]}
{"pmid":"17092466","title":"Childhood-onset spastic paraplegia with NIPAL gene mutation.","abstract":"Hereditary spastic paraplegia is a heterogeneous group of inherited neurodegenerative disorders in which the predominant clinical feature is gait disturbance owing to spasticity and weakness of the lower limbs. Autosomal dominant hereditary spastic paraplegia is the predominant form of the disorder. To date, 10 autosomal dominant hereditary spastic paraplegia gene loci and genes for 6 of them have been identified. Spastic paraplegia 6, with a typical teenage onset and considered to be one of the more severe forms of the disease, is due to mutations in the gene NIPA1. We report a childhood-onset, aggressive, spastic paraparesis in a North American family with a c.316G>A mutation of the NIPA1 gene, confirming c.316 as a mutational hot spot.","variants":[{"Name":"NM_144599.5(NIPA1):c.316G>A (p.Gly106Arg)","Chromosome":"15","Start":"22812252","Stop":"22812252","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17562,"rule_based_match":true,"evidence_text":"c.316G>A","llm_judgment":"PRESENT","evidence":"c.316G>A","abstract_start":669,"abstract_end":677}]}
{"pmid":"17395561","title":"Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene.","abstract":"Pyridoxine-responsive seizures (PRS) and the role of pyridoxine (PN, vitamin B(6)) in hypophosphatasia (HPP) are incompletely understood. Typically, PRS and HPP are rare, independent, metabolic disorders. In PRS, seizures resist standard anticonvulsants apart from PN, yet have a good prognosis. In HPP, inactivation of the tissue nonspecific isoenzyme of alkaline phosphatase (TNSALP) impairs skeletal mineralization and causes rickets in infants that can be fatal. Here, we report a 7-month-old girl, newly diagnosed with infantile HPP, who presented as a neonate with PRS but without bony abnormalities. Analysis of biogenic amines in cerebrospinal fluid (CSF) suggested brain pyridoxal 5'-phosphate (PLP) deficiency, although PLP in CSF was not decreased. She had normal cognitive milestones but failure to thrive and rickets. Nearly undetectable serum ALP activity, elevated plasma PLP and urinary phosphoethanolamine (PEA) and inorganic pyrophosphate (PPi) levels, hypercalcemia, hypercalciuria and nephrocalcinosis were consistent with infantile HPP. Only prednisolone reduced serum calcium levels. Despite improved growth and weight gain, she developed rib fractures and died from respiratory failure at age 9 months. Sequence analysis of the TNSALP gene revealed novel missense mutations in exon 7 (c.677T>C, p.M226T) and exon 10 (c.1112C>T, p.T371I). Our patient demonstrated that PRS in neonates may not necessarily be \"idiopathic\"; instead, such seizures can be caused by severe HPP that becomes clinically apparent later in infancy. The pathophysiology of PRS in HPP differs from the three other genetic defects known to cause PRS, but all may lead to brain PLP deficiency reducing seizure thresholds. All reported HPP patients with neonatal seizures died within 18 months of birth, suggesting that PRS is an indicator of HPP severity and lethal prognosis. We recommend that assessment of any neonate with PRS should include measurement of serum ALP activity.","variants":[{"Name":"NM_000478.6(ALPL):c.1112C>T (p.Thr371Ile)","Chromosome":"1","Start":"21575847","Stop":"21575847","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2898183,"rule_based_match":true,"evidence_text":"c.1112C>T (p.T371I)","llm_judgment":"PRESENT","evidence":"c.1112C>T","abstract_start":1340,"abstract_end":1349},{"Name":"NM_000478.6(ALPL):c.677T>C (p.Met226Thr)","Chromosome":"1","Start":"21568132","Stop":"21568132","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1694391,"rule_based_match":true,"evidence_text":"c.677T>C, p.M226T","llm_judgment":"PRESENT","evidence":"c.677T>C, p.M226T","abstract_start":1308,"abstract_end":1325}]}
{"pmid":"19366998","title":"SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype.","abstract":"OBJECTIVE: Germline loss-of-function mutations in the SPRED1 gene have recently been identified in patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for neurofibromatosis type 1 (NF1) but with no NF1 (neurofibromin 1) mutation found, suggesting a neurofibromatosis type 1-like syndrome.\nMETHODS: 61 index cases with NF1 clinical diagnosis but no identifiable NF1 mutation were screened for SPRED1 mutation.\nRESULTS: We describe one known SPRED1 mutation (c.190C>T leading to p.Arg64Stop) and four novel mutations (c.637C>T leading to p.Gln213Stop, c.2T>C leading to p.Met1Thr, c.46C>T leading to p.Arg16Stop, and c.1048_1060del leading to p.Gly350fs) in five French families. Their NF1-like phenotype was characterised by a high prevalence of café-au-lait spots, freckling, learning disability, and an absence of neurofibromas and Lisch nodules in agreement with the original description. However, we did not observe Noonan-like dysmorphy. It is noteworthy that one patient with the p.Arg16Stop mutation developed a monoblastic acute leukaemia.\nCONCLUSIONS: In our series, SPRED1 mutations occurred with a prevalence of 0.5% in NF1 patients and in 5% of NF1 patients displaying an NF1-like phenotype. SPRED1 mutated patients did not display any specific dermatologic features that were not present in NF1 patients, except for the absence of neurofibromas that seem to be a specific clinical feature of NF1. The exact phenotypic spectrum and the putative complications of this NF1 overlapping syndrome, in particular haematological malignancies, remain to be further characterised. NIH diagnostic criteria for NF1 must be revised in view of this newly characterised Legius syndrome in order to establish a specific genetic counselling.","variants":[{"Name":"NM_152594.3(SPRED1):c.190C>T (p.Arg64Ter)","Chromosome":"15","Start":"38299530","Stop":"38299530","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16852,"rule_based_match":true,"evidence_text":"c.190C>T leading to p.Arg64Stop","llm_judgment":"PRESENT","evidence":"c.190C>T leading to p.Arg64Stop","abstract_start":485,"abstract_end":516},{"Name":"NM_152594.3(SPRED1):c.637C>T (p.Gln213Ter)","Chromosome":"15","Start":"38349476","Stop":"38349476","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16853,"rule_based_match":true,"evidence_text":"c.637C>T leading to p.Gln213Stop","llm_judgment":"PRESENT","evidence":"c.637C>T leading to p.Gln213Stop","abstract_start":544,"abstract_end":576},{"Name":"NM_152594.3(SPRED1):c.46C>T (p.Arg16Ter)","Chromosome":"15","Start":"38299386","Stop":"38299386","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360244,"rule_based_match":true,"evidence_text":"c.46C>T leading to p.Arg16Stop","llm_judgment":"PRESENT","evidence":"c.46C>T leading to p.Arg16Stop","abstract_start":607,"abstract_end":637}]}
{"pmid":"28834196","title":"Advanced cell-based modeling of the royal disease: characterization of the mutated F9 mRNA.","abstract":"Essentials The Royal disease (RD) is a form of hemophilia B predicted to be caused by a splicing mutation. We generated an iPSC-based model of the disease allowing mechanistic studies at the RNA level. F9 mRNA analysis in iPSC-derived hepatocyte-like cells showed the predicted abnormal splicing. Mutated F9 mRNA level was very low but we also found traces of wild type transcripts.\nSUMMARY: Background The royal disease is a form of hemophilia B (HB) that affected many descendants of Queen Victoria in the 19th and 20th centuries. It was found to be caused by the mutation F9 c.278-3A>G. Objective To generate a physiological cell model of the disease and to study F9 expression at the RNA level. Methods Using fibroblasts from skin biopsies of a previously identified hemophilic patient bearing the F9 c.278-3A>G mutation and his mother, we generated induced pluripotent stem cells (iPSCs). Both the patient's and mother's iPSCs were differentiated into hepatocyte-like cells (HLCs) and their F9 mRNA was analyzed using next-generation sequencing (NGS). Results and Conclusion We demonstrated the previously predicted aberrant splicing of the F9 transcript as a result of an intronic nucleotide substitution leading to a frameshift and the generation of a premature termination codon (PTC). The F9 mRNA level in the patient's HLCs was significantly reduced compared with that of his mother, suggesting that mutated transcripts undergo nonsense-mediated decay (NMD), a cellular mechanism that degrades PTC-containing mRNAs. We also detected small proportions of correctly spliced transcripts in the patient's HLCs, which, combined with genetic variability in splicing and NMD machineries, could partially explain some clinical variability among affected members of the European royal families who had lifespans above the average. This work allowed the demonstration of the pathologic consequences of an intronic mutation in the F9 gene and represents the first bona fide cellular model of HB allowing the study of rare mutations at the RNA level.","variants":[{"Name":"NM_000133.4(F9):c.278-3A>G","Chromosome":"X","Start":"139541073","Stop":"139541073","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":97615,"rule_based_match":true,"evidence_text":"F9 c.278-3A>G","llm_judgment":"PRESENT","evidence":"F9 c.278-3A>G","abstract_start":575,"abstract_end":588}]}
{"pmid":"31846209","title":"Holoprosencephaly in Kabuki syndrome.","abstract":"Kabuki syndrome is a rare, multi-systemic disorder of chromatin regulation due to mutations in either KMT2D or KDM6A that encode a H3K4 methyltransferase and an H3K27 demethylase, respectively. The associated clinical phenotype is a direct result of temporal and spatial changes in gene expression in various tissues including the brain. Although mild to moderate intellectual disability is frequently recognized in individuals with Kabuki syndrome, the identification of brain anomalies, mostly involving the hippocampus and related structures remains an exception. Recently, the first two cases with alobar holoprosencephaly and mutations in KMT2D have been reported in the medical literature. We identified a de novo, pathogenic KMT2D variant (c.6295C > T; p.R2099X) using trio whole-exome sequencing in a 2-year-old female with lobar holoprosencephaly, microcephaly and cranio-facial features of Kabuki syndrome. This report expands the spectrum of brain anomalies associated with Kabuki syndrome underscoring the important role of histone modification for early brain development.","variants":[{"Name":"NM_003482.4(KMT2D):c.6295C>T (p.Arg2099Ter)","Chromosome":"12","Start":"49041475","Stop":"49041475","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":512013,"rule_based_match":true,"evidence_text":"c.6295C > T; p.R2099X","llm_judgment":"PRESENT","evidence":"c.6295C > T; p.R2099X","abstract_start":747,"abstract_end":768}]}
{"pmid":"30139988","title":"Genetics of hearing loss in the Arab population of Northern Israel.","abstract":"For multiple generations, much of the Arab population of Northern Israel has lived in communities with consanguineous marriages and large families. These communities have been particularly cooperative and informative for understanding the genetics of recessive traits. We studied the genetics of hearing loss in this population, evaluating 168 families from 46 different villages. All families were screened for founder variants by Sanger sequencing and 13 families were further evaluated by sequencing all known genes for hearing loss using our targeted gene panel HEar-Seq. Deafness in 34 of 168 families (20%) was explained by founder variants in GJB2, SLC26A4, or OTOF. In 6 of 13 families (46%) evaluated using HEar-Seq, deafness was explained by damaging alleles of SLC26A4, MYO15A, OTOG, LOXHD1, and TBC1D24. In some genes critical to hearing, it is particularly difficult to interpret variants that might affect splicing, because the genes are not expressed in accessible tissue. To address this problem for possible splice-altering variants of MYO15A, we evaluated minigenes transfected into HEK293 cells. Results revealed exon skipping in the message of MYO15A c.9083+6T>A, and intron retention in the message of MYO15A c.8340G>A, in each case leading to a premature stop and consistent with co-segregation of homozygosity for each variant with hearing loss. The profile of genetics of hearing loss in this population reflects the genetic heterogeneity of hearing loss and the usefulness of synthetic technologies to evaluate potentially causal variants in genes not expressed in accessible tissues.","variants":[{"Name":"NM_016239.4(MYO15A):c.9083+6T>A","Chromosome":"17","Start":"18158644","Stop":"18158644","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":511041,"rule_based_match":true,"evidence_text":"MYO15A c.9083+6T>A","llm_judgment":"PRESENT","evidence":"MYO15A c.9083+6T>A","abstract_start":1164,"abstract_end":1182}]}
{"pmid":"35509735","title":"Short-Communication: Variable Expression of Clinical Symptoms and an Unexpected Finding of Vacuolar Myopathy Related to a Pathogenic Variant in the CACNA1S Gene in a Previous Case Report.","abstract":"Several clinical phenotypes have been described related to the <i>CACNA1S</i> gene (calcium channel voltage-dependent L-type alpha-1S subunit), such as autosomal dominant hypokalemic periodic paralysis 1 and autosomal dominant malignant hyperthermia susceptibility and are associated with autosomal dominant and recessive congenital myopathy. Recently, an interesting case of a 58-year-old male patient was published describing an unusual clinical presentation of hypokalemic periodic paralysis where a late-onset limb-girdle myopathy had developed 41 years after paralysis occurred when the patient was 11 years old. Muscle biopsy results were consistent with myopathic changes and revealed the presence of vacuoles, without inflammatory reaction. Later, molecular analysis revealed a pathogenic variant c.3716G>A (p.Arg1239His) in exon 30 of the <i>CACNA1S</i> gene. This technical report provides an extension of the molecular findings and evaluates the clinical and histopathological relationship previously published regarding this case.","variants":[{"Name":"NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His)","Chromosome":"1","Start":"201053538","Stop":"201053538","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32662,"rule_based_match":true,"evidence_text":"c.3716G>A (p.Arg1239His)","llm_judgment":"PRESENT","evidence":"c.3716G>A (p.Arg1239His)","abstract_start":805,"abstract_end":829}]}
{"pmid":"36442996","title":"Characterization of a novel deep-intronic variant in","abstract":"Biallelic pathogenic variants in <i>DYNC2H1</i> are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the <i>DYNC2H1</i> gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in <i>DYNC2H1</i> was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited <i>DYNC2H1</i> deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of <i>DYNCH2H1</i> mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.","variants":[{"Name":"NM_001377.3(DYNC2H1):c.10606-14A>G","Chromosome":"11","Start":"103259874","Stop":"103259874","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1671409,"rule_based_match":true,"evidence_text":"c.10606-14A > G","llm_judgment":"PRESENT","evidence":"c.10606-14A > G","abstract_start":1333,"abstract_end":1348}]}
{"pmid":"24366306","title":"Germline CDH1 mutations in bilateral lobular carcinoma in situ.","abstract":"BACKGROUND: Invasive lobular breast cancer (ILC) and lobular carcinoma in situ (LCIS) are characterised by loss of E-cadherin expression. However germline CDH1 mutations are rare in cases of ILC with no family history of hereditary diffuse gastric cancer (HDGC) and have not been described in women with LCIS.\nMETHODS: We screened the CDH1 gene in 50 cases of bilateral LCIS/ILC using Sanger sequencing and MLPA.\nRESULTS: Sanger sequencing revealed four pathogenic germline mutations, including a novel splicing mutation (c.48+1G>A). The remaining three (c.1465insC, c.1942G>T, c.2398delC) have been previously described. All four cases had bilateral LCIS +/- ILC and no family history of gastric cancer.\nCONCLUSION: CDH1 germline mutations have not been previously described in women with LCIS. We have shown that germline CDH1 mutations are associated with early onset of bilateral LCIS with or without ILC in women without a family history of gastric cancer. CDH1 mutation screening should be considered in women with early onset of bilateral LCIS/ILC with no family history of HDGC.","variants":[{"Name":"NM_004360.5(CDH1):c.1942G>T (p.Glu648Ter)","Chromosome":"16","Start":"68823404","Stop":"68823404","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":466596,"rule_based_match":true,"evidence_text":"c.1942G>T","llm_judgment":"PRESENT","evidence":"c.1942G>T","abstract_start":567,"abstract_end":576},{"Name":"NM_004360.5(CDH1):c.2398del (p.Arg800fs)","Chromosome":"16","Start":"68829753","Stop":"68829753","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":166262,"rule_based_match":true,"evidence_text":"c.2398delC","llm_judgment":"PRESENT","evidence":"c.2398delC","abstract_start":578,"abstract_end":588},{"Name":"NM_004360.5(CDH1):c.48+1G>A","Chromosome":"16","Start":"68737464","Stop":"68737464","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":445599,"rule_based_match":true,"evidence_text":"c.48+1G>A","llm_judgment":"PRESENT","evidence":"c.48+1G>A","abstract_start":522,"abstract_end":531}]}
{"pmid":"36927930","title":"Rare Compound Heterozygous Missense Mutation of the SCN5A Gene with Childhood-Onset Sick Sinus Syndrome in Two Chinese Sisters.","abstract":"Sick sinus syndrome (SSS) is a group of syndromes characterized by pathological changes in the sinoatrial node and its adjacent tissues. Although several mutations in the SCN5A gene have been associated with early-onset SSS, pediatric patients are still less common. Here, we report a rare compound missense mutation in the SCN5A gene [c.2893C>T (p. R965C) and c.2431C>T (p. R811C) ] in two sisters with childhood-onset SSS in Chinese population. The proband (5 years and 5 months old) was the second child of a clinically normal and nonconsanguineous couple. Her elder sister was 12 years old and had been implanted with a pacemaker because of the diagnosis of SSS at another hospital one year ago. The proband was presented to the hospital with a slowed heart rate and reduced endurance exercise capacity for more than three months. After a comprehensive clinical examination, she was diagnosed with SSS and underwent pacemaker implantation. Exome and Sanger sequencing were used to determine the compound heterozygous missense mutation of [c.2893C>T (p. R965C) and c.2431C>T (p. R811C) ] in the SCN5A in the patient and her elder sister. Each healthy parent carried a different heterozygous missense mutation. The compound heterozygous mutation of c.2893C>T (p. R965C) and c.2431C>T (p. R811C) rather than the single mutation might be the primary cause of familial early-onset SSS in Chinese population. Our current findings expanded the current understanding of the SCN5A gene mutations. We further confirmed the essential role of the SCN5A gene on the diagnosis, family cascade screening, early intervention, and prognostic evaluation of SSS.","variants":[{"Name":"NM_000335.5(SCN5A):c.2893C>T (p.Arg965Cys)","Chromosome":"3","Start":"38581266","Stop":"38581266","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":78658,"rule_based_match":true,"evidence_text":"c.2893C>T (p. R965C)","llm_judgment":"PRESENT","evidence":"c.2893C>T (p. R965C)","abstract_start":336,"abstract_end":356},{"Name":"NM_000335.5(SCN5A):c.2431C>T (p.Arg811Cys)","Chromosome":"3","Start":"38587405","Stop":"38587405","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":196946,"rule_based_match":true,"evidence_text":"c.2431C>T (p. R811C)","llm_judgment":"PRESENT","evidence":"c.2431C>T (p. R811C)","abstract_start":361,"abstract_end":381}]}
{"pmid":"34074565","title":"A novel Notch 3 mutation (pathogenic variant c.1565G>C) in CADASIL.","abstract":"","variants":[{"Name":"NM_000435.3(NOTCH3):c.1565G>C (p.Cys522Ser)","Chromosome":"19","Start":"15187922","Stop":"15187922","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1861917,"rule_based_match":true,"evidence_text":"c.1565G>C","llm_judgment":"PRESENT","evidence":"c.1565G>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"24707167","title":"Bilateral papillopathy as a presenting sign of pheochromocytoma associated with von Hippel-Lindau disease.","abstract":"A 7-year-old girl presented with decreased vision in both eyes for 1 month. Examination showed visual acuity of 20/50 and 20/60, no afferent pupillary defect, cecocentral scotomas, and bilateral optic disc edema with extensive peripapillary and macular exudates. Magnetic resonance imaging showed multiple cortical and subcortical white matter lesions. Both the laboratory workup and the systemic examination were unrevealing. However, on follow-up, the patient showed episodic elevations of blood pressure as high as 240/160. Further workup revealed elevated urine catecholamines and a right supra-adrenal mass proven to be a pheochromocytoma by histopathologic analysis. The paroxysmal hypertension resolved, and the visual acuity, visual fields, fundus exam, and neuroimaging improved. The patient was lost to follow-up until age 18 when she developed shortness of breath and was found to have multiple pulmonary metastases identified as pheochromocytoma by biopsy. Genetic testing identified a 3p25-26 (c.482 G>A) VHL gene chromosomal mutation consistent with von Hippel-Lindau disease genotype. Multiple peripheral retinal vascular dilations and small retinal capillary hemangioblastomas were also found. This case highlights the importance of recognizing the lability of blood pressure often seen with pheochromocytomas, which may mask the underlying cause of hypertensive papillopathy and retinopathy, a diagnosis of low clinical suspicion in the pediatric population. The case also underscores the importance of thorough systemic workup, including genotyping to detect conditions where pheochromocytoma may be the presenting sign of the disease, such as multiple endocrine neoplasia 2A and 2B, von Hippel-Lindau disease, von Recklinghausen disease, tuberous sclerosis, and Sturge-Weber syndrome.","variants":[{"Name":"NM_000551.4(VHL):c.482G>A (p.Arg161Gln)","Chromosome":"3","Start":"10149805","Stop":"10149805","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":180121,"rule_based_match":true,"evidence_text":"c.482 G>A","llm_judgment":"PRESENT","evidence":"c.482 G>A","abstract_start":1007,"abstract_end":1016}]}
{"pmid":"18185926","title":"Comparison of SLCO1B1 sequence variability among German, Turkish, and African populations.","abstract":"BACKGROUND: OATP1B1 is one of the key hepatocellular uptake transporters providing extraction of diverse compounds, including bile acids, xenobiotics, and a variety of drugs, from portal venous blood into the liver. Polymorphisms of the SLCO1B1 gene have been demonstrated to influence in vitro transport function and the pharmacokinetic profile of compounds.\nOBJECTIVE: The goal of our study was the comparison of SLCO1B1 gene sequence variability in three ethnic groups as a basis for future genetic association studies.\nMETHODS: Eighteen exonic SLCO1B1 single nucleotide polymorphisms (SNPs) were genotyped by PCR and RFLP analysis in 300 German, 94 Turkish, and 115 African subjects. Calculation of pairwise linkage disequilibrium and estimation of population haplotype frequencies were carried out, and haplotype block structure was determined.\nRESULTS: Only eight genotyped SNPs (c.388A>G, c.411G>A, c.463C>A, c.521T>C, c.571C>T, c.597C>T, c.1463G>>C, c.1929A>C) were found in at least one of our German, Turkish, or African samples. A total of 12 haplotypes with a frequency >or=1% in at least one of the three populations could be inferred. Between the Caucasian and African samples, significant differences in sequence variability were observed leading to a different haplotype profile in these populations.\nCONCLUSION: Our results demonstrate a high sequence variability of OATP1B1 within different popuations. In the future, distinct haplotypes should be taken into account when studying the effect of OATP1B1 on drugs in different populations.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.1463G>C (p.Gly488Ala)","Chromosome":"12","Start":"21205999","Stop":"21205999","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":331506,"rule_based_match":false,"evidence_text":"c.1463G>>C","llm_judgment":"PRESENT","evidence":"c.1463G>>C","abstract_start":946,"abstract_end":956}]}
{"pmid":"25373814","title":"Case of multiple sulfatase deficiency and ocular albinism: a diagnostic odyssey.","abstract":"BACKGROUND: Multiple sulfatase deficiency (MSD) is a rare autosomal recessive inborn error of lysosomal metabolism. The clinical phenotypic spectrum encompasses overlapping features of variable severity and is suggestive of individual single sulfatase deficiencies (i.e., metachromatic leukodystrophy, mucopolysaccharidosis, and X-linked ichthyosis).\nCASE REPORT: We describe a 3-year-old male with severe hypotonia, developmental regression and progressive neurodegeneration, coarse facial features, nystagmus (from ocular albinism), and dysmyelinating motor sensory neuropathy. Ethics approval was obtained from the Western University Ontario.\nRESULTS: Extensive investigative work-up identified deficiencies of multiple sulfatases: heparan sulfate sulfamidase: 6.5 nmoles/mg/protein/17 hour (reference 25.0-75.0), iduronate-2-sulfate sulfatase: 9 nmol/mg/protein/4 hour (reference 31-110), and arylsulfatase A: 3.8 nmoles/hr/mg protein (reference 22-50). The identification of compound heterozygous pathogenic mutations in the SUMF1 gene c.836 C>T (p.A279V) and c.1045C>T (p.R349W) confirmed the diagnosis of MSD.\nCONCLUSION: The complex clinical manifestations of MSD and the unrelated coexistence of ocular albinism as in our case can delay diagnosis. Genetic counselling should be provided to all affected families.","variants":[{"Name":"NM_182760.4(SUMF1):c.1045C>T (p.Arg349Trp)","Chromosome":"3","Start":"4362224","Stop":"4362224","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17705,"rule_based_match":true,"evidence_text":"c.1045C>T (p.R349W)","llm_judgment":"PRESENT","evidence":"c.1045C>T (p.R349W)","abstract_start":1065,"abstract_end":1084},{"Name":"NM_182760.4(SUMF1):c.836C>T (p.Ala279Val)","Chromosome":"3","Start":"4417132","Stop":"4417132","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17708,"rule_based_match":true,"evidence_text":"c.836 C>T (p.A279V)","llm_judgment":"PRESENT","evidence":"c.836 C>T (p.A279V)","abstract_start":1041,"abstract_end":1060}]}
{"pmid":"33604243","title":"","abstract":"Steroid 21-hydroxylase deficiency accounts for 95% of congenital adrenal hyperplasia (CAH) cases. Newborn screening has allowed for early detection of the disease, and currently, molecular analysis can identify the genotypes of these patients. Phenotype-genotype correlation has been well described in previous studies. In Costa Rica, there is no data about the genetic background of these patients, nor their phenotypic correlation.\nDESIGN: Observational, retrospective, descriptive study based on the review of patient records who had a diagnosis of CAH and were performed molecular analysis using gene sequencing or MLPA during the period from 2006 to 2018 (<i>N</i> = 58).\nOBJECTIVE: To describe the clinical and genetic characteristics of CAH patients due to 21-hydroxylase deficiency at the National Children's Hospital \"Dr. Carlos Sáenz Herrera\", Caja Costarricense de Seguro Social (CCSS) in Costa Rica.\nRESULTS: 53% (31/58) of the patients were male and 80% (37/46) were born full term; 72% (42/58) had salt wasting phenotype, 9% (5/58) simple virilizing phenotype and 19% (11/58) non-classic phenotype. The most frequent variants were c.292+5G>A in 26% (15/58) of patients and Del/Del in 21% (12/58) of them.\nCONCLUSIONS: The most frequent mutation in our study population was the c.292+5G>A, which was found in 15/58 patients. This rare variant has only been reported in three other studies so far but as an infrequent mutation in CAH patients. The genetic characteristics of Costa Rican patients differ from what has been documented worldwide and could respond to a founder effect.","variants":[{"Name":"NM_000500.9(CYP21A2):c.292+5G>A","Chromosome":"6","Start":"32038816","Stop":"32038816","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3514219,"rule_based_match":true,"evidence_text":"c.292+5G>A","llm_judgment":"PRESENT","evidence":"c.292+5G>A","abstract_start":1145,"abstract_end":1155}]}
{"pmid":"34011663","title":"Rare","abstract":"A 7-year-old girl without a significant previous medical history was diagnosed with X-linked hypophosphatemic rickets (XLHR) due to a rare, most likely pathogenic, <i>PHEX</i> gene variant after a 4-year delayed diagnosis due to mild clinical presentation. At 2 years of age, her intoeing and femoral bowing were attributed to physiologic bowing and borderline vitamin D sufficiency, despite phosphorus not being measured. Hypophosphatemia was eventually detected after incomplete improvement of bowing and leg length discrepancy with suboptimal linear growth. This rare <i>PHEX</i> variant (c.1949T>C, p.Leu650Pro) further supported the clinical diagnosis of XLHR. Treatment with burosumab (an anti-FGF23 monoclonal antibody) normalised phosphorus and alkaline phosphatase levels and improved her bowing. The diverse phenotypic presentation of this variant can result in delayed diagnosis and highlights the importance of prompt assessment of phosphorus levels in patients with skeletal deformities to ensure timely recognition and treatment.","variants":[{"Name":"NM_000444.6(PHEX):c.1949T>C (p.Leu650Pro)","Chromosome":"X","Start":"22226492","Stop":"22226492","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":45336,"rule_based_match":true,"evidence_text":"c.1949T>C, p.Leu650Pro","llm_judgment":"PRESENT","evidence":"c.1949T>C, p.Leu650Pro","abstract_start":592,"abstract_end":614}]}
{"pmid":"32051609","title":"Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer.","abstract":"PURPOSE: CTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied.\nMETHODS: De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers.\nRESULTS: Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers.\nCONCLUSION: CTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.","variants":[{"Name":"NM_001903.5(CTNNA1):c.1351C>T (p.Arg451Ter)","Chromosome":"5","Start":"138904403","Stop":"138904403","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":633383,"rule_based_match":true,"evidence_text":"CTNNA1 c.1351C>T (p.Arg451*)","llm_judgment":"PRESENT","evidence":"CTNNA1 c.1351C>T (p.Arg451*)","abstract_start":357,"abstract_end":385}]}
{"pmid":"27353645","title":"A FBN1 mutation association with different phenotypes of Marfan syndrome in a Chinese family.","abstract":"BACKGROUND: Previous studies demonstrated that patients with different FBN1 mutations often present more considerable phenotypic variation compared to different members of the related family carrying a same mutation. The purpose of our study was to identify pathogenic mutation and provide more information about genotype-phenotypic correlations in a large Chinese family with Marfan syndrome.\nMETHODS: 15 related family members from a Chinese 4-generation pedigree with Marfan syndrome underwent physical, ophthalmologic, radiological and cardiovascular examinations. The propositus has De Bakey III aortic dissection and didn't fulfill the revised Ghent criteria for Marfan syndrome. Nine family members have ectopia lentis and their echocardiogram was normal. Five other family members have no evidence of Marfan syndrome. Genomic DNA was isolated from blood leukocytes. The exome sequencing was employed on the propositus, then the Sanger sequencing was conducted for mutation verification in other 14 participants of this family.\nRESULTS: The causative mutation in FBN1 discovered in the propositus was a known heterozygous missense mutation, c.1633T>G (p.R545C), in exon 14 (NM 000138). This same mutation was also identified in all 9 ectopia lentis patients and one unaffected 8-year-old girl. However, the same mutation was not discovered in other 4 unaffected family members.\nCONCLUSIONS: Our data enhance the information of genotype-phenotype correlation owing to FBN1 mutations. To our current knowledge, we firstly reported that the same FBN1 mutation, c. 1633C>T (Arg545Cys), was detected simultaneously in three different cardinal phenotypes (ectopia lentis, aortic dissection and unaffected) within one family. The unaffected girl with FBN1 mutation may presumably represent a rare case of nonpenetrance.","variants":[{"Name":"NM_000138.5(FBN1):c.1633C>T (p.Arg545Cys)","Chromosome":"15","Start":"48510125","Stop":"48510125","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":178699,"rule_based_match":true,"evidence_text":"c. 1633C>T (Arg545Cys)","llm_judgment":"PRESENT","evidence":"c. 1633C>T (Arg545Cys)","abstract_start":1565,"abstract_end":1587}]}
{"pmid":"29767664","title":"Biochemical and molecular characterization of 3-Methylcrotonylglycinuria in an Italian asymptomatic girl.","abstract":"3-Methylcrotonylglycinuria is an organic aciduria resulting from deficiency of 3-methylcrotonyl-CoA carboxylase (3-MCC), a biotin-dependent mitochondrial enzym carboxylating 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA during leucine catabolism. Its deficiency, due to mutations on MCCC1 and MCCC2 genes, leads to accumulation of 3-methylcrotonyl-CoA metabolites in blood and/or urine, primarily 3-hydroxyisovaleryl-carnitine (C5-OH) in plasma and 3-methylcrotonyl-glycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA) in the urine. The phenotype of 3-MCC deficiency is highly variable, ranging from severe neurological abnormalities and death in infancy to asymptomatic adults. Here we report the biochemical and molecular characterization of an Italian asymptomatic girl, positive for the newborn screening test. Molecular analysis showed two mutations in the MCCC2 gene, an already described missense mutation, c.691A > T (p.I231F), and a novel splicing mutation, c.1150-1G > A. We characterized the expression profile of the splice mutation by functional studies.","variants":[{"Name":"NM_022132.5(MCCC2):c.691A>T (p.Ile231Phe)","Chromosome":"5","Start":"71626706","Stop":"71626706","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1446675,"rule_based_match":true,"evidence_text":"c.691A > T (p.I231F)","llm_judgment":"PRESENT","evidence":"c.691A > T (p.I231F)","abstract_start":916,"abstract_end":936},{"Name":"NM_022132.5(MCCC2):c.1150-1G>A","Chromosome":"5","Start":"71646210","Stop":"71646210","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1892078,"rule_based_match":true,"evidence_text":"c.1150-1G > A","llm_judgment":"PRESENT","evidence":"c.1150-1G > A","abstract_start":969,"abstract_end":982}]}
{"pmid":"24321233","title":"Nonsense-mediated mRNA decay due to a CACNA1C splicing mutation in a patient with Brugada syndrome.","abstract":"BACKGROUND: Brugada syndrome (BrS) is an inherited cardiac arrhythmia associated with sudden death due to ventricular fibrillation. Mutations in genes related to the cardiac L-type calcium channel have been reported to be causative of BrS. Generally, the messenger RNA (mRNA) that contains a nonsense mutation is rapidly degraded via its decay pathway, which is known as nonsense-mediated mRNA decay (NMD). Previously, we reported a male patient with BrS who carried c.1896G>A (the first nucleotide of CACNA1C exon 14), which caused a synonymous mutation, p.R632R.\nOBJECTIVE: To examine how the synonymous CACNA1C mutation p.R632R produces the phenotype of BrS, with a special emphasis on the splicing error and NMD processes.\nMETHODS: We extracted mRNA from leukocytes of the proband and his 2 children and performed reverse transcription polymerase chain reaction. Complementary DNAs were checked by using direct sequencing and quantitative analysis.\nRESULTS: The subsequent sequence electropherogram of the complementary DNAs did not show the substitution of the nucleotide identified in the genomic DNA of the proband. In the mRNA quantification analysis, we confirmed that reduction in the CACNA1C expression level was suspected to be caused by NMD.\nCONCLUSIONS: Mutant mRNA with a c.1896G>A substitution may be diminished by NMD, and the resultant decrease in CACNA1C message leads to a novel mechanism for inducing BrS that is distinct from that reported previously.","variants":[{"Name":"NM_000719.7(CACNA1C):c.1896G>A (p.Arg632=)","Chromosome":"12","Start":"2581590","Stop":"2581590","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":926594,"rule_based_match":true,"evidence_text":"c.1896G>A","llm_judgment":"PRESENT","evidence":"c.1896G>A","abstract_start":467,"abstract_end":476}]}
{"pmid":"33108086","title":"A novel compound heterozygous variant in CYP19A1 resulting in aromatase deficiency with normal ovarian tissue.","abstract":"BACKGROUND: Aromatase deficiency leading to virilization in mother and female fetuses during pregnancy is a rare disease. It is characterized by impaired estrogen production, increased gonadotropins, and ovarian cysts.\nCASE: Herein, we report a clinical phenotype of the virilized female due to a novel compound heterozygous variant in CYP19A1 [IVS10 + 1 G > A; c.344 G > A (p.R115Q)], with normal gonadotropin levels at the time of admission and histologically normal ovarian tissues.\nCONCLUSION: Aromatase deficiency should also be considered even if the initial follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are normal, and ovarian cysts are lacking.","variants":[{"Name":"NM_000103.4(CYP19A1):c.344G>A (p.Arg115Gln)","Chromosome":"15","Start":"51227886","Stop":"51227886","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3817328,"rule_based_match":true,"evidence_text":"c.344 G > A (p.R115Q)","llm_judgment":"PRESENT","evidence":"c.344 G > A (p.R115Q)","abstract_start":362,"abstract_end":383}]}
{"pmid":"21675857","title":"A novel 5-bp deletion in Clarin 1 in a family with Usher syndrome.","abstract":"BACKGROUND: To identify the genetic defect in a Lebanese family with two sibs diagnosed with Usher Syndrome.\nMATERIALS AND METHODS: Exome capture and sequencing were performed on DNA from one affected member using Agilent in solution bead capture, followed by Illumina sequencing.\nRESULTS: This analysis revealed the presence of a novel homozygous 5-bp deletion, in Clarin 1 (CLRN1), a known gene responsible for Usher syndrome type III. The deletion is inherited from both parents and segregates with the disease phenotype in the family. The 5-bp deletion, c.301_305delGTCAT, p.Val101SerfsX27, is predicted to result in a frameshift and protein truncation after 27 amino acids. Sequencing all the coding regions of the CLRN1 gene in the proband did not reveal any other mutation or variant.\nCONCLUSION: Here we describe a novel deletion in CLRN1. Our data support previously reported intra familial variability in the clinical features of Usher syndrome type I and III.","variants":[{"Name":"NM_174878.3(CLRN1):c.301_305del (p.Val101fs)","Chromosome":"3","Start":"150941710","Stop":"150941714","ReferenceAlleleVCF":"AATGAC","AlternateAlleleVCF":"A","allel_id":57309,"rule_based_match":true,"evidence_text":"c.301_305delGTCAT, p.Val101SerfsX27","llm_judgment":"PRESENT","evidence":"c.301_305delGTCAT, p.Val101SerfsX27","abstract_start":558,"abstract_end":593}]}
{"pmid":"26087139","title":"Screening for THAP1 Mutations in Polish Patients with Dystonia Shows Known and Novel Substitutions.","abstract":"The aim of this study was to assess the presence of DYT6 mutations in Polish patients with isolated dystonia and to characterize their phenotype. We sequenced THAP1 exons 1, 2 and 3 including exon-intron boundaries and 5'UTR fragment in 96 non-DYT1 dystonia patients. In four individuals single nucleotide variations were identified. The coding substitutions were: c. 238A>G (p.Ile80Val), found in two patients, and c.167A>G (p.Glu56Gly), found in one patient. The same variations were present also in the patients' symptomatic as well as asymptomatic relatives. Mutation penetration in the analyzed families was 50-66.7%. In the fourth patient, a novel c.-249C>A substitution in the promoter region was identified. The patient, initially suspected of idiopathic isolated dystonia, finally presented with pantothenate kinase 2-associated neurodegeneration phenotype and was a carrier of two PANK2 mutations. This is the first identified NBIA1 case carrying mutations in both PANK2 and THAP1 genes. In all symptomatic THAP1 mutation carriers (four probands and their three affected relatives) the first signs of dystonia occurred before the age of 23. A primary localization typical for DYT6 dystonia was observed in six individuals. Five subjects developed the first signs of dystonia in the upper limb. In one patient the disease began from laryngeal involvement. An uncommon primary involvement of lower limb was noted in the THAP1 and PANK2 mutations carrier. Neither of these THAP1 substitutions were found in 150 unrelated healthy controls. To the contrary, we identified a heterozygous C/T genotype of c.57C>T single nucleotide variation (p.Pro19Pro, rs146087734) in one healthy control, but in none of the patients. Therefore, a previously proposed association between this substitution and DYT6 dystonia seems unlikely. We found also no significant difference between cases and controls in genotypes distribution of the two-nucleotide -237-236 GA>TT (rs370983900 & rs1844977763) polymorphism.","variants":[{"Name":"NM_018105.3(THAP1):c.238A>G (p.Ile80Val)","Chromosome":"8","Start":"42839215","Stop":"42839215","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":438391,"rule_based_match":true,"evidence_text":"c. 238A>G (p.Ile80Val)","llm_judgment":"PRESENT","evidence":"c. 238A>G (p.Ile80Val)","abstract_start":365,"abstract_end":387}]}
{"pmid":"24078562","title":"Genetic analysis and prenatal diagnosis for non-syndromic hearing impairment","abstract":"OBJECTIVE: To detect genetic mutations underlying non-syndromic hearing impairment (NSHI) and establish a method for prenatal diagnosis.\nMETHODS: Sixty six NSHI patients were included in this study. DNA was extracted from peripheral blood. Genetic mutations were detected by gene chip analysis and direct sequencing of GJB2 gene. For 7 pregnant women at high risk, prenatal genetic diagnosis was provided.\nRESULTS: Fourteen cases (21.21%) were found to have GJB2 mutations by both methods (homozygous 235delC mutation in 3 cases, homozygous 176del16 mutation in 2 cases, 235delC and 299delAT compound heterozygous mutation in 2 cases, 299delAT and 176del16 compound heterozygous mutation in 1 case, c.339T > G and 313del12bp compound heterozygous mutation 1 case, and 235delC heterozygous mutation in 5 cases). 13 (19.70%) had SLC26A4 mutations (IVS7-2 A >G homozygous mutation in 2 cases, IVS7-2 A > G homozygous mutation in 2 cases, IVS7-2 A > G and 2168A > G compound heterozygous mutation in 3 cases, 2168A>G heterozygous mutation in 3 cases, and IVS7-2 heterozygous mutation in 3 cases); and 3 had mtDNA12S rRNA mutation (1555A > G mutation in 2 cases, 1494C > T mutation in 1 case). Prenatal diagnosis suggested that 3 fetuses have carried a heterozygous mutation. Two fetuses were detected as normal and confirmed to have normal hearing after birth. Two fetuses were found to have carried compound mutations of GJB2.\nCONCLUSION: Gene chip combined with GJB2 gene analysis is an accurate and effective method for the diagnosis of NSHI. The results can facilitate accurate prenatal diagnosis.","variants":[{"Name":"NM_004004.6(GJB2):c.339T>G (p.Ser113Arg)","Chromosome":"13","Start":"20189243","Stop":"20189243","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":34237,"rule_based_match":true,"evidence_text":"c.339T > G","llm_judgment":"PRESENT","evidence":"c.339T > G","abstract_start":699,"abstract_end":709}]}
{"pmid":"15108279","title":"Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis.","abstract":"Autosomal recessive malignant infantile osteopetrosis (ARO) is characterized by severe osteosclerosis, pathologic fractures, hepatosplenomegaly, and pancytopenia. The pathophysiological basis is inadequate bone resorption due to osteoclast dysfunction. In the majority of cases, mutations in either of two human genes cause this fatal disorder: TCIRG1, encoding a subunit of the osteoclast H(+)-ATPase, and the voltage-gated chloride channel gene CLCN7. We excluded both genes in a small inbred family with malignant infantile osteopetrosis and undertook linkage analysis of several candidate loci that are involved in murine osteopetrosis. A region spanning more than 20 cM between the markers D6S1717 and D6S1608 on chromosome 6q21 was found to be homozygous in the affected child. This locus is syntenic to the genomic region harboring the gene for the osteopetrotic mutant mouse grey-lethal (gl). Recently, mutations in a novel gene of unknown function were described in the grey-lethal mouse and in one human patient. Mutation screening of the grey-lethal gene (OSTM1), revealed a homozygous 2-bp deletion in exon 2 (c.415_416delAG) in the affected child. No mutations could be found in six independent ARO patients who had tested negative for mutations in TCIRG1 and CLCN7. In summary, we describe the identification of a novel mutation in the coding sequence of the human grey-lethal gene, which is the second OSTM1 mutation found in human ARO, confirming the involvement of this gene in the pathogenesis of this severe bone disease.","variants":[{"Name":"NM_014028.4(OSTM1):c.415_416del (p.Gln140fs)","Chromosome":"6","Start":"108064286","Stop":"108064287","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":192452,"rule_based_match":true,"evidence_text":"c.415_416delAG","llm_judgment":"PRESENT","evidence":"c.415_416delAG","abstract_start":1122,"abstract_end":1136}]}
{"pmid":"19557857","title":"De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.","abstract":"We sequenced genes coding for components of the SNARE complex (STX1A, VAMP2, SNAP25) and their regulatory proteins (STXBP1/Munc18-1, SYT1), which are essential for neurotransmission, in 95 patients with idiopathic mental retardation. We identified de novo mutations in STXBP1 (nonsense, p.R388X; splicing, c.169+1G>A) in two patients with severe mental retardation and nonsyndromic epilepsy. Reverse transcriptase polymerase chain reaction and sequencing showed that the splicing mutation creates a stop codon downstream of exon-3. No de novo or deleterious mutations in STXBP1 were found in 190 control subjects, or in 142 autistic patients. These results suggest that STXBP1 disruption is associated with autosomal dominant mental retardation and nonsyndromic epilepsy.","variants":[{"Name":"NM_001032221.6(STXBP1):c.169+1G>A","Chromosome":"9","Start":"127653797","Stop":"127653797","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21770,"rule_based_match":true,"evidence_text":"c.169+1G>A","llm_judgment":"PRESENT","evidence":"c.169+1G>A","abstract_start":306,"abstract_end":316}]}
{"pmid":"33844363","title":"A recurrent MORC2 mutation causes Charcot-Marie-Tooth disease type 2Z.","abstract":"We found a p.Ala406Val (c.1217C > T) mutation in MORC2 in three individuals, from two families. All three individuals were evaluated and clinical electrophysiology was completed. The neuropathy began in childhood to early adulthood, with distal weakness progressing to proximal weakness. Vinblastine (for Hodgkin lymphoma) acutely worsened the weakness in one patient. This finding confirms that that the p.Ala406Val mutation in MORC2 causes severe neuropathy. In addition, we report the first case of vinblastine neurotoxicity in Charcot-Marie-Tooth disease type 2Z.","variants":[{"Name":"NM_001303256.3(MORC2):c.1217C>T (p.Ala406Val)","Chromosome":"22","Start":"30937967","Stop":"30937967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":683110,"rule_based_match":true,"evidence_text":"p.Ala406Val (c.1217C > T)","llm_judgment":"PRESENT","evidence":"p.Ala406Val (c.1217C > T)","abstract_start":11,"abstract_end":36}]}
{"pmid":"32012697","title":"Enhancing Genetic Medicine: Rapid and Cost-Effective Molecular Diagnosis for a","abstract":"In Ghana, gap-junction protein β 2 (<i>GJB2</i>) variants account for about 25.9% of familial hearing impairment (HI) cases. The <i>GJB2</i>-p.Arg143Trp (NM_004004.6:c.427C>T/OMIM: 121011.0009/rs80338948) variant remains the most frequent variant associated with congenital HI in Ghana, but has not yet been investigated in clinical practice. We therefore sought to design a rapid and cost-effective test to detect this variant. We sampled 20 hearing-impaired and 10 normal hearing family members from 8 families segregating autosomal recessive non syndromic HI. In addition, a total of 111 unrelated isolated individuals with HI were selected, as well as 50 normal hearing control participants. A restriction fragment length polymorphism (RFLP) test was designed, using the restriction enzyme NciI optimized and validated with Sanger sequencing, for rapid genotyping of the common <i>GJB2</i>-p.Arg143Trp variant. All hearing-impaired participants from 7/8 families were homozygous positive for the <i>GJB2</i>-p.Arg143Trp mutation using the NciI<i>-</i>RFLP test, which was confirmed with Sanger sequencing. The investigation of 111 individuals with isolated non-syndromic HI that were previously Sanger sequenced found that the sensitivity of the <i>GJB2</i>-p.Arg143Trp NciI<i>-</i>RFLP testing was 100%. All the 50 control subjects with normal hearing were found to be negative for the variant. Although the test is extremely valuable, it is not 100% specific because it cannot differentiate between other mutations at the recognition site of the restriction enzyme. The <i>GJB2-</i>p.Arg143Trp NciI<i>-</i>RFLP-based diagnostic test had a high sensitivity for genotyping the most common <i>GJB2</i> pathogenic and founder variant (p.Arg143Trp) within the Ghanaian populations. We recommend the adoption and implementation of this test for hearing impairment genetic clinical investigations to complement the newborn hearing screening program in Ghana. The present study is a practical case scenario of enhancing genetic medicine in Africa.","variants":[{"Name":"NM_004004.6(GJB2):c.427C>T (p.Arg143Trp)","Chromosome":"13","Start":"20189155","Stop":"20189155","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32048,"rule_based_match":true,"evidence_text":"NM_004004.6:c.427C>T","llm_judgment":"PRESENT","evidence":"NM_004004.6:c.427C>T","abstract_start":154,"abstract_end":174}]}
{"pmid":"24239059","title":"Anoctamin 5 muscular dystrophy associated with a silent p.Leu115Leu mutation resulting in exon skipping.","abstract":"We report a 45year-old patient with an asymmetrical proximal muscle weakness affecting the quadriceps muscle of the right leg starting at the age of 32years. CK was 25-fold increased. MRI of the legs showed signs of fatty degeneration more pronounced in the right side. Biopsy of a thigh muscle showed dystrophic pattern and amyloid deposition in blood vessel walls. The coding region and exon/intron boundaries of the ANO5 gene were amplified and sequenced. The common c.191dupA mutation and a silent novel p.Leu115Leu (c.345G>A) variant were identified. This silent variant was listed neither in the LOVD database nor in the SNP database. To evaluate the pathogenicity of the novel silent mutation in ANO5, cDNA analysis was performed that demonstrated skipping of exon 6. So far, no case with a silent mutation leading to abnormal splicing has been identified in Anoctamin 5 muscular dystrophy. Present findings emphasize that cDNA analysis should be done if a silent variant is not annotated in the databases. In Anoctamin 5 muscular dystrophy a molecular diagnosis is even more important as protein investigation through Western blotting or immunohistochemistry is not yet established.","variants":[{"Name":"NM_213599.3(ANO5):c.345G>A (p.Leu115=)","Chromosome":"11","Start":"22226034","Stop":"22226034","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":838203,"rule_based_match":true,"evidence_text":"c.345G>A","llm_judgment":"PRESENT","evidence":"c.345G>A","abstract_start":521,"abstract_end":529}]}
{"pmid":"32370745","title":"A progressive and complex clinical course in two family members with ERF-related craniosynostosis: a case report.","abstract":"BACKGROUND: ERF-related craniosynostosis are a rare, complex, premature trisutural fusion associated with a broad spectrum of clinical features and heterogeneous aetiology. Here we describe two cases with the same pathogenic variant and a detailed description of their clinical course.\nCASE PRESENTATION: Two subjects; a boy with a BLSS requiring repeated skull expansions and his mother who had been operated once for sagittal synostosis. Both developed intracranial hypertension at some point during the course, which was for both verified by formal invasive intracranial pressure monitoring. Exome sequencing revealed a pathogenic truncating frame shift variant in the ERF gene.\nCONCLUSIONS: Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). Our work provides supplementary evidence in support of previous phenotypic descriptions of ERF-related craniosynostosis, particularly late presentation, an evolving synostotic pattern and variable expressivity even among affected family members.","variants":[{"Name":"NM_006494.4(ERF):c.1201_1202del (p.Lys401fs)","Chromosome":"19","Start":"42248910","Stop":"42248911","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":410626,"rule_based_match":true,"evidence_text":"ERF c.1201_1202delAA (p.Lys401Glufs*10)","llm_judgment":"PRESENT","evidence":"ERF c.1201_1202delAA (p.Lys401Glufs*10)","abstract_start":871,"abstract_end":910}]}
{"pmid":"31431315","title":"3P association (3PAs): Pituitary adenoma and pheochromocytoma/paraganglioma. A heterogeneous clinical syndrome associated with different gene mutations.","abstract":"BACKGROUND: Pituitary adenomas (PA) associated with pheochromocytomas/paragangliomas (Pheo/PGL), also known as \"the three P association\" or \"3PAs\" could be the results of coincidence, but new evidence supports a common pathogenic mechanism in some patients. Our aim is to report the clinical data, surgical outcome, genetic findings of a large case series and review the current knowledge on this topic.\nMETHODS AND RESULTS: In a retrospective multicentre study, we compiled 10 patients with PAs (6 new unreported cases). Six patients were female with mean age of 51.6 ± 18.0 years. PA were: 6 acromegaly, 3 prolactinoma and 1 non-functioning PA (NFPA). Among the Pheo/PGL, 7 patients had a single tumour (4 Pheo and 3 PGL) and 3 patients had multiple or bilateral disease (2 PGL and 1 Pheo). Patients with GH-secreting PA and NFPA underwent surgery, while patients with prolactinoma received medical treatment (one patient required surgery). Unilateral adrenalectomy was carried out in all single Pheo and a bilateral procedure was performed in the patient with bilateral tumour. A single tumour was resected in two patients with multiple PGL. We found 3 germline pathogenic mutations: 2 in SDHB (c.166-170delCCTCA and a gross deletion involving exon 1) and 1 SDHD (p.P81L exon 3). Two variants of uncertain significance: 1 in MEN1 (c.1618C > T; p.Pro540Ser) and 1 in RET (c.2556C > G, p.Ile852Met), and finally a RET<sup>M918T</sup> somatic mutation in a Pheo tissue.\nCONCLUSION: We actively suggest considering the possibility of hereditary disease in all cases with 3PA and performing a complete genetic study.","variants":[{"Name":"NM_020975.6(RET):c.2556C>G (p.Ile852Met)","Chromosome":"10","Start":"43119694","Stop":"43119694","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":36296,"rule_based_match":true,"evidence_text":"c.2556C > G, p.Ile852Met","llm_judgment":"PRESENT","evidence":"c.2556C > G, p.Ile852Met","abstract_start":1374,"abstract_end":1398},{"Name":"NM_001370259.2(MEN1):c.1618C>T (p.Pro540Ser)","Chromosome":"11","Start":"64804549","Stop":"64804549","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":197521,"rule_based_match":true,"evidence_text":"c.1618C > T; p.Pro540Ser","llm_judgment":"PRESENT","evidence":"c.1618C > T; p.Pro540Ser","abstract_start":1334,"abstract_end":1358}]}
{"pmid":"31055806","title":"Analysis of FBN1 gene mutations in two pedigrees affected with Marfan syndrome","abstract":"OBJECTIVE: To detect mutations of fibrillin-1 (FBN1) gene in two pedigrees affected with Marfan syndrome (MFS).\nWETHODS: Peripheral blood samples were collected from MFS patients and their healthy family members for extracting genomic DNA. All of the 65 exons of the FBN1 gene were analyzed by next-generation sequencing. PolyPhen-2 and SIFT was used to predict structural and functional changes in FBN1 protein.\nRESULTS: Patients from both pedigrees presented ocular and skeletal manifestations suggestive of MFS. Two novel heterozygous mutations of the FBN1 gene, including c.1879C>T (p.R627C) in exon 16 and c.2584T>C (p.C862R) in exon 22, were identified. The same mutations were not found among unaffected members. By bioinformatic analysis, the mutations may affect the structure and function of the FBN1 protein.\nCONCLUSION: The c.1879C>T and c.2584T>C mutations of the FBN1 gene probably account for the disease in the two pedigrees, respectively. Identification of the c.2584T>C has enriched the spectrum of FBN1 gene mutations.","variants":[{"Name":"NM_000138.5(FBN1):c.2584T>C (p.Cys862Arg)","Chromosome":"15","Start":"48495216","Stop":"48495216","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":842502,"rule_based_match":true,"evidence_text":"c.2584T>C (p.C862R)","llm_judgment":"PRESENT","evidence":"c.2584T>C (p.C862R)","abstract_start":611,"abstract_end":630}]}
{"pmid":"38166944","title":"A novel missense COL9A3 variant in a pedigree with multiple lumbar disc herniation.","abstract":"Trp3 allele in COL9A3 gene has been widely studied in populations with intervertebral disc disease. We identified a novel pathogenic variant in COL9A3 gene in a pedigree with multiple lumbar disc herniation (LDH). The proband was a 14-year-old boy who developed LDH at the L4/5 and L5/S1 spinal segments. His father, paternal aunt and grandfather were diagnosed with LDH at an age of 35, 30 and 23, respectively. By applying whole exome sequencing, a heterozygous missense variant (c.1150C > T, p.Arg384Trp) in COL9A3 was identified. According to the ACMG guidelines, this variant is predicted to be pathogenic. In addition, prediction tools found COL9A3 protein of this variant a reduced stability, some changed charge properties, and an altered spatial conformation. Findings expanded the mutational spectrum of LDH and contributed to the understanding of COL9A3 in the pathogenesis of LDH.","variants":[{"Name":"NM_001853.4(COL9A3):c.1150C>T (p.Arg384Trp)","Chromosome":"20","Start":"62829808","Stop":"62829808","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1161873,"rule_based_match":true,"evidence_text":"c.1150C > T, p.Arg384Trp","llm_judgment":"PRESENT","evidence":"c.1150C > T, p.Arg384Trp","abstract_start":482,"abstract_end":506}]}
{"pmid":"17982426","title":"Novel MAF mutation in a family with congenital cataract-microcornea syndrome.","abstract":"PURPOSE: To further unravel the molecular genetic background for the association congenital cataract-microcornea (CCMC).\nMETHODS: DNA variation was pointed out by direct DNA sequencing of 13 lens-expressed cataract genes from three CCMC families and one isolated case. The mutation screening included seven crystalline genes, two gap junction protein genes, and four lens expressed regulatory genes.\nRESULTS: A DNA variation in the basic leucine zipper transcription factor V-maf musculoaponeurotic fibrosarcoma oncogene homolog gene (MAF) was identified in one family. The mutation c.895C>A changes arginine 299 to a serine residue, and the substitution destroys the basic region of the DNA binding domain of MAF leucine-zipper. Mutations were not identified in the remaining CCMC patients.\nCONCLUSIONS: One novel mutation affecting a known cataract gene was identified among four unrelated individuals with presumed autosomal dominant congenital cataract-microcornea syndrome. The MAF mutation p.Arg299Ser is the third mutation identified in association with the CCMC phenotype, and all three mutations are located in the basic region of the DNA binding domain in the MAF protein (OMIM 177075). This suggests that the basic region is a hot spot domain for CCMC associated mutations. The identification of a novel mutation associated with the distinct cataract-microcornea phenotype adds a new brick to the puzzle of molecular modeling of the lens-anterior segment structures.","variants":[{"Name":"NM_005360.5(MAF):c.895C>A (p.Arg299Ser)","Chromosome":"16","Start":"79599008","Stop":"79599008","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":188064,"rule_based_match":true,"evidence_text":"c.895C>A","llm_judgment":"PRESENT","evidence":"c.895C>A","abstract_start":583,"abstract_end":591}]}
{"pmid":"22999896","title":"Hypoxanthine-guanine phosphoribosyltransferase deficiency in a patient with a Madrid II mutation.","abstract":"The hypoxanthine-guanine phosphoribosyltransferase deficiency is an inborn error of purine metabolism, linked to the X chromosome. The clinical phenotypes associated with HPRT deficiency varied according to the level of enzyme deficiency, with a large spectrum of neurologic features like self-injurious behaviour in patients with complete deficiency. We report a 20-year-old man who had asymmetric polyarthritis, tophi, hyperuricemia, nephrolithiasis and mild neurologic symptoms with undetectable levels of HPRT activity in lysed erythrocytes. The genetic study identified the c.143G>A mutation in exon 3, GAA CGT (CTT>GAA CAT CTT (48arg>his). The presence of gouty arthropathy and chronic hyperuricemia in a young patient with neurological symptoms, suggests HPRT deficiency for which it is necessary its enzyme and molecular determination.","variants":[{"Name":"NM_000194.3(HPRT1):c.143G>A (p.Arg48His)","Chromosome":"X","Start":"134475189","Stop":"134475189","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38940,"rule_based_match":true,"evidence_text":"c.143G>A","llm_judgment":"PRESENT","evidence":"c.143G>A","abstract_start":579,"abstract_end":587}]}
{"pmid":"24257358","title":"The gene mutation screening of a family with congenital fibrosis of the extraocular muscles associated with corpus callosum agenesis","abstract":"OBJECTIVE: To identify TUBB3 gene mutations in a Chinese family with congenital fibrosis of the extraocular muscle associated with corpus callosum agenesis.\nMETHODS: We have found a family with CFEOM associated with corpus callosum agenesis, including 4 affected individuals in three generations of 11 familial members. 4 affected individuals were sequenced by direct TUBB3 sequencing, 4 unaffected individuals in the family and 100 cases of unrelated normal person as a control.\nRESULTS: This family is in line with Mendelian autosomal dominant inheritance. Clinical manifestations belongs to CFEOM3. All affected individuals were detected with TUBB3 c.1249G > A mutation, the mutation is in exon 4, resulting in wild-type gene encoding the Aspartic acid ( Asp or D ) replaced .by Asparagine (Asn or N ).\nCONCLUSION: Our study supports that TUBB3 gene mutation c.1249G > A (p. Asp417Asn), is the underlying molecular pathogenesis of this family with CFEOM3.","variants":[{"Name":"NM_006086.4(TUBB3):c.1249G>A (p.Asp417Asn)","Chromosome":"16","Start":"89935700","Stop":"89935700","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22005,"rule_based_match":true,"evidence_text":"c.1249G > A","llm_judgment":"PRESENT","evidence":"c.1249G > A","abstract_start":652,"abstract_end":663}]}
{"pmid":"30404926","title":"Novel Factor XIII variant identified through whole-genome sequencing in a child with intracranial hemorrhage.","abstract":"Pediatric stroke can be either hemorrhagic or ischemic, with ∼5% of hemorrhagic strokes being caused by genetic coagulopathies. We report an 8 mo old presenting with a hemorrhagic stroke caused by severe Factor XIII deficiency (OMIM # 613225) in whom rapid whole-genome sequencing identified a novel variant in the <i>F13A1</i> gene c.1352_1353delAT (p.His451ArgfsTer29).","variants":[{"Name":"NM_000129.4(F13A1):c.1352_1353del (p.His451fs)","Chromosome":"6","Start":"6182094","Stop":"6182095","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":552283,"rule_based_match":true,"evidence_text":"c.1352_1353delAT (p.His451ArgfsTer29)","llm_judgment":"PRESENT","evidence":"c.1352_1353delAT (p.His451ArgfsTer29)","abstract_start":333,"abstract_end":370}]}
{"pmid":"28391287","title":"Identification of 2 Potentially Relevant Gene Mutations Involved in Strabismus Using Whole-Exome Sequencing.","abstract":"BACKGROUND The etiology of strabismus has a genetic component. Our study aimed to localize the candidate causative gene mutant in a Chinese family with strabismus and to describe its underlying etiology. MATERIAL AND METHODS Genomic DNA was extracted from the affected individual and his parents in a Chinese pedigree with strabismus. The resulting exomes were sequenced by whole-exome sequencing. After variant calling and filtering, the candidate causative gene mutations were selected for the rarity and predicted damaging effect, which complied with the model of recessive disease transmission. RESULTS We examined a Chinese strabismus pedigree with the parents unaffected and 2 offspring affected. Whole-exome sequencing and bioinformatics filtering identified 2 variants including Abelson helper integration site 1 (AHI1) gene and nebulin (NEB) gene. The variant in the AHI1 gene, c.A3257G (p.E1086G), and the altered amino acid had a damaging effect on the encoded protein predicted by Polyphen2. Moreover, this change was located in the conserved SH3 domain of AHI1. Biallelic pathogenic variant in AHI1 gene can cause Joubert syndrome-related disorders with oculomotor apraxia characteristics. Additionally, c.A914G mutation was found in nebulin (NEB) gene. Therefore, we concluded that AHI1 c.3257A>G and NEB c.914 A>G were potential causal variants in this strabismus pedigree. CONCLUSIONS We detected an AHI1 homozygous mutation in the affected individual. Whole-exome sequencing is a powerful way to identify causally relevant genes, improving the understanding of this disorder.","variants":[{"Name":"NM_001134831.2(AHI1):c.3257A>G (p.Glu1086Gly)","Chromosome":"6","Start":"135323233","Stop":"135323233","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":152870,"rule_based_match":true,"evidence_text":"c.3257A>G (p.E1086G)","llm_judgment":"PRESENT","evidence":"c.3257A>G","abstract_start":1301,"abstract_end":1310}]}
{"pmid":"27113771","title":"Phenotypic features of CRB1-associated early-onset severe retinal dystrophy and the different molecular approaches to identifying the disease-causing variants.","abstract":"PURPOSE: The aim of this study was to determine the molecular genetic basis of an early-onset severe retinal dystrophy in three unrelated consecutive patients of Czech origin and to describe their ocular phenotype.\nMETHODS: DNA samples from two probands were analyzed using a genotyping microarray (Asper) followed by either target analysis of 43 genes implicated in retinal disorders by next generation sequencing or whole-exome sequencing, respectively. The third proband underwent conventional Sanger sequencing of CRB1 based on her ocular findings.\nRESULTS: All three probands harboured a known disease-causing mutation c.2843G>A; p.(Cys948Tyr) in the CRB1 gene. One individual was homozygous for this mutation, while in the other two probands c.2308G>A; p.(Gly770Ser) and c.3121A>G; p.(Met1041Val) were also identified in the heterozygous state, respectively. Both variants were novel and evaluated by in silico analysis as pathogenic. A false-negative result was observed in one of the two samples examined by the genotyping microarray. Disease onset in all patients was before the age of 7 years. Hypermetropic refractive error, bilateral nummular retinal pigmentation, retinal thickening and cystoid spaces in the macula were observed in two probands, aged 6 and 7 years. The third proband, aged 28 years, had bone spicule-like pigmentary changes associated with increased retinal nerve fiber layer.\nCONCLUSIONS: The first study reporting on the molecular genetic cause of non-syndromic early-onset severe retinal dystrophy in Czech patients identified one homozygous and two compound heterozygote probands with CRB1 mutations. Retina nerve fibre layer measurements should be considered an integral part of the clinical evaluation of retinal dystrophies. Detailed clinical examination and imaging can both direct molecular screening and help to confirm or refute disease causation of identified variants.","variants":[{"Name":"NM_201253.3(CRB1):c.3121A>G (p.Met1041Val)","Chromosome":"1","Start":"197434984","Stop":"197434984","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":623793,"rule_based_match":true,"evidence_text":"c.3121A>G; p.(Met1041Val)","llm_judgment":"PRESENT","evidence":"c.3121A>G; p.(Met1041Val)","abstract_start":777,"abstract_end":802},{"Name":"NM_201253.3(CRB1):c.2308G>A (p.Gly770Ser)","Chromosome":"1","Start":"197427633","Stop":"197427633","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":237970,"rule_based_match":true,"evidence_text":"c.2308G>A; p.(Gly770Ser)","llm_judgment":"PRESENT","evidence":"c.2308G>A; p.(Gly770Ser)","abstract_start":748,"abstract_end":772},{"Name":"NM_201253.3(CRB1):c.2843G>A (p.Cys948Tyr)","Chromosome":"1","Start":"197434706","Stop":"197434706","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48213,"rule_based_match":true,"evidence_text":"c.2843G>A; p.(Cys948Tyr)","llm_judgment":"PRESENT","evidence":"c.2843G>A; p.(Cys948Tyr)","abstract_start":624,"abstract_end":648}]}
{"pmid":"19863265","title":"Tracing the origin of L-2-hydroxyglutaric aciduria in a family.","abstract":"We describe late diagnosis of an adult with L-2-hydroxyglutaric aciduria (MIM 236792) on the basis of characteristic metabolite data and mutation analysis in the L2HGDH gene. The patient lacked MRI abnormalities which have been purported to be constant or typical findings in this disease. We further report the genetic status of his parents and his one living sibling. Our observations underline the clinical heterogeneity of the syndrome of L-2-hydroxyglutaric aciduria. This report emphasizes the diagnostic benefit of the assessment of urinary organic acids not only in children, but also in adult patients with unexplained neurological symptoms. The patient was determined to be compound heterozygous for two novel missense mutations in exon 4 of the gene (c.418G>C, c.446T>G), resulting in amino acid exchanges from alanine to proline (p.Ala140Pro) and leucine to arginine (p.Leu149Arg), respectively. The mother of our patient was heterozygous for Ala140Pro, and the father heterozygous for Leu149Arg only. Mutation analysis of a healthy 49-year-old third son of the non-consanguineous parents revealed a normal exon 4.","variants":[{"Name":"NM_024884.3(L2HGDH):c.446T>G (p.Leu149Arg)","Chromosome":"14","Start":"50294209","Stop":"50294209","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2894802,"rule_based_match":true,"evidence_text":"c.446T>G","llm_judgment":"PRESENT","evidence":"c.446T>G","abstract_start":772,"abstract_end":780},{"Name":"NM_024884.3(L2HGDH):c.418G>C (p.Ala140Pro)","Chromosome":"14","Start":"50294237","Stop":"50294237","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1454354,"rule_based_match":true,"evidence_text":"c.418G>C","llm_judgment":"PRESENT","evidence":"c.418G>C","abstract_start":762,"abstract_end":770}]}
{"pmid":"28173647","title":"Analysis of newborn screening for galactosemia and genotype-phenotype of confirmed galatosemia cases","abstract":"<b>Objective:</b> To investigate the prevalence of galactosemia(GAL), and the characteristics of genotype and phenotype of newborns who were confirmed with GAL in newborn screening in Zhejiang province. <b>Method:</b> The number of all live births, newborn screened infants and all clinical data of confirmed newborns with GAL from October 2013 to March 2015 were retrospectively analyzed by reviewing the data of Zhejiang Province screening center database. And the characteristics of genes and the clinical data of GAL cases who were confirmed by correlative gene test and enzyme activity measurement were analyzed. <b>Result:</b> The prevalence of GAL in Zhejiang province was 1/189 857. Among them, there was 1 case confirmed with GAL typeⅠ (prevalence, 1/759 428), with mutations of c. 904+ 1G>T and c. 687G>A, the enzyme activity of galactose-1-phosphate uridyltransferase (GALT) was 56.4% of controls. And there was 1 case of GAL typeⅡ(prevalence, 1/759 428), with mutations of c. 85G>T and c. 502G>A. There were 2 cases confirmed with GAL type Ⅲ(prevalence, 1/379 714), with mutations of c. 505C>T, c. 452G>A, c. 280G>A and c. 925G>A, the enzyme activity of UDP-galactose-4'-epimerase (GALE) were 42% and 38% of controls, respectively. All cases had different abnormal biochemical marks of liver function, and 1 case had combined hyperlactacidemia or hyperammonemia or increase of multiple kinds of amino acids, respectively. The newborn of GAL type Ⅱ had phacoscotasmus before treatment. All the cases were fed with lactose free milk powder, and all the abnormal parameters were improved during following up. <b>Conclusion:</b> The disease of GAL is rare in Zhejiang province, and its genotype distribution is scattered with comparatively mind clinical manifestations, and the cases with early treatment with lactose free milk powder have good prognosis. All cases needed to be treated and followed up for a life-long time. It is recommended that the high risk cases with GAL should be screened as soon as possible.","variants":[{"Name":"NM_001008216.2(GALE):c.505C>T (p.Arg169Trp)","Chromosome":"1","Start":"23797718","Stop":"23797718","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34023,"rule_based_match":true,"evidence_text":"c. 505C>T","llm_judgment":"PRESENT","evidence":"c. 505C>T","abstract_start":1096,"abstract_end":1105},{"Name":"NM_000155.4(GALT):c.904+1G>T","Chromosome":"9","Start":"34649082","Stop":"34649082","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":47152,"rule_based_match":true,"evidence_text":"c. 904+ 1G>T","llm_judgment":"PRESENT","evidence":"c. 904+ 1G>T","abstract_start":788,"abstract_end":800}]}
{"pmid":"28663785","title":"Case Report: Novel mutations in","abstract":"Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the <i>TBC1D24</i> gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband's mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which <i>TBC1D24</i> mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in <i>TBC1D24</i> might cause a dominant susceptibility to epilepsy.","variants":[{"Name":"NM_001199107.2(TBC1D24):c.404C>T (p.Pro135Leu)","Chromosome":"16","Start":"2496552","Stop":"2496552","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":362597,"rule_based_match":true,"evidence_text":"c.404C>T; p.Pro135Leu","llm_judgment":"PRESENT","evidence":"c.404C>T; p.Pro135Leu","abstract_start":637,"abstract_end":658},{"Name":"NM_001199107.2(TBC1D24):c.1078C>T (p.Arg360Cys)","Chromosome":"16","Start":"2498332","Stop":"2498332","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":362598,"rule_based_match":true,"evidence_text":"c.1078C>T; p.Arg360Cys","llm_judgment":"PRESENT","evidence":"c.1078C>T; p.Arg360Cys","abstract_start":610,"abstract_end":632}]}
{"pmid":"18042412","title":"A novel (Leu183Pro-)mutation in the HFE-gene co-inherited with the Cys282Tyr mutation in two unrelated Dutch hemochromatosis patients.","abstract":"We describe a novel heterozygous mutation in exon 3 of the HFE-gene that was co-inherited with Cys282Tyr in two unrelated Dutch men both presenting a classical form of hereditary hemochromatosis. Heterozygosity for this mutation was also found in one out of 100 healthy controls of Dutch descent. This c.548T>C mutation converts a leucine to a proline residue at position 183 in the alpha2-helix of the HFE-protein (Leu183Pro). Standard bioinformatics analysis shows that the mutation is likely to disturb the HFE interaction with TfR1. This disrupting role of the mutation in the iron regulatory pathway is further corroborated by the familial co-occurrence of the observed compound heterozygosity with increased serum iron parameters. Haplotype analysis strongly suggests that this novel mutation arose from a common ancestor in the distant past. These findings may have implications for HFE-testing of iron overloaded heterozygous Cys282Tyr-patients of Northern European origin and their relatives.","variants":[{"Name":"NM_000410.4(HFE):c.548T>C (p.Leu183Pro)","Chromosome":"6","Start":"26091521","Stop":"26091521","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1892263,"rule_based_match":true,"evidence_text":"c.548T>C","llm_judgment":"PRESENT","evidence":"c.548T>C","abstract_start":302,"abstract_end":310}]}
{"pmid":"30850373","title":"De novo missense variant in the GTPase effector domain (GED) of","abstract":"<i>DNM1L</i> encodes a GTPase of the dynamin superfamily, which plays a crucial role in mitochondrial and peroxisomal fission. Pathogenic variants affecting the middle domain and the GTPase domain of <i>DNM1L</i> have been implicated in encephalopathy because of defective mitochondrial and peroxisomal fission 1 (EMPF1, MIM #614388). Patients show variable phenotypes ranging from severe hypotonia leading to death in the neonatal period to developmental delay/regression, with or without seizures. Familial pathogenic variants in the GTPase domain have also been associated with isolated optic atrophy. We present a 27-yr-old woman with static encephalopathy, a history of seizures, and nystagmus, in whom a novel de novo heterozygous variant was detected in the GTPase effector domain (GED) of <i>DNM1L</i> (c.2072A>G, p.Tyr691Cys). Functional studies in <i>Drosophila</i> demonstrate large, abnormally distributed peroxisomes and mitochondria, an effect very similar to that of middle domain missense alleles observed in pediatric subjects with EMPF1. To our knowledge, not only is this the first report of a disease-causing variant in the GED domain in humans, but this is also the oldest living individual reported with EMPF1. Longitudinal data of this kind helps to expand our knowledge of the natural history of a growing list of <i>DNM1L</i>-related disorders.","variants":[{"Name":"NM_012062.5(DNM1L):c.2072A>G (p.Tyr691Cys)","Chromosome":"12","Start":"32742666","Stop":"32742666","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":610426,"rule_based_match":true,"evidence_text":"c.2072A>G, p.Tyr691Cys","llm_judgment":"PRESENT","evidence":"c.2072A>G, p.Tyr691Cys","abstract_start":811,"abstract_end":833}]}
{"pmid":"29704303","title":"Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.","abstract":"Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non-polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma. She carried a novel de novo missense variant, p.R102S (c.304C > A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night-time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On PHOX2B sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C > G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in PHOX2B who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering PHOX2B mutations when encountering atypical CCHS presentations.","variants":[{"Name":"NM_003924.4(PHOX2B):c.234C>G (p.Tyr78Ter)","Chromosome":"4","Start":"41748377","Stop":"41748377","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":857370,"rule_based_match":true,"evidence_text":"c.234C > G","llm_judgment":"PRESENT","evidence":"c.234C > G","abstract_start":1094,"abstract_end":1104}]}
{"pmid":"33377626","title":"Novel mutations in hyper-IgM syndrome type 2 and X-linked agammaglobulinemia detected in three patients with primary immunodeficiency disease.","abstract":"BACKGROUND: Ambiguous or atypical phenotypes can make a definite diagnosis of primary immunodeficiency diseases based on biochemical indices alone challenging. Further, mortality in early life because of infections in patients with these conditions supports the use of genetic tests to facilitate rapid and accurate diagnoses.\nMETHODS: Genetic and clinical analyses of three unrelated Chinese children with clinical manifestations of recurrent infections, who were considered to have primary immunodeficiency diseases, were conducted. Patient clinical features and serum immunological indices were recorded. Next-generation sequencing was used to screen for suspected pathogenic variants. Family co-segregation and in silico analysis were conducted to evaluate the pathogenicity of identified variants, following the American College of Medical Genetics and Genomics guidance.\nRESULTS: All three patients were found to have predominant antibody defects. Sequencing analysis revealed that one had two compound heterozygous variants, c.255C>A and c.295C>T, in the autosomal gene, activation-induced cytidine deaminase (AICDA). The other two patients were each hemizygous for the variants c.1185G>A and c.82C>T in the Bruton's tyrosine kinase (BTK) gene on the X chromosome. In silico analysis revealed that identified substituted amino acids were highly conserved and predicted to cause structural and functional damage to the proteins.\nCONCLUSION: Four pathogenic variants in AICDA and BTK were confirmed to cause different forms of hyper-IgM syndrome type 2 (HIGM2) and X-linked agammaglobulinemia (XLA); two were novel mutations that have never been reported previously. This is the first report of HIGM2 caused by AICDA deficiency in a patient from the Chinese mainland.","variants":[{"Name":"NM_000061.3(BTK):c.82C>T (p.Arg28Cys)","Chromosome":"X","Start":"101375203","Stop":"101375203","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":929530,"rule_based_match":true,"evidence_text":"c.82C>T","llm_judgment":"PRESENT","evidence":"c.82C>T","abstract_start":1200,"abstract_end":1207},{"Name":"NM_020661.4(AICDA):c.295C>T (p.Arg99Ter)","Chromosome":"12","Start":"8605347","Stop":"8605347","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2852348,"rule_based_match":true,"evidence_text":"c.295C>T","llm_judgment":"PRESENT","evidence":"c.295C>T","abstract_start":1045,"abstract_end":1053}]}
{"pmid":"24915601","title":"Evaluation of damaging effects of splicing mutations: validation of an in vitro method for diagnostic laboratories.","abstract":"BACKGROUND: Pre-mRNA splicing defects may have an important impact on clinical phenotype in several diseases, but often their pathogenic role is difficult to demonstrate. The aim of this study was to validate an in vitro method to assess the effects of putative splicing variants.\nMATERIALS AND METHODS: We studied three novel variants in vitro using a novel minigene approach and compared results with in silico and ex vivo strategies from patient samples.\nRESULTS: For the c.1146C>T variant in the LMNA gene, in vitro and ex vivo studies were concordant with the prediction obtained by in silico tools, confirming the loss of 13 bp at the end of exon 6. In the second case (c.1140+1G>A, SCN5A gene), in vitro experiments identified the insertion of 94 intronic bp in exon 9 as well as exon 9 skipping, but these results were not correctly predicted by ex vivo data and in silico tools. In the third case (c.1608+1C>T, LMNA gene) in vitro and ex vivo studies suggested the recognition of an exonic cryptic site leading to the loss of 29 bp in exon 9, not predicted by in silico analysis.\nCONCLUSION: Our results revealed how in silico tools are often unreliable requiring \"wet\" RNA analysis. Since ex vivo studies are not always feasible, the use of an in vitro construct represents an efficient and useful method for the evaluation of damaging effects of unknown splicing variants, especially in diagnostic laboratories.","variants":[{"Name":"NM_170707.4(LMNA):c.1146C>T (p.Gly382=)","Chromosome":"1","Start":"156136110","Stop":"156136110","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":57196,"rule_based_match":true,"evidence_text":"c.1146C>T","llm_judgment":"PRESENT","evidence":"c.1146C>T","abstract_start":475,"abstract_end":484},{"Name":"NM_000335.5(SCN5A):c.1140+1G>A","Chromosome":"3","Start":"38606668","Stop":"38606668","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":178524,"rule_based_match":true,"evidence_text":"c.1140+1G>A","llm_judgment":"PRESENT","evidence":"c.1140+1G>A","abstract_start":676,"abstract_end":687}]}
{"pmid":"27588451","title":"Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects.","abstract":"Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa.","variants":[{"Name":"NM_001330691.3(CEP78):c.499+1G>T","Chromosome":"9","Start":"78240365","Stop":"78240365","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":359174,"rule_based_match":true,"evidence_text":"c.499+1G>T (IVS3+1G>T)","llm_judgment":"PRESENT","evidence":"c.499+1G>T (IVS3+1G>T)","abstract_start":699,"abstract_end":721},{"Name":"NM_001330691.3(CEP78):c.633del (p.Trp212fs)","Chromosome":"9","Start":"78243490","Stop":"78243490","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":359175,"rule_based_match":true,"evidence_text":"c.633del (p.Trp212Glyfs(∗)18)","llm_judgment":"PRESENT","evidence":"p.Trp212Gly","abstract_start":905,"abstract_end":916},{"Name":"NM_001330691.3(CEP78):c.499+5G>A","Chromosome":"9","Start":"78240369","Stop":"78240369","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":359176,"rule_based_match":true,"evidence_text":"c.499+5G>A (IVS3+5G>A)","llm_judgment":"PRESENT","evidence":"c.499+5G>A (IVS3+5G>A)","abstract_start":832,"abstract_end":854}]}
{"pmid":"34066320","title":"Genetic Confirmation and Identification of Novel Variants for Glanzmann Thrombasthenia and Other Inherited Platelet Function Disorders: A Study by the Korean Pediatric Hematology Oncology Group (KPHOG).","abstract":"The diagnosis of inherited platelet function disorders (IPFDs) is challenging owing to the unavailability of essential testing methods, including light transmission aggregometry and flow cytometry, in several medical centers in Korea. This study, conducted by the Korean Pediatric Hematology Oncology Group from March 2017 to December 2020, aimed to identify the causative genetic variants of IPFDs in Korean patients using next-generation sequencing (NGS). Targeted exome sequencing, followed by whole-genome sequencing, was performed for diagnosing IPFDs. Of the 11 unrelated patients with suspected IPFDs enrolled in this study, 10 patients and 2 of their family members were diagnosed with Glanzmann thrombasthenia (GT). The variant c.1913+5G>T of <i>ITGB3</i> was the most common, followed by c.2333A>C (p.Gln778Pro) of <i>ITGB2B</i>. Known variants of GT, including c.917A>C (p.His306Pro) of <i>ITGB3</i> and c.2975del (p.Glu992Glyfs*), c.257T>C (p.Leu86Pro), and c.1750C>T (p.Arg584*) of <i>ITGA2B</i>, were identified. Four novel variants of GT, c.1451G>T (p.Gly484Val) and c.1595G>T (p.Cys532Phe) of <i>ITGB3</i> and c.1184G>T (p.Gly395Val) and c.2390del (p.Gly797Valfs*29) of <i>ITGA2B</i>, were revealed. The remaining patient was diagnosed with platelet type bleeding disorder 18 and harbored two novel <i>RASGRP2</i> variants, c.1479dup (p.Arg494Alafs*54) and c.813+1G>A. We demonstrated the successful application of NGS for the accurate and differential diagnosis of heterogeneous IPFDs.","variants":[{"Name":"NM_000212.3(ITGB3):c.1913+5G>T","Chromosome":"17","Start":"47299535","Stop":"47299535","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":959501,"rule_based_match":true,"evidence_text":"c.1913+5G>T","llm_judgment":"PRESENT","evidence":"c.1913+5G>T","abstract_start":737,"abstract_end":748},{"Name":"NM_000212.3(ITGB3):c.917A>C (p.His306Pro)","Chromosome":"17","Start":"47287209","Stop":"47287209","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1320991,"rule_based_match":true,"evidence_text":"c.917A>C (p.His306Pro) of <i>ITGB3</i>","llm_judgment":"PRESENT","evidence":"c.917A>C (p.His306Pro) of <i>ITGB3</i>","abstract_start":872,"abstract_end":910}]}
{"pmid":"22261628","title":"Paravertebral ligament ossification in vitamin D-resistant rickets: incidence, clinical significance, and genetic evaluation.","abstract":"STUDY DESIGN: A retrospective observational study.\nOBJECTIVE: The objective of this study was to analyze the cases of paravertebral ossification in vitamin D-resistant rickets (VDRR) and elucidate its incidence and clinical significance, and report specific genetic mutations uniquely associated with this phenomenon.\nSUMMARY OF BACKGROUND DATA: Paravertebral ligament ossification has been described in VDRR in a few cases previously. However, supraspinous and interspinous ligament ossification has so far not been described to occur in association with VDRR. We reviewed 6 cases of paravertebral ligament ossification with the added feature of supraspinous and interspinous ligament calcification.\nMETHODS: Forty-four patients with clinical, radiological, and biochemical diagnoses of VDRR, who were positive for mutations in the PHEX gene, were screened for the presence of paravertebral ossification with plain radiographs and computed tomography/magnetic resonance imaging if necessary. This was correlated with the severity of disease, and we looked for specific genetic mutations.\nRESULTS: Six patients had paravertebral ligament ossification, which included supraspinous and interspinous ligament ossification. These patients had a more severe systemic disease, with all patients requiring at least 1 surgery for deformity correction of the limbs, with a total of 10 surgical procedures performed in these 6 patients. c.1601C>T, c.1699C>T, c.1363G>T, and c.466_467insAC were the genetic mutations associated with these cases.\nCONCLUSION: The spinal changes with paravertebral ligament ossification in VDRR were described in this study. Four different gene mutations related to the PHEX gene were detected in them. The presence of these changes was suggestive of a more severe systemic disease.","variants":[{"Name":"NM_000444.6(PHEX):c.1601C>T (p.Pro534Leu)","Chromosome":"X","Start":"22190458","Stop":"22190458","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":264997,"rule_based_match":true,"evidence_text":"c.1601C>T","llm_judgment":"PRESENT","evidence":"c.1601C>T","abstract_start":1427,"abstract_end":1436},{"Name":"NM_000444.6(PHEX):c.1699C>T (p.Arg567Ter)","Chromosome":"X","Start":"22212957","Stop":"22212957","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25861,"rule_based_match":true,"evidence_text":"c.1699C>T","llm_judgment":"PRESENT","evidence":"c.1699C>T","abstract_start":1438,"abstract_end":1447}]}
{"pmid":"29304759","title":"A novel compound heterozygous variant identified in GLDC gene in a Chinese family with non-ketotic hyperglycinemia.","abstract":"BACKGROUND: Non-ketotic hyperglycinemia (NKH) is a rare, devastating autosomal recessive disorder of glycine metabolism with a very poor prognosis. Currently, few studies have reported genetic profiling of Chinese NKH patients. This study aimed to identify the genetic mutations in a Chinese family with NKH.\nMETHODS: A Chinese family of Han ethnicity, with three siblings with NKH was studied. Sanger sequencing and multiplex ligation-dependent probe amplification combined with SYBR green real-time quantitative PCR was used to identify potential mutations in the GLDC, AMT and GCSH genes. The potential pathogenicity of the identified missense mutation was analyzed using SIFT, PolyPhen-2, PROVEAN and MutationTaster software.\nRESULTS: All patients exhibited severe and progressive clinical symptoms, including lethargy, hypotonia and seizures, and had greatly elevated glycine levels in their plasma and CSF. Molecular genetic analysis identified compound heterozygous variants in the GLDC gene in these three siblings, including a novel missense variant c.2680A > G (p.Thr894Ala) in exon 23 and a heterozygous deletion of exon 3, which were inherited respectively from their parents. In silico analysis, using several different types of bioinformatic software, predicted that the novel variant c.2680A > G in the GLDC gene was pathogenic. Moreover, the deletion of exon 3 was identified for the first time in a Chinese population.\nCONCLUSIONS: A novel missense variant and a previously reported deletion in GLDC gene were identified. The two variants of GLDC gene identified probably underlie the pathogenesis of non-ketotic hyperglycinemia in this family, and also enrich the mutational spectrum of GLDC gene.","variants":[{"Name":"NM_000170.3(GLDC):c.2680A>G (p.Thr894Ala)","Chromosome":"9","Start":"6536222","Stop":"6536222","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3856678,"rule_based_match":true,"evidence_text":"c.2680A > G (p.Thr894Ala)","llm_judgment":"PRESENT","evidence":"c.2680A > G (p.Thr894Ala)","abstract_start":1059,"abstract_end":1084}]}
{"pmid":"33290826","title":"The Novel Desmin Variant p.Leu115Ile Is Associated With a Unique Form of Biventricular Arrhythmogenic Cardiomyopathy.","abstract":"BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC but with insufficient evidence to support their pathogenicity.\nMETHODS: We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutations were prospectively screened by whole-exome sequencing.\nRESULTS: A single DES variant (p.Leu115Ile, c.343C>A) was identified in 3 index patients (2%). We assessed the clinical phenotypes within their families and confirmed cosegregation. One carrier required heart transplantation, 2 died suddenly, and 1 died of noncardiac causes. All cases had right- and left-ventricular (LV) involvement. LV late gadolinium enhancement was present in all, and circumferential subepicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically, but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells, and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short protofilaments and small fibrous aggregates.\nCONCLUSIONS: DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis.","variants":[{"Name":"NM_001927.4(DES):c.343C>A (p.Leu115Ile)","Chromosome":"2","Start":"219418805","Stop":"219418805","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1903454,"rule_based_match":true,"evidence_text":"p.Leu115Ile, c.343C>A","llm_judgment":"PRESENT","evidence":"p.Leu115Ile, c.343C>A","abstract_start":647,"abstract_end":668}]}
{"pmid":"28691929","title":"Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia.","abstract":"The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.","variants":[{"Name":"NM_018124.4(RFWD3):c.205_206dup (p.Leu70fs)","Chromosome":"16","Start":"74661243","Stop":"74661244","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CAG","allel_id":917901,"rule_based_match":true,"evidence_text":"c.205_206dupCC","llm_judgment":"PRESENT","evidence":"c.205_206dupCC","abstract_start":399,"abstract_end":413},{"Name":"NM_018124.4(RFWD3):c.1916T>A (p.Ile639Lys)","Chromosome":"16","Start":"74628505","Stop":"74628505","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":439868,"rule_based_match":true,"evidence_text":"c.1916T>A","llm_judgment":"PRESENT","evidence":"c.1916T>A","abstract_start":418,"abstract_end":427}]}
{"pmid":"26475431","title":"Apparent homozygosity due to compound heterozygosity of one point mutation and an overlapping exon deletion mutation in ABCA12: A genetic diagnostic pitfall.","abstract":"BACKGROUND: Harlequin ichthyosis (HI), one of the most severe genetic skin disorders, is autosomal recessively inherited. Mutations in ABCA12, which encodes ATP-binding cassette transporter A12 (ABCA12), are known to be the cause of HI. It is very difficult to make precise genetic diagnosis when an exon deletion mutation overlaps the site of another causative point mutation. This combination of mutations may lead us to conclude incorrectly that the patient has the point mutation homozygously, a phenomenon called \"apparent homozygosity\".\nOBJECTIVE: To demonstrate that the present HI patient has apparent homozygosity in ABCA12 mutations.\nMETHODS: We performed direct sequencing of gDNA in the entire coding region, including exon-intron boundaries, of ABCA12 in the HI patient and her parents. To further elucidate the mutations in the patient, parental mutation segregation study was done and SNP analysis was conducted on the region flanking ABCA12 in the patients and her parents. Quantitative PCR of gDNA in exon 11 of ABCA12 was also performed. Direct sequencing of cDNA from exon 9 to exon 13 and of gDNA between intron 9 and intron 11 of ABCA12 was done in the HI patient and her parents.\nRESULTS: Direct sequencing of gDNA in the entire coding region, including exon-intron boundaries, of ABCA12 seemed to indicate that the patient had the novel homozygous nonsense mutation c.1216A>T (p.Lys406X) in exon 11. However, mutation segregation analysis, SNP analysis, qRTPCR of gDNA in exon 11 of ABCA12 and direct sequencing of cDNA from exon 9 to exon 12 of ABCA12 and of gDNA between intron 9 and intron 11 of ABCA12 in the HI patient and her parents demonstrated that the present patient was compound heterozygous for two ABCA12 mutations: c.1216A>T (p.Lys406X) in exon 11 and g.111346_113217del1872 (p.Leu355_Lys428del, Gln354fs7*) which was overlapping exon deletion mutations involving exons 10 and 11.\nCONCLUSION: When direct sequencing indicates that a patient from a non-consanguineous family has an apparently homozygous non-founder point mutation, the homozygosity may be \"apparent homozygosity\", and we should keep in mind the possibility of overlapping exon deletion mutation.","variants":[{"Name":"NM_173076.3(ABCA12):c.1216A>T (p.Lys406Ter)","Chromosome":"2","Start":"215025744","Stop":"215025744","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2894418,"rule_based_match":true,"evidence_text":"c.1216A>T (p.Lys406X)","llm_judgment":"PRESENT","evidence":"c.1216A>T (p.Lys406X)","abstract_start":1389,"abstract_end":1410}]}
{"pmid":"30879340","title":"FUS-ALS presenting with myoclonic jerks in a 17-year-old man.","abstract":"Fused in sarcoma-related amyotrophic lateral sclerosis (FUS-ALS) accounts for 4% of all familial motor neurone disease, but has a much higher incidence in juvenile ALS. We present a case of a 17-year-old British man with rapidly progressive bulbar and respiratory failure. On examination he had weak periocular muscles, neck flexion weakness, and a wasted, fasciculating and weak tongue. There were no sensory, cerebellar, or extrapyramidal features but he had frequent myoclonic jerks of the limbs. Routine bloods were normal and an MRI of the neuroaxis as well as CT chest, abdomen and pelvis were unremarkable. NCS/EMG was consistent with anterior horn cell disorder and EEG showed multiple paroxysmal generalized spike-wave discharges. DNA sequencing demonstrated that he was heterozygous for the c.1483C>T pathogenic nonsense mutation in exon 14 of the FUS gene, consistent with ALS6. This is the first reported case of FUS-ALS presenting with prominent myoclonus.","variants":[{"Name":"NM_004960.4(FUS):c.1483C>T (p.Arg495Ter)","Chromosome":"16","Start":"31191052","Stop":"31191052","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38662,"rule_based_match":true,"evidence_text":"c.1483C>T","llm_judgment":"PRESENT","evidence":"c.1483C>T","abstract_start":801,"abstract_end":810}]}
{"pmid":"33639315","title":"Compound heterozygous variants in GOSR2 associated with congenital muscular dystrophy: A case report.","abstract":"The homozygous missense variant in the GOSR2 gene (c.430G > T) is known to be associated with progressive myoclonic epilepsy (PME). The clinical presentation of GOSR2-related PME involves the development of ataxia, seizures, scoliosis, areflexia, and mildly elevated creatine kinase. Recently, it has been suggested that some compound heterozygous variants in GOSR2 are associated with a predominant muscular dystrophy phenotype. Here we report a case of a now 22 month old female who presented with congenital hypotonia and persistently elevated creatine kinase levels. Whole exome sequencing showed pathogenic compound heterozygous variants in GOSR2 (c.430G > T and c.82C > T). This case contributes to the expanding clinical spectrum of GOSR2 variants with PME representing the milder end and congenital muscular dystrophy representing the more severe end of the spectrum.","variants":[{"Name":"NM_004287.5(GOSR2):c.430G>T (p.Gly144Trp)","Chromosome":"17","Start":"46935122","Stop":"46935122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39363,"rule_based_match":true,"evidence_text":"c.430G>T","llm_judgment":"PRESENT","evidence":"c.430G > T","abstract_start":51,"abstract_end":61}]}
{"pmid":"38048861","title":"High prevalence and distinctive clinical features of LMNA-associated atrioventricular block in young patients.","abstract":"BACKGROUND AND AIMS: Atrioventricular block (AVB) is a degenerative disease and more commonly encountered in elderly patients, but unusual and often of unknown etiology in young patients. This study aimed to investigate the potential contributions of genetic variations to AVB of unknown reasons in young patients.\nMETHODS: We enrolled 41 patients aged <55 years with high-degree AVB of unknown etiology whose clinical and genetic data were collected.\nRESULTS: Genetic variants were identified in 20 (20/41, 48.8%) patients, 11 (11/20, 55%) of whom had LMNA variants including 3 pathogenic (c.961C > T, c.936+1G > T and c.646C > T), 4 likely pathogenic (c.1489-1G > C, c.265C > A, c.1609-2A > G and c.1129C > T) and 3 of uncertain significance (c.1158-3C > G, c.776A > G and c.674G > T). Compared to those without LMNA variants, patients with LMNA variants demonstrated a later age at onset of AVB (41.45 ± 9.89 years vs 32.93 ± 12.07 years, P = .043), had more prevalent family history of cardiac events (81.8% vs 16.7%, P < .000), suffered more frequently atrial (81.8% vs 10.0%, P < .000) and ventricular (72.7% vs 10.0%, P < .000) arrhythmias, and were more significantly associated with enlargement of left atrium (39.91 ± 7.83 mm vs 34.30 ± 7.54 mm, P = .043) and left ventricle (53.27 ± 8.53 mm vs 47.77 ± 6.66 mm, P = .036).\nCONCLUSIONS: Our findings provide insights into the genetic etiology of AVB in young patients. LMNA variants are predominant in genotype positive patients and relevant to distinctive phenotypic properties.","variants":[{"Name":"NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys)","Chromosome":"1","Start":"156136093","Stop":"156136093","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":57195,"rule_based_match":true,"evidence_text":"c.1129C > T","llm_judgment":"PRESENT","evidence":"c.1129C > T","abstract_start":699,"abstract_end":710}]}
{"pmid":"19268523","title":"Genotyping of resistance to thyroid hormone in South American population. Identification of seven novel missense mutations in the human thyroid hormone receptor beta gene.","abstract":"Thyroid Hormone Receptor beta (THRB) defects, typically transmitted as autosomal dominant traits, cause Resistance to Thyroid Hormone (RTH). We analyzed the THRB gene in thirteen South American patients with clinical evidence RTH from eleven unrelated families. Sequence analysis revealed seven novel missense mutations. Four novel mutations were identified in exon 9. The first, a c.991A>G transition which originates a substitution of asparagine by aspartic acid (p.N331D). The second nucleotide alteration consists of a guanine to cytosine transversion at position 1003 (c.1003G>C) and results in substitution of the alanine at codon 335 by proline (p.A335P). The third mutation, a c.1022T>C transition produces a change of leucine by proline (p.L341P). The fourth mutation detected in exon 9 was a c.1036C>T transition which replaces the leucine at codon 346 by phenylalanine (p.L346F). The sequencing of the exon 10 detected three novel missense mutations. The first, a c.1293A>G transition changing isoleucine 431 for methionine (p.I431M). The second, the cytosine at position 1339 was replaced by adenine (c.1339C>A) resulting in the replacement of proline by threonine (p.P447T). The third mutation detected in exon 10 was a c.1358C>T transition resulting in the substitution of proline at codon 453 by leucine (p.P453L). Finally, sequencing analysis of the THRB gene revealed three substitutions previously described (p.A268G, p.P453T and p.F459C). The p.P453T was found in two patients. In conclusion, we report thirteen patients with RTH caused by heterozygous mutations of the THRB gene. Seven of the identified mutations correspond to novel substitutions.","variants":[{"Name":"NM_001354712.2(THRB):c.1022T>C (p.Leu341Pro)","Chromosome":"3","Start":"24127621","Stop":"24127621","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":981013,"rule_based_match":true,"evidence_text":"c.1022T>C","llm_judgment":"PRESENT","evidence":"c.1022T>C","abstract_start":685,"abstract_end":694},{"Name":"NM_001354712.2(THRB):c.1358C>T (p.Pro453Leu)","Chromosome":"3","Start":"24122912","Stop":"24122912","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2738358,"rule_based_match":true,"evidence_text":"c.1358C>T (p.P453L)","llm_judgment":"PRESENT","evidence":"c.1358C>T","abstract_start":1233,"abstract_end":1242}]}
{"pmid":"22345219","title":"Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites.","abstract":"OBJECTIVE: To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research.\nMETHODS: Movement disorder specialists examined 20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations.\nRESULT: Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p < 0.05). The patients with A-T were remarkable for the absence of notable cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies.\nCONCLUSION: Ataxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia.","variants":[{"Name":"NM_000051.4(ATM):c.6200C>A (p.Ala2067Asp)","Chromosome":"11","Start":"108317374","Stop":"108317374","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":48348,"rule_based_match":true,"evidence_text":"c.6200 C>A (p. A2067D)","llm_judgment":"PRESENT","evidence":"c.6200 C>A (p. A2067D)","abstract_start":397,"abstract_end":419}]}
{"pmid":"23963851","title":"A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).","abstract":"OBJECTIVE: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene were studied in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).\nMETHODS: Exons 1-9 of the HTRA1 gene were amplified and bidirectionally sequenced in a Chinese family with CARASIL. Mutation effects were analysed by three-dimensional modelling of the serine protease HTRA1 protein.\nRESULTS: The proband was found to be homozygous for a novel missense mutation (c.854 C > T) identified in exon 4 of the HTRA1 gene; the parents of the proband were heterozygous for the same missense mutation. This c.854 C > T mutation resulted in a change from proline to leucine (p.P285L) in serine protease HTRA1, and was absent in 260 control chromosomes. Three-dimensional models showed that the change from proline to leucine (p.P285L) could attenuate the hydrogen bond between S284 and S287 residues, which might affect function of serine protease HTRA1.\nCONCLUSION: Discovery of a novel missense mutation (c.854C>T) associated with CARASIL expands the known CARASIL-related mutations in HTRA1.","variants":[{"Name":"NM_002775.5(HTRA1):c.854C>T (p.Pro285Leu)","Chromosome":"10","Start":"122506767","Stop":"122506767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":165896,"rule_based_match":true,"evidence_text":"c.854 C > T","llm_judgment":"PRESENT","evidence":"c.854 C > T","abstract_start":527,"abstract_end":538}]}
{"pmid":"29607617","title":"A novel heterozygous missense mutation of DSP in a Chinese Han pedigree with palmoplantar keratoderma.","abstract":"BACKGROUND: Mutations in the desmoplakin (DSP) gene have been demonstrated to be associated with lethal acantholytic epidermolysis bullosa, cardiomyopathy, and palmoplantar keratoderma (PPK).\nAIMS: To better understand the relationship between PPK and the gene mutations in DSP.\nMETHODS: A pedigree of PPK was subjected to heterozygous missense mutation analysis in the DSP gene. Dermoscopy, reflectance confocal microscopy, and histopathological examination were performed from each epidermis layer in this study. Samples were derived from the blood of patients and normal healthy controls. DSP gene sequence analysis and Q-PCR analysis was performed for evaluating DSP gene mutation and expression.\nRESULTS: A novel heterozygous missense mutation c.3550 C>T in the coding region of the DSP gene, predicting substitution of arginine (Arg,R) by tryptophan (Trp,W) in the desmoplakin polypeptide, was discovered in a Chinese pedigree of PPK. In the meanwhile, this mutation was not found in 100 healthy individuals.\nCONCLUSIONS: The novel missense mutation c.3550 C>T(p.Arg1184Trp) of DSP gene expanded the mutation spectrum in palmoplantar keratoderma.","variants":[{"Name":"NM_004415.4(DSP):c.3550C>T (p.Arg1184Trp)","Chromosome":"6","Start":"7579740","Stop":"7579740","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":614933,"rule_based_match":true,"evidence_text":"c.3550 C>T(p.Arg1184Trp)","llm_judgment":"PRESENT","evidence":"c.3550 C>T(p.Arg1184Trp)","abstract_start":1056,"abstract_end":1080}]}
{"pmid":"33547425","title":"Bi-allelic loss of function variants in SLC30A5 as cause of perinatal lethal cardiomyopathy.","abstract":"Perinatal mortality is a heavy burden for both affected parents and physicians. However, the underlying genetic causes have not been sufficiently investigated and most cases remain without diagnosis. This impedes appropriate counseling or therapy. We describe four affected children of two unrelated families with cardiomyopathy, hydrops fetalis, or cystic hygroma that all deceased perinatally. In the four patients, we found the following homozygous loss of function (LoF) variants in SLC30A5 NM_022902.4:c.832_836del p.(Ile278Phefs*33) and NM_022902.4:c.1981_1982del p.(His661Tyrfs*10). Knockout of SLC30A5 has previously been shown a cardiac phenotype in mouse models and no homozygous LoF variants in SLC30A5 are currently described in gnomAD. Taken together, we present SLC30A5 as a new gene for a severe and perinatally lethal form of cardiomyopathy.","variants":[{"Name":"NM_022902.5(SLC30A5):c.1981_1982del (p.His661fs)","Chromosome":"5","Start":"69123407","Stop":"69123408","ReferenceAlleleVCF":"TAC","AlternateAlleleVCF":"T","allel_id":976826,"rule_based_match":true,"evidence_text":"NM_022902.4:c.1981_1982del p.(His661Tyrfs*10)","llm_judgment":"PRESENT","evidence":"NM_022902.4:c.1981_1982del p.(His661Tyrfs*10)","abstract_start":543,"abstract_end":588},{"Name":"NM_022902.5(SLC30A5):c.832_836del (p.Ile278fs)","Chromosome":"5","Start":"69115972","Stop":"69115976","ReferenceAlleleVCF":"GTTATC","AlternateAlleleVCF":"G","allel_id":964259,"rule_based_match":true,"evidence_text":"NM_022902.4:c.832_836del p.(Ile278Phefs*33)","llm_judgment":"PRESENT","evidence":"NM_022902.4:c.832_836del p.(Ile278Phefs*33)","abstract_start":495,"abstract_end":538}]}
{"pmid":"29149195","title":"Age of heart disease presentation and dysmorphic nuclei in patients with LMNA mutations.","abstract":"Nuclear shape defects are a distinguishing characteristic in laminopathies, cancers, and other pathologies. Correlating these defects to the symptoms, mechanisms, and progression of disease requires unbiased, quantitative, and high-throughput means of quantifying nuclear morphology. To accomplish this, we developed a method of automatically segmenting fluorescently stained nuclei in 2D microscopy images and then classifying them as normal or dysmorphic based on three geometric features of the nucleus using a package of Matlab codes. As a test case, cultured skin-fibroblast nuclei of individuals possessing LMNA splice-site mutation (c.357-2A>G), LMNA nonsense mutation (c.736 C>T, pQ246X) in exon 4, LMNA missense mutation (c.1003C>T, pR335W) in exon 6, Hutchinson-Gilford Progeria Syndrome, and no LMNA mutations were analyzed. For each cell type, the percentage of dysmorphic nuclei, and other morphological features such as average nuclear area and average eccentricity were obtained. Compared to blind observers, our procedure implemented in Matlab codes possessed similar accuracy to manual counting of dysmorphic nuclei while being significantly more consistent. The automatic quantification of nuclear defects revealed a correlation between in vitro results and age of patients for initial symptom onset. Our results demonstrate the method's utility in experimental studies of diseases affecting nuclear shape through automated, unbiased, and accurate identification of dysmorphic nuclei.","variants":[{"Name":"NM_170707.4(LMNA):c.1003C>T (p.Arg335Trp)","Chromosome":"1","Start":"156135967","Stop":"156135967","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45135,"rule_based_match":true,"evidence_text":"LMNA missense mutation (c.1003C>T, pR335W)","llm_judgment":"PRESENT","evidence":"LMNA missense mutation (c.1003C>T, pR335W)","abstract_start":707,"abstract_end":749}]}
{"pmid":"16619239","title":"Long-range PCR facilitates the identification of PMS2-specific mutations.","abstract":"Mutations within the DNA mismatch repair gene, \"postmeiotic segregation increased 2\" (PMS2), have been associated with a predisposition to hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome). The presence of a large family of highly homologous PMS2 pseudogenes has made previous attempts to sequence PMS2 very difficult. Here, we describe a novel method that utilizes long-range PCR as a way to preferentially amplify PMS2 and not the pseudogenes. A second, exon-specific, amplification from diluted long-range products enables us to obtain a clean sequence that shows no evidence of pseudogene contamination. This method has been used to screen a cohort of patients whose tumors were negative for the PMS2 protein by immunohistochemistry and had not shown any mutations within the MLH1 gene. Sequencing of the PMS2 gene from 30 colorectal and 11 endometrial cancer patients identified 10 novel sequence changes as well as 17 sequence changes that had previously been identified. In total, putative pathologic mutations were detected in 11 of the 41 families. Among these were five novel mutations, c.705+1G>T, c.736_741del6ins11, c.862_863del, c.1688G>T, and c.2007-1G>A. We conclude that PMS2 mutation detection in selected Lynch syndrome and Lynch syndrome-like patients is both feasible and desirable.","variants":[{"Name":"NM_000535.7(PMS2):c.705+1G>T","Chromosome":"7","Start":"5999107","Stop":"5999107","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":96839,"rule_based_match":true,"evidence_text":"c.705+1G>T","llm_judgment":"PRESENT","evidence":"c.705+1G>T","abstract_start":1113,"abstract_end":1123},{"Name":"NM_000535.7(PMS2):c.862_863del (p.Gln288fs)","Chromosome":"7","Start":"5995574","Stop":"5995575","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":96851,"rule_based_match":true,"evidence_text":"c.862_863del","llm_judgment":"PRESENT","evidence":"c.862_863del","abstract_start":1145,"abstract_end":1157},{"Name":"NM_000535.7(PMS2):c.1688G>T (p.Arg563Leu)","Chromosome":"7","Start":"5987077","Stop":"5987077","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":50144,"rule_based_match":true,"evidence_text":"c.1688G>T","llm_judgment":"PRESENT","evidence":"c.1688G>T","abstract_start":1159,"abstract_end":1168}]}
{"pmid":"31851867","title":"Next-Generation Sequencing Identifies","abstract":"Telomeres, and telomere length in particular, have broad significance for genome biology and thus are prime research targets for complex diseases such as cancers. In this context, <i>BRCA1</i> and <i>BRCA2</i> gene mutations have been implicated in relationship to telomere length, and breast cancer susceptibility. Yet, the linkages among human genetic variation and telomere length in persons with high hereditary cancer risk are inadequately mapped. We report here original findings in 113 unrelated women at high hereditary risk for breast cancer, who were characterized for the <i>BRCA1</i> and <i>BRCA2</i> mutations using next-generation sequencing. Thirty-one <i>BRCA2</i> and 21 <i>BRCA1</i> mutations were identified in 47 subjects (41.6%). The women with a mutation in <i>BRCA1</i> and/or <i>BRCA2</i> genes had, on average, 12% shorter telomere compared to women with no <i>BRCA1</i> or <i>BRCA2</i> mutation (<i>p</i> = 0.0139). Moreover, the association between telomere length and <i>BRCA</i> mutation status held up upon stratified analysis in those with or without a breast cancer diagnosis. We also indentified two rare mutations, c.536_537insT and c.10078A>G, and a novel mutation c.8680C>G in <i>BRCA2</i> that was studied further by homology modeling of the DNA binding tower domain of <i>BRCA2</i> and the structure of the protein. These data collectively lend evidence to the idea that <i>BRCA1</i> and <i>BRCA2</i> mutations play a role in telomere length in women at high hereditary risk for breast cancer. Further clinical and diagnostics discovery research on <i>BRCA1</i> and <i>BRCA2</i> variation, telomere length, and breast cancer mechanistic linkages are called for in larger study samples.","variants":[{"Name":"NM_000059.4(BRCA2):c.8680C>G (p.Gln2894Glu)","Chromosome":"13","Start":"32376717","Stop":"32376717","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1817414,"rule_based_match":true,"evidence_text":"c.8680C>G","llm_judgment":"PRESENT","evidence":"c.8680C>G","abstract_start":1200,"abstract_end":1209},{"Name":"NM_000059.4(BRCA2):c.10078A>G (p.Lys3360Glu)","Chromosome":"13","Start":"32398591","Stop":"32398591","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":641919,"rule_based_match":true,"evidence_text":"c.10078A>G","llm_judgment":"PRESENT","evidence":"c.10078A>G","abstract_start":1167,"abstract_end":1177}]}
{"pmid":"27792009","title":"Role of Niemann-Pick Type C Disease Mutations in Dementia.","abstract":"BACKGROUND: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance.\nOBJECTIVE: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus.\nMETHODS: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients.\nRESULTS: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2.\nCONCLUSIONS: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.","variants":[{"Name":"NM_000271.5(NPC1):c.1947+8G>C","Chromosome":"18","Start":"23544952","Stop":"23544952","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":98612,"rule_based_match":true,"evidence_text":"c.1947+8G>C","llm_judgment":"PRESENT","evidence":"c.1947+8G>C","abstract_start":1275,"abstract_end":1286},{"Name":"NM_006432.5(NPC2):c.441+1G>A","Chromosome":"14","Start":"74480701","Stop":"74480701","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":106599,"rule_based_match":true,"evidence_text":"c.441+1G>A","llm_judgment":"PRESENT","evidence":"c.441+1G>A","abstract_start":1184,"abstract_end":1194}]}
{"pmid":"19309289","title":"Screening of the DFNB3 locus: identification of three novel mutations of MYO15A associated with hearing loss and further suggestion for two distinctive genes on this locus.","abstract":"Recessive mutations of MYO15A are associated with nonsyndromic hearing loss (HL) in humans (DFNB3) and in the shaker-2 mouse. Human MYO15A has 66 exons and encodes unconventional myosin XVA. Analysis of 77 Tunisian consanguineous families segregating recessive deafness revealed evidence of linkage to microsatellite markers for DFNB3 in four families. In two families, sequencing of MYO15A led to the identification of two novel homozygous mutations: a nonsense (c.4998C>A (p.C1666X) in exon 17 and a splice site mutation in intron 54 (c.9229 + 1G>A). A novel mutation of unknown significance, c.7395 + 3G>C, was identified in the third family, and no mutation was found in the fourth family. In conclusion, we discovered three novel mutations of MYO15A, and our data suggest the possibility that there are two distinct genes at the DFNB3 locus.","variants":[{"Name":"NM_016239.4(MYO15A):c.9229+1G>A","Chromosome":"17","Start":"18159348","Stop":"18159348","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2895168,"rule_based_match":true,"evidence_text":"c.9229 + 1G>A","llm_judgment":"PRESENT","evidence":"c.9229 + 1G>A","abstract_start":537,"abstract_end":550}]}
{"pmid":"20655036","title":"Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase.","abstract":"Retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration, with a worldwide prevalence of 1 in 4000. Over 30 genes and loci have been implicated in nonsyndromic autosomal-recessive (ar) RP. Genome-wide homozygosity mapping was conducted in two sibships from an extended consanguineous Muslim Arab Israeli family segregating ar severe early-onset RP. A shared homozygous region on chromosome 17q25.3 was identified in both sibships, with an overlap of 4.7 Mb. One of the genes located in this interval is PDE6G, encoding for the inhibitory gamma subunit of rod photoreceptor cyclic GMP-phosphodiesterase. Mutations in the genes encoding for the catalytic subunits of this holoenzyme, PDE6A and PDE6B, cause arRP. Sequencing of all coding exons, including exon-intron boundaries, revealed a homozygous single base change (c.187+1G>T) located in the conserved intron 3 donor splice site of PDE6G. This mutation cosegregated with the disease in the extended family. We used an in vitro splicing assay to demonstrate that this mutation leads to incorrect splicing. Affected individuals had markedly constricted visual fields. Both scotopic and photopic electroretinograms were severely reduced or completely extinct. Funduscopy showed typical bone spicule-type pigment deposits spread mainly at the midperiphery, as well as pallor of the optic disk. Macular involvement was indicated by the lack of foveal reflex and typical cystoid macular edema, proved by optical coherence tomography. These findings demonstrate the positive role of the gamma subunit in maintaining phosphodiesterase activity and confirm the contribution of PDE6G to the etiology of RP in humans.","variants":[{"Name":"NM_002602.4(PDE6G):c.187+1G>T","Chromosome":"17","Start":"81651644","Stop":"81651644","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":28141,"rule_based_match":true,"evidence_text":"c.187+1G>T","llm_judgment":"PRESENT","evidence":"c.187+1G>T","abstract_start":847,"abstract_end":857}]}
{"pmid":"30730840","title":"A rare case of congenital hyperinsulinism (CHI) due to dual genetic aetiology involving HNF4A and ABCC8.","abstract":"Background Congenital hyperinsulinism (CHI) occurs due to an unregulated insulin secretion from the pancreatic β-cells resulting in hypoglycaemia. Causative mutations in multiple genes have been reported. Phenotypic variability exists both within and between different genetic subgroups. Case presentation A male infant born at 35+6 weeks' gestation with a birth weight of 4.3 kg [+3.6 standard deviation score (SDS)] had recurrent hypoglycaemic episodes from birth. Biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and the dose was progressively increased to maintain euglycaemia. His father was slim and had been diagnosed with type 2 diabetes in his 30s. Sequence analysis identified a heterozygous hepatocyte nuclear factor 4 alpha (HNF4A) mutation (p.Arg245Pro, c.734G>C) and compound heterozygous ABCC8 mutations (p.Gly92Ser, c.274G>A and p.Ala1185Val, c.3554C>T) in the patient. The p.Ala1185Val ABCC8 mutation was inherited from his unaffected mother and the p.Arg245Pro HNF4A and p.Gly92Ser ABCC8 mutations from his father. All three mutations were predicted to be pathogenic. Identification of the HNF4A mutation in the father established a diagnosis of maturity-onset diabetes of the young (MODY), which enabled medication change resulting in improved glycaemic control. Conclusions We report a rare patient with CHI due to dual genetic aetiology. Although he is currently responsive to the maximum dose of diazoxide, the long-term prognosis remains unclear.","variants":[{"Name":"NM_000352.6(ABCC8):c.274G>A (p.Gly92Ser)","Chromosome":"11","Start":"17474902","Stop":"17474902","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3853549,"rule_based_match":true,"evidence_text":"c.274G>A (p.Gly92Ser)","llm_judgment":"PRESENT","evidence":"p.Gly92Ser","abstract_start":850,"abstract_end":860}]}
{"pmid":"29945942","title":"Reclassification of the","abstract":"The ClinVar database is a useful tool for patients and physicians to view variant interpretations submitted by clinical and nonclinical labs. However, variants of uncertain significance (VUS) in ClinVar can pose a significant burden on patients. If possible, it is important to resolve discrepancies and uncertainties surrounding interpreted variants. Here we highlight a case of a family who received a report of a variant (c.622A>G, p.Ile208Val) in <i>BRAF</i> following prenatal RASopathy testing. The variant had been previously classified by our laboratory as a VUS, so the mother contacted our laboratory via ClinVar for further information, which prompted reevaluation of the variant. Multiple sources of case-level data as well as the presence of the variant in the general population yielded sufficient evidence to reclassify the variant as likely benign. This reclassification alleviated significant concern for the family, and the child was born healthy with no clinical manifestations of Noonan syndrome or a RASopathy.","variants":[{"Name":"NM_004333.6(BRAF):c.622A>G (p.Ile208Val)","Chromosome":"7","Start":"140808049","Stop":"140808049","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":174180,"rule_based_match":true,"evidence_text":"c.622A>G, p.Ile208Val","llm_judgment":"PRESENT","evidence":"c.622A>G, p.Ile208Val","abstract_start":425,"abstract_end":446}]}
{"pmid":"19248180","title":"HDR syndrome: a novel \"de novo\" mutation in GATA3 gene.","abstract":"Human GATA3 haploinsufficiency leads to HDR (hypoparathyroidism, deafness, and renal dysplasia) syndrome. The development of a specific subset of organs in which this transcription factor is expressed appears exquisitely sensitive to gene dosage. We report on a 14-year-old patient with symptomatic hypoparathyroidism, sensorineural bilateral deafness, unilateral renal dysplasia, bilateral palpebral ptosis, and horizontal nystagmus. Fundoscopy displayed symmetrical pseudopapilledema, and brain CT scan revealed basal ganglia calcifications. FISH analysis did not disclose any microdeletion in the 22q11.2 or 10p14 regions. GATA3 mutation analysis identified a heterozygous deletion of GG nucleotides at codon 36 and 37 (c.108_109delGG) in exon 2 causing a frameshift with a premature stop codon after a new 15-aminoacid sequence. Restriction endonuclease analysis performed in parents was negative. Our patient carries a novel \"de novo\" GATA3 mutation, providing further evidence that HDR syndrome is caused by haploinsufficiency of GATA3, which may be responsible for a complex neurologic picture besides the known triad.","variants":[{"Name":"NM_001002295.2(GATA3):c.108_109del (p.Met36fs)","Chromosome":"10","Start":"8055763","Stop":"8055764","ReferenceAlleleVCF":"TGG","AlternateAlleleVCF":"T","allel_id":38647,"rule_based_match":true,"evidence_text":"c.108_109delGG","llm_judgment":"PRESENT","evidence":"c.108_109delGG","abstract_start":723,"abstract_end":737}]}
{"pmid":"30996339","title":"Tyrosinase (TYR) gene sequencing and literature review reveals recurrent mutations and multiple population founder gene mutations as causative of oculocutaneous albinism (OCA) in Pakistani families.","abstract":"PURPOSE: To investigate eight previously unreported Pakistani families with genetically undefined OCA for mutations in TYR.\nMETHODS: Sanger sequencing of TYR has been performed in eight families with OCA phenotype. Mutation analysis was performed to establish the pathogenic role of novel mutation. Bioinformatics analysis was performed to predict the structural and functional impacts on protein due to the mutation.\nRESULTS: In this study, we identified six likely pathogenic variants of TYR (c.272 G>A, c.308 G>A, c.346C>T, c.715 C>T, c.832 C>T and c.1255 G>A), including one novel variant (c.308 G>A; p.Cys103Tyr), segregating as appropriate in each family. Cys103 lies in the highly conserved region of the tyrosinase enzyme, and p.Cys103Tyr is predicted to disturb enzymatic function via alteration of the configurational orientation of TYR leading to a more rigid polypeptide structure. We have also reviewed the mutation spectrum of TYR in Pakistani ethnicity. Published data on OCA families proposed that ~40% have been associated with genetic variations in the TYR gene. The mutations reported in this study have now been described with varying frequencies in Pakistani families, including very rare/unique mutations.\nCONCLUSION: A literature review of TYR gene mutations in Pakistani populations, combined with our genetic data, identified a number of gene mutations likely to represent regional ancestral founder mutations of relevance to Pakistani populations, in addition to sporadic and recurrent 'hotspot' mutations present repeatedly in other regions worldwide.","variants":[{"Name":"NM_000372.5(TYR):c.832C>T (p.Arg278Ter)","Chromosome":"11","Start":"89191214","Stop":"89191214","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105472,"rule_based_match":true,"evidence_text":"c.832 C>T","llm_judgment":"PRESENT","evidence":"c.832 C>T","abstract_start":538,"abstract_end":547},{"Name":"NM_000372.5(TYR):c.272G>A (p.Cys91Tyr)","Chromosome":"11","Start":"89178225","Stop":"89178225","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48497,"rule_based_match":true,"evidence_text":"c.272 G>A","llm_judgment":"PRESENT","evidence":"c.272 G>A","abstract_start":495,"abstract_end":504},{"Name":"NM_000372.5(TYR):c.715C>T (p.Arg239Trp)","Chromosome":"11","Start":"89178668","Stop":"89178668","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1314010,"rule_based_match":true,"evidence_text":"c.715 C>T","llm_judgment":"PRESENT","evidence":"c.715 C>T","abstract_start":527,"abstract_end":536}]}
{"pmid":"21655355","title":"Mutations in the β-subunit of rod phosphodiesterase identified in consanguineous Pakistani families with autosomal recessive retinitis pigmentosa.","abstract":"PURPOSE: This study was designed to identify pathogenic mutations causing autosomal recessive retinitis pigmentosa (RP) in consanguineous Pakistani families.\nMETHODS: Two consanguineous families affected with autosomal recessive RP were identified from the Punjab Province of Pakistan. All affected individuals underwent a thorough ophthalmologic examination. Blood samples were collected, and genomic DNAs were extracted. Exclusion analysis was completed, and two-point LOD scores were calculated. Bidirectional sequencing of the β subunit of phosphodiesterase 6 (PDE6β) was completed.\nRESULTS: During exclusion analyses both families localized to chromosome 4p, harboring PDE6β, a gene previously associated with autosomal recessive RP. Sequencing of PDE6β identified missense mutations: c.1655G>A (p.R552Q) and c.1160C>T (p.P387L) in families PKRP161 and PKRP183, respectively. Bioinformatic analyses suggested that both mutations are deleterious for the native three-dimensional structure of the PDE6β protein.\nCONCLUSIONS: These results strongly suggest that mutations in PDE6β are responsible for the disease phenotype in the consanguineous Pakistani families.","variants":[{"Name":"NM_000283.4(PDE6B):c.1655G>A (p.Arg552Gln)","Chromosome":"4","Start":"662174","Stop":"662174","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":944116,"rule_based_match":true,"evidence_text":"c.1655G>A (p.R552Q)","llm_judgment":"PRESENT","evidence":"c.1655G>A (p.R552Q)","abstract_start":790,"abstract_end":809},{"Name":"NM_000283.4(PDE6B):c.1160C>T (p.Pro387Leu)","Chromosome":"4","Start":"656926","Stop":"656926","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1174270,"rule_based_match":true,"evidence_text":"c.1160C>T (p.P387L)","llm_judgment":"PRESENT","evidence":"c.1160C>T (p.P387L)","abstract_start":814,"abstract_end":833}]}
{"pmid":"35099763","title":"A novel NPHS2 mutation (c.865A > G) identified in a Chinese family with steroid-resistant nephrotic syndrome alters subcellular localization of nephrin.","abstract":"BACKGROUND: NPHS2 is the causative gene of nephrotic syndrome type 2 (MIM 600995) which often clinically manifests as steroid-resistant nephrotic syndrome (SRNS). The NPHS2 gene encodes a slit diaphragm (SD) associated protein podocin.\nOBJECTIVE: This study reported a novel disease-causing mutation of NPHS2 in a Chinese family with SRNS. We also investigated the pathogenic mechanism of the variants in this family.\nMETHOD: A Chinese family with SRNS was recruited. Whole exome sequencing was performed to screen for disease-causing mutation. Sanger sequencing was used to confirm the results. In vitro functional experiments including immunoblotting, co-immunoprecipitation and double immunofluorescence staining were performed to explore the pathogenic mechanisms of mutations.\nRESULTS: In this family, compound heterozygous mutations of NPHS2 (c.467dupT and c.865A > G) were identified and segregated with the disease. The maternal c.865A > G was a novel variant, leading to amino acid substitution (p.K289E). In vitro functional assays indicated that c.467dupT (p.L156FfsX11) mutant lost interaction with nephrin. Both K289E and L156FfsX11 mutants showed sharply diminished plasma membrane localization. Furthermore, abnormal distribution of podocin mutants also altered the cell membrane localization of nephrin.\nCONCLUSION: We reported a family with SRNS caused by compound heterozygous mutations of NPHS2 (c.467dupT and c.865A > G). c.865A > G (p.K289E) in NPHS2 was a novel causative variant associated with SRNS. Both variants in this family not only affected the normal cell membrane localization of podocin, but also altered the cell membrane localization of nephrin which is the major architectural protein of SD.","variants":[{"Name":"NM_014625.4(NPHS2):c.865A>G (p.Lys289Glu)","Chromosome":"1","Start":"179552611","Stop":"179552611","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3046499,"rule_based_match":true,"evidence_text":"c.865A > G","llm_judgment":"PRESENT","evidence":"c.865A > G","abstract_start":863,"abstract_end":873}]}
{"pmid":"37033539","title":"Familial Epilepsy Associated With Concurrent CHRNB2 Mutation and RBFOX1 Exon Deletion: A Case Report.","abstract":"Understanding the genetic basis of epilepsy may lead to an improved understanding of its etiology, more precise medical management, and ultimately improved outcomes. It is imperative for patients with epilepsy to obtain a molecular diagnosis, especially when strong familial epilepsy is discovered. We investigated a multi-generational family with epilepsy. The proband was a 19-year-old female who experienced focal onset seizures, with presenting symptoms of feeling dizzy, disorientation, and loss of consciousness. Her electroencephalography (EEG) studies revealed interictal focal slowing and sharp waves in both the left or right hemispheres independently. EEG monitoring showed that the seizures arose from the left fronto-temporal region and her brain MRI was normal. The proband's sister also suffered from focal onset seizures. Her EEG showed focal epileptiform discharge in the right temporal region, and her brain MRI was unrevealing. Two genetic tests were conducted for the proband: 1) array comparative genomic hybridization (CGH) revealed 16p13.3 deletion but no 22q deletion; and 2) next generation sequencing (NGS) Epilepsy Panel revealed a few variants of uncertain significance (VUS), including in CHRNB2 (c.1423A>G, p.Ile475Val) and RBFOX1 (RNA binding fox-1 homolog 1) (exon1-2 deletion). The proband's sister also carries both the CHRNB2 (cholinergic receptor nicotinic beta 2) variant and RBFOX1 deletion. The proband's father carries the CHRNB2 variant, and her brother and mother carry the deletion of RBFOX1. In this family, the co-expression of the CHRNB2 variant and RBFOX1 deletion may cause the clinical seizures seen in the proband and her sister. It is also possible that the RBFOX1 deletion is associated with an increased risk of seizure disorder with variable expressivity.","variants":[{"Name":"NM_000748.3(CHRNB2):c.1423A>G (p.Ile475Val)","Chromosome":"1","Start":"154575846","Stop":"154575846","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":822767,"rule_based_match":true,"evidence_text":"c.1423A>G, p.Ile475Val","llm_judgment":"PRESENT","evidence":"c.1423A>G, p.Ile475Val","abstract_start":1226,"abstract_end":1248}]}
{"pmid":"24011517","title":"Identification of three ABCA4 sequence variations exclusive to African American patients in a cohort of patients with Stargardt disease.","abstract":"PURPOSE: To describe the clinical and molecular findings in ten unrelated African American patients with Stargardt disease.\nDESIGN: Retrospective, observational case series.\nMETHODS: We reviewed the clinical histories, examinations, and genotypes of 85 patients with molecular diagnoses of Stargardt disease. Three ABCA4 sequence variations identified exclusively in African Americans were evaluated in 300 African American controls and by in silico analysis.\nRESULTS: ABCA4 sequence changes were identified in 85 patients from 80 families, of which 11 patients identified themselves as African American. Of these 11 patients, 10 unrelated patients shared 1 of 3 ABCA4 sequence variations: c.3602T>G (p.L1201R); c.3899G>A (p.R1300Q); or c.6320G>A (p.R2107H). The minor allele frequencies in the African American control population for each variation were 7.5%, 6.3%, and 2%, respectively. This is comparable to the allele frequency in African Americans in the Exome Variant Server. In contrast, the allele frequency of all three of these variations was less than or equal to 0.05% in European Americans. Although both c.3602T>G and c.3899G>A have been reported as likely disease-causing variations, one of our control patients was homozygous for each variant, suggesting that these are nonpathogenic. In contrast, the absence of c.6320G>A in the control population in the homozygous state, combined with the results of bioinformatics analysis, support its pathogenicity.\nCONCLUSIONS: Three ABCA4 sequence variations were identified exclusively in 10 unrelated African American patients: p.L1201R and p.R1300Q likely represent nonpathogenic sequence variants, whereas the p.R2107H substitution appears to be pathogenic. Characterization of population-specific disease alleles may have important implications for the development of genetic screening algorithms.","variants":[{"Name":"NM_000350.3(ABCA4):c.3602T>G (p.Leu1201Arg)","Chromosome":"1","Start":"94040048","Stop":"94040048","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":22942,"rule_based_match":true,"evidence_text":"c.3602T>G (p.L1201R)","llm_judgment":"PRESENT","evidence":"c.3602T>G (p.L1201R)","abstract_start":690,"abstract_end":710},{"Name":"NM_000350.3(ABCA4):c.3899G>A (p.Arg1300Gln)","Chromosome":"1","Start":"94032007","Stop":"94032007","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105135,"rule_based_match":true,"evidence_text":"c.3899G>A (p.R1300Q)","llm_judgment":"PRESENT","evidence":"c.3899G>A (p.R1300Q)","abstract_start":712,"abstract_end":732},{"Name":"NM_000350.3(ABCA4):c.6320G>A (p.Arg2107His)","Chromosome":"1","Start":"94001068","Stop":"94001068","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105337,"rule_based_match":true,"evidence_text":"c.6320G>A (p.R2107H)","llm_judgment":"PRESENT","evidence":"c.6320G>A (p.R2107H)","abstract_start":737,"abstract_end":757}]}
{"pmid":"29383513","title":"A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome.","abstract":"The most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE. The c.130dupG mutation was found in 32 patients (23 families), with 26 patients (19 families, 26.3%) in homozygosis, confirming its high prevalence in different regions of Brazil. Among the homozygous patients, the following characteristics were frequent: onset of symptoms before 2 years of age (92.3%), little functional restriction (92.3%), fluctuating symptoms (100%), ocular muscle impairment (96.1%), ptosis (100%), limb weakness (88.4%), response to pyridostigmine (100%), facial involvement (77%), and bulbar symptoms (70.8%). The pretest probability of finding at least one allele harbouring the c.130dupG mutation was 38.1%. Selecting only patients with impaired eye movement together with limb weakness and improvement with pyridostigmine, the probability increases to 72.2%. This clinical pre-selection of patients is likely a useful tool for regions where CHRNE mutations have a founder effect. In conclusion, the CHRNE mutation c.130dupG leads to fairly benign natural course of the disease with relative homogeneity.","variants":[{"Name":"NM_000080.4(CHRNE):c.130dup (p.Glu44fs)","Chromosome":"17","Start":"4902679","Stop":"4902680","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":244117,"rule_based_match":true,"evidence_text":"c.130dupG","llm_judgment":"PRESENT","evidence":"c.130dupG","abstract_start":237,"abstract_end":246}]}
{"pmid":"21932393","title":"Novel germline PALB2 truncating mutations in African American breast cancer patients.","abstract":"BACKGROUND: It has been demonstrated that the partner and localizer of breast cancer 2 (PALB2) acts as a bridging molecule between the breast cancer 1 (BRCA1) and BRCA2 proteins and is responsible for facilitating BRCA2-mediated DNA repair. Truncating mutations in the PALB2 gene reportedly are enriched in patients with Fanconi anemia and breast cancer in various populations.\nMETHODS: The authors evaluated the contribution of PALB2 germline mutations in 279 African American women with breast cancer, including 29 patients with a strong family history, 29 patients with a moderate family history, 75 patients with a weak family history, and 146 patients with nonfamilial or sporadic breast cancer.\nRESULTS: After direct sequencing of all the coding exons, exon/intron boundaries, and 5' and 3' untranslated regions of PALB2, 3 novel, monoallelic, truncating mutations (1.08%; 3 in 279 patients) were identified (c.758dupT [exon 4], c.1479delC [exon 4], and c.3048delT [exon 10]) together with 50 sequence variants, 27 of which were novel. None of the truncating mutations were identified in a group of 262 controls from the same population.\nCONCLUSIONS: PALB2 mutations were present in both familial and nonfamilial breast cancers among African Americans. Rare PALB2 mutations accounted for a small but substantial proportion of patients with breast cancer.","variants":[{"Name":"NM_024675.4(PALB2):c.1479del (p.Thr494fs)","Chromosome":"16","Start":"23635067","Stop":"23635067","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":132116,"rule_based_match":true,"evidence_text":"c.1479delC","llm_judgment":"PRESENT","evidence":"c.1479delC","abstract_start":935,"abstract_end":945},{"Name":"NM_024675.4(PALB2):c.758dup (p.Ser254fs)","Chromosome":"16","Start":"23635787","Stop":"23635788","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":132279,"rule_based_match":true,"evidence_text":"c.758dupT","llm_judgment":"PRESENT","evidence":"c.758dupT","abstract_start":915,"abstract_end":924},{"Name":"NM_024675.4(PALB2):c.3048del (p.Phe1016fs)","Chromosome":"16","Start":"23621427","Stop":"23621427","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":132217,"rule_based_match":true,"evidence_text":"c.3048delT [exon 10]","llm_judgment":"PRESENT","evidence":"c.3048delT [exon 10]","abstract_start":960,"abstract_end":980}]}
{"pmid":"25952714","title":"CYP1B1 gene analysis and phenotypic correlation in Portuguese children with primary congenital glaucoma.","abstract":"PURPOSE: To investigate the prevalence of CYP1B1 mutations in Portuguese children with primary congenital glaucoma (PCG) and to study the possible correlations between the mutation status and clinical features of the disease.\nMETHODS: DNA sequencing analysis of the CYP1B1 gene was used to screen 21 children with PCG followed on Paediatric Ophthalmology and Medical Genetics consultations at D. Estefânia's Hospital (Centro Hospitalar de Lisboa Central, Portugal). The effect of mutations on the phenotype of the patients was also assessed. Presence and type of mutations in CYP1B1 gene, age at diagnosis, bilaterality, age at first surgery, postoperative intraocular pressure and corneal diameter, final visual acuity, number of surgical reinterventions, and number of antiglaucoma medications required postoperatively were noted.\nRESULTS: Mutations in the CYP1B1 gene in 6 patients (28.57%) were detected, all compound heterozygotes. Seven types of mutations were identified: c.182G&gt;A, c.317C&gt;A, c.535delG, c.1064_1076del, c.1159G&gt;A, c.1310C&gt;T, and c.1390dupT. All patients with these mutations developed bilateral PCG, whereas in the group without mutations only 7 (46.67%) showed bilateral disease. Age at diagnosis was lower in the group of patients with these mutations (0.0 ± 0.00 vs 4.5 ± 2.63 months, p&lt;0.01). In the remaining variables (age at first surgery, postoperative intraocular pressure and corneal diameter, final visual acuity, number of surgical reinterventions and antiglaucoma medications required postoperatively), no significant differences between the groups were detected (p&gt;0.05 for all comparisons).\nCONCLUSIONS: This study is the first to report the variety of mutations in the CYP1B1 gene in a group of Portuguese children with PCG and to describe 2 new mutations. Genetic analysis of PCG must be carried out, although it has not yet been possible to establish a genotype-phenotype correlation, with the exception of bilaterality and early age at diagnosis.","variants":[{"Name":"NM_000104.4(CYP1B1):c.1390dup (p.Ser464fs)","Chromosome":"2","Start":"38070963","Stop":"38070964","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":1314477,"rule_based_match":true,"evidence_text":"c.1390dupT","llm_judgment":"PRESENT","evidence":"c.1390dupT","abstract_start":1064,"abstract_end":1074},{"Name":"NM_000104.4(CYP1B1):c.317C>A (p.Ala106Asp)","Chromosome":"2","Start":"38075072","Stop":"38075072","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2742118,"rule_based_match":false,"evidence_text":"c.317C>A","llm_judgment":"PRESENT","evidence":"c.317C>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"31020813","title":"Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice-site and Charcot-Marie-Tooth phenotype with early onset symptoms.","abstract":"BACKGROUND: Rare variants (RV) in immunoglobulin mu-binding protein 2 (IGHMBP2) [OMIM 600502] can cause an autosomal recessive type of Charcot-Marie-Tooth (CMT) disease [OMIM 616155], an inherited peripheral neuropathy. Over 40 different genes are associated with CMT, with different possible inheritance patterns.\nMETHODS AND RESULTS: An 11-year-old female with motor delays was found to have distal atrophy, weakness, and areflexia without bulbar or sensory findings. Her clinical evaluation was unrevealing. Whole exome sequencing (WES) revealed a maternally inherited IGHMBP2 RV (c.1730T>C) predicted to be pathogenic, but no variant on the other allele was identified. Deletion and duplication analysis was negative. She was referred to the Undiagnosed Disease Network (UDN) for further evaluation. Whole genome sequencing (WGS) confirmed the previously identified IGHMBP2 RV and identified a paternally inherited non-coding IGHMBP2 RV. This was predicted to activate a cryptic splice site perturbing IGHMBP2 splicing. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was consistent with activation of the cryptic splice site. The abnormal transcript was shown to undergo nonsense-mediated decay (NMD), resulting in halpoinsufficiency.\nCONCLUSION: This case demonstrates the deficiencies of WES and traditional molecular analyses and highlights the advantages of utilization of WGS and functional studies.","variants":[{"Name":"NM_002180.3(IGHMBP2):c.1730T>C (p.Leu577Pro)","Chromosome":"11","Start":"68935396","Stop":"68935396","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":513441,"rule_based_match":true,"evidence_text":"c.1730T>C","llm_judgment":"PRESENT","evidence":"c.1730T>C","abstract_start":584,"abstract_end":593}]}
{"pmid":"26453614","title":"The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers.","abstract":"Mutations in the vacuolar-type H(+)-ATPase B1 subunit gene ATP6V1B1 cause autosomal-recessive distal renal tubular acidosis (dRTA). We previously identified a single-nucleotide polymorphism (SNP) in the human B1 subunit (c.481G>A; p.E161K) that causes greatly diminished pump function in vitro To investigate the effect of this SNP on urinary acidification, we conducted a genotype-phenotype analysis of recurrent stone formers in the Dallas and Bern kidney stone registries. Of 555 patients examined, 32 (5.8%) were heterozygous for the p.E161K SNP, and the remaining 523 (94.2%) carried two wild-type alleles. After adjustment for sex, age, body mass index, and dietary acid and alkali intake, p.E161K SNP carriers had a nonsignificant tendency to higher urinary pH on a random diet (6.31 versus 6.09; P=0.09). Under an instructed low-Ca and low-Na diet, urinary pH was higher in p.E161K SNP carriers (6.56 versus 6.01; P<0.01). Kidney stones of p.E161K carriers were more likely to contain calcium phosphate than stones of wild-type patients. In acute NH4Cl loading, p.E161K carriers displayed a higher trough urinary pH (5.34 versus 4.89; P=0.01) than wild-type patients. Overall, 14.6% of wild-type patients and 52.4% of p.E161K carriers were unable to acidify their urine below pH 5.3 and thus, can be considered to have incomplete dRTA. In summary, our data indicate that recurrent stone formers with the vacuolar H(+)-ATPase B1 subunit p.E161K SNP exhibit a urinary acidification deficit with an increased prevalence of calcium phosphate-containing kidney stones. The burden of E161K heterozygosity may be a forme fruste of dRTA.","variants":[{"Name":"NM_001692.4(ATP6V1B1):c.481G>A (p.Glu161Lys)","Chromosome":"2","Start":"70959974","Stop":"70959974","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":53396,"rule_based_match":true,"evidence_text":"c.481G>A; p.E161K","llm_judgment":"PRESENT","evidence":"c.481G>A; p.E161K","abstract_start":221,"abstract_end":238}]}
{"pmid":"28361593","title":"First Report of a Chinese Family Carrying a Double Heterozygosity for Hb Q-Thailand and Hb J-Bangkok.","abstract":"The double heterozygosity for α and β chain variants leads to the formation of abnormal heterodimer hybrids, which could render laboratory diagnostics in a routine setting difficult. The following is the first report of a double heterozygosity for Hb Q-Thailand [α74(EF3)Asp→His; HBA1: c.223G>C] with α<sup>+</sup>-thalassemia (α<sup>+</sup>-thal) and Hb J-Bangkok [β56(D7)Gly→Asp; HBB: c.170G>A] found in a Chinese family. Both subjects were healthy with normal or borderline hematological parameters. Hemoglobin (Hb) analyses showed a novel variant, Hb Q-Thailand and Hb J-Bangkok. Family studies helped in the initial recognition and in making presumptive diagnoses, but definitive diagnoses of these cases with complex α and β chain variants could only be obtained after DNA analysis.","variants":[{"Name":"NM_000518.5(HBB):c.170G>A (p.Gly57Asp)","Chromosome":"11","Start":"5226722","Stop":"5226722","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30253,"rule_based_match":true,"evidence_text":"HBB: c.170G>A","llm_judgment":"PRESENT","evidence":"HBB: c.170G>A","abstract_start":382,"abstract_end":395}]}
{"pmid":"23249953","title":"A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype.","abstract":"Congenital disorders of glycosylation (CDG) are a large group of recessive multisystem disorders caused by impaired protein or lipid glycosylation. The CDG-I subgroup is characterized by protein N-glycosylation defects originating in the endoplasmic reticulum. The genetic defect is known for 17 different CDG-I subtypes. Patients in the few reported DPAGT1-CDG families exhibit severe intellectual disability (ID), epilepsy, microcephaly, severe hypotonia, facial dysmorphism and structural brain anomalies. In this study, we report a non-consanguineous family with two affected adults presenting with a relatively mild phenotype consisting of moderate ID, epilepsy, hypotonia, aggressive behavior and balance problems. Exome sequencing revealed a compound heterozygous missense mutation, c.85A>T (p.I29F) and c.503T>C (p.L168P), in the DPAGT1 gene. The affected amino acids are located in the first and fifth transmembrane domains of the protein. Isoelectric focusing and high-resolution mass spectrometry analyses of serum transferrin revealed glycosylation profiles that are consistent with a CDG-I defect. Our results show that the clinical spectrum of DPAGT1-CDG is much broader than appreciated so far.","variants":[{"Name":"NM_001382.4(DPAGT1):c.85A>T (p.Ile29Phe)","Chromosome":"11","Start":"119101571","Stop":"119101571","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":76382,"rule_based_match":true,"evidence_text":"c.85A>T (p.I29F)","llm_judgment":"PRESENT","evidence":"c.85A>T (p.I29F)","abstract_start":790,"abstract_end":806},{"Name":"NM_001382.4(DPAGT1):c.503T>C (p.Leu168Pro)","Chromosome":"11","Start":"119100402","Stop":"119100402","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":76383,"rule_based_match":true,"evidence_text":"c.503T>C (p.L168P)","llm_judgment":"PRESENT","evidence":"c.503T>C (p.L168P)","abstract_start":811,"abstract_end":829}]}
{"pmid":"24039984","title":"A novel splice-site mutation in the GJB2 gene causing mild postlingual hearing impairment.","abstract":"The DFNB1 subtype of autosomal recessive, nonsyndromic hearing impairment, caused by mutations affecting the GJB2 (connexin-26) [corrected] gene, is highly prevalent in most populations worldwide. DFNB1 hearing impairment is mostly severe or profound and usually appears before the acquisition of speech (prelingual onset), though a small number of hypomorphic missense mutations result in mild or moderate deafness of postlingual onset. We identified a novel GJB2 splice-site mutation, c. -22-2A>C, in three siblings with mild postlingual hearing impairment that were compound heterozygous for c. -22-2A>C and c.35delG. Reverse transcriptase-PCR experiments performed on total RNA extracted from saliva samples from one of these siblings confirmed that c. -22-2A>C abolished the acceptor splice site of the single GJB2 intron, resulting in the absence of normally processed transcripts from this allele. However, we did isolate transcripts from the c. -22-2A>C allele that keep an intact GJB2 coding region and that were generated by use of an alternative acceptor splice site previously unknown. The residual expression of wild-type connexin-26 [corrected] encoded by these transcripts probably underlies the mild severity and late onset of the hearing impairment of these subjects.","variants":[{"Name":"NM_004004.6(GJB2):c.-22-2A>C","Chromosome":"13","Start":"20189605","Stop":"20189605","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":362175,"rule_based_match":true,"evidence_text":"c. -22-2A>C","llm_judgment":"PRESENT","evidence":"c. -22-2A>C","abstract_start":487,"abstract_end":498}]}
{"pmid":"38778723","title":"A new genetic diagnosis strategy for paroxysmal kinesigenic dyskinesia: Targeted high-throughput detection of PRRT2 gene c.649 locus.","abstract":"BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most prevalent kind type of paroxysmal Dyskinesia, characterized by recurrent and transient episodes of involuntary movements. Most PKD cases were attributed to the proline-rich transmembrane protein 2 (PRRT2) gene, in which the c.649 region is a hotspot for known mutations. Even though some patients with PKD have been genetically diagnosed using whole-exome sequencing (WES) and Sanger sequencing, there are still cases of missed diagnoses due to the limitations of sequencing technology and analytic methods on throughput.\nMETHODS: Patients meeting the diagnosis criteria of PKD with negative results of PRRT2-Sanger sequencing and WES were included in this study. Mutation screening and targeted high-throughput sequencing were performed to analyze and verify the sequencing results of the potential mutations.\nRESULTS: Six patients with PKD with high mutation ratios of c.649dupC were screened using our targeted high-throughput sequencing from 26 PKD patients with negative results of PRRT2-Sanger sequencing and WES (frequency = 23.1%), which compensated for the comparatively shallow sequencing depth and statistical flaws in this region. Compared with the local normal population and other patients with PKD, the mutation ratios of c.649dupC of these six patients with PKD were much higher and also had truncated protein structures and differentially altered mRNA expression.\nCONCLUSION: Based on the above studies, we emphasize the routine targeted high-throughput sequencing of the c.649 site in the PRRT2 gene in so-called genetic-testing-negative patients with PKD, and manually calculate the deletion and duplication mutations depth and ratios to lower the rate of clinical misdiagnosis.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC","llm_judgment":"PRESENT","evidence":"c.649dupC","abstract_start":935,"abstract_end":944}]}
{"pmid":"32335882","title":"Analysis of a child with megalencephalic leukoencephalopathy with subcortical cyst type 2B caused by HEPACAM variant","abstract":"OBJECTIVE: To explore the clinical features and genetic variant in a child featuring megalencephalic leukoencephalopathy with subcortical cyst (MLC) type 2B.\nMETHODS: Clinical and imaging data of the child was collected. Potential variant of hepatocyte adhesion molecule (HEPACAM) gene was detected by Sanger sequencing. The growth and development of her mother and uncle was also reviewed.\nRESULTS: The patient, a 1-year-and-7-month female, presented with convulsion, mental retardation and abnormally increased head circumference. Cranial MRI revealed extensive long T1 long T2 signals in the white matter of bilateral cerebral hemisphere, right anterior sac cyst, cerebral gyrus widening, and shallow sulcus. Sanger sequencing identified a c.437C>T missense variant in exon 3 of the HEPACAM gene. The same variant was detected in her mother but not father. Her mother and maternal uncle both had a history of increased head circumference when they were young. In their adulthood, the head circumference was in the normal range but still greater than the average.\nCONCLUSION: The heterozygous variant of the HEPACAM gene probably underlies the MLC2B in this child. The variant has derived from her asymptomatic mother, which suggested incomplete penetrance of the MLC2B.","variants":[{"Name":"NM_152722.5(HEPACAM):c.437C>T (p.Ser146Leu)","Chromosome":"11","Start":"124924001","Stop":"124924001","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3539231,"rule_based_match":true,"evidence_text":"c.437C>T","llm_judgment":"PRESENT","evidence":"c.437C>T","abstract_start":743,"abstract_end":751}]}
{"pmid":"28275242","title":"UQCRC2 mutation in a patient with mitochondrial complex III deficiency causing recurrent liver failure, lactic acidosis and hypoglycemia.","abstract":"An isolated mitochondrial complex III (CIII) defect constitutes a rare cause of mitochondrial disorder. Here we present the second case involving UQCRC2 gene, which encodes core protein 2, one of the 11 structural subunits of CIII. The patient has the same mutation (c.547C>T; p.Arg183Trp) as the first case and presented with neonatal lactic acidosis, hypoglycemia and severe episodes of liver failure. Our study expands the few reported cases of CIII deficiency of nuclear origin.","variants":[{"Name":"NM_003366.4(UQCRC2):c.547C>T (p.Arg183Trp)","Chromosome":"16","Start":"21965440","Stop":"21965440","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":50318,"rule_based_match":true,"evidence_text":"c.547C>T; p.Arg183Trp","llm_judgment":"PRESENT","evidence":"c.547C>T; p.Arg183Trp","abstract_start":267,"abstract_end":288}]}
{"pmid":"23290023","title":"Congenital hypomyelinating neuropathy attributable to a de novo p.Asp61Asn mutation of the myelin protein zero gene.","abstract":"We describe a boy aged 2 years and 11 months with congenital hypomyelinating neuropathy attributable to a de novo heterozygous missense mutation of c.181 G>A (p.Asp61Asn) in the myelin protein zero gene. A nerve conduction study indicated markedly reduced motor conduction velocities in the upper and lower extremities. Stimuli of up to 50-100 mA were necessary for nerve activation, suggesting diseased nerves with greatly decreased excitability. A sural nerve biopsy revealed a marked loss of large myelinated fibers, the absence of myelin breakdown products, occasional basal lamina onion-bulb formations, and tomacula-like structures. The p.Asp61Asn mutation is novel in congenital hypomyelinating neuropathy, but was previously reported in a patient with Charcot-Marie-Tooth disease type 1.","variants":[{"Name":"NM_000530.8(MPZ):c.181G>A (p.Asp61Asn)","Chromosome":"1","Start":"161307311","Stop":"161307311","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":204409,"rule_based_match":true,"evidence_text":"c.181 G>A (p.Asp61Asn)","llm_judgment":"PRESENT","evidence":"c.181 G>A (p.Asp61Asn)","abstract_start":148,"abstract_end":170}]}
{"pmid":"29164086","title":"A Novel Missense Mutation of the NSD1 Gene Associated with Overgrowth in Three Generations of an Italian Family: Case Report, Differential Diagnosis, and Review of Mutations of NSD1 Gene in Familial Sotos Syndrome.","abstract":"Sotos syndrome (SoS) is characterized by overgrowth of prenatal onset, learning disability, and characteristic facial appearance; it is usually due to haploinsufficiency of NSD1 gene at chromosome 5q35. An Italian child was born at 37 weeks of gestation (weight 2,910 g, 25th-50th centiles; length 50 cm, 75th centile; head circumference 36 cm, 97th centile) showing cryptorchidism on the right side, hypertelorism, dolichocephaly, broad and prominent forehead, and narrow jaw; the pregnancy was worsened by maternal preeclampsia and gestational diabetes, and his mother had a previous history of four early miscarriages. The patient showed neonatal jaundice, hypotonia, feeding difficulties, frequent vomiting, and gastroesophageal reflux. After the age of 6 months, his weight, length, and head circumference were above the 97th centile; psychomotor development was delayed. At the age of 9 years, the patient showed also joint laxity and scoliosis. DNA sequence analysis of NSD1 gene detected a novel heterozygous mutation (c.521T>A, p.Val174Asp) in exon 2. The same mutant allele was also found in the mother and in the maternal grandfather of the proband; both the mother and the maternal grandfather of the proband showed isolated overgrowth with height above the 97th centile in absence of other features of SoS. At present 23 familial cases of SoS have been described (two cases with mutation in exon 2 of NSD1 gene); no familial cases of SoS with mutation of NSD1 gene and isolated overgrowth have been reported. Probably, point mutations of NSD1 gene, and particularly mutations between exon 20 and exon 23, are not likely to affect reproductive fitness. Epigenetic mechanisms and intrauterine environment may influence phenotypes, therefore genetic tests are not useful to predict the phenotype but they are indispensable for the diagnosis of SoS. This is the first Italian familial case of SoS with genetic confirmation and the third report in which a missense mutation of NSD1 gene is found in three generations of the same family.","variants":[{"Name":"NM_022455.5(NSD1):c.521T>A (p.Val174Asp)","Chromosome":"5","Start":"177135624","Stop":"177135624","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3742743,"rule_based_match":true,"evidence_text":"c.521T>A, p.Val174Asp","llm_judgment":"PRESENT","evidence":"c.521T>A, p.Val174Asp","abstract_start":1027,"abstract_end":1048}]}
{"pmid":"30003095","title":"Magnetic Resonance Imaging Findings in the Muscle Tissue of Patients with Limb Girdle Muscular Dystrophy Type 2I Harboring the Founder Mutation c.545A>G in the","abstract":"Limb girdle muscular dystrophy type 2I (LGMD2I) is an autosomal recessive muscular dystrophy that is rare in Asia and is caused by mutations in the fukutin-related protein gene (<i>FKRP</i>). The aim of this study was to determine if there are any characteristic features of muscle on magnetic resonance imaging (MRI) in patients with LGMD2I harboring the founder mutation c.545A>G in <i>FKRP</i>. Using MRI, we delineated changes in the thigh muscles of ten patients with genetically confirmed LGMD2I. The majority of muscle biopsy specimens showed reduced glycosylation of <i>α</i>-dystroglycan, decreased expression of laminin <i>α</i>2, and a dystrophic pattern. In our cohort, the muscles with the most severe fatty infiltration were adductor magnus and vastus intermedius, whereas the rectus femoris, sartorius, and gracilis muscles were relatively spared. In seven patients, we identified a concentric fatty infiltration pattern that was most pronounced in the vastus intermedius and vastus medialis muscles around the distal femoral diaphysis. In this disease, the initial fatty infiltration of the posterior thigh muscles gradually progresses anteriorly regardless of the founder mutation in <i>FKRP</i>. Muscle tissue in patients with LGMD2I who have the founder mutation c.545A>G in <i>FKRP</i> shows a distinctive concentric pattern of fatty infiltration and edema on MRI.","variants":[{"Name":"NM_024301.5(FKRP):c.545A>G (p.Tyr182Cys)","Chromosome":"19","Start":"46755995","Stop":"46755995","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":266484,"rule_based_match":true,"evidence_text":"c.545A>G","llm_judgment":"PRESENT","evidence":"c.545A>G","abstract_start":373,"abstract_end":381}]}
{"pmid":"27122458","title":"Mutation screening of 433 families with Duchenne/Becker muscular dystrophy","abstract":"OBJECTIVE: Mutation analysis of unrelated families with Duchenne/Becker muscular dystrophy (DMD/BMD) was performed to investigate the characteristic of DMD gene mutation, especially the distribution pattern of point mutation of DMD gene in Chinese population.\nMETHODS: A total of 433 unrelated DMD/BMD families were collected at the Center of Prenatal Diagnosis of the First Affiliated Hospital of Zhengzhou University from March 2010 to December 2014. The deletions or duplications in 79 exons of DMD gene were screened using multiplex ligation-dependent probe amplification (MLPA). Any single-exon deletion detected by MLPA was further validated by PCR amplification. In the 117 unrelated Chinese families in which large-scale deletions and duplications had been excluded by MLPA, the point mutation in 79 exons of DMD gene were tested in the propositus using next-generation sequencing (NGS), and further verified the point mutation using Sanger sequencing.\nRESULTS: In the 433 unrelated DMD/BMD families, 316 families with DMD deletions/duplications were identified by MLPA. Out of 57 single-exon deletions detected by MLPA, 3 were found as point mutations by PCR and Sanger sequencing, including 2 nonsense mutation (c.1729G>T [p.Glu577X], c. 3346A>T [p.Lys1116X]) and 1 frame-shift mutation (c.8605_8606delGT [p.Val2869ThrfsX25]). Direct sequencing with Ion PGM and Sanger sequencing in 117 families with negative results in MLPA detected 92 different point mutations in 96 families, including 46 novel mutations, 42 previously reported ones, and 4 possible polymorphisms (rs189143447, rs202008454, rs200213555, rs187617705). The 46 novel mutations consisted of 16 nonsense mutations (c.100A>T [p.Lys34X], c. 1201C>T [p.Gln401X], c. 1707C>A [p.Cys569X], c. 1831G>T [p.Glu611X], c. 1912C>T [p.Gln638X], c. 2213C>G [p.Ser738X], c. 3673_3673delA [p.Ile1225X], c. 3774C>A [p.Cys1258X], c. 4858G>T [p.Glu1620X], c. 5764A>T [p.Lys1922X], c. 6035T>G [p.Leu2012X], c. 6408G>A [p.Trp2136X], c. 7717C>T [p.Gln2573X], c. 7864G>T [p.Glu2622X], c. 8184_8185insT [p.Lys2729X], c. 8215C>T [p.Gln2739X]), 5 missense mutations (c.139G>A [p.Gly47Arg], c. 238G>C [p.Ala80Pro], c. 335G>T [p.Trp112Leu], c. 804A>C [p.Leu268Phe], c. 1149G>T [p.Glu383Asp]), 6 splice-site mutations (c.2293-3C>A, c. 2380+ 1G>T, c. 3277-1G>C, c.4519-7A>G, c. 5740-15G>T, c. 7661-1G>C), 16 small deletions (c.688_688delA [p.Met230CysfsX14], c.1760_1791del32 [p.Thr587IlefsX37], c. 2271_2271delA [p.Asp774ThrfsX22], c. 2281_2285delGAAAA [p.Glu761SerfsX10], c. 2527_2527delG [p.Glu843SerfsX3], c. 3405_3405delC [p.Asn1135LysfsX18], c. 4450_4450delC [p.His1484ThrfsX14], c. 4770_4770delA [p.Thr1590ThrfsX5], c. 4937_4937delA [p.Glu1646GlyfsX11], c. 5253_5256delATTA [p.Lys1751LysfsX2], c. 5654_5654delA [p.Gln1885ArgfsX6], c. 7441_7441delG [p.Glu2481AsnfsX13], c. 7860_7860delC [p.Ile2620IlefsX18], c. 8668-8668delG /c.8668+ 1-8668+ 1delG, c. 9009_9009delC [p.Thr3003ThrfsX18], c. 9021_9021delT [p.Ile3007IlefsX14]), and 3 small insertions (c.305_306insG [p.Gly102GlyfsX4], c. 3116_3117insA [p.His1039GlufsX11], c. 9197_9198insATCTC [p.Ser3066SerfsX25]). And 87.4% (83/95) of the pathologic point mutations disrupted the translational reading frame (46 nonsense mutations, 24 frame-shift mutations, and 13 splice-site mutations).\nCONCLUSIONS: Inexpensive and efficient genetic/prenatal diagnosis of DMD/BMD may be plausible by MLPA analysis, NGS, and Sanger sequencing. Most of the mutations identified in this study led to a predictable premature stop codon or splicing defects, resulting in defective function of dystrophin.","variants":[{"Name":"NM_004006.3(DMD):c.3774C>A (p.Cys1258Ter)","Chromosome":"X","Start":"32448468","Stop":"32448468","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1312824,"rule_based_match":true,"evidence_text":"c. 3774C>A [p.Cys1258X]","llm_judgment":"PRESENT","evidence":"c. 3774C>A [p.Cys1258X]","abstract_start":1863,"abstract_end":1886},{"Name":"NM_004006.3(DMD):c.3277-1G>C","Chromosome":"X","Start":"32463595","Stop":"32463595","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1312904,"rule_based_match":true,"evidence_text":"c. 3277-1G>C","llm_judgment":"PRESENT","evidence":"c. 3277-1G>C","abstract_start":2294,"abstract_end":2306},{"Name":"NM_004006.3(DMD):c.8215C>T (p.Gln2739Ter)","Chromosome":"X","Start":"31627675","Stop":"31627675","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1312622,"rule_based_match":true,"evidence_text":"c. 8215C>T [p.Gln2739X]","llm_judgment":"PRESENT","evidence":"c. 8215C>T [p.Gln2739X]","abstract_start":2069,"abstract_end":2092},{"Name":"NM_004006.3(DMD):c.2281_2285del (p.Glu761fs)","Chromosome":"X","Start":"32518015","Stop":"32518019","ReferenceAlleleVCF":"TTTTTC","AlternateAlleleVCF":"T","allel_id":100400,"rule_based_match":true,"evidence_text":"c. 2281_2285delGAAAA [p.Glu761SerfsX10]","llm_judgment":"PRESENT","evidence":"c. 2281_2285delGAAAA [p.Glu761SerfsX10]","abstract_start":2479,"abstract_end":2518},{"Name":"NM_004006.3(DMD):c.6408G>A (p.Trp2136Ter)","Chromosome":"X","Start":"32216946","Stop":"32216946","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":534742,"rule_based_match":true,"evidence_text":"c. 6408G>A [p.Trp2136X]","llm_judgment":"PRESENT","evidence":"c. 6408G>A [p.Trp2136X]","abstract_start":1963,"abstract_end":1986},{"Name":"NM_004006.3(DMD):c.139G>A (p.Gly47Arg)","Chromosome":"X","Start":"32849775","Stop":"32849775","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":999768,"rule_based_match":true,"evidence_text":"c.139G>A [p.Gly47Arg]","llm_judgment":"PRESENT","evidence":"c.139G>A [p.Gly47Arg]","abstract_start":2117,"abstract_end":2138},{"Name":"NM_004006.3(DMD):c.4858G>T (p.Glu1620Ter)","Chromosome":"X","Start":"32365187","Stop":"32365187","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":404218,"rule_based_match":true,"evidence_text":"c. 4858G>T [p.Glu1620X]","llm_judgment":"PRESENT","evidence":"c. 4858G>T [p.Glu1620X]","abstract_start":1888,"abstract_end":1911},{"Name":"NM_004006.3(DMD):c.2213C>G (p.Ser738Ter)","Chromosome":"X","Start":"32518087","Stop":"32518087","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1312666,"rule_based_match":true,"evidence_text":"c. 2213C>G [p.Ser738X]","llm_judgment":"PRESENT","evidence":"c. 2213C>G [p.Ser738X]","abstract_start":1808,"abstract_end":1830}]}
{"pmid":"27492651","title":"Novel Genetic, Clinical, and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia.","abstract":"Hereditary spastic paraplegias (HSPs) are genetically and clinically heterogeneous axonopathies primarily affecting upper motor neurons and, in complex forms, additional neurons. Here, we report two families with distinct recessive mutations in TFG, previously suggested to cause HSP based on findings in a single small family with complex HSP. The first carried a homozygous c.317G>A (p.R106H) variant and presented with pure HSP. The second carried the same homozygous c.316C>T (p.R106C) variant previously reported and displayed a similarly complex phenotype including optic atrophy. Haplotyping and bisulfate sequencing revealed evidence for a c.316C>T founder allele, as well as for a c.316_317 mutation hotspot. Expression of mutant TFG proteins in cultured neurons revealed mitochondrial fragmentation, the extent of which correlated with clinical severity. Our findings confirm the causal nature of bi-allelic TFG mutations for HSP, broaden the clinical and mutational spectra, and suggest mitochondrial impairment to represent a pathomechanistic link to other neurodegenerative conditions.","variants":[{"Name":"NM_006070.6(TFG):c.316C>T (p.Arg106Cys)","Chromosome":"3","Start":"100728759","Stop":"100728759","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":106771,"rule_based_match":true,"evidence_text":"c.316C>T (p.R106C)","llm_judgment":"PRESENT","evidence":"c.316C>T (p.R106C)","abstract_start":471,"abstract_end":489},{"Name":"NM_006070.6(TFG):c.317G>A (p.Arg106His)","Chromosome":"3","Start":"100728760","Stop":"100728760","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1059548,"rule_based_match":true,"evidence_text":"c.317G>A (p.R106H)","llm_judgment":"PRESENT","evidence":"c.317G>A (p.R106H)","abstract_start":376,"abstract_end":394}]}
{"pmid":"12083811","title":"Genetic analysis in nine unrelated Italian patients affected by OTC deficiency: detection of novel mutations in the OTC gene.","abstract":"Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder due to a defect of the mithocondrial enzyme ornithine transcarbamylase (OTC). Genetic analysis in nine unrelated Italian patients affected by OTCD (one male patient and eight female manifesting carriers) led to the detection of three novel mutations and six previously reported mutations in the OTC gene. The analysis was performed by direct sequencing of OTC cDNA, OTC exons, and intron-exon boundaries and enzymatic restriction analysis on the patients' genomic DNA and total RNA isolated from peripheral blood lymphocytes. In the male patient the new mutation S132P due to the nucleotide change c.394T>C was identified. In a manifesting carrier the nucleotide change c.292G>A that leads to the novel amino acid substitution E98K was identified; this mutation is close to the OTC protein's carbamyl phospate binding site. In another manifesting carrier the OTC cDNA analysis revealed the normally spliced transcript and an aberrant transcript with an insertion of two nucleotides (c.77-78insAG). In the patient's genomic DNA we identified a new transvertion IVS1-3C>G at the heterozygous state; this nucleotide change generates a new splice acceptor site in intron 1 that induces an RNA splicing defect. This insertion causes a frame shift in OTC cDNA ORF and leads to a premature stop codon. The previously described mutations N161S, R141Q, T178M, R92X, A208T, M268T were identified in the other six manifesting carriers.","variants":[{"Name":"NM_000531.6(OTC):c.394T>C (p.Ser132Pro)","Chromosome":"X","Start":"38401282","Stop":"38401282","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":103079,"rule_based_match":true,"evidence_text":"c.394T>C","llm_judgment":"PRESENT","evidence":"c.394T>C","abstract_start":678,"abstract_end":686},{"Name":"NM_000531.6(OTC):c.292G>A (p.Glu98Lys)","Chromosome":"X","Start":"38369871","Stop":"38369871","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":103050,"rule_based_match":true,"evidence_text":"c.292G>A","llm_judgment":"PRESENT","evidence":"c.292G>A","abstract_start":750,"abstract_end":758}]}
{"pmid":"33675180","title":"Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic cerebral palsy syndrome.","abstract":"The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G > A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by prominent motor dysfunction.","variants":[{"Name":"NM_024735.5(FBXO31):c.1000G>A (p.Asp334Asn)","Chromosome":"16","Start":"87334283","Stop":"87334283","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1336578,"rule_based_match":true,"evidence_text":"c.1000G > A (p.Asp334Asn)","llm_judgment":"PRESENT","evidence":"c.1000G > A (p.Asp334Asn)","abstract_start":309,"abstract_end":334}]}
{"pmid":"28526010","title":"Next-generation sequencing for D47N mutation in Cx50 analysis associated with autosomal dominant congenital cataract in a six-generation Chinese family.","abstract":"BACKGROUND: Congenital cataract is the most frequent cause of blindness during infancy or early childhood. To date, more than 40 loci associated with congenital cataract have been identified, including at least 26 genes on different chromosomes associated with inherited cataract. This present study aimed to identify the genetic mutation in a six-generation Chinese family affected with congenital cataract.\nMETHODS: A detailed six-generation Chinese cataract family history and clinical data of the family members were recorded. A total of 27 family members, including 14 affected and 13 unaffected individuals were recruited. Whole exome sequencing was performed to determine the disease-causing mutation. Sanger sequencing was used to confirm the results.\nRESULTS: A known missense mutation, c. 139G > A (p. D47N), in Cx50 was identified. This mutation co-segregated with all affected individuals and was not observed in the unaffected family members or in 100 unrelated controls. The homology modeling showed that the structure of the mutant protein was different with that wild-type Cx50.\nCONCLUSIONS: The missense mutation c.139G > A in GJA8 gene is associated with autosomal dominant congenital cataract in a six-generation Chinese family. The result of this present study provides further evidence that the p. D47N mutation in CX50 is a hot-spot mutation.","variants":[{"Name":"NM_005267.5(GJA8):c.139G>A (p.Asp47Asn)","Chromosome":"1","Start":"147908094","Stop":"147908094","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23766,"rule_based_match":true,"evidence_text":"c. 139G > A (p. D47N)","llm_judgment":"PRESENT","evidence":"c. 139G > A (p. D47N)","abstract_start":796,"abstract_end":817}]}
{"pmid":"38041679","title":"Recurrent de novo","abstract":"BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific <i>SPTLC1</i> variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in <i>SPTLC2</i> c.778G>A [p.Glu260Lys] manifesting with juvenile ALS.\nMETHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed.\nRESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that <i>SPTLC2</i> variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing <i>SPTLC2</i> variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported <i>SPTLC1</i> ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in <i>SPTLC1</i> and <i>SPTCL2</i>-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS.\nCONCLUSIONS: <i>SPTLC2</i> is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further.","variants":[{"Name":"NM_004863.4(SPTLC2):c.778G>A (p.Glu260Lys)","Chromosome":"14","Start":"77562468","Stop":"77562468","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":936755,"rule_based_match":true,"evidence_text":"c.778G>A [p.Glu260Lys]","llm_judgment":"PRESENT","evidence":"c.778G>A [p.Glu260Lys]","abstract_start":506,"abstract_end":528}]}
{"pmid":"33272087","title":"Benefits of ketogenic diet in a pediatric patient with Ehlers-Danlos syndrome and","abstract":"PURPOSE/AIM: Ehlers-Danlos syndrome (EDS) is a hereditary connective tissue disease. Epilepsy is not a common neurological finding in EDS. Here we report a pediatric patient with EDS comorbid with <i>STXBP1</i> related epileptic encephalopathy as 'electrical status epilepticus during slow-wave sleep (ESES)' and whose refractory epileptic seizures were controlled with ketogenic diet.\nCASE REPORT: A 6-year-old girl who had EDS presented with refractory seizures and worsening cognitive functions. Her sleep electroencephalography (EEG) revealed electrical status epilepticus during slow-wave sleep (ESES). The epileptic encephalopathy panel revealed a de novo c.560C > T (p.pro187Leu) heterozygous mutation in the <i>STXPB1</i> gene. Ketogenic diet treatment was started for her refractory seizures and seizures stopped in the third month of the 3:1 classical ketogenic diet.\nCONCLUSION: Our case is remarkable due to the coexistence of EDS and epileptic encephalopathy as well as ESES findings in STXBP1-associated epileptic encephalopathy and is therefore presented. Ketogenic diet would be beneficial on the management of refractory seizures in <i>STXBP1-</i>related epileptic encephalopathy and ESES.","variants":[{"Name":"NM_001032221.6(STXBP1):c.560C>T (p.Pro187Leu)","Chromosome":"9","Start":"127663335","Stop":"127663335","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":984340,"rule_based_match":true,"evidence_text":"c.560C > T (p.pro187Leu)","llm_judgment":"PRESENT","evidence":"c.560C > T (p.pro187Leu)","abstract_start":662,"abstract_end":686}]}
{"pmid":"19783390","title":"Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome.","abstract":"Mutations of the gene encoding the alpha2 subunit of the neuronal sodium channel, SCN2A, have been found in benign familial neonatal-infantile seizures (BFNIS). In Dravet syndrome, only one nonsense mutation of SCN2A was identified, while hundreds of mutations were found in the paralogue gene, SCN1A, which encodes the alpha1 subunit. This study examines whether SCN2A mutations are associated with Dravet syndrome. We screened for mutations of SCN1A, SCN2A and GABRG2 (the gene encoding gamma2 subunit of the GABA(A) receptor) in 59 patients with Dravet syndrome and found 29 SCN1A mutations and three missense SCN2A mutations. Among the three, one de novo SCN2A mutation (c.3935G>C: R1312T) identified in a patient was thought to affect an arginine residue in a voltage sensor of the channel and hence, to be pathogenic. This finding suggests that both nonsense mutations and missense SCN2A mutations cause Dravet syndrome.","variants":[{"Name":"NM_001040142.2(SCN2A):c.3935G>C (p.Arg1312Thr)","Chromosome":"2","Start":"165373310","Stop":"165373310","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1784727,"rule_based_match":true,"evidence_text":"c.3935G>C: R1312T","llm_judgment":"PRESENT","evidence":"c.3935G>C: R1312T","abstract_start":675,"abstract_end":692}]}
{"pmid":"30945277","title":"Whole-exome sequencing revealed a nonsense mutation in STKLD1 causing non-syndromic pre-axial polydactyly type A affecting only upper limb.","abstract":"Pre-axial polydactyly (PPD) is characterized by well-developed non-functional 1st digit (thumb) duplication in hands and/or feet. It is mostly inherited in autosomal dominant manner. In the present study, two families of Pakistani origin, demonstrating unilateral PPD type A, have been characterized at clinical and genetic levels. Whole-exome sequencing (WES) revealed a nonsense mutation (c.84C > A, p.Tyr28*) in the STKLD1, located on chromosome 9q34.2, in affected individuals of both the families. Our findings report the first direct involvement of the STKLD1 in the digit development and highlight the importance of inclusion of this gene for screening individuals presenting non-syndromic recessive PPD.","variants":[{"Name":"NM_153710.5(STKLD1):c.84C>A (p.Tyr28Ter)","Chromosome":"9","Start":"133376557","Stop":"133376557","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":653839,"rule_based_match":true,"evidence_text":"c.84C > A, p.Tyr28*","llm_judgment":"PRESENT","evidence":"c.84C > A, p.Tyr28*","abstract_start":391,"abstract_end":410}]}
{"pmid":"32896923","title":"Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families.","abstract":"AIMS: Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN.\nMETHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families.\nRESULTS: The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation.\nCONCLUSIONS: We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.","variants":[{"Name":"NM_000070.3(CAPN3):c.1706T>C (p.Phe569Ser)","Chromosome":"15","Start":"42402963","Stop":"42402963","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":274784,"rule_based_match":true,"evidence_text":"c.1706T> C [p.(Phe569Ser)]","llm_judgment":"PRESENT","evidence":"c.1706T> C [p.(Phe569Ser)]","abstract_start":880,"abstract_end":906},{"Name":"NM_000070.3(CAPN3):c.1327T>C (p.Ser443Pro)","Chromosome":"15","Start":"42399625","Stop":"42399625","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":643172,"rule_based_match":true,"evidence_text":"c.1327T> C [p.(Ser443Pro]","llm_judgment":"PRESENT","evidence":"c.1327T> C [p.(Ser443Pro]","abstract_start":794,"abstract_end":819}]}
{"pmid":"36847845","title":"Biallelic SHQ1 variants in early infantile hypotonia and paroxysmal dystonia as the leading manifestation.","abstract":"Biallelic SHQ1 variant-related neurodevelopmental disorder is extremely rare. To date, only six affected individuals, from four families, have been reported. Here, we report eight individuals, from seven unrelated families, who exhibited neurodevelopmental disorder and/or dystonia, received whole-genome sequencing, and had inherited biallelic SHQ1 variants. The median age at disease onset was 3.5 months old. All eight individuals exhibited normal eye contact, profound hypotonia, paroxysmal dystonia, and brisk deep tendon reflexes at the first visit. Varying degrees of autonomic dysfunction were observed. One individual had cerebellar atrophy at the initial neuroimaging study, however, three individuals showed cerebellar atrophy at follow-up. Seven individuals who underwent cerebral spinal fluid analysis all had a low level of homovanillic acid in neurotransmitter metabolites. Four individuals who received <sup>99m</sup>Tc-TRODAT-1 scan had moderate to severe decreased uptake of dopamine in the striatum. Four novel SHQ1 variants in 16 alleles were identified: 9 alleles (56%) were c.997C > G (p.L333V); 4 (25%) were c.195T > A (p.Y65X); 2 (13%) were c.812T > A (p.V271E); and 1 (6%) was c.146T > C (p.L49S). The four novel SHQ1 variants transfected into human SH-SY5Y neuronal cells resulted in a retardation in neuronal migration, suggestive of SHQ1 variant correlated with neurodevelopmental disorders. During the follow-up period, five individuals still exhibited hypotonia and paroxysmal dystonia; two showed dystonia; and one had hypotonia only. The complex interactions among movement disorders, dopaminergic pathways, and the neuroanatomic circuit needs further study to clarify the roles of the SHQ1 gene and protein in neurodevelopment.","variants":[{"Name":"NM_018130.3(SHQ1):c.997C>G (p.Leu333Val)","Chromosome":"3","Start":"72812734","Stop":"72812734","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2848813,"rule_based_match":true,"evidence_text":"c.997C > G (p.L333V)","llm_judgment":"PRESENT","evidence":"c.997C > G (p.L333V)","abstract_start":1096,"abstract_end":1116}]}
{"pmid":"28559208","title":"Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.","abstract":"Cenani-Lenz syndactyly syndrome (CLSS; MIM-212780) is a rare autosomal recessive limb malformation characterized by complete osseous fusion of all fingers and toes, disorganization of phalangeal elements and severe shortening of the radius and ulna. It is occasionally associated with renal hypoplasia, oro-facial defects, scoliosis of the thoracic spine, hearing loss, and genital anomalies. Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney. The affected individuals were additionally presented with short stature, cleft-lip and hypoplastic shoulder joint with restricted upper limb movement. A novel splice variant in LRP4 (c.316+1G > A) segregated with the phenotype in a five generations family. The mutation is predicted to add 29 non-native amino acids with a premature termination, resulting in approximately 90% length reduction of the wild-type transcript. These findings not only further expand the phenotypic variability of CLSS but also indicate that early truncated and loss-of-function mutations in LRP4 lead to a more severe CLSS phenotype.","variants":[{"Name":"NM_002334.4(LRP4):c.316+1G>A","Chromosome":"11","Start":"46900261","Stop":"46900261","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":420287,"rule_based_match":true,"evidence_text":"c.316+1G > A","llm_judgment":"PRESENT","evidence":"c.316+1G > A","abstract_start":828,"abstract_end":840}]}
{"pmid":"28892570","title":"DNAJC12 and dopa-responsive nonprogressive parkinsonism.","abstract":"Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified DNAJC12 homozygous null variants (c.187A>T;p.K63* and c.79-2A>G;p.V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild nonprogressive, motor symptoms, sustained benefit from small dose of levodopa, and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology, and substantia nigra depigmentation with moderate cell loss. DNAJC12 transcripts were reduced in both patients. Our results suggest that DNAJC12 mutations (absent in 500 early-onset patients with Parkinson's disease) rarely cause dopa-responsive nonprogressive parkinsonism in adulthood, but broaden the clinical spectrum of DNAJC12 deficiency. Ann Neurol 2017;82:640-646.","variants":[{"Name":"NM_021800.3(DNAJC12):c.187A>T (p.Lys63Ter)","Chromosome":"10","Start":"67811634","Stop":"67811634","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":681921,"rule_based_match":true,"evidence_text":"c.187A>T;p.K63*","llm_judgment":"PRESENT","evidence":"c.187A>T;p.K63*","abstract_start":171,"abstract_end":186},{"Name":"NM_021800.3(DNAJC12):c.79-2A>G","Chromosome":"10","Start":"67823394","Stop":"67823394","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":681922,"rule_based_match":true,"evidence_text":"c.79-2A>G","llm_judgment":"PRESENT","evidence":"c.79-2A>G","abstract_start":191,"abstract_end":200}]}
{"pmid":"32487042","title":"Next-generation sequencing-based clinical diagnosis of choroideremia and comprehensive mutational and clinical analyses.","abstract":"BACKGROUND: To report the clinical and genetic findings from seven Chinese patients with choroideremia.\nMETHODS: Five hundred seventy-eight patients with a clinically suspected diagnosis of retinitis pigmentosa (RP) underwent comprehensive ophthalmic examinations. Next-generation sequencing (NGS) was performed on samples from all patients. Detailed clinical characteristics of the patients with choroideremia identified in this study were assessed using multimodal imaging.\nRESULTS: Seven patients with choroideremia were identified, and six novel variants in CHM (c.1960 T > C p.Ter654Gln, c.1257del p.Ile420*fs1, c.1103_1121delATGGCAACACTCCATTTTT p.Tyr368Cysfs35, c.1414-2A > T, and c.1213C > T p.Gln405Ter, c.117-1G > A) were revealed. All variants were deleterious mutations: two were frameshifts, two were nonsense mutations, two were splicing mutations, and one was a readthrough mutation. The clinical phenotypes of these patients were markedly heterogeneous, and they shared many common clinical features with RP, including night blindness, constriction of the visual field and gradually reduced visual acuity. However, patients with choroideremia showed pigment hypertrophy and clumping, and chorioretinal atrophy, and a majority of patients with choroideremia presented with retinal tubulations in the outer layer of the retina.\nCONCLUSIONS: We provide a detailed description of the genotypes and phenotypes of seven patients with choroideremia who were accurately diagnosed using NGS. These findings provide a better understanding of the genetics and phenotypes of choroideremia.","variants":[{"Name":"NM_000390.4(CHM):c.1213C>T (p.Gln405Ter)","Chromosome":"X","Start":"85911292","Stop":"85911292","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360672,"rule_based_match":true,"evidence_text":"c.1213C > T p.Gln405Ter","llm_judgment":"PRESENT","evidence":"c.1213C > T p.Gln405Ter","abstract_start":687,"abstract_end":710},{"Name":"NM_000390.4(CHM):c.1960T>C (p.Ter654Gln)","Chromosome":"X","Start":"85864632","Stop":"85864632","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1691341,"rule_based_match":true,"evidence_text":"c.1960 T > C p.Ter654Gln","llm_judgment":"PRESENT","evidence":"c.1960 T > C p.Ter654Gln","abstract_start":567,"abstract_end":591}]}
{"pmid":"32530348","title":"Unrecognized ROPER in a child with a novel pathogenic variant in ZNF408 gene.","abstract":"BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is a rare hereditary disorder characterized by abnormal or incomplete retinal angiogenesis commonly inherited in an autosomal dominant fashion. Up to 50% of FEVR cases are linked to known genetic mutations affecting retinal vasculature development.\nPURPOSE: To report a case, a novel pathogenic variant of the ZNF408 gene associated with a case of FEVR in a premature male.\nMATERIALS AND METHODS: Case report.\nRESULTS: A 10-month-old male who was born prematurely at 34 weeks' gestation in the Dominican Republic was referred for persistent avascular retina. The baby was treated with bilateral intravitreal ranibizumab injections for retinopathy of prematurity (ROP) with the presence of plus disease. Fundus examination several months after treatment revealed the absence of tortuosity of the vessels with avascular periphery; fluorescein angiography (FA) confirmed peripheral avascularity and demonstrated irregular sprouts of vascularization in the absence of neovascularization. We performed genetic testing under the suspicion of FEVR and results identified a heterozygous mutation in the ZNF408 gene on chromosome 11, c.1307 C > T.\nCONCLUSION: FEVR is an important differential diagnosis in premature infants with retinopathy, as clinical presentation can overlap with common findings in ROP. Maintaining high suspicion for the disease is especially critical in cases with findings unusual for ROP. FEVR in the presence of prematurity has been well described, falling under the proposed term ROPER. Genetic testing is key to confirm diagnosis.","variants":[{"Name":"NM_024741.3(ZNF408):c.1307C>T (p.Pro436Leu)","Chromosome":"11","Start":"46705007","Stop":"46705007","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":838464,"rule_based_match":true,"evidence_text":"c.1307 C > T","llm_judgment":"PRESENT","evidence":"c.1307 C > T","abstract_start":1181,"abstract_end":1193}]}
{"pmid":"33995405","title":"Case Report: Activating","abstract":"Activated phosphoinositide 3-kinase δ syndrome (APDS) is an autosomal dominant primary immunodeficiency caused by gain-of-function (GOF) mutations in <i>PIK3CD</i> or <i>PIK3R1</i> genes. The phenotypes of APDS are highly variable, ranging from asymptomatic adults to profound immunodeficiency causing early death in childhood. Herein, we reported two pediatric patients with APDS presented with recurrent lung infections, sinusitis, hematuria, and positive anti-neutrophil cytoplasmic antibody (ANCA), previously diagnosed as granulomatosis with polyangiitis (GPA). Bronchoscopy showed mucosal nodule lymphoid hyperplasia in the entire airway. Many inflammatory cells infiltrated around the airway and in the lung parenchyma, and numbers of CD3<sup>+</sup> T cells and CD20<sup>+</sup> B cells were significantly increased, especially CD3+ T cells. Whole exome sequencing showed that they had the E1021K (c.3061 G >A) mutation in the <i>PIK3CD</i> gene. These are the first reported cases of APDS presenting as childhood-onset GPA. Pediatricians should suspect of APDS in the differential diagnosis of children who present with GPA-like symptoms. Additionally, timely and repeated bronchoscopies could contribute to providing an important diagnostic clue for APDS.","variants":[{"Name":"NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)","Chromosome":"1","Start":"9726972","Stop":"9726972","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":94255,"rule_based_match":true,"evidence_text":"c.3061 G >A","llm_judgment":"PRESENT","evidence":"c.3061 G >A","abstract_start":906,"abstract_end":917}]}
{"pmid":"28539120","title":"Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability.","abstract":"BACKGROUND: Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients.\nMETHODS: We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches.\nRESULTS: We verified de novo pathogenic single nucleotide variants (SNV) in ARID1B c.1595delG and PHF6 c.820C > T, potentially causative de novo two base indels in SQSTM1 c.115_116delinsTA and UPF1 c.1576_1577delinsA, and de novo SNVs in CACNB3 c.1289G > A, and SPRY4 c.508 T > A, of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including de novo genome assembly. We confirmed a likely contributory 165 kb de novo heterozygous 1q43 microdeletion missed by clinical microarray. The de novo assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation.\nCONCLUSION: This study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses.","variants":[{"Name":"NM_001015877.2(PHF6):c.820C>T (p.Arg274Ter)","Chromosome":"X","Start":"134415106","Stop":"134415106","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":512591,"rule_based_match":true,"evidence_text":"PHF6 c.820C > T","llm_judgment":"PRESENT","evidence":"PHF6 c.820C > T","abstract_start":581,"abstract_end":596}]}
{"pmid":"31750346","title":"Child with Wiskott-Aldrich syndrome underwent atypical immune reconstruction after umbilical cord blood transplantation: A case report.","abstract":"BACKGROUND: Timely reconstitution of a donor-derived immune system is important for recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a case of Wiskott-Aldrich syndrome (WAS) treated by umbilical cord blood transplantation (UCBT) with atypical immune reconstruction.\nCASE SUMMARY: A 1-year-old Chinese male infant was diagnosed with WAS. WAS gene sequencing identified the mutation c.777 + 1G>A (IVS8). On August 8, 2017, he was admitted to our hospital for HSCT. We selected an unrelated Human leukocyte antigen 6/10-matched donor for UCBT. After HSCT, the immune reconstitution process was atypical, the lymphocytes reached 0.5 × 10<sup>9</sup>/L on day 23, and the neutrophils reached 0.5 × 10<sup>9</sup>/L on day 34. The patient's recovery throughout the year was good.\nCONCLUSION: An increase in lymphocytes (especially T cells) earlier than granulocytes may be a marker of a good prognosis in UCBT.","variants":[{"Name":"NM_000377.3(WAS):c.777+1G>A","Chromosome":"X","Start":"48688097","Stop":"48688097","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360647,"rule_based_match":true,"evidence_text":"c.777 + 1G>A (IVS8)","llm_judgment":"PRESENT","evidence":"c.777 + 1G>A (IVS8)","abstract_start":453,"abstract_end":472}]}
{"pmid":"28777935","title":"De Novo Mutations in YWHAG Cause Early-Onset Epilepsy.","abstract":"Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3γ) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n = 1) and YWHAG (n = 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.","variants":[{"Name":"NM_004171.4(SLC1A2):c.244G>A (p.Gly82Arg)","Chromosome":"11","Start":"35315089","Stop":"35315089","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":432363,"rule_based_match":true,"evidence_text":"c.244G>A [p.Gly82Arg]","llm_judgment":"PRESENT","evidence":"c.244G>A [p.Gly82Arg]","abstract_start":769,"abstract_end":790},{"Name":"NM_012479.4(YWHAG):c.394C>T (p.Arg132Cys)","Chromosome":"7","Start":"76329927","Stop":"76329927","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432435,"rule_based_match":true,"evidence_text":"c.394C>T [p.Arg132Cys]","llm_judgment":"PRESENT","evidence":"c.394C>T [p.Arg132Cys]","abstract_start":817,"abstract_end":839}]}
{"pmid":"29271547","title":"Cis variants identified in F508del complex alleles modulate CFTR channel rescue by small molecules.","abstract":"Molecules correcting the trafficking (correctors) and gating defects (potentiators) of the cystic fibrosis causing mutation c.1521_1523delCTT (p.Phe508del) begin to be a useful treatment for CF patients bearing p.Phe508del. This mutation has been identified in different genetic contexts, alone or in combination with variants in cis. Until now, 21 exonic variants in cis of p.Phe508del have been identified, albeit at a low frequency. The aim of this study was to evaluate their impact on the efficacy of CFTR-directed corrector/potentiator therapy (Orkambi). The analysis by minigene showed that two out of 15 cis variants tested increased exon skipping (c.609C > T and c.2770G > A). Four cis variants were studied functionally in the absence of p.Phe508del, one of which was found to be deleterious for protein maturation c.1399C > T (p.Leu467Phe). In the presence of p.Phe508del, this variant was the only to prevent the response to Orkambi treatment. This study showed that some patients carrying p.Phe508del complex alleles are predicted to poorly respond to corrector/potentiator treatments. Our results underline the importance to validate treatment efficacy in the context of complex alleles.","variants":[{"Name":"NM_000492.4(CFTR):c.609C>T (p.Ile203=)","Chromosome":"7","Start":"117535277","Stop":"117535277","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":965216,"rule_based_match":true,"evidence_text":"c.609C > T","llm_judgment":"PRESENT","evidence":"c.609C > T","abstract_start":657,"abstract_end":667},{"Name":"NM_000492.4(CFTR):c.2770G>A (p.Asp924Asn)","Chromosome":"7","Start":"117603644","Stop":"117603644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":68233,"rule_based_match":true,"evidence_text":"c.2770G > A","llm_judgment":"PRESENT","evidence":"c.2770G > A","abstract_start":672,"abstract_end":683},{"Name":"NM_000492.4(CFTR):c.1399C>T (p.Leu467Phe)","Chromosome":"7","Start":"117559470","Stop":"117559470","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67914,"rule_based_match":true,"evidence_text":"c.1399C > T (p.Leu467Phe)","llm_judgment":"PRESENT","evidence":"c.1399C > T (p.Leu467Phe)","abstract_start":825,"abstract_end":850}]}
{"pmid":"22825683","title":"Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma.","abstract":"Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumour suppressor gene are common in sporadic conventional (clear cell) renal cell carcinoma (ccRCC). The effects on VHL expression are unknown but increased understanding may be relevant clinically, either in terms of prognosis or in therapy selection. We have examined the expression of VHL mutant RNA in 84 ccRCC tumours previously screened for mutations in genomic DNA, 56 of which contained 52 unique mutations or polymorphisms. Based on the predicted change to the primary amino acid sequence, 24 of the mutations were missense, 11 resulted in frameshifts with premature truncation, 9 resulted in immediate truncation at the site of the mutation and 2 were frameshifts which extended the reading frame beyond the normal stop codon. Nine tumours had intronic variants, including substitution of invariant residues at splice sites, deletion of nucleotides spanning the exon-intron junction, an intronic variant of unknown function and the polymorphism c.463+43A>G. Four variants were identified which were present in genomic DNA but not in mRNA. Three of these, all encoding apparent missense changes to the primary amino acid sequence, were located close to the ends of exons, reduced the strength of the splice site and function as null rather than missense variants. One nonsense variant was not detectable in mRNA but all other mutations resulting in premature truncation codons (PTCs) were, suggesting truncating VHL mutations may potentially generate truncated VHL protein. An intronic variant, c.341‑11T>A, previously regarded as of unknown function, is associated with an increased level of skipping of exon 2 and may, therefore, reduce production of pVHL. Our data show that the biological consequences of VHL mutations are not necessarily predictable from the sequence change of the mutation and that for the majority of VHL mutations, the potential for the generation of mutant protein exists.","variants":[{"Name":"NM_000551.4(VHL):c.341-11T>A","Chromosome":"3","Start":"10146503","Stop":"10146503","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1471555,"rule_based_match":false,"evidence_text":"c.341‑11T>A","llm_judgment":"PRESENT","evidence":"c.341‑11T>A","abstract_start":1567,"abstract_end":1578}]}
{"pmid":"23810382","title":"Mutations in PIK3R1 cause SHORT syndrome.","abstract":"SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs*18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657*]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.","variants":[{"Name":"NM_181523.3(PIK3R1):c.1945C>T (p.Arg649Trp)","Chromosome":"5","Start":"68296301","Stop":"68296301","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75301,"rule_based_match":true,"evidence_text":"c.1945C>T (p.Arg649Trp)","llm_judgment":"PRESENT","evidence":"c.1945C>T (p.Arg649Trp)","abstract_start":777,"abstract_end":800},{"Name":"NM_181523.3(PIK3R1):c.1906_1907insC (p.Asn636fs)","Chromosome":"5","Start":"68296262","Stop":"68296263","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":75303,"rule_based_match":true,"evidence_text":"c.1906_1907insC (p.Asn636Thrfs*18)","llm_judgment":"PRESENT","evidence":"c.1906_1907insC (p.Asn636Thrfs*18)","abstract_start":527,"abstract_end":561}]}
{"pmid":"28389991","title":"Genotype-phenotype correlation in 18 Egyptian patients with glutaric acidemia type I.","abstract":"Glutaric acidemia I (GAI) is an autosomal recessive metabolic disease caused by a deficiency of glutaryl-CoA dehydrogenase enzyme (GCDH). Patients with GAI are characterized by macrocephaly, acute encephalitis-like crises, dystonia and frontotemporal atrophy. In this study, we investigated 18 Egyptian patients that were diagnosed with GAI based on their clinical, neuroradiological, and biochemical profiles. Of the 18 patients, 16 had developmental delay and/or regression, dystonia was prominent in 75% of the cases, and three patients died. Molecular genetics analysis identified 14 different mutations in the GCDH gene in the 18 patients, of the 14 mutations, nine were missense, three were in the 3'-Untranslated Region (3'-UTR), one was nonsense, and one was a silent mutation. Four novel mutations were identified (c.148 T > A; p.Trp50Arg, c.158C > A; p.Pro53Gln, c.1284C > G; p.Ile428Met, and c.1189G > T; p.Glu397*) that were all absent in 300 normal chromosomes. The 3'-UTR mutation (c.*165A > G; rs8012), was the most frequent mutation observed (0.5; 18/36), followed by the most common mutation among Caucasian patients (p.Arg402Trp; rs121434369) with allele frequency of 0.36 (13/36), and the 3'-UTR mutation (c.*288G > T; rs9384, 0.22; 8/16). The p.Arg257Gln mutation was found with allele frequency of ~0.17 (6/36). The marked homozygosity observed in our patients is probably due to the high level of consanguinity that is observed in 100% of the cases. We used nine in silico prediction tools to predict the pathogenicity (SIFT, PhD-SNP, SNAP, Meta-SNP, PolyPhen2, and Align GVGD) and protein stability (I-Mutant2.0, Mupro, and istable) of the nine missense mutants. The mutant p.Arg402Trp was predicted to be most deleterious by all the six pathogenicity prediction tools and destabilizing by all the three-stability prediction tools, and highly conserved by the ConSurf server. Using the clinical, biochemical, family history of the 18 patients, and the in silico analysis of the missense mutations, our study showed a mix of conclusive and inconclusive genotype-phenotype correlations among our patient's cohort and suggests the usefulness of using various sophisticated computational analysis to be utilized for future variant classifications in the genetic clinics.","variants":[{"Name":"NM_000159.4(GCDH):c.770G>A (p.Arg257Gln)","Chromosome":"19","Start":"12896339","Stop":"12896339","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":533136,"rule_based_match":false,"evidence_text":"c.770G>A (p.Arg257Gln)","llm_judgment":"PRESENT","evidence":"p.Arg257Gln","abstract_start":1263,"abstract_end":1274}]}
{"pmid":"25232504","title":"Concomitant a novel ALAS2 mutation and GATA1 mutation in a newborn: a case report and review of the literature.","abstract":"GATA-1, an X-linked gene, encodes a transcription factor that plays a role in erythropoiesis and megakaryopoiesis. GATA-1 mutations have been associated with various diseases, such as X-linked thrombocytopenia. ALAS2 is an X-linked erythroid-specific isoenzyme expressed during erythropoiesis. Mutations of ALAS2 were associated with X-linked sideroblastic anemia. We report a case of newborn twin boy with anemia and thrombocytopenia at birth. A bone marrow biopsy at 4 months of age showed marked dyserythropoiesis, dysmegakaryopoiesis, and rare ringed sideroblasts. Gene sequencing study showed a previously reported mutation in GATA-1 at c.622G>A location (G208R) and a novel ALAS2 mutation at c.1436G>A location (R479Q).","variants":[{"Name":"NM_002049.4(GATA1):c.622G>A (p.Gly208Arg)","Chromosome":"X","Start":"48792346","Stop":"48792346","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360619,"rule_based_match":true,"evidence_text":"c.622G>A","llm_judgment":"PRESENT","evidence":"c.622G>A","abstract_start":642,"abstract_end":650}]}
{"pmid":"25407000","title":"A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome.","abstract":"Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by marked dilatation of the bladder and microcolon and decreased intestinal peristalsis. Recent studies indicate that heterozygous variants in ACTG2, which codes for a smooth muscle actin, cause MMIHS. However, such variants do not explain MMIHS cases that show an autosomal recessive mode of inheritance. We performed exome sequencing in a newborn with MMIHS and prune belly phenotype whose parents are consanguineous and identified a homozygous variant (c.3598A>T: p.Lys1200Ter) in MYH11, which codes for the smooth muscle myosin heavy chain. Previous studies showed that loss of Myh11 function in mice causes a bladder and intestinal phenotype that is highly reminiscent of MMIHS. All together, these observations strongly suggest that loss-of-function variants in MYH11 cause MMIHS. The documentation of variants in ACTG2 and MYH11 thus points to the involvement of the contractile apparatus of the smooth muscle in MMIHS. Interestingly, dominant-negative variants in MYH11 have previously been shown to cause thoracic aortic aneurism and dilatation. Different mechanisms of MYH11 disruption may thus lead to distinct patterns of smooth muscle dysfunction.","variants":[{"Name":"NM_002474.3(MYH11):c.3598A>T (p.Lys1200Ter)","Chromosome":"16","Start":"15732617","Stop":"15732617","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":166181,"rule_based_match":true,"evidence_text":"c.3598A>T: p.Lys1200Ter","llm_judgment":"PRESENT","evidence":"c.3598A>T: p.Lys1200Ter","abstract_start":539,"abstract_end":562}]}
{"pmid":"36338669","title":"Autosomal dominant retinitis pigmentosa with incomplete penetrance due to an intronic mutation of the","abstract":"Purpose: To identify the molecular mechanisms of the development of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance in an Israeli Muslim Arab family.\nMethods: Two patients with adRP underwent a detailed ophthalmic evaluation, including funduscopic examination, visual field testing, optical coherence tomography, and electroretinography. Genetic analysis was performed using a combination of whole exome sequencing (WES) and Sanger sequencing. The pathogenicity of the identified intronic variant was evaluated in silico using several web-based tools, in vitro using a minigene-based assay, and in vivo using reverse transcription PCR analysis of lymphocyte-derived RNA. The relative abundance of alternatively spliced transcripts was evaluated using amplicon-based next-generation sequencing. The relative expression levels of <i>PRPF31</i> and <i>CNOT3</i> were measured using quantitative PCR (qPCR) analysis.\nResults: The two patients recruited in this study had childhood-onset RP, with night blindness as the initial symptom, followed by concentric restriction of the visual field. The funduscopic findings included narrowed retinal blood vessels and peripheral bone spicule pigmentation. By the third decade of life, the full-field electroretinography findings had been remarkably attenuated. In these patients, we identified a novel heterozygous intronic variant at position +5 of <i>PRPF31</i> intron 11 (c.1146+5G>T). The same variant was also detected in one asymptomatic family member. Through in silico analysis, the variant was predicted to alter the splicing of intron 11. An in vitro splicing assay and a reverse transcription PCR analysis of lymphocyte-derived RNA revealed that the mutant allele yielded mainly a shorter transcript in which exon 11 was skipped. The skipping of exon 11 was expected to cause a frameshift and an aberrant truncated protein (p.Tyr359Ser<i>fs</i>*29). The qPCR analysis revealed reduced <i>PRPF31</i> expression levels in the mutation carriers, without a significant difference between the affected patient and his asymptomatic brother. We evaluated several factors that have been suggested to correlate with non-penetrance of <i>PRPF31</i> mutations, including the number of cis-acting MSR1 elements adjacent to the <i>PRPF31</i> core promoter, <i>CNOT3</i> expression level, and <i>CNOT3</i> rs4806718 single-nucleotide polymorphism. None of these factors correlated with non-penetrance in the family in this study.\nConclusions: We report a novel intronic mutation in <i>PRPF31</i> underlying adRP. This report expands the spectrum of pathogenic mutations in <i>PRPF31</i> and further demonstrates the importance of intronic mutations. Moreover, it demonstrates the phenomenon of incomplete penetrance previously associated with <i>PRPF31</i> mutations. The fact that the non-penetrance in the family in this study could not be explained by any of the known mechanisms suggests the possible contribution of a novel modifier of <i>PRPF31</i> penetrance.","variants":[{"Name":"NM_015629.4(PRPF31):c.1146+5G>T","Chromosome":"19","Start":"54128382","Stop":"54128382","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3407579,"rule_based_match":true,"evidence_text":"c.1146+5G>T","llm_judgment":"PRESENT","evidence":"c.1146+5G>T","abstract_start":1440,"abstract_end":1451}]}
{"pmid":"22462637","title":"A mutation at IVS1 + 5 of the von Hippel-Lindau gene resulting in intron retention in transcripts is not pathogenic in a patient with a tongue cancer?: case report.","abstract":"BACKGROUND: Von Hippel-Lindau disease (VHL) is a dominantly inherited familial cancer syndrome predisposing the patient to a variety of malignant and benign neoplasms, most frequently hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumors. VHL is caused by mutations of the VHL tumor suppressor gene on the short arm of chromosome 3, and clinical manifestations develop if both alleles are inactivated according to the two-hit hypothesis. VHL mutations are more frequent in the coding region and occur occasionally in the splicing region of the gene. Previously, we reported that the loss of heterozygosity (LOH) of the VHL gene is common in squamous cell carcinoma tissues of the tongue.\nCASE PRESENTATION: We describe a case of squamous cell carcinoma in the tongue caused by a point mutation in the splicing region of the VHL gene and discuss its association with VHL disease. Sequence analysis of DNA extracted from the tumor and peripheral blood of the patient with squamous cell carcinoma revealed a heterozygous germline mutation (c. 340 + 5 G > C) in the splice donor sequence in intron 1 of the VHL gene. RT-PCR analysis of the exon1/intron1 junction in RNA from tumor tissue detected an unspliced transcript. Analysis of LOH using a marker with a heterozygous mutation of nucleotides (G or C) revealed a deletion of the mutant C allele in the carcinoma tissues.\nCONCLUSIONS: The fifth nucleotide G of the splice donor site of the VHL gene is important for the efficiency of splicing at that site. The development of tongue cancer in this patient was not associated with VHL disease because the mutation occurred in only a single allele of the VHL gene and that allele was deleted in tumor cells.","variants":[{"Name":"NM_000551.4(VHL):c.340+5G>C","Chromosome":"3","Start":"10142192","Stop":"10142192","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":45562,"rule_based_match":true,"evidence_text":"c. 340 + 5 G > C","llm_judgment":"PRESENT","evidence":"c. 340 + 5 G > C","abstract_start":1063,"abstract_end":1079}]}
{"pmid":"15508018","title":"Mutation in the 5' alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.","abstract":"The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley-Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21-Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation. The combination of the clinical phenotype, consistent with that of the patients with ATR-X syndrome, the skewed X-inactivation pattern in a carrier female, as well as the mapping interval including band Xq13.3, prompted us to consider the XNP/ATR-X gene being involved in this syndrome. Using RT-PCR analysis, we screened the entire XNP/ATR-X gene and found a mutation in exon 2 (c.109C > T) giving rise to a stop codon at position 37 (p.R37X). Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against XNP/ATR-X showed the protein to be present in lymphoblastoid cells from one affected male, despite the premature stop codon. To explain these discordant results, we further analyzed the 5' region of the XNP/ATR-X gene and found three alternative transcripts, which differ in the presence or absence of exon 2, and the length of exon 1. Our data suggest that ChLS is allelic to the ATR-X syndrome with its less severe phenotype being due to the presence of some XNP/ATR-X protein.","variants":[{"Name":"NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)","Chromosome":"X","Start":"77717155","Stop":"77717155","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26781,"rule_based_match":true,"evidence_text":"c.109C > T","llm_judgment":"PRESENT","evidence":"c.109C > T","abstract_start":934,"abstract_end":944}]}
{"pmid":"26637980","title":"De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.","abstract":"Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.","variants":[{"Name":"NM_015895.5(GMNN):c.16A>T (p.Lys6Ter)","Chromosome":"6","Start":"24777262","Stop":"24777262","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":200397,"rule_based_match":true,"evidence_text":"c.16A>T (p.Lys6(∗))","llm_judgment":"PRESENT","evidence":"c.16A>T (p.Lys6(∗))","abstract_start":734,"abstract_end":753},{"Name":"NM_015895.5(GMNN):c.35_38del (p.Ile12fs)","Chromosome":"6","Start":"24777279","Stop":"24777282","ReferenceAlleleVCF":"AAATC","AlternateAlleleVCF":"A","allel_id":200398,"rule_based_match":true,"evidence_text":"c.35_38delTCAA (p.Ile12Lysfs(∗)4)","llm_judgment":"PRESENT","evidence":"c.35_38delTCAA (p.Ile12Lysfs(∗)4)","abstract_start":758,"abstract_end":791},{"Name":"NM_015895.5(GMNN):c.50A>G (p.Lys17Arg)","Chromosome":"6","Start":"24777296","Stop":"24777296","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":200399,"rule_based_match":true,"evidence_text":"c.50A>G (p.Lys17Arg)","llm_judgment":"PRESENT","evidence":"c.50A>G (p.Lys17Arg)","abstract_start":820,"abstract_end":840}]}
{"pmid":"22162627","title":"Ocular phenotypes associated with biallelic mutations in BEST1 in Italian patients.","abstract":"PURPOSE: To report on the phenotype and the genotype of Italian patients carrying BEST1 mutations on both alleles.\nMETHODS: Five Italian patients from four independent pedigrees with retinal dystrophy associated with biallelic BEST1 variants were recruited from different parts of Italy. Molecular genetic analysis of the BEST1 gene was performed with direct sequencing techniques. All the subjects included in the study were clinically evaluated with a standard ophthalmologic examination, fundus photography, optical coherence tomography scan, and electrophysiological investigations.\nRESULTS: Six BEST1 variants were identified. Three, c.1699del (p.Glu557AsnfsX52), c.625delAAC (p.Asn179del), and c.139C>T (p.Arg47Cys), were novel, and three had already been reported in the literature, c.301C>A(p.Pro101Thr), c.934G>A (p.Asp312Asn), and c.638A>G (p.Glu213Gly). Four were missense mutations, and two were deletions. Only one BEST1 mutation was located within one of the four mutational clusters described in typical autosomal dominant Best vitelliform macular dystrophy (BVMD). Four patients showed a BVMD phenotype while one patient presented a clinical picture consistent with autosomal recessive bestrophinopathy (ARB).\nCONCLUSIONS: Biallelic BEST1 sequence variants can be associated with at least two different phenotypes: BVMD and ARB. The phenotypic result of the molecular changes probably depends on the characteristics and the combination of the different BEST1 mutations, but unknown modifying factors such as other genes or the environment may also play a role.","variants":[{"Name":"NM_004183.4(BEST1):c.301C>A (p.Pro101Thr)","Chromosome":"11","Start":"61955771","Stop":"61955771","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":105599,"rule_based_match":true,"evidence_text":"c.301C>A(p.Pro101Thr)","llm_judgment":"PRESENT","evidence":"c.301C>A(p.Pro101Thr)","abstract_start":790,"abstract_end":811},{"Name":"NM_004183.4(BEST1):c.638A>G (p.Glu213Gly)","Chromosome":"11","Start":"61957388","Stop":"61957388","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":994591,"rule_based_match":true,"evidence_text":"c.638A>G (p.Glu213Gly)","llm_judgment":"PRESENT","evidence":"c.638A>G (p.Glu213Gly)","abstract_start":841,"abstract_end":863},{"Name":"NM_004183.4(BEST1):c.934G>A (p.Asp312Asn)","Chromosome":"11","Start":"61959564","Stop":"61959564","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":105675,"rule_based_match":true,"evidence_text":"c.934G>A (p.Asp312Asn)","llm_judgment":"PRESENT","evidence":"c.934G>A (p.Asp312Asn)","abstract_start":813,"abstract_end":835},{"Name":"NM_004183.4(BEST1):c.139C>T (p.Arg47Cys)","Chromosome":"11","Start":"61951945","Stop":"61951945","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":327135,"rule_based_match":true,"evidence_text":"c.139C>T (p.Arg47Cys)","llm_judgment":"PRESENT","evidence":"c.139C>T (p.Arg47Cys)","abstract_start":700,"abstract_end":721}]}
{"pmid":"34324844","title":"Two novel mutations of the LPL gene in two Chinese family cases with familial chylomicronemia syndrome.","abstract":"The aim of this study was to investigate the clinical features and genetic causes of two family cases with familial chylomicronemia syndrome (FCS). Clinical manifestations of proband 1 and her families, and also proband 2 showed severe hypertriglyceridemia, especially the triglycerides levels of two probands were extremely high. Gene sequencing results showed that the LPL genes in each of the two probands had a new mutation site. For the proband 1, a compound heterozygous mutation at c.429 (c.429 + 1G > T) was detected in the LPL gene, which was splicing mutation and inherited from her mother. Homozygous mutation was detected in the LPL gene of proband 2, the nucleotide mutation at c.802 (c.802C > T) exhibited missense mutation, his parents and brother had a heterozygous mutation at the same site. It was confirmed that the conservative lipoprotein lipase superfamily domain changed an amino acid from histidine to tyrosine at p. 268 (p. His268Tyr). Flow cytometry confirmed the deficient expression of LPL protein in two families. These results indicated that the mutation in LPL gene might be the cause of familial chylomicronemia syndrome.","variants":[{"Name":"NM_000237.3(LPL):c.802C>T (p.His268Tyr)","Chromosome":"8","Start":"19955867","Stop":"19955867","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3410340,"rule_based_match":true,"evidence_text":"c.802C>T (p.His268Tyr)","llm_judgment":"PRESENT","evidence":"p. His268Tyr","abstract_start":946,"abstract_end":958}]}
{"pmid":"30006057","title":"Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency.","abstract":"BACKGROUND/AIM: Primary ovarian insufficiency (POI) is characterized by primary or secondary amenorrhea, infertility, low estradiol levels, and increased gonadotropin levels. Most cases of POI remain unsolved even after exhaustive investigation. Here, we performed a targeted massively parallel sequencing to identify the genetic diagnosis of primary ovarian insufficiency (POI) in a Brazilian patient.\nPATIENT AND METHODS: An adopted 21-year-old Brazilian woman with isolated POI was selected. A custom SureSelect<sup>XT</sup> DNA target enrichment panel was designed and sequenced on an Illumina NextSeq 500 sequencer. The variants were confirmed using Sanger sequencing.\nRESULTS: Two rare heterozygous pathogenic variants in the STAG3 gene were identified in our patient. An unpublished 1-bp duplication c.291dupC (p.Asn98Glnfs*2) and one stop codon variant c.1950C > A (p.Tyr650*) were identified in the STAG3 gene. Both undescribed heterozygous variants were absent in the public databases [1000Genomes, Exome Aggregation Consortium (ExAC), National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI/EVS), database of Single Nucleotide Polymorphisms (dbSNP), Genome Aggregation Database (gnomAD)], and Online Archive of Brazilian Mutations (ABraOM) databases. Moreover, neither heterozygous variants were found in 400 alleles from fertile Brazilian women screened by Sanger sequencing. The parents' DNA was not available to segregate these variants.\nCONCLUSION: Our results suggested that POI is caused by pathogenic compound heterozygous variants in the STAG3 gene, supporting the key role of the STAG3 gene in the etiology of primary ovarian insufficiency.","variants":[{"Name":"NM_001282717.2(STAG3):c.291dup (p.Asn98fs)","Chromosome":"7","Start":"100182792","Stop":"100182793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":1319609,"rule_based_match":true,"evidence_text":"c.291dupC (p.Asn98Glnfs*2)","llm_judgment":"PRESENT","evidence":"c.291dupC (p.Asn98Glnfs*2)","abstract_start":807,"abstract_end":833},{"Name":"NM_001282717.2(STAG3):c.1950C>A (p.Tyr650Ter)","Chromosome":"7","Start":"100200858","Stop":"100200858","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1319610,"rule_based_match":true,"evidence_text":"c.1950C > A (p.Tyr650*)","llm_judgment":"PRESENT","evidence":"c.1950C > A (p.Tyr650*)","abstract_start":861,"abstract_end":884}]}
{"pmid":"26964041","title":"De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa.","abstract":"BACKGROUND: Retinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein-altering DNA variants by exome sequencing is a powerful tool for novel variant and disease gene discovery. In this study, exome sequencing analysis was used to search for potentially causal DNA variants in a two-generation pedigree with apparent dominant retinitis pigmentosa.\nMETHODS: Variant identification and analysis of three affected members (mother and two affected offspring) was performed via exome sequencing. Parental samples of the index case were used to establish inheritance. Follow-up testing of 94 additional retinitis pigmentosa pedigrees was performed via retrospective analysis or Sanger sequencing.\nRESULTS AND CONCLUSIONS: A total of 136 high quality coding variants in 123 genes were identified which are consistent with autosomal dominant disease. Of these, one of the strongest genetic and functional candidates is a c.269A>G (p.Tyr90Cys) variant in ARL3. Follow-up testing established that this variant occurred de novo in the index case. No additional putative causal variants in ARL3 were identified in the follow-up cohort, suggesting that if ARL3 variants can cause adRP it is an extremely rare phenomenon.","variants":[{"Name":"NM_004311.4(ARL3):c.269A>G (p.Tyr90Cys)","Chromosome":"10","Start":"102689939","Stop":"102689939","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":578642,"rule_based_match":true,"evidence_text":"c.269A>G (p.Tyr90Cys)","llm_judgment":"PRESENT","evidence":"c.269A>G (p.Tyr90Cys)","abstract_start":1005,"abstract_end":1026}]}
{"pmid":"28385331","title":"Generalized verrucosis and abnormal T cell activation due to homozygous TAOK2 mutation.","abstract":"BACKGROUND: Generalized verrucosis (GV) is a chronic and progressive cutaneous human papillomavirus (HPV) infection resulting in multiple warts and associated with acquired or genetic immune defects. We identified a consanguineous Arab family manifesting GV and recurrent bacterial and viral infections, in association with inflammatory bowel disease (IBD).\nOBJECTIVE: To identify the mutated gene responsible for GV, recurrent infections and IBD, in this family.\nMETHODS: Flow cytometry of peripheral blood mononuclear cells was performed, as well as proliferation and cell cycle assays of T cells. Whole exome sequencing was utilized to detect candidate mutated genes, assuming an autosomal recessive mode of inheritance. Skin fibroblasts from a patient, the mother and control were incubated with sorbitol to detect the phosphorylation ability of TAOK2, and a clonogenic assay was performed to assess the survival and proliferative capacity of fibroblasts' colonies.\nRESULTS: Despite normal immunophenotyping of T and B cells, T cell proliferation upon activation was impaired in a patient compared to a heterozygous family member and a control. Genetic analyses identified a rare homozygous missense variant, c.2098C>T (p.R700C) in the TAOK2 gene, segregating with the disease phenotype in the family. TAOK2 encodes the TAO2 kinase, a mitogen activated protein kinase kinase kinase (MAP3K) in the p38-MAPK cascade. The mutation is predicted to disrupt its normal folding and molecular interaction; however, no impairment was observed in TAOK2 kinase activity toward its downstream target, MEK3/6, in patient's fibroblasts. Despite this normal kinase activity, a noticeably higher survival/proliferation of patient's skin fibroblasts was found.\nCONCLUSIONS: A mutation in TAOK2 appears to cause a novel form of primary immunodeficiency, characterized by an impaired T cell proliferation upon activation. This novel cause of GV gives further support to the importance of the p38-MAPK pathway in the immune response against HPV, and possibly also in the pathogenesis of IBD.","variants":[{"Name":"NM_016151.4(TAOK2):c.2098C>T (p.Arg700Cys)","Chromosome":"16","Start":"29986370","Stop":"29986370","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1353207,"rule_based_match":true,"evidence_text":"c.2098C>T (p.R700C)","llm_judgment":"PRESENT","evidence":"c.2098C>T (p.R700C)","abstract_start":1213,"abstract_end":1232}]}
{"pmid":"29521951","title":"Metastatic Pancreatic Adenocarcinoma in a Patient With Chronic Calcific Pancreatitis and a Heterozygous SPINK1 c.194+2T>C Mutation.","abstract":"","variants":[{"Name":"NM_001379610.1(SPINK1):c.194+2T>C","Chromosome":"5","Start":"147828020","Stop":"147828020","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":136364,"rule_based_match":true,"evidence_text":"SPINK1 c.194+2T>C","llm_judgment":"PRESENT","evidence":"SPINK1 c.194+2T>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"38009286","title":"Clinical and genetic analysis of infants with pontocerebellar hypoplasia type 6 caused by RARS2 variations.","abstract":"OBJECTIVE: Defects in RARS2 cause cerebellopontine hypoplasia type 6 (pontocerebellar hypoplasia type 6, PCH6, OMIM: #611523), a rare autosomal recessive inherited mitochondrial disease. Here, we report two male patients and their respective family histories.\nMETHODS: We describe the clinical presentation and magnetic resonance imaging (MRI) findings of these patients. Whole-exome sequencing was used to identify the genetic mutations.\nRESULTS: One patient showed hypoglycemia, high lactic acid levels (fluctuating from 6.7 to 14.1 mmol/L), and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and pons. The other patient presented with early infantile developmental and epileptic encephalopathies (EIDEEs) with an initial developmental delay followed by infantile epileptic spasm syndrome (IESS) at 5 months old, with no imaging changes. Whole-exome sequencing identified compound heterozygous RARS2 variants c.25A>G (p.I9V) with c.1261C>T (p.Q421*) and c.1A>G (p.M1V) with c.122A>G (p.D41G) in these two patients. Of these loci, c.1261C>T and c.122A>G have not been previously reported.\nSIGNIFICANCE: Our findings have expanded the RARS2 gene variant spectrum and present EIDEEs and IESS as phenotypes which deepened the association between PCH6 and RARS2.\nPLAIN LANGUAGE SUMMARY: Defects in RARS2 cause cerebellopontine hypoplasia type 6, a rare autosomal recessive inherited mitochondrial disease. Two patients with RARS2 variants were reported in this article. One patient showed hypoglycemia, high lactic acid levels, and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and Page 3 of 21 Epilepsia OpenFor Review Only pons. The other patient presented with an initial developmental delay followed by refractory epilepsy at 5 months old, with no imaging changes. Our findings deepened the association between PCH6 and RARS2.","variants":[{"Name":"NM_020320.5(RARS2):c.1A>G (p.Met1Val)","Chromosome":"6","Start":"87589957","Stop":"87589957","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":226903,"rule_based_match":true,"evidence_text":"c.1A>G (p.M1V)","llm_judgment":"PRESENT","evidence":"c.1A>G (p.M1V)","abstract_start":994,"abstract_end":1008}]}
{"pmid":"31957001","title":"BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients.","abstract":"The spectrum and frequency of BRCA1/2 pathogenic variants may be ethnicity-specific. Whether high-frequency founder mutations are present in Chinese women remains largely unknown. In the current study, germline pathogenic variants in the BRCA1/2 genes were determined in 9,505 unselected Chinese Han breast cancer (BC) patients by next-generation and/ or Sanger sequencing. Four hundred and seventy-one (5.0%) BC patients carried BRCA1/2 pathogenic variants in this cohort. A total of 25 recurrent pathogenic variants (at least found in four unrelated patients) were identified in this cohort (8 BRCA1 and 17 BRCA2 recurrent pathogenic variants), 161 patients carried one of these recurrent pathogenic variants in this cohort of 9,505 patients. All of these 25 recurrent pathogenic variants were further explored whether they had founder effect through haplotype analysis. The most common pathogenic variant, BRCA1 c.5470_5477del, was found in 30 BC patients from 29 unrelated families. Twenty-seven of these 29 unrelated patients who carried this BRCA1 c.5470_5477del mutation shared an identical haplotype, indicating that BRCA1 c.5470_5477del was a founder mutation in the Chinese Han population. Furthermore, BRCA1 c.5470_5477del mutation carriers had a significantly worse survival than noncarriers (disease-free survival, p = 0.049; overall survival, p = 0.029). Taken together, our data suggested that BRCA1 c.5470_5477del is a founder mutation in the Chinese Han population and BRCA1 c.5470_5477del mutation carriers have a poor survival.","variants":[{"Name":"NM_007294.4(BRCA1):c.5470_5477del","Chromosome":"17","Start":"43045793","Stop":"43045800","ReferenceAlleleVCF":"CTGCCCAAT","AlternateAlleleVCF":"C","allel_id":70258,"rule_based_match":true,"evidence_text":"BRCA1 c.5470_5477del","llm_judgment":"PRESENT","evidence":"BRCA1 c.5470_5477del","abstract_start":909,"abstract_end":929}]}
{"pmid":"33205917","title":"Whole-exome sequencing identified novel compound heterozygous variants in a Chinese neonate with liver failure and review of literature.","abstract":"BACKGROUND: Liver failure caused by TRMU is a rare hereditary disorder and clinically manifests into metabolic acidosis, hyperlactatemia, and hypoglycemia. Limited spectrum of TRMU pathogenic variants has been reported.\nMETHODS: Whole-exome sequencing was employed for the diagnosis of a 5-day-old female who suffered from severe neonatal hyperlactatemia and hypoglycemia since birth. Sanger sequencing was performed to confirm the origin of the variants subsequently. Variants classification was followed to ACMG guideline.\nRESULTS: A compound heterozygosity of a frameshiftc.34_35dupTC (p.Gly13fs) and a missense c.244T>G (p.Phe82Val) in TRMU was detected, both variants are novel and pathogenic. Analysis of clinical and genetic information including patients reported previously indicated that there is no significant correlation between the genotype and the phenotype of TRMU-caused liver failure.\nCONCLUSION: To the best of our knowledge, this is the first case report of TRMU-caused liver failure in China. Whole-exome sequencing is effective for conclusive diagnosis of this disorder and beneficial for its clinical management.","variants":[{"Name":"NM_018006.5(TRMU):c.244T>G (p.Phe82Val)","Chromosome":"22","Start":"46337940","Stop":"46337940","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1928803,"rule_based_match":true,"evidence_text":"c.244T>G (p.Phe82Val)","llm_judgment":"PRESENT","evidence":"c.244T>G (p.Phe82Val)","abstract_start":615,"abstract_end":636}]}
{"pmid":"33147992","title":"Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town.","abstract":"OBJECTIVE: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (<i>LDLR</i>) mutations account for >90% of cases, apolipoprotein B (<i>APOB</i>) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (<i>PCSK9</i>) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel <i>PCSK9</i> variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays. Approach and Results: Patients with clinically diagnosed FH underwent genetic analysis of <i>LDLR</i>, and if negative, sequential testing of <i>APOB</i> and <i>PCSK9</i>. We analyzed cosegregation of hypercholesterolemia with novel <i>PCSK9</i> variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous <i>PCSK9</i> variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel <i>PCSK9</i> variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; <i>P</i><0.001). In vitro studies demonstrated the pathogenicity of the G516V variant.\nCONCLUSIONS: In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in <i>PCSK9</i>. Pathogenicity is established beyond doubt for the G516V variant.","variants":[{"Name":"NM_174936.4(PCSK9):c.1547G>T (p.Gly516Val)","Chromosome":"1","Start":"55059529","Stop":"55059529","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":424996,"rule_based_match":true,"evidence_text":"c.1547G>T","llm_judgment":"PRESENT","evidence":"c.1547G>T","abstract_start":1292,"abstract_end":1301}]}
{"pmid":"24810334","title":"A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing.","abstract":"BACKGROUND: Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described.\nMETHODS AND FINDINGS: We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient's but not the parents' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3-20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child's newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation.\nCONCLUSION: The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.","variants":[{"Name":"NM_000546.6(TP53):c.743G>A (p.Arg248Gln)","Chromosome":"17","Start":"7674220","Stop":"7674220","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27395,"rule_based_match":true,"evidence_text":"c.743 G>A, p.Arg248Gln (CCDS11118.1)","llm_judgment":"PRESENT","evidence":"c.743 G>A, p.Arg248Gln (CCDS11118.1)","abstract_start":761,"abstract_end":797}]}
{"pmid":"31106925","title":"Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia.","abstract":"Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease. In this study, we performed in vitro characterization of new LDLR variants found in our patients. Genetic analysis was performed by Next Generation Sequencing using a customized panel of 198 genes in DNA samples of 516 subjects with a clinical diagnosis of probable or definitive FH. All new LDLR variants found in our patients were functionally validated in CHO-ldlA7 cells. The LDLR activity was measured by flow cytometry and LDLR expression was detected by immunofluorescence. Seven new variants at LDLR were tested: c.518 G>C;p.(Cys173Ser), c.[684 G>T;694 G>T];p.[Glu228Asp;Ala232Ser], c.926C>A;p.(Pro309His), c.1261A>G;p.(Ser421Gly), c.1594T>A;p.(Tyr532Asn), and c.2138delC;p.(Thr713Lysfs*17). We classified all variants as pathogenic except p.(Ser421Gly) and p.(Ala232Ser). The functional in vitro characterization of rare variants at the LDLR is a useful tool to classify the new variants. This approach allows us to confirm the genetic diagnosis of FH, avoiding the classification as \"uncertain significant variants\", and therefore, carry out cascade family screening.","variants":[{"Name":"NM_000527.5(LDLR):c.518G>C (p.Cys173Ser)","Chromosome":"19","Start":"11105424","Stop":"11105424","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":676937,"rule_based_match":true,"evidence_text":"c.518 G>C;p.(Cys173Ser)","llm_judgment":"PRESENT","evidence":"c.518 G>C;p.(Cys173Ser)","abstract_start":882,"abstract_end":905},{"Name":"NM_000527.5(LDLR):c.684G>T (p.Glu228Asp)","Chromosome":"19","Start":"11105590","Stop":"11105590","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":676938,"rule_based_match":false,"evidence_text":"c.684 G>T;p.(Glu228Asp)","llm_judgment":"PRESENT","evidence":"G>T];p.[Glu228Asp","abstract_start":922,"abstract_end":939},{"Name":"NM_000527.5(LDLR):c.926C>A (p.Pro309His)","Chromosome":"19","Start":"11107500","Stop":"11107500","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":676940,"rule_based_match":true,"evidence_text":"c.926C>A;p.(Pro309His)","llm_judgment":"PRESENT","evidence":"c.926C>A;p.(Pro309His)","abstract_start":952,"abstract_end":974},{"Name":"NM_000527.5(LDLR):c.1261A>G (p.Ser421Gly)","Chromosome":"19","Start":"11113352","Stop":"11113352","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":676942,"rule_based_match":true,"evidence_text":"c.1261A>G;p.(Ser421Gly)","llm_judgment":"PRESENT","evidence":"c.1261A>G;p.(Ser421Gly)","abstract_start":976,"abstract_end":999},{"Name":"NM_000527.5(LDLR):c.1594T>A (p.Tyr532Asn)","Chromosome":"19","Start":"11116101","Stop":"11116101","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":676943,"rule_based_match":true,"evidence_text":"c.1594T>A;p.(Tyr532Asn)","llm_judgment":"PRESENT","evidence":"c.1594T>A;p.(Tyr532Asn)","abstract_start":1001,"abstract_end":1024},{"Name":"NM_000527.5(LDLR):c.2138del (p.Thr713fs)","Chromosome":"19","Start":"11120520","Stop":"11120520","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":676944,"rule_based_match":true,"evidence_text":"c.2138delC;p.(Thr713Lysfs*17)","llm_judgment":"PRESENT","evidence":"c.2138delC;p.(Thr713Lysfs*17)","abstract_start":1030,"abstract_end":1059}]}
{"pmid":"24997715","title":"The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations.","abstract":"The inborn errors of metabolism associated with 3-methylglutaconic aciduria are a diverse group of disorders characterized by the excretion of 3-methylglutaconic and 3-methylglutaric acids in the urine. Mutations in several genes have been identified in association with 3-methylglutaconic aciduria. We describe a patient of Saudi Arabian descent with 3-methylglutaconic aciduria, sensorineural hearing loss, encephalopathy, and Leigh-like pattern on MRI (MEGDEL syndrome), as well as developmental delay and developmental regression, bilateral optic nerve atrophy, microcephaly, and myoclonic epilepsy. The patient had an earlier age of onset of optic atrophy than previously described in other MEGDEL syndrome patients. Whole exome sequencing revealed two loss-of-function mutations in SERAC1 in trans: c.438delC (p.T147Rfs*22) and c.442C>T (p.R148X), confirmed by Sanger sequencing. One of these mutations is novel (c.438delC). This case contributes to refining the MEGDEL phenotype.","variants":[{"Name":"NM_032861.4(SERAC1):c.438del (p.Thr147fs)","Chromosome":"6","Start":"158146831","Stop":"158146831","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":677424,"rule_based_match":true,"evidence_text":"c.438delC (p.T147Rfs*22)","llm_judgment":"PRESENT","evidence":"c.438delC (p.T147Rfs*22)","abstract_start":805,"abstract_end":829},{"Name":"NM_032861.4(SERAC1):c.442C>T (p.Arg148Ter)","Chromosome":"6","Start":"158146827","Stop":"158146827","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44229,"rule_based_match":true,"evidence_text":"c.442C>T (p.R148X)","llm_judgment":"PRESENT","evidence":"c.442C>T (p.R148X)","abstract_start":834,"abstract_end":852}]}
{"pmid":"29899460","title":"Mutation screening of the USH2A gene in retinitis pigmentosa and USHER patients in a Han Chinese population.","abstract":"OBJECTIVES: USH2A encodes for usherin, a basement membrane protein in the inner ear and retina. USH2A can cause retinitis pigmentosa (RP) with or without hearing loss. The aim of this study was to detect USH2A mutations in a Chinese cohort of 75 small RP families and 10 Usher syndrome families.\nMETHODS: We performed a direct Sanger sequencing analysis of the USH2A gene to identify mutations for this cohort.\nRESULTS: We identified a total of eight mutations in four of the 75 small RP families (5.3%) and two mutations in one of the 10 Usher families (10%); all families were detected to have compound heterozygous mutations. In families with nonsyndromic RP, we identified the compound heterozygous mutations p.Pro4818Leuand p.Leu2395Hisfs*19 in family No. 19114, p.Arg4493His and p.His1677Glnfs*15 in family No.19162, c.8559-2A > G and p.Arg1549* in family No.19123 and p.Ser5060Pro and p.Arg34Leufs*41 in family No.19178. We also identified the heterozygous mutations p.Arg3719His and p.Cys934Trp in family No.19124, which was the Usher syndrome family. These mutations were predicted to be harmful by SIFT, PROVEAN, Mutation Taster or PolyPhen-2.\nCONCLUSIONS: Our results revealed six novel mutations in the USH2A gene in a Chinese population, which is beneficial for the clinical use of genetic testing of USH2A in patients with autosomal-recessive or sporadic RP and Usher syndrome.","variants":[{"Name":"NM_206933.4(USH2A):c.2802T>G (p.Cys934Trp)","Chromosome":"1","Start":"216246592","Stop":"216246592","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":152897,"rule_based_match":false,"evidence_text":"p.Cys934Trp","llm_judgment":"PRESENT","evidence":"p.Cys934Trp","abstract_start":991,"abstract_end":1002},{"Name":"NM_206933.4(USH2A):c.8559-2A>G","Chromosome":"1","Start":"215877882","Stop":"215877882","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":57766,"rule_based_match":true,"evidence_text":"c.8559-2A > G","llm_judgment":"PRESENT","evidence":"c.8559-2A > G","abstract_start":823,"abstract_end":836}]}
{"pmid":"21708027","title":"A short in-frame deletion in NTRK1 tyrosine kinase domain caused by a novel splice site mutation in a patient with congenital insensitivity to pain with anhidrosis.","abstract":"BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF).\nCASE PRESENTATION: We present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splice-site mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G>A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A>G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G>A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A>G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain.\nCONCLUSIONS: We present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed.","variants":[{"Name":"NM_002529.4(NTRK1):c.574+1G>A","Chromosome":"1","Start":"156868250","Stop":"156868250","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625730,"rule_based_match":true,"evidence_text":"c.574+1G>A","llm_judgment":"PRESENT","evidence":"c.574+1G>A","abstract_start":1097,"abstract_end":1107}]}
{"pmid":"22330942","title":"The spectrum of mutations identified in Cypriot patients with phenylalanine hydroxylase deficiency detected through neonatal screening.","abstract":"OBJECTIVES: The purpose of this study was to identify the mutations responsible for phenylalanine hydroxylase deficiency in Cypriot patients detected through neonatal screening.\nDESIGN AND METHODS: Analysis of the PAH gene was performed by direct sequencing of the patients' genomic DNA, MLPA analysis and real-time PCR.\nRESULTS: Among 22 independent alleles thirteen previously described mutations were detected (detection rate 100%), all in compound heterozygosity: p.Arg395Gly (18.2%), c.168+5G>C (13.6%), p.EX3del (9%), c.1066-11G>A (9%), p.Ala403Val (9%), p.Glu178Gly (9%), p.Ser70Pro (4.5%), p.Arg241His (4.5%), p.Phe55fs (4.5%), p.Arg158Gln (4.5%), p.Asp222Gly (4.5%), p.Ala300Ser (4.5%), p.Pro225Thr (4.5%). Of the ten different genotypes, three have been previously reported to be associated with a mild clinical phenotype and to respond to tetrahydrobiopterin (BH₄) administration.\nCONCLUSIONS: Marked genetic heterogeneity was found in Cypriot patients with hyperphenylalaninemia with two mutations accounting for 32% of the alleles. Most of the mutations detected have been found in other European and Mediterranean populations.","variants":[{"Name":"NM_000277.3(PAH):c.898G>T (p.Ala300Ser)","Chromosome":"12","Start":"102851701","Stop":"102851701","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":98658,"rule_based_match":false,"evidence_text":"p.Ala300Ser (4.5%)","llm_judgment":"PRESENT","evidence":"p.Ala300Ser (4.5%)","abstract_start":676,"abstract_end":694},{"Name":"NM_000277.3(PAH):c.673C>A (p.Pro225Thr)","Chromosome":"12","Start":"102855169","Stop":"102855169","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":108515,"rule_based_match":false,"evidence_text":"p.Pro225Thr","llm_judgment":"PRESENT","evidence":"p.Pro225Thr","abstract_start":696,"abstract_end":707},{"Name":"NM_000277.3(PAH):c.1208C>T (p.Ala403Val)","Chromosome":"12","Start":"102840507","Stop":"102840507","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":98638,"rule_based_match":false,"evidence_text":"p.Ala403Val (9%)","llm_judgment":"PRESENT","evidence":"p.Ala403Val (9%)","abstract_start":543,"abstract_end":559},{"Name":"NM_000277.3(PAH):c.168+5G>C","Chromosome":"12","Start":"102912786","Stop":"102912786","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":108342,"rule_based_match":true,"evidence_text":"c.168+5G>C","llm_judgment":"PRESENT","evidence":"c.168+5G>C","abstract_start":489,"abstract_end":499},{"Name":"NM_000277.3(PAH):c.722G>A (p.Arg241His)","Chromosome":"12","Start":"102852935","Stop":"102852935","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":108540,"rule_based_match":false,"evidence_text":"p.Arg241His (4.5%)","llm_judgment":"PRESENT","evidence":"p.Arg241His (4.5%)","abstract_start":598,"abstract_end":616},{"Name":"NM_000277.3(PAH):c.533A>G (p.Glu178Gly)","Chromosome":"12","Start":"102855309","Stop":"102855309","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":98653,"rule_based_match":false,"evidence_text":"p.Glu178Gly","llm_judgment":"PRESENT","evidence":"p.Glu178Gly","abstract_start":561,"abstract_end":572},{"Name":"NM_000277.3(PAH):c.1066-11G>A","Chromosome":"12","Start":"102843790","Stop":"102843790","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15646,"rule_based_match":true,"evidence_text":"c.1066-11G>A","llm_judgment":"PRESENT","evidence":"c.1066-11G>A","abstract_start":524,"abstract_end":536}]}
{"pmid":"32482800","title":"Homozygous hypomorphic","abstract":"BACKGROUND: Primary ovarian insufficiency (POI) affects 1% of women under 40 years and is a public health problem. The genetic causes of POI are highly heterogeneous with isolated or syndromic forms. Recently, variants in genes involved in DNA repair have been shown to cause POI. Notably, syndromic POI with Fanconi anaemia (FA) traits related to biallelic <i>BRCA2</i> truncated variants has been reported. Here, we report a novel phenotype of isolated POI with <i>a BRCA2</i> variant in a consanguineous Turkish family.\nMETHODS: Exome sequencing (ES) was performed in the patient. We also performed functional studies, including a homologous recombination (HR) test, cell proliferation, radiation-induced RAD51 foci formation assays and chromosome breakage studies in primary and lymphoblastoid immortalised cells. The expression of <i>BRCA2</i> in human foetal ovaries was studied.\nRESULTS: ES identified a homozygous missense c.8524C>T/p.R2842C<i>-BRCA2</i> variant. BRCA2 defects induce cancer predisposition and FA. Remarkably, neither the patient nor her family exhibited somatic pathologies. The patient's cells showed intermediate levels of chromosomal breaks, cell proliferation and radiation-induced RAD51 foci formation compared with controls and FA cells. R2842C-BRCA2 only partially complemented HR efficiency compared with wild type-BRCA2. BRCA2 is expressed in human foetal ovaries in pachytene stage oocytes, when meiotic HR occurs.\nCONCLUSION: We describe the functional assessment of a homozygous hypomorphic <i>BRCA2</i> variant in a patient with POI without cancer or FA trait. Our findings extend the phenotype of BRCA2 biallelic alterations to fully isolated POI. This study has a major impact on the management and genetic counselling of patients with POI.","variants":[{"Name":"NM_000059.4(BRCA2):c.8524C>T (p.Arg2842Cys)","Chromosome":"13","Start":"32370992","Stop":"32370992","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67278,"rule_based_match":true,"evidence_text":"c.8524C>T/p.R2842C","llm_judgment":"PRESENT","evidence":"c.8524C>T/p.R2842C","abstract_start":931,"abstract_end":949}]}
{"pmid":"28423643","title":"POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer.","abstract":"Germline mutations in POLE and POLD1 have been shown to cause predisposition to colorectal multiple polyposis and a wide range of neoplasms, early-onset colorectal cancer being the most prevalent. In order to find additional mutations affecting the proofreading activity of these polymerases, we sequenced its exonuclease domain in 155 patients with multiple polyps or an early-onset colorectal cancer phenotype without alterations in the known hereditary colorectal cancer genes. Interestingly, none of the previously reported mutations in POLE and POLD1 were found. On the other hand, among the genetic variants detected, only two of them stood out as putative pathogenic in the POLE gene, c.1359 + 46del71 and c.1420G > A (p.Val474Ile). The first variant, detected in two families, was not proven to alter correct RNA splicing. Contrarily, c.1420G > A (p.Val474Ile) was detected in one early-onset colorectal cancer patient and located right next to the exonuclease domain. The pathogenicity of this change was suggested by its rarity and bioinformatics predictions, and it was further indicated by functional assays in Schizosaccharomyces pombe. This is the first study to functionally analyze a POLE genetic variant outside the exonuclease domain and widens the spectrum of genetic changes in this DNA polymerase that could lead to colorectal cancer predisposition.","variants":[{"Name":"NM_006231.4(POLE):c.1420G>A (p.Val474Ile)","Chromosome":"12","Start":"132673217","Stop":"132673217","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":237521,"rule_based_match":true,"evidence_text":"c.1420G > A (p.Val474Ile)","llm_judgment":"PRESENT","evidence":"c.1420G > A (p.Val474Ile)","abstract_start":713,"abstract_end":738}]}
{"pmid":"32297288","title":"17β-hydroxysteroid dehydrogenase type 3 deficiency: female sex assignment and follow-up.","abstract":"BACKGROUND: Deficiency of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a rare autosomal recessive 46,XY disorder of sex development (DSD). It is due to pathogenetic variants in the HSD17B3 gene. Mutated genes encode an abnormal enzyme with absent or reduced ability to convert Δ4-androstenedione (Δ4-A) to testosterone (T) in the fetal testis. Affected individuals are usually raised as females and diagnosis is made at puberty, when they show virilization.\nMETHODS: A girl with a presumptive diagnosis of complete androgen insensitivity syndrome underwent endocrine and genetic assessment. Long-term follow-up was reported.\nRESULTS: The diagnosis of 17β-HSD3 deficiency was made (stimulated T/Δ4-A ratio: 0.15; HSD17B3 gene analysis: c.277+4A>T in intron 3/c.640_645del (p.Glu214_Glu215del) in exon 9. After extensive information, parents decided to maintain female sex. Gonadal removal was performed and histological evaluation demonstrated deep fibrosis of testicular tissue. Follow-up till 8.5 years of age showed somatic and neuro-psychological development fitting with the female sex.\nCONCLUSIONS: Management of a child with the rare 17β-HSD3 deficiency remains challenging. Any decision must be carefully evaluated with parents. Long-term follow-up must be warranted by a multidisciplinary DSD team to evaluate the adequacy of the choices made on quality of life in later life.","variants":[{"Name":"NM_000197.2(HSD17B3):c.277+4A>T","Chromosome":"9","Start":"96254864","Stop":"96254864","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":205160,"rule_based_match":true,"evidence_text":"c.277+4A>T","llm_judgment":"PRESENT","evidence":"c.277+4A>T","abstract_start":744,"abstract_end":754}]}
{"pmid":"37921548","title":"Aortic dissection in a young male with persistent ductus arteriosus and a novel variant in MYLK.","abstract":"Pathogenic variants in several genes involved in the function or regulation of smooth muscle cells (SMC) are known to predispose to congenital heart disease and thoracic aortic aneurysm and dissection (TAAD). Variants in MYLK are primarily known to predispose to TAAD, but a growing body of evidence points toward MYLK also playing an essential role in the regulation of SMC contraction outside the aorta. In this case report, we present a patient with co-occurrence of persistent ductus arteriosus (PDA) and thoracic aortic dissection. Genetic analyses revealed a novel splice acceptor variant (c.3986-1G > A) in MYLK, which segregated with disease in the family. RNA-analyses on fibroblasts showed that the variant induced skipping of exon 24, which resulted in an in-frame deletion of 101 amino acids. These findings suggest that MYLK-associated disease could include a broader phenotypic spectrum than isolated TAAD, including PDA and obstructive pulmonary disease. Genetic analyses could be considered in families with TAAD and PDA or obstructive pulmonary disease.","variants":[{"Name":"NM_053025.4(MYLK):c.3986-1G>A","Chromosome":"3","Start":"123657429","Stop":"123657429","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2671383,"rule_based_match":true,"evidence_text":"c.3986-1G > A","llm_judgment":"PRESENT","evidence":"c.3986-1G > A","abstract_start":596,"abstract_end":609}]}
{"pmid":"21620354","title":"Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy.","abstract":"Linkage analysis of the dominant distal myopathy we previously identified in a large Australian family demonstrated one significant linkage region located on chromosome 7 and encompassing 18.6 Mbp and 151 genes. The strongest candidate gene was FLNC because filamin C, the encoded protein, is muscle-specific and associated with myofibrillar myopathy. Sequencing of FLNC cDNA identified a c.752T>C (p.Met251Thr) mutation in the N-terminal actin-binding domain (ABD); this mutation segregated with the disease and was absent in 200 controls. We identified an Italian family with the same phenotype and found a c.577G>A (p.Ala193Thr) filamin C ABD mutation that segregated with the disease. Filamin C ABD mutations have not been described, although filamin A and filamin B ABD mutations cause multiple musculoskeletal disorders. The distal myopathy phenotype and muscle pathology in the two families differ from myofibrillar myopathies caused by filamin C rod and dimerization domain mutations because of the distinct involvement of hand muscles and lack of pathological protein aggregation. Thus, like the position of FLNA and B mutations, the position of the FLNC mutation determines disease phenotype. The two filamin C ABD mutations increase actin-binding affinity in a manner similar to filamin A and filamin B ABD mutations. Cell-culture expression of the c.752T>C (p.Met251)Thr mutant filamin C ABD demonstrated reduced nuclear localization as did mutant filamin A and filamin B ABDs. Expression of both filamin C ABD mutants as full-length proteins induced increased aggregation of filamin. We conclude filamin C ABD mutations cause a recognizable distal myopathy, most likely through increased actin affinity, similar to the pathological mechanism of filamin A and filamin B ABD mutations.","variants":[{"Name":"NM_001458.5(FLNC):c.752T>C (p.Met251Thr)","Chromosome":"7","Start":"128837450","Stop":"128837450","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":38545,"rule_based_match":true,"evidence_text":"c.752T>C (p.Met251Thr)","llm_judgment":"PRESENT","evidence":"c.752T>C (p.Met251Thr)","abstract_start":389,"abstract_end":411},{"Name":"NM_001458.5(FLNC):c.577G>A (p.Ala193Thr)","Chromosome":"7","Start":"128835550","Stop":"128835550","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38546,"rule_based_match":true,"evidence_text":"c.577G>A (p.Ala193Thr)","llm_judgment":"PRESENT","evidence":"c.577G>A (p.Ala193Thr)","abstract_start":609,"abstract_end":631}]}
{"pmid":"34686677","title":"A novel deep intronic variant strongly associates with Alkaptonuria.","abstract":"Alkaptonuria is a rare autosomal recessive inherited disorder of tyrosine metabolism, which causes ochronosis, arthropathy, cardiac valvular calcification, and urolithiasis. The epidemiology of alkaptonuria in East Asia is not clear. In this study, patients diagnosed with alkaptonuria from January 2010 to June 2020 were reviewed. Their clinical and molecular features were further compared with those of patients from other countries. Three patients were found to have alkaptonuria. Mutation analyses of the homogentisate 1,2-dioxygenase gene (HGD) showed four novel variants c.16-2063 A > C, p.(Thr196Ile), p.(Gly344AspfsTer25), and p.(Gly362Arg) in six mutated alleles (83.3%). RNA sequencing revealed that c.16-2063 A > C activates a cryptic exon, causing protein truncation p.(Tyr5_Ile6insValTer17). A literature search identified another 6 patients with alkaptonuria in East Asia; including our cases, 13 of the 18 mutated alleles have not been reported elsewhere in the world. Alkaptonuria is rare in Taiwan and East Asia, with HGD variants being mostly novel and private.","variants":[{"Name":"NM_000187.4(HGD):c.16-2063A>C","Chromosome":"3","Start":"120677926","Stop":"120677926","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1254248,"rule_based_match":true,"evidence_text":"c.16-2063 A > C","llm_judgment":"PRESENT","evidence":"c.16-2063 A > C","abstract_start":578,"abstract_end":593}]}
{"pmid":"32373561","title":"A Neonate With MuSK Congenital Myasthenic Syndrome Presenting With Refractory Respiratory Failure.","abstract":"This was a Chinese neonatal congenital myasthenic syndromes case caused by muscle skeletal receptor tyrosine kinase gene mutations, which have not been recorded in the Human Gene Mutation Database. The newborn girl had refractory respiratory failure from birth to death, and failed extubation seven times. She had two heterozygous mutations: a non-sense mutation c.2062C>T (p.Q688X) inherited from father and a missense mutation c.2324T>C (p.F775S) inherited from mother, which was predicted pathogenic and harmful by bioinformatic softwares SIFT, PolyPhen_2 and REVEL. She positively responded to Neostigmine, but her parent quitted treatment when Pyridostigmine Bromide (2 mg/kg Q12 h) had been given for 8 days. She died 2 days after she was taken home by her parents on age of 56 days.","variants":[{"Name":"NM_005592.4(MUSK):c.2324T>C (p.Phe775Ser)","Chromosome":"9","Start":"110800702","Stop":"110800702","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3525665,"rule_based_match":true,"evidence_text":"c.2324T>C (p.F775S)","llm_judgment":"PRESENT","evidence":"c.2324T>C (p.F775S)","abstract_start":429,"abstract_end":448}]}
{"pmid":"24641620","title":"Autosomal dominant polycystic kidney disease caused by somatic and germline mosaicism.","abstract":"Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder caused by loss of function mutations of PKD1 or PKD2 genes. Although PKD1 is highly polymorphic and the new mutation rate is relatively high, the role of mosaicism is incompletely defined. Herein, we describe the molecular analysis of ADPKD in a 19-year-old female proband and her father. The proband had a PKD1 truncation mutation c.10745dupC (p.Val3584ArgfsX43), which was absent in paternal peripheral blood lymphocytes (PBL). However, very low quantities of this mutation were detected in the father's sperm DNA, but not in DNA from his buccal cells or urine sediment. Next generation sequencing (NGS) analysis determined the level of this mutation in the father's PBL, buccal cells and sperm to be ∼3%, 4.5% and 10%, respectively, consistent with somatic and germline mosaicism. The PKD1 mutation in ∼10% of her father's sperm indicates that it probably occurred early in embryogenesis. In ADPKD cases where a de novo mutation is suspected because of negative PKD gene testing of PBL, additional evaluation with more sensitive methods (e.g. NGS) of the proband PBL and paternal sperm can enhance detection of mosaicism and facilitate genetic counseling.","variants":[{"Name":"NM_001009944.3(PKD1):c.10745dup (p.Val3584fs)","Chromosome":"16","Start":"2093886","Stop":"2093887","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":512181,"rule_based_match":true,"evidence_text":"c.10745dupC (p.Val3584ArgfsX43)","llm_judgment":"PRESENT","evidence":"c.10745dupC (p.Val3584ArgfsX43)","abstract_start":421,"abstract_end":452}]}
{"pmid":"29633446","title":"A novel INS mutation in a family with maturity-onset diabetes of the young: Variable insulin secretion and putative mechanisms.","abstract":"Insulin gene (INS) mutations cause a rare form of maturity-onset diabetes of the young (MODY), a heterogeneous group of autosomal dominant diabetes with at least 14 confirmed causative genes. Here, we describe a family with MODY due to a novel INS mutation, detected using massively parallel sequencing (MPS). The proband presented aged 11 years with mild diabetic ketoacidosis. She was negative for IA2 and GAD antibodies. She had a strong family history of diabetes affecting both her two siblings and her mother, none of whom had ketosis but who were considered to have type 1 diabetes and managed on insulin, and her maternal grandfather, who was managed for decades on sulfonylureas. Of note, her younger sister had insulin deficiency but an elevated fasting proinsulin:insulin ratio of 76% (ref 5%-30%). Sanger sequencing of HNF4A, HNF1A, and HNF1B in the proband was negative. Targeted MPS using a custom-designed amplicon panel sequenced on an Illumina MiSeq detected a heterozygous INS mutation c.277G>A (p.Glu93Lys). Sanger sequencing confirmed the variant segregated with diabetes within the family. Structural analysis of this variant suggested disruption of a critical hydrogen bond between insulin and the insulin receptor; however, the clinical picture in some individuals also suggested abnormal insulin processing and insulin deficiency. This family has a novel INS mutation and demonstrated variable insulin deficiency. MPS represents an efficient method of MODY diagnosis in families with rarer gene mutations.","variants":[{"Name":"NM_000207.3(INS):c.277G>A (p.Glu93Lys)","Chromosome":"11","Start":"2159908","Stop":"2159908","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1892177,"rule_based_match":true,"evidence_text":"INS mutation c.277G>A (p.Glu93Lys)","llm_judgment":"PRESENT","evidence":"INS mutation c.277G>A (p.Glu93Lys)","abstract_start":991,"abstract_end":1025}]}
{"pmid":"24458587","title":"Hydrops fetalis in a preterm newborn heterozygous for the c.4A>G SHOC2 mutation.","abstract":"Fetal hydrops is a condition resulting from interstitial fluid accumulation in fetal compartments secondary to increased capillary permeability and characterized by high rates of perinatal mortality and morbidity. Clinical features include skin edema, hydrothorax, pericardial effusion, ascites with or without polyhydramnios, and placental edema. While it may occur as associated feature in multiple disorders, it has been documented to recur in Noonan syndrome, the most common disorder among RASopathies, but also in cardiofaciocutaneous and Costello syndromes. Here, we report on the occurrence of severe hydrops in a newborn heterozygous for the invariant c.4A>G missense change in SHOC2 which underlies Noonan-like syndrome with loose anagen hair, documenting that it represents a clinically relevant complication in this condition, shared by RASopathies.","variants":[{"Name":"NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly)","Chromosome":"10","Start":"110964362","Stop":"110964362","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":21860,"rule_based_match":true,"evidence_text":"c.4A>G","llm_judgment":"PRESENT","evidence":"c.4A>G","abstract_start":661,"abstract_end":667}]}
{"pmid":"31211835","title":"Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans.","abstract":"Oculomotor synkinesis is the involuntary movement of the eyes or eyelids with a voluntary attempt at a different movement. The chemokine receptor CXCR4 and its ligand CXCL12 regulate oculomotor nerve development; mice with loss of either molecule have oculomotor synkinesis. In a consanguineous family with congenital ptosis and elevation of the ptotic eyelid with ipsilateral abduction, we identified a co-segregating homozygous missense variant (c.772G>A) in ACKR3, which encodes an atypical chemokine receptor that binds CXCL12 and functions as a scavenger receptor, regulating levels of CXCL12 available for CXCR4 signaling. The mutant protein (p.V258M) is expressed and traffics to the cell surface but has a lower binding affinity for CXCL12. Mice with loss of Ackr3 have variable phenotypes that include misrouting of the oculomotor and abducens nerves. All embryos show oculomotor nerve misrouting, ranging from complete misprojection in the midbrain, to aberrant peripheral branching, to a thin nerve, which aberrantly innervates the lateral rectus (as seen in Duane syndrome). The abducens nerve phenotype ranges from complete absence, to aberrant projections within the orbit, to a normal trajectory. Loss of ACKR3 in the midbrain leads to downregulation of CXCR4 protein, consistent with reports that excess CXCL12 causes ligand-induced degradation of CXCR4. Correspondingly, excess CXCL12 applied to ex vivo oculomotor slices causes axon misrouting, similar to inhibition of CXCR4. Thus, ACKR3, through its regulation of CXCL12 levels, is an important regulator of axon guidance in the oculomotor system; complete loss causes oculomotor synkinesis in mice, while reduced function causes oculomotor synkinesis in humans.","variants":[{"Name":"NM_020311.3(ACKR3):c.772G>A (p.Val258Met)","Chromosome":"2","Start":"236581237","Stop":"236581237","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":576101,"rule_based_match":true,"evidence_text":"c.772G>A","llm_judgment":"PRESENT","evidence":"c.772G>A","abstract_start":448,"abstract_end":456}]}
{"pmid":"28320181","title":"Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype.","abstract":"Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild). Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement. All 3 siblings are compound heterozygous for a previously reported mutation, c.2T>C (p.M1T), and a novel mutation, c.920G>A, causing a missense change (p.C307Y) located in the RING finger domain of PEX10. The present cases suggest that these PEX10 mutations involve not only cerebellar but also more multiple nervous systems including pupillary autonomic, pyramidal and extrapyramidal systems.","variants":[{"Name":"NM_002617.4(PEX10):c.2T>C (p.Met1Thr)","Chromosome":"1","Start":"2412501","Stop":"2412501","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":172125,"rule_based_match":true,"evidence_text":"c.2T>C (p.M1T)","llm_judgment":"PRESENT","evidence":"c.2T>C (p.M1T)","abstract_start":556,"abstract_end":570}]}
{"pmid":"35167739","title":"Reclassification of Five BRCA1/2 Variants with Unknown Significance Using Complex Functional Study.","abstract":"PURPOSE: While BRCA1/2 genes are commonly investigated, variants of unknown significance (VUS) and variants with potential splice effect are still being detected and they represent a substantial challenge in genetic counseling and therapy.\nMATERIALS AND METHODS: Out of genetically tested 3,568 hereditary breast and ovarian cancer probands five, functionally not investigated variants with potential splice-modifying effect were subjected to functional characterization. Transcript-level analysis on peripheral blood-derived RNA of the carriers was performed to test aberrant splicing. The completeness of the aberrant splicing event was also studied, existence and extent of nonsense-mediated decay was even addressed. Clinical and phenotype data, pedigree and co-segregation analyses were also done. Locus-specific loss of heterozygosity (LOH) in tumor tissues was additionally tested.\nRESULTS: In case of the BRCA1:c.4484+4dupA and the BRCA1:c.5407-10G>A variants functional results allowed us to reclassify them from VUS into likely pathogenic category. BRCA1:c.4358-31A>C, by producing incomplete aberrant splicing, was highlighted as strong VUS, but in lack of other supporting evidence, re-categorization was not possible. The likely pathogenic assertion of previously not reported BRCA2:c.8487G>T was reinforced based on its spliceogenic property and tumor LOH, while BRCA2:c.793G>A failed to present aberrant splicing in spite of suggestive predictions, which altered its original VUS evaluation into likely benign class.\nCONCLUSION: We presented molecular and clinical evidence for reclassification of four out of five BRCA1/2 variants. Both up- and down-classification harbour important clinical significance. Patients carrying re-classified pathogenic variants in the future will not be dropped out from medical surveillance, preventive measures, treatment and predictive family screening in relatives at risk.","variants":[{"Name":"NM_007294.4(BRCA1):c.4358-31A>C","Chromosome":"17","Start":"43076645","Stop":"43076645","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3424216,"rule_based_match":true,"evidence_text":"BRCA1:c.4358-31A>C","llm_judgment":"PRESENT","evidence":"BRCA1:c.4358-31A>C","abstract_start":1059,"abstract_end":1077},{"Name":"NM_007294.4(BRCA1):c.5407-10G>A","Chromosome":"17","Start":"43047713","Stop":"43047713","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":102853,"rule_based_match":true,"evidence_text":"BRCA1:c.5407-10G>A","llm_judgment":"PRESENT","evidence":"BRCA1:c.5407-10G>A","abstract_start":940,"abstract_end":958}]}
{"pmid":"23775540","title":"Familial rhabdoid tumour 'avant la lettre'--from pathology review to exome sequencing and back again.","abstract":"Here we provide compelling evidence that next-generation sequencing will revolutionize diagnostics. We reappraised a case from 1991, published in 1993, describing the unique occurrence of an ovarian immature teratoma arising in a young woman and a clonally distinct intracerebral immature teratoma developing in her daughter. We conducted whole-exome sequencing on constitutional DNA from the mother and her daughter and identified a previously unreported nonsense mutation (c.3533G>A; p.Trp1178*) in the chromatin remodelling gene, SMARCA4, that was present in both individuals and was subject to nonsense-mediated decay. Tumour analysis by Sanger sequencing revealed a somatic SMARCA4 mutation in both the mother (c.2438+1G>T) and her daughter (c.3229C>T; p.Arg1077*), which are predicted to be truncating. As immature teratomas are classified as germ cell tumours, we performed a comprehensive mutation survey of 106 apparently sporadic germ cell tumours, but did not find any other clearly deleterious SMARCA4 mutations. Recently, inactivating mutations in SMARCA4 have been found in two cases of rhabdoid tumour predisposition syndrome type 2. In the light of these findings, renewed efforts to locate previously unobtainable tumour samples were successfully undertaken. Histopathological and immunohistochemical re-analysis of the daughter's tumour revealed that it was indeed a rhabdoid tumour (atypical teratoid/rhabdoid tumour). In this context, the original pathology report of the mother's ovarian tumour was re-interpreted as describing a malignant rhabdoid tumour of the ovary. This report raises the question as to whether molecular genetic analysis should be included in tumour classification, alongside more traditional microscopy-based methods. The use of new sequencing technologies, particularly when applied to archived samples, will lead to many more 'molecular rediagnoses'. This is the earliest known case of rhabdoid tumour predisposition syndrome type 2 and the first described case with an autosomal dominant pattern of inheritance, only discovered through an exome sequencing project.","variants":[{"Name":"NM_003072.5(SMARCA4):c.3533G>A (p.Trp1178Ter)","Chromosome":"19","Start":"11030880","Stop":"11030880","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":143131,"rule_based_match":true,"evidence_text":"c.3533G>A; p.Trp1178*","llm_judgment":"PRESENT","evidence":"c.3533G>A; p.Trp1178*","abstract_start":475,"abstract_end":496},{"Name":"NM_003072.5(SMARCA4):c.3229C>T (p.Arg1077Ter)","Chromosome":"19","Start":"11027797","Stop":"11027797","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1685028,"rule_based_match":true,"evidence_text":"c.3229C>T; p.Arg1077*","llm_judgment":"PRESENT","evidence":"c.3229C>T; p.Arg1077*","abstract_start":747,"abstract_end":768}]}
{"pmid":"35568358","title":"Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles.","abstract":"Steel syndrome (MIM# 615155) is an autosomal recessive skeletal disorder, characterized by dislocations of the hips and radial heads, carpal coalition, short stature, facial dysmorphism, and scoliosis. Until date 47 patients have been reported. However, disease causing variants have been identified only in twenty Puerto Rican and nine non-Puerto Rican families. Here we report two monozygotic twins and a boy from two families with novel missense variants, c.295G > A p.(Ala99 Thr), c.3056C > A p.(Pro1019His) and c.2521G > A p.(Gly841Arg) in COL27A1. We describe for the first time, cleft palate and delayed carpal bone ossification as features of Steel syndrome. We reviewed clinical features in all mutation-proven Steel syndrome patients. Short stature and dislocation/subluxation of hip joint are consistently observed. Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay. Seven missense variants and eight null variants are reported in COL27A1 until date. We also looked into the genotype-phenotype correlation in Puerto Rican and non-Puerto Rican patients.","variants":[{"Name":"NM_032888.4(COL27A1):c.295G>A (p.Ala99Thr)","Chromosome":"9","Start":"114167850","Stop":"114167850","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":815877,"rule_based_match":true,"evidence_text":"c.295G > A p.(Ala99 Thr)","llm_judgment":"PRESENT","evidence":"c.295G > A p.(Ala99 Thr)","abstract_start":459,"abstract_end":483}]}
{"pmid":"32028042","title":"Previously undescribed phenotypic findings and novel ACTG1 gene pathogenic variants in Baraitser-Winter cerebrofrontofacial syndrome.","abstract":"Baraitser-Winter cerebrofrontofacial syndrome is an autosomal dominant disease characterized by multiple congenital abnormalities and intellectual disability, which is caused by mutations in either the ACTB or ACTG1 genes. In this report, we described novel phenotypic findings in two Mexican patients with the disorder in whom two novel ACTG1 mutations (c.176A > G, p.Gln59Arg; and c.608C > T, p.Thr203Met) were identified.","variants":[{"Name":"NM_001614.5(ACTG1):c.608C>T (p.Thr203Met)","Chromosome":"17","Start":"81511382","Stop":"81511382","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":791845,"rule_based_match":true,"evidence_text":"c.608C>T (p.Thr203Met)","llm_judgment":"PRESENT","evidence":"p.Thr203Met","abstract_start":395,"abstract_end":406}]}
{"pmid":"22748208","title":"A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system.","abstract":"Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of lysosomal diseases that collectively compose the most common Mendelian form of childhood-onset neurodegeneration. It is estimated that ∼8% of individuals diagnosed with NCL by conservative clinical and histopathologic criteria have been ruled out for mutations in the nine known NCL-associated genes, suggesting that additional genes remain unidentified. To further understand the genetic underpinnings of the NCLs, we performed whole-exome sequencing on DNA samples from a Mexican family affected by a molecularly undefined form of NCL characterized by infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material. Using a recessive model to filter the identified variants, we found a single homozygous variant, c.550C>T in KCTD7, that causes a p.Arg184Cys missense change in potassium channel tetramerization domain-containing protein 7 (KCTD7) in the affected individuals. The mutation was predicted to be deleterious and was absent in over 6,000 controls. The identified variant altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor. Intriguingly, murine cerebellar cells derived from a juvenile NCL model (CLN3) showed enrichment of endogenous KCTD7. Whereas KCTD7 mutations have previously been linked to PME without lysosomal storage, this study clearly demonstrates that KCTD7 mutations also cause a rare, infantile-onset NCL subtype designated as CLN14.","variants":[{"Name":"NM_153033.5(KCTD7):c.550C>T (p.Arg184Cys)","Chromosome":"7","Start":"66638912","Stop":"66638912","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45589,"rule_based_match":true,"evidence_text":"c.550C>T","llm_judgment":"PRESENT","evidence":"c.550C>T","abstract_start":885,"abstract_end":893}]}
{"pmid":"17605093","title":"Malignant mutation in the lamin A/C gene causing progressive conduction system disease and early sudden death in a family with mild form of limb-girdle muscular dystrophy.","abstract":"BACKGROUND: Lamin proteins A and C are major functional and structural components of the nuclear lamina. Mutations of the LMNA gene have been associated with dilated cardiomyopathy, conduction system defects and skeletal muscle dystrophy simultaneously, in variable involvement. We report on a family with a mutation of the lamin A/C gene (c.908-909delCT).\nMETHODS: Thirty five members of the family of a proband were studied and underwent clinical and genetic evaluation. Family members were considered to be affected if they demonstrated conduction system defects, limb-girdle muscular dystrophy, dilated cardiomyopathy, carried the lamin A/C mutation or suffered sudden death.\nRESULTS: Fifteen members of the family were considered to be affected. Conduction system defects were the major feature of the affected members (67%), with variable involvement of dilated cardiomyopathy (33%), and limb-girdle muscular dystrophy (53%). Sudden death occurred in four members (27%) and was the presenting feature in three (20%) of the affected members at an early age. Mutation c.908-909delCT was confirmed in 12 of the affected members. The pattern of inheritance was autosomal dominant.\nCONCLUSION: Lamin c.908-909delCT mutation is malignant compared to other dilated cardiomyopathy-associated mutations of the Lamin A/C gene. Patients with this mutation have rapid progression of atrioventricular conduction abnormalities, and sudden death may be the presenting feature. Early identification of affected families and consideration of an implantable defibrillator is important in this setting.","variants":[{"Name":"NM_170707.4(LMNA):c.908_909del (p.Ser303fs)","Chromosome":"1","Start":"156135280","Stop":"156135281","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":77852,"rule_based_match":false,"evidence_text":"c.908-909delCT","llm_judgment":"PRESENT","evidence":"c.908-909delCT","abstract_start":340,"abstract_end":354}]}
{"pmid":"37272645","title":"A De Novo Mutation in SOX10 in a Chinese Boy with Waardenburg Syndrome Type 2.","abstract":"Waardenburg syndrome is an autosomal dominant inherited syndromic hereditary hearing loss characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. The aim of this study was to analyze the clinical phenotypes and genetic variants of a Chinese boy with Waardenburg syndrome type 2 and to explore the possible molecular pathogenesis of Waardenburg syndrome type 2. Clinical, audiological, and ophthalmologic evaluations were performed on the proband. Clinical data from the principal members in the proband's family were collected through questionnaires. Genetic analysis was conducted, including targeted next-generation sequencing of 144 known deafness genes, Sanger sequencing, and bioinformatic analysis. Waardenburg syndrome type 2was diagnosed in a 4-year-old boy according to the Waardenburg Syndrome Consortium Criteria. The novel missense mutation c.426G>T (p.Trp142Cys) was identified in SOX10 in the proband but was absent in his parents and the controls. A de novo missense mutation in SOX10 was the genetic cause of Waardenburg syndrome type 2 in the proband, which was useful for the molecular diagnosis of Waardenburg syndrome type 2.","variants":[{"Name":"NM_006941.4(SOX10):c.426G>T (p.Trp142Cys)","Chromosome":"22","Start":"37983359","Stop":"37983359","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":789399,"rule_based_match":true,"evidence_text":"c.426G>T (p.Trp142Cys)","llm_judgment":"PRESENT","evidence":"c.426G>T (p.Trp142Cys)","abstract_start":925,"abstract_end":947}]}
{"pmid":"26208961","title":"SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles.","abstract":"OBJECTIVE: To identify the genetic etiology and characterize the clinicopathologic features of a novel distal myopathy.\nMETHODS: We performed whole-exome sequencing on a family with an autosomal dominant distal myopathy and targeted exome sequencing in 1 patient with sporadic distal myopathy, both with rimmed vacuolar pathology. We also evaluated the pathogenicity of identified mutations using immunohistochemistry, Western blot analysis, and expression studies.\nRESULTS: Sequencing identified a likely pathogenic c.1165+1 G>A splice donor variant in SQSTM1 in the affected members of 1 family and in an unrelated patient with sporadic distal myopathy. Affected patients had late-onset distal lower extremity weakness, myopathic features on EMG, and muscle pathology demonstrating rimmed vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions. The c.1165+1 G>A SQSTM1 variant results in the expression of 2 alternatively spliced SQSTM1 proteins: 1 lacking the C-terminal PEST2 domain and another lacking the C-terminal ubiquitin-associated (UBA) domain, both of which have distinct patterns of cellular and skeletal muscle localization.\nCONCLUSIONS: SQSTM1 is an autophagic adaptor that shuttles aggregated and ubiquitinated proteins to the autophagosome for degradation via its C-terminal UBA domain. Similar to mutations in VCP, dominantly inherited mutations in SQSTM1 are now associated with rimmed vacuolar myopathy, Paget disease of bone, amyotrophic lateral sclerosis, and frontotemporal dementia. Our data further suggest a pathogenic connection between the disparate phenotypes.","variants":[{"Name":"NM_003900.5(SQSTM1):c.1165+1G>A","Chromosome":"5","Start":"179833783","Stop":"179833783","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23149,"rule_based_match":true,"evidence_text":"c.1165+1 G>A","llm_judgment":"PRESENT","evidence":"c.1165+1 G>A","abstract_start":517,"abstract_end":529}]}
{"pmid":"30369044","title":"Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant.","abstract":"Heřmanský-Pudlák syndrome (HPS), a rare autosomal recessive disorder, manifests with oculocutaneous albinism and a bleeding diathesis. However, severity of disease can be variable and is typically related to the genetic subtype of HPS; HPS type 6 (HPS-6) is an uncommon subtype generally associated with mild disease. A Caucasian adult female presented with a history of severe bleeding; ophthalmologic examination indicated occult oculocutaneous albinism. The patient was diagnosed with a platelet storage pool disorder, and platelet whole mount electron microscopy demonstrated absent delta granules. Genome-wide SNP analysis showed regions of homozygosity that included the HPS1 and HPS6 genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next-generation sequencing identified a novel homozygous missense variant in HPS6 (c.383 T > C; p.V128A); this was associated with significantly reduced HPS6 mRNA and protein expression in the patient's fibroblasts compared to control cells. These findings highlight the variable severity of disease manifestations in patients with HPS, and illustrate that HPS can be diagnosed in patients with excessive bleeding and occult oculocutaneous albinism. Genetic analysis and platelet electron microscopy are useful diagnostic tests in evaluating patients with suspected HPS. Clinical Trial registration: Registrar: ClinicalTrials.gov Website: www.clinicaltrials.gov Registration Numbers: NCT00001456 and NCT00084305.","variants":[{"Name":"NM_024747.6(HPS6):c.383T>C (p.Val128Ala)","Chromosome":"10","Start":"102065857","Stop":"102065857","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1513611,"rule_based_match":true,"evidence_text":"c.383 T > C; p.V128A","llm_judgment":"PRESENT","evidence":"c.383 T > C; p.V128A","abstract_start":855,"abstract_end":875}]}
{"pmid":"31965605","title":"A novel mutation of keratin 5 in epidermolysis bullosa simplex with migratory circinate erythema.","abstract":"Epidermolysis bullosa simplex migratory circinate erythema (EBS-Migr) is an uncommon subtype of EBS. We report a case of EBS-MIGR with a novel heterozygous pathogenic mutation in exon 9 (frameshift deletion c.1650delC) and likely benign heterozygous mutation in exon 2 (missense c.591C > A) of keratin 5. This novel pathogenic mutation in KRT5 expands the molecular spectrum of this rare subtype of EBS.","variants":[{"Name":"NM_000424.4(KRT5):c.1650del (p.Ser551fs)","Chromosome":"12","Start":"52515065","Stop":"52515065","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":1330409,"rule_based_match":true,"evidence_text":"c.1650delC","llm_judgment":"PRESENT","evidence":"c.1650delC","abstract_start":207,"abstract_end":217}]}
{"pmid":"17804462","title":"Two-tier approach for the detection of alpha-galactosidase A deficiency in a predominantly female haemodialysis population.","abstract":"INTRODUCTION: Fabry's disease (AFD) is an X-linked lysosomal storage disease, resulting from a deficiency in alpha-galactosidase A (AGALA). Untreated, this leads to precocious failure of vital organ function and death. As enzyme replacement therapy is available, it is of vital importance that affected individuals can be traced.\nMATERIALS AND METHODS: We set up a screening in the Flemish haemodialysis population using a two-tier approach. The first tier was a determination of alpha-galactosidase A activity using a dried blood spot on filter paper, in the second tier, patients with the lowest alpha-galactosidase levels were further subjected to mutation analysis of the GLA gene.\nRESULTS: 1284 patients (1047 women, 237 men) were evaluated for inclusion, eliminating patients with definite renal diagnoses. Total 922 patients (71.8 %) were screened (742 women, 180 men). Fifty seven patients were subjected to further genetic analysis. Three GLA mutation carriers were identified: two apparently nonrelated female patients carry the missense mutation p.Ala143Thr (c.427G > A), a missense mutation p.Trp236Arg (c.706T > C) was identified in a man. While the male patient had been clinically diagnosed with AFD, the female patients had remained unrecognized. Additional family based screening resulted in the identification of nine mutation carriers (four males and five females).\nDISCUSSION: We demonstrated that the prevalence of GLA mutation carriers in our haemodialysis population is 0.3%. Our results show that the proposed approach accurately detects AFD patients. We conclude that screening for AFD in high risk populations is a cost-effective, technically feasible and clinically valuable objective.","variants":[{"Name":"NM_000169.3(GLA):c.427G>A (p.Ala143Thr)","Chromosome":"X","Start":"101401752","Stop":"101401752","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25787,"rule_based_match":true,"evidence_text":"c.427G > A","llm_judgment":"PRESENT","evidence":"c.427G > A","abstract_start":1070,"abstract_end":1080}]}
{"pmid":"28514723","title":"Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline","abstract":"We describe a woman with the known pathogenic germline variant <i>CHEK2</i>:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. <i>CHEK2</i> (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The <i>CHEK2</i>:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway (<i>CHEK2</i> germline variant and multiple <i>RAD51B</i> somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting <i>RAD51B</i> and the other breakpoint upstream of <i>HMGA2</i> with very high expression of <i>HMGA2</i> and <i>PLAG1</i> This is the first report of LMS genomic profiling in a patient with the germline <i>CHEK2</i>:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that <i>RAD51B</i> translocation and <i>HMGA2</i> overexpression may play an important role in LMS oncogenesis.","variants":[{"Name":"NM_007194.4(CHEK2):c.1100del (p.Thr367fs)","Chromosome":"22","Start":"28695869","Stop":"28695869","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":133499,"rule_based_match":true,"evidence_text":"CHEK2:c.1100delC","llm_judgment":"PRESENT","evidence":"c.1100delC","abstract_start":76,"abstract_end":86}]}
{"pmid":"29531337","title":"Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis.","abstract":"Biallelic mutations in NDUFAF6 have been identified as responsible for cases of autosomal recessive Leigh syndrome associated with mitochondrial complex I deficiency. Here we report two siblings and two unrelated subjects with Leigh syndrome, in which we found the same compound heterozygous missense (c.532G>C:p.A178P) and deep intronic (c.420+784C>T) variants in NDUFAF6. We demonstrated that the identified intronic variant creates an alternative splice site, leading to the production of an aberrant transcript. A detailed analysis of whole-exome sequencing data together with the functional validation based on mRNA analysis may reveal pathogenic variants even in non-exonic regions.","variants":[{"Name":"NM_152416.4(NDUFAF6):c.420+784C>T","Chromosome":"8","Start":"95036360","Stop":"95036360","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":917814,"rule_based_match":true,"evidence_text":"c.420+784C>T","llm_judgment":"PRESENT","evidence":"c.420+784C>T","abstract_start":339,"abstract_end":351},{"Name":"NM_152416.4(NDUFAF6):c.532G>C (p.Ala178Pro)","Chromosome":"8","Start":"95045599","Stop":"95045599","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":359159,"rule_based_match":true,"evidence_text":"c.532G>C:p.A178P","llm_judgment":"PRESENT","evidence":"c.532G>C:p.A178P","abstract_start":302,"abstract_end":318}]}
{"pmid":"36972931","title":"Clinical characteristics and genetic analysis of a case with adult neuronal ceroid lipofuscinosis type 7 due to variant of MFSD8 gene","abstract":"OBJECTIVE: To explore the clinical characteristics and genetic variants in a patient with adult ceroid lipofuscinosis neuronal type 7 (ACLN7).\nMETHODS: A female patient diagnosed with ACLN7 in Henan Provincial People's Hospital in June 2021 was selected as the study subject. Clinical data, auxiliary examination and result of genetic testing were retrospectively analyzed.\nRESULTS: The patient, a 39-year-old female, has mainly presented progressive visual loss, epilepsy, cerebellar ataxia and mild cognitive decline. Neuroimaging analysis has revealed generalized brain atrophy, prominently cerebellum. Fundus photography has revealed retinitis pigmentosa. Ultrastructural skin examination has revealed granular lipofuscin deposits in the periglandular interstitial cells. Whole exome sequencing revealed that she has harbored compound heterozygous variants of the MSFD8 gene, namely c.1444C>T (p.R482*) and c.104G>A (p.R35Q). Among these, c.1444C>T (p.R482*) was a well established pathogenic variant, while c.104G>A (p.R35Q) was a missense variant unreported previously. Sanger sequencing confirmed that the daughter, son and elder brother of the proband have respectively carried heterozygous c.1444C>T (p.R482*), c.104G>A (p.R35Q), and c.104G>A (p.R35Q) variants of the same gene. The family has therefore fit with the autosomal recessive inheritance pattern of the CLN7.\nCONCLUSION: Compared with previously reported cases, this patient has the latest onset of the disease with a non-lethal phenotype. Her clinical features have involved multiple systems. Cerebellar atrophy and fundus photography may be indicative of the diagnosis. The c.1444C>T (p.R482*) and c.104G>A (p.R35Q) compound heterozygous variants of the MFSD8 gene probably underlay the pathogenesis in this patient.","variants":[{"Name":"NM_001371596.2(MFSD8):c.104G>A (p.Arg35Gln)","Chromosome":"4","Start":"127957551","Stop":"127957551","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":579102,"rule_based_match":true,"evidence_text":"c.104G>A (p.R35Q)","llm_judgment":"PRESENT","evidence":"c.104G>A (p.R35Q)","abstract_start":911,"abstract_end":928}]}
{"pmid":"32087139","title":"Null","abstract":"BACKGROUND: α<sub>1</sub>-Antitrypsin (A1AT) deficiency predisposes patients to pulmonary disease due to inadequate protection against human neutrophil elastase released during inflammatory responses. A1AT deficiency is caused by homozygosity or compound heterozygosity for A1AT variants; individuals with A1AT deficiency most commonly have at least one Z variant allele (c.1096G > A (Glu366Lys)). Null variants that result in complete absence of A1AT in the plasma are much rarer. With one recent exception, all reported A1AT variants are characterized by a single pathogenic variant.\nCASE: An 8 years old patient from Edmonton, Alberta, Canada, was investigated for A1AT deficiency. His A1AT phenotype was determined to be M (wild type)/Null by isoelectric focusing (IEF) but M/Z by targeted genotyping. Gene sequencing revealed two heterozygous variants: Z and Ile100Asn (c.299 T > A). The Ile100Asn substitution is predicted to disrupt the secondary structure of an α-helix in which it resides and the neighbouring tertiary structure, resulting in intracellular degradation of A1AT prior to hepatocyte secretion.\nMETHODS: Family testing was conducted to verify potential inheritance of an A1AT allele carrying the two mutations in cis, as this arrangement of the mutations would explain \"Z\" detection by genotyping but not by IEF. Molecular modeling was used to assess the effect of the variants on A1AT structure and stability.\nDISCUSSION: Carrier status for a novel variant Null<sub>Canada</sub> with in cis mutations (c.[299 T > A;1096G > A], p.[(Ileu100Asn;Glu366Lys)]) was confirmed. A sibling was identified as having A1AT deficiency on the basis of compound heterozygosity for two alleles: Null<sub>Canada</sub> and the common Z allele. A separate pedigree from the Maritimes was subsequently recognized as carrying Null<sub>Canada</sub>.\nCONCLUSION: In cis mutations such as Null<sub>Canada</sub> may be more common than previously described due to failure to detect such mutations using historical testing methods. Combined approaches that include gene sequencing and segregation studies allow recognition of rare A1AT variants, including in cis mutations.","variants":[{"Name":"NM_001127701.1(SERPINA1):c.1096G>A (p.Glu366Lys)","Chromosome":"14","Start":"94378610","Stop":"94378610","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33006,"rule_based_match":true,"evidence_text":"c.1096G > A (Glu366Lys)","llm_judgment":"PRESENT","evidence":"c.1096G > A (Glu366Lys)","abstract_start":372,"abstract_end":395}]}
{"pmid":"22443290","title":"Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A.","abstract":"CONTEXT: Vitamin D-dependent rickets type 1A (VDDR-IA, OMIM 264700) is a rare autosomal recessive disorder and is caused by mutations in the CYP27B1 gene.\nOBJECTIVES: We aim to investigate CYP27B1 mutation in seven patients from four separate families and characterize the genotype-phenotype correlation.\nMETHODS: The entire coding region of the CYP27B1 gene was sequenced, and genotype-phenotype correlation among patients was assessed.\nRESULTS: Sequencing analysis identified biallelic CYP27B1 mutations in all patients and monoallelic mutations in their parents. One patient from the first family was compound heterozygous for c.1166G>A (p.Arg389His) and a novel nonsense mutation c.1079 C>A (p.Ser360*). Two patients from the second family were homozygous for a novel splice donor site mutation in intron 1 (c.195 + 2 T>G), causing partial retention of the intron and a shift in the reading frame. Both novel mutations lead to the complete loss of vitamin D1α-hydroxylase activity. Four patients from families 3 and 4 were homozygous for a previously reported duplication mutation in exon 8 (1319-1325dupCCCACCC, Phe443Profs*24). Interestingly, one patient who was presented with severe hypocalcaemia and seizures at 4 months of age as a result of Phe443Profs*24 has improved spontaneously since 11 years of age and does not need regular treatment. Her laboratory tests showed normal serum calcium and 1,25(OH)(2) D after refusing to take medication for 12 months.\nCONCLUSIONS: There is a good genotype-phenotype correlation in VDDR-IA. However, some patients may recover from the loss of CYP27B1 function, probably due to 1α-hydroxylase activity exerted by a non-CYP27B1 enzyme.","variants":[{"Name":"NM_000785.4(CYP27B1):c.1166G>A (p.Arg389His)","Chromosome":"12","Start":"57764147","Stop":"57764147","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16708,"rule_based_match":true,"evidence_text":"c.1166G>A (p.Arg389His)","llm_judgment":"PRESENT","evidence":"c.1166G>A (p.Arg389His)","abstract_start":630,"abstract_end":653}]}
{"pmid":"23822596","title":"Clinical findings in members of a Czech family with retinitis pigmentosa caused by the c.2426_2427delAG mutation in RPGR","abstract":"PURPOSE: To describe the phenotype of members of the first Czech retinitis pigmentosa family with an identified molecular genetic cause (c.2426_2427delAG in RPGR), followed for more than 13 years.\nMETHODS: Medical records were reviewed and a detailed ophthalmic examination including spectral-domain optical coherence tomography and full-field and multifocal electroretinography (ERG) was performed in two affected males, three female carriers and one unaffected female.\nRESULTS: A 22-year-old male who denied suffering from nyctalopia had a best corrected visual acuity (BCVA) of 0.63 in both eyes. Moderate myopia and myopic astigmatism were present bilaterally. Color vision and contrast sensitivity were normal. There was an eccentric constriction of the visual fields that spared the central 20 degrees in both eyes. Fundus examination revealed bilateral pigmentary changes in the mid-periphery. Full-field ERG documented a 10% rod and 20% cone response. The phenotype of his cousin, also aged 22 years, was more severe. He complained of nyctalopia since 12 years of age. His BCVA was 0.3 in the right eye and 0.5 in the left eye. Myopia and astigmatism were present bilaterally. Contrast sensitivity and color vision were severely impaired. Full field ERG was extinct, but some activity on multifocal ERG was still detectable. The constriction of the visual fields reached 5 degrees in both eyes. Fundus examination showed the typical retinitis pigmentosa appearance. All carriers denied that they suffered from nyctalopia, but two of them had decreased BCVA in at least one eye. None exhibited typical bone spicules or a tapetal-like reflex. Significant refractive errors were present in all eyes of the carriers.\nCONCLUSION: The finding of moderate or high myopia and astigmatism in males with retinitis pigmentosa as well as refractive errors in female relatives indicates possible X-linked inheritance, which may be especially important in pedigrees where the transmission pattern can not be clearly established. Our study highlights the inter-individual variability in phenotype observed in similar aged patients with identical ORF15 RPGR mutations.","variants":[{"Name":"NM_001034853.2(RPGR):c.2426_2427del (p.Glu809fs)","Chromosome":"X","Start":"38286572","Stop":"38286573","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":181395,"rule_based_match":true,"evidence_text":"c.2426_2427delAG in RPGR","llm_judgment":"PRESENT","evidence":"c.2426_2427delAG in RPGR","abstract_start":137,"abstract_end":161}]}
{"pmid":"32476291","title":"Ectrodactyly-ectodermal dysplasia-clefting syndrome presenting with bilateral choanal atresia and rectal stenosis.","abstract":"We present the case of a male who shortly after birth developed acute respiratory distress due to bilateral choanal atresia, following which he was found to have rectal stenosis. Genetic testing for CHARGE syndrome was negative, but whole genome sequencing identified heterozygosity for a pathogenic missense variant in TP63 (c.727C > T, p.(Arg243Trp). He also has partial cutaneous syndactyly of the third and fourth fingers of the right hand, and bilateral lacrimal duct stenosis/aplasia. A later maxillofacial review identified a palpable submucousal cleft and his scalp hair is blond and slightly sparse. Choanal atresia and rectal stenosis are recognized features of ectrodactyly-ectodermal dysplasia-clefting syndrome, but we believe this is the first report of a case presenting with these features in the absence of the cardinal features.","variants":[{"Name":"NM_003722.5(TP63):c.727C>T (p.Arg243Trp)","Chromosome":"3","Start":"189864379","Stop":"189864379","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21566,"rule_based_match":true,"evidence_text":"c.727C > T, p.(Arg243Trp)","llm_judgment":"PRESENT","evidence":"c.727C > T, p.(Arg243Trp)","abstract_start":326,"abstract_end":351}]}
{"pmid":"37827496","title":"Biochemical and biophysical properties of a rare TTRA81V mutation causing mild transthyretin amyloid cardiomyopathy.","abstract":"AIMS: We conducted a presentation on an 84-year-old male patient who has been diagnosed with TTRA81V (p. TTRA101V) hereditary transthyretin cardiac amyloidosis (hATTR-CM). In order to establish its pathogenicity, we extensively investigated the biochemical and biophysical properties of the condition.\nMETHODS AND RESULTS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly acknowledged progressive infiltrative cardiomyopathy that leads to heart failure and potentially fatal arrhythmias. Gaining a comprehensive understanding of the biochemical and biophysical characteristics of genetically mutated TTR proteins serves as the fundamental cornerstone for delivering precise medical care to individuals affected by ATTR. Laboratory assessments indicated a brain natriuretic peptide of 200.12 ng/L (normal range: 0-100 ng/L) and high-sensitivity cardiac troponin I of 0.189 μg/L (normal range: 0-0.1 μg/L). Echocardiography identified left atrial enlargement, symmetrical left ventricular hypertrophy (16 mm septal and 16 mm posterior wall), and a left ventricular ejection fraction of 56%. Cardiac-enhanced magnetic resonance imaging revealed subendocardial late gadolinium enhancement. Tc-99m-PYP nuclear scintigraphy confirmed grade 3 myocardial uptake, showing an increased heart-to-contralateral ratio (H/CL = 2.33). Genetic testing revealed a heterozygous missense mutation in the TTR gene (c.302C>T), resulting in an alanine-to-valine residue change (p. Ala81Val, following the first 20 residues of signal sequence nomenclature). Biochemical analysis of this variant displayed compromised kinetic stability in both the TTRA81V:WT (wild-type) heterozygote protein (half-life, t<sub>1/2</sub>  = 21 h) and the TTRA81V homozygote protein (t<sub>1/2</sub>  = 17.5 h). The kinetic stability fell between that of the TTRWT (t<sub>1/2</sub>  = 42 h) and the early-onset TTRL55P mutation (t<sub>1/2</sub>  = 4.4 h), indicating the patient's late-onset condition. Kinetic stabilizers (Tafamidis, Diflunisal, and AG10) all exhibited the capacity to inhibit TTRA81V acid- and mechanical force-induced fibril formation, albeit less effectively than with TTRWT. Chromatographic assessment of the patient's serum TTR tetramers indicated a slightly lower concentration (3.0 μM) before oral administration of Tafamidis compared with the normal range (3.6-7.2 μM).\nCONCLUSIONS: We identified a patient with hATTR-CM who possesses a rare TTRA81V mutation solely associated with cardiac complications. The slightly reduced kinetic stability of this mutation indicates its late-onset nature and contributes to the gradual progression of the disease.","variants":[{"Name":"NM_000371.4(TTR):c.302C>T (p.Ala101Val)","Chromosome":"18","Start":"31595221","Stop":"31595221","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":488022,"rule_based_match":true,"evidence_text":"c.302C>T","llm_judgment":"PRESENT","evidence":"c.302C>T","abstract_start":1412,"abstract_end":1420}]}
{"pmid":"21160490","title":"Identification of novel MLC1 mutations in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts (MLC).","abstract":"Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal, recessively inherited disease caused by mutations in the MLC1 gene. Most of the previously published studies have been carried out in ethnic populations other than the Chinese. In this study, the analysis of clinical features and MLC1 mutation screening were performed in 13 Chinese patients for the first time. A total of 10 MLC1 mutations were identified in these patients, including five novel missense mutations (c.65G>A, p.R22Q; c.95C>T, p.A32V; c.218G>A, p.G73E; c.823G>A, p.A275T; c.832T>C, p.Y278H), one novel splicing mutation (c.772-1G>C in IVS9-1), one novel small deletion (c.907_930del, p.V303_L310del), one known nonsense mutation (c.593delCTCA, p.Y198X) and two known missense mutations (c.206C>T, p.S69L; c.353C>T, p.T118M). Mutation c.772-1G>C in IVS9-1, accounting for 27.3% (3/11) of the total number of genetically confirmed patients found in this study, is thus a putative hot-spot mutation in the present study group. The existence of a unique MLC1 mutation spectrum in Chinese MLC patients was shown. A systemic study to assess the mutation spectra in different populations should be undertaken.","variants":[{"Name":"NM_015166.4(MLC1):c.95C>T (p.Ala32Val)","Chromosome":"22","Start":"50084808","Stop":"50084808","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":549445,"rule_based_match":true,"evidence_text":"c.95C>T, p.A32V","llm_judgment":"PRESENT","evidence":"c.95C>T, p.A32V","abstract_start":516,"abstract_end":531},{"Name":"NM_015166.4(MLC1):c.218G>A (p.Gly73Glu)","Chromosome":"22","Start":"50083133","Stop":"50083133","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":649543,"rule_based_match":true,"evidence_text":"c.218G>A, p.G73E","llm_judgment":"PRESENT","evidence":"c.218G>A, p.G73E","abstract_start":533,"abstract_end":549},{"Name":"NM_015166.4(MLC1):c.206C>T (p.Ser69Leu)","Chromosome":"22","Start":"50083145","Stop":"50083145","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40300,"rule_based_match":true,"evidence_text":"c.206C>T, p.S69L","llm_judgment":"PRESENT","evidence":"c.206C>T, p.S69L","abstract_start":785,"abstract_end":801},{"Name":"NM_015166.4(MLC1):c.823G>A (p.Ala275Thr)","Chromosome":"22","Start":"50068504","Stop":"50068504","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":849395,"rule_based_match":true,"evidence_text":"c.823G>A, p.A275T","llm_judgment":"PRESENT","evidence":"c.823G>A, p.A275T","abstract_start":551,"abstract_end":568},{"Name":"NM_015166.4(MLC1):c.353C>T (p.Thr118Met)","Chromosome":"22","Start":"50079988","Stop":"50079988","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":849397,"rule_based_match":true,"evidence_text":"c.353C>T (p.T118M)","llm_judgment":"PRESENT","evidence":"c.353C>T","abstract_start":803,"abstract_end":811},{"Name":"NM_015166.4(MLC1):c.65G>A (p.Arg22Gln)","Chromosome":"22","Start":"50084838","Stop":"50084838","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227417,"rule_based_match":true,"evidence_text":"c.65G>A","llm_judgment":"PRESENT","evidence":"c.65G>A","abstract_start":499,"abstract_end":506}]}
{"pmid":"31636600","title":"Novel Phenotypes and Cardiac Involvement Associated With DNA2 Genetic Variants.","abstract":"<b>Objectives:</b> To report two novel <i>DNA2</i> gene mutations causing early onset myopathy with cardiac involvement and late onset mitochondriopathy with rhabdomyolysis. <b>Methods:</b> We performed detailed clinical, muscle histopathology and molecular studies including mitochondrial gene NGS analysis in two patients (Patient 1 and 2), a mother and her son, belonging to a Mexican family, and a third sporadic French patient. <b>Results:</b> Patient 1 and 2 presented with an early onset myopathy associated with ptosis, velopharyngeal weakness, and cardiac involvement. Patient 3 presented rhabdomyolysis unmasking a mitochondrial disease characterized by a sensorineural hearing loss, ptosis, and lipomas. Muscle biopsies performed in all patients showed variable mitochondrial alterations. Patient 3 had multiple mtDNA deletion in his muscle. Genetic studies revealed a novel heterozygous frameshift mutation in <i>DNA2</i> gene (c.2346delT p.Phe782Leufs<sup>*</sup>3) in P1 and P2, and a novel heterozygous missense mutation in <i>DNA2</i> gene (c.578T>C p.Leu193Ser) in the P3. <b>Conclusions:</b> To date only few AD cases presenting either missense or truncating <i>DNA2</i> variants have been reported. None of them presented with a cardiac involvement or rhabdomyolysis. Here we enlarge the genetic and phenotypic spectrum of <i>DNA2</i>-related mitochondrial disorders.","variants":[{"Name":"NM_001080449.3(DNA2):c.578T>C (p.Leu193Ser)","Chromosome":"10","Start":"68465676","Stop":"68465676","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3744541,"rule_based_match":true,"evidence_text":"c.578T>C p.Leu193Ser","llm_judgment":"PRESENT","evidence":"c.578T>C p.Leu193Ser","abstract_start":1057,"abstract_end":1077}]}
{"pmid":"15857086","title":"A novel mutation of the cathepsin C gene in a thai family with Papillon-Lefevre syndrome.","abstract":"BACKGROUND: Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmar- plantar hyperkeratosis and rapid periodontal destruction of both primary and permanent dentitions. It has been shown that the disease is caused by cathepsin C gene (CTSC) mutation leading to the deficiency of cathepsin C enzymatic activity. This study demonstrates the clinical manifestations and CTSC mutational and enzymatic activity analyses in a 5-year-old Thai male PLS patient and his parents.\nMETHODS: Peripheral blood samples were obtained for genomic DNA isolation. All exons of the CTSC gene were amplified by polymerase chain reaction (PCR) using specific primers. Mutations were identified by DNA sequencing. Verification of the mutation was performed by digestion of PCR products by restriction endonucleases. The cathepsin C enzymatic activity was determined using the synthetic substrate glycyl- L-arginine-7-amino-4-methylcoumarin.\nRESULTS: The patient demonstrated classical characteristics of PLS, including hyperkeratotic skin lesions. By the age of 5, all of his primary teeth were extracted due to severe periodontal infection. The parents had no physical abnormalities. The periodontal examination revealed localized mild periodontal destruction. Sequence analysis showed a nucleotide change at position 90 from C >A (c.90C >A) which resulted in a change from cysteine residue to a premature stop codon at the amino acid position 30 in the exon 1. The HpyCH4V digestion revealed that the patient was homozygous, whereas both the father and mother were heterozygous carriers of this mutation. The cathepsin C activity was reduced in the patient's mother, and the activity in the patient was almost completely lost.\nCONCLUSIONS: This is the first study to demonstrate a CTSC gene mutation in a Thai family with PLS. The identified mutation is novel and potentially leads to the drastic reduction of the cathepsin C enzymatic activity. This suggests that the mutation is pathogenetic, causing the PLS. Mutational analysis in more members of the family is warranted to identify whether the mutation is inherited from a common ancestor.","variants":[{"Name":"NM_001814.6(CTSC):c.90C>A (p.Cys30Ter)","Chromosome":"11","Start":"88337583","Stop":"88337583","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3086374,"rule_based_match":true,"evidence_text":"c.90C >A","llm_judgment":"PRESENT","evidence":"c.90C >A","abstract_start":1348,"abstract_end":1356}]}
{"pmid":"31360874","title":"Germline Pathogenic Variants in Homologous Recombination and DNA Repair Genes in an Asian Cohort of Young-Onset Colorectal Cancer.","abstract":"BACKGROUND: Growing evidence suggests a role for cancer susceptibility genes such as <i>BRCA2</i> and <i>PALB2</i> in young-onset colorectal cancers<i>.</i> Using a cohort of young colorectal cancer patients, we sought to identify and provide functional evidence for germline pathogenic variants of DNA repair genes not typically associated with colorectal cancer.\nMETHODS: We recruited 88 patients with young-onset colorectal cancers seen at a general oncology center. Whole-exome sequencing was performed to identify variants in DNA repair and colorectal cancer predisposition genes. Pathogenic <i>BRCA2</i> and <i>PALB2</i> variants were analyzed using immunoblot and immunofluorescence on patient-derived lymphoblastoid cells.\nRESULTS: In general, our cohort displayed characteristic features of young-onset colorectal cancers. Most patients had left-sided tumors and were diagnosed at late stages. Four patients had familial adenomatous polyposis, as well as pathogenic <i>APC</i> variants. We identified 12 pathogenic variants evenly distributed between DNA repair and colorectal cancer predisposition genes. Six patients had pathogenic variants in colorectal cancer genes: <i>APC</i> (n = 4) and <i>MUTYH</i> monoallelic (n = 2). Another six had pathogenic variants in DNA repair genes: <i>ATM</i> (n = 1), <i>BRCA2</i> (n = 1), <i>PALB2</i> (n = 1), <i>NTHL1</i> (n = 1), and <i>WRN</i> (n = 2). Pathogenic variants <i>BRCA2</i> c.9154C>T and <i>PALB2</i> c.1059delA showed deficient homologous recombination repair, evident from the impaired RAD51 nuclear localization and foci formation.\nCONCLUSION: A substantial portion of pathogenic variants in young-onset colorectal cancer was found in DNA repair genes not previously associated with colorectal cancer. This may have implications for the management of patients. Further studies are needed to ascertain the enrichment of pathogenic DNA repair gene variants in colorectal cancers.","variants":[{"Name":"NM_024675.4(PALB2):c.1059del (p.Lys353fs)","Chromosome":"16","Start":"23635487","Stop":"23635487","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":180741,"rule_based_match":true,"evidence_text":"PALB2 c.1059delA","llm_judgment":"PRESENT","evidence":"PALB2</i> c.1059delA","abstract_start":1454,"abstract_end":1474}]}
{"pmid":"32048102","title":"Multimodal imaging in a family with Cockayne syndrome with a novel pathogenic mutation in the ERCC8 gene, and significant phenotypic variability.","abstract":"BACKGROUND: Cockayne syndrome is a rare autosomal recessive neurodegenerative disorder caused by mutations of either the ERCC6/CSB or ERCC8/CSA genes. Here, we describe two sisters with Cockayne syndrome caused by compound heterozygous mutations in the ERCC8 gene using multimodal imaging. Significant ophthalmic and systemic phenotypic variability is discussed.\nMATERIALS AND METHODS: Multimodal imaging was performed in two affected sisters and included electroretinography, optical coherence tomography, ultra-wide-field confocal scanning laser ophthalmoscopy, fundus autofluorescence and fluorescein angiography, and magnetic resonance imaging. Genetic analyses were performed on the affected sisters, both parents, and three unaffected siblings.\nRESULTS: The older sister (Patient 1) had mental retardation, bilateral hearing loss, ataxia, and decreased visual acuity with retinal dystrophy. Radiographic studies revealed microcephaly, cerebral and cerebellar atrophy, ventriculomegaly, and a diffusely thickened skull. Full-field electroretinography waveforms were severely diminished with attenuation of cone and rod responses. The younger sister (Patient 2) had similar clinical features, including ataxia, bilateral hearing loss, and decreased visual acuity with retinal dystrophy. She also had paranoid schizophrenia. Wide-field fundus autofluorescence showed scattered areas of retinal pigment epithelium atrophy, which was different from her sister. Genetic analysis revealed two mutations in the ERCC8 gene shared by the sisters. These include an unreported missense point mutation: p.Thr328Ser:c.983C > G, and another previously reported pathogenic missense mutation: p.Ala205Pro:c.613G > C. Familial testing showed in trans segregation of these mutations with unaffected siblings inheriting one or neither mutation, but not both.\nCONCLUSION: The clinical presentation and genetic studies confirmed a diagnosis of Cockayne syndrome in both sisters caused by compound heterozygous mutations in the ERCC8 gene on chromosome 10. Multimodal ocular imaging and systemic findings revealed wide phenotypic variability between the affected siblings.","variants":[{"Name":"NM_000082.4(ERCC8):c.613G>C (p.Ala205Pro)","Chromosome":"5","Start":"60902446","Stop":"60902446","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":16757,"rule_based_match":true,"evidence_text":"p.Ala205Pro:c.613G > C","llm_judgment":"PRESENT","evidence":"p.Ala205Pro:c.613G > C","abstract_start":1682,"abstract_end":1704}]}
{"pmid":"28819017","title":"Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series.","abstract":"OBJECTIVE: Germline loss-of-function mutations in succinate dehydrogenase (<i>SDHx</i>) genes results in rare tumor syndromes that include pheochromocytoma, paraganglioma, and others. Here we report a case series of patients with adrenocortical carcinoma (ACC) that harbor <i>SDHx</i> mutations.\nPATIENTS AND RESULTS: We report four unrelated patients with ACC and <i>SDHx</i> mutations. All cases presented with Cushing syndrome and large adrenal masses that were confirmed to be ACC on pathology. All four ACC specimens were found to have truncating mutations in either <i>SDHC</i> or <i>SDHA</i>, while cases 1, 2 and 3 also had the mutations confirmed in the germline: Case 1: <i>SDHC</i> c.397C > T, pR133X; Case 2: <i>SDHC</i> c.43C > T, p.R15X; Case 3: <i>SDHA</i> c.91C > T, p.R31X; Case 4: <i>SDHA</i> c.1258C > T, p.Q420X. Notably, Case 1 had a father and daughter who both harbored the same <i>SDHC</i> germline mutation, and the father had a paraganglioma and renal cell carcinoma. A combination of next generation sequencing, and/or immunohistochemistry, and/or mass spectroscopy was used to determine whether there was loss of heterozygosity and/or loss of SDH protein expression or function within the ACC. Potential evidence of loss of heterozygosity was observed only in Case 2.\nCONCLUSIONS: We observed truncating mutations in <i>SDHA</i> or <i>SDHC</i> in the ACC and/or germline of four unrelated patients. Given how statistically improbable the concurrence of ACC and pathogenic germline <i>SDHx</i> mutations is expected to be, these observations raise the question whether ACC may be a rare manifestation of <i>SDHx</i> mutation syndromes. Further studies are needed to investigate the possible role of SDH deficiency in ACC pathogenesis.","variants":[{"Name":"NM_003001.5(SDHC):c.397C>T (p.Arg133Ter)","Chromosome":"1","Start":"161356832","Stop":"161356832","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":181600,"rule_based_match":true,"evidence_text":"SDHC c.397C > T, pR133X","llm_judgment":"PRESENT","evidence":"SDHC</i> c.397C > T, pR133X","abstract_start":684,"abstract_end":711},{"Name":"NM_004168.4(SDHA):c.91C>T (p.Arg31Ter)","Chromosome":"5","Start":"223509","Stop":"223509","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152315,"rule_based_match":true,"evidence_text":"SDHA c.91C > T, p.R31X","llm_judgment":"PRESENT","evidence":"SDHA</i> c.91C > T, p.R31X","abstract_start":763,"abstract_end":789}]}
{"pmid":"29451150","title":"Identification of Seven Novel Mutations in the Acid Alpha-glucosidase Gene in Five Chinese Patients with Late-onset Pompe Disease.","abstract":"BACKGROUND: Pompe disease is a rare lysosomal glycogen storage disorder linked to the acid alpha-glucosidase gene (GAA). A wide clinical and genetic variability exists between patients from different ethnic populations, and the genotype-phenotype correlations are still not well understood. The aim of this study was to report the clinicopathological and genetic characteristics of five Chinese patients with late-onset Pompe disease (LOPD) who carried novel GAA gene mutations.\nMETHODS: Clinical and pathological data of patients diagnosed with glycogen storage disease at our institution from April 1986 to August 2017 were collected, and next-generation sequencing of frozen muscle specimens was conducted.\nRESULTS: Of the five patients included in the study, the median disease onset age was 13 years, with a median 5 years delay in diagnosis. The patients mainly manifested as progressive weakness in the proximal and axial muscles, while one patient developed respiratory insufficiency that required artificial ventilation. In muscle biopsies, vacuoles with variable sizes and shapes appeared inside muscle fibers, and they stained positive for both periodic acid-Schiff and acid phosphatase staining. Ten GAA gene mutations, including seven novel ones (c.796C>A, c.1057C>T, c.1201C>A, c.1780C>T, c.1799G>C, c.2051C>A, c.2235dupG), were identified by genetic tests.\nCONCLUSIONS: The seven novel GAA gene mutations revealed in this study broaden the genetic spectrum of LOPD and highlight the genetic heterogeneity in Chinese LOPD patients.","variants":[{"Name":"NM_000152.5(GAA):c.1780C>T (p.Arg594Cys)","Chromosome":"17","Start":"80112603","Stop":"80112603","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":646899,"rule_based_match":true,"evidence_text":"c.1780C>T","llm_judgment":"PRESENT","evidence":"c.1780C>T","abstract_start":1292,"abstract_end":1301},{"Name":"NM_000152.5(GAA):c.2051C>A (p.Pro684Gln)","Chromosome":"17","Start":"80113228","Stop":"80113228","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1675123,"rule_based_match":true,"evidence_text":"c.2051C>A","llm_judgment":"PRESENT","evidence":"c.2051C>A","abstract_start":1314,"abstract_end":1323}]}
{"pmid":"35011763","title":"Clinical, Histological, and Genetic Features of 25 Patients with Autosomal Dominant Progressive External Ophthalmoplegia (ad-PEO)/PEO-Plus Due to","abstract":"Autosomal dominant mutations in the <i>TWNK</i> gene, which encodes a mitochondrial DNA helicase, cause adult-onset progressive external ophthalmoplegia (PEO) and PEO-plus presentations. In this retrospective observational study, we describe clinical and complementary data from 25 PEO patients with mutations in <i>TWNK</i> recruited from the Hospital 12 de Octubre Mitochondrial Disorders Laboratory Database. The mean ages of onset and diagnosis were 43 and 63 years, respectively. Family history was positive in 22 patients. Ptosis and PEO (92% and 80%) were the most common findings. Weakness was present in 48%, affecting proximal limbs, neck, and bulbar muscles. Exercise intolerance was present in 28%. Less frequent manifestations were cardiac (24%) and respiratory (4%) involvement, neuropathy (8%), ataxia (4%), and parkinsonism (4%). Only 28% had mild hyperCKemia. All 19 available muscle biopsies showed signs of mitochondrial dysfunction. Ten different <i>TWNK</i> mutations were identified, with c.1361T>G (p.Val454Gly) and c.1070G>C (p.Arg357Pro) being the most common. Before definitive genetic confirmation, 56% of patients were misdiagnosed (36% with myasthenia, 20% with oculopharyngeal muscle dystrophy). Accurate differential diagnosis and early confirmation with appropriately chosen complementary studies allow genetic counseling and the avoidance of unnecessary treatments. Thus, mitochondrial myopathies must be considered in PEO/PEO-plus presentations, and particularly, <i>TWNK</i> is an important cause when positive family history is present.","variants":[{"Name":"NM_021830.5(TWNK):c.1070G>C (p.Arg357Pro)","Chromosome":"10","Start":"100989280","Stop":"100989280","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":620340,"rule_based_match":true,"evidence_text":"c.1070G>C (p.Arg357Pro)","llm_judgment":"PRESENT","evidence":"c.1070G>C (p.Arg357Pro)","abstract_start":1039,"abstract_end":1062}]}
{"pmid":"31356216","title":"A Novel Mutation in MARS in a Patient with Charcot-Marie-Tooth Disease, Axonal, Type 2U with Congenital Onset.","abstract":"Charcot-Marie-Tooth disease is a phenotypically and genetically heterogeneous group of disorders affecting both motor and sensory neurons. Exome sequencing has driven discovery of genes responsible for Charcot-Marie-Tooth disease with more than 70 genes now associated with this neuromuscular disease. The MARS gene was recently reported as the cause of Charcot-Marie-Tooth 2U, a slowly progressive axonal sensorimotor polyneuropathy with adult-onset reported in six patients. We report here a patient with a progressive, early childhood-onset, motor-predominant form of Charcot-Marie-Tooth disease. Exome sequencing identified a novel MARS variant (c.1189G>A; p.Ala397Thr) that was not present in her unaffected mother; her unaffected father was unavailable. Further studies using structural modeling and a yeast humanization assay support pathogenicity of the variant. Our study expands the phenotype of Charcot-Marie-Tooth 2U, while highlighting the utility of functional assays to evaluate variant pathogenicity.","variants":[{"Name":"NM_004990.4(MARS1):c.1189G>A (p.Ala397Thr)","Chromosome":"12","Start":"57500418","Stop":"57500418","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":682112,"rule_based_match":true,"evidence_text":"c.1189G>A (p.Ala397Thr)","llm_judgment":"PRESENT","evidence":"p.Ala397Thr","abstract_start":661,"abstract_end":672}]}
{"pmid":"25298746","title":"Limb girdle muscular dystrophy type 2G with myopathic-neurogenic motor unit potentials and a novel muscle image pattern.","abstract":"BACKGROUND: Limb girdle muscular dystrophy type 2G (LGMD2G) is a subtype of autosomal recessive muscular dystrophy caused by mutations in the telethonin gene. There are few LGMD2G patients worldwide reported, and this is the first description associated with early tibialis anterior sparing on muscle image and myopathic-neurogenic motor unit potentials.\nCASE PRESENTATION: Here we report a 31 years old caucasian male patient with progressive gait disturbance, and severe lower limb proximal weakness since the age of 20 years, associated with subtle facial muscle weakness. Computed tomography demonstrated soleus, medial gastrocnemius, and diffuse thigh muscles involvement with tibialis anterior sparing. Electromyography disclosed both neurogenic and myopathic motor unit potentials. Muscle biopsy demonstrated large groups of atrophic and hypertrophic fibers, frequent fibers with intracytoplasmic rimmed vacuoles full of autophagic membrane and sarcoplasmic debris, and a total deficiency of telethonin. Molecular investigation identified the common homozygous c.157C > T in the TCAP gene.\nCONCLUSION: This report expands the phenotypic variability of telethoninopathy/ LGMD2G, including: 1) mixed neurogenic and myopathic motor unit potentials, 2) facial weakness, and 3) tibialis anterior sparing. Appropriate diagnosis in these cases is important for genetic counseling and prognosis.","variants":[{"Name":"NM_003673.4(TCAP):c.157C>T (p.Gln53Ter)","Chromosome":"17","Start":"39665762","Stop":"39665762","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20564,"rule_based_match":true,"evidence_text":"c.157C > T","llm_judgment":"PRESENT","evidence":"c.157C > T","abstract_start":1068,"abstract_end":1078}]}
{"pmid":"19582488","title":"Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation.","abstract":"Schwannomatosis (MIM 162091) is a condition predisposing to the development of central and peripheral schwannomas; most cases are sporadic without a clear family history but a few families with a clear autosomal dominant pattern of transmission have been described. Germline mutations in SMARCB1 are associated with schwannomatosis. We report a family with multiple schwannomas and meningiomas. A SMARCB1 germline mutation in exon 1 was identified. The mutation, c.92A>T (p.Glu31Val), occurs in a highly conserved amino acid in the SMARCB1 protein. In addition, in silico analysis demonstrated that the mutation disrupts the donor consensus sequence of exon 1. RNA studies verified the absence of mRNA transcribed by the mutant allele. This is the first report of a SMARCB1 germline mutation in a family with schwannomatosis characterized by the development of multiple meningiomas.","variants":[{"Name":"NM_003073.5(SMARCB1):c.92A>T (p.Glu31Val)","Chromosome":"22","Start":"23787261","Stop":"23787261","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":23070,"rule_based_match":true,"evidence_text":"c.92A>T (p.Glu31Val)","llm_judgment":"PRESENT","evidence":"c.92A>T (p.Glu31Val)","abstract_start":463,"abstract_end":483}]}
{"pmid":"30244176","title":"Biallelic TOR1A mutations cause severe arthrogryposis: A case requiring reverse phenotyping.","abstract":"Heterozygous mutations in TOR1A gene are known to be responsible for DYT1 dystonia with incomplete penetrance. Autosomal recessive TOR1A disease is a very recently described syndrome characterized by severe arthrogryposis, developmental delay, strabismus and tremor. A 2 month-old boy with severe arthrogryposis and developmental delay was referred to our department for genetic counseling. Dystonic movements were observed on physical examination. Whole exome sequencing revealed a homozygous nonsense variant in exon 5 of TOR1A (c.862C > T, p.Arg288*). Our results expand the phenotypic and mutational spectrum of biallelic TOR1A disease, while emphasizing the importance of reverse phenotyping in the diagnosis of rare genetic disorders.","variants":[{"Name":"NM_000113.3(TOR1A):c.862C>T (p.Arg288Ter)","Chromosome":"9","Start":"129814109","Stop":"129814109","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":550616,"rule_based_match":true,"evidence_text":"c.862C > T, p.Arg288*","llm_judgment":"PRESENT","evidence":"c.862C > T, p.Arg288*","abstract_start":531,"abstract_end":552}]}
{"pmid":"32859164","title":"A case report of adult-onset COQ8B nephropathy presenting focal segmental glomerulosclerosis with granular swollen podocytes.","abstract":"BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiency of genetic origin is one of a few treatable focal segmental glomerulosclerosis (FSGS). Renal morphologic evidence for COQ8B mutation and CoQ10 deficiencies of other gene mutations is assessed using electron microscopy with marked increase of abnormal-shaped mitochondria in podocytes. However, light microscopic morphologic features of deficiencies other than FSGS have not been reported.\nCASE PRESENTATION: A 30-year-old woman was admitted to our hospital because proteinuria was found during four consecutive medical checkups. She had no medical history or family history of proteinuria and severe renal dysfunction. The swollen podocytes were stained to the same extent as mitochondria-rich proximal tubular cells under both Masson's trichrome and hematoxylin-eosin staining, whereas no mitochondrial abnormalities were detected under the first electron microscopic views. As proteinuria and estimated glomerular filtration rate (eGFR) deteriorated after pregnancy, we reevaluated the additional electron microscopic views and detected mitochondrial abnormalities. Genetic testing revealed COQ8B mutation (c.532C > T, p.R178W); therefore, we diagnosed COQ8B nephropathy. CoQ10 supplementation improved proteinuria and stopped eGFR reduction.\nCONCLUSIONS: This is the first report of granular swollen podocytes due to mitochondrial diseases detected under light microscopy. We propose that this finding can be the clue for the diagnosis of both COQ8B nephropathy and the other CoQ10 deficiencies.","variants":[{"Name":"NM_024876.4(COQ8B):c.532C>T (p.Arg178Trp)","Chromosome":"19","Start":"40705140","Stop":"40705140","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":97322,"rule_based_match":true,"evidence_text":"c.532C > T, p.R178W","llm_judgment":"PRESENT","evidence":"c.532C > T, p.R178W","abstract_start":1161,"abstract_end":1180}]}
{"pmid":"28407788","title":"Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation.","abstract":"Recessive mutations in the ubiquitously expressed POLR3A gene cause one of the most frequent forms of childhood-onset hypomyelinating leukodystrophy (HLD): POLR3-HLD. POLR3A encodes the largest subunit of RNA Polymerase III (Pol III), which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs. In order to study the central nervous system pathophysiology of the disease, we introduced the French Canadian founder Polr3a mutation c.2015G > A (p.G672E) in mice, generating homozygous knock-in (KI/KI) as well as compound heterozygous mice for one Polr3a KI and one null allele (KI/KO). Both KI/KI and KI/KO mice are viable and are able to reproduce. To establish if they manifest a motor phenotype, WT, KI/KI and KI/KO mice were submitted to a battery of behavioral tests over one year. The KI/KI and KI/KO mice have overall normal balance, muscle strength and general locomotion. Cerebral and cerebellar Luxol Fast Blue staining and measurement of levels of myelin proteins showed no significant differences between the three groups, suggesting that myelination is not overtly impaired in Polr3a KI/KI and KI/KO mice. Finally, expression levels of several Pol III transcripts in the brain showed no statistically significant differences. We conclude that the first transgenic mice with a leukodystrophy-causing Polr3a mutation do not recapitulate the childhood-onset HLD observed in the majority of human patients with POLR3A mutations, and provide essential information to guide selection of Polr3a mutations for developing future mouse models of the disease.","variants":[{"Name":"NM_007055.4(POLR3A):c.2015G>A (p.Gly672Glu)","Chromosome":"10","Start":"78007761","Stop":"78007761","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40100,"rule_based_match":true,"evidence_text":"c.2015G > A (p.G672E)","llm_judgment":"PRESENT","evidence":"c.2015G > A (p.G672E)","abstract_start":488,"abstract_end":509}]}
{"pmid":"30447469","title":"A Novel Mutation of Aryl Hydrocarbon Receptor Interacting Protein Gene Associated with Familial Isolated Pituitary Adenoma Mediates Tumor Invasion and Growth Hormone Hypersecretion.","abstract":"BACKGROUND: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene were identified in nearly 20% of families with familial isolated pituitary adenoma. Some variants of AIP have been confirmed to induce tumor cell proliferation and invasiveness; however, the mechanism is still unclear.\nMETHODS: A novel missense mutation (c.512C>T, p.T171I) was discovered in 3 patients from a Chinese family with familial isolated pituitary adenoma. In silico and multiplex ligation-dependent probe amplification analysis predicted the mutation to be pathogenic. GH3 and 293FT cell lines were used to verify the variant's effect on cell proliferation (Cell Counting Kit-8), invasiveness (Transwell) and growth hormone (GH) secretion (enzyme-linked immunosorbent assay) by transfection with different vectors: control, blank vector, wild-type AIP, p.T171I variant (experimental group), p.Q315* variant, and AIP small interfering RNA. Furthermore, Zac1, Sstr2, interleukin (IL)-6, and Stat3/phosphorylation-Stat3 expression (reverse transcription polymerase chain reaction, Western blot) in each group was also evaluated.\nRESULTS: The experimental group, p.Q315* variant group, and AIP small interfering RNA-overexpressing group promoted cell proliferation at 24 and 48 hours, respectively (compared with the control group; P < 0.01 for both). Similarly, the cells in the experimental group manifested more invasion and GH secretion compared with the control group (P < 0.01 and P < 0.05, respectively). Furthermore, the experimental group cells expressed less Sstr2 (a prerequisite for the responsiveness to somatostatin analogues) and Zac1 (tumor suppressor gene), but more IL-6 and phosphorylated-Stat3 (GH-secretion related).\nCONCLUSIONS: The novel AIP mutation c.512C>T (p.T171I) is a pathogenic variant that promoted cell proliferation, invasiveness, and GH secretion through regulation of Sstr2, Zac1, and IL-6/phosphorylated-Stat3 expression.","variants":[{"Name":"NM_003977.4(AIP):c.512C>T (p.Thr171Ile)","Chromosome":"11","Start":"67490081","Stop":"67490081","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1047427,"rule_based_match":true,"evidence_text":"c.512C>T (p.T171I)","llm_judgment":"PRESENT","evidence":"c.512C>T (p.T171I)","abstract_start":1776,"abstract_end":1794}]}
{"pmid":"33901312","title":"Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function.","abstract":"We identified nine patients from four unrelated families harboring three biallelic variants in SCN1B (NM_001037.5: c.136C>T; p.[Arg46Cys], c.178C>T; p.[Arg60Cys], and c.472G>A; p.[Val158Met]). All subjects presented with early infantile epileptic encephalopathy 52 (EIEE52), a rare, severe developmental and epileptic encephalopathy featuring infantile onset refractory seizures followed by developmental stagnation or regression. Because SCN1B influences neuronal excitability through modulation of voltage-gated sodium (Na<sub>V</sub> ) channel function, we examined the effects of human SCN1B<sup>R46C</sup> (β1<sup>R46C</sup> ), SCN1B<sup>R60C</sup> (β1<sup>R60C</sup> ), and SCN1B<sup>V158M</sup> (β1<sup>V158M</sup> ) on the three predominant brain Na<sub>V</sub> channel subtypes Na<sub>V</sub> 1.1 (SCN1A), Na<sub>V</sub> 1.2 (SCN2A), and Na<sub>V</sub> 1.6 (SCN8A). We observed a shift toward more depolarizing potentials of conductance-voltage relationships (Na<sub>V</sub> 1.2/β1<sup>R46C</sup> , Na<sub>V</sub> 1.2/β1<sup>R60C</sup> , Na<sub>V</sub> 1.6/β1<sup>R46C</sup> , Na<sub>V</sub> 1.6/β1<sup>R60C</sup> , and Na<sub>V</sub> 1.6/β1<sup>V158M</sup> ) and channel availability (Na<sub>V</sub> 1.1/β1<sup>R46C</sup> , Na<sub>V</sub> 1.1/β1<sup>V158M</sup> , Na<sub>V</sub> 1.2/β1<sup>R46C</sup> , Na<sub>V</sub> 1.2/β1<sup>R60C</sup> , and Na<sub>V</sub> 1.6/β1<sup>V158M</sup> ), and detected a slower recovery from fast inactivation for Na<sub>V</sub> 1.1/β1<sup>V158M</sup> . Combined with modeling data indicating perturbation-induced structural changes in β1, these results suggest that the SCN1B variants reported here can disrupt normal Na<sub>V</sub> channel function in the brain, which may contribute to EIEE52.","variants":[{"Name":"NM_001037.5(SCN1B):c.178C>T (p.Arg60Cys)","Chromosome":"19","Start":"35032665","Stop":"35032665","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":847532,"rule_based_match":true,"evidence_text":"c.178C>T; p.[Arg60Cys]","llm_judgment":"PRESENT","evidence":"c.178C>T; p.[Arg60Cys]","abstract_start":139,"abstract_end":161},{"Name":"NM_001037.5(SCN1B):c.136C>T (p.Arg46Cys)","Chromosome":"19","Start":"35032623","Stop":"35032623","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":469629,"rule_based_match":true,"evidence_text":"NM_001037.5: c.136C>T; p.[Arg46Cys]","llm_judgment":"PRESENT","evidence":"NM_001037.5: c.136C>T; p.[Arg46Cys]","abstract_start":102,"abstract_end":137},{"Name":"NM_001037.5(SCN1B):c.472G>A (p.Val158Met)","Chromosome":"19","Start":"35039140","Stop":"35039140","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188701,"rule_based_match":true,"evidence_text":"c.472G>A; p.[Val158Met]","llm_judgment":"PRESENT","evidence":"c.472G>A; p.[Val158Met]","abstract_start":167,"abstract_end":190}]}
{"pmid":"32062759","title":"Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype.","abstract":"KCNJ10 encodes the inward-rectifying potassium channel (Kir4.1) that is expressed in the brain, inner ear, and kidney. Loss-of-function mutations in KCNJ10 gene cause a complex syndrome consisting of epilepsy, ataxia, intellectual disability, sensorineural deafness, and tubulopathy (EAST/SeSAME syndrome). Patients with EAST/SeSAME syndrome display renal salt wasting and electrolyte imbalance that resemble the clinical features of impaired distal tubular salt transport in Gitelman's syndrome. A key distinguishing feature between these two conditions is the additional neurological (extrarenal) manifestations found in EAST/SeSAME syndrome. Recent reports have further expanded the clinical and mutational spectrum of KCNJ10-related disorders including non-syndromic early-onset cerebellar ataxia. Here, we describe a kindred of three affected siblings with early-onset ataxia, deafness, and progressive spasticity without other prominent clinical features. By using targeted next-generation sequencing, we have identified two novel missense variants, c.488G>A (p.G163D) and c.512G>A (p.R171Q), in the KCNJ10 gene that, in compound heterozygosis, cause this distinctive EAST/SeSAME phenotype in our family. Electrophysiological characterization of these two variants confirmed their pathogenicity. When expressed in CHO cells, the R171Q mutation resulted in 50% reduction of currents compared to wild-type KCNJ10 and G163D showed a complete loss of function. Co-expression of G163D and R171Q had a more pronounced effect on currents and membrane potential than R171Q alone but less severe than single expression of G163D. Moreover, the effect of the mutations seemed less pronounced in the presence of Kir5.1 (encoded by KCNJ16), with whom the renal Kir4.1 channels form heteromers. This partial functional rescue by co-expression with Kir5.1 might explain the lack of renal symptoms in the patients. This report illustrates that a spectrum of disorders with distinct clinical symptoms may result from mutations in different parts of KCNJ10, a gene initially associated only with the EAST/SeSAME syndrome.","variants":[{"Name":"NM_002241.5(KCNJ10):c.512G>A (p.Arg171Gln)","Chromosome":"1","Start":"160042021","Stop":"160042021","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":626986,"rule_based_match":true,"evidence_text":"c.512G>A (p.R171Q)","llm_judgment":"PRESENT","evidence":"c.512G>A (p.R171Q)","abstract_start":1079,"abstract_end":1097}]}
{"pmid":"26664771","title":"The Use of High-Density SNP Array to Map Homozygosity in Consanguineous Families to Efficiently Identify Candidate Genes: Application to Woodhouse-Sakati Syndrome.","abstract":"Two consanguineous Qatari siblings presented for evaluation: a 17-4/12-year-old male with hypogonadotropic hypogonadism, alopecia, intellectual disability, and microcephaly and his 19-year-old sister with primary amenorrhea, alopecia, and normal cognition. Both required hormone treatment to produce secondary sex characteristics and pubertal development beyond Tanner 1. SNP array analysis of both probands was performed to detect shared regions of homozygosity which may harbor homozygous mutations in a gene causing their common features of abnormal pubertal development, alopecia, and variable cognitive delay. Our patients shared multiple homozygous genomic regions; ten shared regions were >1 Mb in length and constituted 0.99% of the genome. DCAF17, encoding a transmembrane nuclear protein of uncertain function, was the only gene identified in a homozygous region known to cause hypogonadotropic hypogonadism. DCAF17 mutations are associated with Woodhouse-Sakati syndrome, a rare disorder characterized by alopecia, hypogonadotropic hypogonadism, sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC). Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation. This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified.","variants":[{"Name":"NM_025000.4(DCAF17):c.436del (p.Ala147fs)","Chromosome":"2","Start":"171448795","Stop":"171448795","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":205728,"rule_based_match":true,"evidence_text":"c.436del","llm_judgment":"PRESENT","evidence":"c.436del","abstract_start":1287,"abstract_end":1295}]}
{"pmid":"27443559","title":"Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy.","abstract":"Myofibrillar myopathies (MFMs) are genetically heterogeneous dystrophies characterized by the disintegration of Z-disks and myofibrils and are associated with mutations in genes encoding Z-disk or Z-disk-related proteins. The c.626 C > T (p.P209L) mutation in the BAG3 gene has been described as causative of a subtype of MFM. We report a sporadic case of a 26-year-old Italian woman, affected by MFM with axonal neuropathy, cardiomyopathy, rigid spine, who carries the c.626 C > T mutation in the BAG3 gene. The patient and her non-consanguineous healthy parents and brother were studied with whole exome sequencing (WES) to further investigate the genetic basis of this complex phenotype. In the patient, we found that the BAG3 mutation is associated with variants in the NRAP and FHL1 genes that encode muscle-specific, LIM domain containing proteins. Quantitative real time PCR, immunohistochemistry and Western blot analysis of the patient's muscular biopsy showed the absence of NRAP expression and FHL1 accumulation in aggregates in the affected skeletal muscle tissue. Molecular dynamic analysis of the mutated FHL1 domain showed a modification in its surface charge, which could affect its capability to bind its target proteins. To our knowledge this is the first study reporting, in a BAG3 MFM, the simultaneous presence of genetic variants in the BAG3 and FHL1 genes (previously described as independently associated with MFMs) and linking the NRAP gene to MFM for the first time.","variants":[{"Name":"NM_004281.4(BAG3):c.626C>T (p.Pro209Leu)","Chromosome":"10","Start":"119672373","Stop":"119672373","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21020,"rule_based_match":true,"evidence_text":"c.626 C > T (p.P209L)","llm_judgment":"PRESENT","evidence":"c.626 C > T (p.P209L)","abstract_start":226,"abstract_end":247}]}
{"pmid":"16358214","title":"SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis.","abstract":"Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10 patients who received the diagnosis of HHRH. The disease mapped to a 1.6-Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaP(i)-IIc. Nucleotide sequence analysis revealed a homozygous single-nucleotide deletion (c.228delC) in this candidate gene in all individuals affected by HHRH. This mutation is predicted to truncate the NaP(i)-IIc protein in the first membrane-spanning domain and thus likely results in a complete loss of function of this protein in individuals homozygous for c.228delC. In addition, compound heterozygous missense and deletion mutations were found in three additional unrelated HHRH kindreds, which supports the conclusion that this disease is caused by SLC34A3 mutations affecting both alleles. Individuals of the investigated kindreds who were heterozygous for a SLC34A3 mutation frequently showed hypercalciuria, often in association with mild hypophosphatemia and/or elevations in 1,25-dihydroxyvitamin D levels. We conclude that NaP(i)-IIc has a key role in the regulation of phosphate homeostasis.","variants":[{"Name":"NM_001177316.2(SLC34A3):c.228del (p.Cys77fs)","Chromosome":"9","Start":"137232626","Stop":"137232626","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":16469,"rule_based_match":true,"evidence_text":"c.228delC","llm_judgment":"PRESENT","evidence":"c.228delC","abstract_start":1035,"abstract_end":1044}]}
{"pmid":"28614222","title":"Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy.","abstract":"Hypertrophic cardiomyopathy (HCM) is a highly heterogeneous disease displaying considerable interfamilial and intrafamilial phenotypic variation, including disease severity, age of onset, and disease progression. This poorly understood variance raises the possibility of genetic modifier effects, particularly in MYBPC3-associated HCM.In a large consanguineous Chinese HCM family, we identified 8 members harboring the MYBPC3 c.3624delC (p.Lys1209Serfs) disease-causing mutation, but with very disparate phenotypes. Genotyping ruled out the modifying effect of previously described variants in renin-angiotensin-aldosterone system. Afterwards, we screened for modifying variants in all known causing genes and closely related genes for cardiomyopathy and channelopathy by performing targeted next-generation sequencing. For first time, we showed that a c.1598C>T (p.Ser533Leu) mutation in voltage-dependent l-type calcium channel subunit beta-2 (CACNB2) was present in all severely affected HCM patients, but not in those moderately affected or genotype-positive phenotype-negative patients. This CACNB2 p.Ser533Leu mutation is extremely conserved in evolution, and was not found in 550 healthy controls.Our results suggest that CACNB2 is a possible candidate genetic modifier of MYBPC3-associated familial HCM, but more genetic evidence and functional experiments are needed to confirm.","variants":[{"Name":"NM_000256.3(MYBPC3):c.3624delC","Chromosome":"11","Start":"47332569","Stop":"47332569","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":51897,"rule_based_match":true,"evidence_text":"MYBPC3 c.3624delC (p.Lys1209Serfs)","llm_judgment":"PRESENT","evidence":"MYBPC3 c.3624delC (p.Lys1209Serfs)","abstract_start":419,"abstract_end":453}]}
{"pmid":"31466887","title":"Clinical presentation, molecular analysis and follow-up of patients with mut methylmalonic acidemia in Shandong province, China.","abstract":"BACKGROUND: The mut methylmalonic acidemia (MMA) caused by the deficiency of methylmalonyl-CoA mutase (MCM) activity, which results from defects in the MUT gene. The aim of this study was to summarize the clinical and biochemical data, spectrum of mutations, treatment regime and follow-up of patients with mut MMA from Jan 2013 to Dec 2017 in Shandong province, China.\nMETHODS: Twenty patients were diagnosed with isolated mut MMA by elevated C3, C3/C2, and urine methylmalonic acid levels without hyperhomocysteinemia. The MUT gene was amplified and sequenced. Most patients received treatment with specific medical nutrition and oral l-carnitine after diagnosis. Metabolic parameters, clinical presentation and mental development were followed up.\nRESULTS: Among 20 patients with mut MMA, 14 had clinical presentations, and 12 presented in the neonatal period. Three patients died of metabolic crises triggered by infection. Twenty-three different mutations were detected, and four mutations (c.613G > A, c.446A > G, c.920-923delTCTT and c.1359delT) were novel. Most patients received timely treatment and had favorable metabolic responses, with reductions in C3, C3/C2 and urine MMA. We obtained 16 records of DQ/IQ assessments. Six patients exhibited normal development, but ten patients suffered from neurological symptoms of varying degrees and had low DQ/IQ scores.\nCONCLUSION: Our study contributes toward expanding the knowledge of the genetic basis of mut MMA. The c.914T > C was the most frequent mutation, and four novel mutations were detected. Patients diagnosed by newborn screening and treated at the presymptomatic stage may have better outcomes. However, these limited data do not allow any definitive statements on possible genotype-phenotype correlations that can influence the outcomes of mut MMA. Nonetheless, it is necessary for high-risk families to have early prenatal diagnoses.","variants":[{"Name":"NM_000255.4(MMUT):c.613G>A (p.Glu205Lys)","Chromosome":"6","Start":"49457831","Stop":"49457831","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1941505,"rule_based_match":true,"evidence_text":"c.613G > A","llm_judgment":"PRESENT","evidence":"c.613G > A","abstract_start":996,"abstract_end":1006}]}
{"pmid":"33832185","title":"A Novel Mutation in the Thyroglobulin Gene Resulting in Neonatal Goiter and Congenital Hypothyroidism in an Eritrean Infant","abstract":"Congenital hypothyroidism (CH) due to dyshormonogenesis may occur due to mutations in any of the key genes involved in thyroid hormone biosynthesis (<i>TG, TPO, DUOX2, DUOXA2, SLC5A5, IYD, SLC26A4</i> and <i>SLC26A7</i>). Mutations in the thyroglobulin gene (<i>TG</i>) are frequently associated with goiter, which may present fetally or neonatally, although a spectrum of phenotypes is reported. We present the case of a woman of Eritrean origin who presented in the third trimester of pregnancy in the early stages of labor. Ultrasound at presentation revealed a fetal neck swelling consistent with a goiter. Following delivery by Caesarian section with minimal respiratory support, the infant was found to be hypothyroid with undetectable serum levels of thyroglobulin. Sequencing of the <i>TG</i> revealed a homozygous donor splice site pathogenic variant (c.5686+1delG) not previously described in the literature. Levothyroxine treatment resulted in normal growth and psychomotor development. Goitrous CH with inappropriately low thyroglobulin has previously been reported in patients harbouring homozygous single nucleotide substitutions at the same <i>TG</i> donor splice site, which result in exon skipping and retention of malformed thyroglobulin by the endoplasmic reticulum. We conclude that the <i>TG</i> c.5686+1delG pathogenic variant is the likely basis for our patient’s fetal goiter and CH, and that the clinical phenotype associated with <i>TG</i> c.5686+1delG is comparable to that seen with single nucleotide substitutions at the same site.","variants":[{"Name":"NM_003235.5(TG):c.5686+1del","Chromosome":"8","Start":"132966698","Stop":"132966698","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":2992287,"rule_based_match":true,"evidence_text":"c.5686+1delG","llm_judgment":"PRESENT","evidence":"c.5686+1delG","abstract_start":861,"abstract_end":873}]}
{"pmid":"26395190","title":"Hearing impairment and renal failure associated with RMND1 mutations.","abstract":"Recently, two research groups reported that mutations in RMND1 were associated with encephalopathy, elevated lactate, hypotonia, and in some patients seizures or myoclonia in individuals from two consanguineous families. A combined respiratory chain deficiency and a defect in mitochondrial protein translation was found. In this study, we report two siblings who are compound heterozygous for the mutations, c.713A>G and c.1003delG, in RMND1. Respiratory chain enzymatic analysis and BN-PAGE showed a combined OXPHOS deficiency. Western blot analysis indicated normal levels of RMND1, but the assembly of the RMND1 homopolymeric complex was highly impaired. The two siblings had a markedly milder phenotype and longer survival compared to previously reported patients. In addition, they had renal failure and hearing impairment. These two newly described patients contribute to delineation of the clinical spectrum associated with RMND1 aberrations.","variants":[{"Name":"NM_017909.4(RMND1):c.713A>G (p.Asn238Ser)","Chromosome":"6","Start":"151430154","Stop":"151430154","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":171703,"rule_based_match":true,"evidence_text":"c.713A>G","llm_judgment":"PRESENT","evidence":"c.713A>G","abstract_start":409,"abstract_end":417}]}
{"pmid":"26024122","title":"Patient-Specific Induced Pluripotent Stem Cell-Derived RPE Cells: Understanding the Pathogenesis of Retinopathy in Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency.","abstract":"PURPOSE: Retinopathy is an important manifestation of trifunctional protein (TFP) deficiencies but not of other defects of fatty acid oxidation. The common homozygous mutation in the TFP α-subunit gene HADHA (hydroxyacyl-CoA dehydrogenase), c.1528G>C, affects the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity of TFP and blindness in infancy. The pathogenesis of the retinopathy is unknown. This study aimed to utilize human induced pluripotent stem cell (hiPSC) technology to create a disease model for the disorder, and to derive clues for retinopathy pathogenesis.\nMETHODS: We implemented hiPSC technology to generate LCHAD deficiency (LCHADD) patient-specific retinal pigment epithelial (RPE) monolayers. These patient and control RPEs were extensively characterized for function and structure, as well as for lipid composition by mass spectrometry.\nRESULTS: The hiPSC-derived RPE monolayers of patients and controls were functional, as they both were able to phagocytose the photoreceptor outer segments in vitro. Interestingly, the patient RPEs had intense cytoplasmic neutral lipid accumulation, and lipidomic analysis revealed an increased triglyceride accumulation. Further, patient RPEs were small and irregular in shape, and their tight junctions were disorganized. Their ultrastructure showed decreased pigmentation, few melanosomes, and more melanolysosomes.\nCONCLUSIONS: We demonstrate that the RPE cell model reveals novel early pathogenic changes in LCHADD retinopathy, with robust lipid accumulation, inefficient pigmentation that is evident soon after differentiation, and a defect in forming tight junctions inducing apoptosis. We propose that LCHADD-RPEs are an important model for mitochondrial TFP retinopathy, and that their early pathogenic changes contribute to infantile blindness of LCHADD.","variants":[{"Name":"NM_000182.5(HADHA):c.1528G>C (p.Glu510Gln)","Chromosome":"2","Start":"26195184","Stop":"26195184","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":23767,"rule_based_match":true,"evidence_text":"c.1528G>C","llm_judgment":"PRESENT","evidence":"c.1528G>C","abstract_start":241,"abstract_end":250}]}
{"pmid":"30925032","title":"The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies.","abstract":"PURPOSE: To identify the accurate clinical diagnosis of rare syndromic inherited retinal diseases (IRDs) based on the combination of clinical and genetic analyses.\nMETHODS: Four unrelated families with various autosomal recessive syndromic inherited retinal diseases were genetically investigated using whole-exome sequencing (WES).\nRESULTS: Two affected subjects in family MOL0760 presented with a distinctive combination of short stature, developmental delay, congenital mental retardation, microcephaly, facial dysmorphism and retinitis pigmentosa (RP). Subjects were clinically diagnosed with suspected Kabuki syndrome. WES revealed a homozygous nonsense mutation (c.5492dup, p.Asn1831Lysfs*8) in VPS13B that is known to cause Cohen syndrome. The index case of family MOL1514 presented with both RP and liver dysfunction, suspected initially to be related. WES identified a homozygous frameshift mutation (c.1787_1788del, p.His596Argfs*47) in AGBL5, associated with nonsyndromic RP. The MOL1592 family included three affected subjects with crystalline retinopathy, skin ichthyosis, short stature and congenital adrenal hypoplasia, and were found to harbour a homozygous nonsense mutation (c.682C>T, p.Arg228Cys) in ALDH3A2, reported to cause Sjögren-Larsson syndrome (SLS). In the fourth family, SJ002, two siblings presented with hypotony, psychomotor delay, dysmorphic facial features, pathologic myopia, progressive external ophthalmoplegia and diffuse retinal atrophy. Probands were suspected to have atypical Kearns-Sayre syndrome, but were diagnosed with combined oxidative phosphorylation deficiency-20 due to a novel suspected missense variant (c.1691C>T, p.Ala564Val) in VARS2.\nCONCLUSION: Our findings emphasize the important complement of WES and thorough clinical investigation in establishing precise clinical diagnosis. This approach constitutes the basis for personalized medicine in rare IRDs.","variants":[{"Name":"NM_000382.3(ALDH3A2):c.682C>T (p.Arg228Cys)","Chromosome":"17","Start":"19657746","Stop":"19657746","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":548031,"rule_based_match":true,"evidence_text":"c.682C>T (p.Arg228Cys)","llm_judgment":"PRESENT","evidence":"p.Arg228Cys","abstract_start":1203,"abstract_end":1214}]}
{"pmid":"28580830","title":"Thrombocytopenia and GBA gene mutation in a patient with adult type 1 Gaucher disease.","abstract":"A 38-year-old female patient was diagnosed with anemia for 3 years. Medical examination showed slight splenomegaly (250 × 62 mm), thrombocytopenia (platelets 51 × 10<sup>9</sup>/L), anemia (Hb levels 107 g/L), and β-glucocerebrosidase activity (GBA) in leukocytes was lower than normal. Microscopic findings of bone marrow smear demonstrated that Gaucher cells in bone marrow and periodic acid-Schiff staining of them were positive. Sequencing of GBA genomic and cDNA identified one novel homozygous mutation, c.484A> G (p.Met162Val). This case suggests that we should pay attention to adult Gaucher disease as a differential diagnosis for cryptogenic thrombocytopenia and one novel homozygous mutation in GBA gene was reported for the first time. The novel mutation in homozygosity is apparently associated with mild, non-neuronopathic type 1 disease which is relatively uncommon in Asian populations.","variants":[{"Name":"NM_000157.4(GBA1):c.484A>G (p.Met162Val)","Chromosome":"1","Start":"155238621","Stop":"155238621","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1698911,"rule_based_match":true,"evidence_text":"c.484A> G (p.Met162Val)","llm_judgment":"PRESENT","evidence":"c.484A> G (p.Met162Val)","abstract_start":510,"abstract_end":533}]}
{"pmid":"31028847","title":"Exome-based search for recurrent disease-causing alleles in Russian population.","abstract":"Exomes of 27 Russian subjects were analyzed for the presence of medically relevant alleles, such as protein-truncating variants (PTVs) in known recessive disease-associated genes and pathogenic missense mutations included in the ClinVar database. 36 variants (24 PTVs and 12 amino acid substitutions) were identified and then subjected to the analysis in 897 population controls. 9/36 mutations were novel, however only two of them (POLH c.490delG associated with xeroderma pigmentosum variant (XPV) and CATSPER1 c.859_860delCA responsible for spermatogenic failure) were shown to be recurrent. 27 out of 36 pathogenic alleles were already described in prior genetic studies; seven of them occurred only in the index cases, while 20 demonstrated evidence for persistence in Russian population. In particular, non-random occurrence was revealed for SERPINA1 c.1096G > A (alpha-1 antitrypsin deficiency), C8B c.1282C > T and c.1653G > A (complement component 8B deficiency), ATP7B c.3207C > A (Wilson disease), PROP1 c.301_302delAG (combined pituitary hormone deficiency), CYP21A2 c.844G > T (non-classical form of adrenogenital syndrome), EYS c.1155T > A (retinitis pigmentosa), HADHA c.1528G > C (LCHAD deficiency), SCO2 c.418G > A (cytochrome c oxidase deficiency), OTOA c.2359G > T (sensorineural deafness), C2 c.839_866del (complement component 2 deficiency), ACADVL c.848T > C (VLCAD deficiency), TGM5 c.337G > T (acral peeling skin syndrome) and VWF c.2561 G > A (von Willebrand disease, type 2N). These data deserve to be considered in future medical genetic activities.","variants":[{"Name":"NM_144672.4(OTOA):c.2359G>T (p.Glu787Ter)","Chromosome":"16","Start":"21736318","Stop":"21736318","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":215511,"rule_based_match":true,"evidence_text":"OTOA c.2359G > T","llm_judgment":"PRESENT","evidence":"OTOA c.2359G > T","abstract_start":1267,"abstract_end":1283}]}
{"pmid":"28247339","title":"Galactose Epimerase Deficiency: Expanding the Phenotype.","abstract":"Galactose epimerase deficiency is an inborn error of metabolism due to uridine diphosphate-galactose-4'-epimerase (GALE) deficiency. We report the clinical presentation, genetic and biochemical studies in two siblings with generalized GALE deficiency.Patient 1: The first child was born with a dysmorphic syndrome. Failure to thrive was noticed during the first year. Episodes of heart failure due to dilated cardiomyopathy, followed by liver failure, occurred between 12 and 42 months. The finding of a serum transferrin isoelectrofocusing (IEF) type 1 pattern led to the suspicion of a congenital disorder of glycosylation (CDG). Follow-up disclosed psychomotor disability, deafness, and nuclear cataracts.Patient 2: The sibling of patient 1 was born with short limbs and hip dysplasia. She is deceased in the neonatal period due to intraventricular hemorrhage in the context of liver failure. Investigation disclosed galactosuria and normal transferrin glycosylation.Next-generation sequence panel analysis for CDG syndrome revealed the previously reported c.280G>A (p.[V94M]) homozygous mutation in the GALE gene. Enzymatic studies in erythrocytes (patient 1) and fibroblasts (patients 1 and 2) revealed markedly reduced GALE activity confirming generalized GALE deficiency. This report describes the fourth family with generalized GALE deficiency, expanding the clinical spectrum of this disorder, since major cardiac involvement has not been reported before.","variants":[{"Name":"NM_001008216.2(GALE):c.280G>A (p.Val94Met)","Chromosome":"1","Start":"23798188","Stop":"23798188","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18721,"rule_based_match":true,"evidence_text":"c.280G>A (p.[V94M])","llm_judgment":"PRESENT","evidence":"c.280G>A (p.[V94M])","abstract_start":1060,"abstract_end":1079}]}
{"pmid":"20937952","title":"Pathological 43-kDa transactivation response DNA-binding protein in older adults with and without severe mental illness.","abstract":"BACKGROUND: Major psychiatric diseases such as schizophrenia and mood disorders have not been linked to a specific pathology, but their clinical features overlap with some aspects of the behavioral variant of frontotemporal lobar degeneration. Although the significance of pathological 43-kDa (transactivation response) DNA-binding protein (TDP-43) for frontotemporal lobar degeneration was appreciated only recently, the prevalence of TDP-43 pathology in patients with severe mental illness vs controls has not been systematically addressed.\nOBJECTIVE: To examine patients with chronic psychiatric diseases, mainly schizophrenia, for evidence of neurodegenerative TDP-43 pathology in comparison with controls.\nDESIGN: Prospective longitudinal clinical evaluation and retrospective medical record review, immunohistochemical identification of pathological TDP-43 in the central nervous system, and genotyping for gene alterations known to cause TDP-43 proteinopathies including the TDP-43 (TARDBP) and progranulin (GRN) genes.\nSETTING: University health system.\nPARTICIPANTS: One hundred fifty-one subjects including 91 patients with severe mental illness (mainly schizophrenia) and 60 controls.\nMAIN OUTCOME MEASURES: Clinical medical record review, neuronal and glial TDP-43 pathology, and TARDP and GRN genotyping status.\nRESULTS: Significant TDP-43 pathology in the amygdala/periamygdaloid region or the hippocampus/transentorhinal cortex was absent in both groups in subjects younger than 65 years but present in elderly subjects (29% [25 of 86] of the psychiatric patients and 29% [10 of 34] of control subjects). Twenty-three percent (8 of 35) of the positive cases showed significant TDP-43 pathology in extended brain scans. There were no evident differences between the 2 groups in the frequency, degree, or morphological pattern of TDP-43 pathology. The latter included (1) subpial and subependymal, (2) focal, or (3) diffuse lesions in deep brain parenchyma and (4) perivascular pathology. A new GRN variant of unknown significance (c.620T>C, p.Met207Thr) was found in 1 patient with schizophrenia with TDP-43 pathology. No known TARDBP mutations or other variants were found in any of the subjects studied herein.\nCONCLUSIONS: The similar findings of TDP-43 pathology in elderly patients with severe mental illness and controls suggest common age-dependent TDP-43 changes in limbic brain areas that may signify that these regions are affected early in the course of a cerebral TDP-43 multisystem proteinopathy. Finally, our data provide an age-related baseline for the development of whole-brain pathological TDP-43 evolution schemata.","variants":[{"Name":"NM_002087.4(GRN):c.620T>C (p.Met207Thr)","Chromosome":"17","Start":"44350712","Stop":"44350712","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1416904,"rule_based_match":true,"evidence_text":"c.620T>C, p.Met207Thr","llm_judgment":"PRESENT","evidence":"c.620T>C, p.Met207Thr","abstract_start":2045,"abstract_end":2066}]}
{"pmid":"33807568","title":"Simultaneous Homozygous Mutations in","abstract":"Gitelman syndrome (GS) and Bartter syndrome (BS) type III are both rare, recessively inherited salt-losing tubulopathies caused by <i>SLC12A3</i> and <i>CLCNKB</i> mutations, respectively. We described a 48-year-old male patient with fatigue, carpopedal spasm, arthralgia, hypokalemic alkalosis, mild renal dysfunction, hypomagnesemia, hypocalciuria, hyperuricemia, normotension, hyperreninemia and chondrocalcinosis in knees and Achilles tendons. His parents are first cousin. Genetic analysis revealed simultaneous homozygous mutations in <i>SLC12A3</i> gene with c.248G>A, p.Arg83Gln and <i>CLCNKB</i> gene with c.1171T>C, p.Trp391Arg. The second younger brother of the proband harbored the same simultaneous mutations in <i>SLC12A3</i> and <i>CLCNKB</i> and exhibited similar clinical features except normomagnesemia and bilateral kidney stones. The first younger brother of the proband harbored the same homozygous mutations in <i>CLCNKB</i> and exhibited clinical features of hypokalemia, normomagnesemia, hypercalciuria and hyperuricemia. Potassium chloride, spironolactone and potassium magnesium aspartate were prescribed to the proband to correct electrolytic disturbances. Benzbromarone and febuxostat were prescribed to correct hyperuricemia. The dose of potassium magnesium aspartate was subsequently increased to alleviate arthralgia resulting from calcium pyrophosphate deposition disease (CPPD). To the best of our knowledge, we are the first to report an exceptionally rare case in an inbred Chinese pedigree with simultaneous homozygous mutations in <i>SLC12A3</i> and <i>CLCNKB</i>. GS and BS type III have significant intrafamilial phenotype heterogeneity. When arthralgia is developed in patients with GS and BS, gout and CPPD should both be considered.","variants":[{"Name":"NM_000085.5(CLCNKB):c.1171T>C (p.Trp391Arg)","Chromosome":"1","Start":"16050992","Stop":"16050992","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3762227,"rule_based_match":true,"evidence_text":"c.1171T>C, p.Trp391Arg","llm_judgment":"PRESENT","evidence":"c.1171T>C, p.Trp391Arg","abstract_start":615,"abstract_end":637},{"Name":"NM_001126108.2(SLC12A3):c.248G>A (p.Arg83Gln)","Chromosome":"16","Start":"56865483","Stop":"56865483","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620550,"rule_based_match":true,"evidence_text":"c.248G>A, p.Arg83Gln","llm_judgment":"PRESENT","evidence":"c.248G>A, p.Arg83Gln","abstract_start":566,"abstract_end":586}]}
{"pmid":"23246293","title":"Whole-exome sequencing identifies LRIT3 mutations as a cause of autosomal-recessive complete congenital stationary night blindness.","abstract":"Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder. Two forms can be distinguished clinically: complete CSNB (cCSNB) and incomplete CSNB. Individuals with cCSNB have visual impairment under low-light conditions and show a characteristic electroretinogram (ERG). The b-wave amplitude is severely reduced in the dark-adapted state of the ERG, representing abnormal function of ON bipolar cells. Furthermore, individuals with cCSNB can show other ocular features such as nystagmus, myopia, and strabismus and can have reduced visual acuity and abnormalities of the cone ERG waveform. The mode of inheritance of this form can be X-linked or autosomal recessive, and the dysfunction of four genes (NYX, GRM6, TRPM1, and GPR179) has been described so far. Whole-exome sequencing in one simplex cCSNB case lacking mutations in the known genes led to the identification of a missense mutation (c.983G>A [p.Cys328Tyr]) and a nonsense mutation (c.1318C>T [p.Arg440(∗)]) in LRIT3, encoding leucine-rich-repeat (LRR), immunoglobulin-like, and transmembrane-domain 3 (LRIT3). Subsequent Sanger sequencing of 89 individuals with CSNB identified another cCSNB case harboring a nonsense mutation (c.1151C>G [p.Ser384(∗)]) and a deletion predicted to lead to a premature stop codon (c.1538_1539del [p.Ser513Cysfs(∗)59]) in the same gene. Human LRIT3 antibody staining revealed in the outer plexiform layer of the human retina a punctate-labeling pattern resembling the dendritic tips of bipolar cells; similar patterns have been observed for other proteins implicated in cCSNB. The exact role of this LRR protein in cCSNB remains to be elucidated.","variants":[{"Name":"NM_198506.5(LRIT3):c.983G>A (p.Cys328Tyr)","Chromosome":"4","Start":"109869732","Stop":"109869732","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48037,"rule_based_match":true,"evidence_text":"c.983G>A (p.Cys328Tyr)","llm_judgment":"PRESENT","evidence":"p.Cys328Tyr","abstract_start":953,"abstract_end":964},{"Name":"NM_198506.5(LRIT3):c.1318C>T (p.Arg440Ter)","Chromosome":"4","Start":"109870067","Stop":"109870067","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48038,"rule_based_match":true,"evidence_text":"c.1318C>T (p.Arg440(*))","llm_judgment":"PRESENT","evidence":"c.1318C>T","abstract_start":992,"abstract_end":1001},{"Name":"NM_198506.5(LRIT3):c.1151C>G (p.Ser384Ter)","Chromosome":"4","Start":"109869900","Stop":"109869900","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":48039,"rule_based_match":true,"evidence_text":"c.1151C>G (p.Ser384(∗))","llm_judgment":"PRESENT","evidence":"c.1151C>G","abstract_start":1238,"abstract_end":1247},{"Name":"NM_198506.5(LRIT3):c.1538_1539del (p.Ser513fs)","Chromosome":"4","Start":"109870285","Stop":"109870286","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":48040,"rule_based_match":true,"evidence_text":"c.1538_1539del","llm_judgment":"PRESENT","evidence":"c.1538_1539del","abstract_start":1323,"abstract_end":1337}]}
{"pmid":"29302266","title":"The First Korean case of combined oxidative phosphorylation deficiency-17 diagnosed by clinical and molecular investigation.","abstract":"Combined oxidative phosphorylation deficiency-17 (COXPD-17) is very rare and is caused by homozygous or compound heterozygous mutations in the <i>ELAC2</i> gene on chromosome 17p12. The <i>ELAC2</i> gene functions as a mitochondrial tRNA processing gene, and only 4 different pathogenic mutations have been reported in <i>ELAC2</i>-associated mitochondrial dysfunction involving oxidative phosphorylation. Affected patients show various clinical symptoms and prognosis, depending on the genotype. We report a novel mutation in the <i>ELAC2</i> gene (c.95C>G [p.Pro32Arg], <i>het</i>), in an infant with COXPD-17 who presented with encephalopathy including central apnea and intractable epilepsy, and growth and developmental retardation. During hospitalization, consistently elevated serum lactic acid levels were noted, indicative of mitochondrial dysfunction. The patient suddenly died of shock of unknown cause at 5 months of age. This is the first case report of COXPD-17 in Korea and was diagnosed based on clinical characteristics and genetic analysis.","variants":[{"Name":"NM_018127.7(ELAC2):c.95C>G (p.Pro32Arg)","Chromosome":"17","Start":"13017853","Stop":"13017853","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":375948,"rule_based_match":true,"evidence_text":"c.95C>G (p.Pro32Arg)","llm_judgment":"PRESENT","evidence":"p.Pro32Arg","abstract_start":559,"abstract_end":569}]}
{"pmid":"29180260","title":"A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID).","abstract":"Common variable immunodeficiency (CVID) is characterised by repeated infection associated with primary acquired hypogammaglobulinemia. CVID frequently has a complex aetiology but, in certain cases, it has a monogenic cause. Recently, variants within the gene encoding the transcription factor STAT3 were implicated in monogenic CVID. Here, we describe a patient presenting with symptoms synonymous with CVID, who displayed reduced levels of IgG and IgA, repeated viral infections and multiple additional co-morbidities. Whole-exome sequencing revealed a de novo novel missense mutation in the coiled-coil domain of STAT3 (c.870A>T; p.K290N). Accordingly, the K290N variant of STAT3 was generated, and a STAT3 responsive dual-luciferase reporter assay revealed that the variant strongly enhances STAT3 transcriptional activity both under basal and stimulated (with IL-6) conditions. Overall, these data complement earlier studies in which CVID-associated STAT3 mutations are predicted to enhance transcriptional activity, suggesting that such patients may respond favourably to IL-6 receptor antagonists (e.g. tocilizumab).","variants":[{"Name":"NM_139276.3(STAT3):c.870A>T (p.Lys290Asn)","Chromosome":"17","Start":"42333977","Stop":"42333977","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":815932,"rule_based_match":true,"evidence_text":"c.870A>T; p.K290N","llm_judgment":"PRESENT","evidence":"c.870A>T; p.K290N","abstract_start":622,"abstract_end":639}]}
{"pmid":"20582465","title":"PALB2 analysis in BRCA2-like families.","abstract":"BRCA2 and PALB2 function together in the Fanconi anemia (FA)-Breast Cancer (BRCA) pathway. Mono-allelic and bi-allelic BRCA2 and PALB2 mutation carriers share many clinical characteristics. Mono-allelic germline mutations of BRCA2 and PALB2 are risk alleles of female breast cancer and have also been reported in familial pancreatic cancer, and bi-allelic mutations cause a severe form of Fanconi anemia. In view of these similarities, we investigated whether the prevalence of PALB2 mutations was increased in breast cancer families with the occurrence of BRCA2 associated tumours other than female breast cancer. PALB2 mutation analysis was performed in 110 non-BRCA1/2 cancer patients: (a) 53 ovarian cancer patients from female breast-and/or ovarian cancer families; (b) 45 breast cancer patients with a first or second degree relative with pancreatic cancer; and (c) 12 male breast cancer patients from female breast cancer families. One truncating PALB2 mutation, c.509_510delGA, resulting in p.Arg170X, was found in a male breast cancer patient. We conclude that germline mutations of PALB2 do not significantly contribute to cancer risk in non-BRCA1/2 cancer families with at least one patient with ovarian cancer, male breast cancer, and/or pancreatic cancer.","variants":[{"Name":"NM_024675.4(PALB2):c.509_510del (p.Arg170fs)","Chromosome":"16","Start":"23636036","Stop":"23636037","ReferenceAlleleVCF":"ATC","AlternateAlleleVCF":"A","allel_id":132267,"rule_based_match":true,"evidence_text":"c.509_510delGA","llm_judgment":"PRESENT","evidence":"c.509_510delGA","abstract_start":970,"abstract_end":984}]}
{"pmid":"26945816","title":"Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber's Disease.","abstract":"OBJECTIVE: To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis.\nMETHODS: Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed.\nRESULTS: The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ∼8% of that in controls, confirming a diagnosis of Farber's disease.\nCONCLUSION: Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far.","variants":[{"Name":"NM_177924.5(ASAH1):c.760A>G (p.Arg254Gly)","Chromosome":"8","Start":"18061402","Stop":"18061402","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":800724,"rule_based_match":true,"evidence_text":"c.760A>G (p.Arg254Gly)","llm_judgment":"PRESENT","evidence":"c.760A>G (p.Arg254Gly)","abstract_start":944,"abstract_end":966},{"Name":"NM_177924.5(ASAH1):c.505T>C (p.Trp169Arg)","Chromosome":"8","Start":"18062422","Stop":"18062422","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":189143,"rule_based_match":true,"evidence_text":"c.505T>C (p.Trp169Arg)","llm_judgment":"PRESENT","evidence":"c.505T>C (p.Trp169Arg)","abstract_start":917,"abstract_end":939}]}
{"pmid":"27324886","title":"X-linked Hyper IgM Syndrome Presenting as Pulmonary Alveolar Proteinosis.","abstract":"PURPOSE: X-linked hyper IgM syndrome (XHIGM) is a combined immunodeficiency caused by mutations in the CD40 ligand (CD40L) gene that typically results in decreased or absent CD40L expression on activated T cells, leading to defective class switching and somatic hypermutation. We describe an infant who presented with respiratory failure due to pulmonary alveolar proteinosis (PAP) with a novel damaging missense mutation in the CD40L gene.\nMETHODS: Whole exome sequencing (WES) was used to identify a mutation in the CD40L gene. CD40L expression and function were determined by flow cytometry.\nRESULTS: A 5-month-old previously-healthy male presented with respiratory failure and diffuse pulmonary ground glass opacities on CT scan of the chest. Laboratory evaluation revealed an undetectable IgG, normal IgA, and elevated IgM. A bronchoalveolar lavage demonstrated pulmonary alveolar proteinosis. WES demonstrated a c.608G > C mutation in the CD40L gene resulting in p.R203T. Flow cytometry demonstrated normal CD40L expression on activated T cells but absent binding of CD40-Ig to CD40L on activated patient T cells.\nCONCLUSIONS: The clinical manifestations of XHIGM in our patient had several unique features, including the presentation with PAP, normal serum IgA, and expression of non-functional CD40L on activated T cells. To our knowledge, this is the first published case of PAP in a patient with XHIGM.","variants":[{"Name":"NM_000074.3(CD40LG):c.608G>C (p.Arg203Thr)","Chromosome":"X","Start":"136659237","Stop":"136659237","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":849683,"rule_based_match":true,"evidence_text":"c.608G > C mutation in the CD40L gene resulting in p.R203T","llm_judgment":"PRESENT","evidence":"c.608G > C mutation in the CD40L gene resulting in p.R203T","abstract_start":918,"abstract_end":976}]}
{"pmid":"18617776","title":"The SPINK1 N34S variant is associated with acute pancreatitis.","abstract":"OBJECTIVE: Acute pancreatitis (AP) is a disease whose pathogenesis remains largely obscure. Genetic research has focussed attention upon the role of the pancreatic protease/protease inhibitor system. The aim of this study was to investigate the prevalence of genetic variants of the trypsin inhibitor, SPINK1, in acute pancreatitis.\nMETHODS: We genotyped 468 patients with AP and 1117 healthy controls for SPINK1 alterations by single-strand conformation polymorphism analysis and by melting curve analysis using fluorescence resonance energy transfer probes.\nRESULTS: The c.101A>G (p.N34S) variant was detected in 24/936 alleles of patients and in 18/2234 alleles of healthy controls (odds ratio=3.240; 95% confidence interval: 1.766-5.945; P<0.001). In the UK patients, the mean age of patients with N34S was 11.9 years younger compared with N34S negative patients (P=0.023), but this was not apparent in the German patients. Allele frequencies for the c.163C>T (p.P55S) variant did not differ between patients and controls.\nCONCLUSION: The SPINK1 N34S variant is associated with acute pancreatitis. This supports the importance of premature protease activation in the pathogenesis of AP and suggests that mutated SPINK1 may predispose certain individuals to develop this disease.","variants":[{"Name":"NM_001379610.1(SPINK1):c.101A>G (p.Asn34Ser)","Chromosome":"5","Start":"147828115","Stop":"147828115","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":28799,"rule_based_match":true,"evidence_text":"c.101A>G (p.N34S)","llm_judgment":"PRESENT","evidence":"c.101A>G (p.N34S)","abstract_start":573,"abstract_end":590}]}
{"pmid":"30499050","title":"Osteoporosis-pseudoglioma syndrome: clinical, genetic, and treatment-response study of 10 new cases in Greece.","abstract":"Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal-recessive disorder, characterized by severe osteoporosis and early-onset blindness. Loss of function mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5) have been established as the genetic defect of the disease. We report the clinical and genetic evaluation of ten OPPG cases in eight related nuclear families and their close relatives. Bone mineral density (BMD) in OPPG patients was assessed by dual-energy X-ray absorptiometry (DXA). Genotyping of LRP5 gene and targeted detection of index mutation were performed by DNA direct sequencing. Four patients were introduced to bisphosphonates. Mutational screening of LRP5 gene revealed the c.2409_2503+79del deletion in homozygous state, expected to result in a truncated protein. Among 44 members of the pedigree, 10 (22%) were identified homozygous and 34 (59%) heterozygous for this mutation. All patients had congenital blindness and 7 of them had also impaired bone mineral density. Four of them received bisphosphonates and responded with decreased bone pain and improvement in BMD; however, 3 patients presented with one fracture during treatment.Conclusion: The current study presents the molecular and clinical profiles of 10 new OPPG cases, being part of an extended pedigree. Patients who received bisphosphonate treatment responded well with increase in their BMD, though fractures occurred during therapy. What is known: • OPPG syndrome is a rare genetic disorder characterized by congenital blindness and juvenile osteoporosis. • Loss of function mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5) is the genetic defect of the disease. What is new: • Genetic and clinical phenotype of 10 new OPPG patients. • The ten new OPPG patients presented with phenotypical variability in osseous manifestations.","variants":[{"Name":"NM_002335.4(LRP5):c.2409_2503+79del","Chromosome":"11","Start":"68411525","Stop":"68411698","ReferenceAlleleVCF":"GTGGGCCGGGCCAACGACCTCACCATTGACTACGCTGACCAGCGCCTCTACTGGACCGACCTGGACACCAACATGATCGAGTCGTCCAACATGCTGGGTGAGGGCCGGGCTGGGGCCTTCTGGTCATGGAGGGCGGGGCAGCCGGGCGTTGGCCACCTCCCAGCCTCGCCGCACA","AlternateAlleleVCF":"G","allel_id":3408964,"rule_based_match":true,"evidence_text":"c.2409_2503+79del","llm_judgment":"PRESENT","evidence":"c.2409_2503+79del","abstract_start":740,"abstract_end":757}]}
{"pmid":"32390314","title":"Identification of two novel mutations in POU4F3 gene associated with autosomal dominant hearing loss in Chinese families.","abstract":"Autosomal dominant non-syndromic hearing loss is genetically heterogeneous with 47 genes identified to date, including POU4F3. In this study, by using a next-generation sequencing panel targeting 127 deafness genes, we identified a pathogenic frameshift mutation c.704_705del and a missense mutation c.593G>A in two three-generation Chinese families with late-onset progressive ADNSHL, respectively. The novel mutations of POU4F3 co-segregated with the deafness phenotype in these two families. c.704_705del caused a frameshift p.T235fs and c.593G>A caused an amino acid substitution of p.R198H. Both mutations led to an abnormal and incomplete protein structure. POU4F3 with either of the two mutations was transiently transfected into HEI-OC1 and HEK 293 cell lines and immunofluorescence assay was performed to investigate the subcellular localization of mutated protein. The results indicated that both c.704_705del (p.T235fs) and c.593G>A (p.R198H) could impair the nuclear localization function of POU4F3. The p.R198H POU4F3 protein was detected as a weak band of the correct molecular weight, indicating that the stability of p.R198H POU4F3 differed from that of the wild-type protein. While, the p.T235fs POU4F3 protein was expressed with a smaller molecular weight, implying this mutation result in a frameshift and premature termination of the POU4F3 protein. In summary, we report two novel mutations of POU4F3 associated with progressive ADNSHL and explored their effects on POU4F3 nuclear localization. These findings expanded the mutation spectrum of POU4F3 and provided new knowledge for the pathogenesis of POU4F3 in hearing loss.","variants":[{"Name":"NM_002700.3(POU4F3):c.593G>A (p.Arg198His)","Chromosome":"5","Start":"146340020","Stop":"146340020","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":536683,"rule_based_match":true,"evidence_text":"c.593G>A (p.R198H)","llm_judgment":"PRESENT","evidence":"c.593G>A (p.R198H)","abstract_start":935,"abstract_end":953}]}
{"pmid":"25402387","title":"Precocious presentation of autoimmune polyglandular syndrome type 2 associated with an AIRE mutation.","abstract":"Autoimmune polyglandular syndrome type 2 (type 2 APS), or Schmidt's syndrome, is defined by the presence of Addison's disease in combination with type 1 diabetes and/or autoimmune thyroid disease. The estimated prevalence of this syndrome is 1.4-4.5 per 100,000 inhabitants and it is more frequent in middle-aged females, whilst it is quite rare in children. Type 2 APS, which shows a pattern of autosomal dominant inheritance with low penetrance, has been associated with HLA specific DR3/DQ2 and DR4/DQ8 haplotypes. However, it has been hypothesized that genetic variability in the AIRE gene, which causing type 1 APS, may play a role in more common organ-specific autoimmune conditions like type 1 diabetes, Hashimoto's disease and type 2 APS, among others. Here we present the case of an 8-year-old girl, with a past medical history of type 1 diabetes diagnosed at the age of 3. She was taken to the Emergency Department because she complained of abdominal pain, nausea and vomiting, and her blood analysis revealed a severe hyponatremia. She also had seizures as a consequence of the hyponatremia and frequent hypoglycemia. She was ultimately found to be suffering from autoimmune primary adrenal insufficiency. The combination of both mentioned conditions, type 1 diabetes and Addison's disease, in the absence of chronic mucocutaneous candidiasis, made a diagnosis of type 2 APS plausible in this girl. The genetic study showed two heterozygous variants: NM_000383.2:C.1411C>T (p. Arg471Cys) in exon 12 and IVS9+6G>A in intron 9 of the AIRE gene. The description of an uncommon case of type 2 APS with precocious presentation associated with an AIRE mutation in a very young girl could help to clarify the role of AIRE in the development of autoimmune diseases.","variants":[{"Name":"NM_000383.4(AIRE):c.1411C>T (p.Arg471Cys)","Chromosome":"21","Start":"44294411","Stop":"44294411","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":133781,"rule_based_match":true,"evidence_text":"NM_000383.2:C.1411C>T (p. Arg471Cys)","llm_judgment":"PRESENT","evidence":"NM_000383.2:C.1411C>T (p. Arg471Cys)","abstract_start":1462,"abstract_end":1498}]}
{"pmid":"21615986","title":"Distinct mutations in MLH1 and MSH2 genes in hereditary non-polyposis colorectal cancer (HNPCC) families from China.","abstract":"Hereditary non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inheritance syndrome. HNPCC is the most common hereditary variant of colorectal cancer (CRC), which accounts for 2-5% CRCs, mainly due to hMLH1 and hMSH2 mutations that impair DNA repair functions. Our study aimed to identify the patterns of hMSH2 and hMLH1 mutations in Chinese HNPCC patients. Ninety-eight unrelated families from China meeting Amsterdam or Bethesda criteria were included in our study. Germline mutations in MLH1 and MSH2 genes, located in the exons and the splice-site junctions, were screened in the 98 probands by direct sequencing. Eleven mutations were found in ten patients (11%), with six in MLH1 (54.5%) and five in MSH2 (45.5%) genes. One patient had mutations in both MLH1 and MSH2 genes. Three novel mutations in MLH1 gene (c.157_160delGAGG, c.2157dupT and c.-64G>T) were found for the first time, and one suspected hotspot in MSH2 (c.1168C>T) was revealed.","variants":[{"Name":"NM_000251.3(MSH2):c.1168C>T (p.Leu390Phe)","Chromosome":"2","Start":"47429833","Stop":"47429833","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":50080,"rule_based_match":true,"evidence_text":"c.1168C>T","llm_judgment":"PRESENT","evidence":"c.1168C>T","abstract_start":939,"abstract_end":948},{"Name":"NM_000249.4(MLH1):c.2157dup (p.Val720fs)","Chromosome":"3","Start":"37050537","Stop":"37050538","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AT","allel_id":95549,"rule_based_match":true,"evidence_text":"c.2157dupT","llm_judgment":"PRESENT","evidence":"c.2157dupT","abstract_start":848,"abstract_end":858}]}
{"pmid":"23211702","title":"Two novel mutations of the GTP cyclohydrolase 1 gene and genotype-phenotype correlation in Chinese Dopa-responsive dystonia patients.","abstract":"The most common form of Dopa-responsive dystonia (DRD) is caused by heterozygous mutations in the GTP cyclohydrolase I (GCH1) gene. We screened two unrelated, DRD-symptomatic Chinese Han individuals, for GCH1 gene mutations by direct sequencing. As the clinical manifestations of DRD are highly variable, we also explored the association between genotype and phenotype in all Chinese DRD patients reported so far in the literature, comprising 62 DRD-affected patients from 36 Chinese families. Two novel missense mutations (T94M, L145F) and a novel variant (c. 453+6 G>T) were identified in our two new patients. None of these variants was detected in 200 healthy controls. On the basis of this and other reports, heterozygous mutations were detected in 90.3% of Chinese Han subjects with DRD. Seeming the age of onset for males and females, the mean age was 13 years older in males than in females (P=0.006). Different mutation types did not show any significant differences in age of onset, gender composition, initial symptoms, or the L-dopa dose that abolished the symptoms. Among DRD patients lacking missense or exon-intron boundary mutations, 68.4% were found to possess a large deletion in GCH1, which were detected by multiplex ligation-dependent probe amplification. Most GCH1 mutations were found to cluster in two regions of the coding sequence, suggesting the probable existence of mutation hotspot for the first time. The genotype-phenotype correlation described here may improve our understanding of DRD in Chinese individuals.","variants":[{"Name":"NM_000161.3(GCH1):c.453+6G>T","Chromosome":"14","Start":"54865321","Stop":"54865321","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1874710,"rule_based_match":true,"evidence_text":"c. 453+6 G>T","llm_judgment":"PRESENT","evidence":"c. 453+6 G>T","abstract_start":558,"abstract_end":570}]}
{"pmid":"25110155","title":"Screening for five prevalent mutations of SLC25A13 gene in Guangdong, China: a molecular epidemiologic survey of citrin deficiency.","abstract":"Citrin is the liver-type aspartate/glutamate carrier isoform 2 (AGC2) encoded by SLC25A13 gene, playing important roles in the urea cycle and the malate-aspartate shuttle. Citrin deficiency (CD) has proven a disease entity with high prevalence in south China, including Guangdong with the largest population, but CD epidemiology in this province has not been well characterized. This study aims to screen for five prevalent SLC25A13 mutations, c.851_854del (p.R284fs286X), c.1638_1660dup (p.A554fs570X), c.615+5G>A (p.A206fs212X), IVS16ins3kb (p.A584fs585X) and c.1399C>T (p.R467X), to calculate the mutation carrier rate in Guangdong. A total of 2,428 used blood samples for health examination were collected as the research subjects, including 1,558 from 5 cities in the Pearl River Delta area and the remaining 870 from 4 peripheral cities, and the 5 mutations screened using High Resolution Melting Assay and HybProbe assay. A total of 52 carriers were detected, including 2 carriers of a novel c.1420G>A (p.V474M) mutation that impairs citrin function, as judged by the functional analysis in the yeast system. The carrier rate was higher in Pearl River Delta area than that in the peripheral cities (26/1,558 vs. 26/870, with χ(2) = 4.639 and P < 0.05). The carrier rate was around 1/47 (52/2,428), theoretically with the CD morbidity of 1/8,800 and the number of CD patients over 11,800 in Guangdong population. This study has provided primary epidemiologic data for the evaluation of CD effect in Guangdong province. Moreover, the newly identified c.1420G>A mutation that impairs AGC2 function has enriched the mutation spectrum of human SLC25A13 gene.","variants":[{"Name":"NM_014251.3(SLC25A13):c.1420G>A (p.Val474Met)","Chromosome":"7","Start":"96146588","Stop":"96146588","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":955266,"rule_based_match":true,"evidence_text":"c.1420G>A (p.V474M)","llm_judgment":"PRESENT","evidence":"c.1420G>A (p.V474M)","abstract_start":999,"abstract_end":1018}]}
{"pmid":"30503518","title":"Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation.","abstract":"FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[<sup>3</sup>H] fucose and [<sup>3</sup>H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-<sup>3</sup>H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway.","variants":[{"Name":"NM_145059.3(FCSK):c.2047C>T (p.Arg683Cys)","Chromosome":"16","Start":"70474586","Stop":"70474586","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":610432,"rule_based_match":true,"evidence_text":"c.2047C>T (p.Arg683Cys)","llm_judgment":"PRESENT","evidence":"c.2047C>T (p.Arg683Cys)","abstract_start":697,"abstract_end":720},{"Name":"NM_145059.3(FCSK):c.2980A>C (p.Lys994Gln)","Chromosome":"16","Start":"70479230","Stop":"70479230","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":610433,"rule_based_match":true,"evidence_text":"c.2980A>C (p.Lys994Gln)","llm_judgment":"PRESENT","evidence":"c.2980A>C (p.Lys994Gln)","abstract_start":767,"abstract_end":790},{"Name":"NM_145059.3(FCSK):c.667T>C (p.Ser223Pro)","Chromosome":"16","Start":"70468852","Stop":"70468852","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":610431,"rule_based_match":true,"evidence_text":"c.667T>C (p.Ser223Pro)","llm_judgment":"PRESENT","evidence":"c.667T>C (p.Ser223Pro)","abstract_start":670,"abstract_end":692}]}
{"pmid":"19162478","title":"Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient.","abstract":"Mutations in BCS1L, a respiratory chain complex III assembly chaperone, constitute a major cause of mitochondrial complex III deficiency and are associated with GRACILE and Björnstad syndromes. Here we describe a 4-year-old infant with hyperlactacidemia, mild liver dysfunction, hypotonia, growth and psychomotor retardation, dysmorphic features and mitochondrial complex III deficiency. Respiratory chain enzyme activities showed an isolated complex III defect in muscle and fibroblasts. Sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis revealed a novel homozygous BCS1L mutation, c.148A>G, which caused a p.T50A substitution at an evolutionarily conserved BCS1L region. The severity of the complex III enzyme defect correlated with decreased amounts of BCS1L and respiratory chain complex III in the affected tissues. Our findings support a pathogenic role for the novel BCS1L mutation in a patient with a singular clinical phenotype.","variants":[{"Name":"NM_001079866.2(BCS1L):c.148A>G (p.Thr50Ala)","Chromosome":"2","Start":"218661135","Stop":"218661135","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":21212,"rule_based_match":true,"evidence_text":"c.148A>G","llm_judgment":"PRESENT","evidence":"c.148A>G","abstract_start":635,"abstract_end":643}]}
{"pmid":"19235233","title":"Functional analysis of three splicing mutations identified in the PMM2 gene: toward a new therapy for congenital disorder of glycosylation type Ia.","abstract":"The congenital disorders of glycosylation (CDG) are a group of diseases caused by genetic defects affecting N-glycosylation. The most prevalent form of CDG-type Ia-is caused by defects in the PMM2 gene. This work reports the study of two new nucleotide changes (c.256-1G>C and c.640-9T>G) identified in the PMM2 gene in CDG1a patients, and of a previously described deep intronic nucleotide change in intron 7 (c.640-15479C>T). Cell-based splicing assays strongly suggest that all these are disease-causing splicing mutations. The c.256-1G>C mutation was found to cause the skipping of exons 3 and 4 in fibroblast cell lines and in a minigene expression system. The c.640-9T>G mutation was found responsible for the activation of a cryptic intronic splice-site in fibroblast cell lines and in a hybrid minigene when cotransfected with certain serine/arginine-rich (SR) proteins. Finally, the deep intronic change c.640-15479C>T was found to be responsible for the activation of a pseudoexon sequence in intron 7. The use of morpholino oligonucleotides allowed the production of correctly spliced mRNA that was efficiently translated into functional and immunoreactive PMM protein. The present results suggest a novel mutation-specific approach for the treatment of this genetic disease (for which no effective treatment is yet available), and open up therapeutic possibilities for several genetic disorders in which deep intronic changes are seen.","variants":[{"Name":"NM_000303.3(PMM2):c.640-15479C>T","Chromosome":"16","Start":"8832245","Stop":"8832245","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":547819,"rule_based_match":true,"evidence_text":"c.640-15479C>T","llm_judgment":"PRESENT","evidence":"c.640-15479C>T","abstract_start":411,"abstract_end":425},{"Name":"NM_000303.3(PMM2):c.256-1G>C","Chromosome":"16","Start":"8806315","Stop":"8806315","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":22766,"rule_based_match":true,"evidence_text":"c.256-1G>C","llm_judgment":"PRESENT","evidence":"c.256-1G>C","abstract_start":262,"abstract_end":272},{"Name":"NM_000303.3(PMM2):c.640-9T>G","Chromosome":"16","Start":"8847715","Stop":"8847715","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":621848,"rule_based_match":true,"evidence_text":"c.640-9T>G","llm_judgment":"PRESENT","evidence":"c.640-9T>G","abstract_start":277,"abstract_end":287}]}
{"pmid":"34289880","title":"Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome.","abstract":"BACKGROUND: Wiedemann-Rautenstrauch syndrome (WRS) is a rare autosomal recessive neonatal progeroid disorder characterized by prenatal and postnatal growth retardation, short stature, a progeroid appearance, hypotonia, and mental impairment.\nCASE PRESENTATION: A 6-year-old patient, who initially presented with multiple postnatal abnormalities, facial dysplasia, micrognathia, skull appearance, hallux valgus, and congenital dislocation of the hip, was recruited in this study. The patient was initially diagnosed with progeria. The mother of the patient had abnormal fetal development during her second pregnancy check-up, and the clinical phenotype of the fetus was similar to that of the patient. Whole-exome sequencing (WES) of the patient was performed, and POLR3B compound heterozygous variants-c.2191G > C:p.E731Q and c.3046G > A:p.V1016M-were identified in the patient. Using Sanger sequencing, we found that the phenotypes and genotypes were segregated within the pedigree. These two variants are novel and not found in the gnomAD and 1000 Genomes databases. The two mutation sites are highly conserved between humans and zebrafish.\nCONCLUSIONS: Our study not only identified a novel WRS-associated gene, POLR3B, but also broadened the mutational and phenotypic spectra of POLR3B. Furthermore, WES may be useful for identifying rare disease-related genetic variants.","variants":[{"Name":"NM_018082.6(POLR3B):c.2191G>C (p.Glu731Gln)","Chromosome":"12","Start":"106454609","Stop":"106454609","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1334234,"rule_based_match":true,"evidence_text":"c.2191G > C:p.E731Q","llm_judgment":"PRESENT","evidence":"c.2191G > C:p.E731Q","abstract_start":802,"abstract_end":821},{"Name":"NM_018082.6(POLR3B):c.3046G>A (p.Val1016Met)","Chromosome":"12","Start":"106501384","Stop":"106501384","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1334235,"rule_based_match":true,"evidence_text":"c.3046G > A:p.V1016M","llm_judgment":"PRESENT","evidence":"c.3046G > A:p.V1016M","abstract_start":826,"abstract_end":846}]}
{"pmid":"25633902","title":"Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.","abstract":"In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.","variants":[{"Name":"NM_005956.4(MTHFD1):c.146C>T (p.Ser49Phe)","Chromosome":"14","Start":"64411109","Stop":"64411109","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439710,"rule_based_match":true,"evidence_text":"c.146C>T (p.Ser49Phe)","llm_judgment":"PRESENT","evidence":"p.Ser49Phe","abstract_start":1397,"abstract_end":1407}]}
{"pmid":"26851524","title":"Somatic mosaicism of the PIK3CA gene identified in a Hungarian girl with macrodactyly and syndactyly.","abstract":"Isolated macrodactyly (OMIM 155500) belongs to a heterogeneous group of overgrowth syndromes. It is a congenital anomaly resulting in enlargement of all tissues localized to the terminal portions of a limb and caused by somatic mutations in the phosphatidylinositol 3-kinase catalytic alpha (PIK3CA, OMIM 171834) gene. Here we report a Hungarian girl with macrodactyly and syndactyly. Genetic screening at hotspots in the PIK3CA gene identified a mosaic mutation (c.1624G > A, p.Glu542Lys) in the affected tissue, but not in the peripheral blood. To date, this somatic mutation has been reported in eight patients affected by different forms of segmental overgrowth syndromes. Detailed analysis of the Hungarian child and previously reported cases suggests high phenotypic diversity associated with the p.Glu542Lys somatic mutation. The identification of the mutation provides a novel therapeutic modality for the affected patients: those who carry somatic mutations in the PIK3CA gene are potential recipients of a novel \"repurposing\" approach of rapamycin treatment.","variants":[{"Name":"NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)","Chromosome":"3","Start":"179218294","Stop":"179218294","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40609,"rule_based_match":true,"evidence_text":"c.1624G > A, p.Glu542Lys","llm_judgment":"PRESENT","evidence":"c.1624G > A, p.Glu542Lys","abstract_start":464,"abstract_end":488}]}
{"pmid":"35393742","title":"Decompensation of cardiorespiratory function and emergence of anemia during pregnancy in a case of mitochondrial myopathy, lactic acidosis, and sideroblastic anemia 2 with compound heterozygous YARS2 pathogenic variants.","abstract":"Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants confer heterogeneous phenotypes ranging from the full MLASA syndrome to a clinically unaffected state. Symptom onset is most common in the first decade of life but can occur in adulthood and has been reported following intercurrent illness. Early death can result from respiratory muscle weakness and cardiomyopathy. We report a case of MLASA2 with compound heterozygous YARS2 pathogenic variants; a known pathogenic nonsense variant [NM_001040436.3:c.98C>A (p.Ser33Ter)] and a likely pathogenic missense variant not previously associated with disease [NM_001040436.3:c.948G>T (p.Arg316Ser)]. The proband initially presented with a relatively mild phenotype of myopathy and lactic acidosis. During pregnancy, anemia emerged as an additional feature and in the postpartum period she experienced severe decompensation of cardiorespiratory function. This is the first reported case of pregnancy-related complications in a patient with YARS2-related mitochondrial disease. This case highlights the need for caution and careful counseling when considering pregnancy in mitochondrial disease, due to the risk of disease exacerbation and pregnancy complications.","variants":[{"Name":"NM_001040436.3(YARS2):c.98C>A (p.Ser33Ter)","Chromosome":"12","Start":"32755777","Stop":"32755777","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1890519,"rule_based_match":true,"evidence_text":"NM_001040436.3:c.98C>A (p.Ser33Ter)","llm_judgment":"PRESENT","evidence":"NM_001040436.3:c.98C>A (p.Ser33Ter)","abstract_start":602,"abstract_end":637}]}
{"pmid":"22137173","title":"Biallelic mutations in PLA2G5, encoding group V phospholipase A2, cause benign fleck retina.","abstract":"Flecked-retina syndromes, including fundus flavimaculatus, fundus albipunctatus, and benign fleck retina, comprise a group of disorders with widespread or limited distribution of yellow-white retinal lesions of various sizes and configurations. Three siblings who have benign fleck retina and were born to consanguineous parents are the basis of this report. A combination of homozygosity mapping and exome sequencing helped to identify a homozygous missense mutation, c.133G>T (p.Gly45Cys), in PLA2G5, a gene encoding a secreted phospholipase (group V phospholipase A(2)). A screen of a further four unrelated individuals with benign fleck retina detected biallelic variants in the same gene in three patients. In contrast, no loss of function or common (minor-allele frequency>0.05%) nonsynonymous PLA2G5 variants have been previously reported (EVS, dbSNP, 1000 Genomes Project) or were detected in an internal database of 224 exomes (from subjects with adult onset neurodegenerative disease and without a diagnosis of ophthalmic disease). All seven affected individuals had fundoscopic features compatible with those previously described in benign fleck retina and no visual or electrophysiological deficits. No medical history of major illness was reported. Levels of low-density lipoprotein were mildly elevated in two patients. Optical coherence tomography and fundus autofluorescence findings suggest that group V phospholipase A(2) plays a role in the phagocytosis of photoreceptor outer-segment discs by the retinal pigment epithelium. Surprisingly, immunohistochemical staining of human retinal tissue revealed localization of the protein predominantly in the inner and outer plexiform layers.","variants":[{"Name":"NM_000929.3(PLA2G5):c.133G>T (p.Gly45Cys)","Chromosome":"1","Start":"20086175","Stop":"20086175","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39116,"rule_based_match":true,"evidence_text":"c.133G>T (p.Gly45Cys)","llm_judgment":"PRESENT","evidence":"c.133G>T (p.Gly45Cys)","abstract_start":469,"abstract_end":490}]}
{"pmid":"29239255","title":"Nonfunctional pancreatic endocrine tumor in the peripancreatic region in a Chinese patient with multiple endocrine neoplasia type 1.","abstract":"Nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) in patients with multiple endocrine neoplasia type 1 (MEN1), which results from a mutation in the MEN1 gene, are commonly small, multiple tumors located in the pancreatic head and inside the pancreatic parenchyma. We herein describe a 35-year-old woman with bone pain and a 7-year history of a prolactinoma. She was clinically diagnosed with MEN1 based on the presence of the prolactinoma and parathyroid hyperplasia. Abdominal computed tomography revealed a 5-cm mass close to the splenic hilum. This soft tissue tumor, which was located outside the pancreatic parenchyma and the tissue origin of which could not be identified preoperatively, was found to be connected to the pancreatic tail. After resection, histological examination revealed a well-differentiated neuroendocrine tumor of pancreatic origin. Genetic testing revealed a heterozygous transition mutation of guanine to adenine at the coding nucleotide 133 in exon 2 (c.133G>A), resulting in an amino acid substitution of glutamic acid with lysine (E45K) in the MEN1 gene. This patient with MEN1 presented with a clinical condition involving a single non-metastatic NF-pNET located outside the pancreatic parenchyma with a missense mutation in the MEN1 gene, which could easily have been misdiagnosed as an accessory spleen.","variants":[{"Name":"NM_001370259.2(MEN1):c.133G>A (p.Glu45Lys)","Chromosome":"11","Start":"64809977","Stop":"64809977","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":419861,"rule_based_match":true,"evidence_text":"c.133G>A","llm_judgment":"PRESENT","evidence":"c.133G>A","abstract_start":990,"abstract_end":998}]}
{"pmid":"17186466","title":"Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy.","abstract":"Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous heart-muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death. Mutations in desmosomal proteins that cause ARVC have been previously described; therefore, we investigated 88 unrelated patients with the disorder for mutations in human desmosomal cadherin desmocollin-2 (DSC2). We identified a heterozygous splice-acceptor-site mutation in intron 5 (c.631-2A-->G) of the DSC2 gene, which led to the use of a cryptic splice-acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identify DSC2 mutations as a cause of ARVC in humans and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function.","variants":[{"Name":"NM_024422.6(DSC2):c.631-2A>G","Chromosome":"18","Start":"31087815","Stop":"31087815","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":31889,"rule_based_match":false,"evidence_text":"c.631-2A-->G","llm_judgment":"PRESENT","evidence":"c.631-2A-->G","abstract_start":524,"abstract_end":536}]}
{"pmid":"32332277","title":"Thrombosis risk of Alport syndrome patients: evaluation of cardiological, clinical, biochemical, genetic and possible causes of inherited thrombophilia and identification of a novel COL4A3 variant.","abstract":": To evaluate cases with Alport syndrome for laboratory, radiological, ophthalmological, auditory tests, cardiological and inherited thrombophilia risk. Laboratory findings, abdominal and urinary ultrasonography, ophthalmological and auditory tests and cardiological examination of 21 Alport syndrome suspicious cases were performed. Also, collagen type IV alpha three chain (COL4A3) gene, four chain (COL4A4) gene and five chain (COL4A5) genes were sequenced by next-generation sequencing system. In addition, possible causes of inherited thrombophilia were evaluated. A novel (c.2806C>T/p.Gln936Ter) variation in COL4A3 gene was detected in three cases. Also c.221G>A/p.Arg74Gln variation in COL4A5 gene of two cases, c.4421C>T/p.Thr1474Met variation in COL4A4 gene of one case, c.665C>T/p.Pro222Leu variation in COL4A4 gene of one case and compound heterozygous c.4421C>T/(p.Thr1474Met) and c.665C>T/p.Pro222Leu variation in COL4A4 gene of one case were detected. Although 10 (47.6%) cases had microscopic hematuria, six (28.6%) cases had macroscopic hematuria, but there were not hematuria in five (23.8%) of cases. Three cases with variation carrier in COL4A genes and one case without variation carrier had vision problem. Also, one case with variation carrier in COL4A gene had hearing loss. All cases with variation carrier in COL4A genes exclude one had at least one cardiac problems. Also, all cases with variation carrier in COL4A genes had possible causes of inherited thrombophilia risk. In addition to developing risk of progressive kidney failure, sensorineural hearing loss and ocular abnormalities, Alport syndrome cases may have increasing cardiac problems and possible causes of inherited thrombophilia risk. Therefore, these cases should be regularly evaluated and followed for cardiac problems and inherited thrombophilia risk.","variants":[{"Name":"NM_000092.5(COL4A4):c.4421C>T (p.Thr1474Met)","Chromosome":"2","Start":"227010414","Stop":"227010414","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":285682,"rule_based_match":true,"evidence_text":"c.4421C>T/p.Thr1474Met","llm_judgment":"PRESENT","evidence":"c.4421C>T/p.Thr1474Met","abstract_start":720,"abstract_end":742}]}
{"pmid":"19763142","title":"Mutational screening of VSX1 in keratoconus patients from the European population.","abstract":"PURPOSE: To perform mutational screening of the visual system homeobox gene 1 (VSX1; MIM#605020) in patients with sporadic and familial keratoconus (MIM#148300) in a European population and, for the first time, report the mutational analysis of the two newly identified VSX1exons.\nMETHODS: VSX1sequence variants in patients with keratoconus were evaluated by direct sequencing of the entire coding region, including two novel exons. In familial keratoconus cases, segregation of potentially pathogenic VSX1variants was assessed to determine pathogenicity. Transcript analysis was carried out on splice site and synonymous sequence variants not detected in controls.\nRESULTS: A total of 66 unrelated patients with keratoconus from the European population (27 with familial keratoconus; 39 with sporadic keratoconus) were analysed for VSX1 mutations. Four sequence variants were not observed in 100 healthy control individuals: c.432C>G (p.D144E), c.479G>A (p.G160D), c.789C>T (p.S263S), and an intronic change c.844-13T>A (numbered with respect to NM_014588). Segregation was not detected for p.D144E and c.844-13T>A. The change in p.G160D was observed in two patients with sporadic keratoconus. Although predicted to alter VSX1 splicing, p.S263S had no effect on transcript processing. Four known SNPs were detected and the following polymorphic variants were observed in keratoconus patients and controls: c.711T>A (NM_199425; p.P237P), c.844-5_-6insT (NM_014588), c.*28G>T (DQ854811/DQ854812), and c.*50G>A (DQ854809/DQ854810).\nCONCLUSIONS: VSX1has a minor role in keratoconus pathogenesis. The pathogenicity of p.G160D remains controversial and this change may represent a rare polymorphism or genetic modifier. Further evidence is provided that the previously reported variant, p.D144E, is a polymorphism.","variants":[{"Name":"NM_014588.6(VSX1):c.479G>A (p.Gly160Asp)","Chromosome":"20","Start":"25079460","Stop":"25079460","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20287,"rule_based_match":true,"evidence_text":"c.479G>A (p.G160D)","llm_judgment":"PRESENT","evidence":"c.479G>A (p.G160D)","abstract_start":946,"abstract_end":964}]}
{"pmid":"32805445","title":"A 34-year-old Japanese patient exhibiting NBAS deficiency with a novel mutation and extended phenotypic variation.","abstract":"Biallelic neuroblastoma amplified sequence (NBAS) gene mutations have recently been identified to cause a reduction in its protein expression and a broad phenotypic spectrum, from isolated short stature, optic nerve atrophy, and Pelger-Huët anomaly (SOPH) syndrome or infantile liver failure syndrome 2 to a combined, multi-systemic disease including skeletal dysplasia and immunological and neurological abnormalities. Herein, we report a 34-year-old patient with a range of phenotypes for NBAS deficiency due to compound heterozygous variants; one is a SOPH-specific variant, p.Arg1914His, and the other is a novel splice site variant, c.6433-2A>G. The patient experienced recurrent acute liver failure until early childhood. Hypogammaglobulinemia, a decrease in natural killer cells, and optic nerve atrophy were evident from infancy to childhood. In adulthood, the patient exhibited novel phenotypic features such as hepatic cirrhosis complicated by portal hypertension and autoimmune hemolytic anemia. The patient also suffered from childhood-onset insulin-requiring diabetes with progressive beta cell dysfunction. The patient had severe short stature and exhibited dysmorphic features compatible with SOPH, intellectual disability, and epilepsy. NBAS protein expression in the patient's fibroblasts was severely low. RNA expression analysis for the c.6433-2A>G variant showed that this variant activated two cryptic splice sites in intron 49 and exon 50, for which the predicted consequences at the protein level were an in-frame deletion/insertion, p.(Ile2199_Asn2202delins16), and a premature termination codon, p.(Ile2199Tyrfs*17), respectively. These findings indicate that NBAS deficiency is a multi-systemic progressive disease. The results of this study extend the spectrum of clinical and genetic findings related to NBAS deficiency.","variants":[{"Name":"NM_015909.4(NBAS):c.6433-2A>G","Chromosome":"2","Start":"15190405","Stop":"15190405","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":963435,"rule_based_match":true,"evidence_text":"c.6433-2A>G","llm_judgment":"PRESENT","evidence":".6433-2A>G.","abstract_start":638,"abstract_end":649}]}
{"pmid":"25516103","title":"Multiple sulfatase deficiency with neonatal manifestation.","abstract":"Multiple Sulfatase Deficiency (MSD; OMIM 272200) is a rare autosomal recessive inborn error of metabolism caused by mutations in the sulfatase modifying factor 1 gene, encoding the formylglycine-generating enzyme (FGE), and resulting in tissue accumulation of sulfatides, sulphated glycosaminoglycans, sphingolipids and steroid sulfates. Less than 50 cases have been published so far. We report a new case of MSD presenting in the newborn period with hypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compound heterozygous for two so far undescribed SUMF1 mutations (c.191C > A; p.S64X and c.818A > G; p.D273G).","variants":[{"Name":"NM_182760.4(SUMF1):c.191C>A (p.Ser64Ter)","Chromosome":"3","Start":"4467055","Stop":"4467055","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":916914,"rule_based_match":true,"evidence_text":"c.191C > A; p.S64X","llm_judgment":"PRESENT","evidence":"c.191C > A; p.S64X","abstract_start":614,"abstract_end":632},{"Name":"NM_182760.4(SUMF1):c.818A>G (p.Asp273Gly)","Chromosome":"3","Start":"4417150","Stop":"4417150","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1016252,"rule_based_match":true,"evidence_text":"c.818A > G; p.D273G","llm_judgment":"PRESENT","evidence":"c.818A > G; p.D273G","abstract_start":637,"abstract_end":656}]}
{"pmid":"37213040","title":"An SPG7 mutation as a novel cause of monogenic progressive muscular atrophy.","abstract":"BACKGROUND: Progressive muscular atrophy (PMA) is a rare adult-onset neurological disease that is characterized by isolated lower motor neuron degeneration. While it is still disputable whether PMA is a subtype of amyotrophic lateral sclerosis (ALS) or an isolated disorder, it is well-established as a clinically defined entity. About 5% of PMA cases are monogenic, and the implicated genes largely overlap with those causing monogenic ALS.\nCASE DESCRIPTION: Here we describe a 68-year-old female patient with progressive and asymmetric upper-limb weakness throughout an 18-month period, with muscle atrophy, dysphagia and slurring of speech. The lower limbs were unaffected, and there was no sign of upper motor neuron dysfunction. Comprehensive genetic testing for single nucleotide and copy-number variants revealed a pathogenic monoallelic variant c.1529C>T, p.(Ala510Val) in the SPG7 gene.\nDISCUSSION: Pathogenic biallelic SPG7 variants have been originally associated with hereditary spastic paraplegia, but other phenotypes are nowadays known to be linked to these variants, such as ALS. However, there is no report of this (or any) other SPG7 variant in association with PMA, whether it progressed to ALS or not. In conclusion, we present the first known case of PMA associated with a monoallelic SPG7 mutation.","variants":[{"Name":"NM_003119.4(SPG7):c.1529C>T (p.Ala510Val)","Chromosome":"16","Start":"89546737","Stop":"89546737","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":51184,"rule_based_match":true,"evidence_text":"c.1529C>T, p.(Ala510Val)","llm_judgment":"PRESENT","evidence":"c.1529C>T, p.(Ala510Val)","abstract_start":853,"abstract_end":877}]}
{"pmid":"26622573","title":"Identification of a rare case of intra-articular osteochondroma manifesting as three loose bodies in a patient with hereditary multiple osteochondromas: A case report.","abstract":"Hereditary multiple osteochondromas (HMO) is an autosomal dominant bone disorder characterised by the presence of multiple benign cartilage-capped tumours. Exostosin-1 (EXT1) and EXT2 are the major morbigenous genes associated with HMO, mutations in which are responsible for 90% of all HMO cases. In patients with HMO, osteochondromas arise adjacent to the metaphysis and typically remain in the metaphyseal region of the long bones. Therefore, it is rare for osteochondromas to be identified intra-articularly, although they may manifest as loose bodies. The present study describes a rare case of HMO manifesting as limited flexing range in the right knee joint of a 27-year-old male patient. Computed tomography and magnetic resonance imaging (MRI) revealed three intra-articular osteochondromas located in the intercondylar fossa of the patient's right knee. The intra-articular osteochondromas and protuberant extra-articular osteochondromas around the right knee were resected, resulting in improved right knee function and no postoperative recurrence. Pathological analysis revealed that the intra-articular osteochondromas had a thinner cartilage cap layer than the extra-articular osteochondromas. In addition, genetic analysis of the patient and the patient's mother was conducted. From this, it was determined that a nonsense mutation, c.115G>T (p.E39X) in exon 1 of the EXT1 gene, was the cause of HMO in this case. Thus, it is proposed that osteochondromas with a pedicle within the knee, may tear and become loose intra-articular bodies, resulting in limited joint function and thereby contributing to the progression of HMO.","variants":[{"Name":"NM_000127.3(EXT1):c.115G>T (p.Glu39Ter)","Chromosome":"8","Start":"118110932","Stop":"118110932","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":925005,"rule_based_match":true,"evidence_text":"c.115G>T (p.E39X)","llm_judgment":"PRESENT","evidence":"c.115G>T (p.E39X)","abstract_start":1348,"abstract_end":1365}]}
{"pmid":"30555098","title":"Identification of a novel","abstract":"Ocular albinism type 1 (OA1) is an X-linked inherited disease characterized by impaired visual acuity, congenital nystagmus, foveal hypoplasia, hypopigmentation of iris and fundus. It is caused by mutations in the G protein-coupled receptor143 (<i>GPR143</i>) gene. The genetic characteristics of OA1 have not been well defined in Asians. In this study, six members from three consecutive generations of a Korean family with OA1 were enrolled. We performed whole-exome sequencing followed by validation and segregation analysis. Two affected patients underwent detailed ophthalmic examinations and eye movement recordings. Of the two affected males, the proband had all classical phenotypes of OA1, but the other showed isolated foveal hypoplasia without nystagmus. We identified a hemizygous missense (c.623C > A, p.Ala208Glu) mutation of <i>GPR143</i> in affected males. This mutation was also present as heterozygous in two obligate female carriers, and was not found in unaffected members. Our data expands thespectrum of phenotypes and genotype in <i>GPR143</i> in Asians, and highlights the phenotypic heterogeneity in OA1.","variants":[{"Name":"NM_000273.3(GPR143):c.623C>A (p.Ala208Glu)","Chromosome":"X","Start":"9746079","Stop":"9746079","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1890560,"rule_based_match":true,"evidence_text":"c.623C > A, p.Ala208Glu","llm_judgment":"PRESENT","evidence":"c.623C > A, p.Ala208Glu","abstract_start":803,"abstract_end":826}]}
{"pmid":"33123925","title":"A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder.","abstract":"At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype.","variants":[{"Name":"NM_000286.3(PEX12):c.1044ACA[1] (p.Gln349del)","Chromosome":"17","Start":"35575813","Stop":"35575815","ReferenceAlleleVCF":"ATGT","AlternateAlleleVCF":"A","allel_id":548808,"rule_based_match":false,"evidence_text":"c.1047_1049del p.(Gln349del)","llm_judgment":"PRESENT","evidence":"c.1047_1049del p.(Gln349del)","abstract_start":424,"abstract_end":452}]}
{"pmid":"30979366","title":"Lethal perinatal hypophosphatasia caused by a novel compound heterozygous mutation: a case report.","abstract":"BACKGROUND: Hypophosphatasia (HPP) is a rare hereditary disorder characterized by defective bone and tooth mineralization and deficiency of tissue non-specific alkaline phosphatase (TNAP) activity. The clinical presentation of HPP is highly variable, and the prognosis for the infantile form is poor.\nCASE PRESENTATION: This study reports a male infant diagnosed with lethal perinatal HPP. His gene analysis showed two heterozygous missense variants c.406C > T (p.R136C) and c.461C > T (p.A154V). The two mutations originated separately from his parents, consistent with autosomal recessive perinatal HPP, and the c.461C > T (p.A154V) was the novel mutation. Three-level structure model provide an explanation of the two mutated alleles correlating with the lethal phenotype of our patient. Results of SIFT, PolyPhen_2, and REVEL showed two mutations were pathogenic.\nCONCLUSIONS: We demonstrated a case of perinatal lethal HPP caused by two heterozygous mutations, and one of which was novel. This finding will prove relevant for genetic counseling and perinatal gene testing for affected families.","variants":[{"Name":"NM_000478.6(ALPL):c.406C>T (p.Arg136Cys)","Chromosome":"1","Start":"21563218","Stop":"21563218","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":941693,"rule_based_match":true,"evidence_text":"c.406C > T (p.R136C)","llm_judgment":"PRESENT","evidence":"c.406C > T (p.R136C)","abstract_start":450,"abstract_end":470}]}
{"pmid":"19265501","title":"Ectopic thymus presenting as a thyroid nodule in a patient with the Carney complex.","abstract":"Ectopic thymic tissue within the thyroid gland is rare. Patients with a complex of myxomas, spotty skin pigmentation, and endocrine overactivity, collectively known as Carney complex (CNC), have a predisposition towards the development of thyroid abnormalities, but there are no reports of thymic defects in CNC. We present the case of a 12-year-old boy with CNC and a growing thyroid nodule. The patient had the c.682 C > T (Arg228X) pathogenic PRKAR1A mutation. Hemithyroidectomy for a Hürthle cell adenoma led to the confirmation of distinct intrathyroidal ectopic thymic tissue. Thymic abnormalities have not been previously reported in CNC.","variants":[{"Name":"NM_002734.5(PRKAR1A):c.682C>T (p.Arg228Ter)","Chromosome":"17","Start":"68525886","Stop":"68525886","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49815,"rule_based_match":true,"evidence_text":"c.682 C > T (Arg228X)","llm_judgment":"PRESENT","evidence":"c.682 C > T (Arg228X)","abstract_start":413,"abstract_end":434}]}
{"pmid":"33059616","title":"Use of patient derived urine renal epithelial cells to confirm pathogenicity of PKHD1 alleles.","abstract":"BACKGROUND: PKHD1 is the main genetic cause of autosomal recessive polycystic kidney disease (ARPKD), a hereditary hepato-renal fibrocystic disorder which is the most important cause of end-stage renal disease during early childhood. ARPKD can also present in adulthood with milder phenotypes. In this study, we describe a 24-year-old woman with atypical polycystic kidney, no family history of renal disease and no obvious extra-renal manifestations who was referred for genetic investigation.\nMETHODS: We used a combination of next generation sequencing, Sanger sequencing and RNA and microscopy studies performed on urine-derived renal epithelial cells (URECs) to provide a genetic diagnosis of ARPKD.\nRESULTS: A next generation sequencing panel of cystic ciliopathy genes allowed the identification of two heterozygous sequence changes in PKHD1 (c.6900C > T; p.(Asn2300=) and c.7964A > C; p.(His2655Pro)). The pathogenicity of the synonymous PKHD1 variant is not clear and requires RNA studies, which cannot be carried out efficiently on RNA extracted from proband blood, due to the low expression levels of PKHD1 in lymphocytes. Using URECs as a source of kidney-specific RNA, we show that PKHD1 is alternatively spliced around exon 43, both in control and proband URECs. The variant p.(Asn2300=) shifts the expression ratio in favour of a shorter, out-of-frame transcript. To further study the phenotypic consequence of these variants, we investigated the ciliary phenotype of patient URECs, which were abnormally elongated and presented multiple blebs along the axoneme.\nCONCLUSIONS: We confirm the power of URECs as a tool for functional studies on candidate variants in inherited renal disease, especially when the expression of the gene of interest is restricted to the kidney and we describe, for the first time, ciliary abnormalities in ARPKD patient cells.","variants":[{"Name":"NM_138694.4(PKHD1):c.7964A>C (p.His2655Pro)","Chromosome":"6","Start":"51847918","Stop":"51847918","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1691907,"rule_based_match":true,"evidence_text":"c.7964A > C; p.(His2655Pro)","llm_judgment":"PRESENT","evidence":"c.7964A > C; p.(His2655Pro)","abstract_start":880,"abstract_end":907},{"Name":"NM_138694.4(PKHD1):c.6900C>T (p.Asn2300=)","Chromosome":"6","Start":"51903693","Stop":"51903693","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544231,"rule_based_match":true,"evidence_text":"c.6900C > T; p.(Asn2300=)","llm_judgment":"PRESENT","evidence":"c.6900C > T; p.(Asn2300=)","abstract_start":850,"abstract_end":875}]}
{"pmid":"33282382","title":"Acute Stanford type B aortic dissection-who benefits from genetic testing?","abstract":"BACKGROUND: Stanford type B aortic dissection is a rare, life-threatening complex phenotype associated with several modifiable and genetic risk factors. In the current study of a hospital-based, consecutive series of aortic dissection patients we propose a selection based on age and family history of aortic disease for genetic testing and detection of causative gene variants.\nMETHODS: In this single center cohort study from 2013 to 2018 patients with acute Stanford type B aortic dissections were consecutively treated and analyzed by next generation sequencing based on selection criteria (age of disease onset ≤45 years and/or positive familial history for aortic disease) to detect genome-wide pathogenic variants in protein-coding sequences and to identify large copy number variants (CNV). Variants in a predefined panel of 30 genes associated with the familial thoracic aortic aneurysm and dissection (TAAD) syndrome were evaluated.\nRESULTS: From 105 patients nine matched selection criteria for genetic testing. Next-generation sequencing analysis revealed causal variants in <i>FBN1</i> (fibrillin-1) in three patients: a pathogenic missense variant [c.6661T>C, p.(Cys2221Arg)] and two truncating variants [c.4786C>T, p.(Arg1596Ter)] and [c.6366C>CA, p.(Asp2123GlufsTer5)]. A fourth patient carried a large (>1,000,000 bp) CNV in the long arm of chromosome 10, deleting eleven genes, including the whole <i>ACTA2</i> (actin alpha 2) gene. The latter two genetic findings have not been reported before.\nCONCLUSIONS: Selection of patients on the basis of young age and familial inheritance of aortic disease favors the identification of disease-causing genetic variants in a clinical cohort of patients with Stanford type B aortic dissection.","variants":[{"Name":"NM_000138.5(FBN1):c.4786C>T (p.Arg1596Ter)","Chromosome":"15","Start":"48465820","Stop":"48465820","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44746,"rule_based_match":true,"evidence_text":"c.4786C>T, p.(Arg1596Ter)","llm_judgment":"PRESENT","evidence":"c.4786C>T, p.(Arg1596Ter)","abstract_start":1219,"abstract_end":1244}]}
{"pmid":"29851656","title":"Postmortem Analysis of 4 Mutation Hotspots of KCNQ1, KCNH2, and SCN5A Genes in Sudden Unexplained Death in Southwest of China.","abstract":"Long QT syndrome (LQTS) is known to be involved in some sudden unexplained death (SUD) cases. To make clear whether the pathogenic genes of LQTS are involved in SUD in Yunnan province, southwest of China, we examined 4 mutation hotspot segments of KCNQ1, KCNH2, and SCN5A genes in 83 SUD cases using polymerase chain reaction and direct DNA sequencing. Genomic DNA was extracted from paraffin-embedded tissues in 83 cases of sudden cardiac death. One novel homozygous missense variant was identified in exon 3 of KCNQ1, c. 575G>T (p.R192L) in one case. One novel heterozygous missense variant was identified in exon 7 of KCNH2, c.1789T>A (p.Y597N) in 1 case. One novel heterozygous missense variant was identified in exon 7 of KCNH2, c.1800C>A (p.S600R) in 9 cases. In addition, 18 individuals were found to have heterozygous missense variant in exon 7 of KCNH2, c.1801G>A (p.G601S). Our study suggests that some SUDs in Yunnan province may be related with the pathogenic genes of LQTS.","variants":[{"Name":"NM_000218.3(KCNQ1):c.575G>T (p.Arg192Leu)","Chromosome":"11","Start":"2570725","Stop":"2570725","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1480390,"rule_based_match":true,"evidence_text":"c. 575G>T (p.R192L)","llm_judgment":"PRESENT","evidence":"c. 575G>T (p.R192L)","abstract_start":520,"abstract_end":539}]}
{"pmid":"30056071","title":"Molecular genetic study of Calpainopathy in Iran.","abstract":"INTRODUCTION: Calpainopathy is an autosomal recessive form of limb girdle muscular dystrophies (LGMDs) caused by mutations in the CAPN3 gene. CAPN3 is a Ca<sup>2+</sup>-dependent cystein protease consisting of 821 amino acids. LGMD is a highly heterogeneous disorder and mutation identification of this disease by Sanger sequencing of all genes is expensive and time consuming. Using autozygosity mapping is an effective approach to address this issue.\nMETHODS: We used two sets of multiplex STR (Short tandem repeat) markers linked to CAPN3, DYSF, SGCA, SGCB, SGCG, SGCD genes following sequencing of the CAPN3 gene. In silico analysis and mutation detection in one hundred ethnically matched healthy individuals were carried out to determine the pathogenicity of novel mutations. Sequence variant interpretation was performed using the American College of Medical Genetics and Genomics (ACMG) guideline.\nRESULTS: Sixteen out of 50 families linked to the CAPN3 gene. In this study, mutations were found in 14 out of 16 families including 4 novel (c.1894A > T, c.567delG, c.2254-2256delAAC, and c.2373C > T) and 9 previously reported mutations consisting of 5 missense (c.2105C > T, c.2243G > A, c.1714C > T, c.291C > A, c.956C > T), 3 splice site (c.2380 + 2 T > G, c.946-2A > G, c.380G > A), and one indel (c.2257delinsAA) mutations.\nDISCUSSION: The c.2105C > T was found to be the most frequent mutation in this study. The results of this study revealed that most cases with splicing, frame shift and nonsense mutations experienced more severe clinical manifestations. Nonetheless, this should be confirmed by further studies on larger sample size.","variants":[{"Name":"NM_000070.3(CAPN3):c.2380+2T>G","Chromosome":"15","Start":"42411002","Stop":"42411002","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":620867,"rule_based_match":true,"evidence_text":"c.2380 + 2 T > G","llm_judgment":"PRESENT","evidence":"c.2380 + 2 T > G","abstract_start":1249,"abstract_end":1265},{"Name":"NM_000070.3(CAPN3):c.2243G>A (p.Arg748Gln)","Chromosome":"15","Start":"42410646","Stop":"42410646","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":134019,"rule_based_match":true,"evidence_text":"c.2243G > A","llm_judgment":"PRESENT","evidence":"c.2243G > A","abstract_start":1183,"abstract_end":1194},{"Name":"NM_000070.3(CAPN3):c.2105C>T (p.Ala702Val)","Chromosome":"15","Start":"42409985","Stop":"42409985","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":267336,"rule_based_match":true,"evidence_text":"c.2105C>T","llm_judgment":"PRESENT","evidence":"c.2105C > T","abstract_start":1170,"abstract_end":1181},{"Name":"NM_000070.3(CAPN3):c.956C>T (p.Pro319Leu)","Chromosome":"15","Start":"42392649","Stop":"42392649","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32656,"rule_based_match":true,"evidence_text":"c.956C > T","llm_judgment":"PRESENT","evidence":"c.956C > T","abstract_start":1221,"abstract_end":1231},{"Name":"NM_000070.3(CAPN3):c.380G>A (p.Gly127Glu)","Chromosome":"15","Start":"42386167","Stop":"42386167","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2671027,"rule_based_match":true,"evidence_text":"c.380G>A","llm_judgment":"PRESENT","evidence":"c.380G > A","abstract_start":1281,"abstract_end":1291}]}
{"pmid":"26805784","title":"Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2.","abstract":"The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). Each of these variants co-segregates with congenital profound hearing impairment in consanguineous Pakistani families with maximum LOD scores of 6.4 for family DEM4154 and 3.3 for family PKDF1400. Neither S1PR2 missense variant was reported among ∼120,000 chromosomes in the Exome Aggregation Consortium database, in 76 unrelated Pakistani exomes, or in 720 Pakistani control chromosomes. Both DNA variants affect highly conserved residues of S1PR2 and are predicted to be damaging by multiple bioinformatics tools. Molecular modeling predicts that these variants affect binding of sphingosine-1-phosphate (p.Arg108Pro) and G protein docking (p.Tyr140Cys). In the previously reported S1pr2(-/-) mice, stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss were observed. Additionally, hair cell defects were seen in both knockout mice and morphant zebrafish. Family PKDF1400 presents with ARNSHI, which is consistent with the lack of gross malformations in S1pr2(-/-) mice, whereas family DEM4154 has lower limb malformations in addition to hearing loss. Our findings suggest the possibility of developing therapies against hair cell damage (e.g., from ototoxic drugs) through targeted stimulation of S1PR2.","variants":[{"Name":"NM_004230.4(S1PR2):c.323G>C (p.Arg108Pro)","Chromosome":"19","Start":"10224583","Stop":"10224583","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":217338,"rule_based_match":true,"evidence_text":"c.323G>C (p.Arg108Pro)","llm_judgment":"PRESENT","evidence":"c.323G>C (p.Arg108Pro)","abstract_start":454,"abstract_end":476},{"Name":"NM_004230.4(S1PR2):c.419A>G (p.Tyr140Cys)","Chromosome":"19","Start":"10224487","Stop":"10224487","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":217271,"rule_based_match":true,"evidence_text":"c.419A>G (p.Tyr140Cys)","llm_judgment":"PRESENT","evidence":"c.419A>G (p.Tyr140Cys)","abstract_start":481,"abstract_end":503}]}
{"pmid":"28588848","title":"A case of megalencephalic leukoencephalopathy with subcortical cysts type 1 was identified with a novel compound heterozygous alteration (c.135delC; c.423+2dupT) in China.","abstract":"We report a compound heterozygous mutation (c.135delC; c.423+2dupT) of <i>MLC1</i> gene in a Chinese patient underlying infantile macrocephaly and neurological deterioration in early childhood. Brain MRI revealed diffusion abnormality in swollen white matter and a subcortical cyst. The cDNA sequencing analysis for the c.423+2dupT variant revealed skipping of exon 5.","variants":[{"Name":"NM_015166.4(MLC1):c.423+2dup","Chromosome":"22","Start":"50079915","Stop":"50079916","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":549163,"rule_based_match":true,"evidence_text":"c.423+2dupT","llm_judgment":"PRESENT","evidence":"c.423+2dupT","abstract_start":55,"abstract_end":66},{"Name":"NM_015166.4(MLC1):c.135del (p.Cys46fs)","Chromosome":"22","Start":"50084768","Stop":"50084768","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":1868615,"rule_based_match":true,"evidence_text":"c.135delC","llm_judgment":"PRESENT","evidence":"c.135delC","abstract_start":44,"abstract_end":53}]}
{"pmid":"22363543","title":"Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population.","abstract":"Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease including autosomal recessive (ar), autosomal dominant (ad), and X-linked inheritance. Recently, arRP has been associated with mutations in EYS (Eyes shut homolog), which is a major causative gene for this disease. This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese arRP patients. To determine the prevalence of EYS mutations, all EYS exons were screened for mutations by polymerase chain reaction amplification, and sequence analysis was performed. We detected 67 sequence alterations in EYS, of which 21 were novel. Of these, 7 were very likely pathogenic mutations, 6 were possible pathogenic mutations, and 54 were predicted non-pathogenic sequence alterations. The minimum observed prevalence of distinct EYS mutations in our study was 18% (18/100, comprising 9 patients with 2 very likely pathogenic mutations and the remaining 9 with only one such mutation). Among these mutations, 2 novel truncating mutations, c.4957_4958insA (p.S1653KfsX2) and c.8868C>A (p.Y2956X), were identified in 16 patients and accounted for 57.1% (20/35 alleles) of the mutated alleles. Although these 2 truncating mutations were not detected in Japanese patients with adRP or Leber's congenital amaurosis, we detected them in Korean arRP patients. Similar to Japanese arRP results, the c.4957_4958insA mutation was more frequently detected than the c.8868C>A mutation. The 18% estimated prevalence of very likely pathogenic mutations in our study suggests a major involvement of EYS in the pathogenesis of arRP in the Japanese population. Mutation spectrum of EYS in 100 Japanese patients, including 13 distinct very likely and possible pathogenic mutations, was largely different from the previously reported spectrum in patients from non-Asian populations. Screening for c.4957_4958insA and c.8868C>A mutations in the EYS gene may therefore be very effective for the genetic testing and counseling of RP patients in Japan.","variants":[{"Name":"NM_001142800.2(EYS):c.4957dup (p.Ser1653fs)","Chromosome":"6","Start":"64590909","Stop":"64590910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":152823,"rule_based_match":false,"evidence_text":"c.4957_4958insA (p.S1653KfsX2)","llm_judgment":"PRESENT","evidence":"c.4957_4958insA (p.S1653KfsX2)","abstract_start":1034,"abstract_end":1064}]}
{"pmid":"24621671","title":"STIM1 and SLC24A4 Are Critical for Enamel Maturation.","abstract":"Dental enamel formation depends upon the transcellular transport of Ca(2+) by ameloblasts, but little is known about the molecular mechanism, or even if the same process is operative during the secretory and maturation stages of amelogenesis. Identifying mutations in genes involved in Ca(2+) homeostasis that cause inherited enamel defects can provide insights into the molecular participants and potential mechanisms of Ca(2+) handling by ameloblasts. Stromal Interaction Molecule 1 (STIM1) is an ER transmembrane protein that activates membrane-specific Ca(2+) influx in response to the depletion of ER Ca(2+) stores. Solute carrier family 24, member 4 (SLC24A4), is a Na(+)/K(+)/Ca(2+) transporter that exchanges intracellular Ca(2+) and K(+) for extracellular Na(+). We identified a proband with syndromic hypomaturation enamel defects caused by a homozygous C to T transition (g.232598C>T c.1276C>T p.Arg426Cys) in STIM1, and a proband with isolated hypomaturation enamel defects caused by a homozygous C to T transition (g.124552C>T; c.437C>T; p.Ala146Val) in SLC24A4. Immunohistochemistry of developing mouse molars and incisors showed positive STIM1 and SLC24A4 signal specifically in maturation-stage ameloblasts. We conclude that enamel maturation is dependent upon STIM1 and SLC24A4 function, and that there are important differences in the Ca(2+) transcellular transport systems used by secretory- and maturation-stage ameloblasts.","variants":[{"Name":"NM_001382567.1(STIM1):c.1276C>T (p.Arg426Cys)","Chromosome":"11","Start":"4083300","Stop":"4083300","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":362275,"rule_based_match":true,"evidence_text":"c.1276C>T p.Arg426Cys","llm_judgment":"PRESENT","evidence":"c.1276C>T p.Arg426Cys","abstract_start":895,"abstract_end":916},{"Name":"NM_153646.4(SLC24A4):c.437C>T (p.Ala146Val)","Chromosome":"14","Start":"92442132","Stop":"92442132","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":150123,"rule_based_match":true,"evidence_text":"c.437C>T; p.Ala146Val","llm_judgment":"PRESENT","evidence":"c.437C>T; p.Ala146Val","abstract_start":1041,"abstract_end":1062}]}
{"pmid":"20672378","title":"Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2.","abstract":"Keratosis Follicularis Spinulosa Decalvans (KFSD) is a rare genetic disorder characterized by development of hyperkeratotic follicular papules on the scalp followed by progressive alopecia of the scalp, eyelashes, and eyebrows. Associated eye findings include photophobia in childhood and corneal dystrophy. Due to the genetic and clinical heterogeneity of similar disorders, a definitive diagnosis of KFSD is often challenging. Toward identification of the causative gene we reanalyzed a large Dutch KFSD family. SNP arrays (1 M) redefined the locus to a 2.9-Mb region at Xp22.12-Xp22.11. Screening of all 14 genes in the candidate region identified MBTPS2 as the candidate gene carrying a c.1523A>G (p.Asn508Ser) missense mutation. The variant was also identified in two unrelated X-linked KFSD families and cosegregated with KFSD in all families. In symptomatic female carriers, skewed X-inactivation of the normal allele matched with increased severity of symptoms. MBTPS2 is required for cleavage of sterol regulatory element-binding proteins (SREBPs). In vitro functional expression studies of the c.1523A>G mutation showed that sterol responsiveness was reduced by half. Other missense mutations in MBTPS2 have recently been identified in patients with IFAP syndrome. We postulate that both phenotypes are in the spectrum of one genetic disorder with a partially overlapping phenotype.","variants":[{"Name":"NM_015884.4(MBTPS2):c.1523A>G (p.Asn508Ser)","Chromosome":"X","Start":"21882618","Stop":"21882618","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":38911,"rule_based_match":true,"evidence_text":"c.1523A>G (p.Asn508Ser)","llm_judgment":"PRESENT","evidence":"c.1523A>G (p.Asn508Ser)","abstract_start":691,"abstract_end":714}]}
{"pmid":"30262571","title":"A unique de novo gain-of-function variant in","abstract":"Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in <i>CAMK4</i>, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters <i>CAMK4</i> pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIV's regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our proband's phenotype is explainable by a dominant <i>CAMK4</i> splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of <i>CAMK4</i> in human neurodevelopment, provide a foundation for future clinical research of <i>CAMK4</i>, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.","variants":[{"Name":"NM_001744.6(CAMK4):c.981+1G>A","Chromosome":"5","Start":"111482938","Stop":"111482938","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":551352,"rule_based_match":true,"evidence_text":"c.981+1G>A","llm_judgment":"PRESENT","evidence":"c.981+1G>A","abstract_start":603,"abstract_end":613}]}
{"pmid":"23988501","title":"Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead to abnormal uromodulin intracellular trafficking.","abstract":"BACKGROUND: Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder characterized by hyperuricemia and progressive chronic kidney disease. Uromodulin gene (UMOD) mutations, leading to abnormalities of uromodulin intracellular trafficking contribute to the progress of the disease.\nMETHODS: We did UMOD screening in three Chinese FJHN families. We thus constructed mutant uromodulin express plasmids by site-mutagenesis from wild type uromodulin vector and transfected them into HEK293 (human embryonic kidney) cells. And then we detected uromodulin expression by western blot and observed intracellular distribution by immunofluorescence.\nRESULTS: We found three heterozygous mutations. Mutation Val109Glu (c.326T/A; p.Val109Glu) and mutation Pro236Gln (c.707C/A; p.Pro236Gln) were newly indentified mutations in two distinct families (family F1 and family F3). Another previously reported UMOD mutation Cys248Trp (c.744C/G; p.Cys248Trp) was detected in family F2. Phenotypes varied both within the same family and between different families. Uromodulin expression is abnormal in the patient biopsy. Functional analysis of mutation showed that mutant types of uromodulin were secreted into the supernatant medium much less when compared with wild type. In mutant type uromodulin transfected cells, intracellular uromodulin localized less in the Golgi apparatus and more in endoplasmic reticulum(ER).\nCONCLUSIONS: Our results suggested that the novel uromodulin mutations found in the Chinese families lead to misfolded protein, which was retained in the endoplasmic reticulum, finally contributed to the phenotype of FJHN.","variants":[{"Name":"NM_003361.4(UMOD):c.744C>G (p.Cys248Trp)","Chromosome":"16","Start":"20348557","Stop":"20348557","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":272113,"rule_based_match":false,"evidence_text":"Cys248Trp (c.744C/G; p.Cys248Trp)","llm_judgment":"PRESENT","evidence":"Cys248Trp (c.744C/G; p.Cys248Trp)","abstract_start":933,"abstract_end":966},{"Name":"NM_003361.4(UMOD):c.326T>A (p.Val109Glu)","Chromosome":"16","Start":"20348975","Stop":"20348975","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":553506,"rule_based_match":false,"evidence_text":"c.326T/A; p.Val109Glu","llm_judgment":"PRESENT","evidence":"c.326T/A; p.Val109Glu","abstract_start":736,"abstract_end":757}]}
{"pmid":"37603299","title":"Clinical and Genetic Description of Hereditary Chronic Pancreatitis in Pakistani Children.","abstract":"BACKGROUND/AIMS: The purpose of this study was to identify the spectrum and frequency of pathogenic variants as well as the clinical and genetic insight of hereditary chronic pancreatitis in Pakistani children.\nMATERIALS AND METHODS: The deoxyribonucleic acid of affected probands of 44 unrelated Pakistani families, having hereditary chronic pancreatitis-affected children, were subjected to massive parallel sequencing for candidate reported genes (SPINK1, PRSS1, CFTR, CPA1, CTRC, CBS, AGL, PHKB, and LPL). Data were analyzed using different bioinformatics tools for the variants and in-silico analysis. All the identified variants were validated by direct sequencing of the targeted exons in the probands and their parents.\nRESULTS: There were 50 patients included in this study with confirmed hereditary chronic pancreatitis. Nine known mutations in SPINK1, PRSS1, CFTR, CTRC, CBS, and AGL genes, and 10 novel variants in LPL, CFTR, CTR, and PHKB genes were identified. The identified variants were found in heterozygous, compound heterozygous, and trans-heterozygous forms, with rare allele frequency in the normal population. The novel variants were [c.378C>T(p.Lys126Asn) and c.719G>A(p.Arg240Gln) in CTRC, c.586-3C>A and c.763A>G(p.Arg255Gly) in CPA1, c.1160_1161insT(p.Lys387Asnfs*26), c.784C>T(p.Gln262*), c.1139+1G>A, c.175G>A(p.Gly59Arg) in LPL, c.388C>G(p.leu130val) in CFTR, and c.2327G>A(p.Arg776His in PHKB)]. The phenotypic characteristics were variable and correlated with the relevant variant.\nCONCLUSIONS: The genetic composition plays a significant role in the predisposition of hereditary chronic pancreatitis. The clinical presentation varies with the genetic determinant involved. This information would help in building up a diagnostic algorithm for our population that can be used for genetic screening services in affected cohorts.","variants":[{"Name":"NM_007272.3(CTRC):c.719G>A (p.Arg240Gln)","Chromosome":"1","Start":"15445676","Stop":"15445676","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":556937,"rule_based_match":true,"evidence_text":"c.719G>A(p.Arg240Gln) in CTRC","llm_judgment":"PRESENT","evidence":"c.719G>A(p.Arg240Gln) in CTRC","abstract_start":1184,"abstract_end":1213}]}
{"pmid":"23813354","title":"PHEX gene mutation in a Chinese family with six cases of X-linked hypophosphatemic rickets.","abstract":"OBJECTIVE: X-linked hypophosphatemic (XLH) rickets is caused by inactivating mutations in the PHEX gene, which encodes a metalloprotease that cleaves small peptide hormone. So far there are only a few reports on XLH patients from China. In the present study, we report on six XLH patients from one family. A PHEX missense mutation was found in exon 22, and a literature review on the mutations of Chinese patients was undertaken.\nCASE DESCRIPTION: The family included six XLH patients with five females and one male (the proband). All the patients showed a low serum phosphorus, increased blood alkaline phosphatase and normal calcium levels. Mutation analysis revealed a PHEX mutation in exon 22 (c.2237G>A). In total, 15 PHEX mutations have been reported in Chinese populations at this time.\nCONCLUSION: These data extend the spectrum of mutations in the PHEX gene in Chinese populations.","variants":[{"Name":"NM_000444.6(PHEX):c.2237G>A (p.Cys746Tyr)","Chromosome":"X","Start":"22247940","Stop":"22247940","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":929672,"rule_based_match":true,"evidence_text":"c.2237G>A","llm_judgment":"PRESENT","evidence":"c.2237G>A","abstract_start":698,"abstract_end":707}]}
{"pmid":"27578104","title":"Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons, mistakes, and the way forward.","abstract":"Familial hypercholesterolemia (FH) is a leading cause of premature atherosclerosis. Genetic defects in the LDLR, APOB and PCSK9 genes cause FH, and confirmation of a gene defect is essential for an indisputable diagnosis of the disease. FH is underdiagnosed and we aimed to revise the genetic defects that have been characterized in FH patients of Greek origin and define an effective, future strategy for genetic studies. A literature search was performed in MEDLINE and EMBASE on genetic studies with FH patients of Greek origin. To date, no APOB and PCSK9 mutations have been found in the Greek population. It must be noted however, that only a small number of patients has been screened for PCSK9 mutations. In total, 41 LDLR defects have been characterized, with 6 common mutations c.1646G>A (p.Gly546Asp), c.858C>A (p.Ser286Arg), c.81C>G (p.Cys27Trp), c.1285G>A (p.Val429Met), c.517T>C (p.Cys173Arg), and c.1775G>A (p.Gly592Glu) that account for >80% of all mutations. Due to geographic isolation, ​founder mutations exist in a subpopulation in North West Greece and the Greek Cypriot population but not in the general population. Genetic testing should focus primarily on LDLR, and subsequently on PCSK9 and APOB. The Greek population is genetically homogeneous, which allows for a quick molecular diagnosis of the disease. Cascade screening is feasible and will certainly facilitate the identification of additional patients.","variants":[{"Name":"NM_000527.5(LDLR):c.517T>C (p.Cys173Arg)","Chromosome":"19","Start":"11105423","Stop":"11105423","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":245609,"rule_based_match":true,"evidence_text":"c.517T>C (p.Cys173Arg)","llm_judgment":"PRESENT","evidence":"c.517T>C (p.Cys173Arg)","abstract_start":883,"abstract_end":905},{"Name":"NM_000527.5(LDLR):c.858C>A (p.Ser286Arg)","Chromosome":"19","Start":"11107432","Stop":"11107432","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":245821,"rule_based_match":true,"evidence_text":"c.858C>A (p.Ser286Arg)","llm_judgment":"PRESENT","evidence":"c.858C>A (p.Ser286Arg)","abstract_start":812,"abstract_end":834}]}
{"pmid":"19464397","title":"Brachydactyly type A1 associated with unusual radiological findings and a novel Arg158Cys mutation in the Indian hedgehog (IHH) gene.","abstract":"Brachydactyly type A1 (BDA1; MIM 112500) is characterized by shortness or absence of the middle phalanx of the hands and feet. The condition is caused by heterozygous mutations in the Indian hedgehog (IHH) gene or a yet unidentified gene on chromosome 5p13. We investigated six affected members of a large Swedish family segregating autosomal dominant brachymesophalangia. Affected individuals show hypoplasia of the ulnar styloid processes, ulna minus, osteoarthritis, normal length of all distal phalanges and shortening or absence of the middle phalanges. Stationary ossicles or sesamoid bones were observed at the metacarpal heads in all patients. Genetic analysis of the family showed that the IHH-gene was linked to the disease (Z(max) 3.42 at theta 0.00) and sequence analysis of IHH revealed a novel c.472C > T transition in all affected family members. The mutation results in a p.158Arg > Cys substitution located in the highly conserved amino-terminal domain of IHH. This domain is of importance for the interaction between IHH and the Patched receptor. Our combined findings add radiological findings to the BDA1 phenotype and confirm a critical functional domain of IHH.","variants":[{"Name":"NM_002181.4(IHH):c.472C>T (p.Arg158Cys)","Chromosome":"2","Start":"219057538","Stop":"219057538","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1925493,"rule_based_match":true,"evidence_text":"c.472C > T","llm_judgment":"PRESENT","evidence":"c.472C > T","abstract_start":808,"abstract_end":818}]}
{"pmid":"29234170","title":"A missense point mutation in COL10A1 identified with whole-genome deep sequencing in a 7-generation Pakistan dwarf family.","abstract":"Disease-associated variants in the human genome are continually being identified using DNA sequencing technologies that are especially effective for Mendelian disorders. Here we sequenced whole genome to high coverage (>30×) of 6 members of a 7-generation family with dwarfism from a consanguineous tribe in Pakistan to determine the causal variant(s). We identified a missense variant rs111033552 (c.2011T>C [p.Ser671Pro]) located in COL10A1 (encodes the alpha chain of type X collagen) as the most likely contributor to the dwarfism. We further confirmed the variant in 22 family members using Sanger sequencing. All affected individuals are heterozygous for the missense mutation rs111033552 and no individual homozygous was observed. Moreover, the mutation was absent in 69,985 individuals representing >150 global populations. Taking advantage of whole-genome sequencing data, we also examined other variant forms, including copy number variation and insertion/deletion, but failed to identify such variants enriched in the affected individuals. Thus rs111033552 had priority for linkage with dwarfism.","variants":[{"Name":"NM_000493.4(COL10A1):c.2011T>C (p.Ser671Pro)","Chromosome":"6","Start":"116120105","Stop":"116120105","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":32516,"rule_based_match":true,"evidence_text":"c.2011T>C (p.Ser671Pro)","llm_judgment":"PRESENT","evidence":"p.Ser671Pro","abstract_start":410,"abstract_end":421}]}
{"pmid":"19562505","title":"Long-term neurodevelopmental effects of early detection and treatment in a 6-year-old patient with argininaemia diagnosed by newborn screening.","abstract":"Newborn screening makes possible the early identification and treatment of asymptomatic ARG1-deficient patients; however, it is unknown whether early intervention prevents neurological insults. We identified a full-term Hispanic male infant with argininaemia by newborn screening with a serum arginine of 327 µmol/L (reference values 0-140); ARG1 was undetectable on enzyme assay. Sequence analysis of ARG1 revealed a heterozygous nonsense mutation, c.223A>T (p.K75X), and a novel heterozygous missense variant, c.425G>A (p.G142E). Dietary protein restriction began from age 3 months, with addition of sodium benzoate at 4 months, and carnitine from 14 months. For the past 6 years, his serum arginine concentrations were maintained between 268 and 763 µmol/L (reference values 10-140). He has normal development without spastic paraplegia, but with mild hepatomegaly and stable hepatic dysfunction. A full neurodevelopmental assessment was conducted at age 5 years. The BASC-2 rated the patient's behaviours as age-appropriate. The Leiter-R assessed his 'Fundamental Visualization', 'Sequential Order', and 'Picture Concept' at 'Average', 'Form Completion' and 'Matching' at 'Low Average', and 'Figure Ground' and 'Repeated Patterns' in the 'Deficit' range. The full-scale IQ and the functioning ability presented in the 'Borderline' range and in the 'Low Average' range, respectively. The VABS/Survey - Spanish Version showed difficulty in receptive and written language and fine and gross motor skills, and his performance to be at younger than his chronological age. The Short Sensory Profile showed some difficulty with taste and smell sensitivity. Long-term observation over 6 years in a patient with early treated argininaemia shows promising neurodevelopmental results.","variants":[{"Name":"NM_000045.4(ARG1):c.425G>A (p.Gly142Glu)","Chromosome":"6","Start":"131581338","Stop":"131581338","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544013,"rule_based_match":true,"evidence_text":"c.425G>A (p.G142E)","llm_judgment":"PRESENT","evidence":"c.425G>A (p.G142E)","abstract_start":512,"abstract_end":530}]}
{"pmid":"35810424","title":"Genetic and prenatal diagnosis of a Chinese pedigree with autosomal recessive Wolfram syndrome 1 due to compound heterozygous variants of WFS1 gene","abstract":"OBJECTIVE: To explore the genetic pathogenicity for a Chinese pedigree affected with severe syndromic deafness.\nMETHODS: High-throughput sequencing was carried out to analyze the 415 genes associated with hereditary deafness in the proband who has hearing loss in association with optic atrophy and hyperglycemia. Candidate variants were verified by Sanger sequencing of the proband, her parents and the fetus.\nRESULTS: The proband was found to harbor compound heterozygous variants of WFS1 gene, namely c.2389G>A (p.Asp797Asn) and c.2345C>T (p.Pro782Leu), which was known to underlie Wolfram syndrome 1. The proband's parents had normal hearing and were both heterozygous carriers for the above variants. The fetus was found to harbor the same compound heterozygous variants and was predicted to have a high risk.\nCONCLUSION: The compound heterozygous variants of c.2389G>A and c.2345C>T of the WFS1 gene probably underlay the pathogenesis of hearing loss in the proband. Above finding has facilitated genetic counseling and prenatal diagnosis for this family.","variants":[{"Name":"NM_006005.3(WFS1):c.2389G>A (p.Asp797Asn)","Chromosome":"4","Start":"6302184","Stop":"6302184","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":496379,"rule_based_match":true,"evidence_text":"c.2389G>A (p.Asp797Asn)","llm_judgment":"PRESENT","evidence":"c.2389G>A (p.Asp797Asn)","abstract_start":504,"abstract_end":527}]}
{"pmid":"27492766","title":"Identification of a Novel β-Globin Mutation (HBB: C.189_195delTCATGGC) in a Chinese Family.","abstract":"β-Thalassemia (β-thal) is one of the most common genetic disorders worldwide. Molecular characterization of β-thal is essential for prevention and understanding the biology of the disease. More and more rare and novel mutations are being reported. Here, we report a novel 7 bp deletion at codons 63-65 (HBB: c.189_195delTCATGGC) in exon 2 of the β-globin gene in a family from Guangxi Province, China. This novel mutation causes a shift in the normal reading frame of the β-globin coding sequence and created a stop codon at codon 87 in exon 2, which leads to a β(0)-thal phenotype.","variants":[{"Name":"NM_000518.5(HBB):c.189_195del (p.His64fs)","Chromosome":"11","Start":"5226697","Stop":"5226703","ReferenceAlleleVCF":"TGCCATGA","AlternateAlleleVCF":"T","allel_id":857467,"rule_based_match":true,"evidence_text":"HBB: c.189_195delTCATGGC","llm_judgment":"PRESENT","evidence":"HBB: c.189_195delTCATGGC","abstract_start":303,"abstract_end":327}]}
{"pmid":"17568394","title":"Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome.","abstract":"Marfan syndrome (MFS) is known as an autosomal-dominant connective tissue disorder (MIM 154,700), involving primarily the skeletal, ocular and cardiovascular systems, and caused by mutations in the gene for fibrillin1 (FBN1). Here, we report on two cousins from a consanguineous family with a homozygous c.1,453C>T FBN1 mutation (p.Arg485Cys) and MFS. All four healthy parents were heterozygous for the c.1,453C>T FBN1 mutation and none fulfilled the Ghent criteria for MFS. This family is the first molecularly confirmed recessive MFS. The demonstration of recessive cases of MFS has obvious implications for genetic counselling as well as for molecular diagnosis.","variants":[{"Name":"NM_000138.5(FBN1):c.1453C>T (p.Arg485Cys)","Chromosome":"15","Start":"48515402","Stop":"48515402","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31505,"rule_based_match":false,"evidence_text":"c.1,453C>T FBN1 mutation (p.Arg485Cys)","llm_judgment":"PRESENT","evidence":"c.1,453C>T FBN1 mutation (p.Arg485Cys)","abstract_start":304,"abstract_end":342}]}
{"pmid":"26204789","title":"The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease.","abstract":"BACKGROUND AND PURPOSE: A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype.\nMETHODS: The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, in silico analysis and luciferase reporter assays.\nRESULTS: A novel c.1226G>A change (p.R409Q) in the EGR2 gene was identified. Patients presented with a typical, late-onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The in silico studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression.\nCONCLUSIONS: This is the first report of an EGR2 mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the EGR2-related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the EGR2 gene.","variants":[{"Name":"NM_000399.5(EGR2):c.1226G>A (p.Arg409Gln)","Chromosome":"10","Start":"62813412","Stop":"62813412","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":221982,"rule_based_match":true,"evidence_text":"c.1226G>A change (p.R409Q)","llm_judgment":"PRESENT","evidence":"c.1226G>A change (p.R409Q)","abstract_start":484,"abstract_end":510}]}
{"pmid":"35271763","title":"Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease.","abstract":"Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper-transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B variant in a number of patients with WD. Synonymous single-nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10<sup>-6</sup> in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10<sup>-5</sup> ; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.","variants":[{"Name":"NM_000053.4(ATP7B):c.2292C>T (p.Phe764=)","Chromosome":"13","Start":"51958374","Stop":"51958374","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":167784,"rule_based_match":true,"evidence_text":"c.2292C>T (p.Phe764=)","llm_judgment":"PRESENT","evidence":"c.2292C>T (p.Phe764=)","abstract_start":448,"abstract_end":469}]}
{"pmid":"37850357","title":"Adding to the evidence of gene-disease association of RAP1B and syndromic thrombocytopenia.","abstract":"Syndromic constitutive thrombocytopenia encompasses a heterogeneous group of disorders characterised by quantitative and qualitative defects of platelets while featuring other malformations. Recently, heterozygous, de novo variants in RAP1B were reported in three cases of syndromic thrombocytopenia. Here, we report two additional, unrelated individuals identified retrospectively in our data repository with heterozygous variants in RAP1B: NM_001010942.2(RAP1B):c.35G>A, p.(Gly12Glu) (de novo) and NM_001010942.2(RAP1B):c.178G>A, p.(Gly60Arg). Both individuals had thrombocytopenia, as well as congenital malformations, and neurological, behavioural, and dysmorphic features, in line with previous reports. Our data supports the causal role of monoallelic RAP1B variants that disrupt RAP1B GTPase activity in syndromic congenital thrombocytopenia.","variants":[{"Name":"NM_001010942.3(RAP1B):c.178G>A (p.Gly60Arg)","Chromosome":"12","Start":"68652046","Stop":"68652046","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2842073,"rule_based_match":true,"evidence_text":"NM_001010942.2(RAP1B):c.178G>A, p.(Gly60Arg)","llm_judgment":"PRESENT","evidence":"NM_001010942.2(RAP1B):c.178G>A, p.(Gly60Arg)","abstract_start":500,"abstract_end":544},{"Name":"NM_001010942.3(RAP1B):c.35G>A (p.Gly12Glu)","Chromosome":"12","Start":"68648759","Stop":"68648759","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2839829,"rule_based_match":true,"evidence_text":"NM_001010942.2(RAP1B):c.35G>A, p.(Gly12Glu)","llm_judgment":"PRESENT","evidence":"NM_001010942.2(RAP1B):c.35G>A, p.(Gly12Glu)","abstract_start":442,"abstract_end":485}]}
{"pmid":"22652532","title":"Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms.","abstract":"BACKGROUND: Therapy related myeloid neoplasms (t-MNs) are complex diseases originating from an interplay between exogenous toxicities and a susceptible organism. It has been hypothesised that in a subset of cases t-MNs develop in the context of hereditary cancer predisposition syndromes.\nMETHODS: The study systematically evaluated pedigrees of patients with t-MNs for cancer incidences and the possibility of a hereditary cancer predisposition syndrome. In addition, mutational analyses were performed using constitutional DNA from index patients, and deleterious heterozygous germline mutations were assessed for loss of heterozygosity in sorted leukaemic cells by single nucleotide polymorphism array.\nRESULTS: A nuclear pedigree was obtained in 51/53 patients with t-MNs resulting in a total of 828 individuals analysed. With a standardised incidence ratio of 1.03 (95% CI 0.74 to 1.39), the tumour incidence of first- degree relatives was not increased. However, six pedigrees were suggestive for a hereditary breast and ovarian cancer syndrome, three of a Li-Fraumeni like syndrome, and three index patients showed multiple primary neoplasms. Mutational analysis revealed two BRCA1 (c.3112G→T, c.5251C→T), one BRCA2 (c.4027A→G), two BARD1 (C557S) and four TP53 germline mutations (g.18508_18761delinsGCC, c.847C→T, c.845_848dupGGCG, c.1146delA) in nine of 53 (17%) index patients with t-MNs. Loss of heterozygosity in leukaemic cells was demonstrated for the BRCA1c.3112G→T and TP53c.845_848dupGGCG mutations, respectively.\nCONCLUSION: It is concluded that a proportion of patients with t-MNs carry cancer susceptibility mutations which are likely to contribute to therapy related leukaemogenesis.","variants":[{"Name":"NM_000546.6(TP53):c.847C>T (p.Arg283Cys)","Chromosome":"17","Start":"7673773","Stop":"7673773","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133281,"rule_based_match":false,"evidence_text":"c.847C→T","llm_judgment":"PRESENT","evidence":"c.847C→T","abstract_start":1312,"abstract_end":1320},{"Name":"NM_007294.4(BRCA1):c.5251C>T (p.Arg1751Ter)","Chromosome":"17","Start":"43057078","Stop":"43057078","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70147,"rule_based_match":false,"evidence_text":"c.5251C→T","llm_judgment":"PRESENT","evidence":"c.5251C→T","abstract_start":1201,"abstract_end":1210},{"Name":"NM_007294.4(BRCA1):c.3112G>T (p.Glu1038Ter)","Chromosome":"17","Start":"43092419","Stop":"43092419","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":46065,"rule_based_match":false,"evidence_text":"c.3112G→T","llm_judgment":"PRESENT","evidence":"c.3112G→T","abstract_start":1190,"abstract_end":1199},{"Name":"NM_000059.4(BRCA2):c.4027A>G (p.Lys1343Glu)","Chromosome":"13","Start":"32338382","Stop":"32338382","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":131572,"rule_based_match":false,"evidence_text":"BRCA2 (c.4027A→G)","llm_judgment":"PRESENT","evidence":"BRCA2 (c.4027A→G)","abstract_start":1217,"abstract_end":1234},{"Name":"NM_000546.6(TP53):c.1146del (p.Lys382fs)","Chromosome":"17","Start":"7669645","Stop":"7669645","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":1500249,"rule_based_match":true,"evidence_text":"c.1146delA","llm_judgment":"PRESENT","evidence":"c.1146delA","abstract_start":1340,"abstract_end":1350}]}
{"pmid":"22147323","title":"Genetic diagnosis of severe myoclonic epilepsy of infancy (Dravet syndrome) with SCN1A mutations in the Hong Kong Chinese patients.","abstract":"Epilepsy is a clinically and genetically heterogeneous group of disorders. The advent of molecular genetics brings unprecedented advancement in diagnostic molecular pathology and reduces over-reliance on traditional clinical classification. Severe myoclonic epilepsy of infancy or Dravet syndrome is a catastrophic infantile-onset epilepsy. We report two unrelated Hong Kong Chinese patients with this condition presenting with febrile seizures, epilepsy with different semiologies, psychomotor retardation, and recurrent status epilepticus. Two different mutations were characterised, viz NM_001165963.1: c.680T>G; NP_001159435.1: p.I227S and NM_001165963.1: c.3953T>G; NP_001159435.1: p.L1318R (novel). Genetic characterisation conveys a definitive diagnosis and is important from the perspective of selecting anti-epileptic drug therapy and genetic counselling.","variants":[{"Name":"NM_001165963.4(SCN1A):c.680T>G (p.Ile227Ser)","Chromosome":"2","Start":"166052866","Stop":"166052866","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":79471,"rule_based_match":true,"evidence_text":"NM_001165963.1: c.680T>G; NP_001159435.1: p.I227S","llm_judgment":"PRESENT","evidence":"NM_001165963.1: c.680T>G; NP_001159435.1: p.I227S","abstract_start":590,"abstract_end":639}]}
{"pmid":"32596134","title":"Mild form of Zellweger Spectrum Disorders (ZSD) due to variants in","abstract":"Peroxisomal biogenesis disorders (PBD) are rare autosomal recessive disorders with various degrees of severity caused by hypomorphic mutations in 13 different peroxin (PEX) genes. In this study, we report the clinical and molecular characterization of a 9-years-old female presenting an apparently isolated pre-lingual sensorineural hearing loss (SNHL) and early onset Retinitis Pigmentosa (RP) that may clinically overlap with Usher syndrome. Genetic testing by clinical exome sequencing identified two variants in <i>PEX1</i>: the missense variant c.274G > C; p.(Val92Leu) that was already reported in a PBD patient, and the variant c.2140_2145dup; p.(Ser714_Gln715dup) which is a novel, non-frameshift variant, absent in control databases. On the basis of the molecular analysis, a thorough clinical examination revealed nail and dental abnormalities, a mild cognitive impairment, learning disabilities and poor feeding, apart from the retinal and audiological features initially identified. The clinical and molecular findings led us to the diagnosis of a mild form of PBD. This study further emphasizes that mild forms of PBD can be a differential diagnosis of Usher syndrome and suggests that patients with mild cognitive impairment associated to visual and hearing loss should perform a comprehensive mutation screening that includes <i>PEX</i> genes.","variants":[{"Name":"NM_000466.3(PEX1):c.2140_2145dup (p.712_713SQ[3])","Chromosome":"7","Start":"92503121","Stop":"92503122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCTGAGA","allel_id":544627,"rule_based_match":true,"evidence_text":"c.2140_2145dup; p.(Ser714_Gln715dup)","llm_judgment":"PRESENT","evidence":"c.2140_2145dup; p.(Ser714_Gln715dup)","abstract_start":635,"abstract_end":671}]}
{"pmid":"31752936","title":"Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture.","abstract":"BACKGROUND: Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture.\nMETHODS: Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies.\nRESULTS: Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways.\nCONCLUSIONS: We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.","variants":[{"Name":"NM_001982.4(ERBB3):c.1253T>C (p.Ile418Thr)","Chromosome":"12","Start":"56093055","Stop":"56093055","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":966797,"rule_based_match":true,"evidence_text":"c.1253 T > C (p.I418T)","llm_judgment":"PRESENT","evidence":"c.1253 T > C (p.I418T)","abstract_start":1185,"abstract_end":1207}]}
{"pmid":"27366019","title":"Two Siblings with Adolescent/Adult Onset Niemann-Pick Disease Type C in Korea.","abstract":"Niemann-Pick disease, type C (NP-C), is caused by NPC1 or NPC2 gene mutations. Progressive neurological, psychiatric, and visceral symptoms are characteristic. Here, we present cases of a brother (Case 1) and sister (Case 2) in their mid-20s with gait disturbance and psychosis. For the Case 1, neurological examination revealed dystonia, ataxia, vertical supranuclear-gaze palsy (VSGP), and global cognitive impairment. Case 2 showed milder, but similar symptoms, with cortical atrophy. Abdominal computed tomography showed hepatosplenomegaly in both cases. NPC1 gene sequencing revealed compound heterozygote for exon 9 (c.1552C>T [R518W]) and exon 18 (c.2780C>T [A927V]). Filipin-staining tests were also positive. When a young patient with ataxia or dystonia shows VSGP, NP-C should be considered.","variants":[{"Name":"NM_000271.5(NPC1):c.1552C>T (p.Arg518Trp)","Chromosome":"18","Start":"23554759","Stop":"23554759","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":549257,"rule_based_match":true,"evidence_text":"c.1552C>T [R518W]","llm_judgment":"PRESENT","evidence":"c.1552C>T [R518W]","abstract_start":623,"abstract_end":640}]}
{"pmid":"21739261","title":"Oculocutaneous albinism type 3 (OCA3): analysis of two novel mutations in TYRP1 gene in two Chinese patients.","abstract":"Oculocutaneous albinism (OCA) is a genetic disease characterized by the reduction or deficiency of melanin in eyes, skin, and hair. OCA exhibits genetic heterogeneity. Presently, there are four types of OCA named as OCA1, OCA2, OCA3, and OCA4. OCA3 is more common in African born blacks but rarely found in other ethnic populations. Our recent genotyping of patients with OCA of Chinese descent has identified two patients who were not OCA1, OCA2, or OCA4. Examination and analysis of the TYRP1 gene identified them to be having OCA3. PCR and DNA sequencing analysis found that the mutant TYPR1 alleles were present in each of the two patients, c.780-791del/c.1067G>A (p.R356Q) and c.625G>TT (p.G209LfsX1)/c.643C>T (p.H215Y). The c.780-791del and c.1067G>A mutations have been already reported. However, the c.625G>TT and c.643C>T mutations have not been previously reported and were found to be maternal and paternal mutations, respectively. Moreover, population screening and bioinformatic analysis were carried out to determine the effects of these two mutations which revealed that both the mutation were pathogenic. Based on the similar mild phenotype of these two patients, we suggest that OCA3 might be prevalent within the Chinese population.","variants":[{"Name":"NM_000550.3(TYRP1):c.643C>T (p.His215Tyr)","Chromosome":"9","Start":"12695772","Stop":"12695772","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2901293,"rule_based_match":true,"evidence_text":"c.643C>T (p.H215Y)","llm_judgment":"PRESENT","evidence":"c.643C>T (p.H215Y)","abstract_start":706,"abstract_end":724},{"Name":"NM_000550.3(TYRP1):c.1067G>A (p.Arg356Gln)","Chromosome":"9","Start":"12702424","Stop":"12702424","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32635,"rule_based_match":true,"evidence_text":"c.1067G>A (p.R356Q)","llm_judgment":"PRESENT","evidence":"c.1067G>A (p.R356Q)","abstract_start":658,"abstract_end":677}]}
{"pmid":"24616599","title":"Different clinical phenotypes in familial severe congenital neutropenia cases with same mutation of the ELANE gene.","abstract":"Severe congenital neutropenia (SCN) is a heterogeneous group of disorders with a defect in granulopoiesis causing marked neutropenia and severe bacterial infections. A 17-month-old girl (patient 1) was admitted due to cervical lymphadenitis caused by methicillin-resistant Staphylococcus aureus, with neutropenia. She had Pseudomonas aeruginosa sepsis and peritonitis with perforated appendicitis at 8-month of age. Her sister, a 37-month-old girl (patient 2), had recurrent stomatitis with profound neutropenia, and her mother, a 32-yr-old woman (patient 3), had had recurrent stomatitis until her early 20s with neutropenia. We found an ELANE gene mutation (c.597+1G > A) from them in direct DNA sequencing analysis. Patients 1 and 2 did not respond to granulocyte colony stimulating factor and patient 1 was treated with prolonged antibiotics and excision. We demonstrated inherited SCN cases showing different severity even with the same mutation of the ELANE gene in a family.","variants":[{"Name":"NM_001972.4(ELANE):c.597+1G>A","Chromosome":"19","Start":"855795","Stop":"855795","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":243869,"rule_based_match":true,"evidence_text":"c.597+1G > A","llm_judgment":"PRESENT","evidence":"c.597+1G > A","abstract_start":660,"abstract_end":672}]}
{"pmid":"34126256","title":"Aberrant splicing and transcriptional activity of TPP1 result in CLN2-like disorder.","abstract":"RNA sequencing (RNAseq) is emerging as a complementary tool to DNA sequencing, providing utility in diagnosis for disorders such as neuronal ceroid lipofuscinosis CLN2 disease. We describe an individual with a presentation suggestive of an attenuated CLN2 phenotype, including a history of regression, recent-onset microcephaly and spasticity from age five years. Exome sequencing revealed two variants inherited in trans in TPP1, NM_000391.4:c.225A>G; p.(Gln75 = ) and NM_000391.4:c.1012C>G; p.(Gln338Glu), both classified as variants of uncertain significance. TPP1 activity was found to be significantly reduced in fibroblasts of the affected individual. RNAseq was performed to assess the impact of compound heterozygous variants in TPP1 and enabled the identification of three aberrant splicing events. The c.225A>G variant introduces a 5 nucleotide truncation of exon 3 and a loss of reading frame. The majority of CLN2 transcripts exclude either exon 8 or exons 7-8, resulting in large in-frame deletions. Isoform specific RT-PCR confirmed the aberrant splicing events are mutually exclusive, suggesting that the paternal exon 8 c.1012C>G variant results in exon skipping. This case study demonstrates how RNAseq can be used as an orthogonal test to inform the interpretation of some variants of unknown significance and its particular importance in disorders where effective disease management requires early diagnosis.","variants":[{"Name":"NM_000391.4(TPP1):c.1012C>G (p.Gln338Glu)","Chromosome":"11","Start":"6616378","Stop":"6616378","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1862027,"rule_based_match":true,"evidence_text":"NM_000391.4:c.1012C>G; p.(Gln338Glu)","llm_judgment":"PRESENT","evidence":"NM_000391.4:c.1012C>G; p.(Gln338Glu)","abstract_start":470,"abstract_end":506},{"Name":"NM_000391.4(TPP1):c.225A>G (p.Gln75=)","Chromosome":"11","Start":"6618780","Stop":"6618780","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":546140,"rule_based_match":true,"evidence_text":"NM_000391.4:c.225A>G; p.(Gln75 = )","llm_judgment":"PRESENT","evidence":"NM_000391.4:c.225A>G; p.(Gln75 = )","abstract_start":431,"abstract_end":465}]}
{"pmid":"25574826","title":"CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease.","abstract":"CODAS syndrome is a multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. Using whole-exome and Sanger sequencing, we identified four LONP1 mutations inherited as homozygous or compound-heterozygous combinations among ten individuals with CODAS syndrome. The individuals come from three different ancestral backgrounds (Amish-Swiss from United States, n = 8; Mennonite-German from Canada, n = 1; mixed European from Canada, n = 1). LONP1 encodes Lon protease, a homohexameric enzyme that mediates protein quality control, respiratory-complex assembly, gene expression, and stress responses in mitochondria. All four pathogenic amino acid substitutions cluster within the AAA(+) domain at residues near the ATP-binding pocket. In biochemical assays, pathogenic Lon proteins show substrate-specific defects in ATP-dependent proteolysis. When expressed recombinantly in cells, all altered Lon proteins localize to mitochondria. The Old Order Amish Lon variant (LONP1 c.2161C>G[p.Arg721Gly]) homo-oligomerizes poorly in vitro. Lymphoblastoid cell lines generated from affected children have (1) swollen mitochondria with electron-dense inclusions and abnormal inner-membrane morphology; (2) aggregated MT-CO2, the mtDNA-encoded subunit II of cytochrome c oxidase; and (3) reduced spare respiratory capacity, leading to impaired mitochondrial proteostasis and function. CODAS syndrome is a distinct, autosomal-recessive, developmental disorder associated with dysfunction of the mitochondrial Lon protease.","variants":[{"Name":"NM_004793.4(LONP1):c.2161C>G (p.Arg721Gly)","Chromosome":"19","Start":"5694546","Stop":"5694546","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1401606,"rule_based_match":true,"evidence_text":"LONP1 c.2161C>G[p.Arg721Gly]","llm_judgment":"PRESENT","evidence":"LONP1 c.2161C>G[p.Arg721Gly]","abstract_start":1018,"abstract_end":1046}]}
{"pmid":"36779069","title":"Case report: Novel","abstract":"Glutaric aciduria type II (GA II) is an autosomal recessive metabolic disorder of fatty acid, amino acid, and choline metabolism. The late-onset form of this disorder is caused by a defect in the mitochondrial electron transfer flavoprotein dehydrogenase or the electron transfer flavoprotein dehydrogenase (<i>ETFDH</i>) gene. Thus far, the high clinical heterogeneity of late-onset GA II has brought a great challenge for its diagnosis. In this study, we reported a 21-year-old Chinese man with muscle weakness, vomiting, and severe pain. Muscle biopsy revealed myopathological patterns of lipid storage myopathy, and urine organic acid analyses showed a slight increase in glycolic acid. All the aforementioned results were consistent with GA II. Whole-exome sequencing (WES), followed by bioinformatics and structural analyses, revealed two compound heterozygous missense mutations: c.1034A > G (p.H345R) on exon 9 and c.1448C>A (p.P483Q) on exon 11, which were classified as \"likely pathogenic\" according to American College of Medical Genetics and Genomics (ACMG). In conclusion, this study described the phenotype and genotype of a patient with late-onset GA II. The two novel mutations in <i>ETFDH</i> were found in this case, which further expands the list of mutations found in patients with GA II. Because of the treatability of this disease, GA II should be considered in all patients with muscular symptoms and acute metabolism decompensation such as hypoglycemia and acidosis.","variants":[{"Name":"NM_004453.4(ETFDH):c.1448C>A (p.Pro483Gln)","Chromosome":"4","Start":"158706351","Stop":"158706351","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3495271,"rule_based_match":true,"evidence_text":"c.1448C>A (p.P483Q)","llm_judgment":"PRESENT","evidence":"c.1448C>A (p.P483Q)","abstract_start":923,"abstract_end":942}]}
{"pmid":"29461981","title":"CYP3A4 mutation causes vitamin D-dependent rickets type 3.","abstract":"Genetic forms of vitamin D-dependent rickets (VDDRs) are due to mutations impairing activation of vitamin D or decreasing vitamin D receptor responsiveness. Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D. Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4). In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites. As CYP3A4 mutations have not previously been linked to rickets, these findings provide insight into vitamin D metabolism and demonstrate that accelerated inactivation of vitamin D metabolites represents a mechanism for vitamin D deficiency.","variants":[{"Name":"NM_017460.6(CYP3A4):c.902T>C (p.Ile301Thr)","Chromosome":"7","Start":"99763979","Stop":"99763979","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":970484,"rule_based_match":true,"evidence_text":"c.902T>C (p.I301T)","llm_judgment":"PRESENT","evidence":"c.902T>C (p.I301T)","abstract_start":561,"abstract_end":579}]}
{"pmid":"34602955","title":"Novel Compound Heterozygous Mutation c.3955_3958dup and c.5825C>T in the","abstract":"Pathogenic and likely pathogenic variants in the <i>ATM</i> gene are associated both with Ataxia-telangiectasia disease or ATM syndrome and an increased cancer risk for heterozygous carriers. We identified a novel compound heterozygous mutation c.3955_3958dup (p.Asp1320delinsValTer) and c.5825C>T (p.Ala1942Val) in the <i>ATM</i> gene in a Peruvian patient with progressive ataxia combined with other movement disorders, mild conjunctival telangiectasia and increased alpha-fetoprotein, without history of recurrent infection or immunodeficiency. We also determined the carrier status of the family members, and we were able to detect gastric and breast cancer at an early stage during the cancer risk assessment in the mother (c.3955_3958dup). Here, we describe clinical evidence for the novel compound heterozygous mutation and c.3955_3958dup not previously reported.","variants":[{"Name":"NM_000051.4(ATM):c.5825C>T (p.Ala1942Val)","Chromosome":"11","Start":"108310222","Stop":"108310222","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":180478,"rule_based_match":true,"evidence_text":"c.5825C>T (p.Ala1942Val)","llm_judgment":"PRESENT","evidence":"c.5825C>T (p.Ala1942Val)","abstract_start":288,"abstract_end":312}]}
{"pmid":"16426410","title":"Monomorphic ventricular tachycardia due to Brugada syndrome successfully treated by hydroquinidine therapy in a 3-year-old child.","abstract":"Mutations in the SCN5A gene can cause Brugada syndrome, a genetically inherited form of idiopathic ventricular fibrillation. We describe the case of a 3-year-old child with a structurally normal heart presenting with monomorphic ventricular tachycardia. Her electrocardiogram suggested a Brugada syndrome and the diagnosis was confirmed by the identification of a Brugada syndrome in her mother and in two other family members. Genetic study led to the identification of a c.2516T-->C SCN5A mutation. The child was treated with quinidine therapy without recurrence of arrhythmic events for a time period of 16 months.","variants":[{"Name":"NM_000335.5(SCN5A):c.2516T>C (p.Leu839Pro)","Chromosome":"3","Start":"38585962","Stop":"38585962","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":78632,"rule_based_match":false,"evidence_text":"c.2516T-->C SCN5A mutation","llm_judgment":"PRESENT","evidence":"c.2516T-->C SCN5A mutation","abstract_start":473,"abstract_end":499}]}
{"pmid":"30975617","title":"Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders.","abstract":"INTRODUCTION: ADCY5-related hyperkinesia encompasses a heterogeneous group of phenotypes, including paroxysmal chorea, myoclonus, and dystonia. The disease is attributed to mutations of ADCY5, which encodes an adenylate cyclase enzyme. The disease can occur in a sporadic or familial pattern. With exception of one study, all reports on familial ADCY5-related hyperkinesia were associated with an autosomal dominant inheritance. Herein, we describe a native Arabian Bedouin family with an autosomal recessive ADCY5-related disorder and expand the genotypic and phenotypic spectrum of this disorder.\nMETHODS: The pedigree included 4 generations of a family with 6 affected individuals. The patients were examined clinically and radiologically. Homozygosity mapping and Whole Exome Sequencing (WES) were used to identify a variant, predicted to be pathogenic, which segregated with disease in this family.\nRESULTS: All patients presented with early-onset dystonia and myoclonus. The patients had delayed motor and language milestones, axial hypotonia, severe anxiety, social phobia, and isolation. One patient had dilated cardiomyopathy. WES of one affected individual revealed a novel homozygous missense mutation (c.1762G > A, p.D588N) of ADCY5, that segregated with disease in an autosomal recessive manner, and was absent in more than 1000 ethnically-matched chromosomes. The mutation replaces a highly conserved nucleotide and is predicted to be deleterious.\nCONCLUSION: This study reports the second family with autosomal recessive childhood-onset ADCY5-related disorder and expands our understanding of phenotype/genotype correlations of this disorder.","variants":[{"Name":"NM_183357.3(ADCY5):c.1762G>A (p.Asp588Asn)","Chromosome":"3","Start":"123328687","Stop":"123328687","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1318053,"rule_based_match":true,"evidence_text":"c.1762G > A, p.D588N","llm_judgment":"PRESENT","evidence":"c.1762G > A, p.D588N","abstract_start":1214,"abstract_end":1234}]}
{"pmid":"24888332","title":"Novel de novo heterozygous FGFR1 mutation in two siblings with Hartsfield syndrome: a case of gonadal mosaicism.","abstract":"Hartsfield syndrome has been recently reported to be associated with mutations in FGFR1 however, to this date; no familial cases have been reported. In this report, we describe two siblings with Hartsfield syndrome and a novel de novo FGFR1 mutation suggesting gonadal mosaicism. The proband presented at our institution at age 6 years with a clinical diagnosis of Hartsfield syndrome and requesting further genetic evaluation. Previous studies included a normal karyotype, oligonucleotide array, and single gene testing for nonsyndromic holoprosencephaly (SHH, SIX3, ZIC2, TGIF). At the age of 6 years, exome sequencing was performed and a de novo novel missense variant was identified in FGFR1 (coding for fibroblast growth factor-1) on chromosome 8p12: c.1880G>C (p.R627T). Subsequently, a younger sibling was born with the same phenotype (holoprosencephaly, ectrodactyly of bilateral hands and feet and bilateral cleft lip and palate). Targeted sequencing of FGFR1 revealed the identical variant that was previously identified in the proband. To our knowledge this observation is the first documentation of familial recurrence of Hartsfield syndrome. As both parents were negative for the sequence variant in FGFR1 gene by testing peripheral blood samples, this suggests gonadal mosaicism. The frequency of gonadal mosaicism in Hartsfield syndrome is not known however given our case, this possibility should be taken in to consideration for recurrence risk estimation in children of clinically unaffected parents.","variants":[{"Name":"NM_023110.3(FGFR1):c.1880G>C (p.Arg627Thr)","Chromosome":"8","Start":"38414876","Stop":"38414876","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":224976,"rule_based_match":true,"evidence_text":"c.1880G>C (p.R627T)","llm_judgment":"PRESENT","evidence":"c.1880G>C (p.R627T)","abstract_start":756,"abstract_end":775}]}
{"pmid":"30385166","title":"PEHO syndrome: KIF1A mutation and decreased activity of mitochondrial respiratory chain complex.","abstract":"We report a child with hypotonia, optic atrophy, progressive encephalopathy and intractable infantile spasms who was diagnosed with PEHO syndrome. Extensive investigation was performed to diagnose an underlying etiology. Electron transport chain activities in muscle biopsies showed an isolated complex IV deficiency. Genetic examination focused on complex IV genes such as mtDNA and relevant nuclear DNA analysis was unremarkable. Whole exome sequencing with trio revealed a heterozygous de novo mutation at c.757G>A (p.E253K) in the KIF1A gene. The protein encoded by this gene functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. The relation between this genetic mutation and decreased activity of the mitochondrial respiratory chain complex is discussed in details. Our study further confirmed that the molecular basis of PEHO syndrome at least in a subset of patients is a dominant KIF1A variant affecting the motor domain of the protein. This is the first description of the decreased activity of mitochondrial respiratory chain complex in association with either PEHO syndrome or KIF1A mutation. This study emphasizes that the results of the mitochondrial enzymes should be interpreted with caution and clinicians should be actively looking for other underlying diagnoses with further comprehensive studies.","variants":[{"Name":"NM_001244008.2(KIF1A):c.757G>A (p.Glu253Lys)","Chromosome":"2","Start":"240783780","Stop":"240783780","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171772,"rule_based_match":true,"evidence_text":"c.757G>A (p.E253K)","llm_judgment":"PRESENT","evidence":"c.757G>A (p.E253K)","abstract_start":509,"abstract_end":527}]}
{"pmid":"15712365","title":"P gene mutations associated with oculocutaneous albinism type II (OCA2).","abstract":"Oculocutaneous albinism type II (OCA2) is the most common form of albinism in humans. OCA2 has been previously associated with mutations of the P gene, the human homologue to the murine pink-eyed dilution gene. The P gene encodes a 110 kDa protein containing 12 potential membrane spanning domains and is associated with melanosomal membranes. The specific function of the P protein is currently unknown but is thought to be involved in tyrosinase processing and transport. We report nine novel mutations in the P gene associated with OCA2. These include two missense mutations, c.1938A>C (p.Ile646Val) and c.1556T>C (p.Val519Ala); one nonsense mutation c.612G>A (p.Trp204X); five frameshift mutations: c.2372_2373delTC, c.1555delG, c.1938_1939insC, c.2050delT, and c.1045_1046delAT; and a splice site mutation c.1951+1G>A. We also report 12 novel polymorphisms including one amino acid substitution, c.2365_2366GC>CA (p.Ala789Glu). At present, there is no functional assay to determine if a mutation is truly pathogenic. The presence of numerous polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, makes molecular diagnosis problematic. To ensure accurate molecular diagnosis, further mutational analysis will be necessary to produce a comprehensive list of mutations associated with OCA2. This information will also help define the critical functional domains of the P protein. Mutations associated with OCA2 can be found in the Albinism Database (http://albinismdb.med.umn.edu).","variants":[{"Name":"NM_000275.3(OCA2):c.1556T>C (p.Val519Ala)","Chromosome":"15","Start":"27966770","Stop":"27966770","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1871244,"rule_based_match":true,"evidence_text":"c.1556T>C (p.Val519Ala)","llm_judgment":"PRESENT","evidence":"c.1556T>C (p.Val519Ala)","abstract_start":607,"abstract_end":630},{"Name":"NM_000275.3(OCA2):c.612G>A (p.Trp204Ter)","Chromosome":"15","Start":"28022535","Stop":"28022535","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1871247,"rule_based_match":true,"evidence_text":"c.612G>A (p.Trp204X)","llm_judgment":"PRESENT","evidence":"c.612G>A (p.Trp204X)","abstract_start":654,"abstract_end":674},{"Name":"NM_000275.3(OCA2):c.1555del (p.Val519fs)","Chromosome":"15","Start":"27966771","Stop":"27966771","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":1468126,"rule_based_match":true,"evidence_text":"c.1555delG","llm_judgment":"PRESENT","evidence":"c.1555delG","abstract_start":721,"abstract_end":731}]}
{"pmid":"27768226","title":"Novel variants of RPGR in X-linked retinitis pigmentosa families and genotype-phenotype correlation.","abstract":"PURPOSE: To identify novel mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene and retinitis pigmentosa 2 (RP2) gene underlying X-linked retinitis pigmentosa (XLRP) and assess genotype-phenotype correlations.\nMETHODS: The patient cohort, consisting of 13 individuals from 3 unrelated XLRP families, underwent comprehensive ophthalmologic examination. The open reading frames of RPGR and RP2 were analyzed with Sanger sequencing in each patient. The identified genetic variants were defined as mutations or polymorphisms on the basis of their pathological effect.\nRESULTS: We found 3 genetic variants: a novel mutation c.1591G>T in exon 14 and a novel polymorphism c.1105C>T in exon 10, resulting in p.Glu531* and p.Arg369Cys of RPGR gene, respectively, and one already known mutation c.413A>G in exon 2, resulting in a p.Glu138Gly of RP2 gene. Considering our XLRP probands, RPGR-related phenotypic damages were similar and less severe than those of the patient with the RP2 mutation. On the other hand, the female carriers of XLRP variants showed different RPGR-related consequences, ranging from rods hypofunctionality in c.1591G>T nonsense heterozygosity to no retinal changes in c.1105C>T polymorphic heterozygosity.\nCONCLUSIONS: These findings broaden the spectrum of RPGR mutations and phenotypic variability of the disease, which will be useful for genetic consultation and diagnosis in the future.","variants":[{"Name":"NM_001034853.2(RPGR):c.1591G>T (p.Glu531Ter)","Chromosome":"X","Start":"38288023","Stop":"38288023","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1878234,"rule_based_match":true,"evidence_text":"c.1591G>T","llm_judgment":"PRESENT","evidence":"c.1591G>T","abstract_start":633,"abstract_end":642},{"Name":"NM_006915.3(RP2):c.413A>G (p.Glu138Gly)","Chromosome":"X","Start":"46853786","Stop":"46853786","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3857435,"rule_based_match":true,"evidence_text":"c.413A>G","llm_judgment":"PRESENT","evidence":"c.413A>G","abstract_start":799,"abstract_end":807}]}
{"pmid":"34510628","title":"Noncoding sequence variants define a novel regulatory element in the first intron of the N-acetylglutamate synthase gene.","abstract":"N-acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder caused either by decreased expression of the NAGS gene or defective NAGS enzyme resulting in decreased production of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1). NAGSD is the only urea cycle disorder that can be effectively treated with a single drug, N-carbamylglutamate (NCG), a stable NAG analog, which activates CPS1 to restore ureagenesis. We describe three patients with NAGSD due to four novel noncoding sequence variants in the NAGS regulatory regions. All three patients had hyperammonemia that resolved upon treatment with NCG. Sequence variants NM_153006.2:c.427-222G>A and NM_153006.2:c.427-218A>C reside in the 547 bp-long first intron of NAGS and define a novel NAGS regulatory element that binds retinoic X receptor α. Sequence variants NC_000017.10:g.42078967A>T (NM_153006.2:c.-3065A>T) and NC_000017.10:g.42078934C>T (NM_153006.2:c.-3098C>T) reside in the NAGS enhancer, within known HNF1 and predicted glucocorticoid receptor binding sites, respectively. Reporter gene assays in HepG2 and HuH-7 cells demonstrated that all four substitutions could result in reduced expression of NAGS. These findings show that analyzing noncoding regions of NAGS and other urea cycle genes can reveal molecular causes of disease and identify novel regulators of ureagenesis.","variants":[{"Name":"NM_153006.3(NAGS):c.427-222G>A","Chromosome":"17","Start":"44005415","Stop":"44005415","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1166603,"rule_based_match":true,"evidence_text":"NM_153006.2:c.427-222G>A","llm_judgment":"PRESENT","evidence":"NM_153006.2:c.427-222G>A","abstract_start":686,"abstract_end":710},{"Name":"NM_153006.3(NAGS):c.427-218A>C","Chromosome":"17","Start":"44005419","Stop":"44005419","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2003677,"rule_based_match":true,"evidence_text":"NM_153006.2:c.427-218A>C","llm_judgment":"PRESENT","evidence":"NM_153006.2:c.427-218A>C","abstract_start":715,"abstract_end":739}]}
{"pmid":"31568062","title":"Concurrent heterozygous Von-Hippel-Lindau and transmembrane-protein-127 gene mutation causing an erythropoietin-secreting pheochromocytoma in a normotensive patient with severe erythrocytosis.","abstract":"BACKGROUND: Mutations of genes related to Krebs cycle enzymes, kinases or to pseudohypoxic signaling pathways, including Von-Hippel-Lindau (VHL) and transmembrane-protein-127 predispose to pheochromocytoma and paraganglioma development. Homozygous loss of function mutation of VHL (VHL 598C>T) gene can associate with polycythemia because of an altered hypoxia sensing.\nPATIENT: A 19-year-old normotensive man presented with headache, fatigue associated with severe erythrocytosis (hematocrit 76%), high hemoglobin (25.3 g/dl) in normoxic condition. Bone marrow biopsy showed marked hyperplasia of erythroid series. The Janus kinase 2 (V617F) mutation was absent. Abdominal computed tomography scan showed a 8-mm left adrenal pheochromocytoma with tracer uptake on GaDOTA-octreotate PET. Twenty-four-hour urinary metanephrine excretion was slightly increased, while normetanephrine, 3-methoxytyramine were normal. Adrenal veins sampling showed high left-side erythropoietin secretion.\nRESULTS: Next-generation sequencing genetic analysis evidenced two concurrent heterozygous mutation of VHL598C>T and of transmembrane-protein-127 c.268G>A. Left side adrenalectomy improved symptoms, erythrocytosis, hemoglobin, and erythropoietin circulating levels. Adrenal histologic sections showed a pheochromocytoma with extensive immunostaining for erythropoietin, but also coexpression of chromogranin A, a marker of chromaffin tissue.\nCONCLUSION: Congenital polycythemia was clinically diagnosed, mimicking Chuvash polycythemia. Chuvash polycythemia is an autosomal recessive disorder that usually harbors a homozygous mutation of VHL598C>T but not predispose to pheochromocytoma development; in contrast our patient showed for the first time that the concurrent heterozygous VHL and TMEM mutations, resulted in a clinical phenotype of a normotensive patient with polycythemia due to erythropoietin-secreting pheochromocytoma that improved after adrenalectomy.","variants":[{"Name":"NM_000551.4(VHL):c.598C>T (p.Arg200Trp)","Chromosome":"3","Start":"10149921","Stop":"10149921","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17271,"rule_based_match":false,"evidence_text":"VHL 598C>T","llm_judgment":"PRESENT","evidence":"VHL 598C>T","abstract_start":282,"abstract_end":292}]}
{"pmid":"20598274","title":"Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.","abstract":"Mitochondrial respiratory chain disorders are a heterogeneous group of disorders in which the underlying genetic defect is often unknown. We have identified a pathogenic mutation (c.156C>G [p.F52L]) in YARS2, located at chromosome 12p11.21, by using genome-wide SNP-based homozygosity analysis of a family with affected members displaying myopathy, lactic acidosis, and sideroblastic anemia (MLASA). We subsequently identified the same mutation in another unrelated MLASA patient. The YARS2 gene product, mitochondrial tyrosyl-tRNA synthetase (YARS2), was present at lower levels in skeletal muscle whereas fibroblasts were relatively normal. Complex I, III, and IV were dysfunctional as indicated by enzyme analysis, immunoblotting, and immunohistochemistry. A mitochondrial protein-synthesis assay showed reduced levels of respiratory chain subunits in myotubes generated from patient cell lines. A tRNA aminoacylation assay revealed that mutant YARS2 was still active; however, enzyme kinetics were abnormal compared to the wild-type protein. We propose that the reduced aminoacylation activity of mutant YARS2 enzyme leads to decreased mitochondrial protein synthesis, resulting in mitochondrial respiratory chain dysfunction. MLASA has previously been associated with PUS1 mutations; hence, the YARS2 mutation reported here is an alternative cause of MLASA.","variants":[{"Name":"NM_001040436.3(YARS2):c.156C>G (p.Phe52Leu)","Chromosome":"12","Start":"32755719","Stop":"32755719","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":16095,"rule_based_match":true,"evidence_text":"c.156C>G [p.F52L]","llm_judgment":"PRESENT","evidence":"c.156C>G [p.F52L]","abstract_start":180,"abstract_end":197}]}
{"pmid":"27082205","title":"Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis.","abstract":"Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy.","variants":[{"Name":"NM_007294.4(BRCA1):c.1140dup (p.Lys381fs)","Chromosome":"17","Start":"43094390","Stop":"43094391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":236141,"rule_based_match":true,"evidence_text":"c.1140 dupG","llm_judgment":"PRESENT","evidence":"c.1140 dupG","abstract_start":828,"abstract_end":839}]}
{"pmid":"24989684","title":"Atypical Aicardi-Goutieres syndrome: is the WRN locus a modifier?","abstract":"We describe a 28-year-old Turkish man with consanguineous parents who presented with an aged appearance with prematurely gray hair and scleroderma-like skin, spastic paraplegia, and apparent disability. The proband and each of his parents were heterozygous for a mutation in WRN, which could not explain his symptoms. Exome sequencing of the proband's blood DNA showed a homozygous c.626-1G > C mutation in intron 5 of the SAMHD1 gene, which encodes a triphosphohydrolase involved in the regulation of intracellular dNTP pools and which is mutated in Aicardi-Goutieres syndrome. The RNA studies confirmed aberrant splicing of exon 6, and family studies showed that both parents are heterozygous for this mutation. We conclude that mutations in SAMHD1 - in addition to causing an early-onset form of encephalopathy in Aicardi-Goutieres syndrome - may present with modest signs of accelerated aging similar to Werner syndrome. The extent to which heterozygosity at the WRN locus may modify the effect of biallelic SAMHD1 mutations is unknown. It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype.","variants":[{"Name":"NM_015474.4(SAMHD1):c.626-1G>C","Chromosome":"20","Start":"36927253","Stop":"36927253","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1408628,"rule_based_match":true,"evidence_text":"c.626-1G > C","llm_judgment":"PRESENT","evidence":"c.626-1G > C","abstract_start":382,"abstract_end":394}]}
{"pmid":"37006978","title":"Genetic Spectrum in F13A1 Detected by Next-Generation Sequencing Among North Indian Patients with FXIII Deficiency.","abstract":"Purpose: The study aimed to explore the molecular defects underlying FXIII deficiency.\nMaterials and Methods: Sixteen unrelated cases were enrolled based on the indication of the urea clot solubility test and Factor XIII-A antigen levels. Cases were further subjected to targeted next-generation sequencing (custom gene panel: <i>F7</i>, <i>F8</i>, <i>VWF</i>, <i>F9</i>, <i>F13A1, F13B).</i> The pathogenic/likely pathogenic variants were validated by Sanger sequencing in the patients and family members.\nResults: Mean age of referral to our center was 27.2 years (8 week-67 years). Consanguinity was found in only one of the 16 cases and 9 cases presented in infancy. The most common symptoms were skin bleeds (69%) and umbilical cord bleed (50%). The clot solubility test was positive in 12, inconclusive in 1, and normal in 3. Mean FXIII-A levels were 15.7 IU/dL (range 0.6 to 49.5 IU/dL). Pathogenic/likely pathogenic variants in <i>F13A1</i> were found in 11 (69%). Nine cases (82%) were homozygous, and two were compound heterozygous. Total eleven variants were found of which four were missense (c.1226G>A; c.998C>T; c.631G>C; c.2134A>C); three deletion (c.521delG; c.742delA; c.1405_1408delCAAA); two nonsense (c.1112G>A; c.1127G>A) and two splice site (c.1909-1G>C; c.2045G>A). No probably pathogenic variant was found in the <i>F13B</i>.\nConclusion: Inherited FXIII deficiency with bleeding is associated with genetic defects in predominantly the <i>F13A1</i> gene. A variety of variants were seen in this cohort. A nonsense variant c.1127G>A found in three of our cases seems to be recurrent. This data will contribute to designing functional studies and antenatal testing in affected families.\nSupplementary Information: The online version contains supplementary material available at 10.1007/s12288-022-01579-1.","variants":[{"Name":"NM_000129.4(F13A1):c.1226G>A (p.Arg409Gln)","Chromosome":"6","Start":"6195876","Stop":"6195876","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3540170,"rule_based_match":true,"evidence_text":"c.1226G>A","llm_judgment":"PRESENT","evidence":"c.1226G>A","abstract_start":1105,"abstract_end":1114},{"Name":"NM_000129.4(F13A1):c.2045G>A (p.Arg682His)","Chromosome":"6","Start":"6151813","Stop":"6151813","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31563,"rule_based_match":true,"evidence_text":"c.2045G>A","llm_judgment":"PRESENT","evidence":"c.2045G>A","abstract_start":1277,"abstract_end":1286}]}
{"pmid":"32314272","title":"Alanyl-tRNA synthetase 1 (AARS1) gene mutation in a family with intermediate Charcot-Marie-Tooth neuropathy.","abstract":"BACKGROUND: Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).\nOBJECTIVE: To identify pathogenic mutation in the Korean patients with CMT and distal hereditary motor neuronopathy (dHMN).\nMETHODS: We screened AARS1 mutations in 373 unrelated CMT families including 318 axonal CMT, 36 dHMN, and 19 intermediate CMT (Int-CMT) who were negative for 17p12 (PMP22) duplication or deletion using whole exome sequencing and targeted sequencing of CMT-related genes.\nRESULTS: This study identified an early onset Int-CMT family harboring an AARS1 p.Arg329His mutation which was previously reported as pathogenic in French and Australian families. The mutation was located in the highly conserved tRNA binding domain and several in silico analyses suggested pathogenic prediction of the mutations. The patients harboring p.Arg329His showed clinically similar phenotypes of the early onset and electrophysiological intermediate type as those in Australian patients with same mutation. We also found a novel c.2564A>G (p.Gln855Arg) in a CMT2 patient, but its' pathogenic role was uncertain (variant of uncertain significance).\nCONCLUSION: This study suggests that the frequency of the AARS1 mutations appears to be quite low in Korean CMT. This is the first report of the AARS1 mutation in Korean CMT patients and will be helpful for the exact molecular diagnosis and treatment of Int-CMT patients.","variants":[{"Name":"NM_001605.3(AARS1):c.986G>A (p.Arg329His)","Chromosome":"16","Start":"70268356","Stop":"70268356","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23505,"rule_based_match":false,"evidence_text":"p.Arg329His","llm_judgment":"PRESENT","evidence":"p.Arg329His","abstract_start":747,"abstract_end":758}]}
{"pmid":"18331837","title":"Molecular investigations of a novel iduronate-2-sulfatase mutant in a Chinese patient.","abstract":"BACKGROUND: Molecular investigations of iduronate-2-sulfatase (IDS) mutants for the X-linked lysosomal storage disease mucopolysaccharidosis type II (MPS II, Hunter disease), commonly depends on transient expression studies to verify a single nucleotide change to be pathogenic. In 2 severely affected patients, IDS missense mutations, c.1016T>C (novel) and c.1016T>G (known) were identified predicting the substitution of an ambivalent cyclic proline and a hydrophilic arginine respectively for the hydrophobic leucine at residue 339. We hypothesized that residue Leu339 may be functionally critical.\nMETHODS: We performed a study for the 2 mutations by in-situ mutagenesis, in vitro expression, and functional analysis.\nRESULTS: Transient expression revealed that both the missense variants had stable mRNA but their residual enzyme activities remained <2.5% of normal level. The effect of the missense mutations on protein expression was detected by Western blot analysis. Both the missense mutations synthesized the precursor form but had reduced mature form of IDS.\nCONCLUSION: The novel mutation p.L339P is a disease-causing mutation affecting maturation of the protein.","variants":[{"Name":"NM_000202.8(IDS):c.1016T>C (p.Leu339Pro)","Chromosome":"X","Start":"149487089","Stop":"149487089","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":222903,"rule_based_match":true,"evidence_text":"c.1016T>C (novel)","llm_judgment":"PRESENT","evidence":"c.1016T>C (novel)","abstract_start":336,"abstract_end":353}]}
{"pmid":"32434131","title":"Familial Cerebral Cavernous Malformation Syndrome with Concomitant Fourth Ventricular Ependymoma: True Association or Mere Coincidence?","abstract":"Familial cerebral cavernous malformation syndromes are most commonly caused by mutations in one of three genes. The overlap of these genetic malformations with other acquired neoplastic lesions and congenital malformations is still under investigation. To the best of our knowledge, the concurrent occurrence of familial cavernous malformations and ependymoma has not been previously reported in the literature. Herein, we describe a patient with familial cerebral cavernous malformation syndrome and posterior fossa ependymoma. A 17-year-old asymptomatic male was referred to our outpatient neurosurgery clinic after genetic testing identified a familial KRIT1 (CCM1) mutation. The patient's sister had presented with a seizure disorder previously; multiple cavernous malformations were discovered, and a symptomatic large cavernous malformation required a craniotomy for resection. Two years later, she was diagnosed with follicular thyroid cancer due to HRAS (c.182A>G) mutation. The patient and his sister were found to have a novel germline KRIT1 disease-causing variant (c.1739deletion, p.ASN580Ilefs*2) and a variant of uncertain significance, potentially pathogenic (c.1988 A>G, p.Asn663Ser) in cis in CCM1 (KRIT1), of paternal inheritance. Due to the presence of genetic abnormalities, the patient underwent screening imaging of his neuraxis. Multiple cavernous malformations were identified, as was an incidental fourth ventricular mass. Resection of the fourth ventricular lesion was performed, and histopathological examination was consistent with ependymoma. We report a unique case of posterior fossa ependymoma in an individual with a familial cerebral cavernous malformation syndrome and a novel genetic abnormality in KRIT1. The association of these two findings may be valuable in determining a potential genetic association between the two pathologies and elucidating the pathogenesis of both cavernous malformations and ependymomas.","variants":[{"Name":"NM_194454.3(KRIT1):c.1739del (p.Asn580fs)","Chromosome":"7","Start":"92213971","Stop":"92213971","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":581354,"rule_based_match":true,"evidence_text":"c.1739deletion, p.ASN580Ilefs*2","llm_judgment":"PRESENT","evidence":"c.1739deletion, p.ASN580Ilefs*2","abstract_start":1077,"abstract_end":1108},{"Name":"NM_194454.3(KRIT1):c.1988A>G (p.Asn663Ser)","Chromosome":"7","Start":"92213232","Stop":"92213232","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":581347,"rule_based_match":true,"evidence_text":"c.1988 A>G, p.Asn663Ser","llm_judgment":"PRESENT","evidence":"c.1988 A>G, p.Asn663Ser","abstract_start":1175,"abstract_end":1198}]}
{"pmid":"23649928","title":"Functional analysis of a de novo ACTB mutation in a patient with atypical Baraitser-Winter syndrome.","abstract":"Exome sequence analysis can be instrumental in identifying the genetic etiology behind atypical disease. We report a patient presenting with microcephaly, dysmorphic features, and intellectual disability with a tentative diagnosis of Dubowitz syndrome. Exome analysis was performed on the patient and both parents. A de novo missense variant was identified in ACTB, c.349G>A, p.E117K. Recent work in Baraitser-Winter syndrome has identified ACTB and ACTG1 mutations in a cohort of individuals, and we rediagnosed the patient with atypical Baraitser-Winter syndrome. We performed functional characterization of the variant actin and show that it alters cell adhesion and polymer formation supporting its role in disease. We present the clinical findings in the patient, comparison of this patient to other patients with ACTB/ACTG1 mutations, and results from actin functional studies that demonstrate novel functional attributes of this mutant protein.","variants":[{"Name":"NM_001101.5(ACTB):c.349G>A (p.Glu117Lys)","Chromosome":"7","Start":"5529175","Stop":"5529175","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76956,"rule_based_match":true,"evidence_text":"c.349G>A, p.E117K","llm_judgment":"PRESENT","evidence":"c.349G>A, p.E117K","abstract_start":366,"abstract_end":383}]}
{"pmid":"17224546","title":"Trimethylaminuria (fish-odor syndrome): a case report.","abstract":"BACKGROUND: Trimethylaminuria (fish-odor syndrome) is a rare metabolic disorder characterized by a body malodor similar to that of decaying fish. The condition results from mutations affecting the flavin-containing monooxygenase 3 (FMO3) gene. Affected individuals may exhibit a variety of psychosocial phenomena. A high index of suspicion for this disorder needs to be maintained when treating individuals presenting with a history of real or perceived body odor. Observation We evaluated a 41-year-old man who presented with a long medical history of a fishy body odor. Results from biochemical investigations confirmed a diagnosis of primary trimethylaminuria, and results of molecular genetic studies revealed homozygosity for a mutation on exon 4 of the FMO3 gene, FMO3/P153L (c.458C --> T). The patient found that information he subsequently obtained about his condition on the Internet and discussion with friends and family members to be the most useful therapeutic approach.\nCONCLUSIONS: Trimethylaminuria is a rare metabolic disorder. Psychological accompaniments are recognized as major sources of distress to affected individuals. We discuss the features of this syndrome and highlight the importance of counseling and support in the treatment of such patients.","variants":[{"Name":"NM_001002294.3(FMO3):c.458C>T (p.Pro153Leu)","Chromosome":"1","Start":"171107811","Stop":"171107811","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31347,"rule_based_match":false,"evidence_text":"c.458C --> T","llm_judgment":"PRESENT","evidence":"c.458C --> T","abstract_start":782,"abstract_end":794}]}
{"pmid":"33465300","title":"Phenylketonuria in Portugal: Genotype-phenotype correlations using molecular, biochemical, and haplotypic analyses.","abstract":"BACKGROUND: The impairment of the hepatic enzyme phenylalanine hydroxylase (PAH) causes elevation of phenylalanine levels in blood and other body fluids resulting in the most common inborn error of amino acid metabolism (phenylketonuria). Persistently high levels of phenylalanine lead to irreversible damage to the nervous system. Therefore, early diagnosis of the affected individuals is important, as it can prevent clinical manifestations of the disease.\nMETHODS: In this report, the biochemical and genetic findings performed in 223 patients diagnosed through the Portuguese Neonatal Screening Program (PNSP) are presented.\nRESULTS: Overall, the results show that a high overlap exists between different types of variants and phenylalanine levels. Molecular analyses reveal a wide mutational spectrum in our population with a total of 56 previously reported variants, most of them found in compound heterozygosity (74% of the patients). Intragenic polymorphic markers were used to assess the haplotypic structure of mutated chromosomes for the most frequent variants found in homozygosity in our population (p.Ile65Thr, p.Arg158Gln, p.Leu249Phe, p.Arg261Gln, p.Val388Met, and c.1066-11G>A).\nCONCLUSION: Our data reveal high heterogeneity at the biochemical and molecular levels and are expected to provide a better understanding of the molecular basis of this disease and to provide clues to elucidate genotype-phenotype correlations.","variants":[{"Name":"NM_000277.3(PAH):c.194T>C (p.Ile65Thr)","Chromosome":"12","Start":"102894893","Stop":"102894893","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15675,"rule_based_match":false,"evidence_text":"p.Ile65Thr","llm_judgment":"PRESENT","evidence":"p.Ile65Thr","abstract_start":1113,"abstract_end":1123}]}
{"pmid":"12655554","title":"Tetrahydrobiopterin sensitivity in German patients with mild phenylalanine hydroxylase deficiency.","abstract":"We report the results of tetrahydrobiopterin (BH4) loading tests in 10 German patients with mild phenylketonuria. A significant decline of phenylalanine values after application of BH4 was observed in all but one patients. Molecular genetic analyses revealed a range of different PAH gene mutations. Re-testing of one patient previously reported as non-responsive to BH4 loading showed a moderate response with a higher dose of BH4. Nevertheless, there appear to be kinetic differences in phenylalanine hydroxylation in patients with the same genotype. Non-responsiveness to 20 mg/kg BH4 was observed only in a single patient who was compound heterozygous for the novel mutation R176P (c.527G>C) and the common null-mutation P281L. In summary, our data are in line with recent reports indicating that BH4 sensitivity is a normal feature of most mild forms of PAH deficiency but may be influenced by other factors.","variants":[{"Name":"NM_000277.3(PAH):c.527G>C (p.Arg176Pro)","Chromosome":"12","Start":"102855315","Stop":"102855315","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":108461,"rule_based_match":true,"evidence_text":"R176P (c.527G>C)","llm_judgment":"PRESENT","evidence":"R176P (c.527G>C)","abstract_start":679,"abstract_end":695}]}
{"pmid":"19359498","title":"Development of genomic reference materials for cystic fibrosis genetic testing.","abstract":"The number of different laboratories that perform genetic testing for cystic fibrosis is increasing. However, there are a limited number of quality control and other reference materials available, none of which cover all of the alleles included in commercially available reagents or platforms. The alleles in many publicly available cell lines that could serve as reference materials have neither been confirmed nor characterized. The Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community as well as Coriell Cell Repositories, have characterized an extended panel of publicly available genomic DNA samples that could serve as reference materials for cystic fibrosis testing. Six cell lines [containing the following mutations: E60X (c.178G>T), 444delA (c.312delA), G178R (c.532G>C), 1812-1G>A (c.1680-1G>A), P574H (c.1721C>A), Y1092X (c.3277C>A), and M1101K (c.3302T>A)] were selected from those existing at Coriell, and seven [containing the following mutations: R75X (c.223C>T), R347H (c.1040G>A), 3876delA (c.3744delA), S549R (c.1646A>C), S549N (c.1647G>A), 3905insT (c.3773_3774insT), and I507V (c.1519A>G)] were created. The alleles in these materials were confirmed by testing in six different volunteer laboratories. These genomic DNA reference materials will be useful for quality assurance, proficiency testing, test development, and research and should help to assure the accuracy of cystic fibrosis genetic testing in the future. The reference materials described in this study are all currently available from Coriell Cell Repositories.","variants":[{"Name":"NM_000492.4(CFTR):c.178G>T (p.Glu60Ter)","Chromosome":"7","Start":"117509047","Stop":"117509047","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":47335,"rule_based_match":true,"evidence_text":"c.178G>T","llm_judgment":"PRESENT","evidence":"c.178G>T","abstract_start":848,"abstract_end":856}]}
{"pmid":"34169149","title":"Adult-Onset Spinal Muscular Atrophy due to Mutations in the","abstract":"OBJECTIVE: To expand our knowledge of the range of clinical phenotypes associated with vaccinia-related kinase 1 (<i>VRK1</i>) gene mutations.\nMETHODS: We present clinical and molecular data of 2 individuals with slowly progressive weakness and a clinical syndrome consistent with adult-onset spinal muscular atrophy without pontocerebellar atrophy.\nRESULTS: Genetic testing revealed likely pathogenic variants in the <i>VRK1</i> gene in both subjects. One individual carried homozygous p.R321C (c.961 C>T), likely pathogenic variants. The other carried compound heterozygous p.V236M (c.706 G>A) and p.R321C (c.961 C>T), likely pathogenic variants. Notably, both patients were of Hispanic descent.\nCONCLUSIONS: We report 2 cases with <i>VRK1</i> mutations presenting as adult-onset spinal muscular atrophy without pontocerebellar hypoplasia and review the current literature of similar cases. Our report expands the clinical spectrum of neurologic disorders associated with <i>VRK1</i> mutations.","variants":[{"Name":"NM_003384.3(VRK1):c.706G>A (p.Val236Met)","Chromosome":"14","Start":"96855353","Stop":"96855353","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":215733,"rule_based_match":true,"evidence_text":"c.706 G>A","llm_judgment":"PRESENT","evidence":"c.706 G>A","abstract_start":585,"abstract_end":594}]}
{"pmid":"27258795","title":"Coinheritance of a Rare Nucleotide Substitution on the β-Globin Gene and Other Known Mutations in the Globin Clusters: Management in Genetic Counseling.","abstract":"A large number of methods for DNA analysis are available to identify defects in globin genes associated with hemoglobin (Hb) disorders. In this study, we report a rare nucleotide (nt) substitution on the β-globin gene, nt 781 in the second intron [IVS-II-781 (C > G); HBB: c.316-70C > G], identified in four patients. This nt substitution was previously described only as a personal communication to the HbVar database and indicated as a β(0) or β(+) mutation. The purpose of this study was to evaluate the clinical implication of this nt change, particularly when coinherited with severe β-thalassemia (β-thal), in order to be able to conduct appropriate genetic counseling. Genetic studies were performed on two subjects, one carried Hb S [β6(A3)Glu→Val; HBB: c.20A > T], and the other carried IVS-I-110 (G > A) (HBB: c.93-21G > A). All these subjects showed this new β nt substitution in association with Hb A2' (or Hb B2) [δ16(A13)Gly→Arg; HBD: c.49G > C]. Another 16 samples, carrying the same δ variant as the probands, were processed by β-globin gene sequencing in order to better understand the correlation between this Hb variant and the rare nt substitution reported in this study. The present investigation emphasizes the importance of sharing the observed nt changes in the globin gene cluster, especially in the case of new or rare undefined mutations, in order to facilitate the determination of their phenotypic expression, the possible interactions with known molecular defects and to formulate appropriate genetic counseling for at-risk couples.","variants":[{"Name":"NM_000518.5(HBB):c.316-70C>G","Chromosome":"11","Start":"5225796","Stop":"5225796","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":44984,"rule_based_match":true,"evidence_text":"HBB: c.316-70C>G","llm_judgment":"PRESENT","evidence":"HBB: c.316-70C > G","abstract_start":268,"abstract_end":286}]}
{"pmid":"34177428","title":"Identification of the","abstract":"Ciliopathies constitute heterogeneous disorders that result from mutations in ciliary proteins. These proteins play an important role in the development of organs, physiology, and signaling pathways, and sequence variations in the genes encoding these proteins are associated with multisystem disorders. In this study, we describe a severe ciliopathy disorder that segregates in an autosomal recessive manner in a nonconsanguineous Saudi family. The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Whole-genome sequencing and Sanger sequencing revealed a homozygous splice site variant (c.4-1G>C; NM_024926.3) in the tetratricopeptide repeat domain 26 (<i>TTC26</i>) gene located in chromosome 7q34, which cosegregated perfectly with the disease phenotype. qRT-PCR revealed a substantial decrease in the expression of the <i>TTC26</i> gene as compared to the normal control, suggesting the pathogenicity of the identified variant. This report further strengthens the evidence that homozygous variants in the <i>TTC26</i> gene cause severe ciliopathies with diverse phenotypes. We named this newly characterized condition as BRENS syndrome, which stands for biliary, renal, neurological, and skeletal features.","variants":[{"Name":"NM_024926.4(IFT56):c.4-1G>C","Chromosome":"7","Start":"139134654","Stop":"139134654","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1241941,"rule_based_match":true,"evidence_text":"c.4-1G>C; NM_024926.3","llm_judgment":"PRESENT","evidence":"c.4-1G>C; NM_024926.3","abstract_start":843,"abstract_end":864}]}
{"pmid":"32950024","title":"Generation of two hiPSC clones (MHHi019-A, MHHi019-B) from a primary ciliary dyskinesia patient carrying a homozygous deletion in the NME5 gene (c.415delA (p.Ile139Tyrfs*8)).","abstract":"Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by defects in motile cilia and is known to occur in about 1 in 20,000 live births (Horani and Ferkol, 2018). Among the many genes associated with PCD, NME5, a gene encoding a protein involved in ciliary function, was recently reported to be involved in PCD (Anderegg et al., 2019; Cho et al., 2020). We have established two human induced pluripotent stem cell clones from a PCD patient carrying a deletion in the NME5 gene (c.415delA (p.Ile139Tyrfs*8)).","variants":[{"Name":"NM_003551.3(NME5):c.415del (p.Ile139fs)","Chromosome":"5","Start":"138128500","Stop":"138128500","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":1704179,"rule_based_match":true,"evidence_text":"c.415delA (p.Ile139Tyrfs*8)","llm_judgment":"PRESENT","evidence":"c.415delA (p.Ile139Tyrfs*8)","abstract_start":493,"abstract_end":520}]}
{"pmid":"34523126","title":"Identification and molecular analysis of 17 novel variants of hydroxymethylbilane synthase in Chinese patients with acute intermittent porphyria.","abstract":"A partial deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase (HMBS) leads to acute intermittent porphyria (AIP), a severe neurovisceral, autosomal dominant disorder with low penetrance. Even though in-depth investigations of the HMBS variants have been carried out by researchers in Britain, France, Russia, and Sweden, this area remains uninvestigated in China owing to the rarity and lack of clinical understanding of the disease. In this study, 78 unrelated AIP patients revealed 48 different HMBS variants, of which 17 were novel. These included 22 missense variants, 9 splicings, 5 nonsense variants, 10 small deletions, 1 repeat insertion, and 1 complex deletion-insertion variant. The variant c.673C > T, found in 10 unrelated patients, was the most frequent variant, followed by the variant c.517C > T, found in 7 unrelated patients. We performed western blotting and immunofluorescence staining with four novel variants (c.653G > A, c.597dupC, c.726-727del, and c.1045_1046delAA) to detect the expression levels of mutant HMBSs. The results showed a variant-mediated decrease in the mutant-HMBS level, suggesting that the variant resulted in impaired gene product functions. Moreover, the in vitro functional verification in this study provided PS3_moderate evidence for American College of Medical Genetics and Genomics (ACMG) to grade the pathogenicity of novel variants in AIP.","variants":[{"Name":"NM_000190.4(HMBS):c.653G>A (p.Gly218Glu)","Chromosome":"11","Start":"119092405","Stop":"119092405","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2085758,"rule_based_match":true,"evidence_text":"c.653G > A","llm_judgment":"PRESENT","evidence":"c.653G > A","abstract_start":951,"abstract_end":961}]}
{"pmid":"32938213","title":"A Novel Recurrent","abstract":"OBJECTIVE: While rare variants in the <i>COL5A1</i> gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in <i>COL5A1</i> underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the <i>COL5A1</i> pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The <i>COL5A1</i> c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for <i>COL5A1</i> variants. In this mFMD cohort, <i>COL5A1</i> c.1540G>A and 6 additional relatively rare <i>COL5A1</i> variants predicted to be deleterious in silico were identified and were associated with arterial dissections (<i>P</i>=0.005).\nCONCLUSIONS: <i>COL5A1</i> c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare <i>COL5A1</i> genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for <i>COL5A1</i> should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.","variants":[{"Name":"NM_000093.5(COL5A1):c.1540G>A (p.Gly514Ser)","Chromosome":"9","Start":"134750587","Stop":"134750587","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":240516,"rule_based_match":true,"evidence_text":"c.1540G>A, p.(Gly514Ser)","llm_judgment":"PRESENT","evidence":"c.1540G>A, p.(Gly514Ser)","abstract_start":443,"abstract_end":467}]}
{"pmid":"29935280","title":"Thiopurine-induced toxicity is associated with dysfunction variant of the human molybdenum cofactor sulfurase gene (xanthinuria type II).","abstract":"BACKGROUND: The aim of our study was to identify the genetic background of thiopurine-induced toxicity in a patient with a wild-type thiopurine methyltransferase genotype and activity. A 38-year-old Caucasian woman presented with cutaneous necrotizing vasculitis pancytopenia one month after starting azathioprine therapy.\nMETHODS: During a routine biochemical follow-up of the patient, undetectable serum uric acid (<10 μl) was observed. A high performance liquid chromatography analysis of urinary purines revealed increased levels of xanthine (137 mmol/mol creatinine). The suspected diagnosis of hereditary xanthinuria, a rare autosomal recessive disorder of the last two steps of purine metabolism, was confirmed by sequence analysis.\nRESULTS: An analysis of XDH/XO and AOX1 revealed common polymorphisms, while analysis of the MOCOS gene identified a rare homozygous variant c.362C > T. Dysfunction of this variant was confirmed by significantly decreased xanthine dehydrogenase/oxidase activity in the patient's plasma (<2% of control mean activity).\nCONCLUSIONS: We present a biochemical, enzymatic, and molecular genetic case study suggesting an important association between a hitherto undescribed dysfunction variant in the MOCOS gene and thiopurine-induced toxicity. The identified variant c.362C > T results in slower thiopurine metabolism caused by inhibition of 6-mercaptopurine oxidation (catabolism) to 6-thioxanthine and 6-thiouric acid, which increases the formation of the nucleotide 6-thioguanine, which is toxic. This is the first clinical case to identify the crucial role of the MOCOS gene in thiopurine intolerance and confirm the impact of genetic variability of purine enzymes on different therapeutic outcomes in patients undergoing thiopurine treatment.","variants":[{"Name":"NM_017947.4(MOCOS):c.362C>T (p.Thr121Met)","Chromosome":"18","Start":"36199745","Stop":"36199745","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1492601,"rule_based_match":true,"evidence_text":"c.362C > T","llm_judgment":"PRESENT","evidence":"c.362C > T","abstract_start":881,"abstract_end":891}]}
{"pmid":"27186704","title":"Pyridoxine-dependent epilepsy in two Turkish patients in Turkey and review of the literature.","abstract":"Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive enzyme defect in the vitamin B6 metabolism characterized by intractable seizures which are usually resistant to all antiepileptic drugs but respond to pharmacological doses of pyridoxine. We present the clinical and molecular genetic findings of two patients with c.1597_1597delG mutations in ALDH7A1 gene. There are different clinical phenotypes in PDE: patients with complete seizure control with pyridoxine and normal development (group 1), patients with complete seizure control with pyridoxine and development delay (group 2), and patients with persistent seizures despite pyridoxine treatment and with development delay (group 3). Our two patients have persistant seizure despite pyridoxine treatment and with development delay. Pyridoxine-dependent epilepsy can be identified in any neonate with signs of encephalopathy and refractory seizures, with no evidence of hypoxic-ischemic damage or other underlying metabolic disturbance. Neurodevelopmental outcomes of patients with PDE is multifactorial; early diagnosis and treatment of these patients is vital.","variants":[{"Name":"NM_001182.5(ALDH7A1):c.1597del (p.Ala533fs)","Chromosome":"5","Start":"126544988","Stop":"126544988","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":33038,"rule_based_match":false,"evidence_text":"c.1597_1597delG","llm_judgment":"PRESENT","evidence":"c.1597_1597delG","abstract_start":330,"abstract_end":345}]}
{"pmid":"18830232","title":"Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements.","abstract":"Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare genetic disorder characterized by congenital great toe malformations and progressive heterotopic ossification transforming skeletal muscles and connective tissues to bone following a well-defined anatomic pattern of progression. Recently, FOP has been associated with a specific mutation of ACVR1, the gene coding for a bone morphogenetic protein type I receptor. The identification of ACVR1 as the causative gene for FOP now allows the genetic screening of FOP patients to identify the frequency of the identified recurrent ACVR1 mutation and to investigate genetic variability that may be associated with this severely debilitating disease. We report the screening for mutations in the ACVR1 gene carried out in a cohort of 17 Italian patients. Fifteen of these displayed the previously described c.617G>A mutation, leading to the R206H substitution in the GS domain of the ACVR1 receptor. In two patients, we found a novel mutation c.774G>C, leading to the R258S substitution in the kinase domain of the ACVR1 receptor. In the three-dimensional model of protein structure, R258 maps in close proximity to the GS domain, a key regulator of ACVR1 activity, where R206 is located. The GS domain is known to bind the regulatory protein FKBP12 and to undergo multiple phosphorylation events that trigger a signaling cascade inside the cell. The novel amino-acid substitution is predicted to influence either the conformation/stability of the GS region or the binding affinity with FKBP12, resulting in a less stringent inhibitory control on the ACVR1 kinase activity.","variants":[{"Name":"NM_001111067.4(ACVR1):c.617G>A (p.Arg206His)","Chromosome":"2","Start":"157774114","Stop":"157774114","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33348,"rule_based_match":true,"evidence_text":"c.617G>A","llm_judgment":"PRESENT","evidence":"c.617G>A","abstract_start":865,"abstract_end":873},{"Name":"NM_001111067.4(ACVR1):c.774G>C (p.Arg258Ser)","Chromosome":"2","Start":"157770384","Stop":"157770384","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":33350,"rule_based_match":true,"evidence_text":"c.774G>C","llm_judgment":"PRESENT","evidence":"c.774G>C","abstract_start":1001,"abstract_end":1009}]}
{"pmid":"30659264","title":"Clinical phenotype, in silico and biomedical analyses, and intervention for an East Asian population-specific c.370G>A (p.G124S) COQ4 mutation in a Chinese family with CoQ10 deficiency-associated Leigh syndrome.","abstract":"COQ4 mutations have recently been shown to cause a broad spectrum of mitochondrial disorders in association with CoQ10 deficiency. Herein, we report the clinical phenotype, in silico and biochemical analyses, and intervention for a novel c.370 G > A (p.G124S) COQ4 mutation in a Chinese family. This mutation is exclusively present in the East Asian population (allele frequency of ~0.001). The homozygous mutation caused CoQ10 deficiency-associated Leigh syndrome with an onset at 1-2 months of age, presenting as respiratory distress, lactic acidosis, dystonia, seizures, failure to thrive, and detectable lesions in the midbrain and basal ganglia. No renal impairment was involved. The levels of CoQ10 and mitochondrial respiratory chain complex (C) II + III activity were clearly lower in cultured fibroblasts derived from the patient than in those from unaffected carriers; the decreased CII + III activity could be increased by CoQ10 treatment. Follow-up studies suggested that our patient benefitted from the oral supplementation of CoQ10, which allowed her to maintain a relatively stable health status. Based on the genetic testing, preimplantation and prenatal diagnoses were performed, confirming that the next offspring of this family was unaffected. Our cases expand the phenotypic spectrum of COQ4 mutations and the genotypic spectrum of Leigh syndrome.","variants":[{"Name":"NM_016035.5(COQ4):c.370G>A (p.Gly124Ser)","Chromosome":"9","Start":"128325849","Stop":"128325849","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":458885,"rule_based_match":true,"evidence_text":"c.370 G > A (p.G124S)","llm_judgment":"PRESENT","evidence":"c.370 G > A (p.G124S)","abstract_start":238,"abstract_end":259}]}
{"pmid":"35507000","title":"Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.","abstract":"PURPOSE: Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 17 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH).\nMETHODS: Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO), Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), DUOX2, Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants.\nRESULTS: Four novel variants have been identified, two in TPO: c.2749-2 A > C and c.2752_2753delAG, [p.Ser918Cysfs*62] and two variants in DUOX2 gene: c.425 C > G [p.Pro142Arg] and c.2695delC [p.Gln899Serfs*21]. Eighteen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic biallelic variants in TPO and DUOX2 in 7 and 2 patients, respectively. We also detected a potentially pathogenic monoallelic variant in TPO and DUOX2 in 7 and 1 patients respectively.\nCONCLUSIONS: 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.","variants":[{"Name":"NM_001363711.2(DUOX2):c.425C>G (p.Pro142Arg)","Chromosome":"15","Start":"45111856","Stop":"45111856","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1679669,"rule_based_match":true,"evidence_text":"c.425 C > G [p.Pro142Arg]","llm_judgment":"PRESENT","evidence":"c.425 C > G [p.Pro142Arg]","abstract_start":1135,"abstract_end":1160}]}
{"pmid":"16434382","title":"Known and new delta globin gene mutations and their diagnostic significance.","abstract":"Mutations in the delta-globin gene (HBD, MIM# 142000) are not pathologically relevant. However, since high HbA2 levels are diagnostic for beta-thalassemia trait and a lowered level for an alpha- or delta-mutation, co-inheritance of delta- and beta-gene defects may lead to misinterpretation of diagnostic results. We examined 29 cases with low HbA2 level diagnosed in our laboratory, in the presence or absence of a second HbA2 fraction. We found a delta globin gene mutation in 20 cases. In total four different known mutations were found, three structural and one expressional. Moreover, two new defects were observed, one causing a structural abnormality and one a beta-thalassemia. The structural abnormality HBD c.431A->G (p.His144Arg)(dcd 143 CAC->CGC) was homologous to the beta-globin gene variant called Hb-Abruzzo and we have named this mutation HbA2 -Abruzzo. The new delta-thalassemia defect HBD c.-118C->T (d -68 C->T) has no homology on the beta-globin gene (HBB, MIM# 141900). All mutations caused a low HbA2 level and through this could lead to misdiagnosis when inherited together with a beta-thalassemia.","variants":[{"Name":"NM_000519.3(HBD):c.-118C>T","Chromosome":"11","Start":"5234551","Stop":"5234551","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1152464,"rule_based_match":false,"evidence_text":"HBD c.-118C->T","llm_judgment":"PRESENT","evidence":"HBD c.-118C->T","abstract_start":904,"abstract_end":918}]}
{"pmid":"32344329","title":"Generation of three iPSC lines (XACHi007-A, XACHi008-A, XACHi009-A) from a Chinese family with long QT syndrome type 5 with heterozygous c.226G>A (p.D76N) mutation in KCNE1gene.","abstract":"Induced pluripotent stem cell lines (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the peripheral blood of an eight months-old boy and the parents. Long QT syndrome type 5 (LQT5) was diagnosed after identifying a heterozygous c.226G>A (p.D76N) variant in KCNE1 gene carried by the boy and inherited from his father who has a prolonged QT in ECG as well. PBMCs were reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, SOX2, KLF4 and C-MYC. iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry KCNE1-D76N mutation, have a normal karyotype. Thus we established 2 new LQT5 iPSC lines and a related control line as useful tools for studying the pathophysiological mechanism of LQT5 and drug testing.","variants":[{"Name":"NM_000219.6(KCNE1):c.226G>A (p.Asp76Asn)","Chromosome":"21","Start":"34449409","Stop":"34449409","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28516,"rule_based_match":true,"evidence_text":"c.226G>A (p.D76N)","llm_judgment":"PRESENT","evidence":"c.226G>A (p.D76N)","abstract_start":264,"abstract_end":281}]}
{"pmid":"18406877","title":"A novel missense MSH2 gene mutation in a patient of a Korean family with hereditary nonpolyposis colorectal cancer.","abstract":"Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer-susceptible syndrome that predisposes to the early development of colorectal cancer. Germline mutations in DNA mismatch repair genes, particularly MLH1 and MSH2, are associated with the clinical phenotype of HNPCC. A previously unreported, novel missense mutation in exon 3 of the MSH2 gene (c.380A>T) was identified in the proband and a different missense mutation in exon 3 of MSH2 gene (c.505A>G) was noted in the mother, with a mutual splice mutation in intron 12 of the MSH2 gene in the proband, mother, and younger brother. Here, we report the clinical implications of a novel mutation in a patient with early-onset colorectal cancer and the significance of a common underlying splice site mutation occurring within a family with HNPCC.","variants":[{"Name":"NM_000251.3(MSH2):c.505A>G (p.Ile169Val)","Chromosome":"2","Start":"47410232","Stop":"47410232","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":96590,"rule_based_match":true,"evidence_text":"c.505A>G","llm_judgment":"PRESENT","evidence":"c.505A>G","abstract_start":472,"abstract_end":480}]}
{"pmid":"15108285","title":"Novel mutations in the TRIM37 gene in Mulibrey Nanism.","abstract":"Mulibrey nanism is an autosomal recessive prenatal-onset growth disorder of unknown pathogenesis. The main clinical features are pre- and postnatal growth failure, characteristic dysmorphic craniofacial features, heart disease, and hepatomegaly. Five truncating mutations in the TRIM37 gene have previously been reported in Mulibrey nanism patients. The TRIM37 protein encodes a novel protein of unknown function. It contains a tripartite motif (TRIM, also denoted the RING-B-box-Coiled-coil or RBCC domain) and a TRAF (tumor necrosis factor-receptor associated factor) domain. TRIM37 localizes to peroxisomes classifying Mulibrey nanism as a peroxisomal disorder. Here we have characterized the genomic structure of the TRIM37 gene, which has 24 exons spanning approximately 109 kb of genomic DNA. Further, we report six novel disease-associated mutations, five of which predict a truncated protein: c.745C>T (p.Gln249X), c.1411C>T (p.Arg471X), c.2056C>T (p.Arg686X), and an 8.6 kb genomic deletion (c.1314+507_1668-207del resulting in p.Arg439fsX4). The sixth mutation (c.965G>T) is the first missense mutation (p.Gly322Val) associated with Mulibrey nanism. It affects the TRAF domain of TRIM37 and results in altered subcellular localization of the mutant TRIM37 protein, further suggesting that it is pathogenic.","variants":[{"Name":"NM_015294.6(TRIM37):c.1411C>T (p.Arg471Ter)","Chromosome":"17","Start":"59049297","Stop":"59049297","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":71204,"rule_based_match":true,"evidence_text":"c.1411C>T (p.Arg471X)","llm_judgment":"PRESENT","evidence":"c.1411C>T (p.Arg471X)","abstract_start":923,"abstract_end":944},{"Name":"NM_015294.6(TRIM37):c.2056C>T (p.Arg686Ter)","Chromosome":"17","Start":"59028616","Stop":"59028616","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":71206,"rule_based_match":true,"evidence_text":"c.2056C>T (p.Arg686X)","llm_judgment":"PRESENT","evidence":"c.2056C>T (p.Arg686X)","abstract_start":946,"abstract_end":967},{"Name":"NM_015294.6(TRIM37):c.745C>T (p.Gln249Ter)","Chromosome":"17","Start":"59070887","Stop":"59070887","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":71209,"rule_based_match":true,"evidence_text":"c.745C>T (p.Gln249X)","llm_judgment":"PRESENT","evidence":"c.745C>T (p.Gln249X)","abstract_start":901,"abstract_end":921},{"Name":"NM_015294.6(TRIM37):c.965G>T (p.Gly322Val)","Chromosome":"17","Start":"59061086","Stop":"59061086","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":71213,"rule_based_match":true,"evidence_text":"c.965G>T (p.Gly322Val)","llm_judgment":"PRESENT","evidence":"p.Gly322Val","abstract_start":1114,"abstract_end":1125}]}
{"pmid":"22784669","title":"Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement.","abstract":"Central Core Disease (CCD) and Multi-minicore Disease (MmD) (the \"core myopathies\") have been mainly associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the selenoprotein N (SEPN1) gene. A proportion of cases remain unresolved. Mutations in MYH7 encoding the beta myosin heavy chain protein have been implicated in cardiac and, less frequently, skeletal muscle disorders. Here we report four patients from two families with a histopathological diagnosis of MmD, presenting in childhood with slowly progressive muscle weakness, more proximal in Family 1 and more distal in Family 2, and variable degrees of cardiorespiratory impairment evolving later in life. There was also a strong family history of sudden death in the first family. Muscle biopsies obtained in early childhood showed multiple minicores as the most prominent feature. Sequencing of the MYH7 gene revealed heterozygous missense mutations, c.4399C>G; p.Leu1467Val (exon 32) in Family 1 and c.4763G>C; p.Arg1588Pro (exon 34) in Family 2. These findings suggest MYH7 mutations as another cause of a myopathy with multiple cores, in particular if associated with dominant inheritance and cardiac involvement. However, clinical features previously associated with this genetic background, namely a more distal distribution of weakness and an associated cardiomyopathy, may only evolve over time.","variants":[{"Name":"NM_000257.4(MYH7):c.4399C>G (p.Leu1467Val)","Chromosome":"14","Start":"23417273","Stop":"23417273","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":52185,"rule_based_match":true,"evidence_text":"c.4399C>G; p.Leu1467Val","llm_judgment":"PRESENT","evidence":"c.4399C>G; p.Leu1467Val","abstract_start":933,"abstract_end":956}]}
{"pmid":"20683927","title":"Mutations in GDF5 presenting as semidominant brachydactyly A1.","abstract":"Brachydactyly A1 (BDA1) is an autosomal dominant disorder characterized by shortness of all middle phalanges of the hands and toes, shortness of the proximal phalanges of the first digit, and short stature. Missense mutations in the Indian Hedgehog gene (IHH) are known to cause BDA1, and a second locus has been mapped to chromosome 5p. In a consanguineous French Canadian kindred with BDA1, both IHH and the 5p locus were excluded. Microsatellites flanking GDF5 on chromosome 20q were found to cosegregate with the disease. Sequencing of the GDF5 coding region revealed that a mildly affected individual in the family was heterozygous, and that all of the severely affected individuals were homozygous for a novel missense c.1195C>T mutation that predicts a p.Arg399Cys substitution at a highly conserved amino acid. Functional analysis demonstrated that although the p.Arg399Cys mutant is able to stimulate chondrogenesis, it is much less effective than wild-type GDF5. This data confirms genetic heterogeneity in BDA1, demonstrates that mutations upstream of IHH can result in BDA1, and shows that BDA1 can result from semidominant mutations in GDF5.","variants":[{"Name":"NM_000557.5(GDF5):c.1195C>T (p.Arg399Cys)","Chromosome":"20","Start":"35434220","Stop":"35434220","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48114,"rule_based_match":true,"evidence_text":"c.1195C>T","llm_judgment":"PRESENT","evidence":"c.1195C>T","abstract_start":725,"abstract_end":734}]}
{"pmid":"30256676","title":"Five Novel Mutations in Chinese Children with Primary Distal Renal Tubular Acidosis.","abstract":"AIM: To analyze the variants of the potential causative genes in five Chinese patients with primary distal renal tubular acidosis (dRTA) from five unrelated families, and to explore their possible genotype-phenotype correlations, so as to raise the awareness of the disease.\nMETHODS: Variants were identified by next generation sequencing. Clinical features and biochemical findings at the first presentation, as well as at follow-up visits were also investigated. One hundred unrelated healthy subjects were selected to evaluate each of the novel mutations found in this study.\nRESULTS: A total of seven different mutations in the ATP6V0A4, ATP6V1B1, and SLC4A1 genes, the three main causative genes of dRTA, were detected in 4/5 patients. In patient I a novel heterozygous intronic mutation (c.639 + 1G>A) in the ATP6V0A4 gene was identified along with a heterozygous nonsense variant (c.580C>T, p.Arg194*). Two novel heterozygous missense mutations of the ATP6V1B1 gene (c.409C>T, p.Pro137Ser; c.904C>T, p.Arg302Trp) were identified in patient II. In patient III 2 novel heterozygous duplications (c.1504dupT, p.Tyr502Leufs*22; c.2351dupT, p.Phe785Ilefs*28) were found. Thus, these three patients all were compound heterozygotes leading to dRTA. These findings are consistent with the known autosomal recessive inheritance pattern of this disease. Furthermore, a de novo heterozygous missense mutation previously reported (c.1765C>A, p.Arg589Ser) in the SLC4A1 gene was observed in patient IV. No mutations in any of the known dRTA-related causative genes were found in the patient V.\nCONCLUSIONS: In the present study we identified 7 mutations, including 5 novel variants, in the three genes previously correlated with dRTA, enriching the human gene mutation database (HGMD). In addition, our lack of findings in these three genes for patient V suggests that other genes may contribute to dRTA in some cases.","variants":[{"Name":"NM_000342.4(SLC4A1):c.1765C>A (p.Arg589Ser)","Chromosome":"17","Start":"44255708","Stop":"44255708","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":32805,"rule_based_match":true,"evidence_text":"c.1765C>A (p.Arg589Ser)","llm_judgment":"PRESENT","evidence":"p.Arg589Ser","abstract_start":1437,"abstract_end":1448}]}
{"pmid":"17620124","title":"Two novel connexin32 mutations cause early onset X-linked Charcot-Marie-Tooth disease.","abstract":"BACKGROUND: X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the connexin32 gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions.\nMETHODS: We describe two novel mutations in the connexin32 gene in two Norwegian families.\nRESULTS: Family 1 had a c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247. This probably results in a shorter non-functional protein structure. Affected individuals had an early age at onset usually in the first decade. The symptoms were more severe in men than women. All had severe muscle weakness in the legs. Several abortions were observed in this family. Family 2 had a c.536 G>A (C179Y) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade. Muscle wasting was severe and correlated with muscle weakness in legs. The men and one woman also had symptom from their hands. The neuropathy is demyelinating and the nerve conduction velocities were in the intermediate range (25-49 m/s). Affected individuals had symmetrical clinical findings, while the neurophysiology revealed minor asymmetrical findings in nerve conduction velocity in 6 of 10 affected individuals.\nCONCLUSION: The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode.","variants":[{"Name":"NM_000166.6(GJB1):c.225del (p.Leu76fs)","Chromosome":"X","Start":"71223931","Stop":"71223931","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":33935,"rule_based_match":true,"evidence_text":"c.225delG (R75fsX83)","llm_judgment":"PRESENT","evidence":"c.225delG (R75fsX83)","abstract_start":296,"abstract_end":316}]}
{"pmid":"23816408","title":"Detection of a large duplication mutation in the myosin-binding protein C3 gene in a case of hypertrophic cardiomyopathy.","abstract":"Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with autosomal dominant inheritance caused by mutations in genes coding for sarcomeric and/or regulatory proteins expressed in cardiomyocytes. In a small cohort of HCM patients (n=8), we searched for mutations in the two most common genes responsible for HCM and found four missense mutations in the MYH7 gene encoding cardiac β-myosin heavy chain (R204H, M493V, R719W, and R870H) and three mutations in the myosin-binding protein C3 gene (MYBPC3) including one missense (A848V) and two frameshift mutations (c.3713delTG and c.702ins26bp). The c.702ins26bp insertion resulted from the duplication of a 26-bp fragment in a 54-year-old female HCM patient presenting with clinical signs of heart failure due to diastolic dysfunction. Although such large duplications (>10 bp) in the MYBPC3 gene are very rare and have been identified only in 4 families reported so far, the identical duplication mutation was found earlier in a Dutch patient, demonstrating that it may constitute a hitherto unknown founder mutation in central European populations. This observation underscores the significance of insertions into the coding sequence of the MYBPC3 gene for the development and pathogenesis of HCM.","variants":[{"Name":"NM_000257.4(MYH7):c.2155C>T (p.Arg719Trp)","Chromosome":"14","Start":"23425971","Stop":"23425971","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29143,"rule_based_match":false,"evidence_text":"R719W","llm_judgment":"PRESENT","evidence":"R719W","abstract_start":425,"abstract_end":430}]}
{"pmid":"23873601","title":"Novel no-stop FLNA mutation causes multi-organ involvement in males.","abstract":"Mutations in FLNA (Filamin A, OMIM 300017) cause X-linked periventricular nodular heterotopia (XL-PNH). XL-PNH-associated mutations are considered lethal in hemizygous males. However, a few males with unusual mutations (including distal truncating and hypomorphic missense mutations), and somatic mosaicism have been reported to survive past infancy. Two brothers had an atypical presentation with failure to thrive and distinct facial appearance including hypertelorism. Evaluations of these brothers and their affected cousin showed systemic involvement including severe intestinal malfunction, malrotation, congenital short bowel, PNH, pyloric stenosis, wandering spleen, patent ductus arteriosus, atrial septal defect, inguinal hernia, and vesicoureteral reflux. The unanticipated finding of PNH led to FLNA testing and subsequent identification of a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). Western blotting and qRT-PCR of patients' fibroblasts showed diminished levels of protein and mRNA. This FLNA mutation, the most distal reported so far, causes in females classical XL-PNH, but in males an unusual, multi-organ phenotype, providing a unique insight into the FLNA-associated phenotypes.","variants":[{"Name":"NM_001110556.2(FLNA):c.7941_7942del (p.Ter2648SerextTer?)","Chromosome":"X","Start":"154348851","Stop":"154348852","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":210455,"rule_based_match":true,"evidence_text":"c.7941_7942delCT, p.(*2648Serext*100)","llm_judgment":"PRESENT","evidence":"c.7941_7942delCT, p.(*2648Serext*100)","abstract_start":884,"abstract_end":921}]}
{"pmid":"23000069","title":"A novel heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED).","abstract":"BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is an autosomal recessive disease due to mutations of the autoimmune regulator (AIRE) gene. Typical manifestations include candidiasis, Addison's disease, and hypoparathyroidism. Type 1 diabetes, alopecia, vitiligo, ectodermal dystrophy, celiac disease and other intestinal dysfunctions, chronic atrophic gastritis, chronic active hepatitis, autoimmune thyroid disorders, pernicious anemia and premature ovarian failure are other rare associated diseases although other conditions have been associated with APECED.\nCASE PRESENTATION: What follows is the clinical, endocrinological and molecular data of a female APECED patient coming from Lithuania. The patient was affected by chronic mucocutaneous candidiasis, hypoparathyroidism and pre-clinical Addison's disease. Using direct sequencing of all the 14 exons of the AIRE gene in the patient's DNA, we identified in exon 6 the known mutation c.769 C>T (p.Arg257X) in compound heterozygosity with the newly discovered mutation c.1214delC (p.Pro405fs) in exon 10. The novel mutation results in a frameshift that is predicted to alter the sequence of the protein starting from amino acid 405 as well as to cause its premature truncation, therefore a non-functional Aire protein.\nCONCLUSIONS: A novel mutation has been described in a patient with APECED with classical clinical components, found in compound heterozygosity with the c.769 C>T variation. Expanded epidemiological investigations based on AIRE gene sequencing are necessary to verify the relevancy of the novel mutation to APECED etiopathogenesis in the Lithuanian population and to prove its diagnostic efficacy in association with clinical and immunological findings.","variants":[{"Name":"NM_000383.4(AIRE):c.1214del (p.Pro405fs)","Chromosome":"21","Start":"44293108","Stop":"44293108","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1441708,"rule_based_match":true,"evidence_text":"c.1214delC (p.Pro405fs)","llm_judgment":"PRESENT","evidence":"c.1214delC (p.Pro405fs)","abstract_start":1071,"abstract_end":1094}]}
{"pmid":"32567228","title":"Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss.","abstract":"BACKGROUND: Hereditary hearing loss (HL) is heterogeneous in terms of their phenotypic features, modes of inheritance, and causative gene mutations. The contribution of genetic variants to sporadic HL remains largely expanding. Either recessive or de novo dominant variants could result in an apparently sporadic occurrence of HL. In an attempt to find such variants we recruited 128 Chinese patients with sporadic nonsyndromic sensorineural HL (NSHL) and performed targeted deafness multigene sequencing in these unrelated trios-families to elucidate the molecular basis.\nMETHODS: We analyzed a total of 384 available members (probands and their two parents) from 128 unrelated Chinese families presenting with bilateral sensorineural HL, in which previous screening had found no mutations with the GJB2, SLC26A4, and MT-RNR1 genes. We used a targeted genomic enrichment platform to simultaneously capture exons, splicing sites, and immediate flanking intron sequences of 127 known deafness genes. Sanger sequencing was used to identify probands and their two parents segregating causative variants in the candidate gene.\nRESULTS: We observed that two heterozygous de novo WFS1 mutations in exon 8: c.2051C>T (p.A684V) and c.2590G>A (p.E864K) in five families. The two de novo WFS1 mutations were found in 3.9% (5/128) of sporadic HL patients. We found that four of the five patients had the same de novo p.A684V mutation, and their audiograms showed symmetrical bilateral and profound sensorineural hearing impairments at all frequencies, but only the proband with de novo p.E864K mutation demonstrated significantly bilateral moderate low-mid frequency sensorineural HL. Our data suggest that this WFS1 p.A684V is likely to be a de novo mutational hot spot.\nCONCLUSIONS: We found 3.9% (5/128) of sporadic NSHL is caused by de novo WFS1 mutations. Our data provide that the de novo p.E864K mutation is first identified and de novo p.A684V mutation is likely to be a mutational hot spot in WFS1. It is the first study to highlight that WFS1 gene with the two de novo mutations has been indicated to classify the distinct hearing impairment phenotypes. Furthermore, de novo p.A684V serves as a WFS1 mutational hot spot that was found in the Chinese population with sporadic childhood NSHL, and our study also provides pointers toward the necessity for sequencing of asymptomatic parents of a sporadic case with an apparent dominant pathogenic variant.","variants":[{"Name":"NM_006005.3(WFS1):c.2051C>T (p.Ala684Val)","Chromosome":"4","Start":"6301846","Stop":"6301846","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39513,"rule_based_match":true,"evidence_text":"c.2051C>T (p.A684V)","llm_judgment":"PRESENT","evidence":"c.2051C>T (p.A684V)","abstract_start":1200,"abstract_end":1219},{"Name":"NM_006005.3(WFS1):c.2590G>A (p.Glu864Lys)","Chromosome":"4","Start":"6302385","Stop":"6302385","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19565,"rule_based_match":true,"evidence_text":"c.2590G>A (p.E864K)","llm_judgment":"PRESENT","evidence":"c.2590G>A (p.E864K)","abstract_start":1224,"abstract_end":1243}]}
{"pmid":"17553121","title":"Severe epilepsy in X-linked creatine transporter defect (CRTR-D).","abstract":"Disorders of creatine synthesis or its transporter resulting in neurological impairment with mental retardation and epilepsy have only been recognized in recent years. To date, the epileptic disorder observed in creatine transporter deficiency (CRTR-D) has been described as a mild phenotype with infrequent seizures and favorable response to common antiepileptic drugs. We report on a 5 year-old boy with known speech delay who presented with severe and refractory epilepsy. After extensive investigations, metabolite analysis and brain 1H-MRS suggested CRTR-D, which was confirmed by the detection of a known pathogenic mutation in the SLC6A8 gene (c.1631C>T; p.Pro544Leu).","variants":[{"Name":"NM_005629.4(SLC6A8):c.1631C>T (p.Pro544Leu)","Chromosome":"X","Start":"153694753","Stop":"153694753","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76600,"rule_based_match":true,"evidence_text":"c.1631C>T; p.Pro544Leu","llm_judgment":"PRESENT","evidence":"c.1631C>T; p.Pro544Leu","abstract_start":651,"abstract_end":673}]}
{"pmid":"16534102","title":"Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia.","abstract":"BACKGROUND: Mutations in the SPG7 gene, which encodes paraplegin, are responsible for an autosomal recessive hereditary spastic paraplegia (HSP).\nOBJECTIVE: To screen the SPG7 gene in a large population of HSP families compatible with autosomal recessive transmission.\nMETHODS: The authors analyzed 136 probands with pure or complex HSP for mutations in the SPG7 using denaturation high-performance liquid chromatography and direct sequencing.\nRESULTS: The authors identified 47 variants including 6 mutations, 27 polymorphisms, and 14 changes with unknown effects. In one family from Morocco, compound c.850_851delTTinsC and c.1742_1744delTGG heterozygous mutations were shown to be causative. This family had complex HSP with cerebellar impairment. Progression of the disease was rapid, resulting in a severe disease after 8 years of duration. Also detected were 20 families with one heterozygous mutation that was not found in a large control population. The mutations produced highly defective proteins in four of these families, suggesting that they were probably causative. Direct sequencing of all exons and reverse transcription PCR experiments demonstrated the absence of a second mutation. However, the p.Ala510Val missense substitution previously described as a polymorphism was shown to be significantly associated with HSP, suggesting that it had a functional effect.\nCONCLUSION: SPG7 mutations account for less than 5% of hereditary spastic paraplegia (HSP) families compatible with autosomal recessive inheritance. Cerebellar signs or cerebellar atrophy on brain imaging were the most frequent additional features in patients with SPG7 HSP. Rare nucleotide variants in SPG7 are frequent, complicating routine diagnosis.","variants":[{"Name":"NM_003119.4(SPG7):c.1529C>T (p.Ala510Val)","Chromosome":"16","Start":"89546737","Stop":"89546737","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":51184,"rule_based_match":false,"evidence_text":"p.Ala510Val","llm_judgment":"PRESENT","evidence":"p.Ala510Val","abstract_start":1213,"abstract_end":1224}]}
{"pmid":"28892125","title":"Novel spondyloepimetaphyseal dysplasia due to UFSP2 gene mutation.","abstract":"Beukes hip dysplasia is an autosomal dominant disease which has to date been described only in a large South African family of Dutch origin. The patients presented with progressive epiphyseal dysplasia limited to femoral capital epiphysis and their height was not significantly reduced. A unique variant of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 (UFSP2) gene (c.868T>C) has been reported in all individuals from Beukes family with clinical and radiological diagnosis of Beukes hip dysplasia. Three individuals, propositus, mother, and grandmother, presented with short stature, joint pain, genu vara and a novel spondyloepimetaphyseal dysplasia involving epiphyses predominantly at hips, but also at knees, ankles, wrists and hands, associated with variable degrees of metaphysis and spine involvement. Exome sequencing allowed us to identify the heterozygous variant c.1277A>C of the UFSP2 gene, leading to the missense change p.D426A, in all 3 patients. This mutation is predicted as damaging and, similarly to the mutation originally described in the Beukes family (p. Y290H), directly affects one of the catalytic residues participating in the active site of the protein. This supports the novel notion that loss of catalytic UFSP2 activity, observed in association with different mutants and already experimentally proven in vitro, may have different clinical outcomes.","variants":[{"Name":"NM_018359.5(UFSP2):c.1277A>C (p.Asp426Ala)","Chromosome":"4","Start":"185403540","Stop":"185403540","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":431489,"rule_based_match":true,"evidence_text":"c.1277A>C","llm_judgment":"PRESENT","evidence":"c.1277A>C","abstract_start":887,"abstract_end":896}]}
{"pmid":"20020398","title":"Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene.","abstract":"Andermann syndrome is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum (ACC), progressive motor-sensory neuropathy, mental retardation and facial features. We report on two siblings with the clinical picture of a demyelinating hereditary motor and sensory neuropathy (HMSN), where only the presence of ACC in the younger brother pointed to the diagnosis of Andermann syndrome. Mutation analysis of the KCC3 (SLC12A6) gene showed a compound heterozygous mutation; a maternal missense mutation c.1616G>A (p.G539D) and a paternal splice mutation c.1118+1G>A in both siblings. We hypothesize that mutations of the KCC3 gene may result in non-syndromic childhood onset HMSN.","variants":[{"Name":"NM_001365088.1(SLC12A6):c.1118+1G>A","Chromosome":"15","Start":"34254347","Stop":"34254347","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":358288,"rule_based_match":true,"evidence_text":"c.1118+1G>A","llm_judgment":"PRESENT","evidence":"c.1118+1G>A","abstract_start":579,"abstract_end":590},{"Name":"NM_001365088.1(SLC12A6):c.1616G>A (p.Gly539Asp)","Chromosome":"15","Start":"34250331","Stop":"34250331","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":625310,"rule_based_match":true,"evidence_text":"c.1616G>A (p.G539D)","llm_judgment":"PRESENT","evidence":"c.1616G>A (p.G539D)","abstract_start":528,"abstract_end":547}]}
{"pmid":"21069576","title":"A new mutation in the menin gene causes the multiple endocrine neoplasia type 1 syndrome with adrenocortical carcinoma.","abstract":"Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome that may be caused by mutations in the MEN1 gene on 11q13. Loss of function of the tumor suppressor gene MEN1 leads to synchronous or metachronous appearance of neuroendocrine tumors arising from neuroendocrine cells of the parathyroid and pituitary glands, the duodenum and pancreatic islets, and other endocrine organs such as the adrenal cortex. We here present a patient with MEN1 who developed hyperparathyroidism, multiple well differentiated functionally inactive neuroendocrine tumors of the pancreas and an adrenal carcinoma. We describe a new mutation at codon 443 in the coding region of exon 9 in the MEN1 gene, where a cytosine residue was exchanged for adenosine (TCC > TAC) and, consequently, serine for tyrosine (p.Ser443Tyr; c.1328C > A). [corrected] Also, we provide clinical data that may add to the genotype-phenotype discussion. We conclude that the novel mutation in the MEN1 gene described herein was clinically relevant.","variants":[{"Name":"NM_001370259.2(MEN1):c.1328C>A (p.Ser443Tyr)","Chromosome":"11","Start":"64805056","Stop":"64805056","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":398711,"rule_based_match":true,"evidence_text":"c.1328C > A","llm_judgment":"PRESENT","evidence":"c.1328C > A","abstract_start":825,"abstract_end":836}]}
{"pmid":"29892664","title":"Juvenile interleukin-36 receptor antagonist deficiency (DITRA) with c.80T>C (p.Leu27Pro) mutation successfully treated with etanercept and acitretin.","abstract":"","variants":[{"Name":"NM_012275.3(IL36RN):c.80T>C (p.Leu27Pro)","Chromosome":"2","Start":"113060902","Stop":"113060902","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39446,"rule_based_match":true,"evidence_text":"c.80T>C (p.Leu27Pro)","llm_judgment":"PRESENT","evidence":"c.80T>C (p.Leu27Pro)","abstract_start":null,"abstract_end":null}]}
{"pmid":"28967191","title":"Missense variants in the X-linked gene PRPS1 cause retinal degeneration in females.","abstract":"Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next-generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation.","variants":[{"Name":"NM_002764.4(PRPS1):c.47C>T (p.Ser16Phe)","Chromosome":"X","Start":"107628675","Stop":"107628675","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439508,"rule_based_match":true,"evidence_text":"c.47C > T, p.(Ser16Phe)","llm_judgment":"PRESENT","evidence":"c.47C > T, p.(Ser16Phe)","abstract_start":361,"abstract_end":384},{"Name":"NM_002764.4(PRPS1):c.586C>T (p.Arg196Trp)","Chromosome":"X","Start":"107645232","Stop":"107645232","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439509,"rule_based_match":true,"evidence_text":"c.586C > T, p.(Arg196Trp)","llm_judgment":"PRESENT","evidence":"c.586C > T, p.(Arg196Trp)","abstract_start":386,"abstract_end":411},{"Name":"NM_002764.4(PRPS1):c.640C>T (p.Arg214Trp)","Chromosome":"X","Start":"107645286","Stop":"107645286","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439510,"rule_based_match":true,"evidence_text":"c.640C > T, p.(Arg214Trp)","llm_judgment":"PRESENT","evidence":"c.640C > T, p.(Arg214Trp)","abstract_start":444,"abstract_end":469},{"Name":"NM_002764.4(PRPS1):c.641G>C (p.Arg214Pro)","Chromosome":"X","Start":"107645287","Stop":"107645287","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":439511,"rule_based_match":true,"evidence_text":"c.641G > C, p.(Arg214Pro)","llm_judgment":"PRESENT","evidence":"c.641G > C, p.(Arg214Pro)","abstract_start":413,"abstract_end":438}]}
{"pmid":"27752409","title":"The First Case of Severe Takotsubo Cardiomyopathy Associated with 5-Fluorouracil in a Patient with Abnormalities of Both Dihydropyrimidine Dehydrogenase (DPYD) and Thymidylate Synthase (TYMS) Genes.","abstract":"5-Fluorouracil (5-FU) is the backbone of the chemotherapy regimens approved for treatment of many malignancies, especially colorectal cancer (CRC). The incidence of cardiotoxicity associated with 5-FU ranges between 1.5% to 18% and is most commonly manifested as anginal symptoms. Cardiomyopathy is very rarely reported with 5-FU and capecitabine. A 35-year-old Caucasian male with T3, N1, M0 rectal cancer after the initial neoadjuvant chemoradiation with 5FU/LV followed by surgical abdominoperineal resection (APR), began mFOLFOX6 in the adjuvant setting. Following the first treatment, he developed severe cardiomyopathy, with a drop in ejection fraction (EF) to 19% from normal. The cardiac workup showed no ischemic or other etiologies to explain this cardiac event. He was a nonsmoker and only occasionally drank alcohol. He had no previous or family history of heart disease and had normal cholesterol level. He was treated for severe congestive heart failure (CHF). When the patient presented to us for second opinion, we decided to examine him for dihydropyrimidine dehydrogenase (DPD) deficiency and thymidylate synthase (TYMS) polymorphism. The patient was found to be heterozygous for the c.85T>C mutation, resulting in reduced DPYD enzymatic activity and homozygous for TYMS 5'TSER genotype 2R/2R *f. Our group first identified and reported P453L (1358C>T) type DPYD germline mutation in a patient who developed 5-FU induced cardiotoxicity. In this paper, we describe the first case of cardiomyopathy related to DPD deficiency and homozygous polymorphism of TYMS in a patient with colon cancer following 5-FU containing regimen. Fluorouracil-related cardiomyopathy has to be anticipated and treated to prevent the serious consequence of cardiac dysfunction. The prospective testing for DPD deficiency in patients might prevent DPD-deficient patients from severe toxicity or even death, and therefore the development of a unified screening method is warranted.","variants":[{"Name":"NM_000110.4(DPYD):c.85T>C (p.Cys29Arg)","Chromosome":"1","Start":"97883329","Stop":"97883329","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15474,"rule_based_match":true,"evidence_text":"c.85T>C","llm_judgment":"PRESENT","evidence":"c.85T>C","abstract_start":1202,"abstract_end":1209}]}
{"pmid":"32420772","title":"Molecular Understanding of Severe Cases of β-Thalassemia in the Nablus Region, West Bank, Palestine.","abstract":"Hemoglobinopathies are common inherited monogenic diseases that are likely to remain a serious regional health problem where thalassemias and sickle cell disease are prevalent. In regions where recessive alleles for hemoglobinopathy disorders are present with high consanguinity rates, such as in Palestine, coinheritance of two different genetic defects becomes anticipated and prevalent. In this report, we characterize the molecular variants of the <i>HBB</i> gene for 16 patients with transfusion-dependent anemia registered at the Thalassemia Patient Friends Society in Nablus governorate, West Bank, Palestine. Analysis revealed that 63.0% (10/16) of the patients were homozygous for β-thalassemia (β-thal), IVS-I-6 (T>C) (<i>HBB</i>: c.92+6T>C) or IVS-I-110 (G>A) (<i>HBB</i>: c.93-21G>A); 19.0% (3/16) homozygous for sickle cell disease or Hb S (<i>HBB</i>: c.20A>T, p.Glu6Val); 13.0% (2/16) were double heterozygotes for Hb S/β-thal, (<i>HBB</i>: c.20A>T/<i>HBB</i>: c.92G>C) and <i>HBB</i>: c.20A>T/<i>HBB</i>: c.321_322insG; and one case was a compound heterozygote for β-thal, codon 39 (C>T) (<i>HBB</i>: c.118C>T) and IVS-I-110. The most common mutation reported in the 16 patients was IVS-I-6 (0.38), followed by IVS-I-110 (0.28) Hb S (0.25) and 0.03 each for codon 39, codons 106/107 (<i>HBB</i>: c.321_322insG) and Hb Monroe (<i>HBB</i>: c.92G>C). In conclusion, in Palestine, a variety of intricate inheritance patterns are encountered in clinical practice.","variants":[{"Name":"NM_000518.5(HBB):c.92+6T>C","Chromosome":"11","Start":"5226924","Stop":"5226924","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":30489,"rule_based_match":true,"evidence_text":"IVS-I-6 (T>C) (<i>HBB</i>: c.92+6T>C)","llm_judgment":"PRESENT","evidence":"IVS-I-6 (T>C) (<i>HBB</i>: c.92+6T>C)","abstract_start":714,"abstract_end":751}]}
{"pmid":"37845805","title":"Reliability of hemoglobin A","abstract":"OBJECTIVES: Accurate quantification of hemoglobin (Hb) A<sub>2</sub> is vital for diagnosing β-thalassemia carriers. This study aimed to assess the precision and diagnostic utility of HbA<sub>2</sub> measurements using the new high-performance liquid chromatography (HPLC) method, Premier Resolution, in comparison to capillary electrophoresis (CE).\nMETHODS: We analyzed 418 samples, previously identified as A2A by CE, using Premier Resolution-HPLC. We compared the results, established correlations, and determined an optimal HbA<sub>2</sub> cutoff value for β-thalassemia screening. Additionally, we prospectively evaluated the chosen cutoff value in 632 samples. Mutations in the β- and α-globin genes were identified using polymerase chain reaction (PCR) techniques and DNA sequencing.\nRESULTS: HbA<sub>2</sub> levels were consistently higher with Premier Resolution, yet there was a significant correlation with CE in all samples (bias, -0.33; r, 0.991), β-thalassemia (bias, -0.27; r, 0.927), and non-β-thalassemia carriers (bias, -0.36; r, 0.928). An HbA<sub>2</sub> cutoff value of ≥4.0 % for β-thalassemia screening achieved 100 % sensitivity and 99.6 % specificity. Further validation yielded sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 97.3 , 99.8, 97.3, 99.8, and 99.7 %, respectively. We also identified a rare β-Hb variant, Hb La Desirade [<i>HBB</i>:c.389C>T], associated with β-thalassemia and co-inherited with a single α-globin gene.\nCONCLUSIONS: The Premier Resolution HPLC is a reliable and accurate method for routine β-thalassemia carrier screening, aligning with existing CE methods.","variants":[{"Name":"NM_000518.5(HBB):c.389C>T (p.Ala130Val)","Chromosome":"11","Start":"5225653","Stop":"5225653","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":30284,"rule_based_match":true,"evidence_text":"Hb La Desirade [<i>HBB</i>:c.389C>T]","llm_judgment":"PRESENT","evidence":"Hb La Desirade [<i>HBB</i>:c.389C>T]","abstract_start":1391,"abstract_end":1427}]}
{"pmid":"21810471","title":"Identification and functional characterization of KCNQ1 mutations around the exon 7-intron 7 junction affecting the splicing process.","abstract":"BACKGROUND: KCNQ1 gene encodes the delayed rectifier K(+) channel in cardiac muscle, and its mutations cause long QT syndrome type 1 (LQT1). Especially exercise-related cardiac events predominate in LQT1. We previously reported that a KCNQ1 splicing mutation displays LQT1 phenotypes.\nMETHODS AND RESULTS: We identified novel mutation at the third base of intron 7 (IVS7 +3A>G) in exercise-induced LQT1 patients. Minigene assay in COS7 cells and RT-PCR analysis of patients' lymphocytes demonstrated the presence of exon 7-deficient mRNA in IVS7 +3A>G, as well as c.1032G>A, but not in c.1022C>T. Real-time RT-PCR demonstrated that both IVS7 +3A>G and c.1032G>A carrier expressed significant amounts of exon-skipping mRNAs (18.8% and 44.8% of total KCNQ1 mRNA). Current recordings from Xenopus oocytes injected cRNA by simulating its ratios of exon skipping displayed a significant reduction in currents to 64.8 ± 4.5% for IVS7 +3A>G and to 41.4 ± 9.5% for c.1032G>A carrier, respectively, compared to the condition without splicing error. Computer simulation incorporating these quantitative results revealed the pronounced QT prolongation under beta-adrenergic stimulation in IVS7 +3A>G carrier model.\nCONCLUSION: Here we report a novel splicing mutation IVS7 +3A>G, identified in a family with mild form LQT1 phenotypes, and examined functional outcome in comparison with three other variants around the exon 7-intron 7 junction. In addition to c.1032G>A mutation, IVS7 +3A>G generates exon-skipping mRNAs, and thereby causing LQT1 phenotype. The severity of clinical phenotypes appeared to differ between the two splicing-related mutations and to result from the amount of resultant mRNAs and their functional consequences.","variants":[{"Name":"NM_000218.3(KCNQ1):c.1032G>A (p.Ala344=)","Chromosome":"11","Start":"2583545","Stop":"2583545","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18174,"rule_based_match":true,"evidence_text":"c.1032G>A","llm_judgment":"PRESENT","evidence":"c.1032G>A","abstract_start":564,"abstract_end":573}]}
{"pmid":"36123612","title":"Immune dysregulation associated with co-occurring germline CBL and SH2B3 variants.","abstract":"BACKGROUND: CBL syndrome is a RASopathy caused by heterozygous germline mutations of the Casitas B-lineage lymphoma (CBL) gene. It is characterized by heterogeneous clinical phenotype, including developmental delay, facial dysmorphisms, cardiovascular malformations and an increased risk of cancer development, particularly juvenile myelomonocytic leukemia (JMML). Although the clinical phenotype has been progressively defined in recent years, immunological manifestations have not been well elucidated to date.\nMETHODS: We studied the genetic, immunological, coagulative, and clinical profile of a family with CBL syndrome that came to our observation after the diagnosis of JMML, with homozygous CBL mutation, in one of the members.\nRESULTS: Variant analysis revealed the co-occurrence of CBL heterozygous mutation (c.1141 T &gt; C) and SH2B3 mutation (c.1697G &gt; A) in two other members. Patients carrying both mutations showed an ALPS-like phenotype characterized by lymphoproliferation, cytopenia, increased double-negative T-cells, impaired Fas-mediated lymphocyte apoptosis, altered cell death in PBMC and low TRECs expression. A coagulative work-up was also performed and showed the presence of subclinical coagulative alterations in patients carrying both mutations.\nCONCLUSION: In the reported family, we described immune dysregulation, as part of the clinical spectrum of CBL mutation with the co-occurrence of SH2B3.","variants":[{"Name":"NM_005188.4(CBL):c.1141T>C (p.Cys381Arg)","Chromosome":"11","Start":"119278211","Stop":"119278211","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":398518,"rule_based_match":false,"evidence_text":"c.1141 T > C","llm_judgment":"PRESENT","evidence":"c.1141 T > C","abstract_start":null,"abstract_end":null}]}
{"pmid":"31152169","title":"A Pitfall in HbA1c Testing Caused by Hb Long Island Hemoglobin Variant.","abstract":"BACKGROUND: Although many factors may interfere with hemoglobin (Hb)A1c measurement, Hb variants are among the most important factors.\nMETHODS: We tested the HbA1c levels of the patient, a 32 year old Manchu Chinese woman, during a routine health check. We used different methods, including high-performance liquid chromatography (HPLC) and capillary electrophoresis, to test specimens from the patient. Next, we tested the specimen further using polymerase chain reaction (PCR) and sequencing.\nRESULTS: We discovered that our patient, who had an HbA1c value of 0, also has an Hb variant, Hb Long Island, which we found during the HbA1c analysis as part of her routine health check at the Health Management Center in the General Hospital of Tianjin Medical University, Tianjin, China. Also, we discovered that the exon 1 of β gene contained transversion mutations, with 1 heterozygous and 1 homozygous variant (HBB:c.8A > C, 9T > C). These gene mutations resulted in an amino-acid change (His to Pro) and a decrease in HbA1c value.\nCONCLUSIONS: When there is no correlation between the clinical signs, glycemic status, and glycated Hb levels of the patient, the chromatogram of HbA1c should be carefully checked to detect possible variants that cause interference in the measurement.","variants":[{"Name":"NM_000518.5(HBB):c.8A>C (p.His3Pro)","Chromosome":"11","Start":"5227014","Stop":"5227014","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":30300,"rule_based_match":true,"evidence_text":"HBB:c.8A > C","llm_judgment":"PRESENT","evidence":"HBB:c.8A > C","abstract_start":911,"abstract_end":923}]}
{"pmid":"31970803","title":"Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians.","abstract":"OBJECTIVE: Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy.\nMETHODS: Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss-of-function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild-type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype.\nRESULTS: Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb-girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild-type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so.\nINTERPRETATION: This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568-583.","variants":[{"Name":"NM_003283.6(TNNT1):c.287T>C (p.Leu96Pro)","Chromosome":"19","Start":"55141208","Stop":"55141208","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2668684,"rule_based_match":true,"evidence_text":"NM_003283.6: c.287T > C; p.Leu96Pro","llm_judgment":"PRESENT","evidence":"NM_003283.6: c.287T > C; p.Leu96Pro","abstract_start":828,"abstract_end":863}]}
{"pmid":"35406697","title":"Concomitant Hereditary Spherocytosis and Pyruvate Kinase Deficiency in a Spanish Family with Chronic Hemolytic Anemia: Contribution of Laser Ektacytometry to Clinical Diagnosis.","abstract":"Background: Hereditary spherocytosis (HS) and pyruvate kinase deficiency (PKD) are the most common causes of hereditary chronic hemolytic anemia. Here, we describe clinical and genetic characteristics of a Spanish family with concomitant β-spectrin (SPTB) c.647G>A variant and pyruvate kinase (PKLR) c.1706G>A variant. Methods: A family of 11 members was studied. Hematological investigation, hemolysis tests, and specific red cell studies were performed in all family members, according to conventional procedures. An ektacytometric study was performed using the osmoscan module of the Lorca ektacytometer (MaxSis. RR Mechatronics). The presence of the SPTB and PKLR variants was confirmed by t-NGS. Results: The t-NGS genetic characterization of the 11 family members showed the presence of a heterozygous mutation for the β-spectrin (SPTB; c.647G>A) in seven members with HS, three of them co-inherited the PKLR variant c.1706G>A. In the remaining four members, no gene mutation was found. Ektacytometry allowed a clear diagnostic orientation of HS, independently from the PKLR variant. Conclusions: This family study allows concluding that the SPTB mutation, (c.647G>A) previously described as likely pathogenic (LP), should be classified as pathogenic (P), according to the recommendations for pathogenicity of the American College of Medical Genetics and the Association for Molecular Pathology. In addition, after 6 years of clinical follow-up of the patients with HS, it can be inferred that the chronic hemolytic anemia may be attributable to the SPTB mutation only, without influence of the concomitant PKLR. Moreover, only the family members with the SPTB mutation exhibited an ektacytometric profile characteristic of HS.","variants":[{"Name":"NM_001355436.2(SPTB):c.647G>A (p.Arg216Gln)","Chromosome":"14","Start":"64801754","Stop":"64801754","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":535260,"rule_based_match":true,"evidence_text":"c.647G>A","llm_judgment":"PRESENT","evidence":"c.647G>A","abstract_start":256,"abstract_end":264}]}
{"pmid":"34697416","title":"Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain.","abstract":"Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Pathological examination of a male fetus in the 18th gestational week revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities. Prenatal trio-exome sequencing identified compound heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sister fetus. Through RNA analyses, we characterized exon 4 skipping affecting the PNKP forkhead-associated (FHA) and phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the paternal c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the splice donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro); c.151G>C, p.(Val51Leu)). RNA-seq showed complex splicing for c.1029+2T>C and c.151G>C. Structural modeling revealed significant clustering of missense variants in the FHA domain with variants generating structural damage. Our clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modeling, we highlight the mutational complexity and exemplify a PNKP-variant characterization framework.","variants":[{"Name":"NM_007254.4(PNKP):c.1029+2T>C","Chromosome":"19","Start":"49862369","Stop":"49862369","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":203593,"rule_based_match":true,"evidence_text":"c.1029+2T>C","llm_judgment":"PRESENT","evidence":"c.1029+2T>C","abstract_start":1134,"abstract_end":1145}]}
{"pmid":"33058741","title":"Identification of Novel","abstract":"<b><i>Purpose:</i></b> Retinitis pigmentosa (RP) is an inherited and progressive degenerative retinal disease that often results in severe vision loss and blindness. However, mutations in known RP disease genes account for only 60% of RP cases, indicating that there are additional pathogenic mutations are yet to be identified. We aimed to identify the causative mutations in the eyes shut homolog (<i>EYS</i>) gene in a cohort of Chinese RP and rod-cone dystrophy families. <b><i>Materials and Methods:</i></b> Targeted next-generation sequencing was applied to identify novel mutations in these patients. Candidate variants were evaluated using bioinformatics tools. Mutations were confirmed by Sanger sequencing. <b><i>Results:</i></b> We identified eight heterozygous mutations in the <i>EYS</i> gene in the four probands, including a novel frameshift deletion mutation, c.8242_8243del (p.L2748fs); a novel insertion mutation, c.5802_5803insT (p.I1935YfsX6); a novel splicing mutation, c.1300-1G>A; two heterozygous stop-gain mutations, c.1750G>T (p.E584X) and c.8805C>A (p.Y2935X); and three novel missense mutations, c.8269G>A (p.V2757I), c.2545C>T (p.R849C) and c.7506C>A (p.S2502R). Only c.8805C>A had been reported previously in RP patients. None of these mutations were present in 1000 control individuals. <b><i>Conclusions:</i></b> We identified seven novel mutations in the <i>EYS</i> gene, expanding the mutational specra of <i>EYS</i> in Chinese patients with RP and rod-cone dystrophy.","variants":[{"Name":"NM_001142800.2(EYS):c.1300-1G>A","Chromosome":"6","Start":"65353618","Stop":"65353618","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2157590,"rule_based_match":true,"evidence_text":"c.1300-1G>A","llm_judgment":"PRESENT","evidence":"c.1300-1G>A","abstract_start":991,"abstract_end":1002}]}
{"pmid":"27671926","title":"A novel NDUFS4 frameshift mutation causes Leigh disease in the Hutterite population.","abstract":"Leigh disease is a progressive, infantile-onset, neurodegenerative disorder characterized by feeding difficulties, failure to thrive, hypotonia, seizures, and central respiratory compromise. Metabolic and neuroimaging investigations typically identify abnormalities consistent with a disorder of mitochondrial energy metabolism. Mutations in more than 35 genes affecting the mitochondrial respiratory chain encoded from both the nuclear and mitochondrial genomes have been associated with Leigh disease. The clinical presentations of five individuals of Hutterite descent with Leigh disease are described herein. An identity-by-descent mapping and candidate gene approach was used to identify a novel homozygous c.393dupA frameshift mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4) gene. The carrier frequency of this mutation was estimated in >1,300 Hutterite individuals to be 1 in 27. © 2017 Wiley Periodicals, Inc.","variants":[{"Name":"NM_002495.4(NDUFS4):c.393dup (p.Glu132fs)","Chromosome":"5","Start":"53658590","Stop":"53658591","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":1934939,"rule_based_match":true,"evidence_text":"c.393dup","llm_judgment":"PRESENT","evidence":"c.393dup","abstract_start":712,"abstract_end":720}]}
{"pmid":"16845277","title":"Novel mutations underlying nephrogenic diabetes insipidus in Arab families.","abstract":"PURPOSE: Nephrogenic Diabetes Insipidus (NDI) is genetically heterogeneous and may be inherited in an X-linked or autosomal recessive manner. We aimed to investigate the molecular basis of NDI among Arab families.\nMETHODS: Direct sequencing of coding regions for AQP2 and AVPR2 was used to identify underlying mutations. One large deletion required Southern blot analysis and a PCR-based strategy to identify deletion junctions.\nRESULTS: We identified two novel missense mutations (AQP2:p.Gly100Arg and p.Gly180Ser) in AQP2 and one novel missense mutation (AVPR2:p.Gly122Asp), one previously reported missense mutation (AVPR2:p.Arg137His) and one novel contiguous deletion (AVPR2:c.25 + 273_ARHGAP4o:2650-420del) affecting AVPR2. We also describe evidence of lyonization associated with the novel deletion.\nCONCLUSIONS: Two novel mutations were identified in each of AVPR2 and AQP2 underlying CNDI in Arab families. Identification of these mutations will facilitate early diagnosis of CNDI, counseling of families and provide opportunities for early intervention aimed at reducing morbidity. The presence of affected females and consanguinity, as is often observed in Arab communities should not be used to rule out AVPR2 as a candidate when considering diagnostic testing. Careful observation of phenotypic heterogeneity should be used in referring such families for both AQP2 and AVPR2 molecular genetic testing.","variants":[{"Name":"NM_000054.7(AVPR2):c.410G>A (p.Arg137His)","Chromosome":"X","Start":"153905916","Stop":"153905916","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25888,"rule_based_match":false,"evidence_text":"AVPR2:p.Arg137His","llm_judgment":"PRESENT","evidence":"AVPR2:p.Arg137His","abstract_start":620,"abstract_end":637},{"Name":"NM_000486.6(AQP2):c.298G>A (p.Gly100Arg)","Chromosome":"12","Start":"49951128","Stop":"49951128","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1309666,"rule_based_match":false,"evidence_text":"AQP2:p.Gly100Arg","llm_judgment":"PRESENT","evidence":"AQP2:p.Gly100Arg","abstract_start":482,"abstract_end":498},{"Name":"NM_000486.6(AQP2):c.538G>A (p.Gly180Ser)","Chromosome":"12","Start":"49954642","Stop":"49954642","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3853517,"rule_based_match":false,"evidence_text":"p.Gly180Ser","llm_judgment":"PRESENT","evidence":"p.Gly180Ser","abstract_start":503,"abstract_end":514},{"Name":"NM_000054.7(AVPR2):c.365G>A (p.Gly122Asp)","Chromosome":"X","Start":"153905871","Stop":"153905871","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3854434,"rule_based_match":false,"evidence_text":"AVPR2:p.Gly122Asp","llm_judgment":"PRESENT","evidence":"AVPR2:p.Gly122Asp","abstract_start":557,"abstract_end":574}]}
{"pmid":"26276046","title":"Novel missense mutation in the GALNS gene in an affected patient with severe form of mucopolysaccharidosis type IVA.","abstract":"Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A, is an autosomal recessive disorder characterized by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which causes major skeletal and connective tissue abnormalities and affects multiple organ systems. In this study, one MPS IVA patient with a severe form from consanguine large Iranian family has been investigated. To find a mutation, all of the 14 exons and intron-exon junctions of GALNS gene were sequenced. Sequencing results were analyzed using bioinformatic analysis in order to predict probable pathogenic effect of the variant. One novel homozygous missense mutation in exon 5, c.542A>G (p.Y181C), was found in the proband. That was predicted as being probably pathogenic by bioinformatics analysis. Segregation and familial study confirmed this pathogenic mutation. In conclusion, we have identified the novel mutation responsible for MPS IVA in an Iranian patient to assist in the diagnosis, genetic counseling and prenatal diagnosis of the affected families.","variants":[{"Name":"NM_000512.5(GALNS):c.542A>G (p.Tyr181Cys)","Chromosome":"16","Start":"88837646","Stop":"88837646","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":190091,"rule_based_match":true,"evidence_text":"c.542A>G (p.Y181C)","llm_judgment":"PRESENT","evidence":"c.542A>G (p.Y181C)","abstract_start":672,"abstract_end":690}]}
{"pmid":"31374204","title":"Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype.","abstract":"Brittle and \"tiger-tail\" hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features including ichthyosis, intellectual disability, decreased fertility, and short stature. As a result of premature abrogation of terminal differentiation, the hair is brittle and fragile and contains reduced cysteine content. Hypersensitivity to UV light is found in about half of individuals with TTD; all of these individuals harbor bi-allelic mutations in components of the basal transcription factor TFIIH, and these mutations lead to impaired nucleotide excision repair and basal transcription. Different genes have been found to be associated with non-photosensitive TTD (NPS-TTD); these include MPLKIP (also called TTDN1), GTF2E2 (also called TFIIEβ), and RNF113A. However, a relatively large group of these individuals with NPS-TTD have remained genetically uncharacterized. Here we present the identification of an NPS-TTD-associated gene, threonyl-tRNA synthetase (TARS), found by next-generation sequencing of a group of uncharacterized individuals with NPS-TTD. One individual has compound heterozygous TARS variants, c.826A>G (p.Lys276Glu) and c.1912C>T (p.Arg638<sup>∗</sup>), whereas a second individual is homozygous for the TARS variant: c.680T>C (p.Leu227Pro). We showed that these variants have a profound effect on TARS protein stability and enzymatic function. Our results expand the spectrum of genes involved in TTD to include genes implicated in amino acid charging of tRNA, which is required for the last step in gene expression, namely protein translation. We previously proposed that some of the TTD-specific features derive from subtle transcription defects as a consequence of unstable transcription factors. We now extend the definition of TTD from a transcription syndrome to a \"gene-expression\" syndrome.","variants":[{"Name":"NM_152295.5(TARS1):c.1912C>T (p.Arg638Ter)","Chromosome":"5","Start":"33466874","Stop":"33466874","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":676989,"rule_based_match":true,"evidence_text":"c.1912C>T (p.Arg638<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"c.1912C>T (p.Arg638<sup>∗</sup>)","abstract_start":1219,"abstract_end":1251},{"Name":"NM_152295.5(TARS1):c.826A>G (p.Lys276Glu)","Chromosome":"5","Start":"33456216","Stop":"33456216","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":676990,"rule_based_match":true,"evidence_text":"c.826A>G (p.Lys276Glu)","llm_judgment":"PRESENT","evidence":"c.826A>G (p.Lys276Glu)","abstract_start":1192,"abstract_end":1214},{"Name":"NM_152295.5(TARS1):c.680T>C (p.Leu227Pro)","Chromosome":"5","Start":"33455691","Stop":"33455691","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":676991,"rule_based_match":true,"evidence_text":"c.680T>C (p.Leu227Pro)","llm_judgment":"PRESENT","evidence":"c.680T>C (p.Leu227Pro)","abstract_start":1317,"abstract_end":1339}]}
{"pmid":"36757047","title":"LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes.","abstract":"Defects of respiratory chain complex III (CIII) result in characteristic but rare mitochondrial disorders associated with distinct neuroradiological findings. The underlying molecular defects affecting mitochondrial CIII assembly factors are few and yet to be identified. LYRM7 assembly factor is required for proper CIII assembly where it acts as a chaperone for the Rieske iron-sulfur (UQCRFS1) protein in the mitochondrial matrix and stabilizing it. We present here the seventeenth individual with LYRM7-associated mitochondrial leukoencephalopathy harboring a previously reported rare pathogenic homozygous LYRM 7 variant, c.2T>C, (p.Met1?). Like previously reported individuals, our 5-year-old male proband presented with recurrent metabolic and lactic acidosis, encephalopathy, and fatigue. Further, he has additional, previously unreported features, including an acute stroke like episode with bilateral central blindness and optic neuropathy, recurrent hyperglycemia and hypertension associated with metabolic crisis. However, he has no signs of psychomotor regression. He has been stable clinically with residual left-sided reduced visual acuity and amblyopia, and no more metabolic crises for 2-year-period while on the mitochondrial cocktail. Although the reported brain MRI findings in other affected individuals are homogenous, it is slightly different in our index, revealing evidence of bilateral almost symmetric multifocal periventricular T2 hyperintensities with hyperintensities of the optic nerves, optic chiasm, and corona radiata but with no cavitation or cystic changes. This report describes new clinical and radiological findings of LYRM7-associated disease. The report also summarizes the clinical and molecular data of previously reported individuals describing the full phenotypic spectrum.","variants":[{"Name":"NM_181705.4(LYRM7):c.2T>C (p.Met1Thr)","Chromosome":"5","Start":"131171022","Stop":"131171022","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1313542,"rule_based_match":true,"evidence_text":"LYRM 7 variant, c.2T>C, (p.Met1?)","llm_judgment":"PRESENT","evidence":"LYRM 7 variant, c.2T>C, (p.Met1?)","abstract_start":611,"abstract_end":644}]}
{"pmid":"16414076","title":"Novel mutation of neurofibromatosis type 1 in a patient with cerebral vasculopathy and fatal ischemic stroke.","abstract":"Vascular lesions are infrequently recognized as manifestations of neurofibromatosis 1 (NF1), but they can produce serious complications and contribute to mortality at younger ages. Here we report the case of a young female patient with NF1 who suffered from a fatal middle cerebral artery (MCA) infarct. In addition to the MCA infarct, head MRI also disclosed old infarcts at bilateral cerebella and multiple intracranial arterial steno-occlusions. Stroke related to NF1 cerebral vasculopathy was highly suggested after other diseases were excluded. Additionally, genetic analysis of the patient identified a novel mutation at the splicing donor site, c. 2,409+2T>G that resulted in a splicing aberration.","variants":[{"Name":"NM_001042492.3(NF1):c.2409+2T>G","Chromosome":"17","Start":"31227608","Stop":"31227608","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":235595,"rule_based_match":false,"evidence_text":"c. 2,409+2T>G","llm_judgment":"PRESENT","evidence":"c. 2,409+2T>G","abstract_start":652,"abstract_end":665}]}
{"pmid":"27588452","title":"Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss.","abstract":"Inherited retinal diseases (IRDs) are a diverse group of genetically and clinically heterogeneous retinal abnormalities. The present study was designed to identify genetic defects in individuals with an uncommon combination of autosomal recessive progressive cone-rod degeneration accompanied by sensorineural hearing loss (arCRD-SNHL). Homozygosity mapping followed by whole-exome sequencing (WES) and founder mutation screening revealed two truncating rare variants (c.893-1G>A and c.534delT) in CEP78, which encodes centrosomal protein 78, in six individuals of Jewish ancestry with CRD and SNHL. RT-PCR analysis of CEP78 in blood leukocytes of affected individuals revealed that the c.893-1G>A mutation causes exon 7 skipping leading to deletion of 65bp, predicted to result in a frameshift and therefore a truncated protein (p.Asp298Valfs(∗)17). RT-PCR analysis of 17 human tissues demonstrated ubiquitous expression of different CEP78 transcripts. RNA-seq analysis revealed three transcripts in the human retina and relatively higher expression in S-cone-like photoreceptors of Nrl-knockout retina compared to rods. Immunohistochemistry studies in the human retina showed intense labeling of cone inner segments compared to rods. CEP78 was reported previously to interact with c-nap1, encoded by CEP250 that we reported earlier to cause atypical Usher syndrome. We conclude that truncating mutations in CEP78 result in a phenotype involving both the visual and auditory systems but different from typical Usher syndrome.","variants":[{"Name":"NM_001330691.3(CEP78):c.893-1G>A","Chromosome":"9","Start":"78248290","Stop":"78248290","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":359177,"rule_based_match":true,"evidence_text":"c.893-1G>A","llm_judgment":"PRESENT","evidence":"c.893-1G>A","abstract_start":469,"abstract_end":479}]}
{"pmid":"30302010","title":"PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia.","abstract":"PLA2G6-associated neurodegeneration (PLAN) comprises heterogeneous neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation 2B, and Parkinson disease 14 (PARK14). In addition, very recently, PLA2G6 mutations have been reported to represent a phenotype of hereditary spastic paraplegia (HSP). In this study, we screened 383 HSP families to clarify the frequency of PLA2G6 mutations in the Japan Spastic Paraplegia Research Consortium, and revealed the clinical characteristics of HSP with PLA2G6 mutations. We found three families with compound heterozygous mutations of the PLA2G6 gene, c.517 C > T/c.1634A > G, c.662 T > C/c.991 G > T, and c.1187-2 A > G/c.1933C > T, and one family with a homozygous mutation of the PLA2G6 gene, c.1904G > A/c.1904G > A. All three families with compound heterozygous mutations presented a uniform phenotype of a complicated form of HSP with infantile/child-onset spastic paraplegia, cerebellar ataxia, and mental retardation. On the other hand, the family with a homozygous mutation presented a late-onset complicated form of HSP with parkinsonism. This study may extend the clinical and genetic findings for PLAN.","variants":[{"Name":"NM_003560.4(PLA2G6):c.1634A>G (p.Lys545Arg)","Chromosome":"22","Start":"38120867","Stop":"38120867","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":169786,"rule_based_match":true,"evidence_text":"c.1634A>G","llm_judgment":"PRESENT","evidence":"c.1634A > G","abstract_start":661,"abstract_end":672},{"Name":"NM_003560.4(PLA2G6):c.1904G>A (p.Arg635Gln)","Chromosome":"22","Start":"38115657","Stop":"38115657","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39323,"rule_based_match":true,"evidence_text":"c.1904G>A/c.1904G>A","llm_judgment":"PRESENT","evidence":"c.1904G > A/c.1904G > A","abstract_start":793,"abstract_end":816}]}
{"pmid":"26622980","title":"Observation of c.260A > G mutation in superoxide dismutase 1 that causes p.Asn86Ser in Iranian amyotrophic lateral sclerosis patient and absence of genotype/phenotype correlation.","abstract":"BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder in European populations. ALS can be sporadic ALS (SALS) or familial ALS (FALS). Among 20 known ALS genes, mutations in C9orf72 and superoxide dismutase 1 (SOD1) are the most common genetic causes of the disease. Whereas C9orf72 mutations are more common in Western populations, the contribution of SOD1 to ALS in Iran is more than C9orf72. At present, a clear genotype/phenotype correlation for ALS has not been identified. We aimed to perform mutation screening of SOD1 in a newly identified Iranian FALS patient and to assess whether a genotype/phenotype correlation for the identified mutation exists.\nMETHODS: The five exons of SOD1 and flanking intronic sequences of a FALS proband were screened for mutations by direct sequencing. The clinical features of the proband were assessed by a neuromuscular specialist (SN). The phenotypic presentations were compared to previously reported patients with the same mutation.\nRESULTS: Heterozygous c.260A > G mutation in SOD1 that causes Asn86Ser was identified in the proband. Age at onset was 34 years and site of the first presentation was in the lower extremities. Comparisons of clinical features of different ALS patients with the same mutation evidenced variable presentations.\nCONCLUSION: The c.260A > G mutation in SOD1 that causes Asn86Ser appears to cause ALS with variable clinical presentations.","variants":[{"Name":"NM_000454.5(SOD1):c.260A>G (p.Asn87Ser)","Chromosome":"21","Start":"31667278","Stop":"31667278","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":471562,"rule_based_match":true,"evidence_text":"c.260A > G","llm_judgment":"PRESENT","evidence":"c.260A > G","abstract_start":1034,"abstract_end":1044}]}
{"pmid":"38158857","title":"Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.","abstract":"PURPOSE: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.\nMETHODS: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.\nRESULTS: In 1 family with 2 affected males, we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation.\nCONCLUSION: We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron-containing genes due to germline variation in ZRSR2.","variants":[{"Name":"NM_005089.4(ZRSR2):c.1211_1212del (p.Gly404fs)","Chromosome":"X","Start":"15823001","Stop":"15823002","ReferenceAlleleVCF":"AGG","AlternateAlleleVCF":"A","allel_id":3526376,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1211_1212del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1211_1212del","abstract_start":678,"abstract_end":704},{"Name":"NM_005089.4(ZRSR2):c.1207_1208del (p.Arg403fs)","Chromosome":"X","Start":"15823000","Stop":"15823001","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":966735,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1207_1208del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1207_1208del","abstract_start":828,"abstract_end":854}]}
{"pmid":"35260566","title":"Pleomorphic rhabdomyosarcoma in a young adult harboring a novel germline MSH2 variant.","abstract":"Most cases of rhabdomyosarcoma (RMS) are sporadic and not associated with the Lynch syndrome (LS) spectrum. We report a young adult patient with RMS and a family history of colorectal cancer. Comprehensive cancer genomic profiling (CGP) of his tumor revealed a likely pathogenic variant of MSH2, NM_000251.3:c.1741delA (p.I581Lfs*9), which was also present in his blood sample. The widespread use of CGP may reveal that RMS can be a rare manifestation of LS.","variants":[{"Name":"NM_000251.3(MSH2):c.1741del (p.Ile581fs)","Chromosome":"2","Start":"47471042","Stop":"47471042","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":983950,"rule_based_match":true,"evidence_text":"NM_000251.3:c.1741delA (p.I581Lfs*9)","llm_judgment":"PRESENT","evidence":"NM_000251.3:c.1741delA (p.I581Lfs*9)","abstract_start":296,"abstract_end":332}]}
{"pmid":"29991546","title":"A novel mutation in Wiskott-Aldrich gene manifesting as macrothrombocytopenia and neutropenia.","abstract":"Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder, described as a clinical triad of microthrombocytopenia, eczema and recurrent infections. Different mutations in WAS gene have been identified, resulting in various phenotypes and a broad range of disease severity, ranging from classic WAS to X-linked thrombocytopenia and X-linked neutropenia. WAS in some cases can be fatal without haematopoietic stem cell transplantation early in life. In this particular case, we present a novel mutation with a unique presentation. An 18-year-old man incidentally found to have macrothrombocytopenia and neutropenia at 16 years of age later found to be hemizygous for c. 869T>C (p.Ile290Thr) mutation in WAS gene. The late presentation, absence of other manifestations of WAS and presence of macrothrombocytopenia, rather than microthrombocytopenia, which is usually a characteristic finding in WAS, misled the initial diagnosis. On review of literature, this mutation has not been reported as causing WAS.","variants":[{"Name":"NM_000377.3(WAS):c.869T>C (p.Ile290Thr)","Chromosome":"X","Start":"48688391","Stop":"48688391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":980208,"rule_based_match":true,"evidence_text":"c. 869T>C (p.Ile290Thr)","llm_judgment":"PRESENT","evidence":"c. 869T>C (p.Ile290Thr)","abstract_start":666,"abstract_end":689}]}
{"pmid":"23052699","title":"GH-releasing hormone receptor gene: a novel splice-disrupting mutation and study of founder effects.","abstract":"BACKGROUND: Mutations in GH-releasing hormone receptor gene (GHRHR) are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD).\nOBJECTIVE: To search for GHRHR mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations.\nMETHODS: The coding region of GHRHR was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking GHRHR were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c.1146G>A (p.E382E) mutation.\nRESULTS: A novel homozygous intronic GHRHR c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation.\nCONCLUSION: We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD.","variants":[{"Name":"NM_000823.4(GHRHR):c.57+1G>A","Chromosome":"7","Start":"30964126","Stop":"30964126","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31029,"rule_based_match":true,"evidence_text":"c.57+1G>A (IVS1+1G>A)","llm_judgment":"PRESENT","evidence":"c.57+1G>A (IVS1+1G>A)","abstract_start":571,"abstract_end":592},{"Name":"NM_000823.4(GHRHR):c.1146G>A (p.Glu382=)","Chromosome":"7","Start":"30977322","Stop":"30977322","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3856535,"rule_based_match":true,"evidence_text":"c.1146G>A (p.E382E)","llm_judgment":"PRESENT","evidence":"c.1146G>A (p.E382E)","abstract_start":715,"abstract_end":734}]}
{"pmid":"37165311","title":"Unravelling the genetic basis of retinal dystrophies in Pakistani consanguineous families.","abstract":"BACKGROUND: Retinitis Pigmentosa (RP) is a clinically and genetically progressive retinal dystrophy associated with severe visual impairments and sometimes blindness, the most common syndromic form of which is Usher syndrome (USH). This study aimed to further increase understanding of the spectrum of RP in the Khyber Pakhtunkhwa region of Pakistan.\nMETHODOLOGY: Four consanguineous families of Pashtun ethnic group were investigated which were referred by the local collaborating ophthalmologists. In total 42 individuals in four families were recruited and investigated using whole exome and dideoxy sequencing. Among them, 20 were affected individuals including 6 in both family 1 and 2, 5 in family 3 and 3 in family 4.\nRESULT: Pathogenic gene variants were identified in all four families, including two in cone dystrophy and RP genes in the same family (PDE6C; c.480delG, p.Asn161ThrfsTer33 and TULP1; c.238 C > T, p.Gln80Ter) with double-homozygous individuals presenting with more severe disease. Other pathogenic variants were identified in MERTK (c.2194C > T, p.Arg732Ter), RHO (c.448G > A, p.Glu150Lys) associated with non-syndromic RP, and MYO7A (c.487G > A, p.Gly163Arg) associated with USH. In addition, the reported variants were of clinical significance as the PDE6C variant was detected novel, whereas TULP1, MERTK, and MYO7A variants were detected rare and first time found segregating with retinal dystrophies in Pakistani consanguineous families.\nCONCLUSIONS: This study increases knowledge of the genetic basis of retinal dystrophies in families from Pakistan providing information important for genetic testing and diagnostic provision particularly from the Khyber Pakhtunkhwa region.","variants":[{"Name":"NM_000539.3(RHO):c.448G>A (p.Glu150Lys)","Chromosome":"3","Start":"129530962","Stop":"129530962","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28085,"rule_based_match":true,"evidence_text":"c.448G > A, p.Glu150Lys","llm_judgment":"PRESENT","evidence":"c.448G > A, p.Glu150Lys","abstract_start":1090,"abstract_end":1113}]}
{"pmid":"34376197","title":"A novel USH2A variant in a patient with hearing loss and prenatal diagnosis of a familial fetus: a case report.","abstract":"BACKGROUND: Usher syndrome (USH) is the most common cause of inherited deaf-blindness. The current study aimed to identify pathogenic variants in a Chinese patient with hearing loss and to report the identification of a novel p.(Phe1583Leufs*10) variant in USH2A, which met the needs of prenatal diagnosis of the patient's mother.\nCASE PRESENTATION: Genomic DNA obtained from a five-year-old girl with hearing loss was analyzed via the hearing loss-targeted gene panels. We identified the compound heterozygous variants c.8559-2A>G and c.4749delT in Usher syndrome type 2A (USH2A) gene as the underlying cause of the patient; the former variation has been reported in the literature, but not the latter. The parents of the girl were heterozygous carriers. The two variants were classified as pathogenic. Based on these findings, amniotic fluid samples were used for prenatal diagnosis of the couple's fetus, which was found to carry c.4749delT but not c.8559-2A>G variation. During the follow-up period of more than 9 months after the birth of the fetus, it was confirmed that the infant was healthy.\nCONCLUSIONS: The results of the present study identified two compound heterozygous USH2A variants in a patient with hearing loss and reported a novel USH2A variant which expands the spectrum of USH2A variants in USH.","variants":[{"Name":"NM_206933.4(USH2A):c.8559-2A>G","Chromosome":"1","Start":"215877882","Stop":"215877882","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":57766,"rule_based_match":true,"evidence_text":"c.8559-2A>G","llm_judgment":"PRESENT","evidence":"c.8559-2A>G","abstract_start":520,"abstract_end":531}]}
{"pmid":"26876133","title":"CDKN2A mutations with p14 loss predisposing to multiple nerve sheath tumours, melanoma, dysplastic naevi and internal malignancies: a case series and review of the literature.","abstract":"An inherited germline mutation in CDKN2A is the most common cause of familial atypical multiple mole melanoma (FAMMM) syndrome. Although it is well known that CDKN2A mutations confer an increased risk for melanoma and pancreatic carcinoma, the association with an increased risk for nerve sheath tumours and other tumour types is under-recognized. We report a family with a missense mutation (c.151-1G>C) at the acceptor splice site of intron 1 of CDKN2A, resulting in loss of function of both tumour suppressor proteins p16(INK) (4) and p14(ARF) . This mutation is associated with a clinical phenotype of FAMMM syndrome in which patients develop numerous benign and malignant mutations, brain tumours, sarcomas and other solid tumours, in addition to melanoma and dysplastic naevi. Our proband initially presented with multiple nerve sheath tumours, leading to diagnostic confusion with Neurofibromatosis type 1. Loss of p14 expression results in increased MDM2-mediated degradation of the tumour suppressor protein p53, and predisposes mutation carriers to multiple benign and malignant neoplasms. This article highlights the importance of considering CDKN2A mutations in patients with dysplastic naevi, melanoma and multiple nerve sheath tumours, specifically those with histological features of both neurofibromas and schwannomas. We also present a discussion of medical management for patients with this high-risk cancer susceptibility syndrome.","variants":[{"Name":"NM_000077.5(CDKN2A):c.151-1G>C","Chromosome":"9","Start":"21971209","Stop":"21971209","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":180319,"rule_based_match":true,"evidence_text":"c.151-1G>C","llm_judgment":"PRESENT","evidence":"c.151-1G>C","abstract_start":393,"abstract_end":403}]}
{"pmid":"29896747","title":"Clinical features and mutational analysis of a case with Sensenbrenner syndrome","abstract":"OBJECTIVE: To explore the clinical characteristics of a patient with Sensenbrenner syndrome (also called cranioectodermal dysplasia type 3) caused by mutation of intraflagellar transport (IFT) 43 gene.\nMETHODS: The clinical data of the patient was retrospectively analyzed. The target genes was the patient were captured and subjected to next generation sequencing. Suspected mutations were verified through Sanger sequencing.\nRESULTS: The patient, a-13 year-and-5-month-old girl, was admitted for anemia and renal dysfunction for 8 months. Clinically, she has featured short stature, short limbs, brachydactylia, tooth agenesis, and retinal dystrophy, high-degree myopia, and chronic renal failure. Gene sequencing showed that she has carried a homozygous c.1A>G (p.M1V) mutation of the IFT43 gene, for which both of her parents were heterozygous carriers.\nCONCLUSION: c.1A>G (p.M1V) mutation of the C14ORF179/IFT43 gene is the cause for praecox chronic renal failure in children. Genetic testing can facilitate the diagnosis of this rare disorder. For affected families, prenatal diagnosis should be provided.","variants":[{"Name":"NM_001102564.3(IFT43):c.1A>G (p.Met1Val)","Chromosome":"14","Start":"75985787","Stop":"75985787","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":40055,"rule_based_match":true,"evidence_text":"c.1A>G (p.M1V)","llm_judgment":"PRESENT","evidence":"c.1A>G (p.M1V)","abstract_start":757,"abstract_end":771}]}
{"pmid":"27942463","title":"Multigene panel next generation sequencing in a patient with cherry red macular spot: Identification of two novel mutations in","abstract":"BACKGROUND: Lysosomal storage diseases (LSD) often manifest with cherry red macular spots. Diagnosis is based on clinical features and specific biochemical and enzymatic patterns. In uncertain cases, genetic testing with next generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes. We report on the diagnostic work-up in a boy with sialidosis type I, presenting initially with marked cherry red macular spots but non-specific urinary oligosaccharide patterns and unusually mild excretion of bound sialic acid.\nMETHODS: Biochemical, enzymatic and genetic tests were performed in the patient. The clinical and electrophysiological data was reviewed and a genotype-phenotype analysis was performed. In addition a systematic literature review was carried out.\nCASE REPORT AND RESULTS: Cherry red macular spots were first noted at 6 years of age after routine screening myopia. Physical examination, psychometric testing, laboratory investigations as well as cerebral MRI were unremarkable at 9 years of age. So far no clinical myoclonic seizures occurred, but EEG displays generalized epileptic discharges and visual evoked potentials are prolonged bilaterally. Urine thin layer chromatography showed an oligosaccharide pattern compatible with different LSD including sialidosis, galactosialidosis, GM1 gangliosidosis or mucopolysaccharidosis type IV B. Urinary bound sialic acid excretion was mildly elevated in spontaneous and 24 h urine samples. In cultured fibroblasts, α-sialidase activity was markedly decreased to < 1%; however, bound and free sialic acid were within normal range. Diagnosis was eventually established by multigene panel next generation sequencing of genes associated to LSD, identifying two novel, compound heterozygous variants in <i>NEU1</i> gene (c.699C > A, p.S233R in exon 4 and c.803A > G; p.Y268C in Exon 5 in <i>NEU1</i> transcript NM_000434.3), leading to amino acid changes predicted to impair protein function.\nDISCUSSION: Sialidosis should be suspected in patients with cherry red macular spots, even with non-significant urinary sialic acid excretion. Multigene panel next generation sequencing can establish a definite diagnosis, allowing for counseling of the patient and family.","variants":[{"Name":"NM_000434.4(NEU1):c.699C>A (p.Ser233Arg)","Chromosome":"6","Start":"31860538","Stop":"31860538","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2767953,"rule_based_match":true,"evidence_text":"c.699C > A, p.S233R","llm_judgment":"PRESENT","evidence":"c.699C > A, p.S233R","abstract_start":1809,"abstract_end":1828},{"Name":"NM_000434.4(NEU1):c.803A>G (p.Tyr268Cys)","Chromosome":"6","Start":"31860260","Stop":"31860260","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1867838,"rule_based_match":true,"evidence_text":"c.803A>G; p.Y268C","llm_judgment":"PRESENT","evidence":"c.803A > G; p.Y268C","abstract_start":1843,"abstract_end":1862}]}
{"pmid":"31571197","title":"A novel homozygous CFAP65 mutation in humans causes male infertility with multiple morphological abnormalities of the sperm flagella.","abstract":"Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare autosomal recessive inherited disorder associated with male infertility. To date, 14 genetic causative genes have been identified in MMAF, which can only explain the genetic causes of ~60% of MMAF cases. Here, we report a man with primary infertility, who had a typical MMAF phenotype. Whole-exome sequencing (WES) was performed on the patient and a homozygous mutation (c. 2675 G>A [p. Trp892*]) was identified in cilia and flagella-associated protein 65 (CFAP65) gene, which is primarily expressed in the testis. Another loss-of-function mutation of CFAP65 has been detected in a MMAF patient, and the orthologue of CFAP65 also plays a vital role in sperm motility in chickens. Our experimental observations on human subjects suggested that CFAP65 is involved in sperm flagellum structure and assembly and that loss-of-function mutations could lead to male infertility in humans by causing the MMAF phenotype.","variants":[{"Name":"NM_194302.4(CFAP65):c.2675G>A (p.Trp892Ter)","Chromosome":"2","Start":"219023352","Stop":"219023352","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":682656,"rule_based_match":true,"evidence_text":"c. 2675 G>A [p. Trp892*]","llm_judgment":"PRESENT","evidence":"c. 2675 G>A [p. Trp892*]","abstract_start":447,"abstract_end":471}]}
{"pmid":"29251008","title":"First Report of the Rare IVS-II-705 (T>G) β-Thalassemia Mutation in a Chinese Family.","abstract":"We have found an example of the mutation at the intronic region of the second intervening sequence of the β-globin gene, IVS-II-705 (T>G) (HBB: c.316-146T>G), in a Chinese family. The two subjects heterozygous for this mutation presented with typical β-thalassemia (β-thal) trait.","variants":[{"Name":"NM_000518.5(HBB):c.316-146T>G","Chromosome":"11","Start":"5225872","Stop":"5225872","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":44976,"rule_based_match":true,"evidence_text":"IVS-II-705 (T>G) (HBB: c.316-146T>G)","llm_judgment":"PRESENT","evidence":"IVS-II-705 (T>G) (HBB: c.316-146T>G)","abstract_start":121,"abstract_end":157}]}
{"pmid":"33600779","title":"A Novel Frameshift Mutation in the ITGB3 Gene Leading to Glanzmann's Thrombasthenia in a Saudi Arabian Family.","abstract":"Glanzmann's thrombasthenia (GT) is an autosomal recessive congenital bleeding disorder of platelet aggregation. Mutations in ITGA2B and ITGB3 genes result in quantitative and/or qualitative abnormalities of the glycoprotein receptor complex IIb/IIIa (integrin αIIbβ3), which in turn impairs platelet aggregation and lead to GT. In this study, whole genome single nucleotide polymorphism (SNP) genotyping as well as whole exome sequencing was performed in a large family segregating GT. Analysis of the genotypes localized the disease region to chromosome 17q21.2-q21.3. Filtration of whole exome data and candidate variants prioritization identified a pathogenic variant in the ITGB3 gene. The single nucleotide deletion variant (c.2113delC) in exon 13 of the ITGB3 gene is predicted to cause a frameshift and absence of vital C-terminal domains including the transmembrane helix and the cytoplasmic domain. Clinical variability of the bleeding phenotype in affected individuals with the same mutation suggests that other genetic and nongenetic factors are responsible for determining GT features.","variants":[{"Name":"NM_000212.3(ITGB3):c.2113del (p.Leu705fs)","Chromosome":"17","Start":"47302818","Stop":"47302818","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":959503,"rule_based_match":true,"evidence_text":"c.2113delC","llm_judgment":"PRESENT","evidence":"c.2113delC","abstract_start":730,"abstract_end":740}]}
{"pmid":"32758660","title":"Genotype-phenotype correlations of UBA2 mutations in patients with ectrodactyly.","abstract":"Interstitial 19q13.11 deletions are associated with ectrodactyly, which has recently been linked to loss-of-function of the UBA2 gene. We report a boy with a de novo frameshift mutation in UBA2 (c.612delA (p.(Glu205Lysfs*63)), presenting with ectrodactyly of the feet associated with learning difficulties and minor physical anomalies. We review genotype-phenotype correlations in patients with chromosomal 19q13.11 microdeletions compared to those with intragenic UBA2 mutations.","variants":[{"Name":"NM_005499.3(UBA2):c.612del (p.Glu205fs)","Chromosome":"19","Start":"34443873","Stop":"34443873","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1688831,"rule_based_match":true,"evidence_text":"c.612delA (p.(Glu205Lysfs*63))","llm_judgment":"PRESENT","evidence":"c.612delA (p.(Glu205Lysfs*63))","abstract_start":195,"abstract_end":225}]}
{"pmid":"23591138","title":"Clinical features in a large Iranian family with a limb-girdle congenital myasthenic syndrome due to a mutation in DPAGT1.","abstract":"Mutations in DPAGT1 are a newly recognised cause of congenital myasthenic syndrome. DPAGT1 encodes an early component of the N-linked glycosylation pathway. Initially mutations in DPAGT1 have been associated with the onset of the severe multisystem disorder - congenital disorder of glycosylation type 1J. However, recently it was established that certain mutations in this gene can cause symptoms restricted to muscle weakness resulting from defective neuromuscular transmission. We report four cases from a large Iranian pedigree with prominent limb-girdle weakness and minimal craniobulbar symptoms who harbour a novel mutation in DPAGT1, c.652C>T, p.Arg218Trp. This myasthenic syndrome may mimic myopathic disorders and is likely under-diagnosed.","variants":[{"Name":"NM_001382.4(DPAGT1):c.652C>T (p.Arg218Trp)","Chromosome":"11","Start":"119098479","Stop":"119098479","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1487162,"rule_based_match":true,"evidence_text":"c.652C>T, p.Arg218Trp","llm_judgment":"PRESENT","evidence":"c.652C>T, p.Arg218Trp","abstract_start":642,"abstract_end":663}]}
{"pmid":"27918309","title":"Intraoperative Presentation of Malignant Hyperthermia (Confirmed by RYR1 Gene Mutation, c.7522C>T; p.R2508C) Leads to Diagnosis of King-Denborough Syndrome in a Child With Hypotonia and Dysmorphic Features: A Case Report.","abstract":"We present the novel case report of a child with hypotonia and dysmorphic features who developed malignant hyperthermia (MH) intraoperatively. Neurology workup revealed the presence of a known causative ryanodine receptor (RYR1) mutation for MH, c.7522C>T; p.R2508C. Furthermore, the neurology workup diagnosed the child with King-Denborough syndrome (KDS). This particular mutation has never been documented in a patient with KDS. Atypical presentation of MH is more likely in patients with RYR1-related myopathy. A high index of suspicion for MH in children with myopathy is important. The MH hotline was helpful in the management of this patient when it was called after the initial dose of dantrolene. A neurology consult was essential for the diagnosis of KDS and future care.","variants":[{"Name":"NM_000540.3(RYR1):c.7522C>T (p.Arg2508Cys)","Chromosome":"19","Start":"38500898","Stop":"38500898","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76889,"rule_based_match":true,"evidence_text":"c.7522C>T; p.R2508C","llm_judgment":"PRESENT","evidence":"c.7522C>T; p.R2508C","abstract_start":246,"abstract_end":265}]}
{"pmid":"28662915","title":"A New Patient With Intermediate Severe Salla Disease With Hypomyelination: A Literature Review for Salla Disease.","abstract":"BACKGROUND: Likely pathogenic variants in SLC17A5 results in allelic disorders of free sialic acid metabolism including (1) infantile free sialic acid storage disease with severe global developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; (2) intermediate severe Salla disease with moderate to severe global developmental delay, hypotonia, and hypomyelination with or without coarse facial features, and (3) Salla disease with normal appearance, mild cognitive dysfunction, and spasticity.\nPATIENT DESCRIPTION: This five-year-old girl presented with infantile-onset severe global developmental delay, truncal hypotonia, and generalized dystonia following normal development during her first six months of life. Brain magnetic resonance imaging showed marked hypomyelination and a thin corpus callosum at age 19 months, both unchanged on follow-up at age 28 months. Urine free sialic acid was moderately elevated. Cerebrospinal fluid free sialic acid was marginally elevated. Sequencing of SLC17A5 revealed compound heterozygous likely pathogenic variants, namely, a known missense (c.291G>A) variant and a novel truncating (c.819+1G>A) variant, confirming the diagnosis of Salla disease at age 3.5 years.\nCONCLUSION: We report a new patient with intermediate severe Salla disease. Normal or marginally elevated urine or cerebrospinal fluid free sialic acid levels cannot exclude Salla disease. In patients with progressive global developmental delay and hypomyelination on brain magnetic resonance imaging, Salla disease should be included into the differential diagnosis.","variants":[{"Name":"NM_012434.5(SLC17A5):c.819+1G>A","Chromosome":"6","Start":"73635381","Stop":"73635381","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":357507,"rule_based_match":true,"evidence_text":"c.819+1G>A","llm_judgment":"PRESENT","evidence":"c.819+1G>A","abstract_start":1154,"abstract_end":1164}]}
{"pmid":"22018287","title":"2 Novel deletions of the sterol 27-hydroxylase gene in a Chinese Family with Cerebrotendinous Xanthomatosis.","abstract":"BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare lipid-storage disease. We investigated the clinic manifestation, histopathology and sterol 27-hydroxylase gene (CYP27A1) in a Chinese family with Cerebrotendinous Xanthomatosis (CTX).\nCASE PRESENTATION: A 36-year-old female with typical CTX clinical manifestation had Spindle-shaped lipid crystal clefts in xanthomas and \"onion-like demyelination\" in sural nerve. The patient was compound heterozygote carrying two deletions in exon 1 (c.73delG) and exon 2 (c.369_375delGTACCCA). The family memebers were carriers.\nCONCLUSIONS: A Chinese family with Cerebrotendinous Xanthomatosis had typical clinical manifestation. CYP27A1 mutations were found in the proband and all other family members.","variants":[{"Name":"NM_000784.4(CYP27A1):c.73del (p.Ala25fs)","Chromosome":"2","Start":"218782252","Stop":"218782252","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":76802,"rule_based_match":true,"evidence_text":"c.73delG","llm_judgment":"PRESENT","evidence":"c.73delG","abstract_start":495,"abstract_end":503}]}
{"pmid":"30046681","title":"Phenotype analysis and clinical management in a large family with a novel truncating mutation in","abstract":"BACKGROUND: Genetic variants in the <i>RASGRP2</i> gene encoding calcium and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) represent a new inherited bleeding disorder linked to major defects of platelet aggregation and activation of αIIbβ3 integrin. They are of major interest as CalDAG-GEFI is receiving attention as a potential target for antiplatelet therapy for prevention and treatment of cardiovascular disorders including arterial thrombosis and atherosclerosis.\nOBJECTIVES: To better understand the phenotypical and clinical profiles of patients with CalDAG-GEFI deficiency.\nPATIENTS: We report a five-generation family with a novel truncating CalDAG-GEFI mutation detailing clinical management and phenotypic variability.\nRESULTS: Patients IV.6 & IV.4 manifested with episodes of serious mucocutanous bleeding or bleeding after surgery not responding to platelet transfusion but responding well to recombinant Factor VIIa infusions. Their blood counts and coagulation parameters were normal but platelet aggregation to ADP and collagen was defective. Further work-up confirmed normal levels of αIIb and β3 in their platelets but decreased αIIbβ3 function. DNA analysis by whole exome sequencing within the BRIDGE-BPD consortium (Cambridge, UK), allowed us to highlight a homozygous c.1490delT predicted to give rise to a p.F497Sfs*22 truncating mutation near to the C-terminal domain of CalDAG-GEFI. Sanger sequencing confirmed that both patients were homozygous for the c.1490delT and 3 out of 4 close family members were heterozygous.\nCONCLUSIONS: A long-term prospective study is warranted for full clinical exploration of CalDAG-GEFI to understand the bleeding phenotyes and their management.","variants":[{"Name":"NM_001098671.2(RASGRP2):c.1490del (p.Phe497fs)","Chromosome":"11","Start":"64730117","Stop":"64730117","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":615449,"rule_based_match":true,"evidence_text":"c.1490del","llm_judgment":"PRESENT","evidence":"c.1490del","abstract_start":1321,"abstract_end":1330}]}
{"pmid":"23980586","title":"PIK3R1 mutations in SHORT syndrome.","abstract":"SHORT syndrome (OMIM 269880) is a rare autosomal-dominant disorder characterized by short stature, hyperextensibility of joints, hernias, ocular depression, ophthalmic anomalies (Rieger anomaly, posterior embryotoxon, glaucoma), teething delay, partial lipodystrophy, insulin resistance and facial dysmorphic signs. Heterozygous mutations in PIK3R1 were recently identified in 14 families with SHORT syndrome. Eight of these families had a recurrent missense mutation (c.1945C>T; p.Arg649Trp). We report on two unrelated patients with typical clinical features of SHORT syndrome and additional problems such as pulmonary stenosis and ectopic kidney. Analysis of PIK3R1 revealed the mutation c.1945C>T; p.Arg649Trp de novo in both patients. These two patients not only provide additional evidence that PIK3R1 mutations cause SHORT syndrome, but also broaden the clinical spectrum of this syndrome and further confirm that the amino acid exchange c.1945C>T; p.Arg649Trp is a hotspot mutation in this gene.","variants":[{"Name":"NM_181523.3(PIK3R1):c.1945C>T (p.Arg649Trp)","Chromosome":"5","Start":"68296301","Stop":"68296301","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75301,"rule_based_match":true,"evidence_text":"c.1945C>T; p.Arg649Trp","llm_judgment":"PRESENT","evidence":"c.1945C>T; p.Arg649Trp","abstract_start":469,"abstract_end":491}]}
{"pmid":"33333757","title":"Genetics of Hearing Impairment in North-Eastern Romania-A Cost-Effective Improved Diagnosis and Literature Review.","abstract":"BACKGROUND: We have investigated the main genetic causes for non-syndromic hearing impairment (NSHI) in the hearing impairment individuals from the North-Eastern Romania and proposed a cost-effective diagnosis protocol.\nMETHODS: MLPA followed by Sanger Sequencing were used for all 291 patients included in this study.\nRESULTS: MLPA revealed abnormal results in 141 cases (48.45%): 57 (40.5%) were c.35delG homozygous, 26 (18.44%) were c.35delG heterozygous, 14 (9.93%) were compound heterozygous and 16 (11.35%) had other types of variants. The entire coding region of <i>GJB2</i> was sequenced and out of 150 patients with normal results at MLPA, 29.33% had abnormal results: variants in heterozygous state: c.71G>A (28%), c.457G>A (20%), c.269T>C (12%), c.109G>A (12%), c.100A>T (12%), c.551G>C (8%). Out of 26 patients with c.35delG in heterozygous state, 38.46% were in fact compound heterozygous.\nCONCLUSIONS: We identified two variants: c.109G>A and c.100A>T that have not been reported in any study from Romania. MLPA is an inexpensive, rapid and reliable technique that could be a cost-effective diagnosis method, useful for patients with hearing impairment. It can be adaptable for the mutation spectrum in every population and followed by Sanger sequencing can provide a genetic diagnosis for patients with different degrees of hearing impairment.","variants":[{"Name":"NM_004004.6(GJB2):c.100A>T (p.Met34Leu)","Chromosome":"13","Start":"20189482","Stop":"20189482","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":793458,"rule_based_match":true,"evidence_text":"c.100A>T","llm_judgment":"PRESENT","evidence":"c.100A>T","abstract_start":773,"abstract_end":781},{"Name":"NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)","Chromosome":"13","Start":"20189313","Stop":"20189313","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":32055,"rule_based_match":true,"evidence_text":"c.269T>C","llm_judgment":"PRESENT","evidence":"c.269T>C","abstract_start":741,"abstract_end":749}]}
{"pmid":"31536828","title":"MED12 missense mutation in a three-generation family. Clinical characterization of MED12-related disorders and literature review.","abstract":"Mutations in MED12 gene have been described in association with syndromic and non-syndromic X-linked intellectual disability (XLID). Up to date at least three distinct XLID syndromes have been described: FG syndrome, Lujan-Fryns syndrome (LS) and Ohdo syndrome (OSMKB). In the last years, thanks to the massive use of next generation sequencing techniques (NGS) it has been possible to discover at least 16 others MED12 mutations and to expand the phenotype of MED12-related disorders. Here we report three subjects from a large non-consanguineous family presenting with a mild to severe ID, important speech delay, behavior problems, dysmorphic facial features and hearing loss. NGS allows us to detect the MED12 missense variant c.3883C > T (p.(Arg1295Cys)) carried by the three patients. This variant has been reported in 2016 by Hu et al. in one family from a big cohort of XLID families. This clinical report contributes to expanding the phenotype associated with MED12-mutations.","variants":[{"Name":"NM_005120.3(MED12):c.3883C>T (p.Arg1295Cys)","Chromosome":"X","Start":"71130050","Stop":"71130050","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":210563,"rule_based_match":true,"evidence_text":"c.3883C > T (p.(Arg1295Cys))","llm_judgment":"PRESENT","evidence":"c.3883C > T (p.(Arg1295Cys))","abstract_start":731,"abstract_end":759}]}
{"pmid":"23830518","title":"Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability.","abstract":"Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism.","variants":[{"Name":"NM_021942.6(TRAPPC11):c.2938G>A (p.Gly980Arg)","Chromosome":"4","Start":"183701783","Stop":"183701783","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":75097,"rule_based_match":true,"evidence_text":"c.2938G>A (p.Gly980Arg)","llm_judgment":"PRESENT","evidence":"c.2938G>A (p.Gly980Arg)","abstract_start":649,"abstract_end":672},{"Name":"NM_021942.6(TRAPPC11):c.1287+5G>A","Chromosome":"4","Start":"183684059","Stop":"183684059","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":75098,"rule_based_match":true,"evidence_text":"c.1287+5G>A","llm_judgment":"PRESENT","evidence":"c.1287+5G>A","abstract_start":773,"abstract_end":784}]}
{"pmid":"23449775","title":"'North Sea' progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation.","abstract":"We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.","variants":[{"Name":"NM_004287.5(GOSR2):c.430G>T (p.Gly144Trp)","Chromosome":"17","Start":"46935122","Stop":"46935122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39363,"rule_based_match":true,"evidence_text":"c.430G>T","llm_judgment":"PRESENT","evidence":"c.430G>T","abstract_start":1320,"abstract_end":1328}]}
{"pmid":"33668384","title":"New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the","abstract":"This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (<i>NMNAT1</i>) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel <i>NMNAT1</i> isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of <i>NMNAT1</i> and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.","variants":[{"Name":"NM_022787.4(NMNAT1):c.439+5G>T","Chromosome":"1","Start":"9981175","Stop":"9981175","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1038904,"rule_based_match":true,"evidence_text":"c.439+5G>T","llm_judgment":"PRESENT","evidence":"c.439+5G>T","abstract_start":416,"abstract_end":426},{"Name":"NM_022787.4(NMNAT1):c.299+526_*968dup","Chromosome":"1","Start":"9976248","Stop":"9976249","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CTGCACTCCAGCCTGGGTGACAGAGCGAGACTCCATCTCAAAAAAAAAAAAAAAAAAAGATGTTTGCTTGCTTGCTACTATGTGATACCACTGTTAGAAAATAGAGGAAGCCTGCCTGGGCTTTCTGTGCCCCAAATGAGAAAGGGAAAATTGCAAGAAGATGTTATTATCATCAGTCTTCCTAAGTATAAAAGAGACAGGCAGATAATTTAAGGAAGAGAAGCATCCAGTGCTGCTTGATCATGGACAGGCCTGATTCGTGTGCTGCTTCCATGACAGCATCTGGGCAGGGAGTCACAGATCTCTGTGCCCATACCTTTGAAGCAGTTCTAGTTAAGGGTTCAAAAACCAGAGTAAGTGACATCTAATTATTTCTCTTTTTTTTTTTTCTTTTTGAGACGGAGTCTCGCTCTGTCACCCAGGCTGGAGTGCAGTGGTGCATTCTCGGCTCACTGCGACCTCTGCCTCCTGGGTTCAAGCAATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGACTACAGGTGACTGCCACCACGCCCCGCTAATGTTTTTGTATTTTTAGTAGAGATGGGGTTCTACCTTGTTGGCCAGGCTGGTCTTGAACTTCTGACCTCAGGTGATCCACCTGTCTCAGCCTCCCAACACCTAATTATTTCTTTTCTTTTCTTTTTTTTTTTGAGATAGAGGTTCACTCTTGTTGCCCAAGCTGGAGTGCAATGGCATGATCTTGGCTCACTGCAACCTCTGCCTCCCGGGTTCAAGCCGTTCCCCTGCCTCAGCCTCCCAAGTAGCTGGGATTACAGGCGCCTGCCACCACGCCCGGCTAATTTTTGTATTTTTAGTAGAGCTGGGGTTTCACCCTGTTGGCCAGGCTGGTCTTGAACTCCTGACCTCAGGTGATCTGCCCATCTCGGGCCTCCCAAAGTGCGGGGATTACAGAGGTGAGCCACCGCACCTGGCTGACACCTAATTATCTCTTAATGTTATTTTGATTTTTTTAAACTTTATTTTCTTTTTTTTGTTGGAGATGGGGCCTCGCTATGTTGCCTATGCTGACTGATCTCAAACTCCTGGCCTCAAGCAATCCTCCCACCTAGGCCTCCCAAAGTGCTGGGATTACAAATGTGAGCTACCATGCCTGGCCTGTTGTTATCTTGAGTTTAAAATGAAAGGGCTTTCTGAAAAGCCTTTCTGTTTAGTATCTGTTCTTAGAGTTCTGAACTTTCCAGTGACTGACTGTATCATTTAGGGTTCAGACTAGGAAATAGAAACCCACTCTGGATATTTTAAGTGGAAAGAGATTTAAGTACTTAGGCAAAAAGTACTTAAAAGAGCTGAGGCCGGGCGTGGTAGCTCATGACTATAATCCCAGCACTTTGGGAGGCTGAGGCCGGCAGATCACCTGAGTCCAGTAGTTCAAGACAAGCCTGGCCAACATGGTGAAACCCTGTCTCTACTAAAAATACAAAATTAGCTGGGCCCATACCTGTAATCCCAGCTACTAGGGAGGCTGAGGCAGGAGAATTGCCTGAGCCTGGGAGGCAGAGGTTACGGTGAACTGAAATTGTGCCACTGCACTCCAGCCTGGGCAGCAGAATGAGACTGTCTCAAAAAACAACAACAAAAAAAAGTAAAAGGGCTGGAGAAGTGGAAGTCAGGGTCACTCCTCCGATGTTGCCGTCAGAGTTCAACAAACCAATTCCGCTTCTGCTGCTATTGAACTGTCTCAGTCTCCTGAAGTTGGTGACGGACAGTGGACTCCAGCGTCTAGCCACCACACCCACACTAGAAAGGATTACTGGCTATAAATAGCGCAATAATAGGATCAGGCCGGGCATGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCCGAGGTGGGTGGATCACCTGAGGTCAGGAGATCGAGACCACCCTGGCCAACATGGCAAACCCCGTCTCTACTAAAAATACAAAAATTAGCCAGGCGTGGTGGCACATGCCTATAGTCCCAGCTACTTGGGAGGCTGAGGTGGGAGAATCCCTTGAACCCGGGAGGTGGAGGTTGCAGTGAGCCGAGATTGCGCCACTGCACTCCAGCCTGGGTGACAGAGTGAGACTCCGTCTCAAAAAAAAAGATTACTTGTCAGGCTCCACAGTCCCAGGATGATGGCCTCTGTCCTCCTTCTGCCTTCCAAATCTCTCAGGAGAGAATCTCATTAGCAGAAATCGCAGTCAAGTCCACAGCCTGCTGCAAGGACCTCTGGGAAGTGTGTTGGGCAGGATTGGGCACTGAGTCAGTAGGAAGTATCTCACACAGTGATCTCTCAAGAGGACTTCCTTTTCAGACTTGGCAGGGAGAAGAGTCTCCACTGCTTGATGGCAAAAAATTCTCCCATGAGGGAGCAAGTTCCTGGGCCACAGCCCTACCCGACCCTCTGGCTTTATAGTAACCTTATTGCCCATTAAATAGTCAACTCAGCTGCTCAGAAGGGTTGGGATGTAGGGGAATAAAGGCCCACAGTTGGATCCCACAAGTGTAGTTGATGTTATTTGGGTAACATTGCACAGTTTGAAAACAGTGGGCACCCTGCTGCCAGCCCAGAATAGAGCTATACACAAATCCTGCTTAGGGCCCCTTCCTTTAAGGCCTCAGGCCCTTGCCGCTCTAGGACCTTCTCCTTGGCGTTCTGGTTCTTTGTCACAAGATTAAGCCACACTCTTCCATGGTCAAGAGTGTGGGCTCTGGACCAGACTGCTGGGGTTCAAGTCCTGGCTCTGCTATTAATACTTTTAAGTTAAATGACCTTAGGCAAATTAGTCAGTGTCCTCTGTCAATGGGGTAATAAACAATTCTGATATGAGAGATGAGCAGCACATTAAAACCAGAAGTATTTTCAGTGAAACTAGCTGCAAGGTGGCAGTAATATAGTCGCTTTGTAATAACCAAAATGTTCAGGCTGATCATGGTGGCTCACATCTATAGTCCCAGCACTTTGGGAGTCTGAGGCAGGAGGATTGCTTGAGGCCAGGAGTTCAAGACCAGTGTGGGCAACATAGTGAGACCTCATCTCTCCAAAAAACTAAAGTTAGCTGAACATGGTGGCACGTGCCTGTAGTCGCAGCTATCTGGGAGGCTGAGGCGGTAGGATCACTTGAGCCCAGGAGTTTTGGTTGCAGCGAGCTATGATTGTGCCACTGTGCTCCATCCTGGGCAATAGAGTGAGCCTGTGTCTCTGAAAAACAAACCAAAAAAACCCCAAAACATTCACTCAATCAAATTGTTATTGAGGCTGGGCGCAGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCTAGGCGGGCAGATCACAAGGTCAGGAGATCGAGACCATCCTGGCTAACATGGTGAAACCCTGTCTCTACTAAAAATACAGAAAAAATTAGCCGGGCGTGGTGGTGGGCGCCTGTAGTCCCAGCTACTCGGGAGGCTGAAGCAGGAGAATGGCGTGAACCTAGGAGACGGAGGTTGCAGTGAGCTGAGATCGTGCCACTGCACTCCAGCCTGGGCGACAGAGTGAGACTCCATCTCAAAAAAAAAAAAAAAAATTGTTATTGAATGCCTCCTCATAGACTCTGCTAGGAGCTGGAGTAGCAACTGTAAGCCTCCTTTCTCCTTCCCTTACGGAGATAATAATATTTATGATATAGGATGTTGAGAAGATTTTTTTTTTCTTTTGAGGCGGAGTTTTGCTCTTGTTGCCCAGGCTGGAGTGCAATAGCGCAATCATGGCTCACTGCAACCTCCACCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGATTATAGGCATGTGCCACCACACCCGGCTAATTTTCTATTTTTAGCAGAGACAGGGTTTCTCCATGTTGGTCAGGCTGTGTCTCGAACTCCTGACCTCAGGTGATCCACCCGCCTTGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACCACGCCCAGTCGAGAAGATTTTTAATTTTTTTTAGTCTTCCACAACAGTCATCTTATGTTGAGAAGACTTAATCAGATAATCCATGTAAAGGATTCAGTGTAATGTGTGGCATATGATAAATAATGTTGGCCAGGCACCTATAATCCCAGCACTTTGGGAGGCTGAGGCGGGCAGATCGCTTGAGGTCAGAAGTTCAAGACCAGCCTGGCCAACATGATGAAACCCCGTCACTACTAAAAATACAAAAAAAAATTGGCTGAGCGTGGTGGTGCGCCCCTGTAATCCCAGCTGCTCGGGAGGCTGAGGCAAGAGAATTGTTTGAACCCAGGAGCCAGAGGTTACAGTGAGCTGAGATCACACACTGCACTCAGCCTGGGCGTCAGAGCAAGACACCATCTCAAAATAATAAATAAATAAATAATGTTAATGATATTCTTTTTTTTTTCTTTTTTTGAGATGGAGTCTCACTCTGTCGCCCAGGTTGGAGTGCAGTGGTGCGGTCTTGGCTCACTGCAACCTCTGCCTCCCAGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGATTACAGGTGCCCGCCACCACACCCGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCGTGTTAGCCAGGATGGTCTCGATCTTCTGACCTCGTGATCCGCCCACCTCGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACTGTGCCCAGCTATAAATAATGTTAATGATATATTCTAATGGAGCATGTGAGAAAGAGAAATATTCTATTGTTTTGTTGTTTTATAGACACCATCAAGAGAAATTGGAGGCTAGTGACTGTGATCACCAGCAGAACTCACCTACTCTAGAAAGGCCTGGAAGGAAGAGGAAGTGGACTGAAACACAAGATTCTAGTCAAAAGAAATCCCTAGAGCCAAAAACAAAAGGTTTGTATGTTTTAGCAGGACCCACGGACTAGAGTTGATAAGATTCTGTAGCTGAGCAAACCCCTGTGTATTTTTTTTTTTTTAGATGGAGTCTCGCTCTATCACCCAGGCTGGAGTGCAGTGGCATGATCTCAGCTCACTGCAAGCTCTGCCTCCTGGGTTCATGCCATTCTCCTGCCTCAGCCTCCTGAGCAGCTGGGACTACAGGTGCCTGCCACCACGCCTGTCTAATTTGTTTGTATTTTTAGTAGAGACGGGGTTGCACCATGTTAGCCAGGATGGTCTTGATCTCCTGACCTCATGATCCGCCCACCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACAGCGCCTGGGCCTTATTTTTTTTGTTTTATAGAGATGGGGTCTCACTATTTTGGCCAGGTTGGTCTTGAACTCCTGGCCCCAAGCAGTCCTCCTGCCTTGGCCTCCCAAAGTGTTAGGATTACAGGTGTCAGCCACTATGCCTGGCCTTTATTTTCATTTTATATTGCATACTTGTGGGTGTCTGGAAAATGCCCCTTGTTAGTTGCATGAAGTGAAGGAGAATAAAAGGCACTTGGAGCTTATTTCTCCTGCAGTGGTCTCTAATCTTTGAGGTGTCCTGGGTCTCTTTTGGGAATCTGATTCTCATAAAATAAAAGCTCATAAAAACTGTGAACTGTCATTCTTTTTTTTTTTTTGAGACAGAGTTTTGCTCTTGTTGCCCAGGCTGGAGTGCGATGGCACAATCTCGGCTTACTGCAACCTCTGCCTCCCGAGTTCAAGTGATTCTCCTGCCTCAGCCTCTCAAGTATCTGGGGTTACAGGCGTGCGCCACCACACCCGGCTAATTTTGTATTTTTAGTAGAAACGGTATTTCACCATGTTGGTCAGGCTGGTCTCAAACTCCTGACCTCAAGTGATCTACCCGCCTCGGCCTCCCAGAGTGCTGGGATTACAGGCTAGAGCCACCGCACTCGGCCTAAGCCCTCATCCTTGAAAAGCACATACGTATCTTCATTTTGATACAGTGGGTTATTAGAAAAGTAAACCCCTTTCCACTTGGAGGAGGTAGAGGGGAAGAAAAAGCATACCCCAAAGCTCTGTTTTATTCTTCCCAGCTGTGCCAAAGGTCAAGCTGCTGTGTGGGGCAGATTTATTGGAGTCCTTTGCTGTTCCCAATTTGTGGAAGAGTGAAGACATCACCCAAATCGTGGCCAACTATGGGCTCATATGTGTTACTCGGGCTGGAAATGATGCTCAGAAGTTTATCTATGAATCGGATGTGCTGTGGAAACACCGGAGCAACATTCACGTGGTGAATGAATGGATCGCTAATGACATCTCATCCACAAAAATCCGGAGAGCCCTCAGAAGGGGCCAGAGCATTCGCTACTTGGTACCAGATCTTGTCCAAGAATACATTGAAAAGCATAATTTGTACAGCTCTGAGAGTGAAGACAGGAATGCTGGGGTCATCCTGGCCCCTTTGCAGAGAAACACTGCAGAAGCTAAGACATAGGAATTCTACAGCATGATATTTCAGACTTCCCATTTGGGGATCTGAAACAATCTGGGAGTTAATAACTGGGGAAAGAAGTTGTGATCTGTTGCCTAAACTAAAGCTTAAAAGTTTAGTAAAAATCGTCTGGGCACAGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCTGAGGCAGGTGGATCACGGGGTCAAGAGATCGAGACCATCCTGGCCAATATGGTGAAACCCCATCTCTACTAAAAATACAAAAATTAGCTGTGTGTGGTGGCACGTGCCTGTAGTCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATCACTTGACCCCAGGTGGTGGAGGTTGCAGTGAGCCAAGATTGCACCATTGCACTCCAGCCTGGCGACAGAGCAAGACTCTGTCTCAAAAAAAAAAAAAAATTTAGTAAAAATCAATGGTAAGCTAAAATAAGTTTTTGTTTGTTTATTTGTTTTTGAGATGGAGTCTCTACTAAAAATACAAAAAATTAGCCAGGCATGGTGCCGCATAACTATAATCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCACAGGTTCCAGTGAGCCAAGGTTGTGCCACTGCACTCCAGCCTGGGCAAAAAAGCAAAACTCCATCTCAAAGAGAAAAAAAAAAAAGACCGGGTGTGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCCTAAGTGGGTGGATCACGTGAGGTCAAGAGTTCAAGACCAGCCTGGCCAATATGGTGAAACCCCATCTCTACTAAGAATACAAAAAATTAGCTGAGCATGGTGGTGGGCTCCTGTAGTCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATCGCTTGAACCTGGGAGGCAGAGGTTGCAGTAAGCCAAGATCGTGCCAT","allel_id":1038903,"rule_based_match":true,"evidence_text":"c.299+526_*968dup","llm_judgment":"PRESENT","evidence":"c.299+526_*968dup","abstract_start":431,"abstract_end":448}]}
{"pmid":"22507243","title":"Paramyotonia congenita: from clinical diagnosis to in silico protein modeling analysis.","abstract":"BACKGROUND: Paramyotonia congenita (PMC) is an autosomal dominant disorder characterized by cold- or exercise-induced myotonia. PMC is caused by a mutation in SCN4A which encodes the α-subunit of the skeletal muscle sodium channel.\nMETHODS: The patient was an 11-year-old Japanese girl who was diagnosed as having PMC. To confirm the diagnosis, an orbital ice-pack test and blinking tests were performed. Next, to identify the mutation, genetic analysis of SCN4A was performed. Finally, to evaluate the mutation effect on the protein structure, in silico protein modeling analysis was performed.\nRESULTS: Cold- and exercise-induced myotonia was reproduced in the patient with non-invasive bedside tests: ice-pack and blinking tests. In the genetic analysis, a missense mutation, c.4343G>A in SCN4A, was identified, which may result in an arginine to histidine substitution at 1448 in the protein sequence (p.Arg1448His). According to the protein modeling analysis, the mutation neutralized the positive electrostatic charge at 1448 in the DIV/S4 segment and disrupted the beginning of the helical structure in the DIV/S3-S4 linker of the SCN4A protein.\nCONCLUSIONS: Diagnostic physical interventions in the patient confirmed the phenotype presentation consistent with PMC, and the in silico protein modeling analysis of p.Arg1448His predicted structural changes which can affect function of the protein. All the data confirmed the diagnosis of PMC in the patient and added to existing literature emphasizing the important role of arginine residue at 1448.","variants":[{"Name":"NM_000334.4(SCN4A):c.4343G>A (p.Arg1448His)","Chromosome":"17","Start":"63941939","Stop":"63941939","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20938,"rule_based_match":true,"evidence_text":"c.4343G>A in SCN4A","llm_judgment":"PRESENT","evidence":"c.4343G>A in SCN4A","abstract_start":779,"abstract_end":797}]}
{"pmid":"27236920","title":"A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome.","abstract":"Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.","variants":[{"Name":"NM_005631.5(SMO):c.1234C>T (p.Leu412Phe)","Chromosome":"7","Start":"129206557","Stop":"129206557","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":245206,"rule_based_match":true,"evidence_text":"c.1234C>T [p.Leu412Phe]","llm_judgment":"PRESENT","evidence":"c.1234C>T [p.Leu412Phe]","abstract_start":728,"abstract_end":751}]}
{"pmid":"30820151","title":"A novel intronic mutation of","abstract":"Purpose: To identify the genetic basis for retinitis pigmentosa (RP) in a cohort of Jewish patients from Caucasia.\nMethods: Patients underwent a detailed ophthalmic evaluation, including funduscopic examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potentials (VEP). Genetic analysis was performed with a combination of whole exome sequencing (WES) and Sanger sequencing. Bioinformatic analysis of the WES results was performed via a customized pipeline. Pathogenicity of the identified intronic variant was evaluated in silico using the web tool Human Splicing Finder, and in vitro, using a minigene-based splicing assay. Linkage disequilibrium (LD) analysis was used to demonstrate a founder effect, and the decay of LD over generations around the mutation in Caucasus Jewish chromosomes was modeled to estimate the age of the most recent common ancestor.\nResults: In eight patients with RP from six unrelated families, all of Caucasus Jewish ancestry, we identified a novel homozygous intronic variant, located at position -9 of <i>PDE6B</i> intron 15. The c.1921-9C>G variant was predicted to generate a novel acceptor splice site, nine bases upstream of the original splice site of intron 15. In vitro splicing assay demonstrated that this novel acceptor splice site is used instead of the wild-type site, leading to an 8-bp insertion into exon 16, which is predicted to cause a frameshift. The presence of a common ancestral haplotype in mutation-bearing chromosomes was compatible with a founder effect.\nConclusions: The <i>PDE6B</i> c.1921-9C>G intronic mutation is a founder mutation that accounts for at least 40% (6/15 families) of autosomal recessive RP among Caucasus Jews. This result is highly important for molecular diagnosis, carrier screening, and genetic counseling in this population.","variants":[{"Name":"NM_000283.4(PDE6B):c.1921-9C>G","Chromosome":"4","Start":"663761","Stop":"663761","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":800688,"rule_based_match":true,"evidence_text":"c.1921-9C>G","llm_judgment":"PRESENT","evidence":"c.1921-9C>G","abstract_start":1157,"abstract_end":1168}]}
{"pmid":"27824213","title":"Combined coagulation factor VIII and factor IX deficiency (CDF8F9) in a patient from Lithuania.","abstract":"Haemophilia A (FVIII deficiency) and haemophilia B (FIX deficiency) are X-linked inherited bleeding disorders. It is a very rare event to identify both haemophilias in the same patient. So far, only two families with such combination are reported in the literature worldwide supported by genetic background.\nPATIENTS AND METHODS: Evaluation of clinical data, determination of FVIII and FIX levels and genetic analysis of F8 and F9 genes by direct sequencing.\nRESULTS: We report on a patient having severe haemophilia B (FIX:C <1 IU dl<sup>-1</sup>) and mild haemophilia A (FVIII:C 18 IU dl<sup>-1</sup> ). FIX deficiency was known since childhood, whereas mild haemophilia A was confirmed at the age of 42 due to unexpected bleeding complications after dental extraction despite adequate substitution with plasma derived FIX concentrate. F9 gene analysis showed a point mutation in exon 2 (c.223C>T, p.R75X), whereas F8 gene analysis revealed a point mutation in exon 4 (c.545A>C, p.D182A). The mother of the patient was heterozygous for F8 mutation, but not for F9 mutation suggesting a de novo F9 mutation. Accidentally, further family from Germany with mild Haemophilia A was identified to have the same F8 mutation. F8 Haplotype analysis revealed that the p.D182A mutation most likely represents a founder mutation with common ancestors of the German and the Lithuanian family.\nCONCLUSIONS: Our results confirm the rare event of Haemophilia A and haemophilia B in the same patient originating from two distinct genetic defects in F8 and F9 genes.","variants":[{"Name":"NM_000133.4(F9):c.223C>T (p.Arg75Ter)","Chromosome":"X","Start":"139537144","Stop":"139537144","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25611,"rule_based_match":true,"evidence_text":"c.223C>T, p.R75X","llm_judgment":"PRESENT","evidence":"c.223C>T, p.R75X","abstract_start":890,"abstract_end":906}]}
{"pmid":"26971647","title":"Monogenic form of diabetes mellitus due to HNF4α mutation (MODY-1) - the first case in Hungary","abstract":"The classification of diabetes mellitus in adolescents and young adults is often difficult. The diagnosis of the monogenic form of diabetes may have substantial influence on quality of life, prognosis and the choice of the appropriate treatment of affected patients. Among MODY (maturity-onset of diabetes in the young) MODY-1 is rarely detected, only 13 families were described in 2000, and 103 different mutations in 173 families were known in 2013 worldwide. The authors present the first Hungarian case of a monogenic form of diabetes due to HNF4α mutation (MODY-1). The diabetes of the index patient No. 1 (42-year-old woman with insulin treated diabetes) was diagnosed as gestational diabetes at age of 20 when she was treated with diet only. Later, insulin treatment has been initiated when marked hyperglycaemia was detected during an episode of acute pneumonia at age of 26. The diabetes of the index patient No. 2 (20-year-old daughter of the index patient No. 1, treated also with insulin) was diagnosed as type 2 diabetes at age of 13 and the patient was treated with diet only. Later the classification was modified to type 1 and insulin therapy was initiated at age of 14. The manifestation of diabetes, the familial occurrence and the low dose insulin requirement were suggestive for monogenic diabetes. Using molecular genetic method a mutation (c.869G>A, p.R290H) of HNF4α gene was found and MODY-1 was diagnosed in both cases. Insulin therapy was switched to treatment with low dose sulfanylurea and an excellent glycaemic control was achieved and sustained at follow-up of 1-year. No further positive cases were found during screening of other family members.","variants":[{"Name":"NM_175914.5(HNF4A):c.869G>A (p.Arg290His)","Chromosome":"20","Start":"44424060","Stop":"44424060","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":793843,"rule_based_match":true,"evidence_text":"c.869G>A, p.R290H","llm_judgment":"PRESENT","evidence":"c.869G>A, p.R290H","abstract_start":1362,"abstract_end":1379}]}
{"pmid":"32869858","title":"EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay.","abstract":"In recent years, several genes have been implicated in the variable disease presentation of global developmental delay (GDD) and intellectual disability (ID). The endoplasmic reticulum membrane protein complex (EMC) family is known to be involved in GDD and ID. Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders. EMC10 is a bone marrow-derived angiogenic growth factor that plays an important role in infarct vascularization and promoting tissue repair. However, this gene has not been previously associated with human disease. Herein, we describe a Saudi family with two individuals segregating a recessive neurodevelopmental disorder. Both of the affected individuals showed mild ID, speech delay, and GDD. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify candidate genes. Further, to elucidate the functional effects of the variant, quantitative real-time PCR (RT-qPCR)-based expression analysis was performed. WES revealed a homozygous splice acceptor site variant (c.679-1G>A) in EMC10 (chromosome 19q13.33) that segregated perfectly within the family. RT-qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients, indicating the pathogenicity of the identified variant. For the first time in the literature, the EMC10 gene variant was associated with mild ID, speech delay, and GDD. Thus, this gene plays a key role in developmental milestones, with the potential to cause neurodevelopmental disorders in humans.","variants":[{"Name":"NM_206538.4(EMC10):c.679-1G>A","Chromosome":"19","Start":"50482148","Stop":"50482148","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1052619,"rule_based_match":true,"evidence_text":"c.679-1G>A","llm_judgment":"PRESENT","evidence":"c.679-1G>A","abstract_start":1105,"abstract_end":1115}]}
{"pmid":"26763875","title":"Identification of a novel mutation confirms the implication of IFT172 (BBS20) in Bardet-Biedl syndrome.","abstract":"Bardet-Biedl syndrome (BBS; MIM 209900) is a recessive heterogeneous ciliopathy characterized by retinitis pigmentosa (RP), postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. So far, 20 BBS genes have been identified, with the last reported ones being found in one or very few families. Whole-exome sequencing was performed in a consanguineous family in which two affected children presented typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism and cognitive impairment) without any mutation identified in known BBS genes at the time of the study. We identified a homozygous splice-site mutation (NM_015662.2: c.4428+3A>G) in both affected siblings in the last reported BBS gene, namely, Intraflagellar Transport 172 Homolog (IFT172). Familial mutation segregation was consistent with autosomal recessive inheritance. IFT172 mutations were initially reported in Jeune and Mainzer-Saldino syndromes. Recently, mutations have also been found in isolated RP and Bardet-Biedl-like ciliopathy. This is the second report of IFT172 mutations in BBS patients validating IFT172 as the twentieth BBS gene (BBS20). Moreover, another IFT gene, IFT27, was already associated with BBS, confirming the implication of IFT genes in the pathogenesis of BBS.","variants":[{"Name":"NM_015662.3(IFT172):c.4428+3A>G","Chromosome":"2","Start":"27448912","Stop":"27448912","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1182186,"rule_based_match":true,"evidence_text":"NM_015662.2: c.4428+3A>G","llm_judgment":"PRESENT","evidence":"NM_015662.2: c.4428+3A>G","abstract_start":673,"abstract_end":697}]}
{"pmid":"23335937","title":"High-resolution melting analysis of the common c.1905+1G>A mutation causing dihydropyrimidine dehydrogenase deficiency and lethal 5-fluorouracil toxicity.","abstract":"Dihydropyrimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with life-threatening toxicity following exposure to the fluoropyrimidine drugs 5-fluorouracil (5-FU) and capecitabine (CAP), widely used for the treatment of colorectal cancer and other solid tumors. The most prominent loss-of-function allele of the DPYD gene is the splice-site mutation c.1905+1G>A. In this study we report the case of a 73-year old woman with metastatic colorectal cancer who died from drug-induced toxicity after the first cycle of 5-FU-containing chemotherapy. Her symptoms included severe neutropenia, thrombocytopenia, mucositis and diarrhea; she died 16 days later despite intensive care measures. Post-mortem genetic analysis revealed that the patient was homozygous for the c.1905+1G>A deleterious allele and several family members consented to being screened for this mutation. This is the first report in Spain of a case of 5-FU-induced lethal toxicity associated with a genetic defect that results in the complete loss of the DPD enzyme. Although the frequency of c.1905+1G>A carriers in the white population ranges between 1 and 2%, the few data available for the Spanish population and the severity of this case prompted us to design a genotyping procedure to prevent future toxic effects of 5-FU/CAP. Since our group had previously developed a high-resolution melting (HRM) assay for the simultaneous detection of KRAS, BRAF, and/or EGFR somatic mutations in colorectal and lung cancer patients considered for EGFR-targeted therapies, we included the DPYD c.1905+1G>A mutation in the screening test that we describe herein. HRM provides a rapid, sensitive, and inexpensive method that can be easily implemented in diagnostic settings for the routine pre-therapeutic testing of a gene mutation panel with implications in the pharmacologic treatment.","variants":[{"Name":"NM_000110.4(DPYD):c.1905+1G>A","Chromosome":"1","Start":"97450058","Stop":"97450058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15471,"rule_based_match":true,"evidence_text":"c.1905+1G>A","llm_judgment":"PRESENT","evidence":"c.1905+1G>A","abstract_start":379,"abstract_end":390}]}
{"pmid":"24668509","title":"Novel homozygous DEAF1 variant suspected in causing white matter disease, intellectual disability, and microcephaly.","abstract":"DEAF1 encodes a transcriptional binding factor and is a regulator of serotonin receptor 1A. Its protein has a significant expression in the neurons of different brain regions and is involved in early embryonic development. In addition, its role in neural tube development is evident from the knockout mouse as many homozygotes have exencephaly. Heterozygous mutations of this gene have been linked to intellectual disability in addition to the gene's involvement in major depression, suicidal tendencies, and panic disorder. In this clinical report, we describe two children from a consanguineous family with intellectual disability, microcephaly, and hypotonia. The brain MRI of both patients showed bilateral and symmetrical white matter abnormalities, and one of the patients had a seizure disorder. Using whole exome sequencing combined with homozygosity mapping, a homozygous p.R226W (c.676C>T) mutation in DEAF1 was found in both patients. Furthermore, sequencing analysis confirmed complete segregation in tested family members and absence of the mutation in control cohort (n = 650). The mutation is located in a highly conserved structural domain that mediates DNA binding and therefore regulates transcriptional activity of its target molecules. This study indicates, for the first time to our knowledge, a hereditary role of DEAF1 in white matter abnormalities, microcephaly and syndromic intellectual disability.","variants":[{"Name":"NM_021008.4(DEAF1):c.676C>T (p.Arg226Trp)","Chromosome":"11","Start":"686986","Stop":"686986","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":153719,"rule_based_match":true,"evidence_text":"c.676C>T","llm_judgment":"PRESENT","evidence":"c.676C>T","abstract_start":890,"abstract_end":898}]}
{"pmid":"23788959","title":"Prevalence of the BRCA1 c.68_69delAG (BIC: 185delAG) mutation in women with breast cancer from north-central Poland and a review of the literature on other regions of the country.","abstract":"AIM OF THE STUDY: Germline mutations in BRCA tumor suppressor genes are strongly associated with breast and ovarian cancer. The lifetime risk of these cancers in women with BRCA1 mutation is 84% and 27%, respectively. Studies on the prevalence of BRCA1 c.68_69delAG congenital mutation, the most frequent in Ashkenazi Jews, among women with breast cancer from north-central Poland and review of the literature on other regions of the country. Evaluation of the c.68_69delAG association with breast cancer risk, with respect to women's age at diagnosis and family history of cancer.\nMATERIAL AND METHODS: 252 women with breast cancer, without any of the mutations c.5266dupC, c.181T > G, or c.4034delA, regardless of histological type and family history of cancer. The mutation was detected using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) assay and confirmed by sequence analysis.\nRESULTS: The c.68_69delAG mutation was disclosed in one out of the 252 women (0.4%), who had been diagnosed with breast cancer at age 43. Family investigations revealed the presence of c.68_69delAG also in the patient's mother, diagnosed with breast cancer at age 68. Sequence analysis confirmed the heterozygous status of the mutation, and family investigation its hereditary character. In the group of families with breast cancer history 1.4% frequency of c.68_69delAG was shown.\nCONCLUSIONS: Among families with breast cancer aggregation, originating from north-central Poland, c.68_69delAG is a rare BRCA1 alteration, similarly to other central regions of the country, investigated by other authors. However, in northern, north-western and south-western parts of Poland, it occurs 2-4 times more frequently than in our region.","variants":[{"Name":"NM_007294.4(BRCA1):c.68_69del (p.Glu23fs)","Chromosome":"17","Start":"43124028","Stop":"43124029","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":32701,"rule_based_match":true,"evidence_text":"c.68_69delAG","llm_judgment":"PRESENT","evidence":"c.68_69delAG","abstract_start":253,"abstract_end":265}]}
{"pmid":"20564469","title":"Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients.","abstract":"Ectopia lentis (EL) is genetically heterogeneous with both autosomal-dominant and -recessive forms. The dominant disorder can be caused by mutations in FBN1, at the milder end of the type-1 fibrillinopathies spectrum. Recently in a consanguineous Jordanian family, recessive EL was mapped to locus 1q21 containing the ADAMTSL4 gene and a nonsense mutation was found in exon 11 (c.1785T>G, p.Y595X). In this study, 36 consecutive probands with EL who did not fulfill the Ghent criteria for MFS were screened for mutations in FBN1 and ADAMTSL4. Causative FBN1 mutations were identified in 23/36 (64%) of probands while homozygous or compound heterozygous ADAMTSL4 mutations were identified in 6/12 (50%) of the remaining probands. Where available, familial screening of these families confirmed the mutation co-segregated with the EL phenotype. This study confirms that homozygous mutations in ADAMTSL4 are associated with autosomal-recessive EL in British families. Furthermore; the first compound heterozygous mutation is described resulting in a PTC and a missense mutation in the PLAC (protease and lacunin) domain. The identification of a causative mutation in ADAMTSL4 may allow the exclusion of Marfan syndrome in these families and guide the clinical management, of particular relevance in young children affected by EL.","variants":[{"Name":"NM_019032.6(ADAMTSL4):c.1785T>G (p.Tyr595Ter)","Chromosome":"1","Start":"150556974","Stop":"150556974","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":16388,"rule_based_match":true,"evidence_text":"c.1785T>G, p.Y595X","llm_judgment":"PRESENT","evidence":"c.1785T>G, p.Y595X","abstract_start":378,"abstract_end":396}]}
{"pmid":"32616716","title":"A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features.","abstract":"Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients' hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients.","variants":[{"Name":"NM_139057.4(ADAMTS17):c.3068G>A (p.Cys1023Tyr)","Chromosome":"15","Start":"99976104","Stop":"99976104","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":323927,"rule_based_match":true,"evidence_text":"c.3068 G > A, p.C1023Y","llm_judgment":"PRESENT","evidence":"c.3068 G > A, p.C1023Y","abstract_start":596,"abstract_end":618}]}
{"pmid":"26683566","title":"Identification of a GJA3 Mutation in a Large Family with Bilateral Congenital Cataract.","abstract":"The congenital cataract has been a clinically important cause of impaired vision development, making up about 10% of the cases of childhood blindness. Mutations of more than 40 genes have been identified causing congenital cataract with Mendelian inheritance, which indicated that it has an extremely high genetic heterogeneity. In this study, we recruited a large congenital cataract family and identified a missense mutation (c.143A>G: p.E48G) within gap junction protein alpha-3 (GJA3) gene in the proband using whole exome sequencing. Subsequent Sanger sequencing of this mutation in all family members revealed that this mutation cosegregated with the phenotype in the family with full penetrance. Our study identified a mutation in GJA3 that correlated with congenital cataract phenotype, which was not reported previously, and would be of benefit to the diagnosis of this genetic disorder. This finding expands the mutation spectrum of GJA3 and provides useful information for further study of the molecular pathogenesis of congenital cataract.","variants":[{"Name":"NM_021954.4(GJA3):c.143A>G (p.Glu48Gly)","Chromosome":"13","Start":"20143146","Stop":"20143146","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3412473,"rule_based_match":true,"evidence_text":"c.143A>G: p.E48G","llm_judgment":"PRESENT","evidence":"c.143A>G: p.E48G","abstract_start":428,"abstract_end":444}]}
{"pmid":"35662016","title":"Identification of novel pathogenic variants in the GCDH gene and assessment of neurodevelopmental outcomes in 24 children with glutaric aciduria type 1.","abstract":"AIM: To evaluate the pathogenic variants in GCDH gene and to assess the neurodevelopmental outcomes in children with Glutaric aciduria type 1 (GA-1).\nMETHOD: Cross-sectional observational study between January 2019 and June 2020 in consecutive North Indian children with a clinical and biochemical suspicion of GA-1. Variants in the coding regions of GCDH gene were identified through Sanger sequencing. Neurodevelopmental and quality of life assessment was done using standardized scales.\nRESULTS: 24 children with GA-1 were identified. The median age at diagnosis was 12 months and the median delay in diagnosis was 3 months. Genetic analysis was done in 14 cases. It revealed 12 variants (11 missense and one nonsense) from 13 patients. Most of the pathogenic variants were in exon 9 and exon 5. Three novel variants were identified in three patients: two missense variants c.169G > A (p.Glu57Lys), c.1048T > C (p.Cys350Arg) and one nonsense variant c.331C > T (p.Lys111Ter). On neurodevelopmental assessment, majority of children with GA-1 were non ambulatory (62.5%), had limited hand skills (58.3%) and impaired communication (58.3%). Overall, poor global development was noted in 43.7%. A pre-existing developmental delay was significantly associated with impaired communication skills (p = 0.03), and the number of episodes of encephalopathy were significantly associated with impaired gross motor skill (p = 0.02). Presence of encephalopathy was significantly associated with poor performance in social emotional (p = 0.01) and cognitive (p = 0.03) domains of Developmental Profile-III scale and development of severe dystonia (p = 0.01).\nCONCLUSION: Our findings highlight the clinical, biochemical, radiological and genetic spectrum of GA-1 in children in North India and report the presence of novel pathogenic variations.","variants":[{"Name":"NM_000159.4(GCDH):c.1048T>C (p.Cys350Arg)","Chromosome":"19","Start":"12897394","Stop":"12897394","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2890714,"rule_based_match":true,"evidence_text":"c.1048T > C (p.Cys350Arg)","llm_judgment":"PRESENT","evidence":"c.1048T > C (p.Cys350Arg)","abstract_start":902,"abstract_end":927},{"Name":"NM_000159.4(GCDH):c.169G>A (p.Glu57Lys)","Chromosome":"19","Start":"12891872","Stop":"12891872","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2852735,"rule_based_match":true,"evidence_text":"c.169G > A (p.Glu57Lys)","llm_judgment":"PRESENT","evidence":"c.169G > A (p.Glu57Lys)","abstract_start":877,"abstract_end":900}]}
{"pmid":"27519304","title":"CIT, a gene involved in neurogenic cytokinesis, is mutated in human primary microcephaly.","abstract":"Autosomal recessive primary microcephaly (MCPH) is a static neurodevelopmental disorder characterized by congenital small head circumference and non-progressive intellectual disability without additional severe brain malformations. MCPH is a genetically heterogeneous disorder. Sixteen genes (MCPH1-MCPH16) have been discovered so far, mutations thereof lead to autosomal recessive primary microcephaly. In a family, segregating MCPH in an autosomal recessive manner, genome-wide homozygosity mapping mapped a disease locus to 16.9-Mb region on chromosome 12q24.11-q24.32. Following this, exome sequencing in three affected individuals of the family discovered a splice site variant (c.753+3A>T) in citron kinase (CIT) gene, segregating with the disorder in the family. CIT co-localizes to the midbody ring during cytokinesis, and its loss of expression results in defects in neurogenic cytokinesis in both humans and mice. Splice site variant in CIT, identified in this study, is predicted to abolish splice donor site. cDNA sequence of an affected individual showed retention of an intron next to the splice donor site. The study, presented here, revealed the first variant in the CIT causing MCPH in the family.","variants":[{"Name":"NM_001206999.2(CIT):c.753+3A>T","Chromosome":"12","Start":"119832768","Stop":"119832768","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":248606,"rule_based_match":true,"evidence_text":"c.753+3A>T","llm_judgment":"PRESENT","evidence":"c.753+3A>T","abstract_start":684,"abstract_end":694}]}
{"pmid":"18716613","title":"The mutation spectrum in RECQL4 diseases.","abstract":"Mutations in the RECQL4 gene can lead to three clinical phenotypes with overlapping features. All these syndromes, Rothmund-Thomson (RTS), RAPADILINO and Baller-Gerold (BGS), are characterized by growth retardation and radial defects, but RAPADILINO syndrome lacks the main dermal manifestation, poikiloderma that is a hallmark feature in both RTS and BGS. It has been previously shown that RTS patients with RECQL4 mutations are at increased risk of osteosarcoma, but the precise incidence of cancer in RAPADILINO and BGS has not been determined. Here, we report that RAPADILINO patients identified as carriers of the c.1390+2delT mutation (p.Ala420_Ala463del) are at increased risk to develop lymphoma or osteosarcoma (6 out of 15 patients). We also summarize all the published RECQL4 mutations and their associated cancer cases and provide an update of 14 novel RECQL4 mutations with accompanying clinical data.","variants":[{"Name":"NM_004260.4(RECQL4):c.1390+2del","Chromosome":"8","Start":"144515324","Stop":"144515324","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":71037,"rule_based_match":true,"evidence_text":"c.1390+2delT","llm_judgment":"PRESENT","evidence":"c.1390+2delT","abstract_start":619,"abstract_end":631}]}
{"pmid":"24127073","title":"A 1,100-year-old founder effect mutation in IL12B gene is responsible for Mendelian susceptibility to mycobacterial disease in Tunisian patients.","abstract":"Mendelian susceptibility to mycobacterial disease (MSMD) is a rare disorder predisposing apparently healthy individuals to infections caused by weakly virulent mycobacteria such as bacille Calmette-Guerin (BCG), environmental mycobacteria, and poorly virulent Salmonella strains. IL-12p40 deficiency is the first reported human disease due to a cytokine gene defect and is one of the deficiencies that cause MSMD. Nine mutant alleles only have been identified in the IL12B gene, and three of them are recurrent mutations due to a founder effect in specific populations. IL-12p40 deficiency has been identified especially in countries where consanguinity is high and where BCG vaccination at birth is universal. We investigated, in such settings, the clinical, cellular, and molecular features of six IL-12p40-deficient Tunisian patients having the same mutation in IL12B gene (c.298_305del). We found that this mutation is inherited as a common founder mutation arousing ~1,100 years ago. This finding facilitates the development of a preventive approach by genetic counseling and prenatal diagnosis especially in affected families.","variants":[{"Name":"NM_002187.3(IL12B):c.298_305del (p.Ser100fs)","Chromosome":"5","Start":"159323113","Stop":"159323120","ReferenceAlleleVCF":"CAGGAGCGA","AlternateAlleleVCF":"C","allel_id":181494,"rule_based_match":true,"evidence_text":"c.298_305del","llm_judgment":"PRESENT","evidence":"c.298_305del","abstract_start":877,"abstract_end":889}]}
{"pmid":"26252091","title":"Genetic and prenatal diagnosis for a Chinese family with primary carnitine deficiency","abstract":"OBJECTIVE: To identify potential mutation of SLC22A5 gene in a 5-month-old boy affected with primary carnitine deficiency and provide genetic counseling and prenatal diagnosis for the members of his family.\nMETHODS: DNA was extracted from peripheral blood samples derived from the proband, his parents and elder sister, as well as amniotic fluid from his pregnant mother. All of the 10 exons of the SLC22A5 gene were amplified by PCR and subjected to Sanger sequencing. The amniotic fluid sample was also subjected to G-banded karyotyping and multiplex ligation-dependent probe amplification (MLPA).\nRESULTS: A homozygous mutation c.760C>T (p.R254X) of the SLC22A5 gene was detected in the proband. Heterozygous mutation c.760C>T (p.R254X) was also found in other family members including the fetus. The karyotyping and chromosomal microdeletion testing for the amniotic fluid sample were both normal.\nCONCLUSION: The newly identified homozygous nonsense c.760C>T (p.R254X) mutation of the SLC22A5 gene probably underlies the primary carnitine deficiency of the proband. Genetic counseling and prenatal diagnosis have been provided for this family.","variants":[{"Name":"NM_003060.4(SLC22A5):c.760C>T (p.Arg254Ter)","Chromosome":"5","Start":"132385435","Stop":"132385435","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21465,"rule_based_match":true,"evidence_text":"c.760C>T (p.R254X)","llm_judgment":"PRESENT","evidence":"c.760C>T (p.R254X)","abstract_start":631,"abstract_end":649}]}
{"pmid":"23158871","title":"Juvenile-onset motor neuron disease caused by novel mutations in β-hexosaminidase.","abstract":"A 12 year-old female presented with a seven-year history of progressive muscle weakness, atrophy, tremor and fasciculations. Cognition was normal. Rectal biopsy revealed intracellular storage material and biochemical testing indicated low hexosaminidase activity consistent with juvenile-onset G(M2)-gangliosidosis. Genetic evaluation revealed compound heterozygosity with two novel mutations in the hexosaminidase β-subunit (c.512-3 C>A and c.1613+15_1613+18dup). Protein analysis was consistent with biochemical findings and indicated only a small portion of β-subunits were properly processed. These results provide additional insight into juvenile-onset G(M2)-gangliosidoses and further expand the number of β-hexosaminidase mutations associated with motor neuron disease.","variants":[{"Name":"NM_000521.4(HEXB):c.1613+15_1613+18dup","Chromosome":"5","Start":"74720760","Stop":"74720761","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TTAAG","allel_id":543913,"rule_based_match":true,"evidence_text":"c.1613+15_1613+18dup","llm_judgment":"PRESENT","evidence":"c.1613+15_1613+18dup","abstract_start":442,"abstract_end":462},{"Name":"NM_000521.4(HEXB):c.512-3C>A","Chromosome":"5","Start":"74696690","Stop":"74696690","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":543730,"rule_based_match":true,"evidence_text":"c.512-3 C>A","llm_judgment":"PRESENT","evidence":"c.512-3 C>A","abstract_start":426,"abstract_end":437}]}
{"pmid":"26365340","title":"Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis.","abstract":"Arthrogryposis multiplex congenita (AMC) is characterized by the presence of multiple joint contractures resulting from reduced or absent fetal movement. Here, we report two unrelated families affected by lethal AMC. By genetic mapping and whole-exome sequencing in a multiplex family, a heterozygous truncating MAGEL2 mutation leading to frameshift and a premature stop codon (c.1996delC, p.Gln666Serfs∗36) and inherited from the father was identified in the probands. In another family, a distinct heterozygous truncating mutation leading to frameshift (c.2118delT, p.Leu708Trpfs∗7) and occurring de novo on the paternal allele of MAGEL2 was identified in the affected individual. In both families, RNA analysis identified the mutated paternal MAGEL2 transcripts only in affected individuals. MAGEL2 is one of the paternally expressed genes within the Prader-Willi syndrome (PWS) locus. PWS is associated with, to varying extents, reduced fetal mobility, severe infantile hypotonia, childhood-onset obesity, hypogonadism, and intellectual disability. MAGEL2 mutations have been recently reported in affected individuals with features resembling PWS and called Schaaf-Yang syndrome. Here, we show that paternal MAGEL2 mutations are also responsible for lethal AMC, recapitulating the clinical spectrum of PWS and suggesting that MAGEL2 is a PWS-determining gene.","variants":[{"Name":"NM_019066.5(MAGEL2):c.1996del (p.Gln666fs)","Chromosome":"15","Start":"23645747","Stop":"23645747","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":434101,"rule_based_match":true,"evidence_text":"c.1996delC, p.Gln666Serfs∗36","llm_judgment":"PRESENT","evidence":"c.1996delC, p.Gln666Serfs∗36","abstract_start":378,"abstract_end":406},{"Name":"NM_019066.5(MAGEL2):c.2118del (p.Leu708fs)","Chromosome":"15","Start":"23645625","Stop":"23645625","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":434102,"rule_based_match":true,"evidence_text":"c.2118delT, p.Leu708Trpfs∗7","llm_judgment":"PRESENT","evidence":"c.2118delT, p.Leu708Trpfs∗7","abstract_start":556,"abstract_end":583}]}
{"pmid":"38503300","title":"Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.","abstract":"Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.","variants":[{"Name":"NM_002801.4(PSMB10):c.601G>A (p.Gly201Arg)","Chromosome":"16","Start":"67934906","Stop":"67934906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3400945,"rule_based_match":true,"evidence_text":"c.601G>A (p.Gly201Arg)","llm_judgment":"PRESENT","evidence":"p.Gly201Arg","abstract_start":1088,"abstract_end":1099},{"Name":"NM_002801.4(PSMB10):c.601G>C (p.Gly201Arg)","Chromosome":"16","Start":"67934906","Stop":"67934906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3400946,"rule_based_match":true,"evidence_text":"c.601G>C (p.Gly201Arg)","llm_judgment":"PRESENT","evidence":"p.Gly201Arg","abstract_start":1088,"abstract_end":1099},{"Name":"NM_002801.4(PSMB10):c.166G>C (p.Asp56His)","Chromosome":"16","Start":"67936291","Stop":"67936291","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3400947,"rule_based_match":true,"evidence_text":"c.166G>C [p.Asp56His]","llm_judgment":"PRESENT","evidence":"c.166G>C [p.Asp56His]","abstract_start":1043,"abstract_end":1064}]}
{"pmid":"22961547","title":"Early-onset Lafora body disease.","abstract":"The most common progressive myoclonus epilepsies are the late infantile and late infantile-variant neuronal ceroid lipofuscinoses (onset before the age of 6 years), Unverricht-Lundborg disease (onset after the age of 6 years) and Lafora disease. Lafora disease is a distinct disorder with uniform course: onset in teenage years, followed by progressively worsening myoclonus, seizures, visual hallucinations and cognitive decline, leading to a vegetative state in status myoclonicus and death within 10 years. Biopsy reveals Lafora bodies, which are pathognomonic and not seen with any other progressive myoclonus epilepsies. Lafora bodies are aggregates of polyglucosans, poorly constructed glycogen molecules with inordinately long strands that render them insoluble. Lafora disease is caused by mutations in the EPM2A or EPM2B genes, encoding the laforin phosphatase and the malin ubiquitin ligase, respectively, two cytoplasmically active enzymes that regulate glycogen construction, ensuring symmetric expansion into a spherical shape, essential to its solubility. In this work, we report a new progressive myoclonus epilepsy associated with Lafora bodies, early-onset Lafora body disease, map its locus to chromosome 4q21.21, identify its gene and mutation and characterize the relationship of its gene product with laforin and malin. Early-onset Lafora body disease presents early, at 5 years, with dysarthria, myoclonus and ataxia. The combination of early-onset and early dysarthria strongly suggests late infantile-variant neuronal ceroid lipofuscinosis, not Lafora disease. Pathology reveals no ceroid lipofuscinosis, but Lafora bodies. The subsequent course is a typical progressive myoclonus epilepsy, though much more protracted than any infantile neuronal ceroid lipofuscinosis, or Lafora disease, patients living into the fourth decade. The mutation, c.781T>C (Phe261Leu), is in a gene of unknown function, PRDM8. We show that the PRDM8 protein interacts with laforin and malin and causes translocation of the two proteins to the nucleus. We find that Phe261Leu-PRDM8 results in excessive sequestration of laforin and malin in the nucleus and that it therefore likely represents a gain-of-function mutation that leads to an effective deficiency of cytoplasmic laforin and malin. We have identified a new progressive myoclonus epilepsy with Lafora bodies, early-onset Lafora body disease, 101 years after Lafora disease was first described. The results to date suggest that PRDM8, the early-onset Lafora body disease protein, regulates the cytoplasmic quantities of the Lafora disease enzymes.","variants":[{"Name":"NM_001099403.2(PRDM8):c.781T>C (p.Phe261Leu)","Chromosome":"4","Start":"80202243","Stop":"80202243","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":214521,"rule_based_match":true,"evidence_text":"c.781T>C (Phe261Leu)","llm_judgment":"PRESENT","evidence":"c.781T>C (Phe261Leu)","abstract_start":1867,"abstract_end":1887}]}
{"pmid":"22339448","title":"Evaluation of 5-fluorouracil pharmacokinetics in cancer patients with a c.1905+1G>A mutation in DPYD by means of a Bayesian limited sampling strategy.","abstract":"BACKGROUND AND OBJECTIVE: Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. So far, only very limited information is available regarding the pharmacokinetics of 5FU in patients with a (partial) DPD deficiency and no limited sampling models have been developed taking into account the non-linear pharmacokinetic behaviour of 5FU. The aim of this study was to evaluate the pharmacokinetics of 5FU and to develop a limited sampling strategy to detect decreased 5FU elimination in patients with a c.1905+1G>A-related DPD deficiency.\nMETHODS: Thirty patients, heterozygous for the c.1905+1G>A mutation in DPYD, and 18 control patients received a dose of 5FU 300 mg/m2 and/or 5FU 450 mg/m2, followed by pharmacokinetic analysis of the 5FU plasma levels. A population pharmacokinetic analysis was performed in order to develop a compartmental pharmacokinetic model suitable for a limited sampling strategy. Clinical aspects of treating DPD-deficient patients with 5FU-based chemotherapy were assessed from the retrospectively collected clinical data.\nRESULTS: In a two-compartment model with Michaelis-Menten elimination, the mean maximum enzymatic conversion capacity (V(max)) value was 40% lower in DPD-deficient patients compared with controls (p < 0.001). Using a limited sampling strategy, with V(max) values calculated from 5FU concentrations at 30 or 60 minutes, significant differences were observed between DPD-deficient patients and controls at both dose levels (p < 0.001). The positive predictive value and negative predictive value for V(max), calculated from 5FU levels at 60 minutes, were 96% and 88%, respectively, in patients treated with a single dose of 5FU 300 mg/m2. All seven DPD-deficient patients (two males and five females) who had been genotyped prior to initiation of standard 5FU-containing chemotherapy developed grade 3-4 toxicity, with one case of lethal toxicity in a female patient. No grade 4 toxicity or lethal outcome was observed in 13 DPD-deficient patients treated with reduced doses of 5FU. The average dose of 5FU in DPD-deficient patients with mild toxicity (grade ≤2) was 61 ± 16% of the normal 5FU dose (n = 10).\nCONCLUSIONS: Profound differences in the elimination of 5FU could be detected between DPD-deficient patients and control patients. Pharmacokinetic 5FU profiling, using a single 5FU concentration at 60 minutes, may be useful for identification of DPD-deficient patients in order to reduce severe toxicity. Furthermore, treatment of DPD-deficient patients with standard 5FU-containing chemotherapy was associated with severe (lethal) toxicity.","variants":[{"Name":"NM_000110.4(DPYD):c.1905+1G>A","Chromosome":"1","Start":"97450058","Stop":"97450058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15471,"rule_based_match":true,"evidence_text":"c.1905+1G>A","llm_judgment":"PRESENT","evidence":"c.1905+1G>A","abstract_start":606,"abstract_end":617}]}
{"pmid":"31943857","title":"A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.","abstract":"BACKGROUND: Mutations in the GBA gene that encodes the lysosomal enzyme acid β-glucocerebrosidase cause Gaucher disease (GD), the most common lysosomal storage disorder. Most of the mutations are missense/nonsense, however, a few splicing mutations within or close to conserved consensus donor or acceptor splice sites have also been described. The aim of the study was to identify the mutation(s) in a Cypriot patient with type I GD.\nMETHODS: The genomic DNA of the proband was screened for nine common mutations using Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. All exons and exon-intron boundaries, and the 5'UTR and 3'UTR regions of the GBA gene, were investigated by Sanger sequencing. RNA analysis was performed using standard procedures, and the abnormal transcript was further cloned into pGEM-T-Easy plasmid vector and sequenced. The relevant intronic region was further sequenced by the Sanger method to identify the genetic variant.\nRESULTS: A novel point mutation, g.12599C > A (c.999 + 242C > A), was detected deep in intron 7 of the GBA gene. This type of mutation has been previously described for other diseases but this is the first time, as far as we know, that it is described for GD. This mutation creates a new donor splice site leading to aberrant splicing and resulting in the insertion of the first 239nt of intron 7 as a pseudoexon in the mRNA, creating a premature stop codon.\nCONCLUSION: This study expands the mutation spectrum of GD and highlights the importance of RNA sequencing for the molecular diagnosis of patients bearing mutations in nonexonic regions.","variants":[{"Name":"NM_000157.4(GBA1):c.999+242C>A","Chromosome":"1","Start":"155237099","Stop":"155237099","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":677160,"rule_based_match":true,"evidence_text":"g.12599C > A (c.999 + 242C > A)","llm_judgment":"PRESENT","evidence":"g.12599C > A (c.999 + 242C > A)","abstract_start":1021,"abstract_end":1052}]}
{"pmid":"28508084","title":"Clinicopathologic and molecular spectrum of","abstract":"OBJECTIVE: Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (<i>RNASEH1</i>) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations.\nMETHODS: <i>RNASEH1</i> was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA. Clinicopathologic and molecular evaluation of the newly identified and previously reported patients harboring <i>RNASEH1</i> mutations was subsequently undertaken.\nRESULTS: Pathogenic c.424G>A p.Val142Ile <i>RNASEH1</i> mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, <i>RNASEH1</i> genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further <i>RNASEH1</i> mutations were confirmed. <i>RNASEH1</i>-related mitochondrial disease was characterized by PEO (100%), cerebellar ataxia (57%), and dysphagia (50%). The ataxia neuropathy spectrum phenotype was observed in 1 patient. Although the c.424G>A p.Val142Ile mutation underpins all reported <i>RNASEH1</i>-related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families.\nCONCLUSIONS: In our cohort, <i>RNASEH1</i> mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in <i>POLG</i>, <i>RRM2B</i>, and <i>TWNK</i>. <i>RNASEH1</i> genetic analysis should also be considered in all patients with <i>POLG</i>-negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation.","variants":[{"Name":"NM_002936.6(RNASEH1):c.424G>A (p.Val142Ile)","Chromosome":"2","Start":"3550458","Stop":"3550458","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359102,"rule_based_match":true,"evidence_text":"c.424G>A p.Val142Ile","llm_judgment":"PRESENT","evidence":"c.424G>A p.Val142Ile","abstract_start":816,"abstract_end":836}]}
{"pmid":"23729109","title":"Early genetic diagnosis in patients with HHT induced severe nosebleed","abstract":"OBJECTIVE: To study the early gene diagnosis of hereditary hemorrhagic telangiectasia (HHT) induced severe nosebleed.\nMETHOD: Clinical features of 23 family members in two HHT pedigrees were examined. Genomic DNA was extracted from peripheral blood samples. PCR amplification was conducted to screen ENG and ACVRL-1 genes with their specific primers. Direct sequencing was performed to detect the mutation. Mutation analysis was carried out to evaluate its significance.\nRESULT: A heterozygous c. 263A > G mutation was identified in exon 3 of ACVRL-1 in 6 out of 11 members in NMG-1 pedigree. In GD-2 pedigree, 5 of 11 members carried c. 199C > G mutation. Mutation detection rate was 100% in subjects with nosebleed history and 25% in family members without epistaxis.\nCONCLUSION: Gene diagnosis characterized by high sensitivity and specificity is of great practi-cal significance and early genetic screening should be a clinical routine test for HHT induced severe nosebleed.","variants":[{"Name":"NM_000020.3(ACVRL1):c.263A>G (p.Tyr88Cys)","Chromosome":"12","Start":"51913300","Stop":"51913300","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1010508,"rule_based_match":true,"evidence_text":"c. 263A > G","llm_judgment":"PRESENT","evidence":"c. 263A > G","abstract_start":494,"abstract_end":505}]}
{"pmid":"26096739","title":"Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability.","abstract":"Loss of function of mismatch repair (MMR) genes, mainly MLH1 and MSH2, manifests as high levels of microsatellite instability (MSI) that occurs in >90% of carcinomas in patients with Lynch syndrome (LS). The MSI-high status has also been described in sporadic colorectal cancer (CRC) associated with BRAF gene mutation (V600E); this mutation was not present in LS-associated cancers. The present study performed MSI analysis on 39 CRC patients selected according to Bethesda guidelines, and BRAF V600E genotyping was performed in 26 cases classified as MSI-high or MSI-low (15 MSI-H and 11 MSI-L). These 26 patients were then screened for MLH1 and MSH2 germ-line mutations. Germ-line mutations in these genes were detected in 11/15 patients with MSI-H tumors (73%) and in 1/11 patients with MSI-L tumors (9%). Overall, 11 germ-line mutations in 12/26 analyzed patients (46%) in these genes were identified. Two of these mutations are novel genetic MLH1 variants not previously described in the literature, c.438A>G and c.1844T>C. A combination of computational approaches, co-segregation analysis and RNA assay suggested that these novel mutations, silent and missense, respectively, were probably pathogenic. The findings of the present study further emphasized the requirement for genetic testing in patients with a risk for hereditary CRC and has broadened the spectrum of known mutations of the MLH1 gene.","variants":[{"Name":"NM_000249.4(MLH1):c.1844T>C (p.Leu615Pro)","Chromosome":"3","Start":"37047631","Stop":"37047631","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":827968,"rule_based_match":true,"evidence_text":"c.1844T>C","llm_judgment":"PRESENT","evidence":"c.1844T>C","abstract_start":1019,"abstract_end":1028},{"Name":"NM_000249.4(MLH1):c.438A>G (p.Gln146=)","Chromosome":"3","Start":"37007048","Stop":"37007048","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":221383,"rule_based_match":true,"evidence_text":"c.438A>G","llm_judgment":"PRESENT","evidence":"c.438A>G","abstract_start":1006,"abstract_end":1014}]}
{"pmid":"21750092","title":"Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7.","abstract":"Juvenile megaloblastic anaemia 1 (OMIM # 261100) is a rare autosomic disorder characterized by selective cobalamin mal-absorption and inconstant proteinuria produced by mutations in either CUBN or AMN genes. Amnionless, the gene product of AMN, is a transmembrane protein that binds tightly to the N-terminal end of cubilin, the gene product of CUBN. Cubilin binds to intrinsic factor-cobalamin complex and is expressed in the distal intestine and the proximal renal tubule. We report a compound AMN heterozygosity with c.742C>T, p.Gln248X and c.208-2A>G mutations in 2 siblings that led to premature termination codon in exon 7 and exon 6, respectively. It produced a dramatic decrease in receptor activity in urine, despite absence of CUBN mutation and normal affinity of the receptor for intrinsic factor binding. Heterozygous carriers for c.742T and c.208-2G had no pathological signs. These results indicate that amnionless is essential for the correct luminal expression of cubilin in humans.","variants":[{"Name":"NM_030943.4(AMN):c.742C>T (p.Gln248Ter)","Chromosome":"14","Start":"102929518","Stop":"102929518","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":71398,"rule_based_match":true,"evidence_text":"c.742C>T, p.Gln248X","llm_judgment":"PRESENT","evidence":"c.742C>T, p.Gln248X","abstract_start":520,"abstract_end":539}]}
{"pmid":"35154276","title":"Whole-Exome Sequencing Implicates Neuronal Calcium Channel with Familial Atrial Fibrillation.","abstract":"<b>Background:</b> Atrial Fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, responsible for considerable morbidity and mortality. The heterogenic and complex pathogenesis of AF remains poorly understood, which contributes to the current limitation in effective treatments. We aimed to identify rare genetic variants associated with AF in patients with familial AF. <b>Methods and results:</b> We performed whole exome sequencing in a large family with familial AF and identified a rare variant in the gene <i>CACNA1A</i> c.5053G > A which co-segregated with AF. The gene encodes for the protein variants Ca<sub>V</sub>2.1-V1686M, and is important in neuronal function. Functional characterization of the CACNA1A, using patch-clamp recordings on transiently transfected mammalian cells, revealed a modest loss-of-function of Ca<sub>V</sub>2.1-V1686M. <b>Conclusion:</b> We identified a rare loss-of-function variant associated with AF in a gene previously linked with neuronal function. The results allude to a novel link between dysfunction of an ion channel previously associated with neuronal functions and increased risk of developing AF.","variants":[{"Name":"NM_001127222.2(CACNA1A):c.5053G>A (p.Val1685Met)","Chromosome":"19","Start":"13235628","Stop":"13235628","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1246535,"rule_based_match":true,"evidence_text":"c.5053G > A","llm_judgment":"PRESENT","evidence":"c.5053G > A","abstract_start":541,"abstract_end":552}]}
{"pmid":"35293990","title":"Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.","abstract":"Voltage-gated calcium (CaV) channels form three subfamilies (CaV1-3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1-4. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the α2δ-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy. Patient 1 has a homozygous frameshift variant c.818_821dup/p.(Ser275Asnfs*13) resulting in nonsense-mediated mRNA decay of the CACNA2D1 transcripts, and absence of α2δ-1 protein detected in patient-derived fibroblasts. Patient 2 is compound heterozygous for an early frameshift variant c.13_23dup/p.(Leu9Alafs*5), highly probably representing a null allele and a missense variant c.626G>A/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of α2δ-1 as a calcium channel subunit, with strongly reduced trafficking of α2δ-1G209D to the cell surface and a complete inability of α2δ-1G209D to increase the trafficking and function of CaV2 channels. Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients. Our results demonstrate the critical importance and non-interchangeability of α2δ-1 and other α2δ proteins for normal human neuronal development.","variants":[{"Name":"NM_000722.4(CACNA2D1):c.818_821dup (p.Ser275fs)","Chromosome":"7","Start":"82060485","Stop":"82060486","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGTTC","allel_id":1859363,"rule_based_match":true,"evidence_text":"c.818_821dup/p.(Ser275Asnfs*13)","llm_judgment":"PRESENT","evidence":"c.818_821dup/p.(Ser275Asnfs*13)","abstract_start":560,"abstract_end":591},{"Name":"NM_000722.4(CACNA2D1):c.13_23dup (p.Leu9fs)","Chromosome":"7","Start":"82443436","Stop":"82443437","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGCCAGCAGGCA","allel_id":1859364,"rule_based_match":true,"evidence_text":"c.13_23dup/p.(Leu9Alafs*5)","llm_judgment":"PRESENT","evidence":"c.13_23dup/p.(Leu9Alafs*5)","abstract_start":800,"abstract_end":826},{"Name":"NM_000722.4(CACNA2D1):c.626G>A (p.Gly209Asp)","Chromosome":"7","Start":"82084801","Stop":"82084801","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1859365,"rule_based_match":true,"evidence_text":"c.626G>A/p.(Gly209Asp)","llm_judgment":"PRESENT","evidence":"c.626G>A/p.(Gly209Asp)","abstract_start":894,"abstract_end":916}]}
{"pmid":"31823625","title":"Homozygous Mutation in TWNK Cases Ataxia, Sensorineural Hearing Loss and Optic Nerve Atrophy.","abstract":"The TWNK (C10orf2) gene encodes Twinkle, an essential helicase for mtDNA replication. Homozygous mutations in TWNK can lead to mitochondrial DNA depletion syndrome 7 (MTDPS7) that usually manifests as Infantile onset spinocerebellar ataxia (IOSCA). Here, we report a 15-year-old Iranian boy with three main symptoms; ataxia, sensorineural hearing loss and optic nerves atrophy which were accompanied by other symptoms including flexion contracture, dysarthric speech, nystagmus, dystonia and borderline intellectual disability. Whole exome sequencing (WES) revealed a homozygous mutation in his TWNK gene. The mutation was a transversion which replaced a C with A (NM_021830.4 (TWNK):c.874C>A). This nucleotide substitution results in replacing a Threonine with Proline in codon 292 of Twinkle protein (p.Pro292Thr). In silico analyses showed that this amino acid change in Twinkle could be deleterious and disease-causing; therefore, we attribute the symptoms of our patient to this mutation. Our study extended the homozygous mutation spectrum of the TWNK gene that leads to IOSCA.","variants":[{"Name":"NM_021830.5(TWNK):c.874C>A (p.Pro292Thr)","Chromosome":"10","Start":"100989084","Stop":"100989084","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":481146,"rule_based_match":true,"evidence_text":"NM_021830.4 (TWNK):c.874C>A","llm_judgment":"PRESENT","evidence":"NM_021830.4 (TWNK):c.874C>A","abstract_start":665,"abstract_end":692}]}
{"pmid":"35611808","title":"Further evidence supporting the role of DUT gene in diabetes with bone marrow failure syndrome.","abstract":"In 2017, a homozygous DUT mutation was reported to cause a syndrome of diabetes and bone marrow failure. However, no further patient with this combination has been reported and the phenotype of heterozygous DUT mutation is unknown. We describe the genotype, phenotype, and post bone marrow transplantation (BMT) data of two unrelated families with this rare syndrome. Whole-exome and/or direct sequencing of the DUT gene were performed in all family members. Each family has two children presented within the first 10 years of life with thrombocytopenia, macrocytosis, with or without anemia, followed by non-autoimmune diabetes. The same homozygous missense DUT mutation, reported in 2017 (c.425A>G p.(Tyr142Cys), was detected in all affected children. The heterozygous carriers have no BM failure, one developed type 2 diabetes, and the rest have normal fasting glucose, insulin, HbA1c, and c-peptide. Multiple nevi were detected in homozygous and heterozygous mutation carriers. Allogenic BMT normalized BM aplasia without impact on diabetes. Post BMT follow-up revealed normal puberty and school performance; but three have height <2.5 SDS. We add two families with this syndrome supporting a role of DUT in bone marrow and β-cell function. The heterozygous carriers of this DUT mutation appear to be healthy.","variants":[{"Name":"NM_001025248.2(DUT):c.425A>G (p.Tyr142Cys)","Chromosome":"15","Start":"48334422","Stop":"48334422","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1704890,"rule_based_match":true,"evidence_text":"c.425A>G p.(Tyr142Cys)","llm_judgment":"PRESENT","evidence":"c.425A>G p.(Tyr142Cys)","abstract_start":691,"abstract_end":713}]}
{"pmid":"24498620","title":"Identification of novel point mutations in splicing sites integrating whole-exome and RNA-seq data in myeloproliferative diseases.","abstract":"Point mutations in intronic regions near mRNA splice junctions can affect the splicing process. To identify novel splicing variants from exome sequencing data, we developed a bioinformatics splice-site prediction procedure to analyze next-generation sequencing (NGS) data (SpliceFinder). SpliceFinder integrates two functional annotation tools for NGS, ANNOVAR and MutationTaster and two canonical splice site prediction programs for single mutation analysis, SSPNN and NetGene2. By SpliceFinder, we identified somatic mutations affecting RNA splicing in a colon cancer sample, in eight atypical chronic myeloid leukemia (aCML), and eight CML patients. A novel homozygous splicing mutation was found in APC (NM_000038.4:c.1312+5G>A) and six heterozygous in GNAQ (NM_002072.2:c.735+1C>T), ABCC 3 (NM_003786.3:c.1783-1G>A), KLHDC 1 (NM_172193.1:c.568-2A>G), HOOK 1 (NM_015888.4:c.1662-1G>A), SMAD 9 (NM_001127217.2:c.1004-1C>T), and DNAH 9 (NM_001372.3:c.10242+5G>A). Integrating whole-exome and RNA sequencing in aCML and CML, we assessed the phenotypic effect of mutations on mRNA splicing for GNAQ, ABCC 3, HOOK 1. In ABCC 3 and HOOK 1, RNA-Seq showed the presence of aberrant transcripts with activation of a cryptic splice site or intron retention, validated by the reverse transcription-polymerase chain reaction (RT-PCR) in the case of HOOK 1. In GNAQ, RNA-Seq showed 22% of wild-type transcript and 78% of mRNA skipping exon 5, resulting in a 4-6 frameshift fusion confirmed by RT-PCR. The pipeline can be useful to identify intronic variants affecting RNA sequence by complementing conventional exome analysis.","variants":[{"Name":"NM_000038.6(APC):c.1312+5G>A","Chromosome":"5","Start":"112819349","Stop":"112819349","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":394347,"rule_based_match":true,"evidence_text":"NM_000038.4:c.1312+5G>A","llm_judgment":"PRESENT","evidence":"NM_000038.4:c.1312+5G>A","abstract_start":708,"abstract_end":731}]}
{"pmid":"22132981","title":"Purine nucleoside phosphorylase deficiency: a mutation update.","abstract":"Purine nucleoside phosphorylase (PNPase) deficiency is an autosomal recessive disorder affecting purine degradation and salvage pathways. Clinically, patients typically present with severe immunodeficiency, neurological dysfunction, and autoimmunity. Biochemically, PNPase deficiency may be suspected in the presence of hypouricemia. We report biochemical and genetic data on a cohort of seven patients from six families identified as PNPase deficient. In all patients, inosine, deoxyinosine, guanosine, and deoxyguanosine were elevated in urine, and mutation analysis revealed seven different mutations of which three were novel. The mutation c.770A>G resulted in the substitution p.His257Arg. A second novel mutation c.257A>G (p.His86Arg) was identified in two siblings and a third novel mutation, c.199C>T (p.Arg67X), was found in a 2-year-old female with delayed motor milestones and recurrent respiratory infections. A review of the literature identified 67 cases of PNPase deficiency from 49 families, including the cases from our own laboratory. PNPase deficiency was confirmed in 30 patients by genotyping and 24 disease causing mutations, including the three novel mutations described in this paper, have been reported to date. In five of the seven patients, plasma uric acid was found to be within the pediatric normal range, suggesting that PNPase deficiency should not be ruled out in the absence of hypouricemia.","variants":[{"Name":"NM_000270.4(PNP):c.199C>T (p.Arg67Ter)","Chromosome":"14","Start":"20474489","Stop":"20474489","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1336742,"rule_based_match":true,"evidence_text":"c.199C>T (p.Arg67X)","llm_judgment":"PRESENT","evidence":"c.199C>T (p.Arg67X)","abstract_start":800,"abstract_end":819}]}
{"pmid":"15896657","title":"Two novel CHS1 (LYST) mutations: clinical correlations in an infant with Chediak-Higashi syndrome.","abstract":"Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by variable degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. Most patients also undergo an accelerated phase of lymphohistiocytosis and die at an early age unless they receive an allogeneic hematopoietic stem cell transplant (SCT). Mutations in the CHS1 (LYST) gene result in CHS. Here, we describe an adopted infant who is compound heterozygous for two novel CHS1 gene mutations, both of which are predicted to result in truncated proteins. The two mutations are a nonsense mutation (c.1540 C>T, CGA>TGA, R514X) in exon 5 and a one base pair deletion (del c.9893T, F3298fsX3304) in exon 43, coding for part of the CHS1 protein's BEACH domain. These two newly described mutations are expected to give rise to a severe phenotype and, indeed, the patient had absolutely no cytotoxicity by natural killer cells or cytotoxic lymphocytes prior to his allogeneic SCT.","variants":[{"Name":"NM_000081.4(LYST):c.1540C>T (p.Arg514Ter)","Chromosome":"1","Start":"235809278","Stop":"235809278","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76441,"rule_based_match":true,"evidence_text":"c.1540 C>T, CGA>TGA, R514X","llm_judgment":"PRESENT","evidence":"c.1540 C>T, CGA>TGA, R514X","abstract_start":641,"abstract_end":667},{"Name":"NM_000081.4(LYST):c.9893del (p.Phe3298fs)","Chromosome":"1","Start":"235712089","Stop":"235712089","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":76460,"rule_based_match":false,"evidence_text":"del c.9893T","llm_judgment":"PRESENT","evidence":"del c.9893T","abstract_start":709,"abstract_end":720}]}
{"pmid":"25981141","title":"Congenital hypofibrinogenemia associated with novel homozygous fibrinogen Aα and heterozygous Bβ chain mutations.","abstract":"We report the molecular characterisation of two novel cases of inherited hypofibrinogenemia. After sequencing all coding regions and intron-exon boundaries of the three fibrinogen genes (FGA, FGB, and FGG), two different novel mutations were found, one homozygous and one heterozygous. The first patient, with a mild bleeding history and mild discrepancy between functional and immunological fibrinogen, showed a novel homozygous nonsense mutation in exon 5 of FGA (p.Trp373*, p.Trp354* according to the mature protein) caused by a G>A transition at nucleotide position 1,119. The resulting truncation in the Aα chain is likely to reduce the efficiency of fibrinogen assembly and secretion. The second patient, referred after ischemic stroke (functional fibrinogen 77mg/dL), had a novel heterozygous splicing mutation in intron 5 of FGB (IVS5+2T>A or c.832+2T>A), which we demonstrated to cause either exon 5 skipping or the inclusion of 75bp belonging to intron 5. Neither splicing defect alters the reading frame: one results in a 38-residue deletion and the other in a 25-residue insertion in the D domain of fibrinogen Bβ chain. This report confirms that genetically determined partial deficiencies of fibrinogen with levels greater than 50mg/dL are rarely associated with significant bleeding symptoms and that homozygous null mutations removing a significant portion of the Aα chain may be associated with mild fibrinogen deficiency.","variants":[{"Name":"NM_021871.4(FGA):c.1119G>A (p.Trp373Ter)","Chromosome":"4","Start":"154586310","Stop":"154586310","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1699572,"rule_based_match":false,"evidence_text":"p.Trp373*, p.Trp354* according to the mature protein) caused by a G>A transition at nucleotide position 1,119","llm_judgment":"PRESENT","evidence":"p.Trp373*, p.Trp354* according to the mature protein) caused by a G>A transition at nucleotide position 1,119","abstract_start":466,"abstract_end":575}]}
{"pmid":"31433521","title":"MSH2 c.1022T>C, p.Leu341Pro is a founder pathogenic variation and a major cause of Lynch syndrome in the North of France.","abstract":"Interpretation of missense variants remains a major challenge for genetic diagnosis, even in well-known genes such as the DNA-mismatch repair (MMR) genes involved in Lynch syndrome. We report the characterization of a variant in MSH2: c.1022T>C, which was identified in 20 apparently unrelated families living in the North of France. A total of 150 patients from 20 families were included in this study. Family segregation studies, tumor analyses and functional analyses at both the RNA and protein levels were performed. Founder effect was evaluated by haplotype analysis.We show that MSH2 c.1022T>C is a missense variant (p.Leu341Pro) that affects protein stability. This variant is frequent in the North of France (7.7% of pathogenic variations identified in MMR genes), and is located on an ancestral haplotype. It is associated with a high risk of a broad tumor spectrum including brain and cutaneous cancers. The MSH2 c.1022T>C variant is a pathogenic founder variation associated with a high risk of cancer. These findings have important implications for genetic counseling and management of variant carriers.","variants":[{"Name":"NM_000251.3(MSH2):c.1022T>C (p.Leu341Pro)","Chromosome":"2","Start":"47416375","Stop":"47416375","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":95982,"rule_based_match":true,"evidence_text":"MSH2 c.1022T>C","llm_judgment":"PRESENT","evidence":"MSH2 c.1022T>C","abstract_start":586,"abstract_end":600}]}
{"pmid":"25288386","title":"GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico.","abstract":"OBJECTIVES: Mutations in the DFNB1 locus are the most common cause of autosomal-recessive nonsyndromic hearing loss (ARNSHL) worldwide. The aim of this study was to identify the most frequent mutations in patients with ARNSHL who reside in Northeastern Mexico.\nMETHODS: We determined the nucleotide sequence the coding region of GJB2 of 78 patients with ARNSHL. Polymerase chain reaction assays were used to detect the GJB2 IVS1+1G>A mutation and deletions within GJB6.\nRESULTS: GJB2 mutations were detected in 9.6% of the alleles, and c.35delG was the most frequent. Six other less-frequent mutations were detected, including an extremely rare variant (c.645_648delTAGA), a novel mutation (c.35G>A), and one of possible Mexican origin (c.34G>T). GJB6 deletions and GJB2 IVS1+1G>A were not detected.\nCONCLUSIONS: These data suggest that mutations in the DFNB1 locus are a rare cause of ARNSHL among the population of Northeastern Mexico. This confirms the genetic heterogeneity of this condition and indicates that further research is required to determine the other mechanisms of pathogenesis of ARNSHL in Mexicans.","variants":[{"Name":"NM_004004.6(GJB2):c.35G>A (p.Gly12Asp)","Chromosome":"13","Start":"20189547","Stop":"20189547","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":547105,"rule_based_match":true,"evidence_text":"c.35G>A","llm_judgment":"PRESENT","evidence":"c.35G>A","abstract_start":691,"abstract_end":698}]}
{"pmid":"26183948","title":"Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients.","abstract":"BACKGROUND: About 3885 women are diagnosed with breast cancer and 1285 die from the disease each year in Bulgaria. However no genetic testing to identify the mutations in high-risk families has been provided so far.\nMETHODS: We evaluated 200 Bulgarian women with primary invasive breast cancer and with personal/ family history of breast cancer for the presence of unequivocally damaging germline mutations in BRCA1/2 using Sanger sequencing.\nRESULTS: Of the 200 patients, 39 (19.5 %) carried a disease predisposing mutation, including 28 (14 %) with a BRCA1 mutation and 11 (5.5 %) with a BRCA2 mutation. At BRCA1, 6 different mutations were identified, including 2 frameshifts, 1 nonsense and 1 missense that had been previously reported (c.5030_5033delCTAA, c.5263_5264insC, c.4603G > T, c.181 T > G), and 2 frameshifts, which were novel to this study (c.464delA, c.5397_5403delCCCTTGG). At BRCA2, 7 different frameshift mutations were identified, including 5 previously reported (5851_5854delAGTT, c.5946delT, c.5718_5719delCT, c.7910_7914delCCTTT,c.9098_9099insA) and 2 novel (c.8532_8533delAA, c.9682delA). A BRCA1 mutation was found in 18.4 % of women diagnosed with breast cancer at/or under the age of 40 compared to 11.2 % of women diagnosed at a later age; a BRCA2 mutation was found in 4 % of women diagnosed at/or under the age of 40 compared to 6.5 % of women diagnosed at a later age. A mutation was present in 26.8 % patients with a positive family history and in 14.4 % of women with a negative family history. The most prevalent mutation observed in 22 patients (11 %) was BRCA1 c.5263_5264insC, a known Slavic mutation with founder effect in Eastern European and AJ communities. Other recurrent mutations were BRCA2 c.9098-9099insA (2 %), BRCA1 c.181T > G (1 %) and BRCA2 c.5851_5854delAGTT (1 %). Notably, BRCA1 c.5263_5264insC represented 56 % of all mutations identified in this series. Of the 22 patients with BRCA1 c.5263_5264insC, 9 were diagnosed with early onset breast cancer, 11 with TNBCs, 4 with bilateral breast cancer, and 6 with both breast and ovarian cancer.\nCONCLUSIONS: This is the first comprehensive study of the BRCA1/2 mutation spectrum in Bulgaria and will assist the establishment of efficient protocols for genetic testing and individualized risk assessment for Bulgarian breast/ovarian cancer patients and healthy individuals at a high-risk.","variants":[{"Name":"NM_007294.4(BRCA1):c.5030_5033del (p.Thr1677fs)","Chromosome":"17","Start":"43067649","Stop":"43067652","ReferenceAlleleVCF":"ATTAG","AlternateAlleleVCF":"A","allel_id":46179,"rule_based_match":true,"evidence_text":"c.5030_5033delCTAA","llm_judgment":"PRESENT","evidence":"c.5030_5033delCTAA","abstract_start":741,"abstract_end":759},{"Name":"NM_007294.4(BRCA1):c.4603G>T (p.Glu1535Ter)","Chromosome":"17","Start":"43074403","Stop":"43074403","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":69903,"rule_based_match":true,"evidence_text":"c.4603G > T","llm_judgment":"PRESENT","evidence":"c.4603G > T","abstract_start":778,"abstract_end":789},{"Name":"NM_000059.4(BRCA2):c.5851_5854del (p.Ser1951fs)","Chromosome":"13","Start":"32340203","Stop":"32340206","ReferenceAlleleVCF":"TGTTA","AlternateAlleleVCF":"T","allel_id":46557,"rule_based_match":true,"evidence_text":"BRCA2 c.5851_5854delAGTT","llm_judgment":"PRESENT","evidence":"BRCA2 c.5851_5854delAGTT","abstract_start":1785,"abstract_end":1809}]}
{"pmid":"21796727","title":"A mutation in SCARB2 is a modifier in Gaucher disease.","abstract":"Lysosomal integral membrane protein type 2 (LIMP-2) is responsible for proper sorting and lysosomal targeting of glucocerebrosidase, the enzyme deficient in Gaucher disease (GD). Mutations in the gene for LIMP-2, SCARB2, are implicated in inherited forms of myoclonic epilepsy, and myoclonic epilepsy is part of the phenotypic spectrum associated with GD. We investigated whether SCARB2 mutations impact the Gaucher phenotype focusing on patients with myoclonic epilepsy, including a pair of siblings with GD who were discordant for myoclonic seizures. Sequencing of SCARB2 genomic and cDNA identified a heterozygous, maternally inherited novel mutation, c.1412A>G (p.Glu471Gly), in the brother with GD and myoclonic epilepsy, absent from his sibling and controls. Glucocerebrosidase activity, Western blots, real-time PCR, and immunofluorescence studies demonstrated markedly decreased LIMP-2 and glucocerebrosidase in cells from the sibling with (p.Glu471Gly) LIMP-2, and diminished glucocerebrosidase in lysosomes. The cells secreted highly glycosylated enzyme and showed mistrafficking of glucocerebrosidase. Sequencing of SCARB2 in 13 other subjects with GD and myoclonic epilepsy and 40 controls failed to identify additional mutations. The study provides further evidence for the association of LIMP-2 and myoclonic epilepsy, explains the drastically different phenotypes encountered in the siblings, and demonstrates that LIMP-2 can serve as a modifier in GD.","variants":[{"Name":"NM_005506.4(SCARB2):c.1412A>G (p.Glu471Gly)","Chromosome":"4","Start":"76161738","Stop":"76161738","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":263762,"rule_based_match":true,"evidence_text":"c.1412A>G (p.Glu471Gly)","llm_judgment":"PRESENT","evidence":"c.1412A>G (p.Glu471Gly)","abstract_start":655,"abstract_end":678}]}
{"pmid":"29682366","title":"Whole Exome Sequencing and Molecular Modeling of a Missense Variant in","abstract":"Chronic urticaria is a common condition characterized by recurrent hives lasting several weeks or months and is usually idiopathic. Approximately half of the individuals with chronic urticaria will present with episodes of angioedema that can be severe and debilitating. In this report, we describe a 47-year-old Hispanic male who presented initially for an evaluation of chronic hives following hospitalization due to hive-induced anaphylaxis. The individual had a history significant for urticaria and angioedema beginning in his early 30s. Interestingly, both the individual's 41-year-old sister and 12-year-old daughter were also affected with chronic urticaria and severe angioedema. Whole exome sequencing of the proband and several family members revealed a heterozygous variant of uncertain significance in exon 2 of <i>TNFAIP3</i>, denoted as c.65G>A (p.R22Q), in all affected members. Variants in <i>TNFAIP3</i> have been associated with multiple autoimmune diseases, susceptibility to allergy and asthma, and periodic fever syndromes, suggesting that this variant could potentially play a role in disease.","variants":[{"Name":"NM_001270508.2(TNFAIP3):c.65G>A (p.Arg22Gln)","Chromosome":"6","Start":"137871292","Stop":"137871292","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1365735,"rule_based_match":true,"evidence_text":"c.65G>A (p.R22Q)","llm_judgment":"PRESENT","evidence":"c.65G>A (p.R22Q)","abstract_start":852,"abstract_end":868}]}
{"pmid":"37005154","title":"A novel homozygous nonsense variant of LMF1 in pregnancy-induced hypertriglyceridemia with acute pancreatitis.","abstract":"Hypertriglyceridemia (HTG)-induced pancreatitis during pregnancy could lead to maternal and fetal death. However, its genetic bases are not fully understood, and its treatment strategies are yet to be established. Here we report a case with a novel homozygous nonsense variant of LMF1 in pregnancy-associated HTG with acute pancreatitis. Our patient had childhood-onset severe HTG that had been well-controlled by dietary management in the non-pregnant period with plasma triglyceride (TG) levels at around 200 mg/dL. Milky plasma was noted at the first-trimester pregnancy checkup, followed by a severe increase in plasma TG (10,500 mg/dL) that resulted in pancreatitis in the last trimester. The implementation of strict dietary fat restriction (less than 4 grams per day) reduced plasma TG levels and led to successful delivery. Exome sequencing revealed a novel homozygous nonsense variant in LMF1 (c.697C>T, p.Arg233Ter). The activities of lipoprotein lipase (LPL) and hepatic lipase in post-heparin plasma were not abolished but reduced. The use of pemafibrate decreased plasma TG levels with a concomitant increase in LPL activity. HTG in childhood or early pregnancy is commonly assumed to be polygenic in origin but should be regarded as a feature suggestive of monogenic hyperchylomicronemia. Adequate TG monitoring and dietary fat restriction should be implemented to prevent potentially lethal events of pancreatitis.","variants":[{"Name":"NM_022773.4(LMF1):c.697C>T (p.Arg233Ter)","Chromosome":"16","Start":"893039","Stop":"893039","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1669571,"rule_based_match":true,"evidence_text":"c.697C>T, p.Arg233Ter","llm_judgment":"PRESENT","evidence":"c.697C>T, p.Arg233Ter","abstract_start":903,"abstract_end":924}]}
{"pmid":"22387237","title":"Novel NaPi-IIc mutations causing HHRH and idiopathic hypercalciuria in several unrelated families: long-term follow-up in one kindred.","abstract":"Homozygous and compound heterozygous mutations in SLC34A3, the gene encoding the sodium-dependent co-transporter NaPi-IIc, cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate-wasting resulting in hypophosphatemia, elevated 1,25(OH)(2) vitamin D levels, hypercalciuria, rickets/osteomalacia, and frequently kidney stones or nephrocalcinosis. Similar albeit less severe biochemical changes are also observed in heterozygous carriers, which are furthermore indistinguishable from those encountered in idiopathic hypercalciuria (IH). We now searched for SLC34A3 mutations (exons and introns) in two previously not reported HHRH kindreds, which resulted in the identification of three novel mutations. The affected members of kindred A were compound heterozygous for two different mutations, c.1046_47del and the intronic mutation c.560+23_561-42del, while the index case in kindred B was homozygous for the nonsense SLC34A3 mutation c.1764C>G (p.Y588X). The patient in kindred C was diagnosed with IH because of bilateral medullary nephrocalcinosis, suppressed PTH levels, and hypercalciuria; she was found to have a novel heterozygous c.1571_1880del mutation. The HHRH patients in kindred A were treated for up to 7years with oral phosphate, which led to reversal of hypophosphatemia, hypercalciuria, and prevention or healing of the mild bone abnormalities. PTH levels were normal throughout the observation period, while 1,25(OH)(2) vitamin D levels remained elevated and may thus be helpful for assessing treatment efficacy and patient compliance in HHRH.","variants":[{"Name":"NM_001177316.2(SLC34A3):c.1046_1047del (p.Val349fs)","Chromosome":"9","Start":"137234227","Stop":"137234228","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":1020610,"rule_based_match":false,"evidence_text":"c.1046_47del","llm_judgment":"PRESENT","evidence":"c.1046_47del","abstract_start":849,"abstract_end":861},{"Name":"NM_001177316.2(SLC34A3):c.1764C>G (p.Tyr588Ter)","Chromosome":"9","Start":"137236380","Stop":"137236380","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3856723,"rule_based_match":true,"evidence_text":"c.1764C>G (p.Y588X)","llm_judgment":"PRESENT","evidence":"c.1764C>G (p.Y588X)","abstract_start":991,"abstract_end":1010}]}
{"pmid":"29261182","title":"Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development.","abstract":"PURPOSE: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.\nMETHODS: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-β (ER-β) was performed in an 8-week-old human male embryo.\nRESULTS: We identified a homozygous ESR2 variant, c.541_543del p.(Asn181del), located in the highly conserved DNA-binding domain of ER-β, in an individual with syndromic 46,XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-β, were found in unrelated, nonsyndromic 46,XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-β immunostaining was positive in the developing intestine and eyes.\nCONCLUSION: Our study supports a role for ESR2 as a novel candidate gene for 46,XY DSD.","variants":[{"Name":"NM_001437.3(ESR2):c.541_543del (p.Asn181del)","Chromosome":"14","Start":"64268904","Stop":"64268906","ReferenceAlleleVCF":"CATT","AlternateAlleleVCF":"C","allel_id":581724,"rule_based_match":true,"evidence_text":"c.541_543del p.(Asn181del)","llm_judgment":"PRESENT","evidence":"c.541_543del p.(Asn181del)","abstract_start":797,"abstract_end":823},{"Name":"NM_001437.3(ESR2):c.1277T>G (p.Leu426Arg)","Chromosome":"14","Start":"64235099","Stop":"64235099","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":581725,"rule_based_match":true,"evidence_text":"c.1277T>G p.(Leu426Arg)","llm_judgment":"PRESENT","evidence":"c.1277T>G p.(Leu426Arg)","abstract_start":1001,"abstract_end":1024}]}
{"pmid":"22187958","title":"Secondary mutation (c.94_95delAG) in a -α3.7 allele associated with Hb H disease in two unrelated African American individuals homozygous for the -α(3.7) deletion (-α3.7/-α3.7T).","abstract":"Hb H disease is rarely seen in individuals of African descent although α-thalassemia (α-thal) is common in this population. Usually α-thal is due either to heterozygosity or homozygosity for the -α(3.7) deletion in this population. We report Hb H disease that is caused by a frameshift mutation on one -α(3.7) allele in two unrelated individuals homozygous for the -α(3.7) deletion. These two cases highlight the importance of further investigation by direct sequencing of the -α(3.7) allele when the thalassemic phenotype does not correlate with the genotype obtained by initial molecular testing.","variants":[{"Name":"NM_000558.5(HBA1):c.94_95del (p.Arg32fs)","Chromosome":"16","Start":"176807","Stop":"176808","ReferenceAlleleVCF":"GGA","AlternateAlleleVCF":"G","allel_id":789593,"rule_based_match":true,"evidence_text":"c.94_95del","llm_judgment":"PRESENT","evidence":"c.94_95del","abstract_start":null,"abstract_end":null}]}
{"pmid":"32864149","title":"A Japanese boy with","abstract":"<i>NAA10</i>-related syndrome is an extremely rare X-chromosomal disorder, the symptoms of which include intellectual disability (ID), ocular anomalies, or congenital heart diseases, such as hypertrophic cardiomyopathy (HCM). Here, we describe a 4-year-old Japanese male patient who exhibited mild ID, HCM, and specific facial features. A hemizygous mutation (NM_003491.3: c.455_458del, p. Thr152Argfs*6) in exon 7 of <i>NAA10</i> was detected. We recommend that patients undergo precise medical follow-up considering the characteristics of <i>NAA10</i>-related syndrome.","variants":[{"Name":"NM_003491.4(NAA10):c.455_458del (p.Thr152fs)","Chromosome":"X","Start":"153930776","Stop":"153930779","ReferenceAlleleVCF":"CTGAG","AlternateAlleleVCF":"C","allel_id":1053438,"rule_based_match":true,"evidence_text":"NM_003491.3: c.455_458del","llm_judgment":"PRESENT","evidence":"NM_003491.3: c.455_458del","abstract_start":360,"abstract_end":385}]}
{"pmid":"31388113","title":"A novel compound heterozygous mutation in AARS2 gene (c.965 G > A, p.R322H; c.334 G > C, p.G112R) identified in a Chinese patient with leukodystrophy involved in brain and spinal cord.","abstract":"Leukodystrophies are genetic disorders leading to progressive white matter degeneration in the central nervous system. Mitochondrial aminoacyl tRNA synthase protein is encoded by the nuclear gene AARS2. An autosomal recessive mutation in this gene has been linked to AARS2 mutation-related adult-onset leukodystrophy (AARS2-L) or infantile mitochondrial cardiomyopathy. To date, only 16 AARS2-L cases have been reported in English literature. Thus, the clinical and genetic characteristics of this disease remain to be defined. Through whole-exome sequencing, we identified a Chinese patient with leukodystrophy related to two novel compounds heterozygous mutation in AARS2 (c.965 G > A, p.R322H; c.334 G > C, p.G112R). These two compounds heterozygous variants in AARS2 gene co-segregated with disease in his family. And pyramidal tracts in the spinal cord were involved. Our findings have important implications on genetic counseling for any case with leukodystrophy and extend the mutational spectrum in AARS2 gene.","variants":[{"Name":"NM_020745.4(AARS2):c.965G>A (p.Arg322His)","Chromosome":"6","Start":"44307324","Stop":"44307324","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1948969,"rule_based_match":true,"evidence_text":"c.965 G > A, p.R322H","llm_judgment":"PRESENT","evidence":"c.965 G > A, p.R322H","abstract_start":675,"abstract_end":695}]}
{"pmid":"16829352","title":"Deleterious mutations in exon 1 of MECP2 in Rett syndrome.","abstract":"The MECP2 gene is responsible for 80-85% of typical cases of Rett syndrome with deleterious mutations affecting exons 3 and 4. Recently, an alternate transcript including exon 1 was discovered with a new protein isoform (MeCP2_e1) much more abundant in brain. We screened exon 1 of MECP2 for mutations and for large rearrangements in a panel of 212 typical cases of Rett syndrome and one family case with atypical Rett syndrome. We identified two deleterious mutations (c.48_55dup and c.62+2_62+3del) and four large rearrangements encompassing exon 1 of MECP2. We also identified the c.16_21dup alteration formerly reported as c.3_4insGCCGCC and give additional support to classify this sequence variation as polymorphic. In our large panel of typical Rett, mutations affecting exon 1 of MECP2 represent 1% of the deleterious alleles. This study confirms that mutations in exon 1 of MECP2 are a rare cause of Rett syndrome.","variants":[{"Name":"NM_001110792.2(MECP2):c.62+2_62+3del","Chromosome":"X","Start":"154097601","Stop":"154097602","ReferenceAlleleVCF":"TCA","AlternateAlleleVCF":"T","allel_id":187558,"rule_based_match":true,"evidence_text":"c.62+2_62+3del","llm_judgment":"PRESENT","evidence":"c.62+2_62+3del","abstract_start":485,"abstract_end":499},{"Name":"NM_001110792.2(MECP2):c.48_55dup (p.Glu19fs)","Chromosome":"X","Start":"154097610","Stop":"154097611","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TCCTCCTCG","allel_id":187563,"rule_based_match":true,"evidence_text":"c.48_55dup","llm_judgment":"PRESENT","evidence":"c.48_55dup","abstract_start":470,"abstract_end":480}]}
{"pmid":"20034068","title":"Homozygosity for the common mutation c.1085dupT in the ZMPSTE24 gene in a Mennonite baby with restrictive dermopathy and placenta abruption.","abstract":"","variants":[{"Name":"NM_005857.5(ZMPSTE24):c.1085dup (p.Leu362fs)","Chromosome":"1","Start":"40290870","Stop":"40290871","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":19310,"rule_based_match":true,"evidence_text":"c.1085dupT","llm_judgment":"PRESENT","evidence":"c.1085dupT","abstract_start":null,"abstract_end":null}]}
{"pmid":"26888048","title":"The rare Costello variant HRAS c.173C>T (p.T58I) with severe neonatal hypertrophic cardiomyopathy.","abstract":"We report a 10-year-old girl presenting with severe neonatal hypertrophic cardiomyopathy (HCM), feeding difficulties, mildly abnormal facial features, and progressive skeletal muscle symptoms but with normal cognitive development. Targeted oligonucleotide-selective sequencing of 101 cardiomyopathy genes revealed the genetic diagnosis, and the mutation was verified by Sanger sequencing in the patient and her parents. To offer insights into the potential mechanism of patient mutation, protein structural analysis was performed using the resolved structure of human activated HRAS protein with bound GTP analogue (PDB id 5P21) in Discovery Studio 4.5 (Dassault Systèmes Biovia, San Diego, CA). The patient with hypertrophic cardiomyopathy and normal cognitive development was diagnosed with an HRAS mutation c.173C>T (p.T58I), a milder variant of Costello syndrome affecting a highly conserved amino acid, threonine 58. Our analysis suggests that the p.G12 mutations slow GTP hydrolysis rendering HRAS unresponsive to GTPase activating proteins, and resulting in permanently active state. The p.T58I mutation likely affects binding of guanidine-nucleotide-exchange factors, thereby promoting the active state but also allowing for slow inactivation. Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome. We expand the clinical and molecular picture of the rare HRAS mutation by reporting the first case in Europe and the fourth case in the literature. Our protein structure analysis offers insights into the mechanism of the mildly activating p.T58I mutation. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_005343.4(HRAS):c.173C>T (p.Thr58Ile)","Chromosome":"11","Start":"533883","Stop":"533883","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27649,"rule_based_match":true,"evidence_text":"HRAS mutation c.173C>T (p.T58I)","llm_judgment":"PRESENT","evidence":"HRAS mutation c.173C>T (p.T58I)","abstract_start":796,"abstract_end":827}]}
{"pmid":"29391521","title":"A clinical and molecular characterisation of CRB1-associated maculopathy.","abstract":"To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.","variants":[{"Name":"NM_201253.3(CRB1):c.498_506del (p.Ile167_Gly169del)","Chromosome":"1","Start":"197328844","Stop":"197328852","ReferenceAlleleVCF":"GGATGGAATT","AlternateAlleleVCF":"G","allel_id":102552,"rule_based_match":true,"evidence_text":"c.498_506del, p.(Ile167_Gly169del)","llm_judgment":"PRESENT","evidence":"c.498_506del, p.(Ile167_Gly169del)","abstract_start":1030,"abstract_end":1064}]}
{"pmid":"32252219","title":"Persistent goiter with congenital hypothyroidism due to mutation in DUOXA2 gene.","abstract":"Thyroid hormones are crucial for development of the central nervous system. Congenital hypothyroidism (CH) is the most common preventable disease resulting in mental retardation. A neonatal screening test (NST) can detect a mild form of CH that can be treated at an early age. Generally after 3 years of age, when most of the brain has matured, clinicians consider reevaluation of thyroid function for CH patients that have been identified with a normal thyroid gland at a normal position. This report presents three CH patients that developed normally, with persistent goiter despite thyroid hormone supplements. The patients' initial thyroid-stimulating hormone (TSH) level after NST was 47, 157, and 57 mIU/L, respectively. Levothyroxine administration began at 1 or 2 months of age and was terminated after reevaluation at the age of 3, 15, and 5 years, respectively. However, 1 or 2 years later, they all resumed their medication due to increased TSH level coupled with newly developed or enlarged goiter. They all showed dual oxidase maturation factor 2 (DUOXA2) gene mutation: a homozygous mutation with DUOXA2 (c.413dupA; p.Tyr138*) in case 1, a presumed compound heterozygotic mutation with DUOXA2 (p.Tyr138*/p.Tyr246*) in case 2, and heterozygous mutations with DUOXA2 (c.738C&gt;G; p.Tyr246*) and TPO (c.2268dupT; p.Glu757*) in case 3. When goiter persists or is newly developed despite a maintained euthyroid status, for those with transient CH history, follow-up to assess the thyroid function is recommended for at least 1 or 2 years, and genetic testing would be helpful. This study presents the first clinical cases of DUOXA2 mutation in Korea.","variants":[{"Name":"NM_207581.4(DUOXA2):c.738C>G (p.Tyr246Ter)","Chromosome":"15","Start":"45117274","Stop":"45117274","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":15483,"rule_based_match":false,"evidence_text":"DUOXA2 (c.738C>G; p.Tyr246*)","llm_judgment":"PRESENT","evidence":"p.Tyr246*","abstract_start":1218,"abstract_end":1227}]}
{"pmid":"29676688","title":"Ophthalmic manifestations of Heimler syndrome due to PEX6 mutations.","abstract":"BACKGROUND/AIMS: Pigmentary retinal dystrophy and macular dystrophy have been previously reported in Heimler syndrome due to mutations in PEX1. Here we reported the ocular manifestations in Heimler syndrome due to mutations in PEX6.\nMATERIALS AND METHODS: Medical records were reviewed to identify patient demographics, ophthalmic and systemic findings, and results of diagnostic testing including whole genome sequencing.\nRESULTS: Patient 1 is 12-year-old boy with a novel mutation c.275T>G (p.Val92Gly) and known mutation c.1802G>A (p.Arg601Gln) in PEX6. Patient 2 is a 7-year-old girl with the same known c.1802G>A (p.Arg601Gln) mutation and another novel missense mutation c.296G>T (p.Arg99Leu). Both patients exhibited a pigmentary retinopathy. Visual acuity in patient 1 was 20/80 and 20/25 following treatment of intraretinal cystoid spaces with carbonic anhydrase inhibitors, while patient 2 had visual acuity of 20/20 in both eyes without intraretinal cysts. Fundus autofluorescence showed a multitude of hyperfluorescent deposits in the paramacular area of both eyes. OCTs revealed significant depletion of photoreceptors in both patients and macular intraretinal cystoid spaces in one patient. Full field electroretinograms showed normal or abnormal photopic but normal scotopic responses. Multifocal electroretinograms were abnormal.\nCONCLUSIONS: Heimler syndrome due to biallelic PEX6 mutations demonstrates a macular dystrophy with characteristic fundus autofluorescence and may be complicated by intraretinal cystoid spaces.","variants":[{"Name":"NM_000287.4(PEX6):c.1802G>A (p.Arg601Gln)","Chromosome":"6","Start":"42967450","Stop":"42967450","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":195870,"rule_based_match":true,"evidence_text":"c.1802G>A (p.Arg601Gln)","llm_judgment":"PRESENT","evidence":"c.1802G>A (p.Arg601Gln)","abstract_start":524,"abstract_end":547}]}
{"pmid":"33517539","title":"Adult polyglucosan body disease-an atypical compound heterozygous with a novel GBE1 mutation.","abstract":"INTRODUCTION: Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy characterized by neurogenic bladder starting after 40 years old, spastic paraparesis and peripheral neuropathy. It is mainly resultant from the GBE1 homozygous p.Tyr329Ser (c.986A>C) mutation, especially in Ashkenazi-Jewish patients, although some cases of compound heterozygous have been reported. A genotype-phenotype correlation is not established, but atypical phenotypes have been described mainly in non-p.Tyr329Ser pathogenic variants.\nCASE REPORT: We describe an atypical case in a 62-year-old Portuguese woman, presenting the typical clinical triad of APBD plus prominent autonomic dysfunction, suggested by orthostatic hypotension and thermoregulatory dysfunction; she has compound heterozygous GBE1 mutations, namely, p.Asn541Asp (c.1621A>G) and p.Arg515Gly (c.1543C>G), the last one not yet reported in literature and whose pathogenicity was suggested by bioinformatics analysis and confirmed by sural nerve biopsy that showed intra-axonal polyglucosan bodies.\nDISCUSSION: Besides the report of a novel GBE1 mutation, this case also expands the phenotypic spectrum of this disorder, reinforcing autonomic dysfunction as a possible and prominent manifestation of APBD, mimicking autosomal dominant leukodystrophy with autonomic disease in some way. Therefore, we questioned a possible relationship between this genotype and the phenotype marked by dysautonomia. Additionally, we review previously reported cases of APBD in non-homozygous p.Tyr329Ser patients with atypical phenotypes.","variants":[{"Name":"NM_000158.4(GBE1):c.1621A>G (p.Asn541Asp)","Chromosome":"3","Start":"81537093","Stop":"81537093","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":828568,"rule_based_match":true,"evidence_text":"c.1621A>G","llm_judgment":"PRESENT","evidence":"c.1621A>G","abstract_start":836,"abstract_end":845},{"Name":"NM_000158.4(GBE1):c.1543C>G (p.Arg515Gly)","Chromosome":"3","Start":"81578000","Stop":"81578000","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3090913,"rule_based_match":true,"evidence_text":"c.1543C>G","llm_judgment":"PRESENT","evidence":"c.1543C>G","abstract_start":864,"abstract_end":873}]}
{"pmid":"30688039","title":"Identification of a pathogenic mutation in ATP2A1 via in silico analysis of exome data for cryptic aberrant splice sites.","abstract":"BACKGROUND: Pathogenic mutations causing aberrant splicing are often difficult to detect. Standard variant analysis of next-generation sequence (NGS) data focuses on canonical splice sites. Noncanonical splice sites are more difficult to ascertain.\nMETHODS: We developed a bioinformatics pipeline that screens existing NGS data for potentially aberrant novel essential splice sites (PANESS) and performed a pilot study on a family with a myotonic disorder. Further analyses were performed via qRT-PCR, immunoblotting, and immunohistochemistry. RNAi knockdown studies were performed in Drosophila to model the gene deficiency.\nRESULTS: The PANESS pipeline identified a homozygous ATP2A1 variant (NC_000016.9:g.28905928G>A; NM_004320.4:c.1287G>A:p.(Glu429=)) that was predicted to cause the omission of exon 11. Aberrant splicing of ATP2A1 was confirmed via qRT-PCR, and abnormal expression of the protein product sarcoplasmic/endoplasmic reticulum Ca<sup>++</sup> ATPase 1 (SERCA1) was demonstrated in quadriceps femoris tissue from the proband. Ubiquitous knockdown of SERCA led to lethality in Drosophila, as did knockdown targeting differentiating or fusing myoblasts.\nCONCLUSIONS: This study confirms the potential of novel in silico algorithms to detect cryptic mutations in existing NGS data; expands the phenotypic spectrum of ATP2A1 mutations beyond classic Brody myopathy; and suggests that genetic testing of ATP2A1 should be considered in patients with clinical myotonia.","variants":[{"Name":"NM_004320.6(ATP2A1):c.1287G>A (p.Glu429=)","Chromosome":"16","Start":"28894607","Stop":"28894607","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":536902,"rule_based_match":true,"evidence_text":"NM_004320.4:c.1287G>A:p.(Glu429=)","llm_judgment":"PRESENT","evidence":"NM_004320.4:c.1287G>A:p.(Glu429=)","abstract_start":722,"abstract_end":755}]}
{"pmid":"38307397","title":"Evaluating the efficacy of a long-read sequencing-based approach in the clinical diagnosis of neonatal congenital adrenocortical hyperplasia.","abstract":"Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders predominantly characterized by impaired corticosteroid synthesis. Clinical phenotypes include hypoadrenocorticism, electrolyte disturbances, abnormal gonadal development, and short stature, of which severe hyponadrenocorticism and salt wasting can be life-threatening. Genetic analysis can help in the clinical diagnosis of CAH. However, the 21-OHD-causing gene CYP21A2 is arranged in tandem with the highly homologous CYP21A1P pseudogene, making it difficult to determine the exact genotypes using the traditional method of multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing or next-generation sequencing (NGS). We applied a long-read sequencing-based approach termed comprehensive analysis of CAH (CACAH) to 48 newborns with CAH that were diagnosed by clinical features and the traditional MLPA plus Sanger sequencing method for retrospective analysis, to evaluate its efficacy in the clinical diagnosis of neonatal CAH. Compared with the MLPA plus Sanger sequencing method, CACAH showed 100 % consistency in detecting SNV/indel variants located in exons and exon-intron boundary regions of CAH-related genes. It can directly determine the cis-trans relationship without the need to analyze parental genotypes, which reduces the time to diagnosis. Moreover, CACAH was able to distinguish different CYP21A1P/CYP21A2 and TNXA/TNXB chimeras, and detect additional variants (CYP21A2 variants c.-121C > T, c.*13G > A, c.*52C > T, c.*440C > T, c.*443 T > C, and TNXB variants c.12463 + 2 T > C, c.12204 + 5G > A). We also identified the TNXB variant c.11435_11524 + 30del alone instead of as a part of the TNXA/TNXB-CH-1 chimera in two newborns, which might be introduced by gene conversion. All of these characteristics enabled clinicians to better explain the phenotype of subjects and manage them more effectively. CACAH has a great advantage over the traditional MLPA and Sanger sequencing methods, showing substantial potential in the genetic diagnosis and screening of neonatal CAH.","variants":[{"Name":"NM_000500.9(CYP21A2):c.*13G>A","Chromosome":"6","Start":"32041147","Stop":"32041147","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":576926,"rule_based_match":true,"evidence_text":"c.*13G > A","llm_judgment":"PRESENT","evidence":"c.*13G > A","abstract_start":1512,"abstract_end":1522}]}
{"pmid":"24522292","title":"Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease.","abstract":"Gaucher disease (GD) is the most common glycolipid storage disorder resulting from glucocerebrosidase deficiency due to mutations in the GBA gene. Study was performed in 33 unrelated patients with low β-glucosidase activity in leukocytes and/or fibroblasts. The exons and exon-intron boundaries of the GBA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and were looked up in public databases, and in silico analysis was carried for novel mutations. We identified two novel missense mutations G289A (c.866G>C) and I466S (c.1397T>G) in exons 7 and 10, respectively, in two (6.06%) patients that destabilize the protein structure. L444P (c.1448T>C) was the most common mutation identified in 20/33 (60.60%) non-neuronopathic and 1/33 (3.03%) sub-acute neuronopathic form based on clinical presentation at the time of investigation. Other nine rare mutations were: R463C (c.1504C>T), R395C (c.1300C>T), R359Q (c.1193G>A), G355D (c.1181G>A), V352M (c.1171G>A) and S356F (c.1184C>T) found in each patient (18.18%). Compound heterozygous mutation L444P (c.1448T>C)/R496C (c.1603C>T) in exon 10/11 and L444P (c.1448T>C)/R329C (c.1102C>T) were observed in exon 10/8 in one each patient (6.06%). Two patients (6.06%) from Sri Lanka showed E326K (c.1093G>A) mutation in exon 8. We conclude that L444P is the most common mutant allele with exons 8 and 10 as the hot spot region of GBA gene observed in Indian GD patients.","variants":[{"Name":"NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys)","Chromosome":"1","Start":"155235196","Stop":"155235196","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19334,"rule_based_match":true,"evidence_text":"c.1504C>T","llm_judgment":"PRESENT","evidence":"c.1504C>T","abstract_start":923,"abstract_end":932},{"Name":"NM_000157.4(GBA1):c.1193G>A (p.Arg398Gln)","Chromosome":"1","Start":"155236276","Stop":"155236276","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2843564,"rule_based_match":true,"evidence_text":"c.1193G>A","llm_judgment":"PRESENT","evidence":"c.1193G>A","abstract_start":961,"abstract_end":970},{"Name":"NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)","Chromosome":"1","Start":"155235252","Stop":"155235252","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19327,"rule_based_match":true,"evidence_text":"c.1448T>C","llm_judgment":"PRESENT","evidence":"c.1448T>C","abstract_start":690,"abstract_end":699}]}
{"pmid":"26637979","title":"SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation.","abstract":"SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably β-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.","variants":[{"Name":"NM_001135146.2(SLC39A8):c.112G>C (p.Gly38Arg)","Chromosome":"4","Start":"102344551","Stop":"102344551","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":215655,"rule_based_match":true,"evidence_text":"c.112G>C (p.Gly38Arg)","llm_judgment":"PRESENT","evidence":"c.112G>C (p.Gly38Arg)","abstract_start":461,"abstract_end":482},{"Name":"NM_001135146.2(SLC39A8):c.1019T>A (p.Ile340Asn)","Chromosome":"4","Start":"102267901","Stop":"102267901","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":215656,"rule_based_match":true,"evidence_text":"c.1019T>A (p.Ile340Asn)","llm_judgment":"PRESENT","evidence":"c.1019T>A (p.Ile340Asn)","abstract_start":487,"abstract_end":510},{"Name":"NM_001135146.2(SLC39A8):c.610G>T (p.Gly204Cys)","Chromosome":"4","Start":"102305054","Stop":"102305054","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":215657,"rule_based_match":true,"evidence_text":"c.610G>T (p.Gly204Cys)","llm_judgment":"PRESENT","evidence":"c.610G>T (p.Gly204Cys)","abstract_start":653,"abstract_end":675},{"Name":"NM_001135146.2(SLC39A8):c.97G>A (p.Val33Met)","Chromosome":"4","Start":"102344566","Stop":"102344566","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215659,"rule_based_match":true,"evidence_text":"c.97G>A (p.Val33Met)","llm_judgment":"PRESENT","evidence":"c.97G>A (p.Val33Met)","abstract_start":577,"abstract_end":597}]}
{"pmid":"36054293","title":"Kyphoscoliotic Ehlers-Danlos syndrome caused by pathogenic variants in FKBP14: Further insights into the phenotypic spectrum and pathogenic mechanisms.","abstract":"The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue diseases. The autosomal recessive kyphoscoliotic EDS results from deficiency of either lysyl hydroxylase 1 (encoded by PLOD1), crucial for collagen cross-linking; or the peptidyl-prolyl cis-trans isomerase family FK506-binding protein 22 kDa (FKBP22 encoded by FKBP14), a molecular chaperone of types III, IV, VI, and X collagen. This study reports the clinical manifestations of three probands with homozygous pathogenic FKBP14 variants, including the previously reported c.362dupC; p.(Glu122Argfs*7) variant, a novel missense variant (c.587A>G; p.(Asp196Gly)) and a start codon variant (c.2T>G; p.?). Consistent clinical features in the hitherto reported individuals (n = 40) are kyphoscoliosis, generalized joint hypermobility and congenital muscle hypotonia. Severe vascular complications have been observed in 12.5%. A previously unreported feature is microcornea observed in two probands reported here. Both the c.587A>G and the c.362dupC variant cause complete loss of FKBP22. With immunocytochemistry on dermal fibroblasts, we provide the first evidence for intracellular retention of types III and VI collagen in EDS-FKBP14. Scratch wound assays were largely normal. Western blot of proteins involved in the unfolded protein response and autophagy did not reveal significant upregulation in dermal fibroblasts.","variants":[{"Name":"NM_017946.4(FKBP14):c.362dup (p.Glu122fs)","Chromosome":"7","Start":"30019110","Stop":"30019111","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":264319,"rule_based_match":true,"evidence_text":"c.362dupC; p.(Glu122Argfs*7)","llm_judgment":"PRESENT","evidence":"c.362dupC; p.(Glu122Argfs*7)","abstract_start":564,"abstract_end":592}]}
{"pmid":"28231849","title":"A novel mutation in the STK11 gene causes heritable Peutz-Jeghers syndrome - a case report.","abstract":"BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare disorder characterized by multiple gastrointestinal hamartomatous polyps and mucocutaneous pigmentation. STK11 has been identified as a causative gene for this disease.\nCASE PRESENTATION: Herein we report a Chinese Han kindred with PJS. Onset for the PJS signs in three of the patients was rarely as early as at birth. We identified a novel heterozygous mutation (c.440_441delGT, p.Arg147Leufs*15) in the gene STK11, causing a short frameshift followed by a deletion of 63% of the amino acids in the STK protein. This mutation co-segregated with the PJS phenotype, and was absent in two hundred of unrelated ethnicity-matched controls. The mutation led to expression decrease of unaffected STK11 protein in patients than in controls, as well in PJ polyps than in circulating leucocytes from the patients. Phosphorylation levels of the downstream kinase AMPKα altered according with the expression of STK11. These results indicated the possibility that haploinsufficiency and epigenetic reduction of STK11 contributed to the pathogenesis of the disease.\nCONCLUSION: This study identifies a novel mutation in the pathogenic gene STK11 leading to PJS.","variants":[{"Name":"NM_000455.5(STK11):c.440_441del (p.Arg147fs)","Chromosome":"19","Start":"1219389","Stop":"1219390","ReferenceAlleleVCF":"CGT","AlternateAlleleVCF":"C","allel_id":362212,"rule_based_match":true,"evidence_text":"c.440_441delGT","llm_judgment":"PRESENT","evidence":"c.440_441delGT","abstract_start":415,"abstract_end":429}]}
{"pmid":"35471564","title":"Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia.","abstract":"OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683).\nMETHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed.\nRESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism.\nINTERPRETATION: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022;92:304-321.","variants":[{"Name":"NM_001776.6(ENTPD1):c.640del (p.Gly216fs)","Chromosome":"10","Start":"95845422","Stop":"95845422","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":2417529,"rule_based_match":true,"evidence_text":"c.640del; p.(Gly216Glufs*75)","llm_judgment":"PRESENT","evidence":"c.640del; p.(Gly216Glufs*75)","abstract_start":859,"abstract_end":887},{"Name":"NM_001776.6(ENTPD1):c.574-6_574-3del","Chromosome":"10","Start":"95845349","Stop":"95845352","ReferenceAlleleVCF":"GTCTT","AlternateAlleleVCF":"G","allel_id":791018,"rule_based_match":true,"evidence_text":"c.574-6_574-3del","llm_judgment":"PRESENT","evidence":"c.574-6_574-3del","abstract_start":1079,"abstract_end":1095},{"Name":"NM_001776.6(ENTPD1):c.1109T>A (p.Leu370Ter)","Chromosome":"10","Start":"95860503","Stop":"95860503","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2417527,"rule_based_match":true,"evidence_text":"c.1109 T > A; p.(Leu370*)","llm_judgment":"PRESENT","evidence":"c.1109 T > A; p.(Leu370*)","abstract_start":1052,"abstract_end":1077}]}
{"pmid":"36699790","title":"Variables in the ACBD5 Gene Leading to Distinct Phenotypes: A Case Report.","abstract":"We report the cases of a father and his daughter, the former diagnosed with retinitis pigmentosa (RP) and the latter with early foveal atrophy; while both shared a novel variant of uncertain significance (VUS) in the <i>ACBD5</i> gene (variant c.431G>A), they exhibited different clinical profiles and disease manifestations. The father was a 48-year-old man who presented with nyctalopia that had persisted since age seven. He had mild disk pallor, vessel attenuation, retinal pigment epithelium (RPE) changes nasal to the fovea, and few mid-peripheral bone spicules. Sequencing analysis showed that he carried seven VUS in five genes: <i>ACBD5</i> c.431G>A (p.Gly144Asp), <i>CYP4V2</i> c.296T>C (p.Met99Thr), <i>EYS</i> c.1852G>A (p.Gly618Ser), <i>HMCN1</i> c.280G>A (p.Val94Met), <i>HMCN1</i> c.8939A>C (p.Asn2980Thr), <i>RP1L1</i> c.575C>A (p.Pro192His), and <i>RP1L1</i> c.1375A>C (p.Thr459Pro). He shared only the <i>ACBD5</i> gene with his 18-year-old daughter. The daughter had 20/20 visual acuity, but further testing showed foveal atrophy and hyperautofluorescence. Intrafamilial phenotypic heterogeneity was detected in our patients. Studies on the role of hormonal factors leading to phenotypic variability are warranted.","variants":[{"Name":"NM_145698.5(ACBD5):c.431G>A (p.Gly144Asp)","Chromosome":"10","Start":"27223397","Stop":"27223397","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":836790,"rule_based_match":true,"evidence_text":"ACBD5 c.431G>A (p.Gly144Asp)","llm_judgment":"PRESENT","evidence":"ACBD5</i> c.431G>A (p.Gly144Asp)","abstract_start":640,"abstract_end":672}]}
{"pmid":"23871674","title":"Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised 2010 task force criteria with inclusion of non-desmosomal phospholamban mutation carriers.","abstract":"Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is frequently associated with desmosomal mutations. However, nondesmosomal mutations may be involved. The aim of this study was to assess the contribution of a phospholamban (PLN) gene mutation to ARVD/C diagnosis according to the revised 2010 task force criteria (TFC). In 142 Dutch patients (106 men, mean age 51 ± 13 years) with proven ARVD/C (fulfillment of 2010 TFC for diagnosis), 5 known desmosomal genes (PKP2, DSP, DSC2, DSG2, and JUP) and the nondesmosomal PLN gene were screened. After genetic analysis, phenotypic characteristics of desmosomal versus PLN mutation carriers were compared. In 59 of 142 patients with ARVD/C (42%), no desmosomal mutation was found. In 19 of 142 patients (13%), the PLN founder mutation c.40_42delAGA (p.Arg14del) was identified. PLN mutation carriers more often had low-voltage electrocardiograms (p = 0.004), inverted T waves in leads V4 to V6 (p <0.001), and additional structural (p = 0.007) or functional (p = 0.017) left ventricular impairment, whereas desmosomal mutation carriers had more solitary right ventricular abnormalities. The revised TFC included 21 of 142 patients with proven ARVD/C who did not meet the 1994 TFC, including 7 PLN mutation carriers. In conclusion, there is a substantial contribution of PLN mutation to ARVD/C diagnosis by the 2010 TFC. In 32% of patients (19 of 59) with genetically unexplained proven ARVD/C, this nondesmosomal mutation was found. PLN mutation carriers have ARVD/C characteristics, including important right ventricular involvement, and additionally more often low-voltage electrocardiograms, inverted T waves in the left precordial leads, and left ventricular involvement.","variants":[{"Name":"NM_002667.5(PLN):c.37AGA[1] (p.Arg14del)","Chromosome":"6","Start":"118558957","Stop":"118558959","ReferenceAlleleVCF":"TAAG","AlternateAlleleVCF":"T","allel_id":53747,"rule_based_match":false,"evidence_text":"the PLN founder mutation c.40_42delAGA (p.Arg14del)","llm_judgment":"PRESENT","evidence":"the PLN founder mutation c.40_42delAGA (p.Arg14del)","abstract_start":771,"abstract_end":822}]}
{"pmid":"36338671","title":"A five-year follow-up of","abstract":"Purpose: To investigate whether the reduced retinal function and morphological retinal changes previously demonstrated in <i>ABCA4</i> carriers had remained stationary or had deteriorated over time at 5-year follow-up to further explore if carriers of an autosomal recessive trait also express a weak phenotype, although this is not expected for an autosomal recessive disorder.\nMethods: Thirteen <i>ABCA4</i> carriers from a previous study that included parents to patients with well known genetically verified <i>ABCA4</i>-associated retinal degenerations were reexamined 5 years after the initial examination. As novel genes and new variants in already established genes are continuously reported, all subjects underwent renewed genetic testing with a next-generation sequencing (NGS) panel that included 288 genes associated with retinal dystrophies and an analysis of deep intronic mutations and copy number variations in the <i>ABCA4</i> gene. Moreover, to evaluate any changes in retinal function and/or structure over time, clinical reassessment with Goldmann perimetry, visual acuity testing, fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal ERG (mfERG) were performed 5 years after the initial investigation. The values of the ffERG parameters were compared between the two time points (the measurements obtained in the initial study versus the measurements at 5-year follow-up) and with the controls. The mfERG results of the carriers were compared with those of the controls.\nResults: The renewed genetic testing confirmed the previously established <i>ABCA4</i> mutations but also revealed the hypomorph <i>ABCA4</i> variant c.5603A>T in five <i>ABCA4</i> carriers. In three of them, the variant was found to be associated with known disease-causing alleles that always carry the c.5603A>T in cis. According to recent publications, the subjects could still be considered <i>ABCA4</i> carriers because both variants are on the same allele. In the remaining two subjects, c.5603A>T could be in trans with the previously known <i>ABCA4</i> variant, and the subjects were therefore excluded from the study since they could no longer be considered as carriers only. Statistical comparison of ffERG parameters showed significant reduction of the isolated rod, -as well as the combined rod-cone amplitudes over the five years of follow-up, but not compared with the controls. Concerning macular function, mfERG amplitudes were reduced for all rings in the carriers compared with the controls. Fundus photographs demonstrated morphological changes in 64% of the carriers, and 36% of them had further changes at follow-up. FAF images showed alterations in 55% of the carriers, with increased changes in 36% of them. Abnormalities on OCT were observed in 82% of the carriers, of whom 9% had newly found abnormalities at follow-up.\nConclusions: At 5-year follow-up, the <i>ABCA4</i> carriers, who previously demonstrated reduced macular function, presented with deterioration of general retinal function, including reduced isolated rod and mixed rod-cone ffERG responses combined with a slight increase in morphological changes in some subjects. This indicates that carriership of at least some <i>ABCA4</i> variants may cause a condition similar to a subgroup of dry age-related macular degeneration (AMD). In the long run, this might be of importance concerning the possibilities to also treat this subgroup of AMD patients with future gene-based and pharmacological drugs targeting <i>ABCA4</i>-associated disorders.","variants":[{"Name":"NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)","Chromosome":"1","Start":"94010911","Stop":"94010911","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":105279,"rule_based_match":true,"evidence_text":"c.5603A>T","llm_judgment":"PRESENT","evidence":"c.5603A>T","abstract_start":1739,"abstract_end":1748}]}
{"pmid":"29250285","title":"A novel de novo mutation in Lamin A/C gene in Emery Dreifuss Muscular Dystrophy patient with atrial paralysis.","abstract":"We present a 26 year old female Indonesian patient with full spectrum Emery Dreifuss Muscular Dystrophy (EDMD) characterized with contracture of elbows, heel cord and pelvic muscle wasting and weakness and atrial paralysis, as rare cardiac findings in EDMD . A novel de novo pathogenic heterozygous missense mutation (NM_170707.3: c.122G>T, p.Arg41Leu) in exon 1 was detected. Preventing atrial paralytic patients from systemic embolism is important. Early diagnosis, intervention, targeted management and counseling are necessary for a better health and life quality of individuals with EDMD.","variants":[{"Name":"NM_170707.4(LMNA):c.122G>T (p.Arg41Leu)","Chromosome":"1","Start":"156115040","Stop":"156115040","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":440360,"rule_based_match":true,"evidence_text":"NM_170707.3: c.122G>T, p.Arg41Leu","llm_judgment":"PRESENT","evidence":"NM_170707.3: c.122G>T, p.Arg41Leu","abstract_start":318,"abstract_end":351}]}
{"pmid":"32597250","title":"A Wide Spectrum Study of α-Globin Chain Variants: Cases from the UK.","abstract":"Over many years, cases of suspected α-globin chain variants were collected from different parts of the UK. The suspicion was based on the clinical picture, high performance liquid chromatography (HPLC) variant percentage, retention time (RT) and isoelectric focusing (IEF). DNA sequencing and the restriction enzyme E<i>ae</i>I were used for definitive diagnosis. One hundred and forty-eight variants were confirmed on one or both of the two α-globin genes (<i>HBA2</i>, <i>HBA1</i>). These cases were identified as 46 different α-globin chain variants. The most common variants were Hb J-Meerut [<i>HBA2</i>: c.362C>A (or <i>HBA1</i>)] (10.1%) and Hb Q-India (<i>HBA1</i>: c.193G>C) (8.1%), followed by Hb J-Paris-I [<i>HBA2</i>: c.38C>A (or <i>HBA1</i>)] and Hb Manitoba II (<i>HBA1</i>: c.309C>A) (7.4% for each). Other α variants were detected at lower frequencies. Two novel alleles were also detected: Hb Walsgrave [α116(GH4)Glu→Val (<i>HBA2</i>: c.350A>T)] and Hb Coombe Park [α127(H10)Lys→Glu (<i>HBA2</i>: c.382A>G)]. The majority of the ethnic origin was Indian. The positive predictive value for α variant identification by HPLC-RT analysis was 65.9%, 41.9% by IEF, and using both RT and IEF, the value was 72.1%. The number of variants was higher in <i>HBA1</i> than in <i>HBA2</i> genes and in exons 1 and 2 than in exon 3. There was no clustering of mutations in consecutive codons. This study, the characterization of a wide spectrum of α-globin chain variants, can facilitate the presumptive diagnosis of these variants prior to screening by a panel of amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), and a definitive diagnosis by DNA sequencing.","variants":[{"Name":"NM_000517.6(HBA2):c.38C>A (p.Ala13Asp)","Chromosome":"16","Start":"172950","Stop":"172950","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":981133,"rule_based_match":true,"evidence_text":"Hb J-Paris-I [<i>HBA2</i>: c.38C>A (or <i>HBA1</i>)]","llm_judgment":"PRESENT","evidence":"Hb J-Paris-I [<i>HBA2</i>: c.38C>A (or <i>HBA1</i>)]","abstract_start":704,"abstract_end":756},{"Name":"NM_000558.3(HBA1):c.193G>C (p.Asp65His)","Chromosome":"16","Start":"177026","Stop":"177026","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":30842,"rule_based_match":true,"evidence_text":"Hb Q-India (HBA1: c.193G>C)","llm_judgment":"PRESENT","evidence":"c.193G>C","abstract_start":674,"abstract_end":682}]}
{"pmid":"25915935","title":"Genetic polymorphisms of dihydropyrimidinase in a Japanese patient with capecitabine-induced toxicity.","abstract":"Dihydropyrimidinase (DHP) is the second enzyme in the catabolic pathway of uracil, thymine, and chemotherapeutic fluoropyrimidine agents such as 5-fluorouracil (5-FU). Thus, DHP deficiency might be associated with 5-FU toxicity during fluoropyrimidine chemotherapy. We performed genetic analyses of the family of a patient with advanced colon cancer who underwent radical colectomy followed by treatment with 5-FU prodrug capecitabine and developed severe toxicity attributable to a lack of DHP. We measured urinary uracil and dihydrouracil, and genotyped DPYS in the patient and her family. We also measured the allele frequency of DPYS polymorphisms in 391 unrelated Japanese subjects. The patient had compound heterozygous missense and nonsense polymorphisms comprising c.1001A>G (p.Gln334Arg) in exon 6 and c.1393C>T (p.Arg465Ter) in exon 8, which are known to result in a DHP enzyme with little or no activity. The urinary dihydrouracil/uracil ratio in the patient was 17.08, while the mean ± SD urinary dihydrouracil/uracil ratio in family members who were heterozygous or homozygous for wild-type DPYS was 0.25 ± 0.06. In unrelated subjects, 8 of 391 individuals were heterozygous for the c.1001A>G mutation, while the c.1393C>T mutation was not identified. This is the first report of a DHP-deficient patient with DPYS compound heterozygous polymorphisms who was treated with a fluoropyrimidine, and our findings suggest that polymorphisms in the DPYS gene are pharmacogenomic markers associated with severe 5-FU toxicity in Japanese patients.","variants":[{"Name":"NM_001385.3(DPYS):c.1393C>T (p.Arg465Ter)","Chromosome":"8","Start":"104392834","Stop":"104392834","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":834031,"rule_based_match":true,"evidence_text":"c.1393C>T (p.Arg465Ter)","llm_judgment":"PRESENT","evidence":"c.1393C>T (p.Arg465Ter)","abstract_start":811,"abstract_end":834},{"Name":"NM_001385.3(DPYS):c.1001A>G (p.Gln334Arg)","Chromosome":"8","Start":"104428071","Stop":"104428071","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":15223,"rule_based_match":true,"evidence_text":"c.1001A>G (p.Gln334Arg)","llm_judgment":"PRESENT","evidence":"c.1001A>G (p.Gln334Arg)","abstract_start":773,"abstract_end":796}]}
{"pmid":"35299674","title":"Epilepsy Combined With Multiple Gene Heterozygous Mutation.","abstract":"The fast pace of gene discovery has resulted in groundbreaking advances in the field of epilepsy genetics. Clinical testing using comprehensive gene panels, exomes, or genomes is now increasingly available and has significantly increased the diagnostic yield for early-onset epilepsies and enabled precision medicine approaches. In this paper, we report a case of epilepsy in a pedigree. The proband had heterozygous mutations in <i>KCNC1</i> (NM_001112741.1:c.959G>A, p. Arg320His), <i>CAPN3</i> (NM_000070.2:c.526G>A, p. Val176Met), and <i>NEFH</i> (NM_021076.3:c. 2595 delC, p. Lys866Argfs<sup>*</sup>51). Sanger sequencing verification was consistent with the results of whole-exome sequencing. The <i>KCNC1</i> mutation was a <i>de novo</i> mutation, and the <i>CAPN3</i> and <i>NEFH</i> mutations were inherited from their father and mother, respectively. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, a heterozygous mutation was found for <i>APOB</i> (NM_000384.2: c.10579C > T, p. Arg3527Trp). The heterozygous mutation at this site was inherent in the pedigree. Coexpression analysis indicated that heterozygous mutations of <i>KCNC1, CAPN3, NEFH</i>, and <i>APOB</i> were closely related to the clinical phenotypes of the patient, and the clinical phenotypic heterogeneity of the disease may be the result of the interaction of multiple genes.","variants":[{"Name":"NM_001112741.2(KCNC1):c.959G>A (p.Arg320His)","Chromosome":"11","Start":"17772053","Stop":"17772053","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":172192,"rule_based_match":true,"evidence_text":"NM_001112741.1:c.959G>A, p. Arg320His","llm_judgment":"PRESENT","evidence":"NM_001112741.1:c.959G>A, p. Arg320His","abstract_start":444,"abstract_end":481}]}
{"pmid":"28459997","title":"Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.","abstract":"Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.","variants":[{"Name":"NM_007055.4(POLR3A):c.1909+22G>A","Chromosome":"10","Start":"78009515","Stop":"78009515","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439194,"rule_based_match":true,"evidence_text":"c.1909+22G>A","llm_judgment":"PRESENT","evidence":"c.1909+22G>A","abstract_start":983,"abstract_end":995}]}
{"pmid":"32964666","title":"Recurrent PROC and novel PROS1 mutations in Vietnamese patients diagnosed with idiopathic deep venous thrombosis.","abstract":"INTRODUCTION: Genetic mutations of PROC and PROS1 are well-known risk factors for deep venous thrombosis (DVT) in the Asian population. However, the genetic profile of Vietnamese patients with DVT remains elusive. This study aimed to investigate the spectrum of genetic mutations of these two genes in Vietnamese patients diagnosed with idiopathic DVT.\nMATERIALS AND METHODS: A total of 50 Vietnamese patients diagnosed with idiopathic DVT were recruited in this study. The entire coding regions of the protein C and protein S genes were amplified and directly sequenced to determine genetic alterations.\nRESULTS: Four and six genetic mutations were detected in protein C and protein S genes, respectively, in 24 Vietnamese DVT patients. PROC c.565C > T (p.R189W) was the most common mutation found in 13 out of 50 patients, while the mutations of PROS1 comprised three missense and three nonsense variants which diffuse along the gene.\nCONCLUSIONS: This study shows that mutations of protein C and protein S genes are prevalent in Vietnamese patients diagnosed with idiopathic DVT, and PROC c.565C > T (p.R189W) was the most common genetic alteration.","variants":[{"Name":"NM_000312.4(PROC):c.565C>T (p.Arg189Trp)","Chromosome":"2","Start":"127426114","Stop":"127426114","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171067,"rule_based_match":true,"evidence_text":"PROC c.565C > T (p.R189W)","llm_judgment":"PRESENT","evidence":"PROC c.565C > T (p.R189W)","abstract_start":738,"abstract_end":763}]}
{"pmid":"19211612","title":"A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension.","abstract":"BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disorder characterised by raised pulmonary artery pressures with pathological changes in small pulmonary arteries. Previous studies have shown that approximately 70% of familial PAH and also 11-40% of idiopathic PAH (IPAH) cases have mutations in the bone morphogenetic protein receptor type II (BMPR2) gene. In addition, mutations in the activin receptor-like kinase 1 (ALK1) gene have been reported in PAH patients. Since both the BMPR2 and ALK1 belonging to the transforming growth factor (TGF)-beta superfamily are known to predispose to PAH, mutations in other genes of the TGF-beta/BMP signalling pathways may also predispose to PAH.\nMETHODS: We screened for mutations in ENDOGLIN(ENG), SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6 and SMAD8 genes, which are involved in the TGF-beta/BMP signallings, in 23 patients with IPAH who had no mutations in BMPR2 or ALK1.\nRESULTS: A nonsense mutation in SMAD8 designated c.606 C>A, p.C202X was identified in one patient. The father of this patient was also identified as having the same mutation. Functional analysis showed the truncated form of the SMAD8 C202X protein was not phosphorylated by constitutively active ALK3 and ALK1. The SMAD8 mutant was also unable to interact with SMAD4. The response to BMP was analysed using promoter-reporter activities with SMAD4 and/or ca-ALK3. The transcriptional activation of the SMAD8 mutant was inefficient compared with the SMAD8 wild type.\nCONCLUSION: We describe the first mutation in SMAD8 in a patient with IPAH. Our findings suggest the involvement of SMAD8 in the pathogenesis of PAH.","variants":[{"Name":"NM_001127217.3(SMAD9):c.606C>A (p.Cys202Ter)","Chromosome":"13","Start":"36872722","Stop":"36872722","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":21554,"rule_based_match":true,"evidence_text":"c.606 C>A, p.C202X","llm_judgment":"PRESENT","evidence":"c.606 C>A, p.C202X","abstract_start":983,"abstract_end":1001}]}
{"pmid":"32185393","title":"CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.","abstract":"Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.","variants":[{"Name":"NM_001378743.1(CYLD):c.2155A>G (p.Met719Val)","Chromosome":"16","Start":"50791604","Stop":"50791604","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":980522,"rule_based_match":true,"evidence_text":"c.2155A>G, p.M719V","llm_judgment":"PRESENT","evidence":"c.2155A>G, p.M719V","abstract_start":530,"abstract_end":548}]}
{"pmid":"28604962","title":"Identification of a novel SLC26A4 mutation in a child with enlarge vestibular aqueduct syndrome","abstract":"OBJECTIVE: To analyze mutations of SLC26A4 gene and explore their origins for a patient with enlarge vestibuar aqueduct syndrome.\nMETHODS: Clinical data and peripheral venous blood samples were collected from the patient and her parents. Genome DNA was extracted from the peripheral blood. All of the 21 exons of the SLC26A4 gene were amplified with PCR and subjected to directly sequencing.\nRESULTS: The patient was found to have carried two mutant alleles of the SLC26A4 gene, namely c.1522A to G and c.1229C to T, which were inherited from her father and mother, respectively.\nCONCLUSION: SLC26A4 c.1522A to G is likely to be a pathogenic mutation. Above results may facilitate genetic counseling and prenatal diagnosis for this family.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1522A>G (p.Thr508Ala)","Chromosome":"7","Start":"107696017","Stop":"107696017","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":174027,"rule_based_match":false,"evidence_text":"c.1522A to G","llm_judgment":"PRESENT","evidence":"c.1522A to G","abstract_start":486,"abstract_end":498},{"Name":"NM_000441.2(SLC26A4):c.1229C>T (p.Thr410Met)","Chromosome":"7","Start":"107690203","Stop":"107690203","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":52668,"rule_based_match":false,"evidence_text":"c.1229C to T","llm_judgment":"PRESENT","evidence":"c.1229C to T","abstract_start":503,"abstract_end":515}]}
{"pmid":"30630233","title":"Clinical and genetic manifestations of immunodeficiency, centromeric instability, and facial anomalies syndrome: a case report and literature review","abstract":"<b>Objective:</b> To analyze the clinical and genetic features of immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome with a case report and literature review. <b>Methods:</b> The clinical data and genetic test of a girl diagnosed with ICF syndrome in the Department of Nephrology and Immunology in Qingdao Women and Children's Hospital in December 2016 were extracted and analyzed. \"ICF syndrome\" \"immunodeficiency, centromeric instability and facial anomalies syndrome\" \"ICF syndrome and DNMT3B\" were used as key words to search Chinese databases and Pubmed for literature until March 2018, and the literature was reviewed. <b>Results:</b> A female patient aged 22 months old with ocular hypertelorism and low-set ears was admitted due to recurrent infection over one year. Laboratory tests showed humoral immune deficiency with IgG<1.34 g/L, IgA<0.060 g/L, and IgM<0.179 g/L, but normal cellular immunity (total T lymphocyte 0.503, hepler T lymphocyte 0.328, cytotoxic T lymphocyte 0.166, natural killer cell 0.184, total B lymphocyte 0.276). Whole-exome sequencing revealed a de novo heterozygous splice site mutation c.922-2A>G in intron 8, and a de novo heterozygous missense mutation c.2477G>A in exon 23 of DNMT3B gene. Chromosome karyotype analysis showed 46, XX, with 64 out of 100 karyotypes showing centromere instability in chromosome 1. Five papers were found which were all in English, with total of 29 patients. Forty-three mutations were reported, including 34 missense, 2 deletion, 1 insertion, 6 splice site mutations. Eleven patients had complex heterozygosis mutations. All patients had centromere instability, humoral immune deficiency and facial dysplasia which were mainly ocular hypertelorism and low-set ears. Most patients had language and motor development delay, and a few were combined with mental retardation. <b>Conclusions:</b> ICF syndrome is a rare autosomal recessive primary immunodeficiency with classic clinical triad manifestations. De novo mutation of DNMT3B gene is one of etiologies according to genetic test.","variants":[{"Name":"NM_006892.4(DNMT3B):c.2477G>A (p.Arg826His)","Chromosome":"20","Start":"32807818","Stop":"32807818","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1014068,"rule_based_match":true,"evidence_text":"c.2477G>A","llm_judgment":"PRESENT","evidence":"c.2477G>A","abstract_start":1218,"abstract_end":1227}]}
{"pmid":"23958762","title":"LAMB3 mutations causing autosomal-dominant amelogenesis imperfecta.","abstract":"Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related.","variants":[{"Name":"NM_000228.3(LAMB3):c.3446_3453del (p.Gly1149fs)","Chromosome":"1","Start":"209615337","Stop":"209615344","ReferenceAlleleVCF":"TCTCCAGTC","AlternateAlleleVCF":"T","allel_id":178844,"rule_based_match":true,"evidence_text":"c.3446_3453del GACTGGAG","llm_judgment":"PRESENT","evidence":"c.3446_3453del GACTGGAG","abstract_start":891,"abstract_end":914}]}
{"pmid":"34828289","title":"Chronic Pancreatitis: The True Pathogenic Culprit within the","abstract":"A diverse range of loss-of-function variants in the <i>SPINK1</i> gene (encoding pancreatic secretory trypsin inhibitor) has been identified in patients with chronic pancreatitis (CP). The haplotype harboring the <i>SPINK1</i> c.101A>G (p.Asn34Ser or N34S) variant (rs17107315:T>C) is one of the most important heritable risk factors for CP as a consequence of its relatively high prevalence worldwide (population allele frequency ≈ 1%) and its considerable effect size (odds ratio ≈ 11). The causal variant responsible for this haplotype has been intensively investigated over the past two decades. The different hypotheses tested addressed whether the N34S missense variant has a direct impact on enzyme structure and function, whether c.101A>G could affect pre-mRNA splicing or mRNA stability, and whether another variant in linkage disequilibrium with c.101A>G might be responsible for the observed association with CP. Having reviewed the currently available genetic and experimental data, we conclude that c.-4141G>T (rs142703147:C>A), which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L <i>cis</i>-regulatory module located ∼4 kb upstream of the <i>SPINK1</i> promoter, can be designated as the causal variant beyond reasonable doubt. This case illustrates the difficulties inherent in determining the identity of the causal variant underlying an initially identified disease association.","variants":[{"Name":"NM_001379610.1(SPINK1):c.101A>G (p.Asn34Ser)","Chromosome":"5","Start":"147828115","Stop":"147828115","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":28799,"rule_based_match":true,"evidence_text":"c.101A>G (p.Asn34Ser or N34S)","llm_judgment":"PRESENT","evidence":"c.101A>G (p.Asn34Ser or N34S)","abstract_start":227,"abstract_end":256}]}
{"pmid":"34946930","title":"Genotype-Specific Lesion Growth Rates in Stargardt Disease.","abstract":"Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed biallelic <i>ABCA4</i> mutations from five genotype groups: c.6079C>T, c.[2588G>C;5603A>T], c.3113C>T, c.5882G>A and c.5603A>T. Fundus autofluorescence (AF) 30° × 30° images were manually segmented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean ± SD age 45 ± 19 years; range 21-86) were recruited. Patients with c.3113C>T or c.6079C>T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; <i>p</i> < 0.001 and 0.14 to 0.21; <i>p</i> < 0.001) respectively, as compared to those patients harbouring c.5882G>A at 0.06 mm/year (95% CI 0.03-0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset.","variants":[{"Name":"NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)","Chromosome":"1","Start":"94010911","Stop":"94010911","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":105279,"rule_based_match":true,"evidence_text":"c.5603A>T","llm_judgment":"PRESENT","evidence":"c.5603A>T","abstract_start":298,"abstract_end":307},{"Name":"NM_000350.3(ABCA4):c.6079C>T (p.Leu2027Phe)","Chromosome":"1","Start":"94005509","Stop":"94005509","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22921,"rule_based_match":true,"evidence_text":"c.6079C>T","llm_judgment":"PRESENT","evidence":"c.6079C>T","abstract_start":241,"abstract_end":250},{"Name":"NM_000350.3(ABCA4):c.3113C>T (p.Ala1038Val)","Chromosome":"1","Start":"94043413","Stop":"94043413","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22933,"rule_based_match":true,"evidence_text":"c.3113C>T","llm_judgment":"PRESENT","evidence":"c.3113C>T","abstract_start":273,"abstract_end":282},{"Name":"NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)","Chromosome":"1","Start":"94008251","Stop":"94008251","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22927,"rule_based_match":true,"evidence_text":"c.5882G>A","llm_judgment":"PRESENT","evidence":"c.5882G>A","abstract_start":284,"abstract_end":293}]}
{"pmid":"34543749","title":"Whole-Genome Sequencing Reveals Large ATP8B1 Deletion/Duplications as Second Mutations Missed by Exome-Based Sequencing.","abstract":"Progressive familial intrahepatic cholestasis type 1 (PFIC1) results from biallelic pathogenic variants in ATP8B1. This study sought second pathogenic variants in ATP8B1 by whole-genome sequencing (WGS) in four unrelated low γ-glutamyl transpeptidase cholestasis patients in whom clinical suspicion of PFIC1 was high and gene-panel or Sanger sequencing had identified only one pathogenic variant in ATP8B1. Sanger sequencing confirmed WGS findings and determined the origin of each variant. Novel nonrecurrent structural variants in three patients (patient 1 to patient 3) were identified in trans: g.55396652_55403080del (6427-bp deletion), g.55335906_55346620dup (10,715-bp duplication), and g.55362063_55364293dup (2231-bp duplication). One synonymous variant in patient 4 was recognized in trans (c.1029G>A, p. Thr343Thr) and demonstrated as deleterious. In conclusion, WGS improves genetic diagnostic yield in PFIC1. These findings expand the gene-variant spectrum associated with familiar intrahepatic cholestasis 1 (FIC1) disease and for the first time report tandem duplication in ATP8B1 associated with cholestasis.","variants":[{"Name":"NM_001374385.1(ATP8B1):c.1029G>A (p.Thr343=)","Chromosome":"18","Start":"57694582","Stop":"57694582","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1153071,"rule_based_match":true,"evidence_text":"c.1029G>A, p. Thr343Thr","llm_judgment":"PRESENT","evidence":"c.1029G>A, p. Thr343Thr","abstract_start":801,"abstract_end":824}]}
{"pmid":"28711549","title":"A case of hypocholesterolemia and steatosis in a carrier of a PCSK9 loss-of-function mutation and polymorphisms predisposing to nonalcoholic fatty liver disease.","abstract":"We report a new case of hypobetalipoproteinemia in a 44-year-old man of Peruvian origin exhibiting a heterozygous PCSK9 missense mutation (c.946 G>T, p. Gly316Cys). In vitro functional studies demonstrated that this mutation leads to a loss of function of PCSK9 on low-density lipoprotein receptor degradation. This patient exhibited liver steatosis; he was neither diabetic, nor obese or alcoholic, but is a carrier of 2 polymorphisms, p.Ile148Met (rs738409) and p.Glu167Lys (rs58542926) on PNPLA3 and TM6SF2 gene, respectively, previously shown to be associated with nonalcoholic steatosis and fibrosis evolution. These data suggested that if a resistance to hepatic steatosis mediated by the PCSK9 deficiency exists, as demonstrated in mice, it is not sufficient to prevent hepatic fatty accumulation in the case of genetic factors predisposing to nonalcoholic fatty liver disease.","variants":[{"Name":"NM_174936.4(PCSK9):c.946G>T (p.Gly316Cys)","Chromosome":"1","Start":"55056139","Stop":"55056139","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3228589,"rule_based_match":true,"evidence_text":"c.946 G>T, p. Gly316Cys","llm_judgment":"PRESENT","evidence":"c.946 G>T, p. Gly316Cys","abstract_start":139,"abstract_end":162}]}
{"pmid":"23449687","title":"One novel and one recurrent mutation in IGHMBP2 gene, causing severe spinal muscular atrophy respiratory distress 1 with onset soon after birth.","abstract":"A family with 2 siblings with severe spinal muscular atrophy with respiratory distress 1 (SMARD1) was genetically proved to be caused by mutations in IGHMBP2 gene. Both patients developed progressive muscular weakness and respiratory distress and died before 6 months of age. One novel deletion, c.780delG;p.(Gln260Hisfs*24), inherited from the father and a nonsense mutation, c.1488C>A;p.(Cys496*), inherited from the mother were detected. An attempt was made to correlate the genetic-clinical data available in the literature. The clinical case presented in this study might be considered as the most severe form of spinal muscular atrophy respiratory distress 1 reported so far, presumably because of the total absence of IGHMBP2 enzyme activity.","variants":[{"Name":"NM_002180.3(IGHMBP2):c.780del (p.Gln260fs)","Chromosome":"11","Start":"68914891","Stop":"68914891","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":625224,"rule_based_match":true,"evidence_text":"c.780delG;p.(Gln260Hisfs*24)","llm_judgment":"PRESENT","evidence":"c.780delG;p.(Gln260Hisfs*24)","abstract_start":296,"abstract_end":324},{"Name":"NM_002180.3(IGHMBP2):c.1488C>A (p.Cys496Ter)","Chromosome":"11","Start":"68933864","Stop":"68933864","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":231807,"rule_based_match":true,"evidence_text":"c.1488C>A;p.(Cys496*)","llm_judgment":"PRESENT","evidence":"c.1488C>A;p.(Cys496*)","abstract_start":377,"abstract_end":398}]}
{"pmid":"29750297","title":"COL2A1 mutation (c.3508G>A) leads to avascular necrosis of the femoral head in a Chinese family: A case report.","abstract":"Avascular necrosis of the femoral head (ANFH) is a consequence of ischemia. Although the majority of cases of ANFH are sporadic, certain familial cases of ANFH have been reported to be associated with collagen type II α1 chain (COL2A1) mutations, which lead to COL2A1 gene dysfunction. The structure of secreted type II collagen contains a core area with a triple helical glycine (Gly)‑X‑Y domain, and the replacement of Gly in this region as a result of COL2A1 mutations may damage the structure of type II collagen. In the present study, a Chinese family with ANFH was recruited and genetic analysis was conducted to determine whether COL2A1 mutations were implicated in this familial ANFH. A three‑generation family containing 31 members, as well as 20 patients with sporadic ANFH, were recruited for investigation. The diagnosis was performed by independent surgeons and radiologists according to internationally recognized criteria. In the present study, a heterozygous c.3508G>A mutation in exon 50 of the COL2A1 gene was identified, which results in the substitution of Gly with serine at codon 1,170. Furthermore, genetic pedigree analysis indicated that this mutation was inherited in an autosomal dominant manner. The present study revealed that a heterozygous c.3508G>A mutation in the COL2A1 gene was involved in ANFH development in one Chinese family. Therefore, it is proposed that individuals who carry this c.3508G>A mutation in the COL2A1 gene should receive genetic counseling and early intervention for ANFH.","variants":[{"Name":"NM_001844.5(COL2A1):c.3508G>A (p.Gly1170Ser)","Chromosome":"12","Start":"47976052","Stop":"47976052","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32432,"rule_based_match":true,"evidence_text":"c.3508G>A","llm_judgment":"PRESENT","evidence":"c.3508G>A","abstract_start":975,"abstract_end":984}]}
{"pmid":"26864977","title":"Hb Agenogi [β90(F6)Glu→Lys (GAG>AAG) HBB: c.271G>A)] in a Pregnant Thai Woman.","abstract":"Hb Agenogi [β90(F6)Glu→Lys (GAG>AAG) HBB: c.271G>A)] is a very rare β-globin chain variant. We report for the first time this hemoglobinopathy in a pregnant 20-year-old Thai woman. She was seen by an obstetrician at her 14th week of gestation. She was pale and had an inflammatory lesion of her lower left leg. The hemoglobin (Hb) analysis by high performance liquid chromatography (HPLC) and low pressure liquid chromatography (LPLC) showed a peak of abnormal Hb at the C window. On capillary electrophoresis (CE), the abnormal Hb peak was observed at electrophoretic zone 4 that corresponded to the Hb E (HBB: c.79G>A) peak. Direct DNA sequencing revealed a GAG>AAG mutation at codon 90 of the β-globin gene. Thus, even though Hb Agenogi is very rare, it can be found in Thai people. The knowledge and understanding of this hemoglobinopathy will be used to assist in diagnosis, management and counseling for patients.","variants":[{"Name":"NM_000518.4(HBB):c.271G>A (p.Glu91Lys)","Chromosome":"11","Start":"5226621","Stop":"5226621","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30130,"rule_based_match":true,"evidence_text":"HBB: c.271G>A","llm_judgment":"PRESENT","evidence":"HBB: c.271G>A","abstract_start":37,"abstract_end":50}]}
{"pmid":"26120850","title":"Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism.","abstract":"Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76_98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans.","variants":[{"Name":"NM_001873.4(CPE):c.76_98del (p.Glu26fs)","Chromosome":"4","Start":"165379290","Stop":"165379312","ReferenceAlleleVCF":"TGGGCGCCGAAGCCCAGGAGCCCG","AlternateAlleleVCF":"T","allel_id":676993,"rule_based_match":true,"evidence_text":"c.76_98del","llm_judgment":"PRESENT","evidence":"c.76_98del","abstract_start":329,"abstract_end":339}]}
{"pmid":"31068177","title":"A novel missense mutation in the MYH7 gene causes an uncharacteristic phenotype of myosin storage myopathy: a case report.","abstract":"BACKGROUND: Few manuscripts have reported phenotypes of skeletal muscle myopathies caused by mutations in the head region of slow/cardiac beta-myosin heavy chain (MyHCI). Among the patients, some of them showed the phenotype of skeletal muscle weakness with the obvious clinical features of cardiomyopathy while others showed pure skeletal muscle weakness with no symptoms of cardiac involvement. Genotype-phenotype relationship regarding the effect of a mutation on MyHCI is complex. Questions regarding why some mutations cause cardiomyopathy or skeletal muscle disorders alone or a combination of both still need to be answered. More findings in genetic variation are needed to extend knowledge of mutations in the MYH7 gene linked to skeletal muscle disorders.\nCASE PRESENTATION: Here we present a female adult patient with a phenotype of childhood onset of muscular disorders and predominant involvement of thigh muscles with biopsy showing intrasarcoplasmic inclusion bodies. Whole exome sequencing showed that variant c.1370 T > G (p.Ile457Arg) in the MYH7 gene is a missense mutation possibly linked to the clinical findings. Our patient likely shows an uncharacteristic myosin storage myopathy associated with respiratory and cardiac involvement linked to a missense mutation in the head of MyHCI.\nCONCLUSIONS: Given this mutation is located within the motor domain of MyHCI, this might affect the regulation of myosin mechano-chemical activity during the contractile cycle. Consequently, this potentially damaging effect can be easily amplified within the network of ~ 300-myosin molecules forming the thick filament and therefore become cumulatively deleterious, affecting, in turn, the overall organization and performance of sarcomere.","variants":[{"Name":"NM_000257.4(MYH7):c.1370T>G (p.Ile457Arg)","Chromosome":"14","Start":"23428992","Stop":"23428992","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":551956,"rule_based_match":true,"evidence_text":"c.1370 T > G (p.Ile457Arg)","llm_judgment":"PRESENT","evidence":"c.1370 T > G (p.Ile457Arg)","abstract_start":1025,"abstract_end":1051}]}
{"pmid":"24212087","title":"Comparison of mRNA splicing assay protocols across multiple laboratories: recommendations for best practice in standardized clinical testing.","abstract":"BACKGROUND: Accurate evaluation of unclassified sequence variants in cancer predisposition genes is essential for clinical management and depends on a multifactorial analysis of clinical, genetic, pathologic, and bioinformatic variables and assays of transcript length and abundance. The integrity of assay data in turn relies on appropriate assay design, interpretation, and reporting.\nMETHODS: We conducted a multicenter investigation to compare mRNA splicing assay protocols used by members of the ENIGMA (Evidence-Based Network for the Interpretation of Germline Mutant Alleles) consortium. We compared similarities and differences in results derived from analysis of a panel of breast cancer 1, early onset (BRCA1) and breast cancer 2, early onset (BRCA2) gene variants known to alter splicing (BRCA1: c.135-1G>T, c.591C>T, c.594-2A>C, c.671-2A>G, and c.5467+5G>C and BRCA2: c.426-12_8delGTTTT, c.7988A>T, c.8632+1G>A, and c.9501+3A>T). Differences in protocols were then assessed to determine which elements were critical in reliable assay design.\nRESULTS: PCR primer design strategies, PCR conditions, and product detection methods, combined with a prior knowledge of expected alternative transcripts, were the key factors for accurate splicing assay results. For example, because of the position of primers and PCR extension times, several isoforms associated with BRCA1, c.594-2A>C and c.671-2A>G, were not detected by many sites. Variation was most evident for the detection of low-abundance transcripts (e.g., BRCA2 c.8632+1G>A Δ19,20 and BRCA1 c.135-1G>T Δ5q and Δ3). Detection of low-abundance transcripts was sometimes addressed by using more analytically sensitive detection methods (e.g., BRCA2 c.426-12_8delGTTTT ins18bp).\nCONCLUSIONS: We provide recommendations for best practice and raise key issues to consider when designing mRNA assays for evaluation of unclassified sequence variants.","variants":[{"Name":"NM_007294.4(BRCA1):c.135-1G>T","Chromosome":"17","Start":"43106534","Stop":"43106534","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":45960,"rule_based_match":true,"evidence_text":"BRCA1: c.135-1G>T","llm_judgment":"PRESENT","evidence":"BRCA1: c.135-1G>T","abstract_start":800,"abstract_end":817},{"Name":"NM_007294.4(BRCA1):c.594-2A>C","Chromosome":"17","Start":"43095924","Stop":"43095924","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":46242,"rule_based_match":true,"evidence_text":"BRCA1, c.594-2A>C","llm_judgment":"PRESENT","evidence":"BRCA1, c.594-2A>C","abstract_start":1373,"abstract_end":1390},{"Name":"NM_007294.4(BRCA1):c.671-2A>G","Chromosome":"17","Start":"43094862","Stop":"43094862","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":262978,"rule_based_match":true,"evidence_text":"c.671-2A>G","llm_judgment":"PRESENT","evidence":"c.671-2A>G","abstract_start":841,"abstract_end":851},{"Name":"NM_000059.4(BRCA2):c.9501+3A>T","Chromosome":"13","Start":"32394936","Stop":"32394936","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":46798,"rule_based_match":true,"evidence_text":"c.9501+3A>T","llm_judgment":"PRESENT","evidence":"c.9501+3A>T","abstract_start":928,"abstract_end":939},{"Name":"NM_000059.4(BRCA2):c.8632+1G>A","Chromosome":"13","Start":"32371101","Stop":"32371101","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67306,"rule_based_match":true,"evidence_text":"BRCA2 c.8632+1G>A","llm_judgment":"PRESENT","evidence":"BRCA2 c.8632+1G>A","abstract_start":1521,"abstract_end":1538},{"Name":"NM_007294.4(BRCA1):c.5467+5G>C","Chromosome":"17","Start":"43047638","Stop":"43047638","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":70253,"rule_based_match":true,"evidence_text":"c.5467+5G>C","llm_judgment":"PRESENT","evidence":"c.5467+5G>C","abstract_start":857,"abstract_end":868}]}
{"pmid":"20850105","title":"A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness.","abstract":"Congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder that can be associated with impaired night vision. The last decade has witnessed huge progress in ophthalmic genetics, including the identification of three genes implicated in the pathogenicity of autosomal-recessive CSNB. However, not all patients studied could be associated with mutations in these genes and thus other genes certainly underlie this disorder. Here, we report a large multigeneration family with five affected individuals manifesting symptoms of night blindness. A genome-wide scan localized the disease interval to chromosome 15q, and recombination events in affected individuals refined the critical interval to a 10.41 cM (6.53 Mb) region that harbors SLC24A1, a member of the solute carrier protein superfamily. Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model. Expression analysis using mouse ocular tissues shows that Slc24a1 is expressed in the retina around postnatal day 7. In situ and immunohistological studies localized both SLC24A1 and Slc24a1 to the inner segment, outer and inner nuclear layers, and ganglion cells of the retina, respectively. Our data expand the genetic basis of CSNB and highlight the indispensible function of SLC24A1 in retinal function and/or maintenance in humans.","variants":[{"Name":"NM_004727.3(SLC24A1):c.1613_1614del (p.Phe538fs)","Chromosome":"15","Start":"65625692","Stop":"65625693","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":39330,"rule_based_match":true,"evidence_text":"c.1613_1614del","llm_judgment":"PRESENT","evidence":"c.1613_1614del","abstract_start":890,"abstract_end":904}]}
{"pmid":"25439729","title":"Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.","abstract":"Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs(∗)6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome.","variants":[{"Name":"NM_152515.5(CKAP2L):c.571dup (p.Ile191fs)","Chromosome":"2","Start":"112756799","Stop":"112756800","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AT","allel_id":172087,"rule_based_match":true,"evidence_text":"c.571dupA (p.Ile191Asnfs(∗)6)","llm_judgment":"PRESENT","evidence":"c.571dupA (p.Ile191Asnfs(∗)6)","abstract_start":531,"abstract_end":560}]}
{"pmid":"27235420","title":"Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy.","abstract":"Mutation of the LMNA gene, encoding nuclear lamin A and lamin C (hereafter lamin A/C), is a common cause of familial dilated cardiomyopathy (DCM). Among Finnish DCM patients, the founder mutation c.427T>C (p.S143P) is the most frequently reported genetic variant. Here, we show that p.S143P lamin A/C is more nucleoplasmic and soluble than wild-type lamin A/C and accumulates into large intranuclear aggregates in a fraction of cultured patient fibroblasts as well as in cells ectopically expressing either FLAG- or GFP-tagged p.S143P lamin A. In fluorescence loss in photobleaching (FLIP) experiments, non-aggregated EGFP-tagged p.S143P lamin A was significantly more dynamic. In in vitro association studies, p.S143P lamin A failed to form appropriate filament structures but instead assembled into disorganized aggregates similar to those observed in patient cell nuclei. A whole-genome expression analysis revealed an elevated unfolded protein response (UPR) in cells expressing p.S143P lamin A/C. Additional endoplasmic reticulum (ER) stress induced by tunicamycin reduced the viability of cells expressing mutant lamin further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability.","variants":[{"Name":"NM_170707.4(LMNA):c.427T>C (p.Ser143Pro)","Chromosome":"1","Start":"156130687","Stop":"156130687","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":77796,"rule_based_match":true,"evidence_text":"c.427T>C (p.S143P)","llm_judgment":"PRESENT","evidence":"c.427T>C (p.S143P)","abstract_start":196,"abstract_end":214}]}
{"pmid":"20544271","title":"Lack of association between ATM C.1066-6T > G mutation and breast cancer risk: a meta-analysis of 8,831 cases and 4,957 controls.","abstract":"Epidemiological studies have evaluated the association between ATM C.1066-6T > G (IVS10-6T > G) mutation and breast cancer risk. However, the results remain conflicting rather than conclusive. In order to derive a more precise estimation of the relationship, we performed this meta-analysis. Systematic searches of PubMed and Medline databases were performed. A total of 11 studies including 8,831 cases and 4,957 controls were identified. The carrier frequency of the ATM C.1066-6T > G mutation was 0.5% (45/8,831) in patients with breast cancer and 0.7% (38/4,957) in healthy controls. When all the 11 studies were pooled into the meta-analysis, there was no evidence for significant association between C.1066-6T > G mutation and breast cancer risk (OR 0.87, 95% CI 0.55-1.37). In the subgroup analyses by source of controls and family history with BRCA1/2 status, no significant association were found in any subgroup of population. When sensitivity analyses were performed, all the results were not materially altered. In summary, the meta-analysis strongly suggests that ATM C.1066-6T > G mutation is not associated with increased breast cancer risk.","variants":[{"Name":"NM_000051.4(ATM):c.1066-6T>G","Chromosome":"11","Start":"108248927","Stop":"108248927","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18077,"rule_based_match":true,"evidence_text":"ATM C.1066-6T > G","llm_judgment":"PRESENT","evidence":"ATM C.1066-6T > G","abstract_start":63,"abstract_end":80}]}
{"pmid":"27437095","title":"Novel Mutation in the ATP-Binding Cassette Transporter A3 (ABCA3) Encoding Gene Causes Respiratory Distress Syndrome in A Term Newborn in Southwest Iran.","abstract":"INTRODUCTION: ABCA3 glycoprotein belongs to the ATP-binding cassette (ABC) superfamily of transporters, which utilize the energy derived from hydrolysis of ATP for the translocation of a wide variety of substrates across the plasma membrane. Mutations in the ABCA3 gene are knowingly causative for fatal surfactant deficiency, particularly respiratory distress syndrome (RDS) in term babies.\nCASE PRESENTATION: In this study, Sanger sequencing of the whole ABCA3 gene (NCBI NM_001089) was performed in a neonatal boy with severe RDS. A homozygous mutation has been identified in the patient. Parents were heterozygous for the same missense mutation GGA > AGA at position 202 in exon 6 of the ABCA3 gene (c.604G > A; p.G202R). Furthermore, 70 normal individuals have been analyzed for the mentioned change with negative results.\nCONCLUSIONS: Regarding Human Genome Mutation Database (HGMD) and other literature recherche, the detected change is a novel mutation and has not been reported before. Bioinformatics mutation predicting tools prefer it as pathogenic.","variants":[{"Name":"NM_001089.3(ABCA3):c.604G>A (p.Gly202Arg)","Chromosome":"16","Start":"2323532","Stop":"2323532","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2895005,"rule_based_match":true,"evidence_text":"c.604G > A; p.G202R","llm_judgment":"PRESENT","evidence":"c.604G > A; p.G202R","abstract_start":704,"abstract_end":723}]}
{"pmid":"27468121","title":"Clinical and Molecular Genetic Analysis in Three Children with Wolfram Syndrome: A Novel WFS1 Mutation (c.2534T>A).","abstract":"Wolfram syndrome (WS) is an autosomal recessive disorder caused by mutations in <i>WFS1</i> gene. The clinical features include diabetes insipidus, diabetes mellitus (DM), optic atrophy, deafness, and other variable clinical manifestations. In this paper, we present the clinical and genetic characteristics of 3 WS patients from 3 unrelated Turkish families. Clinical characteristics of the patients and the age of onset of symptoms were quite different in each pedigree. The first two cases developed all symptoms of the disease in their first decade of life. The heterozygous father of case 2 was symptomatic with bilateral deafness. The first ocular finding of one patient (patient 3) was bilateral cataract which was accompanying DM as a first feature of the syndrome. In this patient's family, there were two members with features suggestive of WS. Previously known homozygous mutations, c.460+1G>A in intron 4 and c.1885C>T in exon 8, were identified in these cases. A novel homozygous c.2534T>A mutation was also detected in the exon 8 of WFS1 gene. Because of the rarity and heterogeneity of WS, detection of specific and nonspecific clinical signs including ocular findings and family history in non-autoimmune, insulinopenic diabetes cases should lead to a tentative diagnosis of WS. Genetic testing is required to confirm the diagnosis.","variants":[{"Name":"NM_006005.3(WFS1):c.460+1G>A","Chromosome":"4","Start":"6289132","Stop":"6289132","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19554,"rule_based_match":true,"evidence_text":"c.460+1G>A","llm_judgment":"PRESENT","evidence":"c.460+1G>A","abstract_start":894,"abstract_end":904},{"Name":"NM_006005.3(WFS1):c.1885C>T (p.Arg629Trp)","Chromosome":"4","Start":"6301680","Stop":"6301680","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1060079,"rule_based_match":true,"evidence_text":"c.1885C>T","llm_judgment":"PRESENT","evidence":"c.1885C>T","abstract_start":921,"abstract_end":930}]}
{"pmid":"30003093","title":"A Novel Heterozygous Intronic Mutation in the","abstract":"Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (<i>FBN1</i>) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic <i>FBN1</i> mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the <i>FBN1</i> gene. RT-PCR and Western blot analyses, using <i>FBN1</i> minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.","variants":[{"Name":"NM_000138.5(FBN1):c.2678-15C>A","Chromosome":"15","Start":"48494269","Stop":"48494269","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":440009,"rule_based_match":true,"evidence_text":"c.2678-15C>A","llm_judgment":"PRESENT","evidence":"c.2678-15C>A","abstract_start":264,"abstract_end":276}]}
{"pmid":"30121372","title":"Recurrent RTTN mutation leading to severe microcephaly, polymicrogyria and growth restriction.","abstract":"Autosomal recessive missense Rotatin (RTTN) mutations are responsible for syndromic forms of malformation of cortical development, ranging from isolated polymicrogyria to microcephaly associated with primordial dwarfism and other major malformations. We identified, by trio based whole exome sequencing, a homozygous missense mutation in the RTTN gene (c.2953A > G; p.(Arg985Gly)) in one Moroccan patient from a consanguineous family. The patient showed early onset primary microcephaly, detected in the fetal period, postnatal growth restriction, encephalopathy with hyperkinetic movement disorders and self-injurious behavior with sleep disturbance. Brain MRI showed an extensive dysgyria associated with nodular heterotopia, large interhemispheric arachnoid cyst and corpus callosum hypoplasia.","variants":[{"Name":"NM_173630.4(RTTN):c.2953A>G (p.Arg985Gly)","Chromosome":"18","Start":"70134474","Stop":"70134474","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":966005,"rule_based_match":true,"evidence_text":"c.2953A > G; p.(Arg985Gly)","llm_judgment":"PRESENT","evidence":"c.2953A > G; p.(Arg985Gly)","abstract_start":353,"abstract_end":379}]}
{"pmid":"28639307","title":"Anti-D in a mother, hemizygous for the variant RHD*DNB gene, associated with hemolytic disease of the fetus and newborn.","abstract":"BACKGROUND: Individuals with the partial D phenotype when exposed to D+ red blood cells (RBCs) carrying the epitopes they lack may develop anti-D specific for the missing epitopes. DNB is the most common partial D in Caucasians and the clinical significance for anti-D in these individuals is unknown.\nSTUDY DESIGN AND METHODS: This article describes the serologic genotyping results and clinical manifestations in two group D+ babies of a mother presenting as group O, D+ with alloanti-D.\nRESULTS: The mother was hemizygous for RHD*DNB gene and sequencing confirmed a single-nucleotide change at c.1063G>A. One baby (group A, D+) displayed bilirubinemia at birth with a normal hemoglobin level. Anti-A and anti-D were eluted from the RBCs. For the next ongoing pregnancy, the anti-D titer increased from 32 to 256. On delivery the baby typed group O and anti-D was eluted from the RBCs. This baby at birth exhibited anemia, reticulocytosis, and hyperbilirubinemia requiring intensive phototherapy treatment from Day 0 to Day 9 after birth and was discharged on Day 13. Intravenous immunoglobulin was also administered. Both babies were heterozygous for RHD and RHD*DNB.\nCONCLUSION: The anti-D produced by this woman with partial D DNB resulted in a case of hemolytic disease of the fetus and newborn (HDFN) requiring intensive treatment in the perinatal period. Anti-D formed by women with the partial D DNB phenotype has the potential to cause HDFN where the fetus is D+. Women carrying RHD*DNB should be offered appropriate prophylactic anti-D and be transfused with D- RBCs if not already alloimmunized.","variants":[{"Name":"NM_016124.6(RHD):c.1063G>A (p.Gly355Ser)","Chromosome":"1","Start":"25306719","Stop":"25306719","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":198601,"rule_based_match":true,"evidence_text":"c.1063G>A","llm_judgment":"PRESENT","evidence":"c.1063G>A","abstract_start":597,"abstract_end":606}]}
{"pmid":"34785479","title":"Generation of two induced pluripotent stem cell lines, SHIPMi001-A from a patient with hypertrophic cardiomyopathy caused by MYBPC3 gene mutation and SHIPMi002-A from a healthy male individual.","abstract":"Hypertrophic cardiomyopathy is a hereditary disease with high incidence of sudden death and heart failure. Myosin-binding protein C3 (MYBPC3) is the most commonly mutation gene. Here, we report the establishment of two human induced pluripotent stem cell (iPSC) lines: one from a patient carrying a heterozygous c.1377delC mutation in MYBPC3 (c.1377delC: p.L460Wfs) and one from a healthy donor. The generated iPSC lines showed comparable pluripotent genes, demonstrated the capacity to differentiate into derivatives of all three germ layers and normal karyotypes. These lines are valuable for the mechanism research and drug development of hypertrophic cardiomyopathy.","variants":[{"Name":"NM_000256.3(MYBPC3):c.1377del (p.Leu460fs)","Chromosome":"11","Start":"47342910","Stop":"47342910","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":186386,"rule_based_match":true,"evidence_text":"c.1377delC mutation in MYBPC3 (c.1377delC: p.L460Wfs)","llm_judgment":"PRESENT","evidence":"c.1377delC mutation in MYBPC3 (c.1377delC: p.L460Wfs)","abstract_start":312,"abstract_end":365}]}
{"pmid":"22541559","title":"Mutations in NSUN2 cause autosomal-recessive intellectual disability.","abstract":"With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227(∗)] and c.1114C>T [p.Gln372(∗)], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs(∗)192]) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development.","variants":[{"Name":"NM_017755.6(NSUN2):c.679C>T (p.Gln227Ter)","Chromosome":"5","Start":"6620242","Stop":"6620242","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40337,"rule_based_match":true,"evidence_text":"c.679C>T [p.Gln227(∗)]","llm_judgment":"PRESENT","evidence":"c.679C>T [p.Gln227(∗)]","abstract_start":388,"abstract_end":410},{"Name":"NM_017755.6(NSUN2):c.1114C>T (p.Gln372Ter)","Chromosome":"5","Start":"6611067","Stop":"6611067","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40338,"rule_based_match":true,"evidence_text":"c.1114C>T [p.Gln372(∗)]","llm_judgment":"PRESENT","evidence":"c.1114C>T [p.Gln372(∗)]","abstract_start":415,"abstract_end":438}]}
{"pmid":"33623275","title":"Identification of a Novel Mutation in","abstract":"We report a 2.5-year-old Turkish boy who first presented with nystagmus, lack of eye contact, and hypotonia at 2 months of age and developed refractory seizures when 6 months old. Extensive metabolic tests and imaging being noncontributory, whole-exome sequencing was carried out which revealed a heterozygote <i>NM_001134407.2:C.3299A>G (p.Glu1100Gly)</i> novel mutation in <i>GRIN2A</i> gene. Topiramate was started and seizures were rapidly brought under control. <i>GRIN2A</i> mutations may result in altered GluN2A membrane trafficking and response to glutamate. This report illustrates the clinical variability of <i>GRIN2A</i> mutations according to the age of onset of symptoms and suggests considering mutations in this gene in cases of global developmental delay, refractory epilepsy, and nystagmus.","variants":[{"Name":"NM_001134407.3(GRIN2A):c.3299A>G (p.Glu1100Gly)","Chromosome":"16","Start":"9764245","Stop":"9764245","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3146327,"rule_based_match":true,"evidence_text":"NM_001134407.2:C.3299A>G (p.Glu1100Gly)","llm_judgment":"PRESENT","evidence":"NM_001134407.2:C.3299A>G (p.Glu1100Gly)","abstract_start":313,"abstract_end":352}]}
{"pmid":"38311799","title":"Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.","abstract":"OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.\nMETHODS: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant.\nRESULTS: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing.\nINTERPRETATION: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.","variants":[{"Name":"NM_001103.4(ACTN2):c.1516A>G (p.Arg506Gly)","Chromosome":"1","Start":"236749124","Stop":"236749124","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":198055,"rule_based_match":true,"evidence_text":"c.1516A>G (p.Arg506Gly)","llm_judgment":"PRESENT","evidence":"c.1516A>G (p.Arg506Gly)","abstract_start":710,"abstract_end":733}]}
{"pmid":"32682435","title":"What is the impact of a novel MED12 variant on syndromic conotruncal heart defects? Analysis of case report on two male sibs.","abstract":"BACKGROUND: Syndromic congenital heart disease accounts for 30% of cases and can be determined by genetic, environmental or multifactorial causes. In many cases the etiology remains uncertain. Many known genes are responsible for specific morphopathogenetic mechanisms during the development of the heart whose alteration can determine specific phenotypes of cardiac malformations.\nCASE PRESENTATION: We report on two cases of association of conotruncal heart defect with facial dysmorphisms in sibs. In both cases the malformations' identification occurred by ultrasound in the prenatal period. It was followed by prenatal invasive diagnosis. The genetic analysis revealed no rearrangements in Array-CGH test, while gene panel sequencing identified a new hemizygous variant of uncertain significance (c.887G > A; p.Arg296Gln) in the MED12 gene, located on the X chromosome and inherited from the healthy mother.\nCONCLUSION: No other reports about the involvement of MED12 gene in syndromic conotruncal heart defects are actually available from the literature and the international genomic databases. This novel variant is a likely pathogenic variant of uncertain significance and it could broaden the spectrum of genes involved in the development of congenital heart diseases and the phenotypic range of MED12-related disorders.","variants":[{"Name":"NM_005120.3(MED12):c.887G>A (p.Arg296Gln)","Chromosome":"X","Start":"71121602","Stop":"71121602","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":512733,"rule_based_match":true,"evidence_text":"c.887G > A; p.Arg296Gln","llm_judgment":"PRESENT","evidence":"c.887G > A; p.Arg296Gln","abstract_start":802,"abstract_end":825}]}
{"pmid":"22553411","title":"Gastric angiodysplasia in a hereditary hemorrhagic telangiectasia type 2 patient.","abstract":"Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominantly inherited disease that occurs in approximately one in 5000 to 8000 people. Clinical diagnosis of HHT is made when a person presents three of the following four criteria: family history, recurrent nosebleeds, mucocutaneous telangiectasis, and arteriovenous malformations (AVM) in the brain, lung, liver and gastrointestinal (GI) tract. Although epistaxis is the most common presenting symptom, AVMs affecting the lungs, brain and GI tract provoke a more serious outcome. Heterozygous mutations in endoglin, activin receptor-like kinase 1 (ACVRL1; ALK1), and SMAD4, the genes involved in the transforming growth factor-β family signaling cascade, cause HHT. We report here the case of a 63 year-old male patient who presented melena and GI bleeding episodes, proven to be caused by bleeding from multiple gastric angiodysplasia. Esophagogastroduodenoscopy revealed multiple angiodysplasia throughout the stomach. Endoscopic argon plasma coagulation was performed to control bleeding from a gastric angiodysplasia. The patient has been admitted several times with episodes of hemoptysis and hematochezia. One year ago, the patient was hospitalized due to right-sided weakness, which was caused by left basal ganglia hemorrhage as the part of HHT presentation. In family history, the patient's mother and elder sister had died, due to intracranial hemorrhage, and his eldest son has been suffered from recurrent epistaxis for 20 years. A genetic study revealed a mutation in exon 3 of ALK1 (c.199C > T; p.Arg67Trp) in the proband and his eldest son presenting epistaxis.","variants":[{"Name":"NM_000020.3(ACVRL1):c.199C>T (p.Arg67Trp)","Chromosome":"12","Start":"51913236","Stop":"51913236","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":414382,"rule_based_match":true,"evidence_text":"c.199C > T; p.Arg67Trp","llm_judgment":"PRESENT","evidence":"c.199C > T; p.Arg67Trp","abstract_start":1562,"abstract_end":1584}]}
{"pmid":"28676969","title":"Genetic study of the PAH locus in the Iranian population: familial gene mutations and minihaplotypes.","abstract":"Phenylketonuria (PKU), one of the most common inborn errors of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene (PAH). PKU has wide allelic heterogeneity, and over 600 different disease-causing mutations in PAH have been detected to date. Up to now, there have been no reports on the minihaplotype (VNTR/STR) analysis of PAH locus in the Iranian population. The aims of the present study were to determine PAH mutations and minihaplotypes in Iranian families with PAH deficiency and to investigate the correlation between them. A total of 81 Iranian families with PAH deficiency were examined using PCR-sequencing of all 13 PAH exons and their flanking intron regions to identify sequence variations. Fragment analysis of the PAH minihaplotypes was performed by capillary electrophoresis for 59 families. In our study, 33 different mutations were found accounting for 95% of the total mutant alleles. The majority of these mutations (72%) were distributed across exons 7, 11, 2 and their flanking intronic regions. Mutation c.1066-11G > A was the most common with a frequency of 20.37%. The less frequent mutations, p.Arg261Gln (8%), p.Arg243Ter (7.4%), p.Leu48Ser (7.4%), p.Lys363Asnfs*37 (6.79%), c.969 + 5G > A (6.17%), p.Pro281Leu (5.56), c.168 + 5G > C (5.56), and p.Arg261Ter (4.94) together comprised about 52% of all mutant alleles. In this study, a total of seventeen PAH gene minihaplotypes were detected, six of which associated exclusively with particular mutations. Our findings indicate a broad PAH mutation spectrum in the Iranian population, which is consistent with previous studies reporting a wide range of PAH mutations, most likely due to ethnic heterogeneity. High prevalence of c.1066-11G > A mutation linked to minihaplotype 7/250 among both Iranian and Mediterranean populations is indicative of historical and geographical links between them. Also, strong association between particular mutations and minihaplotypes could be useful for prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) in affected families.","variants":[{"Name":"NM_000277.3(PAH):c.969+5G>A","Chromosome":"12","Start":"102846890","Stop":"102846890","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":108651,"rule_based_match":true,"evidence_text":"c.969 + 5G > A","llm_judgment":"PRESENT","evidence":"c.969 + 5G > A","abstract_start":1240,"abstract_end":1254}]}
{"pmid":"15643603","title":"Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families.","abstract":"Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterized by lower-limb spasticity, hyperreflexia, progressive spastic gait abnormalities, and an extensor-plantar response. It is genetically very heterogeneous, with 28 Human Genome Organisation (HUGO)-approved IDs in the database (last search: August 8, 2004). Following the identification of the SPG6 gene, NIPA1, we have identified two novel mutations, c.316G>C and c.316G>A, in two independent Chinese families linked to the SPG6 locus. These two mutations would cause a p.G106R substitution, and cosegregated with the disease. Structural predictions suggest that p.G106 is located in the third transmembrane domain of the protein, and that the mutant p.G106R disrupts this structure, causing the intramembrane loop to descend into the cytoplasm. Our results identify two novel mutations responsible for HSP and suggest that c.316 of theNIPA1 gene may be a mutational hotspot.","variants":[{"Name":"NM_144599.5(NIPA1):c.316G>C (p.Gly106Arg)","Chromosome":"15","Start":"22812252","Stop":"22812252","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":17560,"rule_based_match":true,"evidence_text":"c.316G>C","llm_judgment":"PRESENT","evidence":"c.316G>C","abstract_start":429,"abstract_end":437},{"Name":"NM_144599.5(NIPA1):c.316G>A (p.Gly106Arg)","Chromosome":"15","Start":"22812252","Stop":"22812252","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17562,"rule_based_match":true,"evidence_text":"c.316G>A","llm_judgment":"PRESENT","evidence":"c.316G>A","abstract_start":442,"abstract_end":450}]}
{"pmid":"29571850","title":"Phenotypical features of two patients diagnosed with PHARC syndrome and carriers of a new homozygous mutation in the ABHD12 gene.","abstract":"PHARC (Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa and Cataracts) (MIM# 612674) is an autosomal recessive neurodegenerative disease caused by mutations in the ABHD12 gene. We evaluated two Spanish siblings affected with pes cavus, sensorimotor neuropathy, hearing loss, retinitis pigmentosa and juvenile cataracts in whom the genetic test of ABHD12 revealed a novel homozygous frameshift mutation, c.211_223del (p.Arg71Tyrfs*26). The earliest clinical manifestation in these patients was a demyelinating neuropathy manifested with a Charcot-Marie-Tooth phenotype over three decades. Progressive hearing loss, cataracts and retinitis pigmentosa appeared after the age of 30. We herein describe the complete clinical picture of these two patients, and focus particularly on neuropathy characteristics. This study supports the fact that although PHARC is rare, its phenotype is very characteristic and we should include its study in patients affected with demyelinating polyneuropathy, hearing loss and retinopathy.","variants":[{"Name":"NM_001042472.3(ABHD12):c.211_223del (p.Arg71fs)","Chromosome":"20","Start":"25339320","Stop":"25339332","ReferenceAlleleVCF":"ATCTTCCTCAGGCG","AlternateAlleleVCF":"A","allel_id":424226,"rule_based_match":true,"evidence_text":"c.211_223del (p.Arg71Tyrfs*26)","llm_judgment":"PRESENT","evidence":"c.211_223del (p.Arg71Tyrfs*26)","abstract_start":413,"abstract_end":443}]}
{"pmid":"34948168","title":"Availability of mRNA Obtained from Peripheral Blood Mononuclear Cells for Testing Mutation Consequences in Dystrophic Epidermolysis Bullosa.","abstract":"Dystrophic epidermolysis bullosa (DEB) is an inheritable blistering disease caused by mutations in <i>COL7A1</i>, which encodes type VII collagen. To address the issue of genotype-phenotype correlations in DEB, analyzing the consequences of <i>COL7A1</i> mutations using mRNA is indispensable. Herein we established a novel method for testing the effect of mutations in DEB using <i>COL7A1</i> mRNA extracted from peripheral blood mononuclear cells (PBMCs). We investigated the consequences of four <i>COL7A1</i> mutations (c.6573 + 1G > C, c.6216 + 5G > T, c.7270C > T and c.2527C > T) in three Japanese individuals with recessive DEB. The novel method detected the consequences of two recurrent <i>COL7A1</i> mutations (c.6573 + 1G > C, c.6216 + 5G > T) and a novel <i>COL7A1</i> mutation (c.7270C > T) accurately. In addition, it detected aberrant splicing resulting from a <i>COL7A1</i> mutation (c.2527C > T) which was previously reported as a nonsense mutation. Furthermore, we revealed that type VII collagen-expressing cells in PBMCs have similar cell surface markers as mesenchymal stem cells; they were CD105<sup>+</sup>, CD29<sup>+</sup>, CD45<sup>-</sup>, and CD34<sup>-</sup>, suggesting that a small number of mesenchymal stem cells or mesenchymal stromal cells are circulating in the peripheral blood, which enables us to detect <i>COL7A1</i> mRNA in PBMCs. Taken together, our novel method for analyzing mutation consequences using mRNA obtained from PBMCs in DEB will significantly contribute to genetic diagnoses and novel therapies for DEB.","variants":[{"Name":"NM_000094.4(COL7A1):c.7270C>T (p.Arg2424Trp)","Chromosome":"3","Start":"48570863","Stop":"48570863","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1035792,"rule_based_match":true,"evidence_text":"c.7270C > T","llm_judgment":"PRESENT","evidence":"c.7270C > T","abstract_start":558,"abstract_end":569}]}
{"pmid":"23096355","title":"BRCA1 and BRCA2 mutations in breast cancer patients from Venezuela.","abstract":"A sample of 58 familial breast cancer patients from Venezuela were screened for germline mutations in the coding sequences and exon-intron boundaries of BRCA1 (MIM no. 113705) and BRCA2 (MIM no. 600185) genes by using conformation-sensitive gel electrophoresis. Ashkenazi Jewish founder mutations were not found in any of the samples. We identified 6 (10.3%) and 4 (6.9%) patients carrying germline mutations in BRCA1 and BRCA2, respectively. Four pathogenic mutations were found in BRCA1, one is a novel mutation (c.951_952insA), while the other three had been previously reported (c.1129_1135insA, c.4603G>T and IVS20+1G>A). We also found 4 pathogenic mutations in BRCA2, two novel mutations (c.2732_2733insA and c.3870_3873delG) and two that have been already reported (c.3036_3039delACAA and c.6024_6025_delTA). In addition, 17 variants of unknown significance (6 BRCA1 variants and 11 BRCA2 variants), 5 BRCA2 variants with no clinical importance and 22 polymorphisms (12 in BRCA1 and 10 in BRCA2) were also identified. This is the first genetic study on BRCA gene mutations conducted in breast cancer patients from Venezuela. The ethnicity of our population, as well as the heterogeneous and broad spectrum of BRCA genes mutations, must be considered to optimize genetic counseling and disease prevention in affected families.","variants":[{"Name":"NM_007294.4(BRCA1):c.4603G>T (p.Glu1535Ter)","Chromosome":"17","Start":"43074403","Stop":"43074403","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":69903,"rule_based_match":true,"evidence_text":"c.4603G>T","llm_judgment":"PRESENT","evidence":"c.4603G>T","abstract_start":600,"abstract_end":609}]}
{"pmid":"25861491","title":"A Novel PHEX Mutation in Japanese Patients with X-Linked Hypophosphatemic Rickets.","abstract":"X-linked hypophosphatemic rickets (XLH) is a dominant inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. Inactivating mutations in the gene encoding phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) have been found to be associated with XLH. Here, we report a 16-year-old female patient affected by hypophosphatemic rickets. We evaluated her serum fibroblast growth factor 23 (FGF23) levels and conducted sequence analysis of the disease-associated genes of FGF23-related hypophosphatemic rickets: PHEX, FGF23, dentin matrix protein 1, and ectonucleotide pyrophosphatase/phosphodiesterase 1. She was diagnosed with XLH based on her clinical features and family history. Additionally, we observed elevated FGF23 levels and a novel PHEX exon 9 mutation (c.947G>T; p.Gly316Val) inherited from her father. Although bioinformatics showed that the mutation was neutral, Gly316 is perfectly conserved among humans, mice, and rats, and there were no mutations in other FGF23-related rickets genes, suggesting that in silico analysis is limited in determining mutation pathogenicity. In summary, we present a female patient and her father with XLH harboring a novel PHEX mutation that appears to be causative of disease. Measurement of FGF23 for hypophosphatemic patients is therefore useful for the diagnosis of FGF23-dependent hypophosphatemia.","variants":[{"Name":"NM_000444.6(PHEX):c.947G>T (p.Gly316Val)","Chromosome":"X","Start":"22099019","Stop":"22099019","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2901809,"rule_based_match":true,"evidence_text":"c.947G>T; p.Gly316Val","llm_judgment":"PRESENT","evidence":"c.947G>T; p.Gly316Val","abstract_start":864,"abstract_end":885}]}
{"pmid":"34975848","title":"A Novel Homozygous","abstract":"Rare autosomal-recessive variants in tetratricopeptide repeat domain 7A (<i>TTC7A</i>) gene have been shown to cause intestinal and immune disorders of variable severity. Missense mutations in <i>TTC7A</i> gene, usually retaining most of the functional motifs, is associated with relative milder clinical presentations. In this study, we reported a patient who was suffering from severe multiple intestinal atresia (MIA) with combined immunodeficiency (CID) that led to the pyloric diaphragm, ileum atresia, colon stenosis, and multiple episodes of sepsis. In spite of several surgeries and supportive treatment, the patient died of severe sepsis and multiple organ failure at age of 3 months. The whole exome sequencing (WES) of peripheral blood samples identified a novel homozygous <i>TTC7A</i> missense mutation (c. 206T>C, p. L69P), inherited from his parents with consanguineous marriage. <i>In silico</i> analysis revealed that a hydrogen bond present between Gly65 and Leu69 in the wild-type TTC7A was disrupted by the Leu69Pro mutation. Moreover, this homozygous missense mutation led to a reduced TTC7A expression in lymphocytes and intestinal tissues, accompanied by impeded lymphocyte development. Further studies demonstrated that the PI4K-FAM126A-EFR3A pathway was impaired in colon tissues. Our data strongly support the linkage of severe MIA-CID with the missense mutation in <i>TTC7A</i> gene. More knowledge of the TTC7A protein functions will have important therapeutic implications for patients with MIA-CID.","variants":[{"Name":"NM_020458.4(TTC7A):c.206T>C (p.Leu69Pro)","Chromosome":"2","Start":"46950384","Stop":"46950384","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3794251,"rule_based_match":true,"evidence_text":"c. 206T>C, p. L69P","llm_judgment":"PRESENT","evidence":"c. 206T>C, p. L69P","abstract_start":817,"abstract_end":835}]}
{"pmid":"21269315","title":"Dystrophic epidermolysis bullosa pruriginosa of elderly onset.","abstract":"A 71-year-old man with no family history of skin diseases presented with a 4 month history of recalcitrant pruritic papules and nodules on the lower extremities. He had prurigo-like eruptions with tense bullae on the extensor aspect of his lower extremities with multiple adjacent milia. Toenail dystrophy was observed. Mucous membranes were not affected. Skin biopsy from the shin showed a subepidermal blister with milium. Electron microscopy from lesional and perilesional skin of the leg showed scanty, hypoplastic anchoring fibrils. We detected a heterozygous mutation in the COL7A1 gene, a G-to-A substitution in exon 87 (c.6859G>A; p.Gly2287Arg). Thus, the clinicopathological and molecular findings supported a diagnosis of dystrophic epidermolysis bullosa pruriginosa. Assessment of other relatives was not feasible. To the best of our knowledge, this is the oldest clinical onset of this unusual variant of dystrophic epidermolysis bullosa reported to date. Why the onset of skin fragility should have occurred so late is not known, but the case serves as a reminder that this particular mechanobullous disease can have a delayed presentation.","variants":[{"Name":"NM_000094.4(COL7A1):c.6859G>A (p.Gly2287Arg)","Chromosome":"3","Start":"48572712","Stop":"48572712","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32486,"rule_based_match":true,"evidence_text":"c.6859G>A; p.Gly2287Arg","llm_judgment":"PRESENT","evidence":"c.6859G>A; p.Gly2287Arg","abstract_start":628,"abstract_end":651}]}
{"pmid":"30361054","title":"Familial amyloid polyneuropathy with chronic paroxysmal dry cough in Mainland China: A Chinese family with a proven heterozygous missense mutation c.349G>T in the transthyretin gene.","abstract":"Familial amyloid polyneuropathy (FAP) is a rare autosomal dominant disorder characterized by amyloid accumulation in the peripheral nerves and other organs, including the heart, kidney, and eyes. So far, no case with FAP from Mainland China was reported with a heterozygous missense mutation c.349G>T in the Transthyretin (TTR) gene. We report a 58-year-old man presenting with progressive peripheral neuropathy, autonomic failure and chronic paroxysmal dry cough. His father, three elder brothers and an elder sister suffered from the similar symptoms. Diagnostic whole-exome sequencing revealed a proven heterozygous missense mutation c.349G>T in exon 4 of the TTR gene, resulting in replacement of alanine with serine at position 117 of the mature protein (Ala117Ser). This is the first FAP family with a proven missense mutation c.349G>T in Mainland China, as well as the first FAP case with chronic paroxysmal dry cough.","variants":[{"Name":"NM_000371.4(TTR):c.349G>T (p.Ala117Ser)","Chromosome":"18","Start":"31598580","Stop":"31598580","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":28507,"rule_based_match":true,"evidence_text":"c.349G>T","llm_judgment":"PRESENT","evidence":"c.349G>T","abstract_start":292,"abstract_end":300}]}
{"pmid":"36426412","title":"Congenital disorder of glycosylation with defective fucosylation 2 (FCSK gene defect): The third report in the literature with a mild phenotype.","abstract":"BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of heterogeneous disorders caused by abnormal lipid or protein glycosylation. Variants in the FCSK gene have been reported to cause CDG. Defective FCSK-induced CDG (FCSK-CDG) has only been reported previously in three unrelated children.\nMETHODS: In this study, we genetically and clinically examined a 3-year-old proband with resolved infantile spasms and normal development. Standard whole-exome sequencing (WES) and Sanger sequencing were performed to identify the functional impact of the variant.\nRESULTS: WES revealed a rare biallelic missense variant (c.3013G>C; p.Val1005Leu) in FCSK. RT-qPCR showed a significant depletion in FCSK gene expression in the affected individual. Western blotting revealed reduced FCSK expression at the protein level compared to that in the control. Furthermore, 3D protein modeling suggested changes in the secondary structure, which might affect the overall FCSK protein function.\nCONCLUSION: This study broadens the mutation and phenotypic spectrum of FCSK-associated developmental disorders.","variants":[{"Name":"NM_145059.3(FCSK):c.3013G>C (p.Val1005Leu)","Chromosome":"16","Start":"70479263","Stop":"70479263","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2042962,"rule_based_match":true,"evidence_text":"c.3013G>C; p.Val1005Leu","llm_judgment":"PRESENT","evidence":"c.3013G>C; p.Val1005Leu","abstract_start":627,"abstract_end":650}]}
{"pmid":"25782327","title":"DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.","abstract":"AIMS: Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations.\nMETHODS: Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3-4 AEs.\nRESULTS: None of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3-4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c.496A > G and c.1896 T > C.\nCONCLUSIONS: Concomitant assessment of DPYD variants and the UGT1A1*28 allele is a promising strategy needing further validation for dose personalization.","variants":[{"Name":"NM_000110.4(DPYD):c.496A>G (p.Met166Val)","Chromosome":"1","Start":"97699535","Stop":"97699535","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":105993,"rule_based_match":true,"evidence_text":"DPYD c.496A > G","llm_judgment":"PRESENT","evidence":"DPYD c.496A > G","abstract_start":1177,"abstract_end":1192},{"Name":"NM_000110.4(DPYD):c.1129-5923C>G","Chromosome":"1","Start":"97579893","Stop":"97579893","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":623100,"rule_based_match":true,"evidence_text":"c.1129-5923C>G","llm_judgment":"PRESENT","evidence":"c.1129-5923C > G","abstract_start":385,"abstract_end":401},{"Name":"NM_000110.4(DPYD):c.1896T>C (p.Phe632=)","Chromosome":"1","Start":"97450068","Stop":"97450068","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":105965,"rule_based_match":true,"evidence_text":"c.1896 T > C","llm_judgment":"PRESENT","evidence":"c.1896 T > C","abstract_start":406,"abstract_end":418}]}
{"pmid":"27839525","title":"Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature.","abstract":"Cardiomyopathy is a common manifestation in neonates and infants with mitochondrial disorders. In this study, we report two cases manifesting with fatal mitochondrial hypertrophic cardiomyopathy, which include the third known patient with thymidine kinase 2 deficiency and the ninth patient with alanyl-tRNA synthetase 2 deficiency. The girl with thymidine kinase 2 deficiency had hypertrophic cardiomyopathy together with regression of gross motor development at the age of 13 months. Neurological symptoms and cardiac involvement progressed into severe myopathy, psychomotor arrest, and cardiorespiratory failure at the age of 22 months. The imaging methods and autoptic studies proved that she suffered from unique findings of leucoencephalopathy, severe, mainly cerebellar neuronal degeneration, and hepatic steatosis. The girl with alanyl-tRNA synthetase 2 deficiency presented with cardiac failure and underlying hypertrophic cardiomyopathy within 12 hours of life and subsequently died at 9 weeks of age. Muscle biopsy analyses demonstrated respiratory chain complex I and IV deficiencies, and histological evaluation revealed massive mitochondrial accumulation and cytochrome c oxidase-negative fibres in both cases. Exome sequencing in the first case revealed compound heterozygozity for one novel c.209T>C and one previously published c.416C>T mutation in the TK2 gene, whereas in the second case homozygozity for the previously described mutation c.1774C>T in the AARS2 gene was determined. The thymidine kinase 2 mutations resulted in severe mitochondrial DNA depletion (to 12% of controls) in the muscle. We present, for the first time, severe leucoencephalopathy and hepatic steatosis in a patient with thymidine kinase 2 deficiency and the finding of a ragged red fibre-like image in the muscle biopsy in a patient with alanyl-tRNA synthetase 2 deficiency.","variants":[{"Name":"NM_004614.5(TK2):c.209T>C (p.Phe70Ser)","Chromosome":"16","Start":"66541901","Stop":"66541901","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2895056,"rule_based_match":true,"evidence_text":"c.209T>C","llm_judgment":"PRESENT","evidence":"c.209T>C","abstract_start":1307,"abstract_end":1315},{"Name":"NM_020745.4(AARS2):c.1774C>T (p.Arg592Trp)","Chromosome":"6","Start":"44304512","Stop":"44304512","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39897,"rule_based_match":true,"evidence_text":"c.1774C>T","llm_judgment":"PRESENT","evidence":"c.1774C>T","abstract_start":1458,"abstract_end":1467},{"Name":"NM_004614.5(TK2):c.416C>T (p.Ala139Val)","Chromosome":"16","Start":"66529027","Stop":"66529027","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":47593,"rule_based_match":true,"evidence_text":"c.416C>T","llm_judgment":"PRESENT","evidence":"c.416C>T","abstract_start":1345,"abstract_end":1353}]}
{"pmid":"20521171","title":"Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance.","abstract":"In Npc1 null mice, a model for Niemann Pick Disease Type C1, it has been reported that hepatocyte insulin receptor function is significantly impaired, consistent with growing evidence that membrane fluidity and microdomain structure have an important role in insulin signal transduction. However, whether insulin receptor function is also compromised in human Niemann Pick disease Type C1 is unclear. We now report a girl who developed progressive dementia, ataxia and opthalmoplegia from 9 years old, followed by severe acanthosis nigricans, hirsutism and acne at 11 years old. She was diagnosed with Niemann Pick Disease type C1 (OMIM#257220) based on positive filipin staining and reduced cholesterol-esterifying activity in dermal fibroblasts, and homozygosity for the p.Ile1061Thr NPC1 mutation. Further analysis revealed her also to be heterozygous for a novel trinucleotide deletion (c.3659 + 1_3659 + 3delGTG) at the end of exon 20 of INSR, encoding the insulin receptor, leading to deletion of Trp1193 in the intracellular tyrosine kinase domain. INSR mRNA and protein levels were normal in dermal fibroblasts, consistent with a primary signal transduction defect in the mutant receptor. Although the proband was significantly more insulin resistant than her father, who carried the INSR mutation but was only heterozygous for the NPC1 variant, their respective degrees of IR were very similar to those previously reported in a father-daughter pair with the closely related p.Trp1193Leu INSR mutation. This suggests that loss of NPC1 function, with attendant changes in membrane cholesterol composition, does not significantly modify the IR phenotype, even in the context of severely impaired INSR function.","variants":[{"Name":"NM_000271.5(NPC1):c.3182T>C (p.Ile1061Thr)","Chromosome":"18","Start":"23536736","Stop":"23536736","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18006,"rule_based_match":false,"evidence_text":"p.Ile1061Thr","llm_judgment":"PRESENT","evidence":"p.Ile1061Thr","abstract_start":773,"abstract_end":785}]}
{"pmid":"28182360","title":"Mutation Analysis in Classical Phenylketonuria Patients Followed by Detecting Haplotypes Linked to Some PAH Mutations.","abstract":"BACKGROUND: Deficiency of phenylalanine hydroxylase (PAH) enzyme and elevation of phenylalanine in body fluids cause phenylketonuria (PKU). The gold standard for confirming PKU and PAH deficiency is detecting causal mutations by direct sequencing of the coding exons and splicing involved sequences of the PAH gene. Furthermore, haplotype analysis could be considered as an auxiliary approach for detecting PKU causative mutations before direct sequencing of the PAH gene by making comparisons between prior detected mutation linked-haplotypes and new PKU case haplotypes with undetermined mutations.\nMETHODS: In this study, 13 unrelated classical PKU patients took part in the study detecting causative mutations. Mutations were identified by polymerase chain reaction (PCR) and direct sequencing in all patients. After that, haplotype analysis was performed by studying VNTR and PAHSTR markers (linked genetic markers of the PAH gene) through application of PCR and capillary electrophoresis (CE).\nRESULTS: Mutation analysis was performed successfully and the detected mutations were as follows: c.782G>A, c.754C>T, c.842C>G, c.113-115delTCT, c.688G>A, and c.696A>G. Additionally, PAHSTR/VNTR haplotypes were detected to discover haplotypes linked to each mutation.\nCONCLUSIONS: Mutation detection is the best approach for confirming PAH enzyme deficiency in PKU patients. Due to the relatively large size of the PAH gene and high cost of the direct sequencing in developing countries, haplotype analysis could be used before DNA sequencing and mutation detection for a faster and cheaper way via identifying probable mutated exons.","variants":[{"Name":"NM_000277.3(PAH):c.688G>A (p.Val230Ile)","Chromosome":"12","Start":"102855154","Stop":"102855154","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":108520,"rule_based_match":true,"evidence_text":"c.688G>A","llm_judgment":"PRESENT","evidence":"c.688G>A","abstract_start":1145,"abstract_end":1153}]}
{"pmid":"29449720","title":"Biallelic inactivating variants in the GTPBP2 gene cause a neurodevelopmental disorder with severe intellectual disability.","abstract":"Congenital neurological disorders are genetically highly heterogeneous. Rare forms of hereditary neurological disorders are still difficult to be adequately diagnosed. Pertinent studies, especially when reporting only single families, need independent confirmation. We present three unrelated families in which whole-exome sequencing identified the homozygous non-sense variants c.430[C>T];[C>T] p.(Arg144*), c.1219[C>T];[C>T] p.(Gln407*) and c.1408[C>T];[C>T] p.(Arg470*) in GTPBP2. Their clinical presentations include early onset and apparently non-progressive motor and cognitive impairment, and thereby overlap with findings in a recently described family harbouring a homozygous GTPBP2 splice site variant. Notable differences include structural brain abnormalities (e.g., agenesis of the corpus callosum, exclusive to our patients), and evidence for brain iron accumulation (exclusive to the previously described family). This report confirms pathogenicity of biallelic GTPBP2 inactivation and broadens the phenotypic spectrum. It also underlines that a potential involvement of brain iron accumulation needs clarification. Further patients will have to be identified and characterised in order to fully define the core features of GTPBP2-associated neurological disorder, but future approaches to molecular diagnosis of neurodevelopmental disorders should implement GTPBP2.","variants":[{"Name":"NM_019096.5(GTPBP2):c.430C>T (p.Arg144Ter)","Chromosome":"6","Start":"43625833","Stop":"43625833","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":535232,"rule_based_match":false,"evidence_text":"c.430[C>T];[C>T] p.(Arg144*)","llm_judgment":"PRESENT","evidence":"c.430[C>T];[C>T] p.(Arg144*)","abstract_start":379,"abstract_end":407},{"Name":"NM_019096.5(GTPBP2):c.1219C>T (p.Gln407Ter)","Chromosome":"6","Start":"43623950","Stop":"43623950","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":535233,"rule_based_match":false,"evidence_text":"c.1219[C>T];[C>T] p.(Gln407*)","llm_judgment":"PRESENT","evidence":"c.1219[C>T];[C>T] p.(Gln407*)","abstract_start":409,"abstract_end":438},{"Name":"NM_019096.5(GTPBP2):c.1408C>T (p.Arg470Ter)","Chromosome":"6","Start":"43622692","Stop":"43622692","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":535234,"rule_based_match":false,"evidence_text":"c.1408[C>T];[C>T] p.(Arg470*)","llm_judgment":"PRESENT","evidence":"c.1408[C>T];[C>T] p.(Arg470*)","abstract_start":443,"abstract_end":472}]}
{"pmid":"21119707","title":"On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations.","abstract":"The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245 carrier families from 14 different population groups (Russian, Latvian, Ukrainian, Czech, Slovak, Polish, Danish, Dutch, French, German, Italian, Greek, Brazilian and AJ) for seven microsatellite markers and confirmed that all mutation carriers share a common haplotype from a single founder individual. Using a maximum likelihood method that allows for both recombination and mutational events of marker loci, we estimated that the mutation arose some 1800 years ago in either Scandinavia or what is now northern Russia and subsequently spread to the various populations we genotyped during the following centuries, including the AJ population. Age estimates and the molecular evolution profile of the most common linked haplotype in the carrier populations studied further suggest that c.5266dupC likely entered the AJ gene pool in Poland approximately 400-500 years ago. Our results illustrate that (1) BRCA1 c.5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"BRCA1 c.5266dupC","llm_judgment":"PRESENT","evidence":"BRCA1 c.5266dupC","abstract_start":1205,"abstract_end":1221}]}
{"pmid":"35947379","title":"Dominant Cone Rod Dystrophy, Previously Assigned to a Missense Variant in RIMS1, Is Fully Explained by Co-Inheritance of a Dominant Allele of PROM1.","abstract":"Purpose: Autosomal dominant cone rod dystrophy 7 (CORD7) was initially linked to the gene RIMS1 and reported in a 4-generation British family in 1998. The purpose of this study was to investigate the legitimacy of this association, and to correctly characterize the genetic cause of this condition.\nMethods: The allele frequency of RIMS1 c.2459G>A, p.Arg820His, was investigated in the Genomes Aggregation Dataset (gnomAD) datasets and whole genome sequencing (WGS) was performed for 4 members of the CORD7 family with filtering of rare pathogenic variants in a virtual gene panel comprising all genes known to be associated with inherited retinal dystrophy (IRD). Cytogenetic analysis was performed to rule out interchromosomal translocation.\nResults: RIMS1 p.Arg820His has a maximal carrier frequency of >1:5000 in Europeans. A previously well-characterized PROM1 variant: c.1118C>T, p.Arg373Cys, was detected in 9 affected members of the CORD7 family who underwent WGS or direct sequencing. One affected family member is now known to have macular dystrophy in the absence of RIMS1 p.Arg820His. Clinical analysis of affected family members and 27 individuals with retinopathy associated with the same - PROM1 - variant showed consistent phenotypes.\nConclusions: The case for pathogenicity of RIMS1 p.Arg820His is not strong based on its presence on 10 alleles in the gnomAD dataset and absence from additional CORD affected individuals. The finding of a known pathogenic variant in PROM1 correlates well with the phenotypic characteristics of the affected individuals, and is likely to account for the condition. Clear evidence of association between RIMS1 and a retinal dystrophy is yet to be described.","variants":[{"Name":"NM_014989.7(RIMS1):c.2459G>A (p.Arg820His)","Chromosome":"6","Start":"72251007","Stop":"72251007","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19207,"rule_based_match":true,"evidence_text":"RIMS1 c.2459G>A, p.Arg820His","llm_judgment":"PRESENT","evidence":"RIMS1 c.2459G>A, p.Arg820His","abstract_start":332,"abstract_end":360}]}
{"pmid":"32071835","title":"High-dose hydroxocobalamin achieves biochemical correction and improvement of neuropsychiatric deficits in adults with late onset cobalamin C deficiency.","abstract":"Cobalamin C (<i>cblC</i>) deficiency is the most common inborn error of intracellular cobalamin metabolism caused by pathogenic variant(s) in <i>MMACHC</i> and manifests with methylmalonic acidemia, hyperhomocysteinemia, and hypomethioninemia with a variable age of presentation. Individuals with late-onset <i>cblC</i> may be asymptomatic until manifesting neuropsychiatric symptoms, thromboembolic events, and renal disease. Although hydroxocobalamin provides a foundation for therapy, optimal dose regimen for adult patients has not been systematically evaluated. We report three adult siblings with late-onset <i>cblC</i> disease, and their biochemical and clinical responses to high-dose hydroxocobalamin. The 28-year-old proband presented with severe psychosis, progressive neurological deterioration, and deep venous thrombosis complicated by a pulmonary embolism. MRI studies identified lesions in the spinal cord, periventricular white matter, and basal ganglia. Serum homocysteine and methylmalonic acid levels were markedly elevated. Hydroxocobalamin at standard dose (1 mg/day) initially resulted in partial metabolic correction. A regimen of high-dose hydroxocobalamin (25 mg/day) together with betaine and folic acid resulted in rapid and sustainable biochemical correction, resolution of psychosis, improvement of neurological functions, and amelioration of brain and spinal cord lesions. Two siblings who did not manifest neuropsychiatric symptoms or thromboembolism achieved a satisfactory metabolic control with the same high-dose regimen. Hydroxocobalamin injection was then spaced out to 25 mg weekly with good and sustainable metabolic control. All three patients are compound heterozygotes for c.271dupA p.Arg91LysfsX14 and c.389A > G p.Tyr130Cys. This study highlights the importance of evaluating intracellular cobalamin metabolism in adults with neuropsychiatric manifestations and/or thromboembolic events, and demonstrates that high-dose hydroxocobalamin achieves rapid and sustainable metabolic control and improvement in neuropsychiatric outcomes in adults with late-onset <i>cblC</i> disease.","variants":[{"Name":"NM_015506.3(MMACHC):c.389A>G (p.Tyr130Cys)","Chromosome":"1","Start":"45508324","Stop":"45508324","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":282449,"rule_based_match":true,"evidence_text":"c.389A > G p.Tyr130Cys","llm_judgment":"PRESENT","evidence":"c.389A > G p.Tyr130Cys","abstract_start":1746,"abstract_end":1768}]}
{"pmid":"29330115","title":"Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations.","abstract":"Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity.","variants":[{"Name":"NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)","Chromosome":"2","Start":"203870627","Stop":"203870627","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":170953,"rule_based_match":true,"evidence_text":"c.151C>T","llm_judgment":"PRESENT","evidence":"c.151C>T","abstract_start":738,"abstract_end":746},{"Name":"NM_139276.3(STAT3):c.2147C>T (p.Thr716Met)","Chromosome":"17","Start":"42316899","Stop":"42316899","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":226683,"rule_based_match":true,"evidence_text":"c.2147C>T","llm_judgment":"PRESENT","evidence":"c.2147C>T","abstract_start":908,"abstract_end":917}]}
{"pmid":"26316201","title":"Adult-onset glutaric aciduria type I presenting with white matter abnormalities and subependymal nodules.","abstract":"A 55-year-old female presented with a 6-year history of paresthesias, incontinence, spasticity, and gait abnormalities. Neuroimaging revealed white matter abnormalities associated with subependymal nodules. Biochemical evaluation noted increased serum C5-DC glutarylcarnitines and urine glutaric and 3-hydroxyglutaric acids. Evaluation of the glutaryl-CoA dehydrogenase (GCDH) gene revealed compound heterozygosity consisting of a novel variant (c.1219C>G; p.Leu407Val) and pathogenic mutation (c.848delT; p.L283fs). Together, these results were consistent with a diagnosis of adult-onset type I glutaric aciduria.","variants":[{"Name":"NM_000159.4(GCDH):c.1219C>G (p.Leu407Val)","Chromosome":"19","Start":"12897839","Stop":"12897839","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1868404,"rule_based_match":true,"evidence_text":"c.1219C>G; p.Leu407Val","llm_judgment":"PRESENT","evidence":"c.1219C>G; p.Leu407Val","abstract_start":446,"abstract_end":468},{"Name":"NM_000159.4(GCDH):c.848del (p.Leu283fs)","Chromosome":"19","Start":"12896417","Stop":"12896417","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":358599,"rule_based_match":true,"evidence_text":"c.848delT; p.L283fs","llm_judgment":"PRESENT","evidence":"c.848delT; p.L283fs","abstract_start":495,"abstract_end":514}]}
{"pmid":"28931339","title":"Limb-girdle muscular dystrophy type 2I: two Chinese families and a review in Asian patients.","abstract":"BACKGROUND: Limb-girdle muscular dystrophy type 2I (LGMD2I) is an autosomal recessive hereditary disorder caused by mutations in the fukutin-related protein (FKRP) gene. Although the features of the disorder in European patients have been summarized, Asian patients with LGMD2I have rarely been reported. Thus, the clinical differences in LGMD2I between Asian and European patients and the associated genetic changes remain unclear.\nMETHODS: We reported detailed clinical data as well as results from muscle biopsy, muscle MRI and genetic analysis of the FKRP gene in two unrelated Chinese families with LGMD2I. Additionally, a review of the literature focusing on the clinical and mutational features of LGMD2I in Asian patients was performed.\nRESULTS: The muscle biopsy results showed dystrophic features. Immunohistochemical staining revealed decreased glycosylations on α-dystroglycan. The muscle MRI results showed that the gluteus maximus, adductor, biceps femoris, vastus intermedius and vastus lateralis were severely affected. The patients in the two families harbored the same compound heterozygous mutations (c.545A>G and c.948delC). One patient showed significant clinical improvement after corticosteroid treatment.\nCONCLUSION: Our study expanded the reported spectrum of Asian LGMD2I patients. Our literature review revealed that pathogenic mutations in the FKRP gene in Asian LGMD2I patients are compound heterozygous rather than homozygous. Compound heterozygous Asian patients have a mild phenotype but frequently show respiratory and cardiac impairments. Corticosteroids may be beneficial for the treatment of LGMD2I and should be further investigated.","variants":[{"Name":"NM_024301.5(FKRP):c.948del (p.Cys317fs)","Chromosome":"19","Start":"46756393","Stop":"46756393","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":648192,"rule_based_match":true,"evidence_text":"c.948delC","llm_judgment":"PRESENT","evidence":"c.948delC","abstract_start":1133,"abstract_end":1142},{"Name":"NM_024301.5(FKRP):c.545A>G (p.Tyr182Cys)","Chromosome":"19","Start":"46755995","Stop":"46755995","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":266484,"rule_based_match":true,"evidence_text":"c.545A>G","llm_judgment":"PRESENT","evidence":"c.545A>G","abstract_start":1120,"abstract_end":1128}]}
{"pmid":"23474776","title":"A novel homozygous mutation of the nicotinamide nucleotide transhydrogenase gene in a Japanese patient with familial glucocorticoid deficiency.","abstract":"Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by primary hypocortisolism and normal mineralocorticoid production. Recently, NNT encoding the nicotinamide nucleotide transhydrogenase has been identified as a causative gene for FGD. Thus, we examined NNT in six Japanese FGD patients with no recognizable mutation in the previously known four responsible genes for FGD (MC2R, MRAP, STAR, and MCM4), and identified a novel homozygous substitution (c.644T>C; p.Phe215Ser) in a single 17.5-year-old boy. His parents were heterozygous for this mutation. This substitution was absent from 120 Japanese control subjects and was not registered in public databases including JSNP Database. The phenylalanine residue at the 215th codon was evolutionally conserved, and the p.Phe215Ser was assessed to be a pathologic mutation by in silico protein function analyses. The results, in conjunction with the previous data, imply that NNT mutations account for 5-10% of FGD patients, and that underlying factor(s) still remains to be clarified in a substantial fraction of FGD patients.","variants":[{"Name":"NM_182977.3(NNT):c.644T>C (p.Phe215Ser)","Chromosome":"5","Start":"43619076","Stop":"43619076","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":260546,"rule_based_match":true,"evidence_text":"c.644T>C; p.Phe215Ser","llm_judgment":"PRESENT","evidence":"c.644T>C; p.Phe215Ser","abstract_start":493,"abstract_end":514}]}
{"pmid":"33645901","title":"Cerebellofaciodental syndrome in an adult patient: Expanding the phenotypic and natural history characteristics.","abstract":"Cerebellofaciodental syndrome is characterized by facial dysmorphisms, intellectual disability, cerebellar hypoplasia, and dental anomalies. It is an autosomal-recessive condition described in 2015 caused by pathogenic variants in BRF1. Here, we report a Brazilian patient who faced a diagnostic challenge beginning at 11 months of age. Fortunately, whole-exome sequencing (WES) was performed, detecting the BRF1 variants NM_001519.3:c.1649delG:p.(Gly550Alafs*36) and c.421C>T:p.(Arg141Cys) in compound heterozygosity, thus finally achieving a diagnosis of cerebellofaciodental syndrome. The patient is currently 25 years old and is the oldest patient yet reported. The clinical report and a review of published cases are presented. Atlanto-occipital fusion, a reduced foramen magnum and basilar invagination leading to compression of the medulla-spinal cord transition are skeletal findings not reported in previous cases. The description of syndromes with dental findings shows that such anomalies can be an important clue to relevant differential diagnoses. The cooperation of groups from different international centers made possible the resolution of this and other cases and is one of the strategies to bring medical advances to developing countries, where many patients with rare diseases are difficult to diagnose definitively.","variants":[{"Name":"NM_001519.4(BRF1):c.1649del (p.Gly550fs)","Chromosome":"14","Start":"105217667","Stop":"105217667","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":2218260,"rule_based_match":true,"evidence_text":"NM_001519.3:c.1649delG:p.(Gly550Alafs*36)","llm_judgment":"PRESENT","evidence":"NM_001519.3:c.1649delG:p.(Gly550Alafs*36)","abstract_start":422,"abstract_end":463}]}
{"pmid":"24202787","title":"Recessive dystonia-ataxia syndrome in a Turkish family caused by a COX20 (FAM36A) mutation.","abstract":"DYTCA is a syndrome that is characterized by predominant dystonia and mild cerebellar ataxia. We examined two affected siblings with healthy, consanguineous, Turkish parents. Both patients presented with a combination of childhood-onset cerebellar ataxia, dystonia, and sensory axonal neuropathy. In the brother, dystonic features were most pronounced in the legs, while his sister developed torticollis. Routine diagnostic investigations excluded known genetic causes. Biochemical analyses revealed a mitochondrial respiratory chain complex IV and a coenzyme Q10 deficiency in a muscle biopsy. By exome sequencing, we identified a homozygous missense mutation (c.154A >C; p.Thr52Pro) in both patients in exon 2 of the COX20 (FAM36A) gene, which encodes a complex IV assembly factor. This variant was confirmed by Sanger sequencing, was heterozygous in both parents, and was absent from 427 healthy controls. The exact same mutation was recently reported in a patient with ataxia and muscle hypotonia. Among 128 early-onset dystonia and/or ataxia patients, we did not detect any other patient with a COX20 mutation. cDNA sequencing and semi-quantitative analysis were performed in fibroblasts from one of our homozygous mutation carriers and six controls. In addition to the exchange of an amino acid, the mutation led to a shift in splicing. In conclusion, we extend the phenotypic spectrum of a recently identified mutation in COX20 to a recessively inherited, early-onset dystonia-ataxia syndrome that is characterized by reduced complex IV activity. Further, we confirm a pathogenic role of this mutation in cerebellar ataxia, but this mutation seems to be a rather rare cause.","variants":[{"Name":"NM_198076.6(COX20):c.154A>C (p.Thr52Pro)","Chromosome":"1","Start":"244842055","Stop":"244842055","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":70537,"rule_based_match":true,"evidence_text":"c.154A >C; p.Thr52Pro","llm_judgment":"PRESENT","evidence":"c.154A >C; p.Thr52Pro","abstract_start":662,"abstract_end":683}]}
{"pmid":"36212142","title":"Molecular heterogeneity of glucose-6-phosphate dehydrogenase deficiency in neonates in Wuhan: Description of four novel variants.","abstract":"Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common X-linked enzymopathies caused by <i>G6PD</i> gene variant. The aim of this study was to investigate the molecular epidemiological characteristic of the G6PD deficiency among newborn screening population in Wuhan region. A total of 430,806 healthy neonates in Wuhan area of China were screened for G6PD deficiency from November 2016 to December 2021. The positive samples were further detected with gene analysis. Among the 957 neonates with abnormal G6PD enzyme activity, the prevalence of G6PD deficiency in Wuhan was calculated as 0.22%. 38 genotypes were found and the top 5 frequencies of <i>G6PD</i> gene variants were c.1388G > A, c.1376G > T, c.95A > G, c.1024C > T and c.871G > A. Seven rare single variants (c.25C > T, c.152C > T, c.406C > T, c.497G > A, c.679C > T, c.854G > A and c.1057C > T) and two rare multiple variants (IVS-5 637/638T del/c.1311C > T/1365-13T > C and c.406C > T/c.1311C > T/1365-13T > C) were discovered in this study. In addition, four novel variants (c.49C > T, c.691G > A, c.857A > T and c.982G > A) were detected out in our cohort, which have never been reported before. The result indicated that a rich diversity of G6PD genetic variants in Wuhan region, also had its own regional characteristic. Our data provided the basic knowledge for future prevention and research of G6PD deficiency and the findings will be useful for genetic counseling and prenatal diagnosis of G6PD deficiency in the Wuhan region.","variants":[{"Name":"NM_001360016.2(G6PD):c.691G>A (p.Ala231Thr)","Chromosome":"X","Start":"154534114","Stop":"154534114","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3498774,"rule_based_match":true,"evidence_text":"c.691G>A","llm_judgment":"PRESENT","evidence":"c.691G > A","abstract_start":1075,"abstract_end":1085},{"Name":"NM_001360016.2(G6PD):c.982G>A (p.Val328Met)","Chromosome":"X","Start":"154533011","Stop":"154533011","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3498777,"rule_based_match":true,"evidence_text":"c.982G > A","llm_judgment":"PRESENT","evidence":"c.982G > A","abstract_start":1102,"abstract_end":1112},{"Name":"NM_001360016.2(G6PD):c.49C>T (p.Arg17Trp)","Chromosome":"X","Start":"154546107","Stop":"154546107","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3498781,"rule_based_match":true,"evidence_text":"c.49C > T","llm_judgment":"PRESENT","evidence":"c.49C > T","abstract_start":1064,"abstract_end":1073}]}
{"pmid":"30075207","title":"A novel EXT2 mutation in a consanguineous family with severe developmental delay, microcephaly, seizures, feeding difficulties, and osteopenia extends the phenotypic spectrum of autosomal recessive EXT2-related syndrome (AREXT2).","abstract":"We report a consanguineous family where 2 boys presented with developmental delay, hypotonia, microcephaly, seizures, gastro-intestinal abnormalities, osteopenia, and neurological regression. Whole exome sequencing performed in one of the boys revealed the presence of a novel homozygous missense variant in the EXT2 gene: c.11C > T (p.Ser4Leu). Segregation analysis by Sanger sequencing confirmed homozygous by descent autosomal recessive transmission of this mutation. Another family was previously reported with homozygous mutations in this gene in four siblings affected with a nearly similar clinical condition (Farhan et al., 2015). We discuss the similarities and differences between the two syndromes and propose AREXT2 as a new acronym for EXT2-related diseases.","variants":[{"Name":"NM_207122.2(EXT2):c.11C>T (p.Ser4Leu)","Chromosome":"11","Start":"44107723","Stop":"44107723","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":326466,"rule_based_match":true,"evidence_text":"c.11C>T (p.Ser4Leu)","llm_judgment":"PRESENT","evidence":"c.11C > T (p.Ser4Leu)","abstract_start":323,"abstract_end":344}]}
{"pmid":"35711818","title":"Adult-Onset Sandhoff Disease in a Filipino Patient: Asymmetric Weakness, Whole","abstract":"Objective: To describe a Filipino patient with adult-onset Sandhoff disease manifesting with an atypical asymmetric lower motor neuron syndrome due to a novel whole <i>HEXB</i> deletion in <i>trans</i> with a pathogenic missense variant and with a coexisting <i>MYH7</i> pathogenic variant.\nMethods: We performed clinical, laboratory, myopathologic, and genetic evaluation with next-generation sequencing in the proband and targeted mutational analysis in an asymptomatic sibling.\nResults: A 59-year-old Filipino woman presented with 15 years of slowly progressive, asymmetric, proximal-predominant, lower greater than upper extremity weakness, mildly elevated creatine kinase, and generalized cerebellar atrophy. Serum total β-hexosaminidase was significantly reduced, and hexosaminidase A percentage was increased. We identified a novel <i>HEXB</i> whole gene deletion in compound heterozygosity with a pathogenic missense variant (c.1513C>T, p.Arg505Trp) previously described in 1 patient with adult-onset Sandhoff disease. The patient, with a family history of cardiomyopathy, has a coexisting <i>MYH7</i> pathogenic variant (c.3134G>A, p.Arg1045His), causative of cardiomyopathy but without cardiac involvement, likely due to variable penetrance. Myopathic features were absent from skeletal muscle biopsy.\nDiscussion: This patient expands the genotypic, phenotypic, and ethnic spectrum of Sandhoff disease and highlights challenges generated by low-penetrant pathogenic variants, especially when considering a potentially polygenic phenotype.","variants":[{"Name":"NM_000521.4(HEXB):c.1513C>T (p.Arg505Trp)","Chromosome":"5","Start":"74720647","Stop":"74720647","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":963265,"rule_based_match":true,"evidence_text":"c.1513C>T, p.Arg505Trp","llm_judgment":"PRESENT","evidence":"c.1513C>T, p.Arg505Trp","abstract_start":934,"abstract_end":956},{"Name":"NM_000257.4(MYH7):c.3134G>A (p.Arg1045His)","Chromosome":"14","Start":"23422291","Stop":"23422291","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":642286,"rule_based_match":true,"evidence_text":"NM_000257.4(MYH7):c.3134G>A (p.Arg1045His)","llm_judgment":"PRESENT","evidence":"p.Arg1045His","abstract_start":1141,"abstract_end":1153}]}
{"pmid":"24398087","title":"COL4A4-related nephropathy caused by a novel mutation in a large consanguineous Saudi family.","abstract":"INTRODUCTION: Collagen type IV related nephropathies are due to the defects in collagen IV genes COL4A3, COL4A4, or COL4A5 and comprise a spectrum of phenotypes ranging from Alport Syndrome (AS) to its mild variants, termed as familial haematuria or thin basement membrane nephropathy. Classical AS is a progressive renal disease presenting with a triad of progressive hematuric nephritis and typical extra-renal complications, such as sensorineural hearing loss (SNHL) and variable ocular anomalies. The mode of inheritance in AS is X-linked in 85%, autosomal recessive in 15%, and autosomal dominant in rare cases.\nOBJECTIVES: This study aims to identify underlying mutation in multiple individuals from a large consanguineous Saudi family with inherited nephropathy, including our index patient who manifested all the features of classical AS.\nPATIENTS AND METHODS: Patients were diagnosed by nephrologists and clinical geneticists. All the individuals underwent clinical, audiological and ophthalmological evaluation. Blood samples were collected after written informed consent. DNA extraction, homozygosity mapping and PCR amplification followed standard methodologies.\nRESULTS: The disease locus was mapped to 2q36.3, where both COL4A3 and COL4A4 reside. Sanger sequencing of COL4A3 and COL4A4 revealed an underlying novel homozygous disease-causing COL4A4 mutation (c.2420delG; p.G807fsX60) in the affected proband. Considerable phenotypic variability segregating with this COL4A4 mutation in our study family is documented. The homozygous mutants were manifesting end-stage renal disease (ESRD) in their adolescence, while the heterozygous carrier members were presenting with considerable phenotypic heterogeneity ranging from intermittent hematuria to late onset ESRD. In addition, there is a relatively severe involvement of the ear (SNHL) and eye in the homozygotes than the heterozygotes. Fertility problems were also noted in both of the homozygous females.\nCONCLUSION: Identification of the causative mutation is an efficient strategy for conclusive molecular diagnosis in the patients and to establish genotype/phenotype correlation. It is important to study and evaluate asymptomatic carriers, to predict prognosis of the disease and to obviate the need for another renal biopsy in at-risk related family members. While an accurate genetic diagnosis of AS provides valuable information for genetic counseling in the extended family members, it can also facilitate future prenatal diagnosis and planning for pre-implantation genetic diagnosis.","variants":[{"Name":"NM_000092.5(COL4A4):c.2420del (p.Gly807fs)","Chromosome":"2","Start":"227057564","Stop":"227057564","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":189116,"rule_based_match":true,"evidence_text":"c.2420delG; p.G807fsX60","llm_judgment":"PRESENT","evidence":"c.2420delG; p.G807fsX60","abstract_start":1373,"abstract_end":1396}]}
{"pmid":"34200360","title":"","abstract":"<i>RAD51D</i> loss-of-function variants increase lifetime risk of breast and ovarian cancer. Splicing disruption is a frequent pathogenic mechanism associated with variants in susceptibility genes. Herein, we have assessed the splicing and clinical impact of splice-site and exonic splicing enhancer (ESE) variants identified through the study of ~113,000 women of the BRIDGES cohort. A RAD51D minigene with exons 2-9 was constructed in splicing vector pSAD. Eleven BRIDGES splice-site variants (selected by MaxEntScan) were introduced into the minigene by site-directed mutagenesis and tested in MCF-7 cells. The 11 variants disrupted splicing, collectively generating 25 different aberrant transcripts. All variants but one produced negligible levels (<3.4%) of the full-length (FL) transcript. In addition, ESE elements of the alternative exon 3 were mapped by testing four overlapping exonic microdeletions (≥30-bp), revealing an ESE-rich interval (c.202_235del) with critical sequences for exon 3 recognition that might have been affected by germline variants. Next, 26 BRIDGES variants and 16 artificial exon 3 single-nucleotide substitutions were also assayed. Thirty variants impaired splicing with variable amounts (0-65.1%) of the FL transcript, although only c.202G>A demonstrated a complete aberrant splicing pattern without the FL transcript. On the other hand, c.214T>C increased efficiency of exon 3 recognition, so only the FL transcript was detected (100%). In conclusion, 41 <i>RAD51D</i> spliceogenic variants (28 of which were from the BRIDGES cohort) were identified by minigene assays. We show that minigene-based mapping of ESEs is a powerful approach for identifying ESE hotspots and ESE-disrupting variants. Finally, we have classified nine variants as likely pathogenic according to ACMG/AMP-based guidelines, highlighting the complex relationship between splicing alterations and variant interpretation.","variants":[{"Name":"NM_002878.4(RAD51D):c.202G>A (p.Gly68Ser)","Chromosome":"17","Start":"35118562","Stop":"35118562","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":401892,"rule_based_match":true,"evidence_text":"c.202G>A","llm_judgment":"PRESENT","evidence":"c.202G>A","abstract_start":1270,"abstract_end":1278}]}
{"pmid":"33732287","title":"Mutational Spectrum of","abstract":"Familial hypercholesterolemia (FH) is a common, yet underdiagnosed, genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol levels, which can increase the risk of early-onset coronary artery disease (CAD). In the present study, we screened the nucleotide variations of the <i>LDLR and PCSK9</i> genes, as well as a part of the <i>APOB</i> gene, in Iranian patients with FH and premature CAD to find the genetic cause of the disorder. Fifteen unrelated individuals with a clinical diagnosis of FH and premature CAD were recruited. Direct DNA sequencing was applied to screen the whole coding exons and exon-intron boundaries of the <i>LDLR</i> and <i>PCSK9</i> genes and the main parts of their introns, together with exon 26 of the <i>APOB</i> gene. The pathogenicity of the identified mutations was investigated via either segregation analyses in the family or <i>in silico</i> predictive software. Six different point mutations (p.Cys148Tyr, p.Cys216Tyr, p.Cys302Trp, p.Cys338Trp, p.Leu479Gln, and p.G593Afs<sup>∗</sup>72) in <i>LDLR</i> and a double mutation (p.Asp172His and p.Ala53Val) in both <i>LDLR</i> and <i>PCSK9</i> genes were identified in seven families with clinically diagnosed FH (43%), whereas no pathogenic mutations were found in eight families with clinically diagnosed FH. This study is the first to identify 1 pathogenic mutation in the <i>LDLR</i> gene (c.1014C > G [p.Cys338Trp]) and to cosegregate it from the affected individual in the family. No mutations were found in the <i>APOB</i> gene, whereas several silent mutations/polymorphisms were identified in the <i>LDLR</i> and <i>PCSK9</i> genes. Genetic testing and reports on nucleotide alterations in the Iranian population are still limited. Our findings not only further confirm the significant role of FH in the incidence of premature CAD but also enlarge the spectrum of <i>LDLR</i> and <i>PCSK9</i> variations and exhibit the heterogeneity of FH in Iranians. In patients with no mutation in the examined genes, the disease could be begotten either by a polygenic cause or by gene defects occurring in other related genes and regions not targeted in this study.","variants":[{"Name":"NM_000527.5(LDLR):c.647G>A (p.Cys216Tyr)","Chromosome":"19","Start":"11105553","Stop":"11105553","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":245683,"rule_based_match":false,"evidence_text":"p.Cys216Tyr","llm_judgment":"PRESENT","evidence":"p.Cys216Tyr","abstract_start":976,"abstract_end":987},{"Name":"NM_000527.5(LDLR):c.443G>A (p.Cys148Tyr)","Chromosome":"19","Start":"11105349","Stop":"11105349","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":245563,"rule_based_match":false,"evidence_text":"p.Cys148Tyr","llm_judgment":"PRESENT","evidence":"p.Cys148Tyr","abstract_start":963,"abstract_end":974}]}
{"pmid":"28236339","title":"Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.","abstract":"Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here, we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.514G>A, p.Asp172Asn) in the cytoplasmic seryl-tRNA synthetase (SARS) gene. The mutation affects the enzymatic core domain of the protein and impairs its enzymatic activity, probably leading to reduced cytoplasmic tRNA<sup>Ser</sup> concentrations. The mutant protein was predicted to be unstable, which could be substantiated by investigating ectopic mutant SARS in transfected HEK293T cells. In the second family, we found a compound heterozygous genotype of the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, comprising a nonsense mutation (c.325delA, p.Ser109Alafs*15), which very likely entails nonsense-mediated mRNA decay and a missense mutation (c.37T>G, p.Trp13Gly). The latter affects the mitochondrial localization signal of WARS2, causing protein mislocalization. Including AIMP1, which we have recently implicated in the etiology of ID, three genes with a role in tRNA-aminoacylation are now associated with this condition. We therefore suggest that the functional integrity of tRNAs in general is an important factor in the development and maintenance of human cognitive functions.","variants":[{"Name":"NM_006513.4(SARS1):c.514G>A (p.Asp172Asn)","Chromosome":"1","Start":"109230944","Stop":"109230944","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":434549,"rule_based_match":true,"evidence_text":"c.514G>A, p.Asp172Asn","llm_judgment":"PRESENT","evidence":"c.514G>A, p.Asp172Asn","abstract_start":360,"abstract_end":381},{"Name":"NM_015836.4(WARS2):c.325del (p.Ser109fs)","Chromosome":"1","Start":"119076373","Stop":"119076373","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":434542,"rule_based_match":true,"evidence_text":"c.325delA, p.Ser109Alafs*15","llm_judgment":"PRESENT","evidence":"c.325delA, p.Ser109Alafs*15","abstract_start":915,"abstract_end":942},{"Name":"NM_015836.4(WARS2):c.37T>G (p.Trp13Gly)","Chromosome":"1","Start":"119140608","Stop":"119140608","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":434543,"rule_based_match":true,"evidence_text":"c.37T>G (p.Trp13Gly)","llm_judgment":"PRESENT","evidence":"p.Trp13Gly","abstract_start":1034,"abstract_end":1044}]}
{"pmid":"35727972","title":"Mutations in","abstract":"Discovery of deafness genes and elucidating their functions have substantially contributed to our understanding of hearing physiology and its pathologies. Here we report on DNA variants in <i>MINAR2</i>, encoding membrane integral NOTCH2-associated receptor 2, in four families underlying autosomal recessive nonsyndromic deafness. Neurologic evaluation of affected individuals at ages ranging from 4 to 80 y old does not show additional abnormalities. <i>MINAR2</i> is a recently annotated gene with limited functional understanding. We detected three <i>MINAR2</i> variants, c.144G > A (p.Trp48*), c.412_419delCGGTTTTG (p.Arg138Valfs*10), and c.393G > T, in 13 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL). The c.393G > T variant is shown to disrupt a splice donor site. We show that <i>Minar2</i> is expressed in the mouse inner ear, with the protein localizing mainly in the hair cells, spiral ganglia, the spiral limbus, and the stria vascularis. Mice with loss of function of the Minar2 protein (<i>Minar2<sup>tm1b/tm1b</sup></i>) present with rapidly progressive sensorineural HL associated with a reduction in outer hair cell stereocilia in the shortest row and degeneration of hair cells at a later age. We conclude that MINAR2 is essential for hearing in humans and mice and its disruption leads to sensorineural HL. Progressive HL observed in mice and in some affected individuals and as well as relative preservation of hair cells provides an opportunity to interfere with HL using genetic therapies.","variants":[{"Name":"NM_001257308.2(MINAR2):c.144G>A (p.Trp48Ter)","Chromosome":"5","Start":"129748334","Stop":"129748334","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2417435,"rule_based_match":true,"evidence_text":"c.144G > A (p.Trp48*)","llm_judgment":"PRESENT","evidence":"c.144G > A (p.Trp48*)","abstract_start":577,"abstract_end":598},{"Name":"NM_001257308.2(MINAR2):c.412_419del (p.Arg138fs)","Chromosome":"5","Start":"129764900","Stop":"129764907","ReferenceAlleleVCF":"CTGCGGTTT","AlternateAlleleVCF":"C","allel_id":2417436,"rule_based_match":true,"evidence_text":"c.412_419delCGGTTTTG (p.Arg138Valfs*10)","llm_judgment":"PRESENT","evidence":"c.412_419delCGGTTTTG (p.Arg138Valfs*10)","abstract_start":600,"abstract_end":639}]}
{"pmid":"28577551","title":"Clinical diagnostic exome evaluation for an infant with a lethal disorder: genetic diagnosis of TARP syndrome and expansion of the phenotype in a patient with a newly reported RBM10 alteration.","abstract":"BACKGROUND: Diagnostic Exome Sequencing (DES) has been shown to be an effective tool for diagnosis individuals with suspected genetic conditions.\nCASE PRESENTATION: We report a male infant born with multiple anomalies including bilateral dysplastic kidneys, cleft palate, bilateral talipes, and bilateral absence of thumbs and first toes. Prenatal testing including chromosome analysis and microarray did not identify a cause for the multiple congenital anomalies. Postnatal diagnostic exome studies (DES) were utilized to find a molecular diagnosis for the patient. Exome sequencing of the proband, mother, and father showed a previously unreported maternally inherited RNA binding motif protein 10 (RBM10) c.1352_1353delAG (p.E451Vfs*66) alteration. Mutations in RBM10 are associated with TARP syndrome, an X-linked recessive disorder originally described with cardinal features of talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava.\nCONCLUSION: DES established a molecular genetic diagnosis of TARP syndrome for a neonatal patient with a poor prognosis in whom traditional testing methods were uninformative and allowed for efficient diagnosis and future reproductive options for the parents. Other reported cases of TARP syndrome demonstrate significant variability in clinical phenotype. The reported features in this infant including multiple hemivertebrae, imperforate anus, aplasia of thumbs and first toes have not been reported in previous patients, thus expanding the clinical phenotype for this rare disorder.","variants":[{"Name":"NM_005676.5(RBM10):c.1352_1353del (p.Glu451fs)","Chromosome":"X","Start":"47181316","Stop":"47181317","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":420436,"rule_based_match":true,"evidence_text":"c.1352_1353delAG (p.E451Vfs*66)","llm_judgment":"PRESENT","evidence":"c.1352_1353delAG (p.E451Vfs*66)","abstract_start":708,"abstract_end":739}]}
{"pmid":"28350522","title":"The influences of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of simvastatin, in relation to CYP3A4 inhibition.","abstract":"AIM: To investigate the combined effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of simvastatin and its active metabolite simvastatin acid, in relation to CYP3A4 inhibition.\nMETHODS: We conducted a single-dose pharmacokinetic study of simvastatin in 26 healthy volunteers screened for their SLCO1B1 c.521T>C and ABCB1 c.1236C>T-2677G>T-3435C>T genotypes, with and without amlodipine pretreatment. The genetic effects and drug-interaction effect on simvastatin pharmacokinetic parameters were analyzed using a linear-mixed model.\nRESULTS: The SLCO1B1 c.521T>C variant significantly increased exposure to simvastatin acid by around 40% (p < 0.05), similar to that caused by the amlodipine pretreatment. The ABCB1 gene showed no influence on exposure to simvastatin or simvastatin acid.\nCONCLUSION: Only SLCO1B1, not ABCB1 genotype, is likely to be associated with simvastatin-induced myopathy. SLCO1B1 genotyping may be particularly beneficial in simvastatin users who are co-administered CYP3A4 inhibitors.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":true,"evidence_text":"SLCO1B1 c.521T>C","llm_judgment":"PRESENT","evidence":"SLCO1B1 c.521T>C","abstract_start":306,"abstract_end":322}]}
{"pmid":"29619236","title":"Evaluation of the","abstract":"Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. Although the malformation is usually sporadic, a genetic background is supported by an increased recurrence risk in relatives, higher concordance rates in monozygotic twins and several associated chromosomal aberrations. Recently, the <i>ISL1</i> gene was presented as a candidate gene for bladder exstrophy and epispadias complex (BEEC) development in two different studies. In our study, we screened for genetic variants in the <i>ISL1</i> gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis. In addition, we evaluated <i>ISL1</i> expression in RNA of human bladder during embryonic and fetal weeks 5-10 relative to that in lung tissue (week 9). In total, 21 single-nucleotide variants were identified, including a potentially novel missense variant, c.137C>G p.(Ala46Gly), substituting a conserved amino acid. This variant was inherited from an unaffected mother. No structural variants were identified. RNA sequencing revealed <i>ISL1</i> mRNA expression during the critical time frame of human bladder development. In conclusion, we did not detect any known or likely pathogenic variants in the <i>ISL1</i> gene in 125 Swedish BEEC patients, indicating that variation in the <i>ISL1</i> gene is not a common genetic mechanism of BEEC development in the Swedish population.","variants":[{"Name":"NM_002202.3(ISL1):c.137C>G (p.Ala46Gly)","Chromosome":"5","Start":"51384649","Stop":"51384649","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":361293,"rule_based_match":true,"evidence_text":"c.137C>G p.(Ala46Gly)","llm_judgment":"PRESENT","evidence":"c.137C>G p.(Ala46Gly)","abstract_start":895,"abstract_end":916}]}
{"pmid":"24651605","title":"Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.","abstract":"PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.\nMETHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.\nRESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.\nCONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.","variants":[{"Name":"NM_018297.4(NGLY1):c.1201A>T (p.Arg401Ter)","Chromosome":"3","Start":"25733931","Stop":"25733931","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":65632,"rule_based_match":true,"evidence_text":"c.1201A>T (p.R401X)","llm_judgment":"PRESENT","evidence":"c.1201A>T (p.R401X)","abstract_start":958,"abstract_end":977}]}
{"pmid":"22152677","title":"Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type.","abstract":"Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL), leptodactylic (lepto-SEMDJL) or Hall type, is an autosomal-dominant skeletal dysplasia manifesting with short stature, joint laxity with dislocation(s), limb malalignment, and spinal deformity. Its causative gene mutation has not yet been discovered. We captured and sequenced the exomes of eight affected individuals in six unrelated kindreds (three individuals in a family and five simplex individuals). Five novel sequence variants in KIF22, which encodes a member of the kinesin-like protein family, were identified in seven individuals. Sanger sequencing of KIF22 confirmed that c.443C>T (p.Pro148Ser) cosegregated with the phenotype in the affected individuals in the family; c.442C>T (p.Pro148Leu) or c.446G>A (p.Arg149Gln) was present in four of five simplex individuals, but was absent in unaffected individuals in their family and 505 normal cohorts. KIF22 mRNA was detected in human bone, cartilage, joint capsule, ligament, skin, and primary cultured chondrocytes. In silico analysis of KIF22 protein structure indicates that Pro148 and Arg149 are important in maintaining hydrogen bonds in the ATP binding and motor domains of KIF22. We conclude that these mutations in KIF22 cause lepto-SEMDJL.","variants":[{"Name":"NM_007317.3(KIF22):c.446G>A (p.Arg149Gln)","Chromosome":"16","Start":"29798644","Stop":"29798644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39291,"rule_based_match":true,"evidence_text":"c.446G>A (p.Arg149Gln)","llm_judgment":"PRESENT","evidence":"c.446G>A (p.Arg149Gln)","abstract_start":769,"abstract_end":791}]}
{"pmid":"22734612","title":"Molecular genetic studies and delineation of the oculocutaneous albinism phenotype in the Pakistani population.","abstract":"BACKGROUND: Oculocutaneous albinism (OCA) is caused by a group of genetically heterogeneous inherited defects that result in the loss of pigmentation in the eyes, skin and hair. Mutations in the TYR, OCA2, TYRP1 and SLC45A2 genes have been shown to cause isolated OCA. No comprehensive analysis has been conducted to study the spectrum of OCA alleles prevailing in Pakistani albino populations.\nMETHODS: We enrolled 40 large Pakistani families and screened them for OCA genes and a candidate gene, SLC24A5. Protein function effects were evaluated using in silico prediction algorithms and ex vivo studies in human melanocytes. The effects of splice-site mutations were determined using an exon-trapping assay.\nRESULTS: Screening of the TYR gene revealed four known (p.Arg299His, p.Pro406Leu, p.Gly419Arg, p.Arg278*) and three novel mutations (p.Pro21Leu, p.Cys35Arg, p.Tyr411His) in ten families. Ex vivo studies revealed the retention of an EGFP-tagged mutant (p.Pro21Leu, p.Cys35Arg or p.Tyr411His) tyrosinase in the endoplasmic reticulum (ER) at 37°C, but a significant fraction of p.Cys35Arg and p.Tyr411His left the ER in cells grown at a permissive temperature (31°C). Three novel (p.Asp486Tyr, p.Leu527Arg, c.1045-15 T > G) and two known mutations (p.Pro743Leu, p.Ala787Thr) of OCA2 were found in fourteen families. Exon-trapping assays with a construct containing a novel c.1045-15 T > G mutation revealed an error in splicing. No mutation in TYRP1, SLC45A2, and SLC24A5 was found in the remaining 16 families. Clinical evaluation of the families segregating either TYR or OCA2 mutations showed nystagmus, photophobia, and loss of pigmentation in the skin or hair follicles. Most of the affected individuals had grayish-blue colored eyes.\nCONCLUSIONS: Our results show that ten and fourteen families harbored mutations in the TYR and OCA2 genes, respectively. Our findings, along with the results of previous studies, indicate that the p.Cys35Arg, p.Arg278* and p.Gly419Arg alleles of TYR and the p.Asp486Tyr and c.1045-15 T > G alleles of OCA2 are the most common causes of OCA in Pakistani families. To the best of our knowledge, this study represents the first documentation of OCA2 alleles in the Pakistani population. A significant proportion of our cohort did not have mutations in known OCA genes. Overall, our study contributes to the development of genetic testing protocols and genetic counseling for OCA in Pakistani families.","variants":[{"Name":"NM_000372.5(TYR):c.1217C>T (p.Pro406Leu)","Chromosome":"11","Start":"89284805","Stop":"89284805","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18816,"rule_based_match":false,"evidence_text":"p.Pro406Leu","llm_judgment":"PRESENT","evidence":"p.Pro406Leu","abstract_start":779,"abstract_end":790},{"Name":"NM_000372.5(TYR):c.832C>T (p.Arg278Ter)","Chromosome":"11","Start":"89191214","Stop":"89191214","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105472,"rule_based_match":false,"evidence_text":"p.Arg278*","llm_judgment":"PRESENT","evidence":"p.Arg278*","abstract_start":805,"abstract_end":814},{"Name":"NM_000275.3(OCA2):c.1045-15T>G","Chromosome":"15","Start":"27990662","Stop":"27990662","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":609268,"rule_based_match":true,"evidence_text":"c.1045-15 T > G","llm_judgment":"PRESENT","evidence":"c.1045-15 T > G","abstract_start":1214,"abstract_end":1229},{"Name":"NM_000275.3(OCA2):c.1580T>G (p.Leu527Arg)","Chromosome":"15","Start":"27966746","Stop":"27966746","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1048821,"rule_based_match":false,"evidence_text":"p.Leu527Arg","llm_judgment":"PRESENT","evidence":"p.Leu527Arg","abstract_start":1201,"abstract_end":1212},{"Name":"NM_000275.3(OCA2):c.2228C>T (p.Pro743Leu)","Chromosome":"15","Start":"27871170","Stop":"27871170","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15995,"rule_based_match":false,"evidence_text":"p.Pro743Leu","llm_judgment":"PRESENT","evidence":"p.Pro743Leu","abstract_start":1256,"abstract_end":1267}]}
{"pmid":"35176401","title":"Hepatic energy metabolism in a family with a glucokinase gene mutation and dysglycemia.","abstract":"Carriers heterozygous for the D124N (c.370, GAC > AAC in exon 4) variant of GCK not only exhibit reduced insulin-secretion, but also impaired adipose insulin sensitivity, which may shift fatty acids towards the liver. This could contribute to increased hepatic lipid-accumulation and alterations of liver energy metabolism resulting in dysglycemia. ClinicalTrial.gov registration no: NCT01055093.","variants":[{"Name":"NM_000162.5(GCK):c.370G>A (p.Asp124Asn)","Chromosome":"7","Start":"44151069","Stop":"44151069","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":207484,"rule_based_match":false,"evidence_text":"c.370, GAC > AAC in exon 4","llm_judgment":"PRESENT","evidence":"c.370, GAC > AAC in exon 4","abstract_start":37,"abstract_end":63}]}
{"pmid":"23139147","title":"The BMPR2 missense mutation p.K230N and pulmonary arterial hypertension.","abstract":"We present a patient that is the index case of pulmonary arterial hypertension (PAH) in a child due to the bone morphogenetic protein type II (BMPR2) missense mutation p.K230N, also known as c.690A>T. Missense mutations typically have earlier onset and more severe disease in PAH, so pulmonologists should be aware of this in the evaluation of PAH in children.","variants":[{"Name":"NM_001204.7(BMPR2):c.690A>T (p.Lys230Asn)","Chromosome":"2","Start":"202518890","Stop":"202518890","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":414188,"rule_based_match":true,"evidence_text":"c.690A>T","llm_judgment":"PRESENT","evidence":"c.690A>T","abstract_start":191,"abstract_end":199}]}
{"pmid":"26782017","title":"De novo exonic mutation in MYH7 gene leading to exon skipping in a patient with early onset muscular weakness and fiber-type disproportion.","abstract":"Here we report on a case of MYH7-related myopathy in a boy with early onset of muscular weakness and delayed motor development in infancy. His most affected muscles were neck extensors showing a dropped head sign, proximal muscles of lower limbs with positive Gower's sign, and trunk muscles. Brain and spinal cord MRI scans, echocardiography, and laboratory analyses including creatine kinase and lactate did not reveal any abnormalities. Muscle histopathology showed fiber-type disproportion. Whole exome sequencing of the parents-offspring trio revealed a novel de novo c.5655G>A p.(Ala1885=) synonymous substitution of the last nucleotide in exon 38 of the MYH7 gene. Further RNA investigations proved the skipping of exon 38 (p.1854_1885del). This is a first report of an exon-skipping mutation in the MYH7 gene causing myopathy. This report broadens both the phenotypic and genotypic spectra of MYH7-related myopathies.","variants":[{"Name":"NM_000257.4(MYH7):c.5655G>A (p.Ala1885=)","Chromosome":"14","Start":"23414007","Stop":"23414007","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":373755,"rule_based_match":true,"evidence_text":"c.5655G>A p.(Ala1885=)","llm_judgment":"PRESENT","evidence":"c.5655G>A p.(Ala1885=)","abstract_start":573,"abstract_end":595}]}
{"pmid":"33708531","title":"A Chinese newborn with Zellweger syndrome and compound heterozygous mutations novel in the","abstract":"In this study, we report a male newborn with severe Zellweger spectrum disorder (ZSDs) presenting asphyxia, hypotonia, poor feeding, and dysmorphic facial features. Despite intensive supportive treatment, the boy's condition deteriorated progressively. The patient's diagnosis was made by delayed results after his death. His genetic analysis showed that the boy carried novel compound heterozygous mutation in <i>PEX1</i> gene (c.2050C > T and c.782_783del). We conducted a literature search and identified 316 patients with ZSD caused by mutations in the <i>PEX1</i> gene. The p.G843D and p.I700Yfs*42 were the most commonly reported mutations. Among the 316 patients, clinical manifestations were available in 265 patients. The segregation of these patients' manifestation showed that patients with missense <i>PEX1</i> mutations have a milder phenotype than those with truncating mutations, while the common p.G843D mutations are milder than other missense mutations. Nearly all truncating mutations in <i>PEX1</i> except for those with premature stop codons near the end of the gene were associated with a severe disease phenotype. These results indicated that all domains of <i>PEX1</i> were important in the maintenance of normal peroxisome function. The correlation between severity of the disease and type of mutations in <i>PEX1</i> can be helpful in predicting prognosis among patients with ZSD caused by mutated <i>PEX1</i>.","variants":[{"Name":"NM_000466.3(PEX1):c.782_783del (p.Gln261fs)","Chromosome":"7","Start":"92517732","Stop":"92517733","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":186758,"rule_based_match":true,"evidence_text":"c.782_783del","llm_judgment":"PRESENT","evidence":"c.782_783del","abstract_start":445,"abstract_end":457}]}
{"pmid":"29510678","title":"Genetic and clinical characteristics of Chinese children with Glucokinase-maturity-onset diabetes of the young (GCK-MODY).","abstract":"BACKGROUND: There is scarcity of information on the clinical features and genetics of glucokinase-maturity-onset diabetes of the young (GCK-MODY) in China. The aim of the study was to investigate the clinical and molecular characteristics of Chinese children with GCK-MODY.\nMETHODS: Eleven children with asymptomatic hyperglycemia and clinically suspected GCK-MODY were identified from the database of children with diabetes in the biggest children's hospital in South China. Clinical data were obtained from medical records. Blood was collected from the patients and their parents for glucokinase (GCK) gene analysis. Parents without diabetes were tested for fasting glucose and HbA1c. Clinical information and blood for GCK gene analysis were obtained from grandparents with diabetes. GCK gene mutational analysis was performed by polymerase chain reaction and direct sequencing. Patients without a GCK gene mutation were screened by targeted next-generation sequencing (NGS) technology for other MODY genes.\nRESULTS: Nine children tested positive for GCK gene mutations while two were negative. The nine GCK-MODY patients were from unrelated families, aged 1 month to 9 years and 1 month at first detection of hyperglycaemia. Fasting glucose was elevated (6.1-8.5 mmol/L), HbA1c 5.2-6.7% (33.3-49.7 mmol/mol), both remained stable on follow-up over 9 months to 5 years. Five detected mutations had been previously reported: p.Val182Met, c.679 + 1G > A, p.Gly295Ser, p.Arg191Gln and p.Met41Thr. Four mutations were novel: c.483 + 2 T > A, p.Ser151del, p.Met57GlyfsX29 and p.Val374_Ala377del. No mutations were identified in the other two patients, who were also tested by NGS.\nCONCLUSIONS: GCK gene mutations are detected in Chinese children and their family members with typical clinical features of GCK-MODY. Four novel mutations are detected.","variants":[{"Name":"NM_000162.5(GCK):c.883G>A (p.Gly295Ser)","Chromosome":"7","Start":"44146599","Stop":"44146599","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":441097,"rule_based_match":false,"evidence_text":"p.Gly295Ser","llm_judgment":"PRESENT","evidence":"p.Gly295Ser","abstract_start":1456,"abstract_end":1467},{"Name":"NM_000162.5(GCK):c.572G>A (p.Arg191Gln)","Chromosome":"7","Start":"44149976","Stop":"44149976","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":267595,"rule_based_match":false,"evidence_text":"p.Arg191Gln","llm_judgment":"PRESENT","evidence":"p.Arg191Gln","abstract_start":1469,"abstract_end":1480},{"Name":"NM_000162.5(GCK):c.122T>C (p.Met41Thr)","Chromosome":"7","Start":"44153387","Stop":"44153387","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":380273,"rule_based_match":false,"evidence_text":"p.Met41Thr","llm_judgment":"PRESENT","evidence":"p.Met41Thr","abstract_start":1485,"abstract_end":1495},{"Name":"NM_000162.5(GCK):c.544G>A (p.Val182Met)","Chromosome":"7","Start":"44150004","Stop":"44150004","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":134590,"rule_based_match":false,"evidence_text":"p.Val182Met","llm_judgment":"PRESENT","evidence":"p.Val182Met","abstract_start":1427,"abstract_end":1438}]}
{"pmid":"30414531","title":"Identification of a somatic mutation in the RHEB gene through high depth and ultra-high depth next generation sequencing in a patient with Hemimegalencephaly and drug resistant Epilepsy.","abstract":"Malformations of cortical development are a frequent cause of drug-resistant Epilepsy and developmental delay. Hemimegalencephaly is a Malformation of cortical development characterized by enlargement of all or a part of one cerebral hemisphere. Germline and somatic mutation in genes belonging to the Mammalian Target of Rapamycin (mTOR) pathway has been identified in patients suffering from epilepsy secondary to Hemimegalencephaly and focal cortical dysplasia. We present here a patient suffering from severe neonatal Epilepsy since 3 h of life secondary to Hemimegalencephaly, requiring an anatomic hemispherectomy surgical procedure for seizure control, where by means of next-generation sequencing at an ultra-high depth coverage, we were able to identify a novel somatic mutation in the RHEB gene (NM_005614: c.119A > T: p. Glu40Val). The histopathological diagnosis was Cortical Dysplasia type IIB determined by the presence of dysmorphic neurons of variable size with nuclear alteration and balloon cells in the context of Hemimegalencephaly, which are similar to that have been demonstrated in hyperactivating RHEB models. This is the first report of a somatic mutation in RHEB gene in a patient suffering from Epilepsy secondary to Hemimegalencephaly. It highlights different current topics in the fields of genetics of Malformations of cortical development: a-somatic mosaicism is not uncommon in these neurodevelopmental disorders; b-the molecular diagnostic approach should involve the use of state-of-the-art methods and the sampling of different tissues; c-new findings might facilitate therapeutics discoveries while providing an improved understanding of normal brain development.","variants":[{"Name":"NM_005614.4(RHEB):c.119A>T (p.Glu40Val)","Chromosome":"7","Start":"151490948","Stop":"151490948","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":536162,"rule_based_match":true,"evidence_text":"NM_005614: c.119A > T: p. Glu40Val","llm_judgment":"PRESENT","evidence":"NM_005614: c.119A > T: p. Glu40Val","abstract_start":806,"abstract_end":840}]}
{"pmid":"23456831","title":"Description of a novel c.374 G>A mutation in Becker disease.","abstract":"","variants":[{"Name":"NM_000083.3(CLCN1):c.374G>A (p.Gly125Glu)","Chromosome":"7","Start":"143320736","Stop":"143320736","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":945492,"rule_based_match":true,"evidence_text":"c.374 G>A","llm_judgment":"PRESENT","evidence":"c.374 G>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"29992740","title":"A mutation of SCN1B associated with GEFS+ causes functional and maturation defects of the voltage-dependent sodium channel.","abstract":"Voltage-dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These integral membrane proteins are composed of a pore-forming α-subunit, and one or more auxiliary β subunits. Mutation p.Asp25Asn (D25N; c.73G > A) of the β1 subunit, coded by the gene SCN1B, has been reported in a patient with generalized epilepsy with febrile seizure plus type 1 (GEFS+). In human embryonic kidney 293 (HEK) cells, the heterologous coexpression of D25N-β1 subunit with Nav1.2, Nav1.4, and Nav1.5 α subunits, representative of brain, skeletal muscle, and heart voltage gated sodium channels, determines a reduced sodium channel functional expression and a negative shift of the activation and inactivation steady state curves. The D25N mutation of the β1 subunit causes a maturation (glycosylation) defect of the protein, leading to a reduced targeting to the plasma membrane. Also the β1-dependent gating properties of the sodium channels are abolished by the mutation, suggesting that D25N is no more able to interact with the α subunit. Our work underscores the role played by the β1 subunit, highlighting how a defective interaction between the sodium channel constituents could lead to a disabling pathological condition, and opens the possibility to design a mutation-specific GEFS+ treatment based on protein maturation.","variants":[{"Name":"NM_001037.5(SCN1B):c.73G>A (p.Asp25Asn)","Chromosome":"19","Start":"35032560","Stop":"35032560","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188678,"rule_based_match":true,"evidence_text":"c.73G > A","llm_judgment":"PRESENT","evidence":"c.73G > A","abstract_start":254,"abstract_end":263}]}
{"pmid":"30548383","title":"A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings.","abstract":"Biallelic variants in the AEBP1 gene cause a novel autosomal-recessive connective tissue disorder (CTD) reminiscent of Ehlers-Danlos Syndrome (EDS). The four previously reported individuals show considerable clinical variability. Unbiased high-throughput sequencing enables the rapid identification of additional cases for such rare entities. We identified the homozygous nonsense variant c.917dup, p.Tyr306* in AEBP1 using clinical exome sequencing in a female individual with previously unsolved CTD. Segregation testing confirmed homozygosity in the clinically affected brother and heterozygous carrier status in the healthy mother. Chromosomal microarray showed that the variant lies in a run of homozygosity, suggesting a common origin of this genomic segment. RT-PCR analysis in the mother revealed a monoallelic expression of the normal transcript supporting a nonsense-mediated mRNA decay and functional nullizygosity as disease mechanism. We describe two individuals from a fourth family with AEBP1-associated CTD. Our results further verify that autosomal-recessive inherited LOF variants in the AEBP1 gene cause clinical features of different EDS subtypes, but also of the marfanoid spectrum. As identification of further individuals is necessary to inform the clinical characterization, we stress the added value of exome sequencing for such rare diseases.","variants":[{"Name":"NM_001129.5(AEBP1):c.917dup (p.Tyr306Ter)","Chromosome":"7","Start":"44108060","Stop":"44108061","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":536191,"rule_based_match":true,"evidence_text":"c.917dup, p.Tyr306*","llm_judgment":"PRESENT","evidence":"c.917dup, p.Tyr306*","abstract_start":389,"abstract_end":408}]}
{"pmid":"33391157","title":"Identification of","abstract":"<i>SETBP1</i> mutations are associated with the Schinzel-Giedion syndrome (SGS), characterized by profound neurodevelopmental delay, typical facial features, and multiple congenital malformations (OMIM 269150). Refractory epilepsy is a common feature of SGS. Loss of function mutations have been typically associated with a distinct and milder phenotype characterized by intellectual disability and expressive speech impairment. Here we report three variants of <i>SETBP1</i>, two novel <i>de novo</i> truncating mutations, identified by NGS analysis of an Intellectual Disability gene panel in 600 subjects with non-specific neurodevelopmental disorders, and one missense identified by a developmental epilepsy gene panel tested in 56 pediatric epileptic cases. The three individuals carrying the identified <i>SETBP1</i> variants presented mild to severe developmental delay and lacked the cardinal features of classical SGS. One of these subjects, carrying the c.1765C>T (p.Arg589<sup>*</sup>) mutation, had mild Intellectual Disability with speech delay; the second one carrying the c.2199_2203del (p.Glu734Alafs19<sup>*</sup>) mutation had generalized epilepsy, responsive to treatment, and moderate Intellectual Disability; the third patient showed a severe cognitive defects and had a history of drug resistant epilepsy with West syndrome evolved into a Lennox-Gastaut syndrome. This latter subject carries the missense c.2572G>A (p.Glu858Lys) variant, which is absent from the control population, reported as <i>de novo</i> in a subject with ASD, and located close to the <i>SETBP1</i> hot spot for SGS-associated mutations. Our findings contribute to further characterizing the associated phenotypes and suggest inclusion of <i>SETBP1</i> in the list of prioritized genes for the genetic diagnosis of overlapping phenotypes ranging from non-specific neurodevelopmental disorders to \"developmental and epileptic encephalopathy\" (DEE).","variants":[{"Name":"NM_015559.3(SETBP1):c.2572G>A (p.Glu858Lys)","Chromosome":"18","Start":"44951912","Stop":"44951912","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":512354,"rule_based_match":true,"evidence_text":"c.2572G>A (p.Glu858Lys)","llm_judgment":"PRESENT","evidence":"c.2572G>A (p.Glu858Lys)","abstract_start":1427,"abstract_end":1450},{"Name":"NM_015559.3(SETBP1):c.1765C>T (p.Arg589Ter)","Chromosome":"18","Start":"44951105","Stop":"44951105","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":611891,"rule_based_match":true,"evidence_text":"c.1765C>T (p.Arg589<sup>*</sup>)","llm_judgment":"PRESENT","evidence":"c.1765C>T (p.Arg589<sup>*</sup>)","abstract_start":964,"abstract_end":996}]}
{"pmid":"30046692","title":"Defects of splicing in antithrombin deficiency.","abstract":"BACKGROUND: There is increasing evidence supporting the relevance of aberrant splicing in multiple disorders. In antithrombin deficiency only 22 intronic mutations affecting splicing sites (7% of <i>SERPINC1</i> mutations) are considered as splicing mutations.\nMETHODS: <i>SERPINC1</i> was analyzed by Sanger sequencing and MLPA in 141 unrelated cases with antithrombin deficiency. Plasma antithrombin was studied by functional and western blot assays, purified by FPLC and characterized by proteomic analysis. <i>In silico</i> predictions on splicing was done with the Human Splicing Finder software.\nRESULTS: We detected 89 different <i>SERPINC1</i> defects, 13 with potential effect on splicing. Ten cases presented 9 mutations disturbing splicing sites, 5 new. Three gross or small gene defects also disturbed a correct splicing. Interestingly, the first duplication of a single exon ever described (c.1154-13_1218+115dup), caused mild deficiency (75%). A deeper intronic mutation (c.1154-14G>A), identified in three unrelated patients with traces of disulphide dimers of antithrombin in plasma, created a cryptic splicing site that might generate a variant with 4 additional in frame residues according to <i>in silico</i> predictions. This aberrant splicing was confirmed by proteomic analysis of the dimer purified from plasma.\nCONCLUSIONS: A high proportion of cases with antithrombin deficiency (up to 13%) may be explained by an aberrant splicing. Up to 15% of mutations in <i>SERPINC1</i>: splicing site variations, gross gene defects and deep intronic mutations, may affect a correct splicing with three potential consequences type I, type II, and even moderate antithrombin deficiency.","variants":[{"Name":"NM_000488.4(SERPINC1):c.1154-14G>A","Chromosome":"1","Start":"173907528","Stop":"173907528","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":390945,"rule_based_match":true,"evidence_text":"c.1154-14G>A","llm_judgment":"PRESENT","evidence":"c.1154-14G>A","abstract_start":986,"abstract_end":998}]}
{"pmid":"18958496","title":"Noonan syndrome caused by germline KRAS mutation in Taiwan: report of two patients and a review of the literature.","abstract":"Noonan syndrome is a highly variable disorder that has significant phenotypic overlap with Costello syndrome and cardio-facio-cutaneous syndrome. KRAS mutation was the second reported gene for Noonan syndrome. This study screened for mutation of the KRAS gene in 57 unrelated ethnic Chinese children suffering from Noonan syndrome without PTPN11 gene mutation in Taiwan. This work only identified two patients with different missense mutations (c.40G>A, p.Val14Ile; c.108A>G, p.Ile36Met) in the exon 1 of KRAS gene. This study also analyzed the characteristics of 34 reported cases involving KRAS mutations in the literature. All these patients presented with variable phenotypes, including Noonan syndrome (n = 19), cardio-facio-cutaneous syndrome (n = 7), Costello syndrome (n = 6), and Noonan/cardio-facio-cutaneous syndrome (n = 1). The phenotype of KRAS mutations was generally severe, including short stature, mental retardation, heart defects, etc. In conclusion, this investigation demonstrates that KRAS mutations are the cause in a minority of cases of Chinese patients with Noonan syndrome in Taiwan.","variants":[{"Name":"NM_004985.5(KRAS):c.108A>G (p.Ile36Met)","Chromosome":"12","Start":"25245277","Stop":"25245277","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":175716,"rule_based_match":true,"evidence_text":"c.108A>G, p.Ile36Met","llm_judgment":"PRESENT","evidence":"c.108A>G, p.Ile36Met","abstract_start":466,"abstract_end":486},{"Name":"NM_004985.5(KRAS):c.40G>A (p.Val14Ile)","Chromosome":"12","Start":"25245345","Stop":"25245345","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27628,"rule_based_match":true,"evidence_text":"c.40G>A, p.Val14Ile","llm_judgment":"PRESENT","evidence":"c.40G>A, p.Val14Ile","abstract_start":445,"abstract_end":464}]}
{"pmid":"27379765","title":"Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1.","abstract":"PURPOSE: Loss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID).\nMETHODS: Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-γ/IL-17(+) T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer.\nRESULTS: Patient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2 months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4 months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154C > T; p.T385M; P2. c.971G > T; p.C324F). Circulating CD4(+) T cells of both patients exhibited increased interferon-γ and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-β and -γ-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib.\nCONCLUSION: STAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.","variants":[{"Name":"NM_007315.4(STAT1):c.1154C>T (p.Thr385Met)","Chromosome":"2","Start":"190986921","Stop":"190986921","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":153737,"rule_based_match":true,"evidence_text":"c.1154C > T; p.T385M","llm_judgment":"PRESENT","evidence":"c.1154C > T; p.T385M","abstract_start":1235,"abstract_end":1255}]}
{"pmid":"38286424","title":"A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism.","abstract":"Biallelic variants in <i>PTRHD1</i> have been associated with autosomal recessive intellectual disability, spasticity, and juvenile parkinsonism, with few reported cases. Here, we present the clinical and genetic findings of a female of Austrian origin exhibiting infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, consistent with the established phenotypic spectrum. Notably, she developed genetic generalized epilepsy at age 4, persisting into adulthood. Using diagnostic exome sequencing, we identified a homozygous missense variant (c.365G > A, p.(Arg122Gln)) in <i>PTRHD1</i> (NM_001013663). In summary, our findings not only support the existing link between biallelic <i>PTRHD1</i> variants and parkinsonism with neurodevelopmental abnormalities but also suggest a potential extension of the phenotypic spectrum to include generalized epilepsy.","variants":[{"Name":"NM_001013663.2(PTRHD1):c.365G>A (p.Arg122Gln)","Chromosome":"2","Start":"24790469","Stop":"24790469","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222194,"rule_based_match":true,"evidence_text":"c.365G > A, p.(Arg122Gln)","llm_judgment":"PRESENT","evidence":"c.365G > A, p.(Arg122Gln)","abstract_start":598,"abstract_end":623}]}
{"pmid":"36349186","title":"Congenital myopathy associated with a novel mutation in","abstract":"Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozygous or compound heterozygous mutation in the <i>MEGF10</i> gene (OMIM #614399). Phenotypic spectrum of EMARDD is variable, ranging from severe infantile forms in which patients are ventilator-dependent and die in childhood, to milder chronic disorders with a more favorable course (mild variant, mvEMARDD). Here we describe a 22 years old boy, offspring of consanguineous parents, presenting a congenital myopathic phenotype since infancy with elbow contractures and scoliosis. The patient developed a slowly progressive muscle weakness with impaired walking, rhinolalia, dysphagia, and respiratory involvement, which required noninvasive ventilation therapy since the age of 16 years. First muscle biopsy revealed unspecific muscle damage, with fiber size variation, internal nuclei and fibrosis. Myofibrillar alterations were noted at a second muscle biopsy including whorled fibres, cytoplasmic inclusion and minicores. Exome sequencing identified a homozygous mutation in <i>MEGF10</i> gene, c.2096G > C (p.Cys699Ser), inherited by both parents. This variant, not reported in public databases of mutations, is expected to alter the structure of the protein and is therefore predicted to be probably damaging according to ACMG classification. In conclusion, we found a new likely pathogenic mutation in <i>MEGF10</i>, which is responsible for a progressive form of mvEMARDD with myofibrillar alterations at muscle biopsy. Interestingly, the presence of <i>MEGF10</i> mutations has not been reported in Italian population. Early diagnosis of MEGF10 myopathy is essential in light of recent results from in vivo testing demonstrating a potential therapeutic effect of SSRIs compounds.","variants":[{"Name":"NM_001256545.2(MEGF10):c.2096G>C (p.Cys699Ser)","Chromosome":"5","Start":"127435481","Stop":"127435481","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2417669,"rule_based_match":true,"evidence_text":"c.2096G > C (p.Cys699Ser)","llm_judgment":"PRESENT","evidence":"c.2096G > C (p.Cys699Ser)","abstract_start":1094,"abstract_end":1119}]}
{"pmid":"30927251","title":"Recurrent moderate-risk mutations in Finnish breast and ovarian cancer patients.","abstract":"Mutations in BRCA1 and BRCA2 genes predispose to breast and ovarian cancer (BC/OC) with a high lifetime risk, whereas mutations in PALB2, CHEK2, ATM, FANCM, RAD51C and RAD51D genes cause a moderately elevated risk. In the Finnish population, recurrent mutations have been identified in all of these genes, the latest being CHEK2 c.319+2T>A and c.444+1G>A. By genotyping 3,156 cases and 2,089 controls, we estimated the frequencies of CHEK2 c.319+2T>A and c.444+1G>A in Finnish BC patients. CHEK2 c.319+2T>A was detected in 0.7% of the patients, and it was associated with a high risk of BC in the unselected patient group (OR = 5.40 [95% CI 1.58-18.45], p = 0.007) and similarly in the familial patient group. CHEK2 c.444+1G>A was identified in 0.1% of all patients. Additionally, we evaluated the combined prevalence of recurrent moderate-risk gene mutations in 2,487 BC patients, 556 OC patients and 261 BRCA1/2 carriers from 109 families. The overall frequency of the mutations was 13.3% in 1,141 BRCA1/2-negative familial BC patients, 7.5% in 1,727 unselected BC patients and 7.2% in 556 unselected OC patients. At least one moderate-risk gene mutation was found in 12.5% of BRCA1 families and 7.1% of BRCA1 index patients, as well as in 17.0% of BRCA2 families and 11.3% of BRCA2 index patients, and the mutations were associated with an additional risk in the BRCA1/2 index patients (OR = 2.63 [1.15-5.48], p = 0.011). These results support gene panel testing of even multiple members of BC families where several mutations may segregate in different individuals.","variants":[{"Name":"NM_007194.4(CHEK2):c.319+2T>A","Chromosome":"22","Start":"28734401","Stop":"28734401","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":152066,"rule_based_match":true,"evidence_text":"CHEK2 c.319+2T>A","llm_judgment":"PRESENT","evidence":"CHEK2 c.319+2T>A","abstract_start":323,"abstract_end":339},{"Name":"NM_007194.4(CHEK2):c.444+1G>A","Chromosome":"22","Start":"28725242","Stop":"28725242","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":133532,"rule_based_match":true,"evidence_text":"CHEK2 c.444+1G>A","llm_judgment":"PRESENT","evidence":"CHEK2 c.444+1G>A","abstract_start":710,"abstract_end":726}]}
{"pmid":"19238151","title":"Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism.","abstract":"Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.","variants":[{"Name":"NM_080632.3(UPF3B):c.1103G>A (p.Arg368Gln)","Chromosome":"X","Start":"119837956","Stop":"119837956","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1873932,"rule_based_match":true,"evidence_text":"c.1103G>A/p.Arg368Gln","llm_judgment":"PRESENT","evidence":"c.1103G>A/p.Arg368Gln","abstract_start":621,"abstract_end":642}]}
{"pmid":"24891338","title":"SLC39A5 mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia.","abstract":"BACKGROUND: High myopia, with the characteristic feature of refractive error, is one of the leading causes of blindness worldwide. It has a high heritability, but only a few causative genes have been identified and the pathogenesis is still unclear.\nMETHODS: We used whole genome linkage and exome sequencing to identify the causative mutation in a non-syndromic high myopia family. Direct Sanger sequencing was used to screen the candidate gene in additional sporadic cases or probands. Immunofluorescence was used to evaluate the expression pattern of the candidate gene in the whole process of eye development. Real-time quantitative PCR and immunoblot was used to investigate the functional consequence of the disease-associated mutations.\nRESULTS: We identified a nonsense mutation (c.141C>G:p.Y47*) in SLC39A5 co-segregating with the phenotype in a non-syndromic severe high myopia family. The same nonsense mutation (c.141C>G:p.Y47*) was detected in a sporadic case and a missense mutation (c.911T>C:p.M304T) was identified and co-segregated in another family by screening additional cases. Both disease-associated mutations were not found in 1276 control individuals. SLC39A5 was abundantly expressed in the sclera and retina across different stages of eye development. Furthermore, we found that wild-type, but not disease-associated SLC39A5 inhibited the expression of Smadl, a key phosphate protein in the downstream of the BMP/TGF-β (bone morphogenic protein/transforming growth factor-β) pathway.\nCONCLUSIONS: Our study reveals that loss-of-function mutations of SLC39A5 are associated with the autosome dominant non-syndromic high myopia, and interference with the BMP/TGF-β pathway may be one of the molecular mechanisms for high myopia.","variants":[{"Name":"NM_173596.3(SLC39A5):c.141C>G (p.Tyr47Ter)","Chromosome":"12","Start":"56231415","Stop":"56231415","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":153721,"rule_based_match":true,"evidence_text":"c.141C>G:p.Y47*","llm_judgment":"PRESENT","evidence":"c.141C>G:p.Y47*","abstract_start":788,"abstract_end":803},{"Name":"NM_173596.3(SLC39A5):c.911T>C (p.Met304Thr)","Chromosome":"12","Start":"56235666","Stop":"56235666","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":153722,"rule_based_match":true,"evidence_text":"c.911T>C:p.M304T","llm_judgment":"PRESENT","evidence":"c.911T>C:p.M304T","abstract_start":998,"abstract_end":1014}]}
{"pmid":"15365997","title":"Four novel mutations in patients from the Middle East with the infantile form of GM1-gangliosidosis.","abstract":"GM1-gangliosidosis is a lysosomal storage disorder caused by a deficiency of beta-galactosidase. It is mainly characterized by progressive neurodegeneration and in its most severe infantile form it leads to death before the age of four. We have performed molecular analysis of five patients with the infantile form of GM1-gangliosidosis originating from the Middle East (two from Saudi Arabia and three from the United Arab Emirates). We have identified four novel mutations and one previously reported mutation in the GLB1 gene. The first novel mutation found in the homoallelic state in a patient from Saudi Arabia, is a c.171C>G transversion in exon 2 which creates a premature stop codon. Northern blot analysis in fibroblasts from the patient showed no mRNA and expression studies in COS-1 cells showed complete absence of the 85kDa precursor protein and no catalytic activity. The second novel mutation is a splicing error in intron 2, c.245+1G>A. This mutation was found in the heteroallelic state in a patient from Saudi Arabia, the second mutation being the previously described c.145C>T mutation. The third novel mutation is a missense mutation in exon 4, c.451G>T, found in the homoallelic state in a patient from the United Arab Emirates. Expression studies of this mutation in COS-1 cells showed complete absence of the 85kDa precursor protein and no catalytic activity. The fourth novel mutation is a splicing mutation in intron 8, c.914+4A>G, found in the homoallelic state in two siblings from the United Arab Emirates. This study has revealed genetic heterogeneity of the beta-galactosidase deficiency in the Arabic population [corrected]","variants":[{"Name":"NM_000404.4(GLB1):c.171C>G (p.Tyr57Ter)","Chromosome":"3","Start":"33072618","Stop":"33072618","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":98807,"rule_based_match":true,"evidence_text":"c.171C>G","llm_judgment":"PRESENT","evidence":"c.171C>G","abstract_start":623,"abstract_end":631},{"Name":"NM_000404.4(GLB1):c.145C>T (p.Arg49Cys)","Chromosome":"3","Start":"33072644","Stop":"33072644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15962,"rule_based_match":true,"evidence_text":"c.145C>T","llm_judgment":"PRESENT","evidence":"c.145C>T","abstract_start":1088,"abstract_end":1096},{"Name":"NM_000404.4(GLB1):c.245+1G>A","Chromosome":"3","Start":"33072543","Stop":"33072543","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":404764,"rule_based_match":true,"evidence_text":"c.245+1G>A","llm_judgment":"PRESENT","evidence":"c.245+1G>A","abstract_start":942,"abstract_end":952}]}
{"pmid":"34964757","title":"A novel compound heterozygous COL4A4 mutation in a Chinese family with Alport syndrome: A care case report.","abstract":"RATIONALE: Alport syndrome (AS) is an inherited progressive renal failure, characterized by kidney disease, hearing loss, and eye abnormalities.\nPATIENT CONCERNS: A 7-year-old male child was admitted for persistent microscopic hematuria and proteinuria.\nDIAGNOSES: Combined with clinical manifestations, laboratory testing, pathological changes of kidney and sequencing results, the patient was diagnosed as AS.\nINTERVENTIONS: The patient was treated with ACEI and tacrolimus drugs for 2 years, but continued to have hematuria and proteinuria. Thus, a genetic analysis was performed using next-generation sequencing in four affected members from the family.\nOUTCOMES: The findings revealed triple compound heterozygous mutation of COL4A4: three novel variations, c.1045C>T (p. R349X), c.3505+1G>A (splicing), and c.2165G>A (p. G722D).\nLESSONS: This study was novel in finding that a triple variant of the COL4A4 gene simultaneously in trans and in cis. The effects of multiple mutation sites and the type of gene mutation in AS were also underlined.","variants":[{"Name":"NM_000092.5(COL4A4):c.1045C>T (p.Arg349Ter)","Chromosome":"2","Start":"227099674","Stop":"227099674","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":440667,"rule_based_match":true,"evidence_text":"c.1045C>T (p. R349X)","llm_judgment":"PRESENT","evidence":"c.1045C>T (p. R349X)","abstract_start":763,"abstract_end":783}]}
{"pmid":"32597037","title":"Interpretation challenges of novel dual-class missense and splice-impacting variant in POLR3A-related late-onset hereditary spastic ataxia.","abstract":"BACKGROUND: RNA polymerase III (Pol III)-related disorders are autosomal recessive neurodegenerative disorders caused by variants in POLR3A or POLR3B. Recently, a novel phenotype of adult-onset spastic ataxia was identified in individuals with the c.1909+22G>A POLR3A variant in compound heterozygosity.\nMETHODS: Whole-exome sequencing was performed in the proband and parents. Variants were confirmed by Sanger sequencing. RNA sequencing was performed to evaluate splicing implications.\nRESULTS: A 42-year-old female was evaluated for unexplained neurological findings with a slow progressive decline in gait and walking speed since adolescence. WES revealed a novel missense variant (c.3593A>C, p.Lys1198Arg) in exon 27 of POLR3A in compound heterozygosity with the c.1909+22G>A variant. Summary of previously reported clinical features from individuals with pathogenic biallelic alterations in POLR3A and adult-onset phenotype is consistent with our findings. RNA analysis revealed c.3593A>G drives the production of four RNA transcript products each with different functional impacts.\nCONCLUSION: The novel dual-class c.3593A>C variant in POLR3A causes an amino acid substitution and complex disruption of splicing. Our report supports the need to investigate variants near splice junctions for proper interpretation. Current interpretation guidelines need to address best practices for inclusion of predicted or measured transcriptional disruption pending functional activity or reliable transcript abundance estimates.","variants":[{"Name":"NM_007055.4(POLR3A):c.1909+22G>A","Chromosome":"10","Start":"78009515","Stop":"78009515","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439194,"rule_based_match":true,"evidence_text":"c.1909+22G>A","llm_judgment":"PRESENT","evidence":"c.1909+22G>A","abstract_start":248,"abstract_end":260}]}
{"pmid":"26497932","title":"Cervical artery dissections and type A aortic dissection in a family with a novel missense COL3A1 mutation of vascular type Ehlers-Danlos syndrome.","abstract":"Cervical artery dissection (CeAD) is a rare condition. One of the causes is the vascular type of Ehlers-Danlos syndrome (vEDS). A novel missense mutation in COL3A1 was found in a young patient with CeAD as the single manifestation of vEDS. This is a heterozygous c.953G > A mutation in exon 14, disrupting the normal Gly-X-Y repeats of type III procollagen, by converting glycine to aspartic acid.","variants":[{"Name":"NM_000090.4(COL3A1):c.953G>A (p.Gly318Asp)","Chromosome":"2","Start":"188992185","Stop":"188992185","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":517425,"rule_based_match":true,"evidence_text":"c.953G > A","llm_judgment":"PRESENT","evidence":"c.953G > A","abstract_start":263,"abstract_end":273}]}
{"pmid":"17876604","title":"Pendred syndrome among patients with congenital hypothyroidism detected by neonatal screening: identification of two novel PDS/SLC26A4 mutations.","abstract":"Pendred syndrome is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by mutations in the PDS/SLC26A4 gene (OMIM 605646) encoding for pendrin. Hypothyroidism in Pendred syndrome can be--although rarely--present from birth and therefore diagnosed by neonatal screening. The aim of our study was to identify patients with Pendred syndrome among a historical cohort of patients with congenital hypothyroidism (CH) identified by neonatal screening, and to find their mutations in the PDS/SLC26A4 gene. We investigated 197 Czech Caucasian children with CH detected by the neonatal screening between the years 1985 and 2005. The clinical diagnosis of Pendred syndrome was based on the laboratory and sonographic signs of thyroid dyshormonogenesis in association with sensorineural hearing loss. In subjects clinically diagnosed with Pendred syndrome, we sequenced all exons and exon-intron boundaries of the PDS/SLC26A4 gene. Hearing loss was present in 10/197 children with screening-detected CH. Of these, three fulfilled the diagnostic criteria of Pendred syndrome. Two patients were compound heterozygotes for PDS/SLC26A4 mutations: patient 1 carried c.2089+1G>A / c.3G>C and patient 2 carried p.Tyr530His / p.Val422Asp. Two of the four identified mutations were novel (c.3G>C in patient 1 and p.Val422Asp in patient 2). The third patient was free of mutations in the PDS/SLC26A4 gene, representing a phenocopy. In conclusion, our results indicate the rarity of Pendred syndrome as a cause of CH. The identification of two novel mutations expands the spectrum of mutations in the PDS/SLC26A4 gene and emphasizes their marked allelic heterogeneity.","variants":[{"Name":"NM_000441.2(SLC26A4):c.3G>C (p.Met1Ile)","Chromosome":"7","Start":"107661644","Stop":"107661644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":186722,"rule_based_match":true,"evidence_text":"c.3G>C","llm_judgment":"PRESENT","evidence":"c.3G>C","abstract_start":1233,"abstract_end":1239},{"Name":"NM_000441.2(SLC26A4):c.2089+1G>A","Chromosome":"7","Start":"107704386","Stop":"107704386","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":174032,"rule_based_match":true,"evidence_text":"c.2089+1G>A","llm_judgment":"PRESENT","evidence":"c.2089+1G>A","abstract_start":1219,"abstract_end":1230}]}
{"pmid":"32101375","title":"Unveiling a sudden unexplained death case by whole exome sequencing and bioinformatic analysis.","abstract":"BACKGROUND: Sudden unexplained death (SUD) refers to cases of sudden death where autopsy fails to identify any cardiac or extracardiac underlying cause. Guideline-directed standard genetic testing identifies a disease-causing mutation in less than one-third of cases of SUD. Conversely, whole exome sequencing (WES) may provide the key to solve most cases of SUD even after several years from the subject's death.\nMETHODS: We report on a case of sudden unexpected death of a 37-year-old male, with inconclusive autopsy conducted 14 years ago. A recent reevaluation through WES was performed on DNA extracted from left ventricular samples. A multiple step process including several \"in silico\" tools was applied to identify potentially pathogenic variants. Data analysis was based on a 562 gene panel, including 234 candidate genes associated with sudden cardiac death or heart diseases, with the addition of 328 genes highly expressed in the heart. WebGestalt algorithms were used for association enrichment analysis of all genes with detected putative pathogenic variants.\nRESULTS: WES analysis identified four potentially pathogenic variants: RYR2:c.12168G>T, TTN:c.11821C>T (rs397517804), MYBPC3:c.1255C>T (rs368770848), and ACADVL:c.848T>C (rs113994167). WebGestalt algorithms indicated that their combination holds an unfavorable arrhythmic susceptibility which conceivably caused the occurrence of the events leading to our subject's sudden death.\nCONCLUSION: Associating WES technique with online prediction algorithms may allow the recognition of genetic mutations potentially responsible for otherwise unexplained deaths.","variants":[{"Name":"NM_000256.3(MYBPC3):c.1255C>T (p.Arg419Cys)","Chromosome":"11","Start":"47343117","Stop":"47343117","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":51686,"rule_based_match":true,"evidence_text":"MYBPC3:c.1255C>T (rs368770848)","llm_judgment":"PRESENT","evidence":"MYBPC3:c.1255C>T (rs368770848)","abstract_start":1192,"abstract_end":1222},{"Name":"NM_001035.3(RYR2):c.12168G>T (p.Lys4056Asn)","Chromosome":"1","Start":"237783880","Stop":"237783880","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":907091,"rule_based_match":true,"evidence_text":"RYR2:c.12168G>T","llm_judgment":"PRESENT","evidence":"RYR2:c.12168G>T","abstract_start":1145,"abstract_end":1160}]}
{"pmid":"22584530","title":"A newly identified missense mutation of the HR gene is associated with a novel, unusual phenotype of Marie Unna Hereditary Hypotrichosis 1 including limb deformities.","abstract":"Marie Unna Hereditary Hypotrichosis 1 (MUHH1; OMIM 146550), a rare monogenic condition characterized by the development of sparse, twisted hair or complete hair loss, is the consequence of mutations located in the hairless (HR) gene. We have identified a 68-year-old Hungarian woman affected by alopecia universalis and limb deformities of all four extremities. Direct sequencing of the coding regions of the HR gene revealed a novel missense mutation in the third exon of the HR gene (c.974G/A, p.Gly325Asp). The affected family member carried the mutation in a heterozygous form, while the only available, clinically unaffected family member (the son of the patient) and the unrelated controls carried the wild type sequence. The association between the presence of HR gene mutations and the development of alopecia is well-established, however, further studies are needed to elucidate the putative role of this novel HR mutation in the development of limb deformities.","variants":[{"Name":"NM_005144.5(HR):c.974G>A (p.Gly325Asp)","Chromosome":"8","Start":"22127468","Stop":"22127468","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":899316,"rule_based_match":false,"evidence_text":"c.974G/A, p.Gly325Asp","llm_judgment":"PRESENT","evidence":"c.974G/A, p.Gly325Asp","abstract_start":486,"abstract_end":507}]}
{"pmid":"26530398","title":"Bilateral cataracts in a 6-yr-old with new onset diabetes: a novel presentation of a known INS gene mutation.","abstract":"The prevalence of diabetes-related cataracts during childhood is less than 1%. When cataracts occur, it is often in adolescent females with prolonged symptoms and significant hyperglycemia. Cataracts are not a classic feature of monogenic diabetes. We report a case of a 6-yr-old, previously healthy Caucasian male, who presented with bilateral acquired cataracts and was subsequently diagnosed with new onset diabetes. Additional symptoms at presentation included a several year history of polyuria and polydipsia, mild hepatomegaly, and short stature. Pertinent negatives include acanthosis nigricans, lipoatrophy, deafness, muscle weakness, or neuropathy. HbA1c was significantly elevated at diagnosis (>14%, 129.5 mmol/mol) without evidence of ketosis. Autoantibody testing was negative. Features of Mauriac syndrome (short stature, hepatomegaly) as well as acquired cataracts indicated long-standing hyperglycemia with sufficient insulin production to prevent ketone production and development of diabetic ketoacidosis. Whole exome sequencing was conducted and a de novo heterozygous mutation in the INS gene (c.94G>A; p.Gly32Ser) was identified. INS gene mutations are common causes of permanent neonatal diabetes but rare causes of antibody-negative diabetes in children. Importantly, INS gene mutations have not been previously associated with acquired cataracts. Knowledge of a monogenic cause of diabetes allows clinicians to tailor counseling and screening of diabetes-related comorbidities. In summary, this case highlights the need to consider testing for monogenic diabetes, specifically INS gene mutations, in pediatric patients with antibody-negative diabetes, especially if complications of prolonged hyperglycemia are present at diagnosis.","variants":[{"Name":"NM_000207.3(INS):c.94G>A (p.Gly32Ser)","Chromosome":"11","Start":"2160878","Stop":"2160878","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33974,"rule_based_match":true,"evidence_text":"c.94G>A; p.Gly32Ser","llm_judgment":"PRESENT","evidence":"c.94G>A; p.Gly32Ser","abstract_start":1115,"abstract_end":1134}]}
{"pmid":"33869605","title":"Adult onset type 2 familial hemophagocytic lymphohistiocytosis with","abstract":"BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a primary immunodefici-ency disease caused by gene defects. The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease. To the best of our knowledge, this is the first report to detail the clinical features of type 2 FHL (FHL2) with compound heterozygous perforin (<i>PRF1</i>) defects involving the c.163C>T mutation, in addition to correlation analysis and a literature review.\nCASE SUMMARY: We report a case of a 27-year-old male patient with FHL2, who was admitted with a persistent fever and pancytopenia. Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis (HLH)-related genes, we found compound heterozygous mutations of <i>PRF1</i>: c.65delC (p.Pro22Argfs*29) (frameshift mutation, paternal) and c.163C>T (p.Arg55Cys) (missense mutation, maternal). Although he did not receive hematopoietic stem cell transplantation, the patient achieved complete remission after receiving HLH-2004 treatment protocol. To date, the patient has stopped taking drugs for 15 mo, is in a stable condition, and is under follow-up observation.\nCONCLUSION: The delayed onset of FHL2 may be related to the <i>PRF1</i> mutation type, pathogenic variation pattern, triggering factors, and the temperature sensitivity of some <i>PRF1</i> mutations. For individual, the detailed reason for the delay in the onset of FHL warrants further investigation.","variants":[{"Name":"NM_001083116.3(PRF1):c.163C>T (p.Arg55Cys)","Chromosome":"10","Start":"70600740","Stop":"70600740","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":639120,"rule_based_match":true,"evidence_text":"c.163C>T (p.Arg55Cys)","llm_judgment":"PRESENT","evidence":"c.163C>T (p.Arg55Cys)","abstract_start":847,"abstract_end":868}]}
{"pmid":"32255174","title":"Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2.","abstract":"BACKGROUND: Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction.\nOBJECTIVE: To report for the first time the molecular aetiology of JHS.\nPATIENT AND METHODS: Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, mutant protein model construction, and in situ hybridization of Esco2 expression in mouse embryos were performed.\nRESULTS: Clinical findings of the patient consisted of repaired cleft lip/palate, microcephaly, ptosis, short stature, delayed bone age, hypoplastic fingers and thumbs, clinodactyly of the fifth fingers, and humeroradial synostosis leading to elbow restriction. Intelligence is normal. Whole exome sequencing of the whole family showed a novel homozygous base substitution c.1654C>T in ESCO2 of the proband. The sister was homozygous for the wildtype variant. Parents were heterozygous for the mutation. The mutation is predicted to cause premature stop codon p.Arg552Ter. Mutations in ESCO2, a gene involved in cohesin complex formation, are known to cause Roberts/SC phocomelia syndrome. Roberts/SC phocomelia syndrome and JHS share similar clinical findings, including autosomal recessive inheritance, short stature, cleft lip/palate, severe upper limb anomalies, and hypoplastic digits. Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect.\nCONCLUSIONS: Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities. This is the first report demonstrating that mutation in ESCO2 causes JHS, a cohesinopathy.","variants":[{"Name":"NM_001017420.3(ESCO2):c.1654C>T (p.Arg552Ter)","Chromosome":"8","Start":"27799697","Stop":"27799697","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1015450,"rule_based_match":true,"evidence_text":"c.1654C>T","llm_judgment":"PRESENT","evidence":"c.1654C>T","abstract_start":968,"abstract_end":977}]}
{"pmid":"31057598","title":"Noonan Syndrome in South Africa: Clinical and Molecular Profiles.","abstract":"Noonan Syndrome (NS) is a common autosomal dominant multisystem disorder, caused by mutations in more than 10 genes in the Ras/MAPK signaling pathway. Differential mutation frequencies are observed across populations. Clinical expressions of NS are highly variable and include short stature, distinctive craniofacial dysmorphism, cardiovascular abnormalities, and developmental delay. Little is known about phenotypic specificities and molecular characteristics of NS in Africa. The present study has investigated patients with NS in Cape Town (South Africa). Clinical features were carefully documented in a total of 26 patients. Targeted Next-Generation Sequencing (NGS) was performed on 16 unrelated probands, using a multigene panel comprising 14 genes: <i>PTPN11, SOS1, RIT1, A2ML1, BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, SHOC2</i>, and <i>SPRED1</i>. The median age at diagnosis was 4.5 years (range: 1 month-51 years). Individuals of mixed-race ancestry were most represented (53.8%), followed by black Africans (30.8%). Our cohort revealed a lower frequency of pulmonary valve stenosis (34.6%) and a less severe developmental milestones phenotype. Molecular analysis found variants predicted to be pathogenic in 5 / 16 cases (31.2%). Among these mutations, two were previously reported: <i>MAP2K1</i>-c.389A>G (p.Tyr130Cys) and <i>PTPN11</i> - c.1510A>G (p.Met504Val); three are novel: <i>CBL</i>-c.2520T>G (p.Cys840Trp), <i>PTPN11</i>- c.1496C>T (p.Ser499Phe), and <i>MAP2K1</i>- c.200A>C (p.Asp67Ala). Molecular dynamic simulations indicated that novel variants identified impact the stability and flexibility of their corresponding proteins. Genotype-phenotype correlations showed that clinical features of NS were more typical in patients with variants in <i>MAP2K1</i>. This first application of targeted NGS for the molecular diagnosis of NS in South Africans suggests that, while there is no major phenotypic difference compared to other populations, the distribution of genetic variants in NS in South Africans may be different.","variants":[{"Name":"NM_005188.4(CBL):c.2520T>G (p.Cys840Trp)","Chromosome":"11","Start":"119299580","Stop":"119299580","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":639811,"rule_based_match":true,"evidence_text":"CBL-c.2520T>G (p.Cys840Trp)","llm_judgment":"PRESENT","evidence":"p.Cys840Trp","abstract_start":1428,"abstract_end":1439},{"Name":"NM_002834.5(PTPN11):c.1496C>T (p.Ser499Phe)","Chromosome":"12","Start":"112489072","Stop":"112489072","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":969675,"rule_based_match":true,"evidence_text":"PTPN11- c.1496C>T (p.Ser499Phe)","llm_judgment":"PRESENT","evidence":"p.Ser499Phe","abstract_start":1468,"abstract_end":1479}]}
{"pmid":"27916860","title":"Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype.","abstract":"Biallelic <i>PIGT</i> variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous <i>PIGT</i> missense variant c.1079G>T (p.Gly360Val) in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies. <i>PIGT</i> encodes a crucial subunit of the glycosylphosphatidylinositol (GPI) transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novel <i>PIGT</i> variant.","variants":[{"Name":"NM_015937.6(PIGT):c.1079G>T (p.Gly360Val)","Chromosome":"20","Start":"45421428","Stop":"45421428","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":446250,"rule_based_match":true,"evidence_text":"c.1079G>T (p.Gly360Val)","llm_judgment":"PRESENT","evidence":"c.1079G>T (p.Gly360Val)","abstract_start":467,"abstract_end":490}]}
{"pmid":"32703043","title":"A novel MFRP gene variant in a family with posterior microphthalmos, retinitis pigmentosa, foveoschisis, and foveal hypoplasia.","abstract":"BACKGROUND: To characterize the phenotype and genotype of a syndrome associating posterior microphthalmos (PM), retinitis pigmentosa (RP), foveoschisis, and foveal hypoplasia (FH) in a consanguineous Portuguese family.\nMATERIALS AND METHODS: Three siblings were studied and underwent comprehensive eye examinations for best-corrected visual acuity, axial length, refractive error, B-mode ultrasound, electroretinography, retinography, fluorescein angiography (FA), kinetic visual field (VF), and optical coherence tomography (OCT). Molecular analysis was performed by Sanger sequencing of the entire coding region of the <i>MFRP</i> gene.\nRESULTS: All members presented nyctalopia, decreased visual acuity, and constriction of the VF, as well as bilateral shortening of the posterior ocular segment and normal anterior segment dimensions. The fundoscopy and ERG results were compatible with RP. Macular OCT analysis revealed schisis of the outer retinal layer, FH, as well as retinal and choroidal folds. We identified a homozygous mutation in intron 9 of the membrane frizzled-related protein (MFRP) gene (c.1124 + 1 G > A).\nCONCLUSIONS: Our study shows a family with PM and RP due to a mutation in the MFRP gene. The relationship has previously been proven, but this specific mutation has never been described. These gene mutations show wide phenotypic variability, being evident in the presence of foveoschisis, retinal and choroidal folds, and FH, other than PM and RP.","variants":[{"Name":"NM_031433.4(MFRP):c.1124+1G>A","Chromosome":"11","Start":"119343815","Stop":"119343815","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2888756,"rule_based_match":true,"evidence_text":"c.1124+1G>A","llm_judgment":"PRESENT","evidence":"c.1124+1G>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"31175426","title":"A truncating CLDN9 variant is associated with autosomal recessive nonsyndromic hearing loss.","abstract":"While the importance of tight junctions in hearing is well established, the role of Claudin- 9 (CLDN9), a tight junction protein, in human hearing and deafness has not been explored. Through whole-genome sequencing, we identified a one base pair deletion (c.86delT) in CLDN9 in a consanguineous family from Turkey with autosomal recessive nonsyndromic hearing loss. Three affected members of the family had sensorineural hearing loss (SNHL) ranging from moderate to profound in severity. The variant is predicted to cause a frameshift and produce a truncated protein (p.Leu29ArgfsTer4) in this single-exon gene. It is absent in public databases as well as in over 1000 Turkish individuals, and co-segregates with SNHL in the family. Our in vitro studies demonstrate that the mutant protein does not localize to cell membrane as demonstrated for the wild-type protein. Mice-lacking Cldn9 have been shown to develop SNHL. We conclude that CLDN9 is essential for proper audition in humans and its disruption leads to SNHL in humans.","variants":[{"Name":"NM_020982.4(CLDN9):c.86del (p.Leu29fs)","Chromosome":"16","Start":"3013448","Stop":"3013448","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":972822,"rule_based_match":true,"evidence_text":"c.86delT","llm_judgment":"PRESENT","evidence":"c.86delT","abstract_start":256,"abstract_end":264}]}
{"pmid":"30203795","title":"A Rare Missense Variant in Telomerase Reverse Transcriptase is Associated with Idiopathic Pulmonary Fibrosis in a Chinese Han Family.","abstract":"BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an age-related and progressive interstitial lung disease. Up to 20% of cases of IPF cluster in families, genetic factors contribute significantly to the pathogenesis of the disease. This study aimed to explore the association between rare genetic variants and IPF in Chinese Han families.\nMETHODS: A Han family, comprising three IPF patients and five unaffected their first-degree relatives, and 100 ethnically matched control individuals from North China were enrolled in this study. Peripheral blood was collected, and genomic DNA was extracted. To elucidate if rare genetic variants are associated with the familial IPF, we performed whole-exome sequencing of affected members from a Chinese Han IPF family. Candidate rare variants were then confirmed by Sanger sequencing.\nRESULTS: We identified a potentially damaging rare variant-a heterozygous mutation c.2146G>A in exon 6 of the gene encoding for telomerase reverse transcriptase (TERT), which results in an amino acid substitution (p.Ala716Thr). We confirmed the missense mutation by Sanger sequencing in all the affected family members but did not detect this mutation in 100 ethnically matched healthy controls. Patients carried this mutation were characterized by the frequently acute exacerbation of IPF phenotype, with poor prognosis. The mean time to death was 2.8 years after diagnosis.\nCONCLUSION: Using next-generation sequencing technology in familial IPF patients, we identified the heterozygous rare variant in TERT gene, and strengthened the importance of genetic variants in telomere-related pathogenesis in Chinese IPF patients.","variants":[{"Name":"NM_198253.3(TERT):c.2146G>A (p.Ala716Thr)","Chromosome":"5","Start":"1278781","Stop":"1278781","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45606,"rule_based_match":true,"evidence_text":"c.2146G>A","llm_judgment":"PRESENT","evidence":"c.2146G>A","abstract_start":911,"abstract_end":920}]}
{"pmid":"24982679","title":"Clinical Case of Immune Dysregulation, Polyendocrinopaty, Enteropathy, X-Linked (IPEX) Syndrome with Severe Immune Deficiency and Late Onset of Endocrinopathy and Enteropathy.","abstract":"Objective. To describe the clinical characteristics of IPEX syndrome in a child with FOXP3 mutation. Clinical Case. A boy aged 2.3 years was born from first normal pregnancy with a weight of 3420 gr. Family History. Two brothers of the mother died before the age of 3 years with severe infections, diarrhea, erythroderma, and elevated immunoglobulins class E (IgEs). Since first month of life, our patient suffered from septicemia, pneumonias, pyelonephritis, and meningitis, accompanied with eczematous dermatitis and IgEs up to 4000 IU/L (normal <10). At the age of 1.6 years, he developed type 1 diabetes mellitus (T1DM). He was underweighted (-3.42 SDS) and had some phenotypic features like coarse face, muscle hypotonia, joint hyperextensibility, eczematous dermatitis, and subcutaneous cold abscesses. Autoimmune thyroiditis and celiac disease were excluded. After diabetes, intermittent watery diarrhea appeared with progression to severe intractable form. Finally, aggravating symptoms of nephritis, cachexia, and respiratory insufficiency were the cause for his death at the age of 2 years and 3 months. The DNA analysis at the University of Exeter Medical School established mutation at exon 10 of FOXP3 gene c.1010G >A, p. (Arg337Gln), which confirmed IPEX syndrome. The same mutation in heterozygotic state was found in the mother. A prenatal diagnosis of her second pregnancy ensured a daughter carrier of the mutation.","variants":[{"Name":"NM_014009.4(FOXP3):c.1010G>A (p.Arg337Gln)","Chromosome":"X","Start":"49253160","Stop":"49253160","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":939638,"rule_based_match":true,"evidence_text":"c.1010G >A, p. (Arg337Gln)","llm_judgment":"PRESENT","evidence":"c.1010G >A, p. (Arg337Gln)","abstract_start":1220,"abstract_end":1246}]}
{"pmid":"30238602","title":"Novel CNS malformations and skeletal anomalies in a patient with Beaulieu-boycott-Innes syndrome.","abstract":"THO/TREX (transcription/export) is a conserved eukaryotic complex that plays a crucial role in gene expression and prevents DNA damage during mitosis and meiosis. In mammals, TREX is essential during embryogenesis, determining stem cell fate specification by regulating posttranscriptional self-renewal and differentiation in several tissues. It is composed of a core called THO, consisting of THOC1, 2, 5, 6, 7, and additional proteins. Bi-allelic mutations in THOC6 have been associated to Beaulieu-Boycott-Innes syndrome (BBIS), a syndromic form of intellectual disability (ID). To date, nine patients harbouring homozygous or compound heterozygous mutations in THOC6 have been reported. Despite the clinical heterogenity and subtle dysmorphic features in some individuals, distinctive facial features are tall forehead, short and upslanting palpebral fissures, deep set eyes, flat philtrum, and malocclusion. Nonlife threatening congenital anomalies are common, including cardiac and renal malformations, anteriorly displaced anus, cryptorchidism in males, submucous cleft palate, and corpus callosum dysgenesis. Affected patients usually have short stature, mild microcephaly, and mild to moderate ID. Here, we describe an Italian patient with BBIS, carrying two compound heterozygous loss-of-function (LoF) variants in THOC6 (c.577C > T, p.R193* and c.792_793delCA, p.V264Vfs*48). In addition to the common phenotype, she displays cerebellar hypoplasia with severe vermian dysgenesis and hydrocephalus due to aqueductal stenosis, multiple skeletal anomalies and hypergonadotropic hypogonadism. Thus, we review the previous cases and discuss the phenotypic spectrum of BBIS, providing further evidence regarding the pivotal role of TREX complex in human development.","variants":[{"Name":"NM_024339.5(THOC6):c.577C>T (p.Arg193Ter)","Chromosome":"16","Start":"3026772","Stop":"3026772","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":970374,"rule_based_match":true,"evidence_text":"c.577C > T, p.R193*","llm_judgment":"PRESENT","evidence":"c.577C > T, p.R193*","abstract_start":1332,"abstract_end":1351}]}
{"pmid":"31061755","title":"Biotin-Thiamine Responsive Encephalopathy: Report of an Egyptian Family with a Novel","abstract":"Biotin-thiamine responsive basal ganglia disease (BTRBGD) is an autosomal recessive neurometabolic disorder with poor genotype-phenotype correlation, caused by mutations in the <i>SLC19A3</i> gene on chromosome 2q36.6. The disease is characterized by three stages: stage 1 is a sub-acute encephalopathy often triggered by febrile illness; stage 2 is an acute encephalopathy with seizures, loss of motor function, developmental regression, dystonia, external ophthalmoplegia, dysphagia, and dysarthria; stage 3 is represented by chronic or slowly progressive encephalopathy. Clinical and biochemical findings, as well as the magnetic resonance imaging (MRI) pattern, resemble those of Leigh's syndrome, so that BTRBGD can be misdiagnosed as a mitochondrial encephalopathy.Here we report the clinical and radiological phenotypes of two siblings diagnosed with BTRBGD in which a novel <i>SLC19A3</i> mutation (NM_025243.3: c.548C > T; p.Ala183Val) was found by whole exome sequencing (WES) of the family members.","variants":[{"Name":"NM_025243.4(SLC19A3):c.548C>T (p.Ala183Val)","Chromosome":"2","Start":"227699167","Stop":"227699167","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":622868,"rule_based_match":true,"evidence_text":"NM_025243.3: c.548C > T; p.Ala183Val","llm_judgment":"PRESENT","evidence":"NM_025243.3: c.548C > T; p.Ala183Val","abstract_start":907,"abstract_end":943}]}
{"pmid":"22986587","title":"TMEM70: a mutational hot spot in nuclear ATP synthase deficiency with a pivotal role in complex V biogenesis.","abstract":"Mammalian complex V (F1F0-ATP synthase or ATPase) uses the proton gradient to generate ATP during oxidative phosphorylation and requires several helper proteins, including TMEM70, to form the holoenzyme in a stepwise process in which nuclear DNA is combined with mitochondrial DNA-encoded subunits. We report the clinical and molecular findings in three patients presenting lactic acidosis, 3-methylglutaconic aciduria, and hypertrophic cardiomyopathy. All three showed an isolated defect of fully assembled ATP synthase in association with a \"common\" (c.317-2A > G) and a new (c.628A > C/p.T210P) variant in TMEM70. Interestingly, one of the patients also showed nitric oxide-responsive pulmonary arterial hypertension, a finding never before associated with TMEM70 deficiency. In addition to widening the clinical and mutational spectrum of defective ATP synthase, our study also suggests that mutant TMEM70 associates in high molecular weight complexes (470-550 kDa) when expressed in Hela cells and exerts a direct action in ATP synthase biogenesis and assembly, mediating the incorporation of F1 moieties.","variants":[{"Name":"NM_017866.6(TMEM70):c.317-2A>G","Chromosome":"8","Start":"73981153","Stop":"73981153","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15579,"rule_based_match":true,"evidence_text":"c.317-2A > G","llm_judgment":"PRESENT","evidence":"c.317-2A > G","abstract_start":553,"abstract_end":565}]}
{"pmid":"20618352","title":"A founder mutation in BBS2 is responsible for Bardet-Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders.","abstract":"Bardet-Biedl syndrome (BBS) is a multisystem genetically heterogeneous disorder, the clinical features of which are largely the consequence of ciliary dysfunction. BBS is typically inherited in an autosomal recessive fashion, and mutations in at least 14 genes have been identified. Here, we report the identification of a founder mutation in the BBS2 gene as the cause for the increased incidence of this developmental disorder in the Hutterite population. To ascertain the Hutterite BBS locus, we performed a genome-wide single nucleotide polymorphism (SNP) analysis on a single patient and his three unaffected siblings from a Hutterite family. The analysis identified two large SNP blocks that were homozygous in the patient but not in his unaffected siblings, one of these regions contained the BBS2 gene. Sequence analysis and subsequent RNA studies identified and confirmed a novel splice site mutation, c.472-2A>G, in BBS2. This mutation was also found in homozygous form in three subsequently studied Hutterite BBS patients from two different leuts, confirming that this is a founder mutation in the Hutterite population. Further studies are required to determine the frequency of this mutation and its role, if any, in the expression of other ciliopathies in this population.","variants":[{"Name":"NM_031885.5(BBS2):c.472-2A>G","Chromosome":"16","Start":"56510923","Stop":"56510923","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39507,"rule_based_match":true,"evidence_text":"c.472-2A>G","llm_judgment":"PRESENT","evidence":"c.472-2A>G","abstract_start":911,"abstract_end":921}]}
{"pmid":"22572733","title":"Detection of a large heterozygous deletion and a splicing defect in the CFTR transcripts from nasal swab of a Japanese case of cystic fibrosis.","abstract":"Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in CFTR (CF transmembrane conductance regulator). Although CF is the most common hereditary disease in Caucasians, it is rare in Asian populations. Common disease-causing mutations of CFTR in Caucasians are rarely identified in Japanese patients with CF. In the present study, CFTR transcripts from nasal swab were analyzed in a Japanese boy, in addition to conventional PCR and direct sequence of all exons, their boundaries and promoter region of the CFTR gene. The boy was diagnosed with CF by chronic respiratory infection and the elevated sweat chloride level. None of the disease-causing mutations of CFTR was detected by the conventional analysis. Cloning and sequence of the CFTR transcripts revealed a heterozygous deletion spanning exons 16, 17a and 17b. The deletion was confirmed by multiplex ligation-dependent probe amplification and the direct sequence of the junction fragment obtained from the genomic DNA by primer walking, which revealed the mutation c.2908+1085_3367+260del7201. We also identified a splicing defect: deletion/skipping of exon 1 in the CFTR transcript from the other allele. The analysis of CFTR transcripts from nasal swab is recommended in the genetic analysis of CF in Japanese.","variants":[{"Name":"NM_000492.4(CFTR):c.2908+1085_3367+260del","Chromosome":"7","Start":"117604867","Stop":"117612068","ReferenceAlleleVCF":"AGAAGAGTCAGACATGAGCGATGAGGCACAGTGGAAAGAACATGAGCATTGCCTGAGCTCTGAGTTGGCGCTATAAGAGCAGTGATCATGGGCAAGTGACTCTTCTGAGCCTTGGCCTCCTCACCTGTTAAGTGAAGAAAAGAATATTTCAGAAGATCTTTGTGAGAATGAAACAAGGCAATTTACTTGCCTGCTACATAGCCAATGGGAAATCAATATAAGTTCCCCGTGGTTCCCTTCTGTGGGGTTTTGTTCCCACAGAGGGTGCACTGGCCATTCCACTTCTTCTTTTCCAAGCTCCTCATTCCCTTTAACGCTGTTCATAGTTGGTTCCAAACCATTTGAAATATAATAAGCACCAGGATGGTTTTTTCTTTCCACCAAAGCAAATTTCATTTTCTAAACACTGTTTATAAATATCAATGGCTATTTTTTCAATTTTTGATTATCATGAAAATATACAAATATGTTTAATTAAATATGCTAAAGAATGTATTAATAAATATGTATTAAATAATTCCTACATATAAGGCCTTTTTGCTTGGGGTATGGGTGATACAAAATAAATGTGGCATGAACCCACTGACCTCTAGCAATTTATAACCTAGAAAAAGAGTTATGATATGTTTATAAGTTCCTGTGATATAAGACATGCATATAGTCATTATAACAGAGGTGCAAACAAGATGTATCAAGTATGTCCAGAGGAGGAAGAGATTAATCCCAGCTGGAGGAAACACTGATGCTTTCTTGCAGCAGGGGCATTTGAGTTGAGAAAGGGAGGAAACATAGATTTTGACAATGAGAGCTGAGGGGAAAGGGGTTTCAGGTGGAGGGAACCGCATGTGGAAAGCAGGGAGGTAGGAAAGTGTAGAGTGTGTTTAAAGAATAGACCAGTTTGGCTGAAACAGGATATTTGAGCAGAGGAAGCTTGTACTAGGTAGGTGGGTTGAGGCCAAATTATGCAAGGCATTAAATATTAAACTAGGAATTTTGGACTTTATCCTGCAGTTTATGGGGGGTAAATGATAAGATTCAATATCACTTTATTTGTACAGTATTATGTTACATTTTATCTAATTGTTTGTTTAATTCCTGTCTAGACAATGAATTCCTCAAGGGCAAGGAGCATGGCTTATTCACCTCAGTAATTTCAGTGCCTAGCATTGTGCCTGGTACAAAGTGGACACTTGTATATAACCTTTTTTAATTGAAGCAACAAGTTGTCAACCTTACAAATGTGAATCCGTGATTCAGATGACAGGTTGAAATGTAGATTGTCTGCGAAGAGGGCAGAAAGAGAGTATGACAAAGGAGGACAAGACAGTGGGGCAGGCAGGGAGAGAGAGCAGCCAGGGTTTCGGTAGAGGTATGTCAAAAAGGTATGGAAGTCAGAGGAGAAGGAGACCCCTATGTTATAGAATACAAATGGAAGGGAAATGATGACAACAGTAAGTTGTCATTAAATGCAAGGTTGCAAAAGTAAGATTGTAAAGCAGGATGAGTACCCACCTATTCCTGACATAATTTATAGTAAAAGCTATTTCAGAGAAATTGGTCGTTACTTGAATCTTACAAGAATCTGAAACTTTTAAAAAGGTTTAAAAGTAAAAGACAATAACTTGAACACATAATTATTTAGAATGTTTGGAAAGAAACAAAAATTTCTAAGTCTATCTGATTCTATTTGCTAATTCTTATTTGGGTTCTGAATGCGTCTACTGTGATCCAAACTTAGTATTGAATATATTGATATATCTTTAAAAAATTAGTGTTTTTTGAGGAATTTGTCATCTTGTATATTATAGGTGGGATTCTTAATAGATTCTCCAAAGATATAGCAATTTTGGATGACCTTCTGCCTCTTACCATATTTGACTTCATCCAGGTATGTAAAAATAAGTACCGTTAAGTATGTCTGTATTATTAAAAAAACAATAACAAAAGCAAATGTGATTTTGTTTTCATTTTTTATTTGATTGAGGGTTGAAGTCCTGTCTATTGCATTAATTTTGTAATTATCCAAAGCCTTCAAAATAGACATAAGTTTAGTAAATTCAATAATAAGTCAGAACTGCTTACCTGGCCCAAACCTGAGGCAATCCCACATTTAGATGTAATAGCTGTCTACTTGGGAGTGATTTGAGAGGCACAAAGGACCATCTTTCCCAAAATCACTGGCCACAAAGTGTGACATTTTGGCATTGGCATCACTATTTGATGGAAGCCAACCTCCCCCCAAAAGGCCTGTATTAGAATGAAGATGGATTCCCTGGGTGGGTTACACTTGAAACTAGCCTCACCCATGAACACTTTGGCACAGATTAGCTAGCCCATTCCCCCACAGTAAGGACCATAAGGAAGGGACAGAAGCAAAGATAAGTTTTAGAACAAAAGAGAGGGGAAAGAAAAAATCTAGGGTTTTATGAGGGCTGTCCCTGAGTGATAGATGTGAATAGGCCTCCAGGGCAGGCTGGCTCAGAGGCTGACTCTTTGGGTTGGGGTGACTGATTGGTGGTGAGGATGGAGAAGAAAAGGGGAGTGGAGGAGGTGAAAGTGACCTTGGGACATTAGGTCTCCATAAGTGACAGGATTTAAGGAGTGTTGTAAGCTGTGGTTGTTGGACCAGGTTTAAGCACAGCTTCCTGAGCTTCCTGACTGGTTTAGGTCAAGCTCCAGAGAGCAAATGCCACAGTCTCAGTGATCTCCTTGGAGAAACAGTTGGAATAGGATGTTGCCCATGTTGGGATGAGTCATTGTCCGCTCTTGCTCTTTCCCTACCCCTGCAAAATAATAATACTGTATTTGATTGAACATATAAAACAAAAGAAGGATTATCACATAAGTATGTATATATAACCAACATTGGCAGGTGCAGAAAAACCAGACTGTCAGTTTGCCTCATCTGAAATGATTGACACAAACAAATATATTTACTGTCCCAAGTGAACTTTGGCATTTTGGATATCCTTCAGTTGTTCTGTTTAAAGATATAACTTAGAAGCAGCTGATGGAATATTTAAATCCATGCGTTGAATTCATGCATTCAAAGAAACATGTCCTGAGTCACTAAATGCTGACATTTGTTTTTCATGTTAAGAGTGTAAATAACTGGTCCCAAATATAATATTATTACATCAGATAAAAACTGGAATGTGAACCTCTTAACTTGATTGTGAAAGTATTTGCCAATGGTGCCTCTTGATAATTATTTGAGGCTCACTTCAGAACTCCTCTGGAAGGGTTAATTTTTAAATAGTCATTTTATAAATTAACATTTTTGACATATGTGATGGCTCTCAAATTTTTTCTTTTATGCCAGTTTGAATCATTTCTGCTCAATTTTTTTTTTTAATTGGGATGGAGTCTCACTCTGTTGCCCAGGCTGGAGTGCAGTGATGCAATCTTGGCTGACTGCAACCTCCACCTCCTCGGTTCAAGCGATTCTCTCGCATCAGCCTCCAGAGTAGCTGGGATTACAGGCGCGCACCACCATGCCTGGATAATTTTTGTATTATTACTAGAGATGGGGTTTCACCACGTTGGCCAGGCTGGTCTTGAACTCCTGAACTCCTGACCTCAAGTGATCCACCTGCCTCAGCCTCTTAAAGAGCTGGAATTATAGGTGTGAGCCACTGCACCAGGCCCTGTTCAACTTTTAATGCTAAGATTCATTTGTTGTTGTTTCACAAGTGATTAGGCAGAGGTCTTTTATATTAATTTACCCATTTTATTTGTAAGAGAGTCTCATATTAAGGAAGCATAATATATGACAATCCAAATACAGTACAAATTTGGTTAATTTTGATTTTGTTAAATAATTAATCACAGGGGTCCTTCAAATTGTGAGCTCCTCTGGTTATACTTATGTTTTACCTCTGGTTATACTTAATTTCAAACAAATGAAATTTCATTCTATTCATGATATTTCAGAAGCAGATCTGTTGCACAAAATAAAGCATACCTATAAATTTTCTTTTTTTAAAAAAAAGTCTCTGTTCACTCTATTTTCTATTATTTTTCTCTTTTTAAAATTTGAATTTTATTGTGGCAAGTCCACTTAACATGAGATTTACCCTCTTAACAGATTTTTATGTGTAAAATACAATATTGTTCACCATGGGTAAATGTTGCACAGCAGATCTCTGGAACTTATTCATTTTGCACTACTGAAATTTTATACCTGTTGATTAGTATCTCCCCATTTCCCTCTCTCCCCTGTCCTGTTACCCATGGTTCTGTTCTTTGCTTCTTTGAGTTTGAGTATTTTGATACCTCATGTAATCTTCATTCTATTTTCTAACTTTGACAATGTTCTGACAAATTTGCTTTCCGGATTGGAGCACTGTATAGTGAAAATTGAAAATCTTGGTTATTTTCTACAGATTCCCACTATTTTACCTTGAGCAGACACTTATCTTGAAGGGTCTCAGATTTGTCACTTGTAGAATGGGGAATATAAACCTGATAATGGTCCCTTTCAGTTCTAAAGTTATATCAGTTGAAAATACATGTGTCACTTATGGTAACGGGTAGAGAACTGGCTCACTGAACAGCATATGGATATTATAAAGTGGTTTTTTTTAATCCTTTCTGCAGACAGTTACTTTATACTTTATTCAAATGGATTATTGTGAAGTACATGTTAGCGGACTTTGTACCTTTTAAAAATGTATGTATTTGGTGTAATGTAGAAATATAGAAATTTATTAAGTATGATTTATTTCAATGTTAAGCATGAGAAAATATGCTCCGAAAGGTTAGATAGCTTGCCTAAATGACAAGCTTGTATTTCAAGCAGAACTTTCTGAATCAAAAGACTCCAAGACGAATGCCCAGCTTTCAAAAACTGTCTAACCAAAATAAATCCTAAGATTCACCTTCATACTAAAATTATTTAAAAATAGTTTATTTTAAATTAATATTCACTTAAAATGTATTTATCATGCAATACTTTAAAGTGTCTGGGAAATGAAAATATCCAAAGATCAAAGAACACCATGTTTTCAAACTTCAAAAATGTTATCAGTGACCTAAACAATTTTTAAAATTTTCATAGAGCCTATGAAAAATGTACTTGCAAATGGCTACTTTCTGACTAGGAATAGAATGGGGAGAGTATTTAGTCCAACAATGATAGACTGGATTAAGAAAATGTGGCACATATACACCATGGAACACTATGCAGCCATAAAAAATGATGAGTTCATGTCCTTTGTAGGGACATGGATGAAATTGGAAAACATCATTCTCAGTAAACTATCGCAAGAACAAAAAACCAAACACCGCATATTCTCACTCATAGGTGGGAATTGAACAATGAGATCACATGGACACAGGAAGGGGAATATCACACTCTGGGGACTGTTGTGGGGTGGGGGGAGGGGGGAGGGATAGCACTGGGAGATATACCTAATGCTAGATGACGAGTTAGTGGGTGCAGTGCACCAGCATGGCACATGTATACATATGTAACTAACCTGCACAATGTGCACATGTACCCTAAAACTTAAAGTATAATAAAAAAAATAAAAAAAAGTTTGAGGTGTTTAAAGTATGCAAAAAAAAAAAAAGAAATAAATCACTGACACACTTTGTCCACTTTGCAATGTGAAAATGTTTACTCACCAACATGTTTTCTTTGATCTTACAGTTGTTATTAATTGTGATTGGAGCTATAGCAGTTGTCGCAGTTTTACAACCCTACATCTTTGTTGCAACAGTGCCAGTGATAGTGGCTTTTATTATGTTGAGAGCATATTTCCTCCAAACCTCACAGCAACTCAAACAACTGGAATCTGAAGGTATGACAGTGAATGTGCGATACTCATCTTGTAAAAAAGCTATAAGAGCTATTTGAGATTCTTTATTGTTAATCTACTTAAAAAAAATTCTGCTTTTAAACTTTTACATCATATAACAATAATTTTTTTCTACATGCATGTGTATATAAAAGGAAACTATATTACAAAGTACACATGGATTTTTTTTCTTAATTAATGACCATGTGACTTCATTTTGGTTTTAAAATAGGTATATAGAATCTTACCACAGTTGGTGTACAGGACATTCATTTATAATAAACTTATATCAGTCAAATTAAACAAGGATAGTGCTGCTATTACTAAAGGTTTCTCTGGGTTCCCAAATGATACTTGACCAAATTTGTCCCTTTGGCTTGTTGTCTTCAGACACCCTTTCTTCATGTGTTGGAGCTGCCATTTCGTGTGCCCCCAAACTCTACTTGAGCTGTTAGGGAATCACATTTTGCAGTGACAGCCTTAGTGTGGGTGCATTTTCAGGCAATACTTTTTCAGTATATTTCTGCTTTGTAGATTATTAGCTAAATCAAGTCACATAAACTTCCTTAATTTAGATACTTGAAAAAATTGTCTTAAAAGAAAATTTTTTTAGTAAGAATTAATTTAGAATTAGCCAGAAAACTCCCAGTGGTAGCCAAGAAAGAGGAATAAATATTGGTGGTAATTTTTTAAGTTCCCATCTCTGGTAGCCAAGTAAAAAAAGAGGGTAACTCATTAATAAAATAACAAATCATATCTATTCAAAGAATGGCACCAGTGTGAAAAAAAGCTTTTTAACCAATGACATTTGTGATATGATTATTCTAATTTAGTCTTTTTCAGGTACAAGATATTATGAAATTACATTTTGTGTTTATGTTATTTGCAATGTTTTCTATGGAAATATTTCACAGGCAGGAGTCCAATTTTCACTCATCTTGTTACAAGCTTAAAAGGACTATGGACACTTCGTGCCTTCGGACGGCAGCCTTACTTTGAAACTCTGTTCCACAAAGCTCTGAATTTACATACTGCCAACTGGTTCTTGTACCTGTCAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAG","AlternateAlleleVCF":"A","allel_id":621888,"rule_based_match":true,"evidence_text":"c.2908+1085_3367+260del7201","llm_judgment":"PRESENT","evidence":"c.2908+1085_3367+260del7201","abstract_start":1045,"abstract_end":1072}]}
{"pmid":"24556084","title":"POMK mutation in a family with congenital muscular dystrophy with merosin deficiency, hypomyelination, mild hearing deficit and intellectual disability.","abstract":"BACKGROUND: Congenital muscular dystrophies (CMD) with hypoglycosylation of α-dystroglycan are clinically and genetically heterogeneous disorders that are often associated with brain malformations and eye defects. Presently, 16 proteins are known whose dysfunction impedes glycosylation of α-dystroglycan and leads to secondary dystroglycanopathy.\nOBJECTIVE: To identify the cause of CMD with secondary merosin deficiency, hypomyelination and intellectual disability in two siblings from a consanguineous family.\nMETHODS: Autozygosity mapping followed by whole exome sequencing and immunochemistry were used to discover and verify a new genetic defect in two siblings with CMD.\nRESULTS: We identified a homozygous missense mutation (c.325C>T, p.Q109*) in protein O-mannosyl kinase (POMK) that encodes a glycosylation-specific kinase (SGK196) required for function of the dystroglycan complex. The protein was absent from skeletal muscle and skin fibroblasts of the patients. In patient muscle, β-dystroglycan was normally expressed at the sarcolemma, while α-dystroglycan failed to do so. Further, we detected co-localisation of POMK with desmin at the costameres in healthy muscle, and a substantial loss of desmin from the patient muscle.\nCONCLUSIONS: Homozygous truncating mutations in POMK lead to CMD with secondary merosin deficiency, hypomyelination and intellectual disability. Loss of desmin suggests that failure of proper α-dystroglycan glycosylation impedes the binding to extracellular matrix proteins and also affects the cytoskeleton.","variants":[{"Name":"NM_032237.5(POMK):c.325C>T (p.Gln109Ter)","Chromosome":"8","Start":"43122149","Stop":"43122149","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":137085,"rule_based_match":true,"evidence_text":"c.325C>T","llm_judgment":"PRESENT","evidence":"c.325C>T","abstract_start":733,"abstract_end":741}]}
{"pmid":"20567915","title":"Complete BRCA mutation screening in breast and ovarian cancer predisposition families from a North-Eastern Romanian population.","abstract":"Breast cancer is the most common cancer in women worldwide, including Romania, where its incidence has increased significantly during the last decade. Ovarian cancer is the fourth leading cause of mortality by cancer in women. BRCA1 and BRCA2 are major cancer predisposition genes, responsible for a large percentage of hereditary breast and ovarian cancer (HBOC) families. We investigated 17 patients from unrelated HBOC families in north-eastern Romania, screening for mutations in BRCA1 and BRCA2 by mutation-specific PCR and by dideoxy sequencing. We identified four BRCA1 and two BRCA2 mutations in the 17 families. The overall mutation frequency was 41% (7/17; 5 BRCA1 and 2 BRCA2). Two mutations (BRCA1 c.2241dupC and BRCA2 c.8680C>T) were novel and not listed in the BIC database. Two recurrent BRCA1 mutations (c.5266dupC and c.181T>G), previously described among Ashkenazi Jewish and Eastern European populations, were also found. Two unclassified variants (UV) were found, one of which was novel (BRCA2 c.4589A>G). Medical follow-up for mutation carriers was implemented. Our study is the first molecular investigation of the role of the BRCA genes in breast and ovarian cancer in Romania.","variants":[{"Name":"NM_000059.4(BRCA2):c.4589A>G (p.Lys1530Arg)","Chromosome":"13","Start":"32338944","Stop":"32338944","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":66347,"rule_based_match":true,"evidence_text":"BRCA2 c.4589A>G","llm_judgment":"PRESENT","evidence":"BRCA2 c.4589A>G","abstract_start":1008,"abstract_end":1023},{"Name":"NM_007294.4(BRCA1):c.2241dup (p.Lys748fs)","Chromosome":"17","Start":"43093289","Stop":"43093290","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":69178,"rule_based_match":true,"evidence_text":"BRCA1 c.2241dupC","llm_judgment":"PRESENT","evidence":"BRCA1 c.2241dupC","abstract_start":704,"abstract_end":720},{"Name":"NM_000059.4(BRCA2):c.8680C>T (p.Gln2894Ter)","Chromosome":"13","Start":"32376717","Stop":"32376717","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67326,"rule_based_match":true,"evidence_text":"BRCA2 c.8680C>T","llm_judgment":"PRESENT","evidence":"BRCA2 c.8680C>T","abstract_start":725,"abstract_end":740}]}
{"pmid":"23022098","title":"An RMND1 Mutation causes encephalopathy associated with multiple oxidative phosphorylation complex deficiencies and a mitochondrial translation defect.","abstract":"Mutations in the genes composing the mitochondrial translation apparatus are an important cause of a heterogeneous group of oxidative phosphorylation (OXPHOS) disorders. We studied the index case in a consanguineous family in which two children presented with severe encephalopathy, lactic acidosis, and intractable seizures leading to an early fatal outcome. Blue native polyacrylamide gel electrophoretic (BN-PAGE) analysis showed assembly defects in all of the OXPHOS complexes with mtDNA-encoded structural subunits, and these defects were associated with a severe deficiency in mitochondrial translation. Immunoblot analysis showed reductions in the steady-state levels of several structural subunits of the mitochondrial ribosome. Whole-exome sequencing identified a homozygous missense mutation (c.1250G>A) in an uncharacterized gene, RMND1 (required for meiotic nuclear division 1). RMND1 localizes to mitochondria and behaves as an integral membrane protein. Retroviral expression of the wild-type RMND1 cDNA rescued the biochemical phenotype in subject cells, and siRNA-mediated knockdown of the protein recapitulated the defect. BN-PAGE, gel filtration, and mass spectrometry analyses showed that RMND1 forms a high-molecular-weight and most likely homopolymeric complex (∼240 kDa) that does not assemble in subject fibroblasts but that is rescued by expression of RMND1 cDNA. The p.Arg417Gln substitution, predicted to be in a coiled-coil domain, which is juxtaposed to a transmembrane domain at the extreme C terminus of the protein, does not alter the steady-state level of RMND1 but might prevent protein-protein interactions in this complex. Our results demonstrate that the RMND1 complex is necessary for mitochondrial translation, possibly by coordinating the assembly or maintenance of the mitochondrial ribosome.","variants":[{"Name":"NM_017909.4(RMND1):c.1250G>A (p.Arg417Gln)","Chromosome":"6","Start":"151405787","Stop":"151405787","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48364,"rule_based_match":true,"evidence_text":"c.1250G>A","llm_judgment":"PRESENT","evidence":"c.1250G>A","abstract_start":803,"abstract_end":812}]}
{"pmid":"23859418","title":"X-linked chronic granulomatous disease in a male child with an X-CGD carrier, Klinefelter brother.","abstract":"BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency (PID) caused by a dysfunctional respiratory burst enzyme NADPH-oxidase. The concurrence of Klinefelter's Syndrome (KS) and CGD would be extremely rare.\nOBJECTIVE: We describe the study of a family where the youngest male child had X-linked CGD (X-CGD) while his older brother was both an X-CGD carrier and a Klinefelter.\nMETHODS: Flow cytometry was used to study respiratory burst and gp91-phox expression, while genetic investigation was done by RT-PCR, PCR and X-chromosome short tandem repeat (X-STR) analysis.\nRESULTS: The Dihydrorhodamine (DHR) assay showed the patient's neutrophils failed to produce a respiratory burst, while both the mother and an older brother showed a bimodal response. gp91-phox expression was absent in the patient's neutrophils, and bimodal in the mother's and brother's neutrophils. The patient's cDNA showed a C>T change at nucleotide 676 of the CYBB gene. The same change was seen in the patient's gDNA, while the brother and mother were heterozygous, with C and T, in this position. The c.676C>T is a nonsense mutation that leads to premature termination of the gp91-phox protein. The brother karyotyped as 47, XXY and X chromosome analysis showed that he had inherited both his mother's X chromosomes.\nCONCLUSIONS: This study showed that the patient had gp91-phox deficient CGD while his older brother was a CGD carrier and a Klinefelter, who had inherited both his mother's X chromosomes. This is the first report of such a concurrence in an individual, and argues for family members to be included in PID studies.","variants":[{"Name":"NM_000397.4(CYBB):c.676C>T (p.Arg226Ter)","Chromosome":"X","Start":"37798956","Stop":"37798956","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25968,"rule_based_match":true,"evidence_text":"c.676C>T","llm_judgment":"PRESENT","evidence":"c.676C>T","abstract_start":1105,"abstract_end":1113}]}
{"pmid":"25606447","title":"Familial hypercholesterolemia: Molecular characterization of possible cases from the Azores Islands (Portugal).","abstract":"Familial hypercholesterolemia (FH) is an autosomal dominant disorder of the cholesterol metabolism, which constitutes a risk factor for coronary arterial disease (CAD). In the Azores Islands (Portugal), where mortality from CAD doubles its rate comparatively to the rest of the country and where a high frequency of dyslipidemia has been reported, the prevalence and distribution of FH remain unknown. The molecular characterization of a group of 33 possible cases of FH of Azorean background was undertaken in this study. A DNA array was initially used to search mutations in the LDLR, APOB and PCSK9 loci in 10 unrelated possible cases of FH. No mutations were detected in the array; after sequencing the full LDLR gene, 18 variants were identified, corresponding to two missense (c.806G > A; c.1171G > A) and sixteen synonymous alterations. Six of the synonymous variants which are consistently described in the literature as associated with altered cholesterol levels were used to build haplotypes. The most frequent haplotype corresponded to TTCGCC (45%), a \"risk\" haplotype, formed exclusively by alleles that were reported to increase cholesterol levels. Some of the variants detected in the full sequencing of the LDLR gene fell within the ligand-binding domain of this gene, defined by exons 2 to 6. To add information as to the role of such variants, these exons were sequenced in the remaining 23 possible FH cases. Two missense alterations (c.185C > T; c.806G > A) were found in this subset of possible FH cases. The missense alteration c.185C > T, identified in one individual, is novel for the Portuguese population. In silico analysis was not conclusive for this alteration, whose role will have to be further investigated. This study represents the first approach to the establishment of the mutational profile of FH in the Azores Islands.","variants":[{"Name":"NM_000527.5(LDLR):c.806G>A (p.Gly269Asp)","Chromosome":"19","Start":"11106676","Stop":"11106676","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171202,"rule_based_match":true,"evidence_text":"c.806G > A","llm_judgment":"PRESENT","evidence":"c.806G > A","abstract_start":783,"abstract_end":793},{"Name":"NM_000527.5(LDLR):c.185C>T (p.Thr62Met)","Chromosome":"19","Start":"11100340","Stop":"11100340","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171196,"rule_based_match":true,"evidence_text":"c.185C > T","llm_judgment":"PRESENT","evidence":"c.185C > T","abstract_start":1453,"abstract_end":1463}]}
{"pmid":"31203166","title":"Generation of a human iPSC line, INMi003-A, with a missense mutation in CRX associated with autosomal dominant cone-rod dystrophy.","abstract":"We generated an induced pluripotent stem cell (iPSC) line using dermal fibroblasts from a 53 year-old patient with autosomal dominant cone-rod dystrophy (CRD) caused by a missense mutation, c.121C > T, in the CRX gene. Patient fibroblasts were reprogrammed using the non-integrative Sendai virus reprogramming system and the human OSKM transcription factor cocktail. The generated iPSCs contained the congenital mutation in exon 3 of CRX and were pluripotent and genetically stable. This iPSC line will be an important tool for retinal differentiation studies to better understand the CRD phenotype caused by the mutant p.Arg41Trp CRX protein.","variants":[{"Name":"NM_000554.6(CRX):c.121C>T (p.Arg41Trp)","Chromosome":"19","Start":"47836263","Stop":"47836263","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22457,"rule_based_match":true,"evidence_text":"c.121C > T","llm_judgment":"PRESENT","evidence":"c.121C > T","abstract_start":190,"abstract_end":200}]}
{"pmid":"28947073","title":"Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy.","abstract":"INTRODUCTION: Spinocerebellar ataxia types 19 and 22 (SCA19/22) are rare conditions in which relatively isolated cerebellar involvement is frequently associated with cognitive impairment. Here, we report on new clinical features and provide details of the cognitive profile in two SCA19/22 families.\nMETHODS: Two families displaying an autosomal-dominant form of cerebellar ataxia underwent clinical examinations and genetic testing.\nRESULTS: In addition to the classical clinical features of SCA, a wide spectrum of cognitive disorders (including visuospatial impairments) was observed. Eight patients had mild Parkinsonism, and five had epilepsy. Genetic testing showed that the KCND3 mutation (c.679_681delTTC, p.F227del) was present in both families.\nCONCLUSIONS: Our findings broaden the phenotypic spectrum of SCA19/22, and suggest that KCND3 should be included in the list of candidate genes for epilepsy, Parkinsonism and cognitive impairment.","variants":[{"Name":"NM_001378969.1(KCND3):c.677TCT[1] (p.Phe227del)","Chromosome":"1","Start":"111982045","Stop":"111982047","ReferenceAlleleVCF":"CAGA","AlternateAlleleVCF":"C","allel_id":76965,"rule_based_match":false,"evidence_text":"c.679_681delTTC, p.F227del","llm_judgment":"PRESENT","evidence":"c.679_681delTTC, p.F227del","abstract_start":697,"abstract_end":723}]}
{"pmid":"26535115","title":"Case Report: Compound heterozygous nonsense mutations in TRMT10A are associated with microcephaly, delayed development, and periventricular white matter hyperintensities.","abstract":"Microcephaly is a fairly common feature observed in children with delayed development, defined as head circumference less than 2 standard deviations below the mean for age and gender. It may be the result of an acquired insult to the brain, such prenatal or perinatal brain injury (congenital infection or hypoxic ischemic encephalopathy), or be a part of a genetic syndrome. There are over 1000 conditions listed in OMIM (Online Mendelian Inheritance in Man) where microcephaly is a key finding; many of these are associated with specific somatic features and non-CNS anomalies. The term primary microcephaly is used when microcephaly and delayed development are the primary features, and they are not part of another recognized syndrome. In this case report, we present the clinical features of siblings (brother and sister) with primary microcephaly and delayed development, and subtle dysmorphic features. Both children had brain MRI studies that showed periventricular and subcortical T2/FLAIR hyperintensities, without signs of white matter volume loss, and no parenchymal calcifications by CT scan. The family was enrolled in a research study for whole exome sequencing of probands and parents. Analysis of variants determined that the children were compound heterozygotes for nonsense mutations, c.277C>T (p.Arg93*) and c.397C>T (p.Arg133*), in the TRMT10A gene. Mutations in this gene have only recently been reported in children with microcephaly and early onset diabetes mellitus. Our report adds to current knowledge of TRMT10A related neurodevelopmental disorders and demonstrates imaging findings suggestive of delayed or abnormal myelination of the white matter in this disorder. Accurate diagnosis through genomic testing, as in the children described here, allows for early detection and management of medical complications, such as diabetes mellitus.","variants":[{"Name":"NM_001134665.3(TRMT10A):c.277C>T (p.Arg93Ter)","Chromosome":"4","Start":"99558120","Stop":"99558120","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1020026,"rule_based_match":true,"evidence_text":"c.277C>T (p.Arg93*)","llm_judgment":"PRESENT","evidence":"c.277C>T (p.Arg93*)","abstract_start":1304,"abstract_end":1323}]}
{"pmid":"34439939","title":"New Approach for Detection of Normal Alternative Splicing Events and Aberrant Spliceogenic Transcripts with Long-Range PCR and Deep RNA Sequencing.","abstract":"RNA sequencing is a promising technique for detecting normal and aberrant RNA isoforms. Here, we present a new single-gene, straightforward 1-day hands-on protocol for detection of splicing alterations with deep RNA sequencing from blood. We have validated our method's accuracy by detecting previously published normal splicing isoforms of <i>STK11</i> gene. Additionally, the same technique was used to provide the first comprehensive catalogue of naturally occurring alternative splicing events of the <i>NBN</i> gene in blood. Furthermore, we demonstrate that our approach can be used for detection of splicing impairment caused by genetic variants. Therefore, we were able to reclassify three variants of uncertain significance: <i>NBN</i>:c.584G>A, <i>STK11</i>:c.863-5_863-3delCTC and <i>STK11</i>:c.615G>A. Due to the simplicity of our approach, it can be incorporated into any molecular diagnostics laboratory for determination of variant's impact on splicing.","variants":[{"Name":"NM_000455.5(STK11):c.615G>A (p.Ala205=)","Chromosome":"19","Start":"1220598","Stop":"1220598","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":181064,"rule_based_match":true,"evidence_text":"<i>STK11</i>:c.615G>A","llm_judgment":"PRESENT","evidence":"<i>STK11</i>:c.615G>A","abstract_start":792,"abstract_end":813},{"Name":"NM_002485.5(NBN):c.584G>A (p.Ser195Asn)","Chromosome":"8","Start":"89978220","Stop":"89978220","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":999955,"rule_based_match":true,"evidence_text":"NBN:c.584G>A","llm_judgment":"PRESENT","evidence":"c.584G>A","abstract_start":745,"abstract_end":753}]}
{"pmid":"34078411","title":"Effects of WNT1 c.110 T>C and c.505G>T mutations on osteoblast differentiation via the WNT1/β-catenin signaling pathway.","abstract":"BACKGROUND: WNT1 c.110 T>C and c.505G>T missense mutations have been identified in patients with osteogenesis imperfecta (OI). Whether these mutations affect osteoblast differentiation remains to be determined. This study aimed to investigate the effects of WNT1 c.110 T>C and c.505G>T mutations on osteoblast function, gene expression, and pathways involved in OI.\nMETHODS: Empty vector (negative control), wild-type WNT1, WNT1 c.110 T>C, WNT1 c.505G>T, and WNT1 c.884C>A (positive control) mutant plasmids were constructed and transfected into preosteoblast (MC3T3-E1) cells to investigate their effect on osteoblast differentiation. The expressions of osteoblast markers, including BMP2, RANKL, osteocalcin, and alkaline phosphatase (ALP), were determined using quantitative real-time polymerase chain reaction (RT-qPCR), western blotting (WB), enzyme-linked immunosorbent assay, and ALP staining assay, respectively. The mRNA and protein expression levels of WNT1 or the expression levels of the relevant proteins involved in the WNT1/β-catenin signaling pathway were also determined using RT-qPCR, WB, and immunofluorescence (IF) assays after the different plasmids were transfected into MC3T3-E1 cells.\nRESULTS: Compared with those in the wild-type group, in the mutation groups, the mRNA and protein expression levels of BMP2 were suppressed, the expressions of osteocalcin and ALP were inhibited, and the mRNA and protein expression levels of RANKL were enhanced in MC3T3-E1 cells. WB and IF assays revealed that the protein expression levels of WNT1 in MC3T3-E1 cells were downregulated in the mutation groups compared with those in the wild-type WNT1 group. Furthermore, the expression levels of nonphosphorylated β-catenin (non-p-β-catenin) and phosphorylated GSK-3β (p-GSK-3β) were downregulated in the mutation groups compared with those in the wild-type group. However, no significant changes in the expression level of non-p-β-catenin or p-GSK-3β were observed in the mutation groups.\nCONCLUSIONS: WNT1 c.110 T>C and c.505G>T mutations may alter the proliferation and osteogenic phenotype of MC3T3-E1 linked to the progression of OI via the inhibition of the WNT1/β-catenin signaling pathway. This is the first study to confirm the effect of WNT1 c.110 T>C and c.505G>T missense mutations on osteoblast differentiation and propose a new molecular mechanism for OI development.","variants":[{"Name":"NM_005430.4(WNT1):c.505G>T (p.Gly169Cys)","Chromosome":"12","Start":"48980570","Stop":"48980570","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2898856,"rule_based_match":true,"evidence_text":"WNT1 c.505G>T","llm_judgment":"PRESENT","evidence":"WNT1 c.505G>T","abstract_start":440,"abstract_end":453}]}
{"pmid":"35284057","title":"Novel homozygous mutation of PNLIP gene in congenital pancreatic lipase deficiency: an extended family study.","abstract":"Introduction: Congenital pancreatic lipase deficiency (MIM 614338) is a rare genetic disorder caused by homozygous mutation in the PNLIP gene. Few cases have been reported worldwide and among them, few cases were genetically confirmed.\nPatients and methods: A 3-year-old girl presented with abundant greasy diarrhea started at the age of 2 years. Work up of steatorrhea including molecular testing of PNLIP gene in the patient and her family was done.\nResults: A novel homozygous variant c.1257G > A (p. Trp419Ter) of the PNLIP gene was detected in the patient. Her parents and two siblings were carriers for the same mutation. Pancreatic enzyme therapy was introduced, and a multidisciplinary team was involved with the education for the need for the lifelong use of pancreatic enzymes, and genetic counseling was carried out. There was a great improvement of steatorrhea with pancreatic enzymes treatment.\nConclusions: PNLIP deficiency should be suspected in patients with steatorrhea who have low pancreatic lipase and an otherwise normal health and appropriate growth.","variants":[{"Name":"NM_000936.4(PNLIP):c.1257G>A (p.Trp419Ter)","Chromosome":"10","Start":"116561559","Stop":"116561559","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":513080,"rule_based_match":true,"evidence_text":"c.1257G > A (p. Trp419Ter)","llm_judgment":"PRESENT","evidence":"c.1257G > A (p. Trp419Ter)","abstract_start":488,"abstract_end":514}]}
{"pmid":"21251206","title":"The study of the effect of splicing mutations in von Willebrand factor using RNA isolated from patients' platelets and leukocytes.","abstract":"BACKGROUND: In von Willebrand factor (VWF) the effect of mutations potentially affecting mRNA processing or splicing is less predictable than that of other mutations (e.g. nonsense or missense substitutions). Bioinformatic tools can provide a valuable means to determine the consequences of potential splice site mutations (PSSM), but functional studies are mandatory to elucidate the true effect of the variation detected.\nOBJECTIVES, PATIENTS AND METHODS: After identification of PSSM in VWD patients, we began a systematic study of their in vivo effect in RNA extracted from the patients' platelets and leukocytes.\nRESULTS AND CONCLUSIONS: Thirteen pairs of primers were designed for full amplification of VWF mRNA by RT-PCR that, after sequencing of aberrant products, enabled elucidation of the PSSM consequences for mRNA processing. This procedure was used to study seven different PSSM identified in four patients demonstrating diverse molecular mechanisms such as exon skipping (c.533-2A>G and c.8155+3G>C) and the activation of a cryptic splice site (c.7730-1G>C). No visible effect was evident for c.1533+15G>A and c.5170+10C>T and the consequence of c.[546G>A;7082-2A>G] was hidden by nonsense-mediated mRNA decay (NMD). Results were compared with in silico predictions of four splice-site analysis tools. We demonstrate selective degradation of VWF mRNA bearing PSSM by NMD for several mutations, which suggests that NMD represents a general mechanism for truncating mutations in VWF. Furthermore, because NMD efficiency varies between cell types, use of RNA from both platelets and leukocytes for in vivo study of VWF PSSM offers complementary results, particularly in cases in which NMD occurs in the allele carrying the mutation.","variants":[{"Name":"NM_000552.5(VWF):c.5170+10C>T","Chromosome":"12","Start":"6016744","Stop":"6016744","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":106295,"rule_based_match":true,"evidence_text":"c.5170+10C>T","llm_judgment":"PRESENT","evidence":"c.5170+10C>T","abstract_start":1125,"abstract_end":1137}]}
{"pmid":"17546645","title":"Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing.","abstract":"Human MYO15A is located on chromosome 17p11.2, has 66 exons and encodes unconventional myosin XVA. Recessive mutations of MYO15A are associated with profound, nonsyndromic hearing loss DFNB3 in humans, and deafness and circling behavior in shaker 2 mice. In the inner ear, this motor protein is necessary for the development of hair cell stereocilia, which are actin-filled projections on the apical surface and the site of mechanotransduction of sound. The longest isoform of myosin XVA has 3,530 amino acid residues. Two isoform classes of MYO15A are distinguished by the presence or absence of 1,203 residues preceding the motor domain encoded by alternatively-spliced exon 2. It is not known whether this large N-terminal extension of myosin XVA is functionally necessary for hearing. We ascertained approximately 600 consanguineous families segregating hereditary hearing loss as a recessive trait and found evidence of linkage of markers at the DFNB3 locus to hearing loss in 38 of these families ascertained in Pakistan (n=30), India (n=6), and Turkey (n=2). In this study, we describe 16 novel recessive mutations of MYO15A associated with severe to profound hearing loss segregating in 20 of these DFNB3-linked families. Importantly, two homozygous mutant alleles-c.3313G>T (p.E1105X) and c.3334delG (p.G1112fsX1124) of MYO15A-located in exon 2 are associated with severe to profound hearing loss segregating in two families. These data demonstrate that isoform 1, containing the large N-terminal extension, is also necessary for normal hearing.","variants":[{"Name":"NM_016239.4(MYO15A):c.3313G>T (p.Glu1105Ter)","Chromosome":"17","Start":"18122113","Stop":"18122113","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":21996,"rule_based_match":true,"evidence_text":"c.3313G>T (p.E1105X)","llm_judgment":"PRESENT","evidence":"c.3313G>T (p.E1105X)","abstract_start":1273,"abstract_end":1293}]}
{"pmid":"24335149","title":"Genetic analysis of GHR should contain sequencing of all coding exons and specific intron sequences, and screening for exon deletions.","abstract":"BACKGROUND: The work-up of patients with clinical and/or biochemical features of growth hormone insensitivity (GHI) usually contains genetic analysis of the growth hormone receptor (GHR) gene, and if negative, of STAT5B, IGFALS and IGF1. In a previous report we described 2 siblings presenting with short stature, low IGF-1 levels, elevated GH secretion and no increase of IGF-1 after 1 week of GH administration. Repeated analysis of the GHR showed no abnormalities; however, further testing revealed a heterozygous STAT5B defect in both siblings.\nSUBJECTS AND METHODS: Two boys of Surinam-Hindustan origin showed growth failure up to the age of 6-7 years, followed by partial catch-up growth associated with increasing body mass index. Reanalysis of GHR including published intronic sequences was performed on the patients' DNA collected 7 years earlier.\nRESULTS: The heterozygous STAT5B variant proved to be functionally benign. A homozygous intronic mutation of the GHR, c.618+792A>G (IVS6+792A>G), was subsequently found, resulting in the activation of pseudoexon 6ψ, and explaining the GHI phenotype of the patients.\nCONCLUSION: An intronic GHR mutation should be considered in all patients with signs of GHI and no coding exon mutations, even if the phenotype is mild and even if other genetic variants have been found.","variants":[{"Name":"NM_000163.5(GHR):c.618+792A>G","Chromosome":"5","Start":"42700794","Stop":"42700794","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":23694,"rule_based_match":true,"evidence_text":"c.618+792A>G (IVS6+792A>G)","llm_judgment":"PRESENT","evidence":"c.618+792A>G (IVS6+792A>G)","abstract_start":975,"abstract_end":1001}]}
{"pmid":"29674119","title":"NMNAT1 E257K variant, associated with Leber Congenital Amaurosis (LCA9), causes a mild retinal degeneration phenotype.","abstract":"NMNAT1 (nicotinamide mononucleotide adenylyltransferase 1) encodes a rate-limiting enzyme that catalyzes the biosynthesis of NAD<sup>+</sup> and plays a role in neuroprotection. Mutations in NMNAT1 have been identified to cause a recessive, non-syndromic early form of blindness genetically defined as Leber Congenital Amaurosis 9 (LCA9). One of the most common alleles reported so far in NMNAT1 is the c.769G > A (E257K) missense mutation, which occurs in 70% of all LCA9 cases. However, given its relatively high population frequency and the observation of individuals with homozygous E257K variant without phenotype, the pathogenicity of this allele has been questioned. To address this issue, we have studied the pathogenic effects of this allele by generating a knock-in mouse model. Interestingly, no obvious morphological or functional defects are observed in Nmnat1 E257K homozygous mice up to one year old, even after light-damage. Together with the previous clinical reports, we propose that the E257K allele is a weak hypomorphic allele that has significantly reduced penetrance in the homozygous state. In contrast, compound heterozygous Nmnat1<sup>E257K/-</sup> mice exhibit photoreceptor defects which are exacerbated upon exposure to light. Furthermore, retina tissue- specific Nmnat1 conditional knockout mice exhibit photoreceptor degeneration before the retina has terminally differentiated. These findings suggest that NMNAT1 plays an important role in photoreceptors and is likely involved in both retinal development and maintenance of photoreceptor integrity.","variants":[{"Name":"NM_022787.4(NMNAT1):c.769G>A (p.Glu257Lys)","Chromosome":"1","Start":"9982630","Stop":"9982630","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45795,"rule_based_match":true,"evidence_text":"c.769G > A (E257K)","llm_judgment":"PRESENT","evidence":"c.769G > A (E257K)","abstract_start":403,"abstract_end":421}]}
{"pmid":"27999334","title":"Hybridization Capture-Based Next-Generation Sequencing to Evaluate Coding Sequence and Deep Intronic Mutations in the NF1 Gene.","abstract":"Neurofibromatosis 1 (NF1) is one of the most common genetic disorders and is caused by mutations in the <i>NF1</i> gene. <i>NF1</i> gene mutational analysis presents a considerable challenge because of its large size, existence of highly homologous pseudogenes located throughout the human genome, absence of mutational hotspots, and diversity of mutations types, including deep intronic splicing mutations. We aimed to evaluate the use of hybridization capture-based next-generation sequencing to screen coding and noncoding <i>NF1</i> regions. Hybridization capture-based next-generation sequencing, with genomic DNA as starting material, was used to sequence the whole <i>NF1</i> gene (exons and introns) from 11 unrelated individuals and 1 relative, who all had NF1. All of them met the NF1 clinical diagnostic criteria. We showed a mutation detection rate of 91% (10 out of 11). We identified eight recurrent and two novel mutations, which were all confirmed by Sanger methodology. In the Sanger sequencing confirmation, we also included another three relatives with NF1. Splicing alterations accounted for 50% of the mutations. One of them was caused by a deep intronic mutation (c.1260 + 1604A > G). Frameshift truncation and missense mutations corresponded to 30% and 20% of the pathogenic variants, respectively. In conclusion, we show the use of a simple and fast approach to screen, at once, the entire <i>NF1</i> gene (exons and introns) for different types of pathogenic variations, including the deep intronic splicing mutations.","variants":[{"Name":"NM_001042492.3(NF1):c.1260+1604A>G","Chromosome":"17","Start":"31203089","Stop":"31203089","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":420770,"rule_based_match":true,"evidence_text":"c.1260 + 1604A > G","llm_judgment":"PRESENT","evidence":"c.1260 + 1604A > G","abstract_start":1186,"abstract_end":1204}]}
{"pmid":"31734026","title":"Analysis of spinal muscular atrophy-like patients by targeted resequencing.","abstract":"BACKGROUND: Several effective therapies have been developed for spinal muscular atrophy (SMA), but there are multiple diseases that show SMA-like symptoms, necessitating efficient differential genetic diagnostic methods. Advancements in next-generation sequencing (NGS) technology have facilitated the successful diagnosis of many undiagnosed genetic diseases. Here, we applied NGS along with conventional methods for the molecular diagnosis of undiagnosed patients with lower motor neuron (LMN) symptoms who were initially suspected to have SMA.\nMETHODS: We enrolled 157 patients with LMN symptoms who visited the Institute of Medical Genetics, Tokyo Women's Medical University, between 2005 and 2016. We excluded 86 patients diagnosed with SMA after confirming the causative SMN1 gene deletion or variants. Finally, we examined 12 undiagnosed patients from eight families by targeted resequencing using NGS. Variants were selected on the basis of literature search and databases, and mutations in a gene where loss of function is a known mechanism of disease were considered as pathogenic. Candidate variants were validated by Sanger sequencing.\nRESULTS: We detected novel variants for three patients from two families. Patients 1 and 2 (siblings) showed compound heterozygous TTN variants (c.6621delG, p.W2207Cfs*28 and c.23718T>A, p.F7906L), while patient 3 displayed compound heterozygous KIF1A variants of (c.3871C>T, p.R1291C and c.3898G>A, p.V1300M).\nCONCLUSIONS: We detected appropriate variants using our approach of obtaining candidate pathogenic variants by targeted resequencing through NGS and narrowed down the variants in light of patient clinical symptoms. We successfully identified novel causative variants in three undiagnosed patients, which indicated the effectiveness of our approach.","variants":[{"Name":"NM_001244008.2(KIF1A):c.3871C>T (p.Arg1291Cys)","Chromosome":"2","Start":"240740088","Stop":"240740088","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":691098,"rule_based_match":true,"evidence_text":"c.3871C>T, p.R1291C","llm_judgment":"PRESENT","evidence":"c.3871C>T, p.R1291C","abstract_start":1413,"abstract_end":1432}]}
{"pmid":"19332161","title":"Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family.","abstract":"Homozygous mutations in the ASPM gene are a major cause of autosomal recessive primary microcephaly (MCPH). Here we report on a consanguineous Algerian family in which three out of five children presented with severe microcephaly, simplified cortical gyration, mild to severe mental retardation and low to low-normal birth weight. Given the parental consanguinity with the unaffected parents being third cousins once removed, the most probable pattern of inheritance was autosomal recessive. Linkage and mutational analyses identified compound heterozygous truncating mutations within the ASPM gene segregating with MCPH (c.2389C>T [p.Arg797X] and c.7781_7782delAG [p.Gln2594fsX6]). These results highlight some of the pitfalls of genetic analysis in consanguineous families. They also suggest that low birth weight may be a feature of MCPH, a finding that needs confirmation, and confirm that ASPM mutations are associated with simplified cortical gyration.","variants":[{"Name":"NM_018136.5(ASPM):c.2389C>T (p.Arg797Ter)","Chromosome":"1","Start":"197133380","Stop":"197133380","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20004,"rule_based_match":true,"evidence_text":"c.2389C>T [p.Arg797X]","llm_judgment":"PRESENT","evidence":"c.2389C>T [p.Arg797X]","abstract_start":622,"abstract_end":643}]}
{"pmid":"21644213","title":"Identification of novel and recurrent mutations in the calcium binding type III repeats of cartilage oligomeric matrix protein in patients with pseudoachondroplasia.","abstract":"Pseudoachondroplasia is an autosomal dominant osteochondrodysplasia characterized by disproportionate short stature, joint laxity, and early onset osteoarthrosis. Pseudoachondroplasia is caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). We looked for mutations in the COMP gene in three sporadic Chinese pseudoachondroplasia patients and identified two novel mutations, c.1189G>T (p.D397Y) and c.1220G>A (p.C407Y), and one recurrent mutation, c.1318G>C (p.G440R), in the calcium binding type III repeats of COMP. This study confirms the relationship between mutations of the COMP gene and clinical findings of pseudoachondroplasia; it also provides evidence for the importance of the calcium binding domains to the functioning of COMP.","variants":[{"Name":"NM_000095.3(COMP):c.1318G>C (p.Gly440Arg)","Chromosome":"19","Start":"18786136","Stop":"18786136","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":800128,"rule_based_match":true,"evidence_text":"c.1318G>C (p.G440R)","llm_judgment":"PRESENT","evidence":"c.1318G>C (p.G440R)","abstract_start":478,"abstract_end":497},{"Name":"NM_000095.3(COMP):c.1220G>A (p.Cys407Tyr)","Chromosome":"19","Start":"18786566","Stop":"18786566","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2905427,"rule_based_match":true,"evidence_text":"c.1220G>A (p.C407Y)","llm_judgment":"PRESENT","evidence":"c.1220G>A (p.C407Y)","abstract_start":429,"abstract_end":448}]}
{"pmid":"25188413","title":"Novel genetic mutations in a sporadic port-wine stain.","abstract":"IMPORTANCE Port-wine stains (PWSs) are common congenital cutaneous capillary malformations. A somatic GNAQ mutation was recently identified in patients with sporadic PWSs and Sturge-Weber syndrome. However, subsequent studies to confirm or extend this observation are lacking.OBSERVATIONS We report a long-standing, unilateral facial PWS of a man in his early 70s confirmed by histopathological analysis. Staged surgical excision of the vascular malformation was performed, and genomic DNA was extracted from the vascular malformation specimen and normal skin. Targeted next-generation sequencing of the coding sequence of 275 known cancer genes including GNAQ was performed in both specimens. A single-nucleotide variant(c.548G>A, p.Arg183Gln) in GNAQ was identified in the PWS-affected tissue but not in the normal skin sample. In addition, this sequencing approach uncovered several additional novel somatic mutations in the genes SMARCA4, EPHA3, MYB, PDGFR-β, and PIK3CA.CONCLUSIONS AND RELEVANCE Our findings confirm the presence of somatic mutations inGNAQ in the affected skin of a patient with congenital PWS, as well as alterations in several other novel genes of possible importance in the pathogenesis of PWS that may also offer substantial therapeutic targets.","variants":[{"Name":"NM_002072.5(GNAQ):c.548G>A (p.Arg183Gln)","Chromosome":"9","Start":"77797577","Stop":"77797577","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":59839,"rule_based_match":true,"evidence_text":"c.548G>A, p.Arg183Gln","llm_judgment":"PRESENT","evidence":"c.548G>A, p.Arg183Gln","abstract_start":722,"abstract_end":743}]}
{"pmid":"30507891","title":"Clinical and Genetic Features of Patients with Juvenile Amyotrophic Lateral Sclerosis with Fused in Sarcoma (FUS) Mutation.","abstract":"BACKGROUND Juvenile amyotrophic lateral sclerosis (JALS) is a rare form of motor neuron disease and occurs before 25 years of age. Only a few cases of juvenile-onset ALS have been reported. MATERIAL AND METHODS To study genetic and clinicopathological features in Chinese patients with juvenile ALS, we retrospectively reviewed ALS patients in our hospital and screened out 2 patients with disease onset before the age of 25. Genetic analysis was carried out with next-generation sequencing (NGS) to identify ALS causative genes. Sanger sequencing was used to validate identified variants. The clinical, electrophysiological, and pathological data were summarized. RESULTS A novel frameshift mutation c.1510dupG (p.G505Wfs*12) was found in Patient One using next-generation sequencing (NGS). Patient Two had a reported pathogenic mutation c.C1483T(p.R495X) with NGS. The mother of Patient Two carried the same mutation as her son and disease onset was at 1.5 years after the death of her son. CONCLUSIONS We identified a novel frameshift mutation associated with JALS. JALS and generally typical ALS, with the same FUS mutation, can appear in a family and present a phenomenon of anticipation. For diagnosis of central nervous system degeneration in adolescents with bulbar symptoms, great attention should be paid to JALS.","variants":[{"Name":"NM_004960.4(FUS):c.1483C>T (p.Arg495Ter)","Chromosome":"16","Start":"31191052","Stop":"31191052","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38662,"rule_based_match":false,"evidence_text":"c.C1483T(p.R495X)","llm_judgment":"PRESENT","evidence":"c.C1483T(p.R495X)","abstract_start":839,"abstract_end":856}]}
{"pmid":"22848519","title":"Sequence and copy number analyses of HEXB gene in patients affected by Sandhoff disease: functional characterization of 9 novel sequence variants.","abstract":"Sandhoff disease (SD) is a lysosomal disorder caused by mutations in the HEXB gene. To date, 43 mutations of HEXB have been described, including 3 large deletions. Here, we have characterized 14 unrelated SD patients and developed a Multiplex Ligation-dependent Probe Amplification (MLPA) assay to investigate the presence of large HEXB deletions. Overall, we identified 16 alleles, 9 of which were novel, including 4 sequence variation leading to aminoacid changes [c.626C>T (p.T209I), c.634C>A (p.H212N), c.926G>T (p.C309F), c.1451G>A (p.G484E)] 3 intronic mutations (c.1082+5G>A, c.1242+1G>A, c.1169+5G>A), 1 nonsense mutation c.146C>A (p.S49X) and 1 small in-frame deletion c.1260_1265delAGTTGA (p.V421_E422del). Using the new MLPA assay, 2 previously described deletions were identified. In vitro expression studies showed that proteins bearing aminoacid changes p.T209I and p.G484E presented a very low or absent activity, while proteins bearing the p.H212N and p.C309F changes retained a significant residual activity. The detrimental effect of the 3 novel intronic mutations on the HEXB mRNA processing was demonstrated using a minigene assay. Unprecedentedly, minigene studies revealed the presence of a novel alternative spliced HEXB mRNA variant also present in normal cells. In conclusion, we provided new insights into the molecular basis of SD and validated an MLPA assay for detecting large HEXB deletions.","variants":[{"Name":"NM_000521.4(HEXB):c.146C>A (p.Ser49Ter)","Chromosome":"5","Start":"74685406","Stop":"74685406","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":543460,"rule_based_match":true,"evidence_text":"c.146C>A (p.S49X)","llm_judgment":"PRESENT","evidence":"c.146C>A (p.S49X)","abstract_start":630,"abstract_end":647},{"Name":"NM_000521.4(HEXB):c.1082+5G>A","Chromosome":"5","Start":"74715695","Stop":"74715695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":300240,"rule_based_match":true,"evidence_text":"c.1082+5G>A","llm_judgment":"PRESENT","evidence":"c.1082+5G>A","abstract_start":570,"abstract_end":581}]}
{"pmid":"35033039","title":"Novel variants in PDE6A and PDE6B genes and its phenotypes in patients with retinitis pigmentosa in Chinese families.","abstract":"BACKGROUND: Retinitis pigmentosa (RP) is a genetically heterogeneous disease with 89 causative genes identified to date. However, only approximately 60% of RP cases genetically solved to date, predicating that many novel disease-causing variants are yet to be identified. The purpose of this study is to identify novel variants in PDE6A and PDE6B genes and present its phenotypes in patients with retinitis pigmentosa in Chinese families.\nMETHODS: Five retinitis pigmentosa patients with PDE6A variants and three with PDE6B variants were identified through a hereditary eye disease enrichment panel (HEDEP), all patients' medical and ophthalmic histories were collected, and ophthalmological examinations were performed, followed by an analysis of the possible causative variants. Sanger sequencing was used to verify the variants.\nRESULTS: We identified 20 variants in eight patients: 16 of them were identified in either PDE6A or PDE6B in a compound heterozygous state. Additional four heterozygous variants were identified in the genes ADGRA3, CA4, OPTN, RHO. Two novel genetic changes in PDE6A were identified (c.1246G > A and c.1747 T > A), three novel genetic changes in PDE6B were identified (c.401 T > C, c.2293G > C and c.1610-1612del), out of the novel identified variants one was most probably non-pathogenic (c.2293G > C), all other novel variants are pathogenic. Additional variant was identified in CA4 and RHO, which can cause ADRP (c.243G > A, c.688G > A). In addition, a novel variant in ADGRA3 was identified (c.921-1G > A).\nCONCLUSIONS: This study reveals novel and known variants in PDE6A and PDE6B genes in Chinese families with autosomal recessive RP, and expands the clinical and genetic findings of photoreceptor-specific enzyme deficiencies.","variants":[{"Name":"NM_000283.4(PDE6B):c.401T>C (p.Leu134Pro)","Chromosome":"4","Start":"626027","Stop":"626027","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":990258,"rule_based_match":true,"evidence_text":"c.401 T > C","llm_judgment":"PRESENT","evidence":"c.401 T > C","abstract_start":1200,"abstract_end":1211}]}
{"pmid":"23337730","title":"Varied clinical presentations of seven patients with mutations in CYP11A1 encoding the cholesterol side-chain cleavage enzyme, P450scc.","abstract":"CONTEXT: The cholesterol side-chain cleavage enzyme P450scc, encoded by CYP11A1, converts cholesterol to pregnenolone to initiate steroidogenesis. P450scc deficiency can disrupt adrenal and gonadal steroidogenesis, resembling congenital lipoid adrenal hyperplasia clinically and hormonally; only 12 such patients have been reported previously.\nOBJECTIVE: We sought to expand clinical and genetic experience with P450scc deficiency.\nPATIENTS AND METHODS: We sequenced candidate genes in 7 children with adrenal insufficiency who lacked disordered sexual development. P450scc missense mutations were recreated in the F2 vector, which expresses the fusion protein P450scc-Ferredoxin Reductase-Ferredoxin. COS-1 cells were transfected, production of pregnenolone was assayed, and apparent kinetic parameters were calculated. Previously described P450scc mutants were assayed in parallel.\nRESULTS: Four of five Bedouin children in one kindred were compound heterozygotes for mutations c.694C>T (Arg232Stop) and c.644T>C (Phe215Ser). Single-nucleotide polymorphism analysis confirmed segregation of these mutations. The fifth kindred member and another Bedouin patient presented in infancy and were homozygous for Arg232Stop. A patient from Fiji presenting in infancy was homozygous for c.358T>C (Arg120Stop). All mutations are novel. As assayed in the F2 fusion protein, P450scc Phe215Ser retained 2.5% of wild-type activity; previously described mutants Leu141Trp and Ala269Val had 2.6% and 12% of wild-type activity, respectively, and Val415Glu and c.835delA lacked detectable activity.\nCONCLUSIONS: Although P450scc is required to produce placental progesterone required to maintain pregnancy, severe mutations in P450scc are compatible with term gestation; milder P450scc mutations may present later without disordered sexual development. Enlarged adrenals usually distinguish steroidogenic acute regulatory protein deficiency from P450scc deficiency, but only DNA sequencing is definitive.","variants":[{"Name":"NM_000781.3(CYP11A1):c.694C>T (p.Arg232Ter)","Chromosome":"15","Start":"74343924","Stop":"74343924","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1312496,"rule_based_match":true,"evidence_text":"c.694C>T (Arg232Stop)","llm_judgment":"PRESENT","evidence":"c.694C>T (Arg232Stop)","abstract_start":980,"abstract_end":1001}]}
{"pmid":"31878136","title":"Pathogenicity Reclasssification of","abstract":"A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two <i>RPE65</i> missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these <i>RPE65</i> variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic <i>RPE65</i> variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines.","variants":[{"Name":"NM_000329.3(RPE65):c.247T>C (p.Phe83Leu)","Chromosome":"1","Start":"68444882","Stop":"68444882","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1441465,"rule_based_match":true,"evidence_text":"c.247T>C (p.Phe83Leu)","llm_judgment":"PRESENT","evidence":"c.247T>C (p.Phe83Leu)","abstract_start":356,"abstract_end":377},{"Name":"NM_000329.3(RPE65):c.560G>A (p.Gly187Glu)","Chromosome":"1","Start":"68440936","Stop":"68440936","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":789995,"rule_based_match":true,"evidence_text":"c.560G>A (p.Gly187Glu)","llm_judgment":"PRESENT","evidence":"c.560G>A (p.Gly187Glu)","abstract_start":382,"abstract_end":404}]}
{"pmid":"30588852","title":"A novel CFTR gene variant - p.Tyr517* associated with cystic fibrosis: a case report.","abstract":"INTRODUCTION: Cystic fibrosis (CF) is a genetic disease usually diagnosed by clinical findings and abnormal sweat chloride testing.\nCASE REPORT: We report a case of an 18-month-old Indian female with clinical findings suggestive of CF referred for genetic confirmation. The CFTR gene was sequenced for 23 mutations as per American College of Medical Genetics (ACMG) guidelines for CF and showed presence of a known common heterozygous delF508 (c.1521_1523delCTT, p.Phe508 del) variant. In addition to delF508 variant, exon 10 of CFTR gene also showed a novel variant c.1551C > G, p.Tyr517*, which was classified as \"likely pathogenic\" based on recent ACMG variant classification guidelines. The presence of compound heterozygous pathogenic variants along with classical clinical findings, confirmed the diagnosis of CF in this patient.\nCONCLUSION: The novel pathogenic variants (missense/nonsense/deletion/duplication) in CFTR gene are often identified and are associated with CF, thus highlighting the need of comprehensive complete CFTR gene analysis.","variants":[{"Name":"NM_000492.4(CFTR):c.1551C>G (p.Tyr517Ter)","Chromosome":"7","Start":"117559622","Stop":"117559622","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1668753,"rule_based_match":true,"evidence_text":"c.1551C > G, p.Tyr517*","llm_judgment":"PRESENT","evidence":"c.1551C > G, p.Tyr517*","abstract_start":567,"abstract_end":589}]}
{"pmid":"22487817","title":"Rapid prenatal genetic diagnosis of a fetus with a high risk for Morquio A syndrome","abstract":"OBJECTIVE: To provide rapid and accurate prenatal genetic diagnosis for a fetus with high risk of Morquio A syndrome.\nMETHODS: Based on ascertained etiology of the proband and genotypes of the parents, particular mutations of the GALNS gene were screened at 10th gestational week with amplification refractory mutation system (ARMS), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing.\nRESULTS: DHPLC screening has identified abnormal double peaks in the PCR products of exons 1 and 10, whilst only a single peak was detected in normal controls. Amplification of ARMS specific primers derived a specific product for the fetus's gene, whilst no similar product was detected in normal controls. Sequencing of PCR products confirmed that exons 1 and 10 of the GALNS gene from the fetus contained a heterozygous paternal c.106-111 del (p.L36-L37 del) deletion and a heterozygous maternal c.1097 T>C (p.L366P) missense mutation, which resulted in a compound heterozygote status.\nCONCLUSION: The fetus was diagnosed with Morquio A syndrome and a genotype similar to the proband. Termination of the pregnancy was recommended. Combined ARMS, DHPLC and DNA sequencing are effective for rapid and accurate prenatal diagnosis for fetus with a high risk for Morquio A syndrome. Such methods are particularly suitable for early diagnosis when pathogenesis is clear. Furthermore, combined ARMS and DHPLC are suitable for rapid processing of large numbers of samples for the identification of new mutations.","variants":[{"Name":"NM_000512.5(GALNS):c.1097T>C (p.Leu366Pro)","Chromosome":"16","Start":"88826744","Stop":"88826744","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":985762,"rule_based_match":true,"evidence_text":"c.1097 T>C (p.L366P)","llm_judgment":"PRESENT","evidence":"c.1097 T>C (p.L366P)","abstract_start":918,"abstract_end":938}]}
{"pmid":"36101825","title":"Intermittent neurologic decompensation: An underrecognized presentation of tyrosine hydroxylase deficiency.","abstract":"Tyrosine hydroxylase deficiency (THD) is a treatable inborn error of dopamine biosynthesis caused by mutations in <i>TH</i>. Two presentations are described. Type A, milder, presents after 12 months of age with progressive hypokinesis and rigidity. Type B presents before 12 months as a progressive complex encephalopathy. We report a girl with mild THD who had recurrent episodes of neurological decompensations. Before the first episode, she had normal development except for mild head tremor. Episodes occurred at 12, 19, and 25 months of age. After viral infections or vaccination, she developed lethargy, worsened tremor, language, and motor regression including severe axial hypotonia, recuperating over several weeks of intensive rehabilitation but with residual tremor and mild lower limb spasticity. Basal ganglia imaging was normal. Exome sequencing revealed two missense variants of uncertain significance in <i>TH</i>: c.1147G>T and c.1084G>A. Both have low gnomAD allele frequencies and in silico, are predicted to be deleterious. Cerebrospinal fluid analysis showed low homovanillic acid (HVA, 160 nmol/L, reference 233-938) and low HVA/5-hydroxyindolacetic acid molar ratio (1.07, reference .5-3.5). She responded rapidly to L-Dopa/carbidopa without further episodes. Literature review revealed four other THD patients who had a total of seven episodes of marked hypotonia and motor regression following infections, occurring between ages 12 months and 6 years. All improved with L-Dopa/carbidopa treatment. Intermittent THD is treatable, important for genetic counseling, and should be considered after even a single episode of marked hypotonia with recuperation over weeks, especially in patients with preexisting tremor, dystonia, or rigidity.","variants":[{"Name":"NM_000360.4(TH):c.1147G>T (p.Gly383Trp)","Chromosome":"11","Start":"2165721","Stop":"2165721","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2738301,"rule_based_match":true,"evidence_text":"c.1147G>T","llm_judgment":"PRESENT","evidence":"c.1147G>T","abstract_start":931,"abstract_end":940}]}
{"pmid":"23000314","title":"Biochemical and molecular diagnosis of tyrosinemia type I with two novel FAH mutations in a Hong Kong chinese patient: recommendation for expanded newborn screening in Hong Kong.","abstract":"OBJECTIVES: Tyrosinemia type I is an autosomal recessive disorder in tyrosine metabolism. In areas without expanded newborn screening, patients present with acute hepatorenal failure in early infancy. Diagnosis can be elusive when clinical presentation is non-specific and biochemical abnormalities are masked by secondary changes. This is the first Hong Kong Chinese report.\nDESIGN AND METHODS: A two-month-old Chinese male infant with unremarkable antenatal and postnatal history presented with progressive abdominal distension for three days. He suffered from end-stage liver failure, hypoglycemia and hepatic encephalopathy. Diagnostic work-up was complicated starting from rule-out sepsis, intestinal obstruction, volvulus, peritonitis, septic ileus, poisoning to metabolic diseases. Clinical, biochemical and genetic data was described.\nRESULTS: The patient showed increases in multiple plasma amino acids including tyrosine, phenylalanine and methionine, and hyper-excretions of 4-hydroxyphenyl-acetate, -pyruvate, and -lactate, as well as N-acetyltyrosine which could be seen in liver failure due to both tyrosinemia type I and non-metabolic conditions. Because of the volatile nature, succinylacetone was almost undetectable. The diagnosis was confirmed by genetic analysis of FAH with two novel mutations, viz. NM_000137.2:c.1063-1G>A and NM_000137.2:c.1035_1037del. Living-related liver transplantation was done. However, the patient still suffered many complications after the severe metabolic insult with hypoxic ischemic encephalopathy, cerebral atrophy, global developmental delay and cortical visual impairment.\nCONCLUSIONS: Because of the lack of expanded newborn screening in Hong Kong, this child unfortunately presented in the most severe form of tyrosinemia type I. Expanded newborn screening can save life and reduce the burden of diagnostic complexity. This illustrates the need for expanded newborn screening in Hong Kong.","variants":[{"Name":"NM_000137.4(FAH):c.1063-1G>A","Chromosome":"15","Start":"80181041","Stop":"80181041","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":852784,"rule_based_match":true,"evidence_text":"NM_000137.2:c.1063-1G>A","llm_judgment":"PRESENT","evidence":"NM_000137.2:c.1063-1G>A","abstract_start":1321,"abstract_end":1344}]}
{"pmid":"11668628","title":"Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia.","abstract":"Sitosterolemia is an autosomal recessive disorder caused by mutations in two adjacent genes encoding coordinately regulated ATP binding cassette (ABC) half transporters (ABCG5 and ABCG8). In this paper we describe three novel mutations causing sitosterolemia: 1) a frameshift mutation (c.336-337insA) in ABCG5 that results in premature termination of the protein at amino acid 197; 2) a missense mutation that changes a conserved residue c.1311C>G; N437K) in ABCG5 and 3) a splice site mutation in ABCG8 (IVS1-2A>G). This study expands the spectrum of the ABCG5 and ABCG8 mutations that cause sitosterolemia. Nine nonsynonymous polymorphisms are also reported: I523V, C600Y, Q604E, and M622V in ABCG5; and D19H, Y54C, T400K, A632V, and Y641F in ABCG8.","variants":[{"Name":"NM_022436.3(ABCG5):c.1311C>G (p.Asn437Lys)","Chromosome":"2","Start":"43823926","Stop":"43823926","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1925284,"rule_based_match":true,"evidence_text":"c.1311C>G; N437K","llm_judgment":"PRESENT","evidence":"c.1311C>G; N437K","abstract_start":438,"abstract_end":454}]}
{"pmid":"24135642","title":"Mutational spectrum of Xeroderma pigmentosum group A in Egyptian patients.","abstract":"Xeroderma pigmentosum (XP) is a rare autosomal recessive hereditary disease characterized by hyperphotosensitivity, DNA repair defects and a predisposition to skin cancers. The most frequently occurring type worldwide is the XP group A (XPA). There is a close relationship between the clinical features that ranged from severe to mild form and the mutational site in XPA gene. The aim of this study is to carry out the mutational analysis in Egyptian patients with XP-A. This study was carried out on four unrelated Egyptian XP-A families. Clinical features were examined and direct sequencing of the coding region of XPA gene was performed in patients and their parents. Direct sequencing of the whole coding region of the XPA gene revealed the identification of two homozygous nonsense mutations: (c.553C >T; p.(Gln185)) and (c.331G>T; p.(Glu111)), which create premature, stop codon and a homodeletion (c.374delC: p.Thr125Ilefs 15) that leads to frameshift and premature translation termination. We report the identification of one novel XPA gene mutation and two known mutations in four unrelated Egyptian families with Xermoderma pigmentosum. All explored patients presented severe neurological abnormalities and have mutations located in the DNA binding domain. This report gives insight on the mutation spectrum of XP-A in Egypt. This would provide a valuable tool for early diagnosis of this severe disease.","variants":[{"Name":"NM_000380.4(XPA):c.331G>T (p.Glu111Ter)","Chromosome":"9","Start":"97689592","Stop":"97689592","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":545406,"rule_based_match":true,"evidence_text":"c.331G>T (p.Glu111)","llm_judgment":"PRESENT","evidence":"c.331G>T","abstract_start":828,"abstract_end":836},{"Name":"NM_000380.4(XPA):c.553C>T (p.Gln185Ter)","Chromosome":"9","Start":"97687098","Stop":"97687098","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":262038,"rule_based_match":true,"evidence_text":"c.553C >T; p.(Gln185)","llm_judgment":"PRESENT","evidence":"c.553C >T; p.(Gln185)","abstract_start":800,"abstract_end":821}]}
{"pmid":"28397221","title":"Mutation analysis and prenatal diagnosis for a case of spinal muscular atrophy with respiratory distress type 1","abstract":"OBJECTIVE: To detect potential mutation of immunoglobulin μ -binding protein 2 (IGHMBP2) gene in a two-year-old patient with spinal muscular atrophy with respiratory distress type 1 (SMARD1).\nMETHODS: Genomic DNA was extracted from peripheral blood sample from the patient and her parents, as well as cord blood sample from the fetus. Potential mutations of the coding region of the IGHMBP2 gene was detected with PCR and Sanger sequencing.\nRESULTS: A heterozygous missense mutation c.1060G>A and a frameshift mutation c.2356delG was detected in the patient. The mutations were respectively inherited from her father and mother. Neither mutation was found in DNA derived from the cord blood sample.\nCONCLUSION: The missense mutation c.1060G>A and frameshift mutation c.2356delG were probably causative for the disease. Analysis of the IGHMBP2 gene has provided an important clue for the etiology and prenatal diagnosis of SMARD1.","variants":[{"Name":"NM_002180.3(IGHMBP2):c.2356del (p.Ala786fs)","Chromosome":"11","Start":"68936834","Stop":"68936834","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":625254,"rule_based_match":true,"evidence_text":"c.2356delG","llm_judgment":"PRESENT","evidence":"c.2356delG","abstract_start":519,"abstract_end":529},{"Name":"NM_002180.3(IGHMBP2):c.1060G>A (p.Gly354Ser)","Chromosome":"11","Start":"68917883","Stop":"68917883","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":272214,"rule_based_match":true,"evidence_text":"c.1060G>A","llm_judgment":"PRESENT","evidence":"c.1060G>A","abstract_start":483,"abstract_end":492}]}
{"pmid":"36825045","title":"Spectrum of Pediatric to Early Adulthood","abstract":"Background: <i>POLR3A</i> pathogenic variants are associated with hypomyelination, hypodontia, hypogonadism, and movement disorders.\nCases: We describe the range of movement disorders seen in six patients (four female, two male) with <i>POLR3A</i> variants [three novel (c.2214del, c.3775G>A, c.3905G>T) and six previously reported (c.760C>T, c.1771-7C>G, c.1909+22G>A, c.2005C>T, c.2422C>T, c.3337-11T>C)]. Patient 1 presented with a neonatal progeroid syndrome and developed parkinsonism, dystonia, ataxia, and spasticity. Patient 2 presented with infant-onset rapidly progressive chorea, and dystonia. Three patients (patients 3, 5, 6) presented predominantly with ataxia in combination with spasticity and dystonia. Patient 4 developed segmental dystonia during adolescence and ataxia in early adulthood. Four patients had vertical gaze impairment. The most common brain MRI abnormality was T2-weighted/FLAIR hyperintensity of the superior cerebellar peduncles and midbrain.\nConclusion: <i>POLR3A</i>-related disorders exhibit significant phenotypic pleomorphism. Vertical gaze dysfunction and T2-weighted/FLAIR hyperintensity of the superior cerebellar peduncles and midbrain may be useful signs suggestive of this condition.","variants":[{"Name":"NM_007055.4(POLR3A):c.3337-11T>C","Chromosome":"10","Start":"77984023","Stop":"77984023","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":540042,"rule_based_match":true,"evidence_text":"c.3337-11T>C","llm_judgment":"PRESENT","evidence":"c.3337-11T>C","abstract_start":392,"abstract_end":404}]}
{"pmid":"32483275","title":"Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy.","abstract":"Pseudoexon inclusion caused by deep intronic variants is an important genetic cause for various disorders. Here, we present a case of a hypomyelinating leukodystrophy with developmental delay, intellectual disability, autism spectrum disorder, and hypodontia, which are consistent with autosomal recessive POLR3-related leukodystrophy. Whole-exome sequencing identified only a heterozygous missense variant (c.1451G>A) in POLR3A. To explore possible involvement of a deep intronic variant in another allele, we performed whole-genome sequencing of the patient with variant annotation by SpliceAI, a deep-learning-based splicing prediction tool. A deep intronic variant (c.645 + 312C>T) in POLR3A, which was predicted to cause inclusion of a pseudoexon derived from an Alu element, was identified and confirmed by mRNA analysis. These results clearly showed that whole-genome sequencing, in combination with deep-learning-based annotation tools such as SpliceAI, will bring us further benefits in detecting and evaluating possible pathogenic variants in deep intronic regions.","variants":[{"Name":"NM_007055.4(POLR3A):c.1451G>A (p.Arg484Gln)","Chromosome":"10","Start":"78013771","Stop":"78013771","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2848929,"rule_based_match":true,"evidence_text":"c.1451G>A","llm_judgment":"PRESENT","evidence":"c.1451G>A","abstract_start":408,"abstract_end":417}]}
{"pmid":"32176048","title":"A novel EDA1 missense mutation in X-linked hypohidrotic ectodermal dysplasia.","abstract":"A mutation in the epithelial morphogen gene ectodysplasin-A1 (EDA1) is responsible for the disorder X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common form of ectodermal dysplasia. XLHED is characterized by impaired development of hair, eccrine sweat glands, and teeth. This study aimed to identify potentially pathogenic mutations in four Chinese XLHED families.Genomic DNA was extracted from the peripheral blood and sequenced. Sanger sequencing was used to carry out mutational analysis of the EDA1 gene, and the three-dimensional structure of the novel mutant residues in the EDA trimer was determined. Transcriptional activity of NF-κB was tested by Dual luciferin assay.We identified a novel EDA1 mutation (c.1046C>T) and detected 3 other previously-reported mutations (c.146T>A; c.457C>T; c.467G>A). Our findings demonstrated that novel mutation c.1046C>T (p.A349 V) resulted in XLHED. The novel mutation could cause volume repulsion in the protein due to enlargement of the amino acid side chain. Dual luciferase assay revealed that transcriptional NF-κB activation induced by XLHED EDA1 protein was significantly reduced compared with wild-type EDA1.These results extend the spectrum of EDA1 mutations in XLHED patients and suggest a functional role of the novel mutation in XLHED.","variants":[{"Name":"NM_001399.5(EDA):c.457C>T (p.Arg153Cys)","Chromosome":"X","Start":"69957087","Stop":"69957087","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":53360,"rule_based_match":true,"evidence_text":"c.457C>T","llm_judgment":"PRESENT","evidence":"c.457C>T","abstract_start":803,"abstract_end":811}]}
{"pmid":"30228974","title":"Fourteen new mutations of","abstract":"Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder. This disorder is usually caused by mutations in any one of the genes; <i>BCKDHA</i>, <i>BCKDHB</i> and <i>DBT</i>, which represent E1α, E1β and E2 subunits of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, respectively. This study presents the molecular characterization of 31 MSUD patients. Twenty one mutations including 14 new mutations were identified. The <i>BCKDHB</i> gene was the most commonly affected (45.2%) compared to <i>BCKDHA</i> gene (16.1%) and <i>DBT</i> gene (38.7%). <i>In silico</i> webservers predicted all mutations were disease-causing. In addition, structural evaluation disclosed that all new missenses in <i>BCKDHA</i>, <i>BCKDHB</i> and <i>DBT</i> genes affected stability and formation of E1 and E2 subunits. Majority of the patients had neonatal onset MSUD (26 of 31). Meanwhile, the new mutation; c.1196C > G (p.S399C) in <i>DBT</i> gene was noted to be recurrent and found in 9 patients. <i>Conclusion</i>: Our findings have expanded the mutational spectrum of the MSUD and revealed the genetic heterogeneity among Malaysian MSUD patients. We also discovered the p.S399C from <i>DBT</i> gene was noted as a recurrent mutation in Malay community and it suggested the existence of common and unique mutation in Malay population.","variants":[{"Name":"NM_001918.5(DBT):c.1196C>G (p.Ser399Cys)","Chromosome":"1","Start":"100206458","Stop":"100206458","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1324034,"rule_based_match":true,"evidence_text":"c.1196C > G (p.S399C)","llm_judgment":"PRESENT","evidence":"c.1196C > G (p.S399C)","abstract_start":926,"abstract_end":947}]}
{"pmid":"26791099","title":"Novel frameshift variant in gene SALL4 causing Okihiro syndrome.","abstract":"Okihiro syndrome, Duane-radial ray syndrome or acro-reno-ocular syndrome (OMIM #607323) are alternative denominations describing an extremely variable condition, characterized by several radial defects of the upper limbs associated with Duane anomaly. It is a rare autosomal dominant disorder determined by variants in the SALL4 gene which encodes a transcription factor with eight zinc finger motifs. Here we report a novel heterozygous frameshift variant, c.410dupG, present in a Brazilian family. The five affected individuals exhibit a broad spectrum of phenotypes, ranging from the severe one presented by the index case (grossly shortened and deformed forearm, markedly hypoplastic and appendicular thumb, malformed right foot and ear malformation), to the less conspicuous condition presented by his near relatives (usually only triphalangeal or hypoplastic thumbs, sometimes associated with ulnar deviation); Duane's anomaly, however, was not observed in any of the affected family members. The c.410dupG variant is predicted to result in the translation of a truncated protein with 180 amino acid residues, lacking seven of the eight zinc finger motifs, with the same size of the predicted products of the already reported c.496dupC variant, described in two unrelated cases. However, the phenotypes observed in the three families (the one here reported and other two with c.496dupC variant) are very different. The analysis of cases so far published does not permit to establish a clear or direct genotype-phenotype correlation, but the three more severe foot malformation cases are due to variants predicted to encode truncated proteins lacking seven ZFMs. This might indicate a possible correlation between foot malformation and reduced size of the protein, suggesting that the nonsense-mediated-decay mechanism might not be so effective as to eliminate all SALL4 variants harboring premature termination codons.","variants":[{"Name":"NM_020436.5(SALL4):c.410dup (p.Gly138fs)","Chromosome":"20","Start":"51792072","Stop":"51792073","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":215781,"rule_based_match":true,"evidence_text":"c.410dupG","llm_judgment":"PRESENT","evidence":"c.410dupG","abstract_start":458,"abstract_end":467}]}
{"pmid":"26143525","title":"Protracted late infantile ceroid lipofuscinosis due to TPP1 mutations: Clinical, molecular and biochemical characterization in three sibs.","abstract":"OBJECTIVE: This work investigated the molecular cause responsible for a late-onset parkinsonism-dystonia phenotype in three Italian siblings, and clinically characterize this condition.\nMETHODS: Extensive neurophysiological and neuroradiological exams were performed on the three sibs. Most frequent late-onset metabolic diseases were ruled out through laboratory and biochemical analyses. A whole exome sequencing (WES) approach was used to identify the molecular cause underlying this condition.\nRESULTS AND CONCLUSIONS: Peculiar neurologic phenotype was characterized by dystonia-parkinsonism, cognitive impairment, gait ataxia and apraxia, pyramidal signs. WES analysis allowed the identification of a compound heterozygosity for two nucleotide substitutions (c.1340G>A, p.R447H; c.790C>T, p.Q264X) affecting the TPP1 gene in the three affected siblings. Biochemical analyses demonstrated abrogated TPP1 catalytic activity in primary skin fibroblasts, but revealed residual activity in leukocytes. Our findings document that late infantile neuronal ceroid lipofuscinosis (CLN2), which is caused by TPP1 gene mutations, should be considered in the differential diagnosis of autosomal recessive dystonia-parkinsonism syndromes. The availability of enzyme replacement therapy and other therapeutic approaches for ceroid lipofuscinoses emphasizes the value of reaching an early diagnosis in patients with atypical and milder presentation of these disorders.","variants":[{"Name":"NM_000391.4(TPP1):c.790C>T (p.Gln264Ter)","Chromosome":"11","Start":"6616757","Stop":"6616757","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1688538,"rule_based_match":true,"evidence_text":"c.790C>T (p.Q264X)","llm_judgment":"PRESENT","evidence":"c.790C>T","abstract_start":784,"abstract_end":792}]}
{"pmid":"34057927","title":"P.arg102ser is a common Pde6a mutation causing autosomal recessive retinitis pigmentosa in Pakistani families.","abstract":"OBJECTIVE: To explore the genetic cause of autosomal recessive retinitis pigmentosa in consanguineous families.\nMETHODS: The multi-centre study was conducted from July 2015 to June 2018 at Liaquat University of Medical and Health Sciences, Jamshoro, the University of Sindh, Jamshoro, and Islamia University, Bahawalpur, Pakistan, and comprised families affected with non-syndromic autosomal recessive retinitis pigmentosa. Ophthalmological investigations were done to assess the fundus of the patients and the status of the disease. Pedigrees were drawn and family histories were recorded to find out the mode of inheritance. A 10cc sample of whole blood was obtained from each participant and deoxyribonucleic acid was extracted. Homozygosity mapping was performed using three short tandem repeat polymorphisms closely linked to phosphodiesterase 6A gene, and the linked families were Sanger-sequenced for identification of the mutation. Bioinformatic tools were used to design amplification refractory mutation system assay and to assess the protein structure and pathogenic effects of the mutation.\nRESULTS: In the 80 consanguineous families, there were 464 individuals, and, of them, 236(51%) were affected with their age ranging between 4 and 80 years. Family history and pedigree drawings revealed autosomal recessive retinitis pigmentosa with early childhood onset. Linkage analysis indicated the homozygosity in 6(7.5%) families. Sanger-sequencing revealed a common mutation c.304C>A (p.Arg102Ser); segregating with the disease in the linked families.\nCONCLUSION: The findings may offer effective genetic counselling and minimise disease penetration in consanguineous families.","variants":[{"Name":"NM_000440.3(PDE6A):c.304C>A (p.Arg102Ser)","Chromosome":"5","Start":"149944370","Stop":"149944370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":190264,"rule_based_match":true,"evidence_text":"c.304C>A (p.Arg102Ser)","llm_judgment":"PRESENT","evidence":"c.304C>A (p.Arg102Ser)","abstract_start":1484,"abstract_end":1506}]}
{"pmid":"33287145","title":"Five Italian Families with Two Mutations in","abstract":"Double heterozygosity (DH) in <i>BRCA1</i> and <i>BRCA2</i> genes and double mutation (DM) in <i>BRCA1</i> or <i>BRCA2</i> are extremely rare events in the general population, and few cases have been reported worldwide so far. Here, we describe five probands, all women, with breast and/or ovarian cancer and their families. Particularly, we identified two probands with DH in the <i>BRCA1/2</i> genes with a frequency of 0.3% and three probands with DM in the <i>BRCA2</i> gene with a frequency of 0.5%. The DH <i>BRCA1</i> c.547+2T>A (IVS8+2T>A)/<i>BRCA2</i> c.2830A>T (p.Lys944Ter) and <i>BRCA1</i> c.3752_3755GTCT (p.Ser1253fs)/<i>BRCA2</i> c.425+2T>C (IVS4+2T>C) have not been described together so far. The DM in <i>BRCA2</i>, c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T), found in three unrelated probands, was previously reported in further unrelated patients. Due to its peculiarity, it is likely that both pathogenic variants descend from a common ancestor and, therefore, are founder mutations. Interestingly, analyzing the tumor types occurring in DH and DM families, we observed ovarian cancer only in DH families, probably due to the presence in DH patients of <i>BRCA1</i> pathogenic variants, which predispose one more to ovarian cancer onset. Furthermore, male breast cancer and pancreatic cancer ensued in families with DM but not with DH. These data confirm that <i>BRCA2</i> pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.","variants":[{"Name":"NM_000059.4(BRCA2):c.7008-2A>T","Chromosome":"13","Start":"32354859","Stop":"32354859","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":66914,"rule_based_match":true,"evidence_text":"c.7008-2A>T (IVS13-2A>T)","llm_judgment":"PRESENT","evidence":"c.7008-2A>T (IVS13-2A>T)","abstract_start":760,"abstract_end":784},{"Name":"NM_000059.4(BRCA2):c.631G>A (p.Val211Ile)","Chromosome":"13","Start":"32326613","Stop":"32326613","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":66726,"rule_based_match":true,"evidence_text":"c.631G>A (p.Val211Ile)","llm_judgment":"PRESENT","evidence":"c.631G>A (p.Val211Ile)","abstract_start":733,"abstract_end":755},{"Name":"NM_000059.4(BRCA2):c.2830A>T (p.Lys944Ter)","Chromosome":"13","Start":"32337185","Stop":"32337185","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":66023,"rule_based_match":true,"evidence_text":"BRCA2 c.2830A>T (p.Lys944Ter)","llm_judgment":"PRESENT","evidence":"BRCA2</i> c.2830A>T (p.Lys944Ter)","abstract_start":551,"abstract_end":584}]}
{"pmid":"26632398","title":"Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations.","abstract":"PURPOSE: This study was designed to investigate the characteristics of Korean patients with calpainopathy.\nMATERIALS AND METHODS: Thirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed.\nRESULTS: Nine different mutations, including four novel mutations (NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology.\nCONCLUSION: We identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy.","variants":[{"Name":"NM_000070.3(CAPN3):c.1524+1G>T","Chromosome":"15","Start":"42401811","Stop":"42401811","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":547493,"rule_based_match":true,"evidence_text":"NM_000070: c.1524+1G>T","llm_judgment":"PRESENT","evidence":"NM_000070: c.1524+1G>T","abstract_start":397,"abstract_end":419}]}
{"pmid":"28806589","title":"Novel clinical manifestations in patients with KCNA2 mutations.","abstract":"PURPOSE: To report novel clinical manifestations of KCNA2 mutation related epileptic encephalopathy.\nMETHODS: Blood samples were sent for whole exome and Sanger sequencing. Seizure types were characterized by clinical criteria and EEG recording.\nRESULTS: KCNA2 mutations have been reported in 10 cases who presented with focal, absence, generalized tonic-clonic or myoclonic astatic seizures. Here we describe 3 patients with previously unreported, more severe manifestations. Patient 1 is a 5 year-old male with a c.1214 C > T (p.Pro405Leu) mutation, previously reported to be disease causing. He presented at 1year of age with focal seizures and subsequently developed electrical status epilepticus of sleep at age 3. The latter finding to our knowledge has never been reported in patients with KCNA2 mutations. Patient 2 is a 7 year-old female with a novel c.1195 G > A (p.Val399Met) mutation not previously described. She presented with intermittent then continuous polymyoclonus and myoclonic-astatic and generalized tonic clonic seizures. Continuous polymyoclonus is another new manifestation in patients with KCNA2 mutations. Patient 3 is a 23 year-old male with a c.889C > T (p.Arg297Trp) mutation not previously described. He presented at 4 years of age with generalized tonic clonic seizures and later developed recurrent refractory status epilepticus episodes at ages 19, 22 and 23 years, the latter being a novel manifestation in patients with KCNA2 mutations.\nCONCLUSION: We identified 3 patients with KCNA2 mutations with novel characteristics, including electrical status epilepticus of sleep, continuous polymyoclonus and status epilepticus. These results expand KCNA2 mutation epileptic manifestations to include more severe, previously unreported phenotypes.","variants":[{"Name":"NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu)","Chromosome":"1","Start":"110603569","Stop":"110603569","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188152,"rule_based_match":true,"evidence_text":"c.1214 C > T (p.Pro405Leu)","llm_judgment":"PRESENT","evidence":"c.1214 C > T (p.Pro405Leu)","abstract_start":515,"abstract_end":541},{"Name":"NM_004974.4(KCNA2):c.889C>T (p.Arg297Trp)","Chromosome":"1","Start":"110603894","Stop":"110603894","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":974944,"rule_based_match":true,"evidence_text":"c.889C > T (p.Arg297Trp)","llm_judgment":"PRESENT","evidence":"c.889C > T (p.Arg297Trp)","abstract_start":1172,"abstract_end":1196}]}
{"pmid":"33250374","title":"Presynaptic congenital myasthenic syndrome due to three novel mutations in SLC5A7 encoding the sodium-dependant high-affinity choline transporter.","abstract":"SLC5A7 encodes the presynaptic sodium-dependant high-affinity choline transporter 1 (CHT), which uptakes choline to the presynaptic nerve terminal following the breakdown of acetylcholine by the acetylcholinesterase within the synaptic cleft. We report 5 patients from three consanguineous families with congenital myasthenic syndrome type 20 caused by novel mutations in SLC5A7. The individuals from family 1 and 2 were homozygous for c.320G>A; (p.Arg107His) and c.886G>A (p.Ala296Thr), respectively, and their phenotype was characterised by recurrent apnoeic attacks early after birth and learning and speech difficulties in childhood. Individuals from family 3 were homozygous for c.1240T>A (p.Tyr414Asn) and suffered from more severe central and peripheral manifestations with lack of spontaneous movements and respiratory drive and overall minimal response to external stimuli. All individuals tested showed neurophysiological defects compatible with impaired neuromuscular transmission. Combined treatment with cholinesterase inhibitors and β2-adrenergic agonists was beneficial in patients from family 1 and 2. Affected individuals from family 3 died from complications directly related to their underlying genetic condition. This report provides three novel pathogenic variants in SLC5A7 and highlights the variability in the clinical phenotype, severity and prognosis of this syndrome.","variants":[{"Name":"NM_021815.5(SLC5A7):c.320G>A (p.Arg107His)","Chromosome":"2","Start":"107992999","Stop":"107992999","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1867256,"rule_based_match":true,"evidence_text":"c.320G>A; (p.Arg107His)","llm_judgment":"PRESENT","evidence":"c.320G>A; (p.Arg107His)","abstract_start":436,"abstract_end":459}]}
{"pmid":"34313384","title":"The recurrent p.(Pro540Ser) MEN1 genetic variant should be considered nonpathogenic: A case report.","abstract":"Pheochromocytoma/paraganglioma (Pheo/PGL) associated with pituitary adenoma (PA) is rare in clinical practice, and a common pathogenic mechanism has been suggested owing to the germline pathogenic variants found in some cases. Our aim is to propose a reassignment for a recurrent MEN1 genetic variant found in a 54-year-old male patient with bilateral pheochromocytoma and GH-secreting PA. Pheo/PGL genes study was carried out in DNA samples from Pheo as well as PA and no pathological variants or large deletions were detected. Additionally, a MEN1 gene analysis was performed, and a heterozygous germline variant in exon 10: c.1618C>T; p.(Pro540Ser) was found. No MEN1 gene deletions/duplications were detected. In evaluating a causal relationship between the c.1618C>T MEN1 variant and both tumors, we took into account that missense variants are common pathogenic variants in MEN1, and the population frequency of this variant is too high to be considered pathogenic. His son (aged 38 and carrier) is asymptomatic, and computational analysis showed discrepancies. We propose that this recurrent variant, previously considered as likely pathogenic, subsequently as variant of uncertain significance, and likely benign should now be reclassified as benign.","variants":[{"Name":"NM_001370259.2(MEN1):c.1618C>T (p.Pro540Ser)","Chromosome":"11","Start":"64804549","Stop":"64804549","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":197521,"rule_based_match":true,"evidence_text":"c.1618C>T; p.(Pro540Ser)","llm_judgment":"PRESENT","evidence":"c.1618C>T; p.(Pro540Ser)","abstract_start":627,"abstract_end":651}]}
{"pmid":"21745802","title":"Autosomal recessive spastic ataxia of Charlevoix-Saguenay: compound heterozygotes for nonsense mutations of the SACS gene.","abstract":"Mutations of the SACS gene have been reported in patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay from Canada (Quebec), Tunisia, Japan, Turkey, Belgium, Italy, Spain, the Netherlands, and Germany. Features that distinguish autosomal recessive spastic ataxia of Charlevoix-Saguenay from other recessive ataxias include sensory motor polyneuropathy and hypermyelinated retinal nerve fibers. We describe the clinical, electrophysiological, and radiological features in 2 white American siblings diagnosed with autosomal recessive spastic ataxia of Charlevoix-Saguenay. The 2 affected children are compound heterozygotes for nonsense mutations of the SACS gene (c. 3484 G>T, p. E 1162 X; and c. 11,707 C>T, p. R 3903 X). We have measured allele-specific SACS mRNA abundance in peripheral blood and show that these specific mutant mRNAs are not degraded. We suggest that in children with early onset cerebellar ataxia and spasticity, ophthalmological examination and nerve conduction testing may guide genetic testing.","variants":[{"Name":"NM_014363.6(SACS):c.3484G>T (p.Glu1162Ter)","Chromosome":"13","Start":"23340392","Stop":"23340392","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1428667,"rule_based_match":true,"evidence_text":"c. 3484 G>T, p. E 1162 X","llm_judgment":"PRESENT","evidence":"c. 3484 G>T, p. E 1162 X","abstract_start":681,"abstract_end":705},{"Name":"NM_014363.6(SACS):c.11707C>T (p.Arg3903Ter)","Chromosome":"13","Start":"23332169","Stop":"23332169","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":399614,"rule_based_match":false,"evidence_text":"c. 11,707 C>T, p. R 3903 X","llm_judgment":"PRESENT","evidence":"c. 11,707 C>T, p. R 3903 X","abstract_start":711,"abstract_end":737}]}
{"pmid":"29262924","title":"Familial Haemophagocytic Lymphohistiocytosis Occurs in A Fetus at His Third Trimester-A Case Report","abstract":"OBJECTIVE: To analyze the clinical features and pathogenetic gene mutation in a fetus at his third trimester with familial haemophagocytic lymphohistiocytosis (FHL).\nMETHODS: Target region sequencing and high-throughput sequencing were used to detect pathogenetic gene mutations for familial haemophagocytic lymphohistiocytosis in a late onset HLH fetus. Pathogenetic gene mutations of the patient and his parents were verified by Sanger dideoxy sequencing.\nRESULTS: A male neonate, who had right pleural effusion, hepatomegaly and splenomegaly previously revealed by fetus ultrasound, was delivered at full-term by cesarean section. His clinical presentation showed recurrent fever, tachypenea, decreased breath sounds on right side, hepatosplenomegaly etc., which were gradually aggravating Lab.tests results were as follows: WBC 9.88×10<sup>9</sup>/L, Hb 91 g/L, Plt 13×10<sup>9</sup>/L, ALT 18 U/L,AST 69 U/L,TBIL 207.2 µmol/L, DBIL 183.5 µmol/L, TG 3.05 mmol/L, Fib 0.88 g/L, Serum ferritin 3 120 ng/ml and sIL-2R 57 420 U/ml. FCM showed that CD3<sup>-</sup>CD16<sup>+</sup>CD56<sup>+</sup> cells reached to 3.60% in the pripheral blood. Haemophagocytes were occasionally found in the bone marrow. NK/NKT stimulation test showed a severe damage of degranulation of NK cells. Sequence analysis of genomic DNA from his peripheral blood demonstrated the compound heterozygous mutations of UNC13D gene: c.2448-13 G>A in exon26 and c.1055+1 G>A in exon12, both were pathogenetic mutations. In detailed family survey, it was confirmed that the mutation c.2448-13 G>A in exon26 was inherited from his mother and c.1055+1 G>A in exon12 from his father.\nCONCLUSION: A rare case of familial haemophagocytic lymphohistiocytosis type 3 (FHL3) with late fetus onset who carried pathogenetic compound heterozygous mutations of UNC13D gene. Those neonates with recurrent fever, serous effusions and multiple organ failure should be screened for FHL. Identifying the pathogenic gene mutations laid the foundation of conceiving disease-free newborns.","variants":[{"Name":"NM_199242.3(UNC13D):c.2448-13G>A","Chromosome":"17","Start":"75831361","Stop":"75831361","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1508873,"rule_based_match":true,"evidence_text":"c.2448-13 G>A","llm_judgment":"PRESENT","evidence":"c.2448-13 G>A","abstract_start":1404,"abstract_end":1417},{"Name":"NM_199242.3(UNC13D):c.1055+1G>A","Chromosome":"17","Start":"75839838","Stop":"75839838","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1064395,"rule_based_match":true,"evidence_text":"c.1055+1 G>A","llm_judgment":"PRESENT","evidence":"c.1055+1 G>A","abstract_start":1432,"abstract_end":1444}]}
{"pmid":"24162365","title":"Gitelman's syndrome with vomiting manifested by severe metabolic alkalosis and progressive renal insufficiency.","abstract":"Gitelman's syndrome is an autosomal recessive salt-losing tubulopathy showing hypokalemic hypomagnesemic hypocalciuria with metabolic alkalosis and hyperreninemic hyperaldosteronism. This syndrome is caused by mutations in the SLC12A3 gene that encodes sodium-chloride cotransporter expressed at the apical membrane of renal distal convoluted tubule. Symptoms and renal outcomes of Gitelman's syndrome are, in general, mild and benign, and renal insufficiency from Gitelman's syndrome associated with long-standing hypokalemia and volume depletion is extremely rare. Herein, we report a 27-year-old male patient with Gitelman's syndrome who manifested renal failure, hypokalemia, severe metabolic alkalosis and altered mentality. About one year ago, the patient had been transferred to Seoul National University Hospital, because of unsolved hypokalemia, and was diagnosed as Gitelman's syndrome by clinical features and genetic analysis of the SLC12A3 gene. The patient carries a missense mutation at one allele of SLC12A3 gene (c.781C>T, p.Arg261Cys). His mother is also heterozygous for the same mutation and she had a history of hypokalemia. On this admission, the patient had recurrent bouts of vomiting induced by psychiatric eating disorder and showed severe volume depletion with hypotension, azotemia and metabolic alkalosis. Intense hydration therapy and emergency hemodialysis transiently improved his fluid-electrolyte imbalance and renal function. However, renal dysfunction progressively deteriorated despite the medical treatment. Our findings suggest that even in Gitelman's syndrome, constant monitoring for volume status and other comorbid conditions should be employed to prevent progressive renal injury.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.781C>T (p.Arg261Cys)","Chromosome":"16","Start":"56870665","Stop":"56870665","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2843272,"rule_based_match":true,"evidence_text":"c.781C>T, p.Arg261Cys","llm_judgment":"PRESENT","evidence":"c.781C>T, p.Arg261Cys","abstract_start":1030,"abstract_end":1051}]}
{"pmid":"29443755","title":"Argininemia as a cause of severe chronic stunting and partial growth hormone deficiency (PGHD): A case report.","abstract":"RATIONALE: Argininemia is an autosomal recessive inherited disorder of the urea cycle. Because of its atypical symptoms in early age, diagnosis can be delayed until the typical chronic manifestations - including spastic diplegia, deterioration in cognitive function, and epilepsy - appear in later childhood.\nPATIENT CONCERNS: A Chinese boy initially presented with severe stunting and partial growth hormone deficiency (PGHD) at 3 years old and was initially treated with growth hormone replacement therapy. Seven years later (at 10 years old), he presented with spastic diplegia, cognitive function lesions, epilepsy, and peripheral neuropathy.\nDIAGNOSES: Ultimately, the patient was diagnosed with argininemia with homozygous mutation (c.32T>C) of the ARG1 gene at 10 years old. Blood tests showed mildly elevated blood ammonia and creatine kinase, and persistently elevated bilirubin.\nINTERVENTIONS: Protein intake was limited to 0.8 g/kg/day, citrulline (150-200 mg [kg d]) was prescribed.\nOUTCOMES: The patient's mental state and vomiting had improved after 3 months treatment. At 10 years and 9 month old, his height and weight had reached 121cm and 22kg, respectively, but his spastic diplegia symptoms had not improved.\nLESSONS: This case demonstrates that stunting and PGHD that does not respond to growth hormone replacement therapy might hint at inborn errors of metabolism (IEM). IEM should also be considered in patients with persistently elevated bilirubin with or without abnormal liver transaminase, as well as elevated blood ammonia and creatine kinase, in the absence of hepatic disease.","variants":[{"Name":"NM_000045.4(ARG1):c.32T>C (p.Ile11Thr)","Chromosome":"6","Start":"131573314","Stop":"131573314","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":17432,"rule_based_match":true,"evidence_text":"c.32T>C","llm_judgment":"PRESENT","evidence":"c.32T>C","abstract_start":739,"abstract_end":746}]}
{"pmid":"31654588","title":"Loss-of-function mutations in centrosomal protein 112 is associated with human acephalic spermatozoa phenotype.","abstract":"Acephalic spermatozoa, characterized by the headless sperm in the ejaculate, is a rare type of teratozoospermia. Here, we recruited two infertile patients with an acephalic spermatozoa phenotype to investigate the genetic pathology of acephalic spermatozoa. Whole-exome sequencing analysis was performed and found mutations in CEP112 in the two patients: homozygous mutation c.496C > T:p.(Arg166X) in exon 5 from P1; and the biallelic mutations c.2074C > T:p.(Arg692Trp) in exon 20 and c.2104C > T:p.(Arg702Cys) in exon 20 from P2. Sanger sequencing confirmed the CEP112 mutations in the two patients. In silico analysis revealed that these CEP112 mutations are deleterious and rare, and all the mutations impact the coiled-coil domain of CEP112, which may affect the protein function. The c.496C > T:p.Arg166X resulted in a truncated CEP112, which was verified by the mutation expression plasmid. The CEP112 expression was significantly reduced in the P2, suggesting the biallelic mutations c.2074C > T and c.2104C > T may affect the function and stability of CEP112. Therefore, we speculate that the loss-of-function mutations in CEP112 may be account for the human acephalic spermatozoa phenotype.","variants":[{"Name":"NM_001199165.4(CEP112):c.2074C>T (p.Arg692Trp)","Chromosome":"17","Start":"65902241","Stop":"65902241","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":969576,"rule_based_match":true,"evidence_text":"c.2074C > T:p.(Arg692Trp)","llm_judgment":"PRESENT","evidence":"c.2074C > T:p.(Arg692Trp)","abstract_start":445,"abstract_end":470},{"Name":"NM_001199165.4(CEP112):c.2104C>T (p.Arg702Cys)","Chromosome":"17","Start":"65902211","Stop":"65902211","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":969577,"rule_based_match":true,"evidence_text":"c.2104C>T:p.(Arg702Cys)","llm_judgment":"PRESENT","evidence":"c.2104C > T:p.(Arg702Cys)","abstract_start":486,"abstract_end":511},{"Name":"NM_001199165.4(CEP112):c.496C>T (p.Arg166Ter)","Chromosome":"17","Start":"66132738","Stop":"66132738","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":969575,"rule_based_match":true,"evidence_text":"c.496C > T:p.(Arg166X)","llm_judgment":"PRESENT","evidence":"c.496C > T:p.(Arg166X)","abstract_start":375,"abstract_end":397}]}
{"pmid":"25856303","title":"Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.","abstract":"CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G>T, p.Lys250Asn) missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.","variants":[{"Name":"NM_004055.5(CAPN5):c.750G>T (p.Lys250Asn)","Chromosome":"11","Start":"77115445","Stop":"77115445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1047531,"rule_based_match":true,"evidence_text":"c.750G>T (p.Lys250Asn)","llm_judgment":"PRESENT","evidence":"p.Lys250Asn","abstract_start":731,"abstract_end":742}]}
{"pmid":"24749080","title":"Two novel compound heterozygous mutations in","abstract":"OPA3-related 3-methylglutaconic aciduria, or Costeff Optic Atrophy syndrome, is a neuro-ophthalmologic syndrome of early-onset bilateral optic atrophy and later-onset spasticity, and extrapyramidal dysfunction. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is markedly increased. OPA3-related 3-methylglutaconic aciduria is due to mutations in the <i>OPA3</i> gene located at 19q13.2-13.3. Here we describe two siblings with novel compound heterozygous variants in <i>OPA3</i>: c.1A>G (p.1M>V) in the translation initiation codon in exon 1 and a second variant, c.142+5G>C in intron 1. On cDNA sequencing the c.1A>G appeared homozygous, indicating that the allele without the c.1A>G variant is degraded. This is likely due to an intronic variant; possibly the IVS1+5 splice site variant. The older female sibling initially presented with motor developmental delay and vertical nystagmus during her first year of life and was diagnosed subsequently with optic atrophy. Her brother presented with mildly increased hip muscle tone followed by vertical nystagmus within the first 6 months of life, and was found to have elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid, and optic atrophy by 1.5 years of age. Currently, ages 16 and 7, both children exhibit ataxic gaits and dysarthric speech. Immunofluorescence studies on patient's cells showed fragmented mitochondrial morphology. Thus, though the exact function of OPA3 remains unknown, our experimental results and clinical summary provide evidence for the pathogenicity of the identified OPA3 variants and provide further evidence for a mitochondrial pathology in this disease.","variants":[{"Name":"NM_025136.4(OPA3):c.1A>G (p.Met1Val)","Chromosome":"19","Start":"45584764","Stop":"45584764","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1056586,"rule_based_match":true,"evidence_text":"c.1A>G (p.1M>V)","llm_judgment":"PRESENT","evidence":"c.1A>G (p.1M>V)","abstract_start":506,"abstract_end":521},{"Name":"NM_025136.4(OPA3):c.142+5G>C","Chromosome":"19","Start":"45584618","Stop":"45584618","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":548843,"rule_based_match":true,"evidence_text":"c.142+5G>C","llm_judgment":"PRESENT","evidence":"c.142+5G>C","abstract_start":590,"abstract_end":600}]}
{"pmid":"27588307","title":"Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.","abstract":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous <i>AIRE</i> mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common <i>AIRE</i> mutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic <i>AIRE</i> mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4<sup>+</sup> T cells and CD21<sup>lo</sup>CD38<sup>lo</sup> B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.","variants":[{"Name":"NM_000383.4(AIRE):c.967_979del (p.Leu323fs)","Chromosome":"21","Start":"44291180","Stop":"44291192","ReferenceAlleleVCF":"TGCCTGTCCCCTCC","AlternateAlleleVCF":"T","allel_id":18348,"rule_based_match":true,"evidence_text":"c.967_979del13","llm_judgment":"PRESENT","evidence":"c.967_979del13","abstract_start":906,"abstract_end":920}]}
{"pmid":"19438153","title":"Left ventricular non-compaction: a new mutation predisposing to reverse remodeling?","abstract":"Left ventricular non-compaction (LVNC) is a rare disorder of endomyocardial morphogenesis that results in multiple trabeculations and deep intertrabecular recesses filled with direct blood flow from the left ventricular cavity. LVNC is attracting increasing interest as a model for the study of cardiomyopathies, since it is a genetically heterogeneous disorder which varies greatly in clinical presentation and age of onset. The authors present the case of a young black male with progressive congestive heart failure of 2-3 years' evolution. The investigation, which included transthoracic echocardiography (contrast and 3D), transesophageal echocardiography and cardiac magnetic resonance imaging, showed LVNC and severe aortic regurgitation, with severe left ventricular systolic dysfunction. The family history was suggestive of genetically transmitted disease and genetic study of the TAZ gene at locus Xq28 identified the mutation p.Phe128Ser (c.383T>C), the first description of this mutation in a patient with LVNC. The patient underwent aortic valve replacement, with excellent clinical evolution, regression of left ventricular dimensions and global systolic functio Aortic regurgitation (not related to LVNC) was the determining factor in the clinical expression. However, the excellent reverse remodeling that occurred after surgery highlights the heterogeneity of myocardial behavior in LVNC patients.","variants":[{"Name":"NM_000116.5(TAFAZZIN):c.383T>C (p.Phe128Ser)","Chromosome":"X","Start":"154414113","Stop":"154414113","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":51429,"rule_based_match":true,"evidence_text":"c.383T>C","llm_judgment":"PRESENT","evidence":"c.383T>C","abstract_start":951,"abstract_end":959}]}
{"pmid":"38525108","title":"A novel in-frame deletion in KIF5C gene causes infantile onset epilepsy and psychomotor retardation.","abstract":"Motor proteins, encoded by Kinesin superfamily (<i>KIF</i>) genes, are critical for brain development and plasticity. Increasing studies reported <i>KIF</i>'s roles in neurodevelopmental disorders. Here, a 6 years and 3 months-old Chinese boy with markedly symptomatic epilepsy, intellectual disability, brain atrophy, and psychomotor retardation was investigated. His parents and younger sister were phenotypically normal and had no disease-related family history. Whole exome sequencing identified a novel heterozygous <i>in-frame</i> deletion (c.265_267delTCA) in exon 3 of the <i>KIF5C</i> in the proband, resulting in the removal of evolutionarily highly conserved p.Ser90, located in its ATP-binding domain. Sanger sequencing excluded the proband's parents and family members from harboring this variant. The activity of ATP hydrolysis in vitro was significantly reduced as predicted. Immunofluorescence studies showed wild-type KIF5C was widely distributed throughout the cytoplasm, while mutant KIF5C was colocalized with microtubules. The live-cell imaging of the cargo-trafficking assay revealed that mutant KIF5C lost the peroxisome-transporting ability. <i>Drosophila</i> models also confirmed p.Ser90del's essential role in nervous system development. This study emphasized the importance of the <i>KIF5C</i> gene in intracellular cargo-transport as well as germline variants that lead to neurodevelopmental disorders and might enable clinicians for timely and accurate diagnosis and disease management in the future.","variants":[{"Name":"NM_004522.3(KIF5C):c.265TCA[1] (p.Ser90del)","Chromosome":"2","Start":"148929328","Stop":"148929330","ReferenceAlleleVCF":"TTCA","AlternateAlleleVCF":"T","allel_id":495118,"rule_based_match":false,"evidence_text":"c.265_267delTCA","llm_judgment":"PRESENT","evidence":"c.265_267delTCA","abstract_start":547,"abstract_end":562}]}
{"pmid":"29681726","title":"Early onset flecked retinal dystrophy associated with new compound heterozygous","abstract":"Purpose: To report genetic and clinical features of two unrelated Japanese patients with early onset flecked retinal dystrophy.\nMethods: Patients underwent comprehensive ophthalmic examinations that included electroretinography (ERG) after 30 min and 24 h of dark adaptation (DA). Disease-causing gene variants were identified with whole exome sequencing (WES), with identified candidates confirmed with direct sequencing.\nResults: WES identified compound heterozygous <i>RPE65</i> variants in both patients. Variants in patient 1 included c.1543C>T (p.R515W) and c.683A>C (p.Q228P), while patient 2 exhibited c.1028T>A (p.L343*) and c.683A>C (p.Q228P). Although variants p.R515W and p.L343* have been previously reported as pathogenic, variant p.Q228P was reported as uncertain significance. Each unaffected parent carried the variant heterozygously. Both patients had similar ophthalmic findings, including decreased visual acuity with early onset night blindness, numerous dense white dots/flecks occurring mainly outside the vascular arcades, a diffuse and/or disrupted ellipsoid line as shown with optical coherence tomography, and non-recordable rod and combined responses along with decreased cone responses after 30 min of DA. After 24 h of DA, both patients exhibited marked or partial recovery of the combined responses.\nConclusions: The results indicate that the recovery of combined or residual cone responses might be associated with a mild form of <i>RPE65</i>-related early onset flecked retinal dystrophy with new compound heterozygous variants.","variants":[{"Name":"NM_000329.3(RPE65):c.1543C>T (p.Arg515Trp)","Chromosome":"1","Start":"68429835","Stop":"68429835","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28159,"rule_based_match":true,"evidence_text":"c.1543C>T (p.R515W)","llm_judgment":"PRESENT","evidence":"c.1543C>T (p.R515W)","abstract_start":540,"abstract_end":559}]}
{"pmid":"24549056","title":"Attenuated familial adenomatous polyposis manifests as autosomal dominant late-onset colorectal cancer.","abstract":"Colorectal cancer (CRC) risk is well defined for families of patients with classical familial adenomatous polyposis (FAP). However, the risk for those with an attenuated form of FAP is less well characterised. In this study, we estimated CRC risks for carriers of a novel germline mutation in the APC gene that causes attenuated FAP (AFAP). We performed genetic testing on 53 individuals from seven AFAP families harbouring an identical APC:c.288T>A mutation. Using a modified segregation analysis, we estimated relative and absolute CRC risks for mutation carriers. Twenty-three individuals harboured the disease causing mutation. CRC occurred in 28 individuals (mean 61.7 years, range 32-80 years). The estimated CRC relative risks for mutation carriers aged 60-69 and ≥70 years were 19 (95% CI: 1.77-204.08) and 45 (95% CI: 11.32-180.10), respectively, while the absolute CRC lifetime risk for men was 94% (95% CI: 67.5-99.9%), and for women, 84% (95% CI: 50.9-99.0%). This study shows that AFAP can manifest as autosomal dominant late-onset CRC. These findings highlight a subgroup of inherited CRCs that require new criteria for identification and surveillance.","variants":[{"Name":"NM_000038.6(APC):c.288T>A (p.Tyr96Ter)","Chromosome":"5","Start":"112767256","Stop":"112767256","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":180167,"rule_based_match":true,"evidence_text":"APC:c.288T>A","llm_judgment":"PRESENT","evidence":"APC:c.288T>A","abstract_start":437,"abstract_end":449}]}
{"pmid":"28608266","title":"Potentially pathogenic germline CHEK2 c.319+2T>A among multiple early-onset cancer families.","abstract":"To study the potential contribution of genes other than BRCA1/2, PTEN, and TP53 to the biological and clinical characteristics of multiple early-onset cancers in Norwegian families, including early-onset breast cancer, Cowden-like and Li-Fraumeni-like syndromes (BC, CSL and LFL, respectively). The Hereditary Cancer Biobank from the Norwegian Radium Hospital was used to identify early-onset BC, CSL or LFL for whom no pathogenic variants in BRCA1/2, PTEN, or TP53 had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by our in-house designed TruSeq amplicon-based assay for targeted sequencing. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the more likely to affect splicing were experimentally analyzed by minigene assay. We identified a CSL individual carrying a variant in CHEK2 (c.319+2T>A, IVS2), here considered as likely pathogenic. Out of the five VUS (BRCA2, CDH1, CHEK2, MAP3K1, NOTCH3) tested in the minigene splicing assay, only NOTCH3 c.14090C>T (p.Ser497Leu) showed a significant effect on RNA splicing, notably by inducing partial skipping of exon 9. Among 13 early-onset BC, CSL and LFL patients, gene panel sequencing identified a potentially pathogenic variant in CHEK2 that affects a canonical RNA splicing signal. Our study provides new information on genetic loci that may affect the risk of developing cancer in these patients and their families, demonstrating that genes presently not routinely tested in molecular diagnostic settings may be important for capturing cancer predisposition in these families.","variants":[{"Name":"NM_007194.4(CHEK2):c.319+2T>A","Chromosome":"22","Start":"28734401","Stop":"28734401","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":152066,"rule_based_match":true,"evidence_text":"c.319+2T>A","llm_judgment":"PRESENT","evidence":"c.319+2T>A","abstract_start":946,"abstract_end":956}]}
{"pmid":"30715177","title":"Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.","abstract":"The leukodystrophies cause severe neurodevelopmental defects from birth and follow an incurable and progressive course that often leads to premature death. It has recently been reported that abnormalities in aminoacyl t-RNA synthetase (ARS) genes are linked to various unique leukodystrophies and leukoencephalopathies. Aminoacyl t-RNA synthetase proteins are fundamentally known as the first enzymes of translation, catalysing the conjugation of amino acids to cognate tRNAs for protein synthesis. It is known that certain aminoacyl t-RNA synthetase have multiple non-canonical roles in both transcription and translation, and their disruption results in varied and complicated phenotypes. We clinically and genetically studied seven patients (six male and one female; aged 2 to 12 years) from five unrelated families who all showed the same phenotypes of severe developmental delay or arrest (7/7), hypotonia (6/7), deafness (7/7) and inability to speak (6/7). The subjects further developed intractable epilepsy (7/7) and nystagmus (6/6) with increasing age. They demonstrated characteristic laboratory data, including increased lactate and/or pyruvate levels (7/7), and imaging findings (7/7), including calcification and abnormal signals in the white matter and pathological involvement (2/2) of the corticospinal tracts. Through whole-exome sequencing, we discovered genetic abnormalities in lysyl-tRNA synthetase (KARS). All patients harboured the variant [c.1786C>T, p.Leu596Phe] KARS isoform 1 ([c.1702C>T, p.Leu568Phe] of KARS isoform 2) either in the homozygous state or compound heterozygous state with the following KARS variants, [c.879+1G>A; c.1786C>T, p.Glu252_Glu293del; p.Leu596Phe] ([c.795+1G>A; c.1702C>T, p.Glu224_Glu255del; p.Leu568Phe]) and [c.650G>A; c.1786C>T, p.Gly217Asp; p.Leu596Phe] ([c.566G>A; c.1702C>T, p.Gly189Asp; p.Leu568Phe]). Moreover, similarly disrupted lysyl-tRNA synthetase (LysRS) proteins showed reduced enzymatic activities and abnormal CNSs in Xenopus embryos. Additionally, LysRS acts as a non-canonical inducer of the immune response and has transcriptional activity. We speculated that the complex functions of the abnormal LysRS proteins led to the severe phenotypes in our patients. These KARS pathological variants are novel, including the variant [c.1786C>T; p.Leu596Phe] (c.1702C>T; p.Leu568Phe) shared by all patients in the homozygous or compound-heterozygous state. This common position may play an important role in the development of severe progressive leukodystrophy. Further research is warranted to further elucidate this relationship and to investigate how specific mutated LysRS proteins function to understand the broad spectrum of KARS-related diseases.","variants":[{"Name":"NM_005548.3(KARS1):c.1702C>T (p.Leu568Phe)","Chromosome":"16","Start":"75627987","Stop":"75627987","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":985703,"rule_based_match":true,"evidence_text":"c.1702C>T (p.Leu568Phe)","llm_judgment":"PRESENT","evidence":"p.Leu568Phe","abstract_start":1516,"abstract_end":1527}]}
{"pmid":"29261847","title":"TSC1 Mutations in Keratoconus Patients With or Without Tuberous Sclerosis.","abstract":"Purpose: To test candidate genes TSC1 and TSC2 in a family affected by tuberous sclerosis complex (TSC) where proband was also diagnosed with bilateral keratoconus (KC) and to test the hypothesis that defects in the same gene may lead to a nonsyndromic KC.\nMethods: Next-generation sequencing of TSC1 and TSC2 genes was performed in a proband affected by TSC and KC. Identified mutation was confirmed by Sanger DNA sequencing. Whole exome sequencing (WES) was performed in patients with nonsyndromic KC. Sanger DNA sequencing was used to confirm WES results and to screen additional patients. RT-PCR was used to investigate TSC1 expression in seven normal human corneas and eight corneas from patients with KC. Various in silico tools were employed to model functional consequences of identified mutations.\nResults: A heterozygous nonsense TSC1 mutation g.132902703C>T (c.2293C>T, p.Gln765Ter) was identified in a patient with TSC and KC. Two heterozygous missense TSC1 variants g.132896322A>T (c.3408A>T, p.Asp1136Glu) and g.132896452G>A (c.3278G>A, p.Arg1093Gln) were identified in three patients with nonsyndromic KC. Two mutations were not present in The Genome Aggregation (GnomAD), The Exome Aggregation (ExAC), and 1000 Genomes (1000G) databases, while the third one was present in GnomAD and 1000G with minor allele frequencies (MAF) of 0.00001 and 0.0002, respectively. We found TSC1 expressed in normal corneas and KC corneas, albeit with various levels.\nConclusions: Here for the first time we found TSC1 gene to be involved in bilateral KC and TSC as well as with nonsyndromic KC, supporting the hypothesis that diverse germline mutations of the same gene can cause genetic disorders with overlapping clinical features.","variants":[{"Name":"NM_000368.5(TSC1):c.2293C>T (p.Gln765Ter)","Chromosome":"9","Start":"132902703","Stop":"132902703","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":58096,"rule_based_match":true,"evidence_text":"c.2293C>T (p.Gln765Ter)","llm_judgment":"PRESENT","evidence":"p.Gln765Ter","abstract_start":881,"abstract_end":892}]}
{"pmid":"22304929","title":"Life with too much polyprenol: polyprenol reductase deficiency.","abstract":"Congenital disorders of glycosylation (CDG) are caused by a dysfunction of glycosylation, an essential step in the manufacturing process of glycoproteins. This paper focuses on a 6-year-old patient with a new type of CDG-I caused by a defect of the steroid 5α reductase type 3 gene (SRD5A3). The clinical features were psychomotor retardation, pathological nystagmus, slight muscular hypotonia and microcephaly. SRD5A3 was recently identified encoding the polyprenol reductase, an enzyme catalyzing the final step of the biosynthesis of dolichol, which is required for the assembly of the glycans needed for N-glycosylation. Although an early homozygous stop-codon (c.57G>A [W19X]) with no functional protein was found in the patient, about 70% of transferrin (Tf) was correctly glycosylated. Quantification of dolichol and unreduced polyprenol in the patient's fibroblasts demonstrated a high polyprenol/dolichol ratio with normal amounts of dolichol, indicating that high polyprenol levels might compete with dolichol for the initiation of N-glycan assembly but without supporting normal glycosylation and that there must be an alternative pathway for dolichol biosynthesis.","variants":[{"Name":"NM_024592.5(SRD5A3):c.57G>A (p.Trp19Ter)","Chromosome":"4","Start":"55346393","Stop":"55346393","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":102019,"rule_based_match":true,"evidence_text":"c.57G>A [W19X]","llm_judgment":"PRESENT","evidence":"c.57G>A [W19X]","abstract_start":666,"abstract_end":680}]}
{"pmid":"16571645","title":"Polymorphisms in the xylosyltransferase genes cause higher serum XT-I activity in patients with pseudoxanthoma elasticum (PXE) and are involved in a severe disease course.","abstract":"BACKGROUND: Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder caused by mutations in the ABCC6 gene. Fragmentation of elastic fibres and deposition of proteoglycans result in a highly variable clinical picture. The altered proteoglycan metabolism suggests that enzymes from this pathway function as genetic co-factors in the severity of PXE. Therefore, we propose the XYLT genes encoding xylosyltransferase I (XT-I) as the chain-initiating enzyme in the biosynthesis of proteoglycans and the highly homologous XT-II as potential candidate genes.\nMETHODS: We screened all XYLT exons in 65 German PXE patients using denaturing high performance liquid chromatography and analysed the influence of the variations on clinical characteristics.\nRESULTS: We identified 22 variations in the XYLT genes. The missense variation p.A115S (XT-I) is associated with higher serum XT activity (p = 0.005). The amino acid substitution p.T801R (XT-II; c.2402C>G) occurs with significantly higher frequency in patients under 30 years of age at diagnosis (43% v 26%; p = 0.04); all PXE patients with this variation suffer from skin lesions compared to only 75% of the wild type patients (p = 0.002). c.166G>A, c.1569C>T, and c.2402C>G in the XYLT-II gene were found to be more frequent in patients with higher organ involvement (p = 0.04, p = 0.01, and p = 0.02, respectively).\nCONCLUSIONS: Here we show for the first time that variations in the XYLT-II gene are genetic co-factors in the severity of PXE. Furthermore, the higher XT activity in patients with the exchange p.A115S (XT-I) indicates that this polymorphism is a potential marker for increased remodelling of the extracellular matrix.","variants":[{"Name":"NM_022167.4(XYLT2):c.2402C>G (p.Thr801Arg)","Chromosome":"17","Start":"50360095","Stop":"50360095","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":17572,"rule_based_match":true,"evidence_text":"c.2402C>G","llm_judgment":"PRESENT","evidence":"c.2402C>G","abstract_start":956,"abstract_end":965}]}
{"pmid":"19125024","title":"Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling.","abstract":"OBJECTIVE: Hereditary nonsyndromic deafness is an autosomal recessive condition in about 80% of cases, and point mutations in the GJB2 gene (connexin 26) and two deletions in the GJB6 gene (connexin 30), del(GJB6-D13S1830) and del(GJB6-D13S1854), are reported to account for 50% of recessive deafness. Aiming at establishing the frequencies of GJB2 mutations and GJB6 deletions in the Brazilian population, we screened 300 unrelated individuals with hearing impairment, who were not affected by known deafness related syndromes.\nMETHODS: We firstly screened the most frequently reported mutations, c.35delG and c.167delT in the GJB2 gene, and del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene, through specific techniques. The detected c.35delG and c.167delT mutations were validated by sequencing. Other mutations in the GJB2 gene were screened by single-strand conformation polymorphism and the coding region was sequenced when abnormal patterns were found.\nRESULTS: Pathogenic mutations in GJB2 and GJB6 genes were detected in 41 individuals (13.7%), and 80.5% (33/41) presented these mutations in homozygosis or compound heterozygosis, thus explaining their hearing defect. The c.35delG in the GJB2 gene was the most frequent mutation (37/300; 12.4%), detected in 23% familial and 6.2% the sporadic cases. The second most frequent mutation (1%; 3/300) was the del(GJB6-D13S1830), always found associated with the c.35delG mutation. Nineteen different sequence variations were found in the GJB2 gene. In addition to the c.35delG mutation, nine known pathogenic alterations were detected c.167delT, p.Trp24X, p.Val37Ile, c.176_191del16, c.235delC, p.Leu90Pro, p.Arg127His, c.509insA, and p.Arg184Pro. Five substitutions had been previously considered benign polymorphisms: c.-15C>T, p.Val27Ile, p.Met34Thr, p.Ala40Ala, and p.Gly160Ser. Two previously reported mutations of unknown pathogenicity were found (p.Lys168Arg, and c.684C>A), and two novel substitutions, p.Leu81Val (c.G241C) and p.Met195Val (c.A583G), both in heterozygosis without an accompanying mutation in the other allele. None of these latter four variants of undefined status was present in a sample of 100 hearing controls.\nCONCLUSIONS: The present study demonstrates that mutations in the GJB2 gene and del(GJB6 D13S1830) are important causes of hearing impairment in Brazil, thus justifying their screening in a routine basis. The diversity of variants in our sample reflects the ethnic heterogeneity of the Brazilian population.","variants":[{"Name":"NM_004004.6(GJB2):c.167del (p.Leu56fs)","Chromosome":"13","Start":"20189415","Stop":"20189415","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":32049,"rule_based_match":true,"evidence_text":"c.167delT","llm_judgment":"PRESENT","evidence":"c.167delT","abstract_start":611,"abstract_end":620},{"Name":"NM_004004.6(GJB2):c.583A>G (p.Met195Val)","Chromosome":"13","Start":"20188999","Stop":"20188999","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":227350,"rule_based_match":false,"evidence_text":"c.583A>G (p.Met195Val)","llm_judgment":"PRESENT","evidence":"p.Met195Val","abstract_start":2000,"abstract_end":2011},{"Name":"NM_004004.6(GJB2):c.176_191del (p.Gly59fs)","Chromosome":"13","Start":"20189391","Stop":"20189406","ReferenceAlleleVCF":"GCACACGTTCTTGCAGC","AlternateAlleleVCF":"G","allel_id":269143,"rule_based_match":true,"evidence_text":"c.176_191del16","llm_judgment":"PRESENT","evidence":"c.176_191del16","abstract_start":1632,"abstract_end":1646}]}
{"pmid":"30781664","title":"Novel Missense Mutations in","abstract":"To identify <i>Bestrophin 1</i> (<i>BEST1</i>) causative mutations in six Lebanese patients from three families, of whom four had a presumed clinical diagnosis of autosomal recessive bestrophinopathy (ARB) and two showed a phenotype with a single vitelliform lesion, patients were subjected to standard ophthalmic examinations. In addition, <i>BEST1</i> exons and their flanking regions were amplified and sequenced by Sanger sequencing. Co-segregation and detailed bio-informatic analyses were performed. Clinical examination results were consistent with ARB diagnosis for all index patients showing multifocal vitelliform lesions and a markedly reduced light peak in the electrooculogram, including the two patients with a single vitelliform lesion. In all cases, most likely disease-causing <i>BEST1</i> mutations co-segregated with the phenotype. The ARB cases showed homozygous missense variants (M1, c.209A>G, p.(Asp70Gly) in exon 3, M2, c.1403C>T; p.(Pro468Leu) in exon 10 and M3, c.830C>T, p.(Thr277Met) in exon 7), while the two patients with a single vitelliform lesion were compound heterozygous for M1 and M2. To our knowledge, this is the first study describing mutations in Lebanese patients with bestrophinopathy, where novel biallelic <i>BEST1</i> mutations associated with two phenotypes were identified. Homozygous mutations were associated with multifocal lesions, subretinal fluid, and intraretinal cysts, whereas compound heterozygous ones were responsible for a single macular vitelliform lesion.","variants":[{"Name":"NM_004183.4(BEST1):c.830C>T (p.Thr277Met)","Chromosome":"11","Start":"61958261","Stop":"61958261","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":838609,"rule_based_match":true,"evidence_text":"c.830C>T, p.(Thr277Met)","llm_judgment":"PRESENT","evidence":"c.830C>T, p.(Thr277Met)","abstract_start":988,"abstract_end":1011},{"Name":"NM_004183.4(BEST1):c.1403C>T (p.Pro468Leu)","Chromosome":"11","Start":"61962557","Stop":"61962557","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1287506,"rule_based_match":true,"evidence_text":"c.1403C>T; p.(Pro468Leu)","llm_judgment":"PRESENT","evidence":"c.1403C>T; p.(Pro468Leu)","abstract_start":944,"abstract_end":968}]}
{"pmid":"28477318","title":"Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers.","abstract":"This is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C > T) and the most frequently detected mutations were c.68_69delAG, c.212 + 1G > A, c.5123C > A, c.211A > G and c.1918C > T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G > A, c.3264dupT and c.3455T > G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212 + 1G > A appeared in an important percentage of breast and ovarian cancer cases, c.5123C > A in bilateral breast cancer and c.9117G > A in bilateral breast cancer and ovarian cancer. With respect to clinical-pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained.","variants":[{"Name":"NM_007294.4(BRCA1):c.212+1G>A","Chromosome":"17","Start":"43106455","Stop":"43106455","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46002,"rule_based_match":true,"evidence_text":"c.212 + 1G > A","llm_judgment":"PRESENT","evidence":"c.212 + 1G > A","abstract_start":570,"abstract_end":584},{"Name":"NM_000059.4(BRCA2):c.3264dup (p.Gln1089fs)","Chromosome":"13","Start":"32337618","Stop":"32337619","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":46386,"rule_based_match":true,"evidence_text":"c.3264dupT","llm_judgment":"PRESENT","evidence":"c.3264dupT","abstract_start":787,"abstract_end":797},{"Name":"NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)","Chromosome":"13","Start":"32379913","Stop":"32379913","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46771,"rule_based_match":true,"evidence_text":"c.9117G > A","llm_judgment":"PRESENT","evidence":"c.9117G > A","abstract_start":774,"abstract_end":785},{"Name":"NM_007294.4(BRCA1):c.5123C>A (p.Ala1708Glu)","Chromosome":"17","Start":"43063903","Stop":"43063903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":70074,"rule_based_match":true,"evidence_text":"c.5123C > A","llm_judgment":"PRESENT","evidence":"c.5123C > A","abstract_start":586,"abstract_end":597},{"Name":"NM_007294.4(BRCA1):c.68_69del (p.Glu23fs)","Chromosome":"17","Start":"43124028","Stop":"43124029","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":32701,"rule_based_match":true,"evidence_text":"c.68_69delAG","llm_judgment":"PRESENT","evidence":"c.68_69delAG","abstract_start":556,"abstract_end":568},{"Name":"NM_000059.4(BRCA2):c.3455T>G (p.Leu1152Ter)","Chromosome":"13","Start":"32337810","Stop":"32337810","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":66138,"rule_based_match":true,"evidence_text":"c.3455T>G","llm_judgment":"PRESENT","evidence":"c.3455T > G","abstract_start":802,"abstract_end":813},{"Name":"NM_007294.4(BRCA1):c.3205C>T (p.Gln1069Ter)","Chromosome":"17","Start":"43092326","Stop":"43092326","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":913903,"rule_based_match":true,"evidence_text":"c.3205C > T","llm_judgment":"PRESENT","evidence":"c.3205C > T","abstract_start":495,"abstract_end":506}]}
{"pmid":"34156493","title":"A Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut Lesions: A Case Report.","abstract":"Osteogenesis imperfecta (OI) and other decreased bone density disorders comprise a heterogeneous group of heritable diseases with skeletal fragility. Recently, it was discovered that mutations in SGMS2, encoding sphingomyelin synthetase 2, result in aberrant sphingomyelin metabolism and lead to a novel form of OI termed osteoporosis with calvarial doughnut lesions (OP-CDL) with moderate to severe skeletal fragility and variable cranial hyperostotic lesions. This study describes a Japanese family with the skeletal phenotype of OP-CDL. The affected individuals have moderately severe, childhood-onset skeletal fragility with multiple long-bone fractures, scoliosis and bone deformities. In addition, they exhibit multiple CDLs or calvarial bumps with central radiolucency and peripheral radiopacity. However, SGMS2 sequencing was normal. Instead, whole-exome sequencing identified a novel IFITM5 missense mutation c.143A>G (p.N48S) (classified as a VUS by ACMG). IFITM5 encodes an osteoblast-restricted protein BRIL and a recurrent c.-14C>T mutation in its 5' UTR region results in OI type V, a distinctive subtype of OI associated with hyperplastic callus formation and ossification of the interosseous membranes. The patients described here have a phenotype clearly different from OI type V and with hyperostotic cranial lesions, feature previously unreported in association with IFITM5. Our findings expand the genetic spectrum of OP-CDL, indicate diverse phenotypic consequences of pathogenic IFITM5 variants, and imply an important role for BRIL in cranial skeletogenesis.","variants":[{"Name":"NM_001025295.3(IFITM5):c.143A>G (p.Asn48Ser)","Chromosome":"11","Start":"299348","Stop":"299348","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1324229,"rule_based_match":true,"evidence_text":"c.143A>G (p.N48S)","llm_judgment":"PRESENT","evidence":"c.143A>G (p.N48S)","abstract_start":918,"abstract_end":935}]}
{"pmid":"29899372","title":"Developmental epileptic encephalopathy with hypomyelination and brain atrophy associated with PTPN23 variants affecting the assembly of UsnRNPs.","abstract":"PTPN23 encodes a ubiquitously expressed non-receptor type, catalytically inactive protein-tyrosine phosphatase found in all cells including neurons. Recently, we have identified PTPN23 in a cellular screen for the systematic identification of novel regulators of survival motor neuron (SMN) function in the assembly of splicing factors (Uridine-rich small nuclear ribonucleoproteins, UsnRNPs). Based on three families, recessive PTPN23 variants have been associated with human disease tentatively, without functional studies. Here, we describe a pediatric proband with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy on MRI. Whole exome sequencing and family study showed two novel PTPN23 variants, c.1902C>G (p.(Asn634Lys)) and c.2974delC (p.(Leu992Tyrfs*168)), in compound heterozygous state, which are predicted in silico to be damaging. When studying patient's fibroblasts we found similar expression of SMN but a dramatic reduction of cells displaying SMN accumulation in Cajal bodies (CB). SMN strongly accumulated in CB in more than 50% of unrelated control cell fibroblasts as well as in fibroblasts from the parent carrying only the c.2974delC (p.(Leu992Tyrfs*168)) variant (predicted to cause loss-of-function). In contrast, only 22% of cells showed respective SMN accumulations in patient fibroblasts (p = 1.9-2.5 × 10<sup>-7</sup>) while showing a higher level of nucleoplasmic SMN. Furthermore, the remaining accumulations in patient cells displayed weaker SMN signals than control or heterozygous wt/c.2974delC (p.(Leu992Tyrfs*168)) fibroblasts. Our report provides the first description of the clinical phenotype of recessive PTPN23 variants with pathogenicity substantiated by a functional study.","variants":[{"Name":"NM_015466.4(PTPN23):c.2974del (p.Leu992fs)","Chromosome":"3","Start":"47410771","Stop":"47410771","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":904114,"rule_based_match":true,"evidence_text":"c.2974delC (p.(Leu992Tyrfs*168))","llm_judgment":"PRESENT","evidence":"c.2974delC (p.(Leu992Tyrfs*168))","abstract_start":773,"abstract_end":805},{"Name":"NM_015466.4(PTPN23):c.1902C>G (p.Asn634Lys)","Chromosome":"3","Start":"47409521","Stop":"47409521","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":904115,"rule_based_match":true,"evidence_text":"c.1902C>G (p.(Asn634Lys))","llm_judgment":"PRESENT","evidence":"c.1902C>G (p.(Asn634Lys))","abstract_start":743,"abstract_end":768}]}
{"pmid":"20142525","title":"Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin.","abstract":"OBJECTIVE: To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), with emphasis on the unique clinical features in this kindred.\nDESIGN: Antemortem and postmortem characterization of a kindred with a familial neurodegenerative disorder.\nSETTING: Multispecialty group academic medical center.\nPATIENTS: Affected members of a kindred with dementia with or without parkinsonism associated with a unique mutation in PGRN.\nMAIN OUTCOME MEASURE: Genotype-phenotype correlation.\nRESULTS: Of 10 affected individuals identified, 6 presented with early amnestic symptoms which resulted in initial diagnoses of Alzheimer disease or amnestic mild cognitive impairment. Some individuals presented with features characteristic of frontotemporal dementia. Mean age at onset was substantially younger in generation III (75.8 years; range, 69-80 years) than in generation II (60.7 years; range, 55-66 years). The pattern of cerebral atrophy varied widely in the affected individuals. Neuropathologic features in 6 individuals included frontotemporal lobar degeneration with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U with NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), which caused a frameshift (p.Thr52HisfsX2) and, therefore, creation of a premature termination codon and a likely null allele.\nCONCLUSIONS: In this large kindred, most affected individuals had clinical presentations that resembled Alzheimer disease or amnestic mild cognitive impairment associated with a mutation in PGRN and underlying FTLD-U with NII neuropathologic abnormalities. This finding is in distinct contrast to previously reported kindreds, in which clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age at onset between generations requires further study.","variants":[{"Name":"NM_002087.4(GRN):c.154del (p.Thr52fs)","Chromosome":"17","Start":"44349440","Stop":"44349440","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":104019,"rule_based_match":true,"evidence_text":"c.154delA","llm_judgment":"PRESENT","evidence":"c.154delA","abstract_start":1270,"abstract_end":1279}]}
{"pmid":"32871939","title":"Familial hypocalciuric hypercalcemia caused by homozygous CaSR gene mutation: A case report of a family.","abstract":"INTRODUCTION: Familial hypocalciuric hypercalcemia (FHH) is a group of autosomal dominant genetic diseases with persistent hypercalcemia and hypocalciuria. The calcium-sensitive receptor (CaSR) plays an important role in calcium and phosphorus metabolism.\nPATIENT CONCERNS: A 32-year-old man who had diabetes was admitted to our hospital due to poor glycemic control, and was found to have hypercalcemia, hypophosphatemia, and hyperparathyroidism. Single-Photon Emission Computed Tomography (SPECT) (99-mTcMIBI) examination result was negative. The result of 24-h urine calcium was 2.18 mmol/24 h, and the 24-h urinary calcium to creatinine ratio (UCCR) was 0.006. Family survey showed that all of the family members had hypercalcemia.\nDIAGNOSIS: The CaSR gene mutation study revealed that the proband had a homozygous mutation for a T>C nucleotide substitution at c.1664 in exon 6, while both the mother and the father had heterozygous mutations at the same site of exon 6. The clinical diagnosis was considered to be FHH type1.\nINTERVENTIONS: The patient was treated with conventional calcium-lowering therapy which was not effective. Cinacalcet was suggested but not used. The patient received salmon calcitonin nasal spray and furosemide tablets treatment for 1 month after discharge, and then stopped the medication.\nOUTCOMES: On follow up 4 months after being discharged, the serum calcium level was 3.18 mmol/L, and the PTH level was 275.4 ng/mL. He had felt fatigued, intermittent abdominal pain and lost 3.9 kg of weight.\nCONCLUSION: This case studied a family with FHH, and the CaSR gene c.1664T>c mutation was the possible pathogenic cause. If parathyroid location examination is unclear for hyperparathyroidism, the possibility of FHH should be considered. For FHH patients, conventional calcium reduction therapy was ineffective and parathyroid surgery cannot alleviate their hypercalcemia.","variants":[{"Name":"NM_000388.4(CASR):c.1664T>C (p.Ile555Thr)","Chromosome":"3","Start":"122282168","Stop":"122282168","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":792992,"rule_based_match":true,"evidence_text":"c.1664T>C","llm_judgment":"PRESENT","evidence":"c.1664T>c","abstract_start":1598,"abstract_end":1607}]}
{"pmid":"23556337","title":"CYP2C9*3(1075A > C), ABCB1 and SLCO1B1 genetic polymorphisms and gender are determinants of inter-subject variability in pitavastatin pharmacokinetics.","abstract":"A pharmacokinetics study was conducted in 12 Chinese volunteers following a single dose of 1 mg, 2 mg and 4 mg of pitavastatin calcium in an open-label, randomized, three-period crossover design. Plasma concentrations of pitavastatin acid and pitavastatin lactone were determined by a HPLC method. Single-nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLCO1B1, CYP2C9 and CYP3A5 were determined by TaqMan (MGB) genotyping assay. An analysis was performed on the relationship between the aforementioned SNPs and dose-normalized (based on 1 mg) area under the plasma concentration-time curve extrapolated to infinity [AUC(0-infinity)] and peak plasma concentration (Cmax) values of the acid and lactone forms of pitavastatin. Pitavastatin exhibited linear pharmacokinetics and great inter-subject variability. Compared to CYP2C9*1/*1 carriers, CYP2C9*1/*3 carriers had higher AUC(0-infinity) and Cmax of pitavastatin acid and AUC(0-infinity) of pitavastatin lactone (P<0.05). With respect to ABCB1 G2677T/A, non-G carriers had higher Cmax and AUC(0-infinity) of pitavastatin acid, and Cmax of pitavastatin lactone compared to GT, GA or GG genotype carriers (P<0.05). Gene-dose effects of SLCO1B1 c.521T> C and g.11187G > A on pharmacokinetics of the acid and lactone forms were observed. Compared to non-SLCO1B1*17 carriers, SLCO1B1*17 carriers had higher Cmax and AUC(0-infinity) of the acid and lactone forms (P<0.05). Significant sex difference was observed for pharmacokinetics of the lactone. Female SLCO1B1 521TT subjects had higher Cmax and AUC(0-infinity) of pitavastatin lactone compared to male 521TT subjects, however, such gender difference disappeared in 521 TC and 521CC subjects. Pitavastatin pharmacokinetics was not significantly affected by ABCB1 C1236T, ABCB1C3435T, CYP3A5*3, ABCG2 c.34G > A, c.421C > A, SLCO1B1 c.388A>G, c.571T>C and c.597C>T. We conclude that CYP2C9*3, ABCB1 G2677T/A, SLCO1B1 c.521T>C, SLCO1B1 g.11187G > A, SLCO1B1*17 and gender contribute to inter-subject variability in pitavastatin pharmacokinetics. Personalized medicine should be necessary for hypercholesterolaemic patients receiving pitavastatin.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":true,"evidence_text":"SLCO1B1 c.521T>C","llm_judgment":"PRESENT","evidence":"SLCO1B1 c.521T>C","abstract_start":1909,"abstract_end":1925}]}
{"pmid":"19352439","title":"Novel ABCA4 compound heterozygous mutations cause severe progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease.","abstract":"PURPOSE: To identify the gene causing a severe form of progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease and to characterize clinical features in a large American family.\nMETHODS: We characterized an American family who had an unusual retinal dystrophy with clinical features of Stargardt disease and severe progressive cone-rod dystrophy. Family members underwent complete ocular examinations with evaluation of visual acuity, visual fields, fundus examination, fluorescein angiography, and electroretinography. Genome-wide linkage analysis of the family was performed using 408 microsatellite markers spanning the entire human genome. Direct DNA sequence analysis was used for mutational analysis of the ABCA4 gene in all exons and exon-intron boundary regions and for testing cosegregation of the mutations with the disease in the family. DNA sequence analysis was used to determine the presence of the mutations in 200 unrelated controls.\nRESULTS: The proband presented with a clinical phenotype that was initially compatible with Stargardt disease, only to progress to a severe cone-rod dystrophy over the course of a few years. The disease-causing gene in the family was linked to the ABCA4 locus on chromosomal 1p22. One novel mutation, c.655A>T, was identified in exon 6 and another novel splicing mutation, c.5312+3A>T, was identified in intron 37 of ABCA4. The mutations were not present in 200 controls. The two affected sisters in this pedigree were compound heterozygotes for the mutations. Unaffected family members either did not carry either or had only one of the two mutations.\nCONCLUSIONS: We have identified two novel ABCA4 mutations, c.655A>T and c.5312+3A>T. When present as a compound heterozygous state, the mutations cause a phenotype of retinal dystrophy that initially manifests as Stargardt disease and slowly progresses to a severe cone-rod dystrophy. These results expand the wide range of clinical manifestations of ABCA4 mutations.","variants":[{"Name":"NM_000350.3(ABCA4):c.5312+3A>T","Chromosome":"1","Start":"94015736","Stop":"94015736","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":620729,"rule_based_match":true,"evidence_text":"c.5312+3A>T","llm_judgment":"PRESENT","evidence":"c.5312+3A>T","abstract_start":1349,"abstract_end":1360},{"Name":"NM_000350.3(ABCA4):c.655A>T (p.Arg219Ter)","Chromosome":"1","Start":"94098907","Stop":"94098907","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":259684,"rule_based_match":true,"evidence_text":"c.655A>T","llm_judgment":"PRESENT","evidence":"c.655A>T","abstract_start":1277,"abstract_end":1285}]}
{"pmid":"24273071","title":"Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene.","abstract":"Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis.","variants":[{"Name":"NM_001853.4(COL9A3):c.1176_1198del (p.Gln393fs)","Chromosome":"20","Start":"62830374","Stop":"62830396","ReferenceAlleleVCF":"CACAAGGCCCTCCCGGAGCCCCTG","AlternateAlleleVCF":"C","allel_id":171285,"rule_based_match":true,"evidence_text":"c.1176_1198del","llm_judgment":"PRESENT","evidence":"c.1176_1198del","abstract_start":980,"abstract_end":994}]}
{"pmid":"30843739","title":"First Report on the Coinheritance of α-Thalassemia and a Rare β-Thalassemia Compound Heterozygosity for the IVS-I-I(G>A)/IVS-II-705(T>G) Mutations in a Syrian Family.","abstract":"We describe a proband originating from Al-Quneitra Province, Syria. His hematology data was as follows: Hb A 24.7%, Hb F 71.1%, Hb A<sub>2</sub> 4.2%. Molecular analysis, based on DNA sequencing of the β-globin gene mutation, showed for the first time a compound heterozygous IVS-I-1 (G>A) (<i>HBB</i>: c.92+1G>A)/IVS-II-705 (T>G) (<i>HBB</i>: c.316-146T>G) on the β-globin gene. A reverse hybridization technique revealed that the proband was also an α-thalassemia (α-thal) -α<sup>3.7</sup> (rightward) deletion carrier. Haplotypes analysis for the seven polymorphic restriction sites showed that the compound heterozygous mutations, IVS-I-1/IVS-II-705, were linked to two haplotypes: I [+ - - - - + +] and VI [- + + - - - +], respectively. Our results showed, for the first time, the presence of rare β-thalassemia (β-thal) IVS-II-705 (T>G) mutation associated with IVS-I-1 (G>A). Our findings suggest the presence of these mutations resulted from past migrations.","variants":[{"Name":"NM_000518.5(HBB):c.316-146T>G","Chromosome":"11","Start":"5225872","Stop":"5225872","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":44976,"rule_based_match":true,"evidence_text":"IVS-II-705 (T>G) (HBB: c.316-146T>G)","llm_judgment":"PRESENT","evidence":"c.316-146T>G","abstract_start":344,"abstract_end":356},{"Name":"NM_000518.5(HBB):c.92+1G>A","Chromosome":"11","Start":"5226929","Stop":"5226929","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30475,"rule_based_match":true,"evidence_text":"c.92+1G>A","llm_judgment":"PRESENT","evidence":"c.92+1G>A","abstract_start":303,"abstract_end":312}]}
{"pmid":"30782472","title":"Clinical features, molecular characteristics, and treatments of a Chinese girl with sitosterolemia: A case report and literature review.","abstract":"Sitosterolemia is a rare autosomal recessive disease characterized by a significant increase in blood plant sterol levels. Clinical manifestations usually include xanthomas, hypercholesterolemia,premature atherosclerosis and hematological abnormalities. We report here a sitosterolemia patient who presented with multiple xanthomas and profound hypercholesterolemia since 3 years old. The girl was mistreated as familial hypercholesterolemia for 6 years until correct diagnosis was made by detecting serum plant cholesterol levels. Sequence analysis revealed compound heterozygous mutations in ABCG5 gene, including the previously reported mutation c.904+1G＞A and a novel missense mutation c.1528C＞A. Although cholestyramine therapy reduced cholesterol level in association with marked regress of the xanthomas, serum plant sterol levels still remain high. Our study suggests that patients develop severe hypercholesterolemia and xanthomas at early age should be suspected of sitosterolemia. In addition, we also describe a novel missense mutation in exon 11 of the ABCG5 gene, which enriches the genetic mutation spectrum of sitosterolemia.","variants":[{"Name":"NM_022436.3(ABCG5):c.904+1G>A","Chromosome":"2","Start":"43824888","Stop":"43824888","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3578820,"rule_based_match":false,"evidence_text":"c.904+1G＞A","llm_judgment":"PRESENT","evidence":"c.904+1G＞A","abstract_start":649,"abstract_end":659},{"Name":"NM_022436.3(ABCG5):c.1528C>A (p.His510Asn)","Chromosome":"2","Start":"43820036","Stop":"43820036","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":586524,"rule_based_match":false,"evidence_text":"c.1528C＞A","llm_judgment":"PRESENT","evidence":"c.1528C＞A","abstract_start":690,"abstract_end":699}]}
{"pmid":"20399249","title":"Mutation analysis of parkin and PINK1 genes in early-onset Parkinson's disease in China.","abstract":"A series of 69 Han Chinese PD patients (including 66 index cases and 3 relatives) with early-onset Parkinson's disease (EOPD) were studied to assess the frequency of parkin and PINK1 gene mutations. Mutation analysis of the parkin gene was performed by real-time quantitative polymerase chain reaction (QPCR), denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing. For the PINK1 gene, DHPLC and DNA sequencing were used. Nineteen patients (including one relative) had mutation in the parkin gene, and the c.2T > C (p.M1T) was not reported previously. No mutation of the PINK1 gene was found. The onset age of the patients with mutations in the parkin was earlier than that of those without mutation (p < 0.05). We concluded that mutations in parkin gene are common in Chinese EOPD patients, and mainly are exon rearrangements, while mutation in PINK1 might be not common in Chinese EOPD patients.","variants":[{"Name":"NM_004562.3(PRKN):c.2T>C (p.Met1Thr)","Chromosome":"6","Start":"162727667","Stop":"162727667","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":793179,"rule_based_match":true,"evidence_text":"c.2T > C (p.M1T)","llm_judgment":"PRESENT","evidence":"c.2T > C (p.M1T)","abstract_start":528,"abstract_end":544}]}
{"pmid":"38013626","title":"Biallelic variants in the COQ4 gene caused hereditary spastic paraplegia predominant phenotype.","abstract":"INTRODUCTION: Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by progressive degeneration of upper motor neurons. Homozygous or compound heterozygous variants in COQ4 have been reported to cause primary CoQ10 deficiency-7 (COQ10D7), which is a mitochondrial disease.\nAIMS: We aimed to screened COQ4 variants in a cohort of HSP patients.\nMETHODS: A total of 87 genetically unidentified HSP index patients and their available family members were recruited. Whole exome sequencing (WES) was performed in all probands. Functional studies were performed to identify the pathogenicity of those uncertain significance variants.\nRESULTS: In this study, five different COQ4 variants were identified in three Chinese HSP pedigrees and two variants were novel, c.87dupT (p.Arg30*), c.304C>T (p.Arg102Cys). More importantly, we firstly described two early-onset pure HSP caused by COQ4 variants. Functional studies in patient-derived fibroblast lines revealed a reduction cellular CoQ10 levels and the abnormal mitochondrial structure.\nCONCLUSIONS: Our findings revealed that bilateral variants in the COQ4 gene caused HSP predominant phenotype, expanding the phenotypic spectrum of the COQ4-related disorders.","variants":[{"Name":"NM_016035.5(COQ4):c.87dup (p.Arg30Ter)","Chromosome":"9","Start":"128323031","Stop":"128323032","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":2847058,"rule_based_match":true,"evidence_text":"c.87dupT (p.Arg30*)","llm_judgment":"PRESENT","evidence":"c.87dupT (p.Arg30*)","abstract_start":802,"abstract_end":821},{"Name":"NM_016035.5(COQ4):c.304C>T (p.Arg102Cys)","Chromosome":"9","Start":"128325783","Stop":"128325783","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":622394,"rule_based_match":true,"evidence_text":"c.304C>T (p.Arg102Cys)","llm_judgment":"PRESENT","evidence":"c.304C>T (p.Arg102Cys)","abstract_start":823,"abstract_end":845}]}
{"pmid":"32467598","title":"Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia.","abstract":"Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients' movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.","variants":[{"Name":"NM_002599.5(PDE2A):c.1922+5G>A","Chromosome":"11","Start":"72581872","Stop":"72581872","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":983531,"rule_based_match":true,"evidence_text":"c.1922+5G>A","llm_judgment":"PRESENT","evidence":"c.1922+5G>A","abstract_start":852,"abstract_end":863},{"Name":"NM_002599.5(PDE2A):c.446C>T (p.Pro149Leu)","Chromosome":"11","Start":"72596636","Stop":"72596636","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":983532,"rule_based_match":true,"evidence_text":"c.446C>T; p.(Pro149Leu)","llm_judgment":"PRESENT","evidence":"c.446C>T; p.(Pro149Leu)","abstract_start":804,"abstract_end":827},{"Name":"NM_002599.5(PDE2A):c.1180C>T (p.Gln394Ter)","Chromosome":"11","Start":"72586072","Stop":"72586072","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":677070,"rule_based_match":true,"evidence_text":"c.1180C>T; p.(Gln394*)","llm_judgment":"PRESENT","evidence":"c.1180C>T; p.(Gln394*)","abstract_start":698,"abstract_end":720}]}
{"pmid":"20224275","title":"Mutations in the OTOF gene in Taiwanese patients with auditory neuropathy.","abstract":"Mutations in the OTOF gene have been found to be common causes of auditory neuropathy (AN) in Caucasians. However, the prevalence and spectrum of OTOF mutations in other populations have been inadequately documented. To explore the genetic characteristics of East Asian patients with AN, we screened for mutations in the OTOF gene by direct sequencing in 22 unrelated Taiwanese AN families (including 2 multiplex and 20 simplex families) and looked for genotype-phenotype correlations. Among the probands of the 22 AN families, a novel OTOF variant, p.E1700Q (c.5098G→C), was identified in 5 probands (23%), including 4 homozygotes and 1 heterozygote. By using restriction fragment length polymorphism to screen another 500 unrelated patients with idiopathic sensorineural hearing impairment, we further identified 1 p.E1700Q homozygote who also had clinical features compatible with AN. Furthermore, p.E1700Q was not identified in a panel of 100 normal controls, it cosegregated with the AN phenotype in the pedigrees, and the p.E1700 residue is evolutionarily conserved, consistent with its pathogenicity for AN. The associated audiologic features included progressive, prelingual, bilateral moderate-to-profound sensorineural hearing loss with a flat-type audiogram configuration. After genotyping single-nucleotide polymorphisms in the vicinity of p.E1700Q, we found that OTOF alleles with p.E1700Q shared a common haplotype, suggesting a founder effect for p.E1700Q. The predominance of the p.E1700Q mutation and the evidence of its founder effect indicate a distinct OTOF mutation spectrum in Taiwanese patients with AN.","variants":[{"Name":"NM_194248.3(OTOF):c.5098G>C (p.Glu1700Gln)","Chromosome":"2","Start":"26463969","Stop":"26463969","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":57417,"rule_based_match":false,"evidence_text":"c.5098G→C","llm_judgment":"PRESENT","evidence":"c.5098G→C","abstract_start":560,"abstract_end":569}]}
{"pmid":"27521129","title":"Identification of a novel splice site HSPG2 mutation and prenatal diagnosis in Schwartz Jampel Syndrome type 1 using whole exome sequencing.","abstract":"Schwartz-Jampel Syndrome type 1 is a rare autosomal recessive musculoskeletal disorder (OMIM #255800) caused by various mutations in the HSPG2 gene encoding protein perlecan, a ubiquitous heparan sulfate proteoglycan, which is an integral component of basement membranes and possesses angiogenic and growth-promoting attributes primarily by acting as a co-receptor for the basic fibroblast growth factors in human body. We report a novel homozygous intronic 5' splice site mutation in this gene (c.4740 + 5G>A) in a child with clinical features of Schwartz-Jampel syndrome type 1. The mutation was detected by exome sequencing and later confirmed by Sanger sequencing. The mother was found to be heterozygous for the mutation and an ongoing pregnancy found to be unaffected. cDNA analysis revealed skipping of exon 37 of HSPG2 gene in the patient due to the splicing error caused by this mutation. This is likely to result in loss of 38 amino acids from the domain III of the perlecan protein and presumably affects its structure and function as per protein modeling predictions. This report demonstrates the utility of exome sequencing as a routine molecular diagnostic approach of choice for this rare disorder.","variants":[{"Name":"NM_005529.7(HSPG2):c.4740+5G>A","Chromosome":"1","Start":"21864095","Stop":"21864095","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":260932,"rule_based_match":true,"evidence_text":"c.4740 + 5G>A","llm_judgment":"PRESENT","evidence":"c.4740 + 5G>A","abstract_start":496,"abstract_end":509}]}
{"pmid":"31439979","title":"Microduplication of Xp22.31 and","abstract":"Rett syndrome (RS) is a neurodevelopmental infantile disease characterized by an early normal psychomotor development followed by a regression in the acquisition of normal developmental stages. In the majority of cases, it leads to a sporadic mutation in the <i>MECP2</i> gene, which is located on the X chromosome. However, this syndrome has also been associated with microdeletions, gene translocations, and other gene mutations. A 12-year-old female Colombian patient was presented with refractory epilepsy and regression in skill acquisition (especially language with motor and verbal stereotypies, hyperactivity, and autistic spectrum disorder criteria). The patient was born to non-consanguineous parents and had an early normal development until the age of 36 months. Comparative genomic hybridization array-CGH (750K) was performed and Xp22.31 duplication was detected (6866889-8115153) with a size of 1.248 Mb associated with developmental delay, epilepsy, and autistic traits. Given the clinical criteria of RS, <i>MECP2</i> sequencing was performed which showed a de novo pathogenic variant c.338C>G (p.Pro113Arg). The features of RS include intellectual disability, developmental delay, and autism. These features are associated with copy number variations (CNVs) on the X chromosome (Xp22.31 microduplication). Here we present the first reported case of simultaneous CNV and <i>MECP2</i> pathogenic mutation in a patient with RS. We propose that both DNA alterations might have a synergistic effect and could lead to variable expressivity of the phenotype.","variants":[{"Name":"NM_001110792.2(MECP2):c.338C>G (p.Pro113Arg)","Chromosome":"X","Start":"154032282","Stop":"154032282","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":153258,"rule_based_match":true,"evidence_text":"c.338C>G (p.Pro113Arg)","llm_judgment":"PRESENT","evidence":"c.338C>G (p.Pro113Arg)","abstract_start":1102,"abstract_end":1124}]}
{"pmid":"33150274","title":"Multiple Endocrine Neoplasia Type 1 (MEN1) Phenocopy Due to a Cell Cycle Division 73 (","abstract":"Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid tumors, pituitary adenomas, and pancreatic neuroendocrine neoplasms (PNENs). MEN1 is caused by germline <i>MEN1</i> mutations in > 75% of patients, and the remaining 25% of patients may have mutations in unidentified genes or represent phenocopies with mutations in genes such as cell cycle division 73 (<i>CDC73)</i>, the calcium sensing receptor (<i>CASR)</i>, and cyclin-dependent kinase inhibitor 1B (<i>CDKN1B)</i>, which are associated with the hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia type 1, and MEN4, respectively. Here, we report a heterozygous c.1138C>T (p.Leu380Phe) <i>CDC73</i> germline variant in a clinically diagnosed MEN1 patient, based on combined occurrence of primary hyperparathyroidism, acromegaly, and a PNEN. Characterization of the PNEN confirmed it was a neuroendocrine neoplasm as it immuno-stained positively for chromogranin and glucagon. The rare variant p.Leu380Phe occurred in a highly conserved residue, and further analysis using RNA-Scope indicated that it was associated with a significant reduction in <i>CDC73</i> expression in the PNEN. Previously, <i>CDC73</i> mutations have been reported to be associated with tumors of the parathyroids, kidneys, uterus, and exocrine pancreas. Thus, our report of a patient with PNEN and somatotrophinoma who had a <i>CDC73</i> variant, provides further evidence that <i>CDC73</i> variants may result in a MEN1 phenocopy.","variants":[{"Name":"NM_024529.5(CDC73):c.1138C>T (p.Leu380Phe)","Chromosome":"1","Start":"193212461","Stop":"193212461","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3138523,"rule_based_match":true,"evidence_text":"c.1138C>T (p.Leu380Phe)","llm_judgment":"PRESENT","evidence":"c.1138C>T (p.Leu380Phe)","abstract_start":724,"abstract_end":747}]}
{"pmid":"17171570","title":"A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss.","abstract":"Usher syndrome is an autosomal recessive condition characterized by sensorineural hearing loss, variable vestibular dysfunction, and visual impairment due to retinitis pigmentosa (RP). The seven proteins that have been identified for Usher syndrome type 1 (USH1) and type 2 (USH2) may interact in a large protein complex. In order to identify novel USH genes, we followed a candidate strategy, assuming that mutations in proteins interacting with this \"USH network\" may cause Usher syndrome as well. The DFNB31 gene encodes whirlin, a PDZ scaffold protein with expression in both hair cell stereocilia and retinal photoreceptor cells. Whirlin represents an excellent candidate for USH2 because it binds to Usherin (USH2A) and VLGR1b (USH2C). Genotyping of microsatellite markers specific for the DFNB31 gene locus on chromosome 9q32 was performed in a German USH2 family that had been excluded for all known USH loci. Patients showed common haplotypes. Sequence analysis of DFNB31 revealed compound heterozygosity for a nonsense mutation, p.Q103X, in exon 1, and a mutation in the splice donor site of exon 2, c.837+1G>A. DFNB31 mutations appear to be a rare cause of Usher syndrome, since no mutations were identified in an additional 96 USH2 patients. While mutations in the C-terminal half of whirlin have previously been reported in non-syndromic deafness (DFNB31), both alterations identified in our USH2 family affect the long protein isoform. We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function. We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin. Moreover, this is the first case of USH2 that is allelic to non-syndromic deafness.","variants":[{"Name":"NM_015404.4(WHRN):c.837+1G>A","Chromosome":"9","Start":"114478552","Stop":"114478552","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17730,"rule_based_match":true,"evidence_text":"c.837+1G>A","llm_judgment":"PRESENT","evidence":"c.837+1G>A","abstract_start":1110,"abstract_end":1120}]}
{"pmid":"29492181","title":"Frequency of","abstract":"BACKGROUND: Causative variants in <i>BRCA1</i> and <i>BRCA2</i> are well-established risk factors for breast and ovarian cancer. In Poland, the causative founder variants in the <i>BRCA1</i> are responsible for a significant proportion of ovarian cancer cases, however, regional differences in the frequencies of various mutations may exist. The spectrum and frequency of <i>BRCA1/2</i> mutations between ovarian cancer patients have not yet been studied in the region of South-East Poland.\nMETHODS: We examined 158 consecutive unselected cases of ovarian cancer patients from the region of Podkarpacie. We studied 13 Polish causative founder variants in <i>BRCA1</i> (c.5266dupC, c.4035delA, c.5251C > T, c.181 T > G, c.676delT, c.68_69delAG, c.3700_3704delGTAAA, c.1687C > T, c.3756_3759delGTCT) and in <i>BRCA2</i> (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT).\nRESULTS: A <i>BRCA1</i> causative founder variants were detected in 10 of the 158 (6.3%) ovarian cancer cases. <i>BRCA2</i> causative founder variants were not observed. The c.5266dupC mutation was detected in 6 patients, c.181 T > G mutation in 3 patients and the c.676delT mutation in 1 patient. The median age of diagnosis of the 10 hereditary ovarian cancers was 55.5 years of age.\nCONCLUSIONS: The frequency of 13 causative founder variants in Podkarpacie was lower than in other regions of Poland. Testing of three <i>BRCA1</i> mutations (c.5266dupC, c.181 T > G, c.676delT) should be considered a sensitive test panel.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"c.5266dupC","llm_judgment":"PRESENT","evidence":"c.5266dupC","abstract_start":669,"abstract_end":679},{"Name":"NM_007294.4(BRCA1):c.181T>G (p.Cys61Gly)","Chromosome":"17","Start":"43106487","Stop":"43106487","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":32700,"rule_based_match":true,"evidence_text":"c.181 T > G","llm_judgment":"PRESENT","evidence":"c.181 T > G","abstract_start":706,"abstract_end":717}]}
{"pmid":"19258401","title":"Genetics of pheochromocytoma and paraganglioma in Spanish patients.","abstract":"CONTEXT: The presence of familial history in pheochromocytoma/paraganglioma patients, including syndromic antecedents, leads in the majority of cases to a positive genetic testing for mutations in one of the major susceptibility genes described so far. Furthermore, it has been reported that in the absence of familial antecedents, about 11-24% of patients also carry a mutation in one of these related genes. In these cases, other clinical aspects like bilaterality, multiplicity, location of the tumors, or age at onset can help to recognize the underlying genes involved.\nOBJECTIVE: The objective of the study was to discuss clinical criteria helpful in the genetic diagnosis, placing special emphasis on apparently sporadic cases.\nDESIGN: Two hundred thirty-seven nonrelated probands were analyzed for the major susceptibility genes: VHL, RET, SDHB, SDHC, and SDHD. Genetic characterization included both point mutation analysis and gross deletions in the SDH genes performed by multiplex PCR.\nRESULTS: As expected, all syndromic probands were genetically diagnosed with a mutation affecting either RET or VHL. A total of 79.1% (19 of 24) and 18.4% (31 of 168) of patients presenting with either nonsyndromic familial antecedents or apparently sporadic presentation were found to carry a mutation in one of the susceptibility genes. Finally, we found a Spanish founder effect for two mutations: SDHB c.166_170delCCTCA and SDHD c.129G>A.\nCONCLUSIONS: Germline mutations are rare in apparently sporadic probands diagnosed after age 40 yr (3.9% in our series) and mainly involve SDHB. Therefore, we recommend prioritizing SDHB genetic testing in patients developing isolated tumors at any age, especially those with extraadrenal location or malignant behavior.","variants":[{"Name":"NM_003002.4(SDHD):c.129G>A (p.Trp43Ter)","Chromosome":"11","Start":"112087933","Stop":"112087933","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21952,"rule_based_match":true,"evidence_text":"SDHD c.129G>A","llm_judgment":"PRESENT","evidence":"SDHD c.129G>A","abstract_start":1426,"abstract_end":1439},{"Name":"NM_003000.3(SDHB):c.166_170del (p.Pro56fs)","Chromosome":"1","Start":"17044791","Stop":"17044795","ReferenceAlleleVCF":"ATGAGG","AlternateAlleleVCF":"A","allel_id":181622,"rule_based_match":true,"evidence_text":"SDHB c.166_170delCCTCA","llm_judgment":"PRESENT","evidence":"SDHB c.166_170delCCTCA","abstract_start":1399,"abstract_end":1421}]}
{"pmid":"32529721","title":"Identification of a nonsense mutation in TNNI3K associated with cardiac conduction disease.","abstract":"BACKGROUND: Cardiac conduction disease (CCD) is a common cardiovascular disease which can lead to life-threatening conditions. The importance of heredity in CCD has been realized in recent years. Several causal genes have been found to be implicated in CCD such as SCN5A, TRPM4, SCN1B, TNNI3K, LMNA, and NKX2.5. To date, only four genetic mutations in TNNI3K have been identified related to CCD.\nMETHODS: Whole-exome sequencing (WES) was carried out in order to identify the underlying disease-causing mutation in a Chinese family with CCD. The potential mutations were confirmed by Sanger sequencing. Real-time qPCR was used to detect the level of TNNI3K mRNA expression.\nRESULTS: A nonsense mutation in TNNI3K (NM_015978.2: g.170891C > T, c.1441C > T) was identified in this family and validated by Sanger sequencing. Real-time qPCR confirmed that the level of TNNI3K mRNA expression was decreased compared with the controls.\nCONCLUSIONS: This study found the first nonsense TNNI3K mutation associated with CCD in a Chinese family. TNNI3K harboring the mutation (c.1441C > T) implicated a loss-of-function pathogenic mechanism with an autosomal dominant inheritance pattern. This research enriches the phenotypic spectrum of TNNI3K mutations, casting a new light upon the genotype-phenotype correlations between TNNI3K mutations and CCD and indicating the importance of TNNI3K screening in CCD patients.","variants":[{"Name":"NM_015978.3(TNNI3K):c.1441C>T (p.Arg481Ter)","Chromosome":"1","Start":"74369233","Stop":"74369233","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1414271,"rule_based_match":true,"evidence_text":"NM_015978.2: g.170891C > T, c.1441C > T","llm_judgment":"PRESENT","evidence":"NM_015978.2: g.170891C > T, c.1441C > T","abstract_start":713,"abstract_end":752}]}
{"pmid":"34016807","title":"KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant.","abstract":"KIAA0753-related skeletal ciliopathy is a recently described recessive disorder causing skeletal dysplasia and overlapping features of certain ciliopathies; Joubert, Jeune and Oro-facial-digital syndromes. We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia. Testing for FGFR3 achondroplasia-related hotspots and mucopolysaccharidosis were negative. Whole-exome sequencing, aged eight, via skeletal dysplasia panel analysis and subsequent whole-genome sequencing (via the 100,000 genomes project) found no cause. WGS data reanalysis using exomiser uncovered compound heterozygous pathogenic KIAA0753 variants (frameshift and splice site). Further clinical and radiological surveys were consistent with the expected phenotype. We discuss the emerging phenotype of this uncommon disorder. This report details the sixth published case of skeletal dysplasia in all cases of KIAA0753-related disease and the first case to describe a novel c.1830-2A>G splice variant. Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.","variants":[{"Name":"NM_014804.3(KIAA0753):c.1830-2A>G","Chromosome":"17","Start":"6607272","Stop":"6607272","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1186010,"rule_based_match":true,"evidence_text":"c.1830-2A>G","llm_judgment":"PRESENT","evidence":"c.1830-2A>G","abstract_start":1229,"abstract_end":1240}]}
{"pmid":"30533531","title":"TPP2 mutation associated with sterile brain inflammation mimicking MS.","abstract":"OBJECTIVE: To ascertain the genetic cause of a consanguineous family from Syria suffering from a sterile brain inflammation mimicking a mild nonprogressive form of MS.\nMETHODS: We used homozygosity mapping and next-generation sequencing to detect the disease-causing gene in the affected siblings. In addition, we performed RNA and protein expression studies, enzymatic activity assays, immunohistochemistry, and targeted sequencing of further MS cases from Austria, Germany, Canada and Jordan.\nRESULTS: In this study, we describe the identification of a homozygous missense mutation (c.82T>G, p.Cys28Gly) in the tripeptidyl peptidase II (<i>TPP2</i>) gene in all 3 affected siblings of the family. Sequencing of all <i>TPP2</i>-coding exons in 826 MS cases identified one further homozygous missense variant (c.2027C>T, p.Thr676Ile) in a Jordanian MS patient. TPP2 protein expression in whole blood was reduced in the affected siblings. In contrast, TPP2 protein expression in postmortem brain tissue from MS patients without <i>TPP2</i> mutations was highly upregulated.\nCONCLUSIONS: The homozygous <i>TPP2</i> mutation (p.Cys28Gly) is likely responsible for the inflammation phenotype in this family. <i>TPP2</i> is an ubiquitously expressed serine peptidase that removes tripeptides from the N-terminal end of longer peptides. TPP2 is involved in various biological processes including the destruction of major histocompatibility complex Class I epitopes. Recessive loss-of-function mutations in <i>TPP2</i> were described in patients with Evans syndrome, a rare autoimmune disease affecting the hematopoietic system. Based on the gene expression results in our MS autopsy brain samples, we further suggest that <i>TPP2</i> may play a broader role in the inflammatory process in MS.","variants":[{"Name":"NM_001330588.2(TPP2):c.82T>G (p.Cys28Gly)","Chromosome":"13","Start":"102597120","Stop":"102597120","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1015306,"rule_based_match":true,"evidence_text":"c.82T>G, p.Cys28Gly","llm_judgment":"PRESENT","evidence":"c.82T>G, p.Cys28Gly","abstract_start":585,"abstract_end":604}]}
{"pmid":"26225579","title":"Novel CDKN2A mutations in Austrian melanoma patients.","abstract":"CDKN2A is the most prominent familial melanoma gene, with mutations occurring in up to 40% of the families. Numerous mutations in the gene are known, several of them representing regional founder mutations. We sought to determine, for the first time, germline mutations in CDKN2A in Austria to identify novel mutations. In total, 700 individuals (136 patients with a positive family history and 164 with at least two primary melanomas as the high-risk groups; 200 with single primary melanomas; and 200 healthy individuals as the control groups) were Sanger sequenced for CDKN2A exon 1α, 1β, and 2. The 136 patients with affected relatives were also sequenced for CDK4 exon 2. We found the disease-associated mutations p.R24P (8×), p.N71T (1×), p.G101W (1×), and p.V126D (1×) in the group with affected relatives and p.R24P (2×) in the group with several primary melanomas. Furthermore, we discovered four mutations of unknown significance, two of which were novel: p.A34V and c.151-4 G>C, respectively. Computational effect prediction suggested p.A34V as conferring a high risk for melanoma, whereas c.151-4 G>C, although being predicted as a splice site mutation by MutationTaster, could not functionally be confirmed to alter splicing. Moreover, computational effect prediction confirmed accumulation of high-penetrance mutations in high-risk groups, whereas mutations of unknown significance were distributed across all groups. p.R24P is the most common high-risk mutation in Austria. In addition, we discovered two new mutations in Austrian melanoma patients, p.A34V and c.151-4 G>C, respectively.","variants":[{"Name":"NM_000077.5(CDKN2A):c.151-4G>C","Chromosome":"9","Start":"21971212","Stop":"21971212","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":151314,"rule_based_match":true,"evidence_text":"c.151-4 G>C","llm_judgment":"PRESENT","evidence":"c.151-4 G>C","abstract_start":977,"abstract_end":988}]}
{"pmid":"23331056","title":"Lethal Netherton syndrome due to homozygous p.Arg371X mutation in SPINK5.","abstract":"Here we report a lethal case of Netherton syndrome presenting with neurologic complications, hypernatremic dehydration, failure to thrive, and episodes of sepsis. Molecular analysis of the serine protease inhibitor Kazal-type 5 gene identified a homozygous mutation (c.1111C>T, p.Arg371X). This case highlights the importance of early diagnosis to start appropriate care in a timely fashion and prevent disease complications.","variants":[{"Name":"NM_006846.4(SPINK5):c.1111C>T (p.Arg371Ter)","Chromosome":"5","Start":"148100472","Stop":"148100472","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":977213,"rule_based_match":true,"evidence_text":"c.1111C>T, p.Arg371X","llm_judgment":"PRESENT","evidence":"c.1111C>T, p.Arg371X","abstract_start":267,"abstract_end":287}]}
{"pmid":"25553839","title":"Novel WISP3 mutations causing spondyloepiphyseal dysplasia tarda with progressive arthropathy in two unrelated Chinese families.","abstract":"Spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA) is an autosomal recessive skeletal disorder resulting from pathogenic mutations in the Wnt1-inducible signaling pathway protein 3 (WISP3) gene. This disorder predominantly involves the skeletal system, with the leading features of platyspondyly, metaphyseal dysplasia of limbs and extremities, and progressive degeneration of joints. To date, 53 distinct forms of WISP3 mutations have been detected globally, eleven of which originated from Chinese patients. In the current study, we reported the clinical manifestations and radiographic features of two unrelated Chinese SEDT-PA patients. Through genetic analysis, two novel mutations (c.624delA, c.105dupT) as well as one recurrent mutation (c.342T>G) were identified in the WISP3 gene. Our study contributed to the further expansion of the WISP3 mutation spectrum, and demonstrated the genotype-phenotype relationship between mutations in the WISP3 gene and clinical findings of SEDT-PA.","variants":[{"Name":"NM_198239.2(CCN6):c.342T>G (p.Cys114Trp)","Chromosome":"6","Start":"112061284","Stop":"112061284","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1060563,"rule_based_match":true,"evidence_text":"c.342T>G","llm_judgment":"PRESENT","evidence":"c.342T>G","abstract_start":768,"abstract_end":776}]}
{"pmid":"36038257","title":"A founder","abstract":"BACKGROUND: Monogenic disorders are estimated to account for 10%-12% of patients with kidney failure. We report the unexpected finding of an unusual uromodulin <i>(UMOD)</i> variant in multiple pedigrees within the British population and demonstrate a shared haplotype indicative of an ancestral variant.\nMETHODS: Probands from 12 apparently unrelated pedigrees with a family history of kidney failure within a geographically contiguous UK region were shown to be heterozygous for a pathogenic variant of <i>UMOD</i> c.278_289delTCTGCCCCGAAG insCCGCCTCCT.\nRESULTS: A total of 88 clinically affected individuals were identified, all born in the UK and of white British ethnicity. 20 other individuals with the variant were identified in the UK 100,000 Genomes (100K) Project and 9 from UK Biobank (UKBB). A common extended haplotype was present in 5 of the UKBB individuals who underwent genome sequencing which was only present in <1 in 5000 of UKBB controls. Significantly, rare variants (<1 in 250 general population) identified within 1 Mb of the <i>UMOD</i> variant by genome sequencing were detected in all of the 100K individuals, indicative of an extended shared haplotype.\nCONCLUSION: Our data confirm a likely founder <i>UMOD</i> variant with a wide geographical distribution within the UK. It should be suspected in cases of unexplained familial nephropathy presenting in patients of white British ancestry.","variants":[{"Name":"NM_003361.4(UMOD):c.278_289delinsCCGCCTCCT (p.Val93_Gly97delinsAlaAlaSerCys)","Chromosome":"16","Start":"20349012","Stop":"20349023","ReferenceAlleleVCF":"CTTCGGGGCAGA","AlternateAlleleVCF":"AGGAGGCGG","allel_id":243897,"rule_based_match":false,"evidence_text":"c.278_289delTCTGCCCCGAAG insCCGCCTCCT","llm_judgment":"PRESENT","evidence":"c.278_289delTCTGCCCCGAAG insCCGCCTCCT","abstract_start":517,"abstract_end":554}]}
{"pmid":"25804403","title":"Cerebral visual impairment and intellectual disability caused by PGAP1 variants.","abstract":"Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI.","variants":[{"Name":"NM_024989.4(PGAP1):c.274_276del (p.Pro92del)","Chromosome":"2","Start":"196920022","Stop":"196920024","ReferenceAlleleVCF":"CAGG","AlternateAlleleVCF":"C","allel_id":224700,"rule_based_match":true,"evidence_text":"c.274_276del (p.(Pro92del))","llm_judgment":"PRESENT","evidence":"c.274_276del (p.(Pro92del))","abstract_start":554,"abstract_end":581},{"Name":"NM_024989.4(PGAP1):c.921_925del (p.Lys308fs)","Chromosome":"2","Start":"196897133","Stop":"196897137","ReferenceAlleleVCF":"TGTTTA","AlternateAlleleVCF":"T","allel_id":224701,"rule_based_match":true,"evidence_text":"c.921_925del (p.(Lys308Asnfs*25))","llm_judgment":"PRESENT","evidence":"c.921_925del (p.(Lys308Asnfs*25))","abstract_start":586,"abstract_end":619}]}
{"pmid":"38286424","title":"A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism.","abstract":"Biallelic variants in <i>PTRHD1</i> have been associated with autosomal recessive intellectual disability, spasticity, and juvenile Parkinsonism, with few reported cases. Here, we present the clinical and genetic findings of a female of Austrian origin exhibiting infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, consistent with the established phenotypic spectrum. Notably, she developed genetic generalized epilepsy at age 4, persisting into adulthood. Using diagnostic exome sequencing, we identified a homozygous missense variant (c.365G > A, p.(Arg122Gln)) in <i>PTRHD1</i> (NM_001013663). In summary, our findings not only support the existing link between biallelic <i>PTRHD1</i> variants and Parkinsonism with neurodevelopmental abnormalities but also suggest a potential extension of the phenotypic spectrum to include generalized epilepsy.","variants":[{"Name":"NM_001013663.2(PTRHD1):c.365G>A (p.Arg122Gln)","Chromosome":"2","Start":"24790469","Stop":"24790469","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222194,"rule_based_match":true,"evidence_text":"c.365G > A, p.(Arg122Gln)","llm_judgment":"PRESENT","evidence":"c.365G > A, p.(Arg122Gln)","abstract_start":598,"abstract_end":623}]}
{"pmid":"30177912","title":"Homozygous and Heterozygous Nuclear Lamin A p.R582C Mutation: Different Lipodystrophic Phenotypes in the Same Kindred.","abstract":"<b>Background:</b> Dunnigan-type familial partial lipodystrophy (FPLD2) is a rare autosomal dominant disease caused by heterozygous mutations in the <i>LMNA</i> gene that results in regional loss of subcutaneous adipose tissue with onset in puberty. However, a generalized lipodystrophy phenotype has also been associated with heterozygous mutations in this gene, demonstrating the noticeable phenotypic heterogeneity of this disease. <b>Methods:</b> We report and describe clinical and metabolic features of four patients from the same family with the p.R582C <i>LMNA</i> mutation, three homozygous and one in the heterozygous state that present with three distinct lipodystrophic phenotypes. <b>Results:</b> Case description: The proband was a 12-year-old girl who developed severe subcutaneous fat atrophy in limbs and abdomen followed by a remarkable dorsocervical fat accumulation in adulthood along with diabetes at age 23. The proband's sister was a phenotypically normal girl who developed hypertriglyceridemia at age 8, progressive features of partial lipodystrophy at age 11, and diabetes at age 22. The proband's mother was first examined at age 32, presenting diabetes and a severe generalized lipodystrophic phenotype; she developed kidney failure at age 41 and died due to diabetic complications. The proband's father was a 50-year-old man with abdominal fat concentration that was initially considered phenotypically normal. Massively parallel sequencing using a platform of genes related to genetic lipodystrophies, followed by Sanger sequencing, revealed the transversion c.1744C>T at exon 11 of the <i>LMNA</i> gene (p.R582C) in the homozygous (mother and daughters) and heterozygous (father) states. <b>Conclusion:</b> We documented three distinct phenotypes of the homozygous and heterozygous p. R582C <i>LMNA</i> mutation in the same kindred, illustrating that FPLD2 linked to mutations in this gene is a disease of great clinical heterogeneity, possibly due to associated environmental or genetic factors.","variants":[{"Name":"NM_170707.4(LMNA):c.1744C>T (p.Arg582Cys)","Chromosome":"1","Start":"156138533","Stop":"156138533","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":626929,"rule_based_match":true,"evidence_text":"c.1744C>T (p.R582C)","llm_judgment":"PRESENT","evidence":"c.1744C>T","abstract_start":1589,"abstract_end":1598}]}
{"pmid":"21549338","title":"A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa.","abstract":"Retinitis pigmentosa (RP) is an inherited form of retinal degeneration that leads to progressive visual-field constriction and blindness. Although the disease manifests only in the retina, mutations in ubiquitously expressed genes associated with the tri-snRNP complex of the spliceosome have been identified in patients with dominantly inherited RP. We screened for mutations in PRPF6 (NM_012469.3), a gene on chromosome 20q13.33 encoding an essential protein for tri-snRNP assembly and stability, in 188 unrelated patients with autosomal-dominant RP and identified a missense mutation, c.2185C>T (p.Arg729Trp). This change affected a residue that is conserved from humans to yeast and cosegregated with the disease in the family in which it was identified. Lymphoblasts derived from patients with this mutation showed abnormal localization of endogenous PRPF6 within the nucleus. Specifically, this protein accumulated in the Cajal bodies, indicating a possible impairment in the tri-snRNP assembly or recycling. Expression of GFP-tagged PRPF6 in HeLa cells showed that this phenomenon depended exclusively on the mutated form of the protein. Furthermore, analysis of endogenous transcripts in cells from patients revealed intron retention for pre-mRNA bearing specific splicing signals, according to the same pattern displayed by lymphoblasts with mutations in other PRPF genes. Our results identify PRPF6 as the sixth gene involved in pre-mRNA splicing and dominant RP, corroborating the hypothesis that deficiencies in the spliceosome play an important role in the molecular pathology of this disease.","variants":[{"Name":"NM_012469.4(PRPF6):c.2185C>T (p.Arg729Trp)","Chromosome":"20","Start":"64027138","Stop":"64027138","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40046,"rule_based_match":true,"evidence_text":"c.2185C>T (p.Arg729Trp)","llm_judgment":"PRESENT","evidence":"c.2185C>T (p.Arg729Trp)","abstract_start":588,"abstract_end":611}]}
{"pmid":"19657311","title":"Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor.","abstract":"OBJECTIVE: The goal of the study was to investigate the genetic and molecular basis of a novel syndrome of marked hyperglucagonemia and pancreatic alpha cell hyperplasia without glucagonoma syndrome.\nMETHODS: The glucagon receptor (GCGR) gene and the glucagon gene were sequenced in a patient with hyperglucagonemia and pancreatic alpha cell hyperplasia without glucagonoma syndrome. Enhanced green fluorescent protein-conjugated wild type (WT) and mutant GCGR were used to characterize the functions of the mutant GCGR.\nRESULTS: The glucagon gene sequence was normal, but the GCGR sequencing uncovered a homozygous missense mutation, c.256C>T, p.P86S in the extracellular domain of GCGR. When expressed in human embryonic kidney 293 cells, GCGR P86S localized to the plasma membrane but bound 96% less radiolabeled glucagon than WT GCGR. The median effective concentration of glucagon-induced cyclic adenosine monophosphate production was 24 nmol/L for GCGR P86S but 2.4 nmol/L for WT GCGR. The patient's alpha cells also express glucagonlike peptide 1 and pancreatic polypeptide.\nCONCLUSIONS: We hereby report the first homozygous missense mutation in the human GCGR, which is associated with alpha cell hyperplasia and hyperglucagonemia. This mutation lowers the receptor's affinity to glucagon and decreases cyclic adenosine monophosphate production with physiological concentrations of glucagon. Thus, the P86S mutation in GCGR likely causes alpha cell hyperplasia and hyperglucagonemia.","variants":[{"Name":"NM_000160.5(GCGR):c.256C>T (p.Pro86Ser)","Chromosome":"17","Start":"81810917","Stop":"81810917","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1053024,"rule_based_match":true,"evidence_text":"c.256C>T, p.P86S","llm_judgment":"PRESENT","evidence":"c.256C>T, p.P86S","abstract_start":635,"abstract_end":651}]}
{"pmid":"24791140","title":"Detecting genetic variations in hereditary retinal dystrophies with next-generation sequencing technology.","abstract":"PURPOSE: To identify pathogenic mutations responsible for retinal dystrophies (RDs) in three unrelated Chinese families.\nMETHODS: Three probands from unrelated families with RDs were recruited. Genomic DNA prepared from leukocytes was analyzed using gene chip-based next-generation sequencing (NGS) to capture and sequence all of the exons of 100 known RD-associated genes. Candidate variants were validated with PCR and Sanger sequencing in the respective families. Thorough ophthalmic examinations including best-corrected visual acuity, funduscopic examination, and full-field electroretinograms were performed in the affected individuals.\nRESULTS: We successfully identified causative mutations in patients from the Chinese families with RDS: the known mutation IMPDH1 c.942_944delGAA in a family with retinitis pigmentosa, the novel mutation ABCA4 c.1924T>A in a family with Stargardt disease, and the novel mutation NMNAT1 c.272A>G and known mutation NMNAT1 c.196C>T in a family with Leber congenital amaurosis. All variations segregated with the disease phenotypes in the respective families and were absent from ethnically matched control chromosomes. Prediction analysis demonstrated the two novel missense mutations might be damaging.\nCONCLUSIONS: The results strongly suggested these mutations were responsible for different RD phenotypes in the Chinese families. NGS technology provides an accurate and economic method for identifying causative genes for RDs.","variants":[{"Name":"NM_022787.4(NMNAT1):c.196C>T (p.Arg66Trp)","Chromosome":"1","Start":"9975672","Stop":"9975672","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":970652,"rule_based_match":true,"evidence_text":"NMNAT1 c.196C>T","llm_judgment":"PRESENT","evidence":"NMNAT1 c.196C>T","abstract_start":957,"abstract_end":972},{"Name":"NM_000350.3(ABCA4):c.1924T>A (p.Phe642Ile)","Chromosome":"1","Start":"94062590","Stop":"94062590","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1058860,"rule_based_match":true,"evidence_text":"ABCA4 c.1924T>A","llm_judgment":"PRESENT","evidence":"ABCA4 c.1924T>A","abstract_start":847,"abstract_end":862}]}
{"pmid":"33375644","title":"Phenylketonuria Diagnosis by Massive Parallel Sequencing and Genotype-Phenotype Association in Brazilian Patients.","abstract":"Phenylketonuria (PKU) is a common inborn error of amino acid metabolism in which the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine, is functionally impaired due to pathogenic variants in the <i>PAH</i> gene. Thirty-four Brazilian patients with a biochemical diagnosis of PKU, from 33 unrelated families, were analyzed through next-generation sequencing in the Ion Torrent PGM™ platform. Phenotype-genotype correlations were made based on the BioPKU database. Three patients required additional Sanger sequencing analyses. Twenty-six different pathogenic variants were identified. The most frequent variants were c.1315+1G>A (<i>n</i> = 8/66), c.473G>A (<i>n</i> = 6/66), and c.1162G>A (<i>n</i> = 6/66). One novel variant, c.524C>G (p.Pro175Arg), was found in one allele and was predicted as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG) criteria. The molecular modeling of p.Pro175Arg indicated that this substitution can affect monomers binding in the PAH tetramer, which could lead to a change in the stability and activity of this enzyme. Next-generation sequencing was a fast and effective method for diagnosing PKU and is useful for patient phenotype prediction and genetic counseling.","variants":[{"Name":"NM_000277.3(PAH):c.1315+1G>A","Chromosome":"12","Start":"102840399","Stop":"102840399","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15615,"rule_based_match":true,"evidence_text":"c.1315+1G>A","llm_judgment":"PRESENT","evidence":"c.1315+1G>A","abstract_start":641,"abstract_end":652}]}
{"pmid":"25503862","title":"First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China.","abstract":"Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is an autosomal recessive inborn error of mitochondrial fatty acid β-oxidation, caused by mutations in the ACADM gene. As it is the most commonly inherited disorder of the mitochondrial fatty acid oxidation in Caucasians, there are no related reports in China diagnosed by molecular genetic testing. We report here the case of a 2-year-old female patient who had hepatomegaly and abnormal liver function with a common illness, and who had been healthy before. A marked increase found in the concentration of C8-carnitine with the help of tandem mass spectrometry (MS/MS) profile, as well as the presence of hexanoylglycine and cyclohepta acyl glycinate as shown in the urinary gas chromatography/mass spectrometry (GC/MS) were suggestive of MCADD, a diagnosis that was confirmed by genetic analysis that showed compound heterozygosity for a missense mutation, c.362C>T(p.Thr121Ile), and a 4-bp deletion, c.448-453delCTGA, in the medium-chain acyl-coenzyme A dehydrogenase (MCAD) gene, also named ACADM gene. There are no related reports in China. This report broadens the phenotype and genotype of MCADD in China and underlines the difficulty of diagnosis.","variants":[{"Name":"NM_000016.6(ACADM):c.362C>T (p.Thr121Ile)","Chromosome":"1","Start":"75733603","Stop":"75733603","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18638,"rule_based_match":true,"evidence_text":"c.362C>T(p.Thr121Ile)","llm_judgment":"PRESENT","evidence":"c.362C>T(p.Thr121Ile)","abstract_start":922,"abstract_end":943}]}
{"pmid":"31688942","title":"Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course.","abstract":"Ohtahara syndrome, early infantile epileptic encephalopathy with a suppression burst EEG pattern, is an aetiologically heterogeneous condition starting in the first weeks or months of life with intractable seizures and profound developmental disability. Using whole exome sequencing, we identified biallelic DMXL2 mutations in three sibling pairs with Ohtahara syndrome, belonging to three unrelated families. Siblings in Family 1 were compound heterozygous for the c.5135C>T (p.Ala1712Val) missense substitution and the c.4478C>G (p.Ser1493*) nonsense substitution; in Family 2 were homozygous for the c.4478C>A (p.Ser1493*) nonsense substitution and in Family 3 were homozygous for the c.7518-1G>A (p.Trp2507Argfs*4) substitution. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features. Early brain MRI investigations in the first months of life revealed thin corpus callosum with brain hypomyelination in all. Follow-up MRI scans in three patients revealed progressive moderate brain shrinkage with leukoencephalopathy. Five patients died within the first 9 years of life and none achieved developmental, communicative or motor skills following birth. These clinical findings are consistent with a developmental brain disorder that begins in the prenatal brain, prevents neural connections from reaching the expected stages at birth, and follows a progressive course. DMXL2 is highly expressed in the brain and at synaptic terminals, regulates v-ATPase assembly and activity and participates in intracellular signalling pathways; however, its functional role is far from complete elucidation. Expression analysis in patient-derived skin fibroblasts demonstrated absence of the DMXL2 protein, revealing a loss of function phenotype. Patients' fibroblasts also exhibited an increased LysoTracker® signal associated with decreased endolysosomal markers and degradative processes. Defective endolysosomal homeostasis was accompanied by impaired autophagy, revealed by lower LC3II signal, accumulation of polyubiquitinated proteins, and autophagy receptor p62, with morphological alterations of the autolysosomal structures on electron microscopy. Altered lysosomal homeostasis and defective autophagy were recapitulated in Dmxl2-silenced mouse hippocampal neurons, which exhibited impaired neurite elongation and synaptic loss. Impaired lysosomal function and autophagy caused by biallelic DMXL2 mutations affect neuronal development and synapse formation and result in Ohtahara syndrome with profound developmental impairment and reduced life expectancy.","variants":[{"Name":"NM_001378457.1(DMXL2):c.4478C>A (p.Ser1493Ter)","Chromosome":"15","Start":"51498746","Stop":"51498746","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":236880,"rule_based_match":true,"evidence_text":"c.4478C>A (p.Ser1493*)","llm_judgment":"PRESENT","evidence":"c.4478C>A (p.Ser1493*)","abstract_start":603,"abstract_end":625},{"Name":"NM_001378457.1(DMXL2):c.4478C>G (p.Ser1493Ter)","Chromosome":"15","Start":"51498746","Stop":"51498746","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":682582,"rule_based_match":true,"evidence_text":"c.4478C>G (p.Ser1493*)","llm_judgment":"PRESENT","evidence":"c.4478C>G (p.Ser1493*)","abstract_start":521,"abstract_end":543},{"Name":"NM_001378457.1(DMXL2):c.5135C>T (p.Ala1712Val)","Chromosome":"15","Start":"51488036","Stop":"51488036","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":682583,"rule_based_match":true,"evidence_text":"c.5135C>T (p.Ala1712Val)","llm_judgment":"PRESENT","evidence":"c.5135C>T (p.Ala1712Val)","abstract_start":466,"abstract_end":490}]}
{"pmid":"21651515","title":"ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension.","abstract":"Germline mutations in genes encoding members of the transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curaçao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.","variants":[{"Name":"NM_000020.3(ACVRL1):c.1388del (p.Gly463fs)","Chromosome":"12","Start":"51920768","Stop":"51920768","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":414403,"rule_based_match":true,"evidence_text":"c.1388del (p.Gly463fsX2)","llm_judgment":"PRESENT","evidence":"c.1388del (p.Gly463fsX2)","abstract_start":846,"abstract_end":870}]}
{"pmid":"18728241","title":"Pharmacokinetics of efavirenz when co-administered with rifampin in TB/HIV co-infected patients: pharmacogenetic effect of CYP2B6 variation.","abstract":"The goal of this study was to determine the effect of CYP2B6 genetic variation on the steady-state pharmacokinetics of efavirenz (600 mg/d) in TB/HIV co-infected patients receiving concomitant rifampin, a potent CYP inducer. In the 26 patients studied, CYP2B6 c.516GG, GT, and TT genotype frequencies were 0.27, 0.50, and 0.23, respectively. Mean plasma efavirenz area under the curve was significantly higher in patients with CYP2B6 c.516TT than in those with GT (107 vs 27.6 microg x h/mL, P< .0001) or GG genotype (107 vs 23.0 microg x h/mL, P< .0001). Apparent oral clearance (CL/F) was significantly lower in patients with CYP2B6 c.516TT than in those with GT genotype (2.1 vs 8.4 mL/min/kg, P<0.0001) and GG genotype (2.1 vs 9.9 mL/min/kg, P< .0001). No differences in efavirenz exposure or CL/F existed between patients with CYP2B6 c.516GT and GG genotypes. Our results indicate that CYP2B6 c.516TT genotype can be used to identify efavirenz poor metabolizers in patients co-treated with rifampin.","variants":[{"Name":"NM_000767.5(CYP2B6):c.516G>T (p.Gln172His)","Chromosome":"19","Start":"41006936","Stop":"41006936","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":38626,"rule_based_match":false,"evidence_text":"CYP2B6 c.516TT","llm_judgment":"PRESENT","evidence":"CYP2B6 c.516TT","abstract_start":427,"abstract_end":441}]}
{"pmid":"31588815","title":"Delay in the Diagnosis of APECED: A Case Report and Review of Literature from Iran.","abstract":"Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare monogenic autosomal recessive disorder caused by biallelic mutations in the <i>AIRE</i> (autoimmune regulator) gene. Patients with APECED present with heterogeneous endocrine and non-endocrine manifestations. In this study, we report an Iranian patient who presented with Addison disease, chronic mucocutaneous candidiasis, alopecia totalis, keratopathy and asplenia treated as an isolated endocrinopathy for 25 years. In the adulthood, the diagnosis of APECED was made by genetic analysis which demonstrated homozygous nonsense p.R257* (c.769C>T) mutation of AIRE. APECED has been shown to be frequent in some ethnicities including Iranian Jews. Therefore, we reviewed 39 Iranian APECED patients published in the literature. We found that most of the Iranian patients were of Jewish ethnic background and presented hypoparathyroidism, adrenal insufficiency, and candidiasis as the main clinical manifestation.","variants":[{"Name":"NM_000383.4(AIRE):c.769C>T (p.Arg257Ter)","Chromosome":"21","Start":"44289773","Stop":"44289773","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18346,"rule_based_match":true,"evidence_text":"c.769C>T","llm_judgment":"PRESENT","evidence":"c.769C>T","abstract_start":629,"abstract_end":637}]}
{"pmid":"25110237","title":"Identification and surgical repair of familial thoracic aortic aneurysm and dissection caused by TGFBR1 mutation.","abstract":"BACKGROUND: This study aimed at exploring the causative gene and summarizing the clinical characteristics in a Chinese thoracic aortic aneurysm and dissection (TAAD) family.\nMETHODS: Family members were examined for features of syndromic genetic diseases by clinician and geneticist. Genomic DNA was extracted from 2 distantly related members with definite TAAD for exome sequencing.\nRESULTS: A pathogenic mutation (rs111426349, c.1459C >T) of transforming growth factor β receptor 1 (TGFBR1) was confirmed, which result in the amino acid substitution p.R487W. Fourteen TGFBR1 mutation carriers were detected among 39 tested members in this family. The average age at diagnosis of aortic root dilatation or aneurysm was 23.2 ± 12.6 years (range 3-37 years). Early onset of aortic root dilatation was significant in this family without reported phenotypes. The David procedure was performed prophylactically in 3 carriers of this family.\nCONCLUSIONS: Familial TAAD caused by TGFBR1 mutation (c.1459C >T) was confirmed in a large Chinese Han ethnic family using exome sequencing. Aggressively prophylactic David procedure may be not necessary at a smaller aortic size in familial TAAD patients with TGFBR1 mutation and further observation is warranted.","variants":[{"Name":"NM_004612.4(TGFBR1):c.1459C>T (p.Arg487Trp)","Chromosome":"9","Start":"99149252","Stop":"99149252","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27565,"rule_based_match":true,"evidence_text":"c.1459C >T","llm_judgment":"PRESENT","evidence":"c.1459C >T","abstract_start":429,"abstract_end":439}]}
{"pmid":"30982706","title":"Flavin adenine dinucleotide synthase deficiency due to FLAD1 mutation presenting as multiple acyl-CoA dehydrogenation deficiency-like disease: A case report.","abstract":"Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidemia type II, is classically caused by a congenital defect in electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH). Flavin adenine dinucleotide synthase (FADS) deficiency caused by mutations in FLAD1 was recently reported as a novel riboflavin metabolism disorder resembling MADD. Here, we describe a Japanese boy with FADS deficiency due to a novel mutation (p.R249*) in FLAD1. In the asymptomatic male infant born at full term, newborn screening showed positive results with elevated C5 and C14:1 acylcarnitine levels and an increased C14:1/C2 ratio. Biochemical studies were unremarkable except for lactic acidosis (pH 7.197, lactate 61 mg/dL). A diagnosis of MADD was suspected because of mild abnormalities of the acylcarnitine profile and apparent abnormalities of urinary organic acids, although mutations in the ETFA, ETFB, ETFDH, and riboflavin transporter genes (SLC52A1, SLC52A2, and SLC52A3) were not detected. Administration of riboflavin and L-carnitine was initiated at one month of age based on the diagnosis of \"biochemical MADD\" despite a lack of symptoms. Nevertheless, the acylcarnitine profile was not normalized. Symptoms resembling bulbar palsy, such as vocal cord paralysis and dyspnea with stridor, were present from 3 months of age. At 4 months of age, he became bedridden because of hypoxic-ischemic encephalopathy due to fulminant respiratory failure with aspiration pneumonia. At 2 years and 5 months of age, a homozygous c.745C > T (p.R249*) mutation in the FLAD1 gene was identified, confirming the diagnosis of FADS deficiency. His severe clinical course may be caused by this nonsense mutation associated with poor responsiveness to riboflavin. Persistent lactic acidosis and neuropathy, such as bulbar palsy, may be important for diagnosing FADS deficiency. Although the biochemical findings in FADS deficiency are similar to those in MADD, their clinical symptoms and severity may not be identical.","variants":[{"Name":"NM_025207.5(FLAD1):c.745C>T (p.Arg249Ter)","Chromosome":"1","Start":"154988477","Stop":"154988477","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":789852,"rule_based_match":true,"evidence_text":"c.745C > T (p.R249*)","llm_judgment":"PRESENT","evidence":"c.745C > T (p.R249*)","abstract_start":1542,"abstract_end":1562}]}
{"pmid":"30849948","title":"Rare cause of Hemophagocytic Lymphohistiocytosis due to mutation in PRF1 and SH2D1A genes in two children - a case report with a review.","abstract":"BACKGROUND: Hemophagocytic Lymphohistiocytosis (HLH) is a rare, complex, life-threatening hyper-inflammatory condition due to over activation of lymphocytes mediated secretory cytokines in the body. It occurs as a primary HLH due to genetic defect that mostly occurs in the childhood and associated with early neonatal death. Secondary HLH is triggered by secondary to infection and can occur at any age.\nCASE PRESENTATION: The current report presents two cases of HLH. Case 1, three-months-old boy born to second degree consanguineous parents was clinically suspected with HLH. A pathogenic variant in exon 2 of PRF1 gene [c.386G > C (p.Trp129Ser); FLH-type2] was detected. The parents and the fetus under investigation were shown to be heterozygous carriers, while Case-1 was homozygous for the said variant. Case 2, a one and half-year old male child referred for work-up was born to non-consanguineous young parents. His HLH suspicion was in accordance with HLH-2004 Revised diagnostic guidelines (fulfilling 5/8 criteria). Molecular study revealed hemizygous likely pathogenic variant c.138-3C > G in intron 1 of SH2D1A gene. Both the mother and younger sister were confirmed to be the carrier of the same variant.\nCONCLUSION: This study has represented two rare cases of HLH carrying missense variant in PRF1 and splice site variant in SH2D1A gene. Detailed molecular analysis has helped the families with precise genetic counselling and prenatal diagnosis during subsequent pregnancy. It is advocated that male patients presenting with EBV-associated HLH may be screened for XLP that may lead to early diagnosis and therapeutic implication if any.","variants":[{"Name":"NM_001083116.3(PRF1):c.386G>C (p.Trp129Ser)","Chromosome":"10","Start":"70600517","Stop":"70600517","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":539416,"rule_based_match":true,"evidence_text":"c.386G > C (p.Trp129Ser)","llm_judgment":"PRESENT","evidence":"c.386G > C (p.Trp129Ser)","abstract_start":624,"abstract_end":648},{"Name":"NM_002351.5(SH2D1A):c.138-3C>G","Chromosome":"X","Start":"124365758","Stop":"124365758","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":539418,"rule_based_match":true,"evidence_text":"c.138-3C > G","llm_judgment":"PRESENT","evidence":"c.138-3C > G","abstract_start":1090,"abstract_end":1102}]}
{"pmid":"30500922","title":"Divergent Features of Mitochondrial Deficiencies in LGMD2A Associated With Novel Calpain-3 Mutations.","abstract":"Limb girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized by progressive muscle weakness and wasting. LGMD2A is caused by mutations in the calpain-3 gene (CAPN3) that encodes a Ca2+-dependent cysteine protease predominantly expressed in the skeletal muscle. Underlying pathological mechanisms have not yet been fully elucidated. Mitochondrial abnormalities have been variably reported in human subjects with LGMD2A and were more systematically evaluated in CAPN3-knocked out mouse models. We have combined histochemical, immunohistochemical, molecular, biochemical, and ultrastructural analyses in our study in order to better outline mitochondrial features in 2 LGMD2A patients with novel CAPN3-associated mutations. Both patients underwent detailed clinical evaluations, followed by muscle biopsies from the quadriceps muscles. The diagnosis of LGMD2A in both patients was first suspected on the basis of a typical clinical localization of the muscle weakness, and confirmed by molecular investigations. Two novel homozygous mutations, c.2242C>G (p.Arg748Gly) and c.291C>A (p.Phe97Leu) were identified: c.2242C>G (p.Arg748Gly) mutation was associated with a significant mitochondrial mass depletion and myofibrillar disruption in the first patient, while c.291C>A (p.Phe97Leu) mutation was accompanied by reactive mitochondrial proliferation with ragged-red fibers in the second patient. Our results delineate CAPN3 mutation-specific patterns of mitochondrial dysfunction and their ultrastructural characteristics in LGMD2A.","variants":[{"Name":"NM_000070.3(CAPN3):c.291C>A (p.Phe97Leu)","Chromosome":"15","Start":"42360096","Stop":"42360096","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":538622,"rule_based_match":true,"evidence_text":"c.291C>A (p.Phe97Leu)","llm_judgment":"PRESENT","evidence":"c.291C>A (p.Phe97Leu)","abstract_start":1105,"abstract_end":1126}]}
{"pmid":"29324451","title":"Aromatase Deficiency due to a Homozygous CYP19A1 Mutation in a 46,XX Egyptian Patient with Ambiguous Genitalia.","abstract":"Aromatase deficiency (AD) is a very rare disorder resulting from mutations in the CYP19A1 gene encoding aromatase, a cytochrome P450 enzyme that plays a pivotal role in androgen conversion to estrogens. AD is inherited in an autosomal recessive trait, and to date only 35 cases have been described in the literature. Herein, we depict a new patient reared as a male, who presented at the age of 21 years with no palpable testis, hypoplastic scrotum, penis-like phallus (3 cm), and penoscrotal hypospadias. The patient was born to consanguineous parents, his karyotype was 46,XX, and SRY was negative. Pelvic sonar showed a small hypoplastic uterus, and no testis could be identified. Serum testosterone was within the reference range of females along with high gonadotropins. Pathology of gonadal biopsy showed ovarian stroma negative for oocytic follicle consistent with streak gonads. All these data were suggestive of AD, which was subsequently confirmed by molecular investigation of the CYP19A1 gene. A homozygous splice site mutation in the donor splice site of exon 9 was identified, c.1263 + 1G>T. This is the first report of such a rare disorder in an Egyptian patient. Our results reinforce the importance of considering AD in patients with 46,XX disorders of sex development after ruling out congenital adrenal hyperplasia.","variants":[{"Name":"NM_000103.4(CYP19A1):c.1263+1G>T","Chromosome":"15","Start":"51212319","Stop":"51212319","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":920346,"rule_based_match":true,"evidence_text":"c.1263 + 1G>T","llm_judgment":"PRESENT","evidence":"c.1263 + 1G>T","abstract_start":1091,"abstract_end":1104}]}
{"pmid":"24200904","title":"The novel desmin mutant p.A120D impairs filament formation, prevents intercalated disk localization, and causes sudden cardiac death.","abstract":"BACKGROUND: The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy. Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known.\nMETHODS AND RESULTS: We identified the 2 novel variants DES-p.A120D (c.359C>A) and DES-p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D reveal a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation, whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type.\nCONCLUSIONS: Because of the functional in vivo and in vitro characterization, DES-p.A120D has to be regarded as a pathogenic mutation and DES-p.H326R as a rare variant with unknown significance. Presumably, the loss of the desmin-p. A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.","variants":[{"Name":"NM_001927.4(DES):c.359C>A (p.Ala120Asp)","Chromosome":"2","Start":"219418821","Stop":"219418821","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":825776,"rule_based_match":true,"evidence_text":"c.359C>A","llm_judgment":"PRESENT","evidence":"c.359C>A","abstract_start":609,"abstract_end":617}]}
{"pmid":"20232099","title":"A second MNGIE patient without typical mitochondrial skeletal muscle involvement.","abstract":"Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by mutations in the gene encoding thymidine phosphorylase (TYMP). Clinically, MNGIE is characterized by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Most MNGIE patients have signs of mitochondrial dysfunction in skeletal muscle at morphological and enzyme level, as well as mitochondrial DNA depletion, multiple deletions and point mutations. A case without mitochondrial skeletal muscle involvement and with a TYMP splice-acceptor site mutation (c. 215-1 G>C) has been reported. Here, we describe an Italian patient with the same mutation and without mitochondrial skeletal muscle involvement, suggesting a possible genotype-phenotype correlation.","variants":[{"Name":"NM_001953.5(TYMP):c.215-1G>C","Chromosome":"22","Start":"50529339","Stop":"50529339","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":31701,"rule_based_match":true,"evidence_text":"c. 215-1 G>C","llm_judgment":"PRESENT","evidence":"c. 215-1 G>C","abstract_start":618,"abstract_end":630}]}
{"pmid":"28646019","title":"Functionally Null","abstract":"RAD51D is a key player in DNA repair by homologous recombination (HR), and <i>RAD51D</i> truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating <i>RAD51D</i> variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense <i>RAD51D</i> variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic <i>RAD51D</i> missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense <i>RAD51D</i> variants. <i>Cancer Res; 77(16); 4517-29. ©2017 AACR</i>.","variants":[{"Name":"NM_002878.4(RAD51D):c.620C>T (p.Ser207Leu)","Chromosome":"17","Start":"35103501","Stop":"35103501","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":151816,"rule_based_match":true,"evidence_text":"c.620C>T;p.S207L","llm_judgment":"PRESENT","evidence":"c.620C>T;p.S207L","abstract_start":398,"abstract_end":414}]}
{"pmid":"37108800","title":"Identification and Functional Analysis of","abstract":"Mutations in <i>APOB</i> are the second most frequent cause of familial hypercholesterolemia (FH). <i>APOB</i> is highly polymorphic, and many variants are benign or of uncertain significance, so functional analysis is necessary to ascertain their pathogenicity. Our aim was to identify and characterize <i>APOB</i> variants in patients with hypercholesterolemia. Index patients (<i>n</i> = 825) with clinically suspected FH were analyzed using next-generation sequencing. In total, 40% of the patients presented a variant in <i>LDLR</i>, <i>APOB</i>, <i>PCSK9</i> or <i>LDLRAP1</i>, with 12% of the variants in <i>APOB</i>. These variants showed frequencies in the general population lower than 0.5% and were classified as damaging and/or probably damaging by 3 or more predictors of pathogenicity. The variants <i>c.10030A>G</i>;p.(Lys3344Glu) and <i>c.11401T>A</i>;p.(Ser3801Thr) were characterized. The p.(Lys3344Glu) variant co-segregated with high low-density lipoprotein (LDL)-cholesterol in 2 families studied. LDL isolated from apoB p.(Lys3344Glu) heterozygous patients showed reduced ability to compete with fluorescently-labelled LDL for cellular binding and uptake compared with control LDL and was markedly deficient in supporting U937 cell proliferation. LDL that was carrying apoB p.(Ser3801Thr) was not defective in competing with control LDL for cellular binding and uptake. We conclude that the apoB p.(Lys3344Glu) variant is defective in the interaction with the LDL receptor and is causative of FH, whereas the apoB p.(Ser3801Thr) variant is benign.","variants":[{"Name":"NM_000384.3(APOB):c.10030A>G (p.Lys3344Glu)","Chromosome":"2","Start":"21006838","Stop":"21006838","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1829990,"rule_based_match":true,"evidence_text":"c.10030A>G","llm_judgment":"PRESENT","evidence":"c.10030A>G","abstract_start":816,"abstract_end":826}]}
{"pmid":"22211385","title":"FZD6 encoding the Wnt receptor frizzled 6 is mutated in autosomal-recessive nail dysplasia.","abstract":"BACKGROUND: Isolated nail dysplasia is rare and has been reported in only a small number of families.\nOBJECTIVES: To describe and characterize two Pakistani families with an autosomal-recessive inherited nail dysplasia.\nMETHODS: Genome-wide linkage analysis; mutation screening of candidate genes by Sanger sequencing; cloning of FZD6 and protein analyses; immunohistochemistry.\nRESULTS: We mapped this genodermatosis to chromosome 8q22.3, and identified a homozygous nonsense mutation c.1750G>T (p.E584X) in the frizzled 6 (FZD6) gene in all affected individuals. Immunohistochemical analyses in nail sections from healthy individuals revealed strong expression of FZD6 in the ventral nail matrix and a less pronounced expression of FZD6 in the nail bed.\nCONCLUSIONS: FZD6 belongs to a family of proteins that serve as receptors in Wnt signalling pathways, and has been shown to act as a negative regulator of the canonical Wnt/β-catenin signalling cascade and a positive regulator of the noncanonical Wnt or planar cell polarity pathway. The present results therefore suggest that FZD6 plays a pivotal role in the growth and guidance of the nail plate in humans by acting as a molecular switch between different Wnt pathways. Previous studies have identified mutations in the RSPO4 and LMX1B components of the Wnt pathway in patients with the hypoplastic nail disorders anonychia and nail-patella syndrome, respectively. Only recently, FZD6 mutations were identified in isolated nail dysplasia. The present results emphasize the important role of the Wnt pathways in nail development and increase understanding of Wnt-mediated developmental events in general.","variants":[{"Name":"NM_003506.4(FZD6):c.1750G>T (p.Glu584Ter)","Chromosome":"8","Start":"103329863","Stop":"103329863","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39311,"rule_based_match":true,"evidence_text":"c.1750G>T (p.E584X)","llm_judgment":"PRESENT","evidence":"c.1750G>T (p.E584X)","abstract_start":486,"abstract_end":505}]}
{"pmid":"36459342","title":"Novel Loss of Function (G15D) Mutation on RAC2 in a Family with Combined Immunodeficiency and Increased Levels of Immunoglobulin G, A, and E.","abstract":"Ras-related C3 botulinum toxin substrate 2 (RAC2) is a small guanine nucleotide binding molecule that is exclusively expressed in hematopoietic cell lineages as a switcher. Based on in vivo and/or in vitro model experiments, RAC2 plays important roles in different cells through proliferation, secretion, and phagocytosis. It also performs a suppressing function in immunoglobulin (Ig) switching in Rac2-/- animals or cells. Several RAC2 natural mutations have been described in patients with primary immunodeficiency. RAC2 mutations can be classified into loss-of-function inactivating (LoF-I) and gain-of-function activating mutations according to their functional effects. Only two LoF-I mutations on RAC2 have been reported, including a dominant D57N mutation in several cases that exhibit granulocyte function defects and a recessive D56X mutation in cases with common variable immunodeficiency. Regardless of the type of mutation, most of the reported RAC2 mutant cases have shown reduced IgG, IgA, and IgM levels. Herein, we report on a family with three members that suffer from persistent HPV infection, recurrent respiratory infections, bronchiectasis, and autoimmune disease. The immunologic profile suggests that the family was affected by combined immunodeficiency (CID) with increased serum levels of IgG, IgA, and IgE. Exome sequencing identified a de novo RAC2 mutation (c.44G > A/p.G15D) that was co-segregated with the disease in the family. Gene functional experiments identified that such mutation results in reduced guanosine triphosphate binding activity and RAC2 protein expression. In patients' lymphocytes, impaired aggregation and proliferation effects, decreased mitochondrial membrane potential, and increased levels of cell apoptosis were observed, although no functional abnormalities were detected in neutrophils. To our knowledge, this study was the first to identify a LoF-I mutation of RAC2 affecting lymphocyte function that consequently led to CID and increased levels of serum IgG, IgE, and IgA. This study presents a novel subtype of RAC2-related immune disorder.","variants":[{"Name":"NM_002872.5(RAC2):c.44G>A (p.Gly15Asp)","Chromosome":"22","Start":"37241650","Stop":"37241650","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3768072,"rule_based_match":true,"evidence_text":"c.44G > A/p.G15D","llm_judgment":"PRESENT","evidence":"c.44G > A/p.G15D","abstract_start":1387,"abstract_end":1403}]}
{"pmid":"25799227","title":"Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy.","abstract":"Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.","variants":[{"Name":"NM_004958.4(MTOR):c.7280T>C (p.Leu2427Pro)","Chromosome":"1","Start":"11114338","Stop":"11114338","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":404624,"rule_based_match":true,"evidence_text":"MTOR c.7280T>C (p.Leu2427Pro)","llm_judgment":"PRESENT","evidence":"p.Leu2427Pro","abstract_start":558,"abstract_end":570}]}
{"pmid":"30592178","title":"Genetic variations in familial hypercholesterolemia and cascade screening in East Asians.","abstract":"BACKGROUND: Familial hypercholesterolemia (FH) is a monogenic disorder of lipoprotein metabolism leading to an increased risk of premature cardiovascular disease. Genetic testing for FH is not commonly used in Asian countries. We aimed to define the genetic spectrum of FH in Hong Kong and to test the feasibility of cascade genetic screening.\nMETHODS: Ninety-six Chinese subjects with a clinical diagnosis of FH were recruited, and family-based cascade screening incorporating genetic testing results was performed.\nRESULTS: Forty-two distinct mutations were identified in 67% of the index FH cases. The majority of causative mutations were in the LDLR gene. The three commonest mutations in the LDLR gene were NM_000527.4(LDLR): c.1241 T>G, NM_000527.4(LDLR): c.1474G>A, and NM_000527.4(LDLR): c. 682G>A, and nine novel variants were identified. The NM_000384.2(APOB): c.10579 C>T variant of the APOB gene was found in 5% of the index subjects. The presence of causative mutation significantly increased the odds of successful family recruitment for screening with an OR of 3.7 (95% CI: 1.53-9.11, p = 0.004).\nCONCLUSION: Approximately two-third of the subjects in this clinically ascertained sample of patients with FH had a discrete genetic basis. Genetic identification improves the response rate and efficiency of family screening.","variants":[{"Name":"NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg)","Chromosome":"19","Start":"11113332","Stop":"11113332","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":246061,"rule_based_match":true,"evidence_text":"NM_000527.4(LDLR): c.1241 T>G","llm_judgment":"PRESENT","evidence":"NM_000527.4(LDLR): c.1241 T>G","abstract_start":712,"abstract_end":741},{"Name":"NM_000384.3(APOB):c.10579C>T (p.Arg3527Trp)","Chromosome":"2","Start":"21006289","Stop":"21006289","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48709,"rule_based_match":true,"evidence_text":"NM_000384.2(APOB): c.10579 C>T","llm_judgment":"PRESENT","evidence":"NM_000384.2(APOB): c.10579 C>T","abstract_start":852,"abstract_end":882},{"Name":"NM_000527.5(LDLR):c.1474G>A (p.Asp492Asn)","Chromosome":"19","Start":"11113650","Stop":"11113650","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171216,"rule_based_match":true,"evidence_text":"NM_000527.4(LDLR): c.1474G>A","llm_judgment":"PRESENT","evidence":"NM_000527.4(LDLR): c.1474G>A","abstract_start":743,"abstract_end":771}]}
{"pmid":"28993866","title":"CDH1 mutation screen in a BRCA1/2-negative familial breast-/ovarian cancer cohort.","abstract":"PURPOSE: Mutations in the CDH1 gene are linked both to diffuse gastric cancer and invasive lobular carcinoma (ILC). A high mutation rate is found in families fulfilling the diagnostic criteria for hereditary diffuse gastric cancer. Aim of this study was to clarify whether or not there is a significant contribution of CDH1 mutations in hereditary breast-/ovarian cancer (HBOC).\nMETHODS: Ninety-seven unrelated probands fulfilling the diagnostic criteria for HBOC (96 affected, 1 unaffected) but tested negative for pathogenic BRCA1/2 mutations were screened for CDH1 mutations by denaturing high performance liquid chromatography (DHPLC) and subsequent Sanger sequencing of suspicious and positive DHPLC results.\nRESULTS: In total, we found two potentially pathogenic CDH1 alterations, c.1774G > A, pAla592Thr, and c.2512 A > G, p.Ser838Gly, classified as variants of unknown significance according to ClinVar. In addition, we detected a high number of known CDH1 polymorphisms (n = 62), some of them more frequent in patients with lobular (55%) than in those with invasive ductal carcinoma (27%).\nCONCLUSION: Although none of the probands studied carried a clearly pathogenic CDH1 mutation, CDH1 could be considered a potential breast cancer gene, esp. for ILC worth including it in the NGS (next generation sequencing) HBOC panel.","variants":[{"Name":"NM_004360.5(CDH1):c.2512A>G (p.Ser838Gly)","Chromosome":"16","Start":"68833362","Stop":"68833362","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":27272,"rule_based_match":true,"evidence_text":"c.2512 A > G, p.Ser838Gly","llm_judgment":"PRESENT","evidence":"c.2512 A > G, p.Ser838Gly","abstract_start":816,"abstract_end":841}]}
{"pmid":"22594991","title":"Secondary focal and segmental glomerulosclerosis associated with single-nucleotide polymorphisms in the genes encoding complement factor H and C3.","abstract":"Genetic causes of focal and segmental glomerulosclerosis (FSGS) typically involve mutations and allele variants of genes expressed in podocytes or, more rarely, glomerular basement membranes. In this report, we describe a 60-year-old woman with chronic kidney disease whose kidney biopsy showed FSGS. Immunoglobulins and C3 were undetectable in immunofluorescence studies. Electron microscopy showed subendothelial fluffy granular material with occasional double-contour formation suggestive of capillary wall injury and prompting work-up for a prothrombotic state. Evaluation of the alternative pathway of complement showed a novel polymorphism in short consensus repeat (SCR) 12 of complement factor H (CFH; c.2195C>T, p.Thr732Met) and a previously reported but largely uncharacterized polymorphism in complement factor C3 (c.463A>C, p.Lys155Gln). Dysregulation of the alternative pathway is associated with atypical hemolytic syndrome and dense deposit disease, but heretofore has not been associated with FSGS. This case highlights the expanding spectrum of complement-mediated glomerular disease and shows that FSGS with features of capillary wall injury should prompt evaluation for abnormalities in the alternative pathway. This case also expands the list of genetic polymorphisms that can be associated with an FSGS phenotype.","variants":[{"Name":"NM_000186.4(CFH):c.2195C>T (p.Thr732Met)","Chromosome":"1","Start":"196726899","Stop":"196726899","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1427709,"rule_based_match":true,"evidence_text":"c.2195C>T, p.Thr732Met","llm_judgment":"PRESENT","evidence":"c.2195C>T, p.Thr732Met","abstract_start":710,"abstract_end":732},{"Name":"NM_000064.4(C3):c.463A>C (p.Lys155Gln)","Chromosome":"19","Start":"6718135","Stop":"6718135","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":97565,"rule_based_match":true,"evidence_text":"c.463A>C (p.Lys155Gln)","llm_judgment":"PRESENT","evidence":"p.Lys155Gln","abstract_start":836,"abstract_end":847}]}
{"pmid":"35225887","title":"Clinical and Genetic Analysis of a Patient with CMT4J.","abstract":"We report the clinical and genetic analysis of a patient with a rare form of an autosomal recessive genetic neuropathy, Charcot Marie Tooth (CMT) disease type 4J. She presented at age 62 years with signs and symptoms consistent with a mild neuropathy. The onset of symptoms began approximately ten years earlier. Electrophysiological testing confirmed a demyelinating neuropathy and a comprehensive neuropathy screening for common causes of neuropathy was unrevealing. She underwent commercial whole exome sequencing, analyzing more than eighty genes known to cause neuropathy. Two mutations were detected, c.122T > C, p.Ile41Thr and c.2247dupC, p.Ser750GlnX10 in the FIG4 gene. The p.Ile41Thr mutation, which is paternally inherited, is a recurrent mutation reported in a number of unrelated families of European descent. The patient’s father, also of European descent, provides further evidence supporting a founder effect for this mutation. In most patients carrying the p.Ile41Thr mutation, the neuropathy, unlike our patient, is often severe with early onset. The second mutation, c.2247dupC, p.Ser750GlnX10 is maternally inherited and not previously reported. Furthermore, based upon our protein modeling analysis, c.2247dupC is disease producing, representing a novel pathogenic mutation. Our study of this patient expands the clinical and genetic spectrum of patients with CMT 4J.","variants":[{"Name":"NM_014845.6(FIG4):c.2247dup (p.Ser750fs)","Chromosome":"6","Start":"109791436","Stop":"109791437","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":905187,"rule_based_match":true,"evidence_text":"c.2247dupC, p.Ser750GlnX10","llm_judgment":"PRESENT","evidence":"c.2247dupC, p.Ser750GlnX10","abstract_start":634,"abstract_end":660}]}
{"pmid":"23264078","title":"A de novo FLCN mutation in a patient with spontaneous pneumothorax and renal cancer; a clinical and molecular evaluation.","abstract":"Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition due to germline FLCN (folliculin) mutations, characterized by skin fibrofolliculomas, lung cysts, pneumothorax and renal cancer. We identified a de novo FLCN mutation, c.499C>T (p.Gln167X), in a patient who presented with spontaneous pneumothorax. Subsequently, typical skin features and asymptomatic renal cancer were diagnosed. Probably, de novo FLCN mutations are rare. However, they may be under-diagnosed if BHD is not considered in sporadic patients who present with one or more of the syndromic features. Genetic and immunohistochemical analysis of the renal tumour indicated features compatible with a tumour suppressor role of FLCN. The finding that mutant FLCN was expressed in the tumour might indicate residual functionality of mutant FLCN, a notion which will be explored in future studies.","variants":[{"Name":"NM_144997.7(FLCN):c.499C>T (p.Gln167Ter)","Chromosome":"17","Start":"17224041","Stop":"17224041","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":151579,"rule_based_match":true,"evidence_text":"c.499C>T (p.Gln167X)","llm_judgment":"PRESENT","evidence":"c.499C>T (p.Gln167X)","abstract_start":233,"abstract_end":253}]}
{"pmid":"23051780","title":"Clinical and myopathological characteristics of desminopathy caused by a mutation in desmin tail domain.","abstract":"BACKGROUND: Most of the previously described pathogenic mutations in desmin are located in highly conserved α-helical domains that play an important role in intermediate filament assembly. The role of the C-terminus non-α-helical 'tail' domain is much less investigated and until recently mutations in this domain have been implicated in only a few patients. The majority of reported desminopathy cases caused by the tail mutations were sporadic, creating a representation bias regarding the disease frequency and phenotypic characteristics.\nMETHODS: We performed detailed genotype-phenotype analysis of autosomal dominant desminopathy associated with tail domain mutations in a four-generation autosomal dominant family with 16 members affected by a progressive cardiac and/or skeletal myopathy caused by a c.1346A>C (p.Lys449Thr) mutation located in the tail domain of desmin.\nRESULTS: Phenotypic features in patients with tail domain mutations are similar to those in patients with mutations localized in the 1B and 2B α-helical domains.\nCONCLUSION: We recommend that the tail domain is searched for mutations as intensely as desmin coil domains which until recently were considered to be more 'functional'.","variants":[{"Name":"NM_001927.4(DES):c.1346A>C (p.Lys449Thr)","Chromosome":"2","Start":"219425720","Stop":"219425720","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":77297,"rule_based_match":true,"evidence_text":"c.1346A>C (p.Lys449Thr)","llm_judgment":"PRESENT","evidence":"c.1346A>C (p.Lys449Thr)","abstract_start":808,"abstract_end":831}]}
{"pmid":"15024743","title":"Identification of the bruton tyrosine kinase (BTK) gene mutations in 20 Australian families with X-linked agammaglobulinemia (XLA).","abstract":"X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the Bruton tyrosine kinase (BTK) gene. Twenty Australian patients with an XLA phenotype, from 15 unrelated families, were found to have 14 mutations. Five of the mutations were previously described c.83G>A (p.R28H), c.862C>T (p.R288W), c.904G>A (p.R302G), c.1535T>C (p.L512P), c.700C>T (p.Q234X), while nine novel mutations were identified: four missense c.82C>A (p.R28S), c.494G>A (p.C165Y), c.464G>A (p.C155Y), c.1750G>A (p.G584E), one deletion c.142_144delAGAAGA (p.R48_G50del), and four splice site mutations c.241-2A>G, c.839+4A>G, c.1350-2A>G, c.1566+1G>A. Carrier analysis was performed in 10 mothers and 11 female relatives. The results of this study further support the notion that molecular genetic testing represents an important tool for definitive and early diagnosis of XLA and may allow accurate carrier status and prenatal diagnosis.","variants":[{"Name":"NM_000061.3(BTK):c.1350-2A>G","Chromosome":"X","Start":"101356270","Stop":"101356270","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3857511,"rule_based_match":true,"evidence_text":"c.1350-2A>G","llm_judgment":"PRESENT","evidence":"c.1350-2A>G","abstract_start":617,"abstract_end":628},{"Name":"NM_000061.3(BTK):c.1535T>C (p.Leu512Pro)","Chromosome":"X","Start":"101356083","Stop":"101356083","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1471609,"rule_based_match":true,"evidence_text":"c.1535T>C (p.L512P)","llm_judgment":"PRESENT","evidence":"c.1535T>C (p.L512P)","abstract_start":336,"abstract_end":355},{"Name":"NM_000061.3(BTK):c.494G>A (p.Cys165Tyr)","Chromosome":"X","Start":"101362587","Stop":"101362587","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2901980,"rule_based_match":true,"evidence_text":"c.494G>A (p.C165Y)","llm_judgment":"PRESENT","evidence":"c.494G>A (p.C165Y)","abstract_start":453,"abstract_end":471}]}
{"pmid":"22089833","title":"Clinical expression and new SPINK5 splicing defects in Netherton syndrome: unmasking a frequent founder synonymous mutation and unconventional intronic mutations.","abstract":"Netherton syndrome (NS) is a severe skin disease caused by loss-of-function mutations in SPINK5 (serine protease inhibitor Kazal-type 5) encoding the serine protease inhibitor LEKTI (lympho-epithelial Kazal type-related inhibitor). Here, we disclose new SPINK5 defects in 12 patients, who presented a clinical triad suggestive of NS with variations in inter- and intra-familial disease expression. We identified a new and frequent synonymous mutation c.891C>T (p.Cys297Cys) in exon 11 of the 12 NS patients. This mutation disrupts an exonic splicing enhancer sequence and causes out-of-frame skipping of exon 11. Haplotype analysis indicates that this mutation is a founder mutation in Greece. Two other new deep intronic mutations, c.283-12T>A in intron 4 and c.1820+53G>A in intron 19, induced partial intronic sequence retention. A new nonsense c.2557C>T (p.Arg853X) mutation was also identified. All mutations led to a premature termination codon resulting in no detectable LEKTI on skin sections. Two patients with deep intronic mutations showed residual LEKTI fragments in cultured keratinocytes. These fragments retained some functional activity, and could therefore, together with other determinants, contribute to modulate the disease phenotype. This new founder mutation, the most frequent mutation described in European populations so far, and these unusual intronic mutations, widen the clinical and molecular spectrum of NS and offer new diagnostic perspectives for NS patients.","variants":[{"Name":"NM_006846.4(SPINK5):c.1820+53G>A","Chromosome":"5","Start":"148111948","Stop":"148111948","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1377578,"rule_based_match":true,"evidence_text":"c.1820+53G>A","llm_judgment":"PRESENT","evidence":"c.1820+53G>A","abstract_start":761,"abstract_end":773},{"Name":"NM_006846.4(SPINK5):c.891C>T (p.Cys297=)","Chromosome":"5","Start":"148097875","Stop":"148097875","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360867,"rule_based_match":true,"evidence_text":"c.891C>T (p.Cys297Cys)","llm_judgment":"PRESENT","evidence":"c.891C>T (p.Cys297Cys)","abstract_start":451,"abstract_end":473},{"Name":"NM_006846.4(SPINK5):c.2557C>T (p.Arg853Ter)","Chromosome":"5","Start":"148123851","Stop":"148123851","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":612271,"rule_based_match":true,"evidence_text":"c.2557C>T (p.Arg853X)","llm_judgment":"PRESENT","evidence":"c.2557C>T (p.Arg853X)","abstract_start":848,"abstract_end":869}]}
{"pmid":"30961548","title":"Compound heterozygous POMGNT1 mutations leading to muscular dystrophy-dystroglycanopathy type A3: a case report.","abstract":"BACKGROUND: Dystroglycanopathies, which are caused by reduced glycosylation of alpha-dystroglycan, are a heterogeneous group of neurodegenerative disorders characterized by variable brain and skeletal muscle involvement. Muscle-eye-brain disease (or muscular dystrophy-dystroglycanopathy type 3 A) is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities, and lissencephaly.\nCASE PRESENTATION: We report clinical and genetic characteristics of a 6-year-old boy affected by muscular dystrophy-dystroglycanopathy. He has severe a delay in psychomotor and speech development, muscle hypotony, congenital myopia, partial atrophy of the optic nerve disc, increased level of creatine kinase, primary-muscle lesion, polymicrogyria, ventriculomegaly, hypoplasia of the corpus callosum, cysts of the cerebellum. Exome sequencing revealed compound heterozygous mutations in POMGNT1 gene (transcript NM_001243766.1): c.1539 + 1G > A and c.385C > T.\nCONCLUSIONS: The present case report shows diagnostic algorithm step by step and helps better understand the clinical and genetic features of congenital muscular dystrophy.","variants":[{"Name":"NM_017739.4(POMGNT1):c.1539+1G>A","Chromosome":"1","Start":"46192097","Stop":"46192097","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":71221,"rule_based_match":true,"evidence_text":"c.1539 + 1G > A","llm_judgment":"PRESENT","evidence":"c.1539 + 1G > A","abstract_start":953,"abstract_end":968}]}
{"pmid":"28805452","title":"Birt-Hogg-Dube Syndrome with a Novel Mutation in the FLCN Gene.","abstract":"BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) is an autosomal dominant disease characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax; its cause is a heterozygous mutation in the FLCN gene. Colorectal polyps and carcinoma have also been reported in BHDS. FLCN mutations can be detected in patients with isolated primary spontaneous pneumothorax (PSP), so PSP may present as part of BHDS. The aim of this report is to enhance awareness that patients presenting with spontaneous PSP should be evaluated for FLCN mutations.\nMATERIALS AND METHODS: A 44-year-old woman with PSP and her parents were analyzed for FLCN mutations. One of the patient's paternal aunts had a PSP and two of her paternal aunts had colon cancer diagnosed at early ages.\nRESULTS: A novel in-frame deletion in the FLCN gene, c.932_933delCT (P311Rfs*78), was detected in the proband and in her unaffected father.\nCONCLUSIONS: We recommend that molecular analysis of the FLCN gene be performed in patients with PSP and their families, and that mutation carriers be examined for kidney and colon tumors.","variants":[{"Name":"NM_144997.7(FLCN):c.932_933del (p.Pro311fs)","Chromosome":"17","Start":"17219148","Stop":"17219149","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":360794,"rule_based_match":true,"evidence_text":"c.932_933delCT (P311Rfs*78)","llm_judgment":"PRESENT","evidence":"c.932_933delCT (P311Rfs*78)","abstract_start":823,"abstract_end":850}]}
{"pmid":"26411740","title":"Novel EDA mutation in X-linked hypohidrotic ectodermal dysplasia and genotype-phenotype correlation.","abstract":"OBJECTIVES: X-linked hypohidrotic ectodermal dysplasia (XLHED) is characterized by abnormalities of hair, teeth, and sweat glands, while non-syndromic hypodontia (NSH) affects only teeth. Mutations in Ectodysplasin A (EDA) underlie both XLHED and NSH. This study investigated the genetic causes of six hypohidrotic ectodermal dysplasia (HED) patients and genotype-phenotype correlation.\nMETHODS: The EDA gene of six patients with HED was sequenced. Bioinformatics analysis and structural modeling for the mutations were performed. The records of 134 patients with XLHED and EDA-related NSH regarding numbers of missing permanent teeth from this study and 20 articles were reviewed. Nonparametric tests were used to analyze genotype-phenotype correlations.\nRESULTS: In four of the six patients, we identified a novel mutation c.852T>G (p.Phe284Leu) and three reported mutations: c.467G>A (p.Arg156His), c.776C>A (p.Ala259Glu), and c.871G>A (p.Gly291Arg). They were predicted to be pathogenic by bioinformatics analysis and structural modeling. Genotype-phenotype correlation analysis revealed that truncating mutations were associated with more missing teeth. Missense mutations and the mutations affecting the TNF homology domain were correlated with fewer missing teeth.\nCONCLUSIONS: This study extended the mutation spectrum of XLHED and revealed the relationship between genotype and the number of missing permanent teeth.","variants":[{"Name":"NM_001399.5(EDA):c.871G>A (p.Gly291Arg)","Chromosome":"X","Start":"70033475","Stop":"70033475","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":53378,"rule_based_match":true,"evidence_text":"c.871G>A (p.Gly291Arg)","llm_judgment":"PRESENT","evidence":"c.871G>A (p.Gly291Arg)","abstract_start":930,"abstract_end":952}]}
{"pmid":"31131889","title":"Transcriptome analysis of gingival tissues of enamel-renal syndrome.","abstract":"BACKGROUND AND OBJECTIVE: Biallelic loss-of-function mutations of human FAM20A have been known to cause enamel-renal syndrome (ERS), featured by agenesis of dental enamel, nephrocalcinosis, and other orodental abnormalities, including gingival hyperplasia. However, while the histopathology of this gingival anomaly has been analyzed, its underlying molecular mechanism remains largely unknown. This study aimed to unravel the pathogenesis of gingival hyperplasia in ERS.\nMETHODS: Whole-exome sequencing was conducted for an ERS case. Transcriptome analyses, using RNA sequencing, of the patient's gingiva were performed to unravel dysregulated molecules and aberrant biological processes underlying the gingival pathology of ERS, which was further confirmed by histology and immunohistochemistry.\nRESULTS: Two novel frameshift FAM20A mutations in Exon 1 (g.5417delG; c.129delG; p.Cys44Alafs*101) and Exon 5 (g.62248_62249delAG; c.734_735delAG; p.Glu245Glyfs*11) were identified. Transcriptional profiling of patient's gingival tissue revealed a total of 1683 genes whose expression had increased (1129 genes) or decreased (554 genes) at least 2-fold compared to control gingival tissues. There were 951 gene ontology (GO) terms of biological process being significantly over-represented or under-represented. While GOs involved in extracellular matrix organization, angiogenesis, biomineralization, and epithelial cell proliferation appeared to be activated in ERS gingiva, genes related to keratinocyte differentiation, epithelial development, and keratinization were of decreased expression. FAM20A immunohistochemistry revealed a strong reactivity at the suprabasal layers of epithelium in control gingiva but showed a significantly diminished and scattered signal in ERS tissues. For genes showing significant over-expression in the transcriptome analyses, namely ALPL, SPARC, and ACTA2, an increased immunoreactivity was observed.\nCONCLUSION: Our results unraveled a potential role for FAM20A in homeostasis of both gingival epithelium and connective tissues.","variants":[{"Name":"NM_017565.4(FAM20A):c.129del (p.Cys44fs)","Chromosome":"17","Start":"68600538","Stop":"68600538","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":1179040,"rule_based_match":true,"evidence_text":"c.129delG","llm_judgment":"PRESENT","evidence":"c.129delG","abstract_start":868,"abstract_end":877},{"Name":"NM_017565.4(FAM20A):c.734_735del (p.Glu245fs)","Chromosome":"17","Start":"68543706","Stop":"68543707","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":1179039,"rule_based_match":true,"evidence_text":"c.734_735delAG","llm_judgment":"PRESENT","evidence":"c.734_735delAG","abstract_start":929,"abstract_end":943}]}
{"pmid":"38455531","title":"A novel","abstract":"Objectives: Methylmalonic acidemia (MMA) is a rare inborn genetic disorder that is characterized by increased levels of methylmalonic acid in blood plasma and urine. Isolated methylmalonic acidemia is one of the most common types of MMA and is caused by mutations in the gene encoding methyl-malonyl coenzyme A mutase (<i>MMUT</i>). In this study, we investigated the possible mechanisms underlying the symptoms of isolated MMA in a patient by molecular analysis.\nMethods: PCR amplification and Sanger sequencing analysis was performed to identify variants in the <i>MMUT</i> gene in the proband and his family. Furthermore, minigene constructs were generated to validate the splicing defects in the <i>MMUT</i> gene variant identified in the proband.\nResults: The 3-year-old patient was admitted to the hospital with symptoms of MMA, including fever, convulsions, and vomiting. He showed metabolic acidosis, high levels of methylmalonic acid in blood and urine, and normal blood homocysteine levels. Genetic analysis demonstrated that the patient was a compound heterozygous carrier of two variants in the <i>MMUT</i> gene: a missense c.278G > A variant that has already been reported in a patient with the severe mut⁰ phenotype; and a novel splice site variant c.2125-2A > G. RT-PCR analysis showed that, while the novel variant clearly alters splicing, a minor amount of a full-length transcript is generated, suggesting that a wild-type protein may be produced although at a lower quantitative level. The patient's condition improved after treatment with vitamin B12. Serious complications were not reported during follow-up at age 5.\nConclusions: We identified a novel splice site variant that partially disrupts normal splicing of the <i>MMUT</i> pre-mRNA. Production of a reduced amount of full-length transcript is responsible for the mild clinical phenotype observed in this patient. Functional studies have proven useful in exploring the genotype-phenotype association and in providing guidance for the genetic diagnosis of MMA.","variants":[{"Name":"NM_000255.4(MMUT):c.278G>A (p.Arg93His)","Chromosome":"6","Start":"49459189","Stop":"49459189","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16919,"rule_based_match":true,"evidence_text":"c.278G > A","llm_judgment":"PRESENT","evidence":"c.278G > A","abstract_start":1136,"abstract_end":1146}]}
{"pmid":"29287890","title":"A novel pathogenic variant c.975G>A (p.Trp325*) in the POU3F4 gene in Yakut family (Eastern Siberia, Russia) with the X-linked deafness-2 (DFNX2).","abstract":"Here, we report a novel hemizygous transition c.975G>A (p.Trp325*) in POU3F4 gene (Xq21) found in two deaf half-brothers from one Yakut family (Eastern Siberia, Russia) with identical inner ear abnormalities (\"corkscrew\" cochlea with an absence of modiolus) specific to X-linked deafness-2 (DFNX2). Comprehensive clinical evaluation (CT and MR-imaging, audiological and stabilometric examinations) of available members of this family revealed both already known (mixed progressive hearing loss) and additional (enlargement of semicircular canals and postural disorders) clinical DFNX2 features in affected males with c.975G>A (p.Trp325*). Moreover, mild enlargement of semicircular canals, postural abnormalities and different types of hearing thresholds were found in female carrier of this POU3F4-variant.","variants":[{"Name":"NM_000307.5(POU3F4):c.975G>A (p.Trp325Ter)","Chromosome":"X","Start":"83509299","Stop":"83509299","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":590644,"rule_based_match":true,"evidence_text":"c.975G>A (p.Trp325*)","llm_judgment":"PRESENT","evidence":"c.975G>A (p.Trp325*)","abstract_start":46,"abstract_end":66}]}
{"pmid":"34545694","title":"Nicotinamide nucleotide transhydrogenase mutation analysis in Chinese patients with thyroid dysgenesis.","abstract":"Thyroid dysgenesis (TD) accounts for 80% cases of congenital hypothyroidism, which is the most common neonatal disorder. Until now, the gene mutations have been reported associated with TD can only account for 5% cases, suggesting the genetic heterogeneity of the pathology. Nicotinamide nucleotide transhydrogenase (NNT) plays a crucial role in regulating redox homeostasis, patients carrying NNT mutations have been described with a clinical phenotype of hypothyroidism. As TD risk is increased in the context of several syndromes and redox homeostasis is vital for thyroid development and function, NNT might be a candidate gene involved in syndromic TD. Therefore, we performed target sequencing (TS) in 289 TD patients for causative mutations in NNT and conducted functional analysis of the gene mutations. TS and Sanger sequence were used to screen the novel mutations. For functional analysis, we performed western blot, measurement of NADPH/NADP<sub>total</sub> and H<sub>2</sub> O<sub>2</sub> generation, cell proliferation, and wounding healing assay. As a result, three presumably pathogenic mutations (c.811G > A, p.Ala271Ser; c.2078G > A, p.Arg693His; and c.2581G > A, p.Val861Met) in NNT had been identified. Our results showed the damaging effect of NNT mutations on stability and catalytic activity of proteins and redox balance of cells. In conclusion, our findings provided novel insights into the role of the NNT isotype in thyroid physiopathology and broaden the spectrum of pathogenic genes associated with TD. However, the pathogenic mechanism of NNT in TD is still need to be investigated in further study.","variants":[{"Name":"NM_182977.3(NNT):c.2078G>A (p.Arg693His)","Chromosome":"5","Start":"43655858","Stop":"43655858","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1365438,"rule_based_match":true,"evidence_text":"c.2078G > A, p.Arg693His","llm_judgment":"PRESENT","evidence":"c.2078G > A, p.Arg693His","abstract_start":1139,"abstract_end":1163}]}
{"pmid":"33826954","title":"Long-read sequencing identified a novel nonsense and a de novo missense of PPA2 in trans in a Chinese patient with autosomal recessive infantile sudden cardiac failure.","abstract":"BACKGROUND AND AIMS: Biallelic missense variants in PPA2 gene cause infantile sudden cardiac failure (SCFI; OMIM #617222) characterized by sudden cardiac failure, sudden cardiac death in infants. Here, we present an unusual survivor with one inherited plus one de novo variant in PPA2. Since next-generation sequencing (NGS) fails to resolve variant phasing, which require long-read sequencing to clarify the diagnosis.\nMATERIALS AND METHODS: Whole exome and Sanger sequencing were initially performed to identify the causative variants. PCR-based short tandem repeats (STRs) analysis and long-read single molecule real-time (SMRT) sequencing were further implemented for paternity testing and variant phasing. Pathogenicity evaluation of the biallelic variants in PPA2 was conducted according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines based on VarSome.\nRESULTS: Whole exome and Sanger sequencing revealed two variants in PPA2, with one novel nonsense variant (c.524C > G; p.Ser175*) inherited from the mother and one de novo missense variant (c.379C > T; p.Arg127Cys). PCR-based STRs analysis verified the paternity. And long-read SMRT sequencing phased the two variants in trans and identified the paternal origin of the de novo variant. The genetic diagnosis clarified the genetic etiology of the proband and assisted in patient management and counseling.\nCONCLUSION: We identified a rare combination of one inherited plus one de novo variant of PPA2 in a patient with autosomal recessive SCFI, which expanded the mutation spectrum of PPA2 and demonstrated the power of target long-read sequencing to make up the diagnostic gap of prevailing NGS.","variants":[{"Name":"NM_176869.3(PPA2):c.379C>T (p.Arg127Cys)","Chromosome":"4","Start":"105446445","Stop":"105446445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1179785,"rule_based_match":true,"evidence_text":"c.379C > T; p.Arg127Cys","llm_judgment":"PRESENT","evidence":"c.379C > T; p.Arg127Cys","abstract_start":1127,"abstract_end":1150}]}
{"pmid":"31279664","title":"Detection of ten novel FBN1 mutations in Chinese patients with typical or incomplete Marfan syndrome and an overview of the genotype-phenotype correlations.","abstract":"OBJECTIVE: The aim of this study is to identify the mutation spectrum of FBN1 in patients with Marfan syndrome (MFS) or Marfan-Like Phenotypes and to analyze the genotype-phenotype correlations of existing literature.\nMETHODS AND RESULTS: A total of 21 unrelated patients with a definite or suspected clinical diagnosis of MFS were recruited for research. Eleven FBN1 mutations were identified in 12 patients who strictly fulfilled the Ghent criteria for MFS, and 1 FBN1 mutations were detected in 9 patients with suspected MFS by screening the mutations of FBN1. These FBN1 mutations include 10 novel mutations (c.357 C>A, c.493 C>T, c.1374 T>A, c.4143 delG, c. 6987 C>G, c.7238 G>A, c. 7765 A>G, c.8200 A>G, c. 8431 G>A, c.8547 T>G,) and 2 previously reported mutations (c.4567 C>T, c.4615 C>T). By searching PubMed and Embase (from 1990 up to December 2018), twenty nine studies (including the present study) with 890 subjects with MFS or Marfan-like phenotypes were included to analyze the genotype-phenotype correlations. Several genotype-phenotype correlations were founded. Firstly, mutations of premature termination codons (PTC) were associated with an increased risk of major cardiovascular involvements. Secondly, the frequency of patients with major cardiovascular involvement in exons 43-65 group was as high as that in exons 24-32 group (71.4% vs. 77.0%; p = 0.238). Finally, cysteine missense mutations might be associated with major cardiovascular involvements.\nCONCLUSIONS: These results extended the FBN1 mutation spectrum of this rare disease and revealed the genotype-phenotype correlations in MFS by analyzing existing literature.","variants":[{"Name":"NM_000138.5(FBN1):c.7238G>A (p.Cys2413Tyr)","Chromosome":"15","Start":"48425831","Stop":"48425831","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1404907,"rule_based_match":true,"evidence_text":"c.7238 G>A","llm_judgment":"PRESENT","evidence":"c.7238 G>A","abstract_start":673,"abstract_end":683},{"Name":"NM_000138.5(FBN1):c.4615C>T (p.Arg1539Ter)","Chromosome":"15","Start":"48468070","Stop":"48468070","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":51536,"rule_based_match":true,"evidence_text":"c.4615 C>T","llm_judgment":"PRESENT","evidence":"c.4615 C>T","abstract_start":785,"abstract_end":795},{"Name":"NM_000138.5(FBN1):c.8200A>G (p.Asn2734Asp)","Chromosome":"15","Start":"48412595","Stop":"48412595","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":912657,"rule_based_match":true,"evidence_text":"c.8200 A>G","llm_judgment":"PRESENT","evidence":"c.8200 A>G","abstract_start":698,"abstract_end":708},{"Name":"NM_000138.5(FBN1):c.7765A>G (p.Arg2589Gly)","Chromosome":"15","Start":"48420741","Stop":"48420741","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":643314,"rule_based_match":true,"evidence_text":"c.7765 A>G","llm_judgment":"PRESENT","evidence":"c. 7765 A>G","abstract_start":685,"abstract_end":696},{"Name":"NM_000138.5(FBN1):c.493C>T (p.Arg165Ter)","Chromosome":"15","Start":"48596328","Stop":"48596328","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":51543,"rule_based_match":true,"evidence_text":"c.493 C>T","llm_judgment":"PRESENT","evidence":"c.493 C>T","abstract_start":624,"abstract_end":633}]}
{"pmid":"32653833","title":"Detailed Phenotyping and Therapeutic Strategies for Intronic ABCA4 Variants in Stargardt Disease.","abstract":"Stargardt disease is a progressive retinal disorder caused by bi-allelic mutations in the ABCA4 gene that encodes the ATP-binding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease.","variants":[{"Name":"NM_000350.3(ABCA4):c.5196+1137G>A","Chromosome":"1","Start":"94018445","Stop":"94018445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":431618,"rule_based_match":true,"evidence_text":"c.5196+1137G>A","llm_judgment":"PRESENT","evidence":"c.5196+1137G>A","abstract_start":351,"abstract_end":365}]}
{"pmid":"35285020","title":"Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest.","abstract":"The genetic causes of idiopathic premature ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) remain unclear. We performed whole-exome sequencing (WES) in members of a consanguineous family with two POI and two NOA patients to screen for potential pathogenic variants for familial POI and NOA. And a homozygous variant in SPATA22 (c.400C>T:p.R134X) was identified. Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA. The candidate gene was further screened in the in-house WES database of idiopathic POI-affected patients. One additional compound heterozygous variant in SPATA22 (c.900+1G>A and c.31C>T:p.R11X) was found in one patient with sporadic POI and validated by minigene assay. Thus, this is the first report identifying SPATA22 as the causative gene for human POI. Combined with the observations in the familial patient with NOA, our findings highlighted the essential role of meiotic HR genes in gametogenesis and gonadal function maintenance.","variants":[{"Name":"NM_001170698.2(SPATA22):c.400C>T (p.Arg134Ter)","Chromosome":"17","Start":"3449079","Stop":"3449079","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3529597,"rule_based_match":true,"evidence_text":"c.400C>T:p.R134X","llm_judgment":"PRESENT","evidence":"c.400C>T:p.R134X","abstract_start":345,"abstract_end":361},{"Name":"NM_001170698.2(SPATA22):c.31C>T (p.Arg11Ter)","Chromosome":"17","Start":"3469295","Stop":"3469295","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3529598,"rule_based_match":true,"evidence_text":"c.31C>T:p.R11X","llm_judgment":"PRESENT","evidence":"c.31C>T:p.R11X","abstract_start":713,"abstract_end":727}]}
{"pmid":"21321493","title":"Hereditary spastic paraplegia associated with axonal neuropathy: a novel mutation of SPG3A in a large family.","abstract":"Spastic paraplegia Type 3A is an autosomal-dominant pure or uncomplicated hereditary spastic paraplegia. It is caused by mutations in SPG3A, the only gene associated with this condition. We identified a novel mutation, c.1040T>C (p. M347T), in a family with axonal neuropathy in addition to spastic paraplegia. This expands the spectrum of neurologic complications associated with SPG3A and highlights the importance of long-term follow-up and neurological surveillance in this patient population.","variants":[{"Name":"NM_015915.5(ATL1):c.1040T>C (p.Met347Thr)","Chromosome":"14","Start":"50621892","Stop":"50621892","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":793502,"rule_based_match":true,"evidence_text":"c.1040T>C (p. M347T)","llm_judgment":"PRESENT","evidence":"c.1040T>C (p. M347T)","abstract_start":219,"abstract_end":239}]}
{"pmid":"29355723","title":"A case of CHARGE syndrome associated with hyperinsulinemic hypoglycemia in infancy.","abstract":"CHARGE syndrome is a rare autosomal dominant disorder involving multiple organs. Chromodomain helicase DNA binding protein-7 (CHD7) is a major causative gene of CHARGE syndrome. We herein report a male infant born at full term with asphyxia who was diagnosed with CHARGE syndrome based on the typical anomalies. He showed a poor sucking ability and suffered from continuous hypoglycemia in early infancy, ultimately requiring tube feeding. While in a hypoglycemic status, inappropriate high insulin and low growth hormone levels were noticed. Growth hormone replacement therapy partially increased his blood glucose levels, but asymptomatic hypoglycemia with hyperinsulinemia was occasionally noticed. Additional diazoxide treatment stabilized his blood level to within the normal range. A genetic analysis of CHD7 showed the novel heterozygous monoallelic mutation c.2990delT causing a reading frameshift p.Leu997Trpfs*15 in exon 12. This case shows that patients with CHARGE syndrome caused by a CHD7 mutation may present with persistent hyperinsulinemic hypoglycemia, just like other dysmorphic syndromes genetically caused by aberrations in chromatin remodeling.","variants":[{"Name":"NM_017780.4(CHD7):c.2990del (p.Leu997fs)","Chromosome":"8","Start":"60822533","Stop":"60822533","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":434798,"rule_based_match":true,"evidence_text":"c.2990delT","llm_judgment":"PRESENT","evidence":"c.2990delT","abstract_start":866,"abstract_end":876}]}
{"pmid":"29725107","title":"Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia.","abstract":"Complete tyrosine kinase 2 (TYK2) deficiency has been previously described in patients with primary immunodeficiency diseases. The patients were infected with various pathogens, including mycobacteria and/or viruses, and one of the patients developed hyper-IgE syndrome. A detailed immunological investigation of these patients revealed impaired responses to type I IFN, IL-10, IL-12 and IL-23, which are associated with increased susceptibility to mycobacterial and/or viral infections. Herein, we report a recessive partial TYK2 deficiency in two siblings who presented with T-cell lymphopenia characterized by low naïve CD4<sup>+</sup> T-cell counts and who developed Epstein-Barr virus (EBV)-associated B-cell lymphoma. Targeted exome-sequencing of the siblings' genomes demonstrated that both patients carried novel compound heterozygous mutations (c.209_212delGCTT/c.691C > T, p.Cys70Serfs*21/p.Arg231Trp) in the TYK2. The TYK2 protein levels were reduced by 35% in the T cells of the patient. Unlike the response under complete TYK2 deficiency, the patient's T cells responded normally to type I IFN, IL-6, IL-10 and IL-12, whereas the cells displayed an impaired response to IL-23. Furthermore, the level of STAT1 was low in the cells of the patient. These studies reveal a new clinical entity of a primary immunodeficiency with T-cell lymphopenia that is associated with compound heterozygous TYK2 mutations in the patients.","variants":[{"Name":"NM_003331.5(TYK2):c.209_212del (p.Cys70fs)","Chromosome":"19","Start":"10368400","Stop":"10368403","ReferenceAlleleVCF":"GAAGC","AlternateAlleleVCF":"G","allel_id":227400,"rule_based_match":true,"evidence_text":"c.209_212delGCTT","llm_judgment":"PRESENT","evidence":"c.209_212delGCTT","abstract_start":854,"abstract_end":870},{"Name":"NM_003331.5(TYK2):c.691C>T (p.Arg231Trp)","Chromosome":"19","Start":"10365837","Stop":"10365837","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":847060,"rule_based_match":true,"evidence_text":"c.691C > T","llm_judgment":"PRESENT","evidence":"c.691C > T","abstract_start":871,"abstract_end":881}]}
{"pmid":"23667852","title":"Identification of ATM mutations in Korean siblings with ataxia-telangiectasia.","abstract":"Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features of A-T.","variants":[{"Name":"NM_000051.4(ATM):c.2639-19_2639-7del","Chromosome":"11","Start":"108268389","Stop":"108268401","ReferenceAlleleVCF":"AATGAGTGCTTTTT","AlternateAlleleVCF":"A","allel_id":815475,"rule_based_match":true,"evidence_text":"c.2639-19_2639-7del13","llm_judgment":"PRESENT","evidence":"c.2639-19_2639-7del13","abstract_start":764,"abstract_end":785},{"Name":"NM_000051.4(ATM):c.8546G>C (p.Arg2849Pro)","Chromosome":"11","Start":"108345870","Stop":"108345870","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":484709,"rule_based_match":true,"evidence_text":"c.8546G>C; p.Arg2849Pro","llm_judgment":"PRESENT","evidence":"c.8546G>C; p.Arg2849Pro","abstract_start":696,"abstract_end":719}]}
{"pmid":"29848554","title":"Extremely hypomorphic and severe deep intronic variants in the","abstract":"Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the <i>ABCA4</i> gene. Complete sequencing of the <i>ABCA4</i> locus in STGD1 patients identifies two expected disease-causing alleles in ∼75% of patients and only one mutation in ∼15% of patients. Recently, many possibly pathogenic variants in deep intronic sequences of <i>ABCA4</i> have been identified in the latter group. We extended our analyses of deep intronic <i>ABCA4</i> variants and determined that one of these, c.4253+43G>A (rs61754045), is present in 29/1155 (2.6%) of STGD1 patients. The variant is found at statistically significantly higher frequency in patients with only one pathogenic <i>ABCA4</i> allele, 23/160 (14.38%), MAF = 0.072, compared to MAF = 0.013 in all STGD1 cases and MAF = 0.006 in the matching general population (<i>P</i> < 1 × 10<sup>-7</sup>). The variant, which is not predicted to have any effect on splicing, is the first reported intronic \"extremely hypomorphic allele\" in the <i>ABCA4</i> locus; that is, it is pathogenic only when in <i>trans</i> with a loss-of-function <i>ABCA4</i> allele. It results in a distinct clinical phenotype characterized by late onset of symptoms and foveal sparing. In ∼70% of cases the variant was allelic with the c.6006-609T>A (rs575968112) variant, which was deemed nonpathogenic. Another rare deep intronic variant, c.5196+1056A>G (rs886044749), found in 5/834 (0.6%) of STGD1 cases is, conversely, a severe allele. This study determines pathogenicity for three noncoding variants in STGD1 patients of European descent accounting for ∼3% of the disease. Defining disease-associated alleles in the noncoding sequences of the <i>ABCA4</i> locus can be accomplished by integrated clinical and genetic analyses.","variants":[{"Name":"NM_000350.3(ABCA4):c.4253+43G>A","Chromosome":"1","Start":"94030953","Stop":"94030953","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105154,"rule_based_match":true,"evidence_text":"c.4253+43G>A (rs61754045)","llm_judgment":"PRESENT","evidence":"c.4253+43G>A (rs61754045)","abstract_start":509,"abstract_end":534},{"Name":"NM_000350.3(ABCA4):c.5196+1056A>G","Chromosome":"1","Start":"94018526","Stop":"94018526","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":237653,"rule_based_match":true,"evidence_text":"c.5196+1056A>G (rs886044749)","llm_judgment":"PRESENT","evidence":"c.5196+1056A>G (rs886044749)","abstract_start":1382,"abstract_end":1410}]}
{"pmid":"20512159","title":"New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish.","abstract":"Warburg Micro Syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. We have found five new mutations in the RAB3GAP1 gene in seven patients with suspected Micro Syndrome from families with Turkish, Palestinian, Danish, and Guatemalan backgrounds. A thorough clinical investigation of the patients has allowed the delineation of symptoms that are consistently present in the patients and may aid the differential diagnosis of Micro Syndrome for patients in the future. All patients had postnatal microcephaly, micropthalmia, microcornia, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only one patient had microcephaly at birth, highlighting the fact that congenital microcephaly is not a consistent feature of Micro syndrome. Analysis of the brain magnetic resonance imagings (MRIs) revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum, and increased subdural spaces. All patients were homozygous for the mutations detected and all mutations were predicted to result in a truncated RAB3GAP1 protein. The analysis of nine polymorphic markers flanking the RAB3GAP1 gene showed that the mutation c.1410C>A (p.Tyr470X), for which a Danish patient was homozygous, occurred on a haplotype that is shared by the unrelated heterozygous parents of the patient. This suggests a possible founder effect for this mutation in the Danish population.","variants":[{"Name":"NM_012233.3(RAB3GAP1):c.1410C>A (p.Tyr470Ter)","Chromosome":"2","Start":"135133944","Stop":"135133944","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":22100,"rule_based_match":true,"evidence_text":"c.1410C>A (p.Tyr470X)","llm_judgment":"PRESENT","evidence":"c.1410C>A (p.Tyr470X)","abstract_start":1504,"abstract_end":1525}]}
{"pmid":"25335496","title":"Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects.","abstract":"Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p.(Trp792fs) and c.2827C>T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C>T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients.","variants":[{"Name":"NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)","Chromosome":"11","Start":"47335120","Stop":"47335120","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45725,"rule_based_match":true,"evidence_text":"c.2827C>T p.(Arg943*)","llm_judgment":"PRESENT","evidence":"c.2827C>T p.(Arg943*)","abstract_start":1004,"abstract_end":1025}]}
{"pmid":"30794915","title":"Common pathogenic mechanism in patients with dropped head syndrome caused by different mutations in the MYH7 gene.","abstract":"Mutations in the MYH7 gene are the source of an allelic series of diseases, including various cardiomyopathies and skeletal myopathies that usually manifest in adulthood. We observed a 1.5 y.o. male patient with congenital weaknesses of the axial muscles, \"dropped head\" syndrome, and dilated cardiomyopathy. The clinical evaluation included medical history, an echocardiogram, electromyography, and a histopathological study. The genetic evaluation included whole exome sequencing. Muscle biopsy samples from the proband were used for mRNA extraction. We revealed a novel genetic variant c.5655 + 5G > C in the MYH7 gene. The analysis of the cDNA showed an in-frame skipping of exon 38 (p.1854_1885del). This variant and two previously published mutations (c.5655G > A and c.5655 + 1G > A), also presumably leading to exon 38 skipping, were studied by expression analysis in the HEK293T cell line transfected with 4 plasmids containing the MYH7 minigene (wt, c.5655G > C, c.5655 + 1G > A and c.5655 + 5G > A). A quantitative difference in expression was shown for cell lines with each of the three mutant plasmids. All mutation carriers had a similar phenotype and included congenital axial myopathy and variable cardiac involvement. Prominent dropped head syndrome was mentioned in all patients. Early-onset axial myopathy with a dropped head syndrome is a distinct clinical entity within MYH7-related disorders. We suggest that mutations in the MYH7 gene affecting the C-terminal domain of beta-myosin heavy chain should also be considered as a possible cause in cases of early-onset myopathy with \"dropped head\" syndrome.","variants":[{"Name":"NM_000257.4(MYH7):c.5655+5G>C","Chromosome":"14","Start":"23414002","Stop":"23414002","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":682183,"rule_based_match":true,"evidence_text":"c.5655 + 5G > C","llm_judgment":"PRESENT","evidence":"c.5655 + 5G > C","abstract_start":589,"abstract_end":604}]}
{"pmid":"30057544","title":"Mutation in KIF5A c.610C>T Causing Hereditary Spastic Paraplegia with Axonal Sensorimotor Neuropathy.","abstract":"Hereditary spastic paraplegias (HSP) are a rare heterogeneous group of inherited neurodegenerative diseases characterized by progressive lower extremity spasticity and weakness. Mutations of the kinesin family member 5A (KIF5A) gene lead to a spectrum of phenotypes ranging from spastic paraplegia type 10 to Charcot-Marie Tooth Disease type 2. We report the second known case of a mutation in the KIF5A gene at c.610C>T presenting with HSP plus an axonal sensorimotor neuropathy.","variants":[{"Name":"NM_004984.4(KIF5A):c.610C>T (p.Arg204Trp)","Chromosome":"12","Start":"57567514","Stop":"57567514","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":411581,"rule_based_match":true,"evidence_text":"c.610C>T","llm_judgment":"PRESENT","evidence":"c.610C>T","abstract_start":412,"abstract_end":420}]}
{"pmid":"24780881","title":"A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.","abstract":"BACKGROUND: Usher syndrome (USH) is a heterogeneous group of inherited retinitis pigmentosa (RP) and sensorineural hearing loss (SNHL) caused by mutations in at least 12 genes. Our aim is to identify additional USH-related genes.\nMETHODS: Clinical examination included visual acuity test, funduscopy and electroretinography. Genetic analysis included homozygosity mapping and whole exome sequencing (WES).\nRESULTS: A combination of homozygosity mapping and WES in a large consanguineous family of Iranian Jewish origin revealed nonsense mutations in two ciliary genes: c.3289C>T (p.Q1097*) in C2orf71 and c.3463C>T (p.R1155*) in centrosome-associated protein CEP250 (C-Nap1). The latter has not been associated with any inherited disease and the c.3463C>T mutation was absent in control chromosomes. Patients who were double homozygotes had SNHL accompanied by early-onset and severe RP, while patients who were homozygous for the CEP250 mutation and carried a single mutant C2orf71 allele had SNHL with mild retinal degeneration. No ciliary structural abnormalities in the respiratory system were evident by electron microscopy analysis. CEP250 expression analysis of the mutant allele revealed the generation of a truncated protein lacking the NEK2-phosphorylation region.\nCONCLUSIONS: A homozygous nonsense CEP250 mutation, in combination with a heterozygous C2orf71 nonsense mutation, causes an atypical form of USH, characterised by early-onset SNHL and a relatively mild RP. The severe retinal involvement in the double homozygotes indicates an additive effect caused by nonsense mutations in genes encoding ciliary proteins.","variants":[{"Name":"NM_007186.6(CEP250):c.3463C>T (p.Arg1155Ter)","Chromosome":"20","Start":"35497875","Stop":"35497875","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":612044,"rule_based_match":true,"evidence_text":"c.3463C>T (p.R1155*)","llm_judgment":"PRESENT","evidence":"c.3463C>T (p.R1155*)","abstract_start":605,"abstract_end":625}]}
{"pmid":"23652934","title":"Acute kidney injury after acute gastroenteritis in an infant with hereditary hypouricemia.","abstract":"UNLABELLED: Hereditary hypouricemia is a rare disorder characterized by extremely low serum uric acid levels caused by excessive urinary excretion due to an inherited tubular defect in urate handling. Exercise-induced acute kidney injury (AKI) is the main complication of this disorder, though AKI may also be induced by other factors. A 7-month-old boy with hereditary hypouricemia developed AKI associated with severe dehydration caused by rotavirus gastroenteritis. He also showed severe hypernatremia and metabolic acidosis and received continuous renal replacement therapy for 3 days. He showed no signs of hydronephrosis or urolithiasis. However, hypouricemia was noted when his renal function recovered (serum uric acid <0.6 mg/dl). Analysis of the urate transporter 1 gene revealed a homozygous nonsense mutation in exon 4 (c.774G > A, p.W258X). Both parents were heterozygous for the mutation and his younger brother was later determined to have severe hypouricemia (0.6 mg/dl).\nCONCLUSION: Uric acid is an essential factor for scavenging oxidative stressors. In this patient, severe dehydration may have directly caused pre-renal AKI, but susceptibility to oxidative stressors under severe dehydration, as well as exercise, may also contribute to AKI. Careful attention should be paid to dehydration, especially in young children, to avoid the development of AKI in patients with hereditary hypouricemia.","variants":[{"Name":"NM_144585.4(SLC22A12):c.774G>A (p.Trp258Ter)","Chromosome":"11","Start":"64593747","Stop":"64593747","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18551,"rule_based_match":true,"evidence_text":"c.774G > A, p.W258X","llm_judgment":"PRESENT","evidence":"c.774G > A, p.W258X","abstract_start":832,"abstract_end":851}]}
{"pmid":"28294317","title":"The spectrum of BRCA mutations and characteristics of BRCA-associated breast cancers in China: Screening of 2,991 patients and 1,043 controls by next-generation sequencing.","abstract":"To characterize the prevalence of BRCA mutations and characteristics of BRCA carriers in China and to update the clinical recommendations for BRCA testing, we conducted a wide screen for BRCA mutations using next-generation sequencing (NGS). A total of 4,034 Chinese subjects were screened for germline BRCA1/2 mutations, including 2,991 breast cancer patients and 1,043 healthy individuals from the community enrolled as controls. We developed an NGS-based approach to perform BRCA1/2 screening. BRCA mutations were identified in 9.1% (232/2,560) of cases with at least one risk factor, in 3.5% (15/431) of sporadic patients and in 0.38% (4/1,043) of healthy controls. The mutation frequency ranged from 8.9 to 15.2% in cohorts with a single risk factor to 16.6-100% in groups with multiple risk factors. We identified 70 novel BRCA mutations. A high frequency of BRCA1 c.5470_5477del was detected, accounting for 13.9% (16/115) of the BRCA1 mutations detected in our study. Clinical characteristics such as family history, invasive carcinoma, negative human epidermal growth factor receptor 2 (HER2), high Ki67 index, lymph node status, and high tumour grade were closely related to BRCA mutations. BRCA2 carriers had poorer disease-free survival among HER2- or hormone receptor-positive patients (hazard ratio = 1.892; 95% confidence interval: 1.132-3.161; p = 0.013). This study shows that BRCA mutation carriers could be frequently identified among breast cancer patients with multiple risk factors. Importantly, we established an NGS-based pipeline for BRCA1/2 testing in clinical practice and strongly suggest that breast cancer patients of premier- and moderate-grade risks receive BRCA1/2 mutations testing in China.","variants":[{"Name":"NM_007294.4(BRCA1):c.5470_5477del","Chromosome":"17","Start":"43045793","Stop":"43045800","ReferenceAlleleVCF":"CTGCCCAAT","AlternateAlleleVCF":"C","allel_id":70258,"rule_based_match":true,"evidence_text":"BRCA1 c.5470_5477del","llm_judgment":"PRESENT","evidence":"BRCA1 c.5470_5477del","abstract_start":865,"abstract_end":885}]}
{"pmid":"26190011","title":"Atypical presentation of Costeff syndrome-severe psychomotor involvement and electrical status epilepticus during slow wave sleep.","abstract":"BACKGROUND: Costeff syndrome or OPA3-related 3-methylglutaconic aciduria is an autosomal recessive neurodegenerative disorder characterized by early onset optic atrophy and choreoathetosis with later onset of ataxia and spasticity. Costeff syndrome is prevalent among Iraqi Jews.\nMETHODS: We describe a 5 year old girl from Syrian Jewish origin with an atypical presentation of Costeff syndrome.\nRESULTS: The patient presented with asymmetric optic atrophy, severe dystonia and choreoathetosis and global developmental regression at the age of 7 months; no achievement of independent walking and only minimal speech; and appearance of electrical status epilepticus during slow wave sleep in the second year of life with further deterioration. She harbors the classic mutation (c.143-1G > C) in the OPA3 gene.\nCONCLUSION: Costeff syndrome may present in an atypical manner regarding the ethnic origin, clinical manifestations and co-occurrence of epilepsy. Mutations in OPA3 should be evaluated in all cases presenting with the core features of typical Costeff syndrome.","variants":[{"Name":"NM_025136.4(OPA3):c.143-1G>C","Chromosome":"19","Start":"45553912","Stop":"45553912","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":19278,"rule_based_match":true,"evidence_text":"c.143-1G > C","llm_judgment":"PRESENT","evidence":"c.143-1G > C","abstract_start":777,"abstract_end":789}]}
{"pmid":"25972204","title":"Renal function can be impaired in children with primary hyperoxaluria type 3.","abstract":"BACKGROUND: Primary hyperoxaluria type 3 (PH3) is characterized by mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene. PH3 patients are believed to present with a less severe phenotype than those with PH1 and PH2, but the clinical characteristics of PH3 patients have yet to be defined in sufficient detail. The aim of this study was to report our experience with PH3.\nMETHODS: Genetic analysis of HOGA1 was performed in patients with a high clinical suspicion of PH after the presence of mutations in the alanine-glyoxylate aminotransferase gene had been ruled out. Clinical, biochemical and genetic data of the seven patients identified with HOGA1 mutations were subsequently retrospectively reviewed.\nRESULTS: Among the seven patients identified with HOGA1 mutations the median onset of clinical symptoms was 1.8 (range 0.4-9.8) years. Five patients initially presented with urolithiasis, and two other patients presented with urinary tract infection. All patients experienced persistent hyperoxaluria. Seven mutations were found in HOGA1, including two previously unreported ones, c.834 + 1G > T and c.3G > A. At last follow-up, two patients had impaired renal function based on estimated glomerular filtration rates (GFRs) of 77 and 83 mL/min per 1.73 m(2), respectively.\nCONCLUSIONS: We found that the GFR was significantly impaired in two of our seven patients with PH3 diagnosed during childhood. This finding is in contrast to the early-impaired renal function in PH1 and PH2 and appears to refute to preliminary reassuring data on renal function in PH3.","variants":[{"Name":"NM_138413.4(HOGA1):c.3G>A (p.Met1Ile)","Chromosome":"10","Start":"97584706","Stop":"97584706","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2831834,"rule_based_match":true,"evidence_text":"c.3G > A","llm_judgment":"PRESENT","evidence":"c.3G > A","abstract_start":1117,"abstract_end":1125},{"Name":"NM_138413.4(HOGA1):c.834+1G>T","Chromosome":"10","Start":"97601991","Stop":"97601991","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":620826,"rule_based_match":true,"evidence_text":"c.834 + 1G > T","llm_judgment":"PRESENT","evidence":"c.834 + 1G > T","abstract_start":1098,"abstract_end":1112}]}
{"pmid":"23356216","title":"Identification of a distinct mutation spectrum in the SMPD1 gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease.","abstract":"BACKGROUND: Clinical observations and molecular analysis of the SMPD1 gene in Chinese patients with acid sphingomyelinase deficiency Niemann-Pick disease (NPD) are scarce.\nMETHODS: A cohort of 27 Chinese patients diagnosed with acid sphingomyelinase deficiency, within the past five years, were collected and investigated for genotype, phenotype, and their correlations.\nRESULTS: The majority of our patients (25/27) were under 18 years of age. From the cohort group, eight (30%) fulfilled characters of type A. Four other patients experienced neurologic involvement after two years of age, these were classified as intermediate type. The remaining fifteen presented without clear neurologic involvement and were regarded as type B. One patient, from the type B group, presented with the unusual symptom of a secondary amenorrhea. Three patients, one from the type B group and two from the intermediate group, presented with pronounced proteinuria, in the late stages of the disease, indicating possible kidney involvement in NPD. Twenty-four SMPD1 gene mutations had been identified; eighteen of these are novel ones. These included four exonic small deletions/duplications (c.4delC, c.147_150del4, c.842-849dup8, c.1307-1312dup6), one termination mutation (p.Glu248X), and thirteen exonic point mutations (p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Tyr500His, p.Pro533Leu, p.Val559Leu). Notably, eight mutations had more than one occurrence with c.4delC and p.Glu248X accounting for ~30% of all alleles. Correlation analysis of genotype and phenotype indicated eight mutations, c.842-849dup8, p.Glu248X, p.Arg230Cys, p.Trp437Arg, p.His461Pro, p.Ala484Val p.Ser486Arg, and p.Pro533Leu,to be severe mutations. Five mutations, c.4delC, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser and p.Val559Leu were projected to be mild mutations. Interestingly, three intermediate individuals carried combinations of a mild mutation, c.4delC, on one allele and a severe mutation on the other allele.\nCONCLUSIONS: The Chinese population may have a comparably high incidence of sphingomyelinase-deficient Niemann-Pick disease type A. This study has identified some novel genotype and phenotype correlations in this rare and devastating disorder.","variants":[{"Name":"NM_000543.5(SMPD1):c.1286C>T (p.Pro429Leu)","Chromosome":"11","Start":"6393639","Stop":"6393639","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":546080,"rule_based_match":false,"evidence_text":"c.1286C>T (p.Pro429Leu)","llm_judgment":"PRESENT","evidence":"p.Pro429Leu","abstract_start":1347,"abstract_end":1358},{"Name":"NM_000543.5(SMPD1):c.1498T>C (p.Tyr500His)","Chromosome":"11","Start":"6394209","Stop":"6394209","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":546087,"rule_based_match":false,"evidence_text":"p.Tyr500His","llm_judgment":"PRESENT","evidence":"p.Tyr500His","abstract_start":1438,"abstract_end":1449},{"Name":"NM_000543.5(SMPD1):c.1598C>T (p.Pro533Leu)","Chromosome":"11","Start":"6394309","Stop":"6394309","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":195253,"rule_based_match":false,"evidence_text":"p.Pro533Leu","llm_judgment":"PRESENT","evidence":"p.Pro533Leu","abstract_start":1451,"abstract_end":1462},{"Name":"NM_000543.5(SMPD1):c.1458T>G (p.Ser486Arg)","Chromosome":"11","Start":"6394013","Stop":"6394013","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":640229,"rule_based_match":false,"evidence_text":"p.Ser486Arg","llm_judgment":"PRESENT","evidence":"p.Ser486Arg","abstract_start":1425,"abstract_end":1436},{"Name":"NM_000543.5(SMPD1):c.1451C>T (p.Ala484Val)","Chromosome":"11","Start":"6394006","Stop":"6394006","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1877995,"rule_based_match":false,"evidence_text":"p.Ala484Val","llm_judgment":"PRESENT","evidence":"p.Ala484Val","abstract_start":1412,"abstract_end":1423}]}
{"pmid":"34178886","title":"Sitosterolemia With Atherosclerosis in a Child: A Case Report.","abstract":"<b>Introduction:</b> Sitosterolemia is a rare condition in children and is often misdiagnosed as familial hypercholesterolemia. Serious complications can result if not treated promptly and effectively. When pediatric patients are diagnosed with sitosterolemia, vascular, and cardiac studies are important to evaluate for the presence of atherosclerosis. Few cases of severe atherosclerotic heart disease in children with sitosterolemia have been reported, making this case worthy of presentation. <b>Case Presentation:</b> Here, we report a case of sitosterolemia in an 8-year-old child. The patient presented with severe hypercholesterolemia and xanthoma. He was diagnosed two and a half years prior with familial hypercholesterolemia because his father had elevated cholesterol levels. After conventional treatment, the patient was dissatisfied with lipid level control and visited our hospital for further management. Genetic tests of the patient and parents found mutations in intron 7 (NM 022436.2, c.904+1G>A) and intron 9 (NM 022436.2, C. 1324+1de1G) of ABCG5. The 7 intron mutation was from his mother, and the 9 intron mutation was from his father. The patient was diagnosed with sitosterolemia. <b>Results:</b> The child was treated with ezetimibe, a low plant sterol diet, and clopidogrel anticoagulant therapy. After 3 months of treatment, the blood lipid level was significantly lower. <b>Conclusion:</b> Genetic testing should be completed as soon as possible to avoid misdiagnosis in children with abnormally elevated hypercholesterolemia who have a family history of elevated cholesterol. In addition, clinicians should rule out great arterial lesions and be vigilant in evaluating patients for systemic arterial disease and atherosclerosis.","variants":[{"Name":"NM_022436.3(ABCG5):c.904+1G>A","Chromosome":"2","Start":"43824888","Stop":"43824888","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3578820,"rule_based_match":true,"evidence_text":"c.904+1G>A","llm_judgment":"PRESENT","evidence":"c.904+1G>A","abstract_start":1004,"abstract_end":1014}]}
{"pmid":"29326055","title":"A retrospective biochemical, molecular, and neurocognitive review of Saudi patients with argininosuccinic aciduria.","abstract":"A retrospective review was compiled of 54 patients with argininosuccinic aciduria who were either identified through the Saudi National Newborn Screening Program or diagnosed clinically from January 2000 to December 2015. The duration of follow-up is from 2 to 19 years. The majority of patients (65%) originated from the central province of Saudi Arabia. The mean patient age at review was 10 years (2-19 years), 92% received an early diagnosis (<28 days of age) and most were symptomatic at the time of the diagnosis (n = 34). Normal ammonia at diagnosis was reported in 30% of patients, who were detected under the newborn metabolic screen (n = 5/16). A very high rate of consanguinity was observed in our cohort (98%). Developmental delay was the most detectable long term neurocognitive consequence followed by seizure disorder; 90.7% (n = 49) and 62.9% (n = 34) respectively. As expected, the severe neonatal form was the major presentation. The most common variant identified in this cohort was the previously reported founder c.1060C > T; p.(Gln354*) nonsense mutation in the ASL gene. In addition, the frequency of hyperammonemia was higher in patients homozygous for c.1060C > T; p.(Gln354*) compared to the other mutations. Interestingly, frequent thrombocytosis with the mean level of 717 × 10<sup>9</sup>/L (range = 457-1169 × 10<sup>9</sup>/L) was observed in 96% of the patients with no clear explanation.","variants":[{"Name":"NM_000048.4(ASL):c.1060C>T (p.Gln354Ter)","Chromosome":"7","Start":"66089693","Stop":"66089693","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34105,"rule_based_match":true,"evidence_text":"c.1060C > T; p.(Gln354*)","llm_judgment":"PRESENT","evidence":"c.1060C > T; p.(Gln354*)","abstract_start":1034,"abstract_end":1058}]}
{"pmid":"34573377","title":"A Novel Splicing Variant of","abstract":"Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in <i>COL2A1</i>. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of <i>COL2A1</i> in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a <i>COL2A1</i> messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of <i>COL2A1</i> cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in <i>COL2A1</i> may be relevant in determining the phenotype of skeletal dysplasia.","variants":[{"Name":"NM_001844.5(COL2A1):c.1267-2_1269del","Chromosome":"12","Start":"47987174","Stop":"47987178","ReferenceAlleleVCF":"CACCCT","AlternateAlleleVCF":"C","allel_id":1695380,"rule_based_match":true,"evidence_text":"c.1267-2_1269del","llm_judgment":"PRESENT","evidence":"c.1267-2_1269del","abstract_start":446,"abstract_end":462}]}
{"pmid":"38775840","title":"A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.","abstract":"RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4<sup>+</sup> T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOH<sup>C82Y</sup>, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.","variants":[{"Name":"NM_004310.5(RHOH):c.245G>A (p.Cys82Tyr)","Chromosome":"4","Start":"40243631","Stop":"40243631","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3543312,"rule_based_match":true,"evidence_text":"NM_004310.5(RHOH):c.245G>A (p.Cys82Tyr)","llm_judgment":"PRESENT","evidence":"p.Cys82Tyr","abstract_start":303,"abstract_end":313}]}
{"pmid":"31360996","title":"Founder Mutation c.1516A>C in KLHL40 Is a Frequent Cause of Nemaline Myopathy With Hyponatremia in Ethnic Chinese.","abstract":"KLHL40-related nemaline myopathy is a severe autosomal recessive muscle disorder. The current study describes 4 cases of KLHL40-related nemaline myopathy in Hong Kong ethnic Chinese presenting within 3 years, which are confirmed with clinicopathologic features and genetic studies. The incidence is estimated to be at least 1 in 45 226 livebirths (at least 1 in 41 608 among ethnic Chinese livebirths) in Hong Kong. Hyponatremia appears to be another common feature in these patients. Salient histological features include nemaline bodies ranging from 200 to 500 nm in diameters on ultrastructural examination as well as negative KLHL40 immunohistochemistry; type II fiber predominance is obvious in 2 cases. We demonstrate the founder effect associated with genetic variant c.1516A>C (p.Thr506Pro) by polymorphic marker analysis, which revealed a 0.56-0.75-Mb or 0.41-0.78-cM shared haplotype encompassing the disease allele. The mutation is believed to have occurred around 412 generations ago or 6220 BCE, as estimated using DMLE+ and a formula described by Boehnke. We believe the founder variant might possibly underlie a sizable portion of nemaline myopathy in ethnic Chinese. Analysis of the KLHL40 gene may be considered as the first-tier testing of congenital myopathy in this ethnic group.","variants":[{"Name":"NM_152393.4(KLHL40):c.1516A>C (p.Thr506Pro)","Chromosome":"3","Start":"42688963","Stop":"42688963","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":828160,"rule_based_match":true,"evidence_text":"c.1516A>C (p.Thr506Pro)","llm_judgment":"PRESENT","evidence":"c.1516A>C (p.Thr506Pro)","abstract_start":775,"abstract_end":798}]}
{"pmid":"32414585","title":"A Novel Heterozygous Variant in Exon 19 of NOTCH3 in a Saudi Family with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.","abstract":"Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; OMIM #125310) is the most common cause of monogenic familial cerebral small vessel disease. It typically manifests at middle adulthood with highly variable clinical features including migraine with aura, recurrent transient ischemic attacks or ischemic strokes, mood disorders, and progressive cognitive decline. It is caused by mutations in the NOTCH3 gene, which maps to the short arm of chromosome 19 and encode for epidermal growth factor-like repeats. In this article, we report a 40-year-old male patient who presented with a two-year history of progressive cognitive decline including impaired attention, memory, executive functions, and processing speed whose family history was strongly positive for young-onset ischemic stroke and memory impairment. His father, uncle, and grandfather died due to ischemic strokes and cognitive impairment (similar condition). A whole exome sequencing to the patient (proband II-1) revealed a novel heterozygous missense variant c.3009G>T, p.(Trp1003Cys) (chr19;15291625; hg19) in exon 19 of the NOTCH3 gene. Sanger sequencing was used to confirm the variant in other family members. This variant has not been described in the literature so far. The novel mutation described in the present study widened the genetic spectrum of NOTCH3-associated diseases, which will benefit studies addressing this disease in the future. CADASIL remains a disabling disorder leading to medical retirement in our patient due to late clinical presentation, lack of family history taking prior to joining the military, and lack of curative therapy. Further research for therapeutic options is needed including stem cell therapy .","variants":[{"Name":"NM_000435.3(NOTCH3):c.3009G>T (p.Trp1003Cys)","Chromosome":"19","Start":"15180814","Stop":"15180814","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3132852,"rule_based_match":true,"evidence_text":"c.3009G>T, p.(Trp1003Cys)","llm_judgment":"PRESENT","evidence":"c.3009G>T, p.(Trp1003Cys)","abstract_start":1073,"abstract_end":1098}]}
{"pmid":"27069622","title":"A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome.","abstract":"BACKGROUND: Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology.\nRESULTS: Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G > T; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells.\nCONCLUSIONS: Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy.","variants":[{"Name":"NM_014920.5(CILK1):c.358G>T (p.Gly120Cys)","Chromosome":"6","Start":"53031065","Stop":"53031065","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":613488,"rule_based_match":true,"evidence_text":"c.358G>T (p.G120C)","llm_judgment":"PRESENT","evidence":"c.358G > T","abstract_start":682,"abstract_end":692}]}
{"pmid":"25966250","title":"Identification of novel compound heterozygous RECQL4 mutations and prenatal diagnosis of Baller-Gerold syndrome: a case report.","abstract":"Birth defects are structural and/or functional malformations present at birth that cause physical or mental disability and are important public health problems. Our study was aimed at genetic analysis and prenatal diagnosis of congenital anomalies to understand the cause of certain birth defects. Karyotypes and array-comparative genomic hybridization (aCGH) were performed on a pregnant woman, surrounding amniotic fluid, and her husband. A short-stature panel genetic test was conducted in accordance with the phenotype of the fetus. Following examination, it was determined that the karyotype and aCGH results were normal. The RECQL4 gene in the fetus showed compound heterozygous mutations, and each parent was found to be a carrier of one of the mutations. The two heterozygous mutations (c.2059-1G>C and c.2141_2142delAG) were detected in the RECQL4 (NM_004260) gene in the fetus; therefore, the fetus was predicted to have Baller-Gerold syndrome. These two mutations have not previously been reported. In addition, these results identified a 25% risk of the parents having a sec-ond conceptus with this congenital disease. Therefore, prenatal genetic diagnosis was highly recommended for future pregnancies.","variants":[{"Name":"NM_004260.4(RECQL4):c.2141_2142del (p.Glu714fs)","Chromosome":"8","Start":"144513629","Stop":"144513630","ReferenceAlleleVCF":"GCT","AlternateAlleleVCF":"G","allel_id":945954,"rule_based_match":true,"evidence_text":"c.2141_2142delAG","llm_judgment":"PRESENT","evidence":"c.2141_2142delAG","abstract_start":811,"abstract_end":827},{"Name":"NM_004260.4(RECQL4):c.2059-1G>C","Chromosome":"8","Start":"144513713","Stop":"144513713","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":21108,"rule_based_match":true,"evidence_text":"c.2059-1G>C","llm_judgment":"PRESENT","evidence":"c.2059-1G>C","abstract_start":795,"abstract_end":806}]}
{"pmid":"25724305","title":"Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic.","abstract":"Pathogenic germline mutations in the BRCA1 gene predispose carriers to early onset breast and ovarian cancer. Clinical genetic screening of BRCA1 often reveals variants with uncertain clinical significance, complicating patient and family management. Therefore, functional examinations are urgently needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c.5074G>C/p.Asp1692His, c.5074G>A/p.Asp1692Asn, c.5074G>T/p.Asp1692Tyr, c.5332G>A/p.Asp1778Asn, c.5332G>T/p.Asp1778Tyr, and c.5408G>C/p.Gly1803Ala), whereas five BRCA1 variants had no effect on splicing (c.4985T>C/p.Phe1662Ser, c.5072C>A/p.Thr1691Lys, c.5153G>C/p.Trp1718Ser, c.5154G>T/p.Trp1718Cys, and c.5333A>G/p.Asp1778Gly). Eight of the variants having an effect on splicing (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5074G>C/p.Asp1692His, c.5074G>A/p.Asp1692Asn, c.5074G>T/p.Asp1692Tyr, c.5332G>A/p.Asp1778Asn, c.5332G>T/p.Asp1778Tyr, and c.5408G>C/p.Gly1803Ala) were previously determined to have no or an uncertain effect on the protein level, whereas one variant (c.5072C>T/p.Thr1691Ile) were shown to have a strong effect on the protein level as well. In conclusion, our study emphasizes that in silico splicing prediction and mini-gene splicing analysis are important for the classification of BRCA1 missense variants located close to exon/intron boundaries.","variants":[{"Name":"NM_007294.4(BRCA1):c.4988T>A (p.Met1663Lys)","Chromosome":"17","Start":"43067694","Stop":"43067694","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":70016,"rule_based_match":true,"evidence_text":"c.4988T>A/p.Met1663Lys","llm_judgment":"PRESENT","evidence":"c.4988T>A/p.Met1663Lys","abstract_start":861,"abstract_end":883},{"Name":"NM_007294.4(BRCA1):c.5072C>T (p.Thr1691Ile)","Chromosome":"17","Start":"43067610","Stop":"43067610","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46184,"rule_based_match":true,"evidence_text":"c.5072C>T/p.Thr1691Ile","llm_judgment":"PRESENT","evidence":"c.5072C>T/p.Thr1691Ile","abstract_start":885,"abstract_end":907},{"Name":"NM_007294.4(BRCA1):c.5074G>A (p.Asp1692Asn)","Chromosome":"17","Start":"43067608","Stop":"43067608","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46188,"rule_based_match":true,"evidence_text":"c.5074G>A/p.Asp1692Asn","llm_judgment":"PRESENT","evidence":"c.5074G>A/p.Asp1692Asn","abstract_start":933,"abstract_end":955},{"Name":"NM_007294.4(BRCA1):c.5074G>C (p.Asp1692His)","Chromosome":"17","Start":"43067608","Stop":"43067608","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":46189,"rule_based_match":true,"evidence_text":"c.5074G>C/p.Asp1692His","llm_judgment":"PRESENT","evidence":"c.5074G>C/p.Asp1692His","abstract_start":909,"abstract_end":931},{"Name":"NM_007294.4(BRCA1):c.5408G>C (p.Gly1803Ala)","Chromosome":"17","Start":"43047702","Stop":"43047702","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":46224,"rule_based_match":true,"evidence_text":"c.5408G>C/p.Gly1803Ala","llm_judgment":"PRESENT","evidence":"c.5408G>C/p.Gly1803Ala","abstract_start":1033,"abstract_end":1055},{"Name":"NM_007294.4(BRCA1):c.5332G>A (p.Asp1778Asn)","Chromosome":"17","Start":"43051063","Stop":"43051063","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70197,"rule_based_match":true,"evidence_text":"c.5332G>A/p.Asp1778Asn","llm_judgment":"PRESENT","evidence":"c.5332G>A/p.Asp1778Asn","abstract_start":981,"abstract_end":1003},{"Name":"NM_007294.4(BRCA1):c.4985T>C (p.Phe1662Ser)","Chromosome":"17","Start":"43070929","Stop":"43070929","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":70006,"rule_based_match":true,"evidence_text":"c.4985T>C/p.Phe1662Ser","llm_judgment":"PRESENT","evidence":"c.4985T>C/p.Phe1662Ser","abstract_start":1113,"abstract_end":1135},{"Name":"NM_007294.4(BRCA1):c.4987A>T (p.Met1663Leu)","Chromosome":"17","Start":"43067695","Stop":"43067695","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":70015,"rule_based_match":true,"evidence_text":"c.4987A>T/p.Met1663Leu","llm_judgment":"PRESENT","evidence":"c.4987A>T/p.Met1663Leu","abstract_start":837,"abstract_end":859}]}
{"pmid":"26389062","title":"Complex dental anomalies in a belatedly diagnosed cleidocranial dysplasia patient.","abstract":"Cleidocranial dysplasia (CCD) is a rare congenital disorder, typically characterized by persistently open skull sutures, aplastic or hypoplastic clavicles, and supernumerary teeth. Mutations in the gene encoding the runt-related transcription factor 2 (RUNX2) protein are responsible for approximately two thirds of CCD patients. We report a 20-year-old CCD patient presenting not only with typical skeletal changes, but also complex dental anomalies. A previously undiagnosed odontoma, 14 supernumerary teeth, a cystic lesion, and previously unreported fused primary teeth were discovered on cone-beam computed tomography (CBCT) scans. Mutation analysis identified the causal c.578G>A (p.R193Q) mutation in the RUNX2 gene. At 20 years of age, the patient had already missed the optimal period for dental intervention. This report describes the complex dental anomalies in a belatedly diagnosed CCD patient, and emphasizes the significance of CBCT assessment for the detection of dental anomalies and the importance of early treatment to achieve good outcomes.","variants":[{"Name":"NM_001024630.4(RUNX2):c.578G>A (p.Arg193Gln)","Chromosome":"6","Start":"45432017","Stop":"45432017","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1509056,"rule_based_match":true,"evidence_text":"c.578G>A (p.R193Q)","llm_judgment":"PRESENT","evidence":"c.578G>A (p.R193Q)","abstract_start":677,"abstract_end":695}]}
{"pmid":"24573684","title":"The presence of multiple cellular defects associated with a novel G50E iron-sulfur cluster scaffold protein (ISCU) mutation leads to development of mitochondrial myopathy.","abstract":"Iron-sulfur (Fe-S) clusters are versatile cofactors involved in regulating multiple physiological activities, including energy generation through cellular respiration. Initially, the Fe-S clusters are assembled on a conserved scaffold protein, iron-sulfur cluster scaffold protein (ISCU), in coordination with iron and sulfur donor proteins in human mitochondria. Loss of ISCU function leads to myopathy, characterized by muscle wasting and cardiac hypertrophy. In addition to the homozygous ISCU mutation (g.7044G→C), compound heterozygous patients with severe myopathy have been identified to carry the c.149G→A missense mutation converting the glycine 50 residue to glutamate. However, the physiological defects and molecular mechanism associated with G50E mutation have not been elucidated. In this report, we uncover mechanistic insights concerning how the G50E ISCU mutation in humans leads to the development of severe ISCU myopathy, using a human cell line and yeast as the model systems. The biochemical results highlight that the G50E mutation results in compromised interaction with the sulfur donor NFS1 and the J-protein HSCB, thus impairing the rate of Fe-S cluster synthesis. As a result, electron transport chain complexes show significant reduction in their redox properties, leading to loss of cellular respiration. Furthermore, the G50E mutant mitochondria display enhancement in iron level and reactive oxygen species, thereby causing oxidative stress leading to impairment in the mitochondrial functions. Thus, our findings provide compelling evidence that the respiration defect due to impaired biogenesis of Fe-S clusters in myopathy patients leads to manifestation of complex clinical symptoms.","variants":[{"Name":"NM_213595.4(ISCU):c.149G>A (p.Gly50Glu)","Chromosome":"12","Start":"108564313","Stop":"108564313","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15822,"rule_based_match":false,"evidence_text":"c.149G→A","llm_judgment":"PRESENT","evidence":"c.149G→A","abstract_start":605,"abstract_end":613}]}
{"pmid":"29359448","title":"Targeted gene panel sequencing prenatally detects two novel mutations of DYNC2H1 in a fetus with increased biparietal diameter and polyhydramnios.","abstract":"BACKGROUND: Genetic skeletal disorders (GSDs) are clinically and genetically heterogeneous with more than 350 genes accounting for the diversity of disease phenotypes. Prenatal diagnosis of these disorders has been challenging because of the limited but variable prenatal phenotypes, highlighting the need of a novel genetic approach. Short-rib polydactyly syndrome (SRPS) Type III is an autosomal recessive GSD characterized by extreme narrowness of the thorax, severely shortened tubular bones, polydactyly and multiple malformations.\nMETHODS: Cytogenetic and molecular analyses using GTG-banding, single nucleotide polymorphism array and a novel GSDs targeted gene panel sequencing were performed in a 24 weeks fetus with increased biparietal diameter (BPD), short limbs, narrow thorax and polyhydramnios.\nRESULTS: No chromosomal abnormalities and pathogenic copy number variations (CNVs) were detected in the fetus. Two novel compound heterozygous mutations c.2992C > T and c.12836G > C in the DYNC2H1 gene were identified by targeted genes panel sequencing. A literature review was performed to delineate the prenatal phenotype of SRPS Type III.\nCONCLUSION: This is the first report of prenatal diagnosis of DYNC2H1 mutations causing SRPS Type III in a fetus with increased BPD associated with polyhydramnios in China. Our findings expand the mutation spectrum of DYNC2H1 in this rare disease and demonstrate that targeted gene panel capture followed by next-generation sequencing (NGS) is an efficient and cost-effective method to perform a molecular prenatal diagnosis of a rare genetic skeletal disorder.","variants":[{"Name":"NM_001377.3(DYNC2H1):c.2992C>T (p.Arg998Ter)","Chromosome":"11","Start":"103152181","Stop":"103152181","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2891772,"rule_based_match":true,"evidence_text":"c.2992C > T","llm_judgment":"PRESENT","evidence":"c.2992C > T","abstract_start":962,"abstract_end":973}]}
{"pmid":"38184646","title":"Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease.","abstract":"BACKGROUND: 5' untranslated regions (5'UTRs) are essential modulators of protein translation. Predicting the impact of 5'UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5'UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs).\nMETHODS: We performed an isoform-level re-analysis of retinal RNA-seq data to identify the protein-coding transcripts of 378 IRD genes with highest expression in retina. We evaluated the coverage of their 5'UTRs by different whole exome sequencing (WES) kits. The selected 5'UTRs were analyzed in whole genome sequencing (WGS) and WES data from IRD sub-cohorts from the 100,000 Genomes Project (n = 2397 WGS) and an in-house database (n = 1682 WES), respectively. Identified variants were annotated for 5'UTR-relevant features and classified into seven categories based on their predicted functional consequence. We developed a variant prioritization strategy by integrating population frequency, specific criteria for each category, and family and phenotypic data. A selection of candidate variants underwent functional validation using diverse approaches.\nRESULTS: Isoform-level re-quantification of retinal gene expression revealed 76 IRD genes with a non-canonical retina-enriched isoform, of which 20 display a fully distinct 5'UTR compared to that of their canonical isoform. Depending on the probe design, 3-20% of IRD genes have 5'UTRs fully captured by WES. After analyzing these regions in both cohorts, we prioritized 11 (likely) pathogenic variants in 10 genes (ARL3, MERTK, NDP, NMNAT1, NPHP4, PAX6, PRPF31, PRPF4, RDH12, RD3), of which 7 were novel. Functional analyses further supported the pathogenicity of three variants. Mis-splicing was demonstrated for the PRPF31:c.-9+1G>T variant. The MERTK:c.-125G>A variant, overlapping a transcriptional start site, was shown to significantly reduce both luciferase mRNA levels and activity. The RDH12:c.-123C>T variant was found in cis with the hypomorphic RDH12:c.701G>A (p.Arg234His) variant in 11 patients. This 5'UTR variant, predicted to introduce an upstream open reading frame, was shown to result in reduced RDH12 protein but unaltered mRNA levels.\nCONCLUSIONS: This study demonstrates the importance of 5'UTR variants implicated in IRDs and provides a systematic approach for 5'UTR annotation and validation that is applicable to other inherited diseases.","variants":[{"Name":"NM_152443.3(RDH12):c.-123C>T","Chromosome":"14","Start":"67722520","Stop":"67722520","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":872095,"rule_based_match":true,"evidence_text":"RDH12:c.-123C>T","llm_judgment":"PRESENT","evidence":"RDH12:c.-123C>T","abstract_start":2051,"abstract_end":2066}]}
{"pmid":"30535804","title":"De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment.","abstract":"ATP2B2 encodes the PMCA2 Ca<sup>2+</sup> pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca<sup>2+</sup> from the stereocilia to the endolymph. Several mouse models have been described for this gene; mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment. Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2. Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo. Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment. After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years. Subjects had no balance complaints and vestibular testing did not yield abnormalities. There was no evidence for retrocochlear pathology or structural inner ear abnormalities. Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2.","variants":[{"Name":"NM_001001331.4(ATP2B2):c.955del (p.Ala319fs)","Chromosome":"3","Start":"10385313","Stop":"10385313","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1517362,"rule_based_match":true,"evidence_text":"c.955delG (p.Ala319fs)","llm_judgment":"PRESENT","evidence":"c.955delG (p.Ala319fs)","abstract_start":709,"abstract_end":731},{"Name":"NM_001001331.4(ATP2B2):c.2329C>T (p.Arg777Ter)","Chromosome":"3","Start":"10350187","Stop":"10350187","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1517363,"rule_based_match":true,"evidence_text":"c.2329C>T (p.Arg777*)","llm_judgment":"PRESENT","evidence":"c.2329C>T (p.Arg777*)","abstract_start":811,"abstract_end":832},{"Name":"NM_001001331.4(ATP2B2):c.1963G>T (p.Glu655Ter)","Chromosome":"3","Start":"10358864","Stop":"10358864","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1517364,"rule_based_match":true,"evidence_text":"c.1963G>T (p.Glu655*)","llm_judgment":"PRESENT","evidence":"c.1963G>T (p.Glu655*)","abstract_start":683,"abstract_end":704},{"Name":"NM_001001331.4(ATP2B2):c.1998C>A (p.Cys666Ter)","Chromosome":"3","Start":"10358829","Stop":"10358829","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1517365,"rule_based_match":true,"evidence_text":"c.1998C>A (p.Cys666*)","llm_judgment":"PRESENT","evidence":"c.1998C>A (p.Cys666*)","abstract_start":784,"abstract_end":805}]}
{"pmid":"31212395","title":"Cost-effective molecular inversion probe-based ABCA4 sequencing reveals deep-intronic variants in Stargardt disease.","abstract":"PURPOSE: Stargardt disease (STGD1) is caused by biallelic mutations in ABCA4, but many patients are genetically unsolved due to insensitive mutation-scanning methods. We aimed to develop a cost-effective sequencing method for ABCA4 exons and regions carrying known causal deep-intronic variants.\nMETHODS: Fifty exons and 12 regions containing 14 deep-intronic variants of ABCA4 were sequenced using double-tiled single molecule Molecular Inversion Probe (smMIP)-based next-generation sequencing. DNAs of 16 STGD1 cases carrying 29 ABCA4 alleles and of four healthy persons were sequenced using 483 smMIPs. Thereafter, DNAs of 411 STGD1 cases with one or no ABCA4 variant were sequenced. The effect of novel noncoding variants on splicing was analyzed using in vitro splice assays.\nRESULTS: Thirty-four ABCA4 variants previously identified in 16 STGD1 cases were reliably identified. In 155/411 probands (38%), two causal variants were identified. We identified 11 deep-intronic variants present in 62 alleles. Two known and two new noncanonical splice site variants showed splice defects, and one novel deep-intronic variant (c.4539+2065C>G) resulted in a 170-nt mRNA pseudoexon insertion (p.[Arg1514Lysfs*35,=]).\nCONCLUSIONS: smMIPs-based sequence analysis of coding and selected noncoding regions of ABCA4 enabled cost-effective mutation detection in STGD1 cases in previously unsolved cases.","variants":[{"Name":"NM_000350.3(ABCA4):c.4539+2065C>G","Chromosome":"1","Start":"94027380","Stop":"94027380","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3062434,"rule_based_match":true,"evidence_text":"c.4539+2065C>G","llm_judgment":"PRESENT","evidence":"c.4539+2065C>G","abstract_start":1126,"abstract_end":1140}]}
{"pmid":"22935661","title":"Shwachman-Diamond syndrome: diarrhea, no longer required?","abstract":"Exocrine pancreatic insufficiency and diarrhea have been hallmarks in the diagnosis of Shwachman-Diamond syndrome (SDS). We report 2 cases of genetically confirmed SDS in patients who presented with an unusual phenotype. Patient #1 presented with pancytopenia without other system involvement, while patient #2 presented with severe neutropenia, anemia, and a bifid thumb. Neither patient had diarrhea or malabsorption. Both patients had the classic heterozygous mutations c183_184 TA>CT and c.258+2 T>C in the Shwachman-Bodian-Diamond syndrome gene. Incomplete phenotypes may be more common than previously recognized in bone marrow failure syndromes; gastrointestinal symptoms should not be considered a prerequisite for SDS.","variants":[{"Name":"NM_016038.4(SBDS):c.258+2T>C","Chromosome":"7","Start":"66994210","Stop":"66994210","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18235,"rule_based_match":true,"evidence_text":"c.258+2 T>C","llm_judgment":"PRESENT","evidence":"c.258+2 T>C","abstract_start":492,"abstract_end":503}]}
{"pmid":"17764084","title":"Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene.","abstract":"Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. Coexpression of 4F2hc (the heavy chain subunit) and y(+)LAT-1 induces y(+)L activity (CAA transport). So far a total of 43 different mutations of the SLC7A7 gene, nine of which newly reported here, have been identified in a group of 130 patients belonging to at least 98 independent families. The mutations are distributed along the entire gene and include all different types of mutations. Five polymorphisms within the SLC7A7 coding region and two variants found in the 5'UTR have been identified. A genuine founder effect mutation has been demonstrated only in Finland, where LPI patients share the same homozygous mutation, c.895-2A>T. LPI patients show extreme variability in clinical presentation, and no genotype-phenotype correlations have been defined. This phenotypic variability and the lack of a specific clinical presentation have caused various misdiagnoses. At the biochemical level, the elucidation of SLC7A7 function will be necessary to understand precise disease mechanisms and develop more specific and effective therapies. In this review, we summarize the current knowledge of SLC7A7 mutations and their role in LPI pathogenesis.","variants":[{"Name":"NM_003982.4(SLC7A7):c.895-2A>T","Chromosome":"14","Start":"22775938","Stop":"22775938","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":804907,"rule_based_match":true,"evidence_text":"c.895-2A>T","llm_judgment":"PRESENT","evidence":"c.895-2A>T","abstract_start":1020,"abstract_end":1030}]}
{"pmid":"18362431","title":"Association of human SCN5A polymorphisms with idiopathic ventricular arrhythmia in a Chinese Han cohort.","abstract":"BACKGROUND: Mutations of human cardiac sodium channel alpha subunit gene (SCN5A) have been implicated in risk of various cardiac arrhythmias. The present study aimed to investigate whether SCN5A polymorphism was related to the occurrence of idiopathic ventricular arrhythmia (IVA) in Chinese Han patients.\nMETHODS AND RESULTS: Genotyping for polymorphic variance of SCN5A was performed by polymerase chain reaction and automated gene scan sequencing analysis in 31 unrelated Chinese patients with IVA (IVA group) and 103 healthy controls (control group). The allele frequencies of c.87G>A (p.Ala29Ala) and c.1673A>G (p.His558Arg) were higher in men than in women for control group (p=0.023 and p=0.027, respectively). For women, patients with IVA had higher allele frequency of c.87G>A than controls (0.455 vs 0.198, p=0.013, odds ratio (OR) 3.382), whereas for men, minor allele c.1673A>G was significantly less prevalent in IVA patients compared with controls (0.025 vs 0.175, p=0.017, OR 0.121). Significant difference existed in occurrence of ventricular arrhythmia between female patients with 87GA/AA and those with 87GG genotypes (0.348 vs 0.097, p=0.039, OR 4.978) and between male patients with 1673AA and those with 1673AG/GG genotypes (0.311 vs 0.053, p=0.031, OR 8.143). The frequency of haplotype GG (87G-1673G) was significantly lower in IVA patients than in controls (0.016 vs 0.128, p=0.009, OR 0.109).\nCONCLUSIONS: The present study indicates that Chinese Han people have significant difference in distribution of 2 single nucleotide polymorphisms (c.87G>A and c.1673A>G) between healthy male and females. The 87A allele might be associated with an increased risk of IVA in females, whereas 1673G allele might have been positively selected because of its protective effects against ventricular arrhythmia in males.","variants":[{"Name":"NM_000335.5(SCN5A):c.1673A>G (p.His558Arg)","Chromosome":"3","Start":"38603929","Stop":"38603929","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":38447,"rule_based_match":true,"evidence_text":"c.1673A>G (p.His558Arg)","llm_judgment":"PRESENT","evidence":"c.1673A>G (p.His558Arg)","abstract_start":606,"abstract_end":629}]}
{"pmid":"22447717","title":"Mutations in CIZ1 cause adult onset primary cervical dystonia.","abstract":"OBJECTIVE: Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult onset, primary cervical dystonia.\nMETHODS: Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult onset cervical dystonia and matching controls for sequence variants in this mutant gene.\nRESULTS: Exome sequencing led to the identification of an exonic splicing enhancer mutation in exon 7 of CIZ1 (c.790A>G, p.S264G), which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21(Cip1/Waf1) -interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified 2 additional CIZ1 missense mutations (p.P47S and p.R672M).\nINTERPRETATION: Mutations in CIZ1 may cause adult onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system.","variants":[{"Name":"NM_001131016.2(CIZ1):c.790A>G (p.Ser264Gly)","Chromosome":"9","Start":"128180416","Stop":"128180416","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":48307,"rule_based_match":true,"evidence_text":"c.790A>G (p.S264G)","llm_judgment":"PRESENT","evidence":"c.790A>G","abstract_start":777,"abstract_end":785}]}
{"pmid":"15146470","title":"Seven novel mutations of the ADAR gene in Chinese families and sporadic patients with dyschromatosis symmetrica hereditaria (DSH).","abstract":"Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant pigmentary genodermatosis characterized by hyperpigmented and hypopigmented macules of on the extremities and caused by the mutations in the ADAR gene(also called DSRAD) encoding for RNA-specific adenosine deaminase. Here we reported clinical and molecular findings of 6 Chinese multi-generation families and 2 sporadic patients with DSH. We found that the same mutation could lead to different phenotypes even in the same family and we did not establish a clear correlation between genotypes and phenotypes. Seven novel heterozygous mutations of ADAR were identified, which were c.2433_2434delAG (p.T811fs), c.2197G>T (p.E733X), c.3286C>T (p.R1096X), c.2897G>T (p.C966F), c.2797C>T (p.Q933X), c.2375delT (p.L792fs) and c.3203-2A>G respectively. Our data add new variants to the repertoire of ADAR mutations in DSH.","variants":[{"Name":"NM_001111.5(ADAR):c.3286C>T (p.Arg1096Ter)","Chromosome":"1","Start":"154585782","Stop":"154585782","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":973135,"rule_based_match":true,"evidence_text":"c.3286C>T (p.R1096X)","llm_judgment":"PRESENT","evidence":"c.3286C>T (p.R1096X)","abstract_start":699,"abstract_end":719}]}
{"pmid":"35189936","title":"Genetic findings of Sanger and nanopore single-molecule sequencing in patients with X-linked hearing loss and incomplete partition type III.","abstract":"BACKGROUND: POU3F4 is the causative gene for X-linked deafness-2 (DFNX2), characterized by incomplete partition type III (IP-III) malformation of the inner ear. The purpose of this study was to investigate the clinical characteristics and molecular findings in IP-III patients by Sanger or nanopore single-molecule sequencing.\nMETHODS: Diagnosis of IP-III was mainly based on clinical characteristics including radiological and audiological findings. Sanger sequencing of POU3F4 was carried out for these IP-III patients. For those patients with negative results for POU3F4 Sanger sequencing, nanopore long-read single-molecule sequencing was used to identify the possible pathogenic variants. Hearing intervention outcomes of hearing aids (HAs) fitting and cochlear implantation (CI) were also analyzed. Aided pure tone average (PTA) was further compared between two groups of patients according to their different locations of POU3F4 variants: in the exon region or in the upstream region.\nRESULTS: In total, 18 male patients from 14 unrelated families were diagnosed with IP-III. 10 variants were identified in POU3F4 by Sanger sequencing and 6 of these were reported for the first time (p.Gln181*, p.Val215Gly, p.Arg282Gln, p.Gln316*, c.903_912 delins TGCCA and p.Arg205del). Four different deletions that varied from 80 to 486 kb were identified 876-1503 kb upstream of POU3F4 by nanopore long-read single-molecule sequencing. De novo genetic mutations occurred in 21.4% (3/14) of patients with POU3F4 mutations. Among these 18 patients, 7 had bilateral HAs and 10 patients received unilateral CI. The mean aided PTA for HAs and CI users were 41.1 ± 5.18 and 40.3 ± 7.59 dB HL respectively. The mean PTAs for patients with the variants located in the exon and upstream regions were 39.6 ± 6.31 versus 43.0 ± 7.10 dB HL, which presented no significant difference (p = 0.342).\nCONCLUSIONS: Among 14 unrelated IP-III patients, 28.6% (4/14) had no definite mutation in exon region of POU3F4. However, possible pathogenic deletions were identified in upstream region of this gene. De novo genetic mutations occurred in 21.4% (3/14) of patients with POU3F4 mutation. There was no significant difference of hearing intervention outcomes between the IP-III patients with variants located in the exon region and in the upstream region.","variants":[{"Name":"NM_000307.5(POU3F4):c.845G>A (p.Arg282Gln)","Chromosome":"X","Start":"83509169","Stop":"83509169","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2795459,"rule_based_match":false,"evidence_text":"p.Arg282Gln","llm_judgment":"PRESENT","evidence":"p.Arg282Gln","abstract_start":1215,"abstract_end":1226}]}
{"pmid":"24742800","title":"Sarcolemmal alpha and gamma sarcoglycan protein deficiencies in Turkish siblings with a novel missense mutation in the alpha sarcoglycan gene.","abstract":"BACKGROUND: The sarcoglycan alpha gene, also known as the adhalin gene, is located on chromosome 17q21; mutations in this gene are associated with limb-girdle muscular dystrophy type 2D. We describe two Turkish siblings with findings consistent with limb-girdle muscular dystrophy type 2D. The evaluation excluded a dystrophinopathy, which is the most common form of muscular dystrophy.\nPATIENTS: Both siblings had very high levels of creatinine phosphokinase and negative molecular tests for deletions and duplications of the dystrophin gene. The older boy presented at 8 years of age with an inability to climb steps and an abnormal gait. His younger brother was 5 years old and had similar symptoms. The muscle biopsy evaluation was performed only in the older brother.\nRESULTS: The muscle biopsy showed dystrophic features as well as a deficiency in the expression of two different glycoproteins: the alpha sarcoglycan and the gamma sarcoglycan. Sarcolemmal expressions of dystrophin and other sarcoglycans (beta and delta) were diffusely present. DNA analysis demonstrated the presence of previously unknown homozygous mutations [c.226 C > T (p.L76 F)] in exon 3 in the sarcoglycan alpha genes of both siblings. Similar heterozygous point mutations at the same locus were found in both parents, but the genes of beta, delta, and gamma sarcoglycan were normal in the remaining family members.\nCONCLUSIONS: We describe two siblings with limb-girdle muscular dystrophy type 2D with a novel missense mutation. These patients illustrate that the differential diagnosis of muscular dystrophies is impossible with clinical findings alone. Therefore, a muscle biopsy and DNA analysis remain essential methods for diagnosis of muscle diseases.","variants":[{"Name":"NM_000023.4(SGCA):c.226C>T (p.Leu76Phe)","Chromosome":"17","Start":"50167650","Stop":"50167650","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":426229,"rule_based_match":true,"evidence_text":"c.226 C > T (p.L76 F)","llm_judgment":"PRESENT","evidence":"c.226 C > T (p.L76 F)","abstract_start":1135,"abstract_end":1156}]}
{"pmid":"20130272","title":"A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype.","abstract":"PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP). METHODS. DNA samples of the affected family members were genotyped with 250 K genome-wide SNP microarrays. Genetic defects were localized by linkage analysis and homozygosity mapping, and candidate genes were analyzed by sequencing. Patients underwent a full ophthalmic examination. RESULTS. Compound heterozygous mutations in CEP290 were identified in the proband and her two cousins: the frequent c.2991+1655A>G founder mutation and a novel nonsense mutation in exon 7 (c.451C>T, p.Arg151X). The proband had nystagmus, hyperopia, a flat electroretinogram (ERG), and decreased visual acuity (20/250) from birth. The two cousins had minimal scotopic ERG responses at the age of 2. In one of these patients, visual acuity had reached a level of 20/32 at age 5, which is high for patients with CEP290 mutations. Analysis of the CEP290 mRNA in affected individuals revealed altered splice forms in which either exon 7 or exons 7 and 8 were skipped. In both mutant cDNA products, the open reading frame was not disrupted. Furthermore, homozygosity mapping and mutation analysis in the distant family member affected by RP revealed a homozygous mutation in MERTK, but no CEP290 mutations. This MERTK mutation was heterozygously present in the most severely affected (LCA) patient, but was absent in the two more mildly affected cousins. CONCLUSIONS. A novel nonsense mutation in CEP290 results in nonsense-associated altered splicing. That the remaining open reading frame is intact may explain the less severe phenotype observed in the two affected cousins. The additional heterozygous mutation in MERTK may clarify the more severe phenotype in the proband. This study extends the phenotypic spectrum of CEP290-associated diseases at the mild end.","variants":[{"Name":"NM_025114.4(CEP290):c.451C>T (p.Arg151Ter)","Chromosome":"12","Start":"88131209","Stop":"88131209","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360113,"rule_based_match":true,"evidence_text":"c.451C>T (p.Arg151X)","llm_judgment":"PRESENT","evidence":"p.Arg151X","abstract_start":784,"abstract_end":793}]}
{"pmid":"27317439","title":"Molecular analysis in a GALNS study cohort of 15 Tunisian patients: description of a novel mutation.","abstract":"BACKGROUND: Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal recessive disease caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). The purpose of this study was to analyze the GALNS mutations and the haplotypes associated.\nMETHODS: Mutation screening of the GALNS gene was performed by direct sequence analysis using DNA samples from 15 unrelated Tunisian MPS IVA patients. We also analyzed the haplotypes associated with the novel mutation and with the other reported GALNS mutations.\nRESULTS: We have identified an unreported missense mutation p.D288G (c.863A > G) in one patient, the most frequently c.120 + 1G > A (IVS1 + 1G > A) mutation in eleven MPS IVA patients and three previously reported mutations p.G66R, p.A85T and p.R386C on the other MPS IVA patients. All the studied patients were homozygous for these identified mutations. Bioinformatics analysis predicted the novel mutation as being probably pathogenic. These findings with the unobserved p.D288G mutation in controls subjects, suggested that it is a disease-causing mutation, which was correlated with the severe phenotype observed in the patients. We have found that the two GALNS unreported and reported mutations, respectively p.D288G and p.R386C, were associated with a common and specific haplotype.\nCONCLUSION: Our results were in agreement with previous reports from Tunisia, suggesting, on one hand the genotype/phenotype correlations in MPS IVA patients and the other hand the haplotype analyses were useful for determination of mutation origin in Tunisian population.","variants":[{"Name":"NM_000512.5(GALNS):c.120+1G>A","Chromosome":"16","Start":"88856757","Stop":"88856757","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1036417,"rule_based_match":true,"evidence_text":"c.120 + 1G > A (IVS1 + 1G > A)","llm_judgment":"PRESENT","evidence":"c.120 + 1G > A (IVS1 + 1G > A)","abstract_start":659,"abstract_end":689},{"Name":"NM_000512.5(GALNS):c.863A>G (p.Asp288Gly)","Chromosome":"16","Start":"88835248","Stop":"88835248","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1036254,"rule_based_match":true,"evidence_text":"c.863A > G","llm_judgment":"PRESENT","evidence":"c.863A > G","abstract_start":611,"abstract_end":621}]}
{"pmid":"32163377","title":"Inherited human IFN-γ deficiency underlies mycobacterial disease.","abstract":"Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by the Bacille Calmette-Guérin (BCG) vaccine and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-γ immunity due to mutations of 15 genes controlling the production of or response to IFN-γ. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-γ receptor 1 (IFN-γR1) and IFN-γR2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN-γ cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN-γ receptor. We describe 2 Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354_357del), causing a frameshift that generates a premature stop codon (p.T119Ifs4*). The mutant allele is loss of expression and loss of function. We also show that the patients' herpesvirus Saimiri-immortalized T lymphocytes did not produce IFN-γ, a phenotype that can be rescued by retrotransduction with WT IFNG cDNA. The blood T and NK lymphocytes from these patients also failed to produce and secrete detectable amounts of IFN-γ. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGR1 or IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGR1 or IFNGR2. This may account for the rarity of patients with autosomal-recessive, complete IFN-γ deficiency relative to patients with complete IFN-γR1 and IFN-γR2 deficiencies.","variants":[{"Name":"NM_000619.3(IFNG):c.354_357del (p.Thr119fs)","Chromosome":"12","Start":"68157922","Stop":"68157925","ReferenceAlleleVCF":"TAGTC","AlternateAlleleVCF":"T","allel_id":962973,"rule_based_match":true,"evidence_text":"c.354_357del","llm_judgment":"PRESENT","evidence":"c.354_357del","abstract_start":875,"abstract_end":887}]}
{"pmid":"21361913","title":"BAG3-related myofibrillar myopathy in a Chinese family.","abstract":"In contrast to the usual slow disease progression in myofibrillar myopathies, patients with Bag3opathy often have a rapidly progressive and more severe phenotype with a worse prognosis. We describe a Chinese patient, born to non-consanguineous parents, who first presented at age 6 with clumsy walking and difficult climbing staircase. With a history of restrictive lung disease previously diagnosed as asthma, she progressed rapidly with proximal myopathy, rigid spine and bilateral tightening of the Achilles tendons requiring surgical elongation. Hypertrophic cardiomyopathy with restrictive physiology was shown by echocardiogram. Moreover, prolonged QT interval was also noted in the patient. Family history was unremarkable yet her father was incidentally found to have prolonged QT interval. Mutation analysis with genomic DNA of the proband showed heterozygous de novo known mutation c.626C>T (p.Pro209Leu) and a germline variation c.772C>T (p.Arg258Trp) in BAG3. Her father was found to be a carrier of c.772C>T. Muscle biopsy findings were suggestive of myofibrillar myopathy on light microscopy and ultrastructural studies. To our knowledge, this is the first Chinese case of Bag3opathy so far reported.","variants":[{"Name":"NM_004281.3(BAG3):c.772C>T (p.Arg258Trp)","Chromosome":"10","Start":"119672519","Stop":"119672519","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48065,"rule_based_match":true,"evidence_text":"c.772C>T (p.Arg258Trp)","llm_judgment":"PRESENT","evidence":"c.772C>T (p.Arg258Trp)","abstract_start":940,"abstract_end":962},{"Name":"NM_004281.4(BAG3):c.626C>T (p.Pro209Leu)","Chromosome":"10","Start":"119672373","Stop":"119672373","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21020,"rule_based_match":true,"evidence_text":"c.626C>T (p.Pro209Leu)","llm_judgment":"PRESENT","evidence":"c.626C>T (p.Pro209Leu)","abstract_start":892,"abstract_end":914}]}
{"pmid":"29411205","title":"Phenotypic expansion and progression of SPATA7-associated retinitis pigmentosa.","abstract":"PURPOSE: To report an unusual phenotype of retinitis pigmentosa (RP) caused by compound heterozygous mutations in SPATA7, and describe the progression over a two year follow-up period.\nMETHODS: Retrospective case study.\nRESULTS: A 63-year-old man with a long history of nyctalopia, progressive visual field constriction, and a recent subacute decrease in visual acuity of the left eye presented for evaluation of a suspected retinal degeneration. Multimodal retinal imaging and functional assessment with full-field electroretinogram suggested a severe rod-cone dysfunction masquerading as a choroideremia-like phenotype. A vitreous opacity was found to explain recent changes in the left eye and a 25-guage vitrectomy and membrane peel was performed, yielding no change in visual acuity. Whole-exome sequencing revealed compound heterozygous variants in SPATA7 that were predicted to be pathogenic.\nCONCLUSIONS: Compound heterozygous c.1100A > G, p.(Y367C) and c.1102_1103delCT, p.(L368Efs*4) variants in SPATA7 manifest as an unusual RP phenotype in this case, showing extensive choroidal sclerosis and retinal pigment epithelium (RPE) atrophy with evidence of progression over two years on multimodal imaging.","variants":[{"Name":"NM_018418.5(SPATA7):c.1102_1103del (p.Leu368fs)","Chromosome":"14","Start":"88433153","Stop":"88433154","ReferenceAlleleVCF":"ATC","AlternateAlleleVCF":"A","allel_id":620496,"rule_based_match":true,"evidence_text":"c.1102_1103delCT, p.(L368Efs*4)","llm_judgment":"PRESENT","evidence":"c.1102_1103delCT, p.(L368Efs*4)","abstract_start":962,"abstract_end":993},{"Name":"NM_018418.5(SPATA7):c.1100A>G (p.Tyr367Cys)","Chromosome":"14","Start":"88433152","Stop":"88433152","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1685951,"rule_based_match":true,"evidence_text":"c.1100A > G, p.(Y367C)","llm_judgment":"PRESENT","evidence":"c.1100A > G, p.(Y367C)","abstract_start":935,"abstract_end":957}]}
{"pmid":"27440997","title":"Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases.","abstract":"PURPOSE: To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases.\nMETHODS: Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon-intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect.\nRESULTS: The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10(-6)) that affected individuals inherited the causal mutation from a common ancestor.\nCONCLUSIONS: Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families.","variants":[{"Name":"NM_003322.6(TULP1):c.1466A>G (p.Lys489Arg)","Chromosome":"6","Start":"35500010","Stop":"35500010","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":105552,"rule_based_match":true,"evidence_text":"c.1466A>G (p.K489R)","llm_judgment":"PRESENT","evidence":"c.1466A>G (p.K489R)","abstract_start":1228,"abstract_end":1247},{"Name":"NM_003322.6(TULP1):c.1561C>T (p.Pro521Ser)","Chromosome":"6","Start":"35498395","Stop":"35498395","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3540958,"rule_based_match":true,"evidence_text":"c.1561C>T (p.P521S)","llm_judgment":"PRESENT","evidence":"c.1561C>T (p.P521S)","abstract_start":1459,"abstract_end":1478}]}
{"pmid":"34943567","title":"In Vitro Fertilization Using Preimplantation Genetic Testing in a Romanian Couple Carrier of Mutations in the TTN Gene: A Case Report and Literature Review.","abstract":"Severe congenital myopathy with fatal cardiomyopathy (EOMFC) is a rare genetic neuromuscular disorder inherited in an autosomal recessive manner. Here we presented a successful pregnancy obtained by in vitro fertilization (IVF) using preimplantation genetic testing (PGT) in one young Romanian carrier couple that already lost mutation(s) within the TNN gene and whose first baby passed away due to multiple complications. It was delivered via emergency C-section at 36 weeks and fully dependent on artificial ventilation for a couple of months, weighing 2200 g and an APGAR score of 3. The aCGH + SNP analysis revealed an abnormal profile of the first newborn; three areas associated with loss of heterozygosity on chromosome 1 (q25.1-q25.3) of 6115 kb, 5 (p15.2-p15.1) of 2589 kb and 8 (q11.21-q11.23) of 4830 kb, a duplication of 1104 kb on chromosome 10 in the position q11.22, and duplication of 1193 kb on chromosome 16 in the position p11.2p11.1. Subsequently, we proceeded to test the parents and showed that both parents are carriers; confirmed by Sanger and NGS sequencing-father-on Chr2(GRCh37):g.179396832_179396833del-TTN variant c.104509_104510del p.(Leu34837Glufs*12)-exon 358 and mother-on Chr2(GRCh37):g.179479653G>C-TTN variant c.48681C>G p.(Tyr16227*)-exon 260. Their first child died shortly after birth due to multiple organ failures, possessing both parent's mutations; weighing 2200 g at birth and received an APGAR score of 3 following premature delivery via emergency C-section at 36 weeks. Two embryos were obtained following the IVF protocol; one possessed the mother's mutation, and the other had no mutations and was normal (WT). In contrast with the first birth, the second one was uneventful. A healthy female baby weighing 2990 g was delivered by C-section at 38 weeks, receiving an APGAR score of 9.","variants":[{"Name":"NM_001267550.2(TTN):c.104509_104510del (p.Leu34837fs)","Chromosome":"2","Start":"178532105","Stop":"178532106","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":2147039,"rule_based_match":true,"evidence_text":"c.104509_104510del p.(Leu34837Glufs*12)","llm_judgment":"PRESENT","evidence":"c.104509_104510del p.(Leu34837Glufs*12)","abstract_start":1143,"abstract_end":1182}]}
{"pmid":"31709144","title":"Identification of mutations in Malaysian patients with argininosuccinate lyase (ASL) deficiency.","abstract":"Argininosuccinate lyase (ASL) deficiency impairs the function of the urea cycle that detoxifies blood ammonia in the body. Mutation that occurs in the <i>ASL</i> gene is the cause of occurrence of ASL deficiency (ASLD). This deficiency causes hyperammonemia, hepatopathy and neurodevelopmental delay in patients. In this study, the clinical characteristics and molecular analysis of 10 ASLD patients were presented. 8 patients were associated with severe neonatal onset, while the other 2 were associated with late onset. Molecular analysis of <i>ASL</i> gene identified four new missense variants, which were c.778C>T, p.(Leu260Arg), c.1340G>C, p.(Ser447Thr), c.436C>G, p.(Arg146Gly) and c.595C>G, p.(Leu199Val) and four reported missense variants, which were c.638G>A, p.(Arg213Gln); c.556C>T, p.(Arg186Trp), c.578G>A, p.(Arg193Gln) and c.436C>G, p.(Arg146Trp). <i>In silico</i> servers predicted all new and reported variants as disease-causing. Structural examination exhibited that all pathogenic variants affected the stability of the tetrameric ASL structure by disturbing the bonding pattern with the neighboring residues<i>.</i>\nCONCLUSION: This study revealed the genetic heterogeneity among Malaysian ASL patients. This study has also expanded the mutational spectrum of the ASL.","variants":[{"Name":"NM_000048.4(ASL):c.436C>G (p.Arg146Gly)","Chromosome":"7","Start":"66083164","Stop":"66083164","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2742147,"rule_based_match":true,"evidence_text":"c.436C>G, p.(Arg146Gly)","llm_judgment":"PRESENT","evidence":"c.436C>G, p.(Arg146Gly)","abstract_start":661,"abstract_end":684},{"Name":"NM_000048.4(ASL):c.556C>T (p.Arg186Trp)","Chromosome":"7","Start":"66086775","Stop":"66086775","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1038939,"rule_based_match":true,"evidence_text":"c.556C>T, p.(Arg186Trp)","llm_judgment":"PRESENT","evidence":"c.556C>T, p.(Arg186Trp)","abstract_start":786,"abstract_end":809},{"Name":"NM_000048.4(ASL):c.638G>A (p.Arg213Gln)","Chromosome":"7","Start":"66087369","Stop":"66087369","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544253,"rule_based_match":true,"evidence_text":"c.638G>A, p.(Arg213Gln)","llm_judgment":"PRESENT","evidence":"c.638G>A, p.(Arg213Gln)","abstract_start":761,"abstract_end":784}]}
{"pmid":"24728384","title":"A splice mutation and mRNA decay of EXT2 provoke hereditary multiple exostoses.","abstract":"BACKGROUND: Hereditary multiple exostoses (HME) is an autosomal dominant disease. The classical paradigm of mutation screening seeks to relate alterations in the exostosin glycosyltransferase genes, EXT1 and EXT2, which are responsible for over 70% of HME cases. However, the pathological significance of the majority of these mutations is often unclear.\nMETHODS: In a Chinese family with HME, EXT1 and EXT2 genes were screened by direct sequencing. The consequence of a detected mutant was predicted by in silico analysis and confirmed by mRNA analysis. The EXT1 and EXT2 mRNA and protein levels and the HS patterns in the HME patients were compared with those in healthy controls.\nRESULTS: A heterozygous transition (c.743+1G>A) in the EXT2 gene, which co-segregated with the HME phenotype in this family, was identified. The G residue at position +1 in intron 4 of EXT2 was predicted to be a 5' donor splice site. The mRNA analysis revealed an alternative transcript with a cryptic splice site 5 bp downstream of the wild-type site, which harbored a premature stop codon. However, the predicted truncated protein was not detected by western blot analysis. Decay of the mutant mRNA was shown by clone sequencing and quantification analysis. The corresponding downregulation of the EXT2 mRNA will contribute to the abnormal EXT1/EXT2 ratio and HS pattern that were detected in the patients with HME.\nCONCLUSION: The heterozygous mutation c.743+1G>A in the EXT2 gene causes HME as a result of abnormal splicing, mRNA decay, and the resulting haploinsufficiency of EXT2.","variants":[{"Name":"NM_207122.2(EXT2):c.743+1G>A","Chromosome":"11","Start":"44114302","Stop":"44114302","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":259986,"rule_based_match":true,"evidence_text":"c.743+1G>A","llm_judgment":"PRESENT","evidence":"c.743+1G>A","abstract_start":719,"abstract_end":729}]}
{"pmid":"30541486","title":"Doyne honeycomb retinal dystrophy/malattia leventinese induced by EFEMP1 mutation in a Chinese family.","abstract":"BACKGROUND: Doyne honeycomb retinal dystrophy (DHRD)/malattia leventinese (ML) is a rare allelic condition with massive drusen in the posterior fundus caused by EFEMP1 gene mutation. Patients showed decreased vision when the lesion affected the macular area. At present, the treatment efficiency is not satisfactory.\nCASE PRESENTATION: In this study, we presented a family with DHRD/ML disease and analyzed the pathological and genetic information. A 28-year-old female patient presented to our department due to impaired visual acuity for 10 years especially in the right eye with deterioration for 5 months. Gene sequencing was performed by MyGenostics (Peking, China). Gene sequencing results revealed heterozygous mutations in EFEMP1 gene, which were consistent with the DHRD/ ML. Single heterozygous mutation (c.1033C > T) was observed in each of the three blood samples. This missense mutation triggered p.R345W.\nCONCLUSIONS: DHRD/ML is a rare disease associated with EFEMP1 gene mutation. Up to now, we are not sure whether these lesions are associated with the onset of DHRD/ML. In future, we hope to find out the exact relationship between them.","variants":[{"Name":"NM_001039348.3(EFEMP1):c.1033C>T (p.Arg345Trp)","Chromosome":"2","Start":"55871091","Stop":"55871091","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23111,"rule_based_match":true,"evidence_text":"c.1033C > T","llm_judgment":"PRESENT","evidence":"c.1033C > T","abstract_start":815,"abstract_end":826}]}
{"pmid":"31576780","title":"Modification of the","abstract":"<b>Background</b>: The extensive phenotypic heterogeneity of monogenic diseases can be largely traced to intragenic variation; however, recent advances in clinical detection and gene sequencing have uncovered the emerging role of non-allelic variation (i.e. genetic <i>trans</i>-modifiers) in shaping disease phenotypes. Identifying these associations are not only of significant diagnostic value, but also provides scientific insight into the expanded molecular etiology of rare diseases. This reports describes the discordant clinical manifestation of a family segregating mutations in <i>ABCA4</i> and <i>PROM1</i>. <b>Methods</b>: Three patients across a two generation family underwent multimodal imaging and functional testing of the retina including color photography, fundus autofluorescence (AF), spectral domain-optical coherence tomography (SD-OCT) and full-field electroretinography (ffERG). Genetic characterization was carried out by direct Sanger and whole exome sequencing. <b>Results</b>: Clinical examination revealed similar retinal degenerative phenotypes in the proband and her mother. Despite being younger, the proband's phenotype was more advanced and exhibited additional features related to Stargardt disease not found in the mother. Whole exome sequencing identified a pathogenic missense variant in <i>PROM1</i>, c.400C > T, p.(Arg134Cys), as the underlying cause of retinal disease in both the proband and mother. Sequencing of the <i>ABCA4</i> locus uncovered a single disease-causing variant, c.5714 + 5G > A in the daughter segregating from the father who, surprisingly, also exhibited very subtle disease changes associated with STGD1 despite being a heterozygous carrier. <b>Conclusions</b>: Harboring an additional heterozygous <i>ABCA4</i> mutation increases severity and confers STGD1-like features in patients with <i>PROM1</i> disease which provides supporting evidence for their shared pathophysiology and potential treatment prospects.","variants":[{"Name":"NM_006017.3(PROM1):c.400C>T (p.Arg134Cys)","Chromosome":"4","Start":"16033413","Stop":"16033413","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":799346,"rule_based_match":true,"evidence_text":"c.400C > T, p.(Arg134Cys)","llm_judgment":"PRESENT","evidence":"c.400C > T, p.(Arg134Cys)","abstract_start":1341,"abstract_end":1366},{"Name":"NM_000350.3(ABCA4):c.5714+5G>A","Chromosome":"1","Start":"94010795","Stop":"94010795","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105292,"rule_based_match":true,"evidence_text":"c.5714+5G>A","llm_judgment":"PRESENT","evidence":"c.5714 + 5G > A","abstract_start":1524,"abstract_end":1539}]}
{"pmid":"22814392","title":"An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.","abstract":"Chloride intracellular channel 2 (CLIC2) protein is a member of the glutathione transferase class of proteins. Its' only known function is the regulation of ryanodine receptor (RyR) intracellular Ca(2+) release channels. These RyR proteins play a major role in the regulation of Ca(2+) signaling in many cells. Utilizing exome capture and deep sequencing of genes on the X-chromosome, we have identified a mutation in CLIC2 (c.303C>G, p.H101Q) which is associated with X-linked intellectual disability (ID), atrial fibrillation, cardiomegaly, congestive heart failure (CHF), some somatic features and seizures. Functional studies of the H101Q variant indicated that it stimulated rather than inhibited the action of RyR channels, with channels remaining open for longer times and potentially amplifying Ca(2+) signals dependent on RyR channel activity. The overly active RyRs in cardiac and skeletal muscle cells and neuronal cells would result in abnormal cardiac function and trigger post-synaptic pathways and neurotransmitter release. The presence of both cardiomegaly and CHF in the two affected males and atrial fibrillation in one are consistent with abnormal RyR2 channel function. Since the dysfunction of RyR2 channels in the brain via 'leaky mutations' can result in mild developmental delay and seizures, our data also suggest a vital role for the CLIC2 protein in maintaining normal cognitive function via its interaction with RyRs in the brain. Therefore, our patients appear to suffer from a new channelopathy comprised of ID, seizures and cardiac problems because of enhanced Ca(2+) release through RyRs in neuronal cells and cardiac muscle cells.","variants":[{"Name":"NM_001289.6(CLIC2):c.303C>G (p.His101Gln)","Chromosome":"X","Start":"155280059","Stop":"155280059","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":48422,"rule_based_match":true,"evidence_text":"c.303C>G, p.H101Q","llm_judgment":"PRESENT","evidence":"c.303C>G, p.H101Q","abstract_start":425,"abstract_end":442}]}
{"pmid":"28099355","title":"Hereditary spastic paraplegia due to a novel mutation of the REEP1 gene: Case report and literature review.","abstract":"RATIONALE: Hereditary spastic paraplegia (HSP) is a heterogeneous group of diseases little known in clinical practice due to its low prevalence, slow progression, and difficult diagnosis. This results in an underestimation of HSP leading to belated diagnosis and management. In depth diagnosis is based on clinical presentation and identification of genomic mutations. We describe the clinical presentation and pathogeny of HSP through a report of a case due to a novel mutation of the REEP1 gene (SPG31).\nPATIENT CONCERNS: A 64-year-old woman presented gait disturbances due to spasticity of the lower limbs progressing since her third decade. Previous investigations failed to find any cause.\nINTERVENTIONS: DNA analysis was performed to search for HSP causing mutations.\nDIAGNOSES: A novel heterozygote mutation (c.595 + 1G>A) of the REEP1 gene, within the splice site of intron 6, was discovered. This nucleotide change causes exon 6 skipping leading to frame shift and a truncated transcript identified by complementary DNA sequencing of reverse transcription polymerase chain reaction products.\nOUTCOMES: REEP1 is a known protein predominantly located in the upper motor neurons. Mutation of REEP1 primary affects the longest axons explaining predominance of pyramidal syndrome on lower limbs.\nLESSONS: Slow progressive pyramidal syndrome of the lower limbs should elicit a diagnosis of HSP. We describe a novel mutation of the REEP1 gene causing HSP. Pathogeny is based on resulting abnormal REEP1 protein which is involved in the development of longest axons constituting the corticospinal tracts.","variants":[{"Name":"NM_001371279.1(REEP1):c.595+1G>A","Chromosome":"2","Start":"86232624","Stop":"86232624","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":226729,"rule_based_match":true,"evidence_text":"c.595 + 1G>A","llm_judgment":"PRESENT","evidence":"c.595 + 1G>A","abstract_start":816,"abstract_end":828}]}
{"pmid":"23000145","title":"A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency.","abstract":"Whole-exome sequencing was performed in a family affected by dominantly inherited inflammatory disease characterized by recurrent blistering skin lesions, bronchiolitis, arthralgia, ocular inflammation, enterocolitis, absence of autoantibodies, and mild immunodeficiency. Exome data from three samples, including the affected father and daughter and unaffected mother, were filtered for the exclusion of reported variants, along with benign variants, as determined by PolyPhen-2. A total of eight transcripts were identified as possible candidate genes. We confirmed a variant, c.2120C>A (p.Ser707Tyr), within PLCG2 as the only de novo variant that was present in two affected family members and not present in four unaffected members. PLCG2 encodes phospholipase Cγ2 (PLCγ2), an enzyme with a critical regulatory role in various immune and inflammatory pathways. The p.Ser707Tyr substitution is located in an autoinhibitory SH2 domain that is crucial for PLCγ2 activation. Overexpression of the altered p.Ser707Tyr protein and ex vivo experiments using affected individuals' leukocytes showed clearly enhanced PLCγ2 activity, suggesting increased intracellular signaling in the PLCγ2-mediated pathway. Recently, our laboratory identified in individuals with cold-induced urticaria and immune dysregulation PLCG2 exon-skipping mutations resulting in protein products with constitutive phospholipase activity but with reduced intracellular signaling at physiological temperatures. In contrast, the p.Ser707Tyr substitution in PLCγ2 causes a distinct inflammatory phenotype that is not provoked by cold temperatures and that has different end-organ involvement and increased intracellular signaling at physiological temperatures. Our results highlight the utility of exome-sequencing technology in finding causal mutations in nuclear families with dominantly inherited traits otherwise intractable by linkage analysis.","variants":[{"Name":"NM_002661.5(PLCG2):c.2120C>A (p.Ser707Tyr)","Chromosome":"16","Start":"81919549","Stop":"81919549","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":48295,"rule_based_match":true,"evidence_text":"c.2120C>A (p.Ser707Tyr)","llm_judgment":"PRESENT","evidence":"c.2120C>A (p.Ser707Tyr)","abstract_start":578,"abstract_end":601}]}
{"pmid":"28864462","title":"Rapid whole-genome sequencing identifies a novel","abstract":"A 9-mo-old infant was admitted with infantile spasms that improved on administration of topiramate and steroids. He also had developmental delay, esotropia, and hypsarrhythmia on interictal electroencephalogram (EEG), and normal brain magnetic resonance imaging (MRI). West syndrome is the triad of infantile spasms, interictal hypsarrhythmia, and mental retardation. Rapid trio whole-genome sequencing (WGS) revealed a novel, likely pathogenic, de novo variant in the gene encoding γ-aminobutyric acid (GABA) type A receptor, α1 polypeptide (<i>GABRA1</i> c.789G>A, p.Met263Ile) in the proband. <i>GABRA1</i> mutations have been associated with early infantile epileptic encephalopathy type 19 (EIEE19). We suggest that <i>GABRA1</i> p.Met263Ile is associated with a distinct West syndrome phenotype.","variants":[{"Name":"NM_001127644.2(GABRA1):c.789G>A (p.Met263Ile)","Chromosome":"5","Start":"161890983","Stop":"161890983","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":389307,"rule_based_match":true,"evidence_text":"GABRA1 c.789G>A, p.Met263Ile","llm_judgment":"PRESENT","evidence":"GABRA1</i> c.789G>A, p.Met263Ile","abstract_start":546,"abstract_end":578}]}
{"pmid":"31981411","title":"Impact of SLCO1B1 Genetic Variation on Rosuvastatin Systemic Exposure in Pediatric Hypercholesterolemia.","abstract":"This study investigated the impact of SLCO1B1 genotype on rosuvastatin systemic exposure in hypercholesterolemic children and adolescents. Participants (8-21 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 13; 521CC, n = 2) and wild type controls (521TT, n = 13) completed a single oral dose pharmacokinetic study. The variability contributed by SLCO1B1 c.521 sequence variation to rosuvastatin (RVA) systemic exposure among our pediatric cohort was comparable to previous studies in adults. RVA concentration-time curve from 0-24 hours (AUC<sub>0-24</sub> ) was 1.4-fold and 2.2-fold higher in participants with c.521TC and c.521CC genotype compared 521TT participants, respectively. Interindividual variability of RVA exposure within SLCO1B1 genotype groups exceeded the ~ 1.5-fold to 2-fold difference in mean RVA exposure observed among SLCO1B1 genotype groups, suggesting that other factors also contribute to interindividual variability in the rosuvastatin dose-exposure relationship. A multivariate model performed confirmed SLCO1B1 c.521T>C genotype as the primary factor contributing to RVA systemic exposure in this pediatric cohort, accounting for ~ 30% of the variability RVA AUC<sub>0-24</sub> . However, of the statins investigated to date in the pediatric population, RVA has the lowest magnitude of variability in systemic exposure.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":true,"evidence_text":"SLCO1B1 c.521T>C","llm_judgment":"PRESENT","evidence":"SLCO1B1 c.521T>C","abstract_start":202,"abstract_end":218}]}
{"pmid":"17553565","title":"Molecular genetic analysis of Hungarian patients with the hyper-immunoglobulin M syndrome.","abstract":"We have identified 9 disease-causing mutations in 18 hyper-immunoglobulin M (HIGM) syndrome patients from ten unrelated Hungarian families. CD40L mutation resulted in X-linked combined immunodeficiency in 11 patients (6 families) and AICDA mutation caused autosomal recessive HIGM characterized by B cell immunodeficiency in 5 patients (3 families). Two brothers with a genetically undefined form of HIGM and clinical manifestations of B cell deficiency were also included in this study. B cells from these two patients had defective CSR and skewed pattern of somatic hypermutation. Altogether, a novel CD40L truncation mutation (c.470 delA) and a new missense AICDA mutation (p.E58K) were identified. Carrier status was defined in 13 clinically healthy individuals allowing prenatal genetic testing that was performed in two affected families. This is the first comprehensive overview of molecular genetic features of Hungarian patients with HIGM syndrome.","variants":[{"Name":"NM_000074.3(CD40LG):c.470del (p.Asn157fs)","Chromosome":"X","Start":"136659096","Stop":"136659096","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1065170,"rule_based_match":true,"evidence_text":"c.470 delA","llm_judgment":"PRESENT","evidence":"c.470 delA","abstract_start":630,"abstract_end":640}]}
{"pmid":"36459342","title":"Novel Loss of Function (G15D) Mutation on RAC2 in a Family with Combined Immunodeficiency and Increased Levels of Immunoglobulin G, A, and E.","abstract":"Ras-related C3 botulinum toxin substrate 2 (RAC2) is a small guanine nucleotide binding molecule that is exclusively expressed in hematopoietic cell lineages as a switcher. Based on in vivo and/or in vitro model experiments, RAC2 plays important roles in different cells through proliferation, secretion, and phagocytosis. It also performs a suppressing function in immunoglobulin (Ig) switching in Rac2-/- animals or cells. Several RAC2 natural mutations have been described in patients with primary immunodeficiency. RAC2 mutations can be classified into loss-of-function inactivating (LoF-I) and gain-of-function activating mutations according to their functional effects. Only two LoF-I mutations on RAC2 have been reported, including a dominant D57N mutation in several cases that exhibit granulocyte function defects and a recessive D56X mutation in cases with common variable immunodeficiency. Regardless of the type of mutation, most of the reported RAC2 mutant cases have shown reduced IgG, IgA, and IgM levels. Herein, we report on a family with three members that suffer from persistent HPV infection, recurrent respiratory infections, bronchiectasis, and autoimmune disease. The immunologic profile suggests that the family was affected by combined immunodeficiency (CID) with increased serum levels of IgG, IgA, and IgE. Exome sequencing identified a de novo RAC2 mutation (c.44G > A/p.G15D) that was co-segregated with the disease in the family. Gene functional experiments identified that such mutation results in reduced guanosine triphosphate binding activity and RAC2 protein expression. In patients' lymphocytes, impaired aggregation and proliferation effects, decreased mitochondrial membrane potential, and increased levels of cell apoptosis were observed, although no functional abnormalities were detected in neutrophils. To our knowledge, this study was the first to identify a LoF-I mutation of RAC2 affecting lymphocyte function that consequently led to CID and increased levels of serum IgG, IgE, and IgA. This study presents a novel subtype of RAC2-related immune disorder.","variants":[{"Name":"NM_002872.5(RAC2):c.44G>A (p.Gly15Asp)","Chromosome":"22","Start":"37241650","Stop":"37241650","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3768072,"rule_based_match":true,"evidence_text":"c.44G > A/p.G15D","llm_judgment":"PRESENT","evidence":"c.44G > A/p.G15D","abstract_start":1387,"abstract_end":1403}]}
{"pmid":"20923556","title":"A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report.","abstract":"A female patient, with normal familial history, developed at the age of 30 months an episode of diarrhoea, vomiting and lethargy which resolved spontaneously. At the age of 3 years, the patient re-iterated vomiting, was sub-febrile and hypoglycemic, fell into coma, developed seizures and sequels involving right hemi-body. Urinary excretion of hexanoylglycine and suberylglycine was low during this metabolic decompensation. A study of pre- and post-prandial blood glucose and ketones over a period of 24 hours showed a normal glycaemic cycle but a failure to form ketones after 12 hours fasting, suggesting a mitochondrial β-oxidation defect. Total blood carnitine was lowered with unesterified carnitine being half of the lowest control value. A diagnosis of mild MCAD deficiency (MCADD) was based on rates of 1-14C-octanoate and 9, 10-3H-myristate oxidation and of octanoyl-CoA dehydrogenase being reduced to 25% of control values. Other mitochondrial fatty acid oxidation proteins were functionally normal. De novo acylcarnitine synthesis in whole blood samples incubated with deuterated palmitate was also typical of MCADD. Genetic studies showed that the patient was compound heterozygous with a sequence variation in both of the two ACADM alleles; one had the common c.985A>G mutation and the other had a novel c.145C>G mutation. This is the first report for the ACADM gene c.145C>G mutation: it is located in exon 3 and causes a replacement of glutamine to glutamate at position 24 of the mature protein (Q24E). Associated with heterozygosity for c.985A>G mutation, this mutation is responsible for a mild MCADD phenotype along with a clinical story corroborating the emerging literature view that patients with genotypes representing mild MCADD (high residual enzyme activity and low urinary levels of glycine conjugates), similar to some of the mild MCADDs detected by MS/MS newborn screening, may be at risk for disease presentation.","variants":[{"Name":"NM_000016.6(ACADM):c.145C>G (p.Gln49Glu)","Chromosome":"1","Start":"75732670","Stop":"75732670","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3525888,"rule_based_match":true,"evidence_text":"c.145C>G","llm_judgment":"PRESENT","evidence":"c.145C>G","abstract_start":1319,"abstract_end":1327}]}
{"pmid":"24728566","title":"Identification of a novel mutation of the gene for gap junction protein α3 (GJA3) in a Chinese family with congenital cataract.","abstract":"Cataract, defined as any opacity of the crystallin lens, can be divided into early onset (congenital or infantile) and age-related. It is the leading cause of visual disability in children, and mutations in many genes have currently been linked with this disorder. In the present study, we identified a genetic defect in a Chinese family with congenital cataract. Genomic DNA was extracted from the venous blood of the family and 100 normal controls. To screen for the disease-causing mutation, we sequenced eight candidate genes, and to predict the functional consequences of the mutation, a structural model of the protein was developed using the Protein Data Bank and PyMOL 1.1r1. We found a novel variant (c.163 A > G transition) in the gene for gap junction protein α3, or the connexin46 gene. This mutation resulted in the substitution of a highly conserved asparagine at codon 55 by aspartic acid (p.N55D). There were no nucleotide polymorphisms in the other candidate genes sequenced.","variants":[{"Name":"NM_021954.4(GJA3):c.163A>G (p.Asn55Asp)","Chromosome":"13","Start":"20143126","Stop":"20143126","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3412474,"rule_based_match":true,"evidence_text":"c.163 A > G","llm_judgment":"PRESENT","evidence":"c.163 A > G","abstract_start":710,"abstract_end":721}]}
{"pmid":"28923328","title":"Mutation Frequency of Three Neurodegenerative Lysosomal Storage Diseases: From Screening to Treatment?","abstract":"BACKGROUND: The ascertainment of mutation frequencies in the general population may have impact on the population's wellbeing and respective healthcare services. Furthermore, it may help define which approaches will be more effective for certain patients based on the genetic cause of disease.\nAIM OF THE STUDY: Determine the frequency of three mutations, known to be a major cause of three distinct Lysosomal Storage Diseases (LSDs).\nMETHODS: The following pre-requisites were met: each mutation accounted for over 55% of the disease alleles among previously reported unrelated patients, all three diseases were among the most prevalent LSDs in the population under study, they all involved devastating deterioration of the nervous system, lacked curative treatment and may be fatal in childhood or adolescence. The anonymous samples used in this study were representative of the whole population; mutations were tested by PCR based methods, positive results were further confirmed. The diseases studied were Mucopolysaccharidosis type I (Hurler, MIM 607014), Tay Sachs disease variant B1 (TS, MIM 272800) and Metachromatic Leukodystrophy (MLD, MIM 250100); the mutations were, respectively, p.W402X, p.R178C and c.465+1G>A.\nRESULTS AND CONCLUSION: Increased carrier frequencies were found for Tay Sachs disease variant B1 HEXA p.R178C mutation (1:340) and for the infantile MLD ARSA c.465+1G> A mutation (1:350) denoting higher risk for these sub-types of disease in Portugal and possibly in individuals of Iberian ancestry. Carrier screening in target populations may provide the foundations for more effective approaches to precision medicine.","variants":[{"Name":"NM_000487.6(ARSA):c.465+1G>A","Chromosome":"22","Start":"50627165","Stop":"50627165","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18090,"rule_based_match":true,"evidence_text":"c.465+1G>A","llm_judgment":"PRESENT","evidence":"c.465+1G>A","abstract_start":1214,"abstract_end":1224}]}
{"pmid":"15723004","title":"Gln48His is the prevalent myocilin mutation in primary open angle and primary congenital glaucoma phenotypes in India.","abstract":"PURPOSE: Myocilin gene defects have been originally implicated in primary open angle glaucoma (POAG). Based on multiple reports for the occurrence of Gln48His mutation (c.144G>T; HGMD accession number CM023962) among Indian POAG patients, we wanted to estimate the prevalence of this mutation in primary open angle and primary congenital glaucoma (PCG) in India and assess its role in the causation of the disease.\nMETHODS: Two hundred cases each of POAG and PCG were screened for the Gln48His mutation by RFLP (AccI) analysis of the PCR amplicons followed by confirmation of the c.144G>T change by direct sequencing.\nRESULTS: The Gln48His mutation was detected in 9 different glaucoma patients (four POAG and five PCG). While all four POAG cases were heterozygous, among PCG cases, four were heterozygous and one exhibited homozygous genotype for the mutation. One each of POAG and PCG patients was detected to be heterozygous for CYP1B1 mutation (c.1656C>T, Pro437Leu) and (c.1449G>A, Arg368His), respectively. None of the 300 ethnically matched normal controls contained either the MYOC or CYP1B1 mutation(s).\nCONCLUSIONS: The myocilin mutation, Gln48His, represents an allelic condition involving a spectrum of glaucoma phenotypes in Indian populations, and could be a potential risk factor towards disease predisposition among patients of Indian origin. The study also highlights the role of MYOC as a candidate in different glaucoma subtypes that needs to be investigated further.","variants":[{"Name":"NM_000261.2(MYOC):c.144G>T (p.Gln48His)","Chromosome":"1","Start":"171652468","Stop":"171652468","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":22997,"rule_based_match":true,"evidence_text":"c.144G>T","llm_judgment":"PRESENT","evidence":"c.144G>T","abstract_start":169,"abstract_end":177}]}
{"pmid":"22482807","title":"A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome.","abstract":"Kohlschutter-Tonz syndrome (KTS) is a rare autosomal-recessive disorder of childhood onset, and it is characterized by global developmental delay, spasticity, epilepsy, and amelogenesis imperfecta. In 12 KTS-affected individuals from a Druze village in northern Israel, homozygosity mapping localized the gene linked to the disease to a 586,513 bp region (with a LOD score of 6.4) in chromosomal region 16p13.3. Sequencing of genes (from genomic DNA of an affected individual) in the linked region revealed chr16: 4,848,632 G>A, which corresponds to ROGDI c.469C>T (p.Arg157(∗)). The nonsense mutation was homozygous in all affected individuals, heterozygous in 10 of 100 unaffected individuals from the same Druze community, and absent from Druze controls from elsewhere. Wild-type ROGDI localizes to the nuclear envelope; ROGDI was not detectable in cells of affected individuals. All affected individuals suffered seizures, were unable to speak, and had amelogenesis imperfecta. However, age of onset and the severity of mental and motor handicaps and that of convulsions varied among affected individuals homozygous for the same nonsense allele.","variants":[{"Name":"NM_024589.3(ROGDI):c.469C>T (p.Arg157Ter)","Chromosome":"16","Start":"4798631","Stop":"4798631","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40186,"rule_based_match":true,"evidence_text":"ROGDI c.469C>T (p.Arg157(∗))","llm_judgment":"PRESENT","evidence":"ROGDI c.469C>T (p.Arg157(∗))","abstract_start":550,"abstract_end":578}]}
{"pmid":"32083505","title":"Optical coherence tomography and fundus autofluorescence imaging in an infant with","abstract":"<b>Background:</b> Leber congenital amaurosis (LCA) is both genetically and phenotypically heterogeneous group of retinal disorder. Mutations in retinal degeneration 3 (<i>RD3)</i> have been reported as an infrequent cause of LCA which account for less than 1% of all known LCA cases. This case report provides Optical Coherence Tomography (OCT) and Fundus Autofluorescence (FAF) findings of an infant with LCA related to a mutation in <i>RD3</i>.<b>Materials and Methods:</b> Single retrospective case report.<b>Results:</b> TruSight One Expanded Sequencing Panel was applied to the patient on the Illumina NextSeq. Homozygous pathogenic variant (c.112 C > T, p.Arg38Ter) was detected in the RD3 gene. Well-demarcated central foveal atrophy was noted in the infrared imaging. FAF imaging showed perifoveal hyperautofluorescent ring and irregular hyperautofluorescence outside the vascular arcade. An arrest in foveal development and loss of outer retinal structure including outer nuclear layer, external limiting membrane, ellipsoid zone and interdigitation zone at the fovea were detected in the OCT imaging.<b>Conclusion</b>: This study indicates that RD3-related LCA has a very severe phenotype with foveal development arrest and very early loss of all photoreceptor layer and external limiting membrane at the fovea.","variants":[{"Name":"NM_001164688.2(RD3):c.112C>T (p.Arg38Ter)","Chromosome":"1","Start":"211481304","Stop":"211481304","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187662,"rule_based_match":true,"evidence_text":"c.112 C > T, p.Arg38Ter","llm_judgment":"PRESENT","evidence":"c.112 C > T, p.Arg38Ter","abstract_start":648,"abstract_end":671}]}
{"pmid":"36253578","title":"Clinical features and pathogenicity assessment in patients with HTRA1-autosomal dominant disease.","abstract":"BACKGROUND: Heterozygous mutations in HTRA1 were recently found to cause autosomal dominant cerebral small vessel disease (CSVD), and it was named HTRA1-autosomal dominant disease (AD-HTRA1) in the consensus recommendations of the European Academy of Neurology. This study aimed to investigate the clinical features of a mutation in HTRA1 and the effect of HTRA1 mutation on white matter hyperintensity (WMH).\nMETHODS: A proband's brain magnetic resonance imaging (MRI) showed multiple lacunar infarctions and multiple WMH in the lateral ventricle, external capsule, frontal lobe and corpus callosum. The proband and family members were tested for CSVD-related genes by next-generation sequencing and the clinical data of the patients were collected. The published literature on AD-HTRA1 was collected, and the clinical characteristics and pathogenicity of the patients were summarized. Combined Annotation Dependent Depletion (CADD) is a tool for scoring the deleteriousness of single-nucleotide variants and insertion/deletion variants in the human genome. The relationship between the degree of WMH and the pathogenicity of the mutation was further analyzed.\nRESULT: It was found that the proband and her family members had a heterozygous missense mutation of c.854C > T (p.P285L) in the 4 exon of HTRA1 gene. A retrospective analysis of 5 families with c.854C > T mutation found that the patients had an early age of onset, cognitive impairment was more common, and alopecia and spondylosis could be combined at the same time. By univariate analysis, the severity of WMH was found to be significantly associated with the mutated CADD score (p < 0.05, Spearman's rho = 0.266).\nCONCLUSION: The clinical manifestations of AD-HTRA1 with mutation site c.854C > T (p.P285L) are similar to CARASIL, and brain MRI are mainly moderate or severe WMH and lacunar infarction (LI). WMH are affected by mutation sites. Therefore, our pathogenicity score for mutations can predict the severity of WMH.","variants":[{"Name":"NM_002775.5(HTRA1):c.854C>T (p.Pro285Leu)","Chromosome":"10","Start":"122506767","Stop":"122506767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":165896,"rule_based_match":true,"evidence_text":"c.854C > T (p.P285L)","llm_judgment":"PRESENT","evidence":"c.854C > T (p.P285L)","abstract_start":1263,"abstract_end":1283}]}
{"pmid":"31645980","title":"Targeted next-generation sequencing identified a known","abstract":"Emery-Dreifuss muscular dystrophy (EDMD) is a rare X-linked recessive disease characterized by the clinical triad of early childhood joint contractures, progressive weakness in muscles and cardiac involvement and can result in sudden death. Targeted next-generation sequencing was performed for a Chinese patient with EDMD and the previously reported mutation [NM_000117.2: c.251_255del (p.Leu84Profs*7)] in exon 3 of the emerin gene (<i>EMD</i>) was identified.","variants":[{"Name":"NM_000117.3(EMD):c.251_255del (p.Leu84fs)","Chromosome":"X","Start":"154380002","Stop":"154380006","ReferenceAlleleVCF":"TTACTC","AlternateAlleleVCF":"T","allel_id":273723,"rule_based_match":true,"evidence_text":"NM_000117.2: c.251_255del (p.Leu84Profs*7)","llm_judgment":"PRESENT","evidence":"NM_000117.2: c.251_255del (p.Leu84Profs*7)","abstract_start":361,"abstract_end":403}]}
{"pmid":"27349010","title":"Heterozygous Mutations of the DUOXA2 and DUOX2 Genes in Dizygotic Twins with Congenital Hypothyroidism.","abstract":"BACKGROUND: The mutations in the dual oxidase maturation factor 2 (DUOXA2) and dual oxidase 2 (DUOX2) genes have been identified in patients with congenital hypothyroidism (CH). This study reports a set of dizygotic twins with CH due to the mutations in the DUOX2/DUOXA2 system.\nMETHODS: The dizygotic twins, a boy and a girl, both aged 7 years, were born to euthyroid nonconsanguineous parents; they were diagnosed with CH at neonatal screening and were enrolled in this study. The DUOXA2, DUOX2, paired box 8 (PAX8), thyroid peroxidase (TPO), and thyrotropin receptor (TSHR) genes were considered for mutation screening. Genomic DNA was extracted from peripheral blood leukocytes, and Sanger sequencing was used to screen for the mutations in the exon fragments. Family members of the patients were also enrolled and evaluated.\nRESULTS: The fraternal twins each harbored a single heterozygous mutation, including c.738C>G (p.Y246X) in the boy inherited from the paternal DUOXA2 allele and c.2654G>A (p.R885Q) in the girl from the maternal DUOX2 allele. The two mutations have been previously reported. The boy showed enlarged thyroid lobes and a little calcification in the left lobe, while the girl's thyroid gland was severely underdeveloped and the girl had obvious complications due to irregular treatment. The germline mutations from this family were consistent with an autosomal recessive inheritance pattern. No mutations in the PAX8, TPO, and TSHR genes were detected in this study.\nCONCLUSIONS: The inactivating mutations in the DUOXA2 (p.Y246X) and DUOX2 (p.R885Q) genes were identified in a set of dizygotic twins with CH. The girl was more severe in several aspects than her brother. The similar genetic defect resulted in very different outcomes.","variants":[{"Name":"NM_001363711.2(DUOX2):c.2654G>A (p.Arg885Gln)","Chromosome":"15","Start":"45103960","Stop":"45103960","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1491086,"rule_based_match":true,"evidence_text":"c.2654G>A (p.R885Q)","llm_judgment":"PRESENT","evidence":"c.2654G>A (p.R885Q)","abstract_start":991,"abstract_end":1010}]}
{"pmid":"22395865","title":"Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation.","abstract":"Using exome sequencing we searched for the genetic cause of autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVC) in a Swedish family. A heterozygous C-to-T transition, c.1255C>T, p.Pro419Ser in the desmin gene on chromosome 2q35, was identified. Previous studies had demonstrated linkage to chromosome 10q22.3, but no causative mutation had been found in that region. Sanger sequencing of DNA from 17 family members confirmed the heterozygous c.1255C>T desmin mutation in seven out of ten family members that had been classified as affected in the previous study. Our new results demonstrate the usefulness of next-generation sequencing, and the diagnostic difficulties with some forms of dominantly inherited muscle diseases as they can display a wide clinical and morphological variability even within a given family.","variants":[{"Name":"NM_001927.4(DES):c.1255C>T (p.Pro419Ser)","Chromosome":"2","Start":"219423787","Stop":"219423787","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48317,"rule_based_match":true,"evidence_text":"c.1255C>T","llm_judgment":"PRESENT","evidence":"c.1255C>T","abstract_start":216,"abstract_end":225}]}
{"pmid":"32019279","title":"Clinicopathological Features of Patients with the BRCA1 c.5339T>C (p.Leu1780Pro) Variant.","abstract":"PURPOSE: Recent studies revealed the BRCA1 c.5339T>C, p.Leu1780Pro variant (L1780P) is highly suggested as a likely pathogenic. The aim of this study was to evaluate clinicopathologic features of L1780P with breast cancer (BC) using multicenter data from Korea to reinforce the evidence as a pathogenic mutation and to compare L1780P and other BRCA1/2mutations using Korean Hereditary Breast Cancer (KOHBRA) study data.\nMATERIALS AND METHODS: The data of 54 BC patients with L1780P variant from 10 institutions were collected and the clinicopathologic characteristics of the patients were reviewed. The hereditary breast and/or ovarian cancer-related characteristics of the L1780P variant were compared to those of BC patients in the KOHBRA study.\nRESULTS: The median age of all patients was 38 years, and 75.9% of cases showed triple-negative breast cancer. Comparison of cases with L1780P to carriers from the KOHBRA study revealed that the L1780P patients group was more likely to have family history (FHx) of ovarian cancer (OC) (24.1% vs. 19.6% vs. 11.2%, p < 0.001 and p=0.001) and a personal history of OC (16.7% vs. 2.9% vs. 1.3%, p=0.003 and p=0.001) without significant difference in FHx of BC and bilateral BC. The cumulative risk of contralateral BC at 10 years after diagnosis was 31.9%, while the cumulative risk of OC at 50 years of age was 20.0%. Patients with L1780P showed similar features with BRCA1 carriers and showed higher penetrance of OC than patients with other BRCA1 mutations.\nCONCLUSION: L1780P should be considered as a pathogenic mutation. Risk-reducing salpingo-oophorectomy is highly recommended for women with L1780P.","variants":[{"Name":"NM_007294.4(BRCA1):c.5339T>C (p.Leu1780Pro)","Chromosome":"17","Start":"43049188","Stop":"43049188","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":70208,"rule_based_match":true,"evidence_text":"BRCA1 c.5339T>C, p.Leu1780Pro variant (L1780P)","llm_judgment":"PRESENT","evidence":"BRCA1 c.5339T>C, p.Leu1780Pro variant (L1780P)","abstract_start":37,"abstract_end":83}]}
{"pmid":"28667000","title":"Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia.","abstract":"Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited β-globin mutation (<i>HBB</i>:c.93-21G>A, IVS-I-110:G>A), a known cause of β-thalassemia minor. As this mutation alone was inconsistent with the severity of the anemia, we performed WES. Although we could not identify any relevant pathogenic single-nucleotide variants (SNVs) or small indels, copy-number variant (CNV) analyses revealed a likely triplication of the entire α-globin cluster, which was subsequently confirmed by multiplex ligation-dependent probe amplification. Treatment and follow-up was redefined according to the diagnosis of β-thalassemia intermedia resulting from a single β-thalassemia mutation in combination with an α-globin cluster triplication. Thus, we describe a case where the typical WES-based analysis of SNVs and small indels was unrevealing, but WES-based CNV analysis resulted in a definitive diagnosis that informed clinical decision-making. More generally, this case illustrates the value of performing CNV analysis when WES is otherwise unable to elucidate a clear genetic diagnosis.","variants":[{"Name":"NM_000518.5(HBB):c.93-21G>A","Chromosome":"11","Start":"5226820","Stop":"5226820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30493,"rule_based_match":true,"evidence_text":"HBB:c.93-21G>A, IVS-I-110:G>A","llm_judgment":"PRESENT","evidence":"c.93-21G>A","abstract_start":504,"abstract_end":514}]}
{"pmid":"24716902","title":"Familial isolated primary hyperparathyroidism/hyperparathyroidism-jaw tumour syndrome caused by germline gross deletion or point mutations of CDC73 gene in Chinese.","abstract":"OBJECTIVE: Hyperparathyroidism-jaw tumour syndrome (HPT-JT) and familial isolated primary hyperparathyroidism (FIHP) are two subtypes of familial primary hyperparathyroidism, which are rarely reported in Chinese population. Here, we reported three FIHP families and one HPT-JT family with long-term follow-up and genetic analysis.\nDESIGN AND METHODS: A total of 22 patients, from four FIHP/HPT-JT families of Chinese descent, were recruited and genomic DNA was extracted from their peripheral blood lymphocytes. Direct sequencing for MEN1, CDC73, CASR gene was conducted. Reverse transcription PCR (RT-PCR) and quantitative real-time PCR (qRT-PCR) were used to study the effect of splice site mutations and gross deletion mutations. Immunohistochemistry was performed to analyse parafibromin expression in parathyroid tumours. Genotype-phenotype correlations were assessed through clinical characteristics and long-term follow-up data.\nRESULTS: Genetic analysis revealed four CDC73 germline mutations that were responsible for the four kindreds, including two novel point mutation (c.157 G>T and IVS3+1 G>A), one recurrent point mutation (c.664 C>T) and one deletion mutation (c.307+?_513-?del exons 4, 5, 6). RT-PCR confirmed that IVS3+1 G>A generated an aberrant transcript with exon3 deletion. Immunohistochemical analysis demonstrated reduced nuclear parafibromin expression in tumours supporting the pathogenic effects of these mutations.\nCONCLUSIONS: This study supplies information on mutations and phenotypes of HPT-JT/FIHP syndrome in Chinese. Screening for gross deletion and point mutations of the CDC73 gene is necessary in susceptible subjects.","variants":[{"Name":"NM_024529.5(CDC73):c.664C>T (p.Arg222Ter)","Chromosome":"1","Start":"193142001","Stop":"193142001","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":627176,"rule_based_match":true,"evidence_text":"c.664 C>T","llm_judgment":"PRESENT","evidence":"c.664 C>T","abstract_start":1139,"abstract_end":1148},{"Name":"NM_024529.5(CDC73):c.157G>T (p.Glu53Ter)","Chromosome":"1","Start":"193125137","Stop":"193125137","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":952169,"rule_based_match":true,"evidence_text":"c.157 G>T","llm_judgment":"PRESENT","evidence":"c.157 G>T","abstract_start":1082,"abstract_end":1091}]}
{"pmid":"28886344","title":"A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility.","abstract":"Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Genome-wide linkage analyses and whole-exome sequencing revealed a paternally transmitted heterozygous missense mutation of c.400 G>A (p.Ala134Thr) in zona pellucida glycoprotein 3 (ZP3). The same mutation was identified in an unrelated EFS pedigree. Haplotype analysis revealed that the disease allele of these two families came from different origins. Furthermore, in a cohort of 21 cases of EFS, two were also found to have the ZP3 c.400 G>A mutation. Immunofluorescence and histological analysis indicated that the oocytes of the EFS female had degenerated and lacked the zona pellucida (ZP). ZP3 is a major component of the ZP filament. When mutant ZP3 was co-expressed with wild-type ZP3, the interaction between wild-type ZP3 and ZP2 was markedly decreased as a result of the binding of wild-type ZP3 and mutant ZP3, via dominant negative inhibition. As a result, the assembly of ZP was impeded and the communication between cumulus cells and the oocyte was prevented, resulting in oocyte degeneration. These results identified a genetic basis for EFS and oocyte degeneration and, moreover, might pave the way for genetic diagnosis of infertile females with this phenotype.","variants":[{"Name":"NM_001110354.2(ZP3):c.400G>A (p.Ala134Thr)","Chromosome":"7","Start":"76429602","Stop":"76429602","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":431554,"rule_based_match":true,"evidence_text":"c.400 G>A (p.Ala134Thr)","llm_judgment":"PRESENT","evidence":"c.400 G>A (p.Ala134Thr)","abstract_start":511,"abstract_end":534}]}
{"pmid":"36280881","title":"Early embryonic lethality in complex I associated p.L104P Nubpl mutant mice.","abstract":"BACKGROUND: Variants in the mitochondrial complex I assembly factor, NUBPL are associated with a rare cause of complex I deficiency mitochondrial disease. Patients affected by complex I deficiency harboring homozygous NUBPL variants typically have neurological problems including seizures, intellectual disability, and ataxia associated with cerebellar hypoplasia. Thus far only 19 cases have been reported worldwide, and no treatment is available for this rare disease.\nMETHODS: To investigate the pathogenesis of NUBPL-associated complex I deficiency, and for translational studies, we generated a knock-in mouse harboring a patient-specific variant Nubpl c.311T&gt;C; p. L104P reported in three families.\nRESULTS: Similar to Nubpl global knockout mice, the Nubpl p. L104P homozygous mice are lethal at embryonic day E10.5, suggesting that the Nubpl p. L104P variant is likely a hypomorph allele. Given the recent link between Parkinson's disease and loss-of-function NUBPL variants, we also explored aging-related behaviors and immunocytochemical changes in Nubpl hemizygous mice and did not find significant behavioral and pathological changes for alpha-synuclein and oxidative stress markers .\nCONCLUSION: Our data suggest that homozygotes with Nubpl variants, similar to the null mice, are lethal, and heterozygotes are phenotypically and neuropathologically normal. We propose that a tissue-specific knockout strategy is required to establish a mouse model of Nubpl-associated complex I deficiency disorder for future mechanistic and translational studies.","variants":[{"Name":"NM_025152.3(NUBPL):c.311T>C (p.Leu104Pro)","Chromosome":"14","Start":"31599308","Stop":"31599308","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":205774,"rule_based_match":false,"evidence_text":"Nubpl c.311T>C; p. L104P","llm_judgment":"PRESENT","evidence":"p. L104P","abstract_start":671,"abstract_end":679}]}
{"pmid":"29540233","title":"Novel compound heterozygote mutations in the ATP7B gene in an Iranian family with Wilson disease: a case report.","abstract":"BACKGROUND: Wilson disease is an autosomal recessive disorder of copper transport and is characterized by excessive accumulation of cellular copper in the liver and other tissues because of impaired biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. Hepatic failure and neuronal degeneration are the major symptoms of Wilson disease. Mutations in the ATP7B gene are the major cause of Wilson disease.\nCASE PRESENTATION: In this study we have screened one pedigree with several affected members, including a 24-year-old Iranian woman and a 20-year-old Iranian man, who showed psychiatric and neurological symptoms of varying severity, by amplifying the coding regions including exon-intron boundaries with polymerase chain reaction and sequencing. We identified c.1924G>C and c.3809A>G mutations in affected members as compound heterozygote state. These mutations segregated with the disease in the family and they were absent in a cohort of 100 Iranian ethnicity-matched healthy controls.\nCONCLUSIONS: No homozygote state has been reported for these two variants in public databases. In silico predicting tools consider these two variants to be damaging. So this study introduces the novel combination of c.1924G>C and c.3809A>G variants as a cause for Wilson disease.","variants":[{"Name":"NM_000053.4(ATP7B):c.3809A>G (p.Asn1270Ser)","Chromosome":"13","Start":"51937570","Stop":"51937570","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":18898,"rule_based_match":true,"evidence_text":"c.3809A>G","llm_judgment":"PRESENT","evidence":"c.3809A>G","abstract_start":807,"abstract_end":816},{"Name":"NM_000053.4(ATP7B):c.1924G>C (p.Asp642His)","Chromosome":"13","Start":"51961859","Stop":"51961859","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":186903,"rule_based_match":true,"evidence_text":"c.1924G>C","llm_judgment":"PRESENT","evidence":"c.1924G>C","abstract_start":793,"abstract_end":802}]}
{"pmid":"38166944","title":"A novel missense COL9A3 variant in a pedigree with multiple lumbar disc herniation.","abstract":"Trp3 allele in COL9A3 gene has been widely studied in populations with intervertebral disc disease. We identified a novel pathogenic variant in COL9A3 gene in a pedigree with multiple lumbar disc herniation (LDH). The proband was a 14-year-old boy who developed LDH at the L4/5 and L5/S1 spinal segments. His father, paternal aunt and grandfather were diagnosed with LDH at an age of 35, 30 and 23, respectively. By applying whole exome sequencing, a heterozygous missense variant (c.1150C > T, p.Arg384Trp) in COL9A3 was identified. According to the ACMG guidelines, this variant is predicted to be pathogenic. In addition, prediction tools found COL9A3 protein of this variant a reduced stability, some changed charge properties, and an altered spatial conformation. Findings expanded the mutational spectrum of LDH and contributed to the understanding of COL9A3 in the pathogenesis of LDH.","variants":[{"Name":"NM_001853.4(COL9A3):c.1150C>T (p.Arg384Trp)","Chromosome":"20","Start":"62829808","Stop":"62829808","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1161873,"rule_based_match":true,"evidence_text":"c.1150C > T, p.Arg384Trp","llm_judgment":"PRESENT","evidence":"c.1150C > T, p.Arg384Trp","abstract_start":482,"abstract_end":506}]}
{"pmid":"23894113","title":"Endocrine abnormalities in Townes-Brocks syndrome.","abstract":"Townes-Brocks syndrome is a recognizable variable pattern of malformation caused by mutations to the SALL1 gene located on chromosome 16q12.1. Only three known cases of Townes-Brocks syndrome with proven SALL1 gene mutation and concurrent endocrine abnormalities have been previously documented to our knowledge [Kohlhase et al., 1999; Botzenhart et al., 2005; Choi et al., 2010]. We report on two unrelated patients with Townes-Brocks syndrome who share an identical SALL1 mutation (c.3414_3415delAT), who also have endocrine abnormalities. Patient 1 appears to be the first known case of growth hormone deficiency, and Patient 2 extends the number of documented mutation cases with hypothyroidism to four. We suspect endocrine abnormalities, particularly treatable deficiencies, may be an underappreciated component to Townes-Brocks syndrome.","variants":[{"Name":"NM_002968.3(SALL1):c.3414_3415del (p.Cys1139fs)","Chromosome":"16","Start":"51138807","Stop":"51138808","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":409645,"rule_based_match":true,"evidence_text":"c.3414_3415delAT","llm_judgment":"PRESENT","evidence":"c.3414_3415delAT","abstract_start":484,"abstract_end":500}]}
{"pmid":"34524739","title":"Deep clinicopathological phenotyping identifies a previously unrecognized pathogenic EMD splice variant.","abstract":"Exome sequencing (ES) has revolutionized rare disease management, yet only ~25%-30% of patients receive a molecular diagnosis. A limiting factor is the quality of available phenotypic data. Here, we describe how deep clinicopathological phenotyping yielded a molecular diagnosis for a 19-year-old proband with muscular dystrophy and negative clinical ES. Deep phenotypic analysis identified two critical data points: (1) the absence of emerin protein in muscle biopsy and (2) clinical features consistent with Emery-Dreifuss muscular dystrophy. Sequencing data analysis uncovered an ultra-rare, intronic variant in EMD, the gene encoding emerin. The variant, NM_000117.3: c.188-6A > G, is predicted to impact splicing by in silico tools. This case thus illustrates how better integration of clinicopathologic data into ES analysis can enhance diagnostic yield with implications for clinical practice.","variants":[{"Name":"NM_000117.3(EMD):c.188-6A>G","Chromosome":"X","Start":"154379936","Stop":"154379936","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1320986,"rule_based_match":true,"evidence_text":"NM_000117.3: c.188-6A > G","llm_judgment":"PRESENT","evidence":"NM_000117.3: c.188-6A > G","abstract_start":659,"abstract_end":684}]}
{"pmid":"26777464","title":"Systematic Analysis of CCNO Variants in a Defined Population: Implications for Clinical Phenotype and Differential Diagnosis.","abstract":"Reduced generation of multiple motile cilia (RGMC) is a novel chronic destructive airway disease within the group of mucociliary clearance disorders with only few cases reported. Mutations in two genes, CCNO and MCIDAS, have been identified as a cause of this disease, both leading to a greatly reduced number of cilia and causing impaired mucociliary clearance. This study was designed to identify the prevalence of CCNO mutations in Israel and further delineate the clinical characteristics of RGMC. We analyzed 170 families with mucociliary clearance disorders originating from Israel for mutations in CCNO and identified two novel mutations (c.165delC, p.Gly56Alafs*38; c.638T>C, p.Leu213Pro) and two known mutations in 15 individuals from 10 families (6% prevalence). Pathogenicity of the missense mutation (c.638T>C, p.Leu213Pro) was demonstrated by functional analyses in Xenopus. Combining these 15 patients with the previously reported CCNO case reports revealed rapid deterioration in lung function, an increased prevalence of hydrocephalus (10%) as well as increased female infertility (22%). Consistent with these findings, we demonstrate that CCNO expression is present in murine ependyma and fallopian tubes. CCNO is mutated more frequently than expected from the rare previous clinical case reports, leads to severe clinical manifestations, and should therefore be considered an important differential diagnosis of mucociliary clearance disorders.","variants":[{"Name":"NM_021147.5(CCNO):c.165del (p.Gly56fs)","Chromosome":"5","Start":"55233359","Stop":"55233359","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":633985,"rule_based_match":true,"evidence_text":"c.165delC","llm_judgment":"PRESENT","evidence":"c.165delC","abstract_start":646,"abstract_end":655},{"Name":"NM_021147.5(CCNO):c.638T>C (p.Leu213Pro)","Chromosome":"5","Start":"55231790","Stop":"55231790","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":395335,"rule_based_match":true,"evidence_text":"c.638T>C, p.Leu213Pro","llm_judgment":"PRESENT","evidence":"c.638T>C, p.Leu213Pro","abstract_start":674,"abstract_end":695}]}
{"pmid":"23430926","title":"Infantile Progressive Hepatoencephalomyopathy with Combined OXPHOS Deficiency due to Mutations in the Mitochondrial Translation Elongation Factor Gene GFM1.","abstract":"Mitochondrial disorders are a heterogeneous group of often multisystemic and early fatal diseases caused by defects in the oxidative phosphorylation (OXPHOS) system. Given the complexity and intricacy of the OXPHOS system, it is not surprising that the underlying molecular defect remains unidentified in many patients with a mitochondrial disorder. Here, we report the clinical features and diagnostic workup leading to the elucidation of the genetic basis for a combined complex I and IV OXPHOS deficiency secondary to a mitochondrial translational defect in an infant who presented with rapidly progressive liver failure, encephalomyopathy, and severe refractory lactic acidemia. Sequencing of the GFM1 gene revealed two inherited novel, heterozygous mutations: a.539delG (p.Gly180AlafsX11) in exon 4 which resulted in a frameshift mutation, and a second c.688G > A (p.Gly230Ser) mutation in exon 5. This missense mutation is likely to be pathogenic since it affects an amino acid residue that is highly conserved across species and is absent from the dbSNP and 1,000 genomes databases. Review of literature and comparison were made with previously reported cases of this recently identified mitochondrial disorder encoded by a nuclear gene. Although limited in number, nuclear gene defects causing mitochondrial translation abnormalities represent a new, rapidly expanding field of mitochondrial medicine and should potentially be considered in the diagnostic investigation of infants with progressive hepatoencephalomyopathy and combined OXPHOS disorders.","variants":[{"Name":"NM_024996.7(GFM1):c.539del (p.Gly180fs)","Chromosome":"3","Start":"158646912","Stop":"158646912","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":631020,"rule_based_match":false,"evidence_text":"a.539delG (p.Gly180AlafsX11)","llm_judgment":"PRESENT","evidence":"a.539delG (p.Gly180AlafsX11)","abstract_start":765,"abstract_end":793},{"Name":"NM_024996.7(GFM1):c.688G>A (p.Gly230Ser)","Chromosome":"3","Start":"158649156","Stop":"158649156","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":210957,"rule_based_match":true,"evidence_text":"c.688G > A (p.Gly230Ser)","llm_judgment":"PRESENT","evidence":"c.688G > A (p.Gly230Ser)","abstract_start":858,"abstract_end":882}]}
{"pmid":"28951997","title":"Novel compound heterozygous mutations in the GPR98 (USH2C) gene identified by whole exome sequencing in a Moroccan deaf family.","abstract":"In the present work, we identified two novel compound heterozygote mutations in the GPR98 (G protein-coupled receptor 98) gene causing Usher syndrome. Whole-exome sequencing was performed to study the genetic causes of Usher syndrome in a Moroccan family with three affected siblings. We identify two novel compound heterozygote mutations (c.1054C > A, c.16544delT) in the GPR98 gene in the three affected siblings carrying post-linguale bilateral moderate hearing loss with normal vestibular functions and before installing visual disturbances. This is the first time that mutations in the GPR98 gene are described in the Moroccan deaf patients.","variants":[{"Name":"NM_032119.4(ADGRV1):c.1054C>A (p.Pro352Thr)","Chromosome":"5","Start":"90627592","Stop":"90627592","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1481877,"rule_based_match":true,"evidence_text":"c.1054C > A","llm_judgment":"PRESENT","evidence":"c.1054C > A","abstract_start":340,"abstract_end":351}]}
{"pmid":"33306824","title":"Identification of pathological variants of SLC12A3 gene in a pedigree affected with Gitelman syndrome","abstract":"OBJECTIVE: To detect pathological variants of the SLC12A3 gene in a Chinese pedigree affected with Gitelman syndrome (GS).\nMETHODS: Clinical data and peripheral blood samples of the proband and his family members were collected. All exons of the SLC12A3 gene were amplified by PCR and subjected to Sanger sequencing.\nRESULTS: Sanger sequencing has revealed that the proband has carried a c.486_489 delTACG (p.Ile162Met fs*8) deletion and a heterozygous c.2890C>T (p.Arg964Trp) missense variant in the SLC12A3 gene. Neither variant was reported previously and was not found among healthy controls.\nCONCLUSION: The c.486_489delTACG (p.Ile162Met fs*8) and c.2890C>T (p.Arg964Trp) variants of the SLC12A3 gene probably underlay the GS in the proband. Above discovery has enriched the variant spectrum of GS.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.486_489del (p.Ile162fs)","Chromosome":"16","Start":"56868353","Stop":"56868356","ReferenceAlleleVCF":"TTACG","AlternateAlleleVCF":"T","allel_id":2047211,"rule_based_match":true,"evidence_text":"c.486_489 delTACG (p.Ile162Met fs*8)","llm_judgment":"PRESENT","evidence":"c.486_489 delTACG (p.Ile162Met fs*8)","abstract_start":388,"abstract_end":424}]}
{"pmid":"22563226","title":"Two novel insulin receptor gene mutations in a patient with Rabson-Mendenhall syndrome: the first Korean case confirmed by biochemical, and molecular evidence.","abstract":"Rabson-Mendenhall syndrome (RMS) is a rare syndrome manifested by extreme insulin resistance with hyperinsulinemia, acanthosis nigricans, tooth dysplasia and growth retardation. Our patient was first noted at the age of 8 months due to pigmentations on skin-folded areas. Initial laboratory tests showed normal fasting glucose (69 mg/dL). Fasting insulin level was severely elevated, up to 554.6 µIU/mL, and c-peptide level was increased, up to 13.81 ng/mL. However, hemoglobin A1c was within normal range (4.8%). He is now 11 yr old. His growth development followed the 5-10th percentile and oral hypoglycemic agents are being administered. The last laboratory results showed insulin 364.1 µIU/mL, C-peptide 4.30 ng/mL, and hemoglobin A1c 7.6%. The boy was a compound heterozygote for the c.90C > A and c.712G > A mutations of the insulin receptor gene, INSR, which are nonsense and missense mutations. In summary, we report the first Korean case of RMS, which was confirmed by two novel mutations of the INSR.","variants":[{"Name":"NM_000208.4(INSR):c.712G>A (p.Glu238Lys)","Chromosome":"19","Start":"7184578","Stop":"7184578","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1868352,"rule_based_match":true,"evidence_text":"c.712G > A","llm_judgment":"PRESENT","evidence":"c.712G > A","abstract_start":804,"abstract_end":814}]}
{"pmid":"35736209","title":"A recurrent variant in","abstract":"BACKGROUND: Genetically determined cataract is both clinically and molecularly highly heterogeneous. Here, we have identified a heterozygous variant in the lens integral membrane protein LIM2, the second most abundant protein in the lens, responsible for congenital sutural/lamellar cataract in a three-generation Japanese family.\nMETHODS: Whole exome sequencing (WES) was undertaken in one affected and one unaffected individual from a family with autosomal dominant congenital cataract to establish the underlying genetic basis.\nRESULTS: A recurrent missense variant LIM2: c.388C>T; p.R130C was identified and found to co-segregate with disease. In addition, one variant COL11A1:c.3788C>T of unknown significance (VUS) was also identified.\nCONCLUSIONS: We report a variant in LIM2 causing an isolated autosomal-dominant congenital sutural/lamellar cataract in a Japanese family. This is the first report of a LIM2 variant in the Japanese population. Hence, we expand the mutation spectrum of LIM2 variants in different ethnic groups.","variants":[{"Name":"NM_001161748.2(LIM2):c.388C>T (p.Arg130Cys)","Chromosome":"19","Start":"51380577","Stop":"51380577","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":613458,"rule_based_match":true,"evidence_text":"LIM2: c.388C>T; p.R130C","llm_judgment":"PRESENT","evidence":"LIM2: c.388C>T; p.R130C","abstract_start":569,"abstract_end":592}]}
{"pmid":"31645976","title":"Two pedigrees with arrhythmogenic right ventricular cardiomyopathy linked with R49H and F531C mutation in","abstract":"Arrhythmogenic right ventricular cardiomyopathy (ARVC) presents as the progressive fibrofatty replacement of the cardiomyocytes particularly in the right ventricular wall. Here, we report two cases with ARVC. In family A, the proband carries a <i>Desmoglein2</i> (<i>DSG2</i>) gene complex heterozygous mutation NM_001943.4:c.146G>A/p.(Arg49His)and NM_001943.3:c.1592T>G/p.(Phe531Cys). In family B, the proband carries a homozygous mutation NM_001943.3:c.1592T>G/p.(Phe531Cys).","variants":[{"Name":"NM_001943.5(DSG2):c.1592T>G (p.Phe531Cys)","Chromosome":"18","Start":"31536370","Stop":"31536370","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":53450,"rule_based_match":true,"evidence_text":"NM_001943.3:c.1592T>G/p.(Phe531Cys)","llm_judgment":"PRESENT","evidence":"NM_001943.3:c.1592T>G/p.(Phe531Cys)","abstract_start":349,"abstract_end":384}]}
{"pmid":"12655554","title":"Tetrahydrobiopterin sensitivity in German patients with mild phenylalanine hydroxylase deficiency.","abstract":"We report the results of tetrahydrobiopterin (BH4) loading tests in 10 German patients with mild phenylketonuria. A significant decline of phenylalanine values after application of BH4 was observed in all but one patients. Molecular genetic analyses revealed a range of different PAH gene mutations. Re-testing of one patient previously reported as non-responsive to BH4 loading showed a moderate response with a higher dose of BH4. Nevertheless, there appear to be kinetic differences in phenylalanine hydroxylation in patients with the same genotype. Non-responsiveness to 20 mg/kg BH4 was observed only in a single patient who was compound heterozygous for the novel mutation R176P (c.527G>C) and the common null-mutation P281L. In summary, our data are in line with recent reports indicating that BH4 sensitivity is a normal feature of most mild forms of PAH deficiency but may be influenced by other factors.","variants":[{"Name":"NM_000277.3(PAH):c.527G>C (p.Arg176Pro)","Chromosome":"12","Start":"102855315","Stop":"102855315","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":108461,"rule_based_match":true,"evidence_text":"R176P (c.527G>C)","llm_judgment":"PRESENT","evidence":"R176P (c.527G>C)","abstract_start":679,"abstract_end":695}]}
{"pmid":"33150772","title":"Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency.","abstract":"The pathogenesis of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is highly heterogeneous and still unclear. Additional novel variants have been recently detected in the population. The molecular and cellular effects of these previously unreported variants are still poorly understood and require further characterization. To address this problem, we have evaluated the various functions and biochemical consequences of six novel missense variants that lead to mild VLCAD deficiency. Marked deficiencies in fatty acid oxidation (FAO) and other mitochondrial defects were observed in cells carrying one of these six variants (c.541C>T, c.863T>G, c.895A>G, c.1238T>C, c.1276G>A, and c.1505T>A), including reductions in mitochondrial respiratory-chain function and adenosine triphosphate (ATP) production, and increased levels of mitochondrial reactive oxygen species (ROS). Intriguingly, higher apoptosis levels were found in cells carrying the mutant VLCAD under glucose-limited stress. Moreover, the stability of the mutant homodimer was disturbed, and major conformational changes in each mutant VLCAD structure were predicted by molecular dynamics (MD) simulation. The data presented here may provide valuable information for improving management of diagnosis and treatment of VLCAD deficiency and for a better understanding of the general molecular bases of disease variability.","variants":[{"Name":"NM_000018.4(ACADVL):c.1276G>A (p.Ala426Thr)","Chromosome":"17","Start":"7223819","Stop":"7223819","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":646656,"rule_based_match":true,"evidence_text":"c.1276G>A","llm_judgment":"PRESENT","evidence":"c.1276G>A","abstract_start":678,"abstract_end":687},{"Name":"NM_000018.4(ACADVL):c.1238T>C (p.Ile413Thr)","Chromosome":"17","Start":"7223699","Stop":"7223699","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2833910,"rule_based_match":true,"evidence_text":"c.1238T>C","llm_judgment":"PRESENT","evidence":"c.1238T>C","abstract_start":667,"abstract_end":676}]}
{"pmid":"28890726","title":"Next-Generation Sequencing-Aided Rapid Molecular Diagnosis of Occult Macular Dystrophy in a Chinese Family.","abstract":"<b>Purpose:</b> To show early, rapid and accurate molecular diagnosis of occult macular dystrophy (OMD) in a four-generation Chinese family with inherited macular dystrophy. <b>Methods:</b> In the current study, we comprehensively screened 130 genes involved in common inherited non-syndromic eye diseases with next-generation sequencing-based target capture sequencing of the proband of a four-generation Chinese family that has suffered from maculopathy without a definitive diagnosis for over 10 years. Variants were filtered and analyzed to identify possible disease-causing variants before validation by Sanger sequencing. <b>Results:</b> Two heterozygous mutations-<i>RP1L1</i> c.133 C > T (p.Arg45Trp), which is a hot spot for OMD, and <i>ABCA4</i> c.6119 G > A (p.Arg2040Gln), which was identified in Stargardt's disease were found in three patients, but neither of the mutations was found in the unaffected individuals in the same family, who are phenotypically normal or in the normal control volunteers. <b>Conclusion:</b> These results cannot only confirm the diagnosis of OMD in the proband, but also provide presymptomatic diagnosis of the proband's children before the onset of visual acuity impairment and guidance regarding the prognosis and management of these patients. Heterozygous mutations of <i>RP1L1</i> c.133 C > T (p.Arg45Trp) and <i>ABCA4</i> c.6119 G > A (p.Arg2040Gln) are likely responsible for OMD. Our results further extend our current understanding of the genetic basis of OMD, and emphasize the importance of molecular diagnosis and genetic counseling for OMD.","variants":[{"Name":"NM_178857.6(RP1L1):c.133C>T (p.Arg45Trp)","Chromosome":"8","Start":"10623069","Stop":"10623069","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17232,"rule_based_match":true,"evidence_text":"RP1L1 c.133 C > T (p.Arg45Trp)","llm_judgment":"PRESENT","evidence":"RP1L1</i> c.133 C > T (p.Arg45Trp)","abstract_start":674,"abstract_end":708}]}
{"pmid":"25154303","title":"Whole-exome sequencing in an extended family with myocardial infarction unmasks familial hypercholesterolemia.","abstract":"BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal-dominant disease leading to markedly elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature myocardial infarction (MI). Mutation carriers display variable LDL cholesterol levels, which may obscure the diagnosis. We examined by whole-exome sequencing a family in which multiple myocardial infarctions occurred at a young age with unclear etiology.\nMETHODS: Whole-exome sequencing of three affected family members, validation of the identified variant with Sanger-sequencing, and subsequent co-segregation analysis in the family.\nRESULTS: The index patient (LDL cholesterol 188 mg/dL) was referred for molecular-genetic investigations. He had coronary artery bypass graft (CABG) at the age of 59 years; 12 out of 15 1st, 2nd and 3rd degree relatives were affected with coronary artery disease (CAD) and/or premature myocardial infarction (MI). We sequenced the whole-exome of the patient and two cousins with premature MI. After filtering, we were left with a potentially disease causing variant in the LDL receptor (LDLR) gene, which we validated by Sanger-sequencing (nucleotide substitution in the acceptor splice-site of exon 10, c.1359-1G > A). Sequencing of all family members available for genetic analysis revealed co-segregation of the variant with CAD (LOD 3.0) and increased LDLC (>190 mg/dL), following correction for statin treatment (LOD 4.3). Interestingly, mutation carriers presented with highly variable corrected (183-354 mg/dL) and on-treatment LDL levels (116-274 mg/dL) such that the diagnosis of FH in this family was made only after the molecular-genetic analysis.\nCONCLUSION: Even in families with unusual clustering of CAD FH remains to be underdiagnosed, which underscores the need for implementation of systematic screening programs. Whole-exome sequencing may facilitate identification of disease-causing variants in families with unclear etiology of MI and enable preventive treatment of mutation carriers in a more timely fashion.","variants":[{"Name":"NM_000527.5(LDLR):c.1359-1G>A","Chromosome":"19","Start":"11113534","Stop":"11113534","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":172183,"rule_based_match":true,"evidence_text":"c.1359-1G > A","llm_judgment":"PRESENT","evidence":"c.1359-1G > A","abstract_start":1231,"abstract_end":1244}]}
{"pmid":"15998779","title":"A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia.","abstract":"CONTEXT: Mandibuloacral dysplasia (MAD) is a phenotypically heterogeneous, rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, lipodystrophy, and mottled cutaneous pigmentation. MAD patients with type A lipodystrophy with loss of sc fat from the extremities and normal or slight excess in the neck and truncal regions have been previously reported to carry a homozygous Arg527His mutation in LMNA (Lamin A/C) gene. Among those with type B pattern of lipodystrophy with generalized loss of sc fat, we recently reported a patient carrying compound heterozygous mutations in an endoprotease, zinc metalloproteinase (ZMPSTE24), gene that is involved in posttranslational processing of prelamin A to mature lamin A.\nOBJECTIVE: Our objective was to carry out mutational analysis of LMNA in additional patients with MAD and type A lipodystrophy.\nDESIGN AND SETTING: We studied descriptive case reports at a referral center.\nPATIENTS: Subjects were a male and a female patient with MAD who belonged to two pedigrees from Turkey.\nMAIN OUTCOME MEASURES: We assessed genotype-phenotype relationships.\nRESULTS: We now report that both these patients have a novel homozygous missense mutation (c.1586C-->T; c refers to cDNA reference sequence) in LMNA that replaces a well-conserved residue alanine at position 529 to valine. Intragenic single-nucleotide polymorphisms revealed a common haplotype spanning 2.5 kb around the mutated nucleotide in the parents of both the affected subjects, suggesting ancestral origin of the mutation. The female patient had no breast development despite normal menstruation, a phenotype different from that seen in women with MAD and Arg527His LMNA mutation.\nCONCLUSIONS: We conclude that two homozygous missense LMNA mutations involving the arginine 527 and alanine 529 residues cause MAD with subtle variations in phenotype.","variants":[{"Name":"NM_170707.4(LMNA):c.1586C>T (p.Ala529Val)","Chromosome":"1","Start":"156137210","Stop":"156137210","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29552,"rule_based_match":false,"evidence_text":"c.1586C-->T","llm_judgment":"PRESENT","evidence":"c.1586C-->T","abstract_start":1290,"abstract_end":1301}]}
{"pmid":"24194196","title":"Analysis of two Arab families reveals additional support for a DFNB2 nonsyndromic phenotype of MYO7A.","abstract":"Variants in the head and tail domains of the MYO7A gene, encoding myosin VIIA, cause Usher syndrome type 1B (USH1B) and nonsyndromic deafness (DFNB2, DFNA11). In order to identify the genetic defect(s) underling profound deafness in two consanguineous Arab families living in UAE, we have sequenced a panel of 19 genes involved in Usher syndrome and nonsyndromic deafness in the index cases of the two families. This analysis revealed a novel homozygous insertion of AG (c.1952_1953insAG/p.C652fsX11) in exon 17 of the MYO7A gene in an Iraqi family, and a homozygous point mutation (c.5660C>T/p.P1887L) in exon 41 affecting the same gene in a large Palestinian family. Moreover, some individuals from the Palestinian family also harbored a novel heterozygous truncating variant (c.1267C>T/p.R423X) in the DFNB31 gene, which is involved in autosomal recessive nonsyndromic deafness type DFNB31 and Usher syndrome type II. Assuming an autosomal recessive mode of inheritance in the two inbred families, we conclude that the homozygous variants in the MYO7A gene are the disease-causing mutations in these families. Furthermore, given the absence of retinal disease in all affected patients examined, particularly a 28 year old patient, suggests that at least one family may segregate a DFNB2 presentation rather than USH1B. This finding further supports the premise that the MYO7A gene is responsible for two distinct diseases and gives evidence that the p.P1887L mutation in a homozygous state may be responsible for nonsyndromic hearing loss.","variants":[{"Name":"NM_000260.4(MYO7A):c.1952_1953insAG (p.Cys652fs)","Chromosome":"11","Start":"77174772","Stop":"77174773","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TAG","allel_id":52335,"rule_based_match":true,"evidence_text":"c.1952_1953insAG/p.C652fsX11","llm_judgment":"PRESENT","evidence":"c.1952_1953insAG/p.C652fsX11","abstract_start":471,"abstract_end":499}]}
{"pmid":"33243271","title":"The genetic landscape of crystallins in congenital cataract.","abstract":"BACKGROUND: The crystalline lens is mainly composed of a large family of soluble proteins called the crystallins, which are responsible for its development, growth, transparency and refractive index. Disease-causing sequence variants in the crystallins are responsible for nearly 50% of all non-syndromic inherited congenital cataracts, as well as causing cataract associated with other diseases, including myopathies. To date, more than 300 crystallin sequence variants causing cataract have been identified.\nMETHODS: Here we aimed to identify the genetic basis of disease in five multi-generation British families and five sporadic cases with autosomal dominant congenital cataract using whole exome sequencing, with identified variants validated using Sanger sequencing. Following bioinformatics analysis, rare or novel variants with a moderate to damaging pathogenicity score, were filtered out and tested for segregation within the families.\nRESULTS: We have identified 10 different heterozygous crystallin variants. Five recurrent variants were found: family-A, with a missense variant (c.145C>T; p.R49C) in CRYAA associated with nuclear cataract; family-B, with a deletion in CRYBA1 (c.272delGAG; p.G91del) associated with nuclear cataract; and family-C, with a truncating variant in CRYGD (c.470G>A; W157*) causing a lamellar phenotype; individuals I and J had variants in CRYGC (c.13A>C; T5P) and in CRYGD (c.418C>T; R140*) causing unspecified congenital cataract and nuclear cataract, respectively. Five novel disease-causing variants were also identified: family D harboured a variant in CRYGC (c.179delG; R60Qfs*) responsible for a nuclear phenotype; family E, harboured a variant in CRYBB1 (c.656G>A; W219*) associated with lamellar cataract; individual F had a variant in CRYGD (c.392G>A; W131*) associated with nuclear cataract; and individuals G and H had variants in CRYAA (c.454delGCC; A152del) and in CRYBB1 (c.618C>A; Y206*) respectively, associated with unspecified congenital cataract. All novel variants were predicted to be pathogenic and to be moderately or highly damaging.\nCONCLUSIONS: We report five novel variants and five known variants. Some are rare variants that have been reported previously in small ethnic groups but here we extend this to the wider population and record a broader phenotypic spectrum for these variants.","variants":[{"Name":"NM_006891.4(CRYGD):c.418C>T (p.Arg140Ter)","Chromosome":"2","Start":"208121780","Stop":"208121780","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":557824,"rule_based_match":true,"evidence_text":"c.418C>T (R140*)","llm_judgment":"PRESENT","evidence":"c.418C>T","abstract_start":1416,"abstract_end":1424},{"Name":"NM_020989.4(CRYGC):c.13A>C (p.Thr5Pro)","Chromosome":"2","Start":"208129680","Stop":"208129680","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":31982,"rule_based_match":true,"evidence_text":"c.13A>C; T5P","llm_judgment":"PRESENT","evidence":"c.13A>C; T5P","abstract_start":1388,"abstract_end":1400}]}
{"pmid":"31276831","title":"Congenital Sodium Diarrhea by mutation of the SLC9A3 gene.","abstract":"Congenital Sodium Diarrhea (CSD) due to SLC9A3 mutation is a rare cause of neonatal diarrhea explained by dysfunction of the Na+/H+ antiporter 3 in intestine. To date only 10 patients have been described. We report a male patient with typical antenatal symptoms (polyhydramnios and intestinal dilation) and neonatal diarrhea with fecal sodium and bicarbonates loss. Next generation sequencing revealed a missense homozygous mutation in exon 6 of the SLC9A3 gene (NM_004174.3:c.1039G > A, NP_004165.2:p.Glu347Lys). Oral electrolytes supplements (Sodium and Bicarbonates) allowed a normal growth to the child currently aged twenty months. CSD symptomatology usually begins during third trimester of pregnancy. Antenatal signs are polyhydramnios and diffuse intestinal dilation. Main differential diagnoses are intestinal obstruction and Congenital Chloride Diarrhea. Diarrhea begins from the first days of life and its severity is variable. Based on the report and on the literature we suggest that non syndromic CSD can be detected during third trimester of pregnancy. With adequate electrolytes supplementation good evolution is possible.","variants":[{"Name":"NM_004174.4(SLC9A3):c.1039G>A (p.Glu347Lys)","Chromosome":"5","Start":"483376","Stop":"483376","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":614152,"rule_based_match":true,"evidence_text":"NM_004174.3:c.1039G > A, NP_004165.2:p.Glu347Lys","llm_judgment":"PRESENT","evidence":"NM_004174.3:c.1039G > A, NP_004165.2:p.Glu347Lys","abstract_start":463,"abstract_end":511}]}
{"pmid":"28013382","title":"Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome.","abstract":"BACKGROUND: Many COL4A5 splice region variants have been described in patients with X-linked Alport syndrome, but few have been confirmed by functional analysis to actually cause defective splicing. We sought to demonstrate that a novel COL4A5 splice region variant in a family with Alport syndrome is pathogenic using functional studies. We also describe an alternative method of diagnosis.\nMETHODS: Targeted next-generation sequencing results of an individual with Alport syndrome were analyzed and the results confirmed by Sanger sequencing in family members. A splicing reporter minigene assay was used to examine the variant's effect on splicing in transfected cells. Plucked hair follicles from patients and controls were examined for collagen IV proteins using immunofluorescence microscopy.\nRESULTS: A novel splice region mutation in COL4A5, c.1780-6T>G, was identified and segregated with disease in this family. This variant caused frequent skipping of exon 25, resulting in a frameshift and truncation of collagen α5(IV) protein. We also developed and validated a new approach to characterize the expression of collagen α5(IV) protein in the basement membranes of plucked hair follicles. Using this approach we demonstrated reduced collagen α5(IV) protein in affected male and female individuals in this family, supporting frequent failure of normal splicing.\nCONCLUSIONS: Differing normal to abnormal transcript ratios in affected individuals carrying splice region variants may contribute to variable disease severity observed in Alport families. Examination of plucked hair follicles in suspected X-linked Alport syndrome patients may offer a less invasive alternative method of diagnosis and serve as a pathogenicity test for COL4A5 variants of uncertain significance.","variants":[{"Name":"NM_033380.3(COL4A5):c.1780-6T>G","Chromosome":"X","Start":"108598696","Stop":"108598696","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":578132,"rule_based_match":true,"evidence_text":"c.1780-6T>G","llm_judgment":"PRESENT","evidence":"c.1780-6T>G","abstract_start":850,"abstract_end":861}]}
{"pmid":"27881174","title":"Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course.","abstract":"BACKGROUND: The pathophysiological origin of juvenile idiopathic arthritis (JIA) is largely unknown. However, individuals with presumably pathogenic mutations in FAMIN have been reported, associating this gene with a rare subtype of this disorder. FAMIN, that is formerly also referred to as LACC1 or C13orf31, has recently been shown to play a crucial role in immune-metabolic functions and is involved in regulation of inflammasome activation and promotion of ROS production.\nCASE PRESENTATION: We describe two siblings with severe familial forms of juvenile arthritis in which whole-exome-sequencing revealed a novel homozygous frameshift mutation (NM_153218.2:c.827delC¸. p.(T276fs*2) in FAMIN.\nCONCLUSIONS: The observation of a new deleterious mutation adds further evidence that pathogenic mutations in FAMIN are causal for a monogenic form of JIA. Furthermore the associated phenotype is not restricted to systemic JIA, but can also be found in other forms of familial juvenile arthritis.","variants":[{"Name":"NM_153218.4(LACC1):c.827del (p.Thr276fs)","Chromosome":"13","Start":"43883856","Stop":"43883856","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":802251,"rule_based_match":true,"evidence_text":"NM_153218.2:c.827delC","llm_judgment":"PRESENT","evidence":"NM_153218.2:c.827delC","abstract_start":652,"abstract_end":673}]}
{"pmid":"24613577","title":"Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene.","abstract":"We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann-Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid-progeroid-lipodystrophy syndrome) and frameshift mutations at the 3' end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes.","variants":[{"Name":"NM_000138.5(FBN1):c.8226+1G>A","Chromosome":"15","Start":"48412568","Stop":"48412568","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227463,"rule_based_match":true,"evidence_text":"c.8226+1G>A","llm_judgment":"PRESENT","evidence":"c.8226+1G>A","abstract_start":404,"abstract_end":415}]}
{"pmid":"20386867","title":"Identification and characterization of eight novel SMPD1 mutations causing types A and B Niemann-Pick disease.","abstract":"Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM), due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Here we report the identification, characterization and genotype/phenotype correlations of eight novel mutations in six unrelated NPD patients. These mutations included seven missense mutations: c.631T>C (p.W211R), c.757G>C (p.D253H), c.940G>A (p.V314M), c.1280A>G (p.H427R), c.1564A>G (p.N522S), c.1575G>C (p.Q525H) and c.1729A>G (p.H577R), and a novel frameshift mutation, c.1657delACCGCCT (fsT553). Each missense mutation was expressed in 293T or COS-7 cells; mutant enzymes p.W211R, p.D253H, p.H427R and p.H577R had <1% of expressed wild-type activity, whereas p.V314M, p.N522S and p.Q525H had 21.7%, 10.1% and 64% of expressed wild-type activity, respectively. The c.1564A>G mutation obliterated a known N-glycosylation site and its p.N522S mutant enzyme had ~10% of expressed wild-type activity. Western blot analysis revealed that each mutant protein was expressed at near wild-type amounts, despite their differences in residual activity. The novel seven-base deletion occurred at codon 553, leading to a premature truncation after residue 609. The expression studies predicted the clinical phenotypes of the six patients: two type A patients had genotypes with only type A alleles [c.631T>C (p.W211R), c.757G>C (p.D253H) and c.1729A>G (p.H577R)], and the other four type B disease patients had at least one neuroprotective mutant type B allele [c.940G>A (p.V314M), c.1280A>G (p.H427R), c.1564A>G (p.N522S) and c.1575G>C (p.Q525H)] that expressed >5% residual ASM activity. Thus, these new mutations provide novel genotype/phenotype correlations and further document the genetic heterogeneity in types A and B NPD.","variants":[{"Name":"NM_000543.5(SMPD1):c.631T>C (p.Trp211Arg)","Chromosome":"11","Start":"6391696","Stop":"6391696","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1877984,"rule_based_match":true,"evidence_text":"c.631T>C (p.W211R)","llm_judgment":"PRESENT","evidence":"c.631T>C (p.W211R)","abstract_start":375,"abstract_end":393},{"Name":"NM_000543.5(SMPD1):c.1280A>G (p.His427Arg)","Chromosome":"11","Start":"6393633","Stop":"6393633","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":565935,"rule_based_match":true,"evidence_text":"c.1280A>G (p.H427R)","llm_judgment":"PRESENT","evidence":"c.1280A>G (p.H427R)","abstract_start":435,"abstract_end":454},{"Name":"NM_000543.5(SMPD1):c.940G>A (p.Val314Met)","Chromosome":"11","Start":"6392005","Stop":"6392005","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":546070,"rule_based_match":true,"evidence_text":"c.940G>A (p.V314M)","llm_judgment":"PRESENT","evidence":"c.940G>A (p.V314M)","abstract_start":415,"abstract_end":433},{"Name":"NM_000543.5(SMPD1):c.757G>C (p.Asp253His)","Chromosome":"11","Start":"6391822","Stop":"6391822","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":99227,"rule_based_match":true,"evidence_text":"c.757G>C (p.D253H)","llm_judgment":"PRESENT","evidence":"c.757G>C (p.D253H)","abstract_start":395,"abstract_end":413}]}
{"pmid":"25394726","title":"Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.","abstract":"Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C > G (p.Y2221*) or c.6732C > A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain-of-function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu-Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL.","variants":[{"Name":"NM_000435.3(NOTCH3):c.6732C>A (p.Tyr2244Ter)","Chromosome":"19","Start":"15160896","Stop":"15160896","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":226724,"rule_based_match":true,"evidence_text":"c.6732C > A, (p.Y2244*)","llm_judgment":"PRESENT","evidence":"c.6732C > A, (p.Y2244*)","abstract_start":1358,"abstract_end":1381},{"Name":"NM_000435.3(NOTCH3):c.6663C>G (p.Tyr2221Ter)","Chromosome":"19","Start":"15160965","Stop":"15160965","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":226726,"rule_based_match":true,"evidence_text":"c.6663C > G (p.Y2221*)","llm_judgment":"PRESENT","evidence":"c.6663C > G (p.Y2221*)","abstract_start":1332,"abstract_end":1354},{"Name":"NM_000435.3(NOTCH3):c.6461_6486del (p.Gly2154fs)","Chromosome":"19","Start":"15161142","Stop":"15161167","ReferenceAlleleVCF":"GCAGGCCCAGGCTGAGTACACATCCTC","AlternateAlleleVCF":"G","allel_id":226727,"rule_based_match":true,"evidence_text":"c.6461_6486del","llm_judgment":"PRESENT","evidence":"c.6461_6486del","abstract_start":1140,"abstract_end":1154},{"Name":"NM_000435.3(NOTCH3):c.6247A>T (p.Lys2083Ter)","Chromosome":"19","Start":"15161381","Stop":"15161381","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":204348,"rule_based_match":true,"evidence_text":"c.6247A > T (pK2083*)","llm_judgment":"PRESENT","evidence":"c.6247A > T (pK2083*)","abstract_start":1309,"abstract_end":1330}]}
{"pmid":"36467477","title":"Clinical characteristics and genetics of ten Chinese children with PRRT2-associated neurological diseases.","abstract":"Background: Proline-rich transmembrane protein 2 (PRRT2) plays an important role in the central nervous system and mutations in the gene are implicated in a variety of neurological disorders. This study aimed to summarize the clinical characteristics and gene expression analysis of neurological diseases related to the <i>PRRT2</i> gene and explore the clinical characteristics, therapeutic effects, and possible pathogenic mechanisms of related diseases.\nMethods: We enrolled 10 children with <i>PRRT2</i> mutation-related neurological diseases who visited the Children's Hospital affiliated with the Shanghai Jiaotong University School of Medicine/Shanghai Children's Hospital between May 2017 and February 2022. Video electroencephalography (VEEG), cranial imaging, treatment regimens, gene results, and gene expression were analyzed. Genetic testing involved targeted sequencing or whole-exome genome sequencing (WES). We further analyzed the expression and mutation conservation of PRRT2 and synaptosome-associated protein 25 (SNAP25) in blood samples using quantitative polymerase chain reaction (qPCR) and predicted the protein structure. Summary analysis of the reported gene maps and domains was also performed.\nResults: Ten children with <i>PRRT2</i> gene mutations were analyzed, and 4 mutations were identified, consisting of 2 new (c.518A > C, p.Glu173 Ala; c.879 + 112G > A, p.?) and two known (c. 649 dup, p. Arg217Profs * 8; c. 649 del, p. Arg217Glufs * 12) mutations. Among these mutations, one was <i>de novo</i>(P6), and three could not be determined because one parent refused genetic testing. The clinical phenotypes were paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), epilepsy, infantile spasms, and intellectual disability. The qPCR results showed that <i>PRRT2</i> gene expression levels were significantly lower in children and parent carriers than the control group. The <i>SNAP25</i> gene expression level of affected children was significantly lower (<i>P</i> ≤ 0.001) than that of the control group. The mutation sites reported in this study are highly conserved in different species. Among the various drugs used, oxcarbazepine and sodium valproate were the most effective. All 10 children had a good disease prognosis, and 8 were completely controlled with no recurrence, whereas 2 had less severe and fewer seizures.\nConclusion: Mutation of <i>PRRT2</i> led to a significant decrease in its protein expression level and that of SNAP25, suggesting that the mutant protein may lead to the loss of its function and that of related proteins. This mutation site is highly conserved in most species, and there was no significant correlation between specific PRRT2 genotypes and clinical phenotypes. Asymptomatic carriers also have decreased gene expression levels, suggesting that more factors are involved.","variants":[{"Name":"NM_145239.3(PRRT2):c.649del (p.Arg217fs)","Chromosome":"16","Start":"29813695","Stop":"29813695","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":48351,"rule_based_match":true,"evidence_text":"c. 649 del, p. Arg217Glufs * 12","llm_judgment":"PRESENT","evidence":"c. 649 del, p. Arg217Glufs * 12","abstract_start":1442,"abstract_end":1473}]}
{"pmid":"21507207","title":"Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Pakistani population.","abstract":"INTRODUCTION: Glucose-6-phosphate dehydrogenase (G6PD; E.C. 1.1.1.49) deficiency is the commonest inborn error of metabolism with more than 140 genetic variants. The incidence of G6PD deficiency is 2-9% in Pakistan, but G6PD variants were never studied comprehensively. We therefore designed this study to describe the frequency of G6PD variants and their associated enzyme activities in Pakistan.\nMETHODS: Patients diagnosed with G6PD deficiency were enrolled. RFLP-PCR was utilized to identify common mutations previously reported from Asian countries. Where mutational analysis failed, amplification of 9-12 exons with subsequent gene sequencing was performed. G6PD enzyme activity was assessed through the quantitative enzyme assay.\nRESULTS: Two hundred and seventy-six G6PD-deficient subjects (237 male and 39 women) were investigated. G6PD Mediterranean (563C-T) was the most common genetic variant (n=216 or 78%). G6PD Chatham (1003A-G) and G6PD Orissa (131C-G) were observed in 14 (5%) and two (0.7%) subjects respectively. A novel mutation 973 G-A with a predicated amino acid change of asp325asn was identified in exon 9. This was named G6PD Karachi after the place of origin of proband. Polymorphism in position 1311C/T was uniformly observed with all variants. Forty-three or 17% of DNA samples remained uncharacterized. Very low levels of G6PD enzyme activity was observed with 563C-T mutation.\nCONCLUSION: We concluded that 563C-T was the commonest G6PD variant, while 1003A-G and 131C-G were less-frequent genetic variants of G6PD in Pakistani population. A novel genetic variant 973G-A was also identified. Very low levels of G6PD enzyme activity was seen with G6PD 563C-T. Mutational analysis failed in a significant proportion of samples warranting further work.","variants":[{"Name":"NM_001360016.2(G6PD):c.973G>A (p.Asp325Asn)","Chromosome":"X","Start":"154533020","Stop":"154533020","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1014843,"rule_based_match":false,"evidence_text":"973 G-A","llm_judgment":"PRESENT","evidence":"973 G-A","abstract_start":1049,"abstract_end":1056}]}
{"pmid":"37743782","title":"De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities.","abstract":"The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.","variants":[{"Name":"NM_145166.4(ZBTB47):c.2039A>G (p.Glu680Gly)","Chromosome":"3","Start":"42664393","Stop":"42664393","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2403696,"rule_based_match":true,"evidence_text":"c.2039A>G","llm_judgment":"PRESENT","evidence":"c.2039A>G","abstract_start":719,"abstract_end":728}]}
{"pmid":"25487361","title":"Familial cardiofaciocutaneous syndrome in a father and a son with a novel MEK2 mutation.","abstract":"Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder belonging to the group of RASopathies. It is typically characterized by congenital heart defects, short stature, dysmorphic craniofacial features, intellectual disability, failure to thrive, and ectodermal abnormalities such as hyperkeratosis and sparse, brittle, curly hair. CFC syndrome is caused by dominant mutations in one of the four genes BRAF, MEK1, MEK2, and KRAS. Only three familial cases of CFC syndrome have been reported to date, whereas the vast majorities are sporadic cases due to de novo mutations. We report on a fourth familial case with transmission of CFC syndrome from father to son due to a novel heterozygous sequence change c.376A>G (p.N126D) in exon 3 of MEK2 gene. This observation further documents the possibility of vertical transmission of CFC syndrome, which appears to be associated with rare mutations and relatively mild intellectual disability in affected individual. The hypomorphic effect of specific mutations particularly regarding neurocognitive issues may be related to the variable fertility of affected individuals.","variants":[{"Name":"NM_030662.4(MAP2K2):c.376A>G (p.Asn126Asp)","Chromosome":"19","Start":"4110583","Stop":"4110583","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":363055,"rule_based_match":true,"evidence_text":"c.376A>G (p.N126D)","llm_judgment":"PRESENT","evidence":"c.376A>G (p.N126D)","abstract_start":713,"abstract_end":731}]}
{"pmid":"9781015","title":"Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience.","abstract":"We describe variation at the PAH locus in the population of Quebec. We successfully analyzed 135 of 141 chromosomes from phenylketonuria (PKU) probands (95.7% of the sample), and eight additional chromosomes from a small number of probands with non-PKU hyperphenylalaninemia (HPA). The full set of chromosomes harboured 45 different PAH mutations: i) seven polymorphisms (IVS2nt19, IVS3nt-22, IVS6nt-55, Q232Q, V245V, L385L, Y414Y); ii) four mutations causing non-PKU HPA (T92I, E390G, R408Q, D415N); iii) 34 mutations causing PKU. Only six mutations (M1V, R261Q, F299C, S349P, R408W and IVS12nt1) occurred in the whole province at relative frequencies > 5%: most are rare and probably identical by descent. By studying associations of mutations with polymorphic haplotype alleles, we found examples of mutations on different haplotypes that were identical by state, but not by descent because they were recurrent mutations (E280K and R408W); and examples of mutations identical both by state and by descent because of intragenic recombination (S67P, G218V, V245A and IVS12nt1). Ten mutations were first described in Quebec and five are still unique there; three of these 'Quebec' mutations are reported here for the first time (c.125A-->T (K42I); [c.470G-->A; c.471A--C] (R157N); c.707nt-55 (IVS6nt-55). The PAH mutations stratify by geographic region and population, their distributions validating hypotheses about European range expansion to North America during three separate phases of immigration and demographic expansion in the Quebec region over the past four centuries. The PAH homozygosity value (j) is 0.06 for the total Quebec sample (0.5-0.08 by regions), and the corresponding homoallelic fraction of mutant PAH genotypes is 24%. These findings are a documentation of genetic diversity in the Quebec population.","variants":[{"Name":"NM_000277.3(PAH):c.125A>T (p.Lys42Ile)","Chromosome":"12","Start":"102912834","Stop":"102912834","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":108317,"rule_based_match":false,"evidence_text":"c.125A-->T (K42I)","llm_judgment":"PRESENT","evidence":"c.125A-->T (K42I)","abstract_start":1229,"abstract_end":1246}]}
{"pmid":"25157627","title":"Analysis of POFUT1 gene mutation in a Chinese family with Dowling-Degos disease.","abstract":"Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by reticular pigmented anomaly mainly affecting flexures. Though KRT5 has been identified to be the causal gene of DDD, the heterogeneity of this disease was displayed: for example, POFUT1 and POGLUT1 were recently identified and confirmed to be additional pathogenic genes of DDD. To identify other DDD causative genes, we performed genome-wide linkage and exome sequencing analyses in a multiplex Chinese DDD family, in which the KRT5 mutation was absent. Only a novel 1-bp deletion (c.246+5delG) in POFUT1 was found. No other novel mutation or this deletion was detected in POFUT1 in a second DDD family and a sporadic DDD case by Sanger Sequencing. The result shows the genetic-heterogeneity and complexity of DDD and will contribute to the further understanding of DDD genotype/phenotype correlations and to the pathogenesis of this disease.","variants":[{"Name":"NM_015352.2(POFUT1):c.246+5del","Chromosome":"20","Start":"32210197","Stop":"32210197","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":3410900,"rule_based_match":true,"evidence_text":"c.246+5delG","llm_judgment":"PRESENT","evidence":"c.246+5delG","abstract_start":568,"abstract_end":579}]}
{"pmid":"30588330","title":"Rare","abstract":"Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene <i>TP53</i> that disrupt protein function or stability. While more than 70% of pathogenic variants in <i>TP53</i> are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Here, we report an extremely rare <i>TP53</i> missense variant, c.799C > T (p.Arg267Trp), identified in a 2-year-old Saudi proband diagnosed with choroid plexus carcinoma (CPC) and six of his first- and second-degree relatives. CPC is frequently found in families with LFS, and this is the first detailed report of a family with this variant. Intriguingly, the proband's father is homozygous for <i>TP53</i> c.799C > T and phenotypically normal at 39 years of age. While loss of <i>TP53</i> heterozygosity is often observed in tumors from individuals with LFS, homozygous germline <i>TP53</i> pathogenic variants are rare. Based on our analysis of this single family, we hypothesize that <i>TP53</i> c.799C > T has low or variable penetrance for LFS, with predisposition to the development of CPC. The observations from this family have furthered our understanding of the phenotypic variability that may be caused by one variant of <i>TP53</i>, even in the same family, and suggest that other factors (genetic and/or environmental) may play a role in mechanism of disease manifestation in LFS.","variants":[{"Name":"NM_000546.6(TP53):c.799C>T (p.Arg267Trp)","Chromosome":"17","Start":"7673821","Stop":"7673821","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":151478,"rule_based_match":true,"evidence_text":"c.799C > T (p.Arg267Trp)","llm_judgment":"PRESENT","evidence":"c.799C > T (p.Arg267Trp)","abstract_start":559,"abstract_end":583}]}
{"pmid":"30787447","title":"A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway.","abstract":"Hartsfield syndrome (HS) is an ultrarare developmental disorder mainly featuring holoprosencephaly and ectrodactyly. It is caused by heterozygous or biallelic variants in FGFR1. Recently, a dominant-negative effect was suggested for FGFR1 variants associated with HS. Here, exome sequencing analysis in a 12-year-old boy with HS disclosed a novel de novo heterozygous variant c.1934C>T in FGFR1 predicted to cause the p.(Ala645Val) amino-acid substitution. In order to evaluate whether the variant, changing a highly conserved residue of the kinase domain, affects FGFR1 function, biochemical studies were employed. We measured the FGFR1 receptor activity in FGF2-treated cell lines exogenously expressing wild-type or Ala645Val FGFR1 by monitoring the activation status of FGF2/FGFR1 downstream pathways. Our analysis highlighted that RAS/ERK1/2 signaling was significantly perturbed in cells expressing mutated FGFR1, in comparison with control cells. We also provided preliminary evidence showing a modulation of the autophagic process in cells expressing mutated FGFR1. This study expands the FGFR1 mutational spectrum associated with HS, provides functional evidence further supporting a dominant-negative effect of this category of FGFR1 variants and offers initial insights on dysregulation of autophagy in HS.","variants":[{"Name":"NM_023110.3(FGFR1):c.1934C>T (p.Ala645Val)","Chromosome":"8","Start":"38414822","Stop":"38414822","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":793281,"rule_based_match":true,"evidence_text":"c.1934C>T","llm_judgment":"PRESENT","evidence":"c.1934C>T","abstract_start":376,"abstract_end":385}]}
{"pmid":"15375013","title":"Mutation analysis in Spanish patients with hereditary hemorrhagic telangiectasia: deficient endoglin up-regulation in activated monocytes.","abstract":"BACKGROUND: Mutations in the endoglin (ENG) or ALK1 genes are responsible for hereditary hemorrhagic telangiectasia types 1 and 2 (HHT1 and HHT2), respectively, a dominant vascular dysplasia caused by haploinsufficiency. No formal mutation studies of patients with HHT have been conducted in Spain.\nMETHODS: ENG and ALK1 mutation analyses were carried out in 13 Spanish HHT patients diagnosed according to the Curacao criteria. Because endoglin is up-regulated at the cell surface during the monocyte-macrophage transition, endoglin concentrations in activated monocytes were determined by immunofluorescence flow cytometry in a systematic analysis. As controls, 40 non-HHT volunteers were studied for up-regulation of endoglin in activated monocytes.\nRESULTS: The mutation responsible for HHT was identified in eight patients belonging to two unrelated families. One of the families has a nonsense mutation in exon 4 (c.511C>T; R171X) of the ENG gene, and accordingly the disorder was identified as HHT1. The other family has a missense mutation affecting exon 8 (c.1120C>T; R374W) of the ALK1 gene, and hence is a HHT2 family. Interestingly, endoglin up-regulation was deficient in activated monocytes of both HHT1 and HHT2 patients compared with controls. By contrast, endoglin up-regulation was age-independent in control donors across a broad range of ages. The extent of endoglin up-regulation in activated monocytes was most diminished in those patients with the most severe symptoms.\nCONCLUSIONS: Endoglin up-regulation in activated monocytes is impaired in HHT1 and HHT2 patients and is age-dependent in both HHT types. Endoglin expression may predict the clinical severity of HHT.","variants":[{"Name":"NM_000020.3(ACVRL1):c.1120C>T (p.Arg374Trp)","Chromosome":"12","Start":"51916107","Stop":"51916107","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23288,"rule_based_match":true,"evidence_text":"c.1120C>T","llm_judgment":"PRESENT","evidence":"c.1120C>T","abstract_start":1065,"abstract_end":1074},{"Name":"NM_001114753.3(ENG):c.511C>T (p.Arg171Ter)","Chromosome":"9","Start":"127826522","Stop":"127826522","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":433063,"rule_based_match":true,"evidence_text":"c.511C>T; R171X","llm_judgment":"PRESENT","evidence":"c.511C>T; R171X","abstract_start":919,"abstract_end":934}]}
{"pmid":"32760653","title":"","abstract":"Pathogenic variants in <i>RANBP2</i> cause autosomal dominant familial and recurrent Acute Necrotizing Encephalopathy of Childhood (ANEC). Affected children typically experience a 3-stage disease: a 3 to 5 days prodrome of non-specific febrile illness, acute encephalopathy, and recovery with or without neurological sequelae or death. Neuroradiological finding of bilateral symmetrical thalamic lesions raise the suspicion of this diagnosis. A devastating disease, reported mortality approaches 1/3 of those affected and only approximately 10% of patients recover completely without sequelae. We report a Malaysian family with <i>RANBP2</i> pathogenic variant c.1754C>T (p.Thr585Met). The clinical presentation and course over a maximum of 7 years, as well as neuroradiological features of the 3 affected children are described. In contrast to the reported high mortality and morbidity, our patients have recovered with minor sequelae. We would like to highlight the absence of pathogenic variants in both parents' blood, raising the possibility of germline mosaicism in one of the parents as the underlying genetic mechanism of inheritance. To our knowledge, this is the first report of germline mosaicism in RANBP2 Susceptibility to Infection-induced Encephalopathy.","variants":[{"Name":"NM_006267.5(RANBP2):c.1754C>T (p.Thr585Met)","Chromosome":"2","Start":"108751993","Stop":"108751993","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23402,"rule_based_match":true,"evidence_text":"c.1754C>T (p.Thr585Met)","llm_judgment":"PRESENT","evidence":"c.1754C>T (p.Thr585Met)","abstract_start":661,"abstract_end":684}]}
{"pmid":"32707087","title":"Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.","abstract":"We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A (p.Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly inherited DA, a c.98C>T (p.Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.","variants":[{"Name":"NM_013292.5(MYL11):c.98C>T (p.Ala33Val)","Chromosome":"16","Start":"30376146","Stop":"30376146","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":905018,"rule_based_match":true,"evidence_text":"c.98C>T (p.Ala33Val)","llm_judgment":"PRESENT","evidence":"c.98C>T (p.Ala33Val)","abstract_start":611,"abstract_end":631},{"Name":"NM_013292.5(MYL11):c.469T>C (p.Cys157Arg)","Chromosome":"16","Start":"30377859","Stop":"30377859","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":905019,"rule_based_match":true,"evidence_text":"c.469T>C (p.Cys157Arg)","llm_judgment":"PRESENT","evidence":"p.Cys157Arg","abstract_start":295,"abstract_end":306},{"Name":"NM_013292.5(MYL11):c.470G>T (p.Cys157Phe)","Chromosome":"16","Start":"30377860","Stop":"30377860","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":905020,"rule_based_match":true,"evidence_text":"c.470G>T (p.Cys157Phe)","llm_judgment":"PRESENT","evidence":"p.Cys157Phe","abstract_start":269,"abstract_end":280}]}
{"pmid":"32893042","title":"Four novel optineurin mutations in patients with sporadic amyotrophic lateral sclerosis in Mainland China.","abstract":"This study was to investigate the genetic contribution of optineurin (OPTN), a gene associated with primary open-angle glaucoma and amyotrophic lateral sclerosis (ALS), in Chinese patients with ALS. To gain additional insight into the spectrum and pathogenic relevance of this gene for ALS, we sequenced all the coding exons of OPTN and intron-exon boundaries in 398 patients with ALS [33 familial ALS (FALS), 365 unrelated sporadic ALS (SALS)] using next-generation sequencing. Six nonsynonymous variants were identified in 6 unrelated patients with SALS, in which one patient harbored 2 different OPTN variants and another carried an SETX mutation at the same time. Among those 6 variants, 4 were novel missense mutations: c.247C>T (p.R83C), c.676T>C (p.F226L), c.1699A>G (p.Y567A), and c.1713C>G (p.H571Q) (all heterozygous). The remaining 2 were already reported in previous studies. All 6 patients were spinal onset but showed differences in ALS subtypes as well as age of onset and disease progression. Taken together, we detected 4 novel missense OPTN mutations and 2 previously described mutations that might be causal for ALS, accounting for a mutant frequency of 1.10% (4/365) in patients with SALS after excluding 2 benign variants, and confirmed that OPTN mutations are common in Asian populations. In addition, our data suggested that variability in phenotype of the same mutation might partly be due to the oligogenic basis of ALS.","variants":[{"Name":"NM_001008212.2(OPTN):c.247C>T (p.Arg83Cys)","Chromosome":"10","Start":"13110354","Stop":"13110354","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":321188,"rule_based_match":true,"evidence_text":"c.247C>T (p.R83C)","llm_judgment":"PRESENT","evidence":"c.247C>T (p.R83C)","abstract_start":725,"abstract_end":742},{"Name":"NM_001008212.2(OPTN):c.676T>C (p.Phe226Leu)","Chromosome":"10","Start":"13118937","Stop":"13118937","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1421744,"rule_based_match":true,"evidence_text":"c.676T>C (p.F226L)","llm_judgment":"PRESENT","evidence":"c.676T>C (p.F226L)","abstract_start":744,"abstract_end":762}]}
{"pmid":"32532877","title":"Reticular dysgenesis caused by an intronic pathogenic variant in","abstract":"Reticular dysgenesis is a form of severe combined immunodeficiency (SCID) caused by biallelic pathogenic variants in <i>AK2</i> Here we present the case of a boy diagnosed with SCID following a positive newborn screen (NBS). Genetic testing revealed a homozygous variant: <i>AK2</i> c.330 + 5G > A. In silico analyses predicted weakened native donor splice site. However, this variant was initially classified as a variant of uncertain significance (VUS) given lack of direct evidence. To determine the impact on splicing, we analyzed RNA from the proband and his parents, using massively parallel RNA-seq of cloned RT-PCR products. Analysis showed that c.330 + 5G > A results in exon 3 skipping, which encodes a critical region of the AK2 protein. With these results, the variant was upgraded to pathogenic, and the patient was given a diagnosis of reticular dysgenesis. Interpretation of VUS at noncanonical splice site nucleotides presents a challenge. RNA sequencing provides an ideal platform to perform qualitative and quantitative assessment of intronic VUS, which can lead to reclassification if a significant impact on mRNA is observed. Genetic disorders of hematopoiesis and immunity represent fruitful areas to apply RNA-based analysis for variant interpretation given the high expression of RNA in blood.","variants":[{"Name":"NM_001625.4(AK2):c.330+5G>A","Chromosome":"1","Start":"33021588","Stop":"33021588","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":650655,"rule_based_match":true,"evidence_text":"NM_001625.4(AK2):c.330+5G>A","llm_judgment":"PRESENT","evidence":"c.330 + 5G > A","abstract_start":283,"abstract_end":297}]}
{"pmid":"30485715","title":"Autosomal dominant Marfan syndrome caused by a previously reported recessive FBN1 variant.","abstract":"BACKGROUND: Pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome but can also be found in patients presenting with apparently isolated features of Marfan syndrome. Moreover, several families with autosomal recessive Marfan syndrome caused by pathogenic variants in FBN1 have been described. The aim of this report was to underline the clinical variability that can be associated with the pathogenic variant c.1453C>T, p.(Arg485Cys) in FBN1.\nMETHODS: We provide the clinical details of two autosomal dominant families with this specific FBN1 variant, which was previously associated with autosomal recessive Marfan syndrome.\nRESULTS: Clinical data of 14 individuals carrying this variant from these two families were collected retrospectively. In both families, the diagnosis of autosomal dominant Marfan syndrome was established based on the characteristics of the variant and the phenotype which includes aortic aneurysms and dissections. Of interest, in one of the families, multiple relatives were diagnosed with early onset abdominal aortic aneurysms.\nCONCLUSION: In conclusion, FBN1 variant c.1453C>T, p.(Arg485Cys) is a pathogenic variant that can cause autosomal dominant Marfan syndrome characterized by a high degree of clinical variability and apparently isolated early onset familial abdominal aortic aneurysms.","variants":[{"Name":"NM_000138.5(FBN1):c.1453C>T (p.Arg485Cys)","Chromosome":"15","Start":"48515402","Stop":"48515402","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31505,"rule_based_match":true,"evidence_text":"c.1453C>T, p.(Arg485Cys)","llm_judgment":"PRESENT","evidence":"c.1453C>T, p.(Arg485Cys)","abstract_start":423,"abstract_end":447}]}
{"pmid":"35837780","title":"Aromatase deficiency caused by mutation of","abstract":"Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (<i>CYP19A1</i>), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. <i>CYP19A1</i> gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.","variants":[{"Name":"NM_000103.4(CYP19A1):c.1093C>T (p.Arg365Trp)","Chromosome":"15","Start":"51212490","Stop":"51212490","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2671024,"rule_based_match":true,"evidence_text":"c.1093C>T, p.R365W","llm_judgment":"PRESENT","evidence":"c.1093C>T, p.R365W","abstract_start":760,"abstract_end":778}]}
{"pmid":"12522556","title":"Mutations in the calcium-binding motifs of CDH23 and the 35delG mutation in GJB2 cause hearing loss in one family.","abstract":"We have ascertained a multi-generation family with apparent autosomal recessive non-syndromic childhood hearing loss (DFNB). Failure to demonstrate linkage in a genome-wide scan with 300 polymorphic markers has suggested genetic heterogeneity for the hearing loss in this family. This heterogeneity could be demonstrated by analysis of candidate loci and genes for DFNB. Patients in one branch of the family (branch C) are homozygous for the 35delG mutation in the GJB2 gene (DFNB1). Patients in two other branches (A and B) carry two new mutations in the cadherin 23 ( CDH23) gene (DFNB12). A homozygous CDH23 c.6442G-->A (D2148N) mutation is present in branch A. Patients in branch B are compound heterozygous for this mutation and the c.4021G-->A (D1341N) mutation. The substituted aspartic acid residues are highly conserved and are part of the calcium-binding sites of the extracellular cadherin (EC) domains. Molecular modeling of the mutated EC domains of CDH23 based on the structure of E-cadherin indicates that calcium-binding is impaired. In addition, other aspartic and glutamic acid residue substitutions in the highly conserved calcium-binding sites reported to cause DFNB12 are also likely to result in a decreased affinity for calcium. Since calcium provides rigidity to the elongated structure of cadherin molecules enabling homophilic lateral interaction, these mutations are likely to impair interactions of CDH23 molecules either with CDH23 or with other proteins. DFNB12 is the first human disorder that can be attributed to inherited missense mutations in the highly conserved residues of the extracellular calcium-binding domain of a cadherin.","variants":[{"Name":"NM_022124.6(CDH23):c.6442G>A (p.Asp2148Asn)","Chromosome":"10","Start":"71793370","Stop":"71793370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19961,"rule_based_match":false,"evidence_text":"A homozygous CDH23 c.6442G-->A (D2148N) mutation","llm_judgment":"PRESENT","evidence":"A homozygous CDH23 c.6442G-->A (D2148N) mutation","abstract_start":592,"abstract_end":640},{"Name":"NM_022124.6(CDH23):c.4021G>A (p.Asp1341Asn)","Chromosome":"10","Start":"71732292","Stop":"71732292","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19962,"rule_based_match":false,"evidence_text":"c.4021G-->A (D1341N)","llm_judgment":"PRESENT","evidence":"c.4021G-->A (D1341N)","abstract_start":738,"abstract_end":758}]}
{"pmid":"33897349","title":"","abstract":"<i>RYR2</i> encodes ryanodine receptor 2 protein (RYR-2) that is mainly located on endoplasmic reticulum membrane and regulates intracellular calcium concentration. The RYR-2 protein is ubiquitously distributed and highly expressed in the heart and brain. Previous studies have identified the <i>RYR2</i> mutations in the etiology of arrhythmogenic right ventricular dysplasia 2 and catecholaminergic polymorphic ventricular tachycardia. However, the relationship between <i>RYR2</i> gene and epilepsy is not determined. In this study, we screened for novel genetic variants in a group of 292 cases (families) with benign epilepsy of childhood with centrotemporal spikes (BECTS) by trio-based whole-exome sequencing. <i>RYR2</i> mutations were identified in five cases with BECTS, including one heterozygous frameshift mutation (c.14361dup/p.Arg4790Pro fs<sup>∗</sup>6), two heterozygous missense mutations (c.2353G > A/p.Asp785Asn and c.8574G > A/p.Met2858Ile), and two pairs of compound heterozygous mutations (c.4652A > G/p.Asn1551Ser and c.11693T > C/p.Ile3898Thr, c.7469T > C/p.Val2490Ala and c.12770G > A/p.Arg4257Gln, respectively). Asp785Asn was a <i>de novo</i> missense mutation. All the missense mutations were suggested to be damaging by at least three web-based prediction tools. These mutations do not present or at low minor allele frequency in gnomAD database and present statistically higher frequency in the cohort of BECTS than in the control populations of gnomAD. Asp785Asn, Asn1551Ser, and Ile3898Thr were predicted to affect hydrogen bonds with surrounding amino acids. Three affected individuals had arrhythmia (sinus arrhythmia and occasional atrial premature). The two probands with compound heterozygous missense mutations presented mild cardiac structural abnormalities. Strong evidence from ClinGen Clinical Validity Framework suggested an association between <i>RYR2</i> variants and epilepsy. This study suggests that <i>RYR2</i> gene is potentially a candidate pathogenic gene of BECTS. More attention should be paid to epilepsy patients with <i>RYR2</i> mutations, which were associated with arrhythmia and sudden unexpected death in previous reports.","variants":[{"Name":"NM_001035.3(RYR2):c.2353G>A (p.Asp785Asn)","Chromosome":"1","Start":"237500860","Stop":"237500860","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":906613,"rule_based_match":true,"evidence_text":"c.2353G > A/p.Asp785Asn","llm_judgment":"PRESENT","evidence":"c.2353G > A/p.Asp785Asn","abstract_start":908,"abstract_end":931},{"Name":"NM_001035.3(RYR2):c.12770G>A (p.Arg4257Gln)","Chromosome":"1","Start":"237784482","Stop":"237784482","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":907126,"rule_based_match":true,"evidence_text":"c.12770G > A/p.Arg4257Gln","llm_judgment":"PRESENT","evidence":"c.12770G > A/p.Arg4257Gln","abstract_start":1098,"abstract_end":1123}]}
{"pmid":"24829177","title":"X-linked sideroblastic anaemia due to ALAS₂ mutations in the Netherlands: a disease in disguise.","abstract":"BACKGROUND: X-linked sideroblastic anaemia (XLSA; OMIM#300751) is the most common inherited form of sideroblastic anaemia and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene (ALAS₂). This gene encodes for aminolevulinic acid synthase 2 (ALAS₂), the catalytic enzyme involved in the first en rate-limiting step of haem biosynthesis.1-3 The disorder is characterised by mostly mild hypochromic microcytic anaemia with bone marrow ring sideroblasts. Even untransfused patients with mild or no anaemia are at risk for severe systemic iron overload due to ineffective erythropoiesis. To date, 61 different ALAS₂ mutations have been reported in 120 families with XLSA. Descriptions of molecularly confirmed case series from the Netherlands, however, are lacking.\nMETHODS: We reviewed age of presentation, clinical and biochemical features, ALAS₋₂ defects and treatment characteristics of 15 Dutch patients from 11 unrelated families diagnosed with XLSA.\nRESULTS AND CONCLUSIONS: In one family a novel pathogenic c.1412G>A (p.Cys471Tyr) mutation was found. All other families shared the previously described c.1355G>A (p.Arg452His) mutation. Haplotype analysis in seven probands with the p.Arg452His mutation strongly suggests that six of them were ancestrally related. Nevertheless, their phenotype was very different. Our patients illustrate the phenotypical heterogeneity in the presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the diagnosis, follow-up and treatment of the disease. A timely diagnosis avoids unnecessary investigations and allows adequate treatment that can prevent systemic iron load with subsequent severe life-threatening complications. Therefore, we suggest considering XLSA in both male and female patients with unexplained iron overload and÷or (mild) microcytic anaemia, also at older age.","variants":[{"Name":"NM_000032.5(ALAS2):c.1355G>A (p.Arg452His)","Chromosome":"X","Start":"55014829","Stop":"55014829","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":212029,"rule_based_match":true,"evidence_text":"c.1355G>A (p.Arg452His)","llm_judgment":"PRESENT","evidence":"c.1355G>A (p.Arg452His)","abstract_start":1148,"abstract_end":1171}]}
{"pmid":"27247961","title":"Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy.","abstract":"BACKGROUND: Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium, photoreceptors, and choroid, which causes nyctalopia and progressive constriction of visual fields leading to blindness. The CHM gene encodes Rab escort protein 1 (REP-1). In this work, we reviewed the phenotypes and genotypes of affected males with the purpose of understanding the functional effects of CHM mutations and their relationship with the phenotypes.\nMETHODS: A retrospective review of 128 affected males was performed analyzing the onset of symptoms, visual acuity, and visual fields with respect to their mutations in the CHM gene.\nRESULTS: In rank order, reflecting data from this report, the most common mutations found in the CHM gene were nonsense mutations (41%), exon deletions (37%), and splice sites (14%) associated with a loss of functional protein. In the pool of 106 CHM mutations, we discovered four novel missense mutations (c.238C>T; p.L80F, c.819G>T; p.Q273H, c.1327A>G; p.M443V, and c.1370C>T; p.L457P) predicted to be severe changes affecting protein stability and folding with the effect similar to that of other types of mutations. No significant genotype-phenotype correlation was found with respect to the onset of nyctalopia, the onset of other visual symptoms, visual acuity, or width of visual fields.\nCONCLUSION: There is no evidence to support exclusion of CHM patients from clinical trials based on their genotypes or any potential genotype-phenotype correlations.","variants":[{"Name":"NM_000390.4(CHM):c.1327A>G (p.Met443Val)","Chromosome":"X","Start":"85901106","Stop":"85901106","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1878318,"rule_based_match":true,"evidence_text":"c.1327A>G; p.M443V","llm_judgment":"PRESENT","evidence":"c.1327A>G; p.M443V","abstract_start":985,"abstract_end":1003},{"Name":"NM_000390.4(CHM):c.819G>T (p.Gln273His)","Chromosome":"X","Start":"85958861","Stop":"85958861","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2901947,"rule_based_match":true,"evidence_text":"c.819G>T; p.Q273H","llm_judgment":"PRESENT","evidence":"c.819G>T; p.Q273H","abstract_start":966,"abstract_end":983}]}
{"pmid":"29661969","title":"Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy.","abstract":"BACKGROUND: Protein-losing enteropathy (PLE) is characterised by gastrointestinal protein leakage due to loss of mucosal integrity or lymphatic abnormalities. PLE can manifest as congenital diarrhoea and should be differentiated from other congenital diarrhoeal disorders. Primary PLEs are genetically heterogeneous and the underlying genetic defects are currently emerging.\nOBJECTIVES: We report an infant with fatal PLE for whom we aimed to uncover the underlying pathogenic mutation.\nMETHODS: We performed whole exome sequencing (WES) for the index patient. Variants were classified based on the American College of Medical Genetics and Genomics guidelines. WES results and our detailed clinical description of the patient were compared with the literature.\nRESULTS: We discovered a novel homozygous stop mutation (c.988C>T, p.Q330*) in the Plasmalemma Vesicle-Associated Protein (<i>PLVAP</i>) gene in a newborn with fatal PLE, facial dysmorphism, and renal, ocular and cardiac anomalies. The Q330* mutation is predicted to result in complete loss of PLVAP protein expression leading to deletion of the diaphragms of endothelial fenestrae, resulting in plasma protein extravasation and PLE. Recently, another single homozygous stop mutation in <i>PLVAP</i> causing lethal PLE in an infant was reported.\nCONCLUSIONS: Our findings validate <i>PLVAP</i> mutations as a cause of syndromic PLE. Prenatal anomalies, severe PLE and syndromic features may guide the diagnosis of this rare disease.","variants":[{"Name":"NM_031310.3(PLVAP):c.988C>T (p.Gln330Ter)","Chromosome":"19","Start":"17365477","Stop":"17365477","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":581266,"rule_based_match":true,"evidence_text":"c.988C>T, p.Q330*","llm_judgment":"PRESENT","evidence":"c.988C>T, p.Q330*","abstract_start":818,"abstract_end":835}]}
{"pmid":"32673564","title":"Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility.","abstract":"Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.","variants":[{"Name":"NM_001321739.2(M1AP):c.676dup (p.Trp226fs)","Chromosome":"2","Start":"74581766","Stop":"74581767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":794153,"rule_based_match":true,"evidence_text":"c.676dup (p.Trp226LeufsTer4)","llm_judgment":"PRESENT","evidence":"c.676dup (p.Trp226LeufsTer4)","abstract_start":415,"abstract_end":443},{"Name":"NM_001321739.2(M1AP):c.1166C>T (p.Pro389Leu)","Chromosome":"2","Start":"74562332","Stop":"74562332","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":794151,"rule_based_match":true,"evidence_text":"c.1166C>T (p.Pro389Leu)","llm_judgment":"PRESENT","evidence":"c.1166C>T (p.Pro389Leu)","abstract_start":883,"abstract_end":906}]}
{"pmid":"27245663","title":"Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.","abstract":"Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.","variants":[{"Name":"NM_054021.2(GPR101):c.924G>C (p.Glu308Asp)","Chromosome":"X","Start":"137030751","Stop":"137030751","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":178171,"rule_based_match":true,"evidence_text":"c.924G > C (p.E308D)","llm_judgment":"PRESENT","evidence":"c.924G > C (p.E308D)","abstract_start":222,"abstract_end":242}]}
{"pmid":"23835272","title":"Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.","abstract":"BACKGROUND: Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well as β-alanine. Existing reports describe a highly variable clinical and biochemical phenotype, which can make diagnosis a challenge. To date, only three reported cases have been confirmed at the molecular level, through identification of homozygous mutations in ALDH6A1, the gene encoding MMSDH. Confirmation by enzyme assay has until now not been possible, due to the extreme instability of the enzyme substrate.\nMETHODS AND RESULTS: We report a child with severe developmental delays, abnormal myelination on brain MRI, and transient/variable elevations in lactate, methylmalonic acid, 3-hydroxyisobutyric and 3-aminoisobutyric acids. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within exon 6 (c.514 T > C; p. Tyr172His) and exon 12 (c.1603C > T; p. Arg535Cys) of ALDH6A1. The resulting amino acid changes, both occurring in residues conserved among mammals, are predicted to be damaging at the protein level. Subsequent MMSDH enzyme assay demonstrated reduced activity in patient fibroblasts, measuring 2.5 standard deviations below the mean.\nCONCLUSIONS: We present the fourth reported case of MMSDH deficiency with confirmation at the molecular level, and expand on what is already an extremely variable clinical and biochemical phenotype. Furthermore, this is the first report to demonstrate a corresponding reduction in MMSDH enzyme activity. This report illustrates the emerging utilization of whole exome sequencing and variant data filtering using clinical data as an early tool in the diagnosis of rare and variable conditions.","variants":[{"Name":"NM_005589.4(ALDH6A1):c.514T>C (p.Tyr172His)","Chromosome":"14","Start":"74071411","Stop":"74071411","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":204352,"rule_based_match":true,"evidence_text":"c.514 T > C; p. Tyr172His","llm_judgment":"PRESENT","evidence":"c.514 T > C; p. Tyr172His","abstract_start":1022,"abstract_end":1047},{"Name":"NM_005589.4(ALDH6A1):c.1603C>T (p.Arg535Cys)","Chromosome":"14","Start":"74060647","Stop":"74060647","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":204351,"rule_based_match":true,"evidence_text":"c.1603C > T; p. Arg535Cys","llm_judgment":"PRESENT","evidence":"c.1603C > T; p. Arg535Cys","abstract_start":1062,"abstract_end":1087}]}
{"pmid":"32341820","title":"Term Neonate Presenting with the Combined Occurrence of Mucolipidosis Type II and Leigh Syndrome.","abstract":"Mucolipidosis II α/beta (MLII) is an autosomal recessive disease in which a gene mutation leads to improper targeting of lysosomal enzymes with an end result of accumulation of lysosomes in the mitochondria resulting in a dysfunctional mitochondria. 1 Leigh syndrome (LS) is a rare progressive neurodegenerative disorder associated with dysfunctional mitochondria and oxidative phosphorylation. 4 Both disease processes typically present in infancy. 3 7 Herein, we present a case of an infant diagnosed with both mucolipidosis II and Leigh syndrome. Genetic analysis in this case revealed two mutations (NDUFA12 c.178C > T p.Arg60* and GNPTAB c.732_733delAA) on the long arm of chromosome 12 as the etiology of MLII and LS in this neonate, respectively. We are unaware of any previously published cases of the presence of these two diseases occurring in the same patient. The complex clinical presentation of this case led to a delay in the diagnosis, and we believe that the clinical phenotypes of these two conditions were likely worsened. The genetic alterations presented in this case occurred as a result of mutations on chromosome 12. We suggest further investigation into the potential overlap in the pathophysiology, specifically the inheritance pattern, linkage disequilibrium, mitochondrial-lysosomal interaction, or crosstalk contributing to both diseases.","variants":[{"Name":"NM_018838.5(NDUFA12):c.178C>T (p.Arg60Ter)","Chromosome":"12","Start":"94994249","Stop":"94994249","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40164,"rule_based_match":true,"evidence_text":"NDUFA12 c.178C > T p.Arg60*","llm_judgment":"PRESENT","evidence":"NDUFA12 c.178C > T p.Arg60*","abstract_start":604,"abstract_end":631}]}
{"pmid":"21107874","title":"A novel mutation in KIF5A gene causing hereditary spastic paraplegia with axonal neuropathy.","abstract":"Hereditary spastic paraplegias (HSPs) include a group of neurodegenerative diseases, and so far 46 SPG loci have been mapped and 17 genes isolated. Among the autosomal dominant HSPs (AD-HSPs), SPG10 is a rare form due to mutations in KIF5A gene (locus 12q13.3). We describe the clinical, neurophysiological, morphological and genetic study of an Italian family with AD-HSP. The proband presented with an adult onset spastic paraparesis and diffuse paresthesias where neurophysiological and nerve biopsy morphological studies revealed an axonal neuropathy. Molecular genetic analysis identified a new missense mutation (c.608C>G) of KIF5A gene resulting in a serine to cysteine substitution, S203C, located in a highly conserved domain of the protein. This pedigree confirms the occurrence of an axonal peripheral neuropathy in SPG10.","variants":[{"Name":"NM_004984.4(KIF5A):c.608C>G (p.Ser203Cys)","Chromosome":"12","Start":"57567512","Stop":"57567512","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3853536,"rule_based_match":true,"evidence_text":"c.608C>G","llm_judgment":"PRESENT","evidence":"c.608C>G","abstract_start":619,"abstract_end":627}]}
{"pmid":"35886928","title":"Retinal Ciliopathy in the Patient with Transplanted Kidney: Case Report.","abstract":"A review of a rare case of a proven mutation in the RP1 gene (RP1c.2029C>T, p. (ARG677*) in a kidney transplant patient was presented herein. According to his medical history, he had tonsillectomy performed at the age of 20 due to erythrocyturia, and at the age of 32 he was treated for malignant hypertension. The patient had been diagnosed with chronic renal failure at age 56 years. During an eye examination in 2016, retinitis pigmentosa was suspected and the patient was advised to run further tests. After an ophthalmological examination and tests, genetic testing was performed and a mutation in the RP1 gene encoding a family of proteins which are components of microtubules in photoreceptor primary cilia was proven. The literature search found that mutations in the RP1 gene have so far been exclusively associated with a non-syndromic form of retinal degeneration. However, the RP1 protein is expressed in the kidneys, and it remains unclear why the mutation of this gene so far was only specifically related to retinal photoreceptor function and not to arterial hypertension and renal disease. Primary cilia are thought to act as potential mechanosensory fluid-flow receptors in the vascular endothelium and kidney and their dysfunction results in atherosclerotic changes, hypertension, and chronic renal failure.","variants":[{"Name":"NM_006269.2(RP1):c.2029C>T (p.Arg677Ter)","Chromosome":"8","Start":"54625911","Stop":"54625911","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21004,"rule_based_match":true,"evidence_text":"RP1c.2029C>T, p. (ARG677*)","llm_judgment":"PRESENT","evidence":"RP1c.2029C>T, p. (ARG677*)","abstract_start":62,"abstract_end":88}]}
{"pmid":"27391102","title":"Identification of Novel and Recurrent Disease-Causing Mutations in Retinal Dystrophies Using Whole Exome Sequencing (WES): Benefits and Limitations.","abstract":"Inherited retinal dystrophies (IRDs) are Mendelian diseases with tremendous genetic and phenotypic heterogeneity. Identification of the underlying genetic basis of these dystrophies is therefore challenging. In this study we employed whole exome sequencing (WES) in 11 families with IRDs and identified disease-causing variants in 8 of them. Sequence analysis of about 250 IRD-associated genes revealed 3 previously reported disease-associated variants in RHO, BEST1 and RP1. We further identified 5 novel pathogenic variants in RPGRIP1 (p.Ser964Profs*37), PRPF8 (p.Tyr2334Leufs*51), CDHR1 (p.Pro133Arg and c.439-17G>A) and PRPF31 (p.Glu183_Met193dup). In addition to confirming the power of WES in genetic diagnosis of IRDs, we document challenges in data analysis and show cases where the underlying genetic causes of IRDs were missed by WES and required additional techniques. For example, the mutation c.439-17G>A in CDHR1 would be rated unlikely applying the standard WES analysis. Only transcript analysis in patient fibroblasts confirmed the pathogenic nature of this variant that affected splicing of CDHR1 by activating a cryptic splice-acceptor site. In another example, a 33-base pair duplication in PRPF31 missed by WES could be identified only via targeted analysis by Sanger sequencing. We discuss the advantages and challenges of using WES to identify mutations in heterogeneous diseases like IRDs.","variants":[{"Name":"NM_033100.4(CDHR1):c.439-17G>A","Chromosome":"10","Start":"84200584","Stop":"84200584","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1464073,"rule_based_match":true,"evidence_text":"c.439-17G>A","llm_judgment":"PRESENT","evidence":"c.439-17G>A","abstract_start":607,"abstract_end":618}]}
{"pmid":"19656164","title":"Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation.","abstract":"The BRCA1 and BRCA2 genes are the strongest susceptibility genes identified for breast cancer worldwide. However, BRCA1/BRCA2 have been incompletely investigated due to their large size and the genomic rearrangements that occasionally occur within them. Here we performed a comprehensive mutational analysis for BRCA1/BRCA2 in 206 Korean patients with breast cancer. We analyzed all exons and flanking regions of BRCA1/BRCA2 by direct sequencing and screened deletions or duplications involving BRCA1/BRCA2 by multiplex ligation-dependent probe amplification. We reconstructed haplotypes using intragenic single nucleotide polymorphisms (SNPs) to investigate the possibility of a founder effect among recurrent mutations. In our series, 38 patients (18.4%) had one or more BRCA1/BRCA2 mutations including 10 novel ones. Three additional patients carried novel distinct unclassified variants with potentially harmful effects. No large deletions or duplications involving BRCA1/BRCA2 were identified in our series. Haplotype analyses and allele separation suggested that the most frequent mutation in Koreans, BRCA2:c.7480C>T, might have originated from a common ancestor. BRCA1/BRCA2 mutations were more frequent in a group with family history, bilateral cancer or multiple site cancer than in a group without the risk factors described or an unknown risk group. In contrast, mutation frequencies in the early-onset cancer group were not higher than in the unknown risk group. Our results will be helpful to understand the mutation spectrum in BRCA1/BRCA2 genes and establish a genetic screening strategy. In addition, this study suggests the possibility of the first true founder mutation of BRCA1/BRCA2 identified in the Korean population.","variants":[{"Name":"NM_000059.4(BRCA2):c.7480C>T (p.Arg2494Ter)","Chromosome":"13","Start":"32356472","Stop":"32356472","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46655,"rule_based_match":true,"evidence_text":"BRCA2:c.7480C>T","llm_judgment":"PRESENT","evidence":"BRCA2:c.7480C>T","abstract_start":1108,"abstract_end":1123}]}
{"pmid":"35464534","title":"Transient Cytopenias as a Rare Presentation of Classic Galactosemia.","abstract":"Although galactosemia can be detected through neonatal screening, some cases are characterized by rapid and severe presentation before screening results become available. We report the case of a neonate with classic galactosemia presenting with acute liver failure and cytopenias (thrombocytopenia, anemia, and neutropenia). Neonatal screening results showed increased galactose and phenylalanine levels. The diagnosis of galactosemia was confirmed by the measurement of galactose-1-phosphate uridyltransferase (GALT) activity in erythrocytes. Two mutations of the <i>GALT</i> gene (c.563 A>G [p. Q188R] and c.957C>A [p.H319Q]) were revealed. High clinical suspicion of galactosemia is crucial to identify, as early as possible, cases with classical or even unusual presentation, and to initiate early treatment that could change the disease course and improve outcomes. Cytopenias should be included in the broad phenotypic spectrum of galactosemia.","variants":[{"Name":"NM_000155.4(GALT):c.957C>A (p.His319Gln)","Chromosome":"9","Start":"34649462","Stop":"34649462","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":18656,"rule_based_match":true,"evidence_text":"c.957C>A (p.H319Q)","llm_judgment":"PRESENT","evidence":"c.957C>A","abstract_start":608,"abstract_end":616}]}
{"pmid":"27882743","title":"Congenital nephrotic syndrome with a novel NPHS1 mutation.","abstract":"Congenital nephrotic syndrome of the Finnish type (CNF) is a rare autosomal recessive disorder. The incidence of CNF is relatively high in Finland but considerably lower in other countries. We encountered a male newborn with CNF, associated with compound heterozygous mutations in nephrosis 1, congenital, Finnish type (NPHS1). The patient was admitted to hospital as a preterm infant. Physical and laboratory findings fulfilled the diagnostic criteria of nephrotic syndrome, and were compatible with a diagnosis of CNF, but there was no family history of the disease. On genetic analysis of NPHS1 a paternally derived heterozygous frame-shift mutation caused by an 8 bp deletion, resulting in a stop codon in exon 16 (c.2156-2163 delTGCACTGC causing p.L719DfsX4), and a novel, maternally derived nonsense mutation in exon 15 (c.1978G>T causing p.E660X) were identified. Early genetic diagnosis of CNF is important for proper clinical management and appropriate genetic counseling.","variants":[{"Name":"NM_004646.4(NPHS1):c.2156_2163del (p.Leu719fs)","Chromosome":"19","Start":"35844152","Stop":"35844159","ReferenceAlleleVCF":"GGCAGTGCA","AlternateAlleleVCF":"G","allel_id":71102,"rule_based_match":false,"evidence_text":"c.2156-2163 delTGCACTGC causing p.L719DfsX4","llm_judgment":"PRESENT","evidence":"c.2156-2163 delTGCACTGC causing p.L719DfsX4","abstract_start":719,"abstract_end":762}]}
{"pmid":"26329992","title":"Cancer predisposing BARD1 mutations affect exon skipping and are associated with overexpression of specific BARD1 isoforms.","abstract":"BARD1 is the main binding partner of BRCA1 and is required for its stability and tumor-suppressor functions. In breast cancer and other epithelial cell carcinomas, alternatively spliced isoforms of BARD1 are highly upregulated and correlated with poor outcome. Recent data indicate that germline mutations of BARD1 may predispose to breast and/or ovarian cancer. To evaluate the role of BARD1 germline mutations in predisposition to ovarian cancer we scanned a cohort of 255 patients for the presence of previously reported mutations located in exons 5, 8 and 10 using high-resolution melting analysis. Within this group we identified single-patients carrying mutation in exon 8 (c.1690C>T, p.Gln564Ter), two different variants in exon 10 (c.1972C>T, p.Arg658Tyr; c.1977A>G, p.=) and a carrier of novel missense mutation located in exon 5 (c.1361C>T, p.Pro454Leu). Three out of four identified mutations alter exonic splicing enhancing motives and result in expression of incorrect splicing skipping of exons 5, 8, and 2-9, respectively. Our data indicate that BARD1 variants may predispose to ovarian cancer in limited number of patients although based on actual data it is difficult to estimate its actual penetrance.","variants":[{"Name":"NM_000465.4(BARD1):c.1977A>G (p.Arg659=)","Chromosome":"2","Start":"214730435","Stop":"214730435","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":133184,"rule_based_match":true,"evidence_text":"c.1977A>G (p.=)","llm_judgment":"PRESENT","evidence":"c.1977A>G","abstract_start":764,"abstract_end":773},{"Name":"NM_000465.4(BARD1):c.1690C>T (p.Gln564Ter)","Chromosome":"2","Start":"214745842","Stop":"214745842","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133177,"rule_based_match":true,"evidence_text":"c.1690C>T, p.Gln564Ter","llm_judgment":"PRESENT","evidence":"c.1690C>T, p.Gln564Ter","abstract_start":680,"abstract_end":702},{"Name":"NM_000465.4(BARD1):c.1361C>T (p.Pro454Leu)","Chromosome":"2","Start":"214769266","Stop":"214769266","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":232368,"rule_based_match":true,"evidence_text":"c.1361C>T (p.Pro454Leu)","llm_judgment":"PRESENT","evidence":"p.Pro454Leu","abstract_start":851,"abstract_end":862}]}
{"pmid":"36042462","title":"Biallelic variants in CHST3 cause Spondyloepiphyseal dysplasia with joint dislocations in three Pakistani kindreds.","abstract":"BACKGROUND: Skeletal dysplasia is a heterogeneous group of disorders. Spondyloepiphyseal dysplasias comprise one subgroup. Deficiency of carbohydrate sulfotransferase 3 has been reported in a small number of patients with recessively inherited spondyloepiphyseal dysplasia with joint dislocation, short stature and scoliosis. We report here molecular and clinical findings of affected individuals in three consanguineous Pakistani families. Affected individuals in all three families had a uniform phenotype including severe short stature, multiple dislocated joints, progressive scoliosis and facial dysmorphism.\nMETHODS: Clinical evaluation was done for three unrelated families. Radiological survey of bones was completed for patients from two of the families. Whole exome sequencing index patients from each family was performed followed by Sanger sequencing for validation of segregation of identified variants in respective families. In-silico analysis for determining pathogenicity of identified variants and conservation was done.\nRESULTS: Whole-exome sequencing revealed biallelic variants c.590 T > C;p.(Leu197Pro), c.603C > A;p.(Tyr201Ter) and c.661C > T;p.(Arg221Cys) in CHST3 (NM_004273.5) in the three families with eight, five and two affected individuals, respectively. Contrary to previous reports, affected individuals in none of the families exhibited a hearing loss.\nCONCLUSION: We describe genotypic and phenotypic findings of three unrelated families with spondyloepiphyseal dysplasia. Our study confirms phenotypic variability and adds to the genotypic spectrum of spondyloepiphyseal dysplasia.","variants":[{"Name":"NM_004273.5(CHST3):c.661C>T (p.Arg221Cys)","Chromosome":"10","Start":"72007692","Stop":"72007692","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1877897,"rule_based_match":true,"evidence_text":"c.661C>T (p.Arg221Cys)","llm_judgment":"PRESENT","evidence":"c.661C > T","abstract_start":1155,"abstract_end":1165}]}
{"pmid":"33910932","title":"","abstract":"BACKGROUND: Inherited retinal diseases (IRDs) can be caused by variants in >270 genes. The Bardet-Biedl syndrome 1 (<i>BBS1</i>) gene is one of these genes and may be associated with syndromic and non-syndromic autosomal recessive retinitis pigmentosa (RP). Here, we identified a branchpoint variant in <i>BBS1</i> and assessed its pathogenicity by in vitro functional analysis.\nMETHODS: Whole genome sequencing was performed for three unrelated monoallelic <i>BBS1</i> cases with non-syndromic RP. A fourth case received MGCM 105 gene panel analysis. Functional analysis using a midigene splice assay was performed for the putative pathogenic branchpoint variant in <i>BBS1</i>. After confirmation of its pathogenicity, patients were clinically re-evaluated, including assessment of non-ocular features of Bardet-Biedl syndrome.\nRESULTS: Clinical assessments of probands showed that all individuals displayed non-syndromic RP with macular involvement. Through detailed variant analysis and prioritisation, two pathogenic variants in <i>BBS1</i>, the most common missense variant, c.1169T>G (p.(Met390Arg)), and a branchpoint variant, c.592-21A>T, were identified. Segregation analysis confirmed that in all families, probands were compound heterozygous for c.1169T>G and c.592-21A>T. Functional analysis of the branchpoint variant revealed a complex splicing defect including exon 8 and exon 7/8 skipping, and partial in-frame deletion of exon 8.\nCONCLUSION: A putative severe branchpoint variant in <i>BBS1</i>, together with a mild missense variant, underlies non-syndromic RP in four unrelated individuals. To our knowledge, this is the first report of a pathogenic branchpoint variant in IRDs that results in a complex splice defect. In addition, this research highlights the importance of the analysis of non-coding regions in order to provide a conclusive molecular diagnosis.","variants":[{"Name":"NM_024649.5(BBS1):c.1169T>G (p.Met390Arg)","Chromosome":"11","Start":"66526181","Stop":"66526181","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":27182,"rule_based_match":true,"evidence_text":"c.1169T>G (p.(Met390Arg))","llm_judgment":"PRESENT","evidence":"c.1169T>G (p.(Met390Arg))","abstract_start":1081,"abstract_end":1106}]}
{"pmid":"28571903","title":"Next generation sequencing in the diagnosis of Stargardt's disease.","abstract":"INTRODUCTION: Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease.\nPATIENTS AND METHODS: A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes.\nRESULTS: Clinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2.\nCONCLUSIONS: NGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations.","variants":[{"Name":"NM_000350.3(ABCA4):c.3056C>T (p.Thr1019Met)","Chromosome":"1","Start":"94043470","Stop":"94043470","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":273547,"rule_based_match":false,"evidence_text":"c.C3056T:p.T1019M","llm_judgment":"PRESENT","evidence":"c.C3056T:p.T1019M","abstract_start":765,"abstract_end":782}]}
{"pmid":"19365571","title":"Macular corneal dystrophy in a Chinese family related with novel mutations of CHST6.","abstract":"PURPOSE: To identify mutations in the carbohydrate sulfotransferase gene (CHST6) for a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes in the affected cornea.\nMETHODS: A corneal button of the proband was obtained by penetrating keratoplasty. The half button and ultrathin sections from the other half button were examined with special stains under a light microscope (LM) and an electron microscope (EM) separately. Genomic DNA was extracted from peripheral blood of 11 family members, and the coding region of CHST6 was amplified by the polymerase chain reaction (PCR) method. The PCR products were analyzed by direct sequencing and restriction enzyme digestion.\nRESULTS: The positive reaction to colloidal iron stain (extracellular blue accumulations in the stroma) was detected under light microscopy. Transmission electron microscopy revealed the enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. The compound heterozygous mutations, c.892C>T and c.1072T>C, were identified in exon 3 of CHST6 in three patients. The two transversions resulted in the substitution of a stop codon for glutamine at codon 298 (p.Q298X) and a missense mutation at codon 358, tyrosine to histidine (p.Y358H). The six unaffected family individuals carried alternative heterozygous mutations. These two mutations were not detected in any of the 100 control subjects.\nCONCLUSIONS: Those novel compound heterozygous mutations were thought to contribute to the loss of CHST6 function, which induced the abnormal metabolism of keratan sulfate (KS) that deposited in the corneal stroma. It could be proved by the observation of a positive stain reaction and the enlarged collagen fibers as well as hyperplastic fibroblasts under microscopes.","variants":[{"Name":"NM_021615.5(CHST6):c.892C>T (p.Gln298Ter)","Chromosome":"16","Start":"75478937","Stop":"75478937","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":344037,"rule_based_match":true,"evidence_text":"c.892C>T","llm_judgment":"PRESENT","evidence":"c.892C>T","abstract_start":1032,"abstract_end":1040}]}
{"pmid":"23835273","title":"Mutational analyses on X-linked adrenoleukodystrophy reveal a novel cryptic splicing and three missense mutations in the ABCD1 gene.","abstract":"BACKGROUND: X-linked adrenoleukodystrophy is caused by a defective peroxisomal membrane transporter, ABCD1, responsible for transporting very-long-chain fatty acid substrate into peroxisomes for degradation. The main biochemical defect, which is also one of the major diagnostic hallmarks, of X-linked adrenoleukodystrophy is the accumulation of saturated very-long-chain fatty acids in all tissues and body fluids.\nMETHODS: Direct and reverse-transcribed polymerase chain reactions followed by DNA sequencing-based mutational analyses were performed on one Taiwanese and three Malaysian X-linked adrenoleukodystrophy families.\nRESULTS: A novel splicing donor site mutation (c.1272+1g>a) was identified in a Taiwanese X-linked adrenoleukodystrophy patient, resulting in a deletion of 121 bp and a premature stop codon (p.Val425fs*92) in messenger-RNA transcript. This deletion is caused by the activation of a cryptic splicing donor site in exon 4 of the ABCD1 gene, which is consistent with the prediction by several online algorithms. In addition, three previously described missense mutations (c.965T>C, c.1978C>T, and c.2006A>G), leading to aberrant ABCD1 of p.Leu322Pro, p.Arg660Trp, and p.His669Arg, were also identified in Malaysian probands.\nCONCLUSIONS: This is the first report to unveil unequivocally that cryptic splicing-induced aberrant messenger-RNA carrying an internal frameshift deletion results from an intronic mutation in the ABCD1 gene. Furthermore, a polymorphism in intron 9 (c.1992-32c/t; refSNP: rs4898368) of the ABCD1 gene was commonly observed in both Taiwanese and Malaysian populations.","variants":[{"Name":"NM_000033.4(ABCD1):c.1978C>T (p.Arg660Trp)","Chromosome":"X","Start":"153743333","Stop":"153743333","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":576358,"rule_based_match":true,"evidence_text":"c.1978C>T","llm_judgment":"PRESENT","evidence":"c.1978C>T","abstract_start":1107,"abstract_end":1116},{"Name":"NM_000033.4(ABCD1):c.965T>C (p.Leu322Pro)","Chromosome":"X","Start":"153729296","Stop":"153729296","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1065203,"rule_based_match":true,"evidence_text":"c.965T>C","llm_judgment":"PRESENT","evidence":"c.965T>C","abstract_start":1097,"abstract_end":1105},{"Name":"NM_000033.4(ABCD1):c.2006A>G (p.His669Arg)","Chromosome":"X","Start":"153743503","Stop":"153743503","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":939476,"rule_based_match":true,"evidence_text":"c.2006A>G","llm_judgment":"PRESENT","evidence":"c.2006A>G","abstract_start":1122,"abstract_end":1131}]}
{"pmid":"37718511","title":"BRCA1 frameshift variants leading to extended incorrect protein C termini.","abstract":"Carriers of BRCA1 germline pathogenic variants are at substantially higher risk of developing breast and ovarian cancer than the general population. Accurate identification of at-risk individuals is crucial for risk stratification and the implementation of targeted preventive and therapeutic interventions. Despite significant progress in variant classification efforts, a sizable portion of reported BRCA1 variants remain as variants of uncertain clinical significance (VUSs). Variants leading to premature protein termination and loss of essential functional domains are typically classified as pathogenic. However, the impact of frameshift variants that result in an extended incorrect terminus is not clear. Using validated functional assays, we conducted a systematic functional assessment of 17 previously reported BRCA1 extended incorrect terminus variants (EITs) and concluded that 16 constitute loss-of-function variants. This suggests that most EITs are likely to be pathogenic. However, one variant, c.5578dup, displayed a protein expression level, affinity to known binding partners, and activity in transcription and homologous recombination assays comparable to the wild-type BRCA1 protein. Twenty-three additional carriers of c.5578dup were identified at a US clinical diagnostic lab and assessed using a family history likelihood model providing, in combination with the functional data, a likely benign interpretation. These results, consistent with family history data in the current study and available data from ClinVar, indicate that most, but not all, BRCA1 variants leading to an extended incorrect terminus constitute loss-of-function variants and underscore the need for comprehensive assessment of individual variants.","variants":[{"Name":"NM_007294.4(BRCA1):c.5578dup (p.His1860fs)","Chromosome":"17","Start":"43045691","Stop":"43045692","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":46239,"rule_based_match":true,"evidence_text":"c.5578dup","llm_judgment":"PRESENT","evidence":"c.5578dup","abstract_start":1012,"abstract_end":1021}]}
{"pmid":"28196530","title":"R248G cystic fibrosis transmembrane conductance regulator mutation in three siblings presenting with recurrent acute pancreatitis and reproductive issues: a case series.","abstract":"BACKGROUND: Mutational combinations of the cystic fibrosis transmembrane conductance regulator, CFTR, gene have different phenotypic manifestations at the molecular level with varying clinical consequences for individuals possessing such mutations. Reporting cystic fibrosis transmembrane conductance regulator mutations is important in understanding the genotype-phenotype correlations and associated clinical presentations in patients with cystic fibrosis. Understanding the effects of mutations is critical in developing appropriate treatments for individuals affected with cystic fibrosis, non-classic cystic fibrosis, or cystic fibrosis transmembrane conductance regulator-related disorders. This is the first report of related individuals possessing the R248G missense cystic fibrosis transmembrane conductance regulator mutation and we present their associated clinical histories.\nCASE PRESENTATION: All three patients are of Spanish descent. Deoxyribonucleic acid analysis revealed that all three siblings possessed a novel c.742A>G mutation, resulting in a p.Arg248Gly (R248G) amino acid change in exon 6 in trans with the known N1303K mutant allele. Case 1 patient is a 39-year-old infertile man presenting with congenital unilateral absence of the vas deferens and recurrent episodes of epigastric pain. Case 2 patient is a 32-year-old woman presenting with periods of infertility, two previous spontaneous abortions, recurrent epigastric pain, and recurrent pancreatitis. Case 3 patient is a 29-year-old woman presenting with recurrent pancreatitis and epigastric pain.\nCONCLUSIONS: We report the genotype-phenotype correlations and clinical manifestations of a novel R248G cystic fibrosis transmembrane conductance regulator mutation: congenital unilateral absence of the vas deferens in males, reduced female fertility, and recurrent acute pancreatitis. In addition, we discuss the possible functional consequences of the mutations at the molecular level.","variants":[{"Name":"NM_000492.4(CFTR):c.742A>G (p.Arg248Gly)","Chromosome":"7","Start":"117535410","Stop":"117535410","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":544482,"rule_based_match":true,"evidence_text":"c.742A>G","llm_judgment":"PRESENT","evidence":"c.742A>G","abstract_start":1032,"abstract_end":1040}]}
{"pmid":"26205983","title":"One mutation, two phenotypes: a single nonsense mutation of the CTSC gene causes two clinically distinct phenotypes.","abstract":"BACKGROUND: Papillon-Lefévre syndrome (PLS; OMIM 245000) and Haim-Munk syndromes (HMS; OMIM 245010) are phenotypic variants of the same rare disease caused by mutations of the cathepsin C (CTSC) gene, and they exhibit autosomal recessive inheritance.\nAIMS: To identify diseases caused by mutations of the CTSC gene in two Hungarian patients and to perform haplotype analysis to elucidate any familial relationship between them.\nMETHODS: Mutation screening and polymorphism analysis were performed by direct sequencing of the CTSC gene.\nRESULTS: Mutation screening of the CTSC gene from the two patients revealed the presence of the same homozygous nonsense mutation (c.748C/T; p.Arg250X). However, one patient exhibited the PLS phenotype and the other the HMS phenotype. Although these patients were not aware that they were related, haplotype analysis, especially the genotypes of the rs217116 and the rs217115 polymorphisms, clearly indicated that the patients carry the same haplotype, whereas the unrelated healthy controls carried several different haplotypes.\nCONCLUSIONS: Our results demonstrate that PLS and HMS are phenotypic variants of the same disease and, additionally, exclude the presence of a putative genetic modifier factor within the CTSC gene that is responsible for the development of the two phenotypes. We suggest that this putative genetic modifier factor is located outside the CTSC gene, or alternatively, that the development of the different phenotypes is the consequence of different environmental or lifestyle factors.","variants":[{"Name":"NM_001814.6(CTSC):c.748C>T (p.Arg250Ter)","Chromosome":"11","Start":"88300539","Stop":"88300539","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1932154,"rule_based_match":false,"evidence_text":"c.748C/T; p.Arg250X","llm_judgment":"PRESENT","evidence":"c.748C/T; p.Arg250X","abstract_start":667,"abstract_end":686}]}
{"pmid":"21741241","title":"Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes.","abstract":"Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms.","variants":[{"Name":"NM_181882.3(PRX):c.1090C>T (p.Arg364Ter)","Chromosome":"19","Start":"40397262","Stop":"40397262","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625428,"rule_based_match":true,"evidence_text":"c.1090C>T (p.Arg364X)","llm_judgment":"PRESENT","evidence":"c.1090C>T (p.Arg364X)","abstract_start":397,"abstract_end":418}]}
{"pmid":"33208384","title":"A complex DICER1 syndrome phenotype associated with a germline pathogenic variant affecting the RNase IIIa domain of DICER1.","abstract":"BACKGROUND: Germline pathogenic variants in <i>DICER1</i> cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (<i>G</i>lobal developmental delay, <i>L</i>ung cysts, <i>O</i>vergrowth, <i>W</i>ilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.\nMETHODS: Whole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with <i>DICER1</i> RNase III domain mutations were performed.\nRESULTS: A de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of <i>DICER1</i> was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome.\nCONCLUSION: The phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to <i>DICER1</i> hotspot mutations in the RNase IIIb domain. We show that an individual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome ('DICER1 syndrome plus'), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.","variants":[{"Name":"NM_177438.3(DICER1):c.4031C>T (p.Ser1344Leu)","Chromosome":"14","Start":"95103365","Stop":"95103365","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":921334,"rule_based_match":true,"evidence_text":"c.4031C>T (p.S1344L)","llm_judgment":"PRESENT","evidence":"c.4031C>T (p.S1344L)","abstract_start":704,"abstract_end":724}]}
{"pmid":"26392295","title":"Identification of a Novel Mutation in the Titin Gene in a Chinese Family with Limb-Girdle Muscular Dystrophy 2J.","abstract":"Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of genetic myopathies characterized by progressive proximal pelvic and/or shoulder girdle muscle weakness, with the onset ages ranging from early childhood to late adulthood. The identification of these dystrophies through genetic testing will not only inform long-term prognosis but will also assist in directing care more efficiently, including more frequent cardiorespiratory monitoring and prophylactic treatments. The aim of this study was to identify the responsible gene in a five-generation Chinese Han pedigree with autosomal recessive LGMD. Exome sequencing was conducted and a novel mutation c.107788T>C (p.W35930R) in the titin gene (TTN) was identified. The mutation co-segregated with the disorder in the family and was absent in normal controls. Our discovery broadens the mutation spectrum of the TTN gene associated with LGMD2J.","variants":[{"Name":"NM_001267550.2(TTN):c.107788T>C (p.Trp35930Arg)","Chromosome":"2","Start":"178527200","Stop":"178527200","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":490511,"rule_based_match":true,"evidence_text":"c.107788T>C (p.W35930R)","llm_judgment":"PRESENT","evidence":"c.107788T>C (p.W35930R)","abstract_start":676,"abstract_end":699}]}
{"pmid":"34374940","title":"Novel phenotype and genotype spectrum of NARS2 and literature review of previous mutations.","abstract":"BACKGROUND: Mutations in NARS2 (MIM: 612803) are associated with combined oxidative phosphorylation deficiency 24 (COXPD24; MIM: 616239) that is a rare mitochondrial and a multisystem autosomal recessive disorder.\nAIMS: We aimed to detect the underlying genetic factors in two siblings with progressive ataxia, epilepsy, and severe-to-profound hearing impairment.\nMETHODS: After doing medical assessments and pertinent tests (i.e., auditory brainstem responses, pure tone otoacoustic emission test, cardiac examinations, computed tomography, and electroencephalogram), because of the clinical and probable genetic heterogeneity, whole-exome sequencing was performed, and co-segregation analysis was confirmed by Sanger sequencing. Biological impacts of the novel variant were evaluated using sequence-to-function bioinformatics tools.\nRESULTS: A novel homozygous missense variant, NM_024678.6:c.545 T > A; p.(Ile182Lys), in exon 5 of NARS2 was identified in both patients and verified by Sanger sequencing. In silico analyses introduced this variant as pathogenic. Mitral valve prolapses with mild regurgitation, brachymetatarsia, severe hallux valgus, and clubbed fingers were reported as novel manifestations in association with NARS2 gene. By doing a literature review, we also underscored the high heterogeneity of disease phenotype.\nCONCLUSIONS: Herein, we report some novel phenotype and genotype features of two female patients in an Iranian consanguineous family with COXPD24, caused by a variant in NARS2-NM_024678.6: c.545 T > A; p.(Ile182Lys). Moreover, our data expanded the phenotype and genotype spectrum of NARS2-related disorder and confirmed an unpredictable nature of genotype-phenotype correlation in COXPD24.","variants":[{"Name":"NM_024678.6(NARS2):c.545T>A (p.Ile182Lys)","Chromosome":"11","Start":"78559588","Stop":"78559588","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":861035,"rule_based_match":true,"evidence_text":"NM_024678.6:c.545 T > A; p.(Ile182Lys)","llm_judgment":"PRESENT","evidence":"NM_024678.6:c.545 T > A; p.(Ile182Lys)","abstract_start":881,"abstract_end":919}]}
{"pmid":"31813138","title":"Analysis of P gene variations among fourteen patients with oculocutaneous albinism type II","abstract":"OBJECTIVE: To analyze variations of TYR and P genes among 14 patients with clinically diagnosed oculocutaneous albinism.\nMETHODS: Potential variations of the TYR and P genes were detected by Sanger sequencing. Novel variations were predicted with bioinformatics software including SIFT and PolyPhen-2.\nRESULTS: No variation was found in the TYR gene, while 9 types of variations were found in the P gene among the 14 patients, which included c.803-3C>G (7/26), c.1327G>A (p.Val443Ile) (5/26), c.632C>T (p.Pro211Leu) (4/26), c.1832T>C (p.Leu611Pro) (3/26), c.1349C>A (p.Thr450Lys) (2/26), c.2363C>T (p.Ser788Leu) (2/26), c.2228C>T (p.Pro743Leu) (1/26), c.1525A>G (p.Thr509Ala) (1/26), and c.1349C>T (p.Thr450Met) (1/26). Only 1 heterozygous variation was detected in 2 families. c.2363C>T (p.Ser788Leu), c.1832T>C (p.Leu611Pro) and c.1525A>G (p.Thr509Ala) were not reported previously and predicted as \"harmful\" to the protein function.\nCONCLUSION: The main type of ocular albinism is oculocutaneous albinism type II in Liuzhou region, where the most common variations of the P gene were c.803-3C>G and c.1327G>A (p.Val443Ile). Above finding has enriched the variation spectrum of the P gene.","variants":[{"Name":"NM_000275.3(OCA2):c.1349C>A (p.Thr450Lys)","Chromosome":"15","Start":"27985079","Stop":"27985079","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2836267,"rule_based_match":true,"evidence_text":"c.1349C>A (p.Thr450Lys)","llm_judgment":"PRESENT","evidence":"c.1349C>A (p.Thr450Lys)","abstract_start":556,"abstract_end":579},{"Name":"NM_000275.3(OCA2):c.1349C>T (p.Thr450Met)","Chromosome":"15","Start":"27985079","Stop":"27985079","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1201395,"rule_based_match":true,"evidence_text":"c.1349C>T (p.Thr450Met)","llm_judgment":"PRESENT","evidence":"c.1349C>T (p.Thr450Met)","abstract_start":688,"abstract_end":711},{"Name":"NM_000275.3(OCA2):c.2363C>T (p.Ser788Leu)","Chromosome":"15","Start":"27845028","Stop":"27845028","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":615958,"rule_based_match":true,"evidence_text":"c.2363C>T (p.Ser788Leu)","llm_judgment":"PRESENT","evidence":"c.2363C>T (p.Ser788Leu)","abstract_start":588,"abstract_end":611},{"Name":"NM_000275.3(OCA2):c.632C>T (p.Pro211Leu)","Chromosome":"15","Start":"28022515","Stop":"28022515","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":195225,"rule_based_match":true,"evidence_text":"c.632C>T (p.Pro211Leu)","llm_judgment":"PRESENT","evidence":"c.632C>T (p.Pro211Leu)","abstract_start":493,"abstract_end":515}]}
{"pmid":"28736585","title":"Late onset asymptomatic pancreatic neuroendocrine tumor - A case report on the phenotypic expansion for MEN1.","abstract":"BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome associated with several endocrine as well as non-endocrine tumors and is caused by mutations in the <i>MEN1</i> gene. Primary hyperparathyroidism affects the majority of MEN1 individuals by age 50 years. Additionally, <i>MEN1</i> mutations trigger familial isolated hyperparathyroidism. We describe a seemingly unaffected 76-year-old female who presented to our Genetics Clinic with a family history of primary hyperparathyroidism and the identification of a pathogenic <i>MEN1</i> variant.\nCASE PRESENTATION: The patient was a 76 year-old woman who appeared to be unaffected. She had a family history of a known <i>MEN1</i> pathogenic variant. Molecular testing for the known <i>MEN1</i> mutation c.1A > G, as well as, biochemical testing, MRI of the brain and abdomen were all performed using standard methods. Molecular testing revealed our patient possessed the <i>MEN1</i> pathogenic variant previously identified in her two offspring. Physical exam revealed red facial papules with onset in her seventies, involving her cheeks, nose and upper lip. Formerly, she was diagnosed with rosacea by a dermatologist and noted no improvement with treatment. Clinically, these lesions appeared to be facial angiofibromas. Brain MRI was normal. However, an MRI of her abdomen revealed a 1.5 cm lesion at the tail of the pancreas with normal adrenal glands. Glucagon was mildly elevated and pancreatic polypeptide was nearly seven times the upper limit of the normal range. The patient underwent spleen sparing distal pancreatectomy and subsequent pathology was consistent with a well-differentiated pancreatic neuroendocrine tumor (pNET).\nCONCLUSIONS: Age-related penetrance and variable expressivity are well documented in families with MEN1. It is thought that nearly all individuals with MEN1 manifest disease by age 40. We present a case of late-onset MEN1 in the absence of the most common feature, primary hyperparathyroidism, but with the presence of a pNET and cutaneous findings. This family expands the phenotype associated with the c.1A > G pathogenic variant and highlights the importance of providing comprehensive assessment of <i>MEN1</i> mutation carriers in families that at first blush may appear to have isolated hyperparathyroidism.","variants":[{"Name":"NM_001370259.2(MEN1):c.1A>G (p.Met1Val)","Chromosome":"11","Start":"64810109","Stop":"64810109","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":45187,"rule_based_match":true,"evidence_text":"c.1A > G","llm_judgment":"PRESENT","evidence":"c.1A > G","abstract_start":785,"abstract_end":793}]}
{"pmid":"27637299","title":"Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients.","abstract":"BACKGROUND: Defects in the human TSHR gene are reported to be one of the causes of CH due to thyroid dysgenesis, the purpose of this study was to examine the TSHR mutation spectrum and prevalence in congenital hypothyroidism (CH) and subclinical congenital hypothyroidism (SCH) patients in the Guangxi Zhuang Autonomous Region of China and to evaluate the genotype-phenotype correlations.\nMETHODS: Blood samples were collected from 384 patients including 240 CH and 144 SCH patients in Guangxi, China. Genomic DNA was extracted from peripheral blood leukocytes. All exons of the 11 known CH associated genes including TSHR together with their exon-intron boundaries were screened by next-generation sequencing (NGS).\nRESULTS: NGS analysis of TSHR revealed nine different variants in ten individuals. Six (4.2%) of 144 patients with SCH were found to harbor monoallelic TSHR variants. Four (1.6%) of 240 patients with CH harbored TSHR variants combined with another monoallelic mutation in either DUOX2 or TG gene. The present study identified five novel variants c.1838A>G (p.Y613C), c.1576G>A (p.A526T), c.2087T>G (p.F696C), c.1631G>A (p.G544E) and c.2051C>A (p.A684D) in TSHR, seven known pathogenic variants c.1349G>A (p.R450H), c.326G>A (p.R109Q), c.2066T>G (p.V689G) and c.2272G>A (p.E758K) in TSHR, IVS3+2T>G in TG, and c.1588A>T (p.K530X) and c.2635G>A (p.E879K) in DUOX2. The previously reported hotspot mutation p.R450H was found in only one SCH patient.\nCONCLUSION: The prevalence of TSHR mutations was 1.6% in CH patients and 4.2% in SCH patients in Guangxi Zhuang Autonomous Region of China. Monoallelic TSHR pathogenic variants were associated with SCH, while TSHR pathogenic variants combined with monoallelic mutations in DUOX2 or TG gene might contribute to CH. Our study expands the TSHR mutation spectrum and provides the best estimation of mutation rate for SCH and CH patients in this Chinese population.","variants":[{"Name":"NM_000369.5(TSHR):c.2272G>A (p.Glu758Lys)","Chromosome":"14","Start":"81144330","Stop":"81144330","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2252473,"rule_based_match":true,"evidence_text":"c.2272G>A (p.E758K)","llm_judgment":"PRESENT","evidence":"c.2272G>A (p.E758K)","abstract_start":1276,"abstract_end":1295},{"Name":"NM_000369.5(TSHR):c.1349G>A (p.Arg450His)","Chromosome":"14","Start":"81143407","Stop":"81143407","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227362,"rule_based_match":true,"evidence_text":"c.1349G>A (p.R450H)","llm_judgment":"PRESENT","evidence":"c.1349G>A (p.R450H)","abstract_start":1211,"abstract_end":1230},{"Name":"NM_000369.5(TSHR):c.326G>A (p.Arg109Gln)","Chromosome":"14","Start":"81087962","Stop":"81087962","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21477,"rule_based_match":true,"evidence_text":"c.326G>A (p.R109Q)","llm_judgment":"PRESENT","evidence":"c.326G>A (p.R109Q)","abstract_start":1232,"abstract_end":1250},{"Name":"NM_000369.5(TSHR):c.1838A>G (p.Tyr613Cys)","Chromosome":"14","Start":"81143896","Stop":"81143896","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3534593,"rule_based_match":true,"evidence_text":"c.1838A>G (p.Y613C)","llm_judgment":"PRESENT","evidence":"c.1838A>G (p.Y613C)","abstract_start":1063,"abstract_end":1082}]}
{"pmid":"33977023","title":"Familial variability of cerebrotendinous xanthomatosis lacking typical biochemical findings.","abstract":"Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by pathogenic variants in the <i>CYP27A1</i> gene encoding the mitochondrial enzyme sterol 27-hydroxylase. Patients with CTX can present with a wide range of symptoms, but most often have evidence of tendon xanthomas along with possible cataracts, atherosclerosis, or neurological dysfunction. Regardless of clinical phenotype, CTX patients typically exhibit levels of cholestanol and bile acid precursors in the circulation that are many fold increased over normal control concentrations. Here we report two siblings, one with the rare spinal xanthomatosis phenotype and the other with a very mild form of CTX manifesting as minor tendon xanthomatosis and gastrointestinal complaints who both carry compound heterozygous variants in <i>CYP27A1</i>: NM_000784.3: c.410G > A (p.Arg137Gln) and c.1183C > T (p.Arg395Cys). However, biochemical analysis of these patients revealed normal levels of serum cholestanol and relatively mild elevations of the bile acid precursors 7α-hydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-4-cholesten-3-one. The atypical biochemical presentation of these cases represents a diagnostic challenge for a disorder once thought to have a sensitive biomarker in cholestanol and highlight the need for thorough investigation of patients with symptomatology consistent with CTX that includes bile acid precursor biochemical testing and molecular analysis.","variants":[{"Name":"NM_000784.4(CYP27A1):c.1183C>T (p.Arg395Cys)","Chromosome":"2","Start":"218814186","Stop":"218814186","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19294,"rule_based_match":true,"evidence_text":"c.1183C > T (p.Arg395Cys)","llm_judgment":"PRESENT","evidence":"c.1183C > T (p.Arg395Cys)","abstract_start":898,"abstract_end":923}]}
{"pmid":"21919124","title":"SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours.","abstract":"SOX2 is an early developmental transcription factor and marker of stem cells that has recently been implicated in the development of the pituitary gland. Heterozygous SOX2 mutations have been described in patients with hypopituitarism and severe ocular abnormalities. In the majority of published cases, the pituitary gland is either small or normal in size. Here, we report two unrelated patients with SOX2 haploinsufficiency (a heterozygous gene deletion and a novel c.143TC>AA/p.F48X mutation) who developed nonprogressive pituitary tumors of early onset, suggesting a congenital etiology. The truncating mutation resulted in significant loss of function and impaired nuclear localization of the mutant protein, in addition to a failure to repress β-catenin transcriptional activity in vitro. This is the first indication that SOX2 haploinsufficiency is implicated in the generation of pituitary tumors with distinct clinical characteristics, possibly mediated via its effects on the Wnt signaling pathway.","variants":[{"Name":"NM_003106.4(SOX2):c.143_144delinsAA (p.Phe48Ter)","Chromosome":"3","Start":"181712503","Stop":"181712504","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"AA","allel_id":48403,"rule_based_match":false,"evidence_text":"c.143TC>AA/p.F48X","llm_judgment":"PRESENT","evidence":"c.143TC>AA/p.F48X","abstract_start":469,"abstract_end":486}]}
{"pmid":"27476652","title":"GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation.","abstract":"Vascular tumors are among the most common neoplasms in infants and children; 5%-10% of newborns present with or develop lesions within the first 3 months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS, KRAS, NRAS, GNAQ, and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole-exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention.","variants":[{"Name":"NM_004297.4(GNA14):c.614A>T (p.Gln205Leu)","Chromosome":"9","Start":"77429016","Stop":"77429016","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":539144,"rule_based_match":true,"evidence_text":"GNA14 c.614A>T (p.Gln205Leu)","llm_judgment":"PRESENT","evidence":"GNA14 c.614A>T (p.Gln205Leu)","abstract_start":842,"abstract_end":870}]}
{"pmid":"30703226","title":"A novel SLC25A13 variant and the resultant aberrant transcript identified in a pedigree affected with citrin deficiency","abstract":"OBJECTIVE: To explore the clinical and genetic features of an infant with citrin deficiency (CD).\nMETHODS: Clinical data of the patient was collected and analyzed. Genomic DNA was extracted from peripheral blood samples collected from the patient and her parents. Targeted exome sequencing was performed to explore the genetic cause, and Sanger sequencing was used to confirm the detected variants. SLC25A13 mRNA was extracted from peripheral blood lymphocytes of the infant. The effect of novel mutation of SLC25A13 was analyzed by reverse transcription-PCR, cDNA cloning and Sanger sequencing.\nRESULTS: The SLC25A13 genotype of the patient was determined as c.845_c.848+1delG/c.1841+3_1841+4delAA, with the latter having not been reported. The mutation has affected the splicing of the SLC25A13 mRNA, giving rise to an aberrant transcript [r.1841_1842ins1841+1_1841+67; 1841+3_c.1841+4del].\nCONCLUSION: A novel SLC25A13 mutation c.1841+3_1841+4delAA and the resultant abnormal splicing variant were discovered by combined DNA sequencing and cDNA cloning. The finding has enabled definite diagnosis of CD and enriched the spectrum of SLC25A13 mutations.","variants":[{"Name":"NM_014251.3(SLC25A13):c.1841+3_1841+4del","Chromosome":"7","Start":"96121651","Stop":"96121652","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":1941512,"rule_based_match":true,"evidence_text":"c.1841+3_1841+4delAA","llm_judgment":"PRESENT","evidence":"c.1841+3_1841+4delAA","abstract_start":678,"abstract_end":698}]}
{"pmid":"31069783","title":"A novel WARS mutation (p.Asp314Gly) identified in a Chinese distal hereditary motor neuropathy family.","abstract":"Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuropathies characterized by distal limb muscle wasting and weakness with no or minimal sensory abnormalities. To investigate the clinical and genetic features of dHMN caused by WARS mutations in mainland China, we performed Sanger sequencing of the coding and untranslated region (UTR) regions of WARS in 160 unresolved dHMN and Charcot-Marie-Tooth (CMT) index patients. We detected a novel heterozygous variant c.941A>G (p.Asp314Gly) of WARS in an index patient from an autosomal dominant dHMN family including five affected members over three generations. The variant completely co-segregates with the dHMN phenotype in the family, and it was classified as likely pathogenic according to the American College of Medical Genetics and Genomics standards and guidelines. The clinical features included juvenile to adult onset (15-23 years), distal wasting and weakness, minimal sensory disturbance and length-dependent motor axonal degeneration with CMT examination score ranging from 6 to 10. Our report further confirms the role of WARS in dHMN and indicates that the variant c.941A>G (p.Asp314Gly) of WARS is related to a mild to moderate affected and later onset phenotype of dHMN.","variants":[{"Name":"NM_004184.4(WARS1):c.941A>G (p.Asp314Gly)","Chromosome":"14","Start":"100342570","Stop":"100342570","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":963440,"rule_based_match":true,"evidence_text":"c.941A>G (p.Asp314Gly)","llm_judgment":"PRESENT","evidence":"c.941A>G (p.Asp314Gly)","abstract_start":521,"abstract_end":543}]}
{"pmid":"17661373","title":"Altered expression of PGK1 in a family with phosphoglycerate kinase deficiency.","abstract":"The X-linked recessive disease phosphoglycerate kinase (PGK) deficiency is caused by altered expression of the PGK1 enzyme, which causes muscle stiffness, hemolytic anemia, and mental retardation. In this study we characterized the PGK1 gene in a family of two brothers, two sisters, and their parents. A single mutation in exon 6, which was associated with the pattern of inheritance of PGK1 deficiency, was observed. This silent G213G; c.639C>T mutation was localized to the conserved exon-intron boundary. We have developed a method for quantification of PGK1 mRNA and demonstrated a marked reduction in PGK1 mRNA in both brothers with the disease. A smaller decrease in PGK1 expression was observed in one sister with symptoms of PGK deficiency and in her mother. Only the normal PGK1 allele was expressed in the two heterozygous women. Whereas most known PGK1 mutations cause amino acid alterations, our study indicates that inhibition of the transcription mechanism is the cause of PGK deficiency.","variants":[{"Name":"NM_000291.4(PGK1):c.639C>T (p.Gly213=)","Chromosome":"X","Start":"78118168","Stop":"78118168","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":177945,"rule_based_match":true,"evidence_text":"silent G213G; c.639C>T mutation","llm_judgment":"PRESENT","evidence":"silent G213G; c.639C>T mutation","abstract_start":424,"abstract_end":455}]}
{"pmid":"33569515","title":"A novel","abstract":"Neutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder, due to an enzymatic error of lipid metabolism. Patients present always with skeletal muscle myopathy and variable cardiac and hepatic involvement. NLSDM is caused by mutations in the <i>PNPLA2</i> gene, which encodes the adipose triglyceride lipase (ATGL). Here we report the molecular characterization and clinical findings of two NLSDM siblings carrying the novel c.187+1G > C homozygous <i>PNPLA2</i> mutation, localized in the splice site of intron 2. Molecular analyses revealed that neither aberrant <i>PNPLA2</i> mRNA isoforms, nor ATGL mutated protein were detectable in patient's cells. Clinically, both patients presented early onset muscle weakness, in particular of proximal upper limb muscles. In almost 15 years, muscle damage affected also distal upper limbs. This is a NLSDM family, displaying a severe <i>PNPLA2</i> mutation in two siblings with clinical presentation characterized by an early onset, but a slowly evolution of severe myopathy.","variants":[{"Name":"NM_020376.4(PNPLA2):c.187+1G>C","Chromosome":"11","Start":"819906","Stop":"819906","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":511948,"rule_based_match":true,"evidence_text":"c.187+1G > C","llm_judgment":"PRESENT","evidence":"c.187+1G > C","abstract_start":458,"abstract_end":470}]}
{"pmid":"31240149","title":"Pregnancy outcome in Refsum disease: Affected fetuses and children born to an affected mother.","abstract":"We describe the case of a young woman, from a consanguineous family, affected by adult Refsum disease (ARD, OMIM#266500). ARD is a rare peroxisomal autosomal recessive disease due to deficient alpha-oxidation of phytanic acid (PA), a branched-chain fatty acid. The accumulation of PA in organs is thought to be responsible for disease symptoms. The patient presented only bilateral shortening of metatarsals and has been treated with a low-PA diet. She is homoallelic for the c.135-2A > G mutation of <i>PHYH</i>, and she married her first cousin carrying the same mutation. She was pregnant seven times and had two homozygous girls. Due to a potential exacerbation of the disease during the third trimester of pregnancy, her weight and plasma PA levels were monitored. No specific events were noticed for the mother during the pregnancies and postpartum periods. This case also raised the question of potential exposure to PA (and its subsequent toxicity) of a homozygous fetus in a homozygous mother. Despite modestly elevated plasma concentrations of PA at birth (<30 μmol/L), the two affected girls did not present any specific sign of ARD and have so far developed normally. As only a few determinations of plasma PA levels in the mother could be performed during pregnancies, showing mild elevations (<350 μmol/L), it remains difficult to conclude as to a possible transplacental crossing of PA.","variants":[{"Name":"NM_006214.4(PHYH):c.135-2A>G","Chromosome":"10","Start":"13295608","Stop":"13295608","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":22620,"rule_based_match":true,"evidence_text":"c.135-2A > G","llm_judgment":"PRESENT","evidence":"c.135-2A > G","abstract_start":476,"abstract_end":488}]}
{"pmid":"14974081","title":"Mutational analysis of mucopolysaccharidosis type VI patients undergoing a trial of enzyme replacement therapy.","abstract":"Mucopolysaccharidosis type VI (MPS VI), or Maroteaux-Lamy syndrome, is a lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (ARSB). Seven MPS VI patients were chosen for the initial clinical trial of enzyme replacement therapy. Direct sequencing of genomic DNA from these patients was used to identify ARSB mutations. Each individual exon of the ARSB gene was amplified by PCR and subsequently sequenced. Nine substitutions (c.289C>T [p.Q97X], c.629A>G [p.Y210C], c.707T>C [p.L236P], c.936G>T [p.W312C], c.944G>A [p.R315Q], c.962T>C [p.L321P], c.979C>T [p.R327X], c.1151G>A [p.S384N], and c.1450A>G [p.R484G]), two deletions (c.356_358delTAC [p.Y86del] and c.427delG), and one intronic mutation (c.1336+2T>G) were identified. A total of 7 out of the 12 mutations identified were novel (p.Y86del, p.Q97X, p.W312C, p.R327X, c.427delG, p.R484G, and c.1336+2T>G). Two of these novel mutations (p.Y86del and p.W312C) were expressed in Chinese hamster ovary cells and analyzed for residual ARSB activity and mutant ARSB protein. The two common polymorphisms c.1072G>A [p.V358M] and c.1126G>A [p.V376M] were identified among the patients, along with the silent mutation c.1191A>G. Cultured fibroblast ARSB mutant protein and residual activity were determined for each patient, and, together with genotype information, were used to predict the expected clinical severity of each MPS VI patient.","variants":[{"Name":"NM_000046.5(ARSB):c.936G>T (p.Trp312Cys)","Chromosome":"5","Start":"78885790","Stop":"78885790","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":539968,"rule_based_match":true,"evidence_text":"c.936G>T [p.W312C]","llm_judgment":"PRESENT","evidence":"c.936G>T [p.W312C]","abstract_start":520,"abstract_end":538},{"Name":"NM_000046.5(ARSB):c.1336+2T>G","Chromosome":"5","Start":"78781850","Stop":"78781850","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":550408,"rule_based_match":true,"evidence_text":"c.1336+2T>G","llm_judgment":"PRESENT","evidence":"c.1336+2T>G","abstract_start":732,"abstract_end":743},{"Name":"NM_000046.5(ARSB):c.1450A>G (p.Arg484Gly)","Chromosome":"5","Start":"78780549","Stop":"78780549","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":187113,"rule_based_match":true,"evidence_text":"c.1450A>G [p.R484G]","llm_judgment":"PRESENT","evidence":"c.1450A>G [p.R484G]","abstract_start":625,"abstract_end":644},{"Name":"NM_000046.5(ARSB):c.707T>C (p.Leu236Pro)","Chromosome":"5","Start":"78955486","Stop":"78955486","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15918,"rule_based_match":true,"evidence_text":"c.707T>C [p.L236P]","llm_judgment":"PRESENT","evidence":"c.707T>C [p.L236P]","abstract_start":500,"abstract_end":518},{"Name":"NM_000046.5(ARSB):c.979C>T (p.Arg327Ter)","Chromosome":"5","Start":"78885747","Stop":"78885747","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":550447,"rule_based_match":true,"evidence_text":"c.979C>T [p.R327X]","llm_judgment":"PRESENT","evidence":"c.979C>T [p.R327X]","abstract_start":580,"abstract_end":598},{"Name":"NM_000046.5(ARSB):c.962T>C (p.Leu321Pro)","Chromosome":"5","Start":"78885764","Stop":"78885764","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":550449,"rule_based_match":true,"evidence_text":"c.962T>C (p.L321P)","llm_judgment":"PRESENT","evidence":"c.962T>C","abstract_start":560,"abstract_end":568},{"Name":"NM_000046.5(ARSB):c.944G>A (p.Arg315Gln)","Chromosome":"5","Start":"78885782","Stop":"78885782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":177363,"rule_based_match":true,"evidence_text":"c.944G>A [p.R315Q]","llm_judgment":"PRESENT","evidence":"c.944G>A [p.R315Q]","abstract_start":540,"abstract_end":558},{"Name":"NM_000046.5(ARSB):c.629A>G (p.Tyr210Cys)","Chromosome":"5","Start":"78964477","Stop":"78964477","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":15924,"rule_based_match":true,"evidence_text":"c.629A>G [p.Y210C]","llm_judgment":"PRESENT","evidence":"c.629A>G [p.Y210C]","abstract_start":480,"abstract_end":498},{"Name":"NM_000046.5(ARSB):c.289C>T (p.Gln97Ter)","Chromosome":"5","Start":"78984960","Stop":"78984960","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":550517,"rule_based_match":true,"evidence_text":"c.289C>T [p.Q97X]","llm_judgment":"PRESENT","evidence":"c.289C>T [p.Q97X]","abstract_start":461,"abstract_end":478},{"Name":"NM_000046.5(ARSB):c.1151G>A (p.Ser384Asn)","Chromosome":"5","Start":"78839418","Stop":"78839418","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":98263,"rule_based_match":true,"evidence_text":"c.1151G>A [p.S384N]","llm_judgment":"PRESENT","evidence":"c.1151G>A [p.S384N]","abstract_start":600,"abstract_end":619}]}
{"pmid":"24466038","title":"Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions.","abstract":"Spastic paraplegia 7 is an autosomal recessive disorder caused by mutations in the gene encoding paraplegin, a protein located at the inner mitochondrial membrane and involved in the processing of other mitochondrial proteins. The mechanism whereby paraplegin mutations cause disease is unknown. We studied two female and two male adult patients from two Norwegian families with a combination of progressive external ophthalmoplegia and spastic paraplegia. Sequencing of SPG7 revealed a novel missense mutation, c.2102A>C, p.H 701P, which was homozygous in one family and compound heterozygous in trans with a known pathogenic mutation c.1454_1462del in the other. Muscle was examined from an additional, unrelated adult female patient with a similar phenotype caused by a homozygous c.1047insC mutation in SPG7. Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV. Molecular studies in single, microdissected fibres showed multiple mitochondrial DNA deletions segregating at high levels (38-97%) in respiratory deficient fibres. Our findings demonstrate for the first time that paraplegin mutations cause accumulation of mitochondrial DNA damage and multiple respiratory chain deficiencies. While paraplegin is not known to be directly associated with the mitochondrial nucleoid, it is known to process other mitochondrial proteins and it is possible therefore that paraplegin mutations lead to mitochondrial DNA deletions by impairing proteins involved in the homeostasis of the mitochondrial genome. These studies increase our understanding of the molecular pathogenesis of SPG7 mutations and suggest that SPG7 testing should be included in the diagnostic workup of autosomal recessive, progressive external ophthalmoplegia, especially if spasticity is present.","variants":[{"Name":"NM_003119.4(SPG7):c.2102A>C (p.His701Pro)","Chromosome":"16","Start":"89553959","Stop":"89553959","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1701675,"rule_based_match":true,"evidence_text":"c.2102A>C, p.H 701P","llm_judgment":"PRESENT","evidence":"c.2102A>C, p.H 701P","abstract_start":512,"abstract_end":531}]}
{"pmid":"21896204","title":"Genetic screening of Fabry patients with EcoTILLING and HRM technology.","abstract":"BACKGROUND: Anderson-Fabry disease (FD) is caused by a deficit of the α-galactosidase A enzyme which leads to the accumulation of complex sphingolipids, especially globotriaosylceramide (Gb3), in all the cells of the body, causing the onset of a multi-systemic disease with poor prognosis in adulthood. In this article, we describe two alternative methods for screening the GLA gene which codes for the α-galactosidase A enzyme in subjects with probable FD in order to test analysis strategies which include or rely on initial pre-screening.\nFINDINGS: We analyzed 740 samples using EcoTILLING, comparing two mismatch-specificendonucleases, CEL I and ENDO-1, while conducting a parallel screening of the same samples using HRM (High Resolution Melting). Afterwards, all samples were subjected to direct sequencing. Overall, we identified 12 different genetic variations: -10C>T, -12G>A, -30G>A, IVS2-76_80del5, D165H, C172Y, IVS4+16A>G, IVS4 +68 A>G, c.718_719delAA, D313Y, IVS6-22C>T, G395A. This was consistent with the high genetic heterogeneity found in FD patients and carriers. All of the mutations were detected by HRM, whereas 17% of the mutations were not found by EcoTILLING. The results obtained by EcoTILLING comparing the CEL I and ENDO-1 endonucleases were perfectly overlapping.\nCONCLUSION: On the basis of its simplicity, flexibility, repeatability, and sensitivity, we believe thatHRM analysis of the GLA gene is a reliable presequencing screening tool. This method can be applied to any genomic feature to identify known and unknown genetic alterations, and it is ideal for conducting screening and population studies.","variants":[{"Name":"NM_000169.3(GLA):c.718_719del (p.Lys240fs)","Chromosome":"X","Start":"101398867","Stop":"101398868","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":223945,"rule_based_match":true,"evidence_text":"c.718_719delAA","llm_judgment":"PRESENT","evidence":"c.718_719delAA","abstract_start":950,"abstract_end":964}]}
{"pmid":"35551387","title":"Bi-allelic variants in KCNU1 cause impaired acrosome reactions and male infertility.","abstract":"STUDY QUESTION: Are there new genetic factors responsible for male infertility with normal sperm quantity and morphology?\nSUMMARY ANSWER: We identified the bi-allelic variants in KCNU1 and confirmed it a novel pathogenetic gene for male infertility mainly due to impaired sperm acrosome reactions (ARs).\nWHAT IS KNOWN ALREADY: Until now, the underlying genetic determinants for male affected individuals exhibiting normal sperm quantity and morphology have been largely unknown. Potassium/calcium-activated channel subfamily U member 1 (KCNU1) is a sperm-specific potassium channel. The Kcnu1 null mutation in male mice causes infertility due to the impaired progressive motility and AR.\nSTUDY DESIGN, SIZE, DURATION: We recruited a cohort of 126 male infertility individuals with typical asthenospermia or fertilization failure and focused on two infertile males from two consanguineous families from 2015 to 2020; whole-exome sequencing and homozygosity mapping were performed. We identified a homozygous missense variant (c.2144A>G, p.His715Arg) and a homozygous donor splice-site variant (c.1295 + 3A>C, p.Val405Glyfs*8) in KCNU1. Then, we generated a knock-in (KI) mouse model in September 2020 and have now carried out functional studies and possible treatment strategies.\nPARTICIPANTS/MATERIALS, SETTING, METHODS: The affected individuals with infertility were recruited from the Shanghai Ninth Hospital affiliated to Shanghai Jiao Tong University. Genomic DNA from the affected individual was extracted from peripheral blood. Whole-exome sequencing, homozygosity mapping and in silico analyses were used to screen and identify KCNU1 variants, and the variants were confirmed by Sanger sequencing. We used C57BL/6N mouse to construct KI mouse model to mimic the reproductive phenotype in vivo. We performed functional experiments by western blotting, AR assay and immunofluorescent Staining. Finally, we performed IVF and ICSI to explore the treatment strategies.\nMAIN RESULTS AND THE ROLE OF CHANCE: We identified a homozygous missense variant (c.2144A>G, p.His715Arg) and a homozygous donor splice-site variant (c.1295 + 3A>C, p.Val405Glyfs*8) in KCNU1 in two infertile males. We demonstrated that the splice-site variant affected normal alternative splicing of KCNU1, thus leading to the loss of function of KCNU1. Meanwhile, the missense pathogenic variant reduced the KCNU1 protein levels in sperm of both the affected individual and the KI mouse model, resulting in impaired ARs and male infertility. Intracytoplasmic sperm injection was able to rescue the deficiencies.\nLARGE SCALE DATA: N/A.\nLIMITATIONS, REASONS FOR CAUTION: The exact molecular mechanism of KCNU1 and pathways need to be further explore in the future.\nWIDER IMPLICATIONS OF THE FINDINGS: This is the first report that establishes a causal relationship between KCNU1 deficiency and male infertility, confirming the critical role of KCNU1 in human reproduction. Our findings expand our knowledge of the genes that play critical roles in the human sperm AR and provide a new genetic marker for infertility.\nSTUDY FUNDING/COMPETING INTEREST(S): This work was supported by the SHIPM-pi fund no. JY201801 from the Shanghai Institute of Precision Medicine, Ninth People's Hospital Shanghai Jiao Tong University School of Medicine, the National Natural Science Foundation of China (81725006, 81771649, 81822019, 81771581, 81971450, 81971382, 82001538 and 82071642). The authors declare no conflict of interest.\nTRIAL REGISTRATION NUMBER: N/A.","variants":[{"Name":"NM_001031836.3(KCNU1):c.2144A>G (p.His715Arg)","Chromosome":"8","Start":"36909348","Stop":"36909348","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2417450,"rule_based_match":true,"evidence_text":"c.2144A>G, p.His715Arg","llm_judgment":"PRESENT","evidence":"c.2144A>G, p.His715Arg","abstract_start":1025,"abstract_end":1047},{"Name":"NM_001031836.3(KCNU1):c.1295+3A>C","Chromosome":"8","Start":"36834871","Stop":"36834871","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2417451,"rule_based_match":true,"evidence_text":"c.1295 + 3A>C","llm_judgment":"PRESENT","evidence":"c.1295 + 3A>C","abstract_start":1093,"abstract_end":1106}]}
{"pmid":"36292628","title":"Exome Sequencing Identifies a Biallelic GALNS Variant (p.Asp233Asn) Causing Mucopolysaccharidosis Type IVA in a Pakistani Consanguineous Family.","abstract":"Mucopolysaccharidoses (MPS) type IVA is a lysosomal storage disease that mainly affects the skeletal system and is caused by a deficiency of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS). The condition can mistakenly be diagnosed as a primary skeletal dysplasia such as spondylo-epiphyseal dysplasia, which shares many similar phenotypic features. Here, we utilised whole exome sequencing to make the diagnosis of MPS IVA in a resource poor country. We report for the first time the identification of a biallelic GALNS missense variant (c.697G&amp;gt;A, p.Asp233Asn) in the Pakistani population and highlight the potential contribution that academic institutions can make in rare disease diagnosis in the absence of a developed clinical genetic service.","variants":[{"Name":"NM_000512.5(GALNS):c.697G>A (p.Asp233Asn)","Chromosome":"16","Start":"88835786","Stop":"88835786","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1036282,"rule_based_match":false,"evidence_text":"c.697G>A (p.Asp233Asn)","llm_judgment":"PRESENT","evidence":"p.Asp233Asn","abstract_start":561,"abstract_end":572}]}
{"pmid":"29147684","title":"c.207C>G mutation in sepiapterin reductase causes autosomal dominant dopa-responsive dystonia.","abstract":"OBJECTIVE: To elucidate the genetic cause of an Egyptian family with dopa-responsive dystonia (DRD), a childhood-onset dystonia, responding therapeutically to levodopa, which is caused by mutations in various genes.\nMETHODS: Rare variants in all coding exons of <i>GCH1</i> were excluded by Sanger sequencing. Exome sequencing was applied for 1 unaffected and 2 affected family members. To investigate the functional consequences of detected genetic variants, urinary sepiapterin concentrations were determined by high-performance liquid chromatography.\nRESULTS: A heterozygous rare nonsynonymous variant in exon 1 of sepiapterin reductase (<i>SPR</i>, c.207C>G, p.Asp69Glu) was found in all affected family members. Urinary concentrations of sepiapterin were above the standard of normal controls in most <i>SPR</i> mutation carriers, suggesting functional biochemical consequences of the mutation. Variant filtering of all genes involved in the tetrahydrobiopterin pathway, required for levodopa synthesis, revealed an additional common variant in dihydrofolate reductase (<i>DHFR</i>, rs70991108). The presence of both variants was significantly stronger associated with the biochemical abnormality and the clinical disease state as opposed to 1 variant only.\nCONCLUSIONS: The rare <i>SPR</i> mutation can cause autosomal dominant DRD with incomplete penetrance. The common <i>DHFR</i> variant might have synergistic effects on production of tetrahydrobiopterin and levodopa, thereby increasing penetrance.","variants":[{"Name":"NM_003124.5(SPR):c.207C>G (p.Asp69Glu)","Chromosome":"2","Start":"72887639","Stop":"72887639","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":558265,"rule_based_match":true,"evidence_text":"c.207C>G (p.Asp69Glu)","llm_judgment":"PRESENT","evidence":"p.Asp69Glu","abstract_start":663,"abstract_end":673}]}
{"pmid":"29178653","title":"Compound heterozygous CASQ2 mutations and long-term course of catecholaminergic polymorphic ventricular tachycardia.","abstract":"BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited cardiac disorder characterized by episodic ventricular tachycardia during adrenergic stimulation. It is associated with significant morbidity and mortality. Knowledge of the underlying genetic cause, pathogenesis, and the natural history of the disease remains incomplete. Approximately 50% of CPVT cases are caused by dominant mutations in the cardiac ryanodine receptor (RYR2) gene, <5% of cases are accounted for by recessive mutations in cardiac calsequestrin (CASQ2) or Triadin (TRDN).\nMETHODS: We report a family with two CASQ2 gene mutations. A research-based next-generation sequencing (NGS) initiative was used in a patient with a severe CPVT phenotype and her clinically unaffected son. Reverse transcription polymerase chain reaction (RT-PCR) from platelet RNA was used to assess the consequences of predicted splice variants.\nRESULTS: NGS revealed that the proband carried a novel c.199C>T (p.Gln67*) mutation and a previously reported splice site mutation c.532+1G>A in CASQ2. Her son is a heterozygous carrier of the c.199C>T (p.Gln67*) mutation alone and the proband was compound heterozygous at CASQ2. RNA analysis demonstrated that the splice site mutation results in the retention of intron 3 with no full-length CASQ2 mRNA.\nCONCLUSION: This study describes a novel CPVT genotype and further characterizes the effect of a previously reported CASQ2 splice site mutation. The long-term follow-up of 23 years since first symptom provides additional insight into the natural history of CASQ2-associated CPVT.","variants":[{"Name":"NM_001232.4(CASQ2):c.199C>T (p.Gln67Ter)","Chromosome":"1","Start":"115768343","Stop":"115768343","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1849690,"rule_based_match":true,"evidence_text":"c.199C>T (p.Gln67*)","llm_judgment":"PRESENT","evidence":"c.199C>T (p.Gln67*)","abstract_start":1000,"abstract_end":1019}]}
{"pmid":"31845315","title":"VPS26C homozygous nonsense variant in two cousins with neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features.","abstract":"In this report, we describe two cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Genome sequencing failed to identify variants in known disease-associated genes explaining the phenotype. Extended comprehensive analysis of the two affected cousins' genomes, however, revealed that both share the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The potential vital biological role of VPS26C, the nature of the variant which is predicted to result in loss-of-function, expression studies revealing significant reduction in the mutant transcript, and the co-segregation of the homozygous variant with the phenotype in two affected individuals all support that VPS26C is a novel gene associated with a previously unrecognized syndrome characterized by neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features.","variants":[{"Name":"NM_006052.2(VPS26C):c.178G>T (p.Glu60Ter)","Chromosome":"21","Start":"37240519","Stop":"37240519","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":963198,"rule_based_match":true,"evidence_text":"c.178G>T (p.Glu60*)","llm_judgment":"PRESENT","evidence":"c.178G>T (p.Glu60*)","abstract_start":382,"abstract_end":401}]}
{"pmid":"32463173","title":"Fumarate hydratase c.914T > C (p.Phe305Ser) is a pathogenic variant associated with hereditary leiomyomatosis and renal cell cancer syndrome.","abstract":"BACKGROUND: Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC), caused by heterozygous germline pathogenic variants in the FH, confers an increased risk for cutaneous and uterine leiomyomas and renal cancer.\nMETHODS: About 13,722 advanced cancer patients, including 560 with renal cell carcinoma, had germline analysis performed in the context of tumor-normal sequencing under an IRB approved protocol.\nRESULTS: We report two unrelated individuals with early onset kidney cancer who both carried the c.914C > T (p.Phe305Ser) germline variant in the FH. Both tumors exhibited loss of FH staining by immunohistochemistry and/or positive 2SC staining. Subsequent familial testing discovered that a daughter of a proband who carried the variant had both cutaneous and uterine leiomyomas.\nCONCLUSION: This combination of evidence suggests that the FH c.914C > T (p.Phe305Ser) is pathogenic for HLRCC.","variants":[{"Name":"NM_000143.4(FH):c.914T>C (p.Phe305Ser)","Chromosome":"1","Start":"241504236","Stop":"241504236","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":806539,"rule_based_match":true,"evidence_text":"c.914T > C (p.Phe305Ser)","llm_judgment":"PRESENT","evidence":"p.Phe305Ser","abstract_start":526,"abstract_end":537}]}
{"pmid":"31877959","title":"Identification and Functional Characterization of","abstract":"Hunter syndrome (mucopolysaccharidosis II; MPS II) is caused by a defect of the iduronate-2-sulfatase (<i>IDS</i>) gene. Few studies have reported integrated mutation data of Taiwanese MPS II phenotypes. In this study, we summarized genotype and phenotype correlations of confirmed MPS II patients and asymptomatic MPS II infants in Taiwan. Regular polymerase chain reaction and DNA sequencing were used to identify genetic abnormalities of 191 cases, including 51 unrelated patients with confirmed MPS II and 140 asymptomatic infants. <i>IDS</i> activity was analyzed in individual novel <i>IDS</i> variants using in vitro expression studies. Nineteen novel mutations were identified, in which the percentages of IDS activity of the novel missense mutations c.137A>C, c.311A>T, c.454A>C, c.797C>G, c.817C>T, c.998C>T, c.1106C>G, c.1400C>T, c.1402C>T, and c.1403G>A were significantly decreased (<i>p</i> < 0.001), c.254C>T and c.1025A>G were moderately decreased (<i>p</i> < 0.01), and c.851C>T was slightly decreased (<i>p</i> < 0.05) comparing with normal enzyme activity. The activities of the other six missense mutations were reduced but were insignificant. The results of genomic studies and their phenotypes were highly correlated. A greater understanding of the positive correlations may help to prevent the irreversible manifestations of Hunter syndrome, particularly in infants suspected of having asymptomatic MPS II. In addition, urinary glycosaminoglycan assay is important to diagnose Hunter syndrome since gene mutations are not definitive (could be non-pathogenic).","variants":[{"Name":"NM_000202.8(IDS):c.851C>T (p.Pro284Leu)","Chromosome":"X","Start":"149496374","Stop":"149496374","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":743170,"rule_based_match":true,"evidence_text":"c.851C>T","llm_judgment":"PRESENT","evidence":"c.851C>T","abstract_start":987,"abstract_end":995},{"Name":"NM_000202.8(IDS):c.817C>T (p.Arg273Trp)","Chromosome":"X","Start":"149496408","Stop":"149496408","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1863186,"rule_based_match":true,"evidence_text":"c.817C>T","llm_judgment":"PRESENT","evidence":"c.817C>T","abstract_start":799,"abstract_end":807},{"Name":"NM_000202.8(IDS):c.311A>T (p.Asp104Val)","Chromosome":"X","Start":"149503419","Stop":"149503419","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3414425,"rule_based_match":true,"evidence_text":"c.311A>T","llm_judgment":"PRESENT","evidence":"c.311A>T","abstract_start":769,"abstract_end":777},{"Name":"NM_000202.8(IDS):c.1025A>G (p.His342Arg)","Chromosome":"X","Start":"149487080","Stop":"149487080","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3414688,"rule_based_match":true,"evidence_text":"c.1025A>G","llm_judgment":"PRESENT","evidence":"c.1025A>G","abstract_start":928,"abstract_end":937},{"Name":"NM_000202.8(IDS):c.454A>C (p.Ser152Arg)","Chromosome":"X","Start":"149501002","Stop":"149501002","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1351729,"rule_based_match":true,"evidence_text":"c.454A>C","llm_judgment":"PRESENT","evidence":"c.454A>C","abstract_start":779,"abstract_end":787},{"Name":"NM_000202.8(IDS):c.998C>T (p.Ser333Leu)","Chromosome":"X","Start":"149490322","Stop":"149490322","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25526,"rule_based_match":true,"evidence_text":"c.998C>T","llm_judgment":"PRESENT","evidence":"c.998C>T","abstract_start":809,"abstract_end":817},{"Name":"NM_000202.8(IDS):c.1402C>T (p.Arg468Trp)","Chromosome":"X","Start":"149482997","Stop":"149482997","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25536,"rule_based_match":true,"evidence_text":"c.1402C>T","llm_judgment":"PRESENT","evidence":"c.1402C>T","abstract_start":841,"abstract_end":850},{"Name":"NM_000202.8(IDS):c.1106C>G (p.Ser369Ter)","Chromosome":"X","Start":"149486999","Stop":"149486999","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3414730,"rule_based_match":true,"evidence_text":"c.1106C>G","llm_judgment":"PRESENT","evidence":"c.1106C>G","abstract_start":819,"abstract_end":828},{"Name":"NM_000202.8(IDS):c.797C>G (p.Pro266Arg)","Chromosome":"X","Start":"149496428","Stop":"149496428","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3414606,"rule_based_match":true,"evidence_text":"c.797C>G","llm_judgment":"PRESENT","evidence":"c.797C>G","abstract_start":789,"abstract_end":797},{"Name":"NM_000202.8(IDS):c.1400C>T (p.Pro467Leu)","Chromosome":"X","Start":"149482999","Stop":"149482999","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625893,"rule_based_match":true,"evidence_text":"c.1400C>T","llm_judgment":"PRESENT","evidence":"c.1400C>T","abstract_start":830,"abstract_end":839},{"Name":"NM_000202.8(IDS):c.137A>C (p.Asp46Ala)","Chromosome":"X","Start":"149504260","Stop":"149504260","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3414650,"rule_based_match":true,"evidence_text":"c.137A>C","llm_judgment":"PRESENT","evidence":"c.137A>C","abstract_start":759,"abstract_end":767},{"Name":"NM_000202.8(IDS):c.254C>T (p.Ala85Val)","Chromosome":"X","Start":"149503476","Stop":"149503476","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3414397,"rule_based_match":true,"evidence_text":"c.254C>T","llm_judgment":"PRESENT","evidence":"c.254C>T","abstract_start":915,"abstract_end":923}]}
{"pmid":"36655627","title":"Clinical features and molecular characterization of Chinese patients with FKBP10 variants.","abstract":"BACKGROUND: Osteogenesis imperfecta (OI) is a group of rare skeletal dysplasia. Long bone deformity and scoliosis are often associated with progressively deforming types of OI. FKBP65 (encoded by FKBP10, OMIM *607063) plays a crucial role in the processing of type I procollagen. Autosomal recessive variants in FKBP10 result in type XI osteogenesis imperfecta.\nMETHODS: Patients diagnosed with OI were recruited for a genetic test. RT-PCR and Sanger sequencing were applied to confirm the splicing defect in FKBP10 mRNA with the splice-site variant. The bone structure was characterized by Goldner's trichrome staining. Bioinformatic analyses of bulk RNA sequencing data were performed to examine the effect of the FKBP10 variant on gene expression.\nRESULTS: Here we reported three children from a consanguineous family harboured a homozygous splice-site variant (c.918-3C > G) in FKBP10 intron and developed long bone deformity and early onset of scoliosis. We also observed frequent long bone fractures and spinal deformity in another 3 OI patients with different FKBP10 variants. The homozygous splicing variant identified in the fifth intron of FKBP10 (c.918-3C > G) led to abnormal RNA processing and loss of FKBP65 protein and consequently resulted in aberrant collagen alignment and porous bone morphology. Analysis of transcriptomic data indicated that genes involved in protein processing and osteoblast differentiation were significantly affected in the patient-derived osteoblasts.\nCONCLUSION: Our study characterized the clinical features of OI patients with FKBP10 variants and revealed the pathogenesis of the c.918-3C > G variant. The molecular analyses helped to gain insight into the deleterious effects of FKBP10 variants on collagen processing and osteoblast differentiation.","variants":[{"Name":"NM_021939.4(FKBP10):c.918-3C>G","Chromosome":"17","Start":"41819527","Stop":"41819527","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2905165,"rule_based_match":true,"evidence_text":"c.918-3C>G","llm_judgment":"PRESENT","evidence":"c.918-3C > G","abstract_start":865,"abstract_end":877}]}
{"pmid":"33101196","title":"Prevalence of Parathyroid Carcinoma and Atypical Parathyroid Neoplasms in 153 Patients With Multiple Endocrine Neoplasia Type 1: Case Series and Literature Review.","abstract":"<b>Purpose:</b> The occurrence of parathyroid carcinoma (PC) and atypical parathyroid neoplasm (APN) in multiple endocrine neoplasia type 1 (MEN1) is rare. The present paper reports the cases of 3 MEN1-PC/APN patients at our center and discusses the prevalence in a Chinese MEN1 cohort. <b>Methods:</b> This report is a retrospective analysis of 153 MEN1-associated primary hyperparathyroidism (MEN1-HPT) patients at our center, which included 3 MEN1-associated PC/APN (MEN1-PC/APN) patients. The clinical manifestations, biochemical indices, pathological findings, and therapy have been summarized along with the report of the genetic testing of the 3 patients. <b>Results:</b> Of the 153 MEN1-HPT patients, 1 (0.7%) was histopathologically diagnosed with PC and 2 (1.3%) with APN. Three heterozygous mutations were identified in the 3 MEN1-PC/APN patients (c.917 T > G, c.431T > C, and c.549 G > C). The cumulative findings of 3 cases with 18 previously reported MEN1-PC/APN cases revealed that the mean serum calcium (Ca) level was 3.15 ± 0.44 mmol/L and the median parathyroid hormone (PTH) level was 327 pg/mL (214.1, 673.1), both of which were significantly higher as compared to the respective levels in non-PC/APN MEN1 patients at our center [Ca: 2.78 mmol/L [2.61, 2.88], PTH: 185.5 pg/mL [108.3, 297.0]; <i>P</i> = 0.0003, 0.0034, respectively]. <b>Conclusion:</b> MEN 1-PC/APN is a rare disease, with a prevalence of only 2.0% among the MEN1-HPT cohort at our center. The affected patients recorded higher serum Ca level and PTH levels than those with MEN1-associated benign tumors. However, the diagnosis of MEN1-PC/APN is based upon pathology most of the times.","variants":[{"Name":"NM_001370259.2(MEN1):c.431T>C (p.Phe144Ser)","Chromosome":"11","Start":"64809679","Stop":"64809679","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2943956,"rule_based_match":true,"evidence_text":"c.431T > C","llm_judgment":"PRESENT","evidence":"c.431T > C","abstract_start":872,"abstract_end":882}]}
{"pmid":"25728773","title":"Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4.","abstract":"Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3'-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms.","variants":[{"Name":"NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp)","Chromosome":"19","Start":"49862188","Stop":"49862188","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":185664,"rule_based_match":true,"evidence_text":"c.1123G>T (p.Gly375Trp)","llm_judgment":"PRESENT","evidence":"c.1123G>T (p.Gly375Trp)","abstract_start":525,"abstract_end":548}]}
{"pmid":"24767827","title":"Exudative vasculopathy in a child with Leber congenital amaurosis.","abstract":"Leber congenital amaurosis is a severe retinal dystrophy that causes blindness or severe visual impairment, usually before the age of 1 year. We present the case of a 13-year-old girl with Leber congenital amaurosis who developed an exudative vasculopathy. She was successfully treated with cryotherapy and argon green laser. To our knowledge, only 4 cases of this condition in patients with Leber congenital amaurosis have been reported previously. This phenotype may be related to c.2991+1655A>G (p.Cys998X) mutations in the CEP290 gene.","variants":[{"Name":"NM_025114.4(CEP290):c.2991+1655A>G","Chromosome":"12","Start":"88101183","Stop":"88101183","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":16376,"rule_based_match":true,"evidence_text":"c.2991+1655A>G (p.Cys998X)","llm_judgment":"PRESENT","evidence":"c.2991+1655A>G (p.Cys998X)","abstract_start":483,"abstract_end":509}]}
{"pmid":"38061702","title":"Missense Variant c.3301C>T (p.R1101W) in von Willebrand Factor A Sequence in a Patient with Recessive Dystrophic Epidermolysis Bullosa Pruriginosa with Compound Heterozygous","abstract":"Dystrophic epidermolysis bullosa (DEB) pruriginosa is a rare subtype of DEB characterized by multiple, violaceous, and severe pruritic lichenified nodules along with blisters. Here, we report the case of a Korean male who, since the age of 3 years, had multiple pruritic nodules with blisters on both lower extremities. Genetic testing is required to diagnose DEB pruriginosa because its clinical and histologic features are inconclusive. We identified compound heterozygous <i>COL7A1</i> variants of c.5797C>T (p.R1933*) and c.3301C>T (p.R1101W) in the patient, leading to a diagnosis of recessive DEB pruriginosa. Among the variants identified, c.3301C>T is a novel missense variant that has not been reported previously. This variant is in exon 26, which encodes von Willebrand factor A (vWFA) in collagen type VII. vWFA is known to preserve normal dermal structures by interacting with dermal collagens and basement membranes. Considering that this variant contradicts the general concept that autosomal dominant inheritance is more common and that variants typically occur in the triple helical collagenous domain of <i>COL7A1</i> in DEB pruriginosa, we focus on the rarity of this case and the possible pathogenic role of the c.3301C>T (p.R1101W) variant.","variants":[{"Name":"NM_000094.4(COL7A1):c.3301C>T (p.Arg1101Trp)","Chromosome":"3","Start":"48586665","Stop":"48586665","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1435803,"rule_based_match":true,"evidence_text":"c.3301C>T (p.R1101W)","llm_judgment":"PRESENT","evidence":"c.3301C>T (p.R1101W)","abstract_start":526,"abstract_end":546}]}
{"pmid":"23942205","title":"Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB.","abstract":"Mutations in the SQSTM1 gene have been reported to be associated with amyotrophic lateral sclerosis (ALS). We sought to determine the frequency of these mutations in a UK familial ALS (FALS) cohort. Sequences of all eight exons of the SQSTM1 gene were analysed in index cases from 61 different FALS kindred lacking known FALS mutations. Six exonic variants c.463G>A, p.(Glu155Lys), c.822G>C, p.(Glu274Asp), c.888G>T, p.(=), c.954C>T, p.(=), c.1038G>A, p.(=) and c.1175C>T, p.(Pro392Leu) were identified in five FALS index cases, three of which were non-synonymous and three were synonymous. One index case harboured three variants (c.822G>C, c.888G>T and c.954C>T), and a second index case harboured two variants (c.822G>C and c.954C>T). Only the p.(Pro392Leu) and p.(Glu155Lys) mutations were predicted to be pathogenic. In one p.(Pro392Leu) kindred, the carrier developed both ALS and Paget's disease of bone (PDB), and, in the p.(Glu155Lys) kindred, the father of the proband developed PDB. All p.(Pro392Leu) carriers were heterozygous for a previously reported founder haplotype for PDB, where this mutation has an established causal effect. The frequency of the p.(Pro392Leu) mutation in this UK FALS cohort was 2.3% and 0.97% overall including three previously screened FALS cohorts. Our results confirm the presence of the p.(Pro392Leu) SQSTM1 mutation in FALS. This mutation is the most common SQSTM1 mutation found in ALS to date, and a likely pathogenicity is supported by having an established causal role in PDB. The occurrence of the same mutation in ALS and PDB is indicative of a common pathogenic pathway that converges on protein homeostasis.","variants":[{"Name":"NM_003900.5(SQSTM1):c.1175C>T (p.Pro392Leu)","Chromosome":"5","Start":"179836445","Stop":"179836445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23147,"rule_based_match":true,"evidence_text":"c.1175C>T, p.(Pro392Leu)","llm_judgment":"PRESENT","evidence":"c.1175C>T, p.(Pro392Leu)","abstract_start":462,"abstract_end":486},{"Name":"NM_003900.5(SQSTM1):c.463G>A (p.Glu155Lys)","Chromosome":"5","Start":"179824019","Stop":"179824019","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1867824,"rule_based_match":true,"evidence_text":"c.463G>A, p.(Glu155Lys)","llm_judgment":"PRESENT","evidence":"c.463G>A, p.(Glu155Lys)","abstract_start":357,"abstract_end":380}]}
{"pmid":"20457534","title":"The phenylalanine hydroxylase c.30C>G synonymous variation (p.G10G) creates a common exonic splicing silencer.","abstract":"PKU is caused by mutations in PAH. A c.30C>G synonymous variation in exon 1, previously reported as neutral, was observed in two patients. The variation creates a GGG triplet, which is part of several exonic splicing silencer (ESS) motifs. Because the 5'-splice site of PAH exon 1 is intrinsically weak and therefore could be responsive to a new flanking ESS, we hypothesized that c.30C>G could cause aberrant mRNA splicing. We demonstrate that c.30C>G causes aberrant mRNA splicing in two different reporter minigenes, and that this is abolished if a preexisting flanking GGG triplet is disrupted. GGG triplets are part of the consensus motif bound by splicing-inhibitory hnRNPH proteins and we observed a dramatic increase in hnRNPH binding to c.30C>G PAH RNA. We conclude that c.30C>G creates a hnRNPH-binding ESS, which can disrupt mRNA splicing. A disease-causing mutation in HEXB, which has previously been associated with exon skipping in patients also creates a GGG triplet. We show that the mutant HEXB motif causes exon skipping of a reporter minigene and that this is also influenced by a flanking GGG triplet. We suggest that aberrant splicing caused by creation/abolishment of GGG triplets located together with a preexisting flanking GGG triplet, may be an underreported cause of human disease. It is important to recognize that exonic sequence changes may disrupt mRNA splicing. This is particularly important in PAH, since PKU patients harboring such mutations are unlikely to respond to therapy with 6R-tetrahydrobiopterin (BH(4)), despite the fact that the genetic code indicates otherwise.","variants":[{"Name":"NM_000277.3(PAH):c.30C>G (p.Gly10=)","Chromosome":"12","Start":"102917101","Stop":"102917101","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":108385,"rule_based_match":true,"evidence_text":"c.30C>G","llm_judgment":"PRESENT","evidence":"c.30C>G","abstract_start":37,"abstract_end":44}]}
{"pmid":"16411092","title":"Calpain-3 mutations in Turkey.","abstract":"Autosomal recessive limb-girdle muscular dystrophies (LGMD2s) are a clinically and genetically heterogeneous group of disorders, characterized by progressive involvement of the proximal limb girdle muscles; the group includes at least 10 different genetic entities. The calpainopathies (LGMD2A), a subgroup of LGMD2s, are estimated to be the most common forms of LGMD2 in all populations so far investigated. LGMD2A is usually characterized by symmetrical and selective atrophy of pelvic, scapular and trunk muscles and a moderate to gross elevation of serum CK. However, the course is highly variable. It is caused by mutations in the CAPN3 gene, which encodes for the calpain-3 protein. Until now, 161 pathogenic mutations have been found in the CAPN3 gene. In the present study, through screening of 93 unrelated LGMD2 families, we identified 29 families with LGMD2A, 21 (22.6%) of which were identified as having CAPN3 gene mutations. We detected six novel (p.K211N, p.D230G, p.Y322H, p.R698S, p.Q738X, c.2257delGinsAA) and nine previously reported mutations (c.550delA, c.19_23del, c.1746-20C>G, p.R49H, p.R490Q, p.Y336N, p.A702V, p.Y537X, p.R541Q) in the CAPN3 gene. There may be a wide variety of mutations, but clustering of specific mutations (c.550delA: 40%, p.R490Q: 10%) could be used in the diagnostic scheme in Turkey.","variants":[{"Name":"NM_000070.3(CAPN3):c.1746-20C>G","Chromosome":"15","Start":"42403721","Stop":"42403721","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":98319,"rule_based_match":true,"evidence_text":"c.1746-20C>G","llm_judgment":"PRESENT","evidence":"c.1746-20C>G","abstract_start":1087,"abstract_end":1099},{"Name":"NM_000070.3(CAPN3):c.550del (p.Thr184fs)","Chromosome":"15","Start":"42387803","Stop":"42387803","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":32660,"rule_based_match":true,"evidence_text":"c.550delA","llm_judgment":"PRESENT","evidence":"c.550delA","abstract_start":1064,"abstract_end":1073}]}
{"pmid":"18406185","title":"Maroteaux-Lamy syndrome: functional characterization of pathogenic mutations and polymorphisms in the arylsulfatase B gene.","abstract":"Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome) is an autosomal recessive lysosomal disorder caused by deficiency of N-acetylgalactosamine-4-sulfatase (ARSB), which is required for the degradation of dermatan sulfate. We recently reported mutational screening of 12 Spanish and 4 Argentinian MPS VI patients. In the present study, seven missense mutations (c.245T>G [p.L82R], c.413A>G [p.Y138C], c.719C>T [p.S240F], c.922G>A [p.G308R], c.937C>G [p.P313A], c.1340G>T [p.C447F] and c.1415T>C [p.L472P]) were transiently expressed in COS-7 cells and 4-sulfatase activity was measured in cell extracts. All mutations resulted in less than 6% of wild-type enzyme activity, in most cases undetectable. Mutations were expressed in their original haplotype context with respect to two non-synonymous polymorphisms present in the ARSB protein, p.V358M and p.S384N. The three less frequent haplotype combinations yielded an ARSB activity of 16%, 57% and 70%, when compared to the most frequent haplotype (p.358V and p.384S). Western blot analyses showed that the expressed mutations significantly reduced the amount of mature protein. Sub-cellular localization studies of mutant ARSB proteins in fibroblasts of MPS VI patients were performed. RNA analysis confirmed that nonsense-mediated RNA decay had taken place for all mutant alleles (c.1143-1G>C, c.1143-8T>G, p.W322X, c.427delG and c.1142+2T>A) which were candidates for causing RNA degradation by this mechanism. In summary, all the ARSB mutations studied had a significant effect on enzyme activity, protein processing and/or mRNA stability.","variants":[{"Name":"NM_000046.5(ARSB):c.245T>G (p.Leu82Arg)","Chromosome":"5","Start":"78985004","Stop":"78985004","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":438563,"rule_based_match":true,"evidence_text":"c.245T>G [p.L82R]","llm_judgment":"PRESENT","evidence":"c.245T>G [p.L82R]","abstract_start":368,"abstract_end":385},{"Name":"NM_000046.5(ARSB):c.922G>A (p.Gly308Arg)","Chromosome":"5","Start":"78885804","Stop":"78885804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550455,"rule_based_match":true,"evidence_text":"c.922G>A [p.G308R]","llm_judgment":"PRESENT","evidence":"c.922G>A [p.G308R]","abstract_start":427,"abstract_end":445},{"Name":"NM_000046.5(ARSB):c.937C>G (p.Pro313Ala)","Chromosome":"5","Start":"78885789","Stop":"78885789","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":550453,"rule_based_match":true,"evidence_text":"c.937C>G [p.P313A]","llm_judgment":"PRESENT","evidence":"c.937C>G [p.P313A]","abstract_start":447,"abstract_end":465}]}
{"pmid":"19287372","title":"SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred's syndrome in Pakistanis.","abstract":"Pendred's syndrome (PDS) is an autosomal-recessive disorder characterized by sensorineural hearing loss and goiter. PDS is caused by mutations of the SLC26A4 gene encoding pendrin, a transmembrane exchanger of Cl(-), I(-) and HCO(3)(-), which is expressed in the thyroid and inner ear. SLC26A4 mutations can also be associated with non-syndromic deafness, DFNB4. The goal of our study was to define the identities and frequencies of SLC26A4 mutations in 563 large, consanguineous Pakistani families segregating severe-to-profound recessive deafness. Sequence analyses of SLC26A4 in 46 unreported families segregating deafness linked to DFNB4/PDS revealed 16 probable pathogenic variants, 8 of which are novel. The novel variants include three missense substitutions (p.R24L, p.G139V and p.V231M), two splice site mutations (c.304+2T>C and c.1341+3A>C), one frameshift (p.C565MfsX8) and two different genomic deletions affecting exons 1-2 and 11-18. Each of six pathogenic variants (p.V239D, p.Q446R, p.S90L, p.Y556C, p.R24L and p.K715N) was found in more than one family and haplotype analyses suggest that they are founder mutations. Combined with earlier reported data, SLC26A4 mutations were identified in 56 (7.2%; 95% CI: 5.6-9.2%) of 775 families. Therefore, SLC26A4 mutations are the most common known cause of genetic deafness in this population. As p.V239D (30%), p.S90L (18%) and p.Q446R (18%) account for approximately two-third of the mutant alleles of SLC26A4, hierarchical strategies for mutation detection would be feasible and cost-efficient genetic tests for DFNB4 deafness and PDS in Pakistanis.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1341+3A>C","Chromosome":"7","Start":"107694483","Stop":"107694483","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":544386,"rule_based_match":true,"evidence_text":"c.1341+3A>C","llm_judgment":"PRESENT","evidence":"c.1341+3A>C","abstract_start":839,"abstract_end":850},{"Name":"NM_000441.2(SLC26A4):c.269C>T (p.Ser90Leu)","Chromosome":"7","Start":"107663400","Stop":"107663400","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186727,"rule_based_match":false,"evidence_text":"p.S90L","llm_judgment":"PRESENT","evidence":"p.S90L","abstract_start":1000,"abstract_end":1006},{"Name":"NM_000441.2(SLC26A4):c.304+2T>C","Chromosome":"7","Start":"107663437","Stop":"107663437","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":186729,"rule_based_match":true,"evidence_text":"c.304+2T>C","llm_judgment":"PRESENT","evidence":"c.304+2T>C","abstract_start":824,"abstract_end":834}]}
{"pmid":"24530203","title":"Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.","abstract":"Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child.","variants":[{"Name":"NM_001739.2(CA5A):c.697T>C (p.Ser233Pro)","Chromosome":"16","Start":"87891876","Stop":"87891876","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":132597,"rule_based_match":true,"evidence_text":"c.697T>C (p.Ser233Pro)","llm_judgment":"PRESENT","evidence":"c.697T>C (p.Ser233Pro)","abstract_start":493,"abstract_end":515},{"Name":"NM_001739.2(CA5A):c.555G>A (p.Lys185=)","Chromosome":"16","Start":"87902425","Stop":"87902425","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":132598,"rule_based_match":true,"evidence_text":"c.555G>A","llm_judgment":"PRESENT","evidence":"c.555G>A","abstract_start":360,"abstract_end":368}]}
{"pmid":"20405026","title":"Nonsense mutation in TMEM126A causing autosomal recessive optic atrophy and auditory neuropathy.","abstract":"PURPOSE: To define the phenotype and elucidate the molecular basis for an autosomal recessively inherited optic atrophy and auditory neuropathy in a consanguineous family with two affected children.\nMETHODS: Family members underwent detailed ophthalmologic, electrophysiological, and audiological assessments. An autozygosity mapping strategy using high-density single nucleotide polymorphism microarrays and microsatellite markers was used to detect regions of genome homozygosity that might contain the disease gene. Candidate genes were then screened for mutations by direct sequencing.\nRESULTS: Both affected subjects had poor vision from birth and complained of progressive visual loss over time. Current visual acuity ranged from 6/60 to 6/120. Fundus examination revealed bilateral temporal optic nerve pallor in both patients with otherwise normal retinal findings. International-standard full-field electroretinograms were normal in both individuals, with no evidence of generalized retinal dysfunction. Pattern cortical visual evoked potentials were grossly abnormal bilaterally in both cases. The pattern electroretinogram N95:P50 ratio was subnormal, and the P50 was of shortened peak time bilaterally in both patients. The electrophysiological findings were consistent with bilateral retinal ganglion cell/optic nerve dysfunction. Audiological investigation in both siblings revealed abnormalities falling within the auditory neuropathy/dysynchrony spectrum. There were no auditory symptoms and good outer hair cell function (as demonstrated by transient evoked otoacoustic emissions) but impaired inner hair cell/neural function with abnormal stapedial reflex thresholds and abnormal or absent auditory brainstem-evoked responses. The single nucleotide polymorphism microarray data demonstrated a 24.17 Mb region of homozygosity at 11q14.1-11q22.3, which was confirmed by microsatellite marker analysis. The candidate target region contained the transmembrane protein 126A (TMEM126A) gene, and direct sequencing identified a previously described nonsense mutation (c.163C>T; p.Arg55X).\nCONCLUSIONS: We describe the first detailed phenotyping of patients with autosomal recessive TMEM126A-associated optic atrophy and auditory neuropathy. These findings will facilitate the identification of individuals with this recently described disorder.","variants":[{"Name":"NM_032273.4(TMEM126A):c.163C>T (p.Arg55Ter)","Chromosome":"11","Start":"85654139","Stop":"85654139","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15449,"rule_based_match":true,"evidence_text":"c.163C>T; p.Arg55X","llm_judgment":"PRESENT","evidence":"c.163C>T; p.Arg55X","abstract_start":2079,"abstract_end":2097}]}
{"pmid":"38579284","title":"Wiskott-Aldrich Syndrome: A study on 577 patients defining the genotype as a predictive biomarker for disease severity.","abstract":"WAS is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% CI 78-87) at 15 years and 70% (61-80) at 30 years of age. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hotspot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared to 71% (62-81) and 48% (34-68) in patients with any other variant (class II; p<0.0001). The cumulative incidence rates of disease-related complications such as severe bleeding (p=0.007), life-threatening infection (p<0.0001), and autoimmunity (p=0.004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (p=0.6) was not different between classes I and II. This study represents the largest cohort of WAS patients studied so far. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of variant is a biomarker to predict the outcome for WAS patients.","variants":[{"Name":"NM_000377.3(WAS):c.559+5G>A","Chromosome":"X","Start":"48686139","Stop":"48686139","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360692,"rule_based_match":true,"evidence_text":"c.559+5G>A","llm_judgment":"PRESENT","evidence":"c.559+5G>A","abstract_start":779,"abstract_end":789}]}
{"pmid":"30849045","title":"The diagnosis of cystinosis in patients reveals new CTNS gene mutations in the Chinese population.","abstract":"Background Cystinosis is a rare autosomal-recessive disorder caused by a defective transport of cystine across the lysosomal membrane. Previous studies have mapped cystinosis to the CTNS gene which is located on chromosome 17p13, and various CTNS mutations have been identified to correlate them with this disease. Methods We analyzed six patients from five unrelated families who were diagnosed with cystinosis in our hospital. We described the diagnostic procedures for all the patients and proposed alternative therapies for cystinosis patients instead of using cysteamine, an orphan drug which was commercially unavailable in China. Moreover, genetic analysis of all patients' samples was carried out to identify novel CTNS gene mutations. Results and conclusions The patients in this study were followed up from 1 to more than 10 years to monitor their growth and development, which indicated that the alternative therapies we used were helpful to ameliorate the complications of the cystinosis patients without cysteamine. Furthermore, by sequencing the patients' genome, we identified novel mutations in the CTNS gene including: c.477C > G (p.S159R), c.274C > T (p.Q92X) and c.680A > T (p.E227V); these mutations were only observed in cystinosis patients and had never been reported in any other populations, suggesting they might be specific to Chinese cystinosis patients.","variants":[{"Name":"NM_004937.3(CTNS):c.274C>T (p.Gln92Ter)","Chromosome":"17","Start":"3655046","Stop":"3655046","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1064157,"rule_based_match":true,"evidence_text":"c.274C > T (p.Q92X)","llm_judgment":"PRESENT","evidence":"c.274C > T (p.Q92X)","abstract_start":1158,"abstract_end":1177}]}
{"pmid":"33520300","title":"Novel Compound Heterozygous","abstract":"BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare multisystem developmental disorder. In this study, we report the genetic causes and clinical manifestations in two Chinese families with BBS.\nMATERIALS AND METHODS: Two families were recruited in this study. Family A was a four-generation family with four affected and 15 unaffected members participating in the study, and family B was a consanguineous family with one affected and three unaffected members participating. Whole exome sequencing was performed in the two families, followed by a multistep bioinformatics analysis. Sanger sequencing was used to verify the variants and to perform a segregation analysis. Comprehensive ocular and systemic examinations were also conducted.\nRESULTS: Novel compound heterozygous variants c.235T > G (p.T79P) and c.534 + 1G > T were detected in the <i>BBS2</i> gene in family A, and known homozygous variant c.748G > A (p.G250R) was detected in the <i>MKKS</i> gene in family B. Both families presented with retinitis pigmentosa; however, except for polydactyly, all other systemic manifestations were different. All of the affected family members in family A were overweight with a high body mass index (range from 26.5 to 41.9) and high blood pressure. Family A also presented with a delay in the onset of secondary sex characteristics and genital anomalies, while other systemic abnormalities were absent in family B.\nCONCLUSIONS: This study presents one family with two novel <i>BBS2</i> variants, expanding the variant spectrum of BBS, and one family with a known homozygous <i>MKKS</i> variant. The different phenotypes seen between the families with <i>BBS2</i> and <i>MKKS</i> variants will contribute to the literature and our overall understanding of BBS.","variants":[{"Name":"NM_031885.5(BBS2):c.534+1G>T","Chromosome":"16","Start":"56510858","Stop":"56510858","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":547812,"rule_based_match":true,"evidence_text":"c.534 + 1G > T","llm_judgment":"PRESENT","evidence":"c.534 + 1G > T","abstract_start":806,"abstract_end":820},{"Name":"NM_170784.3(MKKS):c.748G>A (p.Gly250Arg)","Chromosome":"20","Start":"10412767","Stop":"10412767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":950981,"rule_based_match":true,"evidence_text":"c.748G > A (p.G250R)","llm_judgment":"PRESENT","evidence":"c.748G > A (p.G250R)","abstract_start":901,"abstract_end":921}]}
{"pmid":"29987841","title":"Report of second case and clinical and molecular characterization of Eiken syndrome.","abstract":"We report a boy with Eiken syndrome caused by a homozygous missense variant in Parathyroid hormone 1 receptor (PTH1R) c.103G > A [p.(Glu35Lys)]. Eiken syndrome is a very rare skeletal dysplasia due to bi-allelic variants in PTH1R. Only one affected family has been known to-date. The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities. The phenotype being described here recapitulates the delayed ossification and modeling abnormalities of Eiken syndrome. In addition, supernumerary epiphyses of the tubular bones of the hands and primary failure of eruption of teeth were observed in our proband. This report characterizes Eiken syndrome and confirms that bi-allelic hypomorphic variants in PTH1R are probably to cause this condition.","variants":[{"Name":"NM_000316.3(PTH1R):c.103G>A (p.Glu35Lys)","Chromosome":"3","Start":"46893934","Stop":"46893934","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":536213,"rule_based_match":true,"evidence_text":"c.103G > A [p.(Glu35Lys)]","llm_judgment":"PRESENT","evidence":"c.103G > A [p.(Glu35Lys)]","abstract_start":118,"abstract_end":143}]}
{"pmid":"20398363","title":"A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report.","abstract":"Congenital disorders of glycosylation (CDG) are an expanding group of inherited metabolic diseases with multisystem involvement. ALG6-CDG (CDGIc) is an endoplasmatic reticulum defect in N-glycan assembly. It is usually milder than PMM2-CDG (CDG-Ia) and so is its natural course. It is characterized by psychomotor retardation, seizures, ataxia, and hypotonia. In contrast to PMM2-CDG (CDGIa), there is no cerebellar hypoplasia. Cardiomyopathy has been reported in a few CDG types and in a number of patients with unexplained CDG. We report an 11 year old Saudi boy with severe psychomotor retardation, seizures, strabismus, inverted nipples, dilated cardiomyopathy, and a type 1 pattern of serum transferrin isoelectrofocusing. Phosphomannomutase and phosphomannose isomerase activities were normal in fibroblasts. Full gene sequencing of the ALG6 gene revealed a novel mutation namely c.482A>G (p.Y161C) and heterozygosity in the parents. This report highlights the importance to consider CDG in the differential diagnosis of unexplained cardiomyopathy.","variants":[{"Name":"NM_013339.4(ALG6):c.482A>G (p.Tyr161Cys)","Chromosome":"1","Start":"63407114","Stop":"63407114","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":620010,"rule_based_match":true,"evidence_text":"c.482A>G (p.Y161C)","llm_judgment":"PRESENT","evidence":"c.482A>G (p.Y161C)","abstract_start":886,"abstract_end":904}]}
{"pmid":"27725551","title":"CADASIL Presenting as Acute Bilateral Multiple Subcortical Infarcts without a Characteristic Temporal Pole or Any External Capsule Lesions.","abstract":"A 37-year-old man was hospitalized for an evaluation of acute bilateral multiple subcortical infarcts. There were no specific signal abnormalities in the temporal pole or external capsule. An abdominal skin biopsy showed granular, electron-dense, osmiophilic material (GOM) in the smooth muscle cells on electron microscopy. A direct sequencing analysis of NOTCH3 revealed a heterozygous c.986G>A substitution in exon 6, resulting in a Cys329Tyr amino acid replacement. According to these findings, the patient was diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencehalopathy (CADASIL). Thus, early phases of CADASIL can present as acute bilateral multiple subcortical infarcts without a characteristic temporal pole or any external capsule lesions.","variants":[{"Name":"NM_000435.3(NOTCH3):c.986G>A (p.Cys329Tyr)","Chromosome":"19","Start":"15191474","Stop":"15191474","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":983136,"rule_based_match":true,"evidence_text":"c.986G>A","llm_judgment":"PRESENT","evidence":"c.986G>A","abstract_start":388,"abstract_end":396}]}
{"pmid":"32037607","title":"Myopathy associated with homozygous PYROXD1 pathogenic variants detected by genome sequencing.","abstract":"Biallelic pathogenic variants in the gene PYROXD1 have recently been described to cause early-onset autosomal recessive myopathy. Myopathy associated with PYROXD1 pathogenic variants is rare and reported in only 17 individuals. Known pathogenic variants in PYROXD1 include missense, insertion and essential splice-site variants. Here we describe a consanguineous family of individuals affected with late-onset myopathy and homozygous PYROXD1 missense variants (NM_024854.5:c.464A>G [p.Asn155Ser]) expanding our understanding of the possible disease phenotypes of PYROXD1-associated myopathy.","variants":[{"Name":"NM_024854.5(PYROXD1):c.464A>G (p.Asn155Ser)","Chromosome":"12","Start":"21452130","Stop":"21452130","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":359188,"rule_based_match":true,"evidence_text":"NM_024854.5:c.464A>G [p.Asn155Ser]","llm_judgment":"PRESENT","evidence":"NM_024854.5:c.464A>G [p.Asn155Ser]","abstract_start":461,"abstract_end":495}]}
{"pmid":"28494813","title":"Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.","abstract":"BACKGROUND: Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy.\nRESULTS: We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients' biological samples, and a clearly fragmented mitochondrial network was observed in patients' fibroblasts.\nCONCLUSIONS: This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature.","variants":[{"Name":"NM_130837.3(OPA1):c.1311A>G (p.Ile437Met)","Chromosome":"3","Start":"193643378","Stop":"193643378","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":59852,"rule_based_match":false,"evidence_text":"c.1311A>G (p.Ile437Met)","llm_judgment":"PRESENT","evidence":"p.Ile437Met","abstract_start":954,"abstract_end":965}]}
{"pmid":"33225636","title":"Report of a rare case of congenital mitral valve prolapse with chronic kidney disease--reconsidered genotype-phenotypic correlations.","abstract":"BACKGROUND: Mitral valve prolapse (MVP) is a common cardiovascular disease defined as a late systolic click or mitral valve lobes that move up into the left atrium during ventricular systole, with or without mitral insufficiency. Dachsous catherin-related 1 (DCHS1) is one of the two known pathogenic genes associated with MVP. However, there is little information about the renal dysfunction caused by MVP and DCHS1 mutations.\nMETHODS: We analyzed the genetic etiology in a rare case of 9-year-old boy affected by chronic renal failure with MVP. Subsequently, we constructed stable cell lines overexpressing wild-type DCHS1 or mutant DCHS1 (c.8309G>A, p.R2770Q) to evaluate the influence of the DCHS1 mutation on the proliferation, apoptosis, and autophagy.\nRESULTS: Complete exome sequencing and pedigree verification revealed a mutation p.R2770Q (c.8309G>A) in exon 21 of the DCHS1 gene carried by the patient, which may affect the DNA binding. No such mutation was detected in his parents, indicating that this was a new mutation. Potential functional impact of sequence variants was predicted using in silico prediction programs including SIFT, Polyphen2, and Condel. This variant was determined to be a pathogenic mutation that has not been reported elsewhere. Subsequently, we used a stable DCHS1 gene-mutated HK-2 cell line to analyse proliferation, apoptosis, and autophagy, showed that kidney volume decreased with increasing cell death associated with a reduced proliferation.\nCONCLUSIONS: Our analysis revealed a heterozygous variation of DCHS1 in a child with MVP. Our observations highlight previously unrecognized phenotypes of the currently recognized MVP genotype, including distinct chronic renal failure.","variants":[{"Name":"NM_003737.4(DCHS1):c.8309G>A (p.Arg2770Gln)","Chromosome":"11","Start":"6623367","Stop":"6623367","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2004664,"rule_based_match":true,"evidence_text":"c.8309G>A (p.R2770Q)","llm_judgment":"PRESENT","evidence":"c.8309G>A","abstract_start":642,"abstract_end":651}]}
{"pmid":"27055476","title":"Evidence of mutations in RIC3 acetylcholine receptor chaperone as a novel cause of autosomal-dominant Parkinson's disease with non-motor phenotypes.","abstract":"BACKGROUND: The known genetic determinants of Parkinson's disease (PD) do not explain all cases investigated to date. Contemporary sequencing technologies hold promise for enhanced causal variant discovery. We attempted to identify the putative causal variant in an Indian PD family by whole exome sequencing (WES).\nMETHODS: WES data generated for two affected cousins from a 14-member PD family with some non-motor phenotypes were analysed. Variants prioritised were checked for segregation with disease by targeted sequencing. An independent PD cohort (n=280) was screened for additional mutations in the prioritised gene. Variants were functionally validated in PC12 cells differentiated into neurons.\nRESULTS: A heterozygous mutation c.169C>A, p.P57T in RIC3 acetylcholine receptor chaperone (11p15) segregated with disease in the family confirming an autosomal-dominant mode of inheritance. Another heterozygous mutation c.502G>C, p.V168L was detected in an unrelated PD case. Both mutations were absent in 144 healthy control and in 74 non-PD WES data available in-house and in 186 age and sex-matched controls screened by PCR sequencing. RIC3 is a known chaperone of neuronal nicotinic acetylcholine receptor subunit α-7 (CHRNA7). Dominant negative effect of RIC3 mutants in transfected PC12 cells was reflected by the reduced levels of endogenous CHRNA7 in the membrane fractions in western blots and lower colocalisation profiles in confocal micrographs.\nCONCLUSION: The novel demonstration of a chaperone-mediated receptor density alteration due to RIC3 mutants provides strong evidence for the role of cholinergic pathway for the first time in PD aetiology. This may also be insightful for some non-motor symptoms and personalised treatment.","variants":[{"Name":"NM_001206671.4(RIC3):c.169C>A (p.Pro57Thr)","Chromosome":"11","Start":"8140149","Stop":"8140149","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":249263,"rule_based_match":true,"evidence_text":"c.169C>A, p.P57T","llm_judgment":"PRESENT","evidence":"c.169C>A, p.P57T","abstract_start":738,"abstract_end":754}]}
{"pmid":"22032251","title":"Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia.","abstract":"BACKGROUND: Mutations in the high penetrance breast and ovarian cancer susceptibility gene BRCA1 account for a significant percentage of hereditary breast and ovarian cancer cases. Genotype-phenotype correlations of BRCA1 mutations located in different parts of the BRCA1 gene have been described previously; however, phenotypic differences of specific BRCA1 mutations have not yet been fully investigated. In our study, based on the analysis of a population-based series of unselected breast and ovarian cancer cases in Latvia, we show some aspects of the genotype-phenotype correlation among the BRCA1 c.4034delA (4153delA) and c.5266dupC (5382insC) founder mutation carriers.\nMETHODS: We investigated the prevalence of the BRCA1 founder mutations c.4034delA and c.5266dupC in a population-based series of unselected breast (n = 2546) and ovarian (n = 795) cancer cases. Among the BRCA1 mutation carriers identified in this analysis we compared the overall survival, age at diagnosis and family histories of breast and ovarian cancers.\nRESULTS: We have found that the prevalence of breast and ovarian cancer cases (breast: ovarian cancer ratio) differs significantly among the carriers of the c.5266dupC and c.4034delA founder mutations (OR = 2.98, 95%CI = 1.58 to 5.62, P < 0.001). We have also found a difference in the prevalence of breast and ovarian cancer cases among the 1st and 2nd degree relatives of the c.4034delA and c.5266dupC mutation carriers. In addition, among the breast cancer cases the c.4034delA mutation has been associated with a later age of onset and worse clinical outcomes in comparison with the c.5266dupC mutation.\nCONCLUSIONS: Our data suggest that the carriers of the c.4034delA and c.5266dupC founder mutations have different risks of breast and ovarian cancer development, different age of onset and prognosis of breast cancer.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"c.5266dupC","llm_judgment":"PRESENT","evidence":"c.5266dupC","abstract_start":630,"abstract_end":640}]}
{"pmid":"36609239","title":"Prenatal diagnosis of Noonan syndrome in a set of monozygotic twins- a case report.","abstract":"BACKGROUND: We report a pair of dichorionic diamniotic (DCDA) twin pregnancy affected by Noonan syndrome (NS) with a novel mutation of LZTR1 determined by genetic analysis.\nCASE PRESENTATION: A pregnant woman with monozygotic twins (DCDA) at 12 + 2 weeks gestation was referred to our center. This was her second pregnancy following a previous delivery of a healthy infant. Nuchal translucency of two fetuses was 11.2 mm (CRL 62.0 mm) and 6.9 mm (CRL 62.1 mm) respectively. Ultrasound examination indicated cystic hygroma and hypoplastic ear. The couple was not consanguineous, and both had normal phenotype. Familial hereditary disease was also excluded. Under ultrasound guidance, 30 mg of chorionic villi was obtained for karyotyping, quantitative fluorescent polymerase chain reaction (QF-PCR), chromosomal microarray analysis(CMA), and Trio-whole-exome sequencing(WES) examination. We used the \"target region capture and sequencing\" for WES, and the BWA (Burrows Wheeler Aligner) Multi-Vision software package for the data analysis. The results of all these tests were normal except WES detected a c.427 A > G mutation in the exonic region of the LZTR1 gene and a p. Asn143Asp novel heterozygous mutation associated with NS in this pair of twins. In addition, WES suggested that the mutation in the twin fetuses originated from the mother. When the mother got the genetic test report, she came to our fetal medicine department for genetic counseling and she declined the appointment with a clinical geneticist. The couple opted to terminate the pregnancy. Because the patient did not choose to terminate the pregnancy at our hospital, we were unable to take further examination. With the help of colleagues in another hospital, photos of the fetuses were taken. Compared with the prenatal ultrasound results, the appearance of the \"cystic hygroma\" and \"hypoplastic ear\" was consistent with the ultrasound. The couple were depressed after knowing this pathogenic result and although we advised the mother to take further investigation, they refused.\nCONCLUSION: The mutant locus might be incompletely dominant, which led to an abnormal fetal phenotype such as cystic hygroma and hypoplastic ear.","variants":[{"Name":"NM_006767.4(LZTR1):c.427A>G (p.Asn143Asp)","Chromosome":"22","Start":"20988036","Stop":"20988036","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3738489,"rule_based_match":true,"evidence_text":"c.427 A > G mutation in the exonic region of the LZTR1 gene and a p. Asn143Asp novel heterozygous mutation","llm_judgment":"PRESENT","evidence":"c.427 A > G mutation in the exonic region of the LZTR1 gene and a p. Asn143Asp novel heterozygous mutation","abstract_start":1103,"abstract_end":1209}]}
{"pmid":"32093671","title":"Mutation screening of the USH2A gene reveals two novel pathogenic variants in Chinese patients causing simplex usher syndrome 2.","abstract":"BACKGROUND: Usher syndrome (USH) is the most prevalent cause of the human genetic deafness and blindness. USH type II (USH2) is the most common form of USH, and USH2A is the major pathogenic gene for USH2. For expanding the spectrum of USH2A mutations and further revealing the role of USH2A in USH2, we performed the USH2A gene variant screening in Chinese patients with USH2.\nMETHODS: Genomic DNA was extracted from peripheral blood of unrelated Chinese USH2 patients, we designed specific primers for amplifying the coding region (exons 2-72) of the USH2A gene. Sanger sequencing was used to study alleles. Silico prediction tools were used to predict the pathogenicity of the variants identified in these patients.\nRESULTS: Five heterozygous pathogenic variants were detected in four patients. Two patients were found to have two-mutations and two patients only have one. Two novel variants c.4217C > A (p.Ser1406X) and c.11780A > G (p.Asp3927Gly)) were predicted deleterious by computer prediction algorithms. In addition, three reported mutations (c.8559-2A > G, c.8232G > C and c.11389 + 3A > T) were also found in this study.\nCONCLUSIONS: We identified five heterozygous pathogenic variants in the USH2A gene in Chinese patients diagnosed with Usher syndrome type 2, two of which were not reported. It expands the spectrum of USH2A variants in USH.","variants":[{"Name":"NM_206933.4(USH2A):c.4217C>A (p.Ser1406Ter)","Chromosome":"1","Start":"216196587","Stop":"216196587","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1380261,"rule_based_match":true,"evidence_text":"c.4217C > A (p.Ser1406X)","llm_judgment":"PRESENT","evidence":"c.4217C > A (p.Ser1406X)","abstract_start":895,"abstract_end":919},{"Name":"NM_206933.4(USH2A):c.8559-2A>G","Chromosome":"1","Start":"215877882","Stop":"215877882","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":57766,"rule_based_match":true,"evidence_text":"c.8559-2A>G","llm_judgment":"PRESENT","evidence":"c.8559-2A > G","abstract_start":1054,"abstract_end":1067},{"Name":"NM_206933.4(USH2A):c.11389+3A>T","Chromosome":"1","Start":"215758592","Stop":"215758592","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":418815,"rule_based_match":true,"evidence_text":"c.11389 + 3A > T","llm_judgment":"PRESENT","evidence":"c.11389 + 3A > T","abstract_start":1085,"abstract_end":1101}]}
{"pmid":"31782998","title":"Punctiform and Polychromatic Pre-Descemet Corneal Dystrophy: Clinical Evaluation and Identification of the Genetic Basis.","abstract":"PURPOSE: This study reports the clinical features and genetic bases of 3 previously unreported families with punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD).\nDESIGN: Observational case series.\nMETHODS: Full ophthalmic assessment was performed for members of 3 unreported families with PPPCD. Structural and biomechanical alterations of the cornea were screened. Whole exome sequencing (WES) was performed in the first family. Novel or rare variants that segregated with the affected status were screened in the other 2 families using Sanger sequencing. Identified variants that segregated with the affected status in all families were characterized by using in silico prediction tools and/or in vitro splice assays. Additionally, 2 previously reported PPPCD families were screened for variants identified in the 3 unreported PPPCD families.\nRESULTS: PPPCD was diagnosed in 12 of the 21 examined members of the 3 unreported families. The only refractive, topographic, or biomechanical abnormality associated with PPPCD was a significantly increased corneal stiffness. WES and Sanger sequencing identified 2 variants that segregated with the affected status in all 3 families: a rare intronic PDZD8 c.872+10A>T variant and a novel missense PRDX3 c.568G>C (p.Asp190His) variant. The same PRDX3 variant was identified in the previously reported PPPCD family expressing the common PPPCD phenotype and was predicted by in silico prediction tools to be damaging to protein function.\nCONCLUSIONS: PPPCD is associated with an alteration of corneal biomechanics and a novel missense variant in PRDX3. Screening of additional families will determine whether all families demonstrate a PRDX3 variant or whether locus heterogeneity may exist for PPPCD.","variants":[{"Name":"NM_006793.5(PRDX3):c.568G>C (p.Asp190His)","Chromosome":"10","Start":"119169326","Stop":"119169326","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1679109,"rule_based_match":true,"evidence_text":"PRDX3 c.568G>C (p.Asp190His)","llm_judgment":"PRESENT","evidence":"PRDX3 c.568G>C (p.Asp190His)","abstract_start":1258,"abstract_end":1286}]}
{"pmid":"15523651","title":"Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1.","abstract":"Holoprosencephaly (HPE) is a relatively common brain malformation resulting in an incomplete separation of the two cerebral hemispheres. A number of mutations in different genes have been linked to this malformation, including three missense mutations in the homeodomain of the transcription factor SIX3. In this study, we investigated the functional consequences of these SIX3 mutations with respect to the ability of the protein to interact with and stimulate the transcriptional activity of the nuclear receptor NOR1 (NR4A3). Using glutathione S-transferase fusion protein pull-down assays and transient cotransfections of Neuro-2a cells with expression and reporter vectors, we found that one mutation, c.676C>G (p.L226V), does not alter the properties of SIX3 toward NOR1. Another mutation, c.749T>C (p.V250A), results in the production of a highly unstable protein in Neuro-2a cells. The third mutation, c.770G>C (p.R257P), results in a mutant SIX3 protein that no longer interacts with NOR1 in vivo. These observations suggest that different SIX3 mutations in HPE2 may affect different signaling pathways, and that one of these pathways may involve the nuclear receptor NOR1.","variants":[{"Name":"NM_005413.4(SIX3):c.676C>G (p.Leu226Val)","Chromosome":"2","Start":"44942780","Stop":"44942780","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":21132,"rule_based_match":true,"evidence_text":"c.676C>G (p.L226V)","llm_judgment":"PRESENT","evidence":"c.676C>G (p.L226V)","abstract_start":707,"abstract_end":725},{"Name":"NM_005413.4(SIX3):c.770G>C (p.Arg257Pro)","Chromosome":"2","Start":"44942874","Stop":"44942874","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":21133,"rule_based_match":true,"evidence_text":"c.770G>C (p.R257P)","llm_judgment":"PRESENT","evidence":"c.770G>C (p.R257P)","abstract_start":910,"abstract_end":928},{"Name":"NM_005413.4(SIX3):c.749T>C (p.Val250Ala)","Chromosome":"2","Start":"44942853","Stop":"44942853","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":21134,"rule_based_match":true,"evidence_text":"c.749T>C (p.V250A)","llm_judgment":"PRESENT","evidence":"c.749T>C (p.V250A)","abstract_start":796,"abstract_end":814}]}
{"pmid":"18554571","title":"A novel mutation confirms MFRP as the gene causing the syndrome of nanophthalmos-renititis pigmentosa-foveoschisis-optic disk drusen.","abstract":"PURPOSE: To describe the clinical and genetic characteristics of the second family with a recently described recessive syndrome characterized by posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disk drusen.\nDESIGN: Observational case report.\nMETHODS: Three affected subjects and one healthy sibling from a consanguineous marriage from Spain were studied. Complete ophthalmologic examinations including A- and B-mode ultrasonography (US), electroretinography (ERG), fluorescein retinal angiography (FA), and optical coherence tomography (OCT) were performed in each individual. Genetic analysis included polymerase chain reaction amplification and direct nucleotide sequencing of the complete MFRP gene.\nRESULTS: All three affected siblings had bilateral shortening of the posterior ocular segment associated with high hyperopia and normal anterior segment dimensions. Best-corrected visual acuity ranged from 20/200 to 20/60. Funduscopy, ERG, and FA were compatible with retinitis pigmentosa, and B-mode ultrasound showed optic disk drusen. OCT analysis revealed outer retinal layer schisis with absence of foveal pit. Inheritance of this syndrome followed an autosomal recessive pattern. Molecular analysis revealed a novel homozygous 1-bp deletion (c.498delC) in exon 5 of MFRP, predicting a prematurely truncated protein (P166fsX190). A healthy sister demonstrated to be a carrier of the mutation.\nCONCLUSIONS: We confirmed that the syndrome of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disk drusen constitutes a distinct autosomal recessive entity. The novel frameshift mutation identified in the family described here validates MFRP as the gene responsible for this particular disease, which characteristically involves structures located at the posterior segment of the eye.","variants":[{"Name":"NM_031433.4(MFRP):c.498del (p.Asn167fs)","Chromosome":"11","Start":"119345563","Stop":"119345563","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":19515,"rule_based_match":true,"evidence_text":"c.498delC","llm_judgment":"PRESENT","evidence":"c.498delC","abstract_start":1274,"abstract_end":1283}]}
{"pmid":"33203071","title":"Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells.","abstract":"Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in <i>SMARCAL1</i>. A phenotype-genotype correlation has been attempted and variable expressivity of biallelic <i>SMARCAL1</i> variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the <i>SMARCAL1</i> gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with <i>SMARCAL1</i> mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.","variants":[{"Name":"NM_014140.4(SMARCAL1):c.1682G>A (p.Arg561His)","Chromosome":"2","Start":"216438457","Stop":"216438457","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1928193,"rule_based_match":true,"evidence_text":"c.1682G>A; p.Arg561His","llm_judgment":"PRESENT","evidence":"c.1682G>A; p.Arg561His","abstract_start":551,"abstract_end":573}]}
{"pmid":"25008357","title":"The BAG3 gene variants in Polish patients with dilated cardiomyopathy: four novel mutations and a genotype-phenotype correlation.","abstract":"BACKGROUND: BAG3 gene mutations have been recently implicated as a novel cause of dilated cardiomyopathy (DCM). Our aim was to evaluate the prevalence of BAG3 mutations in Polish patients with DCM and to search for genotype-phenotype correlations.\nMETHODS: We studied 90 unrelated probands by direct sequencing of BAG3 exons and splice sites. Large deletions/insertions were screened for by quantitative real time polymerase chain reaction (qPCR).\nRESULTS: We found 5 different mutations in 6 probands and a total of 21 mutations among their relatives: the known p.Glu455Lys mutation (2 families), 4 novel mutations: p.Gln353ArgfsX10 (c.1055delC), p.Gly379AlafsX45 (c.1135delG), p.Tyr451X (c.1353C>A) and a large deletion of 17,990 bp removing BAG3 exons 3-4. Analysis of mutation positive relatives of the probands from this study pooled with those previously reported showed higher DCM prevalence among those with missense vs. truncating mutations (OR = 8.33, P = 0.0058) as well as a difference in age at disease onset between the former and the latter in Kaplan-Meier survival analysis (P = 0.006). Clinical data from our study suggested that in BAG3 mutation carriers acute onset DCM with hemodynamic compromise may be triggered by infection.\nCONCLUSIONS: BAG3 point mutations and large deletions are relatively frequent cause of DCM. Delayed DCM onset associated with truncating vs. non-truncating mutations may be important for genetic counseling.","variants":[{"Name":"NM_004281.4(BAG3):c.1353C>A (p.Tyr451Ter)","Chromosome":"10","Start":"119676907","Stop":"119676907","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1314248,"rule_based_match":true,"evidence_text":"c.1353C>A","llm_judgment":"PRESENT","evidence":"c.1353C>A","abstract_start":690,"abstract_end":699}]}
{"pmid":"30025138","title":"Genotype and Phenotype Spectrum of FRMD7-Associated Infantile Nystagmus Syndrome.","abstract":"Purpose: We investigate the genotype and phenotype spectrum of FRMD7-associated infantile nystagmus syndrome in Korean probands.\nMethods: A total of 37 patients with infantile nystagmus syndrome were recruited prospectively for genetic analysis. We performed polymerase chain reaction (PCR)-based direct sequencing and haplotype analysis for FRMD7. Detailed ophthalmic examinations and eye movement recordings were compared between FRMD7 and non-FRMD7 groups.\nResults: In 13 (35%) of 37 patients, five different mutations of FRMD7 were detected: start codon mutation c.1A>G, splice site mutation c.162+6T>C, and three missense mutations (c.575A>C, c.722A>G, and c.875T>C). The latter mutation was identified in seven unrelated patients, and always was accompanied with two single nucleotide polymorphisms of exon 12 (rs6637934, rs5977623). Compared to non-FRMD7 groups, a cup-to-disc ratio was significantly decreased in FRMD7 groups (P < 0.001), and a disc-macula distance to disc diameter ratio markedly increased in the FRMD7 group (P = 0.015). Most patients in the FRMD7 group had at least two types of the nystagmus waveforms, and the most common type was unidirectional jerk nystagmus (75%), such as pure jerk and jerk with extended foveation, followed by pendular (25%), bidirectional jerk (19%), and dual jerk (6%) nystagmus. No significant differences were observed between FRMD7 and non-FRMD7 groups in terms of the nystagmus waveform, presence of periodic alternating nystagmus, and mean foveation time.\nConclusions: We identified five FRMD7 mutations in 35% of our infantile nystagmus syndrome cohort, expanding its mutational spectrum. The missense mutation c.875T>C may be a common mutation arisen from the founder effect in Korea. Optic nerve dysplasia associated with FRMD7 mutations suggests that the abnormal development of afferent visual systems may affect neural circuitry within the oculomotor system.","variants":[{"Name":"NM_194277.3(FRMD7):c.875T>C (p.Leu292Pro)","Chromosome":"X","Start":"132082393","Stop":"132082393","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1314704,"rule_based_match":true,"evidence_text":"c.875T>C","llm_judgment":"PRESENT","evidence":"c.875T>C","abstract_start":662,"abstract_end":670}]}
{"pmid":"28493373","title":"The novel αB-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy.","abstract":"Restrictive cardiomyopathy (RCM) is a rare heart disease characterized by diastolic dysfunction and atrial enlargement. The genetic etiology of RCM is not completely known. We identified by a next-generation sequencing panel the novel CRYAB missense mutation c.326A>G, p.D109G in a small family with RCM in combination with skeletal myopathy with an early onset of the disease. CRYAB encodes αB-crystallin, a member of the small heat shock protein family, which is highly expressed in cardiac and skeletal muscle. In addition to in silico prediction analysis, our structural analysis of explanted myocardial tissue of a mutation carrier as well as in vitro cell transfection experiments revealed abnormal protein aggregation of mutant αB-crystallin and desmin, supporting the deleterious effect of this novel mutation. In conclusion, CRYAB appears to be a novel RCM gene, which might have relevance for the molecular diagnosis and the genetic counseling of further affected families in the future.","variants":[{"Name":"NM_001289808.2(CRYAB):c.326A>G (p.Asp109Gly)","Chromosome":"11","Start":"111908966","Stop":"111908966","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":260536,"rule_based_match":true,"evidence_text":"c.326A>G, p.D109G","llm_judgment":"PRESENT","evidence":"c.326A>G, p.D109G","abstract_start":259,"abstract_end":276}]}
{"pmid":"32355443","title":"Mutations in","abstract":"Purpose: This study was designed to identify the pathogenic variants in three consanguineous families with congenital cataracts segregating as a recessive trait.\nMethods: Consanguineous families with multiple individuals manifesting congenital cataracts were ascertained. All participating members underwent an ophthalmic examination. A small aliquot of the blood sample was collected from all participating individuals, and genomic DNAs were extracted. Homozygosity-based linkage analysis was performed using short tandem repeat (STR) markers. The haplotypes were constructed with alleles of the STR markers, and the two-point logarithm of odds (LOD) scores were calculated. The candidate gene was sequenced bidirectionally to identify the disease-causing mutations.\nResults: Linkage analysis localized the disease interval to chromosome 3p in three families. Subsequently, bidirectional Sanger sequencing identified two novel mutations-a single base deletion resulting in a frameshift (c.3196delC; p.His1066IlefsTer10) mutation and a single base substitution resulting in a nonsense (c.4270C>T; p.Arg1424Ter) mutation-and a known missense (c.4127T>C, p.Leu1376Pro) mutation in <i>FYCO1</i>. All three mutations showed complete segregation with the disease phenotype and were absent in 96 ethnically matched control individuals.\nConclusions: We report two novel mutations and a previously reported mutation in <i>FYCO1</i> in three large consanguineous families. Taken together, mutations in <i>FYCO1</i> contribute nearly 15% to the total genetic load of autosomal recessive congenital cataracts in this cohort.","variants":[{"Name":"NM_024513.4(FYCO1):c.4270C>T (p.Arg1424Ter)","Chromosome":"3","Start":"45923747","Stop":"45923747","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3194354,"rule_based_match":true,"evidence_text":"c.4270C>T; p.Arg1424Ter","llm_judgment":"PRESENT","evidence":"c.4270C>T; p.Arg1424Ter","abstract_start":1086,"abstract_end":1109}]}
{"pmid":"35573960","title":"A Phenotypic-Driven Approach for the Diagnosis of WOREE Syndrome.","abstract":"Background: WOREE syndrome is a rare neurodevelopmental disorder featuring drug-resistant epilepsy and global developmental delay. The disease, caused by biallelic pathogenic variants in the <i>WWOX</i> gene, usually leads to severe disability or death within the first years of life. Clinicians have become more confident with the phenotypic picture of WOREE syndrome, allowing earlier clinical diagnosis. We report a boy with a peculiar clinic-radiological pattern supporting the diagnosis of WOREE syndrome.\nMethods: DNA was extracted from blood samples of the proband and his parents and subjected to Exome Sequencing (ES). Agarose gel electrophoresis, real-time quantitative PCR (Q-PCR), and array-CGH 180K were also performed.\nResults: ES detected a pathogenic stop variant (c.790C > T, p.Arg264*) in one allele of <i>WWOX</i> in the proband and his unaffected mother. A 180K array-CGH analysis revealed a 84,828-bp (g.chr16:78,360,803-78,445,630) deletion encompassing exon 6. The Q-PCR product showed that the proband and his father harbored the same deleted fragment, fusing exons 5 and 7 of <i>WWOX</i>.\nConclusions: Genetic testing remains crucial in establishing the definitive diagnosis of WOREE syndrome and allows prenatal interventions/parental counseling. However, our findings suggest that targeted Next Generation Sequencing-based testing may occasionally show technical pitfalls, prompting further genetic investigation in selected cases with high clinical suspicion.","variants":[{"Name":"NM_016373.4(WWOX):c.790C>T (p.Arg264Ter)","Chromosome":"16","Start":"78425054","Stop":"78425054","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":242512,"rule_based_match":true,"evidence_text":"c.790C > T, p.Arg264*","llm_judgment":"PRESENT","evidence":"c.790C > T, p.Arg264*","abstract_start":781,"abstract_end":802}]}
{"pmid":"35747618","title":"Familial Brain Calcifications With Leukoencephalopathy: A Novel","abstract":"Objective: To describe a family with primary familial brain calcifications (PFBCs) and leukoencephalopathy associated with a novel variant in <i>PDGFB</i>.\nMethods: We present 3 generations of a family with PFBC associated with a previously unreported variant in <i>PDGFB</i>.\nResults: A 24-year-old woman with migraine, bipolar disorder, and functional neurologic disorder was found to have bilateral calcifications of the basal ganglia and frontally predominant periventricular white matter disease. Her father had mild cognitive impairment and action tremor of the hands with basal ganglia and cerebellar calcifications found incidentally on head CT. Her paternal grandmother had severe parkinsonism and dementia with calcifications of the basal ganglia and cerebellum and diffuse, confluent periventricular white matter disease. Genetic testing in both the proband and her father revealed a <i>PDGFB</i> variant (NM_002608.3:c.298C>T:p.Arg100Cys) not reported in publicly available databases. Multiple in silico analysis tools support pathogenicity.\nDiscussion: Our report identifies a novel <i>PDGFB</i> variant associated with PFBC and highlights the rare association of leukoencephalopathy with <i>PDGFB</i>-associated PFBC.","variants":[{"Name":"NM_002608.4(PDGFB):c.298C>T (p.Arg100Cys)","Chromosome":"22","Start":"39231780","Stop":"39231780","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1671303,"rule_based_match":true,"evidence_text":"NM_002608.3:c.298C>T:p.Arg100Cys","llm_judgment":"PRESENT","evidence":"NM_002608.3:c.298C>T:p.Arg100Cys","abstract_start":917,"abstract_end":949}]}
{"pmid":"28275245","title":"Prevalence of Fabry disease and GLA c.196G>C variant in Japanese stroke patients.","abstract":"Fabry disease is an important underlying disease in young cryptogenic stroke patients. However, little is known regarding the frequency of Fabry disease in the general stroke population, especially in elderly patients. A total of 588 stroke patients (61.7% men; average age 74.1±12.5 years) were enrolled in this prospective study. Blood samples were obtained to produce blood spots to determine α-galactosidase A (α-GalA) activity and for GLA gene analysis. One 65-year-old female patient had a known GLA gene mutation, c.2T>C (p.M1T), causing Fabry disease. Five male patients and two female patients had GLA c.196G>C (p.E66Q) variant, which is not associated with the full clinical manifestations of Fabry disease. The allele frequency of GLA c.196G>C was significantly higher in male patients with small-vessel occlusion (odds ratio 3.95, P=0.048) and non-cardioembolism (odds ratio 4.08, P=0.012) than that in the general Japanese population. Fabry disease is rare in the general Japanese stroke population. However, screening identified one elderly female patient with Fabry disease. GLA c.196G>C variant is a genetic risk factor for cerebral small-vessel occlusion and non-cardioembolism in Japanese males but not in females.","variants":[{"Name":"NM_000169.3(GLA):c.196G>C (p.Glu66Gln)","Chromosome":"X","Start":"101403984","Stop":"101403984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":25762,"rule_based_match":true,"evidence_text":"GLA c.196G>C (p.E66Q)","llm_judgment":"PRESENT","evidence":"GLA c.196G>C (p.E66Q)","abstract_start":607,"abstract_end":628}]}
{"pmid":"29271604","title":"The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor.","abstract":"Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.","variants":[{"Name":"NM_002880.4(RAF1):c.1082G>C (p.Gly361Ala)","Chromosome":"3","Start":"12599717","Stop":"12599717","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":49083,"rule_based_match":true,"evidence_text":"c.1082G>C/p.(Gly361Ala)","llm_judgment":"PRESENT","evidence":"c.1082G>C/p.(Gly361Ala)","abstract_start":660,"abstract_end":683}]}
{"pmid":"19374892","title":"Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism.","abstract":"BACKGROUND: Both atorvastatin and rifampicin are substrates of OATP1B1 (organic anion transporting polypeptide 1B1) encoded by SLCO1B1 gene. Rifampicin is a potent inhibitor of SLCO1B1 (IC50 1.5 umol/l) and SLCO1B1 521T>C functional genetic polymorphism alters the kinetics of atorvastatin in vivo. We hypothesize that rifampicin might influence atorvastatin kinetics in a SLCO1B1 polymorphism dependent manner.\nMETHODS: Sixteen subjects with known SLCO1B1 genotypes (6 c.521TT, 6 c.521TC and 4 c.521CC) were divided into 2 groups (atorvastatin-placebo group, n=8; atorvastatin-rifampicin group, n=8) randomly. In this 2-phase crossover study, atorvastatin (40 mg single-oral dose) pharmacokinetics after co-administration of placebo and rifampicin (600 mg single-oral dose) were measured for up to 48 h by liquid chromatography-mass spectrometry (LC-MS). In the third phase, rifampicin (450 mg single-oral dose) pharmacokinetics was measured additionally.\nRESULTS: Rifampicin increased atorvastatin plasma concentration in accordance with SLCO1B1 521T>C genotype while the increasing percentage of AUC((0-48)) among c.521TT, c.521TC and c.521CC individuals were 833+/-245% vs 468+/-233% vs 330+/-223% (P=0.007). However, SLCO1B1 521T>C exerted no impact on rifampicin pharmacokinetics (P>0.05).\nCONCLUSIONS: These results suggested that rifampicin elevated the plasma concentration of atorvastatin depending on SLCO1B1 genotype and rifampicin pharmacokinetics were not altered by SLCO1B1 genotype.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":false,"evidence_text":"SLCO1B1 521T>C","llm_judgment":"PRESENT","evidence":"SLCO1B1 521T>C","abstract_start":207,"abstract_end":221}]}
{"pmid":"27544765","title":"Patients homozygous for DPYD c.1129-5923C>G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines.","abstract":"PURPOSE: Dihydropyrimidine dehydrogenase (DPD) is a critical determinant of 5-fluorouracil pharmacology, and reduced activity of DPD as a result of deleterious polymorphisms in the gene encoding DPD (DPYD) can result in severe treatment-related toxicity. Dosing recommendations to individualize treatment have been provided for three DPYD variants (DPYD*2A, c.2846A>T, and c.1679T>G). A fourth variant, c.1129-5923C>G/HapB3, has been shown to increase the risk of fluoropyrimidine-associated toxicity, but little is known about the functional effects of this variant.\nMETHODS: By performing a large retrospective screen for DPYD variants, we identified three patients who were homozygous for c.1129-5923C>G/HapB3. We describe their clinical course of treatment and analyzed DPD activity and DPYD gene expression, to provide insight into the phenotypic effects of c.1129-5923C>G/HapB3.\nRESULTS: DPD activity could be measured in two patients and was 4.1 and 5.4 nmol/mg/h (DPD activity 41 and 55 % compared to controls, respectively). The fluoropyrimidine dose had to be reduced during treatment in both patients. In line with partial DPD deficiency in both patients, sequence analysis of DPD cDNA demonstrated a normal-sized (wild type) cDNA fragment of 486 bp, as well as a larger-sized (mutant) 530-bp fragment containing an aberrant 44-bp insertion in intron 10. Patient three tolerated treatment well, but DPD activity measurement was not possible as the patient had deceased at the time of performing the study.\nCONCLUSIONS: The presented functional and clinical data indicate that the c.1129-5923C>G variant is both functionally and clinically relevant, and support an upfront dose reduction of the fluoropyrimidine starting dose in patients carrying c.1129-5923C>G homozygously.","variants":[{"Name":"NM_000110.4(DPYD):c.1129-5923C>G","Chromosome":"1","Start":"97579893","Stop":"97579893","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":623100,"rule_based_match":true,"evidence_text":"c.1129-5923C>G","llm_judgment":"PRESENT","evidence":"c.1129-5923C>G","abstract_start":403,"abstract_end":417}]}
{"pmid":"23136403","title":"Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy.","abstract":"AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of juvenile sudden death and is characterized by fibro-fatty replacement of the right ventricle. Mutations in several genes encoding desmosomal proteins have been identified in ARVC. We speculated that αT-catenin, encoded by CTNNA3, might also carry mutations in ARVC patients. Alpha-T-catenin binds plakophilins and this binding contributes to the formation of the area composita, which strengthens cell-cell adhesion in contractile cardiomyocytes.\nMETHODS AND RESULTS: We used denaturing high-performance liquid chromatography and direct sequencing to screen CTNNA3 in 76 ARVC patients who did not carry any mutations in the desmosomal genes commonly mutated in ARVC. Mutations c.281T > A (p.V94D) and c.2293_2295delTTG (p.del765L) were identified in two probands. They are located in important domains of αT-catenin. Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and β-catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells.\nCONCLUSION: These findings might point to a causal relationship between CTNNA3 mutations and ARVC. This first report on the involvement of an area composita gene in ARVC shows that the pathogenesis of this disease extends beyond desmosomes. Since the frequency of CTNNA3 mutations in ARVC patients is not rare, systematic screening for this gene should be considered to improve the clinical management of ARVC families.","variants":[{"Name":"NM_013266.4(CTNNA3):c.281T>A (p.Val94Asp)","Chromosome":"10","Start":"67606868","Stop":"67606868","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":106528,"rule_based_match":true,"evidence_text":"c.281T > A (p.V94D)","llm_judgment":"PRESENT","evidence":"c.281T > A (p.V94D)","abstract_start":758,"abstract_end":777}]}
{"pmid":"29531004","title":"Five Novel","abstract":"BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is an inherited skin disorder with variable severity and heterogeneous genetic involvement. Recessive DEB (RDEB) is a rare heritable blistering skin condition caused by loss-of-function mutations in the <i>COL7A1</i> gene.\nAIM: This study aimed to determine the genetic basis of three Chinese RDEB patients from different families and identify correlations between phenotype and genotype.\nMETHODS: All three patients were diagnosed with RDEB based on typical phenotype. Genomic DNA from both the patients and parents was subjected to amplification of all 118 exons and flanking intron boundaries of the <i>COL7A1</i> gene, followed by Sanger sequencing.\nRESULTS: Sanger sequencing identified six mutations in the three patients: five novel mutations (c.2321_2322insCTGA in exon 18, c.5924-5927delAACG in exon 72, c.4871delC in exon 53, c.8278G>A in exon 111, and c.1A>G in exon 1) and one recurrent mutation (c.8038G>A in exon 108). The first three novel mutations resulted in a premature termination codon (PTC), the remaining two novel mutations caused a glycine substitution and a loss of the primary ATG start codon, respectively. All patients had a heterozygous PTC mutation combined with either a glycine substitution mutation in the critical triple-helical collagenous domain or a loss of the primary ATG start codon.\nCONCLUSION: Our findings expand the mutation spectrum of <i>COL7A1</i> leading to RDEB and confirm that the RDEB phenotype correlates with the compound heterozygous PTC mutation with a missense mutation. This study will aid the molecular diagnosis, genetic counseling and prognosis prediction of RDEB patients.","variants":[{"Name":"NM_000094.4(COL7A1):c.5924_5927del (p.Glu1975fs)","Chromosome":"3","Start":"48575678","Stop":"48575681","ReferenceAlleleVCF":"CCGTT","AlternateAlleleVCF":"C","allel_id":411520,"rule_based_match":false,"evidence_text":"c.5924-5927delAACG","llm_judgment":"PRESENT","evidence":"c.5924-5927delAACG","abstract_start":833,"abstract_end":851},{"Name":"NM_000094.4(COL7A1):c.8038G>A (p.Gly2680Ser)","Chromosome":"3","Start":"48567582","Stop":"48567582","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1059813,"rule_based_match":true,"evidence_text":"c.8038G>A","llm_judgment":"PRESENT","evidence":"c.8038G>A","abstract_start":960,"abstract_end":969}]}
{"pmid":"25494902","title":"Novel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree.","abstract":"BACKGROUND: Molecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP).\nRESULTS: Exome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co-segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet-Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family.\nCONCLUSIONS: The combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1.","variants":[{"Name":"NM_006269.2(RP1):c.5962dup (p.Ile1988fs)","Chromosome":"8","Start":"54629843","Stop":"54629844","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":514574,"rule_based_match":true,"evidence_text":"c.5962dupA","llm_judgment":"PRESENT","evidence":"c.5962dupA","abstract_start":1338,"abstract_end":1348},{"Name":"NM_006269.2(RP1):c.4582_4585del (p.Ile1528fs)","Chromosome":"8","Start":"54628463","Stop":"54628466","ReferenceAlleleVCF":"TAATC","AlternateAlleleVCF":"T","allel_id":1061365,"rule_based_match":true,"evidence_text":"c.4582_4585delATCA; p.I1528Vfs*10","llm_judgment":"PRESENT","evidence":"c.4582_4585delATCA; p.I1528Vfs*10","abstract_start":1300,"abstract_end":1333}]}
{"pmid":"23159873","title":"A new ATP7B gene mutation with severe condition in two unrelated Iranian families with Wilson disease.","abstract":"Wilson disease is associated with a defect in copper metabolism and caused by different mutations in ATP7B gene. The aim of this study was to determine mutation frequency of ATP7B exons 8 and 14 in Wilson disease patients from the south of Iran. The exons 8 and 14 of ATP7B gene were analyzed in 65 unrelated Wilson disease patients by Denaturing High Performance Liquid Chromatography, and samples with abnormal peak profile were selected for direct DNA sequencing. Seven out of 65 (10.8%) patients had mutations at exon 14, including c.3061-1G>A in four and c.3207C>A in three patients. In addition, four different mutations were identified at exon 8 of six patients (9.2%). Three of these mutations have been previously reported, including c.2304delC in two patients, c.2293G>A and 2304dupC each in one patient. Furthermore, a novel mutation, c.2335T>G (p.Trp779Gly), was identified in two unrelated patients. The patients with this novel mutation demonstrated severe neuropsychiatric condition. All together, 13 out of 65 (20%) patients had mutations within exons 8 and 14. We also identified a lower frequency of the most common mutations of exons 8 and 14 in the southern Iranian population.","variants":[{"Name":"NM_000053.4(ATP7B):c.2335T>G (p.Trp779Gly)","Chromosome":"13","Start":"51958331","Stop":"51958331","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":547056,"rule_based_match":true,"evidence_text":"c.2335T>G (p.Trp779Gly)","llm_judgment":"PRESENT","evidence":"c.2335T>G (p.Trp779Gly)","abstract_start":846,"abstract_end":869},{"Name":"NM_000053.4(ATP7B):c.2304del (p.Met769fs)","Chromosome":"13","Start":"51958362","Stop":"51958362","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":94514,"rule_based_match":true,"evidence_text":"c.2304del","llm_judgment":"PRESENT","evidence":"c.2304del","abstract_start":743,"abstract_end":752},{"Name":"NM_000053.4(ATP7B):c.3061-1G>A","Chromosome":"13","Start":"51944292","Stop":"51944292","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1364125,"rule_based_match":true,"evidence_text":"c.3061-1G>A","llm_judgment":"PRESENT","evidence":"c.3061-1G>A","abstract_start":536,"abstract_end":547}]}
{"pmid":"29456477","title":"Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family.","abstract":"Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a \"blended\" phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in <i>EVC2</i> (c.2653C>T; p.Arg885*) and <i>COL11A2</i> (c.966dup; p.Thr323His<i>fs</i>*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.","variants":[{"Name":"NM_080680.3(COL11A2):c.966dup (p.Thr323fs)","Chromosome":"6","Start":"33184297","Stop":"33184298","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":489148,"rule_based_match":true,"evidence_text":"c.966dup","llm_judgment":"PRESENT","evidence":"c.966dup","abstract_start":908,"abstract_end":916},{"Name":"NM_147127.5(EVC2):c.2653C>T (p.Arg885Ter)","Chromosome":"4","Start":"5618531","Stop":"5618531","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39622,"rule_based_match":true,"evidence_text":"c.2653C>T; p.Arg885*","llm_judgment":"PRESENT","evidence":"c.2653C>T; p.Arg885*","abstract_start":866,"abstract_end":886}]}
{"pmid":"37589857","title":"Family and literature analysis demonstrates phenotypic effect of two variants in the calpain-3 gene.","abstract":"Both, recessive (LGMD R1) and dominant (LGMD D4) inheritance occur in calpain 3-related muscular dystrophy. We report a family with calpain-related muscular dystrophy caused by two known variants in the calpain 3 gene (CAPN3, NM_000070.3; (I) c.700G>A, p.Gly234Arg and (II) c.1746-20C>G, p.?). Three family members are compound heterozygous and exhibit a relatively homogeneous phenotype characterized by progressive proximal weakness starting in the third to fourth decade of life in the shoulder girdle and spreading to the legs. Two family members affected only by the p.Gly234Arg heterozygous missense variants show a different phenotype characterized by severe exertional myalgia without overt pareses. We conclude that in our family, the missense variant causes a severe myalgic phenotype without pareses that is aggravated by the second intronic variant and put these findings in the context of previous studies of the same variants.","variants":[{"Name":"NM_000070.3(CAPN3):c.1746-20C>G","Chromosome":"15","Start":"42403721","Stop":"42403721","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":98319,"rule_based_match":true,"evidence_text":"c.1746-20C>G","llm_judgment":"PRESENT","evidence":"c.1746-20C>G","abstract_start":274,"abstract_end":286}]}
{"pmid":"33426078","title":"Auditory Neuropathy Spectrum Disorder (ANSD)-Clinical Characteristics and Pathogenic Variant Analysis of Three Nonsyndromic Deafness Families.","abstract":"OBJECTIVE: To analyze the phenotypic features and pathogenic variants of three unrelated families presenting with nonsyndromic auditory neuropathy spectrum disorder (ANSD).\nMETHODS: Three recruited families that were affected by congenital deafness were clinically evaluated, including a detailed family history and audiological and radiological examination. The peripheral blood of all patients and their parents was collected for DNA extraction, and then, the exonic and flanking regions were enriched and sequenced using targeted capture and high-throughput sequencing technology. Bioinformatics analyses and the Sanger sequencing were carried out to screen and validate candidate pathogenic variants. The pathogenicity of candidate variants was evaluated by an approach that was based on the standards and guidelines for interpreting genetic variants as proposed by the American College of Medical Genetics and Genomics (ACMG).\nRESULTS: Four patients in three families were diagnosed as nonsyndromic ANSD, and all exhibited <i>OTOF</i> gene mutations. Among them, two individuals in family 1 (i.e., fam 1-II-2 and fam 1-II-3) carried homozygous variants c.[2688del];[2688del] (NM_194248.3). Two individuals from family 2 (fam 2-II-1) and family 3 (fam 3-II-4) carried compound heterozygous variants c.[4960G>A];[1469C>G] and c.[2675A>G];[2977_2978del], respectively.\nCONCLUSIONS: Three unrelated pedigrees with ANSD were caused by pathogenic variants in the <i>OTOF</i> gene. Five mutations were found and included c.2688del, c.2675A>G, c.2977_2978del, c.4960G>A, and c.1469C>G, of which the first two are novel and expanded mutational spectrum of the <i>OTOF</i> gene, thus having important implications for genetic counseling of the family.","variants":[{"Name":"NM_194248.3(OTOF):c.1469C>G (p.Pro490Arg)","Chromosome":"2","Start":"26482516","Stop":"26482516","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":57334,"rule_based_match":true,"evidence_text":"c.1469C>G","llm_judgment":"PRESENT","evidence":"c.1469C>G","abstract_start":1572,"abstract_end":1581}]}
{"pmid":"28510626","title":"Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene.","abstract":"Purpose: To determine efficacy outcome measures for clinical trials of Leber congenital amaurosis (LCA) associated with a common intronic mutation in the CEP290 gene.\nMethods: CEP290-LCA patients (ages 5-48) with the intronic mutation (c.2991+1655A>G) were studied as a retrospective observational case series using clinical methods and with full-field sensitivity testing (FST), optical coherence tomography (OCT), autofluorescence imaging (NIR-RAFI), transient pupillary light reflex (TPLR), oculomotor control and instability (OCI), a mobility course, and a questionnaire (NEI-VFQ). Patients were investigated cross-sectionally but a subset was able to be followed longitudinally.\nResults: With FST, there was no rod function; cone sensitivities had a wide range from not detectable to near normal. OCT analyses indicated retained central photoreceptors with abnormal distal laminae. Based on OCT and FST, most patients had dissociation of structure and function. TPLR was nondetectable in the majority of patients, with responders demonstrating severe losses in light sensitivity. OCI was abnormal in most patients. NEI-VFQ scores had a similar range to those of other severe retinopathies. Mobility scores were consistent with FST sensitivities. In patients examined with FST, OCT, and NIR-RAFI over long-term intervals (7-10 years), there was limited but detectable disease progression.\nConclusions: Efficacy would be a quantitative change in foveal cone function and possibly distal laminar structure. FST provides a subjective photoreceptor-based outcome; OCT and NIR-RAFI can assess photoreceptor and RPE structure. TPLR and OCI can provide objective measures of postretinal transmission. Minimal change over a decade indicates that there is no practical value in natural history studies.","variants":[{"Name":"NM_025114.4(CEP290):c.2991+1655A>G","Chromosome":"12","Start":"88101183","Stop":"88101183","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":16376,"rule_based_match":true,"evidence_text":"c.2991+1655A>G","llm_judgment":"PRESENT","evidence":"c.2991+1655A>G","abstract_start":236,"abstract_end":250}]}
{"pmid":"30850373","title":"De novo missense variant in the GTPase effector domain (GED) of","abstract":"<i>DNM1L</i> encodes a GTPase of the dynamin superfamily, which plays a crucial role in mitochondrial and peroxisomal fission. Pathogenic variants affecting the middle domain and the GTPase domain of <i>DNM1L</i> have been implicated in encephalopathy because of defective mitochondrial and peroxisomal fission 1 (EMPF1, MIM #614388). Patients show variable phenotypes ranging from severe hypotonia leading to death in the neonatal period to developmental delay/regression, with or without seizures. Familial pathogenic variants in the GTPase domain have also been associated with isolated optic atrophy. We present a 27-yr-old woman with static encephalopathy, a history of seizures, and nystagmus, in whom a novel de novo heterozygous variant was detected in the GTPase effector domain (GED) of <i>DNM1L</i> (c.2072A>G, p.Tyr691Cys). Functional studies in <i>Drosophila</i> demonstrate large, abnormally distributed peroxisomes and mitochondria, an effect very similar to that of middle domain missense alleles observed in pediatric subjects with EMPF1. To our knowledge, not only is this the first report of a disease-causing variant in the GED domain in humans, but this is also the oldest living individual reported with EMPF1. Longitudinal data of this kind helps to expand our knowledge of the natural history of a growing list of <i>DNM1L</i>-related disorders.","variants":[{"Name":"NM_012062.5(DNM1L):c.2072A>G (p.Tyr691Cys)","Chromosome":"12","Start":"32742666","Stop":"32742666","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":610426,"rule_based_match":true,"evidence_text":"c.2072A>G, p.Tyr691Cys","llm_judgment":"PRESENT","evidence":"c.2072A>G, p.Tyr691Cys","abstract_start":811,"abstract_end":833}]}
{"pmid":"15557452","title":"A homozygosity-based search for mutations in patients with autosomal recessive retinitis pigmentosa, using microsatellite markers.","abstract":"PURPOSE: To identify possible mutations in known candidate genes in patients with autosomal recessive (ar) and simplex retinitis pigmentosa (RP), by using an established strategy of flexible, multiplexed, microsatellite-based homozygosity mapping.\nMETHODS: A total of 78 microsatellite markers corresponding to 16 genes known to be responsible for arRP were selected and used in 18 multiplex amplifications, followed by genotyping. Twelve consanguineous probands and 47 nonconsanguineous probands (59 patients with arRP or simplex RP) agreed to the screening.\nRESULTS: Of the 59 probands examined, 24 had a mean of 1.4 genes showing homozygosity for all markers within the corresponding gene region. Subsequent direct sequencing revealed three homozygous mutations. Two of them were novel mutations in the genes TULP1 (c.1145T-->C, F382S) and CNGB1 (c.3444 + 1G-->A). The other was a mutation in RPE65 (c.1543C-->T, R515W), which is known to cause Leber's congenital amaurosis. The clinical features of each patient, together with the cosegregation analysis, strongly support the pathogenicity of these mutations.\nCONCLUSIONS: This systematic approach facilitated the identification of genes that cause arRP, and the results provide a widened spectrum of the mutation severity associated with a broader range of phenotypic manifestations of arRP.","variants":[{"Name":"NM_000329.3(RPE65):c.1543C>T (p.Arg515Trp)","Chromosome":"1","Start":"68429835","Stop":"68429835","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28159,"rule_based_match":false,"evidence_text":"c.1543C-->T, R515W","llm_judgment":"PRESENT","evidence":"c.1543C-->T, R515W","abstract_start":903,"abstract_end":921},{"Name":"NM_003322.6(TULP1):c.1145T>C (p.Phe382Ser)","Chromosome":"6","Start":"35503816","Stop":"35503816","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":22401,"rule_based_match":false,"evidence_text":"c.1145T-->C","llm_judgment":"PRESENT","evidence":"c.1145T-->C","abstract_start":819,"abstract_end":830}]}
{"pmid":"23031367","title":"Intrafamilial variability for novel TAZ gene mutation: Barth syndrome with dilated cardiomyopathy and heart failure in an infant and left ventricular noncompaction in his great-uncle.","abstract":"BACKGROUND: The tafazzin gene (TAZ) is located at Xq28 and encodes a protein involved in the transacylation of cardiolipin, an essential mitochondrial phospholipid. Mutations in TAZ are associated with Barth syndrome (BTHS), the X-linked recessive condition with dilated cardiomyopathy, skeletal myopathy, growth retardation, neutropenia and organic aciduria. TAZ mutations also contribute to left ventricular noncompaction (LVNC), a cardiomyopathy characterized by loose, trabeculated myocardium.\nCASE REPORT: We report a family with a novel TAZ mutation and the clinical spectrum from severe BTHS in an infant to skeletal myopathy with LVNC in an adult, the oldest individual with BTHS reported. The proband is a 51-year-old male with muscle weakness since early childhood. He remained stable until the age of 43. His initial evaluations found LVNC and borderline neutropenia with no elevation of urine 3-methylglutaconic acid. The proband's great nephew is a 3-year-old who presented at birth with poor feeding, hypotonia, lactic acidosis and hypoglycemia. At three months he was admitted with failure to thrive, lethargy and respiratory distress due to heart failure. Cardiac studies revealed dilated cardiomyopathy with a spongiform trabeculated pattern of the left ventricle. Laboratory studies showed cyclic neutropenia and elevated urine 3-methylglutaconic and 3-methylglutaric acids. At age 11months the patient had a heart transplant. We conducted sequence analysis of the TAZ gene for two affected individuals, the proband first and then his great-nephew. A novel, hemizygous nonsense mutation in TAZ exon 7 (c.583G>T, p.Gly195X) was detected.\nCONCLUSION: At his current age of 51years-old, the proband is the oldest surviving individual reported with a confirmed molecular diagnosis and features of Barth syndrome. Further studies will be conducted to identify the genetic modifying factor(s) associated with the wide phenotypic range seen in this family.","variants":[{"Name":"NM_000116.5(TAFAZZIN):c.583G>T (p.Gly195Ter)","Chromosome":"X","Start":"154419746","Stop":"154419746","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":550110,"rule_based_match":true,"evidence_text":"c.583G>T (p.Gly195X)","llm_judgment":"PRESENT","evidence":"p.Gly195X","abstract_start":1630,"abstract_end":1639}]}
{"pmid":"26812872","title":"New mutations in SERPING1 gene of Brazilian patients with hereditary angioedema.","abstract":"Hereditary Angioedema is an autosomal dominant inherited disease leading to oedema attacks with variable severity and localization predominantly caused by C1-INH deficit. More than 400 mutations have been already identified, however no genetic analysis of a Brazilian cohort of HAE patients with C1-INH deficiency has been published. Our aim was to perform genetic analysis of C1-INH gene (SERPING1) in Brazilian HAE patients. We screened the whole SERPING1 coding region from 30 subjects out of 16 unrelated families with confirmed diagnosis of HAE due to C1-INH deficiency. Clinical diagnosis was based on symptoms and quantitative and/or functional analysis of C1-INH. We identified fifteen different mutations among which eight were not previously described according to databases. We found five small deletions (c.97_115del19; c.553delG; c.776_782del7; c.1075_1089del15 and c.1353_1354delGA), producing frameshifts leading to premature stop codons; seven missense mutations (c.498C>A; c.550G>C; c.752T>C; c.889G>A; c.1376C>A; c.1396C>T; c.1431C>A); one nonsense mutation (c.1480C>T), and two intronic alterations (c.51+1G>T; c.51+2T>C). Despite the small number of participants in this study, our results show mutations not previously identified in SERPING1 gene. This study represents the first Brazilian HAE cohort evaluated for mutations and it introduces the possibility to perform genetic analysis in case of need for differential diagnosis.","variants":[{"Name":"NM_000062.3(SERPING1):c.1396C>T (p.Arg466Cys)","Chromosome":"11","Start":"57614474","Stop":"57614474","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18986,"rule_based_match":true,"evidence_text":"c.1396C>T","llm_judgment":"PRESENT","evidence":"c.1396C>T","abstract_start":1031,"abstract_end":1040},{"Name":"NM_000062.3(SERPING1):c.752T>C (p.Leu251Pro)","Chromosome":"11","Start":"57606076","Stop":"57606076","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":425934,"rule_based_match":true,"evidence_text":"c.752T>C","llm_judgment":"PRESENT","evidence":"c.752T>C","abstract_start":1000,"abstract_end":1008}]}
{"pmid":"30190611","title":"Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.","abstract":"PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.\nMETHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.\nRESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.\nCONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.","variants":[{"Name":"NM_001042492.3(NF1):c.2970_2972del (p.Met992del)","Chromosome":"17","Start":"31229954","Stop":"31229956","ReferenceAlleleVCF":"CAAT","AlternateAlleleVCF":"C","allel_id":15402,"rule_based_match":true,"evidence_text":"c.2970_2972del (p.Met992del)","llm_judgment":"PRESENT","evidence":"c.2970_2972del (p.Met992del)","abstract_start":265,"abstract_end":293}]}
{"pmid":"37239361","title":"The","abstract":"The <i>GJB2</i> (Cx26) gene pathogenic variants are associated with autosomal recessive deafness type 1A (DFNB1A, OMIM #220290). Direct sequencing of the <i>GJB2</i> gene among 165 hearing-impaired individuals living in the Baikal Lake region of Russia identified 14 allelic variants: pathogenic/likely pathogenic-nine variants, benign-three variants, unclassified-one variant, and one novel variant. The contribution of the <i>GJB2</i> gene variants to the etiology of hearing impairment (HI) in the total sample of patients was 15.8% (26 out of 165) and significantly differed in patients of different ethnicity (5.1% in Buryat patients and 28.9% in Russian patients). In patients with DFNB1A (n = 26), HIs were congenital/early onset (92.3%), symmetric (88.5%), sensorineural (100.0%), and variable in severity (moderate-11.6%, severe-26.9% or profound-61.5%). The reconstruction of the SNP haplotypes with three frequent <i>GJB2</i> pathogenic variants (c.-23+1G>A, c.35delG or c.235delC), in comparison with previously published data, supports a major role of the founder effect in the expansion of the c.-23+1G>A and c.35delG variants around the world. Comparative analysis of the haplotypes with c.235delC revealed one major haplotype G A C T (97.5%) in Eastern Asians (Chinese, Japanese and Korean patients) and two haplotypes, G A C T (71.4%) and G A C C (28.6%), in Northern Asians (Altaians, Buryats and Mongols). The variable structure of the c.235delC-haplotypes in Northern Asians requires more studies to expand our knowledge about the origin of this pathogenic variant.","variants":[{"Name":"NM_004004.6(GJB2):c.-23+1G>A","Chromosome":"13","Start":"20192782","Stop":"20192782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32068,"rule_based_match":true,"evidence_text":"c.-23+1G>A","llm_judgment":"PRESENT","evidence":"c.-23+1G>A","abstract_start":958,"abstract_end":968}]}
{"pmid":"33562640","title":"Hemolytic Uremic Syndrome Due to Methylmalonic Acidemia and Homocystinuria in an Infant: A Case Report and Literature Review.","abstract":"Methylmalonic acidemia and homocystinuria cobalamin C (cblC) type is the most common inborn error of the intracellular cobalamin metabolism, associated with multisystem involvement and high mortality rates, especially in the early-onset form of the disease. Hemolytic uremic syndrome (HUS) is a rare manifestation and needs to be distinguished from other causes of renal thrombotic microangiopathy. We describe a case of a 3-month-old infant, with failure to thrive, hypotonia and pallor, who developed HUS in the setting of cblC deficit, along with dilated cardiomyopathy, and presented delayed response to optic stimulation in visual evoked potentials, as well as enlarged bilateral subarachnoid spaces and delayed myelination in brain magnetic resonance imaging. Renal damage was reversed, while neurodevelopmental profile and eye contact improved after supplementation with parenteral hydroxycobalamin, oral folic acid, betaine and levocarnitine. Homozygous mutation of c.271dupA in the MMACHC gene was ultimately detected. In this report, we highlight the diagnostic challenges as well as the significance of early recognition and multidisciplinary management of this unusual condition. A brief review of published case reports of early-onset cblC deficit and related HUS is depicted, pointing out the initial clinical presentation, signs of renal damage and outcome, MMACHC gene type of mutations and accompanying extra-renal manifestations.","variants":[{"Name":"NM_015506.3(MMACHC):c.271dup (p.Arg91fs)","Chromosome":"1","Start":"45507544","Stop":"45507545","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":16460,"rule_based_match":true,"evidence_text":"c.271dupA","llm_judgment":"PRESENT","evidence":"c.271dupA","abstract_start":974,"abstract_end":983}]}
{"pmid":"30582020","title":"The novel","abstract":"Spastic paraplegia 30 is a recently established autosomal recessive disease characterized by a complex form of spastic paraplegia associated with neuropathy. Homozygous mutations of <i>KIF1A</i> reportedly lead to hereditary spastic paraplegia or hereditary sensory and autonomic neuropathy type 2 (HSAN2), whereas heterozygous mutations can cause nonsyndromic and syndromic intellectual disability (MRD9). Here we report the case of a 37-year-old female who presented with gait disturbance complicated with moyamoya disease.\nRESULTS: The patient exhibited hypotonia during infancy, after which intellectual disability, epileptic fits, spastic paraplegia, and cerebellar atrophy occurred. Genetic analysis revealed a novel <i>de novo</i> mutation (c.254C > A, p.A85D) in the motor domain of <i>KIF1A</i>.","variants":[{"Name":"NM_001244008.2(KIF1A):c.254C>A (p.Ala85Asp)","Chromosome":"2","Start":"240788160","Stop":"240788160","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":425482,"rule_based_match":true,"evidence_text":"c.254C > A, p.A85D","llm_judgment":"PRESENT","evidence":"c.254C > A, p.A85D","abstract_start":748,"abstract_end":766}]}
{"pmid":"26947917","title":"Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan.","abstract":"BACKGROUND: Since the first case was detected in 2000, there has been a remarkable increase in Japanese patients diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Genetic analysis has revealed a spectrum of mutations that is quite different from those observed in Caucasian populations. In 2014, Japan initiated nationwide newborn screening (NBS) for MCAD using tandem mass spectrometry (MS/MS). It is an urgent issue to assess the risk of acute metabolic decompensation from the respective novel mutations found thus far.\nMETHODS: To evaluate the pathogenic effect of each mutation, we established a eukaryotic cell expression system and prepared 11 mutant proteins identified in five symptomatic patients and eight MS/MS-NBS-positive newborns, as well as two common Caucasian mutations, p.K329E (c.985G>A) and p.Y67H (c.157C>T) for comparison.\nRESULTS: The expression of four mutant proteins (p.Q45R, p.P92L, p.P128X and p.Y397N) were severely impaired, whereas the others expressed normally, as did p.K329E and p.Y67H. Based on their dehydrogenase activities toward n-octanoyl-CoA, we determined three mutations (p.R53C, p.R281S and p.G362E) to be disease-causing, two mutations having (p.R17H and p.M274V) to be of marginal risk, and two mutations (p.K271E and p.I416T) as benign. Their allele-specific activities were as a whole in accordance with those estimated from the results of measurement in peripheral blood mononuclear cells.\nCONCLUSION: As most of the mutations detected in the Japanese population are unique, prudent genetic and enzymatic analysis is essential to precisely evaluate the latent risk of clinical onset for screening-positive newborns.","variants":[{"Name":"NM_000016.6(ACADM):c.134A>G (p.Gln45Arg)","Chromosome":"1","Start":"75732659","Stop":"75732659","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":265314,"rule_based_match":false,"evidence_text":"c.134A>G (p.Gln45Arg)","llm_judgment":"PRESENT","evidence":"Q45R","abstract_start":917,"abstract_end":921}]}
{"pmid":"24107549","title":"Distinct disease phenotypes linked to different combinations of GAA mutations in a large late-onset GSDII sibship.","abstract":"BACKGROUND: Glycogenosis type II (GSDII or Pompe disease) is an autosomal recessive disease, often characterized by a progressive accumulation of glycogen within lysosomes caused by a deficiency of α-1,4-glucosidase (GAA; acid maltase), a key enzyme of the glycogen degradation pathway. To date, more than 326 different mutations in the GAA gene have been identified in patients with GSDII but the course of the disease is difficult to be predicted on the basis of molecular genetic changes. Studies on large informative families are advisable to better define how genetics and non genetics factors like exercise and diet may influence the clinical phenotype.\nMETHODS AND RESULTS: In this study, we report on clinical, instrumental, and pathological features as well as on molecular analysis of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three mutations segregated in the family, two of which are novel mutations. Siblings showing a more severe phenotype were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G > A [p.N882fs] on GAA, whereas, two patients showing a mild phenotype were compound heterozygous c.2647-7G > A [p.N882fs] and c.2276G > C [p.G759A] mutations. Quantitative expression analysis showed, in the patients carrying p.R40X/ p.N882fs, a significant (p 0.01) correlation between the levels of expression of the mutated allele and the age at onset of the disease.\nCONCLUSIONS: As far as we know, this is the largest informative family with late-onset Pompe disease described in the literature showing a peculiar complex set of mutations of GAA gene that may partially elucidate the clinical heterogeneity of this family.","variants":[{"Name":"NM_000152.5(GAA):c.2647-7G>A","Chromosome":"17","Start":"80118646","Stop":"80118646","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":548461,"rule_based_match":true,"evidence_text":"c.2647-7G > A [p.N882fs]","llm_judgment":"PRESENT","evidence":"c.2647-7G > A [p.N882fs]","abstract_start":1041,"abstract_end":1065},{"Name":"NM_000152.5(GAA):c.118C>T (p.Arg40Ter)","Chromosome":"17","Start":"80104704","Stop":"80104704","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":415589,"rule_based_match":true,"evidence_text":"c.118C > T [p.R40X]","llm_judgment":"PRESENT","evidence":"c.118C > T [p.R40X]","abstract_start":1017,"abstract_end":1036}]}
{"pmid":"19241467","title":"Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: summary of mutations (including 23 novel) and modeling of TGase-1.","abstract":"Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare cornification diseases. Germline mutations in TGM1 are the most common cause of ARCI in the United States. TGM1 encodes for the TGase-1 enzyme that functions in the formation of the cornified cell envelope. Structurally defective or attenuated cornified cell envelop have been shown in epidermal scales and appendages of ARCI patients with TGM1 mutations. We review the clinical manifestations as well as the molecular genetics of ARCI. In addition, we characterized 115 TGM1 mutations reported in 234 patients from diverse racial and ethnic backgrounds (Caucasion Americans, Norwegians, Swedish, Finnish, German, Swiss, French, Italian, Dutch, Portuguese, Hispanics, Iranian, Tunisian, Moroccan, Egyptian, Afghani, Hungarian, African Americans, Korean, Japanese and South African). We report 23 novel mutations: 71 (62%) missense; 20 (17%) nonsense; 9 (8%) deletion; 8 (7%) splice-site, and 7 (6%) insertion. The c.877-2A>G was the most commonly reported TGM1 mutation accounting for 34% (147 of 435) of all TGM1 mutant alleles reported to date. It had been shown that this mutation is common among North American and Norwegian patients due to a founder effect. Thirty-one percent (36 of 115) of all mutations and 41% (29 of 71) of missense mutations occurred in arginine residues in TGase-1. Forty-nine percent (35 of 71) of missense mutations were within CpG dinucleotides, and 74% (26/35) of these mutations were C>T or G>A transitions. We constructed a model of human TGase-1 and showed that all mutated arginines that reside in the two beta-barrel domains and two (R142 and R143) in the beta-sandwich are located at domain interfaces. In conclusion, this study expands the TGM1 mutation spectrum and summarizes the current knowledge of TGM1 mutations. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of 5' methylated CpG dinucleotides.","variants":[{"Name":"NM_000359.3(TGM1):c.877-2A>G","Chromosome":"14","Start":"24259813","Stop":"24259813","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":264584,"rule_based_match":true,"evidence_text":"c.877-2A>G","llm_judgment":"PRESENT","evidence":"c.877-2A>G","abstract_start":996,"abstract_end":1006}]}
{"pmid":"25023085","title":"Prevalence of the β(S) gene among scheduled castes, scheduled tribes and other backward class groups in Central India.","abstract":"Sickle cell disease is an inherited disorder of the blood, and characterized by vasoocclusive crises (VOC), risks for pneumococcal infections and organ toxicities, is associated with morbidity and premature mortality. India, with a population of 1.2 billion individuals, is estimated to be home to over 50.0% of the world's patients with sickle cell disease. The β(S) gene [β6(A3)Glu→Val; HBB: c.20A>T] has the highest prevalence in three socio-economically disadvantaged ethnic categories: the Scheduled Castes (SC), the Scheduled Tribes (ST), and Other Backward Class (OBC) groups in India. The tradition of endogamy practiced by the ethnic groups in India provides the rationale for the screening of individual populations to better understand the distribution of the β(S) gene, guide counseling and awareness programs and aid development of public policy. We undertook a study to describe the prevalence of the β(S) gene in these ethnic groups in the district of Nagpur, Maharashtra in Central India. Through community screening and subsequent targeted screening of high risk individuals, 35,636 individuals were screened, of whom 5466 were found to have sickle cell trait and 1010 were identified with sickle cell disease. Community screening revealed a sickle cell trait prevalence of 13.0% in the SC, 12.0% in the ST and 3.4% in the OBC population. This study describes the prevalence of the β(S) gene within these groups in Central India determined by large scale community screening. This program has uncovered previously undiagnosed cases, provided detailed information to guide population-based disease counseling, prevention and comprehensive care programs.","variants":[{"Name":"NM_000518.5(HBB):c.20A>T (p.Glu7Val)","Chromosome":"11","Start":"5227002","Stop":"5227002","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":30372,"rule_based_match":true,"evidence_text":"HBB: c.20A>T","llm_judgment":"PRESENT","evidence":"HBB: c.20A>T","abstract_start":389,"abstract_end":401}]}
{"pmid":"29718797","title":"CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.","abstract":"BACKGROUND: CEP250 encodes the C-Nap1 protein which belongs to the CEP family of proteins. C-Nap1 has been reported to be expressed in the photoreceptor cilia and is known to interact with other ciliary proteins. Mutations of CEP250 cause atypical Usher syndrome which is characterized by early-onset sensorineural hearing loss (SNHL) and a relatively mild retinitis pigmentosa. This study tested the hypothesis that the mild cone-rod dystrophy (CRD) and SNHL in a non-consanguineous Japanese family was caused by CEP250 mutations.\nMETHODS: Detailed ophthalmic and auditory examinations were performed on the proband and her family members. Whole exome sequencing (WES) was used on the DNA obtained from the proband.\nRESULTS: Electrophysiological analysis revealed a mild CRD in two family members. Adaptive optics (AO) imaging showed reduced cone density around the fovea. Auditory examinations showed a slight SNHL in both patients. WES of the proband identified compound heterozygous variants c.361C>T, p.R121*, and c.562C>T, p.R188* in CEP250. The variants were found to co-segregate with the disease in five members of the family.\nCONCLUSIONS: The variants of CEP250 are both null variants and according to American College of Medical Genetics and Genomics (ACMG) standards and guideline, these variants are classified into the very strong category (PVS1). The criteria for both alleles will be pathogenic. Our data indicate that mutations of CEP250 can cause mild CRD and SNHL in Japanese patients. Because the ophthalmological phenotypes were very mild, high-resolution retinal imaging analysis, such as AO, will be helpful in diagnosing CEP250-associated disease.","variants":[{"Name":"NM_007186.6(CEP250):c.361C>T (p.Arg121Ter)","Chromosome":"20","Start":"35466073","Stop":"35466073","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":612045,"rule_based_match":true,"evidence_text":"c.361C>T, p.R121*","llm_judgment":"PRESENT","evidence":"c.361C>T, p.R121*","abstract_start":996,"abstract_end":1013},{"Name":"NM_007186.6(CEP250):c.562C>T (p.Arg188Ter)","Chromosome":"20","Start":"35467035","Stop":"35467035","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":612046,"rule_based_match":true,"evidence_text":"c.562C>T, p.R188*","llm_judgment":"PRESENT","evidence":"c.562C>T, p.R188*","abstract_start":1019,"abstract_end":1036}]}
{"pmid":"28818065","title":"Case reports of two pedigrees with recessive arrhythmogenic right ventricular cardiomyopathy associated with homozygous Thr335Ala variant in DSG2.","abstract":"BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics.\nCASE PRESENTATION: We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c.1003A > G, p.(Thr335Ala) was discovered in the index patients using next-generation sequencing panels. The presence of this variant in probands' siblings and children was studied by Sanger sequencing. Five homozygotes and nine heterozygotes were found with the mutation. Participants were evaluated clinically where possible, and available medical records were obtained. All patients homozygous for the variant fulfilled the current diagnostic criteria for ARVC, whereas none of the heterozygous subjects had symptoms suggestive of ARVC or other cardiomyopathies.\nCONCLUSIONS: The homozygous DSG2 variant c.1003A > G co-segregated with ARVC, indicating autosomal recessive inheritance and complete penetrance. More research is needed to establish a detailed understanding of the relevance of rare variants in ARVC associated genes, which is essential for informative genetic counseling and rational family member testing.","variants":[{"Name":"NM_001943.5(DSG2):c.1003A>G (p.Thr335Ala)","Chromosome":"18","Start":"31524877","Stop":"31524877","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":53445,"rule_based_match":true,"evidence_text":"c.1003A > G, p.(Thr335Ala)","llm_judgment":"PRESENT","evidence":"c.1003A > G, p.(Thr335Ala)","abstract_start":553,"abstract_end":579}]}
{"pmid":"20596040","title":"Hair roots as an mRNA source for mutation analysis of Usher syndrome-causing genes.","abstract":"mRNA is an important tool to study the effects of particular mutations on the mode of splicing and transcripts. However, it is often difficult to isolate mRNA because the organ or tissue in which the gene is expressed cannot be sampled. We previously identified two probable splicing mutations (c.6485+5G>A and c.8559-2A>G) during the mutation analysis of USH2A in Japanese Usher syndrome (USH) type 2 patients, but we could not observe their effects on splicing because the gene is expressed in only a few tissues/organs, and is not expressed in peripheral lymphocytes. In this study, we used hair roots as a source of mRNA of USH-causing genes, and successfully detected the expression of seven, except USH1C and CLRN1, of the nine USH-causing genes. We used RNA extracted from the hair roots of a patient who has both c.6485+5G>A and c.8559-2A>G mutations in USH2A in a compound heterozygous state to observe the effects of these mutations on transcripts. Reverse-transcription PCR analysis revealed that c.6485+5G>A and c.8559-2A>G inactivated splice donor and splice acceptor sites, respectively, and caused skipping of exons. Thus, RNA extracted from hair roots is a potential powerful and convenient tool for the mutation analysis of USH-causing genes.","variants":[{"Name":"NM_206933.4(USH2A):c.6485+5G>A","Chromosome":"1","Start":"216000398","Stop":"216000398","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":960421,"rule_based_match":true,"evidence_text":"c.6485+5G>A","llm_judgment":"PRESENT","evidence":"c.6485+5G>A","abstract_start":295,"abstract_end":306},{"Name":"NM_206933.4(USH2A):c.8559-2A>G","Chromosome":"1","Start":"215877882","Stop":"215877882","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":57766,"rule_based_match":true,"evidence_text":"c.8559-2A>G","llm_judgment":"PRESENT","evidence":"c.8559-2A>G","abstract_start":311,"abstract_end":322}]}
{"pmid":"21364962","title":"A novel p.E276K IDUA mutation decreasing α-L-iduronidase activity causes mucopolysaccharidosis type I.","abstract":"PURPOSE: To characterize the pathogenic mutations causing mucopolysaccharidosis type I (MPS I) in two Thai patients: one with Hurler syndrome (MPS IH), the most severe form, and the other with Scheie syndrome (MPS IS), the mildest. Both presented with distinctive phenotype including corneal clouding.\nMETHODS: The entire coding regions of the α-L-iduronidase (IDUA) gene were amplified by PCR and sequenced. Functional characterization of the mutant IDUA was determined by transient transfection of the construct into COS-7 cells.\nRESULTS: Mutation analyses revealed that the MPS IH patient was homozygous for a previously reported mutation, c.252insC, while the MPS IS patient was found to harbor a novel c.826G>A (p.E276K) mutation. The novel p.E276K mutation was not detected in 100 unaffected ethnic-matched control chromosomes. In addition, the glutamic acid residue at codon 276 was located at a well conserved residue. Transient transfection of the p.E276K construct revealed a significant reduction of IDUA activity compared to that of the wild-type IDUA suggesting it as a disease-causing mutation.\nCONCLUSIONS: This study reports a novel mutation, expanding the mutational spectrum for MPS I.","variants":[{"Name":"NM_000203.5(IDUA):c.826G>A (p.Glu276Lys)","Chromosome":"4","Start":"1002015","Stop":"1002015","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3392390,"rule_based_match":true,"evidence_text":"c.826G>A (p.E276K)","llm_judgment":"PRESENT","evidence":"c.826G>A (p.E276K)","abstract_start":707,"abstract_end":725}]}
{"pmid":"27627638","title":"FUNDUS ALBIPUNCTATUS ASSOCIATED WITH CONE DYSFUNCTION.","abstract":"PURPOSE: To describe a case of cone dysfunction associated with fundus albipunctatus.\nMETHODS: This report is an observational case report. The examination included multimodal imaging, electrophysiological recordings after standard and prolonged dark adaption, and disease targeted gene panel sequencing.\nRESULTS: In this report, the authors present a 55-year-old Chinese male with findings on fundus examination, optical coherence tomography, and full-field electroretinography after standard and prolonged dark adaption consistent with fundus albipunctatus associated with cone dysfunction. Disease targeted gene panel sequencing revealed two heterozygous mutations in RDH5 (c.124C>T; p.Arg42Cys and c.500G>A; p.Arg167His).\nCONCLUSION: The authors report the case of a patient with ophthalmic findings characteristic for cone dysfunction in the setting of genetically confirmed fundus albipunctatus.","variants":[{"Name":"NM_002905.5(RDH5):c.124C>T (p.Arg42Cys)","Chromosome":"12","Start":"55721308","Stop":"55721308","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2794888,"rule_based_match":true,"evidence_text":"c.124C>T; p.Arg42Cys","llm_judgment":"PRESENT","evidence":"c.124C>T; p.Arg42Cys","abstract_start":677,"abstract_end":697},{"Name":"NM_002905.5(RDH5):c.500G>A (p.Arg167His)","Chromosome":"12","Start":"55721878","Stop":"55721878","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":332166,"rule_based_match":true,"evidence_text":"c.500G>A; p.Arg167His","llm_judgment":"PRESENT","evidence":"c.500G>A; p.Arg167His","abstract_start":702,"abstract_end":723}]}
{"pmid":"21190457","title":"Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia.","abstract":"A patient received a diagnosis of adenocarcinoma of the ampulla of Vater at 34 years of age. Two decades later, adenomatous polyps were found, followed by multiple primary invasive adenocarcinomas of both the colon and the stomach. Premature chromatid separation and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities, were detected in his cells. We identified a germline homozygous intronic mutation, c.2386-11A→G, in the spindle-assembly checkpoint gene BUB1B, which creates a de novo splice site that is favored over the authentic (i.e., preferentially used) site. Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers and provide evidence for the interdependency of the APC protein (encoded by the adenomatous polyposis coli gene) and the BUBR1 protein (encoded by BUB1B) in humans. (Funded by the Turner Family Cancer Research Fund and others.).","variants":[{"Name":"NM_001211.6(BUB1B):c.2386-11A>G","Chromosome":"15","Start":"40212488","Stop":"40212488","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":39235,"rule_based_match":false,"evidence_text":"c.2386-11A→G","llm_judgment":"PRESENT","evidence":"c.2386-11A→G","abstract_start":432,"abstract_end":444}]}
{"pmid":"27389245","title":"Megalencephalic leukoencephalopathy with cysts in twelve Egyptian patients: novel mutations in MLC1 and HEPACAM and a founder effect.","abstract":"Two genes causing megalencephalic leukoencephalopathy with subcortical cysts (MLC) have been discovered so far. Here, we identified MLC1 and HEPACAM mutations in ten and two patients, respectively. The molecular results included an unreported inframe duplication mutation (c.929_930dupCTGCTG; p.L309dup) of MLC1 and a novel missense mutation c.293G>A (p.R98H) of HEPACAM. Further, the previously reported missense (c.278C>T; p.S93L) and the deletion/insertion (c.908_918delinsGCA; p.V303Gfs*96) were found in one and 8 patients (75 %), respectively. The 8 patients carrying the p.V303Gfs*96 shared a similar haplotype suggesting a founder effect. All mutations were in the homozygous state proving the autosomal recessive mode of inheritance. The core phenotype of macrocephaly, subcortical cysts and white matter appeared homogeneous although the patients differed in the onset, clinical course, disease severity and brain imaging findings. Our study expands the spectrum of mutations in MLC1 and HEPACAM and supports the genetic and clinical heterogeneity. Further, It confirms c.908_918delinsGCA (p.V303Gfs*96) as a founder mutation among Egyptian patients. This finding will contribute to provide targeted testing for this mutation in MLC patients in our population.","variants":[{"Name":"NM_015166.4(MLC1):c.908_918delinsGCA (p.Val303fs)","Chromosome":"22","Start":"50064175","Stop":"50064185","ReferenceAlleleVCF":"CAGCAGCAGCA","AlternateAlleleVCF":"TGC","allel_id":1695250,"rule_based_match":true,"evidence_text":"c.908_918delinsGCA (p.V303Gfs*96)","llm_judgment":"PRESENT","evidence":"c.908_918delinsGCA (p.V303Gfs*96)","abstract_start":1080,"abstract_end":1113}]}
{"pmid":"19099775","title":"Identification and diagnosis of three novel mutations in SLC25A13 gene of neonatal intrahepatic cholestasis caused by citrin deficiency","abstract":"OBJECTIVE: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, OMIM #605814) is a novel autosomal recessive disease caused by mutations in the gene SLC25A13 that encodes for citrin, a liver-type aspartate/glutamate carrier located in the mitochondrial inner membrane. SLC25A13 was cloned in 1999 by Kobayashi et al at Kagoshima University in Japan, and until now, most of the NICCD patients reported in the world were Japanese. Most of the Chinese NICCD patients diagnosed by genetic analysis had the same SLC25A13 mutations as Japanese, however, in some cases, known mutations were not detected. This research aimed to identify novel SLC25A13 mutations in Chinese NICCD patients and to explore the experimental conditions for their genetic diagnosis.\nMETHODS: Genomic DNA was extracted from blood samples of 3 NICCD patients from Taiwan (P757), Guangdong (P1194) and Hebei province (P1443) of China, respectively, and all the 18 exons and their flanking sequences of SLC25A13 gene were sequenced. Furthermore, the identified novel mutations were diagnosed by amplification with PCR, digestion with corresponding restriction endonuclease, and agarose gel electrophoresis.\nRESULTS: Three novel mutations identified in SLC25A13 gene of the 3 NICCD patients were an abnormal splicing IVS7-2A > G (P757), a missense A541D (c.1622C > A, P1194) and a nonsense R319X (c.955C > T, P1443). The PCR-restriction fragment length polymorphism (RFLP) procedures for their genetic diagnosis were also established, with specific fragments on electrophoresis after digestion of the PCR products with three different restriction endonucleases Msp I, Hpy188I and Taq I, respectively.\nCONCLUSIONS: So far as we know, the three novel mutations in SLC25A13 gene of Chinese NICCD patients were first identified, suggesting that SLC25A13 mutation distributed in Chinese population is somewhat different from that in Japanese. Moreover, the PCR-RFLP diagnostic procedures established in this research provide valuable tools not only for the genetic diagnosis of NICCD but also for further molecular epidemiologic investigations in Chinese population.","variants":[{"Name":"NM_014251.3(SLC25A13):c.1622C>A (p.Ala541Asp)","Chromosome":"7","Start":"96121967","Stop":"96121967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2742000,"rule_based_match":true,"evidence_text":"c.1622C > A","llm_judgment":"PRESENT","evidence":"c.1622C > A","abstract_start":1337,"abstract_end":1348}]}
{"pmid":"15079010","title":"LGI1 mutations in temporal lobe epilepsies.","abstract":"BACKGROUND AND OBJECTIVES: A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations.\nMETHODS: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4.\nRESULTS: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families.\nCONCLUSION: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.","variants":[{"Name":"NM_005097.4(LGI1):c.124T>G (p.Cys42Gly)","Chromosome":"10","Start":"93758268","Stop":"93758268","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":205002,"rule_based_match":false,"evidence_text":"c.124T-->G","llm_judgment":"PRESENT","evidence":"c.124T-->G","abstract_start":1186,"abstract_end":1196},{"Name":"NM_005097.4(LGI1):c.1418C>T (p.Ser473Leu)","Chromosome":"10","Start":"93797547","Stop":"93797547","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":205004,"rule_based_match":false,"evidence_text":"c.1418C-->T; S473L","llm_judgment":"PRESENT","evidence":"c.1418C-->T; S473L","abstract_start":1211,"abstract_end":1229}]}
{"pmid":"25155776","title":"The complexity of newborn screening follow-up in phenylketonuria.","abstract":"In the United States, and most developed nations, the newborn screening (NBS) panel covers many primary disorders of metabolism, including phenylketonuria (PKU). When an elevated phenylalanine level is identified, the infant is evaluated for PKU and should also be tested for tetrahydrobiopterin (BH4) deficiency. A neonate presented with a phenylalanine level of 254 μmol/L (reference range <138 μmol/L) on newborn screening. The infant's confirmatory phenylalanine was 118 μmol/L (reference range <77 μmol/L). Her urine pterin profile was normal, and initially she had no measurable activity of red blood cell (RBC) dihydropteridine reductase (DHPR). Subsequent study revealed normal levels of CSF tetrahydrobiopterin and neurotransmitter metabolites, and by 18 months of age, her RBC DHPR activity was detectable at 0.5 nmol/min/mgHgb (reference range 0.8-3.9). Sequencing of the QDPR gene for DHPR revealed c.1A>T nucleotide substitution in exon 3 expressed as \"p.MET1?\" Phenylalanine hydroxylase (PAH) gene sequencing revealed compound heterozygosity for L249F and A300S. Although initial testing suggested the child was affected with DHPR deficiency, further analysis, finding increasing levels of DHPR activity and PAH compound mutant heterozygosity, indicated that the primary disorder is mild hyperphenylalaninemia with carrier status for DHPR deficiency. This is an example of newborn screening results leading to confusing findings requiring extensive biochemical studies and genotyping in order to arrive at the appropriate diagnosis.","variants":[{"Name":"NM_000320.3(QDPR):c.1A>T (p.Met1Leu)","Chromosome":"4","Start":"17512054","Stop":"17512054","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":495221,"rule_based_match":true,"evidence_text":"c.1A>T","llm_judgment":"PRESENT","evidence":"c.1A>T","abstract_start":911,"abstract_end":917}]}
{"pmid":"24892813","title":"Validation of ambiguous MLPA results by targeted next-generation sequencing discloses a nonsense mutation in the DMD gene.","abstract":"BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common inherited muscular disease and caused by mutations in the DMD gene on the X-chromosome. Multiplex ligation-dependent probe amplification (MLPA) is recognized as a convenient and reliable technique to detect exon deletion/duplication mutations in the DMD gene. Here, we applied targeted semi-conductor next-generation sequencing to clarify the cause of ambiguous MLPA results.\nMETHODS: Targeted semi-conductor next-generation sequencing was carried out using the Inherited Disease Panel (IDP) on the Ion Torrent Personal Genome Machine (PGM).\nRESULTS: MLPA analysis disclosed unclassifiable relative peak ratio of exon 18 in a DMD boy. His female cousin was indicated to have exon 18 deletion in one allele. To validate these incompatible results, targeted next-generation sequencing was conducted. A nucleotide change, C.2227 C>T creating a premature stop codon, was in exon 18. Concomitantly, both C and T nucleotides were identified in his cousin's genome. Ambiguous values of the relative peak ratio in MLPA were considered due to the one nucleotide mismatch between the genomic sequence and the probe used in MLPA.\nCONCLUSION: Analysis using IDP on PGM disclosed a nonsense mutation in the DMD gene as a cause of ambiguous results of MLPA.","variants":[{"Name":"NM_004006.3(DMD):c.2227C>T (p.Gln743Ter)","Chromosome":"X","Start":"32518073","Stop":"32518073","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":849994,"rule_based_match":true,"evidence_text":"C.2227 C>T","llm_judgment":"PRESENT","evidence":"C.2227 C>T","abstract_start":884,"abstract_end":894}]}
{"pmid":"31940116","title":"POLR3A variants with striatal involvement and extrapyramidal movement disorder.","abstract":"Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant.","variants":[{"Name":"NM_007055.4(POLR3A):c.1771-7C>G","Chromosome":"10","Start":"78009682","Stop":"78009682","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":444659,"rule_based_match":true,"evidence_text":"c.1771-7C>G","llm_judgment":"PRESENT","evidence":"c.1771-7C > G","abstract_start":1131,"abstract_end":1144},{"Name":"NM_007055.4(POLR3A):c.1771-6C>G","Chromosome":"10","Start":"78009681","Stop":"78009681","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":964843,"rule_based_match":true,"evidence_text":"c.1771-6C > G","llm_judgment":"PRESENT","evidence":"c.1771-6C > G","abstract_start":1042,"abstract_end":1055}]}
{"pmid":"25981987","title":"Family with Legius syndrome (neurofibromatosis type 1-like syndrome).","abstract":"Legius syndrome (Online Mendelian Inheritance in Man no. 611431) or neurofibromatosis type 1 (NF1)-like syndrome was first reported by Legius et al. in 2007. We herein report the first instance of Legius syndrome occurring in two female siblings in Japan. Both individuals presented cafe-au-lait macules and freckling. Mutation analysis revealed a mutation of c.349C>T resulting in p.Arg117* in the SPRED1 gene as the cause of the Legius syndrome. The National Institutes of Health criteria for NF1 are insufficient to rule out the condition. For this reason, and because the clinical course of each condition is quite different, we stress the need to differentiate Legius syndrome from NF1 clearly.","variants":[{"Name":"NM_152594.3(SPRED1):c.349C>T (p.Arg117Ter)","Chromosome":"15","Start":"38322382","Stop":"38322382","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16848,"rule_based_match":true,"evidence_text":"c.349C>T","llm_judgment":"PRESENT","evidence":"c.349C>T","abstract_start":360,"abstract_end":368}]}
{"pmid":"17397052","title":"Molecular analysis and characterization of nine novel CTSK mutations in twelve patients affected by pycnodysostosis. Mutation in brief #961. Online.","abstract":"Molecular characterization of twelve unrelated patients affected by the autosomal recessive osteosclerotic skeletal dysplasia, Pycnodysostosis (cathepsin k deficiency), revealed 11 different genotypes. The mutational profile consisted of 12 different mutations, including nine previously unreported ones, spread throughout the whole gene. One mutation occurred in regions coding predomain, two affected the prodomain and nine others occurred in the mature domain. The novel lesions consisted in six missense mutations c.20T>C (p.L7P), c.494A>G (p.Q165R), c.580G>A (p.G194S), c.746T>C (p.I249T), c.749A>G (p.D250G), c.955G>T (p.G319C), two frameshifts c.60_61dupGA (p.I21RfsX29), c.282dupA (p.S95VfsX9) and a splicing mutation c.890G>A (r.785_890del). The six new missense mutations were examined by western blots of COS-7 cells transfected with mutant CTSK genes. The L7P, occurring within the predicted hydrophobic domain of signal peptide, showed a significantly reduced expression level compared to the wild type control. These findings suggested that the mutation affected targeting and translocation of the nascent lysosomal protein across the endoplasmatic reticulum membrane. The novel amino acid changes were also modeled into the three-dimensional structure that predicted incorrect protein folding for all of them. Molecular characterization of the patients is of particular value for genetic counseling of patients and their families as diagnosis of Pycnodysostosis based on enzyme assay is unpractical and thus not offered routinely.","variants":[{"Name":"NM_000396.4(CTSK):c.746T>C (p.Ile249Thr)","Chromosome":"1","Start":"150799582","Stop":"150799582","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":941441,"rule_based_match":true,"evidence_text":"c.746T>C (p.I249T)","llm_judgment":"PRESENT","evidence":"c.746T>C (p.I249T)","abstract_start":575,"abstract_end":593},{"Name":"NM_000396.4(CTSK):c.749A>G (p.Asp250Gly)","Chromosome":"1","Start":"150799579","Stop":"150799579","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":540642,"rule_based_match":true,"evidence_text":"c.749A>G (p.D250G)","llm_judgment":"PRESENT","evidence":"c.749A>G (p.D250G)","abstract_start":595,"abstract_end":613},{"Name":"NM_000396.4(CTSK):c.580G>A (p.Gly194Ser)","Chromosome":"1","Start":"150804059","Stop":"150804059","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1928490,"rule_based_match":true,"evidence_text":"c.580G>A (p.G194S)","llm_judgment":"PRESENT","evidence":"c.580G>A (p.G194S)","abstract_start":555,"abstract_end":573}]}
{"pmid":"23526569","title":"A Novel Frameshift Mutation of the USH2A Gene in a Korean Patient with Usher Syndrome Type II.","abstract":"Usher syndrome type II (USH2) is the most common form of Usher syndrome, characterized by moderate to severe hearing impairment and progressive visual loss due to retinitis pigmentosa. It has been shown that mutations in the USH2A gene are responsible for USH2. The authors herein describe a 34-year-old Korean woman with the typical clinical manifestation of USH2; she had bilateral hearing disturbance and progressive visual deterioration, without vestibular dysfunction. Molecular genetic study of the USH2A gene revealed a novel frameshift mutation (c.2310delA; Glu771LysfsX17). She was heterozygous for this mutation, and no other mutation was found in USH2A, suggesting the possibility of an intronic or large genomic rearrangement mutation. To the best of our knowledge, this is the first report of a genetically confirmed case of USH2 in Korea. More investigations are needed to delineate genotype-phenotype correlations and ethnicity-specific genetic background of Usher syndrome.","variants":[{"Name":"NM_206933.4(USH2A):c.2310del (p.Glu771fs)","Chromosome":"1","Start":"216247084","Stop":"216247084","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":1925204,"rule_based_match":true,"evidence_text":"c.2310delA","llm_judgment":"PRESENT","evidence":"c.2310delA","abstract_start":554,"abstract_end":564}]}
{"pmid":"24357026","title":"Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency.","abstract":"The major cause of lipid storage myopathies (LSM) in China is multiple acyl-CoA dehydrogenase deficiency (MADD) caused by ETFDH mutations. We here present an analysis of the spectrum of ETFDH mutations in the largest cohort of patients with MADD (90 unrelated patients). We identified 61 ETFDH mutations, including 31 novel mutations, which were widely distributed within the coding sequence. Three frequent mutations were identified: c.250G > A (most common in South China), c.770A > G and c.1227A > C (most common in both South and North China). Regional differences of allele frequency and further haplotype analysis suggest the possibility of founder effects of c.250G > A and c.770A > G. These findings promise to provide the basis for implementing a rapid and economical strategy for diagnosing MADD.","variants":[{"Name":"NM_004453.4(ETFDH):c.770A>G (p.Tyr257Cys)","Chromosome":"4","Start":"158695582","Stop":"158695582","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":632070,"rule_based_match":true,"evidence_text":"c.770A>G","llm_judgment":"PRESENT","evidence":"c.770A > G","abstract_start":476,"abstract_end":486},{"Name":"NM_004453.4(ETFDH):c.250G>A (p.Ala84Thr)","Chromosome":"4","Start":"158682269","Stop":"158682269","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27067,"rule_based_match":true,"evidence_text":"c.250G > A","llm_judgment":"PRESENT","evidence":"c.250G > A","abstract_start":435,"abstract_end":445}]}
{"pmid":"33162974","title":"","abstract":"Neonatal hemophagocytic lymphohistiocytosis (HLH) is a medical emergency that can be associated with significant morbidity and mortality. Often these patients present with familial HLH (f-HLH), which is caused by gene mutations interfering with the cytolytic pathway of cytotoxic T-lymphocytes (CTLs) and natural killer cells. Here we describe a male newborn who met the HLH diagnostic criteria, presented with profound cholestasis, and carried a maternally inherited heterozygous mutation in <i>syntaxin-binding protein-2</i> [<i>STXBP2</i>, c.568C>T (p.Arg190Cys)] in addition to a severe pathogenic variant in <i>glucose 6-phosphate dehydrogenase</i> [<i>G6PD</i>, hemizygous c.1153T>C (Cys385Arg)]. Although mutations in <i>STXBP2</i> gene are associated with f-HLH type 5, the clinical and biological relevance of the p.Arg190Cys mutation identified in this patient was uncertain. To assess its role in disease pathogenesis, we performed functional assays and biochemical and microscopic studies. We found that p.Arg190Cys mutation did not alter the expression or subcellular localization of STXBP2 or STX11, neither impaired the STXBP2/STX11 interaction. In contrast, forced expression of the mutated protein into normal CTLs strongly inhibited degranulation and reduced the cytolytic activity outcompeting the effect of endogenous wild-type STXBP2. Interestingly, arginine 190 is located in a structurally conserved region of STXBP2 where other f-HLH-5 mutations have been identified. Collectively, data strongly suggest that STXBP2-R190C is a deleterious variant that may act in a dominant-negative manner by probably stabilizing non-productive interactions between STXBP2/STX11 complex and other still unknown factors such as the membrane surface or Munc13-4 protein and thus impairing the release of cytolytic granules. In addition to the contribution of STXBP2-R190C to f-HLH, the accompanied <i>G6PD</i> mutation may have compounded the clinical symptoms; however, the extent by which <i>G6PD</i> deficiency has contributed to HLH in our patient remains unclear.","variants":[{"Name":"NM_006949.4(STXBP2):c.568C>T (p.Arg190Cys)","Chromosome":"19","Start":"7641843","Stop":"7641843","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":404841,"rule_based_match":true,"evidence_text":"c.568C>T (p.Arg190Cys)","llm_judgment":"PRESENT","evidence":"c.568C>T (p.Arg190Cys)","abstract_start":543,"abstract_end":565}]}
{"pmid":"35916809","title":"Mutational spectrum of the iduronate-2-sulfatase gene in Mexican patients with Hunter syndrome.","abstract":"OBJECTIVE: Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), which is responsible for degrading heparan and dermatan sulfate. The IDS gene is located on chromosome Xq28; pathological variants in this gene mostly consist of missense mutations and small and larger deletions, which produce different phenotypes. However, there is only one record in our population concerning the molecular mechanism of this disease; a genotype-phenotype description is not available.\nPATIENTS AND METHODS: There were included 24 unrelated male patients; clinical features were recorded at a database, fluorometric IDS enzyme activity testing was done for each individual, followed by Sanger sequencing to identify mutations.\nRESULTS: The mutational spectrum was found in 16 out of 24 Mexican patients with MPS II, and its range of phenotypes was described. The most frequent variants were of the missense type. The most affected exons were exon 3 (c.275T>G, c.284_287del, c.325T>C), exon 8 (c.1035G>C, c.550G>A), exon 9 (c.1403G>C, c.1229_1229del), and exon 7 (c.979A>C; this variant has not been previously reported). Exon 5 (c.438C>T, a non-pathogenic variant) was the least frequent. It was also found that the most severely affected patients were those with large deletions (2 out of 24) [rsaIDS: IDSP1 (P164)x0, FMR1, AFF2 (P164)x2] involving genes and pseudogenes. We found 2 patients with a synonymous mutation in exon 4.\nCONCLUSIONS: Our results confirmed reports in the literature, since the most frequent variants were reported in exons 3 and 8. However, this result varies from one previous report in our population, which mentions large deletions and rearrangements as the most frequent alterations, since complex rearrangements were not found. According to what has been previously found, the most severely affected patients are those in which a whole gene has been deleted.","variants":[{"Name":"NM_000202.8(IDS):c.325T>C (p.Trp109Arg)","Chromosome":"X","Start":"149503405","Stop":"149503405","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3414433,"rule_based_match":true,"evidence_text":"c.325T>C","llm_judgment":"PRESENT","evidence":"c.325T>C","abstract_start":1040,"abstract_end":1048},{"Name":"NM_000202.8(IDS):c.979A>C (p.Thr327Pro)","Chromosome":"X","Start":"149490341","Stop":"149490341","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3414658,"rule_based_match":true,"evidence_text":"c.979A>C","llm_judgment":"PRESENT","evidence":"c.979A>C","abstract_start":1129,"abstract_end":1137},{"Name":"NM_000202.8(IDS):c.275T>G (p.Leu92Arg)","Chromosome":"X","Start":"149503455","Stop":"149503455","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3414410,"rule_based_match":true,"evidence_text":"c.275T>G","llm_judgment":"PRESENT","evidence":"c.275T>G","abstract_start":1016,"abstract_end":1024},{"Name":"NM_000202.8(IDS):c.1035G>C (p.Trp345Cys)","Chromosome":"X","Start":"149487070","Stop":"149487070","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3414698,"rule_based_match":true,"evidence_text":"c.1035G>C","llm_judgment":"PRESENT","evidence":"c.1035G>C","abstract_start":1059,"abstract_end":1068},{"Name":"NM_000202.8(IDS):c.284_287del (p.Arg95fs)","Chromosome":"X","Start":"149503443","Stop":"149503446","ReferenceAlleleVCF":"TCTCC","AlternateAlleleVCF":"T","allel_id":3414415,"rule_based_match":true,"evidence_text":"c.284_287del","llm_judgment":"PRESENT","evidence":"c.284_287del","abstract_start":1026,"abstract_end":1038},{"Name":"NM_000202.8(IDS):c.1403G>C (p.Arg468Pro)","Chromosome":"X","Start":"149482996","Stop":"149482996","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":98523,"rule_based_match":true,"evidence_text":"c.1403G>C","llm_judgment":"PRESENT","evidence":"c.1403G>C","abstract_start":1089,"abstract_end":1098}]}
{"pmid":"29219637","title":"First Cases of Hb Agrinio Described in Patients from the Republic of Macedonia.","abstract":"Previous molecular analyses of α-thalassemia (α-thal) in the Republic of Macedonia have identified the following genetic defects: -α<sup>3.7</sup> (rightward), -(α)<sup>20.5</sup> and - -<sup>MED I</sup> deletions and Hb Icaria [α142, Term→Lys (α2), HBA2: c.427T>A] and polyadenylation signal (polyA) [AATAAA>AATGAA (α2), HBA2: c.*92A>G] point mutations. Here, we report two unrelated patients from the Romani population in the Republic of Macedonia, homozygotes for the α2-globin gene variant Hb Agrinio [α29(B10)Leu→Pro; HBA2: c.89T>C]. To date, Hb Agrinio has been described only in individuals of Greek, Cypriot and Spanish origin. Both of our patients had early presentation of the disease (3.5 years and 2 months, respectively) with frequent blood transfusions from early infancy. They have a severe intermediate phenotype of thalassemia (Hb H disease) with hemoglobin (Hb) levels of 7.8 and 7.7 g/dL, respectively. Although the HBA2: c.89T>C mutation results in an α<sup>+</sup> allele, the severe phenotype of the homozygotes is due to the production of hyperunstable α chains that undergo post translational precipitation. This leads to a greater degree of red cell damage and hemolytic anemia. The detection of Hb Agrinio in two unrelated families of Romani ethnic origin, may suggest it is a founder mutation in this population living in the Republic of Macedonia. Considering the severity of the clinical presentation of the homozygotes or compound heterozygotes for this rare Hb variant, a targeted molecular screening for Hb Agrinio mutation carriers should be considered in all patients of Romani ethnic origin with manifested microcytosis.","variants":[{"Name":"NM_000517.6(HBA2):c.89T>C (p.Leu30Pro)","Chromosome":"16","Start":"173001","Stop":"173001","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":30690,"rule_based_match":true,"evidence_text":"HBA2: c.89T>C","llm_judgment":"PRESENT","evidence":"HBA2: c.89T>C","abstract_start":523,"abstract_end":536}]}
{"pmid":"26942920","title":"Late onset and high-frequency dominant hearing loss in a family with MYH9 disorder.","abstract":"MYH9 disorder is a rare autosomal-dominant disorder. We previously reported that it is caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9 disorder causes congenital macrothrombocytopenia accompanied by progressive sensorineural hearing loss, nephropathy, and cataract. However, there are few reports that describe the audiological features of MYH9 disorder. The objective of this study was to characterize auditory and other phenotypes of patients with MYH9 disorder. We examined nine subjects from one Japanese family. Audiological, ophthalmological, hematological, and imaging examinations were used to assess clinical features. We carried out genetic analysis of the causative gene, MYH9. Five subjects exhibited macrothrombocytopenia and neutrophil cytoplasmic inclusion bodies. Immunofluorescence analysis of neutrophil NMMHC-IIA revealed abnormal type II localization. Two subjects had high-frequency dominant hearing loss, which was adult onset and progressive. Only one subject had cataract. MYH9 sequencing analysis of all thrombocytopenic subjects revealed a heterozygous c.4270G>A mutation in exon 30 (p.D1424N). We identified five patients with MYH9 disorder from the family. The hearing impairment associated with MYH9 disorder in this family was characterized as adult onset, progressive, and high-frequency dominant. Hematological manifestations of MYH9 disorder show complete penetrance, whereas extra-hematological manifestations show incomplete penetrance and variable expressivity in this family.","variants":[{"Name":"NM_002473.6(MYH9):c.4270G>A (p.Asp1424Asn)","Chromosome":"22","Start":"36292060","Stop":"36292060","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29121,"rule_based_match":true,"evidence_text":"c.4270G>A","llm_judgment":"PRESENT","evidence":"c.4270G>A","abstract_start":1118,"abstract_end":1127}]}
{"pmid":"29951496","title":"Adult-onset Krabbe disease in two generations of a Chinese family.","abstract":"BACKGROUND: Krabbe disease (KD) is a rare autosomal recessive lysosomal storage disorder caused by deficiency of the galactocerebrosidase (GALC) enzyme. The adult-onset KD is infrequent, and often presenting with slowly progressive spastic paraplegia. Herein, we describe a two-generation concomitant Chinese pedigree of adult-onset KD in which the proband presented with acute hemiplegia at onset.\nMETHODS: We collected the clinical and neuroimaging data of the pedigree. GALC enzyme activity detection and gene analysis were performed to confirm the diagnosis. Moreover, we reviewed all studies available on PubMed to understand the correlationship between phenotype and genotype of the identified mutations.\nRESULTS: The proband presented with sudden-onset weakness of left limbs with selective pyramidal tract involvement on diffusion-weighted imaging (DWI) of brain MRI. The GALC enzyme activity of him was low, and the GALC gene analysis revealed compound heterozygous pathogenic mutations of c.1901T>C and c.1901delT. More interestingly, the homozygous c.1901T>C mutations were found in the proband's asymptomatic father and two paternal uncles. Meanwhile, the literature review revealed the c.1901T>C mutation was only found in the late-onset form of KD.\nCONCLUSIONS: These observations, combined with previous reports, indicate that KD should be considered in the adult patients presenting selective pyramidal tract impairment even with sudden onset.","variants":[{"Name":"NM_000153.4(GALC):c.1901T>C (p.Leu634Ser)","Chromosome":"14","Start":"87939915","Stop":"87939915","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":227363,"rule_based_match":true,"evidence_text":"c.1901T>C","llm_judgment":"PRESENT","evidence":"c.1901T>C","abstract_start":999,"abstract_end":1008}]}
{"pmid":"24857004","title":"Three PHEX gene mutations in Chinese subjects with hypophosphatemic rickets and literature review","abstract":"The clinical data of three Chinese children who had been definitely diagnosed with X-link dominate hypophosphatemic rickets (XLH) by gene mutation analysis of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) were retrospectively studied and the relevant literature was reviewed. PHEX gene mutations were detected in all 3 XLH children; a nonsense mutation (c.58C>T) in one case and splicing mutations (c.1645+1G>A, c.436+1G>A) in the other two cases. Among these mutations, c.436+1G>A was novel. As of January 2014, a total of 329 PHEX gene mutations were reported, primarily within three mutation hot spots, throughout the world. Missense mutations accounted for the highest proportion (24%) among all mutations. There is literature showing geographic differences in the total number of XLH subjects and PHEX mutation types across the world. In the current literature, 89 cases of XLH with 28 types of PHEX mutations have been reported in the population of mainland China. Exon 22 is the most frequent mutation site (18%) and missense mutations are the most common type of mutations (61%). It is concluded that exon 22 is the mutation hot spot and missense mutation is the most common type of mutation in the PHEX gene in Chinese XLH patients and that c.436+1G>A detected in this study is a novel PHEX gene mutation in Chinese with XLH.","variants":[{"Name":"NM_000444.6(PHEX):c.436+1G>A","Chromosome":"X","Start":"22076475","Stop":"22076475","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":446611,"rule_based_match":true,"evidence_text":"c.436+1G>A","llm_judgment":"PRESENT","evidence":"c.436+1G>A","abstract_start":453,"abstract_end":463},{"Name":"NM_000444.6(PHEX):c.1645+1G>A","Chromosome":"X","Start":"22190503","Stop":"22190503","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":264998,"rule_based_match":true,"evidence_text":"c.1645+1G>A","llm_judgment":"PRESENT","evidence":"c.1645+1G>A","abstract_start":440,"abstract_end":451}]}
{"pmid":"15099590","title":"A novel stop codon mutation in the PMP22 gene associated with a variable phenotype.","abstract":"The most frequent inherited peripheral neuropathy is the peripheral myelin protein 22 (PMP22) gene related disease. Duplication, deletion, and point mutations in that gene are associated with phenotypic variability. Here we report a family carrying a novel mutation in the PMP22 gene (c. 327C>A), which results in a premature stop codon (Cys109stop). The family members who carry this mutation have a Charcot-Marie-Tooth type 1 variable phenotype, ranging from asymptomatic to severely affected. These findings suggest that the fourth transmembrane domain of the PMP22 gene may play an important role, although the intrafamilial clinical variability reinforces the observation that pathogenic mutations are not always phenotype determinant and that other factors (genetic or epigenetic) modulate the severity of the clinical course.","variants":[{"Name":"NM_000304.4(PMP22):c.327C>A (p.Cys109Ter)","Chromosome":"17","Start":"15231073","Stop":"15231073","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":213836,"rule_based_match":true,"evidence_text":"c. 327C>A","llm_judgment":"PRESENT","evidence":"c. 327C>A","abstract_start":285,"abstract_end":294}]}
{"pmid":"28604952","title":"IDUA gene mutation analysis and prenatal diagnosis of two families affected with mucopolysaccharidosis type I","abstract":"OBJECTIVE: To analyze mutations of IDUA gene in two pedigrees affected with mucopolysaccharidosis type I and provide prenatal diagnosis for them.\nMETHODS: The 14 exons of the IDUA gene were subjected to PCR amplification and Sanger sequencing.\nRESULTS: For pedigree 1, the proband was found to harbor compound heterozygous mutations c.46-57delTCGCTCCTGGCC (p.Ser16_Ala19del) of exon 1 and c.1147delC (p.Arg383Alafs*57) of exon 8 of the IDUA gene, which were inherited from his father and mother, respectively. The latter was unreported previously. Prenatal diagnosis suggested that the fetus has carried a heterozygous c.46-57delTCGCTCCTGGCC mutation. For family 2, the proband was also found to carry compound mutations of the IDUA gene, namely c.721T to C (p.Cys241Arg) of exon 6 and c.1491delG (p.Thr497fs27) of exon 8, which were inherited from her mother and father, respectively. Neither mutation was reported previously. Prenatal diagnosis suggested that the fetus has carried a heterozygous c.721T to C mutation.\nCONCLUSION: Mutations of the IDUA gene probably underlie the MPS-I in both pedigrees. Above results have enriched the spectrum of IDUA gene mutations and facilitated prenatal diagnosis for both families.","variants":[{"Name":"NM_000203.5(IDUA):c.721T>C (p.Cys241Arg)","Chromosome":"4","Start":"1001810","Stop":"1001810","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3859958,"rule_based_match":false,"evidence_text":"c.721T to C (p.Cys241Arg)","llm_judgment":"PRESENT","evidence":"c.721T to C (p.Cys241Arg)","abstract_start":746,"abstract_end":771}]}
{"pmid":"24039609","title":"An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.","abstract":"Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468. The affected individuals of this family exhibited pre-lingual, severe-to-profound degrees of mixed hearing loss. ELMOD3 belongs to the engulfment and cell motility (ELMO) family, which consists of six paralogs in mammals. Several members of the ELMO family have been shown to regulate a subset of GTPases within the Ras superfamily. However, ELMOD3 is a largely uncharacterized protein that has no previously known biochemical activities. We found that in rodents, within the sensory epithelia of the inner ear, ELMOD3 appears most pronounced in the stereocilia of cochlear hair cells. Fluorescently tagged ELMOD3 co-localized with the actin cytoskeleton in MDCK cells and actin-based microvilli of LLC-PK1-CL4 epithelial cells. The p.Leu265Ser mutation in the ELMO domain impaired each of these activities. Super-resolution imaging revealed instances of close association of ELMOD3 with actin at the plasma membrane of MDCK cells. Furthermore, recombinant human GST-ELMOD3 exhibited GTPase activating protein (GAP) activity against the Arl2 GTPase, which was completely abolished by the p.Leu265Ser mutation. Collectively, our data provide the first insights into the expression and biochemical properties of ELMOD3 and highlight its functional links to sound perception and actin cytoskeleton.","variants":[{"Name":"NM_001135022.2(ELMOD3):c.794T>C (p.Leu265Ser)","Chromosome":"2","Start":"85389806","Stop":"85389806","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":76380,"rule_based_match":true,"evidence_text":"c.794T>C (p.Leu265Ser)","llm_judgment":"PRESENT","evidence":"p.Leu265Ser","abstract_start":105,"abstract_end":116}]}
{"pmid":"31416577","title":"The worldwide mutational landscape of Berardinelli-Seip congenital lipodystrophy.","abstract":"Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare disease characterized by the near total absence of body fat at birth. BSCL etiology involves genetic variations in four different genes: AGPAT2, BSCL2, CAV1, and CAVIN1. The four different biochemical subtypes of the disease are distinguished depending on which gene is mutated. The diagnosis of lipodystrophy can be based on clinical criteria, but the gold standard remains genetic testing. Since many different mutations have already been correlated with the onset of the disease, the most indicative method is DNA sequencing. However, not all laboratories have the resources to perform sequencing. Thus, less expensive techniques that include narrow gene regions may be applied. In such cases, the target mutations to be tested must be carefully determined taking into account the frequency of the description of the mutations in the literature, the nationality of the patient, as well as their phenotype. This review considers the molecular basis of BSCL, including the manual count of the majority of mutations reported in the literature up to the year 2018. Ninety different genetic mutations in 332 cases were reported at different frequencies. Some mutations were distributed homogeneously and others were specific to geographic regions. Type 2 BSCL was mentioned most often in the literature (50.3% of the cases), followed by Type 1 (38.0%), Type 4 (10.2%), and Type 3 (1.5%). The mutations comprised frameshifts (34.4%), nonsense (26.6%), and missense (21.1%). The c.517dupA in the BSCL2 gene was the most frequent (13.3%), followed by c.589-2A>G in the AGPAT2 gene (11.5%), c.507_511delGTATC in the BSCL2 gene (9.7%), c.317-588del in the AGPAT2 gene (7.3%), and c.202C>T in the AGPAT2 gene (4.5%). This information should prove valuable for analysts in making decisions regarding the best therapeutic targets in a population-specific context, which will benefit patients and enable faster and less expensive treatment.","variants":[{"Name":"NM_006412.4(AGPAT2):c.589-2A>G","Chromosome":"9","Start":"136674809","Stop":"136674809","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":21664,"rule_based_match":true,"evidence_text":"c.589-2A>G in the AGPAT2 gene","llm_judgment":"PRESENT","evidence":"c.589-2A>G in the AGPAT2 gene","abstract_start":1606,"abstract_end":1635}]}
{"pmid":"35221599","title":"Birt-Hogg-Dubé Syndrome: Diagnostic Journey of Three Cases from Skin to Gene.","abstract":"Birt-Hogg-Dube syndrome (BHDS) is a rare disorder characterized by the triad of cutaneous lesions, renal tumors, lung cysts and inactivation of the gene <i>folliculin</i> (<i>FLCN</i>). Here, we present three female patients diagnosed with BHDS. First case a 55-year-old female had flesh moles histopathology compatible with angiofibroma, multiple cysts in the lung and kidneys, <i>FLCN</i> gene mutations ('c.1285dupC [p.His429Profs*]' 11th exon and 'c.653G>A [p.Arg258His]' 7th exon). The second case a 76-year-old female had trichodiscoma on her skin, multiple cysts in the lung, spontaneous pneumothorax, <i>FLCN</i> gene mutation 'c.1285dupC (p.His429Profs*27) 11th exon' and, her son had renal carcinoma history under 50 years of age. Our third case, also the daughter of case 2, had dermal papules histopathology compatible with trichodiscoma, spontaneous pneumothorax, <i>FLCN</i> gene mutation 'c.1285dupC (p.His429Profs*27) 11th exon' and, parotid oncocytoma. Through our cases, we document the first case of two mutations ('c.1285dupC [p.His429Profs*]' 11th exon and 'c.653G>A [p.Arg258His]' 7th exon) in the same <i>FLCN</i> gene and the 11th known case of parotid oncocytoma associated with BHDS in the light of the literature.","variants":[{"Name":"NM_144997.7(FLCN):c.1285dup (p.His429fs)","Chromosome":"17","Start":"17216394","Stop":"17216395","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":18402,"rule_based_match":true,"evidence_text":"c.1285dupC (p.His429Profs*27)","llm_judgment":"PRESENT","evidence":"c.1285dupC (p.His429Profs*27)","abstract_start":636,"abstract_end":665}]}
{"pmid":"24158611","title":"Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases.","abstract":"This paper presents a mutation as well as a genotype-phenotype analysis of the GJB2 and GJB6 genes in 476 samples from non-syndromic unrelated Argentinean deaf patients (104 familial and 372 sporadic cases). Most of them were of prelingual onset (82 %) and 27 % were cochlear implanted. Variation of sequences was detected in 171 of the 474 patients (36 %). Overall, 43 different sequence variations were identified in GJB2 and GJB6. Four of them are reported for the first time in GJB2: c.233dupG, p.Ala78Ser, p.Val190Asp and p.Cys211Tyr. Mutations in GJB6 were detected in 3 % of patients [nine del(GJB6-D13S1830) and three del(GJB6-D13S1854)]. Of the 43 different variations identified in GJB2, 6 were polymorphisms and of the others, 10 (27 %) were truncating and 27 (73 %) were nontruncating. Patients with two truncating mutations had significantly worse hearing impairment than all other groups. Moderate phenotypes were observed in a group of patients carrying biallelic mutations (23 %). This work shows the high prevalence of GJB2 mutations in the Argentinean population and presents an analysis of moderate phenotypes in our cohort.","variants":[{"Name":"NM_004004.6(GJB2):c.232G>T (p.Ala78Ser)","Chromosome":"13","Start":"20189350","Stop":"20189350","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":963439,"rule_based_match":false,"evidence_text":"p.Ala78Ser","llm_judgment":"PRESENT","evidence":"p.Ala78Ser","abstract_start":499,"abstract_end":509}]}
{"pmid":"28911151","title":"Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1.","abstract":"Context: Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare.\nObjective: To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort.\nSubjects and Methods: Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing.\nResults: We identified 112 patients with APS-1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-ω were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21).\nConclusions: The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1.","variants":[{"Name":"NM_000383.4(AIRE):c.1302C>A (p.Cys434Ter)","Chromosome":"21","Start":"44293812","Stop":"44293812","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2901700,"rule_based_match":true,"evidence_text":"c.1302C>A (p.C434*)","llm_judgment":"PRESENT","evidence":"c.1302C>A (p.C434*)","abstract_start":1360,"abstract_end":1379},{"Name":"NM_000383.4(AIRE):c.280C>T (p.Gln94Ter)","Chromosome":"21","Start":"44286704","Stop":"44286704","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1868552,"rule_based_match":true,"evidence_text":"c.280C>T (p.Q94*)","llm_judgment":"PRESENT","evidence":"c.280C>T (p.Q94*)","abstract_start":1252,"abstract_end":1269}]}
{"pmid":"20567906","title":"Vascular presentation of cystathionine beta-synthase deficiency in adulthood.","abstract":"Several recent studies describing a solely vascular presentation of cystathionine beta-synthase (CBS) deficiency in adulthood prompted us to analyze the frequency of patients manifesting with vascular complications in the Czech Republic. Between 1980 and 2009, a total of 20 Czech patients with CBS deficiency have been diagnosed yielding an incidence of 1:311,000. These patients were divided into three groups based on symptoms leading to diagnosis: those with vascular complications, with connective tissue manifestation and with neurological presentation. A vascular event such as a clinical feature leading to diagnosis of homocystinuria was present in five patients, while two of them had no other symptoms typical for CBS deficiency at the time of diagnosis. All patients with the vascular manifestation were diagnosed only during the past decade. The median age of diagnosis was 29 years in the vascular, 11.5 years in the connective tissue and 4.5 years in the neurological group. The ratio of pyridoxine responsive to nonresponsive patients was higher in the vascular (4 of 5 patients) and connective tissue groups (6 of 7 patients) than in the neurological group (2 of 8 patients). Mutation c.833T>C (p.I278T) was frequent in patients with vascular (6/10 alleles) and connective tissue presentation (8/14 alleles), while it was not present in patients with neurological involvement (0/16 alleles). During the last decade, we have observed patients with homocystinuria diagnosed solely due to vascular events; this milder form of homocystinuria usually manifests at greater ages, has a high ratio of pyridoxine responsiveness/nonresponsiveness, and the mutation c.833T>C (p.I278T) is often present.","variants":[{"Name":"NM_000071.3(CBS):c.833T>C (p.Ile278Thr)","Chromosome":"21","Start":"43063074","Stop":"43063074","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15159,"rule_based_match":true,"evidence_text":"c.833T>C (p.I278T)","llm_judgment":"PRESENT","evidence":"c.833T>C (p.I278T)","abstract_start":1202,"abstract_end":1220}]}
{"pmid":"29339779","title":"Novel recessive mutations in MSTO1 cause cerebellar atrophy with pigmentary retinopathy.","abstract":"Misato 1, mitochondrial distribution and morphology regulator (encoded by the MSTO1 gene), is involved in mitochondrial distribution and morphology. Recently, MSTO1 mutations have been shown to cause clinical manifestations suggestive of mitochondrial dysfunction, such as muscle weakness, short stature, motor developmental delay, and cerebellar atrophy. Both autosomal dominant and recessive modes of inheritance have been suggested. We performed whole-exome sequencing in two unrelated patients showing cerebellar atrophy, intellectual disability, and pigmentary retinopathy. Three novel mutations were identified: c.836 G > A (p.Arg279His), c.1099-1 G > A (p.Val367Trpfs*2), and c.79 C > T (p.Gln27*). Both patients had compound heterozygous mutations with a combination of protein-truncation mutation and missense mutation, the latter shared by them both. This survey of two patients with recessive and novel MSTO1 mutations provides additional clinical and genetic information on the pathogenicity of MSTO1 in humans.","variants":[{"Name":"NM_018116.4(MSTO1):c.836G>A (p.Arg279His)","Chromosome":"1","Start":"155612440","Stop":"155612440","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":581219,"rule_based_match":true,"evidence_text":"c.836 G > A (p.Arg279His)","llm_judgment":"PRESENT","evidence":"c.836 G > A (p.Arg279His)","abstract_start":618,"abstract_end":643},{"Name":"NM_018116.4(MSTO1):c.1099-1G>A","Chromosome":"1","Start":"155613048","Stop":"155613048","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":975902,"rule_based_match":true,"evidence_text":"c.1099-1 G > A (p.Val367Trpfs*2)","llm_judgment":"PRESENT","evidence":"c.1099-1 G > A (p.Val367Trpfs*2)","abstract_start":645,"abstract_end":677},{"Name":"NM_018116.4(MSTO1):c.79C>T (p.Gln27Ter)","Chromosome":"1","Start":"155610327","Stop":"155610327","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":975903,"rule_based_match":true,"evidence_text":"c.79 C > T (p.Gln27*)","llm_judgment":"PRESENT","evidence":"c.79 C > T (p.Gln27*)","abstract_start":683,"abstract_end":704}]}
{"pmid":"22842227","title":"NMNAT1 mutations cause Leber congenital amaurosis.","abstract":"Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss(1,2). Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes(3) (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD(+)) biosynthesis(4,5). Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA.","variants":[{"Name":"NM_022787.4(NMNAT1):c.25G>A (p.Val9Met)","Chromosome":"1","Start":"9972098","Stop":"9972098","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45801,"rule_based_match":true,"evidence_text":"c.25G>A, p.Val9Met","llm_judgment":"PRESENT","evidence":"c.25G>A, p.Val9Met","abstract_start":333,"abstract_end":351}]}
{"pmid":"35404999","title":"A gain-of-function variant in the Wiskott-Aldrich syndrome gene is associated with a MYH9-related disease-like syndrome.","abstract":"While loss-of-function variants in the WAS gene are associated with Wiskott-Aldrich syndrome and lead to microthrombocytopenia, gain-of-function variants of WAS are associated with X-linked neutropenia (XLN) and the absence of microthrombocytopenia. Only a few XLN families have been reported so far, and their platelet phenotype was not described in detail. To date, no renal involvement was described in XLN. In the present study, we report exome sequencing of individuals from 3 generations of a family with a dominant disease combining neutropenia, macrothrombocytopenia, and renal failure. We identified a heterozygous missense gain-of-function variant in the WAS gene (c.881T>C, p.I294T) that segregates with the disease and is already known to cause XLN. There was no pathogenic variant in MYH9, TUBB1, or ACTN1. This is the first report of a WAS gain-of-function variant associated with both the hematological phenotype of XLN (neutropenia, macrothrombocytopenia) and renal disease (proteinuria, renal failure) with glomerular tip lesion hyalinosis and actin condensations in effaced podocytes foot processes.","variants":[{"Name":"NM_000377.3(WAS):c.881T>C (p.Ile294Thr)","Chromosome":"X","Start":"48688403","Stop":"48688403","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":38922,"rule_based_match":true,"evidence_text":"c.881T>C (p.I294T)","llm_judgment":"PRESENT","evidence":"c.881T>C","abstract_start":675,"abstract_end":683}]}
{"pmid":"33423260","title":"Analysis of TBX19 gene variant in a child with congenital isolated adrenocorticotropic hormone deficiency","abstract":"OBJECTIVE: To analyze the clinical and genetic characteristics of a patient with congenital isolated adrenocorticotropic hormone deficiency (IAD).\nMETHODS: Clinical characteristics of the patient was reviewed. Genomic DNA of the child was subjected to whole exome sequencing.\nRESULTS: Genetic testing has confirmed the diagnosis of congenital IAD by identification of compound heterozygous variants of the TBX19 gene, which included a pathogenic nonsense c.535C>T (p.R179X) variant inherited from his father and a novel missense c.298C>T (p.R100C) variant inherited from his mother.\nCONCLUSION: Congenital IAD due to variants of the TBX19 gene is a rare autosomal recessive disease. It is characterized by low plasma adrenocorticotropic hormone and cortisol levels but normal levels of other pituitary hormones. Delayed diagnosis may lead to severe early-onset adrenal failure and wrong treatment which may result in neonatal mortality. Hydrocortisone replacement is effective. Detection of pathogenic variant of TBX19 gene is the key to diagnosis.","variants":[{"Name":"NM_005149.3(TBX19):c.535C>T (p.Arg179Ter)","Chromosome":"1","Start":"168293210","Stop":"168293210","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":278136,"rule_based_match":true,"evidence_text":"c.535C>T (p.R179X)","llm_judgment":"PRESENT","evidence":"c.535C>T (p.R179X)","abstract_start":455,"abstract_end":473},{"Name":"NM_005149.3(TBX19):c.298C>T (p.Arg100Cys)","Chromosome":"1","Start":"168291254","Stop":"168291254","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1491888,"rule_based_match":true,"evidence_text":"c.298C>T (p.R100C)","llm_judgment":"PRESENT","evidence":"c.298C>T (p.R100C)","abstract_start":529,"abstract_end":547}]}
{"pmid":"27363669","title":"The study of filaggrin gene mutations and copy number variation in atopic dermatitis patients from Volga-Ural region of Russia.","abstract":"Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by age-specific localization, dryness, itch and hypersensitivity to allergens. In our study, we investigated FLG gene mutations and CNVs in AD patients and control subjects of different ethnic origin from Volga-Ural region. AD group included 303 patients (177 Russians, 126 Tatars). Control group consisted of 261 healthy individuals (152 Russians, 109 Tatars). The study revealed 66 FLG mutation carriers and demonstrated an association between c.2282del4 deletion and AD development in Russians and Tatars of Volga-Ural region of Russia. In the analysis of the FLG gene CNVs, the most common was 10-repeat allele in both Russian and Tatar patients and controls. We were unable to find any significant difference in CNV repeats count between AD patients and control individuals.","variants":[{"Name":"NM_002016.2(FLG):c.2282_2285del (p.Ser761fs)","Chromosome":"1","Start":"152312601","Stop":"152312604","ReferenceAlleleVCF":"CACTG","AlternateAlleleVCF":"C","allel_id":31359,"rule_based_match":false,"evidence_text":"c.2282del4","llm_judgment":"PRESENT","evidence":"c.2282del4","abstract_start":522,"abstract_end":532}]}
{"pmid":"27693233","title":"Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number.","abstract":"Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined mitochondrial respiratory chain deficiencies associated with a marked loss of mitochondrial DNA copy number in skeletal muscle. Strikingly, an identical c.239G>A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C>G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked decrease of AAC1 protein levels and loss of respiratory chain complexes containing mitochondrial DNA-encoded subunits. We show that both recombinant AAC1 mutant proteins are severely impaired in ADP/ATP transport, affecting most likely the substrate binding and mechanics of the carrier, respectively. This highly reduced capacity for transport probably affects mitochondrial DNA maintenance and in turn respiration, causing a severe energy crisis. The confirmation of the pathogenicity of these de novo SLC25A4 mutations highlights a third distinct clinical phenotype associated with mutation of this gene and demonstrates that early-onset mitochondrial disease can be caused by recurrent de novo mutations, which has significant implications for the application and analysis of whole-exome sequencing data in mitochondrial disease.","variants":[{"Name":"NM_001151.4(SLC25A4):c.239G>A (p.Arg80His)","Chromosome":"4","Start":"185144891","Stop":"185144891","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247444,"rule_based_match":true,"evidence_text":"c.239G>A (p.Arg80His)","llm_judgment":"PRESENT","evidence":"c.239G>A (p.Arg80His)","abstract_start":786,"abstract_end":807},{"Name":"NM_001151.4(SLC25A4):c.703C>G (p.Arg235Gly)","Chromosome":"4","Start":"185145863","Stop":"185145863","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":247445,"rule_based_match":true,"evidence_text":"c.703C>G (p.Arg235Gly)","llm_judgment":"PRESENT","evidence":"c.703C>G (p.Arg235Gly)","abstract_start":912,"abstract_end":934}]}
{"pmid":"23077400","title":"Identification of a novel nonsense mutation in RP1 that causes autosomal recessive retinitis pigmentosa in an Indonesian family.","abstract":"PURPOSE: The purpose of this study was to identify the underlying molecular genetic defect in an Indonesian family with three affected individuals who had received a diagnosis of retinitis pigmentosa (RP).\nMETHODS: Clinical evaluation of the family members included measuring visual acuity and fundoscopy, and assessing visual field and color vision. Genomic DNA of the three affected individuals was analyzed with Illumina 700k single nucleotide polymorphism (SNP) arrays, and homozygous regions were identified using PLINK software. Mutation analysis was performed with sequence analysis of the retinitis pigmentosa 1 (RP1) gene that resided in one of the homozygous regions. The frequency of the identified mutation in the Indonesian population was determined with TaqI restriction fragment length polymorphism analysis.\nRESULTS: A novel homozygous nonsense mutation in exon 4 of the RP1 gene, c.1012C>T (p.R338*), was identified in the proband and her two affected sisters. Unaffected family members either carried two wild-type alleles or were heterozygous carriers of the mutation. The mutation was not present in 184 Indonesian control samples.\nCONCLUSIONS: Most of the previously reported RP1 mutations are inherited in an autosomal dominant mode, and appear to cluster in exon 4. Here, we identified a novel homozygous p.R338* mutation in exon 4 of RP1, and speculate on the mutational mechanisms of different RP1 mutations underlying dominant and recessive RP.","variants":[{"Name":"NM_006269.2(RP1):c.1012C>T (p.Arg338Ter)","Chromosome":"8","Start":"54624894","Stop":"54624894","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":859675,"rule_based_match":true,"evidence_text":"c.1012C>T (p.R338*)","llm_judgment":"PRESENT","evidence":"c.1012C>T (p.R338*)","abstract_start":897,"abstract_end":916}]}
{"pmid":"28960694","title":"High incidence of FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11: Results from the Yecla study.","abstract":"INTRODUCTION: Factor XI (FXI) deficiency is a rare disorder with molecular heterogeneity in Caucasians but relatively frequent and molecularly homogeneous in certain populations.\nAIM: To characterize FXI deficiency in a Spanish town of 60 000 inhabitants.\nMETHODS: A total of 324 764 APTT tests were screened during 20 years. FXI was evaluated by FXI:C and by Western blot. Genetic analysis of F11 was performed by sequencing, multiplex ligation-dependent probe amplification and genotyping.\nRESULTS: Our study identified 46 unrelated cases and 170 relatives with FXI deficiency carrying 12 different genetic defects. p.Cys56Arg, described as founder mutation in the French-Basque population, was identified in 109 subjects from 24 unrelated families. This mutation was also identified in 2% of the general population. p.Cys416Tyr, c.1693G>A and p.Pro538Leu were identified in 7, 6 and 2 unrelated families, respectively. NGS analysis of the whole F11 gene revealed a common haplotype for each of the four recurrent mutations, suggesting a founder effect. The analysis of plasma FXI of four p.Pro538Leu homozygous carriers revealed that this variant was not activated by FXIIa. We identified four mutations previously described in other Caucasian subjects with FXI deficiency (p.Lys536Asn; p.Thr322Ile, p.Arg268Cys and c.325G>A) and four new gene defects: p.(Cys599Tyr) potentially causing a functional deficiency, p.(Ile426Thr), p.(Ile592Thr) and the first worldwide duplication of 1653 bp involving exons 8 and 9. Bleeding was rare and mild.\nCONCLUSIONS: Our population-cohort study supplies new evidences that FXI deficiency in Caucasians is more common than previously thought and confirmed the wide underlying genetic heterogeneity, caused by both recurrent and sporadic mutations.","variants":[{"Name":"NM_000128.4(F11):c.1247G>A (p.Cys416Tyr)","Chromosome":"4","Start":"186284203","Stop":"186284203","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":357346,"rule_based_match":false,"evidence_text":"p.Cys416Tyr","llm_judgment":"PRESENT","evidence":"p.Cys416Tyr","abstract_start":819,"abstract_end":830},{"Name":"NM_000128.4(F11):c.166T>C (p.Cys56Arg)","Chromosome":"4","Start":"186271719","Stop":"186271719","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":26940,"rule_based_match":false,"evidence_text":"p.Cys56Arg","llm_judgment":"PRESENT","evidence":"p.Cys56Arg","abstract_start":618,"abstract_end":628}]}
{"pmid":"30843326","title":"A novel family with axonal Charcot-Marie-Tooth disease caused by a mutation in the EGR2 gene.","abstract":"EGR2 (Early Growth Response 2) is one of the most important transcription factors involved in myelination in the peripheral nervous system. EGR2 mutations typically cause different forms of demyelinating neuropathy, that is, Charcot-Marie-Tooth type 1D (CMT1D), Dejerine-Sottas Syndrome (DSS), and Congenital Hypomyelinating Neuropathy (CHN). However, the EGR2 gene has been recently associated with an axonal phenotype (CMT2) in a large CMT family. Here, we report another CMT family exhibiting an axonal phenotype associated with a missense change (c.1235A>G, p.E412G) in the EGR2 gene. Neurological evaluation of five affected members of the family showed a classical CMT phenotype including distal muscle atrophy and weakness, absence of deep tendon reflexes, pes cavus, and scoliosis. Electrophysiological examination was consistent with a motor-sensory axonal neuropathy. Sural nerve biopsy performed in one patient showed a loss of myelinated and unmyelinated nerve fibers without de-remyelinating signs and onion bulbs. This study confirms the phenotypical heterogeneity of EGR2-related neuropathy, indicating a role for EGR2 in primary axonal degeneration.","variants":[{"Name":"NM_000399.5(EGR2):c.1235A>G (p.Glu412Gly)","Chromosome":"10","Start":"62813403","Stop":"62813403","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":397504,"rule_based_match":true,"evidence_text":"c.1235A>G, p.E412G","llm_judgment":"PRESENT","evidence":"c.1235A>G, p.E412G","abstract_start":551,"abstract_end":569}]}
{"pmid":"28847925","title":"","abstract":"The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1β secretion. Gain-of-function mutations of <i>NLRP3</i> result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of <i>NLRP3</i> causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1β blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1β. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere's disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.","variants":[{"Name":"NM_001243133.2(NLRP3):c.2753G>A (p.Arg918Gln)","Chromosome":"1","Start":"247444061","Stop":"247444061","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":439865,"rule_based_match":true,"evidence_text":"c.2753G > A","llm_judgment":"PRESENT","evidence":"c.2753G > A","abstract_start":484,"abstract_end":495}]}
{"pmid":"17076561","title":"Atypical haemolytic uraemic syndrome associated with a hybrid complement gene.","abstract":"BACKGROUND: Sequence analysis of the regulators of complement activation (RCA) cluster of genes at chromosome position 1q32 shows evidence of several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for factor H (CFH) and the genes for the five factor H-related proteins (CFHL1-5; aliases CFHR1-5). CFH mutations have been described in association with atypical haemolytic uraemic syndrome (aHUS). The majority of the mutations are missense changes that cluster in the C-terminal region and impair the ability of factor H to regulate surface-bound C3b. Some have arisen as a result of gene conversion between CFH and CFHL1. In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS.\nMETHODS AND FINDINGS: In a family with many cases of aHUS that segregate with the RCA cluster we used cDNA analysis, gene sequencing, and Southern blotting to show that affected individuals carry a heterozygous CFH/CFHL1 hybrid gene in which exons 1-21 are derived from CFH and exons 22/23 from CFHL1. This hybrid encodes a protein product identical to a functionally significant CFH mutant (c.3572C>T, S1191L and c.3590T>C, V1197A) that has been previously described in association with aHUS.\nCONCLUSIONS: CFH mutation screening is recommended in all aHUS patients prior to renal transplantation because of the high risk of disease recurrence post-transplant in those known to have a CFH mutation. Because of our finding it will be necessary to implement additional screening strategies that will detect a hybrid CFH/CFHL1 gene.","variants":[{"Name":"NM_000186.4(CFH):c.3572C>T (p.Ser1191Leu)","Chromosome":"1","Start":"196747189","Stop":"196747189","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31584,"rule_based_match":true,"evidence_text":"c.3572C>T, S1191L","llm_judgment":"PRESENT","evidence":"c.3572C>T, S1191L","abstract_start":1309,"abstract_end":1326}]}
{"pmid":"33335567","title":"Variants of CAPN3 cause limb-girdle muscular dystrophy type 2A in two Chinese families.","abstract":"Limb-girdle muscular dystrophies (LGMDs) are a group of neuromuscular diseases that are characterized by progressive muscle weakness. LGMD type 2A (LGMD2A), caused by variants in the calpain-3 (CAPN3) gene, is the most prevalent type. The present study aimed to analyze pathogenic CAPN3 gene variants in two pedigrees affected by LGMD2A. Each family contains three patients who are siblings and sought genetic counseling. Genomic DNA was extracted from the peripheral blood samples collected from the probands and family members and whole-exome sequencing (WES) was used to detect the pathogenic genes in the probands. Suspected variants were subsequently validated by Sanger sequencing. In family 1, WES revealed that the proband carried the compound heterogeneous variants c.1194-9A>G and c.1437C>T (p.Ser479=) in CAPN3 (NM_000070.2). In family 2, WES identified that the proband carried the compound heterogeneous variants c.632+4A>G and c.1468C>T (p.Arg490Trp) in CAPN3 (NM_000070.2). In conclusion, the present study indicated that the compound heterogeneous variants of the CAPN3 gene were most likely responsible for LGMD2A in the two Chinese families.","variants":[{"Name":"NM_000070.3(CAPN3):c.632+4A>G","Chromosome":"15","Start":"42387890","Stop":"42387890","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":547423,"rule_based_match":true,"evidence_text":"c.632+4A>G","llm_judgment":"PRESENT","evidence":"c.632+4A>G","abstract_start":926,"abstract_end":936}]}
{"pmid":"20175955","title":"Clinical features, lectin staining, and a novel GNE frameshift mutation in hereditary inclusion body myopathy.","abstract":"We present a comprehensive report of two siblings with hereditary inclusion body myopathy (HIBM). The clinical features and histological characteristics of the muscle biopsies showed the typical pattern of predominantly distal vacuolar myopathy with quadriceps sparing. This was confirmed by muscle MRI. PNA lectin staining showed an increased signal at the sarcolemma in patient muscle sections compared to control muscle, indicating reduced sialylation of glycoconjugates. Mutation analysis revealed compound heterozygous mutations in the GNE gene, encoding the key enzyme in sialic acid synthesis UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase: a missense mutation (c.2086G > A; p.V696M) previously described in HIBM patients of Indian origin, and a novel frame shift mutation (c.1295delA; p.K432RfsX17) leading to a premature stopcodon. These findings confirmed the diagnosis of HIBM on the histological, molecular and biochemical level.","variants":[{"Name":"NM_005476.7(GNE):c.2086G>A (p.Val696Met)","Chromosome":"9","Start":"36217448","Stop":"36217448","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21067,"rule_based_match":true,"evidence_text":"c.2086G > A; p.V696M","llm_judgment":"PRESENT","evidence":"c.2086G > A; p.V696M","abstract_start":685,"abstract_end":705}]}
{"pmid":"33955814","title":"Two siblings with Heimler syndrome caused by PEX1 variants: follow-up of ophthalmologic findings.","abstract":"BACKGROUND: Heimler syndrome (OMIM number #234580 and #616617) is a rare condition comprising sensorineural hearing loss (SNHL), nail abnormalities and amelogenesis imperfecta. In addition, patients with this syndrome can have retinal dystrophies. Heimler syndrome is caused by bi-allelic pathogenic variants in the <i>PEX1</i> or <i>PEX6</i> gene. Only few patients with this syndrome have been reported. We hereby describe two siblings with genetically confirmed Heimler syndrome and provide imaging of the ocular phenotype.\nMATERIALS AND METHODS: The medical records of the siblings were reviewed retrospectively.\nRESULTS: Both brother and sister were diagnosed with SNHL and amelogenesis imperfecta of the permanent teeth; one of the affected siblings also had nail abnormalities. Both patients presented to the ophthalmology department with suboptimal visual acuity, fundus abnormalities and intraretinal cystoid spaces. Full-field electroretinogram revealed a cone-rod dysfunction. A genetic analysis revealed a homozygous likely pathogenic variant c.3077 T > C (p.Leu1026Pro) in the <i>PEX1</i> gene in both siblings. The parents are heterozygous carriers of the variant.\nCONCLUSION: We recommend performing regular ophthalmic examination in patients with Heimler syndrome since the ophthalmic manifestations can manifest later in life. Our patients presented with cone-rod dystrophy and intraretinal cystoid spaces. Review of the literature shows that the ocular phenotype can be very variable in patients with Heimler syndrome.","variants":[{"Name":"NM_000466.3(PEX1):c.3077T>C (p.Leu1026Pro)","Chromosome":"7","Start":"92493083","Stop":"92493083","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":544610,"rule_based_match":true,"evidence_text":"c.3077 T > C (p.Leu1026Pro)","llm_judgment":"PRESENT","evidence":"c.3077 T > C (p.Leu1026Pro)","abstract_start":1055,"abstract_end":1082}]}
{"pmid":"23850239","title":"Elevated urinary β2 microglobulin in the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy.","abstract":"Here we report what is to our knowledge the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy. The index case is a 52-year-old man with almost 40years of progressive proximal muscle weakness. High urinary β2 microglobulin, normal serum β2 microglobulin, autophagic vacuoles with sarcolemmal features, and a hemizygous c.164-7T>G mutation in the VMA21 gene were found. His two maternal uncles had similar clinicopathological findings. High urinary β2 microglobulin without obvious renal dysfunction might result from decreased urine acidification in the distal convoluted tubules caused by the VMA21 gene mutation. These findings might prove to be useful as a preliminary marker suggestive of X-linked myopathy with excessive autophagy.","variants":[{"Name":"NM_001017980.4(VMA21):c.164-7T>G","Chromosome":"X","Start":"151404909","Stop":"151404909","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":205362,"rule_based_match":true,"evidence_text":"c.164-7T>G","llm_judgment":"PRESENT","evidence":"c.164-7T>G","abstract_start":357,"abstract_end":367}]}
{"pmid":"25943269","title":"INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients.","abstract":"Recently, mutations in the inverted formin 2 (INF2) gene have been indentified in patients with dominant inherited intermediate Charcot-Marie-Tooth neuropathy (DI-CMT) with focal segmental glomerulosclerosis (FSGS). We report clinical and nerve pathological changes in two Chinese patients. Case 1 is 27 years old and presented with distal muscle weakness and atrophy of legs at the age of 13 and renal failure at the age of 26. Three of his family members died due to pure renal failure. Case 2 is 22 years old and presented with distal muscle weakness and atrophy of the legs with transient attacks of difficulty in speaking at age 17. Proteinuria was found by routine urine test at the same time. Sural nerve biopsy revealed moderate-to-severe loss of myelinated fibers with union bulbs and regeneration clusters in both patients. Ultrastructurally, numerous elongated extensions of Schwann cells of unmyelinated fibers could be seen in both patients. INF2 gene mutation screening revealed c.451 T>C in case 1 and c.341 G>A in case 2. This is the first report of Chinese patients with INF2-related DI-CMT. The c.451 T>C mutant was responsible for both isolated FSGS and a dual phenotype of FSGS and neuropathy within one family. Intrafamilial variability can be found with the same INF2 mutation. The CNS manifestations further broadened the clinical spectrum of INF2- associated disorders.","variants":[{"Name":"NM_022489.4(INF2):c.341G>A (p.Gly114Asp)","Chromosome":"14","Start":"104701706","Stop":"104701706","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625304,"rule_based_match":true,"evidence_text":"c.341 G>A","llm_judgment":"PRESENT","evidence":"c.341 G>A","abstract_start":1017,"abstract_end":1026}]}
{"pmid":"26686503","title":"Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia.","abstract":"Aminoacylase 1 (ACY1) deficiency is an organic aciduria due to mutations in the ACY1 gene. It is considered much underdiagnosed. Most individuals known to be affected by ACY1 deficiency have presented with neurologic symptoms. We report here a cognitively normal 63-year-old woman who around the age of 12 years had developed dystonic symptoms that gradually evolved into generalized dystonia. Extensive investigations, including metabolic diagnostics and diagnostic exome sequencing, were performed to elucidate the cause of dystonia. Findings were only compatible with a diagnosis of ACY1 deficiency: the urinary metabolite pattern with N-acetylated amino acids was characteristic, there was decreased ACY1 activity in immortalized lymphocytes, and two compound heterozygous ACY1 mutations were detected, one well-characterized c.1057C>T (p.Arg353Cys) and the other novel c.325A>G (p.Arg109Gly). Expression analysis in HEK293 cells revealed high residual activity of the enzyme with the latter mutation. However, following co-transfection of cells with stable expression of the c.1057C>T variant with either wild-type ACY1 or the c.325A>G mutant, only the wild-type enhanced ACY1 activity and ACY1 presence in the Western blot, suggesting an inhibiting interference between the two variants. Our report extends the clinical spectrum of ACY1 deficiency to include dystonia and indicates that screening for organic acidurias deserves consideration in patients with unexplained generalized dystonia.","variants":[{"Name":"NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)","Chromosome":"3","Start":"51988821","Stop":"51988821","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33149,"rule_based_match":true,"evidence_text":"c.1057C>T (p.Arg353Cys)","llm_judgment":"PRESENT","evidence":"c.1057C>T (p.Arg353Cys)","abstract_start":830,"abstract_end":853}]}
{"pmid":"27774450","title":"Effects of a Mutation in the","abstract":"We here report molecular investigations of a missense mutation in the <i>HSPE1</i> gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at 3 months of age. Clinical exome sequencing revealed heterozygosity for a <i>HSPE1</i> NM_002157.2:c.217C>T <i>de novo</i> mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature. To evaluate whether the mutation may be disease-associated we investigated its effects by <i>in vitro</i> and <i>ex vivo</i> studies. Our <i>in vitro</i> studies indicated that the purified mutant protein was functional, yet its thermal stability, spontaneous refolding propensity, and resistance to proteolytic treatment were profoundly impaired. Mass spectrometric analysis of patient fibroblasts revealed barely detectable levels of HSP10-p.Leu73Phe protein resulting in an almost 2-fold decrease of the ratio of HSP10 to HSP60 subunits. Amounts of the mitochondrial superoxide dismutase SOD2, a protein whose folding is known to strongly depend on the HSP60/HSP10 complex, were decreased to approximately 20% in patient fibroblasts in spite of unchanged SOD2 transcript levels. As a likely consequence, mitochondrial superoxide levels were increased about 2-fold. Although, we cannot exclude other causative or contributing factors, our experimental data support the notion that the HSP10-p.Leu73Phe mutation could be the cause or a strong contributing factor for the disorder in the described patient.","variants":[{"Name":"NM_002157.3(HSPE1):c.217C>T (p.Leu73Phe)","Chromosome":"2","Start":"197503087","Stop":"197503087","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":625773,"rule_based_match":true,"evidence_text":"NM_002157.2:c.217C>T","llm_judgment":"PRESENT","evidence":"NM_002157.2:c.217C>T","abstract_start":397,"abstract_end":417}]}
{"pmid":"35468813","title":"Damaging novel mutations in PIGN cause developmental epileptic-dyskinetic encephalopathy: a case report.","abstract":"BACKGROUND: Mutations in PIGN, resulting in a glycosylphosphatidylinositol (GPI) anchor deficiency, typically leads to multiple congenital anomalies-hypotonia-seizures syndrome. However, the link between PIGN and epilepsy or paroxysmal non-kinesigenic dyskinesia (PNKD) is not well-described. This study reported a patient with PIGN mutation leading to developmental and epileptic encephalopathy and PNKD, to expand upon the genotype-phenotype correlation of PIGN.\nCASE PRESENTATION: During the first 10 days of life, a girl exhibited paroxysmal staring episodes with durations that ranged from several minutes to hours. These episodes occurred 2-5 times daily and always occurred during wakefulness. Ictal electroencephalography revealed no abnormalities, and PNKD was diagnosed. The patient also exhibited severely delayed psychomotor development and generalized seizures at the age of 4 months. Results of brain magnetic resonance imaging and metabolic screenings were normal, but trio-based whole-exome sequencing identified two novel compound heterozygous PIGN mutations (NM_176787; c.163C > T [p.R55 > X] and c.283C > T [p.R95W]). Flow cytometry analysis of the patient's granulocytes revealed dramatically reduced expression of GPI-anchored proteins. This indicated that the mutations compromised GPI functions. The patient got seizure-free for 1 year, and her dyskinesia episodes reduced significantly (1-2 times/month) after treatment with levetiracetam (600 mg/day) and clonazepam (1.5 mg/day). No progress was observed with respect to psychomotor development; however, no craniofacial dysmorphic features, cleft lip/palate, brachytelephalangy with nail hypoplasia, and internal malformations have been observed until now (6 years of age).\nCONCLUSION: This is the first study to document developmental and epileptic encephalopathy with PNKD in a human with PIGN mutations. This report expanded our understanding of the genotype-phenotype correlation of PIGN, and PIGN may be considered a potentially relevant gene when investigating cases of epilepsy or PNKD.","variants":[{"Name":"NM_176787.5(PIGN):c.283C>T (p.Arg95Trp)","Chromosome":"18","Start":"62157747","Stop":"62157747","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":376041,"rule_based_match":true,"evidence_text":"c.283C > T [p.R95W]","llm_judgment":"PRESENT","evidence":"c.283C > T [p.R95W]","abstract_start":1115,"abstract_end":1134}]}
{"pmid":"26927322","title":"Molecular analysis of the LDLR gene in coronary artery disease patients from the Indian population.","abstract":"BACKGROUND: Cardiovascular disease is a leading cause of mortality in Indian population. Mutations in LDLR, APOB and PCSK9 genes may lead to Familial Hypercholesterolemia, an autosomal dominant disorder which in turn leads to cardiovascular diseases. The primary objective of this study is to analyze these genes in CAD patients of Indian population.\nMETHODS: A total of 30 patients were selected out of 300 CAD patients based on UK-Simon Broome criteria from South India. The gDNA was isolated by organic extraction method and the exons and exon-intron boundaries of LDLR gene, APOB (exon 26) and PCSK9 (exon 7) were screened by PCR-high resolution melt analysis. The amplicons showing shift in melting pattern were sequenced to find out the variation.\nRESULTS: This study reports three novel variations, an intronic deletion c.694+8_694+18del in intron 4, a synonymous variation c.966 C>T [p. (N322=)] in exon 7 and a deletion insertion c.1399_1340delinsTA [p. (T467Y)] in exon 10, two recurrent variations c.862G>A [p. (E288K)] in exon 6 and a splice site variation c.1845+2T>C in exon-intron junction of exon 12 in LDLR gene and PCSK9 gene had c.1180+17C>T change in intron 7. However there are no pathogenic variations in APOB and PCSK9 genes in Indian population. In silico analysis predicted all the variations as pathogenic except the synonymous variation.\nCONCLUSION: This report adds five new variations to the spectrum of LDLR variations in Indian population. This study also suggests that UK Simon Broom criteria can be followed to categorize FH patients in Indian population.","variants":[{"Name":"NM_000527.5(LDLR):c.1845+2T>C","Chromosome":"19","Start":"11117000","Stop":"11117000","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":246371,"rule_based_match":true,"evidence_text":"c.1845+2T>C","llm_judgment":"PRESENT","evidence":"c.1845+2T>C","abstract_start":1069,"abstract_end":1080},{"Name":"NM_000527.5(LDLR):c.862G>A (p.Glu288Lys)","Chromosome":"19","Start":"11107436","Stop":"11107436","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171204,"rule_based_match":true,"evidence_text":"c.862G>A [p. (E288K)]","llm_judgment":"PRESENT","evidence":"c.862G>A [p. (E288K)]","abstract_start":1009,"abstract_end":1030},{"Name":"NM_000527.5(LDLR):c.694+8_694+18del","Chromosome":"19","Start":"11105605","Stop":"11105615","ReferenceAlleleVCF":"TGGGCGGGGCCA","AlternateAlleleVCF":"T","allel_id":619791,"rule_based_match":true,"evidence_text":"c.694+8_694+18del","llm_judgment":"PRESENT","evidence":"c.694+8_694+18del","abstract_start":827,"abstract_end":844},{"Name":"NM_000527.5(LDLR):c.966C>T (p.Asn322=)","Chromosome":"19","Start":"11110677","Stop":"11110677","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":618943,"rule_based_match":true,"evidence_text":"c.966 C>T [p. (N322=)]","llm_judgment":"PRESENT","evidence":"c.966 C>T [p. (N322=)]","abstract_start":881,"abstract_end":903}]}
{"pmid":"32296912","title":"Biallelic rare 17 bp deletion mutation (HBB:c.380_396 del TGCAGGCTGCCTATCAG) in a transfusion depended form of thalassemia.","abstract":"","variants":[{"Name":"NM_000518.5(HBB):c.380_396del (p.Val127fs)","Chromosome":"11","Start":"5225646","Stop":"5225662","ReferenceAlleleVCF":"TCTGATAGGCAGCCTGCA","AlternateAlleleVCF":"T","allel_id":1481230,"rule_based_match":true,"evidence_text":"HBB:c.380_396 del TGCAGGCTGCCTATCAG","llm_judgment":"PRESENT","evidence":"HBB:c.380_396 del TGCAGGCTGCCTATCAG","abstract_start":null,"abstract_end":null}]}
{"pmid":"22351710","title":"Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3.","abstract":"The etiology and pathogenesis of renal cell carcinoma (RCC) are only partially understood. Key findings in hereditary RCC, which may be site specific or a component of a syndrome, have contributed to our current understanding. Important heritable syndromes of RCC are those associated with pheochromocytoma, especially von Hippel-Lindau disease (VHL) associated with germline VHL mutations, and pheochromocytoma and paraganglioma syndrome (PGL) associated with mutations in one of the four genes (SDHA-D) encoding succinate dehydrogenase. A subset of individuals with SDHB and SDHD germline DNA mutations and variants develop RCC. RCC has never been described as a component of SDHC-associated PGL3. The European-American Pheochromocytoma and Paraganglioma Registry comprises 35 registrants with germline SDHC mutations. A new registrant had carotid body tumor (CBT) and his mother had CBT and bilateral RCC. Blood DNA, paragangliomas, and RCCs were analyzed for mutations and loss-of-heterozygosity (LOH) in/flanking SDHC and VHL. The proband with unilateral CBT had a germline SDHC c.3G>A (p.M1I) mutation. His mutation-positive mother had CBT at age 42, clear cell RCC (ccRCC) at age 68, and papillary RCC (pRCC) at age 69. Both paraganglial tumors showed somatic LOH of the SDHC locus. Both ccRCC and pRCC did not have a somatic SDHC mutation but showed LOH for intragenic and flanking markers of the SDHC locus. LOH was also present for the VHL locus. Our findings suggest that RCC is a component of PGL3. Biallelic inactivation of the SDHC gene may represent a new pathway of pathogenesis of syndromic and nonsyndromic RCC, perhaps of both clear cell and papillary histologies.","variants":[{"Name":"NM_003001.5(SDHC):c.3G>A (p.Met1Ile)","Chromosome":"1","Start":"161314408","Stop":"161314408","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22280,"rule_based_match":true,"evidence_text":"SDHC c.3G>A (p.M1I)","llm_judgment":"PRESENT","evidence":"SDHC c.3G>A (p.M1I)","abstract_start":1079,"abstract_end":1098}]}
{"pmid":"30314295","title":"Whole-Exome Sequencing Implicates","abstract":"Although the clinical use of targeted gene sequencing-based diagnostics is valuable, whole-exome sequencing has also emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. Molecular genetic tests for episodic ataxia type 2 (EA2) usually target only the specific calcium channel gene (<i>CACNA1A</i>) that is known to cause EA2. In cases where no mutations are identified in the <i>CACNA1A</i> gene, it is important to identify the causal gene so that more effective treatment can be prioritized for patients. Here we present a case of a proband with a complex episodic ataxias (EA)/seizure phenotype with an EA-affected father; and an unaffected mother, all negative for <i>CACNA1A</i> gene mutations. The trio was studied by whole-exome sequencing to identify candidate genes responsible for causing the complex EA/seizure phenotype. Three rare or novel variants in Sodium channel α2-subunit; <i>SCN2A</i> (c.3973G>T: p.Val1325Phe)<i>,</i> Potassium channel, Kv3.2; <i>KCNC2</i> (c.1006T>C: p.Ser336Pro) and Sodium channel Nav1.6; <i>SCN8A</i> (c.3421C>A: p.Pro1141Thr) genes were found in the proband. While the <i>SCN2A</i> variant is likely to be causal for episodic ataxia, each variant may potentially contribute to the phenotypes observed in this family. This study highlights that a major challenge of using whole-exome/genome sequencing is the identification of the unique causative mutation that is associated with complex disease.","variants":[{"Name":"NM_001330260.2(SCN8A):c.3421C>A (p.Pro1141Thr)","Chromosome":"12","Start":"51769916","Stop":"51769916","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2125922,"rule_based_match":true,"evidence_text":"SCN8A (c.3421C>A: p.Pro1141Thr)","llm_judgment":"PRESENT","evidence":"SCN8A</i> (c.3421C>A: p.Pro1141Thr)","abstract_start":1066,"abstract_end":1101}]}
{"pmid":"32685347","title":"Successful fenofibrate therapy for severe and persistent hypertriglyceridemia in a boy with cirrhosis and glycerol-3-phosphate dehydrogenase 1 deficiency.","abstract":"Glycerol-3-phosphate dehydrogenase 1 deficiency is a rare autosomal recessive disorder caused by mutations in the <i>GPD1</i> gene (GPD1; OMIM*138420). Very few cases are reported in literature. It usually manifests in early infancy with transient hypertriglyceridemia, hepatomegaly, steatosis, and fibrosis. We report the case of a 16-year-old boy followed since the age of 1 year for hepatomegaly, elevated liver enzymes, and persistent hypertriglyceridemia. Abdominal ultrasound showed diffuse liver echogenicity and liver biopsy disclosed cirrhosis with micro and macrovesicular steatosis. Next-generation sequencing for metabolic and genetic liver diseases was conducted with the identification of the homozygous mutation c.895G>A in <i>GPD1</i> gene resulting in the aminocidic substitution p.G299R. Considering the persistent and progressive increase of plasma triglycerides, fenofibrate treatment was started at 15 years of age allowing triglyceride level reduction in the following 1-year follow-up.","variants":[{"Name":"NM_005276.4(GPD1):c.895G>A (p.Gly299Arg)","Chromosome":"12","Start":"50108072","Stop":"50108072","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":796784,"rule_based_match":true,"evidence_text":"c.895G>A","llm_judgment":"PRESENT","evidence":"c.895G>A","abstract_start":727,"abstract_end":735}]}
{"pmid":"30512158","title":"Variant analysis of a patient with dyshormonogenesis due to congenital hypothyroidism","abstract":"OBJECTIVE: To carry out variant analysis for a Chinese boy featuring dyshormonogenesis due to congenital hypothyroidism.\nMETHODS: DNA of the patient and his parents was extracted and sequenced by high-throughput sequencing. The results were validated with Sanger sequencing and analyzed with Bioinformatics software.\nRESULTS: Sequencing result showed that the patient has carried compound variants of c.2654G>T(p.Arg885Leu) and c.943G>T(p.Gly315X) of the DUOX2 gene, which were inherited respectively from his mother and father.\nCONCLUSION: The missense mutation c.2654G>T and nonsense mutation c.943G>T probably underlie the disease in this child.","variants":[{"Name":"NM_001363711.2(DUOX2):c.943G>T (p.Gly315Ter)","Chromosome":"15","Start":"45110650","Stop":"45110650","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3074041,"rule_based_match":true,"evidence_text":"c.943G>T(p.Gly315X)","llm_judgment":"PRESENT","evidence":"c.943G>T(p.Gly315X)","abstract_start":428,"abstract_end":447},{"Name":"NM_001363711.2(DUOX2):c.2654G>T (p.Arg885Leu)","Chromosome":"15","Start":"45103960","Stop":"45103960","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":609269,"rule_based_match":true,"evidence_text":"c.2654G>T(p.Arg885Leu)","llm_judgment":"PRESENT","evidence":"c.2654G>T(p.Arg885Leu)","abstract_start":401,"abstract_end":423}]}
{"pmid":"26908619","title":"Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle and ciliary defects.","abstract":"Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. Whilst >450 skeletal dysplasias have been reported, 30% are genetically uncharacterized. We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies, thoracic dysplasia, pulmonary hypoplasia and protruding abdomen. Single nucleotide polymorphism homozygosity mapping and whole exome sequencing identified a novel homozygous stop-gain mutation in NEK9 (c.1489C>T; p.Arg497*) as the cause of this disorder. NEK9 encodes a never in mitosis gene A-related kinase involved in regulating spindle organization, chromosome alignment, cytokinesis and cell cycle progression. This is the first disorder to be associated with NEK9 in humans. Analysis of NEK9 protein expression and localization in patient fibroblasts showed complete loss of full-length NEK9 (107 kDa). Functional characterization of patient fibroblasts showed a significant reduction in cell proliferation and a delay in cell cycle progression. We also provide evidence to support possible ciliary associations for NEK9. Firstly, patient fibroblasts displayed a significant reduction in cilia number and length. Secondly, we show that the NEK9 orthologue in Caenorhabditis elegans, nekl-1, is almost exclusively expressed in a subset of ciliated cells, a strong indicator of cilia-related functions. In summary, we report the clinical and molecular characterization of a lethal skeletal dysplasia caused by NEK9 mutation and suggest that this disorder may represent a novel ciliopathy.","variants":[{"Name":"NM_033116.6(NEK9):c.1489C>T (p.Arg497Ter)","Chromosome":"14","Start":"75106541","Stop":"75106541","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":244031,"rule_based_match":true,"evidence_text":"c.1489C>T; p.Arg497*","llm_judgment":"PRESENT","evidence":"c.1489C>T; p.Arg497*","abstract_start":593,"abstract_end":613}]}
{"pmid":"27697305","title":"Early cardiac involvement in an infantile Sandhoff disease case with novel mutations.","abstract":"INTRODUCTION: Hepatosplenomegaly is often present in infantile Sanshoff disease. However, cardiac involvement is extremely uncommon.\nCASE REPORT: We describe a 14-month-old female baby who exhibited mitral regurgitation and cardiomegaly at the age of 2months, dilation of the left atrium and left ventricle at age of 6months, followed by regression of developmental milestones after an episode of minor infection at age of 14months. Brain magnetic resonance imaging revealed signal changes over the bilateral thalami, bilateral cerebral white matter and left putamen. An examination of the fundus showed presence of cherry-red spots in both macular areas. The lysosomal enzymatic activities showed a marked reduction of β-hexosaminidase B (HEXB) activity. Two novel mutations of HEXB gene were identified. One of the mutations was a c.1538 T>C mutation, which predicted a p.L513P amino acid substitution of leucine to proline; the other was a c.299+5 G>A mutation, which was a splice site mutation.\nCONCLUSION: Cardiac involvement might occur prior to neurological symptoms in infantile Sandhoff disease, and it should be included in the differential diagnoses of metabolic cardiomyopathies in the infantile stage.","variants":[{"Name":"NM_000521.4(HEXB):c.1538T>C (p.Leu513Pro)","Chromosome":"5","Start":"74720672","Stop":"74720672","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":916961,"rule_based_match":true,"evidence_text":"c.1538 T>C","llm_judgment":"PRESENT","evidence":"c.1538 T>C","abstract_start":833,"abstract_end":843}]}
{"pmid":"36385762","title":"A synonymous variant contributes to a rare Wiedemann-Rautenstrauch syndrome complicated with mild anemia","abstract":"Wiedemann-Rautenstrauch syndrome (WDRTS) is an extremely rare autosomal recessive neonatal disorder. Currently, over 50 cases with variable phenotypes of WDRTS have been reported. In our cohort of prenatal and postnatal growth retardation, a female proband was found to have general growth retardation, neurocutaneous syndrome, and anemia. Karyotype test and array-CGH detected no obvious chromosomal aberrations. Trio-based whole-exome sequencing (Trio-WES) identified bi-allelic compound mutations in the coding sequence (CDS) of <i>POLR3A</i> gene (c.3342C > T, p.Ser1114 = and c.3718G > A, p.Gly1240Ser). For the mild anemia phenotype, the underlying causal genetic factors could be attributed to the compound heterozygous mutations in <i>FANCA</i> gene (c.2832dup, p.Ala945CysfsTer6 and c.1902 T > G, p.Asp634Glu). Mini-gene reporter assays revealed that the synonymous variant of <i>POLR3A</i> and the missense variant of <i>FANCA</i> could affect pre-mRNA splicing of each gene. For <i>POLR3A</i>, the synonymous mutation (c.3342C > T, p.Ser1114=) generated three types of aberrant isoforms. Therefore, the female patient was finally diagnosed as WDRTS caused by <i>POLR3A</i>. For <i>FANCA</i>, the missense variant (c.1902 T > G, p.Asp634Glu) disrupted the normal splicing between exon 21 and 22, and produced two types of abnormal isoforms, one carrying the 1902G and the other spliced between exon 21 and 23 to exclude exon 22. Network analysis showed that POLR3A and FANCA could be STRINGed, indicating both proteins might collaborate for some unknown functions. Current investigation would broaden the knowledge for clinicians and genetic counselors and remind them to interpret those synonymous or predicted \"benign\" variants more carefully.","variants":[{"Name":"NM_000135.4(FANCA):c.1902T>G (p.Asp634Glu)","Chromosome":"16","Start":"89773383","Stop":"89773383","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":957950,"rule_based_match":true,"evidence_text":"c.1902 T > G, p.Asp634Glu","llm_judgment":"PRESENT","evidence":"c.1902 T > G, p.Asp634Glu","abstract_start":792,"abstract_end":817}]}
{"pmid":"33605604","title":"Automated reanalysis, a novel way to diagnose an ultra-rare condition: Fibronectin-1-related spondylometaphyseal dysplasia (SMD-FN1).","abstract":"We report a further case of spondylometaphyseal dysplasia - corner fracture type due to the fibronectin-1 gene (SMD-FN1) in a child originally thought to have metaphyseal chondrodysplasia-Brussels type (MCD Brussels). We highlight phenotypic differences with the SMD-FN1 published reports. This case is unique in terms of the method of molecular confirmation. Findings from the 100 000 Genomes Project were originally negative (in both tier 1 and 2); however, subsequent reanalysis, initiated by an automated search for new gene-disease associations in PanelApp, highlighted a candidate diagnostic variant. Our child had short stature, facial dysmorphism, spondylometaphyseal dysplasia and corner fractures and a heterozygous de novo missense variant in FN1 (c.675C>G p.(Cys225Trp), which was likely pathogenic. The variant matched the clinical and radiological features and a diagnosis of SMD-FN1 was confirmed. We explore the diagnostic journey of this patient, compare her findings with the previous 15 patients reported with SMD-FN1 and discuss the diagnostic utility of automated reanalysis. We consider differences and similarities between MCD Brussels and SMD-FN1, by reviewing literature on both conditions and assess whether they are in fact the same disorder.","variants":[{"Name":"NM_212482.4(FN1):c.675C>G (p.Cys225Trp)","Chromosome":"2","Start":"215430725","Stop":"215430725","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":411547,"rule_based_match":true,"evidence_text":"c.675C>G p.(Cys225Trp)","llm_judgment":"PRESENT","evidence":"c.675C>G p.(Cys225Trp)","abstract_start":759,"abstract_end":781}]}
{"pmid":"29058101","title":"DOCK8 Deficiency Presenting as an IPEX-Like Disorder.","abstract":"PURPOSE: The dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive-combined immunodeficiency whose clinical spectra include recurrent infections, autoimmunity, malignancies, elevated serum IgE, eczema, and food allergies. Here, we report on patients with loss of function DOCK8 mutations with profound immune dysregulation suggestive of an immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like disorder.\nMETHODS: Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry. T regulatory (T<sub>reg</sub>) cells were isolated by cell sorting, and their suppressive activity was analyzed by flow cytometry. Gene mutational analysis was performed by whole-exome and Sanger sequencing.\nRESULTS: Patient 1 (P1) presented at 10 months of age with chronic severe diarrhea and active colitis in the absence of an infectious trigger, severe eczema with elevated serum IgE, and autoimmune hemolytic anemia, suggestive of an IPEX-related disorder. Whole-exome sequencing revealed a homozygous nonsense mutation in DOCK8 at the DOCK-homology region (DHR)-1 (c.1498C>T; p. R500X). Patient P2, a cousin of P1 who carries the same DOCK8 nonsense mutation, presented with eczema and recurrent ear infections in early infancy, and she developed persistent diarrhea by 3 years of age. Patient P3 presented with lymphoproliferation, severe eczema with allergic dysregulation, and chronic diarrhea with colitis. She harbored a homozygous loss of function DOCK8 mutation (c.2402 -1G→A). T<sub>reg</sub> cell function was severely compromised by both DOCK8 mutations.\nCONCLUSION: DOCK8 deficiency may present severe immune dysregulation with features that may overlap with those of IPEX and other IPEX-like disorders.","variants":[{"Name":"NM_203447.4(DOCK8):c.1498C>T (p.Arg500Ter)","Chromosome":"9","Start":"339081","Stop":"339081","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1061669,"rule_based_match":true,"evidence_text":"c.1498C>T; p. R500X","llm_judgment":"PRESENT","evidence":"c.1498C>T; p. R500X","abstract_start":1147,"abstract_end":1166}]}
{"pmid":"23170986","title":"The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families.","abstract":"The MSH2 c.388_389del mutation has occasionally been described in Lynch families worldwide. At the Portuguese Oncology Institute in Porto, Portugal, we have identified 16 seemingly unrelated families with this germline mutation. To evaluate if this alteration is a founder or a recurrent mutation we performed haplotype analysis in the 16 Portuguese index cases and 55 relatives, as well as in four index cases and 13 relatives reported from Germany, Scotland, England, and Argentina. In the Portuguese families we observed a shared haplotype of approximately 10 Mb and all were originated from the north of Portugal. These results suggest that this alteration is a founder mutation in Portugal with a relatively recent origin. In the reported families outside Portugal with this mutation different haplotype backgrounds were observed, supporting the hypothesis that it occurred de novo on multiple occasions. We also conclude that the high proportion of families with the MSH2 c.388_389del mutation indicates that screening for this alteration as a first step may be cost-effective in the genetic testing of Lynch syndrome suspects of Portuguese ancestry, especially those originating from the north of Portugal.","variants":[{"Name":"NM_000251.3(MSH2):c.388_389del (p.Gln130fs)","Chromosome":"2","Start":"47410115","Stop":"47410116","ReferenceAlleleVCF":"TCA","AlternateAlleleVCF":"T","allel_id":96565,"rule_based_match":true,"evidence_text":"MSH2 c.388_389del","llm_judgment":"PRESENT","evidence":"MSH2 c.388_389del","abstract_start":4,"abstract_end":21}]}
{"pmid":"29318572","title":"Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy.","abstract":"MPV17-related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non-consanguineous Black South African heritage. Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in 2 unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122-1/38) with an estimated newborn incidence of 1 in 18 496 (95% CI; 1/59 536-1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterized severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found.","variants":[{"Name":"NM_002437.5(MPV17):c.106C>T (p.Gln36Ter)","Chromosome":"2","Start":"27313074","Stop":"27313074","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":244007,"rule_based_match":true,"evidence_text":"c.106C>T","llm_judgment":"PRESENT","evidence":"c.106C>T","abstract_start":282,"abstract_end":290}]}
{"pmid":"38778723","title":"A new genetic diagnosis strategy for paroxysmal kinesigenic dyskinesia: Targeted high-throughput detection of PRRT2 gene c.649 locus.","abstract":"BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most prevalent kind type of paroxysmal Dyskinesia, characterized by recurrent and transient episodes of involuntary movements. Most PKD cases were attributed to the proline-rich transmembrane protein 2 (PRRT2) gene, in which the c.649 region is a hotspot for known mutations. Even though some patients with PKD have been genetically diagnosed using whole-exome sequencing (WES) and Sanger sequencing, there are still cases of missed diagnoses due to the limitations of sequencing technology and analytic methods on throughput.\nMETHODS: Patients meeting the diagnosis criteria of PKD with negative results of PRRT2-Sanger sequencing and WES were included in this study. Mutation screening and targeted high-throughput sequencing were performed to analyze and verify the sequencing results of the potential mutations.\nRESULTS: Six patients with PKD with high mutation ratios of c.649dupC were screened using our targeted high-throughput sequencing from 26 PKD patients with negative results of PRRT2-Sanger sequencing and WES (frequency = 23.1%), which compensated for the comparatively shallow sequencing depth and statistical flaws in this region. Compared with the local normal population and other patients with PKD, the mutation ratios of c.649dupC of these six patients with PKD were much higher and also had truncated protein structures and differentially altered mRNA expression.\nCONCLUSION: Based on the above studies, we emphasize the routine targeted high-throughput sequencing of the c.649 site in the PRRT2 gene in so-called genetic-testing-negative patients with PKD, and manually calculate the deletion and duplication mutations depth and ratios to lower the rate of clinical misdiagnosis.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC","llm_judgment":"PRESENT","evidence":"c.649dupC","abstract_start":935,"abstract_end":944}]}
{"pmid":"23154058","title":"Epilepsy in adult X-linked adrenoleucodystrophy due to the deletion c.1415-1416delAG in exon 5 of the ABCD1-gene.","abstract":"Seizures in cerebral X-linked adrenoleucodystrophy (X-ALD) more frequently occur in the early-onset compared to the late-onset form. Here we describe an adult in whom X-ALD deteriorated after head trauma and who developed epilepsy with progression of X-ALD. In a 50 year-old Caucasian male, cerebral X-ALD was diagnosed upon progressive gait disturbance, intellectual decline, elevated very-long chain fatty acids in the serum or leucocytes, cerebral MRI, showing extensive, symmetric, homogenous demyelination in the parieto-occipital areas, the splenium corporis callosum, the thalamus, the crura cerebri, the brain stem, and the pedunculi cerebelli, and the deletion c.1415-1416delAG in the ABCD1-gene. After a head trauma the phenotype deteriorated to mutism, dysphagia, and severe spastic quadruparesis. At an age of 50 years the patient experienced his first, self-limiting, tonic-clonic seizure during an infection, which is why valproic acid was started. Recurrence of seizures after discharge required repeated adaptation of the valproic acid-dosage. Adult X-ALD may be associated with late-onset seizures, which respond favourably to valproic acid. Since any type of seizure episode in adult-onset cerebral X-ALD is usually followed by neurological decline, prophylactic treatment with antiepileptic drugs should be considered not only in early-onset but also in adult-onset epilepsy in X-ALD.","variants":[{"Name":"NM_000033.4(ABCD1):c.1415_1416del (p.Gln472fs)","Chromosome":"X","Start":"153737178","Stop":"153737179","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":26342,"rule_based_match":false,"evidence_text":"c.1415-1416delAG","llm_judgment":"PRESENT","evidence":"c.1415-1416delAG","abstract_start":670,"abstract_end":686}]}
{"pmid":"23280837","title":"Mutations in KCND3 cause spinocerebellar ataxia type 22.","abstract":"OBJECTIVE: To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.\nMETHODS: We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.\nRESULTS: We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame 3-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K(+) channel conductance in whole cell patch-clamp recordings.\nINTERPRETATION: Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration.","variants":[{"Name":"NM_001378969.1(KCND3):c.1130C>T (p.Thr377Met)","Chromosome":"1","Start":"111787083","Stop":"111787083","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":614648,"rule_based_match":true,"evidence_text":"c.1130C>T p.T377M","llm_judgment":"PRESENT","evidence":"c.1130C>T p.T377M","abstract_start":1263,"abstract_end":1280}]}
{"pmid":"25998219","title":"New Insights into the Genetics of Fetal Megacystis: ACTG2 Mutations, Encoding γ-2 Smooth Muscle Actin in Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (Berdon Syndrome).","abstract":"OBJECTIVE: To identify the molecular basis for prenatally suspected cases of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) (MIM 249210) in 3 independent families with clinical and radiographic evidence of MMIHS.\nMETHODS: Whole-exome sequencing (WES) and Sanger sequencing of the ACTG2 gene.\nRESULTS: We identified a novel heterozygous de novo missense variant in ACTG2 c.770G>A (p.Arg257His) encoding x03B3;-2 smooth muscle actin (ACTG2) in 2 siblings with MMIHS, suggesting gonadal mosaicism of one of the parents. Two additional de novo missense variants (p.Arg257Cys and p.Arg178His) in ACTG2 were identified in 2 additional MMHIS patients. All of our patients had evidence of fetal megacystis and a normal or slightly increased amniotic fluid volume. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. ACTG2 immunostaining of the intestinal tissue showed an altered muscularis propria, a markedly thinned longitudinal muscle layer, and a reduced amount and abnormal distribution of ACTG2.\nCONCLUSION: Our study demonstrates that de novo mutations in ACTG2 are a cause of fetal megacystis in MMIHS and that gonadal mosaicism may be present in a subset of cases. These findings have implications for the counseling of families with a diagnosis of fetal megacystis with a preserved amniotic fluid volume and associated gastrointestinal findings.","variants":[{"Name":"NM_001615.4(ACTG2):c.533G>A (p.Arg178His)","Chromosome":"2","Start":"73913566","Stop":"73913566","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":136550,"rule_based_match":false,"evidence_text":"p.Arg178His","llm_judgment":"PRESENT","evidence":"p.Arg178His","abstract_start":594,"abstract_end":605},{"Name":"NM_001615.4(ACTG2):c.769C>T (p.Arg257Cys)","Chromosome":"2","Start":"73914835","Stop":"73914835","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":136552,"rule_based_match":false,"evidence_text":"p.Arg257Cys","llm_judgment":"PRESENT","evidence":"p.Arg257Cys","abstract_start":578,"abstract_end":589},{"Name":"NM_001615.4(ACTG2):c.770G>A (p.Arg257His)","Chromosome":"2","Start":"73914836","Stop":"73914836","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205237,"rule_based_match":true,"evidence_text":"c.770G>A (p.Arg257His)","llm_judgment":"PRESENT","evidence":"c.770G>A (p.Arg257His)","abstract_start":389,"abstract_end":411}]}
{"pmid":"15241794","title":"Identification of the molecular defect in patients with peroxisomal mosaicism using a novel method involving culturing of cells at 40 degrees C: implications for other inborn errors of metabolism.","abstract":"The peroxisome biogenesis disorders (PBDs), which comprise Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and infantile Refsum disease (IRD), represent a spectrum of disease severity, with ZS being the most severe, and IRD the least severe disorder. The PBDs are caused by mutations in one of the at least 12 different PEX genes encoding proteins involved in the biogenesis of peroxisomes. We report the biochemical characteristics and molecular basis of a subset of atypical PBD patients. These patients were characterized by abnormal peroxisomal plasma metabolites, but otherwise normal to very mildly abnormal peroxisomal parameters in cultured skin fibroblasts, including a mosaic catalase immunofluorescence pattern in fibroblasts. Since this latter feature made standard complementation analysis impossible, we developed a novel complementation technique in which fibroblasts were cultured at 40 degrees C, which exacerbates the defect in peroxisome biogenesis. Using this method, we were able to assign eight patients to complementation group 3 (CG3), followed by the identification of a single homozygous c.959C>T (p.S320F) mutation in their PEX12 gene. We also investigated various peroxisomal biochemical parameters in fibroblasts at 30 degrees C, 37 degrees C, and 40 degrees C, and found that all parameters showed a temperature-dependent behavior. The principle of culturing cells at elevated temperatures to exacerbate the defect in peroxisome biogenesis, and thereby preventing certain mutations from being missed, may well have a much wider applicability for a range of different inborn errors of metabolism.","variants":[{"Name":"NM_000286.3(PEX12):c.959C>T (p.Ser320Phe)","Chromosome":"17","Start":"35575903","Stop":"35575903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22814,"rule_based_match":true,"evidence_text":"c.959C>T (p.S320F)","llm_judgment":"PRESENT","evidence":"c.959C>T (p.S320F)","abstract_start":1122,"abstract_end":1140}]}
{"pmid":"35365085","title":"High frequency of complex CFTR alleles associated with c.1521_1523delCTT (F508del) in Russian cystic fibrosis patients.","abstract":"Cystic fibrosis (CF, MIM# 219,700) is an autosomal recessive disease caused by pathogenic variants within the CFTR gene. It was shown that genetic variants located in cis can affect disease severity or treatment response because of additive or epistatic effects. Studies on the prevalence of complex alleles in Russian CF patients have just begun. Aim To evaluate frequencies and genetic background of complex alleles carrying c.1521_1523delCTT (F508del) and c.1399C>T (L467F), c.2562T>G (T854=) or c.4389G>A (Q1463=) in cis; to determine clinical consequences of complex allele c.[1399C>T;1521_1523delCTT] ([L467;F508del]) in Russian CF patients. Methods Sequencing of coding regions of CFTR gene and analysis of polymorphic markers in CF patients carrying F508del variant. Comparing of clinical features in two groups patients having genotypes [L467F;F508del];[F508del] (group 1) and [F508del];[F508del] (group 2). Results Frequency of [L467F;F508del] allele linked to 2-2-21-6-17-13 haplotype was 4.42%, of [F508del;T854=;Q1463=] allele linked to haplotype 1-2-21-6-17-13 - 2.2% in F508del chromosomes. No differences in disease severity in patients carrying complex allele [L467F;F508del] and patients homozygous for F508del was found. Conclusion The frequency of complex alleles associated with F508del was at least 6.6% in Russian CF patients, which should be taken into account for the decision on optimal treatment options with CFTR modulators.","variants":[{"Name":"NM_000492.4(CFTR):c.1399C>T (p.Leu467Phe)","Chromosome":"7","Start":"117559470","Stop":"117559470","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67914,"rule_based_match":true,"evidence_text":"c.1399C>T (L467F)","llm_judgment":"PRESENT","evidence":"c.1399C>T (L467F)","abstract_start":459,"abstract_end":476}]}
{"pmid":"21125326","title":"Case report: birth of healthy twins after preimplantation genetic diagnosis of propionic acidemia.","abstract":"PURPOSE: Development of an ad hoc protocol for the preimplantion genetic diagnosis of propionic acidemia in a couple carrying the mutations c.737G>T (G246V) and c.1218del14ins12 (ins/del) in the PCCB gene. Propionic acidemia is an autosomal recessive metabolic disorder where the body is unable to process certain parts of proteins and lipids. Symptoms manifest few days after birth and sometimes progress to more serious medical problems, including heart abnormalities, coma and death.\nMETHODS: Four short tandem repeat markers closely linked to the PCCB gene were tested, in order to support the direct mutation detection diagnosis. Multiplex fluorescent heminested polymerase chain reaction followed by fragment analysis and minisequencing was used.\nRESULTS: Fourteen single blastomeres from nine embryos were tested and two carrier embryos were transferred, resulting in the birth of two healthy boys.\nCONCLUSIONS: Preimplantation genetic diagnosis represents a valid reproductive option for couples affected of propionic acidemia, in order to avoid transmission to offspring.","variants":[{"Name":"NM_000532.5(PCCB):c.737G>T (p.Gly246Val)","Chromosome":"3","Start":"136293838","Stop":"136293838","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1059618,"rule_based_match":true,"evidence_text":"c.737G>T (G246V)","llm_judgment":"PRESENT","evidence":"c.737G>T (G246V)","abstract_start":140,"abstract_end":156}]}
{"pmid":"35468344","title":"Novel RARS2 Variants: Updating the Diagnosis and Pathogenesis of Pontocerebellar Hypoplasia Type 6.","abstract":"BACKGROUND: Pontocerebellar hypoplasia type 6 (PCH6) is an early-onset encephalopathy with/without mitochondrial respiratory complex defects caused by recessive mutations in mitochondrial arginyl-tRNA synthetase (RARS2). Highly heterogeneous clinical phenotypes and numerous missense variations of uncertain significance make diagnosis difficult. Pathogenesis of PCH6 remains unclear.\nMETHODS: Facial characteristics of patients were assessed. Genetic tests were performed. Structure prediction was based on the template from AlphaFold Protein Structure Database. Expression of mutant RARS2 was tested in HEK293T cells. Patient-derived induced pluripotent stem cells (iPSCs) were detected for human mitochondrial tRNA<sup>Arg</sup> (hmtRNA<sup>Arg</sup>) steady-state level, mitochondrial respiratory complex (MRC) activity, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), mitochondrial membrane potential (MMP), reactive oxygen species (ROS) abundance, and apoptosis level.\nRESULTS: The three pedigrees were diagnosed as PCH6 caused by compound heterozygous RARS2 variations. Five RARS2 variants were identified: c.3G>C(p.M1?), c.685C>T(p.R229∗), c.1060T>A(p.F354I), c.1210A>G(p.M404V), and c.1369G>A(p.G457R). RARS2 c.3G>C disrupted protein expression. RARS2 c.685C>T created a truncated protein lacking complete catalytic core and anticodon-binding domain. RARS2 c.1060T>A and c.1369G>A were predicted to cause structural abnormality. The hmtRNA<sup>Arg</sup> steady-state abundance in a patient's iPSCs was unaffected. Mitochondrial energy metabolism was normal, including MRC activity, OCR, ECAR, and MMP, while mitochondria-related cellular characteristics, including ROS (P < 0.001) and apoptosis levels (P < 0.001), increased.\nCONCLUSIONS: This study reports five RARS2 variations among which c.3G>C and c.1060T>A are novel. Summarized facial features of PCH6 patients will facilitate diagnosis. Defective mitochondrial energy metabolism may not be key points, but mitochondria-related abnormal cellular physiology, including apoptosis, may be an underlying pathogenesis.","variants":[{"Name":"NM_020320.5(RARS2):c.1210A>G (p.Met404Val)","Chromosome":"6","Start":"87519610","Stop":"87519610","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2833266,"rule_based_match":true,"evidence_text":"c.1210A>G(p.M404V)","llm_judgment":"PRESENT","evidence":"c.1210A>G(p.M404V)","abstract_start":1192,"abstract_end":1210}]}
{"pmid":"16786512","title":"Identification of a novel mutation of SH3BP2 in cherubism and demonstration that SH3BP2 mutations lead to increased NFAT activation.","abstract":"We describe a novel missense mutation (Aspartic acid to Asparagine, p.D419N (g.1371G>A, c.1255G>A) within exon 9 of SH3BP2 in a patient with cherubism, an autosomal dominant syndrome characterized by excessive osteoclastic bone resorption of the jaw. Two siblings and the father were carriers but lacked phenotypic features. Transient expression of p.D419N (c.1255G>A), as well as three previously described exon 9 mutations from cherubism patients (p.R415Q (c.1244G>A), p.D420E (c.1259G>A), and p.P418R (c.1253C>G)) increased activity of NFAT (nuclear factor of activated T-cells), an osteoclastogenic mediator, indicating that cherubism results from gain of function mutations in SH3BP2.","variants":[{"Name":"NM_001122681.2(SH3BP2):c.1253C>G (p.Pro418Arg)","Chromosome":"4","Start":"2831582","Stop":"2831582","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":22587,"rule_based_match":true,"evidence_text":"p.P418R (c.1253C>G)","llm_judgment":"PRESENT","evidence":"p.P418R (c.1253C>G)","abstract_start":496,"abstract_end":515},{"Name":"NM_001122681.2(SH3BP2):c.1244G>A (p.Arg415Gln)","Chromosome":"4","Start":"2831573","Stop":"2831573","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22590,"rule_based_match":true,"evidence_text":"p.R415Q (c.1244G>A)","llm_judgment":"PRESENT","evidence":"p.R415Q (c.1244G>A)","abstract_start":450,"abstract_end":469}]}
{"pmid":"26485748","title":"HB Puerta del Sol [HBA1:c.148A>C], HB Valdecilla [HBA2:c.3G>T], HB Gran Vía [HBA2:c.98T>G], HB Macarena [HBA2:c.358C>T] and HB El Retiro [HBA2:c.364_366dupGTG]: description of five new hemoglobinopathies.","abstract":"BACKGROUND: Structural hemoglobinopathies do not usually have a clinical impact, but they can interfere with the analytical determination of some parameters, such as the glycated hemoglobin in diabetic patients. Thalassemias represent a serious health problem in areas where their incidence is high. The defects in the post-translational modifications produce hyper-unstable hemoglobin that is not detected by most of electrophoretic or chromatographic methods that are available so far.\nMETHODS: We studied seven patients who belong to six unrelated families. The first two families were studied because they had peak abnormal hemoglobin (Hb) during routine analytical assays. The other four families were studied because they had microcytosis and hypochromia with normal HbA2 and HbF without iron deficiency. HbA2 and F quantification and abnormal Hb separation were performed by chromatographic and electrophoretic methods. The molecular characterization was performed using specific sequencing.\nRESULTS: The Hb Puerta del Sol presents electrophoretic mobility and elution in HPLC that is different from HbA and similar to HbS. The electrophoretic and chromatographic profiles of the four other variants are normal and do not show any anomalies, and their identification was only possible with sequencing.\nCONCLUSIONS: Some variants, such as Hb Valdecilla, Hb Gran Vía, Hb Macarena and Hb El Retiro, have significant clinical impact when they are associated with other forms of α-thalassemia, which could lead to more serious forms of this group of pathologies as for HbH disease. Therefore, it is important to maintain an adequate program for screening these diseases in countries where the prevalence is high to prevent the occurrence of severe forms.","variants":[{"Name":"NM_000517.6(HBA2):c.98T>G (p.Met33Arg)","Chromosome":"16","Start":"173127","Stop":"173127","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":609944,"rule_based_match":true,"evidence_text":"HB Gran Vía [HBA2:c.98T>G]","llm_judgment":"PRESENT","evidence":"Hb Gran Vía","abstract_start":1360,"abstract_end":1371}]}
{"pmid":"26123486","title":"POLG2 disease variants: analyses reveal a dominant negative heterodimer, altered mitochondrial localization and impaired respiratory capacity.","abstract":"Human mitochondrial DNA (mtDNA) is replicated and repaired by the mtDNA polymerase gamma, polγ. Polγ is composed of three subunits encoded by two nuclear genes: (1) POLG codes for the 140-kilodalton (kDa) catalytic subunit, p140 and (2) POLG2 encodes the ∼110-kDa homodimeric accessory subunit, p55. Specific mutations are associated with POLG- or POLG2-related disorders. During DNA replication the p55 accessory subunit binds to p140 and increases processivity by preventing polγ's dissociation from the template. To date, studies have demonstrated that homodimeric p55 disease variants are deficient in the ability to stimulate p140; however, all patients currently identified with POLG2-related disorders are heterozygotes. In these patients, we expect p55 to occur as 25% wild-type (WT) homodimers, 25% variant homodimers and 50% heterodimers. We report the development of a tandem affinity strategy to isolate p55 heterodimers. The WT/G451E p55 heterodimer impairs polγ function in vitro, demonstrating that the POLG2 c.1352G>A/p.G451E mutation encodes a dominant negative protein. To analyze the subcellular consequence of disease mutations in HEK293 cells, we designed plasmids encoding p55 disease variants tagged with green fluorescent protein (GFP). P205R and L475DfsX2 p55 variants exhibit irregular diffuse mitochondrial fluorescence and unlike WT p55, they fail to form distinct puncta associated with mtDNA nucleoids. Furthermore, homogenous preparations of P205R and L475DfsX2 p55 form aberrant reducible multimers. We predict that abnormal protein folding or aggregation or both contribute to the pathophysiology of these disorders. Examination of mitochondrial bioenergetics in stable cell lines overexpressing GFP-tagged p55 variants revealed impaired mitochondrial reserve capacity.","variants":[{"Name":"NM_007215.4(POLG2):c.1352G>A (p.Gly451Glu)","Chromosome":"17","Start":"64477929","Stop":"64477929","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20315,"rule_based_match":true,"evidence_text":"c.1352G>A/p.G451E","llm_judgment":"PRESENT","evidence":"c.1352G>A/p.G451E","abstract_start":1024,"abstract_end":1041}]}
{"pmid":"16446107","title":"Three kinships with ALAS2 P520L (c. 1559 C --> T) mutation, two in association with severe iron overload, and one with sideroblastic anemia and severe iron overload.","abstract":"Mutations in aminolevulinate synthase 2 (ALAS2) are usually associated with sideroblastic anemia and iron overload. The objective of this study was to determine if \"mild\" mutations in ALAS2 might increase the severity of primary iron overload. Direct sequencing of the ALAS2 gene was performed on 24 subjects with primary hemochromatosis and one subject with sideroblastic anemia with severe iron overload. We identified a novel mutation P520L (c. 1559 C --> T) in ALAS2 in three subjects. Two had severe iron overload and no anemia: one also had HFE C282Y homozygosity, and the other was wildtype for HFE and other iron-related genes. The third subject had sideroblastic anemia with iron overload, and was hemizygous for both P520L and R560H (c. 1679 G --> A) mutations in ALAS2. The P520L mutation was found at a frequency of 0.0013 (741 alleles) in white control subjects, but was not found in 158 alleles from black control subjects. The proline in this position is highly conserved across species from humans to zebrafish. However, genotype/phenotype studies of the families demonstrate that the P520L mutation alone has no iron-associated phenotype, but it may act as a modifier of iron overload in the presence of mutations in HFE or other uncharacterized hemochromatosis genes. Thus, ALAS2 mutations might contribute to more severe iron loading in persons with primary hemochromatosis.","variants":[{"Name":"NM_000032.5(ALAS2):c.1559C>T (p.Pro520Leu)","Chromosome":"X","Start":"55013527","Stop":"55013527","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":212027,"rule_based_match":false,"evidence_text":"c. 1559 C --> T","llm_judgment":"PRESENT","evidence":"c. 1559 C --> T","abstract_start":445,"abstract_end":460},{"Name":"NM_000032.5(ALAS2):c.1679G>A (p.Arg560His)","Chromosome":"X","Start":"55009265","Stop":"55009265","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1293342,"rule_based_match":false,"evidence_text":"c. 1679 G --> A","llm_judgment":"PRESENT","evidence":"c. 1679 G --> A","abstract_start":744,"abstract_end":759}]}
{"pmid":"23301227","title":"The first Korean case of mucopolysaccharidosis IIIC (Sanfilippo syndrome type C) confirmed by biochemical and molecular investigation.","abstract":"Mucopolysaccharidosis (MPS) III has 4 enzymatically distinct forms (A, B, C, and D), and MPS IIIC, also known as Sanfilippo C syndrome, is an autosomal recessive lysosomal storage disease caused by a deficiency of heparan acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT). Here, we report a case of MPS IIIC that was confirmed by molecular genetic analysis. The patient was a 2-yr-old girl presenting with skeletal deformity, hepatomegaly, and delayed motor development. Urinary excretion of glycosaminoglycan (GAG) was markedly elevated (984.4 mg GAG/g creatinine) compared with the age-specific reference range (<175 mg GAG/g creatinine), and a strong band of heparan sulfate was recognized on performing thin layer chromatography. HGSNAT enzyme activity in leukocytes was 0.7 nmol/17 hr/mg protein, which was significantly lower than the reference range (8.6-32 nmol/17 hr/mg protein). PCR and direct sequencing of the HGSNAT gene showed 2 mutations: c.234+1G>A (IVS2+1G>A) and c.1150C>T (p.Arg384*). To the best of our knowledge, this is the first case of MPS IIIC to be confirmed by clinical, biochemical, and molecular genetic findings in Korea.","variants":[{"Name":"NM_152419.3(HGSNAT):c.234+1G>A","Chromosome":"8","Start":"43147064","Stop":"43147064","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39789,"rule_based_match":true,"evidence_text":"c.234+1G>A (IVS2+1G>A)","llm_judgment":"PRESENT","evidence":"c.234+1G>A (IVS2+1G>A)","abstract_start":964,"abstract_end":986},{"Name":"NM_152419.3(HGSNAT):c.1150C>T (p.Arg384Ter)","Chromosome":"8","Start":"43191495","Stop":"43191495","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":544423,"rule_based_match":true,"evidence_text":"c.1150C>T (p.Arg384*)","llm_judgment":"PRESENT","evidence":"c.1150C>T (p.Arg384*)","abstract_start":991,"abstract_end":1012}]}
{"pmid":"31693170","title":"Cerebellar ataxia with normal intellect associated with a homozygous truncating variant in CA8.","abstract":"Biallelic pathogenic variants in CA8 cause cerebellar ataxia, mental retardation and dysequilibrium syndrome 3 (CAMRQ3), a rare form of hereditary ataxia characterised by cerebellar hypoplasia/atrophy, variable intellectual disability and often quadrupedal gait. The few cases reported in the medical literature are all caused by pathogenic homozygous or compound heterozygous missense variants in CA8. We report a 9 year-old boy with marked gross motor delay, ataxia and progressive cerebellar atrophy with limited bipedal gait, but without intellectual disability. Singleton whole exome sequencing was performed. A novel homozygous truncating variant in CA8 (c.232C>T) with a predicted premature termination codon at position 78 (p.Arg78*) was identified. Both parents and the proband's healthy sister are heterozygous for the variant. This variant is likely pathogenic and the cause of the condition in this child. Functional evidence in the form of a spontaneous mouse model involving homozygous intragenic deletion of the mouse analogue of CA8 with nonsense-mediated decay and similar clinical features to the proband support pathogenicity. Identification of this truncating variant broadens the genotypic and phenotypic spectrum of CA8-related cerebellar ataxia.","variants":[{"Name":"NM_004056.6(CA8):c.232C>T (p.Arg78Ter)","Chromosome":"8","Start":"60279749","Stop":"60279749","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3494526,"rule_based_match":true,"evidence_text":"c.232C>T","llm_judgment":"PRESENT","evidence":"c.232C>T","abstract_start":661,"abstract_end":669}]}
{"pmid":"34888019","title":"Comprehensive genetic screening reveals wide spectrum of genetic variants in monogenic forms of diabetes among Pakistani population.","abstract":"BACKGROUND: Monogenic forms of diabetes (MFD) are single gene disorders. Their diagnosis is challenging, and symptoms overlap with type 1 and type 2 diabetes.\nAIM: To identify the genetic variants responsible for MFD in the Pakistani population and their frequencies.\nMETHODS: A total of 184 patients suspected of having MFD were enrolled. The inclusion criterion was diabetes with onset below 25 years of age. Brief demographic and clinical information were taken from the participants. The maturity-onset diabetes of the young (MODY) probability score was calculated, and glutamate decarboxylase ELISA was performed. Antibody negative patients and features resembling MODY were selected (<i>n</i> = 28) for exome sequencing to identify the pathogenic variants.\nRESULTS: A total of eight missense novel or very low-frequency variants were identified in 7 patients. Three variants were found in genes for MODY, <i>i.e. HNF1A</i> (c.169C>A, p.Leu57Met), <i>KLF11</i> (c.401G>C, p.Gly134Ala), and <i>HNF1B</i> (c.1058C>T, p.Ser353Leu). Five variants were found in genes other than the 14 known MODY genes, <i>i.e. RFX6</i> (c.919G>A, p.Glu307Lys), <i>WFS1</i> (c.478G>A, p.Glu160Lys) and <i>WFS1</i> (c.517G>A, p.Glu173Lys), <i>RFX6</i> (c.1212T>A, p.His404Gln) and <i>ZBTB20</i> (c.1049G>A, p.Arg350His).\nCONCLUSION: The study showed wide spectrum of genetic variants potentially causing MFD in the Pakistani population. The MODY genes prevalent in European population (<i>GCK, HNF1A, and HNF4a</i>) were not found to be common in our population. Identification of novel variants will further help to understand the role of different genes causing the pathogenicity in MODY patient and their proper management and diagnosis.","variants":[{"Name":"NM_006005.3(WFS1):c.478G>A (p.Glu160Lys)","Chromosome":"4","Start":"6291214","Stop":"6291214","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3174514,"rule_based_match":true,"evidence_text":"WFS1 (c.478G>A, p.Glu160Lys)","llm_judgment":"PRESENT","evidence":"WFS1</i> (c.478G>A, p.Glu160Lys)","abstract_start":1149,"abstract_end":1181}]}
{"pmid":"29637184","title":"Incidence of infantile Pompe disease in the Maroon population of French Guiana.","abstract":"OBJECTIVES: The aim of this study was to describe the epidemiology of infantile Pompe disease (IPD) in French Guiana, a French overseas territory, by combining a retrospective case records study and a prospective anonymous genotyping in a sample of mothers followed in the two major maternity units of French Guiana.\nMETHODS: We identified 19 newborns with IPD born within a 13-year-period in French Guiana, corresponding to 1/4528 births. All children were born within the African-American Maroon (Bushinengue) community originating from slaves who settled along the Maroni river in the 19th century. We also performed an anonymised screening for all women in postpartum, in the two main maternity units of French Guiana.\nRESULTS: Genetic investigations revealed that all patients with IPD were homozygotes or compound heterozygotes for two known pathogenic variations: c.2560C>T p.(Arg854*) that has already been reported in African-Americans and c.1942G>A p.(Gly648Ser), a rare previously considered to be variant. We identified no heterozygotes among 453 mothers of various ethnicities in Cayenne, but 15 heterozygotes among 425 mothers (1/27) in Saint-Laurent-du-Maroni (95% CI 1/45 to 1/17), all from the Maroon community, which corresponds to an expected IPD incidence in Maroons of 1/1727 (95% CI 1/1156 to 1/8100).\nCONCLUSION: The incidence of IPD in the Maroon community is roughly 50 times higher than elsewhere in the world. The presence of only two different variants in all affected patients is compatible with a double founder effect in a relatively small population that has seldom mixed with other regional populations in the past and therefore has a reduced pool of genotypes.","variants":[{"Name":"NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)","Chromosome":"17","Start":"80118271","Stop":"80118271","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19073,"rule_based_match":true,"evidence_text":"c.2560C>T p.(Arg854*)","llm_judgment":"PRESENT","evidence":"c.2560C>T p.(Arg854*)","abstract_start":871,"abstract_end":892},{"Name":"NM_000152.5(GAA):c.1942G>A (p.Gly648Ser)","Chromosome":"17","Start":"80112929","Stop":"80112929","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187012,"rule_based_match":true,"evidence_text":"c.1942G>A p.(Gly648Ser)","llm_judgment":"PRESENT","evidence":"c.1942G>A p.(Gly648Ser)","abstract_start":949,"abstract_end":972}]}
{"pmid":"23124043","title":"Identification of a missense mutation in the melusin-encoding ITGB1BP2 gene in a patient with dilated cardiomyopathy.","abstract":"In a heterogeneous cohort of patients (n=255) with sporadic and familial dilated cardiomyopathy (DCM), we searched for novel disease-associated mutations in the human melusin-encoding ITGB1BP2 gene and found only one missense mutation, which was a substitution of alanine for glycine at position 313 located in the carboxy-terminal spacer region of the molecule. This point mutation (c.938C>G) was identified in a 45-year-old male with familial DCM and severe impairment of left-ventricular function, but was absent in 300 healthy control subjects. However, its functional significance in the context of heart failure is unclear, as this amino acid substitution was predicted to be without disease-causing effects. In this report, we confirm the low prevalence of mutations and single nucleotide polymorphisms in the coding sequence of the human melusin gene in patients with DCM, ruling out the possibility that genetic variations in this myocardially transcribed gene may have a significant impact on the epidemiology of DCM-induced heart failure.","variants":[{"Name":"NM_012278.4(ITGB1BP2):c.938C>G (p.Ala313Gly)","Chromosome":"X","Start":"71305086","Stop":"71305086","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":108166,"rule_based_match":true,"evidence_text":"c.938C>G","llm_judgment":"PRESENT","evidence":"c.938C>G","abstract_start":384,"abstract_end":392}]}
{"pmid":"17889038","title":"Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia.","abstract":"Heterozygous germ-line variants of DNA mismatch repair (MMR) genes predispose individuals to hereditary non-polyposis colorectal cancer. Several independent reports have shown that individuals constitutionally homozygous for MMR allelic variants develop early onset hematological malignancies often associated to features of neurofibromatosis type 1 (NF1) syndrome. The genetic mechanism of NF1 associated to MMR gene deficiency is not fully known. We report here that a child with this form of NF1 displays a heterozygous NF1 gene mutation (c.3721C>T), in addition to a homozygous MLH1 gene mutation (c.676C>T) leading to a truncated MLH1 protein (p.R226X). The parents did not display NF1 features nor the NF1 mutation. This new NF1 gene mutation is recurrent and predicts a truncated neurofibromin (p.R1241X) lacking its GTPase activating function, as well as all C-terminally located functional domains. Our findings suggest that NF1 disease observed in individuals homozygous for deleterious MMR variants may be due to a concomitant NF1 gene mutation. The presence of both homozygous MLH1 and heterozygous NF1 mutation in the child studied here also provides a mechanistic explanation for early onset malignancies that are observed in affected individuals. It also provides a model for cooperation between genetic alterations in human carcinogenesis.","variants":[{"Name":"NM_001042492.3(NF1):c.3721C>T (p.Arg1241Ter)","Chromosome":"17","Start":"31235623","Stop":"31235623","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15400,"rule_based_match":true,"evidence_text":"c.3721C>T","llm_judgment":"PRESENT","evidence":"c.3721C>T","abstract_start":542,"abstract_end":551},{"Name":"NM_000249.4(MLH1):c.676C>T (p.Arg226Ter)","Chromosome":"3","Start":"37012098","Stop":"37012098","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32126,"rule_based_match":true,"evidence_text":"c.676C>T","llm_judgment":"PRESENT","evidence":"c.676C>T","abstract_start":602,"abstract_end":610}]}
{"pmid":"38168645","title":"Recessive TMOD1 mutation causes childhood cardiomyopathy.","abstract":"Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1<sup>R189W</sup> and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1<sup>R189W</sup> demonstrated longer thin filaments than GFP-TMOD1<sup>wt</sup>-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1<sup>R189W</sup> showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant's effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.","variants":[{"Name":"NM_003275.4(TMOD1):c.565C>T (p.Arg189Trp)","Chromosome":"9","Start":"97564115","Stop":"97564115","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222256,"rule_based_match":true,"evidence_text":"c.565C>T, p.R189W","llm_judgment":"PRESENT","evidence":"c.565C>T, p.R189W","abstract_start":236,"abstract_end":253}]}
{"pmid":"29075935","title":"Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits.","abstract":"Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case. Both patients presented similarly in early childhood with global developmental delay, raised CSF lactate and abnormalities on cranial MRI. Sanger sequencing of familial samples confirmed the segregation of bi-allelic GFM2 variants with disease, while investigations into steady-state mitochondrial protein levels revealed respiratory chain subunit defects and loss of mtEFG2 protein in muscle. These data demonstrate the effects of defective mtEFG2 function, caused by previously unreported variants, confirming pathogenicity and expanding the clinical phenotypes associated with GFM2 variants.","variants":[{"Name":"NM_032380.5(GFM2):c.636del (p.Glu213fs)","Chromosome":"5","Start":"74746138","Stop":"74746138","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":434403,"rule_based_match":true,"evidence_text":"c.636delA, p.(Glu213Argfs*3)","llm_judgment":"PRESENT","evidence":"c.636delA, p.(Glu213Argfs*3)","abstract_start":395,"abstract_end":423},{"Name":"NM_032380.5(GFM2):c.275A>C (p.Tyr92Ser)","Chromosome":"5","Start":"74758878","Stop":"74758878","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":434404,"rule_based_match":true,"evidence_text":"c.275A>C, p.(Tyr92Ser)","llm_judgment":"PRESENT","evidence":"c.275A>C, p.(Tyr92Ser)","abstract_start":441,"abstract_end":463},{"Name":"NM_032380.5(GFM2):c.569G>A (p.Arg190Gln)","Chromosome":"5","Start":"74747731","Stop":"74747731","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":211189,"rule_based_match":true,"evidence_text":"c.569G>A, p.(Arg190Gln)","llm_judgment":"PRESENT","evidence":"c.569G>A, p.(Arg190Gln)","abstract_start":370,"abstract_end":393}]}
{"pmid":"22958902","title":"Loss of SUFU function in familial multiple meningioma.","abstract":"Meningiomas are the most common primary tumors of the CNS and account for up to 30% of all CNS tumors. An increased risk of meningiomas has been associated with certain tumor-susceptibility syndromes, especially neurofibromatosis type II, but no gene defects predisposing to isolated familial meningiomas have thus far been identified. Here, we report on a family of five meningioma-affected siblings, four of whom have multiple tumors. No NF2 mutations were identified in the germline or tumors. We combined genome-wide linkage analysis and exome sequencing, and we identified in suppressor of fused homolog (Drosophila), SUFU, a c.367C>T (p.Arg123Cys) mutation segregating with the meningiomas in the family. The variation was not present in healthy controls, and all seven meningiomas analyzed displayed loss of the wild-type allele according to the classic two-hit model for tumor-suppressor genes. In silico modeling predicted the variant to affect the tertiary structure of the protein, and functional analyses showed that the activity of the altered SUFU was significantly reduced and therefore led to dysregulated hedgehog (Hh) signaling. SUFU is a known tumor-suppressor gene previously associated with childhood medulloblastoma predisposition. Our genetic and functional analyses indicate that germline mutations in SUFU also predispose to meningiomas, particularly to multiple meningiomas. It is possible that other genic mutations resulting in aberrant activation of the Hh pathway might underlie meningioma predisposition in families with an unknown etiology.","variants":[{"Name":"NM_016169.4(SUFU):c.367C>T (p.Arg123Cys)","Chromosome":"10","Start":"102550019","Stop":"102550019","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45820,"rule_based_match":true,"evidence_text":"c.367C>T (p.Arg123Cys)","llm_judgment":"PRESENT","evidence":"c.367C>T (p.Arg123Cys)","abstract_start":631,"abstract_end":653}]}
{"pmid":"38565514","title":"Clinical and genetic analysis of two pedigrees affected with Carnitine-acylcarnitine translocase deficiency due to variant of SLC25A20 gene","abstract":"OBJECTIVE: To analyze the clinical phenotype and genotypes of two children with Carnitine-acylcarnitine translocase deficiency (CACTD).\nMETHODS: Two children diagnosed with CACTD at the Gansu Provincial Maternal and Child Health Care Hospital respectively on January 3 and November 19, 2018 were selected as the study subjects. Trio-whole exome sequencing (trio-WES) was carried out, and candidate variants were validated through Sanger sequencing and pathogenicity analysis.\nRESULTS: Both children were males and had manifested mainly with hypoglycemia. Trio-WES and Sanger sequencing showed that child 1 had harbored compound heterozygous variants of the SLC25A20 gene, namely c.49G>C (p.Gly17Arg) and c.106-2A>G, which were inherited from his father and mother, respectively. Child 2 had harbored homozygous c.199-10T>G variants of the SLC25A20 gene, which were inherited from both of his parents. Among these, the c.106-2A>G and c.49G>C variants were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.49G>C (p.Gly17Arg), c.106-2A>G, and c.199-10T>G variants were classified as likely pathogenic (PM2_supporting+PP3+PM3_strong+PP4), pathogenic (PVS1+PM2_supporting+PM5+PP3), and pathogenic (PVS1+PM2_supporting+PP3+PP5), respectively.\nCONCLUSION: Combined with their clinical phenotype and genetic analysis, both children were diagnosed with CACTD. Above finding has provided a basis for their treatment as well as genetic counseling and prenatal diagnosis for their families.","variants":[{"Name":"NM_000387.6(SLC25A20):c.49G>C (p.Gly17Arg)","Chromosome":"3","Start":"48898746","Stop":"48898746","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3525859,"rule_based_match":true,"evidence_text":"c.49G>C (p.Gly17Arg)","llm_judgment":"PRESENT","evidence":"c.49G>C (p.Gly17Arg)","abstract_start":679,"abstract_end":699}]}
{"pmid":"27616479","title":"De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms.","abstract":"Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.","variants":[{"Name":"NM_001273.5(CHD4):c.3443G>T (p.Trp1148Leu)","Chromosome":"12","Start":"6588320","Stop":"6588320","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":260983,"rule_based_match":true,"evidence_text":"c.3443G>T (p.Trp1148Leu)","llm_judgment":"PRESENT","evidence":"c.3443G>T (p.Trp1148Leu)","abstract_start":747,"abstract_end":771},{"Name":"NM_001273.5(CHD4):c.3380G>A (p.Arg1127Gln)","Chromosome":"12","Start":"6588383","Stop":"6588383","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":260981,"rule_based_match":true,"evidence_text":"c.3380G>A (p.Arg1127Gln)","llm_judgment":"PRESENT","evidence":"c.3380G>A (p.Arg1127Gln)","abstract_start":721,"abstract_end":745},{"Name":"NM_001273.5(CHD4):c.3518G>T (p.Arg1173Leu)","Chromosome":"12","Start":"6587897","Stop":"6587897","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":260982,"rule_based_match":true,"evidence_text":"c.3518G>T (p.Arg1173Leu)","llm_judgment":"PRESENT","evidence":"c.3518G>T (p.Arg1173Leu)","abstract_start":773,"abstract_end":797}]}
{"pmid":"29498415","title":"Rare compound heterozygous variants in PNKP identified by whole exome sequencing in a German patient with ataxia-oculomotor apraxia 4 and pilocytic astrocytoma.","abstract":"Ataxia-oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive neurologic disorder. The phenotype is characterized by ataxia, oculomotor apraxia, peripheral neuropathy and dystonia. AOA4 is caused by biallelic pathogenic variants in the PNKP gene encoding a polynucleotide kinase 3'-phosphatase with an important function in DNA-damage repair. By whole exome sequencing, we identified 2 variants within the PNKP gene in a 27-year-old German woman with a clinical AOA phenotype combined with a cerebellar pilocytic astrocytoma diagnosed at 23 years of age. One variant, a duplication in exon 14 resulting in the frameshift c.1253_1269dup p.(Thr424fs*49), has previously been described as pathogenic, for example, in cases of AOA4. The second variant, representing a nonsense mutation in exon 17, c.1545C>G p.(Tyr515*), has not yet been described and is predicted to cause a loss of the 7 C-terminal amino acids. This is the first description of AOA4 in a patient with central European descent. Furthermore, the occurrence of a pilocytic astrocytoma has not been described before in an AOA4 patient. Our data demonstrate compound heterozygous PNKP germline variants in a German patient with AOA4 and provide evidence for a possible link with tumor predisposition. Localization of the 2 variants in human PNKP NP_009185.2. NM_007254.3:c.1253_1269dup p.(Thr424fs*49) is predicted to cause a frameshift within the kinase domain, NM_007254.3:c.1545C>G p.(Tyr515*) is predicted to cause loss of 2 C-terminal amino acids of the kinase domain and 5 additional C-terminal amino acids.","variants":[{"Name":"NM_007254.4(PNKP):c.1253_1269dup (p.Thr424fs)","Chromosome":"19","Start":"49861800","Stop":"49861801","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGTTGTCGATGGCGACCC","allel_id":19886,"rule_based_match":true,"evidence_text":"c.1253_1269dup p.(Thr424fs*49)","llm_judgment":"PRESENT","evidence":"c.1253_1269dup p.(Thr424fs*49)","abstract_start":629,"abstract_end":659}]}
{"pmid":"29168298","title":"Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1.","abstract":"Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.","variants":[{"Name":"NM_052867.4(NALCN):c.2022_2023del (p.Cys675fs)","Chromosome":"13","Start":"101143175","Stop":"101143176","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":2417678,"rule_based_match":true,"evidence_text":"c.2022_2023delAT","llm_judgment":"PRESENT","evidence":"c.2022_2023delAT","abstract_start":688,"abstract_end":704}]}
{"pmid":"38214746","title":"An unusual presentation of de novo RAC3 variation in prenatal diagnosis.","abstract":"Pathogenic variants in RAC3 cause a neurodevelopmental disorder with brain malformations and craniofacial dysmorphism, called NEDBAF. This gene encodes a small GTPase, which plays a critical role in neurogenesis and neuronal migration. We report a 31 weeks of gestation fetus with triventricular dilatation, and temporal and perisylvian polymicrogyria, without cerebellar, brainstem, or callosal anomalies. Trio whole exome sequencing identified a RAC3 (NM_005052.3, GRCh38) probably pathogenic de novo variant c.276 T>A p.(Asn92Lys). Eighteen patients harboring 13 different and essentially de novo missense RAC3 variants were previously reported. All the patients presented with corpus callosum malformations. Gyration disorders, ventriculomegaly (VM), and brainstem and cerebellar malformations have frequently been described. The only previous prenatal case associated with RAC3 variant presented with complex brain malformations, mainly consisting of midline and posterior fossa anomalies. We report the second prenatal case of NEDBAF presenting an undescribed pattern of cerebral anomalies, including VM and polymicrogyria, without callosal, cerebellar, or brainstem malformations. All neuroimaging data were reviewed to clarify the spectrum of cerebral malformations.","variants":[{"Name":"NM_005052.3(RAC3):c.276T>A (p.Asn92Lys)","Chromosome":"17","Start":"82032997","Stop":"82032997","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2831264,"rule_based_match":true,"evidence_text":"c.276 T>A p.(Asn92Lys)","llm_judgment":"PRESENT","evidence":"c.276 T>A p.(Asn92Lys)","abstract_start":511,"abstract_end":533}]}
{"pmid":"34711244","title":"Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis.","abstract":"Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in the MEN1 gene. The variant (c.654C > A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we found a likely pathogenic variant in the MLH1 gene (c.27G > A), and two risk factor variants in the genes CHEK2 and HOXB13. The MLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of the MLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without any findings. We conclude that, in individuals with an unequivocal clinical diagnosis of a specific hereditary cancer syndrome, where standard clinical testing failed to detect a causative variant, re-analysis may lead to a diagnosis.","variants":[{"Name":"NM_000249.4(MLH1):c.27G>A (p.Arg9=)","Chromosome":"3","Start":"36993574","Stop":"36993574","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":182217,"rule_based_match":true,"evidence_text":"c.27G > A","llm_judgment":"PRESENT","evidence":"c.27G > A","abstract_start":940,"abstract_end":949}]}
{"pmid":"27716192","title":"Sequence analysis of four vitamin D family genes (VDR, CYP24A1, CYP27B1 and CYP2R1) in Vogt-Koyanagi-Harada (VKH) patients: identification of a potentially pathogenic variant in CYP2R1.","abstract":"BACKGROUND: VKH is a rare autoimmune disease. Decreased level of vitamin D has recently been found to be involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. This study was designed to screen the vitamin D pathway genes for pathogenic mutations, if any, in VKH patients.\nMETHODS: Genomic DNA was extracted from blood samples collected from patients with VKH disease and healthy controls. Entire coding region, exon-intron junctions of four genes were sequenced in DNA from 39 Saudi VKH patients and 50 ethnically matched healthy individuals. All patients and controls were unrelated.\nRESULTS: Vitamin D levels in VKH patients were found either insufficient (21-29 ng/mL) or deficient (<20 ng/mL). Sequencing analysis of the VDR, CYP24A1, CYP27B1 and CYP2R1 detected twelve nucleotide changes in these genes in our cohort of 39 patients; 4 of which were non-coding, 6 were synonymous coding and 2 were non-synonymous coding sequence changes. All synonymous coding variants were benign polymorphisms with no apparent clinical significance. A non-synonymous coding sequence variant (c.2 T > C; p.1Met?) found in VDR is an initiation coding change and was detected in control individuals as well, while another variant (c.852G > A; p.284 M > I) found in CYP2R1 is predicted to be disease causing by mutationtaster software. This potentially pathogenic variant was found in 17 out of 39 VKH patients.\nCONCLUSIONS: Screening of four Vitamin D pathway genes in 39 VKH patients shows that a potentially pathogenic sequence variant in CYP2R1 may cause VKH in a subset of patients. These findings support the previous observation that low vitamin D levels might play a role in VKH pathogenesis and mutations in genes involved in vitamin D anabolism and catabolism might be of importance in VKH pathobiology.","variants":[{"Name":"NM_024514.5(CYP2R1):c.852G>A (p.Met284Ile)","Chromosome":"11","Start":"14880284","Stop":"14880284","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215428,"rule_based_match":true,"evidence_text":"c.852G > A; p.284 M > I","llm_judgment":"PRESENT","evidence":"c.852G > A; p.284 M > I","abstract_start":1231,"abstract_end":1254}]}
{"pmid":"18955168","title":"XPC initiation codon mutation in xeroderma pigmentosum patients with and without neurological symptoms.","abstract":"Two unrelated xeroderma pigmentosum (XP) patients, with and without neurological abnormalities, respectively, had identical defects in the XPC DNA nucleotide excision repair (NER) gene. Patient XP21BE, a 27-year-old woman, had developmental delay and early onset of sensorineural hearing loss. In contrast, patient XP329BE, a 13-year-old boy, had a normal neurological examination. Both patients had marked lentiginous hyperpigmentation and multiple skin cancers at an early age. Their cultured fibroblasts showed similar hypersensitivity to killing by UV and reduced repair of DNA photoproducts. Cells from both patients had a homozygous c.2T>G mutation in the XPC gene which changed the ATG initiation codon to arginine (AGG). Both had low levels of XPC message and no detectable XPC protein on Western blotting. There was no functional XPC activity in both as revealed by the failure of localization of XPC and other NER proteins at the sites of UV-induced DNA damage in a sensitive in vivo immunofluorescence assay. XPC cDNA containing the initiation codon mutation was functionally inactive in a post-UV host cell reactivation (HCR) assay. Microsatellite markers flanking the XPC gene showed only a small region of identity ( approximately 30kBP), indicating that the patients were not closely related. Thus, the initiation codon mutation resulted in DNA repair deficiency in cells from both patients and greatly increased cancer susceptibility. The neurological abnormalities in patient XP21BE may be related to close consanguinity and simultaneous inheritance of other recessive genes or other gene modifying effects rather than the influence of XPC gene itself.","variants":[{"Name":"NM_004628.5(XPC):c.2T>G (p.Met1Arg)","Chromosome":"3","Start":"14178567","Stop":"14178567","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1055301,"rule_based_match":true,"evidence_text":"c.2T>G","llm_judgment":"PRESENT","evidence":"c.2T>G","abstract_start":639,"abstract_end":645}]}
{"pmid":"38264610","title":"Novel pathogenic variants in Tubulin Tyrosine Like 5 (","abstract":"Purpose: Autosomal recessive cone and cone-rod dystrophies (CD/CRD) are inherited forms of vison loss. Here, we report on and correlate the clinical phenotypes with the underlying genetic mutations.\nMethods: Clinical information was collected from subjects, including a family history with a chart review. They underwent a full ophthalmic examination, including best-corrected visual acuity, direct and indirect ophthalmoscopy, color vision testing, color fundus photography, contrast sensitivity, autofluorescence, and spectral domain-optical coherence tomography (SD-OCT), and full-field electroretinography. Next-generation panel-based genetic testing was used to identify DNA variants in subject buccal swab samples.\nResults: Genetic testing in two patients revealed three novel variants in the <i>TTLL5</i> gene associated with CD/CRD: two missense variants (c.1433G>A;p.(Arg478Gln), c.241C>G;p.(Leu81Val), and one loss-of-function variant (c.2384_2387del;p.(Ala795Valfs*9). Based on <i>in-silico</i> analysis, structural modeling, and comparison to previously reported mutations, these novel variants are very likely to be disease-causing mutations. Combining retinal imaging with SD-OCT analysis, we observed an unusual sheen in the CD/CRD phenotypes.\nConclusion: Based on the protein domain location of novel <i>TTLL5</i> variants and the localization of TTLL5 to the connecting cilium, we conclude that the CD/CRD disease phenotype is characterized as a ciliopathy caused by protein tracking dysfunction. This initially affects cone photoreceptors, where photoreceptor cilia express a high level of TTLL5, but extends to rod photoreceptors over time. Fundus photography correlated with SD-OCT imaging suggests that the macular sheen characteristically seen with <i>TTLL5</i> mutations derives from the photoreceptor's outer segments at the posterior pole.","variants":[{"Name":"NM_015072.5(TTLL5):c.1433G>A (p.Arg478Gln)","Chromosome":"14","Start":"75745527","Stop":"75745527","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":841792,"rule_based_match":true,"evidence_text":"c.1433G>A;p.(Arg478Gln)","llm_judgment":"PRESENT","evidence":"c.1433G>A;p.(Arg478Gln)","abstract_start":864,"abstract_end":887}]}
{"pmid":"27717316","title":"A rare c.183_187dupCTCAC mutation of the acetylcholine receptor CHRNE gene in a South Asian female with congenital myasthenic syndrome: a case report.","abstract":"BACKGROUND: Congenital myasthenic syndromes (CMSs) occur as a result of genetic mutations that cause aberrations in structure and/or function of proteins involved in neuromuscular transmission. Acetylcholine receptor epsilon (ε) subunit (CHRNE) gene mutations account for about 30-50 % of genetically diagnosed cases. We report a rare CHRNE gene mutation in a South Asian female with CMS.\nCASE PRESENTATION: A 17-year-old Maldivian female presented with bilateral partial ptosis, fatigable proximal muscle weakness and slurring of speech noted since the age of 2 years. She could not run, had difficulty negotiating stairs and rising from a seated position, and fatigues when speaking at length. Her birth and past medical histories were otherwise unremarkable. There is no parental consanguinity or family history of muscle disorders. On examination, she had a BMI of 18 kg/m<sup>2</sup>, bilateral fatigable partial ptosis, complete external ophthalmoplegia and fatigable proximal muscle weakness (MRC grade 4/5). Apart from spinal scoliosis the rest of the examination was normal. Haematological and biochemical investigations including serum lactate level and thyroid functions were normal. Acetylcholine receptor antibodies and muscle specific kinase antibodies were not detected in serum. Repetitive nerve stimulation showed marked decrement (>30 %) in nerve-muscle pairs in the face and forearm. Her DNA sequencing revealed a c.183-187dupCTCAC mutation in CHRNE. She remained functionally independent on pyridostigmine treatment.\nCONCLUSIONS: This case describes a rare mutation of the CHRNE gene in CMS and highlights the relevance of genetic diagnosis in CMS. It further adds to map the occurrence of such mutations in Asian populations.","variants":[{"Name":"NM_000080.4(CHRNE):c.183_187dup (p.Leu63fs)","Chromosome":"17","Start":"4902622","Stop":"4902623","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AGTGAG","allel_id":422179,"rule_based_match":true,"evidence_text":"c.183-187dupCTCAC","llm_judgment":"PRESENT","evidence":"c.183-187dupCTCAC","abstract_start":1433,"abstract_end":1450}]}
{"pmid":"32827185","title":"Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.","abstract":"More than two decades ago, a recessive syndromic phenotype affecting kidneys, eyes, and ears, was first described in the endogamous Afrikaner population of South Africa. Using whole-exome sequencing of DNA from two affected siblings (and their carrier parents), we identified the novel RRM2B c.786G>T variant as a plausible disease-causing mutation. The RRM2B gene is involved in mitochondrial integrity, and the observed change was not previously reported in any genomic database. The subsequent screening revealed the variant in two newly presenting unrelated patients, as well as two patients in our registry with rod-cone dystrophy, hearing loss, and Fanconi-type renal disease. All patients with the c.786G>T variant share an identical 1.5 Mb haplotype around this gene, suggesting a founder effect in the Afrikaner population. We present ultrastructural evidence of mitochondrial impairment in one patient, to support our thesis that this RRM2B variant is associated with the renal, ophthalmological, and auditory phenotype.","variants":[{"Name":"NM_015713.5(RRM2B):c.786G>T (p.Glu262Asp)","Chromosome":"8","Start":"102214057","Stop":"102214057","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":965405,"rule_based_match":true,"evidence_text":"RRM2B c.786G>T","llm_judgment":"PRESENT","evidence":"RRM2B c.786G>T","abstract_start":286,"abstract_end":300}]}
{"pmid":"29576327","title":"Parental mosaicism in RYR1-related Central Core Disease.","abstract":"Myopathies due to mutations in the skeletal muscle ryanodine receptor (RYR1) gene are amongst the most common non-dystrophic neuromuscular disorders and have been associated with both dominant and recessive inheritance. Several cases with apparently de novo dominant inheritance have been reported. Here we report two siblings with features of Central Core Disease (CCD) born to unaffected parents. Genetic testing revealed a heterozygous dominant RYR1 c.14582G>A (p. Arg4861His) mutation previously identified in other CCD pedigrees. The variant was absent in blood from the asymptomatic mother but detected at low but variable levels in blood- and saliva-derived DNA from the unaffected father, suggesting that this mutation has arisen as a paternal post-zygotic de novo event. These findings suggest that parental mosaicism should be considered in RYR1-related myopathies, and may provide one possible explanation for the marked intergenerational variability seen in some RYR1 pedigrees.","variants":[{"Name":"NM_000540.3(RYR1):c.14582G>A (p.Arg4861His)","Chromosome":"19","Start":"38580440","Stop":"38580440","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28021,"rule_based_match":true,"evidence_text":"RYR1 c.14582G>A (p. Arg4861His)","llm_judgment":"PRESENT","evidence":"RYR1 c.14582G>A (p. Arg4861His)","abstract_start":448,"abstract_end":479}]}
{"pmid":"22713811","title":"A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders.","abstract":"Gaucher disease (GD) is an autosomal recessive storage disorder that most commonly results from the inheritance of one identifiable mutant glucocerebrosidase (GBA1) allele from each parent. Here, we report two cases of type 2 GD resulting from the inheritance of one identifiable paternal mutant allele and one allele that likely resulted from a maternal germline mutation. Germline mutations or mosiacism are not generally associated with autosomal recessive disorders. The probands from the two unrelated families had the same maternal mutation, leu444pro, that we propose resulted from a de novo maternal germline mutation occurring at this known 'hotspot' for mutation. This first report of a germline mutation for a common point mutation leu444pro (c.1448 T>C;p.leu483pro) in GD has significant implications for molecular diagnostics and genetic counseling in recessive disorders.","variants":[{"Name":"NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)","Chromosome":"1","Start":"155235252","Stop":"155235252","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19327,"rule_based_match":true,"evidence_text":"c.1448 T>C;p.leu483pro","llm_judgment":"PRESENT","evidence":"c.1448 T>C;p.leu483pro","abstract_start":754,"abstract_end":776}]}
{"pmid":"31185933","title":"A novel frameshift mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome using targeted exome sequencing.","abstract":"BACKGROUND: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS.\nMETHODS: An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls.\nRESULTS: All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls.\nCONCLUSIONS: PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.","variants":[{"Name":"NM_000325.6(PITX2):c.515del (p.Gln172fs)","Chromosome":"4","Start":"110618585","Stop":"110618585","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":1685563,"rule_based_match":true,"evidence_text":"c.515delA","llm_judgment":"PRESENT","evidence":"c.515delA","abstract_start":1189,"abstract_end":1198}]}
{"pmid":"31489982","title":"Chinese newborn screening for the incidence of G6PD deficiency and variant of G6PD gene from 2013 to 2017.","abstract":"Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common X-linked enzymopathies caused by G6PD gene variant. We aimed to provide the characteristics of G6PD deficiency and G6PD gene variant distribution in a large Chinese newborn screening population. We investigated the prevalence of G6PD in China from 2013 to 2017. Then, we examined G6PD activity and G6PD gene in representative Chinese birth cohort to explore the distribution of G6PD gene variant in 2016. We then performed multicolor melting curve analysis to classify G6PD gene variants in 10,357 neonates with activity-confirmed G6PD deficiency, and DNA Sanger sequencing for G6PD coding exons if hot site variants were not found. The screened population, organizations, and provinces of G6PD deficiency were increased from 2013 to 2017 in China. The top five frequency of G6PD gene variants were c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, and c.871G>A and varied in different provinces, with regional and ethnic features, and four pathogenic variant sites (c.152C>T, c.290A>T, c.697G>C, and c.1285A>G) were first reported. G6PD deficiency mainly occurs in South China, and the frequency of G6PD gene variant varies in different regions and ethnicities.","variants":[{"Name":"NM_001360016.2(G6PD):c.152C>T (p.Thr51Ile)","Chromosome":"X","Start":"154536147","Stop":"154536147","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1087248,"rule_based_match":true,"evidence_text":"c.152C>T","llm_judgment":"PRESENT","evidence":"c.152C>T","abstract_start":1037,"abstract_end":1045}]}
{"pmid":"23012439","title":"Mutations in TMEM231 cause Joubert syndrome in French Canadians.","abstract":"BACKGROUND: Joubert syndrome (JBTS) is a predominantly autosomal recessive disorder characterised by a distinctive midhindbrain malformation, oculomotor apraxia, breathing abnormalities and developmental delay. JBTS is genetically heterogeneous, involving genes required for formation and function of non-motile cilia. Here we investigate the genetic basis of JBTS in 12 French-Canadian (FC) individuals.\nMETHODS AND RESULTS: Exome sequencing in all subjects showed that six of them carried rare compound heterozygous mutations in CC2D2A or C5ORF42, known JBTS genes. In addition, three individuals (two families) were compound heterozygous for the same rare mutations in TMEM231(c.12T>A[p.Tyr4*];   c.625G>A[p.Asp209Asn]). All three subjects showed a severe neurological phenotype and variable presence of polydactyly, retinopathy and renal cysts. These mutations were not detected among 385 FC controls. TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. siRNA knockdown of TMEM231 was also shown to affect barrier integrity, resulting in a reduction of cilia formation and ciliary localisation of signalling receptors.\nCONCLUSIONS: Our data suggest that mutations in TMEM231 cause JBTS, reinforcing the relationship between this condition and the disruption of the barrier at the ciliary transition zone.","variants":[{"Name":"NM_001077418.3(TMEM231):c.625G>A (p.Asp209Asn)","Chromosome":"16","Start":"75542641","Stop":"75542641","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48421,"rule_based_match":true,"evidence_text":"c.625G>A[p.Asp209Asn]","llm_judgment":"PRESENT","evidence":"c.625G>A[p.Asp209Asn]","abstract_start":700,"abstract_end":721}]}
{"pmid":"30246729","title":"Severe Hyperhomocysteinemia with Two Novel Mutations of c.154T>C and c.457G>A in Cystathionine Beta-Synthase Gene.","abstract":"","variants":[{"Name":"NM_000071.3(CBS):c.457G>A (p.Gly153Arg)","Chromosome":"21","Start":"43065690","Stop":"43065690","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":210437,"rule_based_match":true,"evidence_text":"c.457G>A","llm_judgment":"PRESENT","evidence":"c.457G>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"26563984","title":"Clinical presentation, gene analysis and outcomes in young patients with early-treated combined methylmalonic acidemia and homocysteinemia (cblC type) in Shandong province, China.","abstract":"OBJECTIVES: To estimate the incidence of MMA on newborn screening in Shandong province from May 2011 to May 2014 and summarize the clinical presentation, biochemical features, mutation analysis, and treatment regime of early-treated patients with cblC disease.\nMETHODS: Between May 2011 and May 2014, 35,291 newborns were screened for MMA in Jinan maternal and Child Care Hospital, Shandong province. The levels of C3, C3/C2, methionine and tHcy were measured. Most patients received treatment with intramuscular hydroxocobalamin after diagnosis. Metabolic parameters, clinical presentation and mental development were followed up.\nRESULTS: Nine patients were identified among 35,291 by newborn screening, giving an estimated incidence of 1:3920 live births for MMA, and all were classified as cblC disease. Among them, five patients received treatment with intramuscular hydroxocobalamin and two patients did not receive any treatment. One patient died of metabolic crises triggered by infection at the age of 38 days. Seven different mutations (c.609G>A, c.455_457delCCC, c.394C>T, c.445_446insA, c.658_660delAAG, c.452A>G and IVS1+1G>A) were detected. The mutations (c.455_457delCCC and IVS1+1G>A) are novel. Five patients who received treatment had favorable metabolic response, with both reduction of urine MMA and tHcy and increase of methionine. We obtained 7 records of DQ assessment. The five patients who received treatment presented with developmental delay and obvious neurological manifestations. In two patients who did not receive any treatment, case 8 presented with severe mental retardation and developmental delay, while case 9 had nearly normal DQ values at the age of 1(1/12)years.\nCONCLUSION: Our study characterized variable phenotypes of neurodevelopment in early-treated cblC patients diagnosed on newborn screening. The long-term outcomes of cblC disease are unsatisfactory in spite of conventional treatment and improvement of biochemical abnormalities. Although the number of patients is too small, the information provided in this work is of value in highlighting possible genotype-phenotype correlation that influences outcomes in cblC disease by future studies.","variants":[{"Name":"NM_015506.3(MMACHC):c.658_660del (p.Lys220del)","Chromosome":"1","Start":"45509022","Stop":"45509024","ReferenceAlleleVCF":"CAGA","AlternateAlleleVCF":"C","allel_id":101604,"rule_based_match":true,"evidence_text":"c.658_660delAAG","llm_judgment":"PRESENT","evidence":"c.658_660delAAG","abstract_start":1099,"abstract_end":1114},{"Name":"NM_015506.3(MMACHC):c.394C>T (p.Arg132Ter)","Chromosome":"1","Start":"45508329","Stop":"45508329","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16462,"rule_based_match":true,"evidence_text":"c.394C>T","llm_judgment":"PRESENT","evidence":"c.394C>T","abstract_start":1074,"abstract_end":1082}]}
{"pmid":"29115498","title":"Association between genotype and phenotype of virulence gene in Van der Woude syndrome families.","abstract":"Members from two Van der Woude syndrome (VWS) families were screened to determine the prevalence of interferon regulatory factor 6 (IRF6) as a disease‑causing gene and to analyze the interrelationships between patient genotype and phenotype. The peripheral blood of 24 members from two VWS families and 200 control samples were collected. The family members were interviewed for medical histories and other clinical abnormalities using questionnaires. Polymerase chain reaction was directly performed on the peripheral blood to screen for the coding region of the IRF6 gene. Of the 24 family members, a total of 6 patients had mutations of IRF6 gene. c.1234C>T (p.R412X) heterozygous mutation was detected in 3 members of family 1. In families 2 and 3, members carried the c.1210G>A (p.E404K) heterozygous mutations. The other members of the families, were wild type (wt/wt) for IRF6. Genetic testing demonstrated that the disease mutations c.1234C>T and c.1210G>A co‑segregated with the two families' pathogenic mutations. The existence of genetic heterogeneity and the complexity of the clinical phenotype was demonstrated in Chinese VWS patients.","variants":[{"Name":"NM_006147.4(IRF6):c.1210G>A (p.Glu404Lys)","Chromosome":"1","Start":"209788614","Stop":"209788614","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":214529,"rule_based_match":true,"evidence_text":"c.1210G>A (p.E404K)","llm_judgment":"PRESENT","evidence":"c.1210G>A (p.E404K)","abstract_start":773,"abstract_end":792}]}
{"pmid":"30177296","title":"X-linked Charcot-Marie-Tooth disease type 5 with recurrent weakness after febrile illness.","abstract":"X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) is an X-linked disorder characterized by early-onset sensorineural hearing impairment, peripheral neuropathy, and progressive optic atrophy. It is caused by a loss-of-function mutation in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes isoform I of phosphoribosyl pyrophosphate synthetase (PRS-I). A decreased activity leads to nonsyndromic sensorineural deafness (DFN2), CMTX5, and Arts syndrome depending upon residual PRS-I activity. Clinical and neurophysiological features of pediatric CMTX5 are poorly defined. We report two male siblings with peripheral neuropathy and prelingual sensorineural hearing loss who carried a novel c.319A>G (p.Ile107Val) PRPS1 missense mutation. They exhibited recurrent episodes of transient proximal muscle weakness, showing Gowers' sign and waddling gait after suffering from febrile illness. This transient weakness has not been previously reported in CMTX5. A patient with Arts syndrome was reported to have transient proximal weakness after febrile illness. The transient weakness presenting in both CMTX5 and Arts syndrome suggests an overlap of signs and a continuous spectrum of PRS-I hypoactivity disease. Children presenting with transient neurological signs should be evaluated for peripheral neuropathy and consider genetic analysis for PRPS1.","variants":[{"Name":"NM_002764.4(PRPS1):c.319A>G (p.Ile107Val)","Chromosome":"X","Start":"107640914","Stop":"107640914","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":245174,"rule_based_match":true,"evidence_text":"c.319A>G (p.Ile107Val)","llm_judgment":"PRESENT","evidence":"c.319A>G (p.Ile107Val)","abstract_start":712,"abstract_end":734}]}
{"pmid":"27789400","title":"Establishment of SPAST mutant induced pluripotent stem cells (iPSCs) from a hereditary spastic paraplegia (HSP) patient.","abstract":"Human skin fibroblasts were isolated from a 40-year-old hereditary spastic paraplegia patient carrying an intronic splice site mutation (c.1687+2T>A) in SPAST, leading to hereditary spastic paraplegia type 4 (SPG4). Fibroblasts were reprogrammed using episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC and hLIN28. The generated transgene-free line iPS-SPG4-splice retained the specific mutation with no additional genomic aberrations, expressed pluripotency markers and was able to differentiate into cells of all germ layers in vitro. The generated iPS-SPG4-splice line might be a useful platform to study the pathomechanism of SPG4.","variants":[{"Name":"NM_014946.4(SPAST):c.1687+2T>A","Chromosome":"2","Start":"32145009","Stop":"32145009","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3859717,"rule_based_match":true,"evidence_text":"c.1687+2T>A","llm_judgment":"PRESENT","evidence":"c.1687+2T>A","abstract_start":137,"abstract_end":148}]}
{"pmid":"31907385","title":"Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay.","abstract":"TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria. Here, we identified two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] from a patient with severe anemia, lactic acidosis, and developmental delay. Patient-derived immortalized lymphocytes showed decreased TOM70 expression, oligomerized TOM70 complex, and TOM 20/22/40 complex compared with expression in control lymphocytes. Functional analysis revealed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects, with complex IV being primarily affected. As a result, patient-derived cells grew slower in galactose medium and generated less ATP and more extracellular lactic acid than did control cells. In vitro cell model compensatory experiments confirmed the pathogenicity of TOMM70 variants since only wild-type TOM70, but not mutant TOM70, could restore the complex IV defect and TOM70 expression in TOM70 knockdown U2OS cells. Altogether, we report the first case of mitochondrial disease-causing mutations in TOMM70 and demonstrate that TOM70 is essential for multi-OXPHOS assembly. Mutational screening of TOMM70 should be employed to identify mitochondrial disease-causing gene mutations in the future.","variants":[{"Name":"NM_014820.5(TOMM70):c.1745C>T (p.Ala582Val)","Chromosome":"3","Start":"100365646","Stop":"100365646","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":974936,"rule_based_match":true,"evidence_text":"c.1745C>T (p.A582V)","llm_judgment":"PRESENT","evidence":"c.1745C>T (p.A582V)","abstract_start":180,"abstract_end":199},{"Name":"NM_014820.5(TOMM70):c.794C>T (p.Thr265Met)","Chromosome":"3","Start":"100381705","Stop":"100381705","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":974935,"rule_based_match":true,"evidence_text":"c.794C>T (p.T265M)","llm_judgment":"PRESENT","evidence":"c.794C>T (p.T265M)","abstract_start":157,"abstract_end":175}]}
{"pmid":"28374160","title":"A case of contralateral breast cancer and skin cancer associated with NBN heterozygous pathogenic variant c.698_701delAACA.","abstract":"Approximately 39.6% of people will be diagnosed with cancer during their lifetime. Several factors including, lifestyle, environment and genetics may play a role in its development. Understanding these causes will greatly improve treatment methods, prevention, and survival rates of these patients. Our patient, who has a positive family history of cancer, presented with contralateral breast cancer and multiple skin malignancies. Genetic testing revealed a frameshift variant in NBN. This gene encodes the protein, nibrin, which is involved in maintaining genomic stability. Several reports have identified heterozygous NBN frameshift (c.2028delT, c.2097dupT, c.657-661delACAAA) and splice site variants (c.1397+delG) in patients with breast cancer. However, our report is the first to describe a heterozygous c.698_701delAACA NBN variant in a patient with breast cancer. Since NBN is involved in DNA integrity, loss of functional protein due to pathogenic variants significantly increases the risk of various cancers. Given the family and personal history of our patient, in connection with previous reports of NBN pathogenic variants predisposition to cancer, this variant is predicted to be pathogenic and clinically significant.","variants":[{"Name":"NM_002485.5(NBN):c.698_701del (p.Lys233fs)","Chromosome":"8","Start":"89971174","Stop":"89971177","ReferenceAlleleVCF":"CTGTT","AlternateAlleleVCF":"C","allel_id":133335,"rule_based_match":true,"evidence_text":"c.698_701delAACA NBN variant","llm_judgment":"PRESENT","evidence":"c.698_701delAACA NBN variant","abstract_start":812,"abstract_end":840}]}
{"pmid":"37962568","title":"A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.","abstract":"Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients' T cells show residual TCR signal transduction and proliferation following anti-CD3/CD28 and phytohemagglutinin (PHA) stimulation. We demonstrate in mouse models that complete (Lck-/-) versus partial (LckP440S/P440S) loss-of-function LCK causes disease with differing phenotypes. While both Lck-/- and LckP440S/P440S mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only LckP440S/P440S mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the LckP440S/P440S mice is prevented by CD4+ T cell depletion or regulatory T cell transfer. These findings demonstrate that P440S LCK spares sufficient T cell function to allow the maturation of some conventional T cells but not regulatory T cells-leading to intestinal inflammation.","variants":[{"Name":"NM_005356.5(LCK):c.1318C>T (p.Pro440Ser)","Chromosome":"1","Start":"32280201","Stop":"32280201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3224419,"rule_based_match":true,"evidence_text":"c.1318C>T","llm_judgment":"PRESENT","evidence":"c.1318C>T","abstract_start":192,"abstract_end":201}]}
{"pmid":"27821015","title":"Mutation in a Highly Conserved COOH-Terminal Residue of Krüppel-Like Factor 1 Associated with Elevated Hb F in a Compound Heterozygous β-Thalassemia Patient with a Nontransfusion-Dependent Thalassemia Phenotype.","abstract":"We present a patient with a compound heterozygosity codon 39 (C > T) (β<sup>0</sup>) [or β39(C5)Gln→Stop (G39X); CAG > TAG; HBB: c.118C > T] and -87 (C > T) (β<sup>+</sup>) (HBB: c.-137C > T) β-globin mutations, a non transfusion-dependent thalassemia phenotype and 97.0% fetal hemoglobin. A novel heterozygous mutation was identified in a highly conserved residue in the COOH-terminus of the Krüppel-like factor 1, R360H, that likely altered DNA-binding and impaired transactivation.","variants":[{"Name":"NM_000518.5(HBB):c.118C>T (p.Gln40Ter)","Chromosome":"11","Start":"5226774","Stop":"5226774","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":30441,"rule_based_match":true,"evidence_text":"HBB: c.118C > T","llm_judgment":"PRESENT","evidence":"HBB: c.118C > T","abstract_start":124,"abstract_end":139}]}
{"pmid":"27398169","title":"Mutational analysis of ATP7B in Chinese Wilson disease patients.","abstract":"Wilson Disease (WD) is an inborn error of copper metabolism inherited in an autosomal recessive manner caused by the mutations in the P-type ATPase gene (ATP7B). In this study, we screen and detect the mutations of the ATP7B gene in unrelated Chinese WD patients. A total of 68 individuals from ten provinces of China with WD were recruited. Of them, 43 were males and 25 were females, and their onset ages were from 1 to 48 years with a median onset age of 22.2 years. All the exons and exon/intron boundaries of ATP7B gene of the patients were sequenced and aligned to the referred ATP7B gene sequence. The results suggested that 66 of the 68 patents carried with at least one mutation and 48 different mutations were identified including 34 missense, one synonymous, two nonsense, two splicing, and nine frameshift mutations (five insertion and four deletion). Among these mutations, c.2333G>T, c.2310C>G, c.2975C>T, and c.3443T>C were the most prevalent mutants and c.2310C>G always linked with c.2333G>T. The eighth, 11(th), and 18(th) exons carried more mutations (6/48, 5/48, and 5/48, respectively) than others. After comparing with the mutations reported previously, 22 out of the 48 mutations were identified as novel mutations. A popular algorithm, Polyphen-2, was used to predict the effects of the amino-acid substitution due to the mutations on the structure and function of ATP7B function and the predicted results indicated that all the missense mutations were unfavorable except c.121A>G and c.748G>A. Phenotype/genotype correlation analysis suggested that the patients with c.2975C>T or c.3809A>G often presented WD features before 12 years old while the patients with c.3443T>C almost presented WD after 12 years old. This is the first time to identify the common mutations contributing to early onset age in Chinese WD patients. Our study will broaden our knowledge about ATP7B mutations in WD patients.","variants":[{"Name":"NM_000053.4(ATP7B):c.2975C>T (p.Pro992Leu)","Chromosome":"13","Start":"51946369","Stop":"51946369","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186891,"rule_based_match":true,"evidence_text":"c.2975C>T","llm_judgment":"PRESENT","evidence":"c.2975C>T","abstract_start":909,"abstract_end":918},{"Name":"NM_000053.4(ATP7B):c.2333G>T (p.Arg778Leu)","Chromosome":"13","Start":"51958333","Stop":"51958333","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":18891,"rule_based_match":true,"evidence_text":"c.2333G>T","llm_judgment":"PRESENT","evidence":"c.2333G>T","abstract_start":887,"abstract_end":896},{"Name":"NM_000053.4(ATP7B):c.3443T>C (p.Ile1148Thr)","Chromosome":"13","Start":"51941194","Stop":"51941194","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18902,"rule_based_match":true,"evidence_text":"c.3443T>C","llm_judgment":"PRESENT","evidence":"c.3443T>C","abstract_start":924,"abstract_end":933}]}
{"pmid":"31934343","title":"Normal early development in siblings with novel compound heterozygous variants in","abstract":"Autosomal recessive primary microcephaly 5 (MCPH5) is caused by pathogenic variants in <i>ASPM</i>. Using whole-exome sequencing, we diagnosed two siblings with MCPH5. A known pathogenic variant (NM_018136.4: c.9697C > T, p.(Arg3233*)) and a novel pathogenic variant (c.1402_1406del, p.(Asn468Serfs*2)) of <i>ASPM</i> were identified in affected siblings with normal intelligence. Their pathogenic variants were not located in the critical regions of <i>ASPM</i>, but the relationship between the genotypes and their normal intelligence was unclear.","variants":[{"Name":"NM_018136.5(ASPM):c.9697C>T (p.Arg3233Ter)","Chromosome":"1","Start":"197090328","Stop":"197090328","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34486,"rule_based_match":true,"evidence_text":"NM_018136.4: c.9697C > T, p.(Arg3233*)","llm_judgment":"PRESENT","evidence":"NM_018136.4: c.9697C > T, p.(Arg3233*)","abstract_start":196,"abstract_end":234}]}
{"pmid":"38532569","title":"A Novel Homozygous Variant in the","abstract":"BACKGROUND: Mucolipidosis type IV (MLIV) is a rare, progressive lysosomal storage disorder characterized by severe intellectual disability, delayed motor milestones and ophthalmologic abnormalities. MLIV is an autosomal recessive disease caused by mutations in the <i>MCOLN1</i> gene, encoding mucolipin-1 which is responsible for maintaining lysosomal function.\nOBJECTIVES AND METHODS: Here, we report a family of four Iranian siblings with cognitive decline, progressive visual and pyramidal disturbances, and abnormal movements manifested by severe oromandibular dystonia and parkinsonism. MRI scans of the brain demonstrated signal abnormalities in the white matter and thinning of the corpus callosum.\nRESULTS AND CONCLUSIONS: Whole-exome sequencing identified a novel homozygous variant, c.362C > T:p. Thr121Met in the <i>MCOLN1</i> gene consistent with a diagnosis of MLIV. The presentation of MLIV may overlap with a variety of other neurological diseases, and genetic analysis is an important strategy to clarify the diagnosis. This is an important point that clinicians should be familiar with. The novel variant c.362C > T:p. Thr121Met herein described may be related to a comparatively older age at onset. Our study also expands the clinical spectrum of MLIV associated with the <i>MCOLN1</i> variants and introduces a novel likely pathogenic variant for testing in MLIV cases that remain unresolved.","variants":[{"Name":"NM_020533.3(MCOLN1):c.362C>T (p.Thr121Met)","Chromosome":"19","Start":"7526563","Stop":"7526563","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":858727,"rule_based_match":true,"evidence_text":"c.362C > T:p. Thr121Met","llm_judgment":"PRESENT","evidence":"c.362C > T:p. Thr121Met","abstract_start":794,"abstract_end":817}]}
{"pmid":"36139378","title":"Phenotypic and Genetic Heterogeneity of Adult Patients with Hereditary Spastic Paraplegia from Serbia.","abstract":"Hereditary spastic paraplegia (HSP) is among the most genetically diverse of all monogenic diseases. The aim was to analyze the genetic causes of HSP among adult Serbian patients. The study comprised 74 patients from 65 families clinically diagnosed with HSP during a nine-year prospective period. A panel of thirteen genes was analyzed: L1CAM (SPG1), PLP1 (SPG2), ATL1 (SPG3A), SPAST (SPG4), CYP7B1 (SPG5A), SPG7 (SPG7), KIF5A (SPG10), SPG11 (SPG11), ZYFVE26 (SPG15), REEP1 (SPG31), ATP13A2 (SPG78), DYNC1H1, and BICD2 using a next generation sequencing-based technique. A copy number variation (CNV) test for SPAST, SPG7, and SPG11 was also performed. Twenty-three patients from 19 families (29.2%) had conclusive genetic findings, including 75.0% of families with autosomal dominant and 25.0% with autosomal recessive inheritance, and 15.7% of sporadic cases. Twelve families had mutations in the SPAST gene, usually with a pure HSP phenotype. Three sporadic patients had conclusive findings in the SPG11 gene. Two unrelated patients carried a homozygous pathogenic mutation c.233T>A (p.L78*) in SPG7 that is a founder Roma mutation. One patient had a heterozygous de novo variant in the KIF5A gene, and one had a compound heterozygous mutation in the ZYFVE26 gene. The combined genetic yield of our gene panel and CNV analysis for HSP was around 30%. Our findings broaden the knowledge on the genetic epidemiology of HSP, with implications for molecular diagnostics in this region.","variants":[{"Name":"NM_003119.4(SPG7):c.233T>A (p.Leu78Ter)","Chromosome":"16","Start":"89510539","Stop":"89510539","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":21855,"rule_based_match":true,"evidence_text":"c.233T>A (p.L78*)","llm_judgment":"PRESENT","evidence":"c.233T>A (p.L78*)","abstract_start":1078,"abstract_end":1095}]}
{"pmid":"35716761","title":"Genetic landscape of FOXC2 mutations in lymphedema-distichiasis syndrome: Different mechanism of pathogenicity for mutations in different domains.","abstract":"Lymphedema-dissociated syndrome (LDS), of which the pathogenesis is not fully understood, afflicts many patients. In this study, we investigated the effect of FOXC2 gene loss-of-function on the development of LDS disease. Two Han Chinese families with LDS were recruited in this study, pathogenic mutations were identified by Sanger sequencing. Reverse-transcription PCR, subcellular localization, dual fluorescein enzymes, and other in vitro experiments were used to study the functional effects of eight FOXC2 mutations. Two pathogenic FOXC2 duplication mutations (c.930_936dup and c.931-937dup) were identified in the two families. Both mutations caused uneven distribution in the nucleus and a chromatin contraction phenotype, weakening the DNA binding activity and transcription activity. We then performed functional analysis on six additional mutations in different domains of FOXC2 that were reported to cause LDS. We found mutations located in the forkhead domain and central region dramatically reduced the transactivation ability, while mutations in activation domain-2 enhanced this ability. All 8 mutations down-regulated the transcription of ANGPT2 and affected the activity of the ERK-RAS pathway, which may cause abnormal formation of lymphatic vessels. Our findings also showed that all 8 mutations decreased the ability of interaction between FOXC2 and the Wnt4 promoter, suggesting mutations in FOXC2 may also affect the Wnt4-Frizzled-RYK signaling pathway, leading the abnormal differentiation of the meibomian glands into hair follicle cells during the embryonic period and causing distichiasis. This study expanded and revealed the potential pathogenesis mechanism.","variants":[{"Name":"NM_005251.3(FOXC2):c.930_936dup (p.Tyr313fs)","Chromosome":"16","Start":"86568257","Stop":"86568258","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCGCCGCC","allel_id":805898,"rule_based_match":true,"evidence_text":"c.930_936dup","llm_judgment":"PRESENT","evidence":"c.930_936dup","abstract_start":567,"abstract_end":579}]}
{"pmid":"25156905","title":"The first mutation in CNGA2 in two brothers with anosmia.","abstract":"Isolated congenital anosmia (ICA) is a rare disorder, where otherwise healthy individuals present with an inability to smell since birth. A list of studies have described the genes involved in syndromic anosmia; however, the genetics of ICA is still in its infancy. Studies in mice show that the cyclic nucleotide-gated channel subunit CNGA2, expressed in the olfactory epithelium has a crucial role in olfactory signal transduction. We have identified a novel X-linked stop mutation in CNGA2 (c.634C>T, p.R212*) in two brothers with ICA using exome sequencing. No additional mutations in CNGA2 were identified in a cohort of 31 non-related ICA individuals. Magnetic resonance brain imaging revealed diminished olfactory bulbs and flattened olfactory sulci. This is the first report of a mutation in the cyclic nucleotide-gated gene CNGA2 and supports the critical role of this gene in human olfaction.","variants":[{"Name":"NM_005140.3(CNGA2):c.634C>T (p.Arg212Ter)","Chromosome":"X","Start":"151743137","Stop":"151743137","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359053,"rule_based_match":true,"evidence_text":"c.634C>T, p.R212*","llm_judgment":"PRESENT","evidence":"c.634C>T, p.R212*","abstract_start":494,"abstract_end":511}]}
{"pmid":"22019782","title":"A rare penetrant mutation in CFH confers high risk of age-related macular degeneration.","abstract":"Two common variants in the gene encoding complement factor H (CFH), the Y402H substitution (rs1061170, c.1204C>T)(1-4) and the intronic rs1410996 SNP(5,6), explain 17% of age-related macular degeneration (AMD) liability. However, proof for the involvement of CFH, as opposed to a neighboring transcript, and knowledge of the potential mechanism of susceptibility alleles are lacking. Assuming that rare functional variants might provide mechanistic insights, we used genotype data and high-throughput sequencing to discover a rare, high-risk CFH haplotype with a c.3628C>T mutation that resulted in an R1210C substitution. This allele has been implicated previously in atypical hemolytic uremic syndrome, and it abrogates C-terminal ligand binding(7,8). Genotyping R1210C in 2,423 AMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases versus 1 control, P = 7.0 × 10(-6)) and an association with a 6-year-earlier onset of disease (P = 2.3 × 10(-6)). This result suggests that loss-of-function alleles at CFH are likely to drive AMD risk. This finding represents one of the first instances in which a common complex disease variant has led to the discovery of a rare penetrant mutation.","variants":[{"Name":"NM_000186.4(CFH):c.3628C>T (p.Arg1210Cys)","Chromosome":"1","Start":"196747245","Stop":"196747245","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31597,"rule_based_match":true,"evidence_text":"c.3628C>T","llm_judgment":"PRESENT","evidence":"c.3628C>T","abstract_start":563,"abstract_end":572}]}
{"pmid":"25856402","title":"First Detection of a Splice Site β-Thalassemia Mutation, IVS-I-6 (T > C) (HBB: c.92 + 6T > C) in a Chinese Family.","abstract":"We present the first description of Chinese individuals with the β-thalassemia (β-thal) mutation IVS-I-6 (T > C) (HBB: c.92 + 6T > C). This mutation interferes with mRNA splicing and results in reducing expression of β-globin chains that leads to a β(+)-thal phenotype. The β-globin haplotype anlaysis revealed the IVS-I-6 mutation in our case was linked with haplotype VI [- + + - - - +] and had Mediterranean characteristics.","variants":[{"Name":"NM_000518.5(HBB):c.92+6T>C","Chromosome":"11","Start":"5226924","Stop":"5226924","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":30489,"rule_based_match":true,"evidence_text":"HBB: c.92 + 6T > C","llm_judgment":"PRESENT","evidence":"HBB: c.92 + 6T > C","abstract_start":114,"abstract_end":132}]}
{"pmid":"32572506","title":"MESP2 variants contribute to conotruncal heart defects by inhibiting cardiac neural crest cell proliferation.","abstract":"Conotruncal heart defects (CTDs) are closely related to defective outflow tract (OFT) development, in which cardiac neural crest cells (CNCCs) play an indispensable role. However, the genetic etiology of CTDs remains unclear. Mesoderm posterior 2 (MESP2) is an important transcription factor regulating early cardiogenesis. Nevertheless, MESP2 variants have not been reported in congenital heart defect (CHD) patients. We first identified four MESP2 variants in 601 sporadic nonsyndromic CTD patients that were not detected in 400 healthy controls using targeted sequencing. Reverse transcription-quantitative PCR (RT-qPCR), immunohistochemistry, and immunofluorescence assays revealed MESP2 expression in the OFT of Carnegie stage (CS) 11, CS13, and CS15 human embryos and embryonic day (E) 8.5, E10, and E11.5 mouse embryos. Functional analyses in HEK 293T cells, HL-1 cells, JoMa1 cells, and primary mouse CNCCs revealed that MESP2 directly regulates the transcriptional activities of downstream CTD-related genes and promotes CNCC proliferation by regulating cell cycle factors. Three MESP2 variants, c.346G>C (p.G116R), c.921C>G (p.Y307X), and c.59A>T (p.Q20L), altered the transcriptional activities of MYOCD, GATA4, NKX2.5, and CFC1 and inhibited CNCC proliferation by upregulating p21<sup>cip1</sup> or downregulating Cdk4. Based on our findings, MESP2 variants disrupted MESP2 function by interfering with CNCC proliferation during OFT development, which may contribute to CTDs. KEY MESSAGES: This study first analyzed MESP2 variants identified in sporadic nonsyndromic CTD patients. MESP2 is expressed in the OFT of different stages of human and mouse embryos. MESP2 regulates the transcriptional activities of downstream CTD-related genes and promotes CNCC proliferation by regulating cell cycle factor p21<sup>cip1</sup> or Cdk4.","variants":[{"Name":"NM_001039958.2(MESP2):c.921C>G (p.Tyr307Ter)","Chromosome":"15","Start":"89777278","Stop":"89777278","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":547628,"rule_based_match":true,"evidence_text":"c.921C>G (p.Y307X)","llm_judgment":"PRESENT","evidence":"c.921C>G (p.Y307X)","abstract_start":1125,"abstract_end":1143}]}
{"pmid":"33816400","title":"Case Report: Genetic and Clinical Features of Maternal Uniparental Isodisomy-Induced Thiamine-Responsive Megaloblastic Anemia Syndrome.","abstract":"<b>Background:</b> Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a rare autosomal recessive hereditary disease due to mutations in <i>SLC19A2</i>. Some cases show familial inheritance. <b>Case report:</b> A female patient (from a gravida 1, para 1 mother) of 3.5 years of age was admitted to the Pediatric Hematology Department of Xianyang Caihong Hospital in June 2019. The patient had severe anemia, acupoint-size bleeding spots, and a few ecchymoses all over her body, as well as astigmatism and hyperopia. Hearing was normal. The patient had diabetes. Bone marrow biopsy suggested a myelodysplastic syndrome. The patient had a c.515G>A (p.G172D) homozygous mutation of <i>SLC19A2</i> (NM_006996), indicating TRMA. Genetic testing revealed that the two alleles were inherited from her mother alone due to maternal uniparental isodisomy (UPD). The patient was treated with thiamine and a subcutaneous injection of insulin. The patient recovered well and was discharged. She continued thiamine and insulin at the same dose and was followed once a month. The last follow-up on September 15, 2020, showed no anemia or bleeding. She had a sound hearing and normal blood routine and fasting glucose levels. Hyperopia and astigmatism did not improve. <b>Conclusion:</b> The patient had TRMA induced by the c.515G>A (p.G172D) homozygous mutation of <i>SLC19A2</i> inherited through maternal UPD. The genetic diagnosis of TRMA is of significance for guiding clinical treatment. Early treatment with exogenous thiamine can improve some of the clinical features of TRMA.","variants":[{"Name":"NM_006996.3(SLC19A2):c.515G>A (p.Gly172Asp)","Chromosome":"1","Start":"169477447","Stop":"169477447","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20996,"rule_based_match":true,"evidence_text":"c.515G>A (p.G172D)","llm_judgment":"PRESENT","evidence":"c.515G>A (p.G172D)","abstract_start":645,"abstract_end":663}]}
{"pmid":"22068590","title":"Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype.","abstract":"X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy caused by mutations of MTM1, which encodes the phosphoinositide lipid phosphatase, myotubularin. The Mtm1 knockout (KO) mouse has a severe phenotype and its short lifespan (8 weeks) makes it a challenge to use as a model in the testing of certain preclinical therapeutics. Many MTM patients succumb early in life, but some have a more favorable prognosis. We used human genotype-phenotype correlation data to develop a myotubularin-deficient mouse model with a less severe phenotype than is seen in Mtm1 KO mice. We modeled the human c.205C>T point mutation in Mtm1 exon 4, which is predicted to introduce the p.R69C missense change in myotubularin. Hemizygous male Mtm1 p.R69C mice develop early muscle atrophy prior to the onset of weakness at 2 months. The median survival period is 66 weeks. Histopathology shows small myofibers with centrally placed nuclei. Myotubularin protein is undetectably low because the introduced c.205C>T base change induced exon 4 skipping in most mRNAs, leading to premature termination of myotubularin translation. Some full-length Mtm1 mRNA bearing the mutation is present, which provides enough myotubularin activity to account for the relatively mild phenotype, as Mtm1 KO and Mtm1 p.R69C mice have similar muscle phosphatidylinositol 3-phosphate levels. These data explain the basis for phenotypic variability among human patients with MTM1 p.R69C mutations and establish the Mtm1 p.R69C mouse as a valuable model for the disease, as its less severe phenotype will expand the scope of testable preclinical therapies.","variants":[{"Name":"NM_000252.3(MTM1):c.205C>T (p.Arg69Cys)","Chromosome":"X","Start":"150598660","Stop":"150598660","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26094,"rule_based_match":true,"evidence_text":"c.205C>T","llm_judgment":"PRESENT","evidence":"c.205C>T","abstract_start":614,"abstract_end":622}]}
{"pmid":"27530628","title":"Compound heterozygous NEK1 variants in two siblings with oral-facial-digital syndrome type II (Mohr syndrome).","abstract":"The oral-facial-digital (OFD) syndromes comprise a group of related disorders with a combination of oral, facial and digital anomalies. Variants in several ciliary genes have been associated with subtypes of OFD syndrome, yet in most OFD patients the underlying cause remains unknown. We investigated the molecular basis of disease in two brothers with OFD type II, Mohr syndrome, by performing single-nucleotide polymorphism (SNP)-array analysis on the brothers and their healthy parents to identify homozygous regions and candidate genes. Subsequently, we performed whole-exome sequencing (WES) on the family. Using WES, we identified compound heterozygous variants c.[464G>C];[1226G>A] in NIMA (Never in Mitosis Gene A)-Related Kinase 1 (NEK1). The novel variant c.464G>C disturbs normal splicing in an essential region of the kinase domain. The nonsense variant c.1226G>A, p.(Trp409*), results in nonsense-associated alternative splicing, removing the first coiled-coil domain of NEK1. Candidate variants were confirmed with Sanger sequencing and alternative splicing assessed with cDNA analysis. Immunocytochemistry was used to assess cilia number and length. Patient-derived fibroblasts showed severely reduced ciliation compared with control fibroblasts (18.0 vs 48.9%, P<0.0001), but showed no significant difference in cilia length. In conclusion, we identified compound heterozygous deleterious variants in NEK1 in two brothers with Mohr syndrome. Ciliation in patient fibroblasts is drastically reduced, consistent with a ciliary defect pathogenesis. Our results establish NEK1 variants involved in the etiology of a subset of patients with OFD syndrome type II and support the consideration of including (routine) NEK1 analysis in patients suspected of OFD.","variants":[{"Name":"NM_001199397.3(NEK1):c.1226G>A (p.Trp409Ter)","Chromosome":"4","Start":"169561520","Stop":"169561520","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":440082,"rule_based_match":true,"evidence_text":"c.1226G>A, p.(Trp409*)","llm_judgment":"PRESENT","evidence":"c.1226G>A, p.(Trp409*)","abstract_start":866,"abstract_end":888}]}
{"pmid":"30956829","title":"CPEO and Mitochondrial Myopathy in a Patient with","abstract":"The classic features of deoxyguanosine kinase (<i>DGUOK</i>) deficiency are infantile onset hepatic failure with nystagmus and hypotonia; mitochondrial DNA studies on affected tissue reveal mitochondrial DNA depletion. Later, it has been shown that the mutations in the same gene may present with adult-onset mitochondrial myopathy and mitochondrial DNA multiple deletions in skeletal muscle. Here we report the case of a 42-year-old Italian woman presenting with a chronic progressive external ophthalmoplegia and myopathy with mtDNA multiple deletions and the compound heterozygous c.462T>A (p.Asn154Lys) and c.707+2T>G pathogenic variants in <i>DGUOK</i>.","variants":[{"Name":"NM_080916.3(DGUOK):c.462T>A (p.Asn154Lys)","Chromosome":"2","Start":"73950603","Stop":"73950603","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":210896,"rule_based_match":true,"evidence_text":"c.462T>A (p.Asn154Lys)","llm_judgment":"PRESENT","evidence":"c.462T>A (p.Asn154Lys)","abstract_start":584,"abstract_end":606}]}
{"pmid":"16917947","title":"Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II.","abstract":"Glycogen storage disease type II (GSDII) is a recessively inherited disorder due to the deficiency of acid alpha-glucosidase (GAA) that results in impaired glycogen degradation and its accumulation in the lysosomes. We report here the complete molecular analysis of the GAA gene performed on 40 Italian patients with late onset GSDII. Twelve novel alleles have been identified: missense mutations were functionally characterized by enzyme activity and protein processing in a human GAA-deficient cell line while splicing mutations were studied by RT-PCR and in silico analysis. A complex allele was also identified carrying three different alterations in cis. The c.-32-13T > G was the most frequent mutation, present as compound heterozygote in 85% of the patients (allele frequency 42.3%), as described in other late onset GSDII Caucasian populations. Interestingly, the c.-32-13T > G was associated with the c.2237G > A (p.W746X) in nine of the 40 patients. Genotype-phenotype correlations are discussed with particular emphasis on the subgroup carrying the c.-32-13T > G/c.2237G > A genotype.","variants":[{"Name":"NM_000152.5(GAA):c.2237G>A (p.Trp746Ter)","Chromosome":"17","Start":"80117015","Stop":"80117015","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":265034,"rule_based_match":true,"evidence_text":"c.2237G > A (p.W746X)","llm_judgment":"PRESENT","evidence":"c.2237G > A (p.W746X)","abstract_start":911,"abstract_end":932},{"Name":"NM_000152.5(GAA):c.-32-13T>G","Chromosome":"17","Start":"80104542","Stop":"80104542","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":19066,"rule_based_match":true,"evidence_text":"c.-32-13T > G","llm_judgment":"PRESENT","evidence":"c.-32-13T > G","abstract_start":664,"abstract_end":677}]}
{"pmid":"38013626","title":"Biallelic variants in the COQ4 gene caused hereditary spastic paraplegia predominant phenotype.","abstract":"INTRODUCTION: Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by progressive degeneration of upper motor neurons. Homozygous or compound heterozygous variants in COQ4 have been reported to cause primary CoQ10 deficiency-7 (COQ10D7), which is a mitochondrial disease.\nAIMS: We aimed to screened COQ4 variants in a cohort of HSP patients.\nMETHODS: A total of 87 genetically unidentified HSP index patients and their available family members were recruited. Whole exome sequencing (WES) was performed in all probands. Functional studies were performed to identify the pathogenicity of those uncertain significance variants.\nRESULTS: In this study, five different COQ4 variants were identified in three Chinese HSP pedigrees and two variants were novel, c.87dupT (p.Arg30*), c.304C>T (p.Arg102Cys). More importantly, we firstly described two early-onset pure HSP caused by COQ4 variants. Functional studies in patient-derived fibroblast lines revealed a reduction cellular CoQ10 levels and the abnormal mitochondrial structure.\nCONCLUSIONS: Our findings revealed that bilateral variants in the COQ4 gene caused HSP predominant phenotype, expanding the phenotypic spectrum of the COQ4-related disorders.","variants":[{"Name":"NM_016035.5(COQ4):c.87dup (p.Arg30Ter)","Chromosome":"9","Start":"128323031","Stop":"128323032","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":2847058,"rule_based_match":true,"evidence_text":"c.87dupT (p.Arg30*)","llm_judgment":"PRESENT","evidence":"c.87dupT (p.Arg30*)","abstract_start":802,"abstract_end":821},{"Name":"NM_016035.5(COQ4):c.304C>T (p.Arg102Cys)","Chromosome":"9","Start":"128325783","Stop":"128325783","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":622394,"rule_based_match":true,"evidence_text":"c.304C>T (p.Arg102Cys)","llm_judgment":"PRESENT","evidence":"c.304C>T (p.Arg102Cys)","abstract_start":823,"abstract_end":845}]}
{"pmid":"30569517","title":"Distinct impacts of bi-allelic WNT10A mutations on the permanent and primary dentitions in odonto-onycho-dermal dysplasia.","abstract":"Odonto-onycho-dermal dysplasia (OODD) is a rare autosomal recessive syndrome characterized by multiple ectodermal abnormalities. Mutations of the wingless-type MMTV integration site family member 10A (WNT10A) gene have been associated with OODD. To date, only 11 OODD-associated WNT10A mutations have been reported. In this report, we Characterized the clinical manifestations with focusing on dental phenotypes in four unrelated OODD patients. By Sanger sequencing, we identified five novel mutations in the WNT10A gene, including two homozygous nonsense mutations c.1176C>A (p.Cys392*) and c.742C>T (p.Arg248*), one homozygous frame-shift mutation c.898-899delAT (p.Ile300Profs*126), and a compound heterozygous mutation c.826T>A (p.Cys276Ser) and c.949delG (p.Ala317Hisfs*121). Our findings confirmed that bi-allelic mutations of WNT10A were responsible for OODD and greatly expanded the mutation spectrum of OODD. For the first time, we demonstrated that bi-allelic WNT10A mutations could lead to anodontia of permanent teeth, which enhanced the phenotypic spectrum of WNT10A mutations. Interestingly, we found that bi-allelic mutations in the WNT10A gene preferentially affect the permanent dentition rather the primary dentition, suggesting that the molecular mechanisms regulated by WNT10A in the development of permanent teeth and deciduous teeth might be different.","variants":[{"Name":"NM_025216.3(WNT10A):c.949del (p.Ala317fs)","Chromosome":"2","Start":"218892962","Stop":"218892962","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":550121,"rule_based_match":true,"evidence_text":"c.949delG (p.Ala317Hisfs*121)","llm_judgment":"PRESENT","evidence":"c.949delG (p.Ala317Hisfs*121)","abstract_start":750,"abstract_end":779},{"Name":"NM_025216.3(WNT10A):c.826T>A (p.Cys276Ser)","Chromosome":"2","Start":"218892843","Stop":"218892843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":550123,"rule_based_match":true,"evidence_text":"c.826T>A (p.Cys276Ser)","llm_judgment":"PRESENT","evidence":"c.826T>A (p.Cys276Ser)","abstract_start":723,"abstract_end":745},{"Name":"NM_025216.3(WNT10A):c.742C>T (p.Arg248Ter)","Chromosome":"2","Start":"218890349","Stop":"218890349","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259731,"rule_based_match":true,"evidence_text":"c.742C>T (p.Arg248*)","llm_judgment":"PRESENT","evidence":"c.742C>T (p.Arg248*)","abstract_start":592,"abstract_end":612}]}
{"pmid":"34712195","title":"Charcot-Marie-Tooth Disease With Episodic Rhabdomyolysis Due to Two Novel Mutations in the β Subunit of Mitochondrial Trifunctional Protein and Effective Response to Modified Diet Therapy.","abstract":"A 29-year-old female experienced chronic progressive peripheral neuropathy since childhood and was diagnosed with Charcot-Marie-Tooth disease (CMT) at age 15. She developed recurrent, fever-induced rhabdomyolysis (RM) at age 24. EMG studies showed decreased amplitude of compound muscle action potential, declined motor conductive velocity, and absence of sensor nerve action potential. Acylcarnitine analysis revealed elevated C16-OH, C18-OH, and C18:1-OH. Muscle biopsy showed scattered foci of necrotic myofibers invaded by macrophages, occasional regenerating fibers, and remarkable muscle fiber type grouping. Whole-exome sequencing identified two novel heterozygous mutations: c.490G>A (p.G164S) and c.686G>A (p.R229Q) in <i>HADHB</i> gene encoding the β-subunit of mitochondrial trifunctional protein (MTP). Reduction of long-chain fatty acid <i>via</i> dietary restrictions alleviated symptoms effectively. Our study indicates that the defect of the MTP β-subunit accounts for both CMT and RM in the same patient and expands the clinical spectrum of disorders caused by the HADHB mutations. Our systematic review of all MTPD patients with dietary treatment indicates that the effect of dietary treatment is related to the age of onset and the severity of symptoms.","variants":[{"Name":"NM_000183.3(HADHB):c.686G>A (p.Arg229Gln)","Chromosome":"2","Start":"26279190","Stop":"26279190","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":421381,"rule_based_match":true,"evidence_text":"c.686G>A (p.R229Q)","llm_judgment":"PRESENT","evidence":"c.686G>A (p.R229Q)","abstract_start":706,"abstract_end":724}]}
{"pmid":"34238373","title":"Co-existence of Alport syndrome and C3 glomerulonephritis in a proband with family history.","abstract":"BACKGROUND: Alport syndrome and C3 glomerulonephritis (C3GN) are rare kidney diseases, frequently responsible for familial haematuria, proteinuria, and renal impairment. With the rapid development of molecular genetic testing, Alport syndrome causes have been restricted mostly to variants in the COL4A5 or COL4A3/COL4A4 genes. Moreover, a broad range of genetic contributors in the complement and complement-regulating proteins are definitely implicated in the pathogenesis of C3GN.\nMETHODS: We sought a family with persistent microscopic haematuria associated with renal failure. Clinicopathologic and follow-up data were obtained, and molecular genetic testing was used to screen for pathogenic variants.\nRESULTS: We describe a three-generation family with Alport syndrome showing a dominant maternal inheritance. Notably, renal biopsy showed the concurrent histological evidence of C3GN in the proband harbouring an uncommon heterozygous variation in CFHR5, c.508G > A. The alteration leads to replacement of a highly conserved residue at position 170 of the β-strand subunit of CFHR5 (p.Val170Met). In silico analysis showed that the variation was predicted to deregulate complement activation by altering the structural properties and enhancing C3b binding capacity to compete with Complement Factor H (CFH), which was in line with experimental data previously published.\nCONCLUSIONS: The comorbidity findings between Alport syndrome and C3GN indicate an underlying overlap and require further study.","variants":[{"Name":"NM_030787.4(CFHR5):c.508G>A (p.Val170Met)","Chromosome":"1","Start":"196994157","Stop":"196994157","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":863133,"rule_based_match":true,"evidence_text":"c.508G > A","llm_judgment":"PRESENT","evidence":"c.508G > A","abstract_start":962,"abstract_end":972}]}
{"pmid":"38283795","title":"Two Novel and Three Recurrent Mutations in the Mevalonate Pathway Genes in Chinese Patients with Porokeratosis.","abstract":"Purpose: Porokeratosis (PK) is a chronic autosomal-dominant cutaneous keratinization disorder exhibiting clinical and genetic heterogeneity. Mevalonate decarboxylase (<i>MVD</i>), farnesyl diphosphate synthase (<i>FDPS</i>), phosphomevalonate kinase(<i>PMVK</i>), and mevalonate kinase genes(<i>MVK</i>), which encode the mevalonate pathway, are disease-causing genes in PK.\nPatients and Methods: Data and blood samples were collected from two Chinese families and five sporadic patients with porokeratosis. Whole-exome and Sanger sequencing were performed to detect pathogenic gene mutation in the patients.\nResults: Five heterozygous mutations were identified, including a novel <i>FDPS</i> stop-gain mutation c.438T>G (p.Tyr146Ter), a novel <i>MVD</i> missense mutation c.683G>C (p.R228P), and three previously reported <i>MVD</i> mutations: c.746T>C (p.F249S), c.875A>G (p.N292S), and c.1111_1113del (p.371_371del). The novel <i>FDPS</i> c.438T>G mutation was predicted as \"disease-causing\" (p = 1) by Mutation Taster. The other novel <i>MVD</i> c.683G>C was also predicted as \"deleterious\" (score = 0.00) by Sorting Intolerant From Tolerant (SIFT), \"probably damaging\" (score = 1) by PolyPhen2, and \"disease-causing\" (p = 0.999) by Mutation Taster.\nConclusion: Our results extended the mutation spectrum of mevalonate pathway genes in porokeratosis and provided useful strategies for a more accurate diagnosis and genetic counseling.","variants":[{"Name":"NM_002461.3(MVD):c.746T>C (p.Phe249Ser)","Chromosome":"16","Start":"88655350","Stop":"88655350","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":247450,"rule_based_match":true,"evidence_text":"c.746T>C (p.F249S)","llm_judgment":"PRESENT","evidence":"c.746T>C (p.F249S)","abstract_start":845,"abstract_end":863}]}
{"pmid":"36422197","title":"Identification and Characterization of Novel Mutations in Chronic Kidney Disease (CKD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in Saudi Subjects by Whole-Exome Sequencing.","abstract":"Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G > A). Two missense mutations were identified with a PKD1 (c.1758A > C and c.9774T > G), and one patient had a PKD2 mutation (c.1445T > G). Three detected variants were novel, identified at PKD1 (c.1758A > C), PKD2L2 (c.1364A > T), and TSC2 (deletion of a’a at the 3’UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3’UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein−protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.","variants":[{"Name":"NM_000297.4(PKD2):c.1445T>G (p.Phe482Cys)","Chromosome":"4","Start":"88046767","Stop":"88046767","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":221477,"rule_based_match":true,"evidence_text":"c.1445T > G","llm_judgment":"PRESENT","evidence":"c.1445T > G","abstract_start":1375,"abstract_end":1386}]}
{"pmid":"29501291","title":"GJB2 mutations causing autosomal recessive non-syndromic hearing loss (ARNSHL) in two Iranian populations: Report of two novel variants.","abstract":"OBJECTIVE: Hereditary hearing loss (HL) is a noticeable concern in medicine all over the world. On average, 1 in 166 babies born are diagnosed with HL in Iran, which makes it a major public health issue. Autosomal recessive non-syndromic HL (ARNSHL) is the most prevalent form of HL. Although over 60 genes have been identified for ARNSHL, GJB2 mutations are the most prevalent causes of ARNSHL in many populations. Previous studies have estimated the average frequency of GJB2 mutations to be between 16 and 18% in Iran, but would vary among different ethnic groups. In the present study, we aimed to determine the frequency and mutation profile of 70 deaf patients from two different provinces (center and west) of Iran.\nMETHODS: We enrolled 70 Iranian deaf patients with ARNSHL from Isfahan (40 family) and Hamedan (30 family) provinces. After extraction of genomic DNA, the entire coding region of GJB2 was directly sequenced in all patients. Multiplex PCR was used for detection of del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene. In silico analyses were also performed by available software tools.\nRESULTS: A total of eleven different mutations were detected, nine of which were previously reported and the other two (c.130T > G and c.178T > G) were novel. Homozygous GJB2 mutations were observed in 22.5% and 20% of all the subjects from Isfahan and Hamedan provinces, respectively. c.35delG was the most frequent mutation. One compound heterozygous genotype (c.358_360delGAG/c.35delG) was observed for c.35delG. Screening for the two GJB6 deletions did not reveal any positive sample among heterozygous or GJB2 negative samples.\nCONCLUSIONS: The present study suggests that mutations in the GJB2 gene specially c.35delG are important causes of ARNSHL in the center and west of Iran. Totally, 15% of the patients were heterozygous carriers. Further investigation is needed to detect the genetic cause of HL in the patients with monoallelic GJB2 mutations.","variants":[{"Name":"NM_004004.6(GJB2):c.35del (p.Gly12fs)","Chromosome":"13","Start":"20189547","Stop":"20189547","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":32043,"rule_based_match":true,"evidence_text":"c.35delG","llm_judgment":"PRESENT","evidence":"c.35delG","abstract_start":1401,"abstract_end":1409},{"Name":"NM_004004.6(GJB2):c.178T>G (p.Cys60Gly)","Chromosome":"13","Start":"20189404","Stop":"20189404","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3072798,"rule_based_match":true,"evidence_text":"c.178T > G","llm_judgment":"PRESENT","evidence":"c.178T > G","abstract_start":1250,"abstract_end":1260}]}
{"pmid":"19064330","title":"A novel molecular aspect of Japanese patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD): c.449-452delCTGA is a common mutation in Japanese patients with MCADD.","abstract":"We studied 11 Japanese patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and found a common mutation, c.449-452delCTGA, which accounted for 45% of the mutations. Seven of 10 independent patients carried at least one copy of this mutation. Phenotypes of homozygous patients with the c.449-452delCTGA mutation varied from asymptomatic to life-threatening metabolic decompensation in Japanese patients with MCADD, similar to the phenotypic variations in Caucasians. This study suggests the genotypic difference between those of Caucasians and Japanese regarding MCADD.","variants":[{"Name":"NM_000016.6(ACADM):c.449_452del (p.Thr150fs)","Chromosome":"1","Start":"75734849","Stop":"75734852","ReferenceAlleleVCF":"ATGAC","AlternateAlleleVCF":"A","allel_id":186630,"rule_based_match":false,"evidence_text":"c.449-452delCTGA","llm_judgment":"PRESENT","evidence":"c.449-452delCTGA","abstract_start":121,"abstract_end":137}]}
{"pmid":"12673792","title":"Novel mutations in the CLN6 gene causing a variant late infantile neuronal ceroid lipofuscinosis.","abstract":"The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of autosomal recessive neurodegenerative diseases comprising Batten and other related diseases plus numerous variants. They are characterized by progressive neuronal cell death. The CLN6 gene was recently identified, mutations in which cause one of the variant late infantile forms of NCL (vLINCL). We describe four novel mutations in the CLN6 gene. This brings the total number of CLN6 mutations known to 11 in 38 families. This suggests that the CLN6 gene may be highly mutable. An American patient of Irish/French/Native American origin was heterozygous for a 4-bp insertion (c.267_268insAACG) in exon 3. The other allele had a point mutation (c.898T>C) in exon 7 resulting in a W300R amino acid change. Two Trinidadian siblings of Indian origin were homozygous for a mutation at the 5' donor splice site of exon 4 (IVS4+1G>T), affecting the first base of the invariant GT at the beginning of intron 4. The fourth novel mutation, a double deletion of 4 bp and 1 bp in exon 7 (c.829_832delGTCG;c.837delG), was identified in a Portuguese patient heterozygous for the I154del Portuguese CLN6 mutation. Four of the 11 mutations identified are in exon 4. Three Portuguese patients with clinical profiles similar to CLN6 patients without defects in CLN6 or other known NCL genes are described. We conclude the following: 1) the CLN6 gene may be a highly mutable gene; 2) exon 4 must code for a segment of the protein crucial for function; 3) vLINCL disease in Portugal is genetically heterogeneous; 4) the I154del accounts for 81.25% of affected CLN6 Portuguese alleles; and 5) three vLINCL Portuguese patients may have defects in a new NCL gene.","variants":[{"Name":"NM_017882.3(CLN6):c.898T>C (p.Trp300Arg)","Chromosome":"15","Start":"68208178","Stop":"68208178","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":361660,"rule_based_match":true,"evidence_text":"c.898T>C","llm_judgment":"PRESENT","evidence":"c.898T>C","abstract_start":715,"abstract_end":723}]}
{"pmid":"24090761","title":"Exome sequencing identifies novel compound heterozygous mutations in SPG11 that cause autosomal recessive hereditary spastic paraplegia.","abstract":"Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterized by progressive weakness and spasticity of the lower limbs, in complicated forms, with additional neurological signs. To identify the genotype and characterize the phenotype in a Chinese HSP family, ten subjects from the family were examined through detailed clinical evaluations, auxiliary examinations and genetic tests. Using a combined approach of whole-exome sequencing and candidate mutation validation, we identified novel compound heterozygous mutations in the SPG11 gene of the patients as follows: a nonsense mutation c.6856C>T (p.R2286X) in exon 38 and a deletion mutation c.2863delG (p.Glu955Lysfs*8) in exon 16. Both mutations co-segregated with the phenotype in this family and were absent in 100 normal Chinese individuals. Our finding suggests that the novel compound heterozygous mutations in SPG11 are associated with HSP. We were able to assess the future risk of HSP in healthy younger family members using genetic detection, and provide prenatal diagnoses for the family members. Furthermore, to some extent, this new finding enriches the information on SPG11 and may provide a new basis for the genetic diagnosis of HSP.","variants":[{"Name":"NM_025137.4(SPG11):c.6856C>T (p.Arg2286Ter)","Chromosome":"15","Start":"44565997","Stop":"44565997","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":49777,"rule_based_match":true,"evidence_text":"c.6856C>T (p.R2286X)","llm_judgment":"PRESENT","evidence":"c.6856C>T (p.R2286X)","abstract_start":608,"abstract_end":628}]}
{"pmid":"28983406","title":"Mutation analysis of the","abstract":"Nephropathic cystinosis is an inherited lysosomal transport disorder caused by mutations in the <i>CTNS</i> gene that encodes for a lysosomal membrane transporter, cystinosin. Dysfunction in this protein leads to cystine accumulation in the cells of different organs. The accumulation of cystine in the kidneys becomes apparent with renal tubular Fanconi syndrome between 6 and 12 months of age and leads to renal failure in the first decade of life. The aim of this study was to analyze the <i>CTNS</i> mutations in 20 Iranian patients, from 20 unrelated families, all of whom were afflicted with infantile nephropathic cystinosis. In these patients, seven different mutant alleles were found, including two new mutations, c.517T>C; p.Y173H and c.492_515del, that have not been previously reported. In addition, we observed that c.681G>A, the common Middle Eastern mutation, was the most common mutation in our patients. Moreover, a new minisatellite or variable number of tandem repeat marker (KX499495) was identified at the <i>CTNS</i> gene. Seven different alleles were found for this marker, and its allele frequency and heterozygosity degree were calculated in cystinosis patients and healthy individuals.","variants":[{"Name":"NM_004937.3(CTNS):c.517T>C (p.Tyr173His)","Chromosome":"17","Start":"3656542","Stop":"3656542","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3086474,"rule_based_match":true,"evidence_text":"c.517T>C; p.Y173H","llm_judgment":"PRESENT","evidence":"c.517T>C; p.Y173H","abstract_start":724,"abstract_end":741}]}
{"pmid":"25053872","title":"Mutation survey of candidate genes in 40 Chinese patients with congenital ectopia lentis.","abstract":"PURPOSE: To identify the spectrum and frequency of five candidate genes in Chinese patients with congenital ectopia lentis (EL).\nMETHODS: Forty consecutive and unrelated congenital probands with EL were collected and underwent ocular, skeletal, and cardiovascular examinations. Sanger sequencing was used to analyze all of the coding and adjacent regions of five candidate genes: FBN1, ADAMTS10, ADAMTSL4, TGFBR2, and CBS. Mutation analysis was performed to evaluate the pathogenic variants and to identify the cause of congenital EL.\nRESULTS: The FBN1 gene screen revealed 25 pathogenic variants in 34 of the 40 families with congenital EL, including three novel (c.1955G>T, c.2222delA, and c.4381T>C) and 22 known mutations. The ADAMTSL10 gene screen revealed a compound heterozygous variant (c.1586G>A and c.2485T>A) in a family with Weill-Marchesani syndrome (WMS). In the remaining five probands, no pathogenic variant was detected in any of the five screened genes.\nCONCLUSIONS: In this study, we identified three novel and 22 known mutations in FBN1 in 34 of 40 EL families. The results expand the mutation spectrum of the FBN1 gene and suggest that FBN1 mutations may be the major cause of congenital EL in Chinese patients.","variants":[{"Name":"NM_030957.4(ADAMTS10):c.1586G>A (p.Gly529Glu)","Chromosome":"19","Start":"8592764","Stop":"8592764","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1482373,"rule_based_match":true,"evidence_text":"c.1586G>A","llm_judgment":"PRESENT","evidence":"c.1586G>A","abstract_start":795,"abstract_end":804},{"Name":"NM_000138.5(FBN1):c.4381T>C (p.Cys1461Arg)","Chromosome":"15","Start":"48470712","Stop":"48470712","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1458282,"rule_based_match":true,"evidence_text":"c.4381T>C","llm_judgment":"PRESENT","evidence":"c.4381T>C","abstract_start":692,"abstract_end":701},{"Name":"NM_000138.5(FBN1):c.2222del (p.Asn741fs)","Chromosome":"15","Start":"48497337","Stop":"48497337","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":1871314,"rule_based_match":true,"evidence_text":"c.2222delA","llm_judgment":"PRESENT","evidence":"c.2222delA","abstract_start":676,"abstract_end":686}]}
{"pmid":"24037885","title":"Aromatic L-amino acid decarboxylase deficiency is a cause of long-fasting hypoglycemia.","abstract":"UNLABELLED: OBJECTIVE/CONTEXT: Long-fasting hypoglycemia in children may be induced by neurotransmitter disorders.\nCASE REPORT: A 5-year-old girl with a medical history of chronic diarrhea presented three episodes of severe hypoglycemia (20 mg/dL) between ages 3 and 5 years. She became pale and sweaty with hypothermia (33.5°C), bradycardia (45 bpm), and acidosis and presented a generalized seizure. During the 17-hour fast test performed to determine the etiology of her hypoglycemia, insulin and C-peptide were appropriately low, and human GH, IGF-I, cortisol, amino acids, and acylcarnitines were in the usual range for fasting duration. However, the presence of vanillactic and vanilpyruvic acids in urine led us to investigate the metabolism of dopamine and serotonin in the cerebrospinal fluid. Indeed, these results indicated an aromatic L-amino acid decarboxylase deficiency that impairs the synthesis of serotonin, dopamine, and catecholamines. The diagnosis was confirmed by the low aromatic L-amino acid decarboxylase (AADC) enzyme activity in plasma (5 pmol/min/mL; reference value, 20-130) and the presence of two heterozygous mutations, c.97G>C (p.V33L, inherited from her father) and c.1385G>C (p.R462P, inherited from her mother) in the DCC gene. She was supplemented with pyridoxine and raw cornstarch (1 g/kg) at evening dinner to reduce the night fast. The episodes of hypoglycemia and the chronic diarrhea were suppressed.\nCONCLUSION: Here is the first case report of long-fasting hypoglycemia due to a nontypical AADC deficiency. Hypoglycemia was severe, but the other neurological clinical hallmarks present in AADC-deficient patients were mild to moderate. Thus, neurotransmitter disorders should be considered in any patients presenting hypoglycemia with urine excretion of vanillactic acid.","variants":[{"Name":"NM_001082971.2(DDC):c.1385G>C (p.Arg462Pro)","Chromosome":"7","Start":"50463289","Stop":"50463289","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1868003,"rule_based_match":true,"evidence_text":"c.1385G>C (p.R462P, inherited from her mother)","llm_judgment":"PRESENT","evidence":"c.1385G>C (p.R462P, inherited from her mother)","abstract_start":1201,"abstract_end":1247}]}
{"pmid":"24728577","title":"Clinical and molecular characterization of the BRCA2 p.Asn3124Ile variant reveals substantial evidence for pathogenic significance.","abstract":"Variants of uncertain clinical significance (VUS) in the high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2 represent a major obstacle in genetic counseling of high-risk breast cancer families. We analyzed a missense VUS located in BRCA2 (p.Asn3124Ile; HGVS: BRCA2 c.9371A > T) present in seven independent high-risk breast cancer families that were counseled and genetically tested in South-West Germany. The VUS was identified by DNA sequencing. We analyzed co-occurrence with deleterious BRCA1/2 mutations, segregation, evolutionary conservation, in silico impact prediction, and prevalence in the general population. All carriers of the VUS suffered from breast or ovarian cancer. In two families, an additional high burden of other cancers such as pancreatic, prostate, and gastric cancers was reported, one further family included two cases of male breast cancer. The VUS did not co-occur with deleterious BRCA1/2 mutations and segregated in two affected individuals of one family. In contrast to the 7/1,347 (0,5 %) tested high-risk BC families without clearly pathogenic mutations in BRCA1/2, none of 3,126 healthy population controls sharing the same ethnic and geographical background were found to carry this VUS (p = 0.0002). In-silico prediction revealed strong evolutionary conservation of the asparagine residue, residing in the C-terminal oligonucleotide-binding-fold-3 region, and a most likely damaging impact of this exchange on the protein structure. The BRCA2 p.Asn3124Ile (BRCA2 c.9371A > T) variant is a rare mutation with a damaging effect on the BRCA2 protein that is strongly associated with familial breast and ovarian cancer risk, indicating its most likely pathogenic nature and clinical relevance.","variants":[{"Name":"NM_000059.4(BRCA2):c.9371A>T (p.Asn3124Ile)","Chromosome":"13","Start":"32394803","Stop":"32394803","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":46789,"rule_based_match":true,"evidence_text":"BRCA2 c.9371A > T","llm_judgment":"PRESENT","evidence":"BRCA2 c.9371A > T","abstract_start":275,"abstract_end":292}]}
{"pmid":"21364700","title":"Intellectual disability without epilepsy associated with STXBP1 disruption.","abstract":"STXBP1 (Munc18-1) is a component of the machinery involved in the fusion of secretory vesicles to the presynaptic membrane for the release of neurotransmitters. De novo missense mutations in STXBP1 were recently reported in patients with Ohtahara syndrome, a form of encephalopathy with severe early-onset epilepsy. In addition, sequencing of the coding region of STXBP1 in 95 patients with non-syndromic intellectual disability (NSID) revealed de novo truncating mutations in two patients who also showed severe non-specific epilepsy, suggesting that STXBP1 disruption has the potential of causing a wide spectrum of epileptic disorders in association with intellectual disability. Here, we report on the mutational screening of STXBP1 in a different series of 50 patients with NSID and the identification of a novel de novo truncating mutation (c.1206delT/ p.Y402X) in a male with NSID, but surprisingly with no history of epilepsy. This is the first report of a patient with a truncating mutation in STXBP1 that does not show epilepsy, thus, expanding the clinical spectrum associated with STXBP1 disruption.","variants":[{"Name":"NM_001032221.6(STXBP1):c.1206del (p.Thr401_Tyr402insTer)","Chromosome":"9","Start":"127675899","Stop":"127675899","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":48062,"rule_based_match":true,"evidence_text":"c.1206delT/ p.Y402X","llm_judgment":"PRESENT","evidence":"c.1206delT/ p.Y402X","abstract_start":847,"abstract_end":866}]}
{"pmid":"24599607","title":"Clinical presentation and outcome in a series of 88 patients with the cblC defect.","abstract":"UNLABELLED: The cblC defect is the most common inborn error of vitamin B12 metabolism. Despite therapeutic measures, the long-term outcome is often unsatisfactory. This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients. The questionnaire designed for the study evaluates clinical and biochemical features at both initial presentation and during follow up. Also the development of severity scores allows investigation of individual disease load, statistical evaluation of parameters between the different age of presentation groups, as well as a search for correlations between clinical endpoints and potential modifying factors.\nRESULTS: No major differences were found between neonatal and early onset patients so that these groups were combined as an infantile-onset group representing 88 % of all cases. Hypotonia, lethargy, feeding problems and developmental delay were predominant in this group, while late-onset patients frequently presented with psychiatric/behaviour problems and myelopathy. Plasma total homocysteine was higher and methionine lower in infantile-onset patients. Plasma methionine levels correlated with \"overall impression\" as judged by treating physicians. Physician's impression of patient's well-being correlated with assessed disease load. We confirmed the association between homozygosity for the c.271dupA mutation and infantile-onset but not between homozygosity for c.394C>T and late-onset. Patients were treated with parenteral hydroxocobalamin, betaine, folate/folinic acid and carnitine resulting in improvement of biochemical abnormalities, non-neurological signs and mortality. However the long-term neurological and ophthalmological outcome is not significantly influenced. In summary the survey points to the need for prospective studies in a large cohort using agreed treatment modalities and monitoring criteria.","variants":[{"Name":"NM_015506.3(MMACHC):c.271dup (p.Arg91fs)","Chromosome":"1","Start":"45507544","Stop":"45507545","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":16460,"rule_based_match":true,"evidence_text":"c.271dupA","llm_judgment":"PRESENT","evidence":"c.271dupA","abstract_start":1382,"abstract_end":1391}]}
{"pmid":"29278894","title":"Asymmetric Ataxia, Depression, Memory Loss, Epilepsy, and Axonal Neuropathy Associated with A Heterozygous DNA Polymerase Gamma Variant of Uncertain Significance, c1370G>a (R457Q).","abstract":"INTRODUCTION: Mutations in the gene encoding DNA polymerase gamma (POLG) impair its ability to proofread mitochondrial DNA (mtDNA) during replication [1]. This results in a high frequency of randomly distributed mtDNA mutations and thus a wide range of phenotypes, including seizures, neuropathy, and cerebellar ataxia [1, 2]. We document a phenotype associated with the rare POLG variant c.1370G>A (p.R457Q).\nMETHODS: Over 10 years, we performed electrodiagnostic and neuropsychologic on a patient who presented with a variety of neurologic symptoms.\nRESULTS: Testing revealed an axonal sensorimotor polyneuropathy, depression and executive function difficulties, and asymmetric ataxia. Genetic testing revealed a POLG variant of uncertain significance (c.1370G>A, p.R457Q) in a heterozygous state.\nCONCLUSIONS: We have identified a mutation in POLG that could result in a diverse array of symptoms and signs of our patient. However, interpreting pathogenicity of rare variants such as R457Q is challenging and will likely require identification of patients with similar phenotypes caused by the variant of uncertain significance.","variants":[{"Name":"NM_002693.3(POLG):c.1370G>A (p.Arg457Gln)","Chromosome":"15","Start":"89327230","Stop":"89327230","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":573575,"rule_based_match":true,"evidence_text":"c.1370G>A (p.R457Q)","llm_judgment":"PRESENT","evidence":"c.1370G>A (p.R457Q)","abstract_start":389,"abstract_end":408}]}
{"pmid":"21204229","title":"A novel homozygous COL11A2 deletion causes a C-terminal protein truncation with incomplete mRNA decay in a Turkish patient.","abstract":"Recessive mutations in COL11A2 (collagen, type XI, alpha 2), are responsible for otospondylomegaepiphyseal dysplasia (OSMED) and non-syndromic hearing loss while dominant mutations are associated with Stickler type III, isolated cleft palate, Robin sequence, non-ophthalmic Stickler syndrome, early onset osteoarthritis and autosomal dominant hearing loss. We describe here the clinical findings of two Turkish cousins with OSMED carrying a novel homozygous truncating mutation in exon 38 of COL11A2 gene, c.2763delT, identified on cDNA and confirmed at gDNA. This mutation is located on triple helix repeat domain of the collagen alpha-2(XI) chain, where the majority of the previously identified mutations are located. Real-time RT-PCR experiment provided that mutated transcript does not decay completely. Although our analysis displays the partial survival of the mutant transcript from blood tissue, not from cartilage, we propose that this mechanism may play an important role on the variable expressivity of the heterozygous COL11A2 gene mutations.","variants":[{"Name":"NM_080680.3(COL11A2):c.2763del (p.Gly922fs)","Chromosome":"6","Start":"33173087","Stop":"33173087","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":2904759,"rule_based_match":true,"evidence_text":"c.2763delT","llm_judgment":"PRESENT","evidence":"c.2763delT","abstract_start":506,"abstract_end":516}]}
{"pmid":"26179919","title":"Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder.","abstract":"Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.","variants":[{"Name":"NM_002361.4(MAG):c.399C>G (p.Ser133Arg)","Chromosome":"19","Start":"35295965","Stop":"35295965","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":214840,"rule_based_match":true,"evidence_text":"c.399C>G; p.S133R","llm_judgment":"PRESENT","evidence":"c.399C>G; p.S133R","abstract_start":949,"abstract_end":966}]}
{"pmid":"24941924","title":"Phenylalanine hydroxylase deficiency in Mexico: genotype-phenotype correlations, BH4 responsiveness and evidence of a founder effect.","abstract":"The mutational spectrum of the phenylalanine hydroxylase gene (PAH) in Mexico is unknown, although it has been suggested that PKU variants could have a differential geographical distribution. Genotype-phenotype correlations and genotype-based predictions of responsiveness to tetrahydrobiopterin (BH4 ) have never been performed. We sequenced the PAH gene and determined the geographic origin of each allele, mini-haplotype associated, genotype-phenotype correlations and genotype-based prediction of BH4 responsiveness in 48 Mexican patients. The mutational spectrum included 34 variants with c.60+5G>T being the most frequent (20.8%) and linked to haplotype 4.3 possibly because of a founder effect and/or genetic drift. Two new variants were found c.1A>T and c.969+6T>C. The genotype-phenotype correlation was concordant in 70.8%. The genotype-based prediction to BH4 -responsiveness was 41.7%, this information could be useful for the rational selection of candidates for BH4 testing and therapy.","variants":[{"Name":"NM_000277.3(PAH):c.60+5G>T","Chromosome":"12","Start":"102917066","Stop":"102917066","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":108487,"rule_based_match":true,"evidence_text":"c.60+5G>T","llm_judgment":"PRESENT","evidence":"c.60+5G>T","abstract_start":594,"abstract_end":603},{"Name":"NM_000277.3(PAH):c.1A>T (p.Met1Leu)","Chromosome":"12","Start":"102917130","Stop":"102917130","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":108362,"rule_based_match":true,"evidence_text":"c.1A>T","llm_judgment":"PRESENT","evidence":"c.1A>T","abstract_start":751,"abstract_end":757}]}
{"pmid":"24501276","title":"METTL23, a transcriptional partner of GABPA, is essential for human cognition.","abstract":"Whereas many genes associated with intellectual disability (ID) encode synaptic proteins, transcriptional defects leading to ID are less well understood. We studied a large, consanguineous pedigree of Arab origin with seven members affected with ID and mild dysmorphic features. Homozygosity mapping and linkage analysis identified a candidate region on chromosome 17 with a maximum multipoint logarithm of odds score of 6.01. Targeted high-throughput sequencing of the exons in the candidate region identified a homozygous 4-bp deletion (c.169_172delCACT) in the METTL23 (methyltransferase like 23) gene, which is predicted to result in a frameshift and premature truncation (p.His57Valfs*11). Overexpressed METTL23 protein localized to both nucleus and cytoplasm, and physically interacted with GABPA (GA-binding protein transcription factor, alpha subunit). GABP, of which GABPA is a component, is known to regulate the expression of genes such as THPO (thrombopoietin) and ATP5B (ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide) and is implicated in a wide variety of important cellular functions. Overexpression of METTL23 resulted in increased transcriptional activity at the THPO promoter, whereas knockdown of METTL23 with siRNA resulted in decreased expression of ATP5B, thus revealing the importance of METTL23 as a regulator of GABPA function. The METTL23 mutation highlights a new transcriptional pathway underlying human intellectual function.","variants":[{"Name":"NM_001080510.5(METTL23):c.169_172del (p.His57fs)","Chromosome":"17","Start":"76733060","Stop":"76733063","ReferenceAlleleVCF":"CCTCA","AlternateAlleleVCF":"C","allel_id":153754,"rule_based_match":true,"evidence_text":"c.169_172delCACT","llm_judgment":"PRESENT","evidence":"c.169_172delCACT","abstract_start":539,"abstract_end":555}]}
{"pmid":"34100221","title":"Switching from lipoprotein apheresis to evolocumab in FH siblings on hemodialysis: case reports and discussion.","abstract":"Familial hypercholesterolemia (FH) and chronic kidney disease, especially end-stage renal disease (ESRD), are common and put patients at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). ESRD concomitant with FH may further increase the risk of ASCVD. Achieving target levels of low-density lipoprotein cholesterol (LDL-C) is difficult owing to the limitations of statin administration due to its side effects in ESRD. Therefore, some FH patients with ESRD require lipoprotein apheresis for the prevention of secondary ASCVD events. Although proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors may offer a safe and effective option for lowering lipid levels in such patients, no guidelines are available for their use. Here, we report the case of two male siblings with FH in secondary prevention undergoing hemodialysis combined with PCSK9 inhibitor treatment. The siblings, who showed a heterozygous c.1846-1G>A mutation in the LDLR gene, underwent hemodialysis. In combination with the lipoprotein apheresis, siblings were administered evolocumab, a PCSK9 inhibitor. Both the siblings had coronary artery disease, diabetes, and ESRD, and received hemodialysis. Their LDL-C levels did not reach the target values despite administering statin, ezetimibe, and biweekly lipoprotein apheresis. On the introduction of evolocumab treatment, their LDL-C levels were significantly reduced without any adverse effects, resulting in successful withdrawal from lipoprotein apheresis therapy. Although the effects of switching from lipoprotein apheresis to PCSK9 inhibitors for cardiovascular protection remain unclear in FH patients with and without ESRD, our case report will be helpful in guiding future therapeutic decisions.","variants":[{"Name":"NM_000527.5(LDLR):c.1846-1G>A","Chromosome":"19","Start":"11120091","Stop":"11120091","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":246375,"rule_based_match":true,"evidence_text":"c.1846-1G>A","llm_judgment":"PRESENT","evidence":"c.1846-1G>A","abstract_start":934,"abstract_end":945}]}
{"pmid":"30747360","title":"Mutation spectrum of PAH gene in phenylketonuria patients in Northwest China: identification of twenty novel variants.","abstract":"This study was performed to analyze the mutational spectrum of the phenylalanine hydroxylase (PAH) gene in phenylketonuria (PKU) patients in Northwest China, to identify mutational hot spots, and to determine the correlation between variants and clinical phenotypes of PKU. A large cohort of 475 PKU families in Northwest China was enrolled to analyze PAH gene variants using Sanger sequencing, Multiplex ligation-dependent probe amplification (MLPA), and gap-PCR. Bioinformatics software was used to predict the pathogenicity of novel variants and analyze the correlations between PAH gene variants and phenotypes of PKU patients. A total of 895 variants were detected in the 950 alleles of 475 patients with PKU (detection rate: 94.21%), 20 of which were novel variants. Other 108, previously known variants, were also identified, with the three most frequent variants being p.Arg243Gln (14.00%), c.611A > G (5.58%), and p.Tyr356* (4.95%). Seven different large deletion/duplication variants were identified by the MLPA method, including the large deletion c.-4163_-406del3758 with high frequency. A correlation analysis between patient phenotype and gene variant frequency showed that p.Arg53His and p.Gln419Arg were correlated with mild hyperphenylalaninemia (MHP). In conclusion, the mutational spectrum underlying PKU in Northwest China was established for the first time. Functional analysis of 20 novel PAH gene variants enriched the PAH gene mutational spectrum. Correlation analysis between variants frequencies in compound heterozygous patients and phenotype severity is helpful for phenotypic prediction.","variants":[{"Name":"NM_000277.3(PAH):c.158G>A (p.Arg53His)","Chromosome":"12","Start":"102912801","Stop":"102912801","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":108337,"rule_based_match":false,"evidence_text":"c.158G>A (p.Arg53His)","llm_judgment":"PRESENT","evidence":"p.Arg53His","abstract_start":1188,"abstract_end":1198}]}
{"pmid":"19181627","title":"Carnitine palmitoyltransferase IA polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-I.","abstract":"Carnitine palmitoyltransferase IA, encoded by CPT1A, is a key regulator of fatty acid metabolism. Previously, a loss-of-function mutation, namely, c.1436 C-->T (p.P479L), was reported in CPT1A in the homozygous state in Canadian aboriginal male with presumed CPT1A deficiency. To determine the population frequency of this variant, we determined CPT1A p.P479L genotypes in 1111 Greenland Inuit. Associations between genotype and variation in plasma total cholesterol, triglycerides, LDL, HDL, apolipoprotein (apo) B, and apoA-I was also investigated. We found the L479 allele occurs at a high frequency in this sample (0.73), while it was completely absent in 285 nonaboriginal samples. This suggests that the original proband's symptoms were not likely due to the CPT1A p.P479L mutation because it is very common in Inuit and because symptoms suggesting CPT1A deficiency have not been reported in any carrier subsequently studied. However, CPT1A p.P479L was associated with elevated plasma HDL and apoA-I levels. The association with increased levels of HDL and apoA-I suggest that the polymorphism might protect against atherosclerosis.","variants":[{"Name":"NM_001876.4(CPT1A):c.1436C>T (p.Pro479Leu)","Chromosome":"11","Start":"68780662","Stop":"68780662","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76552,"rule_based_match":false,"evidence_text":"c.1436 C-->T (p.P479L)","llm_judgment":"PRESENT","evidence":"c.1436 C-->T (p.P479L)","abstract_start":147,"abstract_end":169}]}
{"pmid":"15959873","title":"Twenty-six novel EFNB1 mutations in familial and sporadic craniofrontonasal syndrome (CFNS).","abstract":"Craniofrontonasal syndrome (CFNS) is an X-linked disorder characterized by a more severe manifestation in heterozygous females than in hemizygous males. Heterozygous females have craniofrontonasal dysplasia (CFND) and occasionally extracranial manifestations including midline defects and skeletal abnormalities, whereas hemizygous males show no or only mild features such as hypertelorism and rarely show cleft lip or palate. Mutations in the EFNB1 gene in Xq12 are responsible for familial and sporadic CFNS. The EFNB1 gene encodes ephrin-B1, a transmembrane ligand that also exhibits receptor-like effects. We performed mutation analysis in nine unrelated families and 29 sporadic patients with CFNS. DNA sequencing revealed mutations in 33 (86.8%) cases including 26 distinct novel mutations. A recurrent nonsense mutation, c.196C>T/R66X, was detected in one family and four sporadic patients. The majority of mutations (26/33) were located in exons 2 and 3 of the EFNB1 gene encoding the extracellular ephrin domain. The mutation spectrum includes frameshift, nonsense, missense, and splice site mutations, with a predominance of frameshift and nonsense mutations resulting in premature truncation codons. For the first time we describe mutations in exons 4 and 5 of EFNB1. Of particular interest are the frameshift mutations located in the last 25 codons of EFNB1 encoding the carboxyterminal end of ephrin-B1. They result in an extension by 44 residues. These mutations disrupt the intracellular binding sites for Grb4 and PDZ-effector proteins involved in reverse signaling. We conclude that the major causes of familial as well as sporadic CFNS are loss of function mutations in the EFNB1 gene that comprise premature termination or abrogate receptor-ligand interaction, oligomerization, and ephrin-B1 reverse signaling.","variants":[{"Name":"NM_004429.5(EFNB1):c.196C>T (p.Arg66Ter)","Chromosome":"X","Start":"68838684","Stop":"68838684","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26754,"rule_based_match":true,"evidence_text":"c.196C>T/R66X","llm_judgment":"PRESENT","evidence":"c.196C>T/R66X","abstract_start":828,"abstract_end":841}]}
{"pmid":"25980904","title":"Synergistic defects of UNC13D and AP3B1 leading to adult hemophagocytic lymphohistiocytosis.","abstract":"A 32-year-old man of non-consanguineous Chinese parentage, with high-grade fever, rash, joint pain, nausea, and vomiting, was diagnosed as adult-onset still's disease at his initial admission. Although prednisone had been taken, the patient presented with recurrent high-grade fever, rash, splenomegaly, hypertriglyceridemia, cryptogenic hepatitis, apparently elevated levels of serum ferritin(>20,000 μg/L), which met the proposed HLH diagnostic criteria, 2009. Sequence analysis of genomic DNA from the patient's peripheral blood demonstrated heterozygous for UNC13D mutation: c. 1232 G>A, and AP3B1 mutation: c. 1075 A>G, which were predicted to be pathogenic. Unfortunately, at the time, molecular confirmation results for HLH were obtained, and this patient had died from progressive HLH disease with multiple organ dysfunction syndrome caused by shock. FHL should be considered in the differential diagnosis of adults who present with adult-onset still's disease-like symptoms.","variants":[{"Name":"NM_003664.5(AP3B1):c.1075A>G (p.Thr359Ala)","Chromosome":"5","Start":"78175804","Stop":"78175804","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":894697,"rule_based_match":true,"evidence_text":"c. 1075 A>G","llm_judgment":"PRESENT","evidence":"c. 1075 A>G","abstract_start":612,"abstract_end":623}]}
{"pmid":"27657131","title":"Eight Mutations of Three Genes (EDA, EDAR, and WNT10A) Identified in Seven Hypohidrotic Ectodermal Dysplasia Patients.","abstract":"Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of the teeth, hair, and sweat glands. Ectodysplasin A (EDA), Ectodysplasin A receptor (EDAR), and EDAR-associated death domain (EDARADD) are candidate genes for HED, but the relationship between WNT10A and HED has not yet been validated. In this study, we included patients who presented at least two of the three ectodermal dysplasia features. The four genes were analyzed in seven HED patients by PCR and Sanger sequencing. Five EDA and one EDAR heterozygous mutations were identified in families 1-6. Two WNT10A heterozygous mutations were identified in family 7 as a compound heterozygote. c.662G>A (p.Gly221Asp) in EDA and c.354T>G (p.Tyr118*) in WNT10A are novel mutations. Bioinformatics analyses results confirmed the pathogenicity of the two novel mutations. In family 7, we also identified two single-nucleotide polymorphisms (SNPs) that were predicted to affect the splicing of EDAR. Analysis of the patient's total RNA revealed normal splicing of EDAR. This ascertained that the compound heterozygous WNT10A mutations are the genetic defects that led to the onset of HED. Our data revealed the genetic basis of seven HED patients and expended the mutational spectrum. Interestingly, we confirmed WNT10A as a candidate gene of HED and we propose WNT10A to be tested in EDA-negative HED patients.","variants":[{"Name":"NM_001399.5(EDA):c.662G>A (p.Gly221Asp)","Chromosome":"X","Start":"70027992","Stop":"70027992","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2901920,"rule_based_match":true,"evidence_text":"c.662G>A (p.Gly221Asp)","llm_judgment":"PRESENT","evidence":"c.662G>A (p.Gly221Asp)","abstract_start":675,"abstract_end":697}]}
{"pmid":"27460346","title":"Japanese multiple epidermal growth factor 10 (MEGF10) myopathy with novel mutations: A phenotype-genotype correlation.","abstract":"Mutations in the multiple epidermal growth factor-like domains 10 (MEGF10: NM_032446.2) gene are known to cause early-onset myopathy characterized by areflexia, respiratory distress, and dysphagia (EMARDD: OMIM 614399), and a milder phenotype of minicore myopathy. To date, there have been reports of six families with EMARDD and one with a milder disorder. Cysteine mutations in the extracellular EGF-like domain may be responsible for the milder phenotype, but the relationship is not conclusive because of the few reports of this disorder. We here present two Japanese patients with MEGF10 mutations: one with EMARDD phenotype who had a novel homozygous frameshift mutation, c.131_132del, and the other with the milder phenotype who harbored a compound heterozygous mutation, c.2981-2A > G, and a novel missense mutation, p.Cys810Tyr. This is the first report on East Asian patients with MEGF10 myopathy showing two phenotypes, indicating the genotype-phenotype correlation in MEGF10 myopathy.","variants":[{"Name":"NM_001256545.2(MEGF10):c.131_132del (p.Val44fs)","Chromosome":"5","Start":"127339132","Stop":"127339133","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":2417665,"rule_based_match":true,"evidence_text":"c.131_132del","llm_judgment":"PRESENT","evidence":"c.131_132del","abstract_start":678,"abstract_end":690},{"Name":"NM_001256545.2(MEGF10):c.2981-2A>G","Chromosome":"5","Start":"127454564","Stop":"127454564","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2417663,"rule_based_match":true,"evidence_text":"c.2981-2A > G","llm_judgment":"PRESENT","evidence":"c.2981-2A > G","abstract_start":779,"abstract_end":792}]}
{"pmid":"23270881","title":"Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype?","abstract":"BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is considered a predominantly right ventricular (RV) desmosomal disease. However, left-dominant forms due to desmosomal gene mutations, including PKP2 variant c.419C>T, have been described. Recently, a nondesmosomal phospholamban (PLN) mutation (c.40_42delAGA) has been identified, causing dilated cardiomyopathy and arrhythmias.\nOBJECTIVE: To gain more insight into pathogenicity of the PKP2 variant c.419C>T by cosegregation analysis of the PKP2 variant c.419C>T vs the PLN mutation c.40_42delAGA.\nMETHODS: A Dutch family (13 family members, median age 49 years, range 34-71 years) with ventricular tachycardia underwent (1) meticulous phenotypic characterization and (2) screening of 5 desmosomal genes (PKP2, DSC2, DSG2, DSP, JUP) and PLN.\nRESULTS: Six family members fulfilled 2010 AC Task Force Criteria. Seven had signs of left ventricular (LV) involvement (inverted T waves in leads V4-V6, LV wall motion abnormalities and late enhancement, and reduced LV ejection fraction), including 6 family members with proven AC. The PKP2 variant c.419C>T was found as a single variant in 3 family members, combined with the PLN mutation c.40_42delAGA in 3 others. PLN mutation was found in 9 family members, including the 6 with AC and all 7 with LV involvement. The PLN mutation c.40_42delAGA was found as a single mutation in 6, combined with the PKP2 variant c.419C>T in 3 others. A low-voltage electrocardiogram was seen in 4 of 9 PLN mutation-positive subjects. None of the family members with the single PKP2 variant showed any sign of RV or LV involvement.\nCONCLUSIONS: The PLN mutation c.40_42delAGA cosegregates with AC and with electrocardiographic and structural LV abnormalities. In this family, there was no evidence of disease-causing contribution of the PKP2 variant c.419C>T.","variants":[{"Name":"NM_001005242.3(PKP2):c.419C>T (p.Ser140Phe)","Chromosome":"12","Start":"32878461","Stop":"32878461","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":54244,"rule_based_match":true,"evidence_text":"PKP2 variant c.419C>T","llm_judgment":"PRESENT","evidence":"PKP2 variant c.419C>T","abstract_start":193,"abstract_end":214}]}
{"pmid":"19333784","title":"PALB2 sequence variants in young South African breast cancer patients.","abstract":"PALB2 (partner and localizer of BRCA2) is a recently identified breast cancer susceptibility gene, in which mutations confer doubling of breast cancer risk with moderate to low penetrance. Recent studies in various populations report that deleterious mutations in this gene account for approximately 1% of familial or early-onset breast cancer cases. This study aimed to determine the involvement of PALB2 mutations in a cohort of 48 young (29-45 years) South African breast cancer patients unselected for family history of breast cancer. The complete coding region and intron-exon boundaries of PALB2 were analyzed. A novel truncating mutation, c.697delG (V233fs) was identified in one patient. A missense variant (E211G), identified in another patient, appears to be segregating with the disease, but in silico analysis using SIFT, PolyPhen and A-GVGD, indicates that this variant is nonpathogenic. In addition, four other missense, one synonymous and three intronic variants were detected, all of which appear polymorphic. This represents the second study to analyze the role of PALB2 in early-onset breast cancer patients unselected for family history. The first study, of a Chinese population, established that PALB2 was responsible for 1.3% of early-onset breast cancer cases. Our study reports that deleterious mutations in PALB2 account for approximately 2% (1/48) of South African early-onset breast cancer.","variants":[{"Name":"NM_024675.4(PALB2):c.697del (p.Val233fs)","Chromosome":"16","Start":"23635849","Stop":"23635849","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":132274,"rule_based_match":true,"evidence_text":"c.697delG (V233fs)","llm_judgment":"PRESENT","evidence":"c.697delG (V233fs)","abstract_start":646,"abstract_end":664}]}
{"pmid":"26833046","title":"BRCA1/BRCA2 founder mutations and cancer risks: impact in the western Danish population.","abstract":"Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G>A and c.8474delC] were found to account for 23 % of the BRCA1 mutations and for 32 % of the BRCA2 mutations. The BRCA1 mutation c.3319G>T was, compared to other BRCA1 mutations, associated with a higher risk for ovarian cancer. In conclusion, founder mutations in BRCA1 and BRCA2 contribute to up to one-third of the families in western Denmark and among these the BRCA1 c.3319G>T mutation is potentially linked to an increased risk of ovarian cancer.","variants":[{"Name":"NM_007294.4(BRCA1):c.5213G>A (p.Gly1738Glu)","Chromosome":"17","Start":"43057116","Stop":"43057116","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70129,"rule_based_match":true,"evidence_text":"c.5213G>A (p.Gly1738Glu)","llm_judgment":"PRESENT","evidence":"c.5213G>A (p.Gly1738Glu)","abstract_start":831,"abstract_end":855},{"Name":"NM_007294.4(BRCA1):c.3319G>T (p.Glu1107Ter)","Chromosome":"17","Start":"43092212","Stop":"43092212","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":69503,"rule_based_match":true,"evidence_text":"c.3319G>T (p.Glu1107*)","llm_judgment":"PRESENT","evidence":"c.3319G>T (p.Glu1107*)","abstract_start":792,"abstract_end":814}]}
{"pmid":"24508628","title":"Asymptomatic phosphomannose isomerase deficiency (MPI-CDG) initially mistaken for excessive alcohol consumption.","abstract":"CASE REPORT: In a routine company health check-up, a 32-year-old woman presented a highly elevated serum level of carbohydrate-deficient transferrin (CDT), a biomarker for excessive alcohol consumption. The test result (~17% disialotransferrin, reference interval <2.0%; ~3% asialotransferrin, reference 0%) was confirmed by analysis of a second sample, while another alcohol biomarker, phosphatidylethanol (PEth) in whole-blood, was negative. This suggested that her elevated CDT may be unrelated to heavy drinking. The abnormal \"type-1\" transferrin glycoform pattern indicated a defect in N-glycan assembly occurring in congenital disorders of glycosylation (CDG), a family of rare inherited metabolic disorders. Probing for the underlying enzyme defect(s) using cultured skin fibroblasts demonstrated normal activity of phosphomannomutase, whereas the activity of phosphomannose isomerase (MPI) was reduced (0.64 mU/mg protein, reference 2.1-6.9), pointing to CDG of the MPI subtype (formerly called CDG-Ib). The diagnosis was confirmed by sequence analysis of the MPI gene revealing a homozygous missense mutation (c.656G>A) causing replacement of arginine by glutamine (p.R219Q). However, the woman had never experienced any clinical manifestations associated with MPI-CDG. Both parents, being distant relatives, were heterozygous mutation carriers with normal CDT values. Two of three siblings were not affected, whereas one brother was also homozygous for c.656G>A and had a highly elevated CDT and no clinical symptoms.\nCONCLUSION: The finding of MPI-CDG adults without clinical manifestations suggests that this type of the disorder may be underdiagnosed. If asymptomatic MPI-CDG subjects undergo CDT screening, their highly elevated test results may be wrongly interpreted as caused by excessive alcohol consumption.","variants":[{"Name":"NM_002435.3(MPI):c.656G>A (p.Arg219Gln)","Chromosome":"15","Start":"74893306","Stop":"74893306","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29384,"rule_based_match":true,"evidence_text":"c.656G>A","llm_judgment":"PRESENT","evidence":"c.656G>A","abstract_start":1119,"abstract_end":1127}]}
{"pmid":"27230853","title":"Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia.","abstract":"Peroxisomal biogenesis disorders (PBDs) consist of a heterogeneous group of autosomal recessive diseases, in which peroxisome assembly and proliferation are impaired leading to severe multisystem disease and early death. PBDs include Zellweger spectrum disorders (ZSDs) with a relatively mild clinical phenotype caused by PEX1, (MIM# 602136), PEX2 (MIM# 170993), PEX6 (MIM# 601498), PEX10 (MIM# 602859), PEX12 (MIM# 601758), and PEX16 (MIM# 603360) mutations. Three adult patients are reported belonging to a non-consanguineous French family affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal signs. Mental retardation and diabetes mellitus were optional. The age at onset was in childhood or in adolescence (3-15 years). Brain MRI showed marked cerebellar atrophy. Biochemical blood analyses suggested a mild peroxisomal defect. With whole exome sequencing, two mutations in PEX10 were found in the three patients: c.827G>T (novel) causing the missense change p.Cys276Phe and c.932G>A causing the missense change p.Arg311Gln. The phenotypic spectrum related to PEX10 mutations includes slowly progressive, syndromic recessive ataxia.","variants":[{"Name":"NM_002617.4(PEX10):c.932G>A (p.Arg311Gln)","Chromosome":"1","Start":"2405815","Stop":"2405815","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":172124,"rule_based_match":true,"evidence_text":"c.932G>A","llm_judgment":"PRESENT","evidence":"c.932G>A","abstract_start":1011,"abstract_end":1019},{"Name":"NM_002617.4(PEX10):c.827G>T (p.Cys276Phe)","Chromosome":"1","Start":"2406569","Stop":"2406569","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":541153,"rule_based_match":true,"evidence_text":"c.827G>T (novel) causing the missense change p.Cys276Phe","llm_judgment":"PRESENT","evidence":"c.827G>T (novel) causing the missense change p.Cys276Phe","abstract_start":950,"abstract_end":1006}]}
{"pmid":"23594557","title":"Infantile hypertrophic cardiomyopathy associated with a novel MYL3 mutation.","abstract":"Mutations in genes encoding cardiac sarcomeric proteins are thought to be a very rare cause of hypertrophic cardiomyopathy (HCM) in infants and young children. We report on genetic and histopathological findings in a 3-month-old infant presenting with severe progressive HCM arising from a mutation in the gene encoding the essential light chain of myosin (MYL3). The patient was found to have a novel, paternally inherited pathogenic c.530 A>G mutation in exon 5 of the MYL3 gene. His father was asymptomatic. Although, MYL3 mutations have been previously associated with adult-onset HCM, it has not been seen in infantile forms. As such, this case adds to the emerging evidence demonstrating that familial disease associated with mutations in cardiac sarcomere protein genes may have an important role in infants and children with HCM. In addition, this case highlights the marked phenotypic heterogeneity associated with sarcomeric protein mutations both within and between families.","variants":[{"Name":"NM_000258.3(MYL3):c.530A>G (p.Glu177Gly)","Chromosome":"3","Start":"46858413","Stop":"46858413","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":45310,"rule_based_match":true,"evidence_text":"c.530 A>G","llm_judgment":"PRESENT","evidence":"c.530 A>G","abstract_start":435,"abstract_end":444}]}
{"pmid":"22094069","title":"Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene.","abstract":"Myotonia congenita is an inherited muscle disorder caused by mutations in the CLCN1 gene, a voltage-gated chloride channel of skeletal muscle. We have studied 48 families with myotonia, 32 out of them carrying mutations in CLCN1 gene and eight carry mutations in SCN4A gene. We have found 26 different mutations in CLCN1 gene, including 13 not reported previously. Among those 26 mutations, c.180+3A>T in intron 1 is present in nearly one half of the Spanish families in this series, the largest one analyzed in Spain so far. Although scarce data have been published on the frequency of mutation c.180+3A>T in other populations, our data suggest that this mutation is more frequent in Spain than in other European populations. In addition, expression in HEK293 cells of the new missense mutants Tyr137Asp, Gly230Val, Gly233Val, Tyr302His, Gly416Glu, Arg421Cys, Asn567Lys and Gln788Pro, demonstrated that these DNA variants are disease-causing mutations that abrogate chloride currents.","variants":[{"Name":"NM_000083.3(CLCN1):c.1261C>T (p.Arg421Cys)","Chromosome":"7","Start":"143332733","Stop":"143332733","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":441053,"rule_based_match":false,"evidence_text":"Arg421Cys","llm_judgment":"PRESENT","evidence":"Arg421Cys","abstract_start":850,"abstract_end":859},{"Name":"NM_000083.3(CLCN1):c.180+3A>T","Chromosome":"7","Start":"143316395","Stop":"143316395","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":274204,"rule_based_match":true,"evidence_text":"c.180+3A>T","llm_judgment":"PRESENT","evidence":"c.180+3A>T","abstract_start":391,"abstract_end":401}]}
{"pmid":"23838748","title":"Functional characterization of a novel C-terminal ATP1A2 mutation causing hemiplegic migraine and epilepsy.","abstract":"BACKGROUND: We describe a four-generation Italian family with familial hemiplegic migraine (FHM) and epilepsy due to a novel ATP1A2 missense mutation (R1007W).\nCASE RESULTS: Mutational analysis revealed a heterozygous nucleotide substitution c.3019C>T resulting in the missense substitution p.Arg1007Trp (p.R1007W) in seven subjects: Three individuals had hemiplegic migraine, two exhibited a clinical overlap between migraine and epilepsy, one had migraine and one was unaffected. The identified ATP1A2 mutation was not found in an ethnically matched control population of 190 individuals and was not reported in a polymorphisms database. In two-electrode voltage-clamp experiments on XENOPUS oocytes, the ATP1A2 R1007W mutant showed (i) reduced ion pumping activity due to a more profound voltage dependence and (ii) decreased apparent affinity for extracellular K⁺ at voltages around the cellular resting potential. This distinct type of loss of function has not been reported for other FHM2 mutations and can lead to impaired K⁺ clearance and elevated K⁺ levels in the CNS.\nCONCLUSIONS: The functional data and clinical evidence suggest that in FHM2 migraine and epilepsy may originate from the same pathogenic mechanisms associated with genetically determined alterations of ion channels and pumps. Our data also support the hypothesis that the new mutation R1007W in our family may be a susceptibility factor for epilepsy.","variants":[{"Name":"NM_000702.4(ATP1A2):c.3019C>T (p.Arg1007Trp)","Chromosome":"1","Start":"160139969","Stop":"160139969","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1928519,"rule_based_match":true,"evidence_text":"c.3019C>T","llm_judgment":"PRESENT","evidence":"c.3019C>T","abstract_start":242,"abstract_end":251}]}
{"pmid":"33877262","title":"Structural analysis of new compound heterozygous variants in PEPD gene identified in a patient with Prolidase Deficiency diagnosed by exome sequencing.","abstract":"Prolidase Deficiency (PD) is an autosomal recessive rare disorder caused by loss or reduction of prolidase enzymatic activity due to variants in the PEPD gene. PD clinical features vary among affected individuals: skin ulcerations, recurrent infections, and developmental delay are common. In this study, we describe a 16-year-old boy with a mild PD phenotype comprising chronic eczema, recurrent infections and elevated IgE. Whole exome sequencing analysis revealed three PEPD variants: c.575T>C p.(Leu192Pro) inherited from the mother, and c.692_694del p.(Tyr231del) and c.1409G>A p.(Arg470His), both inherited from the father. The variant p.(Tyr231del) has been previously characterized by high-resolution X-ray structure analysis as altering protein dynamics/flexibility. In order to study the effects of the other two prolidase variants, we performed site directed mutagenesis purification and crystallization studies. A high-resolution X-ray structure could only be obtained for the p.(Arg470His) variant, which showed no significant structural differences in comparison to WT prolidase. On the other hand, the p.(Leu192Pro) variant led to significant protein destabilization. Hence, we conclude that the maternal p.(Leu192Pro) variant was likely causally associated with the proband´s disease, together with the known pathogenic paternal variant p.(Tyr231del). Our results demonstrated the utility of exome sequencing to perform diagnosis in PD cases with mild phenotype.","variants":[{"Name":"NM_000285.4(PEPD):c.692_694del (p.Tyr231del)","Chromosome":"19","Start":"33413621","Stop":"33413623","ReferenceAlleleVCF":"GAGT","AlternateAlleleVCF":"G","allel_id":333120,"rule_based_match":true,"evidence_text":"c.692_694del p.(Tyr231del)","llm_judgment":"PRESENT","evidence":"c.692_694del p.(Tyr231del)","abstract_start":542,"abstract_end":568}]}
{"pmid":"29467388","title":"A novel MAP3K7 splice mutation causes cardiospondylocarpofacial syndrome with features of hereditary connective tissue disorder.","abstract":"Heterozygous variants in MAP3K7, encoding the transforming growth factor-β-activated kinase 1 (TAK1), are associated with the ultrarare cardiospondylocarpofacial syndrome (CSCFS). Specific gain-of-function variants in the same gene cause the allelic frontometaphyseal dysplasia type 2. Phenotypic series of frontometaphyseal dysplasia also comprise variants in FLNA (type 1) and two patients with a heterozygous variant in TAB2 (type 3). We report on a 7-year-old girl with CSCFS due to the novel heterozygous c.737-7A>G variant in MAP3K7. The identified variant generates a new splice acceptor site causing an in-frame insertion of 2 amino acid residues (p.Asn245_Gly246insValVal), as demonstrated by RNA study. The patient was originally ascertained for a presumed hereditary connective tissue disorder due to soft/dystrophic skin, extreme joint hypermobility, polyvalvular heart disease, and upper gastrointestinal dismotility. Our study confirms locus homogeneity for CSCFS, expands the mutational spectrum of MAP3K7, and adds data on the existence of a community of connective tissue disorders caused by abnormalities of the TAK1-dependent signaling pathway.","variants":[{"Name":"NM_145331.3(MAP3K7):c.737-7A>G","Chromosome":"6","Start":"90552186","Stop":"90552186","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":963206,"rule_based_match":true,"evidence_text":"c.737-7A>G","llm_judgment":"PRESENT","evidence":"c.737-7A>G","abstract_start":510,"abstract_end":520}]}
{"pmid":"24116921","title":"Ethnic differences in GRHPR mutations in patients with primary hyperoxaluria type 2.","abstract":"The objective of this study was to investigate ethnic differences in the glyoxylate reductase/hydroxypyruvate reductase (GRHPR) gene in patients with primary hyperoxaluria type 2 (PH2). GRHPR was genotyped in Japanese patients with PH2 and all GRHPR mutations described to date were reviewed in terms of geographic and ethnic association. We identified a novel mutation, a two-nucleotide deletion (c.248_249delTG) in exon 3 creating a premature 'stop' at codon 91. Also, we found that the c.864_865delTG mutation was associated with the rs35891798 single-nucleotide polymorphism. The allelic frequencies of the c.103delG, c.494G>A, c.403_404+2 delAAGT, and c.864_865delTG mutations in PH2 patients were 37.8%, 15.6%, 10.0%, and 10.0%, respectively. All patients with the c.103delG mutation were Caucasian. Patients with the c.494G>A mutation and 78% (7/9) of those with the c.403_404+2 delAAGT mutation were from the Indian subcontinent, whereas those with the c.864_865delTG mutation were Chinese or Japanese. Molecular analysis of GRHPR of four Japanese PH2 patients identified a novel mutation (c.248_249delTG in exon 3). Caucasians with PH2 should be screened for the c.103delG mutation; patients from the Indian subcontinent for c.494G>A; and patients of East Asian origin (particularly) for c.864_865delTG. The prevalence of the latter mutation in PH2 patients from East Asia was 75.0%.","variants":[{"Name":"NM_012203.2(GRHPR):c.103del (p.Asp35fs)","Chromosome":"9","Start":"37424862","Stop":"37424862","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":20675,"rule_based_match":true,"evidence_text":"c.103delG","llm_judgment":"PRESENT","evidence":"c.103delG","abstract_start":611,"abstract_end":620},{"Name":"NM_012203.2(GRHPR):c.494G>A (p.Gly165Asp)","Chromosome":"9","Start":"37429732","Stop":"37429732","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":200634,"rule_based_match":true,"evidence_text":"c.494G>A","llm_judgment":"PRESENT","evidence":"c.494G>A","abstract_start":622,"abstract_end":630},{"Name":"NM_012203.2(GRHPR):c.248_249del (p.Val83fs)","Chromosome":"9","Start":"37425953","Stop":"37425954","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":171742,"rule_based_match":true,"evidence_text":"c.248_249delTG","llm_judgment":"PRESENT","evidence":"c.248_249delTG","abstract_start":398,"abstract_end":412}]}
{"pmid":"29152271","title":"c.464A>G variation in the","abstract":"We report two heterozygous carriers of c.464A>G variation in the <i>GJB2</i> gene in a Chinese pedigree. The proband with hearing loss most likely inherited the c.464A>G variation from his mother who also carries heterozygous c.79G>A variation and has normal hearing. The pathological significance of c.464A>G variation remains to be determined.","variants":[{"Name":"NM_004004.6(GJB2):c.464A>G (p.Tyr155Cys)","Chromosome":"13","Start":"20189118","Stop":"20189118","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1683646,"rule_based_match":true,"evidence_text":"c.464A>G","llm_judgment":"PRESENT","evidence":"c.464A>G","abstract_start":39,"abstract_end":47}]}
{"pmid":"26548592","title":"Choline Kinase Beta-Related Muscular Dystrophy, Appearance of Muscle Involvement on Magnetic Resonance Imaging.","abstract":"BACKGROUND: Clinical presentation with motor delay, proximal weakness, and learning difficulties raise the possibility of a dystrophinopathy, dystroglycanopathy, or myotonic dystrophy. This differential should also include the more recently described choline kinase beta-related muscular dystrophy. This condition is typically characterized by large and abnormally distributed mitochondria on muscle biopsy, which can distinguish this condition from the other muscle conditions in the differential.\nMETHODS: We present a boy with choline kinase beta mutations with relatively mild clinical manifestations, including proximal weakness, learning difficulties and elevated creatine kinase. Investigations included muscle magnetic resonance imaging (MRI) with T1 axial sequences through thigh and calves, and needle muscle biopsy of the left vastus lateralis muscle.\nRESULTS: MRI showed involvement mainly of the quadriceps femoris, sartorius, and adductor magnus, with selective sparing of the gracilis, hamstrings, and adductor longus and brevis. Muscle biopsy revealed chronic dystrophic features. Oxidative stains demonstrated enlarged mitochondria accentuated peripherally or present diffusely in a few fibres giving a coarsely stippled appearance. A homozygous C.722A>G (p.Asn241Ser) mutation was detected in exon 6 of the CHKB gene.\nCONCLUSION: This selective pattern of skeletal muscle involvement might be helpful for identifying other patients with this condition, even in the absence of diagnostic muscle pathology.","variants":[{"Name":"NM_005198.5(CHKB):c.722A>G (p.Asn241Ser)","Chromosome":"22","Start":"50580372","Stop":"50580372","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":348182,"rule_based_match":true,"evidence_text":"C.722A>G (p.Asn241Ser)","llm_judgment":"PRESENT","evidence":"C.722A>G (p.Asn241Ser)","abstract_start":1263,"abstract_end":1285}]}
{"pmid":"24709683","title":"A novel GRN mutation (GRN c.708+6_+9delTGAG) in frontotemporal lobar degeneration with TDP-43-positive inclusions: clinicopathologic report of 6 cases.","abstract":"Understanding of frontotemporal lobar degeneration, the underlying pathology most often linked to the clinical diagnosis of frontotemporal dementia, is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings on 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6_+9delTGAG mutation.","variants":[{"Name":"NM_002087.4(GRN):c.708+6_708+9del","Chromosome":"17","Start":"44350801","Stop":"44350804","ReferenceAlleleVCF":"CGTGA","AlternateAlleleVCF":"C","allel_id":577636,"rule_based_match":false,"evidence_text":"GRN c.708+6_+9delTGAG","llm_judgment":"PRESENT","evidence":"GRN c.708+6_+9delTGAG","abstract_start":847,"abstract_end":868}]}
{"pmid":"18348273","title":"A novel nonsense mutation in MYO6 is associated with progressive nonsyndromic hearing loss in a Danish DFNA22 family.","abstract":"Autosomal dominant inheritance is described in about 20% of all nonsyndromic hearing loss with currently 54 distinct loci (DFNA1-54), and >20 different genes identified. Seven different unconventional myosin genes are involved in ten different types of syndromic and nonsyndromic hearing loss with different patterns of inheritance: MYO7A in DFNA11/DFNB2/USH1B, MYH9 in DFNA17, MYH14 in DFNA4, MYO6 in DFNA22/DFNB37, MYO3A in DFNB30, MYO1A in DFNA48, and MYO15A in DFNB3. Two missense mutations in MYO6 (p.C442Y and p.H246R) have been characterized in families of Italian and American Caucasian extraction with autosomal dominant hearing loss, respectively, and the latter was associated with cardiomyopathy in some patients. Three Pakistani families had homozygosity for three MYO6 mutations (c.36insT, p.R1166X, and p.E216V, respectively), and was in one instance associated with retinal degeneration. In the present study, we linked autosomal dominant hearing loss in a large Danish family to a 38.9 Mb interval overlapping with the DFNA22/DFNB37 locus on chromosome 6q13. A novel nonsense mutation in MYO6 exon 25 (c.2545C > T; p.R849X) was identified in the family. The mutation co-segregated with the disease and the mutant allele is predicted to encode a truncated protein lacking the coiled-coil and globular tail domains. These domains are hypothesized to be essential for targeting myosin VI to its cellular compartments. No other system was involved indicating nonsyndromic loss. In conclusion, a novel nonsense MYO6 mutation causes post-lingual, slowly progressive autosomal dominant nonsyndromic moderate to severe hearing loss in a Danish family.","variants":[{"Name":"NM_004999.4(MYO6):c.2545C>T (p.Arg849Ter)","Chromosome":"6","Start":"75886881","Stop":"75886881","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23621,"rule_based_match":true,"evidence_text":"c.2545C > T; p.R849X","llm_judgment":"PRESENT","evidence":"c.2545C > T; p.R849X","abstract_start":1119,"abstract_end":1139}]}
{"pmid":"26944167","title":"Blepharospasm in a multiplex African-American pedigree.","abstract":"BACKGROUND: Isolated blepharospasm (BSP) is a late-onset focal dystonia characterized by involuntary contractions of the orbicularis oculi muscles. Genetic studies of BSP have been limited by the paucity of large multiplex pedigrees. Although sequence variants (SVs) in THAP1 have been reported in rare cases of BSP, the genetic causes of this focal dystonia remain largely unknown. Moreover, in the absence of family history and strong in silico or in vitro evidence of deleteriousness, the pathogenicity of novel SVs in THAP1 and other dystonia-associated genes can be indeterminate.\nMETHODS: A large African-American pedigree with BSP was phenotypically characterized and screened for mutations in THAP1, TOR1A and GNAL with Sanger sequencing. Whole-exome sequencing of the proband was used to examine other dystonia-associated genes for potentially pathogenic SVs. In silico and co-segregation analyses were performed for a novel THAP1 SV identified in the proband.\nRESULTS: Seven family members exhibited increased blinking and/or stereotyped bilateral and synchronous orbicularis oculi spasms with age of onset ranging from early childhood to late adult life (7 to 54 years). The proband was found to harbor a novel THAP1 SV (c.314T>C, p.L105S). However, the p.L105S SV did not co-segregate with blepharospasm in the pedigree. Moreover, in silico analyses suggest that p.L105S is benign. No pathogenic or likely pathogenic SVs in other dystonia-associated genes were identified with whole-exome sequencing.\nCONCLUSIONS: Blepharospasm can be familial and may be hereditary in African-Americans. A comprehensive array of in silico tools, and, if possible, co-segregation analysis should be used to classify SVs in dystonia-associated genes.","variants":[{"Name":"NM_018105.3(THAP1):c.314T>C (p.Leu105Ser)","Chromosome":"8","Start":"42838290","Stop":"42838290","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2884674,"rule_based_match":true,"evidence_text":"c.314T>C, p.L105S","llm_judgment":"PRESENT","evidence":"c.314T>C, p.L105S","abstract_start":1232,"abstract_end":1249}]}
{"pmid":"18718593","title":"Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population.","abstract":"We investigated the LDLR gene mutations in 205 unrelated Japanese FH (familial hypercholesterolemia) heterozygotes to see if there is a prevalence of common mutations in the Japanese population. A total of 53 different small mutations (<25bp) and 10 kinds of large deletions (>25bp) were identified. Among them there were eight relatively frequent mutations: C317S, c.1845+2T>C, K790X, L547V, P664L, D412H, c.2312-3C>A and V776M. The patients with these mutations comprised 32% of the total FH heterozygotes investigated. Comparison of clinical phenotypes of the eight frequent mutations disclosed that a missense mutation, L547V, manifested a milder phenotype than the other mutations. The mild clinical phenotype was shown to be based on the high level of receptor activity remaining on the patient's cell surfaces. When we examined the presence of common mutations in a general population, the L547V mutation was detected with unexpectedly higher frequency than the other mutations, suggesting an underestimation of the frequency of this mutation in FH heterozygote patients. In conclusion, although there is a broad spectrum of LDLR gene mutations in the Japanese population, eight common mutations were observed. Among them, a mild phenotype mutation, L547V, might predominate in the Japanese population.","variants":[{"Name":"NM_000527.5(LDLR):c.1845+2T>C","Chromosome":"19","Start":"11117000","Stop":"11117000","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":246371,"rule_based_match":true,"evidence_text":"c.1845+2T>C","llm_judgment":"PRESENT","evidence":"c.1845+2T>C","abstract_start":366,"abstract_end":377},{"Name":"NM_000527.5(LDLR):c.2312-3C>A","Chromosome":"19","Start":"11128005","Stop":"11128005","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":228204,"rule_based_match":true,"evidence_text":"c.2312-3C>A","llm_judgment":"PRESENT","evidence":"c.2312-3C>A","abstract_start":407,"abstract_end":418}]}
{"pmid":"19206175","title":"Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications.","abstract":"Generalized arterial calcification of infancy (GACI) (OMIM no. 208000) is characterized by calcification of the major arteries and soft tissues and associated with mutations in the ENPP1 gene. Most affected patients die within the first 6 months of life although prolonged survival is increasingly recognized. We report on three siblings with GACI and striking phenotypic variability. Two siblings (including the sibling survivor) were compound heterozygotes for mutations in exon 7 (c.783C>G (p.Y261X)) and exon 8 (c. 878_879delAA (p.K293fsX5)) of the ENPP1 gene confirming the diagnosis of GACI. The sibling survivor did not have calcification on X-ray studies or evidence of hypophosphatemic rickets. GACI may be under recognized and we emphasize consideration of this condition in patients with multiple arterial stenosis even in the absence of radiographic calcification. This adds to the expanding phenotype of GACI and supports a potential role for modifying genes.","variants":[{"Name":"NM_006208.3(ENPP1):c.783C>G (p.Tyr261Ter)","Chromosome":"6","Start":"131858735","Stop":"131858735","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":28636,"rule_based_match":true,"evidence_text":"c.783C>G (p.Y261X)","llm_judgment":"PRESENT","evidence":"c.783C>G (p.Y261X)","abstract_start":484,"abstract_end":502},{"Name":"NM_006208.3(ENPP1):c.878_879del (p.Lys293fs)","Chromosome":"6","Start":"131860468","Stop":"131860469","ReferenceAlleleVCF":"TAA","AlternateAlleleVCF":"T","allel_id":28637,"rule_based_match":true,"evidence_text":"c. 878_879delAA (p.K293fsX5)","llm_judgment":"PRESENT","evidence":"c. 878_879delAA (p.K293fsX5)","abstract_start":516,"abstract_end":544}]}
{"pmid":"38130758","title":"The Effect of Asfotase Alfa on Plasma and Urine Pyrophosphate Levels and Pseudofractures in a Patient With Adult-Onset Hypophosphatasia.","abstract":"Hypophosphatasia (HPP) is an inherited disease caused by variants of the <i>ALPL</i> gene encoding tissue-nonspecific alkaline phosphatase. Adult-onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first-line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64-year-old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the <i>ALPL</i> gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6-minute walk test (525 to 606 m). The EQ-5D-5L index was also improved (0.757 to 0.895). Within a follow-up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the <i>ALPL</i> gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. <i>JBMR Plus</i> published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.","variants":[{"Name":"NM_000478.6(ALPL):c.319G>A (p.Val107Ile)","Chromosome":"1","Start":"21563131","Stop":"21563131","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3394998,"rule_based_match":true,"evidence_text":"c.319G > A; p.Val107Ile","llm_judgment":"PRESENT","evidence":"c.319G > A; p.Val107Ile","abstract_start":780,"abstract_end":803}]}
{"pmid":"25439737","title":"Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs.","abstract":"BACKGROUND: We present clinical and molecular findings of a patient with ceroid-lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL.\nCASE PRESENTATION: A 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years.\nRESULTS: MECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene.\nCONCLUSION: NCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented.","variants":[{"Name":"NM_001371596.2(MFSD8):c.754+2T>A","Chromosome":"4","Start":"127938781","Stop":"127938781","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":76805,"rule_based_match":true,"evidence_text":"c.754 + 2T > A","llm_judgment":"PRESENT","evidence":"c.754 + 2T > A","abstract_start":1134,"abstract_end":1148},{"Name":"NM_001371596.2(MFSD8):c.881C>A (p.Thr294Lys)","Chromosome":"4","Start":"127930800","Stop":"127930800","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":16045,"rule_based_match":true,"evidence_text":"c.881C > A p.Thr294Lys","llm_judgment":"PRESENT","evidence":"c.881C > A p.Thr294Lys","abstract_start":1107,"abstract_end":1129}]}
{"pmid":"31338997","title":"Identification of a novel EVC variant in a Han-Chinese family with Ellis-van Creveld syndrome.","abstract":"BACKGROUND: Ellis-van Creveld syndrome (EVC), a very rare genetic skeletal dysplasia, is clinically characterized by a tetrad consisting of chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac anomalies. The aim of this study was to identify the genetic defect for EVC in a five-generation consanguineous Han-Chinese pedigree.\nMETHODS: A five-generation, 12-member Han-Chinese pedigree was enrolled in this study. Exome sequencing was applied in the proband to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in family members and 200 unrelated ethnicity-matched controls.\nRESULTS: A novel homozygous variant, c.2014C>T, p.(Q672*), in the EvC ciliary complex subunit 1 gene (EVC), was detected in the patient, which was cosegregated with the disease in the family and absent in the controls.\nCONCLUSION: The identified novel homozygous EVC variant, c.2014C>T, p.(Q672*), was responsible for EVC in this Han-Chinese pedigree. The findings in this study extend the EVC mutation spectrum and may provide new insights into EVC causation and diagnosis with implications for genetic counseling and clinical management.","variants":[{"Name":"NM_153717.3(EVC):c.2014C>T (p.Gln672Ter)","Chromosome":"4","Start":"5797149","Stop":"5797149","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":829432,"rule_based_match":true,"evidence_text":"c.2014C>T, p.(Q672*)","llm_judgment":"PRESENT","evidence":"c.2014C>T, p.(Q672*)","abstract_start":671,"abstract_end":691}]}
{"pmid":"11138009","title":"Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D.","abstract":"Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, vestibular dysfunction and visual impairment due to early onset retinitis pigmentosa (RP). So far, six loci (USH1A-USH1F) have been mapped, but only two USH1 genes have been identified: MYO7A for USH1B and the gene encoding harmonin for USH1C. We identified a Cuban pedigree linked to the locus for Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10). Affected individuals present with congenital deafness and a highly variable degree of retinal degeneration. Using a positional candidate approach, we identified a new member of the cadherin gene superfamily, CDH23. It encodes a protein of 3,354 amino acids with a single transmembrane domain and 27 cadherin repeats. In the Cuban family, we detected two different mutations: a severe course of the retinal disease was observed in individuals homozygous for what is probably a truncating splice-site mutation (c.4488G-->C), whereas mild RP is present in individuals carrying the homozygous missense mutation R1746Q. A variable expression of the retinal phenotype was seen in patients with a combination of both mutations. In addition, we identified two mutations, Delta M1281 and IVS51+5G-->A, in a German USH1 patient. Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype. In an accompanying paper, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse.","variants":[{"Name":"NM_022124.6(CDH23):c.4488G>C (p.Gln1496His)","Chromosome":"10","Start":"71739772","Stop":"71739772","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":19954,"rule_based_match":false,"evidence_text":"c.4488G-->C","llm_judgment":"PRESENT","evidence":"c.4488G-->C","abstract_start":1004,"abstract_end":1015}]}
{"pmid":"30087272","title":"Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation.","abstract":"The <i>TUBA1A</i> gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in <i>TUBA1A</i> have been reported to cause a range of brain malformations. We describe four unrelated patients with the same de novo missense mutation in <i>TUBA1A</i>, c.5G>A, p.(Arg2His), as found by next generation sequencing. Detailed comparison revealed similar brain phenotypes with mild variability. Shared features included developmental delay, microcephaly, hypoplasia of the cerebellar vermis, dysplasia or thinning of the corpus callosum, small pons, and dysmorphic basal ganglia. Two of the patients had bilateral perisylvian polymicrogyria. We examined the effects of the p.(Arg2His) mutation by computer-based protein structure modelling and heterologous expression in HEK-293 cells. The results suggest the mutation subtly impairs microtubule function, potentially by affecting inter-dimer interaction. Based on its sequence context, c.5G>A is likely to be a common recurrent mutation. We propose that the subtle functional effects of p.(Arg2His) may allow for other factors (such as genetic background or environmental conditions) to influence phenotypic outcome, thus explaining the mild variability in clinical manifestations.","variants":[{"Name":"NM_006009.4(TUBA1A):c.5G>A (p.Arg2His)","Chromosome":"12","Start":"49186832","Stop":"49186832","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":169007,"rule_based_match":true,"evidence_text":"c.5G>A, p.(Arg2His)","llm_judgment":"PRESENT","evidence":"c.5G>A, p.(Arg2His)","abstract_start":510,"abstract_end":529}]}
{"pmid":"35221871","title":"","abstract":"Three siblings born to Turkish parents from the same village had normal brain development until acute neurological deterioration between 12 months and 8 years of age. Consequent loss of all acquired motor, social, and language functions following infections was associated with a pontine cyst, calcification, and cerebellar atrophy. Exome sequencing revealed a homozygous c.1297G>A (p.Gly433Ser) alteration in <i>BEND4</i>, which was predicted to be deleterious in in silico analysis tools and segregated in multiple affected individuals in the family. <i>BEND4</i> has not been associated with any existing disease. Immunofluorescence microscopy analysis of wild-type and mutant BEND4 expressing Vero cells showed nuclear and cytoplasmic localization. Wild-type BEND4 displayed a network-like distribution, whereas mutant BEND4 showed a juxtanuclear distribution pattern. Differential proteome analysis of Vero cells expressing BEND4 revealed that mutant BEND4 expression caused selective increase in reticulocalbin-1 and endoplasmic reticulum resident protein-29. Both proteins are associated with the endoplasmic reticulum and are primarily involved in protein processing and folding pathways. Any defect or stress in protein folding creates stress on cells and may cause chronic damage. This is the first study showing that pathogenic <i>BEND4</i> variants may lead to an infection-induced acute necrotizing encephalopathy as demonstrated in characteristic neuroimaging findings.","variants":[{"Name":"NM_207406.4(BEND4):c.1297G>A (p.Gly433Ser)","Chromosome":"4","Start":"42120144","Stop":"42120144","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":972510,"rule_based_match":true,"evidence_text":"c.1297G>A (p.Gly433Ser)","llm_judgment":"PRESENT","evidence":"c.1297G>A (p.Gly433Ser)","abstract_start":372,"abstract_end":395}]}
{"pmid":"32025184","title":"Functional characterization of a novel","abstract":"Purpose: To elucidate the clinical phenotypes and pathogenesis of a novel missense mutation in <i>guanylate cyclase activator A1A</i> (<i>GUCA1A</i>) associated with autosomal dominant cone dystrophy (adCOD).\nMethods: The members of a family with adCOD were clinically evaluated. Relevant genes were captured before being sequenced with targeted next-generation sequencing and confirmed with Sanger sequencing. Sequence analysis was made of the conservativeness of mutant residues. An enzyme-linked immunosorbent assay (ELISA) was implemented to detect the cyclic guanosine monophosphate (cGMP) concentration. Then limited protein hydrolysis and an electrophoresis shift were used to assess possible changes in the structure. Coimmunoprecipitation was employed to analyze the interaction between GCAP1 and retGC1. Immunofluorescence staining was performed to observe the colocalization of GCAP1 and retGC1 in human embryonic kidney (HEK)-293 cells.\nResults: A pathogenic mutation in <i>GUCA1A</i> (c.431A>G, p.D144G, exon 5) was revealed in four generations of a family with adCOD. <i>GUCA1A</i> encodes guanylate cyclase activating protein 1 (GCAP1). D144, located in the EF4 loop involving calcium binding, was highly conserved in the species. GCAP1-D144G was more susceptible to hydrolysis, and the mobility of the D144G band became slower in the presence of Ca<sup>2+</sup>. At high Ca<sup>2+</sup> concentrations, GCAP1-D144G stimulated retGC1 in the HEK-293 membrane to significantly increase intracellular cGMP protein concentrations. Compared with wild-type (WT) GCAP1, GCAP1-D144G had an increased interaction with retGC1, as detected in the coimmunoprecipitation assay.\nConclusions: The newly discovered missense mutation in <i>GUCA1A</i> (p.D144G) might lead to an imbalance of Ca<sup>2+</sup> and cGMP homeostasis and eventually, cause a significant variation in adCOD.","variants":[{"Name":"NM_001384910.1(GUCA1A):c.431A>G (p.Asp144Gly)","Chromosome":"6","Start":"42178881","Stop":"42178881","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":963233,"rule_based_match":true,"evidence_text":"c.431A>G, p.D144G","llm_judgment":"PRESENT","evidence":"c.431A>G, p.D144G","abstract_start":998,"abstract_end":1015}]}
{"pmid":"36709796","title":"The third patient of ACACA-related acetyl-CoA carboxylase deficiency with seizure and literature review.","abstract":"Pathogenic variants in ACACA are the cause of acetyl-CoA carboxylase deficiency with an autosomal recessive inheritance that is identified by hypotonia, motor, and intellectual developmental delay. In this article, we describe a seven-year-old boy who is the child of consanguineous parents with a homozygous variant in ACACA (NM_198834.3:c.6641C > A, p.P2214H) that was detected by Whole-Exome Sequencing and confirmed by Sanger sequencing. This is the first reported patient of acetyl-CoA carboxylase deficiency that results from a homozygous pathogenic variant in the ACACA gene in the Iranian family. The proband presents with motor and intellectual developmental delay, muscle weakness, language disorder, facial dysmorphism, and poor growth. The patient discussed here is similar to other patients that were previously published; however, we were able to identify seizure that has hitherto not been reported. This paper describes the third person with a novel variant in the ACACA gene in the world that accounts for acetyl-CoA carboxylase deficiency and implicates the clinical spectrum of the disease. Finally, we describe an individual-based review of the symptoms associated with acetyl-CoA carboxylase deficiency. So far, only two acetyl-CoA carboxylase deficiency patients have been reviewed in the literature.","variants":[{"Name":"NM_198834.3(ACACA):c.6641C>A (p.Pro2214His)","Chromosome":"17","Start":"37097909","Stop":"37097909","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1856844,"rule_based_match":true,"evidence_text":"NM_198834.3:c.6641C > A, p.P2214H","llm_judgment":"PRESENT","evidence":"NM_198834.3:c.6641C > A, p.P2214H","abstract_start":327,"abstract_end":360}]}
{"pmid":"24864645","title":"The Roberts syndrome: a case report of an infant with valvular aortic stenosis and mutation in ESCO2.","abstract":"Roberts syndrome, which is inherited as an autosomal recessive group of disorders, is a rare syndrome characterized with symmetrical extremity defects, craniofacial abnormalities, and prenatal and postnatal growth retardation. Here, we present a case of Roberts Syndrome brought to the clinic with diarrhoea and multiple abnormalities, that had tetra phocomelia, growth and developmental retardation, abnormality of complete cleft lip-palate accompanied with Aortic stenosis and PDA, and in which cytogenetic analysis identified premature centromere separation. Mutation analysis of ESCO2 revealed a splice site mutation [c.1131+1G>A] in intron 6 in homozygous status in the patient and heterozygous status in the parents. Our case is the first Robert- Syndrome with valvular aortic stenosis in the literature, to the best of our knowledge.","variants":[{"Name":"NM_001017420.3(ESCO2):c.1131+1G>A","Chromosome":"8","Start":"27788003","Stop":"27788003","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34085,"rule_based_match":true,"evidence_text":"c.1131+1G>A","llm_judgment":"PRESENT","evidence":"c.1131+1G>A","abstract_start":622,"abstract_end":633}]}
{"pmid":"34504271","title":"Novel variants causing megalencephalic leukodystrophy in Sudanese families.","abstract":"Mutations in MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare form of leukodystrophy characterized by macrocephaly, epilepsy, spasticity, and slow mental deterioration. Genetic studies of MLC are lacking from many parts of the world, especially in Sub-Saharan Africa. Genomic DNA was extracted for 67 leukodystrophic patients from 43 Sudanese families. Mutations were screened using the NGS panel testing 139 leukodystrophies and leukoencephalopathies causing genes (NextSeq500 Illumina). Five homozygous MLC1 variants were discovered in seven patients from five distinct families, including three consanguineous families from the same region of Sudan. Three variants were missense (c.971 T > G, p.Ile324Ser; c.344 T > C, p.Phe115Ser; and c.881 C > T, p.Pro294Leu), one duplication (c.831_838dupATATCTGT, p.Ser280Tyrfs*8), and one synonymous/splicing-site mutation (c.762 C > T, p.Ser254). The segregation pattern was consistent with autosomal recessive inheritance. The clinical presentation and brain MRI of the seven affected patients were consistent with the diagnosis of MLC1. Due to the high frequency of distinct MLC1 mutations found in our leukodystrophic Sudanese families, we analyzed the coding sequence of MLC1 gene in 124 individuals from the Sudanese genome project in comparison with the 1000-genome project. We found that Sudan has the highest proportion of deleterious variants in MLC1 gene compared with other populations from the 1000-genome project.","variants":[{"Name":"NM_015166.4(MLC1):c.881C>T (p.Pro294Leu)","Chromosome":"22","Start":"50068446","Stop":"50068446","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1464403,"rule_based_match":true,"evidence_text":"c.881 C > T, p.Pro294Leu","llm_judgment":"PRESENT","evidence":"c.881 C > T, p.Pro294Leu","abstract_start":774,"abstract_end":798}]}
{"pmid":"26846447","title":"Identification of a de novo DYNC1H1 mutation via WES according to published guidelines.","abstract":"De novo mutations that contribute to rare Mendelian diseases, including neurological disorders, have been recently identified. Whole-exome sequencing (WES) has become a powerful tool for the identification of inherited and de novo mutations in Mendelian diseases. Two important guidelines were recently published regarding the investigation of causality of sequence variant in human disease and the interpretation of novel variants identified in human genome sequences. In this study, a family with supposed movement disorders was sequenced via WES (including the proband and her unaffected parents), and a standard investigation and interpretation of the identified variants was performed according to the published guidelines. We identified a novel de novo mutation (c.2327C > T, p.P776L) in DYNC1H1 gene and confirmed that it was the causal variant. The phenotype of the affected twins included delayed motor milestones, pes cavus, lower limb weakness and atrophy, and a waddling gait. Electromyographic (EMG) recordings revealed typical signs of chronic denervation. Our study demonstrates the power of WES to discover the de novo mutations associated with a neurological disease on the whole exome scale, and guidelines to conduct WES studies and interpret of identified variants are a preferable option for the exploration of the pathogenesis of rare neurological disorders.","variants":[{"Name":"NM_001376.5(DYNC1H1):c.2327C>T (p.Pro776Leu)","Chromosome":"14","Start":"101986552","Stop":"101986552","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360017,"rule_based_match":true,"evidence_text":"c.2327C > T, p.P776L","llm_judgment":"PRESENT","evidence":"c.2327C > T, p.P776L","abstract_start":769,"abstract_end":789}]}
{"pmid":"21110013","title":"Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters.","abstract":"PURPOSE: The anticoagulation response to vitamin K antagonists is characterised by high inter-individual variability. The impact of single nucleotide polymorphisms (SNPs) in several genes of enzymes involved in the vitamin K cycle on phenprocoumon dose variability and phenprocoumon plasma concentrations is still under investigation.\nMETHODS: We assessed the influence of VKORC1 c.-1639G>A, CYP2C9*2, CYP2C9*3, CYP4F2 c.1297G>A, CALU c.*4A>G, EPHX1 c.337T>C, GGCX c.214+597G>A, F7 c.-402G>A, F7 c.-401G>T, PROC c.-228C>T and PROC c.-215G>A along with clinical and demographic parameters on steady-state phenprocoumon therapy in 75 patients. A prediction model was developed for total phenprocoumon plasma concentrations and daily phenprocoumon doses required for therapeutic anticoagulation.\nRESULTS: The VKORC1 c.-1639 genotype was the main predictor of the phenprocoumon daily dose (adjusted R(2) = 37.6%) and the total phenprocoumon concentration (adjusted R(2) = 38.3%). CYP2C9 affected the phenprocoumon concentration, but not the dose requirements. SNPs in the other genes of the vitamin K cycle, concomitant medication, nicotine use and alcohol consumption did not predict phenprocoumon concentrations and phenprocoumon dose requirements in a multiple linear regression model. Phenprocoumon concentrations were predicted by VKORC1 c.-1639, CYP2C9 genotype, age and BMI. The final prediction model for the daily phenprocoumon dose requirements comprised VKORC1 c.-1639 genotype, age and height accounting for 48.6% of the inter-individual variability.\nCONCLUSIONS: A rough prediction of phenprocoumon maintenance doses can be achieved by a limited set of parameters (VKORC1, age, height). The investigated SNPs in CYP4F2, CALU, EPHX1, GGCX, F7, and PROC did not improve the predictive value of a pharmacogenetic-based dosing equation for phenprocoumon.","variants":[{"Name":"NM_024006.4(VKORC1):c.-1639G>A","Chromosome":"16","Start":"31096368","Stop":"31096368","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17250,"rule_based_match":true,"evidence_text":"VKORC1 c.-1639G>A","llm_judgment":"PRESENT","evidence":"VKORC1 c.-1639G>A","abstract_start":373,"abstract_end":390}]}
{"pmid":"31059981","title":"Homozygous missense TPP1 mutation associated with mild late infantile neuronal ceroid lipofuscinosis and the genotype-phenotype correlation.","abstract":"PURPOSE: TPP1 mutations have been identified in patients with variable phenotypes such as late infantile neuronal ceroid lipofuscinosis (LINCL), juvenile neuronal ceroid lipofuscinosis (JNCL), and spinocerebellar ataxia 7. However, the mechanism underlying phenotype variation is unknown. We screened TPP1 mutations in patients with epilepsies and analyzed the genotype-phenotype correlation to explain the phenotypic variations.\nMETHODS: We performed targeted next-generation sequencing in a cohort of 330 patients with epilepsies. All previously reported TPP1 mutations were systematically retrieved from the PubMed and NCL Mutation Database.\nRESULTS: The homozygous missense TPP1 mutation c.646 G > A/ p.Val216Met was identified in a family with two affected siblings. The proband presented with seizures from three years of age, while no ataxia, cognitive regression, or visual abnormalities were observed. Further analysis of all reported TPP1 mutations revealed that the LINCL group had a significantly higher frequency of truncating and invariant splice-site mutations than the JNCL group. In contrast, the JNCL group had a higher frequency of variant splice-site mutations than LINCL. There was a significant correlation between phenotype severity and the frequency of destructive mutation.\nCONCLUSION: This study suggested that the phenotype of mainly epilepsy can be included in the phenotypic spectrum of TPP1 mutations, which are candidate targets for genetic screening in patients with epilepsy. With the development of therapy techniques, early genetic diagnosis may enable the improvement of etiology-targeted treatments. The relationship between phenotype severity and the genotype of TPP1 mutations may help explain the phenotypic variations.","variants":[{"Name":"NM_000391.4(TPP1):c.646G>A (p.Val216Met)","Chromosome":"11","Start":"6617016","Stop":"6617016","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1885655,"rule_based_match":true,"evidence_text":"c.646 G > A/ p.Val216Met","llm_judgment":"PRESENT","evidence":"c.646 G > A/ p.Val216Met","abstract_start":692,"abstract_end":716}]}
{"pmid":"8040340","title":"The molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma corporis diffusum with glycopeptiduria.","abstract":"Angiokeratoma corporis diffusum with glycopeptiduria is a recently recognized inborn error of glycoprotein catabolism resulting from the deficient activity of human alpha-N-acetylgalactosaminidase (E.C. 3.2.1.49; alpha-GalNAc). The first patient with this autosomal recessive disorder, a 46-yr-old consanguineous Japanese woman, presented with diffuse angiokeratoma, mild intellectual impairment, and peripheral neuroaxonal degeneration. Deficient alpha-GalNAc activity also has been reported in consanguineous brothers with an infantile-onset form of neuroaxonal dystrophy resulting from a missense mutation (designated E325K) in the alpha-GalNAc gene. To identify the mutation causing the phenotypically distinct adult-onset disorder, Southern and Northern hybridization analyses of DNA and RNA from the affected homozygote were performed which revealed a grossly normal alpha-GalNAc gene structure and normal transcript size and abundancy. Reverse transcription, amplification, and sequencing of the alpha-GalNAc transcript identified a single C to T transition at nucleotide (nt) 985 that predicted an arginine to tryptophan substitution in residue 329 (designated R329W) of the alpha-GalNAc polypeptide. This base substitution was confirmed by hybridization of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Transient expression of an alpha-GalNAc construct containing the R329W mutation resulted in the expression of an immunoreactive polypeptide which had no detectable alpha-GalNAc activity. Comparison of the biosynthesis and stabilities of the transiently expressed and radiolabeled normal, E325K (infantile-onset) and R329W (adult-onset) alpha-GalNAc polypeptides in COS-1 cells indicated that both the mutant precursors were processed to the mature form; however, the E325K mutant polypeptide was more rapidly degraded than the R329W subunit, thereby providing a basis for the distinctly different infantile- and adult-onset phenotypes.","variants":[{"Name":"NM_000262.3(NAGA):c.985C>T (p.Arg329Trp)","Chromosome":"22","Start":"42061040","Stop":"42061040","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":33202,"rule_based_match":false,"evidence_text":"c.985C>T (p.Arg329Trp)","llm_judgment":"PRESENT","evidence":"R329W","abstract_start":1169,"abstract_end":1174}]}
{"pmid":"28981938","title":"Mutational analysis and prenatal diagnosis of COL1A1 and COL1A2 genes in four Chinese families affected with osteogenesis imperfecta","abstract":"OBJECTIVE: To detect potential mutations of COL1A1 and COL1A2 genes in four Chinese pedigrees affected with osteogenesis imperfecta (OI) and provide prenatal diagnosis for a fetus at 18th gestational week.\nMETHODS: All coding regions and exon/intron boundaries of the COL1A1 and COL1A2 genes were analyzed with targeted next-generation sequencing (NGS). Suspected mutations were confirmed with Sanger sequencing in the probands, unaffected relatives and 200 unrelated healthy individuals. Prenatal diagnosis for a high-risk fetus was carried out through Sanger sequencing.\nRESULTS: The probands of families 1 and 2 have respectively carried a c.760G>A (p.Gly254Arg) and a c.608G>T (p.Gly203Val) mutation of the COL1A1 gene. For family 3, the proband and his daughter have carried a novel c.299-1G>C splicing mutation of the COL1A1 gene. The same mutation was not found in the fetus of this family. For family 4, the proband has carried a novel c.1990G>C (p.Gly664Arg) mutation of the COL1A2 gene. The four mutations were not found in the unaffected relatives and 200 unrelated healthy individuals.\nCONCLUSION: The mutations of the COL1A1 and COL1A2 genes probably underlie the disease in the four families. NGS combined with Sanger sequencing can provide an effective and accurate method for their genetic and prenatal diagnosis.","variants":[{"Name":"NM_000089.4(COL1A2):c.1990G>C (p.Gly664Arg)","Chromosome":"7","Start":"94418517","Stop":"94418517","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2404349,"rule_based_match":true,"evidence_text":"c.1990G>C (p.Gly664Arg)","llm_judgment":"PRESENT","evidence":"c.1990G>C (p.Gly664Arg)","abstract_start":944,"abstract_end":967},{"Name":"NM_000088.4(COL1A1):c.760G>A (p.Gly254Arg)","Chromosome":"17","Start":"50197054","Stop":"50197054","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3853981,"rule_based_match":true,"evidence_text":"c.760G>A (p.Gly254Arg)","llm_judgment":"PRESENT","evidence":"c.760G>A (p.Gly254Arg)","abstract_start":643,"abstract_end":665}]}
{"pmid":"24088667","title":"Novel FIG4 mutations in Yunis-Varon syndrome.","abstract":"Yunis-Varon syndrome (YVS, MIM 216340) is a rare autosomal recessive disorder characterized by skeletal abnormalities and severe neurological impairment with vacuolation of the central nervous system, skeletal muscles and cartilages. Very recently, mutations of the FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing (Saccharomyces cerevisiae)) gene, which encodes a 5'-phosphoinositide phosphatase essential for endosome/lysosome function have been identified as the cause for YVS. Interestingly, FIG4 mutations were previously reported to be responsible for other neurodegenerative diseases such as autosomal recessive Charcot-Marie-Tooth disease type 4J and autosomal dominant amyotrophic lateral sclerosis/primary lateral sclerosis. We analyzed a YVS patient using whole-exome sequencing, and identified novel biallelic FIG4 mutations: c.1750+1delG and c.2284_2285delCT (p.S762Wfs*3). These two mutations were mutations supposed to have null function. To our knowledge, this is the second report of FIG4 mutations in YVS and our result supports the idea that biallelic null mutations of FIG4 cause YVS in human.","variants":[{"Name":"NM_014845.6(FIG4):c.1750+1del","Chromosome":"6","Start":"109766895","Stop":"109766895","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":940830,"rule_based_match":true,"evidence_text":"c.1750+1delG","llm_judgment":"PRESENT","evidence":"c.1750+1delG","abstract_start":850,"abstract_end":862}]}
{"pmid":"29556235","title":"Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case.","abstract":"Background: We investigated the molecular etiology of a young male proband with confirmed immunodeficiency of unknown cause, presenting with recurrent bacterial and Varicella zoster viral infections in childhood and persistent lymphopenia into early adulthood.\nAim: To identify causative functional genetic variants related to an undiagnosed primary immunodeficiency.\nMethod: Whole genome microarray copy number variant (CNV) analysis was performed on the proband followed by whole exome sequencing (WES) and trio analysis of the proband and family members. A >4 kbp deletion identified by repeated CNV analysis of exome sequencing data along with three damaging missense single nucleotide variants were validated by Sanger sequencing in all family members. Confirmation of the causative role of the candidate gene was performed by qPCR and Western Blot analyses on the proband, family members and a healthy control.\nResults: CNV identified our previously reported interleukin 25 amplification in the proband; however, the variant was not validated to be a candidate gene for immunodeficiency. WES trio analysis, data filtering and <i>in silico</i> prediction identified a novel, damaging (SIFT: 0; Polyphen 1; Grantham score: 101) and disease-causing (MutationTaster) single base mutation in the X chromosome (c.511C > T p.Arg171Trp) <i>MSN</i> gene not identified in the UCSC Genome Browser database. The mutation was validated by Sanger sequencing, confirming the proband was hemizygous X-linked recessive (-/T) at this locus and inherited the affected T allele from his non-symptomatic carrier mother (C/T), with other family members (father, sister) confirmed to be wild type (C/C). Western Blot analysis demonstrated an absence of moesin protein in lymphocytes derived from the proband, compared with normal expression in lymphocytes derived from the healthy control, father and mother. qPCR identified significantly lower <i>MSN</i> mRNA transcript expression in the proband compared to an age- and sex-matched healthy control subject in whole blood (<i>p</i> = 0.02), and lymphocytes (<i>p</i> = 0.01). These results confirmed moesin deficiency in the proband, directly causative of his immunodeficient phenotype.\nConclusion: These findings confirm X-linked moesin-associated immunodeficiency in a proband previously undiagnosed up to 24 years of age. This study also highlights the utility of WES for the diagnosis of rare or novel forms of primary immunodeficiency disease.","variants":[{"Name":"NM_002444.3(MSN):c.511C>T (p.Arg171Trp)","Chromosome":"X","Start":"65731150","Stop":"65731150","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359059,"rule_based_match":true,"evidence_text":"c.511C > T p.Arg171Trp","llm_judgment":"PRESENT","evidence":"c.511C > T p.Arg171Trp","abstract_start":1311,"abstract_end":1333}]}
{"pmid":"22822385","title":"LEOPARD Syndrome Caused by Tyr279Cys Mutation in the PTPN11 Gene.","abstract":"LEOPARD syndrome (LS) is an acronym consisting of lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary valve stenosis, abnormal genitalia, retardation of growth and deafness. However, hypertrophic cardiomyopathy, the most frequent cause of sudden cardiac death in young people, is the most common cardiovascular manifestation in LS patients and the major determinant of mortality and morbidity. In approximately 85% of the patients with a definite diagnosis of LS, a missense mutation is found in the protein-tyrosine phosphatase non-receptor type 11 (PTPN11) gene located on chromosome 12q24.1. We report the case of an asymptomatic 17-year-old male with a missense mutation (c.836A>G) in exon 7 (Tyr279Cys) of the PTPN11 gene and a non-obstructive asymmetric anteroseptal hypertrophic cardiomyopathy.","variants":[{"Name":"NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)","Chromosome":"12","Start":"112473023","Stop":"112473023","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28367,"rule_based_match":true,"evidence_text":"c.836A>G","llm_judgment":"PRESENT","evidence":"c.836A>G","abstract_start":704,"abstract_end":712}]}
{"pmid":"26416544","title":"A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability.","abstract":"The genetic basis of intellectual disability (ID) is extremely heterogeneous and relatively little is known about the role of autosomal recessive traits. In a field study performed in a highly inbred area of Northeastern Brazil, we identified and investigated a large consanguineous family with nine adult members affected by severe ID associated with disruptive behavior. The Genome-Wide Human SNP Array 6.0 microarray was used to determine regions of homozygosity by descent from three affected and one normal family member. Whole-exome sequencing (WES) was performed in one affected patient using the Nextera Rapid-Capture Exome kit and Illumina HiSeq2500 system to identify the causative mutation. Potentially deleterious variants detected in regions of homozygosity by descent and not present in either 59 723 unrelated individuals from the Exome Aggregation Consortium (Browser) or 1484 Brazilians were subject to further scrutiny and segregation analysis by Sanger sequencing. Homozygosity-by-descent analysis disclosed a 20.7-Mb candidate region at 8q12.3-q21.2 (lod score: 3.11). WES identified a homozygous deleterious variant in inositol monophosphatase 1 (IMPA1) (NM_005536), consisting of a 5-bp duplication (c.489_493dupGGGCT; chr8: 82,583,247; GRCh37/hg19) leading to a frameshift and a premature stop codon (p.Ser165Trpfs*10) that cosegregated with the disease in 26 genotyped family members. The IMPA1 gene product is responsible for the final step of biotransformation of inositol triphosphate and diacylglycerol, two second messengers. Despite its many physiological functions, no clinical phenotype has been assigned to this gene dysfunction to date. Additionally, IMPA1 is the main target of lithium, a drug that is at the forefront of treatment for bipolar disorder.","variants":[{"Name":"NM_005536.4(IMPA1):c.489_493dup (p.Ser165fs)","Chromosome":"8","Start":"81671011","Stop":"81671012","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GAGCCC","allel_id":362179,"rule_based_match":true,"evidence_text":"c.489_493dupGGGCT","llm_judgment":"PRESENT","evidence":"c.489_493dupGGGCT","abstract_start":1222,"abstract_end":1239}]}
{"pmid":"29385733","title":"Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome.","abstract":"Enhanced S-cone syndrome (ESCS) is mainly associated with mutations in the <i>NR2E3</i> gene. However, rare mutations in the <i>NRL</i> gene have been reported in patients with ESCS. We report on an ESCS phenotype in additional patients with autosomal recessive <i>NRL</i> (ar<i>NRL</i>) mutations. Three Moroccan patients of two different families with ar<i>NRL</i> mutations were enrolled in this study. The mutation in the DNA of one patient, from a consanguineous marriage, was detected by homozygosity mapping. The mutation in the DNA of two siblings from a second family was detected in a targeted next-generation sequencing project. Full ophthalmic examination was performed, including best-corrected visual acuity, slit-lamp biomicroscopy, funduscopy, Goldmann kinetic perimetry, optical coherence tomography, fundus autofluorescence, and extended electroretinography including an amber stimulus on a blue background and a blue stimulus on an amber background. One patient carried a homozygous missense mutation (c.508C>A; p.Arg170Ser) in the <i>NRL</i> gene, whereas the same mutation was identified heterozygously in the two siblings of a second family, in combination with a one base-pair deletion (c.654del; p.Cys219Valfs*4) on the other allele. All patients had reduced visual acuity and showed a typical clumped pigmentary retinal degeneration (CPRD). Foveal schisis-like changes were observed in the oldest patient. An electroretinogram (ERG) under dark-adapted conditions showed absent responses for low stimulus strengths and reduced responses for high stimulus strengths, with constant b-wave latencies despite increasing stimulus strength. A relatively high amplitude was detected with a blue stimulus on an amber background, while an amber stimulus on a blue background showed reduced responses. The ar<i>NRL</i> mutations cause a phenotype with typical CPRD. This phenotype has previously been described in patients with ESCS caused by <i>NR2E3</i> mutations, and rarely by <i>NRL</i> mutations. Based on our findings in ERG testing, we conclude that S-cone function is enhanced in our patients in a similar manner as in patients with <i>NR2E3</i>-associated ESCS, confirming previous reports of <i>NRL</i> as a second gene to cause ESCS.","variants":[{"Name":"NM_001354768.3(NRL):c.654del (p.Cys219fs)","Chromosome":"14","Start":"24081296","Stop":"24081296","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":841332,"rule_based_match":true,"evidence_text":"c.654del (p.Cys219Valfs*4)","llm_judgment":"PRESENT","evidence":"p.Cys219Val","abstract_start":1220,"abstract_end":1231}]}
{"pmid":"23751782","title":"New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations.","abstract":"Mitochondrial HMG-CoA synthase deficiency is a rare inherited metabolic disorder that affects ketone-body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycaemia, dicarboxylic aciduria, and in severe cases, coma. This deficiency may have been under-diagnosed owing to the absence of specific clinical and biochemical markers, limitations in liver biopsy and the lack of an effective method of expression and enzyme assay for verifying the mutations found. To date, eight patients have been reported with nine allelic variants of the HMGCS2 gene. We present a new method of enzyme expression and a modification of the activity assay that allows, for first time, the functional study of missense mutations found in patients with this deficiency. Four of the missense mutations (p.V54M, p.R188H, p.G212R and p.G388R) did not produce proteins that could have been detected in soluble form by western blot; three produced a total loss of activity (p.Y167C, p.M307T and p.R500H) and one, variant p.F174L, gave an enzyme with a catalytic efficiency of 11.5%. This indicates that the deficiency may occur with partial loss of activity of enzyme. In addition, we describe a new patient with this deficiency, in which we detected the missense allelic variant, c.1162G>A (p.G388R) and the nonsense variant c.1270C>T (p.R424X).","variants":[{"Name":"NM_005518.4(HMGCS2):c.1270C>T (p.Arg424Ter)","Chromosome":"1","Start":"119753304","Stop":"119753304","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24297,"rule_based_match":true,"evidence_text":"c.1270C>T (p.R424X)","llm_judgment":"PRESENT","evidence":"c.1270C>T (p.R424X)","abstract_start":1321,"abstract_end":1340},{"Name":"NM_005518.4(HMGCS2):c.1162G>A (p.Gly388Arg)","Chromosome":"1","Start":"119755452","Stop":"119755452","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":442602,"rule_based_match":true,"evidence_text":"c.1162G>A (p.G388R)","llm_judgment":"PRESENT","evidence":"c.1162G>A (p.G388R)","abstract_start":1276,"abstract_end":1295}]}
{"pmid":"27622768","title":"The RAD51C exonic splice-site mutations c.404G>C and c.404G>T are associated with familial breast and ovarian cancer.","abstract":"Whereas RAD51C mutations increase the relative risk for ovarian cancer (OC) to 5.88 (95% confidence interval=2.91-11.88, P=7.65×10), the associated risks for breast cancer (BC) remain largely unknown, as deleterious RAD51C alterations are extremely rare in BC-only families. Here, we report the results of a RAD51C mutational screening in a large series of German familial index patients negative for pathogenic BRCA1/2 mutations and the in-vitro characterization of two novel exonic RAD51C splice-site mutations. A total of 610 index cases derived from BC/OC (n=587) or OC-only families (n=23) were screened for potentially deleterious germline mutations in RAD51C. The frequencies of two splice-site mutations were assessed by single-nucleotide polymorphism genotyping in 1410 additional cases not enriched for OC family history. In three independent families, we identified novel splice-site mutations affecting the last nucleotide of exon 2 (c.404G>C, c.404G>T). Both mutations disrupt proper RAD51C pre-mRNA processing and cause a missense substitution immediately followed by a stop codon (p.Cys135Serfs*2; p.Cys135Leufs*2). Even though both mutations have similar effects on the protein level, they are associated with either BC/OC, OC-only, or BC-only family histories. The rare finding of a clearly truncating RAD51C mutation in an early-onset BC patient with a BC-only family history supports the notion that compromised RAD51C function may result in both BC and OC. Large international collaborative studies are needed to quantify the relative risk of RAD51C alterations for BC and to unravel the genetic modifying factors that determine phenotypic variability with respect to cancer site.","variants":[{"Name":"NM_058216.3(RAD51C):c.404G>T (p.Cys135Phe)","Chromosome":"17","Start":"58695189","Stop":"58695189","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":938053,"rule_based_match":true,"evidence_text":"c.404G>T","llm_judgment":"PRESENT","evidence":"c.404G>T","abstract_start":956,"abstract_end":964},{"Name":"NM_058216.3(RAD51C):c.404G>C (p.Cys135Ser)","Chromosome":"17","Start":"58695189","Stop":"58695189","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":410097,"rule_based_match":true,"evidence_text":"c.404G>C","llm_judgment":"PRESENT","evidence":"c.404G>C","abstract_start":946,"abstract_end":954}]}
{"pmid":"33193653","title":"New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients.","abstract":"A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as <i>APC</i>, <i>POLE</i>, <i>MSH2</i> or <i>PMS2</i>. The <i>MSH2</i> variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The <i>POLE</i> variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be <i>de novo</i>. One pathogenic <i>PMS2</i> variant was novel. We also identified a number of highly interesting variants of unknown significance in <i>APC</i>, <i>BUB1, TP53</i> and <i>RPS20</i>. The <i>RPS20</i> variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple <i>in silico</i> tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in <i>RPS20</i> expands the phenotypic spectrum of <i>RPS20</i>-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.","variants":[{"Name":"NM_000251.3(MSH2):c.2168C>T (p.Ser723Phe)","Chromosome":"2","Start":"47476529","Stop":"47476529","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":96388,"rule_based_match":true,"evidence_text":"c.2168C>T, p.(Ser723Phe)","llm_judgment":"PRESENT","evidence":"c.2168C>T, p.(Ser723Phe)","abstract_start":726,"abstract_end":750}]}
{"pmid":"23890478","title":"Mutational analysis of ACTN4, encoding α-actinin 4, in patients with focal segmental glomerulosclerosis using HRM method.","abstract":"α-Actinin 4, encoded by ACTN4, is an F-actin crosslinking protein which belongs to the spectrin gene superfamily. It has a head-to-tail homodimer structure with three main domains. Mutations in ACTN4 are associated with idiopathic nephrotic syndrome (NS). However, until today only a few mutations have been described in this gene. We used genomic DNA of 48 patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) to screen for ACTN4 mutations by high-resolution melting analysis (HRM). Suspect samples were sequenced and compared with healthy controls. To investigate the prevalence and possible effect of some substitutions found in FSGS/MCD patients we also looked for these changes in patients with IgA nephropathy (IgAN) and membranous glomerulonephritis (MGN). We found 20 exonic and intronic substitutions in the group of 48 Czech patients. The substitution 2242A>G (p.Asn748Asp) is a candidate mutation which was identified in one patient but not in any of the 200 healthy controls. Exon 19 seems to be a variable region due to the amount of revealed polymorphisms. In this region we also found three unreported substitutions in IgAN patients, c.2351C>T (p.Ala784Val), c.2378G>A (p.Cys793Tyr) and c.2393G>A (p.Gly798Asp). These substitutions were not found in any tested healthy controls. To conclude, the ACTN4 mutations are not a frequent cause of FSGS/MCD in Czech adult patients. One new ACTN4 mutation has been identified.","variants":[{"Name":"NM_004924.6(ACTN4):c.2351C>T (p.Ala784Val)","Chromosome":"19","Start":"38727959","Stop":"38727959","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1451676,"rule_based_match":true,"evidence_text":"c.2351C>T (p.Ala784Val)","llm_judgment":"PRESENT","evidence":"c.2351C>T (p.Ala784Val)","abstract_start":1185,"abstract_end":1208}]}
{"pmid":"35395622","title":"Generation of the integration-free induced pluripotent stem cell line (FHUSTCi001-A) from a patient with glomerulopathy with fibronectin deposits harboring FN1 mutation.","abstract":"Glomerulopathy with fibronectin deposits (GFND) is an autosomal dominant kidney disease exhibiting microscopic hematuria, proteinuria, and hypertension that may lead to end-stage renal failure. In this study, using non-integrative episomal vectors an induced pluripotent stem cell (iPSC) line, FHUSTCi001-A, was derived from peripheral blood mononuclear cells of an 11-year-old boy with GFND carrying a heterozygous c.5602G > A (p.V1868M) mutation in the FN1 gene. The generated iPSC line has a normal karyotype, expresses pluripotency markers, and has the capacity to form all three germ layers in vivo. This iPSC line offers a useful cellular model to study the pathogenesis of GFND disease.","variants":[{"Name":"NM_212482.4(FN1):c.5602G>A (p.Val1868Met)","Chromosome":"2","Start":"215379150","Stop":"215379150","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1041050,"rule_based_match":true,"evidence_text":"c.5602G > A (p.V1868M)","llm_judgment":"PRESENT","evidence":"c.5602G > A (p.V1868M)","abstract_start":416,"abstract_end":438}]}
{"pmid":"24382853","title":"A lethal course of hypertrophic cardiomyopathy in Noonan syndrome due to a novel germline mutation in the KRAS gene: case study.","abstract":"Noonan syndrome is a relatively common and heterogeneous genetic disorder, including congenital heart defect in more than half of the cases. If the defect is not large, life expectancy is normal. Here we report on a case of an infant with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy with lethal outcome, in whom we identified a novel mutation in the KRAS gene. This heterozygous unclassified missense variant in exon 3: c.179G> T (p.Gly60Val) might be associated with a lethal form of Noonan syndrome. The malignant clinical course of the disease and the lethal outcome in an infant only a few months old might be connected to RAS-mitogen-activated protein kinase pathway hyperactivation, consequently promoting cell growth and proliferation, leading to rapidly progressive hypertrophic cardiomyopathy. Further biochemical and functional studies are needed to confirm this hypothesis.","variants":[{"Name":"NM_004985.5(KRAS):c.179G>T (p.Gly60Val)","Chromosome":"12","Start":"25227345","Stop":"25227345","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":175855,"rule_based_match":true,"evidence_text":"c.179G> T (p.Gly60Val)","llm_judgment":"PRESENT","evidence":"c.179G> T (p.Gly60Val)","abstract_start":444,"abstract_end":466}]}
{"pmid":"21910239","title":"Madelung deformity in a girl with a novel and de novo mutation in the GNAS gene.","abstract":"Madelung deformity, a congenital anomaly of the wrist with subluxation of the ulna head, is not a widely recognized feature of Albright hereditary osteodystrophy. Here, we describe a young female with a bilateral Madelung deformity, mild cognitive disability, some dysmorphic facial features, and a type E-like brachydactyly, in whom we identified a novel and de novo mutation (c.476T>C; p.Val159Ala) in exon 6 of the GNAS gene.","variants":[{"Name":"NM_000516.7(GNAS):c.476T>C (p.Val159Ala)","Chromosome":"20","Start":"58905426","Stop":"58905426","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3536481,"rule_based_match":true,"evidence_text":"c.476T>C; p.Val159Ala","llm_judgment":"PRESENT","evidence":"c.476T>C; p.Val159Ala","abstract_start":378,"abstract_end":399}]}
{"pmid":"38613168","title":"Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant.","abstract":"Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café-au-lait macules, feeding difficulties, mild dysmorphic features, psychomotor delay, autism spectrum disorder, thrombocytopenia, hepatosplenomegaly, and recurrent hypertransaminasemia. The identified variant affects an evolutionarily conserved residue located in the RING finger domain, a known mutational hot spot of both germline and somatic mutations. Functional studies documented enhanced EGF-induced ERK phosphorylation in transiently transfected COS1 cells. The present findings further support the association of pathogenic CBL variants with immunological and hematological manifestations in the context of a presentation with only minor findings reminiscent of NS or a clinically related RASopathy.","variants":[{"Name":"NM_005188.4(CBL):c.1202G>T (p.Cys401Phe)","Chromosome":"11","Start":"119278272","Stop":"119278272","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":639805,"rule_based_match":true,"evidence_text":"c.1202G>T; p.Cys401Phe","llm_judgment":"PRESENT","evidence":"c.1202G>T; p.Cys401Phe","abstract_start":660,"abstract_end":682}]}
{"pmid":"27039803","title":"BRCA1 Gene Mutation Screening for the Hereditary Breast and/or Ovarian Cancer Syndrome in Breast Cancer Cases: a First High Resolution DNA Melting Analysis in Indonesia.","abstract":"Specific patterns of the hereditary breast and ovarian cancer (HBOC) syndrome are related to mutations in the BRCA1 gene. One hundred unrelated breast cancer patients were interviewed to obtain clinical symptoms and signs, pedigree and familial history of HBOC syndrome related cancer. Subsequently, data were calculated using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk prediction model. Patients with high score of BOADICEA were offered genetic testing. Eleven patients with high score of BOADICEA, 2 patients with low score of BOADICEA, 2 patient's family members and 15 controls underwent BRCA1 genetic testing. Mutation screening using PCR-HRM was carried out in 22 exons (41 amplicons) of BRCA1 gene. Sanger sequencing was subjected in all samples with aberrant graph. This study identified 10 variants in the BRCA1 gene, consisting of 6 missense mutations (c.1480C>A, c.2612C>T, c.2566T>C, c.3113A>G, c.3548 A>G, c.4837 A>G), 3 synonymous mutations (c.2082 C> T, c.2311 T> C and c.4308T>C) and one intronic mutation (c.134+35 G>T). All variants tend to be polymorphisms and unclassified variants. However, no known pathogenic mutations were found.","variants":[{"Name":"NM_007294.4(BRCA1):c.1480C>A (p.Gln494Lys)","Chromosome":"17","Start":"43094051","Stop":"43094051","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2753409,"rule_based_match":true,"evidence_text":"c.1480C>A","llm_judgment":"PRESENT","evidence":"c.1480C>A","abstract_start":922,"abstract_end":931}]}
{"pmid":"31446751","title":"The Prevalence of Fabry Disease Among Turkish Patients with Non-Obstructive Hypertrophic Cardiomyopathy: Insights from a Screening Study","abstract":"Aims: Fabry disease is an X-linked lysosomal storage disorder due to a deficiency of the α-galactosidase A enzyme. Cardiac involvement is present in over 60% of adult cases of Fabry disease. Hypertrophic cardiomyopathy without left ventricular outflow tract obstruction is the most common phenotype. The aim of the study was to screen adult patients with hypertrophic cardiomyopathy without left ventricular outflow tract.\nMethods: A total of 80 patients between the ages of 18 and 65 years old, were referred to a tertiary center for trans-thoracic echocardiography for various clinical indications. They were investigated for the presence of idiopathic left ventricular hypertrophy without resting or dynamic left ventricular outflow tract obstruction. Plasma α-galactosidase A enzyme activity and α-galactosidase GLA gene mutations were investigated.\nResults: The mean age was 41.5±12.7 years and 66.25% of patients were males. The mean echocardiographic parameters were as follows: left ventricular ejection fraction 60.7±7.4%, interventricular septum thickness 18.2±4.4 mm, left ventricular posterior wall 13.5±2.1 mm, left ventricular end-diastolic diameter 47.4±6.2 mm, left ventricular end-systolic diameter 27.8±6.5 mm, and left ventricular mass index 171.05±48.5 g/m². Hemizygous mutations associated with Fabry disease were detected in two male patients (2.50% of the screened population): NM_000169.2:c.334C>T(p.Arg112Cys), NM_000169.2:c.902G>A(p.Arg301Gln).\nConclusion: Fabry disease should be considered in the differential diagnosis in a highly selected patient population with unexplained left ventricular hypertrophy. The cardiologist may play an important role in the screening and diagnosis of the disease.","variants":[{"Name":"NM_000169.3(GLA):c.334C>T (p.Arg112Cys)","Chromosome":"X","Start":"101403846","Stop":"101403846","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38452,"rule_based_match":true,"evidence_text":"NM_000169.2:c.334C>T(p.Arg112Cys)","llm_judgment":"PRESENT","evidence":"NM_000169.2:c.334C>T(p.Arg112Cys)","abstract_start":1401,"abstract_end":1434}]}
{"pmid":"25956449","title":"Aromatic L-amino acid decarboxylase deficiency diagnosed by clinical metabolomic profiling of plasma.","abstract":"Aromatic L-amino acid decarboxylase (AADC) deficiency is an inborn error of metabolism affecting the biosynthesis of serotonin, dopamine, and catecholamines. We report a case of AADC deficiency that was detected using the Global MAPS platform. This is a novel platform that allows for parallel clinical testing of hundreds of metabolites in a single plasma specimen. It uses a state-of-the-art mass spectrometry platform, and the resulting spectra are compared against a library of ~2500 metabolites. Our patient is now a 4 year old boy initially seen at 11 months of age for developmental delay and hypotonia. Multiple tests had not yielded a diagnosis until exome sequencing revealed compound heterozygous variants of uncertain significance (VUS), c.286G>A (p.G96R) and c.260C>T (p.P87L) in the DDC gene, causal for AADC deficiency. CSF neurotransmitter analysis confirmed the diagnosis with elevated 3-methoxytyrosine (3-O-methyldopa). Metabolomic profiling was performed on plasma and revealed marked elevation in 3-methoxytyrosine (Z-score +6.1) consistent with the diagnosis of AADC deficiency. These results demonstrate that the Global MAPS platform is able to diagnose AADC deficiency from plasma. In summary, we report a novel and less invasive approach to diagnose AADC deficiency using plasma metabolomic profiling.","variants":[{"Name":"NM_001082971.2(DDC):c.286G>A (p.Gly96Arg)","Chromosome":"7","Start":"50539944","Stop":"50539944","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":961779,"rule_based_match":true,"evidence_text":"c.286G>A (p.G96R)","llm_judgment":"PRESENT","evidence":"c.286G>A (p.G96R)","abstract_start":750,"abstract_end":767}]}
{"pmid":"34904718","title":"Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis.","abstract":"Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3<sup>C57Y</sup> expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3<sup>C57Y</sup> in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3<sup>C57Y</sup> expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3<sup>C57Y</sup> has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.","variants":[{"Name":"NM_005313.5(PDIA3):c.170G>A (p.Cys57Tyr)","Chromosome":"15","Start":"43753826","Stop":"43753826","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":485864,"rule_based_match":true,"evidence_text":"c.170G>A (p.Cys57Tyr or C57Y)","llm_judgment":"PRESENT","evidence":"c.170G>A (p.Cys57Tyr or C57Y)","abstract_start":161,"abstract_end":190}]}
{"pmid":"24366529","title":"Myotonia in DNM2-related centronuclear myopathy.","abstract":"Centronuclear myopathy (CNM) is a rare hereditary myopathy characterized by centrally located muscle fiber nuclei. Mutations in the dynamin 2 (DNM2) gene are estimated to account for about 50 % of CNM cases. Electromyographic recordings in CNM may show myopathic motor unit potentials without spontaneous activity at rest. Myotonic discharges, a distinctive electrical activity caused by membrane hyperexcitability, are characteristic of certain neuromuscular disorders. Such activity has been reported in only one CNM case without a known genetic cause. We sequenced the DNM2 gene and the genes associated with myotonia (CLCN1, SCN4A, DMPK and ZNF9) in a sporadic adult patient with CNM and myotonic discharges. Sequencing the entire coding region and exon-intron boundaries revealed a heterozygous c.1106g-a substitution in exon 8, resulting in a R369Q change in the DNM2. Sequencing the CLCN1, SCN4A, DMPK and ZNF9 genes ruled out mutations in these genes. This is the first report of DNM2-related CNM presenting with myotonia. The diagnosis of CNM should be considered in patients with myotonic discharges of an unknown cause.","variants":[{"Name":"NM_001005361.3(DNM2):c.1106G>A (p.Arg369Gln)","Chromosome":"19","Start":"10793833","Stop":"10793833","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22318,"rule_based_match":false,"evidence_text":"c.1106g-a","llm_judgment":"PRESENT","evidence":"c.1106g-a","abstract_start":800,"abstract_end":809}]}
{"pmid":"32668217","title":"The Genetic Landscape and Epidemiology of Phenylketonuria.","abstract":"Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.","variants":[{"Name":"NM_000277.3(PAH):c.1241A>G (p.Tyr414Cys)","Chromosome":"12","Start":"102840474","Stop":"102840474","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":15632,"rule_based_match":true,"evidence_text":"c.1241A>G (p.Tyr414Cys)","llm_judgment":"PRESENT","evidence":"c.1241A>G (p.Tyr414Cys)","abstract_start":764,"abstract_end":787}]}
{"pmid":"26481238","title":"A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population.","abstract":"The mutation spectrum for the phenylalanine hydroxylase (PAH) gene was investigated in a cohort of 84 hyperphenylalaninemia (HPA) patients from Romania identified through newborn screening or neurometabolic investigations. Differential diagnosis identified 81 patients with classic PAH deficiency while 3 had tetrahydropterin-cofactor deficiency and/or remained uncertain due to insufficient specimen. PAH-genetic analysis included a combination of Sanger sequencing of exons and exon–intron boundaries, MLPA and NGS with genomic DNA, and cDNA analysis from immortalized lymphoblasts. A diagnostic efficiency of 99.4% was achieved, as for one allele (out of a total of 162 alleles) no mutation could be identified. The most prevalent mutation was p.Arg408Trp which was found in ~ 38% of all PKU alleles. Three novel mutations were identified, including the two missense mutations p.Gln226Lys and p.Tyr268Cys that were both disease causing by prediction algorithms, and the large genomic deletion EX6del7831 (c.509 + 4140_706 + 510del7831) that resulted in skipping of exon 6 based on PAH-cDNA analysis in immortalized lymphocytes. The genomic deletion was present in a heterozygous state in 12 patients, i.e. in ~ 8% of all the analyzed PKU alleles, and might have originated from a Romanian founder.","variants":[{"Name":"NM_000277.3(PAH):c.1222C>T (p.Arg408Trp)","Chromosome":"12","Start":"102840493","Stop":"102840493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15616,"rule_based_match":false,"evidence_text":"p.Arg408Trp","llm_judgment":"PRESENT","evidence":"p.Arg408Trp","abstract_start":747,"abstract_end":758},{"Name":"NM_000277.3(PAH):c.676C>A (p.Gln226Lys)","Chromosome":"12","Start":"102855166","Stop":"102855166","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":920577,"rule_based_match":false,"evidence_text":"c.676C>A (p.Gln226Lys)","llm_judgment":"PRESENT","evidence":"p.Gln226Lys","abstract_start":880,"abstract_end":891},{"Name":"NM_000277.3(PAH):c.803A>G (p.Tyr268Cys)","Chromosome":"12","Start":"102852854","Stop":"102852854","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":610550,"rule_based_match":false,"evidence_text":"p.Tyr268Cys","llm_judgment":"PRESENT","evidence":"p.Tyr268Cys","abstract_start":896,"abstract_end":907}]}
{"pmid":"28132690","title":"Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome.","abstract":"EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.","variants":[{"Name":"NM_001440.4(EXTL3):c.1970A>G (p.Asn657Ser)","Chromosome":"8","Start":"28718029","Stop":"28718029","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":404696,"rule_based_match":true,"evidence_text":"c.1970A>G","llm_judgment":"PRESENT","evidence":"c.1970A>G","abstract_start":261,"abstract_end":270},{"Name":"NM_001440.4(EXTL3):c.1382C>T (p.Pro461Leu)","Chromosome":"8","Start":"28717441","Stop":"28717441","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":404695,"rule_based_match":true,"evidence_text":"c.1382C>T (p.Pro461Leu)","llm_judgment":"PRESENT","evidence":"c.1382C>T (p.Pro461Leu)","abstract_start":415,"abstract_end":438}]}
{"pmid":"25122112","title":"Succinic Semialdehyde Dehydrogenase Deficiency in a Chinese Boy: A Novel ALDH5A1 Mutation With Severe Phenotype.","abstract":"Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessive disorder affecting catabolism of the neurotransmitter gamma-aminobutyric acid (GABA), with a wide range of clinical phenotype. We report a Malaysian Chinese boy with a severe early onset phenotype due to a previously unreported mutation. Urine organic acid chromatogram revealed elevated 4-hydroxybutyric acid. Magnetic resonance imaging (MRI) of the brain demonstrated cerebral atrophy with atypical putaminal involvement. Molecular genetic analysis showed a novel homozygous 3-bp deletion at the ALDH5A1 gene c.1501_1503del (p.Glu501del). Both parents were confirmed to be heterozygotes for the p.Glu501del mutation. The clinical course was complicated by the development of subdural hemorrhage probably as a result of rocking the child to sleep for erratic sleep-wake cycles. This case illustrates the need to recognize that trivial or unintentional shaking of such children, especially in the presence of cerebral atrophy, can lead to subdural hemorrhage.","variants":[{"Name":"NM_001080.3(ALDH5A1):c.1501_1503del (p.Glu501del)","Chromosome":"6","Start":"24533604","Stop":"24533606","ReferenceAlleleVCF":"TGGA","AlternateAlleleVCF":"T","allel_id":1935255,"rule_based_match":true,"evidence_text":"c.1501_1503del (p.Glu501del)","llm_judgment":"PRESENT","evidence":"c.1501_1503del (p.Glu501del)","abstract_start":588,"abstract_end":616}]}
{"pmid":"30025162","title":"Sarcomeric disorganization and nemaline bodies in muscle biopsies of patients with EXOSC3-related type 1 pontocerebellar hypoplasia.","abstract":"INTRODUCTION: Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay, and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date, no distinct features have been identified.\nMETHODS: Clinical data and muscle biopsy findings of 3 unrelated patients with EXOSC3 mutations are described.\nRESULTS: All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harboring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening, and small nemaline bodies.\nCONCLUSIONS: In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. Muscle Nerve 59:137-141, 2019.","variants":[{"Name":"NM_016042.4(EXOSC3):c.92G>C (p.Gly31Ala)","Chromosome":"9","Start":"37784953","Stop":"37784953","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":40351,"rule_based_match":true,"evidence_text":"c.92G>C (p.Gly31Ala)","llm_judgment":"PRESENT","evidence":"p.Gly31Ala","abstract_start":672,"abstract_end":682}]}
{"pmid":"35023948","title":"Novel Compound Heterozygous Variants in the","abstract":"BACKGROUND: Meier-Gorlin syndrome (MGS) is a rare genetic syndrome inherited in an autosomal dominant or autosomal recessive manner. The disorder is characterized by bilateral microtia, absence or hypoplasia of the patella, and an intrauterine growth retardation as well as a number of other characteristic features. The cause of the disease is mutations in genes encoding proteins involved in the regulation of the cell cycle (<i>ORC1, ORC4, ORC6, CDT1, CDC6, GMNN, CDC45L, MCM3, MCM5, MCM7, GINS2</i>, and <i>DONSON</i>). Meier-Gorlin syndrome 5 due to mutations in the <i>CDC6</i> gene is difficult to diagnose, and few clinical data have been described to date. Only one patient (male) with a missense mutation in a homozygous state has been previously reported. This report describes a new clinical case of Meier-Gorlin syndrome 5. This is also the first report of a Russian patient with Meier-Gorlin syndrome.\nCASE PRESENTATION: The patient, a female, had extremely low physical development, neonatal progeroid appearance, lipodystrophy, thin skin, partial alopecia, cyanosis of the face, triangular face, microgenia, arachnodactyly, delayed bone age, hepatomegaly, hypoplasia of the labia majora, and hypertrophy of the clitoris in addition to known clinical signs. Differential diagnosis was performed with chromosomal abnormalities and Hutchinson-Gilford progeria. According to the results of sequencing of the clinical exome, the patient had two previously undescribed variants in the <i>CDC6</i> gene, c.230A>G (p.(Lys77Arg)) and c.232C>T (p.(Gln78Ter)), NM_001254.3, in a compound heterozygous state.\nCONCLUSION: This case allows us to learn more about the clinical features and nature of MGS 5 and improve the speed of diagnostics and quality of genetic counseling for such families.","variants":[{"Name":"NM_001254.4(CDC6):c.230A>G (p.Lys77Arg)","Chromosome":"17","Start":"40291109","Stop":"40291109","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3732932,"rule_based_match":true,"evidence_text":"c.230A>G (p.(Lys77Arg))","llm_judgment":"PRESENT","evidence":"c.230A>G (p.(Lys77Arg))","abstract_start":1513,"abstract_end":1536},{"Name":"NM_001254.4(CDC6):c.232C>T (p.Gln78Ter)","Chromosome":"17","Start":"40291111","Stop":"40291111","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3732933,"rule_based_match":true,"evidence_text":"c.232C>T (p.(Gln78Ter))","llm_judgment":"PRESENT","evidence":"c.232C>T (p.(Gln78Ter))","abstract_start":1541,"abstract_end":1564}]}
{"pmid":"25181484","title":"Genetic diagnosis of two dopa-responsive dystonia families by exome sequencing.","abstract":"Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.","variants":[{"Name":"NM_000161.3(GCH1):c.631_632del (p.Met211fs)","Chromosome":"14","Start":"54844138","Stop":"54844139","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":260057,"rule_based_match":true,"evidence_text":"NM_000161.2: c.631_632delAT, p.Met211ValfsX38","llm_judgment":"PRESENT","evidence":"NM_000161.2: c.631_632delAT, p.Met211ValfsX38","abstract_start":489,"abstract_end":534},{"Name":"NM_000360.4(TH):c.1358G>A (p.Arg453His)","Chromosome":"11","Start":"2164369","Stop":"2164369","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":796546,"rule_based_match":true,"evidence_text":"NM_000360.3: c.1358G>A, p.Arg453His","llm_judgment":"PRESENT","evidence":"NM_000360.3: c.1358G>A, p.Arg453His","abstract_start":698,"abstract_end":733}]}
{"pmid":"27247958","title":"Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families.","abstract":"BACKGROUND: Autosomal recessive distal renal tubular acidosis (dRTA) is a rare disease characterized by a hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis, and conserved glomerular filtration rate. In some cases, neurosensorial deafness is associated. dRTA is developed during the first months of life and the main manifestations are failure to thrive, vomiting, dehydration, and anorexia.\nMETHODS: Nine unrelated families were studied: seven children, a teenager, and an adult with dRTA. Hearing was preserved in four children. Coding regions of the genes responsible for recessive dRTA were analysed by Sanger sequencing.\nRESULTS: Molecular defects were found in the genes ATP6V1B1 and ATP6V0A4. We identified three homozygous variants in ATP6V1B: a frameshift mutation (p.Ile386Hisfs*56), a nucleotide substitution in exon 10 (p.Pro346Arg), and a new splicing mutation in intron 5. Three patients were homozygous for one novel (p.Arg743Trp) and one known (p.Asp411Tyr) missense mutations in the ATP6V0A4 gene. Three patients were compound heterozygous: one proband displayed two novel mutations, the frameshift mutation p.Val52Metfs*25, and a large deletion of exons 18-21; two probands showed the missense mutation p.Asp411Tyr and as a second mutation, p.Arg194Ter and c.1691+2dup, respectively.\nCONCLUSION: ATP6V0A4 and ATP6V1B1 genes were involved in recessive dRTA of Mexican families. All ATP6V1B1 mutations detected were homozygous and all patients developed sensorineural hearing loss (SNHL) early in infancy. ATP6V0A4 mutations were found in one infant and three children without SNHL, and in one teenager and one adult with SNHL confirming the phenotypic variability in this trait. The mutation p.Asp411Tyr detected in four Mexican families was due to a founder effect. Screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA in this population.","variants":[{"Name":"NM_020632.3(ATP6V0A4):c.1231G>T (p.Asp411Tyr)","Chromosome":"7","Start":"138747514","Stop":"138747514","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":369507,"rule_based_match":false,"evidence_text":"p.Asp411Tyr","llm_judgment":"PRESENT","evidence":"p.Asp411Tyr","abstract_start":1029,"abstract_end":1040},{"Name":"NM_001692.4(ATP6V1B1):c.1037C>G (p.Pro346Arg)","Chromosome":"2","Start":"70963289","Stop":"70963289","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":264108,"rule_based_match":false,"evidence_text":"p.Pro346Arg","llm_judgment":"PRESENT","evidence":"p.Pro346Arg","abstract_start":900,"abstract_end":911}]}
{"pmid":"31535215","title":"Rare variants in FANCA induce premature ovarian insufficiency.","abstract":"Premature ovarian insufficiency (POI) is a major cause of reduced female fertility and affects approximately 1% women under 40 years of age. Recent advances emphasize the genetic heterogeneity of POI. Fanconi anemia (FA) genes, traditionally known for their essential roles in DNA repair and cytogenetic instability, have been demonstrated to be involved in meiosis and germ cell development. Here, we conducted whole-exome sequencing (WES) in 50 Han Chinese female patients with POI. Rare missense variants were identified in FANCA (Fanconi anemia complementation group A): c.1772G > A (p.R591Q) and c.3887A > G (p.E1296G). Both variants are heterozygous in the patients and very rare in the human population. In vitro functional studies further demonstrated that these two missense variants of FANCA exhibited reduced protein expression levels compared with the wild type, suggesting the partial loss of function. Moreover, mono-ubiquitination levels of FANCD2 upon mitomycin C stimulation were significantly reduced in cells overexpressing FANCA variants. Furthermore, a loss-of-function mutation of Fanca was generated in C57BL/6 mice for in vivo functional assay. Consistently, heterozygous mutated female mice (Fanca<sup>+/-</sup>) showed reduced fertility and declined numbers of follicles with aging when compared with the wild-type female mice. Collectively, our results suggest that heterozygous pathogenic variants in FANCA are implicated in non-syndromic POI in Han Chinese women, provide new insights into the molecular mechanisms of POI and highlight the contribution of FANCA variants in female subfertility.","variants":[{"Name":"NM_000135.4(FANCA):c.3887A>G (p.Glu1296Gly)","Chromosome":"16","Start":"89740041","Stop":"89740041","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3494651,"rule_based_match":true,"evidence_text":"c.3887A > G (p.E1296G)","llm_judgment":"PRESENT","evidence":"c.3887A > G (p.E1296G)","abstract_start":601,"abstract_end":623}]}
{"pmid":"23033317","title":"Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome.","abstract":"Mutations in the gene encoding the iron-sulfur-containing DNA helicase DDX11 (ChlR1) were recently identified as a cause of a new recessive cohesinopathy, Warsaw breakage syndrome (WABS), in a single patient with severe microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Here, using homozygosity mapping in a Lebanese consanguineous family followed by exome sequencing, we identified a novel homozygous mutation (c.788G>A [p.R263Q]) in DDX11 in three affected siblings with severe intellectual disability and many of the congenital abnormalities reported in the WABS original case. Cultured lymphocytes from the patients showed increased mitomycin C-induced chromosomal breakage, as found in WABS. Biochemical studies of purified recombinant DDX11 indicated that the p.R263Q mutation impaired DDX11 helicase activity by perturbing its DNA binding and DNA-dependent ATP hydrolysis. Our findings thus confirm the involvement of DDX11 in WABS, describe its phenotypical spectrum, and provide novel insight into the structural requirement for DDX11 activity.","variants":[{"Name":"NM_030653.4(DDX11):c.788G>A (p.Arg263Gln)","Chromosome":"12","Start":"31089147","Stop":"31089147","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48508,"rule_based_match":true,"evidence_text":"c.788G>A (p.R263Q)","llm_judgment":"PRESENT","evidence":"c.788G>A","abstract_start":447,"abstract_end":455}]}
{"pmid":"34258137","title":"Human d-lactate dehydrogenase deficiency by","abstract":"BACKGROUND: d-lactate, one of the isomers of lactate, exists in a low concentration in healthy individuals and it can be oxidized to pyruvate catalyzed by d-lactate dehydrogenase. Excessive amount of d-lactate causes d-lactate acidosis associated with neurological manifestations.\nMETHODS AND RESULTS: We report here a patient with developmental delay, cerebellar ataxia, and transient hepatomegaly. Enzyme analysis in the patient's skin fibroblast showed decreased mitochondrial complex IV activity. Using whole exome sequencing, we identified compound heterozygous variants in the <i>LDHD</i> gene, which encodes the d-lactate dehydrogenase, consisting of a splice site variant c.469+1dupG and a missense variant c.752C>T, p.(Thr251Met) which are pathogenic and likely pathogenic respectively according to the American College of Medical Genetics and Genomics (ACMG) classification. The serum d-lactate level was subsequently detected to be elevated (0.61 mmol/L, reference value: 0-0.25 mmol/L).\nCONCLUSION: This is the third report on <i>LDHD</i> mutations associated with d-lactate elevation and was first reported to have decreased mitochondrial complex IV activity. The study provides more information on this rare metabolic condition but the association of <i>LDHD</i> deficiency with the clinical presentations requires further investigations.","variants":[{"Name":"NM_194436.3(LDHD):c.469+1dup","Chromosome":"16","Start":"75114825","Stop":"75114826","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":3540377,"rule_based_match":true,"evidence_text":"c.469+1dupG","llm_judgment":"PRESENT","evidence":"c.469+1dupG","abstract_start":680,"abstract_end":691}]}
{"pmid":"34194850","title":"Lack of Catch-Up Growth with Growth Hormone Treatment in a Child Born Small for Gestational Age Leading to a Diagnosis of Noonan Syndrome with a Pathogenic","abstract":"BACKGROUND: Growth hormone (GH) treatment increases the adult height of short children born small for gestational age (SGA). Catch-up growth is associated with a younger age, shorter height, and prepubertal status at the onset of GH treatment. We report a 12 11/12-year-old girl born SGA who received GH for 5 years without catch-up growth and was diagnosed with Noonan Syndrome (NS).\nRESULTS: A 5-year-and-9-month-old 46, XX girl born SGA was started on GH treatment at a dose of 0.32 mg/kg/week. Her midparental target height is 158.6 cm. Endocrine work up showed an IGF-1 level 69 ng/ml (Normal (N): 55-238 ng/ml), IGFBP3 2.6 mg/L (N: 1.9-5.2 mg/L), TSH 3.2 mIU/L (N: 0.35-5.5 mIU/L), and a normal skeletal survey. Height was 96 cm (0.1%; Ht SDS -2.9), weight 14 kgs (1%; Wt SDS -2.3), and Tanner 1 breast and pubic hair were observed. Due to the poor catch-up growth on GH treatment, she was referred to Genetics to elucidate genetic or syndromic causes of short stature. She was noted to have posteriorly rotated ears and slight down slanting of the palpebral fissures. Genetic findings showed a heterozygous pathogenic variant in <i>PTPN11</i> (c.922A > G (p.Asn308Asp)) diagnostic for NS. This finding is de novo given negative parental testing. She was noted to have a heterozygous missense variant of unknown significance (VUS) in <i>FGFR3</i>: c.746C > A (p.Ser249Tyr). <i>FGFR3</i> is associated with multiple skeletal dysplasias including thanatophoric dysplasia, achondroplasia, and Crouzon syndrome and hypochondroplasia. Clinical correlation is poor for these syndromes.\nCONCLUSION: Diminished catch-up growth and response to GH treatment in a child born SGA led to the diagnosis of NS. The concomitant diagnosis of SGA and NS may have affected the responsiveness of this child to the growth promoting effect of GH treatment.","variants":[{"Name":"NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp)","Chromosome":"12","Start":"112477719","Stop":"112477719","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28365,"rule_based_match":true,"evidence_text":"c.922A > G (p.Asn308Asp)","llm_judgment":"PRESENT","evidence":"c.922A > G (p.Asn308Asp)","abstract_start":1151,"abstract_end":1175}]}
{"pmid":"23836506","title":"Mutations in γ adducin are associated with inherited cerebral palsy.","abstract":"OBJECTIVE: Cerebral palsy is estimated to affect nearly 1 in 500 children, and although prenatal and perinatal contributors have been well characterized, at least 20% of cases are believed to be inherited. Previous studies have identified mutations in the actin-capping protein KANK1 and the adaptor protein-4 complex in forms of inherited cerebral palsy, suggesting a role for components of the dynamic cytoskeleton in the genesis of the disease.\nMETHODS: We studied a multiplex consanguineous Jordanian family by homozygosity mapping and exome sequencing, then used patient-derived fibroblasts to examine functional consequences of the mutation we identified in vitro. We subsequently studied the effects of adducin loss of function in Drosophila.\nRESULTS: We identified a homozygous c.1100G>A (p.G367D) mutation in ADD3, encoding gamma adducin in all affected members of the index family. Follow-up experiments in patient fibroblasts found that the p.G367D mutation, which occurs within the putative oligomerization critical region, impairs the ability of gamma adducin to associate with the alpha subunit. This mutation impairs the normal actin-capping function of adducin, leading to both abnormal proliferation and migration in cultured patient fibroblasts. Loss of function studies of the Drosophila adducin ortholog hts confirmed a critical role for adducin in locomotion.\nINTERPRETATION: Although likely a rare cause of cerebral palsy, our findings indicate a critical role for adducins in regulating the activity of the actin cytoskeleton, suggesting that impaired adducin function may lead to neuromotor impairment and further implicating abnormalities of the dynamic cytoskeleton as a pathogenic mechanism contributing to cerebral palsy.","variants":[{"Name":"NM_016824.5(ADD3):c.1100G>A (p.Gly367Asp)","Chromosome":"10","Start":"110122249","Stop":"110122249","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":243827,"rule_based_match":true,"evidence_text":"c.1100G>A (p.G367D)","llm_judgment":"PRESENT","evidence":"c.1100G>A (p.G367D)","abstract_start":786,"abstract_end":805}]}
{"pmid":"25193411","title":"Extremely severe complicated spastic paraplegia 3A with neonatal onset.","abstract":"BACKGROUND: Spastic paraplegia 3A typically manifests in childhood as an uncomplicated form of hereditary spastic paraplegia with slow progression. Most affected individuals present with spasticity and weakness in the legs before the end of the first decade.\nPATIENT: We describe a 12-year-old boy with neonatal onset of extremely severe complicated spastic paraplegia 3A associated with a de novo c.1226G>A (p.G409D) mutation in ATL1, a gene which encodes atlatsin GTPase 1. He manifested general hypertonia and hypokinesia since the neonatal period and was initially diagnosed with cerebral palsy. He was never able to move without assistance because of severe spastic quadriplegia with distal dominant muscle weakness. He also developed with pseudobulbar palsy; his speech, chewing, and swallowing were severely impaired. Electrophysiological studies revealed severe diffuse axonal neuropathy.\nCONCLUSIONS: Extremely severe complicated spastic paraplegia 3A can be caused by mutations in the linker or three-helix bundle of atlastin 1.","variants":[{"Name":"NM_015915.5(ATL1):c.1226G>A (p.Gly409Asp)","Chromosome":"14","Start":"50628137","Stop":"50628137","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":860108,"rule_based_match":true,"evidence_text":"c.1226G>A (p.G409D)","llm_judgment":"PRESENT","evidence":"c.1226G>A (p.G409D)","abstract_start":398,"abstract_end":417}]}
{"pmid":"24706814","title":"Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.","abstract":"Polycystic livers are seen in the rare inherited disorder isolated polycystic liver disease (PCLD) and are recognized as the most common extrarenal manifestation in autosomal dominant polycystic kidney disease. Hepatic cystogenesis is characterized by progressive proliferation of cholangiocytes, ultimately causing hepatomegaly. Genetically, polycystic liver disease is a heterogeneous disorder with incomplete penetrance and caused by mutations in PRKCSH, SEC63, PKD1, or PKD2. Genome-wide SNP typing and Sanger sequencing revealed no pathogenic variants in hitherto genes in an extended PCLD family. We performed whole-exome sequencing of DNA samples from two members. A heterozygous variant c.3562C > T located at a highly conserved amino acid position (p.R1188W) in the low density lipoprotein receptor-related protein 5 (LRP5) gene segregated with the disease (logarithm of odds score, 4.62) but was not observed in more than 1,000 unaffected individuals. Screening of LRP5 in a PCLD cohort identified three additional mutations in three unrelated families with polycystic livers (p.V454M, p.R1529S, and p.D1551N), again all undetected in controls. All variants were predicted to be damaging with profound structural effects on LRP5 protein domains. Liver cyst tissue and normal hepatic tissue samples from patients and controls showed abundant LRP5 expression by immunohistochemistry. Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation. In conclusion, we demonstrate that germ-line LRP5 missense mutations are associated with hepatic cystogenesis. The findings presented in this study link the pathophysiology of PCLD to deregulation of the canonical wingless signaling pathway.","variants":[{"Name":"NM_002335.4(LRP5):c.3562C>T (p.Arg1188Trp)","Chromosome":"11","Start":"68426112","Stop":"68426112","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":172094,"rule_based_match":true,"evidence_text":"c.3562C > T","llm_judgment":"PRESENT","evidence":"c.3562C > T","abstract_start":695,"abstract_end":706}]}
{"pmid":"29057985","title":"Molecular spectrum of excision repair cross-complementation group 8 gene defects in Chinese patients with Cockayne syndrome type A.","abstract":"There are two genetics complementary groups Cockayne syndrome type A and B (CS-A and CS-B OMIM 216400, 133540), which is a rare autosomal recessive segmental progeroid syndrome. Homozygous or compound heterozygous mutations in the excision repair cross-complementation group 8 gene (ERCC8) result in CS-A, and mutations in ERCC6 result in CS-B. Homozygous ERCC6/ERCC8 mutations also result in UV-sensitive syndrome. In this study, twenty-one Han Chinese patients with CS were investigated to identify mutations in ERCC8/ERCC6, of which thirteen cases with CS-A were identified with the mutations of ERCC8. There are five types mutations of ERCC8 in our study, such as exon 4 rearrangement, c.394_398delTTACA, c.299insA, c.843 + 2 T > C, and c.2 T > A. An estimated frequency of exon 4 rearrangement accounts for 69.23% and c.394_398delTTACA accounts for 11.53% in our cohort. Haplotype analysis revealed that the exon 4 rearrangement and c.394_398delTTACA mutations originated from a common founder in the Chinese population respectively. With the identification of three novel ERCC8 mutations, this study expanded the molecular spectrum of known ERCC8 defects, and furthermore, suggests that the exon 4 rearrangement and c.394_398delTTACA mutations may be a common underlying cause of CS-A in the Chinese population, which is different from that in other populations.","variants":[{"Name":"NM_000082.4(ERCC8):c.394_398del (p.Leu132fs)","Chromosome":"5","Start":"60918266","Stop":"60918270","ReferenceAlleleVCF":"TTGTAA","AlternateAlleleVCF":"T","allel_id":543879,"rule_based_match":true,"evidence_text":"c.394_398delTTACA","llm_judgment":"PRESENT","evidence":"c.394_398delTTACA","abstract_start":690,"abstract_end":707}]}
{"pmid":"23664118","title":"Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder.","abstract":"Proteoglycans are important components of cell plasma membranes and extracellular matrices of connective tissues. They consist of glycosaminoglycan chains attached to a core protein via a tetrasaccharide linkage, whereby the addition of the third residue is catalyzed by galactosyltransferase II (β3GalT6), encoded by B3GALT6. Homozygosity mapping and candidate gene sequence analysis in three independent families, presenting a severe autosomal-recessive connective tissue disorder characterized by skin fragility, delayed wound healing, joint hyperlaxity and contractures, muscle hypotonia, intellectual disability, and a spondyloepimetaphyseal dysplasia with bone fragility and severe kyphoscoliosis, identified biallelic B3GALT6 mutations, including homozygous missense mutations in family 1 (c.619G>C [p.Asp207His]) and family 3 (c.649G>A [p.Gly217Ser]) and compound heterozygous mutations in family 2 (c.323_344del [p.Ala108Glyfs(∗)163], c.619G>C [p.Asp207His]). The phenotype overlaps with several recessive Ehlers-Danlos variants and spondyloepimetaphyseal dysplasia with joint hyperlaxity. Affected individuals' fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming β3GalT6 loss of function. Dermal electron microcopy disclosed abnormalities in collagen fibril organization, in line with the important regulatory role of decorin in this process. A strong reduction in heparan sulfate level was also observed, indicating that β3GalT6 deficiency alters synthesis of both main types of glycosaminoglycans. In vitro wound healing assay revealed a significant delay in fibroblasts from two index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo. Our study emphasizes a crucial role for β3GalT6 in multiple major developmental and pathophysiological processes.","variants":[{"Name":"NM_080605.4(B3GALT6):c.619G>C (p.Asp207His)","Chromosome":"1","Start":"1232897","Stop":"1232897","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":75090,"rule_based_match":true,"evidence_text":"c.619G>C [p.Asp207His]","llm_judgment":"PRESENT","evidence":"c.619G>C [p.Asp207His]","abstract_start":797,"abstract_end":819},{"Name":"NM_080605.4(B3GALT6):c.649G>A (p.Gly217Ser)","Chromosome":"1","Start":"1232927","Stop":"1232927","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":75091,"rule_based_match":true,"evidence_text":"c.649G>A [p.Gly217Ser]","llm_judgment":"PRESENT","evidence":"c.649G>A [p.Gly217Ser]","abstract_start":835,"abstract_end":857},{"Name":"NM_080605.4(B3GALT6):c.323_344del (p.Ala108fs)","Chromosome":"1","Start":"1232595","Stop":"1232616","ReferenceAlleleVCF":"CGGCGCGCCCTGGAGCGGGAGCA","AlternateAlleleVCF":"C","allel_id":75092,"rule_based_match":true,"evidence_text":"c.323_344del","llm_judgment":"PRESENT","evidence":"c.323_344del","abstract_start":908,"abstract_end":920}]}
{"pmid":"36115989","title":"A novel nonsense variant (c.1499C>G) in CRB1 caused Leber congenital amaurosis-8 in a Chinese family and a literature review.","abstract":"BACKGROUND: Leber's congenital amaurosis (LCA) is a severe hereditary retinopathy disease that is characterized by early and severe reduction of vision, nystagmus, and sluggish or absent pupillary responses. To date, the pathogenesis of LCA remains unclear, and the majority of cases are caused by autosomal recessive inheritance. In this study, we explored the variant in the Crumbs homologue 1 (CRB1) gene in a Chinese family with LCA.\nMETHODS: We conducted comprehensive ocular examinations and collected 5 ml of blood samples from members of a Chinese family with LCA. A pathogenic variant was identified by capturing (the panel in NGS) and Sanger sequencing validation.\nRESULTS: A nonsense variant (c.1499C>G) in the 6th exon of CRB1 gene in a Chinese family with LCA was identified, which predicted a change in the protein p. S500*, may lead to loss of gene function. We summarized the 76 variants reported thus far in CRB1 that caused LCA8.\nCONCLUSIONS: This study reported a novel variant c.1499C>G (p. S500*) of the CRB1 gene occurred in a Chinese family with LCA, thus expanding the spectrum of CRB1 variants causing LCA.","variants":[{"Name":"NM_201253.3(CRB1):c.1499C>G (p.Ser500Ter)","Chromosome":"1","Start":"197421327","Stop":"197421327","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1690825,"rule_based_match":true,"evidence_text":"c.1499C>G (p. S500*)","llm_judgment":"PRESENT","evidence":"c.1499C>G (p. S500*)","abstract_start":997,"abstract_end":1017}]}
{"pmid":"18259073","title":"TMC1 but not TMC2 is responsible for autosomal recessive nonsyndromic hearing impairment in Tunisian families.","abstract":"Hereditary nonsyndromic hearing impairment (HI) is extremely heterogeneous. Mutations of the transmembrane channel-like gene 1 (TMC1) have been shown to cause autosomal dominant and recessive forms of nonsyndromic HI linked to the loci DFNA36 and DFNB7/B11, respectively. TMC1 is 1 member of a family of 8 genes encoding transmembrane proteins. In the mouse, MmTmc1 and MmTmc2 are both members of Tmc subfamily A and are highly and almost exclusively expressed in the cochlea. The restricted expression of Tmc2 in the cochlea and its close phylogenetic relationship to Tmc1 makes it a candidate gene for nonsyndromic HI. We analyzed 3 microsatellite markers linked to the TMC1 and TMC2 genes in 85 Tunisian families with autosomal recessive nonsyndromic HI and without mutations in the protein-coding region of the GJB2 gene. Autozygosity by descent analysis of 2 markers bordering the TMC2 gene allowed us to rule out its association with deafness within these families. However, 5 families were found to segregate deafness with 3 different alleles of marker D9S1837, located within the first intron of the TMC1 gene. By DNA sequencing of coding exons of TMC1 in affected individuals, we identified 3 homozygous mutations, c.100C-->T (p.R34X), c.1165C-->T (p.R389X) and the novel mutation c.1764G-->A (p.W588X). We additionally tested 60 unrelated deaf Tunisian individuals for the c.100C-->T mutation. We detected this mutation in a homozygous state in 2 cases. This study confirms that mutations in the TMC1 gene may be a common cause for autosomal recessive nonsyndromic HI.","variants":[{"Name":"NM_138691.3(TMC1):c.1764G>A (p.Trp588Ter)","Chromosome":"9","Start":"72820842","Stop":"72820842","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2844636,"rule_based_match":false,"evidence_text":"c.1764G-->A (p.W588X)","llm_judgment":"PRESENT","evidence":"c.1764G-->A (p.W588X)","abstract_start":1290,"abstract_end":1311},{"Name":"NM_138691.3(TMC1):c.1165C>T (p.Arg389Ter)","Chromosome":"9","Start":"72789258","Stop":"72789258","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":57020,"rule_based_match":false,"evidence_text":"c.1165C-->T (p.R389X)","llm_judgment":"PRESENT","evidence":"c.1165C-->T (p.R389X)","abstract_start":1245,"abstract_end":1266}]}
{"pmid":"16752391","title":"A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.","abstract":"Methylmalonic aciduria (MMA-uria) is an autosomal recessive inborn error of amino acid metabolism, involving valine, threonine, isoleucine, and methionine. This organic aciduria may present in the neonatal period with life-threatening metabolic acidosis, hyperammonemia, feeding difficulties, pancytopenia, and coma. Most affected patients have mutations in the methylmalonyl-coenzyme A (methylmalonyl-CoA) mutase gene. Mildly affected patients may present in childhood with failure to thrive and recurrent attacks of metabolic acidosis. Both a higher residual activity of methylmalonyl-CoA mutase as well as the vitamin B12-responsive defects (cblA and cblB) may form the basis of the mild disorder. A few patients with moderate MMA-uria are known in whom no defect could be identified. Here we present a 16-year-old female patient with persisting moderate MMA-uria (approximately 50 mmol/mol creatinine). She was born to consanguineous Caucasian parents. Her fibroblast mutase activity was normal and no effect of vitamin B12 supplementation could be established. Reduced incorporation of 14C-propionate into macromolecules suggested a defect in the propionate-to-succinate pathway. We found a homozygous nonsense mutation (c.139C>T) in the methylmalonyl-CoA epimerase gene (MCEE), resulting in an early terminating signal (p.R47X). Both parents were heterozygous for this mutation; they were found to excrete normal amounts of methylmalonic acid (MMA). This is the first report of methylmalonyl-CoA epimerase deficiency, thereby unequivocally demonstrating the biochemical role of this enzyme in human metabolism.","variants":[{"Name":"NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)","Chromosome":"2","Start":"71124445","Stop":"71124445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17382,"rule_based_match":true,"evidence_text":"c.139C>T","llm_judgment":"PRESENT","evidence":"c.139C>T","abstract_start":1226,"abstract_end":1234}]}
{"pmid":"20965760","title":"Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death.","abstract":"Left ventricular noncompaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses communicating with the left ventricular cavity. The purpose of this study was to investigate patients with LVNC for possible disease causing mutations. We screened 4 genes (TAZ, LDB3, DTNA and TPM1) in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in three affected members of a family with isolated LVNC. The substitution brings about a change in amino acid charge at a highly conserved residue and could result in aberrant mRNA splicing. This variant was not identified in 200 normal control samples. Pathologic analysis of a right ventricular myocardial specimen from the proband's maternal aunt revealed endocardial and subendocardial fibrosis with prominent elastin deposition, as well as the presence of adipose tissue between muscle layers, pathologic changes that are distinct from those seen in patients with HCM or DCM. Screening of the proband and her mother for variants in other sarcomeric protein-encoding candidate genes, MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3, did not identify any other non-synonymous variants or variants in splice donor-acceptor sequences that were potentially disease causing. We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death.","variants":[{"Name":"NM_001018005.2(TPM1):c.109A>G (p.Lys37Glu)","Chromosome":"15","Start":"63042938","Stop":"63042938","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":40557,"rule_based_match":true,"evidence_text":"c.109A>G: p.Lys37Glu","llm_judgment":"PRESENT","evidence":"c.109A>G: p.Lys37Glu","abstract_start":525,"abstract_end":545}]}
{"pmid":"25008109","title":"A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability.","abstract":"Complex III (cytochrome bc1) is a protein complex of the mitochondrial inner membrane that transfers electrons from ubiquinol to cytochrome c. Its assembly requires the coordinated expression of mitochondrial-encoded cytochrome b and nuclear-encoded subunits and assembly factors. Complex III deficiency is a severe multisystem disorder caused by mutations in subunit genes or assembly factors. Sequence-profile-based orthology predicts C11orf83, hereafter named UQCC3, to be the ortholog of the fungal complex III assembly factor CBP4. We describe a homozygous c.59T>A missense mutation in UQCC3 from a consanguineous patient diagnosed with isolated complex III deficiency, displaying lactic acidosis, hypoglycemia, hypotonia and delayed development without dysmorphic features. Patient fibroblasts have reduced complex III activity and lower levels of the holocomplex and its subunits than controls. They have no detectable UQCC3 protein and have lower levels of cytochrome b protein. Furthermore, in patient cells, cytochrome b is absent from a high-molecular-weight complex III. UQCC3 is reduced in cells depleted for the complex III assembly factors UQCC1 and UQCC2. Conversely, absence of UQCC3 in patient cells does not affect UQCC1 and UQCC2. This suggests that UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and UQCC2 and is consistent with what is known about the function of Cbp4 and of the fungal orthologs of UQCC1 and UQCC2, Cbp3 and Cbp6. We conclude that UQCC3 functions in complex III assembly and that the c.59T>A mutation has a causal role in complex III deficiency.","variants":[{"Name":"NM_001085372.3(UQCC3):c.59T>A (p.Val20Glu)","Chromosome":"11","Start":"62671804","Stop":"62671804","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":170964,"rule_based_match":true,"evidence_text":"c.59T>A","llm_judgment":"PRESENT","evidence":"c.59T>A","abstract_start":562,"abstract_end":569}]}
{"pmid":"19500103","title":"Acral self-healing collodion baby: report of a new clinical phenotype caused by a novel TGM1 mutation.","abstract":"A minority of collodion babies, called 'self-healing collodion babies', heal spontaneously. We describe a novel clinical phenotype of acral self-healing collodion baby caused by a new TGM1 mutation. The proband, born to healthy parents, presented at birth as a collodion baby strictly localized to the extremities. The skin condition returned to normal at the age of 3 weeks. The older sister was born as a generalized collodion baby; the condition then developed into lamellar ichthyosis. Molecular analysis of TGM1 revealed three novel mutations in the family. The proband was compound heterozygous for the p.Val359Met and p.Arg396His mutations, whereas the older sister was compound heterozygous for p.Arg396His and a deletion mutation c.1922_1926+2delGGCCTGT. Structural modelling of the p.Val359Met mutation suggested a minor disruption of the protein structure, whereas a modification of protein-protein interaction was predicted for p.Arg396His. These predictions corroborated the analysis of recombinant transglutaminase (TGase)-1 proteins carrying the p.Val359Met and p.Arg396His mutations. Both showed decreased levels of protein expression: p.Val359Met displayed residual activity (12.8%), while p.Arg396His caused a dramatic loss of activity (3.3%). These observations demonstrate for the first time that TGM1 mutations can be associated with acral self-healing collodion baby, and expand the clinical spectrum of TGase-1 deficiency.","variants":[{"Name":"NM_000359.3(TGM1):c.1075G>A (p.Val359Met)","Chromosome":"14","Start":"24259159","Stop":"24259159","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48131,"rule_based_match":false,"evidence_text":"p.Val359Met","llm_judgment":"PRESENT","evidence":"p.Val359Met","abstract_start":609,"abstract_end":620},{"Name":"NM_000359.3(TGM1):c.1187G>A (p.Arg396His)","Chromosome":"14","Start":"24258646","Stop":"24258646","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48132,"rule_based_match":false,"evidence_text":"p.Arg396His","llm_judgment":"PRESENT","evidence":"p.Arg396His","abstract_start":625,"abstract_end":636}]}
{"pmid":"32759993","title":"New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin.","abstract":"Biallelic variants in the USP53 gene have recently been reported to segregate with normal gamma glutamyltransferase (GGT) cholestasis. Using whole-exome sequencing (WES), we detected two USP53 homozygous variants (c.951delT; p. Phe317fs and c.1744C>T; p. Arg582*) in five additional cases, including an unpublished cousin of a previously described family with intractable itching and normal GGT cholestasis. Three patients, a child and two adults, presented with recurrent episodes of normal GGT cholestasis, consistent with a diagnosis of benign recurrent intrahepatic cholestasis (BRIC). Cholangiopathic changes, possibly autoimmune in origin, were recognized in some patients. Additional phenotypic details in one patient included an enlarged left kidney, and speech/developmental delay. Notably, two patients exhibited a complete response to rifampicin, and one responded to ursodeoxycholic acid (UDCA). Two adult patients were suspected to have autoimmune liver disease and treated with steroids. This report describes new cases of USP53 disease presenting with normal GGT cholestasis or BRIC in three children and two adults. We also describe the novel finding of a dramatic response to rifampicin. The association of cholangiopathy with normal GGT cholestasis provides a diagnostic challenge and remains poorly understood.","variants":[{"Name":"NM_001371395.1(USP53):c.1744C>T (p.Arg582Ter)","Chromosome":"4","Start":"119271604","Stop":"119271604","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2736954,"rule_based_match":true,"evidence_text":"c.1744C>T (p. Arg582*)","llm_judgment":"PRESENT","evidence":"p. Arg582*","abstract_start":252,"abstract_end":262}]}
{"pmid":"26290468","title":"A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.","abstract":"RPL10 encodes ribosomal protein L10 (uL16), a highly conserved multifunctional component of the large ribosomal subunit, involved in ribosome biogenesis and function. Using X-exome resequencing, we identified a novel missense mutation (c.191C>T; p.(A64V)) in the N-terminal domain of the protein, in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED). We assessed the impact of the mutation on the translational capacity of the cell using yeast as model system. The mutation generates a functional ribosomal protein, able to complement the translational defects of a conditional lethal mutation of yeast rpl10. However, unlike previously reported mutations, this novel RPL10 missense mutation results in an increase in the actively translating ribosome population. Our results expand the mutational and clinical spectrum of RPL10 identifying a new genetic cause of SED and highlight the emerging role of ribosomal proteins in the pathogenesis of neurodevelopmental disorders.","variants":[{"Name":"NM_006013.5(RPL10):c.191C>T (p.Ala64Val)","Chromosome":"X","Start":"154399803","Stop":"154399803","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":423405,"rule_based_match":true,"evidence_text":"c.191C>T; p.(A64V)","llm_judgment":"PRESENT","evidence":"c.191C>T; p.(A64V)","abstract_start":236,"abstract_end":254}]}
{"pmid":"36910710","title":"Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant","abstract":"Stargardt disease type 1 (STGD1) is the most common hereditary form of maculopathy and remains untreatable. STGD1 is caused by biallelic variants in the <i>ABCA4</i> gene, which encodes the ATP-binding cassette (type 4) protein (ABCA4) that clears toxic byproducts of the visual cycle. The c.5461-10T>C p.[Thr1821Aspfs∗6,Thr1821Valfs∗13] variant is the most common severe disease-associated variant, and leads to exon skipping and out-of-frame <i>ABCA4</i> transcripts that prevent translation of functional ABCA4 protein. Homozygous individuals typically display early onset STGD1 and are legally blind by early adulthood. Here, we applied antisense oligonucleotides (AONs) to promote exon inclusion and restore wild-type RNA splicing of <i>ABCA4</i> c.5461-10T>C. The effect of AONs was first investigated <i>in vitro</i> using an <i>ABCA4</i> midigene model. Subsequently, the best performing AONs were administered to homozygous c.5461-10T>C 3D human retinal organoids. Isoform-specific digital polymerase chain reaction revealed a significant increase in correctly spliced transcripts after treatment with the lead AON, QR-1011, up to 53% correct transcripts at a 3 μM dose. Furthermore, western blot and immunohistochemistry analyses identified restoration of ABCA4 protein after treatment. Collectively, we identified QR-1011 as a potent splice-correcting AON and a possible therapeutic intervention for patients harboring the severe <i>ABCA4</i> c.5461-10T>C variant.","variants":[{"Name":"NM_000350.3(ABCA4):c.5461-10T>C","Chromosome":"1","Start":"94011395","Stop":"94011395","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":98777,"rule_based_match":true,"evidence_text":"c.5461-10T>C","llm_judgment":"PRESENT","evidence":"c.5461-10T>C","abstract_start":290,"abstract_end":302}]}
{"pmid":"28877251","title":"Identification of a novel GJA3 mutation in a large Chinese family with congenital cataract using targeted exome sequencing.","abstract":"Autosomal dominant congenital cataract (ADCC) is a clinically and genetically heterogeneous ocular disease in children that results in serious visual impairments or even blindness. Targeted exome sequencing (TES) is an efficient method used for genetic diagnoses of inherited diseases. In the present study, we used a custom-made TES panel to identify the genetic defect of a four-generation Chinese family with bilateral pulverulent nuclear cataracts. A novel heterozygous missense mutation c.443C>T (p. T148I) in GJA3 was identified. The results of the bioinformatic analysis showed that the mutation was deleterious to the structure and hemichannel function of Cx46 encoded by GJA3. Plasmids expressing wild-type and mutant human Cx46 were constructed and ectopically expressed in human lens epithelial cells (HLECs) or human embryonic kidney (HEK-293) cells. Fluorescent images indicated aggregated signals of mutant protein in the cytoplasm, and a higher protein level was also detected in T148I stable cell lines. In summary, we identified a novel mutation in GJA3 for ADCC, which provided molecular insights into the pathogenic mechanism of ADCC.","variants":[{"Name":"NM_021954.4(GJA3):c.443C>T (p.Thr148Ile)","Chromosome":"13","Start":"20142846","Stop":"20142846","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":527510,"rule_based_match":true,"evidence_text":"c.443C>T (p. T148I)","llm_judgment":"PRESENT","evidence":"c.443C>T (p. T148I)","abstract_start":492,"abstract_end":511}]}
{"pmid":"38297350","title":"Rare germline mutation and MSH2-&MSH6 + expression in a double primary carcinoma of colorectal carcinoma and endometrial carcinoma: a case report.","abstract":"BACKGROUND: Multiple primary malignancies are rare in cancer patients, and risk factors may include genetics, viral infection, smoking, radiation, and other environmental factors. Lynch syndrome (LS) is the most prevalent form of hereditary predisposition to double primary colorectal and endometrial cancer in females. LS, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a common autosomal dominant condition. Pathogenic germline variants in the DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, and less frequently, deletions in the 3' end of EPCAM cause LS. It manifested itself as loss of MMR nuclear tumor staining (MMR protein deficient, dMMR).\nCASE PRESENTATION: This case study describes a double primary carcinoma in a 49-year-old female. In June 2022, the patient was diagnosed with highly to moderately differentiated endometrioid adenocarcinoma. The patient's mother died of esophageal cancer at age 50, and the father died of undefined reasons at age 70. Immunohistochemical stainings found ER (++), PR (++), P53 (+), MSH2 (-), MSH6 (+), MLH1 (+), and PMS2 (+). MMR gene sequencing was performed on endometrial tumor and peripheral blood samples from this patient. The patient carried two pathogenic somatic mutations in the endometrial tumor, MSH6 c.3261dupC (p.Phe1088LeufsTer5) and MSH2 c.445_448dup (p.Val150fs), in addition to a rare germline mutation MSH6 c.133G > C (p.Gly45Arg). Two years ago, the patient was diagnosed with moderately differentiated adenocarcinoma in the left-half colon. Immunohistochemical stainings found MSH2(-), MSH6(+), MLH1(+), and PMS2(+) (data not shown).\nCONCLUSIONS: In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.","variants":[{"Name":"NM_000179.3(MSH6):c.133G>C (p.Gly45Arg)","Chromosome":"2","Start":"47783366","Stop":"47783366","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":518376,"rule_based_match":true,"evidence_text":"MSH6 c.133G > C (p.Gly45Arg)","llm_judgment":"PRESENT","evidence":"MSH6 c.133G > C (p.Gly45Arg)","abstract_start":1408,"abstract_end":1436}]}
{"pmid":"18424508","title":"Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene.","abstract":"BACKGROUND: Many unclassified variants (UV) of BRCA1 or BRCA2 may have an effect on pre-mRNA splicing. Patient blood samples suitable for RNA extraction are not always available for testing UVs at the RNA level.\nMETHODS: Analyses of RNA from patient peripheral blood were performed, using a one-step reverse transcriptase-PCR (RT-PCR) protocol, and were compared with an ex vivo splicing assay based on PCR-amplified patient DNA inserted into a splicing reporter minigene. Using both methods 20 variants found in 17 patients were examined.\nRESULTS: Data from patient RNA and from the minigene assay were fully concordant, but the ex vivo splicing assay, which is monoallelic, clarified several ambiguities in the patient RNA data. Two intronic variants induced strong splicing defects: BRCA1 c.4987-5T-->A (IVS16-5T-->A) induced exon 17 skipping and BRCA2 c.316+5G-->C (IVS3+5G-->C) induced complete skipping of exon 3. Of the exonic variants, BRCA2 c.7805G-->C (p.Arg2602Thr), at the last base of exon 16, induced both exon skipping and activation of a cryptic exonic donor site, and BRCA2 c.8023A-->G (p.Ile2675Val) generated a strong donor site within exon 18. These four variants were thus classified as pathogenic, because of the total absence of a normal transcript from the corresponding allele. Variant BRCA2 c.9501+3A-->T (IVS25+3A-->T) induced incomplete skipping of exon 25, suggesting a mutation with incomplete penetrance, and BRCA2 c.8257_8259del (p.Leu2753del) modified the alternative splicing of exons 17 and 18.\nCONCLUSIONS: We show that functional analysis using a splicing reporter minigene is sensitive and specific, and should be used for initial screening of potential splicing defects, especially when patient RNA is not readily available.","variants":[{"Name":"NM_007294.4(BRCA1):c.4987-5T>A","Chromosome":"17","Start":"43067700","Stop":"43067700","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":70014,"rule_based_match":false,"evidence_text":"BRCA1 c.4987-5T-->A (IVS16-5T-->A)","llm_judgment":"PRESENT","evidence":"BRCA1 c.4987-5T-->A (IVS16-5T-->A)","abstract_start":786,"abstract_end":820},{"Name":"NM_000059.4(BRCA2):c.8023A>G (p.Ile2675Val)","Chromosome":"13","Start":"32363225","Stop":"32363225","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":67143,"rule_based_match":false,"evidence_text":"BRCA2 c.8023A-->G (p.Ile2675Val)","llm_judgment":"PRESENT","evidence":"BRCA2 c.8023A-->G (p.Ile2675Val)","abstract_start":1085,"abstract_end":1117},{"Name":"NM_000059.4(BRCA2):c.9501+3A>T","Chromosome":"13","Start":"32394936","Stop":"32394936","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":46798,"rule_based_match":false,"evidence_text":"BRCA2 c.9501+3A-->T (IVS25+3A-->T)","llm_judgment":"PRESENT","evidence":"BRCA2 c.9501+3A-->T (IVS25+3A-->T)","abstract_start":1311,"abstract_end":1345},{"Name":"NM_000059.4(BRCA2):c.316+5G>C","Chromosome":"13","Start":"32319330","Stop":"32319330","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":66078,"rule_based_match":false,"evidence_text":"BRCA2 c.316+5G-->C (IVS3+5G-->C)","llm_judgment":"PRESENT","evidence":"BRCA2 c.316+5G-->C (IVS3+5G-->C)","abstract_start":850,"abstract_end":882}]}
{"pmid":"37915296","title":"Genotype and phenotype characterization of primary hypertrophic osteoarthropathy type 2 and chronic enteropathy associated with SLCO2A1: Report of two cases and literature review.","abstract":"Autosomal recessive type 2 primary hypertrophic osteoarthropathy (PHOAR2) and chronic enteropathy associated with SLCO2A1 (CEAS) are two entities caused by pathogenic variants (PVs) in the SLCO2A1 gene that can coexist or occur independently from one another. We report two cases of PHOAR2 in Mexico with concomitant CEAS and conducted a review of the literature of the reported cases of PHOAR2 and/or CEAS to analyze the relationship between their genotype and phenotype presentation. The patients from our Institution with classical PHOAR2 phenotype and CEAS, harbored SLCO2A1 c.547G > A and c.1768del variants. We reviewed 232 cases, of which 86.6% were of Asian origin, and identified 109 different variants in SLCO2A1. Intron 7, exon 13, and exon 4 were predominantly affected. The two most common PVs were c.940 + 1G > A and c.1807C > T. We found a statistically significant association between SLCO2A1 variants located in intron 7, exons 12, and 13 and the development of CEAS. Missense variants were more frequent in isolated PHOAR2, while a greater proportion of protein-truncating variants (PTVs) were found in CEAS. Further investigation is imperative to elucidate the underlying pathophysiological mechanisms associated with CEAS, thereby facilitating the identification of effective therapeutic interventions.","variants":[{"Name":"NM_005630.3(SLCO2A1):c.547G>A (p.Gly183Arg)","Chromosome":"3","Start":"133955044","Stop":"133955044","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":966067,"rule_based_match":true,"evidence_text":"SLCO2A1 c.547G > A","llm_judgment":"PRESENT","evidence":"SLCO2A1 c.547G > A","abstract_start":571,"abstract_end":589},{"Name":"NM_005630.3(SLCO2A1):c.1768del (p.Arg590fs)","Chromosome":"3","Start":"133935820","Stop":"133935820","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":2045062,"rule_based_match":true,"evidence_text":"c.1768del","llm_judgment":"PRESENT","evidence":"c.1768del","abstract_start":594,"abstract_end":603}]}
{"pmid":"31403080","title":"Altered CSF levels of monoamines in hereditary spastic paraparesis 10: A case series.","abstract":"OBJECTIVE: To perform a comprehensive clinical characterization and biochemical CSF profile analyses in 2 Swedish families with hereditary spastic paraparesis (HSP) 10 (SPG10) caused by 2 different mutations in the neuronal kinesin heavy chain gene (<i>KIF5A</i>).\nMETHODS: Structured clinical assessment, genetic studies, and neuroradiologic and electrophysiological evaluations were performed in 4 patients from 2 families with SPG10. Additional CSF analysis was conducted in 3 patients with regard to levels of neurodegenerative markers and monoamine metabolism.\nRESULTS: All patients exhibited a complex form of HSP with a mild to moderate concurrent axonal polyneuropathy. The heterozygous missense mutations c.767A>G and c.967C>T in <i>KIF5A</i> were found. Wide intrafamilial phenotype variability was evident in both families. CSF analysis demonstrated a mild elevation of neurofilament light (NFL) chain in the patient with longest disease duration. Unexpectedly, all patients exhibited increased levels of the dopamine metabolite, homovanillic acid, whereas decreased levels of the noradrenergic metabolite, 3-methoxy-4-hydroxyphenylglycol, were found in 2 of 3 patients.\nCONCLUSIONS: We report on CSF abnormalities in SPG10, demonstrating that NFL elevation is not a mandatory finding but may appear after long-standing disease. Impaired transportation of synaptic proteins may be a possible explanation for the increased dopaminergic turnover and noradrenergic deficiency identified. The reasons for these selective abnormalities, unrelated to obvious clinical features, remain to be explained. Our findings need further confirmation in larger cohorts of patients harboring <i>KIF5A</i> mutations.","variants":[{"Name":"NM_004984.4(KIF5A):c.967C>T (p.Arg323Trp)","Chromosome":"12","Start":"57569403","Stop":"57569403","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":399176,"rule_based_match":true,"evidence_text":"c.967C>T","llm_judgment":"PRESENT","evidence":"c.967C>T","abstract_start":727,"abstract_end":735}]}
{"pmid":"31609695","title":"A Novel De Novo Heterozygous SCN4a Mutation Causing Congenital Myopathy, Myotonia and Multiple Congenital Anomalies.","abstract":"BACKGROUND: The phenotypic spectrum of the skeletal muscle voltage-gated sodium channel gene (SCN4A) mutations has been expanding dramatically with advancements in genetic testing. Previously only known to cause autosomal dominant myotonia or periodic paralysis, now recessive mutations have been found causing congenital myopathies and congenital myasthenic syndromes.\nCASE PRESENTATION: A 27-year-old woman who was born with Arnold-Chiari malformation, hydrocephalus, high-arched palate, bilateral hip dysplasia, and severe scoliosis presented for evaluation of episodic muscle stiffness and weakness. Electrodiagnostic studies revealed myopathy and widespread myotonia. Muscle histopathology showed marked fiber size variability, type I fiber predominance with minimal scattered necrosis and regeneration which was typical of a congenital myopathy with an additional finding of a lobulated structural pattern in type I fibers. Sequential individual gene testing revealed a novel de novo heterozygous c.2386 C > G, p.Leu796Val missense mutation in the SCN4A gene.\nDISCUSSION: To the best of our knowledge, this is the first report of a dominant, heterozygous mutation in SCN4A causing a complex phenotype of congenital myopathy and myotonia with multiple congenital anomalies and unique muscle pathology findings. This case is another addition to the ever expanding phenotype of SCN4A mutations.","variants":[{"Name":"NM_000334.4(SCN4A):c.2386C>G (p.Leu796Val)","Chromosome":"17","Start":"63951891","Stop":"63951891","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":375491,"rule_based_match":true,"evidence_text":"c.2386 C > G, p.Leu796Val","llm_judgment":"PRESENT","evidence":"c.2386 C > G, p.Leu796Val","abstract_start":1003,"abstract_end":1028}]}
{"pmid":"33811063","title":"A description of novel variants and review of phenotypic spectrum in","abstract":"Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in <i>UBA5</i>, a gene involved in a ubiquitin-like post-translational modification system called UFMylation. Here we report five children from four families with biallelic pathogenic variants in <i>UBA5</i> All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Affected individuals in all four families have compound heterozygous pathogenic variants in <i>UBA5</i> All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in <i>trans</i> with a second <i>UBA5</i> variant. One patient has the previously described c.562C > T (p. Arg188*) variant, two other unrelated patients have a novel missense variant, c.907T > C (p.Cys303Arg), and the two siblings have a novel missense variant, c.761T > C (p.Leu254Pro). Functional analyses demonstrate that both the p.Cys303Arg variant and the p.Leu254Pro variants result in a significant decrease in protein function. We also review the phenotypes and genotypes of all 15 previously reported families with biallelic <i>UBA5</i> variants, of which two families have presented with distinct phenotypes, and we describe evidence for some limited genotype-phenotype correlation. The overlap of motor and developmental phenotypes noted in our cohort and literature review adds to the increasing understanding of genetic syndromes with movement disorders-epilepsy.","variants":[{"Name":"NM_024818.6(UBA5):c.1111G>A (p.Ala371Thr)","Chromosome":"3","Start":"132675903","Stop":"132675903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260377,"rule_based_match":true,"evidence_text":"c.1111G > A (p.Ala371Thr)","llm_judgment":"PRESENT","evidence":"c.1111G > A (p.Ala371Thr)","abstract_start":642,"abstract_end":667},{"Name":"NM_024818.6(UBA5):c.907T>C (p.Cys303Arg)","Chromosome":"3","Start":"132675342","Stop":"132675342","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":513414,"rule_based_match":true,"evidence_text":"c.907T > C (p.Cys303Arg)","llm_judgment":"PRESENT","evidence":"c.907T > C (p.Cys303Arg)","abstract_start":861,"abstract_end":885},{"Name":"NM_024818.6(UBA5):c.761T>C (p.Leu254Pro)","Chromosome":"3","Start":"132672126","Stop":"132672126","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1036439,"rule_based_match":true,"evidence_text":"c.761T > C (p.Leu254Pro)","llm_judgment":"PRESENT","evidence":"c.761T > C (p.Leu254Pro)","abstract_start":939,"abstract_end":963}]}
{"pmid":"27476651","title":"Loss-of-Function Mutations in SERPINB8 Linked to Exfoliative Ichthyosis with Impaired Mechanical Stability of Intercellular Adhesions.","abstract":"SERPINS comprise a large and functionally diverse family of serine protease inhibitors. Here, we report three unrelated families with loss-of-function mutations in SERPINB8 in association with an autosomal-recessive form of exfoliative ichthyosis. Whole-exome sequencing of affected individuals from a consanguineous Tunisian family and a large Israeli family revealed a homozygous frameshift mutation, c.947delA (p.Lys316Serfs(∗)90), and a nonsense mutation, c.850C>T (p.Arg284(∗)), respectively. These two mutations are located in the last exon of SERPINB8 and, hence, would not be expected to lead to nonsense-mediated decay of the mRNA; nonetheless, both mutations are predicted to lead to loss of the reactive site loop of SERPINB8, which is crucial for forming the SERPINB8-protease complex. Using Sanger sequencing, a homozygous missense mutation, c.2T>C (p.Met1?), predicted to result in an N-terminal truncated protein, was identified in an additional family from UAE. Histological analysis of a skin biopsy from an individual homozygous for the variant p.Arg284(∗) showed disadhesion of keratinocytes in the lower epidermal layers plus decreased SERPINB8 levels compared to control. In vitro studies utilizing siRNA-mediated knockdown of SERPINB8 in keratinocytes demonstrated that in the absence of the protein, there is a cell-cell adhesion defect, particularly when cells are subjected to mechanical stress. In addition, immunoblotting and immunostaining revealed an upregulation of desmosomal proteins. In conclusion, we report mutations in SERPINB8 that are associated with exfoliative ichthyosis and provide evidence that SERPINB8 contributes to the mechanical stability of intercellular adhesions in the epidermis.","variants":[{"Name":"NM_002640.4(SERPINB8):c.947del (p.Lys316fs)","Chromosome":"18","Start":"63987099","Stop":"63987099","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":248713,"rule_based_match":true,"evidence_text":"c.947delA (p.Lys316Serfs(∗)90)","llm_judgment":"PRESENT","evidence":"c.947delA (p.Lys316Serfs(∗)90)","abstract_start":403,"abstract_end":433},{"Name":"NM_002640.4(SERPINB8):c.2T>C (p.Met1Thr)","Chromosome":"18","Start":"63978310","Stop":"63978310","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":248714,"rule_based_match":true,"evidence_text":"c.2T>C (p.Met1?)","llm_judgment":"PRESENT","evidence":"c.2T>C (p.Met1?)","abstract_start":855,"abstract_end":871},{"Name":"NM_002640.4(SERPINB8):c.850C>T (p.Arg284Ter)","Chromosome":"18","Start":"63987003","Stop":"63987003","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":248715,"rule_based_match":true,"evidence_text":"c.850C>T (p.Arg284(∗))","llm_judgment":"PRESENT","evidence":"c.850C>T (p.Arg284(∗))","abstract_start":460,"abstract_end":482}]}
{"pmid":"30122539","title":"De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism.","abstract":"Neurodevelopment is a transcriptionally orchestrated process. Cyclin K, a regulator of transcription encoded by CCNK, is thought to play a critical role in the RNA polymerase II-mediated activities. However, dysfunction of CCNK has not been linked to genetic disorders. In this study, we identified three unrelated individuals harboring de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region and one individual harboring a de novo nonsynonymous variant c.331A>G (p.Lys111Glu) in CCNK. These four individuals, though from different ethnic backgrounds, shared a common phenotype of developmental delay and intellectual disability (DD/ID), language defects, and distinctive facial dysmorphism including high hairline, hypertelorism, thin eyebrows, dysmorphic ears, broad nasal bridge and tip, and narrow jaw. Functional assay in zebrafish larvae showed that Ccnk knockdown resulted in defective brain development, small eyes, and curly spinal cord. These defects were partially rescued by wild-type mRNA coding CCNK but not the mRNA with the identified likely pathogenic variant c.331A>G, supporting a causal role of CCNK variants in neurodevelopmental disorders. Taken together, we reported a syndromic neurodevelopmental disorder with DD/ID and facial characteristics caused by CCNK variations, possibly through a mechanism of haploinsufficiency.","variants":[{"Name":"NM_001099402.2(CCNK):c.331A>G (p.Lys111Glu)","Chromosome":"14","Start":"99495549","Stop":"99495549","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":576359,"rule_based_match":true,"evidence_text":"c.331A>G (p.Lys111Glu)","llm_judgment":"PRESENT","evidence":"c.331A>G (p.Lys111Glu)","abstract_start":477,"abstract_end":499}]}
{"pmid":"33213388","title":"Characterization of an N-terminal Na","abstract":"BACKGROUND: Alterations in the SCN5A gene encoding the cardiac sodium channel Na<sub>v</sub>1.5 have been linked to a number of arrhythmia syndromes and diseases including long-QT syndrome (LQTS), Brugada syndrome (BrS) and dilative cardiomyopathy (DCM), which may predispose to fatal arrhythmias and sudden death. We identified the heterozygous variant c.316A > G, p.(Ser106Gly) in a 35-year-old patient with survived cardiac arrest. In the present study, we aimed to investigate the functional impact of the variant to clarify the medical relevance.\nMETHODS: Mutant as well as wild type GFP tagged Na<sub>v</sub>1.5 channels were expressed in HEK293 cells. We performed functional characterization experiments using patch-clamp technique.\nRESULTS: Electrophysiological measurements indicated, that the detected missense variant alters Nav1.5 channel functionality leading to a gain-of-function effect. Cells expressing S106G channels show an increase in Na<sub>v</sub>1.5 current over the entire voltage window.\nCONCLUSION: The results support the assumption that the detected sequence aberration alters Na<sub>v</sub>1.5 channel function and may predispose to cardiac arrhythmias and sudden cardiac death.","variants":[{"Name":"NM_000335.5(SCN5A):c.316A>G (p.Ser106Gly)","Chromosome":"3","Start":"38630387","Stop":"38630387","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":828045,"rule_based_match":true,"evidence_text":"c.316A > G, p.(Ser106Gly)","llm_judgment":"PRESENT","evidence":"c.316A > G, p.(Ser106Gly)","abstract_start":354,"abstract_end":379}]}
{"pmid":"16536805","title":"Two novel mutations and evidence for haploinsufficiency of the ADAR gene in dyschromatosis symmetrica hereditaria.","abstract":"BACKGROUND: Dyschromatosis symmetrica hereditaria (DSH, MIM 127400) is a dominantly inherited skin disease associated with mutations in ADAR, the gene that encodes a double-stranded RNA-specific adenosine deaminase. We previously reported two novel ADAR mutations (p.Q513X and p.R916W) and confirmed the role of ADAR in Chinese patients with DSH. Both haploinsufficiency and a dominant-negative effect have been suggested as the potential mechanism by which ADAR mutations cause DSH.\nOBJECTIVES: To identify ADAR mutations in two additional Chinese DSH families and to obtain insight into the pathogenic mechanism of heterozygous ADAR mutations.\nMETHODS: For mutation detection, all ADAR exons and their flanking intronic sequences were amplified and sequenced. Mutations were further confirmed by restriction analysis. Direct sequencing of cDNA fragments produced by reverse transcription-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR were used to examine the expression of ADAR in peripheral lymphocytes isolated from affected individuals.\nRESULTS: A small deletion, c.1555delT (p.C519fs), and a missense mutation, c.3116A>G (p.K1039R), were found in families A and B, respectively. In individuals carrying p.Q513X or p.C519fs, sequencing of cDNA fragments indicated almost total loss of mRNA expression from the mutant alleles, and real-time quantitative RT-PCR showed an approximately 50% reduction of ADAR expression. However, equal abundance of the wild-type and mutant cDNA sequences without reduction of ADAR expression was found in a patient with the missense p.R916W mutation. These results suggest that both the nonsense p.Q513X and frameshift p.C519fs mutations have generated null alleles probably by nonsense-mediated mRNA decay.\nCONCLUSIONS: Two novel ADAR mutations were found in Chinese patients with DSH. Evidence for ADAR haploinsufficiency as a mechanism underlying the molecular pathogenesis of DSH was obtained.","variants":[{"Name":"NM_001111.5(ADAR):c.3116A>G (p.Lys1039Arg)","Chromosome":"1","Start":"154586267","Stop":"154586267","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2112756,"rule_based_match":true,"evidence_text":"c.3116A>G (p.K1039R)","llm_judgment":"PRESENT","evidence":"c.3116A>G (p.K1039R)","abstract_start":1140,"abstract_end":1160}]}
{"pmid":"29097378","title":"","abstract":"BACKGROUND: The occurrence of parathyroid carcinoma in multiple endocrine neoplasia type I (MENI) is rare and the 15 cases of malignant parathyroid tumor reported so far have been associated with MENI in individuals and not with multiple members within a family.\nMETHODS: We report on a 61-year-old male, operated for a 7.3 cm parathyroid carcinoma infiltrating the esophagus. In his brother, a 4.6 cm parathyroid carcinoma was diagnosed histologically, while in the daughter, neck ultrasonography revealed 2 extrathyroidal nodules, yet to be excised.\nRESULTS: Screening of the <i>MEN1</i> gene identified a known germline heterozygous missense mutation (c.1252G>A; p.D418N) in exon 9, in all affected subjects.\nCONCLUSIONS: The occurrence of parathyroid carcinoma in more than one affected member of a single MEN1 family represents the first reported familial case. This suggests that additional constitutional genetic mutations may contribute to the variation in malignant potential and clinical behavior of parathyroid tumors in MEN1.","variants":[{"Name":"NM_001370259.2(MEN1):c.1252G>A (p.Asp418Asn)","Chromosome":"11","Start":"64805132","Stop":"64805132","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31742,"rule_based_match":true,"evidence_text":"c.1252G>A; p.D418N","llm_judgment":"PRESENT","evidence":"c.1252G>A; p.D418N","abstract_start":655,"abstract_end":673}]}
{"pmid":"29040051","title":"Two Novel CAPN5 Variants Associated with Mild and Severe Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy Phenotypes.","abstract":"<i>Purpose</i>: We report two new CAPN5 mutations associated with a phenotype of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy. <i>Methods</i>: We performed next generation sequencing in two patients with ADNIV phenotype; the variants identified were explored further. <i>Results</i>: Patient 1 was heterozygous for CAPN5 c.799G>A, p.(Gly267Ser). Patient 2 was heterozygous for CAPN5 c.1126G>A, p.(Gly376Ser). Both amino acids are highly conserved across species. Patient 1 had a severe phenotype and his mutation lies within the protein's catalytic domain. Patient 2 had a mild phenotype and her mutation is the first ADNIV-causing mutation to be described in the regulatory domain of Calpain-5. <i>Conclusions</i>: Our findings potentially add two new ADNIV-causing CAPN5 mutations to the three previously described. We recommend CAPN5 genetic testing in all patients with a possible ADNIV phenotype, to develop our understanding of Calpain-5; a protein which could potentially provide therapeutically accessible targets for the treatment of many leading causes of blindness.","variants":[{"Name":"NM_004055.5(CAPN5):c.799G>A (p.Gly267Ser)","Chromosome":"11","Start":"77115494","Stop":"77115494","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":947668,"rule_based_match":true,"evidence_text":"CAPN5 c.799G>A, p.(Gly267Ser)","llm_judgment":"PRESENT","evidence":"CAPN5 c.799G>A, p.(Gly267Ser)","abstract_start":332,"abstract_end":361},{"Name":"NM_004055.5(CAPN5):c.1126G>A (p.Gly376Ser)","Chromosome":"11","Start":"77118311","Stop":"77118311","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1486941,"rule_based_match":true,"evidence_text":"CAPN5 c.1126G>A, p.(Gly376Ser)","llm_judgment":"PRESENT","evidence":"CAPN5 c.1126G>A, p.(Gly376Ser)","abstract_start":394,"abstract_end":424}]}
{"pmid":"31577365","title":"POLR3B-associated leukodystrophy: clinical, neuroimaging and molecular-genetic analyses in four patients: clinical heterogeneity and novel mutations in POLR3B gene.","abstract":"INTRODUCTION AND AIM OF THE STUDY: White matter disorders represent a spectrum of neurological diseases frequently associated with an unfavourable prognosis and a delay in diagnostics. We report the broad phenotypic spectrum of a rare hypomyelinating leukodystrophy and three novel mutations. Further, we aim to explore the role of the combined clinical and neuroimaging diagnostic approach in the era of whole exome sequencing.\nMATERIALS AND METHODS: We present a clinical, neuroimaging and molecular-genetic characterisation of four patients from three families suffering from a rare genetic leukoencephalopathy. Two severely affected siblings (P1, P2) manifested a profound developmental delay, cerebellar symptomatology, microcephaly, failure to thrive, short stature and delayed teeth eruption with oligodontia. The other two patients (P3, P4), on the contrary, suffer from substantially less serious impairment with mild to moderate developmental delay and cerebellar symptomatology, delayed teeth eruption, or well-manageable epilepsy. In all four patients, magnetic resonance revealed cerebellar atrophy and supratentorial hypomyelination with T2-weight hypointensities in the areas of the ventrolateral thalamic nuclei, corticospinal tract and the dentate nuclei.\nRESULTS: Using whole-exome sequencing in P1, P2 and P3, and targeted sequencing in P4, pathogenic variants were disclosed in POLR3B, a gene encoding one of 17 subunits of DNA-dependent RNA polymerase III - all patients were compound heterozygotes for point mutations. Three novel mutations c.727A>G (p.Met243Val) and c.2669G>A (p.Arg890His) (P1, P2), and c.1495G>A (p.Met499Val) (P3) were found. Magnetic resonance revealed the characteristic radiological pattern of POLR3-leukodystrophies in our patients.\nCONCLUSION AND CLINICAL IMPLICATIONS: The diagnosis of POLR3-associated leukodystrophies can be significantly accelerated using the combined clinical and neuroradiological recognition pattern. Therefore, it is of crucial importance to raise the awareness of this rare disorder among clinicians. Molecular-genetic analyses are indispensable for a swift diagnosis confirmation in cases of clear clinical suspicion, and for diagnostic search in patients with less pronounced symptomatology. They represent an invaluable tool for unravelling the complex genetic background of heritable white matter disorders.","variants":[{"Name":"NM_018082.6(POLR3B):c.2669G>A (p.Arg890His)","Chromosome":"12","Start":"106463576","Stop":"106463576","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1897096,"rule_based_match":true,"evidence_text":"c.2669G>A (p.Arg890His)","llm_judgment":"PRESENT","evidence":"c.2669G>A (p.Arg890His)","abstract_start":1590,"abstract_end":1613}]}
{"pmid":"23494979","title":"Artery tortuosity syndrome exhibiting early-onset emphysema with novel compound heterozygous SLC2A10 mutations.","abstract":"We report on a 2-year-old Japanese boy with early-onset pulmonary emphysema, exhibiting dysmorphic face, loose skin, and inguinal and Morgagni hernias. He was admitted to our hospital owing to refractory respiratory infection. On the basis of his clinical features, we investigated the SLC2A10 gene and identified novel compound heterozygous mutations of c.417T > A and c.692G > A, leading to the diagnosis of artery tortuosity syndrome (ATS). This syndrome is an extremely rare autosomal recessive disorder characterized by tortuosity and elongation of the large and medium-sized arteries, hyperextensible skin, and diverse hernias, mostly reported from Europe and Middle Eastern countries, but not from Asia. Although chronic obstructive pulmonary disease, namely, emphysema, has not been well documented in ATS, it may be likely because TGF-beta up-regulation is known to be evoked by SLC2A10 mutations, resulting in reconstruction of pulmonary endothelial cells and emphysema. This is the first report of ATS associated with early-onset pulmonary emphysema, suggesting that patients with ATS may also require close attention for chronic obstructive pulmonary disease.","variants":[{"Name":"NM_030777.4(SLC2A10):c.417T>A (p.Tyr139Ter)","Chromosome":"20","Start":"46725453","Stop":"46725453","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":170940,"rule_based_match":true,"evidence_text":"c.417T > A","llm_judgment":"PRESENT","evidence":"c.417T > A","abstract_start":355,"abstract_end":365},{"Name":"NM_030777.4(SLC2A10):c.692G>A (p.Arg231Gln)","Chromosome":"20","Start":"46725728","Stop":"46725728","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":170944,"rule_based_match":true,"evidence_text":"c.692G > A","llm_judgment":"PRESENT","evidence":"c.692G > A","abstract_start":370,"abstract_end":380}]}
{"pmid":"30967659","title":"ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.","abstract":"PURPOSE: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache.\nMETHODS: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members.\nRESULTS: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis.\nCONCLUSION: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.","variants":[{"Name":"NM_025144.4(ALPK1):c.710C>T (p.Thr237Met)","Chromosome":"4","Start":"112427580","Stop":"112427580","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":610429,"rule_based_match":true,"evidence_text":"c.710C>T, [p.Thr237Met]","llm_judgment":"PRESENT","evidence":"c.710C>T, [p.Thr237Met]","abstract_start":640,"abstract_end":663}]}
{"pmid":"28590501","title":"Novel compound heterozygous mutations of ALDH1A3 contribute to anophthalmia in a non-consanguineous Chinese family.","abstract":"Anophthalmia is a rare eye development anomaly resulting in absent ocular globes or tissue in the orbit since birth. Here, we investigated a newborn with bilateral anophthalmia in a Chinese family. Exome sequencing revealed that compound heterozygous mutations c.287G > A (p.(Arg96His)) and c.709G > A (p.(Gly237Arg)) of the ALDH1A3 gene were present in the affected newborn. Both mutations were absent in all of the searched databases, including 10,000 in-house Chinese exome sequences, and these mutations were confirmed as having been transmitted from the parents. Comparative amino acid sequence analysis across distantly related species revealed that the residues at positions 96 and 234 were evolutionarily highly conserved. In silico analysis predicted these changes to be damaging, and in vitro expression analysis revealed that the mutated alleles were associated with decreased protein production and impaired tetrameric protein formation. This study firstly reported that compound heterozygous mutations of the ALDH1A3 gene can result in anophthalmia in humans, thus highlighting those heterozygous mutations in ALDH1A3 should be considered for molecular screening in anophthalmia, particularly in cases from families without consanguineous relationships.","variants":[{"Name":"NM_000693.4(ALDH1A3):c.287G>A (p.Arg96His)","Chromosome":"15","Start":"100887654","Stop":"100887654","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":966340,"rule_based_match":true,"evidence_text":"c.287G > A (p.(Arg96His))","llm_judgment":"PRESENT","evidence":"c.287G > A (p.(Arg96His))","abstract_start":261,"abstract_end":286}]}
{"pmid":"31617495","title":"Epileptic encephalopathy with microcephaly in a patient with asparagine synthetase deficiency: a video-EEG report.","abstract":"Asparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder caused by mutations in the asparagine synthetase gene. It is characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. A decrease in asparagine in CSF or plasma guides subsequent investigations in some cases, but normal values are described in other cases. Therefore, reaching a diagnosis is challenging and relies on exome sequencing. We report the case of a child with progressive microcephaly, irritability, startle reflexes, and jitteriness since birth. Focal clonic and myoclonic seizures, status epilepticus, and infantile spasms appeared in the first months of life. At first, the EEG showed multifocal epileptic activity which later turned into modified hypsarrhythmia and discontinuous activity. Brain MRI showed brain atrophy, a simplified gyral pattern, and poor myelination. Plasma asparagine levels were normal. Due to remote parental consanguinity, a study of contiguous regions of runs of homozygosity was performed, showing a 5-Mb region (chr7:95629078-100679007) including the asparagine synthetase gene. The molecular analysis of this gene led to identification of a novel homozygous missense mutation, c.761G>T(p.Gly254Val), in our patient. The peculiar electroclinical phenotype may lead to diagnostic suspicion and molecular analysis which may benefit genetic counselling. [Published with video sequence].","variants":[{"Name":"NM_001673.5(ASNS):c.761G>T (p.Gly254Val)","Chromosome":"7","Start":"97858868","Stop":"97858868","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1362948,"rule_based_match":true,"evidence_text":"c.761G>T(p.Gly254Val)","llm_judgment":"PRESENT","evidence":"c.761G>T(p.Gly254Val)","abstract_start":1273,"abstract_end":1294}]}
{"pmid":"17937428","title":"Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy.","abstract":"Hypertrophic cardiomyopathy is typically inherited in an autosomal dominant pattern and has a variable age of onset and prognosis. Mutations in the myosin-binding protein C (MYBPC3) gene are one of the most frequent genetic causes of the disease. Patients with MYBPC3 mutations generally have a late onset and a relatively good prognosis. We report here more than 20 Old Order Amish children with severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site mutation in the MYBPC3 gene. The affected children typically presented with signs and symptoms of congestive heart failure during the first 3 weeks of life. Echocardiography revealed hypertrophic non-obstructive cardiomyopathy. These children had a life span averaging 3-4 months. All patients died from heart failure before 1 year of age unless they received a heart transplant. A genome-wide mapping study was performed in three patients. The disease related gene was localized to a 4.6 Mb region on chromosome 11p11.2-p11.12. This homozygous block contained MYBPC3, a previously identified cardiomyopathy related gene. We identified a novel homozygous mutation, c.3330 + 2T > G, in the splice-donor site of MYBPC3 intron 30. The mutation resulted in skipping of the 140-bp exon 30, which led to a frame shift and premature stop codon in exon 31 (p.Asp1064GlyfsX38). We have found a substantial incidence of this phenotype in Old Order Amish communities. It is also concerning that many unidentified heterozygous individuals who are at risk for development of hypertrophic cardiomyopathy do not receive proper medical attention in the communities.","variants":[{"Name":"NM_000256.3(MYBPC3):c.3330+2T>G","Chromosome":"11","Start":"47333192","Stop":"47333192","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":23660,"rule_based_match":true,"evidence_text":"c.3330 + 2T > G","llm_judgment":"PRESENT","evidence":"c.3330 + 2T > G","abstract_start":1147,"abstract_end":1162}]}
{"pmid":"22386973","title":"Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.","abstract":"BACKGROUND: Arginine:glycineamidinotransferase (AGAT/GATM) deficiency has been described in 9 patients across 4 families. Here we describe the clinical outcome and response to creatine supplementation in a patient of the second family affected with AGAT deficiency-a 9-year-old girl.\nPATIENT AND METHODS: Delayed motor milestones were noticed from 4 months of age and at 14 months moderate hypotonia, developmental delay and failure to thrive. Laboratory studies revealed low plasma creatine as well as extremely low levels of guanidinoacetic acid in urine and plasma. Proton magnetic resonance spectroscopy (MRS) of the brain showed absence of creatine. DNA sequence analysis revealed a homozygous mutation (c.484+1G>T) in the AGAT/GATM gene. AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay. At 16 months, Bayley's Infant Development Scale (BIDS) showed functioning at 43% of chronologic age. Oral creatine supplementation (up to 800 mg/kg/day) was begun.\nRESULTS: At age 9 years she demonstrated advanced academic performance. Partial recovery of cerebral creatine levels was demonstrated on MRS at 25 months of age. Brain MRS at 40 months of age revealed a creatine/NAA ratio of about 80% of that in age-matched controls.\nCONCLUSIONS: 8 years post initiation of oral creatine supplementation, patient demonstrates superior nonverbal and academic abilities, with average verbal skills. We emphasize that early diagnosis combined with early treatment onset of AGAT deficiency may lead to improvement of developmental outcome.","variants":[{"Name":"NM_001482.3(GATM):c.484+1G>T","Chromosome":"15","Start":"45369325","Stop":"45369325","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":34151,"rule_based_match":true,"evidence_text":"c.484+1G>T","llm_judgment":"PRESENT","evidence":"c.484+1G>T","abstract_start":709,"abstract_end":719}]}
{"pmid":"34322716","title":"The role of CDHR3 in susceptibility to otitis media.","abstract":"Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. KEY MESSAGES: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.","variants":[{"Name":"NM_152750.5(CDHR3):c.1653+3G>A","Chromosome":"7","Start":"106018075","Stop":"106018075","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1284224,"rule_based_match":true,"evidence_text":"CDHR3 c.1653 + 3G > A","llm_judgment":"PRESENT","evidence":"CDHR3 c.1653 + 3G > A","abstract_start":1800,"abstract_end":1821}]}
{"pmid":"26279205","title":"Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency.","abstract":"Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50—translated from the non-mutated alleles—were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.","variants":[{"Name":"NM_003998.4(NFKB1):c.730+4A>G","Chromosome":"4","Start":"102579043","Stop":"102579043","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":206679,"rule_based_match":true,"evidence_text":"c.730+4A>G","llm_judgment":"PRESENT","evidence":"c.730+4A>G","abstract_start":333,"abstract_end":343},{"Name":"NM_003998.4(NFKB1):c.835+2T>G","Chromosome":"4","Start":"102580641","Stop":"102580641","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":206680,"rule_based_match":true,"evidence_text":"c.835+2T>G","llm_judgment":"PRESENT","evidence":"c.835+2T>G","abstract_start":758,"abstract_end":768}]}
{"pmid":"27225848","title":"Novel HPS6 mutations identified by whole-exome sequencing in two Japanese sisters with suspected ocular albinism.","abstract":"Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction and ceroid deposition. We report suspected ocular albinism in two Japanese sisters, caused by mutations in the HPS6 (Hermansky-Pudlak syndrome 6) gene. Trio-based whole-exome sequencing (WES) identified novel compound heterozygous mutations in HPS6 (c.1898delC: mother origin and c.2038C>T: father origin) in the two sisters. To date, 10 associated mutations have been detected in HPS6. Although we detected no general manifestations, including platelet dysfunction, in the sisters, even in long-term follow-up, we established a diagnosis of HPS type 6 based on the HPS6 mutations and absence of dense bodies in the platelets, indicating that WES can identify cases of HPS type 6. To the best of our knowledge, this is the first report of HPS6 mutations in Japanese patients.","variants":[{"Name":"NM_024747.6(HPS6):c.1898del (p.Pro633fs)","Chromosome":"10","Start":"102067371","Stop":"102067371","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":424579,"rule_based_match":true,"evidence_text":"c.1898delC","llm_judgment":"PRESENT","evidence":"c.1898delC","abstract_start":380,"abstract_end":390},{"Name":"NM_024747.6(HPS6):c.2038C>T (p.Gln680Ter)","Chromosome":"10","Start":"102067512","Stop":"102067512","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":424580,"rule_based_match":true,"evidence_text":"c.2038C>T","llm_judgment":"PRESENT","evidence":"c.2038C>T","abstract_start":410,"abstract_end":419}]}
{"pmid":"26334766","title":"A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing.","abstract":"Mutations of the histone acetyltransferase-encoding KAT6B gene cause the Say-Barber-Biesecker/Young-Simpson (SBBYS) type of blepharophimosis-\"mental retardation\" syndromes and the more severe genitopatellar syndrome. The SBBYS syndrome-causing mutations are clustered in the large exon 18 of KAT6B and almost exclusively lead to predicted protein truncation. An atypical KAT6B mutation, a de novo synonymous variant located in exon 16 (c.3147G>A, p.(Pro1049Pro)) was previously identified in three unrelated patients. This exonic mutation was predicted in silico to cause protein truncation through aberrant splicing. Here, we report three additional unrelated children with typical SBBYS syndrome and the KAT6B c.3147G>A mutation. We show on RNA derived from patient blood that the mutation indeed induces aberrant splicing through the use of a cryptic exonic splice acceptor site created by the sequence variant. Our results thus identify the synonymous variant c.3147G>A as a splice site mutation and a mutational hot spot in SBBYS syndrome.","variants":[{"Name":"NM_012330.4(KAT6B):c.3147G>A (p.Pro1049=)","Chromosome":"10","Start":"75022006","Stop":"75022006","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":264349,"rule_based_match":true,"evidence_text":"c.3147G>A","llm_judgment":"PRESENT","evidence":"c.3147G>A","abstract_start":436,"abstract_end":445}]}
{"pmid":"29342313","title":"Collagen XII myopathy with rectus femoris atrophy and collagen XII retention in fibroblasts.","abstract":"INTRODUCTION: Mutation in the collagen XII gene (COL12A1) was recently reported to induce Bethlem myopathy. We describe a family affected by collagen XII-related myopathy in 3 generations.\nMETHODS: Systematic interview, clinical examination, skin biopsies, and MRI of muscle were used.\nRESULTS: The phenotype was characterized by neonatal hypotonia, contractures, and delayed motor development followed by resolution of contractures and a motor performance limited by reduced endurance. DNA analyses revealed a novel donor splice-site mutation in COL12A1 (c.8100 + 2T>C), which segregated with clinical affection and abnormal collagen XII retention in fibroblasts. MRI disclosed a selective wasting of the rectus femoris muscle.\nDISCUSSION: COL12A1 mutations should be considered in patients with a mild Bethlem phenotype who present with selective wasting of the rectus femoris, absence of the outside-in phenomenon on MRI, and abnormal collagen XII retention in fibroblasts. Muscle Nerve 57: 1026-1030, 2018.","variants":[{"Name":"NM_004370.6(COL12A1):c.8100+2T>C","Chromosome":"6","Start":"75109016","Stop":"75109016","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":851462,"rule_based_match":true,"evidence_text":"c.8100 + 2T>C","llm_judgment":"PRESENT","evidence":"c.8100 + 2T>C","abstract_start":556,"abstract_end":569}]}
{"pmid":"22208444","title":"The anticipation and inheritance pattern of c.487A>G mutation in the GJB2 gene.","abstract":"Mutations in the GJB2 gene are the most common causes of hereditary hearing loss. This study reveals some facts about the inheritance pattern of M163V in the GJB2 gene. This study was performed on two different families with non-syndromic hearing loss. We screened the GJB2 coding region with direct sequencing. There was a substitution of A to G in exon 2 at nucleotide 487 (M163V). This mutation was heterozygous in fathers and children while mothers were normal. Fathers of both families showed late onset hearing impairment, but there was early onset hearing loss in the children, which was more severe compared to the fathers. M163V has been reported as an unknown heterozygous mutation that leads to failure of the homotypic junctional channel formation. Another mutation in this codon is M163L, with an autosomal dominant inheritance, which impairs trafficking through the plasma membrane, resulting in cell death. Assessment of the familial pedigree has revealed anticipation in phenotype and autosomal dominant inheritance. These data in addition to the high conservation of methionine residue in mammalian species suggest that M163V is inherited with an autosomal dominant pattern. Therefore, the risk of inheritance will increase. Genetic counselors and otologists should prioritize the evaluation and prevention of this disorder in patients.","variants":[{"Name":"NM_004004.6(GJB2):c.487A>G (p.Met163Val)","Chromosome":"13","Start":"20189095","Stop":"20189095","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":34240,"rule_based_match":true,"evidence_text":"c.487A>G","llm_judgment":"PRESENT","evidence":"c.487A>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"24658450","title":"In vitro correction of a novel splicing alteration in the BTK gene by using antisense morpholino oligonucleotides.","abstract":"A novel sequence variant, c.240+109C>A, in the Bruton's tyrosine kinase (BTK) gene was identified in a patient with X-linked agammaglobulinemia. This alteration resulted in an incorporation of 106 nucleotides of BTK intron 3 into its mRNA. Administration of the 25-mer antisense morpholino oligonucleotide analog in the patient's cultured peripheral blood mononuclear cells was able to restore correctly spliced BTK mRNA, a potential treatment for X-linked agammaglobulinemia.","variants":[{"Name":"NM_000061.3(BTK):c.240+109C>A","Chromosome":"X","Start":"101374427","Stop":"101374427","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1449690,"rule_based_match":true,"evidence_text":"c.240+109C>A","llm_judgment":"PRESENT","evidence":"c.240+109C>A","abstract_start":26,"abstract_end":38}]}
{"pmid":"34889447","title":"Omenn Syndrome due to RAG1 Mutation Presenting With Nonimmune Hydrops Fetalis in Two Siblings.","abstract":"Omenn syndrome (OS) is a rare variant of severe combined immunodeficiency characterized by susceptibility to severe opportunistic infections and peculiar manifestations, such as protein-losing erythroderma, alopecia, hepatosplenomegaly, lymphadenopathies, and severe diarrhea. The typical form of the disease is caused by hypomorphic mutation of the recombination-activating genes (RAG1 and RAG2), which are critical in initiating the molecular processes leading to lymphocyte and immunoglobulin receptor formation. Affected patients lack B cells, whereas autoreactive oligoclonal T cells infiltrate the skin, gut, spleen, and liver. In the absence of hematopoietic stem cell transplantation, patients with OS usually succumb early in life because of opportunistic infections. The incidence of OS is estimated to be <1 per 1 000 000; however, the actual frequency is difficult to ascertain. We report 2 siblings affected by OS due to a homozygous frameshift mutation (NM_000448.3:c.519delT, p.E174Sfs*26) in the RAG1 gene presenting with nonimmune hydrops fetalis (NIHF). To the best of our knowledge, this is the first reported association between OS and NIHF. NIHF specifically refers to the presence of ≥2 abnormal fluid collections in the fetus, without red blood cell alloimmunization. A broad spectrum of pathologies is associated with NIHF; however, in ∼20% of the cases, the primary cause remains unclear. Understanding the etiology of NIHF is essential for guiding clinical management, determining prognosis, and informing parents regarding recurrence risk. Our case contributes to expanding the spectrum of OS presentation and highlights the importance of a complete immunologic and genetic workup in otherwise unexplained cases of NIHF.","variants":[{"Name":"NM_000448.3(RAG1):c.519del (p.Glu174fs)","Chromosome":"11","Start":"36573823","Stop":"36573823","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":613410,"rule_based_match":true,"evidence_text":"NM_000448.3:c.519delT, p.E174Sfs*26","llm_judgment":"PRESENT","evidence":"NM_000448.3:c.519delT, p.E174Sfs*26","abstract_start":968,"abstract_end":1003}]}
{"pmid":"30122763","title":"Germline gene testing of the RET, VHL, SDHD and SDHB genes in patients with pheochromocytoma/paraganglioma","abstract":"OBJECTIVE: To analyze the germline variations of genes RET, VHL, SDHD and SDHB in patients with pheochromocytoma and/or paraganglioma and to evaluate variations of these genes in Chinese patients.\nMETHODS: Patients who were treated in Peking University First Hospital from September 2012 to March 2014 and diagnosed with pheochromocytoma and/or paraganglioma by pathologists were included in this study. Twelve patients were included in total, of whom 11 had pheochromocytoma, and 1 had paraganglioma. Deoxyribonucleic acid (DNA) was extracted from the leukocytes of peripheral blood of the patients. The exons 10, 11, 13-16 of the RET gene, and all exons of VHL, SDHB and SDHD genes and their nearby introns (±20 bp) were amplified with polymerase chain reactions, and the products were sent to a biotechnology company for sequencing. The sequencing results were compared with wildtype sequences of these genes to identify variations. One of the patients was diagnosed with multiple endocrine neoplasia type 2A. A family analysis was performed in his kindred, and his family members received genetic tests for the related variations.\nRESULTS: Three patients were found to have germline gene variations. A c.136C>T (p.R46X) variation of the SDHB gene was found in a patient with malignant pheochromocytoma. A c.1901G>A (C634Y) variation, as well as c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were found in a patient with multiple endocrine neoplasia type 2A. After a family analysis, five family members of this patient were found to have the same variations. c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were also found in a clinical sporadic patient without evidence of malignancy. A patient with congenital single ventricle malformation and pheochromocytoma was included in this study, and no variation with clinical significance was found in the four genes of this patient.\nCONCLUSION: 25% (3/12) patients with pheochromocytoma or paraganglioma were found to have missense or nonsense germline gene variations in this study, including the c.136C>T (p.R46X) variation of the SDHB gene, the c.1901G>A (C634Y) variation of the RET gene, and c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene. The former two variations have already been confirmed to be pathogenic. The existence of these variations in Chinese patients with pheochromocytoma and/or paraganglioma was validated in this study, which supports the conclusion that genetic testing is necessary to be generally performed in patients with pheochromocytoma and/or paraganglioma.","variants":[{"Name":"NM_003000.3(SDHB):c.136C>T (p.Arg46Ter)","Chromosome":"1","Start":"17044825","Stop":"17044825","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152477,"rule_based_match":true,"evidence_text":"c.136C>T (p.R46X)","llm_judgment":"PRESENT","evidence":"c.136C>T (p.R46X)","abstract_start":1206,"abstract_end":1223}]}
{"pmid":"29360628","title":"PHKG2 mutation spectrum in glycogen storage disease type IXc: a case report and review of the literature.","abstract":"BACKGROUND: PHKG2 gene mutation can lead to liver phosphorylase kinase (PhK) deficiency, which is related to glycogen storage disease type IX (GSD IX). GSD IXc due to PHKG2 mutation is the second most common GSD IX.\nMETHODS: We identified a novel mutation (c.553C>T, p.Arg185X) in PHKG2 in a Chinese family and verified it by next-generation and Sanger sequencing. The mutation spectrum of the PHKG2 gene was summarized based on 25 GSD IXc patients with PHKG2 mutations.\nRESULTS: We found that missense mutation (39%) was the most common type of mutation, followed by nonsense mutation (23%). Mutations were more prevalent in Asian (12/25) and European (9/25) populations than in populations from elsewhere. The exons had more sites of mutation than the introns, and exons 3 and 6 were the most frequent sites of mutations.\nCONCLUSIONS: This study expands our knowledge of the PHKG2 gene mutation spectrum, providing a molecular basis for GSD IXc.","variants":[{"Name":"NM_000294.3(PHKG2):c.553C>T (p.Arg185Ter)","Chromosome":"16","Start":"30753554","Stop":"30753554","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":568095,"rule_based_match":true,"evidence_text":"c.553C>T, p.Arg185X","llm_judgment":"PRESENT","evidence":"c.553C>T, p.Arg185X","abstract_start":257,"abstract_end":276}]}
{"pmid":"32284880","title":"","abstract":"Wilson disease is a recessive genetic disorder caused by pathogenic loss-of-function variants in the <i>ATP7B</i> gene. It is characterized by disrupted copper homeostasis resulting in liver disease and/or neurological abnormalities. The variant NM_000053.3:c.1934T > G (Met645Arg) has been reported as compound heterozygous, and is highly prevalent among Wilson disease patients of Spanish descent. Accordingly, it is classified as pathogenic by leading molecular diagnostic centers. However, functional studies suggest that the amino acid change does not alter protein function, leading one ClinVar submitter to question its pathogenicity. Here, we used a minigene system and gene-edited HepG2 cells to demonstrate that c.1934T > G causes ~70% skipping of exon 6. Exon 6 skipping results in frameshift and stop-gain, leading to loss of <i>ATP7B</i> function. The elucidation of the mechanistic effect for this variant resolves any doubt about its pathogenicity and enables the development of genetic medicines for restoring correct splicing.","variants":[{"Name":"NM_000053.4(ATP7B):c.1934T>G (p.Met645Arg)","Chromosome":"13","Start":"51961849","Stop":"51961849","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":18901,"rule_based_match":true,"evidence_text":"NM_000053.3:c.1934T > G (Met645Arg)","llm_judgment":"PRESENT","evidence":"NM_000053.3:c.1934T > G (Met645Arg)","abstract_start":246,"abstract_end":281}]}
{"pmid":"24520187","title":"Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family.","abstract":"PURPOSE: Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 45 genes. Recently, the FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP.\nMETHODS: We performed a clinical and molecular genetic study of a consanguineous Palestinian family with two three siblings affected with retinitis pigmentosa. DNA samples were collected from the index patient, his father, his affected sister, and two non-affected brothers. DNA sample from the index was subjected to high resolution genome-wide SNP array. Assuming identity-by-descent in this consanguineous family we applied homozygosity mapping to identify disease causing genes.\nRESULTS: The index patient reported night blindness since the age of 20 years, followed by moderate disease progression with decrease of peripheral vision, the development of photophobia and later on reduced central vision. At the age of 40 his visual acuity was counting fingers (CF) for both eyes, color discrimination was not possible and his visual fields were severely constricted. Funduscopic examination revealed a typical appearance of advanced RP with optic disc pallor, narrowed retinal vessels, bone-spicule like pigmentary changes in the mid-periphery and atrophic changes in the macula. His younger affected brother (37 years) was reported with overall milder symptoms, while the youngest sister (21 years) reported problems only with night vision. Applying high-density SNP arrays we identified several homozygous genomic regions one of which included the recently identified FAM161A gene mutated in RP28-linked autosomal recessive RP. Sequencing analysis revealed the presence of a novel homozygous nonsense mutation, c.1003C>T/p.R335X in the index patient and the affected sister.\nCONCLUSION: We identified an RP28-linked RP family in the Palestinian population caused by a novel nonsense mutation in FAM161A. RP in this family shows a typical disease onset with moderate to rapid progression into severe visual impairment including central vision in the index and overall milder symptoms in the younger brother and sister.","variants":[{"Name":"NM_001201543.2(FAM161A):c.1003C>T (p.Arg335Ter)","Chromosome":"2","Start":"61840001","Stop":"61840001","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":489358,"rule_based_match":true,"evidence_text":"c.1003C>T/p.R335X","llm_judgment":"PRESENT","evidence":"c.1003C>T/p.R335X","abstract_start":1761,"abstract_end":1778}]}
{"pmid":"17476356","title":"Revertant mosaicism in junctional epidermolysis bullosa due to multiple correcting second-site mutations in LAMB3.","abstract":"Revertant mosaicism due to in vivo reversion of an inherited mutation has been described in the genetic skin disease epidermolysis bullosa (EB) for the genes KRT14 and COL17A1. Here we demonstrate the presence of multiple second-site mutations, all correcting the germline mutation LAMB3:c.628G-->A;p.E210K, in 2 unrelated non-Herlitz junctional EB patients with revertant mosaicism. Both probands had a severe reduction in laminin-332 expression in their affected skin. Remarkably, the skin on the lower leg of patient 078-01 (c.628G-->A/c.1903C-->T) became progressively clinically healthy, with normal expression of laminin-332 on previously affected skin. In the other proband, 029-01 (c.628G-->A/c.628G-->A), the revertant patches were located at his arms, shoulder, and chest. DNA analysis showed different second-site mutations in revertant keratinocytes of distinct biopsy specimens (c.565-3T-->C, c.596G-->C;p.G199A, c.619A-->C;p.K207Q, c.628+42G-->A, and c.629-1G-->A), implying that there is not a single preferred mechanism for the correction of a specific mutation. Our data offer prospects for EB treatment in particular cases, since revertant mosaicism seems to occur at a higher frequency than expected. This opens the possibility of applying revertant cell therapy in mosaic EB of the LAMB3 gene by using autologous naturally corrected keratinocytes, thereby bypassing the recombinant gene correction phase.","variants":[{"Name":"NM_000228.3(LAMB3):c.628G>A (p.Glu210Lys)","Chromosome":"1","Start":"209633070","Stop":"209633070","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29582,"rule_based_match":false,"evidence_text":"LAMB3:c.628G-->A;p.E210K","llm_judgment":"PRESENT","evidence":"LAMB3:c.628G-->A;p.E210K","abstract_start":282,"abstract_end":306},{"Name":"NM_000228.3(LAMB3):c.596G>C (p.Gly199Ala)","Chromosome":"1","Start":"209633102","Stop":"209633102","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":29589,"rule_based_match":false,"evidence_text":"c.596G>C;p.G199A","llm_judgment":"PRESENT","evidence":"p.G199A","abstract_start":917,"abstract_end":924},{"Name":"NM_000228.3(LAMB3):c.619A>C (p.Lys207Gln)","Chromosome":"1","Start":"209633079","Stop":"209633079","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":29591,"rule_based_match":false,"evidence_text":"c.619A-->C;p.K207Q","llm_judgment":"PRESENT","evidence":"c.619A-->C;p.K207Q","abstract_start":926,"abstract_end":944}]}
{"pmid":"23227268","title":"Novel PAX9 and COL1A2 missense mutations causing tooth agenesis and OI/DGI without skeletal abnormalities.","abstract":"Inherited dentin defects are classified into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia (DD). The genetic etiology of DD-I is unknown. Defects in dentin sialophosphoprotein (DSPP) cause DD type II and DGI types II and III. DGI type I is the oral manifestation of osteogenesis imperfecta (OI), a systemic disease typically caused by defects in COL1A1 or COL1A2. Mutations in MSX1, PAX9, AXIN2, EDA and WNT10A can cause non-syndromic familial tooth agenesis. In this study a simplex pattern of clinical dentinogenesis imperfecta juxtaposed with a dominant pattern of hypodontia (mild tooth agenesis) was evaluated, and available family members were recruited. Mutational analyses of the candidate genes for DGI and hypodontia were performed and the results validated. A spontaneous novel mutation in COL1A2 (c.1171G>A; p.Gly391Ser) causing only dentin defects and a novel mutation in PAX9 (c.43T>A; p.Phe15Ile) causing hypodontia were identified and correlated with the phenotypic presentations in the family. Bone radiographs of the proband's dominant leg and foot were within normal limits. We conclude that when no DSPP mutation is identified in clinically determined isolated DGI cases, COL1A1 and COL1A2 should be considered as candidate genes. PAX9 mutation p.Phe15Ile within the N-terminal β-hairpin structure of the PAX9 paired domain causes tooth agenesis.","variants":[{"Name":"NM_000089.4(COL1A2):c.1171G>A (p.Gly391Ser)","Chromosome":"7","Start":"94410501","Stop":"94410501","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":413957,"rule_based_match":true,"evidence_text":"COL1A2 (c.1171G>A; p.Gly391Ser)","llm_judgment":"PRESENT","evidence":"COL1A2 (c.1171G>A; p.Gly391Ser)","abstract_start":836,"abstract_end":867}]}
{"pmid":"26456284","title":"A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.","abstract":"Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs.","variants":[{"Name":"NM_018896.5(CACNA1G):c.5144G>A (p.Arg1715His)","Chromosome":"17","Start":"50617560","Stop":"50617560","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":223669,"rule_based_match":true,"evidence_text":"c.5144G>A","llm_judgment":"PRESENT","evidence":"c.5144G>A","abstract_start":722,"abstract_end":731}]}
{"pmid":"25936994","title":"Alpha-thalassemia X-linked intellectual disability syndrome identified by whole exome sequencing in two boys with white matter changes and developmental retardation.","abstract":"Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is a genetic syndrome caused by mutation of the ATRX gene associated with chromatin remodeling. Recently, a wide spectrum of brain MRI abnormalities and clinical manifestations has been recognized. We describe two male patients with genetically confirmed ATRX syndrome, both presented with developmental delay and white matter changes without typical clinical characteristics of ATRX. Whole-exome sequencing revealed the presence of ATRX mutations: a novel c.6472A>G mutation in Case 1 and a previously reported c.6532C>T mutation in Case 2. These two cases expanded the genetic and clinical spectrum of ATRX syndrome, including brain MRI abnormalities. Our results suggest that male patients with developmental delay and widespread white matter changes, even without distinctive facial dysmorphism and hematologic abnormalities, should be suspected as ATRX syndrome. We support the clinical utility of whole-exome sequencing, particularly in ultra-rare neurological diseases with nonspecific developmental disabilities and atypical presentation.","variants":[{"Name":"NM_000489.6(ATRX):c.6532C>T (p.Arg2178Trp)","Chromosome":"X","Start":"77557618","Stop":"77557618","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360661,"rule_based_match":true,"evidence_text":"c.6532C>T","llm_judgment":"PRESENT","evidence":"c.6532C>T","abstract_start":579,"abstract_end":588},{"Name":"NM_000489.6(ATRX):c.6472A>G (p.Lys2158Glu)","Chromosome":"X","Start":"77558701","Stop":"77558701","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2307461,"rule_based_match":true,"evidence_text":"c.6472A>G","llm_judgment":"PRESENT","evidence":"c.6472A>G","abstract_start":524,"abstract_end":533}]}
{"pmid":"34904678","title":"Identification of a novel GATA binding protein 5 variant (c.830C>T/p.P277L) damaging the nuclear translocation and causing tetralogy of Fallot.","abstract":"","variants":[{"Name":"NM_080473.5(GATA5):c.830C>T (p.Pro277Leu)","Chromosome":"20","Start":"62465917","Stop":"62465917","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2142497,"rule_based_match":true,"evidence_text":"c.830C>T/p.P277L","llm_judgment":"PRESENT","evidence":"c.830C>T/p.P277L","abstract_start":null,"abstract_end":null}]}
{"pmid":"31189464","title":"Pathological findings in a patient with non-dystrophic myotonia with a mutation of the SCN4A gene; a case report.","abstract":"BACKGROUND: Non-dystrophic myotonias (NDMs) are skeletal muscle disorders involving myotonia distinct from myotonic dystrophy. It has been reported that the muscle pathology is usually normal or comprises mild myopathic changes in NDMs. We describe various pathological findings mimicking those of myotonic dystrophy (DM) in biopsied muscle specimens from a patient with NDMs with a long disease duration.\nCASE PRESENTATION: A 66-year-old Japanease man presented eye closure myotonia, percussion myotonia and grip myotonia together with the warm-up phenomenon and cold aggravation from early childhood. On genetic analysis, a heterozygous mutation of the SCN4A gene (c.2065 C > T, p.L689F), with no mutation of the CLCN1, DMPK, or ZNF9/CNBP gene, was detected. He was diagnosed as having NDMs. A biopsy of the biceps brachii muscle showed increasing fiber size variation, internal nuclei, chained nuclei, necrotic fibers, fiber splitting, endomysial fibrosis, pyknotic nuclear clumps and disorganized intermyofibrillar networks. Sarcoplasmic masses, tubular aggregates and ragged-red fibers were absent.\nCONCLUSION: It is noteworthy that the present study revealed various pathological findings resembling those seen in DM, although the pathology is usually normal or mild in NDMs. The pathological similarities may be due to muscular modification with long-standing myotonia or excessive muscle contraction based on abnormal channel activity.","variants":[{"Name":"NM_000334.4(SCN4A):c.2065C>T (p.Leu689Phe)","Chromosome":"17","Start":"63957473","Stop":"63957473","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":613096,"rule_based_match":true,"evidence_text":"c.2065 C > T, p.L689F","llm_judgment":"PRESENT","evidence":"c.2065 C > T, p.L689F","abstract_start":667,"abstract_end":688}]}
{"pmid":"28295036","title":"A novel recessive TTN founder variant is a common cause of distal myopathy in the Serbian population.","abstract":"Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.","variants":[{"Name":"NM_001267550.2(TTN):c.107635C>T (p.Gln35879Ter)","Chromosome":"2","Start":"178527491","Stop":"178527491","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":198685,"rule_based_match":true,"evidence_text":"c.107635C>T (p.(Gln35879Ter))","llm_judgment":"PRESENT","evidence":"c.107635C>T","abstract_start":213,"abstract_end":224}]}
{"pmid":"29322508","title":"A novel homozygous variant in BMPR1B underlies acromesomelic dysplasia Hunter-Thompson type.","abstract":"Acromesomelic dysplasia is genetically heterogeneous group of skeletal disorders characterized by short stature and acromelia and mesomelia of limbs. Acromesomelic dysplasia segregates in an autosomal recessive pattern and is caused by biallelic sequence variants in three genes (NPR2, GDF5, and BMPR1B). A consanguineous family of Pakistani origin segregating a subtype of acromesomelic dysplasia called Hunter-Thompson was clinically and genetically evaluated. Genotyping of microsatellite markers and linkage analysis revealed a 7.78 Mb homozygous region on chromosome 4q22.3, which harbors BMPR1B. Sequence analysis of the gene revealed a novel homozygous missense variant (c.1190T > G, p.Met397Arg) that segregates with the disease phenotype within the family and produced a Logarithm of odds (LOD) score of 3.9 with the disease phenotype. This study reports on the first familial case of acromesomelic dysplasia Hunter-Thompson type. It is also the first report of BMPR1B underlying the etiology of acromesomelic dysplasia Hunter-Thompson type.","variants":[{"Name":"NM_001203.3(BMPR1B):c.1190T>G (p.Met397Arg)","Chromosome":"4","Start":"95148861","Stop":"95148861","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":984313,"rule_based_match":true,"evidence_text":"c.1190T > G, p.Met397Arg","llm_judgment":"PRESENT","evidence":"c.1190T > G, p.Met397Arg","abstract_start":678,"abstract_end":702}]}
{"pmid":"27148587","title":"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A.","abstract":"Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, SEC23A c.1200G>C (p.M400I) and MAN1B1 c.1000C>T (p.R334C), associated with congenital birth defects in two patients from a consanguineous family. Patients presented with carbohydrate-deficient transferrin, tall stature, obesity, macrocephaly, and maloccluded teeth. The parents were healthy heterozygous carriers for both mutations and an unaffected sibling with tall stature carried the heterozygous mutation in SEC23A only. Mutations in SEC23A are responsible for craniolenticosultura dysplasia (CLSD). CLSD patients are short, have late-closing fontanels, and have reduced procollagen (pro-COL1A1) secretion because of abnormal pro-COL1A1 retention in the endoplasmic reticulum (ER). The mutation we identified in MAN1B1 was previously associated with reduced MAN1B1 protein and congenital disorders of glycosylation (CDG). CDG patients are also short, are obese, and have abnormal glycan remodeling. Molecular analysis of fibroblasts from the family revealed normal levels of SEC23A in all cells and reduced levels of MAN1B1 in cells with heterozygous or homozygous mutations in SEC23A and MAN1B1. Secretion of pro-COL1A1 was increased in fibroblasts from the siblings and patients, and pro-COL1A1 was retained in Golgi of heterozygous and homozygous mutant cells, although intracellular pro-COL1A1 was increased in patient fibroblasts only. We postulate that increased pro-COL1A1 secretion is responsible for tall stature in these patients and an unaffected sibling, and not previously discovered in patients with mutations in either SEC23A or MAN1B1. The patients in this study share biochemical and cellular characteristics consistent with mutations in MAN1B1 and SEC23A, indicating a digenic disease.","variants":[{"Name":"NM_016219.5(MAN1B1):c.1000C>T (p.Arg334Cys)","Chromosome":"9","Start":"137101088","Stop":"137101088","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39372,"rule_based_match":true,"evidence_text":"MAN1B1 c.1000C>T (p.R334C)","llm_judgment":"PRESENT","evidence":"MAN1B1 c.1000C>T (p.R334C)","abstract_start":119,"abstract_end":145}]}
{"pmid":"27588261","title":"Novel mutations in PDE6B causing human retinitis pigmentosa.","abstract":"AIM: To identify the genetic defects of a Chinese patient with sporadic retinitis pigmentosa (RP).\nMETHODS: Ophthalmologic examinations were performed on the sporadic RP patient, 144 genes associated with retinal diseases were scanned with capture next generation sequencing (CNGS) approach. Two heterozygous mutations in PDE6B were confirmed in the pedigree by Sanger sequencing subsequently. The carrier frequency of PDE6B mutations of reported PDE6B mutations based on the available two public exome databases (1000 Genomes Project and ESP6500 Genomes Project) and one in-house exome database was investigated.\nRESULTS: We identified compound heterozygosity of two novel nonsense mutations c.1133G>A (p.W378X) and c.2395C>T (p.R799X) in PDE6B, one reported causative gene for RP. Neither of the two mutations in our study was presented in three exome databases. Two mutations (p.R74C and p.T604I) in PDE6B have relatively high frequencies in the ESP6500 and in-house databases, respectively, while no common dominant mutation in each of the database or across all databases.\nCONCLUSION: We demonstrates that compound heterozygosity of two novel nonsense mutations in PDE6B could lead to RP. These results collectively point to enormous potential of next-generation sequencing in determining the genetic etiology of RP and how various mutations in PDE6B contribute to the genetic heterogeneity of RP.","variants":[{"Name":"NM_000283.4(PDE6B):c.2395C>T (p.Arg799Ter)","Chromosome":"4","Start":"667898","Stop":"667898","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":611617,"rule_based_match":true,"evidence_text":"c.2395C>T (p.R799X)","llm_judgment":"PRESENT","evidence":"c.2395C>T (p.R799X)","abstract_start":717,"abstract_end":736},{"Name":"NM_000283.4(PDE6B):c.1133G>A (p.Trp378Ter)","Chromosome":"4","Start":"656899","Stop":"656899","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1468195,"rule_based_match":true,"evidence_text":"c.1133G>A (p.W378X)","llm_judgment":"PRESENT","evidence":"c.1133G>A (p.W378X)","abstract_start":693,"abstract_end":712}]}
{"pmid":"29720545","title":"Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo","abstract":"OBJECTIVE: To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (<i>PTEN</i>), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases.\nMETHODS: We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts.\nRESULTS: The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) <i>PTEN</i> variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice.\nCONCLUSION: We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway.","variants":[{"Name":"NM_000314.8(PTEN):c.269T>C (p.Phe90Ser)","Chromosome":"10","Start":"87933028","Stop":"87933028","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":964349,"rule_based_match":true,"evidence_text":"c.269T>C, p.(Phe90Ser)","llm_judgment":"PRESENT","evidence":"c.269T>C, p.(Phe90Ser)","abstract_start":1045,"abstract_end":1067}]}
{"pmid":"23834637","title":"Phenotypic and genotypic characterization of 10 Finnish patients with von Willebrand disease type 3: discovery of two main mutations.","abstract":"Severe von Willebrand's disease (VWD) type 3 is a rare autosomal-recessively inherited bleeding disorder, showing considerable genotypic heterogeneity. We investigated the phenotype in correlation with the genotype in Finnish type 3 VWD patients. Ten patients previously diagnosed with VWD type 3 treated at the Coagulation Disorder Unit in Helsinki University Hospital were re-evaluated for bleeding tendency and treatment. Phenotypic characterization included coagulation and platelet function testing confirming the diagnosis. The genotype was assessed by initial screening for the common c.2435delC mutation and subsequently if needed, by analysing all 51 coding exons of the von Willebrand factor gene. Our result confirmed the diagnosis of type 3 VWD for all 10 patients. We discovered two common mutations: nine of the 20 alleles (45%) were found to carry the c.2435delC frameshift mutation, previously described to be frequent in countries surrounding the Baltic Sea. The nonsense mutation c.4975C>T (p.R1659X) was found on 8/20 (40%) of the alleles. In addition, three novel mutations, a potential splice site mutation (c.874+2T>C) and two frameshift mutations (c.1668delC and c.2072delCCinsG) were found. Seven patients were homozygous and three compound heterozygous for the reported mutations. This study indicates that mainly two mutations (c.2435delC and p.R1659X) cause the majority of type 3 VWD in Finland. This result sets future standards for the genetic testing among the Finnish type 3 VWD population.","variants":[{"Name":"NM_000552.5(VWF):c.4975C>T (p.Arg1659Ter)","Chromosome":"12","Start":"6018443","Stop":"6018443","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15336,"rule_based_match":true,"evidence_text":"c.4975C>T (p.R1659X)","llm_judgment":"PRESENT","evidence":"c.4975C>T (p.R1659X)","abstract_start":998,"abstract_end":1018},{"Name":"NM_000552.5(VWF):c.2435del (p.Pro812fs)","Chromosome":"12","Start":"6044298","Stop":"6044298","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":15342,"rule_based_match":true,"evidence_text":"c.2435delC","llm_judgment":"PRESENT","evidence":"c.2435delC","abstract_start":592,"abstract_end":602}]}
{"pmid":"27297285","title":"Super-Transactivation TP53 Variant in the Germline of a Family with Li-Fraumeni Syndrome.","abstract":"Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant familial cancer syndrome, characterized by multiple malignancies and frequent germline alterations in TP53. In this study, we highlight four unclassified exonic TP53 variants detected in patients with a suspected diagnosis of LFS. Most intriguing was the discovery of a \"super-transactivation\" variant within Exon 10 of TP53 (c.1079G>T/p.G360V). Functional analysis of this novel variant revealed a paradoxical \"super-transactivation\" effect on tp53 response elements and a corresponding tumor suppressive effect on colony formation and apoptosis. While unlikely to be disease-causing, we propose that this variant may represent a novel tp53 polymorphism and potential phenotypic modifier in LFS. In the future, the enhanced transactivation effects of p.G360V-tp53 may also prove useful in designing more efficacious tp53-based gene therapies.","variants":[{"Name":"NM_000546.6(TP53):c.1079G>T (p.Gly360Val)","Chromosome":"17","Start":"7670630","Stop":"7670630","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":152266,"rule_based_match":true,"evidence_text":"c.1079G>T/p.G360V","llm_judgment":"PRESENT","evidence":"c.1079G>T/p.G360V","abstract_start":382,"abstract_end":399}]}
{"pmid":"25853564","title":"Functional characterization of the spf/ash splicing variation in OTC deficiency of mice and man.","abstract":"The spf/ash mouse model of ornithine transcarbamylase (OTC) deficiency, a severe urea cycle disorder, is caused by a mutation (c.386G>A; p.R129H) in the last nucleotide of exon 4 of the Otc gene, affecting the 5' splice site and resulting in partial use of a cryptic splice site 48 bp into the adjacent intron. The equivalent nucleotide change and predicted amino acid change is found in OTC deficient patients. Here we have used liver tissue and minigene assays to dissect the transcriptional profile resulting from the \"spf/ash\" mutation in mice and man. For the mutant mouse, we confirmed liver transcripts corresponding to partial intron 4 retention by the use of the c.386+48 cryptic site and to normally spliced transcripts, with exon 4 always containing the c.386G>A (p.R129H) variant. In contrast, the OTC patient exhibited exon 4 skipping or c.386G>A (p.R129H)-variant exon 4 retention by using the natural or a cryptic splice site at nucleotide position c.386+4. The corresponding OTC tissue enzyme activities were between 3-6% of normal control in mouse and human liver. The use of the cryptic splice sites was reproduced in minigenes carrying murine or human mutant sequences. Some normally spliced transcripts could be detected in minigenes in both cases. Antisense oligonucleotides designed to block the murine cryptic +48 site were used in minigenes in an attempt to redirect splicing to the natural site. The results highlight the relevance of in depth investigations of the molecular mechanisms of splicing mutations and potential therapeutic approaches. Notably, they emphasize the fact that findings in animal models may not be applicable for human patients due to the different genomic context of the mutations.","variants":[{"Name":"NM_000531.6(OTC):c.386G>A (p.Arg129His)","Chromosome":"X","Start":"38381429","Stop":"38381429","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26049,"rule_based_match":true,"evidence_text":"c.386G>A (p.R129H)","llm_judgment":"PRESENT","evidence":"c.386G>A (p.R129H)","abstract_start":765,"abstract_end":783}]}
{"pmid":"28874143","title":"CHEK2 c.1100delC mutation is associated with an increased risk for male breast cancer in Finnish patient population.","abstract":"BACKGROUND: Several susceptibility genes have been established for female breast cancer, of which mutations in BRCA1 and especially in BRCA2 are also known risk factors for male breast cancer (MBC). The role of other breast cancer genes in MBC is less well understood.\nMETHODS: In this study, we have genotyped 68 MBC patients for the known breast or ovarian cancer associated mutations in the Finnish population in CHEK2, PALB2, RAD51C, RAD51D, and FANCM genes.\nRESULTS: CHEK2 c.1100delC mutation was found in 4 patients (5.9%), which is significantly more frequent than in the control population (OR: 4.47, 95% CI 1.51-13.18, p = 0.019). Four CHEK2 I157T variants were also detected, but the frequency did not significantly differ from population controls (p = 0.781). No RAD51C, RAD51D, PALB2, or FANCM mutations were found.\nCONCLUSIONS: These data suggest that the CHEK2 c.1100delC mutation is associated with an increased risk for MBC in the Finnish population.","variants":[{"Name":"NM_007194.4(CHEK2):c.1100del (p.Thr367fs)","Chromosome":"22","Start":"28695869","Stop":"28695869","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":133499,"rule_based_match":true,"evidence_text":"CHEK2 c.1100delC","llm_judgment":"PRESENT","evidence":"CHEK2 c.1100delC","abstract_start":472,"abstract_end":488}]}
{"pmid":"21231898","title":"SLC40A1 Q248H allele frequencies and associated SLC40A1 haplotypes in three West African population samples.","abstract":"BACKGROUND: Ferroportin is a transmembrane protein responsible for iron export from enterocytes and macrophages. Mutation c.744G → T (Q248H), located in exon 6 of the ferroportin gene SLC40A1, is found as a polymorphism in populations of African origin. This mutation has been extensively analysed in African-Americans, but poorly studied in native African populations.\nAIM: To increase information about Q248H mutation frequency in native sub-Saharan populations examining three West African populations.\nSUBJECTS AND METHODS: Samples from S. Tomé e Príncipe (n = 115), Angola (n = 156) and Republic of Guinea (n = 170) were analysed for Q248H mutation and for two polymorphisms, IVS1( - 24)G → C and microsatellite (CGG)(n), using standard molecular methodology.\nRESULTS: The estimated frequencies of Q248H allele were 2.2% in S. Tomé e Príncipe, 3.5% in Angola and 4.1% in Republic of Guinea. Analysis of polymorphisms IVS1( - 24)G → C and (CGG)(n) showed mutation allele c.744T to be strongly associated with haplotype IVS1( - 24)G/(CGG)(7).\nCONCLUSIONS: This study confirmed the presence of Q248H mutation at polymorphic frequencies in three native sub-Saharan populations. Analysis of two additional markers in the same gene support a single origin of the mutant allele c.744T in the haplotype background IVS1( - 24)G/(CGG)(7).","variants":[{"Name":"NM_014585.6(SLC40A1):c.744G>T (p.Gln248His)","Chromosome":"2","Start":"189565370","Stop":"189565370","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":283586,"rule_based_match":false,"evidence_text":"c.744G → T (Q248H)","llm_judgment":"PRESENT","evidence":"c.744G → T (Q248H)","abstract_start":122,"abstract_end":140}]}
{"pmid":"17203532","title":"Novel MLH1 frameshift mutation in an extended hereditary nonpolyposis colorectal cancer family.","abstract":"AIM: To present novel frameshift mutation c.31delC [p.L11X] in the MLH1 gene identified in an extended Bulgarian hereditary non-polyposis colorectal cancer (HNPCC) family and to analyze the molecular and clinical findings within the pedigree concerning the proposal of adequate individual prophylactic strategy for all mutation carriers.\nMETHODS: The pedigree of the family consists of 42 members in four generations. Search for mutations in the MLH1 and hMSH2 genes was performed in the proband. After PCR amplification of all exons including flanking intronic regions, amplicons were directly sequenced.\nRESULTS: The mutation was found in nine from the thirteen pedigree members who signed informed consent to participate in the study. In three adenocarcinomas, microsatellite instability and lack of the MLH1 protein expression were detected. The only one tubulovillous adenoma analyzed was microsatellite stable and the MLH1 protein showed an intact staining.\nCONCLUSION: The newly described mutation c.31delC is HNPCC causative. Besides the typical clinical features of the syndrome, we found a specific pathologic manifestation such as moderate to high differentiated adenocarcinomas of the colon. One of the mutation carriers developed a benign giant cell soft tissue tumor. The primary tumor localizations were frequently extracolonic and detailed yearly gastrointestinal and gynecological examinations have been proposed to the mutation carriers. We emphasize the importance of including the HNPCC genetic counseling and testing as well in the following surveillance of all patients at risk in the services covered by the health insurance in Bulgaria.","variants":[{"Name":"NM_000249.4(MLH1):c.31del (p.Leu11fs)","Chromosome":"3","Start":"36993578","Stop":"36993578","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":95640,"rule_based_match":true,"evidence_text":"c.31delC","llm_judgment":"PRESENT","evidence":"c.31delC","abstract_start":42,"abstract_end":50}]}
{"pmid":"23900199","title":"Exome sequencing identifies RDH12 compound heterozygous mutations in a family with severe retinitis pigmentosa.","abstract":"OBJECTIVE: Retinitis pigmentosa (RP) is the most prevalent type of inherited retinal degeneration and one of the commonest causes of genetically determined visual dysfunction worldwide. To date, approximately 35 genes have been associated with nonsyndromic autosomal recessive RP (arRP), however the small contribution of each gene to the total prevalence of arRP and the lack of a clear genotype-phenotype correlation complicate the genetic analysis in affected patients. Next generation sequencing technologies are powerful and cost-effective methods for detecting causative mutations in both sporadic and familial RP cases.\nMETHODS: A Mexican family with 5 members affected from arRP was studied. All patients underwent a complete ophthalmologic examination. Molecular methods included genome-wide SNP homozygosity mapping, exome sequencing analysis, and Sanger-sequencing confirmation of causal mutations.\nRESULTS: No regions of shared homozygosity among affected subjects were identified. Exome sequencing in a single patient allowed the detection of two missense mutations in the RDH12 gene: a c.446T>C transition predicting a novel p.L149P substitution, and a c.295C>A transversion predicting a previously reported p.L99I replacement. Sanger sequencing confirmed that all affected subjects carried both RDH12 mutations.\nCONCLUSIONS: This study adds to the molecular spectrum of RDH12-related retinopathy and offers an additional example of the power of exome sequencing in the diagnosis of recessively inherited retinal degenerations.","variants":[{"Name":"NM_152443.3(RDH12):c.446T>C (p.Leu149Pro)","Chromosome":"14","Start":"67726153","Stop":"67726153","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":856787,"rule_based_match":true,"evidence_text":"c.446T>C","llm_judgment":"PRESENT","evidence":"c.446T>C","abstract_start":1100,"abstract_end":1108},{"Name":"NM_152443.3(RDH12):c.295C>A (p.Leu99Ile)","Chromosome":"14","Start":"67725206","Stop":"67725206","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":17094,"rule_based_match":true,"evidence_text":"c.295C>A","llm_judgment":"PRESENT","evidence":"c.295C>A","abstract_start":1167,"abstract_end":1175}]}
{"pmid":"35308163","title":"Clinical, Biochemical, Molecular, and Outcome Features of Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency in 10 Chinese Patients.","abstract":"<b>Background:</b> Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare autosomal recessive metabolic disorder caused by mutations of the <i>HMGCS2</i> gene. To date, no more than 60 patients have been reported throughout the world. <b>Purpose</b>: To analyze the clinical, biochemical, molecular, and outcome features of HMGCS2D in a case series of 10 new Chinese patients. <b>Methods:</b> This retrospective study includes 10 Chinese patients diagnosed with HMGCS2D. We collected and analyzed clinical data for all patients. We also reviewed clinical data for 39 cases that had been reported previously. <b>Results:</b> All of our patients had experienced their first metabolic crisis before 12 months old. The most common clinical manifestations were anorexia, dyspnea, and disturbance of consciousness (10/10), followed by vomiting (8/10), fever (7/10), cough (4/10), diarrhea, and seizures (3/10). Each patient (10/10) had a different degree of hepatomegaly and increased aminotransferase, severe metabolic acidosis, and hypofibrinogenemia. 9 patients presented with severe hypoglycemia and weak positives on qualitative tests of urinary ketone body. Patient 3 was the only one without hypoglycemia. Five patients had hypocalcemia, five patients had hyperammonemia, four patients had hyperuricemia, and three had hypertriglyceridemia. During the metabolic acidosis episode, we observed high dicarboxylic acid values in urine, and the elevated ratio of blood acetylcarnitine to free carnitine may have been an additional biochemical signature. However, all returned to normal during the interictal interval. Molecular analysis identified 15 variants in the <i>HMGCS2</i> gene, of which 10 were novel (c.220G>A/p.E74K, c.407A>G/p.D136G, c.422T>A/p.V141D, c.719A>C/p.D240A, c.821G>A/p.R274H, c.39dupA/p.L14Tfs*59, c.1394delA/p.N465Tfs*10, c.788delT/p.L263Cfs*36, c.717T>G/p.Y239*, and c.1017-2A>G). Combining these with previous cases, the known mutation c.1201G>T/p.E401* has been found in 6/40 (15.0%) of mutated alleles in 21 Chinese patients from 20 families, while none have been found in other populations. We found that patients with biallelic truncation mutation appeared to show a more severe clinical condition through a literature review. <b>Conclusion:</b> This study analyzed the phenotypic and genetic features of HMGCS2D in a Chinese case series. We also expanded the <i>HMGCS2</i> mutational spectrum with 10 novel variants. The c.1201G>T/p.E401* mutation was the most frequent, representing 15.0% of the mutated alleles in reported unrelated Chinese patients, and thus, it may be a hot spot mutation.","variants":[{"Name":"NM_005518.4(HMGCS2):c.821G>A (p.Arg274His)","Chromosome":"1","Start":"119759147","Stop":"119759147","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1318003,"rule_based_match":true,"evidence_text":"c.821G>A/p.R274H","llm_judgment":"PRESENT","evidence":"c.821G>A/p.R274H","abstract_start":1808,"abstract_end":1824},{"Name":"NM_005518.4(HMGCS2):c.1394del (p.Asn465fs)","Chromosome":"1","Start":"119752575","Stop":"119752575","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":1318004,"rule_based_match":true,"evidence_text":"c.1394delA/p.N465Tfs*10","llm_judgment":"PRESENT","evidence":"c.1394delA/p.N465Tfs*10","abstract_start":1848,"abstract_end":1871}]}
{"pmid":"36267857","title":"Massively Parallel Sequencing of 43 Arrhythmia Genes in a Selected SUDI Cohort from Cape Town.","abstract":"Sudden unexpected death in infants (SUDI) is a devastating event, and unfortunately occurs frequently in developing countries. The emerging molecular autopsy has added value to post-mortem investigations, where genetic variants were able to explain the unexpected demise. Many of these variants have been found in genes involved in arrythmia pathways. The aim of this study was to sequence 43 genes previously associated with cardiac arrhythmia in a selected cohort of SUDI cases ( <i>n</i>  = 19) in South Africa. A total of 335 variants were found among the 19 infants, of which four were novel. The variants were classified as \"likely pathogenic\" ( <i>n</i>  = 1), \"variant of unknown significance\" ( <i>n</i>  = 54), \"likely benign\" ( <i>n</i>  = 56) or \"benign\" ( <i>n</i>  = 224). The likely pathogenic variant was <i>LMNA</i> NM_170707.2:c.1279C > T (p.Arg427Cys) and was found in a 3-week-old male infant of African ancestry. Variants in <i>LMNA</i> have previously been associated with dilated cardiomyopathy, with a typical age of onset in adulthood; therefore, this may be the first report in an infant. The yield of pathogenic or likely pathogenic variants in the classic genes typically associated with channelopathies and sudden death, was less in this study compared with other settings. This finding highlights the importance of population-specific research to develop a molecular autopsy which is locally relevant.","variants":[{"Name":"NM_170707.4(LMNA):c.1279C>T (p.Arg427Cys)","Chromosome":"1","Start":"156136335","Stop":"156136335","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":196479,"rule_based_match":true,"evidence_text":"NM_170707.2:c.1279C > T (p.Arg427Cys)","llm_judgment":"PRESENT","evidence":"NM_170707.2:c.1279C > T (p.Arg427Cys)","abstract_start":833,"abstract_end":870}]}
{"pmid":"19810119","title":"Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling.","abstract":"Autosomal recessive Ellis-van Creveld syndrome and autosomal dominant Weyer acrodental dysostosis are allelic conditions caused by mutations in EVC or EVC2. We performed a mutation screening study in 36 EvC cases and 3 cases of Weyer acrodental dysostosis, and identified pathogenic changes either in EVC or in EVC2 in all cases. We detected 40 independent EVC/EVC2 mutations of which 29 were novel changes in Ellis-van Creveld cases and 2 were novel mutations identified in Weyer pedigrees. Of interest one EvC patient had a T>G nucleotide substitution in intron 7 of EVC (c.940-150T>G), which creates a new donor splice site and results in the inclusion of a new exon. The T>G substitution is at nucleotide +5 of the novel 5' splice site. The three Weyer mutations occurred in the final exon of EVC2 (exon 22), suggesting that specific residues encoded by this exon are a key part of the protein. Using murine versions of EVC2 exon 22 mutations we demonstrate that the expression of a Weyer variant, but not the expression of a truncated protein that mimics an Ellis-van Creveld syndrome mutation, impairs Hedgehog signal transduction in NIH 3T3 cells in keeping with its dominant effect.","variants":[{"Name":"NM_153717.3(EVC):c.940-150T>G","Chromosome":"4","Start":"5747998","Stop":"5747998","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1347311,"rule_based_match":true,"evidence_text":"c.940-150T>G","llm_judgment":"PRESENT","evidence":"c.940-150T>G","abstract_start":574,"abstract_end":586}]}
{"pmid":"30285816","title":"Urea cycle disorders in India: clinical course, biochemical and genetic investigations, and prenatal testing.","abstract":"BACKGROUND: Urea cycle disorders (UCDs) are inherited metabolic disorders that present with hyperammonemia, and cause significant mortality and morbidity in infants and children. These disorders are not well reported in the Indian population, due to lack of a thorough study of the clinical and molecular profile.\nRESULTS: We present data from two major metabolic centres in India, including 123 cases of various UCDs. The majority of them (72/123, 58%) presented in the neonatal period (before 30 days of age) with 88% on or before day 7 of life (classical presentation), and had a high mortality (64/72, 88%). Citrullinemia type 1 was the most common UCD, observed in 61/123 patients. Ornithine transcarbamylase (OTC) deficiency was the next most common, seen in 24 cases. Argininosuccinic aciduria was diagnosed in 20 cases. Deficiencies of arginase, N-acetylglutamate synthase, carbamoyl phosphate synthetase, citrin, and lysinuric protein intolerance were also observed. Molecular genetic analysis revealed two common ASS1 mutations: c.470G > A (p.Arg157His) and c.1168G > A (p.Gly390Arg) (36 of 55 tested patients). In addition, few recurrent point mutations in ASL gene, and a deletion of the whole OTC gene were also noted. A total of 24 novel mutations were observed in the various genes studied. We observed a poor clinical outcome with an overall all time mortality of 63% (70/110 cases with a known follow-up), and disability in 70% (28/40) among the survivors. Prenatal diagnosis was performed in 30 pregnancies in 25 families, including one pre-implantation genetic diagnosis.\nCONCLUSIONS: We report the occurrence of UCDs in India and the spectrum that may be different from the rest of the world. Citrullinemia type 1 was the most common UCD observed in the cohort. Increasing awareness amongst clinicians will improve outcomes through early diagnosis and timely treatment. Genetic diagnosis in the proband will enable prenatal/pre-implantation diagnosis in subsequent pregnancies.","variants":[{"Name":"NM_054012.4(ASS1):c.470G>A (p.Arg157His)","Chromosome":"9","Start":"130466774","Stop":"130466774","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21364,"rule_based_match":true,"evidence_text":"c.470G > A (p.Arg157His)","llm_judgment":"PRESENT","evidence":"c.470G > A (p.Arg157His)","abstract_start":1039,"abstract_end":1063}]}
{"pmid":"38091959","title":"Novel Variants of HPS6 Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of HPS6 Variants.","abstract":"INTRODUCTION: Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of HPS6 variants and their genotype-phenotype correlations.\nMETHODS: Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of family JX. The single coding exon of HPS6 was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of HPS6 reported in the literature were reviewed.\nRESULTS: We identified two different compound heterozygous truncating variants of HPS6 in probands with suspected OA from two independent families. The proband of family JX had c.1674dup and c.503-504del variants, and the other proband from family CZ had a nonsense variant of c.1114C&gt;T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of HPS6 variants and revealed a significant overlap between CpG islands and the variants of HPS6, suggesting a potential link between DNA methylation and HPS6 variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease.\nCONCLUSION: Our research expands the spectrum of HPS6 variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.","variants":[{"Name":"NM_024747.6(HPS6):c.1114C>T (p.Arg372Ter)","Chromosome":"10","Start":"102066588","Stop":"102066588","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1340120,"rule_based_match":false,"evidence_text":"c.1114C>T","llm_judgment":"PRESENT","evidence":"c.1114C>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"26637978","title":"Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.","abstract":"Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.","variants":[{"Name":"NM_001135146.2(SLC39A8):c.112G>C (p.Gly38Arg)","Chromosome":"4","Start":"102344551","Stop":"102344551","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":215655,"rule_based_match":true,"evidence_text":"c.112G>C (p.Gly38Arg)","llm_judgment":"PRESENT","evidence":"c.112G>C (p.Gly38Arg)","abstract_start":602,"abstract_end":623}]}
{"pmid":"29706351","title":"Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.","abstract":"Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.","variants":[{"Name":"NM_016306.6(DNAJB11):c.161C>G (p.Pro54Arg)","Chromosome":"3","Start":"186572187","Stop":"186572187","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":540572,"rule_based_match":false,"evidence_text":"p.Pro54Arg","llm_judgment":"PRESENT","evidence":"p.Pro54Arg","abstract_start":529,"abstract_end":539},{"Name":"NM_016306.6(DNAJB11):c.166_167insTT (p.Arg56fs)","Chromosome":"3","Start":"186572192","Stop":"186572193","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CTT","allel_id":540573,"rule_based_match":true,"evidence_text":"c.166_167insTT","llm_judgment":"PRESENT","evidence":"c.166_167insTT","abstract_start":639,"abstract_end":653}]}
{"pmid":"26786512","title":"A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions.","abstract":"PURPOSE: Corneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.\nDESIGN: Case series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.\nPARTICIPANTS: Four ERED families, including 28 affected and 17 unaffected individuals.\nMETHODS: HumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle-niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.\nMAIN OUTCOME MEASURES: Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.\nRESULTS: Linkage microarray analysis identified a candidate region on chromosome chr10:12,576,562-112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ-TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.\nCONCLUSIONS: The COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium.","variants":[{"Name":"NM_000494.4(COL17A1):c.3156C>T (p.Gly1052=)","Chromosome":"10","Start":"104037688","Stop":"104037688","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205533,"rule_based_match":false,"evidence_text":"COL17A1 c.3156C→T","llm_judgment":"PRESENT","evidence":"COL17A1 c.3156C→T","abstract_start":1639,"abstract_end":1656}]}
{"pmid":"21618644","title":"Functional analysis reveals splicing mutations of the CASQ2 gene in patients with CPVT: implication for genetic counselling and clinical management.","abstract":"Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and severe arrhythmogenic disorder. Although usually transmitted in a recessive form, few cases of dominant mutations have been reported. Thirteen mutations in the CASQ2 gene have been reported so far in association with CPVT. We performed molecular analysis of the CASQ2 gene in 43 probands with CPVT and identified eight mutations in five patients. Six mutations were novel: one was a single nucleotide deletion, three affected consensus splice sites, and two had unknown consequences: the c.939 + 5G>C and the synonymous c.381C>T variations. We demonstrated that these two variations affected CASQ2 splicing using a splicing minigene assay. These data increased significantly the number of CASQ2 mutations described in association with CPVT, revealed the high prevalence of splicing and truncating mutations in this gene and brought new insight regarding the dominant inheritance of the disease. Moreover, our report of the first splicing abnormalities in CASQ2 caused by intronic mutation or synonymous change underlines the absolute necessity to perform extensive molecular analysis for genetic diagnosis and counseling of CPVT.","variants":[{"Name":"NM_001232.4(CASQ2):c.381C>T (p.Gly127=)","Chromosome":"1","Start":"115740767","Stop":"115740767","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":789825,"rule_based_match":true,"evidence_text":"c.381C>T","llm_judgment":"PRESENT","evidence":"c.381C>T","abstract_start":595,"abstract_end":603},{"Name":"NM_001232.4(CASQ2):c.939+5G>C","Chromosome":"1","Start":"115705187","Stop":"115705187","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1464374,"rule_based_match":true,"evidence_text":"c.939 + 5G>C","llm_judgment":"PRESENT","evidence":"c.939 + 5G>C","abstract_start":563,"abstract_end":575}]}
{"pmid":"26191240","title":"A missense mutation in TMEM67 causes Meckel-Gruber syndrome type 3 (MKS3): a family from China.","abstract":"Meckel-Gruber syndrome (MKS) is a lethal autosomal recessive condition characterized by renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. Genetic heterogeneity has been demonstrated at eleven loci, MKS1-11. Here, we present the clinical and molecular characteristics of a Chinese MKS3 family with occipital encephalocele and kidney enlargement. DNA sequencing of affected fetuses revealed a homozygous c.1645C>T substitution in exon 16 of TMEM67, leading to a p.R549C substitution in meckelin. The R549 residue is highly conserved across human, rat, mouse, zebrafish, chicken, wolf and platypus genomes. Hha I restriction analysis demonstrated that the c.1645C>T mutation was absent in 200 unrelated control chromosomes of Chinese background, supporting the hypothesis that it represents causative mutation, not rare polymorphism. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype understanding of MKS.","variants":[{"Name":"NM_153704.6(TMEM67):c.1645C>T (p.Arg549Cys)","Chromosome":"8","Start":"93793267","Stop":"93793267","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":524078,"rule_based_match":true,"evidence_text":"c.1645C>T","llm_judgment":"PRESENT","evidence":"c.1645C>T","abstract_start":542,"abstract_end":551}]}
{"pmid":"32730979","title":"Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A>G.","abstract":"BACKGROUND: For most of the >2000 CFTR gene variants reported, neither the associated disease liability nor the underlying basic defect are known, and yet these are essential for disease prognosis and CFTR-based therapeutics. Here we aimed to characterize two ultra-rare mutations - 1717-2A > G (c.1585-2A > G) and S955P (p.Ser955Pro) - as case studies for personalized medicine.\nMETHODS: Patient-derived rectal biopsies and intestinal organoids from two individuals with each of these mutations and F508del (p.Phe508del) in the other allele were used to assess CFTR function, response to modulators and RNA splicing pattern. In parallel, we used cellular models to further characterize S955P independently of F508del and to assess its response to CFTR modulators.\nRESULTS: Results in both rectal biopsies and intestinal organoids from both patients evidence residual CFTR function. Further characterization shows that 1717-2A > G leads to alternative splicing generating <1% normal CFTR mRNA and that S955P affects CFTR gating. Finally, studies in organoids predict that both patients are responders to VX-770 alone and even more to VX-770 combined with VX-809 or VX-661, although to different levels.\nCONCLUSION: This study demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs to patients with rare mutations.","variants":[{"Name":"NM_000492.4(CFTR):c.1585-2A>G","Chromosome":"7","Start":"117587737","Stop":"117587737","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":67958,"rule_based_match":true,"evidence_text":"c.1585-2A>G","llm_judgment":"PRESENT","evidence":"c.1585-2A > G","abstract_start":296,"abstract_end":309}]}
{"pmid":"31750392","title":"A family with spinocerebellar ataxia and retinitis pigmentosa attributed to an","abstract":"Objective: To identify the genetic cause of autosomal dominant spinocerebellar ataxia and retinitis pigmentosa in a large extended pedigree.\nMethods: Clinical studies were done at 4 referral centers. Ten individuals in the same extended family participated in at least a portion of the study. Records were obtained from an 11th, deceased, individual. Neurologic and dermatological examinations were performed. Ophthalmologic evaluation including funduscopic examination and in some cases ocular coherence tomography were used to identify the presence of retinal disease. Whole exome sequencing (WES), in conjunction with Sanger sequencing and segregation analysis, was used to identify potential genetic mutation.\nResults: Affected individuals reported slowly progressive cerebellar ataxia with age at onset between 38 and 57. Imaging demonstrated cerebellar atrophy (3/3). WES identified a novel heterozygous mutation in the elongation of very long chain fatty acids 4 (<i>ELOVL4</i>) gene (c.512T>C, p.Ile171Thr) that segregated with ataxia in 7 members tested. Four of 8 members who underwent ophthalmologic evaluation were found to have retinitis pigmentosa. No skin findings were identified or reported. Ocular movement abnormalities and pyramidal tract signs were also present with incomplete penetrance.\nConclusions: We report a family with both spinocerebellar ataxia and retinal dystrophy associated with an <i>ELOVL4</i> mutation. In addition, to supporting prior reports that <i>ELOVL4</i> mutations can cause spinocerebellar ataxia, our findings further broaden the spectrum of clinical presentations associated with spinocerebellar ataxia 34.","variants":[{"Name":"NM_022726.4(ELOVL4):c.512T>C (p.Ile171Thr)","Chromosome":"6","Start":"79921654","Stop":"79921654","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":428632,"rule_based_match":true,"evidence_text":"c.512T>C, p.Ile171Thr","llm_judgment":"PRESENT","evidence":"c.512T>C, p.Ile171Thr","abstract_start":992,"abstract_end":1013}]}
{"pmid":"16429402","title":"Functional assays testing pathogenicity of 14 cystathionine-beta synthase mutations.","abstract":"In this study, 14 CBS alleles from homocystinuric patients were expressed heterologously in E. coli and their enzyme activities were assayed in vitro. Additionally, mutant CBS proteins were visualized by Western blot from denaturing and non-denaturing polyacrylamide gels. The 14 mutations characterized were: p.R125W (c.373C>T), p.G148R (c.442G>A), p.M173V (c.517A>G), p.T191M (c.572C>T), p.A226T (c.676G>A), p.C275Y (c.824G>A), p.R336C (c.1006C>T), p.R336H (c.1007G>A), p.L338P (c.1013T>C), p.S349N (c.1046G>A), p.R379Q (c.1136G>A), p.L456P (c.1367T>C), p.G522fsX540 (c.1566delG), and p.R548Q (c.1643G>A). Eleven of the mutant alleles exhibited an activity lower than 4% of the wild-type protein. In contrast, mutations p.A226T and p.M173V presented 20% and 40% of the wild-type activity, respectively, whereas the activity of p.R548Q was up to 60% of the wild-type. This suggests that it is a new rare variant rather than a pathogenic mutation. Most of the mutated proteins exhibited a decreased signal in Western blot analyses. The non-denaturing PAGE revealed that the wild-type protein retained the capacity to form a multimeric quaternary structure, whereas in the mutations p.M173V, p.A226T, and p.G548Q, this structure grade was dramatically reduced and was completely absent in the rest of the mutations.","variants":[{"Name":"NM_000071.3(CBS):c.572C>T (p.Thr191Met)","Chromosome":"21","Start":"43065481","Stop":"43065481","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15171,"rule_based_match":true,"evidence_text":"p.T191M (c.572C>T)","llm_judgment":"PRESENT","evidence":"p.T191M (c.572C>T)","abstract_start":370,"abstract_end":388},{"Name":"NM_000071.3(CBS):c.1013T>C (p.Leu338Pro)","Chromosome":"21","Start":"43062337","Stop":"43062337","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1868548,"rule_based_match":true,"evidence_text":"p.L338P (c.1013T>C)","llm_judgment":"PRESENT","evidence":"p.L338P (c.1013T>C)","abstract_start":472,"abstract_end":491},{"Name":"NM_000071.3(CBS):c.1007G>A (p.Arg336His)","Chromosome":"21","Start":"43062343","Stop":"43062343","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":358635,"rule_based_match":true,"evidence_text":"p.R336H (c.1007G>A)","llm_judgment":"PRESENT","evidence":"p.R336H (c.1007G>A)","abstract_start":451,"abstract_end":470},{"Name":"NM_000071.3(CBS):c.1367T>C (p.Leu456Pro)","Chromosome":"21","Start":"43058245","Stop":"43058245","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":848811,"rule_based_match":true,"evidence_text":"p.L456P (c.1367T>C)","llm_judgment":"PRESENT","evidence":"p.L456P (c.1367T>C)","abstract_start":535,"abstract_end":554},{"Name":"NM_000071.3(CBS):c.1136G>A (p.Arg379Gln)","Chromosome":"21","Start":"43060450","Stop":"43060450","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187054,"rule_based_match":true,"evidence_text":"p.R379Q (c.1136G>A)","llm_judgment":"PRESENT","evidence":"p.R379Q (c.1136G>A)","abstract_start":514,"abstract_end":533},{"Name":"NM_000071.3(CBS):c.373C>T (p.Arg125Trp)","Chromosome":"21","Start":"43066321","Stop":"43066321","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":336881,"rule_based_match":true,"evidence_text":"p.R125W (c.373C>T)","llm_judgment":"PRESENT","evidence":"p.R125W (c.373C>T)","abstract_start":310,"abstract_end":328},{"Name":"NM_000071.3(CBS):c.676G>A (p.Ala226Thr)","Chromosome":"21","Start":"43065263","Stop":"43065263","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":358641,"rule_based_match":true,"evidence_text":"p.A226T (c.676G>A)","llm_judgment":"PRESENT","evidence":"p.A226T (c.676G>A)","abstract_start":390,"abstract_end":408},{"Name":"NM_000071.3(CBS):c.442G>A (p.Gly148Arg)","Chromosome":"21","Start":"43066252","Stop":"43066252","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":358643,"rule_based_match":true,"evidence_text":"p.G148R (c.442G>A)","llm_judgment":"PRESENT","evidence":"p.G148R (c.442G>A)","abstract_start":330,"abstract_end":348},{"Name":"NM_000071.3(CBS):c.1643G>A (p.Arg548Gln)","Chromosome":"21","Start":"43053893","Stop":"43053893","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":210393,"rule_based_match":true,"evidence_text":"p.R548Q (c.1643G>A)","llm_judgment":"PRESENT","evidence":"p.R548Q (c.1643G>A)","abstract_start":587,"abstract_end":606},{"Name":"NM_000071.3(CBS):c.1006C>T (p.Arg336Cys)","Chromosome":"21","Start":"43062344","Stop":"43062344","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":98334,"rule_based_match":true,"evidence_text":"p.R336C (c.1006C>T)","llm_judgment":"PRESENT","evidence":"p.R336C (c.1006C>T)","abstract_start":430,"abstract_end":449}]}
{"pmid":"27871768","title":"Red cell pyruvate kinase deficiency in Spain: A study of 15 cases.","abstract":"BACKGROUND AND OBJECTIVE: Pyruvate kinase deficiency (PKD) is a rare, inherited disease causing chronic hemolysis and anemia of varying intensity. The genetic heterogeneity of PKD is high and, to this day, over 240 different mutations have been identified.\nPATIENTS AND METHODS: 15 unrelated patients affected by PKD have been studied. PKLR gene sequencing was performed by SANGER, including the determination of promoter regions, exonic, intronic flanking and 3'UTR.\nRESULTS: Patients were classified into 3 groups based on the intensity of their clinical symptoms: I) severe and very severe (8 patients); II) moderate (2 patients), and III) mild (5 patients). Six out of the 18 alleles found were new mutations which had not been described previously, with the PKLR c.721G>T mutation being the most prevalent (26.67%), followed by the PKLR c.1456C>T mutation (13.33%).\nCONCLUSIONS: In Spain, the genetic heterogeneity of PKLR is still high but differs from that observed in the previous study carried out in 1998. Total PKLR gene sequencing is necessary for the characterization of all patients with PKD and for genetic counseling.","variants":[{"Name":"NM_000298.6(PKLR):c.721G>T (p.Glu241Ter)","Chromosome":"1","Start":"155294726","Stop":"155294726","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":263974,"rule_based_match":true,"evidence_text":"PKLR c.721G>T","llm_judgment":"PRESENT","evidence":"PKLR c.721G>T","abstract_start":763,"abstract_end":776},{"Name":"NM_000298.6(PKLR):c.1456C>T (p.Arg486Trp)","Chromosome":"1","Start":"155291918","Stop":"155291918","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16552,"rule_based_match":true,"evidence_text":"PKLR c.1456C>T","llm_judgment":"PRESENT","evidence":"PKLR c.1456C>T","abstract_start":837,"abstract_end":851}]}
{"pmid":"24735542","title":"A de novo germline mutation of APC for inheritable colon cancer in a Chinese family using multigene next generation sequencing.","abstract":"Inheritable colorectal cancers (CRC) accounted for about 20% of the CRC cases, such as hereditary nonpolyposis colorectal cancer (HNPCC), Gardner syndrome and familial adenomatous polyposis (FAP). A four-generation Han Chinese family was found affected with polyposis in colons. Inferred from the pedigree structure, the disease in this family showed an autosomal dominant inheritance model. To locate the causal mutations in this family, genomic DNAs were extracted and the next generation sequencing for 5 genes relating to colon cancer performed by Ion Torrent Personal Genome Machine with a 314 chip. The reads were aligned with human reference genome hg19 to call variants in the 5 genes. After analysis, 14 variants were detected in the sequenced sample and 13 been collected in dbSNP database and assigned with a rs identification number. In these variants, 9 were synonymous, 4 missense and 1 non-sense. In them, 2 rare variants (c.694C>T in APC and c.1690A>G in MSH2) might be the putative causal mutations for familial adenomatous polyposis (FAP) since the rarity of the mutated allele in normal controls. c.694C>T was detected in only affected members and generated a premature stop codon in APC. It should be a de novo germline mutation making APC containing this stop codon as targets for nonsense-mediated mRNA decay (NMD). c.1690A>G in MSH2 was not only detected in affected members, but also in normal ones in the family. Functional prediction revealed that the amino acid affected by this variant had no effect on the function of MSH2. Here, we report a de novo germline mutation of APC as the causal variant in a Chinese family with inheritable colon cancer by the next generation sequencing.","variants":[{"Name":"NM_000251.3(MSH2):c.1690A>G (p.Thr564Ala)","Chromosome":"2","Start":"47470993","Stop":"47470993","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":96225,"rule_based_match":true,"evidence_text":"c.1690A>G in MSH2","llm_judgment":"PRESENT","evidence":"c.1690A>G in MSH2","abstract_start":958,"abstract_end":975},{"Name":"NM_000038.6(APC):c.694C>T (p.Arg232Ter)","Chromosome":"5","Start":"112792494","Stop":"112792494","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":51418,"rule_based_match":true,"evidence_text":"c.694C>T in APC","llm_judgment":"PRESENT","evidence":"c.694C>T in APC","abstract_start":938,"abstract_end":953}]}
{"pmid":"32980210","title":"Successful cochlear implantation in a patient with Epstein syndrome during long-term follow-up.","abstract":"Epstein syndrome is a rare disease characterized by macrothrombocytopenia, nephritis and progressive sensorineural hearing loss (SNHL). This syndrome is presently recognized as an autosomal dominant disease caused by mutations of non-muscle myosin heavy chain 9 (MYH9). Little information is available about the progress of SNHL, the efficacy of cochlear implants (CI) or the perioperative management of thrombocytopenia in patients with Epstein syndrome. We herein report a case of a patient with Epstein syndrome with the MYH9:c.2105G>A:p.R702H variant who underwent cochlear implantation after 27 years of follow-up for her progressive SNHL. The deterioration rates of hearing were 3.48 dB/year on the right ear and 2.46 dB/year on the left ear. The patient derived benefits from CI and had a speech recognition test result (for sentences) of 93% at 6-months postoperatively. Thrombocytopenia was successfully managed without any bleeding complications by using eltrombopag, an oral thrombopoietic agent, making transfusion of platelets unnecessary. The accurate diagnosis of Epstein syndrome was made only after long-term follow-up as the thrombocytopenia was initially diagnosed as idiopathic thrombocytopenic purpura. This case report highlights the perioperative management of thrombocytopenia, the progress of SNHL and the potential pitfalls of diagnosis.","variants":[{"Name":"NM_002473.6(MYH9):c.2105G>A (p.Arg702His)","Chromosome":"22","Start":"36305984","Stop":"36305984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29120,"rule_based_match":true,"evidence_text":"MYH9:c.2105G>A:p.R702H","llm_judgment":"PRESENT","evidence":"MYH9:c.2105G>A:p.R702H","abstract_start":524,"abstract_end":546}]}
{"pmid":"23927806","title":"Mutation analysis of FAH gene in patients with tyrosinemia type 1","abstract":"OBJECTIVE: To investigate the clinical features and mutations of the FAH gene.\nMETHOD: Clinical records of two cases were collected, and diagnosis was made according to the diagnostic criteria of the International Organization for Rare Disorders (NORD). Genomic DNA was extracted from peripheral blood leukocytes with QIAamp DNA Mini Kit. The DNA extracts were subjected to direct sequencing for 14 exons together with adjacent fragments of FAH gene using ABI Prism 3730 Genetic Analyzer (Applied Biosystems, Foster City, CA) after PCR based on genomic DNA. The mutation source was verified by analyzing parents' exons corresponding to patients' mutation exons. The homology between human FAH enzyme and that of other species was surveyed using software Clustal X(European Bioinformatics Institute, Hinxton, Saffron Walde, UK). Polyphen (Polymorphism Phenotyping), available online, were used to predict possible impact of an amino acid substitution on structure and function of FAH enzyme. Polyphen calculates position-specific independent counts (PISC) scores for two amino acid variants in polymorphic position. A PISC scores that differ by > 2 were regarded as indicating the probability of damaging variants.\nRESULT: Patient 1 was a 5 months and 21 days-old boy who suffered from persistent diarrhea, hepatomegaly, ascites; Alpha-fetoprotein > 1210 µg/L, levels of tyrosine in blood and succinylacetone in urine were 110.8 µmol/L and 83.7 µmol/L. His sister suffered from tyrosinemia type 1. Direct sequencing showed a G to A transition in CDS position 455 and 1027. He was compound heterozygous for the mutation c.455G > A/c.1027G > A, which predicts a change from tryptophan to a stop codon (TGG > TAG) at position 152 (W152X) and a change from glycine to arginine (GGG > AGG) at position 343 respectively. Patient 2 was a 6 year and 1 month-old girl with late-onset rickets who had signs of hepatosplenomegaly, rachitic rosary, windswept knees. Hypophosphatemia and alkaline phosphatase 1620 IU/L were detected. Alpha-fetoprotein 412.8 µg/L, levels of tyrosine in blood and succinylacetone in urine were 835.8 µmol/L and 27.48 µmol/L. Rickets did not improve after administration of calcium and vitamine D3. She is homozygous for the mutation c.1027G > A/c.1027G > A, which predicts G343R. The parents were mutation carriers. Analysis by Clustal X on the alignment of amino acids residual reservation among different species showed that the locative amino acid was highly conserved. Polyphen software predicted G343R was probably damaging (PISC score 3.235).\nCONCLUSION: Children with tyrosinemia type 1 can have manifestations of persistent diarrhea or late-onset rickets. Physical examination can reveal hepatosplenomegaly, laboratory tests indicate markedly elevated serum concentration of alpha-fetoprotein and alkaline phosphatase in plasma and succinylacetone in urine, other members in family may have tyrosinemias or parents are consanguineous. Mutations c.455G > A and c.1027G > A can be detected in FAH gene of Chinese children.","variants":[{"Name":"NM_000137.4(FAH):c.1027G>A (p.Gly343Arg)","Chromosome":"15","Start":"80180190","Stop":"80180190","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":547616,"rule_based_match":true,"evidence_text":"c.1027G > A","llm_judgment":"PRESENT","evidence":"c.1027G > A","abstract_start":1629,"abstract_end":1640},{"Name":"NM_000137.4(FAH):c.455G>A (p.Trp152Ter)","Chromosome":"15","Start":"80162336","Stop":"80162336","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":358330,"rule_based_match":true,"evidence_text":"c.455G > A","llm_judgment":"PRESENT","evidence":"c.455G > A","abstract_start":1618,"abstract_end":1628}]}
{"pmid":"22944127","title":"A survey of 20 inherited protein C deficiencies in the patients with venous thromboembolism","abstract":"OBJECTIVE: To investigate the incidence of inherited protein C deficiency in the patients with venous thromboembolism (VTE).\nMETHODS: From Apr. of 2010 to Apr. of 2011, 106 patients with VTE totally from Renji hospital were surveyed by a series of laboratory tests including clinical biochemistry tests, coagulation factors activities and anticoagulation factors activities. PROC gene mutations were screened by PCR-direct sequencing in the 20 patients with decreased PC activity.\nRESULTS: Among the 20 patients with decreased PC activity, the median activity of factor II, V, VII, VIII, IX, X, XI, XII were 97.0%, 199.9%, 105.5%, 254.7%, 106.4%, 150.4%, 123.1%, 89.9%, respectively.6 PROC gene mutations were found in 11 patients. Six patients have the same point mutation (c.565C > T), the other five mutations were c.508G > T, c.524G > A, c.1174G > A, c.1157T > C, c.577-579del. All of the six mutations were heterozygous, while the c.508G > T, c.524G > A and c.1157T > C were novel in the world.\nCONCLUSIONS: In this study, we found that PC deficiency is the major inherited risk factor of VTE. The most common PROC mutation identified in this study was heterozygous c.565C > T missense mutation., c.508G > T, c.524G > A and c.1157T > C were novel PROC mutation. The activities of factor V and VIII were elevated dramatically among VTE patients, which may be correlated to the disease.","variants":[{"Name":"NM_000312.4(PROC):c.565C>T (p.Arg189Trp)","Chromosome":"2","Start":"127426114","Stop":"127426114","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171067,"rule_based_match":true,"evidence_text":"c.565C > T","llm_judgment":"PRESENT","evidence":"c.565C > T","abstract_start":775,"abstract_end":785}]}
{"pmid":"33431708","title":"Hypopituitarism in Wilson's disease resolved after copper-chelating therapy.","abstract":"SUMMARY: Wilson's disease (WD) is a rare disorder of copper metabolism usually presenting with variable liver damage and neuropsychiatric symptoms. Here we report a 39-year-old Taiwanese female with late manifestation of WD presenting with gonadotroph, thyreotroph and corticotroph hypopituitarism. Molecular genetic testing revealed compound heterozygosity for two mutations in exons 12 and 14 (c.2828G>A and c.3140A>T). Copper-chelating therapy with D-penicillamine and zinc was initiated along with supplementation of hydrocortisone and L-thyroxine. Hypopituitarism resolved when urinary copper excretion returned to normal levels under copper chelation. This case should raise awareness of pituitary function in WD patients.\nLEARNING POINTS: Hypopituitarism can complicate Wilson's disease (WD) and endocrinologists should be aware of it when caring for hypopituitary patients. Hepatologists should consider endocrinologic testing for hypopituitarism when WD patients present with symptoms of adrenal insufficiency, thyroid or gonadal dysfunction. Copper-chelating treatment is mandatory and may lead to the recovery of pituitary function in such patients.","variants":[{"Name":"NM_000053.4(ATP7B):c.3140A>T (p.Asp1047Val)","Chromosome":"13","Start":"51944212","Stop":"51944212","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1063018,"rule_based_match":true,"evidence_text":"c.3140A>T","llm_judgment":"PRESENT","evidence":"c.3140A>T","abstract_start":410,"abstract_end":419}]}
{"pmid":"29353703","title":"Generation of an induced pluripotent stem cell line (CSC-44) from a Parkinson's disease patient carrying a compound heterozygous mutation (c.823C>T and EX6 del) in the PARK2 gene.","abstract":"Mutations in the PARK2 gene, which encodes PARKIN, are the most frequent cause of autosomal recessive Parkinson's disease (PD). We report the generation of an induced pluripotent stem cell (iPSC) line from a 78-year-old patient carrying a compound heterozygous mutation (c.823C>T and EX6del) in the PARK2 gene. Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver OCT3/4, SOX2, c-MYC and KLF4 factors. The generated cell line CSC-44 exhibits expression of common pluripotency markers, in vitro differentiation into the three germ layers and normal karyotype. This iPSC line can be used to explore the association between PARK2 mutations and PD.","variants":[{"Name":"NM_004562.3(PRKN):c.823C>T (p.Arg275Trp)","Chromosome":"6","Start":"161785820","Stop":"161785820","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22089,"rule_based_match":true,"evidence_text":"c.823C>T","llm_judgment":"PRESENT","evidence":"c.823C>T","abstract_start":271,"abstract_end":279}]}
{"pmid":"31096039","title":"When neonatal inflammation does not mean infection: an early-onset mevalonate kinase deficiency with interstitial lung disease.","abstract":"Systemic inflammation in neonates is attributable to an infection in almost all cases. When inflammation persists, an autoinflammatory disease should be promptly suspected. We report here a case of mevalonate kinase deficiency (MKD) that presented at birth with mild symptoms and signs suggestive for a perinatal infection, together with the uncommon finding of interstitial lung disease. An extensive diagnostic work-up, performed after ineffective antibiotic treatment, demonstrated high levels of mevalonic acid in urine (7024 mM/M of creatinine, normal value <0.1). Next-generation sequencing showed a rare c.709A > T (p.T237S) homozygous mutation in the MVK gene, consistent with MKD. Treatment with anakinra led to a prompt resolution of symptoms and a sharp drop in serum inflammatory markers. The patient is now six months-old, currently undergoing evaluation for hematopoietic stem-cell transplantation. To our knowledge, this is the first case of MKD presenting within the first week of life with interstitial lung disease.","variants":[{"Name":"NM_000431.4(MVK):c.709A>T (p.Thr237Ser)","Chromosome":"12","Start":"109590802","Stop":"109590802","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":103504,"rule_based_match":true,"evidence_text":"c.709A > T (p.T237S)","llm_judgment":"PRESENT","evidence":"c.709A > T (p.T237S)","abstract_start":611,"abstract_end":631}]}
{"pmid":"32174067","title":"Rare Cases of PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome in a Korean Family Identified by Next Generation Sequencing.","abstract":"Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive connective tissue disorder characterized by muscular hypotonia, hyperextensible skin, skin fragility, joint hypermobility, and progressive kyphoscoliosis. The disorder results from a deficiency of the enzyme collagen lysyl hydroxylase 1 due to mutations in the gene <i>PLOD1</i>. We describe the rare cases of kEDS in Korean siblings with two novel compound heterozygous variants, c.926_934del (p.Leu309_Leu311del) and c.2170_2172del (p.Phe724del) in the <i>PLOD1</i> gene. They had congenital hypotonia, joint laxity, skin hyperextensibility, Marfanoid habitus, high myopia and atrophic scarring. The younger sibling had an early-onset progressive kyphoscoliosis, while the older sibling showed mild scoliosis during childhood. Intrafamilial variability of the clinical severity and age of kyphoscoliosis onset observed in our cases.","variants":[{"Name":"NM_000302.4(PLOD1):c.2170_2172del (p.Phe724del)","Chromosome":"1","Start":"11974793","Stop":"11974795","ReferenceAlleleVCF":"CCTT","AlternateAlleleVCF":"C","allel_id":1165444,"rule_based_match":true,"evidence_text":"c.2170_2172del (p.Phe724del)","llm_judgment":"PRESENT","evidence":"c.2170_2172del (p.Phe724del)","abstract_start":490,"abstract_end":518}]}
{"pmid":"33245425","title":"Diagnosis of hepatic nuclear factor 1A monogenic diabetes mellitus (HNF1A-MODY) impacts antihyperglycemic treatment.","abstract":"Monogenic mutations of the hepatocyte nuclear factor 1 homeobox A maturity onset diabetes of the young (HNF1A-MODY) is characterized by early onset, typically before the age of 25 years. Patients are often not clinically recognized; however, the identification of HNF1A-MODY patients is crucial because they require different antihyperglycemic medical treatment than patients with type 1 or type 2 diabetes mellitus. We describe two adult patients with monogenic diabetes, both identified as HNF1A-MODY, genetically c.815G>A, p.Arg272His and c675delC, p.Ser225Argfs*8, respectively. They were misdiagnosed as having type 1 diabetes mellitus, and consequently, initiating insulin therapy led to hypoglycemia and unstable blood glucose control. Usually, sulfonylureas represent the basis of antidiabetic treatment in patients with HNF1A-MODY; however, all medical personnel involved in diabetes care should be aware of monogenic diabetes mellitus and the possibilities for genetic testing. The patients observed have shown the necessity of the identification and appropriate genetic diagnosis of HNF1A-MODY in order to discontinue insulin therapy and to initiate adjusted diabetes management.","variants":[{"Name":"NM_000545.8(HNF1A):c.815G>A (p.Arg272His)","Chromosome":"12","Start":"120994265","Stop":"120994265","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29970,"rule_based_match":true,"evidence_text":"c.815G>A, p.Arg272His","llm_judgment":"PRESENT","evidence":"c.815G>A, p.Arg272His","abstract_start":516,"abstract_end":537}]}
{"pmid":"38546523","title":"Novel PTCH1 Mutation Causes Gorlin-Goltz Syndrome.","abstract":"OBJECTIVE: To analyse the aetiology and pathogenesis of Gorlin-Goltz syndrome (GS; also known as nevoid basal cell carcinoma syndrome [NBCCS] or basal cell nevus syndrome [BCNS]) in a Chinese family.\nMETHODS: Whole-exome sequencing (WES) was performed on genomic DNA samples from the subjects in a family, followed by the investigation of pathogenesis via bioinformatic approaches and conformational analysis.\nRESULTS: A novel heterozygous non-frameshift deletion patched 1 (PTCH1) [NM_000264: c.3512_3526del (p.1171_1176del)] was identified by WES and further validated by Sanger sequencing. Bioinformatic and conformational analysis showed that the mutation caused altered PTCH1 protein structure, which may be related to functional abnormalities.\nCONCLUSION: This study expands the mutation spectrum of PTCH1 in GS and facilitates the early diagnosis and screening of GS. PTCH1 [c.3512_3526del (p.1171_1176del)] may cause structural abnormalities and functional disabilities, leading to GS in families.","variants":[{"Name":"NM_000264.5(PTCH1):c.3512_3526del (p.Leu1171_Ser1176delinsPro)","Chromosome":"9","Start":"95449864","Stop":"95449878","ReferenceAlleleVCF":"GACAAAAGCACGGGAA","AlternateAlleleVCF":"G","allel_id":3414878,"rule_based_match":true,"evidence_text":"c.3512_3526del (p.1171_1176del)","llm_judgment":"PRESENT","evidence":"c.3512_3526del (p.1171_1176del)","abstract_start":494,"abstract_end":525}]}
{"pmid":"29469964","title":"Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics.","abstract":"This study investigated the impact of allelic variation in SLCO1B1, a gene encoding for the liver-specific solute carrier organic anion transporter family member 1B1 protein (SLCO1B1), on simvastatin and simvastatin acid (SVA) systemic exposure in children and adolescents. Participants (8-20 years old) with at least 1 variant SLCO1B1 c.521T>C allele (521TC, n = 15; 521CC, n = 2) and 2 wild-type alleles (521TT, n = 15) completed a single oral dose pharmacokinetic study. At equivalent doses, SVA exposure was 6.3- and 2.5-fold greater in 521CC and TC genotypes relative to 521TT (C<sub>max</sub> , 2.1 ± 0.2 vs 1.0 ± 0.5 vs 0.4 ± 0.3 ng/mL; P < .0001; and AUC, 12.1 ± 0.3 vs 4.5 ± 2.5 vs 1.9 ± 1.8 ng·h/mL; P < .0001). The impact of the SLCO1B1 c.521 genotype was more pronounced in children, although considerable interindividual variability in SVA exposure was observed within genotype groups. In addition, SVA systemic exposure was negligible in 25% of pediatric participants. Further investigation of the ontogeny and genetic variation of SVA formation and SLCO1B1-mediated hepatic uptake is necessary to better understand the variability in SVA exposure in children and its clinical consequences.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":true,"evidence_text":"SLCO1B1 c.521T>C","llm_judgment":"PRESENT","evidence":"SLCO1B1 c.521T>C","abstract_start":328,"abstract_end":344}]}
{"pmid":"27098784","title":"Mutation Analysis of MR-1, SLC2A1, and CLCN1 in 28 PRRT2-negative Paroxysmal Kinesigenic Dyskinesia Patients.","abstract":"BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common subtype of paroxysmal dyskinesias and is caused by mutations in PRRT2 gene. The majority of familial PKD was identified to harbor PRRT2 mutations. However, over two-third of sporadic PKD patients did not carry anyPRRT2 mutation, suggesting an existence of additional genetic mutations or possible misdiagnosis due to clinical overlap.\nMETHODS: A cohort of 28 Chinese patients clinically diagnosed with sporadic PKD and excluded PRRT2 mutations were recruited. Clinical features were evaluated, and all subjects were screened for MR-1, SLC2A1, and CLCN1 genes, which are the causative genes of paroxysmal nonkinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia, and myotonia congenita (MC), respectively. In addition, 200 genetically matched healthy individuals were recruited as controls.\nRESULTS: A total of 16 genetic variants including 4 in MR-1 gene, 8 in SLC2A1 gene, and 4 in CLCN1 gene were detected. Among them, SLC2A1 c.363G>A mutation was detected in one case, and CLCN1 c.1205C>T mutation was detected in other two cases. Neither of them was found in 200 controls as well as 1000 Genomes database and ExAC database. Both mutations were predicted to be pathogenic by SIFT and PolyPhen2. The SLC2A1 c.363G>A mutation was novel.\nCONCLUSIONS: The phenotypic overlap may lead to the difficulty in distinguishing PKD from PNKD and MC. For those PRRT2- negative PKD cases, screening of SLC2A1 and CLCN1 genes are useful in confirming the diagnosis.","variants":[{"Name":"NM_006516.4(SLC2A1):c.363G>A (p.Met121Ile)","Chromosome":"1","Start":"42930779","Stop":"42930779","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3859597,"rule_based_match":true,"evidence_text":"SLC2A1 c.363G>A","llm_judgment":"PRESENT","evidence":"SLC2A1 c.363G>A","abstract_start":1008,"abstract_end":1023},{"Name":"NM_000083.3(CLCN1):c.1205C>T (p.Ala402Val)","Chromosome":"7","Start":"143332457","Stop":"143332457","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":302038,"rule_based_match":true,"evidence_text":"CLCN1 c.1205C>T","llm_judgment":"PRESENT","evidence":"CLCN1 c.1205C>T","abstract_start":1063,"abstract_end":1078}]}
{"pmid":"25928149","title":"A study in Polish patients with cardiomyopathy emphasizes pathogenicity of phospholamban (PLN) mutations at amino acid position 9 and low penetrance of heterozygous null PLN mutations.","abstract":"BACKGROUND: In humans mutations in the PLN gene, encoding phospholamban - a regulator of sarcoplasmic reticulum calcium ATPase (SERCA), cause cardiomyopathy with prevalence depending on the population. Our purpose was to identify PLN mutations in Polish cardiomyopathy patients.\nMETHODS: We studied 161 unrelated subjects referred for genetic testing for cardiomyopathies: 135 with dilated cardiomyopathy, 22 with hypertrophic cardiomyopathy and 4 with other cardiomyopathies. In 23 subjects multiple genes were sequenced by next generation sequencing and in all subjects PLN exons were analyzed by Sanger sequencing. Control group included 200 healthy subjects matched with patients for ethnicity, sex and age. Large deletions/insertions were screened by real time polymerase chain reaction.\nRESULTS: We detected three different heterozygous mutations in the PLN gene: a novel null c.9_10insA:(p.Val4Serfs*15) variant and two missense variants: c.25C > T:(p.Arg9Cys) and c.26G > T:(p.Arg9Leu). The (p.Val4Serfs*15) variant occurred in the patient with Wolff-Parkinson-White syndrome in whom the diagnosis of cardiomyopathy was not confirmed and his mother who had concentric left ventricular remodeling but normal left ventricular mass and function. We did not detect large deletions/insertions in PLN in cohort studied.\nCONCLUSIONS: In Poland, similar to most populations, PLN mutations rarely cause cardiomyopathy. The 9(th) PLN residue is apparently a mutation hot spot whereas a single dose of c.9_10insA, and likely other null PLN mutations, cause the disease only with low penetrance or are not pathogenic.","variants":[{"Name":"NM_002667.5(PLN):c.25C>T (p.Arg9Cys)","Chromosome":"6","Start":"118558946","Stop":"118558946","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28675,"rule_based_match":true,"evidence_text":"c.25C > T:(p.Arg9Cys)","llm_judgment":"PRESENT","evidence":"c.25C > T:(p.Arg9Cys)","abstract_start":946,"abstract_end":967},{"Name":"NM_002667.5(PLN):c.26G>T (p.Arg9Leu)","Chromosome":"6","Start":"118558947","Stop":"118558947","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3856518,"rule_based_match":true,"evidence_text":"c.26G > T:(p.Arg9Leu)","llm_judgment":"PRESENT","evidence":"c.26G > T:(p.Arg9Leu)","abstract_start":972,"abstract_end":993}]}
{"pmid":"34337822","title":"Fumarate Hydratase (FH) c.1431_1433dupAAA (p.Lys477dup) variant is not associated with FH protein deficiency and increased 2SC in two separate patients with renal neoplasia.","abstract":"","variants":[{"Name":"NM_000143.4(FH):c.1431_1433dup (p.Lys477dup)","Chromosome":"1","Start":"241497927","Stop":"241497928","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ATTT","allel_id":51261,"rule_based_match":true,"evidence_text":"FH) c.1431_1433dupAAA (p.Lys477dup)","llm_judgment":"PRESENT","evidence":"FH) c.1431_1433dupAAA (p.Lys477dup)","abstract_start":null,"abstract_end":null}]}
{"pmid":"25445412","title":"NMR-based urinalysis for rapid diagnosis of β-ureidopropionase deficiency in a patient with Dravet syndrome.","abstract":"BACKGROUND: Beta-ureidopropionase deficiency is a rare inborn error of metabolism (IEM) affecting pyrimidine metabolism. To-date, about 30 genetically confirmed cases had been reported. The clinical phenotypes of this condition are variable; some patients were asymptomatic while some may present with developmental delay or autistic features. In severe cases, patients may present with profound neurological deficit including hypotonia, seizures and mental retardation. Using NMR-based urinalysis, this condition can be rapidly diagnosed within 15 min.\nCASE: An 11-month-old Chinese boy had dual molecular diagnoses, β-ureidopropionase deficiency and Dravet syndrome. He presented with intractable and recurrent convulsions, global developmental delay and microcephaly. Urine organic acid analysis using GC-MS and NMR-based urinalysis showed excessive amount of β-ureidopropionic acid and β-ureidoisobutyric acid, the two disease-specific markers for β-ureidopropionase deficiency. Genetic analysis confirmed homozygous known disease-causing mutation UPB1 NM_016327.2: c.977G>A; NP_057411.1:p.R326Q. In addition, genetic analysis for Dravet syndrome showed the presence of heterozygous disease-causing mutation SCN1A NM_001165963.1:c.4494delC; NP_001159435.1:p.F1499Lfs*2.\nCONCLUSIONS: The differentiation between Dravet syndrome and β-ureidopropionase deficiency is clinically challenging since both conditions share overlapping clinical features. The detection of urine β-ureidoisobutyric and β-ureidopropionic acids using NMR or GC-MS is helpful in laboratory diagnosis of β-ureidopropionase deficiency. The disease-causing mutation, c.977G>A of β-ureidopropionase deficiency, is highly prevalent in Chinese population (allele frequency=1.7%); β-ureidopropionase deficiency screening test should be performed for any patients with unexplained neurological deficit, developmental delay or autism.","variants":[{"Name":"NM_016327.3(UPB1):c.977G>A (p.Arg326Gln)","Chromosome":"22","Start":"24523679","Stop":"24523679","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227414,"rule_based_match":true,"evidence_text":"UPB1 NM_016327.2: c.977G>A","llm_judgment":"PRESENT","evidence":"UPB1 NM_016327.2: c.977G>A","abstract_start":1052,"abstract_end":1078}]}
{"pmid":"28962114","title":"Clinical and genetic characteristics of pyridoxine-dependent epilepsy: Case series report of three Chinese patients with phenotypic variability.","abstract":"Pyridoxine-dependent epilepsy (PDE) is a rare disorder caused by aldehyde dehydrogenase 7 family member A1 (ALDH7A1) deficiency. The present study reported on three Chinese cases of PDE with phenotypic variability for providing further insight into this disease. All three patients presented with recurrent seizures and readily responded to treatment with pyridoxine, in line with the typical symptomology of PDE. The three cases varied in their clinical manifestations with regard to the time of onset, seizure type, EEG findings and mental development. Four ALDH7A1 mutations were identified in Case 1 (c.1008+1G>A and c.871+5G>A) and Case 2 (c.977A>G and c.1463A>G). To the best of our knowledge, the present study was the first to report on the mutations c.871+5G>A and c.1463A>G. Early definitive diagnosis and timely treatment with pyridoxine was the cornerstone of management of PDE. Timely treatment was associated with excellent prognosis. A high index of suspicion in cases and early genetic testing may facilitate early diagnosis of this rare disease.","variants":[{"Name":"NM_001182.5(ALDH7A1):c.1008+1G>A","Chromosome":"5","Start":"126559239","Stop":"126559239","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":851833,"rule_based_match":true,"evidence_text":"c.1008+1G>A","llm_judgment":"PRESENT","evidence":"c.1008+1G>A","abstract_start":605,"abstract_end":616}]}
{"pmid":"28771254","title":"Multiplex epithelium dysfunction due to CLDN10 mutation: the HELIX syndrome.","abstract":"PurposeWe aimed to identify the genetic cause to a clinical syndrome encompassing hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (HELIX syndrome), and to comprehensively delineate the phenotype.MethodsWe performed homozygosity mapping, whole-genome sequencing, gene sequencing, expression studies, functional tests, protein bioinformatics, and histological characterization in two unrelated families with HELIX syndrome.ResultsWe identified biallelic missense mutations (c.386C>T, p.S131L and c.2T>C, p.M1T) in CLDN10B in six patients from two unrelated families. CLDN10B encodes Claudin-10b, an integral tight junction (TJ) membrane-spanning protein expressed in the kidney, skin, and salivary glands. All patients had hypohidrosis, renal loss of NaCl with secondary hyperaldosteronism and hypokalemia, as well as hypolacrymia, ichthyosis, xerostomia, and severe enamel wear. Functional testing revealed that patients had a decreased NaCl absorption in the thick ascending limb of the loop of Henle and a severely decreased secretion of saliva. Both mutations resulted in reduced or absent Claudin-10 at the plasma membrane of epithelial cells.ConclusionCLDN10 mutations cause a dysfunction in TJs in several tissues and, subsequently, abnormalities in renal ion transport, ectodermal gland homeostasis, and epidermal integrity.","variants":[{"Name":"NM_006984.5(CLDN10):c.2T>C (p.Met1Thr)","Chromosome":"13","Start":"95552755","Stop":"95552755","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":432259,"rule_based_match":true,"evidence_text":"c.2T>C (p.M1T)","llm_judgment":"PRESENT","evidence":"c.2T>C","abstract_start":538,"abstract_end":544}]}
{"pmid":"22171686","title":"Microphthalmia, late onset keratitis, and iris coloboma/aniridia in a family with a novel PAX6 mutation.","abstract":"Autosomal dominant microphthalmia with late-onset keratitis and iris coloboma/aniridia has not been reported before. Here we report a Chinese family with these phenotypes and a novel PAX6 mutation. Microphthalmia, late-onset keratitis, iris coloboma, and nystagmus were present in the proband. His son had microphthalmia, aniridia, foveal hypoplasia, and nystagmus. A novel c.649C>T (p.Arg217X) mutation in PAX6 was detected in the proband and his affected son. This study expands the phenotypic spectrum of PAX6 mutation and enriched our knowledge of the genetic cause for microphthalmia and late-onset keratitis.","variants":[{"Name":"NM_001368894.2(PAX6):c.649C>T (p.Arg217Ter)","Chromosome":"11","Start":"31794705","Stop":"31794705","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18505,"rule_based_match":true,"evidence_text":"c.649C>T (p.Arg217X)","llm_judgment":"PRESENT","evidence":"c.649C>T (p.Arg217X)","abstract_start":374,"abstract_end":394}]}
{"pmid":"37246471","title":"Elevated erythroferrone distinguishes erythrocytosis with inherited defects in oxygen-sensing pathway from primary familial and congenital polycythaemia.","abstract":"Congenital erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular-genetic analysis of 21 Czech patients with congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and iron homoeostasis. Causative mutations in erythropoietin receptor (EPOR), hypoxia-inducible factor 2 alpha (HIF2A) or Von Hippel-Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or Janus kinase 2 (JAK2) variants with other genetic/non-genetic factors in erythrocytosis manifestation may involve variants of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) or Ten-eleven translocation 2 (TET2), but this requires further research. In two families, hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or hepcidin levels was observed in our cohort. VHL- and HIF2A-mutant erythrocytosis showed increased erythroferrone and suppressed hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or therapy. Understanding the interplay between iron metabolism and erythropoiesis in different subgroups of congenital erythrocytosis may improve current treatment options.","variants":[{"Name":"NM_000551.4(VHL):c.340+770T>C","Chromosome":"3","Start":"10142957","Stop":"10142957","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":804891,"rule_based_match":true,"evidence_text":"c.340+770T>C","llm_judgment":"PRESENT","evidence":"c.340+770T>C","abstract_start":544,"abstract_end":556}]}
{"pmid":"27120253","title":"Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome.","abstract":"HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI-anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5' and 3' UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558-10G>A, that causes an aberrant splice product and a mutation in the 3'UTR, c.*559C>T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway.","variants":[{"Name":"NM_033419.5(PGAP3):c.558-10G>A","Chromosome":"17","Start":"39673660","Stop":"39673660","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":226425,"rule_based_match":true,"evidence_text":"c.558-10G>A","llm_judgment":"PRESENT","evidence":"c.558-10G>A","abstract_start":1118,"abstract_end":1129}]}
{"pmid":"20151268","title":"Mutation spectrum of the CYP1B1 gene for congenital glaucoma in the Japanese population.","abstract":"PURPOSE: Mutations of the CYP1B1 gene cause primary congenital glaucoma (PCG), Peters anomaly, and juvenile open-angle glaucoma (JOAG). The aim of this study was to determine the spectrum and role of the CYP1B1 gene in Japanese patients with PCG or JOAG.\nMETHODS: Genomic DNA was extracted from the leukocytes of 18 unrelated patients with PCG and 21 unrelated patients with JOAG. All of the patients developed high intraocular pressure (IOP) before the age of 35 years. One hundred unrelated healthy adults with normal IOP were examined in the same way. The three exons of the CYP1B1 gene were amplified by polymerase chain reaction and directly sequenced.\nRESULTS: Mutational screening and sequence analyses of the CYP1B1 gene revealed four mutations in four patients with PCG: p.Asp192Val, c.4776insAT, p.Val364Met, and p.Asp430Glu. The first three mutations have been reported in other Japanese PCG patients, but Asp430Glu is a new mutation. No mutations were found in the CYP1B1 gene of the JOAG patients.\nCONCLUSIONS: PCG in approximately 20% of Japanese patients may be associated with CYP1B1 mutations, but JOAG is not. The three mutations p.Asp192Val, c.4776insAT, and p.Val364Met appear to be common in the Japanese population and might be useful in genetic screening for PCG.","variants":[{"Name":"NM_000104.4(CYP1B1):c.575A>T (p.Asp192Val)","Chromosome":"2","Start":"38074814","Stop":"38074814","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2835658,"rule_based_match":false,"evidence_text":"p.Asp192Val","llm_judgment":"PRESENT","evidence":"p.Asp192Val","abstract_start":780,"abstract_end":791},{"Name":"NM_000104.4(CYP1B1):c.1090G>A (p.Val364Met)","Chromosome":"2","Start":"38071264","Stop":"38071264","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1330879,"rule_based_match":false,"evidence_text":"p.Val364Met","llm_judgment":"PRESENT","evidence":"p.Val364Met","abstract_start":806,"abstract_end":817}]}
{"pmid":"25127531","title":"Aberrant hetero-disulfide bond formation by the hypertriglyceridemia-associated p.Gly185Cys APOA5 variant (rs2075291).","abstract":"OBJECTIVE: Apolipoprotein A-V (apoA-V) is a low-abundance plasma protein that modulates triacylglycerol homeostasis. Gene transfer studies were undertaken in apoa5 (-/-) mice to define the mechanism underlying the correlation between the single-nucleotide polymorphism c.553G>T in APOA5 and hypertriglyceridemia.\nAPPROACH AND RESULTS: Adeno-associated virus (AAV) 2/8-mediated gene transfer of wild-type apoA-V induced a dramatic lowering of plasma triacylglycerol in apoa5 (-/-) mice, whereas AAV2/8-Gly162Cys apoA-V (corresponding to the c.553G>T single-nucleotide polymorphism: rs2075291; p.Gly185Cys when numbering includes signal sequence) had a modest effect. Characterization studies revealed that plasma levels of wild-type and G162C apoA-V in transduced mice were similar and within the physiological range. Fractionation of plasma from mice transduced with AAV2/8-G162C apoA-V indicated that, unlike wild-type apoA-V, >50% of G162C apoA-V was recovered in the lipoprotein-free fraction. Nonreducing SDS-PAGE immunoblot analysis provided evidence that G162C apoA-V present in the lipoprotein-free fraction, but not that portion associated with lipoproteins, displayed altered electrophoretic mobility consistent with disulfide-linked heterodimer formation. Immunoprecipitation followed by liquid chromatography/mass spectrometry of human plasma from subjects homozygous for wild-type APOA5 and c.553G>T APOA5 revealed that G162C apoA-V forms adducts with extraneous plasma proteins including fibronectin, kininogen-1, and others.\nCONCLUSIONS: Substitution of Cys for Gly at position 162 of mature apoA-V introduces a free cysteine that forms disulfide bonds with plasma proteins such that its lipoprotein-binding and triacylglycerol-modulation functions are compromised.","variants":[{"Name":"NM_001371904.1(APOA5):c.553G>T (p.Gly185Cys)","Chromosome":"11","Start":"116790676","Stop":"116790676","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":19441,"rule_based_match":true,"evidence_text":"c.553G>T","llm_judgment":"PRESENT","evidence":"c.553G>T","abstract_start":269,"abstract_end":277}]}
{"pmid":"29230160","title":"Whole-Exome Sequencing Identifies a de novo","abstract":"Xia-Gibbs syndrome is an autosomal dominant multisystem developmental disorder characterized by global developmental delay, hypotonia, obstructive sleep apnea, seizures, retrocerebellar cysts, delayed myelination, micrognathia, and mild dysmorphic features. Using whole-exome sequencing, we identified a de novo <i>AHDC1</i> frameshift mutation c.2030_2030delG (p.G677Afs*52) in a Colombian patient, which was absent in both parents. Furthermore, we summarized the phenotypes of patients reported in the literature.","variants":[{"Name":"NM_001371928.1(AHDC1):c.2030del (p.Gly677fs)","Chromosome":"1","Start":"27550086","Stop":"27550086","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":975935,"rule_based_match":false,"evidence_text":"c.2030_2030delG (p.G677Afs*52)","llm_judgment":"PRESENT","evidence":"c.2030_2030delG (p.G677Afs*52)","abstract_start":345,"abstract_end":375}]}
{"pmid":"38286424","title":"A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism.","abstract":"Biallelic variants in PTRHD1 have been linked to autosomal recessive intellectual disability, spasticity, and juvenile parkinsonism with only a limited number of patients reported so far. Here, we describe the clinical and genetic findings of another female individual of Austrian origin who also experienced infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, all of which are in concordance with the known phenotypic spectrum. In addition, she developed genetic generalized epilepsy around the age of 4 years, persisting into adulthood. Using diagnostic exome sequencing, we identified the homozygous missense variant c.365G>A, p.(Arg122Gln) in PTRHD1 (NM_001013663). In conclusion, we confirm previous reports suggesting an association between biallelic PTRHD1 variants and parkinsonism with neurodevelopmental abnormalities. Moreover, we hypothesize that generalized epilepsy may be part of the phenotypic spectrum.","variants":[{"Name":"NM_001013663.2(PTRHD1):c.365G>A (p.Arg122Gln)","Chromosome":"2","Start":"24790469","Stop":"24790469","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222194,"rule_based_match":true,"evidence_text":"c.365G>A, p.(Arg122Gln)","llm_judgment":"PRESENT","evidence":"c.365G>A, p.(Arg122Gln)","abstract_start":680,"abstract_end":703}]}
{"pmid":"38066485","title":"Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions.","abstract":"BACKGROUND: TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations.\nMETHODS: In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity.\nRESULTS: We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability.\nCONCLUSIONS: This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.","variants":[{"Name":"NM_138691.3(TMC1):c.1256T>C (p.Phe419Ser)","Chromosome":"9","Start":"72791917","Stop":"72791917","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1952219,"rule_based_match":true,"evidence_text":"c.1256T > C:p.Phe419Ser","llm_judgment":"PRESENT","evidence":"c.1256T > C:p.Phe419Ser","abstract_start":1155,"abstract_end":1178}]}
{"pmid":"26348468","title":"SPINK1 Promoter Variants in Chronic Pancreatitis.","abstract":"OBJECTIVES: Serine protease inhibitor Kazal type 1 (SPINK1) provides an important line of defense against premature trypsinogen activation within the pancreas. Our aim was to identify pathogenic SPINK1 promoter variants associated with chronic pancreatitis (CP).\nMETHODS: One hundred CP patients (cases) and 100 controls with no pancreatic disease from the Hungarian National Pancreas Registry were enrolled. Direct sequencing of SPINK1 promoter region was performed. Functional characterization of variants was carried out using luciferase reporter gene assay.\nRESULTS: Two common polymorphisms (c.-253T>C and c.-807C>T) were found in both cases and controls. Variant c.253T>C was enriched in cases relative to controls (odds ratio, 2.1; 95% confidence interval, 1.2-3.8; P = 0.015). Variant c.-215G>A was detected in 3 of 100 cases; always linked with the pathogenic variant c.194+2T>C. Novel promoter variants c.-14G>A, c.-108G>T, and c.-246A>G were identified in 1 case each. Functional analysis showed decreased promoter activity for variants c.-14G>A (80%), c.-108G>T (31%), and c.-246A>G (47%) whereas activity of variant c.-215G>A was increased (201%) and variant c.-253T>C was unchanged compared with wild type.\nCONCLUSIONS: The common promoter variant c.-253T>C was associated with CP in this cohort. Two of 3 newly identified SPINK1 promoter variants seem to exhibit significant functional defects and should be considered potential risk factors for CP.","variants":[{"Name":"NM_003122.5(SPINK1):c.-108G>T","Chromosome":"5","Start":"147831685","Stop":"147831685","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":893274,"rule_based_match":true,"evidence_text":"c.-108G>T","llm_judgment":"PRESENT","evidence":"c.-108G>T","abstract_start":923,"abstract_end":932},{"Name":"NM_001379610.1(SPINK1):c.-14G>A","Chromosome":"5","Start":"147831591","Stop":"147831591","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":983958,"rule_based_match":true,"evidence_text":"c.-14G>A","llm_judgment":"PRESENT","evidence":"c.-14G>A","abstract_start":913,"abstract_end":921}]}
{"pmid":"26849110","title":"ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.","abstract":"Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.","variants":[{"Name":"NM_020832.3(ZNF687):c.2810C>G (p.Pro937Arg)","Chromosome":"1","Start":"151289853","Stop":"151289853","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":224708,"rule_based_match":true,"evidence_text":"c.2810C>G (p.Pro937Arg)","llm_judgment":"PRESENT","evidence":"c.2810C>G (p.Pro937Arg)","abstract_start":515,"abstract_end":538}]}
{"pmid":"20370797","title":"High frequency of ETFDH c.250G>A mutation in Taiwanese patients with late-onset lipid storage myopathy.","abstract":"Lipid storage myopathies (LSMs) are characterized pathologically by the accumulation of lipid droplets in muscle fibers due to impaired cellular lipid metabolism. The purpose of this study was to determine etiologies and genetic mutations associated with LSMs in ethnic Han Taiwanese. The usefulness of the blood acylcarnitine (AC) profile for diagnosing LSMs in adult patients was also investigated. Nine patients were diagnosed with late-onset LSMs following a review of muscle biopsies and medical records and were recruited retrospectively. Genetic studies were performed to detect mutations in the SLC22A5 for primary carnitine deficiency, PNPLA2 for neutral lipid storage disease with myopathy, ABHD5 for neutral lipid storage disease with ichthyosis, ETFDH for multiple acyl-CoA dehydrogenation deficiency (MADD), and CPT2 for carnitine palmitoyltransferase II deficiency. Blood AC levels were measured by tandem mass spectrometry. The mutation c.250G>A in ETFDH was detected in seven (78%) patients, six of whom were homozygous for the variant. Patients with ETFDH mutations had elevated blood levels of ACs ranging from C8 to C16 species, a pattern consistent with MADD. ETFDH c.250G>A mutation is common in Taiwanese patients with late-onset LSMs. The blood AC profile is a sensitive biochemical marker for diagnosing MADD arising from ETFDH mutations in adults.","variants":[{"Name":"NM_004453.4(ETFDH):c.250G>A (p.Ala84Thr)","Chromosome":"4","Start":"158682269","Stop":"158682269","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27067,"rule_based_match":true,"evidence_text":"ETFDH c.250G>A","llm_judgment":"PRESENT","evidence":"ETFDH c.250G>A","abstract_start":1180,"abstract_end":1194}]}
{"pmid":"33278322","title":"G970R-CFTR Mutation (c.2908G>C) Results Predominantly in a Splicing Defect.","abstract":"In previous work, participants with a G970R mutation in cystic fibrosis transmembrane conductance regulator (CFTR) (c.2908G>C) had numerically lower sweat chloride responses during ivacaftor treatment than participants with other CFTR gating mutations. The objective of this substudy was to characterize the molecular defect of the G970R mutation in vitro and assess the benefit of ivacaftor in participants with this mutation. This substudy assessed sweat chloride, spirometry findings, and nasal potential difference on and off ivacaftor treatment in three participants with a G970R/F508del genotype. Intestinal organoids derived from rectal biopsy specimens were used to assess ivacaftor response ex vivo and conduct messenger RNA splice and protein analyses. No consistent or meaningful trends were observed between on-treatment and off-treatment clinical assessments. Organoids did not respond to ivacaftor in forskolin-induced swelling assays; no mature CFTR protein was detected in Western blots. Organoid RNA analysis demonstrated that 3 novel splice variants were created by G970R-CFTR: exon 17 truncation, exons 13-15 and 17 skipping, and intron 17 retention. Functional and molecular analyses indicated that the c.2908G>C mutation caused a cryptic splicing defect. Organoids lacked an ex vivo response with ivacaftor and supported identification of the mechanism underlying the CFTR defect caused by c.2908G>C. Analysis of CFTR mutations indicated that cryptic splicing was a rare cause of mutation misclassification in engineered cell lines. This substudy used organoids as an alternative in vitro model for mutations, such as cryptic splice mutations that cannot be fully assessed using cDNA expressed in recombinant cell systems.","variants":[{"Name":"NM_000492.4(CFTR):c.2908G>C (p.Gly970Arg)","Chromosome":"7","Start":"117603782","Stop":"117603782","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":68258,"rule_based_match":true,"evidence_text":"c.2908G>C","llm_judgment":"PRESENT","evidence":"c.2908G>C","abstract_start":116,"abstract_end":125}]}
{"pmid":"33531666","title":"A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features.","abstract":"PURPOSE: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10.\nMETHODS: Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry.\nRESULTS: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein.\nCONCLUSION: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.","variants":[{"Name":"NM_206538.4(EMC10):c.287del (p.Gly96fs)","Chromosome":"19","Start":"50479053","Stop":"50479053","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":976525,"rule_based_match":true,"evidence_text":"EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9)","llm_judgment":"PRESENT","evidence":"EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9)","abstract_start":803,"abstract_end":855}]}
{"pmid":"25778885","title":"Gene analysis in a family of hereditary hemorrhagic telangiectasia","abstract":"OBJECTIVE: To investigate the clinical feature of a family with hereditary hemorrhagic telangiectasia (HHT), and to study the mutation of its related genes.\nMETHODS: Medical histories of the family were analyzed to detect HHT patients according to the diagnostic criteria. ENG and ALK-1 genes of the proband and her two daughters were analyzed. DNA from the three patients' peripheral blood was extracted. The exons 2-10 and their intron-exon boundaries of ALK1 were amplified with PCR, and then the PCR products were sequenced and analyzed to identify the mutation.\nRESULTS: There were 11 people in 41 family members of 4 generations were diagnosed as HHT. The proband and her two daughters suffered from multiple organ damage, the younger daughter appeared only imaging features instead of corresponding clinical symptoms. A missense mutation at the 1321 bp of cDNA (c.1321G>A) was detected in the exon 9 of ALK1, which resulted in valine 441 to methionine replacement in ALK-1 protein (p.Val441Met).\nCONCLUSION: A Chinese family with HHT was studied and a missense mutation (c.1321G>A, p.Val441Met) of ALK-1 was discovered. This mutation is the genetic basis of the family with HHT and is reported for the first time in China. This research will not only help to further investigate molecular mechanism of pathogenesis of HTT, but also provide evidences and references for the following gene screening and genetic counseling on HTT family members.","variants":[{"Name":"NM_000020.3(ACVRL1):c.1321G>A (p.Val441Met)","Chromosome":"12","Start":"51919059","Stop":"51919059","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":609847,"rule_based_match":true,"evidence_text":"c.1321G>A (p.Val441Met)","llm_judgment":"PRESENT","evidence":"p.Val441Met","abstract_start":989,"abstract_end":1000}]}
{"pmid":"25286830","title":"Cranial nerve and cervical root enhancement in an infant with polymerase gamma mutation mitochondrial disease.","abstract":"BACKGROUND: Nuclear polymerase gamma (POLG) mutations are the most common cause of inherited mitochondrial disease. POLG mutation diseases have a broad spectrum of clinical manifestations; the lethal infantile form is myocerebrohepatopathy spectrum.\nPATIENT: A 4-month-old boy was referred for poor feeding, emesis, failure to thrive, and hypotonia.\nRESULTS: Brain computed tomography was normal. Brain magnetic resonance imaging with and without contrast demonstrated bilateral enhancement of cranial nerves III, V-X, and the upper and midcervical nerve roots. Liver biopsy revealed early cirrhosis, steatosis, and focal necrosis. Muscle biopsy did not demonstrate specific abnormalities of mitochondrial morphology or number. Electron transport chain analysis of both fibroblasts and muscle demonstrated deficiencies. Because of suspected mitochondrial depletion disorder, testing was performed for mitochondrial abnormalities including analysis of the POLG gene, which revealed two pathogenic mutations, c.1399G>A (p.A467T) and c.3285C>G (p.S1095R).\nCONCLUSIONS: We report abnormal gadolinium enhancement of multiple cranial nerves and cervical nerve roots in an infant with myocerebrohepatopathy spectrum disease whose brain MRI otherwise revealed only mild atrophy. Mitochondrial disease should be included in the differential diagnosis of cranial nerve enhancement. Contrast-enhanced MRI aids in the diagnostic evaluation of infants with developmental delay and suspected neurological disease.","variants":[{"Name":"NM_002693.3(POLG):c.3285C>G (p.Ser1095Arg)","Chromosome":"15","Start":"89318738","Stop":"89318738","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":376748,"rule_based_match":true,"evidence_text":"c.3285C>G (p.S1095R)","llm_judgment":"PRESENT","evidence":"c.3285C>G (p.S1095R)","abstract_start":1031,"abstract_end":1051},{"Name":"NM_002693.3(POLG):c.1399G>A (p.Ala467Thr)","Chromosome":"15","Start":"89327201","Stop":"89327201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28535,"rule_based_match":true,"evidence_text":"c.1399G>A (p.A467T)","llm_judgment":"PRESENT","evidence":"c.1399G>A (p.A467T)","abstract_start":1007,"abstract_end":1026}]}
{"pmid":"18828154","title":"Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion.","abstract":"We studied six unrelated children with depletion of mitochondrial DNA (mtDNA). They presented with Leigh syndrome, infantile hepatocerebral mtDNA depletion syndrome, or Alpers-Huttenlocher syndrome. Several genes have been implicated in mtDNA depletion. Screening of candidate genes indicated that all six patients were compound heterozygous for missense mutations in the gene for the catalytic subunit of DNA polymerase gamma (POLG). Three of the identified mutations, c.3328C>T (p.H1110Y), c.3401A>G (p.H1134R), and c.3406G>A (p.E1136K), have not been reported earlier. To investigate the functional consequences of the mutations, we carried out a series of biochemical assays in cultured fibroblasts. These studies revealed that fibroblast cultures from the patients with infantile hepatocerebral mtDNA depletion syndrome progressively lost their mtDNA during culturing, whereas fibroblast cultures from patients presenting with Leigh syndrome or Alpers-Huttenlocher syndrome had reduced but stable levels of mtDNA. DNA polymerase gamma activity was below the normal range in all patient cultures, except for one; however, this culture showed low levels of the heterodimeric enzyme and poor DNA polymerase gamma processivity. Parental fibroblast cultures had normal catalytic efficiency of DNA polymerase gamma, consistent with the observation that all carriers are asymptomatic. Thus, we report the first patient with Leigh syndrome caused by POLG mutations. The cell culture experiments established the pathogenicity of the identified POLG mutations and helped to define the molecular mechanisms responsible for mtDNA depletion in the patients' tissues. The assays may facilitate the identification of those patients in whom screening for POLG mutations would be most appropriate.","variants":[{"Name":"NM_002693.3(POLG):c.3328C>T (p.His1110Tyr)","Chromosome":"15","Start":"89318695","Stop":"89318695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1515311,"rule_based_match":true,"evidence_text":"c.3328C>T (p.H1110Y)","llm_judgment":"PRESENT","evidence":"c.3328C>T (p.H1110Y)","abstract_start":470,"abstract_end":490}]}
{"pmid":"31015375","title":"Beyond an Obvious Cause of Cholestasis in a Toddler: Compound Heterozygosity for","abstract":"A 27-month-old girl presented with a short history of jaundice initially attributed to drug-induced liver injury. During the preceding 20 days, she had received a 10-day course of cefprozil and 2 doses of a homeopathic preparation of cantharidin for cystitis. Severe conjugated hyperbilirubinemia was present with normal γ-glutamyl transpeptidase activity. Liver biopsy revealed marked canalicular and hepatocellular cholestasis, with moderate hepatocellular disarray, as well as evidence of chronicity, including moderate portal-tract and perisinusoidal fibrosis. Immunohistochemical studies revealed that bile salt export pump expression was preserved, whereas canalicular γ-glutamyl transpeptidase expression was largely absent. An inherited cholestatic disorder was suspected. The entire coding region of <i>ABCB11</i>, encoding bile salt export pump, was analyzed. The patient was found to be a compound heterozygote for the missense mutation c.3148C>T (p.Arg1050Cys) associated with benign recurrent intrahepatic cholestasis type 2 in the homozygous state and for the nonsense mutation c.3904G>T (p.Glu1302Ter) associated with progressive familial intrahepatic cholestasis type 2. Despite initial improvement with ursodeoxycholic acid, over the course of 5 years the patient developed cirrhosis that required liver transplant. Our report emphasizes the need for molecular studies even in patients with putatively \"explained\" cholestasis to reveal the entire spectrum of inherited cholestatic disorders.","variants":[{"Name":"NM_003742.4(ABCB11):c.3904G>T (p.Glu1302Ter)","Chromosome":"2","Start":"168923684","Stop":"168923684","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1428599,"rule_based_match":true,"evidence_text":"c.3904G>T (p.Glu1302Ter)","llm_judgment":"PRESENT","evidence":"c.3904G>T (p.Glu1302Ter)","abstract_start":1092,"abstract_end":1116},{"Name":"NM_003742.4(ABCB11):c.3148C>T (p.Arg1050Cys)","Chromosome":"2","Start":"168932442","Stop":"168932442","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360825,"rule_based_match":true,"evidence_text":"c.3148C>T (p.Arg1050Cys)","llm_judgment":"PRESENT","evidence":"c.3148C>T (p.Arg1050Cys)","abstract_start":948,"abstract_end":972}]}
{"pmid":"33269076","title":"Identification of novel variants in the","abstract":"Familial hypercholesterolemia (FH) is caused by mutations in various genes, including the <i>LDLR</i>, <i>APOB</i> and <i>PSCK9</i> genes; however, the spectrum of these mutations in Russian individuals has not been fully investigated. In the present study, mutation screening was performed on the <i>LDLR</i> gene and other FH-associated genes in patients with definite or possible FH, using next-generation sequencing. In total, 59 unrelated patients were recruited and sorted into two separate groups depending on their age: Adult (n=31; median age, 49; age range, 23-70) and children/adolescent (n=28; median age, 11; age range, 2-21). FH-associated variants were identified in 18 adults and 25 children, demonstrating mutation detection rates of 58 and 89% for the adult and children/adolescent groups, respectively. In the adult group, 13 patients had FH-associated mutations in the <i>LDLR</i> gene, including two novel variants [NM_000527.4: c.433_434dupG p.(Val145Glyfs*35) and c.1186G>C p.(Gly396Arg)], 3 patients had <i>APOB</i> mutations and two had <i>ABCG5/G8</i> mutations. In the children/adolescent group, 21 patients had FH-causing mutations in the <i>LDLR</i> gene, including five novel variants [NM_000527.4: c.325T>G p.(Cys109Gly), c.401G>C p.(Cys134Ser), c.616A>C p.(Ser206Arg), c.1684_1691delTGGCCCAA p.(Pro563Hisfs*14) and c.940+1_c.940+4delGTGA], and 2 patients had <i>APOB</i> mutations, as well as <i>ABCG8</i> and <i>LIPA</i> mutations, being found in different patients. The present study reported seven novel <i>LDLR</i> variants considered to be pathogenic or likely pathogenic. Among them, four missense variants were located in the coding regions, which corresponded to functional protein domains, and two frameshifts were identified that produced truncated proteins. These variants were observed only once in different patients, whereas a splicing variant in intron 6 (c.940+1_c.940+4delGTGA) was detected in four unrelated individuals. Previously reported variants in the <i>LDLR, APOB, ABCG5/8</i> and <i>LIPA</i> genes were observed in 33 patients. The <i>LDLR</i> p.(Gly592Glu) variant was detected in 6 patients, representing 10% of the FH cases reported in the present study, thus it may be a major variant present in the Russian population. In conclusion, the present study identified seven novel variants of the <i>LDLR</i> gene and broadens the spectrum of mutations in FH-related genes in the Russian Federation.","variants":[{"Name":"NM_000527.5(LDLR):c.401G>C (p.Cys134Ser)","Chromosome":"19","Start":"11105307","Stop":"11105307","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":857606,"rule_based_match":true,"evidence_text":"NM_000527.4: c.401G>C p.(Cys134Ser)","llm_judgment":"PRESENT","evidence":"c.401G>C","abstract_start":1253,"abstract_end":1261}]}
{"pmid":"15923275","title":"Disruption of an exon splicing enhancer in exon 3 of MLH1 is the cause of HNPCC in a Quebec family.","abstract":"BACKGROUND: A 3 bp deletion located at the 5' end of exon 3 of MLH1, resulting in deletion of exon 3 from RNA, was recently identified.\nHYPOTHESIS: That this mutation disrupts an exon splicing enhancer (ESE) because it occurs in a purine-rich sequence previously identified as an ESE in other genes, and ESEs are often found in exons with splice signals that deviate from the consensus signals, as does the 3' splice signal in exon 3 of MLH1.\nDESIGN: The 3 bp deletion and several other mutations were created by polymerase chain reaction mutagenesis and tested using an in vitro splicing assay. Both mutant and wild type exon 3 sequences were cloned into an exon trapping vector and transiently expressed in Cos-1 cells.\nRESULTS: Analysis of the RNA indicates that the 3 bp deletion c.213_215delAGA (gi:28559089, NM_000249.2), a silent mutation c.216T-->C, a missense mutation c.214G-->C, and a nonsense mutation c.214G-->T all cause varying degrees of exon skipping, suggesting the presence of an ESE at the 5' end of exon 3. These mutations are situated in a GAAGAT sequence 3 bp downstream from the start of exon 3.\nCONCLUSIONS: The results of the splicing assay suggest that inclusion of exon 3 in the mRNA is ESE dependent. The exon 3 ESE is not recognised by all available motif scoring matrices, highlighting the importance of RNA analysis in the detection of ESE disrupting mutations.","variants":[{"Name":"NM_000249.4(MLH1):c.214G>T (p.Asp72Tyr)","Chromosome":"3","Start":"37000961","Stop":"37000961","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":519288,"rule_based_match":false,"evidence_text":"c.214G-->T","llm_judgment":"PRESENT","evidence":"c.214G-->T","abstract_start":914,"abstract_end":924}]}
{"pmid":"30911575","title":"Leigh syndrome caused by mutations in","abstract":"Objectives: Mitochondrial methionyl-tRNA formyltransferase (MTFMT) is required for the initiation of translation and elongation of mitochondrial protein synthesis<b>.</b> Pathogenic variants in <i>MTFMT</i> have been associated with Leigh syndrome (LS) and mitochondrial multiple respiratory chain deficiencies. We sought to elucidate the spectrum of clinical, neuroradiological and molecular genetic findings of patients with bi-allelic pathogenic variants in <i>MTFMT</i>.\nMethods: Retrospective cohort study combining new cases and previously published cases.\nResults: Thirty-eight patients with pathogenic variants in <i>MTFMT</i> were identified, including eight new cases. The median age of presentation was 14 months (range: birth to 17 years, interquartile range [IQR] 4.5 years), with developmental delay and motor symptoms being the most frequent initial manifestation. Twenty-nine percent of the patients survived into adulthood. MRI headings in <i>MTFMT</i> pathogenic variants included symmetrical basal ganglia changes (62%), periventricular and subcortical white matter abnormalities (55%), and brainstem lesions (48%). Isolated complex I and combined respiratory chain deficiencies were identified in 31% and 59% of the cases, respectively. Reduction of the mitochondrial complex I and complex IV subunits was identified in the fibroblasts (13/13). Sixteen pathogenic variants were identified, of which c.626C>T was the most common. Seventy-four percent of the patients were alive at their last clinical review (median 6.8 years, range: 14 months to 31 years, IQR 14.5 years).\nInterpretation: Patients that harbour pathogenic variants in <i>MTFMT</i> have a milder clinical phenotype and disease progression compared to LS caused by other nuclear defects. Fibroblasts may preclude the need for muscle biopsy, to prove causality of any novel variant.","variants":[{"Name":"NM_139242.4(MTFMT):c.626C>T (p.Ser209Leu)","Chromosome":"15","Start":"65021533","Stop":"65021533","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48426,"rule_based_match":true,"evidence_text":"c.626C>T","llm_judgment":"PRESENT","evidence":"c.626C>T","abstract_start":1419,"abstract_end":1427}]}
{"pmid":"37715637","title":"A Rare Case of Synchronous Fumarate Hydratase-Deficient Renal Cell Carcinoma and Clear Cell Renal Cell Carcinoma With Fumarate Hydratase and von Hippel-Lindau Gene Mutations: A Clinicopathologic and Molecular Study.","abstract":"Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and aggressive tumor characterized by pathogenic alterations in the fumarate hydratase (<i>FH</i>) gene. Clear cell renal cell carcinoma (clear cell RCC) is a common renal cell carcinoma (RCC) associated with von Hippel-Lindau (<i>VHL</i>) gene variations. Here, we reported a case of bilateral RCCs. A 60-year-old man was admitted to hospital with a 3.6 cm × 3.3 cm mass in the right kidney and a 2.8 cm × 2.3 cm nodule in the left kidney. Pathologically, the right tumor showed a nested growth pattern of cells with clear cytoplasm and was FH positive and 2-succinylcysteine (2SC) negative. The left tumor demonstrated a high-grade papillary pattern and was FH negative and 2SC positive. Whole-exome sequencing and Sanger sequencing identified a germline <i>FH</i> c.563A > T mutation in both the tumors and an additional somatic <i>VHL</i> c.479_480insA mutation in the right tumor, confirming the diagnosis of clear cell RCC and FH-deficient RCC in the right and left kidneys, respectively. We reported a rare case of synchronous bilateral clear cell RCC (right) and FH-deficient RCC (left) likely driven by somatic <i>VHL</i> mutation and germline <i>FH</i> mutation, respectively.","variants":[{"Name":"NM_000143.4(FH):c.563A>T (p.Asn188Ile)","Chromosome":"1","Start":"241508778","Stop":"241508778","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1054825,"rule_based_match":true,"evidence_text":"FH c.563A > T","llm_judgment":"PRESENT","evidence":"FH</i> c.563A > T","abstract_start":839,"abstract_end":856}]}
{"pmid":"28124177","title":"TFG associated hereditary spastic paraplegia: an addition to the phenotypic spectrum.","abstract":"Hereditary spastic paraplegias (HSPs) constitute movement disorders with extreme lower limb spasticity caused by axonopathies of the upper motor neurons. We describe two siblings affected with a recessive form of movement disorder. Whole-exome sequencing revealed a homozygous missense mutation c.64 C>T (p.Arg22Trp) in TFG as cause of the disorder. Comparison of the phenotype of the patients of this study, with that reported previously, revealed differences in the severity of the disorder as well as new clinical findings. These include presence of clonus, undeveloped speech, and sleep disturbances. Our findings extend the phenotypic spectrum associated with the TFG mutations in HSP.","variants":[{"Name":"NM_006070.6(TFG):c.64C>T (p.Arg22Trp)","Chromosome":"3","Start":"100713749","Stop":"100713749","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1432009,"rule_based_match":true,"evidence_text":"c.64 C>T (p.Arg22Trp)","llm_judgment":"PRESENT","evidence":"c.64 C>T (p.Arg22Trp)","abstract_start":295,"abstract_end":316}]}
{"pmid":"33048237","title":"Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy.","abstract":"We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant discovered variants. Immunofluorescence (IF) experiment was performed to investigate the role of the causative gene in neuron development. The large consanguineous family confirms the phenotype-causative relationship with homozygous frameshift variant (NM_004713.6:c.2618del) as revealed by ES. Linkage analysis of the family showed a significant single-point LOD of 4.5 locus. Through collaboration in GeneMatcher, four additional unrelated families' likely pathogenic NEMF variants for a spectrum of central neurological disorders, two homozygous splice-site variants (NM_004713.6:c.574+1G>T and NM_004713.6:c.807-2A>C) and a homozygous frameshift variant (NM_004713.6: c.1234_1235insC) were subsequently identified and segregated with all affected individuals. We further revealed that knockdown (KD) of Nemf leads to impairment of axonal outgrowth and synapse development in cultured mouse primary cortical neurons. Our study demonstrates that disease-causing biallelic NEMF variants result in central nervous system impairment and other variable features. NEMF is an important player in mammalian neuron development.","variants":[{"Name":"NM_004713.6(NEMF):c.2618del (p.Lys873fs)","Chromosome":"14","Start":"49795792","Stop":"49795792","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":974554,"rule_based_match":true,"evidence_text":"NM_004713.6:c.2618del","llm_judgment":"PRESENT","evidence":"NM_004713.6:c.2618del","abstract_start":661,"abstract_end":682},{"Name":"NM_004713.6(NEMF):c.1234_1235insC (p.Asn412fs)","Chromosome":"14","Start":"49828805","Stop":"49828806","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":974556,"rule_based_match":true,"evidence_text":"NM_004713.6: c.1234_1235insC","llm_judgment":"PRESENT","evidence":"NM_004713.6: c.1234_1235insC","abstract_start":1067,"abstract_end":1095},{"Name":"NM_004713.6(NEMF):c.807-2A>C","Chromosome":"14","Start":"49832128","Stop":"49832128","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":920333,"rule_based_match":true,"evidence_text":"NM_004713.6:c.807-2A>C","llm_judgment":"PRESENT","evidence":"NM_004713.6:c.807-2A>C","abstract_start":1006,"abstract_end":1028}]}
{"pmid":"31250519","title":"TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis.","abstract":"Transforming growth factor β-activated kinase 1 (TAK1) mediates multiple biological processes through the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathways. TAK1 activation is tightly regulated by its binding partners (TABs). In particular, binding with TAB2 is crucial for cardiovascular development and extracellular matrix (ECM) homeostasis. In our previous work, we reported a novel multisystem disorder associated with the heterozygous TAB2 c.1398dup variant. Here, we dissect the functional effects of this variant in order to understand its molecular pathogenesis. We demonstrate that TAB2 c.1398dup considerably undergoes to nonsense-mediated messenger RNA decay and encodes a truncated protein that loses its ability to bind TAK1. We also show an alteration of the TAK1 autophosphorylation status and of selected downstream signaling pathways in patients' fibroblasts. Immunofluorescence analyses and ECM-related polymerase chain reaction-array panels highlight that patient fibroblasts display ECM disorganization and altered expression of selected ECM components and collagen-related pathways. In conclusion, we deeply dissect the molecular pathogenesis of the TAB2 c.1398dup variant and show that the resulting phenotype is well explained by TAB2 loss-of-function. Our data also offer initial insights on the ECM homeostasis impairment as a molecular mechanism probably underlying a multisystem disorder linked to TAB2.","variants":[{"Name":"NM_001292034.3(TAB2):c.1398dup (p.Thr467fs)","Chromosome":"6","Start":"149379311","Stop":"149379312","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AT","allel_id":984463,"rule_based_match":true,"evidence_text":"TAB2 c.1398dup","llm_judgment":"PRESENT","evidence":"TAB2 c.1398dup","abstract_start":525,"abstract_end":539}]}
{"pmid":"36134613","title":"Exome sequencing in a Swedish family with PMS2 mutation with varying penetrance of colorectal cancer: investigating the presence of genetic risk modifiers in colorectal cancer risk.","abstract":"OBJECTIVE: Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes, such as the PMS2 gene, and is characterised by a familial accumulation of colorectal cancer. The penetrance of cancer in PMS2 carriers is still not fully elucidated as a colorectal cancer risk has been shown to vary between PMS2 carriers, suggesting the presence of risk modifiers.\nMETHODS: Whole exome sequencing was performed in a Swedish family carrying a PMS2 missense mutation [c.2113G>A, p.(Glu705Lys)]. Thirteen genetic sequence variants were further selected and analysed in a case-control study (724 cases and 711 controls).\nRESULTS: The most interesting variant was an 18 bp deletion in gene BAG1. BAG1 has been linked to colorectal tumour progression with poor prognosis and is thought to promote colorectal tumour cell survival through increased NF-κB activity.\nCONCLUSIONS: We conclude the genetic architecture behind the incomplete penetrance of PMS2 is complicated and must be assessed in a genome wide manner using large families and multifactorial analysis.","variants":[{"Name":"NM_000535.7(PMS2):c.2113G>A (p.Glu705Lys)","Chromosome":"7","Start":"5982885","Stop":"5982885","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":96803,"rule_based_match":true,"evidence_text":"c.2113G>A, p.(Glu705Lys)","llm_judgment":"PRESENT","evidence":"c.2113G>A, p.(Glu705Lys)","abstract_start":477,"abstract_end":501}]}
{"pmid":"25522812","title":"c.1058C>T variant in the SERPINC1 gene is pathogenic for antithrombin deficiency.","abstract":"","variants":[{"Name":"NM_000488.4(SERPINC1):c.1058C>T (p.Pro353Leu)","Chromosome":"1","Start":"173909647","Stop":"173909647","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2898372,"rule_based_match":true,"evidence_text":"c.1058C>T","llm_judgment":"PRESENT","evidence":"c.1058C>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"33076433","title":"A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy.","abstract":"Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, <i>Hsp60</i>) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, <i>CCT</i>). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the <i>CCT5</i> gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous <i>CCT5</i> c.670C>G p.(Leu224Val) variant in the <i>CCT5</i> gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient's clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease.","variants":[{"Name":"NM_012073.5(CCT5):c.670C>G (p.Leu224Val)","Chromosome":"5","Start":"10258250","Stop":"10258250","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1859621,"rule_based_match":true,"evidence_text":"c.670C>G p.(Leu224Val)","llm_judgment":"PRESENT","evidence":"c.670C>G p.(Leu224Val)","abstract_start":940,"abstract_end":962}]}
{"pmid":"29785970","title":"Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.","abstract":"Androgen insensitivity syndrome (AIS), an X-linked recessive genetic disorder of sex development, is caused by mutations in the androgen receptor (AR) gene, and is characterized by partial or complete inability of specific tissues to respond to androgens in individuals with the 46,XY karyotype. This study aimed to investigate AR gene mutations and to characterize genotype-phenotype correlations. Ten patients from unrelated families, aged 2-31 years, were recruited in the study. Based on karyotype, altered hormone profile, and clinical manifestations, nine patients were preliminarily diagnosed with complete AIS and one with partial AIS. Genetic analysis of AR gene revealed the existence of 10 different mutations, of which five were novel (c.2112 C>G[p.S704R], c.2290T>A[p.Y764N], c.2626C>T[p.Q876X], c.933dupC[p.K313Qfs*28], and c.1067delC[p.A356Efs*123]); the other five were previously reported (c.1789G>A[p.A597T], c.2566C>T[p.R856C], c.2668G>A[p.V890M], c.2679C>T[p.P893L], and c.1605C>G[p.Y535X]). Regarding the distribution of these mutations, 60.0% were clustered in the ligand-binding domain of AR gene. Exons 1 and 8 of AR gene each accounted for 30.0% (3/10) of all mutations. Most of the truncation mutations were in exon 1 and missense mutations were mainly located in exons 4-8. Our study expands the spectrum of AR gene mutations and confirms the usefulness of AR gene sequencing to support a diagnosis of AIS and to enable prenatal or antenatal screening.","variants":[{"Name":"NM_000044.6(AR):c.1605C>G (p.Tyr535Ter)","Chromosome":"X","Start":"67546751","Stop":"67546751","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3082670,"rule_based_match":true,"evidence_text":"c.1605C>G[p.Y535X]","llm_judgment":"PRESENT","evidence":"c.1605C>G[p.Y535X]","abstract_start":991,"abstract_end":1009},{"Name":"NM_000044.6(AR):c.1789G>A (p.Ala597Thr)","Chromosome":"X","Start":"67686030","Stop":"67686030","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24852,"rule_based_match":true,"evidence_text":"c.1789G>A[p.A597T]","llm_judgment":"PRESENT","evidence":"c.1789G>A[p.A597T]","abstract_start":907,"abstract_end":925},{"Name":"NM_000044.6(AR):c.2668G>A (p.Val890Met)","Chromosome":"X","Start":"67723746","Stop":"67723746","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":265118,"rule_based_match":true,"evidence_text":"c.2668G>A[p.V890M]","llm_judgment":"PRESENT","evidence":"c.2668G>A[p.V890M]","abstract_start":947,"abstract_end":965}]}
{"pmid":"25748406","title":"Three Chinese children with Niemann-Pick disease type C with neonatal cholestasis as initial presentation","abstract":"OBJECTIVE: To analyze the clinical characteristics of three Chinese cases of Niemann-Pick disease type C patients with neonatal cholestasis as initial presentation, and enhance awareness of Niemann-Pick disease type C among pediatricians.\nMETHOD: Three sporadic cases with confirmed Niemann-Pick disease type C initially presented as neonatal cholestasis were retrospectively reviewed in this study. Their peripheral blood specimens were collected after obtaining informed consent. All exons and the intron-exon boundaries of NPC1 gene were examined by bi-directional sequencing.\nRESULT: Three patients, 1 female and 2 males, aged from 2 months to 5 years and 10 months, all first complained of jaundice in the neonatal period. Laboratory tests showed total bilirubin and direct bilirubin significantly increased with predominant increase of direct bilirubin. Total bile acid, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were also increased, while high-density lipoprotein cholesterol decreased. All patients were also accompanied by hepatosplenomegaly, with two of them having increased bronchovascular markings in chest X-ray. Two heterozygous changes of NPC1 gene, c.2741G>T +c.3020C>G (p. C914F + p. P1007R), c.2177G>C + c.3734_ 3735delCT (p.R726T + p. P1245RfsX12), and c.2054T>C + c.2128C>T(p.I685T + p.Q710X), were identified in patient 1, 2 and 3, respectively.\nCONCLUSION: We reported three cases suffered from Niemann-Pick disease type C with initial presentation as neonatal cholestasis in the mainland of China. For newborns with prolonged jaundice in the neonatal period, as well as neonatal cholestasis, hepatosplenomegaly, Niemann-Pick type C should be included in consideration of differential diagnosis. Genetic testing can identify causative mutations for diagnosis.","variants":[{"Name":"NM_000271.5(NPC1):c.2054T>C (p.Ile685Thr)","Chromosome":"18","Start":"23544420","Stop":"23544420","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":136642,"rule_based_match":true,"evidence_text":"c.2054T>C","llm_judgment":"PRESENT","evidence":"c.2054T>C","abstract_start":1300,"abstract_end":1309}]}
{"pmid":"30345613","title":"Developmental delay and failure to thrive associated with a loss-of-function variant in WHSC1 (NSD2).","abstract":"Wolf-Hirschhorn syndrome (WHS) is a microdeletion syndrome characterized by distinctive facial features consisting of \"Greek warrior helmet\" appearance, prenatal and postnatal growth deficiency, developmental disability, and seizures. This disorder is caused by heterozygous deletions on chromosome 4p16.3 often identified by cytogenetic techniques. Many groups have attempted to identify the critical region within this deletion to establish which genes are responsible for WHS. Herein, clinical whole exome sequencing (WES) was performed on a child with developmental delays, mild facial dysmorphisms, short stature, failure to thrive, and microcephaly, and revealed a de novo frameshift variant, c.1676_1679del (p.Arg559Tfs*38), in WHSC1 (NSD2). While WHSC1 falls within the WHS critical region, individuals with only disruption of this gene have only recently been described in the literature. Loss-of-function de novo variations in WHSC1 were identified in large developmental delay, autism, diagnostic, and congenital cardiac cohorts, as well as recent case reports, suggesting that de novo loss-of-function WHSC1 variants may be related to disease. These findings, along with our patient suggest that loss-of-function variation in WHSC1 may lead to a mild form of Wolf-Hirschhorn syndrome, and also may suggest that the developmental delays, facial dysmorphisms, and short stature seen in WHS may be due to disruption of WHSC1 gene.","variants":[{"Name":"NM_133330.3(NSD2):c.1676_1679del","Chromosome":"4","Start":"1938449","Stop":"1938452","ReferenceAlleleVCF":"TAGAG","AlternateAlleleVCF":"T","allel_id":538368,"rule_based_match":true,"evidence_text":"c.1676_1679del (p.Arg559Tfs*38)","llm_judgment":"PRESENT","evidence":"c.1676_1679del (p.Arg559Tfs*38)","abstract_start":699,"abstract_end":730}]}
{"pmid":"30835354","title":"A single center study of colorectal cancer screening for Lynch syndrome","abstract":"OBJECTIVE: To determine the ratio of deficient mismatch repair (dMMR) proteins and Lynch syndrome among patients undergoing colorectal cancer resection.\nMETHODS: From June 2014 to May 2016, immunohistochemistry for mismatch repair proteins including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2 (PMS2) were carried out on 207 surgically resected specimens. Samples with lost expression of MMR proteins underwent genetic testing.\nRESULTS: Loss of expression of MMR proteins were found among 21 patients and accounted for 10.14% of the colorectal cancers. dMMR was more common in patients ≤50 years old, or with proximal tumor at splenic flexure and mucinous adenocarcinoma. Ten patients underwent genetic testing, with three pathogenic mutations (MSH6 c.3013C>T, MLH1 c.199G>A and a novel MSH6 c.584delT) and four ambiguous mutations identified. At least 1.4% of the colorectal cancers were diagnosed as Lynch syndrome.\nCONCLUSION: Routine screening for Lynch syndrome among patients with colorectal cancer with MMR protein immunohistochemistry as preliminary screening method and MMR gene sequencing as diagnostic method is effective and feasible. It can reduce missed diagnosis of Lynch syndrome and bring lifelong benefit to patients and their families.","variants":[{"Name":"NM_000179.3(MSH6):c.3013C>T (p.Arg1005Ter)","Chromosome":"2","Start":"47800996","Stop":"47800996","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":94804,"rule_based_match":true,"evidence_text":"MSH6 c.3013C>T","llm_judgment":"PRESENT","evidence":"MSH6 c.3013C>T","abstract_start":788,"abstract_end":802}]}
{"pmid":"21204215","title":"ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia.","abstract":"Mutations in the ARX gene cause both nonsyndromic and several forms of syndromic mental retardation (MR). Two polyalanine (polyA) expansions of ARX are recurrent mutations. The most common one, the c.428_451dup, is associated with a wide spectrum of phenotypes, ranging from the most severe West syndrome to Partington syndrome (MR and hand dystonia), and even nonsyndromic X-linked mental retardation (NS-XLMR). Studies of patients not selected for specific clinical signs showed that the c.428_451dup is relatively frequent in families harboring X-linked MR (7.5%), but less common in familial cases compatible with X-linked NR (1%), and very rare in sporadic cases (0.1%). The c.333_334ins(GCG)7 expansion is less frequent and mainly associated with West syndrome. We screened for both ARX polyA expansions in 98 unrelated patients selected for the presence of NR associated with different types of epilepsy and/or with hand dystonia. We also studied two families with an initial diagnosis of NS-XLMR, one of which was identified as showing linkage to the ARX locus. The c.428_451dup was identified in three patients and the c.333_334ins(GCG)7 in one; all of the patients were from families with two affected brothers. We also found the c.428_451dup in the family linked to ARX, and clinical re-evaluation showed subtle, previously undetected signs. Our study illustrates that ARX polyA expansions are primarily associated with syndromic MR and shows a higher yield (18% in our cohort) when these mutations are screened in familial cases of MR with epilepsy and/or dystonia.","variants":[{"Name":"NM_139058.3(ARX):c.428_451dup (p.Gly143_Ala150dup)","Chromosome":"X","Start":"25013543","Stop":"25013544","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCGGCCGCGGCTGCCGCGGCGGCCC","allel_id":26226,"rule_based_match":true,"evidence_text":"c.428_451dup","llm_judgment":"PRESENT","evidence":"c.428_451dup","abstract_start":198,"abstract_end":210}]}
{"pmid":"33965620","title":"Implications of mosaicism in variant interpretation: A case of a de novo homozygous NF1 variant.","abstract":"Neurofibromatosis type 1 is a common multisystem autosomal dominant syndrome caused by pathogenic heterozygous variants in the neurofibromin gene (NF1). It is associated with a substantially increased cancer risk. Mosaicism for NF1 has been clinically well-established for \"second hit\" variants in skin lesions and tumor tissues. Here, we report on a 3-month-old boy with multiple café au lait macules (CAMs) and juvenile myelomonocytic leukemia (JMML) who was found to carry a previously established pathogenic NF1 variant (c.586+5G>A), as revealed by whole-exome sequencing. Surprisingly, however, this variant was detected in the homozygous state in the patient and was absent in the parents and siblings. Deep sequencing of this variant using blood, buccal swabs and skin samples was performed. As expected for an NF1 gene mutation promoting JMML, the variant was detected in 90.6% of the blood DNA reads, in sharp contrast to the mere 5% and 0.74% of reads in the saliva- and skin fibroblast-derived DNA, respectively. Our analysis, therefore, confirmed postzygotic origin of the variant followed by a mitotic event resulting in its homozygosity, although we could not differentiate between the possibilities of a gene conversion and mitotic crossover. Apparently de novo homozygous variants should trigger a careful investigation into mosaicism to achieve accurate interpretation.","variants":[{"Name":"NM_001042492.3(NF1):c.586+5G>A","Chromosome":"17","Start":"31170002","Stop":"31170002","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":401620,"rule_based_match":true,"evidence_text":"c.586+5G>A","llm_judgment":"PRESENT","evidence":"c.586+5G>A","abstract_start":525,"abstract_end":535}]}
{"pmid":"25117323","title":"Multiple nevoid basal cell carcinoma syndrome associated with congenital orbital teratoma, caused by a PTCH1 frameshift mutation.","abstract":"Gorlin-Goltz syndrome, or nevoid basal cell carcinoma syndrome (NBCCS), is a rare autosomal dominant disorder caused by mutations in the PTCH1 gene and shows a high level of penetrance and variable expressivity. The syndrome is characterized by developmental abnormalities or neoplasms and is diagnosed with 2 major criteria, or with 1 major and 2 minor criteria. Here, we report a new clinical manifestation associated with this syndrome in a boy affected by NBCCS who had congenital orbital teratoma at birth. Later, at the age of 15 years, he presented with 4 major and 4 minor criteria of NBCCS, including multiple basal cell carcinoma and 2 odontogenic keratocysts of the jaw, both confirmed by histology, more than 5 palmar pits, calcification of the cerebral falx, extensive meningeal calcifications, macrocephaly, hypertelorism, frontal bosses, and kyphoscoliosis. PTCH1 mutation analysis revealed the heterozygous germline mutation c.290dupA. This mutation generated a frameshift within exon 2 and an early premature stop codon (p.Asn97LysfsX43), predicting a truncated protein with complete loss of function. Identification of this mutation is useful for genetic counseling. Although the clinical symptoms are well-known, our case contributes to the understanding of phenotypic variability in NBCCS, highlighting that PTCH1 mutations cannot be used for predicting disease burden and reinforces the need of a multidisciplinary team in the diagnosis, treatment, and follow-up of NBCCS patients.","variants":[{"Name":"NM_000264.5(PTCH1):c.290dup (p.Asn97fs)","Chromosome":"9","Start":"95506510","Stop":"95506511","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":638577,"rule_based_match":true,"evidence_text":"c.290dupA","llm_judgment":"PRESENT","evidence":"c.290dupA","abstract_start":941,"abstract_end":950}]}
{"pmid":"32714618","title":"Primary Microcephaly with Novel Variant of","abstract":"This study is a clinical report on twin females affected by primary microcephaly who displayed at molecular analysis of heterozygous novel <i>MCPH1</i> variant. The twins at the age of 10 years developed, in coincidental time, a diagnosis of autoimmune juvenile thyroiditis. The main clinical features presented by the twins consisted of primary microcephaly with occipitofrontal circumference measuring -2 or -3 standard deviation, facial dysmorphism, typical nonsyndromic microcephaly, and mild intellectual disability. Molecular analysis of the major genes involved in primary microcephaly was performed and the following result was found in the twins: <i>MCPH1</i> ; chr8.6357416; c.2180 C > T (rs 199861426), p.Pro727. Leu; heterozygous; missense; variant of uncertain significance (class 3). At the age of 10 years, the twins started to have, in coincidental time, marked asthenia and episodes of emotiveness, and laboratory exams disclosed a high level of antithyroid peroxidase leading to the diagnosis of autoimmune juvenile thyroiditis with normal thyroid function. The novel heterozygous <i>MCPH1</i> variant found in the twins may be directly or indirectly involved in the onset of the primary microcephaly. The thyroid disorder in the twins and its onset, in a coincidental time, confirmed the effect of genetic predisposition on the pathogenesis of the immune thyroiditis.","variants":[{"Name":"NM_024596.5(MCPH1):c.2180C>T (p.Pro727Leu)","Chromosome":"8","Start":"6499895","Stop":"6499895","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":191285,"rule_based_match":true,"evidence_text":"c.2180 C > T (rs 199861426), p.Pro727. Leu","llm_judgment":"PRESENT","evidence":"c.2180 C > T (rs 199861426), p.Pro727. Leu","abstract_start":685,"abstract_end":727}]}
{"pmid":"26183434","title":"Novel COL2A1 variant (c.619G>A, p.Gly207Arg) manifesting as a phenotype similar to progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia, Stanescu type.","abstract":"Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type.","variants":[{"Name":"NM_001844.5(COL2A1):c.619G>A (p.Gly207Arg)","Chromosome":"12","Start":"47995910","Stop":"47995910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":226722,"rule_based_match":true,"evidence_text":"c.619G>A (p.Gly207Arg)","llm_judgment":"PRESENT","evidence":"p.Gly207Arg","abstract_start":721,"abstract_end":732}]}
{"pmid":"18159245","title":"Noncompaction of the ventricular myocardium is associated with a de novo mutation in the beta-myosin heavy chain gene.","abstract":"Noncompaction of the ventricular myocardium (NVM) is the morphological hallmark of a rare familial or sporadic unclassified heart disease of heterogeneous origin. NVM results presumably from a congenital developmental error and has been traced back to single point mutations in various genes. The objective of this study was to determine the underlying genetic defect in a large German family suffering from NVM. Twenty four family members were clinically assessed using advanced imaging techniques. For molecular characterization, a genome-wide linkage analysis was undertaken and the disease locus was mapped to chromosome 14ptel-14q12. Subsequently, two genes of the disease interval, MYH6 and MYH7 (encoding the alpha- and beta-myosin heavy chain, respectively) were sequenced, leading to the identification of a previously unknown de novo missense mutation, c.842G>C, in the gene MYH7. The mutation affects a highly conserved amino acid in the myosin subfragment-1 (R281T). In silico simulations suggest that the mutation R281T prevents the formation of a salt bridge between residues R281 and D325, thereby destabilizing the myosin head. The mutation was exclusively present in morphologically affected family members. A few members of the family displayed NVM in combination with other heart defects, such as dislocation of the tricuspid valve (Ebstein's anomaly, EA) and atrial septal defect (ASD). A high degree of clinical variability was observed, ranging from the absence of symptoms in childhood to cardiac death in the third decade of life. The data presented in this report provide first evidence that a mutation in a sarcomeric protein can cause noncompaction of the ventricular myocardium.","variants":[{"Name":"NM_000257.4(MYH7):c.842G>C (p.Arg281Thr)","Chromosome":"14","Start":"23430954","Stop":"23430954","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":179675,"rule_based_match":true,"evidence_text":"c.842G>C","llm_judgment":"PRESENT","evidence":"c.842G>C","abstract_start":863,"abstract_end":871}]}
{"pmid":"34296289","title":"Preliminary results of targeted sequencing of","abstract":"Breast cancer (BC) is the most commonly diagnosed cancer worldwide and a major health concern in Egypt. There is a known association between pathogenic variants identified in breast cancer susceptibility gene (<i>BRCA</i>)1 and 2 and the risk of developing BC. However, the number of studies investigating mutations in <i>BRCA1</i> and <i>BRCA2</i> in Egypt remains limited. Thus, the aim of the present study was to investigate the frequency of <i>BRCA1</i> and <i>BRCA2</i> variants in patients with BC and their relatives. For this purpose, 11 families (11 patients and 16 relatives) were included in the present study. <i>BRCA1</i> and <i>BRCA2</i> variants were investigated using the Ion S5 next‑generation sequencer. It was found that pathogenic variants were more frequent in patients with familial BC (FBC) than in those with sporadic BC, with 71% of variants in <i>BRCA2</i>, including the first reported identification of c.9089del, c.5583_5584dup, c.8243G>A and c.7976G>A pathogenic variants in Egyptian patients with BC. Pathogenic variants in relatives were confined to FBC c.1278delA, c.1960_1961del, and c.1224delT, with a higher incidence of variants of uncertain significance (VUS), such as <i>BRCA2</i> intron 2 c.68‑16delT. Of note, two cold spot benign variants, c.3113A>G and c.4837A>G, were repeatedly found (67%) in patients and relatives. In conclusion, to the best of our knowledge, novel pathogenic variants and VUS in Egyptian patients with BC and their high‑risk relatives were identified for the first time in the present study. These findings should be integrated with other genomic data concerning Egyptian families and carefully interpreted during genetic counseling.","variants":[{"Name":"NM_000059.4(BRCA2):c.7976G>A (p.Arg2659Lys)","Chromosome":"13","Start":"32362693","Stop":"32362693","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46687,"rule_based_match":true,"evidence_text":"c.7976G>A","llm_judgment":"PRESENT","evidence":"c.7976G>A","abstract_start":974,"abstract_end":983}]}
{"pmid":"21078199","title":"Identification of 5 novel germline APC mutations and characterization of clinical phenotypes in Japanese patients with classical and attenuated familial adenomatous polyposis.","abstract":"BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary disease characterized by multiple colorectal adenomatous polyps and frequent extracolonic manifestations. An attenuated form of FAP (AFAP) is diagnosed based on a milder colorectal phenotype, and the colorectal phenotype of (A)FAP has been linked to germline APC mutations. The relationships between the spectrum of mutations and extracolonic manifestations are quite well known, but they need to be further defined.\nFINDINGS: Nine germline APC mutations, but no large deletions, were identified in the APC locus of 8 (A)FAP patients, and 5 of the mutations, c.446A > T (p.Asp149Val), c.448A > T (p.Lys150X), c.454_457insAGAA (p.Glu152ArgfsX17), c.497insA (p.Thr166AsnfsX2), and c.1958G > C (p.Arg653Ser), were novel mutations. In one patient the p.Asp149Val mutation and p.Lys150X mutation were detected in the same APC allele. The c.1958G > C mutation was located in the last nucleotide of exon 14, and RT-PCR analysis revealed that the mutation resulted in abnormal splicing. The above findings meant that a nonsense mutation, a frameshift mutation, or an exonic mutation leading to abnormal splicing was found in every patient. The following phenotypes, especially extracolonic manifestations, were observed in our (A)FAP patients: (1) multiple gastroduodenal adenomas and early-onset gastric carcinoma in AFAP patients with an exon 4 mutation; (2) a desmoid tumor in two FAP patients with a germline APC mutation outside the region between codons 1403 and 1578, which was previously reported to be associated with the development of desmoid tumors in FAP patients; (3) multiple myeloma in an AFAP patient with an exon 4 mutation.\nCONCLUSIONS: Nine germline APC mutations, 5 of them were novel, were identified in 8 Japanese (A)FAP patients, and some associations between germline APC mutations and extracolonic manifestations were demonstrated. These findings should contribute to establishing relationships between germline APC mutations and the extracolonic manifestations of (A)FAP patients in the future.","variants":[{"Name":"NM_000038.6(APC):c.448A>T (p.Lys150Ter)","Chromosome":"5","Start":"112775654","Stop":"112775654","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":239523,"rule_based_match":true,"evidence_text":"c.448A > T (p.Lys150X)","llm_judgment":"PRESENT","evidence":"c.448A > T (p.Lys150X)","abstract_start":670,"abstract_end":692}]}
{"pmid":"18302019","title":"Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families.","abstract":"Recent reports have shown that mutations in the FANCJ/BRIP1 and FANCN/PALB2 Fanconi Anemia (FA) genes confer a moderate breast cancer risk. Discussion has been raised on the phenotypic characteristics of the PALB2-associated families and tumors. The role of FANCB in breast cancer susceptibility has not been tested to date. Likewise PALB2 mutation frequency has not been studied in Spanish population. We analyzed the complete coding sequence and splicing sites of FANCB and PALB2 in 95 index cases of BRCA1/2-negative Spanish breast cancer families. We also performed an exhaustive screening of three previously described rare but recurrent PALB2 mutations in 725 additional probands. Pathogenic changes were not detected in FANCB. We found a novel PALB2 truncating mutation c.1056_1057delGA (p.K353IfsX7) in one of the 95 screened patients, accounting for a mutation frequency of 1% in our series. Further comprehensive screening of the novel mutation and of previously reported rare but recurrent PALB2 mutations did not reveal any carrier patient. We report the first example of LOH occurring in a PALB2-associated tumor. Our results rule out a major contribution of FANCB to hereditary breast cancer. Our data are consistent with the notion of individually rare PALB2 mutations, lack of mutational hot-spots in the gene and existence of between-population disease-allele heterogeneity. We show evidence that PALB2 loss of function might also conform to the inactivation model of a classic tumor-suppressor gene and present data that adds to the clinically relevant discussion about the existence of a PALB2-breast cancer phenotype.","variants":[{"Name":"NM_024675.4(PALB2):c.1056_1057del (p.Lys353fs)","Chromosome":"16","Start":"23635489","Stop":"23635490","ReferenceAlleleVCF":"TTC","AlternateAlleleVCF":"T","allel_id":132097,"rule_based_match":true,"evidence_text":"c.1056_1057delGA (p.K353IfsX7)","llm_judgment":"PRESENT","evidence":"c.1056_1057delGA (p.K353IfsX7)","abstract_start":777,"abstract_end":807}]}
{"pmid":"23485543","title":"Intravenous pamidronate in the treatment of severe idiopathic infantile hypercalcemia.","abstract":"Idiopathic infantile hypercalcemia (IIH) is a rare disorder caused by CYP24A1 loss-of-function mutation, resulting in impaired degradation of 1,25-dihydroxyvitamin D3. Pamidronate, an intravenously administered bisphosphonate, which is a potent inhibitor of bone resorption, has been reported only once for treatment IIH. We present a case of a previously healthy 5-month-old boy with IIH, where calcemia peaked to 5 mmol/L. Treatment with methylprednisone and furosemide had only minor effects; therefore, 2 intravenous infusions of pamidronate (0.6 mg/kg per dose) corrected the serum calcium level to 2.95 mmol/L. Furthermore, CYP24A1 homozygous mutation p.R396W (c.1186c&gt;t) was identified in this patient, confirming the clinical diagnosis of IIH. In conclusion, IIH has a favorable outcome once properly detected and appropriately treated. Pamidronate has a beneficial effect in those patients with IIH where glucocorticoids and furosemide fail to meet the expectations. &nbsp;","variants":[{"Name":"NM_000782.5(CYP24A1):c.1186C>T (p.Arg396Trp)","Chromosome":"20","Start":"54158136","Stop":"54158136","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38634,"rule_based_match":false,"evidence_text":"c.1186c&gt;t","llm_judgment":"PRESENT","evidence":"c.1186c&gt;t","abstract_start":667,"abstract_end":679}]}
{"pmid":"32236096","title":"TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway.","abstract":"BACKGROUND: TBX5 is a transcription factor that has an important role in development of heart. TBX5 variants in the region encoding the T-box domain have been shown to cause cardiac defects, such as atrial septal defect or ventricular septal defect, while TBX5 variants have also been identified in a few cardiomyopathy patients and considered causative. We identified a TBX5 variant (c.791G>A, p.Arg264Lys), that is over-represented in cardiomyopathy patients. This variant is located outside of the T-box domain, and its pathogenicity has not been confirmed by functional analyses.\nOBJECTIVE: To investigate whether the TBX5 R264K is deleterious and could contribute to the pathogenesis of cardiomyopathy.\nMETHODS AND RESULTS: We developed mice expressing Tbx5 R264K. Mice homozygous for this variant displayed compensated dilated cardiomyopathy; mild decreased fractional shortening, dilatation of the left ventricle, left ventricular wall thinning and increased heart weight without major heart structural disorders. There was no difference in activation of the ANF promotor, a transcriptional target of Tbx5, compared to wild-type. However, analysis of RNA isolated from left ventricular samples showed significant increases in the expression of Acta1 in left ventricle with concomitant increases in the protein level of ACTA1.\nCONCLUSIONS: Mice homozygous for Tbx5 R264K showed compensated dilated cardiomyopathy. Thus, TBX5 R264K may have a significant pathogenic role in some cardiomyopathy patients independently of T-box domain pathway.","variants":[{"Name":"NM_181486.4(TBX5):c.791G>A (p.Arg264Lys)","Chromosome":"12","Start":"114366356","Stop":"114366356","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":330698,"rule_based_match":true,"evidence_text":"c.791G>A (p.Arg264Lys)","llm_judgment":"PRESENT","evidence":"p.Arg264Lys","abstract_start":395,"abstract_end":406}]}
{"pmid":"20970104","title":"Mutations in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy.","abstract":"Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is characterized by increased ventricular wall thickness that cannot be explained by underlying conditions, cadiomyocyte hypertrophy and disarray, and increased myocardial fibrosis. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that more genes may be involved. Nexilin, encoded by NEXN, is a cardiac Z-disc protein recently identified as a crucial protein that functions to protect cardiac Z-discs from forces generated within the sarcomere. We screened NEXN in 121 unrelated HCM patients who did not carry any mutation in eight genes commonly mutated in myofilament disease. Two missense mutations, c.391C>G (p.Q131E) and c.835C>T (p.R279C), were identified in exons 5 and 8 of NEXN, respectively, in two probands. Each of the two mutations segregated with the HCM phenotype in the family and was absent in 384 control chromosomes. In silico analysis revealed that both of the mutations affect highly conserved amino acid residues, which are predicted to be functionally deleterious. Cellular transfection studies showed that the two mutations resulted in local accumulations of nexilin and that the expressed fragment of actin-binding domain containing p.Q131E completely lost the ability to bind F-actin in C2C12 cells. Coimmunoprecipitation assay indicated that the p.Q131E mutation decreased the binding of full-length NEXN to α-actin and abolished the interaction between the fragment of actin-binding domain and α-actin. Therefore, the mutations in NEXN that we describe here may further expand the knowledge of Z-disc genes in the pathogenesis of HCM.","variants":[{"Name":"NM_144573.4(NEXN):c.391C>G (p.Gln131Glu)","Chromosome":"1","Start":"77918217","Stop":"77918217","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":39950,"rule_based_match":true,"evidence_text":"c.391C>G (p.Q131E)","llm_judgment":"PRESENT","evidence":"c.391C>G (p.Q131E)","abstract_start":711,"abstract_end":729},{"Name":"NM_144573.4(NEXN):c.835C>T (p.Arg279Cys)","Chromosome":"1","Start":"77926863","Stop":"77926863","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39951,"rule_based_match":true,"evidence_text":"c.835C>T (p.R279C)","llm_judgment":"PRESENT","evidence":"c.835C>T (p.R279C)","abstract_start":734,"abstract_end":752}]}
{"pmid":"34069211","title":"Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning.","abstract":"Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in <i>BCKDHA</i>, <i>BCKDHB</i>, or <i>DBT</i> genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and progression in myelination. Her clinical phenotype, including protein tolerance, correlated with intermediate MSUD. Molecular analysis of all three genes identified two variants of uncertain significance, c.434-15_434-4del and c.365A>G (p. Tyr122Cys) in the <i>DBT</i> gene. The rate of leucine decarboxylation in fibroblasts was reduced, but not to the extent observed in classical MSUD patients, supporting an intermediate form of MSUD. Previously reported mRNA splicing studies supported a deleterious effect of the c.434-15_434-4del variant. This functional evidence and confirmation that the variants were in trans, permitted their reclassification as pathogenic and likely pathogenic, respectively, facilitating subsequent prenatal testing. This report highlights the challenges in identifying intermediate MSUD by newborn screening, reinforcing the importance of functional studies to confirm variant pathogenicity in this era of molecular diagnostics.","variants":[{"Name":"NM_001918.5(DBT):c.365A>G (p.Tyr122Cys)","Chromosome":"1","Start":"100230801","Stop":"100230801","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":176923,"rule_based_match":true,"evidence_text":"c.365A>G (p. Tyr122Cys)","llm_judgment":"PRESENT","evidence":"c.365A>G (p. Tyr122Cys)","abstract_start":1243,"abstract_end":1266}]}
{"pmid":"32400067","title":"Identification of two novel mutations in three Chinese families with Kallmann syndrome using whole exome sequencing.","abstract":"Kallmann syndrome (KS) is a rare developmental disorder that manifests as congenital hypogonadotropic hypogonadism with anosmia. More than 19 genes have been found to be associated with KS. However, approximately 70% of the causes of KS remain unclear. Here, we studied seven KS patients, from three families, who had delayed puberty and olfactory bulb dysplasia. However, the families of these patients showed a range of other unique clinical features, including hearing loss, anosmia (to varying degrees) and unilateral renal agenesis. We performed whole exome sequencing and copy number variation (CNV) sequencing on samples acquired from these patients. We identified two novel mutations (c.844delC in ANOS1, c.475C>T in SOX10) and a novel trigenic pattern, PROKR2/CHD7/FEZF1 (c.337T>C in PROKR2, c.748C>G in FEZF1, c.8773G>A in CHD7). The c.844delC mutation in the ANOS1 gene was predicted to generate a truncated form of the anosmin-1 protein. SIFT and PolyPhen-2 predicted that the c.475C>T mutation in SOX10 had a damaging effect. The PROKR2 mutation (c.337T>C) was previously reported as harmful. No pathogenic copy number alterations were detected. Our study expands the genotypic and phenotypic spectrum of KS, a disease that shows considerable clinical and genetic heterogeneity. The application of whole exome sequencing could facilitate our understanding of the pathogenesis of KS.","variants":[{"Name":"NM_144773.4(PROKR2):c.337T>C (p.Tyr113His)","Chromosome":"20","Start":"5314033","Stop":"5314033","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":345522,"rule_based_match":true,"evidence_text":"c.337T>C in PROKR2","llm_judgment":"PRESENT","evidence":"c.337T>C in PROKR2","abstract_start":781,"abstract_end":799}]}
{"pmid":"19358837","title":"Citrullinemia type I, classical variant. Identification of ASS-p~G390R (c.1168G>A) mutation in families of a limited geographic area of Argentina: a possible population cluster.","abstract":"OBJECTIVE: Citrullinemia type I (CTLN1) is an urea cycle defect caused by mutations in the argininosuccinate synthetase gene. We report the first identification in Argentina of patients with CTLN1 in a limited geographic area.\nDESIGN AND METHODS: Molecular analysis in patient/relatives included PCR, sequencing and restriction enzyme assay.\nRESULTS: The studied families showed the same mutation: ASS~p.G390R, associated with the early-onset/severe phenotype.\nCONCLUSION: We postulate a possible population cluster. A program to know the carrier frequency in that population is in progress.","variants":[{"Name":"NM_054012.4(ASS1):c.1168G>A (p.Gly390Arg)","Chromosome":"9","Start":"130499545","Stop":"130499545","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21368,"rule_based_match":true,"evidence_text":"c.1168G>A","llm_judgment":"PRESENT","evidence":"c.1168G>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"32412696","title":"Missense NR2F1 variant in monozygotic twins affected with the Bosch-Boonstra-Schaaf optic atrophy syndrome.","abstract":"BACKGROUND: The Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder (OMIM615722) mostly characterized by optic atrophy and/or hypoplasia, mild intellectual disability, hypotonia, seizures/infantile epilepsy. This disorder is caused by loss-of-function alterations of NR2F1 (i.e., either whole gene deletions or single nucleotide variants) and, to date, 40 patients have been identified with deletions or mutations in this gene. Here we describe two monozygotic twins harboring a de novo missense variant in the DNA-binding domain of NR2F1 (c.313G>A, p.Gly105Ser), with well-characterized features associated to BBSOAS.\nMETHODS: Patients' DNA was analyzed by exome sequencing identifying the missense variant c.313G>A in NR2F1 (NM_005654.4). Furthermore, molecular modeling was performed to evaluate putative differences in DNA binding between wild-type and mutated NR2F1.\nRESULTS: The missense variant is predicted to be likely pathogenetic following the ACMG (American College of Medical Genetics and Genomics)/AMP (Association for Molecular Pathology) guidelines. Indeed, dynamic simulation experiments highlighted that the Gly105Ser substitution let the formation of a hydrogen bond between the S105 side chain and R142 and a base (G5) of the DNA sequence, allowing us to hypothesize that the G105 residue might be evolutionary conserved due to the absence of a side chain, besides glycine conformational features. Therefore, the G105S variation seems to cause a stiffening and a possible deformation in the protein-DNA complex due to the interaction of residues R142-S105 and G5 on the DNA, compared to the wild-type.\nCONCLUSION: In summary, we described two monozygotic twins harboring a novel Gly105Ser mutation in NR2F1 DNA binding domain, displaying the classical phenotype of BBSOAS-affected patients. Our computational data suggest a dominant negative effect of this newly characterized missense variant. To date, this is the first genetic report analyzing in silico structural consequences of NR2F1 Gly105Ser substitution.","variants":[{"Name":"NM_005654.6(NR2F1):c.313G>A (p.Gly105Ser)","Chromosome":"5","Start":"93585336","Stop":"93585336","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":443836,"rule_based_match":true,"evidence_text":"c.313G>A (p.Gly105Ser)","llm_judgment":"PRESENT","evidence":"p.Gly105Ser","abstract_start":586,"abstract_end":597}]}
{"pmid":"31772641","title":"Known and novel mutations responsible for epidermolysis bullosa simplex cases in a Chinese population.","abstract":"Epidermolysis bullosa simplex, generalized severe (EBS-gen sev) is one of the major forms of EBS, caused by mutations of the keratin 5 (<i>KRT5)</i> or keratin 14 (<i>KRT14)</i>. However, it is rarely reported in the Chinese population. The current study was performed on three unrelated Chinese families with five patients clinically suspicious for distinct stages of EBS. Mutation screening was performed by direct sequencing of the entire coding regions of <i>KRT5</i> and <i>KRT14</i> genes. A diagnosis of EBS-gen sev for patients in these three families was confirmed by revealing missense mutations c.373C>T (p.Arg125Cys), c.374G>T (p.Arg125Leu), and a novel frameshift mutation c.1231delG (p.Glu411Argfs*31) in <i>KRT14</i>. Considering two previously reported cases and the results of the current report, amino acid residue 125 is likely the most frequent hotspot of EBS-gen sev in the Chinese population. The current study further indicated that the symptoms of EBS-gen sev patients decline with age.","variants":[{"Name":"NM_000526.5(KRT14):c.374G>T (p.Arg125Leu)","Chromosome":"17","Start":"41586461","Stop":"41586461","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":77246,"rule_based_match":true,"evidence_text":"c.374G>T (p.Arg125Leu)","llm_judgment":"PRESENT","evidence":"c.374G>T (p.Arg125Leu)","abstract_start":630,"abstract_end":652}]}
{"pmid":"16490061","title":"Three novel and six common mutations in 11 patients with methylmalonic acidemia.","abstract":"BACKGROUND: Patients with a defect in methylmalonyl-coenzyme A mutase (MCM) are classified as having methylmalonic acidemia, which is divided into two subclasses: mut(0) and mut(-). Fifty-five disease-causing mutations have been identified. Although most are private mutations, only three (E117X, G717V, and N219Y) are reportedly common in Japanese, Black, and Caucasian populations, respectively. Here we identified mutations in 11 Japanese patients with MCM deficiency.\nMETHODS: Mutational analysis was performed in 11 unrelated Japanese patients with MCM deficiency using polymerase chain reaction and direct sequencing.\nRESULTS: Three novel (L494X, R727X, and 449_461del) and six previously reported (R93H, E117X, N219Y, R369H, G648D and IVS2 + 5G>A) mutations were identified. The L494X mutation was found in three unrelated patients, and the R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations occurred more than once. Two of the patients were classified as mut(-) phenotype because of residual [(14)C]-propionate incorporation in the presence of a high concentration of hydroxocobalamin. The two mut(-) patients were heterozygous for the G648D mutation and presented with lethargy and metabolic acidosis after 2 years of life. Their psychomotor development has been documented as normal. The patients with the R727X or c.374_385del [corrected] mutations clinically exhibited mut(0) phenotype. Two patients with mut(0) phenotype died in infancy. One presented early in the neonatal period; the other was symptomatic in the late infantile period.\nCONCLUSIONS: The L494X, R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations are found in more than two unrelated families in the Japanese population. The short-term outcome was generally poor in patients with mut(0), and therefore alternative treatments should be considered.","variants":[{"Name":"NM_000255.4(MMUT):c.278G>A (p.Arg93His)","Chromosome":"6","Start":"49459189","Stop":"49459189","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16919,"rule_based_match":false,"evidence_text":"c.278G>A (p.Arg93His)","llm_judgment":"PRESENT","evidence":"R93H","abstract_start":705,"abstract_end":709}]}
{"pmid":"16769864","title":"Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?","abstract":"BACKGROUND: Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous PINK1 mutations is less clear.\nOBJECTIVE: To investigate the role of homozygous and heterozygous PINK1 mutations in a large German pedigree (family W).\nDESIGN: Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating.\nSETTINGS: University of Lübeck.\nPARTICIPANTS: Twenty family members.\nMAIN OUTCOME MEASURES: The PINK1 genotype and PD status of all family members.\nRESULTS: The index patient of family W carried a homozygous nonsense mutation (c.1366C>T; p.Q456X) and presented with a phenotype closely resembling idiopathic PD but with an onset at 39 years of age. The family included a total of 4 affected homozygous members (age, 60-71 years; age at onset, 39-61 years), 6 members with slight or mild signs of PD (affected) and a heterozygous mutation (age, 31-49 years), and 5 unaffected heterozygous mutation carriers (age, 34-44 years). Although none of the heterozygous affected family members was aware of their signs (asymptomatic), the clinical findings were unequivocal and predominantly or exclusively present on their dominant right-hand side, eg, unilaterally reduced or absent arm swing and unilateral rigidity. The heterozygous members were all considerably younger than the affected homozygous mutation carriers.\nCONCLUSIONS: Heterozygous PINK1 mutations may predispose to PD, as was previously suggested by the presence of dopamine hypometabolism in asymptomatic mutation carriers. Long-term follow-up of our large family W provides an excellent opportunity to further evaluate the role of single heterozygous PINK1 mutations later in life, which will have major implications on genetic counseling.","variants":[{"Name":"NM_032409.3(PINK1):c.1366C>T (p.Gln456Ter)","Chromosome":"1","Start":"20649109","Stop":"20649109","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17454,"rule_based_match":true,"evidence_text":"c.1366C>T; p.Q456X","llm_judgment":"PRESENT","evidence":"c.1366C>T; p.Q456X","abstract_start":758,"abstract_end":776}]}
{"pmid":"32393189","title":"A novel electron transfer flavoprotein dehydrogenase (ETFDH) gene mutation identified in a newborn with glutaric acidemia type II: a case report of a Chinese family.","abstract":"BACKGROUND: Glutaric acidemia type II (GA II) or multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM 231680) is an inherited autosomal recessive disease affecting fatty acid, amino acid and choline metabolism, due to mutations in one of three genes namely, electron transfer flavoprotein alpha-subunit, ETFA, electron transfer flavoprotein β-subunit, ETFB and electron transfer flavoprotein dehydrogenase, ETFDH. Currently, few studies have reported genetic profiling of neonatal-onset GA II. This study aimed to identify the genetic mutations in a Chinese family with GA II.\nCASE PRESENTATION: We reported a case of GA II with purulent meningitis and septicemia and identified a novel ETFDH gene mutation in a female infant. The patient developed an episode of hypoglycemia and hypotonicity on the postnatal first day. Laboratory investigations revealed elevations of multiple acylcarnitines indicating glutaric acidemia type II in newborn screening analysis. Urinary organic acids were evaluated for the confirmation and revealed a high glutaric acid excretion. Genetic analysis revealed two mutations in the ETFDH gene (c.623_626 del / c. 1399G > C), which were considered to be the etiology for the disease. The novel mutation c.623_626 del was identified in the proband infant and her father, her mother was carriers of the mutation c.1399G > C.\nCONCLUSIONS: A novel variant (c.623_626 del) and a previously reported missense (c.1399G > C) in the ETFDH gene have been identified in the family. The two variants of ETFDH gene identified probably underlie the pathogenesis of Glutaric acidemia type II in this family, and also enlarge ETFDH genotype-phenotype correlations spectrum.","variants":[{"Name":"NM_004453.4(ETFDH):c.1399G>C (p.Gly467Arg)","Chromosome":"4","Start":"158706302","Stop":"158706302","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":828925,"rule_based_match":true,"evidence_text":"c.1399G > C","llm_judgment":"PRESENT","evidence":"c.1399G > C","abstract_start":1341,"abstract_end":1352}]}
{"pmid":"18458655","title":"A novel delins mutation in the alpha-TTP gene in a family segregating ataxia with isolated vitamin E deficiency.","abstract":"Ataxia with isolated vitamin E deficiency is a rare autosomal recessive neurodegenerative disease due to mutations in the alpha-tocopherol transfer protein gene. In ataxia with isolated vitamin E deficiency, the biochemical hallmark is the low plasmatic levels of vitamin E and, in most of the patients, vitamin E supplementation allows a stabilization of the neurologic conditions. We have investigated the genetic cause of ataxia and reduced levels of vitamin E, and apolipoproteins A1 and B in a 16-y-old patient. Results revealed that our propositus is a compound heterozygote for the c.227_229delinsATT/c.744delA mutations in the alpha-tocopherol transfer protein gene, each inherited from one of the two parents. His sister is also a compound heterozygote for both mutations, and she presents a biochemical pattern similar to that of his brother. After receiving the vitamin E supplementation, plasmatic levels of vitamin E and apolipoprotein A1 have been normalized in the propositus. The detected mutations would justify the undetectable levels of vitamin E, but would not explain the also decreased levels of the apolipoproteins, as neither that after treatment with vitamin E, the levels of apolipoprotein B do not become normal. These findings suggest that other genes may play a role in producing this atypical biochemical profile.","variants":[{"Name":"NM_000370.3(TTPA):c.227_229delinsATT (p.Trp76_Arg77delinsTyrTer)","Chromosome":"8","Start":"63073064","Stop":"63073066","ReferenceAlleleVCF":"TCC","AlternateAlleleVCF":"AAT","allel_id":544853,"rule_based_match":true,"evidence_text":"c.227_229delinsATT","llm_judgment":"PRESENT","evidence":"c.227_229delinsATT","abstract_start":589,"abstract_end":607}]}
{"pmid":"38141607","title":"A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.","abstract":"Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAX<sup>Arg60Gln</sup> (Max<sup>∗Arg60Gln</sup>) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAX<sup>Arg60Gln</sup> individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.","variants":[{"Name":"NM_002382.5(MAX):c.179G>A (p.Arg60Gln)","Chromosome":"14","Start":"65078029","Stop":"65078029","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":948631,"rule_based_match":true,"evidence_text":"c.179G>A (p.Arg60Gln)","llm_judgment":"PRESENT","evidence":"c.179G>A (p.Arg60Gln)","abstract_start":318,"abstract_end":339}]}
{"pmid":"24066033","title":"Mutational screening of LCA genes emphasizing RPE65 in South Indian cohort of patients.","abstract":"BACKGROUND: Leber congenital amaurosis (LCA) is the most severe form of inherited retinal visual impairment in children. So far, mutations in more than 20 genes have been known to cause LCA and among them, RPE65 is a suitable candidate for gene therapy. The mutational screenings of RPE65 and other LCA genes are requisite in support of emerging gene specific therapy for LCA. Therefore, we have carried out a comprehensive LCA genes screening using a combined approach of direct sequencing and DNA microarray based Asper chip analysis.\nMETHODOLOGY/PRINCIPAL FINDINGS: Thirty clinically diagnosed index LCA cases from Southern India were screened for coding and flanking intronic regions of RPE65 through direct sequencing. Among thirty, 25 cases excluded from RPE65 mutations were subjected to Asper chip analysis, testing 784 known pathogenic variations in 15 major LCA genes. In RPE65 screening, four different pathogenic variations including two novel (c.361insT & c.939T>A) and two known (c.394G>A & c.361delT) mutations were identified in five index cases. In the chip analysis, seven known pathogenic mutations were identified in six index cases, involving genes GUCY2D, RPGRIP1, AIPL1, CRX and IQCB1. Overall, 11 out of 30 LCA cases (36.6%) revealed pathogenic variations with the involvement of RPE65 (16.6%), GUCY2D (10%), RPGRIP1 (3.3%), AIPL1 (3.3%) and CRX & IQCB1 (3.3%).\nCONCLUSIONS/SIGNIFICANCE: Our study suggests that such combined screening approach is productive and cost-effective for mutation detection and can be applied in Indian LCA cohort for molecular diagnosis and genetic counselling.","variants":[{"Name":"NM_000329.3(RPE65):c.394G>A (p.Ala132Thr)","Chromosome":"1","Start":"68444632","Stop":"68444632","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28158,"rule_based_match":true,"evidence_text":"c.394G>A","llm_judgment":"PRESENT","evidence":"c.394G>A","abstract_start":994,"abstract_end":1002}]}
{"pmid":"25731711","title":"Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations.","abstract":"Cathepsin K (CTSK) is an important protease responsible for degrading type I collagen, osteopontin, and other bone matrix proteins. The mutations in the CTSK gene can cause pycnodysostosis (OMIM 265800), a rare autosomal recessive bone dysplasia. Patients with pycnodysostosis have been reported to present specific dental abnormalities; however, whether these dental abnormalities are related to dysfunctional CTSK has never been reported. Here we investigated the histologic changes of cementum and alveolar bone in a pycnodysostosis patient, caused by novel compound heterozygous mutations in the CTSK gene (c.87 G>A p.W29X and c.848 A>G p.Y283C). The most impressive manifestations in tooth were extensive periradicular high-density clumps with unclear periodontal space by orthopantomography examination and micro-computed tomography scanning analysis. Hematoxylin/eosin and toluidine blue staining and atomic force microscopy analysis showed that the cementum became significantly thickened, softened, and full of cementocytes. The disorganized bone structure was the main character of alveolar bone. The p.W29X mutation may represent the loss-of-function allele with an earlier termination codon in the precursor CTSK polypeptide. Residue Y283 is highly conserved among papain-like cysteine proteases. Three-dimensional structure modeling analysis found that the loss of the hydroxybenzene residue in the Y283C mutation would interrupt the hydrogen network and possibly affect the self-cleavage of the CTSK enzyme. Furthermore, p.Y283C mutation did not affect the mRNA and protein levels of overexpressed CTSK in COS-7 system but did reduce CTSK enzyme activity. In conclusion, the histologic and ultrastructural changes of cementum and alveolar bone might be affected by CTSK mutation via reduction of its enzyme activity (clinical trial registration: ChiCTR-TNC-10000876).","variants":[{"Name":"NM_000396.4(CTSK):c.87G>A (p.Trp29Ter)","Chromosome":"1","Start":"150806719","Stop":"150806719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3859644,"rule_based_match":true,"evidence_text":"c.87 G>A p.W29X","llm_judgment":"PRESENT","evidence":"c.87 G>A p.W29X","abstract_start":611,"abstract_end":626}]}
{"pmid":"18253096","title":"ABCC6 mutations in pseudoxanthoma elasticum: an update including eight novel ones.","abstract":"PURPOSE: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of connective tissue, affecting the retina, the skin, and the cardiovascular system. PXE is caused by mutations in ABCC6. Up to now, the literature reports that there are 180 different ABCC6 mutations in PXE. The purpose of this paper is to report eight novel mutations in ABCC6 and to update the spectrum and frequency of ABCC6 mutations in PXE patients.\nMETHODS: Eye, skin, and DNA examinations were performed using standard methodologies. We newly investigated the gene in 90 probands by denaturing high-performance liquid chromatography (dHPLC) and direct sequencing. We examined a total of 166 probands.\nRESULTS: Eight novel ABCC6 mutations (c.1685T>C, p.Met562Thr; c.2477T>C, p.Leu826Pro; c.2891G>C, p.Arg964Pro; c.3207C>A, p.Tyr1069X; c.3364delT, p.Ser1122fs; c.3717T>G, p.Tyr1293X; c.3871G>A, p.Ala1291Thr; c.4306_4312del, p.Thr1436fs) were found in seven unrelated patients. Currently, our mutation detection score is at least one ABCC6 mutation in 87% of patients with a clinical diagnosis of PXE.\nCONCLUSIONS: Our results support that ABCC6 is the most important, and probably the only, causative gene of PXE. In total, 188 different ABCC6 mutations have now been reported in PXE in the literature.","variants":[{"Name":"NM_001171.6(ABCC6):c.3717T>G (p.Tyr1239Ter)","Chromosome":"16","Start":"16159500","Stop":"16159500","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":426855,"rule_based_match":true,"evidence_text":"c.3717T>G","llm_judgment":"PRESENT","evidence":"c.3717T>G","abstract_start":842,"abstract_end":851},{"Name":"NM_001171.6(ABCC6):c.3207C>A (p.Tyr1069Ter)","Chromosome":"16","Start":"16165722","Stop":"16165722","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":426888,"rule_based_match":true,"evidence_text":"c.3207C>A, p.Tyr1069X","llm_judgment":"PRESENT","evidence":"c.3207C>A, p.Tyr1069X","abstract_start":794,"abstract_end":815},{"Name":"NM_001171.6(ABCC6):c.4306_4312del (p.Thr1436fs)","Chromosome":"16","Start":"16150669","Stop":"16150675","ReferenceAlleleVCF":"AGCTCCGT","AlternateAlleleVCF":"A","allel_id":426793,"rule_based_match":true,"evidence_text":"c.4306_4312del, p.Thr1436fs","llm_judgment":"PRESENT","evidence":"c.4306_4312del, p.Thr1436fs","abstract_start":890,"abstract_end":917},{"Name":"NM_001171.6(ABCC6):c.2477T>C (p.Leu826Pro)","Chromosome":"16","Start":"16177565","Stop":"16177565","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":426930,"rule_based_match":true,"evidence_text":"c.2477T>C, p.Leu826Pro","llm_judgment":"PRESENT","evidence":"c.2477T>C, p.Leu826Pro","abstract_start":746,"abstract_end":768},{"Name":"NM_001171.6(ABCC6):c.1685T>C (p.Met562Thr)","Chromosome":"16","Start":"16188925","Stop":"16188925","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":426999,"rule_based_match":true,"evidence_text":"c.1685T>C, p.Met562Thr","llm_judgment":"PRESENT","evidence":"c.1685T>C, p.Met562Thr","abstract_start":722,"abstract_end":744},{"Name":"NM_001171.6(ABCC6):c.2891G>C (p.Arg964Pro)","Chromosome":"16","Start":"16169750","Stop":"16169750","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":426905,"rule_based_match":true,"evidence_text":"c.2891G>C, p.Arg964Pro","llm_judgment":"PRESENT","evidence":"c.2891G>C, p.Arg964Pro","abstract_start":770,"abstract_end":792},{"Name":"NM_001171.6(ABCC6):c.3364del (p.Ser1122fs)","Chromosome":"16","Start":"16163135","Stop":"16163135","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":426879,"rule_based_match":true,"evidence_text":"c.3364delT, p.Ser1122fs","llm_judgment":"PRESENT","evidence":"c.3364delT, p.Ser1122fs","abstract_start":817,"abstract_end":840}]}
{"pmid":"37092250","title":"RNASEH2C c.194G>A is a Chinese-specific founder mutation in three unrelated patients with Aicardi-Goutières syndrome 3.","abstract":"Biallelic pathogenic variants in RNASEH2C cause Aicardi-Goutières syndrome 3 (AGS3, MIM #610329), a rare early-onset encephalopathy characterized by intermittent unexplained fever, chilblains, irritability, progressive microcephaly, dystonia, spasticity, severe psychomotor retardation and abnormal brain imaging. Currently, approximately 50 individuals with AGS3 and 19 variants in RNASEH2C have been revealed. Here, we reported the novel clinical manifestations and genotypic information of three unrelated Chinese patients with AGS3 caused by pathogenic variants in RNASEH2C. In addition to three novel missense variants (c.101G>A, p.Cys34Tyr; c.401T>A, p.Leu134Gln and c.434G>T, p.Arg145Leu), one missense variant (c.194G>A, p.Gly65Asp) reoccurred in all patients but was completely absent in South Asian and other ethnicities. Our study expanded the variant spectrum of RNASEH2C and identified RNASEH2C c.194G>A as a Chinese-specific founder mutation. The novel phenotypes, including mouth ulcers, hip dysplasia, retarded dentition and hypogonadism, observed in our patients greatly enriched the clinical characteristics of AGS3.","variants":[{"Name":"NM_032193.4(RNASEH2C):c.434G>T (p.Arg145Leu)","Chromosome":"11","Start":"65720079","Stop":"65720079","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":640326,"rule_based_match":true,"evidence_text":"c.434G>T, p.Arg145Leu","llm_judgment":"PRESENT","evidence":"c.434G>T, p.Arg145Leu","abstract_start":673,"abstract_end":694}]}
{"pmid":"33845545","title":"Clinical features and gene mutations of 6 patients with carnitine palmitoyltransferase 1A deficiency","abstract":"The clinical and biochemical data and gene sequencing results of patients with carnitine palmitoyltransferase 1A deficiency were analyzed, in order to improve the understanding of the disease. Six patients (5 males and 1 female, aged from 1 to 8 years old) with carnitine palmitoyltransferase 1A deficiency from Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital between 2008 and 2019 were included. Two cases were detected by neonatal screening and had no clinical symptoms. The remaining 4 cases all showed seizures induced by fever, vomiting or diarrhea. All the 6 patients showed increased serum free carnitine (C0), decreased hexadecanoylcarnitine (C16) and octadecanoylcarnitine (C18), and increased C0/(C16+C18). Meanwhile, compound heterozygous mutations of CPT1A gene were detected in all 6 patients, of which 2 were reported mutations (c.281+1G>A and c.968-8C>T), and 10 were new mutations. The new mutations included 6 missense mutations, 1 nonsense mutation, 1 deletion mutation and 2 splicing mutations. Detection of free carnitine and acyl carnitine by tandem mass spectrometry is helpful for early screening and diagnosis of carnitine palmitoyltransferase 1A deficiency.","variants":[{"Name":"NM_001876.4(CPT1A):c.281+1G>A","Chromosome":"11","Start":"68812436","Stop":"68812436","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":99875,"rule_based_match":true,"evidence_text":"c.281+1G>A","llm_judgment":"PRESENT","evidence":"c.281+1G>A","abstract_start":873,"abstract_end":883}]}
{"pmid":"29113160","title":"Germline cytotoxic lymphocytes defective mutations in Chinese patients with lymphoma.","abstract":"Certain patients with lymphoma may harbor mutations in perforin 1 (PRF1), unc-13 homolog D (UNC13D), syntaxin 11 (STX11), STXBP2 (syntaxin binding protein 2) or SH2 domain containing 1A (SH2D1A), which causes functional defects of cytotoxic lymphocytes. Data regarding the association between genetic defects and the development of lymphoma in Chinese patients are limited to date. In the present study, 90 patients with lymphoma were analyzed for UNC13D, PRF1, STXBP2, STX11, SH2D1A and X-linked inhibitor of apoptosis. Mutations were observed in 24 (26.67%) patients; 16 patients exhibited mutations in UNC13D, 7 exhibited PRF1 mutations, and 1 exhibited monoallelic mutation in STX11. UNC13D c.2588G>A/p.G863D mutation was detected in 9 patients (10.00%) and in 4/210 controls (1.90%). This mutation was predicted to be pathogenic and it predominantly existed in the Chinese population. These findings suggest that impaired cytotoxic machinery may represent a predisposing factor for the development of lymphoma. Furthermore, these data describe a distinct mutation spectrum in Chinese patients with lymphoma, whereby UNC13D is the most frequently mutated gene. In addition, these findings suggest UNC13D c.2588G>A mutation is a founder mutation in Chinese patients.","variants":[{"Name":"NM_199242.3(UNC13D):c.2588G>A (p.Gly863Asp)","Chromosome":"17","Start":"75831135","Stop":"75831135","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227397,"rule_based_match":true,"evidence_text":"UNC13D c.2588G>A/p.G863D mutation","llm_judgment":"PRESENT","evidence":"UNC13D c.2588G>A/p.G863D mutation","abstract_start":688,"abstract_end":721}]}
{"pmid":"31283065","title":"Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease.","abstract":"Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive condition caused by variants in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). We update on the spectrum of TPP1 variants associated with CLN2 disease, comprising 131 unique variants from 389 individuals (717 alleles) collected from the literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1-specific database. Two known pathogenic variants, c.509-1 G>C and c.622 C>T (p.(Arg208*)), collectively occur in 60% of affected individuals in the sample, and account for 50% of disease-associated alleles. At least 86 variants (66%) are private to single families. Homozygosity occurs in 45% of individuals where both alleles are known (87% of reported individuals). Atypical CLN2 disease, TPP1 enzyme deficiency with disease onset and/or progression distinct from classic late-infantile CLN2, represents 13% of individuals recorded with associated phenotype. NCBI ClinVar currently holds records for 37% of variants collected here. Effective CLN2 disease management requires early diagnosis; however, irreversible neurodegeneration occurs before a diagnosis is typically reached at age 5. Timely classification and public reporting of TPP1 variants is essential as molecular testing increases in use as a first-line diagnostic test for pediatric-onset neurological disease.","variants":[{"Name":"NM_000391.4(TPP1):c.509-1G>C","Chromosome":"11","Start":"6617154","Stop":"6617154","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":17683,"rule_based_match":true,"evidence_text":"c.509-1 G>C","llm_judgment":"PRESENT","evidence":"c.509-1 G>C","abstract_start":549,"abstract_end":560}]}
{"pmid":"31439510","title":"Rare Saposin A deficiency: Novel variant and psychosine analysis.","abstract":"Saposin A is a post-translation product of the prosaposin (PSAP) gene that serves as an activator protein of the galactocerebrosidase (GALC) enzyme, and is necessary for the degradation of certain glycosphingolipids. Deficiency of saposin A leads to a clinical picture identical to that of early-infantile Krabbe disease caused by GALC enzyme deficiency. Galactosylsphingosine, also known as psychosine, is a substrate of the GALC enzyme that is known to be elevated in classic Krabbe disease. We present the case of an 18-month-old male with clinical and radiological findings concerning for Krabbe disease who had preserved GALC enzyme activity and negative GALC gene sequencing, but was found to have a homozygous variant, c.257 T > A (p.I86N), in the saposin A peptide of PSAP. Psychosine determination on dried blood spot at 18 months of age was elevated to 12 nmol/L (normal <3 nmol/L). We present this case to add to the literature on the rare diagnosis of atypical Krabbe disease due to saposin A deficiency, to report a novel presumed pathogenic variant within PSAP, and to suggest that individuals with saposin A deficiency may have elevated levels of psychosine, similar to children with classic Krabbe disease due to GALC deficiency.","variants":[{"Name":"NM_002778.4(PSAP):c.257T>A (p.Ile86Asn)","Chromosome":"10","Start":"71831244","Stop":"71831244","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":511874,"rule_based_match":true,"evidence_text":"c.257 T > A (p.I86N)","llm_judgment":"PRESENT","evidence":"c.257 T > A (p.I86N)","abstract_start":726,"abstract_end":746}]}
{"pmid":"23375728","title":"Exome sequencing reveals a homozygous mutation in TWINKLE as the cause of multisystemic failure including renal tubulopathy in three siblings.","abstract":"Three deceased infants from a Pakistani consanguineous family presented with a similar phenotype of cholestatic liver disease, hypotonia, severe failure to thrive, recurrent vomiting, renal tubulopathy, and a progressive neurodegenerative course. Mitochondrial DNA depletion syndrome was considered in view of multisystem involvement. Exome sequencing, revealed a homozygous novel mutation c.1183T>C (p.F395L) in exon 1 of the C10orf2 TWINKLE gene. The hepatocerebral phenotype is well recognized in association with recessive mutations involving the C10orf2 TWINKLE gene. The feature of renal tubulopathy adds to the multisystemic presentation in our patients and further demonstrates an expansion of the phenotype in mitochondrial DNA depletion syndrome associated with TWINKLE gene mutations. The absence of features of an epileptic encephalopathy appears to be of added interest.","variants":[{"Name":"NM_021830.5(TWNK):c.1183T>C (p.Phe395Leu)","Chromosome":"10","Start":"100989393","Stop":"100989393","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":425857,"rule_based_match":true,"evidence_text":"c.1183T>C (p.F395L)","llm_judgment":"PRESENT","evidence":"c.1183T>C (p.F395L)","abstract_start":390,"abstract_end":409}]}
{"pmid":"37067535","title":"The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition.","abstract":"Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 through genetic testing, which poses a significant clinical challenge because the contribution of these VUSs to cancer predisposition has not yet been determined. Here, we report 10 Japanese patients from seven families with breast or ovarian cancer harboring the BRCA2 c.7847C>T (p.Ser2616Phe) variant that was interpreted as a VUS. This variant recurs only in families from Japan and has not been reported in the global general population databases. A Japanese patient with Fanconi anemia with compound heterozygous variants c.7847C>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 was reported. In silico predictions and quantitative cosegregation analysis suggest a high probability of pathogenicity. The clinical features of the variant carriers were not specific to, but were consistent with, those of patients with hereditary breast and ovarian cancer. A validated functional assay, called the mixed-all-nominated-in-one-BRCA (MANO-B) method and the accurate BRCA companion diagnostic (ABCD) test, demonstrated the deleterious effects of the variant. Altogether, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, this variant satisfied the \"PS3,\" \"PM2,\" \"PM3,\" and \"PP3\" criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a \"likely pathogenic\" variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition.","variants":[{"Name":"NM_000059.4(BRCA2):c.7847C>T (p.Ser2616Phe)","Chromosome":"13","Start":"32362564","Stop":"32362564","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":618146,"rule_based_match":true,"evidence_text":"BRCA2 c.7847C>T (p.Ser2616Phe)","llm_judgment":"PRESENT","evidence":"BRCA2 c.7847C>T (p.Ser2616Phe)","abstract_start":359,"abstract_end":389}]}
{"pmid":"30186825","title":"A Novel PCCA Mutation in a Patient With Late-Onset Propionic Acidemia Identified by Genetic Diagnosis Panel.","abstract":"<b>Background:</b> Propionic acidemia (PA) is an extremely rare autosomal recessive disorder which is caused by the deficiency of propionyl-CoA carboxylase (PCC) and associated with pathogenic variants in PCCA or PCCB gene. <b>Case Report:</b> Detection of PA in neonates is possible using Propionyl carnitine (C3) analysis by tandem mass spectrometry (MS/MS) in dried blood spots (DBS). Here we report one patient with PA. C3 in this case was normal in the initial screening and recall check and only manifested as the slightly increase of C3/C2, 3-hydroxypropionate in urine was only slightly elevated. Then two pathogenic mutations (c.802C>T/c.827delG) were detected in the PCCA gene by Genetic diagnosis panel. Among them, the variation rs774738181 (c.802C>T) was present on the dbSNP database which appeared to be \"Likely pathogenic\" in GenBank dbSNP (100915068). c.827delG was a novel frameshift mutation, leading to p.Gly276ValfsX46 mutation of amino acid sequence in PCCA. The patient underwent 1 year of follow-up, had total of 7 times and remain asymptomatic whose blood ammonia and liver function were normal. When the child was 1 year of age (in May of 2017), C3 and 3-Hydroxypropionate sudden elevated significantly, that proved pathogenicity of c.802C>T and c.827delG. <b>Conclusion:</b> Two novel mutations (c. 802C>T and c.827delG) in PCCA gene may be associated with late-onset PA, expanding its mutational spectrum. Maybe there is relation between the severity of propionyl-CoA carboxylase (PCC) activity defects and different genotypes.","variants":[{"Name":"NM_000282.4(PCCA):c.802C>T (p.Arg268Cys)","Chromosome":"13","Start":"100262814","Stop":"100262814","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":273639,"rule_based_match":true,"evidence_text":"c.802C>T","llm_judgment":"PRESENT","evidence":"c.802C>T","abstract_start":636,"abstract_end":644}]}
{"pmid":"30858171","title":"Homozygosity for CHEK2 p.Gly167Arg leads to a unique cancer syndrome with multiple complex chromosomal translocations in peripheral blood karyotype.","abstract":"BACKGROUND: Chromosomal instability, as reflected by structural or copy-number changes, is a known cancer characteristic but are rarely observed in healthy tissue. Mutations in DNA repair genes disrupt the maintenance of DNA integrity and predispose to hereditary cancer syndromes.\nOBJECTIVE: To clinically characterise and genetically diagnose two reportedly unrelated patients with unique cancer syndromes, including multiorgan tumourogenesis (patient 1) and early-onset acute myeloid leukaemia (patient 2), both displaying unique peripheral blood karyotypes.\nMETHODS: Genetic analysis in patient 1 included TruSight One panel and whole-exome sequencing, while patient 2 was diagnosed by FoundationOne Heme genomic analysis; Sanger sequencing was used for mutation confirmation in both patients. Karyotype analysis was performed on peripheral blood, bone marrow and other available tissues.\nRESULTS: Both patients were found homozygous for <i>CHEK2</i> c.499G>A; p.Gly167Arg and exhibited multiple different chromosomal translocations in 30%-60% peripheral blood lymphocytes. This karyotype phenotype was not observed in other tested tissues or in an ovarian cancer patient with a different homozygous missense mutation in <i>CHEK2</i> (c.1283C>T; p.Ser428Phe).\nCONCLUSIONS: The multiple chromosomal translocations in patient lymphocytes highlight the role of CHK2 in DNA repair. We suggest that homozygosity for p.Gly167Arg increases patients' susceptibility to non-accurate correction of DNA breaks and possibly explains their increased susceptibility to either multiple primary tumours during their lifetime or early-onset tumourigenesis.","variants":[{"Name":"NM_007194.4(CHEK2):c.499G>A (p.Gly167Arg)","Chromosome":"22","Start":"28725070","Stop":"28725070","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152238,"rule_based_match":true,"evidence_text":"c.499G>A; p.Gly167Arg","llm_judgment":"PRESENT","evidence":"c.499G>A; p.Gly167Arg","abstract_start":955,"abstract_end":976}]}
{"pmid":"12938097","title":"Five novel inactivating mutations in the thyroid peroxidase gene responsible for congenital goiter and iodide organification defect.","abstract":"Thyroid peroxidase (TPO) defects, typically transmitted as autosomal recessive traits, result in hypothyroid goiters with failure to convert iodide into organic iodine. We analyzed the TPO gene in 14 unrelated patients with clinical evidence of iodide organification defects. Seven of the affected individuals harbored mutations in the TPO gene; one was compound heterozygous, the others were simply heterozygous for TPO mutations. Five novel mutations have been identified, one of which was found to be a single nucleotide deletion, while the other four were single nucleotide substitutions. A frameshift mutation c.387delC was detected in exon 5 which leads to an early termination signal in exon 7 (p.N129fsX208). Two missense mutations were identified in exon 8. The first, a c.920A>C transversion that results in a p.N307T substitution, was found in two patients. The second, a c.1297G>A transition, results in p.V433M. A c.1496C>T transition was detected in exon 9 that caused the substitution p.P499L. Finally, in exon 14 a c.2422T>C transition was identified, causing a p.C808R change. In addition, the previously reported GGCC duplication in exon 8 (c.1186_1187insGGCC; p.R396fsX472) was also detected in two affected individuals, one of whom was a compound heterozygous (p.R396fsX472/p.V433M).","variants":[{"Name":"NM_001206744.2(TPO):c.920A>C (p.Asn307Thr)","Chromosome":"2","Start":"1477186","Stop":"1477186","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2417934,"rule_based_match":true,"evidence_text":"c.920A>C","llm_judgment":"PRESENT","evidence":"c.920A>C","abstract_start":780,"abstract_end":788}]}
{"pmid":"29652087","title":"Expanding the clinical spectrum of biallelic ZNF335 variants.","abstract":"ZNF335 plays an essential role in neurogenesis and biallelic variants in ZNF335 have been identified as the cause of severe primary autosomal recessive microcephaly in 2 unrelated families. We describe, herein, 2 additional affected individuals with biallelic ZNF335 variants, 1 individual with a homozygous c.1399 T > C, p.(Cys467Arg) variant, and a second individual with compound heterozygous c.2171_2173delTCT, p.(Phe724del) and c.3998A > G, p.(Glu1333Gly) variants with the latter variant predicted to affect splicing. Whereas the first case presented with early death and a severe phenotype characterized by anterior agyria with prominent extra-axial spaces, absent basal ganglia, and hypoplasia of the brainstem and cerebellum, the second case had a milder clinical presentation with hypomyelination and otherwise preserved brain structures on MRI. Our findings expand the clinical spectrum of ZNF335-associated microcephaly.","variants":[{"Name":"NM_022095.4(ZNF335):c.1399T>C (p.Cys467Arg)","Chromosome":"20","Start":"45963607","Stop":"45963607","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":610404,"rule_based_match":true,"evidence_text":"c.1399 T > C, p.(Cys467Arg)","llm_judgment":"PRESENT","evidence":"c.1399 T > C, p.(Cys467Arg)","abstract_start":308,"abstract_end":335},{"Name":"NM_022095.4(ZNF335):c.3998A>G (p.Glu1333Gly)","Chromosome":"20","Start":"45948984","Stop":"45948984","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":446252,"rule_based_match":true,"evidence_text":"c.3998A > G, p.(Glu1333Gly)","llm_judgment":"PRESENT","evidence":"c.3998A > G, p.(Glu1333Gly)","abstract_start":433,"abstract_end":460}]}
{"pmid":"36002240","title":"","abstract":"BACKGROUND: Dystonia involves repetitive movements and muscle contractions leading to abnormal postures. We investigated patients in two families, DYAF11 and M, exhibiting dystonic or involuntary movement disorders.\nMETHODS: Clinical investigations were performed for all patients. Genetic analyses included genome-wide linkage analysis and exome sequencing followed by Sanger sequencing validation. <i>MRM2-</i>specific transcripts were analysed from participants' blood samples in Family DYAF11 after cloning of gene-specific cDNA.\nRESULTS: Four affected siblings in Family DYAF11 had progressive dystonic features. Two patients in Family M exhibited a neurodevelopmental disorder accompanied by involuntary movements. In Family DYAF11, linkage was detected to the telomere at chromosome 7p22.3, spanning <2 Mb. Exome sequencing identified a donor splice-site variant, c.8+1G>T in <i>MRM2,</i> which segregated with the phenotype, corresponding to the linkage data since all affected individuals were homozygous while the obligate unaffected carriers were heterozygous for the variant. In the <i>MRM2</i> c.8+1G>T allele, an aberrant alternative acceptor splice-site located within exon 2 was used in a subset of the transcripts, creating a frameshift in the open reading frame. Exome sequencing in Family M revealed a rare missense variant c.242C>T, p.(Ala81Val), which affected a conserved amino acid.\nCONCLUSIONS: Our results expand the clinical and allelic spectrum of <i>MRM2</i> variants. Previously, these descriptions were based on observations in a single patient, diagnosed with mitochondrial DNA depletion syndrome 17, in whom movement disorder was accompanied by recurrent strokes and epilepsy. We also demonstrate a subset of correctly spliced tt-ag <i>MRM2</i> transcripts, raising the possibility to develop treatment by understanding the disease mechanism.","variants":[{"Name":"NM_013393.3(MRM2):c.8+1G>T","Chromosome":"7","Start":"2242161","Stop":"2242161","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3189218,"rule_based_match":true,"evidence_text":"c.8+1G>T","llm_judgment":"PRESENT","evidence":"c.8+1G>T","abstract_start":871,"abstract_end":879},{"Name":"NM_013393.3(MRM2):c.242C>T (p.Ala81Val)","Chromosome":"7","Start":"2239474","Stop":"2239474","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1333550,"rule_based_match":true,"evidence_text":"c.242C>T, p.(Ala81Val)","llm_judgment":"PRESENT","evidence":"c.242C>T, p.(Ala81Val)","abstract_start":1343,"abstract_end":1365}]}
{"pmid":"23981984","title":"Identification of a known GJB6 mutation in an autosomal dominant inherited Chinese family with hidrotic ectodermal dysplasia.","abstract":"OBJECTIVE: Mutation in the gap junction beta 6 (GJB6) gene has been reported to be associated with an autosomal dominant disorder hidrotic ectodermal dysplasia (HED), characterized by congenital nail clubbing, alopecia and palmoplantar keratoderma. The aim of this study is to investigate relationship between genetic mutation in GJB6 and HED in an affected Chinese family.\nMETHODS: We selected a Chinese HED family consisting of a total of 17 individuals including 8 HED patients (5 males and 3 females). The whole coding region of GJB6 was amplified by polymerase chain reaction and sequenced.\nRESULTS: Sequence analysis identified a heterozygous missense mutation c.31G>A (p.G11R) in GJB6 gene of affected individuals, but not in healthy individuals.\nCONCLUSION: A c.31G>A (p.G11R) missense mutation in GJB6 gene is the genotypic characteristic for HED in Chinese population.","variants":[{"Name":"NM_001110219.3(GJB6):c.31G>A (p.Gly11Arg)","Chromosome":"13","Start":"20223450","Stop":"20223450","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20583,"rule_based_match":true,"evidence_text":"c.31G>A (p.G11R)","llm_judgment":"PRESENT","evidence":"c.31G>A (p.G11R)","abstract_start":667,"abstract_end":683}]}
{"pmid":"27551680","title":"Whole-exome sequencing of a patient with severe and complex hemostatic abnormalities reveals a possible contributing frameshift mutation in C3AR1.","abstract":"The increasing availability of genome-wide analysis has made it possible to rapidly sequence the exome of patients with undiagnosed or unresolved medical conditions. Here, we present the case of a 64-yr-old male patient with schistocytes in the peripheral blood smear and a complex and life-threatening coagulation disorder causing recurrent venous thromboembolic events, severe thrombocytopenia, and subdural hematomas. Whole-exome sequencing revealed a frameshift mutation (C3AR1 c.355-356dup, p.Asp119Alafs*19) resulting in a premature stop codon in C3AR1 (Complement Component 3a Receptor 1). Based on this finding, atypical hemolytic uremic syndrome was suspected because of a genetic predisposition, and a targeted treatment regime with eculizumab was initiated. Life-threatening hemostatic abnormalities would most likely have persisted had it not been for the implementation of whole-exome sequencing in this particular clinical setting.","variants":[{"Name":"NM_004054.4(C3AR1):c.355_356dup (p.Asp119fs)","Chromosome":"12","Start":"8059829","Stop":"8059830","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ATC","allel_id":224677,"rule_based_match":false,"evidence_text":"C3AR1 c.355-356dup, p.Asp119Alafs*19","llm_judgment":"PRESENT","evidence":"C3AR1 c.355-356dup, p.Asp119Alafs*19","abstract_start":476,"abstract_end":512}]}
{"pmid":"26549787","title":"Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late-onset Alzheimer's disease.","abstract":"Alzheimer's disease (AD) is a neurodegenerative disease affecting over 20 million people worldwide, mainly adult subjects in advanced age. Over 240 different fully penetrant autosomal dominant mutations in 532 families around the world have been described in three genes [i.e., amyloid precursor protein (APP), and presenilins (PSEN1 and PSEN2)] causing 50% of all Familial AD. We report a new mutation (p.Ile408Thr, c. 1223T>C) in the PSEN1 gene in one autosomal dominant Late Onset AD patient. The genetic variation occurred in a conserved domain of the protein and was present in the proband and in the younger sister who is likely to be prodromal AD. Thus, we suggest that this variant will have probably a pathogenic effect, hypothesizing a possible key role of this new mutation in the pathogenesis of Alzheimer's disease for this family.","variants":[{"Name":"NM_000021.4(PSEN1):c.1223T>C (p.Ile408Thr)","Chromosome":"14","Start":"73217219","Stop":"73217219","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2109512,"rule_based_match":true,"evidence_text":"c. 1223T>C","llm_judgment":"PRESENT","evidence":"c. 1223T>C","abstract_start":417,"abstract_end":427}]}
{"pmid":"32014045","title":"Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns.","abstract":"BACKGROUND: The necessity of early treatment for lysosomal storage diseases (LSDs) has triggered the development of newborn screening for LSDs in recent years. Here we report the first 70,000 newborns screened for Mucopolysaccharidosis (MPS) type 4A (Morquio syndrome) and other LSDs by an 8-plex assay including the original 4-plex LSD screening tandem mass spectrometry (MS/MS) assay for Pompe disease, Fabry disease, Gaucher disease, and MPS I disease.\nMETHODS: The additional reaction for MPS II, MPS 3B, MPS 4A, and MPS 6 enzymes was performed separately from the 4-plex reaction. The two reactions were quenched and extracted, then combined before carrying out a single 2-min UPLC-MS/MS analysis.\nRESULTS: From Mar. 2018 to Apr. 2019, 73,743 newborns were screened with the 8-plex LSD screening assay. The 8-plex assay revealed a better analytical precision than the previous 4-plex assay possibly because the 8-plex was carried out using UPLC-MS/MS. Six newborns were found to have low MPS-4A enzyme (N-acetylgalactosamine-6-sulfatase) activity and biallelic GALNS pathogenic mutations in trans; these patients are presumably affected with MPS4A, making an incidence of one in 12,291 (95% confident interval (CI): 5633-26,817). One mutation, c.857C > T (p.T286 M) of the GALNS gene, accounted 5 of the 12 mutated alleles. These newborns had immature vertebral bodies at 1 month of age, and one case was treated with elosulfase alfa 2 mg/kg/week starting from 4 months of age. Among other MPSs screened, one case of MPS I, 3 cases of MPS II, and 3 cases of MPS 3B were detected. One case of mucolipidosis type III was also diagnosed. In conjunction with another 9 patients of Pompe disease, Gaucher disease, and classical Fabry disease, making an incidence of LSDs as one in 3206 newborns (95% CI: 2137 - 4811). The one with infantile-onset Pompe disease and the one with Gaucher disease were treated since the age of 8 days and 41 days respectively.\nCONCLUSIONS: Routine newborn screening of MPS 4A and other LSDs were made possible by the 8-plex LSD screening assay. However, detailed phenotype prediction and the time to start treatment will need further elucidation.","variants":[{"Name":"NM_000512.5(GALNS):c.857C>T (p.Thr286Met)","Chromosome":"16","Start":"88835254","Stop":"88835254","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":621552,"rule_based_match":true,"evidence_text":"c.857C > T (p.T286 M)","llm_judgment":"PRESENT","evidence":"c.857C > T (p.T286 M)","abstract_start":1249,"abstract_end":1270}]}
{"pmid":"25919557","title":"Analysis of MLC1 gene mutation in a Chinese family with megalencephalic leukoencephalopathy with subcortical cysts","abstract":"The clinical data of a patient with megalencephalic leukoencephalopathy (MLC) with subcortical cysts and her parents were collected. MLC1 gene mutation was detected by polymerase chain reaction and direct DNA sequencing. The patient presented with motor developmental delay and giant skull, and brain magnetic resonance imaging showed diffuse white matter swelling accompanied by subcortical cysts in bilateral frontal and parietal lobes. Gene sequencing identified two heterozygous mutations of MLC1, including missense mutation in exon 3 (c.217G>A, p.Gly73Arg) and splice site mutation in intron 9 (c.772-1G>C in IVS9-1). The patient's parents both had heterozygous mutation c.772-1G>C in IVS9-1 with normal phenotype. It can be presumed that c.772-1G>C in IVS9-1 comes from the parents, and c.217G>A (p.Gly73Arg) is a de novo mutation.","variants":[{"Name":"NM_015166.4(MLC1):c.217G>A (p.Gly73Arg)","Chromosome":"22","Start":"50083134","Stop":"50083134","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2901753,"rule_based_match":true,"evidence_text":"c.217G>A (p.Gly73Arg)","llm_judgment":"PRESENT","evidence":"c.217G>A (p.Gly73Arg)","abstract_start":794,"abstract_end":815}]}
{"pmid":"24115525","title":"Congenital heart defects in oculodentodigital dysplasia: Report of two cases.","abstract":"Oculodentodigital dysplasia is caused by mutations in the GJA1 gene. Oculodentodigital dysplasia presents with a spectrum of clinical features including craniofacial, ocular, dental, and limb anomalies. Although recent findings implicate the major role of GJA1 during cardiac organogenesis, congenital heart defects are infrequently reported in oculodentodigital dysplasia. Here we report on two patients with GJA1 mutations presenting with cardiac malformations and type III syndactyly. Patient 1 presented with pulmonary atresia, an intact septum, right ventricular hypoplasia and tricuspid stenosis. The infant had a small nose, thin columella and bilateral 4-5 syndactyly of the fingers. A de novo c.226C>T (p.Arg76Cys) mutation was identified. Patient 2 presented at 6 months with a ventricular septal defect. The child had hypoplastic alae nasi with a thin columella and bilateral 4-5 syndactyly of the digits. A de novo missense mutation, c.145C>G (p.Gln49Glu) was found. Our two patients underscore the importance of cardiac evaluations as part of the initial workup for patients with findings of oculodentodigital dysplasia. Conversely, those patients with type III syndactyly and congenital heart defect should be screened for GJA1 mutations.","variants":[{"Name":"NM_000165.5(GJA1):c.226C>T (p.Arg76Cys)","Chromosome":"6","Start":"121447073","Stop":"121447073","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2904851,"rule_based_match":true,"evidence_text":"c.226C>T (p.Arg76Cys)","llm_judgment":"PRESENT","evidence":"c.226C>T (p.Arg76Cys)","abstract_start":702,"abstract_end":723}]}
{"pmid":"25026867","title":"Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment.","abstract":"BACKGROUND: X-linked Ornithine Transcarbamylase deficiency (OTCD) is often unrecognized in adults, as clinical manifestations are non-specific, often episodic and unmasked by precipitants, and laboratory findings can be normal outside the acute phase. It may thus be associated with significant mortality if not promptly recognized and treated. The aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations.\nMETHODS: We carried out a clinical, biochemical and molecular study on five unrelated adult patients (one female and four males) with late onset OTCD, who presented to the Emergency Department (ED) with initial fatal encephalopathy. The molecular study consisted of OTC gene sequencing in the probands and family members and in silico characterization of the newly detected mutations.\nRESULTS: We identified two new, c.119G>T (p.Arg40Leu) and c.314G>A (p.Gly105Glu), and three known OTC mutations. Both new mutations were predicted to cause a structural destabilization, correlating with late onset OTCD. We also identified, among the family members, 8 heterozygous females and 2 hemizygous asymptomatic males. Patients' histories revealed potential environmental triggering factors, including steroid treatment, chemotherapy, diet changes and hormone therapy for in vitro fertilization.\nCONCLUSIONS: This report raises awareness of the ED medical staff in considering OTCD in the differential diagnosis of sudden neurological and behavioural disorders associated with hyperammonemia at any age and in both genders. It also widens the knowledge about combined effect of genetic and environmental factors in determining the phenotypic expression of OTCD.","variants":[{"Name":"NM_000531.6(OTC):c.119G>T (p.Arg40Leu)","Chromosome":"X","Start":"38367332","Stop":"38367332","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2901879,"rule_based_match":true,"evidence_text":"c.119G>T (p.Arg40Leu)","llm_judgment":"PRESENT","evidence":"c.119G>T (p.Arg40Leu)","abstract_start":972,"abstract_end":993}]}
{"pmid":"25149867","title":"Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia.","abstract":"We describe two pairs of siblings from a consanguineous family manifesting autosomal recessive hereditary spastic paraplegia caused by a novel mutation in the EXOSC3 gene, previously reported in pontocerebellar hypoplasia type 1. Clinical findings included delayed motor milestones, early-onset spastic paraplegia, variable cognitive disability, and cerebellar signs. Cerebral imaging demonstrated enlarged cisterna magna and mild hypoplasia and atrophy of the lower vermis with a normal pons. Genetic analysis using homozygosity mapping followed by whole exome sequencing identified homozygous c.571G>T; p.G191C mutation in the EXOSC3 gene. We suggest that EXOSC3 mutations may present not only as pontocerebellar hypoplasia type 1, but also as a complicated form of hereditary spastic paraplegia without pontine hypoplasia or atrophy.","variants":[{"Name":"NM_016042.4(EXOSC3):c.571G>T (p.Gly191Cys)","Chromosome":"9","Start":"37782041","Stop":"37782041","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":181189,"rule_based_match":true,"evidence_text":"c.571G>T; p.G191C","llm_judgment":"PRESENT","evidence":"c.571G>T; p.G191C","abstract_start":595,"abstract_end":612}]}
{"pmid":"30687093","title":"Phenotype-Driven Virtual Panel Is an Effective Method to Analyze WES Data of Neurological Disease.","abstract":"<b>Objective:</b> Whole Exome Sequencing (WES) is an effective diagnostic method for complicated and multi-system involved rare diseases. However, annotation and analysis of the WES result, especially for single case analysis still remain a challenge. Here, we introduce a method called phenotype-driven designing \"virtual panel\" to simplify the procedure and assess the diagnostic rate of this method. <b>Methods:</b> WES was performed in samples of 30 patients, core phenotypes of probands were then extracted and inputted into an in-house software, \"Mingjian\" to calculate and generate associated gene list of a virtual panel. Mingjian is a self-updating genetic disease computer supportive diagnostic system that based on the databases of HPO, OMIM, HGMD. The virtual panel that generated by Mingjian system was then used to filter and annotate candidate mutations. Sanger sequencing and co-segregation analysis among the family were then used to confirm the filtered mutants. <b>Result:</b> We first used phenotype-driven designing \"virtual panel\" to analyze the WES data of a patient whose core phenotypes are ataxia, seizures, esotropia, puberty and gonadal disorders, and global developmental delay. Two mutations, c.430T > C and c.640G > C in PMM2 were identified by this method. This result was also confirmed by Sanger sequencing among the family. The same analysing method was then used in the annotation of WES data of other 29 neurological rare disease patients. The diagnostic rate was 65.52%, which is significantly higher than the diagnostic rate before. <b>Conclusion:</b> Phenotype-driven designing virtual panel could achieve low-cost individualized analysis. This method may decrease the time-cost of annotation, increase the diagnostic efficiency and the diagnostic rate.","variants":[{"Name":"NM_000303.3(PMM2):c.430T>C (p.Phe144Leu)","Chromosome":"16","Start":"8811161","Stop":"8811161","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":194819,"rule_based_match":true,"evidence_text":"c.430T > C","llm_judgment":"PRESENT","evidence":"c.430T > C","abstract_start":1223,"abstract_end":1233}]}
{"pmid":"31926053","title":"Expanding the genotype-phenotype correlation of de novo heterozygous missense variants in YWHAG as a cause of developmental and epileptic encephalopathy.","abstract":"Developmental and Epileptic encephalopathies (DEE) describe heterogeneous epilepsy syndromes, characterized by early-onset, refractory seizures and developmental delay (DD). Several DEE associated genes have been reported. With increased access to whole exome sequencing (WES), new candidate genes are being identified although there are fewer large cohort papers describing the clinical phenotype in such patients. We describe 6 unreported individuals and provide updated information on an additional previously reported individual with heterozygous de novo missense variants in YWHAG. We describe a syndromal phenotype, report 5 novel, and a recurrent p.Arg132Cys YWHAG variant and compare developmental trajectory and treatment strategies in this cohort. We provide further evidence of causality in YWHAG variants. WES was performed in five patients via Deciphering Developmental Disorders Study and the remaining two were identified via Genematcher and AnnEX databases. De novo variants identified from exome data were validated using Sanger sequencing. Seven out of seven patients in the cohort have de novo, heterozygous missense variants in YWHAG including 2/7 patients with a recurrent c.394C > T, p.Arg132Cys variant; 1/7 has a second, pathogenic variant in STAG1. Characteristic features included: early-onset seizures, predominantly generalized tonic-clonic and absence type (7/7) with good response to standard anti-epileptic medications; moderate DD; Intellectual Disability (ID) (5/7) and Autism Spectrum Disorder (3/7). De novo YWHAG missense variants cause EE, characterized by early-onset epilepsy, ID and DD, supporting the hypothesis that YWHAG loss-of-function causes a neurological phenotype. Although the exact mechanism of disease resulting from alterations in YWHAG is not fully known, it is possible that haploinsufficiency of YWHAG in developing cerebral cortex may lead to abnormal neuronal migration resulting in DEE.","variants":[{"Name":"NM_012479.4(YWHAG):c.394C>T (p.Arg132Cys)","Chromosome":"7","Start":"76329927","Stop":"76329927","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432435,"rule_based_match":true,"evidence_text":"c.394C > T, p.Arg132Cys","llm_judgment":"PRESENT","evidence":"c.394C > T, p.Arg132Cys","abstract_start":1194,"abstract_end":1217}]}
{"pmid":"30298498","title":"Clinical and genetic analysis of a case with atypical ethyl malonate encephalopathy","abstract":"OBJECTIVE: To delineate the clinical and genetic characteristics of a girl featuring motor retardation, language retardation and regression, and light persisting diarrhea.\nMETHODS: The patient was clinically examined and tested by tandem mass spectrometry and next generation sequencing.\nRESULTS: The proband could not stand and walk alone, and had light persisting diarrhea. She manifested language development retardation and regression. Laboratory tests were all normal, but the screening of metabolic disorders for urine and blood showed deficiency of short chain coenzyme A dehydrogenase due to elevated ethylmalonic acid and butyryl carnitine. By next generation sequencing, two compound heterozygous mutations of the ETHE1 gene, c.2T>A and c.488G>A, were discovered in the proband, which were respectively inherited from her father and mother. Bioinformatics analysis predicted both mutations to be pathogenic. The patient was diagnosed with ethylmalonic encephalopathy. Vitamin B1, B2, Coenzyme Q10, and L-carnitine were prescribed. The patient deteriorated and required liver transplantation at 4-year-1-month.\nCONCLUSION: Based on the clinical and genetic analysis, the proband was diagnosed with ethylmalonic encephalopathy caused by ETHE1 gene mutation. Next generation sequencing has provided a powerful tool for the diagnosis of such disorders.","variants":[{"Name":"NM_014297.5(ETHE1):c.2T>A (p.Met1Lys)","Chromosome":"19","Start":"43527176","Stop":"43527176","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1892389,"rule_based_match":true,"evidence_text":"c.2T>A","llm_judgment":"PRESENT","evidence":"c.2T>A","abstract_start":736,"abstract_end":742},{"Name":"NM_014297.5(ETHE1):c.488G>A (p.Arg163Gln)","Chromosome":"19","Start":"43511454","Stop":"43511454","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":211889,"rule_based_match":true,"evidence_text":"c.488G>A","llm_judgment":"PRESENT","evidence":"c.488G>A","abstract_start":747,"abstract_end":755}]}
{"pmid":"33713115","title":"A recurrent ZSWIM7 mutation causes male infertility resulting from decreased meiotic recombination.","abstract":"STUDY QUESTION: Are mutations in the zinc finger SWIM domain-containing protein 7 gene (ZSWIM7) associated with human male infertility?\nSUMMARY ANSWER: The homozygous frameshift mutation (c.231_232del) in ZSWIM7 causes decreased meiotic recombination, spermatogenesis arrest, and infertility in men.\nWHAT IS KNOWN ALREADY: ZSWIM7 is a SWIM domain-containing Shu2/SWS1 protein family member and a subunit of the Shu complex. Zswim7 knockout mice were infertile due to impaired meiotic recombination. However, so far there is no direct evidence that mutations of ZSWIM7 cause human infertility.\nSTUDY DESIGN, SIZE, DURATION: Screening for mutations of ZSWIM7 was performed using in-house whole-exome sequencing data from 60 men with non-obstructive azoospermia (NOA). Mice with a corresponding Zswim7 mutation were generated for functional verification.\nPARTICIPANTS/MATERIALS, SETTING, METHODS: Sixty Chinese patients, who were from different regions of China, were enrolled. All the patients were diagnosed with NOA owing to spermatocyte maturation arrest based on histopathological analyses and/or immunostaining of spermatocyte chromosome spreads. ZSWIM7 mutations were screened from the whole-exome sequencing data of these patients, followed by functional verification in mice.\nMAIN RESULTS AND THE ROLE OF CHANCE: A homozygous frameshift mutation (c.231_232del) in ZSWIM7 was found in two out of the 60 unrelated NOA patients. Both patients displayed small testicular size and spermatocyte maturation arrest in testis histology. Spermatocyte chromosome spreads of one patient revealed meiotic maturation arrest in a pachytene-like stage, with incomplete synapsis and decreased meiotic recombination. Male mice carrying a homozygous mutation similar to that of our patients were generated and also displayed reduced recombination, meiotic arrest and azoospermia, paralleling the spermatogenesis defects in our patients.\nLIMITATIONS, REASONS FOR CAUTION: As Zswim7 is also essential for meiosis in female mice, future studies should evaluate the ZSWIM7 mutations more in depth and in larger cohorts of infertile patients, including males and females, to validate the findings.\nWIDER IMPLICATIONS OF THE FINDINGS: These findings provide direct clinical and functional evidence that the recurrent ZSWIM7 mutation (c.231_232del) causes decreased meiotic recombination and leads to male infertility, illustrating the genotype-phenotype correlations of meiotic recombination defects in humans.\nSTUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (31890780, 31630050, 32061143006, 82071709, and 31871514), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000), and the National Key Research and Developmental Program of China (2018YFC1003900 and 2019YFA0802600).\nTRIAL REGISTRATION NUMBER: Not applicable.","variants":[{"Name":"NM_001042697.2(ZSWIM7):c.231_232del (p.Cys78fs)","Chromosome":"17","Start":"15981114","Stop":"15981115","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":1001325,"rule_based_match":true,"evidence_text":"c.231_232del","llm_judgment":"PRESENT","evidence":"c.231_232del","abstract_start":188,"abstract_end":200}]}
{"pmid":"24140112","title":"SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant.","abstract":"Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions.","variants":[{"Name":"NM_078480.3(PUF60):c.505C>T (p.His169Tyr)","Chromosome":"8","Start":"143818378","Stop":"143818378","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":97544,"rule_based_match":true,"evidence_text":"c.505C>T","llm_judgment":"PRESENT","evidence":"c.505C>T","abstract_start":862,"abstract_end":870}]}
{"pmid":"26242193","title":"Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing.","abstract":"Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development.","variants":[{"Name":"NM_016239.4(MYO15A):c.3871C>T (p.Leu1291Phe)","Chromosome":"17","Start":"18126795","Stop":"18126795","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3857034,"rule_based_match":true,"evidence_text":"c.3871C>T (p.L1291F)","llm_judgment":"PRESENT","evidence":"c.3871C>T (p.L1291F)","abstract_start":152,"abstract_end":172}]}
{"pmid":"38503300","title":"Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.","abstract":"Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.","variants":[{"Name":"NM_002801.4(PSMB10):c.601G>A (p.Gly201Arg)","Chromosome":"16","Start":"67934906","Stop":"67934906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3400945,"rule_based_match":true,"evidence_text":"c.601G>A (p.Gly201Arg)","llm_judgment":"PRESENT","evidence":"p.Gly201Arg","abstract_start":1088,"abstract_end":1099},{"Name":"NM_002801.4(PSMB10):c.601G>C (p.Gly201Arg)","Chromosome":"16","Start":"67934906","Stop":"67934906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3400946,"rule_based_match":true,"evidence_text":"c.601G>C (p.Gly201Arg)","llm_judgment":"PRESENT","evidence":"p.Gly201Arg","abstract_start":1088,"abstract_end":1099},{"Name":"NM_002801.4(PSMB10):c.166G>C (p.Asp56His)","Chromosome":"16","Start":"67936291","Stop":"67936291","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3400947,"rule_based_match":true,"evidence_text":"c.166G>C [p.Asp56His]","llm_judgment":"PRESENT","evidence":"c.166G>C [p.Asp56His]","abstract_start":1043,"abstract_end":1064}]}
{"pmid":"37652172","title":"Punctate inner choroidopathy in common variable immunodeficiency associated with a pathogenic variant in the tumour necrosis factor receptor superfamily 13b (TNFRSF13B) gene - Case report and review of the literature.","abstract":"BACKGROUND: Common variable immunodeficiency (CVID) has been recognised as the most common primary immunodeficiency in adulthood, and is characterised by increased susceptibility to infection, autoimmunity and increased risk of malignancies. Although ocular manifestations are not common in CVID, rare associated inflammatory eye conditions have been reported including submacular choroiditis.\nOBJECTIVE: To report a case of punctate inner choroidopathy in a patient with common variable immunodeficiency.\nCASE PRESENTATION: A 40-year-old lady with CVID and associated autoimmune thrombocytopenia, who was treated with immunoglobulin replacement and Eltrombopag, experienced gradually deteriorating right eye vision. Fundal examination and optical coherence tomography (OCT) revealed right multifocal retinal choroidal lesions consistent with a diagnosis of unilateral punctate inner choroidopathy (PIC) with secondary choroidal neovascularisation (CNV). Anti-VEGF injections led to stabilised fundal appearances. Genetic testing revealed a heterozygous sequence change c.260 T > Ap.(IIe87Asn), pathogenic variant in the Tumour Necrosis Factor Superfamily 13B (TNFRSF13B) gene, which is reported as being associated with ∼10% of CVID cases.\nCONCLUSION: Autoimmunity may be the dominant clinical presenting feature of CVID. Punctuate inner choroidopathy is an idiopathic inflammatory chorioretinopathy, and to the best of our knowledge, has not been previously reported in CVID. A better understanding of the molecular bases of autoimmune diseases in CVID may provide novel therapeutic targets for autoimmune diseases in this patient population.","variants":[{"Name":"NM_012452.3(TNFRSF13B):c.260T>A (p.Ile87Asn)","Chromosome":"17","Start":"16948923","Stop":"16948923","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":610057,"rule_based_match":true,"evidence_text":"c.260 T > A p.(IIe87Asn)","llm_judgment":"PRESENT","evidence":"c.260 T > A p.(IIe87Asn)","abstract_start":null,"abstract_end":null}]}
{"pmid":"20486940","title":"Multiple sequence variations in SLC5A1 gene are associated with glucose-galactose malabsorption in a large cohort of Old Order Amish.","abstract":"Glucose-galactose malabsorption (GGM) is an autosomal recessive disease with life-threatening newborn diarrhea caused by mutations in the Na(+) /glucose cotransporter gene SLC5A1. Because of its rarity, the clinical course of the disease has not been well studied. Here, we report 33 patients with GGM from a large Old Order Amish pedigree and the associated mutations in SLC5A1 gene. Clinically, all affected individuals presented with classic watery diarrhea and dehydration. The increased bowel sounds, distended abdomen, vigorous nursing regardless of their illness, and irritability and apathy were also noted as part of the initial presentation. Patients underwent a dramatic turnaround with an immediate cease of the diarrhea and a quick rehydration if they were correctly diagnosed and adequately managed, followed by a normal growth and development pattern afterwards; whereas a prolonged clinical course would follow if the disease was not recognized. Sequence analysis of the 15 protein-coding exons and the corresponding exon-intron boundaries of SLC5A1 gene revealed four homozygous missense mutations, c.152A>G (p.N51S), c.1231G>A (p.A411T), c.1673G>A (p.R558H), and c.1845C>G (p.H615Q), that co-segregate with the GGM phenotype in all of the affected individuals. These findings suggest that founder effect of the SLC5A1 mutations associated with the disease in Amish and a population specific genetic testing is in need to pursue an early diagnosis which is critical for a favorable outcome.","variants":[{"Name":"NM_000343.4(SLC5A1):c.1673G>A (p.Arg558His)","Chromosome":"22","Start":"32104793","Stop":"32104793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132588,"rule_based_match":true,"evidence_text":"c.1673G>A (p.R558H)","llm_judgment":"PRESENT","evidence":"c.1673G>A (p.R558H)","abstract_start":1156,"abstract_end":1175}]}
{"pmid":"30079398","title":"","abstract":"<i>SIGMAR1</i> gene encodes a non-opioid endoplasmic reticulum (ER) protein which is involved in a large diversity of cell functions and is expressed ubiquitously in both central and peripheral nervous systems. Alterations of its normal function may contribute to two different phenotypes: juvenile amyotrophic lateral sclerosis (ALS 16) and distal hereditary motor neuropathies (dHMN). We present the case of a female patient, of 37-years-old, with distal muscle weakness and atrophy beginning in childhood and slowly progressive in the first two decades of life. Neurological examination revealed a symmetrical severe muscle wasting and weakness in distal lower and upper limbs, with claw hands, footdrop with equinovarus deformity and hammer toes, generalized areflexia and normal sensory examination. The electrodiagnostic study revealed a pure chronic motor peripheral nerve involvement without signs of demyelination. The molecular study found the deletion c.561_576del on exon 4 and a deletion of all exon 4, in the <i>SIGMAR1</i> gene.","variants":[{"Name":"NM_005866.4(SIGMAR1):c.561_576del (p.Asp188fs)","Chromosome":"9","Start":"34635728","Stop":"34635743","ReferenceAlleleVCF":"TGCTGAAGACAGTGTCG","AlternateAlleleVCF":"T","allel_id":424598,"rule_based_match":true,"evidence_text":"c.561_576del","llm_judgment":"PRESENT","evidence":"c.561_576del","abstract_start":963,"abstract_end":975}]}
{"pmid":"25665141","title":"Deep intronic GBE1 mutation in manifesting heterozygous patients with adult polyglucosan body disease.","abstract":"IMPORTANCE: We describe a deep intronic mutation in adult polyglucosan body disease. Similar mechanisms can also explain manifesting heterozygous cases in other inborn metabolic diseases.\nOBJECTIVE: To explain the genetic change consistently associated with manifesting heterozygous patients with adult polyglucosan body disease.\nDESIGN, SETTING, AND PARTICIPANTS: This retrospective study took place from November 8, 2012, to November 7, 2014. We studied 35 typical patients with adult polyglucosan body disease, of whom 16 were heterozygous for the well-known c.986A>C mutation in the glycogen branching enzyme gene (GBE1) but harbored no other known mutation in 16 exons.\nMAIN OUTCOMES AND MEASURES: All 16 manifesting heterozygous patients had lower glycogen branching activity compared with homozygous patients, which showed inactivation of the apparently normal allele. We studied the messenger ribonucleic acid (mRNA) structure and the genetic change due to the elusive second mutation.\nRESULTS: When we reverse transcribed and sequenced the mRNA of GBE1, we found that all manifesting heterozygous patients had the c.986A>C mutant mRNA and complete lack of mRNA encoded by the second allele. We identified a deep intronic mutation in this allele, GBE1-IVS15+5289_5297delGTGTGGTGGinsTGTTTTTTACATGACAGGT, which acts as a gene trap, creating an ectopic last exon. The mRNA transcript from this allele missed the exon 16 and 3'UTR and encoded abnormal GBE causing further decrease of enzyme activity from 18% to 8%.\nCONCLUSIONS AND RELEVANCE: We identified the deep intronic mutation, which acts as a gene trap. This second-most common adult polyglucosan body disease mutation explains another founder effect in all Ashkenazi-Jewish cases.","variants":[{"Name":"NM_000158.4(GBE1):c.986A>C (p.Tyr329Ser)","Chromosome":"3","Start":"81642787","Stop":"81642787","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":17816,"rule_based_match":true,"evidence_text":"c.986A>C","llm_judgment":"PRESENT","evidence":"c.986A>C","abstract_start":562,"abstract_end":570}]}
{"pmid":"35475074","title":"Genetic Evaluation of Late-Onset Hypertrophic Cardiomyopathy: An Autobiographical Case Report.","abstract":"Cardiomyopathy, also known as a pathology with a cardiovascular cause, can be further differentiated into multiple categories including genetic. Strong correlations between genetic mutations in sarcomeric proteins and presentation of cardiomyopathies have been made. This case report describes the clinical diagnosis of my late-onset hypertrophic cardiomyopathy, which was brought upon by symptoms of chest pain and palpitations that started approximately two years ago and had mostly gone unnoticed during this period. As a geneticist, I decided to undergo genetic test upon diagnosis. These tests found a heterozygous variant of uncertain significance (VUS) in the <i>ALPK3</i> gene, c.399dup (p.Gly134ArgfsTer30), and a heterozygous c.7552G>A (p.Val2518Ile) VUS in the desmoplakin (<i>DSP</i>) gene. This autobiographical case report hopes to shed light on the importance of genetic screening in the search for the etiology of clinical symptoms.","variants":[{"Name":"NM_020778.4(ALPK3):c.399dup (p.Gly134Argfs)","Chromosome":"15","Start":"84817239","Stop":"84817240","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":1430855,"rule_based_match":true,"evidence_text":"c.399dup (p.Gly134ArgfsTer30)","llm_judgment":"PRESENT","evidence":"c.399dup (p.Gly134ArgfsTer30)","abstract_start":686,"abstract_end":715},{"Name":"NM_004415.4(DSP):c.7552G>A (p.Val2518Ile)","Chromosome":"6","Start":"7584814","Stop":"7584814","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":245279,"rule_based_match":true,"evidence_text":"c.7552G>A (p.Val2518Ile)","llm_judgment":"PRESENT","evidence":"c.7552G>A (p.Val2518Ile)","abstract_start":736,"abstract_end":760}]}
{"pmid":"16326120","title":"Analysis of nonsense-mediated mRNA decay in mutant alleles identified in Spanish Gaucher disease patients.","abstract":"Most of the mutations described in the GBA gene as responsible for Gaucher disease are missense mutations. Nevertheless, other alterations, including nonsense and frameshift mutations, have been reported. These mutations generate premature termination codons (PTC) that could trigger the degradation of mRNA through a mechanism known as nonsense-mediated decay (NMD). It has been established that NMD requires the presence of at least one intron downstream of the PTC, and that this PTC should be at least 50-55 nucleotides upstream of the 3'-most exon-exon junction. In this study, we analyse four GBA truncating mutations - c.108G > A (W(-4)X; HGVS recommended nomenclature: p.W36X), c.886C > T (R257X; HGVS: p.R296X), c.1098_1099insA and c.1451_1452delAC - found in Spanish Gaucher disease patients in order to determine whether they undergo mRNA decay and, if so, whether this occurs via the NMD pathway. RT-PCR showed a clear reduction of RNA for three of the alleles: W(-4)X, R257X and c.1098_1099insA. After treatment with cycloheximide (CHX), a known inhibitor of both protein synthesis and NMD, two of the mutant alleles, R257X and c.1098_1099insA, showed a partial recovery of the amount of mRNA. The third mutation, W(-4)X, did not show any significant CHX-induced recovery, while allele c.1451_1452delAC did not show mRNA decay at all. Real-time PCR confirmed these results and allowed the decay and recovery to be quantified. Finally, the protein truncation test was performed to detect the corresponding proteins. Expected products for alleles R257X, c.1451_1452delAC and c.1098_1099insA, but not for W(-4)X, were observed.","variants":[{"Name":"NM_000157.4(GBA1):c.886C>T (p.Arg296Ter)","Chromosome":"1","Start":"155237454","Stop":"155237454","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":549499,"rule_based_match":true,"evidence_text":"c.886C>T (R257X; HGVS: p.R296X)","llm_judgment":"PRESENT","evidence":"c.886C > T (R257X; HGVS: p.R296X)","abstract_start":686,"abstract_end":719},{"Name":"NM_000157.4(GBA1):c.108G>A (p.Trp36Ter)","Chromosome":"1","Start":"155240637","Stop":"155240637","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":963246,"rule_based_match":true,"evidence_text":"c.108G > A (W(-4)X; HGVS recommended nomenclature: p.W36X)","llm_judgment":"PRESENT","evidence":"c.108G > A (W(-4)X; HGVS recommended nomenclature: p.W36X)","abstract_start":626,"abstract_end":684}]}
{"pmid":"12126929","title":"Immune consequences of mutations in the human common gamma-chain gene.","abstract":"A mutation (c.878T>A) in the common gamma chain (gamma(c)) causes an X-linked combined immunodeficiency (XCID) in a large kindred of British origin. In the disease, gamma(c) is expressed, but its binding to Jak3 is reduced. The immune deficiencies and clinical course were less marked in toddlers and school age children with XCID(L293Q) than in severe combined immunodeficiency (SCID). However, affected newborns were profoundly deficient in thymic size and T cells. In some affected infants, thymic size and numbers of T cells gradually increased during the first year. Their clinical course was relatively benign. In affected infants of one lineage, the number of blood T cells failed to increase substantially. They succumbed to opportunistic infections. T cell deficiencies in XCID(L293Q) progressively worsened during adolescence. Decreased thymic function, failure to rescue T cells from apoptosis, and replication senescence were possible causes. Blood T cells with the phenotype CD45RA(+)CD62L(+) (unstimulated T cells) were most depressed. CD4(+) T cells were also deficient in a specific marker of recent thymic emigrants, episomal DNA deletion circles created during TcR gene rearrangements. Apoptosis of T cells was increased, but neither apoptosis nor cell death was age-related. In contrast, telomere shortening in T cells increased with age. Unlike murine gamma(c) gene deletions, gamma delta T cells were prominent in affected adolescents and young adults. Furthermore, T cells with a V delta 2/V gamma 9 specificity declined with age and were replaced in the oldest male with a V delta 1 specificity. Thus, the mutation provides many insights concerning the role of gamma(c) in the biology of T cells.","variants":[{"Name":"NM_000206.3(IL2RG):c.878T>A (p.Leu293Gln)","Chromosome":"X","Start":"71108323","Stop":"71108323","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":25062,"rule_based_match":true,"evidence_text":"c.878T>A","llm_judgment":"PRESENT","evidence":"c.878T>A","abstract_start":12,"abstract_end":20}]}
{"pmid":"18807267","title":"A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer.","abstract":"Blood relatives of patients with ataxia-telangiectasia (A-T) have an increased risk to develop breast cancer. Allelic heterogeneity has made it difficult to confirm the role of ATM, the gene mutated in A-T, for breast cancer susceptibility in the general population. We now report that a nonsense mutation, p.E1978X (c.5932G>T), is both a classical A-T mutation and a breast cancer susceptibility allele in Eastern European populations. In a case-control study from Belarus, the E1978X mutation was identified in 10/1,891 Byelorussian breast cancer cases (0.5%) compared with 1/1,019 population controls [odds ratio (OR): 5.4; 95% confidence interval (95% CI), 0.7-42.4, P = 0.1]. A second case-control study from Russia identified the E1978X mutation in two Russian and one Ukrainian cases out of 611 breast cancer patients but not in any Russian or Ukrainian controls (P = 0.1). In a third case-control study from Poland, E1978X was observed in 7/3,910 Polish breast cancer cases (0.2%) compared with 1/2,010 cancer-free population controls (OR: 3.6; 95% CI: 0.4-29.3, P = 0.4). In the combined analysis, E1978X was significantly associated with breast cancer (Mantel-Haenszel OR: 5.6, 95% CI: 1.3-21.4, P = 0.01). Taken together, this study provides first evidence for the association of a common A-T causing mutation with breast cancer in Eastern European founder populations.","variants":[{"Name":"NM_000051.4(ATM):c.5932G>T (p.Glu1978Ter)","Chromosome":"11","Start":"108312424","Stop":"108312424","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":132871,"rule_based_match":true,"evidence_text":"c.5932G>T","llm_judgment":"PRESENT","evidence":"c.5932G>T","abstract_start":317,"abstract_end":326}]}
{"pmid":"21147011","title":"Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population.","abstract":"BACKGROUND: The prevalence of phenylalanine hydroxylase (PAH)-deficient phenylketonuria (PKU) in Turkey is high (1 in 6500 births), but data concerning the genotype distribution and impact of the genotype on tetrahydrobiopterin (BH(4)) therapy are scarce.\nOBJECTIVE: To characterize the phenotypic and genotypic variability in the Turkish PKU population and to correlate it with physiological response to BH(4) challenge.\nMETHODS: We genotyped 588 hyperphenylalaninemic patients and performed a BH(4) loading test (20mg/kg bw) in 462 patients. Residual PAH activity of mutant proteins was calculated from available in vitro expression data. Data were tabulated in the BIOPKU database (www.biopku.org).\nRESULTS: Eighty-eight mutations were observed, the most common missense mutations being the splice variant c.1066-11G>A (24.6%). Twenty novel mutations were detected (11 missense, 4 splice-site, and 5 deletion/insertions). Two mutations were observed in 540/588 patients (91.8%) but in 9 patients atypical genotypes with >2 mutations were found (8 with p.R155H in cis with another variant) and in 19 patients mutations were found in BH(4)-metabolizing genes. The most common genotype was c.1066-11G>A/c.1066-11G>A (15.5%). Approximately 22% of patients responded to BH(4) challenge. A substantial in vitro residual activity (average >25% of the wild-type enzyme) was associated with response to BH(4). In homozygous genotypes (n=206), both severity of the phenotype (r=0.83) and residual PAH activity (r=0.85) correlate with BH(4) responsiveness.\nCONCLUSION: Together with the BH(4) challenge, these data enable the genotype-based classification of BH(4) responsiveness and document importance of residual PAH activity. This first report of a large-scale genotype assessment in a population of Turkish PKU patients also documents a high prevalence (47%) of the severe classic phenotype.","variants":[{"Name":"NM_000277.3(PAH):c.1066-11G>A","Chromosome":"12","Start":"102843790","Stop":"102843790","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15646,"rule_based_match":true,"evidence_text":"c.1066-11G>A","llm_judgment":"PRESENT","evidence":"c.1066-11G>A","abstract_start":809,"abstract_end":821}]}
{"pmid":"32805447","title":"X-linked myotubular myopathy mimics hereditary spastic paraplegia in two female manifesting carriers of pathogenic MTM1 variant.","abstract":"X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy caused by pathogenic variants in the myotubularin 1 (MTM1) gene. XLMTM leads to severe weakness in male infants and majority of them die in the early postnatal period due to respiratory failure. Disease manifestations in female carriers vary from asymptomatic to severe, generalized congenital weakness. The symptomatic female carriers typically have limb-girdle weakness, asymmetric muscle weakness and skeletal size, urinary incontinence, facial weakness, ptosis and ophthalmoplegia. Here we describe a Finnish family with two females with lower limb spasticity and hyperreflexia resembling spastic paraplegia, gait difficulties and asymmetric muscle weakness in the limbs. A whole exome sequencing identified a heterozygous pathogenic missense variant MTM1 c.1262G > A, p.(Arg421Gln) segregating in the family. The variant has previously been detected in male and female patients with XLMTM. Muscle biopsy of one of the females showed variation in the myofiber diameter, atrophic myofibers, central nuclei and necklace fibers consistent with a diagnosis of XLMTM. This report suggests association between spastic paraplegia and pathogenic MTM1 variants expanding the phenotypic spectrum potentially associated with XLMTM, but the possible association needs to be confirmed by additional cases.","variants":[{"Name":"NM_000252.3(MTM1):c.1262G>A (p.Arg421Gln)","Chromosome":"X","Start":"150659665","Stop":"150659665","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":170043,"rule_based_match":true,"evidence_text":"MTM1 c.1262G > A, p.(Arg421Gln)","llm_judgment":"PRESENT","evidence":"MTM1 c.1262G > A, p.(Arg421Gln)","abstract_start":822,"abstract_end":853}]}
{"pmid":"26942290","title":"Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.","abstract":"Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.","variants":[{"Name":"NM_023110.3(FGFR1):c.1966A>G (p.Lys656Glu)","Chromosome":"8","Start":"38414790","Stop":"38414790","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":226760,"rule_based_match":true,"evidence_text":"c.1966A>G (p.Lys656Glu)","llm_judgment":"PRESENT","evidence":"c.1966A>G (p.Lys656Glu)","abstract_start":918,"abstract_end":941},{"Name":"NM_023110.3(FGFR1):c.1638C>A (p.Asn546Lys)","Chromosome":"8","Start":"38417331","Stop":"38417331","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":226759,"rule_based_match":true,"evidence_text":"c.1638C>A (p.Asn546Lys)","llm_judgment":"PRESENT","evidence":"c.1638C>A (p.Asn546Lys)","abstract_start":890,"abstract_end":913}]}
{"pmid":"15037712","title":"SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I.","abstract":"Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.","variants":[{"Name":"NM_006415.4(SPTLC1):c.1160G>C (p.Gly387Ala)","Chromosome":"9","Start":"92038342","Stop":"92038342","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":19841,"rule_based_match":false,"evidence_text":"c.1160G-->C; p.G387A","llm_judgment":"PRESENT","evidence":"c.1160G-->C; p.G387A","abstract_start":386,"abstract_end":406}]}
{"pmid":"21376300","title":"Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.","abstract":"Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.","variants":[{"Name":"NM_007327.4(GRIN1):c.1679_1681dup (p.Ser560dup)","Chromosome":"9","Start":"137162216","Stop":"137162217","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GAGC","allel_id":38681,"rule_based_match":true,"evidence_text":"c.1679_1681dup/p.Ser560dup","llm_judgment":"PRESENT","evidence":"c.1679_1681dup/p.Ser560dup","abstract_start":1178,"abstract_end":1204}]}
{"pmid":"16834740","title":"Sequencing of the factor 8(F8) coding regions in 10 Turkish hemophilia A patients reveals three novel pathological mutations, and one rediagnosis of von Willebrand's disease type 2N.","abstract":"The most common cause for severe cases of hemophilia A is the homologous recombination involving intron 22 and related sequences outside the F8 gene. F8 coding regions of the gene including the exon/intron junctions were sequenced in 10 Turkish hemophilia A patients all of whom have been typed negative for intron 22 inversion and who did not have a detectable change by DGGE analysis. Pathological changes including two novel deletions (c. 205del CT and c. 3699del ACAT), one novel missense mutation (9546A) and two recurrent missense mutations were observed in five patients. The c. 2110C > T is another novel pathological change affecting exonic splicing enhancer site in two patients. One of the remaining three patients had a recurrent vWD type 2N mutation in the F8 binding site of the vWF (C788R). The S1269S polymorphism (c. 3864A > C) detected phenotype. Conclusively, sequencing of the promoter and the coding regions of 10 hemophilia A patients contributes four novel pathological mutations to the F8 mutations list and reveals a rediagnosis of hemophilia A but is still not sufficient to confirm hemophilia A phenotype in two patients.","variants":[{"Name":"NM_000132.4(F8):c.3864A>C (p.Ser1288=)","Chromosome":"X","Start":"154929926","Stop":"154929926","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":49422,"rule_based_match":true,"evidence_text":"c. 3864A > C","llm_judgment":"PRESENT","evidence":"c. 3864A > C","abstract_start":831,"abstract_end":843}]}
{"pmid":"22633641","title":"Brown-Vialetto-Van Laere syndrome: a riboflavin-unresponsive patient with a novel mutation in the C20orf54 gene.","abstract":"Brown-Vialetto-Van Laere syndrome (Online Mendelian Inheritance in Man number 211530) is a neurodegenerative disorder characterized by pontobulbar palsy affecting cranial nerves (mainly VII-XII). Sensorineural deafness is often the leading sign, followed by other neurologic signs. Inheritance is often autosomal recessive, with mutations in the C20orf54 gene (Online Mendelian Inheritance in Man number 613350). Three previous patients with mutations in the C20orf54 gene and clinical signs of Brown-Vialetto-Van Laere or Fazio-Londe syndrome revealed a metabolic profile suggesting a multiple acyl-coenzyme A dehydrogenase defect. They benefited from riboflavin. We describe a 3-year-old girl with early-onset Brown-Vialetto-Van Laere syndrome and a novel mutation in the C20orf54 gene (c.989G>T). On T(2)-weighted imaging, increased signal intensity of the vestibular nuclei bilaterally, the pedunculus cerebellaris superior and the central tegmental tract were observed during acute clinical deterioration. Her metabolic profile was normal. Trials with steroids, immunoglobulins, and riboflavin produced no effect. The patient recovered slowly during subsequent months, with residual deficits. Brown-Vialetto-Van Laere syndrome should be considered in patients with sensorineural hearing loss and pontobulbar palsy. Patients should be screened for riboflavin deficiency and a therapy with riboflavin may provide effective treatment in some affected patients.","variants":[{"Name":"NM_033409.4(SLC52A3):c.989G>T (p.Gly330Val)","Chromosome":"20","Start":"763582","Stop":"763582","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":206615,"rule_based_match":true,"evidence_text":"c.989G>T","llm_judgment":"PRESENT","evidence":"c.989G>T","abstract_start":789,"abstract_end":797}]}
{"pmid":"30448303","title":"Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes.","abstract":"LBR (Lamin B Receptor) encodes a bifunctional protein important for cholesterol biosynthesis and heterochromatin organization on the inner nuclear membrane. Pathogenic variants in LBR are associated with marked phenotypic variability, ranging from the benign Pelger-Huët anomaly to lethal Greenberg Dysplasia. We performed trio exome sequencing (ES) on two patients with atypical variants of skeletal dysplasia and their unaffected parents. Patient 1 exhibited frontal bossing, mid-face hypoplasia, short stature with rhizomelic limb shortening, and relative macrocephaly at birth. Although remained short, Patient 1 later showed spontaneous improvement in her skeletal findings. Exome sequencing revealed two novel variants in LBR, c.1504C > G (p.Arg502Gly) in exon 12 and c.1748G > T (p.Arg583Leu) in exon 14, which were inherited from her unaffected father and mother, respectively. Sterol analysis revealed an increased level of cholesta‑8,14‑dien‑3β‑ol to 2.9% of total sterols, consistent with a functional deficiency of 3β‑hydroxysterol Δ14‑reductase. Patient 2 presented at birth with short stature and marked rhizomelic limb shortening but later exhibited decreasing severity of shortening of the long bones and improvement in the radiographic skeletal abnormalities although he continued to be significantly short at age 10 years. Exome sequencing revealed that Patient 2 is homozygous for a pathogenic variant c.1534C > T (p.Arg512Trp) in exon 12 of LBR, which was inherited from his unaffected consanguineous parents. This report provides further evidence for a phenotypic spectrum of LBR-associated disorders and expands the genotypic spectrum by describing 3 novel disease-causing variants that have not been previously associated with a disease. Moreover, our data on Patient 1 demonstrate that variants throughout the gene appear to influence both the sterol reductase and nuclear functions of LBR.","variants":[{"Name":"NM_002296.4(LBR):c.1504C>G (p.Arg502Gly)","Chromosome":"1","Start":"225404686","Stop":"225404686","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":421211,"rule_based_match":true,"evidence_text":"c.1504C > G (p.Arg502Gly)","llm_judgment":"PRESENT","evidence":"c.1504C > G (p.Arg502Gly)","abstract_start":733,"abstract_end":758},{"Name":"NM_002296.4(LBR):c.1748G>T (p.Arg583Leu)","Chromosome":"1","Start":"225403403","Stop":"225403403","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":405067,"rule_based_match":true,"evidence_text":"c.1748G > T (p.Arg583Leu)","llm_judgment":"PRESENT","evidence":"c.1748G > T (p.Arg583Leu)","abstract_start":774,"abstract_end":799}]}
{"pmid":"27270415","title":"Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.","abstract":"We report an individual who presented with severe neurodevelopmental delay and an intractable infantile-onset seizure disorder. Exome sequencing identified a homozygous single nucleotide change that abolishes a splice donor site in the ARV1 gene (c.294 + 1G > A homozygous). This variant completely prevented splicing in minigene assays, and resulted in exon skipping and an in-frame deletion of 40 amino acids in primary human fibroblasts (NP_073623.1: p.(Lys59_Asn98del). The p.(Lys59_Asn98del) and previously reported p.(Gly189Arg) ARV1 variants were evaluated for protein expression and function. The p.(Gly189Arg) variant partially rescued the temperature-dependent growth defect in arv1Δ yeast, while p.(Lys59-Asn98del) completely failed to rescue at restrictive temperature. In contrast to wild type human ARV1, neither variant expressed detectable levels of protein in mammalian cells. Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood. Our data support ARV1 deficiency as a cause of autosomal recessive epileptic encephalopathy.","variants":[{"Name":"NM_022786.3(ARV1):c.294+1G>A","Chromosome":"1","Start":"230988440","Stop":"230988440","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":226233,"rule_based_match":true,"evidence_text":"c.294 + 1G > A","llm_judgment":"PRESENT","evidence":"c.294 + 1G > A","abstract_start":247,"abstract_end":261}]}
{"pmid":"31131889","title":"Transcriptome analysis of gingival tissues of enamel-renal syndrome.","abstract":"BACKGROUND AND OBJECTIVE: Biallelic loss-of-function mutations of human FAM20A have been known to cause enamel-renal syndrome (ERS), featured by agenesis of dental enamel, nephrocalcinosis, and other orodental abnormalities, including gingival hyperplasia. However, while the histopathology of this gingival anomaly has been analyzed, its underlying molecular mechanism remains largely unknown. This study aimed to unravel the pathogenesis of gingival hyperplasia in ERS.\nMETHODS: Whole-exome sequencing was conducted for an ERS case. Transcriptome analyses, using RNA sequencing, of the patient's gingiva were performed to unravel dysregulated molecules and aberrant biological processes underlying the gingival pathology of ERS, which was further confirmed by histology and immunohistochemistry.\nRESULTS: Two novel frameshift FAM20A mutations in Exon 1 (g.5417delG; c.129delG; p.Cys44Alafs*101) and Exon 5 (g.62248_62249delAG; c.734_735delAG; p.Glu245Glyfs*11) were identified. Transcriptional profiling of patient's gingival tissue revealed a total of 1683 genes whose expression had increased (1129 genes) or decreased (554 genes) at least 2-fold compared to control gingival tissues. There were 951 gene ontology (GO) terms of biological process being significantly over-represented or under-represented. While GOs involved in extracellular matrix organization, angiogenesis, biomineralization, and epithelial cell proliferation appeared to be activated in ERS gingiva, genes related to keratinocyte differentiation, epithelial development, and keratinization were of decreased expression. FAM20A immunohistochemistry revealed a strong reactivity at the suprabasal layers of epithelium in control gingiva but showed a significantly diminished and scattered signal in ERS tissues. For genes showing significant over-expression in the transcriptome analyses, namely ALPL, SPARC, and ACTA2, an increased immunoreactivity was observed.\nCONCLUSION: Our results unraveled a potential role for FAM20A in homeostasis of both gingival epithelium and connective tissues.","variants":[{"Name":"NM_017565.4(FAM20A):c.129del (p.Cys44fs)","Chromosome":"17","Start":"68600538","Stop":"68600538","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":1179040,"rule_based_match":true,"evidence_text":"c.129delG","llm_judgment":"PRESENT","evidence":"c.129delG","abstract_start":868,"abstract_end":877},{"Name":"NM_017565.4(FAM20A):c.734_735del (p.Glu245fs)","Chromosome":"17","Start":"68543706","Stop":"68543707","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":1179039,"rule_based_match":true,"evidence_text":"c.734_735delAG","llm_judgment":"PRESENT","evidence":"c.734_735delAG","abstract_start":929,"abstract_end":943}]}
{"pmid":"32675277","title":"A Rare","abstract":"Germline mutations in <i>TP53</i> cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare <i>TP53</i> tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of <i>TP53</i>. The majority of families were of Ashkenazi Jewish descent, and the <i>TP53</i> c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with <i>TP53</i> normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including <i>PCLO, PLTP, PLXNB3</i>, and <i>LCN15</i>) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that <i>TP53</i> c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE: <i>TP53</i> c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.","variants":[{"Name":"NM_000546.6(TP53):c.1000G>C (p.Gly334Arg)","Chromosome":"17","Start":"7670709","Stop":"7670709","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":180990,"rule_based_match":true,"evidence_text":"c.1000G>C;p.G334R","llm_judgment":"PRESENT","evidence":"c.1000G>C;p.G334R","abstract_start":189,"abstract_end":206}]}
{"pmid":"33912852","title":"Cutaneous and hepatic vascular lesions due to a recurrent somatic","abstract":"The term \"cavernous hemangioma\" has been used to describe vascular anomalies with histology featuring dilated vascular spaces, vessel walls consisting mainly of fibrous stromal bands lined by a layer of flattened endothelial cells, and an irregular outer rim of interrupted smooth muscle cells. Hepatic hemangiomas (HHs) and cutaneous venous malformations (VMs) share this histologic pattern, and we examined lesions in both tissues to identify genetic drivers. Paired whole-exome sequencing (WES) of lesional tissue and normal liver in HH subjects revealed a recurrent <i>GJA4</i> c.121G>T (p.Gly41Cys) somatic mutation in four of five unrelated individuals, and targeted sequencing in paired tissue from 9 additional HH individuals identified the same mutation in 8. In cutaneous lesions, paired targeted sequencing in 5 VMs and normal epidermis found the same <i>GJA4</i> c.121G>T (p.Gly41Cys) somatic mutation in three. <i>GJA4</i> encodes gap junction protein alpha 4, also called connexin 37 (Cx37), and the p.Gly41Cys mutation falls within the first transmembrane domain at a residue highly conserved among vertebrates. We interrogated the impact of the Cx37 mutant via lentiviral transduction of primary human endothelial cells. We found that the mutant induced changes in cell morphology and activated serum/glucocorticoid-regulated kinase 1 (SGK1), a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation. Treatment with spironolactone, an inhibitor of angiogenesis, suppressed mutant SGK1 activation and reversed changes in cell morphology. These findings identify a recurrent somatic <i>GJA4</i> c.121G>T mutation as a driver of hepatic and cutaneous VMs, revealing a new pathway for vascular anomalies, with spironolactone a potential pathogenesis-based therapy.","variants":[{"Name":"NM_002060.3(GJA4):c.121G>T (p.Gly41Cys)","Chromosome":"1","Start":"34794334","Stop":"34794334","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":984467,"rule_based_match":true,"evidence_text":"GJA4 c.121G>T (p.Gly41Cys)","llm_judgment":"PRESENT","evidence":"GJA4</i> c.121G>T (p.Gly41Cys)","abstract_start":573,"abstract_end":603}]}
{"pmid":"25823529","title":"Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.","abstract":"Mutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.","variants":[{"Name":"NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe)","Chromosome":"1","Start":"216247118","Stop":"216247118","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":17395,"rule_based_match":true,"evidence_text":"c.2276G>T (p.C759F)","llm_judgment":"PRESENT","evidence":"c.2276G>T (p.C759F)","abstract_start":119,"abstract_end":138},{"Name":"NM_000283.4(PDE6B):c.1678C>T (p.Arg560Cys)","Chromosome":"4","Start":"662197","Stop":"662197","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":214454,"rule_based_match":true,"evidence_text":"c.1678C>T (p.R560C)","llm_judgment":"PRESENT","evidence":"c.1678C>T","abstract_start":679,"abstract_end":688}]}
{"pmid":"23559863","title":"Novel compound heterozygous mutations in MYO7A in a Chinese family with Usher syndrome type 1.","abstract":"PURPOSE: To identify the disease-causing mutation(s) in a Chinese family with autosomal recessive Usher syndrome type 1 (USH1).\nMETHODS: An ophthalmic examination and an audiometric test were conducted to ascertain the phenotype of two affected siblings. The microsatellite marker D11S937, which is close to the candidate gene MYO7A (USH1B locus), was selected for genotyping. From the DNA of the proband, all coding exons and exon-intron boundaries of MYO7A were sequenced to identify the disease-causing mutation(s). Restriction fragment length polymorphism (RFLP) analysis was performed to exclude the alternative conclusion that the mutations are non-pathogenic rare polymorphisms.\nRESULTS: Based on severe hearing impairment, unintelligible speech, and retinitis pigmentosa, a clinical diagnosis of Usher syndrome type 1 was made. The genotyping results did not exclude the USH1B locus, which suggested that the MYO7A gene was likely the gene associated with the disease-causing mutation(s) in the family. With direct DNA sequencing of MYO7A, two novel compound heterozygous mutations (c.3742G>A and c.6051+1G>A) of MYO7A were identified in the proband. DNA sequence analysis and RFLP analysis of other family members showed that the mutations cosegregated with the disease. Unaffected members, including the parents, uncle, and sister of the proband, carry only one of the two mutations. The mutations were not present in the controls (100 normal Chinese subjects=200 chromosomes) according to the RFLP analysis.\nCONCLUSIONS: In this study, we identified two novel mutations, c.3742G>A (p.E1248K) and c.6051+1G>A (donor splice site mutation in intron 44), of MYO7A in a Chinese non-consanguineous family with USH1. The mutations cosegregated with the disease and most likely cause the phenotype in the two affected siblings who carry these mutations compound heterozygously. Our finding expands the mutational spectrum of MYO7A.","variants":[{"Name":"NM_000260.4(MYO7A):c.6051+1G>A","Chromosome":"11","Start":"77208804","Stop":"77208804","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":546721,"rule_based_match":true,"evidence_text":"c.6051+1G>A","llm_judgment":"PRESENT","evidence":"c.6051+1G>A","abstract_start":1105,"abstract_end":1116}]}
{"pmid":"27751652","title":"A case of congenital spinal muscular atrophy with pain due to a mutation in TRPV4.","abstract":"We present a patient with congenital spinal muscular atrophy associated with pain, subjective sensory loss, right talipes equinovarus, delayed walking, and progressive gait impairment. A sister and niece reportedly had Charcot-Marie-Tooth 1A, but the patient's electromyogram showed an axonal motor neuropathy or neuronopathy. We identified a c.806G>A TRPV4 gene mutation causing an Arg269His amino acid substitution. TRPV4 mutations cause variable phenotypes including axonal sensorimotor neuropathy and motor neuropathy or neuronopathy. Associated features may include arthrogryposis, skeletal dysplasia, vocal cord paresis, sensorineural hearing loss and respiratory weakness. Skeletal X-rays can identify orthopedic causes of pain in patients with TRPV4 mutations, and imaging evidence of bone deformities in patients with suspected hereditary axonal neuropathy, pain and an unknown genetic diagnosis may help lead to a diagnosis of a TRPV4 mutation. Even when a patient's genetic diagnosis is presumed to be known, electrodiagnostic testing is warranted to verify the diagnosis.","variants":[{"Name":"NM_021625.5(TRPV4):c.806G>A (p.Arg269His)","Chromosome":"12","Start":"109800665","Stop":"109800665","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20039,"rule_based_match":true,"evidence_text":"c.806G>A","llm_judgment":"PRESENT","evidence":"c.806G>A","abstract_start":343,"abstract_end":351}]}
{"pmid":"34856468","title":"Generation of two induced pluripotent stem cell lines from Brugada syndrome affected patients carrying SCN5A mutations.","abstract":"SCN5A gene loss-of-function mutations are commonly associated with Brugada syndrome, which represents a risk of lethal arrhythmias and sudden cardiac death. The present report describes the generation of two human induced pluripotent stem cell (iPSC) lines reprogrammed from two Brugada syndrome affected patients carrying SCN5A mutations, c.53506 G>A and c.2102 C>T, respectively. Pluripotency markers, karyotype stability, and differentiation capability into derivatives of the three germ layers were assessed and described in the present report. These lines can be used as a reliable cell model for Brugada syndrome investigations and characterization of leading cellular mechanisms.","variants":[{"Name":"NM_000335.5(SCN5A):c.2102C>T (p.Pro701Leu)","Chromosome":"3","Start":"38597889","Stop":"38597889","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":78608,"rule_based_match":true,"evidence_text":"c.2102 C>T","llm_judgment":"PRESENT","evidence":"c.2102 C>T","abstract_start":356,"abstract_end":366}]}
{"pmid":"27693882","title":"Aromatase deficiency in a male patient - Case report and review of the literature.","abstract":"OBJECTIVE: Aromatase, or CYP19A1, is a type II cytochrome CYP450 enzyme that catalyzes the conversion of C19 androgens to C18 estrogens. Its crucial role in both female and male physiology has been deduced from human and animal studies using aromatase inhibitors, genetically altered mice, and patients with aromatase deficiency. The latter is an extremely rare disorder. Its diagnosis is particularly difficult in males, who go through puberty normally and therefore usually present as adults with elevated testosterone, bone abnormalities (e.g., delayed bone age and low bone mass), and metabolic syndrome. In this report, we describe a new case of a male patient with aromatase deficiency harboring a known mutation who presented with less severe clinical and biochemical features.\nCASE REPORT: The patient presented with low bone mass and delayed bone age after a finger fracture at age 25years. FSH, LH and testosterone levels were normal, but estradiol and estrone levels were absent or barely detectable, raising suspicion for aromatase deficiency. A homozygous c.628G>A mutation in exon 5 was confirmed by direct sequencing. Unlike previously reported cases of aromatase deficiency, he did not display biochemical features of insulin resistance, dyslipidemia, or overweight/obese status. Therapy with estradiol led to the closure of growth plates and a dramatic increase in bone mass.\nCONCLUSIONS: Here we explore genotype/phenotype associations of this new case compared to cases reported previously. We conclude that the specific nature of mutation c.628G>A, which can potentially result in several different forms of the aromatase enzyme, may lend an explanation to the variable phenotypes associated with this particular genotype.","variants":[{"Name":"NM_000103.4(CYP19A1):c.628G>A (p.Glu210Lys)","Chromosome":"15","Start":"51222349","Stop":"51222349","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32865,"rule_based_match":true,"evidence_text":"c.628G>A","llm_judgment":"PRESENT","evidence":"c.628G>A","abstract_start":1069,"abstract_end":1077}]}
{"pmid":"18409202","title":"Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus.","abstract":"Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is an autosomal dominant condition caused by heterozygous germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. Rare cases have been reported of an inherited bi-allelic deficiency of MMR genes, associated with multiple café-au-lait spots, early onset CNS tumors, hematological malignancies, and early onset gastrointestinal neoplasia. We report on a patient with vitiligo in segments of the integument who developed systemic lupus erythematosus (SLE) at the age of 16, and four synchronous colorectal cancers at age 17 years. Examination of the colorectal cancer tissue showed high microsatellite instability (MSI-H) and an exclusive loss of expression of the MSH6 protein. Immunohistochemical analysis of normal colon tissue also showed loss of MSH6, pointing to a bi-allelic MSH6 mutation. Sequencing of the MSH6 gene showed the two germline mutations; c.1806_1809delAAAG;p.Glu604LeufsX5 and c.3226C > T;p.Arg1076Cys. We confirmed that the two mutations are on two different alleles by allele-specific PCR. To our knowledge, neither parent is clinically affected. They did not wish to be tested for the mutations identified in their daughter. These data suggest that bi-allelic mutations of one of the MMR genes should be considered in patients who develop early-onset multiple HNPCC-associated tumors and autoimmune disorders, even in absence of either hematological malignancies or brain tumors.","variants":[{"Name":"NM_000179.3(MSH6):c.1806_1809del (p.Glu604fs)","Chromosome":"2","Start":"47799789","Stop":"47799792","ReferenceAlleleVCF":"CAAAG","AlternateAlleleVCF":"C","allel_id":94698,"rule_based_match":true,"evidence_text":"c.1806_1809delAAAG;p.Glu604LeufsX5","llm_judgment":"PRESENT","evidence":"c.1806_1809delAAAG;p.Glu604LeufsX5","abstract_start":953,"abstract_end":987},{"Name":"NM_000179.3(MSH6):c.3226C>T (p.Arg1076Cys)","Chromosome":"2","Start":"47803473","Stop":"47803473","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":94831,"rule_based_match":true,"evidence_text":"c.3226C > T;p.Arg1076Cys","llm_judgment":"PRESENT","evidence":"c.3226C > T;p.Arg1076Cys","abstract_start":992,"abstract_end":1016}]}
{"pmid":"19764028","title":"Czech dysplasia occurring in a Japanese family.","abstract":"Czech dysplasia (OMIM 609162) is a recently established COL2A1 disorder characterized by normal height, early-onset osteoarthritis, platyspondyly, short metatarsals, and the absence of ophthalmological complications or cleft palate. A specific missense mutation (c.823C > T, R275C) in the exon 13 of the COL2A1 gene, coding for the triple helical domain of the alpha 1 chain of the type II collagen, has been linked to Czech dysplasia, which is quite a unique situation among the COL2A1 disorders. Since all of the 11 families and patients reported to date were of European ancestry, an ancient single origin of the R275C mutation was speculated about. Here we report on a Japanese family consisting of three patients with Czech dysplasia, each member showing valgus knees in addition to remarkably uniform manifestation of the clinical and radiological abnormalities. Mutation analysis documented the COL2A1 c.823C > T mutation in all affected individuals. In conclusion, this report provides novel evidence for the independent occurrence of Czech dysplasia among the populations.","variants":[{"Name":"NM_001844.5(COL2A1):c.823C>T (p.Arg275Cys)","Chromosome":"12","Start":"47994041","Stop":"47994041","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32407,"rule_based_match":true,"evidence_text":"c.823C > T","llm_judgment":"PRESENT","evidence":"c.823C > T","abstract_start":263,"abstract_end":273}]}
{"pmid":"23446635","title":"Subnormal levels of POLγA cause inefficient initiation of light-strand DNA synthesis and lead to mitochondrial DNA deletions and progressive external ophthalmoplegia [corrected].","abstract":"The POLG1 gene encodes the catalytic subunit of mitochondrial DNA (mtDNA) polymerase γ (POLγ). We here describe a sibling pair with adult-onset progressive external ophthalmoplegia, cognitive impairment and mitochondrial myopathy characterized by DNA depletion and multiple mtDNA deletions. The phenotype is due to compound heterozygous POLG1 mutations, T914P and the intron mutation c.3104 + 3A > T. The mutant genes produce POLγ isoforms with heterozygous phenotypes that fail to synthesize longer DNA products in vitro. However, exon skipping in the c.3104 + 3A > T mutant is not complete, and the presence of low levels of wild-type POLγ explains patient survival. To better understand the underlying pathogenic mechanisms, we characterized the effects of POLγ depletion in vitro and found that leading-strand DNA synthesis is relatively undisturbed. In contrast, initiation of lagging-strand DNA synthesis is ineffective at lower POLγ concentrations that uncouples leading strand from lagging-strand DNA synthesis. In vivo, this effect leads to prolonged exposure of the heavy strand in its single-stranded conformation that in turn can cause the mtDNA deletions observed in our patients. Our findings, thus, suggest a molecular mechanism explaining how POLγ mutations can cause mtDNA deletions in vivo.","variants":[{"Name":"NM_002693.3(POLG):c.3104+3A>T","Chromosome":"15","Start":"89319225","Stop":"89319225","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":580246,"rule_based_match":true,"evidence_text":"c.3104 + 3A > T","llm_judgment":"PRESENT","evidence":"c.3104 + 3A > T","abstract_start":384,"abstract_end":399}]}
{"pmid":"20693550","title":"The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein.","abstract":"BACKGROUND: Succinate-CoA ligase deficiency is responsible for encephalomyopathy with mitochondrial DNA depletion and mild methylmalonic aciduria. Mutations in SUCLA2, the gene encoding a β subunit of succinate-CoA ligase, have been reported in 17 patients until now. Mutations in SUCLG1, encoding the α subunit of the enzyme, have been described in two pedigrees only.\nMETHODS AND FINDINGS: In this study, two unrelated patients harbouring three novel pathogenic mutations in SUCLG1 were reported. The first patient had a severe disease at birth. He was compound heterozygous for a missense mutation (p.Pro170Arg) and a c.97+3G>C mutation, which leads to the complete skipping of exon 1 in a minigene expression system. The involvement of SUCLG1 was confirmed by western blot analysis, which showed absence of SUCLG1 protein in fibroblasts. The second patient has a milder phenotype, similar to that of patients with SUCLA2 mutations, and is still alive at 12 years of age. Western blot analysis showed some residual SUCLG1 protein in patient's fibroblasts.\nCONCLUSIONS: Our results suggest that SUCLG1 mutations that lead to complete absence of SUCLG1 protein are responsible for a very severe disorder with antenatal manifestations, whereas a SUCLA2-like phenotype is found in patients with residual SUCLG1 protein. Furthermore, it is shown that in the absence of SUCLG1 protein, no SUCLA2 protein is found in fibroblasts by western blot analysis. This result is consistent with a degradation of SUCLA2 when its heterodimer partner, SUCLG1, is absent.","variants":[{"Name":"NM_003849.4(SUCLG1):c.97+3G>C","Chromosome":"2","Start":"84459170","Stop":"84459170","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":33450,"rule_based_match":true,"evidence_text":"c.97+3G>C","llm_judgment":"PRESENT","evidence":"c.97+3G>C","abstract_start":621,"abstract_end":630}]}
{"pmid":"26122121","title":"Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission.","abstract":"Defects of mitochondrial dynamics are emerging causes of neurological disease. In two children presenting with severe neurological deterioration following viral infection we identified a novel homozygous STAT2 mutation, c.1836 C>A (p.Cys612Ter), using whole exome sequencing. In muscle and fibroblasts from these patients, and a third unrelated STAT2-deficient patient, we observed extremely elongated mitochondria. Western blot analysis revealed absence of the STAT2 protein and that the mitochondrial fission protein DRP1 (encoded by DNM1L) is inactive, as shown by its phosphorylation state. All three patients harboured decreased levels of DRP1 phosphorylated at serine residue 616 (P-DRP1(S616)), a post-translational modification known to activate DRP1, and increased levels of DRP1 phosphorylated at serine 637 (P-DRP1(S637)), associated with the inactive state of the DRP1 GTPase. Knockdown of STAT2 in SHSY5Y cells recapitulated the fission defect, with elongated mitochondria and decreased P-DRP1(S616) levels. Furthermore the mitochondrial fission defect in patient fibroblasts was rescued following lentiviral transduction with wild-type STAT2 in all three patients, with normalization of mitochondrial length and increased P-DRP1(S616) levels. Taken together, these findings implicate STAT2 as a novel regulator of DRP1 phosphorylation at serine 616, and thus of mitochondrial fission, and suggest that there are interactions between immunity and mitochondria. This is the first study to link the innate immune system to mitochondrial dynamics and morphology. We hypothesize that variability in JAK-STAT signalling may contribute to the phenotypic heterogeneity of mitochondrial disease, and may explain why some patients with underlying mitochondrial disease decompensate after seemingly trivial viral infections. Modulating JAK-STAT activity may represent a novel therapeutic avenue for mitochondrial diseases, which remain largely untreatable. This may also be relevant for more common neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's diseases, in which abnormalities of mitochondrial morphology have been implicated in disease pathogenesis.","variants":[{"Name":"NM_005419.4(STAT2):c.1836C>A (p.Cys612Ter)","Chromosome":"12","Start":"56346844","Stop":"56346844","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":214789,"rule_based_match":true,"evidence_text":"c.1836 C>A (p.Cys612Ter)","llm_judgment":"PRESENT","evidence":"c.1836 C>A (p.Cys612Ter)","abstract_start":220,"abstract_end":244}]}
{"pmid":"21596602","title":"Heterozygous mutation in the X chromosomal NDUFA1 gene in a girl with complex I deficiency.","abstract":"Respiratory chain enzymes consist of multiple subunits encoded either by the mitochondrial or by the nuclear genome. Recently the first X-chromosomal mutations in complex I deficient males have been described. Heterozygous female carriers did not seem to be affected. Here, we describe a girl initially presenting with mild muscular hypotonia, a moderate lactic acidosis and an increased beta-hydroxybutyrate/acetoacetate ratio. Biochemical investigations of a muscle biopsy revealed a deficiency in the amount and activity of complex I. Mutation screening of all structural subunits of complex I identified a heterozygous mutation c.94G>C, p.Gly32Arg in the X-chromosomal NDUFA1 gene. Analysis of the cDNA showed that 72% of the expressed mRNA was mutated in the muscle biopsy sample. Investigation of the X-inactivation pattern demonstrated that 74% of the paternally inherited allele was active in the muscle. This is the first report of an X-chromosomally inherited respiratory chain defect in a heterozygous female.","variants":[{"Name":"NM_004541.4(NDUFA1):c.94G>C (p.Gly32Arg)","Chromosome":"X","Start":"119872005","Stop":"119872005","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":45630,"rule_based_match":true,"evidence_text":"c.94G>C, p.Gly32Arg","llm_judgment":"PRESENT","evidence":"c.94G>C, p.Gly32Arg","abstract_start":632,"abstract_end":651}]}
{"pmid":"22341969","title":"Germline mutation in ATR in autosomal- dominant oropharyngeal cancer syndrome.","abstract":"ATR (ataxia telangiectasia and Rad3 related) is an essential regulator of genome integrity. It controls and coordinates DNA-replication origin firing, replication-fork stability, cell-cycle checkpoints, and DNA repair. Previously, autosomal-recessive loss-of-function mutations in ATR have been demonstrated in Seckel syndrome, a developmental disorder. Here, however, we report on a different kind of genetic disorder that is due to functionally compromised ATR activity, which translates into an autosomal-dominant inherited disease. The condition affects 24 individuals in a five-generation pedigree and comprises oropharyngeal cancer, skin telangiectases, and mild developmental anomalies of the hair, teeth, and nails. We mapped the disorder to a ∼16.8 cM interval in chromosomal region 3q22-24, and by sequencing candidate genes, we found that ATR contained a heterozygous missense mutation (c.6431A>G [p.Gln2144Arg]) that segregated with the disease. The mutation occurs within the FAT (FRAP, ATM, and TRRAP) domain-which can activate p53-of ATR. The mutation did not lead to a reduction in ATR expression, but cultured fibroblasts showed lower p53 levels after activation of ATR with hydroxyurea than did normal control fibroblasts. Moreover, loss of heterozygosity for the ATR locus was noted in oropharyngeal-tumor tissue. Collectively, the clinicopathological and molecular findings point to a cancer syndrome and provide evidence implicating a germline mutation in ATR and susceptibility to malignancy in humans.","variants":[{"Name":"NM_001184.4(ATR):c.6431A>G (p.Gln2144Arg)","Chromosome":"3","Start":"142469458","Stop":"142469458","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39121,"rule_based_match":true,"evidence_text":"c.6431A>G (p.Gln2144Arg)","llm_judgment":"PRESENT","evidence":"p.Gln2144Arg","abstract_start":909,"abstract_end":921}]}
{"pmid":"31840411","title":"Whole exome sequencing identified a homozygous novel variant in CEP290 gene causes Meckel syndrome.","abstract":"Meckel syndrome (MKS) is a pre- or perinatal multisystemic ciliopathic lethal disorder with an autosomal recessive mode of inheritance. Meckel syndrome is usually manifested with meningo-occipital encephalocele, polycystic kidney dysplasia, postaxial polydactyly and hepatobiliary ductal plate malformation. Germline variants in CEP290 cause MKS4. In this study, we investigated a 35-years-old Chinese female who was 17+1 weeks pregnant. She had a history of adverse pregnancy of having foetus with multiple malformations. We performed ultrasonography and identified the foetus with occipital meningoencephalocele and enlarged cystic dysplastic kidneys. So, she decided to terminate her pregnancy and further genetic molecular analysis was performed. We identified the aborted foetus without postaxial polydactyly. Histological examination of foetal kidney showed cysts in kidney and thinning of the renal cortex with glomerular atrophy. Whole exome sequencing identified a novel homozygous variant (c.2144T>G; p.L715<sup>*</sup> ) in exon 21 of the CEP290 in the foetus. Sanger sequencing confirmed that both the parents of the foetus were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters of the foetus as well as in the 100 healthy individuals. Western blot analysis showed that this variant leads to the formation of truncated CEP290 protein with the molecular weight of 84 KD compared with the wild-type CEP290 protein of 290 KD. Hence, it is a loss-of-function variant. We also found that the mutant cilium appears longer in length than the wild-type cilium. Our present study reported the first variant of CEP290 associated with MKS4 in Chinese population.","variants":[{"Name":"NM_025114.4(CEP290):c.2144T>G (p.Leu715Ter)","Chromosome":"12","Start":"88111767","Stop":"88111767","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2838998,"rule_based_match":true,"evidence_text":"c.2144T>G; p.L715<sup>*</sup>","llm_judgment":"PRESENT","evidence":"c.2144T>G; p.L715<sup>*</sup>","abstract_start":1000,"abstract_end":1029}]}
{"pmid":"29663639","title":"A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin creases.","abstract":"Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder characterized by multiple joint contractures often in association with other congenital abnormalities. Pretibial linear vertical creases are a rare finding associated with arthrogryposis, and the etiology of the specific condition is unknown. We aimed to genetically and clinically characterize a boy from a consanguineous family, presenting with AMC and pretibial vertical linear creases on the shins. Whole exome sequencing and variant analysis revealed homozygous novel missense variants of ECEL1 (c.1163T > C, p.Leu388Pro, NM_004826) and MUSK (c.2572C > T, p.Arg858Cys, NM_005592). Both variants are predicted to have deleterious effects on the protein function, with amino acid positions highly conserved among species. The variants segregated in the family, with healthy mother, father, and sister being heterozygous carriers and the index patient being homozygous for both mutations. We report on a unique patient with a novel ECEL1 homozygous mutation, expanding the phenotypic spectrum of Distal AMC Type 5D to include vertical linear skin creases. The homozygous mutation in MUSK is of unknown clinical significance. MUSK mutations have previously shown to cause congenital myasthenic syndrome, a neuromuscular disorder with defects in the neuromuscular junction.","variants":[{"Name":"NM_005592.4(MUSK):c.2572C>T (p.Arg858Cys)","Chromosome":"9","Start":"110800950","Stop":"110800950","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1017107,"rule_based_match":true,"evidence_text":"NM_005592.4(MUSK):c.2572C>T (p.Arg858Cys)","llm_judgment":"PRESENT","evidence":"p.Arg858Cys","abstract_start":630,"abstract_end":641}]}
{"pmid":"18684293","title":"A case of catecholaminergic polymorphic ventricular tachycardia caused by two calsequestrin 2 mutations.","abstract":"Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon heritable disease presenting with syncope or sudden cardiac death. Two genes involved in calcium homeostasis, the ryanodine receptor gene and the calsequestrin 2 (CASQ2) gene, have been implicated in this disease. We describe a young man presenting with exercise-induced syncope, clinically diagnosed as CPVT. Genetic analysis revealed two mutations, p.Y55C (c.164A>G) and p.P308L (c.923C>T), in the CASQ2 gene. Subsequent familial analysis indicates a compound heterozygous form of inheritance.","variants":[{"Name":"NM_001232.4(CASQ2):c.923C>T (p.Pro308Leu)","Chromosome":"1","Start":"115705208","Stop":"115705208","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188307,"rule_based_match":true,"evidence_text":"p.P308L (c.923C>T)","llm_judgment":"PRESENT","evidence":"p.P308L (c.923C>T)","abstract_start":449,"abstract_end":467},{"Name":"NM_001232.4(CASQ2):c.164A>G (p.Tyr55Cys)","Chromosome":"1","Start":"115768378","Stop":"115768378","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":419261,"rule_based_match":true,"evidence_text":"p.Y55C (c.164A>G)","llm_judgment":"PRESENT","evidence":"p.Y55C (c.164A>G)","abstract_start":427,"abstract_end":444}]}
{"pmid":"36051698","title":"Case report: Disease phenotype associated with simultaneous biallelic mutations in","abstract":"Inherited retinal diseases (IRDs) represent a spectrum of clinically and genetically heterogeneous disorders. Our study describes an IRD patient carrying <i>ABCA4</i> and <i>USH2A</i> pathogenic biallelic mutations as a result of paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-year-old girl born from non-consanguineous parents. Both parents were asymptomatic and denied family history of ocular disease. Clinical history and ophthalmologic examination of the proband were consistent with Stargardt disease. Whispered voice testing disclosed moderate hearing loss. Next-generation sequencing and Sanger sequencing identified pathogenic variants in <i>ABCA4</i> (c.4926C>G and c.5044_5058del) and <i>USH2A</i> (c.2276G>T). All variants were present homozygously in DNA from the proband and heterozygously in DNA from the father. No variants were found in maternal DNA. Further analysis of single nucleotide polymorphisms confirmed paternal UPD of chromosome 1. This is the first known patient with confirmed UPD for two recessively mutated IRD genes. Our study expands on the genetic heterogeneity of IRDs and highlights the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents. Moreover, a long-term follow-up is essential for the identification of retinal features that may develop as a result of <i>USH2A</i>-related conditions.","variants":[{"Name":"NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe)","Chromosome":"1","Start":"216247118","Stop":"216247118","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":17395,"rule_based_match":true,"evidence_text":"c.2276G>T","llm_judgment":"PRESENT","evidence":"c.2276G>T","abstract_start":733,"abstract_end":742}]}
{"pmid":"25287185","title":"Consanguinity and founder effect for Gaucher disease mutation G377S in a population from Tabuleiro do Norte, Northeastern Brazil.","abstract":"Gaucher's disease (GD) is caused by a β-glucocerebrosidase deficiency, leading to the accumulation of glucocerebroside in the reticuloendothelial system. The prevalence of GD in Tabuleiro do Norte (TN) (1:4000) is the highest in Brazil. The purpose of this study was to present evidence of consanguinity and founder effect for the G377S mutation (c.1246G>A) among GD patients in TN based on enzyme, molecular and genealogical studies. Between March 2009 and December 2010, 131 subjects at risk for GD (GC in dried blood ≤2.19 nmol/h/ml) and 5 confirmed GD patients from the same community were submitted for molecular analysis to characterize the genetic profile of the population. Based on the enzymatic and molecular analysis, the subjects were classified into three categories: affected (n = 5), carrier (n = 20) and non-carrier (n = 111). All carriers were (G377S/wt). Affected subjects were homozygous (G377S/G377S). The identification of a single mutation in carriers and homozygotes from different generations, the history of the community and the genealogy study suggest that the high prevalence of GD in this population may be due to a combination of consanguinity and founder effect for the G377S mutation.","variants":[{"Name":"NM_000157.4(GBA1):c.1246G>A (p.Gly416Ser)","Chromosome":"1","Start":"155235823","Stop":"155235823","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19366,"rule_based_match":true,"evidence_text":"c.1246G>A","llm_judgment":"PRESENT","evidence":"c.1246G>A","abstract_start":347,"abstract_end":356}]}
{"pmid":"28595629","title":"Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene.","abstract":"Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin-related receptor 1 (SORL1), have been suggested to be potentially causative. To identify AD causative variants, we performed whole-exome sequencing on five individuals from a family with EOAD and a missense variant, p.Arg1303Cys (c.3907C > T) was identified in SORL1 which segregated with disease and was further characterized with immunohistochemistry on two post mortem autopsy cases from the same family. In a targeted re-sequencing effort on independent index patients from 35 EOAD-families, a second SORL1 variant, c.3050-2A > G, was found which segregated with the disease in 3 affected and was absent in one unaffected family member. The c.3050-2A > G variant is located two nucleotides upstream of exon 22 and was shown to cause exon 22 skipping, resulting in a deletion of amino acids Gly1017- Glu1074 of SORL1. Furthermore, a third SORL1 variant, c.5195G > C, recently identified in a Swedish case control cohort included in the European Early-Onset Dementia (EU EOD) consortium study, was detected in two affected siblings in a third family with familial EOAD. The finding of three SORL1-variants that segregate with disease in three separate families with EOAD supports the involvement of SORL1 in AD pathology. The cause of these rare monogenic forms of EOAD has proven difficult to find and the use of exome and genome sequencing may be a successful route to target them.","variants":[{"Name":"NM_003105.6(SORL1):c.5195G>C (p.Gly1732Ala)","Chromosome":"11","Start":"121608132","Stop":"121608132","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1483321,"rule_based_match":true,"evidence_text":"c.5195G > C","llm_judgment":"PRESENT","evidence":"c.5195G > C","abstract_start":1326,"abstract_end":1337},{"Name":"NM_003105.6(SORL1):c.3907C>T (p.Arg1303Cys)","Chromosome":"11","Start":"121588112","Stop":"121588112","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3853476,"rule_based_match":true,"evidence_text":"c.3907C > T","llm_judgment":"PRESENT","evidence":"c.3907C > T","abstract_start":699,"abstract_end":710}]}
{"pmid":"17564971","title":"Recurrent mutation in the first zinc finger of the orphan nuclear receptor NR2E3 causes autosomal dominant retinitis pigmentosa.","abstract":"\"Autosomal dominant retinitis pigmentosa\" (adRP) refers to a genetically heterogeneous group of retinal dystrophies, in which 54% of all cases can be attributed to 17 disease loci. Here, we describe the localization and identification of the photoreceptor cell-specific nuclear receptor gene NR2E3 as a novel disease locus and gene for adRP. A heterozygous mutation c.166G-->A (p.Gly56Arg) was identified in the first zinc finger of NR2E3 in a large Belgian family affected with adRP. Overall, this missense mutation was found in 3 families affected with adRP among 87 unrelated families with potentially dominant retinal dystrophies (3.4%), of which 47 were affected with RP (6.4%). Interestingly, affected members of these families display a novel recognizable NR2E3-related clinical subtype of adRP. Other mutations of NR2E3 have previously been shown to cause autosomal recessive enhanced S-cone syndrome, a specific retinal phenotype. We propose a different pathogenetic mechanism for these distinct dominant and recessive phenotypes, which may be attributed to the dual key role of NR2E3 in the regulation of photoreceptor-specific genes during rod development and maintenance.","variants":[{"Name":"NM_014249.4(NR2E3):c.166G>A (p.Gly56Arg)","Chromosome":"15","Start":"71811530","Stop":"71811530","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20572,"rule_based_match":false,"evidence_text":"c.166G-->A (p.Gly56Arg)","llm_judgment":"PRESENT","evidence":"c.166G-->A (p.Gly56Arg)","abstract_start":366,"abstract_end":389}]}
{"pmid":"31813735","title":"NOTCH3 Gene Mutation in a Chilean Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Family.","abstract":"INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke disorder caused by mutations in the NOTCH3 gene. We report the first Chilean CADASIL family with complete radiological and histological studies.\nMETHODS: The family tree was constructed from an autopsy-confirmed confirmed patient, and includes 3 generations. We performed clinical, pathologic, genetic, and radiologic examinations on members of a family with CADASIL.\nRESULTS: In the second generation, findings compatible with CADASIL were identified in 6 individuals, all of whom had a missense mutation in exon 3 (c.268C>T) resulting in an arginine to cysteine amino acid substitution at position 90 (R90C). In the third generation, a missense mutation was detected in one of the 4 asymptomatic individuals.\nCONCLUSIONS: There are similarities in clinical presentation between this family and previously described Asian and European series with R90C mutations. Detecting genotypes with a gain or loss of cysteine residues opens the door to future gene transfection-based therapies.","variants":[{"Name":"NM_000435.3(NOTCH3):c.268C>T (p.Arg90Cys)","Chromosome":"19","Start":"15192449","Stop":"15192449","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":442180,"rule_based_match":true,"evidence_text":"c.268C>T","llm_judgment":"PRESENT","evidence":"c.268C>T","abstract_start":660,"abstract_end":668}]}
{"pmid":"30905399","title":"De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.","abstract":"The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.","variants":[{"Name":"NM_001260.3(CDK8):c.185C>T (p.Ser62Leu)","Chromosome":"13","Start":"26337623","Stop":"26337623","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":794317,"rule_based_match":true,"evidence_text":"c.185C>T (p.Ser62Leu)","llm_judgment":"PRESENT","evidence":"c.185C>T (p.Ser62Leu)","abstract_start":772,"abstract_end":793}]}
{"pmid":"33803191","title":"Partial Lipodystrophy and LMNA p.R545H Variant.","abstract":"Laminopathies are disorders caused by <i>LMNA</i> gene mutations, which selectively affect different tissues and organ systems, and present with heterogeneous clinical and pathological traits. The molecular mechanisms behind these clinical differences and tissue specificity have not been fully clarified. We herein examine the case of a patient carrying a heterozygous <i>LMNA</i> c.1634G>A (p.R545H) variant with a mild, transient myopathy, who was referred to our center for the suspicion of lipodystrophy. At physical examination, an abnormal distribution of subcutaneous fat was noticed, with fat accumulation in the anterior regions of the neck, resembling the fat distribution pattern of familial partial lipodystrophy type 2 (FPLD2). The R545H missense variant has been found at very low allelic frequency in public databases, and in silico analysis showed that this amino acid substitution is predicted to have a damaging role. Other patients carrying the heterozygous <i>LMNA</i> p.R545H allele have shown a marked clinical heterogeneity in terms of phenotypic body fat distribution and severity of organ system involvement. These findings indicate that the <i>LMNA</i> p.R545H heterozygous variant exhibits incomplete penetrance and highly variable expressivity. We hypothesized that additional genetic factors, epigenetic mechanisms, or environmental triggers might explain the variable expressivity of phenotypes among various patients.","variants":[{"Name":"NM_170707.4(LMNA):c.1634G>A (p.Arg545His)","Chromosome":"1","Start":"156137679","Stop":"156137679","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":172489,"rule_based_match":true,"evidence_text":"NM_170707.4(LMNA):c.1634G>A (p.Arg545His)","llm_judgment":"PRESENT","evidence":"c.1634G>A","abstract_start":382,"abstract_end":391}]}
{"pmid":"27008691","title":"First case report of rare congenital adrenal insufficiency caused by mutations in the CYP11A1 gene in the Czech Republic.","abstract":"We characterized a case of congenital adrenal insufficiency caused by cholesterol side-chain cleavage enzyme (P450scc) deficiency. The patient presented after birth with cardiopulmonary instability, hyponatremia, hyperkalemia, hypoglycemia and metabolic acidosis. We confirmed primary adrenal insufficiency. There were no signs of the external genitalia virilism. The replacement therapy with glucocorticoids and mineralocorticoids led to normal laboratory results. At the age of 12 years, we confirmed hypergonadotropic hypogonadism, which revealed disorder of steroidogenesis in the adrenal glands and in the gonads. The enzymatic block was found at the beginning of steroidogenesis. The mutation was confirmed in the CYP11A1 gene. The patient is compound heterozygote for the novel CYP11A1 missense mutation c.412G>A (p.Gly138Arg) in exon 2 and frameshift mutation c.508_509delCT (p.Leu170Valfs*30) in exon 3. The CYP11A1: c.412G>A (p.Gly138Arg) was predicted as pathogenic by in silico analysis. So far, only 19 patients with CYP11A1 mutations causing P450scc deficiency have been reported worldwide. There are no related reports in the Czech Republic.","variants":[{"Name":"NM_000781.3(CYP11A1):c.412G>A (p.Gly138Arg)","Chromosome":"15","Start":"74347913","Stop":"74347913","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3494987,"rule_based_match":true,"evidence_text":"c.412G>A (p.Gly138Arg)","llm_judgment":"PRESENT","evidence":"c.412G>A (p.Gly138Arg)","abstract_start":811,"abstract_end":833}]}
{"pmid":"22552000","title":"Giant angiofibromas in tuberous sclerosis complex: a possible role for localized lymphedema in their pathogenesis.","abstract":"BACKGROUND: Giant angiofibromas in patients with tuberous sclerosis complex (TSC) are rare.\nOBJECTIVE: We sought to report two patients who had TSC with unusually large and disfiguring facial angiofibromas and to identify underlying histopathologic changes that may possibly explain the clinical features.\nMETHODS: We performed a clinicopathologic, immunohistochemical, and molecular biologic study using 42 lesional specimens and peripheral blood from one of the two patients. The immunohistochemical investigations were mainly focused on the vascular moiety of the lesions. TSC1 and TSC2 alterations were studied using multiplex ligation-dependent probe amplification for large deletion/duplication mutations, whereas screening for small mutations was performed using polymerase chain reaction amplification of individual coding exons and exon-intron junctions of both genes followed by an analysis on denaturation gradient gel electrophoresis.\nRESULTS: Histopathologic examination revealed, in addition to findings typical of angiofibroma, several unusual features including multinucleated giant cells containing multiple intracytoplasmic vacuoles, Touton-like cells, emperipolesis, pagetoid dyskeratosis, vacuolar alteration at the dermoepidermal junction, Civatte bodies, and melanophages in the subjacent dermis. Numerous dilated lymphatic vessels were detected indicating localized lymphostasis, probably caused by secondary lymphedema. The lymphatic nature of the vessels was confirmed by immunohistochemical study. Genetic testing for TSC1 and TSC2 gene mutations revealed a substitution on position c.2251C>T resulting in a nonsense mutation R751X in fragment 20.2.\nLIMITATIONS: Histopathologic specimens and peripheral blood were available from only one patient.\nCONCLUSION: Localized lymphedema may contribute to the formation of large disfiguring angiofibromas in patients with TSC.","variants":[{"Name":"NM_000548.5(TSC2):c.2251C>T (p.Arg751Ter)","Chromosome":"16","Start":"2072879","Stop":"2072879","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":59293,"rule_based_match":true,"evidence_text":"c.2251C>T","llm_judgment":"PRESENT","evidence":"c.2251C>T","abstract_start":1609,"abstract_end":1618}]}
{"pmid":"16652348","title":"The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer.","abstract":"Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants; 18 variants were analyzed in one of two large population-based studies from the U.S. and Poland, and four variants were analyzed in all 2,856 breast cancer cases and 3,344 controls from the two studies. The missense mutation Ser49Cys (c.146C>G, p.S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69 (95% CI, 1.19-2.40; P=0.004). Another missense mutation at approximately 2% frequency, Phe858Leu (c.2572T>C, p.F858L), was associated with a significant increased risk in the U.S. study but not in Poland, and had a combined OR of 1.44 (95% CI, 0.98-2.11; P=0.06). These analyses provide the most convincing evidence thus far that missense mutations in ATM, particularly p.S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations.","variants":[{"Name":"NM_000051.4(ATM):c.2572T>C (p.Phe858Leu)","Chromosome":"11","Start":"108267276","Stop":"108267276","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":136484,"rule_based_match":true,"evidence_text":"Phe858Leu (c.2572T>C, p.F858L)","llm_judgment":"PRESENT","evidence":"Phe858Leu (c.2572T>C, p.F858L)","abstract_start":660,"abstract_end":690},{"Name":"NM_000051.4(ATM):c.146C>G (p.Ser49Cys)","Chromosome":"11","Start":"108227849","Stop":"108227849","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":18087,"rule_based_match":true,"evidence_text":"c.146C>G (p.S49C)","llm_judgment":"PRESENT","evidence":"c.146C>G","abstract_start":417,"abstract_end":425}]}
{"pmid":"29241935","title":"Identification of a c.544C>T mutation in WDR34 as a deleterious recessive allele of short rib-polydactyly syndrome.","abstract":"OBJECTIVE: Single-nucleotide polymorphism (SNP) microarrays and whole-exome sequencing (WES) are tools to precisely diagnose rare autosomal recessive (AR) diseases. In this study, SNP chip and WES were used to identify a mutated location in WDR34 in a baby born to consanguineous parents.\nCASE REPORT: The baby, born at 36 gestational weeks had a small thoracic cage, symmetric short proximal bones, and polydactyly. Radiography showed short ribs with reduced lung volume and pulmonary opacities, compatible with asphyxiating thoracic dystrophy or short rib-polydactyly syndrome (SRPS). At 4 months of age, she died of pulmonary hypoplasia and sepsis. SNP microarray and evaluation tool confirmed WDR34 as the candidate gene. WES detected an AR mutation at c.554C > T [p.Arg182Trp] in WDR34.\nCONCLUSION: This study was the first to identify c.544C > T [p.Arg182Trp] mutation in WDR34 in a patient with SRPS. According to the database, the homozygous mutation of c.544C > T in WDR34 was deleterious and the prevalence of heterozygous mutation was relatively higher in Asian population. More studies of this mutation in patients with SRPS are required.","variants":[{"Name":"NM_052844.4(DYNC2I2):c.544C>T (p.Arg182Trp)","Chromosome":"9","Start":"128636919","Stop":"128636919","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":440115,"rule_based_match":true,"evidence_text":"c.544C>T [p.Arg182Trp]","llm_judgment":"PRESENT","evidence":"c.544C > T [p.Arg182Trp]","abstract_start":841,"abstract_end":865}]}
{"pmid":"29263825","title":"Familial","abstract":"We characterize a novel human cohesinopathy originated from a familial germline mutation of the gene encoding the cohesin subunit STAG2, which we propose to call <i>STAG2</i>-related X-linked Intellectual Deficiency. Five individuals carry a <i>STAG2</i> p.Ser327Asn (c.980 G > A) variant that perfectly cosegregates with a phenotype of syndromic mental retardation in a characteristic X-linked recessive pattern. Although patient-derived cells did not show overt sister-chromatid cohesion defects, they exhibited altered cell cycle profiles and gene expression patterns that were consistent with cohesin deficiency. The protein level of STAG2 in patient cells was normal. Interestingly, STAG2 S327 is located at a conserved site crucial for binding to SCC1 and cohesin regulators. When expressed in human cells, the STAG2 p.Ser327Asn mutant is defective in binding to SCC1 and other cohesin subunits and regulators. Thus, decreased amount of intact cohesin likely underlies the phenotypes of <i>STAG2</i>-SXLID. Intriguingly, recombinant STAG2 p.Ser327Asn binds normally to SCC1, WAPL, and SGO1 in vitro, suggesting the existence of unknown in vivo mechanisms that regulate the interaction between STAG2 and SCC1.","variants":[{"Name":"NM_001042750.2(STAG2):c.980G>A (p.Ser327Asn)","Chromosome":"X","Start":"124050272","Stop":"124050272","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":612203,"rule_based_match":true,"evidence_text":"c.980 G > A","llm_judgment":"PRESENT","evidence":"c.980 G > A","abstract_start":268,"abstract_end":279}]}
{"pmid":"28737456","title":"Significance of the monitoring and screening for hereditary nonpolyposis colorectal carcinoma syndrome patients by presenting a case of a family tree","abstract":"INTRODUCTION: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is an autosomal dominant disease, which shows familial clustering.\nAIM: We would like to emphasize the importance of monitoring the HNPCC syndrome patients by presenting a case of a proven MMR gene mutation carrier and her family tree encompassing 10 years.\nMATERIALS AND METHOD: To screen a suspected HNPCC Hungarian family member we are taking thorough family histories. If the diagnosis of HNPCC was further supported by immunohistology and the microsatellite status, sequencing of the MMR genes was carried out.\nRESULTS: A novel mutation in exon 6 of the hMSH2 gene leading to the deletion of two nucleotide pairs [c.969-970delTC] was detected in our patient. During the 10-year follow-up period of our patient new HNPCC-associated tumors have developed in several family members. Conslusion: Close surveillance of the patient and its family members at risk was effective, although it requires compliance from the subjects. Orv Hetil. 2017; 158(30): 1182-1187.","variants":[{"Name":"NM_000251.3(MSH2):c.969_970del (p.Gln324fs)","Chromosome":"2","Start":"47416319","Stop":"47416320","ReferenceAlleleVCF":"GCT","AlternateAlleleVCF":"G","allel_id":3235086,"rule_based_match":false,"evidence_text":"c.969-970delTC","llm_judgment":"PRESENT","evidence":"c.969-970delTC","abstract_start":686,"abstract_end":700}]}
{"pmid":"28513614","title":"Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree.","abstract":"Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.","variants":[{"Name":"NM_001754.5(RUNX1):c.601C>T (p.Arg201Ter)","Chromosome":"21","Start":"34859486","Stop":"34859486","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":362897,"rule_based_match":true,"evidence_text":"c.601C>T (p.(Arg201*))","llm_judgment":"PRESENT","evidence":"c.601C>T (p.(Arg201*))","abstract_start":406,"abstract_end":428}]}
{"pmid":"23918663","title":"CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.","abstract":"Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference, reduction in the size of the cerebral cortex with otherwise grossly normal brain structure and variable intellectual disability. MCPH is caused by mutations of 11 different genes which code for proteins implicated in cell division and cell cycle regulation. We studied a consanguineous eight-generation family from Pakistan with ten microcephalic children using homozygosity mapping and found a new MCPH locus at HSA 7q21.11-q21.3. Sanger sequencing of the most relevant candidate genes in this region revealed a homozygous single nucleotide substitution c.589G>A in CDK6, which encodes cyclin-dependent kinase 6. The mutation changes a highly conserved alanine at position 197 into threonine (p.Ala197Thr). Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. CDK6 is an important protein for the control of the cell cycle and differentiation of various cell types. We show here for the first time that CDK6 associates with the centrosome during mitosis; however, this was not observed in patient fibroblasts. Moreover, the mutant primary fibroblasts exhibited supernumerary centrosomes, disorganized microtubules and mitotic spindles, an increased centrosome nucleus distance, reduced cell proliferation and impaired cell motility and polarity. Upon ectopic expression of the mutant protein and knockdown of CDK6 through shRNA, we noted similar effects. We propose that the identified CDK6 mutation leads to reduced cell proliferation and impairs the correct functioning of the centrosome in microtubule organization and its positioning near the nucleus which are key determinants during neurogenesis.","variants":[{"Name":"NM_001145306.2(CDK6):c.589G>A (p.Ala197Thr)","Chromosome":"7","Start":"92671484","Stop":"92671484","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":167369,"rule_based_match":true,"evidence_text":"c.589G>A (p.Ala197Thr)","llm_judgment":"PRESENT","evidence":"p.Ala197Thr","abstract_start":790,"abstract_end":801}]}
{"pmid":"24003324","title":"Multiplex ARMS PCR to Detect 8 Common Mutations of ATP7B Gene in Patients With Wilson Disease.","abstract":"BACKGROUND: Wilson disease is a rare disorder of copper metabolism due to mutation in ATP7B gene. Proper counseling of patients with Wilson disease, and their families necessitates finding mutation in ATP7B gene. Finding mutations in ATP7B gene with 21 exons, and more than 500 mutations is expensive and time-consuming.\nOBJECTIVES: The aim of this study was to provide a simple multiplex amplification refractory mutation system PCR (M-ARMS-PCR) for screening eight common mutations in ATP7B gene.\nPATIENTS AND METHODS: Two sets of ARMS mutant and normal specific primer pairs were designed for genotyping of p.R778L, p.R969Q, p.H1069Q, and p.3400delC mutations as Set 1 and p.W779G, c.3061-1G > A, p.I1102T, and p.N1270S mutations as Set 2. The Multiplex ARMS assay was then subsequently tested in 65 patients with Wilson disease with known and unknown ATP7B mutations.\nRESULTS: Using these two sets, we identified H1069Q mutation in four patients, c.2335T > G mutation in three, c.3061-1G > A splice site mutation in five, c.3305T > C mutation in one, and c.3809A > G mutation in two patients.\nCONCLUSIONS: The Multiplex ARMS assay used in this study can be an efficient, reliable, and cost effective method as a primary screen for patients with Wilson disease.","variants":[{"Name":"NM_000053.4(ATP7B):c.2335T>G (p.Trp779Gly)","Chromosome":"13","Start":"51958331","Stop":"51958331","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":547056,"rule_based_match":true,"evidence_text":"c.2335T > G","llm_judgment":"PRESENT","evidence":"c.2335T > G","abstract_start":951,"abstract_end":962},{"Name":"NM_000053.4(ATP7B):c.3061-1G>A","Chromosome":"13","Start":"51944292","Stop":"51944292","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1364125,"rule_based_match":true,"evidence_text":"c.3061-1G > A","llm_judgment":"PRESENT","evidence":"c.3061-1G > A","abstract_start":685,"abstract_end":698},{"Name":"NM_000053.4(ATP7B):c.3305T>C (p.Ile1102Thr)","Chromosome":"13","Start":"51942493","Stop":"51942493","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":424263,"rule_based_match":true,"evidence_text":"c.3305T > C","llm_judgment":"PRESENT","evidence":"c.3305T > C","abstract_start":1026,"abstract_end":1037}]}
{"pmid":"21599812","title":"NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy.","abstract":"BACKGROUND AND PURPOSE:   Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized in the 'pure' phenotype by progressive spasticity and weakness of the lower limbs. In the 'complex' phenotype, additional neurologic symptoms or signs are found. Mutations in the NIPA1 gene have been reported to cause spastic paraplegia type 6 (SPG6) in 10 families. SPG6 is a rare form of autosomal dominantly inherited HSP associated with a pure phenotype; however, in one complex SPG6 family, idiopathic generalized epilepsy (IGE) has been described and in addition, recurrent microdeletions at 15q11.2 including NIPA1 have been identified in patients with IGE. The purpose was to identify NIPA1 mutations in patients with pure and complex HSP.\nMETHODS:   Fifty-two patients with HSP were screened for mutations in NIPA1.\nRESULTS:   One previously reported missense mutation c.316G>A, p.Gly106Arg, was identified in a complex HSP patient with spastic dysarthria, facial dystonia, atrophy of the small hand muscles, upper limb spasticity, and presumably IGE. The epilepsy co-segregated with HSP in the family.\nCONCLUSION:   NIPA1 mutations were rare in our population of patients with HSP, but can be found in patients with complex HSP. Epilepsy might be more common in SPG6 than in other forms of HSP because of a genetic risk factor closely linked to NIPA1.","variants":[{"Name":"NM_144599.5(NIPA1):c.316G>A (p.Gly106Arg)","Chromosome":"15","Start":"22812252","Stop":"22812252","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17562,"rule_based_match":true,"evidence_text":"c.316G>A, p.Gly106Arg","llm_judgment":"PRESENT","evidence":"c.316G>A, p.Gly106Arg","abstract_start":937,"abstract_end":958}]}
{"pmid":"32221274","title":"Clinical histopathological features and CDKN2A/CDK4/MITF mutational status of patients with multiple primary melanomas from Bologna: Italy is a fascinating but complex mosaic.","abstract":"BACKGROUND: The incidence of cutaneous melanoma (cM) has increased in the last decades. Germline mutations in the high-penetrance melanoma susceptibility gene CDKN2A (Cyclin-dependent kinase inhibitor 2A) are associated with a younger age at diagnosis and an increased risk to develop pancreatic cancer.\nMETHODS: We retrospectively analyzed the data of patients with prior diagnosis of cM referring to our service from January 2005 to May 2017. The aim was to investigate the rate of multiple cMs (MPM), assessing their clinical/pathological features. Moreover, the genetic tests of patients who had undergone CDKN2A/CDKN2B, CDK4 and MITF screening were evaluated.\nRESULTS: One hundred fifteen patients (9.26%) were diagnosed with MPMs: 70 males (60.87%) and 45 women (39.13%). 75 patients (43 males and 32 females) underwent genetic screening for germline mutations. The screening revealed that 4/75 patients (5.33%) were carriers of the non-synonymous missense variation c.442G>A (p.Ala148Thr) in CDKN2A exon 2 in heterozygosis, 3 of whom had at least one in-situ melanoma. In 1 patient (1.33%) we detected the variation c.249C>A, p.His83Gln in CDKN2A exon 2 in heterozygosis and in 1 patient (1.33%) the mutation c.952G>A (p.Glu318Lys) in MITF gene was found.\nCONCLUSIONS: This study confirms the need for a full body skin examination and a prolonged surveillance in patients affected by cM, as MPMs were detected in up to 10% of total cases in our series and synchronous lesions in 1/5. Moreover, it reflects the great variability of cM high-susceptibility genes mutational status within the Italian territory. Patients carrying c.952G>A (p.Glu318Lys) MITF mutation have a higher risk to develop a nodular cM.","variants":[{"Name":"NM_000077.5(CDKN2A):c.249C>A (p.His83Gln)","Chromosome":"9","Start":"21971110","Stop":"21971110","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":421038,"rule_based_match":true,"evidence_text":"c.249C>A, p.His83Gln","llm_judgment":"PRESENT","evidence":"c.249C>A, p.His83Gln","abstract_start":1123,"abstract_end":1143}]}
{"pmid":"23942138","title":"SLCO1B1 genetic variant associated with statin-induced myopathy: a proof-of-concept study using the clinical practice research datalink.","abstract":"This study aimed to determine whether patients with statin-induced myopathy could be identified using the United Kingdom Clinical Practice Research Datalink, whether DNA could be obtained, and whether previously reported associations of statin myopathy with the SLCO1B1 c.521T>C and COQ2 rs4693075 polymorphisms could be replicated. Seventy-seven statin-induced myopathy patients (serum creatine phosphokinase (CPK) > 4× upper limit of normal (ULN)) and 372 statin-tolerant controls were identified and recruited. Multiple logistic regression analysis showed the SLCO1B1 c.521T>C single-nucleotide polymorphism to be a significant risk factor (P = 0.009), with an odds ratio (OR) per variant allele of 2.06 (1.32-3.15) for all myopathy and 4.09 (2.06-8.16) for severe myopathy (CPK > 10× ULN, and/or rhabdomyolysis; n = 23). COQ2 rs4693075 was not associated with myopathy. Meta-analysis showed an association between c.521C>T and simvastatin-induced myopathy, although power for other statins was limited. Our data replicate the association of SLCO1B1 variants with statin-induced myopathy. Furthermore, we demonstrate how electronic medical records provide a time- and cost-efficient means of recruiting patients with severe adverse drug reactions for pharmacogenetic studies.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":true,"evidence_text":"SLCO1B1 c.521T>C","llm_judgment":"PRESENT","evidence":"SLCO1B1 c.521T>C","abstract_start":262,"abstract_end":278}]}
{"pmid":"22305531","title":"The phenotype of a germline mutation in PIGA: the gene somatically mutated in paroxysmal nocturnal hemoglobinuria.","abstract":"Phosphatidylinositol glycan class A (PIGA) is involved in the first step of glycosylphosphatidylinositol (GPI) biosynthesis. Many proteins, including CD55 and CD59, are anchored to the cell by GPI. Loss of CD55 and CD59 on erythrocytes causes complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH), a disease that manifests after clonal expansion of hematopoietic cells with somatic PIGA mutations. Although somatic PIGA mutations have been identified in many PNH patients, it has been proposed that germline mutations are lethal. We report a family with an X-linked lethal disorder involving cleft palate, neonatal seizures, contractures, central nervous system (CNS) structural malformations, and other anomalies. An X chromosome exome next-generation sequencing screen identified a single nonsense PIGA mutation, c.1234C>T, which predicts p.Arg412(∗). This variant segregated with disease and carrier status in the family, is similar to mutations known to cause PNH as a result of PIGA dysfunction, and was absent in 409 controls. PIGA-null mutations are thought to be embryonic lethal, suggesting that p.Arg412(∗) PIGA has residual function. Transfection of a mutant p.Arg412(∗) PIGA construct into PIGA-null cells showed partial restoration of GPI-anchored proteins. The genetic data show that the c.1234C>T (p.Arg412(∗)) mutation is present in an affected child, is linked to the affected chromosome in this family, is rare in the population, and results in reduced, but not absent, biosynthesis of GPI anchors. We conclude that c.1234C>T in PIGA results in the lethal X-linked phenotype recognized in the reported family.","variants":[{"Name":"NM_002641.4(PIGA):c.1234C>T (p.Arg412Ter)","Chromosome":"X","Start":"15321727","Stop":"15321727","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38943,"rule_based_match":true,"evidence_text":"c.1234C>T (p.Arg412(∗))","llm_judgment":"PRESENT","evidence":"c.1234C>T (p.Arg412(∗))","abstract_start":1319,"abstract_end":1342}]}
{"pmid":"27748876","title":"Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site.","abstract":"Beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is an autosomal recessive disease caused by mutations in the acetyl‑CoA acetyltransferase 1 (ACAT1) gene. A German T2‑deficient patient that developed a severe ketoacidotic episode at the age of 11 months, was revealed to be a compound heterozygote of a previously reported null mutation, c.472A>G (p.N158D) and a novel mutation, c.949G>A (p.D317N), in ACAT1. The c.949G>A mutation was suspected to cause aberrant splicing as it is located within an exonic splicing enhancer sequence (c. 947CTGACGC) that is a potential binding site for serine/arginine‑rich splicing factor 1. A mutation in this sequence, c.951C>T, results in exon 10 skipping. A minigene construct was synthesized that included exon 9‑truncated intron 9‑exon 10‑truncated intron 10‑exon 11, and the splicing of this minigene revealed that the c.949G>A mutant construct caused exon 10 skipping in a proportion of the transcripts. Furthermore, additional substitution of G for C at the first nucleotide of exon 10 (c.941G>C) abolished the effect of the c.949G>A mutation. Transient expression analysis of the c.949G>A mutant cDNA revealed no residual T2 activity in the mutated D317N enzyme. Therefore, c.949G>A (D317N) is a pathogenic missense mutation, and diminishes the effect of an exonic splicing enhancer and causes exon 10 skipping. The present study demonstrates that a missense mutation, or even a synonymous substitution, may disrupt enzyme function by interference with splicing.","variants":[{"Name":"NM_000019.4(ACAT1):c.949G>A (p.Asp317Asn)","Chromosome":"11","Start":"108143991","Stop":"108143991","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":654063,"rule_based_match":true,"evidence_text":"c.949G>A (p.D317N)","llm_judgment":"PRESENT","evidence":"c.949G>A (p.D317N)","abstract_start":430,"abstract_end":448}]}
{"pmid":"32351701","title":"Duchenne muscular dystrophy-like phenotype in an LGMD2I patient with novel","abstract":"A 32-year-old man initially received a diagnosis of Duchenne muscular dystrophy (DMD). Genetic analysis revealed two novel heterozygous <i>FKRP</i> variants: c.169G>A (p.Glu57Lys) and c.692G>A (p.Trp231*). These results indicated that the patient had limb-girdle muscular dystrophy type 2I (LGMD2I) caused by recessive <i>FKRP</i> variants. Patients with LGMD2I and DMD have many overlapping phenotypes. LGMD2I should be considered in patients who have a DMD phenotype but not a DMD pathogenic variant.","variants":[{"Name":"NM_024301.5(FKRP):c.692G>A (p.Trp231Ter)","Chromosome":"19","Start":"46756142","Stop":"46756142","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1984562,"rule_based_match":true,"evidence_text":"c.692G>A (p.Trp231*)","llm_judgment":"PRESENT","evidence":"c.692G>A (p.Trp231*)","abstract_start":184,"abstract_end":204},{"Name":"NM_024301.5(FKRP):c.169G>A (p.Glu57Lys)","Chromosome":"19","Start":"46755619","Stop":"46755619","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":267542,"rule_based_match":true,"evidence_text":"c.169G>A (p.Glu57Lys)","llm_judgment":"PRESENT","evidence":"c.169G>A (p.Glu57Lys)","abstract_start":158,"abstract_end":179}]}
{"pmid":"24170412","title":"Recurrent central nervous system white matter changes in charcot-Marie-tooth type X disease.","abstract":"INTRODUCTION: X-linked Charcot-Marie-Tooth (CMT1X) disease is caused by mutations in the GJB1 gene. We describe a young man who presented with recurrent central nervous symptoms and transient white matter changes in the setting of a novel mutation in the GJB1 gene.\nMETHODS: Evaluation included clinical examination, neuroimaging, electrophysiological, and molecular genetic studies.\nRESULTS: Clinical examination on 2 admissions 5 years apart demonstrated hemiparesis with findings of underlying peripheral neuropathy. Electrophysiologic studies revealed a sensorimotor polyneuropathy. MRI studies from both admissions revealed white matter changes, with improvement on an intervening study. Mutation analysis showed a novel mutation (c.98T>A; p.Ile33Asn) in the GJB1 gene.\nCONCLUSIONS: Mutations in GJB1 can result in recurrent central nervous system symptoms with transient white matter signal changes on MRI. In patients presenting with hemiparesis, the presence of signs of a peripheral neuropathy may facilitate identification of CMT1X, and is likely to affect clinical management.","variants":[{"Name":"NM_000166.6(GJB1):c.98T>A (p.Ile33Asn)","Chromosome":"X","Start":"71223805","Stop":"71223805","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":625486,"rule_based_match":true,"evidence_text":"c.98T>A; p.Ile33Asn","llm_judgment":"PRESENT","evidence":"c.98T>A; p.Ile33Asn","abstract_start":736,"abstract_end":755}]}
{"pmid":"36484953","title":"New splice site mutations in MYO7A causing Usher syndrome type 1: a study on a Chinese consanguineous family.","abstract":"PURPOSE: This study investigated the new splice site mutations of Myosin VIIA (MYO7A) in patients with Usher syndrome type 1 (USH1) from a three-generation Chinese consanguineous family.\nMETHODS: All subjects underwent comprehensive ophthalmic examinations and an audiometric test. Demographic data, family history, and peripheral blood leukocytes were collected. We performed whole exome sequencing (WES) to analyze the genomic DNA of the family. DNA sequence and restriction fragment length polymorphism (RFLP) analyses were also done. The identified genetic variants were validated by conducting polymerase chain reaction (PCR) in 100 healthy control subjects and comparing with the NCBI VARIANT database and the 1000 Genomes Project. The functional consequences were further analyzed.\nRESULTS: WES identified two new splice site mutations (c.5648G > A(rs111033215) and c.6238-1G > C) in MYO7A in two patients with USH1, i.e., the proband and her elder brother. DNA sequence and RFLP analyses showed that other members without USH1 carried only one of the two mutations. In the analysis of healthy controls, neither mutation existed. Both mutations were predicted to be damaging and were most likely associated with USH1.\nCONCLUSION: In the three-generation Chinese consanguineous family with USH1, c.5648G > A(rs111033215) and c.6238-1G > C mutations in MYO7A are most likely associated with the disease. Our findings expand the mutational spectrum of MYO7A, which will enhance the understanding of the genetic abnormalities in USH1 and provide more evidence for future investigations on therapeutic strategies such as precise gene replacement or gene editing.","variants":[{"Name":"NM_000260.4(MYO7A):c.5648G>A (p.Arg1883Gln)","Chromosome":"11","Start":"77206108","Stop":"77206108","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":52464,"rule_based_match":true,"evidence_text":"c.5648G > A(rs111033215)","llm_judgment":"PRESENT","evidence":"c.5648G > A(rs111033215)","abstract_start":844,"abstract_end":868}]}
{"pmid":"34172529","title":"Loss-of-function variants in","abstract":"BACKGROUND: Developmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in <i>DNM1</i>.\nMETHODS: We performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families.\nRESULTS: We excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the <i>DNM1</i> gene, indicating that biallelic, loss-of-function pathogenic variants in <i>DNM1</i> cause DEE.\nCONCLUSION: Our finding that homozygous, loss-of-function variants in <i>DNM1</i> cause DEE expands the spectrum of pathogenic variants in <i>DNM1</i>. All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in <i>DNM1</i> determines the pattern of inheritance.","variants":[{"Name":"NM_004408.4(DNM1):c.850C>T (p.Gln284Ter)","Chromosome":"9","Start":"128222197","Stop":"128222197","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":792777,"rule_based_match":true,"evidence_text":"c.850C>T; p.(Gln284*)","llm_judgment":"PRESENT","evidence":"c.850C>T; p.(Gln284*)","abstract_start":837,"abstract_end":858},{"Name":"NM_004408.4(DNM1):c.97C>T (p.Gln33Ter)","Chromosome":"9","Start":"128203567","Stop":"128203567","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2483096,"rule_based_match":true,"evidence_text":"c.97C>T; p.(Gln33*)","llm_judgment":"PRESENT","evidence":"c.97C>T; p.(Gln33*)","abstract_start":801,"abstract_end":820}]}
{"pmid":"28371260","title":"Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp.","abstract":"Costello syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.","variants":[{"Name":"NM_005343.4(HRAS):c.38G>A (p.Gly13Asp)","Chromosome":"11","Start":"534285","Stop":"534285","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27643,"rule_based_match":true,"evidence_text":"c.38G>A; p.Gly13Asp","llm_judgment":"PRESENT","evidence":"c.38G>A; p.Gly13Asp","abstract_start":609,"abstract_end":628}]}
{"pmid":"37141942","title":"Cervical Instability and Quadriparesis Requiring Stabilization in Pediatric Patient Caused by a Mutation in COL2A1.","abstract":"A 3-year-old male with no past medical history presented with flaccid plegia of his upper extremities and significant weakness in his lower extremities after wrestling with his brother. Cervical spine magnetic resonance imaging was consistent with cord edema and intraparenchymal hemorrhage at C1-C2. A nonossified tissue mass at the expected location of the upper dens created narrowing of the canal at the C1-2 level and mass effect on the cord. Head computed tomography showed periventricular leukomalacia. Initial findings favored dysplasia of the odontoid with associated soft tissue mass/pannus caused by a possible underlying genetic or metabolic bone dyscrasia. The patient underwent suboccipital craniotomy/C1 laminectomy and occiput to C4 fusion, for decompression and stabilization. Genetic testing showed a COL2A1 collagen disorder, with the child harboring a de novo mutation for c.3455 G>T (p.G1152V). The patient was discharged to inpatient acute rehabilitation, with gradual improvement in strength in all 4 extremities.","variants":[{"Name":"NM_001844.5(COL2A1):c.3455G>T (p.Gly1152Val)","Chromosome":"12","Start":"47976548","Stop":"47976548","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3859770,"rule_based_match":true,"evidence_text":"c.3455 G>T (p.G1152V)","llm_judgment":"PRESENT","evidence":"c.3455 G>T (p.G1152V)","abstract_start":893,"abstract_end":914}]}
{"pmid":"20157782","title":"The first case of mitochondrial acetoacetyl-CoA thiolase deficiency identified by expanded newborn metabolic screening in Italy: the importance of an integrated diagnostic approach.","abstract":"A pilot expanded newborn screening programme to detect inherited metabolic disorders by means of liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) began in the Campania region, southern Italy, in 2007. By October 2009, >8,800 dried blood samples on filter paper from 11 hospitals had been screened. Within this screening programme, we identified a case of mitochondrial acetoacetyl-coenzyme A (CoA) thiolase deficiency [β-ketothiolase (β-KT) deficiency] by analysing the acylcarnitine profile from a dried blood spot with LC-MS/MS. Gas chromatography coupled with mass spectrometry analysis of urinary organic acids and LC-MS/MS analysis of urinary acylcarnitines were in line with this disorder. In fact, concentrations were well beyond the cut-off values of tiglyl carnitine, 3-hydroxybutyrylcarnitine and 2-methyl-3-hydroxybutyrylcarnitine, 2-methyl-3-hydroxybutyric acid and tiglyl glycine. The absence of 2-methylacetoacetic acid in urine may be attributed to: (i) the instability of this β-ketoacid because it undergoes spontaneous decarboxylation to 2-butanone, which is highly volatile and thus difficult to detect, and (ii) the good health of the patient in the first days of life. β-KT deficiency was subsequently diagnosed in the patient's older sister, who showed increased levels of the same metabolites but also small amounts of 2-methylacetoacetic acid, which is considered a key marker for β-KT diagnosis. Genomic analysis revealed mutation c.1189C >G in exon 12 of the ACAT1 gene, which results in a severe defect because of the p.H397D amino acid change in both alleles of both patients.","variants":[{"Name":"NM_000019.4(ACAT1):c.1189C>G (p.His397Asp)","Chromosome":"11","Start":"108147295","Stop":"108147295","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":654077,"rule_based_match":true,"evidence_text":"c.1189C >G","llm_judgment":"PRESENT","evidence":"c.1189C >G","abstract_start":1478,"abstract_end":1488}]}
{"pmid":"27871249","title":"Benign clear cell \"sugar\" tumor of the lung in a patient with Birt-Hogg-Dubé syndrome: a case report.","abstract":"BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a rare inherited autosomal genodermatosis and caused by germline mutation of the folliculin (FLCN) gene, a tumor suppressor gene of which protein product is involved in mechanistic target of rapamycin (mTOR) signaling pathway regulating cell growth and metabolism. Clinical manifestations in BHD syndrome is characterized by fibrofolliculomas of the skin, pulmonary cysts with or without spontaneous pneumothorax, and renal neoplasms. There has been no pulmonary neoplasm reported in BHD syndrome, although the condition is due to deleterious sequence variants in a tumor suppressor gene. Here we report, for the first time to our knowledge, a patient with BHD syndrome who was complicated with a clear cell \"sugar\" tumor (CCST) of the lung, a benign tumor belonging to perivascular epithelioid cell tumors (PEComas) with frequent causative relation to tuberous sclerosis complex 1 (TSC1) or 2 (TSC2) gene.\nCASE PRESENTATION: In a 38-year-old Asian woman, two well-circumscribed nodules in the left lung and multiple thin-walled, irregularly shaped cysts on the basal and medial area of the lungs were disclosed by chest roentgenogram and computer-assisted tomography (CT) during a preoperative survey for a bilateral faucial tonsillectomy. Analysis of the resected tumor showed large polygonal cells with clear cytoplasm proliferating in a solid pattern. Immunohistochemistry revealed that these tumor cells were positive for microphthalmia-transcription factor, S100, and CD1a but negative for HMB45, indicating that the tumor was a CCST. Genetic testing indicated that the patient had a germline mutation on exon 12 of the FLCN gene, i.e., insertion of 7 nucleotides (CCACCCT) (c.1347_1353dupCCACCCT). Direct sequencing of the FLCN exon 12 using genomic DNA obtained from her microdissected CCST cells clearly revealed loss of the wild-type FLCN sequence, which confirmed complete functional loss of the FLCN gene. On the other hand, no loss of heterozygosity around TCS1- or TSC2-associated genetic region was demonstrated.\nCONCLUSION: To our knowledge, this is the first report of CCST of the lung in a patient with BHDS, indicating that CCST should be added to the spectrum of pulmonary manifestations of BHDS.","variants":[{"Name":"NM_144997.7(FLCN):c.1347_1353dup (p.Val452fs)","Chromosome":"17","Start":"17215263","Stop":"17215264","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CAGGGTGG","allel_id":1063851,"rule_based_match":true,"evidence_text":"c.1347_1353dupCCACCCT","llm_judgment":"PRESENT","evidence":"c.1347_1353dupCCACCCT","abstract_start":1726,"abstract_end":1747}]}
{"pmid":"30559311","title":"Concomitant diagnosis of immune deficiency and","abstract":"X-linked agammaglobulinemia (XLA, OMIM#300300) is a rare monogenic primary immunodeficiency caused by mutations in the Bruton tyrosine kinase (<i>BTK</i>) gene. XLA is characterized by insufficient immunoglobulin levels and susceptibility to life-threatening bacterial infections. We report on a patient that presented with ecthyma gangrenosum and septicemia. Rapid trio whole-genome sequencing (rWGS) revealed an apparently de novo hemizygous pathogenic variant (c.726dupT; p.Ile243TyrfsTer15) in the <i>BTK</i> gene. Metagenomic analysis of rWGS sequences that did not align to the human genome revealed 770 aligned to the <i>Pseudomonas aeruginosa</i> PAO1 genome. The patient was diagnosed with XLA and pseudomonal sepsis.","variants":[{"Name":"NM_000061.3(BTK):c.726dup (p.Ile243fs)","Chromosome":"X","Start":"101360617","Stop":"101360618","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":553416,"rule_based_match":true,"evidence_text":"c.726dupT; p.Ile243TyrfsTer15","llm_judgment":"PRESENT","evidence":"c.726dupT; p.Ile243TyrfsTer15","abstract_start":464,"abstract_end":493}]}
{"pmid":"32764743","title":"Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia.","abstract":"Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, reduced fertility, and randomization of the left/right body axis. It is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious axonemal defect for pathogenic variants using whole exome capture, next generation sequencing, and bioinformatic analysis assuming an autosomal recessive trait. We identified one subject with an apparently homozygous nonsense variant [(c.1762C>T), p.(Arg588*)] in the uncharacterized CFAP57 gene. Interestingly, the variant results in the skipping of exon 11 (58 amino acids), which may be due to disruption of an exonic splicing enhancer. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Nasal cells from the PCD patient express a shorter, mutant version of CFAP57 and the protein is not incorporated into the axoneme. The missing 58 amino acids include portions of WD repeats that may be important for loading onto the intraflagellar transport (IFT) complexes for transport or docking onto the axoneme. A reduced beat frequency and an alteration in ciliary waveform was observed. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is highly conserved in organisms that assemble motile cilia. CFAP57 is allelic with the BOP2/IDA8/FAP57 gene identified previously in Chlamydomonas reinhardtii. Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass tag (TMT) mass spectroscopy shows that FAP57 is missing, and the \"g\" inner dyneins (DHC7 and DHC3) and the \"d\" inner dynein (DHC2) are reduced, but the FAP57 paralog FBB7 is increased. Together, our data identify a homozygous variant in CFAP57 that causes PCD that is likely due to a defect in the inner dynein arm assembly process.","variants":[{"Name":"NM_001378189.1(CFAP57):c.1762C>T (p.Arg588Ter)","Chromosome":"1","Start":"43209749","Stop":"43209749","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1336511,"rule_based_match":true,"evidence_text":"c.1762C>T","llm_judgment":"PRESENT","evidence":"c.1762C>T","abstract_start":505,"abstract_end":514}]}
{"pmid":"30827496","title":"Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.","abstract":"Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.","variants":[{"Name":"NM_001375524.1(TRRAP):c.3127G>A (p.Ala1043Thr)","Chromosome":"7","Start":"98927318","Stop":"98927318","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":622718,"rule_based_match":true,"evidence_text":"c.3127G>A p.(Ala1043Thr)","llm_judgment":"PRESENT","evidence":"c.3127G>A p.(Ala1043Thr)","abstract_start":1081,"abstract_end":1105}]}
{"pmid":"16601880","title":"Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy.","abstract":"Glycine encephalopathy, or nonketotic hyperglycinaemia (NKH; Mckusick 238300) is a severe autosomal recessive disease due to a defect in the glycine cleavage system (GCS), which is a complex of four subunits: P-, T-, H- and L-proteins. A P-protein (glycine decarboxylase or GLDC) deficiency was reported in about 80% of NKH patients. We performed mutation analysis of the complete coding sequence of the GLDC gene in 28 unrelated patients with neonatal NKH using denaturing high-performance liquid chromatography (DHPLC) and sequencing. Forty different gene alterations were identified, confirming the large molecular heterogeneity of the GLDC gene. Eighteen alterations were clearly disease-causing: two large deletions, four one-base deletions (c.28delC, c.1175delC, c.2186delC, c.2422delA), one 1-base insertion (c.1002_1003insT), one 4-base insertion (c.1285_1286insCAAA), one insertion/deletion (c.2153_2155delinsTCCTGGTTTA), five nonsense mutations (p.E153X, p.R236X, p.E270X, p.R337X, p.R424X) and four splice site mutations (c.861+1G > T, c.1402-1C > G, c.2316-1G > A, c.2919+1G > A). Additionally, we identified one intronic mutation outside the consensus splice sites (c.2838+5G > A) and 21 nucleotide substitutions leading to amino acid change (including three previously described mutations: p.T269M, p.R461Q, p.G771R), the pathogenicity of which should be confirmed by expression studies (p.S132W, p.Y138F, p.G171A, p.T187K, p.R212K, p.T269M, p.R373W, p.I440N, p.R461Q, p.N533Y, p.C644F, p.H651R, p.V705M, p.N732K, p.G771R, p.H775R, p.T830M, p.A841P, p.D880V, p.S957P and p.R966G). Mutation analysis allowed us to identify sequence alterations in both alleles for 19 patients and in one allele for 7 patients One patient was carrying three mutations (p.Y138F, p.T269M and p.E153X) and one patient was carrying two amino acid substitutions on the same allele (p.V705M and p.R212K) and an unidentified mutation on the other allele. No mutation could be found in two patients, suggesting possible defects in the H-protein or gene alterations that could not be identified by our technique. The potential use of genotype determination for prenatal diagnosis is emphasized.","variants":[{"Name":"NM_000170.3(GLDC):c.1175del (p.Ala392fs)","Chromosome":"9","Start":"6595100","Stop":"6595100","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":70678,"rule_based_match":true,"evidence_text":"c.1175delC","llm_judgment":"PRESENT","evidence":"c.1175delC","abstract_start":757,"abstract_end":767},{"Name":"NM_000170.3(GLDC):c.1285_1286insCAAA (p.Leu429fs)","Chromosome":"9","Start":"6592966","Stop":"6592967","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ATTTG","allel_id":70680,"rule_based_match":true,"evidence_text":"c.1285_1286insCAAA","llm_judgment":"PRESENT","evidence":"c.1285_1286insCAAA","abstract_start":856,"abstract_end":874},{"Name":"NM_000170.3(GLDC):c.2153_2155delinsTCCTGGTTTA (p.His718_Gln719delinsLeuLeuValTer)","Chromosome":"9","Start":"6556200","Stop":"6556202","ReferenceAlleleVCF":"GAT","AlternateAlleleVCF":"TAAACCAGGA","allel_id":70699,"rule_based_match":true,"evidence_text":"c.2153_2155delinsTCCTGGTTTA","llm_judgment":"PRESENT","evidence":"c.2153_2155delinsTCCTGGTTTA","abstract_start":901,"abstract_end":928},{"Name":"NM_000170.3(GLDC):c.2186del (p.Ala729fs)","Chromosome":"9","Start":"6556169","Stop":"6556169","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":70701,"rule_based_match":true,"evidence_text":"c.2186delC","llm_judgment":"PRESENT","evidence":"c.2186delC","abstract_start":769,"abstract_end":779},{"Name":"NM_000170.3(GLDC):c.2316-1G>A","Chromosome":"9","Start":"6553510","Stop":"6553510","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70712,"rule_based_match":true,"evidence_text":"c.2316-1G > A","llm_judgment":"PRESENT","evidence":"c.2316-1G > A","abstract_start":1062,"abstract_end":1075},{"Name":"NM_000170.3(GLDC):c.2422del (p.Ser808fs)","Chromosome":"9","Start":"6553403","Stop":"6553403","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":70716,"rule_based_match":true,"evidence_text":"c.2422delA","llm_judgment":"PRESENT","evidence":"c.2422delA","abstract_start":781,"abstract_end":791},{"Name":"NM_000170.3(GLDC):c.2838+5G>A","Chromosome":"9","Start":"6536059","Stop":"6536059","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70726,"rule_based_match":true,"evidence_text":"c.2838+5G > A","llm_judgment":"PRESENT","evidence":"c.2838+5G > A","abstract_start":1179,"abstract_end":1192},{"Name":"NM_000170.3(GLDC):c.28del (p.Leu10fs)","Chromosome":"9","Start":"6645472","Stop":"6645472","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":70731,"rule_based_match":true,"evidence_text":"c.28delC","llm_judgment":"PRESENT","evidence":"c.28delC","abstract_start":747,"abstract_end":755},{"Name":"NM_000170.3(GLDC):c.2919+1G>A","Chromosome":"9","Start":"6534707","Stop":"6534707","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70732,"rule_based_match":true,"evidence_text":"c.2919+1G > A","llm_judgment":"PRESENT","evidence":"c.2919+1G > A","abstract_start":1077,"abstract_end":1090},{"Name":"NM_000170.3(GLDC):c.861+1G>T","Chromosome":"9","Start":"6605130","Stop":"6605130","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":70746,"rule_based_match":true,"evidence_text":"c.861+1G > T","llm_judgment":"PRESENT","evidence":"c.861+1G > T","abstract_start":1033,"abstract_end":1045}]}
{"pmid":"38286424","title":"A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism.","abstract":"Biallelic variants in <i>PTRHD1</i> have been associated with autosomal recessive intellectual disability, spasticity, and juvenile parkinsonism, with few reported cases. Here, we present the clinical and genetic findings of a female of Austrian origin exhibiting infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, consistent with the established phenotypic spectrum. Notably, she developed genetic generalized epilepsy at age 4, persisting into adulthood. Using diagnostic exome sequencing, we identified a homozygous missense variant (c.365G > A, p.(Arg122Gln)) in <i>PTRHD1</i> (NM_001013663). In summary, our findings not only support the existing link between biallelic <i>PTRHD1</i> variants and parkinsonism with neurodevelopmental abnormalities but also suggest a potential extension of the phenotypic spectrum to include generalized epilepsy.","variants":[{"Name":"NM_001013663.2(PTRHD1):c.365G>A (p.Arg122Gln)","Chromosome":"2","Start":"24790469","Stop":"24790469","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222194,"rule_based_match":true,"evidence_text":"c.365G > A, p.(Arg122Gln)","llm_judgment":"PRESENT","evidence":"c.365G > A, p.(Arg122Gln)","abstract_start":598,"abstract_end":623}]}
{"pmid":"30446867","title":"Clinical and molecular characterization of non-syndromic retinal dystrophy due to c.175G>A mutation in ceroid lipofuscinosis neuronal 3 (CLN3).","abstract":"PURPOSE: Mutation of the CLN3 gene, associated with juvenile neuronal ceroid lipofuscinosis, has recently been associated with late-onset, non-syndromic retinal dystrophy. Herein we describe the multimodal imaging, immunological and systemic features of an adult with compound heterozygous CLN3 mutations.\nMETHODS: A 50-year-old female with non-syndromic retinal dystrophy from the age of 36 years underwent multimodal retinal imaging, electroretinography, neuroimaging, immunological studies and genetic testing. CLN3 transcripts were amplified from patient leukocytes by reverse transcriptase polymerase chain reaction and characterized by Sanger sequencing.\nRESULTS: Visual acuity declined to 6/12 and 6/76 due to asymmetrical central scotoma. ERG responses became electronegative and patient's serum contained anti-retinal antibodies. Final visual acuity stabilized at 6/60 bilaterally 3 years after peri-ocular steroid and rituximab infusion. Genetic testing revealed compound heterozygous CLN3 mutations: the 1.02 kb deletion and a novel missense mutation (c.175G>A). In silico, analyses predicted the c.175G>A mutation disrupted an exonic splice enhancer site in exon 3. In patient leukocytes, CLN3 expression was reduced and novel CLN3 transcripts lacking exon 3 were detected.\nCONCLUSIONS: Our case study shows that (1) non-syndromic CLN3 disease leads to rod and delayed primary cone degeneration resulting in constricting peripheral field and enlarging central scotoma and, (2) the c.175G>A CLN3 mutation, altered splicing of the CLN3 gene. Overall, we provide comprehensive clinical characterization of a patient with non-syndromic CLN3 disease.","variants":[{"Name":"NM_001042432.2(CLN3):c.175G>A (p.Ala59Thr)","Chromosome":"16","Start":"28489337","Stop":"28489337","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":927760,"rule_based_match":true,"evidence_text":"c.175G>A","llm_judgment":"PRESENT","evidence":"c.175G>A","abstract_start":1063,"abstract_end":1071}]}
{"pmid":"35695473","title":"A case of G6PD Utrecht associated with β-thalassemia responding to splenectomy.","abstract":"Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disease caused by a pathogenic G6PD mutation. An 8-year-old Chinese male child was investigated because of chronic nonspherocytic hemolytic anemia (CNSHA) associated with hepatosplenomegaly. Genetic analysis unraveled co-inheritance of a hemizygous mutation c.1225C>T (p.Pro409Ser) in G6PD (G6PD Utrecht, previously reported only in The Netherlands) and heterozygote HBB mutation c.316-197C>T (IVS-Ⅱ-654 C>T). Because IVS-Ⅱ-654 C>T on its own does not cause CNSHA, we believe that the clinical manifestations in this patient are essentially due to the G6PD c.1225C>T mutation. The boy gained transfusion independence after splenectomy.","variants":[{"Name":"NM_001360016.2(G6PD):c.1225C>T (p.Pro409Ser)","Chromosome":"X","Start":"154532629","Stop":"154532629","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1780190,"rule_based_match":true,"evidence_text":"c.1225C>T (p.Pro409Ser)","llm_judgment":"PRESENT","evidence":"c.1225C>T (p.Pro409Ser)","abstract_start":333,"abstract_end":356}]}
{"pmid":"20014264","title":"Two patients with EP300 mutations and facial dysmorphism different from the classic Rubinstein-Taybi syndrome.","abstract":"Rubinstein-Taybi syndrome (RTS) is characterized by mental retardation, broad thumbs and great toes and a recognizable craniofacial phenotype. Causative mutations have been described in the CREBBP and EP300 genes. Here we present a 19-year-old woman and an unrelated 3-year-old boy, both with broad thumbs and halluces, but with facial aspects distinct from those of typical RTS. The woman had a marked learning disability, but no mental retardation. We identified a de novo c.7100delC mutation in EP300 (which predicts p.P2366RfsX35) in the woman and an apparently de novo c.638delG mutation in the boy, which predicts p.G213EfsX6. Mutations in EP300 are a known but rare cause of RTS. Only five other patients have been reported. We propose that individuals with EP300 mutations may exhibit a slightly different phenotype compared to individuals with CREBBP mutations, with milder cognitive impairment, more pronounced microcephaly, absent or mild downslanting of palpebral fissures, distinct arched eyebrows, and greater degree of retrognathia.","variants":[{"Name":"NM_001429.4(EP300):c.638del (p.Gly213fs)","Chromosome":"22","Start":"41117728","Stop":"41117728","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":39232,"rule_based_match":true,"evidence_text":"c.638delG","llm_judgment":"PRESENT","evidence":"c.638delG","abstract_start":574,"abstract_end":583}]}
{"pmid":"16819703","title":"Acrodermatitis enteropathica (AE) is caused by mutations in the zinc transporter gene SLC39A4","abstract":"BACKGROUND: Acrodermatitis enteropathica (AE) is an autosomal recessively inherited disease caused by a decreased intestinal zinc resorption and characterized by severe dermatitis (preferably hands, feet, mouth, genital region), chronic diarrhoea, retardation of growth and development, alopecia and increased proneness to infections. In 2002 it was shown that mutations in the zinc transporter gene SLC39A4 is the cause of AE.\nCASE REPORT: Here we report 4 patients with typical clinical signs since early childhood. Under regular substitution with zinc all patients are more or less free of symptoms. The first patient revealed compound-heterozygous missense/nonsense mutations (P200L/ W401X), the three other patients were homozygous for a mutation in intron 1 (c.192 + 19G > A) of the SLC39A4 gene.\nCONCLUSION: The diagnosis of hereditary acrodermatitis enteropathica can now easily be confirmed by mutation analysis of the SLC39A4 gene.","variants":[{"Name":"NM_130849.4(SLC39A4):c.192+19G>A","Chromosome":"8","Start":"144416579","Stop":"144416579","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1380121,"rule_based_match":true,"evidence_text":"c.192 + 19G > A","llm_judgment":"PRESENT","evidence":"c.192 + 19G > A","abstract_start":765,"abstract_end":780}]}
{"pmid":"37377599","title":"Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases.","abstract":"<b>Background:</b> Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed. <b>Methods:</b> Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents. <b>Results:</b> Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides (<i>AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG</i>, and <i>TK2</i>) in 12 patients from nine families and four variants in genes encoding important for muscle structure (<i>CAPN3, DYSF,</i> and <i>TCAP</i>) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes (<i>MT-ATP6</i> and <i>MT-TL1</i>). Nine variants in five genes are reported for the first time with disease association: (<i>AARS2</i>: c.277C>T/p.(R93*), c.845C>G/p.(S282C); <i>EARS2</i>: c.319C>T/p.(R107C), c.1283delC/p.(P428Lfs*); <i>ECHS1</i>: c.161G>A/p.(R54His); c.202G>A/p.(E68Lys); <i>NDUFAF6</i>: c.479delA/p.(N162Ifs*27); and <i>OXCT1</i>: c.1370C>T/p.(T457I), c.1173-139G>T/p.(?). <b>Conclusion:</b> Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene.","variants":[{"Name":"NM_004092.4(ECHS1):c.161G>A (p.Arg54His)","Chromosome":"10","Start":"133370685","Stop":"133370685","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":790950,"rule_based_match":true,"evidence_text":"c.161G>A/p.(R54His)","llm_judgment":"PRESENT","evidence":"c.161G>A/p.(R54His)","abstract_start":1779,"abstract_end":1798},{"Name":"NM_000436.4(OXCT1):c.1370C>T (p.Thr457Ile)","Chromosome":"5","Start":"41749576","Stop":"41749576","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1052976,"rule_based_match":true,"evidence_text":"c.1370C>T/p.(T457I)","llm_judgment":"PRESENT","evidence":"c.1370C>T/p.(T457I)","abstract_start":1881,"abstract_end":1900},{"Name":"NM_000436.4(OXCT1):c.1173-139G>T","Chromosome":"5","Start":"41794217","Stop":"41794217","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1052977,"rule_based_match":true,"evidence_text":"c.1173-139G>T/p.(?)","llm_judgment":"PRESENT","evidence":"c.1173-139G>T/p.(?)","abstract_start":1902,"abstract_end":1921},{"Name":"NM_020745.4(AARS2):c.845C>G (p.Ser282Cys)","Chromosome":"6","Start":"44310348","Stop":"44310348","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1052978,"rule_based_match":true,"evidence_text":"c.845C>G/p.(S282C)","llm_judgment":"PRESENT","evidence":"c.845C>G/p.(S282C)","abstract_start":1686,"abstract_end":1704},{"Name":"NM_020745.4(AARS2):c.277C>T (p.Arg93Ter)","Chromosome":"6","Start":"44312230","Stop":"44312230","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1052979,"rule_based_match":true,"evidence_text":"c.277C>T/p.(R93*)","llm_judgment":"PRESENT","evidence":"c.277C>T/p.(R93*)","abstract_start":1667,"abstract_end":1684},{"Name":"NM_004092.4(ECHS1):c.202G>A (p.Glu68Lys)","Chromosome":"10","Start":"133370644","Stop":"133370644","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2000050,"rule_based_match":true,"evidence_text":"c.202G>A/p.(E68Lys)","llm_judgment":"PRESENT","evidence":"c.202G>A/p.(E68Lys)","abstract_start":1800,"abstract_end":1819},{"Name":"NM_001083614.2(EARS2):c.1283del (p.Pro428fs)","Chromosome":"16","Start":"23529571","Stop":"23529571","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":961566,"rule_based_match":true,"evidence_text":"c.1283delC/p.(P428Lfs*)","llm_judgment":"PRESENT","evidence":"c.1283delC/p.(P428Lfs*)","abstract_start":1740,"abstract_end":1763},{"Name":"NM_001083614.2(EARS2):c.319C>T (p.Arg107Cys)","Chromosome":"16","Start":"23544680","Stop":"23544680","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":961567,"rule_based_match":true,"evidence_text":"c.319C>T/p.(R107C)","llm_judgment":"PRESENT","evidence":"c.319C>T/p.(R107C)","abstract_start":1720,"abstract_end":1738}]}
{"pmid":"24281368","title":"Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy.","abstract":"Isolated metabolic myopathies encompass a heterogeneous group of disorders, with mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness. In this study, we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy. Analysis of enzyme activities of the five respiratory chain complexes in our patients' skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase. We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein. The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria. Fdx2 is the second component of the Fe-S cluster biogenesis machinery, the first being IscU that is associated with isolated mitochondrial myopathy. We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III.","variants":[{"Name":"NM_001397406.1(FDX2):c.1A>T (p.Met1Leu)","Chromosome":"19","Start":"10315996","Stop":"10315996","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":152778,"rule_based_match":true,"evidence_text":"c.1A>T","llm_judgment":"PRESENT","evidence":"c.1A>T","abstract_start":756,"abstract_end":762}]}
{"pmid":"19618435","title":"Clinical and genetic analysis of Korean patients with congenital insensitivity to pain with anhidrosis.","abstract":"Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease characterized by anhidrosis, insensitivity to noxious stimuli, and mental retardation. Mutations in the NTRK1 gene are associated with the pathogenesis of CIPA. In this study, we performed a clinical and genetic analysis on the NTRK1 gene in four Korean patients with CIPA. All patients had typical clinical manifestations of CIPA, including anhidrosis, recurrent fever, absent pain perception, and developmental delay. Sequencing analysis revealed one predominant mutation, c.851-33T>A, in four affected alleles and three novel mutations, including c.287+2dupT, c.2155G>A (p.Glu719Lys), and c.1218delC (p.Pro407ArgfsX), in each affected allele. For one patient, who was heterozygous for c.851-33T>A, another mutation could not be identified, suggesting that a possible hidden intronic or large genomic mutation may have been present. This study extends the spectrum of mutations in the NTRK1 gene and confirms that Korean patients with CIPA have the same genetic background as other ethnicities.","variants":[{"Name":"NM_002529.4(NTRK1):c.851-33T>A","Chromosome":"1","Start":"156873600","Stop":"156873600","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":34160,"rule_based_match":true,"evidence_text":"c.851-33T>A","llm_judgment":"PRESENT","evidence":"c.851-33T>A","abstract_start":569,"abstract_end":580}]}
{"pmid":"22902309","title":"Phenotypic overlap among paroxysmal dyskinesia subtypes: Lesson from a family with PRRT2 gene mutation.","abstract":"Paroxysmal dyskinesia (PD) is a group of rare neurological conditions which was divided into paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD) and paroxysmal exercise-induced dyskinesia (PED) according to their clinical features. PRRT2 gene was initially identified as the major gene responsible for PKD followed by presence of various PRRT2 mutations discovered in families with benign familial infantile convulsions (BFIC) and infantile convulsions and choreoathetosis (ICCA). We describe a family with characteristic PD showing overlaps in clinical pictures among the three PD subgroups, and a nonsense PRRT2 mutation c.649C>T (p.Arg217X) was also detected. This broadens the phenotypic spectrum in PRRT2-related disorders. In addition, an unusual exercise trigger observed in the proband, likely representing an underestimated occurrence, together with the current clinical PD classification is also elucidated.","variants":[{"Name":"NM_145239.3(PRRT2):c.649C>T (p.Arg217Ter)","Chromosome":"16","Start":"29813703","Stop":"29813703","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":466366,"rule_based_match":true,"evidence_text":"c.649C>T (p.Arg217X)","llm_judgment":"PRESENT","evidence":"c.649C>T (p.Arg217X)","abstract_start":657,"abstract_end":677}]}
{"pmid":"25545912","title":"H-ABC syndrome and DYT4: Variable expressivity or pleiotropy of TUBB4 mutations?","abstract":"Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 (\"hereditary whispering dysphonia\"). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations.","variants":[{"Name":"NM_006087.4(TUBB4A):c.900G>T (p.Met300Ile)","Chromosome":"19","Start":"6495599","Stop":"6495599","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":263160,"rule_based_match":true,"evidence_text":"c.900G>T (p.Met300Ile)","llm_judgment":"PRESENT","evidence":"p.Met300Ile","abstract_start":1235,"abstract_end":1246},{"Name":"NM_006087.4(TUBB4A):c.941C>T (p.Ala314Val)","Chromosome":"19","Start":"6495558","Stop":"6495558","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":263159,"rule_based_match":true,"evidence_text":"c.941C>T; p.Ala314Val","llm_judgment":"PRESENT","evidence":"c.941C>T; p.Ala314Val","abstract_start":1199,"abstract_end":1220}]}
{"pmid":"31183366","title":"Whole-Exome Sequencing Identified a Novel Compound Heterozygous Genotype in","abstract":"Pathogenic variants in the argininosuccinate lyase (<i>ASL</i>) gene have been shown to cause argininosuccinate lyase deficiency (ASLD); therefore, sequencing analysis offers advantages for prenatal testing and counseling in families afflicted with this condition. Here, we performed a genetic analysis of an ASLD patient and his family with an aim to offer available information for clinical diagnosis. The research subjects were a 23-month-old patient with a high plasma level of citrulline and his unaffected parents. Whole-exome sequencing identified potential related <i>ASL</i> gene mutations in this trio. Enzymatic activity was detected spectrophotometrically by a coupled assay using arginase and measuring urea production. We identified a novel nonsynonymous mutation (c.206A>G, p.Lys69Arg) and a stop mutation (c.637C>T, p.Arg213∗) in <i>ASL</i> in a Chinese Han patient with ASLD. The enzymatic activity of a p.Lys69Arg ASL construct in human embryonic kidney 293T cells was significantly reduced compared to that of the wild-type construct, and no significant activity was observed for the p.Arg213∗ construct. Compound heterozygous p.Lys69Arg and p.Arg213∗ mutations that resulted in reduced ASL enzyme activity were found in a patient with ASLD. This finding expands the clinical spectrum of ASL pathogenic variants.","variants":[{"Name":"NM_000048.4(ASL):c.637C>T (p.Arg213Ter)","Chromosome":"7","Start":"66087368","Stop":"66087368","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":415107,"rule_based_match":true,"evidence_text":"c.637C>T (p.Arg213∗)","llm_judgment":"PRESENT","evidence":"c.637C>T","abstract_start":822,"abstract_end":830}]}
{"pmid":"38130397","title":"","abstract":"Context: A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the <i>GCM2</i> [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ).\nObjective: To evaluate the presence of the <i>GCM2</i> p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management.\nMethod: Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the <i>GCM2</i> p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database.\nResults: A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight <i>CASR</i> and two <i>AP2S1</i> mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the <i>GCM2</i> p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the <i>GCM2</i> p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the <i>GCM2</i> p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%.\nConclusion: In contrast to previous observations, the <i>GCM2</i> p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.","variants":[{"Name":"NM_004752.4(GCM2):c.1181A>C (p.Tyr394Ser)","Chromosome":"6","Start":"10874335","Stop":"10874335","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":298705,"rule_based_match":true,"evidence_text":"(NM_ 004752.4) c.1181A> C; p.Tyr394Ser","llm_judgment":"PRESENT","evidence":"(NM_ 004752.4) c.1181A> C; p.Tyr394Ser","abstract_start":159,"abstract_end":197}]}
{"pmid":"33746036","title":"Alkaptonuria in Turkey: Clinical and molecular characteristics of 66 patients.","abstract":"Alkaptonuria (AKU) is an inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase (HGD) as a result of a defect in the HGD gene. HGD enzyme deficiency results in accumulation of homogentisic acid (HGA) in the body, which in turn leads to multisystemic clinical symptoms. The present study aimed to investigate the presenting symptoms, age at diagnosis, and clinical and genetic characteristics of AKU patients followed-up in different centers in Turkey. In this cross-sectional, multicenter, descriptive study, medical records of 66 AKU patients were retrospectively evaluated. Patients' data regarding demographic, clinical and genetic characteristics were recorded. HGD database (http://hgddatabase.cvtisr.sk/) was used to identify HGD gene variants. Of the patients, 37 (56.1%) presented with isolated dark urine and 29 (43.9%) were diagnosed based on the clinical symptoms or family screening. One of these patients was on follow-up for 2 years due to Parkinsonism and was diagnosed with AKU on further analyses. Signs of ochronosis such as joint pain, low back pain and renal stones developed in childhood in 7 patients. Eight patients were diagnosed with depression via psychiatric evaluation. There were 14 (21.2%) patients operated on for ochronosis. The most frequent mutation observed in the patients was c.175delA, which was followed by c.674G > A and c.1007-2A > T mutations. Four novel mutations (c.189G > A, c.549+1G > T, c.1188+1G > A, and c.334 T > G) were identified in the patients included in the study. In addition to the known signs such as dark urine and skin pigmentation, symptoms involving different systems such as neurological findings and depression can also be encountered in AKU patients. The presence of a change in urine color needs to be questioned in patients presenting with different symptoms such as arthralgia/arthritis, renal stones or low-back pain, particularly in childhood, when skin ochronosis is not pronounced, and further examination should be performed.","variants":[{"Name":"NM_000187.4(HGD):c.549+1G>T","Chromosome":"3","Start":"120646972","Stop":"120646972","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2752330,"rule_based_match":true,"evidence_text":"c.549+1G>T","llm_judgment":"PRESENT","evidence":"c.549+1G > T","abstract_start":1450,"abstract_end":1462},{"Name":"NM_000187.4(HGD):c.334T>G (p.Phe112Val)","Chromosome":"3","Start":"120652600","Stop":"120652600","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2794354,"rule_based_match":true,"evidence_text":"c.334 T > G","llm_judgment":"PRESENT","evidence":"c.334 T > G","abstract_start":1483,"abstract_end":1494}]}
{"pmid":"18485777","title":"PNPO deficiency: an under diagnosed inborn error of pyridoxine metabolism.","abstract":"The rare autosomal recessive disorder pyridoxine 5'-phosphate oxidase (PNPO) deficiency is a recently described cause of neonatal and infantile seizures. Clinical evaluation, and biochemical and genetic testing, were performed on a neonate with intractable seizures who did not respond to anticonvulsant drugs and pyridoxine. Sequencing of the PNPO gene revealed a novel homozygous c.284G>A transition in exon 3, resulting in arginine to histidine substitution and reduced activity of the PNPO mutant to 18% relative to the wild type. This finding enabled molecular prenatal diagnosis in a subsequent pregnancy, accurate genetic counseling in the large inbred family, and population screening.","variants":[{"Name":"NM_018129.4(PNPO):c.284G>A (p.Arg95His)","Chromosome":"17","Start":"47944636","Stop":"47944636","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":845554,"rule_based_match":true,"evidence_text":"c.284G>A","llm_judgment":"PRESENT","evidence":"c.284G>A","abstract_start":382,"abstract_end":390}]}
{"pmid":"36894310","title":"Comprehensive laboratory diagnosis of Fanconi anaemia: comparison of cellular and molecular analysis.","abstract":"BACKGROUND: Fanconi anaemia (FA) is a rare inherited bone marrow failure disease caused by germline pathogenic variants in any of the 22 genes involved in the FA-DNA interstrand crosslink (ICL) repair pathway. Accurate laboratory investigations are required for FA diagnosis for the clinical management of the patients. We performed chromosome breakage analysis (CBA), FANCD2 ubiquitination (FANCD2-Ub) analysis and exome sequencing of 142 Indian patients with FA and evaluated the efficiencies of these methods in FA diagnosis.\nMETHODS: We performed CBA and FANCD2-Ub analysis in the blood cells and fibroblasts of patients with FA. Exome sequencing with improved bioinformatics to detect the single number variants and CNV was carried out for all the patients. Functional validation of the variants with unknown significance was done by lentiviral complementation assay.\nRESULTS: Our study showed that FANCD2-Ub analysis and CBA on peripheral blood cells could diagnose 97% and 91.5% of FA cases, respectively. Exome sequencing identified the FA genotypes consisting of 45 novel variants in 95.7% of the patients with FA. <i>FANCA</i> (60.2%), <i>FANCL</i> (19.8%) and <i>FANCG</i> (11.7%) were the most frequently mutated genes in the Indian population. A <i>FANCL</i> founder mutation c.1092G>A; p.K364=was identified at a very high frequency (~19%) in our patients.\nCONCLUSION: We performed a comprehensive analysis of the cellular and molecular tests for the accurate diagnosis of FA. A new algorithm for rapid and cost-effective molecular diagnosis for~90% of FA cases has been established.","variants":[{"Name":"NM_018062.4(FANCL):c.1092G>A (p.Lys364=)","Chromosome":"2","Start":"58160108","Stop":"58160108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":918140,"rule_based_match":true,"evidence_text":"c.1092G>A; p.K364=","llm_judgment":"PRESENT","evidence":"c.1092G>A; p.K364=","abstract_start":1289,"abstract_end":1307}]}
{"pmid":"37580814","title":"A novel PRKDC mutation caused B lymphocytes V(D)J rearrangement disorder in the SLE-DAH like symptoms patient.","abstract":"BACKGROUND: Analyzed the clinical features and treatment process of the patient suffering from immunodeficiency with systemic lupus erythematosus(SLE)-like syndrome in a novel mutation of PRKDC.\nCASE PRESENTATION: The patient had multiple positive auto-antibodies, chest CT and bronchoscopy showed Diffuse alveolar hemorrhage(DAH), and psychiatric symptoms showed brain atrophy by magnetic resonance imaging (MRI). Whole exon sequencing showed that novel complex heterozygous mutations of PRKDC gene (C. 1777 - 710_1777-709INSA (IVS16/IC16), C.1337T > A(p.Phe446Tyr). The mature B cell (CD19 + CD27 + CD38 dimIgD IgM-) were absent. The treatment of high-dose methylprednisolone (MP) and cyclophosphamide(CTX) can quickly relieve the symptoms of the patient.\nCONCLUSION: We described the case of an infant immunodeficiency with SLE like-syndrome, which may cause by PRKDC mutation, treated successfully with high-dose MP and CTX.","variants":[{"Name":"NM_006904.7(PRKDC):c.1337T>A (p.Phe446Tyr)","Chromosome":"8","Start":"47935842","Stop":"47935842","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":458481,"rule_based_match":true,"evidence_text":"c.1337T>A(p.Phe446Tyr)","llm_judgment":"PRESENT","evidence":"C.1337T > A(p.Phe446Tyr)","abstract_start":542,"abstract_end":566}]}
{"pmid":"31567691","title":"TCIRG1 Transgenic Rescue of Osteoclast Function Using Induced Pluripotent Stem Cells Derived from Patients with Infantile Malignant Autosomal Recessive Osteopetrosis.","abstract":"BACKGROUND: Osteoclasts are hematopoietic stem cell-derived multinucleated cells necessary for bone remodeling and resorption. TCIRG1 encodes a protein that is an adenosine triphosphate (ATP)-dependent vacuolar proton pump required for this process. Recessive loss-of-function mutations in both copies of this gene lead to impairment of osteoclast function, with increased bone density, increased skeletal mass, and early mortality.\nMETHODS: We isolated fibroblasts from a patient with the compound heterozygous TCIRG1 mutations c.1549G>A (p.517D>N) and c.2236C>T (p.746Q>X), and reprogrammed them into iPS (induced pluripotent stem) cells. The function of osteoclasts derived from these cells was then rescued by transgenic expression of TCIRG1 cDNA.\nRESULTS: In addition to the known effects of TCIRG1 loss of function, iPS cell-derived osteoclasts from this patient had reduced expression of the bone remodeling enzymes cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP), leading to reduced in vitro bone remodeling. Expression of both genes and pit formation were restored in iPS cell-derived osteoclasts following transgenic restoration of TCIRG1 expression.\nCONCLUSIONS: Transgenic overexpression of TCIRG1 was sufficient to restore osteoclast function in iPS cell-derived osteoclasts from a patient with infantile malignant autosomal-recessive osteopetrosis.\nCLINICAL RELEVANCE: This work provides a proof of concept for an autologous approach to treating osteopetrosis, potentially avoiding the risks associated with hematopoietic stem cell transplantation in a young patient population.","variants":[{"Name":"NM_006019.4(TCIRG1):c.1549G>A (p.Asp517Asn)","Chromosome":"11","Start":"68047967","Stop":"68047967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":963283,"rule_based_match":true,"evidence_text":"c.1549G>A (p.517D>N)","llm_judgment":"PRESENT","evidence":"c.1549G>A (p.517D>N)","abstract_start":529,"abstract_end":549}]}
{"pmid":"24052401","title":"Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease-like phenotype with multicystic leucodystrophy.","abstract":"Defects in dystroglycan post-translational modification result in congenital muscular dystrophy with or without additional eye and brain involvement, are referred to as secondary dystroglycanopathies and have been associated with mutations in 11 different genes encoding glycosyltransferases or associated proteins. However, only one patient with a mutation in the dystroglycan encoding gene DAG1 itself has been described before. We here report a homozygous novel DAG1 missense mutation c.2006G>T predicted to result in the amino acid substitution p.Cys669Phe in the β-subunit of dystroglycan in two Libyan siblings. The affected girls presented with a severe muscle-eye-brain disease-like phenotype with distinct additional findings of macrocephaly and extended bilateral multicystic white matter disease, overlapping with the cerebral findings in patients with megalencephalic leucoencephalopathy with subcortical cysts. This novel clinical phenotype observed in our patients further expands the clinical spectrum of dystroglycanopathies and suggests a role of DAG1 not only for dystroglycanopathies but also for some forms of more extensive and multicystic leucodystrophy.","variants":[{"Name":"NM_004393.6(DAG1):c.2006G>T (p.Cys669Phe)","Chromosome":"3","Start":"49532517","Stop":"49532517","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":205059,"rule_based_match":true,"evidence_text":"c.2006G>T","llm_judgment":"PRESENT","evidence":"c.2006G>T","abstract_start":488,"abstract_end":497}]}
{"pmid":"19830424","title":"Familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3.","abstract":"OBJECTIVE: To report on the biochemistry and clinical and genetic findings of two siblings, the younger sister presenting with recurrent bone pain of the radius and ulna, and medullary sclerosis, and the older brother with soft tissue calcific deposits (tumoral calcinosis) but who later developed bone pain. Both were found to be hyperphosphaturic.\nMATERIALS AND METHODS: The index family comprised four individuals (father, mother, brother, sister). The affected siblings were the offspring of a non-consanguineous Indian family of Tamil origin. Bidirectional sequencing was performed on the DNA from the index family and on 160 alleles from a population of 80 unrelated unaffected control individuals of Tamil extraction and 72 alleles from individuals of non-Tamil origin.\nRESULTS: Two symptomatic siblings were found to harbour previously unreported compound heterozygous missense UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3) mutations in exon 4 c.842A>G and exon 5 c.1097T>G. This sequence variation was not detected in the control DNA. This is the first report of siblings exhibiting stigmata of familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome with documented evidence of autosomal recessive missense GALNT3 mutations.\nCONCLUSION: The findings from this family add further evidence to the literature that familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are manifestations of the same disease and highlight the importance of appropriate metabolic and genetic investigations.","variants":[{"Name":"NM_004482.4(GALNT3):c.1097T>G (p.Leu366Arg)","Chromosome":"2","Start":"165758841","Stop":"165758841","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3021923,"rule_based_match":true,"evidence_text":"c.1097T>G","llm_judgment":"PRESENT","evidence":"c.1097T>G","abstract_start":1033,"abstract_end":1042},{"Name":"NM_004482.4(GALNT3):c.842A>G (p.Glu281Gly)","Chromosome":"2","Start":"165759567","Stop":"165759567","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2898621,"rule_based_match":true,"evidence_text":"c.842A>G","llm_judgment":"PRESENT","evidence":"c.842A>G","abstract_start":1013,"abstract_end":1021}]}
{"pmid":"32439808","title":"Mutation in the MICOS subunit gene","abstract":"BACKGROUND: Mitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) complex is known as the 'mitoskeleton' due to its role in maintaining IMM architecture. <i>APOO</i> encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated.\nMETHODS: We have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in <i>APOO</i>. Knockout models in <i>Drosophila melanogaster</i> and <i>Saccharomyces cerevisiae</i> were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.\nRESULTS: A likely pathogenic c.350T>C transition was found in <i>APOO</i> predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and <i>D. melanogaster</i> models.\nCONCLUSION: This is the first case of pathogenic mutation in <i>APOO</i>, causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.","variants":[{"Name":"NM_024122.5(APOO):c.350T>C (p.Ile117Thr)","Chromosome":"X","Start":"23868631","Stop":"23868631","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":964792,"rule_based_match":true,"evidence_text":"c.350T>C","llm_judgment":"PRESENT","evidence":"c.350T>C","abstract_start":1175,"abstract_end":1183}]}
{"pmid":"25597651","title":"Spontaneous ruptured dissection of the right common iliac artery in a patient with classic Ehlers-Danlos syndrome phenotype.","abstract":"Unlike vascular Ehlers-Danlos syndrome (EDS), classic EDS is rarely associated with vascular manifestation. We report the case of a 39-year-old man who presented with acute abdominal pain. At the time of presentation, the patient was in hypovolemic shock, and computed tomography angiogram demonstrated common iliac artery dissection with rupture. He underwent an attempted endovascular repair that was converted to an open repair of a ruptured right common iliac artery dissection. Subsequent genetic testing revealed a substitution of arginine for cysteine in type I collagen, COL1A1 exon 14 c.934C>T mutation, consistent with a rare variant of classic EDS.","variants":[{"Name":"NM_000088.4(COL1A1):c.934C>T (p.Arg312Cys)","Chromosome":"17","Start":"50196337","Stop":"50196337","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32382,"rule_based_match":true,"evidence_text":"c.934C>T","llm_judgment":"PRESENT","evidence":"c.934C>T","abstract_start":594,"abstract_end":602}]}
{"pmid":"35756861","title":"A novel","abstract":"Mitochondrial DNA (mtDNA) depletion syndromes are disorders characterized by infantile-onset, severe progression, and the drastic loss of mtDNA content in affected tissues. In a patient who showed severe hypotonia, proximal tubulopathy and sensorineural hearing loss after birth, we observed severe mtDNA depletion and impaired respiratory chain activity in muscle due to heterozygous variants c.686G > T and c.551-2A > G in <i>RRM2B,</i> encoding the p53R2 subunit of the ribonucleotide reductase.","variants":[{"Name":"NM_015713.5(RRM2B):c.686G>T (p.Gly229Val)","Chromosome":"8","Start":"102214157","Stop":"102214157","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":20431,"rule_based_match":true,"evidence_text":"c.686G > T","llm_judgment":"PRESENT","evidence":"c.686G > T","abstract_start":394,"abstract_end":404}]}
{"pmid":"22319038","title":"Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia.","abstract":"CONTEXT: Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain.\nOBJECTIVE: The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins.\nDESIGN AND PARTICIPANTS: A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in genes implicated in the etiology of KS (FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro.\nRESULTS: Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C>T, p.T112T). One patient had a synonymous change in FGF8 (c.216G>A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in PROKR2 (p.R85G, p.R85H, p.R268C).\nCONCLUSIONS: Mutations in FGFR1/FGF8/PROKR2 contributed to 7.8% of our patients with CPHD/SOD. These data suggest a significant genetic overlap between conditions affecting the development of anterior midline in the human forebrain.","variants":[{"Name":"NM_023110.3(FGFR1):c.1349C>T (p.Ser450Phe)","Chromosome":"8","Start":"38418309","Stop":"38418309","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1293359,"rule_based_match":false,"evidence_text":"p.S450F","llm_judgment":"PRESENT","evidence":"p.S450F","abstract_start":724,"abstract_end":731},{"Name":"NM_144773.4(PROKR2):c.802C>T (p.Arg268Cys)","Chromosome":"20","Start":"5302393","Stop":"5302393","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":266582,"rule_based_match":false,"evidence_text":"p.R268C","llm_judgment":"PRESENT","evidence":"p.R268C","abstract_start":1043,"abstract_end":1050}]}
{"pmid":"21109228","title":"Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy.","abstract":"Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of inherited muscular disorders manifesting symmetric, proximal, and slowly progressive muscle weakness. Using Affymetrix 250K SNP Array genotyping and homozygosity mapping, we mapped an autosomal-recessive LGMD phenotype to the telomeric portion of chromosome 8q in a consanguineous Turkish family with three affected individuals. DNA sequence analysis of PLEC identified a homozygous c.1_9del mutation containing an initiation codon in exon 1f, which is an isoform-specific sequence of plectin isoform 1f. The same homozygous mutation was also detected in two additional families during the analysis of 72 independent LGMD2-affected families. Moreover, we showed that the expression of PLEC was reduced in the patient's muscle and that there was almost no expression for plectin 1f mRNA as a result of the mutation. In addition to dystrophic changes in muscle, ultrastructural alterations, such as membrane duplications, an enlarged space between the membrane and sarcomere, and misalignment of Z-disks, were observed by transmission electron microscopy. Unlike the control skeletal muscle, no sarcolemmal staining of plectin was detected in the patient's muscle. We conclude that as a result of plectin 1f deficiency, the linkage between the sarcolemma and sarcomere is broken, which could affect the structural organization of the myofiber. Our data show that one of the isoforms of plectin plays a key role in skeletal muscle function and that disruption of the plectin 1f can cause the LGMD2 phenotype without any dermatologic component as was previously reported with mutations in constant exons of PLEC.","variants":[{"Name":"NM_201378.4(PLEC):c.1_9del (p.Met1_Gly3del)","Chromosome":"8","Start":"143973464","Stop":"143973472","ReferenceAlleleVCF":"GGCCGGCCAT","AlternateAlleleVCF":"G","allel_id":39127,"rule_based_match":true,"evidence_text":"c.1_9del","llm_judgment":"PRESENT","evidence":"c.1_9del","abstract_start":461,"abstract_end":469}]}
{"pmid":"29989513","title":"A novel SLC1A4 homozygous mutation causing congenital microcephaly, epileptic encephalopathy and spastic tetraparesis: a video-EEG and tractography - case study.","abstract":"Biallelic mutations in the SLC1A4 gene have been identified as a very rare cause of neurodevelopmental disorders. l-serine transport deficiency has been regarded as the causal molecular mechanism underlying the neurological phenotype of SLC1A4 mutation patients. To date this genetic condition has been reported almost exclusively in a limited number of Ashkenazi-Jewish individuals and as a result the SLC1A4 gene is not routinely included in the majority of the genetic diagnostic panels for neurological diseases. We hereby report a 7-year-old boy from a Southern Italian family, presenting with epileptic encephalopathy, congenital microcephaly, global developmental delay, severe hypotonia, spasticity predominant at the lower limbs, and thin corpus callosum. Whole exome sequencing identified a novel segregating SLC1A4 gene homozygous mutation (c.1141G > A: p.Gly381Arg) as the likely cause of the disease in our family. In order to deeply characterize the electro-clinical and neurological phenotype in our index patient, long-term systematic video-electroencephalograms (EEG) as well as repeated brain imaging studies (which included tractographic reconstructions) were performed on a regular basis during a 7 years follow-up time. In conclusion, we suggest to carefully considering SLC1A4 biallelic mutations in individuals presenting an early onset severe neurodevelopmental disorder with variable spasticity and seizures, regardless the patients' ethnic background.","variants":[{"Name":"NM_003038.5(SLC1A4):c.1141G>A (p.Gly381Arg)","Chromosome":"2","Start":"65018177","Stop":"65018177","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":920467,"rule_based_match":true,"evidence_text":"c.1141G > A: p.Gly381Arg","llm_judgment":"PRESENT","evidence":"c.1141G > A: p.Gly381Arg","abstract_start":852,"abstract_end":876}]}
{"pmid":"29269672","title":"Prominent Tendon Xanthomas and Abdominal Aortic Aneurysm Associated with Cerebrotendinous Xanthomatosis Identified Using Whole Exome Sequencing.","abstract":"A 63-year-old man was hospitalized due to an abdominal pulsatile mass. Computed tomography revealed a saccular type abdominal aortic aneurysm, the diameter of which was 52 mm. A physical examination revealed prominent Achilles tendon thickness and plantar xanthomas. He was born in a family of consanguineous marriage, where his parents were second cousins. He had no familial history of high low-density lipoprotein cholesterol, tendon xanthomas, or premature atherosclerosis. Whole-exome sequencing assuming recessive inheritance determined his genetic diagnosis to be cerebrotendinous xanthomatosis caused by homozygous mutations (c.410G>A or p.Arg137Gln) in the cytochrome P450 subfamily 27 A1 (CYP27A1) gene.","variants":[{"Name":"NM_000784.4(CYP27A1):c.410G>A (p.Arg137Gln)","Chromosome":"2","Start":"218809731","Stop":"218809731","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76837,"rule_based_match":true,"evidence_text":"c.410G>A or p.Arg137Gln","llm_judgment":"PRESENT","evidence":"c.410G>A or p.Arg137Gln","abstract_start":634,"abstract_end":657}]}
{"pmid":"35418825","title":"Bi-Allelic c.1746G>T; p.Leu582= Variants in","abstract":"Bi-allelic mutations in the <i>TUBGCP4</i> gene have been recently associated with autosomal recessive microcephaly with chorioretinopathy. However, little is known about the genotype-phenotype characteristics of this disorder. Here, we describe a 5-year-old male patient with autism and a normal occipitofrontal circumference. No retinal abnormalities were observed. Brain MRI revealed the presence of enlarged sheaths of both tortuous optic nerves; both eyes had shorter axial lengths. Whole-exome sequencing in trio revealed synonymous <i>TUBGCP4</i> variants in homozygous state: c.1746G>T; p.Leu582=. This synonymous variant has been previously described and probably leads to skipping of exon 16 of <i>TUBGCP4</i>. These results broaden the clinical spectrum of this new syndrome and suggest that <i>TUBGCP4</i> bi-allelic mutations may underlie complex neurodevelopmental disorders.","variants":[{"Name":"NM_014444.5(TUBGCP4):c.1746G>T (p.Leu582=)","Chromosome":"15","Start":"43403697","Stop":"43403697","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":187955,"rule_based_match":true,"evidence_text":"c.1746G>T; p.Leu582=","llm_judgment":"PRESENT","evidence":"c.1746G>T; p.Leu582=","abstract_start":584,"abstract_end":604}]}
{"pmid":"26578240","title":"Neuroblastoma Amplified Sequence (NBAS) mutation in recurrent acute liver failure: Confirmatory report in a sibship with very early onset, osteoporosis and developmental delay.","abstract":"BACKGROUND: Recently, biallelic mutations in the Neuroblastoma Amplified Sequence NBAS gene have been identified in ten patients that present recurrent acute liver failure (RALF) in early infancy. In addition to severe liver dysfunction, some of these individuals also suffered from other comorbidities including cardiomyopathy, neurologic phenotypes and gastrointestinal immune defects. Here we report on a consanguineous Lebanese family with three siblings affected by RALF. Of note, neonatal spontaneous fractures, developmental delay, prominent eyes, generalized hirsutism, gum hypertrophy, and hepato-splenomegaly ​were also present.\nMETHODS: Whole-genome SNP genotyping in all the patients, followed by exome sequencing was performed in one of the affected siblings.\nRESULTS: A homozygous c.409C > T (p.Arg137Trp) missense mutation in NBAS was identified in all patients.\nCONCLUSION: Overall, our findings confirm the involvement of NBAS in the pathogenesis of this condition characterized by severe liver dysfunction and help expand its phenotypical spectrum.","variants":[{"Name":"NM_015909.4(NBAS):c.409C>T (p.Arg137Trp)","Chromosome":"2","Start":"15539327","Stop":"15539327","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":215173,"rule_based_match":true,"evidence_text":"c.409C > T (p.Arg137Trp)","llm_judgment":"PRESENT","evidence":"c.409C > T (p.Arg137Trp)","abstract_start":795,"abstract_end":819}]}
{"pmid":"27308839","title":"Newborn genetic screening for hearing impairment: a population-based longitudinal study.","abstract":"PURPOSE: The feasibility of genetic screening for deafness-causing mutations in newborns has been reported in several studies. The aim of this study was to investigate the long-term results in those who screened positive for deafness mutations; these results are crucial to determine the cost-effectiveness to justify population-wide genetic screening.\nMETHODS: We performed simultaneous hearing screening and genetic screening targeting four common deafness mutations (p.V37I and c.235delC of GJB2, c.919-2A>G of SLC26A4, and the mitochondrial m.1555A>G) in 5173 newborns at a tertiary hospital between 2009 and 2015. Serial audiometric results up to 6 years old were then analyzed in children with conclusive genotypes.\nRESULTS: Newborn genetic screening identified 82 (1.6%) babies with conclusive genotypes, comprising 62 (1.2%) with GJB2 p.V37I/p.V37I, 16 (0.3%) with GJB2 p.V37I/c.235delC, and 4 (0.1%) with m.1555A>G. Of these, 46 (56.1%) passed hearing screening at birth. Long-term follow-up demonstrated progressive hearing loss in children with the GJB2 p.V37I/p.V37I and p.V37I/c.235delC genotypes; this hearing loss deteriorated by approximately 1 decibel hearing level (dBHL) per year.\nCONCLUSIONS: We delineated the longitudinal auditory features of the highly prevalent GJB2 p.V37I mutation on a general population basis and confirmed the utility of newborn genetic screening in identifying infants with late-onset or progressive hearing impairment undetectable by newborn hearing screening.Genet Med 19 1, 6-12.","variants":[{"Name":"NM_004004.6(GJB2):c.109G>A (p.Val37Ile)","Chromosome":"13","Start":"20189473","Stop":"20189473","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32062,"rule_based_match":false,"evidence_text":"p.V37I","llm_judgment":"PRESENT","evidence":"p.V37I","abstract_start":470,"abstract_end":476}]}
{"pmid":"24814856","title":"Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage.","abstract":"Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive cerebellar ataxia associated with mutations in SETX, which encodes the senataxin protein, a DNA/RNA helicase. We describe the clinical phenotype and molecular characterization of a Colombian AOA2 patient who is compound heterozygous for a c.994 C>T (p.R332W) missense mutation in exon 7 and a c.6848_6851delCAGA (p.T2283KfsX32) frameshift deletion in SETX exon 21. Immunocytochemistry of patient-derived fibroblasts revealed a normal cellular distribution of the senataxin protein, suggesting that these mutations do not lead to loss or mis-localization of the protein, but rather that aberrant function of senataxin underlies the disease pathogenesis. Furthermore, we used the alkaline comet assay to demonstrate that patient-derived fibroblast cells exhibit an increased susceptibility to oxidative DNA damage. This assay provides a novel and additional means to establish pathogenicity of SETX mutations.","variants":[{"Name":"NM_015046.6(SETX):c.6848_6851delCAGA","Chromosome":"9","Start":"132277144","Stop":"132277147","ReferenceAlleleVCF":"TTCTG","AlternateAlleleVCF":"T","allel_id":101565,"rule_based_match":true,"evidence_text":"c.6848_6851delCAGA (p.T2283KfsX32)","llm_judgment":"PRESENT","evidence":"c.6848_6851delCAGA (p.T2283KfsX32)","abstract_start":364,"abstract_end":398}]}
{"pmid":"28350539","title":"Personalized precision medicine in extreme preterm infants with transient neonatal diabetes mellitus.","abstract":"Although hyperglycemia is common in neonates, especially preterm infants, a diagnosis of neonatal diabetes mellitus (NDM) is rarely made. NDM can be permanent (45%), transient (45%) or syndromic (10%). Of the 95% of identifiable mutations for NDM, methylation defects in 6q24, KCNJ11, ABCC8, and INS account for the majority. Two cases of transient NDM in extremely preterm, 24 weeks' gestational age (GA) triplets, due to a missense mutation c.685G>A in the KCNJ11 gene are presented. Both patients were successfully transitioned from insulin to Glyburide (Glibenclamide) at 2 months of age. Comprehensive genetic testing with targeted next-generation sequencing and 6q24 methylation analysis helps identify monogenic diabetes early, thereby improving metabolic and glycemic control when patients with potassium channel mutations are started on sulfonylurea (SU) treatment.","variants":[{"Name":"NM_000525.4(KCNJ11):c.685G>A (p.Glu229Lys)","Chromosome":"11","Start":"17387407","Stop":"17387407","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":168868,"rule_based_match":true,"evidence_text":"c.685G>A","llm_judgment":"PRESENT","evidence":"c.685G>A","abstract_start":443,"abstract_end":451}]}
{"pmid":"32810830","title":"Generation of two induced pluripotent stem cell lines from a patient with Stargardt Macular Dystrophy caused by the c.768G>T and c.6079C>T mutations in ABCA4.","abstract":"Autosomal recessive Stargardt disease is the most common cause of inherited retinal disease. In this report, we describe the generation and characterization of two human induced pluripotent stem cell (iPSC) lines from a patient with compound heterozygous mutations in the ABCA4 gene (c.[768G>T];[6079C>T]). Patient dermal fibroblasts were reprogrammed using episomal plasmids encoding OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for P53. The clonal iPSC lines LEIi012-A and LEIi012-B were established. Both lines had a normal karyotype, displayed iPSC morphology, expressed pluripotency genes at similar levels to control iPSC and displayed trilineage differentiation potential during embryoid body differentiation.","variants":[{"Name":"NM_000350.3(ABCA4):c.6079C>T (p.Leu2027Phe)","Chromosome":"1","Start":"94005509","Stop":"94005509","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22921,"rule_based_match":true,"evidence_text":"c.6079C>T","llm_judgment":"PRESENT","evidence":"c.6079C>T","abstract_start":null,"abstract_end":null},{"Name":"NM_000350.3(ABCA4):c.768G>T (p.Val256=)","Chromosome":"1","Start":"94098794","Stop":"94098794","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":105394,"rule_based_match":true,"evidence_text":"c.768G>T","llm_judgment":"PRESENT","evidence":"c.[768G>T","abstract_start":284,"abstract_end":293}]}
{"pmid":"22876553","title":"The earlier described mutation (c.307c > T [p.R103X]) in the SRD5A2 gene causing a 46,XY female phenotype.","abstract":"Deletions and mutations in the 5-alpha-reductase type 2 (SRD5A2) gene have been identified in 46,XY disorders of sexual differentiation (DSD). The clinical spectrum is heterogeneous, varying from a normal female external genital appearance to clitoromegaly and isolated micropenis or microphallus associated with hypospadias of various degrees. We describe a 46,XY DSD patient with a homozygous c.307C>T (p.R103X) mutation in the SRD5A2 gene. The case presented with a normal female external genital phenotype.","variants":[{"Name":"NM_000348.4(SRD5A2):c.307C>T (p.Arg103Ter)","Chromosome":"2","Start":"31533741","Stop":"31533741","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":85484,"rule_based_match":true,"evidence_text":"c.307C>T (p.R103X)","llm_judgment":"PRESENT","evidence":"c.307C>T (p.R103X)","abstract_start":395,"abstract_end":413}]}
{"pmid":"30556349","title":"A homozygous canonical splice acceptor site mutation in PRUNE1 is responsible for a rare childhood neurodegenerative disease in Manitoba Cree families.","abstract":"Autosomal recessive PRUNE1 mutations are reported to cause a severe neurodevelopmental disorder with microcephaly, hypotonia, and brain malformations. We describe clinical and neuropathological features in a cohort of nine individuals of Cree descent who, because of a founder effect, are homozygous for the same PRUNE1 mutation. They follow the course of a combined neuromuscular and neurodegenerative disease, rather than a pure failure of normal development. This cohort presented in infancy with features of lower motor neuron disease, such as hypotonia, contractures, tongue fasciculations, and feeding difficulties in the absence of congenital brain anomalies and microcephaly. A neurodegenerative course followed with onset of seizures, spasticity, and respiratory insufficiency. Muscle biopsies showed denervation/reinnervation features, nonspecific atrophy and end-stage atrophy. Autopsy findings in two patients are also described, suggesting length dependent central motor axon degeneration, peripheral motor axon degeneration, possible spinal motor neuron degeneration, and accumulation of beta amyloid precursor protein inclusions in select brainstem nuclei. Exome sequencing and homozygosity mapping identified a homozygous PRUNE1 mutation in a canonical splice site, which produces two abnormal PRUNE1 mRNA products. Based on our studies and the histopathology and phenotypic data, we provide further evidence that this disorder leads to a neurodegenerative disease affecting both the peripheral and central nervous systems and suggest that the pathogenic c.521-2A>G mutation could lead to an altered effect on tubulin dynamics.","variants":[{"Name":"NM_021222.3(PRUNE1):c.521-2A>G","Chromosome":"1","Start":"151025513","Stop":"151025513","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":259624,"rule_based_match":true,"evidence_text":"c.521-2A>G","llm_judgment":"PRESENT","evidence":"c.521-2A>G","abstract_start":1571,"abstract_end":1581}]}
{"pmid":"28085675","title":"Glycogen storage disease type IX and growth hormone deficiency presenting as severe ketotic hypoglycemia.","abstract":"BACKGROUND: Glycogen storage disease (GSD) type IX and growth hormone (GH) deficiency cause ketotic hypoglycemia via different mechanisms and are not known to be associated. We describe a patient presenting with severe ketotic hypoglycemia found to have both GSD IX and isolated GH deficiency.\nCASE PRESENTATION: A 3-year-and-11-month-old boy with a history of prematurity, autism, developmental delay, seizures, and feeding difficulty was admitted for poor weight gain and symptomatic hypoglycemia. He was nondysmorphic, with a height of 93.8 cm (2%, -1.97 SDS), and has no hepatomegaly. He developed symptomatic hypoglycemia, with a serum glucose level of 37 mg/dL after 14 h of fasting challenge. Critical sample showed a GH of 0.24 ng/mL. GH provocative stimulation testing was done with a peak GH of 2.8 ng/mL. Brain magnetic resonance imaging showed a hypoplastic pituitary gland. Given the clinical symptoms, suspicion for mitochondrial disease was high. Dual Genome Panel by Massively Parallel Sequencing revealed a hemizygous variant c.721A>G (p1241V) in the X-linked PHKA2 gene, a causative gene for GSD IX. Red blood cell PhK enzyme activity testing was low, supporting the diagnosis.\nCONCLUSIONS: Given the patient's developmental delays that were not explained by GH deficiency alone, further investigation showed two unrelated conditions resulting in deranged metabolic adaptation to fasting leading to severe hypoglycemia.","variants":[{"Name":"NM_000292.3(PHKA2):c.721A>G (p.Ile241Val)","Chromosome":"X","Start":"18941672","Stop":"18941672","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":649919,"rule_based_match":true,"evidence_text":"c.721A>G (p1241V)","llm_judgment":"PRESENT","evidence":"c.721A>G (p1241V)","abstract_start":1043,"abstract_end":1060}]}
{"pmid":"28819299","title":"The correlation between CRB1 variants and the clinical severity of Brazilian patients with different inherited retinal dystrophy phenotypes.","abstract":"Inherited retinal dystrophies are characterized by progressive retina degeneration and mutations in at least 250 genes have been associated as disease-causing. CRB1 is one of many genes analyzed in molecular diagnosis for inherited retinal dystrophy. Crumbs homolog-1 protein encoded by CRB1 is important for cell-to-cell contact, polarization of epithelial cells and the morphogenesis of photoreceptors. Pathogenic variants in CRB1 lead to a huge variety of phenotypes ranging from milder forms of inherited retinal dystrophy, such as retinitis pigmentosa to more severe phenotypes such as Leber congenital amaurosis. In this study, seven novel likely-pathogenic variants were identified: four missense variants (p.Leu479Pro, p.Ala921Pro, p.Cys948Arg and p.Asp1031Asn), two frameshift deletions (c.2536_2542del7 and c.3460_3461delTG) and one frameshift indel variant (c.276_294delinsTGAACACTGTAC). Furthermore, two patients with cone-rod dystrophy due to mutations in CRB1 were reported, supporting previous data, in which mutations in CRB1 can also cause cone-rod dystrophy. Finally, our data suggested there was a direct relation between phenotype severity and the mutation effect on protein functionality in 15 Brazilian CRB1 patients.","variants":[{"Name":"NM_201253.3(CRB1):c.1436T>C (p.Leu479Pro)","Chromosome":"1","Start":"197421264","Stop":"197421264","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":855874,"rule_based_match":false,"evidence_text":"p.Leu479Pro","llm_judgment":"PRESENT","evidence":"p.Leu479Pro","abstract_start":714,"abstract_end":725},{"Name":"NM_201253.3(CRB1):c.276_294delinsTGAACACTGTAC (p.Arg92fs)","Chromosome":"1","Start":"197328627","Stop":"197328645","ReferenceAlleleVCF":"GAGCTTTCTGTGCAAATGT","AlternateAlleleVCF":"TGAACACTGTAC","allel_id":2147791,"rule_based_match":true,"evidence_text":"c.276_294delinsTGAACACTGTAC","llm_judgment":"PRESENT","evidence":"c.276_294delinsTGAACACTGTAC","abstract_start":869,"abstract_end":896},{"Name":"NM_201253.3(CRB1):c.3091G>A (p.Asp1031Asn)","Chromosome":"1","Start":"197434954","Stop":"197434954","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1294806,"rule_based_match":false,"evidence_text":"p.Asp1031Asn","llm_judgment":"PRESENT","evidence":"p.Asp1031Asn","abstract_start":756,"abstract_end":768},{"Name":"NM_201253.3(CRB1):c.2842T>C (p.Cys948Arg)","Chromosome":"1","Start":"197429614","Stop":"197429614","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":418814,"rule_based_match":false,"evidence_text":"p.Cys948Arg","llm_judgment":"PRESENT","evidence":"p.Cys948Arg","abstract_start":740,"abstract_end":751}]}
{"pmid":"32567010","title":"Rod bipolar cell dysfunction in POLG retinopathy.","abstract":"OBJECTIVE: To report the clinical and novel electrophysiological features in a child with POLG-related sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO).\nMETHODS: The proband, a male child of Indian descent, underwent serial systemic and ophthalmological evaluations from birth until 14 years of age. Eye examinations included visual acuity and extraocular movement assessments, fundus photography, spectral domain optical coherence tomography and full-field electroretinography (ERG). Detailed genetic testing was also performed.\nRESULTS: The child carried a homozygous mutation in POLG (c.911T > G/p.Leu304Arg) and manifested systemic features such as seizures, headaches, areflexia, hypotonia, myopathy and vomiting. The child's distance visual acuity was 0.50 and 0.40 LogMAR in the right and left eyes, respectively. Bilateral ophthalmoplegia and ptosis were observed at 5 years of age. The dark-adapted (DA) ERG responses to 2.29 cd s m<sup>-2</sup> and 7.6 cd s m<sup>-2</sup> stimuli showed a markedly reduced b/a ratio; an electronegative configuration was noted to a DA 7.6 ERG.\nCONCLUSION: This is the first documented case of an electronegative ERG in a POLG-related disorder consistent with generalized rod ON-bipolar dysfunction. The rest of the proband's systemic and ophthalmological features were consistent with SANDO but some features overlapped with other POLG-related disorders such as Alpers-Huttenlocher syndrome and autosomal dominant progressive external ophthalmoplegia demonstrating the wide phenotypic overlap expected due to POLG mutations.","variants":[{"Name":"NM_002693.3(POLG):c.911T>G (p.Leu304Arg)","Chromosome":"15","Start":"89329055","Stop":"89329055","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":28536,"rule_based_match":true,"evidence_text":"c.911T > G/p.Leu304Arg","llm_judgment":"PRESENT","evidence":"c.911T > G/p.Leu304Arg","abstract_start":606,"abstract_end":628}]}
{"pmid":"21933806","title":"Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy.","abstract":"Mitochondrial neurogastrointestinal encephalomyopathy is a rare multisystemic autosomic recessive disorder characterized by: onset typically before the age of 30 years; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and leucoencephalopathy. The disease is caused by mutations in the TYMP gene encoding thymidine phosphorylasethymine phosphorylase. Anecdotal reports suggest that allogeneic haematopoetic stem cell transplantation may be beneficial for mitochondrial neurogastrointestinal encephalomyopathy, but is associated with a high mortality. After selecting patients who fulfilled the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy and had severe thymidine phosphorylase deficiency in the buffy coat (<10% of normal activity), we reviewed their medical records and laboratory studies. We identified 102 patients (50 females) with mitochondrial neurogastrointestinal encephalomyopathy and an average age of 32.4 years (range 11-59 years). We found 20 novel TYMP mutations. The average age-at-onset was 17.9 years (range 5 months to 35 years); however, the majority of patients reported the first symptoms before the age of 12 years. The patient distribution suggests a relatively high prevalence in Europeans, while the mutation distribution suggests founder effects for a few mutations, such as c.866A>G in Europe and c.518T>G in the Dominican Republic, that could guide genetic screening in each location. Although the sequence of clinical manifestations in the disease varied, half of the patients initially had gastrointestinal symptoms. We confirmed anecdotal reports of intra- and inter-familial clinical variability and absence of genotype-phenotype correlation in the disease, suggesting genetic modifiers, environmental factors or both contribute to disease manifestations. Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial. We observed endocrine/exocrine pancreatic insufficiency, which had not previously been reported. Kaplan-Meier analysis revealed significant mortality between the ages of 20 and 40 years due to infectious or metabolic complications. Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed. Early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for allogeneic haematopoetic stem cell transplantation.","variants":[{"Name":"NM_001953.5(TYMP):c.518T>G (p.Met173Arg)","Chromosome":"22","Start":"50527716","Stop":"50527716","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":224756,"rule_based_match":true,"evidence_text":"c.518T>G","llm_judgment":"PRESENT","evidence":"c.518T>G","abstract_start":1415,"abstract_end":1423}]}
{"pmid":"38747280","title":"Genetic profile of Brazilian patients with LAMA2-related dystrophies.","abstract":"LAMA2-related dystrophies (LAMA2-RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype-phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2-RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960-17C>A) and revealed an out-of-frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype-genotype correlations and provided valuable insights, particularly regarding the Latin American population.","variants":[{"Name":"NM_000426.4(LAMA2):c.3976C>T (p.Arg1326Ter)","Chromosome":"6","Start":"129316089","Stop":"129316089","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":98863,"rule_based_match":true,"evidence_text":"c.3976 C>T","llm_judgment":"PRESENT","evidence":"c.3976 C>T","abstract_start":625,"abstract_end":635}]}
{"pmid":"32166861","title":"Compound heterozygous mutations in ABCG5 or ABCG8 causing Chinese familial Sitosterolemia.","abstract":"BACKGROUND: Sitosterolemia (STSL), also known as phytosterolemia, is a rare autosomal recessive hereditary disease caused by mutations in the ABCG5 or ABCG8 genes. The disease is a result of disorders in lipoprotein metabolism, and is characterized by tendinous and tuberous xanthomas, elevated plasma cholesterol and phytosterol levels, and thrombocytopenia and hemolytic anemia in several patients. The manifestations of STSL are diverse and can easily be misdiagnosed. In recent years, cases of this disease in children have been reported in succession. There is therefore a need for clinicians to improve identification of STSL and perform early intervention.\nMETHODS: We evaluated four children with STSL caused by genetic mutations in ABCG5 or ABCG8, as well as their family members, by analyzing their clinical characteristics and performing Trio-whole exome sequencing. The biological consequences of the mutations were analyzed using various bioinformatics software. We also analyzed the consequences of a mutation commonly observed in STSL patients on the structure of the protein involved.\nRESULTS: We identified five previously unreported pathogenic mutations of different phenotypes of STSL: ABCG5 NM_022436:c.1337G>A; ABCG8 NM_022437:c.965-1G>A, c.323-1G>C, c.1418C>G and c.1534G>A. We also report the structural changes brought about by a mutation common in STSL patients, as well as the possible consequences of these changes.\nCONCLUSIONS: Our findings further broaden the genotypic and phenotypic profiles of the onset of STSL in the pediatric population and provide information for the diagnosis and treatment of this disease.","variants":[{"Name":"NM_022436.3(ABCG5):c.1337G>A (p.Arg446Gln)","Chromosome":"2","Start":"43822923","Stop":"43822923","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":826482,"rule_based_match":true,"evidence_text":"ABCG5 NM_022436:c.1337G>A","llm_judgment":"PRESENT","evidence":"ABCG5 NM_022436:c.1337G>A","abstract_start":1205,"abstract_end":1230}]}
{"pmid":"38158857","title":"Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.","abstract":"PURPOSE: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.\nMETHODS: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.\nRESULTS: In 1 family with 2 affected males, we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation.\nCONCLUSION: We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron-containing genes due to germline variation in ZRSR2.","variants":[{"Name":"NM_005089.4(ZRSR2):c.1211_1212del (p.Gly404fs)","Chromosome":"X","Start":"15823001","Stop":"15823002","ReferenceAlleleVCF":"AGG","AlternateAlleleVCF":"A","allel_id":3526376,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1211_1212del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1211_1212del","abstract_start":678,"abstract_end":704},{"Name":"NM_005089.4(ZRSR2):c.1207_1208del (p.Arg403fs)","Chromosome":"X","Start":"15823000","Stop":"15823001","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":966735,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1207_1208del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1207_1208del","abstract_start":828,"abstract_end":854}]}
{"pmid":"31408864","title":"Autosomal Recessive Alport Syndrome Unveiled by Pregnancy.","abstract":"Alport syndrome is a hereditary disease affecting Type IV collagen characterized by hematuria, progressive renal failure, sensorineural hearing loss, and ocular abnormalities. Most cases are X-linked and involve the COL4A5 gene with a minority of patients having autosomal recessive mutations in the COL4A3 or COL4A4 genes encoding the α3(IV) or α4(IV) chain respectively. Here, we describe the case of a 31-year-old woman who presented during pregnancy with hematuria and proteinuria and was diagnosed with autosomal recessive Alport syndrome (ARAS) post-partum. Her biopsy was notable for findings of segmental glomerulosclerosis with some collapsing features, in addition to thin basement membranes and rare \"splitting\". Genetic testing identified 2 novel mutations in the COL4A4 gene: a truncating frame shift mutation c.3861delinsCTC and a missense mutation c.4708G>A (p.Glu1570Lys), both of which we assert to be pathogenic. She had normal full-term delivery without complications. This case has several unique features including the relatively mild disease phenotype and the findings of glomerular scarring with collapsing features on renal biopsy. The successful pregnancy outcome and her clinical presentation add to the growing body of evidence that ARAS can have a variable phenotype.","variants":[{"Name":"NM_000092.5(COL4A4):c.4708G>A (p.Glu1570Lys)","Chromosome":"2","Start":"227008119","Stop":"227008119","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":622521,"rule_based_match":true,"evidence_text":"c.4708G>A (p.Glu1570Lys)","llm_judgment":"PRESENT","evidence":"c.4708G>A (p.Glu1570Lys)","abstract_start":863,"abstract_end":887},{"Name":"NM_000092.5(COL4A4):c.3861delinsCTC","Chromosome":"2","Start":"227030555","Stop":"227030555","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"GAG","allel_id":622522,"rule_based_match":true,"evidence_text":"c.3861delinsCTC","llm_judgment":"PRESENT","evidence":"c.3861delinsCTC","abstract_start":823,"abstract_end":838}]}
{"pmid":"30010053","title":"A homozygous CEP57 c.915_925dupCAATGTTCAGC mutation in a patient with mosaic variegated aneuploidy syndrome with rhizomelic shortening in the upper and lower limbs and a narrow thorax.","abstract":"Mosaic variegated aneuploidy syndrome (MVA) is a rare autosomal recessive disorder characterized by random chromosome gains and losses. Mutations in BUB1B and CEP57 genes have been involved in MVA. Here we report on a male child with MVA due to c.915_925dupCAATGTTCAGC mutation in the CEP57 gene. Our patient was homozygous for this mutation and he is the first case with rhizomelic shortening of both the upper and lower limbs and mild respiratory insufficiency due to a narrow thorax. It is also the second MVA Mexican family reported with this mutation that lives in the northwestern region of Mexico, suggesting a \"local founding effect\". Additional cases are needed to better understand the MVA genotype-phenotype relationship.","variants":[{"Name":"NM_014679.5(CEP57):c.915_925dup (p.Leu309fs)","Chromosome":"11","Start":"95827811","Stop":"95827812","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TAGCCAATGTTC","allel_id":39648,"rule_based_match":true,"evidence_text":"c.915_925dupCAATGTTCAGC mutation","llm_judgment":"PRESENT","evidence":"c.915_925dupCAATGTTCAGC mutation","abstract_start":245,"abstract_end":277}]}
{"pmid":"26118460","title":"A Common Mutation of Long QT Syndrome Type 1 in Japan.","abstract":"BACKGROUND: Previous studies of long QT syndrome (LQTS) have revealed the presence of country-specific hot spots in KCNQ1 mutations, and the purpose of this study was to evaluate the influence of a common mutation on clinical phenotypes in Japanese LQT1 patients.\nMETHODS AND RESULTS: We retrospectively studied the frequency of each mutation in 190 LQT1 Japanese probands and evaluated the clinical severity of LQT1 among carriers with a common mutation. We also compared it with that of carriers with other mutations. In the Japanese cohort, the most common mutation was p. A344spl (c.1032 G>A), comprising a substitution of a guanine for an adenine at the last base of exon 7, and it was found in 17 probands (8.9%). Regarding the clinical characteristics of A344spl carriers, the mean age-of-onset was 10±4 years, >40% were symptomatic, and the mean corrected QT interval was 461±30 ms. The prognosis for carriers of the A344spl mutation (n=31) was intermediate between that for the A341V mutation reported to be associated with severe phenotypes (n=24) and other mutations (n=290).\nCONCLUSIONS: The A344spl mutation was a frequent LQTS genotype in Japan, which indicates that the influence of country-specific hot spots should be considered when studying LQT1 clinical phenotypes.","variants":[{"Name":"NM_000218.3(KCNQ1):c.1032G>A (p.Ala344=)","Chromosome":"11","Start":"2583545","Stop":"2583545","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18174,"rule_based_match":true,"evidence_text":"c.1032 G>A","llm_judgment":"PRESENT","evidence":"c.1032 G>A","abstract_start":585,"abstract_end":595}]}
{"pmid":"19743957","title":"Novel rare alleles of ABCA1 are exclusively associated with extreme high-density lipoprotein-cholesterol levels among the Han Chinese.","abstract":"BACKGROUND: High-density lipoprotein (HDL) is a major plasma lipoprotein directly associated with cholesterol metabolism. The ATP binding cassette transporter 1 gene (ABCA1) is one of the major genes modulating plasma levels of HDL-cholesterol (HDL-C). Rare alleles of ABCA1 associated with extreme HDL-C concentrations have not been previously investigated in the Chinese.\nMETHODS: Blood samples were collected from 470 subjects whose HDL-C concentrations were within the top 5% of the distribution, 335 subjects in the lowest 5%, and 220 within the range 5%-95%. First, we sequenced all exons of the ABCA1 gene from 50 subjects from the group with extremely high HDL-C, and 50 from the group with extremely low HDL-C concentrations. Next, in the remaining subjects, we genotyped the non-synonymous variants identified exclusively with either extreme group.\nRESULTS: Four novel non-synonymous alleles were identified; all were rare. Alleles c.3029C>T (p.Ala1010Val) and c.5399A>G (p.Asn1800Ser) were found exclusively in the low group, c.2031C>A (p.Asp677Glu) and c.2660G>T (p.Cys887Phe) exclusively in the high group.\nCONCLUSIONS: Our results show that some rare alleles of ABCA1 are associated with marked phenotypes, supporting the \"rare-variant common-disease\" hypothesis. Certain alleles also provide tools for identifying individuals at high risk of dyslipidaemia, allowing for early therapeutic intervention.","variants":[{"Name":"NM_005502.4(ABCA1):c.2660G>T (p.Cys887Phe)","Chromosome":"9","Start":"104822664","Stop":"104822664","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":227328,"rule_based_match":true,"evidence_text":"c.2660G>T (p.Cys887Phe)","llm_judgment":"PRESENT","evidence":"c.2660G>T (p.Cys887Phe)","abstract_start":1065,"abstract_end":1088}]}
{"pmid":"38158857","title":"Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.","abstract":"PURPOSE: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.\nMETHODS: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.\nRESULTS: In one family with 2 affected males we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), while 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation.\nCONCLUSION: We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron containing genes due to germline variation in ZRSR2.","variants":[{"Name":"NM_005089.4(ZRSR2):c.1211_1212del (p.Gly404fs)","Chromosome":"X","Start":"15823001","Stop":"15823002","ReferenceAlleleVCF":"AGG","AlternateAlleleVCF":"A","allel_id":3526376,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1211_1212del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1211_1212del","abstract_start":679,"abstract_end":705},{"Name":"NM_005089.4(ZRSR2):c.1207_1208del (p.Arg403fs)","Chromosome":"X","Start":"15823000","Stop":"15823001","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":966735,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1207_1208del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1207_1208del","abstract_start":827,"abstract_end":853}]}
{"pmid":"27309958","title":"Whole Exome Sequencing and Segregation Analysis Confirms That a Mutation in COL17A1 Is the Cause of Epithelial Recurrent Erosion Dystrophy in a Large Dominant Pedigree Previously Mapped to Chromosome 10q23-q24.","abstract":"PURPOSE: To report identification of a COL17A1 mutation in a family with a corneal dystrophy previously mapped to chromosome 10q23-q24.\nMETHODS: Whole-exome sequencing was performed on DNA samples from five affected family members and two unrelated, unaffected individuals. Identified variants were filtered for those that were: located in the linked interval on chromosome 10q23-q24; novel or rare (minor allele frequency ≤0.01); heterozygous; present in all affected individuals and not in controls; and present in genes that encode proteins expressed in human corneal epithelial cells (reads per kilobase per million ≥1). Sanger sequencing of identified variants (SNVs) was performed in additional family members. In silico analysis was used to predict the functional impact of non-synonymous variants.\nRESULTS: Three SNVs located in two genes were identified that met the filtering criteria: one rare synonymous c.3156C>T variant in the collagen, type XVII, alpha I (COL17A1) gene; and two rare variants, one synonymous and one missense, in the dynamin binding protein (DNMBP) gene. Sanger sequencing of additional family members determined that only the COL17A1 variant segregates with the affected phenotype. In silico analysis predicts that the missense variant in DNMBP would be tolerated.\nCONCLUSIONS: The corneal dystrophy mapped to chromosome 10q23-q24 is associated with the c.3156C>T variant in COL17A1. As this variant has recently been identified in five other families with early onset recurrent corneal erosions, and has been shown in vitro to introduce a cryptic splice donor site, this dystrophy is likely caused by aberrant splicing of COL17A1 and should be classified as epithelial recurrent erosion dystrophy.","variants":[{"Name":"NM_000494.4(COL17A1):c.3156C>T (p.Gly1052=)","Chromosome":"10","Start":"104037688","Stop":"104037688","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205533,"rule_based_match":true,"evidence_text":"c.3156C>T","llm_judgment":"PRESENT","evidence":"c.3156C>T","abstract_start":916,"abstract_end":925}]}
{"pmid":"27789394","title":"Generation of Mucopolysaccharidosis type II (MPS II) human induced pluripotent stem cell (iPSC) line from a 7-year-old male with pathogenic IDS mutation.","abstract":"Peripheral blood was collected from a 7-year-old male patient with an X-linked recessive mutation of Iduronate 2-sulfatase (IDS) gene (NM_000202.7(IDS):c.182C>T) causing MPS II (OMIM 309900). Peripheral blood mononuclear cells (PBMCs) were reprogrammed by lentiviral delivery of a self-silencing hOKSM polycistronic vector. The pluripotency of the iPSC line was confirmed by the expression of pluripotency-associated markers and in vitro spontaneous differentiation towards the 3 germ layers. The iPSC line showed normal karyotype. The cell line offers a good platform to study MPS II pathophysiology, for drug testing, early biomarker discovery and gene therapy studies.","variants":[{"Name":"NM_000202.8(IDS):c.182C>T (p.Ser61Phe)","Chromosome":"X","Start":"149504215","Stop":"149504215","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1054183,"rule_based_match":true,"evidence_text":"NM_000202.7(IDS):c.182C>T","llm_judgment":"PRESENT","evidence":"NM_000202.7(IDS):c.182C>T","abstract_start":135,"abstract_end":160}]}
{"pmid":"34751098","title":"An eleven-year history of Vanishing White Matter Disease in an adult patient with no cognitive decline and","abstract":"Vanishing White Matter Disease (VWMD) is a rare autosomal recessive leukoencephalopathy . The classical presentation is characterized by a severe cerebellar ataxia, spasticity, neurological deterioration with a chronic progressive course and episodes of acute neurological deterioration after stress conditions.We report a 52-year-old man with VWMD and atypical features who manifested two major events of transient aphasia eleven years apart with complete recovery in 48 hours. No cognitive decline was present. Brain MRI revealed typical aspects of VWMD including diffuse leukoencephalopathy with relative sparing of U-fibers. We identified the presence of c.592G>A (p.Glu198Lys) and c.1360 C>T (p.Pro454Ser) mutations in <i>EIF2B5</i>.","variants":[{"Name":"NM_003907.3(EIF2B5):c.1360C>T (p.Pro454Ser)","Chromosome":"3","Start":"184142294","Stop":"184142294","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2749013,"rule_based_match":true,"evidence_text":"c.1360 C>T (p.Pro454Ser)","llm_judgment":"PRESENT","evidence":"c.1360 C>T (p.Pro454Ser)","abstract_start":686,"abstract_end":710}]}
{"pmid":"27523286","title":"Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with later diabetes onset and heterotopic gastric mucosa.","abstract":"Mitchell-Riley syndrome, an autosomal recessive disorder caused by mutations in the RFX6 gene, is defined as a combination of neonatal diabetes mellitus and serious congenital gastrointestinal defects. We describe Mitchell-Riley syndrome in two sisters with two novel compound heterozygous variants in the RFX6 gene: c.1154G > A, p.(Arg385Gln), and c.1316_1319delTCTA, p.(Ile439Thrfs*13). Both sisters present milder forms of the syndrome, likely due to possible residual activity of the p.Arg385Gln variant, which is localized in a dimerization domain of the RFX6 transcription factor. We propose that the prognosis is dependent on patient RFX6 genotype and possible residual activity of RFX6 transcription factor. Both sisters had atypical later onset of diabetes, at 2 years and 10 months and 2 years and 7 months, respectively. This supports the need of extending the definition of diabetes in Mitchell-Riley syndrome from neonatal to childhood onset and regular glyceamia check in patients with gastrointestinal tract malformations typical for Mitchell-Riley syndrome. The clinical course in both sisters improved significantly after surgical removal of parts of the small intestine with heterotopic gastric mucosa. We suggest that gastric mucosa heterotopy is an important actionable part of Mitchell-Riley syndrome and could have been responsible for the malabsorption, failure to thrive and severe anemia present in previously reported patients with Mitchell-Riley syndrome.","variants":[{"Name":"NM_173560.4(RFX6):c.1154G>A (p.Arg385Gln)","Chromosome":"6","Start":"116919268","Stop":"116919268","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":578353,"rule_based_match":true,"evidence_text":"c.1154G > A, p.(Arg385Gln)","llm_judgment":"PRESENT","evidence":"c.1154G > A, p.(Arg385Gln)","abstract_start":317,"abstract_end":343},{"Name":"NM_173560.4(RFX6):c.1316_1319del (p.Ile439fs)","Chromosome":"6","Start":"116920441","Stop":"116920444","ReferenceAlleleVCF":"GTATC","AlternateAlleleVCF":"G","allel_id":578354,"rule_based_match":true,"evidence_text":"c.1316_1319delTCTA, p.(Ile439Thrfs*13)","llm_judgment":"PRESENT","evidence":"c.1316_1319delTCTA, p.(Ile439Thrfs*13)","abstract_start":349,"abstract_end":387}]}
{"pmid":"29923089","title":"Extrapolation of Variant Phase in Mitochondrial Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency.","abstract":"Loss-of-function and hypomorphic ECHS1 variants are associated with mitochondrial short-chain enoyl-CoA hydratase deficiency, an inborn error of valine metabolism. We report an 8-year-old boy with developmental delay, ataxia, hemiplegia, and hearing loss with abnormalities in the basal ganglia. Biochemical studies were essentially normal except for a persistent mildly elevated CSF alanine. This patient demonstrates an intermediate phenotype between a Leigh-like, early-onset presentation and paroxysmal exercise-induced dyskinesia. Two novel ECHS1 variants (c.79T>G; p.Phe27Val and c.789_790del; p.Phe263fs) were identified via exome sequencing in the proband, and pathogenicity was confirmed by enzyme assay performed on patient fibroblasts. Neither of the ECHS1 variants detected in the child were present in the mother. However, due to nearby polymorphisms, it was possible to determine that p.Phe263fs occurred de novo on the maternal chromosome and that p.Phe27Val likely derived from the paternal chromosome. Nearby polymorphisms can help set phase of variants when only a single parent is available for testing or when an identified variant occurs de novo.","variants":[{"Name":"NM_004092.4(ECHS1):c.79T>G (p.Phe27Val)","Chromosome":"10","Start":"133373255","Stop":"133373255","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1458986,"rule_based_match":true,"evidence_text":"c.79T>G; p.Phe27Val","llm_judgment":"PRESENT","evidence":"c.79T>G; p.Phe27Val","abstract_start":562,"abstract_end":581}]}
{"pmid":"28490766","title":"SCA42 mutation analysis in a case series of Japanese patients with spinocerebellar ataxia.","abstract":"Spinocerebellar ataxia (SCA) is a group of dominantly inherited heterogeneous disorders in which 43 subtypes have been identified to date. Recently, Japanese and French families with SCA type 42 (SCA42) were found to have a missense mutation (c.5144G>A; R1715H) in CACNA1G. We performed genetic analysis of 84 unrelated families to find the prevalence of SCA42 in Japan. Two families were found to have the previously reported missense mutation. Clinical presentations of the affected members of these families were similar to those of the previously reported French and Japanese families. Our study demonstrates that SCA42 exists in small numbers in Japan, and further supports the idea that SCA42 is a slowly progressive, pure cerebellar ataxia.","variants":[{"Name":"NM_018896.5(CACNA1G):c.5144G>A (p.Arg1715His)","Chromosome":"17","Start":"50617560","Stop":"50617560","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":223669,"rule_based_match":true,"evidence_text":"c.5144G>A; R1715H","llm_judgment":"PRESENT","evidence":"c.5144G>A; R1715H","abstract_start":243,"abstract_end":260}]}
{"pmid":"31729143","title":"Clinical and neurocognitive issues associated with Bosch-Boonstra-Schaaf optic atrophy syndrome: A case study.","abstract":"Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced nonverbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities.","variants":[{"Name":"NM_005654.6(NR2F1):c.82C>T (p.Gln28Ter)","Chromosome":"5","Start":"93585105","Stop":"93585105","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1036550,"rule_based_match":true,"evidence_text":"NM_005654.5:c.82C > T, p.Gln28*","llm_judgment":"PRESENT","evidence":"NM_005654.5:c.82C > T, p.Gln28*","abstract_start":532,"abstract_end":563}]}
{"pmid":"33545641","title":"Human-induced pluripotent stem cell lines (CMCi006-A and CMCi007-A) from a female and male patient with Fabry disease carrying the same frameshift deletion mutation.","abstract":"Human-induced pluripotent stem cell lines (hiPSCs) derived from the peripheral blood mononuclear cells (PBMCs) of a woman (CMCi007-A) and her son (CMCi006-A) diagnosed with Fabry disease (FD) caused by the frameshift deletion mutation c.969delC in the alpha-galactosidase A (GLA) gene were generated. These hiPSCs showed typical human embryonic stem cell-like morphology and expressed pluripotency-associated markers, and directly differentiated into all three germ-layers. Karyotyping showed normal 46, XY (CMCi006-A) and 46, XX (CMCi007-A). In summary, we generated novel patient-specific hiPSC lines from both a female and male containing the same mutation, which may provide additional insight into the pathophysiology of FD.","variants":[{"Name":"NM_000169.3(GLA):c.969del (p.Leu324fs)","Chromosome":"X","Start":"101398400","Stop":"101398400","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":1038952,"rule_based_match":true,"evidence_text":"c.969delC","llm_judgment":"PRESENT","evidence":"c.969delC","abstract_start":235,"abstract_end":244}]}
{"pmid":"31883394","title":"Severe growth failure associated with a novel heterozygous nonsense mutation in the GHR transmembrane domain leading to elevated growth hormone binding protein.","abstract":"OBJECTIVE: To report a novel mutation in GHR and to characterize a novel mechanism of nonclassical growth hormone insensitivity.\nCONTEXT: Laron syndrome (LS) is a well-described disorder of growth hormone insensitivity due to mutations in the growth hormone receptor (GHR) that leads to short stature. Biochemically, LS patients classically have elevated levels of growth hormone (GH), but low levels of insulin-like growth factor (IGF)-1, IGF binding protein (IGFBP)-3 and GH binding protein (GHBP).\nDESIGN: Case presentation with in vitro functional studies.\nPATIENTS: A young male Caucasian child with short stature was found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP.\nMEASUREMENTS: Growth hormone stimulation tests revealed baseline GH level of 20.9 µg/L and maximum stimulated GH level of 52.7 µg/L and GHBP level of 4868 pmol/L. GHR gene sequencing revealed a novel heterozygous nonsense mutation (c.800G > A, p.Trp267*) in the transmembrane domain of the receptor. Immunoblot analysis of transfected GHR p.Trp267* in HEK293 revealed inhibition of GH-induced STAT5 signalling that was overcome with increasing doses of recombinant human GH.\nRESULTS: Using an in vitro model, we show that elevated levels of GHBP inhibit the action of GH. Furthermore, our studies demonstrate that this inhibition by GHBP can be overcome by increasing doses of recombinant human GH.\nCONCLUSIONS: To our knowledge, this is the first study to demonstrate in vitro that elevated levels of GHBP attenuate the effect of GH and inhibit GH-induced signalling, thereby leading to short stature. Though this inhibition was overcome in vitro with supraphysiologic doses of GH, significantly above endogenously available GH, it remains to be seen whether such an effect can be replicated in vivo.","variants":[{"Name":"NM_000163.5(GHR):c.800G>A (p.Trp267Ter)","Chromosome":"5","Start":"42713444","Stop":"42713444","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3747726,"rule_based_match":true,"evidence_text":"c.800G > A, p.Trp267*","llm_judgment":"PRESENT","evidence":"c.800G > A, p.Trp267*","abstract_start":944,"abstract_end":965}]}
{"pmid":"31721179","title":"Functional characterization of novel MFSD8 pathogenic variants anticipates neurological involvement in juvenile isolated maculopathy.","abstract":"Biallelic MFSD8 variants are an established cause of severe late-infantile subtype of neuronal ceroid lipofuscinosis (v-LINCL), a severe lysosomal storage disorder, but have also been associated with nonsyndromic adult-onset maculopathy. Here, we functionally characterized two novel MFSD8 variants found in a child with juvenile isolated maculopathy, in order to establish a refined prognosis. ABCA4 locus resequencing was followed by the analysis of other inherited retinal disease genes by whole exome sequencing (WES). Minigene assays and cDNA sequencing were used to assess the effect of a novel MFSD8 splice variant. MFSD8 expression was quantified with qPCR and overexpression studies were analyzed by immunoblotting. Transmission electron microscopy (TEM) was performed on a skin biopsy and ophthalmological and neurological re-examinations were conducted. WES revealed two novel MFSD8 variants: c.[590del];[439+3A>C] p.[Gly197Valfs*2];[Ile67Glufs*3]. Characterization of the c.439+3A>C variant via splice assays showed exon-skipping (p.Ile67Glufs*3), while overexpression studies of the corresponding protein indicated expression of a truncated polypeptide. In addition, a significantly reduced MFSD8 RNA expression was noted in patient's lymphocytes. TEM of a skin biopsy revealed typical v-LINCL lipopigment inclusions while neurological imaging of the proband displayed subtle cerebellar atrophy. Functional characterization demonstrated the pathogenicity of two novel MFSD8 variants, found in a child with an initial diagnosis of juvenile isolated maculopathy but likely evolving to v-LINCL with a protracted disease course. Our study allowed a refined neurological prognosis in the proband and expands the natural history of MFSD8-associated disease.","variants":[{"Name":"NM_001371596.2(MFSD8):c.590del (p.Gly197fs)","Chromosome":"4","Start":"127939961","Stop":"127939961","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":805379,"rule_based_match":false,"evidence_text":"c.590del","llm_judgment":"PRESENT","evidence":"c.[590del","abstract_start":904,"abstract_end":913}]}
{"pmid":"33968654","title":"Novel bi-allelic mutations in","abstract":"BACKGROUND: Male infertility is a major health concern and approximately 10-15% of cases are caused by genetic abnormalities. Defects in the sperm flagella are closely related to male infertility, since flagellar beating allows sperm to swim. The sperm of males afflicted with multiple morphological abnormalities of the flagella (MMAF) possess severe defects of the sperm flagella, may impair sperm motility and lead to male infertility. Currently, known genetic defects only account for MMAF in about 60% of patients and need more intensive efforts to explore the relationship between genes and MMAF.\nMETHODS: The whole-exome sequencing (WES) was performed to analyze the genetic cause of the MMAF patient. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to observe the morphology of sperm cells and to identify the ultrastructural characteristics of the flagella in the patient. The expression of DNAH1 was analyzed by sperm immunofluorescence staining.\nRESULTS: We identified the negative effects produced by the <i>DNAH1</i> mutations c. 8170.C>T (p. R2724*) and c. 4670C>T (p. T1557M) on <i>DNAH1</i> expression and the development of sperm flagella.\nCONCLUSIONS: Our findings suggest that <i>DNAH1</i> is associated with the formation of sperm flagella and homozygous loss-of-function mutations in <i>DNAH1</i> can impair sperm motility and cause male infertility.","variants":[{"Name":"NM_015512.5(DNAH1):c.8170C>T (p.Arg2724Ter)","Chromosome":"3","Start":"52383879","Stop":"52383879","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1902844,"rule_based_match":false,"evidence_text":"c. 8170.C>T (p. R2724*)","llm_judgment":"PRESENT","evidence":"c. 8170.C>T (p. R2724*)","abstract_start":1080,"abstract_end":1103},{"Name":"NM_015512.5(DNAH1):c.4670C>T (p.Thr1557Met)","Chromosome":"3","Start":"52360409","Stop":"52360409","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":631653,"rule_based_match":true,"evidence_text":"c. 4670C>T (p. T1557M)","llm_judgment":"PRESENT","evidence":"c. 4670C>T (p. T1557M)","abstract_start":1108,"abstract_end":1130}]}
{"pmid":"26270344","title":"R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL.","abstract":"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.","variants":[{"Name":"NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys)","Chromosome":"19","Start":"15197537","Stop":"15197537","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":442187,"rule_based_match":true,"evidence_text":"c.160C>T (p.Arg54Cys)","llm_judgment":"PRESENT","evidence":"p.Arg54Cys","abstract_start":305,"abstract_end":315}]}
{"pmid":"29976978","title":"Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency.","abstract":"Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T > C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C > T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C > T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population-specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations.","variants":[{"Name":"NM_007103.4(NDUFV1):c.1156C>T (p.Arg386Cys)","Chromosome":"11","Start":"67611972","Stop":"67611972","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":408448,"rule_based_match":true,"evidence_text":"NDUFV1 c.1156C > T (p.(Arg386Cys))","llm_judgment":"PRESENT","evidence":"NDUFV1 c.1156C > T (p.(Arg386Cys))","abstract_start":965,"abstract_end":999},{"Name":"NM_007103.4(NDUFV1):c.1118T>C (p.Phe373Ser)","Chromosome":"11","Start":"67611934","Stop":"67611934","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":424968,"rule_based_match":true,"evidence_text":"c.1118T > C (p.(Phe373Ser))","llm_judgment":"PRESENT","evidence":"c.1118T > C (p.(Phe373Ser))","abstract_start":628,"abstract_end":655}]}
{"pmid":"24190153","title":"A novel mutation of the GAA gene in a patient with adult-onset Pompe disease lacking a disease-specific pathology.","abstract":"We herein report a novel compound heterozygous mutation of the acid α-glucosidase (GAA) gene in a 23-year-old man with adult-onset Pompe disease. The patient was admitted for respiratory failure and a highly elevated serum level of creatine kinase (CK). His muscle pathology did not show typical vacuolated fibers; however, globular inclusion bodies with acid phosphatase (ACP) activity was observed. A molecular genetic analysis of the GAA gene revealed a novel compound heterozygous mutation, c.1544 T>A (M515K), combined with a previously reported mutation, c.1309 C>T (R437C). The presence of ACP-positive globular inclusion bodies is a useful diagnostic marker for adult-onset Pompe disease, even when typical vacuolated fibers are absent.","variants":[{"Name":"NM_000152.5(GAA):c.1309C>T (p.Arg437Cys)","Chromosome":"17","Start":"80108811","Stop":"80108811","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187001,"rule_based_match":true,"evidence_text":"c.1309 C>T (R437C)","llm_judgment":"PRESENT","evidence":"c.1309 C>T (R437C)","abstract_start":561,"abstract_end":579}]}
{"pmid":"28967462","title":"Myophosphorylase (PYGM) mutations determined by next generation sequencing in a cohort from Turkey with McArdle disease.","abstract":"This study aimed to identify PYGM mutations in patients with McArdle disease from Turkey by next generation sequencing (NGS). Genomic DNA was extracted from the blood of the McArdle patients (n = 67) and unrelated healthy volunteers (n = 53). The PYGM gene was sequenced with NGS and the observed mutations were validated by direct Sanger sequencing. A diagnostic algorithm was developed for patients with suspected McArdle disease. A total of 16 deleterious PYGM mutations were identified, of which 5 were novel, including 1 splice-site donor, 1 frame-shift, and 3 non-synonymous variants. The p.Met1Val (27-patients/11-families) was the most common PYGM mutation, followed by p.Arg576* (6/4), c.1827+7A>G (5/4), c.772+2_3delTG (5/3), p.Phe710del (4/2), p.Lys754Asnfs (2/1), and p.Arg50* (1/1). A molecular diagnostic flowchart is proposed for the McArdle patients in Turkey, covering the 6 most common PYGM mutations found in Turkey as well as the most common mutation in Europe. The diagnostic algorithm may alleviate the need for muscle biopsies in 77.6% of future patients. A prevalence of any of the mutations to a geographical region in Turkey was not identified. Furthermore, the NGS approach to sequence the entire PYGM gene was successful in detecting a common missense mutation and discovering novel mutations in this population study.","variants":[{"Name":"NM_005609.4(PYGM):c.2125TTC[1] (p.Phe710del)","Chromosome":"11","Start":"64750423","Stop":"64750425","ReferenceAlleleVCF":"TGAA","AlternateAlleleVCF":"T","allel_id":143234,"rule_based_match":false,"evidence_text":"p.Phe710del","llm_judgment":"PRESENT","evidence":"p.Phe710del","abstract_start":736,"abstract_end":747},{"Name":"NM_005609.4(PYGM):c.1A>G (p.Met1Val)","Chromosome":"11","Start":"64759898","Stop":"64759898","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":17348,"rule_based_match":false,"evidence_text":"p.Met1Val","llm_judgment":"PRESENT","evidence":"p.Met1Val","abstract_start":595,"abstract_end":604}]}
{"pmid":"27976805","title":"Mutations in CRLF1 cause familial achalasia.","abstract":"We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease-associated genes by a next-generation sequencing (NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor-like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold-induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor-like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1-related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing.","variants":[{"Name":"NM_004750.5(CRLF1):c.713dup (p.Pro239fs)","Chromosome":"19","Start":"18597033","Stop":"18597034","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":213653,"rule_based_match":true,"evidence_text":"c.713dupC (p.Pro239Alafs*91)","llm_judgment":"PRESENT","evidence":"c.713dupC (p.Pro239Alafs*91)","abstract_start":652,"abstract_end":680}]}
{"pmid":"20583550","title":"Early presentation of familial paraganglioma with SDHB mutation in a 13 year old child and its mother.","abstract":"Paragangliomas are extradadrenal neuroendocrine tumors, recently associated with gene mutations in the succinate dehydrogenase complex (SDH). These mutations are thought to be responsible for the familial paraganglioma syndrome. Average age of tumor diagnosis for SDH mutation carriers is about 30 years of age, but patients younger than 10 years have been reported. We present the case of a 13 year-old boy with abdominal paraganglioma, whose mother also had a history of thoracic paraganglioma diagnosed at 14 years of age. Both were found to carry a mutation in exon 4 of the SDHB gene, heterozygous for c.418G>T, p.Val140Phe sequence. Compared to the other SDH subtypes, SDHB associated tumors have been found to be much more aggressive. This has led to current recommendations that tumor screening of asymptomatic SDHB carriers should start as early as 10 years of age. An even earlier initiation seems warranted for the identified carriers in this family.","variants":[{"Name":"NM_003000.3(SDHB):c.418G>T (p.Val140Phe)","Chromosome":"1","Start":"17028605","Stop":"17028605","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":33493,"rule_based_match":true,"evidence_text":"c.418G>T, p.Val140Phe","llm_judgment":"PRESENT","evidence":"c.418G>T, p.Val140Phe","abstract_start":607,"abstract_end":628}]}
{"pmid":"35860951","title":"Phenotypic continuum between POLE-related recessive disorders: A case report and literature review.","abstract":"POLE is a pleiotropic gene with phenotypic expression of pathogenic variants depending on the type of variant, impact on the protein, and mode of inheritance. Heterozygous missense variants located within the exonuclease domain have been shown to result in polymerase proofreading-associated polyposis (PPAP) which is characterized by an increased risk for colon polyps and colorectal cancer. Biallelic variants resulting in markedly reduced amounts of normal protein have been reported in two separate recessive pediatric syndromes: facial dysmorphism, immunodeficiency, livedo, and short stature as well as intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genital anomalies. Here we report two siblings identified to have POLE c.1686 + 32C > G in trans with POLE p.(Glu709*) via exome sequencing. A detailed review of the reported phenotypes in these two siblings and from available literature revealed that individuals with biallelic POLE pathogenic variants resulting in partial loss-of-function present with a similar phenotype: short stature and facial dysmorphism with or without immunodeficiency. These data suggest a phenotypic continuum between the previously reported POLE-related recessive disorders.","variants":[{"Name":"NM_006231.4(POLE):c.1686+32C>G","Chromosome":"12","Start":"132672595","Stop":"132672595","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":610483,"rule_based_match":true,"evidence_text":"c.1686 + 32C > G","llm_judgment":"PRESENT","evidence":"c.1686 + 32C > G","abstract_start":771,"abstract_end":787}]}
{"pmid":"27348394","title":"Novel Col12A1 variant expands the clinical picture of congenital myopathies with extracellular matrix defects.","abstract":"INTRODUCTION: Mutations in the COL12A1 (collagen, type XII, alpha 1) gene have been described in a milder Bethlem-like myopathy in 6 patients from 3 families (dominant missense), and in a severe congenital form with failure to attain ambulation in 2 patients in a single pedigree (recessive loss-of-function).\nMETHODS: We describe an 8-year-old girl of Polish origin who presented with profound hypotonia and joint hyperlaxity at birth after a pregnancy complicated by oligohydramnios and intrauterine growth retardation.\nRESULTS: We identified a novel, potentially pathogenic heterozygous missense COL12A1 c.8329G>C (p.Gly2777Arg) variant using a targeted sequencing panel. Patient fibroblast studies confirmed intracellular retention of the COL12A1 protein, consistent with a dominant-negative mutation.\nCONCLUSIONS: As our patient showed a more intermediate phenotype, this case expands the phenotypic spectrum for COL12A1 disorders. So far, COL12A1 disorders seem to cover much of the severity range of an Ehlers-Danlos/Bethlem-like myopathy overlap syndrome associated with both connective tissue abnormalities and muscle weakness. Muscle Nerve 55: 277-281, 2017.","variants":[{"Name":"NM_004370.6(COL12A1):c.8329G>C (p.Gly2777Arg)","Chromosome":"6","Start":"75102683","Stop":"75102683","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2670429,"rule_based_match":true,"evidence_text":"COL12A1 c.8329G>C (p.Gly2777Arg)","llm_judgment":"PRESENT","evidence":"COL12A1 c.8329G>C (p.Gly2777Arg)","abstract_start":599,"abstract_end":631}]}
{"pmid":"25029497","title":"FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease.","abstract":"Mutations in the F-box only protein 7 gene (FBXO7), the substrate-specifying subunit of SCF E3 ubiquitin ligase complex, cause Parkinson's disease (PD)-15 (PARK15). To identify new variants, we sequenced FBXO7 cDNA in 80 Taiwanese early onset PD patients (age at onset ≤ 50) and only two known variants, Y52C (c.155A>G) and M115I (c.345G>A), were found. To assess the association of Y52C and M115I with the risk of PD, we conducted a case-control study in a cohort of PD and ethnically matched controls. There was a nominal difference in the Y52C G allele frequency between PD and controls (p = 0.045). After combining data from China [1], significant difference in the Y52C G allele frequency between PD and controls (p = 0.012) and significant association of G allele with decreased PD risk (p = 0.017) can be demonstrated. Upon expressing EGFP-tagged Cys52 FBXO7 in cells, a significantly reduced rate of FBXO7 protein decay was observed when compared with cells expressing Tyr52 FBXO7. In silico modeling of Cys52 exhibited a more stable feature than Tyr52. In cells expressing Cys52 FBXO7, the level of TNF receptor-associated factor 2 (TRAF2) was significantly reduced. Moreover, Cys52 FBXO7 showed stronger interaction with TRAF2 and promoted TRAF2 ubiquitination, which may be responsible for the reduced TRAF2 expression in Cys52 cells. After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth. We therefore hypothesize that Cys52 variant of FBXO7 may contribute to reduced PD susceptibility in Chinese.","variants":[{"Name":"NM_012179.4(FBXO7):c.155A>G (p.Tyr52Cys)","Chromosome":"22","Start":"32479013","Stop":"32479013","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":891137,"rule_based_match":true,"evidence_text":"c.155A>G","llm_judgment":"PRESENT","evidence":"c.155A>G","abstract_start":310,"abstract_end":318}]}
{"pmid":"28150229","title":"Identification of TP53BP2 as a Novel Candidate Gene for Primary Open Angle Glaucoma by Whole Exome Sequencing in a Large Multiplex Family.","abstract":"Primary open angle glaucoma (POAG) is a major type of glaucoma characterized by progressive loss of retinal ganglion cells with associated visual field loss without an identifiable secondary cause. Genetic factors are considered to be major contributors to the pathogenesis of glaucoma. The aim of the study was to identify the causative gene in a large family with POAG by applying whole exome sequencing (WES). WES was performed on the DNA of four affected family members. Rare pathogenic variants shared among the affected individuals were filtered. Polymerase chain reaction and Sanger sequencing were used to analyze variants segregating with the disease in additional family members. WES analysis identified a variant in TP53BP2 (c.109G>A; p.Val37Met) that segregated heterozygously with the disease. In silico analysis of the substitution predicted it to be pathogenic. The variant was absent in public databases and in 180 population-matched controls. A novel genetic variant in the TP53BP2 gene was identified in a family with POAG. Interestingly, it has previously been demonstrated that the gene regulates apoptosis in retinal ganglion cells. This supports that the TP53BP2 variant may represent the cause of POAG in this family. Additional screening of the gene in patients with POAG from different populations is required to confirm its involvement in the disease.","variants":[{"Name":"NM_001031685.3(TP53BP2):c.109G>A (p.Val37Met)","Chromosome":"1","Start":"223821286","Stop":"223821286","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2852780,"rule_based_match":true,"evidence_text":"c.109G>A; p.Val37Met","llm_judgment":"PRESENT","evidence":"c.109G>A; p.Val37Met","abstract_start":736,"abstract_end":756}]}
{"pmid":"24339620","title":"Multiple sulfatase deficiency: A case series of four children.","abstract":"Multiple sulfatase deficiency is biochemically characterized by the accumulation of sulfated lipids and acid mucopolysaccharides. The gene sulfatase-modifying factor 1 (SUMF1), recently identified, encodes the enzyme responsible for post-translational modification of a cysteine residue, which is essential for the activity of sulfatases. We describe clinical findings and mutation analysis of four patients. The patients presented with hypotonia, developmental delay, coarse face, ichthyosis, and hepatosplenomegaly. The diagnosis was made through clinical findings, enzymatic assays, and mutation analysis. We were detected to be homozygous for a novel missense mutation c. 739G > C causing a p.G247R amino acid substitution in the SUMF1 protein.","variants":[{"Name":"NM_182760.4(SUMF1):c.739G>C (p.Gly247Arg)","Chromosome":"3","Start":"4417229","Stop":"4417229","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":357324,"rule_based_match":true,"evidence_text":"c. 739G > C","llm_judgment":"PRESENT","evidence":"c. 739G > C","abstract_start":673,"abstract_end":684}]}
{"pmid":"28860541","title":"Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.","abstract":"COACH syndrome is an autosomal recessive developmental disorder, a subtype of Joubert syndrome and related disorders, characterized by cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Although mutations in TMEM67 (transmembrane protein 67)/MKS3 (Meckel-Gruber syndrome, type 3) were reported to cause COACH syndrome, this causality has not verified by functional studies. In a 20-year-old Korean man, we found cerebellar ataxia, isolated elevation in serum γ-glutamyl transpeptidase (γ-GTP) activity, oligophrenia, the molar tooth sign (MTS) in the brain MR images and congenital hepatic fibrosis (CHF). Two novel compound heterozygous mutations were found in TMEM67 in the patient: i) missense mutation (c.395 G > C and p.Gly132Ala) in exon 3, and ii) deletion in exon 26 (c.2758delT and p.Tyr920ThrfsX40). Western blotting showed that the p.Tyr920ThrfsX40 mutation accelerates turnover of the TMEM67 protein. Although wild-type human TMEM67 RNA rescued phenotypes of zebrafish embryos injected with anti-sense oligonucleotide morpholinos against tmem67, the two human TMEM67 RNAs individually harboring the two mutations did not. Finally, Wnt signaling, but not Hedgehog signaling, was suppressed in tmem67 morphants. To the best of our knowledge, this is the first report verifying the causality between COACH syndrome and TMEM67, which will further our understanding of molecular pathogenesis of the syndrome.","variants":[{"Name":"NM_153704.6(TMEM67):c.395G>C (p.Gly132Ala)","Chromosome":"8","Start":"93758565","Stop":"93758565","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2668774,"rule_based_match":true,"evidence_text":"c.395 G > C and p.Gly132Ala","llm_judgment":"PRESENT","evidence":"c.395 G > C and p.Gly132Ala","abstract_start":740,"abstract_end":767}]}
{"pmid":"34052850","title":"FBXO43 variants in patients with female infertility characterized by early embryonic arrest.","abstract":"STUDY QUESTION: Can any new genetic factors responsible for early embryonic arrest in infertile patients be identified, together with the mechanism of pathogenic variants?\nSUMMARY ANSWER: We identified three homozygous variants in the F-box protein 43 gene (FBXO43) in infertile patients and studies on the effects of the variants in HEK293T cells and mouse oocytes provided evidence for a causal relation between FBXO43 and female infertility.\nWHAT IS KNOWN ALREADY: FBXO43, an inhibitor of the anaphase-promoting complex/cyclosome, mediates Metaphase II arrest as a component of the cytostatic factor in oocytes. Both male and female Fbxo43 knockout mice are viable but sterile. FBXO43, therefore, appears to be an essential component of the mammalian cell-cycle machinery that regulates both male and female meiosis. Until now, only one article has reported a homozygous FBXO43 variant associated with teratozoospermia, but the causal relationship was not established with functional evidence.\nSTUDY DESIGN, SIZE, DURATION: Whole-exome sequencing (WES) and homozygosity mapping were performed in 24 probands from consanguineous families who suffered from early embryonic arrest, and two different homozygous variants in FBXO43 were identified in two independent families. WES data from a further 950 infertile women with early embryonic arrest were screened for homozygous and compound heterozygous variants in FBXO43, and a third individual with an additional homozygous variant in FBXO43 was identified. The infertile patients presenting with early embryonic arrest were recruited from August 2016 to May 2020.\nPARTICIPANTS/MATERIALS, SETTING, METHODS: The women diagnosed with primary infertility were recruited from the reproduction centers of local hospitals. Genomic DNA samples from the affected individuals, their family members, and healthy controls were extracted from peripheral blood. The FBXO43 variants were identified using WES, homozygosity mapping, in silico analysis, and variant screening. All of the variants were confirmed by Sanger sequencing, and the effects of the variants were investigated in human embryonic kidney (HEK) 293T cells by western blotting and in mouse oocytes by complementary RNA injection.\nMAIN RESULTS AND THE ROLE OF CHANCE: We identified three homozygous variants in FBXO43 (NM_001029860.4)-namely, c.1490_1497dup (p.(Glu500Serfs*2)), c.1747C>T (p.(Gln583*)), and c.154delG (p.(Asp52Thrfs*30))-in three independent families. All of the homozygous variants reduced the protein level of FBXO43 and reduced the level of its downstream target Cyclin B1 in HEK293T cells. In addition, the variants reduced the ability of exogenous human FBXO43 to rescue the parthenogenetic activation phenotype in Fbxo43 knockdown mouse oocytes.\nLIMITATIONS, REASONS FOR CAUTION: Owing to the lack of in vivo data from the oocytes of patients, the exact molecular mechanism remains unknown and should be further investigated using knock out or knock in mice.\nWIDER IMPLICATIONS OF THE FINDINGS: Our study has identified three pathogenic variants in FBXO43 that are involved in human early embryonic arrest. These findings contribute to our understanding of the role of FBXO43 in human early embryonic development and provide a new genetic marker for female infertility.\nSTUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research and Development Program of China (2018YFC1003800, 2017YFC1001500, and 2016YFC1000600), the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, 81971382, and 82001552), the project supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the Project of the Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500), the Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (18SG03), the Foundation of the Shanghai Health and Family Planning Commission (20154Y0162), the Capacity Building Planning Program for Shanghai Women and Children's Health Service, and the collaborative innovation center project construction for Shanghai Women and Children's Health. None of the authors have any competing interests.\nTRIAL REGISTRATION NUMBER: N/A.","variants":[{"Name":"NM_001029860.4(FBXO43):c.1747C>T (p.Gln583Ter)","Chromosome":"8","Start":"100134292","Stop":"100134292","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1323620,"rule_based_match":true,"evidence_text":"c.1747C>T (p.(Gln583*))","llm_judgment":"PRESENT","evidence":"c.1747C>T (p.(Gln583*))","abstract_start":2383,"abstract_end":2406},{"Name":"NM_001029860.4(FBXO43):c.1490_1497dup (p.Glu500delinsSerTer)","Chromosome":"8","Start":"100140756","Stop":"100140757","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CTGTTAAGA","allel_id":1323621,"rule_based_match":true,"evidence_text":"c.1490_1497dup (p.(Glu500Serfs*2))","llm_judgment":"PRESENT","evidence":"c.1490_1497dup (p.(Glu500Serfs*2))","abstract_start":2347,"abstract_end":2381},{"Name":"NM_001029860.4(FBXO43):c.154del (p.Asp52fs)","Chromosome":"8","Start":"100142100","Stop":"100142100","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":1323622,"rule_based_match":true,"evidence_text":"c.154delG (p.(Asp52Thrfs*30))","llm_judgment":"PRESENT","evidence":"c.154delG (p.(Asp52Thrfs*30))","abstract_start":2412,"abstract_end":2441}]}
{"pmid":"30028003","title":"Distal renal tubular acidosis caused by tryptophan-aspartate repeat domain 72 (WDR72) mutations.","abstract":"Hereditary distal renal tubular acidosis (dRTA) is a rare genetic disease that is caused by mutations in SLC4A1, ATP6V1B1, or ATP6V0A4. However, there are many families with hereditary dRTA in whom the disease-causing genes are unknown. Accordingly, we performed whole exome sequencing and genetic studies of the members of a family with autosomal recessive dRTA of an unknown genetic etiology. Here, we report compound heterozygous pathogenic variations in tryptophan-aspartate repeat domain 72 (WDR72) (c.1777A>G [p.R593G] and c.2522T>A [p.L841Q]) in three affected siblings of a family with dRTA. Both variants segregated with dRTA in the family and were not observed in normal control subjects. Homologous modeling and in silico mutagenesis indicated that R593G and L841Q alter the H-bond formations in the nearby residues, affecting the WDR72 protein structure. All these evidences indicate that the identified WDR72 variations were probably to have caused hereditary dRTA in the reported family. In addition, homozygous nonsense mutation (c.2686C>T [p.R896X]) was identified in another family, strongly supporting the causal role of WDR72 in dRTA. Based on our literature review, WDR72 mutations associated with dRTA have not been previously described. This is the first identification of pathogenic variations in WDR72 as a cause of hereditary dRTA.","variants":[{"Name":"NM_182758.4(WDR72):c.2686C>T (p.Arg896Ter)","Chromosome":"15","Start":"53615520","Stop":"53615520","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":513221,"rule_based_match":true,"evidence_text":"c.2686C>T (p.R896X)","llm_judgment":"PRESENT","evidence":"c.2686C>T","abstract_start":1045,"abstract_end":1054},{"Name":"NM_182758.4(WDR72):c.2522T>A (p.Leu841Gln)","Chromosome":"15","Start":"53615684","Stop":"53615684","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":513222,"rule_based_match":true,"evidence_text":"c.2522T>A (p.L841Q)","llm_judgment":"PRESENT","evidence":"c.2522T>A","abstract_start":529,"abstract_end":538},{"Name":"NM_182758.4(WDR72):c.1777A>G (p.Arg593Gly)","Chromosome":"15","Start":"53665757","Stop":"53665757","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":513223,"rule_based_match":true,"evidence_text":"c.1777A>G [p.R593G]","llm_judgment":"PRESENT","evidence":"c.1777A>G [p.R593G]","abstract_start":505,"abstract_end":524}]}
{"pmid":"24715573","title":"Entire CAPN3 gene deletion in a patient with limb-girdle muscular dystrophy type 2A.","abstract":"Limb-girdle muscular dystrophy type 2A (LGMD2A) due to mutations in the CAPN3 gene is one of the most common of autosomal recessive limb-girdle muscular dystrophies. We describe a patient who had a typical LGMD2A phenotype and posterior compartment involvement on MRI. Different genetic analyses were performed, including microarray analysis. There was an apparently homozygous mutation in exon 24, c.2465G>T, p.(*822Leuext62*), and a lack of correlation in the disease segregation analyses. This suggested the presence of a genomic rearrangement. In fact, a heterozygous deletion of the entire CAPN3 gene was found. This novel deletion comprised the terminal region of the GANC gene and the entire CAPN3 gene. This finding points out the need to reconsider and adapt our current strategy of molecular diagnosis in order to detect these types of genomic rearrangements that escape standard mutation screening procedures.","variants":[{"Name":"NM_000070.3(CAPN3):c.2465G>T (p.Ter822Leu)","Chromosome":"15","Start":"42411772","Stop":"42411772","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":568795,"rule_based_match":true,"evidence_text":"c.2465G>T","llm_judgment":"PRESENT","evidence":"c.2465G>T","abstract_start":399,"abstract_end":408}]}
{"pmid":"23255486","title":"Identification of a novel oligomerization disrupting mutation in CRYΑA associated with congenital cataract in a South Australian family.","abstract":"Congenital cataract is a heterogeneous disorder causing severe visual impairment in affected children. We screened four South Australian families with autosomal dominant congenital cataract for mutations in 10 crystallin genes known to cause congenital cataract. We identified a novel segregating heterozygous mutation, c.62G>A (p.R21Q), in the CRYΑA gene in one family. Western blotting of proteins freshly extracted from cataractous lens material of the proband demonstrated a marked reduction in the amount of the high-molecular-weight oligomers seen in the lens material of an unaffected individual. We conclude that the p.R21Q mutation, which is located in the highly conserved and structurally significant N-terminal region of the protein, is responsible for the cataract phenotype observed in the family as this mutation likely reduces the formation of the functional oligomeric alpha-crystallin.","variants":[{"Name":"NM_000394.4(CRYAA):c.62G>A (p.Arg21Gln)","Chromosome":"21","Start":"43169161","Stop":"43169161","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":79353,"rule_based_match":true,"evidence_text":"c.62G>A (p.R21Q)","llm_judgment":"PRESENT","evidence":"c.62G>A (p.R21Q)","abstract_start":320,"abstract_end":336}]}
{"pmid":"30986545","title":"Novel EXOSC3 pathogenic variant results in a mild course of neurologic disease with cerebellum involvement.","abstract":"EXOSC3-related autosomal recessive neurodevelopmental disorders are rare entities with variable clinical course and prognosis. They are characterized by hypoplasia of cerebellar structures and pons, degeneration of the anterior horn cells and motor as well as neurocognitive impairment. Phenotypic expression is variable with an overall poor outcome. Current research suggests clear genotype-phenotype correlations among EXOSC3-pathogenic-variants carriers. Homozygosity for the EXOSC3 variant c.395A > C, p.(Asp132Ala) is proposed to lead to a rather mild phenotype compared to compound-heterozygous EXOSC3-pathogenic-variants carriers with lethal neurological disease in very early childhood. In this study, we report two siblings (21- and 8-year-old) affected by PCH1B with an unusual presentation. We identified compound heterozygosity for the well-established EXOSC3 variant c.395A > C, p.(Asp132Ala) and the novel variant c.572G > A, p.(Gly191Asp), expanding the genetic spectrum. Phenotypic presentation of the siblings was strikingly different from that of literature reports with a surprisingly mild disease manifestation and an unexpected intrafamilial variability. This study demonstrates the extensive clinical heterogeneity and the broad phenotypic spectrum associated with EXOSC3-associated disorders. Enlargement of sample sizes and reports of novel cases will be essential for the delineation of associated phenotypes.","variants":[{"Name":"NM_016042.4(EXOSC3):c.572G>A (p.Gly191Asp)","Chromosome":"9","Start":"37782040","Stop":"37782040","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":207721,"rule_based_match":true,"evidence_text":"c.572G > A, p.(Gly191Asp)","llm_judgment":"PRESENT","evidence":"c.572G > A, p.(Gly191Asp)","abstract_start":928,"abstract_end":953},{"Name":"NM_016042.4(EXOSC3):c.395A>C (p.Asp132Ala)","Chromosome":"9","Start":"37783993","Stop":"37783993","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":40348,"rule_based_match":true,"evidence_text":"c.395A > C, p.(Asp132Ala)","llm_judgment":"PRESENT","evidence":"c.395A > C, p.(Asp132Ala)","abstract_start":494,"abstract_end":519}]}
{"pmid":"29305691","title":"The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.","abstract":"Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.","variants":[{"Name":"NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys)","Chromosome":"19","Start":"41970275","Stop":"41970275","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":166024,"rule_based_match":true,"evidence_text":"c.2452G>A, p.Glu818Lys","llm_judgment":"PRESENT","evidence":"c.2452G>A, p.Glu818Lys","abstract_start":186,"abstract_end":208}]}
{"pmid":"19880769","title":"Two novel HADHB gene mutations in a Korean patient with mitochondrial trifunctional protein deficiency.","abstract":"Mitochondrial trifunctional protein (MTP) is a heterocomplex composed of 4 alpha-subunits containing LCEH (long-chain 2,3-enoyl-CoA hydratase) and LCHAD (long-chain 3-hydroxyacyl CoA dehydrogenase) activity, and 4 beta-subunits that harbor LCKT (long-chain 3-ketoacyl-CoA thiolase) activity. MTP deficiency is an autosomal recessive disorder that causes a clinical spectrum of diseases ranging from severe infantile cardiomyopathy to mild chronic progressive polyneuropathy. Here, we report the case of a Korean male newborn who presented with severe lactic acidosis, seizures, and heart failure. A newborn screening test and plasma acylcarnitine profile analysis by tandem mass spectrometry showed an increase of 3-hydroxy species: 3-OH-palmitoylcarnitine, 0.44 nmol/ml (reference range, RR <0.07); 3-OH-linoleylcarnitine, 0.31 nmol/ml (RR <0.06); and 3-OH-oleylcarnitine, 0.51 nmol/ml (RR <0.04). These findings suggested either long-chain 3-hydroxyacyl-coA dehydrogenase deficiency or complete MTP deficiency. By molecular analysis of the HADHB gene, the patient was found to be a compound heterozygote for c.358dupT (p.A120CfsX8) and c.1364T>G (p.V455G) mutations. These 2 mutations of the HADHB gene were novel and inherited. Although the patient was treated by reduction of glucose administration and supplementation of a medium-chain triglyceride-based diet with L-carnitine, he died 2 mo after birth due to advanced cardiac failure.","variants":[{"Name":"NM_000183.3(HADHB):c.1364T>G (p.Val455Gly)","Chromosome":"2","Start":"26285546","Stop":"26285546","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":29888,"rule_based_match":true,"evidence_text":"c.1364T>G (p.V455G)","llm_judgment":"PRESENT","evidence":"c.1364T>G (p.V455G)","abstract_start":1138,"abstract_end":1157}]}
{"pmid":"15523648","title":"Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited case of mucolipidosis IV.","abstract":"A patient with mucolipidosis-IV heterozygous for two mutations in MCOLN1 expressed only her father's cDNA mutation c.1207C>T predicting an R403C change in mucolipin. She inherited a 93bp segment from mitochondrial NADH dehydrogenase 5 (MTND5) from her mother that was inserted in-frame prior to the last nucleotide of exon 2 of MCOLN1 (c.236_237ins93). This alteration abolished proper splicing of MCOLN1. The splice site at the end of the exon was not used due to an inhibitory effect of the inserted segment, resulting in two aberrant splice products containing stop codons in the downstream intron. These products were eliminated via nonsense-mediated decay. This is the first report of an inherited transfer of mitochondrial nuclear DNA causing a genetic disease. The elimination of the splice site by the mitochondrial DNA requires a change in splicing prediction models.","variants":[{"Name":"NM_020533.3(MCOLN1):c.236_237insCCATTATGTAAAATCCATTGTCGCATCCACCTTTATTATCAGTCTCTTCCCCACAACAATATTCATGTGCCTAGACCAAGAAGTTATTATCTC (p.Gln79delinsHisHisTyrValLysSerIleValAlaSerThrPheIleIleSerLeuPheProThrThrIlePheMetCysLeuAspGlnGluValIleIleSer)","Chromosome":"19","Start":"7525165","Stop":"7525166","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ACCATTATGTAAAATCCATTGTCGCATCCACCTTTATTATCAGTCTCTTCCCCACAACAATATTCATGTGCCTAGACCAAGAAGTTATTATCTC","allel_id":3074437,"rule_based_match":false,"evidence_text":"c.236_237ins93","llm_judgment":"PRESENT","evidence":"c.236_237ins93","abstract_start":336,"abstract_end":350},{"Name":"NM_020533.3(MCOLN1):c.1207C>T (p.Arg403Cys)","Chromosome":"19","Start":"7529173","Stop":"7529173","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20176,"rule_based_match":true,"evidence_text":"c.1207C>T","llm_judgment":"PRESENT","evidence":"c.1207C>T","abstract_start":115,"abstract_end":124},{"Name":"NM_020533.3(MCOLN1):c.236_237ins[NC_012920.1:m.12435_12527] (p.Gln79delinsHisHisTyrValLysSerIleValAlaSerThrPheIleIleSerLeuPheProThrThrIlePheMetCysLeuAspGlnGluValIleIleSer)","Chromosome":"19","Start":"7525165","Stop":"7525166","ReferenceAlleleVCF":"na","AlternateAlleleVCF":"na","allel_id":204285,"rule_based_match":false,"evidence_text":"c.236_237ins93","llm_judgment":"PRESENT","evidence":"c.236_237ins93","abstract_start":336,"abstract_end":350}]}
{"pmid":"28411331","title":"Glutaric Acidemia Type 1: A Case of Infantile Stroke.","abstract":"BACKGROUND: Glutaric acidemia Type 1 (GA-1) is an autosomal recessively inherited metabolic disorder which is associated with GCDH gene mutations which alters the glutaryl-CoA dehydrogenase, an enzyme playing role in the catabolic pathways of the amino acids lysine, hydroxylysine, and tryptophan. Clinical findings are often encephalopathic crises, dystonia, and extrapyramidal symptoms.\nCASE REPORT: A 9-month-old male infant referred to our department with focal tonic-clonic seizures during rotavirus infection and acute infarcts in MRI. Clinical manifestation, MRI findings, and metabolic investigations directed thoughts towards GA-I. Molecular genetic testing revealed a homozygous c.572T>C (p.M191T) mutation in GCDH gene which confirmed the diagnosis. Application of protein restricted diet, carnitine and riboflavin supplementations prevented the progression of Magnetic Resonance Imaging (MRI) and clinical pathologic findings during the 1 year of follow-up period.\nCONCLUSION: This case is of great importance since it shows possibility of infantile stroke in GA-1, significance of early diagnosis and phenotypic variability of disease.","variants":[{"Name":"NM_000159.4(GCDH):c.572T>C (p.Met191Thr)","Chromosome":"19","Start":"12896058","Stop":"12896058","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":195557,"rule_based_match":true,"evidence_text":"c.572T>C (p.M191T)","llm_judgment":"PRESENT","evidence":"c.572T>C (p.M191T)","abstract_start":689,"abstract_end":707}]}
{"pmid":"33405357","title":"Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients.","abstract":"We describe the clinical, electrodiagnostic, and genetic findings of three homozygous FIG4-c.122T>C patients suffering from Charcot-Marie-Tooth disease type 4J (AR-CMT-FIG4). This syndrome usually involves compound heterozygosity associating FIG4-c.122T>C, a hypomorphic allele coding an unstable FIG4-p.Ile41Thr protein, and a null allele. While the compound heterozygous patients presenting with early onset usually show rapid progression, the homozygous patients described here show the signs of relative clinical stability. As FIG4 activity is known to be dose dependent, these patients' observations could suggest that the therapeutic perspective of increasing levels of the protein to improve the phenotype of AR-CMT-FIG4-patients might be efficient.","variants":[{"Name":"NM_014845.6(FIG4):c.122T>C (p.Ile41Thr)","Chromosome":"6","Start":"109715133","Stop":"109715133","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":16760,"rule_based_match":true,"evidence_text":"FIG4-c.122T>C","llm_judgment":"PRESENT","evidence":"FIG4-c.122T>C","abstract_start":86,"abstract_end":99}]}
{"pmid":"31209944","title":"Homozygous loss-of-function variants of TASP1, a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies.","abstract":"We report four unrelated children with homozygous loss-of-function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure-to-thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5-11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.Thr234Met), affecting the active site of the encoded enzyme, and the fourth had a homozygous nonsense variant, c.199 C>T (p.Arg67*). TASP1 encodes taspase 1 (TASP1), which is responsible for cleaving, thus activating, the lysine methyltransferases KMT2A and KMT2D, which are essential for histone methylation and transcription regulation. The consistency of the phenotype, the critical biological function of TASP1, the deleterious nature of the TASP1 variants, and the overlapping features with Wiedemann-Steiner and Kabuki syndromes respectively caused by pathogenic variants in KMT2A and KMT2D all support that TASP1 is a disease-related gene.","variants":[{"Name":"NM_017714.3(TASP1):c.199C>T (p.Arg67Ter)","Chromosome":"20","Start":"13625199","Stop":"13625199","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":622041,"rule_based_match":true,"evidence_text":"c.199 C>T (p.Arg67*)","llm_judgment":"PRESENT","evidence":"c.199 C>T (p.Arg67*)","abstract_start":602,"abstract_end":622},{"Name":"NM_017714.3(TASP1):c.701C>T (p.Thr234Met)","Chromosome":"20","Start":"13534116","Stop":"13534116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":622207,"rule_based_match":true,"evidence_text":"c.701 C>T (p.Thr234Met)","llm_judgment":"PRESENT","evidence":"c.701 C>T (p.Thr234Met)","abstract_start":478,"abstract_end":501}]}
{"pmid":"16244682","title":"Malignant hyperthermia--a hereditary and potentially life-threatening condition","abstract":"BACKGROUND: Malignant hyperthermia is a rare and possibly life-threatening complication to anaesthesia. It manifests in susceptible individuals as a hypermetabolic response on exposure to halogenated anaesthetics and depolarising muscle relaxants. Susceptibility to malignant hyperthermia is inherited as an autosomal dominant disorder and is associated with myopathies.\nMATERIAL AND METHODS: We present a Norwegian family with central core disease and malignant hyperthermia susceptibility. A novel mutation (c.14558C>T) in the ryanodine receptor gene (RYR1), causing an amino acid change of a highly conserved residue (Thr4853Ile), has been identified in this family. We present a review of the literature on this disorder.\nRESULTS AND INTERPRETATION: Modern medical treatment, including the use of dantrolene, has significantly reduced the mortality of malignant hyperthermia. The identification of susceptibility to malignant hyperthermia in patients can possibly further reduce the risk of death during and after anaesthesia. A contracture test of muscular tissue is performed in patients with suspected malignant hyperthermia and should be considered in family members. Molecular genetic examinations might be considered in some cases.","variants":[{"Name":"NM_000540.3(RYR1):c.14558C>T (p.Thr4853Ile)","Chromosome":"19","Start":"38580416","Stop":"38580416","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":533057,"rule_based_match":true,"evidence_text":"c.14558C>T","llm_judgment":"PRESENT","evidence":"c.14558C>T","abstract_start":510,"abstract_end":520}]}
{"pmid":"23906836","title":"A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling.","abstract":"Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.","variants":[{"Name":"NM_001015877.2(PHF6):c.914G>T (p.Cys305Phe)","Chromosome":"X","Start":"134417248","Stop":"134417248","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":143192,"rule_based_match":true,"evidence_text":"c.914G>T (p.Cys305Phe)","llm_judgment":"PRESENT","evidence":"p.Cys305Phe","abstract_start":666,"abstract_end":677}]}
{"pmid":"20583295","title":"First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function.","abstract":"Sclerosteosis is a rare bone dysplasia characterized by greatly increased bone mass, especially of the long bones and the skull. Patients are tall, show facial asymmetry and often have syndactyly. Clinical complications are due to entrapment of cranial nerves. The disease is thought to be due to loss-of-function mutations in the SOST gene. The SOST gene product, sclerostin, is secreted by osteocytes and transported to the bone surface where it inhibits osteoblastic bone formation by antagonizing Wnt signaling. In a small Turkish family with sclerosteosis, we identified a missense mutation (c.499T>C; p.Cys167Arg) in exon 2 of the SOST gene. This type of mutation has not been previously reported and using different functional approaches, we show that it has a devastating effect on the biological function of sclerostin. The affected cysteine is the last cysteine residue of the cystine-knot motif and loss of this residue leads to retention of the mutant protein in the ER, possibly as a consequence of impaired folding. Together with a significant reduced ability to bind to LRP5 and inhibit Wnt signaling, the p.Cys167Arg mutation leads to a complete loss of function of sclerostin and thus to the characteristic sclerosteosis phenotype.","variants":[{"Name":"NM_025237.3(SOST):c.499T>C (p.Cys167Arg)","Chromosome":"17","Start":"43755485","Stop":"43755485","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1667689,"rule_based_match":true,"evidence_text":"c.499T>C (p.Cys167Arg)","llm_judgment":"PRESENT","evidence":"p.Cys167Arg","abstract_start":607,"abstract_end":618}]}
{"pmid":"29506905","title":"Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study.","abstract":"PURPOSE: Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder caused by pathogenic variants in GAMT. Brain creatine depletion and guanidinoacetate accumulation cause developmental delay, seizures and movement disorder. Treatment consists of creatine, ornithine and arginine-restricted diet. We initiated an international treatment registry using Research Electronic Data Capture (REDCap) software to evaluate treatment outcome.\nMETHODS: Physicians completed an online REDCap questionnaire. Clinical severity score applied pre-treatment and on treatment.\nRESULTS: There were 22 patients. All had developmental delay, 18 had seizures and 8 had movement disorder. Based on the clinical severity score, 5 patients had a severe, 14 patients had a moderate and 3 patients had a mild phenotype. All patients had pathogenic variants in GAMT. The phenotype ranged from mild to moderate in patients with the most common c.327G > A variant. The phenotype ranged from mild to severe in patients with truncating variants. All patients were on creatine, 18 patients were on ornithine and 15 patients were on arginine- or protein-restricted diet. Clinical severity score improved in 13 patients on treatment. Developmental delay improved in five patients. One patient achieved normal development. Eleven patients became seizure free. Movement disorder resolved in four patients.\nCONCLUSION: In our small patient cohort, there seems to be no phenotype-genotype correlation. Creatine and ornithine and/or arginine- or protein-restricted diet were the most useful treatment to improve phenotype.","variants":[{"Name":"NM_000156.6(GAMT):c.327G>A (p.Lys109=)","Chromosome":"19","Start":"1399793","Stop":"1399793","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33917,"rule_based_match":true,"evidence_text":"c.327G > A","llm_judgment":"PRESENT","evidence":"c.327G > A","abstract_start":945,"abstract_end":955}]}
{"pmid":"32337346","title":"Cerebellar ataxia, neuropathy, hearing loss, and intellectual disability due to AIFM1 mutation.","abstract":"OBJECTIVE: To describe the clinical and molecular genetic findings in a family segregating a novel mutation in the <i>AIFM1</i> gene on the X chromosome.\nMETHODS: We studied the clinical features and performed brain MRI scans, nerve conduction studies, audiometry, cognitive testing, and clinical exome sequencing (CES) in the proband, his mother, and maternal uncle. We used in silico tools, X chromosome inactivation assessment, and Western blot analysis to predict the consequences of an <i>AIFM1</i> variant identified by CES and demonstrate its pathogenicity.\nRESULTS: The proband and his maternal uncle presented with childhood-onset nonprogressive cerebellar ataxia, hearing loss, intellectual disability (ID), peripheral neuropathy, and mood and behavioral disorder. The proband's mother had mild cerebellar ataxia, ID, and mood and behavior disorder, but no neuropathy or hearing loss. The 3 subjects shared a variant (c.1195G>A; p.Gly399Ser) in exon 12 of the <i>AIFM1</i> gene, which is not reported in the exome/genome sequence databases, affecting a critical amino acid for protein function involved in NAD(H) binding and predicted to be pathogenic with very high probability by variant analysis programs. X chromosome inactivation was highly skewed in the proband's mother. The mutation did not cause quantitative changes in protein abundance.\nCONCLUSIONS: Our report extends the molecular and phenotypic spectrum of <i>AIFM1</i> mutations. Specific findings include limited progression of neurologic abnormalities after the first decade and the coexistence of mood and behavior disorder. This family also shows the confounding effect on the phenotype of nongenetic factors, such as alcohol and drug use and side effects of medication.","variants":[{"Name":"NM_004208.4(AIFM1):c.1195G>A (p.Gly399Ser)","Chromosome":"X","Start":"130136155","Stop":"130136155","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3092028,"rule_based_match":true,"evidence_text":"c.1195G>A; p.Gly399Ser","llm_judgment":"PRESENT","evidence":"c.1195G>A; p.Gly399Ser","abstract_start":928,"abstract_end":950}]}
{"pmid":"35252061","title":"Case Report: Identification and Functional Analysis of a Homozygous Synonymous Variant in the","abstract":"BACKGROUND: Kyphoscoliotic Ehlers-Danlos syndrome (kEDS; OMIM225400) is a rare autosomal recessive genetic disease caused by variants in the <i>PLOD1</i> gene. This research was conducted to verify the disease-causing gene in a Chinese neonatal family with the EDS.\nMETHODS: We recruited a Han Chinese neonate with <i>PLOD1</i>-related kEDS without kyphoscoliosis. Detailed clinical examination and laboratory tests were performed and whole exome sequencing (WES) was used to detect the pathogenic genes of the proband. <i>In vivo</i> experiments (reverse-transcription PCR, quantitative real-time PCR) and <i>in vitro</i> experiments (minigene analysis) were used to verify the function of variants suspected of affecting the splicing process. The effect of the splice site variant on the <i>PLOD1</i> transcript was analyzed using splice prediction programs NetGene2 and Alternative Splice Site Predictor (ASSP).\nRESULTS: A homozygous synonymous variant c.1095C>T (p.Gly365, rs1032781250) in the <i>PLOD1</i> gene was found and verified in the family with kEDS. This splicing variant resulted in a premature termination codon of exon 10 and affected the expression of the four bases GCGC.\nCONCLUSION: Our research showed that the homozygous synonymous variant in <i>PLOD1</i> was the pathogenic cause in the proband. The combined application of WES and functional studies verified the effect of uncertain gene variants on splicing, upgrading pathogenicity evidence, and determining the cause of disease. This is helpful for the early diagnosis and treatment of kEDS.","variants":[{"Name":"NM_000302.4(PLOD1):c.1095C>T (p.Gly365=)","Chromosome":"1","Start":"11960765","Stop":"11960765","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":556889,"rule_based_match":true,"evidence_text":"c.1095C>T (p.Gly365, rs1032781250)","llm_judgment":"PRESENT","evidence":"c.1095C>T (p.Gly365, rs1032781250)","abstract_start":956,"abstract_end":990}]}
{"pmid":"33376055","title":"A novel mutation in NEB causing foetal nemaline myopathy with arthrogryposis during early gestation.","abstract":"Nemaline myopathies are a clinically and genetically heterogeneous group of congenital myopathies, mainly characterized by muscle weakness, hypotonia and respiratory insufficiency. Here, we report a male foetus of consanguineous parents with a severe congenital syndrome characterized by arthrogryposis detected at 13 weeks of gestation. We describe severe complex dysmorphic facial and musculoskeletal features by post mortem fetal examination confirming the prenatal diagnosis. Histomorphological and ultrastructural studies of skeletal muscle reveal mini-rods in myotubes caused by a novel homozygous splice-site mutation in NEB (NM_001164508, chr2:g.152,417,623C>A GRCh37.p11 | c.19,102-1G>T ENST00000397345.3). No rods were seen in the myocardium. We discuss the relevance of this mutation in the context of nemaline myopathies associated with early developmental musculoskeletal disorders.","variants":[{"Name":"NM_001164508.2(NEB):c.19102-1G>T","Chromosome":"2","Start":"151561109","Stop":"151561109","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1109009,"rule_based_match":false,"evidence_text":"c.19,102-1G>T","llm_judgment":"PRESENT","evidence":"c.19,102-1G>T","abstract_start":682,"abstract_end":695}]}
{"pmid":"34382758","title":"Compound Heterozygous Variants in","abstract":"Kenny-Caffey syndrome (KCS) is a rare autosomal recessive (AR)/dominant disease characterized by hypoparathyroidism, skeletal dysplasia, dwarfism, and dysmorphism. <i>FAM111A</i> or TBCE gene mutations are responsible for this syndrome. Osteocraniostenosis (OCS) is a lethal syndrome with similar features to KCS, and it can be a severe form of KCS type 2 which results from the <i>FAM111A</i> gene mutation. The <i>FAM111A</i> mutation is generally characterized by the autosomal dominant transition. We present a male case having compound heterozygous variants (c.976T>A and c.1714_1716del) in the <i>FAM111A</i> gene with an AR inheritance pattern. Hypocalcemia developed on the second day of life. The patient and his older sister had a dysmorphic face, skeletal dysplasia, and they were diagnosed with hypoparathyroidism. Both siblings died due to septicemia. He is the first reported patient with the <i>FAM111A</i> mutation in Turkey. The phenotype of the patient is compatible with OCS, and the detected variants may explain the disease genetically.","variants":[{"Name":"NM_001312909.2(FAM111A):c.1714_1716del (p.Ile572del)","Chromosome":"11","Start":"59153382","Stop":"59153384","ReferenceAlleleVCF":"CATT","AlternateAlleleVCF":"C","allel_id":1383485,"rule_based_match":true,"evidence_text":"c.1714_1716del","llm_judgment":"PRESENT","evidence":"c.1714_1716del","abstract_start":577,"abstract_end":591}]}
{"pmid":"20307994","title":"Maple syrup urine disease: further evidence that newborn screening may fail to identify variant forms.","abstract":"Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has allowed for early detection and initiation of treatment in many patients with maple syrup urine disease (MSUD) (OMIM 248600), however, a recent report suggests that variants forms may be missed. Information on these patients is limited. We present clinical, biochemical and molecular information on patients with variant forms of MSUD not detected by the California Newborn Screening Program. Between July 2005 and July 2009, 2200,000 newborns were screened in California by MS/MS. Seventeen cases of MSUD were detected and three (two siblings) were missed. Additionally, the NBS cards of two siblings with late onset MSUD, who were born pre-expanded NBS, were retrospectively analyzed. None of the five patients met criteria to be considered presumptive positive for MSUD (leucine>200micromol/L and a ratio of leucine/alanine>or=1.5). Alloisoleucine (allo-ile) was subsequently analyzed in the NBS cards of all five patients, two of whom were found to have elevated levels. The proband in each family was diagnosed following symptoms triggered by an intercurrent illness or increased protein intake. At diagnosis, leucine levels ranged between 561 and >4528micromol/L, and allo-ile ranged from 137 to 239micromol/L. Two affected siblings had normal plasma amino acids when asymptomatic; however, their biochemical profiles were diagnostic of MSUD during intercurrent illnesses. The median age at diagnosis of all patients was one year (range 0.8-6.7). Heterozygous BCKDHB (E1beta) mutations (c.832G>A/c.970C>T) were identified in one family and a homozygous DBT (E2) sequence variant (c.1430 T>G) in another. The third family had one identifiable DBT mutation (c.827T>G), however, a second mutation was not detected. This report provides further evidence that NBS by MS/MS is unable to detect all cases of MSUD. Second-tier testing with allo-ile may improve sensitivity; however, some children with variant forms will invariably be missed.","variants":[{"Name":"NM_183050.4(BCKDHB):c.832G>A (p.Gly278Ser)","Chromosome":"6","Start":"80201023","Stop":"80201023","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76679,"rule_based_match":true,"evidence_text":"c.832G>A","llm_judgment":"PRESENT","evidence":"c.832G>A","abstract_start":1557,"abstract_end":1565},{"Name":"NM_001918.5(DBT):c.1430T>G (p.Met477Arg)","Chromosome":"1","Start":"100196274","Stop":"100196274","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":99896,"rule_based_match":true,"evidence_text":"c.1430 T>G","llm_judgment":"PRESENT","evidence":"c.1430 T>G","abstract_start":1650,"abstract_end":1660}]}
{"pmid":"20122277","title":"A novel germline PALB2 deletion in Polish breast and ovarian cancer patients.","abstract":"BACKGROUND: PALB2 protein was recently identified as a partner of BRCA1 and BRCA2 which determines their proper function in DNA repair.\nMETHODS: Initially, the entire coding sequence of the PALB2 gene with exon/intron boundaries was evaluated by the PCR-SSCP and direct sequencing methods on 70 ovarian carcinomas. Sequence variants of interest were further studied on enlarged groups of ovarian carcinomas (total 339 non-consecutive ovarian carcinomas), blood samples from 334 consecutive sporadic and 648 consecutive familial breast cancer patients, and 1310 healthy controls from central Poland.\nRESULTS: Ten types of sequence variants were detected, and among them four novel polymorphisms: c.2996+58T>C in intron 9; c.505C>A (p.L169I), c.618T>G (p.L206L), both in exon 4; and c.2135C>T (A712V) in exon 5 of the PALB2 gene. Another two polymorphisms, c.212-58A>C and c.2014G>C (E672Q) were always detected together, both in cancer (7.5% of patients) and control samples (4.9% of controls, p = 0.2). A novel germline truncating mutation, c.509_510delGA (p.R170fs) was found in exon 4: in 2 of 339 (0.6%) unrelated ovarian cancer patients, in 4 of 648 (0.6%) unrelated familial breast cancer patients, and in 1 of 1310 controls (0.08%, p = 0.1, p = 0.044, respectively). One ovarian cancer patient with the PALB2 mutation had also a germline nonsense mutation of the BRCA2 gene.\nCONCLUSIONS: The c.509_510delGA is a novel PALB2 mutation that increases the risk of familial breast cancer. Occurrence of the same PALB2 alteration in seven unrelated women suggests that c.509_510delGA (p.R170fs) is a recurrent mutation for Polish population.","variants":[{"Name":"NM_024675.4(PALB2):c.509_510del (p.Arg170fs)","Chromosome":"16","Start":"23636036","Stop":"23636037","ReferenceAlleleVCF":"ATC","AlternateAlleleVCF":"A","allel_id":132267,"rule_based_match":true,"evidence_text":"c.509_510delGA (p.R170fs)","llm_judgment":"PRESENT","evidence":"c.509_510delGA (p.R170fs)","abstract_start":1041,"abstract_end":1066}]}
{"pmid":"35810428","title":"Clinical and genetic analysis of a patient with isolated 17,20 lyase deficiency presenting with pubertal gynecomastia","abstract":"OBJECTIVE: To explore the clinical and genetic basis for a patient with isolated 17,20 lyase deficiency presenting with pubertal gynecomastia.\nMETHODS: Clinical manifestation, steroid analysis as well as genetic testing were carried out for a 14-year-old boy featuring puberty gynecomastia.\nRESULTS: The patient was admitted due to puberty gynecomastia for 2 years. Physical examination showed Tanner B5, G2 and normal blood pressure. Laboratory examination showed normal range of serum potassium and blood gas. Steroid analysis revealed extremely high pregnenolone, progesterone, 17-hydropregnenolone and 17-hydroprogesterone, Correspondingly, the DHEA, androstenedione, testosterone and dihydrotestosterone were low. He was found to harbor compound heterozygous variants of CYP17A1 gene (c.1304T>C/p.F435S and c.1346G>A/p.R449H), among which the R449H variant may result in isolated 17,20 lyase deficiency by altering the structure of redox-partner binding site.\nCONCLUSION: Isolated 17,20 lyase is a rare cause for puberty gynecomastia. The p.R449H variant of the CYP17A1 gene can result in isolated 17,20 lyase deficiency.","variants":[{"Name":"NM_000102.4(CYP17A1):c.1346G>A (p.Arg449His)","Chromosome":"10","Start":"102830883","Stop":"102830883","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2040911,"rule_based_match":true,"evidence_text":"c.1346G>A/p.R449H","llm_judgment":"PRESENT","evidence":"c.1346G>A/p.R449H","abstract_start":812,"abstract_end":829}]}
{"pmid":"25026126","title":"Two novel mutations in acid α-glucosidase gene in two patients with Pompe disease.","abstract":"Pompe disease is an autosomal recessive lysosomal glycogen storage disorder (GSD) caused by acid α-glucosidase (GAA) deficiency. Pompe disease has a broad genotypic and phenotypic spectrum. The infantile-onset form is the most severe form and presents with hypotonia and cardiomyopathy in early infancy. The probands who died were found to have GSD type II based on clinical and biochemical findings. We report two families with Pompe disease in whom the parents' molecular analysis revealed two novel mutations: c.2045A>G (p.Q682R) and c.763C>T (p.Q255X).","variants":[{"Name":"NM_000152.5(GAA):c.2045A>G (p.Gln682Arg)","Chromosome":"17","Start":"80113222","Stop":"80113222","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":549182,"rule_based_match":true,"evidence_text":"c.2045A>G (p.Q682R)","llm_judgment":"PRESENT","evidence":"c.2045A>G (p.Q682R)","abstract_start":513,"abstract_end":532}]}
{"pmid":"22882256","title":"A novel RNASEH2B splice site mutation responsible for Aicardi-Goutieres syndrome in the Faroe Islands.","abstract":"AIM: The aim of the study was to identify the genetic background for Aicardi-Goutieres syndrome (AGS) in the Faroe Islands.\nMETHODS: Four patients with AGS were identified. The patients had a variable phenotype, from a severe prenatal form with intrauterine foetal death to a milder phenotype, albeit still with an early onset, within the first 2-3 months.\nRESULTS: A genome-wide search for homozygosity revealed one single 15.6 Mb region of homozygosity on chromosome 13, which included RNASEH2B, where a splice site mutation c.322-3C>G was identified. Screening of 170 anonymous Faroese controls revealed a carrier frequency of approximately 1.8%, corresponding to an incidence of AGS in the Faroe Islands of around 1 in 12,300.\nCONCLUSION: The previously identified RNASEH2B mutations comprise altogether 20 mutations (missense, nonsense and splice site) with all patients harbouring at least one missense mutation. The severe phenotype of the Faroese patients compared with the previously reported patients with RNASEH2B mutations may be caused by the presence of two null alleles (although some residual normal splicing cannot be ruled out), whereas patients with one or two missense mutations may have some, albeit abnormal, RNASEH2B proteins, and hence some residual activity of RNASEH2B, explaining their milder phenotype.","variants":[{"Name":"NM_024570.4(RNASEH2B):c.322-3C>G","Chromosome":"13","Start":"50934882","Stop":"50934882","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2852936,"rule_based_match":true,"evidence_text":"c.322-3C>G","llm_judgment":"PRESENT","evidence":"c.322-3C>G","abstract_start":527,"abstract_end":537}]}
{"pmid":"19738637","title":"Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X).","abstract":"Aristaless-related homeobox (ARX) gene mutations cause a diverse spectrum of disorders of the human brain, including lissencephaly, various forms of epilepsy and non-syndromic mental retardation. We have identified a novel mutation, c.81C>G (p.Y27X), within the ARX gene in a family with two affected male cousins. One of the boys was diagnosed with an early infantile epileptic encephalopathy also known as Ohtahara syndrome, whereas his cousin had been diagnosed with West syndrome (WS). Both patients have normal genitalia and neither have lissencephaly. The ARX mutation identified is predicted to yield a severely truncated protein of only 26 amino acids and can be considered as a null mutation. Somewhat surprisingly, however, it does not yield the X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome. We proposed that the ARX mRNA translation re-initiated at the next AUG codon at position c.121-123 (aa 41) and, thus, partly rescued these patients from XLAG. Our in vitro studies show that this N-terminally truncated ARX protein (p.M41_C562) is detected by western immunoblot in lysates from cells transiently transfected with an ARX over-expression construct containing the c.81C>G mutation. Although these findings widen the spectrum of clinical phenotypes because of mutations in the ARX gene, they also emphasize the molecular pathogenetic effect of individual mutations as well as the effect of genetic background resulting in intrafamilial clinical heterogeneity for these mutations.","variants":[{"Name":"NM_139058.3(ARX):c.81C>G (p.Tyr27Ter)","Chromosome":"X","Start":"25015657","Stop":"25015657","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":38919,"rule_based_match":true,"evidence_text":"c.81C>G (p.Y27X)","llm_judgment":"PRESENT","evidence":"c.81C>G (p.Y27X)","abstract_start":233,"abstract_end":249}]}
{"pmid":"37052241","title":"A unique case of Bloom syndrome with a combination of genetic hits: A lesson from trio‑based exome sequencing: A case report.","abstract":"Pathogenic variants affecting the <i>BLM</i> gene are responsible for the manifestation of extremely rare cancer‑predisposing Bloom syndrome. The present study reports on a case of an infant with a congenital hypotrophy, short stature and abnormal facial appearance. Initially she was examined using a routine molecular diagnostic algorithm, including the cytogenetic analysis of her karyotype, microarray analysis and methylation‑specific MLPA, however, she remained undiagnosed on a molecular level. Therefore, she and her parents were enrolled in the project of trio‑based exome sequencing (ES) using Human Core Exome kit. She was revealed as a carrier of an extremely rare combination of causative sequence variants altering the <i>BLM</i> gene (NM_000057.4), c.1642C>T and c.2207_2212delinsTAGATTC in the compound heterozygosity, resulting in a diagnosis of Bloom syndrome. Simultaneously, a mosaic loss of heterozygosity of chromosome 11p was detected and then confirmed as a borderline imprinting center 1 hypermethylation on chromosome 11p15. The diagnosis of Bloom syndrome and mosaic copy‑number neutral loss of heterozygosity of chromosome 11p increases a lifetime risk to develop any types of malignancy. This case demonstrates the trio‑based ES as a complex approach for the molecular diagnostics of rare pediatric diseases.","variants":[{"Name":"NM_000057.4(BLM):c.2207_2212delinsTAGATTC (p.Tyr736fs)","Chromosome":"15","Start":"90766923","Stop":"90766928","ReferenceAlleleVCF":"ATCTGA","AlternateAlleleVCF":"TAGATTC","allel_id":20493,"rule_based_match":true,"evidence_text":"c.2207_2212delinsTAGATTC","llm_judgment":"PRESENT","evidence":"c.2207_2212delinsTAGATTC","abstract_start":778,"abstract_end":802}]}
{"pmid":"23510777","title":"Homozygosity mapping identifies a novel GIPC3 mutation causing congenital nonsyndromic hearing loss in a Saudi family.","abstract":"Hearing loss is one of the most common sensory disorders in humans and has a genetic cause in 50% of the cases. Our recent studies indicate that nonsyndromic hearing loss (NSHL) in the Saudi Arabian population is genetically heterogeneous and is not caused by mutations in GJB2 and GJB6, the most common genes for deafness in various populations worldwide. Identification of the causative gene/mutation in affected families is difficult due to extreme genetic heterogeneity and lack of phenotypic variability. We utilized an SNP array-based whole-genome homozygosity mapping approach in search of the causative gene, for the phenotype in a consanguineous Saudi family, with five affected individuals presenting severe to profound congenital NSHL. A single shared block of homozygosity was identified on chromosome 19p13.3 encompassing GIPC3, a recently identified hearing loss gene. Subsequently, a novel mutation c.122 C>A (p.T41K) in GIPC3 was found. This is the first report of GIPC3 mutation in a Saudi family. The presence of the GIPC3 mutations in only one of 100 Saudi families with congenital NSHL suggests that it appears to be a rare cause of familial or sporadic deafness in this population.","variants":[{"Name":"NM_133261.3(GIPC3):c.122C>A (p.Thr41Lys)","Chromosome":"19","Start":"3585719","Stop":"3585719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":176723,"rule_based_match":true,"evidence_text":"c.122 C>A (p.T41K)","llm_judgment":"PRESENT","evidence":"c.122 C>A (p.T41K)","abstract_start":914,"abstract_end":932}]}
{"pmid":"23248352","title":"Giant axonal neuropathy caused by a novel compound heterozygous mutation in the gigaxonin gene.","abstract":"Giant axonal neuropathy is a rare autosomal recessive disorder, which typically involves both central and peripheral nervous system. Yet the phenotypic-genotypic correlation remains obscure. We report a novel compound heterozygous mutation with the c. 805C>T in exon 4(Arg545His missense mutation) and the c. 1634G>A in exon 11(Arg269Trp missense mutation) in an 11-year-old Chinese giant axonal neuropathy case. This patient had an atypical giant axonal neuropathy phenotype rather similar to Charcot-Marie-Tooth disease, without tightly curled hair and mental retardation. The patient had a slowly progressive sensory motor neuropathy since age 3 years, and she also had nystagmus, feet deformities, scoliosis, and cerebellar tonsillar protrusion. Electrophysiological studies indicated a predominantly axonal sensory-motor neuropathy. The diagnosis was confirmed by sural nerve biopsy and direct sequencing of all the 11 gigaxonin exons. The proband's parents are heterozygotes of the disease without symptoms. Our findings extend the number of gigaxonin mutations that cause giant axonal neuropathy.","variants":[{"Name":"NM_022041.4(GAN):c.805C>T (p.Arg269Trp)","Chromosome":"16","Start":"81356956","Stop":"81356956","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":568387,"rule_based_match":true,"evidence_text":"c. 805C>T","llm_judgment":"PRESENT","evidence":"c. 805C>T","abstract_start":249,"abstract_end":258}]}
{"pmid":"16862115","title":"Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.","abstract":"Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions (both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, we identified a mutation within the splice donor site of intron 0 (IVS0 + 5G > C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family. Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation (c.3G > A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis.","variants":[{"Name":"NM_002087.4(GRN):c.3G>A (p.Met1Ile)","Chromosome":"17","Start":"44349167","Stop":"44349167","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31048,"rule_based_match":true,"evidence_text":"c.3G > A","llm_judgment":"PRESENT","evidence":"c.3G > A","abstract_start":1300,"abstract_end":1308}]}
{"pmid":"31501477","title":"Design of a multiplex ligation-dependent probe amplification assay for SLC20A2: identification of two novel deletions in primary familial brain calcification.","abstract":"Primary familial brain calcification (PFBC) is a rare disease characterized by brain calcifications that mainly affect the basal ganglia, thalamus, and cerebellum. Among the four autosomal-dominant genes known to be associated with the disease, SLC20A2 pathogenic variants are the most common, accounting for up to 40% of PFBC dominant cases; variants include both point mutations, small insertions/deletions and intragenic deletions. Over the last 7 years, we have collected a group of 50 clinically diagnosed PFBC patients, who were screened for single nucleotide changes and small insertions/deletions in SLC20A2 by Sanger sequencing. We found seven pathogenic/likely pathogenic variants: four were previously described by our group, and three are reported here (c.303delG, c.21delG, and c.1795-1G>A). We developed and validated a synthetic Multiplex Ligation-dependent Probe Amplification (MLPA) assay for SLC20A2 deletions, covering all ten coding exons and the 5' UTR (SLC20A2-MLPA). Using this method, we screened a group of 43 PFBC-patients negative for point mutations and small insertions/deletions, and identified two novel intragenic deletions encompassing exon 6 NC_000008.10:g.(42297172_42302163)_(423022281_42317413)del, and exons 7-11 including the 3'UTR NC_000008.10:g.(?_42275320)_(42297172_42302163)del. Overall, SLC20A2 deletions may be highly underestimated PFBC cases, and we suggest MLPA should be included in the routine molecular test for PFBC diagnosis.","variants":[{"Name":"NM_001257180.2(SLC20A2):c.21del (p.Leu7fs)","Chromosome":"8","Start":"42472370","Stop":"42472370","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":622734,"rule_based_match":true,"evidence_text":"c.21delG","llm_judgment":"PRESENT","evidence":"c.21delG","abstract_start":777,"abstract_end":785}]}
{"pmid":"29039721","title":"A recurrent splice-site mutation in EPHA2 causing congenital posterior nuclear cataract.","abstract":"Intoduction: Inherited cataract, opacification of the lens, is the most common worldwide cause of blindness in children. We aimed to identify the genetic cause of autosomal dominant (AD) posterior nuclear cataract in a four generation British family.\nMETHODS: Whole genome sequence (WGS) was performed on two affected and one unaffected individual of the family and further validated by direct sequencing. Haplotype analysis was performed via genotying.\nRESULTS: A splice-site mutation c.2826-9G>A in the gene EPHA2, encoding EPH receptor A2 was identified and found to co-segregate with disease.\nCONCLUSIONS: We have identified a recurrent splice-site mutation c.2826-9G>A in EPHA2 causing isolated posterior nuclear cataract, providing evidence of further phenotypic heterogeneity associated with this variant.","variants":[{"Name":"NM_004431.5(EPHA2):c.2826-9G>A","Chromosome":"1","Start":"16125329","Stop":"16125329","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":263955,"rule_based_match":true,"evidence_text":"c.2826-9G>A","llm_judgment":"PRESENT","evidence":"c.2826-9G>A","abstract_start":486,"abstract_end":497}]}
{"pmid":"37201161","title":"Unusual Cause of Thrombocytopenia and Renal Failure in a 14-Year-Old Boy (MYH9-Associated Disorders).","abstract":"MYH9-associated disorders represent rare group of autosomal dominant diseases and are caused by pathogenic mutations in the <i>MYH9</i> gene. Clinically, they are represented by macro-platelet-thrombocytopenia, various degrees of renal dysfunction, hearing loss, and early onset cataracts. We describe the case of 14-year-old boy in medical follow-up from birth for thrombocytopenia. Systolic hypertension and nephrotic proteinuria were detected at preventive health check. Renal biopsy revealed sing of segmental glomerulosclerosis. Dialysis treatment was needed. Before transplantation due to the finding of chronic tonsillitis with positive bacterial capture in the culture examination, tonsillectomy was indicated. Postoperative period was complicated with arterial post-tonsillectomy hemorrhage. Six months after tonsillectomy, the patient underwent primary deceased-donor kidney transplantation without complication. Blood platelets showed fluctuating character in the zone of severe thrombocytopenia. However, no signs of bleeding were present. Three months after successful transplantation gene sequencing of whole exon was performed. The presence of the variant c.2105G>A [p.(Arg702HIS)] in exon 17 of the <i>MYH9</i> gene has been detected. The variant c.2105G>A may be clinically manifested by progressive proteinuria with rapid deterioration of renal function. This case is an example of the delayed diagnosis of rare disease and highlights the usefulness of genetic testing.","variants":[{"Name":"NM_002473.6(MYH9):c.2105G>A (p.Arg702His)","Chromosome":"22","Start":"36305984","Stop":"36305984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29120,"rule_based_match":true,"evidence_text":"c.2105G>A [p.(Arg702HIS)]","llm_judgment":"PRESENT","evidence":"c.2105G>A [p.(Arg702HIS)]","abstract_start":1171,"abstract_end":1196}]}
{"pmid":"37141942","title":"Cervical Instability and Quadriparesis Requiring Stabilization in Pediatric Patient Caused by a Mutation in COL2A1.","abstract":"A 3-year-old male with no past medical history presented with flaccid plegia of his upper extremities and significant weakness in his lower extremities after wrestling with his brother. Cervical spine magnetic resonance imaging was consistent with cord edema and intraparenchymal hemorrhage at C1-C2. A nonossified tissue mass at the expected location of the upper dens created narrowing of the canal at the C1-2 level and mass effect on the cord. Head computed tomography showed periventricular leukomalacia. Initial findings favored dysplasia of the odontoid with associated soft tissue mass/pannus caused by a possible underlying genetic or metabolic bone dyscrasia. The patient underwent suboccipital craniotomy/C1 laminectomy and occiput to C4 fusion, for decompression and stabilization. Genetic testing showed a COL2A1 collagen disorder, with the child harboring a de novo mutation for c.3455 G>T (p.G1152V). The patient was discharged to inpatient acute rehabilitation, with gradual improvement in strength in all 4 extremities.","variants":[{"Name":"NM_001844.5(COL2A1):c.3455G>T (p.Gly1152Val)","Chromosome":"12","Start":"47976548","Stop":"47976548","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3859770,"rule_based_match":true,"evidence_text":"c.3455 G>T (p.G1152V)","llm_judgment":"PRESENT","evidence":"c.3455 G>T (p.G1152V)","abstract_start":893,"abstract_end":914}]}
{"pmid":"35181021","title":"A novel nonsense mutation of TGFBR1 in a fetus with untypical Loeys-Dietz syndrome 1.","abstract":"OBJECTIVE: We present a rare untypical Loeys-Dietz syndrome 1 case in prenatal setting and report a novel mutation in the TGFBR1 gene.\nCASE REPORT: A pregnant woman came for medical attention due to the fetal ultrasound anomaly. The fetus was found to have short long bones. Trio-based WES was applied to the family. A novel de novo nonsense mutation c.1237C > T was detected in the TGFBR1 gene. A diagnosis of Loeys-Dietz syndrome 1 (LDS1) was plausible, but the fetus did not demonstrate the characteristic phenotype of the syndrome.\nCONCLUSION: In prenatal setting, fetal phenotypes are difficult to be fully observed, putting stress on the utility of molecular techniques. LDS1 in fetuses could present untypical features such as skeletal dysplasia.","variants":[{"Name":"NM_004612.4(TGFBR1):c.1237C>T (p.Arg413Ter)","Chromosome":"9","Start":"99146591","Stop":"99146591","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":911135,"rule_based_match":true,"evidence_text":"c.1237C > T","llm_judgment":"PRESENT","evidence":"c.1237C > T","abstract_start":351,"abstract_end":362}]}
{"pmid":"36599940","title":"Clinical variability in DYNC2H1-related skeletal ciliopathies includes Ellis-van Creveld syndrome.","abstract":"Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles.","variants":[{"Name":"NM_001377.3(DYNC2H1):c.6140-5A>G","Chromosome":"11","Start":"103179021","Stop":"103179021","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2964922,"rule_based_match":true,"evidence_text":"c.6140-5A>G","llm_judgment":"PRESENT","evidence":"c.6140-5A>G","abstract_start":692,"abstract_end":703}]}
{"pmid":"30682498","title":"Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency.","abstract":"Human methylmalonyl-CoA epimerase (MCEE) catalyzes the interconversion of d-methylmalonyl-CoA and l-methylmalonyl-CoA in propionate catabolism. Autosomal recessive pathogenic variations in MCEE reportedly cause methylmalonic aciduria (MMAuria) in eleven patients. We investigated a cohort of 150 individuals suffering from MMAuria of unknown origin, identifying ten new patients with pathogenic variations in MCEE. Nine patients were homozygous for the known nonsense variation p.Arg47* (c.139C > T), and one for the novel missense variation p.Ile53Arg (c.158T > G). To understand better the molecular basis of MCEE deficiency, we mapped p.Ile53Arg, and two previously described pathogenic variations p.Lys60Gln and p.Arg143Cys, onto our 1.8 Å structure of wild-type (wt) human MCEE. This revealed potential dimeric assembly disruption by p.Ile53Arg, but no clear defects from p.Lys60Gln or p.Arg143Cys. We solved the structure of MCEE-Arg143Cys to 1.9 Å and found significant disruption of two important loop structures, potentially impacting surface features as well as the active-site pocket. Functional analysis of MCEE-Ile53Arg expressed in a bacterial recombinant system as well as patient-derived fibroblasts revealed nearly undetectable soluble protein levels, defective globular protein behavior, and using a newly developed assay, lack of enzymatic activity - consistent with misfolded protein. By contrast, soluble protein levels, unfolding characteristics and activity of MCEE-Lys60Gln were comparable to wt, leaving unclear how this variation may cause disease. MCEE-Arg143Cys was detectable at comparable levels to wt MCEE, but had slightly altered unfolding kinetics and greatly reduced activity. These studies reveal ten new patients with MCEE deficiency and rationalize misfolding and loss of activity as molecular defects in MCEE-type MMAuria.","variants":[{"Name":"NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)","Chromosome":"2","Start":"71124445","Stop":"71124445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17382,"rule_based_match":true,"evidence_text":"c.139C > T","llm_judgment":"PRESENT","evidence":"c.139C > T","abstract_start":488,"abstract_end":498}]}
{"pmid":"33358585","title":"Fecal microbiota transplantation before hematopoietic stem cell transplantation in a pediatric case of chronic diarrhea with a FOXP3 mutation.","abstract":"BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder caused by mutation of the forkhead box protein 3 (FOXP3) gene, often leading to intractable and life-threatening diarrhea. Fecal microbiota transplantation (FMT), has been regarded in recent years as an available approach to reconstruct disrupted gut microbiome and successfully used to attenuates diarrhea induced by different underlying diseases. Therefore, FMT may have curative potential on the symptoms of enteropathy in patients with IPEX syndrome.\nMETHODS: Physical and laboratory examinations were performed, and clinical data were collected. FMT was administered via frozen fecal microbial solution, and the fecal microbiota composition was analyzed using 16S rDNA sequencing before and after FMT.\nRESULTS: The patient was diagnosed with IPEX syndrome with a mutation detected in the FOXP3 gene, which was identified as c.767T > C (p.M256T). He presented with recurrent watery diarrhea and respiratory infections after birth and developed a significant failure to thrive. Disturbances in the gut microbiota composition and marked decreased bacterial diversity were observed to be involved in the persistent and refractory diarrhea. After receiving FMT treatment, the patient responded with remission of the diarrhea without apparent side effects. His stool output significantly decreased, corresponding to increased microbial diversity and modification of his microbiota composition. The patient finally achieved full recovery after hematopoietic stem cell transplantation (HSCT).\nCONCLUSION: Our data suggest an association between the gut microbiota and clinical symptoms of patient with IPEX syndrome and demonstrate FMT as an alternative therapy for severe diarrhea unresponsive to routine therapy in these patients.","variants":[{"Name":"NM_014009.4(FOXP3):c.767T>C (p.Met256Thr)","Chromosome":"X","Start":"49255478","Stop":"49255478","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3540095,"rule_based_match":true,"evidence_text":"c.767T > C (p.M256T)","llm_judgment":"PRESENT","evidence":"c.767T > C (p.M256T)","abstract_start":940,"abstract_end":960}]}
{"pmid":"24604124","title":"Palmoplantar keratoderma of the Gamborg-Nielsen type is caused by mutations in the SLURP1 gene and represents a variant of Mal de Meleda.","abstract":"Palmoplantar keratoderma of the Gamborg-Nielsen type (PPK-GN) is a rare autosomal recessive skin disorder described in patients from Sweden. Mal de Meleda (MDM) is also a rare autosomal recessive inherited PPK first reported in 5 families from the island of Meleda. The 2 conditions phenotypically overlap and are characterised by palmoplantar erythematous hyperkeratotic plaques. The genetic background giving rise to PPK-GN has hitherto been unknown, whereas MDM is known to be caused by mutations in the gene encoding secreted Ly-6/uPAR-related protein 1, SLURP-1. In the present study we scrutinised individuals affected by PPK-GN for mutations in the SLURP1 gene and identified 2 different mutations. Fourteen Swedish patients were homozygous for a previously described mutation, c.43T>C, while one individual was a compound heterozygote with one copy of a novel mutation, c.280T>A, in addition to one copy of the c.43T>C mutation. Hereby we confirm that PPK-GN is an allelic variant of MDM.","variants":[{"Name":"NM_020427.3(SLURP1):c.43T>C (p.Trp15Arg)","Chromosome":"8","Start":"142742343","Stop":"142742343","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19644,"rule_based_match":true,"evidence_text":"c.43T>C","llm_judgment":"PRESENT","evidence":"c.43T>C","abstract_start":785,"abstract_end":792}]}
{"pmid":"31560489","title":"Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina.","abstract":"INTRODUCTION: RASopathies are a set of syndromes with phenotypic overlapping features caused by gene mutations involved in the RAS/MAPK pathway. They are autosomal dominantly inherited and share common clinical characteristics, including short stature, craniofacial dysmorphisms, congenital heart disease, ectodermal manifestations, and a higher risk for cancer. A molecular diagnosis is a key factor.\nOBJECTIVE: To identify PTPN11, SOS1, RAF1, BRAF, and HRAS mutations and compare the main clinical characteristics of patients with molecular confirmation. Population and methods. Children with a clinical diagnosis of RASopathy assessed between August 2013 and February 2017.\nRESULTS: Mutations were identified in 71 % (87/122) of patients. The molecular test confirmed diagnosis in 73 % of patients with Noonan syndrome. The most prevalent mutation was c.922A>G (p.Asn308Asp) in the PTPN11 gene. A previously undescribed variant in RAF1 was detected: c.1467G>>C (p.Leu489Phe). Cardiofaciocutaneous syndrome was confirmed in 67 % of cases with BRAF mutations. Costello syndrome and Noonan syndrome with multiple lentigines were confirmed in all cases.\nCONCLUSION: The confirmation of clinical diagnosis allowed for a more accurate differential diagnosis. The prevalence of PTPN11 (58 %), SOS1 (10 %), and RAF1 mutations (5 %) in children with Noonan syndrome, of PTPN11 mutations (100 %) in those with Noonan syndrome with multiple lentigines, of BRAF mutations (67 %) in those with cardiofaciocutaneous syndrome, and of HRAS mutations (100 %) in those with Costello syndrome was determined.","variants":[{"Name":"NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp)","Chromosome":"12","Start":"112477719","Stop":"112477719","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28365,"rule_based_match":true,"evidence_text":"c.922A>G (p.Asn308Asp)","llm_judgment":"PRESENT","evidence":"c.922A>G (p.Asn308Asp)","abstract_start":855,"abstract_end":877}]}
{"pmid":"20477750","title":"Mutations in LAMA2 and CAPN3 genes associated with genetic and phenotypic heterogeneities within a single consanguineous family involving both congenital and progressive muscular dystrophies.","abstract":"LGMD (limb-girdle muscular dystrophy) and CMD (congenital muscular dystrophy) are two common forms of neuromuscular disorders which are distinguishable by their age of onset but with probably a similar underlying pathway. In the present study, we report immunohistochemical, Western-blot and genetic analyses in a large consanguineous Tunisian family with two branches, including seven patients sharing similar LGMD2 phenotype in one branch and one CMD patient in the other branch. Linkage analyses were compatible with the LGMD2A locus in one branch and the MDC1A (muscular dystrophy congenital type 1A) locus in the other branch. This result was supported by deficiency in merosin and calpain3 in the CMD patient and LGMD patients respectively. Mutation analysis revealed two distinct mutations: a c.8005delT frameshift deletion in exon 56 of the LAMA2 (laminin-α2) gene (MDC1A) was found in the CMD patient and a new homozygous mutation c.1536+1G>T in the donor splice site of intron 12 of the CAPN3 (calpain3) gene (LGMD2A) was found in the LGMD patients. RT-PCR (reverse transcription-PCR) performed on total RNA from a LGMD2A patient's muscle biopsy showed complete retention of intron 12 in CAPN3 cDNA, generating a PTC (premature termination codon) that potentially elicits degradation of the nonsense mRNA by NMD (nonsense-mediated mRNA decay). Our results indicate that mRNA analysis is necessary to clarify the primary effect of genomic mutations on splicing efficiency that alters mRNA processing and expression level.","variants":[{"Name":"NM_000070.3(CAPN3):c.1536+1G>T","Chromosome":"15","Start":"42402136","Stop":"42402136","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1915534,"rule_based_match":true,"evidence_text":"c.1536+1G>T","llm_judgment":"PRESENT","evidence":"c.1536+1G>T","abstract_start":940,"abstract_end":951}]}
{"pmid":"12116277","title":"A novel germline point mutation, c.2304 G-->T, in codon 768 of the RET proto-oncogene in a patient with medullary thyroid carcinoma.","abstract":"","variants":[{"Name":"NM_020975.6(RET):c.2304G>T (p.Glu768Asp)","Chromosome":"10","Start":"43118392","Stop":"43118392","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":47215,"rule_based_match":false,"evidence_text":"c.2304 G-->T","llm_judgment":"PRESENT","evidence":"c.2304 G-->T","abstract_start":null,"abstract_end":null}]}
{"pmid":"19208381","title":"Aplasia of cochlear nerves and olfactory bulbs in association with SOX10 mutation.","abstract":"A 17-month-old boy was referred with profound sensorineural hearing loss (SNHL), severe visual impairment and developmental delay. Neuroimaging identified hypomyelination and cochlear nerve aplasia. He was noted to have fair skin and hair and multiple areas of cutaneous hyperpigmentation. Previous investigations including karyotype, array comparative genomic hybridization (aCGH) and a full metabolic screen were normal. A novel missense mutation of the highly conserved high mobility group (HMG) domain of SOX10 was identified (Q174P:c.521A>C). This case represents the first description of aplasia of the cochlear nerve due to a SOX10 mutation.","variants":[{"Name":"NM_006941.4(SOX10):c.521A>C (p.Gln174Pro)","Chromosome":"22","Start":"37978043","Stop":"37978043","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":22449,"rule_based_match":true,"evidence_text":"Q174P:c.521A>C","llm_judgment":"PRESENT","evidence":"Q174P:c.521A>C","abstract_start":531,"abstract_end":545}]}
{"pmid":"28554554","title":"Expanding the phenotypic spectrum associated with mutations of DYNC1H1.","abstract":"Autosomal dominant mutations of DYNC1H1 cause a range of neurogenetic diseases, including mental retardation with cortical malformations, hereditary spastic paraplegia and spinal muscular atrophy. Using SNP array, linkage analysis and next generation sequencing, we identified two families and one isolated proband sharing a known spinal muscular atrophy, lower extremity predominant (SMALED) causing mutation DYNC1H1 c.1792C>T, p.Arg598Cys, and another family harbouring a c.2327C>T, p.Pro776Leu mutation. Here, we present a detailed clinical and pathological examination of these patients, and show that patients with DYNC1H1 mutations may present with a phenotype mimicking a congenital myopathy. We also highlight features that increase the phenotypic overlap with BICD2, which causes SMALED2. Serial muscle biopsies were available for several patients, spanning from infancy and early childhood to middle age. These provide a unique insight into the developmental and pathological origins of SMALED, suggesting in utero denervation with reinnervation by surrounding intact motor neurons and segmental anterior horn cell deficits. We characterise biopsy features that may make diagnosis of this condition easier in the future.","variants":[{"Name":"NM_001376.5(DYNC1H1):c.2327C>T (p.Pro776Leu)","Chromosome":"14","Start":"101986552","Stop":"101986552","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360017,"rule_based_match":true,"evidence_text":"c.2327C>T, p.Pro776Leu","llm_judgment":"PRESENT","evidence":"c.2327C>T, p.Pro776Leu","abstract_start":474,"abstract_end":496},{"Name":"NM_001376.5(DYNC1H1):c.1792C>T (p.Arg598Cys)","Chromosome":"14","Start":"101986017","Stop":"101986017","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":143271,"rule_based_match":true,"evidence_text":"DYNC1H1 c.1792C>T, p.Arg598Cys","llm_judgment":"PRESENT","evidence":"DYNC1H1 c.1792C>T, p.Arg598Cys","abstract_start":410,"abstract_end":440}]}
{"pmid":"23950000","title":"A transient myelodysplastic/myeloproliferative neoplasm in a patient with cardio-facio-cutaneous syndrome and a germline BRAF mutation.","abstract":"A male infant, born at 32 weeks gestation by cesarean because of hydrops fetalis, presented with multiple anomalies, such as sparse and curly scalp hair, absent eyebrows, frontal bossing, an atrial septal defect, pulmonary artery stenosis, and whole myocardial thickening. He was clinically diagnosed with cardio-facio-cutaneous (CFC) syndrome, and was confirmed to have a germline V-raf murine sarcoma viral oncogene homologue B1 (BRAF) c.721 A>C mutation. At 1 month of age, he presented with a transient myelodysplastic/myeloproliferative neoplasm (MDS/MPN), which improved within a month without the administration of antineoplastic agents. This is the first report of CFC syndrome with MDS/MPN. The coexistence of MDS/MPN may be related to this BRAF c.721 A>C mutation.","variants":[{"Name":"NM_004333.6(BRAF):c.721A>C (p.Thr241Pro)","Chromosome":"7","Start":"140801551","Stop":"140801551","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":38762,"rule_based_match":true,"evidence_text":"BRAF c.721 A>C","llm_judgment":"PRESENT","evidence":"BRAF c.721 A>C","abstract_start":750,"abstract_end":764}]}
{"pmid":"29393969","title":"Worldwide distribution of common IDUA pathogenic variants.","abstract":"Mucopolysaccharidosis type I (MPS I) is a rare disorder caused by deleterious sequence variants in the α-L-iduronidase (IDUA) gene. More than 200 pathogenic variants have been described so far, but their frequencies have not yet been analyzed on a worldwide scale. To address this, we analyzed the genotypes of MPS I patients from 35 published studies papers. The most common pathogenic variant observed was p.Trp402Ter. With frequencies of up to 63%, it was the major allele in most European countries, America and Australia. The variant p.Gln70Ter was also frequent; it was found mainly in Northern and Eastern Europe. The most frequent variant in North African countries was p.Pro533Arg; in Morocco, it represented more than 90% of mutant alleles. Variants observed in East Asians were not found in Western populations, including c.1190-1G>A, p.Ala79Val, p.Leu346Arg and c.613_617dupTGCTC. Conversely, p.Trp402Ter and p.Pro533Arg were not found in patients from East Asia. In conclusion, the most common pathogenic IDUA variant in MPS I patients are p.Trp402Ter, p.Gln70Ter and p.Pro533Arg. Knowledge about the genetic background of MPS I for each population is essential when developing new genotype-targeted therapies, as well as to enable faster genetic analysis and improve patient management.","variants":[{"Name":"NM_000203.5(IDUA):c.1205G>A (p.Trp402Ter)","Chromosome":"4","Start":"1002747","Stop":"1002747","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26947,"rule_based_match":false,"evidence_text":"p.Trp402Ter","llm_judgment":"PRESENT","evidence":"p.Trp402Ter","abstract_start":408,"abstract_end":419}]}
{"pmid":"36936415","title":"Novel and recurrent genetic variants of","abstract":"<b>Background:</b> Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors arising from chromaffin cells in the adrenal medulla and extra-adrenal ganglia, respectively. The study was aimed to investigate the clinical and genetic characteristics of 22 individuals from six families. <b>Methods:</b> The medical records of six PPGL probands who presented to our hospital between 2016 and 2021 were retrospectively studied. DNA isolated from the probands was analyzed using whole exome sequencing. The identified genetic variants were confirmed by Sanger sequencing and undergone bioinformatic analysis. <b>Results:</b> Six different genetic variants in the six probands were identified, respectively, of which three were novel. A novel von Hippel-Lindau <i>(VHL)</i> variant, c.602T>C (p.L201P), in exon 3 was found. Two novel genetic variants in <i>SDHB</i> (succinate dehydrogenases subunit B), c.423 + 1 G>T and c.662A>G (p.D221G), were identified. Two recurrent genetic variants of <i>VHL</i>, c.C284G (p.P95R) and c.558_560AGAdel (p.186Edel), and one in <i>RET</i> (ret proto-oncogene), c.1901G>A (p.C634Y), were also found. The ClinVar accession number for the present variants are SCV002028348, and SCV002028352 to SCV002028361. <b>Conclusion:</b> Genetic variants in <i>VHL</i>, <i>SDHB</i> and <i>RET</i> were identified in Chinese PPGL patients, which contributed to the knowledge of the genetic etiology and clinical outcome of these tumors.","variants":[{"Name":"NM_000551.4(VHL):c.558_560del (p.Glu186del)","Chromosome":"3","Start":"10149879","Stop":"10149881","ReferenceAlleleVCF":"CGAA","AlternateAlleleVCF":"C","allel_id":613596,"rule_based_match":false,"evidence_text":"c.558_560AGAdel (p.186Edel)","llm_judgment":"PRESENT","evidence":"c.558_560AGAdel (p.186Edel)","abstract_start":1034,"abstract_end":1061}]}
{"pmid":"26667307","title":"Novel Compound Heterozygous CBS Mutations Cause Homocystinuria in a Han Chinese Family.","abstract":"The cystathionine β-synthase (CBS) gene has been shown to be related to homocystinuria. This study was aimed to detect the mutations in CBS in a Han Chinese family with homocystinuria. A four-generation family from Shandong Province of China was recruited in this study. All available members of the family underwent comprehensive medical examinations. Genomic DNA was collected from peripheral blood of all the participants. The coding sequence of CBS was amplified by polymerase chain reaction (PCR), followed by direct DNA sequencing. Among all the family members, three affected individuals showed typical clinical features of homocystinuria. Two novel compound heterozygous mutations in the CBS gene, c.407T > C (p. L136P) and c.473C > T (p.A158V), were identified by sequencing analysis in this family. Both of the two missense mutations were detected in the three patients. Other available normal individuals, including the patients' parents, grand parents, her younger sister and brother in this family either carried one of the two mutations, or none. In addition, the two mutations were not found in 600 ethnically matched normal controls. This study provides a mutation spectrum of CBS resulting in homocystinuriain a Chinese population, which may shed light on the molecular pathogenesis and clinical diagnosis of CBS-associated homocystinuria.","variants":[{"Name":"NM_000071.3(CBS):c.407T>C (p.Leu136Pro)","Chromosome":"21","Start":"43066287","Stop":"43066287","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2838807,"rule_based_match":true,"evidence_text":"c.407T > C (p. L136P)","llm_judgment":"PRESENT","evidence":"c.407T > C (p. L136P)","abstract_start":706,"abstract_end":727}]}
{"pmid":"35698919","title":"A monoallelic variant in EYA1 is associated with Branchio-Otic syndrome in a Malian family.","abstract":"BACKGROUND: Branchio-otic syndrome (BO) is one of the most common types of syndromic hearing impairment (HI) with an incidence of 1/40,000 globally. It is an autosomal dominant disorder typically characterized by the coexistence of branchial cysts or fistulae, malformations of the external, middle, and inner ears with preauricular pits or tags and a variable degree of HI. Most cases of BO have been reported in populations of European ancestry. To date, only few cases have been reported in people from African descent.\nMETHODS: After a careful clinical examination, a pure tone audiometry was performed. DNA was extracted from peripheral blood and whole exome, and Sanger sequencing were performed for genetic analysis.\nRESULTS: Eight individuals from a large non-consanguineous Malian family, with autosomal dominant inheritance were enrolled. The ages at diagnosis ranged from 8 to 54 years. A high phenotypic variability was noted among the affected individuals. Four patients presented with a post-lingual and mixed type of HI, one individual had conductive HI while three had normal hearing but presented other BO features namely branchial fistulae and preauricular sinus. Serum creatinine level and renal ultrasonography were normal in three affected individuals who performed them. Genetic testing identified a monoallelic pathogenic variant in EYA1 (c.1286A > G; p.Asp429Gly) segregating with BO syndrome in the family.\nCONCLUSION: This is the first genetically confirmed case of BO syndrome caused by EYA1 variant in the sub-Saharan African population, expanding the genetic spectrum of the condition.","variants":[{"Name":"NM_000503.6(EYA1):c.1286A>G (p.Asp429Gly)","Chromosome":"8","Start":"71216766","Stop":"71216766","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3543109,"rule_based_match":true,"evidence_text":"c.1286A > G; p.Asp429Gly","llm_judgment":"PRESENT","evidence":"c.1286A > G; p.Asp429Gly","abstract_start":1362,"abstract_end":1386}]}
{"pmid":"24169249","title":"Clinical features and acid alpha-glucosidase gene mutation in 7 Chinese patients with glycogen storage disease type II","abstract":"OBJECTIVE: To explore the clinical features and acid alpha-glucosidase (GAA) gene mutations of Chinese patients with glycogen storage disease typeII(GSDII).\nMETHODS: Seven patients with GSDII were diagnosed by muscle pathology examination at Department of Neurology, Peking University First Hospital from 2003 to 2011. One patient with infant-onset presented development retardation, generalized muscle weakness, dyspnea, cardiomegaly and hepatomegaly. Six cases were of late-onset ranging from 1 to 29 years. Their main clinical features included progressive muscle weakness. Two patients developed respiratory insufficiency. Increased serum creatine kinase was detected in all of them. Electromyography studies showed myopathic (n = 5) and neuropathic (n = 1) changes. Muscle biopsies showed basophilic vacuoles in muscle fibers containing a large amounts of glycogen on electron microscopy. GAA gene mutation was detected by direct sequencing of polymerase chain reaction (PCR) product. Novel mutations were screened in 100 normal controls.\nRESULTS: GAA gene mutations were found in all of them, including 10 point mutations and 1 frameshift deletion. Six mutations (p. P361L, p. P266S, p.R437C, p.R600C, p.W746S and p.W746*) have been reported before. And five novel mutations (p.R168Q, p.R168P, p.E521V, p.R594H and c.827_845del) were found in this study. None of these novel mutations were found in 100 normal controls except for p.R168Q mutation in two normal controls. p. P361L and p.W746* were detected in two unrelated GSDII patients while other mutations were carried by only one patient.\nCONCLUSIONS: In our study, we found several novel GAA mutations in Chinese patients with GSDII. No hot spot mutation of GAA gene existed in our patient group. However, p. P266S, p. P361L and p.R437C might be associated with late-onset GSDII.","variants":[{"Name":"NM_000152.5(GAA):c.1309C>T (p.Arg437Cys)","Chromosome":"17","Start":"80108811","Stop":"80108811","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187001,"rule_based_match":false,"evidence_text":"p.R437C","llm_judgment":"PRESENT","evidence":"p.R437C","abstract_start":1190,"abstract_end":1197}]}
{"pmid":"34921061","title":"Novel variants identified in","abstract":"Pathogenic variants in <i>CKAP2L</i> have previously been reported in Filippi syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than 10 patients with pathogenic variants in <i>CKAP2L</i> associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine), and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole-exome sequencing of the family identified a missense variant, c.2066G > A;p.(Arg689His), in <i>trans</i> with a frameshift variant, c.1169_1173del;p.(Ile390LysfsTer4), in <i>CKAP2L</i> To our knowledge, these are the first patients with FS to be reported with a missense variant in <i>CKAP2L</i> and only the second family to be reported with two variants in <i>trans</i>.","variants":[{"Name":"NM_152515.5(CKAP2L):c.2066G>A (p.Arg689His)","Chromosome":"2","Start":"112738995","Stop":"112738995","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1023672,"rule_based_match":true,"evidence_text":"c.2066G > A;p.(Arg689His)","llm_judgment":"PRESENT","evidence":"c.2066G > A;p.(Arg689His)","abstract_start":780,"abstract_end":805}]}
{"pmid":"28033443","title":"Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer.","abstract":"IMPORTANCE: Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2, explain fewer than half of all familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C>T (p.GIn1701Ter [rs147021911]) and c.5791C>T (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending.\nOBJECTIVES: To assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk.\nDESIGN, SETTING, AND PARTICIPANTS: For the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016.\nMAIN OUTCOMES AND MEASURES: FANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history.\nRESULTS: In this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27).\nCONCLUSIONS AND RELEVANCE: Based on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis.","variants":[{"Name":"NM_020937.4(FANCM):c.5101C>T (p.Gln1701Ter)","Chromosome":"14","Start":"45189123","Stop":"45189123","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":400207,"rule_based_match":true,"evidence_text":"c.5101C>T (p.GIn1701Ter [rs147021911])","llm_judgment":"PRESENT","evidence":"c.5101C>T (p.GIn1701Ter [rs147021911])","abstract_start":287,"abstract_end":325}]}
{"pmid":"22921319","title":"Stiffness as a presenting symptom of an odd clinical condition caused by multiple sclerosis and myotonia congenita.","abstract":"A 24-year-old woman complained of a 4-year history of muscle cramps, stiffness of the right lower limb and walking difficulties. After clinical and laboratory investigations, a diagnosis of multiple sclerosis was made. However, her family history revealed that her father and an older sister had lifelong symptoms of impaired muscle relaxation following contraction, improving with physical exercise. Molecular genetic studies in both sisters confirmed the diagnosis of myotonia congenita, due to a c.568GG>TC (Gly190Ser) pathogenic mutation in CLCN1 gene. Occurrence of two different neurological conditions in the same patient, both manifesting with stiffness, is quite unusual and suggests the opportunity of an accurate differential diagnosis.","variants":[{"Name":"NM_000083.3(CLCN1):c.568_569delinsTC (p.Gly190Ser)","Chromosome":"7","Start":"143321720","Stop":"143321721","ReferenceAlleleVCF":"GG","AlternateAlleleVCF":"TC","allel_id":205753,"rule_based_match":false,"evidence_text":"c.568GG>TC (Gly190Ser)","llm_judgment":"PRESENT","evidence":"c.568GG>TC (Gly190Ser)","abstract_start":499,"abstract_end":521}]}
{"pmid":"31513304","title":"A founder variant in the South Asian population leads to a high prevalence of FANCL Fanconi anemia cases in India.","abstract":"Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, predisposition to cancer, and congenital abnormalities. FA is caused by pathogenic variants in any of 22 genes involved in the DNA repair pathway responsible for removing interstrand crosslinks. FANCL, an E3 ubiquitin ligase, is an integral component of the pathway, but patients affected by disease-causing FANCL variants are rare, with only nine cases reported worldwide. We report here a FANCL founder variant, anticipated to be synonymous, c.1092G>A;p.K364=, but demonstrated to induce aberrant splicing, c.1021_1092del;p.W341_K364del, that accounts for the onset of FA in 13 cases from South Asia, 12 from India and one from Pakistan. We comprehensively illustrate the pathogenic nature of the variant, provide evidence for a founder effect, and propose including this variant in genetic screening of suspected FA patients in India and Pakistan, as well as those with ancestry from these regions of South Asia.","variants":[{"Name":"NM_018062.4(FANCL):c.1092G>A (p.Lys364=)","Chromosome":"2","Start":"58160108","Stop":"58160108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":918140,"rule_based_match":true,"evidence_text":"c.1092G>A;p.K364=","llm_judgment":"PRESENT","evidence":"c.1092G>A;p.K364=","abstract_start":529,"abstract_end":546}]}
{"pmid":"37558808","title":"Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54.","abstract":"Biallelic hypomorphic variants in PRORP have been recently described as causing the autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a phenotypic spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy. Here, we report three additional families with homozygous missense PRORP variants with pleiotropic phenotypes. Each missense variant altered a highly conserved residue within the metallonuclease domain. In vitro mitochondrial tRNA processing assays with recombinant TRMT10C, SDR5C1 and PRORP indicated two COXPD54-associated PRORP variants, c.1159A>G (p.Thr387Ala) and c.1241C>T (p.Ala414Val), decreased pre-tRNA<sup>Ile</sup> cleavage, consistent with both variants impacting tRNA processing. No significant decrease in tRNA processing was observed with PRORP c.1093T>C (p.Tyr365His), which was identified in an individual with leukodystrophy. These data provide independent evidence that PRORP variants are associated with COXPD54 and that the assessment of 5' leader mitochondrial tRNA processing is a valuable assay for the functional analysis and clinical interpretation of novel PRORP variants.","variants":[{"Name":"NM_014672.4(PRORP):c.1159A>G (p.Thr387Ala)","Chromosome":"14","Start":"35127603","Stop":"35127603","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1935266,"rule_based_match":true,"evidence_text":"c.1159A>G (p.Thr387Ala)","llm_judgment":"PRESENT","evidence":"c.1159A>G (p.Thr387Ala)","abstract_start":656,"abstract_end":679},{"Name":"NM_014672.4(PRORP):c.1241C>T (p.Ala414Val)","Chromosome":"14","Start":"35180743","Stop":"35180743","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1935267,"rule_based_match":true,"evidence_text":"c.1241C>T (p.Ala414Val)","llm_judgment":"PRESENT","evidence":"c.1241C>T (p.Ala414Val)","abstract_start":684,"abstract_end":707}]}
{"pmid":"26774355","title":"A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.","abstract":"Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.","variants":[{"Name":"NM_004656.4(BAP1):c.1777C>T (p.Gln593Ter)","Chromosome":"3","Start":"52403251","Stop":"52403251","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":406342,"rule_based_match":true,"evidence_text":"c.1777C>T","llm_judgment":"PRESENT","evidence":"c.1777C>T","abstract_start":339,"abstract_end":348}]}
{"pmid":"33811063","title":"A description of novel variants and review of phenotypic spectrum in","abstract":"Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in <i>UBA5</i>, a gene involved in a ubiquitin-like post-translational modification system called UFMylation. Here we report five children from four families with biallelic pathogenic variants in <i>UBA5</i> All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Affected individuals in all four families have compound heterozygous pathogenic variants in <i>UBA5</i> All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in <i>trans</i> with a second <i>UBA5</i> variant. One patient has the previously described c.562C > T (p. Arg188*) variant, two other unrelated patients have a novel missense variant, c.907T > C (p.Cys303Arg), and the two siblings have a novel missense variant, c.761T > C (p.Leu254Pro). Functional analyses demonstrate that both the p.Cys303Arg variant and the p.Leu254Pro variants result in a significant decrease in protein function. We also review the phenotypes and genotypes of all 15 previously reported families with biallelic <i>UBA5</i> variants, of which two families have presented with distinct phenotypes, and we describe evidence for some limited genotype-phenotype correlation. The overlap of motor and developmental phenotypes noted in our cohort and literature review adds to the increasing understanding of genetic syndromes with movement disorders-epilepsy.","variants":[{"Name":"NM_024818.6(UBA5):c.1111G>A (p.Ala371Thr)","Chromosome":"3","Start":"132675903","Stop":"132675903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260377,"rule_based_match":true,"evidence_text":"c.1111G > A (p.Ala371Thr)","llm_judgment":"PRESENT","evidence":"c.1111G > A (p.Ala371Thr)","abstract_start":642,"abstract_end":667},{"Name":"NM_024818.6(UBA5):c.907T>C (p.Cys303Arg)","Chromosome":"3","Start":"132675342","Stop":"132675342","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":513414,"rule_based_match":true,"evidence_text":"c.907T > C (p.Cys303Arg)","llm_judgment":"PRESENT","evidence":"c.907T > C (p.Cys303Arg)","abstract_start":861,"abstract_end":885},{"Name":"NM_024818.6(UBA5):c.761T>C (p.Leu254Pro)","Chromosome":"3","Start":"132672126","Stop":"132672126","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1036439,"rule_based_match":true,"evidence_text":"c.761T > C (p.Leu254Pro)","llm_judgment":"PRESENT","evidence":"c.761T > C (p.Leu254Pro)","abstract_start":939,"abstract_end":963}]}
{"pmid":"35254173","title":"Mutations of","abstract":"PURPOSE: To identify <i>TOPORS</i> mutations in patients with retinitis pigmentosa (RP) from our cohort and summarize the genotypes and phenotypes of <i>TOPORS</i> reported previously.\nMETHOD: Probands with RP phenotypes were recruited from our genetic retinopathy screening work. DNA was extracted from the peripheral venous blood, and exome sequencing was performed. We further examined the clinical data and family history in detail in these patients. <i>TOPORS</i> mutations associated with RP were searched and summarized from the previous reports, and the results were combined with the data presented in our study. The mutation spectrum of <i>TOPORS</i> was systematically analyzed, and the phenotypes of truncated mutations and missense mutations were compared and described.\nRESULT: Mutations in <i>TOPORS</i> were detected in three families, including two novel mutations (c.2017C>T, p.Arg673Cys, c.2371A>T, p.Lys791Term) and a known frameshift mutation (c.2554_2557delGAGA, p. Glu852fsTer13). A comprehensive analysis showed that 64.1% (25/39) of the mutant alleles are truncated mutations, and 34.3% (12/39) are missense mutations. About 89.7% (35/39) of the mutations are located in the terminal half of exon 3, which affected the C-terminal of the TOPORS protein. Night blindness was a common onset symptom, and <i>TOPORS</i>-related ERG changes can be observed in early stage. In addition, patients with missense mutations retained better central vision in older age compared to the patients with truncated mutations.\nCONCLUSION: We expand the mutation spectrum and assess the possible genotype-phenotype correlations of <i>TOPORS</i>, which can provide a valuable reference for exploring the pathogenesis of adRP caused by <i>TOPORS</i> mutations.","variants":[{"Name":"NM_005802.5(TOPORS):c.2017C>T (p.Arg673Cys)","Chromosome":"9","Start":"32542508","Stop":"32542508","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1348583,"rule_based_match":true,"evidence_text":"c.2017C>T, p.Arg673Cys","llm_judgment":"PRESENT","evidence":"c.2017C>T, p.Arg673Cys","abstract_start":883,"abstract_end":905}]}
{"pmid":"25147095","title":"CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations.","abstract":"BACKGROUND: Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%-10% of patients. In the most serious cases (1.3%) this can manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).\nMETHODS: DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases.\nRESULTS: An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30% of individuals possessed at least one c.983T>C versus 16% in the tolerant group [P = 0.006; OR (95% CI) 2.24 (1.27-3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95% CI) 4.33 (0.80-23.57)]. Combined analysis resulted in an OR of 2.52 (95% CI 1.48-4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes.\nCONCLUSIONS: Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5%-10% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic-specific predisposing factor.","variants":[{"Name":"NM_000767.5(CYP2B6):c.983T>C (p.Ile328Thr)","Chromosome":"19","Start":"41012316","Stop":"41012316","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":227805,"rule_based_match":true,"evidence_text":"c.983T>C","llm_judgment":"PRESENT","evidence":"c.983T>C","abstract_start":638,"abstract_end":646}]}
{"pmid":"28539984","title":"Birt-Hogg-Dubé Syndrome - report of two cases with two new mutations.","abstract":"INTRODUCTION: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant genodermatosis characterized by cutaneous fibrofolliculomas and/or trichodiscomas, lung cysts, spontaneous pneumothorax and renal tumors. However, its clinical expression is highly variable. This syndrome is caused by germline mutations in the <i>folliculin</i> gene (<i>FLCN</i>) on chromosome 17p11.2.\nMAIN OBSERVATIONS: Two men, 60 and 39-year-old, presented with a several year history of asymptomatic whitish papules scattered over the face and neck. Skin biopsies revealed fibrofolliculomas. The clinical diagnosis of BHDS was corroborated by identification of new heterozygotic mutations in <i>FLCN</i> gene, in exon 6 (C.573_574delinsT) and in exon 9 (c.1015C>T), respectively. Computed tomography scan of the thorax and abdomen showed pulmonary cysts with no suspicious kidneys lesions, and, in the case of the second patient, a mass in left adrenal gland. Laparoscopic left adrenalectomy was performed and histopathological examination was compatible with a malignant perivascular epithelioid cell tumor.\nCONCLUSIONS: The presence of multiple fibrofolliculomas should raise the suspicion of BHDS. Patients with this syndrome, regardless of the detected mutation, should be carefully monitored to ensure that potentially serious disease-related conditions can be detected early.","variants":[{"Name":"NM_144997.7(FLCN):c.1015C>T (p.Gln339Ter)","Chromosome":"17","Start":"17219066","Stop":"17219066","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1468118,"rule_based_match":true,"evidence_text":"c.1015C>T","llm_judgment":"PRESENT","evidence":"c.1015C>T","abstract_start":734,"abstract_end":743}]}
{"pmid":"23332917","title":"Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity.","abstract":"Autosomal-recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders with more than 20 different forms currently recognized, many of which are also associated with increased tone and some of which have limb spasticity. Gaucher disease is a lysosomal storage disease resulting from a defect in the enzyme acid β-glucosidase 1. β-glucosidase 2 is an enzyme with similar glucosylceramidase activity but to date has not been associated with a monogenic disorder. We studied four unrelated consanguineous families of Tunisian decent diagnosed with cerebellar ataxia of unknown origin. We performed homozygosity mapping and whole-exome sequencing in an attempt to identify the genetic origin of their disorder. We were able to identify mutations responsible for autosomal-recessive ataxia in these families within the gene encoding β-glucosidase 2, GBA2. Two nonsense mutations (c.363C>A [p.Tyr121(∗)] and c.1018C>T [p.Arg340(∗)]) and a substitution (c.2618G>A [p.Arg873His]) were identified, probably resulting in nonfunctional enzyme. This study suggests GBA2 mutations are a cause of recessive spastic ataxia and responsible for a form of glucosylceramide storage disease in humans.","variants":[{"Name":"NM_020944.3(GBA2):c.1018C>T (p.Arg340Ter)","Chromosome":"9","Start":"35740833","Stop":"35740833","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":49928,"rule_based_match":true,"evidence_text":"c.1018C>T [p.Arg340(∗)]","llm_judgment":"PRESENT","evidence":"c.1018C>T [p.Arg340(∗)]","abstract_start":949,"abstract_end":972},{"Name":"NM_020944.3(GBA2):c.2618G>A (p.Arg873His)","Chromosome":"9","Start":"35737335","Stop":"35737335","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49929,"rule_based_match":true,"evidence_text":"c.2618G>A [p.Arg873His]","llm_judgment":"PRESENT","evidence":"c.2618G>A [p.Arg873His]","abstract_start":994,"abstract_end":1017},{"Name":"NM_020944.3(GBA2):c.363C>A (p.Tyr121Ter)","Chromosome":"9","Start":"35744703","Stop":"35744703","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":626076,"rule_based_match":true,"evidence_text":"c.363C>A [p.Tyr121(∗)]","llm_judgment":"PRESENT","evidence":"c.363C>A [p.Tyr121(∗)]","abstract_start":922,"abstract_end":944}]}
{"pmid":"17880784","title":"Detection of new mutations in the dystrophin gene by denaturing high-performance liquid chromatography","abstract":"OBJECTIVE: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by dystrophin gene mutations; 55%-65% of these pathogenic mutations are large deletion and duplication mutations that can be detected by multiplexed polymerase chain reaction. However, finding the remaining micro-mutations (substitutions, deletions or insertions of one or several nucleotides) cannot be achieved in this way. The aim of the present study was to detect mutations of the dystrophin gene in individuals with Duchenne muscular dystrophy (DMD) by denaturing high-performance liquid chromatography (DHPLC) and to establish a rapid and sensitive screening platform for micro-mutations leading to DMD.\nMETHODS: Twenty patients negative for large deletions in the dystrophin gene by multiplex PCR were selected for further screening by DHPLC and 20 normal male without DMD family history as the control cohort. Dystrophin exons and their flanking sequences were individually amplified by genomic PCR and the amplicons showing abnormal DHPLC profile were directly sequenced to identify the position and the type of the mutations.\nRESULTS: After screening 68 exons covering the two deletion hotspots and 3'UTR region, four pathogenic mutations, including c.6808_6811del TTAA, c.4959_4960insA, c.8656C > T and c.8608C > T, were found in four DMD patients. Moreover, c.6808_6811del TTAA, c.4959_4960ins and c.8656C > T have not been reported previously. The first two frameshift mutations were predicted to produce premature stop codons, p.Leu2270MetfsX9 and p.Ser1654LysfsX5, respectively. The remaining two were nonsense mutations, leading to p.R2886X and p.R2870X, respectively.\nCONCLUSION: Three novel and one recurrent dystrophin mutations have been identified in Chinese DMD patients. This study has demonstrated that DHPLC is an effective screening method for micro-mutation associated with DMD.","variants":[{"Name":"NM_004006.3(DMD):c.8656C>T (p.Gln2886Ter)","Chromosome":"X","Start":"31478995","Stop":"31478995","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":195172,"rule_based_match":true,"evidence_text":"c.8656C > T","llm_judgment":"PRESENT","evidence":"c.8656C > T","abstract_start":1284,"abstract_end":1295},{"Name":"NM_004006.3(DMD):c.8608C>T (p.Arg2870Ter)","Chromosome":"X","Start":"31479043","Stop":"31479043","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":100710,"rule_based_match":true,"evidence_text":"c.8608C > T","llm_judgment":"PRESENT","evidence":"c.8608C > T","abstract_start":1300,"abstract_end":1311}]}
{"pmid":"35413566","title":"Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants.","abstract":"Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder characterized by a thick left ventricular wall and an increased risk of arrhythmias, heart failure, and sudden cardiac death. The MYBPC3 and PRAKG2 are known causal genes for HCM. Here we generated two human-induced pluripotent stem cell lines from two HCM patients carrying two heterozygous mutations in MYBPC3 (c.459delC) and PRKAG2 (c.1703C > T). Both iPSC lines expressed pluripotent markers, had a normal karyotype, and were able to differentiate into three germ layers, making them potentially valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to these two variants.","variants":[{"Name":"NM_016203.4(PRKAG2):c.1703C>T (p.Thr568Met)","Chromosome":"7","Start":"151557208","Stop":"151557208","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":179111,"rule_based_match":true,"evidence_text":"c.1703C > T","llm_judgment":"PRESENT","evidence":"c.1703C > T","abstract_start":403,"abstract_end":414}]}
{"pmid":"35448982","title":"Long delay in diagnosis of a case with MEN1 due to concomitant presence of AIMAH with insulinoma: a case report and literature review.","abstract":"BACKGROUND: ACTH-independent macronodular hyperplasia (AIMAH) is an uncommon disorder characterized by massive enlargement of both adrenal glands and hypersecretion of cortisol. Concomitant AIMAH and multiple endocrine neoplasia type1 (MEN1) is rare to our knowledge.\nCASE PRESENTATION: Herein, we describe a 32 year old woman with long history of prolactinoma and secondary ammonhrea presented with not-severe manifestation of hypoglycemia due to concomitant presence of insulinoma with AIMAH leading to 12 years delay of MEN1 diagnosis. Laboratory tests showed severe hypoglycemia associated with hyper insulinemia (non-fasting blood sugar = 43 mg/dl, insulin = 80.6 μIU /ml, C-peptide = 9.3 ng/ml) hyperparathyroidism (calcium = 10.3 mg/dl, phosphor = 3.1 mg/dl, PTH = 280 pg/ml) and chemical evidence of an ACTH-independent hypercortisolism (serum cortisol value of 3.5, after 1 mg dexamethasone suppression test serum ACTH value of 17 pg/ml, and high urinary cortisol level). Abdominal CT scan demonstrated two enhancing well-defined masses 27*20 mm and 37*30 mm in the tail and body of the pancreas, respectively, and a 36*15 mm mass in left adrenal gland (seven Hounsfield units). Dynamic pituitary MRI revealed a partial empty sella. The physical examination of the patient was unremarkable. Distal pancreatectomy and a left adrenalectomy were performed. After the surgery, we observed clinical and biochemical remission of hyper insulinemia and gradual decrease in urinary cortisol. The histological features of the removed left adrenal gland were consistent with AIMAH. Histological examination of the pancreatic lesions revealed well differentiated neuroendocrine tumors. Genetic abnormalities in the MEN1, heterozygote for pathogenic variant chr11; 645,773,330-64577333AGAC, c.249-252delGTCT, p. (11e85Serfs Ter33) in exon 2 were found. It was recommended the patient undergoes parathyroidectomy as soon as possible.\nCONCLUSION: Given the history and presentation of our case, we recommend that the clinicians consider the possibility of autonomous cortisol production in MEN1 patients who do not show severe symptoms of hypoglycemia in the presence of insulinoma.","variants":[{"Name":"NM_001370259.2(MEN1):c.249_252del (p.Ile85fs)","Chromosome":"11","Start":"64809858","Stop":"64809861","ReferenceAlleleVCF":"TAGAC","AlternateAlleleVCF":"T","allel_id":31732,"rule_based_match":false,"evidence_text":"c.249-252delGTCT","llm_judgment":"PRESENT","evidence":"c.249-252delGTCT","abstract_start":1787,"abstract_end":1803}]}
{"pmid":"18486607","title":"Genetic analysis of mucopolysaccharidosis type VI in Taiwanese patients.","abstract":"BACKGROUND: Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) is an autosomal recessive lysosomal storage disease induced by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase (arylsulfatase B, ARSB). The deficiency of ARSB leads to an accumulation of dermatan sulfate (DS) in lysosomes and gross excretion in the urine. The prevalence of these mutations in Asian MPS VI patients has not yet been thoroughly investigated. We studied the ARSB gene profile of 9 Taiwanese MPS VI patients.\nMETHODS: To validate the patients' type of MPS, urine mucopolysaccharide was defined by 2-dimensional electrophoresis and leukocyte ARSB activity was determined by fluorogenic assay. Direct sequencing was used to identify any mutation in the patients' ARSB gene.\nRESULTS: Abnormal excretion of DS and low leukocyte ARSB activity was observed in the urine samples of all 9 patients studied. A total of 8 mutations within the ARSB gene were revealed by molecular analysis. Four mutations, c.574T>C (p.Cys192Arg) and c.943C>T (p.Arg315Stop) mutations had been observed in other populations and c.716A>G (p.Gln239Arg) and c.1197C>G (p.Phe399Leu) were previously reported by our group. The other 4 mutations c.395T>C (p.Leu132Pro), c.908G>A (p.Gly303Glu), c.1228 C>A (p.His430Asn) and c.1394C>G (p.Ser465X), had not been reported before. The c.1197C>G (p.Phe399Leu) and c.395T>C (p.Leu132Pro) mutations were the most common missense mutation in the patients studied (8 in 18 mutant alleles). According to statistical data, the incidence of MPS VI in Taiwan is approximately 1 in 833,000 in live birth.\nCONCLUSION: The ARSB gene mutation profile in Taiwanese MPS VI patients may be different from MPS VI patients from other countries.","variants":[{"Name":"NM_000046.5(ARSB):c.1394C>G (p.Ser465Ter)","Chromosome":"5","Start":"78780605","Stop":"78780605","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":550401,"rule_based_match":true,"evidence_text":"c.1394C>G (p.Ser465X)","llm_judgment":"PRESENT","evidence":"c.1394C>G (p.Ser465X)","abstract_start":1291,"abstract_end":1312},{"Name":"NM_000046.5(ARSB):c.908G>A (p.Gly303Glu)","Chromosome":"5","Start":"78885818","Stop":"78885818","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550456,"rule_based_match":true,"evidence_text":"c.908G>A (p.Gly303Glu)","llm_judgment":"PRESENT","evidence":"c.908G>A (p.Gly303Glu)","abstract_start":1238,"abstract_end":1260},{"Name":"NM_000046.5(ARSB):c.1197C>G (p.Phe399Leu)","Chromosome":"5","Start":"78839372","Stop":"78839372","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":550424,"rule_based_match":true,"evidence_text":"c.1197C>G (p.Phe399Leu)","llm_judgment":"PRESENT","evidence":"c.1197C>G (p.Phe399Leu)","abstract_start":1129,"abstract_end":1152}]}
{"pmid":"27233228","title":"Next generation sequencing of patients with mut methylmalonic aciduria: Validation of somatic cell studies and identification of 16 novel mutations.","abstract":"Mutations in the MUT gene, which encodes the mitochondrial enzyme methylmalonyl-CoA mutase, are responsible for the mut form of methylmalonic aciduria (MMA). In this study, a next generation sequencing (NGS) based gene panel was used to analyze 53 patients that had been diagnosed with mut MMA by somatic cell complementation analysis. A total of 54 different mutations in MUT were identified in 48 patients; 16 novel mutations were identified, including 1 initiation site mutation (c.2T>C [p.M1?]), 1 missense mutation (c.566A>T [p.N189I]), 2 nonsense mutations (c.129G>A [p.W43*] and c.1975C>T [p.Q659*]), 2 mutations affecting splice sites (c.753+3A>G and c.754-2A>G), 8 small insertions, deletions, and duplications (c.29dupT [p.L10Ffs*39], c.55dupG [p.V19Gfs*30], c.631_633delGAG [p.E211del], c.795_796insT [p.M266Yfs*7], c.1061delCinsGGA [p.S354Wfs*20], c.1065_1068dupATGG [p.S357Mfs*5], c.1181dupT [p.L394Ffs*30], c.1240delG [p.E414Kfs*17]), a large insertion (c.146_147ins279), and a large deletion involving exon 13. Phenotypic rescue and cDNA analysis were used to confirm that the c.146_147ins279 and c.631_633delGAG mutations were associated with the decreased methylmalonyl-CoA mutase function observed in the patient fibroblasts. In five patients, the NGS panel did not confirm the diagnosis made by complementation analysis. One of these patients was found to carry 2 novel mutations (c.433G > A [p.E145K] and c.511A>C [p.N171H]) in the SUCLG1 gene.","variants":[{"Name":"NM_000255.4(MMUT):c.566A>T (p.Asn189Ile)","Chromosome":"6","Start":"49457878","Stop":"49457878","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":224646,"rule_based_match":true,"evidence_text":"c.566A>T [p.N189I]","llm_judgment":"PRESENT","evidence":"c.566A>T [p.N189I]","abstract_start":521,"abstract_end":539},{"Name":"NM_000255.4(MMUT):c.29dup (p.Leu10fs)","Chromosome":"6","Start":"49459437","Stop":"49459438","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":544025,"rule_based_match":true,"evidence_text":"c.29dupT [p.L10Ffs*39]","llm_judgment":"PRESENT","evidence":"c.29dupT [p.L10Ffs*39]","abstract_start":721,"abstract_end":743},{"Name":"NM_000255.4(MMUT):c.754-2A>G","Chromosome":"6","Start":"49456239","Stop":"49456239","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":543721,"rule_based_match":true,"evidence_text":"c.754-2A>G","llm_judgment":"PRESENT","evidence":"c.754-2A>G","abstract_start":659,"abstract_end":669},{"Name":"NM_000255.4(MMUT):c.1975C>T (p.Gln659Ter)","Chromosome":"6","Start":"49435605","Stop":"49435605","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":224622,"rule_based_match":true,"evidence_text":"c.1975C>T (p.Q659*)","llm_judgment":"PRESENT","evidence":"c.1975C>T","abstract_start":586,"abstract_end":595}]}
{"pmid":"22845787","title":"Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine.","abstract":"PRRT2 is the gene recently associated with paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy, and choreoathetosis infantile convulsions. We report four family members with PRRT2 mutations who had heterogeneous paroxysmal disorders. The index patient had transient infantile paroxysmal torticollis, then benign infantile epilepsy that responded to carbamazepine. The index patient's father had PKD and migraine with aphasia, and his two brothers had hemiplegic migraine with onset in childhood. All four family members had the same PRRT2 c.649dupC mutation. We conclude that heterogeneous paroxysmal disorders are associated with PRRT2 mutations and include paroxysmal torticollis and hemiplegic migraine. We propose that PRRT2 is a new gene for hemiplegic migraine.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"PRRT2 c.649dupC","llm_judgment":"PRESENT","evidence":"PRRT2 c.649dupC","abstract_start":557,"abstract_end":572}]}
{"pmid":"29292490","title":"Two Uneventful Pregnancies in a Woman with Glutaric Aciduria Type 1.","abstract":"Glutaric aciduria type 1 (GA1) is an autosomal recessive rare disorder caused by mutations in the GCDH gene resulting in deficiency of glutaryl-CoA dehydrogenase, leading to accumulation of the amino acids lysine, hydroxylysine and tryptophan and other metabolites. The phenotypic spectrum of disease is broad. Stress caused by infection and fever and possibly pregnancy may lead to worsening of the signs and symptoms, often with uncertain recovery.We describe a case of a female patient with GA1 who had two clinically uneventful pregnancies.At the age of 11 she was diagnosed with GA1 by family screening. The cultured skin fibroblast showed reduced glutaryl-CoA dehydrogenase activity (0.16 mg protein per min).The initial diagnostic urine glutaric acid level for this patient was 1,784 μmol/mmol creatinine. Mutation analysis showed compound heterozygosity for the p.(Gly185Arg), c.553G>A in exon 7 and p.(Arg402Trp), c.1204C.T in exon 11 mutations of the GCDH.Her pregnancy at the age of 23 was complicated by pre-eclampsia and required treatment with beta-blockers. Four years later the second pregnancy was uncomplicated. The management plan during the caesarean section included intravenous dextrose and lipid infusions. The patient rapidly recovered from both surgeries.Both babies have had normal development to date. On newborn screening, plasma acylcarnitine showed a transient increase in glutarylcarnitine, and the urine organic acid analysis showed a trace of 3-hydroxyglutarylcarnitine, likely to be of maternal transfer.The multidisciplinary team, consisting of metabolic, dietetic and obstetric care providers, have responsibility to ensure the risk of acute decompensation in pregnant GA1 women is minimal.","variants":[{"Name":"NM_000159.4(GCDH):c.553G>A (p.Gly185Arg)","Chromosome":"19","Start":"12896039","Stop":"12896039","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":647711,"rule_based_match":true,"evidence_text":"c.553G>A","llm_judgment":"PRESENT","evidence":"c.553G>A","abstract_start":885,"abstract_end":893}]}
{"pmid":"33876391","title":"Hypoglycemia due to PI3K/AKT/mTOR signaling pathway defects: two novel cases and review of the literature.","abstract":"INTRODUCTION: The PI3K/AKT/mTOR signaling pathway is important for the regulation of multiple biological processes, including cellular growth and glucose metabolism. Defects of the PI3K/AKT/mTOR signaling pathway are not usually considered among the genetic causes of recurrent hypoglycemia in childhood. However, accumulating evidence links hypoglycemia with defects of this pathway.\nCASE REPORTS AND REVIEW: We describe here two cases of macrocephaly and hypoglycemia bearing genetic defects in genes involved in the PI3K/AKT/mTOR pathway. The first patient was diagnosed with a PTEN hamartoma tumour syndrome (PTHS) due to the de novo germline missense mutation c.[492 + 1G > A] of the PTEN gene. The second patient presented the autosomal dominant mental retardation-35 (MDR35) due to the heterozygous missense mutation c.592G > A in the PPP2R5D gene. A review of the literature on hypoglycemia and PI3K/AKT/mTOR signaling pathway defects, with a special focus on the metabolic characterization of hypoglycemia, is included.\nCONCLUSIONS: PI3K/AKT/mTOR pathway defects should be included in the differential diagnosis of patients with hypoglycemia and macrocephaly. Clinical suspicion and molecular confirmation are important, not just for an accurate genetic counselling but also for defining the follow-up management, including cancer surveillance. The biochemical profile of hypoglycemia varies among patients. While most patients are characterized by low plasmatic insulin levels, hyperinsulinemia has also been observed. Large patient cohorts are needed to gain a comprehensive profile of the biochemical patterns of hypoglycemia in such defects and eventually guide targeted therapeutic interventions.","variants":[{"Name":"NM_000314.8(PTEN):c.492+1G>A","Chromosome":"10","Start":"87933252","Stop":"87933252","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1202442,"rule_based_match":false,"evidence_text":"c.492 + 1G > A","llm_judgment":"PRESENT","evidence":"c.[492 + 1G > A","abstract_start":665,"abstract_end":680}]}
{"pmid":"31647904","title":"Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish.","abstract":"Mutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD). We describe a novel fibrovascular proliferation in the retina of two affected members of a KCNJ13-related LCA family with a homozygous c.458C > T, p.(Thr153Ile) missense mutation. Optical coherence tomography retinal imaging of the kcnj13 mutant zebrafish (obelix<sup>td15</sup> c.502T > C, p.[Phe168Leu]) revealed a late onset retinal degeneration at 12 months, with retinal thinning and associated retinovascular changes, including increased vessel calibre and vitreous deposits. Both human and zebrafish variants are missense and located within the conserved transmembrane M2 protein domain, suggesting that disruption of this region may contribute to retinovascular changes as an additional feature to the previously described LCA phenotype. Close monitoring of other patients with similar mutations may be required to minimise the ensuing retinal damage.","variants":[{"Name":"NM_002242.4(KCNJ13):c.458C>T (p.Thr153Ile)","Chromosome":"2","Start":"232770905","Stop":"232770905","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":213535,"rule_based_match":true,"evidence_text":"c.458C > T, p.(Thr153Ile)","llm_judgment":"PRESENT","evidence":"c.458C > T, p.(Thr153Ile)","abstract_start":279,"abstract_end":304}]}
{"pmid":"30385778","title":"Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1.","abstract":"Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features. Most of the reported FOXP1 mutations occur on the C-terminus of the protein and cluster around to the forkhead domain. All reported FOXP1 pathogenic variants result in abnormal cellular localization and loss of transcriptional repression activity of the protein product. Here we present three patients with the same FOXP1 mutation, c.1574G>A (p.R525Q), that results in the characteristic loss of transcription repression activity. This mutation, however, represents the first reported FOXP1 mutation that does not result in cytoplasmic or nuclear aggregation of the protein but maintains normal nuclear localization.","variants":[{"Name":"NM_001349338.3(FOXP1):c.1574G>A (p.Arg525Gln)","Chromosome":"3","Start":"70972633","Stop":"70972633","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":511508,"rule_based_match":true,"evidence_text":"c.1574G>A (p.R525Q)","llm_judgment":"PRESENT","evidence":"c.1574G>A (p.R525Q)","abstract_start":548,"abstract_end":567}]}
{"pmid":"18030493","title":"A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression.","abstract":"Mutations in the potassium channel gene KCNQ4 underlie DFNA2, a subtype of autosomal dominant progressive, high-frequency hearing loss. Based on a phenotype-guided mutational screening we have identified a novel mutation c.886G>A, leading to the p.G296S substitution in the pore region of KCNQ4 channel. The possible impact of this mutation on total KCNQ4 protein expression, relative surface expression and channel function was investigated. When the G296S mutant was expressed in Xenopus oocytes, electrophysiological recordings did not show voltage-activated K(+) currents. The p.G296S mutation impaired KCNQ4 channel activity in two manners. It greatly reduced surface expression and, secondarily, abolished channel function. The deficient expression at the cell surface membrane was further confirmed in non-permeabilized NIH-3T3 cells transfected with the mutant KCNQ4 tagged with the hemagglutinin epitope in the extracellular S1-S2 linker. Co-expression of mutant and wild type KCNQ4 in oocytes was performed to mimic the heterozygous condition of the p.G296S mutation in the patients. The results showed that the G296S mutant exerts a strong dominant-negative effect on potassium currents by reducing the wild type KCNQ4 channel expression at the cell surface. This is the first study to identify a trafficking-dependent dominant mechanism for the loss of KCNQ4 channel function in DFNA2.","variants":[{"Name":"NM_004700.4(KCNQ4):c.886G>A (p.Gly296Ser)","Chromosome":"1","Start":"40819926","Stop":"40819926","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21288,"rule_based_match":true,"evidence_text":"c.886G>A","llm_judgment":"PRESENT","evidence":"c.886G>A","abstract_start":221,"abstract_end":229}]}
{"pmid":"25105228","title":"Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis.","abstract":"Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. qRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.","variants":[{"Name":"NM_020928.2(ZSWIM6):c.3487C>T (p.Arg1163Trp)","Chromosome":"5","Start":"61544156","Stop":"61544156","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":165524,"rule_based_match":true,"evidence_text":"c.3487C>T [p. Arg1163Trp]","llm_judgment":"PRESENT","evidence":"c.3487C>T [p. Arg1163Trp]","abstract_start":398,"abstract_end":423}]}
{"pmid":"25665175","title":"Exon-Specific U1s Correct SPINK5 Exon 11 Skipping Caused by a Synonymous Substitution that Affects a Bifunctional Splicing Regulatory Element.","abstract":"The c.891C>T synonymous transition in SPINK5 induces exon 11 (E11) skipping and causes Netherton syndrome (NS). Using a specific RNA-protein interaction assay followed by mass spectrometry analysis along with silencing and overexpression of splicing factors, we showed that this mutation affects an exonic bifunctional splicing regulatory element composed by two partially overlapping silencer and enhancer sequences, recognized by hnRNPA1 and Tra2β splicing factors, respectively. The C-to-T substitution concomitantly increases hnRNPA1 and weakens Tra2β-binding sites, leading to pathological E11 skipping. In hybrid minigenes, exon-specific U1 small nuclear RNAs (ExSpe U1s) that target by complementarity intronic sequences downstream of the donor splice site rescued the E11 skipping defect caused by the c.891C>T mutation. ExSpe U1 lentiviral-mediated transduction of primary NS keratinocytes from a patient bearing the mutation recovered the correct full-length SPINK5 mRNA and the corresponding functional lympho-epithelial Kazal-type related inhibitor protein in a dose-dependent manner. This study documents the reliability of a mutation-specific, ExSpe U1-based, splicing therapy for a relatively large subset of European NS patients. Usage of ExSpe U1 may represent a general approach for correction of splicing defects affecting skin disease genes.","variants":[{"Name":"NM_006846.4(SPINK5):c.891C>T (p.Cys297=)","Chromosome":"5","Start":"148097875","Stop":"148097875","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360867,"rule_based_match":true,"evidence_text":"c.891C>T","llm_judgment":"PRESENT","evidence":"c.891C>T","abstract_start":4,"abstract_end":12}]}
{"pmid":"33719328","title":"A Comprehensive Analysis and Splicing Characterization of Naturally Occurring Synonymous Variants in the","abstract":"Next-generation sequencing is effective for the molecular diagnosis of genetic diseases. However, the identification of the clinical significance of synonymous variants remains a challenge. Our previous study showed that some synonymous variants in <i>ATP7B</i> gene produced splicing disruptions, leading to Wilson disease (WD). To test the hypothesis that synonymous variants of <i>ATP7B</i> cause abnormal splicing by disrupting authentic splice sites or splicing regulatory elements, we used computational tools and minigene assays to characterize 253 naturally occurring <i>ATP7B</i> gene synonymous variants in this study. Human Splicing Finder (HSF) and ESE Finder 3.0 were used to predict the impact of these rare synonymous variants on pre-mRNA splicing. Then, we cloned 14 different wild-type Minigene_ATP7B_ex constructs for <i>in vitro</i> minigene assay, including 16 exons of <i>ATP7B</i> gene. After computational prediction, 85 candidate variants were selected to be introduced into the corresponding Minigene_ATP7B_ex constructs for splicing assays. Using this two-step procedure, we demonstrated that 11 synonymous variants in ExAc database (c.1620C>T, c.3888C>T, c.1554C>T, c.1677C>T, c.1830G>A, c.1875T>A, c.2826C>A, c.4098G>A, c.2994C>T, c.3243G>A, and c.3747G>A) disrupted RNA splicing <i>in vitro</i>, and two (c.1620C>T and c.3243G>A) of these caused a complete exon skipping. The results not only provided a reliable experimental basis for the genetic diagnosis of WD patients but also offered some new insights into the pathogenicity of synonymous variants in genetic diseases.","variants":[{"Name":"NM_000053.4(ATP7B):c.3747G>A (p.Val1249=)","Chromosome":"13","Start":"51937632","Stop":"51937632","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1080133,"rule_based_match":true,"evidence_text":"c.3747G>A","llm_judgment":"PRESENT","evidence":"c.3747G>A","abstract_start":1274,"abstract_end":1283},{"Name":"NM_000053.4(ATP7B):c.2994C>T (p.Gly998=)","Chromosome":"13","Start":"51946350","Stop":"51946350","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":725510,"rule_based_match":true,"evidence_text":"c.2994C>T","llm_judgment":"PRESENT","evidence":"c.2994C>T","abstract_start":1248,"abstract_end":1257},{"Name":"NM_000053.4(ATP7B):c.1677C>T (p.Tyr559=)","Chromosome":"13","Start":"51968474","Stop":"51968474","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1123429,"rule_based_match":true,"evidence_text":"c.1677C>T","llm_judgment":"PRESENT","evidence":"c.1677C>T","abstract_start":1193,"abstract_end":1202},{"Name":"NM_000053.4(ATP7B):c.1554C>T (p.Ser518=)","Chromosome":"13","Start":"51968597","Stop":"51968597","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":979403,"rule_based_match":true,"evidence_text":"c.1554C>T","llm_judgment":"PRESENT","evidence":"c.1554C>T","abstract_start":1182,"abstract_end":1191},{"Name":"NM_000053.4(ATP7B):c.3888C>T (p.Asp1296=)","Chromosome":"13","Start":"51937491","Stop":"51937491","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":769590,"rule_based_match":true,"evidence_text":"c.3888C>T","llm_judgment":"PRESENT","evidence":"c.3888C>T","abstract_start":1171,"abstract_end":1180},{"Name":"NM_000053.4(ATP7B):c.1620C>T (p.Leu540=)","Chromosome":"13","Start":"51968531","Stop":"51968531","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":254870,"rule_based_match":true,"evidence_text":"c.1620C>T","llm_judgment":"PRESENT","evidence":"c.1620C>T","abstract_start":1160,"abstract_end":1169},{"Name":"NM_000053.4(ATP7B):c.2826C>A (p.Ile942=)","Chromosome":"13","Start":"51949701","Stop":"51949701","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1162073,"rule_based_match":true,"evidence_text":"c.2826C>A","llm_judgment":"PRESENT","evidence":"c.2826C>A","abstract_start":1226,"abstract_end":1235},{"Name":"NM_000053.4(ATP7B):c.4098G>A (p.Val1366=)","Chromosome":"13","Start":"51935619","Stop":"51935619","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3233143,"rule_based_match":true,"evidence_text":"c.4098G>A","llm_judgment":"PRESENT","evidence":"c.4098G>A","abstract_start":1237,"abstract_end":1246}]}
{"pmid":"25584046","title":"Congenital hyperinsulinism: clinical and molecular characterisation of compound heterozygous ABCC8 mutation responsive to Diazoxide therapy.","abstract":"BACKGROUND: Mutations in ABCC8 and KCNJ11 are the most common cause of congenital hyperinsulinism (CHI). Recessive as well as dominant acting ABCC8/KCNJ11 mutations have been described. Diazoxide, which is the first line medication for CHI, is usually ineffective in recessive ABCC8 mutations. We describe the clinical and molecular characterisation of a recessive ABCC8 mutation in a CHI patient that is diazoxide response.\nCLINICAL CASE: A term macrosomic female infant presented with symptomatic persistent hypoglycaemia confirmed to be secondary to CHI. She exhibited an excellent response to moderate doses of diazoxide (10 mg/kg/day). Molecular genetic analysis of the proband confirmed a biallelic ABCC8 mutation - missense R526C inherited from an unaffected mother and a frameshift c.1879delC mutation (H627Mfs*20) inherited from an unaffected father. Follow-up highlighted persistent requirement for diazoxide to control CHI. Functional analysis of mutants confirmed them to result in diazoxide-responsive CHI, consistent with the clinical phenotype.\nCONCLUSION: Biallelic ABCC8 mutations may result in diazoxide-responsive CHI. Irrespective of the molecular genetic analysis results, accurate assessment of the response to diazoxide should be undertaken before classifying a patient as diazoxide-responsive or unresponsive CHI.","variants":[{"Name":"NM_000352.6(ABCC8):c.1879del (p.His627fs)","Chromosome":"11","Start":"17428609","Stop":"17428609","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":357949,"rule_based_match":true,"evidence_text":"c.1879delC mutation (H627Mfs*20)","llm_judgment":"PRESENT","evidence":"c.1879delC mutation (H627Mfs*20)","abstract_start":790,"abstract_end":822}]}
{"pmid":"35379526","title":"Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1.","abstract":"INTRODUCTION: Next generation sequencing technologies allow detection of very rare pathogenic gene variants and uncover cerebral palsy. Herein, we describe two siblings with cerebral palsy due to ELOVL1 splice site mutation in autosomal recessive manner. ELOVL1 catalyzes fatty acid elongation to produce very long-chain fatty acids (VLCFAs; ≥C21), most of which are components of sphingolipids such as ceramides and sphingomyelins. Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies (MIM: 618527) stem from ELOVL1 gene deficiency in human.\nMETHODS: We have studied a consanguineous family with whole exome sequencing (WES) and performed in depth analysis of cryptic splicing on the molecular level using RNA. Comprehensive analysis of ceramides in the skin stratum corneum of patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS). ELOVL1 protein structure was computationally modelled.\nRESULTS: The novel c.376-2A > G (ENST00000372458.8) homozygous variant in the affected siblings causes exon skipping. Comprehensive analysis of ceramides in the skin stratum corneum of patients using LC-MS/MS demonstrated significant shortening of fatty acid moieties and severe reduction in the levels of acylceramides.\nDISCUSSION: It has recently been shown that disease associated variants of ELOVL1 segregate in an autosomal dominant manner. However, our study for the first time demonstrates an alternative autosomal recessive inheritance model for ELOVL1. In conclusion, we suggest that in ultra-rare diseases, being able to identify the inheritance patterns of the disease-associated gene or genes can be an important guide to identifying the molecular mechanism of genetic cerebral palsy.","variants":[{"Name":"NM_022821.4(ELOVL1):c.376-2A>G","Chromosome":"1","Start":"43364649","Stop":"43364649","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1678994,"rule_based_match":true,"evidence_text":"c.376-2A>G","llm_judgment":"PRESENT","evidence":"c.376-2A > G","abstract_start":949,"abstract_end":961}]}
{"pmid":"30221392","title":"Gene mutation and pedigree analysis of tetrahydrobiopterin deficiency in a Uygur family of China.","abstract":"BACKGROUND: Tetrahydrobiopterin (BH<sub>4</sub> ) deficiency is an autosomal recessive disorder, which is caused by an enzyme deficiency involved in its synthetic or metabolic pathways. Clinical symptoms may include microcephaly, hypoevolutism, severe ataxia, and seizures. The purposes of this study are to analyze the genotype-phenotype and the pedigree of the first case of BH<sub>4</sub> deficiency in the Uygur of China.\nMETHODS: (a) This patient received tandem mass spectrometry, urinary neopterin and biopterin analysis, and determination of dihydropteridine reductase (DHPR) activity in dried blood spots. (b) Blood DNA samples of this patient and her three family members were collected for gene sequencing and mutation analysis.\nRESULTS: (a) The basic urinary neopterin and biopterin were 1.07 mmol/mol Cr and 3.12 mmol/mol Cr, respectively, and biopterin percentage was 74.42%. The DHPR activity of this patient was 31.11% of normal control. (b) Sanger sequencing of PAH gene in this patient was negative but positive of her sister, which carries 2 heterozygous mutation c.781C>T and c.1238G>C. Next-generation sequencing on the patient identified a homozygous mutation in the quinoid dihydropteridine reductase (QDPR) gene at c.508G>A, which was confirmed by Sanger sequencing.\nCONCLUSION: (a) The patient was the first case of clinical diagnosis of BH<sub>4</sub> deficiency in the Uighur. And there are two types of hyperphenylalaninemia (HPA) in the same family. (b) The mild HPA patient with severe nervous system damage should pay more attention to the BH<sub>4</sub> deficiency. (c) Using next-generation sequencing technology can increase the mutation detection rate when the hereditary diseases are highly suspected in clinic.","variants":[{"Name":"NM_000320.3(QDPR):c.508G>A (p.Gly170Ser)","Chromosome":"4","Start":"17492269","Stop":"17492269","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1055421,"rule_based_match":true,"evidence_text":"c.508G>A","llm_judgment":"PRESENT","evidence":"c.508G>A","abstract_start":1239,"abstract_end":1247}]}
{"pmid":"25234635","title":"Progressive hyperpigmentation in a Taiwanese child due to an inborn error of vitamin B12 metabolism (cblJ).","abstract":"The physiology of human skin pigmentation is varied and complex, with an extensive melanogenic paracrine network involving mesenchymal and epithelial cells, contributing to the regulation of melanocyte survival and proliferation and melanogenesis. Mutations in several genes, involving predominantly the KIT ligand/c-Kit and Ras/mitogen-activated protein kinase signalling pathways, have been implicated in a spectrum of diseases in which there is hyperpigmentation, hypopigmentation or both. Here, we report on a 12-year-old girl from Taiwan with a 6-year history of diffuse progressive skin hyperpigmentation resulting from a different aetiology: an inborn metabolic disorder of vitamin B12 (cobalamin), designated cblJ. Using whole-exome sequencing we identified a homozygous mutation in ABCD4 (c.423C>G; p.Asn141Lys), which encodes an ATP-binding cassette transporter with a role in the intracellular processing of cobalamin. The patient had biochemical and haematological evidence of cobalamin deficiency but no other clinical abnormalities apart from a slight lightening of her previously black hair. Of note, she had no neurological symptoms or signs. Treatment with oral cobalamin (3 mg daily) led to metabolic correction and some reduction in the skin hyperpigmentation at the 3-month follow-up. This case demonstrates that defects or deficiencies of cobalamin should be remembered in the differential diagnosis of diffuse hyperpigmentary skin disorders.","variants":[{"Name":"NM_005050.4(ABCD4):c.423C>G (p.Asn141Lys)","Chromosome":"14","Start":"74297932","Stop":"74297932","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1335298,"rule_based_match":true,"evidence_text":"c.423C>G (p.Asn141Lys)","llm_judgment":"PRESENT","evidence":"p.Asn141Lys","abstract_start":808,"abstract_end":819}]}
{"pmid":"38459354","title":"PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss.","abstract":"Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.","variants":[{"Name":"NM_177531.6(PKHD1L1):c.385G>A (p.Gly129Ser)","Chromosome":"8","Start":"109382539","Stop":"109382539","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3380118,"rule_based_match":false,"evidence_text":"p.[(Gly129Ser)]","llm_judgment":"PRESENT","evidence":"p.[(Gly129Ser)]","abstract_start":610,"abstract_end":625},{"Name":"NM_177531.6(PKHD1L1):c.1813G>A (p.Gly605Arg)","Chromosome":"8","Start":"109406478","Stop":"109406478","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3380122,"rule_based_match":true,"evidence_text":"c.1813G>A p.(Gly605Arg)","llm_judgment":"PRESENT","evidence":"c.1813G>A p.(Gly605Arg)","abstract_start":1644,"abstract_end":1667}]}
{"pmid":"25217959","title":"An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.","abstract":"Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A > T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.","variants":[{"Name":"NM_001199138.2(NLRC4):c.1009A>T (p.Thr337Ser)","Chromosome":"2","Start":"32250855","Stop":"32250855","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":166229,"rule_based_match":true,"evidence_text":"c.1009A > T, encoding p.Thr337Ser","llm_judgment":"PRESENT","evidence":"c.1009A > T, encoding p.Thr337Ser","abstract_start":485,"abstract_end":518}]}
{"pmid":"24973495","title":"Molecular analysis of Cypriot patients with Glutaric aciduria type I: identification of two novel mutations.","abstract":"OBJECTIVES: The purpose of this study was to identify the mutations in the glutaryl-CoA dehydrogenase gene (GCDH) in ten Cypriot patients with Glutaric aciduria type I (GAI).\nDESIGN AND METHODS: Molecular analysis of the GCDH gene was performed by direct sequencing of the patients' genomic DNA. In silico tools were applied to predict the effect of the novel variants on the structure and function of the protein.\nRESULTS: All disease alleles were characterized (mutation detection rate 100%). Five missense mutations were identified: c.192G>T (p.Glu64Asp) and c.803G>T (p.Gly268Val), which are novel, and three previously described mutations, c.1123T>C (p.Cys375Arg), c.1204C>T (p.Arg402Trp) and c.1286C>T (p.Thr429Met).\nCONCLUSIONS: Two novel mutations, p.Glu64Asp and p.Gly268Val, account for the majority of disease alleles (76.5%) in Cypriot patients with Glutaric aciduria type I. A founder effect for the p.Glu64Asp and the p.Gly268Val can be suggested based on the place of origin of the carriers of these mutations. Identification of the causative mutations of GAI in Cypriot patients will facilitate carrier detection as well as post- and pre-natal diagnosis.","variants":[{"Name":"NM_000159.4(GCDH):c.192G>T (p.Glu64Asp)","Chromosome":"19","Start":"12891895","Stop":"12891895","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":548707,"rule_based_match":true,"evidence_text":"c.192G>T (p.Glu64Asp)","llm_judgment":"PRESENT","evidence":"c.192G>T (p.Glu64Asp)","abstract_start":536,"abstract_end":557},{"Name":"NM_000159.4(GCDH):c.1204C>T (p.Arg402Trp)","Chromosome":"19","Start":"12897824","Stop":"12897824","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17124,"rule_based_match":true,"evidence_text":"c.1204C>T (p.Arg402Trp)","llm_judgment":"PRESENT","evidence":"c.1204C>T (p.Arg402Trp)","abstract_start":670,"abstract_end":693},{"Name":"NM_000159.4(GCDH):c.803G>T (p.Gly268Val)","Chromosome":"19","Start":"12896372","Stop":"12896372","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1289721,"rule_based_match":true,"evidence_text":"c.803G>T (p.Gly268Val)","llm_judgment":"PRESENT","evidence":"c.803G>T (p.Gly268Val)","abstract_start":562,"abstract_end":584},{"Name":"NM_000159.4(GCDH):c.1286C>T (p.Thr429Met)","Chromosome":"19","Start":"12899510","Stop":"12899510","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":548729,"rule_based_match":true,"evidence_text":"c.1286C>T (p.Thr429Met)","llm_judgment":"PRESENT","evidence":"c.1286C>T (p.Thr429Met)","abstract_start":698,"abstract_end":721},{"Name":"NM_000159.4(GCDH):c.1123T>C (p.Cys375Arg)","Chromosome":"19","Start":"12897743","Stop":"12897743","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1441468,"rule_based_match":true,"evidence_text":"c.1123T>C (p.Cys375Arg)","llm_judgment":"PRESENT","evidence":"c.1123T>C (p.Cys375Arg)","abstract_start":645,"abstract_end":668}]}
{"pmid":"19107570","title":"A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family.","abstract":"Leigh syndrome is a neurodegenerative disorder of infancy or childhood generally due to mutations in nuclear or mitochondrial genes involved in mitochondrial energy metabolism. We performed linkage analysis in an Ashkenazi Jewish (AJ) family without consanguinity with three affected children. Linkage to microsatellite markers D5S1969 and D5S407 led to evaluation of the complex I gene NDUFS4, in which we identified a novel homozygous c.462delA mutation that disrupts the reading frame. The resulting protein lacks a cAMP-dependent protein kinase phosphorylation site required for activation of mitochondrial respiratory chain complex I. In a random sample of 5000 healthy AJ individuals, the carrier frequency of the NDUFS4 mutation c.462delA was 1 in 1000, suggesting that it should be considered in all AJ patients with Leigh syndrome.","variants":[{"Name":"NM_002495.4(NDUFS4):c.462del (p.Lys154fs)","Chromosome":"5","Start":"53683152","Stop":"53683152","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":48741,"rule_based_match":true,"evidence_text":"c.462delA","llm_judgment":"PRESENT","evidence":"c.462delA","abstract_start":437,"abstract_end":446}]}
{"pmid":"29726989","title":"A splicing mutation in aryl hydrocarbon receptor associated with retinitis pigmentosa.","abstract":"Retinitis pigmentosa (RP) refers to a group of retinal degenerative diseases, which often lead to vision loss. Although 70 genes have been identified in RP patients, the genetic cause of approximately 30% of RP cases remains unknown. We aimed to identify the cause of the disease in a cohort of RP families by whole exome sequencing. A rare homozygous splicing variant, c.1160 + 1G>A, which introduced skipping of exon 9 of the aryl hydrocarbon receptor (AHR), was identified in family RD-134. This variant is very rare in several exome databases and leads to skipping of exon 9 in the transcript. AHR is expressed in the human retina and is a ligand-activated transcription factor with multiple functions. Mutant AHR failed to promote 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced xenobiotic responsive element (XRE) luciferase activity. In parallel, mutation in AHR abolished activation of its downstream target gene, such as CYP1A1 and CYP1A2. To investigate the in vivo roles of Ahr in the retina, we generated a retina-specific conditional knockout mouse model of Ahr. Comparing with wild-type mouse, Ahr knockout mice exhibited reduced electroretinogram responses at 9 months of age. Retinal histology revealed retinal histology showed the degeneration of photoreceptors with a thinner outer nuclear layer. Thus, our data demonstrate that AHR is associated with RP.","variants":[{"Name":"NM_001621.5(AHR):c.1160+1G>A","Chromosome":"7","Start":"17335787","Stop":"17335787","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":610634,"rule_based_match":true,"evidence_text":"c.1160+1G>A","llm_judgment":"PRESENT","evidence":"c.1160 + 1G>A","abstract_start":370,"abstract_end":383}]}
{"pmid":"32552675","title":"Clinical characteristics and prenatal diagnosis for 22 families in Henan Province of China with X-linked agammaglobulinemia (XLA) related to Bruton's tyrosine kinase (BTK) gene mutations.","abstract":"BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease for which recurrent severe infection is the major clinical symptom. BTK is the main causative gene, with X chromosome recessive inheritance. However, the mutations reported to date do not fully explain the disorder.\nMETHODS: We detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by flow cytometry and rate scatter immunoturbidimetry, and investigated the BTK mutation profile in 22 XLA patients using Sanger sequencing and real-time PCR .\nRESULTS: We evaluated the clinical symptoms of 22 XLA patients and investigated genetic mutations present, identifying six novel mutations in the BTK gene: 2 missense mutations (c.23G > T and c.112 T > C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631 + 2 T > C). Prenatal diagnoses were performed in six families (F10, F11, F15, F18, F20 and F21), with the following results: the male fetus in Family 10 (F10) did not carry the c.922_923delGA mutation; the male fetus in Family 15 (F15) did not carry the c.1631 + 1G > T splicing mutation; the female fetus in Family 20 (F20) did not carry the c.1931 T > C mutation; the female fetus in Family 21 (F21) did not carry the large deletion mutation. Hence, these four fetuses are not likely to develop XLA. Male fetuses with c.1060delA and c.1684C > T mutations were identified in Family 11 and Family 18, respectively. The pregnant woman in F18 chose to terminate the pregnancy, whereas the pregnant woman in F11 chose to continue the pregnancy.\nCONCLUSION: We confirmed the diagnosis of 22 XLA patients from 22 unrelated families and detected six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat infections in XLA children, saving their lives.","variants":[{"Name":"NM_000061.3(BTK):c.1931T>C (p.Phe644Ser)","Chromosome":"X","Start":"101349934","Stop":"101349934","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1460311,"rule_based_match":true,"evidence_text":"c.1931T>C","llm_judgment":"PRESENT","evidence":"c.1931T>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"29499638","title":"Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus.","abstract":"BACKGROUND: Congenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments. However, the adverse effects of CH can be reduced if the condition is detected and treated early. Earlier reports demonstrated that some CH cases are caused by mutations in L1CAM gene encoding the neural cell adhesion molecule L1. On the other hand, recent studies have implicated the multiple PDZ domain (MPDZ) gene in some severe forms of CH, inherited in an autosomal recessive pattern.\nMETHODS: In this study, whole-exome and Sanger sequencing were performed on a 9 months old Emirati child clinically diagnosed by CH. In addition, in silico, cellular, and molecular assays have been conducted to confirm pathogenicity of the identified variants and to establish disease mechanism.\nRESULTS: Whole exome sequencing revealed two compound heterozygous novel variants (c.394G > A and c.1744C > G) in the affected child within the MPDZ gene. Segregation analysis revealed that each of the parents is heterozygous for one of the two variants and therefore passed that variant to their child. The outcome of the in silico and bioinformatics analyses came in line with the experimental data, suggesting that the two variants are most likely disease causing.\nCONCLUSIONS: The compound heterozygous variants identified in this study are the most likely cause of CH in the affected child. The study further confirms MPDZ as a gene underlying some CH cases.","variants":[{"Name":"NM_001378778.1(MPDZ):c.394G>A (p.Gly132Ser)","Chromosome":"9","Start":"13223710","Stop":"13223710","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":980246,"rule_based_match":true,"evidence_text":"c.394G > A","llm_judgment":"PRESENT","evidence":"c.394G > A","abstract_start":955,"abstract_end":965}]}
{"pmid":"20130569","title":"ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin.","abstract":"The ATP-binding cassette G2 (ABCG2) c.421C>A (rs2231142) polymorphism influences the pharmacokinetics of rosuvastatin. We examined whether this polymorphism influences the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of the drug. In 305 Chinese patients with hypercholesterolemia who were treated with rosuvastatin at a dosage of 10 mg daily, the c.421A variant was found to be significantly associated with greater reduction in LDL-C level, in a gene-dose-dependent manner. As compared with subjects with the c.421CC genotype, those with the c.421AA genotype showed a 6.9% greater reduction in LDL-C level, which would be equivalent to the effect obtained by doubling the dose of rosuvastatin.","variants":[{"Name":"NM_004827.3(ABCG2):c.421C>A (p.Gln141Lys)","Chromosome":"4","Start":"88131171","Stop":"88131171","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39346,"rule_based_match":true,"evidence_text":"ABCG2 c.421C>A (rs2231142)","llm_judgment":"PRESENT","evidence":"c.421C>A","abstract_start":36,"abstract_end":44}]}
{"pmid":"34545288","title":"Functional Analysis of Ectodysplasin-A Mutations in X-Linked Nonsyndromic Hypodontia and Possible Involvement of X-Chromosome Inactivation.","abstract":"BACKGROUND: Mutations of the Ectodysplasin-A (EDA) gene are generally associated with syndrome hypohidrotic ectodermal dysplasia or nonsyndromic tooth agenesis. The influence of EDA mutations on dentinogenesis and odontoblast differentiation has not been reported. The aim of this study was to identify genetic clues for the causes of familial nonsyndromic oligodontia and explore the underlying mechanisms involved, while focusing on the role of human dental pulp stem cells (hDPSCs).\nMATERIALS AND METHODS: Candidate gene sequences were obtained by PCR amplification and Sanger sequencing. Functional analysis was conducted, and the pathogenesis associated with <i>EDA</i> mutations in hDPSCs was investigated to explore the impact of the identified mutation on the phenotype. Capillary electrophoresis (CE) was used to detect X-chromosome inactivation (XCI) in the blood of female carriers.\nRESULTS: In this study, we identified an <i>EDA</i> mutation in a Chinese family: the missense mutation c.1013C>T (Thr338Met). Transfection of hDPSCs with a mutant <i>EDA</i> lentivirus decreased the expression of EDA and dentin sialophosphoprotein (DSPP) compared with transfection of control EDA lentivirus. Mechanistically, mutant EDA inhibited the activation of the NF-<i>κ</i>B pathway. The CE results showed that symptomatic female carriers had a skewed XCI with a preferential inactivation of the X chromosome that carried the normal allele.\nCONCLUSIONS: In summary, we demonstrated that <i>EDA</i> mutations result in nonsyndromic tooth agenesis in heterozygous females and that, mechanistically, EDA regulates odontogenesis through the NF-<i>κ</i>B signalling pathway in hDPSCs. Due to the large heterogeneity of tooth agenesis, this study provided a genetic basis for individuals who exhibit similar clinical phenotypes.","variants":[{"Name":"NM_001399.5(EDA):c.1013C>T (p.Thr338Met)","Chromosome":"X","Start":"70035446","Stop":"70035446","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26087,"rule_based_match":true,"evidence_text":"c.1013C>T (Thr338Met)","llm_judgment":"PRESENT","evidence":"c.1013C>T (Thr338Met)","abstract_start":998,"abstract_end":1019}]}
{"pmid":"22653152","title":"Identification of two novel mutations in SLC29A3 encoding an equilibrative nucleoside transporter (hENT3) in two distinct Syrian families with H syndrome: expression studies of SLC29A3 (hENT3) in human skin.","abstract":"BACKGROUND: H syndrome is a rare autosomal recessive genetic disorder which involves the skin and other systemic organs and is caused by mutations in the SLC29A3 gene.\nOBJECTIVES: To disclose the molecular basis of H syndrome in two Syrian families, and to determine the localization of hENT3 in human skin.\nMETHODS: DNA from two Syrian families with H syndrome was analyzed through direct sequencing, and the expression of hENT3 in normal human skin was investigated by in situ hybridization and immunostaining.\nRESULTS: We identified two novel mutations in the SLC29A3 gene: a homozygous splice site mutation IVS1+2T>G predicted to cause a splicing error, and a homozygous missense mutation c.1157G>A (p.R386Q) which substituted highly conserved amino acid residue in a transmembrane domain of hENT3. Furthermore, we demonstrate that hENT3 is expressed in histiocytes as well as in endothelium of blood and lymphatic vessels in normal human skin.\nCONCLUSIONS: Our results further enhance the mutation spectrum of the SLC29A3 gene for this rare genetic disorder, and also suggest potential pathomechanisms for the skin lesions resulting from SLC29A3 mutations.","variants":[{"Name":"NM_018344.6(SLC29A3):c.1157G>A (p.Arg386Gln)","Chromosome":"10","Start":"71362337","Stop":"71362337","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48469,"rule_based_match":true,"evidence_text":"c.1157G>A (p.R386Q)","llm_judgment":"PRESENT","evidence":"c.1157G>A (p.R386Q)","abstract_start":693,"abstract_end":712}]}
{"pmid":"25442981","title":"The novel ADAMTS13-p.D187H mutation impairs ADAMTS13 activity and secretion and contributes to thrombotic thrombocytopenic purpura in mice.","abstract":"BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) is characterized by mutations in the ADAMTS13 gene, which either impair protein secretion or influence ADAMTS13 (A Disintegrin-like And Metalloprotease domain with ThromboSpondin type-1 motif, member 13) activity. Phenotypic consequences of these mutations have not yet been evaluated in animal models for TTP.\nOBJECTIVES: To identify the in vitro effect of a novel ADAMTS13 mutation and to investigate whether this mutation induces TTP in vivo.\nMETHODS: All 29 ADAMTS13 exons with exon-intron boundaries of a patient with pregnancy-onset TTP were sequenced. Wild-type and mutant ADAMTS13 proteins were both transiently and stably expressed in human embryonic kidney cells, and their activity was evaluated in vitro using fluorescence resonance energy transfer and flow assays. Molecular dynamics simulations were performed to study Ca(2+) stability. Adamts13(-/-) mice were hydrodynamically injected with wild-type and mutant expression plasmids and triggered with recombinant human von Willebrand factor.\nRESULTS: We identified a novel heterozygous c.559G>C mutation in exon 6 of the proposita's ADAMTS13 gene. This mutation resulted in a p.Asp187His substitution (p.D187H), which was located in the high affinity Ca(2+) -binding site in the metalloprotease domain of ADAMTS13. The homozygous p.D187H mutation down-regulated ADAMTS13 activity in vitro. Impaired proteolytic activity was linked to unstable Ca(2+) binding as visualized using a molecular dynamics simulation. In addition, the p.D187H mutation affects protein secretion in vitro. In Adamts13(-/-) mice, the homozygous p.D187H mutation reduced ADAMTS13 secretion and activity and contributed to TTP when these mice were triggered with recombinant human von Willebrand factor.\nCONCLUSIONS: Our data indicate that the p.D187H mutation impairs ADAMTS13 activity and secretion and is responsible for TTP onset in mice.","variants":[{"Name":"NM_139027.6(ADAMTS13):c.559G>C (p.Asp187His)","Chromosome":"9","Start":"133426218","Stop":"133426218","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":620324,"rule_based_match":true,"evidence_text":"c.559G>C","llm_judgment":"PRESENT","evidence":"c.559G>C","abstract_start":1116,"abstract_end":1124}]}
{"pmid":"31185933","title":"A novel frameshift mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome using targeted exome sequencing.","abstract":"BACKGROUND: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS.\nMETHODS: An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls.\nRESULTS: All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls.\nCONCLUSIONS: PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.","variants":[{"Name":"NM_000325.6(PITX2):c.515del (p.Gln172fs)","Chromosome":"4","Start":"110618585","Stop":"110618585","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":1685563,"rule_based_match":true,"evidence_text":"c.515delA","llm_judgment":"PRESENT","evidence":"c.515delA","abstract_start":1189,"abstract_end":1198}]}
{"pmid":"25342395","title":"Homozygosity for HBA1: c.179G > A: Hb Adana in an infant.","abstract":"Hb Adana (HBA1: c.179G > A) is a very rare, unstable form of α-globin variant that results from deficient synthesis of functional α chains. We present a 2-month-old boy with hypochromic microcytic anemia, and remarkable anisocytosis, target cells and basophilic stippling on his peripheral blood smear. α-Globin gene analysis of the patient determined homozygosity for HBA1: c.179G > A, a mutation known as Hb Adana. On his follow-up visit, hemoglobin (Hb) levels were stable at 9.0-9.5 g/dL and mean corpuscular volume (MCV) was 62.2-62.5 fL without the need for a blood transfusion. Clinical and hematological findings of our case were comparable to Hb H (β4) or β-thalassemia intermedia (β-TI)-like phenotypes, despite the fact that he carried an α1 gene mutation. Heterozygosity for the HBA1: c.179G > A mutation may also lead to microcytosis only as seen in his parents. According to our current knowledge, this is the first described case with homozygosity for the Hb Adana mutation, carried on the α1 gene. The relatively mild presentation of the case highlights the milder phenotypic consequences of nondeletional α mutations in the α1 vs. the α2 gene.","variants":[{"Name":"NM_000558.3(HBA1):c.179G>A (p.Gly60Asp)","Chromosome":"16","Start":"177012","Stop":"177012","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":30888,"rule_based_match":true,"evidence_text":"HBA1: c.179G > A","llm_judgment":"PRESENT","evidence":"HBA1: c.179G > A","abstract_start":10,"abstract_end":26}]}
{"pmid":"30179711","title":"Corneal arcus as the presenting sign of familial hypercholesterolemia in a young child.","abstract":"A 2.6-year-old boy presented with prominent corneal arcus. This clinical sign is rarely seen at such a young age and led to the diagnosis of familial hypercholesterolemia (FH). Genetic analysis detected biallelic pathogenic sequence variants c.1069G>A and c.2034C>A in the LDLR gene. There is significant cardiovascular morbidity and mortality associated with FH, hence early diagnosis and treatment is imperative.","variants":[{"Name":"NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys)","Chromosome":"19","Start":"11111522","Stop":"11111522","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":245971,"rule_based_match":true,"evidence_text":"c.1069G>A","llm_judgment":"PRESENT","evidence":"c.1069G>A","abstract_start":242,"abstract_end":251}]}
{"pmid":"33071830","title":"Identification of Novel SCN5A Single Nucleotide Variants in Brugada Syndrome: A Territory-Wide Study From Hong Kong.","abstract":"BACKGROUND: The aim of this study is to report on the genetic composition of Brugada syndrome (BrS) patients undergoing genetic testing in Hong Kong.\nMETHODS: Patients with suspected BrS who presented to the Hospital Authority of Hong Kong between 1997 and 2019, and underwent genetic testing, were analyzed retrospectively.\nRESULTS: A total of 65 subjects were included (<i>n</i> = 65, 88% male, median presenting age 42 [30-54] years old, 58% type 1 pattern). Twenty-two subjects (34%) showed abnormal genetic test results, identifying the following six novel, pathogenic or likely pathogenic mutations in SCN5A: c.674G > A, c.2024-11T > A, c.2042A > C, c.4279G > T, c.5689C > T, c.429del. Twenty subjects (31%) in the cohort suffered from spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) and 18 (28%) had incident VT/VF over a median follow-up of 83 [Q1-Q3: 52-112] months. Univariate Cox regression demonstrated that syncope (hazard ratio [HR]: 4.27 [0.95-19.30]; <i>P</i> = 0.059), prior VT/VF (HR: 21.34 [5.74-79.31; <i>P</i> < 0.0001) and T-wave axis (HR: 0.970 [0.944-0.998]; <i>P</i> = 0.036) achieved <i>P</i> < 0.10 for predicting incident VT/VF. After multivariate adjustment, only prior VT/VF remained a significant predictor (HR: 12.39 [2.97-51.67], <i>P</i> = 0.001).\nCONCLUSION: This study identified novel mutations in SCN5A in a Chinese cohort of BrS patients.","variants":[{"Name":"NM_000335.5(SCN5A):c.2042A>C (p.His681Pro)","Chromosome":"3","Start":"38597949","Stop":"38597949","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":78602,"rule_based_match":true,"evidence_text":"c.2042A > C","llm_judgment":"PRESENT","evidence":"c.2042A > C","abstract_start":643,"abstract_end":654},{"Name":"NM_000335.5(SCN5A):c.674G>A (p.Arg225Gln)","Chromosome":"3","Start":"38613772","Stop":"38613772","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":78925,"rule_based_match":true,"evidence_text":"c.674G > A","llm_judgment":"PRESENT","evidence":"c.674G > A","abstract_start":615,"abstract_end":625}]}
{"pmid":"32715858","title":"A novel","abstract":"BACKGROUND: Sorsby Fundus Dystrophy is an inherited macular degeneration caused by pathogenic variants in the <i>TIMP3</i> gene. Clinical exam findings typically drusen -like deposits beneath the RPE or reticular pseudo drusen deposits above the RPE with a majority of patients developing choroidal neovascularization.\nMATERIALS AND METHODS: Case report of two members of a family that present with atypical clinical exam findings. Protein modeling of the novel Y137CTIMP3 variant was performed and compared with other known variants.\nRESULTS: In this study we describe a father and son initially diagnosed with retinitis pigmentosa of unknown genetic origin. More recent genetic testing of the patients, identified a novel c.410A>G; p.Tyr137Cys variant of uncertain clinical significance in the Tissue Inhibitor of Metalloproteinase-3 (<i>TIMP3</i>) gene. The atypical clinical findings led us to compare the theoretical molecular effects of this variant on the TIMP3 protein structure and interactions with other proteins using homology modeling and machine learning predictions.\nCONCLUSIONS: It is important to consider mutations in TIMP3 in atypical cases of Retinitis Pigmentosa particularly in the absence of known variants.","variants":[{"Name":"NM_000362.5(TIMP3):c.410A>G (p.Tyr137Cys)","Chromosome":"22","Start":"32858110","Stop":"32858110","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1290619,"rule_based_match":true,"evidence_text":"c.410A>G; p.Tyr137Cys","llm_judgment":"PRESENT","evidence":"c.410A>G; p.Tyr137Cys","abstract_start":724,"abstract_end":745}]}
{"pmid":"32939518","title":"Two Novel Pathogenic","abstract":"Marfan syndrome is an autosomal dominant disease affecting connective tissue involving the ocular, skeletal systems with a prevalence of 1/5,000 to 1/10,000 cases. Especially cardiovascular system disorders (aortic root dilatation and enlargement of the pulmonary artery) may be life-threatening. We report here the genetic analysis results of three unrelated cases clinically diagnosed as Marfan syndrome. Deoxyribonucleic acid (DNA) was isolated from EDTA (ethylenediaminetetraacetic acid)-blood samples of the patients. A next-generation sequencing panel containing 15 genes including <i>FBN1</i> was used to determine the underlying pathogenic variants of Marfan syndrome. Three different variations, NM_000138.4( <i>FBN1</i> ):c.229G > A(p.Gly77Arg), NM_000138.4( <i>FBN1</i> ):c.165-2A > G (novel), NM_000138.4( <i>FBN1</i> ):c.399delC (p.Cys134ValfsTer8) (novel) were determined in our three cases referred with a prediagnosis of Marfan syndrome. Our study has confirmed the utility of molecular testing in Marfan syndrome to support clinical diagnosis. With an accurate diagnosis and genetic counseling for prognosis of patients and family testing, the prenatal diagnosis will be possible.","variants":[{"Name":"NM_000138.5(FBN1):c.229G>A (p.Gly77Arg)","Chromosome":"15","Start":"48613028","Stop":"48613028","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":197824,"rule_based_match":true,"evidence_text":"NM_000138.4( <i>FBN1</i> ):c.229G > A(p.Gly77Arg)","llm_judgment":"PRESENT","evidence":"NM_000138.4( <i>FBN1</i> ):c.229G > A(p.Gly77Arg)","abstract_start":705,"abstract_end":754}]}
{"pmid":"25574475","title":"Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype.","abstract":"OBJECTIVE: Nonsense mutations account for 5-70% of all genetic disorders. In the United States, nonsense mutations in the CLN1/PPT1 gene underlie >40% of the patients with infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative lysosomal storage disease. We sought to generate a reliable mouse model of INCL carrying the most common Ppt1 nonsense mutation (c.451C>T) found in the United States patient population to provide a platform for evaluating nonsense suppressors in vivo.\nMETHODS: We knocked-in c.451C>T nonsense mutation in the Ppt1 gene in C57 embryonic stem (ES) cells using a targeting vector in which LoxP flanked the Neo cassette, which was removed from targeted ES cells by electroporating Cre. Two independently targeted ES clones were injected into blastocysts to generate syngenic C57 knock-in mice, obviating the necessity for extensive backcrossing.\nRESULTS: Generation of Ppt1-KI mice was confirmed by DNA sequencing, which showed the presence of c.451C>T mutation in the Ppt1 gene. These mice are viable and fertile, although they developed spasticity (a \"clasping\" phenotype) at a median age of 6 months. Autofluorescent storage materials accumulated throughout the brain regions and in visceral organs. Electron microscopic analysis of the brain and the spleen showed granular osmiophilic deposits. Increased neuronal apoptosis was particularly evident in cerebral cortex and abnormal histopathological and electroretinographic (ERG) analyses attested striking retinal degeneration. Progressive deterioration of motor coordination and behavioral parameters continued until eventual death.\nINTERPRETATION: Our findings show that Ppt1-KI mice reliably recapitulate INCL phenotype providing a platform for testing the efficacy of existing and novel nonsense suppressors in vivo.","variants":[{"Name":"NM_000310.4(PPT1):c.451C>T (p.Arg151Ter)","Chromosome":"1","Start":"40089495","Stop":"40089495","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23943,"rule_based_match":true,"evidence_text":"c.451C>T","llm_judgment":"PRESENT","evidence":"c.451C>T","abstract_start":382,"abstract_end":390}]}
{"pmid":"25612910","title":"Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1.","abstract":"BACKGROUND: Tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1) and there is wide clinical variability of the tibial dysplasia in NF1, suggesting the possibility of genetic modifiers. Double inactivation of NF1 is postulated to be necessary for the development of tibial pseudarthrosis, but tissue or cell of origin of the 'second hit' mutation remains unclear.\nMETHODS: Exome sequencing of different sections of surgically resected NF1 tibial pseudarthrosis tissue was performed and compared to germline (peripheral blood).\nRESULTS: A germline NF1 splice site mutation (c.61-2A>T, p.L21 M68del) was identified from DNA extracted from peripheral blood. Exome sequencing of DNA extracted from tissue removed during surgery of the tibial pseudarthrosis showed a somatic mutation of NF1 (c.3574G>T, p.E1192*) in the normal germline allele. Further analysis of different regions of the tibial pseudarthrosis sample showed enrichment of the somatic mutation in the soft tissue within the pseudarthrosis site and absence of the somatic mutation in cortical bone. In addition, a germline variant in PTPN11 (c.1658C>T, p.T553M), a gene involved in the RAS signal transduction pathway was identified, although the clinical significance is unknown.\nCONCLUSIONS: Given that the NF1 somatic mutation was primarily detected in the proliferative soft tissue at the pseudarthrosis site, it is likely that the second hit occurred in mesenchymal progenitors from the periosteum. These results are consistent with a defect of differentiation, which may explain why the mutation is found in proliferative cells and not within cortical bone tissue, as the latter by definition contains mostly mature differentiated osteoblasts and osteocytes.","variants":[{"Name":"NM_002834.5(PTPN11):c.1658C>T (p.Thr553Met)","Chromosome":"12","Start":"112502202","Stop":"112502202","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49040,"rule_based_match":true,"evidence_text":"c.1658C>T (p.T553M)","llm_judgment":"PRESENT","evidence":"c.1658C>T","abstract_start":1120,"abstract_end":1129},{"Name":"NM_001042492.3(NF1):c.61-2A>T","Chromosome":"17","Start":"31155981","Stop":"31155981","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":420760,"rule_based_match":true,"evidence_text":"c.61-2A>T","llm_judgment":"PRESENT","evidence":"c.61-2A>T","abstract_start":591,"abstract_end":600}]}
{"pmid":"32342993","title":"Novel CAPN3 variant associated with an autosomal dominant calpainopathy.","abstract":"AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies.\nMETHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance.\nRESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice.\nCONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.","variants":[{"Name":"NM_000070.3(CAPN3):c.1333G>A (p.Gly445Arg)","Chromosome":"15","Start":"42399631","Stop":"42399631","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":268752,"rule_based_match":true,"evidence_text":"c.1333G>A [p.(Gly445Arg)]","llm_judgment":"PRESENT","evidence":"c.1333G>A [p.(Gly445Arg)]","abstract_start":865,"abstract_end":890}]}
{"pmid":"18832460","title":"WGA allows the molecular characterization of a novel large CFTR rearrangement in a black South African cystic fibrosis patient.","abstract":"By performing extensive scanning of whole coding and flanking sequences of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene, we had previously identified the CF-causing mutations in black South African patients of different ethnic groups suspected with the disease. Of ten samples analyzed, there were six remaining that had either one (n = 2) or two (n = 4) unidentified CFTR alleles that have now been tested for large rearrangements using a semiquantitative fluorescent PCR assay. A novel deletion encompassing CFTR exon 2 was detected in one patient who was heterozygous for the mutation 3120+1G>A. The Caucasian deletion involving the same exon [c.54-5811_c.164+2186del8108ins182] was ruled out. The DNA had been stored for more than 12 years and only minute quantities remained. We thus used a whole-genome amplification method based on multiple displacement amplification to generate sufficient amounts of DNA to characterize the intronic breakpoints and identify the deletion at the genomic level. Mapping and sequencing the breakpoint junctions revealed a novel large deletion [c.54-1161_c.164+1603del2875]. We have designed a simple test to specifically detect the presence or absence of this large rearrangement. This study reports the first large CFTR rearrangement in a black South African CF patient, further defining the molecular spectrum of CF that will be useful for improving genetic testing and counseling in this region.","variants":[{"Name":"NM_000492.4(CFTR):c.54-1161_164+1603del","Chromosome":"7","Start":"117503087","Stop":"117505961","ReferenceAlleleVCF":"AAAATGTTTGCATTTGGCATAGCCCTTTCTCTTTTTGTTCTGAATGGCTTTGCTAGAATATCTTTTCTATAATGAATTTATCCTGCTTCTCAGATATTGCTAAAGCACTCCCTTTTGAATTTTGGTGCTTTAACATGCATTTTGATACATTACCAAATAAGGTCTGAATGACACAAATTTTAGAACTCTCCAGAGAAAAGAAAGATGCTGAGGGAAAAAGCATAGGTTTGGGACTCACTAAATCCCAGTTCAATTCCTTTCTTTAATAAATATATTCAATTTTACCTGAGAAAGCTCTCGTGCTCTCGAATTTTATTTAGAAATTTCTCTTTGTACATGATTGATTTCACAATCCTTCTTCTGCCTCCTCTTCTACTTTCTTCTTTCTAGATTTTCCTATCTTTATGAAGATTATTCTGCCTTATCCTCAACAGTTAGAAACAATATTTTTGAAAATCACTACGGTATCCTGCATAGTGATTTCCCATGCCAACTTTACTAATTTCCATTATAAATTATTATTTATTGATGCCTAGAGGGCAGATGAGTGTAGCTGCTATGGAGTGAGGAGACAAAACATAAGAAAGTTATGATCCTACCCTCAGGTAATGATTCAGACATGATAATTAAGTCAACAAATTGATAGAAACTAATCACTAACTCTCTGGCTATAGTCATTCTTTCAATGAATAGCTCATTACTGAGTATGCATGCTACAGTAACAAAATTATATAAGGCTGTTGATTAAATGTTGATTAAGTGCATGTCTTATTCAGAGTTTTTTTATATTTGAAATGGAAGAGGCTGGACTTCAGTAATTTGCTATAAACTGCTAGTATATGATTATTTGGGGGCAGTTATTTTTTAAAGAATAATTTAAATATGGAATGTTTAGCAGTTTGTTTTTTCCCTGGGAAAAACCATACTATTATTCCCTCCCAATCCCTTTGACAAAGTGACAGTCACATTAGTTCAGAGATATTGATGTTTTATACAGGTGTAGCCTGTAAGAGATGAAGCCTGGTATTTATAGAAATTGACTTATTTTATTCTCATATTTACATGTGCATAATTTTCCATATGCCAGAAAAGTTGAATAGTATCAGATTCCAAATCTGTATGGAGACCAAATCAAGTGAATATCTGTTCCTCCTCTCTTTATTTTAGCTGGACCAGACCAATTTTGAGGAAAGGATACAGACAGCGCCTGGAATTGTCAGACATATACCAAATCCCTTCTGTTGATTCTGCTGACAATCTATCTGAAAAATTGGAAAGGTATGTTCATGTACATTGTTTAGTTGAAGAGAGAAATTCATATTATTAATTATTTAGAGAAGAGAAAGCAAACATATTATAAGTTTAATTCTTATATTTAAAAATAGGAGCCAAGTATGGTGGCTAATGCCTGTAATCCCAACTATTTGGGAGGCCAAGATGAGAGGATTGCTTGAGACCAGGAGTTTGATACCAGCCTGGGCAACATAGCAAGATGTTATCTCTACACAAAATAAAAAAGTTAGCTGGGAATGGTAGTGCATGCTTGTATTCCCAGCTACTCAGGAGGCTGAAGCAGGAGGGTTACTTGAGCCCAGGAGTTTGAGGTTGCAGTGAGCTATGATTGTGCCACTGCACTCCAGCTTGGGTGACACAGCAAAACCCTCTCTCTCTAAAAAAAAAAAAAAAAAGGAACATCTCATTTTCACACTGAAATGTTGACTGAAATCATTAAACAATAAAATCATAAAAGAAAAATAATCAGTTTCCTAAGAAATGATTTTTTTTCCTGAAAAATACACATTTGGTTTCAGAGAATTTGTCTTATTAGAGACCATGAGATGGATTTTGTGAAAACTAAAGTAACACCATTATGAAGTAAATCGTGTATATTTGCTTTCAAAACCTTTATATTTGAATACAAATGTACTCCCTGGGAAGTCTTAAGGTAATGGCTACTGGTTATCAAACAAATGTAAAAATTGTATATTTTTGAGTACCTGTTACATGCCAGGTAGAATATCTCCTCTCAGCCACTCTGAGTGGAAAGCATCATTATCTCTATTTTACAGAAAAGCAAACTGAGGCTCAGAGAGATAATATACTTTGCCAGTTAATGAATGATGGAGCCATGATTCCAGCTGAGGTCTGTATTGCCTTGCTCTCTAGGAATGGTAGTCCCCCCCATAAAGAATCTCTCAGTTTCCTTTCCAATCAAAAGGTTAGGATCCTTTTGATTGCCAGTGACAGAAACCCAATTTACTAGCTTAAGTAAATAAAAGGAACGAATTTATTGGCTCATGAAGCCTGAACTATGTGAAGACCTAGGTGGAGAACTGGCCTTAGGAACTCAATGGGACCAAGGACTCAAATGCCACCTGGTGGCATTTGCCTTATGCTGGTTTTATTTTCTCAGACCGGACCAGCTTTCTACATAAAGTGGGTCCCTGGTTAGAACTCTTTGCTCCTATCTTTAAGGACCACGAAAGAAGGAGCCCTTTGTCCTTGGCTAAATGTGAAAAATCCCAGAGACTCTTGAGTCATAGTGCTTACCCCTTGGGCCACTCATAGTCTAGAATGAACTAGGCTGAGTCTCGTGCCAACAGCACAGGCCTGATGCCAGATAAAAGGGTGAGTGAAGGGGGATAAAAAATAAGACATAGCTACTAAATTATTGCACCAAAGTAAAAACATTGAGTTGACTTGCAATTTGTTTCTTTTAATTAAATTCATTTCCTTTTTTTGGCATTTTGAAGGCAAAGTAAGATATTAAACTTTATTTTTATTGATTTTATTCAAAGAATTAAGCTAGTGGGAGTAGCAGATTCACACTTCTAAGATCAAGGGCCAGCTTCTATTATTGAACACTTGGTGTGTGC","AlternateAlleleVCF":"A","allel_id":68661,"rule_based_match":false,"evidence_text":"c.54-1161_c.164+1603del2875","llm_judgment":"PRESENT","evidence":"c.54-1161_c.164+1603del2875","abstract_start":1111,"abstract_end":1138}]}
{"pmid":"17203532","title":"Novel MLH1 frameshift mutation in an extended hereditary nonpolyposis colorectal cancer family.","abstract":"AIM: To present novel frameshift mutation c.31delC [p.L11X] in the MLH1 gene identified in an extended Bulgarian hereditary non-polyposis colorectal cancer (HNPCC) family and to analyze the molecular and clinical findings within the pedigree concerning the proposal of adequate individual prophylactic strategy for all mutation carriers.\nMETHODS: The pedigree of the family consists of 42 members in four generations. Search for mutations in the MLH1 and hMSH2 genes was performed in the proband. After PCR amplification of all exons including flanking intronic regions, amplicons were directly sequenced.\nRESULTS: The mutation was found in nine from the thirteen pedigree members who signed informed consent to participate in the study. In three adenocarcinomas, microsatellite instability and lack of the MLH1 protein expression were detected. The only one tubulovillous adenoma analyzed was microsatellite stable and the MLH1 protein showed an intact staining.\nCONCLUSION: The newly described mutation c.31delC is HNPCC causative. Besides the typical clinical features of the syndrome, we found a specific pathologic manifestation such as moderate to high differentiated adenocarcinomas of the colon. One of the mutation carriers developed a benign giant cell soft tissue tumor. The primary tumor localizations were frequently extracolonic and detailed yearly gastrointestinal and gynecological examinations have been proposed to the mutation carriers. We emphasize the importance of including the HNPCC genetic counseling and testing as well in the following surveillance of all patients at risk in the services covered by the health insurance in Bulgaria.","variants":[{"Name":"NM_000249.4(MLH1):c.31del (p.Leu11fs)","Chromosome":"3","Start":"36993578","Stop":"36993578","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":95640,"rule_based_match":true,"evidence_text":"c.31delC","llm_judgment":"PRESENT","evidence":"c.31delC","abstract_start":42,"abstract_end":50}]}
{"pmid":"18379723","title":"Gap junction beta 1 (GJB1) gene mutations in Italian patients with X-linked Charcot-Marie-Tooth disease.","abstract":"X-linked Charcot-Marie-Tooth disease (CMT1X) is a peripheral neuropathy transmitted in a dominant manner and caused by mutations in the Connexin 32 (Cx32) gene (GJB1, gap junction beta 1). Here we report the mutation analysis of the GJB1 gene in 76 subjects with possible CMT1 and absence of 17p11.2 duplication, and in 38 CMT2 patients without mutations in CMT2-associated-genes, selected from a cohort of 684 patients with peripheral sensory-motor neuropathy. The analysis was performed by direct sequencing of the coding sequence and exon/intron boundaries of the GJB1 gene. The mutation screening identified 22 mutations in GJB1, eight of which have not been previously published: six point mutations (c.50C > G, c.107T > A, c.545C > T, c.545C > G, c.548G > C, c.791G > T) and two deletions (c.84delC, c.573_581delCGTCTTCAT). The GJB1 mutation frequency (19.3%) and the clinical heterogeneity of our patients suggest searching for GJB1 mutations in all CMT cases without the 17p11.2 duplication, regardless of the gender of the proband, as well as in CMT2 patients with possible X-linked inheritance.","variants":[{"Name":"NM_000166.6(GJB1):c.548G>C (p.Arg183Pro)","Chromosome":"X","Start":"71224255","Stop":"71224255","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":625664,"rule_based_match":true,"evidence_text":"c.548G > C","llm_judgment":"PRESENT","evidence":"c.548G > C","abstract_start":753,"abstract_end":763},{"Name":"NM_000166.6(GJB1):c.84del (p.Phe29fs)","Chromosome":"X","Start":"71223791","Stop":"71223791","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":625482,"rule_based_match":true,"evidence_text":"c.84delC","llm_judgment":"PRESENT","evidence":"c.84delC","abstract_start":796,"abstract_end":804},{"Name":"NM_000166.6(GJB1):c.50C>G (p.Ser17Cys)","Chromosome":"X","Start":"71223757","Stop":"71223757","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":438507,"rule_based_match":true,"evidence_text":"c.50C > G","llm_judgment":"PRESENT","evidence":"c.50C > G","abstract_start":706,"abstract_end":715},{"Name":"NM_000166.6(GJB1):c.791G>T (p.Arg264Leu)","Chromosome":"X","Start":"71224498","Stop":"71224498","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":625708,"rule_based_match":true,"evidence_text":"c.791G > T","llm_judgment":"PRESENT","evidence":"c.791G > T","abstract_start":765,"abstract_end":775},{"Name":"NM_000166.6(GJB1):c.545C>G (p.Ser182Cys)","Chromosome":"X","Start":"71224252","Stop":"71224252","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":625661,"rule_based_match":true,"evidence_text":"c.545C>G","llm_judgment":"PRESENT","evidence":"c.545C > G","abstract_start":741,"abstract_end":751},{"Name":"NM_000166.6(GJB1):c.545C>T (p.Ser182Phe)","Chromosome":"X","Start":"71224252","Stop":"71224252","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":625662,"rule_based_match":true,"evidence_text":"c.545C > T","llm_judgment":"PRESENT","evidence":"c.545C > T","abstract_start":729,"abstract_end":739}]}
{"pmid":"36403623","title":"","abstract":"The Moloney sarcoma oncogene (<i>MOS)</i> encodes a protein serine/threonine kinase and <i>MOS</i> is expressed at high levels in oocytes undergoing meiotic maturation. The MOS/MAPK pathway is normally required for the maintenance of microtubules and chromatin in a metaphasic state during the meiotic divisions. To determine the pathogenic genes in a female infertile patient due to large polar body oocytes, whole-exome sequencing was performed on the patient and available family members. We identified a novel homozygous missense mutation c.591T > G in <i>MOS</i>. Bioinformatics analysis showed that the mutation is harmful. These findings suggest that <i>MOS</i> mutation results in oocytes with a large polar body and poor embryonic development in patients. The <i>MOS</i> variant may regulate oocyte asymmetric division by MAPK/WAVE2/Arp2/3/actin signaling pathway. This will help to understand the comprehensive role of MOS in early human reproductive process and provide genetic markers for future genetic counseling for more individualized treatments.","variants":[{"Name":"NM_005372.1(MOS):c.591T>G (p.Ile197Met)","Chromosome":"8","Start":"56113392","Stop":"56113392","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2543817,"rule_based_match":true,"evidence_text":"c.591T > G","llm_judgment":"PRESENT","evidence":"c.591T > G","abstract_start":543,"abstract_end":553}]}
{"pmid":"28060055","title":"Genetic counselling and high-penetrance susceptibility gene analysis reveal the novel CDKN2A p.D84V (c.251A>T) mutation in melanoma-prone families from Italy.","abstract":"Genetic susceptibility to primary cutaneous melanoma (PCM) may account for up to 12% of PCMs, presenting as the familial atypical mole/multiple melanoma syndrome (FAMMM), an autosomal dominant condition with incomplete penetrance and variable expressivity, characterized by PCM in at least two relatives and/or more than one PCMs in the same patient. To identify individuals at high genetic risk of PCM, from 1 January 2012 to 31 December 2015, we offered genetic counselling and molecular analysis of the two high-penetrance FAMMM susceptibility genes, cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4), to 92 consecutive, unrelated patients with FAMMM. Age at diagnosis and number of PCMs were obtained from medical records; the number of PCMs and affected relatives were recorded for each family. The diagnostic work-up consisted of genetic counselling and cascade genetic testing in patients and further extension to relatives of those identified as mutation carriers. All exons and exon/intron boundaries of CDKN2A and CDK4 genes were screened by direct bidirectional sequencing. We identified CDKN2A mutations in 19 of the 92 unrelated patients (20.6%) and in 14 additional, clinically healthy relatives. Eleven of these latter subsequently underwent excision of dysplastic nevi, but none developed PCM during a median follow-up of 37.3 months. In three patients from unrelated families, the novel CDKN2A p.D84V (c.251A>T) mutation was observed, associated with PCM in each pedigree. Genetic screening of FAMMM patients and their relatives can contribute towards specific primary and secondary prevention programmes for individuals at high genetic risk of PCM. The novel CDKN2A p.D84V (c.251A>T) mutation adds to the known mutations associated with FAMMM.","variants":[{"Name":"NM_000077.5(CDKN2A):c.251A>T (p.Asp84Val)","Chromosome":"9","Start":"21971108","Stop":"21971108","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1877759,"rule_based_match":true,"evidence_text":"CDKN2A p.D84V (c.251A>T)","llm_judgment":"PRESENT","evidence":"CDKN2A p.D84V (c.251A>T)","abstract_start":1437,"abstract_end":1461}]}
{"pmid":"24259409","title":"Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.","abstract":"The signal pathway of the C-type natriuretic (CNP) and its receptor, natriuretic peptide receptor 2 (NPR2) is involved in the longitudinal growth of long bones. Loss of function mutations at NPR2 cause acromesomelic dysplasia, type Maroteaux, while overproduction of CNP by chromosomal translocation and a gain-of-function mutation at NPR2 have been reported to be responsible for an overgrowth syndrome in three cases and one family, respectively. We identified a four-generation family with an overgrowth syndrome characterized by tall stature, macrodactyly of the great toes, scoliosis, coxa valga and slipped capital femoral epiphysis, similar to those previously reported in association with CNP/NPR2 overactivity. The serum level of amino-terminal proCNP was normal in the proband. A novel missense mutation of NPR2, c.1462G>C (p.Ala488Pro) was found to co-segregate with the phenotype in this family. In vitro transfection assay of the mutant NPR2 revealed overactivity of the mutant receptor at baseline as well as with the ligand. This overgrowth syndrome caused by a gain-of-function mutation at NPR2 should be differentiated from Marfan or related syndromes, and may be categorized along with the overgrowth syndrome caused by overproduction of CNP due to its phenotypical similarity as overgrowth CNP/NPR2 signalopathy.","variants":[{"Name":"NM_003995.4(NPR2):c.1462G>C (p.Ala488Pro)","Chromosome":"9","Start":"35801668","Stop":"35801668","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":152774,"rule_based_match":true,"evidence_text":"c.1462G>C (p.Ala488Pro)","llm_judgment":"PRESENT","evidence":"c.1462G>C (p.Ala488Pro)","abstract_start":823,"abstract_end":846}]}
{"pmid":"26246498","title":"A new variant in signal peptide of the human luteinizing hormone receptor (LHCGR) affects receptor biogenesis causing leydig cell hypoplasia.","abstract":"The human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) plays a fundamental role in male and female reproduction. In males, loss-of-function mutations in LHCGR have been associated with distinct degrees of impairment in pre- and postnatal testosterone secretion resulting in a variable phenotypic spectrum, classified as Leydig cell hypoplasia (LCH) type 1 (complete LH resistance and disorder of sex differentiation) and type 2 (partial LH resistance with impaired masculinization and fertility). Here, we report the case of an adolescent who came to the pediatric endocrinologist at the age of 12 years old for micropenis and cryptorchidism. Testis biopsy showed profound LCH and absent germinal line elements (Sertoli-only syndrome). The sequence analysis of the LHCGR gene showed the presence of a compound heterozygosity, being one variation, c.1847C>A p.S616Y, already described in association to Hypergonadotropic Hypogonadism, and the other, c.29 C>T p.L10P, a new identified variant in the putative signal peptide (SP) of LHCGR. Functional and structural studies provide first evidence that LHCGR have a functional and cleavable SP required for receptor biogenesis. Moreover, we demonstrate the pathogenic role of the novel p.L10P allelic variant, which has to be considered a loss-of-function mutation significantly contributing, in compound heterozygosity with p.S616Y, to the LCH type 2 observed in our patient.","variants":[{"Name":"NM_000233.4(LHCGR):c.1847C>A (p.Ser616Tyr)","Chromosome":"2","Start":"48687950","Stop":"48687950","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":29432,"rule_based_match":true,"evidence_text":"c.1847C>A p.S616Y","llm_judgment":"PRESENT","evidence":"c.1847C>A p.S616Y","abstract_start":862,"abstract_end":879}]}
{"pmid":"25471517","title":"Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy.","abstract":"Aminoacylation is the process of attaching amino acids to their cognate tRNA, and thus is essential for the translation of mRNA into protein. This direct interaction of tRNA with amino acids is catalyzed by aminoacyl-tRNA synthetases. Using whole-exome sequencing, we identified compound heterozygous mutations [c.169T>C (p.Tyr57His) and c.1485dup (p.Lys496*)] in QARS, which encodes glutaminyl-tRNA synthetase, in two siblings with early-onset epileptic encephalopathy (EOEE). Recessive mutations in QARS, including the loss-of-function missense mutation p.Tyr57His, have been reported to cause intractable seizures with progressive microcephaly. The p.Lys496* mutation is novel and causes truncation of the QARS protein, leading to a deletion of part of the catalytic domain and the entire anticodon-binding domain. Transient expression of the p.Lys496* mutant in neuroblastoma 2A cells revealed diminished and aberrantly aggregated expression, indicating the loss-of-function nature of this mutant. Together with the previous report, our data suggest that abnormal aminoacylation is one of the underlying pathologies of EOEE.","variants":[{"Name":"NM_005051.3(QARS1):c.1485dup (p.Lys496Ter)","Chromosome":"3","Start":"49099550","Stop":"49099551","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":1059844,"rule_based_match":true,"evidence_text":"c.1485dup (p.Lys496*)","llm_judgment":"PRESENT","evidence":"c.1485dup (p.Lys496*)","abstract_start":338,"abstract_end":359}]}
{"pmid":"22026499","title":"A novel SGCE gene mutation causing myoclonus dystonia in a family with an unusual phenotype.","abstract":"BACKGROUND: Myoclonus dystonia is an autosomal dominant dystonia-plus syndrome, characterized by symptom variability within families. Most often is the myoclonus the most debilitating symptom, and many patients report myoclonus reduction after alcohol intake. In several families, mutations in the SGCE gene have been identified.\nMETHOD: We report of a three-generation family with myoclonus dystonia displaying a varied phenotype and maternal imprinting. Additionally, this family displays some unusual clinical presentations including alcohol-induced dystonia in an adult man, which will be discussed.\nRESULTS: A novel mutation c.386T>C [p.I129T] was found within exon 3 of the SGCE gene in all three affected family members. In addition, two additional mutations [c.305G>A and IVS3+15G>A], judged to be polymorphisms in the SGCE gene, were found in two affected and one healthy family member.\nCONCLUSIONS: This report presents a novel mutation in the SGCE gene causing myoclonus dystonia and extends the phenotype of myoclonus dystonia to also include alcohol-induced dystonia.","variants":[{"Name":"NM_003919.3(SGCE):c.386T>C (p.Ile129Thr)","Chromosome":"7","Start":"94628206","Stop":"94628206","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":924957,"rule_based_match":true,"evidence_text":"c.386T>C [p.I129T]","llm_judgment":"PRESENT","evidence":"c.386T>C [p.I129T]","abstract_start":630,"abstract_end":648},{"Name":"NM_003919.3(SGCE):c.305G>A (p.Arg102Gln)","Chromosome":"7","Start":"94628287","Stop":"94628287","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1045198,"rule_based_match":true,"evidence_text":"c.305G>A","llm_judgment":"PRESENT","evidence":"c.305G>A","abstract_start":767,"abstract_end":775}]}
{"pmid":"31455599","title":"Macrozoospermia associated with mutations of AURKC gene: First case report in Latin America and literature review.","abstract":"A Chilean 35-year-old male patient with a history of primary infertility made an appointment at the Unit of Reproductive Medicine at Clínica Las Condes, Santiago, Chile. Multiple semen analyses revealed abnormal sperm morphology as the most prevalent finding. Multiflagellated and macrocephalic spermatozoa were observed and indicated a possible macrozoospermic phenotype. The constant presence of abnormal sperm morphology led the scope of the study to include Aurora Kinase C (AURKC) gene sequencing. The patient was diagnosed with a homozygous mutation of this gene. The mutation was detected in exon 6, type c.744C>G+/+ (P.Y248*) variant. As previously described in the Human Gene Mutation Database (HGMD), this pathogenic variant is associated with macrozoospermia. Although this mutation is not the most frequently observed, it is the first of its kind reported in Latin America.","variants":[{"Name":"NM_001015878.2(AURKC):c.744C>G (p.Tyr248Ter)","Chromosome":"19","Start":"57235043","Stop":"57235043","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1018644,"rule_based_match":true,"evidence_text":"c.744C>G+/+ (P.Y248*)","llm_judgment":"PRESENT","evidence":"c.744C>G+/+ (P.Y248*)","abstract_start":612,"abstract_end":633}]}
{"pmid":"21673748","title":"Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes.","abstract":"A large fraction of sequence variants of unknown significance (VUS) of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 may induce splicing defects. We analyzed 53 VUSs of BRCA1 or BRCA2, detected in consecutive molecular screenings, by using five splicing prediction programs, and we classified them into two groups according to the strength of the predictions. In parallel, we tested them by using functional splicing assays. A total of 10 VUSs were predicted by two or more programs to induce a significant reduction of splice site strength or activation of cryptic splice sites or generation of new splice sites. Minigene-based splicing assays confirmed four of these predictions. Five additional VUSs, all at internal exon positions, were not predicted to induce alterations of splice sites, but revealed variable levels of exon skipping, most likely induced by the modification of exonic splicing regulatory elements. We provide new data in favor of the pathogenic nature of the variants BRCA1 c.212+3A>G and BRCA1 c.5194-12G>A, which induced aberrant out-of-frame mRNA forms. Moreover, the novel variant BRCA2 c.7977-7C>G induced in frame inclusion of 6 nt from the 3' end of intron 17. The novel variants BRCA2 c.520C>T and BRCA2 c.7992T>A induced incomplete skipping of exons 7 and 18, respectively. This work highlights the contribution of splicing minigene assays to the assessment of pathogenicity, not only when patient RNA is not available, but also as a tool to improve the accuracy of bioinformatics predictions.","variants":[{"Name":"NM_007294.4(BRCA1):c.212+3A>G","Chromosome":"17","Start":"43106453","Stop":"43106453","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":69134,"rule_based_match":true,"evidence_text":"BRCA1 c.212+3A>G","llm_judgment":"PRESENT","evidence":"BRCA1 c.212+3A>G","abstract_start":1012,"abstract_end":1028},{"Name":"NM_000059.4(BRCA2):c.520C>T (p.Arg174Cys)","Chromosome":"13","Start":"32326502","Stop":"32326502","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":66486,"rule_based_match":true,"evidence_text":"BRCA2 c.520C>T","llm_judgment":"PRESENT","evidence":"BRCA2 c.520C>T","abstract_start":1231,"abstract_end":1245},{"Name":"NM_007294.4(BRCA1):c.5194-12G>A","Chromosome":"17","Start":"43057147","Stop":"43057147","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70118,"rule_based_match":true,"evidence_text":"BRCA1 c.5194-12G>A","llm_judgment":"PRESENT","evidence":"BRCA1 c.5194-12G>A","abstract_start":1033,"abstract_end":1051}]}
{"pmid":"24934289","title":"A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.","abstract":"Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.","variants":[{"Name":"NM_213720.3(CHCHD10):c.176C>T (p.Ser59Leu)","Chromosome":"22","Start":"23767459","Stop":"23767459","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":150458,"rule_based_match":true,"evidence_text":"c.176C>T (p.Ser59Leu)","llm_judgment":"PRESENT","evidence":"p.Ser59Leu","abstract_start":1016,"abstract_end":1026}]}
{"pmid":"31730716","title":"Whole MYBPC3 NGS sequencing as a molecular strategy to improve the efficiency of molecular diagnosis of patients with hypertrophic cardiomyopathy.","abstract":"Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, historically believed to affect 1 of 500 people. MYBPC3 pathogenic variations are the most frequent cause of familial HCM and more than 90% of them introduce a premature termination codon. The current study aims to determine the prevalence of deep intronic MYBPC3 pathogenic variations that could lead to splice mutations. To improve molecular diagnosis, a next-generation sequencing (NGS) workflow based on whole MYBPC3 sequencing of a cohort of 93 HCM patients, for whom no putatively causative point mutations were identified after NGS sequencing of a panel of 48 cardiomyopathy-causing genes, was performed. Our approach led us to reconsider the molecular diagnosis of six patients of the cohort (6.5%). These HCM probands were carriers of either a new large MYBPC3 rearrangement or splice intronic variations (five cases). Four pathogenic intronic variations, including three novel ones, were detected. Among them, the prevalence of one of them (NM_000256.3:c.1927+ 600 C>T) was estimated at about 0.35% by the screening of 1,040 unrelated HCM individuals. This study suggests that deep MYBPC3 splice mutations account for a significant proportion of HCM cases (6.5% of this cohort). Consequently, NGS sequencing of MYBPC3 intronic sequences have to be performed systematically.","variants":[{"Name":"NM_000256.3(MYBPC3):c.1927+600C>T","Chromosome":"11","Start":"47340403","Stop":"47340403","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":679857,"rule_based_match":true,"evidence_text":"NM_000256.3:c.1927+600 C>T","llm_judgment":"PRESENT","evidence":"NM_000256.3:c.1927+ 600 C>T","abstract_start":1030,"abstract_end":1057}]}
{"pmid":"28253502","title":"Short Stature in a Boy with Multiple Early-Onset Autoimmune Conditions due to a STAT3 Activating Mutation: Could Intracellular Growth Hormone Signalling Be Compromised?
.","abstract":"BACKGROUND: Germline STAT3 gain-of-function (GOF) mutations cause multiple endocrine and haematologic autoimmune disorders, lymphoproliferation, and growth impairment. As the JAK-STAT pathway is known to transduce the growth hormone (GH) signalling, and STAT3 interacts with STAT5 in growth regulation, we hypothesised that short stature in STAT3 GOF mutations results mostly from GH insensitivity via involving activation of STAT5.\nCASE REPORT: A boy with a novel STAT3 c.2144C>T (p.Pro715Leu) mutation presented with short stature (-2.60 SD at 5.5 years). He developed diabetes mellitus at 11 months, generalised lympho-proliferation, autoimmune thyroid disease, and immune bicytopenia in the subsequent years. At 5.5 years, his insulin-like growth factor-1 (IGF-I) was 37 µg/L (-2.22 SD) but stimulated GH was 27.7 µg/L. Both a standard IGF-I generation test (GH 0.033 mg/kg/day sc; 4 days) and a high-dose prolonged IGF-I generation test (GH 0.067 mg/kg/day sc; 14 days) failed to significantly increase IGF-I levels (37-46 and 72-87 µg/L, respectively). The boy underwent haematopoietic stem cell transplantation at 6 years due to severe neutropenia and massive lymphoproliferation, but unfortunately deceased 42 days after transplantation from reactivated generalised adenoviral infection.\nCONCLUSIONS: Our findings confirm the effect of STAT3 GOF mutation on the downstream activation of STAT5 resulting in partial GH insensitivity. 
.","variants":[{"Name":"NM_139276.3(STAT3):c.2144C>T (p.Pro715Leu)","Chromosome":"17","Start":"42317182","Stop":"42317182","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":409927,"rule_based_match":true,"evidence_text":"STAT3 c.2144C>T (p.Pro715Leu)","llm_judgment":"PRESENT","evidence":"STAT3 c.2144C>T (p.Pro715Leu)","abstract_start":465,"abstract_end":494}]}
{"pmid":"30450322","title":"X-linked juvenile retinoschisis: phenotypic and genetic characterization.","abstract":"Juvenile X-linked retinoschisis (XLRS, MIM#312700) belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography (SD-OCT) images. The mean central foveal thickness was 569.7 µm. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio (<1.0) in all patients. <i>RS1</i> (NM_000330.3) gene coding exons Sanger sequencing was performed. <i>RS1</i> c.599G>T (p.R200L) mutation was detected in one case, showing to be pathogenic in silico analysis. c. (92_97) insC (p.W33fs) mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422C>G (p.R141H), HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits.","variants":[{"Name":"NM_000330.4(RS1):c.599G>T (p.Arg200Leu)","Chromosome":"X","Start":"18642080","Stop":"18642080","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3835984,"rule_based_match":true,"evidence_text":"RS1 c.599G>T (p.R200L)","llm_judgment":"PRESENT","evidence":"RS1</i> c.599G>T (p.R200L)","abstract_start":662,"abstract_end":688}]}
{"pmid":"26282398","title":"EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss.","abstract":"BACKGROUND: More than 70 % of the cases of congenital deafness are of genetic origin, of which approximately 80 % are non-syndromic and show autosomal recessive transmission (DFNB forms). To date, 60 DFNB genes have been identified, most of which cause congenital, severe to profound deafness, whereas a few cause delayed progressive deafness in childhood. We report the study of two Algerian siblings born to consanguineous parents, and affected by progressive hearing loss.\nMETHOD: After exclusion of GJB2 (the gene most frequently involved in non-syndromic deafness in Mediterranean countries), we performed whole-exome sequencing in one sibling.\nRESULTS: A frame-shift variant (c.1014delC; p.Ser339Alafs*15) was identified in EPS8L2, encoding Epidermal growth factor receptor Pathway Substrate 8 L2, a protein of hair cells' stereocilia previously implicated in progressive deafness in the mouse. This variant predicts a truncated, inactive protein, or no protein at all owing to nonsense-mediated mRNA decay. It was detected at the homozygous state in the two clinically affected siblings, and at the heterozygous state in the unaffected parents and one unaffected sibling, whereas it was never found in a control population of 150 Algerians with normal hearing or in the Exome Variant Server database.\nCONCLUSION: Whole-exome sequencing allowed us to identify a new gene responsible for childhood progressive hearing loss transmitted on the autosomal recessive mode.","variants":[{"Name":"NM_022772.4(EPS8L2):c.1014del (p.Ser339fs)","Chromosome":"11","Start":"722117","Stop":"722117","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":427103,"rule_based_match":true,"evidence_text":"c.1014delC; p.Ser339Alafs*15","llm_judgment":"PRESENT","evidence":"c.1014delC; p.Ser339Alafs*15","abstract_start":682,"abstract_end":710}]}
{"pmid":"30017359","title":"A new case expanding the mutation and phenotype spectrum of TMEM5-related alpha-dystroglycanopathy.","abstract":"Dystroglycanopathies are a diverse group of neuromuscular disorders caused by aberrant glycosylation of alpha-dystroglycan. TMEM5 is one of many glycosyltransferases recently described to be associated with alpha-dystroglycanopathies. We report the case of a 15-year-old boy suffering from a congenital muscular dystrophy with elevated serum creatine kinase levels and an almost complete absence of alpha-dystroglycan in muscle biopsy. The clinical course was milder than any previously reported case and did not include brain or eye defects. Standard next-generation sequencing analysis revealed a homozygous mutation in the donor splice site region of exon 5 in TMEM5 (c.914+6 T>G). Available in-silico prediction tools anticipated a reduced efficiency of the splice site. Subsequent cDNA sequencing confirmed the expression of a truncated transcript of TMEM5 lacking exon 5, hence leading to an in-frame deletion in the exostosin domain of the protein. This report expands the clinical and mutation spectrum of alpha-dystroglycanopathies.","variants":[{"Name":"NM_014254.3(RXYLT1):c.914+6T>G","Chromosome":"12","Start":"63805410","Stop":"63805410","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":421948,"rule_based_match":true,"evidence_text":"c.914+6 T>G","llm_judgment":"PRESENT","evidence":"c.914+6 T>G","abstract_start":671,"abstract_end":682}]}
{"pmid":"31794942","title":"Generation of an integration-free induced pluripotent stem cell line (PUMCHi001-A) from a patient with familial partial lipodystrophy type 2 (FPLD2) carrying a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene.","abstract":"Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant metabolic disorder caused by heterozygous mutations in the LMNA gene, which encodes for the lamin A/C. A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) of a 30 year-old male patient with FPLD2 who had a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene using non-integrating episomal vector technique. This iPSC line offers a useful resource to investigate pathogenic mechanisms in FPLD2, as well as a cell-based model for drug development to treat FPLD2.","variants":[{"Name":"NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)","Chromosome":"1","Start":"156136009","Stop":"156136009","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77659,"rule_based_match":true,"evidence_text":"c.1045C>T (p.Arg349Trp)","llm_judgment":"PRESENT","evidence":"c.1045C > T","abstract_start":363,"abstract_end":374}]}
{"pmid":"29783990","title":"Severe hepatopathy and neurological deterioration after start of valproate treatment in a 6-year-old child with mitochondrial tryptophanyl-tRNA synthetase deficiency.","abstract":"BACKGROUND: The first subjects with deficiency of mitochondrial tryptophanyl-tRNA synthetase (WARS2) were reported in 2017. Their clinical characteristics can be subdivided into three phenotypes (neonatal phenotype, severe infantile onset phenotype, Parkinson-like phenotype).\nRESULTS: Here, we report on a subject who presented with early developmental delay, motor weakness and intellectual disability and who was considered during several years as having a non-progressive encephalopathy. At the age of six years, she had an epileptic seizure which was treated with sodium valproate. In the months after treatment was started, she developed acute liver failure and severe progressive encephalopathy. Although valproate was discontinued, she died six months later. Spectrophotometric analysis of the oxidative phosphorylation complexes in liver revealed a deficient activity of complex III and low normal activities of the complexes I and IV. Activity staining in the BN-PAGE gel confirmed the low activities of complex I, III and IV and, in addition, showed the presence of a subcomplex of complex V. Histochemically, a mosaic pattern was seen in hepatocytes after cytochrome c oxidase staining. Using Whole Exome Sequencing two known pathogenic variants were detected in WARS2 (c.797delC, p.Pro266ArgfsTer10/ c.938 A > T, p.Lys313Met).\nCONCLUSION: This is the first report of severe hepatopathy in a subject with WARS2 deficiency. The hepatopathy occurred soon after start of sodium valproate treatment. In the literature, valproate-induced hepatotoxicity was reported in the subjects with pathogenic mutations in POLG and TWNK. This case report illustrates that the course of the disease in the subjects with a mitochondrial defect can be non-progressive during several years. The subject reported here was first diagnosed as having cerebral palsy. Only after a mitochondriotoxic medication was started, the disease became progressive, and the diagnosis of a mitochondrial defect was made.","variants":[{"Name":"NM_015836.4(WARS2):c.938A>T (p.Lys313Met)","Chromosome":"1","Start":"119033056","Stop":"119033056","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":434545,"rule_based_match":true,"evidence_text":"c.938 A > T, p.Lys313Met","llm_judgment":"PRESENT","evidence":"c.938 A > T, p.Lys313Met","abstract_start":1313,"abstract_end":1337}]}
{"pmid":"34132027","title":"Expanding the genetic landscape of oral-facial-digital syndrome with two novel genes.","abstract":"Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy-spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.","variants":[{"Name":"NM_005802.5(TOPORS):c.29C>A (p.Pro10Gln)","Chromosome":"9","Start":"32550943","Stop":"32550943","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":969161,"rule_based_match":true,"evidence_text":"c.29 C>A; (p.Pro10Gln)","llm_judgment":"PRESENT","evidence":"c.29 C>A; (p.Pro10Gln)","abstract_start":1269,"abstract_end":1291}]}
{"pmid":"17662246","title":"Null mutations and lethal congenital form of glycogen storage disease type IV.","abstract":"Glycogen branching enzyme deficiency (glycogen storage disease type IV, GSD-IV) is a rare autosomal recessive disorder of the glycogen synthesis with high mortality. Two female newborns showed severe hypotonia at birth and both died of cardiorespiratory failure, at 4 and 12 weeks, respectively. In both patients, muscle biopsies showed deposits of PAS-positive diastase-resistant material and biochemical analysis in cultured fibroblasts showed markedly reduced glycogen branching enzyme activity. Direct sequencing of GBE1 gene revealed that patient 1 was homozygous for a novel c.691+5 g>c in intron 5 (IVS5+5 g>c). RT-PCR analysis of GBE1 transcripts from fibroblasts cDNA showed that this mutation produce aberrant splicing. Patient 2 was homozygous for a novel c.1643G>A mutation leading to a stop at codon 548 in exon 13 (p.W548X). These data underscore that in GSD-IV a severe phenotype correlates with null mutations, and indicate that RNA analysis is necessary to characterize functional consequences of intronic mutations.","variants":[{"Name":"NM_000158.4(GBE1):c.1643G>A (p.Trp548Ter)","Chromosome":"3","Start":"81537071","Stop":"81537071","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17832,"rule_based_match":true,"evidence_text":"c.1643G>A","llm_judgment":"PRESENT","evidence":"c.1643G>A","abstract_start":767,"abstract_end":776},{"Name":"NM_000158.4(GBE1):c.691+5G>C","Chromosome":"3","Start":"81648851","Stop":"81648851","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":17831,"rule_based_match":true,"evidence_text":"c.691+5 g>c","llm_judgment":"PRESENT","evidence":"c.691+5 g>c","abstract_start":581,"abstract_end":592}]}
{"pmid":"34565654","title":"Successful treatment of congenital myasthenic syndrome caused by a novel compound heterozygous variant in RAPSN.","abstract":"BACKGROUND: Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous neuromuscular disorder characterized by muscle weakness and caused by mutations in more than 35 different genes. This condition should not be overlooked as a subset of patients with CMS are treatable. However, the diagnosis of CMS is often difficult due to the broad variability in disease severity and course.\nCASE REPORT: A five-year-old boy without remarkable family history was born with marked general muscle hypotonia and weakness, respiratory insufficiency, anomalies, and multiple joint contractures. Congenital myopathy was suspected based upon type 1 fiber predominance on muscle biopsy. However, he was diagnosed with CMS at age 4 years when his ptosis and ophthalmoplegia were found to be improved by edrophonium chloride and repetitive nerve stimulation showed attenuation of compound muscle action potentials. An exome sequencing identified a compound heterozygous missense variant of c.737C > T (p.A246V) and a novel intronic insertion c.1166 + 4_1166 + 5insAAGCCCACCAC in RAPSN. RT-PCR analysis which showed the skipping of exon 7 in a skeletal muscle sample confirmed that the intronic insertion was pathogenic. His myasthenic symptoms were remarkably improved by pyridostigmine.\nCONCLUSION: The patient's diagnosis of CMS was confirmed by exome sequencing, and RT-PCR revealed that the skipping of exon 7 in RAPSN was caused by a novel intronic insertion. The genetic information uncovered in this case should therefore be added to the collection of tools for diagnosing and treating CMS.","variants":[{"Name":"NM_005055.5(RAPSN):c.737C>T (p.Ala246Val)","Chromosome":"11","Start":"47441875","Stop":"47441875","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":194409,"rule_based_match":true,"evidence_text":"c.737C > T (p.A246V)","llm_judgment":"PRESENT","evidence":"c.737C > T (p.A246V)","abstract_start":994,"abstract_end":1014}]}
{"pmid":"33497524","title":"Gene correction of the CLN3 c.175G>A variant in patient-derived induced pluripotent stem cells prevents pathological changes in retinal organoids.","abstract":"BACKGROUND: Mutations in CLN3 cause Batten disease, however non-syndromic CLN3 disease, characterized by retinal-specific degeneration, has been also described. Here, we characterized an induced pluripotent stem cell (iPSC)-derived disease model derived from a patient with non-syndromic CLN3-associated retinopathy.\nMETHODS: Patient-iPSC, carrying the 1 kb-deletion and c.175G>A variants in CLN3, coisogenic iPSC, in which the c.175G>A variant was corrected, and control iPSC were differentiated into neural retinal organoids (NRO) and cardiomyocytes. CLN3 transcripts were analyzed by Sanger sequencing. Gene expression was characterized by qPCR and western blotting. NRO were characterized by immunostaining and electron microscopy.\nRESULTS: Novel CLN3 transcripts were detected in adult human retina and control-NRO. The major transcript detected in patient-NRO displayed skipping of exons 2 and 4-9. Accumulation of subunit-C of mitochondrial ATPase (SCMAS) protein was demonstrated in patient-derived cells. Photoreceptor progenitor cells in patient-NRO displayed accumulation of peroxisomes and vacuolization of inner segments. Correction of the c.175G>A variant restored CLN3 mRNA and protein expression and prevented SCMAS and inner segment vacuolization.\nCONCLUSION: Our results demonstrate the expression of novel CLN3 transcripts in human retinal tissues. The c.175G>A variant alters splicing of the CLN3 pre-mRNA, leading to features consistent with CLN3 deficiency, which were prevented by gene correction.","variants":[{"Name":"NM_001042432.2(CLN3):c.175G>A (p.Ala59Thr)","Chromosome":"16","Start":"28489337","Stop":"28489337","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":927760,"rule_based_match":true,"evidence_text":"c.175G>A","llm_judgment":"PRESENT","evidence":"c.175G>A","abstract_start":371,"abstract_end":379}]}
{"pmid":"20005757","title":"A novel PCFT gene mutation (p.Cys66LeufsX99) causing hereditary folate malabsorption.","abstract":"Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder which is characterized by impaired intestinal folate malabsorption and impaired folate transport into the central nervous system. Mutations in the intestinal folate transporter PCFT have been reported previously in only 10 individuals with this disorder. The purpose of the current study was to describe the clinical phenotype and determine the molecular basis for this disorder in a family with four affected individuals. A consanguineous family of Pakistani origin with autosomal recessive HFM was ascertained and clinically phenotyped. After genetic linkage studies all coding exons of the PCFT gene were screened for mutations by direct sequencing. The clinical phenotype of four affected patients is described. Direct sequencing of PCFT revealed a novel homozygous frameshift mutation (c.194dupG) at a mononucleotide repeat in exon 1 predicted to result in a truncated protein (p.Cys66LeufsX99). This report extends current knowledge on the phenotypic manifestations of HFM and the PCFT mutation spectrum.","variants":[{"Name":"NM_080669.6(SLC46A1):c.194dup (p.Cys66fs)","Chromosome":"17","Start":"28405920","Stop":"28405921","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76658,"rule_based_match":true,"evidence_text":"c.194dup","llm_judgment":"PRESENT","evidence":"c.194dup","abstract_start":868,"abstract_end":876}]}
{"pmid":"19917958","title":"Unexpected occurrence of xeroderma pigmentosum in an uncle and nephew.","abstract":"BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by a decreased ability to repair DNA damaged by UV radiation and the early development of cutaneous and ocular malignant neoplasms. Approximately 20% of patients with XP also develop progressive neurologic degeneration.\nOBSERVATIONS: We describe a boy who was found to have XP after a severe burn following minimal sun exposure. His maternal uncle, now age 20 years, had been diagnosed with XP after a similar sunburn in infancy. The uncle has the typical skin pigmentary findings of XP along with severe progressive neurologic involvement. Although the infant's parents were not known to be blood relatives, the infant and his affected uncle proved to be compound heterozygotes for the same 2 frameshift mutations in the XPA DNA repair gene (c.288delT and c.349_353del). After the diagnosis of XP in the infant, genealogic investigation identified a common Dutch ancestor for both of his grandfathers 5 generations back.\nCONCLUSIONS: Counseling families at risk for a rare inherited disease is not always straightforward. The sociocultural and demographic backgrounds of the families must be considered for evaluation of risk assessment.","variants":[{"Name":"NM_000380.4(XPA):c.349_353del (p.Leu117fs)","Chromosome":"9","Start":"97689570","Stop":"97689574","ReferenceAlleleVCF":"CATAAG","AlternateAlleleVCF":"C","allel_id":16033,"rule_based_match":true,"evidence_text":"c.349_353del","llm_judgment":"PRESENT","evidence":"c.349_353del","abstract_start":849,"abstract_end":861},{"Name":"NM_000380.4(XPA):c.288del (p.Val97fs)","Chromosome":"9","Start":"97689635","Stop":"97689635","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":2901332,"rule_based_match":true,"evidence_text":"c.288delT","llm_judgment":"PRESENT","evidence":"c.288delT","abstract_start":835,"abstract_end":844}]}
{"pmid":"36214804","title":"De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder.","abstract":"PURPOSE: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20.\nMETHODS: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed.\nRESULTS: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface.\nCONCLUSION: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.","variants":[{"Name":"NM_014458.4(KLHL20):c.1069G>A (p.Gly357Arg)","Chromosome":"1","Start":"173757077","Stop":"173757077","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":857425,"rule_based_match":true,"evidence_text":"NM_014458.4:c.1069G>A p.[Gly357Arg]","llm_judgment":"PRESENT","evidence":"NM_014458.4:c.1069G>A p.[Gly357Arg]","abstract_start":966,"abstract_end":1001}]}
{"pmid":"22039234","title":"Autosomal dominant retinitis pigmentosa with intrafamilial variability and incomplete penetrance in two families carrying mutations in PRPF8.","abstract":"PURPOSE: The aim of this study was to report detailed genotype/phenotype correlation in two British autosomal dominant retinitis pigmentosa (adRP) families with recently described mutations in PRPF8.\nMETHODS: Ten affected members from the two families (excluded for PRPF31 mutations) were assessed clinically. Seven subjects had fundus photography; some had electrophysiology, autofluorescence imaging, and visual field testing. Linkage analysis was performed from genomic DNA in one family. RNA was extracted from lymphocytes of the proband from both families, reverse transcribed into cDNA and subsequently screened for mutations in PRPF8. Segregation of mutations in each family was tested by direct genomic sequencing of the specific exons carrying the mutation.\nRESULTS: All affected members complained of nyctalopia with variable age of onset. In the first family, there was marked variation in the clinical phenotype among affected individuals ranging from severe rod-cone dystrophy to a 67-year-old patient with a normal retinal appearance and mild rod dysfunction on scotopic electroretinography (ERG). The second family demonstrated similar variability and a history of a nonpenetrant individual. Linkage analysis in the first family showed strong evidence for linkage to markers on chromosome 17p implicating PRPF8 as a candidate gene. A c.6353 C>T change causing a nonconservative missense mutation p.S2118F was found in exon 38 of PRPF8 by direct sequencing of the cDNA. The mutation c.6930G>C (p.R2310S) was found in the second family.\nCONCLUSIONS: This is the first report of marked intrafamilial variability associated with mutations in the PRPF8 gene, including incomplete penetrance. PRPF8 mutations should be suspected in patients with adRP and variable expressivity.","variants":[{"Name":"NM_006445.4(PRPF8):c.6353C>T (p.Ser2118Phe)","Chromosome":"17","Start":"1653558","Stop":"1653558","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39623,"rule_based_match":true,"evidence_text":"c.6353 C>T","llm_judgment":"PRESENT","evidence":"c.6353 C>T","abstract_start":1349,"abstract_end":1359},{"Name":"NM_006445.4(PRPF8):c.6930G>C (p.Arg2310Ser)","Chromosome":"17","Start":"1650880","Stop":"1650880","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":39624,"rule_based_match":true,"evidence_text":"c.6930G>C (p.R2310S)","llm_judgment":"PRESENT","evidence":"c.6930G>C (p.R2310S)","abstract_start":1497,"abstract_end":1517}]}
{"pmid":"21868108","title":"De novo dominant mutation of GJB2 in two Chinese families with nonsyndromic hearing loss.","abstract":"BACKGROUND: Mutations in the GJB2 gene are the most common cause of nonsyndromic autosomal recessive sensorineural hearing loss. A few mutations in GJB2 have also been reported to cause dominant nonsyndromic or syndromic hearing loss. However, de novo or dominant mutation in GJB2 is not common in Chinese populations.\nMETHODS: Two probands with hearing impairment from unrelated Chinese families are reported here. Temporal CT scan, complete physical (including skin and hair) and otoscopic examinations, and an audiological study, including tympanometry, auditory brainstem response (ABR), auditory steady-state response (ASSR), and 40Hz-auditory event-related potential (40 Hz-AERP), were carried out. The two exons of GJB2, the coding exons of SLC26A4, and mitochondrial 12S rRNA were sequenced.\nRESULTS: Sequencing of GJB2 in the two cases showed a heterozygous c.551G>A(p.R184Q) mutation, which was not found in other family members. Additionally, no other mutation in GJB2 was identified in the two family members. Paternity was confirmed by genotype analysis of 15 informative short tandem repeats (STRs) from the chromosomes. Sequence analysis of the coding exons of SLC26A4 and mitochondrial 12S rRNA was performed but no sequence aberration or deletion was found.\nCONCLUSIONS: A de novo GJB2 p.R184Q mutation can cause severe-to-profound bilateral sensorineural hearing impairment. Although not common in Chinese patients with hearing loss, it is important to identify the specific phenotype and genotype correlations of the de novo dominant mutation in GJB2.","variants":[{"Name":"NM_004004.6(GJB2):c.551G>A (p.Arg184Gln)","Chromosome":"13","Start":"20189031","Stop":"20189031","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38617,"rule_based_match":true,"evidence_text":"c.551G>A(p.R184Q)","llm_judgment":"PRESENT","evidence":"c.551G>A(p.R184Q)","abstract_start":867,"abstract_end":884}]}
{"pmid":"16705713","title":"Hepatic and neuromuscular forms of glycogenosis type III: nine mutations in AGL.","abstract":"Glycogenosis type III (Cori disease) is an autosomal recessive disorder caused by the deficiency of the glycogen debranching enzyme, encoded by the AGL gene, and existing in six isoforms alternately spliced in a tissue-specific way. Generally, disease onset occurs early on starting from the first year of life, with hepatomegaly, hypoglycemia, hyperlipidemia, increased CK levels, and, in some cases, short stature and slight mental retardation. Frequently, hepatomegaly tends to resolve spontaneously and inexplicably during childhood, when myopathy, often associated with cardiomyopathy, arises. This disease is known to lack almost invariably clear links between the genotype and clinical phenotype. We describe nine new mutations in Italian patients: four nonsense (p.Arg285X, p.Lys422X, p.Arg910X, p.Arg977X), three frameshift (c.442delA, c.753_756delGACA, c.3963delG), and two missense (p.Ala1120Pro, p.Arg524His). Particularly, the nonsense p.Arg285X is linked to an exonic splicing enhancer and it was found to produce two species of transcripts at the same time. Moreover, we discuss a subgroup of subjects carrying c.2681+1G>A, which has proven to be the most frequent mutation among our patients. The previously described c.664+3A>G was also detected in two patients, both homozygous. The present work is yet another confirmation that the individual genetic background plays a pivotal role in influencing the phenotypes, as occurs in other metabolic diseases.","variants":[{"Name":"NM_000642.3(AGL):c.1571G>A (p.Arg524His)","Chromosome":"1","Start":"99877788","Stop":"99877788","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":824583,"rule_based_match":false,"evidence_text":"c.1571G>A (p.Arg524His)","llm_judgment":"PRESENT","evidence":"p.Arg524His","abstract_start":908,"abstract_end":919},{"Name":"NM_000642.3(AGL):c.442del (p.Arg148fs)","Chromosome":"1","Start":"99862405","Stop":"99862405","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"T","allel_id":357197,"rule_based_match":true,"evidence_text":"c.442delA","llm_judgment":"PRESENT","evidence":"c.442delA","abstract_start":834,"abstract_end":843},{"Name":"NM_000642.3(AGL):c.664+3A>G","Chromosome":"1","Start":"99864592","Stop":"99864592","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":186640,"rule_based_match":true,"evidence_text":"c.664+3A>G","llm_judgment":"PRESENT","evidence":"c.664+3A>G","abstract_start":1234,"abstract_end":1244},{"Name":"NM_000642.3(AGL):c.2681+1G>A","Chromosome":"1","Start":"99884704","Stop":"99884704","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":265466,"rule_based_match":true,"evidence_text":"c.2681+1G>A","llm_judgment":"PRESENT","evidence":"c.2681+1G>A","abstract_start":1126,"abstract_end":1137}]}
{"pmid":"25802487","title":"Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin.","abstract":"PURPOSE: To investigate the molecular basis of retinitis pigmentosa in two consanguineous families of Pakistani origin with multiple affected members.\nMETHODS: Homozygosity mapping and Sanger sequencing of candidate genes were performed in one family while the other was analyzed with whole exome next-generation sequencing. A minigene splicing assay was used to confirm the splicing defects.\nRESULTS: In family MA48, a novel homozygous nucleotide substitution in C8orf37, c.244-2A>C, that disrupted the consensus splice acceptor site of exon 3 was found. The minigene splicing assay revealed that this mutation activated a cryptic splice site within exon 3, causing a 22 bp deletion in the transcript that is predicted to lead to a frameshift followed by premature protein truncation. In family MA13, a novel homozygous null mutation in C8orf37, c.555G>A, p.W185*, was identified. Both mutations segregated with the disease phenotype as expected in a recessive manner and were absent in 8,244 unrelated individuals of South Asian origin.\nCONCLUSIONS: In this report, we describe C8orf37 mutations that cause retinal dystrophy in two families of Pakistani origin, contributing further data on the phenotype and the spectrum of mutations in this form of retinitis pigmentosa.","variants":[{"Name":"NM_177965.4(CFAP418):c.244-2A>C","Chromosome":"8","Start":"95260534","Stop":"95260534","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":404688,"rule_based_match":true,"evidence_text":"c.244-2A>C","llm_judgment":"PRESENT","evidence":"c.244-2A>C","abstract_start":473,"abstract_end":483},{"Name":"NM_177965.4(CFAP418):c.555G>A (p.Trp185Ter)","Chromosome":"8","Start":"95247686","Stop":"95247686","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":404689,"rule_based_match":true,"evidence_text":"c.555G>A, p.W185*","llm_judgment":"PRESENT","evidence":"c.555G>A, p.W185*","abstract_start":847,"abstract_end":864}]}
{"pmid":"31525260","title":"The homozygous variant c.245G > A/p.G82D in PNPLA2 is associated with arrhythmogenic cardiomyopathy phenotypic manifestations.","abstract":"Arrhythmogenic cardiomyopathy (ACM) is a familial cardiomyopathy featured by fibrofatty replacement of cardiomyocytes. Responsible genetic factors are not discernible in approximately one-third of ACM probands. To investigate this further, we performed whole genome sequencing in 14 mutation-negative ACM probands who underwent cardiac transplantation, and we identified one ACM proband with a rare homozygous missense variant in PNPLA2 (c.245G > A, p.G82D), a rate-limiting enzyme that hydrolyzes triglycerides into fatty acids and diacylglycerol. Bioinformatic analysis suggested that this missense variant may lead to loss of function and therefore impair lipid catabolism. Genetic screening in this proband's family also inferred that the homozygous variant cosegregated with disease. To validate the pathogenicity of this variant and confirm its association with ACM, we established a knockin mouse model carrying the orthologous human homozygous PNPLA2 variant. Interestingly, mice with the homozygous variant presented with arrhythmias and significant cardiac dysfunction at 12 weeks, whereas heterozygous mice were not affected. Moreover, those homozygous mice suffered sudden death and/or heart failure by the age of 14 weeks. Pathological examination showed that extensive lipogenesis in cardiomyocytes and cardiac fibrosis were prominent in the myocardium. Herein, our data demonstrated that the homozygous missense variant PNPLA2 (c.245G > A, p.G82D) associated with a recessive form of ACM.","variants":[{"Name":"NM_020376.4(PNPLA2):c.245G>A (p.Gly82Asp)","Chromosome":"11","Start":"821685","Stop":"821685","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3061027,"rule_based_match":true,"evidence_text":"c.245G > A, p.G82D","llm_judgment":"PRESENT","evidence":"c.245G > A, p.G82D","abstract_start":438,"abstract_end":456}]}
{"pmid":"24260153","title":"SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15).","abstract":"Autosomal dominant non-syndromic hearing loss (AD-NSHL) is one of the most common genetic diseases in human and is well-known for the considerable genetic heterogeneity. In this study, we utilized whole exome sequencing (WES) and linkage analysis for direct genetic diagnosis in AD-NSHL. The Korean family had typical AD-NSHL running over 6 generations. Linkage analysis was performed by using genome-wide single nucleotide polymorphism (SNP) chip and pinpointed a genomic region on 5q31 with a significant linkage signal. Sequential filtering of variants obtained from WES, application of the linkage region, bioinformatic analyses, and Sanger sequencing validation identified a novel missense mutation Arg326Lys (c.977G>A) in the POU homeodomain of the POU4F3 gene as the candidate disease-causing mutation in the family. POU4F3 is a known disease gene causing AD-HSLH (DFNA15) described in 5 unrelated families until now each with a unique mutation. Arg326Lys was the first missense mutation affecting the 3(rd) alpha helix of the POU homeodomain harboring a bipartite nuclear localization signal sequence. The phenotype findings in our family further supported previously noted intrafamilial and interfamilial variability of DFNA15. This study demonstrated that WES in combination with linkage analysis utilizing bi-allelic SNP markers successfully identified the disease locus and causative mutation in AD-NSHL.","variants":[{"Name":"NM_002700.3(POU4F3):c.977G>A (p.Arg326Lys)","Chromosome":"5","Start":"146340404","Stop":"146340404","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":102599,"rule_based_match":true,"evidence_text":"c.977G>A","llm_judgment":"PRESENT","evidence":"c.977G>A","abstract_start":715,"abstract_end":723}]}
{"pmid":"30144375","title":"TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton.","abstract":"Transient receptor potential vanilloid 6 (TRPV6) functions in tetramer form for calcium transport. Until now, TRPV6 has not been linked with skeletal development disorders. An infant with antenatal onset thoracic insufficiency required significant ventilatory support. Skeletal survey showed generalized marked undermineralization, hypoplastic fractured ribs, metaphyseal fractures, and extensive periosteal reaction along femoral, tibial, and humeral diaphyses. Parathyroid hormone (PTH) elevation (53.4-101 pmol/L) initially suggested PTH signaling disorders. Progressively, biochemical normalization with radiological mineralization suggested recovery from in utero pathophysiology. Genomic testing was undertaken and in silico protein modeling of variants. No abnormalities in antenatal CGH array or UPD14 testing. Postnatal molecular genetic analysis found no causative variants in CASR, GNA11, APS21, or a 336 gene skeletal dysplasia panel investigated by whole exome sequencing. Trio exome analysis identified compound heterozygous TRPV6 likely pathogenic variants: novel maternally inherited missense variant, c.1978G > C p.(Gly660Arg), and paternally inherited nonsense variant, c.1528C > T p.(Arg510Ter), confirming recessive inheritance. p.(Gly660Arg) generates a large side chain protruding from the C-terminal hook into the interface with the adjacent TRPV6 subunit. In silico protein modeling suggests steric clashes between interface residues, decreased C-terminal hook, and TRPV6 tetramer stability. The p.(Gly660Arg) variant is predicted to result in profound loss of TRPV6 activity. This first case of a novel dysplasia features severe but improving perinatal abnormalities. The TRPV6 compound heterozygous variants appear likely to interfere with fetoplacental calcium transfer crucial for in utero skeletal development. Astute clinical interpretation of evolving perinatal abnormalities remains valuable in complex calcium and bone pathophysiology and informs exome sequencing interpretation.","variants":[{"Name":"NM_018646.6(TRPV6):c.1978G>C (p.Gly660Arg)","Chromosome":"7","Start":"142872409","Stop":"142872409","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":806433,"rule_based_match":true,"evidence_text":"c.1978G > C p.(Gly660Arg)","llm_judgment":"PRESENT","evidence":"c.1978G > C p.(Gly660Arg)","abstract_start":1118,"abstract_end":1143}]}
{"pmid":"37385809","title":"A case of combined oxidative phosphorylation deficiency 32 caused by MRPS34 gene variation and literature review","abstract":"<b>Objective:</b> To investigate the clinical features and genetic features of combined oxidative phosphorylation deficiency 32 (COXPD32) caused by MRPS34 gene variation. <b>Methods:</b> The clinical data and genetic test of a child with COXPD32 hospitalized in the Department of Neurology, Children's Hospital, Capital Institute of Pediatrics in March 2021 were extracted and analyzed. A literature search was implemented using Wanfang, China biology medicine disc, China national knowledge infrastructure, ClinVar, human gene mutation database (HGMD) and Pubmed databases with the key words \"MRPS34\" \"MRPS34 gene\" and \"combined oxidative phosphorylation deficiency 32\" (up to February 2023). Clinical and genetic features of COXPD32 were summarized. <b>Results:</b> A boy aged 1 year and 9 months was admitted due to developmental delay. He showed mental and motor retardation, and was below the 3<sup>rd</sup> percentile for height, weight, and head circumference of children of the same age and gender. He had poor eye contact, esotropia, flat nasal bridge, limbs hypotonia, holding instability and tremors. In addition, Grade Ⅲ/6 systolic murmur were heard at left sternal border. Arterial blood gases suggested that severe metabolic acidosis with lactic acidosis. Brain magnetic resonance imaging (MRI) showed multiple symmetrical abnormal signals in the bilateral thalamus, midbrain, pons and medulla oblongata. Echocardiography showed atrial septal defect. Genetic testing identified the patient as a compound heterozygous variation of MRPS34 gene, c.580C>T (p.Gln194Ter) and c.94C>T (p.Gln32Ter), with c.580C>T being the first report and a diagnosis of COXPD32. His parents carried a heterozygous variant, respectively. The child improved after treatment with energy support, acidosis correction, and \"cocktail\" therapy (vitaminB<sub>1</sub>, vitaminB<sub>2</sub>, vitaminB<sub>6</sub>, vitaminC and coenzyme Q10). A total of 8 cases with COXPD32 were collected through 2 English literature reviews and this study. Among the 8 patients, 7 cases had onset during infancy and 1 was unknown, all had developmental delay or regression, 7 cases had feeding difficulty or dysphagia, followed by dystonia, lactic acidosis, ocular symptoms, microcephaly, constipation and dysmorphic facies(mild coarsening of facial features, small forehead, anterior hairline extending onto forehead,high and narrow palate, thick gums, short columella, and synophrys), 2 cases died of respiratory and circulatory failure, and 6 were still alive at the time of reporting, with an age range of 2 to 34 years. Blood and (or) cerebrospinal fluid lactate were elevated in all 8 patients. MRI in 7 cases manifested symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia. Urine organic acid test were all normal but 1 patient had alanine elevation. Five patients underwent respiratory chain enzyme activity testing, and all had varying degrees of enzyme activity reduction. Six variants were identified, 6 patients were homozygous variants, with c.322-10G>A was present in 4 patients from 2 families and 2 compound heterozygous variants. <b>Conclusions:</b> The clinical phenotype of COXPD32 is highly heterogenous and the severity of the disease varies from development delay, feeding difficulty, dystonia, high lactic acid, ocular symptoms and reduced mitochondrial respiratory chain enzyme activity in mild cases, which may survive into adulthood, to rapid death due to respiratory and circulatory failure in severe cases. COXPD32 needs to be considered in cases of unexplained acidosis, hyperlactatemia, feeding difficulties, development delay or regression, ocular symptoms, respiratory and circulatory failure, and symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia, and genetic testing can clarify the diagnosis.","variants":[{"Name":"NM_023936.2(MRPS34):c.94C>T (p.Gln32Ter)","Chromosome":"16","Start":"1773026","Stop":"1773026","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432256,"rule_based_match":true,"evidence_text":"c.94C>T (p.Gln32Ter)","llm_judgment":"PRESENT","evidence":"c.94C>T (p.Gln32Ter)","abstract_start":1584,"abstract_end":1604}]}
{"pmid":"27519266","title":"Mutation analysis of the COL1A1 and COL1A2 genes in Vietnamese patients with osteogenesis imperfecta.","abstract":"BACKGROUND: The genetics of osteogenesis imperfecta (OI) have not been studied in a Vietnamese population before. We performed mutational analysis of the COL1A1 and COL1A2 genes in 91 unrelated OI patients of Vietnamese origin. We then systematically characterized the mutation profiles of these two genes which are most commonly related to OI.\nMETHODS: Genomic DNA was extracted from EDTA-preserved blood according to standard high-salt extraction methods. Sequence analysis and pathogenic variant identification was performed with Mutation Surveyor DNA variant analysis software. Prediction of the pathogenicity of mutations was conducted using Alamut Visual software. The presence of variants was checked against Dalgleish's osteogenesis imperfecta mutation database.\nRESULTS: The sample consisted of 91 unrelated osteogenesis imperfecta patients. We identified 54 patients with COL1A1/2 pathogenic variants; 33 with COL1A1 and 21 with COL1A2. Two patients had multiple pathogenic variants. Seventeen novel COL1A1 and 10 novel COL1A2 variants were identified. The majority of identified COL1A1/2 pathogenic variants occurred in a glycine substitution (36/56, 64.3 %), usually serine (23/36, 63.9 %). We found two pathogenic variants of the COL1A1 gene c.2461G > A (p.Gly821Ser) in four unrelated patients and one, c.2005G > A (p.Ala669Thr), in two unrelated patients.\nCONCLUSION: Our data showed a lower number of collagen OI pathogenic variants in Vietnamese patients compared to reported rates for Asian populations. The OI mutational profile of the Vietnamese population is unique and related to the presence of a high number of recessive mutations in non-collagenous OI genes. Further analysis of OI patients negative for collagen mutations, is required.","variants":[{"Name":"NM_000088.4(COL1A1):c.2005G>A (p.Ala669Thr)","Chromosome":"17","Start":"50192003","Stop":"50192003","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1012867,"rule_based_match":true,"evidence_text":"c.2005G > A (p.Ala669Thr)","llm_judgment":"PRESENT","evidence":"c.2005G > A (p.Ala669Thr)","abstract_start":1317,"abstract_end":1342},{"Name":"NM_000088.4(COL1A1):c.2461G>A (p.Gly821Ser)","Chromosome":"17","Start":"50190099","Stop":"50190099","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":413995,"rule_based_match":true,"evidence_text":"c.2461G > A (p.Gly821Ser)","llm_judgment":"PRESENT","evidence":"c.2461G > A (p.Gly821Ser)","abstract_start":1255,"abstract_end":1280}]}
{"pmid":"28157837","title":"A novel surfactant protein C mutation resulting in aberrant protein processing and altered subcellular localization causes infantile interstitial lung disease.","abstract":"BACKGROUND: Mutations in the surfactant protein C gene (SFTPC) result in interstitial lung disease (ILD). Our objective was to report a novel SFTPC mutation and evaluate the effect of this mutant on protein synthesis and processing.\nMETHODS: Genomic DNA was extracted from whole blood of a Chinese infant with ILD and candidate genes associated with ILD were sequenced by next-generation sequencing. Subclones of wild-type and mutant SFTPC were transiently transfected into A549 cells. The functional characterization of mutant surfactant protein C (SP-C) was evaluated by Western blotting, transmission electron microscopy, and immunofluorescence.\nRESULTS: A novel heterozygous mutation SFTPC: c.337T>T/C, p.Y113H was identified in this ILD infant. Neither of the parents carries this mutation. Using A549 cells expressing wild-type and mutant SP-C isoforms, Western blotting revealed a significant reduction of proSP-C and a band with abnormal molecular weight in the mutant SP-C compared to the wild-type. Ultrastructural analysis showed abnormal cytoplasmic organelles. Immunofluorescence demonstrated mutant SP-C was scarcely trafficked to lamellar bodies but localized well to early endosomes, which was in marked contrast to the wild type protein.\nCONCLUSION: We detected a novel mutation in SFTPC causing ILD in infancy. The mutation results in aberrant proSP-C processing and altered subcellular localization.","variants":[{"Name":"NM_001317778.2(SFTPC):c.337T>C (p.Tyr113His)","Chromosome":"8","Start":"22163448","Stop":"22163448","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1785802,"rule_based_match":false,"evidence_text":"SFTPC: c.337T>T/C, p.Y113H","llm_judgment":"PRESENT","evidence":"SFTPC: c.337T>T/C, p.Y113H","abstract_start":688,"abstract_end":714}]}
{"pmid":"36308023","title":"Mild phenotypes of phosphoglycerate dehydrogenase deficiency by a novel mutation of PHGDH gene: Case report and literature review.","abstract":"Phosphoglycerate dehydrogenase (PHGDH) deficiency is a rare autosomal recessive genetic disease of serine biosynthesis. Its typical features are congenital microcephaly, epileptic seizures, and psychomotor developmental delay. Here, we reported the first Chinese familial cases with genetically confirmed PHGDH deficiency and reviewed several previous reports. Two siblings in this family presented with microcephaly, psychomotor retardation, and epilepsy in early juvenile. Brain magnetic resonance imaging (MRI) showed only a slight change of enlarged ventricle. Biochemical investigations revealed low serum serine and glycine concentrations. The whole-exome sequencing (WES) results identified a missense variant in the PHGDH gene (NM_006623.4: exon11: c.1211T>A, p. Val404Asp). Although two patients in this Chinese family carried the same pathogenic mutation in the PHGDH, their symptoms and responses to treatment were not exactly the same. We found a novel variant in the PHGDH gene and expanded the genotypic and phenotypic spectrum of serine biosynthesis disorders.","variants":[{"Name":"NM_006623.4(PHGDH):c.1211T>A (p.Val404Asp)","Chromosome":"1","Start":"119742808","Stop":"119742808","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3184452,"rule_based_match":true,"evidence_text":"NM_006623.4: exon11: c.1211T>A, p. Val404Asp","llm_judgment":"PRESENT","evidence":"NM_006623.4: exon11: c.1211T>A, p. Val404Asp","abstract_start":736,"abstract_end":780}]}
{"pmid":"29101630","title":"Biotin Thiamin Responsive Basal Ganglia Disease in Siblings.","abstract":"Biotin Thiamine responsive Basal Ganglia Disease (BTBGD) is a rare treatable autosomal recessive metabolic disorder caused by mutations in SLC19A3 gene. It usually presents with encephalopathy and dystonia; if not treated, can progress to quadriparesis and death. Two Indian siblings born to a consanguineous marriage presented with regression of milestones, epilepsy and dystonia. Neuroimaging showed signal changes in basal ganglia and thalami. Genetic testing showed a homozygous missense substitution p.Gly23Val (c.68G > T) in exon 2 of the SLC19A3 gene. Thus to conclude, any child who presents with neuroregression, epilepsy and dystonia in the background of basal ganglia changes on neuroimaging, a possibility of biotin thiamine responsive basal ganglia disease should be considered.","variants":[{"Name":"NM_025243.4(SLC19A3):c.68G>T (p.Gly23Val)","Chromosome":"2","Start":"227702251","Stop":"227702251","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":19601,"rule_based_match":true,"evidence_text":"c.68G > T (p.Gly23Val)","llm_judgment":"PRESENT","evidence":"p.Gly23Val","abstract_start":505,"abstract_end":515}]}
{"pmid":"25899282","title":"Identification of a novel mutation, c.686delAins18 (p.Asp229Glyfs*22), in the LIPH gene as a compound heterozygote with c.736T>A (p.Cys246Ser) in autosomal recessive woolly hair/hypotrichosis.","abstract":"","variants":[{"Name":"NM_139248.3(LIPH):c.736T>A (p.Cys246Ser)","Chromosome":"3","Start":"185519292","Stop":"185519292","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":227256,"rule_based_match":true,"evidence_text":"c.736T>A (p.Cys246Ser)","llm_judgment":"PRESENT","evidence":"c.736T>A (p.Cys246Ser)","abstract_start":null,"abstract_end":null}]}
{"pmid":"37268502","title":"The natural history of autosomal dominant polycystic kidney disease. A strategy for grouping families and mutations.","abstract":"Autosomal dominant polycystic kidney disease (ADPKD) is a main cause of end-stage renal disease. Today, knowledge of its genetic basis has made it possible to develop strategies that prevent the transmission of the disease.\nOBJECTIVES: The objective of the study was to analyze the natural history of ADPKD in the province of Córdoba and to design a database that allows grouping families with different mutations.\nPATIENTS AND METHODS: All patients (n = 678) diagnosed with ADPKD followed by the Córdoba nephrology service are included. Various clinical variables (age and sex), genetic variables (mutation in PKD1, PKD2) and the need for renal replacement therapy (RRT) were retrospectively analyzed.\nRESULTS: The prevalence was 61 cases per 100,000 inhabitants. Median renal survival was significantly worse in PKD1 (57.5 years) than in PKD2 (70 years) (log-rank p = 0.000). We have genetically identified 43.8% of the population, detecting PKD1 mutations in 61.2% and PKD2 mutations in 37.4% of cases, respectively. The most frequent mutation, in PKD2 (c.2159del), appeared in 68 patients belonging to 10 different families. The one with the worst renal prognosis was a truncating mutation in PKD1 (c.9893 G > A). These patients required RRT at a median age of 38.7 years.\nCONCLUSIONS: Renal survival of ADPKD in the province of Córdoba is similar to that described in the literature. We detected PKD2 mutations in 37.4% of cases. This strategy allows us to know the genetic basis of a large proportion of our population while saving resources. This is essential to be able to offer primary prevention of ADPKD through preimplantation genetic diagnosis.","variants":[{"Name":"NM_000297.4(PKD2):c.2159del (p.Asn720fs)","Chromosome":"4","Start":"88065407","Stop":"88065407","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":433000,"rule_based_match":true,"evidence_text":"c.2159del","llm_judgment":"PRESENT","evidence":"c.2159del","abstract_start":1057,"abstract_end":1066}]}
{"pmid":"15689447","title":"CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms.","abstract":"BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation).\nMETHODS: Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls.\nRESULTS: We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found.\nCONCLUSION: Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type.","variants":[{"Name":"NM_001323289.2(CDKL5):c.2635_2636del (p.Leu879fs)","Chromosome":"X","Start":"18628509","Stop":"18628510","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":153541,"rule_based_match":true,"evidence_text":"c.2635_2636delCT","llm_judgment":"PRESENT","evidence":"c.2635_2636delCT","abstract_start":1402,"abstract_end":1418},{"Name":"NM_001323289.2(CDKL5):c.163_166del (p.Glu55fs)","Chromosome":"X","Start":"18575368","Stop":"18575371","ReferenceAlleleVCF":"CAAAG","AlternateAlleleVCF":"C","allel_id":153511,"rule_based_match":true,"evidence_text":"c.163_166delGAAA","llm_judgment":"PRESENT","evidence":"c.163_166delGAAA","abstract_start":1358,"abstract_end":1374}]}
{"pmid":"34888509","title":"Early Death of 2 Siblings Related to Mutations in","abstract":"We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.1537C > T, p.Arg513*) in <i>Leiomodin 2</i> (<i>LMOD2</i>), a recently documented cause of early DCM. The phenotype in mice and humans consists of early, severe cardiac dilation and dysfunction related to decreased functional LMOD2, which results in abnormal actin filaments and abnormal myocardial contractility. Our cases confirm mutations in <i>LMOD2</i> as a cause of DCM in humans and highlight the rapid changes occurring in cardiac genetics and the importance of reviewing previously negative genetic test results in the context of emerging literature.","variants":[{"Name":"NM_207163.3(LMOD2):c.1243_1244del (p.Leu415fs)","Chromosome":"7","Start":"123662827","Stop":"123662828","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":1679346,"rule_based_match":true,"evidence_text":"c.1243_1244del","llm_judgment":"PRESENT","evidence":"c.1243_1244del","abstract_start":135,"abstract_end":149},{"Name":"NM_207163.3(LMOD2):c.1537C>T (p.Arg513Ter)","Chromosome":"7","Start":"123663123","Stop":"123663123","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1679347,"rule_based_match":true,"evidence_text":"c.1537C > T, p.Arg513*","llm_judgment":"PRESENT","evidence":"c.1537C > T, p.Arg513*","abstract_start":173,"abstract_end":195}]}
{"pmid":"22527616","title":"Genetic analysis in a patient presenting with meningioma and familial isolated pituitary adenoma (FIPA) reveals selective involvement of the R81X mutation of the AIP gene in the pathogenesis of the pituitary tumor.","abstract":"Familial isolated pituitary adenoma (FIPA), defined as the occurrence of at least two cases of pituitary adenoma in a family that does not exhibit features of syndromic diseases, such as Carney complex or Multiple Endocrine Neoplasia type 1 or 4, is a rare autosomal dominant disease with low penetrance. About 20 % of the families with FIPA harbor inactivating mutation in aryl hydrocarbon receptor-interacting protein gene (AIP) associated with loss of heterozygosity of the same genetic locus (11q13) in the tumor. Rarely different types of extra-pituitary tumors have been described in the setting of AIP mutation-positive FIPA. We present the case of a patient who was diagnosed with acromegaly due to the AIP mutation c.241C>T (p.R81X) at the age of 34 years, and treated by transsphenoidal surgery. At the age of 43 years she was diagnosed with a meningioma, and at age 46 had recurrence of the somatotropinoma. Genetic studies demonstrated loss of the normal allele (by sequencing and microsatellite analysis) in DNA from the pituitary adenoma but not from the meningioma, suggesting a selective involvement of AIP mutation in the pathogenesis of the pituitary adenoma, and a casual association with the meningioma. Further investigations are required to define the exact role of AIP in non-pituitary tumorigenesis.","variants":[{"Name":"NM_003977.4(AIP):c.241C>T (p.Arg81Ter)","Chromosome":"11","Start":"67487147","Stop":"67487147","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49589,"rule_based_match":true,"evidence_text":"c.241C>T (p.R81X)","llm_judgment":"PRESENT","evidence":"c.241C>T (p.R81X)","abstract_start":724,"abstract_end":741}]}
{"pmid":"31117334","title":"An Unusual Presentation of Carney Complex","abstract":"Carney complex (CNC) is a multiple neoplasia syndrome, characterized by pigmented lesions of the skin and mucosa, cardiac, cutaneous and other myxomas and multiple endocrine and non-endocrine tumors. Most of the cases have an inactivating mutation in the <i>PRKAR1A</i> gene. Osteochondromyxoma (OMX) is an extremely rare myxomatous tumor of bone, affecting 1% of CNC patients. Large cell calcifying Sertoli cell tumor (LCCSCT) is a testicular tumor affecting more than 75% of males with CNC. Here, we report an atypical case of CNC without typical pigmented skin lesions, presenting with a bone based tumor as the first manifestation. Initial presentation was for a recurrent, locally invasive intranasal tumor without definite diagnosis. Further clinical developments during follow up, central precocious puberty and testicular tumor with calcification, led to the diagnosis of LCCSCT, a CNC-related tumor. Histopathologic examination of the intranasal tumor was re-evaluated with this knowledge and OMX was diagnosed. Coexistence of OMX and LCCSCT suggested CNC. Genetic analysis revealed a heterozygous non-sense p.Trp 224* (c.672G>A) in the <i>PRKAR1A</i> gene. In our case, the diagnosis of OMX was delayed, because it is extremely rare and little is known about this tumor. Thus the aim of this report was to alert other clinicians to consider CNC if OMX is diagnosed.","variants":[{"Name":"NM_002734.5(PRKAR1A):c.672G>A (p.Trp224Ter)","Chromosome":"17","Start":"68525876","Stop":"68525876","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":445874,"rule_based_match":true,"evidence_text":"c.672G>A","llm_judgment":"PRESENT","evidence":"c.672G>A","abstract_start":1129,"abstract_end":1137}]}
{"pmid":"22778364","title":"Novel POLG1 mutations in a patient with adult-onset progressive external ophthalmoplegia and encephalopathy.","abstract":"Mutations in POLG1 are an important cause of human mitochondrial disease. We describe a woman who presented with bilateral ptosis and external ophthalmoplegia at 64 years of age. Neurological examination revealed symptoms of diffuse encephalopathy. The symptoms were progressive and at 67 years she was severely cognitively impaired, had severe bilateral ptosis and complete external ophthalmoplegia. Frequent cytochrome c oxidase-negative fibres were detected in muscle. Electrophysiological examination revealed myopathic changes and axonal neuropathy. Standard laboratory tests were normal. Brain CT showed general, moderate cortical atrophy. Molecular analysis of muscle DNA revealed multiple mitochondrial DNA deletions. Sequencing of the entire POLG1 gene revealed two changes c.2993C>T (p.998S>L) and c.3550G>C (p.1184D>H). Both mutations are previously unreported and confirmed to be compound heterozygous. Late-onset progressive external ophthalmoplegia with severe encephalopathy is an unusual combination in patients with POLG1 mutations. POLG-associated disease should be considered in any patient with unexplained or unusual neurological features.","variants":[{"Name":"NM_002693.3(POLG):c.2993C>T (p.Ser998Leu)","Chromosome":"15","Start":"89319339","Stop":"89319339","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":842776,"rule_based_match":true,"evidence_text":"c.2993C>T (p.998S>L)","llm_judgment":"PRESENT","evidence":"c.2993C>T (p.998S>L)","abstract_start":783,"abstract_end":803}]}
{"pmid":"22300680","title":"Identification of the mutations in the tissue-nonspecific alkaline phosphatase gene in two Chinese families with hypophosphatasia.","abstract":"BACKGROUND AND AIMS: Hypophosphatasia is a genetic disorder characterized by defective bone and tooth mineralization and a deficiency of serum and bone alkaline phosphatase activity. To date, few studies have identified gene mutations in Chinese patients with hypophosphatasia. We sought to characterize the clinical manifestations and identify the mutations associated with the disease in Chinese hypophosphatasia patients.\nMETHODS: All 12 exons and the exon-intron boundaries of the ALPL gene were amplified and directly sequenced in two probands from unrelated Chinese families. The mutation sites were identified in other unaffected members of these two families and 100 healthy controls.\nRESULTS: In family 1, the proband displayed one novel splice site mutation, c.298-1G>A, which consisted of a homozygous G>A transition at nucleotide 298-1 in intron 4. The proband's mother displayed the heterozygous G/A ALPL gene mutation, but her father was identified as G/G homozygous. A paternity test ruled out false paternity and therefore confirmed that this splicing mutation occurred de novo either in the paternal germline or in the early development of the patient. In family 2, the proband revealed a novel missense mutation (c.1271T>C) in exon 11, which resulted in p.Val424Ala in the mature ALPL polypeptide. Furthermore, c.298-1G>A and c.1271T>C mutations were not found in unaffected family members of these two Chinese families and 100 unrelated controls.\nCONCLUSIONS: Our study shows that the novel de novo splicing mutation c.298-1G>A in intron 4 and the missense mutation c.1271T>C in exon 11 of the ALPL gene are responsible for hypophosphatasia in some Chinese patients.","variants":[{"Name":"NM_000478.6(ALPL):c.1271T>C (p.Val424Ala)","Chromosome":"1","Start":"21576603","Stop":"21576603","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1477155,"rule_based_match":true,"evidence_text":"c.1271T>C (p.Val424Ala)","llm_judgment":"PRESENT","evidence":"p.Val424Ala","abstract_start":1272,"abstract_end":1283}]}
{"pmid":"18996815","title":"A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3.","abstract":"OBJECTIVE: To determine if there was a genetic contribution to our patient's unusual clinical presentation of nephrolithiasis and nonhealing stress fracture.\nMETHODS: We describe a 31-year-old man who had rickets as a child and developed a femur insufficiency fracture and recurrent nephrolithiasis as an adult after moving to the United States from India. The patient's clinical course and results from radiographic and biochemical analyses are described. Analysis of the SLC34A3 gene was performed using genomic DNA samples from the patient and his family members.\nRESULTS: Before referral to the Yale Bone Center, the patient was treated with calcitriol, ergocalciferol, and phosphate. Changing therapy to phosphate alone led to clinical improvement. Genetic analysis revealed that the patient is a compound heterozygote for mutations in the SLC34A3 gene. On 1 allele, he has a previously described missense mutation in exon 7: c.575C>T (p.Ser192Leu). The other allele carries a novel nonsense mutation in exon 3: c.145C>T (p.Gln49X). One unaffected sibling is a carrier of the missense mutation and 1 sister with a history of flank pain is a carrier of the novel mutation.\nCONCLUSIONS: Hereditary hypophosphatemic rickets with hypercalciuria is a rare metabolic disorder associated with mutations in SLC34A3, the gene that encodes the renal sodium phosphate cotransporter NaPi-IIc. Although hypercalciuria is a distinguishing feature of the disease, nephrolithiasis is rarely described. The patient's atypical clinical presentation illustrates that both environmental and genetic factors potentially affect phenotypic expression of SLC34A3 mutations.","variants":[{"Name":"NM_001177316.2(SLC34A3):c.575C>T (p.Ser192Leu)","Chromosome":"9","Start":"137233223","Stop":"137233223","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":195771,"rule_based_match":true,"evidence_text":"c.575C>T (p.Ser192Leu)","llm_judgment":"PRESENT","evidence":"c.575C>T (p.Ser192Leu)","abstract_start":931,"abstract_end":953},{"Name":"NM_001177316.2(SLC34A3):c.145C>T (p.Gln49Ter)","Chromosome":"9","Start":"137232131","Stop":"137232131","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1406254,"rule_based_match":true,"evidence_text":"c.145C>T (p.Gln49X)","llm_judgment":"PRESENT","evidence":"c.145C>T (p.Gln49X)","abstract_start":1017,"abstract_end":1036}]}
{"pmid":"23712482","title":"Multivariate analysis of MLH1 c.1664T>C (p.Leu555Pro) mismatch repair gene variant demonstrates its pathogenicity.","abstract":"Genetic testing of an Irish kindred identified an exonic nucleotide substitution c.1664T>C (p.Leu555Pro) in the MLH1 mismatch repair (MMR) gene. This previously unreported variant is classified as a \"variant of uncertain significance\" (VUS). Immunohistochemical (IHC) analysis and microsatellite instability (MSI) studies, genetic testing, a literature and online MMR mutation database review, in silico phenotype prediction tools, and an in vitro MMR activity assay were used to study the clinical significance of this variant. The MLH1 c.1664T>C (p.Leu555Pro) VUS co-segregated with three cases of classic Lynch syndrome-associated malignancies over two generations, with consistent loss of MLH1 and PMS2 protein expression on IHC, and evidence of the MSI-High mutator phenotype. The leucine at position 555 is well conserved across a number of species, and this novel variant has not been reported as a normal polymorphism in the general population. In silico and in vitro analyses suggest that this variant may have a deleterious effect on the MLH1 protein and abrogate MMR activity. Evidence from clinical, histological, immunohistochemical, and molecular genetic data suggests that MLH1 c.1664T>C (p.Leu555Pro) is likely to be the pathogenic cause of Lynch syndrome in this family.","variants":[{"Name":"NM_000249.4(MLH1):c.1664T>C (p.Leu555Pro)","Chromosome":"3","Start":"37040291","Stop":"37040291","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":95296,"rule_based_match":true,"evidence_text":"c.1664T>C (p.Leu555Pro)","llm_judgment":"PRESENT","evidence":"c.1664T>C (p.Leu555Pro)","abstract_start":81,"abstract_end":104}]}
{"pmid":"23856421","title":"Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy.","abstract":"Congenital disorders of glycosylation (CDG) are rare genetic defects mainly in the post-translational modification of proteins via attachment of carbohydrate chains. We describe an infant with the phenotype of a congenital muscular dystrophy, with borderline microcephaly, hypotonia, camptodactyly, severe motor delay, and elevated creatine kinase. Muscle biopsy showed muscular dystrophy and reduced α-dystroglycan immunostaining with glycoepitope-specific antibodies in a pattern diagnostic of dystroglycanopathy. Carbohydrate deficient transferrin testing showed a pattern pointing to a CDG type I. Sanger sequencing of DPM1 (dolichol-P-mannose synthase subunit 1) revealed a novel Gly > Val change c.455G > T missense mutation resulting in p.Gly152Val) of unknown pathogenicity and deletion/duplication analysis revealed an intragenic deletion from exons 3 to 7 on the other allele. DPM1 activity in fibroblasts was reduced by 80%, while affinity for the substrate was not depressed, suggesting a decrease in the amount of active enzyme. Transfected cells expressing tagged versions of wild type and the p.Gly152Val mutant displayed reduced binding to DPM3, an essential, non-catalytic subunit of the DPM complex, suggesting a mechanism for pathogenicity. The present case is the first individual described with DPM1-CDG (CDG-Ie) to also have clinical and muscle biopsy findings consistent with dystroglycanopathy.","variants":[{"Name":"NM_003859.3(DPM1):c.455G>T (p.Gly152Val)","Chromosome":"20","Start":"50942070","Stop":"50942070","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":106508,"rule_based_match":true,"evidence_text":"c.455G > T missense mutation resulting in p.Gly152Val","llm_judgment":"PRESENT","evidence":"c.455G > T missense mutation resulting in p.Gly152Val","abstract_start":702,"abstract_end":755}]}
{"pmid":"27281386","title":"Recessive Retinopathy Consequent on Mutant G-Protein β Subunit 3 (GNB3).","abstract":"IMPORTANCE: Mutations in phototransduction and retinal signaling genes are implicated in many retinopathies. To our knowledge, GNB3 encoding the G-protein β subunit 3 (Gβ3) has not previously been implicated in human disease.\nOBSERVATIONS: In this brief report, whole-exome sequencing was conducted on a patient with distinct inherited retinal disease presenting in childhood, with a phenotype characterized by nystagmus, normal retinal examination, and mild disturbance of the central macula on detailed retinal imaging. This sequencing revealed a homozygous GNB3 nonsense mutation (c.124C>T; p.Arg42Ter). Whole-exome sequencing was conducted from April 2015 to July 2015.\nCONCLUSIONS AND RELEVANCE: Expressed in cone photoreceptors and ON-bipolar cells, Gβ3 is essential in phototransduction and ON-bipolar cell signaling. Knockout of Gnb3 in mice results in dysfunction of cone photoreceptors and ON-bipolar cells and a naturally occurring chicken mutation leads to retinal degeneration. Identification of further affected patients may allow description of the phenotypic and genotypic spectrum of disease associated with GNB3 retinopathy.","variants":[{"Name":"NM_002075.4(GNB3):c.124C>T (p.Arg42Ter)","Chromosome":"12","Start":"6842997","Stop":"6842997","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2898811,"rule_based_match":true,"evidence_text":"c.124C>T; p.Arg42Ter","llm_judgment":"PRESENT","evidence":"c.124C>T; p.Arg42Ter","abstract_start":584,"abstract_end":604}]}
{"pmid":"26806154","title":"Mutated MCM9 is associated with predisposition to hereditary mixed polyposis and colorectal cancer in addition to primary ovarian failure.","abstract":"Mutations in MCM9, which encodes DNA helicase, were recently shown to cause a clinical phenotype of primary ovarian failure and chromosomal instability. MCM9 plays an essential role in homologous recombination-mediated double-strand break repair. We describe a multiplex family with early colorectal carcinoma and mixed polyposis associated with primary hypergonadotropic hypogonadism. A combination of whole genome homozygosity mapping as well as exome sequencing and targeted gene sequencing identified a homozygous c.672_673delGGinsC mutation that predicts a truncated protein, p.Glu225Lysfs*4. Our data expand the phenotypic spectrum of MCM9 mutations and suggest a link between MCM9 and inherited predisposition to mixed polyposis and early-onset colorectal cancer.","variants":[{"Name":"NM_017696.3(MCM9):c.672_673delinsC (p.Glu225fs)","Chromosome":"6","Start":"118922035","Stop":"118922036","ReferenceAlleleVCF":"CC","AlternateAlleleVCF":"G","allel_id":3413587,"rule_based_match":false,"evidence_text":"c.672_673delGGinsC","llm_judgment":"PRESENT","evidence":"c.672_673delGGinsC","abstract_start":518,"abstract_end":536}]}
{"pmid":"30564628","title":"Optical coherence tomography features in brothers with aspartylglucosaminuria.","abstract":"Aspartylglucosaminuria is a lysosomal storage disorder enriched in Finland. We report on a pair of non-Finnish siblings with aspartylglucosaminuria with autofluorescent inclusion bodies on optical coherence tomography, a finding not previously reported in this disorder. We performed a record review, neurological and neuropsychological evaluation, brain MRI, and optical coherence tomography for each patient. They are compound heterozygous for a 34-kb deletion and a c.365C>A novel variant of the <i>AGA</i> gene. Autofluorescent inclusion bodies were found on optical coherence tomography in the older, more severely affected brother. We hypothesize the finding represents a noninvasive biomarker of disease severity for aspartylglucosaminuria.","variants":[{"Name":"NM_000027.4(AGA):c.365C>A (p.Thr122Lys)","Chromosome":"4","Start":"177439605","Stop":"177439605","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":543390,"rule_based_match":true,"evidence_text":"c.365C>A","llm_judgment":"PRESENT","evidence":"c.365C>A","abstract_start":469,"abstract_end":477}]}
{"pmid":"25634536","title":"High myopia-excavated optic disc anomaly associated with a frameshift mutation in the MYC-binding protein 2 gene (MYCBP2).","abstract":"PURPOSE: To investigate the ocular and neurologic manifestations, and to identify the causative mutation in a family with an excavated optic disc anomaly, high myopia, enlarged axial lengths, and abnormal visual evoked response (VER).\nDESIGN: Prospective observational case series with whole exome sequencing.\nMETHODS: Institutional study of 8 family members from 3 generations. Clinical examination included visual field examination, optical coherence tomography, axial length measurement, audiometry, visual evoked response (VER), orbital and cerebral magnetic resonance imaging (MRI), and renal ultrasound. DNA was analyzed by whole exome sequencing and Sanger sequencing. Main outcome measures were clinical and radiological findings, and DNA sequence data.\nRESULTS: Three affected family members, a father and his 2 daughters, were examined. The parents and siblings of the father were healthy. Affected individuals presented with excavated optic discs, high myopia (-1.00 to -16.00 diopters), and increased axial lengths. Reduced visual acuity (0.05-0.8) and decreased sensitivity on visual field examination were observed. VER revealed prolonged latency times. Affected eyes appeared ovoid on MRI and the father had thin optic nerves. Exome sequencing revealed that the father was heterozygous for a de novo 5 bp deletion in MYCBP2, c.5906_5910del; p.Glu1969Valfs*26. The same mutation was found in his 2 affected daughters, but not in his parents or siblings, or in public databases.\nCONCLUSION: We describe a distinct excavated optic disc anomaly associated with high myopia and increased axial length. The condition appears to follow an autosomal dominant pattern and segregate with a deletion in MYCBP2. We suggest naming this entity high myopia-excavated optic disc anomaly.","variants":[{"Name":"NM_015057.5(MYCBP2):c.5906_5910del (p.Glu1969fs)","Chromosome":"13","Start":"77168632","Stop":"77168636","ReferenceAlleleVCF":"AGACTT","AlternateAlleleVCF":"A","allel_id":513886,"rule_based_match":true,"evidence_text":"c.5906_5910del; p.Glu1969Valfs*26","llm_judgment":"PRESENT","evidence":"c.5906_5910del; p.Glu1969Valfs*26","abstract_start":1340,"abstract_end":1373}]}
{"pmid":"20806042","title":"A novel mutation in GJA8 causing congenital cataract-microcornea syndrome in a Chinese pedigree.","abstract":"PURPOSE: To identify the underlying genetic defect in a four-generation family of Chinese origin with autosomal dominant congenital cataract-microcornea syndrome (CCMC).\nMETHODS: All individuals in the study underwent a full clinical examination and the details of history were collected . Genomic DNA extracted from peripheral blood was amplified by polymerase chain reaction (PCR) method and the exons of all candidate genes were sequenced.\nRESULTS: Direct sequencing of the encoding regions of the candidate genes revealed a heterozygous mutation c.592C-->T in exon 2 of the gap junction protein, alpha 8 (GJA8) gene. This mutation was responsible for the familial disorder through the substitution of a highly conserved arginine to tryptophan at codon 198 (p.R198W). This change co-segregated with all affected members of the family, but was not detected either in the non-carrier relatives or in the 100 normal controls.\nCONCLUSIONS: This report is the first to relate p.R198W mutation in GJA8 with CCMC. The result expands the mutation spectrum of GJA8 in associated with congenital cataract and microcornea, and implies that this gene has direct involvement with the development of the lens as well as the other anterior segment of the eye.","variants":[{"Name":"NM_005267.5(GJA8):c.592C>T (p.Arg198Trp)","Chromosome":"1","Start":"147908547","Stop":"147908547","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2748597,"rule_based_match":false,"evidence_text":"c.592C-->T","llm_judgment":"PRESENT","evidence":"c.592C-->T","abstract_start":550,"abstract_end":560}]}
{"pmid":"33634872","title":"New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.","abstract":"Carnitine acyl-carnitine translocase deficiency (CACTD) is a rare autosomal recessive disorder of mitochondrial long-chain fatty-acid transport. Most patients present in the first 2 days of life, with hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy or arrhythmia, hepatomegaly and elevated liver enzymes. Multi-centre international retrospective chart review of clinical presentation, biochemistry, treatment modalities including diet, subsequent complications, and mode of death of all patients. Twenty-three patients from nine tertiary metabolic units were identified. Seven attenuated patients of Pakistani heritage, six of these homozygous c.82G>T, had later onset manifestations and long-term survival without chronic hyperammonemia. Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15). Where recorded, ammonia levels were elevated in all but one severe case (13/14 measured) and 14/16 had hypoglycaemia. Nine classical patients survived longer-term-most with feeding difficulties and cognitive delay. Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises. High-energy intake seems necessary to prevent decompensation. Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases. CACTD is a rare disorder of fatty acid oxidation with a preponderance to severe cardiac dysfunction. Long-term survival is possible in classical early-onset cases with long-chain fat restriction, judicious use of glucose infusions, and medium chain triglyceride supplementation. Adjunctive therapies supporting anaplerosis may improve longer-term outcomes.","variants":[{"Name":"NM_000387.6(SLC25A20):c.82G>T (p.Gly28Cys)","Chromosome":"3","Start":"48898713","Stop":"48898713","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1293021,"rule_based_match":true,"evidence_text":"c.82G>T","llm_judgment":"PRESENT","evidence":"c.82G>T","abstract_start":655,"abstract_end":662}]}
{"pmid":"12384776","title":"Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene.","abstract":"Argininosuccinic aciduria is an urea cycle disorder caused by argininosuccinate lyase (ASL) deficiency and is inherited as an autosomal-recessive trait. To date, mutation analysis has been limited because of incomplete sequence information about the human ASL gene. As a consequence, only 12 different mutations in 12 patients have been reported, so far. This study aimed at the completion of the structure and the sequence of the human ASL gene, the development of a genomic DNA-based system for mutation analysis and, finally, the characterisation of the molecular genetic background of ASL deficiency in 27 unrelated patients. This report provides transcript variants, the complete sequence of the human ASL gene and a complete ASL homologue on chromosome 22. The homologue was formerly thought to be a pseudogene but was found, in this study, to be correlated with an immunoglobulin-lambda-like mRNA. On the basis of the novel sequence data, a polymerase reaction chain system for mutation-screening in all 16 coding exons of the ASL gene was established and applied to the analysis of the ASL-deficient patients. We found mutations in all of the 54 investigated alleles and identified 23 (19 novel) different mutations. Some mutational hot-spots were identified (mainly in exons 4, 5, and 7) as were several predominant mutations: IVS5+1G-->A (15 alleles), c.532G-->A (7), c.346C-->T (6), c.1153C-->T (4). This study introduces a system for mutation analysis in the ASL gene, thereby elucidating the genetic background of ASL deficiency, which was found to be associated with considerable allelic heterogeneity.","variants":[{"Name":"NM_000048.4(ASL):c.1153C>T (p.Arg385Cys)","Chromosome":"7","Start":"66092566","Stop":"66092566","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17440,"rule_based_match":false,"evidence_text":"c.1153C-->T","llm_judgment":"PRESENT","evidence":"c.1153C-->T","abstract_start":1394,"abstract_end":1405},{"Name":"NM_000048.4(ASL):c.532G>A (p.Val178Met)","Chromosome":"7","Start":"66086751","Stop":"66086751","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17441,"rule_based_match":false,"evidence_text":"c.532G-->A","llm_judgment":"PRESENT","evidence":"c.532G-->A","abstract_start":1362,"abstract_end":1372}]}
{"pmid":"25804400","title":"SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract.","abstract":"Congenital cataract (CC) is one of the most important causes for blindness or visual impairment in infancy. A substantial proportion of isolated CCs has monogenic causes. The disease is genetically heterogeneous, and all Mendelian modes of inheritance have been reported. We mapped a locus for isolated CC on 19p13.1-q13.2 in a distantly consanguineous German family with two sisters affected by dense white cataracts. Whole-exome sequencing identified a homozygous nonsense variant c.4489C>T (p.(R1497*)) in SIPA1L3 (signal-induced proliferation-associated 1 like 3) in both affected children. SIPA1L3 encodes a GTPase-activating protein (GAP), which interacts with small GTPases of the Rap family via its Rap-GAP-domain. The suggested role of Rap GTPases in cell growth, differentiation and organization of the cytoskeleton in the human lens, and lens-enriched expression of the murine ortholog gene Sipa1l3 in embryonic mice indicates that this gene is crucial for early lens development. Our results provide evidence that sequence variants in human SIPA1L3 cause autosomal recessive isolated CC and give new insight into the molecular pathogenesis underlying human cataracts.","variants":[{"Name":"NM_015073.3(SIPA1L3):c.4489C>T (p.Arg1497Ter)","Chromosome":"19","Start":"38192203","Stop":"38192203","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":224974,"rule_based_match":true,"evidence_text":"c.4489C>T (p.(R1497*))","llm_judgment":"PRESENT","evidence":"c.4489C>T (p.(R1497*))","abstract_start":483,"abstract_end":505}]}
{"pmid":"27389523","title":"Expanding the Phenotype of TRNT1-Related Immunodeficiency to Include Childhood Cataract and Inner Retinal Dysfunction.","abstract":"IMPORTANCE: A multiorgan syndromic disorder characterized by sideroblastic anemia, immunodeficiency, periodic fever, and developmental delay with an uncharacterized retinal dystrophy is caused by TRNT1. This report of a family with a homozygous mutation in TRNT1 expands the ocular phenotype to include cataract and inner retinal dysfunction and details a mild systemic phenotype.\nOBSERVATIONS: A consanguineous family with 3 affected children was investigated. Key clinical features comprised hypogammaglobulinemia, short stature with microcephaly, cataract, and inner retinal dysfunction without sideroblastic anemia or developmental delay. Two siblings had poor balance and 1 sibling had sensorineural hearing loss. The oldest sibling had primary ovarian failure diagnosed at age 14.5 years. Exome sequencing identified a homozygous missense variant in TRNT1, c.295C>T (p.Arg99Trp) in all 3 patients. The sibling with hearing loss also harbored a homozygous mutation in GJB2, c.71G>A (p.Trp24*), which is an established cause of sensorineural hearing loss.\nCONCLUSIONS AND RELEVANCE: This family expands the ocular and systemic phenotypes associated with mutations in TRNT1, demonstrating phenotypic variability and highlighting the need for ophthalmic review of these patients.","variants":[{"Name":"NM_182916.3(TRNT1):c.295C>T (p.Arg99Trp)","Chromosome":"3","Start":"3137406","Stop":"3137406","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":631150,"rule_based_match":true,"evidence_text":"c.295C>T (p.Arg99Trp)","llm_judgment":"PRESENT","evidence":"c.295C>T (p.Arg99Trp)","abstract_start":863,"abstract_end":884}]}
{"pmid":"21820099","title":"Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.","abstract":"Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPα). These mutations-causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively-are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPα in neuronal cells. The resulting depletion of functional CSPα might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPα in humans and demonstrates the need for detailed investigation of CSPα in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation.","variants":[{"Name":"NM_025219.3(DNAJC5):c.344T>G (p.Leu115Arg)","Chromosome":"20","Start":"63930873","Stop":"63930873","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":39851,"rule_based_match":true,"evidence_text":"c.344T>G","llm_judgment":"PRESENT","evidence":"c.344T>G","abstract_start":602,"abstract_end":610}]}
{"pmid":"17052965","title":"Mild variable Noonan syndrome in a family with a novel PTPN11 mutation.","abstract":"Noonan syndrome (OMIM 163950) is a common genetic condition with variable clinical expression and genetic heterogeneity. About half of the cases can be accounted to activating mutations in the PTPN11 gene encoding SHP-2. We report on a family with mild, variable expression of Noonan syndrome in five individuals. Clinical manifestations included short stature, craniofacial anomalies and thorax deformity, but none of the affected family members had a heart defect. Sequencing of the entire coding region of PTPN11 revealed a novel mutation c.1226G-->C in exon 11 predicting the amino acid exchange G409A. This mutation is not located in the previously known mutation clusters. Our observation and the recent report of a mutation affecting a neighbouring residue (T411M) in a family with a variable phenotype suggest that mutations in this particular region of SHP-2 may have effects on the protein that differ from those of the classical mutations.","variants":[{"Name":"NM_002834.5(PTPN11):c.1226G>C (p.Gly409Ala)","Chromosome":"12","Start":"112486476","Stop":"112486476","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":53763,"rule_based_match":false,"evidence_text":"c.1226G-->C","llm_judgment":"PRESENT","evidence":"c.1226G-->C","abstract_start":542,"abstract_end":553}]}
{"pmid":"26864382","title":"Identification of a founder BRCA1 mutation in the Moroccan population.","abstract":"Breast cancer (BC) is the most frequent cancer among women in Morocco. However, the role of the most prevalent BC-predisposing genes, BRCA1 and BRCA2, has been largely unexplored. To help define the role of BRCA1 in BC in Morocco, we characterized the first potential BRCA1 founder mutation in this population. Genetic testing of BRCA1 and BRCA2 in BC high-risk families identified mutation BRCA1 c.5309G>T, p.(Gly1770Val) or G1770V in five independent families from Morocco, suggesting a founder effect. To confirm this hypothesis, haplotype construction was performed using seven intragenic and flanking BRCA1 microsatellite markers. Clinical data were also compiled. Clinical data from carriers of mutation G1770V correspond to data from carriers of BRCA1 pathogenic mutations. Microsatellite analysis showed a common haplotype for the five families in a region comprising 1.54 Mb, confirming G1770V as the first specific founder BRCA1 mutation in the Moroccan population. Our findings contribute to a better understanding of BC genetics in the Moroccan population. Nevertheless, comprehensive studies of mutation G1770V in large series of BC patients from Morocco are needed to assess the real prevalence of this mutation and to improve genetic testing and risk assessment in this population.","variants":[{"Name":"NM_007294.4(BRCA1):c.5309G>T (p.Gly1770Val)","Chromosome":"17","Start":"43051086","Stop":"43051086","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":404710,"rule_based_match":true,"evidence_text":"BRCA1 c.5309G>T, p.(Gly1770Val)","llm_judgment":"PRESENT","evidence":"BRCA1 c.5309G>T, p.(Gly1770Val)","abstract_start":391,"abstract_end":422}]}
{"pmid":"32767280","title":"Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients.","abstract":"BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive genetic disease due to mutations in the AIRE (AutoImmune REgulator) gene. The clinical diagnosis is classically based on the presence of at least two of the three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Patients often suffer from other endocrine or non-endocrine autoimmune conditions throughout life. APECED etiopathogenesis is mediated by T lymphocytes. Autoantibodies against proteins of the affected organs are found in the serum of APECED patients as well as neutralizing antibodies against cytokines. We report here the clinical and genetic characteristics of 45 Indian APECED patients in comparison to Finnish, Sardinian, Turkish and North/South American cohorts from their published results. We also report a new case of APECED of Indian origin, a 2-year old child suffering from chronic mucocutaneous candidiasis since the age of 8 months, with confirmatory AIRE homozygous mutation c.274C > T (p.R92W).\nCONCLUSION: With the inherent limitations of a retrospective study, analysis of Indian APECED patients suggested that compared to classic criteria, application of Ferre/Lionakis criteria validated in North/South American patients could help in earlier diagnosis in 3 of 8 (37.5%) patients for whom adequate information for evaluation was available.","variants":[{"Name":"NM_000383.4(AIRE):c.274C>T (p.Arg92Trp)","Chromosome":"21","Start":"44286698","Stop":"44286698","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":378471,"rule_based_match":true,"evidence_text":"c.274C > T (p.R92W)","llm_judgment":"PRESENT","evidence":"c.274C > T (p.R92W)","abstract_start":1124,"abstract_end":1143}]}
{"pmid":"31519519","title":"Founder effect of Fabry disease due to p.F113L mutation: Clinical profile of a late-onset phenotype.","abstract":"BACKGROUND: Knowledge on clinical profiles of late-onset phenotypes of Fabry disease (FD) is essential to better define their natural history. Our study aims to demonstrate a founder effect of FD due to the GLA gene mutation c.337T>C (p.F113L) in the Portuguese region of Guimarães; and to characterize the clinical profile of this late-onset phenotype in a large cohort of genetically related adult patients, living in the same region.\nMETHODS AND RESULTS: FD screening was performed in 150 adult patients with hypertrophic cardiomyopathy (HCM) and found 25 Fabry patients (16.6%). The p.F113L mutation was found in 21 of them, leading to a genealogy study and haplotype analysis of the p.F113L patients. Genealogy research revealed a 12-generation family tree with a common ancestor to p.F113L patients, suggesting a founder effect that was supported by haplotype findings. Pedigree analysis was performed and 120 consecutive p.F113L patients underwent a predefined diagnostic evaluation of FD multiorgan involvement. This late-onset phenotype was characterized by common and/or potentially severe cardiac manifestations (left ventricular hypertrophy 40.8%, atrial fibrillation 5%, non-sustained ventricular tachycardia 12.5%, atrioventricular block 18.3%, bifascicular block 13.4%). Extracardiac manifestations included albuminuria>30 mg/24 h 36.1%, chronic kidney disease≥G3 7.6%, brain white matter lesions 54.4%, stroke 3.3%, sensorineural deafness 44.5%, cornea verticillata 13.9%. Plasma lyso-GB3 was undetectable in females, regardless of clinical manifestations.\nCONCLUSION: A founder effect of FD due to p.F113L mutation was documented by genealogy and genetics in a Portuguese region. In this late-onset phenotype, although cardiac manifestations carry the highest prognostic impact, extracardiac involvement is common.","variants":[{"Name":"NM_000169.3(GLA):c.337T>C (p.Phe113Leu)","Chromosome":"X","Start":"101403843","Stop":"101403843","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":224087,"rule_based_match":true,"evidence_text":"c.337T>C (p.F113L)","llm_judgment":"PRESENT","evidence":"c.337T>C (p.F113L)","abstract_start":225,"abstract_end":243}]}
{"pmid":"32105826","title":"Insights into the molecular pathogenesis of cardiospondylocarpofacial syndrome: MAP3K7 c.737-7A > G variant alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy.","abstract":"Transforming growth factor beta-activated kinase 1 (TAK1) is a highly conserved kinase protein encoded by MAP3K7, and activated by multiple extracellular stimuli, growth factors and cytokines. Heterozygous variants in MAP3K7 cause the cardiospondylocarpofacial syndrome (CSCFS) which is characterized by short stature, dysmorphic facial features, cardiac septal defects with valve dysplasia, and skeletal anomalies. CSCFS has been described in seven patients to date and its molecular pathogenesis is only partially understood. Here, the functional effects of the MAP3K7 c.737-7A > G variant, previously identified in a girl with CSCFS and additional soft connective tissue features, were explored. This splice variant generates an in-frame insertion of 2 amino acid residues in the kinase domain of TAK1. Computational analysis revealed that this in-frame insertion alters protein dynamics in the kinase activation loop responsible for TAK1 autophosphorylation after binding with its interactor TAB1. Co-immunoprecipitation studies demonstrate that the ectopic expression of TAK1-mutated protein impairs its ability to physically bind TAB1. In patient's fibroblasts, MAP3K7 c.737-7A > G variant results in reduced TAK1 autophosphorylation and dysregulation of the downstream TAK1-dependent signaling pathway. TAK1 loss-of-function is associated with an impaired TGFβ-mediated α-SMA cytoskeleton assembly and cell migration, and defective autophagy process. These findings contribute to our understanding of the molecular pathogenesis of CSCFS and might offer the rationale for the design of novel therapeutic targets.","variants":[{"Name":"NM_145331.3(MAP3K7):c.737-7A>G","Chromosome":"6","Start":"90552186","Stop":"90552186","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":963206,"rule_based_match":true,"evidence_text":"MAP3K7 c.737-7A > G","llm_judgment":"PRESENT","evidence":"MAP3K7 c.737-7A > G","abstract_start":564,"abstract_end":583}]}
{"pmid":"29436111","title":"A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis.","abstract":"Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.","variants":[{"Name":"NM_032208.3(ANTXR1):c.1312C>T (p.Arg438Cys)","Chromosome":"2","Start":"69182619","Stop":"69182619","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2200905,"rule_based_match":true,"evidence_text":"c.1312C>T","llm_judgment":"PRESENT","evidence":"c.1312C>T","abstract_start":566,"abstract_end":575}]}
{"pmid":"38433265","title":"Heterozygous THBS2 pathogenic variant causes Ehlers-Danlos syndrome with prominent vascular features in humans and mice.","abstract":"Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2<sup>Cys896Arg</sup> KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.","variants":[{"Name":"NM_003247.5(THBS2):c.2686T>C (p.Cys896Arg)","Chromosome":"6","Start":"169225232","Stop":"169225232","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3222252,"rule_based_match":true,"evidence_text":"NM_003247.5:c.2686T>C, p.Cys896Arg","llm_judgment":"PRESENT","evidence":"NM_003247.5:c.2686T>C, p.Cys896Arg","abstract_start":905,"abstract_end":939}]}
{"pmid":"28634279","title":"In-frame seven amino-acid duplication in","abstract":"OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (<i>AIP</i>) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events.\nDESIGN AND METHODS: Observational, inferential and experimental study, including: <i>AIP</i> mutation testing; reconstruction of 14 <i>AIP</i>-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments.\nRESULTS: Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around <i>AIP</i> with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the 'English founder', with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9-113 generations, equivalent to 225-2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability.\nCONCLUSIONS: The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein-protein interactions and AIP protein stability.","variants":[{"Name":"NM_003977.4(AIP):c.805_825dup (p.Phe269_His275dup)","Chromosome":"11","Start":"67490802","Stop":"67490803","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TACTTCAAGCGGGGCAAGGCCC","allel_id":49630,"rule_based_match":true,"evidence_text":"c.805_825dup","llm_judgment":"PRESENT","evidence":"c.805_825dup","abstract_start":819,"abstract_end":831}]}
{"pmid":"25079578","title":"Severe 5,10-methylenetetrahydrofolate reductase deficiency and two MTHFR variants in an adolescent with progressive myoclonic epilepsy.","abstract":"BACKGROUND: 5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is an inborn error of the folate-recycling pathway that affects the remethylation of homocysteine to methionine. The clinical presentation of MTHFR deficiency is highly variable ranging from early neurological deterioration and death in infancy to a mild thrombophilia in adults.\nPATIENT AND METHODS: We describe an adolescent girl with a history of mild learning disabilities who presented at age 14 years with an epilepsy syndrome initially thought to be juvenile myoclonic epilepsy. She later developed intractable epilepsy with myoclonus, leg weakness, cognitive decline, and ataxia consistent with the syndrome of progressive myoclonic epilepsy. This prompted further evaluation that revealed elevated plasma homocysteine and decreased plasma methionine. The diagnosis of MTHFR deficiency was confirmed based on extremely reduced fibroblast MTHFR activity (0.3 nmol CHO/mg prot/hr) as well as mutation analysis that revealed two variants in the MTHFR gene, a splice site mutation p (IVS5-1G>A), as well as a missense mutation (c.155 G>A; p. Arg52Gln). Therapy with folinic acid, betaine, and methionine has produced significant clinical improvement, including improved strength, less severe ataxia, and decreased seizure frequency, as well as improvements in her electroencephalography and electromyography.\nCONCLUSION: This patient demonstrates the importance of considering MTHFR deficiency in the differential diagnosis of progressive myoclonic epilepsy because it is one of the few causes for which specific treatment is available.","variants":[{"Name":"NM_005957.5(MTHFR):c.155G>A (p.Arg52Gln)","Chromosome":"1","Start":"11802962","Stop":"11802962","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":556564,"rule_based_match":true,"evidence_text":"c.155 G>A; p. Arg52Gln","llm_judgment":"PRESENT","evidence":"c.155 G>A; p. Arg52Gln","abstract_start":1104,"abstract_end":1126}]}
{"pmid":"16332247","title":"Clinical, genetic, and biochemical findings in two siblings with Papillon-Lefèvre Syndrome.","abstract":"BACKGROUND: Papillon-Lefèvre Syndrome (PLS) is an autosomal recessive disease characterized by palmoplantar hyperkeratosis and severe periodontitis affecting both primary and secondary dentitions. Cathepsin C (CTSC) gene mutations are etiologic for PLS. The resultant loss of CTSC function is responsible for the severe periodontal destruction seen clinically.\nMETHODS: A 4-year-old female (case 1) and her 10-year-old sister (case 2) presented with palmoplantar skin lesions, tooth mobility, and advanced periodontitis. Based on clinical findings, the cases were diagnosed with PLS. Mutational screening of the CTSC gene was conducted for the cases, and their clinically unaffected parents and brother. Biochemical analysis was performed for CTSC, cathepsin G (CTSG), and elastase activity in neutrophils for all members of the nuclear family. The initial treatment included oral hygiene instruction, scaling and root planing, and systemic amoxicillin-metronidazole therapy.\nRESULTS: CTSC mutational screening identified a c.415G>A transition mutation. In the homozygous state, this mutation was associated with an almost complete loss of activity of CTSC, CTSG, and elastase. Although monthly visits, including scaling, polishing, and 0.2% chlorhexidine digluconate irrigation were performed to stabilize the periodontal condition, case 1 lost all her primary teeth. In case 2, some of the permanent teeth could be maintained.\nCONCLUSIONS: This report describes two siblings with a cathepsin C gene mutation that is associated with the inactivity of cathepsin C and several neutrophil serine proteases. The failure of patients to respond to periodontal treatment is discussed in the context of these biological findings.","variants":[{"Name":"NM_001814.6(CTSC):c.415G>A (p.Gly139Arg)","Chromosome":"11","Start":"88312458","Stop":"88312458","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3086373,"rule_based_match":true,"evidence_text":"c.415G>A","llm_judgment":"PRESENT","evidence":"c.415G>A","abstract_start":1024,"abstract_end":1032}]}
{"pmid":"28185117","title":"A lesson from a reported pathogenic variant in Peutz-Jeghers syndrome: a case report.","abstract":"Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous hyperpigmentation, gastrointestinal (GI) hamartmatous polyps, and an increased risk of various malignancies. Pathogenic variants in the LKB1 tumor suppressor gene (also known as STK11) are the major cause of PJS. In this study, compound heterozygous variants of LKB1, c.890G > A/ c.1062C > G and del(exon1)/ c.1062C > G, were identified in two sporadic Chinese PJS cases respectively. Although all these three variants had been related to the autosomal dominant PJS in previous studies, all evidences collected in this study including de novo data, segregation data, population data, in-silico data, and functional data indicated that del(exon1) and c.890G > A are pathogenic in these two PJS families rather than c.1062C > G. This finding would contribute to genetic counseling for individuals carrying the variant c.1062C > G with or without PJS phenotypes. Moreover, this finding reminds genetic counselors that it is necessary to reevaluate the pathogenicity of reported variants in a known Mendelian disorder in order to avoid a misleading decision.","variants":[{"Name":"NM_000455.5(STK11):c.890G>A (p.Arg297Lys)","Chromosome":"19","Start":"1221976","Stop":"1221976","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":618991,"rule_based_match":true,"evidence_text":"c.890G > A","llm_judgment":"PRESENT","evidence":"c.890G > A","abstract_start":366,"abstract_end":376}]}
{"pmid":"25985877","title":"Genetic testing of leiomyoma tissue in women younger than 30 years old might provide an effective screening approach for the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC).","abstract":"We have studied the viability of targeted molecular screening for the identification of female patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Affected patients harbor a germ-line heterozygous mutation of the fumarate hydratase (FH) gene. Clinically, some patients present with aggressive renal cell carcinoma. Concerning women, in almost all cases, this is preceded by symptomatic uterine leiomyoma. We aimed to identify women operated on for symptomatic leiomyoma by the age of 30. Archived paraffin-embedded leiomyoma tissue was tested for the FH gene mutation in 14 cases. Two patients with multiple leiomyomas and with the confirmed germ-line mutations c.1433_1434dupAAA, p.(Lys477dup) and c.953A>T, p.(His318Leu) were identified and enrolled in a surveillance program. Statistically significant correlation between the presence of multiple uterine leiomyomas (more than seven in our experience) and the FH gene mutation was found. The immunohistochemical expression pattern, of simultaneous FH absence and S-(2-succino)cysteine (2SC) positivity, correlated with the results of the molecular genetic study in only one case. The histomorphologically simultaneous detection of enlarged nucleoli with a clear halo of leiomyocyte nuclei, their fibrillary cytoplasm, the presence of eosinophilic globules, and staghorn vessels proved to be only a partially sensitive indicator of HLRCC-associated leiomyoma and fully correlated with immunohistochemistry and molecular genetic study only in one case. Molecular genetic testing is presently the only reliable diagnostic tool able to identify HLRCC patients. The sensitivity and specificity of the presence of multiple leiomyomas in women with the FH gene mutation who are younger than 30 years old should be confirmed in larger scale studies. The applied targeted molecular screening protocol proved to be effective, resulting in identification of two positive patients out of fourteen tested individuals.","variants":[{"Name":"NM_000143.4(FH):c.1431_1433dup (p.Lys477dup)","Chromosome":"1","Start":"241497927","Stop":"241497928","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ATTT","allel_id":51261,"rule_based_match":false,"evidence_text":"c.1433_1434dupAAA, p.(Lys477dup)","llm_judgment":"PRESENT","evidence":"c.1433_1434dupAAA, p.(Lys477dup)","abstract_start":690,"abstract_end":722},{"Name":"NM_000143.4(FH):c.953A>T (p.His318Leu)","Chromosome":"1","Start":"241504197","Stop":"241504197","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1054823,"rule_based_match":true,"evidence_text":"c.953A>T, p.(His318Leu)","llm_judgment":"PRESENT","evidence":"c.953A>T, p.(His318Leu)","abstract_start":727,"abstract_end":750}]}
{"pmid":"25249269","title":"Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature.","abstract":"BACKGROUND: Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) and Hyperphosphatemic Hyperostosis Syndrome (HHS) are associated with autosomal recessive mutations in three different genes, FGF23, GALNT3 and KL, leading to reduced levels of fibroblast growth factor 23 (FGF23) and subsequent clinical effects.\nRESULTS: We describe a consanguineous family with two affected siblings with HFTC and HHS caused by a novel homozygous G-to T substitution in exon 3 of GALNT3 (c.767 G > T; p.Gly256Val), demonstrating great phenotypic variation and long asymptomatic intervals. Calcific tumors appeared at 14 years of age in the male, and the female displayed episodic diaphysitis from age 9 years. Symptoms of eye involvement were present in both from childhood, and progressed into band keratopathy in the female. Abnormal dental roots and tooth loss, as well as myalgia were present in both from their mid-twenties, while the female also had calcifications in the placenta, the iliac vessels and thyroid cartilage. New calcific tumors appeared more than 20 years after the initial episodes, delaying diagnosis and treatment until the ages of 37 and 50 years, respectively. Both siblings had elevated serum phosphate levels, inappropriately elevated tubular maximum phosphate reabsorption per unit glomerular filtration rate (TmP/GFR), reduced levels of intact FGF23 and increased levels of c-terminal FGF23. Review of all 54 previously published cases of GALNT3, FGF23, and KL associated HFTC and HHS demonstrated that more subjects than previously recognized have a combined phenotype.\nCONCLUSION: We have described HFTC and HHS in a consanguineous Caucasian family with a novel GALNT3 mutation, demonstrating new phenotypic features and significant variability in the natural course of the disease. A review of the literature, show that more subjects than previously recognized have a combined phenotype of HFTC and HHS. HHS and HFTC are two distinct phenotypes in a spectrum of GALNT3 mutation related calcification disorders, where the additional factors determining the phenotypic expression, are yet to be clarified.","variants":[{"Name":"NM_004482.4(GALNT3):c.767G>T (p.Gly256Val)","Chromosome":"2","Start":"165761976","Stop":"165761976","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2898622,"rule_based_match":true,"evidence_text":"c.767 G > T; p.Gly256Val","llm_judgment":"PRESENT","evidence":"c.767 G > T; p.Gly256Val","abstract_start":471,"abstract_end":495}]}
{"pmid":"23279346","title":"Myelin protein zero Arg36Gly mutation with very late onset and rapidly progressive painful neuropathy.","abstract":"Mutations in myelin protein zero (MPZ) protein result in a wide spectrum of peripheral neuropathies, from congenital hypomyelinating to late onset sensory and motor axonal forms. In some patients, neuropathic pain can be a prominent symptom, making the diagnosis challenging mainly in those with other risk factors for neuropathy. We describe a 77-year-old woman with impaired glucose tolerance presenting with rapidly progressive axonal neuropathy leading to excruciating pain and severe weakness of lower limbs within 2 years from the onset. Her son abruptly complained of similar painful symptoms at the age of 47 years. Molecular analysis revealed a novel heterozygous missense mutation (c.106A>G) in MPZ exon 2, causing the substitution of arginine-36 with glycine in the extracellular domain. Our observation suggests that MPZ-related neuropathy should be considered in the diagnostic work up of patients with painful axonal neuropathy even presenting with rapid progression and at a very late age of onset.","variants":[{"Name":"NM_000530.8(MPZ):c.106A>G (p.Arg36Gly)","Chromosome":"1","Start":"161307386","Stop":"161307386","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":404971,"rule_based_match":true,"evidence_text":"c.106A>G","llm_judgment":"PRESENT","evidence":"c.106A>G","abstract_start":692,"abstract_end":700}]}
{"pmid":"21521295","title":"Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism.","abstract":"OBJECTIVE: Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations in the GNAS locus.\nDESIGN: Investigation of clinical characteristics and molecular analysis in PHP and PPHP.\nPATIENTS: Fourteen subjects from 13 unrelated families including subjects with PPHP (n = 1), PHP-Ia (n = 6) and PHP-Ib (n = 7) were enrolled.\nMEASUREMENTS: Clinical data, including age at presentation, presenting symptom, auxological findings, family history, presence of Albright hereditary osteodystrophy (AHO) features and hormonal and biochemical findings, were analysed. The GNAS locus was subjected to direct sequencing and methylation analysis using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).\nRESULTS: Of the 13 PHP subjects, 10 (three PHP-Ia and seven PHP-Ib) presented with hypocalcemic tetany at ages ranging from 7 to 14·8 years. Subcutaneous calcification was observed as an early manifestation of AHO in one PHP-Ia patient (age, 2·9 years) and one PPHP patient (age, 7 months). Six PHP-Ia and one PPHP harboured four different heterozygous mutations within the coding region of GNAS, p.Asp189_Tyr190delinsMetfxX14, p.Val117fsX23, p.Tyr190CysfsX19, and a splicing mutation (c.659 + 1G>A), of which the latter two were novel. Five subjects with PHP-Ib exhibited complete loss of the maternal-specific methylation pattern. The remaining two PHP-Ib showed a loss of methylation of exon 1A on the maternal allele as a consequence of heterozygous 3-kb microdeletions within the STX16 gene.\nCONCLUSIONS: GNAS mutation analyses and MS-MLPA assays are useful molecular tools for understanding the molecular bases and confirming the diagnosis of PHP and PPHP.","variants":[{"Name":"NM_000516.7(GNAS):c.659+1G>A","Chromosome":"20","Start":"58909424","Stop":"58909424","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1501501,"rule_based_match":true,"evidence_text":"c.659 + 1G>A","llm_judgment":"PRESENT","evidence":"c.659 + 1G>A","abstract_start":1286,"abstract_end":1298}]}
{"pmid":"24746455","title":"Evidence for genotype-phenotype correlation for OTOF mutations.","abstract":"OBJECTIVES: The aim of this study is to evaluate the auditory phenotype in subjects with OTOF gene mutations to describe genotype-phenotype correlations.\nMETHODS: Twenty-two affected members from three families with homozygous OTOF mutations were included. Nine subjects were evaluated audiologically with otoscopic examination, pure-tone audiometry, tympanometry with acoustic reflex testing, auditory brain stem responses, and otoacoustic emission tests.\nRESULTS: Homozygous c.4718T>C (p.Ile1573Thr) mutation was associated with the auditory neuropathy/auditory dys-synchrony (AN/AD) phenotype and with progressive sensorineural hearing loss in four siblings in one family, while homozygous c.4467dupC (p.I1490HfsX19) was associated with severe to profound sensorineural hearing loss without AN/AD in four relatives in another family. Homozygous c.1958delC (p.Pro653LeufsX13) mutation was associated with moderate sensorineural hearing loss without AN/AD in one affected person in an additional family.\nCONCLUSIONS: The audiological phenotype associated with different OTOF mutations appears to be consistently different suggesting the presence of a genotype-phenotype correlation.","variants":[{"Name":"NM_194248.3(OTOF):c.4467dup (p.Ile1490fs)","Chromosome":"2","Start":"26466746","Stop":"26466747","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":204282,"rule_based_match":true,"evidence_text":"c.4467dupC (p.I1490HfsX19)","llm_judgment":"PRESENT","evidence":"c.4467dupC (p.I1490HfsX19)","abstract_start":693,"abstract_end":719},{"Name":"NM_194248.3(OTOF):c.4718T>C (p.Ile1573Thr)","Chromosome":"2","Start":"26465753","Stop":"26465753","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":57404,"rule_based_match":true,"evidence_text":"Homozygous c.4718T>C (p.Ile1573Thr) mutation","llm_judgment":"PRESENT","evidence":"Homozygous c.4718T>C (p.Ile1573Thr) mutation","abstract_start":466,"abstract_end":510}]}
{"pmid":"26348712","title":"Effects of CYP2B6 and CYP1A2 Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients.","abstract":"The extremely high prevalence of HIV/AIDS in sub-Saharan Africa and limitations of current antiretroviral medicines demand new tools to optimize therapy such as pharmacogenomics for person-to-person variations. African populations exhibit greater genetic diversity than other world populations, thus making it difficult to extrapolate findings from one population to another. Nevirapine, an antiretroviral medicine, displays large plasma concentration variability which adversely impacts therapeutic virological response. This study, therefore, aimed to identify sources of variability in nevirapine pharmacokinetics and pharmacodynamics, focusing on genetic variation in CYP2B6 and CYP1A2. Using a cross-sectional study design, 118 HIV-infected adult Zimbabwean patients on nevirapine-containing highly active antiretroviral therapy (HAART) were characterized for three key functional single nucleotide polymorphisms (SNPs), CYP2B6 c.516G>T (rs3745274), CYP2B6 c.983T>C (rs28399499), and CYP1A2 g.-163C>A (rs762551). We investigated whether genotypes at these loci were associated with nevirapine plasma concentration, a therapeutic biomarker, and CD4 cell count, a biomarker of disease progression. CYP2B6 and CYP1A2 were chosen as the candidate genes based on reports in literature, as well as their prominence in the metabolism of efavirenz, a drug in the same class with nevirapine. Nevirapine plasma concentration was determined using LC-MS/MS. The mean nevirapine concentration for CYP2B6 c.516T/T genotype differed significantly from that of 516G/G (p < 0.001) and 516G/T (p < 0.01) genotypes, respectively. There were also significant differences in mean nevirapine concentration between CYP2B6 c.983T > C genotypes (p = 0.04). Importantly, the CYP1A2 g.-163C>A SNP was significantly associated with the pharmacodynamics endpoint, the CD4 cell count (p = 0.012). Variant allele frequencies for the three SNPs observed in this Zimbabwean group were similar to other African population groups but different to observations among Caucasian and Asian populations. We conclude that CYP2B6 c.516G>T and CYP2B6 c.983T>C could be important sources of nevirapine pharmacokinetic variability that could be considered for dosage optimization, while CYP1A2 g.-163C>A seems to be associated with HIV disease progression. These inter- and intra-population pharmacokinetic and pharmacodynamics differences suggest that a single prescribed dosage may not be appropriate for the treatment of disease. Further research into a personalized nevirapine regimen is required.","variants":[{"Name":"NM_000767.5(CYP2B6):c.516G>T (p.Gln172His)","Chromosome":"19","Start":"41006936","Stop":"41006936","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":38626,"rule_based_match":true,"evidence_text":"CYP2B6 c.516G>T","llm_judgment":"PRESENT","evidence":"CYP2B6 c.516G>T","abstract_start":926,"abstract_end":941}]}
{"pmid":"29132460","title":"Genetic diagnosis of 10 neonates with primary carnitine deficiency","abstract":"OBJECTIVE: To study the gene mutation profile of primary carnitine deficiency (PCD) in neonates, and to provide a theoretical basis for early diagnosis and treatment, genetic counseling, and prenatal diagnosis of PCD.\nMETHODS: Acylcarnitine profile analysis was performed by tandem mass spectrometry using 34 167 dry blood spots on filter paper. The SLC22A5 gene was sequenced and analyzed in neonates with free carnitine (C0) levels lower than 10 μmol/L as well as their parents.\nRESULTS: In the acylcarnitine profile analysis, a C0 level lower than 10 μmol/L was found in 10 neonates, but C0 level was not reduced in their mothers. The 10 neonates had 10 types of mutations at 20 different sites in the SLC22A5 gene, which included 4 previously unreported mutations: c.976C>T, c.919delG, c.517delC, and c.338G>A. Bioinformatics analysis showed that the four new mutations were associated with a risk of high pathogenicity.\nCONCLUSIONS: Tandem mass spectrometry combined with SLC22A5 gene sequencing may be useful for the early diagnosis of PCD. Identification of new mutations enriches the SLC22A5 gene mutation profile.","variants":[{"Name":"NM_003060.4(SLC22A5):c.976C>T (p.Gln326Ter)","Chromosome":"5","Start":"132388945","Stop":"132388945","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1451068,"rule_based_match":true,"evidence_text":"c.976C>T","llm_judgment":"PRESENT","evidence":"c.976C>T","abstract_start":769,"abstract_end":777}]}
{"pmid":"26486472","title":"West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.","abstract":"West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births. To get better insights on the genetic of this pathology, we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings. GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis. The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor. Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments. We suggest a new link between improper assembly of respiratory chain complexes and WS.","variants":[{"Name":"NM_021927.3(GUF1):c.1825G>T (p.Ala609Ser)","Chromosome":"4","Start":"44695724","Stop":"44695724","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":247507,"rule_based_match":true,"evidence_text":"c.1825G>T/p.(Ala609Ser)","llm_judgment":"PRESENT","evidence":"c.1825G>T/p.(Ala609Ser)","abstract_start":363,"abstract_end":386}]}
{"pmid":"19692347","title":"ALX4 dysfunction disrupts craniofacial and epidermal development.","abstract":"Genetic control of craniofacial morphogenesis requires a complex interaction of numerous genes encoding factors essential for patterning and differentiation. We present two Turkish families with a new autosomal recessive frontofacial dysostosis syndrome characterized by total alopecia, a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, hypogonadism, callosal body agenesis and mental retardation. Using homozygosity mapping, we mapped the entity to chromosome 11p11.2-q12.3 and subsequently identified a homozygous c.793C-->T nonsense mutation in the human ortholog of the mouse aristaless-like homeobox 4 (ALX4) gene. This mutation is predicted to result in a premature stop codon (p.R265X) of ALX4 truncating 146 amino acids of the protein including a part of the highly conserved homeodomain and the C-terminal paired tail domain. Although the RNA is stable and not degraded by nonsense-mediated RNA decay, the mutant protein is likely to be non-functional. In a skin biopsy of an affected individual, we observed a hypomorphic interfollicular epidermis with reduced suprabasal layers associated with impaired interfollicular epidermal differentiation. Hair follicle-like structures were present but showed altered differentiation. Our data indicate that ALX4 plays a critical role both in craniofacial development as in skin and hair follicle development in human.","variants":[{"Name":"NM_021926.4(ALX4):c.793C>T (p.Arg265Ter)","Chromosome":"11","Start":"44267607","Stop":"44267607","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20059,"rule_based_match":false,"evidence_text":"c.793C-->T","llm_judgment":"PRESENT","evidence":"c.793C-->T","abstract_start":589,"abstract_end":599}]}
{"pmid":"26866448","title":"A Novel Splicing Mutation Identified in a Chinese Family with X-linked Alport Syndrome Using Targeted Next-Generation Sequencing.","abstract":"AIMS: Alport syndrome (AS) is a genetically heterogeneous disorder, characterized by hematuria, progressive renal failure, sensorineural hearing loss, and ocular abnormalities caused by mutations in the COL4A3, COL4A4, and COL4A5 genes. The aim of this study was to identify underlying mutations in individuals from a Chinese family with X-linked AS.\nMETHODS: We performed targeted next-generation sequencing (NGS) to identify mutations associated with AS. The results were processed and visualized using an Integrated Genomics Viewer software. The most likely disease-causing variants were identified and confirmed by Sanger sequencing of reverse transcription-polymerase chain reaction products.\nRESULTS: Visual inspection using Integrative Genomics Viewer software found that COL4A5 exon 10 was not covered by the disease panel, while coverage of exons 4, 17, 20, 21, 37, and 45 was incomplete. Sanger sequencing of these regions identified a novel splice-site mutation in intron 9 (c.547-3C>A) of the COL4A5 gene. Subsequent cDNA analysis revealed that c.547-3C>A led to skipping of exon 10, which resulted in an in-frame deletion of 21 amino acids from the α5 chain of type IV collagen.\nCONCLUSION: We determined the molecular basis of AS in a Chinese family by targeted NGS and cDNA analysis. This is the first report of the novel c.547-3C>A splicing mutation in the collagen domain of COL4A5 gene.","variants":[{"Name":"NM_033380.3(COL4A5):c.547-3C>A","Chromosome":"X","Start":"108575907","Stop":"108575907","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":578069,"rule_based_match":true,"evidence_text":"c.547-3C>A","llm_judgment":"PRESENT","evidence":"c.547-3C>A","abstract_start":986,"abstract_end":996}]}
{"pmid":"27109384","title":"A genetic analysis of 23 Chinese patients with hemophilia B.","abstract":"Hemophilia B (HB) is an X-linked recessive bleeding disorder caused by mutations in the coagulation factor IX (FIX) gene. Genotyping patients with HB is essential for genetic counseling and provides useful information for patient management. In this study, the F9 gene from 23 patients with HB was analyzed by direct sequencing. Nineteen point mutations were identified, including a novel missense variant (c.520G > C, p.Val174Leu) in a patient with severe HB and a previously unreported homozygous missense mutation (c.571C > T, p.Arg191Cys) in a female patient with mild HB. Two large F9 gene deletions with defined breakpoints (g.10413_11363del, g.12163_23369del) were identified in two patients with severe HB using a primer walking strategy followed by sequencing. The flanking regions of the two breakpoints revealed recombination-associated elements (repetitive elements, non-B conformation forming motifs) with a 5-bp microhomology in the breakpoint junction of g.12163_23369del. These findings imply that non-homologous end joining and microhomology-mediated break-induced replication are the putative mechanisms for the deletions of the F9 gene. Because the g.12163_23369del deletion caused exons to be absent without a frameshift mutation occurring, a smaller FIX protein was observed in western blot analyses.","variants":[{"Name":"NM_000133.4(F9):c.571C>T (p.Arg191Cys)","Chromosome":"X","Start":"139551112","Stop":"139551112","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25623,"rule_based_match":true,"evidence_text":"c.571C > T, p.Arg191Cys","llm_judgment":"PRESENT","evidence":"c.571C > T, p.Arg191Cys","abstract_start":518,"abstract_end":541}]}
{"pmid":"23580368","title":"Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type.","abstract":"Combined methylmalonic aciduria and homocystinuria, cblC type (MMACHC), is the most common inborn error of cellular vitamin B12 metabolism and is caused by mutations in the MMACHC gene. This metabolic disease results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, coenzymes for the methylmalonyl-CoA mutase and methionine synthase enzymes, respectively. The inability to produce normal levels of these two coenzymes leads to increased concentrations of methylmalonic acid and homocysteine in plasma and urine, together with normal or decreased concentration of methionine in plasma. Here, we report a novel homozygous deletion mutation (NM_015506.2:c.392_394del) resulting in an in-frame deletion of amino acid Gln131 and late-onset disease in a 23-year-old male. The patient presented with sensory and motoric disabilities, urine and fecal incontinence, and light cognitive impairment. There was an excessive urinary excretion of methylmalonic acid and greatly elevated plasma homocysteine. The clinical symptoms and the laboratory abnormalities responded partly to treatment with hydroxycobalamin, folinic acid, methionine, and betaine. Studies on patient fibroblasts together with spectroscopic activity assays on recombinant MMACHC protein reveal that Gln131 is crucial in order to maintain enzyme activity. Furthermore, structural analyses show that Gln131 is one of only two residues making hydrogen bonds to the tail of cobalamin. Circular dichroism spectroscopy indicates that the 3D structure of the deletion mutant is folded but perturbed compared to the wild-type protein.","variants":[{"Name":"NM_015506.3(MMACHC):c.392_394del (p.Gln131del)","Chromosome":"1","Start":"45508326","Stop":"45508328","ReferenceAlleleVCF":"CCAA","AlternateAlleleVCF":"C","allel_id":541237,"rule_based_match":true,"evidence_text":"NM_015506.2:c.392_394del","llm_judgment":"PRESENT","evidence":"NM_015506.2:c.392_394del","abstract_start":668,"abstract_end":692}]}
{"pmid":"25077176","title":"A-TWinnipeg: Pathogenesis of rare ATM missense mutation c.6200C>A with decreased protein expression and downstream signaling, early-onset dystonia, cancer, and life-threatening radiotoxicity.","abstract":"We studied 10 Mennonite patients who carry the c.6200C>A missense mutation (p.A2067D) in the ATM gene, all of whom exhibited a phenotypic variant of ataxia-telangiectasia (A-T) that is characterized by early-onset dystonia and late-onset mild ataxia, as previously described. This report provides the pathogenetic evidence for this mutation on cellular functions. Several patients have developed cancer and subsequently experienced life-threatening adverse reactions to radiation (radiotoxicity) and/or chemotherapy. As the c.6200C>A mutation is, thus far, unique to the Mennonite population and is always associated with the same haplotype or haplovariant, it was important to rule out any possible confounding DNA variant on the same haplotype. Lymphoblastoid cells derived from Mennonite patients expressed small amounts of ATM protein, which had no autophosphorylation activity at ATM Ser1981, and trace-to-absent transphosphorylation of downstream ATM targets. A-T lymphoblastoid cells stably transfected with ATM cDNA which had been mutated for c.6200C>A did not show a detectable amount of ATM protein. The same stable cell line with mutated ATM cDNA also showed a trace-to-absent transphosphorylation of downstream ATM targets SMC1pSer966 and KAP1pSer824. From these results, we conclude that c.6200A is the disease-causing ATM mutation on this haplotype. The presence of at least trace amounts of ATM kinase activity on some immunoblots may account for the late-onset, mild ataxia of these patients. The cause of the dystonia remains unclear. Because this dystonia-ataxia phenotype is often encountered in the Mennonite population in association with cancer and adverse reactions to chemotherapy, an early diagnosis is important.","variants":[{"Name":"NM_000051.4(ATM):c.6200C>A (p.Ala2067Asp)","Chromosome":"11","Start":"108317374","Stop":"108317374","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":48348,"rule_based_match":true,"evidence_text":"c.6200C>A (p.A2067D)","llm_judgment":"PRESENT","evidence":"c.6200C>A","abstract_start":47,"abstract_end":56}]}
{"pmid":"37273692","title":"Multiple genetic variants involved in both autoimmunity and autoinflammation detected in Chinese patients with sporadic Meniere's disease: a preliminary study.","abstract":"Background: The mechanisms of Meniere's disease (MD) remain largely unknown. The purpose of this study was to identify possible genetic variants associated with immune regulation in MD.\nMethods: The whole immune genome of 16 Chinese patients diagnosed with sporadic MD was sequenced using next-generation sequencing.\nResults: Definite pathological variants of <i>MEFV</i> (c.1223G>A, c.1105C>T), <i>COL7A1</i> (c.5287C>T), and <i>ADA</i> (c.445C>T) contributing to the clinical phenotype were found in three patients. Limited and likely pathological variants of <i>TLR3</i> (c.2228G>A) and <i>RAB27A</i> (c.560G>A) were detected in one patient each. The following definite pathological variants impairing the structure and function of translated proteins were detected in 10 patients, and multigene variants occurred in five patients: <i>PRF1</i> (<i>c.710C</i>><i>A</i>), <i>UNC13D</i> (c.1228A>C), <i>COLEC11</i> (c.169C>T), <i>RAG2</i> (c.200G>C), <i>BLM</i> (c.1937G>T), <i>RNF31</i> (c.2533G>A), <i>FAT4</i> (c.11498A>G), <i>PEPD</i> (c.788A>G), <i>TNFSF12</i> (c.470G>A), <i>VPS13B</i> (c.11972A>T), <i>TNFRSF13B</i> (c.226G>A), <i>ERCC6L2</i> (c.4613A>G), <i>TLR3</i> (c.2228G>A), <i>ADA</i> (c.445C>T), <i>PEPD</i> (c.151G>A), and <i>MOGS</i> (c.2470G>A). The following limited pathological variants impairing the structure and function of translated proteins were detected in five patients, with double gene variants identified in one patient: <i>EXTL3</i> (c.1396G>A), <i>MTHFD1</i> (c.2057G>A), <i>FANCA</i> (c.2039T>C), <i>LPIN2</i> (c.1814C>T), <i>NBAS</i> (c.4049T>C), and <i>FCN3</i> (c.734G>A).\nConclusion: Patients with sporadic MD carry multiple genetic variants involved in multiple steps of immune regulation, which might render patients susceptible to developing inflammation via both autoimmune and autoinflammation mechanisms upon internal stress.","variants":[{"Name":"NM_183235.3(RAB27A):c.560G>A (p.Arg187Gln)","Chromosome":"15","Start":"55205613","Stop":"55205613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":237033,"rule_based_match":true,"evidence_text":"c.560G>A","llm_judgment":"PRESENT","evidence":"c.560G>A","abstract_start":605,"abstract_end":613}]}
{"pmid":"21493957","title":"Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.","abstract":"BACKGROUND: This study reports on a hitherto undescribed autosomal recessive syndrome characterised by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death, and the identification of a gene involved in the pathogenesis of the disease.\nMETHODS: Homozygosity mapping was performed using Affymetrix Human Mapping 250k NspI arrays. Sequencing of all coding exons of the candidate genes was performed with primer sets designed using the Primer3 program. Fluorescence activated cell sorting was performed using conjugated antibody to CD59. Staining, acquisition and analysis were performed on a FACSCalibur flow cytometer.\nRESULTS: Using homozygosity mapping, the study mapped the disease locus to 18q21.32-18q22.1 and identified the disease-causing mutation, c.2126G→A (p.Arg709Gln), in PIGN, which encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase 1, a protein involved in GPI-anchor biosynthesis. Arginine at the position 709 is a highly evolutionarily conserved residue located in the PigN domain. The expression of GPI linked protein CD59 on fibroblasts from patients as compared to that in a control individual showed a 10-fold reduction in expression, confirming the pathogenic consequences of the mutation on GPI dependent protein expression.\nCONCLUSIONS: The abundant expression of PIGN in various tissues is compatible with the diverse phenotypic features observed in the patients and with the involvement of multiple body systems. The presence of developmental delay, hypotonia, and epilepsy combined with multiple congenital anomalies, especially anorectal anomalies, should lead a clinician to suspect a GPI deficiency related disorder.","variants":[{"Name":"NM_176787.5(PIGN):c.2126G>A (p.Arg709Gln)","Chromosome":"18","Start":"62095902","Stop":"62095902","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39506,"rule_based_match":false,"evidence_text":"c.2126G→A (p.Arg709Gln)","llm_judgment":"PRESENT","evidence":"c.2126G→A (p.Arg709Gln)","abstract_start":844,"abstract_end":867}]}
{"pmid":"19128366","title":"Molecular analysis of novel PROP1 mutations associated with combined pituitary hormone deficiency (CPHD).","abstract":"OBJECTIVE: Homozygous mutations in the gene encoding the pituitary transcription factor PROP1 are associated with combined pituitary hormone deficiency (CPHD) in both mice and humans with a highly variable phenotype with respect to the severity and time of initiation of pituitary hormone deficiency. We have ascertained three pedigrees with PROP1 mutations from a large cohort of patients with variable degrees of CPHD who were screened for mutations in PROP1.\nRESULTS: Affected individuals from all three pedigrees were found to harbour novel PROP1 mutations. We have identified two siblings in one family who were homozygous for an intronic mutation (c.343-11C > G) that disrupts correct splicing resulting in the loss of exon 3 from the PROP1 transcript. Two siblings from a second, unrelated family are compound heterozygotes for two point mutations in the coding region, a missense mutation (p.R125W) that leads to impaired transcriptional activation, and a deletion of a single nucleotide (c.310delC) resulting in a frameshift and nonfunctional mutant protein. Additionally, we identified a homozygous deletion of the PROP1 locus in two patients born to consanguineous parents.\nCONCLUSION: Mutations in PROP1 are a frequent cause of familial CPHD. We have described four novel mutations in PROP1 in 3 pedigrees, all resulting in PROP1 deficiency by different mechanisms. The phenotypic variation observed in association with PROP1 mutations both within and between families, together with the evolving nature of hormone deficiencies and sometimes changing pituitary morphology indicates a need for continual monitoring of these patients.","variants":[{"Name":"NM_006261.5(PROP1):c.310del (p.Arg104fs)","Chromosome":"5","Start":"177994138","Stop":"177994138","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":186697,"rule_based_match":true,"evidence_text":"c.310delC","llm_judgment":"PRESENT","evidence":"c.310delC","abstract_start":997,"abstract_end":1006}]}
{"pmid":"29896744","title":"Mutation analysis of FBN1 gene in a child with Marfan syndrome","abstract":"OBJECTIVE: To detect potential mutations of fibrillin-1 (FBN1) gene in a child with Marfan syndrome (MFS) and explore its molecular pathogenesis.\nMETHODS: The 66 exons of the FBN1 gene were analyzed by direct sequencing. SIFT and PolyPhen-2 were used to predict the structural and functional changes at the protein level.\nRESULTS: A novel heterozygous mutation c.3998 G>A (p.Cys1333Tyr) was found in exon 32 in the child. The same mutation was not found among his unaffected family members and 683 healthy controls. Multiple sequence alignment showed that this novel mutation was located in a highly conserved region of the FBN1 protein across various species and may induce structural change to a functional domain.\nCONCLUSION: The novel c.3998G>A (p.Cys1333Tyr) mutation of the FBN1 gene probably predisposed the MFS in the child. Above finding has enriched the spectrum of FBN1 mutations.","variants":[{"Name":"NM_000138.5(FBN1):c.3998G>A (p.Cys1333Tyr)","Chromosome":"15","Start":"48474617","Stop":"48474617","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1017924,"rule_based_match":true,"evidence_text":"c.3998 G>A (p.Cys1333Tyr)","llm_judgment":"PRESENT","evidence":"c.3998 G>A (p.Cys1333Tyr)","abstract_start":361,"abstract_end":386}]}
{"pmid":"32605921","title":"Novel frameshift variant (c.409dupG) in","abstract":"AIMS: Congenital sideroblastic anaemias (CSAs) are a group of rare disorders with the presence of ring sideroblasts in the bone marrow. Pathogenic variants are inherited in an autosomal recessive/X-linked fashion. The study was aimed at characterising the spectrum of mutations in <i>SLC25A38</i> and <i>ALAS2</i> genes in sideroblastic anaemia patients, exploring the genotype-phenotype correlation and identifying the haplotype associated with any recurrent mutation.\nPATIENTS AND METHODS: Twenty probable CSA patients were retrospectively analysed for genetic variants in <i>ALAS2</i> and <i>SLC25A38</i> genes by direct bidirectional sequencing. Real-time PCR was used to quantify gene expression in a case with promoter region variant in <i>ALAS2</i>. Three single nucleotide polymorphisms were used to establish the haplotype associated with a recurrent variant in the <i>SLC25A38</i> gene.\nRESULTS: Six patients had causative variants in <i>ALAS2</i> (30%) and 11 had variants in <i>SLC25A38</i> (55%). The <i>ALAS2</i> mutated cases presented at a significantly later age than the <i>SLC25A38</i> cases. A frameshift variant in <i>SLC25A38</i> (c.409dupG) was identified in six unrelated patients and was a common variant in our population exhibiting 'founder effect'.\nCONCLUSION: This is the largest series of sideroblastic anaemia cases with molecular characterisation from the Indian subcontinent.","variants":[{"Name":"NM_017875.4(SLC25A38):c.409dup (p.Ala137fs)","Chromosome":"3","Start":"39391572","Stop":"39391573","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":1161599,"rule_based_match":true,"evidence_text":"c.409dupG","llm_judgment":"PRESENT","evidence":"c.409dupG","abstract_start":1153,"abstract_end":1162}]}
{"pmid":"20456450","title":"Clinical and in silico evidence for and against pathogenicity of 11 new mutations in the MPZ gene.","abstract":"Mutations in the myelin protein zero (MPZ) gene are one of the frequent causes of Charcot-Marie-Tooth (CMT) hereditary neuropathies. Because the mutation rate of MPZ gene is rather high and some mutations are reported as polymorphisms, the proper clinical, electrophysiological examination and the segregation of the new mutation in larger families are crucial for the correct interpretation of the pathogenic or non-pathogenic character of each novel mutation. We examined 11 families with novel MPZ mutations. Eight of the mutations (L48Q, T65N, E97fs, G103W, P132T, T143R, V146G, c.645+1G>T) seem to be pathogenic on the basis of perfect segregation with the CMT phenotype and two (G213R and D246N), on the contrary, seem to be non-pathogenic/rare polymorphisms because they are present in healthy relatives. The character of the V46M mutation is difficult to interpret definitely; it may cause a sensory neuropathy or may also be a rare polymorphism. Phenotypes associated with each of the new mutations include severe hereditary motor and sensory neuropathy type III (HMSN III), and mild phenotype CMT1B presented mostly with only decreased or absent reflexes, foot deformities and mild or even absent atrophies in the lower limbs. Our report and careful family investigations with genotype-phenotype correlations should help to improve genetic counselling and correct interpretation of DNA testing results in further isolated patients or smaller families worldwide where these novel mutations might be found.","variants":[{"Name":"NM_000530.8(MPZ):c.307G>T (p.Gly103Trp)","Chromosome":"1","Start":"161306849","Stop":"161306849","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":625051,"rule_based_match":false,"evidence_text":"c.307G>T (p.Gly103Trp)","llm_judgment":"PRESENT","evidence":"G103W","abstract_start":555,"abstract_end":560}]}
{"pmid":"23112559","title":"A de novo germline MLH1 mutation in a Lynch syndrome patient with discordant immunohistochemical and molecular biology test results.","abstract":"We describe a patient with a Homo sapiens mutL homolog 1 (MLH1)-associated Lynch syndrome with previous diagnoses of two distinct primary cancers: a sigmoid colon cancer at the age of 39 years, and a right colon cancer at the age of 50 years. The mutation identified in his blood and buccal cells, c.1771delG, p.Asp591Ilefs*25, appears to be a de novo event, as it was not transmitted by either of his parents. This type of de novo event is rare in MLH1 as only three cases have been reported in the literature so far. Furthermore, the discordant results observed between replication error phenotyping and immunohistochemistry highlight the importance of the systematic use of both pre-screening tests in the molecular diagnosis of Lynch syndrome.","variants":[{"Name":"NM_000249.4(MLH1):c.1771del (p.Asp591fs)","Chromosome":"3","Start":"37047558","Stop":"37047558","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":1838457,"rule_based_match":true,"evidence_text":"c.1771delG, p.Asp591Ilefs*25","llm_judgment":"PRESENT","evidence":"c.1771delG, p.Asp591Ilefs*25","abstract_start":298,"abstract_end":326}]}
{"pmid":"23664116","title":"Mutations in BICD2, which encodes a golgin and important motor adaptor, cause congenital autosomal-dominant spinal muscular atrophy.","abstract":"Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.","variants":[{"Name":"NM_001003800.2(BICD2):c.320C>T (p.Ser107Leu)","Chromosome":"9","Start":"92729157","Stop":"92729157","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70511,"rule_based_match":true,"evidence_text":"c.320C>T (p.Ser107Leu)","llm_judgment":"PRESENT","evidence":"c.320C>T (p.Ser107Leu)","abstract_start":679,"abstract_end":701},{"Name":"NM_001003800.2(BICD2):c.2108C>T (p.Thr703Met)","Chromosome":"9","Start":"92717947","Stop":"92717947","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70512,"rule_based_match":true,"evidence_text":"c.2108C>T (p.Thr703Met)","llm_judgment":"PRESENT","evidence":"c.2108C>T (p.Thr703Met)","abstract_start":1235,"abstract_end":1258},{"Name":"NM_001003800.2(BICD2):c.563A>C (p.Asn188Thr)","Chromosome":"9","Start":"92722699","Stop":"92722699","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":70513,"rule_based_match":true,"evidence_text":"c.563A>C (p.Asn188Thr)","llm_judgment":"PRESENT","evidence":"c.563A>C (p.Asn188Thr)","abstract_start":1351,"abstract_end":1373}]}
{"pmid":"28323927","title":"Exome Sequencing Reveals Mutations in AIRE as a Cause of Isolated Hypoparathyroidism.","abstract":"Context: Most cases of autosomal recessive hypoparathyroidism (HYPO) are caused by loss-of-function mutations in GCM2 or PTH.\nObjective: The objective of this study was to identify the underlying genetic basis for isolated HYPO in a kindred in which 3 of 10 siblings were affected.\nSubjects: We studied the parents and the three adult affected subjects, each of whom was diagnosed with HYPO in the first decade of life.\nMethods: We collected clinical and biochemical data and performed whole exome sequencing analysis on DNA from the three affected subjects after negative genetic testing for known causes of HYPO.\nResults: Whole exome sequencing followed by Sanger sequencing revealed that all three affected subjects were compound heterozygous for two previously reported mutations, c.967_979delCTGTCCCCTCCGC:p.(L323SfsX51) and c.995+(3_5)delGAGinsTAT, in AIRE, which encodes the autoimmune regulator protein that is defective in autoimmune polyglandular syndrome type 1 (APS-1). Each parent carries one mutation, and all of the children of the patients are either heterozygous for one mutation or wild type. The affected sister developed premature ovarian failure, but the two affected brothers have no other features of APS-1 despite elevated serum levels of anti-interferon-α antibodies.\nConclusions: Our findings indicate that biallelic mutations in AIRE can cause isolated HYPO as well as syndromic APS-1. The presence of antibodies to interferon-α provides a highly sensitive indicator for loss of AIRE function and represents a useful marker for isolated HYPO due to AIRE mutations.","variants":[{"Name":"NM_000383.4(AIRE):c.967_979del (p.Leu323fs)","Chromosome":"21","Start":"44291180","Stop":"44291192","ReferenceAlleleVCF":"TGCCTGTCCCCTCC","AlternateAlleleVCF":"T","allel_id":18348,"rule_based_match":true,"evidence_text":"c.967_979delCTGTCCCCTCCGC:p.(L323SfsX51)","llm_judgment":"PRESENT","evidence":"c.967_979delCTGTCCCCTCCGC:p.(L323SfsX51)","abstract_start":785,"abstract_end":825}]}
{"pmid":"30303820","title":"Novel pathogenic variants in GBE1 causing fetal akinesia deformation sequence and severe neuromuscular form of glycogen storage disease type IV.","abstract":"Glycogen storage disease IV (GSD IV), caused by a defect in GBE1, is a clinically heterogeneous disorder. A classical hepatic form and a neuromuscular form have been described. The severe neuromuscular form presents as a fetal akinesia deformation sequence or a congenital subtype. We ascertained three unrelated families with fetuses/neonates who presented with fetal akinesia deformation sequence to our clinic for genetic counseling. We performed a detailed clinical evaluation, exome sequencing, and histopathology examination of two fetuses and two neonates from three unrelated families presenting with these perinatally lethal neuromuscular forms of GSD IV. Exome sequencing in the affected fetuses/neonates identified four novel pathogenic variants (c.1459G>T, c.144-1G>A, c.1680C>G, and c.1843G>C) in GBE1 (NM_000158). Histopathology examination of tissues from the affected fetuses/neonate was consistent with the diagnosis. Here, we add three more families with the severe perinatally lethal neuromuscular forms of GSD IV to the GBE1 mutation spectrum.","variants":[{"Name":"NM_000158.4(GBE1):c.1680C>G (p.Tyr560Ter)","Chromosome":"3","Start":"81537034","Stop":"81537034","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3083489,"rule_based_match":true,"evidence_text":"c.1680C>G","llm_judgment":"PRESENT","evidence":"c.1680C>G","abstract_start":781,"abstract_end":790}]}
{"pmid":"24387993","title":"Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease.","abstract":"Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4*), c.652C>T (p.Arg218*), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218*) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.","variants":[{"Name":"NM_152305.3(POGLUT1):c.11G>A (p.Trp4Ter)","Chromosome":"3","Start":"119469032","Stop":"119469032","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132052,"rule_based_match":true,"evidence_text":"c.11G>A (p.Trp4*)","llm_judgment":"PRESENT","evidence":"c.11G>A (p.Trp4*)","abstract_start":551,"abstract_end":568},{"Name":"NM_152305.3(POGLUT1):c.652C>T (p.Arg218Ter)","Chromosome":"3","Start":"119486846","Stop":"119486846","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":132053,"rule_based_match":true,"evidence_text":"c.652C>T (p.Arg218*)","llm_judgment":"PRESENT","evidence":"c.652C>T (p.Arg218*)","abstract_start":570,"abstract_end":590},{"Name":"NM_152305.3(POGLUT1):c.798-2A>C","Chromosome":"3","Start":"119490549","Stop":"119490549","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":132054,"rule_based_match":true,"evidence_text":"c.798-2A>C","llm_judgment":"PRESENT","evidence":"c.798-2A>C","abstract_start":596,"abstract_end":606}]}
{"pmid":"30393954","title":"Hereditary elliptocytosis-associated alpha-spectrin mutation p.L155dup as a modifier of sickle cell disease severity.","abstract":"The broad phenotypic variability among individuals with sickle cell disease (SCD) suggests the presence of modifying factors. We identified two unrelated SCD patients with unusually severe clinical and laboratory phenotype that were found to carry the hereditary elliptocytosis-associated alpha-spectrin mutation c.460_462dupTTG (p.L155dup), a mutation enriched due to positive selective pressure of malaria, similar to the SCD globin mutations. A high index of suspicion for additional hematologic abnormalities may be indicated for challenging patients with SCD. These cases highlight the validity of specialized testing such as ektacytometry and next-generation sequencing for patients and family members to assess genotype/phenotype correlations.","variants":[{"Name":"NM_003126.4(SPTA1):c.460_462dup (p.Leu155dup)","Chromosome":"1","Start":"158681595","Stop":"158681596","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCAA","allel_id":27886,"rule_based_match":true,"evidence_text":"c.460_462dupTTG (p.L155dup)","llm_judgment":"PRESENT","evidence":"c.460_462dupTTG (p.L155dup)","abstract_start":313,"abstract_end":340}]}
{"pmid":"35142290","title":"A novel gene","abstract":"Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis which is featured as a localized or generalized overgrowth of gingivae. Currently two genes (<i>SOS1</i> and <i>REST</i>), as well as four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15), have been identified as associated with HGF in a dominant inheritance pattern. Here, we report 13 individuals with autosomal-dominant HGF from a four-generation Chinese family. Whole-exome sequencing followed by further genetic co-segregation analysis was performed for the family members across three generations. A novel heterozygous missense mutation (c.2812G > A) in zinc finger protein 862 gene (<i>ZNF862</i>) was identified, and it is absent among the population as per the Genome Aggregation Database. The functional study supports a biological role of <i>ZNF862</i> for increasing the profibrotic factors particularly COL1A1 synthesis and hence resulting in HGF. Here, for the first time we identify the physiological role of <i>ZNF862</i> for the association with the HGF.","variants":[{"Name":"NM_001099220.3(ZNF862):c.2812G>A (p.Ala938Thr)","Chromosome":"7","Start":"149861972","Stop":"149861972","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":858733,"rule_based_match":true,"evidence_text":"c.2812G > A","llm_judgment":"PRESENT","evidence":"c.2812G > A","abstract_start":640,"abstract_end":651}]}
{"pmid":"29132927","title":"Whole exome sequencing identified a pathogenic mutation in RYR2 in a Chinese family with unexplained sudden death.","abstract":"OBJECTIVE: This study aimed to identify the pathogenic mutation in a Chinese family with unexplained sudden death (USD) or occasional syncope.\nMATERIALS AND METHODS: Whole exome sequencing and target capture sequencing were respectively conducted for two related patients. The genetic data was screened using the 1000 genomes project and SNP database (PubMed), and the identified mutations were assessed for predicted pathogenicity using the SIFT and Polyphen-2 algorithms.\nRESULTS: We identified a heterozygous mutation in the RYR2 gene at c.490C>T (p.P164S), highly conserved across all species, in three family members of USD, syncope and malignant ventricular tachycardias induced by treadmill exercise test, while another heterozygous de novo mutation in SCN5A at c.5576G>A p.R1859H was detected in one family member. Both variants were verified by Sanger sequencing. Importantly, RYR2 p.P164S is associated with the risk of sudden cardiac death, such as in catecholaminergic polymorphic ventricular tachycardia.\nCONCLUSIONS: A pathogenic mutation in RYR2 (p.P164S) is the likely cause of USD in a Chinese family associated with malignant ventricular arrhythmias. Whole exome and target capture sequencing can be useful for discovering the genetic causes of USD.","variants":[{"Name":"NM_001035.3(RYR2):c.490C>T (p.Pro164Ser)","Chromosome":"1","Start":"237377349","Stop":"237377349","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1925236,"rule_based_match":true,"evidence_text":"c.490C>T (p.P164S)","llm_judgment":"PRESENT","evidence":"c.490C>T (p.P164S)","abstract_start":541,"abstract_end":559}]}
{"pmid":"28649550","title":"Analysis of six novel flavin-containing monooxygenase 3 (","abstract":"Polymorphic human flavin-containing monooxygenase 3 (FMO3) is associated with the inherited disorder trimethylaminuria. Several FMO3 variants have been observed in a variety of ethnic groups, including a Japanese cohort suffering from trimethylaminuria. The aim of this study was to screen another self-reported Japanese trimethylaminuria cohort for novel FMO3 variants and to investigate these new variants. Subjects with low FMO3 metabolic capacities were identified by measuring the urinary trimethylamine and trimethylamine <i>N</i>-oxide concentrationsin171 Japanese volunteers. The <i>FMO3</i> genes from these subjects and their family members were then sequenced. Heterozygotes or homozygotes for novel single-nucleotide polymorphisms c.20 T > C p.(Ile7Thr), c.122 G > A p.(Trp41Ter), c.127T > A p.(Phe43Ile), c.488 T > C p.(Leu163Pro), and c.1127G > A p.(Gly376Glu) and a heterozygote for the novel duplication c.850_860dupTTTAACGATGA p.(Glu287AspfsTer17) were identified. In addition, the known (but as yet uncharacterized) single-nucleotide polymorphism c.929 C > T p.(Ser310Leu) was found. Pedigree analysis revealed the p.(Ser310Leu) <i>FMO3</i> allele in <i>cis</i> configuration with c.929 C > T p.(Glu158Lys). These variant FMO3 proteins recombinantly expressed in <i>Escherichia coli</i> membranes exhibited decreased <i>N</i>-oxygenation activities toward trimethylamine and benzydamine. Although the allele frequencies of these seven variants were low, the present results suggest that individuals homozygous or heterozygous for any of these novel missense or duplication<i>FMO3</i> variants or known nonsense mutations such as p.(Cys197Ter) may possess abnormal activities toward trimethylamine <i>N</i>-oxygenation.","variants":[{"Name":"NM_001002294.3(FMO3):c.929C>T (p.Ser310Leu)","Chromosome":"1","Start":"171114108","Stop":"171114108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":619969,"rule_based_match":true,"evidence_text":"c.929 C > T p.(Ser310Leu)","llm_judgment":"PRESENT","evidence":"c.929 C > T p.(Ser310Leu)","abstract_start":1065,"abstract_end":1090}]}
{"pmid":"19813197","title":"Non-lethal neonatal neuromuscular variant of glycogenosis type IV with novel GBE1 mutations.","abstract":"We report a recent case of the severe congenital variant of glycogen storage disease type IV with prolonged survival. The patient was found to be a compound heterozygote for two novel mutations, a missense mutation in exon 5 (p.H188P, c.563A>C) and a severe mutation in intron 5 (c.691+2T>C). We propose that the genotype and the quality of medical care may account for the severe but non-lethal phenotype.","variants":[{"Name":"NM_000158.4(GBE1):c.691+2T>C","Chromosome":"3","Start":"81648854","Stop":"81648854","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":205142,"rule_based_match":true,"evidence_text":"c.691+2T>C","llm_judgment":"PRESENT","evidence":"c.691+2T>C","abstract_start":280,"abstract_end":290}]}
{"pmid":"20042663","title":"Autosomal recessive retinitis pigmentosa with early macular affectation caused by premature truncation in PROM1.","abstract":"PURPOSE: To identify the genetic basis of a large consanguineous Spanish pedigree affected with autosomal recessive retinitis pigmentosa (arRP) with premature macular atrophy and myopia.\nMETHODS: After a high-throughput cosegregation gene chip was used to exclude all known RP and Leber congenital amaurosis (LCA) candidates, genome-wide screening and linkage analysis were performed. Direct mutational screening identified the pathogenic mutation, and primers were designed to obtain the RT-PCR products for isoform characterization.\nRESULTS: Mutational analysis detected a novel homozygous PROM1 mutation, c.869delG in exon 8 cosegregating with the disease. This variant causes a frameshift that introduces a premature stop codon, producing truncation of approximately two-thirds of the protein. Analysis of PROM1 expression in the lymphocytes of patients, carriers, and control subjects revealed an aberrant transcript that is degraded by the nonsense-mediated decay pathway, suggesting that the disease is caused by the absence of the PROM1 protein. Three (s2, s11 and s12) of the seven alternatively spliced isoforms reported in humans, accounted for 98% of the transcripts in the retina. Given that these three contained exon 8, no PROM1 isoform is expected in the affected retinas.\nCONCLUSIONS: A remarkable clinical finding in the affected family is early macular atrophy with concentric spared areas. The authors propose that the hallmark of PROM1 truncating mutations is early and severe progressive degeneration of both rods and cones and highlight this gene as a candidate of choice to prioritize in the molecular genetic study of patients with noncanonical clinical peripheral and macular affectation.","variants":[{"Name":"NM_006017.3(PROM1):c.869del (p.Ser290fs)","Chromosome":"4","Start":"16018456","Stop":"16018456","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":790455,"rule_based_match":true,"evidence_text":"c.869delG","llm_judgment":"PRESENT","evidence":"c.869delG","abstract_start":608,"abstract_end":617}]}
{"pmid":"29265763","title":"Manifestation of recessive combined D-2-, L-2-hydroxyglutaric aciduria in combination with 22q11.2 deletion syndrome.","abstract":"22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2-hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.","variants":[{"Name":"NM_005984.5(SLC25A1):c.18_24dup (p.Ala9fs)","Chromosome":"22","Start":"19178649","Stop":"19178650","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CGCGCGGG","allel_id":1709108,"rule_based_match":true,"evidence_text":"c.18_24dup (p.Ala9Profs*82)","llm_judgment":"PRESENT","evidence":"c.18_24dup (p.Ala9Profs*82)","abstract_start":1214,"abstract_end":1241}]}
{"pmid":"23451239","title":"Study of USH1 splicing variants through minigenes and transcript analysis from nasal epithelial cells.","abstract":"Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital profound deafness, vestibular areflexia and prepubertal retinitis pigmentosa. The first purpose of this study was to determine the pathologic nature of eighteen USH1 putative splicing variants found in our series and their effect in the splicing process by minigene assays. These variants were selected according to bioinformatic analysis. The second aim was to analyze the USH1 transcripts, obtained from nasal epithelial cells samples of our patients, in order to corroborate the observed effect of mutations by minigenes in patient's tissues. The last objective was to evaluate the nasal ciliary beat frequency in patients with USH1 and compare it with control subjects. In silico analysis were performed using four bioinformatic programs: NNSplice, Human Splicing Finder, NetGene2 and Spliceview. Afterward, minigenes based on the pSPL3 vector were used to investigate the implication of selected changes in the mRNA processing. To observe the effect of mutations in the patient's tissues, RNA was extracted from nasal epithelial cells and RT-PCR analyses were performed. Four MYO7A (c.470G>A, c.1342_1343delAG, c.5856G>A and c.3652G>A), three CDH23 (c.2289+1G>A, c.6049G>A and c.8722+1delG) and one PCDH15 (c.3717+2dupTT) variants were observed to affect the splicing process by minigene assays and/or transcripts analysis obtained from nasal cells. Based on our results, minigenes are a good approach to determine the implication of identified variants in the mRNA processing, and the analysis of RNA obtained from nasal epithelial cells is an alternative method to discriminate neutral Usher variants from those with a pathogenic effect on the splicing process. In addition, we could observe that the nasal ciliated epithelium of USH1 patients shows a lower ciliary beat frequency than control subjects.","variants":[{"Name":"NM_000260.4(MYO7A):c.3652G>A (p.Gly1218Arg)","Chromosome":"11","Start":"77190041","Stop":"77190041","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":52386,"rule_based_match":true,"evidence_text":"c.3652G>A","llm_judgment":"PRESENT","evidence":"c.3652G>A","abstract_start":1222,"abstract_end":1231},{"Name":"NM_000260.4(MYO7A):c.5856G>A (p.Lys1952=)","Chromosome":"11","Start":"77207402","Stop":"77207402","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":546845,"rule_based_match":true,"evidence_text":"c.5856G>A","llm_judgment":"PRESENT","evidence":"c.5856G>A","abstract_start":1208,"abstract_end":1217},{"Name":"NM_022124.6(CDH23):c.2289+1G>A","Chromosome":"10","Start":"71694260","Stop":"71694260","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":496950,"rule_based_match":true,"evidence_text":"c.2289+1G>A","llm_judgment":"PRESENT","evidence":"c.2289+1G>A","abstract_start":1247,"abstract_end":1258},{"Name":"NM_022124.6(CDH23):c.6049G>A (p.Gly2017Ser)","Chromosome":"10","Start":"71790413","Stop":"71790413","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":55165,"rule_based_match":true,"evidence_text":"c.6049G>A","llm_judgment":"PRESENT","evidence":"c.6049G>A","abstract_start":1260,"abstract_end":1269}]}
{"pmid":"24844923","title":"Frequency of SPINK1 N34S mutation in acute and recurrent acute pancreatitis.","abstract":"BACKGROUND: Several studies have reported association of c.101A>G (p.N34S) mutation in SPINK1 gene with chronic pancreatitis; however, the data on its relationship with acute pancreatitis (AP) and recurrent acute pancreatitis (RAP) are limited.\nMETHODS: We studied 183 unrelated patients with AP and RAP and 168 healthy controls for p.N34S variant in SPINK1 gene using sequencing of genomic DNA.\nRESULTS: SPINK1 p.N34S mutation was found in four of 168 (2.4%; all heterozygotes) controls and 22 of 183 (12.0%; including one homozygote) patients with AP (P = 0.006). On subgroup analysis, seven of 70 (10.0%) patients with gallstone-related AP, eight of 59 (13.6%; including one homozygote) patients with idiopathic AP, and six of 44 (14.6%) patients with alcohol-related AP had the p.N34S mutation (P = 0.027, 0.002 and 0.006, respectively, compared to controls). Frequency of this mutation was similar in patients with one episode of AP and those with recurrent AP (12% each). The first attack of AP occurred earlier in patients with p.N34S mutation than in those without it (mean ± SD age: 32.0 ± 9.7 versus 39.1 ± 13.4 years; P = 0.004). No patient had any other mutation in the exon 3 of the SPINK1 gene, whereas one control had a heterozygous p.P55S mutation.\nCONCLUSIONS: The p.N34S mutation in SPINK1 gene was found more frequently in patients with AP in the Indian population, irrespective of disease etiology and whether the disease was recurrent or not, and was associated with disease onset at an earlier age. These findings suggest that p.N34S mutation lowers the threshold for occurrence of AP irrespective of the causative insult.","variants":[{"Name":"NM_001379610.1(SPINK1):c.101A>G (p.Asn34Ser)","Chromosome":"5","Start":"147828115","Stop":"147828115","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":28799,"rule_based_match":true,"evidence_text":"c.101A>G (p.N34S)","llm_judgment":"PRESENT","evidence":"c.101A>G (p.N34S)","abstract_start":57,"abstract_end":74}]}
{"pmid":"29300302","title":"Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease.","abstract":"Mutations in the <i>OCRL</i> gene are associated with both Lowe syndrome and Dent-2 disease. Patients with Lowe syndrome present congenital cataracts, mental disabilities and a renal proximal tubulopathy, whereas patients with Dent-2 disease exhibit similar proximal tubule dysfunction but only mild, or no additional clinical defects. It is not yet understood why some <i>OCRL</i> mutations cause the phenotype of Lowe syndrome, while others develop the milder phenotype of Dent-2 disease. Our goal was to gain new insights into the consequences of <i>OCRL</i> exonic mutations on pre-mRNA splicing. Using predictive bioinformatics tools, we selected thirteen missense mutations and one synonymous mutation based on their potential effects on splicing regulatory elements or splice sites. These mutations were analyzed in a minigene splicing assay. Results of the RNA analysis showed that three presumed missense mutations caused alterations in pre-mRNA splicing. Mutation c.741G>T; p.(Trp247Cys) generated splicing silencer sequences and disrupted splicing enhancer motifs that resulted in skipping of exon 9, while mutations c.2581G>A; p.(Ala861Thr) and c.2581G>C; p.(Ala861Pro) abolished a 5' splice site leading to skipping of exon 23. Mutation c.741G>T represents the first <i>OCRL</i> exonic variant outside the conserved splice site dinucleotides that results in alteration of pre-mRNA splicing. Our results highlight the importance of evaluating the effects of <i>OCRL</i> exonic mutations at the mRNA level.","variants":[{"Name":"NM_000276.4(OCRL):c.2581G>C (p.Ala861Pro)","Chromosome":"X","Start":"129589956","Stop":"129589956","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1439848,"rule_based_match":true,"evidence_text":"c.2581G>C; p.(Ala861Pro)","llm_judgment":"PRESENT","evidence":"c.2581G>C; p.(Ala861Pro)","abstract_start":1157,"abstract_end":1181},{"Name":"NM_000276.4(OCRL):c.2581G>A (p.Ala861Thr)","Chromosome":"X","Start":"129589956","Stop":"129589956","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1862838,"rule_based_match":true,"evidence_text":"c.2581G>A; p.(Ala861Thr)","llm_judgment":"PRESENT","evidence":"c.2581G>A; p.(Ala861Thr)","abstract_start":1128,"abstract_end":1152}]}
{"pmid":"32902138","title":"Recessive MYH3 variants cause \"Contractures, pterygia, and variable skeletal fusions syndrome 1B\" mimicking Escobar variant multiple pterygium syndrome.","abstract":"The multiple pterygium syndromes (MPS) are rare disorders with disease severity ranging from lethal to milder forms. The nonlethal Escobar variant MPS (EVMPS) is characterized by multiple pterygia and arthrogryposis, as well as various additional features including congenital anomalies. The genetic etiology of EVMPS is heterogeneous and the diagnosis has been based either on the detection of pathogenic CHRNG variants (~23% of patients), or suggestive clinical features. We describe four patients with a clinical suspicion of EVMPS who manifested with multiple pterygia, mild flexion contractures of several joints, and vertebral anomalies. We revealed recessively inherited MYH3 variants as the underlying cause in all patients: two novel variants, c.1053C>G, p.(Tyr351Ter) and c.3102+5G>C, as compound heterozygous with the hypomorphic MYH3 variant c.-9+1G>A. Recessive MYH3 variants have been previously associated with spondylocarpotarsal synostosis syndrome. Our findings now highlight multiple pterygia as an important feature in patients with recessive MYH3 variants. Based on all patients with recessive MYH3 variants reported up to date, we consider that this disease entity should be designated as \"Contractures, pterygia, and variable skeletal fusions syndrome 1B,\" as recently suggested by OMIM. Our findings underline the importance of analyzing MYH3 in the differential diagnosis of EVMPS, particularly as the hypomorphic MYH3 variant might remain undetected by routine exome sequencing.","variants":[{"Name":"NM_002470.4(MYH3):c.-9+1G>A","Chromosome":"17","Start":"10656089","Stop":"10656089","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":578665,"rule_based_match":true,"evidence_text":"c.-9+1G>A","llm_judgment":"PRESENT","evidence":"c.-9+1G>A","abstract_start":854,"abstract_end":863}]}
{"pmid":"31434271","title":"Identification and Characterization of New Variants in","abstract":"Complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase) is the largest complex of the mitochondrial oxidative phosphorylation system (OXPHOS) system. Forty-four subunits encoded in nuclear and mitochondrial genomes compose this multiprotein complex, its assembly being a highly complex process involving at least 15 additional nuclear encoded assembly factors. Complex I deficiency is a mitochondrial disorder usually associated with early-onset severe multisystem disorders characterized by highly variable clinical manifestations. Flavin adenine dinucleotide (FAD)-dependent oxidoreductase domain-containing protein 1 (FOXRED1) is a complex I assembly factor. To date, only five patients with mitochondrial complex I deficiency due to mutations in <i>FOXRED1</i> have been characterized. Here, we describe a child with ataxia, epilepsy and psychomotor developmental delay carrying two heterozygous <i>FOXRED1</i> variants, c.920G>A (p.Gly307Glu) and c.733+1G>A. We demonstrate the molecular mechanism supporting the pathogenicity of the FOXRED1 variants, showing a clear deficiency of complex I activity. The reduction in the steady-state level of complex I holoenzyme in patient fibroblasts, confirmed the pathogenicity of the variants and showed the molecular mechanism behind their pathogenicity. A comparison of the clinical presentation of the index case with the previously described cases allowed deepening our knowledge about the clinical variability associated with <i>FOXRED1</i> defects.","variants":[{"Name":"NM_017547.4(FOXRED1):c.733+1G>A","Chromosome":"11","Start":"126275429","Stop":"126275429","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1699554,"rule_based_match":true,"evidence_text":"c.733+1G>A","llm_judgment":"PRESENT","evidence":"c.733+1G>A","abstract_start":976,"abstract_end":986},{"Name":"NM_017547.4(FOXRED1):c.920G>A (p.Gly307Glu)","Chromosome":"11","Start":"126276168","Stop":"126276168","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":211510,"rule_based_match":true,"evidence_text":"c.920G>A (p.Gly307Glu)","llm_judgment":"PRESENT","evidence":"c.920G>A (p.Gly307Glu)","abstract_start":949,"abstract_end":971}]}
{"pmid":"31944631","title":"Whole-exome sequencing identified a novel variant in an Iranian patient affected by pycnodysostosis.","abstract":"BACKGROUND: Whole-exome sequencing (WES) has emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. In this study, we aimed to find the potential genetic cause of skeletal disease, a heterogeneous disease, revealing the obvious short stature phenotype. In an Iranian family, we used solo-WES in a suspected patient to decipher the potential genetic cause(s).\nMETHODS: A comprehensive clinical and genotyping examination was applied to suspect the disease of the patient. The solo clinical WES was exploited, and the derived data were filtered according to the standard pipelines. In order to validate the WES finding, the region harboring the candidate variant in the CTSK gene was amplified from genomic DNA and sequenced directly by Sanger sequencing.\nRESULTS: Sequence analysis revealed a rare novel nonsense variant, p.(Trp320*); c.905G>A, in the CTSK gene (NM_000396.3). In silico analysis shed light on the contribution of the variant to the pathogenicity of pycnodysostosis. This variant was confirmed by Sanger sequencing and further clinical examinations of the patient confirmed the disease.\nCONCLUSION: The present study shows a rare variant of the CTSK gene, which inherited as autosomal recessive, in an Iranian male patient with pycnodysostosis. Taken together, the novel nonsense CTSK variant meets the criteria of being likely pathogenic according to the American College of Medical Genetics and Genomics-the Association for Molecular Pathology (ACMG-AMP) variant interpretation guidelines.","variants":[{"Name":"NM_000396.4(CTSK):c.905G>A (p.Trp302Ter)","Chromosome":"1","Start":"150796884","Stop":"150796884","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":672319,"rule_based_match":true,"evidence_text":"c.905G>A","llm_judgment":"PRESENT","evidence":"c.905G>A","abstract_start":865,"abstract_end":873}]}
{"pmid":"29257216","title":"Molecular mechanisms of Ellis‑van Creveld gene variations in ventricular septal defect.","abstract":"The Ellis-van Creveld (EVC) gene is associated with various congenital heart diseases. However, studies on EVC gene variations in ventricular septal defect (VSD) and the underlying molecular mechanisms are sparse. The present study detected 11 single‑nucleotide polymorphisms (SNPs) in 65 patients with VSD and 210 control patients from the Chinese Han population. Of the identified SNPs only the c.1727G>A SNP site was positively associated with the development of VSD (P<0.007). A known mutation, c.343C>G, was also identified, which causes a leucine to valine substitution at amino acid 115 of the EVC protein (p.L115V). The results of functional prediction indicated that c.343C>G may be a pathogenic mutation. In addition, in NIH3T3 mouse embryonic fibroblast cells, the EVC c.343C>G mutation significantly decreased cell proliferation and increased apoptosis. Further investigation demonstrated that in NIH3T3 cells, overexpression of EVC c.343C>G mutation reduced the binding between EVC and smoothened, which further downregulated the activity of the hedgehog (Hh) signaling pathway and the expression of downstream cyclin D1 and B‑cell lymphoma 2 proteins with SAG. The c.1727G>A SNP of the EVC gene increased VSD susceptibility in patients from the Chinese Han population. The molecular mechanism underlying the development of VSD induced by the EVC c.343C>G mutation may be due to a reduction in the anti‑apoptotic and proliferative abilities of cardiomyocytes via downregulation of Hh pathway activity. The results of the present study may provide novel targets for the diagnosis and treatment of patients with VSD.","variants":[{"Name":"NM_153717.3(EVC):c.343C>G (p.Leu115Val)","Chromosome":"4","Start":"5729349","Stop":"5729349","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3498457,"rule_based_match":true,"evidence_text":"c.343C>G","llm_judgment":"PRESENT","evidence":"c.343C>G","abstract_start":499,"abstract_end":507}]}
{"pmid":"30723317","title":"Homozygous frame shift variant in ATP7B exon 1 leads to bypass of nonsense-mediated mRNA decay and to a protein capable of copper export.","abstract":"Wilson disease (WD) is an autosomal recessive disease of copper excess due to pathogenic variants in the ATP7B gene coding for a copper-transporting ATPase. We present a 5-year-old girl with the homozygous frame shift variant NM_000053.3: c.19_20del in exon 1 of ATP7B (consecutive exon numbering with c.1 as first nucleotide of exon 1), detected by whole-exome sequencing as a secondary finding. The variant leads to a premature termination codon in exon 2. The girl exhibited no WD symptoms and no abnormalities in liver biopsy. ATP7B liver mRNA expression was comparable to healthy controls suggesting that nonsense-mediated mRNA decay (NMD) could be bypassed by the mechanism of translation reinitiation. To verify this hypothesis, a CMV-driven ATP7B minigene (pcDNA3) was equipped with the authentic ATP7B 5' untranslated region  and a truncated intron 2. We introduced c.19_20del by site-directed mutagenesis and overexpressed the constructs in HEK293T cells. We analyzed ATP7B expression by qRT-PCR, northern and western blot, and examined protein function by copper export capacity assays. Northern blot, qRT-PCR, and western blot revealed that c.19_20del ATP7B mRNA and protein is expressed in size and amount comparable to wild-type. Copper export capacity was also comparable to wild-type. Our results indicate that c.19_20del in ATP7B is able to bypass NMD by translation reinitiation, demonstrating that the classification of truncating variants as pathogenic without additional investigations should be done carefully.","variants":[{"Name":"NM_000053.4(ATP7B):c.19_20del (p.Gln7fs)","Chromosome":"13","Start":"52011318","Stop":"52011319","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":409038,"rule_based_match":true,"evidence_text":"c.19_20del","llm_judgment":"PRESENT","evidence":"c.19_20del","abstract_start":239,"abstract_end":249}]}
{"pmid":"23495813","title":"Polymicrogyria with dysmorphic basal ganglia? Think tubulin!","abstract":"Dominant mutations in TUBB2B have been reported in patients with polymicrogyria. We further explore the phenotype associated with mutations in TUBB2B. Twenty patients with polymicrogyria (five unilateral) were tested for mutations in TUBB2B by Sanger sequencing. We identified two novel de novo mutations, c.743C>T (p.Ala248Val) and c.1139G>T (p.Arg380Leu) in exon 4 of TUBB2B in three unrelated families. Brain magnetic resonance images showed polymicrogyria involving predominantly the perisylvian regions. In addition, there was a dysmorphic appearance of the basal ganglia, thin corpus callosum, enlargement of the ventricles, thinning of the white matter and hypoplasia of pons and cerebellar vermis. This combination of associated features was absent in all 17 patients with polymicrogyria in whom no mutation was identified. This report underlines that the association of polymicrogyria with thin or absent corpus callosum, dysmorphic basal ganglia, brainstem and vermis hypoplasia is highly likely to result from mutations in TUBB2B and provides further insight in how mutations in TUBB2B affect protein function.","variants":[{"Name":"NM_178012.5(TUBB2B):c.743C>T (p.Ala248Val)","Chromosome":"6","Start":"3225346","Stop":"3225346","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":369100,"rule_based_match":true,"evidence_text":"c.743C>T (p.Ala248Val)","llm_judgment":"PRESENT","evidence":"c.743C>T (p.Ala248Val)","abstract_start":306,"abstract_end":328}]}
{"pmid":"28503735","title":"WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia: A consistent neurodevelopmental syndrome.","abstract":"The advancement in genomic sequencing has greatly improved the diagnostic yield for neurodevelopmental disorders and led to the discovery of large number of novel genes associated with these disorders. WDR45B has been identified as a potential intellectual disability gene through genomic sequencing of 2 large cohorts of affected individuals. In this report we present 6 individuals from 3 unrelated families with homozygous pathogenic variants in WDR45B: c.799C>T (p.Q267*) in 1 family and c.673C>T (p.R225*) in 2 families. These individuals shared a similar phenotype including profound development delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations. Neuroimaging showed ventriculomegaly, reduced cerebral white matter volume, and thinning of cerebral gray matter. The consistency in the phenotype strongly supports that WDR45B is associated with this disease.","variants":[{"Name":"NM_019613.4(WDR45B):c.673C>T (p.Arg225Ter)","Chromosome":"17","Start":"82619074","Stop":"82619074","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188893,"rule_based_match":true,"evidence_text":"c.673C>T (p.R225*)","llm_judgment":"PRESENT","evidence":"c.673C>T (p.R225*)","abstract_start":492,"abstract_end":510},{"Name":"NM_019613.4(WDR45B):c.799C>T (p.Gln267Ter)","Chromosome":"17","Start":"82617303","Stop":"82617303","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":514319,"rule_based_match":true,"evidence_text":"c.799C>T (p.Q267*)","llm_judgment":"PRESENT","evidence":"c.799C>T (p.Q267*)","abstract_start":457,"abstract_end":475}]}
{"pmid":"15151504","title":"Study of the WFS1 gene and mitochondrial DNA in Spanish Wolfram syndrome families.","abstract":"Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by early onset diabetes mellitus and progressive optic atrophy. Patients with WS frequently develop deafness, diabetes insipidus, renal tract abnormalities, and diverse psychiatric illnesses, among others. A gene responsible for WS was identified on 4p16.1 (WFS1). It encodes a putative 890 amino acid transmembrane protein present in a wide spectrum of tissues. A new locus for WS has been located on 4q22-24, providing evidence for the genetic heterogeneity of this syndrome. Six Spanish families with a total of seven WS patients were screened for mutations in the WFS1-coding region by direct sequencing. We found three previously undescribed mutations c.873C > A, c.1949_50delAT, and c.2206G > C, as well as the duplication c.409_424dup16, formerly published as 425ins16. Several groups had detected deletions in the mitochondrial DNA (mtDNA) of WS patients. For this reason, we also studied the presence of mtDNA rearrangements as well as Leber's hereditary optic neuropathy, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, and A1555G point mutations in the WS families. No mtDNA abnormalities were detected.","variants":[{"Name":"NM_006005.3(WFS1):c.2206G>C (p.Gly736Arg)","Chromosome":"4","Start":"6302001","Stop":"6302001","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2894673,"rule_based_match":true,"evidence_text":"c.2206G > C","llm_judgment":"PRESENT","evidence":"c.2206G > C","abstract_start":778,"abstract_end":789},{"Name":"NM_006005.3(WFS1):c.1949_1950del (p.Tyr650fs)","Chromosome":"4","Start":"6301743","Stop":"6301744","ReferenceAlleleVCF":"CTA","AlternateAlleleVCF":"C","allel_id":918251,"rule_based_match":false,"evidence_text":"c.1949_50delAT","llm_judgment":"PRESENT","evidence":"c.1949_50delAT","abstract_start":758,"abstract_end":772},{"Name":"NM_006005.3(WFS1):c.409_424dup (p.Val142fs)","Chromosome":"4","Start":"6289078","Stop":"6289079","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AGGGCCGTCGCGAGGCT","allel_id":19558,"rule_based_match":true,"evidence_text":"c.409_424dup16","llm_judgment":"PRESENT","evidence":"c.409_424dup16","abstract_start":818,"abstract_end":832}]}
{"pmid":"18205204","title":"Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase.","abstract":"Published mutations in deoxyguanosine kinase (DGUOK) cause mitochondrial DNA depletion and a clinical phenotype that consists of neonatal liver failure, nystagmus and hypotonia. In this series, we have identified 15 different mutations in the DGUOK gene from 9 kindreds. Among them, 12 have not previously been reported. Nonsense, splice site, or frame-shift mutations that produce truncated proteins predominate over missense mutations. All patients who harbor null mutations had early onset liver failure and significant neurological disease. These patients have all died before 2-years of age. Conversely, two patients carrying missense mutations had isolated liver disease and are alive in their 4th year of life without liver transplant. Five subjects were detected by newborn screening, with elevated tyrosine or phenylalanine. Consequently, this disease should be considered if elevated tyrosine is identified by newborn screening. Mitochondrial DNA content was below 10% of controls in liver in all but one case and modestly reduced in blood cells. With this paper a total of 39 different mutations in DGUOK have been identified. The most frequent mutation, c.763_c.766dupGATT, occurs in 8 unrelated kindreds. 70% of mutations occur in only one kindred, suggesting full sequencing of this gene is required for diagnosis. The presentation of one case with apparent viral hepatitis, without neurological disease, suggests that this disease should be considered in patients with infantile liver failure regardless of the presence of neurological features or apparent infectious etiology.","variants":[{"Name":"NM_080916.3(DGUOK):c.763_766dup (p.Phe256Ter)","Chromosome":"2","Start":"73958199","Stop":"73958200","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ATGAT","allel_id":23194,"rule_based_match":false,"evidence_text":"c.763_c.766dupGATT","llm_judgment":"PRESENT","evidence":"c.763_c.766dupGATT","abstract_start":1166,"abstract_end":1184}]}
{"pmid":"23430512","title":"The Acid Sphingomyelinase Sequence Variant p.A487V Is Not Associated With Decreased Levels of Enzymatic Activity.","abstract":"Rare loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene are known to dramatically decrease the catalytic activity of acid sphingomyelinase (ASM), resulting in an autosomal recessive lysosomal storage disorder known as Niemann-Pick disease (NPD) type A and B. In contrast to the general low frequency of those deleterious mutations, we found a relatively high frequency for the proposed type B NPD variant c.1460C>T (p.A487V) in our sample of 58 patients suffering from Major Depressive Disorder. We therefore investigated the biochemical consequences of this variant more closely. Our in vivo data derived from blood cell analyses indicated cellular ASM activity levels in the normal range. The secreted ASM activity levels in blood plasma were slightly lower, but still above those levels reported for type B NPD patients. In vitro expression studies of this ASM variant in different cell lines confirmed these results, showing cellular and secreted enzymatic activities equivalent to those of wild-type ASM and similar expression levels. Thus, we conclude that the ASM variant c.1460C>T (p.A487V) is not a rare missense mutation but an SMPD1 sequence variant that yields a protein with functional catalytic characteristics.","variants":[{"Name":"NM_000543.5(SMPD1):c.1460C>T (p.Ala487Val)","Chromosome":"11","Start":"6394015","Stop":"6394015","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":237172,"rule_based_match":true,"evidence_text":"c.1460C>T (p.A487V)","llm_judgment":"PRESENT","evidence":"c.1460C>T (p.A487V)","abstract_start":435,"abstract_end":454}]}
{"pmid":"17551081","title":"Autosomal recessive postlingual hearing loss (DFNB8): compound heterozygosity for two novel TMPRSS3 mutations in German siblings.","abstract":"Mutations in the transmembrane protease, serine 3 (TMPRSS3) gene, encoding a transmembrane serine protease, cause autosomal recessive deafness childhood (DFNB8) or congenital onset (DFNB10). TMPRSS3 mutations have been mainly identified in patients from Asian and Mediterranean countries and seem to be a rare finding in the Northern European population so far. The identification of two novel pathogenic TMPRSS3 mutations (c.646C-->T - R216C; c.916G-->A - A306T) is described in four affected siblings of German origin with postlingual hearing loss, treated by bilateral cochlear implantation with good results. Although TMPRSS3 mutations are supposed to be a rare cause of autosomal recessive hearing loss, in families with postlingual disease onset TMPRSS3 is the most favourable candidate gene after exclusion of GJB2 mutations.","variants":[{"Name":"NM_001256317.3(TMPRSS3):c.916G>A (p.Ala306Thr)","Chromosome":"21","Start":"42382101","Stop":"42382101","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":55296,"rule_based_match":false,"evidence_text":"c.916G-->A - A306T","llm_judgment":"PRESENT","evidence":"c.916G-->A - A306T","abstract_start":444,"abstract_end":462},{"Name":"NM_001256317.3(TMPRSS3):c.646C>T (p.Arg216Cys)","Chromosome":"21","Start":"42383169","Stop":"42383169","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1165206,"rule_based_match":false,"evidence_text":"c.646C-->T - R216C","llm_judgment":"PRESENT","evidence":"c.646C-->T - R216C","abstract_start":424,"abstract_end":442}]}
{"pmid":"27390512","title":"Mutation survey and genotype-phenotype analysis of COL2A1 and COL11A1 genes in 16 Chinese patients with Stickler syndrome.","abstract":"PURPOSE: To identify mutations in COL2A1 and COL11A1 genes and to examine the genotype-phenotype correlation in a cohort of Chinese patients with Stickler syndrome.\nMETHODS: A total of 16 Chinese probands with Stickler syndrome were recruited, including nine with a family history of an autosomal dominant pattern and seven sporadic cases. All patients underwent full ocular and systemic examinations. Sanger sequencing was used to analyze all coding and adjacent regions of the COL2A1 and COL11A1 genes. Multiplex ligation-dependent probe amplification was performed to detect the gross indels of COL2A1 and COL11A1. Bioinformatics analysis was performed to evaluate the pathogenicity of the variants.\nRESULTS: Five mutations in COL2A1 were identified in six of 16 probands, including three novel (c.85C>T, c.3356delG, c.3401delG) mutations and two known mutations (c.1693C>T, c.2710C>T). Of the five mutations, three were truncated mutations, and the other two were missense mutations. Putative pathogenic mutations of the COL11A1 gene were absent in this cohort of patients. Gross indels were not found in COL2A1 or COL11A1 in any of the probands. High myopia was the most frequent initial ocular phenotype of Stickler syndrome. In this study, 12 Chinese probands lacked obvious systemic phenotypes.\nCONCLUSIONS: In this study, three novel and two known mutations in the COL2A1 gene were identified in six of 16 Chinese patients with Stickler syndrome. This is the first study in a cohort of Chinese patients with Stickler syndrome, and the results expand the mutation spectrum of the COL2A1 gene. Analysis of the genotype-phenotype correlation showed that the early onset of high myopia with vitreous abnormalities may serve as a key indicator of Stickler syndrome, while the existence of mandibular protrusion in pediatric patients may be an efficient indicator for the absence of mutations in COL2A1 and COL11A1.","variants":[{"Name":"NM_001844.5(COL2A1):c.2710C>T (p.Arg904Cys)","Chromosome":"12","Start":"47979534","Stop":"47979534","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32418,"rule_based_match":true,"evidence_text":"c.2710C>T","llm_judgment":"PRESENT","evidence":"c.2710C>T","abstract_start":878,"abstract_end":887},{"Name":"NM_001844.5(COL2A1):c.85C>T (p.Gln29Ter)","Chromosome":"12","Start":"48004237","Stop":"48004237","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":859971,"rule_based_match":true,"evidence_text":"c.85C>T","llm_judgment":"PRESENT","evidence":"c.85C>T","abstract_start":799,"abstract_end":806},{"Name":"NM_001844.5(COL2A1):c.1693C>T (p.Arg565Cys)","Chromosome":"12","Start":"47985575","Stop":"47985575","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32422,"rule_based_match":true,"evidence_text":"c.1693C>T","llm_judgment":"PRESENT","evidence":"c.1693C>T","abstract_start":867,"abstract_end":876},{"Name":"NM_001844.5(COL2A1):c.3356del (p.Gly1119fs)","Chromosome":"12","Start":"47976891","Stop":"47976891","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":514639,"rule_based_match":true,"evidence_text":"c.3356delG","llm_judgment":"PRESENT","evidence":"c.3356delG","abstract_start":808,"abstract_end":818}]}
{"pmid":"29989442","title":"A Novel EXT1 Mutation Identified in a Family with Multiple Osteochondromas.","abstract":"AIMS: Multiple exostoses (MO), also referred to as hereditary multiple exostoses (HME), is an autosomal dominant inherited skeletal disorder that has been found to be associated with mutations in the EXT1 and EXT2 genes. In the present study, we report a Chinese family with HME and our mutational analyses of the EXT1 and EXT2 genes in affected and unaffected individuals.\nMETHODS: All exons of the EXT1 and EXT2 genes in seven family members were polymerase chain reaction amplified from blood and sequenced.\nRESULTS: A heterozygous mutation (c.1056G>T) was identified in exon 2 of the EXT1 gene in the proband and other affected family members; this mutation was not found in the unaffected family members.\nDISCUSSION: This c.1056G>T mutation is located in the exostosin domain of the EXT1 protein and leads to an amino acid change of Glutamine (Gln) to Histidine (His) at position 352. Homology searches reveal that Gln352 is highly conserved in many species and may play an essential role in the normal function of the EXT1 protein.\nCONCLUSIONS: This study contributes to a better understanding of the genetic basis of HME, expands the known mutational spectrum of EXT1, and provides a reference for genetic counseling and prenatal diagnosis of this family.","variants":[{"Name":"NM_000127.3(EXT1):c.1056G>T (p.Gln352His)","Chromosome":"8","Start":"117837108","Stop":"117837108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":945839,"rule_based_match":true,"evidence_text":"c.1056G>T","llm_judgment":"PRESENT","evidence":"c.1056G>T","abstract_start":545,"abstract_end":554}]}
{"pmid":"25612912","title":"A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A.","abstract":"BACKGROUND: Trichothiodystrophy (TTD) is a group of rare autosomal recessive disorders that variably affect a wide range of organs derived from the neuroectoderm. The key diagnostic feature is sparse, brittle, sulfur deficient hair that has a 'tiger-tail' banding pattern under polarising light microscopy.\nPATIENTS AND METHODS: We describe two male cousins affected by TTD associated with microcephaly, profound intellectual disability, sparse brittle hair, aged appearance, short stature, facial dysmorphism, seizures, an immunoglobulin deficiency, multiple endocrine abnormalities, cerebellar hypoplasia and partial absence of the corpus callosum, in the absence of cellular photosensitivity and ichthyosis. Obligate female carriers showed 100% skewed X-chromosome inactivation. Linkage analysis and Sanger sequencing of 737 X-chromosome exons and whole exome sequencing was used to find the responsible gene and mutation.\nRESULTS: Linkage analysis localised the disease allele to a 7.75 Mb interval from Xq23-q25. We identified a nonsense mutation in the highly conserved RNF113A gene (c.901 C>T, p.Q301*). The mutation segregated with the disease in the family and was not observed in over 100,000 control X chromosomes. The mutation markedly reduced RNF113A protein expression in extracts from lymphoblastoid cell lines derived from the affected individuals.\nCONCLUSIONS: The association of RNF113A mutation with non-photosensitive TTD identifies a new locus for these disorders on the X chromosome. The extended phenotype within this family includes panhypopituitarism, cutis marmorata and congenital short oesophagus.","variants":[{"Name":"NM_006978.3(RNF113A):c.901C>T (p.Gln301Ter)","Chromosome":"X","Start":"119870713","Stop":"119870713","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":190169,"rule_based_match":true,"evidence_text":"c.901 C>T, p.Q301*","llm_judgment":"PRESENT","evidence":"c.901 C>T, p.Q301*","abstract_start":1090,"abstract_end":1108}]}
{"pmid":"23838540","title":"A Novel mutation in the SLC26A4 gene in a Chinese family with Pendred syndrome.","abstract":"OBJECTIVE: To investigate the mutations in the SLC26A4 gene in a Chinese patient with Pendred syndrome.\nMETHODS: The diagnosis of Pendred syndrome was confirmed by the family history, pure tone audiogram, perchlorate discharge test (PDT), and computed tomography (CT) of the temporal bone. DNA extraction, PCR and DNA sequencing were performed according to standard procedures. Mutations in the SLC26A4 gene were compared with 100 unrelated subjects to exclude common polymorphism. Splice-site mutation was further confirmed by restriction enzyme length polymorphism (RFLP) with the specifically designed primers.\nRESULTS: The proband presented with typical features of bilateral sensorineural deafness since childhood and goiter development in the early adulthood. Thyroid studies disclosed euthyroidism with elevated thyroglobulin, but negative for PDT. Marked enlargement of bilateral vestibular aqueduct (>1.5 mm) was found by CT of the temporal bone. A novel SLC26A4 splice-site mutation c.1263+1G>A (IVS10+1G>A) was identified in compound heterozygosity with the missense mutation c.1079C>T (p.A360V) in the proband. Both mutations were not found in the 100 unrelated Chinese.\nCONCLUSIONS: Our results support previous findings that Pendred syndrome can be caused by compound heterozygous mutation in the SLC26A4 gene, in which IVS10+1G>A is a novel pathogenic mutation.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1079C>T (p.Ala360Val)","Chromosome":"7","Start":"107689130","Stop":"107689130","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186734,"rule_based_match":true,"evidence_text":"c.1079C>T (p.A360V)","llm_judgment":"PRESENT","evidence":"c.1079C>T (p.A360V)","abstract_start":1087,"abstract_end":1106},{"Name":"NM_000441.2(SLC26A4):c.1263+1G>A","Chromosome":"7","Start":"107690238","Stop":"107690238","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":357543,"rule_based_match":true,"evidence_text":"c.1263+1G>A (IVS10+1G>A)","llm_judgment":"PRESENT","evidence":"c.1263+1G>A (IVS10+1G>A)","abstract_start":993,"abstract_end":1017}]}
{"pmid":"22906837","title":"Molecular characterization of glucose-6-phosphate dehydrogenase deficiency among Jordanians.","abstract":"BACKGROUND/AIMS: In Jordan, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a significant health problem, and the incidence was reported to be about 3.6%. The aims of this study are to investigate the most common molecular mutations of the G6PD gene among Jordanians in northern Jordan and to examine the correlation between the genotype and phenotype of this enzyme deficiency.\nMETHODS: Seventy-five blood samples were collected from patients attending King Abdullah University Hospital and Princess Rahma Teaching Hospital. The G6PD gene was scanned for mutations using a DNA sequencing technique.\nRESULTS: Our results showed 11 variations (7 exonic and 4 intronic) as follows: c.202 G>A (rs1050828), c.376 A>G (rs1050829), c.404 A>C (CM962574 single-nucleotide polymorphism), c.542 A>T (rs5030872), c.563 C>T (rs5030868), c.1003 G>A (rs5030869), c.1311 C>T (rs2230037), c.486-90 C>T, c.486-60 C>G (rs2515904), c.770+175 C>T (rs2515905) and c.1311 C>T (rs2230037). Among these, G6PD Mediterranean (c.563 C>T) was the most common in our patients, with a frequency of 76.2%, followed by G6PD A- (c.202 G>A + c.376 A>G) with 19%, and an equal frequency of 1.6% was found for G6PD Chatham (c.1003 G>A), G6PD Santamaria (c.542 A>T + c.376 A>G) and G6PD Cairo (c.404 A>C).\nCONCLUSION: This is the first report of G6PD Santamaria and Cairo among our Jordanian population.","variants":[{"Name":"NM_001360016.2(G6PD):c.404A>C (p.Asn135Thr)","Chromosome":"X","Start":"154535249","Stop":"154535249","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":849843,"rule_based_match":true,"evidence_text":"c.404 A>C","llm_judgment":"PRESENT","evidence":"c.404 A>C","abstract_start":733,"abstract_end":742}]}
{"pmid":"23877401","title":"A truncating mutation in B3GNT1 causes severe Walker-Warburg syndrome.","abstract":"Walker-Warburg syndrome (WWS) is a genetically heterogeneous form of congenital muscular dystrophy with significant brain and ocular involvement. In a multiplex consanguineous family with severe WWS phenotype, autozygome-guided sequencing of previously reported WWS genes was negative. Exome sequencing followed by autozygome filtration revealed a homozygous two-base pair insertion in B3GNT1 (NM_006876.2:c.821_822insTT), leading to premature truncation of the protein (p.Glu274Aspfs*94). Recently, two missense mutations in this gene have been reported as probably causal in a family with WWS. This report describes the first truncating mutation in B3GNT1 and confirms that this gene, which plays a role in αDG glycosylation, is a bona fide disease gene in WWS.","variants":[{"Name":"NM_006876.3(B4GAT1):c.821_822insTT (p.Glu274fs)","Chromosome":"11","Start":"66346724","Stop":"66346725","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CAA","allel_id":181432,"rule_based_match":true,"evidence_text":"NM_006876.2:c.821_822insTT","llm_judgment":"PRESENT","evidence":"NM_006876.2:c.821_822insTT","abstract_start":394,"abstract_end":420}]}
{"pmid":"33008772","title":"A rare HCN4 variant with combined sinus bradycardia, left atrial dilatation, and hypertrabeculation/left ventricular noncompaction phenotype.","abstract":"INTRODUCTION AND OBJECTIVES: HCN4 variants have been reported to cause combined sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy. This relationship has been proven in few cases and no previous patients have associated left atrial dilatation (LAD). Our objective was to study a familial disorder characterized by SSS, LAD, and hypertrabeculation/LVNC and to identify the underlying genetic and electrophysiological characteristics.\nMETHODS: A family with SSS and LVNC underwent a clinical, genetic, and electrophysiological assessment. They were studied via electrocardiography, Holter recording, echocardiography, and exercise stress tests; cardiac magnetic resonance imaging was additionally performed in affected individuals. Genetic testing was undertaken with targeted next-generation sequencing, as well as a functional study of the candidate variant in Chinese hamster ovary cells.\nRESULTS: Twelve members of the family had sinus bradycardia, associated with complete criteria of LVNC in 4 members and hypertrabeculation in 6 others, as well as LAD in 9 members. A HCN4 c.1123C>T;(p.R375C) variant was present in heterozygosis in all affected patients and absent in unaffected individuals. Electrophysiological analyses showed that the amplitude and densities of the HCN4 currents (I<sub>HCN4</sub>) generated by mutant p.R375C HCN4 channels were significantly lower than those generated by wild-type channels.\nCONCLUSIONS: The combined phenotype of SSS, LAD, and LVNC is associated with the heritable HCN4 c.1123C>T;(p.R375C) variant. HCN4 variants should be included in the genetic diagnosis of LVNC cardiomyopathy and of patients with familial forms of SSS, as well as of individuals with sinus bradycardia and LAD.","variants":[{"Name":"NM_005477.3(HCN4):c.1123C>T (p.Arg375Cys)","Chromosome":"15","Start":"73343471","Stop":"73343471","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":573524,"rule_based_match":true,"evidence_text":"HCN4 c.1123C>T;(p.R375C)","llm_judgment":"PRESENT","evidence":"HCN4 c.1123C>T;(p.R375C)","abstract_start":1105,"abstract_end":1129}]}
{"pmid":"23807894","title":"A case of familial X-linked thrombocytopenia with a novel WAS gene mutation.","abstract":"Wiskott-Aldrich syndrome (WAS) is an inherited X-linked disorder. The WAS gene is located on the X chromosome and undergoes mutations, which affect various domains of the WAS protein, resulting in recurrent infection, eczema, and thrombocytopenia. However, the clinical features and severity of the disease vary according to the type of mutations in the WAS gene. Here, we describe the case of a 4-year-old boy with a history of marked thrombocytopenia since birth, who presented with recurrent herpes simplex infection and late onset of eczema. Examination of his family history revealed that older brother, who died from intracranial hemorrhage, had chronic idiopathic thrombocytopenia. Therefore, we proceeded with genetic analysis and found a new deletion mutation in the WAS gene: c.858delC (p.ser287Leufs(*)21) as a hemizygous form.","variants":[{"Name":"NM_000377.3(WAS):c.858del (p.Ser287fs)","Chromosome":"X","Start":"48688379","Stop":"48688379","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":650086,"rule_based_match":true,"evidence_text":"c.858delC (p.ser287Leufs(*)21)","llm_judgment":"PRESENT","evidence":"c.858delC (p.ser287Leufs(*)21)","abstract_start":786,"abstract_end":816}]}
{"pmid":"23606313","title":"A Novel Exonic Splicing Mutation in the TAZ (G4.5) Gene in a Case with Atypical Barth Syndrome.","abstract":"OBJECTIVE: Barth syndrome is an X-linked recessive disorder characterized by dilated cardiomyopathy, neutropenia, 3-methylglutaconic aciduria, abnormal mitochondria, variably expressed skeletal myopathy, and growth delay. The disorder is caused by mutations in the tafazzin (TAZ/G4.5) gene located on Xq28. We report a novel exonic splicing mutation in the TAZ gene in a patient with atypical Barth syndrome.\nPATIENT & METHODS: The 4-month-old proband presented with respiratory distress, neutropenia, and dilated cardiomyopathy with reduced ejection fraction of 10%. No 3-methylglutaconic aciduria was detected on repeated urine organic acid analyses. Family history indicated that his maternal uncle died of endocardial fibroelastosis and dilated cardiomyopathy at 26 months. TAZ DNA sequencing, mRNA analysis, and cardiolipin analysis were performed.\nRESULTS: A novel nucleotide substitution c.553A>G in exon 7 of the TAZ gene was identified in the proband, predicting an amino acid substitution p.Met185Val. However, this mutation created a new splice donor signal within exon 7 causing mis-splicing of the message, producing two messages that only differ in the presence/absence of exon 5; these retain intron 6 and have only 11 bases of exon 7. Cardiolipin analysis confirmed the loss of tafazzin activity. The proband's mother, maternal aunt, and grandmother carry the same mutation.\nCONCLUSIONS: The identification of a TAZ gene mutation, mRNA analysis, and monolysocardiolipin/cardiolipin ratio determination were important for the diagnosis and genetic counseling in this family with atypical Barth syndrome that was not found to be associated with 3-methylglutaconic aciduria.","variants":[{"Name":"NM_000116.5(TAFAZZIN):c.553A>G (p.Met185Val)","Chromosome":"X","Start":"154419716","Stop":"154419716","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1878465,"rule_based_match":true,"evidence_text":"c.553A>G","llm_judgment":"PRESENT","evidence":"c.553A>G","abstract_start":895,"abstract_end":903}]}
{"pmid":"37316763","title":"Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma.","abstract":"The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis.245 words.","variants":[{"Name":"NM_003153.5(STAT6):c.1255G>C (p.Asp419His)","Chromosome":"12","Start":"57102879","Stop":"57102879","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2750259,"rule_based_match":true,"evidence_text":"STAT6 c.1255G > C, p.D419H","llm_judgment":"PRESENT","evidence":"STAT6 c.1255G > C, p.D419H","abstract_start":280,"abstract_end":306}]}
{"pmid":"31708252","title":"The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation.","abstract":"BACKGROUND: Wilson's disease (WD) is a rare inherited disorder caused by mutations in the ATP7B gene resulting in copper accumulation in different organs. However, data on ATP7B mutation spectrum in Russia and worldwide are insufficient and contradictory. The objective of the present study was estimation of the frequency of ATP7B gene mutations in the Russian population of WD patients.\nMATERIALS AND METHODS: 75 WDpatients were examined by next-generation sequencing (NGS). A targeted panel NimbleGen SeqCap EZ Choice: 151012_HG38_CysFib_EZ_HX3 (ROCHE)was designed for analysis of ATP7B gene and possible modifier genes. Retrospective assessment of a diagnostic WD score (Leipzig, 2001) was also performed.\nRESULTS: 31 mutations in ATP7B gene were detected. Two most frequent mutations were c.3207C > A (51,85% of alleles) and c.3190 G > A (8,64% of alleles). Single rare mutations were detected in 29% of cases. In 96% cases mutations of both copies of the ATP7B were revealed. We also observed 3 novel potentially pathogenic variants which were not previously described (c.1870-8A > G, c.3655A > T (p.Ile1219Phe), c.3036dupC (p.Lys1013fs). For 25% of patients at the time of the manifestation the diagnosis WD could not be established using the earlier proposed diagnostic score. There was a remarkable delay in diagnosis for the majority of patients. Only 33% of patients WD was diagnosed in three months after the first symptoms, 29%patients - in 3-12 months, 30% - in 1-10 years, in 8% - more than 10 years. Generally, clinical appearance of WD may be rather variable at manifestation and genetic profiling at this step is the only way to confirm the presence of WD.","variants":[{"Name":"NM_000053.4(ATP7B):c.3036dup (p.Lys1013fs)","Chromosome":"13","Start":"51946307","Stop":"51946308","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":487600,"rule_based_match":true,"evidence_text":"c.3036dupC (p.Lys1013fs)","llm_judgment":"PRESENT","evidence":"c.3036dupC (p.Lys1013fs)","abstract_start":1119,"abstract_end":1143},{"Name":"NM_000053.4(ATP7B):c.3207C>A (p.His1069Gln)","Chromosome":"13","Start":"51944145","Stop":"51944145","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":18887,"rule_based_match":true,"evidence_text":"c.3207C > A","llm_judgment":"PRESENT","evidence":"c.3207C > A","abstract_start":794,"abstract_end":805}]}
{"pmid":"26957899","title":"Exome sequencing identified null mutations in LOXL3 associated with early-onset high myopia.","abstract":"PURPOSE: To identify null mutations in novel genes associated with early-onset high myopia using whole exome sequencing.\nMETHODS: Null mutations, including homozygous and compound heterozygous truncations, were selected from whole exome sequencing data for 298 probands with early-onset high myopia. These data were compared with those of 507 probands with other forms of eye diseases. Null mutations specific to early-onset high myopia were considered potential candidates. Candidate mutations were confirmed with Sanger sequencing and were subsequently evaluated in available family members and 480 healthy controls.\nRESULTS: A homozygous frameshift mutation (c.39dup; p.L14Afs*21) and a compound heterozygous frameshift mutation (c.39dup; p.L14Afs*21 and c.594delG; p.Q199Kfs*35) in LOXL3 were separately identified in two of the 298 probands with early-onset high myopia. These mutations were confirmed with Sanger sequencing and were not detected in 1,974 alleles of the controls from the same region (507 individuals with other conditions and 480 healthy control individuals). These two probands were singleton cases, and their parents had only heterozygous mutations. A homozygous missense mutation in LOXL3 was recently reported in a consanguineous family with Stickler syndrome.\nCONCLUSIONS: Our results suggest that null mutations in LOXL3 are likely associated with autosomal recessive early-onset high myopia. LOXL3 is a potential candidate gene for high myopia, but this possibility should be confirmed in additional studies. LOXL3 null mutations in human beings are not lethal, providing a phenotype contrary to that in mice.","variants":[{"Name":"NM_032603.5(LOXL3):c.39dup (p.Leu14fs)","Chromosome":"2","Start":"74552595","Stop":"74552596","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":1334746,"rule_based_match":true,"evidence_text":"c.39dup","llm_judgment":"PRESENT","evidence":"c.39dup","abstract_start":662,"abstract_end":669},{"Name":"NM_032603.5(LOXL3):c.594del (p.Gln199fs)","Chromosome":"2","Start":"74549467","Stop":"74549467","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1334747,"rule_based_match":true,"evidence_text":"c.594delG; p.Q199Kfs*35","llm_judgment":"PRESENT","evidence":"c.594delG; p.Q199Kfs*35","abstract_start":758,"abstract_end":781}]}
{"pmid":"25236466","title":"Genetic analysis of the UPB1 gene in two new Chinese families with β-ureidopropionase deficiency and the carrier frequency of the mutation c.977G>A in Northern China.","abstract":"PURPOSE: The purpose of the study was to investigate mutations of the UPB1 gene in two Chinese families with β-ureidopropionase deficiency and the heterozygous carrier frequency in Chinese.\nMETHODS: Genomic DNA was extracted from peripheral blood leukocytes from all available family members and 500 unrelated healthy controls. Then, all exons and flanking intron regions of the UPB1 gene were amplified by PCR and analyzed by direct sequencing in two patient-families. Finally, the carrier frequency of the c.977G>A (p.R326Q) mutation was identified by PCR restriction fragment length polymorphism in 500 healthy controls.\nRESULTS: The two patients had the same homozygous missense mutation in exon 9 (c.977G>A; p.R326Q), and the carrier frequency of this mutation was 2.8 % in the Northern Chinese population, which suggests that about 1:5,102 Chinese are expected to suffer from UPB1 deficiency.\nCONCLUSIONS: The c.977G>A (p.R326Q) is the most common mutation of the UPB1 gene in Chinese. The predicted incidence indicates that β-ureidopropionase deficiency is significantly underdiagnosed in the Chinese population. It should be necessary to add β-ureidopropionase deficiency to high-risk screening for the symptomatic patients group.","variants":[{"Name":"NM_016327.3(UPB1):c.977G>A (p.Arg326Gln)","Chromosome":"22","Start":"24523679","Stop":"24523679","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227414,"rule_based_match":true,"evidence_text":"c.977G>A (p.R326Q)","llm_judgment":"PRESENT","evidence":"c.977G>A (p.R326Q)","abstract_start":508,"abstract_end":526}]}
{"pmid":"25959358","title":"Acute simultaneous multiple lacunar infarcts as the initial presentation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.","abstract":"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset, dominantly inherited small-vessel disease of the brain caused by NOTCH3 mutations and characterized by recurrent subcortical infarctions, dementia, migraine with aura, and mood disturbance. We report a patient with unusual presentation of CADASIL with acute simultaneous multiple subcortical lacunar infarcts as the first manifestation. A 69-year-old man developed confusion, drowsiness, right hemiparesis, and slurred speech following orthopedic surgeries. Brain magnetic resonance imaging revealed diffuse leukoencephalopathy and multiple acute subcortical lacunar infarcts. Brain magnetic resonance angiography, echocardiography and 24-hour electrocardiography were unremarkable. The symptoms improved quickly after treatment with fluid hydration and antiplatelet agent, and his consciousness and mentality totally recovered within 3 days. The NOTCH3 genetic testing showed a heterozygous missense mutation, c.1630C>T (p. Arg544Cys). The experience in this case suggests that brain imaging is important in managing postoperative confusion, and any patient with diffuse leukoencephalopathy of unknown etiology may need to be tested for NOTCH3 mutations. Surgery is an important factor of encephalopathy and acute infarction in individuals with NOTCH3 mutations. Comprehensive presurgical evaluations and proactive perioperative precautions to avoid dehydration and anemia are necessary for patients with CADASIL who are about to receive anesthesia and surgery.","variants":[{"Name":"NM_000435.3(NOTCH3):c.1630C>T (p.Arg544Cys)","Chromosome":"19","Start":"15187315","Stop":"15187315","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":536981,"rule_based_match":true,"evidence_text":"c.1630C>T (p. Arg544Cys)","llm_judgment":"PRESENT","evidence":"c.1630C>T (p. Arg544Cys)","abstract_start":1031,"abstract_end":1055}]}
{"pmid":"26651493","title":"Uncommon dihydropyrimidine dehydrogenase mutations and toxicity by fluoropyrimidines: a lethal case with a new variant.","abstract":"DPD is the rate-limiting enzyme involved in the metabolism of 5-fluorouracil and its prodrugs, capecitabine and tegafur. Many cases of severe toxicities by fluoropyrimidines are reported in the literature, sometimes with lethal outcome, due to a poor or null metabolizer phenotype. The exon 14-skipping mutation IVS14+1G>A and the c.2846A>T are the most common deficient variants. However, many additional variants of the DPYD gene with unclear functional significance have been reported. We describe a patient with metastatic breast cancer who received capecitabine and trastuzumab at standard doses. Six days after beginning capecitabine, the patient developed fever, leucopenia and neutropenia, mucositis, hand-foot syndrome, multiple organ dysfunction and eventually died. Since the toxicity profile was compatible with capecitabine administration, complete exon sequencing of DPYD was carried out and the patient was found to be compound heterozygous for the rare mutation c.257C>T in exon 4, c.496A>G in exon 6, the new variant c.1850C>T in exon 14 and c.2194G>A in exon 18. Given the marginal role of c.496A>G and c.2194G>A in DPD deficiency, the cause of death was suggested to be dependent on the novel c.1850C>T in combination with c.257C>T. The complexity of DPD pharmacogenetics suggests the need to develop cost-effective screening approaches to identify patients at risk of severe toxicities.","variants":[{"Name":"NM_000110.4(DPYD):c.257C>T (p.Pro86Leu)","Chromosome":"1","Start":"97740456","Stop":"97740456","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1015813,"rule_based_match":true,"evidence_text":"c.257C>T","llm_judgment":"PRESENT","evidence":"c.257C>T","abstract_start":978,"abstract_end":986},{"Name":"NM_000110.4(DPYD):c.2194G>A (p.Val732Ile)","Chromosome":"1","Start":"97305364","Stop":"97305364","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105957,"rule_based_match":true,"evidence_text":"c.2194G>A","llm_judgment":"PRESENT","evidence":"c.2194G>A","abstract_start":1059,"abstract_end":1068}]}
{"pmid":"27577507","title":"Novel homozygous sequence variants in the GDF5 gene underlie acromesomelic dysplasia type-grebe in consanguineous families.","abstract":"Acromesomelic dysplasia Grebe type (AMDG) is characterized by severe knob like non-functional fingers and short acromesomelic limbs, and is inherited in an autosomal recessive manner. Disease causing sequence variants in the GDF5 (Growth Differentiation Factor 5) gene located on chromosome 20q11.22 are responsible for causing AMDG. In the study, presented here, two consanguineous families with AMDG were clinically and genetically characterized. After establishing linkage in the two families (A and B) to GDF5 gene on chromosome 20q11.22, Sanger DNA sequencing was performed in all available affected and unaffected members. Sequence analysis of the GDF5 gene revealed two novel variants including a duplication (c.157_158dupC, p.Leu53Profs*41) in family A, and a nonsense (p.Trp291*) in family B. Our findings extend the body of evidence that supports the importance of GDF5 in the development of limbs.","variants":[{"Name":"NM_000557.5(GDF5):c.157dup (p.Leu53fs)","Chromosome":"20","Start":"35437771","Stop":"35437772","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":806071,"rule_based_match":false,"evidence_text":"c.157_158dupC","llm_judgment":"PRESENT","evidence":"c.157_158dupC","abstract_start":717,"abstract_end":730}]}
{"pmid":"28028301","title":"Biochemical and molecular characteristics of Malaysian patients with lysinuric protein intolerance.","abstract":"Lysinuric protein intolerance (LPI) is an inborn error of dibasic amino acid transport due to a defect in the dibasic amino acid transporter in the renal and intestine and has a heterogenous presentation. Three Malaysian patients with LPI were studied and their biochemical and molecular findings compared. There were differences and similarities in the biochemical and molecular findings. Molecular analysis of SLC7A7 gene revealed a novel mutation c.235G>A; p.(Gly79Arg) in exon three in Patient 1 and a mutation c.1417C>T; p.(Arg473*) in exon 10 in patient 2 and 3. The degree of concentration of dibasic amino acids may determine the type of disease of the cell membrane transport, however, a positive molecular confirmation will secure the diagnosis.","variants":[{"Name":"NM_003982.4(SLC7A7):c.235G>A (p.Gly79Arg)","Chromosome":"14","Start":"22813164","Stop":"22813164","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3410647,"rule_based_match":true,"evidence_text":"c.235G>A; p.(Gly79Arg)","llm_judgment":"PRESENT","evidence":"c.235G>A; p.(Gly79Arg)","abstract_start":450,"abstract_end":472},{"Name":"NM_003982.4(SLC7A7):c.1417C>T (p.Arg473Ter)","Chromosome":"14","Start":"22773945","Stop":"22773945","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70999,"rule_based_match":true,"evidence_text":"c.1417C>T; p.(Arg473*)","llm_judgment":"PRESENT","evidence":"c.1417C>T; p.(Arg473*)","abstract_start":515,"abstract_end":537}]}
{"pmid":"30604053","title":"Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain.","abstract":"Limb-girdle muscular dystrophies (LGMD) are a group of clinically and genetically heterogeneous diseases characterized by weakness and wasting of the pelvic and shoulder girdle muscles. Twenty-four recessive LGMD (types R1-R24) and five dominant LGMD (types D1-D5) have been identified with characterization of mutations in various genes. To date, LGMD D3 (previously known as LGMD1G) has been characterized in only two families with Brazilian or Uruguayan origin. Each was caused by a distinct mutation at codon 378 in the prion-like domain of HNRNPDL encoding heterogeneous nuclear ribonucleoprotein D like (HNRNPDL), an RNA processing protein. Our study characterized eight patients suffering from LGMD D3 in a Chinese family spanning three generations. Muscle biopsy specimens from two patients showed a myopathy with rimmed vacuoles. Sequencing analysis revealed a heterozygous c.1132G > A (p.D378N) mutation in HNRNPDL that co-segregated with disease phenotype in the family. The same mutation has been identified previously in the Brazilian family with LGMD D3. However, most patients in the current family showed distal as well as proximal limb weakness rather than weakness of toe and finger flexor muscles that were typical features in the other two LGMD D3 families reported previously. The present study indicates that the same mutation in HNRNPDL results in various phenotypes of LGMD D3. That all mutations in three unrelated families with different ethnic background occur at the same position in codon 378 of HNRNPDL gene suggests a mutation hotspot. Acceleration of intrinsic self-aggregation of HNRNPDL caused by mutation of the prior-like domain may contribute to the pathogenesis of the disease.","variants":[{"Name":"NM_031372.4(HNRNPDL):c.1132G>A (p.Asp378Asn)","Chromosome":"4","Start":"82426523","Stop":"82426523","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":153824,"rule_based_match":true,"evidence_text":"c.1132G > A (p.D378N)","llm_judgment":"PRESENT","evidence":"c.1132G > A (p.D378N)","abstract_start":883,"abstract_end":904}]}
{"pmid":"22206013","title":"The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in Taiwan.","abstract":"BACKGROUND: Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese.\nMETHODOLOGY AND PRINCIPAL FINDINGS: Genomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%).\nCONCLUSIONS AND SIGNIFICANCE: This study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese.","variants":[{"Name":"NM_014874.4(MFN2):c.475-1G>T","Chromosome":"1","Start":"11997296","Stop":"11997296","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":625725,"rule_based_match":true,"evidence_text":"c.475-1G>T","llm_judgment":"PRESENT","evidence":"c.475-1G>T","abstract_start":899,"abstract_end":909},{"Name":"NM_001540.5(HSPB1):c.490A>G (p.Thr164Ala)","Chromosome":"7","Start":"76304045","Stop":"76304045","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":625151,"rule_based_match":false,"evidence_text":"p.T164A in HSPB1","llm_judgment":"PRESENT","evidence":"p.T164A in HSPB1","abstract_start":629,"abstract_end":645}]}
{"pmid":"32677908","title":"Novel ECHS1 mutations in Leigh syndrome identified by whole-exome sequencing in five Chinese families: case report.","abstract":"BACKGROUND: Short-chain enoyl-CoA hydratase deficiency (ECHS1D), also known as ECHS1 deficiency, is a rare inborn metabolic disorder with clinical presentations characterized by Leigh syndrome (LS). Thirty-four different pathogenic mutations have been identified from over 40 patients to date.\nCASE PRESENTATION: Here, we report five Chinese patients with clinical syndromes typified as LS. Despite different initial symptoms, all patients presented developmental regression, dystonia, common radiological features such as symmetrical bilateral brain abnormalities, and similar metabolic results such as elevated plasma lactate and 2,3-dihydroxy-2-methylbutyrate. Utilizing whole-exome sequencing (WES), we identified eight distinct variants in ECHS1, with six novel variants, and the remaining two variants have been previously reported. Interestingly, one of the six novel variants, c.463G > A (p.Gly155Ser), was detected in three patients from unrelated families, suggesting a potential founder effect already described for a few mutations in LS. Incorporating both genetic analysis and medical results, including magnetic resonance imaging (MRI), electroencephalography (EEG), and biochemical testing, our study enriched the mutation spectrum of the ECHS1 gene and confirmed the phenotypic presentations of LS.\nCONCLUSIONS: The severity of ECHS1 deficiency seems to vary. It was affected by both genetics and external environmental factors that lead to increased metabolism. Our study enriched the mutation spectrum of the ECHS1 gene, confirmed the phenotypic presentations, and highlighted the importance of the valine catabolic pathway in Leigh syndrome. Further studies are required to examine the potential founder mutation c.463G > A (p.Gly155Ser) and the role of ECHS1 in relevant pathways.","variants":[{"Name":"NM_004092.4(ECHS1):c.463G>A (p.Gly155Ser)","Chromosome":"10","Start":"133368974","Stop":"133368974","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":444574,"rule_based_match":true,"evidence_text":"c.463G > A (p.Gly155Ser)","llm_judgment":"PRESENT","evidence":"c.463G > A (p.Gly155Ser)","abstract_start":885,"abstract_end":909}]}
{"pmid":"31312213","title":"A Nonsense Mutation in COL4A4 Gene Causing Isolated Hematuria in Either Heterozygous or Homozygous State.","abstract":"Alport syndrome (AS) is a hereditary nephropathy characterized by glomerular basement membrane lesions. AS shows a relatively rare entity with autosomal dominant gene mutation (accounts for less than 5% of AS cases) and is widely believed to be a consequence of heterozygous variants in the <b><i>COL4A3</i></b> and <b><i>COL4A4</i></b> genes. Until now, there have been no reports of homozygous variants in genes in AS patients, and it is scarce to detect both homozygous and heterozygous variants in a single AS pedigree. We performed genetic analysis by exome sequencing (exome-seq) in a Chinese family with AS and found four individuals harboring the <b><i>COL4A4</i></b> c.4599T > G variant, a novel <i>COL4A4</i> nonsense mutation that gains stop codon and results in a truncated protein. The proband and her two siblings were determined to be heterozygous, whereas their mother was homozygous. The proband satisfied the criteria for the diagnosis of AS, which included clinical manifestations of microscopic hematuria and proteinuria, and pathological features of the glomerular basement membrane (GBM), including irregular thickening and splitting. However, the other three individuals who were homozygous or heterozygous for the variant exhibited mild clinical features with isolated microscopic hematuria. In summary, we identified a novel pathogenic variant in either the heterozygous or homozygous state of the <b><i>COL4A4</i></b> gene in a Chinese family with AS. Our results also suggest that the severity of clinical manifestations may not be entirely attributed to by the <b><i>COL4A4</i></b> genetic variant itself in patients.","variants":[{"Name":"NM_000092.5(COL4A4):c.4599T>G (p.Tyr1533Ter)","Chromosome":"2","Start":"227008228","Stop":"227008228","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":541808,"rule_based_match":true,"evidence_text":"c.4599T > G","llm_judgment":"PRESENT","evidence":"c.4599T > G","abstract_start":676,"abstract_end":687}]}
{"pmid":"25712943","title":"Shifting the CARASIL paradigm: report of a non-Asian family and literature review.","abstract":"BACKGROUND AND PURPOSE: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare form of nonhypertensive cerebral small-vessel disease caused by mutations in the HTRA1 gene. CARASIL is characterized by early adulthood onset of subcortical infarcts, cognitive impairment, alopecia, and spondylosis. Until recently, this disorder was almost exclusively reported in the Asian population.\nMETHODS: Description of the clinical, imaging, and genetic study of 2 siblings with CARASIL, with a brief comparative review of published non-Asian cases of the disease.\nRESULTS: Both patients exhibited the typical phenotype: cerebral small-vessel disease, spondylosis, and abnormal hair lost. Mutation screening was performed for NOTCH3 and HTRA1 genes. No mutations were found in NOTCH3. The study revealed the presence of a homozygous c.496C>T substitution in HTRA1 in both siblings.\nCONCLUSION: This report highlights the need of considering this entity in the differential diagnosis of cerebral small-vessel disease in young patients, even in the non-Asian populations.","variants":[{"Name":"NM_002775.5(HTRA1):c.496C>T (p.Arg166Cys)","Chromosome":"10","Start":"122488925","Stop":"122488925","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1316080,"rule_based_match":true,"evidence_text":"c.496C>T","llm_judgment":"PRESENT","evidence":"c.496C>T","abstract_start":878,"abstract_end":886}]}
{"pmid":"19184172","title":"Clinical and genetic analysis of long QT syndrome in children from six families in Saudi Arabia: are they different?","abstract":"Congenital long QT syndrome (LQTS) is an inherited cardiac arrhythmia disorder characterized by prolongation of the QT interval; patients are predisposed to ventricular tachyarrhythmias and fibrillation leading to recurrent syncope or sudden cardiac death. We performed clinical and genetic studies in six Saudi Arabian families with a history of sudden unexplained death of children. Clinical symptoms, ECG phenotypes, and genetic findings led to the diagnosis of LQT1 in two families (recessive) and LQT2 in four families (three recessive and one dominant). Onset of arrhythmia was more severe in the recessive carriers and occurred during early childhood in all recessive LQT1 patients. Arrhythmia originated at the intrauterine stages of life in the recessive LQT2 patients. LQT1, causing mutation c.387-5 T > A in the KCNQ1 gene, and LQT2, causing mutation c.3208 C > T in the KCNH2 gene, are presumably founder mutations in the Assir province of Saudi Arabia. Further, all LQTS causing mutations detected in this study are novel and have not been reported in other populations.","variants":[{"Name":"NM_000218.3(KCNQ1):c.387-5T>A","Chromosome":"11","Start":"2527923","Stop":"2527923","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":197422,"rule_based_match":true,"evidence_text":"c.387-5 T > A","llm_judgment":"PRESENT","evidence":"c.387-5 T > A","abstract_start":802,"abstract_end":815},{"Name":"NM_000238.4(KCNH2):c.3208C>T (p.Gln1070Ter)","Chromosome":"7","Start":"150946999","Stop":"150946999","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3069434,"rule_based_match":true,"evidence_text":"c.3208 C > T","llm_judgment":"PRESENT","evidence":"c.3208 C > T","abstract_start":862,"abstract_end":874}]}
{"pmid":"19933090","title":"Identification of a novel mutation of IDS gene from a Chinese pedigree with MPS II","abstract":"The purpose of this study was to understand the molecular genetic mechanism of mucopolysaccharidosis type II (MPS II) and to provide a prerequisite for future prenatal gene diagnosis. A preliminary diagnosis was made by qualitative detection of Urinary Glycosaminoglycans of the suspected MPS II proband. Then, mutation detection was performed on the proband and his family members with PCR and direct sequencing of PCR products. After the novel mutation of c.876 del 2 in IDS gene was detected, sequence analysis was performed on exon 6 of IDS gene of the 135 cases, which consisted of 120 randomly selected normal controls, and other 15 patients with MPS I, IV, and VI other than MPS II. Besides, the patho-genicity of the novel mutation was analyzed with the following 2 methods: conservative analysis of the sequence of muta-tion spots of different species and the direct test of the IDS enzyme activity of the patient and his relative family members. The result of uroscopy of the proband was strong positive (GAGs +++). There was a novel deletion mutation of c.876-877 del TC in the coding region of exon 6 of IDS gene, which was a hemizygous mutation. However, the mutation of his mother and sister was a heterozygous mutation. Detection of the exon 6 of IDS gene showed that the mutation was not found among normal controls and other patients with MPS I, IV, and VI other than MPS II. Homology comparison of amino acid sequences from different species showed that the phenylalanine (F) glutamine (Q) of the mutation site of c.876-877 del TC located in p.292-293 was highly conserved. The activity of IDS enzyme of the proband was only 2.3 nmol/4 h/mL, which was much lower than normal; but the activity of IDS enzyme of his father, mother and sister was 641.9 nmol/4 h/mL, 95.8 nmol/4h/mL and 103.2 nmol/4h/mL, respectively. These results illustrated that the deletion and frame-shift mutation of c.876-877 del TC detected was a novel pathologic mutation, which was the underlying cause of MPS II of this patient.","variants":[{"Name":"NM_000202.8(IDS):c.876_877del (p.Phe292fs)","Chromosome":"X","Start":"149496348","Stop":"149496349","ReferenceAlleleVCF":"TGA","AlternateAlleleVCF":"T","allel_id":3414627,"rule_based_match":false,"evidence_text":"c.876-877 del TC","llm_judgment":"PRESENT","evidence":"c.876-877 del TC","abstract_start":1065,"abstract_end":1081}]}
{"pmid":"36246652","title":"Development of a clinically validated","abstract":"<b>Purpose:</b> The addition of Pompe disease (Glycogen Storage Disease Type II) to the Recommended Uniform Screening Panel in the United States has led to an increase in the number of variants of uncertain significance (VUS) and novel variants identified in the <i>GAA</i> gene. This presents a diagnostic challenge, especially in the setting of late-onset Pompe disease when symptoms are rarely apparent at birth. There is an unmet need for validated functional studies to aid in classification of <i>GAA</i> variants. <b>Methods:</b> We developed an <i>in vitro</i> mammalian cell expression and functional analysis system based on guidelines established by the Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group for PS3/BS3. We validated the assay with 12 control variants and subsequently analyzed eight VUS or novel variants in <i>GAA</i> identified in patients with a positive newborn screen for Pompe disease without phenotypic evidence of infantile-onset disease. <b>Results:</b> The control variants were analyzed in our expression system and an activity range was established. The pathogenic controls had GAA activity between 0% and 11% of normal. The benign or likely benign controls had an activity range of 54%-100%. The pseudodeficiency variant had activity of 17%. These ranges were then applied to the variants selected for functional studies. Using the threshold of <11%, we were able to apply PS3_ supporting to classify two variants as likely pathogenic (c.316C > T and c.1103G > A) and provide further evidence to support the classification of likely pathogenic for two variants (c.1721T > C and c.1048G > A). One variant (c.1123C > T) was able to be reclassified based on other supporting evidence. We were unable to reclassify three variants (c.664G > A, c.2450A > G, and c.1378G > A) due to insufficient or conflicting evidence. <b>Conclusion:</b> We investigated eight <i>GAA</i> variants as proof of concept using our validated and reproducible <i>in vitro</i> expression and functional analysis system. While additional work is needed to further refine our system with additional controls and different variant types in order to apply the PS3/BS3 criteria at a higher level, this tool can be utilized for variant classification to meet the growing need for novel <i>GAA</i> variant classification in the era of newborn screening for Pompe disease.","variants":[{"Name":"NM_000152.5(GAA):c.1048G>A (p.Val350Met)","Chromosome":"17","Start":"80108382","Stop":"80108382","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":549152,"rule_based_match":true,"evidence_text":"c.1048G > A","llm_judgment":"PRESENT","evidence":"c.1048G > A","abstract_start":1647,"abstract_end":1658},{"Name":"NM_000152.5(GAA):c.316C>T (p.Arg106Cys)","Chromosome":"17","Start":"80104902","Stop":"80104902","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":958353,"rule_based_match":true,"evidence_text":"c.316C > T","llm_judgment":"PRESENT","evidence":"c.316C > T","abstract_start":1505,"abstract_end":1515},{"Name":"NM_000152.5(GAA):c.1123C>T (p.Arg375Cys)","Chromosome":"17","Start":"80108536","Stop":"80108536","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":274462,"rule_based_match":true,"evidence_text":"c.1123C > T","llm_judgment":"PRESENT","evidence":"c.1123C > T","abstract_start":1674,"abstract_end":1685}]}
{"pmid":"31951326","title":"Clinical findings and genetic analysis of the patients with IL-12Rβ1 deficiency from southeast Turkey.","abstract":"Doğruel D, Gündeşlioğlu ÖÖ, Yılmaz M, Alabaz D, Altıntaş DU, Kocabaş E. Clinical findings and genetic analysis of the patients with IL- 12Rβ1 deficiency from southeast Turkey. Turk J Pediatr 2019; 61: 174-179. IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to poorly pathogenic mycobacteria, salmonella and candida species. We aimed to analyze the clinical manifestations, immunological and genetic features of IL-12Rβ1 deficiency in 10 Turkish patients from a single center. We retrospectively studied the clinical manifestations and genetic analysis of the IL-12Rβ1 deficiency patients from 2008 to 2016. Ten patients were diagnosed and followed for eight years. The mean age at onset and diagnosis were 24.1±42.5 (med:10.5) and 52.3±6.83 (med:20) months, respectively. Parental consanguinity rate was 81.8%. All patients were BCG vaccinated. Abscess and axillary lymphadenopathy in the vaccinated area was the most common initial presentation following the BCG vaccination, six patients had recurring oral candidiasis. Active infections were treated appropriately, in addition to prophylactic therapy with IFNɣ. We identified 6 different mutations in the IL12RB1 gene in 10 patients including 5 splice-site mutations, 3 missense, 1 frameshift, 1 premature stop codon. One of these mutations was novel. The most common mutation was IVS8+1G > A(c.783+1G > A) followed by p.R175W(c.523C > T). This study emphasizes that patients presented with abscess and axillary lymphadenopathy associated with BCG vaccination should be evaluated for IL-12Rβ1 deficiency.","variants":[{"Name":"NM_005535.3(IL12RB1):c.523C>T (p.Arg175Trp)","Chromosome":"19","Start":"18077542","Stop":"18077542","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1868412,"rule_based_match":true,"evidence_text":"p.R175W(c.523C > T)","llm_judgment":"PRESENT","evidence":"p.R175W(c.523C > T)","abstract_start":1412,"abstract_end":1431}]}
{"pmid":"28471114","title":"Phenotype-genotype correlation with Sanger sequencing identified retinol dehydrogenase 12 (RDH12) compound heterozygous variants in a Chinese family with Leber congenital amaurosis.","abstract":"BACKGROUND: Leber congenital amaurosis (LCA) is a group of clinically and genetically heterogeneous retinal dystrophy. To date, 22 genes are known to be responsible for LCA, and some specific phenotypic features could provide significant prognostic information for a potential genetic etiology. This study is to identify gene variants responsible for LCA in a Chinese family using direct Sanger sequencing, with the help of phenotype-genotype correlations.\nMETHODS: A Chinese family with six members including two individuals affected with LCA was studied. All patients underwent a complete ophthalmic examination. Based on phenotype-genotype correlation, direct Sanger sequencing was performed to identify the candidate gene on all family members and normal controls. Targeted next-generation sequencing was used to exclude other known LCA genes.\nRESULTS: By Sanger sequencing, we identified two novel missense variants in the retinol dehydrogenase 12 (RDH12) gene: a c.164C>A transversion predicting a p.T55K substitution, and a c.535C>G transversion predicting a p.H179D substitution. The two affected subjects carried both RDH12 variants, while their parents and offspring carried only one of heterozygous variants, showing complete cosegregation of the variants. The compound heterozygous variants were not present in 600 normal controls. Besides, the RDH12 variants were confirmed by targeted next-generation sequencing.\nCONCLUSIONS: The RDH12 compound heterozygous variants might be the cause of the LCA family. Our study adds to the molecular spectrum of RDH12-related retinopathy and offers an effective example of the power of phenotype-genotype correlations in molecular diagnosis of LCA.","variants":[{"Name":"NM_152443.3(RDH12):c.535C>G (p.His179Asp)","Chromosome":"14","Start":"67727067","Stop":"67727067","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":936692,"rule_based_match":true,"evidence_text":"c.535C>G","llm_judgment":"PRESENT","evidence":"c.535C>G","abstract_start":1031,"abstract_end":1039}]}
{"pmid":"26553276","title":"A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia.","abstract":"Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by spasticity of the lower limbs due to pyramidal tract dysfunction. Here, we report that a missense homozygous mutation c.424G>T (p.D142Y) in the FARS2 gene, which encodes a mitochondrial phenylalanyl tRNA synthetase (mtPheRS), causes HSP in a Chinese consanguineous family by using combination of homozygous mapping and whole-exome sequencing. Immunohistochemical experiments were performed showing that the FARS2 protein was highly expressed in the Purkinje cells of rat cerebellum. The aminoacylation activity of mtPheRS was severely disrupted by the p.D142Y substitution in vitro not only in the first aminoacylation step but also in the last transfer step. Taken together, our results indicate that a missense mutation in FARS2 contributes to HSP, which has the clinical significance of the regulation of tRNA synthetases in human neurodegenerative diseases.","variants":[{"Name":"NM_006567.5(FARS2):c.424G>T (p.Asp142Tyr)","Chromosome":"6","Start":"5368994","Stop":"5368994","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":247571,"rule_based_match":true,"evidence_text":"c.424G>T (p.D142Y)","llm_judgment":"PRESENT","evidence":"c.424G>T (p.D142Y)","abstract_start":254,"abstract_end":272}]}
{"pmid":"30410870","title":"Two Missense Variants Detected in Breast Cancer Probands Preventing BRCA2-PALB2 Protein Interaction.","abstract":"PALB2 (partner and localizer of BRCA2) was initially identified as a binding partner of BRCA2. It interacts also with BRCA1 forming a complex promoting DNA repair by homologous recombination. Germline pathogenic variants in <i>BRCA1, BRCA2</i> and <i>PALB2</i> DNA repair genes are associated with high risk of developing breast cancer. Mutation screening in these breast cancer predisposition genes is routinely performed and allows the identification of individuals who carry pathogenic variants and are at risk of developing the disease. However, variants of uncertain significance (VUSs) are often detected and establishing their pathogenicity and clinical relevance remains a central challenge for the risk assessment of the carriers and the clinical decision-making process. Many of these VUSs are missense variants leading to single amino acid substitutions, whose impact on protein function is uncertain. Typically, VUSs are rare and due to the limited genetic, clinical, and pathological data the multifactorial approaches used for classification cannot be applied. Thus, these variants can only be characterized through functional analyses comparing their effect with that of normal and mutant gene products used as positive and negative controls. The two missense variants <i>BRCA2</i>:c.91T >G (p.Trp31Gly) and <i>PALB2</i>:c.3262C >T (p.Pro1088Ser) were detected in two breast cancer probands originally ascertained at Breast Cancer Units of Institutes located in Milan and Bergamo (Northern Italy), respectively. These variants were located in the BRCA2-PALB2 interacting domains, were predicted to be deleterious by <i>in silico</i> analyses, and were very rare and clinically not classified. Therefore, we initiate to study their functional effect by exploiting a green fluorescent protein (GFP)-reassembly <i>in vitro</i> assay specifically designed to test the BRCA2-PALB2 interaction. This functional assay proved to be easy to develop, robust and reliable. It also allows testing variants located in different genes. Results from these functional analyses showed that the <i>BRCA2</i>:p.Trp31Gly and the <i>PALB2</i>:p.Pro1088Ser prevented the BRCA2-PALB2 binding. While caution is warranted when the interpretation of the clinical significance of rare VUSs is based on functional studies only, our data provide initial evidences in favor of the possibility that these variants are pathogenic.","variants":[{"Name":"NM_024675.4(PALB2):c.3262C>T (p.Pro1088Ser)","Chromosome":"16","Start":"23607952","Stop":"23607952","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":567939,"rule_based_match":true,"evidence_text":"PALB2:c.3262C >T (p.Pro1088Ser)","llm_judgment":"PRESENT","evidence":"p.Pro1088Ser","abstract_start":1348,"abstract_end":1360},{"Name":"NM_000059.4(BRCA2):c.91T>G (p.Trp31Gly)","Chromosome":"13","Start":"32319100","Stop":"32319100","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":476823,"rule_based_match":true,"evidence_text":"BRCA2:c.91T >G (p.Trp31Gly)","llm_judgment":"PRESENT","evidence":"p.Trp31Gly","abstract_start":1307,"abstract_end":1317}]}
{"pmid":"17010210","title":"A novel mutation in STK11 gene is associated with Peutz-Jeghers Syndrome in Indian patients.","abstract":"BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare multi-organ cancer syndrome and understanding its genetic basis may help comprehend the molecular mechanism of familial cancer. A number of germ line mutations in the STK11 gene, encoding a serine threonine kinase have been reported in these patients. However, STK11 mutations do not explain all PJS cases. An earlier study reported absence of STK11 mutations in two Indian families and suggested another potential locus on 19q13.4 in one of them.\nMETHODS: We sequenced the promoter and the coding region including the splice-site junctions of the STK11 gene in 16 affected members from ten well-characterized Indian PJS families with a positive family history.\nRESULTS: We did not observe any of the reported mutations in the STK11 gene in the index patients from these families. We identified a novel pathogenic mutation (c.790_793 delTTTG) in the STK11 gene in one index patient (10%) and three members of his family. The mutation resulted in a frame-shift leading to premature termination of the STK11 protein at 286th codon, disruption of kinase domain and complete loss of C-terminal regulatory domain. Based on these results, we could offer predictive genetic testing, prenatal diagnosis and genetic counselling to other members of the family.\nCONCLUSION: Ours is the first study reporting the presence of STK11 mutation in Indian PJS patients. It also suggests that reported mutations in the STK11 gene are not responsible for the disease and novel mutations also do not account for many Indian PJS patients. Large-scale genomic deletions in the STK11 gene or another locus may be associated with the PJS phenotype in India and are worth future investigation.","variants":[{"Name":"NM_000455.5(STK11):c.790_793del (p.Phe264fs)","Chromosome":"19","Start":"1221265","Stop":"1221268","ReferenceAlleleVCF":"GTTGT","AlternateAlleleVCF":"G","allel_id":360512,"rule_based_match":true,"evidence_text":"c.790_793 delTTTG","llm_judgment":"PRESENT","evidence":"c.790_793 delTTTG","abstract_start":875,"abstract_end":892}]}
{"pmid":"16752389","title":"Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss.","abstract":"In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the \"hurry scurry\" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea.","variants":[{"Name":"NM_182548.4(LHFPL5):c.494C>T (p.Thr165Met)","Chromosome":"6","Start":"35814627","Stop":"35814627","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16736,"rule_based_match":true,"evidence_text":"c.494C>T (p.Thr165Met)","llm_judgment":"PRESENT","evidence":"c.494C>T (p.Thr165Met)","abstract_start":740,"abstract_end":762}]}
{"pmid":"23773965","title":"Two homozygous nonsense mutations of GNPTAB gene in two Chinese families with mucolipidosis II alpha/beta using targeted next-generation sequencing.","abstract":"Mucolipidosis II alpha/beta (ML II alpha/beta; I-cell disease) is a rare, inherited, metabolic disease and has often been clinically misdiagnosed. ML II alpha/beta results from a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT), which causes the lysosomal enzymes to accumulate in plasma. We identified two new Chinese patients with ML II alpha/beta by lysosomal enzyme assay. Using targeted next-generation sequencing genetic analysis, we located two homozygous nonsense mutations in the GNPTAB gene, c.1071G>A (p.W357X) and c.1090C>T (p.R364X). These results were confirmed by Sanger sequencing. To our knowledge, the c.1071G>A mutation has not been previously reported. Our findings add to the number of reported cases of this rare illness and to the GNPTAB pathogenic mutation database. This work also demonstrates the application of lysosomal enzyme assay and targeted next-generation sequencing for the genetic screening analysis and diagnosis of ML II alpha/beta.","variants":[{"Name":"NM_024312.5(GNPTAB):c.1090C>T (p.Arg364Ter)","Chromosome":"12","Start":"101770429","Stop":"101770429","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":47624,"rule_based_match":true,"evidence_text":"c.1090C>T (p.R364X)","llm_judgment":"PRESENT","evidence":"c.1090C>T (p.R364X)","abstract_start":555,"abstract_end":574},{"Name":"NM_024312.5(GNPTAB):c.1071G>A (p.Trp357Ter)","Chromosome":"12","Start":"101770448","Stop":"101770448","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1393469,"rule_based_match":true,"evidence_text":"c.1071G>A (p.W357X)","llm_judgment":"PRESENT","evidence":"c.1071G>A (p.W357X)","abstract_start":531,"abstract_end":550}]}
{"pmid":"24498881","title":"A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer.","abstract":"BACKGROUND: An early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted.\nCASE PRESENTATION: We describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one.\nCONCLUSION: This case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN-associated carcinogenesis.","variants":[{"Name":"NM_000314.8(PTEN):c.71A>T (p.Asp24Val)","Chromosome":"10","Start":"87864540","Stop":"87864540","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1458873,"rule_based_match":true,"evidence_text":"c.71A > T (p.Asp24Val)","llm_judgment":"PRESENT","evidence":"c.71A > T (p.Asp24Val)","abstract_start":915,"abstract_end":937}]}
{"pmid":"29935994","title":"Limb girdle muscular dystrophy 2G in a religious minority of Bulgarian Muslims homozygous for the c.75G>A, p.Trp25X mutation.","abstract":"Mutations in TCAP gene cause autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G), congenital muscular dystrophy and autosomal dominant dilated and hypertrophic cardiomyopathy. We studied 18 affected individuals from 12 pedigrees, belonging to a Bulgarian Muslim minority from the South-West of Bulgaria, homozygous for the c.75G>A, p.Trp25X mutation in TCAP gene. The heterozygous carrier rate of p.Trp25X among 100 newborns in this region was found to be 2%. The clinical features in the Bulgarian TCAP group include disease onset in the first to the third decade of life, proximal muscle weakness in the lower limbs, followed or accompanied by difficulties in ankle dorsiflexion and involvement of the proximal muscles of the upper limbs 5-9 years after the disease onset. Asymmetry between left and right was present in more than 20% of the affected. Respiratory and cardiac functions were not affected. On the MRI the muscles of the posterior pelvic area, thigh and anterior leg were predominantly affected, while sartorius, gracilis and biceps femoris muscles remained relatively spared. In conclusion, LGMD2G appears to be a common form among Bulgarian Muslims. Homozygosity for c.75G>A, p.Trp25X is associated with a homogeneous clinical presentation, but the clinical course and severity of the disease show inter- and intra-familial variation.","variants":[{"Name":"NM_003673.4(TCAP):c.75G>A (p.Trp25Ter)","Chromosome":"17","Start":"39665434","Stop":"39665434","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":802218,"rule_based_match":true,"evidence_text":"c.75G>A, p.Trp25X","llm_judgment":"PRESENT","evidence":"c.75G>A, p.Trp25X","abstract_start":339,"abstract_end":356}]}
{"pmid":"33179229","title":"Analysis of gene variant in a Chinese child affected with dihydropyrimidinase deficiency","abstract":"OBJECTIVE: To analyze the molecular etiology of a Chinese child affected with dihydropyrimidinase deficiency.\nMETHODS: Genomic DNA was extracted from peripheral blood samples of the family members. Pathogenic variant was determined by whole exome sequencing and verified by Sanger sequencing.\nRESULTS: The child was found to harbor homozygous c.905G>A (p.Arg302Gln) variants in exon 5 of the DPYS gene, for which her parents were both heterozygous carriers.\nCONCLUSION: The homozygous c.905G>A (p.Arg302Gln) variants of the DPYS gene probably underlies the dihydropyrimidinase deficiency in the child. Above result has enabled genetic counseling and prenatal diagnosis for this family.","variants":[{"Name":"NM_001385.3(DPYS):c.905G>A (p.Arg302Gln)","Chromosome":"8","Start":"104429590","Stop":"104429590","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":619920,"rule_based_match":true,"evidence_text":"c.905G>A (p.Arg302Gln)","llm_judgment":"PRESENT","evidence":"c.905G>A (p.Arg302Gln)","abstract_start":343,"abstract_end":365}]}
{"pmid":"26551569","title":"Autosomal recessive hyper IgM syndrome associated with activation-induced cytidine deaminase gene in three Turkish siblings presented with tuberculosis lymphadenitis - Case report.","abstract":"The hyper-immunoglobulin M (HIGM) syndrome is a heterogeneous group of genetic disorders characterized by recurrent infections, decreased serum levels of immunoglobulin G (IgG) and IgA, and normal/increased serum levels of IgM. Herein, we describe three Turkish siblings with HIGM syndrome who had a homozygous missense mutation (c.70C>T, p.Arg24Trp) in the activation-induced cytidine deaminase gene which results in autosomal recessive HIGM syndrome. Two of the siblings, sibling 1 and sibling 3, presented with cervical deep abscess and cervical tuberculosis lymphadenitis, respectively.","variants":[{"Name":"NM_020661.4(AICDA):c.70C>T (p.Arg24Trp)","Chromosome":"12","Start":"8606951","Stop":"8606951","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20161,"rule_based_match":true,"evidence_text":"c.70C>T, p.Arg24Trp","llm_judgment":"PRESENT","evidence":"c.70C>T, p.Arg24Trp","abstract_start":330,"abstract_end":349}]}
{"pmid":"23592335","title":"Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome.","abstract":"Aicardi-Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full-length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.","variants":[{"Name":"NM_006397.3(RNASEH2A):c.69G>A (p.Val23=)","Chromosome":"19","Start":"12806742","Stop":"12806742","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76971,"rule_based_match":true,"evidence_text":"c.69G>A (p.Val23Val)","llm_judgment":"PRESENT","evidence":"c.69G>A (p.Val23Val)","abstract_start":262,"abstract_end":282}]}
{"pmid":"30517686","title":"SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency.","abstract":"CONTEXT: Multiple autosomal recessive genes have been etiologically linked to primary adrenal insufficiency (PAI). Recently, sphingosine-1-phosphate lyase 1 (SGPL1) gene mutations were recognized as a cause of steroid-resistant nephrotic syndrome type 14 (NPHS14), a sphingolipidosis with multisystemic manifestations, including PAI.\nOBJECTIVE: To check if SGPL1 mutations are involved in the pathogenesis of PAI in patients who do not exhibit nephrotic syndrome.\nMETHODS: Sequencing of the SGPL1 gene in 21 patients with familial glucocorticoid disease or triple A syndrome.\nRESULTS: We identified two missense SGPL1 variants in four patients, two of whom were first cousins. We describe in detail the proband, a boy born to Saudi Arabian consanguineous parents with a homozygous c.665G>A, p.R222Q SGPL1 variant. The patient presented with hypoglycemia and seizures at age 2 years and was ultimately diagnosed with PAI (isolated glucocorticoid deficiency). Brain MRI showed abnormalities in the basal ganglia consistent with a degenerative process albeit the patient had no neurologic symptoms.\nCONCLUSIONS: New genetic causes of PAI continue to be identified. We suggest that screening for SGPL1 mutations should not be reserved only for patients with nephrotic syndrome but may also include patients with PAI who lack other clinical manifestations of NPHS14 because, in certain cases, kidney disease and accompanying features might develop. Timely diagnosis of this specific sphingolipidosis while the kidneys still function normally can lead to prompt initiation of therapy and improve outcome.","variants":[{"Name":"NM_003901.4(SGPL1):c.665G>A (p.Arg222Gln)","Chromosome":"10","Start":"70868394","Stop":"70868394","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":424406,"rule_based_match":true,"evidence_text":"c.665G>A, p.R222Q","llm_judgment":"PRESENT","evidence":"c.665G>A, p.R222Q","abstract_start":781,"abstract_end":798}]}
{"pmid":"30051457","title":"A novel CYCS mutation in the α-helix of the CYCS C-terminal domain causes non-syndromic thrombocytopenia.","abstract":"We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain. In silico structural analysis suggested that this mutation results in protein folding instability. CYCS is one of the key factors regulating the intrinsic apoptotic pathway and the mitochondrial respiratory chain. Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies thrombocytopenia. The clinical features of known CYCS variants have been reported to be confined to mild or asymptomatic thrombocytopenia, as was observed for the patient in our study. This study clearly demonstrates that thrombocytopenia can result from CYCS loss-of-function variants.","variants":[{"Name":"NM_018947.6(CYCS):c.301_303del (p.Lys101del)","Chromosome":"7","Start":"25123716","Stop":"25123718","ReferenceAlleleVCF":"CTTT","AlternateAlleleVCF":"C","allel_id":590721,"rule_based_match":true,"evidence_text":"c.301_303del:p.Lys101del","llm_judgment":"PRESENT","evidence":"c.301_303del:p.Lys101del","abstract_start":421,"abstract_end":445}]}
{"pmid":"27377014","title":"MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum.","abstract":"Joubert syndrome (JS) is a clinically and genetically heterogeneous ciliopathy characterized by episodic hyperpnea and apnea, hypotonia, ataxia, cognitive impairment and ocular motor apraxia. The \"molar tooth sign\" is pathognomonic of this condition. Mutations in the MKS1 gene are a major cause of Meckel-Gruber syndrome (MKS), the most common form of syndromic neural tube defects, frequently resulting in perinatal lethality. We present the phenotype and genotype of a child with severe JS and agenesis of the corpus callosum (ACC). In our patient, a next generation sequencing (NGS) approach revealed the following two variants of the MKS1 gene: first, a novel missense variant [ c.240G > T (p.Trp80Cys)], which affects a residue that is evolutionarily highly conserved in mammals and ciliates; second, a 29 bp deletion in intron 15 [c.1408-35_1408-7del29], a founder mutation, which in a homozygous state constitutes the major cause of MKS in Finland. We review the MKS1-variants in all of the eleven JS patients reported to date and compare these patients to our case. To our knowledge, this is the first patient with Joubert syndrome and agenesis of the corpus callosum where a potentially causal genotype is provided.","variants":[{"Name":"NM_017777.4(MKS1):c.240G>T (p.Trp80Cys)","Chromosome":"17","Start":"58216687","Stop":"58216687","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":243896,"rule_based_match":true,"evidence_text":"c.240G > T (p.Trp80Cys)","llm_judgment":"PRESENT","evidence":"c.240G > T (p.Trp80Cys)","abstract_start":684,"abstract_end":707}]}
{"pmid":"32655337","title":"Whole-Exome Sequencing Identifies Three Candidate Homozygous Variants in a Consanguineous Iranian Family with Autism Spectrum Disorder and Skeletal Problems.","abstract":"Autism spectrum disorder (ASD) is characterized by 3 core symptoms with impaired social communication, repetitive behavior, and/or restricted interests in early childhood. As a complex neurodevelopmental disorder (NDD), the phenotype and severity of autism are extremely heterogeneous. Genetic factors have a key role in the etiology of autism. In this study, we investigated an Azeri Turkish family with 2 ASD-affected individuals to identify probable ASD-causing variants. First, the affected individuals were karyotyped in order to exclude chromosomal abnormalities. Then, whole-exome sequencing was carried out in one affected sibling followed by cosegregation analysis for the candidate variants in the family. In addition, SNP genotyping was carried out in the patients to identify possible homozygosity regions. Both proband and sibling had a normal karyotype. We detected 3 possible causative variants in this family: c.5443G>A; p.Gly1815Ser, c.1027C>T; p.Arg343Trp, and c.382A>G; p.Lys128Glu, which are in the <i>FBN1</i>, <i>TF</i>, and <i>PLOD2</i> genes, respectively. All of the variants cosegregated in the family, and SNP genotyping revealed that these 3 variants are located in the homozygosity regions. This family serves as an example of a multimodal polygenic risk for a complex developmental disorder. Of these 3 genes, confluence of the variants in <i>FBN1</i> and <i>PLOD2</i> may contribute to the autistic features of the patient in addition to skeletal problems. Our study highlights the genetic complexity and heterogeneity of NDDs such as autism. In other words, in some patients with ASD, multiple rare variants in different loci rather than a monogenic state may contribute to the development of phenotypes.","variants":[{"Name":"NM_000138.5(FBN1):c.5443G>A (p.Gly1815Ser)","Chromosome":"15","Start":"48452664","Stop":"48452664","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":197676,"rule_based_match":true,"evidence_text":"c.5443G>A; p.Gly1815Ser","llm_judgment":"PRESENT","evidence":"c.5443G>A; p.Gly1815Ser","abstract_start":926,"abstract_end":949},{"Name":"NM_182943.3(PLOD2):c.382A>G (p.Lys128Glu)","Chromosome":"3","Start":"146110405","Stop":"146110405","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":289796,"rule_based_match":true,"evidence_text":"c.382A>G; p.Lys128Glu","llm_judgment":"PRESENT","evidence":"c.382A>G; p.Lys128Glu","abstract_start":979,"abstract_end":1000}]}
{"pmid":"32384692","title":"Whole Exome Sequencing Reveals Novel and Recurrent Disease-Causing Variants in Lens Specific Gap Junctional Protein Encoding Genes Causing Congenital Cataract.","abstract":"Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G>C, p.Gly60Arg) in <i>GJA8</i> with lamellar cataract; family B, with a recurrent variant in <i>GJA8</i> (c.262C>T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in <i>GJA3</i> (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in <i>GJA3</i> (c.82G>T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to co-segregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in <i>GJA8</i> causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant.","variants":[{"Name":"NM_021954.4(GJA3):c.771dup (p.Ser258fs)","Chromosome":"13","Start":"20142517","Stop":"20142518","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":3412485,"rule_based_match":true,"evidence_text":"c.771dupC, p.Ser258GlnfsTer68","llm_judgment":"PRESENT","evidence":"c.771dupC, p.Ser258GlnfsTer68","abstract_start":686,"abstract_end":715},{"Name":"NM_005267.5(GJA8):c.262C>T (p.Pro88Ser)","Chromosome":"1","Start":"147908217","Stop":"147908217","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23760,"rule_based_match":true,"evidence_text":"c.262C>T (p.Pro88Ser)","llm_judgment":"PRESENT","evidence":"p.Pro88Ser","abstract_start":589,"abstract_end":599},{"Name":"NM_021954.4(GJA3):c.82G>T (p.Val28Leu)","Chromosome":"13","Start":"20143207","Stop":"20143207","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3412509,"rule_based_match":true,"evidence_text":"c.82G>T (p.Val28Leu)","llm_judgment":"PRESENT","evidence":"p.Val28Leu","abstract_start":805,"abstract_end":815},{"Name":"NM_005267.5(GJA8):c.178G>C (p.Gly60Arg)","Chromosome":"1","Start":"147908133","Stop":"147908133","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3412510,"rule_based_match":true,"evidence_text":"c.178G>C, p.Gly60Arg","llm_judgment":"PRESENT","evidence":"c.178G>C, p.Gly60Arg","abstract_start":467,"abstract_end":487}]}
{"pmid":"20005757","title":"A novel PCFT gene mutation (p.Cys66LeufsX99) causing hereditary folate malabsorption.","abstract":"Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder which is characterized by impaired intestinal folate malabsorption and impaired folate transport into the central nervous system. Mutations in the intestinal folate transporter PCFT have been reported previously in only 10 individuals with this disorder. The purpose of the current study was to describe the clinical phenotype and determine the molecular basis for this disorder in a family with four affected individuals. A consanguineous family of Pakistani origin with autosomal recessive HFM was ascertained and clinically phenotyped. After genetic linkage studies all coding exons of the PCFT gene were screened for mutations by direct sequencing. The clinical phenotype of four affected patients is described. Direct sequencing of PCFT revealed a novel homozygous frameshift mutation (c.194dupG) at a mononucleotide repeat in exon 1 predicted to result in a truncated protein (p.Cys66LeufsX99). This report extends current knowledge on the phenotypic manifestations of HFM and the PCFT mutation spectrum.","variants":[{"Name":"NM_080669.6(SLC46A1):c.194dup (p.Cys66fs)","Chromosome":"17","Start":"28405920","Stop":"28405921","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76658,"rule_based_match":true,"evidence_text":"c.194dup","llm_judgment":"PRESENT","evidence":"c.194dup","abstract_start":868,"abstract_end":876}]}
{"pmid":"23384994","title":"Hereditary motor and sensory neuropathy (HMSN) type X1 in an Argentinean family reveals independent GJB1/Cx32 mutations at the identical nucleotide position.","abstract":"X-linked Charcot-Marie-Tooth disease (CMT Type X1, OMIM: 302800) represents a frequent cause of hereditary peripheral motor and sensory neuropathies and is associated with mutations in GJB1 encoding the gap junction beta 1 protein connexin 32 (Cx32). Studying an Argentinean family of Italian origin with seven affected males in three generations exhibiting clinical signs of CMT, eight obligate female carriers were identified genealogically. DNA sequencing of exon 2 and adjacent regions of the GJB1 gene in two symptomatic males whose respective maternal grandfathers, both affected, were brothers, revealed mutations in GJB1/Cx32. Surprisingly, each of the two affected patients had a different mutation in hemizygous state at the same nucleotide position: c.383C>T (p.S128L) and c.383C>A (p.S128X). In both cases, the identified mutation was present in heterozygous state in the corresponding maternal genomic DNA. Furthermore, X-chromosomal microsatellite analysis showed identical marker alleles in both patients. Together with the genealogical information, these molecular data imply that a primarily mutated allele mutated for a second time. In conclusion, two different mutations at the same nucleotide position in this Argentinean family represent a finding with a very low probability of occurrence.","variants":[{"Name":"NM_000166.6(GJB1):c.383C>A (p.Ser128Ter)","Chromosome":"X","Start":"71224090","Stop":"71224090","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":625591,"rule_based_match":true,"evidence_text":"c.383C>A (p.S128X)","llm_judgment":"PRESENT","evidence":"c.383C>A (p.S128X)","abstract_start":784,"abstract_end":802}]}
{"pmid":"26165328","title":"Leber congenital amaurosis: first genotyped Hungarian patients and report of 2 novel mutations in the CRB1 and CEP290 genes.","abstract":"PURPOSE: To introduce the first Hungarian patients with genetically defined Leber congenital amaurosis (LCA) and to report 2 novel mutations.\nMETHODS: Seven otherwise healthy patients (4-29 years, 5 male and 2 female) who had an onset of severe visual impairment before age 2 years were investigated. The diagnosis was established in all individuals by medical history, funduscopy, and full-field electroretinogram (ERG). Ocular examination included visual acuity testing, digital fundus photography, and in 6 patients retinal imaging with optical coherence tomography (OCT). Arrayed primer extension microarray screening was performed in all probands. In 2 patients, further Sanger sequencing and targeted next-generation sequencing revealed the second disease allele.\nRESULTS: A cone-rod type LCA was revealed in 4 patients and a rod-cone type disease in 3 patients. Five patients presented with maculopathy. Optical coherence tomography (OCT) imaging showed diffuse retinal thickening in 3 probands with severe macular atrophy in one. Full-field ERGs were undetectable or residual in all patients. Genetic screening revealed AIPL1, CRB1, and CEP290 gene-related pathology in 6 patients; in 1 proband, no mutation was found. Three homozygous and 3 compound heterozygous mutations were identified. Two novel variants were detected: c.2536G&gt;T (p.G846X) in the CRB1 gene and c.4929delA (p.Lys1643fsX2) in the CEP290 gene.\nCONCLUSIONS: Genetic subtypes identified are among the most common ones in LCA; the phenotypes are consistent with those reported previously. Both novel mutations are predicted to result in a premature translation termination. The phenotype related to the novel CRB1 mutation results in severe atrophic maculopathy.","variants":[{"Name":"NM_201253.3(CRB1):c.2536G>T (p.Gly846Ter)","Chromosome":"1","Start":"197427861","Stop":"197427861","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2837256,"rule_based_match":false,"evidence_text":"c.2536G>T (p.G846X)","llm_judgment":"PRESENT","evidence":"p.G846X","abstract_start":1347,"abstract_end":1354}]}
{"pmid":"17851452","title":"Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness.","abstract":"Nonsyndromic autosomal recessive deafness accounts for 80% of hereditary deafness. To date, 52 loci responsible for autosomal recessive deafness have been mapped and 24 genes identified. Here, we report a large inbred Brazilian pedigree with 26 subjects affected by prelingual deafness. Given the extensive consanguinity found in this pedigree, the most probable pattern of inheritance is autosomal recessive. However, our linkage and mutational analysis revealed, instead of an expected homozygous mutation in a single gene, two different mutant alleles and a possible third undetected mutant allele in the MYO15A gene (DFNB3 locus), as well as evidence for other causes for deafness in the same pedigree. Among the 26 affected subjects, 15 were homozygous for the novel c.10573delA mutation in the MYO15A gene, 5 were compound heterozygous for the mutation c.10573delA and the novel deletion c.9957_9960delTGAC and one inherited only a single c.10573delA mutant allele, while the other one could not be identified. Given the extensive consanguinity of the pedigree, there might be at least one more deafness locus segregating to explain the condition in some of the subjects whose deafness is not clearly associated with MYO15A mutations, although overlooked environmental causes could not be ruled out. Our findings illustrate a high level of etiological heterogeneity for deafness in the family and highlight some of the pitfalls of genetic analysis of large genes in extended pedigrees, when homozygosity for a single mutant allele is expected.","variants":[{"Name":"NM_016239.4(MYO15A):c.10573del (p.Ser3525fs)","Chromosome":"17","Start":"18178850","Stop":"18178850","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":22000,"rule_based_match":true,"evidence_text":"c.10573delA","llm_judgment":"PRESENT","evidence":"c.10573delA","abstract_start":772,"abstract_end":783}]}
{"pmid":"30243293","title":"A case report: autosomal recessive Myotonia congenita caused by a novel splice mutation (c.1401 + 1G > A) in CLCN1 gene of a Chinese Han patient.","abstract":"BACKGROUND: Autosomal recessive Myotonia congenita (Becker's disease) is caused by mutations in the CLCN1 gene. The condition is characterized by muscle stiffness during sustained muscle contraction and variable degree of muscle weakness that tends to improve with repeated contractions.\nCASE PRESENTATION: A 21-year-old man presented with transient muscle stiffness since the last 10 years. He had difficulty in initiating movement and experienced muscle weakness after rest, which typically improved after repeated contraction (warm-up phenomenon). There was no significant family history. Medical examination showed generalized muscle hypertrophy. Serum creatine kinase level was 2-fold higher than the normal value. Electromyogram showed myotonic discharges. DNA sequence analysis identified a novel splice mutation (c.1401 + 1G > A) and a known mutation (c.1657A > T,p.Ile553Phe). He rapidly responded to treatment with mexiletine 100 mg three times a day for 6 months.\nCONCLUSIONS: This case report of autosomal recessive Myotonia congenita caused by a novel compound heterozygous mutation expands the genotypic spectrum of CLCN1 gene.","variants":[{"Name":"NM_000083.3(CLCN1):c.1401+1G>A","Chromosome":"7","Start":"143332874","Stop":"143332874","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1364332,"rule_based_match":true,"evidence_text":"c.1401 + 1G > A","llm_judgment":"PRESENT","evidence":"c.1401 + 1G > A","abstract_start":821,"abstract_end":836},{"Name":"NM_000083.3(CLCN1):c.1657A>T (p.Ile553Phe)","Chromosome":"7","Start":"143342003","Stop":"143342003","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1868086,"rule_based_match":true,"evidence_text":"c.1657A > T,p.Ile553Phe","llm_judgment":"PRESENT","evidence":"c.1657A > T,p.Ile553Phe","abstract_start":860,"abstract_end":883}]}
{"pmid":"35356632","title":"Compound Heterozygous Factor VII Deficiency c.1025G>A p.(Arg342Gln) With Novel Missense Variant c.194C>G p.(Ala65Gly).","abstract":"Factor VII (FVII) deficiency manifests as prolonged prothrombin time (PT) and reduced FVII activity. We report a case of an asymptomatic 60-year-old gentleman with discrepancies in PT and FVII coagulant activity levels (FVII:C) on three different thromboplastin reagents used. Further sequence analysis on genomic DNA showed double heterozygosity for c.1025G>A p.Arg342Gln and c.194C>G p.Ala65Gly in the <i>F7</i> gene. To date, p.Ala65Gly in exon 2 of the <i>F7</i> gene represents a novel variant in patients with FVII deficiency and is classified as likely pathogenic. Computational prediction tools support a deleterious effect on the gene. The genotype-phenotype association and the clinical significance of this exon 2 missense variant is proposed in this case report.","variants":[{"Name":"NM_019616.4(F7):c.1025G>A (p.Arg342Gln)","Chromosome":"13","Start":"113118698","Stop":"113118698","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":408803,"rule_based_match":true,"evidence_text":"c.1025G>A p.Arg342Gln","llm_judgment":"PRESENT","evidence":"c.1025G>A p.Arg342Gln","abstract_start":351,"abstract_end":372}]}
{"pmid":"24708999","title":"Periodic fevers in adult Greeks: clinical and molecular presentation.","abstract":"OBJECTIVES: Hereditary periodic fever syndromes (HPFS) are rare diseases characterised by recurrent, self-limited episodes of fever and localised inflammation, which arise from monogenic defects. In the present study we describe the clinical features, laboratory parameters and genetic profile of adult patients.\nMETHODS: Samples examined between May 2010 and December 2012 at the laboratory of genetic molecular diagnosis of the department of Pathophysiology of School of Medicine, National University of Athens.\nRESULTS: Of the MEFV gene variants the most frequent genotype was the E148Q heterozygosity, with patients presenting with the typical clinical picture, two patients were positive for the pR92Q/c.362G>A mutation in heterozygosity. The testing for the Hyper IgD Syndrome was positive for the pV377I/c.1129 G>A heterozygosity in a patient with the corresponding typical picture and the testing for the CAPS syndromes was positive for a new mutation, pR170H/c.509G>A in heterozygosity, in a case with less typical clinical features.\nCONCLUSIONS: Availability of genetic testing in everyday clinical practice can provide valuable information regarding the clinical diversity, geographic distribution and genetic characteristics of these rare disease in all age groups.","variants":[{"Name":"NM_001243133.2(NLRP3):c.509G>A (p.Arg170His)","Chromosome":"1","Start":"247423958","Stop":"247423958","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3859699,"rule_based_match":true,"evidence_text":"pR170H/c.509G>A","llm_judgment":"PRESENT","evidence":"pR170H/c.509G>A","abstract_start":961,"abstract_end":976}]}
{"pmid":"31268351","title":"Coinheritance of Hb City of Hope (","abstract":"More than 900 abnormal hemoglobin (Hb) β chain variants have now been characterized. The majority are due to point mutations resulting in a single amino acid substitution within the globin gene involved, with nearly twice as many β chain variants identified compared to α chain variants. Although most of these variants are clinically and hematologically silent, they can interact with different thalassemia mutations, which could sometimes render laboratory diagnostics in a routine setting difficult. In this study, we present a case of coinheritance of Hb City of Hope [β69(E13)Gly→Ser; <i>HBB</i>: c.208G>A] and β-thalassemia (β-thal), that compromises the molecular diagnosis of β-thal trait.","variants":[{"Name":"NM_000518.4(HBB):c.208G>A (p.Gly70Ser)","Chromosome":"11","Start":"5226684","Stop":"5226684","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30177,"rule_based_match":true,"evidence_text":"<i>HBB</i>: c.208G>A","llm_judgment":"PRESENT","evidence":"<i>HBB</i>: c.208G>A","abstract_start":590,"abstract_end":610}]}
{"pmid":"15241680","title":"Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis.","abstract":"Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the fibroblast growth factor receptor type 3 gene (FGFR3). This frequently occurs as a new mutation, manifesting one of the highest documented rates for any transversion in the human genome. To understand the biology of this mutation, we have investigated its parental origin, and the ages of the parents, in 19 families with de novo c.749C>G mutations. All ten informative cases originated from the paternal allele (95% confidence interval 74-100% paternal); the average paternal age at birth overall was 34.7 years. An exclusive paternal origin of mutations, and increased paternal age, were previously described for a different mutation (c.1138G>A) of the FGFR3 gene causing achondroplasia, as well as for mutations of the related FGFR2 gene causing Apert, Crouzon and Pfeiffer syndromes. We conclude that similar biological processes are likely to shape the occurrence of this c.749C>G mutation as for other mutations of FGFR3 as well as FGFR2.","variants":[{"Name":"NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg)","Chromosome":"4","Start":"1801844","Stop":"1801844","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":31379,"rule_based_match":true,"evidence_text":"c.749C>G","llm_judgment":"PRESENT","evidence":"c.749C>G","abstract_start":150,"abstract_end":158}]}
{"pmid":"30531807","title":"Identification of novel LFNG mutations in spondylocostal dysostosis.","abstract":"Spondylocostal dysostosis (SCDO) is a heterogeneous group of skeletal disorders characterized by multiple segmentation defects involving vertebrae and ribs. Seven disease genes have been reported as causal genes for SCDO: DLL3, MESP2, TBX6, HES7, RIPPLY2, DMRT2, and LFNG. Here we report a Japanese SCDO case with multiple severe vertebral anomalies from cervical to sacral spine. The patient was a compound heterozygote for c.372delG (p.K124Nfs*) and c.601G>A (p.D201N) variants of LFNG, which encodes a glycosyltransferase (O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase). The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. This is the second report of LFNG mutations in SCDO.","variants":[{"Name":"NM_001040167.2(LFNG):c.601G>A (p.Asp201Asn)","Chromosome":"7","Start":"2525433","Stop":"2525433","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":610534,"rule_based_match":true,"evidence_text":"c.601G>A (p.D201N)","llm_judgment":"PRESENT","evidence":"c.601G>A (p.D201N)","abstract_start":452,"abstract_end":470},{"Name":"NM_001040167.2(LFNG):c.372del (p.Lys124fs)","Chromosome":"7","Start":"2520233","Stop":"2520233","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":610535,"rule_based_match":true,"evidence_text":"c.372delG (p.K124Nfs*)","llm_judgment":"PRESENT","evidence":"c.372delG (p.K124Nfs*)","abstract_start":425,"abstract_end":447}]}
{"pmid":"38158857","title":"Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.","abstract":"PURPOSE: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.\nMETHODS: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.\nRESULTS: In 1 family with 2 affected males, we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation.\nCONCLUSION: We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron-containing genes due to germline variation in ZRSR2.","variants":[{"Name":"NM_005089.4(ZRSR2):c.1211_1212del (p.Gly404fs)","Chromosome":"X","Start":"15823001","Stop":"15823002","ReferenceAlleleVCF":"AGG","AlternateAlleleVCF":"A","allel_id":3526376,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1211_1212del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1211_1212del","abstract_start":678,"abstract_end":704},{"Name":"NM_005089.4(ZRSR2):c.1207_1208del (p.Arg403fs)","Chromosome":"X","Start":"15823000","Stop":"15823001","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":966735,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1207_1208del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1207_1208del","abstract_start":828,"abstract_end":854}]}
{"pmid":"38158857","title":"Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.","abstract":"PURPOSE: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.\nMETHODS: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.\nRESULTS: In 1 family with 2 affected males, we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation.\nCONCLUSION: We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron-containing genes due to germline variation in ZRSR2.","variants":[{"Name":"NM_005089.4(ZRSR2):c.1211_1212del (p.Gly404fs)","Chromosome":"X","Start":"15823001","Stop":"15823002","ReferenceAlleleVCF":"AGG","AlternateAlleleVCF":"A","allel_id":3526376,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1211_1212del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1211_1212del","abstract_start":678,"abstract_end":704},{"Name":"NM_005089.4(ZRSR2):c.1207_1208del (p.Arg403fs)","Chromosome":"X","Start":"15823000","Stop":"15823001","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":966735,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1207_1208del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1207_1208del","abstract_start":828,"abstract_end":854}]}
{"pmid":"22471336","title":"Detection of KCNJ11 gene mutations in a family with neonatal diabetes mellitus: implications for therapeutic management of family members with long-standing disease.","abstract":"BACKGROUND: Activating mutations of potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11), which encodes Kir6.2 (beta-cell adenosine triphosphate-sensitive potassium [K(ATP)] channel subunit), have been associated with neonatal diabetes mellitus (NDM) in different studies. Treatment with oral sulfonylureas in place of exogenous insulin injections results in improved glycemic control in most patients carrying these mutations. Exploration of genetic causes of NDM occurring before the age of 6 months has been proposed as an important issue in identification of monogenic forms of diabetes, which might be critical in their therapeutic management, as a consequence.\nMETHODS: Mutation screening of the KCNJ11 gene was carried out using PCR amplification followed by direct sequencing in three family members: the proband, ND1, diagnosed at 40 days of age (current age 7 years); his sibling, ND2, diagnosed at 2 years of age (current age 14 years); and their father, ND3, diagnosed at 15 years of age (current age 35 years), who had been exclusively treated with insulin. The effect of the E227K mutation was also examined in a homology model of Kir6.2.\nRESULTS: Our results revealed the presence of the heterozygous missense mutation c. 679 G/A (E227K) in all three patients, who were all able to successfully transfer from insulin injections to an oral sulfonylurea, with improved glycemic control.\nCONCLUSION: We found that three members of a family with highly variable age of onset of insulin-treated diabetes, diagnosed at 40 days, 2 years, and 15 years of age, all carried the E227K mutation in KCNJ11 and could switch to an oral sulfonylurea. This mutation has been previously reported in patients with permanent and transient NDM, as well as later-onset diabetes; this report adds to the variability in phenotypic presentation and further supports genetic testing in all diabetic members of any family affected by NDM.","variants":[{"Name":"NM_000525.4(KCNJ11):c.679G>A (p.Glu227Lys)","Chromosome":"11","Start":"17387413","Stop":"17387413","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":168869,"rule_based_match":false,"evidence_text":"c. 679 G/A (E227K)","llm_judgment":"PRESENT","evidence":"c. 679 G/A (E227K)","abstract_start":1252,"abstract_end":1270}]}
{"pmid":"23866855","title":"A synonymous change, p.Gly16Gly in MECP2 Exon 1, causes a cryptic splice event in a Rett syndrome patient.","abstract":"BACKGROUND: Mutations in MECP2 are the main cause of Rett Syndrome. To date, no pathogenic synonymous MECP2 mutation has yet been identified. Here, we investigated a de novo synonymous variant c.48C>T (p.Gly16Gly) identified in a girl presenting with a typical RTT phenotype.\nMETHODS: In silico analyses to predict the effects of sequence variation on mRNA splicing were employed, followed by sequencing and quantification of lymphocyte mRNAs from the subject for splice variants MECP2_E1 and MECP2_E2.\nRESULTS: Analysis of mRNA confirmed predictions that this synonymous mutation activates a splice-donor site at an early position in exon 1, leading to a deletion (r.[=, 48_63del]), codon frameshift and premature stop codon (p.Glu17Lysfs*16) for MECP2_E1. For MECP2_E2, the same premature splice site is used, but as this is located in the 5'untranslated region, no effect on the amino acid sequence is predicted. Quantitative analysis that specifically measured this cryptic splice variant also revealed a significant decrease in the quantity of the correct MECP2_E1 transcript, which indicates that this is the etiologically significant mutation in this patient.\nCONCLUSION: These findings suggest that synonymous variants of MECP2 as well as other known disease genes-and de novo variants in particular- should be re-evaluated for potential effects on splicing.","variants":[{"Name":"NM_001110792.2(MECP2):c.48C>T (p.Gly16=)","Chromosome":"X","Start":"154097618","Stop":"154097618","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187565,"rule_based_match":true,"evidence_text":"c.48C>T (p.Gly16Gly)","llm_judgment":"PRESENT","evidence":"c.48C>T (p.Gly16Gly)","abstract_start":193,"abstract_end":213}]}
{"pmid":"27812022","title":"The mutation p.E113K in the Schiff base counterion of rhodopsin is associated with two distinct retinal phenotypes within the same family.","abstract":"The diagnoses of retinitis pigmentosa (RP) and stationary night blindness (CSNB) are two distinct clinical entities belonging to a group of clinically and genetically heterogeneous retinal diseases. The current study focused on the identification of causative mutations in the RP-affected index patient and in several members of the same family that reported a phenotype resembling CSNB. Ophthalmological examinations of the index patient confirmed a typical form of RP. In contrast, clinical characterizations and ERGs of another affected family member showed the Riggs-type CSNB lacking signs of RP. Applying whole exome sequencing we detected the non-synonymous substitution c.337G > A, p.E113 K in the rhodopsin (RHO) gene. The mutation co-segregated with the diseases. The identification of the pathogenic variant p.E113 K is the first description of a naturally-occurring mutation in the Schiff base counterion of RHO in human patients. The heterozygous mutation c.337G > A in exon 1 was confirmed in the index patient as well as in five CSNB-affected relatives. This pathogenic sequence change was excluded in a healthy family member and in 199 ethnically matched controls. Our findings suggest that a mutation in the biochemically well-characterized counterion p.E113 in RHO can be associated with RP or Riggs-type CSNB, even within the same family.","variants":[{"Name":"NM_000539.3(RHO):c.337G>A (p.Glu113Lys)","Chromosome":"3","Start":"129529070","Stop":"129529070","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1429377,"rule_based_match":true,"evidence_text":"c.337G > A, p.E113 K","llm_judgment":"PRESENT","evidence":"c.337G > A, p.E113 K","abstract_start":678,"abstract_end":698}]}
{"pmid":"38050059","title":"Clinical and functional analysis of the germline","abstract":"<i>TP53</i> plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline <i>TP53</i> p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify <i>TP53</i> p.K164E as a likely pathogenic variant.","variants":[{"Name":"NM_000546.6(TP53):c.490A>G (p.Lys164Glu)","Chromosome":"17","Start":"7675122","Stop":"7675122","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":245075,"rule_based_match":true,"evidence_text":"NM_000546.5: c.490A>G","llm_judgment":"PRESENT","evidence":"NM_000546.5: c.490A>G","abstract_start":397,"abstract_end":418}]}
{"pmid":"15662592","title":"Identification of a novel calcium-sensing receptor gene mutation causing familial hypocalciuric hypercalcemia by single-strand conformation polymorphism analysis.","abstract":"Calcium-sensing receptor gene (CASR) mutations that alter the function of the G protein coupled Ca (2+)-sensing receptor are reported in patients with familial hypocalciuric hypercalcemia (FHH), autosomal dominant hypocalcemia (ADH), and neonatal severe hyperparathyroidism (NSHPT). In search for novel disease causing mutations in the CASR gene, we screened exons 2 - 7 of the CASR gene of a family with FHH using single-strand conformation polymorphism analysis. We identified a novel CASR mutation (c.518 T > C; L173 P) in exon 4 encoding for the extracellular domain of the Ca (2+)-sensing receptor. This region seems to represent a hot spot within the CASR gene with at least 13 reported disease causing mutations thus far.","variants":[{"Name":"NM_000388.4(CASR):c.518T>C (p.Leu173Pro)","Chromosome":"3","Start":"122261553","Stop":"122261553","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1288796,"rule_based_match":true,"evidence_text":"c.518 T > C; L173 P","llm_judgment":"PRESENT","evidence":"c.518 T > C; L173 P","abstract_start":502,"abstract_end":521}]}
{"pmid":"16705691","title":"Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta.","abstract":"Mutations in the type I collagen genes COL1A1 and COL1A2 are responsible for the dominantly inherited connective tissue disorder osteogenesis imperfecta (OI). The severity of OI is diverse, ranging from perinatal lethality to a very mild phenotype that is characterized by normal stature and the absence of deformities. Although there have been several studies on the mutational spectra of COL1A1 and/or COL1A2 in Western populations, very few cases have been reported from Asia. In this study, we investigated 67 unrelated Korean probands with OI and used nucleotide sequence analysis to detect COL1A1 and COL1A2 mutations. Thirty-five different mutations were identified in the two genes, including 24 novel mutations. Among the 35 kinds of detected mutations, 15 were glycine substitutions (seven in COL1A1 and eight in COL1A2), one was a nonsense mutation, four were frameshift mutations in COL1A1, three were in-frame duplications in COL1A2, and 12 were splice site mutations (seven in COL1A1 and five in COL1A2). Until now, mutations in the COL1A1 and COL1A2 genes known to cause OI were unique and rarely repeated in other families. Interestingly, the c.982G>A (p.Gly328Ser) mutation in COL1A2 was found recurrently and was the causative mutation in five independent OI probands. Haplotype analysis of the COL1A2 gene revealed that four probands from five independent OI probands with c.982G>A (p.Gly328Ser) had a common haplotype. Our clinical data showed the heterogeneity even within a specific genotype, which suggested the complex expression of this disease.","variants":[{"Name":"NM_000089.4(COL1A2):c.982G>A (p.Gly328Ser)","Chromosome":"7","Start":"94409768","Stop":"94409768","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":457703,"rule_based_match":true,"evidence_text":"c.982G>A (p.Gly328Ser)","llm_judgment":"PRESENT","evidence":"c.982G>A (p.Gly328Ser)","abstract_start":1159,"abstract_end":1181}]}
{"pmid":"22595425","title":"Mild fumarase deficiency and a trial of low protein diet.","abstract":"We report clinical findings in a 12-year-old girl with a mild case of fumarase deficiency who continues to make progress. She has two novel mutations of the fumarase gene [c.521C>G (p.P174R) and c.908T>C (p.L303S)]. A trial of low protein diet did not reduce fumaric aciduria.","variants":[{"Name":"NM_000143.4(FH):c.521C>G (p.Pro174Arg)","Chromosome":"1","Start":"241512001","Stop":"241512001","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":38660,"rule_based_match":true,"evidence_text":"c.521C>G (p.P174R)","llm_judgment":"PRESENT","evidence":"c.521C>G (p.P174R)","abstract_start":172,"abstract_end":190},{"Name":"NM_000143.4(FH):c.908T>C (p.Leu303Ser)","Chromosome":"1","Start":"241504242","Stop":"241504242","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":50023,"rule_based_match":true,"evidence_text":"c.908T>C (p.L303S)","llm_judgment":"PRESENT","evidence":"c.908T>C (p.L303S)","abstract_start":195,"abstract_end":213}]}
{"pmid":"29154021","title":"Diagnosis of Fanconi Anaemia by ionising radiation- or mitomycin C-induced micronuclei.","abstract":"Fanconi Anaemia (FA) is an autosomal recessive disorder characterised by defects in DNA repair, associated with chromosomal instability and cellular hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC). The FA repair pathway involves complex DNA repair mechanisms crucial for genomic stability. Deficiencies in DNA repair genes give rise to chromosomal radiosensitivity. FA patients have shown increased clinical radiosensitivity by exhibiting adverse normal tissue side-effects. The study aimed to investigate chromosomal radiosensitivity of homozygous and heterozygous carriers of FA mutations using three micronucleus (MN) assays. The G0 and S/G2MN assays are cytogenetic assays to evaluate DNA damage induced by ionising radiation in different phases of the cell cycle. The MMC MN assay detects DNA damage induced by a crosslinking agent in the G0 phase. Patients with a clinical diagnosis of FA and their parents were screened for the complete coding region of 20 FA genes. Blood samples of all FA patients and parents were exposed to ionising radiation of 2 and 4Gy. Chromosomal radiosensitivity was evaluated in the G0 and S/G2 phase. Most of our patients were homozygous for the founder mutation FANCG c.637_643delTACCGCC; p.(Tyr213Lysfs*6) while one patient was compound heterozygous for FANCG c.637_643delTACCGCC and FANCG c.1379G > A, p.(Gly460Asp), a novel missense mutation. Another patient was compound heterozygous for two deleterious FANCA mutations. In FA patients, the G0- and S/G2-MN assays show significantly increased chromosomal radiosensitivity and genomic instability. Moreover, chromosomal damage was significantly elevated in MMC treated FA cells. We also observed an increase in chromosomal radiosensitivity and genomic instability in the parents using 3 assays. The effect was significant using the MMC MN assay. The MMC MN assay is advantageous as it is less labour intense, time effective and has potential as a reliable alternative method for detecting FA patients from parents and controls.","variants":[{"Name":"NM_004629.2(FANCG):c.1379G>A (p.Gly460Asp)","Chromosome":"9","Start":"35075519","Stop":"35075519","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2947346,"rule_based_match":true,"evidence_text":"FANCG c.1379G > A, p.(Gly460Asp)","llm_judgment":"PRESENT","evidence":"FANCG c.1379G > A, p.(Gly460Asp)","abstract_start":1345,"abstract_end":1377}]}
{"pmid":"30606148","title":"Prevalence of BRCA1 and BRCA2 pathogenic and likely pathogenic variants in non-selected ovarian carcinoma patients in Brazil.","abstract":"BACKGROUND: BRCA1/2 pathogenic (P) and likely pathogenic (LP) germline variants are frequent among patients with ovarian carcinoma. However, these variants have not been extensively characterized in patients with ovarian cancer in Brazil.\nMETHODS: In this retrospective study we evaluated clinical characteristics and BRCA1/2 genetic test results from patients with ovarian carcinoma who underwent genetic counseling at A.C.Camargo Cancer Center (Brazil) between 2015 and 2017 and had performed germline genetic testing of BRCA1/2 genes.\nRESULTS: Among 158 patients, 33 P and LP variants and were found (20.8%), 27 in BRCA1 and six in BRCA2, and six variants of unknown clinical significance (VUS). Thirteen percent of the patients did not have Multiplex Ligation-dependent Probe Amplification (MLPA) results. Three P variants in BRCA1 were found in more than one patient: c.5266dupC (p.Gln1756Profs*74), c.3331_3334delCAAG (p.Gln1111Asnfs5*), and c.211A > G (p.Arg71Gly). One LP variant in BRCA1 had not been previously described, c.4153_4154delCT (p.Leu1385Ilefs*5). Patients with previous diagnosis of breast cancer were carriers of P or LP variant in 8 of 12 cases (66.7%), and patients with a family history of ovarian or breast cancer in first- or second-degree relatives were carriers of P or LP variant in 26.7% of cases compared to 16.9% for patients without family history (p = 0.166).\nCONCLUSION: Prevalence of BRCA1/2 germline P and LP variants is slightly higher than previously described by the largest occidental studies, with a high prevalence of variant c.5266dupC (p.Gln1756Profs*74) in BRCA1 observed. Moreover, we identified a new LP variant.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"c.5266dupC (p.Gln1756Profs*74)","llm_judgment":"PRESENT","evidence":"c.5266dupC (p.Gln1756Profs*74)","abstract_start":873,"abstract_end":903},{"Name":"NM_007294.4(BRCA1):c.211A>G (p.Arg71Gly)","Chromosome":"17","Start":"43106457","Stop":"43106457","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":32732,"rule_based_match":true,"evidence_text":"c.211A > G (p.Arg71Gly)","llm_judgment":"PRESENT","evidence":"c.211A > G (p.Arg71Gly)","abstract_start":948,"abstract_end":971}]}
{"pmid":"31697046","title":"A novel heterozygous loss-of-function DCC Netrin 1 receptor variant in prenatal agenesis of corpus callosum and review of the literature.","abstract":"Agenesis of the corpus callosum (ACC) is a common prenatally-detected brain anomaly. Recently, an association between mutations in the DCC Netrin 1 receptor (DCC) gene and ACC, with or without mirror movements, has been demonstrated. In this manuscript, we present a family with a novel heterozygous frameshift mutation in DCC, review the available literature, and discuss the challenges involved in the genetic counseling for recently discovered disorders with paucity of medical information. We performed whole exome sequencing in a healthy nonconsanguineous couple that underwent two pregnancy terminations due to prenatal diagnosis of ACC. A heterozygous variant c.2774dupA (p.Asn925Lysfs*17) in the DCC gene was demonstrated in fetal and paternal DNA samples, as well as in a healthy 4-year-old offspring. When directly questioned, both father and child reported having mirror movements not affecting quality of life. Segregation analysis demonstrated the variant in three paternal siblings, two of them having mirror movements. Brain imaging revealed normal corpus callosum. Summary of literature data describing heterozygous loss-of-function variants in DCC (n = 61) revealed 63.9% penetrance for mirror movements, 9.8% for ACC, and 5% for both. No significant neurodevelopmental abnormalities were reported among the seven published patients with DCC loss-of-function variants and ACC. Prenatal diagnosis of ACC should prompt a specific anamnesis regarding any neurological disorder, as well as intentional physical examination of both parents aimed to detect mirror movements. In suspicious cases, detection of DCC pathogenic variants might markedly improve the predicted prognosis, alleviate the parental anxiety, and possibly prevent pregnancy termination.","variants":[{"Name":"NM_005215.4(DCC):c.2774dup (p.Asn925fs)","Chromosome":"18","Start":"53397387","Stop":"53397388","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":1290542,"rule_based_match":true,"evidence_text":"c.2774dupA (p.Asn925Lysfs*17)","llm_judgment":"PRESENT","evidence":"c.2774dupA (p.Asn925Lysfs*17)","abstract_start":667,"abstract_end":696}]}
{"pmid":"33269433","title":"Homozygous mutations in Pakistani consanguineous families with prelingual nonsyndromic hearing loss.","abstract":"Autosomal recessive nonsyndromic hearing loss (DFNB) is relatively frequent in Pakistan, which is thought to be mainly due to relatively frequent consanguinity. DFNB genes vary widely in their kinds and functions making molecular diagnosis difficult. This study determined the genetic causes in five Pakistani DFNB families with prelingual onset. The familial genetic analysis identified four pathogenic or likely pathogenic homozygous mutations by whole exome sequencing: two splicing donor site mutations of c.787+1G>A in ESRRB (DFNB35) and c.637+1G>T in CABP2 (DFNB93) and two missense mutations of c.7814A>G (p.Asn2605Ser) in CDH23 (DFNB12) and c.242G>A (p.Arg81His) in TMIE (DFNB6). The ESRRB and TMIE mutations were novel, and the TMIE mutation was observed in two families. The two missense mutations were located at well conserved sites and in silico analysis predicted their pathogenicity. This study identified four homozygous mutations as the underlying cause of DFNB including two novel mutations. This study will be helpful for the exact molecular diagnosis and treatment of deafness patients.","variants":[{"Name":"NM_147196.3(TMIE):c.242G>A (p.Arg81His)","Chromosome":"3","Start":"46709156","Stop":"46709156","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3760762,"rule_based_match":true,"evidence_text":"c.242G>A (p.Arg81His)","llm_judgment":"PRESENT","evidence":"c.242G>A (p.Arg81His)","abstract_start":649,"abstract_end":670},{"Name":"NM_016366.3(CABP2):c.637+1G>T","Chromosome":"11","Start":"67519792","Stop":"67519792","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":588259,"rule_based_match":true,"evidence_text":"c.637+1G>T","llm_judgment":"PRESENT","evidence":"c.637+1G>T","abstract_start":543,"abstract_end":553}]}
{"pmid":"10679943","title":"Detection of eight novel palmitoyl protein thioesterase (PPT) mutations underlying infantile neuronal ceroid lipofuscinosis (INCL;CLN1).","abstract":"The infantile form of neuronal ceroid lipofuscinosis (INCL; CLN1) is the earliest onset form of the neuronal ceroid lipofuscinoses (NCL), a group of progressive encephalopathies of children. INCL is caused by mutations in the palmitoyl protein thioesterase (PPT) gene, and we report here eight novel INCL mutations in PPT. Five of the mutations, c.456C>A, c.162-163insA, c.174-175delG, c.774-775insA, and a splice acceptor mutation IVS1-2A>G in intron 1, caused the generation of a premature STOP codon either directly or after a frameshift. One mutation was a three-bp insertion in exon 2 (c. 132-133insTGT) leading to insertion of one extra cysteine (Ser44-insCys-Cys45), and another mutation, a 3-bp deletion in exon 3 (c.249-251delCTT), led to deletion of Phe84 in PPT. A splice acceptor mutation IVS6-1G>T in intron 6 can be predicted to cause skipping of exon 7 in PPT. All of these novel mutations were associated with the classical phenotype of INCL, with the first symptoms starting around 12 months of age. The severe phenotypes could be explained by the nature of the novel mutations: five are predicted to lead to premature translational termination, thus abolishing the active site of PPT, and three will probably cause a misfolding of the nascent polypeptide. Thirty-five percent (7/20) of the disease alleles in these 11 families contained the most prevalent c.451C>T missense mutation outside Finland [Das et al., 1998]. Consequently, 31 different mutations underlying INCL have been found so far, the majority leading to classical INCL.","variants":[{"Name":"NM_000310.4(PPT1):c.451C>T (p.Arg151Ter)","Chromosome":"1","Start":"40089495","Stop":"40089495","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23943,"rule_based_match":true,"evidence_text":"c.451C>T","llm_judgment":"PRESENT","evidence":"c.451C>T","abstract_start":1374,"abstract_end":1382}]}
{"pmid":"19765682","title":"A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles.","abstract":"Desmosomes are the major players in epidermis and cardiac muscles and contribute to intercellular binding and maintenance of tissue integrity. Two important constituents of desmosomes are transmembrane cadherins named desmogleins and desmocollins. The critical role of these desmosomal proteins in epithelial integrity has been illustrated by their disruption in mouse models and human diseases. In the present study, we have investigated a large family from Afghanistan in which four individuals are affected with hereditary hypotrichosis and the appearance of recurrent skin vesicle formation. All four affected individuals showed sparse and fragile hair on scalp, as well as absent eyebrows and eyelashes. Vesicles filled with thin, watery fluid were observed on the affected individuals' scalps and on most of the skin covering their bodies. A scalp-skin biopsy of an affected individual showed mild hair-follicle plugging. Candidate-gene-based homozygosity linkage mapping assigned the disease locus to 8.30 cM (8.51 Mbp) on chromosome 18q12.1. A maximum multipoint LOD score of 3.30 (theta = 0.00) was obtained at marker D18S877. Sequence analysis of four desmoglein and three desmocollin genes, contained within the linkage interval, revealed a homozygous nonsense mutation (c.2129T>G [p.Leu710X]) in exon-14 of the desmocollin-3 (DSC3) gene.","variants":[{"Name":"NM_001941.5(DSC3):c.2129T>G (p.Leu710Ter)","Chromosome":"18","Start":"31001724","Stop":"31001724","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":24270,"rule_based_match":true,"evidence_text":"c.2129T>G [p.Leu710X]","llm_judgment":"PRESENT","evidence":"c.2129T>G [p.Leu710X]","abstract_start":1282,"abstract_end":1303}]}
{"pmid":"30249361","title":"Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis.","abstract":"Charcot-Marie-Tooth (CMT) disease type 1 is an inherited peripheral neuropathy characterized by demyelination and reduced nerve conduction velocities. We present a multi-generational family with peripheral neuropathy in whom clinical CMT panel testing failed to conclude a molecular diagnosis. We found a PMP2 pathogenic variant c.155T > C, p.(Ile52Thr) that segregates with disease suggesting that PMP2 variants should be considered in patients with neuropathy and that it may be prudent to include in clinical CMT gene panels.","variants":[{"Name":"NM_002677.5(PMP2):c.155T>C (p.Ile52Thr)","Chromosome":"8","Start":"81444908","Stop":"81444908","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":590743,"rule_based_match":true,"evidence_text":"c.155T > C, p.(Ile52Thr)","llm_judgment":"PRESENT","evidence":"c.155T > C, p.(Ile52Thr)","abstract_start":329,"abstract_end":353}]}
{"pmid":"34245816","title":"Primary Hyperoxaluria Type 3 Can Also Result in Kidney Failure: A Case Report.","abstract":"Primary hyperoxaluria (PH) is a group of genetic disorders that result in an increased hepatic production of oxalate. PH type 3 (PH3) is the most recently identified subtype and results from mutations in the mitochondrial 4-hydroxy-2-oxoglutarate aldolase gene (HOGA1). To date, there have been 2 cases of kidney failure reported in PH3 patients. We present a case of a young man with a history of recurrent urinary tract infections and voiding dysfunction who developed kidney failure at 33 years of age. He developed a bladder stone and bilateral staghorn calculi at 12 years of age. Initial metabolic evaluation revealed hyperoxaluria with very low urinary citrate excretion on multiple measurements for which he was placed on oral citrate supplements. Further investigation of the hyperoxaluria was not completed as the patient was lost to follow-up observation until he presented at 29 years of age with chronic kidney disease stage 4 (estimated glomerular filtration rate 24mL/min/1.73m<sup>2</sup>). Hemodialysis 3 times a week was started at 33 years of age, and subsequent genetic testing revealed a homozygous HOGA1 mutation (C.973G>A p.Gly325Ser) diagnostic of PH3. The patient is currently being evaluated for all treatment options including possible liver/kidney transplantation. All cases of a childhood history of recurrent urinary stone disease with marked hyperoxaluria should prompt genetic testing for the 3 known PH types. Hyperhydration and crystallization inhibitors (citrate) are standard of care, but the role of RNA interference agents for all 3 forms of PH is also under active study.","variants":[{"Name":"NM_138413.4(HOGA1):c.973G>A (p.Gly325Ser)","Chromosome":"10","Start":"97611648","Stop":"97611648","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":200684,"rule_based_match":true,"evidence_text":"C.973G>A p.Gly325Ser","llm_judgment":"PRESENT","evidence":"C.973G>A p.Gly325Ser","abstract_start":1136,"abstract_end":1156}]}
{"pmid":"30120852","title":"Characterization of mutation spectrum and identification of novel mutations in ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications.","abstract":"Wilson disease (WD), a copper metabolism disorder, occurs due to the presence of mutations in the gene encoding ATP7B, a protein that primarily facilitates hepatic copper excretion. A better understanding of spectrum and functional significance of ATP7B variants is critical to formulating targeted and personalized therapies. Henceforth, we screened and sequenced 21 exons of ATP7B gene from 50 WD patients and 60 healthy subjects. We identified 28 variants comprising, seven novels in 20% alleles, while eight variations affecting 23% alleles were first time reported in Indian cohort. The c.813C>A, p.(Cys271*) (10%) was the most frequent mutation. Bioinformatics analysis revealed five of seven novel variants viz. c.1600C>A, p.(Pro534Thr); c.1616C>A, p.(Pro539His); c.1924G>T, p.(Asp642Tyr); c.2168G>C, p.(Arg723Thr); c.2174G>C, p.(Arg725Thr) resulted in protein misfolding. Sequence conservation analysis of ATP7B regions containing novel variants documented an evolutionarily conserved nature. Functional analysis of these novel variants in five different cell lines lacking inherent ATP7B expression demonstrated sensitivity to CuCl<sub>2</sub> -treatment, experiencing augmented cellular copper retention and decreased copper excretion as well as ceruloplasmin secretion to that of wildtype-ATP7B expressing cells. Interestingly, pharmacological chaperone 4-phenylbutyrate, a clinically approved compound, partially restored protein function of ATP7B mutants. These findings might enable novel treatment strategies in WD by clinically enhancing the protein expression of mutant ATP7B with residual copper export activity.","variants":[{"Name":"NM_000053.4(ATP7B):c.1924G>T (p.Asp642Tyr)","Chromosome":"13","Start":"51961859","Stop":"51961859","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":527826,"rule_based_match":true,"evidence_text":"c.1924G>T, p.(Asp642Tyr)","llm_judgment":"PRESENT","evidence":"c.1924G>T, p.(Asp642Tyr)","abstract_start":771,"abstract_end":795}]}
{"pmid":"27762305","title":"Novel mutations in FKBP10 in Chinese patients with osteogenesis imperfecta and their treatment with zoledronic acid.","abstract":"Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by decreased bone mass and increased fracture risk. The majority of OI cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen. OI cases of autosomal recessive inheritance are rare, and OI type XI is attributable to mutation of the FKBP10 gene. Here, we used next-generation sequencing and Sanger sequencing to detect mutations in FKBP10 and to analyze their relation to the phenotypes of OI type XI in three Chinese patients. We also evaluated the efficacy of zoledronic acid treatment in these patients. Two of the affected patients had novel compound heterozygous mutations, one patient with c.343C>T (p.R115X) in exon 2 and c.1085delC (p.A362fsX1) in exon 7, and the other patient with c.879C>G (p.Y293X) in exon 5 and c.918-3C>G in intron 5. In the third proband, we identified a homozygous single base-pair duplication, c.831dupC (p.G278RfsX95) in exon 5. In conclusion, we report for the first time that these novel pathogenic mutations of FKBP10 can lead to the extremely rare type XI OI without contractures, which expands the genotypic spectrum of OI. The phenotypes of these patients are similar to patients with types III or IV OI, and zoledronic acid is effective in increasing BMD, inhibiting bone resorption biomarkers and reducing fractures of these patients.","variants":[{"Name":"NM_021939.4(FKBP10):c.343C>T (p.Arg115Ter)","Chromosome":"17","Start":"41817155","Stop":"41817155","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1288563,"rule_based_match":true,"evidence_text":"c.343C>T (p.R115X)","llm_judgment":"PRESENT","evidence":"c.343C>T (p.R115X)","abstract_start":743,"abstract_end":761},{"Name":"NM_021939.4(FKBP10):c.918-3C>G","Chromosome":"17","Start":"41819527","Stop":"41819527","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2905165,"rule_based_match":true,"evidence_text":"c.918-3C>G","llm_judgment":"PRESENT","evidence":"c.918-3C>G","abstract_start":871,"abstract_end":881},{"Name":"NM_021939.4(FKBP10):c.831dup (p.Gly278fs)","Chromosome":"17","Start":"41819306","Stop":"41819307","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":432334,"rule_based_match":true,"evidence_text":"c.831dupC (p.G278RfsX95)","llm_judgment":"PRESENT","evidence":"c.831dupC (p.G278RfsX95)","abstract_start":974,"abstract_end":998}]}
{"pmid":"34948281","title":"Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome.","abstract":"Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. <i>AGK</i>, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. <i>AGK</i> mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. We describe the case of an infant carrying a novel homozygous <i>AGK</i> variant, c.518+1G>A, who was born with congenital cataracts, pielic ectasia, critical congenital dilated myocardiopathy, and hyperlactacidemia and died 20 h after birth. Using the patient's DNA, we performed targeted sequencing of 314 nuclear genes encoding respiratory chain complex subunits and proteins implicated in mitochondrial oxidative phosphorylation (OXPHOS). A decrease of 96-bp in the length of the <i>AGK</i> cDNA sequence was detected. Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient's fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. We demonstrate a clear defect in mitochondrial function in the patient's fibroblasts and describe the possible molecular mechanism underlying the pathogenicity of this novel <i>AGK</i> variant. Experimental validation using in vitro analysis allowed an accurate characterization of the disease-causing variant.","variants":[{"Name":"NM_018238.4(AGK):c.518+1G>A","Chromosome":"7","Start":"141615566","Stop":"141615566","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1699555,"rule_based_match":true,"evidence_text":"c.518+1G>A","llm_judgment":"PRESENT","evidence":"c.518+1G>A","abstract_start":630,"abstract_end":640}]}
{"pmid":"27817865","title":"MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.","abstract":"Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285<sup>∗</sup>), c.247_250del (p.Asn83Hisfs<sup>∗</sup>4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.","variants":[{"Name":"NM_016011.5(MECR):c.695G>A (p.Gly232Glu)","Chromosome":"1","Start":"29202004","Stop":"29202004","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":361783,"rule_based_match":true,"evidence_text":"c.695G>A (p.Gly232Glu)","llm_judgment":"PRESENT","evidence":"c.695G>A (p.Gly232Glu)","abstract_start":908,"abstract_end":930},{"Name":"NM_016011.5(MECR):c.855T>G (p.Tyr285Ter)","Chromosome":"1","Start":"29196234","Stop":"29196234","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":361784,"rule_based_match":true,"evidence_text":"c.855T>G (p.Tyr285<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"c.855T>G (p.Tyr285<sup>∗</sup>)","abstract_start":728,"abstract_end":759},{"Name":"NM_016011.5(MECR):c.854A>G (p.Tyr285Cys)","Chromosome":"1","Start":"29196235","Stop":"29196235","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":361786,"rule_based_match":true,"evidence_text":"c.854A>G (p.Tyr285Cys)","llm_judgment":"PRESENT","evidence":"c.854A>G (p.Tyr285Cys)","abstract_start":932,"abstract_end":954},{"Name":"NM_016011.4(MECR):c.772C>T (p.Arg258Trp)","Chromosome":"1","Start":"29200574","Stop":"29200574","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":361787,"rule_based_match":true,"evidence_text":"c.772C>T (p.Arg258Trp)","llm_judgment":"PRESENT","evidence":"c.772C>T (p.Arg258Trp)","abstract_start":960,"abstract_end":982},{"Name":"NM_016011.5(MECR):c.247_250del (p.Asn83fs)","Chromosome":"1","Start":"29216612","Stop":"29216615","ReferenceAlleleVCF":"GGATT","AlternateAlleleVCF":"G","allel_id":361788,"rule_based_match":true,"evidence_text":"c.247_250del (p.Asn83Hisfs<sup>∗</sup>4)","llm_judgment":"PRESENT","evidence":"c.247_250del (p.Asn83Hisfs<sup>∗</sup>4)","abstract_start":761,"abstract_end":801}]}
{"pmid":"29226631","title":"Novel compound heterozygous mutations in GPT2 linked to microcephaly, and intellectual developmental disability with or without spastic paraplegia.","abstract":"We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic-pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c.400C>T (p.R134C) and c.1435G>A (p.V479M), reside in the pyridoxal phosphate-dependent aminotransferase domain. The missense variants affect highly conserved amino acids and are classified to be disease-causing by meta-SVM. The candidate variants were not found in the Exome Aggregation Consortium (ExAC) dataset or in dbSNP. Both GPT2 variants have an allele frequency of 0% (0/ ∼ 600) in the whole-exome sequenced Turkish cohort. Upon Sanger sequencing, we confirmed these mutations in all affected family members and showed that the index patient and his affected sister inherited one mutant allele from each unaffected parent. To the best of our knowledge, this is the first family in which a novel compound heterozygous variant in the GPT2 gene was identified.","variants":[{"Name":"NM_133443.4(GPT2):c.400C>T (p.Arg134Cys)","Chromosome":"16","Start":"46900748","Stop":"46900748","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":971605,"rule_based_match":true,"evidence_text":"c.400C>T (p.R134C)","llm_judgment":"PRESENT","evidence":"c.400C>T (p.R134C)","abstract_start":510,"abstract_end":528},{"Name":"NM_133443.4(GPT2):c.1435G>A (p.Val479Met)","Chromosome":"16","Start":"46926991","Stop":"46926991","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":971606,"rule_based_match":true,"evidence_text":"c.1435G>A (p.V479M)","llm_judgment":"PRESENT","evidence":"c.1435G>A (p.V479M)","abstract_start":533,"abstract_end":552}]}
{"pmid":"31569255","title":"Developmental Regression and Epilepsy of Infancy with Migrating Focal Seizures Caused by TBCD Mutation: A Case Report and Review of the Literature.","abstract":"Microtubule dynamics plays a crucial role in neuronal development and function. Variants in the tubulin cofactor D (<i>TBCD</i>) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/β-tubulin heterodimers, may lead to neurodevelopmental disorders. We aimed to study the clinical, electroencephalographic, and imaging features of a male patient with <i>TBCD</i> variants, and to provide a detailed review of the previously reported cases of <i>TBCD</i>-related neurological disorders. The patient presented with early-onset developmental regression, secondary microcephaly, epilepsy of infancy with migrating focal seizures, hypotonia, and brain atrophy with thin corpus callosum on brain magnetic resonance imaging. Genetic analyses of the family members revealed a compound heterozygous variant of c.230A > G (p.H77R) in the proband and deletion of exons 28 to 39 of <i>TBCD</i>, which has not been previously reported and was inherited from his carrier parents. Epilepsy of the patient was refractory to numerous antiepileptic drugs. The review of 33 previously reported patients revealed that the age at the onset was very early, and all the patients had presentations during the first year of life. This case report provides insight regarding the clinical features and genetic etiology of <i>TBCD</i>-related tubulinopathy. Identification of phenotypes and genotypes in patients may help in early diagnosis and appropriate genetic counseling.","variants":[{"Name":"NM_005993.5(TBCD):c.230A>G (p.His77Arg)","Chromosome":"17","Start":"82756210","Stop":"82756210","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":613102,"rule_based_match":true,"evidence_text":"c.230A > G (p.H77R)","llm_judgment":"PRESENT","evidence":"c.230A > G (p.H77R)","abstract_start":839,"abstract_end":858}]}
{"pmid":"14635116","title":"Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5-fluorouracil-related side effects.","abstract":"Complete or partial loss of dihydropyrimidine dehydrogenase (DPD or DYPD) function has been described in cancer patients experiencing severe side effects upon administration of the fluoropyrimidine anticancer drug 5-fluorouracil (5-FU). To investigate a genetic predisposition for 5-FU intolerance due to inherited DPD defects, we established a mutation detection assay based on denaturing HPLC. Analyzing four individuals with symptoms of 5-FU-related toxicity, we detected six distinct sequence variants in the dihydropyrimidine dehydrogenase gene (DPYD): one novel mutation, c.775A>G (K259E); four known missense mutations, c.85T>C (C29R), c.496A>G (M166V), c.1601G>A (S534N), c.1627A>G (I543V); and one silent mutation c.1896T>C affecting the codon for F632. One cancer patient possessing a total of four gene mutations resulting in four amino acid substitutions (C29R, M166V, S534N, I543V) displayed significantly reduced DPD activity. The rare combination of the highly conserved mutation sites M166V and S534N was additionally found in one of the other patients. DPD enzyme activity was low, but yet within normal range. The K259E mutation did not provoke a decrease in DPD function in a heterozygous individual. Based on the protein structure of crystalline pig DPD and the deduced homology models, we have additionally investigated the amino acid positions in their three-dimensional network which correspond to the five missense mutations discovered in the patients.","variants":[{"Name":"NM_000110.4(DPYD):c.496A>G (p.Met166Val)","Chromosome":"1","Start":"97699535","Stop":"97699535","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":105993,"rule_based_match":true,"evidence_text":"c.496A>G (M166V)","llm_judgment":"PRESENT","evidence":"c.496A>G (M166V)","abstract_start":643,"abstract_end":659},{"Name":"NM_000110.4(DPYD):c.1896T>C (p.Phe632=)","Chromosome":"1","Start":"97450068","Stop":"97450068","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":105965,"rule_based_match":true,"evidence_text":"c.1896T>C","llm_judgment":"PRESENT","evidence":"c.1896T>C","abstract_start":723,"abstract_end":732},{"Name":"NM_000110.4(DPYD):c.1627A>G (p.Ile543Val)","Chromosome":"1","Start":"97515839","Stop":"97515839","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":105969,"rule_based_match":true,"evidence_text":"c.1627A>G (I543V)","llm_judgment":"PRESENT","evidence":"c.1627A>G (I543V)","abstract_start":680,"abstract_end":697},{"Name":"NM_000110.4(DPYD):c.85T>C (p.Cys29Arg)","Chromosome":"1","Start":"97883329","Stop":"97883329","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15474,"rule_based_match":true,"evidence_text":"c.85T>C (C29R)","llm_judgment":"PRESENT","evidence":"c.85T>C (C29R)","abstract_start":627,"abstract_end":641},{"Name":"NM_000110.4(DPYD):c.1601G>A (p.Ser534Asn)","Chromosome":"1","Start":"97515865","Stop":"97515865","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105971,"rule_based_match":true,"evidence_text":"c.1601G>A (S534N)","llm_judgment":"PRESENT","evidence":"c.1601G>A (S534N)","abstract_start":661,"abstract_end":678},{"Name":"NM_000110.4(DPYD):c.775A>G (p.Lys259Glu)","Chromosome":"1","Start":"97679170","Stop":"97679170","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":237147,"rule_based_match":true,"evidence_text":"c.775A>G (K259E)","llm_judgment":"PRESENT","evidence":"c.775A>G (K259E)","abstract_start":578,"abstract_end":594}]}
{"pmid":"32506814","title":"Maternal SLE and brachytelephalangic chondrodysplasia punctata in a patient with unrelated de novo RAF1 and SIX2 variants.","abstract":"Our improved tools to identify the aetiologies in patients with multiple abnormalities resulted in the finding that some patients have more than a single genetic condition and that some of the diagnoses made in the past are acquired rather than inherited. However, limited knowledge has been accumulated regarding the phenotypic outcome of the interaction between different genetic conditions identified in the same patients. We report a newborn girl with brachytelephalangic chondrodysplasia punctata (BCDP) as well as frontonasal dysplasia, ptosis, bilateral hearing loss, vertebral anomalies, and pulmonary hypoplasia who was found, by whole exome sequencing, to have a de novo pathogenic variant in RAF1 (c.770C>T, [p.Ser257Leu]) and a likely pathogenic variant in SIX2 (c.760G>A [p.A254T]), as well as maternal systemic lupus erythematosus (SLE). This case shows that BCDP is most probably not a diagnostic entity and can be associated with various conditions associated with CDP including maternal SLE.","variants":[{"Name":"NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)","Chromosome":"3","Start":"12604200","Stop":"12604200","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28996,"rule_based_match":true,"evidence_text":"c.770C>T","llm_judgment":"PRESENT","evidence":"c.770C>T","abstract_start":709,"abstract_end":717}]}
{"pmid":"23112235","title":"Atypical hereditary sensory and autonomic neuropathy type IV with neither mental retardation nor pain insensitivity.","abstract":"Hereditary sensory and autonomic neuropathy type IV is an autosomal recessive disorder characterized by severe mental retardation and self-mutilation-related complications. Recently, we investigated a 16-year-old Korean boy with normal intelligence. He had preserved pain sensation but was suspected of having hereditary sensory and autonomic neuropathy type IV because of the recurrent bone fractures and painless joint destruction in the absence of any predisposing medical conditions. Genetic analysis of the NTRK1 gene revealed compound heterozygous mutations including c.851-33T>A and c.2303C>T (p.Pro768Leu) in the NTRK1 gene. The p.Pro768Leu mutation has been identified in 2 Japanese patients with a mild phenotype. Therefore, although it is rare, hereditary sensory and autonomic neuropathy type IV should be considered in patients with recurrent bone fractures and painless joint destruction who do not have any predisposing conditions even when they do not have typical clinical features such as mental retardation or pain insensitivity.","variants":[{"Name":"NM_002529.4(NTRK1):c.851-33T>A","Chromosome":"1","Start":"156873600","Stop":"156873600","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":34160,"rule_based_match":true,"evidence_text":"c.851-33T>A","llm_judgment":"PRESENT","evidence":"c.851-33T>A","abstract_start":574,"abstract_end":585},{"Name":"NM_002529.4(NTRK1):c.2303C>T (p.Pro768Leu)","Chromosome":"1","Start":"156881554","Stop":"156881554","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":624990,"rule_based_match":true,"evidence_text":"c.2303C>T (p.Pro768Leu)","llm_judgment":"PRESENT","evidence":"c.2303C>T (p.Pro768Leu)","abstract_start":590,"abstract_end":613}]}
{"pmid":"25192047","title":"Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy.","abstract":"Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies.","variants":[{"Name":"NM_177402.5(SYT2):c.920A>C (p.Asp307Ala)","Chromosome":"1","Start":"202599351","Stop":"202599351","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":166147,"rule_based_match":true,"evidence_text":"c.920A>C","llm_judgment":"PRESENT","evidence":"c.920A>C","abstract_start":470,"abstract_end":478},{"Name":"NM_177402.5(SYT2):c.923C>T (p.Pro308Leu)","Chromosome":"1","Start":"202599348","Stop":"202599348","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":166148,"rule_based_match":true,"evidence_text":"c.923C>T (p.Pro308Leu)","llm_judgment":"PRESENT","evidence":"p.Pro308Leu","abstract_start":682,"abstract_end":693}]}
{"pmid":"25798947","title":"Whole exome sequencing identifies mutations in Usher syndrome genes in profoundly deaf Tunisian patients.","abstract":"Usher syndrome (USH) is an autosomal recessive disorder characterized by combined deafness-blindness. It accounts for about 50% of all hereditary deafness blindness cases. Three clinical subtypes (USH1, USH2, and USH3) are described, of which USH1 is the most severe form, characterized by congenital profound deafness, constant vestibular dysfunction, and a prepubertal onset of retinitis pigmentosa. We performed whole exome sequencing in four unrelated Tunisian patients affected by apparently isolated, congenital profound deafness, with reportedly normal ocular fundus examination. Four biallelic mutations were identified in two USH1 genes: a splice acceptor site mutation, c.2283-1G>T, and a novel missense mutation, c.5434G>A (p.Glu1812Lys), in MYO7A, and two previously unreported mutations in USH1G, i.e. a frameshift mutation, c.1195_1196delAG (p.Leu399Alafs*24), and a nonsense mutation, c.52A>T (p.Lys18*). Another ophthalmological examination including optical coherence tomography actually showed the presence of retinitis pigmentosa in all the patients. Our findings provide evidence that USH is under-diagnosed in Tunisian deaf patients. Yet, early diagnosis of USH is of utmost importance because these patients should undergo cochlear implant surgery in early childhood, in anticipation of the visual loss.","variants":[{"Name":"NM_173477.5(USH1G):c.1195_1196del (p.Leu399fs)","Chromosome":"17","Start":"74919640","Stop":"74919641","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":2905219,"rule_based_match":true,"evidence_text":"c.1195_1196delAG (p.Leu399Alafs*24)","llm_judgment":"PRESENT","evidence":"c.1195_1196delAG (p.Leu399Alafs*24)","abstract_start":838,"abstract_end":873},{"Name":"NM_000260.4(MYO7A):c.2283-1G>T","Chromosome":"11","Start":"77179044","Stop":"77179044","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":52348,"rule_based_match":true,"evidence_text":"c.2283-1G>T","llm_judgment":"PRESENT","evidence":"c.2283-1G>T","abstract_start":680,"abstract_end":691},{"Name":"NM_000260.4(MYO7A):c.5434G>A (p.Glu1812Lys)","Chromosome":"11","Start":"77204183","Stop":"77204183","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620422,"rule_based_match":true,"evidence_text":"c.5434G>A (p.Glu1812Lys)","llm_judgment":"PRESENT","evidence":"c.5434G>A (p.Glu1812Lys)","abstract_start":724,"abstract_end":748}]}
{"pmid":"21796138","title":"Identification of two HEXA mutations causing infantile-onset Tay-Sachs disease in the Persian population.","abstract":"The β-hexosaminidase A (HEXA) mutations in the first reported cases of infantile Tay-Sachs disease in the Persian population were identified in two unrelated consanguineous families. The clinical diagnoses of the affected infants were confirmed by their markedly deficient levels of HEXA activity in plasma or peripheral leukocytes. The specific causative mutation in each family was determined by sequencing the HEXA alleles in both sets of related parents. Two mutations were identified: c.1A>G (p.MIV), which obliterated the initiating methionine in codon 1, and c.1177C>T (p.R393X), which predicted a termination codon or nonsense mutation.","variants":[{"Name":"NM_000520.6(HEXA):c.1177C>T (p.Arg393Ter)","Chromosome":"15","Start":"72346680","Stop":"72346680","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18944,"rule_based_match":true,"evidence_text":"c.1177C>T (p.R393X)","llm_judgment":"PRESENT","evidence":"c.1177C>T (p.R393X)","abstract_start":566,"abstract_end":585},{"Name":"NM_000520.6(HEXA):c.1A>G (p.Met1Val)","Chromosome":"15","Start":"72375972","Stop":"72375972","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":18953,"rule_based_match":true,"evidence_text":"c.1A>G (p.MIV)","llm_judgment":"PRESENT","evidence":"c.1A>G (p.MIV)","abstract_start":490,"abstract_end":504}]}
{"pmid":"20053607","title":"A rare blood group: p phenotype","abstract":"A rare blood group is usually defined as the absence of a high prevalence antigen or the absence of several antigens within a single blood group system. These individuals may develop clinically significant red cell antibodies to the high incidence red cell antigens they lack. A 33-year-old alloimmunized woman was referred to our center at the 12th week of her third pregnancy for evaluation and follow up. The laboratory work-up grouped her as belonging to \"p\" phenotype, associated with difficulties to find compatible blood for transfusion and a high incidence of recurrent miscarriage. At 36 weeks, a baby girl was born by induced labor due to fetal suffering. With a negative direct antiglobulin test but a positive elution test, she was in the neonatology ward for one week receiving luminotherapy. Homozygosity for a missense mutation at position 752 (c.752C > T) in the A4GALT gene was found to be responsible for the p phenotype. This mutation changes a proline to a leucine at codon 251 of the 4-?-galactosyltransferase. Recently, due to an imminent chirurgical intervention and the impossibility to have compatible blood available for transfusion, an autologous donation plan was designed to satisfy probable demand. This case showed the need for blood bank facilities capable to respond satisfactorily to these situations in Argentina. This would facilitate the storage of cryopreserved blood from individuals with rare blood groups for homologous use or to develop rare blood donors programs.","variants":[{"Name":"NM_017436.7(A4GALT):c.752C>T (p.Pro251Leu)","Chromosome":"22","Start":"42693200","Stop":"42693200","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17732,"rule_based_match":true,"evidence_text":"c.752C > T","llm_judgment":"PRESENT","evidence":"c.752C > T","abstract_start":860,"abstract_end":870}]}
{"pmid":"35967554","title":"Case report: Effectiveness of sirolimus in a","abstract":"Background: The autoimmune lymphoproliferative syndrome (ALPS) is a rare disease characterized by defective function of the FAS death receptor, which results in chronic, non-malignant lymphoproliferation and autoimmunity accompanied by elevated numbers of double-negative (DN) T cells (T-cell receptor α/β + CD4-CD8-) and an increased risk of developing malignancies later in life.\nCase description: Here, we report a patient with a <i>de novo</i> FAS mutation with a severe phenotype of ALPS-FAS. The FAS gene identified as a novel spontaneous germline heterozygous missense mutation (c.857G > A, p.G286E) in exon 9, causing an amino acid exchange and difference in hydrogen bond formation. Consequently, the treatment with sirolimus was initiated. Subsequently, the patient's clinical condition improved rapidly. Moreover, DNT ratio continuously decreased during sirolimus application.\nConclusion: We described a novel germline FAS mutation (c.857G > A, p.G286E) associated with a severe clinical phenotype of ALPS-FAS. Sirolimus effectively improved the patient clinical manifestations with obvious reduction of the DNT ratio.","variants":[{"Name":"NM_000043.6(FAS):c.857G>A (p.Gly286Glu)","Chromosome":"10","Start":"89014299","Stop":"89014299","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2136335,"rule_based_match":true,"evidence_text":"c.857G > A, p.G286E","llm_judgment":"PRESENT","evidence":"c.857G > A, p.G286E","abstract_start":586,"abstract_end":605}]}
{"pmid":"26904320","title":"Osteoporosis-Pseudoglioma in a Mauritanian Child due to a Novel Mutation in LRP5.","abstract":"Osteoporosis-pseudoglioma (OPPG) syndrome is a very rare autosomal recessive disorder, caused by mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. It manifests by severe juvenile osteoporosis with congenital or infancy-onset visual loss. We describe a case of OPPG due to novel mutation in LRP5 gene, occurring in a female Mauritanian child. This 10-year-old female child was born blind, and after then multiple fragility fractures appeared. PCR amplification and sequencing revealed a novel homozygous nonsense mutation in exon 10 of the LRP5 gene (c.2270G>A; pTrP757(⁎)); this mutation leads to the production of a truncated protein containing 757 amino acids instead of 1615, located in the third β-propeller domain of the LRP5 protein. Both parents were heterozygous for the mutation. This is the first case of the OPPG described in black Africans, which broadens the spectrum of LRP5 gene mutations in OPPG.","variants":[{"Name":"NM_002335.4(LRP5):c.2270G>A (p.Trp757Ter)","Chromosome":"11","Start":"68410092","Stop":"68410092","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1062485,"rule_based_match":true,"evidence_text":"c.2270G>A; pTrp757(⁎)","llm_judgment":"PRESENT","evidence":"c.2270G>A; pTrP757(⁎)","abstract_start":581,"abstract_end":602}]}
{"pmid":"31844156","title":"R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome.","abstract":"Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the I<sub>Kr</sub> inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of I<sub>Kr</sub> on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane.","variants":[{"Name":"NM_000238.4(KCNH2):c.1600C>T (p.Arg534Cys)","Chromosome":"7","Start":"150951793","Stop":"150951793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":78116,"rule_based_match":true,"evidence_text":"c.1600C > T in KCNH2, p.R534C in hERG","llm_judgment":"PRESENT","evidence":"c.1600C > T in KCNH2, p.R534C in hERG","abstract_start":267,"abstract_end":304}]}
{"pmid":"27928380","title":"Facial Dystonia with Facial Grimacing and Vertical Gaze Palsy with \"Round the Houses\" Sign in a 29-Year-Old Woman.","abstract":"A 29-year-old woman developed progressive dysarthria and coordination problems from the age of 15. Examination showed dysarthria, facial dystonia, bibrachial dystonia, hyperreflexia, ataxia, and emotional incontinence. Downward supranuclear gaze palsy was prominent with a \"Round the Houses\" sign. Magnetic resonance imaging of the brain and medulla, electroneurography, and cerebrospinal fluid were normal. A computed tomography scan showed hepatosplenomegaly. This combination of progressive neurological symptoms together with hepatosplenomegaly was suggestive of inborn error of metabolism. A bone marrow biopsy showed an increased number of macrophages with foamy content, highly suggestive of lysosomal disease. Plasmatic chitotriosidase activity and CCL18 were increased. Genetic testing showed heterozygosis for the variation c.1070C→T (p.Ser357Leu) and c.1843→T (Arg615Cys), confirming the diagnosis of Niemann-Pick type C (NPC). The \"Round the Houses\" sign has only been described in patients with progressive supranuclear palsy (PSP). This sign is described as an inability to produce pure vertical saccades along the midline and instead moving the eyes in a lateral arc to accomplish the movement. The observation of this sign in a patient with NPC indicates that this bedside finding is not specific for PSP, but a sign of medial longitudinal fasciculus dysfunction. The presence of facial dystonia with facial grimacing together with supranuclear gaze palsy is highly characteristic and useful for the diagnosis of NPC. NPC is an important underdiagnosed condition, given the availability of treatment and a mean diagnostic delay of 6 years.","variants":[{"Name":"NM_000271.5(NPC1):c.1070C>T (p.Ser357Leu)","Chromosome":"18","Start":"23556499","Stop":"23556499","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":532171,"rule_based_match":false,"evidence_text":"c.1070C→T (p.Ser357Leu)","llm_judgment":"PRESENT","evidence":"c.1070C→T (p.Ser357Leu)","abstract_start":834,"abstract_end":857},{"Name":"NM_000271.5(NPC1):c.1843C>T (p.Arg615Cys)","Chromosome":"18","Start":"23545064","Stop":"23545064","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":572547,"rule_based_match":false,"evidence_text":"c.1843→T (Arg615Cys)","llm_judgment":"PRESENT","evidence":"c.1843→T (Arg615Cys)","abstract_start":862,"abstract_end":882}]}
{"pmid":"23286897","title":"MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing.","abstract":"BACKGROUND: Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor.\nMETHODS: We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions.\nRESULTS: A recessive genetic defect was suspected in two siblings of healthy, but consanguineous parents. Homozygosity mapping revealed three shared homozygous regions and exome sequencing, revealed a novel homozygous c.367 G>A [p.Asp123Asn] mutation in the α-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of α-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169 μmol/L, normal <1.5 μmol/L). MRI studies showed characteristic degeneration of cerebellar afferents and efferents, including the dentatothalamic tract and thalamic lesions in both patients.\nCONCLUSIONS: Metabolic diseases presenting late are diagnostically challenging. We show that appropriately applied, homozygosity mapping and exome sequencing can be decisive for establishing diagnoses such as late onset α-methylacyl-coA racemase deficiency, an autosomal recessive peroxisomal disorder with accumulation of pristanic acid. Our study also highlights radiological features that may assist in diagnosis. Early diagnosis is important as patients with this disorder may benefit from restricted dietary phytanic and pristanic acid intake.","variants":[{"Name":"NM_014324.6(AMACR):c.367G>A (p.Asp123Asn)","Chromosome":"5","Start":"34005780","Stop":"34005780","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1418223,"rule_based_match":true,"evidence_text":"c.367 G>A [p.Asp123Asn]","llm_judgment":"PRESENT","evidence":"c.367 G>A [p.Asp123Asn]","abstract_start":833,"abstract_end":856}]}
{"pmid":"25304119","title":"R368X mutation in MID1 among recurrent mutations in patients with X-linked Opitz G/BBB syndrome.","abstract":"Opitz G/BBB syndrome is a genetically heterogeneous condition, with both autosomal dominant and X-linked forms. The MID1 gene is associated with X-linked Opitz G/BBB syndrome. Most mutations identified are unique, which makes it difficult to assess possible genotype/phenotype correlations. We report on a familial c.1102C>T (p.R368X) mutation in the MID1 gene, previously reported by Cox et al. (Hum Mol Genet 9:2553-2562, 2000), and document it as a recurrent mutation causing Opitz G/BBB syndrome. This mutation may result in various midline defects, including cleft lip/palate, laryngeal cleft, hypertelorism, Dandy-Walker malformation, ventricular septal defect and hypospadias in male patients, with intrafamilial variability. Seven other mutations (c.712G>T, c.829C>T, c.1108A>G, c.1444_1447dupAACA, c.1483C>T, c.1798dupC and entire gene deletions) have been previously reported as recurrent mutations. The presented family with the c.1102C>T mutation provides additional information about the clinical consequences of the nonsense mutation causing premature truncation of the protein at the level of the COS domain.","variants":[{"Name":"NM_000381.4(MID1):c.1102C>T (p.Arg368Ter)","Chromosome":"X","Start":"10474662","Stop":"10474662","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1695251,"rule_based_match":true,"evidence_text":"c.1102C>T (p.R368X)","llm_judgment":"PRESENT","evidence":"c.1102C>T (p.R368X)","abstract_start":315,"abstract_end":334}]}
{"pmid":"34916232","title":"Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency.","abstract":"BACKGROUND: Mucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I-IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of <i>Arsk</i> in mice was consistent with mild storage pathology, but no human phenotype has yet been described.\nMETHODS: In this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in <i>ARSK</i>, respectively. Functional consequences of the two <i>ARSK</i> variants were assessed by mutation-specific <i>ARSK</i> constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis.\nRESULTS: The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS.\nCONCLUSION: Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X.","variants":[{"Name":"NM_198150.3(ARSK):c.250C>T (p.Arg84Cys)","Chromosome":"5","Start":"95566121","Stop":"95566121","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1323646,"rule_based_match":true,"evidence_text":"c.250C>T, p.(Arg84Cys)","llm_judgment":"PRESENT","evidence":"c.250C>T, p.(Arg84Cys)","abstract_start":655,"abstract_end":677},{"Name":"NM_198150.3(ARSK):c.560T>A (p.Leu187Ter)","Chromosome":"5","Start":"95583059","Stop":"95583059","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1323647,"rule_based_match":true,"evidence_text":"c.560T>A, p.(Leu187Ter)","llm_judgment":"PRESENT","evidence":"c.560T>A, p.(Leu187Ter)","abstract_start":682,"abstract_end":705}]}
{"pmid":"24997086","title":"Exome sequencing identifies a CHKB mutation in Spanish patient with megaconial congenital muscular dystrophy and mtDNA depletion.","abstract":"BACKGROUND: Choline kinase beta gene (CHKB) mutations have been identified in Megaconial Congenital Muscular Dystrophy (MDCMC) patients, but never in patients with an additional combined deficiency of complexes I, III and IV and mitochondrial DNA (mtDNA) depletion.\nAIMS: To report mutations in carry genes for MDCMC with respiratory chain defects and mtDNA depletion.\nMETHODS: Whole-exome sequencing (WES) was used to identify the carry genes in a Spanish child with muscle weakness, mild hypotonia at lower limb muscles, mildly elevated creatine kinase (CK), enlarged mitochondria in the periphery of the fibers, combined deficiency of complex I, III and IV and depletion of mtDNA.\nRESULTS: With WES data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The first filter of WES data with the nuclear-encoded mitochondrial genes (MitoCarta) did not get any candidate. However, the analysis of whole exome uncovered a homozygous nonsense pathogenic mutation in CHKB gene (NM_005198.4:c.810T>A, p.Tyr270*).\nCONCLUSIONS: Our data confirm the role of CHKB in MDCMC and point to this gene as unique candidate for the combined deficiency of respiratory chain and mtDNA depletion observed in this patient.","variants":[{"Name":"NM_005198.5(CHKB):c.810T>A (p.Tyr270Ter)","Chromosome":"22","Start":"50580198","Stop":"50580198","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":39909,"rule_based_match":true,"evidence_text":"NM_005198.4:c.810T>A, p.Tyr270*","llm_judgment":"PRESENT","evidence":"NM_005198.4:c.810T>A, p.Tyr270*","abstract_start":1025,"abstract_end":1056}]}
{"pmid":"24731844","title":"Clinical, radiological, and genetic survey of patients with muscle-eye-brain disease caused by mutations in POMGNT1.","abstract":"BACKGROUND: To evaluate clinical, genetic, and radiologic features of our patients with muscle-eye-brain disease.\nMETHODS: The data of patients who were diagnosed with muscle-eye-brain disease from a cohort of patients with congenital muscular dystrophy in the Division of Pediatric Neurology of Dokuz Eylül University School of Medicine and Gaziantep Children's Hospital between 2005 and 2013 were analyzed retrospectively.\nRESULTS: From a cohort of 34 patients with congenital muscular dystrophy, 12 patients from 10 families were diagnosed with muscle-eye-brain disease. The mean age of the patients was 9 ± 5.5 years (2-19 years). Mean serum creatine kinase value was 2485.80 ± 1308.54 IU/L (700-4267 IU/L). All patients presented with muscular hypotonia at birth followed by varying degrees of spasticity and exaggerated deep tendon reflexes in later stages of life. Three patients were able to walk. The most common ophthalmologic and radiologic abnormalities were cataracts, retinal detachment, periventricular white matter abnormalities, ventriculomegaly, pontocerebellar hypoplasia, and multiple cerebellar cysts. All of the patients had mutations in the POMGNT1 gene. The most common mutation detected in 66% of patients was c.1814 G > A (p.R605H). Two novel mutations were identified.\nCONCLUSIONS: We suggest that muscle-eye-brain disease is a relatively common muscular dystrophy in Turkey. It should be suspected in patients with muscular hypotonia, increased creatine kinase, and structural eye and brain abnormalities. The c.1814 G > A mutation in exon 21 of the POMGNT1 gene is apparently a common mutation in the Turkish population. Individuals with this mutation show classical features of muscle-eye-brain disease, but others may exhibit a milder phenotype and retain the ability to walk independently. Congenital muscular dystrophy patients from Turkey carrying the clinical and radiologic features of muscle-eye-brain disease should be evaluated for mutations in POMGNT1 gene.","variants":[{"Name":"NM_017739.4(POMGNT1):c.1814G>A (p.Arg605His)","Chromosome":"1","Start":"46189539","Stop":"46189539","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":71228,"rule_based_match":true,"evidence_text":"c.1814 G > A (p.R605H)","llm_judgment":"PRESENT","evidence":"c.1814 G > A (p.R605H)","abstract_start":1235,"abstract_end":1257}]}
{"pmid":"26833332","title":"CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation.","abstract":"Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma.","variants":[{"Name":"NM_032357.4(CCDC115):c.31G>T (p.Asp11Tyr)","Chromosome":"2","Start":"130342095","Stop":"130342095","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":216009,"rule_based_match":true,"evidence_text":"c.31G>T (p.Asp11Tyr)","llm_judgment":"PRESENT","evidence":"c.31G>T (p.Asp11Tyr)","abstract_start":749,"abstract_end":769},{"Name":"NM_032357.4(CCDC115):c.92T>C (p.Leu31Ser)","Chromosome":"2","Start":"130342034","Stop":"130342034","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":216019,"rule_based_match":true,"evidence_text":"c.92T>C (p.Leu31Ser)","llm_judgment":"PRESENT","evidence":"c.92T>C (p.Leu31Ser)","abstract_start":436,"abstract_end":456}]}
{"pmid":"30138677","title":"Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome.","abstract":"Activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome is a newly defined and relatively common primary immunodeficiency, which is caused by heterozygous gain-of-function (GOF) mutations in PIK3CD or PIK3R1. Here, we report a novel de novo GOF mutation (c.1570 T > A, p.Y524N) in PIK3CD in a 6-year-old Chinese girl. The patient suffered recurrent sinopulmonary infection, bronchiectasis, lymphoproliferation, herpesvirus infection, and distinctive nodular lymphoid hyperplasia of mucosal surfaces. Immunological analysis revealed increased CD4+ T cell senescence and B cell immaturity. Further analysis revealed an increase in almost all CD4+ T cell subsets to varying degrees, including effector T cells and Treg cells. Increased levels of plasma T cell-related cytokines corroborated these results. Hyperactivation of the PI3Kδ-Akt-mTOR signaling pathway was also confirmed. Treatment with rapamycin ameliorated the lymphoproliferative immunodeficiency caused by hyperactivation of mTOR. These results expand genetic spectrum of APDS and will facilitate further study of the genotype-phenotype correlation in those with PIK3CD mutations.","variants":[{"Name":"NM_005026.5(PIK3CD):c.1570T>A (p.Tyr524Asn)","Chromosome":"1","Start":"9720790","Stop":"9720790","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1486924,"rule_based_match":true,"evidence_text":"c.1570 T > A, p.Y524N","llm_judgment":"PRESENT","evidence":"c.1570 T > A, p.Y524N","abstract_start":254,"abstract_end":275}]}
{"pmid":"11734061","title":"Discrimination of three mutational events that result in a disruption of the R122 primary autolysis site of the human cationic trypsinogen (PRSS1) by denaturing high performance liquid chromatography.","abstract":"BACKGROUND: R122, the primary autolysis site of the human cationic trypsinogen (PRSS1), constitutes an important \"self-destruct\" or \"fail-safe\" defensive mechanism against premature trypsin activation within the pancreas. Disruption of this site by a missense mutation, R122H, was found to cause hereditary pancreatitis. In addition to a c.365G>A (CGC>CAC) single nucleotide substitution, a c.365 through 366GC>AT (CGC>CAT) gene conversion event in exon 3 of PRSS1 was also found to result in a R122H mutation. This imposes a serious concern on the genotyping of pancreatitis by a widely used polymerase chain reaction-restriction fragment length polymorphism assay, which could only detect the commonest c.365G>A variant.\nMATERIALS AND METHODS: DNA samples containing either the known c.365G>A or c.365 through 366GC>AT variant in exon 3 of PRSS1 were used as positive controls to establish a denaturing high performance liquid chromatography (DHPLC) assay.\nRESULTS: DHPLC could readily discriminate the two known different mutational events resulting in the R122H mutation. More importantly, under the same experimental conditions, it identified a further mutational event that also occurs in the R122 primary autolysis site but results in a different amino acid substitution: c.364C>T (CGC>TGC; R122C).\nCONCLUSIONS: A rapid, simple, and low-cost assay for detecting both the known and new mutations occuring in the R122 primary autolysis site of PRSS1 was established. In addition, the newly found R122C variant represents a likely pancreatitis-predisposing mutation.","variants":[{"Name":"NM_002769.5(PRSS1):c.364C>T (p.Arg122Cys)","Chromosome":"7","Start":"142751937","Stop":"142751937","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26922,"rule_based_match":true,"evidence_text":"c.364C>T (CGC>TGC; R122C)","llm_judgment":"PRESENT","evidence":"c.364C>T (CGC>TGC; R122C)","abstract_start":1279,"abstract_end":1304}]}
{"pmid":"33515434","title":"Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease.","abstract":"Mutations of the genes encoding aminoacyl-tRNA synthetases are highly associated with various central nervous system disorders. Recurrent mutations, including c.5A>G, p.D2G; c.1367C>T, p.S456L; c.1535G>A, p.R512Q and c.1846_1847del, p. Y616Lfs*6 of RARS1 gene, which encodes two forms of human cytoplasmic arginyl-tRNA synthetase (hArgRS), are linked to Pelizaeus-Merzbacher-like disease (PMLD) with unclear pathogenesis. Among these mutations, c.5A>G is the most extensively reported mutation, leading to a p.D2G mutation in the N-terminal extension of the long-form hArgRS. Here, we showed the detrimental effects of R512Q substitution and ΔC mutations on the structure and function of hArgRS, while the most frequent mutation c.5A>G, p.D2G acted in a different manner without impairing hArgRS activity. The nucleotide substitution c.5A>G reduced translation of hArgRS mRNA, and an upstream open reading frame contributed to the suppressed translation of the downstream main ORF. Taken together, our results elucidated distinct pathogenic mechanisms of various RARS1 mutations in PMLD.","variants":[{"Name":"NM_002887.4(RARS1):c.1367C>T (p.Ser456Leu)","Chromosome":"5","Start":"168510601","Stop":"168510601","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":260554,"rule_based_match":true,"evidence_text":"c.1367C>T, p.S456L","llm_judgment":"PRESENT","evidence":"c.1367C>T, p.S456L","abstract_start":174,"abstract_end":192}]}
{"pmid":"26602028","title":"A novel homozygous LMNA mutation (p.Met540Ile) causes mandibuloacral dysplasia type A.","abstract":"Mandibuloacral dysplasia with type A lipodystrophy (MADA) is a rare genetic disorder inherited in an autosomal recessive fashion characterized by hypoplasia of the mandible and clavicles, acroosteolysis and lipodystrophy due to mutations in the LMNA or ZMPSTE24 genes. In the current study, we have investigated a consanguineous family clinically diagnosed with mandibuloacral dysplasia type A having an affected child for the LMNA gene alteration(s). Mother is now 15weeks pregnant, seeking advice on the health of her fetus. Peripheral blood was obtained from all family members after informed consent was achieved. Genomic DNA was isolated. The sequence of the LMNA gene, including all exons and intron boundaries was analyzed by PCR and Sanger sequencing. Chorionic villus was collected from the placenta to reveal the condition of the fetus. Molecular analysis ascertained a homozygous mutation c.1620G>A (p.M540I) in the proband and heterozygous alteration in the family. Genomic DNA isolated from the CVS was amplified using specific primers for identified deleterious mutation and analyzed by Sanger sequencing. Two pathogenic mutations c.1620G>A and c.1698C>T were identified in the fetus. Genetic counseling as well as justified rapid and sensitive genetic testing can provide reassurance for the families to prevent the high burden of genetic disorders. We have also applied several online tools including PolyPhen2, MUpro, SIFT, PoPMuSiC, Project HOPE and Mutation Taster to predict the impact of p.Met540Ile substitution as a hotspot region within LMNA. All tools showed reduction in the stability of the protein structure. We conclude that p.M540I mutation may causes disease in the homozygous state.","variants":[{"Name":"NM_170707.4(LMNA):c.1620G>A (p.Met540Ile)","Chromosome":"1","Start":"156137665","Stop":"156137665","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":106555,"rule_based_match":true,"evidence_text":"c.1620G>A (p.M540I)","llm_judgment":"PRESENT","evidence":"c.1620G>A (p.M540I)","abstract_start":900,"abstract_end":919}]}
{"pmid":"31146325","title":"","abstract":"Methylmalonic aciduria (MMA-uria) is seen in several inborn errors of metabolism (IEM) affecting intracellular cobalamin pathways. Methylmalonyl-CoA epimerase (MCE) is an enzyme involved in the mitochondrial cobalamin-dependent pathway generating succinyl-CoA. Homozygous mutations in the corresponding <i>MCEE</i> gene have been shown in children to cause MCE deficiency with isolated MMA-uria and a variable clinical phenotype. We describe a 78-year-old man with Parkinson's disease, dementia and stroke in whom elevated serum levels of methylmalonic acid had been evident for many years. Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin. Whole genome sequencing was performed, with data analysis targeted towards genes known to cause IEM. Compound heterozygous mutations were identified in the <i>MCEE</i> gene, c.139C>T (p.Arg47X) and c.419delA (p.Lys140fs), of which the latter is novel. To our knowledge, this is the first report of an adult patient with <i>MCEE</i> mutations and MMA-uria, thus adding novel data to the possible phenotypical spectrum of MCE deficiency. Although clinical implications are uncertain, it can be speculated whether intermittent hyperammonemia during episodes of metabolic stress could have precipitated the patient's ongoing neurodegeneration attributed to Parkinson's disease.","variants":[{"Name":"NM_032601.4(MCEE):c.419del (p.Lys140fs)","Chromosome":"2","Start":"71110082","Stop":"71110082","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":1016097,"rule_based_match":true,"evidence_text":"c.419delA (p.Lys140fs)","llm_judgment":"PRESENT","evidence":"c.419delA (p.Lys140fs)","abstract_start":950,"abstract_end":972},{"Name":"NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)","Chromosome":"2","Start":"71124445","Stop":"71124445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17382,"rule_based_match":true,"evidence_text":"c.139C>T (p.Arg47X)","llm_judgment":"PRESENT","evidence":"c.139C>T (p.Arg47X)","abstract_start":926,"abstract_end":945}]}
{"pmid":"30632081","title":"Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene.","abstract":"Impairment of saposin B causes rare atypical metachromatic leukodystrophy (MLD). It is encoded (together with saposin A, C, and D) by the PSAP gene. Only ten pathogenic variants were described in the PSAP gene in MLD patients to date. We report on two novel variants in the PSAP gene - c.679_681delAAG in the saposin B encoding exon 6 and c.1268delT in the saposin D encoding exon 11 in a patient with MLD. We discuss the fact, that variants resulting in PSAP null allele can be shared in patients with the deficit of other saposins (A-D) or whole prosaposin. The patient's phenotype depends then on the nature of the second allele - atypical Gaucher disease in case of saposin A, MLD in case of saposin B, and Krabbe disease in case of saposin C impairing mutations. The clinically most severe prosaposin deficit is caused by the presence of two PSAP null alleles. Thus, the assessment of a variant impact is needed to prevent delayed diagnosis or misdiagnosis in patients with PSAP mutations.","variants":[{"Name":"NM_002778.4(PSAP):c.1268del (p.Leu423fs)","Chromosome":"10","Start":"71819547","Stop":"71819547","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":553410,"rule_based_match":true,"evidence_text":"c.1268delT","llm_judgment":"PRESENT","evidence":"c.1268delT","abstract_start":339,"abstract_end":349},{"Name":"NM_002778.4(PSAP):c.679_681del (p.Lys227del)","Chromosome":"10","Start":"71828053","Stop":"71828055","ReferenceAlleleVCF":"CCTT","AlternateAlleleVCF":"C","allel_id":553411,"rule_based_match":true,"evidence_text":"c.679_681delAAG","llm_judgment":"PRESENT","evidence":"c.679_681delAAG","abstract_start":286,"abstract_end":301}]}
{"pmid":"21077766","title":"A dyserythropoietic anemia associated with homozygous Hb Plasencia [α125(H8)Leu→Arg (α2)] (HBA2:c.377T>G), a variant with an unstable α chain.","abstract":"A female patient of Portuguese origin, who was born to consanguineous parents, presented with moderate anemia, mild jaundice and splenomegaly. Bone marrow aspiration showed an erythroid hyperplasia and binucleate erythroblasts, evoking a congenital dyserythropoietic anemia, type II (CDA II). Although microcytosis cast some doubt on the diagnosis, investigation was pursued along this line. The CDA II was finally ruled out as underglycosylation of band 3, remnants of endoplasmic reticulum cisternae and mutations in the SEC23B gene were all missing. On the other hand, analysis of the α-globin genes showed a base substitution at codon 125 (CTG→CGG) of the α2-globin gene, ascertaining a homozygosity for Hb Plasencia (HBA2:c.377T>G). This variant has an unstable α chain. In the absence of a thorough work-up, dyserythropoietic anemia associated with hemoglobin (Hb) variants having a moderately unstable α chain, may be mistaken for CDA II.","variants":[{"Name":"NM_000517.6(HBA2):c.377T>G (p.Leu126Arg)","Chromosome":"16","Start":"173548","Stop":"173548","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":30729,"rule_based_match":true,"evidence_text":"HBA2:c.377T>G","llm_judgment":"PRESENT","evidence":"HBA2:c.377T>G","abstract_start":722,"abstract_end":735}]}
{"pmid":"27886254","title":"Two novel mutations in PRPF3 causing autosomal dominant retinitis pigmentosa.","abstract":"Retinitis pigmentosa (RP) is a heterogeneous set of hereditary eye diseases, characterized by selective death of photoreceptor cells in the retina, resulting in progressive visual impairment. Approximately 20-40% of RP cases are autosomal dominant RP (ADRP). In this study, a Chinese ADRP family previously localized to the region between D1S2819 and D1S2635 was sequenced via whole-exome sequencing and a variant c.1345C > G (p.R449G) was identified in PRPF3. The Sanger sequencing was performed in probands of additional 95 Chinese ADRP families to investigate the contribution of PRPF3 to ADRP in Chinese population and another variant c.1532A > C (p.H511P) was detected in one family. These two variants, co-segregate with RP in two families respectively and both variants are predicted to be pathological. This is the first report about the spectrum of PRPF3 mutations in Chinese population, leading to the identification of two novel PRPF3 mutations. Only three clustered mutations in PRPF3 have been identified so far in several populations and all are in exon 11. Our study expands the spectrum of PRPF3 mutations in RP. We also demonstrate that PRPF3 mutations are responsible for 2.08% of ADRP families in this cohort indicating that PRPF3 mutations might be relatively rare in Chinese ADRP patients.","variants":[{"Name":"NM_004698.4(PRPF3):c.1345C>G (p.Arg449Gly)","Chromosome":"1","Start":"150343371","Stop":"150343371","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":855854,"rule_based_match":true,"evidence_text":"c.1345C > G (p.R449G)","llm_judgment":"PRESENT","evidence":"c.1345C > G (p.R449G)","abstract_start":414,"abstract_end":435}]}
{"pmid":"24100867","title":"COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.","abstract":"IMPORTANCE: Isolated cytochrome-c oxidase (COX) deficiency is one of the most frequent respiratory chain defects seen in human mitochondrial disease. Typically, patients present with severe neonatal multisystem disease and have an early fatal outcome. We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.\nOBSERVATIONS: Whole-exome sequencing detected 1 known pathogenic and 1 novel COX10 mutation: c.1007A>T; p.Asp336Val, previously associated with fatal infantile COX deficiency, and c.1015C>T; p.Arg339Trp. Muscle COX holoenzyme and subassemblies were undetectable on immunoblots of blue-native gels, whereas denaturing gels and immunocytochemistry showed reduced core subunit MTCO1. Heme absorption spectra revealed low heme aa3 compatible with heme A:farnesyltransferase deficiency due to COX10 dysfunction. Both mutations demonstrated respiratory deficiency in yeast, confirming pathogenicity. A COX10 protein model was used to predict the structural consequences of the novel Arg339Trp and all previously reported substitutions.\nCONCLUSIONS AND RELEVANCE: These findings establish that COX10 mutations cause adult mitochondrial disease. Nuclear modifiers, epigenetic phenomenon, and/or environmental factors may influence the disease phenotype caused by reduced COX activity and contribute to the variable clinical severity related to COX10 dysfunction.","variants":[{"Name":"NM_001303.4(COX10):c.1015C>T (p.Arg339Trp)","Chromosome":"17","Start":"14206896","Stop":"14206896","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1871538,"rule_based_match":true,"evidence_text":"c.1015C>T; p.Arg339Trp","llm_judgment":"PRESENT","evidence":"c.1015C>T; p.Arg339Trp","abstract_start":701,"abstract_end":723},{"Name":"NM_001303.4(COX10):c.1007A>T (p.Asp336Val)","Chromosome":"17","Start":"14206888","Stop":"14206888","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":22564,"rule_based_match":true,"evidence_text":"c.1007A>T; p.Asp336Val","llm_judgment":"PRESENT","evidence":"c.1007A>T; p.Asp336Val","abstract_start":614,"abstract_end":636}]}
{"pmid":"32569165","title":"Primary hyperoxaluria Type 1: A case report in an extended family with a novel AGXT gene mutation.","abstract":"INTRODUCTION: Primary hyperoxaluria type 1 (PH1) is a genetic autosomal recessively inherited disorder due to mutation in the alanine-glyoxylate aminotransferase (AGXT) gene. It usually presents in children with nephrolithiasis and/or nephrocalcinosis and progressive renal function impairment and end stage renal disease (ESRD).\nPATIENT CONCERNS: A 13 years old Saudi boy with history of recurrent urolithiasis since the age of 2 years presented to us with picture of ESRD. He has strong family history of urolithiasis.\nDIAGNOSIS: Working up the patient suggested the diagnosis of PH1 based on the typical clinical, laboratory, and imaging findings which was genetically proved by positive AXGT gene mutation. The mutation detected was not previously reported in literature. The mutation detected was not previously reported in literature. The novel mutation c. 799A>T p. (IIe267Phe) detected in our patient extend the spectrum of the known AGXT gene mutations.\nINTERVENTIONS AND OUTCOMES: Hemodialysis as a temporary step followed by renal transplantation which is the only cure.\nCONCLUSION: High index of suspicion of PH1 before ESRD should be considered in any patient who has recurrent urolithiasis since early life especially in presence of strong family history.","variants":[{"Name":"NM_000030.3(AGXT):c.799A>T (p.Ile267Phe)","Chromosome":"2","Start":"240875957","Stop":"240875957","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2842235,"rule_based_match":true,"evidence_text":"c. 799A>T p. (IIe267Phe)","llm_judgment":"PRESENT","evidence":"c. 799A>T p. (IIe267Phe)","abstract_start":860,"abstract_end":884}]}
{"pmid":"30907348","title":"Application of next-generation sequencing in the molecular diagnosis of Duchenne muscular dystrophy","abstract":"The purpose of this study is to analyze the family's clinical data of 22 children who were given an intended clinical diagnosis of Duchenne muscular dystrophy (DMD), and to explore the clinical value of next-generation sequencing (NGS) in the molecular diagnosis of DMD. The probands were simultaneously tested by NGS for a gene panel associated with hereditary neuromuscular disease and multiplex ligation-dependent probe amplification (MLPA) for the Dystrophin gene. The exon deletion/repetition mutations of the Dystrophin gene determined by both methods were compared and the point mutations of the Dystrophin gene were verified by Sanger sequencing. Dystrophin gene mutations were found in all the 22 probands, including 14 exon deletion/repetition mutations and 8 point mutations/minor variations. The results of MLPA detection were consistent with those of NGS. The results of Sanger sequencing showed that the point mutations and minor variations determined by NGS were correct. One missense mutation (c.6290G>T), 1 nonsense mutation (c.3487C>T) and 4 minor deletion-induced frameshift mutations (c.1208delG, c.7497_7506delGGTGGGTGAC, c.9421_9422delAA and c.8910_8913delTCTC) had not been reported in the Human Gene Mutation Database, and thus were considered as novel mutations of the Dystrophin gene. The results of this study showed that NGS can detect variations in the Dystrophin gene, including exon deletion/repetition, point mutation, minor deletion and intron mutation. Therefore, NGS is of certain clinical value in the molecular diagnosis of DMD and is worthy of recommendation.","variants":[{"Name":"NM_004006.3(DMD):c.6290G>T (p.Gly2097Val)","Chromosome":"X","Start":"32287529","Stop":"32287529","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1899662,"rule_based_match":true,"evidence_text":"c.6290G>T","llm_judgment":"PRESENT","evidence":"c.6290G>T","abstract_start":1010,"abstract_end":1019},{"Name":"NM_004006.3(DMD):c.3487C>T (p.Gln1163Ter)","Chromosome":"X","Start":"32454778","Stop":"32454778","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":411318,"rule_based_match":true,"evidence_text":"c.3487C>T","llm_judgment":"PRESENT","evidence":"c.3487C>T","abstract_start":1043,"abstract_end":1052}]}
{"pmid":"20138856","title":"High resolution melting analysis facilitates mutation screening of ETFDH gene: applications in riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.","abstract":"BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) or gluaric aciduria type II is an autosomal recessive disease caused by defects in mitochondrial electron transfer system and metabolism of fatty acid. Recently, ETFDH mutations were reported to be major causes of riboflavin-responsive MADD. The present study is aimed at screening ETFDH mutations.\nMETHODS: High resolution melting (HRM) analysis was performed to screen ETFDH mutations. Genomic DNA was extracted from peripheral blood samples of the 9 patients with MADD and normal controls. Total 13 exons of ETFDH were screened by HRM analysis. The results were subsequently confirmed by direct DNA sequencing.\nRESULTS: This diagnostic strategy proved to be feasible in detecting 3 known (c.250G>A, c380T>A, c.524G>T) and 1 novel (c.1831G>A) ETFDH mutations. Each mutation could be readily and accurately identified in the difference plot curves. We estimated the carrier frequency of the hotspot mutation, c.250G>A, in the Taiwanese population to be 1:125 (0.8%).\nCONCLUSIONS: HRM analysis can be successfully applied to screen ETFDH mutations. Since riboflavin-responsive MADD is often treatable, especially with mutations in ETFDH, identifying ETFDH mutations is crucial for these patients.","variants":[{"Name":"NM_004453.4(ETFDH):c.1831G>A (p.Gly611Arg)","Chromosome":"4","Start":"158708504","Stop":"158708504","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2794709,"rule_based_match":true,"evidence_text":"c.1831G>A","llm_judgment":"PRESENT","evidence":"c.1831G>A","abstract_start":796,"abstract_end":805},{"Name":"NM_004453.4(ETFDH):c.524G>T (p.Arg175Leu)","Chromosome":"4","Start":"158685137","Stop":"158685137","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":27068,"rule_based_match":true,"evidence_text":"c.524G>T","llm_judgment":"PRESENT","evidence":"c.524G>T","abstract_start":773,"abstract_end":781},{"Name":"NM_004453.4(ETFDH):c.380T>A (p.Leu127His)","Chromosome":"4","Start":"158682399","Stop":"158682399","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":27069,"rule_based_match":false,"evidence_text":"c380T>A","llm_judgment":"PRESENT","evidence":"c380T>A","abstract_start":764,"abstract_end":771}]}
{"pmid":"33372566","title":"Long-term follow-up of a Chinese patient with","abstract":"<b>Purpose</b>: To characterize and monitor the clinical and electrophysiological features of a Chinese patient with <i>KCNV2</i> retinopathy.<b>Methods</b>: A 17-year-old Chinese male with the diagnosis of cone dystrophy with supernormal rod response (CDSRR) was followed-up for 5 years, with full ophthalmological examinations, including decimal best corrected visual acuity (BCVA), fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG). Genetic screening was performed to detect the sequence variations in the retinal dystrophy associated genes in the patient and his parents.<b>Results</b>: The patient demonstrated the characteristic full-field electroretinography (ERG) features of CDSRR, namely a profound enlargement of the dark-adapted ERG b-wave amplitude with increasing flash strength and a broadened a-wave trough; this case also had undetectable light-adapted ERGs. A BCVA of 0.15 was maintained over 5 years in both eyes; while progressive macular atrophy was identified. Molecular genetic analyses revealed two novel disease-causing <i>KCNV2</i> variants in compound heterozygous state: c.1408 G > C (p.Gly470Arg) and c.1500 C > G (p.Tyr500Ter).<b>Conclusions</b>: This is the first long-term case study of an East Asian patient with molecularly confirmed CDSRR. The progressive atrophy with maintained VA demonstrated in this case will be valuable for increasing the understanding of the natural course of <i>KCNV2</i> retinopathy and it will help in counselling patients with this disease.","variants":[{"Name":"NM_133497.4(KCNV2):c.1500C>G (p.Tyr500Ter)","Chromosome":"9","Start":"2729589","Stop":"2729589","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2157711,"rule_based_match":true,"evidence_text":"c.1500 C > G (p.Tyr500Ter)","llm_judgment":"PRESENT","evidence":"c.1500 C > G (p.Tyr500Ter)","abstract_start":1233,"abstract_end":1259}]}
{"pmid":"25389632","title":"Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation.","abstract":"CONTEXT: The phenotype of familial pheochromocytoma (PHEO) associated with germline TMEM127 mutations (TMEM127-related PHEO) has not been clearly defined.\nOBJECTIVE: This study aimed to investigate the penetrance, full phenotypic spectrum and effectiveness of clinical/genetic screening in TMEM127-related PHEO.\nDESIGN, SETTING, AND PARTICIPANTS: Clinical and genetic screening, and genetic counseling were offered to 151 individuals from a six-generation family carrying a TMEM127 germline mutation in a referral center.\nINTERVENTION AND MAIN OUTCOME MEASURES: TMEM127 genetic testing was offered to at-risk relatives and clinical surveillance for pheochromocytoma was performed in mutation-positive carriers.\nRESULTS: Forty seven individuals carried the c.410-2A>C TMEM127 mutation. Clinical data were obtained from 34 TMEM127-mutation carriers followed up for 8.7 ± 8.1 years (range, 1-20 y). Pheochromocytoma was diagnosed in 11 carriers (32%) at a median age of 43 years. In nine patients, symptoms started at 29 years (range, 10-55 y) and two cases were asymptomatic. Tumors were multicentric in five (45%) and bilateral in five (45%) patients. Six patients (54%) had at least one adrenomedullary nodule less than 10 mm. No paragangliomas, distant metastases, or other manifestations were detected. Cumulative penetrance of pheochromocytoma was 0% at 0-20 years, 3% at 21-30 years, 15% at 31-40 years, 24% at 41-50 years, and 32% at 51-65 years. The youngest case was diagnosed at 22 years and the earliest symptoms were reported at age 10.\nCONCLUSIONS: Tumor multicentricity, nodular adrenomedullary hyperplasia, and the occurrence of symptoms more than a decade earlier than the age at diagnosis are novel findings in TMEM127-related PHEO. The high penetrance of pheochromocytoma in this condition validates the benefits of genetic testing of at-risk relatives. We thus recommend that TMEM127 genetic testing should be offered to at-risk individuals at age 22 years and mutation carriers should undergo clinical surveillance annually.","variants":[{"Name":"NM_017849.4(TMEM127):c.410-2A>C","Chromosome":"2","Start":"96254117","Stop":"96254117","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":15146,"rule_based_match":true,"evidence_text":"c.410-2A>C","llm_judgment":"PRESENT","evidence":"c.410-2A>C","abstract_start":756,"abstract_end":766}]}
{"pmid":"29594000","title":"Nonimmune hydrops fetalis due to autosomal recessive hereditary spherocytosis.","abstract":"BACKGROUND: Hereditary spherocytosis is the most common form of inherited hemolytic anemia and is characterized by a structural defect in the RBC membrane. The disorder is commonly inherited in an autosomal dominant fashion and leads to a mild to moderate anemia. The autosomal recessive form of hereditary spherocytosis is rarely reported in association with fetal anemia and hydrops fetalis.\nCASE: A 25 year old G5 P2112 at 25 2/7 weeks gestation presents with severe fetal anemia and nonimmune hydrops fetalis requiring multiple fetal intrauterine transfusions. After delivery, the neonate required several double volume exchange transfusions and ultimately was diagnosed with autosomal recessive hereditary spherocytosis weeks after birth. The neonate was identified to have a rare homozygous genetic mutation, SPTA1c.6154delG, which leads to absent production of normal α-spectrin.\nCONCLUSION: The case highlights the importance of considering less common genetic mutations involving the RBC structural proteins when patients present with severe fetal anemia and nonimmune hydrops fetalis.","variants":[{"Name":"NM_003126.4(SPTA1):c.6154del (p.Ala2052fs)","Chromosome":"1","Start":"158620433","Stop":"158620433","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1781116,"rule_based_match":true,"evidence_text":"SPTA1c.6154delG","llm_judgment":"PRESENT","evidence":"SPTA1c.6154delG","abstract_start":815,"abstract_end":830}]}
{"pmid":"27384765","title":"Association of Epidermolysis Bullosa Simplex With Mottled Pigmentation and EXPH5 Mutations.","abstract":"Importance: Epidermolysis bullosa simplex (EBS) is a group of clinically and genetically diverse mechanobullous genodermatoses characterized by the fragility of skin and mucous membranes. Recently, mutations in EXPH5 encoding exophilin-5 (also known as Slac2-b, an effector protein involved in intracellular vesicle trafficking and exosome secretion) have been implicated in the pathophysiology of EBS. Herein, we report a novel homozygous nonsense mutation in EXPH5 responsible for an EBS subtype with mottled pigmentation.\nObjective: To identify the gene mutation(s) accountable for the mottled pigmentation phenotype in a patient with suspected inherited skin fragility disorder.\nDesign, Setting, and Participant: Data for this case report were acquired in an outpatient clinic and concern a referral from the primary care physician to the national Center for Blistering Diseases in The Netherlands. Data were acquired and analyzed from 2014 to 2016.\nMain Outcomes and Measures: Clinical examination and investigation were performed of the molecular basis of patient's skin fragility and mottled pigmentation phenotype. Electron microscopy studies described the underlying abnormalities on an ultrastructural level.\nResults: The clinical phenotype is characterized by mild generalized skin fragility, trauma-induced skin blistering since infancy, and development of remarkable diffuse mottled pigmentation on the trunk and proximal extremities. Sequencing the complete set of genes associated with epidermolysis bullosa revealed a homozygous nonsense mutation in exon 6 of EXPH5: c.3917C>G, p.Ser1306*. Electron microscopy revealed disruption of keratin filament cytoskeleton and accumulation of melanosomes in a disordered distribution in the keratinocytes.\nConclusions and Relevance: To our knowledge, the current study illustrates the first clinically well-documented, mottled pigmentation phenotype related to a novel EXPH5 mutation. In addition, by means of electron microscopy image analysis, it proposes a hypothesis for the pigmentary changes in this rare autosomal recessive EBS subtype. These findings expand the genetic and phenotypic spectrum of human inherited skin fragility disorders, and we propose the addition of EBS resulting from EXPH5 mutations to the EBS-mottled pigmentation subtype.","variants":[{"Name":"NM_015065.3(EXPH5):c.3917C>G (p.Ser1306Ter)","Chromosome":"11","Start":"108511590","Stop":"108511590","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1295248,"rule_based_match":true,"evidence_text":"c.3917C>G, p.Ser1306*","llm_judgment":"PRESENT","evidence":"c.3917C>G, p.Ser1306*","abstract_start":1583,"abstract_end":1604}]}
{"pmid":"35896117","title":"Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis.","abstract":"Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.","variants":[{"Name":"NM_013338.5(ALG5):c.703_704del (p.Gln235fs)","Chromosome":"13","Start":"36965644","Stop":"36965645","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":1706458,"rule_based_match":true,"evidence_text":"c.703_704delCA","llm_judgment":"PRESENT","evidence":"c.703_704delCA","abstract_start":557,"abstract_end":571}]}
{"pmid":"28859624","title":"Living kidney transplantation between brothers with unrecognized renal amyloidosis as the first manifestation of familial Mediterranean fever: a case report.","abstract":"BACKGROUND: Familial Mediterranean fever is an autosomal recessive disease characterized by recurrent episodes of fever and polyserositis and by the onset of reactive amyloid-associated amyloidosis. Amyloidosis due to familial Mediterranean fever can lead to end-stage renal disease, culminating in kidney transplantation for some patients. In this study, we report the clinical outcome of two brothers with familial Mediterranean fever who were the inadvertent donor and recipient, respectively, of a kidney. Subsequently, they were diagnosed with renal amyloidosis secondary to familial Mediterranean fever and were successfully treated with anakinra and colchicine.\nCASE PRESENTATION: Two brothers with familial Mediterranean fever and renal amyloidosis were the inadvertent donor and recipient, respectively, of a kidney. The recipient had presented recurrent acute febrile episodes of familial Mediterranean fever, developed nephrotic syndrome secondary to amyloidosis and needed bilateral nephrectomy and chronic dialysis. His elder brother, in apparent good health, donated his left kidney to his brother. Immediately after the kidney transplantation, both the donor and recipient presented massive proteinuria, impaired renal function and elevated serum amyloid A levels. Biopsies of the brothers' kidneys showed amyloidosis. Genetic studies thereafter revealed a homozygous variant for the MEFV gene (NM_000243.2.c.2082G > A; p.M694I) in both brothers. At this point, both the donor and recipient were treated with colchicine and anakinra, resulting in improved renal function, decreased proteinuria, undetectable serum amyloid A levels and stable renal function at 62 months of follow-up and no major adverse effects.\nCONCLUSIONS: In familial Mediterranean fever, analyses of the MEFV gene should be performed in potential live kidney donors from a direct family member (either between siblings or between parents and children). In addition, genetic studies are required when consanguinity is suspected between members involved in the living transplant. Finally, anakinra could be a safe adjuvant therapy combined with colchicine for patients with familial Mediterranean fever and amyloidosis, including those with successful kidney transplantation.","variants":[{"Name":"NM_000243.3(MEFV):c.2082G>A (p.Met694Ile)","Chromosome":"16","Start":"3243405","Stop":"3243405","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17578,"rule_based_match":true,"evidence_text":"NM_000243.2.c.2082G > A; p.M694I","llm_judgment":"PRESENT","evidence":"NM_000243.2.c.2082G > A; p.M694I","abstract_start":1410,"abstract_end":1442}]}
{"pmid":"30140060","title":"A Novel NDUFS3 mutation in a Chinese patient with severe Leigh syndrome.","abstract":"Leigh syndrome is one of the most common subtypes of mitochondrial disease. Mutations in encoding genes of oxidative phosphorylation complexes have been frequently reported, of which, MTATP6 was one of the most frequently reported genes for Leigh syndrome. In this study, by using next-generation sequencing targeted to MitoExome in a patient with clinical manifestations of Leigh syndrome, two missense mutations of NDUFS3 (c.418 C > T/p.R140W and c.595 C > T/p.R199W) were identified, of which c.418 C > T was novel. Functionally, the patient derived lymphoblastoid cells showed decreased amount of NDUFS3 and complex I assembly when compared with two control cells. Although NDUFS3 mutations have been related to late onset Leigh syndrome, we found that the patient carrying these two mutations developed an early onset Leigh syndrome. To our knowledge, this is the second study on patient carrying NDUFS3 mutations. In conclusion, we identified a novel Leigh syndrome causing NDUFS3 mutation and expanded the clinical spectrum caused by NDUFS3 mutations in this study.","variants":[{"Name":"NM_004551.3(NDUFS3):c.595C>T (p.Arg199Trp)","Chromosome":"11","Start":"47582436","Stop":"47582436","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21059,"rule_based_match":true,"evidence_text":"c.595 C > T/p.R199W","llm_judgment":"PRESENT","evidence":"c.595 C > T/p.R199W","abstract_start":449,"abstract_end":468},{"Name":"NM_004551.3(NDUFS3):c.418C>T (p.Arg140Trp)","Chromosome":"11","Start":"47582124","Stop":"47582124","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":626077,"rule_based_match":true,"evidence_text":"c.418 C > T/p.R140W","llm_judgment":"PRESENT","evidence":"c.418 C > T/p.R140W","abstract_start":425,"abstract_end":444}]}
{"pmid":"25999675","title":"Mutation analysis in 129 genes associated with other forms of retinal dystrophy in 157 families with retinitis pigmentosa based on exome sequencing.","abstract":"PURPOSE: Mutations in 60 known genes were previously identified by exome sequencing in 79 of 157 families with retinitis pigmentosa (RP). This study analyzed variants in 129 genes associated with other forms of hereditary retinal dystrophy in the same cohort.\nMETHODS: Apart from the 73 genes previously analyzed, a further 129 genes responsible for other forms of hereditary retinal dystrophy were selected based on RetNet. Variants in the 129 genes determined by whole exome sequencing were selected and filtered by bioinformatics analysis. Candidate variants were confirmed by Sanger sequencing and validated by analysis of available family members and controls.\nRESULTS: A total of 90 candidate variants were present in the 129 genes. Sanger sequencing confirmed 83 of the 90 variants. Analysis of family members and controls excluded 76 of these 83 variants. The remaining seven variants were considered to be potential pathogenic mutations; these were c.899A>G, c.1814C>G, and c.2107C>T in BBS2; c.1073C>T and c.1669C>T in INPP5E; and c.3582C>G and c.5704-5C>G in CACNA1F. Six of these seven mutations were novel. The mutations were detected in five unrelated patients without a family history, including three patients with homozygous or compound heterozygous mutations in BBS2 and INPP5E, and two patients with hemizygous mutations in CACNA1F. None of the patients had mutations in the genes associated with autosome dominant retinal dystrophy.\nCONCLUSIONS: Only a small portion of patients with RP, about 3% (5/157), had causative mutations in the 129 genes associated with other forms of hereditary retinal dystrophy.","variants":[{"Name":"NM_019892.6(INPP5E):c.1669C>T (p.Arg557Cys)","Chromosome":"9","Start":"136430410","Stop":"136430410","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":415176,"rule_based_match":true,"evidence_text":"c.1669C>T","llm_judgment":"PRESENT","evidence":"c.1669C>T","abstract_start":1016,"abstract_end":1025},{"Name":"NM_019892.6(INPP5E):c.1073C>T (p.Pro358Leu)","Chromosome":"9","Start":"136433241","Stop":"136433241","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1008520,"rule_based_match":true,"evidence_text":"c.1073C>T","llm_judgment":"PRESENT","evidence":"c.1073C>T","abstract_start":1002,"abstract_end":1011},{"Name":"NM_031885.5(BBS2):c.1814C>G (p.Ser605Ter)","Chromosome":"16","Start":"56497063","Stop":"56497063","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":547788,"rule_based_match":true,"evidence_text":"c.1814C>G","llm_judgment":"PRESENT","evidence":"c.1814C>G","abstract_start":968,"abstract_end":977},{"Name":"NM_031885.5(BBS2):c.2107C>T (p.Arg703Ter)","Chromosome":"16","Start":"56484820","Stop":"56484820","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":487920,"rule_based_match":true,"evidence_text":"c.2107C>T","llm_judgment":"PRESENT","evidence":"c.2107C>T","abstract_start":983,"abstract_end":992}]}
{"pmid":"20950398","title":"Aberrant PKD2 splicing due to a presumed novel missense mutation in autosomal-dominant polycystic kidney disease.","abstract":"Autosomal-dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder characterized by abnormal proliferation of renal tubular epithelium, leading to massive kidney enlargement and progressive chronic kidney disease. ADPKD is caused by mutations in PKD1 and PKD2 genes. Herein, we describe and characterize a novel missense mutation in the PKD2 gene (c.1320G>T) in a 41-year-old White man with kidney cysts and a family history of ADPKD. This mutation abolishes a conserved acceptor splice site of intron 5, resulting in a premature termination following the addition of three aberrant amino acids (PKD2 p.L441C fsX4). We demonstrate that the aberrantly spliced transcript is found in substantial amounts in the patient's peripheral blood leukocytes (PBL), and show that this alternative splicing of exon 6 occurs, to a lesser magnitude, in other patients with ADPKD and in normal control individuals. The biological and clinical significance of this splice variant in ADPKD is currently unknown.","variants":[{"Name":"NM_000297.4(PKD2):c.1320G>T (p.Arg440Ser)","Chromosome":"4","Start":"88046642","Stop":"88046642","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":799381,"rule_based_match":true,"evidence_text":"c.1320G>T","llm_judgment":"PRESENT","evidence":"c.1320G>T","abstract_start":370,"abstract_end":379}]}
{"pmid":"32239545","title":"Comprehensive germline mutation analysis and clinical profile in a large cohort of Brazilian xeroderma pigmentosum patients.","abstract":"BACKGROUND: Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system.\nOBJECTIVES: To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP.\nMETHODS: Twenty-seven families were screened for germline variants in eight XP-related genes.\nRESULTS: All patients (N = 32) were diagnosed with bi-allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251-1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2/XPD, DDB2/XPE and ERCC5/XPG variants were found in a few patients. Aside from melanoma and non-melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma.\nCONCLUSIONS: We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP-related genes, unexpected non-skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described.","variants":[{"Name":"NM_004628.5(XPC):c.2251-1G>C","Chromosome":"3","Start":"14148732","Stop":"14148732","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":187975,"rule_based_match":true,"evidence_text":"c.2251-1G>C","llm_judgment":"PRESENT","evidence":"c.2251-1G>C","abstract_start":630,"abstract_end":641}]}
{"pmid":"21203893","title":"Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1.","abstract":"We present clinical, neuroimaging, and molecular data on the identification of a new homozygous c.1783A>G (p.Thr595Ala) mutation in NDUFS1 in two inbred siblings with isolated complex I deficiency associated to a progressive cavitating leukoencephalopathy, a clinical and neuroradiological entity originally related to unknown defects of the mitochondrial energy metabolism. In both sibs, the muscle biopsy showed severe reduction of complex I enzyme activity, which was not obvious in fibroblasts. We also observed complex I dysfunction in a Neurospora crassa model of the disease, obtained by insertional mutagenesis, and in patient fibroblasts grown in galactose. Altogether, these results indicate that the NDUFS1 mutation is responsible for the disease and complex I deficiency. Clinical presentation of complex I defect is heterogeneous and includes an ample array of clinical phenotypes. Expanding the number of allelic variants in NDUFS1, our findings also contribute to a better understanding on the function of complex I.","variants":[{"Name":"NM_005006.7(NDUFS1):c.1783A>G (p.Thr595Ala)","Chromosome":"2","Start":"206127898","Stop":"206127898","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40569,"rule_based_match":true,"evidence_text":"c.1783A>G (p.Thr595Ala)","llm_judgment":"PRESENT","evidence":"c.1783A>G (p.Thr595Ala)","abstract_start":96,"abstract_end":119}]}
{"pmid":"27629860","title":"Myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK) is caused by heterozygous KCNC1 mutations.","abstract":"Progressive myoclonus epilepsy (PME) is a distinct group of seizure disorders characterized by gradual neurological decline with ataxia, myoclonus and recurring seizures. There are several forms of PME, among which the most recently described is MEAK - myoclonus epilepsy and ataxia due to potassium channel mutation. This particular subtype is caused by a recurrent de novo heterozygous mutation (c.959G>A, p.Arg320His) in the KCNC1 gene, which maps to chromosome 11 and encodes for the Kv3.1 protein (a subunit of the Kv3 subfamily of voltage-gated potassium channels). Loss of Kv3 function disrupts the firing properties of fast-spiking neurons, affects neurotransmitter release and induces cell death. Specifically regarding Kv3.1 malfunctioning, the most affected neurons include inhibitory GABAergic interneurons and cerebellar neurons. Impairment of the former cells is believed to contribute to myoclonus and seizures, whereas dysfunction of the latter to ataxia and tremor. Phenotypically, MEAK patients generally have a normal early development. At the age of 6 to 14 years, they present with myoclonus, which tends to progressively worsen with time. Tonic-clonic seizures may or may not be present, and some patients develop mild cognitive impairment following seizure onset. Typical electroencephalographic features comprise generalized epileptiform discharges and, in some cases, photosensitivity. Brain imaging is either normal or shows cerebellar atrophy. The identification of MEAK has both expanded the phenotypic and genotypic spectra of PME and established an emerging role for de novo mutations in PME.","variants":[{"Name":"NM_001112741.2(KCNC1):c.959G>A (p.Arg320His)","Chromosome":"11","Start":"17772053","Stop":"17772053","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":172192,"rule_based_match":true,"evidence_text":"c.959G>A, p.Arg320His","llm_judgment":"PRESENT","evidence":"c.959G>A, p.Arg320His","abstract_start":398,"abstract_end":419}]}
{"pmid":"36891747","title":"An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant.","abstract":"Ethylmalonic encephalopathy (EE) is a rare, severe, autosomal recessive condition caused by pathogenic variants in ETHE1 leading to progressive encephalopathy, hypotonia evolving to dystonia, petechiae, orthostatic acrocyanosis, diarrhea, and elevated ethylmalonic acid in urine. In this case report, we describe a patient with only mild speech and gross motor delays, subtle biochemical abnormalities, and normal brain imaging found to be homozygous for a pathogenic ETHE1 variant (c.586G>A) via whole exome sequencing. This case highlights the clinical heterogeneity of ETHE1 mutations and the utility of whole-exome sequencing in diagnosing mild cases of EE.","variants":[{"Name":"NM_014297.5(ETHE1):c.586G>A (p.Asp196Asn)","Chromosome":"19","Start":"43508784","Stop":"43508784","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":481376,"rule_based_match":true,"evidence_text":"c.586G>A","llm_judgment":"PRESENT","evidence":"c.586G>A","abstract_start":483,"abstract_end":491}]}
{"pmid":"22963789","title":"Two new class III G6PD variants [G6PD Tunis (c.920A>C: p.307Gln>Pro) and G6PD Nefza (c.968T>C: p.323 Leu>Pro)] and overview of the spectrum of mutations in Tunisia.","abstract":"We screened 423 patients referred to our laboratory after hemolysis triggered by fava beans ingestion, neonatal jaundice or drug hemolysis. Others were asymptomatic but belonged to a family with a history of G6PD deficiency. The determination of enzymatic activity using spectrophotometric method, revealed 293 deficient (143 males and 150 females). The molecular analysis was performed by a combination of PCR-RFLP and DNA sequencing to characterize the mutations causing G6PD deficiency. 14 different genotypes have been identified : G6PD A(-) (376A>G;202G>A) (46.07%) and G6PD Med (33.10%) were the most common variants followed by G6PD Santamaria (5.80%), G6PD Kaiping (3.75%), the association [c.1311T and IVS11 93c] (3.75%), G6PD Chatham (2.04%), G6PD Aures (1.70%), G6PD A(-) Betica (0.68%), the association [ 376G;c.1311T;IVS11 93c] (0.68%), G6PD Malaga, G6PD Canton and G6PD Abeno respectively (0.34%). Two novel missense mutations were identified (c.920A>C: p.307Gln>Pro and c.968T>C: p.323 Leu>Pro). We designated these two class III variants as G6PD Tunis and G6PD Nefza. A mechanism which could account for the defective activity is discussed.","variants":[{"Name":"NM_001360016.2(G6PD):c.968T>C (p.Leu323Pro)","Chromosome":"X","Start":"154533025","Stop":"154533025","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":25427,"rule_based_match":true,"evidence_text":"c.968T>C: p.323 Leu>Pro","llm_judgment":"PRESENT","evidence":"c.968T>C: p.323 Leu>Pro","abstract_start":985,"abstract_end":1008},{"Name":"NM_001360016.2(G6PD):c.920A>C (p.Gln307Pro)","Chromosome":"X","Start":"154533073","Stop":"154533073","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1780117,"rule_based_match":true,"evidence_text":"c.920A>C: p.307Gln>Pro","llm_judgment":"PRESENT","evidence":"c.920A>C: p.307Gln>Pro","abstract_start":958,"abstract_end":980}]}
{"pmid":"22857006","title":"Mutation analysis in Chinese patients with Cornelia de Lange syndrome.","abstract":"AIMS: Cornelia de Lange syndrome (CdLS) is a dominant multisystem developmental disorder and related to mutations of the NIPBL, SMC1A, and SMC3 genes. So far, there has been no report of a mutation analysis in Chinese patients with CdLS, while 12 cases have been clinically described. In the present study, we tried to search for pathogenic mutations of the NIPBL, SMC1A, and SMC3 genes in four patients with CdLS from four unrelated Chinese families.\nRESULTS: The mutational analysis of the NIPBL, SMC1A, and SMC3 genes by direct sequencing revealed a heterozygous splice-site mutation c.4321G>T(p.V1441L) at exon 20 of NIPBL in proband 2 and a novel heterozygous splice-site mutation c.6589+5G>C at intron 38 of NIPBL in proband 3, which was showed by reverse transcription polymerase chain reaction to generate both the full-length and an alternatively spliced transcript with an exon 38 deletion.\nCONCLUSIONS: This is the first report of the mutation analysis of NIPBL in China and our findings both expand the mutation spectrum of NIPBL and provide data for further understanding of the diverse and variable effects of NIPBL mutations.","variants":[{"Name":"NM_133433.4(NIPBL):c.4321G>T (p.Val1441Leu)","Chromosome":"5","Start":"37008623","Stop":"37008623","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":178376,"rule_based_match":true,"evidence_text":"c.4321G>T(p.V1441L)","llm_judgment":"PRESENT","evidence":"c.4321G>T(p.V1441L)","abstract_start":587,"abstract_end":606}]}
{"pmid":"19995443","title":"Three synchronous primary carcinomas in a patient with HNPCC associated with a novel germline mutation in MLH1: Case report.","abstract":"BACKGROUND: MLH1 is one of six known genes responsible for DNA mismatch repair (MMR), whose inactivation leads to HNPCC. It is important to develop genotype-phenotype correlations for HNPCC, as is being done for other hereditary cancer syndromes, in order to guide surveillance and treatment strategies in the future.\nCASE PRESENTATION: We report a 47 year-old male with hereditary nonpolyposis colorectal cancer (HNPCC) associated with a novel germline mutation in MLH1. This patient expressed a rare and severe phenotype characterized by three synchronous primary carcinomas: ascending and splenic flexure colon adenocarcinomas, and ureteral carcinoma. Ureteral neoplasms in HNPCC are most often associated with mutations in MSH2 and rarely with mutations in MLH1. The reported mutation is a two base pair insertion into exon 10 (c.866_867insCA), which results in a premature stop codon.\nCONCLUSION: Our case demonstrates that HNPCC patients with MLH1 mutations are also at risk for ureteral neoplasms, and therefore urological surveillance is essential. This case adds to the growing list of disease-causing MMR mutations, and contributes to the development of genotype-phenotype correlations essential for assessing individual cancer risk and tailoring of optimal surveillance strategies. Additionally, our case draws attention to limitations of the Amsterdam Criteria and the need to maintain a high index of suspicion when newly diagnosed colorectal cancer meets the Bethesda Criteria. Establishment of the diagnosis is the crucial first step in initiating appropriate surveillance for colorectal cancer and other HNPCC-associated tumors in at-risk individuals.","variants":[{"Name":"NM_000249.4(MLH1):c.866_867dup (p.Pro290fs)","Chromosome":"3","Start":"37017574","Stop":"37017575","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AAC","allel_id":95876,"rule_based_match":false,"evidence_text":"c.866_867insCA","llm_judgment":"PRESENT","evidence":"c.866_867insCA","abstract_start":832,"abstract_end":846}]}
{"pmid":"24700572","title":"A novel EBP c.224T>A mutation supports the existence of a male-specific disorder independent of CDPX2.","abstract":"Mutations in the Emopamil-binding protein (EBP) gene cause X-linked dominant chondrodysplasia punctata 2 (CDPX2), a disorder in which at least 95% of liveborn individuals are female and male intrauterine lethality is assumed. Several affected males with mutations in EBP have been reported. These males exhibit a phenotype similar to CDPX2 due to either somatic mosaicism or a 47, XXY karyotype in association with a null EBP allele. Alternatively, affected males may exhibit a distinct phenotype if they are hemizygous for a hypomorphic allele of EBP. Recently, we described a novel X-linked phenotype associated with digital abnormalities, intellectual disability and short stature, and mapped it to Xp11.4-p11.21. X-exome sequencing was performed to identify the mutated gene responsible for this phenotype. A novel missense variant, c.224T>A (p.I75N), was identified in EBP. SIFT and PolyPhen-2 predicted this change to be deleterious. The pathogenicity of this variant was subsequently supported by increased plasma levels of 8(9)-cholestenol in the proband and his mother. The molecular and biochemical evidence convincingly supports the pathogenicity and association of the p.I75N mutation with this newly described phenotype. This study expands the current phenotypic spectrum of males with hypomorphic EBP mutations and supports to the hypothesis that there exists an X-linked recessive entity independent of CDPX2.","variants":[{"Name":"NM_006579.3(EBP):c.224T>A (p.Ile75Asn)","Chromosome":"X","Start":"48523995","Stop":"48523995","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":205599,"rule_based_match":true,"evidence_text":"c.224T>A (p.I75N)","llm_judgment":"PRESENT","evidence":"c.224T>A (p.I75N)","abstract_start":837,"abstract_end":854}]}
{"pmid":"27061915","title":"Novel mutations in TGM1 and ABCA12 cause autosomal recessive congenital ichthyosis in five Saudi families.","abstract":"BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a rare disorder of keratinization. Infants (10-15%) born with this condition are encapsulated in hyperkeratotic membrane covering the entire body and are called \"collodion babies.\" So far, mutations in nine different genes have been identified as causative and implicated in the pathogenesis of the clinically and genetically heterogeneous group of ARCI disorders. Among these, TGM1 is the gene most commonly mutated in ARCI.\nMETHODS: We identified 11 patients from five consanguineous but unrelated families affected by ARCI. These patients manifested thick adherent polygonal large scales all over the body. All six patients with TGM1 mutations were born with collodion membrane and had ectropion and eclabium, while none of the patients with ABCA12 mutations had these features. Molecular investigations were performed using the combined approach of homozygosity mapping and Sanger sequencing.\nRESULTS: Here we report two novel mutations c.397_398insAGTATGAGTA (p.Tyr136Ter); c.977-978delCT (p.Ser326Cysfs*8) in TGM1 in three different, unrelated Saudi families and one novel mutation c.6900C>A (p.Phe2300Leu) and one reported mutation c.3470C>T (p.Ser1157Leu) in the ABCA12 gene in two unrelated Saudi families with ARCI.\nCONCLUSIONS: The identification of these homozygous variants using combined approaches of homozygosity mapping with direct sequencing are the disease causing mutations in these families. Furthermore, these findings are essential for the genetic diagnostic and prognostic workup with ARCI in Saudi patients.","variants":[{"Name":"NM_173076.3(ABCA12):c.3470C>T (p.Ser1157Leu)","Chromosome":"2","Start":"214990856","Stop":"214990856","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2894415,"rule_based_match":true,"evidence_text":"c.3470C>T (p.Ser1157Leu)","llm_judgment":"PRESENT","evidence":"c.3470C>T (p.Ser1157Leu)","abstract_start":1203,"abstract_end":1227}]}
{"pmid":"24635075","title":"Kindler syndrome with severe mucosal involvement in childhood.","abstract":"Kindler syndrome (KS) is an inherited dermatosis linked to the FERMT1 gene, and is characterized clinically by trauma-induced acral skin blisters in infancy and childhood, photosensitivity, and progressive poikiloderma. We report a case of KS in a 7-year-old Indian girl with severe mucosal involvement of the oral cavity and genitourinary tract. Mutation analysis in the girl showed a homozygous FERMT1 mutation, c.862C>T, p.R288*. The clinical manifestations in patients with KS show significant inter individual variation, even with the same type of mutations and within members of the same family. Our case highlights the role of environmental modifiers in regulating the clinical features of KS.","variants":[{"Name":"NM_017671.5(FERMT1):c.862C>T (p.Arg288Ter)","Chromosome":"20","Start":"6097619","Stop":"6097619","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17757,"rule_based_match":true,"evidence_text":"c.862C>T","llm_judgment":"PRESENT","evidence":"c.862C>T","abstract_start":414,"abstract_end":422}]}
{"pmid":"29237418","title":"A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients.","abstract":"BACKGROUND: Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2) are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive neurodegenerative disorder mainly characterized by diabetes mellitus, optic atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations in the CISD2 gene have been reported. Among these mutations, the homozygous c.103 + 1G > A substitution was identified in the donor splice site of intron 1 in two Italian sisters and was predicted to cause a exon 1 to be skipped.\nMETHODS: Here, we employed molecular assays to characterize the c.103 + 1G > A mutation using the patient's peripheral blood mononuclear cells (PBMCs). 5'-RACE coupled with RT-PCR were used to analyse the effect of the c.103 + 1G > A mutation on mRNA splicing. Western blot analysis was used to analyse the consequences of the CISD2 mutation on the encoded protein.\nRESULTS: We demonstrated that the c.103 + 1G > A mutation functionally impaired mRNA splicing, producing multiple splice variants characterized by the whole or partial absence of exon 1, which introduced amino acid changes and a premature stop. The affected mRNAs resulted in either predicted targets for nonsense mRNA decay (NMD) or non-functional isoforms.\nCONCLUSIONS: We concluded that the c.103 + 1G > A mutation resulted in the loss of functional CISD2 protein in the two Italian WFS2 patients.","variants":[{"Name":"NM_001008388.5(CISD2):c.103+1G>A","Chromosome":"4","Start":"102869188","Stop":"102869188","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":626087,"rule_based_match":true,"evidence_text":"c.103+1G>A","llm_judgment":"PRESENT","evidence":"c.103 + 1G > A","abstract_start":392,"abstract_end":406}]}
{"pmid":"16786513","title":"McArdle disease: the mutation spectrum of PYGM in a large Italian cohort.","abstract":"Deficiency of the muscle isozyme of glycogen phosphorylase is causative of McArdle disease or Glycogen storage disease type V (GSD-V), the most common autosomal recessive disorder of glycogen metabolism. The typical clinical presentation is characterized by exercise intolerance with cramps, and recurrent myoglobinuria. To date, 46 mutations in the PYGM gene have been detected in GSD-V patients. We report the mutational spectrum in 68 Italian patients. We identified 30 different mutations in the PYGM gene, including 19 mutations that have not been reported previously. The novel mutations include: eight missense mutations (c.475G>A, p.G159R; c.689C>G, p.P230R; c.1094C>T, p.A365E; c.1151C>A, p.A384D; c.1182C>T, p.R428C; c.1471C>T, p.R491C; c.2444A>C, p.D815A; c.2477G>C, p.W826S), two nonsense mutations (c.1475G>A, p.W492X; c.1627A>T, p.K543X), five splice site mutations (c.855 +1G>C; c.1092 +1G>A; c. 1093-1G>T; c.1239 +1G>A; c.2380 +1G>A), and four deletions (c.715_717delGTC, p.V239del; c.304delA, p.N102DfsX4; c.1970_2177del, p.V657_G726; c.2113_2114delGG, p.G705RfsX16). Whereas we confirmed lack of direct correlation between the clinical phenotype and the genotype, we also found that the so-called 'common mutation' (p.R50X) accounted for about 43% of alleles in our cohort and that no population-related mutations are clearly identified in Italian patients.","variants":[{"Name":"NM_005609.4(PYGM):c.1093-1G>T","Chromosome":"11","Start":"64754026","Stop":"64754026","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":546400,"rule_based_match":true,"evidence_text":"c. 1093-1G>T","llm_judgment":"PRESENT","evidence":"c. 1093-1G>T","abstract_start":908,"abstract_end":920},{"Name":"NM_005609.4(PYGM):c.1092+1G>A","Chromosome":"11","Start":"64754252","Stop":"64754252","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":358010,"rule_based_match":true,"evidence_text":"c.1092 +1G>A","llm_judgment":"PRESENT","evidence":"c.1092 +1G>A","abstract_start":894,"abstract_end":906},{"Name":"NM_005609.4(PYGM):c.1239+1G>A","Chromosome":"11","Start":"64753878","Stop":"64753878","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":565956,"rule_based_match":true,"evidence_text":"c.1239 +1G>A","llm_judgment":"PRESENT","evidence":"c.1239 +1G>A","abstract_start":922,"abstract_end":934},{"Name":"NM_005609.4(PYGM):c.475G>A (p.Gly159Arg)","Chromosome":"11","Start":"64758299","Stop":"64758299","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":546552,"rule_based_match":true,"evidence_text":"c.475G>A, p.G159R","llm_judgment":"PRESENT","evidence":"c.475G>A, p.G159R","abstract_start":629,"abstract_end":646}]}
{"pmid":"29782060","title":"Autosomal-dominant early-onset spastic paraparesis with brain calcification due to IFIH1 gain-of-function.","abstract":"We describe progressive spastic paraparesis in two male siblings and the daughter of one of these individuals. Onset of disease occurred within the first decade, with stiffness and gait difficulties. Brisk deep tendon reflexes and extensor plantar responses were present, in the absence of intellectual disability or dermatological manifestations. Cerebral imaging identified intracranial calcification in all symptomatic family members. A marked upregulation of interferon-stimulated gene transcripts was recorded in all three affected individuals and in two clinically unaffected relatives. A heterozygous IFIH1 c.2544T>G missense variant (p.Asp848Glu) segregated with interferon status. Although not highly conserved (CADD score 10.08 vs. MSC-CADD score of 19.33) and predicted as benign by in silico algorithms, this variant is not present on publically available databases of control alleles, and expression of the D848E construct in HEK293T cells indicated that it confers a gain-of-function. This report illustrates, for the first time, the occurrence of autosomal-dominant spastic paraplegia with intracranial calcifications due to an IFIH1-related type 1 interferonopathy.","variants":[{"Name":"NM_022168.4(IFIH1):c.2544T>G (p.Asp848Glu)","Chromosome":"2","Start":"162272298","Stop":"162272298","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":800766,"rule_based_match":true,"evidence_text":"IFIH1 c.2544T>G missense variant (p.Asp848Glu)","llm_judgment":"PRESENT","evidence":"IFIH1 c.2544T>G missense variant (p.Asp848Glu)","abstract_start":608,"abstract_end":654}]}
{"pmid":"19508970","title":"Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases.","abstract":"BACKGROUND: Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone. SLC35D1 (solute carrier-35D1) is a nucleotide-sugar transporter involved in proteoglycan synthesis. Recently, based on human and mouse genetic studies, we showed that loss-of-function mutations of the SLC35D1 gene (SLC35D1) cause SBD.\nOBJECT: To explore further the range of SLC35D1 mutations in SBD and elucidate whether SLC35D1 mutations cause other skeletal dysplasias that belong to the SSDD group.\nMETHODS AND RESULTS: We searched for SLC35D1 mutations in five families with SBD and 15 patients with other SSDD group diseases, including achodrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian type and fibrochondrogenesis. We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families. Exon trapping assay showed IVS4+3A>G caused skipping of exon 4 and a frameshift (p.L109fsX18). Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars. Therefore, all these mutations result in loss of function. No SLC35D1 mutations were identified in all patients with other SSDD group diseases.\nCONCLUSION: Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD.","variants":[{"Name":"NM_015139.3(SLC35D1):c.319C>T (p.Arg107Ter)","Chromosome":"1","Start":"67052776","Stop":"67052776","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16165,"rule_based_match":true,"evidence_text":"c.319C>T (p.R107X)","llm_judgment":"PRESENT","evidence":"c.319C>T (p.R107X)","abstract_start":999,"abstract_end":1017},{"Name":"NM_015139.3(SLC35D1):c.193A>C (p.Thr65Pro)","Chromosome":"1","Start":"67053821","Stop":"67053821","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":16168,"rule_based_match":true,"evidence_text":"c.193A>C (p. T65P)","llm_judgment":"PRESENT","evidence":"c.193A>C (p. T65P)","abstract_start":1098,"abstract_end":1116}]}
{"pmid":"33190430","title":"Lymphatic system malformations in Noonan syndrome: Two case reports and imaging analysis.","abstract":"L ymphedema is a well-known complication of Noonan syndrome (NS) but the lymphatic malformations in NS are poorly understood. We report clinical, genetic, and imaging information about a boy and girl with NS and late-onset lower extremity lymphedema. A de novo missense mutation of RIT1 (NM_006912.5) c.246T>A, p.Phe82Leu was identified in the girl, who also showed systemic lymphatic hyperplasia and dysfunction. Magnetic resonance lymphangiography (MRL) of the boy clearly demonstrated segmental dilated and hyperplastic lymphatics with impaired transport function in an affected limb and pelvic region. Indocyanine green lymphography (ICGL) showed delayed and partial enhancement of the lymph vessels in the affected limb but no lymph reflux was detected. No causative mutation was identified in the second case. Lymphoscintigraphy (LSG) failed to show lymph vessels in either of the children. Our study showed that MRL is a reliable and accurate test that can be used to demonstrate morpho-logical and functional defects of the lymphatic system. Moreover, ICGL is sufficiently sensitive to determine the functional condition of peripheral lymph vessels. The combined use of imaging modalities can give an accurate diagnosis of complex lymphatic system anomalies in NS and other syndromic diseases.","variants":[{"Name":"NM_006912.6(RIT1):c.246T>A (p.Phe82Leu)","Chromosome":"1","Start":"155904494","Stop":"155904494","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":354275,"rule_based_match":true,"evidence_text":"c.246T>A, p.Phe82Leu","llm_judgment":"PRESENT","evidence":"c.246T>A, p.Phe82Leu","abstract_start":301,"abstract_end":321}]}
{"pmid":"27135621","title":"Compound heterozygous mutations (p.T561M and c.2422delT) in the TPO gene associated with congenital hypothyroidism.","abstract":"BACKGROUND: The objective of the study was to determine the genetic basis of goitrous congenital hypothyroidism (GCH) in Chinese siblings.\nMETHODS: The proband and her younger brother with GCH were enrolled for molecular analysis of the dual oxidase 2 (DUOX2), dual oxidase maturation factor 2 (DUOXA2), and thyroid peroxidase (TPO) genes. Mutation screening was performed by Sanger sequencing the fragments amplified from genomic DNA. The detected mutations were verified among the close relatives of the patients and 105 controls. All participants underwent clinical examination and laboratory tests.\nRESULTS: Analysis of the TPO gene revealed two heterozygous mutations, the frameshift mutation c.2422delT in the exon14 of the TPO gene, that has been reported previously, and a novel missense mutation c.1682C>T (p.T561M) in the exon10 of the TPO gene. Nine family members of the patients were enrolled for mutation screening. The patients' parents and grandfathers harbored a single heterozygous mutation. The germline mutations from this family were consistent with an autosomal recessive inheritance pattern. No mutations in the DUOXA2 and DUOX2 genes were observed.\nCONCLUSIONS: The inactivating mutations (c.2422delT and p.T561M) in the TPO gene were identified in the Chinese siblings with GCH. The compound heterozygous mutations can cause GCH.","variants":[{"Name":"NM_001206744.2(TPO):c.1682C>T (p.Thr561Met)","Chromosome":"2","Start":"1487905","Stop":"1487905","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2898461,"rule_based_match":true,"evidence_text":"c.1682C>T (p.T561M)","llm_judgment":"PRESENT","evidence":"c.1682C>T (p.T561M)","abstract_start":805,"abstract_end":824}]}
{"pmid":"23234264","title":"Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.","abstract":"A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.","variants":[{"Name":"NM_000156.6(GAMT):c.577C>T (p.Gln193Ter)","Chromosome":"19","Start":"1397493","Stop":"1397493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2668800,"rule_based_match":true,"evidence_text":"c.577C > T","llm_judgment":"PRESENT","evidence":"c.577C > T","abstract_start":960,"abstract_end":970},{"Name":"NM_000156.6(GAMT):c.289C>T (p.Gln97Ter)","Chromosome":"19","Start":"1399831","Stop":"1399831","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1064665,"rule_based_match":true,"evidence_text":"c.289C > T","llm_judgment":"PRESENT","evidence":"c.289C > T","abstract_start":975,"abstract_end":985}]}
{"pmid":"20577007","title":"The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor.","abstract":"Homozygous mutations of the telomeric SMN1 gene lead to degeneration of motor neurons causing spinal muscular atrophy (SMA). A highly similar centromeric gene (SMN2) can only partially compensate for SMN1 deficiency. The c.859G>C variant in SMN2 has been recently reported as a positive disease modifier. We identified the variant in 10 unrelated chronic SMA patients with a wide spectrum of phenotypes ranging from type II patients who can only sit to adult walkers. Haplotype analysis strongly suggests that the variant originated from a common ancestor. Our results confirm that the c.859G>C variant is a milder SMN2 allele and predict a direct correlation between SMN activity and phenotypic severity.","variants":[{"Name":"NM_017411.4(SMN2):c.859G>C (p.Gly287Arg)","Chromosome":"5","Start":"70076545","Stop":"70076545","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":23001,"rule_based_match":true,"evidence_text":"c.859G>C","llm_judgment":"PRESENT","evidence":"c.859G>C","abstract_start":221,"abstract_end":229}]}
{"pmid":"24664876","title":"Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes.","abstract":"Disorders of cobalamin deficiency are a heterogeneous group of disorders with at least 19 autosomal recessive-associated genes. Familial samples of an infant who died due to presumed cobalamin deficiency were referred for clinical exome sequencing. The patient died before obtaining a blood sample or skin biopsy, autopsy was declined, and DNA yielded from the newborn screening blood spot was insufficient for diagnostic testing. Whole-exome sequencing of the mother, father, and unaffected sister and tailored bioinformatics analysis was applied to search for mutations in underlying disorders with recessive inheritance. This approach identified alterations within two genes, each of which was carried by one parent. The mother carried a missense alteration in the MTR gene (c.3518C>T; p.P1173L) which was absent in the father and the sister. The father carried a translational frameshift alteration in the LMBRD1 gene (c.1056delG; p.L352Lfs*18) which was absent in the mother and present in the heterozygous state in the sister. These mutations in the MTR (MIM# 156570) and LMBRD1 (MIM# 612625) genes have been described in patients with disorders of cobalamin metabolism complementation groups cblG and cblF, respectively. The child's clinical presentation and biochemical results demonstrated overlap with both cblG and cblF. Sanger sequencing using DNA from the infant's blood spot confirmed the inheritance of the two alterations in compound heterozygous form. We present the first example of exome sequencing leading to a diagnosis in the absence of the affected patient. Furthermore, the data support the possibility for potential digenic inheritance associated with cobalamin deficiency.","variants":[{"Name":"NM_018368.4(LMBRD1):c.1056del (p.Asn353fs)","Chromosome":"6","Start":"69701470","Stop":"69701470","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":226902,"rule_based_match":true,"evidence_text":"c.1056delG","llm_judgment":"PRESENT","evidence":"c.1056delG","abstract_start":923,"abstract_end":933}]}
{"pmid":"30210231","title":"Novel homozygous splicing mutations in","abstract":"Purpose: Mutations in <i>ARL2BP,</i> encoding ADP-ribosylation factor-like 2 binding protein, have recently been implicated as a cause of autosomal recessive retinitis pigmentosa (arRP), with three homozygous variants identified to date. In this study, we performed next-generation sequencing to reveal additional arRP cases associated with <i>ARL2BP</i> variants.\nMethods: Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in 1,051 unrelated individuals recruited for the UK Inherited Retinal Disease Consortium and NIHR-BioResource Rare Diseases research studies. Sanger sequencing was used to validate the next-generation sequencing data, and reverse transcriptase (RT)-PCR analysis was performed on RNA extracted from blood from affected individuals to test for altered splicing of <i>ARL2BP</i>. Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography.\nResults: Homozygous variants in <i>ARL2BP</i> (NM_012106.3) were identified in two unrelated individuals with RP. The variants, c.207+1G>A and c.390+5G>A, at conserved splice donor sites for intron 3 and intron 5, respectively, were predicted to alter the pre-mRNA splicing of <i>ARL2BP</i>. RT-PCR spanning the affected introns revealed that both variants caused abnormal splicing of <i>ARL2BP</i> in samples from affected individuals.\nConclusions: This study identified two homozygous variants in <i>ARL2BP</i> as a rare cause of arRP. Further studies are required to define the underlying disease mechanism causing retinal degeneration as a result of mutations in <i>ARL2BP</i> and any phenotype-genotype correlation associated with residual levels of the wild-type transcript.","variants":[{"Name":"NM_012106.4(ARL2BP):c.207+1G>A","Chromosome":"16","Start":"57248644","Stop":"57248644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":431790,"rule_based_match":true,"evidence_text":"c.207+1G>A","llm_judgment":"PRESENT","evidence":"c.207+1G>A","abstract_start":1146,"abstract_end":1156}]}
{"pmid":"29339498","title":"","abstract":"The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing <i>MAFA</i> variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense <i>MAFA</i> mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic <i>MAFA</i> mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense <i>MAFA</i> mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe <i>MAFA</i> missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.","variants":[{"Name":"NM_201589.4(MAFA):c.191C>T (p.Ser64Phe)","Chromosome":"8","Start":"143430216","Stop":"143430216","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":488127,"rule_based_match":true,"evidence_text":"c.191C>T (p.Ser64Phe)","llm_judgment":"PRESENT","evidence":"p.Ser64Phe","abstract_start":585,"abstract_end":595}]}
{"pmid":"26078401","title":"A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.","abstract":"OBJECTIVE: To identify the underlying genetic cause in a consanguineous Chinese family segregating distal hereditary motor neuropathy (dHMN) in an autosomal recessive pattern.\nMETHODS: We used whole-exome sequencing and homozygosity mapping to detect the genetic variant in 2 affected individuals of the consanguineous Chinese family with dHMN. RNA analysis of peripheral blood leukocytes and immunofluorescence and immunoblotting of stable cell lines were performed to support the pathogenicity of the identified mutation.\nRESULTS: We identified 3 shared novel homozygous variants in 3 shared homozygous regions of the affected individuals. Sequencing of these 3 variants in family members revealed the c.151+1G>T mutation in SIGMAR1 gene, which located in homozygous region spanning approximately 5.3 Mb at chromosome 9p13.1-p13.3, segregated with the dHMN phenotype. The mutation causes an alternative splicing event and generates a transcript variant with an in-frame deletion of 60 base pairs in exon 1 (c.92_151del), and results in an internally shortened protein σ1R(31_50del). The proteasomal inhibitor treatment increased the intracellular amount of σ1R(31_50del) and led to the formation of nuclear aggregates. Stable expressing σ1R(31_50del) induced endoplasmic reticulum stress and enhanced apoptosis.\nCONCLUSION: The homozygous c.151+1G>T mutation in SIGMAR1 caused a novel form of autosomal recessive dHMN in a Chinese consanguineous family. Endoplasmic reticulum stress may have a role in the pathogenesis of dHMN.","variants":[{"Name":"NM_005866.4(SIGMAR1):c.151+1G>T","Chromosome":"9","Start":"34637546","Stop":"34637546","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":204390,"rule_based_match":true,"evidence_text":"c.151+1G>T","llm_judgment":"PRESENT","evidence":"c.151+1G>T","abstract_start":704,"abstract_end":714}]}
{"pmid":"26484845","title":"The Frequency of c.550delA Mutation of the CANP3 Gene in the Polish LGMD2A Population.","abstract":"BACKGROUND: Limb girdle muscular dystrophy 2A (LGMD2A) is the most frequent LGMD variant in the European population, representing about 40% of LGMD. The c.550delA mutation in the CANP3 (calcium activated neutral protease 3) gene is the most commonly reported mutation in LGMD2A. Prevalence of this mutation in the Polish population has not been previously investigated. The aim of this study was to identify and estimate the frequency of the c.550delA mutation in Polish LGMD2A patients.\nMETHODS: Polymerase chain reaction-sequencing analysis, restriction fragment length polymorphism polymerase chain reaction method.\nRESULTS: We analyzed 76 families affected with LGMD and identified 62 probands with mutations in the CANP3 gene. C.550delA was the most common mutation identified, being found in 78% of the LGMD2A families. The remaining mutations observed multiple times were as follows: c.598-612del15ntd; c.2242C>T; c.418dupC; c.1356insT, listed in terms of decreasing frequency. Two novel variants in the CANP3 gene, that is, c.700G>A Gly234Arg and c.661G>A Gly221Ser were also characterized. Overall, mutations in the LGMD2A gene were estimated to be present in 81% of patients with the LGMD phenotype who were without sarcoglycans and dysferlin deficiency on immunocytochemical analysis. The frequency of the heterozygous c.550delA mutation in the healthy Polish population was estimated at 1/124.\nCONCLUSIONS: The c.550delA is the most frequent CANP3 mutation in the Polish population, thus sequencing of exon 4 of this gene could identify the majority of LGMD2A patients in Poland.","variants":[{"Name":"NM_000070.3(CAPN3):c.550del (p.Thr184fs)","Chromosome":"15","Start":"42387803","Stop":"42387803","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":32660,"rule_based_match":true,"evidence_text":"c.550delA","llm_judgment":"PRESENT","evidence":"c.550delA","abstract_start":153,"abstract_end":162},{"Name":"NM_000070.3(CAPN3):c.661G>A (p.Gly221Ser)","Chromosome":"15","Start":"42388956","Stop":"42388956","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1446263,"rule_based_match":true,"evidence_text":"c.661G>A Gly221Ser","llm_judgment":"PRESENT","evidence":"c.661G>A Gly221Ser","abstract_start":1055,"abstract_end":1073}]}
{"pmid":"25900864","title":"Early onset ectopia lentis due to a FBN1 mutation with non-penetrance.","abstract":"Isolated ectopia lentis is usually autosomal dominant and commonly due to the mutations of FBN1 gene. We report on a family with ectopia lentis. The propositus is a 6-year-old boy with bilateral superior-temporal ectopia lentis. His echocardiogram was normal and he did not meet the revised Ghent criteria for Marfan syndrome. Molecular genetic testing revealed c.1948 C>T (p.Arg650Cys) in FBN1. The mother has visual acuity of 20/20 with -4.50 right eye and -2.50 left eye. She has no evidence of ectopia lentis. DNA analysis revealed that she has the same FBN1 mutation. Seven other maternal family members also have ectopia lentis. In conclusion, we report on a case of early-onset autosomal dominant isolated ectopia lentis caused by FBN1 mutation that has previously been reported only in Marfan syndrome. The child's mother presumably represents a rare case of nonpenetrance.","variants":[{"Name":"NM_000138.5(FBN1):c.1948C>T (p.Arg650Cys)","Chromosome":"15","Start":"48505037","Stop":"48505037","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44706,"rule_based_match":true,"evidence_text":"c.1948 C>T (p.Arg650Cys)","llm_judgment":"PRESENT","evidence":"c.1948 C>T (p.Arg650Cys)","abstract_start":362,"abstract_end":386}]}
{"pmid":"33794876","title":"De novo ATP1A2 variants in two Chinese children with alternating hemiplegia of childhood upgraded the gene-disease relationship and variant classification: a case report.","abstract":"BACKGROUND: ATP1A2 gene mutation has been indicated to cause alternating hemiplegia of childhood (AHC); however, limited evidence supports this relationship so far.\nCASE PRESENTATION: We reported two Chinese patients with de novo ATP1A2 variants (c.970G>A and c.889G>A). Both patients presented with episodes of alternating hemiplegia, seizures and mild developmental delay. Brain magnetic resonance imaging revealed abnormal signals in both patients.\nCONCLUSIONS: The new genetic evidence we reported here strengthened the gene-disease relationship, and the gene curation level between ATP1A2 and AHC became \"Moderate\" following the ClinGen Standard Operation Procedure. Consequently, the two variants can be reclassified as likely pathogenic.","variants":[{"Name":"NM_000702.4(ATP1A2):c.970G>A (p.Gly324Ser)","Chromosome":"1","Start":"160127773","Stop":"160127773","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":626996,"rule_based_match":true,"evidence_text":"c.970G>A","llm_judgment":"PRESENT","evidence":"c.970G>A","abstract_start":247,"abstract_end":255}]}
{"pmid":"30039904","title":"A genome-wide analysis of colorectal cancer in a child with Noonan syndrome.","abstract":"Noonan syndrome (NS) is a developmental syndrome caused by germline mutations in the Ras signaling pathway. No association has been shown between NS and pediatric colorectal cancer (CRC). We report the case of CRC in a pediatric patient with NS. The patient underwent whole genome sequencing. A germline SOS1 mutation c.1310T>C (p. Ile437Thr) confirmed NS diagnosis. No known hereditary cancer syndromes were identified. Tumor analysis revealed two mutations: a TP53 missense mutation c.481G>A (p. Ala161Tyr) and NCOR1 nonsense mutation c.6052C>T (p. Arg2018*). This report highlights the complexity of Ras signaling and the interplay between developmental syndromes and cancer.","variants":[{"Name":"NM_005633.4(SOS1):c.1310T>C (p.Ile437Thr)","Chromosome":"2","Start":"39023118","Stop":"39023118","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":54512,"rule_based_match":true,"evidence_text":"c.1310T>C (p. Ile437Thr)","llm_judgment":"PRESENT","evidence":"c.1310T>C (p. Ile437Thr)","abstract_start":318,"abstract_end":342}]}
{"pmid":"28649543","title":"Tyrosinemia type III in an asymptomatic girl.","abstract":"Tyrosinemia type 3 (HT3) is a rare inborn error of tyrosine metabolism caused by mutations in the <i>HPD</i> gene encoding 4-hydroxyphenyl-pyruvate dioxygenase, which is transmitted in an autosomal recessive trait. The disorder is characterized by tyrosine accumulation in body fluids and massive excretion of tyrosine derivatives into urine (www.orpha.net). Since it is the least frequent form of tyrosinemia, only few cases with the variable but rather mild clinical features have been described so far. We report an 11 year old girl presenting with no clinical symptoms and with normal mental development who has been diagnosed with HT3 through metabolic screening on the basis of elevated serum level of tyrosine ranging from 425 to 535 μmol/L (normal values: 29-86 μmol/L), and elevated urinary excretion of p-hydroxyphenyl derivatives confirmed genetically with the homozygous c.479A > G (p.Tyr160Cys) missense change in the <i>HPD</i> gene. The girl has been only presenting with recurrent proteinuria of unknown etiology. A phenylalanine- and tyrosine-restricted diet has never been administered. Presented case may suggest that high tyrosine concentration itself does not participate directly in neuronal damage described in patients with tyrosinemia type 3.","variants":[{"Name":"NM_002150.3(HPD):c.479A>G (p.Tyr160Cys)","Chromosome":"12","Start":"121849726","Stop":"121849726","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":16612,"rule_based_match":true,"evidence_text":"c.479A > G (p.Tyr160Cys)","llm_judgment":"PRESENT","evidence":"c.479A > G (p.Tyr160Cys)","abstract_start":883,"abstract_end":907}]}
{"pmid":"21242547","title":"Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene.","abstract":"OBJECTIVE: To identify the genetic etiology in a family with autosomal dominant progressive sensorineural hearing loss.\nDESIGN: Prospective molecular genetic research study.\nSETTING: Academic genetic research laboratory.\nPARTICIPANTS: Seventeen members of a family with dominant progressive nonsyndromic sensorineural hearing loss: 9 affected, 6 unaffected, and 2 spouses.\nINTERVENTIONS: Clinical data from questionnaires, interviews, serial audiograms, and medical records; genetic data from genome-wide linkage analysis and candidate gene mutation analysis.\nMAIN OUTCOME MEASURES: Symptoms, age at onset, serial audiometric data, and the presence or absence of a deafness-associated mutation.\nRESULTS: Affected individuals in this family presented with autosomal dominant nonsyndromic high-frequency progressive sensorineural hearing loss, with age at onset ranging from 1 to 21 years. Genome-wide linkage analysis of single-nucleotide polymorphisms yielded evidence of linkage to an 18.9-Mb region on chromosome 1p34-p36, with a multipoint logarithm of odds score of 3.6. This interval contains a known deafness gene, KCNQ4, which underlies DNFA2 deafness. Sequencing of the 14 coding exons and intron-exon junctions of KCNQ4 revealed a novel heterozygous missense mutation, c.859G>C, p.Gly287Arg. The mutation disrupts the highly conserved GYG motif (glycine-tyrosine-glycine) of the phosphate-binding loop, hypothesized to be critical in maintaining pore structure and function. All 274 controls were negative for the mutation.\nCONCLUSIONS: Autosomal dominant high-frequency hearing loss is genetically heterogeneous, and linkage analysis is an efficient means of identifying the etiology in larger families. Deafness in this family is caused by a novel mutation in KCNQ4.","variants":[{"Name":"NM_004700.4(KCNQ4):c.859G>C (p.Gly287Arg)","Chromosome":"1","Start":"40819899","Stop":"40819899","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":166117,"rule_based_match":true,"evidence_text":"c.859G>C, p.Gly287Arg","llm_judgment":"PRESENT","evidence":"c.859G>C, p.Gly287Arg","abstract_start":1278,"abstract_end":1299}]}
{"pmid":"33358637","title":"Status dystonicus associated with CLN8 disease.","abstract":"BACKGROUND: Status dystonicus is an underdiagnosed condition, probably due to heterogeneous etiology, presentation and course. Herein, we report the first case of CLN8 disease in the literature presenting with status dystonicus who responded well to pharmacological intervention.\nCASE: A boy aged five years and three months presented with fever, loss of appetite, intermittent excessive dystonic contractions, opisthotonus with retrocollis, and irritability for three days. His developmental milestones were reported as normal up to the age of three years and six months. At this age, he developed seizures, ataxia, and vision problems. Deterioration in developmental milestones was observed from the age of four. Laboratory tests demonstrated leukocytosis, abnormal renal function, mild metabolic acidosis, elevated creatine kinase and transaminase levels. The brain magnetic resonance imaging demonstrated cerebral and cerebellar atrophy. Homozygous missense mutation of c.709G > A (p.G237R) in the CLN8 gene was revealed. With all these clinical and laboratory findings, he was diagnosed with status dystonicus associated with CLN8 disease. Antibiotherapy, anticonvulsant drugs, and intravenous hydration with alkaline fluids were initiated. Due to irregular breathing, dysphagia, and worsening of dystonic contractions, mechanical ventilation was performed, and baclofen, haloperidol, midazolam infusion and chloral hydrate were administered, respectively. Finally, serum creatine kinase levels decreased, and dystonic contractions improved on the 15th day of hospitalization.\nCONCLUSION: To the best of our knowledge, our case is the first report describing the status dystonicus in a patient with CLN8 disease. Our report suggested that neuronal ceroid lipofuscinoses should be kept in mind in the etiology of status dystonicus.","variants":[{"Name":"NM_018941.4(CLN8):c.709G>A (p.Gly237Arg)","Chromosome":"8","Start":"1780415","Stop":"1780415","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186761,"rule_based_match":true,"evidence_text":"Homozygous missense mutation of c.709G > A (p.G237R) in the CLN8 gene","llm_judgment":"PRESENT","evidence":"Homozygous missense mutation of c.709G > A (p.G237R) in the CLN8 gene","abstract_start":942,"abstract_end":1011}]}
{"pmid":"19568825","title":"Type II sialidosis: review of the clinical spectrum and identification of a new splicing defect with chitotriosidase assessment in two patients.","abstract":"Sialidosis is a lysosomal storage disease caused by the deficiency of alpha-N-acetyl neuraminidase-1 (NEU1). Sialidosis is classified into two main clinical variants: Type I, the milder form of the disease, and Type II, which can in turn be subdivided into three forms: congenital, infantile and juvenile. We report herein the clinical, biochemical and molecular characterisation of two patients with Type II sialidosis exhibiting the congenital (P1) and infantile forms (P2). We also review clinical data on the rare Type II forms of sialidosis in the hope of improving understanding of the disorder and facilitating its diagnosis. The genetic characterization of the two patients showed one known [c. 679G > A (p.G227R)] NEU1 missense mutation (detected in P2), and the new c.807 + 1G > A splicing defect (detected in P1), a genetic lesion that is extremely rare in this disease. Interestingly, P2 presented an extremely elevated level of chitotriosidase in plasma. This is the first pathological detection of chitotriosidase in sialidosis patients.","variants":[{"Name":"NM_000434.4(NEU1):c.679G>A (p.Gly227Arg)","Chromosome":"6","Start":"31860558","Stop":"31860558","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":421583,"rule_based_match":true,"evidence_text":"c. 679G > A (p.G227R)","llm_judgment":"PRESENT","evidence":"c. 679G > A (p.G227R)","abstract_start":700,"abstract_end":721}]}
{"pmid":"32758448","title":"Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease.","abstract":"The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10<sup>-6</sup> and p = 3.6 × 10<sup>-5</sup>, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10<sup>-10</sup>. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.","variants":[{"Name":"NM_000250.2(MPO):c.1705C>T (p.Arg569Trp)","Chromosome":"17","Start":"58272835","Stop":"58272835","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18665,"rule_based_match":true,"evidence_text":"c.1705C>T (p.Arg569Trp)","llm_judgment":"PRESENT","evidence":"c.1705C>T (p.Arg569Trp)","abstract_start":959,"abstract_end":982},{"Name":"NM_000250.2(MPO):c.2031-2A>C","Chromosome":"17","Start":"58270865","Stop":"58270865","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18671,"rule_based_match":true,"evidence_text":"c.2031-2A>C","llm_judgment":"PRESENT","evidence":"c.2031-2A>C","abstract_start":479,"abstract_end":490}]}
{"pmid":"36078153","title":"","abstract":"Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) <i>ACTN2</i> gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this <i>ACTN2</i> variant, which may contribute to human <i>ACTN2</i>-associated cardiomyopathies.","variants":[{"Name":"NM_001103.4(ACTN2):c.740C>T (p.Thr247Met)","Chromosome":"1","Start":"236735677","Stop":"236735677","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":823617,"rule_based_match":true,"evidence_text":"c.740C>T","llm_judgment":"PRESENT","evidence":"c.740C>T","abstract_start":143,"abstract_end":151}]}
{"pmid":"32052416","title":"New missense variants in RELT causing hypomineralised amelogenesis imperfecta.","abstract":"Amelogenesis imperfecta (AI) is a heterogeneous group of genetic diseases characterised by dental enamel malformation. Pathogenic variants in at least 33 genes cause syndromic or non-syndromic AI. Recently variants in RELT, encoding an orphan receptor in the tumour necrosis factor (TNF) superfamily, were found to cause recessive AI, as part of a syndrome encompassing small stature and severe childhood infections. Here we describe four additional families with autosomal recessive hypomineralised AI due to previously unreported homozygous mutations in RELT. Three families carried a homozygous missense variant in the fourth exon (c.164C>T, p.(T55I)) and a fourth family carried a homozygous missense variant in the 11th exon (c.1264C>T, p.(R422W)). We found no evidence of additional syndromic symptoms in affected individuals. Analyses of tooth microstructure with computerised tomography and scanning electron microscopy suggest a role for RELT in ameloblasts' coordination and interaction with the enamel matrix. Microsatellite genotyping in families segregating the T55I variant reveals a shared founder haplotype. These findings extend the RELT pathogenic variant spectrum, reveal a founder mutation in the UK Pakistani population and provide detailed analysis of human teeth affected by this hypomineralised phenotype, but do not support a possible syndromic presentation in all those with RELT-variant associated AI.","variants":[{"Name":"NM_152222.2(RELT):c.164C>T (p.Thr55Ile)","Chromosome":"11","Start":"73390798","Stop":"73390798","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":682209,"rule_based_match":true,"evidence_text":"c.164C>T, p.(T55I)","llm_judgment":"PRESENT","evidence":"c.164C>T, p.(T55I)","abstract_start":635,"abstract_end":653},{"Name":"NM_152222.2(RELT):c.1264C>T (p.Arg422Trp)","Chromosome":"11","Start":"73395462","Stop":"73395462","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":682210,"rule_based_match":true,"evidence_text":"c.1264C>T, p.(R422W)","llm_judgment":"PRESENT","evidence":"c.1264C>T, p.(R422W)","abstract_start":731,"abstract_end":751}]}
{"pmid":"19513315","title":"A double mutation of the ryanodine receptor type 1 gene in a malignant hyperthermia family with multiminicore myopathy.","abstract":"BACKGROUND AND PURPOSE: At least 100 Ryanodine receptor type 1 (RYR1) mutations associated with malignant hyperthermia (MH) and central core disease (CCD) have been identified, but 2 RYR1 mutations accompanying multiminicore myopathy in an MH and/or CCD family have been reported only rarely.\nMETHODS: Fifty-three members of a large MH family were investigated with clinical, histopathologic, RYR1 mutation, and haplotyping studies. Blood creatine kinase (CK) and myoglobin levels were also measured where possible.\nRESULTS: Sequencing of the entire RYR1 coding region identified a double RYR1 mutation (R2435H and A4295V) in MH/CCD regions 2 and 3. Haplotyping analysis revealed that the two missense heterozygous mutations (c.7304G>A and c.12891C>T) were always present on a common haplotype allele, and were closely cosegregated with histological multiminicores and elevated serum CK. All the subjects with the double mutation showed elevated serum CK and myoglobin, and the obtained muscle biopsy samples showed multiminicore lesions, but only two family members presented a late-onset, slowly progressive myopathy.\nCONCLUSIONS: We found multiminicore myopathy with clinical and histological variability in a large MH family with an unusual double RYR1 mutation, including a typical CCD-causing known mutant. These results suggest that multiminicore lesions are associated with the presence of more than two mutations in the RYR1 gene.","variants":[{"Name":"NM_000540.3(RYR1):c.7304G>A (p.Arg2435His)","Chromosome":"19","Start":"38499997","Stop":"38499997","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28005,"rule_based_match":true,"evidence_text":"c.7304G>A","llm_judgment":"PRESENT","evidence":"c.7304G>A","abstract_start":726,"abstract_end":735}]}
{"pmid":"22716240","title":"WTX R353X mutation in a family with osteopathia striata and cranial sclerosis (OS-CS): case report and literature review of the disease clinical, genetic and radiological features.","abstract":"Osteopathia striata with cranial sclerosis (OS-CS) or Horan-Beighton syndrome is a rare X-linked dominant inherited bone dysplasia, characterized by longitudinal striations of long bones and cranial sclerosis. Patients can be asymptomatic or present with typical facial dysmorphism, sensory defects, internal organs anomalies, growth and mental retardation, depending on the severity of the disease. WTX gene (Xq11) has been recently identified as the disease causing gene. Aim of this article is to present the case of a 6 year old girl initially evaluated for bilateral hearing loss. Patient's head CT scan pointed out sclerosis of skull base and mastoid cells, and abnormal middle-ear ossification. Clinical examination of the patient and her mother were suspicious for OS-CS. The diagnosis was confirmed by X-rays examination showing typical longitudinal striation. Genetic analysis allowed the identification of maternally transmitted heterozygous nonsense c.1057C>T (p.R353X) WTX gene mutation. We also provide a systematic review of currently available knowledge about clinical, radiologic and genetic features typical of the OS-CS.","variants":[{"Name":"NM_152424.4(AMER1):c.1057C>T (p.Arg353Ter)","Chromosome":"X","Start":"64192230","Stop":"64192230","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25746,"rule_based_match":true,"evidence_text":"c.1057C>T (p.R353X)","llm_judgment":"PRESENT","evidence":"c.1057C>T (p.R353X)","abstract_start":962,"abstract_end":981}]}
{"pmid":"31729143","title":"Clinical and neurocognitive issues associated with Bosch-Boonstra-Schaaf optic atrophy syndrome: A case study.","abstract":"Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced nonverbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities.","variants":[{"Name":"NM_005654.6(NR2F1):c.82C>T (p.Gln28Ter)","Chromosome":"5","Start":"93585105","Stop":"93585105","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1036550,"rule_based_match":true,"evidence_text":"NM_005654.5:c.82C > T, p.Gln28*","llm_judgment":"PRESENT","evidence":"NM_005654.5:c.82C > T, p.Gln28*","abstract_start":532,"abstract_end":563}]}
{"pmid":"31718331","title":"Description of a rare β-globin gene mutation, IVS-II-848 (C>A) (","abstract":"β-Thalassemia (β-thal) is a hereditary and heterogeneous group of disorders caused by mutations on the β-globin gene that result in the reduced or non production of β-globin chains. We report a rare β-globin mutation, IVS-II-848 (C>A) (<i>HBB</i>: c.316-3C>A), which was found in a female Syrian patient. This mutation was associated with the IVS-I-1 (G>A) (<i>HBB</i>: c.92+1G>A) mutation, and the genotype is a compound heterozygote for IVS-I-1(G>A)/IVS-II-848(C>A). This combination was found for the first time in Syria.","variants":[{"Name":"NM_000518.5(HBB):c.316-3C>A","Chromosome":"11","Start":"5225729","Stop":"5225729","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":30490,"rule_based_match":true,"evidence_text":"c.316-3C>A","llm_judgment":"PRESENT","evidence":"c.316-3C>A","abstract_start":248,"abstract_end":258},{"Name":"NM_000518.5(HBB):c.92+1G>A","Chromosome":"11","Start":"5226929","Stop":"5226929","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30475,"rule_based_match":true,"evidence_text":"c.92+1G>A","llm_judgment":"PRESENT","evidence":"c.92+1G>A","abstract_start":370,"abstract_end":379}]}
{"pmid":"31086307","title":"Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease.","abstract":"PURPOSE: To characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date.\nMETHODS: Patients aged ≥1 year with confirmed Pompe disease previously receiving 160 L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments.\nRESULTS: Of 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n = 23), c.-32-13T>G (n = 13), and c.525delT (n = 12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean ± SD, median, range): overall 46.3 ± 33.0% (47.9%, 0.0-100.0%), IOPD 41.6 ± 31.64% (38.9%, 0.0-99.7%), LOPD: 61.8 ± 33.2 (70.9%, 0.0-100.0%).\nCONCLUSION: ADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.","variants":[{"Name":"NM_000152.5(GAA):c.525del (p.Glu176fs)","Chromosome":"17","Start":"80105111","Stop":"80105111","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":19072,"rule_based_match":true,"evidence_text":"c.525delT","llm_judgment":"PRESENT","evidence":"c.525delT","abstract_start":943,"abstract_end":952},{"Name":"NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)","Chromosome":"17","Start":"80118271","Stop":"80118271","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19073,"rule_based_match":true,"evidence_text":"c.2560C>T","llm_judgment":"PRESENT","evidence":"c.2560C>T","abstract_start":897,"abstract_end":906},{"Name":"NM_000152.5(GAA):c.-32-13T>G","Chromosome":"17","Start":"80104542","Stop":"80104542","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":19066,"rule_based_match":true,"evidence_text":"c.-32-13T>G","llm_judgment":"PRESENT","evidence":"c.-32-13T>G","abstract_start":917,"abstract_end":928}]}
{"pmid":"31392188","title":"Variable clinical features and genotype-phenotype correlations in 18 patients with late-onset Pompe disease.","abstract":"BACKGROUND: Pompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alpha-glucosidase (<i>GAA</i>) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement.\nMETHODS: We report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years' duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies.\nRESULTS: Genetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves' disease and testicular cancer.\nCONCLUSIONS: Our study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.","variants":[{"Name":"NM_000152.5(GAA):c.1594G>A (p.Gly532Ser)","Chromosome":"17","Start":"80110983","Stop":"80110983","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":646895,"rule_based_match":true,"evidence_text":"c.1594G>A","llm_judgment":"PRESENT","evidence":"c.1594G>A","abstract_start":1248,"abstract_end":1257}]}
{"pmid":"28228639","title":"GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.","abstract":"N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1 mutations (c.1858 G>A and c.1858 G>C; both p.G620R). Both individuals presented at birth with developmental delay and hypotonia associated with behavioral abnormalities and stereotypical movements. Recombinant NMDARs containing the mutant GluN1-G620R together with either GluN2A or GluN2B were evaluated for changes in their trafficking to the plasma membrane and their electrophysiological properties. GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg<sup>2+</sup> block, and a significant reduction of current responses to a maximal effective concentration of agonists. GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface associated with similarly altered electrophysiology. These results indicate these individuals may have suffered neurodevelopmental deficits as a result of the decreased presence of GluN1-G620R/GluN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of GluN1-G620R-containing NMDARs after birth. These cases emphasize the importance of comprehensive functional characterization of de novo mutations and illustrates how a combination of several distinct features of NMDAR expression, trafficking and function can be present and influence phenotype.","variants":[{"Name":"NM_007327.4(GRIN1):c.1858G>C (p.Gly620Arg)","Chromosome":"9","Start":"137162510","Stop":"137162510","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":205760,"rule_based_match":true,"evidence_text":"c.1858 G>C","llm_judgment":"PRESENT","evidence":"c.1858 G>C","abstract_start":196,"abstract_end":206},{"Name":"NM_007327.4(GRIN1):c.1858G>A (p.Gly620Arg)","Chromosome":"9","Start":"137162510","Stop":"137162510","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":480559,"rule_based_match":true,"evidence_text":"c.1858 G>A","llm_judgment":"PRESENT","evidence":"c.1858 G>A","abstract_start":181,"abstract_end":191}]}
{"pmid":"23929434","title":"The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins.","abstract":"BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germ line mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with 11 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 [west Castilla y León (WCL)], 20 [east Castilla y León (ECL)] and 6 (South of Spain) families. Mutation age was estimated with the Disequilibrium Mapping using Likelihood Estimation software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G > A, were located in a double-hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923 bp fragment of BRCA2, and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G > A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin loop of c.2808_2811del, and one affected the same position (c.2808A > G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG, BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin loops, suggesting that these structures may represent mutational hotspots.","variants":[{"Name":"NM_000059.3(BRCA2):c.2808_2811del (p.Ala938Profs)","Chromosome":"13","Start":"32337161","Stop":"32337164","ReferenceAlleleVCF":"TAAAC","AlternateAlleleVCF":"T","allel_id":24361,"rule_based_match":true,"evidence_text":"BRCA2-c.2808_2811del (3036delACAA)","llm_judgment":"PRESENT","evidence":"BRCA2-c.2808_2811del (3036delACAA)","abstract_start":0,"abstract_end":34}]}
{"pmid":"23430499","title":"β-Galactosidosis in Patient with Intermediate GM1 and MBD Phenotype.","abstract":"A 5-year-old girl with clinical and biochemical phenotypes encompassing both GM1-gangliosidosis (GM1) and Morquio B disease (MBD) is described. Mild generalized skeletal dysplasia and keratan sulfaturia were consistent with a diagnosis of MBD, while developmental delay and GM1-specific oligosacchariduria were consistent with GM1 gangliosidosis. No observable β-galactosidase activity was detected in leukocytes, and two mutations, p.R201H (c.602G>A) and p.G311R (c.931G>A), were identified by gene sequencing. The R201H substitution has been previously reported in patients with both GM1 and MBD, and G311R is a novel mutation. Our patient represents a further example of the clinical heterogeneity that can result from mutations at the β-galactosidase locus.","variants":[{"Name":"NM_000404.4(GLB1):c.931G>A (p.Gly311Arg)","Chromosome":"3","Start":"33051782","Stop":"33051782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":827904,"rule_based_match":true,"evidence_text":"c.931G>A","llm_judgment":"PRESENT","evidence":"c.931G>A","abstract_start":465,"abstract_end":473},{"Name":"NM_000404.4(GLB1):c.602G>A (p.Arg201His)","Chromosome":"3","Start":"33058220","Stop":"33058220","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":195238,"rule_based_match":true,"evidence_text":"c.602G>A","llm_judgment":"PRESENT","evidence":"c.602G>A","abstract_start":442,"abstract_end":450}]}
{"pmid":"35784482","title":"Myosin Heavy Chain Converter Domain Mutations Drive Early-Stage Changes in Extracellular Matrix Dynamics in Hypertrophic Cardiomyopathy.","abstract":"More than 60% of hypertrophic cardiomyopathy (HCM)-causing mutations are found in the gene loci encoding cardiac myosin-associated proteins including myosin heavy chain (MHC) and myosin binding protein C (MyBP-C). Moreover, patients with more than one independent HCM mutation may be at increased risk for more severe disease expression and adverse outcomes. However detailed mechanistic understanding, especially at early stages of disease progression, is limited. To identify early-stage HCM triggers, we generated single (<i>MYH7 c.2167C > T</i> [R723C] with a known pathogenic significance in the MHC converter domain) and double (<i>MYH7 c.2167C > T</i> [R723C]; <i>MYH6 c.2173C > T</i> [R725C] with unknown significance) myosin gene mutations in human induced pluripotent stem cells (hiPSCs) using a base-editing strategy. Cardiomyocytes (CMs) derived from hiPSCs with either single or double mutation exhibited phenotypic characteristics consistent with later-stage HCM including hypertrophy, multinucleation, altered calcium handling, metabolism, and arrhythmia. We then probed mutant CMs at time points prior to the detection of known HCM characteristics. We found <i>MYH7/MYH6</i> dual mutation dysregulated extracellular matrix (ECM) remodeling, altered integrin expression, and interrupted cell-ECM adhesion by limiting the formation of focal adhesions. These results point to a new phenotypic feature of early-stage HCM and reveal novel therapeutic avenues aimed to delay or prohibit disease onset.","variants":[{"Name":"NM_000257.4(MYH7):c.2167C>T (p.Arg723Cys)","Chromosome":"14","Start":"23425814","Stop":"23425814","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29134,"rule_based_match":true,"evidence_text":"MYH7 c.2167C > T [R723C]","llm_judgment":"PRESENT","evidence":"MYH7 c.2167C > T</i> [R723C]","abstract_start":528,"abstract_end":556}]}
{"pmid":"32228492","title":"Post-mortem histology in transient receptor potential cation channel subfamily V member 6 (TRPV6) under-mineralising skeletal dysplasia suggests postnatal skeletal recovery: a case report.","abstract":"BACKGROUND: The calcium-selective channel TRPV6 (transient receptor potential cation channel subfamily V member 6) is crucial for maternal-fetal calcium transport across the placenta. TRPV6 mutations have recently been associated with an antenatally severe under-mineralising skeletal dysplasia accompanied by postnatal biochemical abnormalities. This is the first post-mortem report in a patient with TRPV6 skeletal dysplasia.\nCASE PRESENTATION: The female infant had severe antenatal and postnatal skeletal abnormalities by 20 weeks gestation and was ventilator-dependent from birth. These skeletal abnormalities were apparent at an earlier gestational age than in previous reported cases and a more severe clinical course ensued. Biochemical and skeletal abnormalities, including bone density, improved postnatally but cardiac arrest at 4 months of age led to withdrawal of intensive care. Compound heterozygous TRPV6 variants (c.1978G > C p.(Gly660Arg) and c.1528C > T p.(Arg510Ter)) were identified on exome sequencing. Post-mortem identified skeletal abnormalities but no specific abnormalities in other organ systems. No placental pathology was found, multi-organ histological features reflected prolonged intensive care only. Post-mortem macroscopic examination indicated reduced thoracic size and short, pale and pliable ribs. Histological examination identified reduced number of trabeculae in the diaphyses (away from the growth plates), whereas metaphyses showed adequate mineralisation and normal number of trabeculae, but with slightly enlarged reactive chondrocytes, indicating post-natal skeletal growth recovery. Post-mortem radiological findings demonstrated improved bone density, improved rib width, healed fractures, although ribs were still shorter than normal. Long bones (especially humerus and femur) had improved from initial poorly defined metaphyses and reduced bone density to sharply defined metaphyses, prominent growth restart lines in distal diaphyses and bone-in-bone appearance along diaphyses.\nCONCLUSIONS: This case provide bone histological confirmation that human skeletal development is compromised in the presence of TRPV6 pathogenic variants. Post-mortem findings were consistent with abnormal in utero skeletal mineralisation due to severe calcium deficit from compromised placental calcium transfer, followed by subsequent phenotypic improvement with adequate postnatal calcium availability. Significant skeletal recovery occurs in the early weeks of postnatal life in TRPV6 skeletal dysplasia.","variants":[{"Name":"NM_018646.6(TRPV6):c.1978G>C (p.Gly660Arg)","Chromosome":"7","Start":"142872409","Stop":"142872409","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":806433,"rule_based_match":true,"evidence_text":"c.1978G > C p.(Gly660Arg)","llm_judgment":"PRESENT","evidence":"c.1978G > C p.(Gly660Arg)","abstract_start":931,"abstract_end":956}]}
{"pmid":"23438842","title":"Exome sequencing is a useful diagnostic tool for complicated forms of hereditary spastic paraplegia.","abstract":"Hereditary spastic paraplegias constitute a heterogeneous group of neurodegenerative diseases encompassing pure and complicated forms, for which at least 52 loci and 31 causative genes have been identified. Although mutations in the SPAST gene explain approximately 40% of the pure autosomal dominant forms, molecular diagnosis can be challenging for the sporadic and recessive forms, which are often complicated and clinically overlap with a broad number of movement disorders. The validity of exome sequencing as a routine diagnostic approach in the movement disorder clinic needs to be assessed. The main goal of this study was to explore the usefulness of an exome analysis for the diagnosis of a complicated form of spastic paraplegia. Whole-exome sequencing was performed in two Spanish siblings with a neurodegenerative syndrome including upper and lower motor neuron, ocular and cerebellar signs. Exome sequencing revealed that both patients carry a novel homozygous nonsense mutation in exon 15 of the SPG11 gene (c.2678G>A; p.W893X), which was not found in 584 Spanish control chromosomes. After many years of follow-up and multiple time-consuming genetic testing, we were able to diagnose these patients by making use of whole-exome sequencing, showing that this is a cost-efficient diagnostic tool for the movement disorder specialist.","variants":[{"Name":"NM_025137.4(SPG11):c.2678G>A (p.Trp893Ter)","Chromosome":"15","Start":"44620346","Stop":"44620346","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1458246,"rule_based_match":true,"evidence_text":"c.2678G>A (p.W893X)","llm_judgment":"PRESENT","evidence":"c.2678G>A","abstract_start":1023,"abstract_end":1032}]}
{"pmid":"19251976","title":"Novel mutations in patients with McArdle disease by analysis of skeletal muscle mRNA.","abstract":"OBJECTIVE: To identify pathogenic mutant alleles of the PYGM gene in \"genetic manifesting heterozygous\" patients with McArdle disease-that is, those in whom we could only find a sole mutant allele by genomic DNA analysis.\nMETHODS: We studied four unrelated patients. PCR-RFLP, gene sequencing, and muscle cDNA analysis were performed to search for mutations in the PYGM gene. The effects of the mutations were evaluated by in silico analysis, and gene expression was assessed by real-time polymerase chain reaction (PCR).\nRESULTS: Patient 1 was a compound heterozygous for the p.G205S missense mutation and for a novel \"in frame\" mutation, p.Q176_M177insVQ, resulting from a retention of six nucleotides from the 3'-end sequence of intron 4. Patient 2 was heterozygous for the common nonsense mutation p.R50X, and for a 1094 bp, c.1969+214_2177+369del mutation, spanning from intron 16 to intron 17 sequences. Furthermore, mRNA expression level was dramatically reduced consistent with nonsense mediated decay. Patient 3 was heterozygous for the p.R50X substitution, and patient 4 was heterozygous for the relatively common private Spanish mutation p.W798R. These two patients harboured a heterozygous exonic synonymous variant, p.K215K. Quantification of gene transcripts in patient 3 revealed a drastic decrease in the relative expression of the gene, which strongly supports the possibility of nonsense mediated decay.\nCONCLUSIONS: Our results indicate that skeletal muscle cDNA studies in \"genetic manifesting heterozygous\" patients with McArdle disease are prone to identify their second mutant allele.","variants":[{"Name":"NM_005609.4(PYGM):c.613G>A (p.Gly205Ser)","Chromosome":"11","Start":"64757826","Stop":"64757826","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17338,"rule_based_match":false,"evidence_text":"p.G205S","llm_judgment":"PRESENT","evidence":"p.G205S","abstract_start":577,"abstract_end":584}]}
{"pmid":"28050600","title":"Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in","abstract":"Variants in <i>NDUFB11,</i> which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in <i>NDUFB11</i> (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in <i>HCCS</i> (which encodes an important mitochondrially targeted protein) and <i>COX7B,</i> which, like <i>NDUFB11,</i> encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that <i>NDUFB11</i> variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related).","variants":[{"Name":"NM_001135998.3(NDUFB11):c.262C>T (p.Arg88Ter)","Chromosome":"X","Start":"47142690","Stop":"47142690","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188131,"rule_based_match":true,"evidence_text":"c.262C > T; p.[Arg88*]","llm_judgment":"PRESENT","evidence":"c.262C > T; p.[Arg88*]","abstract_start":418,"abstract_end":440}]}
{"pmid":"31840929","title":"Renpenning syndrome in a female.","abstract":"Renpenning syndrome (OMIM: 309500) is a rare X-linked disorder that causes intellectual disability, microcephaly, short stature, a variety of eye anomalies, and characteristic craniofacial features. This condition results from pathogenic variation of PQBP1, a polyglutamine-binding protein involved in transcription and pre-mRNA splicing. Renpenning syndrome has only been reported in affected males. Carrier females do not usually have clinical features, and in reported families with Renpenning syndrome, most female carriers exhibit favorable skewing of X-chromosome inactivation. We describe a female with syndromic features typical of Renpenning syndrome. She was identified by exome sequencing to have a de novo heterozygous c.459_462delAGAG mutation in PQBP1 (Xp11.23), affecting the AG hexamer in exon 4, which is the most common causative mutation in this syndrome. Streaky hypopigmentation of the skin was observed, supporting a hypothesized presence of an actively expressed, PQBP1 mutation-bearing X-chromosome in some cells. X-inactivation studies on peripheral blood cells demonstrated complete skewing in both the proband and her mother with preferential inactivation of the maternal X chromosome in the child. We demonstrated expression of the PQBP1 mutant transcript in leukocytes of the affected girl. Therefore, it is highly likely that the PQBP1 mutation arose from the paternal X chromosome.","variants":[{"Name":"NM_001032382.2(PQBP1):c.459_462del (p.Arg153fs)","Chromosome":"X","Start":"48902391","Stop":"48902394","ReferenceAlleleVCF":"CAGAG","AlternateAlleleVCF":"C","allel_id":26019,"rule_based_match":true,"evidence_text":"c.459_462delAGAG","llm_judgment":"PRESENT","evidence":"c.459_462delAGAG","abstract_start":731,"abstract_end":747}]}
{"pmid":"37619988","title":"Compound heterozygous variants in RAB34 in a rare skeletal ciliopathy syndrome.","abstract":"Skeletal ciliopathies are a heterogenous group of congenital disorders characterized by multiple internal abnormalities, and distinct radiographic presentation. Pathogenic variants in at least 30 cilia genes are known to cause skeletal ciliopathies. Here we report a fetus with an atypical skeletal ciliopathy phenotype and compound heterozygous variants in the RAB34 gene. The affected fetus had multiple malformations, including posterior neck edema, micrognathia, low-set and small ears, auricular hypoplasia, cleft lip and palate, short extremities, and a combination of rarely occurring pre- and postaxial polydactyly. Genome sequencing identified compound heterozygous variants in the RAB34 gene: maternal c.254T>C, p.(Ile85Thr), and paternal c.691C>T, p.(Arg231*) variants. Only the paternal variant was present in the unaffected sibling. Evidence in the literature indicated that Rab34<sup>-/-</sup> mice displayed a ciliopathy phenotype with cleft palate and polydactyly. These features were consistent with malformations detected in our patient supporting the pathogenicity of the identified RAB34 variants. Overall, this case report further expands genetic landscape of human ciliopathy syndromes and suggests RAB34 as a candidate gene for skeletal ciliopathies.","variants":[{"Name":"NM_031934.6(RAB34):c.254T>C (p.Ile85Thr)","Chromosome":"17","Start":"28715860","Stop":"28715860","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2671947,"rule_based_match":true,"evidence_text":"c.254T>C, p.(Ile85Thr)","llm_judgment":"PRESENT","evidence":"c.254T>C, p.(Ile85Thr)","abstract_start":712,"abstract_end":734},{"Name":"NM_031934.6(RAB34):c.691C>T (p.Arg231Ter)","Chromosome":"17","Start":"28714814","Stop":"28714814","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2671948,"rule_based_match":true,"evidence_text":"c.691C>T, p.(Arg231*)","llm_judgment":"PRESENT","evidence":"c.691C>T, p.(Arg231*)","abstract_start":749,"abstract_end":770}]}
{"pmid":"25352739","title":"Severe retinal degeneration in women with a c.2543del mutation in ORF15 of the RPGR gene.","abstract":"PURPOSE: To describe the genotype-phenotype correlation and serial observations in a five-generation Czech family with X-linked retinitis pigmentosa (XLRP) associated with severe visual impairment in women.\nMETHODS: Comprehensive ophthalmological examination including spectral domain optical coherence tomography (SD-OCT) was performed. Based on the pedigree structure and women being severely affected, autosomal dominant inheritance was suspected, and screening for known mutations by genotyping microarray was performed. Subsequently, direct sequencing of ORF15 RPGR was undertaken.\nRESULTS: Eighteen family members (nine women and nine men) were examined. A pathogenic variant, c.2543del in ORF15 of RPGR, was found to segregate with disease. The oldest woman and her two sisters had no perception of light in their sixth decade. Four women and five men had signs and symptoms of typical XLRP, including moderate to high myopia. Three other women also had moderate to high myopia and myopic astigmatism but without the presence of bone spicule-like formation. Severe disruption of macular architecture on SD-OCT was equally common in both sexes. Only one 32-year-old female carrier had clinically normal findings. Subfoveal choroidal thickness was decreased in all affected men and in all female carriers, except the only carrier with a normal fundus examination.\nCONCLUSIONS: The c.2543del mutation in ORF15 of RPGR is associated with a severe phenotype in the women in this family. The presence of a significant myopic refractive error, in the absence of male-to-male transmission, may be indicative of X-linked inheritance. Measurements of choroidal thickness may help in clinically identifying carrier status.","variants":[{"Name":"NM_001034853.2(RPGR):c.2543del (p.Glu848fs)","Chromosome":"X","Start":"38286456","Stop":"38286456","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":857007,"rule_based_match":true,"evidence_text":"c.2543del","llm_judgment":"PRESENT","evidence":"c.2543del","abstract_start":683,"abstract_end":692}]}
{"pmid":"36175619","title":"Mutation of the proline P81 into a serine modifies the tumour suppressor function of the von Hippel-Lindau gene in the ccRCC.","abstract":"BACKGROUND: The von Hippel-Lindau disease is an autosomal dominant syndrome associated with tumour formation in various tissues, such as retina, central nervous system, kidney, and adrenal glands. VHL gene deletion or mutations support the development of various cancers. Unclassified VHL variants also referred as \"of unknown significance\" result from gene mutations that have an unknown or unclear effect on protein functions. The P81S mutation has been linked to low penetrance Type 1 disease but its pathogenic function was not clearly determined.\nMETHODS: We established a stable cell line expressing the pVHL<sub>213</sub> (c.241C>T, P81S) mutant. Using biochemical and physiological approaches, we herein analysed pVHL folding, stability and function in the context of this VHL single missense mutation.\nRESULTS: The P81S mutation mostly affects the non-canonical function of the pVHL protein. The cells expressing the pVHL<sub>213</sub>P81S acquire invasive properties in relation with modified architecture network.\nCONCLUSION: We demonstrated the pathogenic role of this mutation in tumour development in vhl patients and confirm a medical follow up of family carrying the c.241C>T, P81S.","variants":[{"Name":"NM_000551.4(VHL):c.241C>T (p.Pro81Ser)","Chromosome":"3","Start":"10142088","Stop":"10142088","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17272,"rule_based_match":true,"evidence_text":"c.241C>T","llm_judgment":"PRESENT","evidence":"c.241C>T","abstract_start":630,"abstract_end":638}]}
{"pmid":"31834604","title":"Thirteen novel CLCNKB variants and genotype/phenotype association study in 42 Chinese patients with Bartter syndrome type 3.","abstract":"PURPOSE: Analyze the genotype of 42 Chinese patients with Bartter syndrome type 3 (BS3) and investigate their correlation between genotype and phenotype.\nMETHODS: Identify CLCNKB gene variants by the next-generation sequencing and the multiplex ligation-dependent probe amplification (MLPA), and then evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines.\nRESULTS: Thirty-six different variants in CLCNKB gene, including 13 novel ones, were found. The whole gene deletion of CLCNKB gene was the most frequent mutation (40%), and the rate of large deletions is up to 55%. Among 36 variants, six (c.1244T>A, c.1468G>A, c.849_851delCTT, c.359G>T, c.1052G>T, and c.1309G>A) and three (c.228A>C, c.1294_1295TA>CT, and c.1333T>G) variants were classified as \"likely pathogenic variants\" and \"variants with uncertain significance (VUS),\" respectively. The other 27 variants were classified as \"pathogenic variants\". The most common symptoms included: growth retardation (38/42), polydipsia and polyuria (35/42), constipation (31/42), and vomiting (27/42). All patients presented with hypokalemia, hypochloremia, and metabolic alkalosis. The genotype and phenotype association study revealed that who had mutations probably resulting in complete loss of function of both alleles might have severer phenotype. After the treatment that based on indomethacin and potassium chloride, most patients could achieve obvious recovery of growth rate and restoration of hypokalemia.\nCONCLUSIONS: The present study have found 36 variants of CLCNKB gene, including 13 novel ones, which enrich the human gene mutation database and provide valuable references to diagnosis, treatment, and the genetic counseling of Chinese population.","variants":[{"Name":"NM_000085.5(CLCNKB):c.1309G>A (p.Gly437Arg)","Chromosome":"1","Start":"16051721","Stop":"16051721","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":789869,"rule_based_match":true,"evidence_text":"c.1309G>A","llm_judgment":"PRESENT","evidence":"c.1309G>A","abstract_start":737,"abstract_end":746}]}
{"pmid":"20567907","title":"Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications.","abstract":"Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), caused by mutated ACADM gene, is a potentially fatal fatty acid oxidation defect. Detection of MCADD is now part of tandem mass spectrometry (MS-MS)-based newborn screening programs worldwide. To date, more than 67 mutations have been reported to cause MCADD with a single allele, c.985A>G, being the most common in patients of northwestern European descent. In Saudi Arabia, the Newborn Screening Program, officially launched in 2005, screens for 16 disorders including MCADD. Over a period of 3 years, 237,812 newborns were screened; 13 were identified to have MCADD giving an incidence of 1:18,293. Since the introduction of MS-MS to our institution, however, a total of 30 patients were detected to have MCADD. These cases were either newborns, at high-risk family members, or clinically suspected. The C8-carnitine levels (median 3.31, range 0.81-16.33 µM) were clearly diagnostic in all analyzed samples. Sequencing ACADM in 20 DBS revealed two novel mutations: c.362C>T (p.T121I) and c.347G>A (p.C116Y) substitutions, neither of which were detected in 300 chromosomes from controls. Eighteen (90%) patients were homozygous for the T121I mutation and two (10%) were compound heterozygous (T121I/C116Y). Our molecular data lend further support to MS-MS biochemical screening for MCADD and provide evidence for the relatively high incidence of MCADD in the Arab population. The identification of a founder mutation for MCADD has important implications for the preventive screening programs not only in Saudi Arabia but potentially also in other countries in the region.","variants":[{"Name":"NM_000016.6(ACADM):c.347G>A (p.Cys116Tyr)","Chromosome":"1","Start":"75733588","Stop":"75733588","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227873,"rule_based_match":true,"evidence_text":"c.347G>A (p.C116Y)","llm_judgment":"PRESENT","evidence":"c.347G>A (p.C116Y)","abstract_start":1047,"abstract_end":1065},{"Name":"NM_000016.6(ACADM):c.362C>T (p.Thr121Ile)","Chromosome":"1","Start":"75733603","Stop":"75733603","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18638,"rule_based_match":true,"evidence_text":"c.362C>T (p.T121I)","llm_judgment":"PRESENT","evidence":"c.362C>T (p.T121I)","abstract_start":1024,"abstract_end":1042}]}
{"pmid":"21057703","title":"Impact of pharmacokinetic (CYP2C9) and pharmacodynamic (VKORC1, F7, GGCX, CALU, EPHX1) gene variants on the initiation and maintenance phases of phenprocoumon therapy.","abstract":"Compared to warfarin, little is known about the effect of pharmacogenomics on the inter-individual variability of phenprocoumon therapy. In a retrospective cohort study, we investigated the impact of VKORC1 c.-1639G>A; CYP2C9*2 , CYP2C9*3 ; GGCX c.214+597G>A; CALU c.*4A>G; EPHX1 c.337T>C; F7 c.-402G>A, and F7 c.-401G>T on the initiation (n=54) and maintenance phases (n=91) of phenprocoumon therapy. We assessed the following outcome parameters: time to stable international normalised ratio (INR), time to first supra-therapeutic INR, time out of INR range, probability of over-anticoagulation, number of anticoagulation clinic visits. During the initiation phase, homozygotes for the VKORC1 c.-1639 A and G alleles achieved stable INRs later (p<0.001), spent more time at supra-therapeutic INRs (p<0.001), had increased risks of over-anticoagulation (odds ratio 19.83, p=0.003 and 4.45, p=0.045, respectively), and had higher frequencies of anticoagulation clinic visits (p<0.001) compared to GA carriers. CYP2C9*2, *3 carriers reached stable INRs faster (p=0.024) with fewer anticoagulation clinic visits (p=0.001) than wild-type carriers. EPHX1 c.337 C carrier spent significantly more time above range in the initiation phase (p=0.023). GGCX , CALU , and F7 gene variants did not affect outcome parameters of the initiation phase and none of the genotypes had an impact on maintenance phase parameters. Compared to the VKORC1 genotype, early INR values were less informative in the prediction of outcome parameters such as time to stable INR and time above the INR range. Our study is limited by the retrospective study design with no standardised protocol in a usual care setting. Therefore, our findings should be validated in a larger, controlled prospective study.","variants":[{"Name":"NM_024006.4(VKORC1):c.-1639G>A","Chromosome":"16","Start":"31096368","Stop":"31096368","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17250,"rule_based_match":true,"evidence_text":"VKORC1 c.-1639G>A","llm_judgment":"PRESENT","evidence":"VKORC1 c.-1639G>A","abstract_start":200,"abstract_end":217}]}
{"pmid":"26917049","title":"Mutation analysis of the phospholamban gene in 315 South Africans with dilated, hypertrophic, peripartum and arrhythmogenic right ventricular cardiomyopathies.","abstract":"Cardiomyopathy is an important cause of heart failure in Sub-Saharan Africa, accounting for up to 30% of adult heart failure hospitalisations. This high prevalence poses a challenge in societies without access to resources and interventions essential for disease management. Over 80 genes have been implicated as a cause of cardiomyopathy. Mutations in the phospholamban (PLN) gene are associated with dilated cardiomyopathy (DCM) and severe heart failure. In Africa, the prevalence of PLN mutations in cardiomyopathy patients is unknown. Our aim was to screen 315 patients with arrhythmogenic right ventricular cardiomyopathy (n = 111), DCM (n = 95), hypertrophic cardiomyopathy (n = 40) and peripartum cardiomyopathy (n = 69) for disease-causing PLN mutations by high resolution melt analysis and DNA sequencing. We detected the previously reported PLN c.25C > T (p.R9C) mutation in a South African family with severe autosomal dominant DCM. Haplotype analysis revealed that this mutation occurred against a different haplotype background to that of the original North American family and was therefore unlikely to have been inherited from a common ancestor. No other mutations in PLN were detected (mutation prevalence = 0.2%). We conclude that PLN is a rare cause of cardiomyopathy in African patients. The PLN p.R9C mutation is not well-tolerated, emphasising the importance of this gene in cardiac function.","variants":[{"Name":"NM_002667.5(PLN):c.25C>T (p.Arg9Cys)","Chromosome":"6","Start":"118558946","Stop":"118558946","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28675,"rule_based_match":true,"evidence_text":"PLN c.25C > T (p.R9C)","llm_judgment":"PRESENT","evidence":"PLN c.25C > T (p.R9C)","abstract_start":851,"abstract_end":872}]}
{"pmid":"38253347","title":"Neuronal ceroid lipofuscinosis type 11 diagnosed patient with bi-allelic variants in","abstract":"OBJECTIVES: Neuronal ceroid lipofuscinosis type 11 (NCL11) is a rare disease that presents with progressive cognitive decline, epilepsy, visual impairment, retinal atrophy, cerebellar ataxia and cerebellar atrophy. We present herein a case of NCL11 in a patient diagnosed with neuromotor developmental delay, epilepsy, bronchiolitis obliterans and hypothyroidism.\nCASE PRESENTATION: A 4-year-old male patient was admitted to our clinic with global developmental delay and a medical history that included recurrent hospitalizations for pneumonia at the age of 17 days, and in months 4, 5 and 7. Family history revealed a brother with similar clinical findings (recurrent pneumonia, hypothyroidism, hypotonicity, swallowing dysfunction and neuromotor delay) who died from pneumonia at the age of 22 months. Computed tomography of the thorax was consistent with bronchiolitis obliterans, while epileptic discharges were identified on electroencephalogram with a high incidence of bilateral fronto-centro-temporal and generalized spike-wave activity but no photoparoxysmal response. Cranial MRI revealed T2 hyperintense areas in the occipital periventricular white matter and volume loss in the white matter, a thin corpus callosum and vermis atrophy. A whole-exome sequencing molecular analysis revealed compound heterozygous c.430G>A (p.Asp144Asn) and c.415T>C (p.Cys139Arg) variants in the GRN gene.\nCONCLUSIONS: The presented case indicates that NCL11 should be taken into account in patients with epilepsy and neurodegenerative diseases.","variants":[{"Name":"NM_002087.4(GRN):c.415T>C (p.Cys139Arg)","Chromosome":"17","Start":"44350293","Stop":"44350293","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":580336,"rule_based_match":true,"evidence_text":"c.415T>C (p.Cys139Arg)","llm_judgment":"PRESENT","evidence":"c.415T>C (p.Cys139Arg)","abstract_start":1350,"abstract_end":1372}]}
{"pmid":"26743058","title":"The natural history of elevated tetradecenoyl-L-carnitine detected by newborn screening in New Zealand: implications for very long chain acyl-CoA dehydrogenase deficiency screening and treatment.","abstract":"Very long chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM #201475) has been increasingly diagnosed since the advent of expanded newborn screening (NBS). Elevated levels of tetradecenoyl-L-carnitine (C14:1) in newborn screening blood spot samples are particularly common in New Zealand, however this has not translated into increased VLCADD clinical presentations. A high proportion of screen-positive cases in NZ are of Maori or Pacific ethnicity and positive for the c.1226C > T (p.Thr409Met) ACADVL gene variant. We performed a retrospective, blinded, case-control study of 255 cases, born between 2006 and 2013, with elevated NBS C14:1 levels between 0.9 and 2.4 μmol/L, below the NZ C14:1 notification cut-off of 2.5 μmol/L. Coded healthcare records were audited for cases and age- and ethnicity- matched controls. The clinical records of those with possible VLCADD-related symptoms were reviewed. The follow-up period was 6 months to 7 years. Two of 247 cases (0.8 %) had possible VLCADD-like symptoms while four of 247 controls (2 %) had VLCADD-like symptoms (p = 0.81). Maori were overrepresented (68 % of the cohort vs 15 % of population). Targeted analysis of the c.1226 locus revealed the local increase in screening C14:1 levels is associated with the c.1226C > T variant (97/152 alleles tested), found predominantly in Maori and Pacific people. There was no increase in clinically significant childhood disease, irrespective of ethnicity. The study suggests that children with elevated C14:1, between 0.9-2.4 μmol/L, on NBS are at very low risk of clinically significant childhood disease. A minimally interventional approach to managing these patients is indicated, at least in the New Zealand population.","variants":[{"Name":"NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met)","Chromosome":"17","Start":"7223687","Stop":"7223687","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33865,"rule_based_match":true,"evidence_text":"c.1226C > T (p.Thr409Met)","llm_judgment":"PRESENT","evidence":"c.1226C > T (p.Thr409Met)","abstract_start":474,"abstract_end":499}]}
{"pmid":"33768492","title":"ETV6-related thrombocytopenia associated with a transient decrease in von Willebrand factor.","abstract":"ETV6-related thrombocytopenia is an autosomal dominant thrombocytopenia, characterized by a bleeding tendency and predisposition to hematological malignancies. The similarity in symptoms makes differentiating immune and congenital thrombocytopenia challenging. We report a 5-year-old girl who presented with chronic thrombocytopenia associated with repetitive and long-lasting epistaxis, leading to blood transfusion for severe anemia. Blood tests showed thrombocytopenia (52 × 10<sup>3</sup>/µL) with normal-sized platelets and transiently low von Willebrand factor (VWF) levels (VWF:RCo 13%, VWF:Ag 50%); therefore, von Willebrand disease type 2 was initially suspected. Repetition of the blood tests revealed normal levels of VWF. Exome and Sanger sequencing identified a germline ETV6 heterozygous variant, c.641C > T:p.(P214L). No additional pathogenic variants were found, including VWF, in the gene panel testing of the 53 known target causative genes for thrombocytopenia. High-throughput exome sequencing for chronic thrombocytopenia can be utilized to differentially diagnose ETV6-related thrombocytopenia from chronic/intractable immune thrombocytopenia and to effectively monitor malignancy.","variants":[{"Name":"NM_001987.5(ETV6):c.641C>T (p.Pro214Leu)","Chromosome":"12","Start":"11869601","Stop":"11869601","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171928,"rule_based_match":true,"evidence_text":"c.641C > T:p.(P214L)","llm_judgment":"PRESENT","evidence":"c.641C > T:p.(P214L)","abstract_start":811,"abstract_end":831}]}
{"pmid":"17666473","title":"Role of a founder c.201_202delCT mutation and new phenotypic features of congenital lipoid adrenal hyperplasia in Palestinians.","abstract":"CONTEXT: Congenital lipoid adrenal hyperplasia (CLAH), caused by mutations in steroidogenic acute regulatory protein (StAR), is most frequent in Japanese and Palestinians. We report eight Palestinians from four unrelated families with CLAH.\nOBJECTIVE: The objective of the study was to identify the mutation(s) in StAR, correlate genotype with phenotype, and determine whether the common mutation represents a founder mutation.\nPATIENTS AND SETTING: Clinical, histopathological, and molecular genetic characterization was performed in these eight patients.\nRESULTS: All affected individuals (three XY, five XX) presented neonatally with undetectable adrenocortical hormones and are responding to replacement therapy. Only two sisters had neurodevelopmental deficits. Histopathological findings of excised XY gonads included accumulation of fat in Leydig cells. Significantly, already at 1 yr of age, positive placental alkaline phosphatase and octamer binding transcription factor staining indicated neoplastic potential. Sequence analysis of StAR revealed homozygosity for c.201_202delCT mutation in all eight cases, causing premature termination of the StAR protein. This mutation was confirmed to be a founder mutation using both an intragenic microsatellite and several single nucleotide polymorphism markers. Screening of 100 normal Jerusalem Palestinians detected no carriers of this mutation.\nCONCLUSION: CLAH is rare in the general Palestinian population. In most Palestinian cases, a founder c.201_202delCT mutation in StAR is the cause. The observed early neonatal presentation may reflect the major StAR protein truncation caused by this mutation. A crucial role for StAR in the central nervous system was not supported with normal neurological examinations in six of eight cases. Finally, we advocate early gonadectomy in XY CLAH cases, given the early onset of neoplastic changes observed histologically.","variants":[{"Name":"NM_000349.3(STAR):c.201_202del (p.Tyr68fs)","Chromosome":"8","Start":"38148304","Stop":"38148305","ReferenceAlleleVCF":"TAG","AlternateAlleleVCF":"T","allel_id":577060,"rule_based_match":true,"evidence_text":"c.201_202delCT","llm_judgment":"PRESENT","evidence":"c.201_202delCT","abstract_start":1074,"abstract_end":1088}]}
{"pmid":"34162028","title":"Molecular and clinical findings of Turkish patients with hereditary fructose intolerance.","abstract":"OBJECTIVES: Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a deficiency in aldolase B that can result in hypoglycemia, nausea, vomiting, abdominal pain, liver and kidney dysfunction, coma, and even death. This study aims to represent the clinical features and molecular genetic analysis data of the patients diagnosed with HFI in our study population.\nMETHODS: The medical records of the 26 patients with HFI were evaluated retrospectively. Age, gender, clinical findings, metabolic crises, and the results of molecular analyses were recorded.\nRESULTS: The patients with HFI had a good prognosis and the aversion to sugar-containing foods was the main complaint. Seven different variants were identified in the Aldolase B (<i>ALDOB</i>) gene in HFI patients. The most frequent mutations were p.Ala150Pro, p.Ala175Asp had a prevalence of 61 and 30%, respectively, in agreement with the literature and other known variants were found with minor frequencies c.360-363del4(3.8%), p.Asn335Lys(3.8%), and three novel mutations c.113-1_15del4 (3.8%), p.Ala338Val(7.6%), and p.Asp156His(3.8%) were identified at a heterozygous, homozygous, or compound heterozygous level.\nCONCLUSIONS: This study results revealed three novel mutations in patients with HFI. On the basis of age of presentation, clinical symptoms, and metabolic crisis, there was no clear-cut genotype-phenotype correlation. This article also demonstrates the importance of screening suspected infants in cases of acute liver failure for prompt diagnosis and treatment of HFI.","variants":[{"Name":"NM_000035.4(ALDOB):c.1013C>T (p.Ala338Val)","Chromosome":"9","Start":"101421891","Stop":"101421891","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186775,"rule_based_match":false,"evidence_text":"p.Ala338Val(7.6%)","llm_judgment":"PRESENT","evidence":"p.Ala338Val(7.6%)","abstract_start":1080,"abstract_end":1097}]}
{"pmid":"34711244","title":"Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis.","abstract":"Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in the MEN1 gene. The variant (c.654C > A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we found a likely pathogenic variant in the MLH1 gene (c.27G > A), and two risk factor variants in the genes CHEK2 and HOXB13. The MLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of the MLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without any findings. We conclude that, in individuals with an unequivocal clinical diagnosis of a specific hereditary cancer syndrome, where standard clinical testing failed to detect a causative variant, re-analysis may lead to a diagnosis.","variants":[{"Name":"NM_000249.4(MLH1):c.27G>A (p.Arg9=)","Chromosome":"3","Start":"36993574","Stop":"36993574","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":182217,"rule_based_match":true,"evidence_text":"c.27G > A","llm_judgment":"PRESENT","evidence":"c.27G > A","abstract_start":940,"abstract_end":949}]}
{"pmid":"24427140","title":"First description of phosphofructokinase deficiency in spain: identification of a novel homozygous missense mutation in the PFKM gene.","abstract":"Phosphofructokinase deficiency is a very rare autosomal recessive disorder, which belongs to group of rare inborn errors of metabolism called glycogen storage disease. Here we report on a new mutation in the phosphofructokinase (PFK) gene PFKM identified in a 65-years-old woman who suffered from lifelong intermittent muscle weakness and painful spasms of random occurrence, episodic dark urines, and slight haemolytic anemia. After ruling out the most common causes of chronic haemolytic anemia, the study of a panel of 24 enzyme activities showed a markedly decreased PFK activity in red blood cells (RBCs) from the patient. DNA sequence analysis of the PFKM gene subsequently revealed a novel homozygous mutation: c.926A>G; p.Asp309Gly. This mutation is predicted to severely affect enzyme catalysis thereby accounting for the observed enzyme deficiency. This case represents a prime example of classical PFK deficiency and is the first reported case of this very rare red blood cell disorder in Spain.","variants":[{"Name":"NM_000289.6(PFKM):c.926A>G (p.Asp309Gly)","Chromosome":"12","Start":"48135373","Stop":"48135373","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1704278,"rule_based_match":true,"evidence_text":"c.926A>G; p.Asp309Gly","llm_judgment":"PRESENT","evidence":"c.926A>G; p.Asp309Gly","abstract_start":718,"abstract_end":739}]}
{"pmid":"28808495","title":"The most frequent ABCA3 nonsense mutation -p.Tyr1515* (Y1515X) causing lethal neonatal respiratory failure in a term neonate.","abstract":"Defects in the surfactant biosynthesis are associated with respiratory distress syndrome, commonly occurring in premature infants due to lung immaturity. However, interstitial lung diseases have also been observed in full-term infants with mutations in the SFTPC, SFTPB, NKX2-1, or ABCA3 genes, involved in the surfactant metabolism. Herein, we report a newborn baby with neonatal respiratory distress and diffuse lung disease caused by ABCA3 mutation. The baby died at 5 weeks of age after developing pulmonary hypertension. Genomic DNA was analyzed for four genes involved in surfactant metabolism out of which the c. 4545C>G (p.Tyr1515*) homozygous mutation in exon 29 of ABCA3 was identified which is one of the most frequent mutation causing lethal neonatal respiratory failure in a term neonate. This case study emphasizes the importance of raising awareness about this diagnosis in the clinical settings for fruitful outcomes in health-care delivery.","variants":[{"Name":"NM_001089.3(ABCA3):c.4545C>G (p.Tyr1515Ter)","Chromosome":"16","Start":"2278945","Stop":"2278945","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":980956,"rule_based_match":true,"evidence_text":"c. 4545C>G (p.Tyr1515*)","llm_judgment":"PRESENT","evidence":"c. 4545C>G (p.Tyr1515*)","abstract_start":617,"abstract_end":640}]}
{"pmid":"28594869","title":"Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction.","abstract":"Glycyl-tRNA synthetase (GARS; OMIM 600287) is one of thirty-seven tRNA-synthetase genes that catalyses the synthesis of glycyl-tRNA, which is required to insert glycine into proteins within the cytosol and mitochondria. To date, eighteen mutations in GARS have been reported in patients with autosomal-dominant Charcot-Marie-Tooth disease type 2D (CMT2D; OMIM 601472), and/or distal spinal muscular atrophy type V (dSMA-V; OMIM 600794). In this study, we report a patient with clinical and biochemical features suggestive of a mitochondrial respiratory chain (MRC) disorder including mild left ventricular posterior wall hypertrophy, exercise intolerance, and lactic acidosis. Using whole exome sequencing we identified compound heterozygous novel variants, c.803C>T; p.(Thr268Ile) and c.1234C>T; p.(Arg412Cys), in GARS in the proband. Spectrophotometric evaluation of the MRC complexes showed reduced activity of Complex I, III and IV in patient skeletal muscle and reduced Complex I and IV activity in the patient liver, with Complex IV being the most severely affected in both tissues. Immunoblot analysis of GARS protein and subunits of the MRC enzyme complexes in patient fibroblast extracts showed significant reduction in GARS protein levels and Complex IV. Together these studies provide evidence that the identified compound heterozygous GARS variants may be the cause of the mitochondrial dysfunction in our patient.","variants":[{"Name":"NM_002047.4(GARS1):c.1234C>T (p.Arg412Cys)","Chromosome":"7","Start":"30617153","Stop":"30617153","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":523290,"rule_based_match":true,"evidence_text":"c.1234C>T; p.(Arg412Cys)","llm_judgment":"PRESENT","evidence":"c.1234C>T; p.(Arg412Cys)","abstract_start":786,"abstract_end":810},{"Name":"NM_002047.4(GARS1):c.803C>T (p.Thr268Ile)","Chromosome":"7","Start":"30609652","Stop":"30609652","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186076,"rule_based_match":true,"evidence_text":"c.803C>T; p.(Thr268Ile)","llm_judgment":"PRESENT","evidence":"c.803C>T; p.(Thr268Ile)","abstract_start":758,"abstract_end":781}]}
{"pmid":"32825426","title":"Fetal Anomalies Associated with Novel Pathogenic Variants in TMEM94.","abstract":"BACKGROUND: Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a newly described disorder. It is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Biallelic pathogenic variants of <i>TMEM94</i> are associated with IDDCDF.\nMETHODS AND RESULTS: In a prenatal setting, where fetal abnormalities were detected using antenatal sonography, we used trio-exome sequencing (trio-ES) in conjunction with chromosomal microarray analysis (CMA) to identify two novel homozygous loss of function variants in the <i>TMEM94</i> gene (c.606dupG and c.2729-2A>G) in two unrelated Saudi Arabian families.\nCONCLUSIONS: This study provides confirmation that <i>TMEM94</i> variants may cause IDDCDF. For the first time we describe the pathogenicity of <i>TMEM94</i> defects detected during the prenatal period.","variants":[{"Name":"NM_014738.6(TMEM94):c.606dup (p.Ile203fs)","Chromosome":"17","Start":"75488123","Stop":"75488124","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":1166868,"rule_based_match":true,"evidence_text":"c.606dupG","llm_judgment":"PRESENT","evidence":"c.606dupG","abstract_start":673,"abstract_end":682},{"Name":"NM_014738.6(TMEM94):c.2729-2A>G","Chromosome":"17","Start":"75495282","Stop":"75495282","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1166869,"rule_based_match":true,"evidence_text":"c.2729-2A>G","llm_judgment":"PRESENT","evidence":"c.2729-2A>G","abstract_start":687,"abstract_end":698}]}
{"pmid":"33292549","title":"Hereditary angioedema caused by a premature stop codon mutation in the SERPING1 gene.","abstract":"BACKGROUND: Hereditary angioedema with deficient and dysfunctional C1 inhibitor (C1-INH-HAE) is a rare genetic disorder. The majority of the cases with this disease are caused by mutations in the C1-inbitor gene SERPING1 and are classified as type 1 and type 2. We aimed to detect mutations in the SERPING1 gene and evaluate its expression in nine probands with hereditary angioedema from nine different families.\nMETHODS: Nine probands with hereditary angioedema from nine different families and 53 healthy controls were recruited in this study. All eight exons and intron-exon boundaries in the SERPING1 gene were amplified by PCR and then sequenced. Mutations were identified by alignment with reference sequences. mRNA expression was measured by real-time PCR.\nRESULTS: All probands were diagnosed with HAE type 1. Nine mutations were found in nine patients: c.44delT, c.289C<T, c.296_303delCCATCCAA, c.538C<T, c.786_787insT, c.794 G < A, c.939delT, c.1214_1223delCCAGCCAGGA, and c.1279delC. All mutations formed a premature stop codon that might lead to the impaired synthesis of C1 inhibitor and result in the deficiency of this protein. None of the detected mutations were observed in the controls. In the C1-INH-HAE group, SERPING1 mRNA expression was significantly reduced (20% of the normal average level) compared to controls.\nCONCLUSIONS: Three known and six novel mutations in the SERPING1 gene were identified, and they produced a truncated nonfunctional C1 inhibitor without a reactive central loop. All the mutations led to reduced expression of SERPING1 mRNA in peripheral blood and low antigenic C1 inhibitor levels.","variants":[{"Name":"NM_000062.3(SERPING1):c.794G>A (p.Trp265Ter)","Chromosome":"11","Start":"57606118","Stop":"57606118","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3495400,"rule_based_match":false,"evidence_text":"c.794 G < A","llm_judgment":"PRESENT","evidence":"c.794 G < A","abstract_start":930,"abstract_end":941},{"Name":"NM_000062.3(SERPING1):c.44del (p.Leu15fs)","Chromosome":"11","Start":"57598314","Stop":"57598314","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":3414241,"rule_based_match":true,"evidence_text":"c.44delT","llm_judgment":"PRESENT","evidence":"c.44delT","abstract_start":863,"abstract_end":871}]}
{"pmid":"19428278","title":"Cystathionine gamma-lyase: Clinical, metabolic, genetic, and structural studies.","abstract":"We report studies of six individuals with marked elevations of cystathionine in plasma and/or urine. Studies of CTH, the gene that encodes cystathionine gamma-lyase, revealed the presence among these individuals of either homozygous or compound heterozygous forms of a novel large deletion, p.Gly57_Gln196del, two novel missense mutations, c.589C>T (p.Arg197Cys) and c.932C>T (p.Thr311Ile), and one previously reported alteration, c.200C>T (p.Thr67Ile). Another novel missense mutation, c.185G>T (p.Arg62His), was found in heterozygous form in three mildly hypercystathioninemic members of a Taiwanese family. In one severely hypercystathioninemic individual no CTH mutation was found. Brief clinical histories of the cystathioninemic/cystathioninuric patients are presented. Most of the novel mutations were expressed and the CTH activities of the mutant proteins determined. The crystal structure of the human enzyme, hCTH, and the evidence available as to the effects of the mutations in question, as well as those of the previously reported p.Gln240Glu, on protein structure, enzymatic activity, and responsiveness to vitamin B(6) administration are discussed. Among healthy Czech controls, 9.3% were homozygous for CTH c.1208G>T (p.Ser403Ile), previously found homozygously in 7.5% of Canadians for whom plasma total homocysteine (tHcy) had been measured. Compared to wild-type homozygotes, among the 55 Czech c.1208G>T (p.Ser403Ile) homozygotes a greater level of plasma cystathionine was found only after methionine loading. Three of the four individuals homozygous or compound heterozygous for inactivating CTH mutations had mild plasma tHcy elevations, perhaps indicating a cause-and-effect relationship. The experience with the present patients provides no evidence that severe loss of CTH activity is accompanied by adverse clinical effects.","variants":[{"Name":"NM_001902.6(CTH):c.200C>T (p.Thr67Ile)","Chromosome":"1","Start":"70415987","Stop":"70415987","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17978,"rule_based_match":true,"evidence_text":"c.200C>T (p.Thr67Ile)","llm_judgment":"PRESENT","evidence":"c.200C>T (p.Thr67Ile)","abstract_start":431,"abstract_end":452}]}
{"pmid":"29217198","title":"Clinical, Molecular, and Computational Analysis in two cases with mitochondrial encephalomyopathy associated with SUCLG1 mutation in a consanguineous family.","abstract":"Deficiency of the mitochondrial enzyme succinyl COA ligase (SUCL) is associated with encephalomyopathic mtDNA depletion syndrome and methylmalonic aciduria. This disorder is caused by mutations in both SUCL subunits genes: SUCLG1 (α subnit) and SUCLA2 (β subnit). We report here, two Tunisian patients belonging to a consanguineous family with mitochondrial encephalomyopathy, hearing loss, lactic acidosis, hypotonia, psychomotor retardation and methylmalonic aciduria. Mutational analysis of SUCLG1 gene showed, for the first time, the presence of c.41T > C in the exon 1 at homozygous state. In-silico analysis revealed that this mutation substitutes a conserved methionine residue to a threonine at position 14 (p.M14T) located at the SUCLG1 protein mitochondrial targeting sequence. Moreover, these analysis predicted that this mutation alter stability structure and mitochondrial translocation of the protein. In Addition, a decrease in mtDNA copy number was revealed by real time PCR in the peripheral blood leukocytes in the two patients compared with controls.","variants":[{"Name":"NM_003849.4(SUCLG1):c.41T>C (p.Met14Thr)","Chromosome":"2","Start":"84459229","Stop":"84459229","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":620095,"rule_based_match":true,"evidence_text":"c.41T>C","llm_judgment":"PRESENT","evidence":"c.41T > C","abstract_start":550,"abstract_end":559}]}
{"pmid":"33748123","title":"Autosomal Recessive Rod-Cone Dystrophy Associated With Compound Heterozygous Variants in","abstract":"<b>Purpose:</b> <i>ARL3</i> (ADP-ribosylation factor-like 3) variants cause autosomal dominant retinitis pigmentosa (RP) or autosomal recessive Joubert syndrome. We found a family with rod-cone dystrophy (RCD) and verified it was associated with compound heterozygous variants in <i>ARL3</i> gene. <b>Methods:</b> Ophthalmic examinations including optical coherence tomography and electroretinogram (ERG) were performed. Targeted next generation sequencing (NGS) was performed for the proband using a custom designed panel. Sanger sequencing and co-segregation were conducted in the family members. Changes of protein structure mediated by the variants were studied <i>in vitro</i>. ARL3 protein stability and its interaction with RP2 protein were assessed by cycloheximide chase assay and co-immunoprecipitation (Co-IP) assay. <b>Results:</b> Visual acuity of the 18-year-old male proband was 0.25 in the right and 0.20 in the left eye, while his non-consanguineous parents and sister was normal. The proband showed signs of RCD, including nyctalopia, peripheral field loss, bone-spicule deposits in the retina, and reduced ERG responses. The father, aged 50 years old, showed visual acuity of 1.0 in both eyes. Unlike the proband, he presented late onset and mild cone-rod dystrophy (CRD), including macular atrophy, central scotomata, moderate reduction in photopic ERG responses. None of all the family members had hearing abnormality, mental dysplasia or gait instability. We identified two novel compound heterozygous variants (c.91A>G, p.T31A; c.353G>T, p.C118F) in <i>ARL3</i> in the proband, while his father only had variant c.91A>G. Bioinformatics analysis indicated amino acid positions of the two variants are highly conserved among species. The <i>in silico</i> tools predicted the variants to be harmful. Protein structure analysis showed the two variants had potential to alter the protein structure. Based on the ACMG guidelines, the two variants were likely pathogenic. In addition, the <i>ARL3</i> mutations destabilized ARL3 protein, and the mutation c.353G>T disrupted the interaction between ARL3 and RP2 in HEK293T cells. <b>Conclusions:</b> We showed novel compound heterozygous variants in <i>ARL3</i> were associated with early onset of autosomal recessive RCD, while c.91A>G along may be associated with a late onset of dominant CRD. The two variants in <i>ARL3</i> could be causative by destabilizing ARL3 protein and impairing its interaction with RP2 protein.","variants":[{"Name":"NM_004311.4(ARL3):c.353G>T (p.Cys118Phe)","Chromosome":"10","Start":"102685964","Stop":"102685964","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":985691,"rule_based_match":true,"evidence_text":"c.353G>T (p.C118F)","llm_judgment":"PRESENT","evidence":"c.353G>T","abstract_start":1551,"abstract_end":1559}]}
{"pmid":"25480037","title":"Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome.","abstract":"Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.","variants":[{"Name":"NM_014305.4(TGDS):c.298G>T (p.Ala100Ser)","Chromosome":"13","Start":"94590868","Stop":"94590868","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":172130,"rule_based_match":true,"evidence_text":"c.298G>T (p.Ala100Ser)","llm_judgment":"PRESENT","evidence":"c.298G>T (p.Ala100Ser)","abstract_start":431,"abstract_end":453},{"Name":"NM_014305.4(TGDS):c.700T>C (p.Tyr234His)","Chromosome":"13","Start":"94578130","Stop":"94578130","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":172131,"rule_based_match":true,"evidence_text":"c.700T>C (p.Tyr234His)","llm_judgment":"PRESENT","evidence":"c.700T>C (p.Tyr234His)","abstract_start":505,"abstract_end":527},{"Name":"NM_014305.4(TGDS):c.269A>G (p.Glu90Gly)","Chromosome":"13","Start":"94590897","Stop":"94590897","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":172132,"rule_based_match":true,"evidence_text":"c.269A>G (p.Glu90Gly)","llm_judgment":"PRESENT","evidence":"c.269A>G (p.Glu90Gly)","abstract_start":478,"abstract_end":499},{"Name":"NM_014305.4(TGDS):c.294T>G (p.Phe98Leu)","Chromosome":"13","Start":"94590872","Stop":"94590872","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":172133,"rule_based_match":true,"evidence_text":"c.294T>G (p.Phe98Leu)","llm_judgment":"PRESENT","evidence":"c.294T>G (p.Phe98Leu)","abstract_start":455,"abstract_end":476},{"Name":"NM_014305.4(TGDS):c.270_271del (p.Lys91fs)","Chromosome":"13","Start":"94590895","Stop":"94590896","ReferenceAlleleVCF":"TTC","AlternateAlleleVCF":"T","allel_id":172134,"rule_based_match":true,"evidence_text":"c.270_271del (p.Lys91Asnfs(∗)22)","llm_judgment":"PRESENT","evidence":"c.270_271del (p.Lys91Asnfs(∗)22)","abstract_start":397,"abstract_end":429},{"Name":"NM_014305.4(TGDS):c.892A>G (p.Asn298Asp)","Chromosome":"13","Start":"94576404","Stop":"94576404","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":172135,"rule_based_match":true,"evidence_text":"c.892A>G (p.Asn298Asp)","llm_judgment":"PRESENT","evidence":"c.892A>G (p.Asn298Asp)","abstract_start":373,"abstract_end":395}]}
{"pmid":"31332433","title":"SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.","abstract":"Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation. It catalyses the transformation of the superoxide anion (O2•-) into hydrogen peroxide. Heterozygous variants in SOD1 are a common cause of familial amyotrophic lateral sclerosis. In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity. The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype. These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease and should be considered before application of previously proposed SOD1 silencing as a treatment option for amyotrophic lateral sclerosis.","variants":[{"Name":"NM_000454.5(SOD1):c.335dup (p.Cys112fs)","Chromosome":"21","Start":"31667352","Stop":"31667353","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":613175,"rule_based_match":true,"evidence_text":"c.335dupG (p.C112Wfs*11)","llm_judgment":"PRESENT","evidence":"c.335dupG (p.C112Wfs*11)","abstract_start":383,"abstract_end":407}]}
{"pmid":"33124170","title":"Correlation between Genotype and Phenotype in 69 Chinese Patients with USH2A Mutations: A comparative study of the patients with Usher Syndrome and Nonsyndromic Retinitis Pigmentosa.","abstract":"PURPOSE: The aim of this study was to analyse 69 Chinese patients with USH2A mutations and to assess the genotype-phenotype correlation.\nMETHODS: All 36 Usher syndrome type IIA patients and 33 nonsyndromic RP (retinitis pigmentosa) patients underwent clinical examinations. Eye examinations included best-corrected visual acuity, slit-lamp biomicroscopy, fundus examination with dilated pupils, fundus fluorescent angiography, visual field test, full-field electroretinography and optic coherence tomography; audiological assessment included pure tone audiometry and hearing thresholds. The molecular diagnosis of genotype combined the single-gene Sanger sequencing and next-generation sequencing. This study is a retrospective study.\nRESULTS: The mean age of first symptoms with Usher syndrome type IIa and nonsyndromic RP patients was 13.7 versus 29.8 years (ocular phenotypes, p < 0.001); 17.7 versus 29.9 years (nyctalopia, p < 0.001); 44.7 versus 54.8 years (low vision based on VF, p < 0.001); 41.7 versus 54.7 years (low vision based on VA, p < 0.001); and 46.0 versus 56.7 years (legal blindness based on VF, p < 0.001). There was significant difference in variants in the two groups (p < 0.05). Among patients with mutation c.2802T > G (p.Cys934Trp), more (66.7%) presented with normal hearing. All patients (3/3, 100%) with the variant c.8232G > C (p.Trp2744Cys) had hearing loss. Furthermore, we identified 23 novel variants in USH2A.\nCONCLUSIONS: Patients with Usher syndrome type IIa had an earlier onset of the disease, inferior visual function and presented with more truncating variants, compared with the nonsyndromic RP patients.","variants":[{"Name":"NM_206933.4(USH2A):c.2802T>G (p.Cys934Trp)","Chromosome":"1","Start":"216246592","Stop":"216246592","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":152897,"rule_based_match":true,"evidence_text":"c.2802T>G (p.Cys934Trp)","llm_judgment":"PRESENT","evidence":"c.2802T > G (p.Cys934Trp)","abstract_start":1233,"abstract_end":1258}]}
{"pmid":"31842807","title":"Novel mutations identified in Chinese families with autosomal dominant congenital cataracts by targeted next-generation sequencing.","abstract":"BACKGROUND: Congenital cataract is a clinically and genetically heterogeneous visual impairment. The aim of this study was to identify causative mutations in five unrelated Chinese families diagnosed with congenital cataracts.\nMETHODS: Detailed family history and clinical data were collected, and ophthalmological examinations were performed using slit-lamp photography. Genomic DNA was extracted from peripheral blood of all available members. Thirty-eight genes associated with cataract were captured and sequenced in 5 typical nonsyndromic congenital cataract probands by targeted next-generation sequencing (NGS), and the results were confirmed by Sanger sequencing. Bioinformatics analysis was performed to predict the functional effect of mutant genes.\nRESULTS: Results from the DNA sequencing revealed five potential causative mutations: c.154 T > C(p.F52 L) in GJA8 of Family 1, c.1152_1153insG(p.S385Efs*83) in GJA3 of Family 2, c.1804 G > C(p.G602R) in BFSP1 of Family 3, c.1532C > T(p.T511 M) in EPHA2 of Family 4 and c.356G > A(p.R119H) in HSF4 of Family 5. These mutations co-segregated with all affected individuals in the families and were not found in unaffected family members nor in 50 controls. Bioinformatics analysis from several prediction tools supported the possible pathogenicity of these mutations.\nCONCLUSIONS: In this study, we identified five novel mutations (c.154 T > C in GJA8, c.1152_1153insG in GJA3, c.1804G > C in BFSP1, c.1532C > T in EPHA2, c.356G > A in HSF4) in five Chinese families with hereditary cataracts, respectively. NGS can be used as an effective tool for molecular diagnosis of genetically heterogeneous disorders such as congenital cataract, and the results can provide more effective clinical diagnosis and genetic counseling for the five families.","variants":[{"Name":"NM_005267.5(GJA8):c.154T>C (p.Phe52Leu)","Chromosome":"1","Start":"147908109","Stop":"147908109","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3412505,"rule_based_match":true,"evidence_text":"c.154 T > C(p.F52 L)","llm_judgment":"PRESENT","evidence":"c.154 T > C(p.F52 L)","abstract_start":846,"abstract_end":866},{"Name":"NM_021954.4(GJA3):c.1152dup (p.Ser385fs)","Chromosome":"13","Start":"20142136","Stop":"20142137","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":3412490,"rule_based_match":false,"evidence_text":"c.1152_1153insG(p.S385Efs*83)","llm_judgment":"PRESENT","evidence":"c.1152_1153insG(p.S385Efs*83)","abstract_start":888,"abstract_end":917}]}
{"pmid":"23462608","title":"Clinical and genetic analysis of a Korean patient with X-linked chondrodysplasia punctata: identification of a novel splicing mutation in the ARSE gene.","abstract":"X-linked recessive chondrodysplasia punctata (CDPX1) is a rare congenital disorder of bone and cartilage development, characterized by punctate calcification in areas of endochondral bone formation, leading to stippled epiphyses, severe nasal and midfacial hypoplasia, short stature, and brachytelephalangy. CDPX1 is caused by mutations in the arylsulfatase E (ARSE) gene located on chromosome Xp22.3. Although most affected males have milder symptoms, some have significant medical problems including respiratory compromise and cervical spinal stenosis due to dysplastic vertebrae. Herein, we present the case of a male infant with the characteristic features of CDPX1 and severe spinal cord compression. Direct sequencing analysis revealed a novel variation (c.430G>A) in the ARSE gene that was thought to be a missense mutation (p.Gly144Arg), but proved to be a novel splicing mutation (r.[430g>a; 430_431ins430+1_430+21) adding seven amino acids between p.Ile143 and p.Gly144 (p.Ile143_Gly-144insSerMetTyrValPheLysSer). This report expands the spectrum of mutations of the ARSE gene and, to the best of our knowledge, is the first clinically and genetically confirmed case of CDPX1 with severe spinal cord compression in Korea.","variants":[{"Name":"NM_000047.3(ARSL):c.430G>A (p.Gly144Arg)","Chromosome":"X","Start":"2953143","Stop":"2953143","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1862747,"rule_based_match":true,"evidence_text":"c.430G>A","llm_judgment":"PRESENT","evidence":"c.430G>A","abstract_start":761,"abstract_end":769}]}
{"pmid":"27872820","title":"Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación Jiménez Díaz.","abstract":"BACKGROUND: Fundación Jiménez Díaz (FJD) is a reference center for genetic diagnosis of Gaucher disease (GD) in Spain. Genetic analyses of acid β-glucosidase (<i>GBA</i>) gene using different techniques were performed to search for new mutations, in addition to those previously and most frequently found in the Spanish population. Additionally, the study of the chitotriosidase (<i>CHIT1)</i> gene was used to assess the inflammatory status of patients in the follow-up of enzyme replacement therapy (ERT). We present the genetic data gathered during the last nine years at FJD.\nMETHODS: Blood samples from patients with suspected GD were collected for enzymatic and genetic analyses. The genetic analysis was performed on DNA from 124 unrelated suspected cases and 57 relatives from 2007 to 2015, starting with a mutational screening kit, followed by Sanger sequencing of the entire gene and other techniques to look for deletions. <i>CHIT1</i> was also studied to assess the reliability of this biomarker.\nRESULTS: In 46 out of 93 GD patients (49.5%) the two mutant alleles were found. We detected 21 different mutations. The most common mutation was N370S (c.126A > G; p.Asp409Ser current nomenclature) (in 50.5% of patients), followed by L444P (c.1448T > C; p.Leu483Pro current nomenclature) (in 24.7%). The most common heterozygous compound genotype observed (18.3%) was c.1226A > G/c.1448T > C (N370S/L444P). Two novel mutations were found (del. Ex.4-11 and c.1296G > T; pW432C), as well as p.S146L, only once previously reported. Two patients showed the homozygous state for the duplication of <i>CHIT1</i>.\nCONCLUSION: N370S and L444P are the most common mutations and other mutations associated to Parkinson's disease have been observed. This should be taken into account in the genetic counseling of GD patients.","variants":[{"Name":"NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)","Chromosome":"1","Start":"155235843","Stop":"155235843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":19329,"rule_based_match":true,"evidence_text":"c.1226A>G","llm_judgment":"PRESENT","evidence":"c.1226A > G","abstract_start":1377,"abstract_end":1388}]}
{"pmid":"22761713","title":"Glucokinase (GCK) mutations and their characterization in MODY2 children of southern Italy.","abstract":"Type 2 Maturity Onset Diabetes of the Young (MODY2) is a monogenic autosomal disease characterized by a primary defect in insulin secretion and hyperglycemia. It results from GCK gene mutations that impair enzyme activity. Between 2006 and 2010, we investigated GCK mutations in 66 diabetic children from southern Italy with suspected MODY2. Denaturing High Performance Liquid Chromatography (DHPLC) and sequence analysis revealed 19 GCK mutations in 28 children, six of which were novel: p.Glu40Asp, p.Val154Leu, p.Arg447Glyfs, p.Lys458_Cys461del, p.Glu395_Arg397del and c.580-2A>T. We evaluated the effect of these 19 mutations using bioinformatic tools such as Polymorphism Phenotyping (Polyphen), Sorting Intolerant From Tolerant (SIFT) and in silico modelling. We also conducted a functional study to evaluate the pathogenic significance of seven mutations that are among the most severe mutations found in our population, and have never been characterized: p.Glu70Asp, p.His137Asp, p.Phe150Tyr, p.Val154Leu, p.Gly162Asp, p.Arg303Trp and p.Arg392Ser. These seven mutations, by altering one or more kinetic parameters, reduced enzyme catalytic activity by >40%. All mutations except p.Glu70Asp displayed thermal-instability, indeed >50% of enzyme activity was lost at 50°C/30 min. Thus, these seven mutations play a pathogenic role in MODY2 insurgence. In conclusion, this report revealed six novel GCK mutations and sheds some light on the structure-function relationship of human GCK mutations and MODY2.","variants":[{"Name":"NM_000162.5(GCK):c.907C>T (p.Arg303Trp)","Chromosome":"7","Start":"44146575","Stop":"44146575","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44928,"rule_based_match":false,"evidence_text":"p.Arg303Trp","llm_judgment":"PRESENT","evidence":"p.Arg303Trp","abstract_start":1027,"abstract_end":1038},{"Name":"NM_000162.5(GCK):c.449T>A (p.Phe150Tyr)","Chromosome":"7","Start":"44150990","Stop":"44150990","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":134588,"rule_based_match":false,"evidence_text":"c.449T>A (p.Phe150Tyr)","llm_judgment":"PRESENT","evidence":"p.Phe150Tyr","abstract_start":988,"abstract_end":999}]}
{"pmid":"29845787","title":"LRSAM1 Depletion Affects Neuroblastoma SH-SY5Y Cell Growth and Morphology: The LRSAM1 c.2047-1G>A Loss-of-Function Variant Fails to Rescue The Phenotype.","abstract":"OBJECTIVE: Deleterious variants in LRSAM1, a RING finger ubiquitin ligase which is also known as TSG101-associated ligase (TAL), have recently been associated with Charcot-Marie-Tooth disease type 2P (CMT2P). The mechanism by which mutant LRSAM1 contributes to the development of neuropathy is currently unclear. The aim of this study was to induce LRSAM1 deficiency in a neuronal cell model, observe its effect on cell growth and morphology and attempt to rescue the phenotype with ancestral and mutant LRSAM1 transfections.\nMATERIALS AND METHODS: In this experimental study, we investigated the effect of LRSAM1 downregulation on neuroblastoma SH-SY5Y cells by siRNA technology where cells were transfected with siRNA against LRSAM1. The effects on the expression levels of TSG101, the only currently known LRSAM1 interacting molecule, were also examined. An equal dosage of ancestral or mutant LRSAM1 construct was transfected in LRSAM1-downregulated cells to investigate its effect on the phenotype of the cells and whether cell proliferation and morphology could be rescued.\nRESULTS: A significant reduction in TSG101 levels was observed with the downregulation of LRSAM1. In addition, LRSAM1 knockdown significantly decreased the growth rate of SH-SY5Y cells which is caused by a decrease in cell proliferation. An effect on cell morphology was also observed. Furthermore, we overexpressed the ancestral and the c.2047-1G>A mutant LRSAM1 in knocked down cells. Ancestral LRSAM1 recovered cell proliferation and partly the morphology, however, the c.2047-1G>A mutant did not recover cell proliferation and further aggravated the observed changes in cell morphology.\nCONCLUSION: Our findings suggest that depletion of LRSAM1 affects neuroblastoma cells growth and morphology and that overexpression of the c.2047-1G>A mutant form, unlike the ancestral LRSAM1, fails to rescue the phenotype.","variants":[{"Name":"NM_001005373.4(LRSAM1):c.2047-1G>A","Chromosome":"9","Start":"127502773","Stop":"127502773","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":49853,"rule_based_match":true,"evidence_text":"c.2047-1G>A","llm_judgment":"PRESENT","evidence":"c.2047-1G>A","abstract_start":1418,"abstract_end":1429}]}
{"pmid":"30607703","title":"Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome.","abstract":"Pentatricopeptide repeat domain proteins are a large family of RNA-binding proteins involved in mitochondrial RNA editing, stability, and translation. Mitochondrial translation machinery defects are an expanding group of genetic diseases in humans. We describe a patient who presented with low birth weight, mental retardation, and optic atrophy. Brain MRI showed abnormal bilateral signals at the basal ganglia and brainstem, and the patient was diagnosed as Leigh syndrome. Exome sequencing revealed two potentially loss-of-function variants [c.415-2A>G, and c.1747_1748insCT (p.Phe583Serfs*3)] in PTCD3 (also known as MRPS39). PTCD3, a member of the pentatricopeptide repeat domain protein family, is a component of the small mitoribosomal subunit. The patient had marked decreases in mitochondrial complex I and IV levels and activities, oxygen consumption and ATP biosynthesis, and generalized mitochondrial translation defects in fibroblasts. Quantitative proteomic analysis revealed decreased levels of the small mitoribosomal subunits. Complementation experiments rescued oxidative phosphorylation complex I and IV levels and activities, ATP biosynthesis, and MT-RNR1 rRNA transcript level, providing functional validation of the pathogenicity of identified variants. This is the first report of an association of PTCD3 mutations with Leigh syndrome along with combined oxidative phosphorylation deficiencies caused by defects in the mitochondrial translation machinery.","variants":[{"Name":"NM_017952.6(PTCD3):c.415-2A>G","Chromosome":"2","Start":"86118919","Stop":"86118919","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":970152,"rule_based_match":true,"evidence_text":"c.415-2A>G","llm_judgment":"PRESENT","evidence":"c.415-2A>G","abstract_start":545,"abstract_end":555}]}
{"pmid":"31574885","title":"Management of tooth extraction in a patient with ELANE gene mutation-induced cyclic neutropenia: A case report.","abstract":"INTRODUCTION: Cyclic neutropenia (CyN) is a rare hematological disease, and patients with CyN often experience an early onset of severe periodontitis and are forced to undergo tooth extraction. Here, we report a case of a patient with CyN who showed different periodicity and oscillations of neutrophil count compared with her mother, despite sharing the same novel genetic mutation.\nPATIENT CONCERNS: A 17-year-old Japanese girl who had been diagnosed with CyN shortly after birth presented to our hospital with a complaint of mobility of her teeth and gingivitis. Upon presentation, an intraoral examination was performed and revealed redness and swelling of the marginal and attached gingiva. Radiographs revealed extreme resorption of the alveolar bone and apical lesions in her mandibular lateral incisors. The patient's hematologic data demonstrated a lack of blood neutrophils (0/μL). The patient had no history of dental extraction, and her mother also had a history of CyN.\nDIAGNOSES: The patient was diagnosed with severe periodontitis that was associated with CyN. Gene testing showed a novel heterozygous mutation in exon 4 of the ELANE gene (c.538delC, p.Leu180Ser fsX11).\nINTERVENTIONS: Based on the clinical findings, we planned to extract the patient's mandibular lateral incisors. Although the tooth extraction was scheduled considering the cyclic variation in neutrophil count, the patient's neutrophil count was 0/μL on the day before the planned extraction. Therefore, granulocyte-colony stimulating factor (G-CSF) was administered to increase the patient's neutrophil count. On the day of the patient's admission for the tooth extraction, she presented with fever (body temperature, 38.5°C), tonsillitis, and stomatitis. The extraction was subsequently delayed, and the patient was administered antibiotics and G-CSF for 4 days. At this time, the neutrophil count increased to 750/μL, and the tooth extraction was carried out safely.\nOUTCOMES: The postoperative course was uneventful, and the healing process at the extraction site was excellent.\nCONCLUSION: There is a possibility that the periodicity and oscillations of neutrophil count may change with growth in patients with CyN. Therefore, it is important to frequently examine and treat patients with fluctuating neutrophil levels for the management of invasive dental treatment in patients with CyN.","variants":[{"Name":"NM_001972.4(ELANE):c.538del (p.Leu180fs)","Chromosome":"19","Start":"855733","Stop":"855733","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":1978410,"rule_based_match":true,"evidence_text":"c.538delC","llm_judgment":"PRESENT","evidence":"c.538delC","abstract_start":1155,"abstract_end":1164}]}
{"pmid":"21332471","title":"First HPSE2 missense mutation in urofacial syndrome.","abstract":"Urofacial syndrome (UFS) describes the combination of urological problems and an inverted facial expression upon attempts to smile. Seventeen independent familial cases from different ethnicities have been described so far. Some of these have been linked to chromosome 10q. Very recently, homozygous loss-of-function mutations affecting the gene HPSE2 were identified in nine cases. Here, we describe a consanguineous UFS family from Pakistan with three of six siblings affected. We establish linkage to the chromosome 10q critical region and identify two non-synonymous HPSE2 variants. In silico analysis and screening of controls defines c.631T>C (p.Y211H) as a novel benign SNP and c.1628A>T (p.N543I) as the disease-causing mutation. Our study exemplifies the challenges in proper clinical diagnosis of UFS and, thereby, supports the hypothesis of the disease being under diagnosed. By identifying the first HPSE2 missense mutation it also provides a starting point for studies aimed at functionally understanding the unusual combination of symptoms as characterizing UFS.","variants":[{"Name":"NM_021828.5(HPSE2):c.1628A>T (p.Asn543Ile)","Chromosome":"10","Start":"98459725","Stop":"98459725","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":75281,"rule_based_match":true,"evidence_text":"c.1628A>T (p.N543I)","llm_judgment":"PRESENT","evidence":"c.1628A>T (p.N543I)","abstract_start":685,"abstract_end":704}]}
{"pmid":"29361385","title":"Mutation screening of INS and KCNJ11 genes in Taiwanese children with type 1B diabetic onset before the age of 5 years.","abstract":"Type 1 diabetes (T1D) is caused by β-cell destruction, usually leading to absolute insulin deficiency. T1D is a heterogeneous disease and is divided into two subtypes according to the presence or absence of pancreatic autoantibodies: type 1A (immune mediated) and type 1B (idiopathic). Genes such as KCNJ11 or INS, which play key roles in β-cell function, provide some insight into the pathogenesis of type 1B diabetes. In this study, we screened 110 Taiwanese children (61 males and 49 females) with T1D onset before the age of 5 years for mutations of INS and KCNJ11. We identified one missense heterozygous mutation in KCNJ11 (c.989A>G, p.Y330C) and no INS mutations among 28 probands. This is the first study to screen patients with autoantibody-negative T1D diagnosed before the age of 5 years for INS and KCNJ11 mutations in Taiwan. Although KCNJ11 mutations are always reported in patients with permanent neonatal diabetes, this gene mutation can be detected after 6 months of age. Further studies in other patients with type 1B diabetes and their families are required to elucidate the contributions of the KCNJ11 mutation to the T1D phenotype.","variants":[{"Name":"NM_000525.4(KCNJ11):c.989A>G (p.Tyr330Cys)","Chromosome":"11","Start":"17387103","Stop":"17387103","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":34056,"rule_based_match":true,"evidence_text":"c.989A>G, p.Y330C","llm_judgment":"PRESENT","evidence":"c.989A>G, p.Y330C","abstract_start":630,"abstract_end":647}]}
{"pmid":"31305444","title":"A novel de novo mutation in MYH7 gene in a patient with early onset muscular weakness and severe kyphoscoliosis: A case report.","abstract":"INTRODUCTION: Various phenotypes have been identified for MYH7 gene mutation-related myopathy. Here, we describe a patient with severe muscular weakness and skeletal deformity with de novo heterozygous MYH7 gene mutation.\nPATIENT CONCERNS: A 33-year-old woman presented with early onset of muscular weakness, with delayed motor development during infancy. At age 8 years, she was unable to walk, with signs of skeletal deformity, including the progression of kyphoscoliosis. At age 31 years, she developed dyspnea.\nDIAGNOSIS: She diagnosed with esophageal hiatal hernia with abdominal CT. In electromyography, short duration, small amplitude motor unit action potential (MUAP), and early recruitment patterns were observed in the involved proximal muscles, suggesting myopathy. Muscle histopathology showed fiber-type disproportion.\nINTERVENTIONS: Next-generation sequencing study revealed a heterozygous in-frame deletion variation in the exon 14 of the MYH7 gene (c.1498_1500del/p.Glu500del), which is a novel variation confirmed by conventional Sanger sequencing. Compared with the parental test, this variant was concluded as de novo.\nOUTCOMES: She received laparoscopic hiatal hernia repair and Nissen fundoplication for esophageal hiatal hernia. After surgery, her postural dyspnea improved. As there is no fundamental treatment for MYH7-related myopathies, she continued conservative treatment for her symptoms.\nCONCLUSION: Here, we presented a rare case of de novo mutation of the myosin head domain in the MYH7 gene. This report broadens both the phenotypic and genotypic spectra of MYH7-related myopathies.","variants":[{"Name":"NM_000257.4(MYH7):c.1495GAG[1] (p.Glu500del)","Chromosome":"14","Start":"23428578","Stop":"23428580","ReferenceAlleleVCF":"ACTC","AlternateAlleleVCF":"A","allel_id":528125,"rule_based_match":false,"evidence_text":"c.1498_1500del/p.Glu500del","llm_judgment":"PRESENT","evidence":"c.1498_1500del/p.Glu500del","abstract_start":966,"abstract_end":992}]}
{"pmid":"21273643","title":"In vitro functional effects of XPC gene rare variants from bladder cancer patients.","abstract":"The XPC gene is involved in repair of bulky DNA adducts formed by carcinogenic metabolites and oxidative DNA damage, both known bladder cancer risk factors. Single nucleotide polymorphisms (SNPs) in XPC have been associated with increased bladder cancer risk. Recently, rarer genetic variants have been identified but it is difficult to ascertain which are of functional importance. During a mutation screen of XPC in DNA from 33 bladder tumour samples and matched blood samples, we identified five novel variants in the patients' germ line DNA. In a case-control study of 771 bladder cancer cases and 800 controls, c.905T>C (Phe302Ser), c.1177C>T (Arg393Trp), c.*156G>A [3' untranslated region (UTR)] and c.2251-37C>A (in an intronic C>G SNP site) were found to be rare variants, with a combined odds ratio of 3.1 (95% confidence interval 1.0-9.8, P=0.048) for carriage of one variant. The fifth variant was a 2% minor allele frequency SNP not associated with bladder cancer. The two non-synonymous coding variants were predicted to have functional effects using analytical algorithms; a reduced recruitment of GFP-tagged XPC plasmids containing either c.905T>C or c.1177C>T to sites of 408 nm wavelength laser-induced oxidative DNA damage was found in vitro. c.*156G>A appeared to be associated with reduced messenger RNA stability in an in vitro plasmid-based assay. Although the laser microbeam assay is relevant to a range of DNA repair genes, our 3' UTR assay based on Green fluorescent protein(GFP) has widespread applicability and could be used to assess any gene. These assays may be useful in determining which rare variants are functional, prior to large genotyping efforts.","variants":[{"Name":"NM_004628.5(XPC):c.*156G>A","Chromosome":"3","Start":"14145785","Stop":"14145785","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":542951,"rule_based_match":true,"evidence_text":"c.*156G>A","llm_judgment":"PRESENT","evidence":"c.*156G>A","abstract_start":661,"abstract_end":670},{"Name":"NM_004628.5(XPC):c.1177C>T (p.Arg393Trp)","Chromosome":"3","Start":"14158706","Stop":"14158706","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":139223,"rule_based_match":true,"evidence_text":"c.1177C>T (Arg393Trp)","llm_judgment":"PRESENT","evidence":"c.1177C>T (Arg393Trp)","abstract_start":638,"abstract_end":659}]}
{"pmid":"27914478","title":"Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil.","abstract":"BACKGROUND: Approximately 8-15% epithelial ovarian cancer patients are BRCA1 or BRCA2 germline mutation carriers. Brazilian inhabitants may have peculiar genetic characteristics associated with ethnic diversity, and studies focusing on the entire BRCA1/BRCA2 gene sequencing in Brazilian ovarian cancer patients are still lacking. The aim of this study was to evaluate BRCA1/2 mutations, through entire gene sequencing, in a Brazilian population of women with epithelial ovarian cancer.\nMETHODS: In a cross sectional study performed in one reference centre for cancer treatment in São Paulo, Brazil, 100 patients diagnosed with epithelial ovarian cancer unselected for family history of breast and/or ovarian cancer were included. The complete coding sequence of BRCA1/2 genes was evaluated through Next-Generation or capillary sequencing. Large deletions were investigated through Multiplex Ligation-dependent Probe Amplification (MLPA).\nRESULTS: Nineteen pathogenic mutations (BRCA1: n = 17 and BRCA2: n = 2) featuring 14 different mutations, including two large deletions in BRCA1 (exon 1-2 deleted and exon 5-7 deleted) were identified. Three mutations were detected more than once (c.3331_3334delCAAG, c.5266dupC and c.4484G > T). Two novel frameshift mutations were identified, one in BRCA1 (c.961_962delTG) and one in BRCA2 (c.1963_1963delC). BRCA1/2 mutations were seen in 35.5% of the patients with first and/or second-degree relatives with breast and/or ovarian cancer. Nineteen variants of uncertain significance (VUS) were detected (BRCA1: n = 2 and BRCA2: n = 17), including five distinct missense variants (BRCA1: c.5348 T > C; BRCA2: c.2350A > G, c.3515C > T, c.7534C > T, and c.8351G > A).\nCONCLUSIONS: Among epithelial ovarian cancer patients unselected for family history of cancer, 19% were BRCA1/2 germline mutation carriers. Almost ¾ of the BRCA mutations, including two large deletions, were detected only once. Our work emphasizes the need of entire gene sequencing and MLPA screening in Brazil.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"c.5266dupC","llm_judgment":"PRESENT","evidence":"c.5266dupC","abstract_start":1207,"abstract_end":1217},{"Name":"NM_007294.4(BRCA1):c.3331_3334del (p.Gln1111fs)","Chromosome":"17","Start":"43092197","Stop":"43092200","ReferenceAlleleVCF":"TCTTG","AlternateAlleleVCF":"T","allel_id":46079,"rule_based_match":true,"evidence_text":"c.3331_3334delCAAG","llm_judgment":"PRESENT","evidence":"c.3331_3334delCAAG","abstract_start":1187,"abstract_end":1205}]}
{"pmid":"35031858","title":"Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant.","abstract":"GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient. We identified a hemizygous de novo missense variant in GRIA3 in a boy with an NDD: c.1844C > T (p.Ala615Val) using whole-exome sequencing. His neurological signs, such as hypertonia and hyperreflexia, were opposite to those in previous cases having LOF GRIA3 variants. His seizures and hypertonia were ameliorated by carbamazepine, inhibiting glutamate release from presynapses. Patch-clamp recordings showed that the human GluA3 mutant (p.Ala615Val) had slower desensitization and deactivation kinetics. A fly line expressing a human GluA3 mutant possessing our variant and the Lurcher variant, which makes ion channels leaky, showed developmental defects, while one expressing a mutant possessing either of them did not. Collectively, these results suggest that p.Ala615Val has GOF effects. GRIA3 GOF variants may cause an NDD phenotype distinctive from that of LOF variants, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype. This study should help in refining the clinical management of GRIA3-related NDDs.","variants":[{"Name":"NM_007325.5(GRIA3):c.1844C>T (p.Ala615Val)","Chromosome":"X","Start":"123417745","Stop":"123417745","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1336285,"rule_based_match":true,"evidence_text":"c.1844C > T (p.Ala615Val)","llm_judgment":"PRESENT","evidence":"c.1844C > T (p.Ala615Val)","abstract_start":432,"abstract_end":457}]}
{"pmid":"25540807","title":"Unusual Stüve-Wiedemann syndrome with complete maternal chromosome 5 isodisomy.","abstract":"A woman was isozygous for a novel mutation in the leukemia inhibitory factor receptor gene (LIFR) (c.2170C>G; p.Pro724Ala) which disrupts LIFR downstream signaling and results in Stüve-Wiedemann syndrome (STWS). She inherited two identical chromosomes 5 from her mother, heterozygous for the LIFR mutation. The presentation was typical for STWS, except there was no long bone dysplasia. Prominent cold-induced sweating and heat intolerance lead to an initial diagnosis of cold-induced sweating syndrome, excluded by exome sequencing. Skin biopsies provide the first human evidence of failed postnatal cholinergic differentiation of sympathetic neurons innervating sweat glands in cold-induced sweating, and of a neuropathy.","variants":[{"Name":"NM_001127671.2(LIFR):c.2170C>G (p.Pro724Ala)","Chromosome":"5","Start":"38489243","Stop":"38489243","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":213921,"rule_based_match":true,"evidence_text":"c.2170C>G; p.Pro724Ala","llm_judgment":"PRESENT","evidence":"c.2170C>G; p.Pro724Ala","abstract_start":99,"abstract_end":121}]}
{"pmid":"30482216","title":"Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics.","abstract":"BACKGROUND: While auditory neuropathy spectrum disorder (ANSD) is a heterogeneous disorder and its management quite varies depending upon the etiology, even including self-resolution, OTOF is an important molecular etiology of prelingual ANSD and has emerged as an attractive target for implementation of precision medicine in terms of timing and prognosis prediction of auditory rehabilitation. However, to date, the literature is lacking in the genotype-phenotype relationship of this gene as well as efficient molecular testing strategy in the clinic in many populations and to make things more complicated in Koreans, the most prevalent variant p.Arg1939Gln among Korean ANSD children frequently evaded detection by next generation sequencing (NGS), resulting in delayed genetic diagnosis and late cochlear implantation (CI). The aims of this study are to document the mutational and phenotypic spectrum of OTOF-related ANSD (DFNB9) in the Korean population, further establishing genotype-phenotype correlation and proposing a set of the most commonly found OTOF variants to be screened first.\nMETHODS: Genetic diagnosis through the NGS-based sequencing was made on patients with ANSD in two tertiary hospitals. Genotype and phenotypes of eleven DFNB9 patients were reviewed. For data analysis, Mann-Whitney test and Fisher's exact test were applied.\nRESULTS: This study disclosed four prevalent variants in Koreans: p.Arg1939Gln with an allele frequency of 40.9%, p.Glu841Lys (13.6%), p.Leu1011Pro and p.Arg1856Trp (9.1%). Three novel variants (c.4227 + 5G > C, p.Gly1845Glu, and p.Pro1931Thr) were identified. Interestingly, a significant association of p.Arg1939Gln with worse ASSR thresholds was observed despite consistently no ABR response. Ten of 11 DFNB9 patients received CI for auditory rehabilitation, showing favorable outcomes with more rapid improvement on early-CI group (age at CI ≤ 18 mo.) than late-CI group.\nCONCLUSIONS: This study included the largest Korean DFNB9 cohort to date and proposed a set of the most frequent four OTOF variants, allowing the potential prioritization of exons during Sanger sequencing. Further, a significant association of p.Arg1939Gln homozygotes with poor residual hearing was observed. We may have to suspect p.Arg1939Gln homozygosity in cases of poor auditory thresholds in ANSD children with putative negative OTOF variants solely screened by NGS. Reciprocal feedback between bench and clinics regarding DFNB9 would complement each other.","variants":[{"Name":"NM_194248.3(OTOF):c.2521G>A (p.Glu841Lys)","Chromosome":"2","Start":"26477174","Stop":"26477174","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1293058,"rule_based_match":false,"evidence_text":"p.Glu841Lys (13.6%)","llm_judgment":"PRESENT","evidence":"p.Glu841Lys (13.6%)","abstract_start":1469,"abstract_end":1488},{"Name":"NM_194248.3(OTOF):c.5566C>T (p.Arg1856Trp)","Chromosome":"2","Start":"26460998","Stop":"26460998","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":57427,"rule_based_match":false,"evidence_text":"p.Arg1856Trp","llm_judgment":"PRESENT","evidence":"p.Arg1856Trp","abstract_start":1507,"abstract_end":1519},{"Name":"NM_194248.3(OTOF):c.5816G>A (p.Arg1939Gln)","Chromosome":"2","Start":"26460203","Stop":"26460203","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21175,"rule_based_match":false,"evidence_text":"p.Arg1939Gln","llm_judgment":"PRESENT","evidence":"p.Arg1939Gln","abstract_start":649,"abstract_end":661}]}
{"pmid":"21255986","title":"A lethal variant of Netherton syndrome in a large inbred family","abstract":"Netherton syndrome is a rare autosomal recessive disorder characterized by the triad of ichthyosiform erythrodermia, typical hair dysplasia, and severe atopic features. The broad range of variable expression of this disease is well described and 20% of complications occur during the neonatal period such as hypernatremic dehydration, electrolyte imbalances, recurrent or severe infections, and failure to thrive. Mutation of the SPINK5 gene has been identified as disease-causing in Netherton syndrome, but the pathophysiology still remains unclear. Almost all SPINK5 mutations result in the absence of the serine-protease inhibitor LEKTI protein in both keratinocytes and lymphocytes. In this study, we report on a severe form of Netherton syndrome observed in three patients within a large inbred Rom family. All of them died in the first months of life despite early treatment. They were found to be homozygous for the c.1431-12G>A SPINK5 gene mutation, which has not been associated with a lethal form of the disease thus far. This family illustrates the extreme phenotype of Netherton disease of neonatal onset. Molecular diagnosis allowed further genetic counseling and prenatal testing during other pregnancies.","variants":[{"Name":"NM_006846.4(SPINK5):c.1431-12G>A","Chromosome":"5","Start":"148104940","Stop":"148104940","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":359552,"rule_based_match":true,"evidence_text":"c.1431-12G>A","llm_judgment":"PRESENT","evidence":"c.1431-12G>A","abstract_start":923,"abstract_end":935}]}
{"pmid":"33158149","title":"The","abstract":"The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the <i>CHEK2</i> recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The <i>CHEK2</i> missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with <i>CHEK2</i> c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.","variants":[{"Name":"NM_007194.4(CHEK2):c.349A>G (p.Arg117Gly)","Chromosome":"22","Start":"28725338","Stop":"28725338","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":133528,"rule_based_match":true,"evidence_text":"c.349A>G","llm_judgment":"PRESENT","evidence":"c.349A>G","abstract_start":280,"abstract_end":288}]}
{"pmid":"26349192","title":"A NOVEL MUTATION IN NPR2 GENE IN A PATIENT WITH ACROMESOMELIC DYSPLASIA, MAROTEAUX TYPE.","abstract":"Acromesomelic dysplasia, Maroteaux type (AMDM) is a rare autosomal recessive disease characterized by disproportionate shortening of skeletal elements, predominantly affecting the middle segments (forearms and forelegs) and distal segments (hands and feet) of appendicular skeleton. Furthermore it is related to axial skeleton and leads to wedging of vertebral bodies, with shorter dorsal margins than the ventral margins. Bartels et al. defined mutations in NPR2 gene, encoding natriuretic peptide receptor B (NPR-B), underlying Acromesomelic dysplasia, type Maroteaux. We present here molecular and clinical findings of a case with AMDM. In a patient, a novel homozygous mutation c.1435C>T p.R479X in exon 7 of NPR2 gene was found. Further testing confirmed the heterozygous carrier status of the parents. Our findings expand the spectrum of causative mutations in AMDM.","variants":[{"Name":"NM_003995.4(NPR2):c.1435C>T (p.Arg479Ter)","Chromosome":"9","Start":"35801153","Stop":"35801153","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":362062,"rule_based_match":true,"evidence_text":"c.1435C>T p.R479X","llm_judgment":"PRESENT","evidence":"c.1435C>T p.R479X","abstract_start":682,"abstract_end":699}]}
{"pmid":"32504006","title":"Severe cardiac involvement with preserved truncated dystrophin expression in Becker muscular dystrophy by +1G>A DMD splice-site mutation: a case report.","abstract":"Becker muscular dystrophy (BMD) is caused by specific mutations in the DMD gene that causes progressive muscle weakness and primarily affects skeletal and cardiac muscle. Although cardiac involvement is a significant cause of mortality in BMD, the genetic-phenotype correlation for skeletal and cardiac muscles has not been elucidated. Here, we described a 39-year-old man with BMD, who presented with subtle skeletal muscle weakness in the right leg in his 20s and underwent left ventricular restoration for severe dilated cardiomyopathy at the age of 29. He had difficulty climbing stairs after the age of 35. Neither duplication nor deletion of exons was detected by multiplex ligation-dependent probe amplification. A hemizygous c.264 + 1G>A mutation in intron 4 of the DMD was identified by next-generation sequencing. Furthermore, exon 4 skipping of the DMD was confirmed in both skeletal and cardiac muscles evaluated by reverse transcriptase PCR. Endomyocardial and skeletal muscle biopsies revealed dystrophic pathology characterized by muscle fiber atrophy and hypertrophy with a mild degree of interstitial fibrosis. Interestingly, dystrophin immunohistochemistry demonstrated patchy and faint staining of the skeletal muscle membranes but almost normal staining of the cardiac muscle membranes. Western blot analysis revealed a decreased amount of truncated dystrophin in skeletal muscle but surprisingly almost normal amount in cardiac muscle. This case indicates that BMD patients may have severe cardiac dysfunction despite preserved cardiac truncated dystrophin expression.","variants":[{"Name":"NM_004006.3(DMD):c.264+1G>A","Chromosome":"X","Start":"32844782","Stop":"32844782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":584878,"rule_based_match":true,"evidence_text":"c.264 + 1G>A","llm_judgment":"PRESENT","evidence":"c.264 + 1G>A","abstract_start":733,"abstract_end":745}]}
{"pmid":"26306640","title":"Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX.","abstract":"Mutations in the Aristaless-related homeobox gene (ARX) lead to a range of X-linked intellectual disability phenotypes, with truncating variants generally resulting in severe X-linked lissencephaly with ambiguous genitalia (XLAG), and polyalanine expansions and missense variants resulting in infantile spasms. We report two male patients with early-onset infantile spasms in whom a novel c.34G>T (p.(E12*)) variant was identified in the ARX gene. A similar variant c.81C>G (p.(Y27*)), has previously been described in two affected cousins with early-onset infantile spasms, leading to reinitiation of ARX mRNA translation resulting in an N-terminal truncated protein. We show that the novel c.34G>T (p.(E12*)) variant also reinitiated mRNA translation at the next AUG codon (c.121-123 (p.M41)), producing the same N-terminally truncated protein. The production of both of these truncated proteins was demonstrated to be at markedly reduced levels using in vitro cell assays. Using luciferase reporter assays, we demonstrate that transcriptional repression capacity of ARX was diminished by both the loss of the N-terminal corepressor octapeptide domain, as a consequence of truncation, and the marked reduction in mutant protein expression. Our study indicates that premature termination mutations very early in ARX lead to reinitiation of translation to produce N-terminally truncated protein at markedly reduced levels of expression. We conclude that even low levels of N-terminally truncated ARX is sufficient to improve the patient's phenotype compared with the severe phenotype of XLAG that includes malformations of the brain and genitalia normally seen in complete loss-of-function mutations in ARX.","variants":[{"Name":"NM_139058.3(ARX):c.34G>T (p.Glu12Ter)","Chromosome":"X","Start":"25015704","Stop":"25015704","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":167605,"rule_based_match":true,"evidence_text":"c.34G>T (p.(E12*))","llm_judgment":"PRESENT","evidence":"c.34G>T (p.(E12*))","abstract_start":389,"abstract_end":407}]}
{"pmid":"26346709","title":"A Mayan founder mutation is a common cause of deafness in Guatemala.","abstract":"Over 5% of the world's population has varying degrees of hearing loss. Mutations in GJB2 are the most common cause of autosomal recessive non-syndromic hearing loss (ARNHL) in many populations. The frequency and type of mutations are influenced by ethnicity. Guatemala is a multi-ethnic country with four major populations: Maya, Ladino, Xinca, and Garifuna. To determine the mutation profile of GJB2 in a ARNHL population from Guatemala, we sequenced both exons of GJB2 in 133 unrelated families. A total of six pathogenic variants were detected. The most frequent pathogenic variant is c.131G>A (p.Trp44*) detected in 21 of 266 alleles. We show that c.131G>A is associated with a conserved haplotype in Guatemala suggesting a single founder. The majority of Mayan population lives in the west region of the country from where all c.131G>A carriers originated. Further analysis of genome-wide variation of individuals carrying the c.131G>A mutation compared with those of Native American, European, and African populations shows a close match with the Mayan population.","variants":[{"Name":"NM_004004.6(GJB2):c.131G>A (p.Trp44Ter)","Chromosome":"13","Start":"20189451","Stop":"20189451","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186861,"rule_based_match":true,"evidence_text":"c.131G>A (p.Trp44*)","llm_judgment":"PRESENT","evidence":"c.131G>A (p.Trp44*)","abstract_start":588,"abstract_end":607}]}
{"pmid":"22097895","title":"DFNB49 is an important cause of non-syndromic deafness in Czech Roma patients but not in the general Czech population.","abstract":"Due to endogamy, the Roma have a higher risk for autosomal recessive (AR) disorders. We used homozygosity mapping on single-nucleotide polymorphism chips in one Czech Roma consanguineous family with non-syndromic hearing loss (NSHL). The second largest homozygous region in a deaf patient was mapped to the previously reported DFNB49 region. The MARVELD2 gene was recently reported as a causal gene for NSHL DFNB49. Sequencing of the MARVELD2 gene revealed a previously reported homozygous mutation c.1331+2 T>C (IVS4 + 2 T>C) in the deaf child. Subsequently, the same mutation was found in two more Roma families from an additional 19 unrelated Czech Roma patients with deafness tested for the MARVELD2 gene. To explore the importance of MARVELD2 mutations and DFNB49 for the general Czech and Central European population with early hearing loss we also tested 40 unrelated Czech patients with AR NSHL. No pathogenic mutation in the MARVELD2 gene was found in a group of 40 Czech non-Roma patients. Mutations in the MARVELD2 gene seem to be a significant cause of early NSHL in Czech Roma and this gene should be tested in this group of patients after GJB2.","variants":[{"Name":"NM_001038603.3(MARVELD2):c.1331+2T>C","Chromosome":"5","Start":"69432677","Stop":"69432677","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":859444,"rule_based_match":true,"evidence_text":"c.1331+2 T>C (IVS4 + 2 T>C)","llm_judgment":"PRESENT","evidence":"c.1331+2 T>C (IVS4 + 2 T>C)","abstract_start":499,"abstract_end":526}]}
{"pmid":"23635807","title":"A novel MYO6 splice site mutation causes autosomal dominant sensorineural hearing loss type DFNA22 with a favourable outcome after cochlear implantation.","abstract":"Mutations in MYO6 encoding an atypical myosin motor protein important for inner ear hair cell function have been associated with autosomal recessive (DFNB37) and autosomal dominant (DFNA22) types of hearing loss in a few families worldwide. After genome-wide linkage analysis, we identified a novel MYO6 mutation at the splice acceptor site of exon 7 (c.554-1G>A) in an extended German family with autosomal dominant postlingual non-syndromic hearing impairment. Analysis of blood-derived cDNA revealed different aberrantly spliced mRNAs caused by the mutation, which are predicted to severely interfere with protein function. Two of the family members underwent cochlear implantation at ages 53 and 65. Here, we present detailed clinical data of this family which suggest a favourable outcome of cochlear implantation in hearing-impaired individuals with a MYO6 mutation.","variants":[{"Name":"NM_004999.4(MYO6):c.554-1G>A","Chromosome":"6","Start":"75840584","Stop":"75840584","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2904824,"rule_based_match":true,"evidence_text":"c.554-1G>A","llm_judgment":"PRESENT","evidence":"c.554-1G>A","abstract_start":352,"abstract_end":362}]}
{"pmid":"19797833","title":"Distal myopathy in multi-minicore disease.","abstract":"A 52-year-old man noted distal dominant slowly progressive muscle weakness at age 36 years. On muscle CT, the red muscles of the soleus, anterior tibial and paraspinal muscles, where type 1 fiber is known to predominate, were almost totally replaced by fat tissue while quadriceps femoris, gastrocnemius and upper extremity muscles were relatively spared. Quadriceps muscle biopsy revealed multi-minicores in addition to occasional larger cores, in about 70% of the type 1 fibers. A novel heterozygous nucleotide change c.5869T > A (p.S1957T) was identified in RYR1. Although pathogenicity was not confirmed, this nucleotide change was absent in 100 control DNA. We did not find a mutation in either multi-minicore disease-associated gene, SEPN1, or major distal myopathy-related genes, including GNE, ZASP, MYOT, exons 32-36 of MYH7, and the last exon of TTN. This is probably a unique form of distal myopathy characterized by the presence of multi-minicores with preferential involvement of type 1 fibers.","variants":[{"Name":"NM_000540.3(RYR1):c.5869T>A (p.Ser1957Thr)","Chromosome":"19","Start":"38490130","Stop":"38490130","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1428180,"rule_based_match":true,"evidence_text":"c.5869T > A (p.S1957T)","llm_judgment":"PRESENT","evidence":"c.5869T > A (p.S1957T)","abstract_start":520,"abstract_end":542}]}
{"pmid":"21431957","title":"Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant.","abstract":"Sepiapterin reductase (SR) catalyzes the final step in the de novo synthesis of tetrahydrobiopterin, essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. SR deficiency is a very rare disease resulting in monoamine neurotransmitter depletion. Most patients present with clinical symptoms before the first year of age corresponding to a dopa-responsive dystonia phenotype with diurnal fluctuations, although some patients exhibit more complex motor and neurological phenotypes. Herein, we describe four new cases from Spain, their clinical phenotype and the biochemical and genetic analyses. Two mutations in the SPR gene were functionally expressed to provide a basis to establish genotype-phenotype correlations. Mutation c.751A>T is functionally null, correlating with the severe phenotype observed. The novel mutation c.304G>T was identified in three siblings with a strikingly mild phenotype without cognitive delay and close to asymptomatic in the eldest sister. Minigene analysis demonstrated that this mutation located in the last nucleotide of exon 1 affects splicing although some normal transcripts can be produced, resulting in the missense mutant p.G102C that retains partial activity. These results may account for the mild phenotype and the variable clinical presentations observed, which could depend on interindividual differences in relative abundance of correctly spliced and aberrant transcripts.","variants":[{"Name":"NM_003124.5(SPR):c.304G>T (p.Gly102Cys)","Chromosome":"2","Start":"72887736","Stop":"72887736","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":40573,"rule_based_match":true,"evidence_text":"c.304G>T","llm_judgment":"PRESENT","evidence":"c.304G>T","abstract_start":844,"abstract_end":852}]}
{"pmid":"29643536","title":"Genetic diagnosis of Caroli syndrome with autosomal recessive polycystic kidney disease: a case report and literature review","abstract":"This case report is about one genetically specified diagnosed infant case of Caroli syndrome with autosomal recessive polycystic kidney disease (ARPKD) in China. The patient in this case report was an eight-month infant boy with an atypical onset and the main clinical manifestation was non-symptomatic enlargement of the liver and kidneys. The imaging study demonstrated a diffused cystic dilatation of intrahepatic bile ducts as well as polycystic changes in bilateral kidneys. The basic blood biochemical tests indicated a normal hepatorenal function. Four serum biomarkers of hepatic fibrosis were all elevated and the urine test for an early detection of the renal injury was positive. The genetic sequencing proved two heterozygous missense mutations of polycystic kidney and hepatic disease 1 (PKHD1) gene, c.9292G>A and c.2507T>C, inherited from each of his parents respectively. The former was a novel mutation that had been verified as disease causing through the predicting software while the latter had been reported from one recent case study on Chinese twins, which was possibly unique among Chinese population. The relations between the gene type and the clinical phenotype were not clarified yet. Up till a follow-up eleven months later after the discharge, the patient had a normal hepatorenal function without occurrence of any severe complication yet. The clinical symptoms of Caroli syndrome with ARPKD at infant stage were atypical and the enlargement of liver and kidney was usually the sole symptom. From the above systematic retrospective clinical analysis, as well as the relevant literature review, it's been concluded that the features of the hepatorenal images in patients with Caroli syndrome and ARPKD were distinctive. Genetic testing combined with the imaging study benefits a definite diagnosis as well as a differentiation from other hepatorenal fibrocystic diseases. Specific to the long-term management of this kind of patients, it's necessary to schedule a regular follow-up to monitor the hepatorenal function and the occurrence of various complications for an appropriate intervention, meantime to devote efforts to the genetic counseling work for the patients' family.","variants":[{"Name":"NM_138694.4(PKHD1):c.2507T>C (p.Val836Ala)","Chromosome":"6","Start":"52046089","Stop":"52046089","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":620237,"rule_based_match":true,"evidence_text":"c.2507T>C","llm_judgment":"PRESENT","evidence":"c.2507T>C","abstract_start":828,"abstract_end":837}]}
{"pmid":"29846619","title":"Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism.","abstract":"Context: Autosomal dominant hypocalcemia type 1 (ADH1) is caused by heterozygous activating mutations in the calcium-sensing receptor gene (CASR). Whether polymorphisms that are benign in the heterozygous state pathologically alter receptor function in the homozygous state is unknown.\nObjective: To identify the genetic defect in an adolescent female with a history of surgery for bilateral cataracts and seizures. The patient has hypocalcemia, hyperphosphatemia, and low serum PTH level. The parents of the proband are healthy.\nMethods: Mutation testing of PTH, GNA11, GCM2, and CASR was done on leukocyte DNA of the proband. Functional analysis in transfected cells was conducted on the gene variant identified. Public single nucleotide polymorphism (SNP) databases were searched for the presence of the variant allele.\nResults: No mutations were identified in PTH, GNA11, and GCM2 in the proband. However, a germline homozygous variant (c.1631G>A; p.R544Q) in exon 6 of the CASR was identified. Both parents are heterozygous for the variant. The variant allele frequency was near 0.1% in SNP databases. By in vitro functional analysis, the variant was significantly more potent in stimulating both the Ca2+i and MAPK signaling pathways than wild type when transfected alone (P < 0.05) but not when transfected together with wild type. The overactivity of the mutant CaSR is due to loss of a critical structural cation-π interaction.\nConclusions: The patient's hypoparathyroidism is due to homozygosity of a variant in the CASR that normally has weak or no phenotypic expression in heterozygosity. Although rare, this has important implications for genetic counseling and clinical management.","variants":[{"Name":"NM_000388.4(CASR):c.1631G>A (p.Arg544Gln)","Chromosome":"3","Start":"122282135","Stop":"122282135","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":239066,"rule_based_match":true,"evidence_text":"c.1631G>A; p.R544Q","llm_judgment":"PRESENT","evidence":"c.1631G>A; p.R544Q","abstract_start":941,"abstract_end":959}]}
{"pmid":"23800802","title":"NPHS2 homozygous p.R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis.","abstract":"BACKGROUND: The pathogenicity of the NPHS2 homozygous p.R229Q variant in steroid-resistant nephrotic syndrome (SRNS) is doubtful. While it has been reported in unaffected controls, it is enriched in patients with SRNS, suggesting pathogenicity.\nCASE-DIAGNOSIS/TREATMENT: A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his 59 year-old father and his 40 year-old brother, both unaffected with no proteinuria. The affected son also harbors a heterozygous de novo, truncating PAX2 mutation (c.76dupG, p.V26Gfs*28), which can explain his chronic renal failure but which is rarely associated with FSGS.\nCONCLUSIONS: This family provides further evidence that homozygous p.R229Q in itself may not cause FSGS. Nevertheless, the rare association of FSGS to a PAX2 mutation may reflect the modifier effect of p.R229Q in the homozygous state. Such a modifier effect can also explain its enrichment in SRNS patients. Patients with homozygous p.R229Q should be screened for the causative mutation in a second gene.","variants":[{"Name":"NM_014625.4(NPHS2):c.686G>A (p.Arg229Gln)","Chromosome":"1","Start":"179557079","Stop":"179557079","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20409,"rule_based_match":false,"evidence_text":"p.R229Q","llm_judgment":"PRESENT","evidence":"p.R229Q","abstract_start":54,"abstract_end":61}]}
{"pmid":"31016899","title":"Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans.","abstract":"BACKGROUND: Craniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and short squat appearing thumbs, and great toes without deviation. The additional MRI findings of choanal stenosis and a Chiari I malformation suggested a diagnosis of Pfeiffer syndrome. First tier molecular testing did not reveal a pathogenic variant.\nMETHODS: Whole exome sequencing on DNA samples from the proband and her unaffected parents was utilized to delineate the variant causative for the Pfeiffer syndrome diagnosis.\nRESULTS: On whole exome sequencing, a de novo NM_000142.4:c.1428C>A missense variant causing a p.Ala391Glu amino acid change in FGFR3 has been identified. The p.Ala391Glu change has been predominantly identified in patients with Crouzon syndrome with acanthosis nigricans.\nCONCLUSIONS: This finding illustrates the first reported case of a child with an overlap with Pfeiffer syndrome to have the p.Ala391Glu variant.","variants":[{"Name":"NM_000142.5(FGFR3):c.1172C>A (p.Ala391Glu)","Chromosome":"4","Start":"1804426","Stop":"1804426","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":31368,"rule_based_match":false,"evidence_text":"p.Ala391Glu","llm_judgment":"PRESENT","evidence":"p.Ala391Glu","abstract_start":1012,"abstract_end":1023}]}
{"pmid":"30851139","title":"Two CFTR mutations within codon 970 differently impact on the chloride channel functionality.","abstract":"Pharmacological rescue of mutant cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c.2909G>A) mutation could benefit from CFTR pharmacotherapy since a similar missense mutant p.Gly970Arg (c.2908G>C) was previously found to be sensitive to potentiators in vitro but not in vivo. By complementary DNA transfection, we found that both mutations are associated with defective CFTR function amenable to pharmacological treatment. However, analysis of messenger RNA (mRNA) from patient's cells revealed that c.2908G>C impairs RNA splicing whereas c.2909G>A does not perturb splicing and leads to the expected p.Gly970Asp mutation. In agreement with these results, nasal epithelial cells from the p.Gly970Asp patient showed significant improvement of CFTR function upon pharmacological treatment. Our results underline the importance of controlling the effect of CF mutation at the mRNA level to determine if the pharmacotherapy of CFTR basic defect is appropriate.","variants":[{"Name":"NM_000492.4(CFTR):c.2908G>C (p.Gly970Arg)","Chromosome":"7","Start":"117603782","Stop":"117603782","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":68258,"rule_based_match":true,"evidence_text":"c.2908G>C","llm_judgment":"PRESENT","evidence":"c.2908G>C","abstract_start":344,"abstract_end":353},{"Name":"NM_000492.4(CFTR):c.2909G>A (p.Gly970Asp)","Chromosome":"7","Start":"117606674","Stop":"117606674","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44518,"rule_based_match":true,"evidence_text":"c.2909G>A","llm_judgment":"PRESENT","evidence":"c.2909G>A","abstract_start":239,"abstract_end":248}]}
{"pmid":"35460558","title":"Somatic Mutation Profiling in Head and Neck Paragangliomas.","abstract":"CONTEXT: Head and neck paragangliomas (HNPGLs) are rare neoplasms with a high degree of heritability. Paragangliomas present as polygenic diseases caused by combined alterations in multiple genes; however, many driver changes remain unknown.\nOBJECTIVE: The objective of the study was to analyze somatic mutation profiles in HNPGLs.\nMETHODS: Whole-exome sequencing of 42 tumors and matched normal tissues obtained from Russian patients with HNPGLs was carried out. Somatic mutation profiling included variant calling and utilizing MutSig and SigProfiler packages.\nRESULTS: 57% of patients harbored germline and somatic variants in paraganglioma (PGL) susceptibility genes or potentially related genes. Somatic variants in novel genes were found in 17% of patients without mutations in any known PGL-related genes. The studied cohort was characterized by 6 significantly mutated genes: SDHD, BCAS4, SLC25A14, RBM3, TP53, and ASCC1, as well as 4 COSMIC single base substitutions (SBS)-96 mutational signatures (SBS5, SBS29, SBS1, and SBS7b). Tumors with germline variants specifically displayed SBS11 and SBS19, when an SBS33-specific mutational signature was identified for cases without those. Beta allele frequency analysis of copy number variations revealed loss of heterozygosity of the wild-type allele in 1 patient with germline mutation c.287-2A>G in the SDHB gene. In patients with germline mutation c.A305G in the SDHD gene, frequent potential loss of chromosome 11 was observed.\nCONCLUSION: These results give an understanding of somatic changes and the mutational landscape associated with HNPGLs and are important for the identification of molecular mechanisms involved in tumor development.","variants":[{"Name":"NM_003000.3(SDHB):c.287-2A>G","Chromosome":"1","Start":"17028738","Stop":"17028738","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":404981,"rule_based_match":true,"evidence_text":"c.287-2A>G","llm_judgment":"PRESENT","evidence":"c.287-2A>G","abstract_start":1342,"abstract_end":1352}]}
{"pmid":"26937389","title":"A rare case of Niemann-Pick disease type C without neurological involvement in a 66-year-old patient.","abstract":"UNLABELLED: The case of a 66 year-old female - the oldest known living patient with Niemann-Pick disease type C (NP-C) who remains free of any neurological or psychiatric manifestations 18 years after presentation - is presented. An incidental finding of massive splenomegaly was detected during a routine pelvic ultrasound. The pathology report after splenectomy showed the presence of lipid-laden macrophages. Fibroblasts cultured in LDL-enriched medium revealed abnormal filipin staining consistent with cholesterol-filled vesicles and the rate of cholesterol esterification in response to stimulation of LDL-cholesterol uptake was significantly depressed at 6% of that seen in cells from normal controls, but at a level similar to that observed in an NP-C positive control. Molecular genetic testing later revealed a compound heterozygous mutant NP-C genotype comprising two previously described disease-causing mutations in the NPC1 gene, one in exon 8 (c.1133T>C [V378A]) and one in exon 13 (c.1990G>A [V664M]). These findings confirmed the diagnosis of NP-C. Only three patients with this disorder aged > 53 years have previously been reported, all of whom presented with neurological or neuropsychiatric manifestations. Our patient is the first reported NP-C patient, now in her seventh decade of life, who has to date only manifested splenomegaly. This case highlights the extreme clinical variability of NP-C, and the need to consider this disease in the differential diagnosis of organomegaly, even in the absence of neurological, psychiatric and related clinical signs.\nSYNOPSIS: An elderly female patient with confirmed NP-C and isolated splenomegaly has remained asymptomatic for neurological, cognitive, psychiatric or ophthalmologic abnormailities into her seventh decade of life.","variants":[{"Name":"NM_000271.5(NPC1):c.1133T>C (p.Val378Ala)","Chromosome":"18","Start":"23556436","Stop":"23556436","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18009,"rule_based_match":true,"evidence_text":"c.1133T>C [V378A]","llm_judgment":"PRESENT","evidence":"c.1133T>C [V378A]","abstract_start":959,"abstract_end":976},{"Name":"NM_000271.5(NPC1):c.1990G>A (p.Val664Met)","Chromosome":"18","Start":"23544484","Stop":"23544484","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":358532,"rule_based_match":true,"evidence_text":"c.1990G>A [V664M]","llm_judgment":"PRESENT","evidence":"c.1990G>A [V664M]","abstract_start":998,"abstract_end":1015}]}
{"pmid":"27620334","title":"Deficient cMyBP-C protein expression during cardiomyocyte differentiation underlies human hypertrophic cardiomyopathy cellular phenotypes in disease specific human ES cell derived cardiomyocytes.","abstract":"AIMS: Mutations of cardiac sarcomere genes have been identified to cause HCM, but the molecular mechanisms that lead to cardiomyocyte hypertrophy and risk for sudden death are uncertain. The aim of this study was to examine HCM disease mechanisms at play during cardiac differentiation of human HCM specific pluripotent stem cells.\nMETHODS AND RESULTS: We generated a human embryonic stem cell (hESC) line carrying a naturally occurring mutation of MYPBC3 (c.2905 +1 G >A) to study HCM pathogenesis during cardiac differentiation. HCM-specific hESC-derived cardiomyocytes (hESC-CMs) displayed hallmark aspects of HCM including sarcomere disarray, hypertrophy and impaired calcium impulse propagation. HCM hESC-CMs presented a transient haploinsufficiency of cMyBP-C during cardiomyocyte differentiation, but by day 30 post-differentiation cMyBP-C levels were similar to control hESC-CMs. Gene transfer of full-length MYBPC3 during differentiation prevented hypertrophy, sarcomere disarray and improved calcium impulse propagation in HCM hESC-CMs.\nCONCLUSION(S): These findings point to the critical role of MYBPC3 during sarcomere assembly in cardiac myocyte differentiation and suggest developmental influences of MYBPC3 truncating mutations on the mature hypertrophic phenotype.","variants":[{"Name":"NM_000256.3(MYBPC3):c.2905+1G>A","Chromosome":"11","Start":"47335041","Stop":"47335041","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":51836,"rule_based_match":true,"evidence_text":"c.2905 +1 G >A","llm_judgment":"PRESENT","evidence":"c.2905 +1 G >A","abstract_start":457,"abstract_end":471}]}
{"pmid":"18358876","title":"Unilateral presentation of X-linked myotubular myopathy (XLMTM) in two out of three female carriers in a family with no affected male","abstract":"INTRODUCTION: X-linked myotubular myopathy (XLMTM), a recessive disorder, is caused by mutations affecting the myotubulatin (MTM1) gene located on the X chromosome. Most of the affected males die in the early postnatal period whereas female carriers are usually asymptomatic.\nCASE REPORTS: We report a family in which two females (45 and 27 years old) in two different generations, presented unilateral weakness which had worsened since adolescence, and one 48-year-old woman presented minimal symptoms. In agreement with the computed tomography and magnetic resonance imaging findings, the EMG was compatible with myopathy. Serum creatine kinase was elevated in the second patient. The histological study showed centronuclear myopathy aspects, more severe in the second patient. Both presented c.1420C>T, p.Arg474X in exon 13 of the MTM1 gene, whereas the third patients with less pronounced manifestation, had a skewed pattern of X chromosome inactivation.\nDISCUSSION: Symptomatic female carriers of XLMTM can present with asymmetric malformations, which must be distinguished from an autosomal-dominant centronuclear myopathy.\nCONCLUSION: Unilateral presentation of weakness cannot rule out a diagnosis of myopathy. Detection of symptomatic female carriers of an X linked recessive disease, with a severe presentation in males, is important for genetic counselling.","variants":[{"Name":"NM_000252.3(MTM1):c.1420C>T (p.Arg474Ter)","Chromosome":"X","Start":"150660437","Stop":"150660437","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":170060,"rule_based_match":true,"evidence_text":"c.1420C>T, p.Arg474X","llm_judgment":"PRESENT","evidence":"c.1420C>T, p.Arg474X","abstract_start":795,"abstract_end":815}]}
{"pmid":"30533232","title":"Birt-Hogg-Dubé Syndrome Caused by a Novel Mutation in the FLCL Gene.","abstract":"BACKGROUND: Birt-Hogg-Dubé syndrome is a genetic disorder characterized by skin fibrofolliculomas, cystic lung disease, and bilateral renal tumors. It has also been implicated in the formation of tumors in other organs, particularly thyroid and colon. This case presents a young female presenting with only cystic lung disease and kidney tumors, identified as having a never before identified heterozygous mutation in the folliculin (<i>FLCN</i>) gene which is the likely cause of her syndrome.\nCASE PRESENTATION: A 34-year-old female was found to have bilateral renal masses, 2.4 cm on the right and 7.6 cm on the left, as well as multiple, small cysts in the lungs. Chest imaging further characterized the lung cysts as being basilar predominant with the largest measuring 1.6cm. The left kidney mass was resected with a partial nephrectomy with final pathologic diagnosis of an oncocytoma. Genetic testing was undertaken as she did not have characteristic skin findings. A previously undescribed mutation in the <i>FLCN</i> gene (c.780-2A>G) was identified with no matches in the human genetic mutation database (HGMD). Review of that database identified over 160 separate mutations in the <i>FLCN</i> gene. Extensive history did not identify any family members who had similar disease processes suggesting that this could be a spontaneous mutation in the proband.\nCONCLUSIONS: This case highlights that the traditional view of Birt-Hogg-Dubé syndrome as having a strong familial component may be incorrect and that spontaneous mutation may be more common than previously thought. Also notable is the fact that this patient had no characteristically described fibrofolliculomas that traditionally are the hallmark of the condition. This case suggests that genetic testing should be obtained in all suspected cases of Birt-Hogg-Dubé syndrome as the patient may not present with the typical skin findings and may also present with no family history consistent with this disorder.","variants":[{"Name":"NM_144997.7(FLCN):c.780-2A>G","Chromosome":"17","Start":"17221630","Stop":"17221630","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":445702,"rule_based_match":true,"evidence_text":"c.780-2A>G","llm_judgment":"PRESENT","evidence":"c.780-2A>G","abstract_start":1033,"abstract_end":1043}]}
{"pmid":"33107701","title":"Autosomal dominant segregation of CAPN3 c.598_612del15 associated with a mild form of calpainopathy.","abstract":"","variants":[{"Name":"NM_000070.3(CAPN3):c.598_612del (p.Phe200_Leu204del)","Chromosome":"15","Start":"42387851","Stop":"42387865","ReferenceAlleleVCF":"AGTTCTGGAGTGCTCT","AlternateAlleleVCF":"A","allel_id":177545,"rule_based_match":true,"evidence_text":"c.598_612del15","llm_judgment":"PRESENT","evidence":"c.598_612del15","abstract_start":null,"abstract_end":null}]}
{"pmid":"17075691","title":"Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia.","abstract":"Methylmalonic acidemia (MMA) is caused by a deficiency in the activity of L: -methylmalonyl-CoA mutase (MCM), a vitamin B12 (or cobalamin, Cbl)-dependent enzyme. Apoenzyme-deficient MMA (mut MMA) results from mutations in the nuclear gene MUT. Most of the MUT mutations are thought to be private or restricted to only a few pedigrees. Our group elucidated the spectrum of mutations of Japanese mut MMA patients by performing mutation and haplotype analyses in 29 patients with mut MMA. A sequence analysis identified mutations in 95% (55/58) of the disease alleles. Five mutations were relatively frequent (p.E117X, c.385 + 5G > A, p.R369H, p.L494X, and p.R727X) and four were novel (p.M1V, c.753_753 + 5delGGTATA, c.1560G > C, and c.2098_2099delAT). Haplotype analysis suggested that all of the frequent mutations, with the exception of p.R369H, were spread by the founder effect. Among 46 Japanese patients investigated in the present and previous studies, 76% (70/92) of the mutations were located in exons 2, 6, 8, and 13. This finding - that a limited number of mutations account for most of the mutations in Japanese mut MMA patients - is in contrast with results of a previous study in Caucasian patients.","variants":[{"Name":"NM_000255.4(MMUT):c.385+5G>A","Chromosome":"6","Start":"49459077","Stop":"49459077","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":544024,"rule_based_match":true,"evidence_text":"c.385 + 5G > A","llm_judgment":"PRESENT","evidence":"c.385 + 5G > A","abstract_start":616,"abstract_end":630}]}
{"pmid":"26066897","title":"Chimeric CYP11B2/CYP11B1 causing 11β-hydroxylase deficiency in Chinese patients with congenital adrenal hyperplasia.","abstract":"CYP11B1 and CYP11B2 are highly homologous genes that can form chimera following unequal crossing-over during meiosis. A chimeric CYP11B1/CYP11B2 gene causes glucocorticoid-remediable aldosteronism (GRA), while the rare CYP11B2/CYP11B1 chimeric gene leads to 11β-hydroxylase deficiency (11-OHD). The aim of the study was to find the underlying genetic causes of three distinct Chinese pedigrees with 11-OHD. The family history, clinical data, laboratory findings and alterations in the CYP11B1 gene sequence were analyzed in all patients. We found that patient 1 and patient 2 harbored novel homozygotic chimeric CYP11B2/CYP11B1 genes consisting of the promoter, exons 1-6 of CYP11B2, and exons 7-9 of CYP11B1. Patient 3 had compound heterozygotic mutation with one allele containing the promoter and exons 1-6 of CYP11B2 and exons 7-9 of CYP11B1, and the other allele comprising novel, previously undescribed p.W56X (c.168G>A) mutation in exon 1 of CYP11B1. The breakpoints to form Chimeric CYP11B2/CYP11B1 were not the same for the three patients. Rare chimeric CYP11B2/CYP11B1 gene mutations are the underlying cause of disease in three patients with 11-OHD. We hypothesize that the lack expression of CYP11B1 under the control of the CYP11B2 promoter in zona fasciculata may contribute to a cortisol defect as well as the resultant 11-OHD.","variants":[{"Name":"NM_000497.4(CYP11B1):c.168G>A (p.Trp56Ter)","Chromosome":"8","Start":"142879646","Stop":"142879646","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":544743,"rule_based_match":true,"evidence_text":"c.168G>A","llm_judgment":"PRESENT","evidence":"c.168G>A","abstract_start":917,"abstract_end":925}]}
{"pmid":"30410802","title":"Epileptic Encephalopathy and Cerebellar Atrophy Resulting from Compound Heterozygous","abstract":"<i>CACNA2D2</i> encodes an auxiliary subunit of the voltage-dependent calcium channel. To date, there have only been two reports of individuals with early-infantile epileptic encephalopathy due to <i>CACNA2D2</i> mutations. In both reports, patients were homozygous for the identified variants. Here, we report a patient with epileptic encephalopathy and cerebellar atrophy who was found to have two novel variants in the <i>CACNA2D2</i> gene: c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro), by whole-exome sequencing. The variants were shown to be inherited in <i>trans</i> and the unaffected parents were confirmed to be heterozygous carriers. This is the third report of recessive <i>CACNA2D2</i> variants associated with disease and the first report of compound heterozygous variants. The clinical description of this new case highlights the phenotypic similarities amongst individuals with <i>CACNA2D2</i>-related disease and suggests that <i>CACNA2D2</i> should be considered as a differential diagnosis in individuals with cerebellar dysfunction and multiple seizure types that begin in the first year of life.","variants":[{"Name":"NM_006030.4(CACNA2D2):c.3137T>C (p.Leu1046Pro)","Chromosome":"3","Start":"50365146","Stop":"50365146","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":624843,"rule_based_match":true,"evidence_text":"c.3137T>C (p.Leu1046Pro)","llm_judgment":"PRESENT","evidence":"c.3137T>C (p.Leu1046Pro)","abstract_start":471,"abstract_end":495},{"Name":"NM_006030.4(CACNA2D2):c.782C>T (p.Pro261Leu)","Chromosome":"3","Start":"50380997","Stop":"50380997","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":519725,"rule_based_match":true,"evidence_text":"c.782C>T (p.Pro261Leu)","llm_judgment":"PRESENT","evidence":"c.782C>T (p.Pro261Leu)","abstract_start":444,"abstract_end":466}]}
{"pmid":"19177532","title":"Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis.","abstract":"The neuronal ceroid lipofuscinoses (NCL) are a group of genetically heterogeneous neurodegenerative disorders. The recent identification of the MFSD8/CLN7 gene in a variant-late infantile form of NCL (v-LINCL) in affected children from Turkey prompted us to examine the relative frequency of variants in this gene in Italian patients with v-LINCL. We identified nine children harboring 11 different mutations in MFSD8/CLN7. Ten mutations were novel and included three nonsense (p.Arg35Stop, p.Glu381Stop, p.Arg482Stop), four missense (p.Met1Thr, p.Gly52Arg, p.Thr294Lys, p.Pro447Leu), two splice site mutations (c.863+3_4insT, c.863+1G>C), and a 17-bp deletion predicting a frameshift and premature protein truncation (c.627_643del17/p.Met209IlefsX3). The clinical phenotype, which was similar to that of the Turkish v-LINCL cases, was not influenced by type and location of the mutation nor the length of the predicted residual gene product. As well as identifying novel variants in MFSD8/CLN7, this study contributes to a better molecular characterization of Italian NCL cases, and will facilitate medical genetic counseling in such families. The existence of a subset of v-LINCL cases without mutations in any of the known NCL genes suggests further genetic heterogeneity.","variants":[{"Name":"NM_001371596.2(MFSD8):c.863+3_863+4insT","Chromosome":"4","Start":"127932981","Stop":"127932982","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":172084,"rule_based_match":false,"evidence_text":"c.863+3_4insT","llm_judgment":"PRESENT","evidence":"c.863+3_4insT","abstract_start":612,"abstract_end":625},{"Name":"NM_001371596.2(MFSD8):c.627_643del (p.Met209fs)","Chromosome":"4","Start":"127939908","Stop":"127939924","ReferenceAlleleVCF":"AAAACTGGTGTTGTATAC","AlternateAlleleVCF":"A","allel_id":802151,"rule_based_match":true,"evidence_text":"c.627_643del17/p.Met209IlefsX3","llm_judgment":"PRESENT","evidence":"c.627_643del17/p.Met209IlefsX3","abstract_start":719,"abstract_end":749},{"Name":"NM_001371596.2(MFSD8):c.863+1G>C","Chromosome":"4","Start":"127932984","Stop":"127932984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2894697,"rule_based_match":true,"evidence_text":"c.863+1G>C","llm_judgment":"PRESENT","evidence":"c.863+1G>C","abstract_start":627,"abstract_end":637},{"Name":"NM_001371596.2(MFSD8):c.2T>C (p.Met1Thr)","Chromosome":"4","Start":"127965132","Stop":"127965132","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2894698,"rule_based_match":false,"evidence_text":"p.Met1Thr","llm_judgment":"PRESENT","evidence":"p.Met1Thr","abstract_start":535,"abstract_end":544}]}
{"pmid":"36873085","title":"Autonomic instability, arrhythmia and visual impairment in a new presentation of","abstract":"Mitochondrial methionyl-tRNA formyltransferase (MTFMT) is required for the initiation of translation in mitochondria. Pathogenic variants in <i>MTFMT</i> have been described in association with clinical presentations with Leigh syndrome, as well with as multisystem involvement (particularly cardiac and ocular involvement). There is a spectrum of severity, but many reported presentations have been milder with a better prognosis than other pathogenic variants associated with Leigh syndrome. We describe the case of a 9-year-old boy homozygous for a pathogenic <i>MTFMT</i> variant (c.626C > T/p.Ser209Leu) who presented with hypertensive crisis on a background of hyperphagia and visual impairment. His clinical course was complicated by supraventricular tachycardia and severe autonomic instability, requiring intensive care unit admission. He also developed seizures, neurogenic bladder and bowel and had a markedly abnormal eye examination with bilateral optic atrophy. Magnetic resonance image brain showed abnormal high T2/fluid-attenuated inversion recovery signal within the dorsal brainstem and in the right globus pallidus with some reduced diffusivity. Despite recovery from the acute neurological and cardiac manifestations, he has ongoing deficits in his gross motor skills and continues to have hyperphagia with rapid weight gain (approx. 20 kg in 2 years). Ophthalmic findings are persistent. This case expands the phenotype associated with <i>MTFMT</i> disease.","variants":[{"Name":"NM_139242.4(MTFMT):c.626C>T (p.Ser209Leu)","Chromosome":"15","Start":"65021533","Stop":"65021533","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48426,"rule_based_match":true,"evidence_text":"c.626C > T/p.Ser209Leu","llm_judgment":"PRESENT","evidence":"c.626C > T/p.Ser209Leu","abstract_start":585,"abstract_end":607}]}
{"pmid":"28394649","title":"ADAMTSL4 assessment in ectopia lentis reveals a recurrent founder mutation in Polynesians.","abstract":"BACKGROUND: To clinically characterize a cohort of patients with ectopia lentis (EL), or Marfanoid features in whom a definite genetic diagnosis of Marfan syndrome (MFS) had been excluded (atypical MFS), and to evaluate the contribution of mutations in ADAMTSL4 (OMIM * 610113), and P3H2 (LEPREL1; OMIM * 610341) to disease in this population.\nMATERIALS AND METHODS: Subjects underwent comprehensive ophthalmic examination, including keratometry. Mutational analysis of ADAMTSL4 and P3H2 was undertaken using PCR, high resolution melting analysis, and sequencing. The frequency of c.2237G>A; p.(Arg746His) was determined in an unaffected Polynesian cohort. Haplotype analysis used tagged single nucleotide polymorphic markers.\nRESULTS: Mutational analysis of ADAMTSL4 identified two pathogenic variants in ADAMTSL4 in 11/31 (35%) probands, consistent with the autosomal recessive EL phenotype. A recurrent, rare missense variant in ADAMTSL4, c.2237G>A; p.(Arg746His), was present in 10 probands -(8 homozygotes), predominantly of Polynesian descent, and all shared the same haplotype. p.(Arg746His) affects the Thrombospondin1 (TSP1) domain of the protein and is predicted to be pathogenic. No pathogenic variants in P3H2 were identified.\nCONCLUSION: A recurrent pathogenic ADAMTSL4 variant is a major cause of early onset autosomal recessive EL in a Cook Island Māori population and associated with a common haplotype, suggesting a founder effect. Children presenting under the age of 5 years, particularly of Cook Island or New Zealand Māori descent, with isolated ectopia lentis, should in the first instance be tested for this single variant.","variants":[{"Name":"NM_019032.6(ADAMTSL4):c.2237G>A (p.Arg746His)","Chromosome":"1","Start":"150558004","Stop":"150558004","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1471323,"rule_based_match":true,"evidence_text":"c.2237G>A; p.(Arg746His)","llm_judgment":"PRESENT","evidence":"c.2237G>A; p.(Arg746His)","abstract_start":581,"abstract_end":605}]}
{"pmid":"25982780","title":"Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III.","abstract":"A 26-year-old woman with a past history of fetal skeletal dysplasia was referred to our institution at 24weeks of gestation following a routine sonographic diagnosis of short limbs in the fetus. A fetal ultrasound showed short limbs, a narrow thorax, short ribs with marginal spurs, and polydactyly. Conventional cytogenetics analysis of cultured amniocytes demonstrated that the fetal karyotype was normal. Using targeted exome sequencing of 226 known genes implicated in inherited skeletal dysplasia, we identified compound heterozygous mutations in the DYNC2H1 gene in the fetus with short rib-polydactyly syndrome, type III (SRPS III), c.1151 C>T(p.Ala384Val) and c.4351 C>T (p.Gln1451*), which were inherited from paternally and maternally, respectively. These variants were further confirmed using Sanger sequencing and have not been previously reported. To our knowledge, this is the first report of DYNC2H1 mutations causing SRPS III, in the Chinese population. Our findings expand the number of reported cases of this rare disease, and indicate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia.","variants":[{"Name":"NM_001377.3(DYNC2H1):c.1151C>T (p.Ala384Val)","Chromosome":"11","Start":"103120705","Stop":"103120705","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":440125,"rule_based_match":true,"evidence_text":"c.1151 C>T(p.Ala384Val)","llm_judgment":"PRESENT","evidence":"c.1151 C>T(p.Ala384Val)","abstract_start":640,"abstract_end":663}]}
{"pmid":"16834950","title":"SLC7A9 gene variation: impact of 13 frequent mutations in the etiology of cystinuria in a Spanish Mediterranean population","abstract":"BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the presence of the most prevalent mutation in the SLC7A9 gene in families of the Mediterranean Spanish population and their association with clinical phenotypes.\nPATIENTS AND METHOD: Twenty cystinuria families were studied (6 type I, 12 non type I, and 2 unknown type), including 48 cystinuria patients and 44 relatives. DNA was isolated and molecular analysis of 13 variations (P52L, N58_G79del22, G63R, G105R, T123M, V170M, A182T, V188M, c.614dupA, G259R, L283F, A316V and R333W) in the SLC7A9 gene was undertaken. Association studies between these mutations and urinary aminoacid concentrations, stones, urinary infections, colics and other clinical traits were carried out.\nRESULTS: Of the 13 investigated mutations, the most prevalent mutation in cystinuria patients was c.614dupA (17.1%), which was found in 13 patients in heterozygous state (17.1%) and in 2 relatives, all of them belonging to 4 non type I families. Mutations G105R (9.2%), T123M (3.9%) and N58_G79del22 (2.6%) were detected only in non type I cystinuria patients. Meanwhile, a R333W carrier allele was found in a patient of a unknown family, and a G105R allele in a relative of a non type I family. No mutation was found in type I families and no patients with mutations in both SLC3A1 and SLC7A9 genes were found in any family.\nCONCLUSIONS: Although we have not carried out the whole screening of SLC7A9 gene, the detection rate of variations in SLC7A9 gene suggests a greater impact of this gene in the etiology of cystinuria in our population than variations in the previously screened SLC3A1 gene. The wide variation of phenotypical traits in subjects of families with the same mutations suggests that further investigation of other genetic and/or environmental factors should be carried out.","variants":[{"Name":"NM_014270.5(SLC7A9):c.614dup (p.Asn206fs)","Chromosome":"19","Start":"32862207","Stop":"32862208","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":272434,"rule_based_match":true,"evidence_text":"c.614dupA","llm_judgment":"PRESENT","evidence":"c.614dupA","abstract_start":508,"abstract_end":517}]}
{"pmid":"32069299","title":"Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation.","abstract":"Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry.","variants":[{"Name":"NM_173483.4(CYP4F22):c.1303C>T (p.His435Tyr)","Chromosome":"19","Start":"15549170","Stop":"15549170","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15948,"rule_based_match":true,"evidence_text":"c.1303C>T; p.(His435Tyr)","llm_judgment":"PRESENT","evidence":"c.1303C>T; p.(His435Tyr)","abstract_start":765,"abstract_end":789}]}
{"pmid":"27117572","title":"Mild Microcytic Anemia in an Infant with a Compound Heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A).","abstract":"We report an infant with a compound heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A) and a phenotype of mild microcytic anemia with target cell morphology but without overt hemolysis.","variants":[{"Name":"NM_000518.4(HBB):c.157G>A (p.Asp53Asn)","Chromosome":"11","Start":"5226735","Stop":"5226735","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30341,"rule_based_match":true,"evidence_text":"HBB: c.157G > A","llm_judgment":"PRESENT","evidence":"HBB: c.157G > A","abstract_start":104,"abstract_end":119},{"Name":"NM_000518.4(HBB):c.19G>A (p.Glu7Lys)","Chromosome":"11","Start":"5227003","Stop":"5227003","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30165,"rule_based_match":true,"evidence_text":"HBB: c.19G > A","llm_judgment":"PRESENT","evidence":"HBB: c.19G > A","abstract_start":61,"abstract_end":75}]}
{"pmid":"32819290","title":"A novel delins (c.773_819+47delinsAA) mutation of the PCCA gene associated with neonatal-onset propionic acidemia: a case report.","abstract":"BACKGROUND: Propionic acidemia (PA)(OMIM#606054) is an inborn error of branched-chain amino acid metabolism, caused by defects in the propionyl-CoA carboxylase (PCC) enzyme which encoded by the PCCA and PCCB genes.\nCASE PRESENTATION: Here we report a Chinese neonate diagnosed with suspected PA based on the clinical symptoms, gas chromatography-mass spectrometry (GC/MS), and brain imaging tests. Targeted next-generation sequencing (NGS) was performed on the proband. We detected only one heterozygous recurrent nonsense variant (c.937C > T, p.Arg313Ter) in the PCCA gene. When we manually checked the binary alignment map (BAM) diagram of PCCA gene, we found a heterozygous deletion chr13:100915039-100915132delinsAA (c.773_819 + 47delinsAA) (GRCh37.p13) inside the exon 10 in the PCCA gene. The results were validated by Sanger sequencing and qPCR method in the family: the variant (c.937C > T, p.Arg313Ter) was in the maternal allele, and the delins was in the paternal allele. When the mother was pregnant again, prenatal diagnosis was carried out through amniocentesis at 18 weeks gestation, the fetus carried neither of the two mutations. After birth, newborn screening was undertaken, the result was negative.\nCONCLUSIONS: We identified a recurrent c.937C > T and a novel c.773_819 + 47delinsAA mutations in the PCCA gene, which may be the genetic cause of the phenotype of this patient. Our findings expanded the spectrum of causative genotype-phenotype of the PCCA gene. For the cases, the NGS results revealed only a heterozygous mutation in autosomal recessive disease when the gene is associated with phenotypes, it is necessary to manually check the BAM diagram to improve the detection rate. Targeted NGS is an effective technique to detect the various genetic lesions responsible for the PA in one step. Genetic testing is essential for genetic counselling and prenatal diagnosis in the family to avoid birth defects.","variants":[{"Name":"NM_000282.4(PCCA):c.937C>T (p.Arg313Ter)","Chromosome":"13","Start":"100273218","Stop":"100273218","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":47475,"rule_based_match":true,"evidence_text":"c.937C > T, p.Arg313Ter","llm_judgment":"PRESENT","evidence":"c.937C > T, p.Arg313Ter","abstract_start":532,"abstract_end":555}]}
{"pmid":"31564433","title":"Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly.","abstract":"Intellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing (ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5, c.344_345delGA (p.Arg115Asnfs<sup>∗</sup>19) and c.571_572delAA (p.Lys191Valfs<sup>∗</sup>10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function.","variants":[{"Name":"NM_014168.4(METTL5):c.571_572del (p.Lys191fs)","Chromosome":"2","Start":"169812476","Stop":"169812477","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":676955,"rule_based_match":true,"evidence_text":"c.571_572delAA (p.Lys191Valfs<sup>∗</sup>10)","llm_judgment":"PRESENT","evidence":"c.571_572delAA (p.Lys191Valfs<sup>∗</sup>10)","abstract_start":435,"abstract_end":479},{"Name":"NM_014168.4(METTL5):c.344_345del (p.Arg115fs)","Chromosome":"2","Start":"169821153","Stop":"169821154","ReferenceAlleleVCF":"TTC","AlternateAlleleVCF":"T","allel_id":676971,"rule_based_match":true,"evidence_text":"c.344_345delGA (p.Arg115Asnfs<sup>∗</sup>19)","llm_judgment":"PRESENT","evidence":"c.344_345delGA (p.Arg115Asnfs<sup>∗</sup>19)","abstract_start":386,"abstract_end":430}]}
{"pmid":"29096607","title":"Hypotonia and intellectual disability without dysmorphic features in a patient with PIGN-related disease.","abstract":"BACKGROUND: Defects in the human glycosylphosphatidylinositol anchor biosynthetic pathway are associated with inherited glycosylphosphatidylinositol (GPI)-deficiencies characterized by a broad range of clinical phenotypes including multiple congenital anomalies, dysmorphic faces, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGN, encoding phosphatidylinositol-glycan biosynthesis class N have been recently associated with multiple congenital anomalies hypotonia seizure syndrome.\nCASE PRESENTATION: Our patient is a 2 year old male with hypotonia, global developmental delay, and focal epilepsy. Trio whole-exome sequencing revealed heterozygous variants in PIGN, c.181G > T (p.Glu61*) and c.284G > A (p.Arg95Gln). Analysis of FLAER and anti-CD59 by flow-cytometry demonstrated a shift in this patient's granulocytes, confirming a glycosylphosphatidylinositol-biosynthesis defect, consistent with PIGN-related disease.\nCONCLUSIONS: To date, a total of 18 patients have been reported, all but 2 of whom have congenital anomalies and/or obvious dysmorphic features. Our patient has no significant dysmorphic features or multiple congenital anomalies, which is consistent with recent reports linking non-truncating variants with a milder phenotype, highlighting the importance of functional studies in interpreting sequence variants.","variants":[{"Name":"NM_176787.5(PIGN):c.181G>T (p.Glu61Ter)","Chromosome":"18","Start":"62161173","Stop":"62161173","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":360497,"rule_based_match":true,"evidence_text":"c.181G > T (p.Glu61*)","llm_judgment":"PRESENT","evidence":"c.181G > T (p.Glu61*)","abstract_start":690,"abstract_end":711},{"Name":"NM_176787.5(PIGN):c.284G>A (p.Arg95Gln)","Chromosome":"18","Start":"62157746","Stop":"62157746","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":647394,"rule_based_match":true,"evidence_text":"c.284G > A (p.Arg95Gln)","llm_judgment":"PRESENT","evidence":"c.284G > A (p.Arg95Gln)","abstract_start":716,"abstract_end":739}]}
{"pmid":"27783806","title":"A novel homozygous mutation in the solute carrier family 12 member 3 gene in a Chinese family with Gitelman syndrome.","abstract":"Loss of function of mutated solute carrier family 12 member 3 (SLC12A3) gene is the most frequent etiology for Gitelman syndrome (GS), which is mainly manifested by hypokalemia, hypomagnesemia and hypocalciuria. We report the genetic characteristics of one suspicious Chinese GS pedigree by gene sequencing. Complete sequencing analysis of the SLC12A3 gene revealed that both the proband and his elder sister had a novel homozygous SLC12A3 mutation: c.2099T>C and p.Leu700Pro. Moreover, the SLC12A3 genes of his mother and daughter encoded the same mutated heterozygote. It was noted that in this pedigree, only the proband complained about recurrent episodes of bilateral lower limb weakness over 8 years, while his elder sister, mother and daughter did not present symptoms. The inconsistent clinical features of this pedigree implied that besides diverse phenotypes possibly originated from the same genotype, gender difference may also dominate the variant GS phenotypes. Further genetic and proteomic research are needed to investigate the precise mechanisms of GS, including the study of specific ethnicities.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.2099T>C (p.Leu700Pro)","Chromosome":"16","Start":"56887014","Stop":"56887014","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3393045,"rule_based_match":true,"evidence_text":"c.2099T>C and p.Leu700Pro","llm_judgment":"PRESENT","evidence":"c.2099T>C and p.Leu700Pro","abstract_start":450,"abstract_end":475}]}
{"pmid":"29191498","title":"A report of three families with FBN1-related acromelic dysplasias and review of literature for genotype-phenotype correlation in geleophysic dysplasia.","abstract":"Acromelic dysplasia is a heterogeneous group of rare skeletal dysplasias characterized by distal limb shortening. Weill-Marchesani syndrome (WMS), Geleophysic dysplasia (GD) and Acromicric dysplasia (AD) are clinically distinct entities within this group of disorders and are characterized by short stature, short hands, stiff joints, skin thickening, facial anomalies, normal intelligence and skeletal abnormalities. Mutations of the Fibrillin-1 (FBN1) gene have been reported to cause AD, GD and related phenotypes. We reported three families with acromelic short stature. FBN1 analysis showed that all affected individuals carry a heterozygous missense mutation c.5284G > A (p.Gly1762Ser) in exon 42 of the FBN1 gene. This mutation was previously reported to be associated with GD. We reviewed the literature and compared the clinical features of the patients with FBN1 mutations to those with A Distintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2) mutations. We found that tip-toeing gait, long flat philtrum and thin upper upper lip were more consistently found in GD patients with ADAMTSL2 mutations than in those with FBN1 mutations. The results have shed some light on the phenotype-genotype correlation in this group of skeletal disorders. A large scale study involving multidisciplinary collaboration would be needed to consolidate our findings.","variants":[{"Name":"NM_000138.5(FBN1):c.5284G>A (p.Gly1762Ser)","Chromosome":"15","Start":"48460258","Stop":"48460258","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38652,"rule_based_match":true,"evidence_text":"c.5284G > A (p.Gly1762Ser)","llm_judgment":"PRESENT","evidence":"c.5284G > A (p.Gly1762Ser)","abstract_start":665,"abstract_end":691}]}
{"pmid":"25759469","title":"A mutation in FRIZZLED2 impairs Wnt signaling and causes autosomal dominant omodysplasia.","abstract":"Autosomal dominant omodysplasia is a rare skeletal dysplasia characterized by short humeri, radial head dislocation, short first metacarpals, facial dysmorphism and genitourinary anomalies. We performed next-generation whole-exome sequencing and comparative analysis of a proband with omodysplasia, her unaffected parents and her affected daughter. We identified a de novo mutation in FRIZZLED2 (FZD2) in the proband and her daughter that was not found in unaffected family members. The FZD2 mutation (c.1644G>A) changes a tryptophan residue at amino acid 548 to a premature stop (p.Trp548*). This altered protein is still produced in vitro, but we show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2. We therefore conclude that the FRIZZLED2 mutation is a de novo, novel cause for autosomal dominant omodysplasia.","variants":[{"Name":"NM_001466.4(FZD2):c.1644G>A (p.Trp548Ter)","Chromosome":"17","Start":"44559332","Stop":"44559332","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":609006,"rule_based_match":true,"evidence_text":"c.1644G>A","llm_judgment":"PRESENT","evidence":"c.1644G>A","abstract_start":502,"abstract_end":511}]}
{"pmid":"32673564","title":"Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility.","abstract":"Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.","variants":[{"Name":"NM_001321739.2(M1AP):c.676dup (p.Trp226fs)","Chromosome":"2","Start":"74581766","Stop":"74581767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":794153,"rule_based_match":true,"evidence_text":"c.676dup (p.Trp226LeufsTer4)","llm_judgment":"PRESENT","evidence":"c.676dup (p.Trp226LeufsTer4)","abstract_start":415,"abstract_end":443},{"Name":"NM_001321739.2(M1AP):c.1166C>T (p.Pro389Leu)","Chromosome":"2","Start":"74562332","Stop":"74562332","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":794151,"rule_based_match":true,"evidence_text":"c.1166C>T (p.Pro389Leu)","llm_judgment":"PRESENT","evidence":"c.1166C>T (p.Pro389Leu)","abstract_start":883,"abstract_end":906}]}
{"pmid":"22166137","title":"Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2.","abstract":"BACKGROUND: Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene that encodes the laminin α2 chain, a component of the skeletal muscle extracellular matrix protein laminin-211. The clinical spectrum of the disease is more heterogeneous than previously thought, particularly in terms of motor achievement and disease progression. We investigated clinical findings and performed molecular genetic analysis in 3 families from Saudi Arabia and 1 from Sudan in whom congenital muscular dystrophy 1A was suspected based on homozygosity mapping and laminin α2 chain deficiency.\nMETHODS: We investigated 9 affected individuals from 1 Sudanese and 3 Saudi families in whom MDC1A was suggested by clinical, neuroimaging and/or pathological findings and by homozygosity mapping at the LAMA2 locus. Morphological and immunohistochemical analysis were performed in 3 patients from the 3 Saudi families. SSCP analysis, DNA sequencing and microsatellite analysis were carried out in the 4 index cases.\nRESULTS: A previously described mutation in the LAMA2 gene, a homozygous T > C substitution at position +2 of the consensus donor splice site of exon 26, was found in the 4 index patients. Clinical evaluation of 9 patients from the 4 families revealed variable disease severity particularly as regards motor achievement and disease progression. Microsatellite analysis showed an identical mutation-associated haplotype in the 4 index cases indicating a founder effect of the mutation in all 4 families.\nCONCLUSIONS: Our data provide further evidence that the clinical spectrum of MDC1A due to a single mutation is heterogeneous, particularly in terms of motor achievement and disease progression, making it difficult to give a reliable prognosis even in patients with identical LAMA2-associated haplotype. The c.3924 + 2 T > C mutation to date has been found only in patients originating from the Middle East or Sudan; therefore laminin 2 chain deficiency in patients from those regions should initially prompt a search for this mutation.","variants":[{"Name":"NM_000426.4(LAMA2):c.3924+2T>C","Chromosome":"6","Start":"129315952","Stop":"129315952","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":440912,"rule_based_match":true,"evidence_text":"c.3924 + 2 T > C","llm_judgment":"PRESENT","evidence":"c.3924 + 2 T > C","abstract_start":1823,"abstract_end":1839}]}
{"pmid":"29878067","title":"De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene.","abstract":"Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy. Here, we investigated a cohort of 47 patients with early onset cerebellar atrophy and/or hypoplasia using a custom gene panel as well as whole exome sequencing. De novo mutations were identified in 35% of patients while 27% had mutations inherited in an autosomal recessive manner. Understanding if these de novo events act through a loss or a gain of function effect is critical for treatment considerations. To gain a better insight into the disease mechanisms causing these cerebellar defects, we focused on CACNA1G, a gene not yet associated with the early-onset form. This gene encodes the Cav3.1 subunit of T-type calcium channels highly expressed in Purkinje neurons and deep cerebellar nuclei. We identified four patients with de novo CACNA1G mutations. They all display severe motor and cognitive impairment, cerebellar atrophy as well as variable features such as facial dysmorphisms, digital anomalies, microcephaly and epilepsy. Three subjects share a recurrent c.2881G>A/p.Ala961Thr variant while the fourth patient has the c.4591A>G/p.Met1531Val variant. Both mutations drastically impaired channel inactivation properties with significantly slower kinetics (∼5 times) and negatively shifted potential for half-inactivation (>10 mV). In addition, these two mutations increase neuronal firing in a cerebellar nuclear neuron model and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. This study highlights the prevalence of de novo mutations in early-onset cerebellar atrophy and demonstrates that A961T and M1531V are gain of function mutations. Moreover, it reveals that aberrant activity of Cav3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment.","variants":[{"Name":"NM_018896.5(CACNA1G):c.4591A>G (p.Met1531Val)","Chromosome":"17","Start":"50607905","Stop":"50607905","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":550304,"rule_based_match":true,"evidence_text":"c.4591A>G/p.Met1531Val","llm_judgment":"PRESENT","evidence":"c.4591A>G/p.Met1531Val","abstract_start":1587,"abstract_end":1609},{"Name":"NM_018896.5(CACNA1G):c.2881G>A (p.Ala961Thr)","Chromosome":"17","Start":"50592063","Stop":"50592063","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":265019,"rule_based_match":true,"evidence_text":"c.2881G>A/p.Ala961Thr","llm_judgment":"PRESENT","evidence":"c.2881G>A/p.Ala961Thr","abstract_start":1524,"abstract_end":1545}]}
{"pmid":"32554798","title":"A germline","abstract":"<i>PALB2</i> (partner and localizer of BRCA2) gene encodes a protein that colocalizes with <i>BRCA2</i> in nuclear foci and likely permits the stable intranuclear localization and accumulation of <i>BRCA2</i><i>PALB2</i> plays a critical role in maintaining genome integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. It has a known loss-of-function disease mechanism. Biallelic <i>PALB2</i> pathogenic variants have been described in autosomal recessive Fanconi anemia. Heterozygous pathogenic variants in <i>PALB2</i> are associated with increased risk for female and male breast cancer and pancreatic cancer (<i>Science</i> 324: 217; <i>Cancer Res</i> 71: 2222-2229; <i>N Engl J Med</i> 371: 497-506). Heterozygous germline <i>PALB2</i> mutations have also been observed in patients with medulloblastoma (<i>Lancet Oncol</i> 19: 785-798). However, <i>PALB2</i>-related cancer predisposition to high-grade gliomas has not been reported. Here we report a germline <i>PALB2</i> pathogenic variant (c.509_510delGA, p.Arg170Ilefs*14, NM_024675.3) found in a pediatric patient with high-grade glioma. This variant was first identified by tumor sequencing using the Children's Hospital of Philadelphia (CHOP) Comprehensive Solid Tumor Panel and then confirmed to be a germline change using the CHOP Comprehensive Hereditary Cancer Panel on DNA from a blood sample of this patient. Parental studies showed that this variant was paternally inherited. Further studies are needed to illustrate if pathogenic variants in <i>PALB2</i> convey increased risk to developing brain tumor. This case also highlights the potential of identifying germline mutation through tumor sequencing.","variants":[{"Name":"NM_024675.4(PALB2):c.509_510del (p.Arg170fs)","Chromosome":"16","Start":"23636036","Stop":"23636037","ReferenceAlleleVCF":"ATC","AlternateAlleleVCF":"A","allel_id":132267,"rule_based_match":true,"evidence_text":"c.509_510delGA, p.Arg170Ilefs*14, NM_024675.3","llm_judgment":"PRESENT","evidence":"c.509_510delGA, p.Arg170Ilefs*14, NM_024675.3","abstract_start":1044,"abstract_end":1089}]}
{"pmid":"19486366","title":"Clinical and haematological features in a compound heterozygote (HBB:c.92 + 5G > C/HBB:c.93-2A > C) case of thalassaemia major.","abstract":"An Indian Muslim boy was diagnosed with thalassaemia major at 3 months of age. His blood investigations revealed haemoglobin: 5.3 gm%, MCV: 68 fl, MCH 26.6 pg, MCHC: 39%, haemoglobin variant analysis: HbA(2): 2.8%, HbF: 20.3% and HbA: 75.2% (post-transfusion). His fathers' haemoglobin was 10.2 gm%, MCV: 68 fl, MCH: 23.9 pg, MCHC: 35% HbA(2): 4.7%, HbF: 0.7% and HbA: 85.2% and his mothers' haemoglobin was 10.9 gm%, MCV: 67.4 fl, MCH 22.6 pg, MCHC: 33.5%, HbA(2): 5.3%, HbF: 0% and HbA: 85.4%. The boy was found to be compound heterozygote for beta globin gene mutations (HBB:c.92 + 5G > C/HBB:c.93-2A > C). The mutation HBB:c.93-2A > C was inherited from his father. This report confirms the presence of HBB:c.93-2A > C in the Indian subcontinent and has important implications for screening and prenatal diagnosis of beta thalassaemia. This report also supports inclusion of this mutation in the beta globin gene mutation database.","variants":[{"Name":"NM_000518.5(HBB):c.92+5G>C","Chromosome":"11","Start":"5226925","Stop":"5226925","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":30486,"rule_based_match":true,"evidence_text":"HBB:c.92 + 5G > C","llm_judgment":"PRESENT","evidence":"HBB:c.92 + 5G > C","abstract_start":574,"abstract_end":591},{"Name":"NM_000518.5(HBB):c.93-2A>C","Chromosome":"11","Start":"5226801","Stop":"5226801","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":432695,"rule_based_match":true,"evidence_text":"HBB:c.93-2A > C","llm_judgment":"PRESENT","evidence":"HBB:c.93-2A > C","abstract_start":592,"abstract_end":607}]}
{"pmid":"29392648","title":"The first two confirmed sub-Saharan African families with germline TP53 mutations causing Li-Fraumeni syndrome.","abstract":"Li-Fraumeni syndrome is a rare inherited cancer syndrome characterised by the early onset of specific cancers. Li-Fraumeni syndrome (LFS) is associated with germline mutations in the tumour suppressor gene, TP53. This study reports the first cases of molecularly confirmed LFS germline mutations in sub-Saharan Africa. Three black African patients, all with LFS-associated cancers, were seen through the Clinical and Counselling Section of the Division of Human Genetics at the National Health Laboratory Service and University of the Witwatersrand in Johannesburg, South Africa, during 2011-2012. All three patients (two were related) were recruited into this research study. Sequence analysis of the coding region of the TP53 gene identified a Class IV (likely pathogenic) variant, c.326T > C (p.Phe109Ser), in the two related patients, and a known pathogenic mutation, c.1010G > A (p.Arg337His), also referred to as the Brazilian founder mutation, in the other patient. A confirmed diagnosis in these patients will assist in tailored medical management (it is recommended that individuals carrying a germline TP53 mutation avoid radiotherapy as this might cause secondary radiotherapy-induced malignancies) and in addition, genetic testing of at-risk family members can be offered. Very little is known and documented on LFS in African individuals. Despite the small number of patients in this study, the results support the need for diagnostic genetic testing for LFS in South Africa.","variants":[{"Name":"NM_000546.6(TP53):c.326T>C (p.Phe109Ser)","Chromosome":"17","Start":"7676043","Stop":"7676043","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":410280,"rule_based_match":true,"evidence_text":"c.326T > C (p.Phe109Ser)","llm_judgment":"PRESENT","evidence":"c.326T > C (p.Phe109Ser)","abstract_start":784,"abstract_end":808},{"Name":"NM_000546.6(TP53):c.1010G>A (p.Arg337His)","Chromosome":"17","Start":"7670699","Stop":"7670699","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27418,"rule_based_match":true,"evidence_text":"c.1010G > A (p.Arg337His)","llm_judgment":"PRESENT","evidence":"c.1010G > A (p.Arg337His)","abstract_start":872,"abstract_end":897}]}
{"pmid":"31206626","title":"Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.","abstract":"BACKGROUND: Breast cancer (BC) is the most common cancer and related cause of mortality among Hispanics, yet susceptibility has been understudied. BRCA1 and BRCA2 (BRCA) mutations explain less than one-half of hereditary BC, and the proportion associated with other BC susceptibility genes is unknown.\nMETHODS: Germline DNA from 1054 BRCA-mutation-negative Hispanic women with hereditary BC (BC diagnosed at age <51 years, bilateral BC, breast and ovarian cancer, or BC diagnosed at ages 51-70 years with ≥2 first-degree or second-degree relatives who had BC diagnosed at age <70 years), 312 local controls, and 887 multiethnic cohort controls was sequenced and analyzed for 12 known and suspected, high-penetrance and moderate-penetrance cancer susceptibility genes (ataxia telangiectasia mutated [ATM], breast cancer 1 interacting protein C-terminal helicase 1 [BRIP1], cadherin 1 [CDH1], checkpoint kinase 2 [CHEK2], nibrin [NBN], neurofibromatosis type 1 [NF1], partner and localizer of BRCA2 [PALB2], phosphatase and tensin homolog [PTEN], RAD51 paralog 3 [RAD51C], RAD51D, serine/threonine kinase 11 [STK11], and TP53).\nRESULTS: Forty-nine (4.6%) pathogenic or likely pathogenic variants (PVs) in 47 of 1054 participants (4.5%), including 21 truncating frameshift, 20 missense, 5 nonsense, and 4 splice variants, were identified in CHEK2 (n = 20), PALB2 (n = 18), ATM (n = 5), TP53 (n = 3), BRIP1 (n = 2), and CDH1 and NF1 (both n = 1) and none were identified in NBN, PTEN, STK11, RAD51C, or RAD51D. Nine participants carried the PALB2 c.2167_2168del PV (0.85%), and 14 carried the CHEK2 c.707T>C PV (1.32%).\nCONCLUSIONS: Of 1054 BRCA-negative, high-risk Hispanic women, 4.5% carried a PV in a cancer susceptibility gene, increasing understanding of hereditary BC in this population. Recurrent PVs in PALB2 and CHEK2 represented 47% (23 of 49) of the total, suggesting a founder effect. Accurate classification of variants was enabled by carefully controlling for ancestry and the increased identification of at-risk Hispanics for screening and prevention.","variants":[{"Name":"NM_024675.4(PALB2):c.2167_2168del (p.Met723fs)","Chromosome":"16","Start":"23629986","Stop":"23629987","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":139844,"rule_based_match":true,"evidence_text":"PALB2 c.2167_2168del","llm_judgment":"PRESENT","evidence":"PALB2 c.2167_2168del","abstract_start":1537,"abstract_end":1557},{"Name":"NM_007194.4(CHEK2):c.707T>C (p.Leu236Pro)","Chromosome":"22","Start":"28711994","Stop":"28711994","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":152162,"rule_based_match":true,"evidence_text":"CHEK2 c.707T>C","llm_judgment":"PRESENT","evidence":"CHEK2 c.707T>C","abstract_start":1589,"abstract_end":1603}]}
{"pmid":"31976142","title":"A Novel Pathogenic Variant of the","abstract":"Cystic fibrosis is a chronic multisystemic disease originating from functional alterations in CFTR (cystic fibrosis transmembrane conductance regulator) protein. To date, more than 300 pathogenic variants have been described in the literature. However, the diagnosis of CF, which was thought to become easier after the <i>CFTR</i> gene was identified, became more complicated due to the enormous amount of variations. In this study, we present a patient whose clinical findings were consistent with cystic fibrosis (CF) and showed a homozygous missense change that is not previously reported in the CFTR gene as pathogenic. In the next-generation sequencing analysis, homozygous c.4096A > T single-nucleotide exchange (I1366F [p.Ile1366Phe], missense) was shown in both alleles of the patient' <i>CFTR</i> gene. According to our database analysis, this variant has not yet been previously reported (VarSome, ClinVar, MutationTaster, Ensembl, dbSNP, PubMed). We do consider the change as pathogenic since the patient's findings were compatible with CF and the data analysis was in favor of pathogenicity. The most recent consensus report published in 2017 emphasized the importance of <i>CFTR</i> gene analysis, and this study emphasizes the difficulties of associating <i>CFTR</i> gene variations with a clinical picture and constitutes a new data on the genotype-phenotype correlation of <i>CFTR</i> variants. Also, considering the frequency of CF (according to World Health Organization data, every 1 out of 2,000-3,000 infants is born with CF in European Union countries and every 1 out of 3,500 in the United States) as well as the increasing rate of molecular studies performed on CF patients worldwide, reporting novel variation has an additional value.","variants":[{"Name":"NM_000492.4(CFTR):c.4096A>T (p.Ile1366Phe)","Chromosome":"7","Start":"117664820","Stop":"117664820","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":621251,"rule_based_match":true,"evidence_text":"c.4096A > T","llm_judgment":"PRESENT","evidence":"c.4096A > T","abstract_start":679,"abstract_end":690}]}
{"pmid":"32014045","title":"Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns.","abstract":"BACKGROUND: The necessity of early treatment for lysosomal storage diseases (LSDs) has triggered the development of newborn screening for LSDs in recent years. Here we report the first 70,000 newborns screened for Mucopolysaccharidosis (MPS) type 4A (Morquio syndrome) and other LSDs by an 8-plex assay including the original 4-plex LSD screening tandem mass spectrometry (MS/MS) assay for Pompe disease, Fabry disease, Gaucher disease, and MPS I disease.\nMETHODS: The additional reaction for MPS II, MPS 3B, MPS 4A, and MPS 6 enzymes was performed separately from the 4-plex reaction. The two reactions were quenched and extracted, then combined before carrying out a single 2-min UPLC-MS/MS analysis.\nRESULTS: From Mar. 2018 to Apr. 2019, 73,743 newborns were screened with the 8-plex LSD screening assay. The 8-plex assay revealed a better analytical precision than the previous 4-plex assay possibly because the 8-plex was carried out using UPLC-MS/MS. Six newborns were found to have low MPS-4A enzyme (N-acetylgalactosamine-6-sulfatase) activity and biallelic GALNS pathogenic mutations in trans; these patients are presumably affected with MPS4A, making an incidence of one in 12,291 (95% confident interval (CI): 5633-26,817). One mutation, c.857C > T (p.T286 M) of the GALNS gene, accounted 5 of the 12 mutated alleles. These newborns had immature vertebral bodies at 1 month of age, and one case was treated with elosulfase alfa 2 mg/kg/week starting from 4 months of age. Among other MPSs screened, one case of MPS I, 3 cases of MPS II, and 3 cases of MPS 3B were detected. One case of mucolipidosis type III was also diagnosed. In conjunction with another 9 patients of Pompe disease, Gaucher disease, and classical Fabry disease, making an incidence of LSDs as one in 3206 newborns (95% CI: 2137 - 4811). The one with infantile-onset Pompe disease and the one with Gaucher disease were treated since the age of 8 days and 41 days respectively.\nCONCLUSIONS: Routine newborn screening of MPS 4A and other LSDs were made possible by the 8-plex LSD screening assay. However, detailed phenotype prediction and the time to start treatment will need further elucidation.","variants":[{"Name":"NM_000512.5(GALNS):c.857C>T (p.Thr286Met)","Chromosome":"16","Start":"88835254","Stop":"88835254","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":621552,"rule_based_match":true,"evidence_text":"c.857C > T (p.T286 M)","llm_judgment":"PRESENT","evidence":"c.857C > T (p.T286 M)","abstract_start":1249,"abstract_end":1270}]}
{"pmid":"38050059","title":"Clinical and functional analysis of the germline","abstract":"<i>TP53</i> plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline <i>TP53</i> p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify <i>TP53</i> p.K164E as a likely pathogenic variant.","variants":[{"Name":"NM_000546.6(TP53):c.490A>G (p.Lys164Glu)","Chromosome":"17","Start":"7675122","Stop":"7675122","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":245075,"rule_based_match":true,"evidence_text":"NM_000546.5: c.490A>G","llm_judgment":"PRESENT","evidence":"NM_000546.5: c.490A>G","abstract_start":397,"abstract_end":418}]}
{"pmid":"38648771","title":"Novel Gain-of-Function Mutation in the Kv11.1 Channel Found in the Patient with Brugada Syndrome and Mild QTc Shortening.","abstract":"Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter I<sub>Kr</sub>-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on I<sub>Kr</sub> reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the I<sub>Kr</sub> density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.","variants":[{"Name":"NM_000238.4(KCNH2):c.1189C>T (p.Arg397Cys)","Chromosome":"7","Start":"150952793","Stop":"150952793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":395706,"rule_based_match":true,"evidence_text":"c.1189C>T (p.R397C)","llm_judgment":"PRESENT","evidence":"c.1189C>T (p.R397C)","abstract_start":404,"abstract_end":423}]}
{"pmid":"30994193","title":"Classic galactosaemia in the Greek Cypriot population: An epidemiological and molecular study.","abstract":"Classic galactosaemia is an inherited metabolic disorder of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT) resulting from mutations in the GALT gene. The objectives of the present study were the determination of the carrier frequency of classic galactosaemia in the Greek Cypriot population and the molecular characterization of the disease alleles. We performed an epidemiological study involving 528 Greek Cypriots originating from all parts of Cyprus. Carriers were identified by measuring GALT activity in red blood cells and were subsequently subjected to mutation analysis. A total of five mutations were identified in patients and carriers of classic galactosaemia: a large deletion of 8.5 kb previously reported by us (55% of alleles), the known mutations p.Lys285Asn (30%), p.Pro185Ser (5%), and c.820+13A>G (5%), and a novel mutation c.378-12G>A (5%). Interestingly, the most common mutation in European populations, p.Gln188Arg, was not identified in this Cypriot cohort. The carrier frequency for classic galactosaemia among Greek Cypriots was estimated to be 1:88, predicting a homozygote incidence of 1:31,000 births. The Duarte 1 and Duarte 2 variants were found to be present at a frequency of 5.5% and 2.5%, respectively.","variants":[{"Name":"NM_000155.4(GALT):c.820+13A>G","Chromosome":"9","Start":"34648907","Stop":"34648907","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":36603,"rule_based_match":true,"evidence_text":"c.820+13A>G","llm_judgment":"PRESENT","evidence":"c.820+13A>G","abstract_start":861,"abstract_end":872}]}
{"pmid":"37907725","title":"Distal hereditary motor neuronopathy as a new phenotype associated with variants in BAG3.","abstract":"OBJECTIVE: To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy.\nMETHODS: This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3.\nRESULTS: Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novel heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members.\nCONCLUSIONS: We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adult-onset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies.","variants":[{"Name":"NM_004281.4(BAG3):c.1513_1514insGGAC (p.Val505fs)","Chromosome":"10","Start":"119677067","Stop":"119677068","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGGAC","allel_id":3735976,"rule_based_match":true,"evidence_text":"c.1513_1514insGGAC (p.Val505GlyfsTer6)","llm_judgment":"PRESENT","evidence":"c.1513_1514insGGAC (p.Val505GlyfsTer6)","abstract_start":1138,"abstract_end":1176}]}
{"pmid":"31955980","title":"Mutations in the J domain of DNAJB6 cause dominant distal myopathy.","abstract":"Eight patients from five families with undiagnosed dominant distal myopathy underwent clinical, neurophysiological and muscle biopsy examinations. Molecular genetic studies were performed using targeted sequencing of all known myopathy genes followed by segregation of the identified mutations in the affected families using Sanger sequencing. Two novel mutations in DNAJB6 J domain, c.149C>T (p.A50V) and c.161A>C (p.E54A), were identified as the cause of disease. The muscle involvement with p.A50V was distal calf-predominant, and the p.E54A was more proximo-distal. Histological findings were similar to those previously reported in DNAJB6 myopathy. In line with reported pathogenic mutations in the glycine/phenylalanine (G/F) domain of DNAJB6, both the novel mutations showed reduced anti-aggregation capacity by filter trap assay and TDP-43 disaggregation assays. Modeling of the protein showed close proximity of the mutated residues with the G/F domain. Myopathy-causing mutations in DNAJB6 are not only located in the G/F domain, but also in the J domain. The identified mutations in the J domain cause dominant distal and proximo-distal myopathy, confirming that mutations in DNAJB6 should be considered in distal myopathy cases.","variants":[{"Name":"NM_058246.4(DNAJB6):c.149C>T (p.Ala50Val)","Chromosome":"7","Start":"157363244","Stop":"157363244","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":491727,"rule_based_match":true,"evidence_text":"c.149C>T (p.A50V)","llm_judgment":"PRESENT","evidence":"c.149C>T (p.A50V)","abstract_start":384,"abstract_end":401}]}
{"pmid":"31321892","title":"Expansion of the Primrose syndrome phenotype through the comparative analysis of two new case reports with ZBTB20 variants.","abstract":"Primrose syndrome (PRIMS), a rare genetic disorder with several clinical findings including intellectual disability, macrocephaly, typical facial features, and muscle wasting, is caused by heterozygous variants in the ZBTB20 gene. We report the cases of two males diagnosed with PRIMS at different ages, emphasizing the likely progressive nature of the disorder, as well as the differences and similarities of presentation during infancy and adulthood. Patient 1 is a 2-year-old American male with a medical history marked by impaired hearing, developmental delays, and fainting spells. Patient 2 is a 28-year-old Brazilian male, who presents with a phenotype similar to that seen in Patient 1 with additional features of ectopic calcifications and prominent muscular and skeletal abnormalities. Additionally, Patient 2 has a history of fainting spells and diminished body height and weight, with the latter features having only been reported in one PRIMS patient so far. Both Patients 1 and 2 were found to carry heterozygous likely pathogenic missense variants, detected in the last coding exon of ZBTB20 (c.1822T>C, p.Cys608Arg, de novo, and c.1873A>G, p.Met625Val, respectively), consistent with PRIMS. Overall, these case reports highlight PRIMS's likely progressive nature and contribute to the understanding of the natural history of this condition.","variants":[{"Name":"NM_001348800.3(ZBTB20):c.1822T>C (p.Cys608Arg)","Chromosome":"3","Start":"114339409","Stop":"114339409","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":614642,"rule_based_match":true,"evidence_text":"c.1822T>C, p.Cys608Arg","llm_judgment":"PRESENT","evidence":"c.1822T>C, p.Cys608Arg","abstract_start":1108,"abstract_end":1130},{"Name":"NM_001348800.3(ZBTB20):c.1873A>G (p.Met625Val)","Chromosome":"3","Start":"114339358","Stop":"114339358","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":406085,"rule_based_match":true,"evidence_text":"c.1873A>G, p.Met625Val","llm_judgment":"PRESENT","evidence":"c.1873A>G, p.Met625Val","abstract_start":1145,"abstract_end":1167}]}
{"pmid":"29225857","title":"","abstract":"Our results prove that c.1871-14T>G is causative of type I PS deficiency, highlighting the importance of performing mRNA-based studies in order to evaluate variants pathogenicity. We evidence the increased risk of venous thromboembolism associated with this cryptic splice-site variant if present in patients with PS deficiency.","variants":[{"Name":"NM_000313.4(PROS1):c.1871-14T>G","Chromosome":"3","Start":"93874419","Stop":"93874419","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":790423,"rule_based_match":true,"evidence_text":"c.1871-14T>G","llm_judgment":"PRESENT","evidence":"c.1871-14T>G","abstract_start":23,"abstract_end":35}]}
{"pmid":"25751282","title":"Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.","abstract":"IMPORTANCE: The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients.\nOBJECTIVE: To identify the genetic cause for a novel form of pure autosomal dominant HSP.\nDESIGN, SETTING, AND PARTICIPANTS: We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened.\nMAIN OUTCOME AND MEASURE: Mutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene.\nRESULTS: We identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0.01]; P < .05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c-/- mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation.\nCONCLUSIONS AND RELEVANCE: This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.","variants":[{"Name":"NM_001199753.2(CPT1C):c.109C>T (p.Arg37Cys)","Chromosome":"19","Start":"49692361","Stop":"49692361","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187089,"rule_based_match":true,"evidence_text":"c.109C>T","llm_judgment":"PRESENT","evidence":"c.109C>T","abstract_start":1237,"abstract_end":1245}]}
{"pmid":"27578112","title":"Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia.","abstract":"BACKGROUND: Type 1 hyperlipoproteinemia is a rare autosomal recessive disorder most often caused by mutations in the lipoprotein lipase (LPL) gene resulting in severe hypertriglyceridemia and pancreatitis.\nOBJECTIVES: The aim of this study was to identify novel mutations in the LPL gene causing type 1 hyperlipoproteinemia and to understand the molecular mechanisms underlying the severe hypertriglyceridemia.\nMETHODS: Three patients presenting classical features of type 1 hyperlipoproteinemia were recruited for DNA sequencing of the LPL gene. Pre-heparin and post-heparin plasma of patients were used for protein detection analysis and functional test. Furthermore, in vitro experiments were performed in HEK293 cells. Protein synthesis and secretion were analyzed in lysate and medium fraction, respectively, whereas medium fraction was used for functional assay.\nRESULTS: We identified two novel mutations in the LPL gene causing type 1 hyperlipoproteinemia: a two base pair deletion (c.765_766delAG) resulting in a frameshift at position 256 of the protein (p.G256TfsX26) and a nucleotide substitution (c.1211 T > G) resulting in a methionine to arginine substitution (p.M404 R). LPL protein and activity were not detected in pre-heparin or post-heparin plasma of the patient with p.G256TfsX26 mutation or in the medium of HEK293 cells over-expressing recombinant p.G256TfsX26 LPL. A relatively small amount of LPL p.M404 R was detected in both pre-heparin and post-heparin plasma and in the medium of the cells, whereas no LPL activity was detected.\nCONCLUSIONS: We conclude that these two novel mutations cause type 1 hyperlipoproteinemia by inducing a loss or reduction in LPL secretion accompanied by a loss of LPL enzymatic activity.","variants":[{"Name":"NM_000237.3(LPL):c.765_766del (p.Gly256fs)","Chromosome":"8","Start":"19954337","Stop":"19954338","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":983658,"rule_based_match":true,"evidence_text":"c.765_766delAG","llm_judgment":"PRESENT","evidence":"c.765_766delAG","abstract_start":991,"abstract_end":1005}]}
{"pmid":"26075213","title":"N1303K (c.3909C>G) mutation and splicing: implication of its c.[744-33GATT(6); 869+11C>T] complex allele in CFTR exon 7 aberrant splicing.","abstract":"Cystic Fibrosis is the most common recessive autosomal rare disease found in Caucasians. It is caused by mutations on the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) that encodes a protein located on the apical membrane of epithelial cells. c.3909C>G (p.Asn1303Lys, old nomenclature: N1303K) is one of the most common worldwide mutations. This mutation has been found at high frequencies in the Mediterranean countries with the highest frequency in the Lebanese population. Therefore, on the genetic level, we conducted a complete CFTR gene screening on c.3909C>G Lebanese patients. The complex allele c.[744-33GATT(6); 869+11C>T] was always associated with the c.3909C>G mutation in cis in the Lebanese population. In cellulo splicing studies, realized by hybrid minigene constructs, revealed no impact of the c.3909C>G mutation on the splicing process, whereas the associated complex allele induces minor exon skipping.","variants":[{"Name":"NM_000492.4(CFTR):c.3909C>G (p.Asn1303Lys)","Chromosome":"7","Start":"117652877","Stop":"117652877","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":22175,"rule_based_match":true,"evidence_text":"c.3909C>G","llm_judgment":"PRESENT","evidence":"c.3909C>G","abstract_start":261,"abstract_end":270}]}
{"pmid":"38286424","title":"A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism.","abstract":"Biallelic variants in <i>PTRHD1</i> have been associated with autosomal recessive intellectual disability, spasticity, and juvenile parkinsonism, with few reported cases. Here, we present the clinical and genetic findings of a female of Austrian origin exhibiting infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, consistent with the established phenotypic spectrum. Notably, she developed genetic generalized epilepsy at age 4, persisting into adulthood. Using diagnostic exome sequencing, we identified a homozygous missense variant (c.365G > A, p.(Arg122Gln)) in <i>PTRHD1</i> (NM_001013663). In summary, our findings not only support the existing link between biallelic <i>PTRHD1</i> variants and parkinsonism with neurodevelopmental abnormalities but also suggest a potential extension of the phenotypic spectrum to include generalized epilepsy.","variants":[{"Name":"NM_001013663.2(PTRHD1):c.365G>A (p.Arg122Gln)","Chromosome":"2","Start":"24790469","Stop":"24790469","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222194,"rule_based_match":true,"evidence_text":"c.365G > A, p.(Arg122Gln)","llm_judgment":"PRESENT","evidence":"c.365G > A, p.(Arg122Gln)","abstract_start":598,"abstract_end":623}]}
{"pmid":"26727311","title":"DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast cancer.","abstract":"Germline pathogenic mutations in BRCA1 increase risk of developing breast cancer. Screening for mutations in BRCA1 frequently identifies sequence variants of unknown pathogenicity and recent work has aimed to develop methods for determining pathogenicity. We previously observed that tumor DNA methylation can differentiate BRCA1-mutated from BRCA1-wild type tumors. We hypothesized that we could predict pathogenicity of variants based on DNA methylation profiles of tumors that had arisen in carriers of unclassified variants. We selected 150 FFPE breast tumor DNA samples [47 BRCA1 pathogenic mutation carriers, 65 BRCAx (BRCA1-wild type), 38 BRCA1 test variants] and analyzed a subset (n=54) using the Illumina 450K methylation platform, using the remaining samples for bisulphite pyrosequencing validation. Three validated markers (BACH2, C8orf31, and LOC654342) were combined with sequence bioinformatics in a model to predict pathogenicity of 27 variants (independent test set). Predictions were compared with standard multifactorial likelihood analysis. Prediction was consistent for c.5194-12G>A (IVS 19-12 G>A) (P>0.99); 13 variants were considered not pathogenic or likely not pathogenic using both approaches. We conclude that tumor DNA methylation data alone has potential to be used in prediction of BRCA1 variant pathogenicity but is not independent of estrogen receptor status and grade, which are used in current multifactorial models to predict pathogenicity.","variants":[{"Name":"NM_007294.4(BRCA1):c.5194-12G>A","Chromosome":"17","Start":"43057147","Stop":"43057147","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70118,"rule_based_match":true,"evidence_text":"c.5194-12G>A (IVS 19-12 G>A)","llm_judgment":"PRESENT","evidence":"c.5194-12G>A (IVS 19-12 G>A)","abstract_start":1092,"abstract_end":1120}]}
{"pmid":"32190315","title":"Infantile macrocephaly and multiple subcutaneous lipomas diagnosed with","abstract":"A heterozygous loss-of-function mutation of the <i>PTEN</i> gene, one of the tumor suppressor genes, causes a wide variety of disorders, ranging from macrocephaly/autism syndrome to <i>PTEN</i> hamartoma tumor syndrome, including Cowden disease that causes thyroid and breast cancer mainly in the adolescence and young adult generation. An 8-month-old male infant with simple macrocephaly developed a café-au-lait spot and two subcutaneous tumors at the age of 1 year. One of the tumors developed rapidly was resected at the age of 1 year and 9 months and identified as benign lipoma. From the age of 2 years, the patient often threw a tantrum. At the age of 2 years and 9 months, a pathogenic germline mutation was identified in the <i>PTEN</i> gene (NM_000314.7), c.195C>A, p.Y65<sup>*</sup> in the form of a heterozygous germline variant. Developmental delay was noted but no tumors were found in the thyroid gland and breasts. Immunohistochemistry for PTEN in the resected lipoma demonstrated that the PTEN expression pattern was similar to that in a subcutaneous adipose tissue from a normal subject, suggesting that two-hit was not likely involved in the rapid growth of this lipoma. At the age of 5 years, the patient was diagnosed with autism spectrum disorders with moderate developmental delay. A long-term follow-up is underway to examine developmental changes in psychomotor disorders and possible tumor formation.","variants":[{"Name":"NM_000314.8(PTEN):c.195C>A (p.Tyr65Ter)","Chromosome":"10","Start":"87925543","Stop":"87925543","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":419704,"rule_based_match":true,"evidence_text":"c.195C>A","llm_judgment":"PRESENT","evidence":"c.195C>A","abstract_start":766,"abstract_end":774}]}
{"pmid":"32181232","title":"A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in","abstract":"<b>Background:</b> Infantile X-linked spinal muscular atrophy (SMAX2) is a rare type of spinal muscular atrophy associated with <i>UBA1</i> variants. <b>Methods:</b> Clinical imaging and neurophysiological tests were performed on a Chinese patient with SMAX2. Further, focused panel sequencing of <i>UBA1</i> was carried out on samples of both the proband and his maternal relatives. <b>Results:</b> The proband, a 4-year-old boy with the SMAX2 phenotype, suffered from reduced exercise capacity since infancy. His other symptoms included speech difficulties, severe nasal tone, reduced distal muscle strength, areflexia, and inadequate sucking ability. The brain MRI of the proband's showed normal results but the electromyography results showed multiple peripheral neurogenic lesions. Five male members of the proband's family were affected with the SMAX2 phenotype. They presented similar symptoms and had experienced a long and autonomous life. Molecular analysis revealed a novel missense variant (c.1617G>A, p.Met539Ile) in the exon 15 of <i>UBA1</i>. The proband's mother, as well as grandmother, carried the heterozygous missense <i>UBA1</i> variant; whereas, the male patients from the family carried the hemizygotic variant. <b>Conclusions:</b> The affected members in this Chinese family showed unique features such as extended life span, no fractures, and cramps as compared with previously reported SMAX2 cases. The novel missense variant (c.1617G>A (p.Met539Ile) in UBA1 highlights the critical role of this gene in causing SMAX2 phenotype.","variants":[{"Name":"NM_003334.4(UBA1):c.1617G>A (p.Met539Ile)","Chromosome":"X","Start":"47205989","Stop":"47205989","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1491749,"rule_based_match":true,"evidence_text":"c.1617G>A (p.Met539Ile)","llm_judgment":"PRESENT","evidence":"c.1617G>A (p.Met539Ile)","abstract_start":1453,"abstract_end":1476}]}
{"pmid":"32700293","title":"Triple A (Allgrove) syndrome due to AAAS gene mutation with a rare association of amyotrophy.","abstract":"INTRODUCTION: Triple A (Allgrove) syndrome is a rare autosomal recessive disorder characterized by cardinal features of primary adrenal insufficiency (AI) due to adrenocorticotropic hormone (ACTH) resistance, achalasia, and alacrima. It is frequently associated with neurological manifestations such as autonomic dysfunction, cognitive dysfunction, cranial nerve, or motor involvement. Amyotrophy/motor neuron disease is a rare association.\nCASE PRESENTATION: We herein report a 19-year-old boy diagnosed with triple A syndrome (TAS), with the classic triad of ACTH-resistant adrenal insufficiency, achalasia, and alacrima. Additionally, he had distal spinal muscle amyotrophy. Alacrima was the earliest feature evident in early childhood, followed by achalasia at 12 years of age. He was diagnosed with AI at the age of 19 years, with involvement of the mineralocorticoid axis. Further evaluation showed a neurogenic pattern on electromyography, consistent with a diagnosis of motor neuron disease. A nerve conduction study revealed no significant neuropathy. Genetic analysis confirmed a pathogenic homozygous mutation in the AAAS gene c.43C>A, p.Gln15Lys. He improved with glucocorticoid and mineralocorticoid supplements for AI, and nifedipine for achalasia and artificial tears. He is planned for esophagomyotomy.\nCONCLUSION: In any young patient with AI not due to congenital adrenal hyperplasia, Allgrove syndrome should be ruled out. Though mineralocorticoid sparing pattern is classical, it can rarely be involved, as seen in the index case. Various components of the syndrome, as well as amyotrophy and other neurologic features, may present in a metachronous fashion. Hence, a high index of clinical suspicion can aid in early diagnosis and management.","variants":[{"Name":"NM_015665.6(AAAS):c.43C>A (p.Gln15Lys)","Chromosome":"12","Start":"53321423","Stop":"53321423","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":20083,"rule_based_match":true,"evidence_text":"c.43C>A, p.Gln15Lys","llm_judgment":"PRESENT","evidence":"c.43C>A, p.Gln15Lys","abstract_start":1138,"abstract_end":1157}]}
{"pmid":"27650164","title":"Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.","abstract":"The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304<sup>*</sup> (or p.R304<sup>*</sup> ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304<sup>*</sup> carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304<sup>*</sup> prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304<sup>*</sup> is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.","variants":[{"Name":"NM_003977.4(AIP):c.910C>T (p.Arg304Ter)","Chromosome":"11","Start":"67490910","Stop":"67490910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19927,"rule_based_match":true,"evidence_text":"NM_003977.3:c.910C>T, p.Arg304Ter","llm_judgment":"PRESENT","evidence":"NM_003977.3:c.910C>T, p.Arg304Ter","abstract_start":115,"abstract_end":148}]}
{"pmid":"22479503","title":"SEPTIN12 genetic variants confer susceptibility to teratozoospermia.","abstract":"It is estimated that 10-15% of couples are infertile and male factors account for about half of these cases. With the advent of intracytoplasmic sperm injection (ICSI), many infertile men have been able to father offspring. However, teratozoospermia still remains a big challenge to tackle. Septins belong to a family of cytoskeletal proteins with GTPase activity and are involved in various biological processes e.g. morphogenesis, compartmentalization, apoptosis and cytokinesis. SEPTIN12, identified by c-DNA microarray analysis of infertile men, is exclusively expressed in the post meiotic male germ cells. Septin12(+/+)/Septin12(+/-) chimeric mice have multiple reproductive defects including the presence of immature sperm in the semen, and sperm with bent neck (defect of the annulus) and nuclear DNA damage. These facts make SEPTIN12 a potential sterile gene in humans. In this study, we sequenced the entire coding region of SEPTIN12 in infertile men (n = 160) and fertile controls (n = 200) and identified ten variants. Among them is the c.474 G>A variant within exon 5 that encodes part of the GTP binding domain. The variant creates a novel splice donor site that causes skipping of a portion of exon 5, resulting in a truncated protein lacking the C-terminal half of SEPTIN12. Most individuals homozygous for the c.474 A allele had teratozoospermia (abnormal sperm <14%) and their sperm showed bent tail and de-condensed nucleus with significant DNA damage. Ex vivo experiment showed truncated SEPT12 inhibits filament formation in a dose-dependent manner. This study provides the first causal link between SEPTIN12 genetic variant and male infertility with distinctive sperm pathology. Our finding also suggests vital roles of SEPT12 in sperm nuclear integrity and tail development.","variants":[{"Name":"NM_144605.5(SEPTIN12):c.474G>A (p.Val158=)","Chromosome":"16","Start":"4783969","Stop":"4783969","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45783,"rule_based_match":true,"evidence_text":"c.474 G>A","llm_judgment":"PRESENT","evidence":"c.474 G>A","abstract_start":1049,"abstract_end":1058}]}
{"pmid":"32170493","title":"Novel DNAAF6 variants identified by whole-exome sequencing cause male infertility and primary ciliary dyskinesia.","abstract":"PURPOSE: To identify the genetic cause of patients with primary ciliary dyskinesia (PCD) and male infertility from two unrelated Han Chinese families.\nMETHODS: We conducted whole-exome sequencing of three individuals with PCD and male infertility from two unrelated Chinese families, and performed a targeted look-up for DNAAF6 variants in our previously reported cohort of 442 individuals (219 with isolated oligoasthenospermia and 223 fertile controls). Ultrastructural and immunostaining analyses of patients' spermatozoa were performed. The pathogenicity of the variants was validated using patient's spermatozoa and HEK293T cells. Intracytoplasmic sperm injection (ICSI) treatment was conducted in two patients.\nRESULTS: We identified one novel hemizygous frameshift variant (NM_173494, c.319_329del: p.R107fs) of DNAAF6 gene (previously named PIH1D3) in family 1 and one novel hemizygous missense variant (c.290G>T: p.G97V) in family 2. No hemizygous deleterious variants in DNAAF6 were detected in the control cohort of 442 individuals. Ultrastructural and immunostaining analyses of patients' spermatozoa showed the absence of outer and inner dynein arms in sperm flagella. Both variants were proven to lead to DNAAF6 protein degradation in HEK293T cells. Both patients carrying DNAAF6 variants underwent one ICSI cycle and delivered one healthy child each.\nCONCLUSION: We identified novel DNAAF6 variants causing male infertility and PCD in Han Chinese patients. This finding extended the spectrum of variants in DNAAF6 and revealed new light on the impact of DNAAF6 variants in sperm flagella.","variants":[{"Name":"NM_173494.2(DNAAF6):c.290G>T (p.Gly97Val)","Chromosome":"X","Start":"107218927","Stop":"107218927","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":905813,"rule_based_match":true,"evidence_text":"c.290G>T: p.G97V","llm_judgment":"PRESENT","evidence":"c.290G>T: p.G97V","abstract_start":912,"abstract_end":928}]}
{"pmid":"24256811","title":"Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated with a specific lipoylation defect of the 2-ketoacid dehydrogenase complexes.","abstract":"Cofactor disorders of mitochondrial energy metabolism are a heterogeneous group of diseases with a wide variety of clinical symptoms, particular metabolic profiles and variable enzymatic defects. Mutations in NFU1, BOLA3, LIAS and IBA57 have been identified in patients with deficient lipoic acid-dependent enzymatic activities and defects in the assembly and activity of the mitochondrial respiratory chain complexes. Here, we report a patient with an early onset fatal lactic acidosis presenting a biochemical phenotype compatible with a combined defect of pyruvate dehydrogenase (PDHC) and 2-ketoglutarate dehydrogenase (2-KGDH) activities, which suggested a deficiency in lipoic acid metabolism. Immunostaining analysis showed that lipoylated E2-PDH and E2-KGDH were extremely reduced in this patient. However, the absence of glycine elevation, the normal activity of the glycine cleavage system and the normal lipoylation of the H protein suggested a defect of lipoic acid transfer to particular proteins rather than a general impairment of lipoic acid biosynthesis as the potential cause of the disease. By analogy with yeast metabolism, we postulated LIPT1 as the altered candidate gene causing the disease. Sequence analysis of the human LIPT1 identified two heterozygous missense mutations (c.212C>T and c.292C>G), segregating in different alleles. Functional complementation experiments in patient's fibroblasts demonstrated that these mutations are disease-causing and that LIPT1 protein is required for lipoylation and activation of 2-ketoacid dehydrogenases in humans. These findings expand the spectrum of genetic defects associated with lipoic acid metabolism and provide the first evidence of a lipoic acid transfer defect in humans.","variants":[{"Name":"NM_145199.3(LIPT1):c.292C>G (p.Arg98Gly)","Chromosome":"2","Start":"99162249","Stop":"99162249","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":187696,"rule_based_match":true,"evidence_text":"c.292C>G","llm_judgment":"PRESENT","evidence":"c.292C>G","abstract_start":1313,"abstract_end":1321},{"Name":"NM_145199.3(LIPT1):c.212C>T (p.Ser71Phe)","Chromosome":"2","Start":"99162169","Stop":"99162169","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187695,"rule_based_match":true,"evidence_text":"c.212C>T","llm_judgment":"PRESENT","evidence":"c.212C>T","abstract_start":1300,"abstract_end":1308}]}
{"pmid":"25676728","title":"Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED).","abstract":"Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.","variants":[{"Name":"NM_000494.4(COL17A1):c.2816C>T (p.Thr939Ile)","Chromosome":"10","Start":"104039613","Stop":"104039613","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205532,"rule_based_match":true,"evidence_text":"c.2816C>T, p.T939I","llm_judgment":"PRESENT","evidence":"c.2816C>T, p.T939I","abstract_start":448,"abstract_end":466},{"Name":"NM_000494.4(COL17A1):c.3156C>T (p.Gly1052=)","Chromosome":"10","Start":"104037688","Stop":"104037688","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205533,"rule_based_match":true,"evidence_text":"c.3156C>T","llm_judgment":"PRESENT","evidence":"c.3156C>T","abstract_start":686,"abstract_end":695}]}
{"pmid":"32557990","title":"A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity.","abstract":"Recessively inherited limb girdle muscular dystrophy (LGMD) type 2A is the most common LGMD worldwide. Here, we report the first single missense variant in CAPN3 causing dominantly inherited calpainopathy. A 43-year-old proband, his father and two sons were heterozygous for a c.1715G>C p.(Arg572Pro) variant in CAPN3. Affected family members had at least three of the following; muscle pain, a LGMD2A pattern of muscle weakness and wasting, muscle fat replacement on magnetic resonance imaging, myopathic muscle biopsy, and elevated creatine kinase. Total calpain 3 protein expression was 4 ± 3% of normal. In vitro analysis of c.1715G>C and the previously described c.643_663del variant indicated that the mutant proteins lack autolytic and proteolytic activity and decrease the quantity of wild-type CAPN3 protein. Our findings suggest that dominantly inherited calpainopathy is not unique to the previously reported c.643_663del mutation of CAPN3, and that dominantly inherited calpainopathy should be considered for other single variations in CAPN3.","variants":[{"Name":"NM_000070.3(CAPN3):c.1715G>C (p.Arg572Pro)","Chromosome":"15","Start":"42402972","Stop":"42402972","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":271368,"rule_based_match":true,"evidence_text":"c.1715G>C p.(Arg572Pro)","llm_judgment":"PRESENT","evidence":"c.1715G>C p.(Arg572Pro)","abstract_start":277,"abstract_end":300}]}
{"pmid":"29803542","title":"A novel ZC4H2 gene mutation, K209N, in Japanese siblings with arthrogryposis multiplex congenita and intellectual disability: characterization of the K209N mutation and clinical findings.","abstract":"OBJECTIVE: To reveal a molecular lesion in the ZC4H2 gene in a Japanese family with arthrogryposis multiplex congenita (AMC) and intellectual disability (ID), and to characterize clinical features of patients with ZC4H2 gene mutations through a literature review.\nPATIENTS: The probands are male siblings. The elder brother is an 11-year-old boy who showed AMC and ID and frequent postprandial hypoglycemia since 3 years of age. The younger brother also showed AMC, ID, and subclinical postprandial hypoglycemia. The boys' mother also showed a minor malformation of the left toes.\nMETHOD AND RESULT: Using Sanger sequencing, a hemizygous one base substitution designated c.627G > C, which is predicted to substitute asparagine for lysine at amino acid residue 209 (K209N), was identified in the siblings. The mother was heterozygous for this mutation. In silico analysis predicted K209N to be a constituent of a motif required for subcellular localization of the ZC4H2 protein in the nucleus. Transient expression studies of subcellular localization in COS-7 cells showed that compared to the wild-type protein, the transport of the mutant protein into the nucleus was inhibited, thus confirming K209N as a molecular lesion in this family. The literature reviews revealed postprandial hypoglycemia as a new clinical feature that should be considered in ZC4H2 gene-mutation disorders.\nCONCLUSION: A Japanese family with AMC and ID caused by a novel ZC4H2 gene mutation was reported. Hypoglycemia should be considered one of the features in this disorder.","variants":[{"Name":"NM_018684.4(ZC4H2):c.627G>C (p.Lys209Asn)","Chromosome":"X","Start":"64917831","Stop":"64917831","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1052516,"rule_based_match":true,"evidence_text":"c.627G>C","llm_judgment":"PRESENT","evidence":"c.627G > C","abstract_start":671,"abstract_end":681}]}
{"pmid":"15024723","title":"Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.","abstract":"Hereditary hemmorrhagic telangiectasia (HHT, or Osler-Rendu-Weber syndrome) is an autosomal dominant disease characterized by arteriovenous malformations, affecting 1 out of 10,000 individuals in France. The disease is caused by mutations of two genes: ENG and ALK1 (ACVRL1). We screened the coding sequence of ENG and ALK1 in 160 unrelated French index cases. A germline mutation was identified in 100 individuals (62.5%). A total of 36 mutations were found in ENG, including three nonsense mutations, 19 small insertions/deletions leading to a frameshift, two inframe deletions, seven missense mutations, and five intronic or splice-site mutations. Of the 36 mutations, 33 were novel mutations. A total of 64 mutations were found in ALK1, including six nonsense mutations, 28 small insertions/deletions leading to a frameshift, one inframe deletion, 27 missense mutations, and two intronic or splice-site mutations. Of the 64 mutations, 27 were novel mutations. Mutations were found in most parts of the coding sequence for both genes, except ALK1 exon 5 and ENG exons 12 to 14. Missense mutations in ALK1 were more frequent in exons 7, 8, and 10. ENG cDNA was sequenced for three intronic mutations: c.689+2T>C produced an abnormal transcript excluding exon 5, c.1103+3_1103+8del activated a cryptic splice site 22 bp upstream, and c.1428G>A produced two abnormal transcripts, one including intron 11 and the other excluding exon 10. Although most of the mutations were private, some recurrent mutations in ALK1 were of particular interest. Mutation c.1112_1113dupG (p.Gly371fsX391) was found in 17 unrelated individuals sharing a common haplotype, strongly suggesting a founder effect related to the concentration of patients previously reported in a specific French region (Rhône-Alpes). Three missense mutations involved the same codon: c.1231C>T (p.Arg411Trp), c.1232G>C (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one patients, respectively. Haplotype analysis was in favor of both a founder effect and a mutation hot-spot.","variants":[{"Name":"NM_000020.3(ACVRL1):c.1232G>C (p.Arg411Pro)","Chromosome":"12","Start":"51916219","Stop":"51916219","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":23296,"rule_based_match":true,"evidence_text":"c.1232G>C (p.Arg411Pro)","llm_judgment":"PRESENT","evidence":"c.1232G>C (p.Arg411Pro)","abstract_start":1868,"abstract_end":1891},{"Name":"NM_001114753.3(ENG):c.1428G>A (p.Gln476=)","Chromosome":"9","Start":"127818716","Stop":"127818716","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3856709,"rule_based_match":true,"evidence_text":"c.1428G>A","llm_judgment":"PRESENT","evidence":"c.1428G>A","abstract_start":1335,"abstract_end":1344},{"Name":"NM_000020.3(ACVRL1):c.1232G>A (p.Arg411Gln)","Chromosome":"12","Start":"51916219","Stop":"51916219","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23282,"rule_based_match":true,"evidence_text":"c.1232G>A (p.Arg411Gln)","llm_judgment":"PRESENT","evidence":"c.1232G>A (p.Arg411Gln)","abstract_start":1897,"abstract_end":1920},{"Name":"NM_000020.3(ACVRL1):c.1231C>T (p.Arg411Trp)","Chromosome":"12","Start":"51916218","Stop":"51916218","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23290,"rule_based_match":true,"evidence_text":"c.1231C>T (p.Arg411Trp)","llm_judgment":"PRESENT","evidence":"c.1231C>T (p.Arg411Trp)","abstract_start":1843,"abstract_end":1866}]}
{"pmid":"22710133","title":"Multiple ovarian antral follicles in a preterm infant with neonatal intrahepatic cholestasis caused by citrin deficiency: a clinical, genetic and transcriptional analysis.","abstract":"Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disease caused by the dysfunction of citrin, an aspartate/glutamate carrier encoded by the SLC25A13 gene. Considerable progress has been made on the diagnosis and treatment of NICCD, but its clinical and molecular features still remain far from being completely elucidated and generally understood. The infant, a preterm female delivered at a gestational age of 31 weeks, was referred to our hospital at the age of 8 months because of jaundice lasting for 4.5 months and ovarian masses uncovered for 3 months. Besides serum indices indicating cholestasis, elevated serum levels of luteinizing hormone, follicle stimulating hormone and estradiol were also detected. Abdominal magnetic resonance imaging demonstrated bilateral multi-cystic ovarian masses, with the largest size being 7.4 × 6.2 × 9.6 mm(3). SLC25A13 gene analysis revealed that the patient was a compound heterozygote of c.1177+1G>A and c.754G>A. The paternally-inherited mutation c.754G>A was a novel one with a carrier rate of less than 1%. SLC25A13 transcriptional study in peripheral blood lymphocytes (PBLs) documented a novel splice variant r.616_848del which resulted from c.754G>A, with another variant r.1019_1177del from the maternally-inherited c.1177+1G>A mutation. The diagnoses were NICCD and multiple ovarian antral follicles (minipuberty), and the patient responded well to a galactose-free and medium chain triglyceride (MCT)-enriched formula. The findings in this paper expanded the clinical and molecular spectrum of the SLC25A13 gene, and lent support to the concept that PBLs could be taken as a feasible specimen source for SLC25A13 transcriptional analysis.","variants":[{"Name":"NM_014251.3(SLC25A13):c.754G>A (p.Glu252Lys)","Chromosome":"7","Start":"96191109","Stop":"96191109","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1438680,"rule_based_match":true,"evidence_text":"c.754G>A","llm_judgment":"PRESENT","evidence":"c.754G>A","abstract_start":997,"abstract_end":1005},{"Name":"NM_014251.3(SLC25A13):c.1177+1G>A","Chromosome":"7","Start":"96184276","Stop":"96184276","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21041,"rule_based_match":true,"evidence_text":"c.1177+1G>A","llm_judgment":"PRESENT","evidence":"c.1177+1G>A","abstract_start":981,"abstract_end":992}]}
{"pmid":"21332470","title":"Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds.","abstract":"Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a combination of neurological symptoms and hamartomatous growths, and caused by mutations in the TSC1 and TSC2 genes. Overall, TSC2 mutations are associated with a more severe disease phenotype. We identified the c.3598C>T (R1200W) change in the TSC2 gene in seven different families. The clinical phenotypes in the families were mild, characterized by mild skin lesions, remitting epilepsy and a lack of severe mental retardation or major organ involvement. Functional analysis of the TSC2 R1200W variant, and four other TSC2 missense variants associated with a mild TSC phenotype, confirmed that the changes disrupted the TSC1-TSC2 function. Interestingly however, in each case, the TSC1-TSC2 interaction was not affected by the amino acid substitution.","variants":[{"Name":"NM_000548.5(TSC2):c.3598C>T (p.Arg1200Trp)","Chromosome":"16","Start":"2080365","Stop":"2080365","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":58932,"rule_based_match":true,"evidence_text":"c.3598C>T (R1200W)","llm_judgment":"PRESENT","evidence":"c.3598C>T (R1200W)","abstract_start":297,"abstract_end":315}]}
{"pmid":"32987391","title":"A Novel Variant in G6PD (c.1375C>G) Identified from a Hispanic Neonate with Extreme Hyperbilirubinemia and Low G6PD Enzymatic Activity.","abstract":"We report a novel glucose-6-phosphate dehydrogenase (G6PD) variant (c.1375C>G) discovered in a 3-day-old Hispanic male child from Salt Lake City, UT, USA. This newborn presented with severe hyperbilirubinemia (29.8 mg/dL or 510 μmol/L) and marked hemolysis evidenced by elevated end-tidal carbon monoxide concentration (5.9 ppm, normal <1.7 ppm). Despite a very low prevalence of G6PD deficiency in Hispanic populations, we pursued testing for this condition and found he had low erythrocyte G6PD enzyme activity (2.8 U/g Hb, normal 9.9-16.6 U/g Hb) and a novel G6PD variant. His mother was heterozygous for this same variant, and she had a moderate decrease in G6PD enzyme activity (7.1 U/g Hb). On the basis of these findings, we propose this variant as a novel pathogenic mutation.","variants":[{"Name":"NM_001360016.2(G6PD):c.1375C>G (p.Arg459Gly)","Chromosome":"X","Start":"154532270","Stop":"154532270","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1780147,"rule_based_match":true,"evidence_text":"c.1375C>G","llm_judgment":"PRESENT","evidence":"c.1375C>G","abstract_start":68,"abstract_end":77}]}
{"pmid":"30809044","title":"SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections.","abstract":"SMAD4 pathogenic variants cause juvenile polyposis (JPS) and hereditary hemorrhagic telangiectasia (HHT), and 40% of affected individuals also have thoracic aortic disease. At the same time, SMAD4 pathogenic variants have not been reported in thoracic aortic disease families without JPS-HHT. A SMAD4 heterozygous variant, c.290G>T, p.(Arg97Leu), not present in population databases and predicted to be damaging to protein function, was identified in a family with thoracic aortic disease and no evidence of HHT or JPS. Cellular studies revealed that the SMAD4 p.(Arg97Leu) alteration increased SMAD4 ubiquitination and 26S proteasome-mediated protein degradation. Smooth muscle cells (SMCs) infected with lentivirus expressing the SMAD4 p.(Arg97Leu) variant demonstrated reduced contractile protein gene expression when compared to that of wild-type SMAD4. In addition, two rare variants were identified in individuals with early age of onset of thoracic aortic dissection. These results suggest that SMAD4 rare missense variants can lead to thoracic aortic disease in individuals who do not have JPS or HHT.","variants":[{"Name":"NM_005359.6(SMAD4):c.290G>T (p.Arg97Leu)","Chromosome":"18","Start":"51048726","Stop":"51048726","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":550879,"rule_based_match":true,"evidence_text":"c.290G>T, p.(Arg97Leu)","llm_judgment":"PRESENT","evidence":"c.290G>T, p.(Arg97Leu)","abstract_start":323,"abstract_end":345}]}
{"pmid":"16426447","title":"Microsatellite instability analysis in hereditary non-polyposis colon cancer using the Bethesda consensus panel of microsatellite markers in the absence of proband normal tissue.","abstract":"BACKGROUND: Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant syndrome predisposing to the early development of various cancers including those of colon, rectum, endometrium, ovarium, small bowel, stomach and urinary tract. HNPCC is caused by germline mutations in the DNA mismatch repair genes, mostly hMSH2 or hMLH1. In this study, we report the analysis for genetic counseling of three first-degree relatives (the mother and two sisters) of a male who died of colorectal adenocarcinoma at the age of 23. The family fulfilled strict Amsterdam-I criteria (AC-I) with the presence of extracolonic tumors in the extended pedigree. We overcame the difficulty of having a proband post-mortem non-tumor tissue sample for MSI testing by studying the alleles carried by his progenitors.\nMETHODS: Tumor MSI testing is described as initial screening in both primary and metastasis tumor tissue blocks, using the reference panel of 5 microsatellite markers standardized by the National Cancer Institute (NCI) for the screening of HNPCC (BAT-25, BAT-26, D2S123, D5S346 and D17S250). Subsequent mutation analysis of the hMLH1 and hMSH2 genes was performed.\nRESULTS: Three of five microsatellite markers (BAT-25, BAT-26 and D5S346) presented different alleles in the proband's tumor as compared to those inherited from his parents. The tumor was classified as high frequency microsatellite instability (MSI-H). We identified in the HNPCC family a novel germline missense (c.1864C>A) mutation in exon 12 of hMSH2 gene, leading to a proline 622 to threonine (p.Pro622Thr) amino acid substitution.\nCONCLUSION: This approach allowed us to establish the tumor MSI status using the NCI recommended panel in the absence of proband's non-tumor tissue and before sequencing the obligate carrier. According to the Human Gene Mutation Database (HGMD) and the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Database this is the first report of this mutation.","variants":[{"Name":"NM_000251.3(MSH2):c.1864C>A (p.Pro622Thr)","Chromosome":"2","Start":"47475129","Stop":"47475129","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":96280,"rule_based_match":true,"evidence_text":"c.1864C>A","llm_judgment":"PRESENT","evidence":"c.1864C>A","abstract_start":1481,"abstract_end":1490}]}
{"pmid":"21156417","title":"A new mutation in the hMSH2 gene in a Spanish Lynch syndrome family.","abstract":"We report a new germline mutation in exon 13 of the hMSH2 gene (c.2081T>C; F694S) in a patient diagnosed with colorectal carcinoma. The patient's family fulfilled the clinical criteria of the Bethesda guidelines for Lynch syndrome. The segregation analysis determined the presence of the mutation in the proband's mother (breast cancer younger than 40 years old) and in two healthy daughters. The mutation was not present in 116 normal controls screened. The medical implications for the carrier relatives are discussed.","variants":[{"Name":"NM_000251.3(MSH2):c.2081T>C (p.Phe694Ser)","Chromosome":"2","Start":"47476442","Stop":"47476442","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":419396,"rule_based_match":true,"evidence_text":"c.2081T>C","llm_judgment":"PRESENT","evidence":"c.2081T>C","abstract_start":64,"abstract_end":73}]}
{"pmid":"28283652","title":"","abstract":"Breast cancer risks conferred by many germline missense variants in the <i>BRCA1</i> and <i>BRCA2</i> genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; <i>P</i> = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; <i>P</i> = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; <i>P</i> = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; <i>P</i> = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. <i>Cancer Res; 77(11); 2789-99. ©2017 AACR</i>.","variants":[{"Name":"NM_000059.4(BRCA2):c.9104A>C (p.Tyr3035Ser)","Chromosome":"13","Start":"32379900","Stop":"32379900","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":46767,"rule_based_match":true,"evidence_text":"BRCA2 c.9104A>C, p.Tyr3035Ser","llm_judgment":"PRESENT","evidence":"BRCA2 c.9104A>C, p.Tyr3035Ser","abstract_start":553,"abstract_end":582},{"Name":"NM_000059.4(BRCA2):c.7522G>A (p.Gly2508Ser)","Chromosome":"13","Start":"32356514","Stop":"32356514","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67015,"rule_based_match":true,"evidence_text":"BRCA2 c.7522G>A, p.Gly2508Ser","llm_judgment":"PRESENT","evidence":"BRCA2 c.7522G>A, p.Gly2508Ser","abstract_start":775,"abstract_end":804},{"Name":"NM_000059.4(BRCA2):c.8187G>T (p.Lys2729Asn)","Chromosome":"13","Start":"32363389","Stop":"32363389","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":46698,"rule_based_match":true,"evidence_text":"c.8187G>T, p.Lys2729Asn","llm_judgment":"PRESENT","evidence":"c.8187G>T, p.Lys2729Asn","abstract_start":840,"abstract_end":863},{"Name":"NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln)","Chromosome":"17","Start":"43063930","Stop":"43063930","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46192,"rule_based_match":true,"evidence_text":"BRCA1 c.5096G>A, p.Arg1699Gln","llm_judgment":"PRESENT","evidence":"BRCA1 c.5096G>A, p.Arg1699Gln","abstract_start":617,"abstract_end":646}]}
{"pmid":"15795540","title":"gammaAla82Gly represents a common fibrinogen gamma-chain variant in Caucasians.","abstract":"Screening of 200 blood donors for the presence of polymorphisms in three fibrinogen genes (FGA, FGB, FGG), revealed two individuals with a heterozygous missense mutation (c.323C > G, gammaAla82Gly) in the FGG gene. This mutation has been reported previously to cause mild hypofibrinogenaemia. Analysis of an additional 416 blood donors showed two more heterozygous gammaAla82Gly mutations, resulting in an overall gammaAla82Gly allele frequency of 0.0032. Haplotype analysis demonstrated that the gammaAla82Gly mutation originated from a common founder. From these data we estimated that homozygous individuals for gammaAla82Gly should occur at a frequency of 1: 95 000, suggesting that hypofibrinogenaemia represents a more frequent condition in the population than so far believed.","variants":[{"Name":"NM_021870.3(FGG):c.323C>G (p.Ala108Gly)","Chromosome":"4","Start":"154611883","Stop":"154611883","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":538367,"rule_based_match":true,"evidence_text":"c.323C > G","llm_judgment":"PRESENT","evidence":"c.323C > G","abstract_start":171,"abstract_end":181}]}
{"pmid":"34943336","title":"Novel Compound Heterozygous Variants in","abstract":"Mutations in tubulin-specific chaperon D (TBCD), the gene encoding one of the co-chaperons required for the assembly and disassembly of the α/β-tubulin heterodimers, have been reported to cause perturbed microtubule dynamics, resulting in debilitating early-onset progressive neurodegenerative disorder. Here, we identified two novel <i>TBCD</i> variants, c.1340C>T (p.Ala447Val), and c.817+2T>C, presented as compound heterozygotes in two affected siblings born to unaffected carrier parents. Clinical features included early-onset neurodegeneration, failure to thrive, respiratory failure, hypotonia, muscle weakness and atrophy and seizures. We established the genotype-phenotype relationship of these <i>TBCD</i> pathogenic variants and provided insight into the protein structural alteration that may contribute to this chaperone-associated tubulinopathy.","variants":[{"Name":"NM_005993.5(TBCD):c.817+2T>C","Chromosome":"17","Start":"82797804","Stop":"82797804","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2951066,"rule_based_match":true,"evidence_text":"c.817+2T>C","llm_judgment":"PRESENT","evidence":"c.817+2T>C","abstract_start":385,"abstract_end":395}]}
{"pmid":"32272826","title":"Simple virilising congenital adrenal hyperplasia in monozygotic twins: A rare report and review of previous cases.","abstract":"Congenital adrenal hyperplasia (CAH) occurring in twins is extremely rare. Most of these cases are of classic salt-wasting CAH due to 21-hydroxylase enzyme deficiency. Only two cases of the simple virilising form of CAH have been reported previously, with variable clinical presentations. In this report, we describe a pair of monozygotic twins with classic simple virilising form of CAH, who had a simultaneous onset and similar severity of clinical manifestations. Genetic analysis of the CYP21A2 gene in twin 1 showed the pres-ence of two heterozygous pathogenic sequence variants, c.518T>A and c.955C>T in the CYP21A2 gene, consistent with a diagnosis of CAH due to 21-hydroxylase deficiency. We also present a brief review of previous cases of twins with CAH.","variants":[{"Name":"NM_000500.7(CYP21A2):c.955C>T (p.Gln319Ter)","Chromosome":"6","Start":"32040421","Stop":"32040421","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27208,"rule_based_match":true,"evidence_text":"c.955C>T","llm_judgment":"PRESENT","evidence":"c.955C>T","abstract_start":598,"abstract_end":606}]}
{"pmid":"32706452","title":"Farber disease in a patient from China.","abstract":"Farber disease (FD) is a rare lysosomal storage disorder caused by mutation of the ASAH1 gene. Classic symptoms of FD include subcutaneous nodules, joint pain and hoarseness. Most patients die during childhood. Here we report a 25-year-old female FD patient with rare osteolytic changes of bilateral hands and toes. Genetic analysis revealed novel compound heterozygous mutations in the ASAH1 gene (c.427T>G and c.358G>C). Further research is needed to elucidate the pathophysiological course.","variants":[{"Name":"NM_177924.5(ASAH1):c.358G>C (p.Ala120Pro)","Chromosome":"8","Start":"18067244","Stop":"18067244","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1289233,"rule_based_match":true,"evidence_text":"c.358G>C","llm_judgment":"PRESENT","evidence":"c.358G>C","abstract_start":412,"abstract_end":420}]}
{"pmid":"21644215","title":"Identification of a novel mutation of GALNS gene from a Chinese pedigree with mucopolysaccharidosis type IV A","abstract":"OBJECTIVE: To study the molecular genetic mechanism of mucopolysaccharidosis type IV A(MPS IV A), and reveal the relationship between the genotype and phenotype, and provide a basis for prenatal gene diagnosis in the future.\nMETHODS: A preliminary diagnosis was made by qualitative detection of urinary glycosaminoglycans of the suspected MPS IV A proband. Then, mutation detection was performed on the proband and her family members with PCR and direct sequencing of the PCR products. After a novel c.1567T to G mutation was detected, Xsp I restriction enzyme digestion and amplification refractory mutation system (ARMS) fast specific identification were established to analyze the sequences of exon 14 in GALNS gene, including 110 randomly selected healthy controls, the proband and other pedigree members. At the same time, bioinformatic approaches for protein secondary, tertiary structure prediction were applied to identify the novel pathologic mutation.\nRESULTS: The proband's urine GAGs test was a weak positive(± ), and a c.1567T to G heterozygous termination codon mutation in exon 14 and a c.374C to T heterozygous missense mutation in exon 4 were found. The proband was compound heterozygous of the two mutations, so was her younger sister. Her mother was a carrier with only a c.1567T to G heterozygous mutation in exon 14. Her father had a heterozygous mutation of c.374C to T in exon 4. After Xsp I restriction enzyme digestion, healthy controls had three bands including 28 bp, 120 bp and 399 bp, while the proband and her mother had four bands consisting of 28 bp, 120 bp, 148 bp and 399 bp. For amplification by ARMS specific primers, it was negative for the controls, while it was positive for the proband and the carrier. The results of protein secondary and tertiary structure prediction showed that the c.1567T to G mutation located in the stop codon, resulted in stop codon (TAG) changing to glutamic acid (GAG), with the peptide chain extending 92 amino acid residues, and secondary and tertiary protein structure change, which were not found in the controls. The result of enzyme assay showed that the activity of GALNS enzyme in the affected child was 8.3 nmol/17h/mg pr, which was obviously lower than the normal value (the normal range is 41.9-92.1 nmol/17h/mg pr).\nCONCLUSION: These results illustrate that the c.1567 T to G is a novel pathologic mutation, which is the main cause of the disease in this family.","variants":[{"Name":"NM_000512.5(GALNS):c.1567T>G (p.Ter523Glu)","Chromosome":"16","Start":"88814441","Stop":"88814441","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1036112,"rule_based_match":false,"evidence_text":"c.1567T to G","llm_judgment":"PRESENT","evidence":"c.1567T to G","abstract_start":500,"abstract_end":512}]}
{"pmid":"25241384","title":"Mutation analysis of androgen receptor gene: multiple uses for a single test.","abstract":"Androgen receptor gene mutations are one of the leading causes of disorders of sex development (DSD) exhibited by sexual ambiguity or sex reversal. In this study, 2 families with patients whom diagnosed clinically as androgen insensitivity syndrome (AIS) were physically and genetically examined. This evaluation carried out by cytogenetic and molecular analysis including karyotype and sequencing of SRY and AR genes. In family 1, two brothers and their mother were hemizygous and heterozygous respectively for c.2522G>A variant, while one of their healthy brother was a completely normal hemizygote. Family 2 assessment demonstrated the c.639G>A (rs6152) mutation in two siblings who were reared as girls. The SRY gene was intact in all of the study's participants. Our findings in family 1 could be a further proof for the pathogenicity of the c.2522G>A variant. Given the importance of AR mutations in development of problems such as sex assignment in AIS patients, definitive diagnosis and phenotype-genotype correlation could be achieved by molecular genetic tests that in turn could have promising impacts in clinical management and also in prenatal diagnosis of prospect offspring. In this regard, phenotype-genotype correlation could be helpful and achieved by molecular genetic tests. This could influence the clinical management of the patients as well as prenatal diagnosis for the prospective offspring.","variants":[{"Name":"NM_000044.6(AR):c.2522G>A (p.Arg841His)","Chromosome":"X","Start":"67722899","Stop":"67722899","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24868,"rule_based_match":true,"evidence_text":"c.2522G>A","llm_judgment":"PRESENT","evidence":"c.2522G>A","abstract_start":512,"abstract_end":521}]}
{"pmid":"25951352","title":"Electroclinical features of epileptic encephalopathy caused by SCN8A mutation.","abstract":"Voltage-gated sodium channel Nav 1.6, encoded by the gene SCN8A, plays a crucial role in controlling neuronal excitability. SCN8A mutations that cause increased channel activity are associated with seizures. We describe a patient with epileptic encephalopathy caused by de novo SCN8A mutation (c.5614C>T, p.Arg1872Trp). Seizures began 10 days after birth at which time brain magnetic resonance imaging (MRI) and electroencephalography (EEG) were normal. Seizure recurrence increased with age, leading to the development of frequent status epilepticus from 1 year of age. Seizure type included generalized tonic seizures and focal motor seizures. EEG first showed focal epileptic activity at the age of 4 months, and thereafter showed multifocal spikes. Serial MRI demonstrated brain atrophy, which appeared to progress with seizure aggravation. Clinical features that may give a clue to the diagnosis include normal EEG despite frequent seizures in early infancy and an increase in epileptic activity that occurs with aging.","variants":[{"Name":"NM_001330260.2(SCN8A):c.5614C>T (p.Arg1872Trp)","Chromosome":"12","Start":"51807100","Stop":"51807100","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":202756,"rule_based_match":true,"evidence_text":"c.5614C>T, p.Arg1872Trp","llm_judgment":"PRESENT","evidence":"c.5614C>T, p.Arg1872Trp","abstract_start":294,"abstract_end":317}]}
{"pmid":"24803844","title":"A late-onset and mild form of Charcot-Marie-Tooth disease type 2 caused by a novel splice-site mutation within the Mitofusin-2 gene.","abstract":"Charcot-Marie-Tooth type 2A disease (CMT2A) caused by mutations in the Mitofusin 2 gene (Mfn2) has been shown to be an early-onset axonal neuropathy with severe clinical course in the majority of the patients. In this study we present a unique phenotype of CMT2A disease characterized by late-onset polyneuropathy with a very mild clinical course. This rare form of CMT2A disease is caused by a new splice-site (c.311+1G>T) mutation within the MFN2 gene. Due to disturbance of the MFN2 splicing process, this mutation generates a short transcript which encodes a very short fragment of MFN2 protein. The c.311+1G>T mutation within the MFN2 gene results in the late -onset CMT2 disease.","variants":[{"Name":"NM_014874.4(MFN2):c.311+1G>T","Chromosome":"1","Start":"11992691","Stop":"11992691","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":625723,"rule_based_match":true,"evidence_text":"c.311+1G>T","llm_judgment":"PRESENT","evidence":"c.311+1G>T","abstract_start":412,"abstract_end":422}]}
{"pmid":"26133172","title":"Platelet functional alterations in a Bernard-Soulier syndrome patient with filamin A mutation.","abstract":"Defects in filamin A (FLNA) gene could lead to low platelet counts and decreased surface expression of glycoprotein (GP) Ibα. Here, we report and investigate the FLNA genomic alteration of a case with Bernard-Soulier syndrome (BSS), a rare hereditary bleeding disorder caused by quantitative or qualitative abnormalities in the GP Ib-IX-V receptor. DNA sequencing analysis reveals the presence of a GP Ibα c.987G > A mutation and a FLNA c.1582 G > A mutation in this patient. Transient transfection studies show that GP Ibα c.987G > A mutation abolishes the surface expression of GP Ibα on the transfected CHO cells. On the other hand, abnormal responses to collagen, including the platelet aggregation, secretion, and GP VI signaling pathways, are associated with FLNA c.1582G > A mutation. Our findings confirm a central role for FLNA in platelet-adhesive functions. The interaction between FLNA and GP Ibα in platelets deserves to be investigated.","variants":[{"Name":"NM_000173.7(GP1BA):c.987G>A (p.Trp329Ter)","Chromosome":"17","Start":"4933591","Stop":"4933591","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3410382,"rule_based_match":true,"evidence_text":"GP Ibα c.987G > A","llm_judgment":"PRESENT","evidence":"GP Ibα c.987G > A","abstract_start":399,"abstract_end":416}]}
{"pmid":"32548621","title":"The first case report of polymerase proofreading-associated polyposis in POLD1 variant, c.1433G>A p.S478N, in Japan.","abstract":"Polymerase proofreading-associated polyposis, caused by germline variants in the exonuclease domains of POLD1 and POLE, is a dominantly inherited rare condition characterized by oligo-adenomatous polyposis and increased risk of colorectal cancer, endometrial cancer and brain tumours. We report the first Japanese case of polymerase proofreading-associated polyposis carrying a POLD1 variant. The proband was a Japanese woman who had undergone resections of early colorectal carcinomas repeatedly and a hysterectomy with bilateral oophorectomy for endometrial cancer, all of which were diagnosed within 2 years after the first colectomy at 49 year old. Colonoscopic examinations demonstrated at least 14 non-cancerous polypoid lesions, some of which were histologically confirmed to be adenoma. Multigene panel sequencing identified a missense variant in POLD1 (c.1433G>A). Although her relatives did not undergo genetic testing, her father and paternal grandfather died of brain tumours at 53 and ~30 years of age, respectively.","variants":[{"Name":"NM_002691.4(POLD1):c.1433G>A (p.Ser478Asn)","Chromosome":"19","Start":"50406456","Stop":"50406456","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48558,"rule_based_match":true,"evidence_text":"c.1433G>A","llm_judgment":"PRESENT","evidence":"c.1433G>A","abstract_start":862,"abstract_end":871}]}
{"pmid":"36378562","title":"BEST1 novel mutation causes Bestrophinopathies in six families with distinct phenotypic diversity.","abstract":"PURPOSE: To report novel BEST1 variants in six Chinese families with bestrophinopathies of two different inheritance modes and analyze the intrafamilial phenotypic diversity.\nMETHOD: A total of 25 participants including 13 patients and 12 healthy family members from 6 Chinese families with bestrophinopathies were available for genetic and clinical analysis. All of the patients were subjected to comprehensive ophthalmic evaluations and exome sequencing was performed on the probands to detect the causative variants. The pathogenicity of gene variants was predicted using silico analysis and evaluated according to ACMG guidelines. All (likely) pathogenic variants were determined by Sanger sequencing and co-segregation analyses were performed on available family members. The relevant original literature previously reported was retrieved to explore the relationship between BEST1-related gene variants and clinical features.\nRESULTS: In the 6 families, 3 families (10 patients) were assigned as autosomal dominant bestrophinopathies (VMD) and 3 families (3 patients) were assigned as Autosomal recessive Bestrophinopathies (ARB). A total of 9 variants on the BEST1 gene were identified, containing 7 missense variants, 1 nonsense variant, and 1 frameshift variant, respectively, of which 3 variants c.88A > G (p.Lys30Glu), c.764G > A (p.Arg255Gln) and c.233dupT (p.Ser79Phefs*153) were novel variants. Three families with ARB were detected with heterozygous variants on the BEST1 gene.2 families (8 patients) with BVMD showed markedly irregular dominant inheritance, and the severity of macular lesions varies greatly among individuals of the same family. Among them, the probands showed typical vitelliform lesions in the macula, while the other six patients had no visible signs of the disease by fundus photography (ophthalmoscopy) and minor lesions could be detected on OCT in two patients, the continuity of the ellipsoidal band was interrupted with the chimeric band. The phenotypes of the patients in the three ARB families ranged from typical/atypical vitelliform lesions to extensive extramacular deposits (peripheral spots).\nCONCLUSION: This study provided evidence that the phenotype of BVMD manifested irregular dominant inheritance, with patients carrying a pathogenic heterozygous variant of BEST1 to develop obvious intrafamilial phenotypic diversity, and the patients who harbor two pathogenic alleles showed recessive inheritance bestrophinopathies with distinct phenotypic diversity. Our study also emphasized the importance of comprehensive genetic analysis in patients with bestrophinopathies, and in such challenging families with distinct intrafamilial phenotypic diversity, it shall provide novel insights into phenotypic assessments of bestrophinopathies, and contribute to better diagnosis, prognosis, and treatment for these patients.","variants":[{"Name":"NM_004183.4(BEST1):c.764G>A (p.Arg255Gln)","Chromosome":"11","Start":"61958195","Stop":"61958195","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3415478,"rule_based_match":true,"evidence_text":"c.764G > A (p.Arg255Gln)","llm_judgment":"PRESENT","evidence":"c.764G > A (p.Arg255Gln)","abstract_start":1329,"abstract_end":1353},{"Name":"NM_004183.4(BEST1):c.88A>G (p.Lys30Glu)","Chromosome":"11","Start":"61951894","Stop":"61951894","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3415476,"rule_based_match":true,"evidence_text":"c.88A > G (p.Lys30Glu)","llm_judgment":"PRESENT","evidence":"c.88A > G (p.Lys30Glu)","abstract_start":1305,"abstract_end":1327}]}
{"pmid":"33141179","title":"Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy.","abstract":"Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.","variants":[{"Name":"NM_003365.3(UQCRC1):c.931A>C (p.Ile311Leu)","Chromosome":"3","Start":"48601010","Stop":"48601010","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1052912,"rule_based_match":true,"evidence_text":"c.931A>C (p.Ile311Leu)","llm_judgment":"PRESENT","evidence":"c.931A>C (p.Ile311Leu)","abstract_start":884,"abstract_end":906},{"Name":"NM_003365.3(UQCRC1):c.941A>C (p.Tyr314Ser)","Chromosome":"3","Start":"48601000","Stop":"48601000","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1052911,"rule_based_match":true,"evidence_text":"c.941A>C (p.Tyr314Ser)","llm_judgment":"PRESENT","evidence":"c.941A>C (p.Tyr314Ser)","abstract_start":472,"abstract_end":494}]}
{"pmid":"34712946","title":"A Case Report of a Rare Heterozygous Variant in the","abstract":"Hypertrophic cardiomyopathy (HCM) is the primary cause of sudden cardiac death in children and adolescents. Patients with HCM frequently have ventricular tachycardia and ventricular fibrillation, although complete atrioventricular block (CAVB) is very rare. We report a case of HCM with CAVB in an 8-year-old girl who underwent transvenous implantable cardioverter-defibrillator placement after resuscitation. In this patient, we identified a <i>de novo</i> heterozygous missense variant, Arg406Trp (c.1216C > T), in the desmin (<i>DES)</i> gene. Pathogenic variants in the <i>DES</i> gene result in cardiomyopathy, conduction disorders, and skeletal muscle weakness. This recently identified variant may cause HCM with CAVB.","variants":[{"Name":"NM_001927.4(DES):c.1216C>T (p.Arg406Trp)","Chromosome":"2","Start":"219421532","Stop":"219421532","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31865,"rule_based_match":true,"evidence_text":"Arg406Trp (c.1216C > T)","llm_judgment":"PRESENT","evidence":"Arg406Trp (c.1216C > T)","abstract_start":489,"abstract_end":512}]}
{"pmid":"30847200","title":"Novel mutation in the","abstract":"MED23 deficiency causes the autosomal recessive Intellectual Disability (ID). Here we report an Iranian case with nonsyndromic ID presenting with developmental delay, microcephaly, hypotonia, severe ID, speech delay, and spasticity, who was homozygous for the novel MED23 c.670C>G variant. These results expand the clinical and mutation spectrum of MED23 deficiency.","variants":[{"Name":"NM_004830.4(MED23):c.670C>G (p.Arg224Gly)","Chromosome":"6","Start":"131618517","Stop":"131618517","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":430994,"rule_based_match":true,"evidence_text":"MED23 c.670C>G","llm_judgment":"PRESENT","evidence":"MED23 c.670C>G","abstract_start":266,"abstract_end":280}]}
{"pmid":"33401012","title":"Whole exome sequencing identifies a novel homozygous MECR mutation in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy.","abstract":"Childhood-onset dystonia with optic atrophy and basal ganglia abnormalities is an extremely rare autosomal recessive mitochondrial disease caused by biallelic mutations in MECR. Using whole-exome sequencing, we identified a novel homozygous MECR mutation (c.910G > T, p.Asp304Tyr) in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy. With lipoic acid treatment, the disease progression was under control, and neither visual impairment nor optic atrophy was observed. To our knowledge, this is the first study about MECR-related mitochondrial disease in a Chinese patient and the first to report that supplementation with lipoic acid is a possible effective therapeutic strategy for this disease.","variants":[{"Name":"NM_016011.5(MECR):c.910G>T (p.Asp304Tyr)","Chromosome":"1","Start":"29195995","Stop":"29195995","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1163060,"rule_based_match":true,"evidence_text":"c.910G>T (p.Asp304Tyr)","llm_judgment":"PRESENT","evidence":"p.Asp304Tyr","abstract_start":268,"abstract_end":279}]}
{"pmid":"26822784","title":"CLTC as a clinically novel gene associated with multiple malformations and developmental delay.","abstract":"Diagnostic exome sequencing has recently emerged as an invaluable tool in determining the molecular etiology of cases involving dysmorphism and developmental delay that are otherwise unexplained by more traditional methods of genetic testing. Our patient was large for gestational age at 35 weeks, delivered to a 27-year-old primigravid Caucasian whose pregnancy was complicated by preeclampsia. Neonatal period was notable for hypoglycemia, apnea, bradycardia, hyperbilirubinemia, grade I intraventricular hemorrhage, subdural hematoma, laryngomalacia, hypotonia, and feeding difficulties. The patient had numerous minor dysmorphic features. At three and a half years of age, she has global developmental delays and nystagmus, and is being followed for a mediastinal neuroblastoma that is currently in remission. Karyotype and oligo-microarray were normal. Whole-exome, next generation sequencing (NGS) coupled to bioinformatic filtering and expert medical review at Ambry Genetics revealed 14 mutations in 9 genes, and these genes underwent medical review. A heterozygous de novo frameshift mutation, c.2737_2738dupGA p.D913Efs*59, in which two nucleotides are duplicated in exon 17 of the CLTC gene, results in substitution of glutamic acid for aspartic acid at position 913 of the protein, as well as a frame shift that results in a premature termination codon situated 58 amino acids downstream. Clathrin Heavy Chain 1 (CHC1) has been shown to play an important role in the brain for vesicle recycling and neurotransmitter release at pre-synaptic nerve terminals. There is also evidence implicating it in the proper development of the placenta during the early stages of pregnancy. The CLTC alteration identified herein is likely to provide an explanation for the patient's adverse phenotype. Ongoing functional studies will further define the impact of this alteration on CHC1 function and consequently, human disease.","variants":[{"Name":"NM_004859.4(CLTC):c.2737_2738dup (p.Asp913fs)","Chromosome":"17","Start":"59677123","Stop":"59677124","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AAG","allel_id":205306,"rule_based_match":true,"evidence_text":"c.2737_2738dupGA p.D913Efs*59","llm_judgment":"PRESENT","evidence":"c.2737_2738dupGA p.D913Efs*59","abstract_start":1103,"abstract_end":1132}]}
{"pmid":"36733345","title":"Case Report: Early diagnosis of lethal multiple pterygium syndrome with micrognathia: Two novel mutations in the","abstract":"Lethal multiple pterygium syndrome (LMPS) is a rare disease with genetic and phenotypic heterogeneity and is inherited in an autosomal recessive (AR) pattern. Here, we have presented clinically significant results describing two novel mutations of <i>CHRND</i> gene: NM_000751.2: c.1006C>T p.(Arg336Ter) and NM_000751.2:c.973_975delGTG p.(Val325del), and measurement of the facial angle for determining micrognathia by prenatal diagnosis in the first trimester of pregnancy for a Lethal multiple pterygium syndrome case. In conclusion, this report complements the spectrum of genetic variants and phenotype of Lethal multiple pterygium syndrome and provides reliable recommendation for the counseling of future pregnancies in families with the disease.","variants":[{"Name":"NM_000751.3(CHRND):c.1006C>T (p.Arg336Ter)","Chromosome":"2","Start":"232531615","Stop":"232531615","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1314356,"rule_based_match":true,"evidence_text":"NM_000751.2: c.1006C>T p.(Arg336Ter)","llm_judgment":"PRESENT","evidence":"NM_000751.2: c.1006C>T p.(Arg336Ter)","abstract_start":267,"abstract_end":303}]}
{"pmid":"29656518","title":"Genotype-specific progression of hereditary medullary thyroid cancer.","abstract":"Although already 25 years into the genomic era, age-related progression of hereditary medullary thyroid cancer (MTC), the prevalence of which is estimated at one in 80,000 inhabitants, remains to be delineated for most unique RET (REarranged during Transfection) mutations. Included in this study were 567 RET carriers. The age-related progression of MTC across histopathological groups (normal thyroid/C-cell hyperplasia; node-negative MTC; node-positive MTC) was statistically significant for 13 unique RET mutations (p.Cys611Phe/c.1832G > T; p.Cys611Tyr; p.Cys618Ser/c.1852T > A; p.Cys620Arg; p.Cys634Arg; p.Cys634Phe; p.Cys634Ser; p.Cys634Tyr; p.Glu768Asp; p.Leu790Phe/c.2370G > T; p.Val804Met; p.Ser891Ala; p.Met918Thr), whereas two unique RET mutations (p.Cys618Phe; p.Cys634Gly) trended toward statistical significance. When grouped by mutational risk (highest; high; moderate-high; low-moderate; polymorphism), the age-related progression of MTC was significant for all four categories of RET mutations, which differed significantly across and within the three histopathological groups. For high, for moderate-high, and for low-moderate risk RET mutations, the age-related progression of MTC by mutated codon was broadly comparable across and within the three histopathological groups, and essentially unaffected by the amino acid substitutions examined. These data argue in favor of splitting the American Thyroid Association's moderate-risk category into moderate-high and low-moderate risk categories, while emphasizing the need to contradistinguish the latter from rare nonpathogenic polymorphisms.","variants":[{"Name":"NM_020975.6(RET):c.2370G>T (p.Leu790Phe)","Chromosome":"10","Start":"43118458","Stop":"43118458","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":47216,"rule_based_match":true,"evidence_text":"p.Leu790Phe/c.2370G>T","llm_judgment":"PRESENT","evidence":"p.Leu790Phe/c.2370G > T","abstract_start":661,"abstract_end":684},{"Name":"NM_020975.6(RET):c.2304_2307delinsCCTT (p.Glu768Asp)","Chromosome":"10","Start":"43118392","Stop":"43118395","ReferenceAlleleVCF":"GCTG","AlternateAlleleVCF":"CCTT","allel_id":2738194,"rule_based_match":false,"evidence_text":"p.Glu768Asp","llm_judgment":"PRESENT","evidence":"p.Glu768Asp","abstract_start":648,"abstract_end":659},{"Name":"NM_020975.6(RET):c.1853G>T (p.Cys618Phe)","Chromosome":"10","Start":"43113649","Stop":"43113649","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":36243,"rule_based_match":false,"evidence_text":"c.1853G>T (p.Cys618Phe)","llm_judgment":"PRESENT","evidence":"p.Cys618Phe","abstract_start":760,"abstract_end":771},{"Name":"NM_020975.6(RET):c.2753T>C (p.Met918Thr)","Chromosome":"10","Start":"43121968","Stop":"43121968","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":28958,"rule_based_match":false,"evidence_text":"p.Met918Thr","llm_judgment":"PRESENT","evidence":"p.Met918Thr","abstract_start":712,"abstract_end":723}]}
{"pmid":"27489563","title":"An","abstract":"OBJECTIVES: Current study was the first to report a consanguineous Iranian pedigree with <i>ABCD1</i> mutation.\nMETHODS: Targeted molecular analysis was initially performed in three affected individuals in one family suspected to have X-ALD due to chronic progressive spasticity. Upon confirmation of genetic diagnosis, further neurologic and genetic evaluation of all family members was done.\nRESULTS: A mutation in <i>ABCD1</i> was identified in 35 affected individuals (out 96 pedigree members). The c. 253dup, in exon 1, leads to a frame shift and a premature stop codon at amino acid position 194 (p.Arg85Profs*110). Surprisingly, affected individuals in our cohort show some variability in phenotype, including childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes, expanding the phenotype of X-ALD with p.Arg85Profs*110.\nCONCLUSION: This report characterizes the clinical spectrum of an expanded Iranian pedigree with X-ALD due to an <i>ABCD1</i> mutation. Given a high frequency of carriers in this region, we expect the prevalence of X-ALD to be higher, underscoring the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities.","variants":[{"Name":"NM_000033.4(ABCD1):c.253dup (p.Arg85fs)","Chromosome":"X","Start":"153725514","Stop":"153725515","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":171860,"rule_based_match":true,"evidence_text":"c. 253dup","llm_judgment":"PRESENT","evidence":"c. 253dup","abstract_start":503,"abstract_end":512}]}
{"pmid":"30965144","title":"An extremely severe case of Aicardi-Goutières syndrome 7 with a novel variant in IFIH1.","abstract":"We describe herein an extremely severe case of Aicardi-Goutières syndrome 7 (AGS7). The female patient was the daughter of nonconsanguineous parents and developed cardiomegaly, pericardial effusion, splenomegaly, and intracranial calcification during the fetal period. Because her cardiotocogram showed a non-reassuring fetal status, she was delivered at 29 weeks and 4 days of gestation by an emergency cesarean section. After birth, she suffered from respiratory distress, pulmonary hypertension, refractory fever, recurrent thrombocytopenia, and abdominal distention caused by hepatomegaly and ascites. She showed a lenticulostriate vasculopathy, which was compatible with the fetal intracranial calcification. Despite various intensive care procedures, she died of gradually progressive pulmonary hypertension at 3 months of age. After her death, whole exome sequencing on the patient and the parents was performed and revealed a novel, de novo, heterozygous mutation in the IFIH1 gene (IFIH1:NM_022168:exon12:c.2439A > T:p.Glu813Asp). On the basis of the mutation and the clinical features, the diagnosis was AGS7. Although AGS7 has been regarded as a relatively mild subtype of Aicardi-Goutières syndrome, this case indicates that the c.2439A > T variant of AGS7 can be fatal in early infancy.","variants":[{"Name":"NM_022168.4(IFIH1):c.2439A>T (p.Glu813Asp)","Chromosome":"2","Start":"162273810","Stop":"162273810","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":612450,"rule_based_match":true,"evidence_text":"c.2439A > T:p.Glu813Asp","llm_judgment":"PRESENT","evidence":"c.2439A > T:p.Glu813Asp","abstract_start":1014,"abstract_end":1037}]}
{"pmid":"22877996","title":"The PRRT2 mutation c.649dupC is the so far most frequent cause of benign familial infantile convulsions.","abstract":"PURPOSE: Mutations in the PRRT2 gene have been recently described as a cause of paroxysmal kinesigenic dyskinesia, infantile convulsions with choreoathetosis syndrome and, less often, infantile convulsions. We have analysed the frequency of PRRT2 mutations in families with benign familial infantile convulsions without paroxysmal kinesigenic dyskinesia.\nMETHODS AND RESULTS: Direct sequencing of the coding region identified the PRRT2 mutation c.649dupC in 5/5 families with infantile convulsions. The mutation was present in 23 family members, of which 18 were clinically affected and 2 were obligate carriers. The affected carriers of this mutation presented with different types of epileptic seizures during early childhood but did not develop additional neurological symptoms later in life.\nCONCLUSION: Our data demonstrate that the PRRT2 mutation c.649dupC is a frequent cause of benign familial infantile convulsions.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC","llm_judgment":"PRESENT","evidence":"c.649dupC","abstract_start":445,"abstract_end":454}]}
{"pmid":"35782625","title":"A novel","abstract":"Coenzyme Q<sub>10</sub> (CoQ<sub>10</sub>) is necessary as electron transporter in mitochondrial respiration and other cellular functions. CoQ<sub>10</sub> is synthesized by all cells and defects in the synthesis pathway result in primary CoQ<sub>10</sub> deficiency that frequently leads to severe mitochondrial disease syndrome. CoQ<sub>10</sub> is exceedingly hydrophobic, insoluble, and poorly bioavailable, with the result that dietary CoQ<sub>10</sub> supplementation produces no or only minimal relief for patients. We studied a patient from Turkey and identified and characterized a new mutation in the CoQ<sub>10</sub> biosynthetic gene <i>COQ7</i> (c.161G > A; p.Arg54Gln). We find that unexpected neuromuscular pathology can accompany CoQ<sub>10</sub> deficiency caused by a <i>COQ7</i> mutation. We also show that by-passing the need for COQ7 by providing the unnatural precursor 2,4-dihydroxybenzoic acid, as has been proposed, is unlikely to be an effective and safe therapeutic option. In contrast, we show for the first time in human patient cells that the respiratory defect resulting from CoQ<sub>10</sub> deficiency is rescued by providing CoQ<sub>10</sub> formulated with caspofungin (CF/CoQ). Caspofungin is a clinically approved intravenous fungicide whose surfactant properties lead to CoQ<sub>10</sub> micellization, complete water solubilization, and efficient uptake by cells and organs in animal studies. These findings reinforce the possibility of using CF/CoQ in the clinical treatment of CoQ<sub>10</sub>-deficient patients.","variants":[{"Name":"NM_016138.5(COQ7):c.161G>A (p.Arg54Gln)","Chromosome":"16","Start":"19072015","Stop":"19072015","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":578526,"rule_based_match":true,"evidence_text":"c.161G > A; p.Arg54Gln","llm_judgment":"PRESENT","evidence":"c.161G > A; p.Arg54Gln","abstract_start":659,"abstract_end":681}]}
{"pmid":"34445920","title":"Novel mutation in","abstract":"BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is a rare retinal disorder characterised by incomplete retinal vascular development. Symptoms vary widely from none to blindness even within the same family. Multiple genes related to the Wnt pathway have been found to be associated with FEVR. Recent studies identified tetraspanin 12 (<i>TSPAN12</i>) as a cause of the autosomal dominant inheritance form of FEVR. Here, we describe a novel <i>TSPAN12</i> mutation in a Chinese family with FEVR.\nMETHODS: Targeted next-generation sequencing was performed on the proband to define the <i>TSPAN12</i> mutation. Sanger sequencing was used to confirm the mutation in five family members (I-1, II-2, II-3, II-4, and III-3) in a three-generation FEVR pedigree. Ophthalmologic examinations and diagnostic imaging related to FEVR were performed.\nRESULTS: The proband (II-3) was a 32-year-old man with early-stage peripheral retinal vascular anomalies, but no visual acuity problems. DNA sequencing identified a heterozygous missense mutation (c.241 G > A: p.Gly81Arg) in <i>TSPAN12</i> in the proband. The mutation was in a highly conserved region and was predicted to affect the normal protein structure. The patient's father and daughter were also diagnosed with FEVR and carried the same mutation, with varying degrees of manifestations. Other family members had good vision and normal eye examinations with negative genetic testing.\nCONCLUSIONS: We identified a novel missense mutation in <i>TSPAN12</i> associated with autosomal dominant FEVR. These results will facilitate the diagnosis, prognosis, and genetic counselling for this disease. Further studies are needed to identify the mechanisms underlying clinical variations among individuals in the family.","variants":[{"Name":"NM_012338.4(TSPAN12):c.241G>A (p.Gly81Arg)","Chromosome":"7","Start":"120838821","Stop":"120838821","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2088587,"rule_based_match":true,"evidence_text":"c.241 G > A: p.Gly81Arg","llm_judgment":"PRESENT","evidence":"c.241 G > A: p.Gly81Arg","abstract_start":1041,"abstract_end":1064}]}
{"pmid":"31851094","title":"MSH6 gene pathogenic variant identified in familial pancreatic cancer in the absence of colon cancer.","abstract":"OBJECTIVES: Lynch syndrome is characterized by pathogenetic variants in the mismatch repair genes and autosomal dominant inheritance with incomplete penetrance. Lynch syndrome is characterized by colorectal and, with lesser and variable extent, extracolonic cancers. We describe a family with MSH6-dependent Lynch syndrome and familial pancreatic cancer and other tumours (gastric and endometrial), in the absence of colorectal neoplasia.\nMETHODS: Patients were analysed by sequencing, Next Generation or Sanger, to identify germinal pathogenic variants in hereditary cancer genes.\nRESULTS: We identified the MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter) in a family with hereditary pancreatic cancer without diagnosed cases of colorectal adenocarcinoma. Seven family members were affected by the MSH6 pathogenic variant. Three had pancreatic adenocarcinoma at 65, 57 and 44 years; one had endometrial cancer at 36 years. None of the remaining three subjects (75, 45 and 17 years old) had developed any cancer yet.\nCONCLUSIONS: Lynch syndrome should be suspected in families with familial pancreatic cancer, even in the absence of colon cancers. Specifically, our observation supports the association between the MSH6 c.2194C>T pathogenic variant and extracolonic tumours and it suggests that MSH6 pathogenic variants are associated with familial pancreatic cancer more frequently than assumed.","variants":[{"Name":"NM_000179.3(MSH6):c.2194C>T (p.Arg732Ter)","Chromosome":"2","Start":"47800177","Stop":"47800177","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":94736,"rule_based_match":true,"evidence_text":"MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter)","llm_judgment":"PRESENT","evidence":"MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter)","abstract_start":609,"abstract_end":662}]}
{"pmid":"30071302","title":"A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation.","abstract":"Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inborn errors of metabolism with around 100 types described so far. Because of the limited number of reported cases in each type except PMM2-CDG, the complete clinical picture of other types is not known. RFT1-CDG is a rare type, with ten cases reported in the literature. Our patient presented as a floppy neonate with severe respiratory insufficiency and ventilator dependence in the newborn period. He had fetal growth restriction, facial dysmorphism, high arched palate, bilateral cryptorchidism, hypoplastic pons and cerebellum and probable hearing impairment. He succumbed to the illness on day 24 of life. There was a similar history of two previous sibling deaths in the early neonatal period due to respiratory insufficiency and history of multiple neonatal and infant deaths in the extended family. Transferrin iso-electric focusing was normal. Clinical exome sequencing revealed a novel homozygous missense mutation (c.1018 G > A) in RFT1 gene [NM_052859; c.1018G > A; p.G340S; ENST00000296292] and the parents were heterozygous for the same (ClinVar SVC000778540). The pathogenic variants so far reported are all missense variants affecting the luminal loops; whereas the variant in our case is in the trans-membrane helical domain. A strong family history of neonatal deaths and similar presentations in the previous 2 siblings suggests the homogenous phenotype of this mutation. Severe respiratory insuffiency and ventilator dependence shows the lethality of the disease phenotype and incompatibility with survival beyond the neonatal period.","variants":[{"Name":"NM_052859.4(RFT1):c.1018G>A (p.Gly340Ser)","Chromosome":"3","Start":"53104037","Stop":"53104037","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":536137,"rule_based_match":true,"evidence_text":"c.1018G > A; p.G340S","llm_judgment":"PRESENT","evidence":"c.1018G > A; p.G340S","abstract_start":1044,"abstract_end":1064}]}
{"pmid":"21935370","title":"Variants of OTOF and PJVK genes in Chinese patients with auditory neuropathy spectrum disorder.","abstract":"BACKGROUND: Mutations in OTOF and PJVK genes cause DFNB9 and DFNB59 types of hearing loss, respectively. The patients carrying pathogenic mutations in either of these genes may show the typical phenotype of auditory neuropathy spectrum disorder (ANSD). The aim of the present study was to identify OTOF and PJVK mutations in sporadic ANSD patients.\nMETHODS AND FINDINGS: A total of 76 unrelated Chinese non-syndromic ANSD patients were sequenced on the gene OTOF and PJVK exon by exon. Variants were valued in 105 controls with normal hearing to verify the carrying rate. We identified one pathogenic mutation (c.1194T>A) and three novel, possibly pathogenic, variants (c.3570+2T>C, c.4023+1 G>A, and c.1102G>A) in the OTOF gene, and one novel, possibly pathogenic, variant (c.548G>A) in PJVK. Moreover, we found three novel missense mutations within the exons of OTOF.\nCONCLUSIONS: As we identified 4 and 1 possible pathogenic variants of the OTOF gene and the PJVK gene, respectively, we believe that screening in these genes are important in sporadic ANSD patients. The pathogenicity of these novel mutations needs further study because of their single heterozygous nature. Knowledge on the mutation spectra of these genes in Chinese would be beneficial in understanding the genetic character of this worldwide disease.","variants":[{"Name":"NM_194248.3(OTOF):c.4023+1G>A","Chromosome":"2","Start":"26470592","Stop":"26470592","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":57393,"rule_based_match":true,"evidence_text":"c.4023+1 G>A","llm_judgment":"PRESENT","evidence":"c.4023+1 G>A","abstract_start":683,"abstract_end":695},{"Name":"NM_194248.3(OTOF):c.1194T>A (p.Asp398Glu)","Chromosome":"2","Start":"26484485","Stop":"26484485","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":57330,"rule_based_match":true,"evidence_text":"c.1194T>A","llm_judgment":"PRESENT","evidence":"c.1194T>A","abstract_start":611,"abstract_end":620},{"Name":"NM_001042702.5(PJVK):c.548G>A (p.Arg183Gln)","Chromosome":"2","Start":"178456150","Stop":"178456150","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":490780,"rule_based_match":true,"evidence_text":"c.548G>A","llm_judgment":"PRESENT","evidence":"c.548G>A","abstract_start":775,"abstract_end":783}]}
{"pmid":"30170160","title":"MHC-II Deficiency Among Egyptians: Novel Mutations and Unique Phenotypes.","abstract":"BACKGROUND: MHC class II deficiency leads to defective CD4<sup>+</sup> T-cell function that results from impaired antigen presentation. A genetic disorder in 1 of 4 genes results in this syndrome that is associated with the clinical phenotype of combined immunodeficiency.\nOBJECTIVE: To describe the clinical, immunological, and molecular characteristics of 10 Egyptian patients from 9 different families having presented with MHC class II deficiency between 2012 and 2017.\nMETHODS: An initial diagnosis based on the combination of clinical features and low HLA-DR expression by flow cytometry was confirmed by genetic analyses.\nRESULTS: Symptoms included failure to thrive (n = 9), persistent diarrhea (n = 5), and pneumonia (n = 8). Septicemia due to coagulase-negative staphylococci (n = 1) and Candida krusei (n = 1) was diagnosed. Nine patients orally received the live attenuated polio vaccine, of whom 3 developed acute flaccid paralysis thereafter. Nine patients received the BCG vaccine and none developed obvious signs of BCGitis. Four patients carried RFXANK gene mutations, 3 carried RFX5 gene mutations, 1 carried a CIITA gene mutation, and none carried RFXAP gene mutations. Six of the 7 detected mutations were previously unreported mutations: c.431T>C, c.247_250delTCAG, and c.600delG in the RFXANK gene; c.116+1G>A and c.715C>T in the RFX5 gene; and c.929delA in the CIITA gene.\nCONCLUSIONS: Given that Egypt is a North African country with a high rate of consanguinity, MHC class II deficiency is not rare. However, the molecular defects differ from those reported in nearby countries. Early diagnosis must be based on suspicious clinical signs and laboratory diagnosis because the defect can be missed by T-cell receptor excision circles based on neonatal screening.","variants":[{"Name":"NM_003721.4(RFXANK):c.600del (p.Asn201fs)","Chromosome":"19","Start":"19198690","Stop":"19198690","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":1892384,"rule_based_match":true,"evidence_text":"c.600delG in the RFXANK gene","llm_judgment":"PRESENT","evidence":"c.600delG in the RFXANK gene","abstract_start":1291,"abstract_end":1319},{"Name":"NM_001025603.2(RFX5):c.715C>T (p.Arg239Ter)","Chromosome":"1","Start":"151343723","Stop":"151343723","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1882063,"rule_based_match":true,"evidence_text":"c.715C>T in the RFX5 gene","llm_judgment":"PRESENT","evidence":"c.715C>T in the RFX5 gene","abstract_start":1336,"abstract_end":1361}]}
{"pmid":"31215171","title":"A novel homozygous initiation codon variant associated with infantile alpha-Bcrystallinopathy in a Chinese family.","abstract":"BACKGROUND: Due to inconsistencies with reported myofibrillar myopathy (MFM), including autosomal dominant inheritance, late onset and a slowly progressive course, the severe, recessively inherited form of CRYAB (alpha-B crystallin) gene-related infantile MFM has been suggested. Here, we report an infant in a Chinese family with fatal neonatal-onset hypertonic MFM with a novel CRYAB homozygous variant (c.3G > A (p.Met1?)).\nMETHODS: Muscle biopsy indicated that muscle fibers showed a uniformly small diameter, cell atrophy, and visible focal muscle fiber degeneration and necrosis consistent with myogenic myopathy. We performed the whole exome sequencing of pathogenic genes and identified it as MFM.\nRESULTS: The proband presented with profound muscle stiffness, progressive respiratory distress and a concurrent abnormal increase in myocardial enzymogram, and the patient died in the 17th month of life. Muscle biopsy and electron microscopy results were consistent with ultramicroscopic myogenic damage and pathological changes. Mutation analysis of the proband identified a novel rare homozygous mutation in the initiation codon of the CRYAB gene, which was inherited from currently asymptomatic, heterozygous carrier parents, and his heterozygous biological brother is unaffected.\nCONCLUSIONS: This article reports one infant with CRYAB-related neonatal onset MFM with a novel homozygous variant in CRYAB. To our knowledge, this is the first reported case of infantile alpha-Bcrystallinopathy in the Chinese population.","variants":[{"Name":"NM_001289808.2(CRYAB):c.3G>A (p.Met1Ile)","Chromosome":"11","Start":"111911722","Stop":"111911722","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":53403,"rule_based_match":true,"evidence_text":"c.3G > A (p.Met1?)","llm_judgment":"PRESENT","evidence":"c.3G > A (p.Met1?)","abstract_start":406,"abstract_end":424}]}
{"pmid":"23541342","title":"Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.","abstract":"The genetic causes of premature ovarian failure (POF) are highly heterogeneous, and causative mutations have been identified in more than ten genes so far. In two families affected by POF accompanied by hearing loss (together, these symptoms compose Perrault syndrome), exome sequencing revealed mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase: homozygous c.1565C>A (p.Thr522Asn) in a consanguineous Palestinian family and compound heterozygous c.1077delT and c.1886C>T (p.Thr629Met) in a nonconsanguineous Slovenian family. LARS2 c.1077delT leads to a frameshift at codon 360 of the 901 residue protein. LARS2 p.Thr522Asn occurs in the LARS2 catalytic domain at a site conserved from bacteria through mammals. LARS2 p.Thr629Met occurs in the LARS2 leucine-specific domain, which is adjacent to a catalytic loop critical in all species but for which primary sequence is not well conserved. A recently developed method of detecting remote homologies revealed threonine at this site in consensus sequences derived from multiple-species alignments seeded by human and E. coli residues at this region. Yeast complementation indicated that LARS2 c.1077delT is nonfunctional and that LARS2 p.Thr522Asn is partially functional. LARS2 p.Thr629Met was functional in this assay but might be insufficient as a heterozygote with the fully nonfunctional LARS2 c.1077delT allele. A known C. elegans strain with the protein-truncating alteration LARS-2 p.Trp247Ter was confirmed to be sterile. After HARS2, LARS2 is the second gene encoding mitochondrial tRNA synthetase to be found to harbor mutations leading to Perrault syndrome, further supporting a critical role for mitochondria in the maintenance of ovarian function and hearing.","variants":[{"Name":"NM_015340.4(LARS2):c.1565C>A (p.Thr522Asn)","Chromosome":"3","Start":"45496316","Stop":"45496316","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":70522,"rule_based_match":true,"evidence_text":"c.1565C>A (p.Thr522Asn)","llm_judgment":"PRESENT","evidence":"c.1565C>A (p.Thr522Asn)","abstract_start":374,"abstract_end":397},{"Name":"NM_015340.4(LARS2):c.1886C>T (p.Thr629Met)","Chromosome":"3","Start":"45516118","Stop":"45516118","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70523,"rule_based_match":true,"evidence_text":"c.1886C>T (p.Thr629Met)","llm_judgment":"PRESENT","evidence":"c.1886C>T (p.Thr629Met)","abstract_start":478,"abstract_end":501},{"Name":"NM_015340.4(LARS2):c.1077del (p.Ile360fs)","Chromosome":"3","Start":"45485749","Stop":"45485749","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":70524,"rule_based_match":true,"evidence_text":"c.1077delT","llm_judgment":"PRESENT","evidence":"c.1077delT","abstract_start":463,"abstract_end":473}]}
{"pmid":"32017041","title":"An M1AP homozygous splice-site mutation associated with severe oligozoospermia in a consanguineous family.","abstract":"Severe oligozoospermia (SO) is an important cause of male infertility. Its etiology and pathogenesis are associated with genetic abnormalities; however, the genetic causes of the majority of idiopathic human SO remain unclear. Here, we report a homozygous splice-site mutation in M1AP (meiosis 1 associated protein; NM_138804, c.1435-1G>A) observed in a patient with SO from a consanguineous Han Chinese family. His parents and fertile brother were heterozygous for the mutation. The splice variant led to a lack of M1AP protein in the patient's spermatozoa. Ultrastructural and immunostaining analyses of patient's spermatozoa showed highly aberrant swollen mitochondrial sheaths with normal axonemal structures. Subsequent mutation screening identified three additional heterozygous M1AP variants in 4/243 subjects with idiopathic SO, but no M1AP variants among 223 fertile subjects. Additionally, a previously study reported that M1ap knock-out mice exhibited SO due to meiotic arrest. Hence, our findings indicate that M1AP mutation might represent novel genetic alteration responsible for human SO.","variants":[{"Name":"NM_001321739.2(M1AP):c.1435-1G>A","Chromosome":"2","Start":"74558875","Stop":"74558875","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":858300,"rule_based_match":true,"evidence_text":"NM_138804, c.1435-1G>A","llm_judgment":"PRESENT","evidence":"NM_138804, c.1435-1G>A","abstract_start":316,"abstract_end":338}]}
{"pmid":"23535506","title":"The genetic spectrum of familial hypercholesterolemia in Pakistan.","abstract":"BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes coding for the low density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type-9 (PCSK9) or apo-lipoprotein B-100 (APOB). The aim of the present work was to determine the genetic basis of dyslipidemia in 11 unrelated Pakistani families.\nMETHODS: High resolution melting (HRM), sequencing and restriction fragment length polymorphism (RFLP).\nRESULTS: Probands were screened for the promoter and all coding regions, including intron/exon boundaries, of LDLR and PCSK9 and part of exon 26 of APOB including p.(R3527Q). Two families were identified with previously unreported LDLR mutations (c.1019_1020delinsTG, p.(C340L) and c.1634G>A, p.(G545E)). Both probands had tendon xanthomas or xanthelasma and/or a history of cardiovascular disease. Co-segregation with hypercholesterolemia was demonstrated in both families. In silico studies predicted these variations to be damaging. In two families, novel PCSK9 variations were identified (exon2; c.314G>A, p.(R105Q) and exon3; c.464C>T, p.(P155L)). In silico studies suggested both were likely to be damaging, and family members carrying the p.(105Q) allele had lower total cholesterol levels, suggesting this is a loss-of-function mutation. For c.464C>T p.(P155L) the small number of relatives available precluded any strong inference.\nCONCLUSION: This report brings to seven the number of different LDLR mutations reported in FH patients from Pakistan and, as expected in this heterogeneous population, no common LDLR mutation has been identified.","variants":[{"Name":"NM_000527.5(LDLR):c.1019_1020delinsTG (p.Cys340Leu)","Chromosome":"19","Start":"11110730","Stop":"11110731","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"TG","allel_id":245924,"rule_based_match":true,"evidence_text":"c.1019_1020delinsTG, p.(C340L)","llm_judgment":"PRESENT","evidence":"c.1019_1020delinsTG, p.(C340L)","abstract_start":722,"abstract_end":752},{"Name":"NM_000527.5(LDLR):c.1634G>A (p.Gly545Glu)","Chromosome":"19","Start":"11116141","Stop":"11116141","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":246250,"rule_based_match":true,"evidence_text":"c.1634G>A, p.(G545E)","llm_judgment":"PRESENT","evidence":"c.1634G>A, p.(G545E)","abstract_start":757,"abstract_end":777},{"Name":"NM_174936.4(PCSK9):c.464C>T (p.Pro155Leu)","Chromosome":"1","Start":"55046587","Stop":"55046587","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":616154,"rule_based_match":true,"evidence_text":"c.464C>T (p.(P155L))","llm_judgment":"PRESENT","evidence":"c.464C>T","abstract_start":1106,"abstract_end":1114},{"Name":"NM_174936.4(PCSK9):c.314G>A (p.Arg105Gln)","Chromosome":"1","Start":"55043949","Stop":"55043949","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":538522,"rule_based_match":true,"evidence_text":"c.314G>A","llm_judgment":"PRESENT","evidence":"c.314G>A","abstract_start":1075,"abstract_end":1083}]}
{"pmid":"21549339","title":"A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia.","abstract":"The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi.","variants":[{"Name":"NM_004287.5(GOSR2):c.430G>T (p.Gly144Trp)","Chromosome":"17","Start":"46935122","Stop":"46935122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39363,"rule_based_match":true,"evidence_text":"c.430G>T (p.Gly144Trp)","llm_judgment":"PRESENT","evidence":"p.Gly144Trp","abstract_start":482,"abstract_end":493}]}
{"pmid":"32524016","title":"UNUSUAL PRESENTATIONS OF","abstract":"OBJECTIVE: Lipodystrophy represents a group of rare diseases characterized by loss of body fat. While patients with generalized lipodystrophy exhibit near-total lack of fat, partial lipodystrophy is associated with selective fat loss affecting certain parts of the body. Although classical familial partial lipodystrophy (FPLD) is a well-described entity, recent reports indicate phenotypic heterogeneity among carriers of <i>LMNA</i> pathogenic variants.\nMETHODS: We have encountered 2 unique cases with complex phenotypes, generalized fat loss, and very low leptin levels that made the distinction between generalized versus partial lipodystrophy quite challenging.\nRESULTS: We present a 61-year-old female with generalized fat loss, harboring the heterozygous pathogenic variant p.R541P (c.1622G>C) on the <i>LMNA</i> gene. The discovery of the pathogenic variant led to correct clinical diagnosis of her muscle disease, identification of significant heart disease, and a recommendation for the implantation of a defibrillator. She was able to start metreleptin based on her generalized fat loss pattern and demonstration of the genetic variant. Secondly, we report a 40-year-old Turkish female with generalized fat loss associated with a novel heterozygous <i>LMNA</i> pathogenic variant p.K486E (c.1456A>G), who developed systemic B cell follicular lymphoma.\nCONCLUSION: Clinicians need to recognize that the presence of an <i>LMNA</i> variant does not universally lead to FPLD type 2, but may lead to a phenotype that is more complex and may resemble more closely generalized lipo-dystrophy. Additionally, providers should recognize the multisystem features of laminopathies and should screen for these features in affected patients, especially if the variant is not at the known hotspot for FPLD type 2.","variants":[{"Name":"NM_170707.4(LMNA):c.1622G>C (p.Arg541Pro)","Chromosome":"1","Start":"156137667","Stop":"156137667","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":77758,"rule_based_match":true,"evidence_text":"c.1622G>C","llm_judgment":"PRESENT","evidence":"c.1622G>C","abstract_start":791,"abstract_end":800}]}
{"pmid":"27430617","title":"Molecular analysis of FGFR 2 and associated clinical observations in two Chinese families with Crouzon syndrome.","abstract":"Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak‑like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811‑812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of our knowledge, the identification of two novel FGFR 2 gene mutations in Chinese patients with Crouzon syndrome.","variants":[{"Name":"NM_000141.5(FGFR2):c.842A>G (p.Tyr281Cys)","Chromosome":"10","Start":"121520076","Stop":"121520076","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":361719,"rule_based_match":true,"evidence_text":"c.842A>G (P.Tyr281Cys or Y281C)","llm_judgment":"PRESENT","evidence":"c.842A>G (P.Tyr281Cys or Y281C)","abstract_start":1615,"abstract_end":1646}]}
{"pmid":"25578555","title":"Uniparental disomy as a cause of spinal muscular atrophy and progressive myoclonic epilepsy: phenotypic homogeneity due to the homozygous c.125C>T mutation in ASAH1.","abstract":"Spinal muscular atrophy and progressive myoclonic epilepsy (SMAPME, OMIM#159950) is a rare autosomal recessive disorder characterized by the combination of progressive myoclonic epilepsy and muscular weakness due to lower motor neuron disease. Mutations in ASAH1, previously associated only to Farber disease, have been recently described in seven patients with SMAPME. A homozygous c.125C>T mutation was initially found in six patients with a clinical homogeneous phenotype. A heterozygous compound mutation found in an additional patient has broadened the clinical and genetic spectrum of clinical SMAPME. We report a new case of a 13-year-old girl with SMAPME with the homozygous ASAH1 c.125C>T mutation, unique in that it is due to paternal uniparental disomy. She experienced muscle weakness from the age of three due to lower motor neuron involvement that lead to severe handicap and onset in late childhood of a progressive myoclonic epilepsy. This clinical picture fully overlaps with that of previously reported patients with this mutation and supports our view that the clinical phenotype associated with the homozygous c.125C>T mutation constitutes a clinically homogenous and recognizable disease.","variants":[{"Name":"NM_177924.5(ASAH1):c.125C>T (p.Thr42Met)","Chromosome":"8","Start":"18075541","Stop":"18075541","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44215,"rule_based_match":true,"evidence_text":"c.125C>T","llm_judgment":"PRESENT","evidence":"c.125C>T","abstract_start":383,"abstract_end":391}]}
{"pmid":"22126643","title":"dRTA and hemolytic anemia: first detailed description of SLC4A1 A858D mutation in homozygous state.","abstract":"Mutations in the anion exchanger 1 (AE1) gene encoding the erythroid and kidney anion (chloride-bicarbonate) exchanger 1 may result in familial distal renal tubular acidosis (dRTA) in association with membrane defect hemolytic anemia. Seven children presenting with hyperchloremic normal anion gap metabolic acidosis, failure to thrive, and compensated hemolytic anemia were studied. Analysis of red cell AE1/Band 3 surface expression by Eosin 5'-maleimide (E5M) was performed in patients and their family members using flow cytometry. Genetic studies showed that all patients carried a common SLC4A1 mutation, c.2573C>A; p.Ala858Asp in exon 19, found as homozygous (A858D/A858D) mutation in the patients and heterozygous (A858D/N) in the parents. Analysis by flowcytometry revealed a single uniform fluorescence peak, with the mean channel fluorescence (MCF) markedly reduced in cases with homozygous mutation, along with a left shift of fluorescence signal but was only mildly reduced in the heterozygous state. Red cell morphology showed striking acanthocytosis in the homozygous state [patients] and only a mild acanthocytosis in heterozygous state [parents]. In conclusion, this is the first description of a series of homozygous cases with the A858D mutation. The E5M flowcytometry test is specific for reduction in the Band 3 membrane protein and was useful in conjunction with a careful morphological examination of peripheral blood smears in our patient cohort.","variants":[{"Name":"NM_000342.4(SLC4A1):c.2573C>A (p.Ala858Asp)","Chromosome":"17","Start":"44251241","Stop":"44251241","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":32810,"rule_based_match":true,"evidence_text":"c.2573C>A; p.Ala858Asp","llm_judgment":"PRESENT","evidence":"c.2573C>A; p.Ala858Asp","abstract_start":611,"abstract_end":633}]}
{"pmid":"27142856","title":"Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant.","abstract":"BACKGROUND: Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma.\nMETHODS: To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations.\nRESULTS: p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed.\nCONCLUSIONS: We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option.","variants":[{"Name":"NM_000169.3(GLA):c.427G>A (p.Ala143Thr)","Chromosome":"X","Start":"101401752","Stop":"101401752","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25787,"rule_based_match":true,"evidence_text":"c.427G > A","llm_judgment":"PRESENT","evidence":"c.427G > A","abstract_start":272,"abstract_end":282}]}
{"pmid":"19936001","title":"Genetic analysis (PKD2) of autosomal dominant polycystic kidney disease","abstract":"Autosomal dominant polycystic kidney disease is a multi-organic hereditary disorder. It is responsible for 7-10% of cases of end stage renal failure. It is caused by mutations in the genes PKD1 and PKD2. Both polycystic kidney disease's forms have a pathogeny and similar clinic, but in the patients with mutation in PKD2, the clinical manifestations appear later and the progression to end stage renal failure happens 10 years later than in the patients with mutation in PKD1. The diagnosis of this disease can be performed through ultrasounds, but the molecular diagnosis offers some advantages, such as the early detection of asymptomatic individuals who carry this genetic defect, in order to perform a preventive monitoring and genetic counselling. In this work, we present the results of the mutational analysis of the PKD2 gene in 18 patients diagnosed with autosomal dominant polycystic kidney disease. The objectives of this work were to analyze the profitability of the genetic study compared with the radiologic study, and perform an early genetic diagnosis in the descendants of patients who were affected by a mutation in the PKD2 gene, trying to establish a correlation between phenotype and genotype. After the genetic analysis, only one family was diagnosed with a mutation in exon 13 of the PKD2 gene (5.56%), which consists on a substitution of the nucleotide adenosine by cytosine (c.2398A>C), which implies that the amino acid methionine is replaced by leucine (p.800Met>Leu). In our population, contrary to what was published in the literature, the mutation of the gene was clinically significant and did segregate with the disease. All the members with a clinical and ultrasound diagnosis of polycystic renal disease presented the above mentioned mutation. We could not confirm any clinical-genetic correlation. Due to the high prevalence of chronic renal failure and terminal chronic renal failure secondary to polycystic kidney disease in our study, an early genetic diagnosis would involve a better prognosis in connection with a closer clinical monitoring.","variants":[{"Name":"NM_000297.4(PKD2):c.2398A>C (p.Met800Leu)","Chromosome":"4","Start":"88067937","Stop":"88067937","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":221479,"rule_based_match":true,"evidence_text":"c.2398A>C","llm_judgment":"PRESENT","evidence":"c.2398A>C","abstract_start":1401,"abstract_end":1410}]}
{"pmid":"21293852","title":"Three novel mutations in the PHEX gene in Chinese subjects with hypophosphatemic rickets extends genotypic variability.","abstract":"Mutations in the phosphate-regulating endopeptidase homolog, X-linked, gene (PHEX), which encodes a zinc-dependent endopeptidase that is involved in bone mineralization and renal phosphate reabsorption, cause the most common form of hypophosphatemic rickets, X-linked hypophosphatemic rickets (XLH). The distribution of PHEX mutations is extensive, but few mutations have been identified in Chinese with XLH. We extracted genomic DNA and total RNA from leukocytes obtained from nine unrelated Chinese subjects (three males and six females, age range 11-36 years) who were living in Taiwan. The PHEX gene was amplified from DNA by PCR, and the amplicons were directly sequenced. Expression studies were performed by reverse-transcription PCR of leukocyte RNA. Serum levels of FGF23 were significantly greater in the patients than in normal subjects (mean 69.4 ± 18.8 vs. 27.2 ± 8.4 pg/mL, P < 0.005), and eight of the nine patients had elevated levels of FGF23. Germline mutations in the PHEX gene were identified in five of 9 patients, including novel c.1843 delA, donor splice site mutations c.663+2delT and c.1899+2T>A, and two previously reported missense mutations, p.C733Y and p.G579R. These data extend the spectrum of mutations in the PHEX gene in Han Chinese and confirm variability for XLH in Taiwan.","variants":[{"Name":"NM_000444.6(PHEX):c.1843del (p.Thr615fs)","Chromosome":"X","Start":"22221682","Stop":"22221682","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1065312,"rule_based_match":true,"evidence_text":"c.1843 delA","llm_judgment":"PRESENT","evidence":"c.1843 delA","abstract_start":1052,"abstract_end":1063}]}
{"pmid":"32722784","title":"Noncanonical type 2B von Willebrand disease associated with mutations in the VWF D'D3 and D4 domains.","abstract":"We observed a 55-year-old Italian man who presented with mucosal and cutaneous bleeding. Results of his blood analysis showed low levels of von Willebrand factor (VWF) antigen and VWF activity (both VWF ristocetin cofactor and VWF collagen binding), mild thrombocytopenia, increased ristocetin-induced platelet aggregation, and a deficiency of high-molecular-weight multimers, all typical phenotypic hallmarks of type 2B von Willebrand disease (VWD). The analysis of the VWF gene sequence revealed heterozygous in cis mutations: (1) c.2771G>A and (2) c.6532G>T substitutions in the exons 21 and 37, respectively. The first mutation causes the substitution of an Arg residue with a Gln at position 924, in the D'D3 domain. The second mutation causes an Ala to Ser substitution at position 2178 in the D4 domain. The patient's daughter did not present the same fatherly mutations but showed only the heterozygous polymorphic c.3379C>T mutation in exon 25 of the VWF gene causing the p.P1127S substitution, inherited from her mother. The in vitro expression of the heterozygous in cis VWF mutant rVWFWT/rVWF924Q-2178S confirmed and recapitulated the ex vivo VWF findings. Molecular modeling showed that these in cis mutations stabilize a partially stretched and open conformation of the VWF monomer. Transmission electron microscopy and atomic force microscopy showed in the heterozygous recombinant form rVWFWT/rVWF924Q-2178S a stretched conformation, forming strings even under static conditions. Thus, the heterozygous in cis mutations 924Q/2178S promote conformational transitions in the VWF molecule, causing a type 2B-like VWD phenotype, despite the absence of typical mutations in the A1 domain of VWF.","variants":[{"Name":"NM_000552.5(VWF):c.2771G>A (p.Arg924Gln)","Chromosome":"12","Start":"6031493","Stop":"6031493","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":106117,"rule_based_match":true,"evidence_text":"c.2771G>A","llm_judgment":"PRESENT","evidence":"c.2771G>A","abstract_start":533,"abstract_end":542}]}
{"pmid":"30476629","title":"Molecular analysis of 19 Spanish patients with mixed porphyrias.","abstract":"Porphyrias are rare diseases caused by alterations in the heme biosynthetic pathway. Depending on the afected enzyme, porphyrin precursors or porphyrins are overproduced, causing acute neurovisceral attacks or dermal photosensitivity, respectively. Hereditary Coproporphyria (HCP) and Variegate Porphyria (VP) are mixed porphyrias since they can present acute and/or cutaneous symptoms. These diseases are caused by a deficiency of coproporphyrinogen oxidase (CPOX) in HCP, and protoporphyrinogen oxidase (PPOX) in VP. Herein, we studied nineteen unrelated Spanish patients with mixed porphyrias. The diagnosis of either, HCP or VP was made on the basis of clinical symptoms, biochemical findings and the identification of the mutation responsible in the CPOX or PPOX genes. Two patients presented both acute and cutaneous symptoms. In most patients, the biochemical data allowed the diagnosis. Among eleven patients with HCP, ten CPOX mutations were identified, including six novel ones: two frameshift (c.32delG and c.1102delC), two nonsense (p.Cys239Ter and p.Tyr365Ter), one missense (p.Trp275Arg) and one amino acid deletion (p.Gly336del). Moreover, seven previously described PPOX mutations were identified in eight patients with VP. The impacts of CPOX mutations p.Trp275Arg and p.Gly336del, were evaluated using prediction softwares and their functional consequences were studied in a prokaryotic expression system. Both alterations were predicted as deleterious by in silico analysis. Aditionally, when these alleles were expressed in E. coli, only p.Trp275Arg retained some residual activity. These results emphasize the usefulness of integrated the biochemical tests and molecular studies in the diagnosis. Furthermore, they extend knowledge on the molecular heterogeneity of mixed porphyrias in Spain.","variants":[{"Name":"NM_000097.7(CPOX):c.32del (p.Gly11fs)","Chromosome":"3","Start":"98593473","Stop":"98593473","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1454697,"rule_based_match":true,"evidence_text":"c.32delG","llm_judgment":"PRESENT","evidence":"c.32delG","abstract_start":1005,"abstract_end":1013}]}
{"pmid":"19953642","title":"Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1).","abstract":"Phenocopies may confound the clinical diagnoses of hereditary disorders. We report phenocopies in Multiple Endocrine Neoplasia type 1 (MEN1), an autosomal dominant disorder, characterised by the combined occurrence of parathyroid, pituitary and pancreatic tumours. We studied 261 affected individuals from 74 families referred with a clinical diagnosis of MEN1 and sought inconsistencies between the mutational and clinical data. We identified four patients from unrelated families with phenocopies. Patients 1 and 2 from families with MEN1, developed prolactinomas as the sole endocrinopathy but they did not harbour the germline MEN1 mutation present in their affected relatives. Patient 3, had acromegaly and recurrent hypercalcaemia following parathyroidectomy, whilst patient 4 had parathyroid tumours and a microprolactinoma. Patients 3 and 4 and their relatives did not have MEN1 mutations, but instead had familial hypocalciuric hypercalcaemia (FHH) due to a calcium-sensing receptor mutation (p.Arg680Cys), and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome due to a hyperparathyroidism type 2 deletional-frameshift mutation (c.1239delA), respectively. Phenocopies may mimic MEN1 either by occurrence of a single sporadic endocrine tumour in a patient with familial MEN1, or occurrence of two endocrine abnormalities associated with different aetiologies. Phenocopies arose in >5% of MEN1 families, and awareness of them is important in the clinical management of MEN1 and other hereditary disorders.","variants":[{"Name":"NM_000388.4(CASR):c.2038C>T (p.Arg680Cys)","Chromosome":"3","Start":"122283992","Stop":"122283992","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":393278,"rule_based_match":false,"evidence_text":"p.Arg680Cys","llm_judgment":"PRESENT","evidence":"p.Arg680Cys","abstract_start":1002,"abstract_end":1013}]}
{"pmid":"23822871","title":"CODON 30 (-GAG) (α2): hematological parameters in heterozygotes and also patients with Hb H disease.","abstract":"We describe five Chinese individuals carrying a codon 30 (-GAG) (α2) (HBA2: c.91_93del) mutation, including three heterozygotes and two patients with Hb H (β4) disease. The heterozygotes presented hematological parameters of microcytosis and hypochromia. The Hb H disease patients were transfusion-independent and had survived to adulthood. Screening for this nondeletional allele, and correlation of genotype with phenotype in Hb H disease is important for genetic counseling.","variants":[{"Name":"NM_000517.6(HBA2):c.91_93del (p.Glu31del)","Chromosome":"16","Start":"173002","Stop":"173004","ReferenceAlleleVCF":"TGGA","AlternateAlleleVCF":"T","allel_id":432845,"rule_based_match":true,"evidence_text":"HBA2: c.91_93del","llm_judgment":"PRESENT","evidence":"HBA2: c.91_93del","abstract_start":70,"abstract_end":86}]}
{"pmid":"32638197","title":"Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance.","abstract":"PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder that manifests with fever, early-onset vasculitis, strokes, and hematologic dysfunction. This study aimed to identify disease-causing variants by conventional Sanger and whole exome sequencing in two families suspected to have DADA2 and non-confirmatory genotypes. ADA2 enzymatic assay confirmed the clinical diagnosis of DADA2. Molecular diagnosis was important to accurately identify other family members at risk.\nMETHODS: We used a variety of sequencing technologies, ADA2 enzymatic testing, and molecular methods including qRT-PCR and MLPA.\nRESULTS: Exome sequencing identified heterozygosity for the known pathogenic variant ADA2: c.1358A>G, p.Tyr453Cys in a 14-year-old female with a history of ischemic strokes, livedo, and vasculitis. No second pathogenic variant could be identified. ADA2 enzymatic testing in combination with quantitative RT-PCR suggested a loss-of-function allele. Subsequent genome sequencing identified a canonical splice site variant, c.-47+2T>C, within the 5'UTR of ADA2. Two of her unaffected siblings were found to carry the same two pathogenic variants. A homozygous 800-bp duplication comprising exon 7 of ADA2 was identified in a 5-year-old female with features consistent with Diamond-Blackfan anemia (DBA). The duplication was missed by Sanger sequencing of ADA2, chromosomal microarray, and exome sequencing but was detected by MLPA in combination with long-read PCR sequencing. The exon 7 duplication was also identified in her non-symptomatic father and younger sister.\nCONCLUSIONS: ADA2 pathogenic variants may not be detected by conventional sequencing and genetic testing and may require the incorporation of additional diagnostic methods. A definitive molecular diagnosis is crucial for all family members to make informed treatment decisions.","variants":[{"Name":"NM_001282225.2(ADA2):c.-47+2T>C","Chromosome":"22","Start":"17219354","Stop":"17219354","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2523737,"rule_based_match":true,"evidence_text":"c.-47+2T>C","llm_judgment":"PRESENT","evidence":"c.-47+2T>C","abstract_start":1054,"abstract_end":1064}]}
{"pmid":"28851564","title":"X-linked Parkinsonism with Intellectual Disability caused by novel mutations and somatic mosaicism in RAB39B gene.","abstract":"BACKGROUND: RAB39B pathogenic variants cause X-linked Parkinsonism associated with Intellectual Disability, known as Waisman syndrome, a very rare disorder that has been mainly identified through exome sequencing in large Parkinson's disease cohorts. In this study we searched for pathogenic variants in RAB39B in two Italian families affected by X-linked early-onset Parkinsonism and Intellectual Disability.\nMETHODS: Three patients received neurological evaluation and underwent RAB39B sequencing.\nRESULTS: Two novel RAB39B frameshift variants were found to result in the absence of RAB39B protein (family 1: c.137dupT; family 2: c.371delA). Patients showed unilateral rest tremor and bradykinesia; one of them also displayed an early-onset postural tremor. Paramagnetic substance deposition in the substantia nigra, globus pallidi, red nucleus, putamen and pulvinar was assessed by brain imaging. Two patients also showed moderate calcification of globus pallidi.\nCONCLUSION: In this study we highlight the evidence that X-linked early-onset Parkinsonism associated with Intellectual Disability occurs as a pattern of clinical and neuroimaging features attributable to RAB39B pathogenic variants.","variants":[{"Name":"NM_171998.4(RAB39B):c.137dup (p.Ser47fs)","Chromosome":"X","Start":"155264151","Stop":"155264152","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":1684077,"rule_based_match":true,"evidence_text":"c.137dupT","llm_judgment":"PRESENT","evidence":"c.137dupT","abstract_start":611,"abstract_end":620}]}
{"pmid":"25317407","title":"Frameshift Mutations (Deletion at Codon 1309 and Codon 849) in the APC Gene in Iranian FAP Patients: a Case Series and Review of the Literature.","abstract":"Familial adenomatous polyposis (FAP) is responsible for <1% of colorectal cancer (CRC) cases and is inherited an autosomal dominant trait. Patients generally present hundreds to thousands of adenomas and develop colorectal cancer by age 35- 40 if left untreated. Here we report four patients with germline frameshift mutation (small deletion) at exon 15 of adenomatous polyposis coli (APC) tumor suppressor gene. Peripheral blood samples were collected from patients and Exon 15 of the APC gene was studied by direct sequencing after genomic DNA extraction. Four frameshift mutations were detected. Two patients had 5 bp deletion, c.3927_3931delAAAGA and two siblings presented deletion at codon 849 (c.2547_2548delTA p.Asp849fsX62). This study was the first report of genetic screening in Iranian FAP patients. In contrast to other studies we revealed that one patient with mutation at codon 1309 had an attenuated phenotype.","variants":[{"Name":"NM_000038.6(APC):c.3927_3931del (p.Glu1309fs)","Chromosome":"5","Start":"112839515","Stop":"112839519","ReferenceAlleleVCF":"TAAAAG","AlternateAlleleVCF":"T","allel_id":15855,"rule_based_match":true,"evidence_text":"c.3927_3931delAAAGA","llm_judgment":"PRESENT","evidence":"c.3927_3931delAAAGA","abstract_start":631,"abstract_end":650}]}
{"pmid":"29753918","title":"A new phenotype of severe dilated cardiomyopathy associated with a mutation in the LAMP2 gene previously known to cause hypertrophic cardiomyopathy in the context of Danon disease.","abstract":"Danon disease is a rare X-linked cardiac and skeletal muscle disorder with multisystem clinical manifestations. Genetic defects at the lysosome-associated membrane 2 protein (LAMP2) are the cause of the disorder. Due to the rarity of the disease, there is limited progress in understanding the correlation between genotype and phenotype, and explaining the large variability of the clinical features of the disease. In this study, we report two patients, twin sisters, referred to our hospital for end stage heart failure due to dilated cardiomyopathy, requiring heart transplant evaluation. Genetic analysis, using targeted next generation sequencing, showed that the proband carried a LAMP2 missense variant, c.928G > A. The mutation was also detected in her twin sister by sanger sequencing. This variant has already been reported by other investigators and was correlated with the clinical triad of Danon disease i.e. hypertrophic cardiomyopathy, mental retardation and peripheral myopathy. The new phenotype of dilated cardiomyopathy associated with this mutation, confirms the phenotypic heterogeneity of the particular mutation, as well as of Danon disease.","variants":[{"Name":"NM_002294.3(LAMP2):c.928G>A (p.Val310Ile)","Chromosome":"X","Start":"120442599","Stop":"120442599","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25021,"rule_based_match":true,"evidence_text":"c.928G > A","llm_judgment":"PRESENT","evidence":"c.928G > A","abstract_start":711,"abstract_end":721}]}
{"pmid":"34638534","title":"Super-Resolution Imaging of the A- and B-Type Lamin Networks: A Comparative Study of Different Fluorescence Labeling Procedures.","abstract":"A- and B-type lamins are type V intermediate filament proteins. Mutations in the genes encoding these lamins cause rare diseases, collectively called laminopathies. A fraction of the cells obtained from laminopathy patients show aberrations in the localization of each lamin subtype, which may represent only the minority of the lamina disorganization. To get a better insight into more delicate and more abundant lamina abnormalities, the lamin network can be studied using super-resolution microscopy. We compared confocal scanning laser microscopy and stimulated emission depletion (STED) microscopy in combination with different fluorescence labeling approaches for the study of the lamin network. We demonstrate the suitability of an immunofluorescence staining approach when using STED microscopy, by determining the lamin layer thickness and the degree of lamin A and B1 colocalization as detected in fixed fibroblasts (co-)stained with lamin antibodies or (co-)transfected with EGFP/YFP lamin constructs. This revealed that immunofluorescence staining of cells does not lead to consequent changes in the detected lamin layer thickness, nor does it influence the degree of colocalization of lamin A and B1, when compared to the transfection approach. Studying laminopathy patient dermal fibroblasts (<i>LMNA</i> c.1130G>T (p.(Arg377Leu)) variant) confirmed the suitability of immunofluorescence protocols in STED microscopy, which circumvents the need for less convenient transfection steps. Furthermore, we found a significant decrease in lamin A/C and B1 colocalization in these patient fibroblasts, compared to normal human dermal fibroblasts. We conclude that super-resolution light microscopy combined with immunofluorescence protocols provides a potential tool to detect structural lamina differences between normal and laminopathy patient fibroblasts.","variants":[{"Name":"NM_170707.4(LMNA):c.1130G>T (p.Arg377Leu)","Chromosome":"1","Start":"156136094","Stop":"156136094","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":77675,"rule_based_match":true,"evidence_text":"c.1130G>T (p.(Arg377Leu))","llm_judgment":"PRESENT","evidence":"c.1130G>T (p.(Arg377Leu))","abstract_start":1319,"abstract_end":1344}]}
{"pmid":"26477546","title":"Joubert Syndrome in French Canadians and Identification of Mutations in CEP104.","abstract":"Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.","variants":[{"Name":"NM_014704.4(CEP104):c.735+2T>C","Chromosome":"1","Start":"3839606","Stop":"3839606","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":222985,"rule_based_match":true,"evidence_text":"c.735+2T>C","llm_judgment":"PRESENT","evidence":"c.735+2T>C","abstract_start":704,"abstract_end":714},{"Name":"NM_014704.4(CEP104):c.1328_1329insT (p.Tyr444fs)","Chromosome":"1","Start":"3835081","Stop":"3835082","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":222986,"rule_based_match":true,"evidence_text":"c.1328_1329insT (p.Tyr444fs*3)","llm_judgment":"PRESENT","evidence":"c.1328_1329insT","abstract_start":1020,"abstract_end":1035},{"Name":"NM_014704.4(CEP104):c.496C>T (p.Arg166Ter)","Chromosome":"1","Start":"3844977","Stop":"3844977","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":222987,"rule_based_match":true,"evidence_text":"c.496C>T [p.Arg166*]","llm_judgment":"PRESENT","evidence":"c.496C>T [p.Arg166*]","abstract_start":890,"abstract_end":910},{"Name":"NM_014704.4(CEP104):c.2572-2A>G","Chromosome":"1","Start":"3816372","Stop":"3816372","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":222988,"rule_based_match":true,"evidence_text":"c.2572-2A>G","llm_judgment":"PRESENT","evidence":"c.2572-2A>G","abstract_start":948,"abstract_end":959}]}
{"pmid":"15131404","title":"Intron 4 mutation in APC gene results in splice defect and attenuated FAP phenotype.","abstract":"The adenomatous polyposis coli (APC) protein is a tumor suppressor frequently involved in the development of inherited and sporadic colon cancers. Somatic mutations of the APC gene are found in 80% of all colon cancers. Inherited mutations result in familial adenomatous polyposis (FAP) as well as an attenuated form of this syndrome. FAP is characterized by the early age onset of hundreds to thousands of colonic adenomatous polyps and a virtual certainty of colon cancer unless the colon is removed. The attenuated form of FAP (AFAP) is characterized by fewer adenomas, later onset of adenomas and cancer, and a decreased lifetime cancer risk. We report a 37-year-old man with a history of more than 50 colonic adenomatous polyps, located predominately in the right colon. An insertion of a single thymidine between the second and third base pairs of intron 4 of the APC gene was identified (c.531+2_531+3insT). Monoallelic hybrid cells harboring a single copy of human chromosome 5 were generated from patient lymphoblasts. Sequencing of the APC cDNA product from these cells revealed a single RNA transcript with aberrant splicing in the mutant mRNA whereby exon 4 is deleted. The translational reading frame is shifted after codon 140 and a translational stop is generated predicting a truncated protein of 147 amino acids, thus indicating that the intronic mutation is disease causing. The lack of a secondary transcript from the mutant allele suggests that incomplete exon skipping is not the molecular mechanism behind the attenuated phenotype.","variants":[{"Name":"NM_000038.6(APC):c.531+2dup","Chromosome":"5","Start":"112775738","Stop":"112775739","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":394197,"rule_based_match":false,"evidence_text":"c.531+2_531+3insT","llm_judgment":"PRESENT","evidence":"c.531+2_531+3insT","abstract_start":895,"abstract_end":912}]}
{"pmid":"22056721","title":"Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8.","abstract":"BACKGROUND: Adenosine triphosphate (ATP)-sensitive potassium cardiac channels consist of inward-rectifying channel subunits Kir6.1 or Kir6.2 (encoded by KCNJ8 or KCNJ11) and the sulfonylurea receptor subunits SUR2A (encoded by ABCC9).\nOBJECTIVE: To examine the association of mutations in KCNJ8 with Brugada syndrome (BrS) and early repolarization syndrome (ERS) and to elucidate the mechanism underlying the gain of function of ATP-sensitive potassium channel current.\nMETHODS: Direct sequencing of KCNJ8 and other candidate genes was performed on 204 BrS and ERS probands and family members. Whole-cell and inside-out patch-clamp methods were used to study mutated channels expressed in TSA201 cells.\nRESULTS: The same missense mutation, p.Ser422Leu (c.1265C>T) in KCNJ8, was identified in 3 BrS and 1 ERS probands but was absent in 430 alleles from ethnically matched healthy controls. Additional genetic variants included CACNB2b-D601E. Whole-cell patch-clamp studies showed a 2-fold gain of function of glibenclamide-sensitive ATP-sensitive potassium channel current when KCNJ8-S422L was coexpressed with SUR2A-wild type. Inside-out patch-clamp evaluation yielded a significantly greater half maximal inhibitory concentration for ATP in the mutant channels (785.5 ± 2 vs 38.4 ± 3 μM; n = 5; P <.01), pointing to incomplete closing of the ATP-sensitive potassium channels under normoxic conditions. Patients with a CACNB2b-D601E polymorphism displayed longer QT/corrected QT intervals, likely owing to their effect to induce an increase in L-type calcium channel current (I(Ca-L)).\nCONCLUSIONS: Our results support the hypothesis that KCNJ8 is a susceptibility gene for BrS and ERS and point to S422L as a possible hotspot mutation. Our findings suggest that the S422L-induced gain of function in ATP-sensitive potassium channel current is due to reduced sensitivity to intracellular ATP.","variants":[{"Name":"NM_004982.4(KCNJ8):c.1265C>T (p.Ser422Leu)","Chromosome":"12","Start":"21765733","Stop":"21765733","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":167406,"rule_based_match":true,"evidence_text":"c.1265C>T","llm_judgment":"PRESENT","evidence":"c.1265C>T","abstract_start":753,"abstract_end":762}]}
{"pmid":"23430840","title":"Relevance of expanded neonatal screening of medium-chain acyl co-a dehydrogenase deficiency: outcome of a decade in galicia (Spain).","abstract":"Neonatal screening of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is of major importance due to the significant morbidity and mortality in undiagnosed patients. MCADD screening has been performed routinely in Galicia since July 2000, and until now 199,943 newborns have been screened. We identified 11 cases of MCADD, which gives an incidence of 1/18,134. During this period, no false negative screens have been detected. At diagnosis, all identified newborns were asymptomatic. Our data showed that octanoylcarnitine (C8) and C8/C10 ratio are the best markers for screening of MCADD. C8 was increased in all patients and C8/C10 was increased in all but one patient.The common mutation, c.985A > G, was found in homozygosity in seven newborns and in compound heterozygosity in three, while one patient did not carry the common mutation at all. In addition, two novel mutations c.245G > C (p.W82S) and c.542A > G (p.D181G) were identified. Ten of the 11 identified newborns did not experience any episodes of decompensation. The patient with the highest level of medium chain acylcarnitines at diagnosis, who was homozygous for the c.985A > G mutation, died at the age of 2 years due to a severe infection.This is the first report of the results from neonatal screening for MCADD in Spain. Our data provide further evidence of the benefits of MCADD screening and contribute to better understanding of this disease.","variants":[{"Name":"NM_000016.6(ACADM):c.542A>G (p.Asp181Gly)","Chromosome":"1","Start":"75740053","Stop":"75740053","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":541363,"rule_based_match":true,"evidence_text":"c.542A > G (p.D181G)","llm_judgment":"PRESENT","evidence":"c.542A > G (p.D181G)","abstract_start":912,"abstract_end":932}]}
{"pmid":"26820065","title":"Evidence for an association between infant mortality and homozygosity for the arctic variant of carnitine palmitoyltransferase 1A.","abstract":"PURPOSE: Infant mortality in Alaska is highest among Alaska Native people from western/northern Alaska, a population with a high prevalence of a genetic variant (c.1436C>T; the arctic variant) of carnitine palmitoyltransferase 1A (CPT1A).\nMETHODS: We performed an unmatched case-control study to determine the relationship between the arctic variant and infant mortality. The cases were 110 Alaska Native infant deaths from 2006 to 2010 and the controls were 395 Alaska Native births from the same time period. In addition to the overall analysis, we conducted two subanalyses, one limited to subjects from western/northern Alaska and one limited to infants heterozygous or homozygous for the arctic variant.\nRESULTS: Among western/northern Alaska residents, 66% of cases and 61% of controls were homozygous (adjusted odds ratio (aOR): 2.5; 95% confidence interval (CI): 1.3, 5.0). Among homozygous or heterozygous infants, 58% of cases and 44% of controls were homozygous (aOR: 2.3; 95% CI: 1.3, 4.0). Deaths associated with infection were more likely to be homozygous (OR: 2.9; 95% CI: 1.0-8.0). Homozygosity was strongly associated with a premorbid history of pneumonia, sepsis, or meningitis.\nCONCLUSION: Homozygosity for the arctic variant is associated with increased risk of infant mortality, which may be mediated in part by an increase in infectious disease risk. Further studies are needed to determine whether the association we report represents a causal association between the CPT1A arctic variant and infectious disease-specific mortality.Genet Med 18 9, 933-939.","variants":[{"Name":"NM_001876.4(CPT1A):c.1436C>T (p.Pro479Leu)","Chromosome":"11","Start":"68780662","Stop":"68780662","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76552,"rule_based_match":true,"evidence_text":"c.1436C>T","llm_judgment":"PRESENT","evidence":"c.1436C>T","abstract_start":162,"abstract_end":171}]}
{"pmid":"18267044","title":"An unusual succinate dehydrogenase gene mutation C in a case of laryngeal paraganglioma.","abstract":"OBJECTIVE: To report a rare case of a laryngeal paraganglioma related to succinate dehydrogenase gene mutation C.\nMETHOD: A case report and a review of the world literature concerning succinate dehydrogenase mutations and laryngeal paraganglioma are presented.\nRESULTS: We identified a laryngeal paraganglioma in a 38-year-old woman, related to a very rare, deleterious in exon 4 of the succinate dehydrogenase mutation C. This mutation was a non-sense mutation: c.183G >A leading to p.Trp61X. No other neuroendocrine tumour was identified in this case, but a thyroid papillary carcinoma was concomitantly discovered and cured.\nCONCLUSION: To our knowledge, this is the first report in the world literature of laryngeal paraganglioma related to a succinate dehydrogenase mutation C. The case presented underlines the fact that every patient with paraganglioma should be tested for succinate dehydrogenase genetic mutations, even if a family history of paraganglioma is absent, in order to enable appropriate clinical management and to improve our knowledge of familial paraganglioma.","variants":[{"Name":"NM_003001.5(SDHC):c.183G>A (p.Trp61Ter)","Chromosome":"1","Start":"161340597","Stop":"161340597","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3386665,"rule_based_match":true,"evidence_text":"c.183G >A","llm_judgment":"PRESENT","evidence":"c.183G >A","abstract_start":463,"abstract_end":472}]}
{"pmid":"20738328","title":"Novel homozygous mutation in DSP causing skin fragility-woolly hair syndrome: report of a large family and review of the desmoplakin-related phenotypes.","abstract":"Desmoplakin is an important cytoskeletal linker for the function of the desmosomes. Linking desmoplakin to certain types of cardiocutaneous syndromes has been a hot topic recently. Skin fragility-woolly hair syndrome is a rare autosomal recessive disorder involving the desmosomes and is caused by mutation in the desmoplakin gene (DSP). We report five members from a large family with skin fragility-woolly hair syndrome. The index is a 14-year-old girl with palmoplantar keratoderma, woolly hair, variable alopecia, dystrophic nails, and excessive blistering to trivial mechanical trauma. No cardiac symptoms were reported. Although formal cardiac examination was not feasible, the echocardiographic evaluation of the other two affected younger siblings was normal. Homozygosity mapping and linkage analysis revealed a high LOD score region in the short arm of chromosome 6 that harbors the DSP. Full sequencing of the DSP showed a novel homozygous c.7097 G>A (p.R2366H) mutation in all affected members, and the parents were heterozygous. This is the report of the third case/family of the skin fragility-woolly hair syndrome in the literature. We also present a clinical and molecular review of various desmoplakin-related phenotypes, with emphasis on onset of cardiomyopathy. The complexity of the desmoplakin and its variable presentations warrant introducing the term 'desmoplakinopathies' to describe all the phenotypes related to defects in the desmoplakin.","variants":[{"Name":"NM_004415.4(DSP):c.7097G>A (p.Arg2366His)","Chromosome":"6","Start":"7584359","Stop":"7584359","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38627,"rule_based_match":true,"evidence_text":"c.7097 G>A (p.R2366H)","llm_judgment":"PRESENT","evidence":"c.7097 G>A (p.R2366H)","abstract_start":951,"abstract_end":972}]}
{"pmid":"27501283","title":"Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency.","abstract":"OBJECTIVE: Recessive mutations in GHRHR are associated with severe isolated growth hormone deficiency (IGHD), with a final height in untreated patients of 130 cm ± 10 cm (-7.2 ± 1.6 SDS; males) and 114 ± 0.7 cm (-8.3 ± 0.1 SDS; females).\nDESIGN: We hypothesized that a consanguineous Pakistani family with IGHD in three siblings (two males, one female) would have mutations in GH1 or GHRHR.\nRESULTS: Two novel homozygous missense variants [c.11G>A (p.R4Q), c.236C>T (p.P79L)] at conserved residues were identified in all three siblings. Both were absent from control databases, aside from pR4Q appearing once in heterozygous form in the Exome Aggregation Consortium Browser. The brothers were diagnosed with GH deficiency at 9.8 and 6.0 years (height SDS: -2.24 and -1.23, respectively), with a peak GH of 2.9 μg/liter with low IGF-1/IGF binding protein 3. Their sister presented at 16 years with classic GH deficiency (peak GH <0.1 μg/liter, IGF-1 <3.3 mmol/liter) and attained an untreated near-adult height of 144 cm (-3.0 SDS); the tallest untreated patient with GHRHR mutations reported. An unrelated Pakistani female IGHD patient was also compound homozygous. All patients had a small anterior pituitary on magnetic resonance imaging. Functional analysis revealed a 50% reduction in maximal cAMP response to stimulation with GHRH by the p.R4Q/p.P79L double mutant receptor, with a 100-fold increase in EC50.\nCONCLUSION: We report the first coexistence of two novel compound homozygous GHRHR variants in two unrelated pedigrees associated with a partial loss of function. Surprisingly, the patients have a relatively mild IGHD phenotype. Analysis revealed that the pP79L mutation is associated with the compromise in function, with the residual partial activity explaining the mild phenotype.","variants":[{"Name":"NM_000823.4(GHRHR):c.11G>A (p.Arg4Gln)","Chromosome":"7","Start":"30964079","Stop":"30964079","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2039644,"rule_based_match":true,"evidence_text":"c.11G>A (p.R4Q)","llm_judgment":"PRESENT","evidence":"c.11G>A (p.R4Q)","abstract_start":440,"abstract_end":455}]}
{"pmid":"26716959","title":"BESTROPHINOPATHY: A Spectrum of Ocular Abnormalities Caused by the c.614T>C Mutation in the BEST1 Gene.","abstract":"PURPOSE: To describe the variable ocular phenotype associated with a heterozygous mutation in the BEST1 gene.\nMETHODS: Clinical and genetic assessment was performed in five members of the same family. Molecular genetic analysis of the BEST1 gene was performed by direct sequencing. Extensive ophthalmic examination included color fundus imaging, spectral domain optical coherence tomography, fundus autofluorescence, electro-oculography (EOG), and full-field electroretinography (ERG). The main outcome measures were BEST1 mutations, imaging, and electroretinography findings.\nRESULTS: All affected family members carried a single heterozygous c.614T>C (p.I205T) mutation in exon 5 of the BEST1 gene. The 46-year-old proband showed nanophthalmos with chorioretinal atrophy in the macula, extensive coarse hyperpigmentation in the (mid) peripheral retina with tractional vitreous strands. Full-field ERG revealed nonrecordable cone and rod responses, and EOG showed an absent light rise. The daughter and son of the proband showed a phenotype resembling autosomal recessive bestrophinopathy, including short axial lengths, cystoid fluid collections, and shallow serous subretinal fluid accumulation on spectral domain optical coherence tomography throughout the macula in combination with mild retinal pigment epithelium changes. The son of the proband also showed subretinal yellowish deposits inferiorly in the macula as well as outside the temporal vascular arcade, that were hyperfluorescent on fundus autofluorescence, similar to those seen in autosomal recessive bestrophinopathy. Full-field ERG revealed a reduced rod and cone response and a markedly reduced or absent EOG light peak in both brother and sister of the proband.\nCONCLUSION: The clinical spectrum of bestrophinopathy may encompass severe ocular phenotypes that affect the development and function of the entire eye. A clinical picture similar to autosomal recessive bestrophinopathy can also be caused by a single heterozygous mutation in the BEST1 gene, such as the c.614T>C (p.I205T) variant in this family.","variants":[{"Name":"NM_004183.4(BEST1):c.614T>C (p.Ile205Thr)","Chromosome":"11","Start":"61956976","Stop":"61956976","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":17786,"rule_based_match":true,"evidence_text":"c.614T>C (p.I205T)","llm_judgment":"PRESENT","evidence":"c.614T>C (p.I205T)","abstract_start":644,"abstract_end":662}]}
{"pmid":"27698074","title":"Successful IVF pregnancy despite inadequate ovarian steroidogenesis due to congenital lipoid adrenal hyperplasia (CLAH): a case report.","abstract":"Steroidogenic acute regulatory protein (StAR) mutations are the most frequent aetiologies of congenital lipoid adrenal hyperplasia (CLAH). Phenotypes may vary, and puberty may be absent in affected individuals. To date, only two pregnancies have been described in 46,XX CLAH patients with StAR mutations; these patients exhibited ovarian steroidogenesis along with spontaneous puberty and menarche and normal menses. The patient described here presented with CLAH caused by the homozygous (unreported, 1 bp) deletion c.719del in the StAR gene, which was diagnosed after acute adrenal insufficiency when the patient was 10 days old. The patient did not undergo spontaneous puberty, so puberty was induced by HRT when the patient was 13 years old. At the age of 25 years, the patient was referred to our reproductive unit because she desired to conceive. An initial cycle of clomiphene, stimulation produced follicular growth with two mature follicles measuring 18 and 15 mm, respectively, but the plasma oestradiol levels remained low (18 pg/ml) and the endometrium was thin (3 mm). Pregnancy was finally achieved after ovarian stimulation, IVF and transfer of frozen-thawed embryos after endometrial preparation with HRT. A normal female child was delivered following a 40 weeks' uneventful pregnancy. We therefore report the first IVF pregnancy achieved in a 46,XX CLAH patient homozygous for a StAR mutation, with inadequate ovarian steroidogenesis and no spontaneous puberty.","variants":[{"Name":"NM_000349.3(STAR):c.719del (p.Thr240fs)","Chromosome":"8","Start":"38145247","Stop":"38145247","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":1061336,"rule_based_match":true,"evidence_text":"c.719del","llm_judgment":"PRESENT","evidence":"c.719del","abstract_start":517,"abstract_end":525}]}
{"pmid":"28000888","title":"Genetic heterogeneity in patients with Bartter syndrome type 1.","abstract":"Bartter syndrome (BS) type 1 is an autosomal recessive kidney disorder caused by loss‑of‑function mutations in the solute carrier family 12 member 1 (SLC12A1) gene. To date, 72 BS type 1 patients harboring SLC12A1 mutations have been documented. Of these 144 alleles studied, 68 different disease‑causing mutations have been detected in 129 alleles, and no mutation was detected in the remaining 15 alleles. The mutation types included missense/nonsense mutations, splicing mutations and small insertions and deletions ranging from 1 to 4 nucleotides. A large deletion encompassing a whole exon in the SLC12A1 gene has not yet been reported. The current study initially identified an undocumented homozygous frameshift mutation (c.1833delT) by Sanger sequencing analysis of a single infant with BS type 1. However, in a subsequent analysis, the mutation was detected only in the father's DNA. Upon further investigation using a next‑generation sequencing approach, a deletion in exons 14 and 15 in both the patient and patient's mother was detected. The deletion was subsequently confirmed by use of a long‑range polymerase chain reaction and was determined to be 3.16 kb in size based on sequencing of the junction fragment. The results of the present study demonstrated that pathogenic variants of SLC12A1 are heterogeneous. Large deletions appear to serve an etiological role in BS type 1, and may be more prevalent than previously thought.","variants":[{"Name":"NM_000338.3(SLC12A1):c.1833del (p.Phe611fs)","Chromosome":"15","Start":"48251657","Stop":"48251657","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":380142,"rule_based_match":true,"evidence_text":"c.1833delT","llm_judgment":"PRESENT","evidence":"c.1833delT","abstract_start":729,"abstract_end":739}]}
{"pmid":"26318470","title":"Identification of 2 novel homozygous mutations in the methylmalonyl-CoA mutase gene in Saudi patients.","abstract":"The aim of this report is to analyze the clinical features, and mutations of the methylmalonyl CoA mutase (MUT) gene in 2 patients with methylmalonic aciduria (MMA) attending King Saud University Medical City, Riyadh, Saudi Arabia in January 2014. The infants  aged 6 days (patient 1) and 3 months (patient 2) with sepsis-like picture, metabolic acidosis, and hyperammonemia were presented. Investigations revealed high propionylcarnitine (C3), elevated urinary methylmalonic acids, 3-hydroxypropionic acids and methylcitrate, consistent with MMA. Sanger-sequencing detected a homozygous novel mutation (c.329A&gt;G; p.Y110C) in the MUT gene in patient 1 and a heterozygous in parents. This mutation is predicted to have a damaging effect on the protein structure and function. In patient 2, we detected a novel homozygous nonsense mutation (c.2200C&gt;T; p.Q734X) and a heterozygous in parents. This mutation leads to a premature stop-codon at codon 734 of the MUT gene. We identified 2 novel mutations in the MUT gene causing isolated MMA.","variants":[{"Name":"NM_000255.4(MMUT):c.2200C>T (p.Gln734Ter)","Chromosome":"6","Start":"49431781","Stop":"49431781","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":224618,"rule_based_match":false,"evidence_text":"c.2200C>T (p.Q734X)","llm_judgment":"PRESENT","evidence":"p.Q734X","abstract_start":856,"abstract_end":863}]}
{"pmid":"33594065","title":"Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh.","abstract":"Collectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet-Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.","variants":[{"Name":"NM_024312.5(GNPTAB):c.2972dup (p.Met991fs)","Chromosome":"12","Start":"101761289","Stop":"101761290","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":3099419,"rule_based_match":true,"evidence_text":"c.2972dupT (p.Met991Ilefs*)","llm_judgment":"PRESENT","evidence":"c.2972dupT (p.Met991Ilefs*)","abstract_start":875,"abstract_end":902}]}
{"pmid":"34256108","title":"Genetic, clinical and neuroimaging profiles of sporadic and autosomal recessive hereditary spastic paraplegia cases in Chinese.","abstract":"Spastic paraplegias (SPGs) are a group of clinically and genetically heterogeneous neurodegenerative diseases. Mutations in 78 genes have been identified in autosomal dominant hereditary SPG (AD-HSP) and autosomal recessive hereditary SPG (AR-HSP). Compared to familial HSP, much less is known about the genetic and clinical profiles of sporadic SPGs. In this study, we have screened mutations for 18 sporadic SPGs or AR-HSP patients (mainly Northern Chinese) by whole-exome sequencing. We identified 12 mutations in five genes in 9 (50%) patients, including 9 novel ones: SPG5A/CYP7B1 (c.851C > A; c.122 + 2 T > G), SPG11/KIAA1840 (c.1735 + 3_ 1735 + 6del AAGT); SPG7/SPG7 (c.1454G > A; c.1892_ 1906dup GAGGACGGGCCTCGG); SPG39/PNPLA6 (c.1591G > A; c. 2990C > T); SPG15/ ZFYVE26 (c. 4804C > T; c. 4278 G > A). Among all the mutations, 7 were detected in the SPG5A and SPG11. Age at onset was significantly younger in cases with mutations (15.45 ± 6.78 years) than those without mutations (25.56 ± 10.90 years) (P = 0.03). Except for two cases with the SPG5A mutations, all cases presented with complicated SPGs. Three cases carrying mutations in SPG7, SPG15, SPG39 showed symptoms and signs of ataxia. One case carrying the homozygous c.259 + 2 T > C mutation in CYP7B1 showed serum parameters indicating liver impairment. Magnetic resonance imaging showed significantly thinned corpus callosum in cases with SPG11 and SPG15, but not in those with SPG5A, SPG7 or SPG39. In contrast, cerebellar atrophy was prominent in the SPG7 and SPG39 cases. These findings expand the spectrum of genetic, clinical and imaging features of sporadic SPG and AR-HSP, and have important implications in genetic counselling, molecular mechanisms and precise diagnosis of the disease.","variants":[{"Name":"NM_003119.4(SPG7):c.1892_1906dup (p.Ser635_Glu636insGlyGlyArgAlaSer)","Chromosome":"16","Start":"89553088","Stop":"89553089","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGGGAGGACGGGCCTC","allel_id":3494940,"rule_based_match":true,"evidence_text":"c.1892_ 1906dup GAGGACGGGCCTCGG","llm_judgment":"PRESENT","evidence":"c.1892_ 1906dup GAGGACGGGCCTCGG","abstract_start":688,"abstract_end":719}]}
{"pmid":"18511318","title":"A novel single-base substitution (c.1124A>G) that activates a 5-base upstream cryptic splice donor site within exon 11 in the human mitochondrial acetoacetyl-CoA thiolase gene.","abstract":"Most mutations related to aberrant splicing occur in conserved splice acceptor and donor sites. Some exonic mutations also affect splicing. We identified and characterized a point mutation (c.1124A>G) in an Australian patient (GK43) with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. GK43 is a homozygote of c.1124A>G, which activates a cryptic splice donor site 5 bases upstream from c.1124A>G within exon 11, causing aberrant splicing in most transcripts. The aberrant splicing results in c.1120-1163 (44-base) deletion, causing a frameshift in T2 mRNA. A mini-gene splicing experiment confirmed that the c.1124A>G substitution was responsible for this aberrant splicing. This cryptic splice site has a Shapiro and Senapathy score (70.0) in a normal sequence but if mutated, the score (84.3) becomes higher than the one in the authentic splice donor site of intron 11 (81.4). This is an example in which a point mutation activates a cryptic splice donor site motif that is used preferentially over a downstream authentic splice site.","variants":[{"Name":"NM_000019.4(ACAT1):c.1124A>G (p.Asn375Ser)","Chromosome":"11","Start":"108146320","Stop":"108146320","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":654073,"rule_based_match":true,"evidence_text":"c.1124A>G","llm_judgment":"PRESENT","evidence":"c.1124A>G","abstract_start":190,"abstract_end":199}]}
{"pmid":"22190468","title":"Novel and recurrent mutations of ITGA2B and ITGB3 genes in Korean patients with Glanzmann thrombasthenia.","abstract":"Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder caused by defective glycoprotein, αIIb and β3, encoded by ITGA2B and ITGB3 genes, respectively. We herein describe four unrelated Korean patients with genetically confirmed GT. Two patients were homozygous for c.1913+5G>T (IVS11+5G>T) mutation of ITGB3 with a signature of founder effect. The other two patients were compound heterozygous for two mutations of ITGA2B: c.[2333A>C];[2975delA] (p.[Q778P];[E992Gfs*30]) and c.[1750C>T];[2333A>C] (p.[R584X];[Q778P]). The c.2975delA mutation was a novel frameshift mutation of ITGA2B. Although from a limited number of patients, these results suggests c.1913+5G>T of ITGB3 is a recurrent mutation in Korean patients with GT.","variants":[{"Name":"NM_000419.5(ITGA2B):c.2333A>C (p.Gln778Pro)","Chromosome":"17","Start":"44376323","Stop":"44376323","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":227425,"rule_based_match":false,"evidence_text":"c.2333A>C","llm_judgment":"PRESENT","evidence":"c.[2333A>C","abstract_start":442,"abstract_end":452},{"Name":"NM_000419.5(ITGA2B):c.1750C>T (p.Arg584Ter)","Chromosome":"17","Start":"44380004","Stop":"44380004","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17931,"rule_based_match":false,"evidence_text":"c.1750C>T","llm_judgment":"PRESENT","evidence":"c.[1750C>T","abstract_start":494,"abstract_end":504}]}
{"pmid":"31945341","title":"Genetic and functional analysis of two missense mutations in CD46 predispose to postpartum atypical hemolytic uremic syndrome.","abstract":"Pregnancy associated atypical hemolytic uremic syndrome (p-aHUS) is a disease with a triad of hemolytic anemia, thrombocytopenia and acute renal failure, which might be attributed to the uncontrolled complement activation. Herein, we sequenced a postpartum-aHUS patient and found the two missense variants of CD46, a novel mutation (c.403G > C, p.G135R) from her father and a once reported mutation (c.293C > T, p.T98I) without expressional and functional tests from her mother. The G135R mutation caused a significantly reduced membrane expression of CD46 in peripheral blood lymphocyte and renal cells. The T98I mutation caused a mild decrease membrane expression of CD46 in peripheral blood lymphocyte cells. Moreover, the expressed G135R protein was in precursor form, indicating that this mutant was retained intracellularly. The C3b binding ability of T98I mutant was slightly decreased while the C4b binding ability is not significantly changed. The cofactor ability of the two mutants for factor I in the degradation of C3b was demonstrated to be impaired. This study reported the first case of a four-generation postpartum-aHUS pedigree with isolated CD46 variants and the detailed disease progression, treatment, and prognosis provided more meaningful information for the understanding the disease.","variants":[{"Name":"NM_172351.3(CD46):c.293C>T (p.Thr98Ile)","Chromosome":"1","Start":"207757546","Stop":"207757546","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":863373,"rule_based_match":true,"evidence_text":"c.293C > T, p.T98I","llm_judgment":"PRESENT","evidence":"c.293C > T, p.T98I","abstract_start":400,"abstract_end":418}]}
{"pmid":"18947413","title":"Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene.","abstract":"BACKGROUND: Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.\nMETHODS: Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the EVC/EVC2 locus. The results did not exclude linkage, so samples were sequenced for mutations.\nRESULTS: We identified a c.1868T>C mutation in EVC, which predicts p.L623P, and was homozygous in affected individuals.\nCONCLUSION: We conclude that this EVC mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. EVC mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.","variants":[{"Name":"NM_153717.3(EVC):c.1868T>C (p.Leu623Pro)","Chromosome":"4","Start":"5793699","Stop":"5793699","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":543585,"rule_based_match":true,"evidence_text":"c.1868T>C","llm_judgment":"PRESENT","evidence":"c.1868T>C","abstract_start":701,"abstract_end":710}]}
{"pmid":"21681855","title":"A novel GJA3 mutation associated with congenital nuclear pulverulent and posterior polar cataract in a Chinese family.","abstract":"Congenital cataract (CC) is the leading cause of visual disability in children. To date, mutations in many genes have been linked to CC. In a four-generation Chinese family with congenital nuclear pulverulent and posterior polar cataracts, we detected a heterozygous c.5G>A transition in the second exon of GJA3, resulting in the substitution of a highly conserved glycine with aspartic acid (p.G2D) at the N-terminus of the connexin46 (Cx46) protein. Wild type (wt) and mutant Cx46 plasmids were transfected into HeLa cells to examine the molecular basis of cataract formation. Unlike wt Cx46, Cx46G2D mutant formed gap junction plaques inefficiently, changed hemichannel permeability, and caused apoptosis. These results suggest that the glycine residue at the second position of the N-terminus is important for gap junction plaque formation and hemichannel function.","variants":[{"Name":"NM_021954.4(GJA3):c.5G>A (p.Gly2Asp)","Chromosome":"13","Start":"20143284","Stop":"20143284","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":65605,"rule_based_match":true,"evidence_text":"c.5G>A","llm_judgment":"PRESENT","evidence":"c.5G>A","abstract_start":267,"abstract_end":273}]}
{"pmid":"20513532","title":"Three novel mutations of the APC gene in Korean patients with familial adenomatous polyposis.","abstract":"Germline mutations within the adenomatous polyposis coli (APC) gene are associated with familial adenomatous polyposis (FAP), an autosomal dominant disease predisposing individuals to colorectal cancer. Identification of APC mutations has important implications for genetic counseling and management of FAP patients. We examined the APC mutation status of 10 Korean FAP patients by polymerase chain reaction-direct sequencing method and found six APC mutations, including three novel mutations. Testing for MUTYH mutation was done for FAP patients in whom no mutation in the APC gene was identified. Three novel mutations (c.1654_1663delTCTTGGCGAG, c.3709C>T, and c.6092_6094delinsTT) and three previously reported mutations (c.3631_3632delAT, c.4438C>T, and c.4612_4613delGA) were detected. The MUTYH mutation was not detected in any of the four FAP patients without an APC mutation. This finding of three novel mutations in a group of Korean FAP patients broadens the spectrum of APC mutations.","variants":[{"Name":"NM_000038.6(APC):c.4438C>T (p.Gln1480Ter)","Chromosome":"5","Start":"112840032","Stop":"112840032","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1454739,"rule_based_match":true,"evidence_text":"c.4438C>T","llm_judgment":"PRESENT","evidence":"c.4438C>T","abstract_start":744,"abstract_end":753},{"Name":"NM_000038.6(APC):c.3631_3632del (p.Met1211fs)","Chromosome":"5","Start":"112839223","Stop":"112839224","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":454429,"rule_based_match":true,"evidence_text":"c.3631_3632delAT","llm_judgment":"PRESENT","evidence":"c.3631_3632delAT","abstract_start":726,"abstract_end":742},{"Name":"NM_000038.6(APC):c.4612_4613del (p.Glu1538fs)","Chromosome":"5","Start":"112840205","Stop":"112840206","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":15862,"rule_based_match":true,"evidence_text":"c.4612_4613delGA","llm_judgment":"PRESENT","evidence":"c.4612_4613delGA","abstract_start":759,"abstract_end":775},{"Name":"NM_000038.6(APC):c.3709C>T (p.Gln1237Ter)","Chromosome":"5","Start":"112839303","Stop":"112839303","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1060151,"rule_based_match":true,"evidence_text":"c.3709C>T","llm_judgment":"PRESENT","evidence":"c.3709C>T","abstract_start":649,"abstract_end":658}]}
{"pmid":"36307211","title":"Autosomal recessive LRP1-related syndrome featuring cardiopulmonary dysfunction, bone dysmorphology, and corneal clouding.","abstract":"We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.11420G > C (p.Cys3807Ser) and c.12407T > G (p.Val4136Gly) in <i>LRP1</i>, in which segregation analysis helped dismiss additional variants of interest. <i>LRP1</i> analysis using multiple human/mouse data sets reveals a correlation to patient phenotypes of Peters plus syndrome with additional severe cardiomyopathy and blood vessel development complications linked to neural crest cells.","variants":[{"Name":"NM_002332.3(LRP1):c.12407T>G (p.Val4136Gly)","Chromosome":"12","Start":"57209836","Stop":"57209836","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1696683,"rule_based_match":true,"evidence_text":"c.12407T > G (p.Val4136Gly)","llm_judgment":"PRESENT","evidence":"c.12407T > G (p.Val4136Gly)","abstract_start":431,"abstract_end":458},{"Name":"NM_002332.3(LRP1):c.11420G>C (p.Cys3807Ser)","Chromosome":"12","Start":"57205435","Stop":"57205435","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1696684,"rule_based_match":true,"evidence_text":"c.11420G > C (p.Cys3807Ser)","llm_judgment":"PRESENT","evidence":"c.11420G > C (p.Cys3807Ser)","abstract_start":399,"abstract_end":426}]}
{"pmid":"35151251","title":"Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia.","abstract":"BACKGROUND: VPS13D is a large ubiquitin-binding protein playing an essential role in mitophagy by regulating mitochondrial fission. Recently, VPS13D biallelic pathogenic variants have been reported in patients displaying variable neurological phenotypes, with an autosomic recessive inheritance. The objectives of the study were to determine the genetic etiology of a patient with early onset sporadic progressive spastic ataxia, and to investigate the pathogenicity of VPS13D variants through functional studies on patient's skin fibroblasts.\nCASE PRESENTATION: We report the case of a 51-year-old patient with spastic ataxia, with an acute onset of the disease at age 7. Walking difficulties slowly worsened over time, with the use of a wheelchair since age 26. We have used trio-based whole-exome sequencing (WES) to identify genes associated with spastic ataxia. The impact of the identified variants on mitochondrial function was assessed in patient's fibroblasts by imaging mitochondrial network and measuring level of individual OXPHOS complex subunits. Compound heterozygous variants were identified in VPS13D: c.946C > T, p.Arg316* and c.12416C > T, p.(Ala4139Val). Primary fibroblasts obtained from this patient revealed an altered mitochondrial morphology, and a decrease in levels of proteins from complex I, III and IV.\nCONCLUSIONS: Our findings confirmed implication of VPS13D in spastic ataxia and provided further support for mitochondrial defects in patient's skin fibroblasts with VPS13D variants. This report of long-term follow up showed a slowly progressive course of the spastic paraplegia with cerebellar features. Furthermore, the performed functional studies could be used as biomarker helping diagnosis of VPS13D-related neurological disorders when molecular results are uneasy to interpret.","variants":[{"Name":"NM_015378.4(VPS13D):c.12416C>T (p.Ala4139Val)","Chromosome":"1","Start":"12456080","Stop":"12456080","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":921195,"rule_based_match":true,"evidence_text":"c.12416C > T, p.(Ala4139Val)","llm_judgment":"PRESENT","evidence":"c.12416C > T, p.(Ala4139Val)","abstract_start":1145,"abstract_end":1173}]}
{"pmid":"26656312","title":"Clinical and molecular investigation in Chinese patients with glutaric aciduria type I.","abstract":"Glutaric aciduria type I (GA-I) is a rare autosomal recessive metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH), leading to an abnormal metabolism of lysine, hydroxylysine and tryptophan. It results in accumulations of glutaric acid, 3-hydroxyglutaric acid and glutaconic acid. Clinical features include the sudden onset of encephalopathy, hypotonia and macrocephaly usually before age 18months. Here we report five cases of GA-I confirmed with mutation analysis. GCDH gene mutations were identified in all five probands with GA-I. Three of them had compound heterozygous mutations and two had homozygous mutations. Mutations of two alleles (c.334G>T and IVS11-11A>G) were novel and both of them were confirmed to be splice site mutations by reverse transcription PCR.","variants":[{"Name":"NM_000159.4(GCDH):c.334G>T (p.Gly112Ter)","Chromosome":"19","Start":"12892178","Stop":"12892178","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":548714,"rule_based_match":true,"evidence_text":"c.334G>T","llm_judgment":"PRESENT","evidence":"c.334G>T","abstract_start":669,"abstract_end":677}]}
{"pmid":"35296718","title":"Expanding the clinical spectrum of COL2A1 related disorders by a mass like phenotype.","abstract":"MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1. We report four patients from three families presenting with a MASS-like phenotype consisting of tall stature, arachnodactyly, spinal deformations, dural ectasia, pectus and/or feet deformations, osteoarthritis, and/or high arched palate. Gene panel sequencing was negative for FBN1 variants. However, it revealed likely pathogenic missense variants in three individuals [c.3936G > T p.(Lys1312Asn), c.193G > A p.(Asp65Asn)] and a missense variant of unknown significance in the fourth patient [c.4013G > A p.(Ser1338Asn)] in propeptide coding regions of COL2A1. Pathogenic COL2A1 variants are associated with type II collagenopathies comprising a remarkable clinical variablility. Main features include skeletal dysplasia, ocular anomalies, and auditory defects. A MASS-like phenotype has not been associated with COL2A1 variants before. Thus, the identification of likely pathogenic COL2A1 variants in our patients expands the phenotypic spectrum of type II collagenopathies and suggests that a MASS-like phenotype can be assigned to various hereditary disorders of connective tissue. We compare the phenotypes of our patients with related disorders of connective tissue and discuss possible pathomechanisms and genotype-phenotype correlations for the identified COL2A1 variants. Our data recommend COL2A1 sequencing in FBN1-negative patients suggestive for MASS/Marfan-like phenotype (without aortopathy).","variants":[{"Name":"NM_001844.5(COL2A1):c.4013G>A (p.Ser1338Asn)","Chromosome":"12","Start":"47974736","Stop":"47974736","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1053014,"rule_based_match":true,"evidence_text":"c.4013G > A p.(Ser1338Asn)","llm_judgment":"PRESENT","evidence":"c.4013G > A p.(Ser1338Asn)","abstract_start":628,"abstract_end":654}]}
{"pmid":"26404900","title":"ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases.","abstract":"BACKGROUND: Limb Girdle Muscular Dystrophy (LGMD), caused by defective α-dystroglycan (α-DG) glycosylation, was recently associated with mutations in Isoprenoid synthase domain-containing (ISPD) and GDP-mannose pyrophosphorylase B (GMPPB) genes. The frequency of ISPD and GMPPB gene mutations in the LGMD population is unknown.\nMETHODS: We investigated the contributions of ISPD and GMPPB genes in a cohort of 174 Italian patients with LGMD, including 140 independent probands. Forty-one patients (39 probands) from this cohort had not been genetically diagnosed. The contributions of ISPD and GMPPB were estimated by sequential α-DG immunohistochemistry (IHC) and mutation screening in patients with documented α-DG defect, or by direct DNA sequencing of both genes when muscle tissue was unavailable.\nRESULTS: We performed α-DG IHC in 27/39 undiagnosed probands: 24 subjects had normal α-DG expression, two had a partial deficiency, and one exhibited a complete absence of signal. Direct sequencing of ISPD and GMPPB revealed two heterozygous ISPD mutations in the individual who lacked α-DG IHC signal: c.836-5 T > G (which led to the deletion of exon 6 and the production of an out-of-frame transcript) and c.676 T > C (p.Tyr226His). This patient presented with sural hypertrophy and tip-toed walking at 5 years, developed moderate proximal weakness, and was fully ambulant at 42 years. The remaining 12/39 probands did not exhibit pathogenic sequence variation in either gene.\nCONCLUSION: ISPD mutations are a rare cause of LGMD in the Italian population, accounting for less than 1% of the entire cohort studied (FKRP mutations represent 10%), while GMPPB mutations are notably absent in this patient sample. These data suggest that the genetic heterogeneity of LGMD with and without α-DG defects is greater than previously realized.","variants":[{"Name":"NM_001101426.4(CRPPA):c.676T>C (p.Tyr226His)","Chromosome":"7","Start":"16376100","Stop":"16376100","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":945548,"rule_based_match":true,"evidence_text":"c.676 T > C (p.Tyr226His)","llm_judgment":"PRESENT","evidence":"c.676 T > C (p.Tyr226His)","abstract_start":1211,"abstract_end":1236}]}
{"pmid":"29449315","title":"Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity.","abstract":"Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-yr-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting <i>NF1</i> or <i>SPRED1</i>, revealing a heterozygous germline single-nucleotide variant (SNV) in exon 21 of <i>NF1</i> at c.2709G>A, Chr 17: 29556342. By report, this variant disrupts pre-mRNA splicing of <i>NF1</i> transcripts. No pathogenic mutations were identified in <i>SPRED1</i> A potential association between MBC and NF1 was reported in eight previous cases, but none underwent detailed genomics analysis. To identify additional candidate germline variants potentially predisposing to MBC, we conducted targeted exome sequencing of 279 established cancer-causing genes in a control blood sample, disclosing four rare SNVs. Analysis of her breast tumor showed markedly altered variant allelic fractions (VAFs) for two (50%) of them, revealing somatic loss of heterozygosity (LOH) at germline SNVs. Of these, only the VAF of the pathogenic SNV in <i>NF1</i> was increased in the tumor. Tumor sequencing demonstrated five somatic mutations altering <i>TP53</i>, <i>BRCA1</i>, and other genes potentially contributing to cancer formation. Because somatic LOH at certain germline SNVs can enhance their impacts, we conclude that increased allelic imbalance of the pathogenic SNV in <i>NF1</i> likely contributed to tumorigenesis. Our results highlight a need to assess predisposing genetic factors and LOH that can cause rare, aggressive diseases such as MBC in NF1.","variants":[{"Name":"NM_001042492.3(NF1):c.2709G>A (p.Val903=)","Chromosome":"17","Start":"31229324","Stop":"31229324","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":361012,"rule_based_match":true,"evidence_text":"c.2709G>A","llm_judgment":"PRESENT","evidence":"c.2709G>A","abstract_start":491,"abstract_end":500}]}
{"pmid":"23085344","title":"Late-onset combined immune deficiency associated to skin granuloma due to heterozygous compound mutations in RAG1 gene in a 14 years old male.","abstract":"We report a male with atypical severe combined immunodeficiency caused by heterozygous compound mutations c.256-257del and c.C1331T in RAG1 gene. The patient presents with recurrent bronchopneumonias with obstruction, chronic fibrosing alveolitis, complicated by respiratory failure, pulmonary hypertension and hepatosplenomegaly. He was diagnosed with agammaglobulinemia at the age of 9. His condition was complicated by granulomatous skin disease at the age of 12 despite regular IVIg substitution. Immunological presentation included profound hypogammaglobulinemia and absence of B cells. Under immunoglobulin substitution for 5 years patient has permanent lymphopenia, skewed phenotype of T cells and diminished number of recent thymic emigrants.","variants":[{"Name":"NM_000448.3(RAG1):c.256_257del (p.Lys86fs)","Chromosome":"11","Start":"36573560","Stop":"36573561","ReferenceAlleleVCF":"TAA","AlternateAlleleVCF":"T","allel_id":269282,"rule_based_match":false,"evidence_text":"c.256-257del","llm_judgment":"PRESENT","evidence":"c.256-257del","abstract_start":106,"abstract_end":118},{"Name":"NM_000448.3(RAG1):c.1331C>T (p.Ala444Val)","Chromosome":"11","Start":"36574635","Stop":"36574635","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":79573,"rule_based_match":false,"evidence_text":"c.C1331T","llm_judgment":"PRESENT","evidence":"c.C1331T","abstract_start":123,"abstract_end":131}]}
{"pmid":"26744326","title":"A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium.","abstract":"Inherited retinal dystrophies are clinically and genetically heterogeneous with significant number of cases remaining genetically unresolved. We studied a large family from the West Indies islands with a peculiar retinal disease, the Martinique crinkled retinal pigment epitheliopathy that begins around the age of 30 with retinal pigment epithelium (RPE) and Bruch's membrane changes resembling a dry desert land and ends with a retinitis pigmentosa. Whole-exome sequencing identified a heterozygous c.518T>C (p.Leu173Pro) mutation in MAPKAPK3 that segregates with the disease in 14 affected and 28 unaffected siblings from three generations. This unknown variant is predicted to be damaging by bioinformatic predictive tools and the mutated protein to be non-functional by crystal structure analysis. MAPKAPK3 is a serine/threonine protein kinase of the p38 signaling pathway that is activated by a variety of stress stimuli and is implicated in cellular responses and gene regulation. In contrast to other tissues, MAPKAPK3 is highly expressed in the RPE, suggesting a crucial role for retinal physiology. Expression of the mutated allele in HEK cells revealed a mislocalization of the protein in the cytoplasm, leading to cytoskeleton alteration and cytodieresis inhibition. In Mapkapk3-/- mice, Bruch's membrane is irregular with both abnormal thickened and thinned portions. In conclusion, we identified the first pathogenic mutation in MAPKAPK3 associated with a retinal disease. These findings shed new lights on Bruch's membrane/RPE pathophysiology and will open studies of this signaling pathway in diseases with RPE and Bruch's membrane alterations, such as age-related macular degeneration.","variants":[{"Name":"NM_001243925.2(MAPKAPK3):c.518T>C (p.Leu173Pro)","Chromosome":"3","Start":"50644422","Stop":"50644422","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":248662,"rule_based_match":true,"evidence_text":"c.518T>C (p.Leu173Pro)","llm_judgment":"PRESENT","evidence":"c.518T>C (p.Leu173Pro)","abstract_start":501,"abstract_end":523}]}
{"pmid":"32901138","title":"A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.","abstract":"Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.","variants":[{"Name":"NM_016146.6(TRAPPC4):c.454+3A>G","Chromosome":"11","Start":"119020256","Stop":"119020256","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":373902,"rule_based_match":true,"evidence_text":"NM_016146.5:c.454+3A>G","llm_judgment":"PRESENT","evidence":"NM_016146.5:c.454+3A>G","abstract_start":515,"abstract_end":537}]}
{"pmid":"28295209","title":"A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.","abstract":"Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole-exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with 2 affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.","variants":[{"Name":"NM_018131.5(CEP55):c.256C>T (p.Arg86Ter)","Chromosome":"10","Start":"93503185","Stop":"93503185","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":431496,"rule_based_match":true,"evidence_text":"c.256C>T (p.Arg86*)","llm_judgment":"PRESENT","evidence":"c.256C>T (p.Arg86*)","abstract_start":758,"abstract_end":777}]}
{"pmid":"24078573","title":"Clinical and mutational features of maternal 3-methylcrotonyl coenzyme deficiency","abstract":"OBJECTIVE: To report on 5 patients with maternal 3-methylcrotonyl coenzyme A carboxylase deficiency (MCCD) and to confirm the clinical diagnosis through mutation analysis.\nMETHODS: Five neonates with higher blood 3-hydroxy isovalerylcarnitine (C5-OH) concentration detected upon newborn screening with tandem mass spectrometry and their mothers were recruited. Urinary organic acids were analyzed with gas chromatography mass spectrometry. Gene mutation and protein function analysis were performed by PCR direct sequencing and PolyPhen-2 software.\nRESULTS: Higher blood C5-OH concentrations (5.11-21.77 μmol/L) and abnormal 3-hydroxy isovalerate and 3-methylcrotonyl glycine in urine were detected in the five asymptomatic mothers, who were diagnosed as benign MCCD. Higher C5-OH concentration was also detected in their neonates by tandem mass spectrometry, which had gradually decreased to normal levels in three neonates. Four new variations, i.e., c.ins1680A(25%), c.203C > T (p.A68V), c.572T > C (p.L191P) and c.639+5G > T were detected in the MCCC1 gene, in addition with 2 mutations [c.1406G > T (p.R469L, novel variation) and c.592C > T (p.Q198X)]. The novel variations were predicted to have affected protein structure and function.\nCONCLUSION: For neonates with higher C5-OH concentration detected upon neonatal screening, their mothers should be also tested to rule out MCCD. Mutations in MCCC1 gene are quite common.","variants":[{"Name":"NM_020166.5(MCCC1):c.639+5G>T","Chromosome":"3","Start":"183071205","Stop":"183071205","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1055322,"rule_based_match":true,"evidence_text":"c.639+5G>T","llm_judgment":"PRESENT","evidence":"c.639+5G > T","abstract_start":1016,"abstract_end":1028}]}
{"pmid":"32787476","title":"Two novel","abstract":"<b>Background:</b> Achromatopsia (ACHM) is an inherited retinal disease affecting the cone cell function. To date, six pathogenic genes of ACHM have been identified. However, the diagnostic and therapeutic methods of this disorder remain limited. Herein, to characterize the clinical features and genetic causes of three affected siblings in a Chinese family with ACHM, we used target next-generation sequencing (NGS) and found new pathogenic factors associated with ACHM in this family. <b>Materials and methods:</b> Three patients with ACHM and three healthy family members were included in this study. All participants received comprehensive ophthalmic tests. NGS approach was performed on the patients to determine the causative mutation for this family. The silico analysis was also applied to predict the pathogenesis of identified mutations. <b>Results:</b> Genetic assessments revealed compound heterozygous mutations of the <i>PDE6C</i> gene (c.1413 + 1 G > C, c.305 G > A), carried by all three patients. Both mutations were novel and predicted to be deleterious by six types of online predictive software. The heterozygous <i>PDE6C</i> missense mutation (c.305 G > A) was found from the mother and the heterozygous <i>PDE6C</i> splice site mutation (c.1413 + 1 G > C) was found in the father and all the children. All patients in the family showed typical signs and symptoms of ACHM. <b>Conclusions:</b> We report novel compound heterozygous <i>PDE6C</i> mutations in causing ACHM and further confirm the clinical diagnosis. Our study extends the genotypic spectrums for <i>PDE6C</i>-ACHM and better illustrates its genotype-phenotype correlations, which would help the ACHM patients with better genetic diagnosis, prognosis, and gene treatment.","variants":[{"Name":"NM_006204.4(PDE6C):c.305G>A (p.Arg102Gln)","Chromosome":"10","Start":"93613030","Stop":"93613030","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1491036,"rule_based_match":true,"evidence_text":"c.305 G > A","llm_judgment":"PRESENT","evidence":"c.305 G > A","abstract_start":970,"abstract_end":981}]}
{"pmid":"25117148","title":"Novel ABCC8 (SUR1) gene mutations in Asian Indian children with congenital hyperinsulinemic hypoglycemia.","abstract":"Congenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the β-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619-629delCCCGAGGACCT, Gln444*, Leu724Pro, Ala847Thr, Trp898*, IVS30-2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598*) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling.","variants":[{"Name":"NM_000352.6(ABCC8):c.267del (p.Ile89fs)","Chromosome":"11","Start":"17474909","Stop":"17474909","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1517421,"rule_based_match":true,"evidence_text":"c.267delT","llm_judgment":"PRESENT","evidence":"c.267delT","abstract_start":799,"abstract_end":808},{"Name":"NM_000352.6(ABCC8):c.4361T>G (p.Leu1454Arg)","Chromosome":"11","Start":"17395222","Stop":"17395222","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1517425,"rule_based_match":false,"evidence_text":"Leu1454Arg","llm_judgment":"PRESENT","evidence":"Leu1454Arg","abstract_start":891,"abstract_end":901},{"Name":"NM_000352.6(ABCC8):c.331G>A (p.Gly111Arg)","Chromosome":"11","Start":"17470182","Stop":"17470182","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":207858,"rule_based_match":false,"evidence_text":"Gly111Arg","llm_judgment":"PRESENT","evidence":"Gly111Arg","abstract_start":928,"abstract_end":937},{"Name":"NM_000352.6(ABCC8):c.2539G>A (p.Ala847Thr)","Chromosome":"11","Start":"17412683","Stop":"17412683","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":586039,"rule_based_match":false,"evidence_text":"Ala847Thr","llm_judgment":"PRESENT","evidence":"Ala847Thr","abstract_start":855,"abstract_end":864}]}
{"pmid":"31204009","title":"RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities.","abstract":"Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset ≤3 years of age have splice alterations at the same position (c.1333+1G>A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or infection, Golgi-to-ER transport is suppressed and autophagy is promoted through UVRAG regulation by mTOR. Aberrant autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.","variants":[{"Name":"NM_021930.6(RINT1):c.1333+1G>A","Chromosome":"7","Start":"105550487","Stop":"105550487","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":538391,"rule_based_match":true,"evidence_text":"c.1333+1G>A","llm_judgment":"PRESENT","evidence":"c.1333+1G>A","abstract_start":527,"abstract_end":538},{"Name":"NM_021930.6(RINT1):c.1333+1G>T","Chromosome":"7","Start":"105550487","Stop":"105550487","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":680031,"rule_based_match":false,"evidence_text":"c.1333+1G>T","llm_judgment":"PRESENT","evidence":"c.1333+1G>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"27641950","title":"Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism.","abstract":"PURPOSE: Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism.\nRESULTS: The patient was diagnosed with hemophilia B at age 4months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32years of age due to unexplained oculocutaneous albinism. His factor IX level was markedly reduced at 13%; whole exome and Sanger sequencing showed the Durham mutation in F9 (NM_000133.3). The diagnosis of Hermansky-Pudlak syndrome subtype 6 was established by demonstrating absence of platelet delta granules on whole mount electron microscopy, an abnormal secondary wave in platelet aggregation studies, and a novel homozygous c.1114 C>T (p.Arg372*) mutation in HPS6 (NM_024747.5) on exome analysis and Sanger sequencing. Clinical phenotyping revealed no evidence of recurrent or unusual infections, interstitial lung disease or pulmonary fibrosis, or neurological disorders. The patient was treated with fresh frozen plasma, recombinant factor IX, and aminocaproic acid. Treatment with desmopressin was added to his regimen after he was diagnosed with Hermansky-Pudlak syndrome. Treatment of bleeding episodes results in effective hemostasis, and the patient has not required platelet or blood product transfusions.\nCONCLUSIONS: This report highlights the need to consider Hermansky-Pudlak syndrome as an etiology of oculocutaneous albinism even in patients with known hematologic disorders associated with bleeding. Identification of a novel mutation in HPS6 in an individual with hemophilia B shows that, although quite rare, patients may be diagnosed with two independent inherited bleeding disorders. No evidence of lung disease was found in this adult patient with Hermansky-Pudlak syndrome subtype 6.","variants":[{"Name":"NM_024747.6(HPS6):c.1114C>T (p.Arg372Ter)","Chromosome":"10","Start":"102066588","Stop":"102066588","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1340120,"rule_based_match":true,"evidence_text":"c.1114 C>T (p.Arg372*)","llm_judgment":"PRESENT","evidence":"c.1114 C>T (p.Arg372*)","abstract_start":989,"abstract_end":1011}]}
{"pmid":"29275168","title":"Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism.","abstract":"Thyroid dyshormonogenesis due to thyroglobulin (TG) gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. Up to now, one hundred seventeen deleterious mutations in the TG gene have been identified and characterized. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report eight patients from seven unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and image evaluation. Sequencing of DNA, genotyping, as well as bioinformatics analysis were performed. Molecular analyses revealed three novel inactivating TG mutations: c.5560G>T [p.E1835*], c.7084G>C [p.A2343P] and c.7093T>C [p.W2346R], and four previously reported mutations: c.378C>A [p.Y107*], c.886C>T [p.R277*], c.1351C>T [p.R432*] and c.7007G>A [p.R2317Q]. Two patients carried homozygous mutations (p.R277*/p.R277*, p.W2346R/p.W2346R), four were compound heterozygous mutations (p.Y107*/p.R277* (two unrelated patients), p.R432*/p.A2343P, p.Y107*/p.R2317Q) and two siblings from another family had a single p.E1835* mutated allele. Additionally, we include the analysis of 48 patients from 31 unrelated families with TG mutations identified in our present and previous studies. Our observation shows that mutations in both TG alleles were found in 27 families (9 as homozygote and 18 as heterozygote compound), whereas in the remaining four families only one mutated allele was detected. The majority of the detected mutations occur in exons 4, 7, 38 and 40. 28 different mutations were identified, 33 of the 96 TG alleles encoded the change p.R277*. In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of the predicted TG misfolding and therefore thyroid hormone formation as a consequence of truncated TG proteins and/or missense mutations located within its ACHE-like domain.","variants":[{"Name":"NM_003235.5(TG):c.1351C>T (p.Arg451Ter)","Chromosome":"8","Start":"132886723","Stop":"132886723","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1020436,"rule_based_match":true,"evidence_text":"c.1351C>T [p.R432*]","llm_judgment":"PRESENT","evidence":"c.1351C>T [p.R432*]","abstract_start":895,"abstract_end":914}]}
{"pmid":"28190860","title":"Activated phosphoinositide 3-kinase δ syndrome presenting with gut-associated T-cell lymphoproliferative disease.","abstract":"A 13-year-old boy was admitted to our hospital because of persistent diarrhea, abdominal pain, and bloody stools. The patient had experienced repeated hospitalizations for the treatment of respiratory infections since early childhood. Colonoscopic and pathological studies led to a diagnosis of gut-associated T-cell lymphoproliferative disease (T-cell LPD). Laboratory data showed T-lymphocytopenia (492/µl), increased serum IgG levels (1,984 mg/dl), and low serum antibody titers for specific pathogens. Combined immunodeficiency accompanied by T-LPD suggested the diagnosis of activated PI3Kδ syndrome (APDS). Genetic analyses identified a heterozygous mutation of the PIK3CD gene (c.1573 G to A p.Glu525Lys). Although prednisolone and cyclosporine therapy has controlled the T-cell LPD, this patient awaits allogeneic hematopoietic cell transplantation to achieve a complete cure of his APDS.","variants":[{"Name":"NM_005026.5(PIK3CD):c.1573G>A (p.Glu525Lys)","Chromosome":"1","Start":"9720793","Stop":"9720793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":136556,"rule_based_match":false,"evidence_text":"c.1573 G to A p.Glu525Lys","llm_judgment":"PRESENT","evidence":"c.1573 G to A p.Glu525Lys","abstract_start":685,"abstract_end":710}]}
{"pmid":"25704016","title":"The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.","abstract":"Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig-1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials.","variants":[{"Name":"NM_005866.4(SIGMAR1):c.304G>C (p.Glu102Gln)","Chromosome":"9","Start":"34637268","Stop":"34637268","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":39194,"rule_based_match":true,"evidence_text":"c.304G > C","llm_judgment":"PRESENT","evidence":"c.304G > C","abstract_start":436,"abstract_end":446}]}
{"pmid":"32436339","title":"High prevalence of autosomal recessive congenital ichthyosis in a Mexican population caused by a new mutation in the TGM1 gene: epidemiological evidence of a founder effect.","abstract":"BACKGROUND: Autosomal recessive congenital ichthyoses (ARCI) are inherited disorders produced by mutations in essential genes for the skin function. A low prevalence of this disease has been resported worldwide; however, in a recent study, we identified a large cluster of ARCI families who resided in the High Mountains Region from the Veracruz State, Mexico. Thus, we aimed to identify the causative mutation of ARCI and describe the high prevalence of this disease in this region.\nMETHODS: We selected seven familiar trios and performed whole-exome sequencing to identify the mutation associated with ARCI. To validate the identified mutation, we performed Sanger sequencing in 62 patients, 30 unaffected relatives, and 100 healthy volunteers. Finally, we performed molecular modeling to investigate the possible functional consequences produced by the mutation.\nRESULTS: We identified a novel homozygous mutation (c.1054C>G [p.Pro352Ala]) in the exon 7 of the TGM1 gene in all the patients. We calculated a prevalence rate of ARCI of 74:100,000 (1:1,348) in the studied communities. Molecular modeling revealed that the mutation leads to a nonconservative amino acid substitution, which is very probably damaging to the protein structure/function.\nCONCLUSIONS: We report a novel mutation in the TGM1 gene in 62 Mexican patients. The unusually high frequency of this mutation suggests a founder effect; however, further haplotype analysis is necessary to corroborate this hypothesis. In this respect, to our knowledge, the prevalence of ARCI found in the studied communities is the highest observed worldwide.","variants":[{"Name":"NM_000359.3(TGM1):c.1054C>G (p.Pro352Ala)","Chromosome":"14","Start":"24259180","Stop":"24259180","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":682508,"rule_based_match":true,"evidence_text":"c.1054C>G (p.Pro352Ala)","llm_judgment":"PRESENT","evidence":"p.Pro352Ala","abstract_start":929,"abstract_end":940}]}
{"pmid":"32557834","title":"APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort.","abstract":"BACKGROUND AND AIMS: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas.\nAPPROACH AND RESULTS: Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH.\nCONCLUSIONS: APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.","variants":[{"Name":"NM_000383.4(AIRE):c.967_979del (p.Leu323fs)","Chromosome":"21","Start":"44291180","Stop":"44291192","ReferenceAlleleVCF":"TGCCTGTCCCCTCC","AlternateAlleleVCF":"T","allel_id":18348,"rule_based_match":true,"evidence_text":"c.967_979del","llm_judgment":"PRESENT","evidence":"c.967_979del","abstract_start":1769,"abstract_end":1781}]}
{"pmid":"33986768","title":"Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: High Incidence of Detected Patients With Expanded Newborn Screening Program.","abstract":"Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare autosomal recessive disorder of fatty acid metabolism with a variable presentation. The aim of this study was to describe five patients with VLCADD diagnosed through the pilot study and expanded newborn screening (NBS) program that started in 2018 in Slovenia. Four patients were diagnosed through the expanded NBS program with tandem mass spectrometry; one patient was previously diagnosed in a pilot study preceding the NBS implementation. Confirmatory testing consisted of acylcarnitines analysis in dried blood spots, organic acids profiling in urine, genetic analysis of <i>ACADVL</i> gene, and enzyme activity determination in lymphocytes or fibroblasts. Four newborns with specific elevation of acylcarnitines diagnostic for VLCADD and disease-specific acylcarnitines ratios (C14:1, C14, C14:2, C14:1/C2, C14:1/C16) were confirmed with genetic testing: all were compound heterozygotes, two of them had one previously unreported <i>ACDVL</i> gene variant each (NM_000018.3) c.1538C > G; (NP_000009) p.(Ala513Gly) and c.661A > G; p.(Ser221Gly), respectively. In addition, one patient diagnosed in the pilot study also had a specific elevation of acylcarnitines. Subsequent <i>ACDVL</i> genetic analysis confirmed compound heterozygosity. In agreement with the diagnosis, enzyme activity was reduced in five patients tested. In seven other newborns with positive screening results, only single allele variants were found in the <i>ACDVL</i> gene, so the diagnosis was not confirmed. Among these, two variants were novel, c.416T > C and c.1046C > A, respectively (p.Leu139Pro and p.Ala349Glu). In the first 2 years of the expanded NBS program in Slovenia altogether 30,000 newborns were screened. We diagnosed four cases of VLCADD. The estimated VLCADD incidence was 1:7,500 which was much higher than that of the medium-chain acyl-CoA dehydrogenase deficiency (MCADD) cases in the same period. Our study also provided one of the first descriptions of <i>ACADVL</i> variants in Central-Southeastern Europe and reported on 4 novel variants.","variants":[{"Name":"NM_000018.4(ACADVL):c.661A>G (p.Ser221Gly)","Chromosome":"17","Start":"7221990","Stop":"7221990","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1454255,"rule_based_match":true,"evidence_text":"c.661A > G; p.(Ser221Gly)","llm_judgment":"PRESENT","evidence":"c.661A > G; p.(Ser221Gly)","abstract_start":1092,"abstract_end":1117}]}
{"pmid":"21811973","title":"Mutation analysis of GCDH gene in eight patients with glutaric aciduria type I","abstract":"OBJECTIVE: To investigate the mutations of glutaryl-CoA dehydrogenase (GCDH) gene in patients with glutaric aciduria type I(GA-1).\nMETHODS: Genomic DNA was extracted from peripheral blood cells of the eight probands with GA-1 who were diagnosed by urine and blood analyses. By PCR and direct sequencing, all 11 exons and their flanking sequences of the GCDH gene were examined. Mutation search was also performed in some of their family members.\nRESULTS: Among the eight patients diagnosed by metabolic screening, seven patients belonged to classical infantile-onset. One patient, however, was adult-onset, who was admitted to the hospital because of suffering from ischemic cerebral stroke. The GCDH gene mutations were identified in all the eight probands with GA-1: five of them had compound heterozygous mutations, while the other three harbored only one heterozygous mutation. Totally, nine different mutations of the GCDH gene were identified in the eight probands, four of them were novel, i.e., c.148T>C, c.371G>A, 909delC and c.263G>A.\nCONCLUSION: GCDH gene mutations are identified in 8 patients with GA-1 in mainland China, including one adult patient with late onset. Four novel mutations of GCDH gene are found which expanded the mutational spectrum of the GCDH gene.","variants":[{"Name":"NM_000159.4(GCDH):c.148T>C (p.Trp50Arg)","Chromosome":"19","Start":"12891851","Stop":"12891851","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2742131,"rule_based_match":true,"evidence_text":"c.148T>C","llm_judgment":"PRESENT","evidence":"c.148T>C","abstract_start":1003,"abstract_end":1011}]}
{"pmid":"33558980","title":"Inherited CARD9 Deficiency in a Child with Invasive Disease Due to Exophiala dermatitidis and Two Older but Asymptomatic Siblings.","abstract":"PURPOSE: Autosomal recessive CARD9 deficiency predisposes patients to invasive fungal disease. Candida and Trichophyton species are major causes of fungal disease in these patients. Other CARD9-deficient patients display invasive diseases caused by other fungi, such as Exophiala spp. The clinical penetrance of CARD9 deficiency regarding fungal disease is surprisingly not complete until adulthood, though the age remains unclear. Moreover, the immunological features of genetically confirmed yet asymptomatic individuals with CARD9 deficiency have not been reported.\nMETHODS: Identification of CARD9 mutations by gene panel sequencing and characterization of the cellular phenotype by quantitative PCR, immunoblot, luciferase reporter, and cytometric bead array assays were performed.\nRESULTS: Gene panel sequencing identified compound heterozygous CARD9 variants, c.1118G>C (p.R373P) and c.586A>G (p.K196E), in a 4-year-old patient with multiple cerebral lesions and systemic lymphadenopathy due to Exophiala dermatitidis. The p.R373P is a known disease-causing variant, whereas the p.K196E is a private variant. Although the patient's siblings, a 10-year-old brother and an 8-year-old sister, were also compound heterozygous, they have been asymptomatic to date. Normal CARD9 mRNA and protein expression were found in the patient's CD14<sup>+</sup> monocytes. However, these cells exhibited markedly impaired pro-inflammatory cytokine production in response to fungal stimulation. Monocytes from both asymptomatic siblings displayed the same cellular phenotype.\nCONCLUSIONS: CARD9 deficiency should be considered in previously healthy patients with invasive Exophiala dermatitidis disease. Asymptomatic relatives of all ages should be tested for CARD9 deficiency. Detecting cellular defects in asymptomatic individuals is useful for diagnosing CARD9 deficiency.","variants":[{"Name":"NM_052813.5(CARD9):c.1118G>C (p.Arg373Pro)","Chromosome":"9","Start":"136367788","Stop":"136367788","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":94420,"rule_based_match":true,"evidence_text":"c.1118G>C (p.R373P)","llm_judgment":"PRESENT","evidence":"c.1118G>C (p.R373P)","abstract_start":867,"abstract_end":886}]}
{"pmid":"27652356","title":"A novel missense mutation in the C2C domain of otoferlin causes profound hearing impairment in an Omani family with auditory neuropathy.","abstract":"OBJECTIVES: To identify genetic defects in an Omani family diagnosed with deafness. \nMETHODS: A cross-sectional association study was conducted at the Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, Oman and the Centre of Medical Genetics, University of Antwerp, Antwerp, Belgium between August 2010 and September 2014. Microsatellites markers for nine non-syndromic genes were used to genotype the defective locus using the extracted DNA from family members. Sanger sequencing method was used to identify the disease causative mutation. Eazy linkage 5.05 was used to calculate the logarithm of odds score. Lasergene suite was used to detect the mutation position, and Phyre2, SMART, Rasmol, and GOR IV were used to predict the effects of the defect on protein structure and function. \nRESULTS: The disease was linked to markers located on chromosome-2 and covering the OTOF (DFNB9) gene. A novel missense mutation that changed nucleotide C to G at position c.1469 and consequently the amino acid Proline to Arginine (P490R) on exon 15 was detected. Protein modeling analysis revealed the impact of the mutation on protein structure and the relevant C2C domain. The mutation seems to create a new protein isoform homologous to the complement component C1q. \nCONCLUSION: These findings suggest that the mutation found in C2C domain of the OTOF gene is likely to cause deafness in the studied family reflecting the importance of C2 domains of otoferlin in hearing loss.","variants":[{"Name":"NM_194248.3(OTOF):c.1469C>G (p.Pro490Arg)","Chromosome":"2","Start":"26482516","Stop":"26482516","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":57334,"rule_based_match":false,"evidence_text":"c.1469C>G (p.Pro490Arg)","llm_judgment":"PRESENT","evidence":"P490R","abstract_start":1075,"abstract_end":1080}]}
{"pmid":"28262468","title":"Congenital myopathy with \"corona\" fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A.","abstract":"We describe two brothers with lower facial weakness, highly arched palate, scaphocephaly due to synostosis of the sagittal and metopic sutures, axial hypotonia, proximal muscle weakness, and mild scoliosis. The muscle MRI of the younger sibling revealed a selective pattern of atrophy of the gluteus maximus, adductor magnus and soleus muscles. Muscle biopsy of the younger sibling revealed myofibres with internalized nuclei, myofibrillar disarray, and \"corona\" fibres. Both affected siblings were found to be compound heterozygous for c.3425G>A (p.Arg1142Gln) and c.1123T>C (p.Cys375Arg) mutations in SCN4A on exome sequencing, and the parents were confirmed carriers of one of the mutations. Electrophysiological characterization of the mutations revealed the Cys375Arg confers full and Arg1142Gln mild partial loss-of-function. Loss of function of the Na<sub>v</sub>1.4 channel leads to a decrement of the action potential and subsequent reduction of muscle contraction. The unusual muscle biopsy features suggest a more complex pathomechanism, and broaden the phenotype associated with SCN4A mutations.","variants":[{"Name":"NM_000334.4(SCN4A):c.3425G>A (p.Arg1142Gln)","Chromosome":"17","Start":"63947061","Stop":"63947061","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":468539,"rule_based_match":true,"evidence_text":"c.3425G>A (p.Arg1142Gln)","llm_judgment":"PRESENT","evidence":"c.3425G>A (p.Arg1142Gln)","abstract_start":537,"abstract_end":561},{"Name":"NM_000334.4(SCN4A):c.1123T>C (p.Cys375Arg)","Chromosome":"17","Start":"63966221","Stop":"63966221","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2524620,"rule_based_match":true,"evidence_text":"c.1123T>C (p.Cys375Arg)","llm_judgment":"PRESENT","evidence":"c.1123T>C (p.Cys375Arg)","abstract_start":566,"abstract_end":589}]}
{"pmid":"33671400","title":"De Novo Development of mtDNA Deletion Due to Decreased POLG and SSBP1 Expression in Humans.","abstract":"Defects in the mitochondrial genome (mitochondrial DNA (mtDNA)) are associated with both congenital and acquired disorders in humans. Nuclear-encoded DNA polymerase subunit gamma (<i>POLG</i>) plays an important role in mtDNA replication, and proofreading and mutations in <i>POLG</i> have been linked with increased mtDNA deletions. <i>SSBP1</i> is also a crucial gene for mtDNA replication. Here, we describe a patient diagnosed with Pearson syndrome with large mtDNA deletions that were not detected in the somatic cells of the mother. Exome sequencing was used to evaluate the nuclear factors associated with the patient and his family, which revealed a paternal <i>POLG</i> mutation (c.868C > T) and a maternal <i>SSBP1</i> mutation (c.320G > A). The patient showed lower <i>POLG</i> and <i>SSBP1</i> expression than his healthy brothers and the general population of a similar age. Notably, c.868C in the wild-type allele was highly methylated in the patient compared to the same site in both his healthy brothers. These results suggest that the co- deficient expression of <i>POLG</i> and <i>SSBP1</i> genes could contribute to the development of mtDNA deletion.","variants":[{"Name":"NM_002693.3(POLG):c.868C>T (p.Arg290Cys)","Chromosome":"15","Start":"89329098","Stop":"89329098","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":860199,"rule_based_match":true,"evidence_text":"c.868C > T","llm_judgment":"PRESENT","evidence":"c.868C > T","abstract_start":689,"abstract_end":699}]}
{"pmid":"30835345","title":"Retrospective analysis on clinical data and genetic variations of patients with beta-ketothiolase deficiency","abstract":"OBJECTIVE: To summarize the clinical, biochemical and molecular characteristics of 8 patients with beta-ketothiolase deficiency (BKD).\nMETHODS: Clinical characteristics, biochemical markers detected by tandem mass spectrometry (MS-MS) and gas chromatography-mass spectrometry (GC-MS), and variations of ACAT1 gene of the 8 patients were reviewed.\nRESULTS: Three patients were diagnosed by newborn screening and were asymptomatic. Five patients showed dyspnea and metabolic acidosis through high risk screening. Blood methylcrotonyl carnitine (C5:1) were 0.43 (0.20-0.89) μmol/L and 3-hydroxyisovaleryl carnitine(C5-OH) were 1.37 (0.98-3.40) μmol/L. Both were significantly higher than those of healthy controls (P<0.01). Urinary 2-methyl-3-hydroxybutyric acid was 56.04 (7.69-182.20) and methylcrotonyl glycine was 42.83 (9.20-127.01), both were higher than normal levels. In 5 patients urinary 2-methyl-3-hydroxybutyric acid level was remarkably decreased (P<0.05) after treatment. Analysis of ACAT1 gene mutation was performed in six families. Missense variations were detected in 78.6% of the cases. 42.8% of the 7 BKD patients have carried c.1124A>G (p.N375S) variant, which accounted for 28.6% of all 14 mutant alleles. Four novel variants, namely c.229delG (p.E77KfsTer10), c.373G>T (p.V125F), c.419T>G (p.L140R) and c.72+1G>A, were discovered. Pathogenicity assessment of two highly conservative missense variants (p.V125F) and (p.L140R) were 0.994 and 1.0 (Scores obtained from PolyPhen2), and PROVEAN scores were -4.652 and -5.399, respectively. c.72+1g>a was suspected (by Human Splicing Finder) to alter the wild type donor motif and most probably affect the splicing.\nCONCLUSION: Clinicians should consider MS/MS and GC/MS testing for those with unexplained neurological symptoms and metabolic acidosis in order to attain early diagnosis of BKD. Genetic testing should be used to confirm the diagnosis.","variants":[{"Name":"NM_000019.4(ACAT1):c.1124A>G (p.Asn375Ser)","Chromosome":"11","Start":"108146320","Stop":"108146320","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":654073,"rule_based_match":true,"evidence_text":"c.1124A>G (p.N375S)","llm_judgment":"PRESENT","evidence":"c.1124A>G (p.N375S)","abstract_start":1144,"abstract_end":1163}]}
{"pmid":"22425360","title":"Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population.","abstract":"Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs*31], c.4804C>T [p.Arg1602*], and c.7477C>T [p.Arg2493*]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS.","variants":[{"Name":"NM_001384732.1(CPLANE1):c.4006C>T (p.Arg1336Trp)","Chromosome":"5","Start":"37187488","Stop":"37187488","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40176,"rule_based_match":true,"evidence_text":"c.4006C>T [p.Arg1336Trp]","llm_judgment":"PRESENT","evidence":"c.4006C>T [p.Arg1336Trp]","abstract_start":877,"abstract_end":901},{"Name":"NM_001384732.1(CPLANE1):c.7400+1G>A","Chromosome":"5","Start":"37167046","Stop":"37167046","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40177,"rule_based_match":true,"evidence_text":"c.7400+1G>A","llm_judgment":"PRESENT","evidence":"c.7400+1G>A","abstract_start":957,"abstract_end":968},{"Name":"NM_001384732.1(CPLANE1):c.4804C>T (p.Arg1602Ter)","Chromosome":"5","Start":"37183377","Stop":"37183377","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40179,"rule_based_match":true,"evidence_text":"c.4804C>T (p.Arg1602*)","llm_judgment":"PRESENT","evidence":"p.Arg1602*","abstract_start":1150,"abstract_end":1160}]}
{"pmid":"26752331","title":"De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum.","abstract":"De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy. Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion [c.2364del, p.(Asn788Lysfs*10)], predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product [p.(Leu808Argfs*6)]. By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations.","variants":[{"Name":"NM_006306.4(SMC1A):c.2364del (p.Asn788fs)","Chromosome":"X","Start":"53403622","Stop":"53403622","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":855091,"rule_based_match":true,"evidence_text":"c.2364del, p.(Asn788Lysfs*10)","llm_judgment":"PRESENT","evidence":"c.2364del, p.(Asn788Lysfs*10)","abstract_start":684,"abstract_end":713}]}
{"pmid":"34897289","title":"Natural history of NF1 c.2970_2972del p.(Met992del): confirmation of a low risk of complications in a longitudinal study.","abstract":"Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by café-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associated complications. Examining large cohorts of patients over time with this specific genotype is important to confirm the presentation and associated risks of this variant across the lifespan. Forty-one individuals with the in-frame NF1 deletion p.Met992del were identified from 31 families. Clinicians completed a standardised clinical questionnaire for each patient and the resulting data were collated and compared to published cohorts. Thirteen patients have been previously reported, and updated clinical information has been obtained for these individuals. Both CALs and intertriginous freckling were present in the majority of individuals (26/41, 63%) and the only confirmed features in 11 (27%). 34/41 (83%) of the cohort met NIH diagnostic criteria. There was a notable absence of all NF1-associated tumour types (neurofibroma and glioma). Neurofibroma were observed in only one individual-a subcutaneous lesion (confirmed histologically). Nineteen individuals were described as having a learning disability (46%). This study confirms that individuals with p.Met992del display a mild tumoural phenotype compared to those with 'classical', clinically diagnosed NF1, and this appears to be the case longitudinally through time as well as at presentation. Learning difficulties, however, appear to affect a significant proportion of NF1 subjects with this phenotype. Knowledge of this genotype-phenotype association is fundamental to accurate prognostication for families and caregivers.","variants":[{"Name":"NM_001042492.3(NF1):c.2970_2972del (p.Met992del)","Chromosome":"17","Start":"31229954","Stop":"31229956","ReferenceAlleleVCF":"CAAT","AlternateAlleleVCF":"C","allel_id":15402,"rule_based_match":true,"evidence_text":"NM_000267.3(NF1):c.2970_2972del p.(Met992del)","llm_judgment":"PRESENT","evidence":"NM_000267.3(NF1):c.2970_2972del p.(Met992del)","abstract_start":46,"abstract_end":91}]}
{"pmid":"23947675","title":"Keratinocyte cell lines derived from severe generalized recessive epidermolysis bullosa patients carrying a highly recurrent COL7A1 homozygous mutation: models to assess cell and gene therapies in vitro and in vivo.","abstract":"Recessive dystrophic epidermolysis bullosa (RDEB) is caused by deficiency of type VII collagen due to COL7A1 mutations such as c.6527insC, recurrently found in the Spanish RDEB population. Assessment of clonal correction-based therapeutic approaches for RDEB requires large expansions of cells, exceeding the replication capacity of human primary keratinocytes. Thus, immortalized RDEB cells with enhanced proliferative abilities would be valuable. Using either the SV40 large T antigen or papillomavirus HPV16-derived E6-E7 proteins, we immortalized and cloned RDEB keratinocytes carrying the c.6527insC mutation. Clones exhibited high proliferative and colony-forming features. Cytogenetic analysis revealed important differences between T antigen-driven and E6-E7-driven immortalization. Immortalized cells responded to differentiation stimuli and were competent for epidermal regeneration and recapitulation of the blistering RDEB phenotype in vivo. These features make these cell lines useful to test novel therapeutic approaches including those aimed at editing mutant COL7A1.","variants":[{"Name":"NM_000094.4(COL7A1):c.6527dup (p.Gly2177fs)","Chromosome":"3","Start":"48573864","Stop":"48573865","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":359567,"rule_based_match":false,"evidence_text":"c.6527insC","llm_judgment":"PRESENT","evidence":"c.6527insC","abstract_start":127,"abstract_end":137}]}
{"pmid":"22818990","title":"Alexander disease with mild dorsal brainstem atrophy and infantile spasms.","abstract":"We present the case of a Japanese male infant with Alexander disease who developed infantile spasms at 8 months of age. The patient had a cluster of partial seizures at 4 months of age. He presented with mild general hypotonia and developmental delay. Macrocephaly was not observed. Brain magnetic resonance imaging (MRI) findings fulfilled all MRI-based criteria for the diagnosis of Alexander disease and revealed mild atrophy of the dorsal pons and medulla oblongata with abnormal intensities. DNA analysis disclosed a novel heterozygous missense mutation (c.1154 C>T, p.S385F) in the glial fibrillary acidic protein gene. At 8 months of age, tonic spasms occurred, and electroencephalography (EEG) revealed hypsarrhythmia. Lamotrigine effectively controlled the infantile spasms and improved the abnormal EEG findings. Although most patients with infantile Alexander disease have epilepsy, infantile spasms are rare. This comorbid condition may be associated with the distribution of the brain lesions and the age at onset of Alexander disease.","variants":[{"Name":"NM_002055.5(GFAP):c.1154C>T (p.Ser385Phe)","Chromosome":"17","Start":"44910632","Stop":"44910632","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188163,"rule_based_match":true,"evidence_text":"c.1154 C>T, p.S385F","llm_judgment":"PRESENT","evidence":"c.1154 C>T, p.S385F","abstract_start":560,"abstract_end":579}]}
{"pmid":"19657838","title":"Alpha-thalassemia mutations in Gilan Province, North Iran.","abstract":"One hundred and three patients from Gilan Province, Iran, presenting with hypochromic and microcytic anemia parameters without iron deficiency were included in this study. Using gap-polymerase chain reaction (gap-PCR), reverse hybridization StripAssay and DNA sequencing, we detected a total of 113 alpha-globin mutations in 94 (91.3%) of these patients. Most prevalent of the 16 different alpha-thalassemia (alpha-thal) alleles was -alpha(3.7) (42.5%), followed by the polyadenylation signal (poly A2) (AATAAA>AATGAA) (12.4%), Hb Constant Spring [Hb CS, alpha142, Term-->Gln (TAA>CAA in alpha2] (10.6%), --(MED) (8.8%), IVS-I donor site [GAG GTG AGG>GAG G-----, alpha(-5 nt) (-TGAGG)] (7.1%), -alpha(4.2) (4.4%) and poly A1 (AATAAA>AATAAG) (3.5%). An additional nine mutations were observed at frequencies below 2%. We also found two novel alpha1 gene mutations: alpha(-9) (HBA1: c.-9 G>C) and alpha(IVS-I-4) (HBA1: c.95+4 A>G). Our new findings will be valuable for improving targeted thalassemia screening and prevention strategies in this area.","variants":[{"Name":"NM_000558.5(HBA1):c.-9G>C","Chromosome":"16","Start":"176708","Stop":"176708","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3731098,"rule_based_match":true,"evidence_text":"alpha(-9) (HBA1: c.-9 G>C)","llm_judgment":"PRESENT","evidence":"alpha(-9) (HBA1: c.-9 G>C)","abstract_start":864,"abstract_end":890}]}
{"pmid":"30239254","title":"A novel p.Gly187Arg TP53 variant appears to result in Li-Fraumeni syndrome.","abstract":"Li-Fraumeni syndrome is an autosomal dominant cancer syndrome characterized by pathogenic variants in the TP53 gene on chromosome 17. The most common cancers in Li-Fraumeni kindreds include sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma. We report a 9-month-old male who was diagnosed with an adrenocortical tumor and later found to harbor a novel TP53 c.559 G > C germline variant, resulting in p.Gly187Arg. Family history included early-onset breast cancer in his paternal grandmother and paternal great-grandfather, as well as colon cancer at age 31 in a paternal cousin. The same TP53 variant was later confirmed in his paternal grandmother. Based on this information, his father (age 28, obligate carrier for the variant) was referred for colonoscopic screening and found to have multiple adenomatous polyps. This previously undescribed variant lies at an exon/intron boundary and is predicted to decrease splice site efficiency with resulting altered splicing or exon skipping. Our patient's family history provides limited evidence that this variant is a cause of Li-Fraumeni syndrome.","variants":[{"Name":"NM_000546.6(TP53):c.559G>C (p.Gly187Arg)","Chromosome":"17","Start":"7675053","Stop":"7675053","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":623216,"rule_based_match":true,"evidence_text":"TP53 c.559 G > C germline variant, resulting in p.Gly187Arg","llm_judgment":"PRESENT","evidence":"TP53 c.559 G > C germline variant, resulting in p.Gly187Arg","abstract_start":369,"abstract_end":428}]}
{"pmid":"23249834","title":"Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens.","abstract":"Brooke-Spiegler syndrome (BSS) is a rare, inherited, autosomal dominant disorder characterized by development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. The syndrome of multiple familial trichoepitheliomas (MFT) is considered a phenotypic variant of BSS in which patients present with trichoepitheliomas only. We studied germline and somatic mutations of the CYLD gene by direct sequencing in patients with BSS (n = 49) and MFT (n = 18) using peripheral blood and 90 samples of frozen or formalin-fixed paraffin-embedded tumor tissue selected from 379 available histology specimens. Germline CYLD mutations were found in 51 patients (76%) from 36 families (75%). Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%). Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS, whereas 1 frameshift, 5 nonsense, and 2 splice site mutations were identified in the MFT cohort. Five novel mutations were identified including 4 frameshift mutations (c.1027dupA/p.T343NfsX7, c.2155dupA/p.M719NfsX5, c.2288_2289delTT/p.F763X, and c.2641delG/p.D881TfsX32) and 1 nonsense mutation (c.2713C>T/p. Q905X). Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types. Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity. In the remaining 9 cases (12%), the somatic changes remained unknown. A germline CYLD mutation was not detected in 14 tumor samples from 8 patients. In these 14 tumors, somatic mutations were identified in 6 samples (43%), all consisting of sequence alterations (1 sample showed 2 different sequence alterations). In the remaining 8 samples (53%), neither germline nor somatic mutations were found in the lesional tissue. Our study increases the catalog of known CYLD mutations in patients with BSS/MFT to 86 and documents the variability of somatic mutations that may occur in them. We confirm the absence of firm genotype-phenotype correlations and the existence of a subset of patients with BSS/MFT who lack a demonstrable germline CYLD mutation. Further studies are needed to explain the reasons for this phenomenon.","variants":[{"Name":"NM_001378743.1(CYLD):c.2288_2289del (p.Asp762_Phe763insTer)","Chromosome":"16","Start":"50792642","Stop":"50792643","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":3860293,"rule_based_match":true,"evidence_text":"c.2288_2289delTT/p.F763X","llm_judgment":"PRESENT","evidence":"c.2288_2289delTT/p.F763X","abstract_start":1177,"abstract_end":1201},{"Name":"NM_001378743.1(CYLD):c.2713C>T (p.Gln905Ter)","Chromosome":"16","Start":"50796350","Stop":"50796350","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3860294,"rule_based_match":true,"evidence_text":"c.2713C>T/p. Q905X","llm_judgment":"PRESENT","evidence":"c.2713C>T/p. Q905X","abstract_start":1257,"abstract_end":1275}]}
{"pmid":"27650967","title":"Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy.","abstract":"It has been well documented that variants in genes encoding centrosomal proteins cause primary autosomal recessive microcephaly, although the association between centrosomal defects and the etiology of microcephaly syndromes is not fully understood. Polo-like kinase 4 (PLK4) is one of the centrosomal proteins required for centriole duplication. We here describe a patient with microcephaly and chorioretinopathy that harbors compound heterozygous missense variants, c.[442A>G]; [2336G>A], in the PLK4 gene. One of these variants, c.442A>G (p.(M148V)), resides in the kinase domain, and the other, c.2336G>A (p.(C779Y)), in the polo-box domain. Aberrant spindle formation was observed in a LCL derived from this patient. Overexpression experiments of the variant PLK4 proteins demonstrated that the p.(C779Y) but not the p.(M148V) had lost centriole overduplication ability. The altered mobility pattern of both variant proteins on a western blot further suggested alterations in post-translation modification. Our data lend support to the hypothesis that impaired centriole duplication caused by PLK4 variants may be involved in the etiology of microcephaly disorder.","variants":[{"Name":"NM_014264.5(PLK4):c.442A>G (p.Met148Val)","Chromosome":"4","Start":"127885812","Stop":"127885812","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1411607,"rule_based_match":true,"evidence_text":"c.442A>G (p.(M148V))","llm_judgment":"PRESENT","evidence":"c.442A>G (p.(M148V))","abstract_start":532,"abstract_end":552}]}
{"pmid":"21967858","title":"Tay-Sachs disease in an Arab family due to c.78G>A HEXA nonsense mutation encoding a p.W26X early truncation enzyme peptide.","abstract":"Tay-Sachs disease (TSD), a pan-ethnic, autosomal recessive, neurodegenerative, lysosomal disease, results from deficient β-hexosaminidase A activity due to β-hexosaminidase α-subunit (HEXA) mutations. Prenatal/premarital carrier screening programs in the Ashkenazi Jewish community have markedly reduced disease occurrence. We report the first Jordanian Arab TSD patient diagnosed by deficient β-hexosaminidase A activity. HEXA mutation analysis revealed homozygosity for a nonsense mutation, c.78G>A (p.W26X). Previously reported in Arab patients, this mutation is a candidate for TSD screening in Arab populations.","variants":[{"Name":"NM_000520.6(HEXA):c.78G>A (p.Trp26Ter)","Chromosome":"15","Start":"72375895","Stop":"72375895","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18950,"rule_based_match":true,"evidence_text":"c.78G>A (p.W26X)","llm_judgment":"PRESENT","evidence":"c.78G>A (p.W26X)","abstract_start":493,"abstract_end":509}]}
{"pmid":"36397839","title":"Developmental regression and movement disorder as a phenotypic variant of POLR3A Mutation-Case report.","abstract":"POLR3A is a main subunit encoding RNA polymerase III, which is involved in transcription of many RNA structures. Here, we report a new presentation of c.1771-6C > G intronic variant presenting as developmental regression, seizure, and dystonia in a 6-year-old boy associated with striatum involvement in the brain MRI.","variants":[{"Name":"NM_007055.4(POLR3A):c.1771-6C>G","Chromosome":"10","Start":"78009681","Stop":"78009681","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":964843,"rule_based_match":true,"evidence_text":"c.1771-6C > G","llm_judgment":"PRESENT","evidence":"c.1771-6C > G","abstract_start":151,"abstract_end":164}]}
{"pmid":"26358359","title":"CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.","abstract":"BACKGROUND: Rare highly penetrant gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) can lead to psoriasis, a chronic inflammatory disease of the skin and other organs.\nOBJECTIVES: To investigate the contribution of rare CARD14 variants to psoriasis in the Tunisian population and to expand knowledge of CARD14 variants in the European population.\nMETHODS: CARD14 coding exons were resequenced in patients with psoriasis and controls from Tunisia and Europe, including 16 European cases with generalized pustular psoriasis (GPP). Novel variants were evaluated for their effect on nuclear factor (NF)-κB signalling.\nRESULTS: Rare variants in CARD14 were significantly enriched in Tunisian cases compared with controls. Three were collectively found in 5% of Tunisian cases, and all affected the N-terminal region of the protein harbouring its caspase recruitment domain or coiled-coil domain. These variants were c.349G>A (p.Gly117Ser), c.205C>T (p.Arg69Trp) and c.589G>A (p.Glu197Lys). c.589G>A (p.Glu197Lys) led to upregulation of NF-κB activity in a similar manner to that of previously described psoriasis-associated mutations. p.Arg69Trp led to sevenfold downregulation of NF-κB activity. One Tunisian case harboured a c.1356+5G>A splice alteration that is predicted to lead to loss of exon 9, which encodes part of the coiled-coil domain. No cases of GPP harboured an interleukin-36RN mutation, but one of 16 cases of GPP with a family history of psoriasis vulgaris harboured a c.1805C>T (p.Ser602Leu) mutation in CARD14.\nCONCLUSIONS: These observations provide further insights into the genetic basis of psoriasis in the Tunisian population and provide functional information on novel CARD14 variants seen in cases from Tunisia and other populations.","variants":[{"Name":"NM_001366385.1(CARD14):c.1356+5G>A","Chromosome":"17","Start":"80192624","Stop":"80192624","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":852802,"rule_based_match":true,"evidence_text":"c.1356+5G>A","llm_judgment":"PRESENT","evidence":"c.1356+5G>A","abstract_start":1256,"abstract_end":1267},{"Name":"NM_001366385.1(CARD14):c.1805C>T (p.Ser602Leu)","Chromosome":"17","Start":"80198545","Stop":"80198545","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":532003,"rule_based_match":true,"evidence_text":"c.1805C>T (p.Ser602Leu)","llm_judgment":"PRESENT","evidence":"c.1805C>T (p.Ser602Leu)","abstract_start":1516,"abstract_end":1539},{"Name":"NM_001366385.1(CARD14):c.205C>T (p.Arg69Trp)","Chromosome":"17","Start":"80181643","Stop":"80181643","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":646918,"rule_based_match":true,"evidence_text":"c.205C>T (p.Arg69Trp)","llm_judgment":"PRESENT","evidence":"c.205C>T (p.Arg69Trp)","abstract_start":969,"abstract_end":990}]}
{"pmid":"25449608","title":"A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations.","abstract":"Arctic populations live in an environment characterized by extreme cold and the absence of plant foods for much of the year and are likely to have undergone genetic adaptations to these environmental conditions in the time they have been living there. Genome-wide selection scans based on genotype data from native Siberians have previously highlighted a 3 Mb chromosome 11 region containing 79 protein-coding genes as the strongest candidates for positive selection in Northeast Siberians. However, it was not possible to determine which of the genes might be driving the selection signal. Here, using whole-genome high-coverage sequence data, we identified the most likely causative variant as a nonsynonymous G>A transition (rs80356779; c.1436C>T [p.Pro479Leu] on the reverse strand) in CPT1A, a key regulator of mitochondrial long-chain fatty-acid oxidation. Remarkably, the derived allele is associated with hypoketotic hypoglycemia and high infant mortality yet occurs at high frequency in Canadian and Greenland Inuits and was also found at 68% frequency in our Northeast Siberian sample. We provide evidence of one of the strongest selective sweeps reported in humans; this sweep has driven this variant to high frequency in circum-Arctic populations within the last 6-23 ka despite associated deleterious consequences, possibly as a result of the selective advantage it originally provided to either a high-fat diet or a cold environment.","variants":[{"Name":"NM_001876.4(CPT1A):c.1436C>T (p.Pro479Leu)","Chromosome":"11","Start":"68780662","Stop":"68780662","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76552,"rule_based_match":true,"evidence_text":"c.1436C>T (p.Pro479Leu)","llm_judgment":"PRESENT","evidence":"p.Pro479Leu","abstract_start":751,"abstract_end":762}]}
{"pmid":"27143075","title":"Molecular diagnosis of two Chinese cystic fibrosis children and literature review","abstract":"OBJECTIVE: To investigate the clinical manifestations and molecular features of cystic fibrosis in Chinese children.\nMETHOD: A retrospective analysis of two pediatric cystic fibrosis cases diagnosed by gene test in Beijing Children's Hospital, Capital Medical University from 2010 to 2015, and Chinese cystic fibrosis reported patients searched of\"cystic fibrosis, Chinese\"on Chinese databases (CNKI, Wanfang Data) and PubMed from 1975 to 2015.The clinical manifestations and molecular features were analyzed.\nRESULT: One of the two newly diagnosed cystic fibrosis cases was a 10-year old girl who suffered from reccurent cough with expectoration and associated with cirrhosis.Sweat tests showed increased chloride twice with the lower level of 306.82 mmol/L.The other was an 8-month old boy with reccurent pneumonia from neonate, failure to thrive and fatty diarrhea.Two children had various degrees of bronchiectasis and massive sticky secretion on the bronchoscopy.They had no family history and their parents had no consanguineous marriage.CFTR mutations of c. 595C>T and c. 2290C>T were found in gene tests.On the database, twenty-one reports involving thirty-six Chinese patients (16 males and 20 females) were retrieved.Together with this group of 2 cases, a total of 38 cases were involved.The age at diagnosis was 4 months to 28 years with a median age of 10 years.All patients had reccurent respiratory infections, twenty-seven cases (71%) had malnutrition, fifteen (39%)had chronic diarrhea, and 16 cases (42%) had other digestive manifestations, including jaundice (4 cases), hepatomegaly (11 cases), ascites (2 cases) and pancreatic atrophy (3 cases). Five cases had a positive family history and six cases had a suspicious family history.Consanguineous marriage was found in three families.Sweat test revealed elevated chloride (52-327 mmol/L) in 28 cases.Eight of the 16 patients who performed pancreatic exocrine function examination showed pancreatic insufficiency.Eighteen of the 20 patients described the image manifestation of bronchiectasis.The age at death of 13 patients(34%) was 4 months to 25 years with a median of 11 years.Twenty-nine rare CFTR mutations were found in 25 tested patients, and c. 1766+ 5G>T(5 cases), c.2083dupG and c. 2684G>A (3 cases) held the top three mutation patterns.\nCONCLUSION: Respiratory symptoms and bronchiectasis are the main manifestations of Chinese cystic fibrosis patients, although some of them may be associated with malnutrition, digestive symptoms and pancreatic insufficiency. CFTR mutations are various and rare in Caucasians.","variants":[{"Name":"NM_000492.4(CFTR):c.595C>T (p.His199Tyr)","Chromosome":"7","Start":"117535263","Stop":"117535263","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":68685,"rule_based_match":true,"evidence_text":"c. 595C>T","llm_judgment":"PRESENT","evidence":"c. 595C>T","abstract_start":1062,"abstract_end":1071}]}
{"pmid":"24662630","title":"Focal sclerosis of semicircular canals with severe DFNA9 hearing impairment caused by a P51S COCH-mutation: is there a link?","abstract":"HYPOTHESIS: Focal sclerosis of one or more semicircular canals on computed tomographic (CT) scans and a corresponding signal loss on magnetic resonance (MR) imaging are radiologic lesions that are linked to patients who are suffering from advanced otovestibular impairment caused by hereditary DFNA9 hearing loss.\nBACKGROUND: DFNA9 is a hereditary hearing loss that is characterized by late-onset progressive imbalance and hearing deterioration, caused by mutations in the COCH gene. To date, no radiologic lesions have been associated with this condition.\nSTUDY DESIGN: A retrospective chart review\nSETTING: Tertiary referral center\nSUBJECTS: The radiologic data of 9 patients who presented between 2007 and 2012 with otovestibular deterioration caused by a mutation in the COCH gene were reviewed.\nRESULTS: All 9 subjects were carriers of the same c.151C > T, p.Pro51Ser (P51S) - missense mutation in the COCH gene. In 8 of them similar sclerotic lesions and/or narrowing were demonstrated in one or more semicircular canals on computed tomography CT scan, with a signal loss at corresponding areas on T2-weighted magnetic resonance (MR) images. In 1 patient, the posterior part of the vestibule was also affected. The posterior canals were affected in most cases (58%), compared with the superior (21%) and lateral canals (16%) or the vestibule (5%). Only 68.4% of the lesions on MR images were also visible on CT scans, suggesting a fibrotic process without calcification. Ears presenting radiologic lesions showed significantly more severe hearing loss (median PTA 104 dB HL) compared with unaffected ears (58 dB HL).\nCONCLUSION: Eight of 9 subjects with the same P51S mutation in the COCH gene showed similar radiologic lesions, affecting the PSCC in the majority of the cases. These radiologic abnormalities occurred in more advanced stages of the otovestibular deterioration, supporting the hypothesis that these lesions might represent the end phase of a low-grade chronic inflammation or protein deposition. A new phenotypic and characteristic radiologic feature of DFNA9 has been discovered.","variants":[{"Name":"NM_004086.3(COCH):c.151C>T (p.Pro51Ser)","Chromosome":"14","Start":"30877640","Stop":"30877640","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21650,"rule_based_match":true,"evidence_text":"c.151C > T, p.Pro51Ser (P51S)","llm_judgment":"PRESENT","evidence":"c.151C > T, p.Pro51Ser (P51S)","abstract_start":850,"abstract_end":879}]}
{"pmid":"29034877","title":"Generation of an induced pluripotent stem cell (iPSC) line from a patient with autosomal dominant retinitis pigmentosa due to a mutation in the NR2E3 gene.","abstract":"A human iPSC line was generated from fibroblasts of a patient affected with autosomal dominant Retinitis Pigmentosa (RP) carrying the mutation p.Gly56Arg in the NR2E3 gene. The transgene-free iPSCs were generated with the human OSKM transcription factors using the Sendai-virus reprogramming system. iPSCs contained the expected c.166G>A substitution in exon 2 of NR2E3, expressed the expected pluripotency markers, displayed in vivo differentiation potential to the three germ layers and had normal karyotype. This cellular model will provide a powerful tool to study the pathogenesis of NR2E3-associated RP. Resource table.","variants":[{"Name":"NM_014249.4(NR2E3):c.166G>A (p.Gly56Arg)","Chromosome":"15","Start":"71811530","Stop":"71811530","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20572,"rule_based_match":true,"evidence_text":"c.166G>A","llm_judgment":"PRESENT","evidence":"c.166G>A","abstract_start":329,"abstract_end":337}]}
{"pmid":"24599433","title":"At high altitude in the Netherlands: secondary erythrocytosis due to HB-Malmö.","abstract":"We describe two patients, a father and a son, presenting with erythrocytosis. Evaluation showed no pulmonal or cardial disorders. Owing to an elevated erythropoietin level after phlebotomy, a physiological secondary polycythaemia was suspected. A haemoglobin electrophoresis showed that our patients have a haemoglobinopathy with high affinity for oxygen, called Hb-Malmö (exon 3: c.294 C>G p.His98Gln). Hb-Malmö is a congenital disorder located on a gene at chromosome 11, in the B-chain on codon 97, decoding the α-subunit and β-subunit of the haemoglobin. Through a mutation (CAC→CAG), histidine is replaced by glutamine. The mutation causes a disorder in the connection between the α1-subunit and β2-subunit of the haemoglobin structure. These connections are important sites for binding oxygen. Mutated haemoglobin has a preference for an oxygenated status, which implicates that there is an increased binding and decreased release of oxygen. To compensate, there will be an erythrocytosis to transport sufficient oxygen to the peripheral tissues.","variants":[{"Name":"NM_000518.5(HBB):c.294C>G (p.His98Gln)","Chromosome":"11","Start":"5226598","Stop":"5226598","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":789498,"rule_based_match":true,"evidence_text":"c.294 C>G p.His98Gln","llm_judgment":"PRESENT","evidence":"c.294 C>G p.His98Gln","abstract_start":381,"abstract_end":401}]}
{"pmid":"22453305","title":"Hereditary thrombocythemia caused by a thrombopoietin (THPO) gain-of-function mutation associated with multiple myeloma and congenital limb defects.","abstract":"Hereditary thrombocythemia (HT) has been described as a rare benign disorder caused by mutations in the thrombopoietin (THPO) or the c-Mpl receptor genes. Here we report two families with HT resulting from a THPO c.13+1 G>C mutation in the splice donor of intron 3. In one family there were coexisting distal limb defects, whereas in the other one member developed early-onset multiple myeloma. These observations, together with previously reported patients, suggest that THPO gain of function may dysregulate the hemangioblast and disturb vasculogenesis and hematopoietic development. Overstimulation of the THPO pathway might therefore predispose to clonal hematopoietic disease and to congenital abnormalities.","variants":[{"Name":"NM_000460.4(THPO):c.13+1G>C","Chromosome":"3","Start":"184376246","Stop":"184376246","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":24547,"rule_based_match":true,"evidence_text":"c.13+1 G>C","llm_judgment":"PRESENT","evidence":"c.13+1 G>C","abstract_start":213,"abstract_end":223}]}
{"pmid":"21839475","title":"Novel THAP1 gene mutations in patients with primary dystonia from southwest China.","abstract":"BACKGROUND: Clinical presentation and DYT6/THAP1 mutations among Chinese patients with primary dystonia have not been well studied.\nMETHODS: Patients with primary pure dystonia from Southwest China who did not have a mutation in DYT1 exon 5 were included in the present study. Mutations of the THAP1 gene were screened by direct sequencing.\nRESULTS: A total of 231 patients were examined. Cervical dystonia (58.47%) was found to be the most frequent form of focal dystonia. Novel heterozygous missense mutation [c.521A>G (p.E174G)] was found in exon 3 of the THAP1 gene in one patient and one insertion mutation [c.214_215InsA (p.L72fsX86)] in exon 2 in another. Initial symptoms of patients with these mutations were early-onset cervical dystonia. Both patients had no dysarthria. A silent change [c.489C>G (p.L63L)] in exon 3 was identified in three patients with Meige syndrome.\nCONCLUSION: The mutation frequency of the THAP1 gene was 0.87% in Chinese patients with primary pure dystonia, similar to the mutation frequency found in other ethnic groups. Patients presenting with early-onset cervical dystonia should be screened for THAP1 gene mutations to fully assess all the possible etiologies of dystonia. Further studies are needed for p.L63L in THAP1 in Meige syndrome.","variants":[{"Name":"NM_018105.3(THAP1):c.489C>G (p.Leu163=)","Chromosome":"8","Start":"42838115","Stop":"42838115","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":305393,"rule_based_match":true,"evidence_text":"c.489C>G (p.L63L)","llm_judgment":"PRESENT","evidence":"c.489C>G (p.L63L)","abstract_start":799,"abstract_end":816}]}
{"pmid":"9792857","title":"Phenotype-genotype relationships in complementation group 3 of the peroxisome-biogenesis disorders.","abstract":"The peroxisome-biogenesis disorders (PBDs) are a set of often lethal genetic diseases characterized by mental retardation and defective peroxisomal matrix protein import. Mutations in PEX12 are known to underlie the disease in two patients from complementation group 3 of the PBDs. Here we show that all patients from this group carry mutations on both alleles of PEX12. A comparison between PEX12 genotypes and the clinical and cellular phenotypes of the corresponding PBD patients suggests a relatively straightforward relationship between genotype and phenotype in this group of the PBDs, such that the loss of PEX12 function leads to more-severe cellular and clinical phenotypes. However, one patient who presented relatively mild clinical and cellular phenotypes was a compound heterozygote for two seemingly severe mutations on each PEX12 allele. PEX12 mRNA present in the patient's cells was derived from only one allele, the one that carried a 2-bp deletion early in the PEX12 coding region, c.26,27Delta. The deduced protein product of this mRNA would contain only the first eight amino acids of the protein, and yet this mutant PEX12 cDNA displayed significant PEX12 activity in a functional complementation assay. Surprisingly, the PEX12/c.26, 27Delta cDNA directed the synthesis of a 29-kD PEX12 protein in vitro, a result that is consistent with translation initiation at a downstream AUG codon. Transfection studies confirmed the expression of similarly sized PEX12 proteins from the PEX12/c.26,27Delta allele. Thus, it appears that translation initiation at internal AUG codons may modulate disease phenotypes and should be considered whenever unexpectedly mild phenotypes result from severe mutations early in the coding region.","variants":[{"Name":"NM_000286.3(PEX12):c.26_27del (p.Thr9fs)","Chromosome":"17","Start":"35577995","Stop":"35577996","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":22815,"rule_based_match":false,"evidence_text":"c.26,27Delta","llm_judgment":"PRESENT","evidence":"c.26,27Delta","abstract_start":1000,"abstract_end":1012}]}
{"pmid":"26899772","title":"New-onset diabetes after renal transplantation in a patient with a novel HNF1B mutation.","abstract":"CAKUT are the most frequent causes of ESRD in children. Mutations in the gene encoding HNF1B, a transcription factor involved in organ development and maintenance, cause a multisystem disorder that includes CAKUT, diabetes, and liver dysfunction. Here, we describe the case of a patient with renal hypodysplasia who developed NODAT presenting with liver dysfunction. The NODAT was initially thought to be steroid and FK related. However, based on the patient's clinical features, including renal hypodysplasia and recurrent elevations of transaminase, screening for an HNF1B mutation was performed. Direct sequencing identified a novel splicing mutation of HNF1B, designated c.344 + 2T>C. Because CAKUT is the leading cause of ESRD in children and HNF1B mutations can cause both renal hypodysplasia and diabetes, HNF1B mutations may account for a portion of the cases of NODAT in pediatric patients who have undergone kidney transplantation. NODAT is a serious and major complication of solid organ transplantation and is associated with reduced graft survival. Therefore, for the appropriate management of kidney transplantation, screening for HNF1B mutations should be considered in pediatric patients with transplants caused by CAKUT who develop NODAT and show extra-renal symptoms.","variants":[{"Name":"NM_000458.4(HNF1B):c.344+2T>C","Chromosome":"17","Start":"37744539","Stop":"37744539","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":623568,"rule_based_match":true,"evidence_text":"c.344 + 2T>C","llm_judgment":"PRESENT","evidence":"c.344 + 2T>C","abstract_start":675,"abstract_end":687}]}
{"pmid":"31902742","title":"A novel heterozygous STAT5B variant in a patient with short stature and partial growth hormone insensitivity (GHI).","abstract":"BACKGROUND: The most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure.\nOBJECTIVE: To characterize the molecular defect in a patient with short stature and partial GHI.\nPATIENT AND METHODS: The boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2 years, he presented proportionate short stature (height -2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed.\nRESULTS: Biochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8 ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency.\nCONCLUSIONS: We reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.","variants":[{"Name":"NM_012448.4(STAT5B):c.1896G>T (p.Lys632Asn)","Chromosome":"17","Start":"42210181","Stop":"42210181","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2419805,"rule_based_match":true,"evidence_text":"c.1896G>T, p.K632N","llm_judgment":"PRESENT","evidence":"c.1896G>T, p.K632N","abstract_start":1163,"abstract_end":1181}]}
{"pmid":"24939587","title":"Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP)--pure coincidence?","abstract":"Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly--thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 × coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 × coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.","variants":[{"Name":"NM_002834.5(PTPN11):c.1529A>G (p.Gln510Arg)","Chromosome":"12","Start":"112489105","Stop":"112489105","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28384,"rule_based_match":true,"evidence_text":"c.1529A>G; p.(Gln510Arg)","llm_judgment":"PRESENT","evidence":"c.1529A>G; p.(Gln510Arg)","abstract_start":719,"abstract_end":743}]}
{"pmid":"29566461","title":"Surfactant deficiency syndrome in an infant with a C-terminal frame shift in ABCA3: A case report.","abstract":"Deficiency in ATP binding cassette A3 (ABCA3) causes neonatal respiratory distress, hypoxemic respiratory failure, and interstitial lung disease. ABCA3 transports phospholipids into the lamellar bodies of type II alveolar cells, a critical step in alveolar surfactant production. We report a term infant with ABCA3 surfactant deficiency syndrome with the E292V (c.875A>T; p.Glu292Val) mutation in trans with a novel C-terminal frame shift mutation (c.4938delC; p.Met1647fs). This mutation removes the final 58 amino acids and substitutes 33 incorrect amino acids. The frame shift spares membrane spanning and nucleotide binding domains, but disrupts a highly conserved C-terminal domain, which includes sequence motifs necessary for the function of human paralogs ABCA1, ABCA4, and the bacterial homolog DrrA. This observation suggests the C-terminal domain is also required for normal function of ABCA3.","variants":[{"Name":"NM_001089.3(ABCA3):c.875A>T (p.Glu292Val)","Chromosome":"16","Start":"2317763","Stop":"2317763","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":199803,"rule_based_match":true,"evidence_text":"c.875A>T (p.Glu292Val)","llm_judgment":"PRESENT","evidence":"p.Glu292Val","abstract_start":372,"abstract_end":383}]}
{"pmid":"18054510","title":"Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin.","abstract":"We report 10 children (7 male, 3 female), 3 homozygous for c.319C>T mutation and 7 heterozygous for c.319C>T on one allele and c.625G>A variant on the other in the short-chain acyl-CoA dehydrogenase (SCAD) gene (ACADS). All were of Ashkenazi Jewish origin in which group we found a c.319C>T heterozygote frequency of 1:15 suggesting the presence of a founder mutation or selective advantage. Phenotype was variable with onset from birth to early childhood. Features included hypotonia (8/10), developmental delay (8/10), myopathy (4/10) with multicore changes in two and lipid storage in one, facial weakness (3/10), lethargy (5/10), feeding difficulties (4/10) and congenital abnormalities (3/7). One female with multiminicore myopathy had progressive external ophthalmoplegia, ptosis and cardiomyopathy with pneumonia and respiratory failure. Two brothers presented with psychosis, pyramidal signs, and multifocal white matter abnormalities on MRI brain suggesting additional genetic factors. Two other infants also had white matter changes. Elevated butyrylcarnitine (4/8), ethylmalonic aciduria (9/9), methylsuccinic aciduria (6/7), decreased butyrate oxidation in lymphoblasts (2/4) and decreased SCAD activity in fibroblasts or muscle (3/3) were shown. Expression studies of c.319C>T in mouse liver mitochondria showed it to be inactivating. c.625G>A is a common variant in ACADS that may confer disease susceptibility. Five healthy parents were heterozygous for c.319C>T and c.625G>A, suggesting reduced penetrance or broad clinical spectrum. We conclude that the c.319C>T mutation can lead to wide clinical and biochemical phenotypic variability, suggesting a complex multifactorial/polygenic condition. This should be screened for in individuals with multicore myopathy, particularly among the Ashkenazim.","variants":[{"Name":"NM_000017.4(ACADS):c.319C>T (p.Arg107Cys)","Chromosome":"12","Start":"120737094","Stop":"120737094","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18865,"rule_based_match":true,"evidence_text":"c.319C>T","llm_judgment":"PRESENT","evidence":"c.319C>T","abstract_start":59,"abstract_end":67}]}
{"pmid":"30071891","title":"Many pitfalls in diagnosis of acute intermittent porphyria: a case report.","abstract":"BACKGROUND: Acute intermittent porphyria is a rare autosomal dominant disorder caused by a deficiency of the enzyme, hydroxymethylbilane synthase. Recognition of acute neurovisceral attacks can be difficult due to the nonspecific nature of symptoms.\nCASE PRESENTATION: We report a case of 33-year-old male patient who presented with recurrent episodes of severe abdominal pain, nausea, vomiting, constipation and numbness of bilateral lower limb extremities. These nonspecific neurovisceral attacks were subject to medical and surgical misdiagnoses of acute appendicitis, sinus tachycardia, renal calculi, drug-induced acute interstitial nephritis and two episodes of partial intestinal obstruction. The sixth acute attack raised the suspicion of an acute porphyria. Watson and Schwartz test was positive for porphobilinogen in urine. Mutation analysis by DNA sequencing of the extracted DNA of the proband revealed a previously reported missense mutation, c.517C>T encoding p.R173W in the HMBS gene, confirming the diagnosis of Acute Intermittent Porphyria. Four out of five family members who underwent targeted mutation analyses were mutation-positive.\nCONCLUSION: The most common clinical presentation of Acute Intermittent Porphyria is abdominal pain with neurovisceral manifestations which are common to several medical, psychiatric and surgical pathologies. This leads to underdiagnosis and misdiagnosis of this disorder, incorrect management, and severe complications. Therefore, a high index of suspicion and awareness of front line laboratory investigations are important for diagnosis. Definitive diagnosis enables implementation of strategies to prevent acute attacks, and also triggers genetic testing and genetic counseling of at-risk family members.","variants":[{"Name":"NM_000190.4(HMBS):c.517C>T (p.Arg173Trp)","Chromosome":"11","Start":"119091431","Stop":"119091431","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":639782,"rule_based_match":true,"evidence_text":"c.517C>T encoding p.R173W","llm_judgment":"PRESENT","evidence":"c.517C>T encoding p.R173W","abstract_start":957,"abstract_end":982}]}
{"pmid":"36332686","title":"Ceramide Analysis in Combination With Genetic Testing May Provide a Precise Diagnosis for Self-Healing Collodion Babies.","abstract":"Self-healing collodion baby (SHCB), also called \"self-improving collodion baby\", is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.","variants":[{"Name":"NM_173483.4(CYP4F22):c.1189C>T (p.Arg397Cys)","Chromosome":"19","Start":"15548160","Stop":"15548160","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3543900,"rule_based_match":true,"evidence_text":"c.1189C>T (p.(Arg397Cys))","llm_judgment":"PRESENT","evidence":"c.1189C>T (p.(Arg397Cys))","abstract_start":596,"abstract_end":621}]}
{"pmid":"19967541","title":"Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation.","abstract":"Mutations in the fused in sarcoma gene (FUS) were recently found in patients with familial amyotrophic lateral sclerosis (ALS). The present study aimed to clarify unique features of familial ALS caused by FUS mutation in the Japanese population. We carried out clinical, neuropathological, and genetic studies on a large Japanese pedigree with familial ALS. In six successive generations of this family, 16 individuals of both sexes were affected by progressive muscle atrophy and weakness, indicating an autosomal dominant trait. Neurological examination of six patients revealed an age at onset of 48.2+/-8.1 years in fourth generation patients, while it was 31 and 20 years in fifth and sixth generation patients, respectively. Motor paralysis progressed rapidly in these patients, culminating in respiratory failure within 1 year. The missense mutation c.1561 C>T (p.R521C) was found in exon 15 of FUS in the four patients examined. Neuropathological study of one autopsied case with the FUS mutation revealed multiple system degeneration in addition to upper and lower motor neuron involvement: the globus pallidus, thalamus, substantia nigra, cerebellum, inferior olivary nucleus, solitary nucleus, intermediolateral horn, Clarke's column, Onuf's nucleus, central tegmental tract, medial lemniscus, medial longitudinal fasciculus, superior cerebellar peduncle, posterior column, and spinocerebellar tract were all degenerated. Argyrophilic and basophilic neuronal or glial cytoplasmic inclusions immunoreactive for FUS, GRP78/BiP, p62, and ubiquitin were detected in affected lesions. The FUS R521C mutation in this Japanese family caused familial ALS with pathological features of multiple system degeneration and neuronal basophilic inclusions.","variants":[{"Name":"NM_004960.4(FUS):c.1561C>T (p.Arg521Cys)","Chromosome":"16","Start":"31191418","Stop":"31191418","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31263,"rule_based_match":true,"evidence_text":"c.1561 C>T (p.R521C)","llm_judgment":"PRESENT","evidence":"c.1561 C>T (p.R521C)","abstract_start":857,"abstract_end":877}]}
{"pmid":"23748066","title":"Identification of novel mutations in STAR gene in patients with lipoid congenital adrenal hyperplasia: a first report from India.","abstract":"Lipoid congenital adrenal hyperplasia (LCAH), a rare disorder of steroid biosynthesis, is the most severe form of CAH. We report novel molecular findings of three unrelated infants with LCAH diagnosed at our center. A known missense mutation c.653C>T (p.A218V) and two novel mutations [premature termination c.441G>A (or p.W147X) and frameshift deletion c.del815G (or p.R272PfsX35)] were identified after complete sequencing of the STAR gene. Prenatal diagnosis was carried out for the family with mutation c.815delG by molecular testing wherein the fetus was found to be homozygous for the mutation. This is the first report of molecular diagnosis and prenatal testing for LCAH from India.","variants":[{"Name":"NM_000349.3(STAR):c.653C>T (p.Ala218Val)","Chromosome":"8","Start":"38145313","Stop":"38145313","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24032,"rule_based_match":true,"evidence_text":"c.653C>T (p.A218V)","llm_judgment":"PRESENT","evidence":"c.653C>T (p.A218V)","abstract_start":242,"abstract_end":260},{"Name":"NM_000349.3(STAR):c.441G>A (p.Trp147Ter)","Chromosome":"8","Start":"38146313","Stop":"38146313","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1438852,"rule_based_match":true,"evidence_text":"c.441G>A (or p.W147X)","llm_judgment":"PRESENT","evidence":"c.441G>A (or p.W147X)","abstract_start":308,"abstract_end":329}]}
{"pmid":"32252220","title":"Identification of a novel variant in the PHEX gene using targeted gene panel sequencing in a 24-month-old boy with hypophosphatemic rickets.","abstract":"Familial hypophosphatemic rickets (FHR) is a disorder characterized by phosphate wasting and hypophosphatemia due to defects in renal phosphate transport regulation. There are 4 known inherited forms of FHR that differ in their molecular causes. Very few studies have been conducted that focused on the molecular analysis of FHR in Koreans. Eighteen mutations of the PHEX gene have been identified to this date in Korea. Herein, we report the clinical case of a 24-month-old boy presenting with bowed legs and short stature. The biochemical profile showed hypophosphatemia with decreased tubular reabsorption of phosphate. Several family members were identified with short stature and genu varum. Therefore, he was diagnosed with FHR. To identify the molecular causes of FHR, we performed targeted gene panel sequencing and found a novel hemizygous missense variant, c.1949T&gt;C (p.Leu650Pro), in the PHEX gene. This variant was also detected in the boy's mother who exhibited genu varum and short stature.","variants":[{"Name":"NM_000444.6(PHEX):c.1949T>C (p.Leu650Pro)","Chromosome":"X","Start":"22226492","Stop":"22226492","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":45336,"rule_based_match":false,"evidence_text":"c.1949T>C (p.Leu650Pro)","llm_judgment":"PRESENT","evidence":"p.Leu650Pro","abstract_start":881,"abstract_end":892}]}
{"pmid":"26801501","title":"Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.","abstract":"PURPOSE: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency.\nMETHODS: Genetic etiology was identified by whole exome sequencing of genomic DNA from two siblings, combined with linkage analysis in the wider family. MST1 protein expression was assessed by immunoblotting. The ability of patient lymphocytes to adhere to ICAM-1 under flow conditions was measured, and transwell assays were used to assess chemotaxis. Chemokine receptor expression was examined by flow cytometry and receptor signalling by immunoblotting.\nRESULTS: A homozygous nonsense mutation in STK4 (c.442C > T, p.Arg148Stop) was found in the patients, leading to a lack of MST1 protein expression. Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding.\nCONCLUSION: The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes. By analogy with murine Mst1 deficiency and other defects of leucocyte trafficking, this is likely to contribute to immunodeficiency by impairing key aspects of T-cell development and function such as positive selection in the thymus, thymic egress and immune synapse formation in the periphery.","variants":[{"Name":"NM_006282.5(STK4):c.442C>T (p.Arg148Ter)","Chromosome":"20","Start":"44987213","Stop":"44987213","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1064834,"rule_based_match":true,"evidence_text":"c.442C > T, p.Arg148Stop","llm_judgment":"PRESENT","evidence":"c.442C > T, p.Arg148Stop","abstract_start":961,"abstract_end":985}]}
{"pmid":"23111317","title":"RFT1-CDG in adult siblings with novel mutations.","abstract":"RFT1-CDG is a rare N-glycosylation disorder. Only 6 children with RFT1-CDG have been described, all with failure to thrive, feeding problems, hypotonia, developmental delay, epilepsy, decreased vision, deafness and thrombotic complications. We report on two young adult siblings with RFT1-CDG, compound heterozygotes for the novel missense mutations c.1222A>G (p.M408V) and c.1325G>A (p.R442Q) in RFT1 gene. Similar to the previously described patients, these siblings have profound intellectual disability but no feeding problems or failure to thrive. Their epilepsy is well controlled and coagulopathy is mild without clinical consequences. In addition, visual acuity is normal in both patients and hearing impairment is present only in one. Our findings extend the phenotype associated with RFT1-CDG.","variants":[{"Name":"NM_052859.4(RFT1):c.1222A>G (p.Met408Val)","Chromosome":"3","Start":"53092605","Stop":"53092605","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":204232,"rule_based_match":true,"evidence_text":"c.1222A>G (p.M408V)","llm_judgment":"PRESENT","evidence":"c.1222A>G (p.M408V)","abstract_start":350,"abstract_end":369},{"Name":"NM_052859.4(RFT1):c.1325G>A (p.Arg442Gln)","Chromosome":"3","Start":"53092502","Stop":"53092502","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":204233,"rule_based_match":true,"evidence_text":"c.1325G>A (p.R442Q)","llm_judgment":"PRESENT","evidence":"c.1325G>A (p.R442Q)","abstract_start":374,"abstract_end":393}]}
{"pmid":"26497373","title":"Investigation of ITGB2 gene in 12 new cases of leukocyte adhesion deficiency-type I revealed four novel mutations from Iran.","abstract":"BACKGROUND: Leukocyte adhesion deficiency type I (LAD-I) is a rare, autosomal recessive inherited immunodeficiency disease. LAD-I is caused by mutations in the ITGB2 gene and characterized by recurrent severe bacterial infections, as well as impaired wound healing with lack of pus formation.\nMETHODS: In this study, we investigated ITGB2 gene mutations in 12 patients and their parents. Genomic DNA was extracted from whole blood samples. All coding regions of the ITGB2 gene were amplified using PCR and followed by direct sequencing.\nRESULTS: Genetic analysis revealed 12 different homozygous mutations, including six missense (c.382G>A, c.2146G>C, c.715G>A, c.691G>C, c.1777C and new c.1686C>A), two new nonsense (c.1336G>T and c.1821C>A), three-frame shift (c.1143delc, c.1907delA and new c.474dupC) and a splice site (c.1877+2T>C). Flow cytometry analysis of CD11/CD18 expression on neutrophils revealed defect in CD18 in all twelve cases (1.4% to 42%), CD11a in ten cases (0.1% to 26.7%), CD11b in nine cases (1.2% to 58.8%), and CD11c in all cases (0 % to 18.1%). The patients' parents were both heterozygous carriers.\nCONCLUSION: Our findings showed four new mutations in the ITGB2 gene. These results can be used for decisive genetic diagnosis, genetic counseling, as well as  prenatal diagnosis for all patients who are suspended to LADI.","variants":[{"Name":"NM_000211.5(ITGB2):c.382G>A (p.Asp128Asn)","Chromosome":"21","Start":"44903482","Stop":"44903482","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":24506,"rule_based_match":true,"evidence_text":"c.382G>A","llm_judgment":"PRESENT","evidence":"c.382G>A","abstract_start":631,"abstract_end":639}]}
{"pmid":"32040869","title":"Mutation HOXB13 c.853delT in Martinican prostate cancer patients.","abstract":"BACKGROUND: In Martinique, prostate cancer (Pca) incidence rates are nowadays among the highest worldwide with a high incidence of early-onset and familial forms. Despite the demonstration of a strong familial component, identification of the genetic basis for hereditary Pca is challenging. The HOXB13 germline variant G84E (rs138213197) was described in men of European descent with Pca risk.\nMETHODS: To investigate the potential involvement of HOXB13 mutations in Martinique, we performed sequencing of the HOXB13 coding regions of 46 index cases with early-onset Pca (before the age of 51). Additional breast cancers and controls were performed. All cancer cases analyzed in this study have been observed in the context of genetic counseling.\nRESULTS: We identified a rare heterozygous germline variant c.853delT (p.Ter285Lysfs) rs77179853, reported only among patients of African ancestry with a minor allele frequency of 3.2%. This variant is a stop loss reported only among patients of African ancestry with a frequency of 0.2%.\nCONCLUSION: In conclusion, we think that this study provides supplementary arguments that HOXB13 variants are involved in Pca.","variants":[{"Name":"NM_006361.6(HOXB13):c.853del (p.Ter285LysextTer?)","Chromosome":"17","Start":"48726792","Stop":"48726792","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"T","allel_id":180897,"rule_based_match":true,"evidence_text":"c.853delT (p.Ter285Lysfs)","llm_judgment":"PRESENT","evidence":"c.853delT (p.Ter285Lysfs)","abstract_start":808,"abstract_end":833}]}
{"pmid":"30046681","title":"Phenotype analysis and clinical management in a large family with a novel truncating mutation in","abstract":"BACKGROUND: Genetic variants in the <i>RASGRP2</i> gene encoding calcium and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) represent a new inherited bleeding disorder linked to major defects of platelet aggregation and activation of αIIbβ3 integrin. They are of major interest as CalDAG-GEFI is receiving attention as a potential target for antiplatelet therapy for prevention and treatment of cardiovascular disorders including arterial thrombosis and atherosclerosis.\nOBJECTIVES: To better understand the phenotypical and clinical profiles of patients with CalDAG-GEFI deficiency.\nPATIENTS: We report a five-generation family with a novel truncating CalDAG-GEFI mutation detailing clinical management and phenotypic variability.\nRESULTS: Patients IV.6 & IV.4 manifested with episodes of serious mucocutanous bleeding or bleeding after surgery not responding to platelet transfusion but responding well to recombinant Factor VIIa infusions. Their blood counts and coagulation parameters were normal but platelet aggregation to ADP and collagen was defective. Further work-up confirmed normal levels of αIIb and β3 in their platelets but decreased αIIbβ3 function. DNA analysis by whole exome sequencing within the BRIDGE-BPD consortium (Cambridge, UK), allowed us to highlight a homozygous c.1490delT predicted to give rise to a p.F497Sfs*22 truncating mutation near to the C-terminal domain of CalDAG-GEFI. Sanger sequencing confirmed that both patients were homozygous for the c.1490delT and 3 out of 4 close family members were heterozygous.\nCONCLUSIONS: A long-term prospective study is warranted for full clinical exploration of CalDAG-GEFI to understand the bleeding phenotyes and their management.","variants":[{"Name":"NM_001098671.2(RASGRP2):c.1490del (p.Phe497fs)","Chromosome":"11","Start":"64730117","Stop":"64730117","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":615449,"rule_based_match":true,"evidence_text":"c.1490del","llm_judgment":"PRESENT","evidence":"c.1490del","abstract_start":1321,"abstract_end":1330}]}
{"pmid":"32253145","title":"Congenital myasthenia syndrome in a Chinese family with mutations in MUSK: A hotspot mutation and literature review.","abstract":"Congenital myasthenic syndrome (CMS) caused by mutations in MUSK is very rare and the genotype-phenotype relationship in MUSK related CMS is still unclear. Here we identified two patients carrying a homozygous hotspot mutation, c.308A > G in MUSK from a Chinese family. Both of them presented predominant bulbar weakness and atrophy of bilateral temporalis and masticatory muscles. To address the phenotype-genotype relationship, a total of 27 MUSK related CMS patients were reviewed. Patients with nonsense, frameshift or splicing mutations showed earlier onset (10/13 vs 2/14 neonatal onset, p = 0.0018) and more occurrence of vocal cord paralysis or stridor (8/13 vs 0/14, p = 0.0006), indicating a more severe phenotype. Comparing with patients carrying other missense mutations, the four patients carrying a homozygous c.308A > G mutation showed the female predominance (4/10 vs 4/4) and dramatic exacerbation after emotional or physiological stresses (2/10 vs 4/4) like pregnancy, menstrual periods and infection. All these indicated a genotype-phenotype relationship in MUSK-related CMS.","variants":[{"Name":"NM_005592.4(MUSK):c.308A>G (p.Asn103Ser)","Chromosome":"9","Start":"110687218","Stop":"110687218","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":215099,"rule_based_match":true,"evidence_text":"c.308A>G","llm_judgment":"PRESENT","evidence":"c.308A > G","abstract_start":228,"abstract_end":238}]}
{"pmid":"32184166","title":"A novel pathogenic variant in MYO18B associating early-onset muscular hypotonia, and characteristic dysmorphic features, delineation of the phenotypic spectrum of MYO18B-related conditions.","abstract":"Homozygous loss-of-function variants in MYO18B have been associated with congenital myopathy, facial dysmorphism and Klippel-Feil anomaly. So far, only four patients have been reported. Comprehensive description of new cases that help to highlight recurrent features and to further delineate the phenotypic spectrum are still missing. We present the fifth case of MYO18B-associated disease in a newborn male patient. Trio exome sequencing identified the previously unreported homozygous nonsense variant c.6433C>T, p.(Arg2145*) in MYO18B (NM_032608.5). While most phenotypic features of our patient align with previously reported cases, we describe the prenatal features for the first time. Taking the phenotypic description of our patient into account, we propose that the core phenotype comprises a severe congenital myopathy with feeding difficulties in infancy and characteristic dysmorphic features.","variants":[{"Name":"NM_032608.7(MYO18B):c.6433C>T (p.Arg2145Ter)","Chromosome":"22","Start":"26004818","Stop":"26004818","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":798769,"rule_based_match":true,"evidence_text":"c.6433C>T, p.(Arg2145*)","llm_judgment":"PRESENT","evidence":"c.6433C>T, p.(Arg2145*)","abstract_start":504,"abstract_end":527}]}
{"pmid":"35471564","title":"Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia.","abstract":"OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683).\nMETHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed.\nRESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism.\nINTERPRETATION: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022;92:304-321.","variants":[{"Name":"NM_001776.6(ENTPD1):c.640del (p.Gly216fs)","Chromosome":"10","Start":"95845422","Stop":"95845422","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":2417529,"rule_based_match":true,"evidence_text":"c.640del; p.(Gly216Glufs*75)","llm_judgment":"PRESENT","evidence":"c.640del; p.(Gly216Glufs*75)","abstract_start":859,"abstract_end":887},{"Name":"NM_001776.6(ENTPD1):c.574-6_574-3del","Chromosome":"10","Start":"95845349","Stop":"95845352","ReferenceAlleleVCF":"GTCTT","AlternateAlleleVCF":"G","allel_id":791018,"rule_based_match":true,"evidence_text":"c.574-6_574-3del","llm_judgment":"PRESENT","evidence":"c.574-6_574-3del","abstract_start":1079,"abstract_end":1095},{"Name":"NM_001776.6(ENTPD1):c.1109T>A (p.Leu370Ter)","Chromosome":"10","Start":"95860503","Stop":"95860503","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2417527,"rule_based_match":true,"evidence_text":"c.1109 T > A; p.(Leu370*)","llm_judgment":"PRESENT","evidence":"c.1109 T > A; p.(Leu370*)","abstract_start":1052,"abstract_end":1077}]}
{"pmid":"19353676","title":"Finding twinkle in the eyes of a 71-year-old lady: a case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease.","abstract":"Progressive external ophthalmoplegia (PEO) can be caused by a disorder characterized by multiple mitochondrial DNA (mtDNA) deletions due to mutations in the TWINKLE gene, encoding a mtDNA helicase. We describe a 71-year-old woman who had developed PEO at age 55 years. She had cataracts, diabetes, paresthesias, cognitive defects, memory problems, hearing loss, and sensory ataxia. She had muscle weakness with ragged red fibers on biopsy. MRI showed static white matter changes. A c.908G>A substitution (p.R303Q) in the TWINKLE gene was identified. Multiple mtDNA deletions were detected in muscle but not blood by a PCR-based method, but not by Southern blot analysis. MtDNA copy number was maintained in blood and muscle. A systematic literature search was used to identify the genotypic and phenotypic spectrum of dominant TWINKLE-related disease. Patients were adults with PEO and symptoms including myopathy, neuropathy, dysarthria or dysphagia, sensory ataxia, and parkinsonism. Diabetes, cataract, memory loss, hearing loss, and cardiac problems were infrequent. All reported mutations clustered between amino acids 303 and 508 with no mutations at the N-terminal half of the gene. The TWINKLE gene should be analyzed in adults with PEO even in the absence of mtDNA deletions in muscle on Southern blot analysis, and of a family history for PEO. The pathogenic mutations identified 5' beyond the linker region suggest a functional role for this part of the protein despite the absence of a primase function in humans. In our patient, the pathogenesis involved multiple mtDNA deletions without reduction in mtDNA copy number.","variants":[{"Name":"NM_021830.5(TWNK):c.908G>A (p.Arg303Gln)","Chromosome":"10","Start":"100989118","Stop":"100989118","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19667,"rule_based_match":true,"evidence_text":"c.908G>A substitution (p.R303Q)","llm_judgment":"PRESENT","evidence":"c.908G>A substitution (p.R303Q)","abstract_start":482,"abstract_end":513}]}
{"pmid":"33240976","title":"Novel mutation of","abstract":"BACKGROUND: Congenital cataracts is the most common cause of childhood visual impairment and blindness worldwide. It is reported that about one quarter of congenital cataracts caused by genetic defects. Various gene mutations have been identified in hereditary cataracts so far. The purpose of the present study was to investigate the relationship between gap junction protein alpha 8 (<i>GJA8</i>) gene mutation and congenital cataract.\nMETHODS: A pedigree with autosomal dominant congenital cataract was investigated and the peripheral venous blood was extracted from 18 family members. After the high-throughput targeted capture and whole exome sequencing for the proband, bioinformatics analysis was performed. By combining the proband clinical symptoms, candidate variations were eliminated which were significantly not consistent with the clinical phenotype. And disease-causing variant was identified.\nRESULTS: Gene sequencing revealed the heterozygous missense mutation in exon 2 of the <i>GJA8</i> gene (c.178G>A), which co-segregated with the disease phenotype in the family and resulted in the substitution of glycine to serine at position 178 (p.G60S). This missense mutation was located in the hotspot mutation region, and might be harmful.\nCONCLUSIONS: This study reports a novel disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract in the Chinese population, caused by the missense mutation of <i>GJA8</i> (c.178G>A). Our data expand the spectrum of <i>GJA8</i> variants and associated phenotypes, facilitate clinical diagnosis and support the presence of relationship between genetic basis and human disease.","variants":[{"Name":"NM_005267.5(GJA8):c.178G>A (p.Gly60Ser)","Chromosome":"1","Start":"147908133","Stop":"147908133","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2739720,"rule_based_match":true,"evidence_text":"c.178G>A","llm_judgment":"PRESENT","evidence":"c.178G>A","abstract_start":1013,"abstract_end":1021}]}
{"pmid":"32441320","title":"Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity.","abstract":"Primary immune deficiencies are usually attributed to genetic defects and, therefore, frequently referred to as inborn errors of immunity (IEI). We subjected the genomic DNA of 333 patients with clinical signs of IEI to next generation sequencing (NGS) analysis of 344 immunity-related genes and, in some instances, additional genetic techniques. Genetic causes of the disease were identified in 69/333 (21%) of subjects, including 11/18 (61%) of children with syndrome-associated IEIs, 45/202 (22%) of nonsyndromic patients with Jeffrey Modell Foundation (JMF) warning signs, 9/56 (16%) of subjects with periodic fever, 3/30 (10%) of cases of autoimmune cytopenia, 1/21 (5%) of patients with unusually severe infections and 0/6 (0%) of individuals with isolated elevation of IgE level. There were unusual clinical observations: twins with severe immunodeficiency carried a de novo CHARGE syndrome-associated SEMA3E c.2108C>T (p.S703L) allele; however, they lacked clinical features of CHARGE syndrome. Additionally, there were genetically proven instances of Netherton syndrome, Х-linked agammaglobulinemia, severe combined immune deficiency (SCID), IPEX and APECED syndromes, among others. Some patients carried recurrent pathogenic alleles, such as AIRE c.769C>T (p.R257*), NBN c.657del5, DCLRE1C c.103C>G (p.H35D), NLRP12 c.1054C>T (p.R352C) and c.910C>T (p.H304Y). NGS is a powerful tool for high-throughput examination of patients with malfunction of immunity.","variants":[{"Name":"NM_012431.3(SEMA3E):c.2108C>T (p.Ser703Leu)","Chromosome":"7","Start":"83367806","Stop":"83367806","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17544,"rule_based_match":true,"evidence_text":"SEMA3E c.2108C>T (p.S703L)","llm_judgment":"PRESENT","evidence":"SEMA3E c.2108C>T (p.S703L)","abstract_start":909,"abstract_end":935}]}
{"pmid":"34096032","title":"Diagnosis of a case of autosomal recessive polycystic kidney disease with combined prenatal imaging and genetic testing","abstract":"OBJECTIVE: To explore the genetic basis for a fetus with renal abnormalities through whole exome sequencing and imaging examination.\nMETHODS: Clinical data and result of medical imaging of the fetus was collected. Amniotic fluid sample was collected for the extraction of fetal DNA. Whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing.\nRESULTS: Prenatal ultrasonography showed that the fetus had bilateral enlargement of the kidneys with hyperechogenicity and diffuse renal cysts. Whole exome sequencing revealed that the fetus carried compound heterozygous variants of the PKHD1 gene, namely c.5137G>T and c.2335_2336delCA, which were derived from its mother and father, respectively.\nCONCLUSION: The fetus was diagnosed with autosomal recessive polycystic kidney disease through combined prenatal ultrasonography and whole exome sequencing. The compound heterozygous variants of the PKHD1 gene probably underlay the pathogenesis in the fetus. The results have enabled prenatal diagnosis and genetic counseling for its parents.","variants":[{"Name":"NM_138694.4(PKHD1):c.5137G>T (p.Glu1713Ter)","Chromosome":"6","Start":"52024673","Stop":"52024673","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3776274,"rule_based_match":true,"evidence_text":"c.5137G>T","llm_judgment":"PRESENT","evidence":"c.5137G>T","abstract_start":635,"abstract_end":644}]}
{"pmid":"20685856","title":"Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly.","abstract":"CONTEXT: GLI2 is a transcription factor downstream in Sonic Hedgehog signaling, acting early in ventral forebrain and pituitary development. GLI2 mutations were reported in patients with holoprosencephaly (HPE) and pituitary abnormalities.\nOBJECTIVE: The aim was to report three novel frameshift/nonsense GLI2 mutations and the phenotypic variability in the three families.\nSETTING: The study was conducted at a university hospital.\nPATIENTS AND METHODS: The GLI2 coding region of patients with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency was amplified by PCR using intronic primers and sequenced.\nRESULTS: Three novel heterozygous GLI2 mutations were identified: c.2362_2368del p.L788fsX794 (family 1), c.2081_2084del p.L694fsX722 (family 2), and c.1138 G>T p.E380X (family 3). All predict a truncated protein with loss of the C-terminal activator domain. The index case of family 1 had polydactyly, hypoglycemia, and seizures, and GH, TSH, prolactin, ACTH, LH, and FSH deficiencies. Her mother and seven relatives harboring the same mutation had polydactyly, including two uncles with IGHD and one cousin with GH, TSH, LH, and FSH deficiencies. In family 2, a boy had cryptorchidism, cleft lip and palate, and GH deficiency. In family 3, a girl had hypoglycemia, seizures, excessive thirst and polyuria, and GH, ACTH, TSH, and antidiuretic hormone deficiencies. Magnetic resonance imaging of four patients with GLI2 mutations and hypopituitarism showed a hypoplastic anterior pituitary and an ectopic posterior pituitary lobe without HPE.\nCONCLUSION: We describe three novel heterozygous frameshift or nonsense GLI2 mutations, predicting truncated proteins lacking the activator domain, associated with IGHD or combined pituitary hormone deficiency and ectopic posterior pituitary lobe without HPE. These phenotypes support partial penetrance, variable polydactyly, midline facial defects, and pituitary hormone deficiencies, including diabetes insipidus, conferred by heterozygous frameshift or nonsense GLI2 mutations.","variants":[{"Name":"NM_001374353.1(GLI2):c.1138G>T (p.Glu380Ter)","Chromosome":"2","Start":"120972019","Stop":"120972019","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":143123,"rule_based_match":true,"evidence_text":"c.1138 G>T p.E380X","llm_judgment":"PRESENT","evidence":"c.1138 G>T p.E380X","abstract_start":775,"abstract_end":793}]}
{"pmid":"31153816","title":"The island of Gran Canaria: A genetic isolate for familial hypercholesterolemia.","abstract":"BACKGROUND: Genetic diagnosis of familial hypercholesterolemia (FH) has not been universally performed in the Canary Islands (Spain).\nOBJECTIVES: This study aimed to genetically characterize a cohort of patients with FH in the island of Gran Canaria.\nMETHODS: Study subjects were 70 unrelated index cases attending a tertiary hospital in Gran Canaria, with a clinical diagnosis of FH, according to the criteria of the Dutch Lipid Clinic Network. Given that 7 of the first 10 cases with positive genetic study were carriers of a single mutation in the LDLR gene [p.(Tyr400_Phe402del)], a specific polymerase chain reaction-based assay was developed for the detection of this variant as a first screening step on the remaining subjects. In those without this mutation, molecular diagnosis was completed using a next-generation sequencing panel including LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, and LIPA genes and incorporating copy number variation detection in LDLR.\nRESULTS: On the whole, 44 subjects (62%) had a positive genetic study, of whom 30 (68%) were heterozygous carriers of the p.(Tyr400_Phe402del) variant. Eleven subjects carried other mutations in LDLR, including the novel mutation NM_000527.4: c.877dupG; NP_000518.1: p.(Asp293Glyfs*8). An unclassified PCSK9 gene variant was found in one subject [(NM_174936.3:c.1496G>A; NP_777596.2: p.(Arg499His)]. Other single patients had mutations in APOB (heterozygous) and in LIPA (homozygous). All identified variants co-segregated with the disease phenotype.\nCONCLUSIONS: These findings suggest a founder effect for the p.(Tyr400_Phe402del) LDLR mutation in Gran Canaria. A cost-effective local screening strategy for genetic diagnosis of FH could be implemented in this region.","variants":[{"Name":"NM_000527.5(LDLR):c.1199_1207del (p.Tyr400_Phe402del)","Chromosome":"19","Start":"11113288","Stop":"11113296","ReferenceAlleleVCF":"CCTACCTCTT","AlternateAlleleVCF":"C","allel_id":246041,"rule_based_match":false,"evidence_text":"p.(Tyr400_Phe402del)","llm_judgment":"PRESENT","evidence":"p.(Tyr400_Phe402del)","abstract_start":562,"abstract_end":582}]}
{"pmid":"28302194","title":"Clinical and molecular genetic study of nonketotic hyperglycinemia in a Chinese family","abstract":"Nonketotic hyperglycinemia (NKH) is a rare, inborn error of metabolism. In this case report, a Chinese male infant was diagnosed with NKH caused by GLDC gene mutation. The clinical characteristics and genetic diagnosis were reported. The infant presented with an onset of early metabolic encephalopathy and Ohtahara syndrome. Both blood and urinary levels of metabolites were in the normal range. Brain MRI images indicated a poor development of corpus callosum, and a burst suppression pattern was found in the EEG. Results of target gene sequencing technology combined with multiplex ligation-dependent probe amplification (MLPA) indicated a heterozygous missense mutation of c.1786 C>T (p.R596X) in maternal exon 15 and a loss of heterozygosity of 4-15 exon gross deletions in paternal GLDC gene. These definite pathogenic mutations confirmed the diagnosis of NKH. The infant's clinical condition was not improved after treatment with adreno-cortico-tropic-hormone, topiramate and dextromethorphan, and he finally died at 4 months of age. Patients with NKH often exhibit complicated clinical phenotypes and are lack of specific symptoms. NKH could be diagnosed by metabolic screening and molecular genetic analysis.","variants":[{"Name":"NM_000170.3(GLDC):c.1786C>T (p.Arg596Ter)","Chromosome":"9","Start":"6587205","Stop":"6587205","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70689,"rule_based_match":true,"evidence_text":"c.1786 C>T (p.R596X)","llm_judgment":"PRESENT","evidence":"c.1786 C>T (p.R596X)","abstract_start":678,"abstract_end":698}]}
{"pmid":"25491159","title":"Histopathological comparison of eyes from patients with autosomal recessive retinitis pigmentosa caused by novel EYS mutations.","abstract":"To evaluate the retinal histopathology in donor eyes from patients with autosomal recessive retinitis pigmentosa (arRP) caused by EYS mutations. Eyes from a 72-year-old female (donor 1, family 1), a 91-year-old female (donor 2, family 2), and her 97-year-old sister (donor 3, family 2) were evaluated with macroscopic, scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT) imaging. Age-similar normal eyes and an eye donated by donor 1's asymptomatic mother (donor 4, family 1) were used as controls. The perifovea and peripheral retina were processed for microscopy and immunocytochemistry with markers for cone and rod photoreceptor cells. DNA analysis revealed EYS mutations c.2259 + 1G > A and c.2620C > T (p.Q874X) in family 1, and c.4350_4356del (p.I1451Pfs*3) and c.2739-?_3244 + ?del in family 2. Imaging studies revealed the presence of bone spicule pigment in arRP donor retinas. Histology of all three affected donor eyes showed very thin retinas with little evidence of stratified nuclear layers in the periphery. In contrast, the perifovea displayed a prominent inner nuclear layer. Immunocytochemistry analysis demonstrated advanced retinal degenerative changes in all eyes, with near-total absence of rod photoreceptors. In addition, we found that the perifoveal cones were more preserved in retinas from the donor with the midsize genomic rearrangement (c.4350_4356del (p.I1451Pfs*3) and c.2739-?_3244 + ?del) than in retinas from the donors with the truncating (c.2259 + 1G > A and c.2620C > T (p.Q874X) mutations. Advanced retinal degenerative changes with near-total absence of rods and preservation of some perifoveal cones are observed in arRP donor retinas with EYS mutations.","variants":[{"Name":"NM_001142800.2(EYS):c.2259+1G>A","Chromosome":"6","Start":"64997581","Stop":"64997581","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":543937,"rule_based_match":true,"evidence_text":"c.2259 + 1G > A","llm_judgment":"PRESENT","evidence":"c.2259 + 1G > A","abstract_start":699,"abstract_end":714},{"Name":"NM_001142800.2(EYS):c.4350_4356del (p.Ile1451fs)","Chromosome":"6","Start":"64591511","Stop":"64591517","ReferenceAlleleVCF":"CAGCTATA","AlternateAlleleVCF":"C","allel_id":193097,"rule_based_match":true,"evidence_text":"c.4350_4356del (p.I1451Pfs*3)","llm_judgment":"PRESENT","evidence":"c.4350_4356del (p.I1451Pfs*3)","abstract_start":758,"abstract_end":787},{"Name":"NM_001142800.2(EYS):c.2620C>T (p.Gln874Ter)","Chromosome":"6","Start":"64912505","Stop":"64912505","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":431711,"rule_based_match":true,"evidence_text":"c.2620C>T (p.Q874X)","llm_judgment":"PRESENT","evidence":"c.2620C > T (p.Q874X)","abstract_start":719,"abstract_end":740}]}
{"pmid":"34800363","title":"Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia.","abstract":"The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs<sup>∗</sup>16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.","variants":[{"Name":"NM_018245.3(OGDHL):c.2554C>G (p.Pro852Ala)","Chromosome":"10","Start":"49737822","Stop":"49737822","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1325037,"rule_based_match":false,"evidence_text":"p.Pro852Ala","llm_judgment":"PRESENT","evidence":"p.Pro852Ala","abstract_start":550,"abstract_end":561},{"Name":"NM_018245.3(OGDHL):c.2018G>A (p.Arg673Gln)","Chromosome":"10","Start":"49740832","Stop":"49740832","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1325038,"rule_based_match":false,"evidence_text":"c.2018G>A (p.Arg673Gln)","llm_judgment":"PRESENT","evidence":"p.Arg673Gln","abstract_start":650,"abstract_end":661},{"Name":"NM_018245.3(OGDHL):c.1464T>C (p.Val488=)","Chromosome":"10","Start":"49745810","Stop":"49745810","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1325039,"rule_based_match":true,"evidence_text":"c.1464T>C (p.Val488Val)","llm_judgment":"PRESENT","evidence":"p.Val488Val","abstract_start":662,"abstract_end":673},{"Name":"NM_018245.3(OGDHL):c.730C>T (p.Arg244Trp)","Chromosome":"10","Start":"49751846","Stop":"49751846","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1325040,"rule_based_match":false,"evidence_text":"p.Arg244Trp","llm_judgment":"PRESENT","evidence":"p.Arg244Trp","abstract_start":563,"abstract_end":574},{"Name":"NM_018245.3(OGDHL):c.895A>G (p.Arg299Gly)","Chromosome":"10","Start":"49750840","Stop":"49750840","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1325041,"rule_based_match":false,"evidence_text":"c.895A>G (p.Arg299Gly)","llm_judgment":"PRESENT","evidence":"p.Arg299Gly","abstract_start":580,"abstract_end":591}]}
{"pmid":"34845833","title":"Two closely spaced missense COL3A1 variants in cis cause vascular Ehlers-Danlos syndrome in one large Chinese family.","abstract":"Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe hereditary connective tissue disease arising from a mutation in the type III collagen alpha I chain (COL3A1) gene, with a poor prognosis due to exceptional vascular ruptures and premature death. Herein, starting from a 36-year-old Chinese male patient with a complaint of upper abdominal pain, we collected clinical data of and performed a genetic analysis of a total of 20 family members. We identified two closely spaced COL3A1 missense variants in cis, p.Leu734Phe (c.2199_2200TC>AT) and p.Gly741Ser (c.2221G>A), as the cause of vEDS in this family. p.Gly741Ser, a glycine substitution mutation, has been previously reported, whereas p.Leu734Phe, a non-glycine substitution mutation, is novel. We analysed their independent and combined effects on the COL3A1 level in transfected skin fibroblast cells by means of Western blotting. We found that both variants independently led to a reduced COL3A1 level and, when combined, led to an even more reduced COL3A1 level compared to the wild type. Thus, each missense variant can be independently classified as a pathogenic variant, albeit with a synergetic effect when occurring together. Moreover, our genetic findings provide an explanation for four previous sudden deaths and identified two high-risk carriers in the family.","variants":[{"Name":"NM_000090.4(COL3A1):c.2221G>A (p.Gly741Ser)","Chromosome":"2","Start":"188999569","Stop":"188999569","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":107191,"rule_based_match":true,"evidence_text":"c.2221G>A","llm_judgment":"PRESENT","evidence":"c.2221G>A","abstract_start":564,"abstract_end":573}]}
{"pmid":"28446513","title":"Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration.","abstract":"BACKGROUND: Variation in the <i>ABCA4</i> gene is causal for, or associated with, a wide range of phenotypes from early onset Mendelian retinal dystrophies to late-onset complex disorders such as age-related macular degeneration (AMD). Despite substantial progress in determining the causal genetic variation, even complete sequencing of the entire open reading frame and splice sites of <i>ABCA4</i> identifies biallelic mutations in only 60%-70% of cases; 20%-25% remain with one mutation and no mutations are found in 10%-15% of cases with clinically confirmed ABCA4 disease. This study was designed to identify missing causal variants specifically in monoallelic cases of ABCA4 disease.\nMETHODS: Direct sequencing and analysis were performed in a large familial ABCA4 disease cohort of predominately European descent (n=643). Patient phenotypes were assessed from clinical and retinal imaging data.\nRESULTS: We determined that a hypomorphic <i>ABCA4</i> variant c.5603A>T (p.Asn1868Ile), previously considered benign due to high minor allele frequency (MAF) (~7%) in the general population, accounts for 10% of the disease, >50% of the missing causal alleles in monoallelic cases, ~80% of late-onset cases and distinguishes ABCA4 disease from AMD. It results in a distinct clinical phenotype characterised by late-onset of symptoms (4th decade) and foveal sparing (85%). Intragenic modifying effects involving this variant and another, c.2588G>C (p.Gly863Ala) allele, were also identified.\nCONCLUSIONS: These findings substantiate the causality of frequent missense variants and their phenotypic outcomes as a significant contribution to ABCA4 disease, particularly the late-onset phenotype, and its clinical variation. They also suggest a significant revision of diagnostic screening and assessment of <i>ABCA4</i> variation in aetiology of retinal diseases.","variants":[{"Name":"NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala)","Chromosome":"1","Start":"94051698","Stop":"94051698","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":22918,"rule_based_match":true,"evidence_text":"c.2588G>C (p.Gly863Ala)","llm_judgment":"PRESENT","evidence":"c.2588G>C (p.Gly863Ala)","abstract_start":1440,"abstract_end":1463},{"Name":"NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)","Chromosome":"1","Start":"94010911","Stop":"94010911","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":105279,"rule_based_match":true,"evidence_text":"c.5603A>T (p.Asn1868Ile)","llm_judgment":"PRESENT","evidence":"c.5603A>T (p.Asn1868Ile)","abstract_start":966,"abstract_end":990}]}
{"pmid":"16611310","title":"The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients.","abstract":"Much of the variability in the sensitivity to warfarin in anticoagulated patients is associated with the c.-1639G > A polymorphism of the vitamin K-epoxide reductase (VKORC1) gene. However, its association with the acenocoumarol dose in patients under anticoagulant therapy has not been studied. The c.-1639G > A genotype of VKORC1 was determined in 113 patients on stable anticoagulation requiring low (n = 42), medium (n = 42) or high (n = 21) acenocoumarol doses. To evaluate the association between acenocoumarol requirements and the c.-1639G > A variant, multivariate logistic regression models were fitted, adjusting for age, gender, and the c.430C > T and c.1075A > C variants of cytochrome P450 2C9 (CYP2C9). A total of 90.5% of the patients in the low acenocoumarol dose group carried the A allele of VKORC1:c.-1639G > A. The A allele independently increased the odds of requiring a low acenocoumarol dose [odds ratio (OR) 9.4; 95% confidence interval (CI) 1.9-46.4; P = 0.006], especially when the homozygous form was present (OR 44.2; 95% CI 5.5-354.6; P < 0.001). The A allele was less frequent in the high dose group showing an inverse association with the requirement for high doses (OR 0.04; 95% CI 0.01-0.22; P < 0.001). The A allele of the c.-1639G > A polymorphism of VKORC1 is therefore associated with a low-dose requirement for acenocoumarol in patients receiving anticoagulant therapy.","variants":[{"Name":"NM_024006.4(VKORC1):c.-1639G>A","Chromosome":"16","Start":"31096368","Stop":"31096368","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17250,"rule_based_match":true,"evidence_text":"c.-1639G > A","llm_judgment":"PRESENT","evidence":"c.-1639G > A","abstract_start":105,"abstract_end":117}]}
{"pmid":"33502047","title":"Severe congenital lactic acidosis and hypertrophic cardiomyopathy caused by an intronic variant in NDUFB7.","abstract":"Mutations in structural subunits and assembly factors of complex I of the oxidative phosphorylation system constitute the most common cause of mitochondrial respiratory chain defects. Such mutations can present a wide range of clinical manifestations, varying from mild deficiencies to severe, lethal disorders. We describe a patient presenting intrauterine growth restriction and anemia, which displayed postpartum hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and a severe complex I defect with fatal outcome. Whole genome sequencing revealed an intronic biallelic mutation in the NDUFB7 gene (c.113-10C>G) and splicing pattern alterations in NDUFB7 messenger RNA were confirmed by RNA Sequencing. The detected variant resulted in a significant reduction of the NDUFB7 protein and reduced complex I activity. Complementation studies with expression of wild-type NDUFB7 in patient fibroblasts normalized complex I function. Here we report a case with a primary complex I defect due to a homozygous mutation in an intron region of the NDUFB7 gene.","variants":[{"Name":"NM_004146.6(NDUFB7):c.113-10C>G","Chromosome":"19","Start":"14566943","Stop":"14566943","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":985484,"rule_based_match":true,"evidence_text":"c.113-10C>G","llm_judgment":"PRESENT","evidence":"c.113-10C>G","abstract_start":612,"abstract_end":623}]}
{"pmid":"21868336","title":"GNE gene mutation analysis in 5 patients with distal myopathy with rimmed vacuoles","abstract":"OBJECTIVE: To investigate GNE gene mutations in 5 Chinese patients with distal myopathy with rimmed vacuoles (DMRV).\nMETHODS: Five patients with typical clinical and pathological features of DMRV were studied. All the 11 coding exons and the flanking intron sequences of GNE gene were amplified by PCR and sequenced. Four family members of case 5 were also examined for GNE gene mutations.\nRESULTS: All the patients were identified to have different GNE gene mutations: Cases 1-4 had complex heterozygous mutations and case 5 had homozygous mutation. Six reported mutations had been identified, including 1 nonsense mutation (p.R8X) and 5 missense mutations (p.D176V, p.I298T, p.A591T, P.A631V, and p.V696M). A novel mutation (c.317T>C, p.I106T) was identified in case 2.\nCONCLUSION: This is the first report of p.R8X, p.I298T, p.A591T and p.V696M mutations in GNE gene in Chinese population, and a novel mutation p.I106T was identified. These findings further expand the clinical and genetic spectrum of DMRV in China.","variants":[{"Name":"NM_005476.7(GNE):c.317T>C (p.Ile106Thr)","Chromosome":"9","Start":"36246330","Stop":"36246330","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":272538,"rule_based_match":true,"evidence_text":"c.317T>C, p.I106T","llm_judgment":"PRESENT","evidence":"c.317T>C, p.I106T","abstract_start":727,"abstract_end":744}]}
{"pmid":"19752569","title":"Novel and recurrent mutations in the C1NH gene of Arab patients affected with hereditary angioedema.","abstract":"BACKGROUND: Autosomal dominant hereditary angioedema (HAE) results in episodes of subcutaneous edema in any body part and/or submucosal edema of the upper respiratory or gastrointestinal tracts. This disorder is caused by mutations in the C1NH gene, many of which have been described primarily in European patients. However, the genetic cause of HAE in Middle Eastern Arab patients has not yet been determined.\nMETHODS: Four unrelated Arab families, in which 15 patients were diagnosed with HAE, were studied. DNA from 13 patients was analyzed for mutations in the C1NH gene by DNA sequencing.\nRESULTS: Three novel and 2 recurrent mutations were identified in the C1NH gene of HAE patients. In family 1, the patient was heterozygous for a novel c.856C>T and a recurrent c.1361T>A missense mutation encoding for p.Arg264Cys and p.Val432Glu, respectively. In patients from family 2, a novel c.509C>T missense mutation encoding for a p.Ser148Phe was identified. In patients from family 3, a novel c.1142delC nonsense mutation encoding for a p.Ala359AlafsX15 was discovered. In family 4, a recurrent c.1397G>A missense mutation encoding for a p.Arg444His was present.\nCONCLUSION: This is the first ever report of C1NH gene mutations in Middle Eastern Arab patients. Our study suggests that, despite the numerous existing mutations in the C1NH gene, there are novel and recurrent mutations in HAE patients of non-European origin. We conclude that the spectrum of C1NH gene mutations in HAE patients is wider due to the likely presence of novel and recurrent mutations in patients of other ethnicities.","variants":[{"Name":"NM_000062.3(SERPING1):c.856C>T (p.Arg286Cys)","Chromosome":"11","Start":"57606180","Stop":"57606180","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3813116,"rule_based_match":true,"evidence_text":"c.856C>T","llm_judgment":"PRESENT","evidence":"c.856C>T","abstract_start":745,"abstract_end":753}]}
{"pmid":"23225040","title":"Analysis of clinical features and GCDH gene mutations in four patients with glutaric academia type I","abstract":"OBJECTIVE: To review clinical features of four male patients with glutaric academia type I and screen glutaryl-CoA dehydrogenase (GCDH) gene mutations.\nMETHODS: The 4 patients underwent brain computer tomography (CT) and magnetic resonance imaging (MRI) analyses. Blood acylcarnitine and urine organic acid were analyzed with tandem mass spectrometry and gas chromatographic mass spectrometry. Genomic DNA was extracted from peripheral blood samples. The 11 exons and flanking sequences of GCDH gene were amplified with PCR and subjected to direct DNA sequencing.\nRESULTS: All patients have manifested macrocephaly, with head circumference measured 50 cm (14 months), 47 cm (9 months), 46 cm (5 months) and 51 cm (14 months), respectively. Imaging analyses also revealed dilation of Sylvian fissure and lateral ventricles, frontotemporal atrophy, subarachnoid space enlargement and cerebellar vermis abnormalities. All patients had elevated glutarylcarnitine (5.8 umol/L, 7.5 umol/L, 8.3 umol/L and 7.9 umol/L, respectively) and high urinary excretion of glutaric acid. Seven mutations were identified among the patients, among which c.146_149del4, IVS6-4_Ex7+4del8, c.508A>G (p.K170E), c.797T>C (p.M266T) and c.420del10 were first discovered.\nCONCLUSION: Macrocephaly and neurological impairment are the most prominent features of glutaric academia type I. Blood tandem mass spectrometry and urine gas chromatographic mass spectrometry analysis can facilitate the diagnosis. The results can be confirmed by analysis of GCDH gene mutations.","variants":[{"Name":"NM_000159.4(GCDH):c.797T>C (p.Met266Thr)","Chromosome":"19","Start":"12896366","Stop":"12896366","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":574878,"rule_based_match":true,"evidence_text":"c.797T>C (p.M266T)","llm_judgment":"PRESENT","evidence":"c.797T>C (p.M266T)","abstract_start":1187,"abstract_end":1205}]}
{"pmid":"22197489","title":"Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome.","abstract":"The autosomal-recessive form of popliteal pterygium syndrome, also known as Bartsocas-Papas syndrome, is a rare, but frequently lethal disorder characterized by marked popliteal pterygium associated with multiple congenital malformations. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this malformation syndrome to chromosomal region 21q22.3. Direct sequencing of RIPK4 (receptor-interacting serine/threonine kinase protein 4) showed a homozygous transversion (c.362T>A) that causes substitution of a conserved isoleucine with asparagine at amino acid position 121 (p.Ile121Asn) in the serine/threonine kinase domain of the protein. Additional pathogenic mutations-a homozygous transition (c.551C>T) that leads to a missense substitution (p.Thr184Ile) at a conserved position and a homozygous one base-pair insertion mutation (c.777_778insA) predicted to lead to a premature stop codon (p.Arg260ThrfsX14) within the kinase domain-were observed in two families. Molecular modeling of the kinase domain showed that both the Ile121 and Thr184 positions are critical for the protein's stability and kinase activity. Luciferase reporter assays also demonstrated that these mutations are critical for the catalytic activity of RIPK4. RIPK4 mediates activation of the nuclear factor-κB (NF-κB) signaling pathway and is required for keratinocyte differentiation and craniofacial and limb development. The phenotype of Ripk4(-/-) mice is consistent with the human phenotype presented herein. Additionally, the spectrum of malformations observed in the presented families is similar, but less severe than the conserved helix-loop-helix ubiquitous kinase (CHUK)-deficient human fetus phenotype; known as Cocoon syndrome; this similarity indicates that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth.","variants":[{"Name":"NM_020639.3(RIPK4):c.362T>A (p.Ile121Asn)","Chromosome":"21","Start":"41756637","Stop":"41756637","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":39470,"rule_based_match":true,"evidence_text":"c.362T>A","llm_judgment":"PRESENT","evidence":"c.362T>A","abstract_start":494,"abstract_end":502}]}
{"pmid":"33333735","title":"Comprehensive Functional Characterization and Clinical Interpretation of 20 Splice-Site Variants of the","abstract":"Hereditary breast and/or ovarian cancer is a highly heterogeneous disease with more than 10 known disease-associated genes. In the framework of the BRIDGES project (Breast Cancer Risk after Diagnostic Gene Sequencing), the <i>RAD51C</i> gene has been sequenced in 60,466 breast cancer patients and 53,461 controls. We aimed at functionally characterizing all the identified genetic variants that are predicted to disrupt the splicing process. Forty <i>RAD51C</i> variants of the intron-exon boundaries were bioinformatically analyzed, 20 of which were selected for splicing functional assays. To test them, a splicing reporter minigene with exons 2 to 8 was designed and constructed. This minigene generated a full-length transcript of the expected size (1062 nucleotides), sequence, and structure (Vector exon V1- <i>RAD51C</i> exons_2-8- Vector exon V2). The 20 candidate variants were genetically engineered into the wild type minigene and functionally assayed in MCF-7 cells. Nineteen variants (95%) impaired splicing, while 18 of them produced severe splicing anomalies. At least 35 transcripts were generated by the mutant minigenes: 16 protein-truncating, 6 in-frame, and 13 minor uncharacterized isoforms. According to ACMG/AMP-based standards, 15 variants could be classified as pathogenic or likely pathogenic variants: c.404G > A, c.405-6T > A, c.571 + 4A > G, c.571 + 5G > A, c.572-1G > T, c.705G > T, c.706-2A > C, c.706-2A > G, c.837 + 2T > C, c.905-3C > G, c.905-2A > C, c.905-2_905-1del, c.965 + 5G > A, c.1026 + 5_1026 + 7del, and c.1026 + 5G > T.","variants":[{"Name":"NM_058216.3(RAD51C):c.571+4A>G","Chromosome":"17","Start":"58696863","Stop":"58696863","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":133664,"rule_based_match":true,"evidence_text":"c.571 + 4A > G","llm_judgment":"PRESENT","evidence":"c.571 + 4A > G","abstract_start":1356,"abstract_end":1370},{"Name":"NM_058216.3(RAD51C):c.706-2A>G","Chromosome":"17","Start":"58709857","Stop":"58709857","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":133666,"rule_based_match":true,"evidence_text":"c.706-2A>G","llm_judgment":"PRESENT","evidence":"c.706-2A > G","abstract_start":1428,"abstract_end":1440},{"Name":"NM_058216.3(RAD51C):c.571+5G>A","Chromosome":"17","Start":"58696864","Stop":"58696864","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":213348,"rule_based_match":true,"evidence_text":"c.571 + 5G > A","llm_judgment":"PRESENT","evidence":"c.571 + 5G > A","abstract_start":1372,"abstract_end":1386},{"Name":"NM_058216.3(RAD51C):c.705G>T (p.Lys235Asn)","Chromosome":"17","Start":"58703329","Stop":"58703329","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":213350,"rule_based_match":true,"evidence_text":"c.705G>T","llm_judgment":"PRESENT","evidence":"c.705G > T","abstract_start":1402,"abstract_end":1412},{"Name":"NM_058216.3(RAD51C):c.905-2A>C","Chromosome":"17","Start":"58724038","Stop":"58724038","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":213354,"rule_based_match":true,"evidence_text":"c.905-2A>C","llm_judgment":"PRESENT","evidence":"c.905-2A > C","abstract_start":1472,"abstract_end":1484},{"Name":"NM_058216.3(RAD51C):c.965+5G>A","Chromosome":"17","Start":"58724105","Stop":"58724105","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":402642,"rule_based_match":true,"evidence_text":"c.965 + 5G > A","llm_judgment":"PRESENT","evidence":"c.965 + 5G > A","abstract_start":1504,"abstract_end":1518},{"Name":"NM_058216.3(RAD51C):c.1026+5_1026+7del","Chromosome":"17","Start":"58732548","Stop":"58732550","ReferenceAlleleVCF":"CAGT","AlternateAlleleVCF":"C","allel_id":133658,"rule_based_match":true,"evidence_text":"c.1026 + 5_1026 + 7del","llm_judgment":"PRESENT","evidence":"c.1026 + 5_1026 + 7del","abstract_start":1520,"abstract_end":1542},{"Name":"NM_058216.3(RAD51C):c.404G>A (p.Cys135Tyr)","Chromosome":"17","Start":"58695189","Stop":"58695189","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":236214,"rule_based_match":true,"evidence_text":"c.404G > A","llm_judgment":"PRESENT","evidence":"c.404G > A","abstract_start":1330,"abstract_end":1340},{"Name":"NM_058216.3(RAD51C):c.706-2A>C","Chromosome":"17","Start":"58709857","Stop":"58709857","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":619734,"rule_based_match":true,"evidence_text":"c.706-2A>C","llm_judgment":"PRESENT","evidence":"c.706-2A > C","abstract_start":1414,"abstract_end":1426},{"Name":"NM_058216.3(RAD51C):c.905-2_905-1del","Chromosome":"17","Start":"58724038","Stop":"58724039","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":151482,"rule_based_match":true,"evidence_text":"c.905-2_905-1del","llm_judgment":"PRESENT","evidence":"c.905-2_905-1del","abstract_start":1486,"abstract_end":1502}]}
{"pmid":"32012848","title":"Novel Mutations Found in Individuals with Adult-Onset Pompe Disease.","abstract":"Pompe disease, or glycogen storage disease II is a rare, progressive disease leading to skeletal muscle weakness due to deficiency of the acid α-1,4-glucosidase enzyme (GAA). The severity of disease and observed time of onset is subject to the various combinations of heterozygous <i>GAA</i> alleles. Here we have characterized two novel mutations: c.2074C>T and c.1910_1918del, and a previously reported c.1082C>G mutation of uncertain clinical significance. These mutations were found in three unrelated patients with adult-onset Pompe disease carrying the common c.-32-13T>G mutation. The c.2074 C>T nonsense mutation has obvious consequences on <i>GAA</i> expression but the c.1910_1918del (deletion of 3 amino acids) and c.1082C>G missense variants are more subtle DNA changes with catastrophic consequences on GAA activity. Molecular and clinical analyses from the three patients corresponded with the anticipated pathogenicity of each mutation.","variants":[{"Name":"NM_000152.5(GAA):c.1910_1918del (p.Leu637_Val639del)","Chromosome":"17","Start":"80112894","Stop":"80112902","ReferenceAlleleVCF":"CTGCTGGGGG","AlternateAlleleVCF":"C","allel_id":798952,"rule_based_match":true,"evidence_text":"c.1910_1918del","llm_judgment":"PRESENT","evidence":"c.1910_1918del","abstract_start":363,"abstract_end":377},{"Name":"NM_000152.5(GAA):c.2074C>T (p.Gln692Ter)","Chromosome":"17","Start":"80113251","Stop":"80113251","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":798953,"rule_based_match":true,"evidence_text":"c.2074C>T","llm_judgment":"PRESENT","evidence":"c.2074C>T","abstract_start":349,"abstract_end":358},{"Name":"NM_000152.5(GAA):c.-32-13T>G","Chromosome":"17","Start":"80104542","Stop":"80104542","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":19066,"rule_based_match":true,"evidence_text":"c.-32-13T>G","llm_judgment":"PRESENT","evidence":"c.-32-13T>G","abstract_start":566,"abstract_end":577},{"Name":"NM_000152.5(GAA):c.1082C>G (p.Pro361Arg)","Chromosome":"17","Start":"80108495","Stop":"80108495","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":273604,"rule_based_match":true,"evidence_text":"c.1082C>G","llm_judgment":"PRESENT","evidence":"c.1082C>G","abstract_start":405,"abstract_end":414}]}
{"pmid":"36171877","title":"Detection of BRCA1/2 pathogenic variants in patients with breast and/or ovarian cancer and their families. Analysis of 3,458 cases from Lower Silesia (Poland) according to the diagnostic algorithm of the National Cancer Control Programme.","abstract":"Breast and ovarian cancers are among the most common malignancies in the female population, with approximately 5-10% of cases being hereditary. <i>BRCA1</i> and <i>BRCA2</i> with other homologous recombination genes are the most tested genes in hereditary breast and ovarian cancer (HBOC) patients. As next-generation sequencing (NGS) has become a standard and popular technique, such as for HBOC, it has greatly simplified and accelerated molecular diagnosis of cancer. The study group included 3,458 HBOC patients or their relatives from Lower Silesia (Poland) (a voivodeship located in south-west Poland inhabited by 2.9 million people). All patients were tested according to the recommendations from the National Cancer Control Programme of the Ministry of Health for the years 2018-21. We tested 3,400 patients for recurrent pathogenic variants for the Polish population: five <i>BRCA1</i> founder variants (c.5266dup, c.181T>G, c.4035del, c.3700_3704del, and c.68_69del), two <i>PALB2</i> variants (c.509_510del, c.172_175del) and three <i>CHEK2</i> variants [c.1100del, c.444+1G>A, g.27417113-27422508del (del5395)]. Next 260 patients from the study group were chosen for the <i>BRCA1/2</i> NGS panel, and additionally selected marker pathogenic variants were tested using Sanger sequencing and MLPA methods in 45 and 13 individuals, respectively. The analysis of <i>BRCA1/2</i> in the 3,458 patients with HBOC or their relatives revealed 144 carriers of 37 different pathogenic variants (22 in <i>BRCA1</i> and 15 in <i>BRCA2</i>). Among all detected variants, 71.53% constituted founder pathogenic <i>BRCA1</i> variants. Our study has revealed that for the Lower Silesian population, the first-line <i>BRCA1/2</i> molecular test may be limited to only three variants in <i>BRCA1</i>-c.5266dup, c.181T>G, and c.4035del-but the aim should be to provide a full screening test of HBOC critical genes. The key and still growing role of molecular diagnostics of neoplasms, which includes HBOC, is undeniable. Therefore, it is necessary to provide complete and optimal therapeutic and prophylactic algorithms in line with current medical knowledge.","variants":[{"Name":"NM_007294.4(BRCA1):c.3700_3704del (p.Val1234fs)","Chromosome":"17","Start":"43091827","Stop":"43091831","ReferenceAlleleVCF":"GTTTAC","AlternateAlleleVCF":"G","allel_id":46098,"rule_based_match":true,"evidence_text":"c.3700_3704del","llm_judgment":"PRESENT","evidence":"c.3700_3704del","abstract_start":945,"abstract_end":959}]}
{"pmid":"17968484","title":"Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency.","abstract":"Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency appears to be the most frequent organic aciduria detected in tandem mass spectrometry (MS/MS) screening programs in the United States, Australia, and Europe. A pilot study of newborn screening using MS/MS has recently been commenced in Japan. Our group detected two asymptomatic MCC deficiency patients by the pilot screening and collected data on another three MCC deficiency patients to study the molecular bases of the MCC deficiency in Japan. Molecular analyses revealed novel mutations in one of the causative genes, MCCA or MCCB, in all five of the patients: nonsense and frameshift mutations in MCCA (c.1750C > T/c.901_902delAA) in patient 1, nonsense and frameshift mutations in MCCB (c.1054_1055delGG/c.592C > T) in patient 2, frameshift and missense mutations in MCCB (c.1625_1626insGG/c.653_654CA > TT) in patient 3, a homozygous missense mutation in MCCA (c.1380T > G/ 1380T > G) in patient 4, and compound heterozygous missense mutations in MCCB (c.569A > G/ c.838G > T) in patient 5. No obvious clinical symptoms were observed in patients 1, 2, and 3. Patient 4 had severe neurological impairment and patient 5 developed Reye-like syndrome. The increasing use of MS/MS newborn screening in Japan will further clarify the clinical and genetic heterogeneity among patients with MCC deficiency in the Japanese population.","variants":[{"Name":"NM_022132.5(MCCC2):c.592C>T (p.Gln198Ter)","Chromosome":"5","Start":"71604436","Stop":"71604436","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1086980,"rule_based_match":true,"evidence_text":"c.592C > T","llm_judgment":"PRESENT","evidence":"c.592C > T","abstract_start":769,"abstract_end":779},{"Name":"NM_022132.5(MCCC2):c.569A>G (p.His190Arg)","Chromosome":"5","Start":"71604413","Stop":"71604413","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":16965,"rule_based_match":true,"evidence_text":"c.569A > G","llm_judgment":"PRESENT","evidence":"c.569A > G","abstract_start":1019,"abstract_end":1029},{"Name":"NM_020166.5(MCCC1):c.1380T>G (p.Ile460Met)","Chromosome":"3","Start":"183037432","Stop":"183037432","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":16974,"rule_based_match":true,"evidence_text":"c.1380T > G/ 1380T > G","llm_judgment":"PRESENT","evidence":"c.1380T > G/ 1380T > G","abstract_start":927,"abstract_end":949}]}
{"pmid":"19806373","title":"Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant.","abstract":"The Forkhead box G1 (FOXG1) is a transcription factor that is critical for forebrain development, where it promotes progenitor proliferation and suppresses premature neurogenesis. Recently, the FOXG1 gene was implicated in the molecular aetiology of the congenital variant of Rett syndrome. So far, 15 FOXG1 molecular alterations, including only eight point mutations, have been reported. We screened the FOXG1 gene in a cohort of 206 MECP2 and CDKL5 mutation negative patients (136 females and 70 males) with severe encephalopathy and microcephaly. The screening was negative in all males, but two de novo mutations (c.1248C>G, p.Y416X and c.460_461dupG, p.E154GfsX300) were identified in two unrelated girls. Both patients showed neurological symptoms from the neonatal period with poor reactivity, hypotonia, and severe microcephaly. During the first year of life, both patients had feeding difficulties and made slow developmental progress. At 5 years old, the girls were significantly neurologically impaired with gross hypotonia, no language, convergent strabismus, and no voluntary hand use. Moreover, they presented a combination of jerky movements, hand-mouthing, and hand-washing stereotypies. Hence, FOXG1 mutation patients demonstrate severe encephalopathy compatible with the congenital variant, as well as additional features such as absent eye contact, inconsolable crying during the perinatal period, and delayed myelination with thin to hypoplastic corpus callosum. Although the overall frequency of mutations in FOXG1 in females with severe mental retardation and microcephaly appears to be low (1.5%), our findings suggest the requirement to investigate both point mutations and gene dosage in the FOXG1 gene in patients with severe encephalopathy with microcephaly and some Rett-like features.","variants":[{"Name":"NM_005249.5(FOXG1):c.1248C>G (p.Tyr416Ter)","Chromosome":"14","Start":"28768527","Stop":"28768527","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":187415,"rule_based_match":true,"evidence_text":"c.1248C>G, p.Y416X","llm_judgment":"PRESENT","evidence":"c.1248C>G, p.Y416X","abstract_start":618,"abstract_end":636},{"Name":"NM_005249.5(FOXG1):c.460dup (p.Glu154fs)","Chromosome":"14","Start":"28767732","Stop":"28767733","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":101167,"rule_based_match":false,"evidence_text":"c.460_461dupG","llm_judgment":"PRESENT","evidence":"c.460_461dupG","abstract_start":641,"abstract_end":654}]}
{"pmid":"36513904","title":"Two unique BAP1 pathogenic variants identified in the same family by panel cascade testing.","abstract":"Germline pathogenic variants in the tumor suppressor gene BAP1 are associated with the hereditary tumor predisposition syndrome with susceptibility to uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and other cancers. Germline BAP1 pathogenic variants are rare in the non-cancer general population with an estimated carrier frequency of 1:19,898 but more common in cancer patients with a carrier frequency of 1:1299. In the following we present the first report of a family with two unique BAP1 pathogenic variants. Retrospective case report of a family with two unique pathogenic variants in BAP1. A male (proband) was referred to our ocular oncology clinic for second opinion for his multiple independent uveal melanomas at ages 65, 68 and 71. Given his personal history of squamous cell carcinoma at age 61, renal cell carcinoma at age 63, and family history of atypical meningioma, basal cell carcinoma, pancreatic and prostate cancers he was assessed for germline pathogenic variants in BAP1 through our ongoing research study. Sanger sequencing identified the American founder pathogenic variant, c.1717delC, pL573Wfs*3, that was confirmed in a clinical laboratory. Both the proband's brother and nephew tested negative for the familial variant through single site cascade genetic testing. However, based on the personal history of multiple basal cell carcinoma in the nephew and family history of pancreatic and laryngeal cancers (both not known to be associated with BAP1-TPDS), a large cancer panel testing was recommended for the nephew. His panel testing revealed a different BAP1 pathogenic variant, c.605G>A, p. Trp202*. This variant was not detected in the proband or the proband's brother. Based on the frequency of germline BAP1 variants in the cancer population, the chance of occurrence of two different BAP1 variants in a family with cancer history is 5.9 × 10<sup>-7</sup>. This case report provides support for the importance of offering large panel cascade genetic testing, rather than single site testing for only the family pathogenic variant, for all at risk family members especially when the family variant cannot explain all the cancers in the family.","variants":[{"Name":"NM_004656.4(BAP1):c.605G>A (p.Trp202Ter)","Chromosome":"3","Start":"52406883","Stop":"52406883","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1436368,"rule_based_match":true,"evidence_text":"c.605G>A, p. Trp202*","llm_judgment":"PRESENT","evidence":"c.605G>A, p. Trp202*","abstract_start":1636,"abstract_end":1656}]}
{"pmid":"24377952","title":"Sjögren-Larsson syndrome: optical coherence tomography and a novel mutation.","abstract":"CASE REPORT: A case is presented of a thirty year-old male with ichthyosis, mental retardation, epilepsy and spasticity. Ocular examination showed a best-corrected visual acuity of 0.5 and bilateral crystalline maculopathy. Optical coherence tomography (OCT) revealed focal hyperreflective spots and intrafoveal microcystoid spaces. The diagnosis of Sjögren-Larsson syndrome (SLS) was made, and confirmed by genetic analysis.\nDISCUSSION: SLS is caused by mutations in the ALDH3A2 gene. A previously unreported novel mutation was identified, c.681-14T>G. Macular OCT makes it possible to find even funduscopy invisible changes. Its use is important because the OCT features of SLS are specific and, therefore, it can help to diagnose this rare systemic disease.","variants":[{"Name":"NM_000382.3(ALDH3A2):c.681-14T>G","Chromosome":"17","Start":"19657731","Stop":"19657731","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":445724,"rule_based_match":true,"evidence_text":"c.681-14T>G","llm_judgment":"PRESENT","evidence":"c.681-14T>G","abstract_start":541,"abstract_end":552}]}
{"pmid":"24535598","title":"Detection of CRB1 mutations in families with retinal dystrophy through phenotype-oriented mutational screening.","abstract":"Mutations in the crumbs homolog (CRB)1 gene are among the common causes of severe early onset retinal dystrophy. Some characteristic clinical phenotypes are frequently associated with mutations in CRB1. The aim of this study was to examine whether characteristic phenotype-directed mutational screening facilitated the detection of CRB1 mutations. The study included 22 probands with at least one of the potential CRB1-associated phenotypes for retinal dystrophy. Variants were detected using Sanger sequencing. The complete sequences of the coding and adjacent intronic regions of CRB1 were analyzed, revealing homozygous or compound heterozygous mutations in CRB1 in seven of 22 probands, involving six novel (c.136delA, c.1841G>T, c.3017C>A, c.3488G>T, c.3991C>T and c.4089dupTGTTGCTT) and four known (c.2222T>C, c.2671T>G, c.3676G>T and c.4005+2T>G) mutations. The mutations were present in three of four probands with macular nummular pigmentation and in four of seven probands with early onset retinitis pigmentosa with macular involvement. The results suggested that macular nummular pigmentation is a gene-specific indication for CRB1‑associated retinal dystrophy and confirm that CRB1 mutations are also common causes of early onset retinitis pigmentosa. Identification of gene-specific phenotypes is uselful in identifying genetic defects underlying heterogeneous retinal dystrophy.","variants":[{"Name":"NM_201253.3(CRB1):c.3991C>T (p.Arg1331Cys)","Chromosome":"1","Start":"197442278","Stop":"197442278","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":855900,"rule_based_match":true,"evidence_text":"c.3991C>T","llm_judgment":"PRESENT","evidence":"c.3991C>T","abstract_start":756,"abstract_end":765},{"Name":"NM_201253.3(CRB1):c.3017C>A (p.Ser1006Tyr)","Chromosome":"1","Start":"197434880","Stop":"197434880","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2543901,"rule_based_match":true,"evidence_text":"c.3017C>A","llm_judgment":"PRESENT","evidence":"c.3017C>A","abstract_start":734,"abstract_end":743},{"Name":"NM_201253.3(CRB1):c.3488G>T (p.Cys1163Phe)","Chromosome":"1","Start":"197435351","Stop":"197435351","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":823134,"rule_based_match":true,"evidence_text":"c.3488G>T","llm_judgment":"PRESENT","evidence":"c.3488G>T","abstract_start":745,"abstract_end":754},{"Name":"NM_201253.3(CRB1):c.1841G>T (p.Gly614Val)","Chromosome":"1","Start":"197421669","Stop":"197421669","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":930207,"rule_based_match":true,"evidence_text":"c.1841G>T","llm_judgment":"PRESENT","evidence":"c.1841G>T","abstract_start":723,"abstract_end":732}]}
{"pmid":"23932794","title":"Changing c.106delG (p.Ala36fs*6) loss syndrome associated with congenital Finnish type: first case diagnosed in Togo","abstract":"OBJECTIVE: To report the first case of congenital nephrotic syndrome of the Finnish type (SNCF) in Togo associated with a new mutation of NPHS1.\nOBSERVATION: Our study focused on a female infant of 10months, born premature at 34weeks 6days, followed from birth to pure SNC discovered the 10th day of life. Monitoring and pregnancy outcome unremarkable. It is the third in a family of three children, the first two are killed in a similar table but not explored before 1year of age. The diagnosis is confirmed by the SNCF genetic study NPHS1 gene encoding nephrin performed in our patient and her parents showed a double mutation of which c.[106delG]+[2728T>C] and p. at the nucleotide level. [Ala36fs*6]+[Ser91OPro] at the protein level inherited from each parent. The change was made to the 10th month of death in life after sepsis in a third of cortico-resistance.\nCONCLUSION: The SNCF, autosomal recessive disease early, which remains a serious diagnosis, is genetic. This new mutation could she explained the severity of the SNCF in this family?","variants":[{"Name":"NM_004646.4(NPHS1):c.2728T>C (p.Ser910Pro)","Chromosome":"19","Start":"35841802","Stop":"35841802","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1056564,"rule_based_match":false,"evidence_text":"c.2728T>C","llm_judgment":"PRESENT","evidence":"c.2728T>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"38493358","title":"A loss of function mutation in CLDN25 causing Pelizaeus-Merzbacher-like leukodystrophy.","abstract":"Claudin-25 (CLDN-25), also known as Claudin containing domain 1, is an uncharacterized claudin family member. It has less conserved amino acid sequences when compared to other claudins. It also has a very broad tissue expression profile and there is currently a lack of functional information from murine knockout models. Here, we report a de novo missense heterozygous variant in CLDN25 (c. 745G>C, p. A249P) found in a patient diagnosed with Pelizaeus-Merzbacher-like leukodystrophy and presenting with symptoms such as delayed motor development, several episodes of tonic absent seizures and generalized dystonia. The variant protein does not localize to the cell-cell borders where it would normally be expected to be expressed. Amino acid position 249 is located 4 amino acids from the C-terminal end of the protein where most claudin family members have a conserved binding motif for the key scaffolding protein ZO-1. However, CLDN-25 does not contain this motif. Here, we show that the C-terminal end of CLDN-25 is required for its junctional localization in a ZO-1 independent manner. The A249P mutant protein as well as a deletion mutant lacking its last 5 C-terminal amino acids also failed to localize to the cell-cell border in vitro. Intriguingly, cellular knockout of CLDN25, in vitro, appeared to increase the integrity of the tight junction between 2 contacting cells, while driving highly unusual increased movement of solutes between cells. We propose that the barrier function of CLDN-25 is akin to a decoy claudin, whereby decreasing its expression in \"leaky\" epithelial cells and endothelial cells will drive dynamic changes in the adhesion and interaction capacity of cell-cell contact points. While it remains unclear how this de novo CLDN-25 mutant induces leukodystrophy, our findings strongly suggest that this mutation induces haploinsufficiency of CLDN-25. Elucidating the function of this uncharacterized claudin protein will lead to a better understanding of the role of claudin proteins in health and disease.","variants":[{"Name":"NM_001040181.2(CLDND1):c.745G>C (p.Ala249Pro)","Chromosome":"3","Start":"98516676","Stop":"98516676","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3494613,"rule_based_match":true,"evidence_text":"c. 745G>C, p. A249P","llm_judgment":"PRESENT","evidence":"c. 745G>C, p. A249P","abstract_start":389,"abstract_end":408}]}
{"pmid":"23031740","title":"Li-Fraumeni syndrome with simultaneous osteosarcoma and liver cancer: increased expression of a CD44 variant isoform after chemotherapy.","abstract":"BACKGROUND: Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome that is commonly associated with a germline mutation in the tumor suppressor gene p53. Loss of p53 results in increased expression of CD44, a cancer stem cell (CSC) marker, which is involved in the scavenging of reactive oxygen species (ROS). Here, we report a change in the expression of a CD44 variant isoform (CD44v8-10) in an 8-year-old female LFS patient with osteosarcoma and atypical liver cancer after chemotherapy.\nCASE PRESENTATION: The patient visited a clinic with a chief complaint of chronic pain in a bruise on her right knee. Magnetic resonance imaging (MRI) raised the possibility of a bone malignancy. Biochemical testing also revealed significantly elevated levels of AFP, which strongly suggested the existence of a primary malignancy in the liver. MRI imaging showed the simultaneous development of osteosarcoma and liver cancer, both of which were confirmed upon biopsy. Combined therapy with surgical resection after chemotherapy was successful in this patient. Regardless of the absence of a familial history of hereditary cancer, a germline mutation in p53 was identified (a missense mutation defined as c.722 C>T, p.Ser241Phe). To better understand the cancer progression and response to treatment, immunohistochemical (IHC) analysis of biopsy specimens obtained before and after chemotherapy was performed using a specific antibody against CD44v8-10.\nCONCLUSION: This case demonstrates the ectopic up-regulation of CD44v8-10 in a biopsy sample obtained after cytotoxic chemotherapy, which confers high levels of oxidative stress on cancer cells. Because the alternative splicing of CD44 is tightly regulated epigenetically, it is possible that micro-environmental stress resulting from chemotherapy caused the ectopic induction of CD44v8-10 in vivo.","variants":[{"Name":"NM_000546.6(TP53):c.722C>T (p.Ser241Phe)","Chromosome":"17","Start":"7674241","Stop":"7674241","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27398,"rule_based_match":true,"evidence_text":"c.722 C>T (p.Ser241Phe)","llm_judgment":"PRESENT","evidence":"p.Ser241Phe","abstract_start":1226,"abstract_end":1237}]}
{"pmid":"25256213","title":"Muscle fiber type disproportion (FTD) in a family with mutations in the LMNA gene.","abstract":"INTRODUCTION: Mutations in the lamin A/C protein cause laminopathies, a heterogeneous group of disorders that include recessive axonal neuropathy (CMT2B1), Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), dilated cardiomyopathy with conduction defect, and different forms of lipodystrophy and progeria.\nMETHODS: We provide clinical, histopathological, muscle imaging, and cardiac features of a family with heterozygous mutation in the LMNA gene.\nRESULTS: We identified heterozygous mutations (c.80C> T; pT27I) in the LMNA gene in 3 family members who had the LGMD phenotype with onset in their early thirties and cardiac conduction defects or dilated cardiomyopathy. Interestingly, muscle biopsies showed changes consistent with fiber type disproportion (FTD).\nCONCLUSIONS: Fiber type disproportion has been reported only anecdotally in muscle biopsies of patients with LMNA mutations. Our report further supports this association and suggests inclusion of molecular testing for LMNA in the differential diagnosis of myopathies with FTD due to the risk for life threatening events.","variants":[{"Name":"NM_170707.4(LMNA):c.80C>T (p.Thr27Ile)","Chromosome":"1","Start":"156114998","Stop":"156114998","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":792654,"rule_based_match":true,"evidence_text":"c.80C> T; pT27I","llm_judgment":"PRESENT","evidence":"c.80C> T; pT27I","abstract_start":525,"abstract_end":540}]}
{"pmid":"33832920","title":"Bloom syndrome in a Mexican American family with rhabdomyosarcoma: evidence of a Mexican founder mutation.","abstract":"Bloom syndrome is a rare autosomal recessive disorder with less than 300 cases reported in the literature. Bloom syndrome is characterized by chromosome instability, physical stigmata, growth deficiency, immunodeficiency, and a predisposition to cancer, most commonly leukemias, although solid tumors are reported as well. Bloom syndrome occurs in multiple ethnic groups with a higher incidence in persons of Ashkenazi Jewish origin. Few patients of Hispanic ethnicity have been reported. We report here a Mexican American family with a <i>BLM</i> pathogenic variant, c.2506_2507delAG, previously reported in a single patient from Mexico. In this family of four siblings, three have phenotypic features of Bloom syndrome, and <i>BLM</i> gene mutation was homozygous in these affected individuals. Our proband developed a rhabdomyosarcoma. Analysis of surrounding markers in the germline DNA revealed a common haplotype, suggesting a previously unrecognized founder mutation in the Hispanic population of Mexican origin.","variants":[{"Name":"NM_000057.4(BLM):c.2506_2507del (p.Arg836fs)","Chromosome":"15","Start":"90769537","Stop":"90769538","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":51237,"rule_based_match":true,"evidence_text":"c.2506_2507delAG","llm_judgment":"PRESENT","evidence":"c.2506_2507delAG","abstract_start":568,"abstract_end":584}]}
{"pmid":"25211641","title":"First Japanese family with primary familial brain calcification due to a mutation in the PDGFB gene: an exome analysis study.","abstract":"AIMS: Primary familial brain calcification (PFBC) is a rare disorder characterized by abnormal deposits of calcium in the basal ganglia and cerebellum. PFBC can present with a spectrum of neuropsychiatric symptoms resembling those seen in dementia and schizophrenia. Mutations in a few genes have been identified as causing PFBC: namely, the SLC20A2 gene that codes for the sodium-dependent phosphate transporter and the PDGFRB gene that codes for the platelet-derived growth factor receptor β (PDGF-Rβ). A recent study identified mutations in PDGFB coding for PDGF-B, the main ligand for PDGF-Rβ, in six families with PFBC. Here we report the first Japanese family with PFBC carrying a mutation in PDGFB, which causes the substitution of an arginine with a stop codon at amino acid 149 of the PDGF-B protein (p. Arg149*).\nMETHODS: Clinical histories and computed tomography scan images were provided. Sanger sequencing was performed for the exome analysis of SLC20A2 and PDGFB genes.\nRESULTS: One family member began to complain of auditory hallucination at 16 years of age and had been treated for schizophrenia. His father suffered from memory and gait disturbances in his late 60s. A computed tomography scan revealed a symmetrical area of calcification over the basal ganglia in both cases. A known mutation in PDGFB (c.445C>T, p.Arg149*) was consistently detected in both PFBC cases by Sanger sequencing. No mutations in SLC20A2 were detected.\nCONCLUSIONS: Our findings suggest that this mutation in PDGF-B is responsible for PFBC in this Japanese family and that abnormal PDGF signaling may be involved in the pathophysiology of certain psychiatric disorders.","variants":[{"Name":"NM_002608.4(PDGFB):c.445C>T (p.Arg149Ter)","Chromosome":"22","Start":"39231633","Stop":"39231633","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":86134,"rule_based_match":true,"evidence_text":"c.445C>T (p.Arg149*)","llm_judgment":"PRESENT","evidence":"p.Arg149*","abstract_start":1333,"abstract_end":1342}]}
{"pmid":"33473340","title":"Genetic characterization of the Albanian Gaucher disease patient population.","abstract":"Gaucher disease (GD) is a recessive metabolic disorder caused by a deficiency of the <i>GBA</i> gene-encoded enzyme β-glucocerebrosidase. We characterized a cohort of 36 Albanian GD patients, 31 with GD type 1 and 5 affected by GD types 2, 3, and an intermediate GD phenotype between type 2 and type 3. Of the 12 different <i>GBA</i> alleles that we detected, the most frequently observed was p.Asn409Ser, followed by p.[Asp448His;His294Gln]. The prevalence of the p.Leu483Pro allele was approximately 10-fold lower than reported in other populations. We identified a novel pathogenic missense variant (c.1129G>A; p.Ala377Thr). All five of our non-type 1 patients had genotypes consisting of the p.[Asp448His;His294Gln] allele in combination with another severe <i>GBA</i> allele. The median Lyso-Gb1 level of treated patients carrying the p.[Asp448His;His294Gln] and no p.Asn409Ser allele was significantly higher than that of treated individuals homozygous or compound heterozygous for the p.Asn409Ser allele. In conclusion, the most important distinguishing features of the Albanian GD patient population are the underrepresentation of the p.Leu483Pro allele and an unusually high number of p.[Asp448His;His294Gln] alleles originating from a common Balkan founder event. The presence of at least one p.Asn409Ser allele is associated with mild disease and low Lyso-Gb1 biomarker levels, while compound heterozygosity involving p.[Asp448His;His294Gln] and no p.Asn409Ser entails severe phenotypes and high Lyso-Gb1 levels.","variants":[{"Name":"NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)","Chromosome":"1","Start":"155235843","Stop":"155235843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":19329,"rule_based_match":false,"evidence_text":"p.Asn409Ser","llm_judgment":"PRESENT","evidence":"p.Asn409Ser","abstract_start":393,"abstract_end":404}]}
{"pmid":"24583203","title":"Novel de novo SPOCK1 mutation in a proband with developmental delay, microcephaly and agenesis of corpus callosum.","abstract":"Whole exome sequencing made it possible to identify novel de novo mutations in genes that might be linked to human syndromes (genotype first analysis). We describe a female patient with a novel de novo SPOCK1 variant, which has not been previously been associated with a human phenotype. Her features include intellectual disability with dyspraxia, dysarthria, partial agenesis of corpus callosum, prenatal-onset microcephaly and atrial septal defect with aberrant subclavian artery. Previous genetic, cytogenomic and metabolic studies were unrevealing. At age 13 years, exome sequencing on the patient and her parents revealed a de novo novel missense mutation in SPOCK1 (coding for Testican-1) on chromosome 5q31: c.239A>T (p.D80V). This mutation affects a highly evolutionarily conserved area of the gene, replacing a polar aspartic acid with hydrophobic nonpolar valine, and changing the chemical properties of the protein product, likely representing a pathogenic variant. Previous microdeletions of 5q31 including SPOCK1 have suggested genes on 5q31 as candidates for intellectual disability. No mutations or variants in other genes potentially linked to her phenotype were identified. Testicans are proteoglycans belonging to the BM-40/SPARC/osteonectin family of extracellular calcium-binding proteins. Testican-1 is encoded by the SPOCK1 gene, and mouse models have been shown it to be strongly expressed in the brain and to be involved in neurogenesis. We hypothesize that because this gene function is critical for neurogenesis, mutations could potentially lead to a phenotype with developmental delay and microcephaly.","variants":[{"Name":"NM_004598.4(SPOCK1):c.239A>T (p.Asp80Val)","Chromosome":"5","Start":"137140688","Stop":"137140688","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":132589,"rule_based_match":true,"evidence_text":"c.239A>T (p.D80V)","llm_judgment":"PRESENT","evidence":"c.239A>T (p.D80V)","abstract_start":716,"abstract_end":733}]}
{"pmid":"35846276","title":"Case Report: Inactivating PTH/PTHrP Signaling Disorder Type 1 Presenting With PTH Resistance.","abstract":"PTH resistance is characterized by elevated parathyroid hormone (PTH) levels, hypocalcemia, hyperphosphatemia and it is classically associated with <i>GNAS</i> locus genetic or epigenetic defects. Inactivating PTH/PTHrP signaling disorders (iPPSD) define overlapping phenotypes based on their molecular etiology. iPPSD1 is associated with <i>PTH1R</i> variants and variable phenotypes including ossification anomalies and primary failure of tooth eruption but no endocrine disorder. Here we report on a 10-month-old child born from consanguineous parents, who presented with mild neurodevelopmental delay, seizures, enlarged fontanelles, round face, and bilateral clinodactyly. Hand x-rays showed diffuse delayed bone age, osteopenia, short metacarpal bones and cone-shaped distal phalanges. A diagnosis of PTH resistance was made on the basis of severe hypocalcemia, hyperphosphatemia, elevated PTH and normal vitamin D levels on blood sample. The patient was treated with calcium carbonate and alfacalcidol leading to rapid bio-clinical improvement. Follow-up revealed multiple agenesis of primary teeth and delayed teeth eruption, as well as Arnold-Chiari type 1 malformation requiring a ventriculoperitoneal shunt placement. <i>GNAS</i> gene analysis showed no pathogenic variation, but a likely pathogenic homozygous substitution c.723C>G p.(Asp241Glu) in <i>PTH1R</i> gene was found by trio-based whole exome sequencing. We studied the deleterious impact of the variant on the protein conformation with bioinformatics tools. In conclusion, our study reports for the first time PTH resistance in a child with a biallelic <i>PTH1R</i> mutation, extending thereby the clinical spectrum of iPPSD1 phenotypes.","variants":[{"Name":"NM_000316.3(PTH1R):c.723C>G (p.Asp241Glu)","Chromosome":"3","Start":"46898746","Stop":"46898746","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1292186,"rule_based_match":true,"evidence_text":"c.723C>G p.(Asp241Glu)","llm_judgment":"PRESENT","evidence":"c.723C>G p.(Asp241Glu)","abstract_start":1335,"abstract_end":1357}]}
{"pmid":"27456987","title":"A novel MIP mutation in familial congenital nuclear cataracts.","abstract":"We screened 60 known genes which are involved in inherited cataract in a pregnant woman with a four-generation family history of autosomal dominant congenital nuclear cataract through next-generation sequencing (NGS) and identified a heterozygous mutation, c.508dupC (p.L170fs), in the major intrinsic protein (MIP) gene. This mutation results in a frame-shift in MIP and has not been previously reported. The correlation of the mutation with disease was validated by Sanger sequencing of DNA from the other affected or unaffected members of the family. Therefore, our data expand the mutation spectrum of MIP mutation, and suggest that NGS is an accurate, rapid, and cost-effective method in the genetic diagnosis of congenital nuclear cataract.","variants":[{"Name":"NM_012064.4(MIP):c.508dup (p.Leu170fs)","Chromosome":"12","Start":"56453607","Stop":"56453608","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":364277,"rule_based_match":true,"evidence_text":"c.508dupC (p.L170fs)","llm_judgment":"PRESENT","evidence":"c.508dupC (p.L170fs)","abstract_start":257,"abstract_end":277}]}
{"pmid":"33381078","title":"Genetic and Clinical Features in 24 Chinese Distal Hereditary Motor Neuropathy Families.","abstract":"<b>Background and Objectives:</b> Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuropathies. The objectives of this study were to report the clinical and genetic features of dHMN patients in a Chinese cohort. <b>Aims and Methods:</b> We performed clinical assessments and whole-exome sequencing in 24 dHMN families from Mainland China. We conducted a retrospective analysis of the data and investigated the frequency and clinical features of patients with a confirmed mutation. <b>Results:</b> Two novel heterozygous mutations in <i>GARS</i>, c.373G>C (p.E125Q) and c.1015G>A (p.G339R), were identified and corresponded to the typical dHMN-V phenotype. Together with families with <i>WARS, SORD, SIGMAR1</i>, and <i>HSPB1</i> mutations, 29.2% of families (7/24) acquired a definite genetic diagnosis. One novel heterozygous variant of uncertain significance, c.1834G>A (p.G612S) in <i>LRSAM1</i>, was identified in a patient with mild dHMN phenotype. <b>Conclusion:</b> Our study expanded the mutation spectrum of <i>GARS</i> mutations and added evidence that <i>GARS</i> mutations are associated with both axonal Charcot-Marie-Tooth and dHMN phenotypes. Mutations in genes encoding aminoamide tRNA synthetase (ARS) might be a frequent cause of autosomal dominant-dHMN, and <i>SORD</i> mutation might account for a majority of autosomal recessive-dHMN cases. The relatively low genetic diagnosis yield indicated more causative dHMN genes need to be discovered.","variants":[{"Name":"NM_002047.4(GARS1):c.1015G>A (p.Gly339Arg)","Chromosome":"7","Start":"30612229","Stop":"30612229","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1316471,"rule_based_match":true,"evidence_text":"c.1015G>A (p.G339R)","llm_judgment":"PRESENT","evidence":"c.1015G>A (p.G339R)","abstract_start":628,"abstract_end":647}]}
{"pmid":"31803247","title":"A","abstract":"Autosomal dominant mental retardation-7 (MRD7) is a rare anomaly, characterized by severe intellectual disability, feeding difficulties, behavior abnormalities, and distinctive facial features, including microcephaly, deep-set eyes, large simple ears, and a pointed or bulbous nasal tip. Some studies show that the disorder has a close correlation with variants in <i>DYRK1A</i>. Herein we described a Chinese girl presenting typical clinical features diagnosed at 4 years old. Whole-exome sequencing of the familial genomic DNA identified a novel mutation c.930C > A (p.Tyr310*) in exon 7 of <i>DYRK1A</i> in the proband. The nonsense mutation was predicted to render the truncation of the protein. Our results suggested that the <i>de novo</i> heterozygous mutation in <i>DYRK1A</i> was responsible for the MRD7 in this Chinese family, which both extended the knowledge of mutation spectrum in MRD7 patients and highlighted the clinical application of exome sequencing.","variants":[{"Name":"NM_001347721.2(DYRK1A):c.930C>A (p.Tyr310Ter)","Chromosome":"21","Start":"37493022","Stop":"37493022","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1978470,"rule_based_match":true,"evidence_text":"c.930C > A (p.Tyr310*)","llm_judgment":"PRESENT","evidence":"c.930C > A (p.Tyr310*)","abstract_start":557,"abstract_end":579}]}
{"pmid":"28050124","title":"Novel compound heterozygous mutations in","abstract":"PURPOSE: Stargardt disease (STGD) is a common macular dystrophy in juveniles that is commonly inherited as an autosomal recessive trait. Mutations in five genes (<i>ABCA4</i>, <i>PROM1</i>, <i>ELOVL4</i>, <i>BEST1</i>, and <i>PRPH2</i>) have been reported to be associated with STGD. In the present study, we aimed to identify the pathogenic mutations in affected members in a Chinese STGD pedigree.\nMETHODS: One patient was selected for whole-exome sequencing. Variants in five candidate genes were identified initially, followed by several filtering steps against public and private variation databases (1000Genomes, ESP6500si, ExAC, and in-house database), as well as bioinformatic analysis of the putative pathogenic roles. Sanger sequencing was used for cosegregation analysis among all members with available DNA.\nRESULTS: Two mutations in <i>ABCA4</i> (NM_000350.2; c.5646G>A; p.Met1882Ile and NM_000350.2; c.3523-2A>G) were found using whole-exome sequencing. Cosegregation analysis confirmed all the affected members carried the compound heterozygous mutations while the other healthy members had at most one. The missense mutation was extremely rare in public databases and predicted to be deleterious. The splice-site mutation was absent from all public and private databases and was predicted to alter the splice pattern, resulting in an exon skip and a frameshift.\nCONCLUSIONS: Using whole-exome sequencing, we found novel compound heterozygous mutations in <i>ABCA4</i> in a Chinese STGD pedigree. These mutations are reported for the first time, therefore widening the mutation spectrum of Stargardt disease. The present study also illustrates the potential of whole-exome sequencing in determining the genetic cause of STGD.","variants":[{"Name":"NM_000350.3(ABCA4):c.5646G>A (p.Met1882Ile)","Chromosome":"1","Start":"94010868","Stop":"94010868","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":365434,"rule_based_match":true,"evidence_text":"NM_000350.2; c.5646G>A; p.Met1882Ile","llm_judgment":"PRESENT","evidence":"NM_000350.2; c.5646G>A; p.Met1882Ile","abstract_start":860,"abstract_end":896}]}
{"pmid":"28581210","title":"Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function.","abstract":"Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early-onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI-anchored proteins (GPI-APs) that can be measured by flow cytometry. No significant differences in GPI-APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI-linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI-anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency.","variants":[{"Name":"NM_001127178.3(PIGG):c.1640G>A (p.Trp547Ter)","Chromosome":"4","Start":"523484","Stop":"523484","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1678922,"rule_based_match":true,"evidence_text":"NM_001127178.1:c.1640G>A, p.Trp547*","llm_judgment":"PRESENT","evidence":"NM_001127178.1:c.1640G>A, p.Trp547*","abstract_start":506,"abstract_end":541}]}
{"pmid":"33205897","title":"Missense mutations in EDA and EDAR genes cause dominant syndromic tooth agenesis.","abstract":"BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is the most common form of ectodermal dysplasia and is mainly associated with mutations in the EDA, EDAR, and EDARADD responsible for the development of ectodermal-derived structures. HED displays different modes of inheritance according to the gene that is involved, with X-linked EDA-related HED being the most frequent form of the disease.\nMETHODS: Two families with tooth agenesis and manifestations of HED underwent clinical examination and EDA, EDAR, and EDARADD genetic analysis. The impact of the novel variant on the protein was evaluated through bioinformatics tools, whereas molecular modeling was used to predict the effect on the protein structure.\nRESULTS: A novel missense variant was identified in the EDAR (c.287T>C, p.Phe96Ser) of a female child proband and her mother, accounting for autosomal dominant HED. The genetic variant c.866G>A (p.Arg289His) in EDA, which has been previously described, was observed in the male proband of another family confirming its role in X-linked HED. The inheritance model of the missense mutation showed a different relationship with X-linked HED and non-syndromic tooth agenesis.\nCONCLUSION: Our findings provide evidence of variable expression of HED in heterozygous females, which should be considered for genetic counseling, and different modes of inheritance related to tooth development.","variants":[{"Name":"NM_001399.5(EDA):c.866G>A (p.Arg289His)","Chromosome":"X","Start":"70033470","Stop":"70033470","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":231292,"rule_based_match":true,"evidence_text":"c.866G>A (p.Arg289His)","llm_judgment":"PRESENT","evidence":"c.866G>A (p.Arg289His)","abstract_start":899,"abstract_end":921},{"Name":"NM_022336.4(EDAR):c.287T>C (p.Phe96Ser)","Chromosome":"2","Start":"108929267","Stop":"108929267","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":961039,"rule_based_match":true,"evidence_text":"c.287T>C, p.Phe96Ser","llm_judgment":"PRESENT","evidence":"c.287T>C, p.Phe96Ser","abstract_start":776,"abstract_end":796}]}
{"pmid":"23289006","title":"Mutation screening of the BRCA1 gene in early onset and familial breast/ovarian cancer in Moroccan population.","abstract":"Worldwide variation in the distribution of BRCA mutations is well recognised, and for the Moroccan population no comprehensive studies about BRCA mutation spectra or frequencies have been published. We therefore performed mutation analysis of the BRCA1 gene in 121 Moroccan women diagnosed with breast cancer. All cases completed epidemiology and family history questionnaires and provided a DNA sample for BRCA testing. Mutation analysis was performed by direct DNA sequencing of all coding exons and flanking intron sequences of the BRCA1 gene. 31.6 % (6/19) of familial cases and 1 % (1/102) of early-onset sporadic (< 45 years)were found to be associated with BRCA1 mutations. The pathogenic mutations included two frame-shift mutations (c.798_799delTT, c.1016dupA), one missense mutation (c.5095C>T),and one nonsense mutation (c.4942A>T). The c.798_799delTT mutation was also observed in Algerian and Tunisian BC families, suggesting the first non-Jewish founder mutation to be described in Northern Africa. In addition, ten different unclassified variants were detected in BRCA1, none of which were predicted to affect splicing. Most unclassified variants were placed in Align-GVGD classes suggesting neutrality. c.5117G>C involves a highly conserved amino acid suggestive of interfering with function (Align-GVGD class C55), but has been observed in conjunction with a deleterious mutation in a Tunisian family. These findings reflect the genetic heterogeneity of the Moroccan population and are relevant to genetic counselling and clinical management. The role of BRCA2 in BC is also under study.","variants":[{"Name":"NM_007294.4(BRCA1):c.1016dup (p.Val340fs)","Chromosome":"17","Start":"43094514","Stop":"43094515","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":68769,"rule_based_match":true,"evidence_text":"c.1016dupA","llm_judgment":"PRESENT","evidence":"c.1016dupA","abstract_start":758,"abstract_end":768},{"Name":"NM_007294.4(BRCA1):c.4942A>T (p.Lys1648Ter)","Chromosome":"17","Start":"43070972","Stop":"43070972","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":645933,"rule_based_match":true,"evidence_text":"c.4942A>T","llm_judgment":"PRESENT","evidence":"c.4942A>T","abstract_start":832,"abstract_end":841},{"Name":"NM_007294.4(BRCA1):c.798_799del (p.Ser267fs)","Chromosome":"17","Start":"43094732","Stop":"43094733","ReferenceAlleleVCF":"GAA","AlternateAlleleVCF":"G","allel_id":46254,"rule_based_match":true,"evidence_text":"c.798_799delTT","llm_judgment":"PRESENT","evidence":"c.798_799delTT","abstract_start":742,"abstract_end":756},{"Name":"NM_007294.4(BRCA1):c.5095C>T (p.Arg1699Trp)","Chromosome":"17","Start":"43063931","Stop":"43063931","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70063,"rule_based_match":true,"evidence_text":"c.5095C>T","llm_judgment":"PRESENT","evidence":"c.5095C>T","abstract_start":794,"abstract_end":803}]}
{"pmid":"33679784","title":"Case Report: A Novel Synonymous ARPC1B Gene Mutation Causes a Syndrome of Combined Immunodeficiency, Asthma, and Allergy With Significant Intrafamilial Clinical Heterogeneity.","abstract":"Recently, a novel syndrome of combined immune deficiency, infections, allergy, and inflammation has been attributed to mutations in the gene encoding actin-related protein 2/3 complex subunit 1B (ARPC1B), which is a key molecule driving the dynamics of the cytoskeleton. Homozygous mutations in the ARPC1B gene have been found to result in the disruption of the protein structure and cause an autosomal recessive syndrome of combined immune deficiency, impaired T-cell migration and proliferation, increased levels of immunoglobulin E (IgE) and immunoglobulin A (IgA), and thrombocytopenia. To date, only a few individuals have been diagnosed with the ARPC1B deficiency syndrome worldwide. In this case series, we report the wide spectrum of phenotype in 3 siblings of a consanguineous family from Afghanistan with a novel homozygous synonymous pathogenic variant c.783G>A, p. (Ala261Ala) of the ARPC1B gene that causes a similar syndrome but no thrombocytopenia. Targeted RNA studies demonstrated that the variant affects the splicing process of mRNA, resulting in a marked reduction of the levels of primary (normal) RNA transcript of the ARPC1B gene in the affected patients and likely premature termination from the abnormally spliced mRNA. The next generation sequencing (NGS) studies facilitated the diagnosis of this rare combined immunodeficiency and led to the decision to treat the affected patients with hematopoietic cell transplant (HCT) from an human leukocyte antigen (HLA)-matched healthy sibling.","variants":[{"Name":"NM_005720.4(ARPC1B):c.783G>A (p.Ala261=)","Chromosome":"7","Start":"99391253","Stop":"99391253","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1016978,"rule_based_match":true,"evidence_text":"c.783G>A, p. (Ala261Ala)","llm_judgment":"PRESENT","evidence":"c.783G>A, p. (Ala261Ala)","abstract_start":864,"abstract_end":888}]}
{"pmid":"23246290","title":"Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex.","abstract":"Hypotrichosis simplex (HS) comprises a group of hereditary isolated alopecias that are characterized by a diffuse and progressive loss of hair starting in childhood and shows a wide phenotypic variability. We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family. By direct sequencing, we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript. We identified the same mutation in a simplex HS case from the UK and an additional mutation (c.133G>A [p.Gly45Ser]) in a simplex HS case originating from Tunisia. SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome. The missense mutation c.133G>A leads to a glycine to serine substitution and is predicted to disrupt the structure of SNRPE. Western blot analyses of HEK293T cells expressing SNRPE c.1A>G revealed an N-terminally truncated protein, and therefore the mutation might result in use of an alternative in-frame downstream start codon. Subcellular localization of mutant SNRPE by immunofluorescence analyses as well as incorporation of mutant SNRPE proteins into U snRNPs was found to be normal, suggesting that the function of U snRNPs in splicing, rather than their biogenesis, is affected. In this report we link a core component of the spliceosome to hair loss, thus adding another specific factor in the complexity of hair growth. Furthermore, our findings extend the range of human phenotypes that are linked to the splicing machinery.","variants":[{"Name":"NM_003094.4(SNRPE):c.1A>G (p.Met1Val)","Chromosome":"1","Start":"203861660","Stop":"203861660","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":48104,"rule_based_match":true,"evidence_text":"c.1A>G (p.Met1?)","llm_judgment":"PRESENT","evidence":"c.1A>G (p.Met1?)","abstract_start":358,"abstract_end":374},{"Name":"NM_003094.4(SNRPE):c.133G>A (p.Gly45Ser)","Chromosome":"1","Start":"203863714","Stop":"203863714","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48105,"rule_based_match":true,"evidence_text":"c.133G>A (p.Gly45Ser)","llm_judgment":"PRESENT","evidence":"p.Gly45Ser","abstract_start":546,"abstract_end":556}]}
{"pmid":"30446360","title":"Autosomal recessive hereditary spastic paraplegia type SPG35 due to a novel variant in the FA2H gene in a Czech patient.","abstract":"Biallelic pathogenic variants in FA2H gene have been repeatedly described as a cause of hereditary spastic paraplegia (HSP) type35 (SPG35). Targeted massive parallel sequencing (MPS) of the HSP genes panel revealed a novel homozygous variant c.130C > T (p.P44S) in the FA2H gene in the 30-year-old patient presenting with spastic paraplegia. The patient originated form the Czech minority in Romania. The patient manifests typical clinical signs for SPG35 (youth onset gait impairment, progressive spastic paraparesis on lower limbs, dysarthria, white matter changes in MRI).","variants":[{"Name":"NM_024306.5(FA2H):c.130C>T (p.Pro44Ser)","Chromosome":"16","Start":"74774626","Stop":"74774626","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":445611,"rule_based_match":true,"evidence_text":"c.130C > T (p.P44S)","llm_judgment":"PRESENT","evidence":"c.130C > T (p.P44S)","abstract_start":242,"abstract_end":261}]}
{"pmid":"24157261","title":"ALG1-CDG: a new case with early fatal outcome.","abstract":"Congenital disorders of glycosylation (CDG) are a growing group of inherited metabolic disorders where enzymatic defects in the formation or processing of glycolipids and/or glycoproteins lead to variety of different diseases. The deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase, encoded by the human ortholog of ALG1 from yeast, is known as ALG1-CDG (CDG-Ik). The phenotypical, molecular and biochemical analysis of a severely affected ALG1-CDG patient is the focus of this paper. The patient's main symptoms were feeding problems and diarrhea, profound hypoproteinemia with massive ascites, muscular hypertonia, seizures refractory to treatment, recurrent episodes of apnoea, cardiac and hepatic involvement and coagulation anomalies. Compound heterozygosity for the mutations c.1145T>C (M382T) and c.1312C>T (R438W) was detected in the patient's ALG1-coding sequence. In contrast to a previously reported speculation on R438W we confirmed both mutations as disease-causing in ALG1-CDG.","variants":[{"Name":"NM_019109.5(ALG1):c.1312C>T (p.Arg438Trp)","Chromosome":"16","Start":"5084798","Stop":"5084798","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":678020,"rule_based_match":true,"evidence_text":"c.1312C>T (R438W)","llm_judgment":"PRESENT","evidence":"c.1312C>T (R438W)","abstract_start":815,"abstract_end":832},{"Name":"NM_019109.5(ALG1):c.1145T>C (p.Met382Thr)","Chromosome":"16","Start":"5082631","Stop":"5082631","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":860272,"rule_based_match":true,"evidence_text":"c.1145T>C (M382T)","llm_judgment":"PRESENT","evidence":"c.1145T>C (M382T)","abstract_start":793,"abstract_end":810}]}
{"pmid":"38337174","title":"Oculocutaneous albinism type 4: Novel compound heterozygous mutations in the SLC45A2 gene in a Chinese case.","abstract":"BACKGROUND: Oculocutaneous albinism type 4 (OCA4) is a rare autosomal recessive disorder characterized by a reduction of pigmentation in skin, hair, and eyes, and OCA4 is mainly seen in the SLC45A2 gene variants.\nOBJECTIVE: To report a Chinese patient suspected of oculocutaneous albinism and identify the causing mutation.\nMETHODS: Genomic DNA was extracted from the peripheral blood samples of the patient, his parents, and elder brother. Whole exome sequencing was performed in the family, and Sanger sequencing was then used to verify the mutations.\nRESULTS: Compound heterozygous variants, c.1304C>A (p.S435Y) and c.301C>G (p.R101G) in SLC45A2 gene, were detected in the proband, which were inherited from his father and mother respectively. Based on the ACMG guidelines, we can interpret the c.1304C>A (p.S435Y) variant as a suspected pathogenic variant and the c.301C>G (p.R101G) variant as a clinically significant unspecified variant. The diagnosis of OCA4 is confirmed.\nCONCLUSION: We firstly reported this case of OCA4 with the compound heterozygous variants in the SLC45A2 gene. Our findings further enrich the reservoir of SLC45A2 mutations in OCA4.","variants":[{"Name":"NM_016180.5(SLC45A2):c.1304C>A (p.Ser435Tyr)","Chromosome":"5","Start":"33947227","Stop":"33947227","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3222590,"rule_based_match":true,"evidence_text":"c.1304C>A (p.S435Y)","llm_judgment":"PRESENT","evidence":"c.1304C>A (p.S435Y)","abstract_start":595,"abstract_end":614},{"Name":"NM_016180.5(SLC45A2):c.301C>G (p.Arg101Gly)","Chromosome":"5","Start":"33984283","Stop":"33984283","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3222591,"rule_based_match":true,"evidence_text":"c.301C>G (p.R101G)","llm_judgment":"PRESENT","evidence":"c.301C>G (p.R101G)","abstract_start":619,"abstract_end":637}]}
{"pmid":"16406649","title":"Aldolase B mutations and prevalence of hereditary fructose intolerance in a Polish population.","abstract":"We studied 28 Polish hereditary fructose intolerant (HFI) patients (26 unrelated) by direct sequencing of the ALDOB coding region/splice sites. Eight different mutations were found including two novel ones (each found in two unrelated individuals): c.250delC (frameshift) and c.522 C > G (p.Y174X). The most frequent mutation c.448 G > C (p.A150P, 67% of chromosomes) was screened for in a group of 1049 randomly selected unrelated individuals. Eight (1:131) carriers were found allowing to estimate the HFI prevalence in Poland as 1:31,000.","variants":[{"Name":"NM_000035.4(ALDOB):c.522C>G (p.Tyr174Ter)","Chromosome":"9","Start":"101427500","Stop":"101427500","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":545030,"rule_based_match":true,"evidence_text":"c.522 C > G (p.Y174X)","llm_judgment":"PRESENT","evidence":"c.522 C > G (p.Y174X)","abstract_start":276,"abstract_end":297},{"Name":"NM_000035.4(ALDOB):c.448G>C (p.Ala150Pro)","Chromosome":"9","Start":"101427574","Stop":"101427574","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":15503,"rule_based_match":true,"evidence_text":"c.448 G > C (p.A150P, 67% of chromosomes)","llm_judgment":"PRESENT","evidence":"c.448 G > C (p.A150P, 67% of chromosomes)","abstract_start":326,"abstract_end":367}]}
{"pmid":"31439038","title":"Clinical exome sequencing identifies two novel mutations of the SCN1A and SCN2A genes in Moroccan patients with epilepsy: a case series.","abstract":"BACKGROUND: Epilepsy is the most common neurological disorder that causes spontaneous, unprovoked, and recurrent seizures. Epilepsy is clinically and genetically heterogeneous with various modes of inheritance. The complexity of epilepsy presents a challenge and identification of the causal genetic mutation allows diagnosis, genetic counseling, predicting prognosis, and, in some cases, treatment decisions. Clinical exome sequencing is actually becoming a powerful approach for molecular diagnosis of heterogeneous neurological disorders in clinical practice.\nCASE PRESENTATION: We report our observations of three unrelated Moroccan patients referred to our genetics department for molecular diagnosis of epilepsy: a 4-year-old Moroccan boy, a 3-year-old Moroccan girl, and a 7-year-old Moroccan boy. Due to the heterogeneity and complexity of epilepsy, we performed clinical exome sequencing followed by targeted analysis of 936 epilepsy genes. A total of three mutations were identified in known epilepsy genes (SCN1A, SCN2A). By clinical exome sequencing, we identified two novel mutations: c.4973C>A (p.Thr1658Lys) in SCN1A gene and c.1283A>G (p.Tyr428Cys) in the SCN2A gene, whereas the third mutation c.3295G>T (p.Glu1099*) was already described in patients with Dravet syndrome.\nCONCLUSION: This study demonstrates that clinical exome sequencing is an effective diagnosis tool to investigate this group of diseases with huge diversity and defends its use in clinical routine.","variants":[{"Name":"NM_001165963.4(SCN1A):c.4973C>A (p.Thr1658Lys)","Chromosome":"2","Start":"165992302","Stop":"165992302","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":850557,"rule_based_match":true,"evidence_text":"c.4973C>A (p.Thr1658Lys)","llm_judgment":"PRESENT","evidence":"c.4973C>A (p.Thr1658Lys)","abstract_start":1098,"abstract_end":1122}]}
{"pmid":"25226867","title":"Further evidence for pathogenicity of the TP53 tetramerization domain mutation p.Arg342Pro in Li-Fraumeni syndrome.","abstract":"Li-Fraumeni syndrome (LFS) is a rare genetic disease with a highly significant predisposition to multiple early-onset neoplasms. These neoplasms include adrenocortical carcinoma, sarcoma, leukemia and CNS tumors in children and sarcoma, breast cancer and lung cancer in adults. LFS is inherited in an autosomal dominant manner. In most patients germline mutations in the tumor suppressor gene TP53 are found. As the majority of known mutations affect the DNA-binding domain of the p53 protein, there are only a few case reports showing the clinical presentation of mutations outside of this mutational hotspot. Here we present a family with a typical LFS pedigree with patients suffering from early-onset lung cancer, bilateral breast cancer and osteosarcoma. TP53 sequence analysis of the index patient revealed the germline mutation c.1025G > C in a heterozygous state, resulting in an amino acid exchange from arginine to proline (p.Arg342Pro) in the tetramerization domain of p53. Using DNA from an old bedside blood typing test, the same mutation was found in the mother of the index patient, who had died of breast cancer 29 years ago. In conclusion, we provide evidence for the co-segregation of a TP53 tetramerization domain mutation and cancer phenotypes, but also report pre-symptomatic mutation carriers within the family. We review published recommendations for clinical management and surveillance of high-risk members in Li-Fraumeni kindreds.","variants":[{"Name":"NM_000546.6(TP53):c.1025G>C (p.Arg342Pro)","Chromosome":"17","Start":"7670684","Stop":"7670684","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":213385,"rule_based_match":true,"evidence_text":"c.1025G > C","llm_judgment":"PRESENT","evidence":"c.1025G > C","abstract_start":835,"abstract_end":846}]}
{"pmid":"26746779","title":"Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9.","abstract":"Congenital insensitivity to pain (CIP) comprises the rare heritable disorders without peripheral neuropathy that feature inability to feel pain. Fracturing and joint destruction are common complications, but lack detailed studies of mineral and skeletal homeostasis and bone histology. In 2013, discovery of a heterozygous gain-of-function mutation in SCN11A encoding voltage-gated sodium channel 1.9 (Nav1.9) established a distinctive CIP in three unrelated patients who suffered multiple painless fractures, self-inflicted mutilation, chronic diarrhea, and hyperhidrosis. Here, we studied a mother and two children with CIP by physical examination, biochemical testing, radiological imaging including DXA, iliac crest histology, and mutation analysis. She suffered fractures primarily of her lower extremities beginning at age two years, and had Charcot deformity of both ankles and joint hypermobility. Nerve conduction velocity together with electromyography were normal. Her children had recurrent major fractures beginning in early childhood, joint hypermobility, and chronic diarrhea. She had an excoriated external nare, and both children had hypertrophic scars from scratching. Skin collagen studies were normal. Radiographs revealed fractures and deformities. However, lumbar spine and total hip BMD Z-scores, biochemical parameters of mineral and skeletal homeostasis, and iliac crest histology of the mother (after in vivo tetracycline labeling) were normal. Genomic DNA from the children revealed a unique heterozygous missense mutation in exon 23 (c.3904C>T, p.Leu1302Phe) of SCN11A that is absent in SNP databases and alters an evolutionarily conserved amino acid. This autosomal dominant CIP reflects the second gain-of-function mutation of SCN11A. Perhaps joint hypermobility is an unreported feature. How mutation of Nav1.9 causes fracturing remains unexplained. Lack of injury awareness is typically offered as the reason, and was supported by our unremarkable biochemical, radiological, and histological findings indicating no skeletal pathobiology. However, low-trauma fracturing in these patients suggests an uncharacterized defect in bone quality.","variants":[{"Name":"NM_001349253.2(SCN11A):c.3904C>T (p.Leu1302Phe)","Chromosome":"3","Start":"38867368","Stop":"38867368","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":496112,"rule_based_match":true,"evidence_text":"c.3904C>T, p.Leu1302Phe","llm_judgment":"PRESENT","evidence":"c.3904C>T, p.Leu1302Phe","abstract_start":1562,"abstract_end":1585}]}
{"pmid":"32244552","title":"Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants.","abstract":"AIMS: We aimed to validate the pathogenicity of genetic variants identified in inherited retinal dystrophy (IRD) patients, which were located in non-canonical splice sites (NCSS).\nMETHODS: After next generation sequencing (NGS) analysis (target gene panels or whole exome sequencing (WES)), NCSS variants were prioritized according to <i>in silico</i> predictions. <i>In vivo</i> and <i>in vitro</i> functional tests were used to validate their pathogenicity.\nRESULTS: Four novel NCSS variants have been identified. They are located in intron 33 and 34 of <i>ABCA4</i> (c.4774-9G>A and c.4849-8C>G, respectively), intron 2 of <i>POC1B</i> (c.101-3T>G) and intron 3 of <i>RP2</i> (c.884-14G>A). Functional analysis detected different aberrant splicing events, including intron retention, exon skipping and intronic nucleotide addition, whose molecular effect was either the disruption or the elongation of the open reading frame of the corresponding gene.\nCONCLUSIONS: Our data increase the genetic diagnostic yield of IRD patients and expand the landscape of pathogenic variants, which will have an impact on the genotype-phenotype correlations and allow patients to opt for the emerging gene and cell therapies.","variants":[{"Name":"NM_006915.3(RP2):c.884-14G>A","Chromosome":"X","Start":"46877491","Stop":"46877491","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":792458,"rule_based_match":true,"evidence_text":"c.884-14G>A","llm_judgment":"PRESENT","evidence":"c.884-14G>A","abstract_start":680,"abstract_end":691},{"Name":"NM_172240.3(POC1B):c.101-3T>G","Chromosome":"12","Start":"89497345","Stop":"89497345","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":852516,"rule_based_match":true,"evidence_text":"c.101-3T>G","llm_judgment":"PRESENT","evidence":"c.101-3T>G","abstract_start":640,"abstract_end":650}]}
{"pmid":"30478739","title":"Hereditary brain tumor with a homozygous germline mutation in PMS2: pedigree analysis and prenatal screening in a family with constitutional mismatch repair deficiency (CMMRD) syndrome.","abstract":"Precise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of multiple cases of childhood brain tumors. Six affected individuals died of brain tumors at very early ages and three were confirmed as having a homozygous mutation in exon 6 of the PMS2 gene (c.543delT). Fifteen members of the family were identified as heterozygous carriers of this mutation with a lack of cancer incidence. Both clinical manifestations and genetic test results of brain tumor patients in the family support the diagnosis of constitutional mismatch repair deficiency (CMMRD) syndrome, a condition in which individuals carry homozygous germline mutations in mismatch repair machinery genes with an early onset of malignancies such as glioma. This information was used to guide prenatal diagnosis with genetic testing on chorionic villus samples for the family. This is the first report of prenatal genetic diagnosis of hereditary brain tumor.","variants":[{"Name":"NM_000535.7(PMS2):c.543del (p.Glu180_Tyr181insTer)","Chromosome":"7","Start":"5999270","Stop":"5999270","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":96833,"rule_based_match":true,"evidence_text":"c.543delT","llm_judgment":"PRESENT","evidence":"c.543delT","abstract_start":444,"abstract_end":453}]}
{"pmid":"26443629","title":"Novel missense mutation in CLN8 in late infantile neuronal ceroid lipofuscinosis: The first report of a CLN8 mutation in Japan.","abstract":"Neuronal ceroid lipofuscinoses (NCLs) are clinically and genetically heterogeneous neurodegenerative lysosomal diseases. Fourteen distinct NCL subtypes (CLN1-CLN14) are known, and they are caused by mutations in different genes. CLN8 was first identified in Finnish patients, and the phenotype was subsequently found in Turkish, Italian, and Pakistani patients. We report a 6-year-old Japanese boy with NCL with a novel missense mutation in CLN8. At the age of 3years, he manifested frequent drop seizures, and then progressively developed motor difficulties with an ataxic gait, myoclonus, left conjugate deviation, and rotational nystagmus. At age 5, he developed profound visual difficulty and dysphagia, and he has now lost his mobility. A bone marrow examination at age 5 showed sea-blue histiocytes. An electroretinogram was non-recordable. No giant somatosensory evoked potentials were found. Brain magnetic resonance imaging revealed bilateral diffuse hyperintensities in the white matter around the lateral ventricles and cerebellar and pontine atrophy on T2-weighted images. In a lysosomal enzyme study, the palmitoyl-protein-thioesterase and pepinase activity was within normal limits. Whole-exome sequencing revealed a homozygous CLN8 mutation: c.620T>G (p.L207R). His parents were both heterozygous for this mutation. To our knowledge, this is the first report of a CLN8 mutation in late infantile NCL in Japan.","variants":[{"Name":"NM_018941.4(CLN8):c.620T>G (p.Leu207Arg)","Chromosome":"8","Start":"1780326","Stop":"1780326","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3856600,"rule_based_match":true,"evidence_text":"c.620T>G (p.L207R)","llm_judgment":"PRESENT","evidence":"c.620T>G (p.L207R)","abstract_start":1257,"abstract_end":1275}]}
{"pmid":"32863293","title":"Longest survival by the combination of radiation-therapy and resection in patient with metastatic spinal paragangliomas from primary-neck lesion with succinate dehydrogenase subunit B (SDHB) mutation.","abstract":"Metastatic paraganglioma (MPG) of the spine is a rare condition, with no established management. Herein, we report the longest survival case of a primary neck tumor that caused spinal MPG with a succinate dehydrogenase subunit B (SDHB) mutation (c.470delT, p.L157X) which could have promoted its malignancy. This male patient initially presented with a left neck PG which was diagnosed by a biopsy when he was 54 years-old. Simultaneously performed additional examinations revealed the spinal metastatic tumors on the T5-7 vertebrae and L3 vertebra-sacrum. These primary neck and metastatic spinal tumors' growths were once suppressed under the radiation therapy. Nineteen years later, he developed acute progressive paraparesis due to a mass located at the T2-3 level, tightly compressing the spinal cord, and protruding into the left thoracic cavity. We resected the maximum possible area of tumor in the spinal canal, confirmed MPG by histological examination, and then, we administered radiation therapy of 40 Gy in 20 fractions. Eventually, the patient was able to walk unaided with no evidential tumor recurrence for 3 years after treatment. Generally, clinical feature of MPG with SDHB mutation from abdominal lesion is thought to be poor prognosis. However, our case suggests the possibility of long-term control of spinal MPG with the adequate combination of radiation therapy and resection if metastatic lesions from primary-neck lesion with an SDHB mutation are remained to spine.","variants":[{"Name":"NM_003000.3(SDHB):c.470del (p.Tyr156_Leu157insTer)","Chromosome":"1","Start":"17027819","Stop":"17027819","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":980139,"rule_based_match":true,"evidence_text":"c.470delT, p.L157X","llm_judgment":"PRESENT","evidence":"c.470delT, p.L157X","abstract_start":246,"abstract_end":264}]}
{"pmid":"22190446","title":"Genome-wide analysis of familial dysautonomia and kinetin target genes with patient olfactory ecto-mesenchymal stem cells.","abstract":"Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder. The most common mutation is a c.2204+6T>C transition in the 5' splice site (5'ss) of IKBKAP intron 20, which causes a tissue-specific skipping of exon 20, resulting in lower synthesis of IKAP/hELP1 protein. To better understand the specificity of neuron loss in FD, we modeled the molecular mechanisms of IKBKAP mRNA splicing by studying human olfactory ecto-mesenchymal stem cells (hOE-MSCs) derived from FD patient nasal biopsies. We explored how the modulation of IKBKAP mRNA alternative splicing impacts the transcriptome at the genome-wide level. We found that the FD transcriptional signature was highly associated with biological functions related to the development of the nervous system. In addition, we identified target genes of kinetin, a plant cytokinin that corrects IKBKAP mRNA splicing and increases the expression of IKAP/hELP1. We identified this compound as a putative regulator of splicing factors and added new evidence for a sequence-specific correction of splicing. In conclusion, hOE-MSCs isolated from FD patients represent a promising avenue for modeling the altered genetic expression of FD, demonstrating a methodology that can be applied to a host of other genetic disorders to test the therapeutic potential of candidate molecules.","variants":[{"Name":"NM_003640.5(ELP1):c.2204+6T>C","Chromosome":"9","Start":"108899816","Stop":"108899816","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":21124,"rule_based_match":true,"evidence_text":"c.2204+6T>C","llm_judgment":"PRESENT","evidence":"c.2204+6T>C","abstract_start":105,"abstract_end":116}]}
{"pmid":"38297350","title":"Rare germline mutation and MSH2-&MSH6 + expression in a double primary carcinoma of colorectal carcinoma and endometrial carcinoma: a case report.","abstract":"BACKGROUND: Multiple primary malignancies are rare in cancer patients, and risk factors may include genetics, viral infection, smoking, radiation, and other environmental factors. Lynch syndrome (LS) is the most prevalent form of hereditary predisposition to double primary colorectal and endometrial cancer in females. LS, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a common autosomal dominant condition. Pathogenic germline variants in the DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, and less frequently, deletions in the 3' end of EPCAM cause LS. It manifested itself as loss of MMR nuclear tumor staining (MMR protein deficient, dMMR).\nCASE PRESENTATION: This case study describes a double primary carcinoma in a 49-year-old female. In June 2022, the patient was diagnosed with highly to moderately differentiated endometrioid adenocarcinoma. The patient's mother died of esophageal cancer at age 50, and the father died of undefined reasons at age 70. Immunohistochemical stainings found ER (++), PR (++), P53 (+), MSH2 (-), MSH6 (+), MLH1 (+), and PMS2 (+). MMR gene sequencing was performed on endometrial tumor and peripheral blood samples from this patient. The patient carried two pathogenic somatic mutations in the endometrial tumor, MSH6 c.3261dupC (p.Phe1088LeufsTer5) and MSH2 c.445_448dup (p.Val150fs), in addition to a rare germline mutation MSH6 c.133G > C (p.Gly45Arg). Two years ago, the patient was diagnosed with moderately differentiated adenocarcinoma in the left-half colon. Immunohistochemical stainings found MSH2(-), MSH6(+), MLH1(+), and PMS2(+) (data not shown).\nCONCLUSIONS: In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.","variants":[{"Name":"NM_000179.3(MSH6):c.133G>C (p.Gly45Arg)","Chromosome":"2","Start":"47783366","Stop":"47783366","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":518376,"rule_based_match":true,"evidence_text":"MSH6 c.133G > C (p.Gly45Arg)","llm_judgment":"PRESENT","evidence":"MSH6 c.133G > C (p.Gly45Arg)","abstract_start":1408,"abstract_end":1436}]}
{"pmid":"28875337","title":"Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene.","abstract":"Hydroxysteroid (17β) dehydrogenase 10 (HSD10) and mitochondrial acetoacetyl-CoA thiolase (β-KT) are two adjacent enzymes for the degradation of isoleucine, thus HSD10 and β-KT deficiencies are confusing at an early stage because of nearly the same elevation of typical metabolites in urine, such as 2-methyl-3-hydroxybutyric acid (2M3HBA) and tiglylglycine (TG). In order to better understand the differences between these two disorders, we described the clinical and molecular characteristics of two HSD10 deficiency patients and four β-KT deficiency patients. β-KT deficiency patients had a much more favorable outcome than that of HSD10 deficiency patients, indicating that the multifunction of HSD10, especially neurosteroid metabolic activity, other than only enzymatic degradation of isoleucine, is involved in the pathogenesis of HSD10 deficiency. Two different mutations, a novel mutation p.Ile175Met and a reported mutation p.Arg226Gln, were detected in the HSD17B10 gene of HSD10 deficiency patients. Six different mutations, including four known mutations: p.Ala333Pro, p.Thr297Lys, c.83_84delAT, c.1006-1G > C, and two novel mutations: p.Thr277Pro and c.121-3C > G were identified in the ACAT1 gene of β-KT deficiency patients. In general, DNA diagnosis played an important role in distinguishing between these two disorders.","variants":[{"Name":"NM_000019.4(ACAT1):c.121-3C>G","Chromosome":"11","Start":"108133817","Stop":"108133817","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":654082,"rule_based_match":true,"evidence_text":"c.121-3C>G","llm_judgment":"PRESENT","evidence":"c.121-3C > G","abstract_start":1164,"abstract_end":1176},{"Name":"NM_000019.4(ACAT1):c.1006-1G>C","Chromosome":"11","Start":"108146201","Stop":"108146201","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":421815,"rule_based_match":true,"evidence_text":"c.1006-1G > C","llm_judgment":"PRESENT","evidence":"c.1006-1G > C","abstract_start":1108,"abstract_end":1121},{"Name":"NM_000019.4(ACAT1):c.997G>C (p.Ala333Pro)","Chromosome":"11","Start":"108144039","Stop":"108144039","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":17884,"rule_based_match":false,"evidence_text":"p.Ala333Pro","llm_judgment":"PRESENT","evidence":"p.Ala333Pro","abstract_start":1068,"abstract_end":1079}]}
{"pmid":"28276523","title":"Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype.","abstract":"Loss-of-function mutations in the WRN helicase gene cause Werner syndrome- a progeroid syndrome with an elevated risk of cancer and other age-associated diseases. Large numbers of single nucleotide polymorphisms have been identified in WRN. We report here the organismal, cellular, and molecular phenotypes of variant rs3087425 (c. 2500C > T) that results in an arginine to cysteine substitution at residue 834 (R834C) and up to 90% reduction of WRN helicase activity. This variant is present at a high (5%) frequency in Mexico, where we identified 153 heterozygous and three homozygous individuals among 3,130 genotyped subjects. Family studies of probands identified ten additional TT homozygotes. Biochemical analysis of WRN protein purified from TT lymphoblast cell lines confirmed that the R834C substitution strongly and selectively reduces WRN helicase, but not exonuclease activity. Replication track analyses showed reduced replication fork progression in some homozygous cells following DNA replication stress. Among the thirteen TT homozygotes, we identified a previously unreported and statistically significant gender bias in favor of males (p = 0.0016), but none of the clinical findings associated with Werner syndrome. Our results indicate that WRN helicase activity alone is not rate-limiting for the development of clinical WS.","variants":[{"Name":"NM_000553.6(WRN):c.2500C>T (p.Arg834Cys)","Chromosome":"8","Start":"31120294","Stop":"31120294","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":47491,"rule_based_match":true,"evidence_text":"c. 2500C > T","llm_judgment":"PRESENT","evidence":"c. 2500C > T","abstract_start":329,"abstract_end":341}]}
{"pmid":"30384382","title":"Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson's Disease.","abstract":"BACKGROUND: Wilson's disease (WD) is an autosomal recessive disease, which is characterized by an excessive copper accumulation in the liver and brain, leading to subsequent hepatic and/or neurological disorders. The causative gene for WD has been identified as the ATPase Cu2+ transporting beta polypeptide gene (ATP7B), which encodes a protein called copper-transporting ATPase 2. ATP7B mutations may lead to reduced biliary excretion of excess copper and disrupted copper homeostasis, resulting in various clinical symptoms of WD.\nMETHODS: Direct sequencing of the ATP7B gene was performed in 7 Han Chinese families with WD, and haplotype analysis was conducted in families having the same mutation.\nRESULTS: Nine ATP7B gene mutations were identified, including 7 missense mutations (p.Asp765Gly, p.Arg778Leu, p.Thr888Pro, p.Pro992Leu, p.Asp1047Val, p.Ile1148Thr and p.Ala1295Val), 1 duplication mutation (c.525dupA), and 1 nonsense mutation (p.Gly837*). Combined with our previous data, haplotype analysis revealed that the founder effect accounted for 48% of alleles in Han Chinese, constituted by high allele frequency mutations p.Arg778Leu, p.Pro992Leu and p.Ala1295Val.\nCONCLUSION: This study revealed genetic defects of 7 Han Chinese families with WD, and has implications for their genetic counseling and clinical management.","variants":[{"Name":"NM_000053.4(ATP7B):c.2294A>G (p.Asp765Gly)","Chromosome":"13","Start":"51958372","Stop":"51958372","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":487525,"rule_based_match":false,"evidence_text":"p.Asp765Gly","llm_judgment":"PRESENT","evidence":"p.Asp765Gly","abstract_start":787,"abstract_end":798},{"Name":"NM_000053.4(ATP7B):c.3140A>T (p.Asp1047Val)","Chromosome":"13","Start":"51944212","Stop":"51944212","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1063018,"rule_based_match":false,"evidence_text":"p.Asp1047Val","llm_judgment":"PRESENT","evidence":"p.Asp1047Val","abstract_start":839,"abstract_end":851},{"Name":"NM_000053.4(ATP7B):c.2333G>T (p.Arg778Leu)","Chromosome":"13","Start":"51958333","Stop":"51958333","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":18891,"rule_based_match":false,"evidence_text":"p.Arg778Leu","llm_judgment":"PRESENT","evidence":"p.Arg778Leu","abstract_start":800,"abstract_end":811},{"Name":"NM_000053.4(ATP7B):c.3443T>C (p.Ile1148Thr)","Chromosome":"13","Start":"51941194","Stop":"51941194","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18902,"rule_based_match":false,"evidence_text":"p.Ile1148Thr","llm_judgment":"PRESENT","evidence":"p.Ile1148Thr","abstract_start":853,"abstract_end":865}]}
{"pmid":"24746959","title":"Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome.","abstract":"Homozygosity for a recurrent 290 kb deletion of NPHP1 is the most frequent cause of isolated nephronophthisis (NPHP) in humans. A deletion of the same genomic interval has also been detected in individuals with Joubert syndrome (JBTS), and in the mouse, Nphp1 interacts genetically with Ahi1, a known JBTS locus. Given these observations, we investigated the contribution of NPHP1 in Bardet-Biedl syndrome (BBS), a ciliopathy of intermediate severity. By using a combination of array-comparative genomic hybridization, TaqMan copy number assays, and sequencing, we studied 200 families affected by BBS. We report a homozygous NPHP1 deletion CNV in a family with classical BBS that is transmitted with autosomal-recessive inheritance. Further, we identified heterozygous NPHP1 deletions in two more unrelated persons with BBS who bear primary mutations at another BBS locus. In parallel, we identified five families harboring an SNV in NPHP1 resulting in a conserved missense change, c.14G>T (p.Arg5Leu), that is enriched in our Hispanic pedigrees; in each case, affected individuals carried additional bona fide pathogenic alleles in another BBS gene. In vivo functional modeling in zebrafish embryos demonstrated that c.14G>T is a loss-of-function variant, and suppression of nphp1 in concert with each of the primary BBS loci found in our NPHP1-positive pedigrees exacerbated the severity of the phenotype. These results suggest that NPHP1 mutations are probably rare primary causes of BBS that contribute to the mutational burden of the disorder.","variants":[{"Name":"NM_001128178.3(NPHP1):c.14G>T (p.Arg5Leu)","Chromosome":"2","Start":"110204955","Stop":"110204955","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":135260,"rule_based_match":true,"evidence_text":"c.14G>T (p.Arg5Leu)","llm_judgment":"PRESENT","evidence":"c.14G>T (p.Arg5Leu)","abstract_start":983,"abstract_end":1002}]}
{"pmid":"30457409","title":"Molecular characterization of Axenfeld-Rieger spectrum and other anterior segment dysgeneses in a sample of Mexican patients.","abstract":"BACKGROUND: Anterior segment dysgenesis (ASD) and Axenfeld-Rieger spectrum (ARS) are mainly due to PITX2 and FOXC1 defects, but it is difficult in some patients to differentiate among PITX2-, FOXC1-, PAX6- and CYP1B1-related disorders. Here, we set out to characterize the pathogenic variants (PV) in PITX2, FOXC1, CYP1B1 and PAX6 in nine unrelated Mexican ARS/ASD patients and in their available affected/unaffected relatives.\nMATERIALS AND METHODS: Automated Sanger sequencing of PITX2, FOXC1, PAX6 and CYP1B1 was performed; those patients without a PV were subsequently analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA) for PITX2, FOXC1 and PAX6. Missense variants were evaluated with the MutPred, Provean, PMUT, SIFT, PolyPhen-2, CUPSAT and HOPE programs.\nRESULTS: We identified three novel PV in PITX2 (NM_153427.2:c.217G>A, c.233T>C and c.279del) and two in FOXC1 [NM_001453.2:c.274C>T (novel) and c.454T>A] in five ARS patients. The previously reported FOXC1 c.367C>T or p.(Gln123*) variant was identified in a patient with ASD. The ocular phenotype related to FOXC1 included aniridia, corneal opacity and early onset glaucoma, while an asymmetric ocular phenotype and aniridia were associated with PITX2. No gene rearrangements were documented by MLPA analysis, nor were any PV identified in PAX6 or CYP1B1.\nCONCLUSIONS: Heterozygous PV in the PITX2 and FOXC1 genes accounted for 66% (6/9) of the ARS/ASD cases. The absence of PAX6 or CYP1B1 abnormalities could reflect our small sample size, although their analysis could be justified in ARS/ASD patients that present with congenital glaucoma or aniridia.","variants":[{"Name":"NM_001453.3(FOXC1):c.367C>T (p.Gln123Ter)","Chromosome":"6","Start":"1610812","Stop":"1610812","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":831736,"rule_based_match":true,"evidence_text":"FOXC1 c.367C>T or p.(Gln123*)","llm_judgment":"PRESENT","evidence":"FOXC1 c.367C>T or p.(Gln123*)","abstract_start":978,"abstract_end":1007},{"Name":"NM_001453.3(FOXC1):c.274C>T (p.Gln92Ter)","Chromosome":"6","Start":"1610719","Stop":"1610719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1685579,"rule_based_match":true,"evidence_text":"NM_001453.2:c.274C>T","llm_judgment":"PRESENT","evidence":"NM_001453.2:c.274C>T","abstract_start":889,"abstract_end":909}]}
{"pmid":"27862672","title":"Clinical and genetic spectra of Charcot-Marie-Tooth disease in Chinese Han patients.","abstract":"Charcot-Marie-Tooth disease (CMT) is a common hereditary motor and sensory neuropathy. Epidemiological data for Chinese CMT patients are few. This study aimed to analyze the electrophysiological and genetic characteristics of Chinese Han patients. A total of 106 unrelated patients with the clinical diagnosis of CMT were included. Clinical examination, nerve conduction studies (NCS), next-generation sequencing (NGS), and bioinformatic analyses were performed. Genetic testing was performed for 82 patients; 27 (33%) patients carried known CMT-associated gene mutations. PMP22 duplication was detected in 10 (12%) patients and GJB1 mutations in 9 (11%) patients. The mutation rate was higher in patients with a positive family history than in the sporadic cases (50% vs. 27%, p < 0.05). Six novel CMT-associated gene mutations including BSCL2 (c.461C>T), LITAF (c.32C>G), MFN2 (c.497C>T), GARS (c.794C>T), NEFL (c.280C>T), and MPZ (c.440T>C) were discovered. All except the LITAF (c.32C>G) mutation were identified as \"disease causing\" via bioinformatic analyses. In this Chinese Han population, the frequency of PMP22 gene duplication in those with CMT1 was slightly (50% vs. 70%-80%) less than in Western/Caucasian populations. The novel CMT-associated gene mutations broaden the mutation diversity of CMT1. NGS should be considered for genetic analyses in CMT patients.","variants":[{"Name":"NM_014874.4(MFN2):c.497C>T (p.Ala166Val)","Chromosome":"1","Start":"11997319","Stop":"11997319","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":556900,"rule_based_match":true,"evidence_text":"MFN2 (c.497C>T)","llm_judgment":"PRESENT","evidence":"MFN2 (c.497C>T)","abstract_start":874,"abstract_end":889},{"Name":"NM_002047.4(GARS1):c.794C>T (p.Ser265Phe)","Chromosome":"7","Start":"30609643","Stop":"30609643","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":457766,"rule_based_match":true,"evidence_text":"c.794C>T","llm_judgment":"PRESENT","evidence":"c.794C>T","abstract_start":897,"abstract_end":905},{"Name":"NM_001122955.4(BSCL2):c.461C>T (p.Ser154Leu)","Chromosome":"11","Start":"62702493","Stop":"62702493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19583,"rule_based_match":true,"evidence_text":"BSCL2 (c.461C>T)","llm_judgment":"PRESENT","evidence":"BSCL2 (c.461C>T)","abstract_start":839,"abstract_end":855}]}
{"pmid":"19103789","title":"Simultaneous detection of mitochondrial DNA depletion and single-exon deletion in the deoxyguanosine gene using array-based comparative genomic hybridisation.","abstract":"Intragenic exonic deletions, which cannot be detected by direct DNA sequencing, are a common cause of Mendelian disease. Array-based comparative genomic hybridisation (aCGH) is now widely used for the clinical diagnosis of large chromosomal deletions, but not small deletions or analysis of the mitochondrial genome. An oligonucleotide-based microarray that provides high-density coverage of the entire mitochondrial genome and nuclear genes related to mitochondrial disorders has been developed. In this report, the case of an infant referred with tyrosinaemia on newborn screening who developed liver failure is presented. DNA sequencing revealed a heterozygous missense mutation (c.679G>A, p.E227K) in the deoxyguanosine gene (DGUOK). Oligonucleotide aCGH allowed simultaneous detection of an intragenic heterozygous deletion of exon 4 of DGUOK and mitochondrial DNA depletion in blood and liver. Screening of the parents' DNA samples indicated that the patient was compound heterozygous for these mutations. An older sibling who had died from liver failure was then retrospectively diagnosed with the same mutations. This report shows the clinical utility of this oligoarray in the detection of changes in DNA copy number in both the mitochondrial and nuclear genomes, thus greatly improving the molecular diagnosis of mitochondrial disorders caused by nuclear genes involved in mitochondrial DNA biosynthesis.","variants":[{"Name":"NM_080916.3(DGUOK):c.679G>A (p.Glu227Lys)","Chromosome":"2","Start":"73957212","Stop":"73957212","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23197,"rule_based_match":true,"evidence_text":"c.679G>A, p.E227K","llm_judgment":"PRESENT","evidence":"c.679G>A, p.E227K","abstract_start":683,"abstract_end":700}]}
{"pmid":"22498944","title":"A low-grade ovarian carcinoma case with coincident LOH of PTCH1 and BRCA1, and a mutation in BRCA1.","abstract":"We report a case of a 53-year-old woman with Grade 1 serous cystadenocarcinoma on her left ovary and metastatic serous adenocarcinoma on her right ovary. Serous carcinoma is the most common type of ovarian cancer, representing approximately half of all cases. Because of positive family history, the patient was referred for BRCA1/2 screening. Germline BRCA1 mutation c.676delT (p.C226VfsX8) was found, and in tumor tissue the normal allele was lost. Tumor tissue also had loss of heterozygosity in the PTCH1 gene, one of the major members of the Hedgehog-Gli (Hh-Gli) pathway. Gene expression analysis showed upregulation of the Hh-Gli pathway in both ovaries compared with healthy ovarian tissue. Primary cell culture was developed from the patient's tissue and showed downregulation of gene expression in response to cyclopamine, a Hh-Gli pathway inhibitor. The Hh-Gli signaling pathway may play a role in malignant transformation and metastasis of ovarian cancer.","variants":[{"Name":"NM_007294.4(BRCA1):c.676del (p.Cys226fs)","Chromosome":"17","Start":"43094855","Stop":"43094855","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":46249,"rule_based_match":true,"evidence_text":"c.676delT (p.C226VfsX8)","llm_judgment":"PRESENT","evidence":"c.676delT (p.C226VfsX8)","abstract_start":368,"abstract_end":391}]}
{"pmid":"23225041","title":"Analysis of clinical data and genetic mutations in three Chinese patients with tyrosinemia type I","abstract":"OBJECTIVE: To analyze clinical data and gene mutations in 3 Chinese patients with tyrosinemia type I, and to explore the correlation between genotypes and phenotypes.\nMETHODS: Three patients suspected with tyrosinemia I were tested by tandem mass spectrometry for the level of tyrosine, phenylalanine and succinylacetone in the blood, and by gas chromatography-mass spectrometry to determine the level of succinylacetone and organic acid in their urine. With the diagnosis established, the FAH gene was analyzed with polymerase chain reaction (PCR) and direct sequencing.\nRESULTS: Two patients had acute onset of the disease, while another had subacute onset of the disease, with features including hepatomegaly and remarkably increased tyrosine and succinylacetone in the blood. Five mutations were detected in the FAH gene, which included c.455G>A (W152X), c.520C>T (R174X), c.974_976delCGAinsGC, c.1027 G>A (G343R) and c.1100 G>A (W367X), among which c.455G>A (W152X), c.974_976delCGAinsGC and c.1100 G>A (W367X) were not reported previously.\nCONCLUSION: Tyrosinemia type I may be effectively diagnosed with the level of tyrosine and succinylacetone by tandem mass spectrometry and succinylacetone in the urine by gas chromatography mass spectrometry. Detection of underlying mutations mutations will be helpful for genetic counseling and further research.","variants":[{"Name":"NM_000137.4(FAH):c.1027G>A (p.Gly343Arg)","Chromosome":"15","Start":"80180190","Stop":"80180190","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":547616,"rule_based_match":true,"evidence_text":"c.1027 G>A (G343R)","llm_judgment":"PRESENT","evidence":"c.1027 G>A (G343R)","abstract_start":899,"abstract_end":917},{"Name":"NM_000137.4(FAH):c.455G>A (p.Trp152Ter)","Chromosome":"15","Start":"80162336","Stop":"80162336","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":358330,"rule_based_match":true,"evidence_text":"c.455G>A (W152X)","llm_judgment":"PRESENT","evidence":"c.455G>A (W152X)","abstract_start":841,"abstract_end":857},{"Name":"NM_000137.4(FAH):c.520C>T (p.Arg174Ter)","Chromosome":"15","Start":"80168116","Stop":"80168116","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186943,"rule_based_match":true,"evidence_text":"c.520C>T (R174X)","llm_judgment":"PRESENT","evidence":"c.520C>T (R174X)","abstract_start":859,"abstract_end":875}]}
{"pmid":"23384994","title":"Hereditary motor and sensory neuropathy (HMSN) type X1 in an Argentinean family reveals independent GJB1/Cx32 mutations at the identical nucleotide position.","abstract":"X-linked Charcot-Marie-Tooth disease (CMT Type X1, OMIM: 302800) represents a frequent cause of hereditary peripheral motor and sensory neuropathies and is associated with mutations in GJB1 encoding the gap junction beta 1 protein connexin 32 (Cx32). Studying an Argentinean family of Italian origin with seven affected males in three generations exhibiting clinical signs of CMT, eight obligate female carriers were identified genealogically. DNA sequencing of exon 2 and adjacent regions of the GJB1 gene in two symptomatic males whose respective maternal grandfathers, both affected, were brothers, revealed mutations in GJB1/Cx32. Surprisingly, each of the two affected patients had a different mutation in hemizygous state at the same nucleotide position: c.383C>T (p.S128L) and c.383C>A (p.S128X). In both cases, the identified mutation was present in heterozygous state in the corresponding maternal genomic DNA. Furthermore, X-chromosomal microsatellite analysis showed identical marker alleles in both patients. Together with the genealogical information, these molecular data imply that a primarily mutated allele mutated for a second time. In conclusion, two different mutations at the same nucleotide position in this Argentinean family represent a finding with a very low probability of occurrence.","variants":[{"Name":"NM_000166.6(GJB1):c.383C>A (p.Ser128Ter)","Chromosome":"X","Start":"71224090","Stop":"71224090","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":625591,"rule_based_match":true,"evidence_text":"c.383C>A (p.S128X)","llm_judgment":"PRESENT","evidence":"c.383C>A (p.S128X)","abstract_start":784,"abstract_end":802}]}
{"pmid":"28796317","title":"Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations.","abstract":"In addition to BRCA1 and BRCA2, RAD51C, PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C, PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non-synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second-degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.","variants":[{"Name":"NM_032043.3(BRIP1):c.736A>G (p.Ile246Val)","Chromosome":"17","Start":"61808649","Stop":"61808649","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":468505,"rule_based_match":true,"evidence_text":"c.736A>G","llm_judgment":"PRESENT","evidence":"c.736A>G","abstract_start":571,"abstract_end":579},{"Name":"NM_032043.3(BRIP1):c.918+2T>C","Chromosome":"17","Start":"61808465","Stop":"61808465","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":815705,"rule_based_match":true,"evidence_text":"c.918+2T>C","llm_judgment":"PRESENT","evidence":"c.918+2T>C","abstract_start":627,"abstract_end":637},{"Name":"NM_032043.3(BRIP1):c.2131A>G (p.Thr711Ala)","Chromosome":"17","Start":"61744558","Stop":"61744558","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":468415,"rule_based_match":true,"evidence_text":"c.2131A>G","llm_judgment":"PRESENT","evidence":"c.2131A>G","abstract_start":584,"abstract_end":593}]}
{"pmid":"37107582","title":"The Expanding Phenotypical Spectrum of","abstract":"Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (<i>WARS2</i>) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor-parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor-parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T>G; p.Trp13Gly) either together with a previously described truncating variant (NM_015836.4: c.797Cdel; p.Pro266ArgfsTer10), a novel truncating variant (NM_015836.4: c.346C>T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G>A), or a novel missense variant (NM_015836.4: c.475A>C, p.Thr159Pro). We investigated the mitochondrial function in patients and found increased levels of mitochondrially encoded cytochrome C Oxidase II as part of the mitochondrial respiratory chain as well as decreased mitochondrial integrity and branching. Finally, we conducted a literature review and here summarize the broad phenotypical spectrum of reported <i>WARS2</i>-related disorders. In conclusion, <i>WARS2</i>-related disorders are diagnostically challenging diseases due to the broad phenotypic spectrum and the disease relevance of a relatively common missense change that is often filtered out in a diagnostic setting since it occurs in ~0.5% of the general European population.","variants":[{"Name":"NM_015836.4(WARS2):c.37T>G (p.Trp13Gly)","Chromosome":"1","Start":"119140608","Stop":"119140608","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":434543,"rule_based_match":true,"evidence_text":"NM_015836.4: c.37T>G; p.Trp13Gly","llm_judgment":"PRESENT","evidence":"NM_015836.4: c.37T>G; p.Trp13Gly","abstract_start":420,"abstract_end":452}]}
{"pmid":"27414491","title":"Variable bleeding phenotype in an Amish pedigree with von Willebrand disease.","abstract":"Through a cross-sectional study design, the bleeding phenotype in the Amish in Indiana (IN) and Wisconsin (WI) was described using two different bleeding scores. von Willebrand factor (VWF) testing was performed and bleeding questionnaires from Centers for Disease Control and Prevention (CDC) and European MCMDM-1 (Tosetto bleeding score (BS)) were administered to the IN and WI cohort respectively. Seven hundred and seventy nine subjects were recruited, 17% were diagnosed with VWD based on Ristocetin cofactor, VWF:RCo < 30 IU/dl. Majority of the affected (AF), 67%, were tested and had a common mutation c.4120 C > T. The WI AF were much younger at a mean age 15 years vs 26 years in IN AF cohort. The AF subjects had a median VWF:RCo of 13IU/dl with a statistically significant higher median BS 1 versus 0 in the WI AF vs WI Unaffected (UA), 2 vs 1 in the IN AF vs IN UA, P < 0.01. Adults had a higher median BS compared to children in the WI and IN cohort, 2 vs 1 and 3 vs 1 respectively (P < 0.05) but there was no statistically significant difference in the BS between males and females in either cohort. The common symptoms reported were epistaxis and gingival oozing. BS ≥ 3 and BS ≥ 4 were observed in 46% of AF IN and 16.6% of AF WI, respectively. There was significant variability in the bleeding phenotype, with an overall low BS in the affected Amish with VWD, despite a unifying mutation. Am. J. Hematol. 91:E431-E435, 2016. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_000552.5(VWF):c.4120C>T (p.Arg1374Cys)","Chromosome":"12","Start":"6019298","Stop":"6019298","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":106206,"rule_based_match":true,"evidence_text":"c.4120 C > T","llm_judgment":"PRESENT","evidence":"c.4120 C > T","abstract_start":609,"abstract_end":621}]}
{"pmid":"23863954","title":"Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population.","abstract":"BACKGROUND: Dominant mutations in cellular junction proteins are the major cause of arrhythmogenic cardiomyopathy, whereas recessive mutations in those proteins cause cardiocutaneous syndromes such as Naxos and Carvajal syndrome. The Hutterites are distinct genetic isolates who settled in North America in 1874. Descended from <100 founders, they trace their origins to 16th-century Europe.\nMETHODS AND RESULTS: We clinically and genetically evaluated 2 large families of the Alberta Hutterite population with a history of sudden death and found several individuals with severe forms of biventricular cardiomyopathy characterized by mainly left-sided localized aneurysms, regions of wall thinning with segmental akinesis, in addition to typical electric and histological features known for arrhythmogenic right ventricular cardiomyopathy. We identified a homozygous truncation mutation, c.1660C>T (p.Q554X) in desmocollin-2 (DSC2), in affected individuals and determined a carrier frequency of this mutation of 9.4% (1 in 10.6) among 1535 Schmiedeleut Hutterites, suggesting a common founder in that subgroup. Immunohistochemistry of endomyocardial biopsy samples revealed altered expression of the truncated DSC2 protein at the intercalated discs but only minor changes in immunoreactivity of other desmosomal proteins. Recombinant expressed mutant DSC2 protein in cells confirmed a stable, partially processed truncated protein with cytoplasmic and membrane localization.\nCONCLUSIONS: A homozygous truncation mutation in DSC2 leads to a cardiac-restricted phenotype of an early onset biventricular arrhythmogenic cardiomyopathy. The truncated protein remains partially stable and localized at the intercalated discs. These data suggest that the processed DSC2 protein plays a role in maintaining desmosome integrity and function.","variants":[{"Name":"NM_024422.6(DSC2):c.1660C>T (p.Gln554Ter)","Chromosome":"18","Start":"31079850","Stop":"31079850","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":237539,"rule_based_match":true,"evidence_text":"c.1660C>T (p.Q554X)","llm_judgment":"PRESENT","evidence":"c.1660C>T (p.Q554X)","abstract_start":888,"abstract_end":907}]}
{"pmid":"23810379","title":"SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling.","abstract":"The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85α regulatory subunit, encoded by PIK3R1. Using whole-exome sequencing, we identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome). This mutation led to impaired interaction between p85α and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling.","variants":[{"Name":"NM_181523.3(PIK3R1):c.1945C>T (p.Arg649Trp)","Chromosome":"5","Start":"68296301","Stop":"68296301","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75301,"rule_based_match":true,"evidence_text":"c.1945C>T (p.Arg649Trp)","llm_judgment":"PRESENT","evidence":"p.Arg649Trp","abstract_start":313,"abstract_end":324}]}
{"pmid":"29344738","title":"Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia.","abstract":"PURPOSE: The aim of this study was to analyze the genetic and functional role of a novel RYR1 variant c.251 C > T (p.Thr84Met) identified in a patient with muscle weakness demonstrating MH susceptibility.\nMETHODS: DNA testing of family members was conducted for assessment of pathogenicity of the genetic variant. For functional analysis, Ca<sup>2+</sup> measurement using patient-derived myotubes and p.Thr84Met RYR1-transfected human embryonic kidney (HEK)-293 cells was performed to evaluate reactivity to RYR1 activators. The half-maximal effective concentration (EC<sub>50</sub>) values of two RYR1 activators, caffeine and 4-chloro-m-cresol (4CmC), were calculated from the acquired dose-response curves. The EC<sub>50</sub> was compared between two groups: for myotubes, the control group and the patient, and for HEK-293 cells, WT and p.Thr84Met.\nRESULTS: Dose-response curves for caffeine and 4CmC were shifted to the left in both myotubes and HEK-293 cells compared to controls. The 50% effective concentration values for caffeine and 4CmC were significantly lower in both myotubes and HEK-293 cells compared to controls (P < 0.001 for all comparisons).\nCONCLUSIONS: Our results of functional testing indicated RYR1 hypersensitivity to caffeine and 4CmC. We conclude that the genetic variant was associated with MH susceptibility.","variants":[{"Name":"NM_000540.3(RYR1):c.251C>T (p.Thr84Met)","Chromosome":"19","Start":"38442434","Stop":"38442434","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":797800,"rule_based_match":true,"evidence_text":"c.251 C > T (p.Thr84Met)","llm_judgment":"PRESENT","evidence":"c.251 C > T (p.Thr84Met)","abstract_start":102,"abstract_end":126}]}
{"pmid":"34804722","title":"Vacuolar Myopathy Associated to CACNA1S Mutation as a Rare Cause of Late-Onset Limb-Girdle Myopathy: A Case Report.","abstract":"Late-onset limb-girdle myopathies pose a diagnostic challenge. The most common etiologies are inflammatory, followed by genetic and metabolic. Rare cases include limb-girdle dystrophies and permanent myopathies (vacuolar), such as those associated with hypokalemic periodic paralysis (HypoPP). We present the case of a 59-year-old male who initiated with episodic acute severe weakness when he was 11, during which serum potassium levels of <2.5 meq/L were revealed during workup. Potassium reposition reversed these episodes. They occurred every three to five years, and the last episode was five years prior to the current illness. When he was 58, he presented progressive pelvic girdle weakness. On examination, he presented decreased strength in the iliopsoas and quadriceps. The laboratory results showed mildly elevated creatine kinase. Muscle biopsy revealed a vacuolar myopathy, and genetic testing identified a pathogenic variant in the CACNA1S gene, locus 1q32.1 <i>[c.3716G> A (p.Arg1239His), heterozygous state].</i>","variants":[{"Name":"NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His)","Chromosome":"1","Start":"201053538","Stop":"201053538","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32662,"rule_based_match":true,"evidence_text":"c.3716G> A (p.Arg1239His)","llm_judgment":"PRESENT","evidence":"c.3716G> A (p.Arg1239His)","abstract_start":977,"abstract_end":1002}]}
{"pmid":"29422660","title":"Deep intronic variation in splicing regulatory element of the ERCC8 gene associated with severe but long-term survival Cockayne syndrome.","abstract":"Cockayne syndrome is an autosomal recessive multisystem disorder characterized by intellectual disability, microcephaly, severe growth failure, sensory impairment, peripheral neuropathy, and cutaneous sensitivity. This rare disease is linked to disease-causing variations in the ERCC6 (CSB) and ERCC8 (CSA) genes. Various degrees of severity have been described according to age at onset and survival, without any clear genotype-phenotype correlation. All types of nucleotide changes have been observed in CS genes, including splice variations mainly affecting the splice site consensus sequences. We report here the case of two brothers from a consanguineous family presenting a severe but long-term survival phenotype of Cockayne syndrome. We identified in the patients a homozygous deep intronic nucleotide variation causing the insertion of a cryptic exon in the ERCC8 (CSA) transcript, by modifying intronic regulatory elements important for exon definition. The pathogenesis of the nucleotide variant NG_009289.1(NM_000082.3):c.173+1119G>C was validated in vitro with a reporter minigene system. To our knowledge, these are the first Cockayne patients described with this kind of disease-causing variation, though molecular mechanism underlying early onset symptoms and unexpected slow raise of progression of the disease remain to be elucidated.","variants":[{"Name":"NM_000082.4(ERCC8):c.173+1119G>C","Chromosome":"5","Start":"60927745","Stop":"60927745","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":384613,"rule_based_match":true,"evidence_text":"NG_009289.1(NM_000082.3):c.173+1119G>C","llm_judgment":"PRESENT","evidence":"NG_009289.1(NM_000082.3):c.173+1119G>C","abstract_start":1007,"abstract_end":1045}]}
{"pmid":"27227907","title":"Variants of the CDH1 (E-Cadherin) Gene Associated with Oral Clefts in the Thai Population.","abstract":"OBJECTIVE: The etiology of oral clefts in humans is genetically complex and mutations in multiple genes have been linked with clefting. CDH1 (E-cadherin) has been found to be involved in lip and palate development, and CDH1 mutations are associated with oral clefts in some populations.\nMATERIALS AND METHODS: To determine if there is an association between CDH1 and oral clefting in a Thai population, we sequenced the entire 6.5-kb coding region of the CDH1 gene in 80 oral cleft patients and compared the identified variants with those found in 138 unrelated Thai individuals who did not have oral clefts, as genotyped by exome sequencing.\nRESULTS: Among the oral cleft patients, four nonsynonymous single nucleotide variants (SNVs), c.1235T>C (p.V412A), c.1273G>A (p.V425I), c.1565C>T (p.T522I), and c.1888C>G (p.L630V), were identified. Only one nonsynonymous variant (c.1409C>T; p.T470I) was found among the 138 noncleft exomes. The frequency of nonsynonymous SNVs on the CDH1 gene in oral cleft patients (4/80) was significantly higher than that in the control group (1/138) (p = 0.042).\nCONCLUSION: We found that nonsynonymous variants of CDH1 were associated with oral clefts in the Thai population.","variants":[{"Name":"NM_004360.5(CDH1):c.1235T>C (p.Val412Ala)","Chromosome":"16","Start":"68813410","Stop":"68813410","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":949504,"rule_based_match":true,"evidence_text":"c.1235T>C (p.V412A)","llm_judgment":"PRESENT","evidence":"c.1235T>C (p.V412A)","abstract_start":737,"abstract_end":756},{"Name":"NM_004360.5(CDH1):c.1888C>G (p.Leu630Val)","Chromosome":"16","Start":"68822177","Stop":"68822177","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":137585,"rule_based_match":true,"evidence_text":"c.1888C>G (p.L630V)","llm_judgment":"PRESENT","evidence":"c.1888C>G (p.L630V)","abstract_start":804,"abstract_end":823},{"Name":"NM_004360.5(CDH1):c.1565C>T (p.Thr522Ile)","Chromosome":"16","Start":"68815759","Stop":"68815759","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":213204,"rule_based_match":true,"evidence_text":"c.1565C>T (p.T522I)","llm_judgment":"PRESENT","evidence":"c.1565C>T (p.T522I)","abstract_start":779,"abstract_end":798},{"Name":"NM_004360.5(CDH1):c.1273G>A (p.Val425Ile)","Chromosome":"16","Start":"68813448","Stop":"68813448","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133366,"rule_based_match":true,"evidence_text":"c.1273G>A (p.V425I)","llm_judgment":"PRESENT","evidence":"c.1273G>A (p.V425I)","abstract_start":758,"abstract_end":777},{"Name":"NM_004360.5(CDH1):c.1409C>T (p.Thr470Ile)","Chromosome":"16","Start":"68815603","Stop":"68815603","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":133370,"rule_based_match":true,"evidence_text":"c.1409C>T; p.T470I","llm_judgment":"PRESENT","evidence":"c.1409C>T; p.T470I","abstract_start":874,"abstract_end":892}]}
{"pmid":"22865819","title":"Mutations of ANK3 identified by exome sequencing are associated with autism susceptibility.","abstract":"Autism spectrum disorders (ASDs) are common neurodevelopmental disorders with a strong genetic etiology. However, due to the extreme genetic heterogeneity of ASDs, traditional approaches for gene discovery are challenging. Next-generation sequencing technologies offer an opportunity to accelerate the identification of the genetic causes of ASDs. Here, we report the results of whole-exome sequence in a cohort of 20 ASD patients. By extensive bioinformatic analysis, we identified novel mutations in seven genes that are implicated in synaptic function and neurodevelopment. After sequencing an additional 47 ASD samples, we identified three different missense mutations in ANK3 in four unrelated ASD patients, one of which, c.4705T>G (p.S1569A), is a de novo mutation. Given the fact that ANK3 has been shown to strongly associate with schizophrenia and bipolar disorder, our findings support an association between ANK3 mutations and ASD susceptibility and imply a shared molecular pathophysiology between ASDs and other neuropsychiatric disorders.","variants":[{"Name":"NM_020987.5(ANK3):c.4705T>G (p.Ser1569Ala)","Chromosome":"10","Start":"60076176","Stop":"60076176","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":94237,"rule_based_match":true,"evidence_text":"c.4705T>G (p.S1569A)","llm_judgment":"PRESENT","evidence":"c.4705T>G (p.S1569A)","abstract_start":727,"abstract_end":747}]}
{"pmid":"28145909","title":"Novel TBX3 mutation in a family of Cypriot ancestry with ulnar-mammary syndrome.","abstract":"Ulnar-mammary syndrome (UMS) is an autosomal dominant disorder resulting from TBX3 haploinsufficiency. It typically affects limb, apocrine gland, hair, tooth and genital development and shows marked intrafamilial and interfamilial variability in phenotypic expression. We report a family (twin brothers and their father) affected with UMS because of a novel TBX3 mutation. The twin brothers showed classical features of UMS, whereas their father was mildly affected. The c.1423C>T (p.Q475*) nonsense mutation in exon 6 of the TBX3 gene identified in the patients by targeted Sanger sequencing is predicted to lead to premature termination of translation. This is the first report of a Cypriot family with UMS resulting from a novel TBX3 mutation. This report provides additional evidence in support of the rich variability in phenotypic expression, the mutational heterogeneity and ethnic diversity associated with this rare condition.","variants":[{"Name":"NM_005996.4(TBX3):c.1423C>T (p.Gln475Ter)","Chromosome":"12","Start":"114674452","Stop":"114674452","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":404621,"rule_based_match":true,"evidence_text":"c.1423C>T (p.Q475*)","llm_judgment":"PRESENT","evidence":"c.1423C>T (p.Q475*)","abstract_start":471,"abstract_end":490}]}
{"pmid":"15365995","title":"Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families.","abstract":"Hereditary non-polyposis colorectal cancer (HNPCC), the most common hereditary colon cancer syndrome, is a dominant disorder caused by germline defects in mismatch repair (MMR) genes. Identification of MMR gene mutations can have direct clinical implications in counseling and management of HNPCC families. We screened 44 HNPCC and 97 suspected HNPCC Korean families for germline mutations in three MMR genes: MLH1, MSH2 and MSH6. We identified twelve novel mutations: nine in MLH1(c.632_633insT, c.808_811delACTT, c.845C>G, c.1625A>C, c.1730+1delG, c.1907T>C, c.1918C>T, c.2104-2A>G and c.2170T>A), two in MSH2 (c.1886A>G, c.1316_1318delCCT) and one in MSH6 (c.3488A>T). In addition, two statically significant cSNPs in MLH1: c.1128T>C ( p=0.008 in HNPCC and p=0.037 in early-onset CRC) and c.2168C>A ( p<0.001 in HNPCC). Interestingly, the most frequent mutation, c.1757_1758insC in MLH1, was a founder mutation inherited from a common Korean ancestor.","variants":[{"Name":"NM_000179.3(MSH6):c.3488A>T (p.Glu1163Val)","Chromosome":"2","Start":"47804959","Stop":"47804959","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":94874,"rule_based_match":true,"evidence_text":"c.3488A>T","llm_judgment":"PRESENT","evidence":"c.3488A>T","abstract_start":660,"abstract_end":669},{"Name":"NM_000249.4(MLH1):c.2104-2A>G","Chromosome":"3","Start":"37050484","Stop":"37050484","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":95528,"rule_based_match":true,"evidence_text":"c.2104-2A>G","llm_judgment":"PRESENT","evidence":"c.2104-2A>G","abstract_start":572,"abstract_end":583},{"Name":"NM_000249.4(MLH1):c.1907T>C (p.Leu636Pro)","Chromosome":"3","Start":"37048527","Stop":"37048527","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":95414,"rule_based_match":true,"evidence_text":"c.1907T>C","llm_judgment":"PRESENT","evidence":"c.1907T>C","abstract_start":550,"abstract_end":559},{"Name":"NM_000249.4(MLH1):c.1918C>T (p.Pro640Ser)","Chromosome":"3","Start":"37048538","Stop":"37048538","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":95419,"rule_based_match":true,"evidence_text":"c.1918C>T","llm_judgment":"PRESENT","evidence":"c.1918C>T","abstract_start":561,"abstract_end":570},{"Name":"NM_000249.4(MLH1):c.845C>G (p.Ala282Gly)","Chromosome":"3","Start":"37017560","Stop":"37017560","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":95865,"rule_based_match":true,"evidence_text":"c.845C>G","llm_judgment":"PRESENT","evidence":"c.845C>G","abstract_start":515,"abstract_end":523}]}
{"pmid":"16684598","title":"Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia.","abstract":"Spastic paraplegia type 4 is caused by mutations in the gene that encodes spastin (SPG4), a member of the AAA protein family. A cohort of 34 unrelated Italian patients with pure spastic paraplegia, of which 18 displayed autosomal dominant inheritance and 16 were apparently sporadic, were screened for mutations in the SPG4 gene by denaturing high performance liquid chromatography. We identified a previously reported mutation in a sporadic patient with pure hereditary spastic paraplegia. We also identified eight unrelated patients with pure autosomal dominant hereditary spastic paraplegia carrying five novel mutations in the SPG4 gene (one missense mutation, c.1304 C>T; one nonsense mutation, c.807C>A; two frameshift mutations, c.1281dupT, c.1514_1515insATA; and one splicing mutation, c.1322-2A>C). The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44.4%. This study contributes to expand the spectrum of SPG4 mutations in Italian population.","variants":[{"Name":"NM_014946.4(SPAST):c.1304C>T (p.Pro435Leu)","Chromosome":"2","Start":"32136621","Stop":"32136621","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1389587,"rule_based_match":true,"evidence_text":"c.1304 C>T","llm_judgment":"PRESENT","evidence":"c.1304 C>T","abstract_start":665,"abstract_end":675}]}
{"pmid":"33026150","title":"De novo variant in AMOTL1 in infant with cleft lip and palate, imperforate anus and dysmorphic features.","abstract":"AMOTL1 belongs to the Motin family of proteins that are involved in organogenesis and tumorigenesis through regulation of cellular migration, tube formation, and angiogenesis. While involvement of all AMOTs in development or suppression of cancers is relatively well described, little is known about the congenital phenotype of pathogenic variants in these genes in humans. Recently, a heterozygous variant in AMOTL1 was published in association with orofacial clefts and cardiac abnormalities in an affected father and his daughter. However, studies in mice did not recapitulate the human phenotype and the case was summarized as inconclusive. We present a female infant with cleft lip and palate, imperforate anus and dysmorphic features, in whom trio exome sequencing revealed a de novo variant in AMOTL1 affecting a highly conserved amino acid (c.479C>T; p.[Pro160Leu]). Bioinformatic predictions and in silico modeling supported pathogenicity. This case reinforces the conjecture regarding the disruptive effect of pathogenic variants in AMOTL1 on organ formation in humans. Studies of additional families will reveal the full phenotypic spectrum associated with this multiple malformation syndrome.","variants":[{"Name":"NM_130847.3(AMOTL1):c.479C>T (p.Pro160Leu)","Chromosome":"11","Start":"94799669","Stop":"94799669","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":917804,"rule_based_match":true,"evidence_text":"c.479C>T; p.[Pro160Leu]","llm_judgment":"PRESENT","evidence":"c.479C>T; p.[Pro160Leu]","abstract_start":849,"abstract_end":872}]}
{"pmid":"35136953","title":"NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.","abstract":"Mutations in nitrogen permease regulator-like 3 (NPRL3), a component of the GATOR1 complex within the mTOR pathway, are associated with epilepsy and malformations of cortical development. Little is known about the effects of NPRL3 loss on neuronal mTOR signalling and morphology, or cerebral cortical development and seizure susceptibility. We report the clinical phenotypic spectrum of a founder NPRL3 pedigree (c.349delG, p.Glu117LysFS; n = 133) among Old Order Mennonites dating to 1727. Next, as a strategy to define the role of NPRL3 in cortical development, CRISPR/Cas9 Nprl3 knockout in Neuro2a cells in vitro and in foetal mouse brain in vivo was used to assess the effects of Nprl3 knockout on mTOR activation, subcellular mTOR localization, nutrient signalling, cell morphology and aggregation, cerebral cortical cytoarchitecture and network integrity. The NPRL3 pedigree exhibited an epilepsy penetrance of 28% and heterogeneous clinical phenotypes with a range of epilepsy semiologies, i.e. focal or generalized onset, brain imaging abnormalities, i.e. polymicrogyria, focal cortical dysplasia or normal imaging, and EEG findings, e.g. focal, multi-focal or generalized spikes, focal or generalized slowing. Whole exome analysis comparing a seizure-free group (n = 37) to those with epilepsy (n = 24) to search for gene modifiers for epilepsy did not identify a unique genetic modifier that explained the variability in seizure penetrance in this cohort. Nprl3 knockout in vitro caused mTOR pathway hyperactivation, cell soma enlargement and the formation of cellular aggregates seen in time-lapse videos that were prevented with the mTOR inhibitors rapamycin or torin1. In Nprl3 knockout cells, mTOR remained localized on the lysosome in a constitutively active conformation, as evidenced by phosphorylation of ribosomal S6 and 4E-BP1 proteins, even under nutrient starvation (amino acid-free) conditions, demonstrating that Nprl3 loss decouples mTOR activation from neuronal metabolic state. To model human malformations of cortical development associated with NPRL3 variants, we created a focal Nprl3 knockout in foetal mouse cortex by in utero electroporation and found altered cortical lamination and white matter heterotopic neurons, effects which were prevented with rapamycin treatment. EEG recordings showed network hyperexcitability and reduced seizure threshold to pentylenetetrazol treatment. NPRL3 variants are linked to a highly variable clinical phenotype which we propose results from mTOR-dependent effects on cell structure, cortical development and network organization.","variants":[{"Name":"NM_001077350.3(NPRL3):c.349del (p.Glu117fs)","Chromosome":"16","Start":"117345","Stop":"117345","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":842983,"rule_based_match":true,"evidence_text":"c.349delG, p.Glu117LysFS","llm_judgment":"PRESENT","evidence":"c.349delG, p.Glu117LysFS","abstract_start":413,"abstract_end":437}]}
{"pmid":"28425126","title":"Novel sequence variants in the LIPH and LPAR6 genes underlies autosomal recessive woolly hair/hypotrichosis in consanguineous families.","abstract":"Autosomal-recessive woolly hair/hypotrichosis (ARWH/H) is a rare genetic disorder of hair caused by variants in the LIPH and LPAR6 genes. The disease is characterized by congenital tightly curled hair leading to sparse hair later in life. In the present report genetic characterization of three consanguineous families of Pakistani origin, displaying clinical features of ARWH/H, was performed. Haplotype and DNA sequence analysis of the LIPH gene revealed a novel homozygous nonsense variant (c.688C > T; p.Gln230*) in family A. In two other families, B and C, sequence analysis of the LPAR6 gene revealed a novel homozygous frameshift variant (c.68_69dupGCAT; p.Phe24Hisfs*29) and a previously reported missense variant (c.188A > T; p.Asp63Val), respectively. Taken together, our findings will expand the spectrum of variants reported in the LIPH and LPAR6 genes.","variants":[{"Name":"NM_001162498.3(LPAR6):c.188A>T (p.Asp63Val)","Chromosome":"13","Start":"48412236","Stop":"48412236","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":214140,"rule_based_match":true,"evidence_text":"c.188A > T (p.Asp63Val)","llm_judgment":"PRESENT","evidence":"c.188A > T","abstract_start":723,"abstract_end":733}]}
{"pmid":"30558828","title":"Cryptic intronic NBAS variant reveals the genetic basis of recurrent liver failure in a child.","abstract":"BACKGROUND: In almost half of patients with acute liver failure the cause is unknown, making targeted treatment and decisions about liver transplantation a challenge. Monogenic disorders may contribute to a significant proportion of these undiagnosed patients, and so the incorporation of technologies such as next generation sequencing (NGS) in the clinic could aid in providing a definitive diagnosis. However, this technology may present a major challenge in interpretation of sequence variants, particularly those in non-coding regions.\nRESULTS: In this report we describe a case of Infantile liver failure syndrome 2 (ILFS2; MIM 616483) due to novel bi-allelic variants in the NBAS gene. A missense variant NM_015909.3(NBAS):c.2617C > T, NP_056993.2(NBAS):p.(Arg873Trp) was identified by whole genome sequencing (WGS). By combining WGS and reverse transcription-polymerase chain reaction (RT-PCR) we were able to identify a novel deep intronic variant, NM_015909.3(NBAS):c.2423 + 404G > C, leading to the inclusion of a pseudo-exon. This mechanism has not been described previously in this syndrome.\nCONCLUSIONS: This study highlights the utility of analyzing NGS data in conjunction with investigating complementary DNA (cDNA) using techniques such as RT-PCR for detection of variants that otherwise would be likely to be missed in common NGS bioinformatic analysis pipelines. Combining these approaches, particularly when the phenotype match is strong, could lead to an increase in the diagnostic yield in acute liver failure and thus aid in targeted treatment, accurate genetic counseling and restoration of reproductive confidence.","variants":[{"Name":"NM_015909.4(NBAS):c.2617C>T (p.Arg873Trp)","Chromosome":"2","Start":"15417673","Stop":"15417673","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":857610,"rule_based_match":true,"evidence_text":"NM_015909.3(NBAS):c.2617C > T, NP_056993.2(NBAS):p.(Arg873Trp)","llm_judgment":"PRESENT","evidence":"NM_015909.3(NBAS):c.2617C > T, NP_056993.2(NBAS):p.(Arg873Trp)","abstract_start":712,"abstract_end":774},{"Name":"NM_015909.4(NBAS):c.2423+404G>C","Chromosome":"2","Start":"15427307","Stop":"15427307","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":857627,"rule_based_match":true,"evidence_text":"NM_015909.3(NBAS):c.2423 + 404G > C","llm_judgment":"PRESENT","evidence":"NM_015909.3(NBAS):c.2423 + 404G > C","abstract_start":958,"abstract_end":993}]}
{"pmid":"29684050","title":"Intronic PAH gene mutations cause a splicing defect by a novel mechanism involving U1snRNP binding downstream of the 5' splice site.","abstract":"Phenylketonuria (PKU), one of the most common inherited diseases of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Recently, PAH exon 11 was identified as a vulnerable exon due to a weak 3' splice site, with different exonic mutations affecting exon 11 splicing through disruption of exonic splicing regulatory elements. In this study, we report a novel intron 11 regulatory element, which is involved in exon 11 splicing, as revealed by the investigated pathogenic effect of variants c.1199+17G>A and c.1199+20G>C, identified in PKU patients. Both mutations cause exon 11 skipping in a minigene system. RNA binding assays indicate that binding of U1snRNP70 to this intronic region is disrupted, concomitant with a slightly increased binding of inhibitors hnRNPA1/2. We have investigated the effect of deletions and point mutations, as well as overexpression of adapted U1snRNA to show that this splicing regulatory motif is important for regulation of correct splicing at the natural 5' splice site. The results indicate that U1snRNP binding downstream of the natural 5' splice site determines efficient exon 11 splicing, thus providing a basis for development of therapeutic strategies to correct PAH exon 11 splicing mutations. In this work, we expand the functional effects of non-canonical intronic U1 snRNP binding by showing that it may enhance exon definition and that, consequently, intronic mutations may cause exon skipping by a novel mechanism, where they disrupt stimulatory U1 snRNP binding close to the 5' splice site. Notably, our results provide further understanding of the reported therapeutic effect of exon specific U1 snRNA for splicing mutations in disease.","variants":[{"Name":"NM_000277.3(PAH):c.1199+20G>C","Chromosome":"12","Start":"102843626","Stop":"102843626","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":108294,"rule_based_match":true,"evidence_text":"c.1199+20G>C","llm_judgment":"PRESENT","evidence":"c.1199+20G>C","abstract_start":546,"abstract_end":558}]}
{"pmid":"23430493","title":"Identification and Functional Characterization of GAA Mutations in Colombian Patients Affected by Pompe Disease.","abstract":"Pompe disease (PD) is a recessive metabolic disorder characterized by acid α-glucosidase (GAA) deficiency, which results in lysosomal accumulation of glycogen in all tissues, especially in skeletal muscles. PD clinical course is mainly determined by the nature of the GAA mutations. Although ~400 distinct GAA sequence variations have been described, the genotype-phenotype correlation is not always evident.In this study, we describe the first clinical and genetic analysis of Colombian PD patients performed in 11 affected individuals. GAA open reading frame sequencing revealed eight distinct mutations related to PD etiology including two novel missense mutations, c.1106 T > C (p.Leu369Pro) and c.2236 T > C (p.Trp746Arg). In vitro functional studies showed that the structural changes conferred by both mutations did not inhibit the synthesis of the 110 kD GAA precursor form but affected the processing and intracellular transport of GAA. In addition, analysis of previously described variants located at this position (p.Trp746Gly, p.Trp746Cys, p.Trp746Ser, p.Trp746X) revealed new insights in the molecular basis of PD. Notably, we found that p.Trp746Cys mutation, which was previously described as a polymorphism as well as a causal mutation, displayed a mild deleterious effect. Interestingly and by chance, our study argues in favor of a remarkable Afro-American and European ancestry of the Colombian population. Taken together, our report provides valuable information on the PD genotype-phenotype correlation, which is expected to facilitate and improve genetic counseling of affected individuals and their families.","variants":[{"Name":"NM_000152.5(GAA):c.2236T>G (p.Trp746Gly)","Chromosome":"17","Start":"80117014","Stop":"80117014","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":549190,"rule_based_match":false,"evidence_text":"p.Trp746Gly","llm_judgment":"PRESENT","evidence":"p.Trp746Gly","abstract_start":1027,"abstract_end":1038},{"Name":"NM_000152.5(GAA):c.1106T>C (p.Leu369Pro)","Chromosome":"17","Start":"80108519","Stop":"80108519","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1033723,"rule_based_match":true,"evidence_text":"c.1106 T > C (p.Leu369Pro)","llm_judgment":"PRESENT","evidence":"c.1106 T > C (p.Leu369Pro)","abstract_start":669,"abstract_end":695},{"Name":"NM_000152.5(GAA):c.2236T>C (p.Trp746Arg)","Chromosome":"17","Start":"80117014","Stop":"80117014","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":490717,"rule_based_match":true,"evidence_text":"c.2236 T > C (p.Trp746Arg)","llm_judgment":"PRESENT","evidence":"c.2236 T > C (p.Trp746Arg)","abstract_start":700,"abstract_end":726}]}
{"pmid":"25146893","title":"Identification of a novel pax8 gene sequence variant in four members of the same family: from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism.","abstract":"BACKGROUND: Congenital hypothyroidism is often secondary to thyroid dysgenesis, including thyroid agenesis, hypoplasia, ectopic thyroid tissue or cysts. Loss of function mutations in TSHR, PAX8, NKX2.1, NKX2.5 and FOXE1 genes are responsible for some forms of inherited congenital hypothyroidism, with or without hypoplastic thyroid. The aim of this study was to analyse the PAX8 gene sequence in several members of the same family in order to understand whether the variable phenotypic expression, ranging from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism, could be associated to the genetic variant in the PAX8 gene, detected in the proband.\nMETHODS: We screened a hypothyroid child with thyroid hypoplasia for mutations in PAX8, TSHR, NKX2.1, NKX2.5 and FOXE1 genes. We studied the inheritance of the new variant R133W detected in the PAX8 gene in the proband's family, and we looked for the same substitution in 115 Caucasian European subjects and in 26 hypothyroid children. Functional studies were performed to assess the in vitro effect of the newly identified PAX8 gene variant.\nRESULTS: A new heterozygous nucleotide substitution was detected in the PAX8 DNA-binding motif (c.397C/T, R133W) in the proband, affected by congenital hypothyroidism with thyroid hypoplasia, in his older sister, displaying a subclinical hypothyroidism associated with thyroid hypoplasia and thyroid nodules, in his father, affected by hypothyroidism with thyroid hypoplasia and thyroid nodules, and his first cousin as well, who revealed only a subclinical hypothyroidism. Functional studies of R133W-PAX8 in the HEK293 cells showed activation of the TG promoter comparable to the wild-type PAX8.\nCONCLUSIONS: In vitro data do not prove that R133W-PAX8 is directly involved in the development of the thyroid phenotypes reported for family members carrying the substitution. However, it is reasonable to conceive that, in the cases of transcriptions factors, such as Pax8, which establish several interactions in different protein complexes, genetic variants could have an impact in vivo.","variants":[{"Name":"NM_003466.4(PAX8):c.397C>T (p.Arg133Trp)","Chromosome":"2","Start":"113242771","Stop":"113242771","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":976570,"rule_based_match":false,"evidence_text":"c.397C/T, R133W","llm_judgment":"PRESENT","evidence":"c.397C/T, R133W","abstract_start":1223,"abstract_end":1238}]}
{"pmid":"38307397","title":"Evaluating the efficacy of a long-read sequencing-based approach in the clinical diagnosis of neonatal congenital adrenocortical hyperplasia.","abstract":"Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders predominantly characterized by impaired corticosteroid synthesis. Clinical phenotypes include hypoadrenocorticism, electrolyte disturbances, abnormal gonadal development, and short stature, of which severe hyponadrenocorticism and salt wasting can be life-threatening. Genetic analysis can help in the clinical diagnosis of CAH. However, the 21-OHD-causing gene CYP21A2 is arranged in tandem with the highly homologous CYP21A1P pseudogene, making it difficult to determine the exact genotypes using the traditional method of multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing or next-generation sequencing (NGS). We applied a long-read sequencing-based approach termed comprehensive analysis of CAH (CACAH) to 48 newborns with CAH that were diagnosed by clinical features and the traditional MLPA plus Sanger sequencing method for retrospective analysis, to evaluate its efficacy in the clinical diagnosis of neonatal CAH. Compared with the MLPA plus Sanger sequencing method, CACAH showed 100 % consistency in detecting SNV/indel variants located in exons and exon-intron boundary regions of CAH-related genes. It can directly determine the cis-trans relationship without the need to analyze parental genotypes, which reduces the time to diagnosis. Moreover, CACAH was able to distinguish different CYP21A1P/CYP21A2 and TNXA/TNXB chimeras, and detect additional variants (CYP21A2 variants c.-121C > T, c.*13G > A, c.*52C > T, c.*440C > T, c.*443 T > C, and TNXB variants c.12463 + 2 T > C, c.12204 + 5G > A). We also identified the TNXB variant c.11435_11524 + 30del alone instead of as a part of the TNXA/TNXB-CH-1 chimera in two newborns, which might be introduced by gene conversion. All of these characteristics enabled clinicians to better explain the phenotype of subjects and manage them more effectively. CACAH has a great advantage over the traditional MLPA and Sanger sequencing methods, showing substantial potential in the genetic diagnosis and screening of neonatal CAH.","variants":[{"Name":"NM_000500.9(CYP21A2):c.*13G>A","Chromosome":"6","Start":"32041147","Stop":"32041147","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":576926,"rule_based_match":true,"evidence_text":"c.*13G > A","llm_judgment":"PRESENT","evidence":"c.*13G > A","abstract_start":1512,"abstract_end":1522}]}
{"pmid":"31427715","title":"Lysinuric protein intolerance with homozygous SLC7A7 mutation caused by maternal uniparental isodisomy of chromosome 14.","abstract":"Lysinuric protein intolerance (LPI) is caused by mutations in the SLC7A7 gene at 14q11.2. Its clinical presentation includes failure to thrive, protein intolerance due to a secondary urea cycle defect, interstitial lung disease, renal tubulopathy, and immune disorders. Maternal uniparental disomy 14 (UPD14mat) is the most common cause of Temple syndrome (TS14), which is characterized by severe intrauterine and postnatal growth failure. Here, we describe a severe form of LPI accompanied by TS14 in an 11-month-old girl, which presented as profound failure to thrive and delayed development. LPI was diagnosed by the detection of a homozygous mutation of c.713 C>T (p.Ser238Phe) in SLC7A7, which was eventually found to co-occur with UPD14mat. Despite receiving a protein-restricted diet with citrulline and lysine supplementation, the severe failure to thrive has persisted at follow-up of the patient at 4 years of age.","variants":[{"Name":"NM_003982.4(SLC7A7):c.713C>T (p.Ser238Phe)","Chromosome":"14","Start":"22778850","Stop":"22778850","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":71015,"rule_based_match":true,"evidence_text":"c.713 C>T (p.Ser238Phe)","llm_judgment":"PRESENT","evidence":"c.713 C>T (p.Ser238Phe)","abstract_start":658,"abstract_end":681}]}
{"pmid":"14635119","title":"NDP gene mutations in 14 French families with Norrie disease.","abstract":"Norrie disease is a rare X-inked recessive condition characterized by congenital blindness and occasionally deafness and mental retardation in males. This disease has been ascribed to mutations in the NDP gene on chromosome Xp11.1. Previous investigations of the NDP gene have identified largely sixty disease-causing sequence variants. Here, we report on ten different NDP gene allelic variants in fourteen of a series of 21 families fulfilling inclusion criteria. Two alterations were intragenic deletions and eight were nucleotide substitutions or splicing variants, six of them being hitherto unreported, namely c.112C>T (p.Arg38Cys), c.129C>G (p.His43Gln), c.133G>A (p.Val45Met), c.268C>T (p.Arg90Cys), c.382T>C (p.Cys128Arg), c.23479-1G>C (unknown). No NDP gene sequence variant was found in seven of the 21 families. This observation raises the issue of misdiagnosis, phenocopies, or existence of other X-linked or autosomal genes, the mutations of which would mimic the Norrie disease phenotype.","variants":[{"Name":"NM_000266.4(NDP):c.268C>T (p.Arg90Cys)","Chromosome":"X","Start":"43949933","Stop":"43949933","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":361098,"rule_based_match":true,"evidence_text":"c.268C>T (p.Arg90Cys)","llm_judgment":"PRESENT","evidence":"c.268C>T (p.Arg90Cys)","abstract_start":685,"abstract_end":706},{"Name":"NM_000266.4(NDP):c.112C>T (p.Arg38Cys)","Chromosome":"X","Start":"43958534","Stop":"43958534","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":975628,"rule_based_match":true,"evidence_text":"c.112C>T (p.Arg38Cys)","llm_judgment":"PRESENT","evidence":"c.112C>T (p.Arg38Cys)","abstract_start":616,"abstract_end":637}]}
{"pmid":"29226118","title":"Identification of a Novel Heterozygous","abstract":"INTRODUCTION: Congenital anomalies of the kidney and urinary tract (CAKUT) represent the primary cause of chronic kidney disease in children. Many genes have been attributed to the genesis of this disorder. Recently, haploinsufficiency of <i>PBX1</i> caused by microdeletions has been shown to result in bilateral renal hypoplasia and other organ malformations.\nMATERIALS AND METHODS: Here, we report on a 14-year-old male patient with congenital bilateral dysplastic kidneys, cryptorchidism, hypoplastic clavicles, developmental delay, impaired intelligence, and minor dysmorphic features. Presuming a syndromic origin, we performed SNP array analysis to scan for large copy number variations (CNVs) followed by whole-exome sequencing (WES). Sanger sequencing was done to confirm the variant's <i>de novo</i> status.\nRESULTS: SNP array analysis did not reveal any microdeletions or -duplications larger than 50 or 100 kb, respectively. WES identified a novel heterozygous 7-bp frameshift deletion in <i>PBX1</i> (c.413_419del, p.Gly138Valfs*40) resulting in a loss-of-function. The <i>de novo</i> status could be confirmed by Sanger sequencing.\nDISCUSSION: By WES, we identified a novel heterozygous <i>de novo</i> 7-bp frameshift deletion in <i>PBX1</i>. Our findings expand the spectrum of causative variants in <i>PBX1</i>-related CAKUT. In this case, WES proved to be the apt technique to detect the variant responsible for the patient's phenotype, as single gene testing is not feasible given the multitude of genes involved in CAKUT and SNP array analysis misses rare single-nucleotide variants and small Indels.","variants":[{"Name":"NM_002585.4(PBX1):c.413_419del (p.Gly138fs)","Chromosome":"1","Start":"164792640","Stop":"164792646","ReferenceAlleleVCF":"AGGGGCAG","AlternateAlleleVCF":"A","allel_id":481435,"rule_based_match":true,"evidence_text":"c.413_419del","llm_judgment":"PRESENT","evidence":"c.413_419del","abstract_start":1014,"abstract_end":1026}]}
{"pmid":"19629655","title":"Novel mutations in TACI (TNFRSF13B) causing common variable immunodeficiency.","abstract":"INTRODUCTION: Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production. The disorder is also characterized by co-occurrence of autoimmune, lymphoproliferative, and granulomatous diseases. Mutations in the gene encoding TACI (Transmembrane Activator and CAML Interactor, TNFRSF13B) were previously found to be associated with CVID.\nMATERIALS AND METHODS: We therefore sequenced TNFRSF13B gene in a cohort of 48 Iranian CVID patients. Expression of TACI and binding of A proliferation-inducing ligand (APRIL) were tested by FACS.\nRESULTS: We identified one patient with a homozygous G to T substitution in the TNFRSF13B gene at the splice site of intron 1 (c.61+1G>T), which abolished expression of the TACI molecule and binding capacity of APRIL. This represents the second CVID patient in the world with a complete absence of TACI expression. B cell lines from family members carrying the same mutation in a heterozygous form showed a reduced level of TACI expression and APRIL-binding capacity, suggesting a gene dosage effect. In addition, we found the previously recognized C104R and C172Y mutations in a heterozygous form in two patients with CVID and one, novel, heterozygous P42T mutation.\nCONCLUSION: TACI mutations were observed in Iran CVID patients in a similar frequency as in other Caucasian populations. The novel mutations identified in this study support the notion of a crucial role for TACI in B cell differentiation.","variants":[{"Name":"NM_012452.3(TNFRSF13B):c.61+1G>T","Chromosome":"17","Start":"16972014","Stop":"16972014","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":652888,"rule_based_match":true,"evidence_text":"c.61+1G>T","llm_judgment":"PRESENT","evidence":"c.61+1G>T","abstract_start":718,"abstract_end":727}]}
{"pmid":"34122512","title":"Four New Cases of SLC35A2-CDG With Novel Mutations and Clinical Features.","abstract":"SLC35A2-CDG is a rare type of X-linked CDG with more than 60 reported cases. We retrospectively analyzed clinical phenotypes and <i>SLC35A2</i> genotypes of four cases of SLC35A2-CDG from four unrelated families of Han ethnicity in China. All patients had infantile onset epilepsies that were completely or partly resistant to multiple anti-epileptic medications or ketogenic diet. Three patients had severe developmental delay. All patients were female patients carrying <i>de novo</i> deleterious mutations in <i>SLC35A2</i> (NM_001042498.2) gene, including one canonical splice-site mutation (c.426+1G > A), one large deletion (c.-322_c.274+1del), and two frameshift mutations leading to premature stop codon (c.781delC/p.Arg289ValfsTer88 and c.601delG/p.Ala201GlnfsTer148). Novel clinical features in some of our patients include anemia, hypertriglyceridemia, hypertonia, small ears, extra folds on earlobes, and maternal oligohydramnios or hypothyroidism during pregnancy. In one patient, concomitant Marfan syndrome was confirmed for having positive family history, carrying a heterozygous known disease-causing mutation in FBN1 gene (c.7240C > T/p.Arg2414Ter), and presence of typical features (rachnodactyly, ventrical septal defect, and mitral valve regurgitation). In conclusion, we expanded clinical phenotype and genetic mutation spectrum of SLC35A2-CDG by reporting four new cases with novel pathogenic variants and novel clinical features.","variants":[{"Name":"NM_000138.5(FBN1):c.7240C>T (p.Arg2414Ter)","Chromosome":"15","Start":"48425829","Stop":"48425829","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":510546,"rule_based_match":true,"evidence_text":"c.7240C > T/p.Arg2414Ter","llm_judgment":"PRESENT","evidence":"c.7240C > T/p.Arg2414Ter","abstract_start":1141,"abstract_end":1165}]}
{"pmid":"33407246","title":"Clinical and genetic characteristics of concomitant Mucopolysaccharidosis type IVA and neurogenic bladder in children: two case reports and literature review.","abstract":"BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a rare autosomal recessive lysosomal storage disorder. Up to now, reports on the clinical characteristics of MPS IVA mainly focused on patients with progressive bone dysplasia and multiple organ damage, while the effects of this disorder on neurogenic bladder have not been reported. Therefore, the aim of the present study is to report two cases of nocturnal enuresis finally diagnosed as neurogenic bladder in MPS IVA.\nCASE PRESENTATION: Both children were characterized by the presence of pectus carinatum, kyphoscoliosis, nocturnal enuresis, urinary incontinence, normal intelligence, and loss of strength in the legs, diagnosed as neurogenic bladder in association with MPS IVA through the analysis of the clinical characteristics, enzyme activity and genetic testing. In addition, the terminator codon mutation c.1567T > G (p.X523E) and a novel missense mutation c.575A > G (p.E192G) were found in the coding region of the GALNS gene of the 1<sup>st</sup> patient, while the missense mutation c.488C > A (p.P163H) was found in the coding region of the GALNS gene of the 2<sup>nd</sup> patient.\nCONCLUSIONS: Neurogenic bladder may occur in patients with MPS IVA after spinal cord injury. It is necessary to screen for the diagnosis of MPS IVA in patients with atypical enuresis and skeletal abnormalities through the analysis of the clinical characteristics, enzyme activity and genetic testing.","variants":[{"Name":"NM_000512.5(GALNS):c.1567T>G (p.Ter523Glu)","Chromosome":"16","Start":"88814441","Stop":"88814441","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1036112,"rule_based_match":true,"evidence_text":"c.1567T > G (p.X523E)","llm_judgment":"PRESENT","evidence":"c.1567T > G (p.X523E)","abstract_start":888,"abstract_end":909},{"Name":"NM_000512.5(GALNS):c.575A>G (p.Glu192Gly)","Chromosome":"16","Start":"88836259","Stop":"88836259","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3534527,"rule_based_match":true,"evidence_text":"c.575A > G (p.E192G)","llm_judgment":"PRESENT","evidence":"c.575A > G (p.E192G)","abstract_start":940,"abstract_end":960}]}
{"pmid":"16400612","title":"Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency.","abstract":"Congenital lactase deficiency (CLD) is a severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. We initially assigned the CLD locus by linkage and linkage disequilibrium on 2q21 in 19 Finnish families. Here we report the molecular background of CLD via characterization of five distinct mutations in the coding region of the lactase (LCT) gene. Twenty-seven patients out of 32 (84%) were homozygous for a nonsense mutation, c.4170T-->A (Y1390X), designated \"Fin(major).\" Four rare mutations--two that result in a predicted frameshift and early truncation at S1666fsX1722 and S218fsX224 and two point mutations that result in substitutions Q268H and G1363S of the 1,927-aa polypeptide--confirmed the lactase mutations as causative for CLD. These findings facilitate genetic testing in clinical practice and enable genetic counseling for this severe disease. Further, our data demonstrate that, in contrast to common adult-type hypolactasia (lactose intolerance) caused by a variant of the regulatory element, the severe infancy form represents the outcome of mutations affecting the structure of the protein inactivating the enzyme.","variants":[{"Name":"NM_002299.4(LCT):c.4170T>A (p.Tyr1390Ter)","Chromosome":"2","Start":"135807131","Stop":"135807131","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":21625,"rule_based_match":false,"evidence_text":"c.4170T-->A (Y1390X)","llm_judgment":"PRESENT","evidence":"c.4170T-->A (Y1390X)","abstract_start":505,"abstract_end":525}]}
{"pmid":"33507482","title":"Concurrent germline BRCA1, BRCA2, and CHEK2 pathogenic variants in hereditary breast cancer: a case series.","abstract":"BACKGROUND: Concurrent germline (g) pathogenic variants related to hereditary breast cancer represent a rare occurrence. While double heterozygosity in gBRCA1 and gBRCA2 has been reported in the past, herein we describe the first case of three known concurrent pathogenic variants identified in a family with a strong history of breast cancer. Case presentation The proband is a 55-year-old female diagnosed with synchronous bilateral breast cancers. She underwent a multi-gene panel testing indicating the presence of 3 concurrent heterozygous germline deleterious variants in BRCA1 (c.181T > G), BRCA2 (c.4398_4402delACATT), and CHEK2 (1100delC). The patient's two daughters (34 and 29 years-old) were found to be transheterozygous for inherited pathogenic variants in BRCA1 (c.181T > G) and CHEK2 (1100delC) genes.\nCONCLUSION: The cancer risk and phenotypic manifestations associated with transheterozygous or multiple concurrent deleterious germline variants in hereditary breast cancer requires further investigation. A personalized approach to counseling, screening, and risk reduction should be undertaken for these individuals.","variants":[{"Name":"NM_007294.4(BRCA1):c.181T>G (p.Cys61Gly)","Chromosome":"17","Start":"43106487","Stop":"43106487","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":32700,"rule_based_match":true,"evidence_text":"c.181T > G","llm_judgment":"PRESENT","evidence":"c.181T > G","abstract_start":585,"abstract_end":595}]}
{"pmid":"26722403","title":"A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma.","abstract":"Succinate dehydrogenase (SDH), which is located on the mitochondrial inner membrane, is essential to the Krebs cycle. Mutations of the SDH gene are associated with many tumors, such as renal cell carcinoma, wild type gastrointestinal stromal tumors (WT GISTs) and hereditary paragangliomas/pheochromocytomas. Herein we present a rare case diagnosed as a WT GIST complicated with a renal chromophobe cell tumor and detected a novel germline heterozygous mutation (c.2T>C: p.M1T) in the initiation codon of the SDHA gene. We also conduct a preliminary exploration for the mechanism of reduced expression of SDHB without mutation of SDHB gene. Our case enriches the mutation spectrum of the SDH gene. After reviewing previous studies, we found it to be the first case diagnosed as a WT GIST complicated with a synchronous renal chromophobe cell tumor and identified a novel germline heterozygous mutation. It was also the second reported case of a renal cell carcinoma associated with an SDHA mutation.","variants":[{"Name":"NM_004168.4(SDHA):c.2T>C (p.Met1Thr)","Chromosome":"5","Start":"218357","Stop":"218357","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":394857,"rule_based_match":true,"evidence_text":"c.2T>C: p.M1T","llm_judgment":"PRESENT","evidence":"c.2T>C: p.M1T","abstract_start":463,"abstract_end":476}]}
{"pmid":"35107634","title":"C18orf32 loss-of-function is associated with a neurodevelopmental disorder with hypotonia and contractures.","abstract":"Glycosylphosphatidylinositol (GPI) functions to anchor certain proteins to the cell surface. Although defects in GPI biosynthesis can result in a wide range of phenotypes, most affected patients present with neurological abnormalities and their diseases are grouped as inherited-GPI deficiency disorders. We present two siblings with global developmental delay, brain anomalies, hypotonia, and contractures. Exome sequencing revealed a homozygous variant, NM_001035005.4:c.90dupC (p.Phe31Leufs*3) in C18orf32, a gene not previously associated with any disease in humans. The encoded protein is known to be important for GPI-inositol deacylation. Knockout of C18orf32 in HEK293 cells followed by a transfection rescue assay revealed that the PIPLC (Phosphatidylinositol-Specific Phospholipase C) sensitivity of GPI-APs (GPI-anchored proteins) was restored only by the wild type and not the mutant C18orf32. Immunofluorescence revealed that the mutant C18orf32 was localized to the endoplasmic reticulum and was also found as aggregates in the nucleus. In conclusion, we identified a pathogenic variant in C18orf32 as the cause of a novel autosomal recessive neurodevelopmental disorder with hypotonia and contractures. Our results demonstrate the importance of C18orf32 in the biosynthesis of GPI-anchors, the molecular impact of the variant on the protein function, and add a novel candidate gene to the existing repertoire of genes implicated in neurodevelopmental disorders.","variants":[{"Name":"NM_001035005.4(C18orf32):c.90dup (p.Phe31fs)","Chromosome":"18","Start":"49483658","Stop":"49483659","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":1900227,"rule_based_match":true,"evidence_text":"NM_001035005.4:c.90dupC (p.Phe31Leufs*3)","llm_judgment":"PRESENT","evidence":"NM_001035005.4:c.90dupC (p.Phe31Leufs*3)","abstract_start":456,"abstract_end":496}]}
{"pmid":"30131598","title":"Identification of a de novo fetal variant in osteogenesis imperfecta by targeted sequencing-based noninvasive prenatal testing.","abstract":"Noninvasive prenatal testing (NIPT), which involves analysis of circulating cell-free fetal DNA (cffDNA) from maternal plasma, is highly effective for detecting feto-placental chromosome aneuploidy. However, recent studies suggested that coverage-based shallow-depth NIPT cannot accurately detect smaller single or multi-loci genetic variants. To assess the fetal genotype of any locus using maternal plasma, we developed a novel genotyping algorithm named pseudo tetraploid genotyping (PTG). We performed paired-end captured sequencing of the plasma cell-free DNA (cfDNA), in which case a phenotypically healthy woman is suspected to be carrying a fetus with genetic defect. After a series of independent filtering of 111,407 SNPs, we found one variant in COL1A1 graded with high pathogenic potential which might cause osteogenesis imperfecta (OI). Then, we verified this mutation by Sanger sequencing of fetal and parental blood cells. In addition, we evaluated the accuracy and detection rate of the PTG algorithm through direct sequencing of the genomic DNA from maternal and fetal blood cells. Collectively, our study developed an intuitive and cost-effective method for the noninvasive detection of pathogenic mutations, and successfully identified a de novo variant in COL1A1 (c.2596 G > A, p.Gly866Ser) in the fetus implicated in OI.","variants":[{"Name":"NM_000088.4(COL1A1):c.2596G>A (p.Gly866Ser)","Chromosome":"17","Start":"50189876","Stop":"50189876","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":413991,"rule_based_match":true,"evidence_text":"c.2596 G > A, p.Gly866Ser","llm_judgment":"PRESENT","evidence":"c.2596 G > A, p.Gly866Ser","abstract_start":1284,"abstract_end":1309}]}
{"pmid":"20491894","title":"Evaluating the effect of spastin splice mutations by quantitative allele-specific expression assay.","abstract":"BACKGROUND: mutations in the SPG4/SPAST gene are the most common cause for hereditary spastic paraplegia (HSP). The splice-site mutations make a significant contribution to HSP and account for 17.4% of all types of mutations and 30.8% of point mutations in the SPAST gene. However, only few studies with limited molecular approach were conducted to investigate and decipher the role of SPAST splice-site mutations in HSP.\nMETHODS: a reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and quantitative allele-specific expression assay were performed.\nRESULTS: we have characterized the consequence of two novel splice-site mutations (c.1493 + 1G>A and c.1414-1G>A) in the SPAST gene in two different families with pure HSP. The RT-PCR analysis revealed that both spastin mutations are indeed splice-site mutations and cause skipping of exon 12. Furthermore, RT-PCR data suggested that these splice-site mutations may cause leaky splicing. By means of a quantitative allele-specific expression assay, we could confirm that both splice-site mutations cause leaky splicing, as the relative expression of the exon 12-skipped transcript was reduced (21.1 ± 3.6 compared to expected 50%).\nCONCLUSIONS: our finding supports a \"threshold-effect-model\" for functional spastin in HSP. A higher level (78.8 ± 3.9%) of functional spastin than the expected ratio of 50% owing to leaky splicing might cause late age at onset of HSP. Remarkably, we could show that a quantitative allele-specific expression assay is a simple and effective tool to evaluate the role of most types of spastin splice-site mutations in HSP.","variants":[{"Name":"NM_014946.4(SPAST):c.1493+1G>A","Chromosome":"2","Start":"32137189","Stop":"32137189","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":940709,"rule_based_match":true,"evidence_text":"c.1493 + 1G>A","llm_judgment":"PRESENT","evidence":"c.1493 + 1G>A","abstract_start":648,"abstract_end":661}]}
{"pmid":"27081569","title":"A novel COL11A1 missense mutation in siblings with non-ocular Stickler syndrome.","abstract":"Stickler syndrome (STL) is an autosomal, dominantly inherited, clinically variable and genetically heterogeneous connective tissue disorder characterized by ocular, auditory, orofacial and skeletal abnormalities. We conducted targeted resequencing using a next-generation sequencer for molecular diagnosis of a 2-year-old girl who was clinically suspected of having STL with Pierre Robin sequence. We detected a novel heterozygous missense mutation, NM_001854.3:n.4838G>A [NM_001854.3 (COL11A1_v001):c.4520G>A], in COL11A1, resulting in a Gly to Asp substitution at position 1507 [NM_001854.3(COL11A1_i001)] within one of the collagen-like domains of the triple helical region. The same mutation was detected in her 4-year-old brother with cleft palate and high-frequency sensorineural hearing loss.","variants":[{"Name":"NM_001854.4(COL11A1):c.4520G>A (p.Gly1507Asp)","Chromosome":"1","Start":"102888757","Stop":"102888757","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1392615,"rule_based_match":true,"evidence_text":"NM_001854.3:n.4838G>A [NM_001854.3 (COL11A1_v001):c.4520G>A]","llm_judgment":"PRESENT","evidence":"NM_001854.3:n.4838G>A [NM_001854.3 (COL11A1_v001):c.4520G>A]","abstract_start":450,"abstract_end":510}]}
{"pmid":"16971895","title":"The congenital \"ant-egg\" cataract phenotype is caused by a missense mutation in connexin46.","abstract":"PURPOSE: \"Ant-egg\" cataract is a rare, distinct variety of congenital/infantile cataract that was reported in a large Danish family in 1967. This cataract phenotype is characterized by ant-egg-like bodies embedded in the lens in a laminar configuration and is inherited as an autosomal dominant trait. We retrieved the family and performed linkage analysis to determine the disease locus and identify the mutated gene.\nMETHODS: The family (CC00103) was identified in a National Register of Hereditary Eye Diseases and updated based on The Danish Civil Register System. Genome wide linkage analysis and haplotyping using STS marker systems were carried out to achieve a LOD score above 3. The disease-causing candidate gene was sequenced and the mutation was identified and verified by restriction enzyme digestion of genomic DNA from all individuals in family CC00103 and 60 healthy controls.\nRESULTS: Linkage analysis resulted in a LOD score of 3.91 for marker D13S1275 located close to the known cataract gene GJA3. A novel missense mutation c.32T > C (L11S), was found by sequencing DNA from two affected members. The mutation was present in all affected individuals and was neither found in unaffected family members nor in 60 healthy individuals by restriction enzyme digests.\nCONCLUSIONS: The congenital \"ant-egg\" cataract phenotype is caused by a L11S mutation in connexin46 (Cx46) located in the signal peptide domain. Further studies are needed to unravel the mechanism leading to the formation of the \"ant-eggs\".","variants":[{"Name":"NM_021954.4(GJA3):c.32T>C (p.Leu11Ser)","Chromosome":"13","Start":"20143257","Stop":"20143257","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3412487,"rule_based_match":true,"evidence_text":"c.32T > C (L11S)","llm_judgment":"PRESENT","evidence":"c.32T > C (L11S)","abstract_start":1044,"abstract_end":1060}]}
{"pmid":"36949502","title":"Genotypic and phenotypic characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Guangzhou, China.","abstract":"BACKGROUND: G6PD deficiency is a common inherited disorder worldwide and has a higher incidence rate in southern China. Many variants of G6PD result from point mutations in the G6PD gene, leading to decreased enzyme activity. This study aimed to analyse the genotypic and phenotypic characteristics of G6PD deficiency in Guangzhou, China.\nMETHODS: In this study, a total of 20,208 unrelated participants were screened from 2020 to 2022. G6PD deficiency was further analysed by quantitative enzymatic assay and G6PD mutation analysis. The unidentified genotype of the participants was further ascertained by direct DNA sequencing.\nRESULTS: A total of 12 G6PD mutations were identified. Canton (c.1376G>T) and Kaiping (c.1388G>A) were the most common variants, and different mutations led to varying levels of G6PD enzyme activity. Comparing the enzyme activities of the 6 missense mutations between the sexes, we found significant differences (P < 0.05) in the enzyme activities of both male hemizygotes and female heterozygotes. Two previously unreported mutations (c.1438A>T and c.946G>A) were identified.\nCONCLUSIONS: This study provided detailed genotypes of G6PD deficiency in Guangzhou, which could be valuable for diagnosing and researching G6PD deficiency in this area.","variants":[{"Name":"NM_001360016.2(G6PD):c.1438A>T (p.Ile480Phe)","Chromosome":"X","Start":"154532207","Stop":"154532207","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3498780,"rule_based_match":true,"evidence_text":"c.1438A>T","llm_judgment":"PRESENT","evidence":"c.1438A>T","abstract_start":1066,"abstract_end":1075},{"Name":"NM_001360016.2(G6PD):c.946G>A (p.Gly316Ser)","Chromosome":"X","Start":"154533047","Stop":"154533047","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3498775,"rule_based_match":true,"evidence_text":"c.946G>A","llm_judgment":"PRESENT","evidence":"c.946G>A","abstract_start":1080,"abstract_end":1088}]}
{"pmid":"32482800","title":"Homozygous hypomorphic","abstract":"BACKGROUND: Primary ovarian insufficiency (POI) affects 1% of women under 40 years and is a public health problem. The genetic causes of POI are highly heterogeneous with isolated or syndromic forms. Recently, variants in genes involved in DNA repair have been shown to cause POI. Notably, syndromic POI with Fanconi anaemia (FA) traits related to biallelic <i>BRCA2</i> truncated variants has been reported. Here, we report a novel phenotype of isolated POI with <i>a BRCA2</i> variant in a consanguineous Turkish family.\nMETHODS: Exome sequencing (ES) was performed in the patient. We also performed functional studies, including a homologous recombination (HR) test, cell proliferation, radiation-induced RAD51 foci formation assays and chromosome breakage studies in primary and lymphoblastoid immortalised cells. The expression of <i>BRCA2</i> in human foetal ovaries was studied.\nRESULTS: ES identified a homozygous missense c.8524C>T/p.R2842C<i>-BRCA2</i> variant. BRCA2 defects induce cancer predisposition and FA. Remarkably, neither the patient nor her family exhibited somatic pathologies. The patient's cells showed intermediate levels of chromosomal breaks, cell proliferation and radiation-induced RAD51 foci formation compared with controls and FA cells. R2842C-BRCA2 only partially complemented HR efficiency compared with wild type-BRCA2. BRCA2 is expressed in human foetal ovaries in pachytene stage oocytes, when meiotic HR occurs.\nCONCLUSION: We describe the functional assessment of a homozygous hypomorphic <i>BRCA2</i> variant in a patient with POI without cancer or FA trait. Our findings extend the phenotype of BRCA2 biallelic alterations to fully isolated POI. This study has a major impact on the management and genetic counselling of patients with POI.","variants":[{"Name":"NM_000059.4(BRCA2):c.8524C>T (p.Arg2842Cys)","Chromosome":"13","Start":"32370992","Stop":"32370992","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67278,"rule_based_match":true,"evidence_text":"c.8524C>T/p.R2842C","llm_judgment":"PRESENT","evidence":"c.8524C>T/p.R2842C","abstract_start":931,"abstract_end":949}]}
{"pmid":"18203197","title":"DLX3 c.561_562delCT mutation causes attenuated phenotype of tricho-dento-osseous syndrome.","abstract":"The distal-less homeobox gene DLX3 is expressed in a variety of tissues including placenta, skin, hair, teeth, and bone. Mutation of DLX3 (c.571_574delGGGG) causes the tricho-dento-osseous syndrome (TDO), characterized by abnormal hair, teeth, and bone. Evaluation of a kindred segregating the DLX3 c.561_562delCT mutation revealed distinct changes in the hair, teeth, and bones as has been observed with the DLX3 c.571_574delGGGG mutation. Previously, the DLX3 c.561_562delCT mutation was associated with autosomal dominant amelogenesis imperfecta with taurodontism. The present study shows that the DLX3 c.560_561delCT mutation causes an attenuated TDO phenotype with less severe hair, tooth, and bone manifestations compared with individuals having the DLX3 c.571_574delGGGG mutation. Careful phenotyping of individuals with allelic DLX3 mutations reveals marked differences in phenotypic severity indicating that the carboxy-terminus of the DLX3 protein is critical in determining its function during development in these different tissues.","variants":[{"Name":"NM_005220.3(DLX3):c.561_562del (p.Tyr188fs)","Chromosome":"17","Start":"49991819","Stop":"49991820","ReferenceAlleleVCF":"TAG","AlternateAlleleVCF":"T","allel_id":24112,"rule_based_match":true,"evidence_text":"DLX3 c.561_562delCT mutation","llm_judgment":"PRESENT","evidence":"DLX3 c.561_562delCT mutation","abstract_start":294,"abstract_end":322}]}
{"pmid":"20397747","title":"Cyclin-dependent kinase-like 5 (CDKL5) mutation screening in Rett syndrome and related disorders.","abstract":"Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n=102), males with X-linked mental retardation (n=9), patients with West syndrome (n=52), patients with autism (n=59), patients with epileptic encephalopathy (n=33), patients with Aicardi syndrome (n=7) and other patients with intellectual disability with or without seizures (n=54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1-3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.","variants":[{"Name":"NM_001323289.2(CDKL5):c.2504del (p.Pro835fs)","Chromosome":"X","Start":"18628377","Stop":"18628377","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":153537,"rule_based_match":true,"evidence_text":"c.2504delC [p.P835fs]","llm_judgment":"PRESENT","evidence":"c.2504delC [p.P835fs]","abstract_start":1120,"abstract_end":1141},{"Name":"NM_001323289.2(CDKL5):c.58G>C (p.Gly20Arg)","Chromosome":"X","Start":"18507154","Stop":"18507154","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":153560,"rule_based_match":true,"evidence_text":"c.58G>C [p.G20R]","llm_judgment":"PRESENT","evidence":"c.58G>C [p.G20R]","abstract_start":1102,"abstract_end":1118}]}
{"pmid":"30656474","title":"Phenotypic spectrum of autosomal recessive retinitis pigmentosa without posterior column ataxia caused by mutations in the FLVCR1 gene.","abstract":"PURPOSE: Posterior column ataxia and retinitis pigmentosa (PCARP) is a rare form of syndromic RP associated with mutations in the FLVCR1 gene. Recent evidence has suggested a spectrum in the phenotype depending on the genotype.\nMETHODS: Six individuals with retinitis pigmentosa (RP) carrying mutations in the FLVCR1 gene underwent detailed ophthalmological examinations at the Center for Ophthalmology and two of these also an extensive neurological examination at the Department of Neurology in Tuebingen, Germany.\nRESULTS: The mutation spectrum in our cohort comprised one nonsense mutation, one 1-bp deletion, two missense variants, and one splice site variant (c.1092+5G>A). Three patients presented with a typical clinical picture of autosomal recessive RP, two patients presented with atypical RP, and one patient presented with a particularly mild form of RP. The findings of the patients that underwent detailed neurological and neurophysiological testing were not suggestive for the presence of progressive PCA, but one patient showed mild cerebellar signs without worsening over time. Five out of six of our cases carry the splice site variant c.1092+5G>A at least on one allele possibly providing evidence as to that this splice site variant may cause a milder form of non-syndromic autosomal recessive RP.\nCONCLUSIONS: Mutations in FLVCR1 can present with the clinical picture of a non-syndromic autosomal recessive RP (in this case RP without PCA), RP with mild cerebellar signs, but also PCARP. Additionally, we show evidence for a spectrum of the severity of the retinal involvement likely depending on the genotype.","variants":[{"Name":"NM_014053.4(FLVCR1):c.1092+5G>A","Chromosome":"1","Start":"212883443","Stop":"212883443","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":361654,"rule_based_match":true,"evidence_text":"c.1092+5G>A","llm_judgment":"PRESENT","evidence":"c.1092+5G>A","abstract_start":666,"abstract_end":677}]}
{"pmid":"29159868","title":"Tarsal-carpal coalition syndrome: Report of a novel missense mutation in NOG gene and phenotypic delineation.","abstract":"We report a family of Indian origin presenting with Tarsal-carpal coalition syndrome (TCC), which is a rare genetic disorder of skeletal abnormalities, inherited in autosomal dominant manner. In this family, three individuals (mother and two children) were found to be similarly affected with slight intrafamilial individual variability in the phenotype. Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family. Until now only six mutations have been reported in different families affected with TCC syndrome worldwide. This report further delineates the phenotypic spectrum of this rare disorder with the addition of a new variant to the mutation spectrum.","variants":[{"Name":"NM_005450.6(NOG):c.611G>A (p.Arg204Gln)","Chromosome":"17","Start":"56594834","Stop":"56594834","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":362070,"rule_based_match":true,"evidence_text":"NM_005450.4:c.611G>A","llm_judgment":"PRESENT","evidence":"NM_005450.4:c.611G>A","abstract_start":434,"abstract_end":454}]}
{"pmid":"33814268","title":"Investigation of ALPL variant states and clinical outcomes: An analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa.","abstract":"BACKGROUND: Hypophosphatasia (HPP), a rare metabolic disease, can be inherited in an autosomal recessive (biallelic) or an autosomal dominant (monoallelic) manner. Most of the severe, early-onset, frequently lethal HPP in infants is acquired through recessive inheritance; less severe, later-onset, typically nonlethal HPP phenotypes are acquired through either dominant or recessive inheritance. HPP's variable clinical presentation arises from >400 identified ALPL pathogenic variants with likely variable penetrance, especially with autosomal dominant inheritance. This post hoc analysis investigated the relationship between ALPL variant state (biallelic and monoallelic) and clinical outcomes with asfotase alfa in HPP.\nMETHODS: Data were pooled from two phase 2, randomized, open-label studies in adolescents and adults with HPP; one study evaluated the efficacy and safety of different doses of asfotase alfa (n = 25), and the other assessed the pharmacodynamics and safety of asfotase alfa (n = 19). Patients were grouped by ALPL variant state (biallelic or monoallelic). Available data from both studies included ALPL pathogenic variant state, Baseline characteristics, HPP-specific medical history, and Baseline TNSALP substrate levels (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) concentrations). Clinical outcomes over 5 years of treatment were available from only the efficacy and safety study.\nRESULTS: In total, 44 patients with known variant status were included in the pooled analysis (biallelic, n = 30; monoallelic, n = 14). The most common pathogenic variant was c.571G > A (p.Glu191Lys) in biallelic patients (allele frequency: 19/60) and c.1133A > T (p.Asp378Val) in monoallelic patients (allele frequency: 7/28). Median (min, max) Baseline PPi concentrations were significantly higher in patients with a biallelic vs monoallelic variant state (5.3 [2.2, 12.1] vs 4.3 [3.5, 7.4] μM; P = 0.0113), as were Baseline PLP concentrations (221.4 [62.4, 1590.0] vs 75.1 [28.8, 577.0] ng/mL; P= 0.0022). HPP-specific medical history was generally similar between biallelic and monoallelic patients in terms of incidence and type of manifestations; notable exceptions included fractures, which were more common among monoallelic patients, and delayed walking and bone deformities such as abnormally shaped chest and head and bowing of arms or legs, which were more common among biallelic patients. Data from the efficacy and safety study (n = 19) showed that median PPi and PLP concentrations were normalized over 5 years of treatment in patients with both variant states. Median % predicted distance walked on the 6-Minute Walk Test remained within the normal range for monoallelic patients over 4 years of treatment, and improved from below normal (<84%) to normal in biallelic patients.\nCONCLUSIONS: Although patients with biallelic variants had significantly higher Baseline PPi and PLP levels than monoallelic variants, both groups generally showed similar pretreatment Baseline clinical characteristics. Treatment with asfotase alfa for up to 5 years normalized TNSALP substrate concentrations and improved functional outcomes, with no clear differences between biallelic and monoallelic variant states. This study suggests that patients with HPP have significant disease burden, regardless of ALPL variant state.","variants":[{"Name":"NM_000478.6(ALPL):c.1133A>T (p.Asp378Val)","Chromosome":"1","Start":"21575868","Stop":"21575868","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":28710,"rule_based_match":true,"evidence_text":"c.1133A > T (p.Asp378Val)","llm_judgment":"PRESENT","evidence":"c.1133A > T (p.Asp378Val)","abstract_start":1680,"abstract_end":1705}]}
{"pmid":"29100093","title":"De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.","abstract":"Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/P<sub>i</sub> carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H<sub>2</sub>O<sub>2</sub> exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/P<sub>i</sub> transport to the development of skeletal and connective tissue.","variants":[{"Name":"NM_013386.5(SLC25A24):c.650G>A (p.Arg217His)","Chromosome":"1","Start":"108157481","Stop":"108157481","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":354272,"rule_based_match":true,"evidence_text":"c.650G>A (p.Arg217His)","llm_judgment":"PRESENT","evidence":"c.650G>A (p.Arg217His)","abstract_start":385,"abstract_end":407},{"Name":"NM_013386.5(SLC25A24):c.649C>T (p.Arg217Cys)","Chromosome":"1","Start":"108157482","Stop":"108157482","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":354197,"rule_based_match":true,"evidence_text":"c.649C>T (p.Arg217Cys)","llm_judgment":"PRESENT","evidence":"c.649C>T (p.Arg217Cys)","abstract_start":412,"abstract_end":434}]}
{"pmid":"32199931","title":"Hb Sun Prairie: A rare cause of chronic hemolysis in an Indian patient.","abstract":"Haemolytic anaemia is a commonly encountered condition in clinical haematology practise. Dissecting the aetiology of haemolytic anaemia is of paramount importance for appropriate management. We describe a 29-years-old lady of Indian origin, who presented with fatigue and recurrent jaundice for 2 years. Examination revealed pallor, mild icterus, and splenomegaly. Blood tests showed anaemia, reticulocytosis, indirecthyperbilirubinemia, and high serum lactate dehydrogenase, consistent with haemolytic anaemia. Peripheral smear showed severely microcytic hypochromic red cells and polychromasia. Heinz bodies and inclusion bodies were seen with supravital staining. Haemoglobin high pressure liquid chromatography showed low HbA2 and normal HbF. Work-up for iron deficiency was negative. Polymerase chain reaction of the genomic DNA failed to identify common deletions in the HBA genes. Sangers sequencing of HBA2 gene revealed a homozygous missense mutation NM_000517.6: c.391G > C (p.Ala131Pro) leading to a highly unstable hemoglobin, Hb Sun Prairie. Mother was heterozygous for the same mutation, and father was unavailable for genetic testing. We highlight the role of sangers sequencing in unravelling the underlying aetiology of haemolytic anaemia. Pathophysiology and existing literature of Hb Sun Prairie has been discussed.","variants":[{"Name":"NM_000517.6(HBA2):c.391G>C (p.Ala131Pro)","Chromosome":"16","Start":"173562","Stop":"173562","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":30679,"rule_based_match":true,"evidence_text":"NM_000517.6: c.391G > C (p.Ala131Pro)","llm_judgment":"PRESENT","evidence":"NM_000517.6: c.391G > C (p.Ala131Pro)","abstract_start":960,"abstract_end":997}]}
{"pmid":"37664053","title":"Constitutional mismatch repair deficiency syndrome with atypical features caused by a homozygous","abstract":"Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare autosomal recessive genetic disorder caused by biallelic germline mutations in one of the mismatch repair genes. Carriers are at exceptionally high risk for developing, typically in early life, hematological and brain malignancies, as well as cancers observed in Lynch syndrome. We report a homozygous <i>MLH1</i> missense variant (c.1918C>A p.(Pro640Thr)) in a Tunisian patient with CMMRD syndrome and a family history of early-age colorectal cancer. The proband presented initially with colonic oligopolyposis and adenosquamous carcinoma of the caecum. He later developed several malignancies, including undifferentiated carcinoma of the parotid, grade 4 IDH-mutant astrocytoma, and ampulla of Vater adenocarcinoma. The patient was older than typical for this disease and had a remarkably prolonged survival despite developing four distinct aggressive malignancies. The current report highlights the challenges in assessing the pathogenicity of the identified variant and the remarkable phenotypic diversity in CMMRD.","variants":[{"Name":"NM_000249.4(MLH1):c.1918C>A (p.Pro640Thr)","Chromosome":"3","Start":"37048538","Stop":"37048538","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":485609,"rule_based_match":true,"evidence_text":"c.1918C>A p.(Pro640Thr)","llm_judgment":"PRESENT","evidence":"c.1918C>A p.(Pro640Thr)","abstract_start":401,"abstract_end":424}]}
{"pmid":"23509830","title":"Functional evaluation of mutations in the tissue-nonspecific alkaline phosphatase gene.","abstract":"OBJECTIVE: To explore the relationship between the genotypes and phenotypes of these hypophosphatasia patients caused by gene mutations of tissue-nonspecific alkaline phosphatase (TNSALP).\nMETHODS: Based on the genotypes of these patients, site-directed mutations of TNSALP cDNA at c.1162T>C or c.1120G>A or c.668G>A or c.535G>A were performed in the expression plasmids, respectively. The plasmids were transfected into U2OS cells and the alkaline phosphatase activity of the cells were measured. Transfected U2OS cells were induced to mineral formation, and mineralisation assay were performed by Alizarin Red staining.\nRESULTS: The cells transfected with mutated TNSALP (c.1162T>C, c.1120G>A, c.668G>A, and c.535G>A) showed 39.7%, 57.6%, 2.9%, and 10.9% of alkaline phosphatase activity and 48.5%, 74.4%, 10.4%, and 16.7% mineralisation ability compared to those cells transfected with the wild-type TNSALP.\nCONCLUSION: Our results suggested that the new mutation c.1162T>C would moderately decrease the function of TNSALP while the mutations c.1120G>A and c.668G>A would mildly and severely decrease the function of TNSALP, respectively.","variants":[{"Name":"NM_000478.6(ALPL):c.668G>A (p.Arg223Gln)","Chromosome":"1","Start":"21568123","Stop":"21568123","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":364747,"rule_based_match":true,"evidence_text":"c.668G>A","llm_judgment":"PRESENT","evidence":"c.668G>A","abstract_start":308,"abstract_end":316},{"Name":"NM_000478.6(ALPL):c.1162T>C (p.Tyr388His)","Chromosome":"1","Start":"21575897","Stop":"21575897","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":930291,"rule_based_match":true,"evidence_text":"c.1162T>C","llm_judgment":"PRESENT","evidence":"c.1162T>C","abstract_start":282,"abstract_end":291},{"Name":"NM_000478.6(ALPL):c.1120G>A (p.Val374Met)","Chromosome":"1","Start":"21575855","Stop":"21575855","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1441523,"rule_based_match":true,"evidence_text":"c.1120G>A","llm_judgment":"PRESENT","evidence":"c.1120G>A","abstract_start":295,"abstract_end":304},{"Name":"NM_000478.6(ALPL):c.535G>A (p.Ala179Thr)","Chromosome":"1","Start":"21564103","Stop":"21564103","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28701,"rule_based_match":true,"evidence_text":"c.535G>A","llm_judgment":"PRESENT","evidence":"c.535G>A","abstract_start":320,"abstract_end":328}]}
{"pmid":"26600529","title":"Mutation analysis of four Chinese families with pure hereditary spastic paraplegia: pseudo- X-linked dominant inheritance and male lethality due to a novel ATL1 mutation.","abstract":"We studied four Chinese families with pure hereditary spastic paraplegia (HSP) to investigate the clinical features and associated genetic mutations. Linkage analysis was performed for all families to map the disease locus onto autosomal chromosomes, and related loci involved in HSP on the X chromosome were also examined. Polymerase chain reaction (PCR) sequencing was used to detect gene mutations. To confirm the influence of a splice-site mutation on mRNA, we used reverse transcription-PCR and direct sequencing. Linkage analysis and ATL1 gene sequencing of amniocytes were performed for prenatal genetic diagnosis. One missense variant (c.1517T>A) and a splice-site mutation (c.1245+1G>A) in SPAST, and two missense variants (c.715C>T, c.1204T>G) in ATL1 were identified. The c.1245+1G>A mutation caused a deletion of exon 9 in the SPAST gene. Prenatal genetic diagnosis showed that fetus did not carry the ALT1 c.1204T>G mutation. Follow-up was maintained for 5 years, and the negative result was confirmed by evidence of a healthy growing boy. We identified two novel mutations and two previously reported mutations in SPAST and ATL1, respectively. The family with the ATL1 c.1204T>G mutation exhibited male-lethality, female infancy-onset, and pseudo- X-linked dominant transmission, which had never been previously reported for HSP. Characteristic facial features were also noticed. The boy on whom prenatal gene diagnosis was performed is healthy and without unusual facies, suggesting that the c.1204T>G mutation might be related to these features. The results extend the genetic spectrum of HSP and suggest that linkage analysis remains a powerful tool in gene discovery studies.","variants":[{"Name":"NM_014946.4(SPAST):c.1245+1G>A","Chromosome":"2","Start":"32128480","Stop":"32128480","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227916,"rule_based_match":true,"evidence_text":"c.1245+1G>A","llm_judgment":"PRESENT","evidence":"c.1245+1G>A","abstract_start":683,"abstract_end":694}]}
{"pmid":"33063682","title":"Genotypic and Phenotypic Characteristics of Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Korean Patients.","abstract":"BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome. HLRCC is characterized by the development of cutaneous leiomyomas, early-onset uterine leiomyomas, and HLRCC-associated renal cell cancer (RCC) and caused by germline fumarate hydratase (FH) deficiency. We investigated the genotypic and phenotypic characteristics of Korean patients with HLRCC.\nMETHODS: We performed direct sequencing analysis of <i>FH</i> in 13 patients with suspected HLRCC and their family members. A chromosomal microarray test was performed in female patients with negative sequencing results but highly suspected HLRCC. In addition, we analyzed the clinical characteristics and evaluated the genotype-phenotype correlations in Korean patients with HLRCC.\nRESULTS: We identified six different pathogenic or likely pathogenic <i>FH</i> variants in six of the 13 patients (46.2%). The variants included two nonsense variants, two splicing variants, one frameshift variant, and one missense variant. Of the six variants, two (33.3%) were novel (c.132+1G>C, and c.243dup). RCC and early-onset uterine leiomyoma were frequently observed in families with HLRCC, while cutaneous leiomyoma was less common. No significant genotype-phenotype correlation was observed.\nCONCLUSIONS: We describe the genotypic and phenotypic spectrum in a small series of Korean patients with HLRCC. Our data reveal the unique characteristics of Korean patients with HLRCC and suggest a need for establishing an optimal diagnostic approach for them.","variants":[{"Name":"NM_000143.4(FH):c.132+1G>C","Chromosome":"1","Start":"241519590","Stop":"241519590","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3669336,"rule_based_match":true,"evidence_text":"c.132+1G>C","llm_judgment":"PRESENT","evidence":"c.132+1G>C","abstract_start":1089,"abstract_end":1099}]}
{"pmid":"28050599","title":"Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo","abstract":"We describe a woman who presented with cataracts, optic atrophy, lipodystrophy/lipoatrophy, and peripheral neuropathy. Exome sequencing identified a c.235C > G p.(Leu79Val) variant in the optic atrophy 3 (<i>OPA3</i>) gene that was confirmed to be de novo. This report expands the severity of the phenotypic spectrum of autosomal dominant <i>OPA3</i> mutations.","variants":[{"Name":"NM_025136.4(OPA3):c.235C>G (p.Leu79Val)","Chromosome":"19","Start":"45553819","Stop":"45553819","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":227093,"rule_based_match":true,"evidence_text":"c.235C > G p.(Leu79Val)","llm_judgment":"PRESENT","evidence":"c.235C > G p.(Leu79Val)","abstract_start":149,"abstract_end":172}]}
{"pmid":"23632773","title":"Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives.","abstract":"Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum α-fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient.","variants":[{"Name":"NM_000051.4(ATM):c.8851-1G>T","Chromosome":"11","Start":"108365081","Stop":"108365081","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":357928,"rule_based_match":true,"evidence_text":"c.8851-1G>T","llm_judgment":"PRESENT","evidence":"c.8851-1G>T","abstract_start":686,"abstract_end":697},{"Name":"NM_000051.4(ATM):c.8122G>A (p.Asp2708Asn)","Chromosome":"11","Start":"108335080","Stop":"108335080","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152505,"rule_based_match":true,"evidence_text":"c.8122G>A (p.Asp2708Asn)","llm_judgment":"PRESENT","evidence":"c.8122G>A (p.Asp2708Asn)","abstract_start":657,"abstract_end":681}]}
{"pmid":"36092886","title":"Case Report: Three novel pathogenic","abstract":"<b>Background:</b> Dubin-Johnson syndrome (DJS) is a rare autosomal recessive genetic disease which is caused by mutations in the <i>ABCC2</i> gene; it is characterized by chronic hyperbilirubinemia. Here, we report two pedigrees affected with DJS which were caused by three novel pathogenic <i>ABCC2</i> mutations. <b>Case summary:</b> The two patients exhibited intermittent low-grade, predominantly conjugated hyperbilirubinemia and showed no other abnormalities. They were diagnosed clinically with DJS. Three novel pathogenic <i>ABCC2</i> mutations-c.2980delA, c.1834C>T, and c.4465_4473delinsGGCCCACAG-were identified by whole-exome sequencing. These mutations could be responsible for DJS in the two pedigrees. The genetic test confirmed the diagnosis of DJS. <b>Conclusion:</b> These results contributed to the genetic diagnosis of the two patients with DJS and expanded the variant database for the <i>ABCC2</i> gene.","variants":[{"Name":"NM_000392.5(ABCC2):c.4465_4473delinsGGCCCACAG (p.Ile1489_Ile1491delinsGlyProGln)","Chromosome":"10","Start":"99850753","Stop":"99850761","ReferenceAlleleVCF":"ATCACCATC","AlternateAlleleVCF":"GGCCCACAG","allel_id":3494650,"rule_based_match":true,"evidence_text":"c.4465_4473delinsGGCCCACAG","llm_judgment":"PRESENT","evidence":"c.4465_4473delinsGGCCCACAG","abstract_start":581,"abstract_end":607}]}
{"pmid":"21357407","title":"Cellular expression and siRNA-mediated interference of rhodopsin cis-acting splicing mutants associated with autosomal dominant retinitis pigmentosa.","abstract":"PURPOSE: To investigate the cellular expression of cis-acting splicing mutations in the rhodopsin gene (RHO) that lead to autosomal dominant or recessive retinitis pigmentosa (adRP/arRP) and the role of nonsense-mediated mRNA decay (NMD) in its pathogenic mechanism. To design a potential therapeutic RNAi-based suppression strategy for cis-acting adRP splicing mutants.\nMETHODS: Cells were transfected with genomic constructs encoding the human wild-type (WT) and c.531-2A>G, c.936+1G>T, c.937-1G>T and c.745G>T RHO mutants. Total RNA was quantified by RT-PCR and protein was analyzed by immunocytochemistry. Three small interfering (si)RNAs directed against adRP mutant transcripts were designed and assayed in COS7 cells.\nRESULTS: The RHO cis-acting splicing mutations causing adRP, c.531-2A>G and c.937-1G>T, induce cryptic splicing. In contrast, the c.936+1G>T mutation, which causes arRP, results in exon skipping. Although the c.531-2A>G and c.745G>T RHO sequence predicted a premature termination codon (PTC) that should be a target for NMD, these mutant proteins were detected in transfected cells. The siRNAs designed to interfere with adRP mutants silenced the corresponding mRNA with varying efficiency.\nCONCLUSIONS: Although two RHO mutations that cause different RP phenotypes were the target for the NMD mechanism, a fraction of mutant RNA transcript may circumvent the NMD mechanism and be translated into protein. Thus, different levels of mutant protein may be necessary to trigger the RP phenotype. The findings demonstrate the potential use of siRNA to interfere with cis-acting splicing RHO transcripts. However, limitations in the mutation sequence and incomplete mutant transcript elimination should be considered in a therapeutic approach for adRP.","variants":[{"Name":"NM_000539.3(RHO):c.936+1G>T","Chromosome":"3","Start":"129532773","Stop":"129532773","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":851025,"rule_based_match":true,"evidence_text":"c.936+1G>T","llm_judgment":"PRESENT","evidence":"c.936+1G>T","abstract_start":477,"abstract_end":487},{"Name":"NM_000539.3(RHO):c.531-2A>G","Chromosome":"3","Start":"129532249","Stop":"129532249","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1934722,"rule_based_match":true,"evidence_text":"c.531-2A>G","llm_judgment":"PRESENT","evidence":"c.531-2A>G","abstract_start":465,"abstract_end":475},{"Name":"NM_000539.3(RHO):c.937-1G>T","Chromosome":"3","Start":"129533607","Stop":"129533607","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2894595,"rule_based_match":true,"evidence_text":"c.937-1G>T","llm_judgment":"PRESENT","evidence":"c.937-1G>T","abstract_start":489,"abstract_end":499}]}
{"pmid":"15221449","title":"Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11).","abstract":"Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant hearing impairment that clinically resembles the previously published DFNA11 family. The affected family members show a flat audiogram at young ages and only modest progression, most clearly at the high frequencies. In addition, they suffer from minor vestibular symptoms. Linkage analysis yielded a maximum two-point lodscore of 3.43 for marker D11S937 located within 1 cM of the myosin VIIA gene. The myosin VIIA gene was sequenced and 11 nucleotide variations were found. Ten nucleotide changes represent benign intronic variants, silent exon mutations or non-pathologic amino acid substitutions. One variant, a c.1373A-->T transversion that is heterozygously present in all affected family members and absent in 300 healthy individuals, is predicted to result in an Asn458Ile amino acid substitution. Asn458 is located in a region of the myosin VIIA motor domain that is highly conserved in different classes of myosins and in myosins of different species. To evaluate whether the Asn458Ile mutation was indeed responsible for the hearing impairment, a molecular model of myosin VIIA was built based on the known structure of the myosin II heavy chain from Dictyostelium discoideum. In this model, conformational changes in the protein caused by the amino acid substitution Asn458Ile are predicted to disrupt ATP/ADP binding and impair the myosin power-stroke, which would have a severe effect on the function of the myosin VIIA protein.","variants":[{"Name":"NM_000260.4(MYO7A):c.1373A>T (p.Asn458Ile)","Chromosome":"11","Start":"77162149","Stop":"77162149","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":26902,"rule_based_match":false,"evidence_text":"c.1373A-->T","llm_judgment":"PRESENT","evidence":"c.1373A-->T","abstract_start":909,"abstract_end":920}]}
{"pmid":"30221392","title":"Gene mutation and pedigree analysis of tetrahydrobiopterin deficiency in a Uygur family of China.","abstract":"BACKGROUND: Tetrahydrobiopterin (BH<sub>4</sub> ) deficiency is an autosomal recessive disorder, which is caused by an enzyme deficiency involved in its synthetic or metabolic pathways. Clinical symptoms may include microcephaly, hypoevolutism, severe ataxia, and seizures. The purposes of this study are to analyze the genotype-phenotype and the pedigree of the first case of BH<sub>4</sub> deficiency in the Uygur of China.\nMETHODS: (a) This patient received tandem mass spectrometry, urinary neopterin and biopterin analysis, and determination of dihydropteridine reductase (DHPR) activity in dried blood spots. (b) Blood DNA samples of this patient and her three family members were collected for gene sequencing and mutation analysis.\nRESULTS: (a) The basic urinary neopterin and biopterin were 1.07 mmol/mol Cr and 3.12 mmol/mol Cr, respectively, and biopterin percentage was 74.42%. The DHPR activity of this patient was 31.11% of normal control. (b) Sanger sequencing of PAH gene in this patient was negative but positive of her sister, which carries 2 heterozygous mutation c.781C>T and c.1238G>C. Next-generation sequencing on the patient identified a homozygous mutation in the quinoid dihydropteridine reductase (QDPR) gene at c.508G>A, which was confirmed by Sanger sequencing.\nCONCLUSION: (a) The patient was the first case of clinical diagnosis of BH<sub>4</sub> deficiency in the Uighur. And there are two types of hyperphenylalaninemia (HPA) in the same family. (b) The mild HPA patient with severe nervous system damage should pay more attention to the BH<sub>4</sub> deficiency. (c) Using next-generation sequencing technology can increase the mutation detection rate when the hereditary diseases are highly suspected in clinic.","variants":[{"Name":"NM_000320.3(QDPR):c.508G>A (p.Gly170Ser)","Chromosome":"4","Start":"17492269","Stop":"17492269","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1055421,"rule_based_match":true,"evidence_text":"c.508G>A","llm_judgment":"PRESENT","evidence":"c.508G>A","abstract_start":1239,"abstract_end":1247}]}
{"pmid":"18360822","title":"Reversible optic neuropathy with OPA1 exon 5b mutation.","abstract":"A new c.740G>A (R247H) mutation in OPA1 alternate spliced exon 5b was found in a patient presenting with bilateral optic neuropathy followed by partial, spontaneous visual recovery. R247H fibroblasts from the patient and his unaffected father presented unusual highly tubular mitochondrial network, significant increased susceptibility to apoptosis, oxidative phosphorylation uncoupling, and altered OPA1 protein profile, supporting the pathogenicity of this mutation. These results suggest that the clinical spectrum of the OPA1-associated optic neuropathies may be larger than previously described, and that spontaneous recovery may occur in cases harboring an exon 5b mutation.","variants":[{"Name":"NM_130837.3(OPA1):c.740G>A (p.Arg247His)","Chromosome":"3","Start":"193626153","Stop":"193626153","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76663,"rule_based_match":true,"evidence_text":"c.740G>A (R247H)","llm_judgment":"PRESENT","evidence":"c.740G>A (R247H)","abstract_start":6,"abstract_end":22}]}
{"pmid":"17015053","title":"SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin.","abstract":"OBJECTIVE: Pravastatin is a hydrophilic substrate and fluvastatin a lipophilic substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 encoded by SLCO1B1. Our aim was to compare the effects of SLCO1B1 polymorphism on the pharmacokinetics of pravastatin and fluvastatin.\nMETHODS: We recruited 4 healthy volunteers (3 men and 1 woman) with the homozygous SLCO1B1 c.521CC genotype, 12 (7 men and 5 women) with the heterozygous c.521TC genotype, and 16 (8 men and 8 women) with the homozygous c.521TT genotype (control subjects). In a crossover study each subject ingested a single 40-mg dose of fluvastatin and pravastatin with a washout period of at least 1 week. Plasma fluvastatin and pravastatin concentrations were measured for 12 hours.\nRESULTS: In men with the c.521CC genotype, the mean peak concentration in plasma and area under the plasma concentration-time curve from time 0 to infinity of pravastatin were 274% (95% confidence interval [CI], 92%-456%; P = .001) and 232% (95% CI, 74%-391%; P = .002) greater than those in men with the c.521TT genotype and 120% (95% CI, 11%-230%; P = .026) and 102% (95% CI, 3%-200%; P = .040) greater than those in men with the c.521TC genotype. In addition, women with the c.521TT genotype had a 147% (95% CI, 12%-281%; P = .028) greater peak concentration in plasma and a 142% (95% CI, 7%-242%; P = .034) greater area under the plasma concentration-time curve from time 0 to infinity than men with the c.521TT genotype. The pharmacokinetic variables of pravastatin were approximately similar among women with different SLCO1B1 genotypes. No significant differences were seen in the pharmacokinetics of fluvastatin between subjects with different SLCO1B1 genotypes or between the sexes.\nCONCLUSIONS: SLCO1B1 polymorphism has a large effect on the pharmacokinetics of pravastatin but not fluvastatin. This suggests that the lipophilic fluvastatin can penetrate the hepatocyte plasma membrane via passive diffusion or that uptake transporters other than organic anion transporting polypeptide 1B1 mainly mediate its hepatic uptake. Moreover, the results suggest that sex may affect the pharmacokinetics of pravastatin and possibly the functional consequences of SLCO1B1 polymorphism.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":false,"evidence_text":"c.521T>C","llm_judgment":"PRESENT","evidence":"c.521T>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"27081525","title":"Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation.","abstract":"We present here a case of attenuated familial adenomatous polyposis (AFAP) with a family history of desmoids and thyroid tumors. This patient had no colonic polyps but did have multiple desmoids. Genetic analysis identified a 4-bp deletion in codon 2644 (c.7932_7935delTTAT: p.Tyr2645LysfsX14) of the adenomatous polyposis coli (APC) gene. In cases with limited numbers of colonic polyps and desmoids, AFAP may be caused by a mutation in the 3' region of APC.","variants":[{"Name":"NM_000038.6(APC):c.7932_7935del (p.Tyr2645fs)","Chromosome":"5","Start":"112843524","Stop":"112843527","ReferenceAlleleVCF":"AATTT","AlternateAlleleVCF":"A","allel_id":474038,"rule_based_match":true,"evidence_text":"c.7932_7935delTTAT: p.Tyr2645LysfsX14","llm_judgment":"PRESENT","evidence":"c.7932_7935delTTAT: p.Tyr2645LysfsX14","abstract_start":255,"abstract_end":292}]}
{"pmid":"23842455","title":"Mutations in STT3A and STT3B cause two congenital disorders of glycosylation.","abstract":"We describe two unreported types of congenital disorders of glycosylation (CDG) which are caused by mutations in different isoforms of the catalytic subunit of the oligosaccharyltransferase (OST). Each isoform is encoded by a different gene (STT3A or STT3B), resides in a different OST complex and has distinct donor and acceptor substrate specificities with partially overlapping functions in N-glycosylation. The two cases from unrelated consanguineous families both show neurologic abnormalities, hypotonia, intellectual disability, failure to thrive and feeding problems. A homozygous mutation (c.1877T > C) in STT3A causes a p.Val626Ala change and a homozygous intronic mutation (c.1539 + 20G > T) in STT3B causes the other disorder. Both mutations impair glycosylation of a GFP biomarker and are rescued with the corresponding cDNA. Glycosylation of STT3A- and STT3B-specific acceptors is decreased in fibroblasts carrying the corresponding mutated gene and expression of the STT3A (p.Val626Ala) allele in STT3A-deficient HeLa cells does not rescue glycosylation. No additional cases were found in our collection or in reviewing various databases. The STT3A mutation significantly impairs glycosylation of the biomarker transferrin, but the STT3B mutation only slightly affects its glycosylation. Additional cases of STT3B-CDG may be missed by transferrin analysis and will require exome or genome sequencing.","variants":[{"Name":"NM_152713.5(STT3A):c.1877T>C (p.Val626Ala)","Chromosome":"11","Start":"125618475","Stop":"125618475","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":108185,"rule_based_match":true,"evidence_text":"c.1877T > C","llm_judgment":"PRESENT","evidence":"c.1877T > C","abstract_start":599,"abstract_end":610},{"Name":"NM_178862.3(STT3B):c.1539+20G>T","Chromosome":"3","Start":"31622328","Stop":"31622328","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":108191,"rule_based_match":true,"evidence_text":"c.1539 + 20G > T","llm_judgment":"PRESENT","evidence":"c.1539 + 20G > T","abstract_start":685,"abstract_end":701}]}
{"pmid":"32830254","title":"The combined novel KCNQ1 frameshift I145Sfs*92 and nonsense W392X variants caused Jervell and Lange-Nielsen syndrome in a Chinese infant presenting with sustained foetal bradycardia.","abstract":"AIMS: We report clinical and molecular analysis of an infant presenting with foetal bradycardia and clinical outcome of Jervell and Lange-Nielsen syndrome (JLNS).\nMETHODS AND RESULTS: Clinical, electrocardiogram (ECG), and echocardiographic data were collected from members in a three-generation family. Whole exomes were amplified and sequenced for proband. The identified variants were verified in the remaining members. The pathogenicity of candidate variants was predicted using multiple software programmes. A 28-year-old non-consanguineous Chinese woman at 23 weeks' gestation presenting with sustained foetal bradycardia of 100 b.p.m. Immunological disorders and infection were excluded. The infant was delivered at 37 weeks' gestation with 2700-g birthweight. QTc was prolonged in both ECG and Holter recording. Hearing tests confirmed bilateral sensorineural hearing loss. Genetic testing demonstrated that the infant carried a novel frameshift c.431delC (p.I145Sfs*92) and a novel nonsense c.1175G>A (p.W392X) compound variants of KCNQ1 inherited from mother and father, respectively, in autosomal recessive inheritance. Only relative II-5 carrying heterozygous KCNQ1-I145Sfs*92 variant had prolonged QTc, while the other carriers did not have prolonged QT, suggesting an autosomal dominant inheritance of LQT1 phenotype with incomplete penetrance in the family.\nCONCLUSION: We report the novel frameshift KCNQ1-I145Sfs*92 and nonsense KCNQ1-W392X compound variants in autosomal recessive inheritance that caused JLNS presenting as sustained foetal bradycardia for the first time. Meanwhile, KCNQ1-I145Sfs*92 heterozygous variant demonstrated LQT1 phenotype in autosomal dominant inheritance with incomplete penetrance.","variants":[{"Name":"NM_000218.3(KCNQ1):c.1175G>A (p.Trp392Ter)","Chromosome":"11","Start":"2587616","Stop":"2587616","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":398597,"rule_based_match":true,"evidence_text":"c.1175G>A (p.W392X)","llm_judgment":"PRESENT","evidence":"c.1175G>A (p.W392X)","abstract_start":1000,"abstract_end":1019}]}
{"pmid":"35575118","title":"A novel substitution of proline (P32L) destabilises β2-microglobulin inducing hereditary systemic amyloidosis.","abstract":"BACKGROUND: β2-microglobulin amyloidosis was first described in the 1980s as a protein deposition disease associated with long-term haemodialysis. More recently, two inherited forms resulting from separate point mutations in the β2-microglobulin gene have been identified. In this report, we detail a novel β2M variant, P32L, caused by a unique dinucleotide mutation that is linked to systemic hereditary β2-microglobulin amyloidosis.\nMETHODS: Three family members from a Portuguese kinship featured cardiomyopathy, requiring organ transplantation in one case, along with soft tissue involvement; other involvements included gastrointestinal, neuropathic and sicca syndrome. <i>In vitro</i> studies with recombinant P32L, P32G, D76N and wild-type β2-microglobulin were undertaken to compare the biophysical properties of the proteins.\nRESULTS: The P32L variant was caused by the unique heterozygous dinucleotide mutation c.154_155delinsTT. Amyloid disease featured lowered serum β2-microglobulin levels with near equal amounts of circulating P32L and wild-type proteins; amyloid deposits were composed exclusively of P32L variant protein. <i>In vitro</i> studies of P32L demonstrated thermodynamic and chemical instability and enhanced susceptibility to proteolysis with rapid formation of pre-fibrillar oligomeric structures by N- and C-terminally truncated species under physiological conditions.\nCONCLUSIONS: This work provides both clinical and experimental evidence supporting the critical role of P32 residue replacement in β2M amyloid fibrillogenesis.","variants":[{"Name":"NM_004048.4(B2M):c.154_155delinsTT (p.Pro52Leu)","Chromosome":"15","Start":"44715509","Stop":"44715510","ReferenceAlleleVCF":"CC","AlternateAlleleVCF":"TT","allel_id":1036494,"rule_based_match":true,"evidence_text":"c.154_155delinsTT","llm_judgment":"PRESENT","evidence":"c.154_155delinsTT","abstract_start":921,"abstract_end":938}]}
{"pmid":"31595668","title":"Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum.","abstract":"Myhre syndrome is a rare multisystem connective tissue disorder, characterized by short stature, facial dysmorphology, variable intellectual disability, skeletal abnormalities, arthropathy, cardiopathy, laryngotracheal anomalies, and stiff skin. So far, all molecularly confirmed cases harbored a de novo heterozygous gain-of-function mutation in SMAD4, encoding the SMAD4 transducer protein required for both transforming growth factor-beta and bone morphogenic proteins signaling. We report on four novel patients (one female proband and her two affected children, and one male proband) with Myhre syndrome harboring the recurrent c.1486C>T (p.Arg496Cys) mutation in SMAD4. The female proband presented with a congenital heart defect, vertebral anomalies, and facial dysmorphic features. She developed severe tracheal stenosis requiring a total laryngectomy. With assisted reproductive treatment, she gave birth to two affected children. The second proband presented with visual impairment following lensectomy in childhood, short stature, brachydactyly, stiff skin, and decreased peripheral sensitivity. Transmission electron microscopy (TEM) of the dermis shows irregular elastin cores with globular deposits and almost absent surrounding microfibrils and suggests age-related increased collagen deposition. We report on the first familial case of Myhre syndrome and illustrate the variable clinical spectrum of the disorder. Despite the primarily fibrotic nature of the disease, TEM analysis mainly indicates elastic fiber anomalies.","variants":[{"Name":"NM_005359.6(SMAD4):c.1486C>T (p.Arg496Cys)","Chromosome":"18","Start":"51078294","Stop":"51078294","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":94253,"rule_based_match":true,"evidence_text":"c.1486C>T (p.Arg496Cys)","llm_judgment":"PRESENT","evidence":"c.1486C>T (p.Arg496Cys)","abstract_start":633,"abstract_end":656}]}
{"pmid":"29704306","title":"Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness.","abstract":"Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta-analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK-related CMS.","variants":[{"Name":"NM_005592.4(MUSK):c.1742T>A (p.Ile581Asn)","Chromosome":"9","Start":"110785682","Stop":"110785682","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2752720,"rule_based_match":true,"evidence_text":"c.1742T > A; p.I581N","llm_judgment":"PRESENT","evidence":"c.1742T > A; p.I581N","abstract_start":467,"abstract_end":487}]}
{"pmid":"19410294","title":"Molecular characterization of a large cohort of patients with Chronic Granulomatous Disease and identification of novel CYBB mutations: an Italian multicenter study.","abstract":"Chronic Granulomatous Disease (CGD) is a rare inherited disorder in which phagocytes fail to produce antimicrobial superoxide because NADPH oxidase activity is absent. In about 65% of the cases, the disease is due to mutations affecting the X-linked CYBB gene, encoding the gp91(phox) subunit of NADPH oxidase. We investigated 34 CGD male patients by DHPLC and direct sequencing. A mutation was found in the CYBB gene of 33 patients and 9 of these were novel: one non-sense mutation (c.1123 G>T), three missense mutations (c.58G>A; c.1076 G>C; c.1357 T>A), two splice site mutations (c.141+5G>T; c.142-1G>A), one duplication (c.42_45dupCATT), one deletion (c.184delT), and one rare deletion of two non-contiguous nucleotides (c.1287delT+c.1290delC). One patient had the most frequent GT homozygous deletion in exon2 of the NCF-1 gene encoding the p47(phox) subunit of NADPH oxidase. The carrier analysis was performed in 23 patients' mothers and 16 female relatives through molecular and FISH studies. No clear correlation between the severity of clinical symptoms and the type of mutation could be demonstrated. This study further supports the great heterogeneity of the disease and the notion that genetic analysis is a critical step in obtaining a definitive diagnosis for CGD.","variants":[{"Name":"NM_000397.4(CYBB):c.58G>A (p.Gly20Arg)","Chromosome":"X","Start":"37782100","Stop":"37782100","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":850017,"rule_based_match":true,"evidence_text":"c.58G>A","llm_judgment":"PRESENT","evidence":"c.58G>A","abstract_start":523,"abstract_end":530}]}
{"pmid":"26309368","title":"Presence of c.3956delC mutation in familial adenomatous polyposis patients from Brazil.","abstract":"AIM: To characterize APC gene mutations and correlate them with patient phenotypes in individuals diagnosed with familial adenomatous polyposis (FAP) in northern Brazil.\nMETHODS: A total of 15 individuals diagnosed with FAP from 5 different families from the north of Brazil were analyzed in this study. In addition to patients with histopathological diagnosis of FAP, family members who had not developed the disease were also tested in order to identify mutations and for possible genetic counseling. All analyzed patients or their guardians signed a consent form approved by the Research Ethics Committee of the João de Barros Barreto University Hospital (Belem, Brazil). DNA extracted from the peripheral blood of a member of each of the affected families was subjected to direct sequencing. The proband of each family was sequenced to identify germline mutations using the Ion Torrent platform. To validate the detected mutations, Sanger sequencing was also performed. The samples from all patients were also tested for the identification of mutations by real-time quantitative polymerase chain reaction using the amplification refractory mutation system.\nRESULTS: Through interviews with relatives and a search of medical records, it was possible to construct genograms for three of the five families included in the study. All 15 patients from the five families with FAP exhibited mutations in the APC gene, and all mutations were detected in exon 15 of the APC gene. In addition to the patients with a histological diagnosis of FAP, family members without disease symptoms showed the mutation in the APC gene. In the present study, we detected two of the three most frequent germline mutations in the literature: the mutation at codon 1309 and the mutation at codon 1061. The presence of c.3956delC mutation was found in all families from this study, and suggests that this mutation was introduced in the population of the State of Pará through ancestor immigration (i.e., a de novo mutation that arose in one member belonging to this state from Brazil).\nCONCLUSION: Regardless of its origin, the c.3956delC mutation is a strong candidate biomarker of this hereditary cancer syndrome in families of northern Brazil.","variants":[{"Name":"NM_000038.6(APC):c.3956del (p.Pro1319fs)","Chromosome":"5","Start":"112839549","Stop":"112839549","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":358777,"rule_based_match":true,"evidence_text":"c.3956delC","llm_judgment":"PRESENT","evidence":"c.3956delC","abstract_start":1796,"abstract_end":1806}]}
{"pmid":"34073554","title":"Absence of Genotype/Phenotype Correlations Requires Molecular Diagnostic to Ascertain Stargardt and Stargardt-Like Swiss Patients.","abstract":"We genetically characterized 22 Swiss patients who had been diagnosed with Stargardt disease after clinical examination. We identified in 11 patients (50%) pathogenic bi-allelic <i>ABCA4</i> variants, c.1760+2T>C and c.4496T>C being novel. The dominantly inherited pathogenic <i>ELOVL4</i> c.810C>G p.(Tyr270*) and <i>PRPH2</i>-c.422A>G p.(Tyr141Cys) variants were identified in eight (36%) and three patients (14%), respectively. All patients harboring the <i>ELOVL4</i> c.810C>G p.(Tyr270*) variant originated from the same small Swiss area, identifying a founder mutation. In the <i>ABCA4</i> and <i>ELOVL4</i> cohorts, the clinical phenotypes of \"flecks\", \"atrophy\", and \"bull\"s eye like\" were observed by fundus examination. In the small number of patients harboring the pathogenic <i>PRPH2</i> variant, we could observe both \"flecks\" and \"atrophy\" clinical phenotypes. The onset of disease, progression of visual acuity and clinical symptoms, inheritance patterns, fundus autofluorescence, and optical coherence tomography did not allow discrimination between the genetically heterogeneous Stargardt patients. The genetic heterogeneity observed in the relatively small Swiss population should prompt systematic genetic testing of clinically diagnosed Stargardt patients. The resulting molecular diagnostic is required to prevent potentially harmful vitamin A supplementation, to provide genetic counseling with respect to inheritance, and to schedule appropriate follow-up visits in the presence of increased risk of choroidal neovascularization.","variants":[{"Name":"NM_000350.3(ABCA4):c.1760+2T>C","Chromosome":"1","Start":"94063110","Stop":"94063110","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3062437,"rule_based_match":true,"evidence_text":"c.1760+2T>C","llm_judgment":"PRESENT","evidence":"c.1760+2T>C","abstract_start":201,"abstract_end":212},{"Name":"NM_022726.4(ELOVL4):c.810C>G (p.Tyr270Ter)","Chromosome":"6","Start":"79916743","Stop":"79916743","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":19980,"rule_based_match":true,"evidence_text":"c.810C>G p.(Tyr270*)","llm_judgment":"PRESENT","evidence":"c.810C>G p.(Tyr270*)","abstract_start":290,"abstract_end":310}]}
{"pmid":"22425665","title":"BRCA1 and BRCA2 germline mutations in Moroccan breast/ovarian cancer families: novel mutations and unclassified variants.","abstract":"OBJECTIVE: Breast cancer is the most common female cancer in Morocco. About 5 to 10% are due to hereditary predisposition and mutations in BRCA1 and BRCA2 genes are responsible for an important proportion of high-risk breast/ovarian cancer families. The relevance of BRCA1/2 mutations in the Moroccan population was not studied. The main objective of this study is to investigate the spectrum of BRCA1 and BRCA2 germline mutations in early onset and familial breast/ovarian cancer among Moroccan women.\nMETHODS: We screened the entire coding sequences and intron/exon boundaries of BRCA1 and BRCA2 genes in 40 patients by direct sequencing.\nRESULTS: Nine pathogenic mutations were detected in ten unrelated families, five deleterious mutations in BRCA1 gene and four mutations in BRCA2 gene. Four novel mutations were found: one in BRCA1 (c.2805delA/2924delA) and three in BRCA2 (c.3381delT/3609delT; c.7110delA/7338delA and c.7235insG/7463insG). We also identified 51 distinct polymorphisms and unclassified variants (three described for the first time).\nCONCLUSIONS: Our data suggest that BRCA1 and BRCA2 mutations are responsible for a significant proportion of familial breast cancer in Moroccan patients. Therefore full BRCA1/2 screening should be offered to patients with a family history of breast/ovarian cancer.","variants":[{"Name":"NM_007294.4(BRCA1):c.2805del (p.Asp936fs)","Chromosome":"17","Start":"43092726","Stop":"43092726","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":69351,"rule_based_match":true,"evidence_text":"c.2805delA/2924delA","llm_judgment":"PRESENT","evidence":"c.2805delA/2924delA","abstract_start":839,"abstract_end":858}]}
{"pmid":"33014402","title":"Compound heterozygous variants in the","abstract":"Sitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the <i>ABCG8</i> gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.","variants":[{"Name":"NM_022437.3(ABCG8):c.1256_1257delinsAA (p.Ile419Lys)","Chromosome":"2","Start":"43873831","Stop":"43873832","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"AA","allel_id":1294800,"rule_based_match":false,"evidence_text":"c.1256_1257delTCinsAA (p.Ile419Lys)","llm_judgment":"PRESENT","evidence":"c.1256_1257delTCinsAA (p.Ile419Lys)","abstract_start":352,"abstract_end":387}]}
{"pmid":"23949913","title":"Boston type craniosynostosis: report of a second mutation in MSX2.","abstract":"We describe a family that segregated an autosomal dominant form of craniosynostosis characterized by variable expression and limited extra-cranial features. Linkage analysis and genome sequencing were performed to identify the underlying genetic mutation. A c.443C>T missense mutation in MSX2, which predicts p.Pro148Leu was identified and segregated with the disease in all affected family members. One other family with autosomal dominant craniosynostosis (Boston type) has been reported to have a missense mutation in MSX2. These data confirm that missense mutations altering the proline at codon 148 of MSX2 cause dominantly inherited craniosynostosis.","variants":[{"Name":"NM_002449.5(MSX2):c.443C>T (p.Pro148Leu)","Chromosome":"5","Start":"174729222","Stop":"174729222","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":217218,"rule_based_match":true,"evidence_text":"c.443C>T","llm_judgment":"PRESENT","evidence":"c.443C>T","abstract_start":258,"abstract_end":266}]}
{"pmid":"38648771","title":"Novel Gain-of-Function Mutation in the Kv11.1 Channel Found in the Patient with Brugada Syndrome and Mild QTc Shortening.","abstract":"Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter I<sub>Kr</sub>-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on I<sub>Kr</sub> reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the I<sub>Kr</sub> density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.","variants":[{"Name":"NM_000238.4(KCNH2):c.1189C>T (p.Arg397Cys)","Chromosome":"7","Start":"150952793","Stop":"150952793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":395706,"rule_based_match":true,"evidence_text":"c.1189C>T (p.R397C)","llm_judgment":"PRESENT","evidence":"c.1189C>T (p.R397C)","abstract_start":404,"abstract_end":423}]}
{"pmid":"31630374","title":"Genetic and Clinical Profile of Chinese Patients with Autosomal Dominant Spastic Paraplegia.","abstract":"BACKGROUND: Hereditary spastic paraplegia (HSP) refers to a group of neurodegenerative disorders characterized by bilateral weakness, spasticity, and hyperreflexia in the lower limbs. The autosomal dominant HSP (ADHSP) predominantly presents as the pure form, but the clinical profiles and causal genetic variants underlying ADHSP are complex, and many remain unknown.\nMETHODS: A cohort of 15 Chinese HSP pedigrees (including 35 patients and their 22 relatives) were screened by multiplex ligation-dependent probe amplification (MLPA) or whole-exome sequencing (WES). Neurological assessments were also conducted.\nRESULTS: The main subtypes of HSP above detected in our cohort were SPG4, SPG3A, and SPG6. Fifteen HSP-inducing mutations were identified, among which six were novel mutations: SPAST c.1277T>C, c.1292G>C, c.1562T>C, and c.1693A>T, NIPA1 c.748A>C, and KIDINS220 c.4448C>G. As expected, the most common presentation of the ADHSP cases was the pure form, manifesting spasticity of lower limbs and hyperreflexia, as well as pyramidal signs. Differing substantially from previous reports for KIDINS220 variants, our study family exhibited autosomal dominant inheritance, and only presented with spastic paraplegia, with no signs of intellectual disability, nystagmus, or obesity.\nCONCLUSION: Our work reveals a non-classical spastic paraplegia, intellectual disability, nystagmus, and obesity phenotype for a KIDINS220 mutation, which broadens both the clinical and genetic spectrum for ADHSP. Beyond underscoring the utility of using both MLPA and WES in studies of HSP, our work deepens the scientific understanding of phenotypes for ADHSP and defines new genetic variants to facilitate future diagnoses.","variants":[{"Name":"NM_144599.5(NIPA1):c.748A>C (p.Lys250Gln)","Chromosome":"15","Start":"22823997","Stop":"22823997","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1401915,"rule_based_match":true,"evidence_text":"NIPA1 c.748A>C","llm_judgment":"PRESENT","evidence":"NIPA1 c.748A>C","abstract_start":845,"abstract_end":859}]}
{"pmid":"36934406","title":"Identification of a homozygous frameshift mutation in the FGF3 gene in a consanguineous Iranian family: First report of labyrinthine aplasia, microtia, and microdontia syndrome in Iran and literature review.","abstract":"BACKGROUND: To date, over 400 syndromes with hearing impairment have been identified which altogether constitute almost 30% of hereditary hearing loss (HL) cases around the globe. Manifested as complete or partial labyrinthine aplasia (severe malformations of the inner ear structure), type I microtia (smaller outer ear with shortened auricles), and microdontia (small and widely spaced teeth), labyrinthine aplasia, microtia, and microdontia (LAMM) syndrome (OMIM 610706) is an extremely rare autosomal recessive condition caused by bi-allelic mutations in the FGF3 gene.\nMETHODS: Using the whole-exome sequencing (WES) data of the proband, we analyzed a consanguineous Iranian family with three affected members presenting with congenital bilateral HL, type I microtia, and microdontia.\nRESULTS: We discovered the homozygous deletion c.45delC in the first exon of the FGF3 gene, overlapping a 38.72 Mb homozygosity region in chromosome 11. Further investigations using Sanger sequencing revealed that this variant co-segregated with the phenotype observed in the family.\nCONCLUSION: Here, we report the first identified case of LAMM syndrome in Iran, and by identifying a frameshift variant in the first exon of the FGF3 gene, our result will help better clarify the phenotype-genotype relation of LAMM syndrome.","variants":[{"Name":"NM_005247.4(FGF3):c.45del (p.Trp16fs)","Chromosome":"11","Start":"69818889","Stop":"69818889","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":2401818,"rule_based_match":true,"evidence_text":"c.45delC","llm_judgment":"PRESENT","evidence":"c.45delC","abstract_start":837,"abstract_end":845}]}
{"pmid":"27739455","title":"Novel CHM mutations identified in Chinese families with Choroideremia.","abstract":"Choroideremia is a bilateral and progressive X-linked inherited disease characterized by widespread chorioretinal atrophy with relative sparing of the macular region. It is caused by mutations in the ubiquitously expressed CHM gene, which lead to the absence of the Rab escort protein 1 (REP-1), resulting in prenylation deficiency. Typical fundus appearances for choroideremia were found in 3 probands from three unrelated Chinese families in our study. We firstly used the targeted exome sequencing (TES) technology to detect mutations in CHM gene. Based on an established filtering strategy of data analyses, along with confirmation by co-segregation, a previously reported mutation (c.1584_1587del TGTT, p.V529Hfs*7) was identified in one family, while two novel mutations (c.227_232delinsTGTCATTTCA, p.Q76Lfs*7; c.710dupA, p.Y237_S238delinsX) were identified in the other two families. These findings not only expands the currently limited spectrum of Chinese disease-causing variants in CHM gene, but also increases our understanding of the phenotypic and genotypic correlations of choroideremia, and may potentially lead to improved genetic counseling and specific treatment for families with choroideremia as well.","variants":[{"Name":"NM_000390.4(CHM):c.1584_1587del (p.Val529fs)","Chromosome":"X","Start":"85878987","Stop":"85878990","ReferenceAlleleVCF":"GAACA","AlternateAlleleVCF":"G","allel_id":26191,"rule_based_match":true,"evidence_text":"c.1584_1587del TGTT","llm_judgment":"PRESENT","evidence":"c.1584_1587del TGTT","abstract_start":687,"abstract_end":706}]}
{"pmid":"32974842","title":"Identification and in silico characterization of a novel PKLR genotype in a Turkish newborn.","abstract":"Pyruvate kinase deficiency (PKD) is the most common glycolytic defect leading to chronic nonspherocytic hemolytic anemia (CNSHA). Clinical manifestations of PKD reflect the symptoms and complications of the chronic hemolysis, including anemia, jaundice, bilirubin gallstones due to hyperbilirubinemia, splenomegaly and iron overload. In this study, we report the finding of a 5-months-old Turkish male newborn with moderate CNSHA and PKD. Mutation screening of Pyruvate Kinase Liver/Red (PKLR) gene revealed that the patient carried the known pathogenic variant (PV) c.1456C > T (p.Arg486Trp) and an unreported variant c.1067T > G (p.Met356Arg). Computational variant analysis (CVA) highlighted the deleterious structural effects on the mutant PK enzyme, suggesting its pathogenic role. In this patient, the molecular evaluation of PKD, that allowed the identification of the novel PKLR genotype, coupled with CVA led to the definitive and correct diagnosis of CNSHA.","variants":[{"Name":"NM_000298.6(PKLR):c.1456C>T (p.Arg486Trp)","Chromosome":"1","Start":"155291918","Stop":"155291918","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16552,"rule_based_match":true,"evidence_text":"c.1456C > T (p.Arg486Trp)","llm_judgment":"PRESENT","evidence":"c.1456C > T (p.Arg486Trp)","abstract_start":567,"abstract_end":592}]}
{"pmid":"20406103","title":"Mutation analysis of the HBB gene in selected Bangladeshi beta-thalassemic individuals: presence of rare mutations.","abstract":"INTRODUCTION AND AIMS: Bangladesh has a large number of thalassemic patients. However, no extensive analysis of the mutations in the HBB gene of thalassemic patients has been previously carried out. We have conducted a systematic research to reveal thalassemia mutations in the Bangladeshi population. In this preliminary analysis of 587 bp of the HBB gene in selected thalassemic individuals, some rare mutations in world perspective have been found to be significantly high in the Bangladeshi population, together with the common mutations for thalassemia.\nRESULTS: A 587-bp segment of the HBB gene from 32 chromosomes of 16 beta-thalassemic individuals was analyzed for molecular characterization of the disease. Splice junction mutation IVS-I-5 was found to be the most common. The analysis also revealed some rare mutations HBB: c.-80T>C, HBB: c. 92G>C, HBB: c-92C>G, which are not prevalent in geographically adjacent populations.\nCONCLUSION: This is a first of this kind of study in the Bangladeshi population. Although the small sample size makes it difficult to make any population genetics inference, this study can be regarded as the seminal research for a large-scale study to determine the complete mutation profile underlying thalassemia in the Bangladeshi population. The complete mutation profile will provide invaluable strategies (e.g., prenatal diagnosis and genetic counseling) for better management of thalassemia in the Bangladeshi population.","variants":[{"Name":"NM_000518.5(HBB):c.-80T>C","Chromosome":"11","Start":"5227101","Stop":"5227101","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":857535,"rule_based_match":true,"evidence_text":"HBB: c.-80T>C","llm_judgment":"PRESENT","evidence":"HBB: c.-80T>C","abstract_start":829,"abstract_end":842}]}
{"pmid":"33390354","title":"ABCB4 variants in adult patients with cholestatic disease are frequent and underdiagnosed.","abstract":"BACKGROUND: Heterozygous ABCB4 variants are not routinely tested in adults with cholestasis because of their supposed rarity and high costs.\nMETHODS: Nineteen adult patients presenting with unexplained cholestasis, and/or recurrent gallstones were included; genotyping was not done in five due to lack of health insurance approval.\nRESULTS: heterozygous ABCB4 variants were identified in seven patients, followed by cascade testing of 12 family members: one patient underwent liver transplantation at age 40 for end-stage liver disease; one had compensated cirrhosis; all symptomatic adults had gallstones, including four with low phospholipid-associated cholelithiasis; four had intrahepatic cholestasis of pregnancy; all children and one 54-year old female were asymptomatic. Genotype: Families A and C: c.2211G>A (p.Ala737=) combined with c.959C>T (p.Ser320Phe) in one subject; Family B: c.1130T>C (p.Ile377Thr); Family D: large deletion removing ABCB4 exons 1-4 plus ABCB1, RUNDC3B, SLC25A40, DBF4, ADAM22 exons 1-3; Family E: c.1565T>C (p.Phe522Ser) ; Family F: c.1356+2T>C combined with c.217C>G (p.Leu73Val). All patients responded to ursodeoxycholic acid.\nCONCLUSIONS: We found ABCB4 variants in half of the adults with unexplained cholestasis and/or recurrent gallstones presenting at our center, suggesting that this condition is underdiagnosed and undertreated, with serious consequences not only for the patients and their families, but also in terms of healthcare costs.","variants":[{"Name":"NM_000443.4(ABCB4):c.2211G>A (p.Ala737=)","Chromosome":"7","Start":"87423906","Stop":"87423906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":585404,"rule_based_match":true,"evidence_text":"c.2211G>A (p.Ala737=)","llm_judgment":"PRESENT","evidence":"c.2211G>A (p.Ala737=)","abstract_start":806,"abstract_end":827},{"Name":"NM_000443.4(ABCB4):c.217C>G (p.Leu73Val)","Chromosome":"7","Start":"87462827","Stop":"87462827","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":361407,"rule_based_match":true,"evidence_text":"c.217C>G (p.Leu73Val)","llm_judgment":"PRESENT","evidence":"c.217C>G (p.Leu73Val)","abstract_start":1093,"abstract_end":1114}]}
{"pmid":"23239455","title":"Cardiac anomalies in Axenfeld-Rieger syndrome due to a novel FOXC1 mutation.","abstract":"Axenfeld-Rieger syndrome (ARS) is an autosomal dominant condition characterized by ophthalmologic anterior segment abnormalities and extraocular findings including dental anomalies and redundant periumbilical skin. Intragenic mutations in the homeobox gene PITX2 or the transcription factor encoding FOXC1 were identified, and genomic rearrangements encompassing either gene also cause ARS. A molecular etiology is identified in 40-60%. Extraocular anomalies occur more often with intragenic PITX2 than FOXC1 mutations. We report on a patient with infantile glaucoma presenting at age 21 months with congestive heart failure due to a dysplastic arcade mitral valve necessitating valve replacement, and mildly hypoplastic left ventricular outflow tract and aortic arch. Family history included early onset glaucoma in four relatives; congenital hip dysplasia requiring surgery in three; and an atrial septal defect in the affected maternal grandmother. Despite the absence of dental or umbilical abnormalities, anterior chamber abnormalities consistent with ARS were present in affected individuals. Molecular testing revealed a novel FOXC1 mutation (c.508C>T; p.Arg170Trp) in the proband and his affected mother; other family members were unavailable. A literature review revealed four reports of congenital heart disease associated with intragenic FOXC1 mutations, and none with intragenic PITX2 mutations. Previously, mouse studies showed Foxc1 (Mf1) expression in the developing valves and atrial septum, supporting a causal relationship of FOXC1 mutations for valvar anomalies and ASD. Hip dysplasia in three family members suggests a role for FOXC1 in the femoral head dysplasia of de Hauwere syndrome with 6p25 deletions. Further reports of clinical and molecular diagnoses will clarify genotype-phenotype correlation.","variants":[{"Name":"NM_001453.3(FOXC1):c.508C>T (p.Arg170Trp)","Chromosome":"6","Start":"1610953","Stop":"1610953","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":634763,"rule_based_match":true,"evidence_text":"c.508C>T; p.Arg170Trp","llm_judgment":"PRESENT","evidence":"c.508C>T; p.Arg170Trp","abstract_start":1150,"abstract_end":1171}]}
{"pmid":"19266496","title":"Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families.","abstract":"OBJECTIVE: Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of alpha-dystroglycan (alpha-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS.\nMETHOD: We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis.\nRESULTS: We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults.\nCONCLUSION: These data suggest that the c.1167insA FKTN mutation described by us is a founder mutation that can be used to target diagnostic testing and carrier screening in the Ashkenazi Jewish population.","variants":[{"Name":"NM_001079802.2(FKTN):c.1167dup (p.Phe390fs)","Chromosome":"9","Start":"105620049","Stop":"105620050","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":18242,"rule_based_match":false,"evidence_text":"c.1167insA","llm_judgment":"PRESENT","evidence":"c.1167insA","abstract_start":695,"abstract_end":705}]}
{"pmid":"18348272","title":"Association of homozygous LMNA mutation R471C with new phenotype: mandibuloacral dysplasia, progeria, and rigid spine muscular dystrophy.","abstract":"We report on a 7-year-old girl with a phenotype combining mandibuloacral dysplasia (MAD), progeria, and rigid spine muscular dystrophy. Mild proximal weakness, contractures, and rigidity of the spine were the primary findings. Although present since birth, dysmorphic manifestations typical for MAD and progeroid features became more prominent with time, and the full clinical phenotype was recognizable at early school age. Her phenotype was caused by a homozygous mutation in LMNA (c.1411C > T, which predicts p.R471C) inherited from the heterozygous, consanguineous, unaffected parents. This mutation has only been reported in compound heterozygous state and was associated with a milder phenotype. Some LMNA mutations are known to cause MAD and overlapping phenotypes (MAD spectrum) in an autosomal recessive pattern. The p.R471C homozygous LMNA mutation causes a severe phenotype of the MAD spectrum. This case extends the clinical spectrum of MAD and further expands the phenotypic range of lamin A/C associated diseases.","variants":[{"Name":"NM_170707.4(LMNA):c.1411C>T (p.Arg471Cys)","Chromosome":"1","Start":"156136951","Stop":"156136951","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29542,"rule_based_match":true,"evidence_text":"c.1411C > T","llm_judgment":"PRESENT","evidence":"c.1411C > T","abstract_start":484,"abstract_end":495}]}
{"pmid":"33748275","title":"Novel Mutations of","abstract":"Alport syndrome (AS) is an inherited kidney disease caused by defects in type IV collagen, which is characterized by hematuria, progressive nephritis or end-stage renal disease (ESRD), hearing loss, and occasionally ocular lesions. Approximately 80% of AS cases are caused by X-linked mutations in the <i>COL4A5</i> gene. This study explored novel deletion and missense mutations in <i>COL4A5</i> responsible for renal disorder in two Han Chinese families. In pedigree 1, the five male patients all had ESRD at a young age, while the affected female members only presented with microscopic hematuria. Whole exome sequencing and Sanger sequencing identified a novel frameshift deletion mutation (c.422_428del, p.Leu142Valfs∗11) in exon 7 of <i>COL4A5</i>. In pedigree 2, the 16-year-old male proband had elevated serum creatinine (309 <i>μ</i>mol/L) without extrarenal manifestations, while his mother only manifested with hematuria. A missense mutation (c.476G>T, p.Gly159Val) was found in exon 9 of the <i>COL4A5</i> gene. Neither of these mutations was present in the Exome Variant Server of the NHLBI-ESP database, nor was it found in the ExAC or 1000 Genomes databases. Through the literature review, it was found that male Chinese patients with X-linked AS carried <i>COL4A5</i> deletion or missense mutations had a more severe phenotype than female patients, particularly in proteinuria and impaired renal function. Compared to male patients with missense mutations, patients in whom deletion mutations were found were more likely to progress to ESRD (15.4% vs. 36.0%, <i>P</i> = 0.041). This study identified two novel <i>COL4A5</i> mutations in Chinese families with X-linked AS, expanded the mutational spectrum of the <i>COL4A5</i> gene, and presented findings that are significant for the screening and genetic diagnosis of AS.","variants":[{"Name":"NM_033380.3(COL4A5):c.476G>T (p.Gly159Val)","Chromosome":"X","Start":"108573584","Stop":"108573584","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2929252,"rule_based_match":true,"evidence_text":"c.476G>T (p.Gly159Val)","llm_judgment":"PRESENT","evidence":"p.Gly159Val","abstract_start":964,"abstract_end":975}]}
{"pmid":"26804609","title":"Mutational analysis of TBK1 in Taiwanese patients with amyotrophic lateral sclerosis.","abstract":"Mutations in the TBK1 gene were just recently identified to cause amyotrophic lateral sclerosis (ALS), and their role in ALS in various populations remains unclear. The aim of this study was to determine the frequency and spectrum of mutations in TBK1 in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of TBK1 were carried out by direct nucleotide sequencing in a cohort of 207 unrelated patients with ALS. Among them, the genetic diagnoses of 168 patients remained elusive after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, HNRNPA2B1, MATR3, CHCHD10, and TUBA4A had been excluded. We identified one nonsense mutation, p.R444X (c.1330C>T), in one patient with apparently sporadic ALS-frontotemporal dementia. In vitro functional study demonstrated the p.R444X mutation resulting in a truncated TANK-binding kinase 1 (TBK1) protein product, low protein expression, and loss of kinase function and interaction with optineurin. The frequency of TBK1 mutations in ALS patients in Taiwan is, therefore, approximately 0.5% (1/207). This study reports a novel TBK1 mutation and stresses on the importance to consider TBK1 mutation as a possible etiology of ALS.","variants":[{"Name":"NM_013254.4(TBK1):c.1330C>T (p.Arg444Ter)","Chromosome":"12","Start":"64486007","Stop":"64486007","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":260891,"rule_based_match":true,"evidence_text":"c.1330C>T","llm_judgment":"PRESENT","evidence":"c.1330C>T","abstract_start":692,"abstract_end":701}]}
{"pmid":"24461908","title":"Incidence and carrier frequency of Sandhoff disease in Saskatchewan determined using a novel substrate with detection by tandem mass spectrometry and molecular genetic analysis.","abstract":"Sandhoff disease is a rare progressive neurodegenerative genetic disorder with a high incidence among certain isolated communities and ethnic groups around the world. Previous reports have shown a high occurrence of Sandhoff disease in northern Saskatchewan. Newborn screening cards from northern Saskatchewan were retrospectively screened in order to investigate the incidence and determine the carrier frequency of Sandhoff disease in these communities. PCR-based screening was conducted for the c.115delG (p.(Val39fs)) variant in the HEXB gene that was previously found in 4 Sandhoff disease patients from this area. The carrier frequency for this allele was estimated to be ~1:27. MS/MS-based screening of hexosaminidase activity along with genetic sequencing allowed for the identification of additional variants based on low total hexosaminidase activity and high % hexosaminidase A activity relative to c.115delG carriers. In total 4 pathogenic variants were discovered in the population (c.115delG, c.619A>G, c.1601G>T, and c.1652G>A) of which two are previously unreported (c.1601G>T and c.1652G>A). The combined carrier frequency of these alleles in the study area was estimated at ~1:15. Based on the number of cases of Sandhoff disease from this area we estimate the incidence to be ~1:390 corresponding to a child being born with the disease every 1-2 years on average. The results from our study were then compared with variants in the HEXB gene from the genomes available from the 1000 Genomes project. A total of 19 HEXB variants were found in the 1092 genomes of which 5 are suspected of having a deleterious effect on hexosaminidase activity. The estimated carrier frequency of Sandhoff disease in Saskatchewan at 1:15 is more than 3 times higher than the carrier frequency in the global sample provided by the 1000 Genomes project at 1:57.","variants":[{"Name":"NM_000521.4(HEXB):c.1652G>A (p.Cys551Tyr)","Chromosome":"5","Start":"74721156","Stop":"74721156","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":177100,"rule_based_match":true,"evidence_text":"c.1652G>A","llm_judgment":"PRESENT","evidence":"c.1652G>A","abstract_start":1032,"abstract_end":1041},{"Name":"NM_000521.4(HEXB):c.1601G>T (p.Cys534Phe)","Chromosome":"5","Start":"74720735","Stop":"74720735","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":177231,"rule_based_match":true,"evidence_text":"c.1601G>T","llm_judgment":"PRESENT","evidence":"c.1601G>T","abstract_start":1017,"abstract_end":1026},{"Name":"NM_000521.4(HEXB):c.115del (p.Val39fs)","Chromosome":"5","Start":"74685374","Stop":"74685374","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":99101,"rule_based_match":true,"evidence_text":"c.115delG (p.(Val39fs))","llm_judgment":"PRESENT","evidence":"c.115delG (p.(Val39fs))","abstract_start":498,"abstract_end":521}]}
{"pmid":"21225464","title":"Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome.","abstract":"Lynch syndrome (LS) is an autosomal dominant condition that predisposes to colorectal cancer and specific other tumors. Extracolonic tumors occur mainly in the endometrium, stomach, ovary, small intestine and urinary tract. The presence of rare tumors in patients belonging to families who have Lynch syndrome is always interesting, because the question arises whether these tumors should be considered as a coincidence or are related with the syndrome. In this last case, they are also the result of the defect in the mismatch repair system, opening the possibility of extending the tumor spectrum associated with the syndrome. Here we describe a patient from a Lynch syndrome family with a germline mutation c.2063T>G (p.M688R) in the MSH2 gene, who developed an adrenal cortical carcinoma, a tumor not usually associated with LS. We analyzed the adrenocortical tumour for microsatellite instability (MSI), LOH and the presence of the germline c.2063T>G (M688R) mutation. The adrenal cortical carcinoma showed the MSH2 mutation, loss of heterozygosity of the normal allele in the MSH2 gene and loss of immunohistochemical expression for MSH2 protein, but no microsatellite instability. Additionally, the adrenal cortical carcinoma did not harbour a TP53 mutation. The molecular study indicates that this adrenal cortical cancer is probably due to the mismatch repair defect.","variants":[{"Name":"NM_000251.3(MSH2):c.2063T>G (p.Met688Arg)","Chromosome":"2","Start":"47476424","Stop":"47476424","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":96349,"rule_based_match":true,"evidence_text":"c.2063T>G (p.M688R)","llm_judgment":"PRESENT","evidence":"c.2063T>G (p.M688R)","abstract_start":710,"abstract_end":729}]}
{"pmid":"30853297","title":"Novel WWOX deleterious variants cause early infantile epileptic encephalopathy, severe developmental delay and dysmorphism among Yemenite Jews.","abstract":"The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.","variants":[{"Name":"NM_016373.4(WWOX):c.689A>C (p.Gln230Pro)","Chromosome":"16","Start":"78424953","Stop":"78424953","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":802014,"rule_based_match":true,"evidence_text":"c.689A > C, p.Gln230Pro","llm_judgment":"PRESENT","evidence":"c.689A > C, p.Gln230Pro","abstract_start":743,"abstract_end":766}]}
{"pmid":"28233300","title":"A novel DNAJB6 mutation causes dominantly inherited distal-onset myopathy and compromises DNAJB6 function.","abstract":"BACKGROUND: Mutations in the DNAJB6 gene have been identified as a rare cause of dominantly inherited limb-girdle muscular dystrophy or distal-onset myopathy.\nMATERIALS AND METHODS: Exome sequencing was performed to investigate a Taiwanese family with a dominantly inherited distal-onset myopathy. Functional effects of the causal mutation were investigated in vitro.\nRESULTS: Exome sequencing of the two affected individuals in this family identified a heterozygous mutation, c.287C>T (p.Pro96Leu) in the DNAJB6 gene, which co-segregated with the myopathy within all 12 family members. Notably, this mutation is novel and localizes within the glycine and phenylalanine-rich (G/F) domain and alters an amino acid residue previously reported with a different mutation. Furthermore, immunofluorescence analyses and filter trap assay demonstrated that the c.287C>T (p.Pro96Leu) mutation possessed a dominant negative effect on the anti-aggregation function of DNAJB6 protein.\nCONCLUSION: This study expands the molecular spectrum of DNAJB6 mutations and also emphasizes the pathogenic role of DNAJB6 dysfunction in distal-onset myopathy.","variants":[{"Name":"NM_058246.4(DNAJB6):c.287C>T (p.Pro96Leu)","Chromosome":"7","Start":"157367424","Stop":"157367424","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1868102,"rule_based_match":true,"evidence_text":"c.287C>T (p.Pro96Leu)","llm_judgment":"PRESENT","evidence":"c.287C>T (p.Pro96Leu)","abstract_start":477,"abstract_end":498}]}
{"pmid":"30926181","title":"6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects.","abstract":"BACKGROUND: Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders.\nMETHOD: We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency.\nRESULTS: Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?).\nCONCLUSION: The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.","variants":[{"Name":"NM_000317.3(PTS):c.238A>G (p.Met80Val)","Chromosome":"11","Start":"112230677","Stop":"112230677","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":359983,"rule_based_match":true,"evidence_text":"c.238A>G; p.M80V","llm_judgment":"PRESENT","evidence":"c.238A>G; p.M80V","abstract_start":1084,"abstract_end":1100}]}
{"pmid":"30348990","title":"K120R mutation inactivates p53 by creating an aberrant splice site leading to nonsense-mediated mRNA decay.","abstract":"The point mutation that substitutes lysine with arginine at position 120 of human p53 has been characterized as a missense mutation. The K120R mutation renders the p53 protein disabled for acetylation and, as a result, defective for apoptotic function, which provides a mechanistic link between the missense mutation and tumorigenesis. However, we noticed the failures of tumorigenesis in mice with the mutation, and of the related studies to notice that it has arbitrarily reflected in amino acid change through a sequence modification (AGA) of the original tumor mutation (AGG) by codon degeneracy. Unlike this modified version, we also discovered a novel splicing site the original mutation, TP53 c.359A>G, may induce. Using a human induced pluripotent stem cell line that was engineered to be homozygous for the original mutation, we here identified that the accidental splicing site generates a defective transcript variant with a frame-shifted premature termination codon which is subjected to nonsense-mediated mRNA decay. The authentic splicing still occurs but in extremely low amounts. Taken together, this mutation causes depletion of cellular p53 via defective mRNA, suggesting a new link to tumorigenesis.","variants":[{"Name":"NM_000546.6(TP53):c.359A>G (p.Lys120Arg)","Chromosome":"17","Start":"7676010","Stop":"7676010","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1473972,"rule_based_match":true,"evidence_text":"TP53 c.359A>G","llm_judgment":"PRESENT","evidence":"TP53 c.359A>G","abstract_start":695,"abstract_end":708}]}
{"pmid":"22862814","title":"Two novel mutations in the 3' untranslated region of the beta-globin gene that are associated with the mild phenotype of beta thalassemia.","abstract":"INTRODUCTION: There are approximately 800 different genomic alterations of the β-globin gene described in the human hemoglobin variant (HbVar) database. In this study, we have identified two novel putative mutations (HBB:c.*+108 A>G and HBB:c.*+132 C>T) in the 3' untranslated region (3'-UTR) of the β-globin gene and describe their clinical implications.\nMETHODS: Four patients from two unrelated families, all with hematological and clinical features associated with beta-thalassemia (β-thal), and their family members were included. The molecular diagnoses of the β-globin gene mutations were performed by direct sequencing.\nRESULTS: A novel mutation, HBB:c.*+108 A>G, was found in combination with the IVS-I-110 G>A (HBB:c.93-21 G>A) mutation in three siblings (two brothers and one sister) from one of the families involved in our study. Their mother was found to be a carrier for HBB:c.*+108 A>G with normal HbA₂ levels. The other novel mutation, HBB:c.*+132 C>T, was found in combination with IVS-I-1 G>A (HBB:c.92 + 1G>A) in a 7-year-old boy diagnosed as β-thal intermedia from the second family. His father and two brothers were all carriers of HBB:c.*+132 C>T with borderline HbA₂ levels.\nCONCLUSION: Based on the observed β-thal intermedia phenotypes and the accompanying mutations, we conclude that these novel β-globin gene 3' UTR mutations are associated with the mild phenotype of β-thal.","variants":[{"Name":"NM_000518.5(HBB):c.*132C>T","Chromosome":"11","Start":"5225466","Stop":"5225466","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432668,"rule_based_match":false,"evidence_text":"HBB:c.*+132 C>T","llm_judgment":"PRESENT","evidence":"HBB:c.*+132 C>T","abstract_start":237,"abstract_end":252}]}
{"pmid":"32757322","title":"Demyelinating Charcot-Marie-Tooth neuropathy associated with FBLN5 mutations.","abstract":"BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 whilst point mutations in PMP22 and other genes are rare causes. Recently, FBLN5 mutations have been reported in CMT1 families.\nMETHODS: Individuals with FBLN5-associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients' visits at our centres or primary care sites.\nRESULTS: Nineteen CMT1 families containing 38 carriers of three different FBLN5 missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the common PMP22 duplication, individuals with FBLN5 variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits.\nCONCLUSIONS: Our study confirms the relevance of FBLN5 mutations in CMT1. It is proposed to include FBLN5 in the genetic work-up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement. FBLN5-associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme.","variants":[{"Name":"NM_006329.4(FBLN5):c.1117C>T (p.Arg373Cys)","Chromosome":"14","Start":"91877555","Stop":"91877555","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":215085,"rule_based_match":true,"evidence_text":"c.1117C>T (p.Arg373Cys)","llm_judgment":"PRESENT","evidence":"c.1117C>T (p.Arg373Cys)","abstract_start":859,"abstract_end":882}]}
{"pmid":"22493702","title":"Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia.","abstract":"Heterozygous glucokinase (GCK) mutations cause a subtype of maturity-onset diabetes of the young (GCK-MODY). Over 600 GCK mutations have been reported of which ∼65% are missense. In many cases co-segregation has not been established and despite the importance of functional studies in ascribing pathogenicity for missense variants these have only been performed for <10% of mutations. The aim of this study was to determine the minimum prevalence of GCK-MODY amongst diabetic subjects in Slovakia by sequencing GCK in 100 Slovakian probands with a phenotype consistent with GCK-MODY and to explore the pathogenicity of identified variants through family and functional studies. Twenty-two mutations were identified in 36 families (17 missense) of which 7 (I110N, V200A, N204D, G258R, F419S, c.580-2A>C, c.1113-1114delGC) were novel. Parental DNA was available for 22 probands (covering 14/22 mutations) and co-segregation established in all cases. Bioinformatic analysis predicted all missense mutations to be damaging. Nine (I110N, V200A, N204D, G223S, G258R, F419S, V244G, L315H, I436N) mutations were functionally evaluated. Basic kinetic analysis explained pathogenicity for 7 mutants which showed reduced glucokinase activity with relative activity indices (RAI) between 0.6 to <0.001 compared to wild-type GCK (1.0). For the remaining 2 mutants additional molecular mechanisms were investigated. Differences in glucokinase regulatory protein (GKRP) -mediated-inhibition of GCK were observed for both L315H & I436N when compared to wild type (IC(50) 14.6±0.1 mM & 20.3±1.6 mM vs.13.3±0.1 mM respectively [p<0.03]). Protein instability as assessed by thermal lability studies demonstrated that both L315H and I436N show marked thermal instability compared to wild-type GCK (RAI at 55°C 8.8±0.8% & 3.1±0.4% vs. 42.5±3.9% respectively [p<0.001]). The minimum prevalence of GCK-MODY amongst Slovakian patients with diabetes was 0.03%. In conclusion, we have identified 22 GCK mutations in 36 Slovakian probands and demonstrate that combining family, bioinformatic and functional studies can aid the interpretation of variants identified by molecular diagnostic screening.","variants":[{"Name":"NM_000162.5(GCK):c.731T>G (p.Val244Gly)","Chromosome":"7","Start":"44147782","Stop":"44147782","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1822832,"rule_based_match":false,"evidence_text":"c.731T>G (p.Val244Gly)","llm_judgment":"PRESENT","evidence":"V244G","abstract_start":1068,"abstract_end":1073}]}
{"pmid":"26930193","title":"Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity.","abstract":"BACKGROUND: Recent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson's disease (PD). Among the mutations, LRRK2 c.4883G>C (R1628P) variant was identified to have a significant association with the risk of PD in ethnic Han-Chinese populations. But the molecular pathological mechanisms of R1628P mutation in PD is still unknown.\nPRINCIPLE FINDINGS: Unlike other LRRK2 mutants in the Roc-COR-Kinase domain, the R1628P mutation didn't alter the LRRK2 kinase activity and promote neuronal death directly. LRRK2 R1628P mutation increased the binding affinity of LRRK2 with Cyclin-dependent kinase 5 (Cdk5). Interestingly, R1628P mutation turned its adjacent amino acid residue S1627 on LRRK2 protein to a novel phosphorylation site of Cdk5, which could be defined as a typical type II (+) phosphorylation-related single nucleotide polymorphism. Importantly, we showed that the phosphorylation of S1627 by Cdk5 could activate the LRRK2 kinase, and neurons ectopically expressing R1628P displayed a higher sensitivity to 1-methyl-4-phenylpyridinium, a bioactive metabolite of environmental toxin MPTP, in a Cdk5-dependent manner.\nCONCLUSION: Our data indicate that Parkinson-related LRRK2 mutation R1628P leads to Cdk5 phosphorylation of LRRK2 at S1627, which would upregulate the kinase activity of LRRK2 and consequently cause neuronal death.","variants":[{"Name":"NM_198578.4(LRRK2):c.4883G>C (p.Arg1628Pro)","Chromosome":"12","Start":"40320043","Stop":"40320043","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":47804,"rule_based_match":true,"evidence_text":"LRRK2 c.4883G>C (R1628P)","llm_judgment":"PRESENT","evidence":"LRRK2 c.4883G>C (R1628P)","abstract_start":180,"abstract_end":204}]}
{"pmid":"23010210","title":"Integrated multiplex ligation dependent probe amplification (MLPA) assays for the detection of alterations in the HEXB, GM2A and SMARCAL1 genes to support the diagnosis of Morbus Sandhoff, M. Tay-Sachs variant AB and Schimke immuno-osseous dysplasia in humans.","abstract":"Multiplex ligation dependent probe amplification (MLPA) assays were designed for the genes HEXB (OMIM: 606873), GM2A (OMIM: 613109) and SMARCAL1 (OMIM: 606622) of humans. Two sets of synthetic MLPA probes for these coding exons were tested. Changes in copy numbers were detected as well as single nucleotide polymorphisms (SNPs) by complementary DNA sequence analyses. The MLPA method was shown to be reliable for mutation detection and identified five published and 12 new mutations. In all cases from a Morbus Sandhoff cohort of patients, exclusively one variation in copy number was observed and linked to a nucleotide alteration called c.1614-14C>A. This deletion comprised exons 1-5. One of these cases is described in detail. Deletions were neither detected in the GM2A nor the SMARCAL1 genes. The MLPA assays complement routine diagnostics for M. Sandhoff (OMIM: 268800), M. Tay-Sachs variant AB (OMIM: 272750) and Schimke immuno-osseous dysplasia (OMIM: 242900).","variants":[{"Name":"NM_000521.4(HEXB):c.1614-14C>A","Chromosome":"5","Start":"74721104","Stop":"74721104","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":99106,"rule_based_match":true,"evidence_text":"c.1614-14C>A","llm_judgment":"PRESENT","evidence":"c.1614-14C>A","abstract_start":640,"abstract_end":652}]}
{"pmid":"33964374","title":"New compound heterozygous CYP4V2 mutations in bietti crystalline corneoretinal dystrophy.","abstract":"Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy which is caused by the mutations of CYP4V2, usually progressing to legal blindness by the 5th or 6th decade of life. Here we identified CYP4V2 compound heterozygous mutations in two female siblings with BCD without subjective symptoms. After 381 pathogenic genes related to retinal diseases were screened by targeted sequence capture array techniques and confirmed by Sanger sequencing, two compound heterozygous mutations in CYP4V2 were found. One was missense mutation c.1198C>T (p.R400C) and the other was frameshift mutation c.802-8_810delinsGC (p.V268_E329del). Optical coherence tomography (OCT) showed that the ellipsoid zone was absent in the macular regions and electroretinogram (ERG) revealed poor cone and rod responses. Compound heterozygous mutations in CYP4V2 are related to the BCD. Our study expands our knowledge of heterogenic phenotypes and genotypes through genetic diagnosis of the BCD patients.","variants":[{"Name":"NM_207352.4(CYP4V2):c.1198C>T (p.Arg400Cys)","Chromosome":"4","Start":"186208972","Stop":"186208972","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":47859,"rule_based_match":true,"evidence_text":"c.1198C>T (p.R400C)","llm_judgment":"PRESENT","evidence":"c.1198C>T (p.R400C)","abstract_start":564,"abstract_end":583}]}
{"pmid":"27588307","title":"Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.","abstract":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous <i>AIRE</i> mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common <i>AIRE</i> mutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic <i>AIRE</i> mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4<sup>+</sup> T cells and CD21<sup>lo</sup>CD38<sup>lo</sup> B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.","variants":[{"Name":"NM_000383.4(AIRE):c.967_979del (p.Leu323fs)","Chromosome":"21","Start":"44291180","Stop":"44291192","ReferenceAlleleVCF":"TGCCTGTCCCCTCC","AlternateAlleleVCF":"T","allel_id":18348,"rule_based_match":true,"evidence_text":"c.967_979del13","llm_judgment":"PRESENT","evidence":"c.967_979del13","abstract_start":906,"abstract_end":920}]}
{"pmid":"31233164","title":"Chronic Choroidal Neovascular Membrane in Choroideremia Treated With Intravitreal Bevacizumab.","abstract":"Choroidal neovascular membrane (CNVM) is a rare complication of choroideremia. The authors report a case of a 13-year-old male presenting with metamorphopsia and decreased central vision of 1-year duration. Genetic testing was significant for a pathogenic c.1437dupA mutation in the CHM gene. Fundus biomicroscopy showed a subfoveal membrane; diagnosis of CNVM was substantiated with fluorescein angiography and swept-source optical coherence tomography angiography (SS-OCTA). The patient received six injections of intravitreal bevacizumab during a 13-month period with functional and anatomic improvement. Lesion area on SS-OCTA remained stable. CNVM should be suspected in young patients with choroideremia presenting with acute decrease in central vision. Treatment with anti-vascular endothelial growth factor should be considered even in chronic cases. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e188-e192.].","variants":[{"Name":"NM_000390.4(CHM):c.1437dup (p.Glu480fs)","Chromosome":"X","Start":"85894260","Stop":"85894261","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":360696,"rule_based_match":true,"evidence_text":"c.1437dup","llm_judgment":"PRESENT","evidence":"c.1437dup","abstract_start":256,"abstract_end":265}]}
{"pmid":"21042819","title":"Novel mutation of TCIRG1 and clinical pictures of two infantile malignant osteopetrosis patients.","abstract":"Infantile malignant osteopetrosis (IMO) (OMIM 259700) is a lethal autosomal recessive disease. The underlying gene in most IMO patients is TCIRG1. This codes for the TCIRG1 protein involved in the cellular proton pump, which is highly expressed on surfaces of osteoclasts. We have characterized a family comprising two affected siblings born to healthy parents. The sister and her younger brother both presented classical X-ray images of IMO at 17 h and 16 weeks, respectively, after birth, and both died after the appearance of fever and flu-like symptoms months later. Radiographs revealed normal bone density in both parents. Mutation detection of the TCIRG1 gene was performed in the boy and the parents. The novel mutation c.242delC (p.Pro81ArgfsX85) and the known mutation c.1114C>T (p.Gln372X) were both identified in the boy. Both mutations are predicted to introduce premature stop codons, with deletion of 666 amino acids from the C terminus of the TCIRG1 protein of one allele and 459 from the other. Both mutations involve loss of part or the whole of the ATPase V0-complex domain of the protein. The father carries the c.242delC (p.Pro81ArgfsX85) mutation and the mother the c.1114C>T (p.Gln372X). Our findings provide new data for pre- and post-natal genetic diagnosis and identification of heterozygous carriers of the disease.","variants":[{"Name":"NM_006019.4(TCIRG1):c.1114C>T (p.Gln372Ter)","Chromosome":"11","Start":"68045051","Stop":"68045051","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":818395,"rule_based_match":true,"evidence_text":"c.1114C>T (p.Gln372X)","llm_judgment":"PRESENT","evidence":"c.1114C>T (p.Gln372X)","abstract_start":779,"abstract_end":800},{"Name":"NM_006019.4(TCIRG1):c.242del (p.Pro81fs)","Chromosome":"11","Start":"68042684","Stop":"68042684","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":546189,"rule_based_match":true,"evidence_text":"c.242delC (p.Pro81ArgfsX85)","llm_judgment":"PRESENT","evidence":"c.242delC (p.Pro81ArgfsX85)","abstract_start":728,"abstract_end":755}]}
{"pmid":"27622479","title":"Li-Fraumeni syndrome.","abstract":"The Li-Fraumeni syndrome is characterized clinically by the appearance of tumors in multiple organs generally at an early age. This hereditary condition is caused by germinal mutations in the TP53 gene, which codifies for the tumoural suppressor gene p53. We present the case of a patient aged 31 with clinical and molecular diagnosis of Li-Fraumeni syndrome who presented two synchronous tumors: a leiomyosarcoma on the forearm and a phyllodes breast tumour. She had a family history of cancer, including a son diagnosed with a cortical adrenal carcinoma when he was three years old, who died at five from the disease. Furthermore, her maternal grandmother and great-grandmother died of stomach cancer at 56 and 60 years old, respectively, while her other great-grandmother and a great aunt presented with breast cancer at the ages of 60 and 40, respectively. After genetic counseling, complete sequencing and analysis of duplications and deletions in the TP53 gene were ordered prior to diagnosis. The molecular analysis of a DNA sample taken from peripheral blood lymphocytes revealed the germinal mutation c.527G>T (p.Cys176Phe) on exon 5 of the TP53 gene, a deleterious mutation described previously in tumoural tissues. To our knowledge, this is the first published case in Colombia of Li-Fraumeni syndrome with confirmed molecular diagnosis. The diagnosis and management of Li-Fraumeni syndrome should be performed by a multidisciplinary team, and genetic counselling should be offered to patients and their relatives.","variants":[{"Name":"NM_000546.6(TP53):c.527G>T (p.Cys176Phe)","Chromosome":"17","Start":"7675085","Stop":"7675085","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":363448,"rule_based_match":true,"evidence_text":"c.527G>T (p.Cys176Phe)","llm_judgment":"PRESENT","evidence":"c.527G>T (p.Cys176Phe)","abstract_start":1110,"abstract_end":1132}]}
{"pmid":"25265376","title":"Mutational Analysis of the Rhodopsin Gene in Sector Retinitis Pigmentosa.","abstract":"BACKGROUND: To determine the role of rhodopsin (RHO) gene mutations in patients with sector retinitis pigmentosa (RP) from Northern Ireland.\nDESIGN: A case series of sector RP in a tertiary ocular genetics clinic.\nPARTICIPANTS: Four patients with sector RP were recruited from the Royal Victoria Hospital (Belfast, Northern Ireland) and Altnagelvin Hospital (Londonderry, Northern Ireland) following informed consent.\nMETHODS: The diagnosis of sector RP was based on clinical examination, International Society for Clinical Electrophysiology of Vision (ISCEV) standard electrophysiology, and visual field analysis. DNA was extracted from peripheral blood leucocytes and the coding regions and adjacent flanking intronic sequences of the RHO gene were polymerase chain reaction (PCR) amplified and cycle sequenced.\nMAIN OUTCOME MEASURE: Rhodopsin mutational status.\nRESULTS: A heterozygous missense mutation in RHO (c.173C > T) resulting in a non-conservative substitution of threonine to methionine (p. Thr58Met) was identified in one patient and was absent from 360 control individuals. This non-conservative substitution (p.Thr58Met) replaces a highly evolutionary conserved polar hydrophilic threonine residue with a non-polar hydrophobic methionine residue at position 58 near the cytoplasmic border of helix A of RHO.\nCONCLUSIONS: The study identified a RHO gene mutation (p.Thr58Met) not previously reported in RP in a patient with sector RP. These findings outline the phenotypic variability associated with RHO mutations. It has been proposed that the regional effects of RHO mutations are likely to result from interplay between mutant alleles and other genetic, epigenetic and environmental factors.","variants":[{"Name":"NM_000539.3(RHO):c.173C>T (p.Thr58Met)","Chromosome":"3","Start":"129528906","Stop":"129528906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":953335,"rule_based_match":true,"evidence_text":"c.173C > T","llm_judgment":"PRESENT","evidence":"c.173C > T","abstract_start":915,"abstract_end":925}]}
{"pmid":"23537992","title":"Complement component C6 deficiency in a Spanish family: implications for clinical and molecular diagnosis.","abstract":"Complement component C6 deficiency is a genetic disease presenting as increased susceptibility to invasive Neisseria meningitidis infections. This disorder has rarely been diagnosed in the Spanish population. In this work we report the immunochemical and molecular characterization of complement C6 deficiency in a Spanish patient showing no detectable functional activity of either the classical or alternative complement pathways and reporting a history of several episodes of meningococcal meningitis. The levels of individual complement components C3, C4, C5, C7, C8 and C9 were within the normal range. However, C6 level was low in the patient's serum as measured by radial immunodiffusion. Exon-specific polymerase chain reaction and sequencing of the C6 gene revealed a previously described homozygous single base deletion in exon 6 (c.821delA), leading to a shift in the reading frame that caused the generation of a downstream stop codon, which, in turn, provoked the truncation of the C6 protein (p.Gln274fs). To our knowledge, this is the first report on the c.821delA mutation in the Spanish population, which has previously only been identified in individuals of African ancestry. Characterization of this mutation was thought interesting in order to elucidate its source and help understand the molecular basis of this uncommon deficiency in our population. Moreover, this report highlights the importance of complement screening in cases of repeated meningococcal infections in order to establish its involvement and to consider adequate clinical recommendations such as prophylactic antibiotics or meningococcal vaccines and, subsequently, for genetic counselling.","variants":[{"Name":"NM_000065.5(C6):c.821del (p.Gln274fs)","Chromosome":"5","Start":"41181465","Stop":"41181465","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":985963,"rule_based_match":true,"evidence_text":"c.821delA","llm_judgment":"PRESENT","evidence":"c.821delA","abstract_start":841,"abstract_end":850}]}
{"pmid":"24019772","title":"Acral peeling skin syndrome resembling epidermolysis bullosa simplex in a 10-month-old boy.","abstract":"The acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder clinically characterized by asymptomatic desquamation of the skin limited to the hands and feet and histologically by cleavage at the stratum granulosum and stratum corneum level [Kiritsi et al.: J Invest Dermatol 2010;130:1741-1746]. We report on a 10-month-old boy with a history of skin peeling limited to the hands and feet since 2 months of age. Clinical examination revealed erythematous erosions with peripheral desquamation and flaccid blisters. DNA mutation analysis detected two heterozygous TGM5 mutations: c.2T>C, p.M1T in exon 1 and c.337G>T, p.G113C in exon 3 in keeping with the diagnosis of APSS. The clinical presentation of APSS alone might be confusing and strongly resemble epidermolysis bullosa simplex making the differential diagnosis difficult.","variants":[{"Name":"NM_201631.4(TGM5):c.337G>T (p.Gly113Cys)","Chromosome":"15","Start":"43260151","Stop":"43260151","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":21078,"rule_based_match":true,"evidence_text":"c.337G>T, p.G113C","llm_judgment":"PRESENT","evidence":"c.337G>T, p.G113C","abstract_start":624,"abstract_end":641}]}
{"pmid":"26405151","title":"NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia.","abstract":"","variants":[{"Name":"NM_018283.4(NUDT15):c.415C>T (p.Arg139Cys)","Chromosome":"13","Start":"48045719","Stop":"48045719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227129,"rule_based_match":true,"evidence_text":"NUDT15 c.415C>T","llm_judgment":"PRESENT","evidence":"NUDT15 c.415C>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"23649551","title":"X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients.","abstract":"INTRODUCTION: Data regarding Charcot-Marie-Tooth disease is lacking in Southeast Asian populations. We investigated the frequency of the common genetic mutations in a multiethnic Malaysian cohort.\nMETHODS: Patients with features of Charcot-Marie-Tooth disease or hereditary liability to pressure palsies were investigated for PMP22 duplication, deletion, and point mutations and GJB1, MPZ, and MFN2 point mutations.\nRESULTS: Over a period of 3 years, we identified 25 index patients. A genetic diagnosis was reached in 60%. The most common were point mutations in GJB1, accounting for X-linked Charcot-Marie-Tooth disease (24% of the total patient population), followed by PMP22 duplication causing Charcot-Marie-Tooth disease type 1A (20%). We also discovered 2 novel GJB1 mutations, c.521C>T (Proline174Leucine) and c.220G>A (Valine74Methionine).\nCONCLUSIONS: X-linked Charcot-Marie-Tooth disease was found to predominate in our patient cohort. We also found a better phenotype/genotype correlation when applying a more recently recommended genetic approach to Charcot-Marie-Tooth disease.","variants":[{"Name":"NM_000166.6(GJB1):c.521C>T (p.Pro174Leu)","Chromosome":"X","Start":"71224228","Stop":"71224228","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":625646,"rule_based_match":true,"evidence_text":"c.521C>T (Proline174Leucine)","llm_judgment":"PRESENT","evidence":"c.521C>T (Proline174Leucine)","abstract_start":785,"abstract_end":813},{"Name":"NM_000166.6(GJB1):c.220G>A (p.Val74Met)","Chromosome":"X","Start":"71223927","Stop":"71223927","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625535,"rule_based_match":true,"evidence_text":"c.220G>A (Valine74Methionine)","llm_judgment":"PRESENT","evidence":"c.220G>A (Valine74Methionine)","abstract_start":818,"abstract_end":847}]}
{"pmid":"34082469","title":"Novel ALDH3A2 mutations in structural and functional domains of FALDH causing diverse clinical phenotypes in Sjögren-Larsson syndrome patients.","abstract":"Mutations in ALDH3A2 cause Sjögren-Larsson syndrome (SLS), a neuro-ichthyotic condition due to the deficiency of fatty aldehyde dehydrogenase (FALDH). We screened for novel mutations causing SLS among Indian ethnicity, characterized the identified mutations in silico and in vitro, and retrospectively evaluated their role in phenotypic heterogeneity. Interestingly, asymmetric distribution of nonclassical traits was observed in our cases. Nerve conduction studies suggested intrinsic-minus-claw hands in two siblings, a novel neurological phenotype to SLS. Genetic testing revealed five novel homozygous ALDH3A2 mutations in six cases: Case-1-NM_000382.2:c.50C>A, NP_000373.1:p.(Ser17Ter); Case-2-NM_000382.2:c.199G>T, NP_000373.1:p.(Glu67Ter); Case-3-NM_000382.2:c.1208G>A, NP_000373.1:p.(Gly403Asp); Case-4-NM_000382.2:c.1325C>T, NP_000373.1:p.(Pro442Leu); Case-5 and -6 NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter). The mutations identified were predicted to be pathogenic and disrupt the functional domains of the FALDH. p.(Pro442Leu) at the C-terminal α-helix, might impair the substrate gating process. Mammalian expression studies with exon-9 mutants confirmed the profound reduction in the enzyme activity. Diminished aldehyde-oxidizing activity was observed with cases-2 and 3. Cases-2 and 3 showed epidermal hyperplasia with mild intracellular edema, spongiosis, hypergranulosis, and perivascular-interstitial lymphocytic infiltrate and a leaky eosinophilic epidermis. The presence of keratin-containing milia-like lipid vacuoles implies defective lamellar secretion with p.(Gly403Asp). This study improves our understanding of the clinical and mutational diversity in SLS, which might help to fast-track diagnostic and therapeutic interventions of this debilitating disorder.","variants":[{"Name":"NM_000382.3(ALDH3A2):c.1349G>A (p.Trp450Ter)","Chromosome":"17","Start":"19671862","Stop":"19671862","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2944120,"rule_based_match":true,"evidence_text":"NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter)","llm_judgment":"PRESENT","evidence":"NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter)","abstract_start":875,"abstract_end":923}]}
{"pmid":"36890748","title":"Solitary median maxillary central incisor in Kabuki syndrome 2 with novel missense mutation of","abstract":"Kabuki syndrome (KS) is an epigenetic machinery multisystem disorder with peculiar facial gestalt and dental-oral anomalies. This report describes the case of a KS patient with congenital hyperinsulinism, growth hormone deficiency and novel heterogenous missense mutations in exon 25 of the <i>KDM6A</i> (c.3715T>G, p.Trp1239Gly) and exon 1 of the <i>ABCC8</i> (c.94A>G, p.Asn32Asp) genes. She presented with solitary median maxillary central incisor (SMMCI) and mandibular incisor hypodontia, which could be a unique dental manifestation in KS 2.","variants":[{"Name":"NM_000352.6(ABCC8):c.94A>G (p.Asn32Asp)","Chromosome":"11","Start":"17476683","Stop":"17476683","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3543901,"rule_based_match":true,"evidence_text":"c.94A>G, p.Asn32Asp","llm_judgment":"PRESENT","evidence":"c.94A>G, p.Asn32Asp","abstract_start":362,"abstract_end":381}]}
{"pmid":"15880785","title":"Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro.","abstract":"Mutations in claudin 14 (CLDN14) cause nonsyndromic DFNB29 deafness in humans. The analysis of a murine model indicated that this phenotype is associated with degeneration of hair cells, possibly due to cation overload. However, the mechanism linking these alterations to CLDN14 mutations is unknown. To investigate this mechanism, we compared the ability of wild-type and missense mutant CLDN14 to form tight junctions. Ectopic expression in L mouse fibroblasts (LM cells) of wild-type CLDN14 protein induced the formation of tight junctions, while both the c.254T>A (p.V85D) mutant, previously identified in a Pakistani family, and the c.301 G>A (p.G101R) mutant, identified in this study through the screen of 183 Spanish and Greek patients affected with sporadic nonsyndromic deafness, failed to form such junctions. However, the two mutant proteins differed in their ability to localize at the plasma membrane. We further identified hitherto undescribed exons of CLDN14 that are utilized in alternative spliced transcripts. We demonstrated that different mutations of CLDN14 impaired by different mechanisms the ability of the protein to form tight junctions. Our results indicate that the ability of CLDN14 to be recruited to these junctions is crucial for the hearing process.","variants":[{"Name":"NM_001146079.2(CLDN14):c.254T>A (p.Val85Asp)","Chromosome":"21","Start":"36461442","Stop":"36461442","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":19890,"rule_based_match":true,"evidence_text":"c.254T>A (p.V85D)","llm_judgment":"PRESENT","evidence":"c.254T>A (p.V85D)","abstract_start":559,"abstract_end":576},{"Name":"NM_001146079.2(CLDN14):c.301G>A (p.Gly101Arg)","Chromosome":"21","Start":"36461395","Stop":"36461395","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19891,"rule_based_match":true,"evidence_text":"c.301 G>A (p.G101R)","llm_judgment":"PRESENT","evidence":"c.301 G>A (p.G101R)","abstract_start":638,"abstract_end":657}]}
{"pmid":"30160831","title":"A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: A second gene that may contribute to the 1q41-q42 deletion phenotype.","abstract":"Chromosome 1q41-q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41-q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41-q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3-year-old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41-q42 MDS. Through a familial whole-exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41-q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41-q42 gene deletion syndrome.","variants":[{"Name":"NM_015176.4(FBXO28):c.972_973delinsG (p.Arg325fs)","Chromosome":"1","Start":"224157611","Stop":"224157612","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"G","allel_id":1335096,"rule_based_match":false,"evidence_text":"c.972_973delACinsG (p.Arg325GlufsX3)","llm_judgment":"PRESENT","evidence":"c.972_973delACinsG (p.Arg325GlufsX3)","abstract_start":1042,"abstract_end":1078}]}
{"pmid":"28013294","title":"Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms.","abstract":"Mucopolysaccharidoses (MPS) are a group of genetic deficiencies of lysosomal enzymes that catabolize glycosaminoglycans (GAG). Here we describe a novel MPS-like disease caused by a specific mutation in the VPS33A gene. We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG. However, these patients could not be diagnosed enzymatically as MPS. They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients. Additionally, most patients developed heart, kidney, and hematopoietic disorders, which are not typical symptoms for conventional MPS, leading to a fatal outcome between 1 and 2-years old. Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients. VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways. Lysosomal over-acidification and HS accumulation were detected in patient-derived and VPS33A-depleted cells, suggesting a novel role of this gene in lysosomal functions. We hence propose a new type of MPS that is not caused by an enzymatic deficiency.","variants":[{"Name":"NM_022916.6(VPS33A):c.1492C>T (p.Arg498Trp)","Chromosome":"12","Start":"122232917","Stop":"122232917","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":361893,"rule_based_match":true,"evidence_text":"c.1492C > T (p.Arg498Trp)","llm_judgment":"PRESENT","evidence":"c.1492C > T (p.Arg498Trp)","abstract_start":915,"abstract_end":940}]}
{"pmid":"27683084","title":"SPATA5 mutations cause a distinct autosomal recessive phenotype of intellectual disability, hypotonia and hearing loss.","abstract":"We examined an extended, consanguineous family with seven individuals with severe intellectual disability and microcephaly. Further symptoms were hearing loss, vision impairment, gastrointestinal disturbances, and slow and asymmetric waves in the EEG. Linkage analysis followed by exome sequencing revealed a homozygous variant in SPATA5 (c.1822_1824del; p.Asp608del), which segregates with the phenotype in the family. Molecular modelling suggested a deleterious effect of the identified alterations on the protein function. In an unrelated family, we identified compound heterozygous variants in SPATA5 (c.[2081G > A];[989_991delCAA]; p.[Gly694Glu];[.Thr330del]) in a further individual with global developmental delay, infantile spasms, profound dystonia, and sensorineural hearing loss. Molecular modelling suggested an impairment of protein function in the presence of both variants.SPATA5 is a member of the ATPase associated with diverse activities (AAA) protein family and was very recently reported in one publication to be mutated in individuals with intellectual disability, epilepsy and hearing loss. Our results describe new, probably pathogenic variants in SPATA5 that were identified in individuals with a comparable phenotype. We thus independently confirm that bi-allelic pathogenic variants in SPATA5 cause a syndromic form of intellectual disability, and we delineate its clinical presentation.","variants":[{"Name":"NM_145207.3(AFG2A):c.2081G>A (p.Gly694Glu)","Chromosome":"4","Start":"123056388","Stop":"123056388","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":443568,"rule_based_match":false,"evidence_text":"c.2081G>A (p.Gly694Glu)","llm_judgment":"PRESENT","evidence":"c.[2081G > A","abstract_start":606,"abstract_end":618}]}
{"pmid":"28475449","title":"IVS-II-648/649 (-T) (HBB: c.316-202del) Triggers a Novel β-Thalassemia Phenotype.","abstract":"Thalassemia is the most common inherited disorder in Iran. There are approximately 800 different genomic alterations of the β-globin gene described in the HbVar database. In this study, we identified a novel mutation in a 21-year-old woman [IVS-II-648/649 (-T); HBB: c.316-202del)] and describe its clinical implications. Two other members of this family, all with hematological and clinical features associated with β-thalassemia (β-thal), also carried this mutation. The molecular diagnosis of the β-globin gene mutation was performed by direct sequencing. Based on the observed β-thal phenotype and in silico analysis results, we concluded that this novel β-globin gene mutation was associated with the mild phenotype of β-thal.","variants":[{"Name":"NM_000518.5(HBB):c.316-202del","Chromosome":"11","Start":"5225928","Stop":"5225928","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"T","allel_id":857559,"rule_based_match":true,"evidence_text":"HBB: c.316-202del","llm_judgment":"PRESENT","evidence":"HBB: c.316-202del","abstract_start":262,"abstract_end":279}]}
{"pmid":"16757525","title":"Recurrence of the R947X mutation in unrelated families with autosomal dominant pseudohypoaldosteronism type 1: evidence for a mutational hot spot in the mineralocorticoid receptor gene.","abstract":"BACKGROUND: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease characterized by congenital mineralocorticoid resistance of the kidney. Twenty-two different loss-of-function mutations in the mineralocorticoid receptor gene have been described in families with PHA1. These mutations were not recurrent and resulted in a large phenotypic variability.\nOBJECTIVE: The objective of this study is to analyze the recurrence of an inactivating mutation in the mineralocorticoid receptor gene in unrelated families with autosomal dominant PHA1.\nPATIENTS: Seventeen members from three unrelated families with autosomal dominant PHA1 were studied, including 11 affected patients with variable clinical manifestations. Fifty healthy subjects were used as controls.\nMETHODS: Genomic DNA was extracted, and the entire coding region of the mineralocorticoid receptor gene was submitted to automatic sequencing. Four dinucleotide microsatellite markers spanning a region of 3.2 cM in the human mineralocorticoid receptor gene locus, and two intragenic polymorphisms were used for haplotype analysis.\nRESULTS: A heterozygous point mutation at codon 947 (c.2839C>T) changing arginine to stop codon (R947X) was found in the three families. Different haplotypes segregated with the R947X mutation in each family, demonstrating the absence of a founder effect for this mutation.\nCONCLUSION: Codon 947 of the mineralocorticoid receptor is the first mutational hot spot for autosomal dominant PHA1.","variants":[{"Name":"NM_000901.5(NR3C2):c.2839C>T (p.Arg947Ter)","Chromosome":"4","Start":"148081460","Stop":"148081460","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23606,"rule_based_match":true,"evidence_text":"c.2839C>T","llm_judgment":"PRESENT","evidence":"c.2839C>T","abstract_start":1159,"abstract_end":1168}]}
{"pmid":"24027061","title":"SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease.","abstract":"OBJECTIVE: To investigate whether mutations in the SURF1 gene are a cause of Charcot-Marie-Tooth (CMT) disease.\nMETHODS: We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A>G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A>G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed.\nRESULTS: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities <25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A>G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts.\nCONCLUSIONS: We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy.","variants":[{"Name":"NM_003172.4(SURF1):c.107-2A>G","Chromosome":"9","Start":"133354959","Stop":"133354959","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":214997,"rule_based_match":true,"evidence_text":"c.107-2A>G","llm_judgment":"PRESENT","evidence":"c.107-2A>G","abstract_start":283,"abstract_end":293}]}
{"pmid":"19241098","title":"Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes.","abstract":"It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903_904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T > C p.Ile72Thr and c.380A > G p.His127Arg (present in a mosaic condition) found in two girls with the most severe clinical presentation, while the remaining are the splicing c.145 + 2 T > C and c.2376 + 5G > A, the c.1648C > T p.Arg550X and the MPLA-identified c.162_99del261 mutation. RNA characterisation of four mutations revealed the aberrant transcript of the missense allele (case 2) and not the stop mutation (case 3), but also allowed the splicing mutation (case 1) and the c.-162_99del261 (case 4) to be categorised as truncating. The obtained data reinforce the view that a more severe phenotype is due more to an altered protein than haploinsufficiency. Furthermore, the mutational repertoire of the CDKL5 gene is shown to be expanded by testing patients with phenotypical overlap to Rett syndrome and applying multiplex ligation-dependent probe amplification.","variants":[{"Name":"NM_001323289.2(CDKL5):c.1648C>T (p.Arg550Ter)","Chromosome":"X","Start":"18604572","Stop":"18604572","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":153512,"rule_based_match":true,"evidence_text":"c.1648C > T p.Arg550X","llm_judgment":"PRESENT","evidence":"c.1648C > T p.Arg550X","abstract_start":911,"abstract_end":932},{"Name":"NM_001323289.2(CDKL5):c.215T>C (p.Ile72Thr)","Chromosome":"X","Start":"18575423","Stop":"18575423","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":26542,"rule_based_match":true,"evidence_text":"c.215 T > C p.Ile72Thr","llm_judgment":"PRESENT","evidence":"c.215 T > C p.Ile72Thr","abstract_start":688,"abstract_end":710},{"Name":"NM_001323289.2(CDKL5):c.380A>G (p.His127Arg)","Chromosome":"X","Start":"18579945","Stop":"18579945","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":153550,"rule_based_match":true,"evidence_text":"c.380A > G p.His127Arg","llm_judgment":"PRESENT","evidence":"c.380A > G p.His127Arg","abstract_start":715,"abstract_end":737},{"Name":"NM_001323289.2(CDKL5):c.2376+5G>A","Chromosome":"X","Start":"18619971","Stop":"18619971","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":165878,"rule_based_match":true,"evidence_text":"c.2376 + 5G > A","llm_judgment":"PRESENT","evidence":"c.2376 + 5G > A","abstract_start":890,"abstract_end":905}]}
{"pmid":"23587236","title":"Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation.","abstract":"BACKGROUND: Primary autosomal recessive microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with pronounced reduction in brain volume, particularly of the neocortex, simplified cortical gyration and intellectual disability. Homozygous mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 are the cause of MCPH3. Despite considerable interest in MCPH as a model disorder for brain development, the underlying pathomechanism has not been definitively established and only four pedigrees with three CDK5RAP2 mutations have been reported. Specifically for MCPH3, no detailed radiological or histological descriptions exist.\nMETHODS/RESULTS: We sought to characterize the clinical and radiological features and pathological cellular processes that contribute to the human MCPH3 phenotype. Haplotype analysis using microsatellite markers around the MCPH1-7 and PNKP loci in an Italian family with two sons with primary microcephaly, revealed possible linkage to the MCPH3 locus. Sequencing of the coding exons and exon/intron splice junctions of the CDK5RAP2 gene identified homozygosity for the novel nonsense mutation, c.4441C > T (p.Arg1481*), in both affected sons. cMRI showed microcephaly, simplified gyral pattern and hypogenesis of the corpus callosum. The cellular phenotype was assessed in EBV-transformed lymphocyte cell lines established from the two affected sons and compared with healthy male controls. CDK5RAP2 protein levels were below detection level in immortalized lymphocytes from the patients. Moreover, mitotic spindle defects and disrupted γ-tubulin localization to the centrosome were apparent.\nCONCLUSION: These results suggest that spindle defects and a disruption of centrosome integrity play an important role in the development of microcephaly in MCPH3.","variants":[{"Name":"NM_018249.6(CDK5RAP2):c.4441C>T (p.Arg1481Ter)","Chromosome":"9","Start":"120409290","Stop":"120409290","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":168720,"rule_based_match":true,"evidence_text":"c.4441C > T (p.Arg1481*)","llm_judgment":"PRESENT","evidence":"c.4441C > T (p.Arg1481*)","abstract_start":1210,"abstract_end":1234}]}
{"pmid":"37091525","title":"VCP-related myopathy: a case series and a review of literature.","abstract":"The valosin-containing protein (VCP), a widely expressed protein, controls the ubiquitin-proteasome system, endolysosomal sorting, and autophagy to maintain cellular proteostasis. Frontotemporal dementia (FTD), inclusion body myopathy, and Paget's disease of the bone (PDB) are all caused by dominant missense mutations in the VCP gene, which interfere with these mechanisms and cause a multisystem proteinopathy. We describe phenotypic and genetic findings of five patients with four different mutations in <i>VCP</i> gene (NM_007126): c.278G > A (p.R93H), c.463C > T (p.R155C), c.410C > T (p.P137L), c.464G > A (p.R155H), c.410C > T (p.P137L). We analysed the patient' biopsies, all characterized by a muscular phenotype, and we executed immunofluorescence staining to evaluate the presence of proteins: p62, VCP, desmin, myotilin, TDP-43. Eventually we performed a brief literature review to compare our cases with those already reported. Our report strongly suggest that <i>VCP</i> gene mutations can be related with a predominant skeletal muscle phenotype without any central nervous system involvement, as occasionally reported in the literature. Particularly, our patient with R93H shows only myopathic involvement while this mutation has been described once associated only to Hereditary Spastic Paraplegia. Further study will be necessary to understand such a broad and different clinical spectrum.","variants":[{"Name":"NM_007126.5(VCP):c.278G>A (p.Arg93His)","Chromosome":"9","Start":"35067915","Stop":"35067915","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":444478,"rule_based_match":true,"evidence_text":"c.278G > A (p.R93H)","llm_judgment":"PRESENT","evidence":"c.278G > A (p.R93H)","abstract_start":537,"abstract_end":556}]}
{"pmid":"24388491","title":"Severe phenotypes of SMARD1 associated with novel mutations of the IGHMBP2 gene and nuclear degeneration of muscle and Schwann cells.","abstract":"Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a very rare autosomal recessive form of spinal muscular atrophy manifested in low birth weight, diaphragmatic palsy and distal muscular atrophy. Caused by a mutation in the IGHMBP2 gene, the disease is addressed here by reference to five Polish patients in which SMARD1 has been confirmed genetically. All presented a severe form of the disease and had evident symptoms during the second month of life; with four displaying weak cries, feeding difficulties and hypotonia from birth. Two were afflicted by severe dysfunction of the autonomic nervous system. Ultrastructural analysis of a muscle biopsy revealed progressive degeneration within the nuclei of the muscle cells and Schwann cells. Neuromuscular junctions were also defective. It proved possible to identify in our patients 6 novel IGHMBP2 mutations: three missense (c.595G>C, c.1682T>C and c.1794C>A), two nonsense (c.94C>T and c.1336C>T) and one in-frame deletion (c.1615_1623del). One nonsense mutation (c.429C>T) that had been described previously was also identified. Observation of our patients makes it clear that clinical picture is still the most important factor suggesting diagnosis of SMARD1, though further investigations concerning some of the symptoms are required. As the IGHMBP2 gene is characterized by significant heterogeneity, genetic counseling of affected families is rendered more complex. IGHMBP2 protein deficiency can lead to the degeneration of nuclei, in both muscle and Schwann cells.","variants":[{"Name":"NM_002180.3(IGHMBP2):c.595G>C (p.Ala199Pro)","Chromosome":"11","Start":"68911487","Stop":"68911487","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":625216,"rule_based_match":true,"evidence_text":"c.595G>C","llm_judgment":"PRESENT","evidence":"c.595G>C","abstract_start":896,"abstract_end":904},{"Name":"NM_002180.3(IGHMBP2):c.1336C>T (p.Gln446Ter)","Chromosome":"11","Start":"68933399","Stop":"68933399","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":611754,"rule_based_match":true,"evidence_text":"c.1336C>T","llm_judgment":"PRESENT","evidence":"c.1336C>T","abstract_start":958,"abstract_end":967},{"Name":"NM_002180.3(IGHMBP2):c.94C>T (p.Gln32Ter)","Chromosome":"11","Start":"68906076","Stop":"68906076","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":625206,"rule_based_match":true,"evidence_text":"c.94C>T","llm_judgment":"PRESENT","evidence":"c.94C>T","abstract_start":946,"abstract_end":953},{"Name":"NM_002180.3(IGHMBP2):c.1615_1623del (p.Ser539_Tyr541del)","Chromosome":"11","Start":"68934540","Stop":"68934548","ReferenceAlleleVCF":"TCTCGCCATA","AlternateAlleleVCF":"T","allel_id":625239,"rule_based_match":true,"evidence_text":"c.1615_1623del","llm_judgment":"PRESENT","evidence":"c.1615_1623del","abstract_start":996,"abstract_end":1010},{"Name":"NM_002180.3(IGHMBP2):c.1682T>C (p.Ile561Thr)","Chromosome":"11","Start":"68935348","Stop":"68935348","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":625241,"rule_based_match":true,"evidence_text":"c.1682T>C","llm_judgment":"PRESENT","evidence":"c.1682T>C","abstract_start":906,"abstract_end":915},{"Name":"NM_002180.3(IGHMBP2):c.1794C>A (p.Asn598Lys)","Chromosome":"11","Start":"68936274","Stop":"68936274","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":625247,"rule_based_match":true,"evidence_text":"c.1794C>A","llm_judgment":"PRESENT","evidence":"c.1794C>A","abstract_start":920,"abstract_end":929}]}
{"pmid":"25374739","title":"A precocious cerebellar ataxia and frequent Fever episodes in a 16-month-old infant revealing ataxia-telangiectasia syndrome.","abstract":"Ataxia-telangiectasia (AT) is the most frequent progressive cerebellar ataxia in infancy and childhood. Immunodeficiency which includes both cellular and humoral arms has variable severity. Since the clinical presentation is extremely variable, a high clinical suspicion will allow an early diagnosis. Serum alpha-fetoprotein is elevated in 80-85% of patients and therefore could be used as a screening tool. Here, we present a case of a 5-year-old female infant who was admitted to our department at the age of 16 months because of gait disorders and febrile episodes that had begun at 5 months after the cessation of breastfeeding. Serum alfa-fetoprotein level was elevated. Other investigations showed leukocytopenia with lymphopenia, reduced IgG2 and IgA levels, and low titers of specific postimmunization antibodies against tetanus toxoid and Haemophilus B polysaccharide. Peripheral lymphocytes subsets showed reduction of T cells with a marked predominance of T cells with a memory phenotype and a corresponding reduction of naïve T cells; NK cells were very increased (41%) with normal activity. The characterization of the ATM gene mutations revealed 2 specific mutations (c.5692C > T/c.7630-2A > C) compatible with AT diagnosis. It was concluded that AT syndrome should be considered in children with precocious signs of cerebellar ataxia and recurrent fever episodes.","variants":[{"Name":"NM_000051.4(ATM):c.7630-2A>C","Chromosome":"11","Start":"108331877","Stop":"108331877","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":132904,"rule_based_match":true,"evidence_text":"c.7630-2A>C","llm_judgment":"PRESENT","evidence":"c.7630-2A > C","abstract_start":1195,"abstract_end":1208},{"Name":"NM_000051.4(ATM):c.5692C>T (p.Arg1898Ter)","Chromosome":"11","Start":"108307914","Stop":"108307914","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":475938,"rule_based_match":true,"evidence_text":"c.5692C > T","llm_judgment":"PRESENT","evidence":"c.5692C > T","abstract_start":1183,"abstract_end":1194}]}
{"pmid":"31957062","title":"Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4.","abstract":"OBJECTIVE: To determine the clinical and molecular features in patients with amyotrophic lateral sclerosis 4 (ALS4) due to mutations in the senataxin (SETX) gene and to develop tools for evaluating SETX variants.\nMETHODS: Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual-energy x-ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function.\nRESULTS: We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlates with disease duration (thigh fat fraction R<sup>2</sup> = 0.35, p = 0.01; lower leg fat fraction R<sup>2</sup> = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than upper extremities (average fat z scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function.\nINTERPRETATION: We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R-loop levels in patient-derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. ANN NEUROL 2020;87:547-555.","variants":[{"Name":"NM_015046.7(SETX):c.1153G>A (p.Glu385Lys)","Chromosome":"9","Start":"132330445","Stop":"132330445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":524123,"rule_based_match":true,"evidence_text":"c.1153 G>A (p.Glu385Lys)","llm_judgment":"PRESENT","evidence":"c.1153 G>A (p.Glu385Lys)","abstract_start":340,"abstract_end":364}]}
{"pmid":"38091959","title":"Novel variants of HPS6 cause suspected ocular albinism: A report of two cases and the profile of HPS6 variants.","abstract":"INTRODUCTION: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of HPS6 variants and their genotype-phenotype correlations.\nMETHODS: Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of Family JX. The single coding exon of HPS6 was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of HPS6 reported in the literatures were reviewed.\nRESULTS: We identified two different compound heterozygous truncating variants of HPS6 in probands with suspected OA from two independent families. The proband of Family JX had c.1674dup and c.503-504del variants, and the other proband from Family CZ had a nonsense variant of c.1114C>T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of HPS6 variants and revealed a significant overlap between CpG islands and variants of HPS6, suggesting a potential link between DNA methylation and HPS6 variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease.\nCONCLUSION: Our research expands the spectrum of HPS6 variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.","variants":[{"Name":"NM_024747.6(HPS6):c.1114C>T (p.Arg372Ter)","Chromosome":"10","Start":"102066588","Stop":"102066588","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1340120,"rule_based_match":true,"evidence_text":"c.1114C>T","llm_judgment":"PRESENT","evidence":"c.1114C>T","abstract_start":1161,"abstract_end":1170}]}
{"pmid":"24576347","title":"Sanfilippo type A: new clinical manifestations and neuro-imaging findings in patients from the same family in Israel: a case report.","abstract":"INTRODUCTION: Sanfilippo syndrome type A (mucopolysaccharidosis IIIA - MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by a deficiency in sulfamidase.\nCASE PRESENTATION: Two daughters (13 and 11 years old) of a consanguineous Palestinian family from the Israeli Arab community were investigated clinically and genetically for the presence of progressive neurodegenerative disease, psychomotor retardation and behavioral abnormalities. Development was normal up to one year of age. Thereafter, progressive motor and speech delay started. Metabolic screening including glycosaminoglycans, karyotype testing and magnetic resonance imaging were normal. Later in the disease, they developed severe spasticity and intellectual disability with autistic features and incontinence. Magnetic resonance imaging revealed diffuse hypomyelination with thinning of the corpus callosum. Genetic examination through whole exome sequencing revealed a homozygous mutation c.416C >T (p.T139M) in the N-sulfoglucosamine sulfohydrolase (SGSH) gene. Repeated biochemical testing at age 11 and 13 revealed increased levels of glycosaminoglycans confirming the diagnosis of Sanfilippo syndrome type A.\nCONCLUSION: These cases were considered to be the first report of Sanfilippo syndrome in Israel. We recommend that if similar clinical features are present during childhood, it is preferred to go directly and primarily for a genetic diagnosis of Sanfilippo syndrome, then secondarily for other lysosomal storage disorders that may also be involved.","variants":[{"Name":"NM_000199.5(SGSH):c.416C>T (p.Thr139Met)","Chromosome":"17","Start":"80214705","Stop":"80214705","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":548468,"rule_based_match":true,"evidence_text":"c.416C >T (p.T139M)","llm_judgment":"PRESENT","evidence":"c.416C >T (p.T139M)","abstract_start":975,"abstract_end":994}]}
{"pmid":"22392582","title":"Prenatal screening for β-thalassemia major reveals new and rare mutations in the Pakistani population.","abstract":"β-Thalassemia is the most common genetic disorder in Pakistan, where more than 6000 affected children are born annually, and the carrier population is around 10 million. The objective was to study β-globin gene mutations in chorionic villous biopsy samples. Prenatal screening of 383 pregnant women between 2003 and 2010 was carried out using a panel of 13 mutation primers and amplification refractory mutations system (ARMS)-PCR. In addition, DNA sequencing was used to confirm uncharacterized mutations and in some cases fetal disease status was confirmed by linkage analysis. Families enrolled in this study represented major ethnic groups in Pakistan. Of the 13 mutations tested, three mutations accounted 71% of the total, including IVS1-5(G-C)[HBB:c.92+5G>C], codon 8/9(+G) [HBB:c.27_28insG] and del 619[NG_000007.3:g71609-72227del619]. Mutations in four uncharacterized samples were later confirmed by DNA sequencing as -88(C-T)[HBB:c.-138C>G], -90(C-T)[HBB:c.-140C>T] and codon 59(+T)[HBB:c.178_179insT]. To our knowledge, this is the first report of these mutations in Pakistan. Moreover, 19.2% fetal samples were normal and 52.3% heterozygous, whereas 26.4% were affected with thalassemia major. IVS1-5:IVS1-5 was the most common genotype in fetal samples. Prenatal diagnosis of β-thalassemia using ARMS PCR is an efficient approach for reducing the burden of this disease in Pakistan. In addition, rare mutations reported in this study should be incorporated in the diagnostic strategy.","variants":[{"Name":"NM_000518.4(HBB):c.-138C>G","Chromosome":"11","Start":"5227159","Stop":"5227159","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":857539,"rule_based_match":true,"evidence_text":"HBB:c.-138C>G","llm_judgment":"PRESENT","evidence":"HBB:c.-138C>G","abstract_start":937,"abstract_end":950},{"Name":"NM_000518.5(HBB):c.92+5G>C","Chromosome":"11","Start":"5226925","Stop":"5226925","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":30486,"rule_based_match":true,"evidence_text":"IVS1-5(G-C)[HBB:c.92+5G>C]","llm_judgment":"PRESENT","evidence":"IVS1-5(G-C)[HBB:c.92+5G>C]","abstract_start":739,"abstract_end":765}]}
{"pmid":"25090642","title":"Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.","abstract":"Inherited forms of cataract are a clinically important and genetically heterogeneous cause of visual impairment that usually present at an early age with or without systemic and/or other ocular abnormalities. Here we have identified a new locus for inherited cataract and high-tension glaucoma with variable anterior segment defects, and characterized an underlying mutation in the gene coding for transient receptor potential cation channel, subfamily M, member-3 (TRPM3, melastatin-2). Genome-wide linkage analysis mapped the ocular disease locus to the pericentric region of human chromosome 9. Whole exome and custom-target next-generation sequencing detected a heterozygous A-to-G transition in exon-3 of TRPM3 that co-segregated with disease. As a consequence of alternative splicing this missense mutation was predicted to result in the substitution of isoleucine-to-methionine at codon 65 (c.195A>G; p.I65 M) of TRPM3 transcript variant 9, and at codon 8 (c.24A>G; p.I8 M) of a novel TRPM3 transcript variant expressed in human lens. In both transcript variants the I-to-M substitution was predicted in silico to exert damaging effects on protein function. Furthermore, transient expression studies of a recombinant TRPM3-GFP reporter product predicted that the I-to-M substitution introduced an alternative translation start-site located 89 codons upstream from the native initiator methionine found in eight other TRPM3 transcript variants (1-8). Collectively, these studies have provided the first evidence that TRPM3 is associated with inherited ocular disease in humans, and further provide support for the important role of this cation channel in normal eye development.","variants":[{"Name":"NM_001366145.2(TRPM3):c.195A>G (p.Ile65Met)","Chromosome":"9","Start":"70864494","Stop":"70864494","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2417434,"rule_based_match":true,"evidence_text":"c.195A>G; p.I65 M","llm_judgment":"PRESENT","evidence":"c.195A>G; p.I65 M","abstract_start":898,"abstract_end":915}]}
{"pmid":"33507209","title":"Association of the Recurrent Rare Variant c.415T>C p.Phe139Leu in CLN5 With a Recessively Inherited Macular Dystrophy.","abstract":"Importance: Homozygous variants in the neuronal ceroid lipofuscinosis type 5 (CLN5) gene are associated with neuronal ceroid lipofuscinosis, a progressive neurologic disorder that leads to ataxia, seizures, and early death. The association between a homozygous variant in this gene and a macular dystrophy is described here.\nObjective: To describe an autosomal recessive macular dystrophy associated with a recurrent variant in CLN5.\nDesign, Setting, and Participants: This cohort study took place at a national referral center and had a follow-up duration ranging between 1 and 5 years. All patients who were identified to carry a specific homozygous missense variant in CLN5, among more than 2000 patients who were diagnosed with or suspected to have retinal dystrophies, who did not carry this variant, were included. Data were collected between June 2014 and September 2020.\nExposures: All patients who were sampled for DNA analysis due to molecularly unconfirmed retinal dystrophy and who were subsequently identified to carry the homozygous missense variant c.415T>C (p.Phe139Leu) in CLN5 were included, while patients who did not carry the variant were excluded.\nMain Outcomes and Measures: Retinal phenotype associated with this specific homozygous missense variant in CLN5.\nResults: Seven affected patients (mean [SD] age, 43 [18] years; age range, 33-52 years; 5 male) carried the homozygous missense in CLN5. All patients were diagnosed as having a macular dystrophy. Four patients had mild electroretinographic alterations. All patients had hypoautofluorescent maculas with retinal thinning (central subfield thickness, 80 µm). Visual acuity ranged between 2/200 and 20/100. Neurologic symptoms were mild (dizziness) in 5 patients and absent in 2 patients. Neuroimaging demonstrated cerebellar atrophy and white matter lesions, respectively, in 2 patients.\nConclusions and Relevance: These results suggest that CLN5, similar to CLN7, may be associated with isolated macular dystrophy as well as neuronal ceroid lipofuscinosis. The variant c.415T>C p.Phe139Leu does not seem to be associated with any prominent neurologic disease at least until the fourth to sixth decades of life. These findings may imply a specific role of CLN5 in macular neurons. Additional study is suggested, such as molecular screening for this variant in cohorts of patients with undiagnosed macular dystrophies and biological studies of its molecular effects.","variants":[{"Name":"NM_006493.4(CLN5):c.415T>C (p.Phe139Leu)","Chromosome":"13","Start":"76995977","Stop":"76995977","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":193599,"rule_based_match":true,"evidence_text":"c.415T>C (p.Phe139Leu)","llm_judgment":"PRESENT","evidence":"c.415T>C (p.Phe139Leu)","abstract_start":1064,"abstract_end":1086}]}
{"pmid":"28624463","title":"Insights from genotype-phenotype correlations by novel SPEG mutations causing centronuclear myopathy.","abstract":"Centronuclear myopathies (CNM) are a clinically and genetically heterogeneous group of congenital myopathies, defined histologically by increased number of fibres with centrally located nuclei, and type I fibre predominance in muscle biopsy. Myotubular myopathy, the X-linked form of CNM caused by mutations in the phosphoinositide phosphatase MTM1, is histologically characteristic since muscle fibres resemble myotubes. Here we present two unrelated patients with CNM and typical myotubular fibres in the muscle biopsy caused by mutations in striated muscle preferentially expressed protein kinase (SPEG). Next generation sequencing revealed novel biallelic homozygous mutations in SPEG in both cases. Patient 1 showed the c.1627_1628insA (p.Thr544Aspfs*48) mutation and patient 2 the c.9586C>T (p.Arg3196*) mutation. The clinical phenotype was distinctive in the two patients since patient 2 developed a dilated cardiomyopathy with milder myopathy features, while patient 1 showed only myopathic features without cardiac involvement. These findings expand the genotype-phenotype correlations after the initial report. Additionally, we describe whole body muscle MRI of patient 2 and we argue on the different SPEG isoforms in skeletal muscle and heart as the possible explanation leading to variable phenotypes of SPEG mutations.","variants":[{"Name":"NM_005876.5(SPEG):c.9586C>T (p.Arg3196Ter)","Chromosome":"2","Start":"219492235","Stop":"219492235","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3798573,"rule_based_match":true,"evidence_text":"c.9586C>T (p.Arg3196*)","llm_judgment":"PRESENT","evidence":"c.9586C>T (p.Arg3196*)","abstract_start":787,"abstract_end":809}]}
{"pmid":"28449981","title":"Recessive AFG3L2 Mutation Causes Progressive Microcephaly, Early Onset Seizures, Spasticity, and Basal Ganglia Involvement.","abstract":"BACKGROUND: Mutations in AFG3L2, a gene encoding a subunit of the mitochondrion m-AAA protease, cause spinocerebellar ataxia type 28 and recessive spastic ataxia type 5. Neuroimaging shows cerebellar atrophy.\nMETHODS: Retrospective review of the patient charts including their clinical evaluation and molecular genetic, neurodiagnostic, and neuroradiological investigations.\nRESULTS: We describe five members of a large consanguineous family with a severe mitochondrial disease phenotype in the form of regression of the developmental milestones in the first year of life, refractory epilepsy, progressive microcephaly, increased blood lactate, basal ganglia involvement, and premature death. Exome sequencing showed homozygous mutation of the AFG3L2 gene in all individuals: c.1714G>A (p.Ala572Thr).\nCONCLUSIONS: Our findings add to the phenotypic, neuroradiological, genetic, and biochemical spectrum of AFG3L2 mutations.","variants":[{"Name":"NM_006796.3(AFG3L2):c.1714G>A (p.Ala572Thr)","Chromosome":"18","Start":"12344197","Stop":"12344197","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2832182,"rule_based_match":true,"evidence_text":"c.1714G>A (p.Ala572Thr)","llm_judgment":"PRESENT","evidence":"c.1714G>A (p.Ala572Thr)","abstract_start":776,"abstract_end":799}]}
{"pmid":"16438163","title":"The molecular basis of mucopolysaccharidosis type I in two Thai patients.","abstract":"Two Thai patients diagnosed with Hurler syndrome (mucopolysaccharidosis type 1, MPS I) were found to have no detectable alpha-iduronidase (E.C. 3.2.1.76) activity in leukocytes, while normal Thai children all had significant activity, with a mean of 135 +/- 30 nmol/mg/18h. One patient was heterozygous for A75T (311G>A) and S633L (1986C>T) mutation, previously reported to cause MPS I, together with 9 other heterozygous polymorphisms also found in normal controls. The other patient had the previously described frameshift mutation 252insert C and a new nonsense mutation E299X (983G>T).","variants":[{"Name":"NM_000203.5(IDUA):c.223G>A (p.Ala75Thr)","Chromosome":"4","Start":"987873","Stop":"987873","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":224719,"rule_based_match":false,"evidence_text":"A75T (311G>A)","llm_judgment":"PRESENT","evidence":"A75T (311G>A)","abstract_start":307,"abstract_end":320}]}
{"pmid":"25760803","title":"A novel endoglin mutation in hereditary hemorrhagic telangiectasia type 1: a case report.","abstract":"Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by aberrant vascular development. Mutations in two genes, endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) are associated with HHT. The present case study revealed the molecular diagnosis in a family exhibiting the clinical features of HHT disease. The coding exon and flanking intronic regions of the ENG and ACVRL1 genes were sequenced and a novel mutation in exon 10 of ENG was observed in the family. The mutation (c.1426C>T) in exon 10 of the ENG gene caused a G476X mutation, which results in a premature stop codon and a truncated ENG protein. This finding demonstrated a novel mutation in the ENG gene in a Chinese family, which suggested that a truncated ENG protein may cause HHT. The present study established a genetic test to confirm the clinical diagnosis in individuals and provide an opportunity for early detection and management of the disease.","variants":[{"Name":"NM_001114753.3(ENG):c.1426C>T (p.Gln476Ter)","Chromosome":"9","Start":"127818718","Stop":"127818718","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1061551,"rule_based_match":true,"evidence_text":"c.1426C>T","llm_judgment":"PRESENT","evidence":"c.1426C>T","abstract_start":521,"abstract_end":530}]}
{"pmid":"34777456","title":"A Mosaic Mutation in the","abstract":"Merosine deficient congenital muscular dystrophy is one of the most common forms of congenital muscular dystrophy. This disease is caused by a primary deficiency or a functionally inactive form of the protein merosin in muscle tissue. The type of inheritance of this disease is autosomal recessive. <i>De novo</i> variants with this type of inheritance are rare, and it is quite possible that the <i>de novo</i> variant may hide a mosaic form in the parent of an affected child. We present a birth family with two affected children who inherited a previously undescribed pathogenic variant c.1755del from their mother and a previously described pathogenic variant c.9253C > T in the <i>LAMA2</i> gene from their mosaic father. <i>LAMA2</i> gene mutation analysis was performed by mass parallel sequencing and direct sequencing of genomic DNAs.","variants":[{"Name":"NM_000426.4(LAMA2):c.9253C>T (p.Arg3085Ter)","Chromosome":"6","Start":"129516231","Stop":"129516231","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29330,"rule_based_match":true,"evidence_text":"c.9253C > T","llm_judgment":"PRESENT","evidence":"c.9253C > T","abstract_start":664,"abstract_end":675}]}
{"pmid":"21204226","title":"Contractions in the second polyA tract of ARX are rare, non-pathogenic polymorphisms.","abstract":"Aristaless related homeobox (ARX) is a transcription factor containing highly conserved octapeptide, homeobox, acidic, and aristaless domains, as well as four polyA tracts. The most frequent ARX mutation found to date in patients with X-linked infantile spasms, Partington syndrome or X-linked mental retardation, is a duplication of 24 bp in exon 2, resulting in the expansion of the second polyA tract. Although the pathogenic role of this expansion has been well characterized, the effect of contractions in the same polyA tract is still debated since different reports have associated contractions to either mental retardation or a normal phenotype. Here, we report two unrelated girls with epilepsy and mental retardation who inherited from their unaffected parents, of either sex, a deletion of 24 bp (c.441_464del), resulting in a contraction of eight alanines in the second polyA tract of ARX. Segregation studies revealed the c.441_464del also in two healthy relatives of one of the patients. This finding supports the hypothesis that this contraction represents a rare, benign polymorphism.","variants":[{"Name":"NM_139058.3(ARX):c.441_464del (p.Ala148_Ala155del)","Chromosome":"X","Start":"25013531","Stop":"25013554","ReferenceAlleleVCF":"GGCCGCGGCGGCCGCGGCCGCGGCT","AlternateAlleleVCF":"G","allel_id":102348,"rule_based_match":true,"evidence_text":"c.441_464del","llm_judgment":"PRESENT","evidence":"c.441_464del","abstract_start":808,"abstract_end":820}]}
{"pmid":"37359369","title":"Whole exome sequencing identified five novel variants in","abstract":"<b>Introduction:</b> Epilepsy is a group of neurological disorders characterized by recurring seizures and fits. The Epilepsy genes can be classified into four distinct groups, based on involvement of these genes in different pathways leading to Epilepsy as a phenotype. Genetically the disease has been associated with various pathways, leading to pure epilepsy-related disorders caused by <i>CNTN2</i> variations, or involving physical or systemic issues along with epilepsy caused by <i>CARS2</i> and <i>ARSA</i>, or developed by genes that are putatively involved in epilepsy lead by <i>CLCN4</i> variations. <b>Methods:</b> In this study, five families of Pakistani origin (EP-01, EP-02, EP-04, EP-09, and EP-11) were included for molecular diagnosis. <b>Results:</b> Clinical presentations of these patients included neurological symptoms such as delayed development, seizures, regression, myoclonic epilepsy, progressive spastic tetraparesis, vision and hearing impairment, speech problems, muscle fibrillation, tremors, and cognitive decline. Whole exome sequencing in index patients and Sanger sequencing in all available individuals in each family identified four novel homozygous variants in genes <i>CARS2</i>: c.655G>A p.Ala219Thr (EP-01), <i>ARSA</i>: c.338T>C: p.Leu113Pro (EP-02), c.938G>T p.Arg313Leu (EP-11), <i>CNTN2</i>: c.1699G>T p.Glu567Ter (EP-04), and one novel hemizygous variant in gene <i>CLCN4</i>: c.2167C>T p.Arg723Trp (EP-09). <b>Conclusion:</b> To the best of our knowledge these variants were novel and had not been reported in familial epilepsy. These variants were absent in 200 ethnically matched healthy control chromosomes. Three dimensional protein analyses revealed drastic changes in the normal functions of the variant proteins. Furthermore, these variants were designated as \"pathogenic\" as per guidelines of American College of Medical Genetics 2015. Due to overlapping phenotypes, among the patients, clinical subtyping was not possible. However, whole exome sequencing successfully pinpointed the molecular diagnosis which could be helpful for better management of these patients. Therefore, we recommend that exome sequencing be performed as a first-line molecular diagnostic test in familial cases.","variants":[{"Name":"NM_001830.4(CLCN4):c.2167C>T (p.Arg723Trp)","Chromosome":"X","Start":"10220852","Stop":"10220852","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":951568,"rule_based_match":true,"evidence_text":"CLCN4: c.2167C>T p.Arg723Trp","llm_judgment":"PRESENT","evidence":"p.Arg723Trp","abstract_start":1437,"abstract_end":1448},{"Name":"NM_005076.5(CNTN2):c.1699G>T (p.Glu567Ter)","Chromosome":"1","Start":"205065792","Stop":"205065792","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1517652,"rule_based_match":true,"evidence_text":"c.1699G>T p.Glu567Ter","llm_judgment":"PRESENT","evidence":"c.1699G>T p.Glu567Ter","abstract_start":1341,"abstract_end":1362}]}
{"pmid":"17956895","title":"CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro.","abstract":"The charged multivesicular body protein 2B gene (CHMP2B) was recently associated with frontotemporal lobar degeneration (FTLD) linked to chromosome 3 in a Danish FTLD family (FTD-3). In this family, a mutation in the acceptor splice site of exon 6 produced two aberrant transcripts predicting two C-truncated CHMP2B proteins due to a read through of intron 5 (p.Met178ValfsX2) and a cryptic splicing event within exon 6 (p.Met178LeufsX30). Extensive mutation analysis of CHMP2B in Belgian patients (N = 146) identified one nonsense mutation in exon 5 (c.493C>T) in a familial FTLD patient, predicting a C-truncated protein p.Gln165X analogous to the Danish mutant proteins. Overexpression of Belgian p.Gln165X in human neuroblastoma SK-N-SH cells showed the formation of large, aberrant endosomal structures that were highly similar to those observed for Danish p.Met178ValfsX2. Together, these data suggest that C-truncating mutations in CHMP2B might underlie the pathogenic mechanism in FTLD by disturbing endosome function. We also describe a missense mutation in exon 5 of CHMP2B (p.Asn143Ser) in a familial patient with cortical basal degeneration. However, the pathogenic character of this mutation remains elusive.","variants":[{"Name":"NM_014043.4(CHMP2B):c.493C>T (p.Gln165Ter)","Chromosome":"3","Start":"87253472","Stop":"87253472","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16694,"rule_based_match":true,"evidence_text":"c.493C>T","llm_judgment":"PRESENT","evidence":"c.493C>T","abstract_start":552,"abstract_end":560}]}
{"pmid":"19191323","title":"Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism.","abstract":"We investigated the biochemical properties and cellular expression of the c.346C>T (p.R116C) human cationic trypsinogen (PRSS1) mutant, which we identified in a German family with autosomal dominant hereditary pancreatitis. This mutation leads to an unpaired Cys residue with the potential to interfere with protein folding via incorrect disulfide bond formation. Recombinantly expressed p.R116C trypsinogen exhibited a tendency for misfolding in vitro. Biochemical analysis of the correctly folded, purified p.R116C mutant revealed unchanged activation and degradation characteristics compared to wild type trypsinogen. Secretion of mutant p.R116C from transfected 293T cells was reduced to approximately 20% of wild type. A similar secretion defect was observed with another rare PRSS1 variant, p.C139S, whereas mutants p.A16V, p.N29I, p.N29T, p.E79K, p.R122C, and p.R122H were secreted normally. All mutants were detected in cell extracts at comparable levels but a large portion of mutant p.R116C was present in an insoluble, protease-sensitive form. Consistent with intracellular retention of misfolded trypsinogen, the endoplasmic reticulum (ER) stress markers immunoglobulin-binding protein (BiP) and the spliced form of the X-box binding protein-1 (XBP1s) were elevated in cells expressing mutant p.R116C. The results indicate that mutation-induced misfolding and intracellular retention of human cationic trypsinogen causes hereditary pancreatitis in carriers of the p.R116C mutation. ER stress triggered by trypsinogen misfolding represents a new potential disease mechanism for chronic pancreatitis.","variants":[{"Name":"NM_002769.5(PRSS1):c.346C>T (p.Arg116Cys)","Chromosome":"7","Start":"142751919","Stop":"142751919","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38878,"rule_based_match":true,"evidence_text":"c.346C>T (p.R116C)","llm_judgment":"PRESENT","evidence":"c.346C>T (p.R116C)","abstract_start":74,"abstract_end":92}]}
{"pmid":"32042915","title":"Early infantile epileptic-dyskinetic encephalopathy due to biallelic","abstract":"OBJECTIVE: To describe clinical, biochemical, and molecular genetic findings in a large inbred family in which 4 children with a severe early-onset epileptic-dyskinetic encephalopathy, with suppression burst EEG, harbored homozygous mutations of phosphatidylinositol glycan anchor biosynthesis, class P (<i>PIGP</i>), a member of the large glycosylphosphatidylinositol (GPI) anchor biosynthesis gene family.\nMETHODS: We studied clinical features, EEG, brain MRI scans, whole-exome sequencing (WES), and measured the expression of a subset of GPI-anchored proteins (GPI-APs) in circulating granulocytes using flow cytometry.\nRESULTS: The 4 affected children exhibited a severe neurodevelopmental disorder featuring severe hypotonia with early dyskinesia progressing to quadriplegia, associated with infantile spasms, focal, tonic, and tonic-clonic seizures and a burst suppression EEG pattern. Two of the children died prematurely between age 2 and 12 years; the remaining 2 children are aged 2 years 7 months and 7 years 4 months. The homozygous c.384del variant of <i>PIGP</i>, present in the 4 patients, introduces a frame shift 6 codons before the expected stop signal and is predicted to result in the synthesis of a protein longer than the wild type, with impaired functionality. We demonstrated a reduced expression of the GPI-AP CD16 in the granulocytic membrane in affected individuals.\nCONCLUSIONS: <i>PIGP</i> mutations are consistently associated with an epileptic-dyskinetic encephalopathy with the features of early infantile epileptic encephalopathy with profound disability and premature death. CD16 is a valuable marker to support a genetic diagnosis of inherited GPI deficiencies.","variants":[{"Name":"NM_153682.3(PIGP):c.384del (p.Glu129fs)","Chromosome":"21","Start":"37065603","Stop":"37065603","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":384446,"rule_based_match":true,"evidence_text":"The homozygous c.384del variant of <i>PIGP</i>","llm_judgment":"PRESENT","evidence":"The homozygous c.384del variant of <i>PIGP</i>","abstract_start":1031,"abstract_end":1077}]}
{"pmid":"27524508","title":"Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer's disease identifies a homozygous CTSF mutation.","abstract":"We have previously reported the whole genome genotyping analysis of 2 consanguineous siblings clinically diagnosed with early onset Alzheimer's disease (AD). In this analysis, we identified several large regions of homozygosity shared between both affected siblings, which we suggested could be candidate loci for a recessive genetic lesion underlying the early onset AD in these cases. We have now performed exome sequencing in one of these siblings and identified the potential cause of disease: the CTSF c.1243G>A:p.Gly415Arg mutation in homozygosity. Biallelic mutations in this gene have been shown to cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis with some cases resembling the impairment seen in AD.","variants":[{"Name":"NM_003793.4(CTSF):c.1243G>A (p.Gly415Arg)","Chromosome":"11","Start":"66564636","Stop":"66564636","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1427001,"rule_based_match":true,"evidence_text":"CTSF c.1243G>A:p.Gly415Arg","llm_judgment":"PRESENT","evidence":"CTSF c.1243G>A:p.Gly415Arg","abstract_start":502,"abstract_end":528}]}
{"pmid":"32071838","title":"An ancestral variant causing type I xanthinuria in Turkmen and Arab families is predicted to prevail in the Afro-Asian stone-forming belt.","abstract":"Classical xanthinuria is a rare autosomal recessive metabolic disorder characterized by lack of xanthine dehydrogenase activity that often manifests as xanthine urolithiasis and risk of drug toxicity. Variants in the <i>XDH</i> or <i>HMCS</i> gene underlie classical xanthinuria type I and type II, respectively. Here we present two Israeli Arab families affected by type I xanthinuria in whom a c.2164A>T (Lys722Ter) variant in the <i>XDH</i> gene, previously reported in a Turkish family of Turkmen origin, was identified. Analysis of polymorphic markers surrounding the variant site revealed common haplotypes spanning 0.6 Mbp shared by all three, and 1.7 Mbp shared by two of the studied families. By applying Bayesian methods to a simple model of crossover events through generations in the chromosomes carrying the variant, the most recent common ancestor of these families was found to be 179 (95% credible limit 70) generations old. The estimated antiquity of the variant, the historical genealogy of the affected families and the history and present day dispersion of their people strongly suggest prevalence of this variant in the Afro-Asian stone-forming belt. As far as we are aware, this is a first report of an ancient variant causing xanthinuria with potential wide geographical dispersion.","variants":[{"Name":"NM_000379.4(XDH):c.2164A>T (p.Lys722Ter)","Chromosome":"2","Start":"31367994","Stop":"31367994","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1414376,"rule_based_match":true,"evidence_text":"c.2164A>T (Lys722Ter)","llm_judgment":"PRESENT","evidence":"c.2164A>T (Lys722Ter)","abstract_start":396,"abstract_end":417}]}
{"pmid":"37840311","title":"Re-evaluation of a Fibrillin-1 Gene Variant of Uncertain Significance Using the ClinGen Guidelines.","abstract":"Background: Marfan syndrome (MFS) is caused by fibrillin-1 gene (<i>FBN1</i>) variants. Mutational hotspots and/or well-established critical functional domains of <i>FBN1</i> include cysteine residues, calcium-binding consensus sequences, and amino acids related to interdomain packaging. Previous guidelines for variant interpretation do not reflect the features of genes or related diseases. Using the Clinical Genome Resource (ClinGen) <i>FBN1</i> variant curation expert panel (VCEP), we re-evaluated <i>FBN1</i> germline variants reported as variants of uncertain significance (VUSs).\nMethods: We re-evaluated 26 VUSs in <i>FBN1</i> reported in 161 patients with MFS. We checked the variants in the Human Genome Mutation Database, ClinVar, and VarSome databases and assessed their allele frequencies using the gnomAD database. Patients' clinical information was reviewed.\nResults: Four missense variants affecting cysteines (c.460T>C, c.1006T>C, c.5330G>C, and c.8020T>C) were reclassified as likely pathogenic and were assigned PM1_strong or PM1. Two intronic variants were reclassified as benign by granting BA1 (stand-alone). Four missense variants were reclassified as likely benign. BP5 criteria were applied in cases with an alternate molecular basis for disease, one of which (c.7231G>A) was discovered alongside a pathogenic <i>de novo</i> COL3A1 variant (c.1988G>T, p.Gly633Val).\nConclusions: Considering the high penetrance of <i>FBN1</i> variants and clinical variability of MFS, the detection of pathogenic variants is important. The ClinGen <i>FBN1</i> VCEP encompasses mutational hotspots and/or well-established critical functional domains and adjusts the criteria specifically for MFS; therefore, it is beneficial not only for identifying pathogenic <i>FBN1</i> variants but also for distinguishing these variants from those that cause other connective tissue disorders with overlapping clinical features.","variants":[{"Name":"NM_000138.5(FBN1):c.460T>C (p.Cys154Arg)","Chromosome":"15","Start":"48596361","Stop":"48596361","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3732829,"rule_based_match":true,"evidence_text":"c.460T>C","llm_judgment":"PRESENT","evidence":"c.460T>C","abstract_start":930,"abstract_end":938}]}
{"pmid":"31600923","title":"Identification of c.1531C>T Pathogenic Variant in the","abstract":"Germline pathogenic variants in the <i>CDH1</i> gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize <i>CDH1</i> mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the <i>CDH1</i> gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at ≤50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the <i>CDH1</i> gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband's sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the <i>CDH1</i> in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in <i>CDH1</i> negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.","variants":[{"Name":"NM_004360.5(CDH1):c.1531C>T (p.Gln511Ter)","Chromosome":"16","Start":"68815725","Stop":"68815725","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":420600,"rule_based_match":true,"evidence_text":"c.1531C>T","llm_judgment":"PRESENT","evidence":"c.1531C>T","abstract_start":1020,"abstract_end":1029}]}
{"pmid":"30065953","title":"Carey-Fineman-Ziter syndrome with mutations in the myomaker gene and muscle fiber hypertrophy.","abstract":"OBJECTIVE: To describe the long-term clinical follow-up in 3 siblings with Carey-Fineman-Ziter syndrome (CFZS), a form of congenital myopathy with a novel mutation in the myomaker gene (<i>MYMK</i>).\nMETHODS: We performed clinical investigations, repeat muscle biopsy in 2 of the siblings at ages ranging from 11 months to 18 years, and whole-genome sequencing.\nRESULTS: All the siblings had a marked and characteristic facial weakness and variable dysmorphic features affecting the face, hands, and feet, and short stature. They had experienced muscle hypotonia and generalized muscle weakness since early childhood. The muscle biopsies revealed, as the only major abnormality at all ages, a marked hypertrophy of both type 1 and type 2 fibers with more than twice the diameter of that in age-matched controls. Genetic analysis revealed biallelic mutations in the <i>MYMK</i> gene, a novel c.235T>C; p.(Trp79Arg), and the previously described c.271C>A; p.(Pro91Thr).\nCONCLUSIONS: Our study expands the genetic and clinical spectrum of <i>MYMK</i> mutations and CFZS. The marked muscle fiber hypertrophy identified from early childhood, despite apparently normal muscle bulk, indicates that defective fusion of myoblasts during embryonic muscle development results in a reduced number of muscle fibers with compensatory hypertrophy and muscle weakness.","variants":[{"Name":"NM_001080483.3(MYMK):c.271C>A (p.Pro91Thr)","Chromosome":"9","Start":"133519002","Stop":"133519002","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":424384,"rule_based_match":true,"evidence_text":"c.271C>A; p.(Pro91Thr)","llm_judgment":"PRESENT","evidence":"c.271C>A; p.(Pro91Thr)","abstract_start":944,"abstract_end":966}]}
{"pmid":"32737394","title":"Biallelic ZNF407 mutations in a neurodevelopmental disorder with ID, short stature and variable microcephaly, hypotonia, ocular anomalies and facial dysmorphism.","abstract":"We describe five members of a consanguineous Pakistani family (Family I) plus two affected children from families of different ethnic origins presenting with neurodevelopmental disorders with overlapping features. All affected individuals from families have intellectual disability (ID), ranging from mild to profound, and reduced motor and cognitive skills plus variable features including short stature, microcephaly, developmental delay, hypotonia, dysarthria, deafness, visual problems, enuresis, encopresis, behavioural anomalies, delayed pubertal onset and facial dysmorphism. We first mapped the disease locus in the large family (Family I), and by exome sequencing identified homozygous ZNF407 c.2814_2816dup (p.Val939dup) in four affected members where DNA samples were available. By exome sequencing we detected homozygous c.2405G>T (p.Gly802Val) in the affected member of Family II and compound heterozygous variants c.2884C>G (p.Arg962Gly) and c.3642G>C (p.Lys1214Asn) in the affected member of Family III. Homozygous c.5054C>G (p.Ser1685Trp) has been reported in two brothers with an ID syndrome. Affected individuals we present did not exhibit synophrys, midface hypoplasia, kyphosis, 5th finger camptodactyly, short 4th metatarsals or limited knee mobility observed in the reported family.","variants":[{"Name":"NM_017757.3(ZNF407):c.2814_2816dup (p.Val939dup)","Chromosome":"18","Start":"74633832","Stop":"74633833","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CAGT","allel_id":536164,"rule_based_match":true,"evidence_text":"c.2814_2816dup (p.Val939dup)","llm_judgment":"PRESENT","evidence":"c.2814_2816dup (p.Val939dup)","abstract_start":702,"abstract_end":730}]}
{"pmid":"22357538","title":"Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions.","abstract":"Breast cancer is the most common cancer in women in developed countries and has a well-established genetic component. Germline mutations in a network of genes encoding BRCA1, BRCA2, and their interacting partners confer hereditary susceptibility to breast cancer. Abraxas directly interacts with the BRCA1 BRCT (BRCA1 carboxyl-terminal) repeats and contributes to BRCA1-dependent DNA damage responses, making Abraxas a candidate for yet unexplained disease susceptibility. Here, we have screened 125 Northern Finnish breast cancer families for coding region and splice-site Abraxas mutations and genotyped three tagging single-nucleotide polymorphisms within the gene from 991 unselected breast cancer cases and 868 female controls for common cancer-associated variants. A novel heterozygous alteration, c.1082G>A (Arg361Gln), that results in abrogated nuclear localization and DNA response activities was identified in three breast cancer families and in one additional familial case from an unselected breast cancer cohort, but not in healthy controls (P = 0.002). On the basis of its exclusive occurrence in familial cancers, disease cosegregation, evolutionary conservation, and disruption of critical BRCA1 functions, the recurrent Abraxas c.1082G>A mutation connects to cancer predisposition. These findings contribute to the concept of a BRCA-centered tumor suppressor network and provide the identity of Abraxas as a new breast cancer susceptibility gene.","variants":[{"Name":"NM_139076.3(ABRAXAS1):c.1082G>A (p.Arg361Gln)","Chromosome":"4","Start":"83462617","Stop":"83462617","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":632488,"rule_based_match":true,"evidence_text":"c.1082G>A (Arg361Gln)","llm_judgment":"PRESENT","evidence":"c.1082G>A (Arg361Gln)","abstract_start":804,"abstract_end":825}]}
{"pmid":"26244261","title":"Dihydropyrimidinase and β-ureidopropionase gene variation and severe fluoropyrimidine-related toxicity.","abstract":"AIMS: To assess the association of DPYS and UPB1 genetic variation, encoding the catabolic enzymes downstream of dihydropyrimidine dehydrogenase, with early-onset toxicity from fluoropyrimidine-based chemotherapy.\nPATIENTS & METHODS: The coding and exon-flanking regions of both genes were sequenced in a discovery subset (164 patients). Candidate variants were genotyped in the full cohort of 514 patients.\nRESULTS & CONCLUSIONS: Novel rare deleterious variants in DPYS (c.253C > T and c.1217G > A) were detected once each in toxicity cases and may explain the occurrence of severe toxicity in individual patients, and associations of common variants in DPYS (c.1-1T > C: p(adjusted) = 0.003; OR = 2.53; 95% CI: 1.39-4.62, and c.265-58T > C: p(adjusted) = 0.039; OR = 0.61; 95% CI: 0.38-0.97) with 5-fluorouracil toxicity were replicated.","variants":[{"Name":"NM_001385.3(DPYS):c.253C>T (p.Gln85Ter)","Chromosome":"8","Start":"104466668","Stop":"104466668","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1928850,"rule_based_match":true,"evidence_text":"c.253C > T","llm_judgment":"PRESENT","evidence":"c.253C > T","abstract_start":472,"abstract_end":482}]}
{"pmid":"37671043","title":"Case report: A rare case of pyruvate kinase deficiency and Crigler-Najjar syndrome type II with a novel pathogenic variant of","abstract":"Pyruvate Kinase Deficiency (PKD) and Crigler-Najjar syndrome are rare autosomal recessive liver diseases. PKD is caused by homozygous or compound heterozygous mutations in the <i>PKLR</i> gene, leading to non-spherocytic hereditary hemolytic anemia. On the other hand, Crigler-Najjar syndrome (CNS-II) is characterized by the loss or reduced activity of UDP-glucuronosyltransferase, resulting in elevated levels of unconjugated bilirubin, which is the primary cause of disease manifestation. To date, there have been no reported cases of patients with both conditions. In this case report, we present the unique clinical course of a 15-year-old Chinese patient with both PKD and CNS-II. The patient was admitted for evaluation of hyperbilirubinemia and exhibited yellowish skin color, icteric sclera, and splenomegaly upon physical examination. Extensive laboratory examinations ruled out viral, hemolytic, autoimmune, and inborn or acquired metabolic etiologies of liver injury. Histopathological findings indicated benign recurrent intrahepatic cholestasis (BRIC) and hemosiderosis. Surprisingly, targeted next-generation sequencing (NGS) of the patient's blood did not reveal any mutation sites associated with BRIC. Instead, it identified a novel homozygous pathogenic variant of the <i>PKLR</i> gene [c.1276C>T (p.Arg426Trp)] and a rare heterozygous variant of <i>UGT1A1</i> gene [c.-55_-54insAT, c.1091C>T (p.Pro364Leu)]. These findings strongly suggest a diagnosis of PKD and CNS-II in the patient. Treatment with 500 mg/day of ursodeoxycholic acid proved to be effective, rapidly reducing the patient's total bilirubin levels and shortening the symptomatic period. This case highlights the importance of genetic diagnosis in accurately identifying the underlying cause of hyperbilirubinemia, especially in patients with rare hereditary diseases. Furthermore, NGS can provide valuable insights into the genotype-phenotype correlation of PKD and CNS-II.","variants":[{"Name":"NM_000463.3(UGT1A1):c.1091C>T (p.Pro364Leu)","Chromosome":"2","Start":"233768226","Stop":"233768226","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":206952,"rule_based_match":true,"evidence_text":"c.1091C>T (p.Pro364Leu)","llm_judgment":"PRESENT","evidence":"c.1091C>T (p.Pro364Leu)","abstract_start":1402,"abstract_end":1425}]}
{"pmid":"25544989","title":"Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.","abstract":"This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.","variants":[{"Name":"NM_001029883.3(PCARE):c.1795T>C (p.Cys599Arg)","Chromosome":"2","Start":"29072467","Stop":"29072467","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1925264,"rule_based_match":true,"evidence_text":"c.1795T>C; p.Cys599Arg","llm_judgment":"PRESENT","evidence":"c.1795T>C; p.Cys599Arg","abstract_start":734,"abstract_end":756},{"Name":"NM_001034853.2(RPGR):c.2405_2406del (p.Glu802fs)","Chromosome":"X","Start":"38286593","Stop":"38286594","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":96865,"rule_based_match":false,"evidence_text":"c.2405-2406delAG; p.Glu802Glyfs*31","llm_judgment":"PRESENT","evidence":"c.2405-2406delAG; p.Glu802Glyfs*31","abstract_start":917,"abstract_end":951},{"Name":"NM_000350.3(ABCA4):c.6088C>T (p.Arg2030Ter)","Chromosome":"1","Start":"94005500","Stop":"94005500","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22946,"rule_based_match":true,"evidence_text":"c.6088C>T; p.R2030*","llm_judgment":"PRESENT","evidence":"c.6088C>T; p.R2030*","abstract_start":873,"abstract_end":892},{"Name":"NM_000350.3(ABCA4):c.2041C>T (p.Arg681Ter)","Chromosome":"1","Start":"94060656","Stop":"94060656","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":105003,"rule_based_match":true,"evidence_text":"c.2041C>T; p.R681*","llm_judgment":"PRESENT","evidence":"c.2041C>T; p.R681*","abstract_start":850,"abstract_end":868}]}
{"pmid":"23291369","title":"New TRPC6 gain-of-function mutation in a non-consanguineous Dutch family with late-onset focal segmental glomerulosclerosis.","abstract":"BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome. Hereditary FSGS is frequently caused by mutations in important structural podocyte proteins, including the slit diaphragm-associated transient receptor potential channel C6 (TRPC6).\nMETHODS: In five patients with biopsy-proven autosomal-dominant FSGS from five different Dutch families, all 13 exons of TRPC6 were sequenced. Upon identification of a novel TRPC6 sequence variant, the resultant amino acid change was introduced in the wild-type TRPC6 protein and functionally tested using patch-clamp analyses and cell-surface biotinylation experiments.\nRESULTS: None of the previously described TRPC6 mutations were found in our cohort. In one family, we identified a novel c.524G>A sequence variant resulting in a p.Arg175Gln (R175Q) substitution in the TRPC6 protein. This sequence variant was absent in 449 control subjects and from public SNP databases. The mutation was located in the third ankyrin repeat domain (ANK3) in the cytoplasmic N-tail of TRPC6, important for protein-protein interaction and regulation of ion channel activity. Patch-clamp analyses of the mutant channel indeed showed an increased TRPC6 channel-mediated current. However, cell-surface expression of the mutant channel was not increased.\nCONCLUSIONS: We identified a novel TRPC6 p.Arg175Gln gain-of-function mutation that shows increased TRPC6-mediated current, which is not due to altered cell-surface expression. This is the first mutation identified in ANK3 of the TRPC6 N-tail and is most likely responsible for the late-onset autosomal dominant FSGS in this family.","variants":[{"Name":"NM_004621.6(TRPC6):c.524G>A (p.Arg175Gln)","Chromosome":"11","Start":"101504445","Stop":"101504445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":818286,"rule_based_match":true,"evidence_text":"c.524G>A (p.Arg175Gln)","llm_judgment":"PRESENT","evidence":"p.Arg175Gln","abstract_start":829,"abstract_end":840}]}
{"pmid":"30612286","title":"Triple A syndrome: two siblings with a novel mutation in the AAAS gene.","abstract":"OBJECTIVE: Triple A syndrome is a rare autosomal recessive disorder caused by mutations in the AAAS gene on chromosome 12q13. Its main clinical features are alacrima, achalasia, and adrenal insufficiency, with most patients also having neurological symptoms and autonomic dysfunction. The neurologic manifestations are less well-understood, especially in children. Here, we examine two siblings who were found to have a novel mutation in the AAAS gene and who were found to have subtle, but important, neurologic findings.\nDESIGN: This is a case report of two siblings.\nRESULTS: We discuss two siblings exhibiting different signs of the disorder including neurologic dysfunction found at varying ages. Genetic analysis revealed that both patients have the same compound heterozygous mutations in the AAAS gene consisting of one novel mutation (c.500 C>A, A167E) and one previously described mutation (c.1331+1G> A/IVS14+1 G>A). A diagnosis of triple A syndrome was reached based on their clinical and genetic findings.\nCONCLUSIONS: The unique characteristic of these two cases is the novel mutation in the AAAS gene, which is likely pathogenic. In addition, they showcase the genotype-phenotype variability of the disease, as well as the importance of early identification of the neurologic abnormalities, which can result in early intervention and possibly improved outcomes.","variants":[{"Name":"NM_015665.6(AAAS):c.500C>A (p.Ala167Glu)","Chromosome":"12","Start":"53314796","Stop":"53314796","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":360129,"rule_based_match":true,"evidence_text":"c.500 C>A, A167E","llm_judgment":"PRESENT","evidence":"c.500 C>A, A167E","abstract_start":844,"abstract_end":860}]}
{"pmid":"27449533","title":"Morphological alterations in two siblings with autosomal recessive congenital ichthyosis associated with CYP4F22 mutations.","abstract":"Autosomal recessive congenital ichthyosis (ARCI) caused by mutations in CYP4F22 is very rare. CyP4F22, a protein of the cytochrome-P450 family 4, encodes an epidermal ω-hydroxylase decisive in the formation of acylceramides, which is hypothesized to be crucial for skin-barrier function. We report a girl with consanguineous parents presenting as collodion baby with contractures of the great joints and palmoplantar hyperlinearity. In the course of the disease she developed fine scaling of the skin with erythroderma, the latter disappearing until the age of 6 months. Her sister showed a generalized fine-scaling phenotype, and, interestingly, was born without a collodion membrane. The analysis of all known candidate genes for ARCI in parallel with a next-generation sequencing approach using a newly designed dermatogenetics gene panel revealed a previously unknown homozygous splice-site mutation c.549+5G>C in CYP4F22 in both girls, confirming the diagnosis of ARCI. Ultrastructural analysis by transmission electron microscopy in both patients showed epidermal hyperplasia, orthohyperkeratosis with persistence of corneodesmosomes into the outer stratum corneum layers, fragmented and disorganized lamellar lipid bilayers, which could be ascribed to inhomogeneous lamellar body secretion, as well as lamellar body and lipid entombment in the corneocytes. These findings correlated with increased transepidermal water loss on the functional level. For the first time, we report a collodion baby phenotype and epidermal barrier impairment in CyP4F22-deficient epidermis at both the ultrastructural and functional level, and corroborate the importance of CyP4F22 for epidermal maturation and barrier function.","variants":[{"Name":"NM_173483.4(CYP4F22):c.549+5G>C","Chromosome":"19","Start":"15537667","Stop":"15537667","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":551365,"rule_based_match":true,"evidence_text":"c.549+5G>C","llm_judgment":"PRESENT","evidence":"c.549+5G>C","abstract_start":904,"abstract_end":914}]}
{"pmid":"20031247","title":"Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins' diet.","abstract":"BACKGROUND & AIMS: Late-onset symptoms of urea-cycle disorder may lead to a life-threatening disease which is often undetected. We report the clinical and metabolic manifestations of acute hyperammonemic encephalopathy in a 47-year-old asymptomatic man with ornithine transcarbamylase (OTC) deficiency. The hyperammonemic encephalopathy was unmasked by a high-protein Atkins diet.\nMETHODS: Genetic analysis of the patient's family, 89 unrelated Ashkenazi Jewish and 50 unrelated Europeans subjects was performed using polymerase chain reaction amplification and DNA sequencing of the OTC gene.\nRESULTS: Treatment with hemodialysis, provision of adequate calories to prevent catabolism, and protein elimination for 24h followed by protein restriction and ammonia scavenging medications effectively lowered the patient's plasma ammonia level and resulted in full recovery. Genetic analysis of the OTC gene revealed a novel hemizygous missense mutation in exon 5 (c.477T>G), leading to an isoleucine-to-methionine substitution in codon 159 (Ile159Met). Further genetic analysis of the patient's family yielded the mutation in many of them, although findings were negative in 89 unrelated Ashkenazi Jewish and 50 unrelated Europeans subjects.\nCONCLUSIONS: This is the first reported case of an adult urea-cycle defect unmasked by the Atkins diet. Measurements of serum ammonia level must be part of the basic work-up in all patients presenting with encephalopathy of unknown origin even in the absence of liver dysfunction. Awareness of this important association can contribute to prompt diagnosis and life-saving treatment. Correct diagnosis is also important to prevent future recurrences and to provide genetic counselling for family members.","variants":[{"Name":"NM_000531.6(OTC):c.477T>G (p.Ile159Met)","Chromosome":"X","Start":"38401365","Stop":"38401365","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2839474,"rule_based_match":true,"evidence_text":"c.477T>G","llm_judgment":"PRESENT","evidence":"c.477T>G","abstract_start":961,"abstract_end":969}]}
{"pmid":"18950795","title":"Birth prevalence of homocystinuria in Central Europe: frequency and pathogenicity of mutation c.1105C>T (p.R369C) in the cystathionine beta-synthase gene.","abstract":"OBJECTIVES: To estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme.\nSTUDY DESIGN: Mutation c.1105C>T was analyzed in 600 anonymous Czech newborn blood spots. Catalytic activity and quaternary structure of the p.R369C mutant was evaluated after expression in 2 cellular systems.\nRESULTS: Population frequency of the c.1105C>T mutation was 0.005, predicting the birth prevalence of homocystinuria of 1:40000, which increased to 1:15500 in a model including 10 additional mutations. In Escherichia coli the p.R369C mutant misfolded, and its activity was severely reduced, and expression in Chinese hamster ovary cells enabled proper folding with activity decreased to 63% of the wild-type enzyme. This decreased activity was not due to impaired K(m) for both substrates but resulted from V(max) lowered to 55% of the normal cystathionine beta-synthase enzyme.\nCONCLUSIONS: The c.1105C>T (p.R369C) allele is common also in the Czech population. Although the p.R369C mutation impairs folding and decreases velocity of the enzymatic reaction, our data are congruent with rather mild clinical phenotype in homozygotes or compound heterozygotes carrying this mutation.","variants":[{"Name":"NM_000071.3(CBS):c.1105C>T (p.Arg369Cys)","Chromosome":"21","Start":"43060481","Stop":"43060481","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":210412,"rule_based_match":true,"evidence_text":"c.1105C>T (p.R369C)","llm_judgment":"PRESENT","evidence":"c.1105C>T (p.R369C)","abstract_start":1034,"abstract_end":1053}]}
{"pmid":"35126455","title":"A Novel Heterozygous Pathogenic Variation in","abstract":"<b>Aim:</b> To determine the etiology of a Chinese family with thrombocytopenia by analyzing the clinical features and genetic variation. <b>Methods:</b> Clinical profiles and genomic DNA extracts of the family members were collected for the study. Whole exome sequencing and Sanger sequencing was used to detect the associated genetic variation and verify the family co-segregation respectively. Bioinformatics analysis assessed the pathogenicity of missense mutations. <b>Results:</b> The study reported a 3-generation pedigree including eight family members with thrombocytopenia. The platelet counts of the patients were varied, ranging from 38 to 110 × 10<sup>9</sup>/L (reference range: 150-450 x 10<sup>9</sup>/L). The mean volumes and morphology of the sampled platelet were both normal. The bleeding abnormality and mitochondriopathy were not observed in all the patients. Clinical signs of thrombocytopenia were mild. A novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified in <i>CYCS</i> gene associated with autosomal dominant thrombocytopenia. <b>Conclusion:</b> We report the first large family with autosomal dominant non-syndromic thrombocytopenia 4 in a Chinese family, a novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified. The whole exome sequencing is an efficient tool for screening the variants specifically associated with the disease. The finding enriches the mutation spectrum of <i>CYCS</i> gene and laid a foundation for future studies on the correlation between genotype and phenotype.","variants":[{"Name":"NM_018947.6(CYCS):c.79C>T (p.His27Tyr)","Chromosome":"7","Start":"25124041","Stop":"25124041","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1200164,"rule_based_match":true,"evidence_text":"c.79C > T (p.His27Tyr)","llm_judgment":"PRESENT","evidence":"c.79C > T (p.His27Tyr)","abstract_start":966,"abstract_end":988}]}
{"pmid":"26399558","title":"The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease.","abstract":"OBJECTIVE: To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD).\nMETHODS: We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest.\nRESULTS: We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting.\nCONCLUSIONS: Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders.","variants":[{"Name":"NM_171998.4(RAB39B):c.574G>A (p.Gly192Arg)","Chromosome":"X","Start":"155260871","Stop":"155260871","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215090,"rule_based_match":true,"evidence_text":"c.574G > A; p.G192R","llm_judgment":"PRESENT","evidence":"c.574G > A; p.G192R","abstract_start":640,"abstract_end":659}]}
{"pmid":"23692385","title":"Mesoaxial polydactyly is a major feature in Bardet-Biedl syndrome patients with LZTFL1 (BBS17) mutations.","abstract":"Ciliopathies are heterogeneous disorders sharing different clinical signs due to a defect at the level of the primary cilia/centrosome complex. Postaxial polydactyly is frequently reported in ciliopathies, especially in Bardet-Biedl syndrome (BBS). Clinical features and genetic results observed in a pair of dizygotic twins with BBS are reported. The following manifestations were present: retinitis pigmentosa, bilateral insertional polydactyly, cognitive impairment and renal dysfunction. X-rays of the hands confirmed the presence of a 4th mesoaxial extra-digit with Y-shaped metacarpal bones. The sequencing of LZTFL1 identified a missense mutation (NM_020347.2: p.Leu87Pro; c.260T>C) and a nonsense mutation (p.Glu260*; c.778G>T), establishing a compound heterozygous status for the twins. A major decrease of LZTFL1 transcript and protein was observed in the patient's fibroblasts. This is the second report of LZTFL1 mutations in BBS patients confirming LZTFL1 as a BBS gene. Interestingly, the only two families reported in literature thus far with LZTFL1 mutations have in common mesoaxial polydactyly, a very uncommon feature for BBS. This special subtype of polydactyly in BBS patients is easily identified on clinical examination and prompts for priority sequencing of LZTFL1 (BBS17).","variants":[{"Name":"NM_020347.4(LZTFL1):c.260T>C (p.Leu87Pro)","Chromosome":"3","Start":"45835653","Stop":"45835653","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":131913,"rule_based_match":true,"evidence_text":"NM_020347.2: p.Leu87Pro; c.260T>C","llm_judgment":"PRESENT","evidence":"NM_020347.2: p.Leu87Pro; c.260T>C","abstract_start":655,"abstract_end":688},{"Name":"NM_020347.4(LZTFL1):c.778G>T (p.Glu260Ter)","Chromosome":"3","Start":"45827459","Stop":"45827459","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":131914,"rule_based_match":true,"evidence_text":"c.778G>T","llm_judgment":"PRESENT","evidence":"c.778G>T","abstract_start":726,"abstract_end":734}]}
{"pmid":"23434763","title":"Mutations in WNT1 are a cause of osteogenesis imperfecta.","abstract":"BACKGROUND: Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually due to dominant mutations in COL1A1 or COL1A2. Rare recessive forms of OI, caused by mutations in genes involved in various aspects of bone formation, have been described as well.\nOBJECTIVE: To identify the cause of OI in eight children with severe bone fragility and a clinical diagnosis of OI type IV who had had negative results on COL1A1/COL1A2 Sanger sequencing.\nMETHODS: Whole exome sequencing was performed in genomic DNA samples from all eight individuals.\nRESULTS: WNT1 mutations were found in four children from three families. WNT1 was the only gene where mutations were found in all of these four patients. Two siblings from a consanguineous family had a homozygous missense mutation affecting a highly conserved cysteine residue in WNT1 (c.428G>T (p.Cys143Phe)). One girl had a homozygous frameshift deletion (c.287_300del(p.Gln96Profs)). A girl from a third family was compound heterozygous for a frameshift insertion and a missense mutation affecting a conserved amino acid (c.946_949insAACA (p.Ser317Lysfs); c.1063G>T (p.Val355Phe)). All of these children had short stature, low bone density, and severe vertebral compression fractures in addition to multiple long bone fractures in the first years of life. The Wnt signalling pathway is one of the key regulators of osteoblast activity.\nCONCLUSIONS: Recessive inactivating mutations in WNT1 are a new cause of OI type IV.","variants":[{"Name":"NM_005430.4(WNT1):c.1063G>T (p.Val355Phe)","Chromosome":"12","Start":"48981590","Stop":"48981590","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":59409,"rule_based_match":true,"evidence_text":"c.1063G>T (p.Val355Phe)","llm_judgment":"PRESENT","evidence":"c.1063G>T (p.Val355Phe)","abstract_start":1120,"abstract_end":1143},{"Name":"NM_005430.4(WNT1):c.287_300del (p.Gln96fs)","Chromosome":"12","Start":"48979648","Stop":"48979661","ReferenceAlleleVCF":"GGCAGTTCCGGAATC","AlternateAlleleVCF":"G","allel_id":1481322,"rule_based_match":true,"evidence_text":"c.287_300del(p.Gln96Profs)","llm_judgment":"PRESENT","evidence":"c.287_300del(p.Gln96Profs)","abstract_start":919,"abstract_end":945}]}
{"pmid":"18978175","title":"Minigene analysis of intronic variants in common SPINK1 haplotypes associated with chronic pancreatitis.","abstract":"BACKGROUND AND AIMS: Two common haplotypes of the serine protease inhibitor Kazal type 1 (SPINK1) gene have been shown to increase the risk for chronic pancreatitis. A haplotype comprising the c.101A>G (p.N34S) missense variant and four intronic alterations has been found worldwide, whereas a second haplotype consisting of the c.-215G>A promoter variant and the c.194+2T>C intronic alteration has been observed frequently in Japan.\nMETHODS: In the present study, the functional significance of the intronic variants in the pathogenic SPINK1 haplotypes was examined by utilising minigenes, which harbour individual introns placed in the appropriate context of the full-length SPINK1 cDNA. Cells transfected with the SPINK1 minigenes secrete active trypsin inhibitor, thereby allowing evaluation of mutational effects simultaneously on transcription, splicing, translation and secretion.\nRESULTS: It was found that the c.194+2T>C intronic alteration abolished SPINK1 expression at the mRNA level, with consequent loss of inhibitor secretion, whereas the p.N34S-associated intronic variants had no detectable functional effect.\nCONCLUSIONS: Taken together with previous studies, the results indicate that all known variants within the p.N34S-associated haplotype are functionally innocuous, suggesting that an as yet unidentified variant within this haplotype is responsible for the pathogenic effect. The marked negative impact of the c.194+2T>C variant on SPINK1 expression supports the notion that SPINK1 variants increase the risk of chronic pancreatitis by diminishing protective trypsin inhibitor levels.","variants":[{"Name":"NM_001379610.1(SPINK1):c.194+2T>C","Chromosome":"5","Start":"147828020","Stop":"147828020","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":136364,"rule_based_match":true,"evidence_text":"c.194+2T>C","llm_judgment":"PRESENT","evidence":"c.194+2T>C","abstract_start":364,"abstract_end":374}]}
{"pmid":"20725928","title":"Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias.","abstract":"Spinocerebellar ataxia type 28 is an autosomal dominant form of cerebellar ataxia (ADCA) caused by mutations in AFG3L2, a gene that encodes a subunit of the mitochondrial m-AAA protease. We screened 366 primarily Caucasian ADCA families, negative for the most common triplet expansions, for point mutations in AFG3L2 using DHPLC. Whole-gene deletions were excluded in 300 of the patients, and duplications were excluded in 129 patients. We found six missense mutations in nine unrelated index cases (9/366, 2.6%): c.1961C>T (p.Thr654Ile) in exon 15, c.1996A>G (p.Met666Val), c.1997T>G (p.Met666Arg), c.1997T>C (p.Met666Thr), c.2011G>A (p.Gly671Arg), and c.2012G>A (p.Gly671Glu) in exon 16. All mutated amino acids were located in the C-terminal proteolytic domain. In available cases, we demonstrated the mutations segregated with the disease. Mutated amino acids are highly conserved, and bioinformatic analysis indicates the substitutions are likely deleterious. This investigation demonstrates that SCA28 accounts for ∼3% of ADCA Caucasian cases negative for triplet expansions and, in extenso, to ∼1.5% of all ADCA. We further confirm both the involvement of AFG3L2 gene in SCA28 and the presence of a mutational hotspot in exons 15-16. Screening for SCA28, is warranted in patients who test negative for more common SCAs and present with a slowly progressive cerebellar ataxia accompanied by oculomotor signs.","variants":[{"Name":"NM_006796.3(AFG3L2):c.1961C>T (p.Thr654Ile)","Chromosome":"18","Start":"12340220","Stop":"12340220","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46948,"rule_based_match":true,"evidence_text":"c.1961C>T (p.Thr654Ile)","llm_judgment":"PRESENT","evidence":"c.1961C>T (p.Thr654Ile)","abstract_start":514,"abstract_end":537},{"Name":"NM_006796.3(AFG3L2):c.1997T>C (p.Met666Thr)","Chromosome":"18","Start":"12337519","Stop":"12337519","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":46950,"rule_based_match":true,"evidence_text":"c.1997T>C (p.Met666Thr)","llm_judgment":"PRESENT","evidence":"c.1997T>C (p.Met666Thr)","abstract_start":600,"abstract_end":623},{"Name":"NM_006796.3(AFG3L2):c.1996A>G (p.Met666Val)","Chromosome":"18","Start":"12337520","Stop":"12337520","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39380,"rule_based_match":true,"evidence_text":"c.1996A>G (p.Met666Val)","llm_judgment":"PRESENT","evidence":"c.1996A>G (p.Met666Val)","abstract_start":550,"abstract_end":573},{"Name":"NM_006796.3(AFG3L2):c.1997T>G (p.Met666Arg)","Chromosome":"18","Start":"12337519","Stop":"12337519","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":39381,"rule_based_match":true,"evidence_text":"c.1997T>G (p.Met666Arg)","llm_judgment":"PRESENT","evidence":"c.1997T>G (p.Met666Arg)","abstract_start":575,"abstract_end":598},{"Name":"NM_006796.3(AFG3L2):c.2011G>A (p.Gly671Arg)","Chromosome":"18","Start":"12337505","Stop":"12337505","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39382,"rule_based_match":true,"evidence_text":"c.2011G>A (p.Gly671Arg)","llm_judgment":"PRESENT","evidence":"c.2011G>A (p.Gly671Arg)","abstract_start":625,"abstract_end":648}]}
{"pmid":"32105286","title":"Novel mutation in ENG gene causing Hereditary Hemorrhagic Telangiectasia in a Peruvian family.","abstract":"Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disorder of vascular development. Common manifestations include epistaxis, telangiectasias and arteriovenous malformations (AVMs) in multiple organs. Most patients have deletions or missense mutations in the ENG or ACVRL1 gene respectively, significantly affecting endothelium homeostasis. We analyzed the ENG gene in five members of a Peruvian family affected by HHT. One novel mutation was found in exon four of the ENG gene c.408delA, at aminoacid residue 136. This mutation changes the subsequent reading frame producing an early stop at residue 162, preserving only one fourth of the normal protein of 658 aa. This mutation was found in the four affected members of family.","variants":[{"Name":"NM_001114753.3(ENG):c.408del (p.Glu137fs)","Chromosome":"9","Start":"127826625","Stop":"127826625","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":508963,"rule_based_match":true,"evidence_text":"c.408delA","llm_judgment":"PRESENT","evidence":"c.408delA","abstract_start":481,"abstract_end":490}]}
{"pmid":"16404748","title":"Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation.","abstract":"OBJECTIVE: To determine whether the devastating outcome of neonatal-onset glycine encephalopathy (NKH) could be improved by instituting treatment immediately at birth rather than after symptoms are already well established.\nMETHODS: A newborn with NKH diagnosed prenatally following the neonatal death of a previous affected sibling was treated from birth with oral sodium benzoate (250 mg/kg/day) and the NMDA receptor antagonist ketamine (15 mg/kg/day) immediately after sampling cord blood and cerebrospinal fluid (CSF) for glycine determination. Glycine cleavage system (CGS) activity was determined in placental tissue. Mutation analysis was performed by sequencing all GLDC, GCSH and AMT exons.\nRESULTS: CSF glycine (99 micromol/L, reference 3.8-8.0) was already markedly elevated at birth. GCS activity in placental tissue was severely reduced (2.6% of controls). A novel homozygous GLDC c.482A-->G(Y161C) missense mutation was identified. Neonatal hypotonia and apnea did not occur but the long-term outcome was poor, with intractable seizures and severe psychomotor retardation. This contrasts with the favorable outcome with early treatment in variant NKH with mild GCS deficiency (Ann Neuol 2004;56:139-143).\nINTERPRETATION: Prospective treatment with this regimen can favorably modify the early neonatal course of severe NKH but does not prevent the poor long-term outcome, suggesting glycine-induced prenatal injury and/or ongoing postnatal damage.","variants":[{"Name":"NM_000170.3(GLDC):c.482A>G (p.Tyr161Cys)","Chromosome":"9","Start":"6610345","Stop":"6610345","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":70737,"rule_based_match":false,"evidence_text":"GLDC c.482A-->G(Y161C)","llm_judgment":"PRESENT","evidence":"GLDC c.482A-->G(Y161C)","abstract_start":890,"abstract_end":912}]}
{"pmid":"25480036","title":"MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability.","abstract":"Premature ovarian failure (POF) is genetically heterogeneous and manifests as hypergonadotropic hypogonadism either as part of a syndrome or in isolation. We studied two unrelated consanguineous families with daughters exhibiting primary amenorrhea, short stature, and a 46,XX karyotype. A combination of SNP arrays, comparative genomic hybridization arrays, and whole-exome sequencing analyses identified homozygous pathogenic variants in MCM9, a gene implicated in homologous recombination and repair of double-stranded DNA breaks. In one family, the MCM9 c.1732+2T>C variant alters a splice donor site, resulting in abnormal alternative splicing and truncated forms of MCM9 that are unable to be recruited to sites of DNA damage. In the second family, MCM9 c.394C>T (p.Arg132(∗)) results in a predicted loss of functional MCM9. Repair of chromosome breaks was impaired in lymphocytes from affected, but not unaffected, females in both families, consistent with MCM9 function in homologous recombination. Autosomal-recessive variants in MCM9 cause a genomic-instability syndrome associated with hypergonadotropic hypogonadism and short stature. Preferential sensitivity of germline meiosis to MCM9 functional deficiency and compromised DNA repair in the somatic component most likely account for the ovarian failure and short stature.","variants":[{"Name":"NM_017696.3(MCM9):c.1732+2T>C","Chromosome":"6","Start":"118827925","Stop":"118827925","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":166440,"rule_based_match":true,"evidence_text":"MCM9 c.1732+2T>C","llm_judgment":"PRESENT","evidence":"MCM9 c.1732+2T>C","abstract_start":553,"abstract_end":569},{"Name":"NM_017696.3(MCM9):c.394C>T (p.Arg132Ter)","Chromosome":"6","Start":"118924038","Stop":"118924038","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":166441,"rule_based_match":true,"evidence_text":"MCM9 c.394C>T (p.Arg132(∗))","llm_judgment":"PRESENT","evidence":"MCM9 c.394C>T (p.Arg132(∗))","abstract_start":755,"abstract_end":782}]}
{"pmid":"24607278","title":"Pathogenicity evaluation of BRCA1 and BRCA2 unclassified variants identified in Portuguese breast/ovarian cancer families.","abstract":"Hereditary breast/ovarian cancer syndrome is caused by germline deleterious mutations in BRCA1 and BRCA2. A major problem of genetic testing and counseling is the finding of variants of uncertain significance (VUS). We sought to ascertain the pathogenicity of 25 BRCA1 and BRCA2 VUS identified in Portuguese families during genetic testing. We performed cosegregation analysis of VUS with cancer in families, evaluated their frequency in unaffected controls, and looked for loss of heterozygosity in tumors. In addition, three different bioinformatic algorithms were used (Interactive Biosoftware, ESEfinder, and PolyPhen). Finally, six VUS located in exon-intron boundaries were analyzed by RT-PCR. We found that seven variants segregated with the disease, six variants co-occurred with a pathogenic mutation in the same gene, and four variants co-occurred with a deleterious mutation in the other BRCA gene. By RT-PCR, we observed that four variants (BRCA1 c.4484G>T, BRCA2 c.682-2A>C, BRCA2 c.8488-1G>A, and BRCA2 c.8954-5A>G) disrupted splicing. After the combined analysis, we were able to classify 4 splicing variants as pathogenic mutations, 16 variants as neutral, and 3 variants as polymorphisms; only 2 variants remained classified as VUS. This work highlights the contribution of DNA, RNA, and in silico data to assess the pathogenicity of BRCA1/2 VUS, which, in turn, allows more accurate genetic counseling and clinical management of the families carrying them.","variants":[{"Name":"NM_000059.4(BRCA2):c.8488-1G>A","Chromosome":"13","Start":"32370955","Stop":"32370955","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46720,"rule_based_match":true,"evidence_text":"BRCA2 c.8488-1G>A","llm_judgment":"PRESENT","evidence":"BRCA2 c.8488-1G>A","abstract_start":988,"abstract_end":1005},{"Name":"NM_000059.4(BRCA2):c.682-2A>C","Chromosome":"13","Start":"32330917","Stop":"32330917","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":262814,"rule_based_match":true,"evidence_text":"BRCA2 c.682-2A>C","llm_judgment":"PRESENT","evidence":"BRCA2 c.682-2A>C","abstract_start":970,"abstract_end":986},{"Name":"NM_000059.4(BRCA2):c.8954-5A>G","Chromosome":"13","Start":"32379745","Stop":"32379745","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":262850,"rule_based_match":true,"evidence_text":"BRCA2 c.8954-5A>G","llm_judgment":"PRESENT","evidence":"BRCA2 c.8954-5A>G","abstract_start":1011,"abstract_end":1028},{"Name":"NM_007294.4(BRCA1):c.4484G>T (p.Arg1495Met)","Chromosome":"17","Start":"43076488","Stop":"43076488","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":46154,"rule_based_match":true,"evidence_text":"BRCA1 c.4484G>T","llm_judgment":"PRESENT","evidence":"BRCA1 c.4484G>T","abstract_start":953,"abstract_end":968}]}
{"pmid":"34057104","title":"Childhood onset homozygous recessive GDAP1 (p.Pro231Leu) mutation in a 9-year-old puerto rican pediatric female with axonal Charcot-Marie-Tooth disease: A case report.","abstract":"Charcot-Marie-Tooth disease (CMT) is a progressive hereditary neuromuscular neuropathy with pathology in the myelin sheath or the axon. CMT caused by mutations in the Ganglioside-induced differentiation associated protein 1 (GDAP1) gene has been described by a spectrum of phenotypic presentations. GDAP1 is a mitochondrial protein responsible for protecting neuronal bodies from oxidative stress. It is associated with axonal and demyelinating pathophysiology with recessive and dominant modes of inheritance.We describe a case of a 9-year-old Puerto Rican female with clinical and electrodiagnostic results compatible with an axonal sensory-motor neuropathy where a genetic test describes a homozygous GDAP1 missense mutation at the c.692C>T (p.Pro231Leu), previously undetected in a pediatric Latino patient. Mutations in GDAP1 have been previously described in Tunisian, Old Order Amish, European and Japanese families with varying modes of inheritance. To our knowledge, this homozygous variant presentation of the GDAP1 gene is the first to be described in a pediatric Puerto Rican patient without a family history of hereditary sensory motor neuropathy.","variants":[{"Name":"NM_018972.4(GDAP1):c.692C>T (p.Pro231Leu)","Chromosome":"8","Start":"74363051","Stop":"74363051","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19241,"rule_based_match":true,"evidence_text":"c.692C>T (p.Pro231Leu)","llm_judgment":"PRESENT","evidence":"c.692C>T (p.Pro231Leu)","abstract_start":735,"abstract_end":757}]}
{"pmid":"18401176","title":"Papillon-Lefèvre syndrome and malignant melanoma. A high incidence of melanoma development in Japanese palmoplantar keratoderma patients.","abstract":"Papillon-Lefèvre syndrome (PLS) is a rare autosomal-recessive genodermatosis characterized by palmoplantar hyperkeratosis and severe early-onset periodontitis. The development of malignant cutaneous neoplasms within the hyperkeratotic lesions of the syndrome is quite rare. Here, we report on a 51-year-old Japanese woman with PLS associated with recurrent malignant melanoma (MM). Mutation analysis of the cathepsin C gene revealed that the proband was homozygous for a missense mutation, c.415G-->A, which is predicted to result in the amino acid substitution p.G139R. Including our case, 4 families have been described as having PLS with MM, 3 of which are Japanese, implying a high incidence of melanoma development in Japanese PLS patients. We suggest that hereditary palmoplantar keratoderma (PPK) in Japanese patients might be predisposed to MM. A literature review revealed that in 18 cases of MM-associated PPK, 13 (76%) were Japanese, suggesting a high incidence of MM in Japanese PPK patients. This tendency might be attributable to the high frequency of acral lentiginous melanoma in Japanese subjects, in contrast to a lower frequency of this subtype in Caucasians.","variants":[{"Name":"NM_001814.6(CTSC):c.415G>A (p.Gly139Arg)","Chromosome":"11","Start":"88312458","Stop":"88312458","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3086373,"rule_based_match":false,"evidence_text":"c.415G-->A","llm_judgment":"PRESENT","evidence":"c.415G-->A","abstract_start":490,"abstract_end":500}]}
{"pmid":"27826022","title":"Functional characterization of arylsulfatase B mutations in Indian patients with Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI).","abstract":"MPS VI is an autosomal recessive disorder which occurs due to the deficiency of N-acetyl galactosamine-4-sulfatase (Arylsulfatase B - ARSB) involved in catabolism of dermatan sulfate resulting from disease-causing variations in the ARSB gene. Human Gene Mutation Database (HGMD) search revealed 200 different mutations in ARSB worldwide. In the present study we carried out molecular and functional analyses to characterize the mutations reported by us in Indian population. Mutation analysis of 19 MPS VI patients revealed presence of a total of 15 different mutations of which twelve were novel [p.Asp53Asn (c.157G>A; p.D53N), p.Leu98Arg (c.293T>G; p.L98R), p.Tyr103Serfs*9 (c.306_312delCTACCAG+146del; p.Y103Sfs*9), p.Phe166Leufs*18 (c.496delT; p.F166Lfs*18), p.Ile220Serfs*5 (c.659_660delTA; p.I220Sfs*5), p.Ile350Phe (c.1048A>T; p.I350F), p.Trp353* (c.1059G>A; p.W353*), p.His393Arg (c.1178A>G; p.H393R), p.Ser403Tyrfs* (c.1208delC; p.S403Yfs*), p.Pro445Leu (c.1334C>T; p.P445L), p.Trp450Leu (c.1349G>T; p.W450L) and p.Trp450Cys (c.1350G>C; p.W450C)] and three were known mutations [p.Asp54Asn (c.160G>A; p.D54N), p.Ala237Asp (c.710C>A; p.A237D) and p.Ser320Arg (c.960C>G; p.S320R)]. Functional characterization using site-directed mutagenesis followed by cell transfection assays, immunoblot, reverse transcriptase PCR and immunofluorescence studies for the putative pathogenic variants detected in our MPS VI patient cohort helped us to confirm the pathogenic potential of the variants in ARSB.","variants":[{"Name":"NM_000046.5(ARSB):c.1350G>C (p.Trp450Cys)","Chromosome":"5","Start":"78780649","Stop":"78780649","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":550404,"rule_based_match":true,"evidence_text":"c.1350G>C (p.W450C)","llm_judgment":"PRESENT","evidence":"c.1350G>C","abstract_start":1035,"abstract_end":1044},{"Name":"NM_000046.5(ARSB):c.1048A>T (p.Ile350Phe)","Chromosome":"5","Start":"78885678","Stop":"78885678","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":550441,"rule_based_match":true,"evidence_text":"c.1048A>T (p.I350F)","llm_judgment":"PRESENT","evidence":"c.1048A>T","abstract_start":823,"abstract_end":832},{"Name":"NM_000046.5(ARSB):c.1334C>T (p.Pro445Leu)","Chromosome":"5","Start":"78781854","Stop":"78781854","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":550411,"rule_based_match":true,"evidence_text":"c.1334C>T (p.P445L)","llm_judgment":"PRESENT","evidence":"c.1334C>T","abstract_start":964,"abstract_end":973},{"Name":"NM_000046.5(ARSB):c.960C>G (p.Ser320Arg)","Chromosome":"5","Start":"78885766","Stop":"78885766","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":421553,"rule_based_match":true,"evidence_text":"c.960C>G (p.S320R)","llm_judgment":"PRESENT","evidence":"c.960C>G","abstract_start":1168,"abstract_end":1176},{"Name":"NM_000046.5(ARSB):c.160G>A (p.Asp54Asn)","Chromosome":"5","Start":"78985089","Stop":"78985089","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550549,"rule_based_match":true,"evidence_text":"c.160G>A (p.D54N)","llm_judgment":"PRESENT","evidence":"c.160G>A","abstract_start":1100,"abstract_end":1108},{"Name":"NM_000046.5(ARSB):c.157G>A (p.Asp53Asn)","Chromosome":"5","Start":"78985092","Stop":"78985092","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550550,"rule_based_match":true,"evidence_text":"c.157G>A (p.Asp53Asn)","llm_judgment":"PRESENT","evidence":"p.Asp53Asn","abstract_start":598,"abstract_end":608},{"Name":"NM_000046.5(ARSB):c.1178A>G (p.His393Arg)","Chromosome":"5","Start":"78839391","Stop":"78839391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":550426,"rule_based_match":true,"evidence_text":"c.1178A>G (p.H393R)","llm_judgment":"PRESENT","evidence":"c.1178A>G","abstract_start":889,"abstract_end":898}]}
{"pmid":"15712338","title":"Molecular characterization of Italian nevoid basal cell carcinoma syndrome patients.","abstract":"Mutations in the PTCH gene, the human homolog of the Drosophila patched gene, have been found to lead to the autosomal dominant disorder termed Nevoid Basal Cell Carcinoma Syndrome (NBCCS, also called Gorlin Syndrome). Patients display an array of developmental anomalies and are prone to develop a variety of tumors, with multiple Basal Cell Carcinomas occurring frequently. We provide here the results of molecular testing of a set of Italian Nevoid Basal Cell Carcinoma Syndrome patients. Twelve familial patients belonging to 7 kindreds and 5 unaffected family members, 6 non-familial patients and an additional set of 7 patients with multiple Basal Cell Carcinoma but no other criteria for the disease were examined for mutations in the PTCH gene. All of the Nevoid Basal Cell Carcinoma Syndrome patients were found to carry variants of the PTCH gene. We detected nine novel mutations (1 of which occurring twice): 1 missense mutation (c.1436T>G [p.L479R]), 1 nonsense mutation (c.1138G>T [p.E380X]), 6 frameshift mutations (c.323_324ins2, c.2011_2012dup, c.2535_2536dup, c.2577_2583del, c.3000_3005del, c.3050_3051del), 1 novel splicing variant (c.6552A>T) and 3 mutations that have been previously reported (c.3168+5G>A, c.1526G>T [p.G509V], and c.3499G>A [p.G1167R]). None of the patients with multiple Basal Cell Carcinoma but no other criteria for the syndrome, carried germline coding region mutations.","variants":[{"Name":"NM_000264.5(PTCH1):c.1138G>T (p.Glu380Ter)","Chromosome":"9","Start":"95479077","Stop":"95479077","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":836423,"rule_based_match":true,"evidence_text":"c.1138G>T (p.E380X)","llm_judgment":"PRESENT","evidence":"c.1138G>T","abstract_start":984,"abstract_end":993},{"Name":"NM_000264.5(PTCH1):c.3499G>A (p.Gly1167Arg)","Chromosome":"9","Start":"95449891","Stop":"95449891","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":420458,"rule_based_match":true,"evidence_text":"c.3499G>A (p.G1167R)","llm_judgment":"PRESENT","evidence":"c.3499G>A","abstract_start":1253,"abstract_end":1262},{"Name":"NM_000264.5(PTCH1):c.3168+5G>A","Chromosome":"9","Start":"95458008","Stop":"95458008","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":651981,"rule_based_match":true,"evidence_text":"c.3168+5G>A","llm_judgment":"PRESENT","evidence":"c.3168+5G>A","abstract_start":1215,"abstract_end":1226}]}
{"pmid":"37924809","title":"RAB1A haploinsufficiency phenocopies the 2p14-p15 microdeletion and is associated with impaired neuronal differentiation.","abstract":"Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C>T [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and a mosaic missense mutation (c.83T>C [p.Leu28Pro]), were identified in three individuals with similar neurodevelopmental presentations. In rescue experiments, production of the full-length, but not the truncated, RAB1a rescued Golgi structure and cell proliferation in Rab1-depleted cells. In contrast, the missense-variant RAB1a disrupted Golgi structure despite intact Rab1 expression, suggesting a dominant-negative function of the mosaic missense mutation. Knock-down of RAB1A in cultured human embryonic stem cell-derived neurons resulted in impaired neuronal arborization. Finally, RAB1A is located within the 2p14-p15 microdeletion syndrome locus. The similar clinical presentations of individuals with RAB1A loss-of-function mutations and the 2p14-p15 microdeletion syndrome implicate loss of RAB1A in the pathogenesis of neurodevelopmental manifestations of this microdeletion syndrome. Our study identifies a RAB1A-related neurocognitive disorder with speech and motor delay, demonstrates an essential role for RAB1a in neuronal differentiation, and implicates RAB1A in the etiology of the neurodevelopmental sequelae associated with the 2p14-p15 microdeletion syndrome.","variants":[{"Name":"NM_004161.5(RAB1A):c.523C>T (p.Arg175Ter)","Chromosome":"2","Start":"65088588","Stop":"65088588","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3806232,"rule_based_match":true,"evidence_text":"c.523C>T (p.Arg175Ter)","llm_judgment":"PRESENT","evidence":"p.Arg175Ter","abstract_start":422,"abstract_end":433}]}
{"pmid":"26076395","title":"Molecular Basis of β-Thalassemia in the Population of the Aegean Region of Turkey: Identification of A Novel Deletion Mutation.","abstract":"β-Thalassemia (β-thal) is the most common monogenic disorder in Turkey. The aim of this study was to investigate the spectrum of β-thal mutations in the Aegean region of Turkey. The data was derived from 1171 unrelated β-thal subjects, detected in a regional reference hospital between November 2004 and December 2013. Screening for the 22 common mutations was performed using the polymerase chain reaction (PCR)-reverse dot-blot method, and direct automated DNA sequencing for the unknown samples. Thirty-one different β-thal alleles were identified. Seven mutations, namely IVS-I-110 (G > A) (41.7%), IVS-I-1 (G > A) (8.9%), IVS-II-745 (C > G) (8.6%), codon 8 (-AA) (7.7%), IVS-II-1 (G > A) (7.2%), IVS-I-6 (T > C) (6.6%), codon 39 (C > T) (4.6%) accounted for 85.3% of the mutated alleles. Frequencies of the remaining 24 β-thal mutations were less than 2.2%; these included one novel mutation [HBB: c.206_212del (p.Leu69Profs*19)], and four others [-56 (G > C), codon 16 (-C), IVS-I (-3) (C > T) (codon 29), codon 76 (-C)] found in Turkey for the first time. The results will help to prevent severe β-thal through genetic counseling and prenatal diagnosis (PND) in the Aegean region of Turkey.","variants":[{"Name":"NM_000518.5(HBB):c.206_212del (p.Leu69fs)","Chromosome":"11","Start":"5226680","Stop":"5226686","ReferenceAlleleVCF":"GGCACCGA","AlternateAlleleVCF":"G","allel_id":857463,"rule_based_match":true,"evidence_text":"HBB: c.206_212del (p.Leu69Profs*19)","llm_judgment":"PRESENT","evidence":"HBB: c.206_212del (p.Leu69Profs*19)","abstract_start":898,"abstract_end":933}]}
{"pmid":"15605410","title":"Wolfram syndrome in French population: characterization of novel mutations and polymorphisms in the WFS1 gene.","abstract":"Wolfram syndrome (WS), a rare autosomal recessive neurodegenerative disorder, results in most cases from mutations in the WFS1 gene. In this study, a total of 19 patients with Wolfram syndrome and 36 relatives from 17 families were screened for mutations in the WFS1 gene. WFS1 mutations were identified on both alleles in 16 of 19 patients and on 1 allele of 3 patients, showing that WFS1 is the major gene involved in WS in the french population. We identified 25 different mutations, twelve of which were novel. We found 6 frameshift mutations, 6 nonsense mutations, 6 missense mutations, 6 in-frame deletions, and one new homozygous mutation in the splice donor site of exon 7 (c.861+1G>A) resulting in a frameshift. Most patients were compound heterozygotes. No common founder mutation or mutational hot spot were found in the WFS1 gene. Although most mutations occurred in exon 8, in some cases molecular screening requires analysis of all exons, including the non-coding exon 1. We also identified 3 new polymorphisms. Furthermore, genotype-phenotype correlation suggests that the presence of inactivating mutations on both alleles may be associated with an early onset of diabetes mellitus.","variants":[{"Name":"NM_006005.3(WFS1):c.861+1G>A","Chromosome":"4","Start":"6295190","Stop":"6295190","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3859965,"rule_based_match":true,"evidence_text":"c.861+1G>A","llm_judgment":"PRESENT","evidence":"c.861+1G>A","abstract_start":682,"abstract_end":692}]}
{"pmid":"20696606","title":"Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut.","abstract":"Carnitine palmitoyltransferase 1A (CPT1A), encoded by the gene CPT1A, is the hepatic isoform of CPT1 and is a major regulatory point in long-chain fatty acid oxidation. CPT1A deficiency confers risk for hypoketotic hypoglycaemia, hepatic encephalopathy, seizures, and sudden unexpected death in infancy (SUDI). It remains controversial whether the CPT1A gene variant, c.1436C>T (p.P479L), identified in Inuit, First Nations, and Alaska Native infants, causes susceptibility to decompensation, in particular during times of fever and intercurrent illness. Although newborn screening for the P479L variant occurs in some jurisdictions, background knowledge about the presence of the variant in Canadian Aboriginal populations is lacking. In an effort to understand the population implications of the variant in northern Canada, overall frequencies of the variant were assessed. Further studies are underway to determine associated risk. Ethics approval was obtained from university REBs, local research institutes, and with consultation with territorial Aboriginal groups. Newborn screening blood spots from all infants born in 2006 in the three territories were genotyped for the p.P479L variant. p.P479L (c.1436C>T) allele frequencies in the three territories were 0.02, 0.08, and 0.77 in Yukon (n=325), Northwest Territories (n=564), and Nunavut (n=695), respectively. Homozygosity rates were 0%, 3%, and 64%. Aboriginal status was available only in NWT, with allele frequencies of 0.04, 0.44, 0.00, and 0.01 for First Nations, Inuvialuit/Inuit, Métis, and non-Aboriginal populations. Although individual blood spots were not identified for Aboriginal ethnicity in Nunavut infants, ~90% of infants in Nunavut are born to Inuit women. The allele frequency and rate of homozygosity for the CPT1A P479L variant were high in Inuit and Inuvialuit who reside in northern coastal regions. The variant is present at a low frequency in First Nations populations, who reside in areas less coastal than the Inuit or Inuvialuit in the two western territories. The significance of the population and geographic distribution remains unclear, but the high population frequencies of the variant suggest a historically low penetrance for adverse outcomes. Further evidence is needed to determine if there is an increased risk for infant mortality and morbidity and whether newborn screening will be indicated on a population basis.","variants":[{"Name":"NM_001876.4(CPT1A):c.1436C>T (p.Pro479Leu)","Chromosome":"11","Start":"68780662","Stop":"68780662","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76552,"rule_based_match":true,"evidence_text":"c.1436C>T (p.P479L)","llm_judgment":"PRESENT","evidence":"c.1436C>T (p.P479L)","abstract_start":368,"abstract_end":387}]}
{"pmid":"33889637","title":"Melatonin for an obese child with","abstract":"BACKGROUND: Abnormalities in the <i>melanocortin receptor 4</i> (<i>MC4R</i>) gene often lead to obesity, but are rarely associated with other conditions such as epilepsy and sleep disorder.\nCASE SUMMARY: Here, we present a case of a male obese child with a heterozygous variant in <i>MC4R</i> (c.494G>A, p.Arg165Gln) inherited from his father, who presented with disordered sleep and abnormal facial movements. Examination through melatonin rhythm testing and electroencephalography led to a diagnosis of sleep disorder and epilepsy, as his melatonin rhythm was markedly distorted and the electroencephalography revealed epileptic discharges. He received treatment with an antiepileptic drug; however, the therapy was ineffective and the sleep disorder appeared to be deteriorating. Subsequently, we initiated adjuvant treatment with melatonin. Upon re-examination, his body mass index had decreased, the sleep disturbance had resolved, and his seizures were well controlled. Electro-encephalography review was normal, and a typical melatonin rhythm was restored.\nCONCLUSION: We concluded that, in addition to causing obesity, abnormalities in the <i>MC4R</i> gene may contribute to the development of sleep disorders and epilepsy, and that melatonin can be used as an adjuvant therapy to alleviate these symptoms.","variants":[{"Name":"NM_005912.3(MC4R):c.494G>A (p.Arg165Gln)","Chromosome":"18","Start":"60371856","Stop":"60371856","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":347739,"rule_based_match":true,"evidence_text":"c.494G>A, p.Arg165Gln","llm_judgment":"PRESENT","evidence":"c.494G>A, p.Arg165Gln","abstract_start":295,"abstract_end":316}]}
{"pmid":"25556185","title":"Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia.","abstract":"Functional defects of the mitochondrial translation machinery, as a result of mutations in nuclear-encoded genes, have been associated with combined oxidative phosphorylation (OXPHOS) deficiencies. We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver. One of the siblings had a more severe phenotype showing progressive hepatic and renal failure. Whole-exome sequencing revealed a homozygous mutation in the gene encoding mitochondrial ribosomal protein S7 (MRPS7), a c.550A>G transition that encodes a substitution of valine for a highly conserved methionine (p.Met184Val) in both affected siblings. MRPS7 is a 12S ribosomal RNA-binding subunit of the small mitochondrial ribosomal subunit, and is required for the assembly of the small ribosomal subunit. Pulse labeling of mitochondrial protein synthesis products revealed impaired mitochondrial protein synthesis in patient fibroblasts. Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function. Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7. Our data demonstrate the pathogenicity of the identified MRPS7 mutation as a novel cause of mitochondrial RC dysfunction, congenital sensorineural deafness and progressive hepatic and renal failure.","variants":[{"Name":"NM_015971.4(MRPS7):c.550A>G (p.Met184Val)","Chromosome":"17","Start":"75265744","Stop":"75265744","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":482317,"rule_based_match":true,"evidence_text":"c.550A>G (p.Met184Val)","llm_judgment":"PRESENT","evidence":"p.Met184Val","abstract_start":712,"abstract_end":723}]}
{"pmid":"28739549","title":"Mutations in the ABCG8 gene are associated with sitosterolaemia in the homozygous form and xanthelasmas in the heterozygous form.","abstract":"Sitosterol is the most abundant plant sterol found in our diet. Sitosterolemia (OMIM 210250), also known as phytosterolaemia, is a rare autosomal recessive disease caused by the inability to efficiently excrete plant sterol, and is characterized by cutaneous xanthomas and accelerated atherosclerosis. Sitosterolaemia is caused by homozygous or compound heterozygous mutations in either ABCG5 or ABCG8 (both on chromosome 2p21), which encode the sterol efflux transporter ABCG5 (sterolin-1) and ABCG8 (sterolin-2), respectively. To investigate a Tunisian family with several members who manifested with generalized cutaneous xanthomas, whereas others had only isolated xanthelasmas. Genetic analysis was performed based on exome sequencing of DNA obtained from five affected individuals and one unaffected individual from a Tunisian family.\nRESULTS: A novel mutation in the ABCG8 gene, designated c.965-1G>C, was identified by exome sequencing in the members of this family. The homozygous form was associated with generalized cutaneous xanthomatosis while the heterozygous form was linked to isolated xanthelasmas. Our results indicate a gene dosage effect of ABCG8 and suggest that individuals at risk should be followed closely.","variants":[{"Name":"NM_022437.3(ABCG8):c.965-1G>C","Chromosome":"2","Start":"43871975","Stop":"43871975","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":536628,"rule_based_match":true,"evidence_text":"c.965-1G>C","llm_judgment":"PRESENT","evidence":"c.965-1G>C","abstract_start":897,"abstract_end":907}]}
{"pmid":"20434380","title":"Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.","abstract":"Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or \"variant of unknown significance (VUS),\" presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.","variants":[{"Name":"NM_000016.6(ACADM):c.199T>C (p.Tyr67His)","Chromosome":"1","Start":"75732724","Stop":"75732724","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":18636,"rule_based_match":true,"evidence_text":"c.199T>C","llm_judgment":"PRESENT","evidence":"c.199T>C","abstract_start":1046,"abstract_end":1054}]}
{"pmid":"24026985","title":"Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18).","abstract":"BACKGROUND: Bardet-Biedl syndrome (BBS) is a recessive and genetically heterogeneous ciliopathy characterised by retinitis pigmentosa, obesity, kidney dysfunction, postaxial polydactyly, behavioural dysfunction and hypogonadism. 7 of the 17 BBS gene products identified to date assemble together with the protein BBIP1/BBIP10 into the BBSome, a protein complex that ferries signalling receptors to and from cilia.\nMETHODS AND RESULTS: Exome sequencing performed on a sporadic BBS case revealed for the first time a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. This mutation is pathogenic since no BBIP1 protein could be detected in fibroblasts from the patient, and BBIP1[Leu58*] is unable to associate with the BBSome subunit BBS4.\nCONCLUSIONS: These findings identify BBIP1 as the 18th BBS gene (BBS18) and suggest that BBSome assembly may represent a unifying pathomechanism for BBS.","variants":[{"Name":"NM_001195305.3(BBIP1):c.173T>G (p.Leu58Ter)","Chromosome":"10","Start":"110900466","Stop":"110900466","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":131912,"rule_based_match":true,"evidence_text":"NM_001195306: c.173T>G, p.Leu58*","llm_judgment":"PRESENT","evidence":"NM_001195306: c.173T>G, p.Leu58*","abstract_start":541,"abstract_end":573}]}
{"pmid":"26688439","title":"Identification of a recurrent frameshift mutation at the LDLR exon 14 (c.2027delG, p.(G676Afs*33)) causing familial hypercholesterolemia in Saudi Arab homozygous children.","abstract":"Familial hypercholesterolemia (FH) is an autosomal dominant disease, predominantly caused by variants in the low-density lipoprotein (LDL) receptor gene (LDLR). Herein, we describe genetic analysis of severely affected homozygous FH patients who were mostly resistant to statin therapy and were managed on an apheresis program. We identified a recurrent frameshift mutation p.(G676Afs*33) in exon 14 of the LDLR gene in 9 probands and their relatives in an apparently unrelated Saudi families. We also describe a three dimensional homology model of the LDL receptor protein (LDLR) structure and examine the consequence of the frameshift mutation p.(G676Afs*33), as this could affect the LDLR structure in a region involved in dimer formation, and protein stability. This finding of a recurrent mutation causing FH in the Saudi population could serve to develop a rapid genetic screening procedure for FH, and the 3D-structure analysis of the mutant LDLR, may provide tools to develop a mechanistic model of the LDLR function.","variants":[{"Name":"NM_000527.5(LDLR):c.2027del (p.Gly676fs)","Chromosome":"19","Start":"11120408","Stop":"11120408","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":228196,"rule_based_match":true,"evidence_text":"c.2027delG","llm_judgment":"PRESENT","evidence":"c.2027delG","abstract_start":null,"abstract_end":null}]}
{"pmid":"29090612","title":"Hermansky-Pudlak syndrome subtype 5 (HPS-5) novel mutation in a 65 year-old with oculocutaneous hypopigmentation and mild bleeding diathesis: The importance of recognizing a subtle phenotype.","abstract":"Hermansky-Pudlak syndrome (HPS) - characterized by the distinct clinical phenotypes of both oculocutaneous albinism and mild bleeding diathesis-is caused by mutations in genes that have crucial roles in the assembly of cellular organelles (skin melanosomes, platelet delta [dense] granules, lung lamellar bodies, and cytotoxic T-cell lymphocyte granules). Immunodeficiency, pulmonary fibrosis and granulomatous colitis are associated with some, but not all subtypes of HPS, with varying degrees of clinical severity. We describe a patient diagnosed with platelet dense granule storage pool deficiency (DG-SPD) at age 38 years after he presented with spontaneous intracranial hemorrhage. His mild oculocutaneous hypopigmentation was subtle. In the following 27 years, he did not develop severe bleeding nor pulmonary or gastrointestinal complications. A novel homozygous c.1960A>T; p.Lys654* mutation in the HPS-5 protein gene (HPS5) was identified through next generation sequencing, (NGS) which is consistent with the patient's clinical and laboratory phenotypes. This case underscores the importance of recognizing the mild clinical phenotype of HPS-5 and utilization of both laboratory and molecular testing for diagnosis, prognostication, and surveillance for end organ damage in patients affected with HPS.","variants":[{"Name":"NM_181507.2(HPS5):c.1960A>T (p.Lys654Ter)","Chromosome":"11","Start":"18291922","Stop":"18291922","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1062294,"rule_based_match":true,"evidence_text":"c.1960A>T; p.Lys654*","llm_judgment":"PRESENT","evidence":"c.1960A>T; p.Lys654*","abstract_start":870,"abstract_end":890}]}
{"pmid":"28008423","title":"","abstract":"OBJECTIVE: To identify novel dilated cardiomyopathy (DCM) causing genes, and to elucidate the pathological mechanism leading to DCM by utilizing zebrafish as a model organism.\nBACKGROUND: DCM, a major cause of heart failure, is frequently familial and caused by a genetic defect. However, only 50% of DCM cases can be attributed to a known DCM gene variant, motivating the ongoing search for novel disease genes.\nMETHODS: We performed whole exome sequencing (WES) in two multigenerational Italian families and one US family with arrhythmogenic DCM without skeletal muscle defects, in whom prior genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation testing among affected individuals within the families. We performed function assays and generated a zebrafish morpholino knockdown model.\nRESULTS: A novel filamin C gene splicing variant (<i>FLNC</i> c.7251+1 G>A) was identified by WES in all affected family members in the two Italian families. A separate novel splicing mutation (<i>FLNC</i> c.5669-1delG) was identified in the US family. Western blot analysis of cardiac heart tissue from an affected individual showed decreased <i>FLNC</i> protein, supporting a haploinsufficiency model of pathogenesis. To further analyze this model, a morpholino knockdown of the ortholog filamin Cb in zebrafish was created which resulted in abnormal cardiac function and ultrastructure.\nCONCLUSIONS: Using WES, we identified two novel <i>FLNC</i> splicing variants as the likely cause of DCM in three families. We provided protein expression and <i>in vivo</i> zebrafish data supporting haploinsufficiency as the pathogenic mechanism leading to DCM.","variants":[{"Name":"NM_001458.5(FLNC):c.7251+1G>A","Chromosome":"7","Start":"128855315","Stop":"128855315","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":523023,"rule_based_match":true,"evidence_text":"FLNC c.7251+1 G>A","llm_judgment":"PRESENT","evidence":"FLNC</i> c.7251+1 G>A","abstract_start":919,"abstract_end":940}]}
{"pmid":"33105479","title":"NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity.","abstract":"Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.","variants":[{"Name":"NM_021222.3(PRUNE1):c.383G>A (p.Arg128Gln)","Chromosome":"1","Start":"151024658","Stop":"151024658","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":364483,"rule_based_match":true,"evidence_text":"c.383G > A (p.Arg128Gln)","llm_judgment":"PRESENT","evidence":"c.383G > A (p.Arg128Gln)","abstract_start":594,"abstract_end":618}]}
{"pmid":"37921548","title":"Aortic dissection in a young male with persistent ductus arteriosus and a novel variant in MYLK.","abstract":"Pathogenic variants in several genes involved in the function or regulation of smooth muscle cells (SMC) are known to predispose to congenital heart disease and thoracic aortic aneurysm and dissection (TAAD). Variants in MYLK are primarily known to predispose to TAAD, but a growing body of evidence points toward MYLK also playing an essential role in the regulation of SMC contraction outside the aorta. In this case report, we present a patient with co-occurrence of persistent ductus arteriosus (PDA) and thoracic aortic dissection. Genetic analyses revealed a novel splice acceptor variant (c.3986-1G > A) in MYLK, which segregated with disease in the family. RNA-analyses on fibroblasts showed that the variant induced skipping of exon 24, which resulted in an in-frame deletion of 101 amino acids. These findings suggest that MYLK-associated disease could include a broader phenotypic spectrum than isolated TAAD, including PDA and obstructive pulmonary disease. Genetic analyses could be considered in families with TAAD and PDA or obstructive pulmonary disease.","variants":[{"Name":"NM_053025.4(MYLK):c.3986-1G>A","Chromosome":"3","Start":"123657429","Stop":"123657429","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2671383,"rule_based_match":true,"evidence_text":"c.3986-1G > A","llm_judgment":"PRESENT","evidence":"c.3986-1G > A","abstract_start":596,"abstract_end":609}]}
{"pmid":"25346251","title":"An augmented ABCA4 screen targeting noncoding regions reveals a deep intronic founder variant in Belgian Stargardt patients.","abstract":"Autosomal-recessive Stargardt disease (STGD1) is hallmarked by a large proportion of patients with a single heterozygous causative variant in the disease gene ABCA4. Braun et al. () reported deep intronic variants of ABCA4 in STGD1 patients with one coding variant, prompting us to perform an augmented screen in 131 Belgian STGD1 patients with one or no ABCA4 variant to uncover deep intronic causal ABCA4 variants. This revealed a second variant in 28.6% of cases. Twenty-six percent of these carry the same causal variant c.4539+2001G>A (V4). Haplotyping in V4 carriers showed a common region of 63 kb, suggestive of a founder mutation. Genotype-phenotype correlations suggest a moderate-to-severe impact of V4 on the STGD1 phenotype. In conclusion, V4 occurs in a high fraction of Belgian STGD1 patients and represents the first deep intronic founder mutation in ABCA4. This emphasizes the importance of augmented molecular genetic testing of ABCA4 in Belgian STGD1.","variants":[{"Name":"NM_000350.3(ABCA4):c.4539+2001G>A","Chromosome":"1","Start":"94027444","Stop":"94027444","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":551522,"rule_based_match":true,"evidence_text":"c.4539+2001G>A (V4)","llm_judgment":"PRESENT","evidence":"c.4539+2001G>A (V4)","abstract_start":525,"abstract_end":544}]}
{"pmid":"29239743","title":"Phenotypic and Molecular Spectrum of Aicardi-Goutières Syndrome: A Study of 24 Patients.","abstract":"BACKGROUND: Aicardi-Goutières syndrome is a rare genetic neurological disorder with variable clinical manifestations. Molecular detection of specific mutations is required to confirm the diagnosis. The aim of this study was to review the clinical and molecular diagnostic findings in 24 individuals with Aicardi-Goutières syndrome who presented during childhood in an Arab population.\nMATERIALS AND METHODS: We reviewed the records of 24 patients from six tertiary hospitals in different Arab countries. All included patients had a molecular diagnosis of Aicardi-Goutières syndrome.\nRESULTS: Six individuals with Aicardi-Goutières syndrome (25%) had a neonatal presentation, whereas the remaining patients presented during the first year of life. Patients presented with developmental delay (24 cases, 100%); spasticity (24 cases, 100%); speech delay (23 cases, 95.8%); profound intellectual disability (21 cases, 87.5%); truncal hypotonia (21 cases, 87.5%); seizures (eighteen cases, 75%); and epileptic encephalopathy (15 cases, 62.5%). Neuroimaging showed white matter abnormalities (22 cases, 91.7%), cerebral atrophy (75%), and small, multifocal calcifications in the lentiform nuclei and deep cerebral white matter (54.2%). Homozygous mutations were identified in RNASEH2B (54.2%), RNASEH2A (20.8%), RNASEH2C (8.3%), SAMHD1 (8.3%), TREX1 (4.2%), and heterozygous mutations in IFIH1 (4.2%), with c.356A>G (p.Asp119Gly) in RNASEH2B being the most frequent mutation. Three novel mutations c.987delT and c.625 + 1G>A in SAMHD1 gene and c.961G>T in the IFIHI1 gene were identified.\nCONCLUSIONS: This is the largest molecularly confirmed Aicardi-Goutières syndrome cohort from Arabia. By presenting these clinical and molecular findings, we hope to raise awareness of Aicardi-Goutières syndrome and to demonstrate the importance of specialist referral and molecular diagnosis.","variants":[{"Name":"NM_015474.4(SAMHD1):c.625+1G>A","Chromosome":"20","Start":"36930759","Stop":"36930759","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":789389,"rule_based_match":true,"evidence_text":"c.625+1G>A in SAMHD1 gene","llm_judgment":"PRESENT","evidence":"c.625 + 1G>A in SAMHD1 gene","abstract_start":1506,"abstract_end":1533}]}
{"pmid":"37246508","title":"Whole-exome sequencing reveals a likely pathogenic LMNA variant causing hypertrophic cardiomyopathy.","abstract":"OBJECTIVE: We studied the clinical and molecular features of a family with hypertrophic cardiomyopathy (HCM).\nBACKGROUND: A very heterogeneous disease affecting the heart muscle, HCM is mostly caused by variants in the proteins of sarcomeres. The detection of HCM pathogenic variants can affect the handling of patients and their families.\nMETHODS: Whole-exome sequencing (WES) was performed to assess the genetic cause(s) of HCM in a consanguineous Iranian family.\nRESULTS: Missense likely pathogenic variant c.1279C>T (p.Arg427Cys) within exon 7 of the LMNA gene (NM_170707) was found. The segregations were confirmed by polymerase chain reaction-based Sanger sequencing.\nCONCLUSIONS: Variant c.1279C>T (p.Arg427Cys) in the LMNA gene seemed to have been the cause of HCM in the family. A few LMNA gene variants related to HCM phenotypes have been recognized so far. Identifying HCM genetic basis confers significant opportunities to understand how the disease can develop and, by extension, how this progression can be arrested. Our study supports WES effectiveness for first-tier variant screening of HCM in a clinical setting.","variants":[{"Name":"NM_170707.4(LMNA):c.1279C>T (p.Arg427Cys)","Chromosome":"1","Start":"156136335","Stop":"156136335","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":196479,"rule_based_match":true,"evidence_text":"c.1279C>T (p.Arg427Cys)","llm_judgment":"PRESENT","evidence":"c.1279C>T (p.Arg427Cys)","abstract_start":510,"abstract_end":533}]}
{"pmid":"35106624","title":"Osteoporosis-pseudoglioma syndrome in four new patients: identification of two novel LRP5 variants and insights on patients' management using bisphosphonates therapy.","abstract":"This study describes the clinical, radiological, and molecular data of four new patients with osteoporosis-pseudoglioma syndrome and assesses their response to bisphosphonate therapy.\nINTRODUCTION: Osteoporosis-pseudoglioma syndrome (OPPG) is a very rare disorder characterized mainly by severe juvenile osteoporosis and congenital blindness. OPPG is caused by biallelic mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5).\nMETHODS: We present the clinical, radiological, and molecular findings of four new patients with OPPG from Egypt. We also assessed patients' response to oral and intravenous bisphosphonate therapy.\nRESULTS: All patients had reduced bone mineral density (BMD) with variable number of fractures per year, in addition to bone abnormalities and the characteristic eye phenotype associated with OPPG. Mutation analyses of LRP5 gene revealed three different homozygous variants including two novel ones, c.7delG (p.A3Qfs*80) and c.3280G > A (p.E1094K). The c.3280G > A (p.E1094K) was recurrent in two unrelated patients who shared a unique haplotype suggesting a possible founder effect. The use of bisphosphonate therapy was beneficial; however, intravenous bisphosphonate administration led to a more favorable response.\nCONCLUSION: Our study described the phenotypic and genetic features of four patients with OPPG and identified two new LRP5 variants, thus expanding the mutational spectrum of OPPG. In addition, our study reinforces the efficiency of using intravenous bisphosphonates in the management of patients with OPPG.","variants":[{"Name":"NM_002335.4(LRP5):c.3280G>A (p.Glu1094Lys)","Chromosome":"11","Start":"68425145","Stop":"68425145","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":994739,"rule_based_match":true,"evidence_text":"c.3280G > A (p.E1094K)","llm_judgment":"PRESENT","evidence":"c.3280G > A (p.E1094K)","abstract_start":984,"abstract_end":1006}]}
{"pmid":"35034425","title":"Genetic of preimplantation diagnosis of dysmorphic facial features and intellectual developmental disorder (CHDFIDD) without congenital heart defects.","abstract":"BACKGROUND: Cyclin-dependent kinase 13 plays a critical role in the regulation of gene transcription. Recent evidence suggests that heterozygous variants in CDK13 are associated with a syndromic form of mental deficiency and developmental delay, which is inherited in an autosomal dominant manner.\nMETHODS: A mentally retarded mother (33-year-old) and son (10-year-old boy) in our hospital with CDK13 variant (c.2149 (exon 4) G>A. p.Gly717Arg) were detected by whole-exome sequencing (WES). All published CDK13 variant syndrome cases as of November 11, 2021, were searched, and their clinical information was recorded and summarized.\nRESULTS: We studied two patients in a Chinese family with a heterozygous constitutional CDK13 variant (c.2149 (exon 4) G>A. p.Gly717Arg), exhibiting the classical characteristics of dysmorphic facial features and intellectual developmental disorder (CHDFIDD, OMIM # 617360), without congenital heart defects. This is the first reported case of an adult patient with a CDK13 variant that gave birth to the next generation with the same variant. Preimplantation genetic testing for monogenic disease (PGT-M) was performed for the proband and her husband with full informed consent and successfully blocked the inheritance of the disease.\nCONCLUSION: Our study is of great significance for molecular diagnosis and genetic counseling of patients with CDHFIDD and extends the variant spectrum of CDK13.","variants":[{"Name":"NM_003718.5(CDK13):c.2149G>A (p.Gly717Arg)","Chromosome":"7","Start":"39999467","Stop":"39999467","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":362622,"rule_based_match":false,"evidence_text":"c.2149 (exon 4) G>A. p.Gly717Arg","llm_judgment":"PRESENT","evidence":"c.2149 (exon 4) G>A. p.Gly717Arg","abstract_start":410,"abstract_end":442}]}
{"pmid":"30701169","title":"Diabetes Mellitus in a Patient With Lafora Disease: Possible Links With Pancreatic β-Cell Dysfunction and Insulin Resistance.","abstract":"Lafora disease (LD) is a rare autosomal recessive disorder characterized by progressive myoclonic epilepsy followed by continuous neurological decline, culminating in death within 10 years. LD leads to accumulation of insoluble, abnormal, glycogen-like structures called Lafora bodies (LBs). It is caused by mutations in the gene encoding glycogen phosphatase (<i>EPM2A)</i> or the E3 ubiquitin ligase malin (<i>EPM2B/NHLRC1)</i>. These two proteins are involved in an intricate, however, incompletely elucidated pathway governing glycogen metabolism. The formation of EPM2A and malin signaling complex promotes the ubiquitination of proteins participating in glycogen metabolism, where dysfunctional mutations lead to the formation of LBs. Herein, we describe a 13-years-old child with LD due to a <i>NHLRC1</i> (c.386C > A, p.Pro129His) mutation, who has developed diabetes mellitus and was treated with metformin. We discuss how basic mechanisms of LD could be linked to β-cell dysfunction and insulin resistance.","variants":[{"Name":"NM_198586.3(NHLRC1):c.386C>A (p.Pro129His)","Chromosome":"6","Start":"18122221","Stop":"18122221","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":201961,"rule_based_match":true,"evidence_text":"c.386C > A, p.Pro129His","llm_judgment":"PRESENT","evidence":"c.386C > A, p.Pro129His","abstract_start":814,"abstract_end":837}]}
{"pmid":"30791064","title":"Hypomyelinating Leukodystrophy with Spinal Cord Involvement Caused by a Novel Variant in RARS: Report of Two Unrelated Patients.","abstract":"Leukodystrophies are heterogeneous group of genetic white matter disorders with a wide range of neurologic and systemic manifestations. Defects in genes encoding aminoacyl tRNA (transfer ribonucleic acid) synthetase enzymes (aaRSs) are recently identified as the etiology of some leukodystrophies. Herein, we described two unrelated children referred to Children's Medical Center, Tehran, Iran, with developmental delay, nystagmus, seizures, psuedo-bulbar palsy and dystonia. Whole exome sequencing (WES) in both patients identified a homozygous (c.2T > C) variant in exon one of <i>RARS</i> gene, encoding cytoplasmic arginyl-tRNA synthetase. Our finding was confirmed by segregation analysis. In silico analyses of the c.2T > C variant showed its possible pathogenic role due to the absence of the start codon. Severe hypomyelination was the common neuroimaging finding of both cases. Spinal cord involvement was found in one of our patients which was not previously reported in studies. We, therefore, showed that <i>RARS</i>-related hypomyelination might affect spinal cord.","variants":[{"Name":"NM_002887.4(RARS1):c.2T>C (p.Met1Thr)","Chromosome":"5","Start":"168486500","Stop":"168486500","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":368072,"rule_based_match":true,"evidence_text":"c.2T>C","llm_judgment":"PRESENT","evidence":"c.2T > C","abstract_start":547,"abstract_end":555}]}
{"pmid":"36429068","title":"The Predicted Splicing Variant c.11+5G>A in","abstract":"Pathogenic variants in <i>RPE65</i> lead to retinal diseases, causing a vision impairment. In this work, we investigated the pathomechanism behind the frequent <i>RPE65</i> variant, c.11+5G>A. Previous in silico predictions classified this change as a splice variant. Our prediction using novel software's suggested a 124-nt exon elongation containing a premature stop codon. This elongation was validated using midigenes-based approaches. Similar results were observed in patient-derived induced pluripotent stem cells (iPSC) and photoreceptor precursor cells. However, the splicing defect in all cases was detected at low levels and thereby does not fully explain the recessive condition of the resulting disease. Long-read sequencing discarded other rearrangements or variants that could explain the diseases. Subsequently, a more relevant model was employed: iPSC-derived retinal pigment epithelium (RPE) cells. In patient-derived iPSC-RPE cells, the expression of <i>RPE65</i> was strongly reduced even after inhibiting a nonsense-mediated decay, contradicting the predicted splicing defect. Additional experiments demonstrated a cell-specific gene expression reduction due to the presence of the c.11+5G>A variant. This decrease also leads to the lack of the RPE65 protein, and differences in size and pigmentation between the patient and control iPSC-RPE. Altogether, our data suggest that the c.11+5G>A variant causes a cell-specific defect in the expression of <i>RPE65</i> rather than the anticipated splicing defect which was predicted in silico.","variants":[{"Name":"NM_000329.3(RPE65):c.11+5G>A","Chromosome":"1","Start":"68449890","Stop":"68449890","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":104715,"rule_based_match":true,"evidence_text":"c.11+5G>A","llm_judgment":"PRESENT","evidence":"c.11+5G>A","abstract_start":182,"abstract_end":191}]}
{"pmid":"27195816","title":"The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.","abstract":"PURPOSE: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients' phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype.\nMETHODS: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant.\nRESULTS: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints.\nCONCLUSION: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med 19 1, 45-52.","variants":[{"Name":"NM_019066.5(MAGEL2):c.1996dup (p.Gln666fs)","Chromosome":"15","Start":"23645746","Stop":"23645747","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":187954,"rule_based_match":true,"evidence_text":"c.1996dupC (p.Q666fs)","llm_judgment":"PRESENT","evidence":"c.1996dupC (p.Q666fs)","abstract_start":1064,"abstract_end":1085},{"Name":"NM_019066.5(MAGEL2):c.1996del (p.Gln666fs)","Chromosome":"15","Start":"23645747","Stop":"23645747","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":434101,"rule_based_match":true,"evidence_text":"c.1996delC (p.Q666fs)","llm_judgment":"PRESENT","evidence":"c.1996delC (p.Q666fs)","abstract_start":1121,"abstract_end":1142}]}
{"pmid":"29704303","title":"Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.","abstract":"Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non-polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma. She carried a novel de novo missense variant, p.R102S (c.304C > A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night-time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On PHOX2B sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C > G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in PHOX2B who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering PHOX2B mutations when encountering atypical CCHS presentations.","variants":[{"Name":"NM_003924.4(PHOX2B):c.234C>G (p.Tyr78Ter)","Chromosome":"4","Start":"41748377","Stop":"41748377","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":857370,"rule_based_match":true,"evidence_text":"c.234C > G","llm_judgment":"PRESENT","evidence":"c.234C > G","abstract_start":1094,"abstract_end":1104}]}
{"pmid":"22084217","title":"Phenotypic characterization of 3 families with autosomal dominant retinitis pigmentosa due to mutations in KLHL7.","abstract":"OBJECTIVE: To characterize the visual phenotype caused by mutations in the BTB-Kelch protein, KLHL7, responsible for the RP42 form of autosomal dominant retinitis pigmentosa (RP).\nMETHODS: Comprehensive ophthalmic testing included visual acuity, static visual field, kinetic visual field, dark adaptometry, full-field electroretinography, spectral-domain optical coherence tomography, and fundus photography. Longitudinal visual function data (range, 15-27 years) were available for some of the affected individuals.\nRESULTS: We report a phenotypic assessment of 3 unrelated families, each harboring different KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). The fundi showed classic signs of RP. Best-corrected visual acuity was 20/50 or better in at least one eye up to age 65 years. Static and kinetic visual fields showed concentric constriction to central 10° to 20° by age 65 years; 2 patients with Goldmann perimetry exhibited bilateral visual field retention in the far periphery. Both rod and cone full-field electroretinographic amplitudes were substantially lower than normal, with a decline rate of 3% per year in cone 31-Hz flicker response. Rod and cone activation and inactivation variables were abnormal. Spectral-domain optical coherence tomography indicated retention of foveal inner segment-outer segment junction through age 65 years.\nCONCLUSIONS: Mutations in KLHL7 are associated with a late-onset form of autosomal dominant retinal degeneration that preferentially affects the rod photoreceptors. Full-field electroretinographic findings, including recovery kinetics, are consistent with those observed in other forms of autosomal dominant RP.\nCLINICAL RELEVANCE: The phenotypes are similar among patients with 3 types of KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). Strong retention of foveal function and bilateral concentric constriction of visual fields with far periphery sparing may guide mutation screening in autosomal dominant RP.","variants":[{"Name":"NM_001031710.3(KLHL7):c.449G>A (p.Ser150Asn)","Chromosome":"7","Start":"23140775","Stop":"23140775","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16047,"rule_based_match":true,"evidence_text":"c.449G>A","llm_judgment":"PRESENT","evidence":"c.449G>A","abstract_start":637,"abstract_end":645}]}
{"pmid":"31860975","title":"PMS2 germline mutation c.1577delA (p.Asp526Alafs*69)-induced Lynch syndrome-associated endometrial cancer: A case report.","abstract":"RATIONALE: Lynch syndrome (LS) is an autosomal dominant cancer predisposition condition caused by germline heterozygous mutations in mismatch repair (MMR) genes. However, as one of the MMR genes, PMS2 mutation-induced LS-associated endometrial cancer (LSAEC) was rarely reported.\nPATIENT CONCERNS: A 26-year-old female patient suffered from prolonged menstrual period and increased menstrual flow for 2 months.\nDIAGNOSES: The patient was diagnosed with cervix CIN III, endometrial cancer (EC), anemia, and LS.\nINTERVENTIONS: Total hysterectomy, bilateral salpingectomy, pelvic lymphadenectomy were performed for treating EC, while ovariectomy was refused by the patient. The patient underwent postoperative chemotherapy with paclitaxel combined with carboplatin for 6 courses of treatment. Laparoscopic partial enterectomy was applied for treating colon cancer 5 years later after the surgery treatment for EC. Besides, Sanger sequencing and high-throughput genome sequencing were employed to detect the genetic status of the family that included two generations with four members. Immunohistochemistry (IHC) staining was used to identify the function of PMS2 mutation.\nOUTCOMES: The 26-year-old Chinese patient suffered from LSAEC and recovered well after surgery. A PMS2 germline heterozygous mutation (c.1577delA) was confirmed by gene sequencing 5 years later. In addition, PMS2 mutation was verified by IHC. The patient was followed up for 7 years.\nLESSONS: Carrying PMS2 germline mutation (c.1577delA) confers an extremely high susceptibility of suffering from LS-associated cancers. Thus, close clinical monitoring and prophylactic surgery are highly recommended to reduce the morbidity and mortality of LS-associated cancers.","variants":[{"Name":"NM_000535.7(PMS2):c.1577del (p.Asp526fs)","Chromosome":"7","Start":"5987188","Stop":"5987188","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":1977868,"rule_based_match":true,"evidence_text":"c.1577delA","llm_judgment":"PRESENT","evidence":"c.1577delA","abstract_start":1305,"abstract_end":1315}]}
{"pmid":"34562182","title":"A Novel De Novo TUBB3 Variant Causing Developmental Delay, Epilepsy and Mild Ophthalmological Symptoms in a Chinese Child.","abstract":"Heterozygous missense mutations in TUBB3 have been implicated in various neurological disorders encompassing either isolated congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or complex cortical dysplasia with other brain malformations 1 (CDCBM1). The description of seizures in patients with TUBB3 mutations is rare. Here, we reported a patient who had febrile seizures before and focal seizure this time, which was diagnosed as epilepsy in combination with an abnormal EEG. MRI showed hypoplastic corpus callosum. Mutation analysis showed a novel de novo heterozygous variant of the TUBB3 gene (NM_006086), c.763G > A (p.V255I). The patient had global developmental delay, photophobia and elliptic pupils, but lacking extraocular muscle involvement and malformations of cortical development, which might be a less severe phenotype of TUBB3 mutations. This is the first report of elliptic pupils in a patient with TUBB3 mutations and expands the spectrum of TUBB3 phenotypes. It indicates that the phenotypic range of TUBB3 mutations might exist on more of a continuum than as a discrete entity, with severity ranging from mild to severe. Further studies are needed to elucidate the complete spectrum of TUBB3-related phenotypes.","variants":[{"Name":"NM_006086.4(TUBB3):c.763G>A (p.Val255Ile)","Chromosome":"16","Start":"89935214","Stop":"89935214","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360273,"rule_based_match":true,"evidence_text":"c.763G > A (p.V255I)","llm_judgment":"PRESENT","evidence":"c.763G > A (p.V255I)","abstract_start":622,"abstract_end":642}]}
{"pmid":"36010119","title":"Familial Aggregation of a Novel Missense Variant of","abstract":"We present two cases of family members (first cousins) with short extremities caused by a novel variant of COL2A1 gene (NM_001844.5). Case 1 description: A 29-year-old woman presented in her first pregnancy for a second trimester anomaly scan at 23 weeks of gestation. Fetal long bones were measured below the third centile for gestational age. Follow-up scans revealed fetal long bone growth deceleration. Initial genetic work-up was negative and the rest of the maternal follow-up was unremarkable. A male baby weighing 3180 g was delivered at 39 weeks and 4 days of gestation. Case 2 description: A 33-year-old pregnant woman presented for a routine second trimester anomaly scan at 20 weeks and 4 days of gestation. All fetal measurements were appropriate for the gestational age. The routine growth scan performed at 32 weeks showed fetal long bone measurements below the third centile for gestational age, while the follow-up growth scan at 36 weeks and 4 days of gestation revealed consistent, below the third centile, fetal long bone growth. Given that the fetuses of these two cases were related (first cousins), whole exome sequencing (WES) was performed on Case 2. WES revealed a novel heterozygous missense variant c.1132G>A (p. Gly378Ser) of COL2A1 gene (NM_001844.5). Subsequently, targeted genetic sequencing for the variant was performed on Case 1 and the same novel variant was found. Targeted sequencing revealed the same variant in the mother of Case 1 and the father of Case 2 (siblings). A female baby weighing 3200 g was delivered at 40 weeks and 4 days of gestation.","variants":[{"Name":"NM_001844.5(COL2A1):c.1132G>A (p.Gly378Ser)","Chromosome":"12","Start":"47987700","Stop":"47987700","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1184703,"rule_based_match":true,"evidence_text":"c.1132G>A (p. Gly378Ser)","llm_judgment":"PRESENT","evidence":"c.1132G>A (p. Gly378Ser)","abstract_start":1227,"abstract_end":1251}]}
{"pmid":"22520355","title":"Ataxia-telangiectasia presenting with a novel immunodeficiency.","abstract":"Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, and variable degrees of immunodeficiency. Immunologic evaluations of affected patients often reveal anomalies of humoral and cell-mediated immunity. We describe a case of ataxia-telangiectasia with an atypical immunodeficiency and a novel mutation in the ATM gene. The patient presented at age 3 years with a perineal cellulitis associated with profound neutropenia and T-cell lymphopenia. Serum immunoglobulin levels and antibody titers were normal. Neurologic evaluation revealed minimal hypotonia and wide-based gait, without other signs of cerebellar dysfunction. The alpha-fetoprotein level was elevated, and molecular genetic testing confirmed the diagnosis of ataxia-telangiectasia, uncovering a novel ATM gene mutation c.3931C>T (p.Gln1311X) in exon 28. This patient presents a unique immunologic pattern with normal immunoglobulin levels, significant lymphopenia, and profound neutropenia. The diagnosis of ataxia-telangiectasia should be considered in children presenting with gait disorder and immunologic defects, regardless of subtype and severity.","variants":[{"Name":"NM_000051.4(ATM):c.3931C>T (p.Gln1311Ter)","Chromosome":"11","Start":"108284411","Stop":"108284411","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":132835,"rule_based_match":true,"evidence_text":"c.3931C>T (p.Gln1311X)","llm_judgment":"PRESENT","evidence":"c.3931C>T (p.Gln1311X)","abstract_start":868,"abstract_end":890}]}
{"pmid":"29895852","title":"ZP2 pathogenic variants cause in vitro fertilization failure and female infertility.","abstract":"PURPOSE: The oocyte-borne genetic causes leading to fertilization failure are largely unknown. We aimed to identify novel human pathogenic variants (PV) and genes causing fertilization failure.\nMETHODS: We performed exome sequencing for a consanguineous family with a recessive inheritance pattern of female infertility characterized by oocytes with a thin zona pellucida (ZP) and fertilization failure in routine in vitro fertilization. Subsequent PV screening of ZP2 was performed in additional eight unrelated infertile women whose oocytes exhibited abnormal ZP and similar fertilization failure. Expression of ZP proteins was assessed in mutant oocytes by immunostaining, and functional studies of the wild-type and mutant proteins were carried out in CHO-K1 cells.\nRESULTS: Two homozygous s PV (c.1695-2A>G, and c.1691_1694dup (p.C566Wfs*5), respectively) of ZP2 were identified in the affected women from two unrelated consanguineous families. All oocytes carrying PV were surrounded by a thin ZP that was defective for sperm-binding. Immunostaining indicated a lack of ZP2 protein in the thin ZP. Studies in CHO cells showed that both PV resulted in a truncated ZP2 protein, which might be intracellularly sequestered and prematurely interacted with other ZP proteins.\nCONCLUSION: We identified loss-of-function PV of ZP2 causing a structurally abnormal and dysfunctional ZP, resulting in fertilization failure and female infertility.","variants":[{"Name":"NM_001376232.1(ZP2):c.1695-2A>G","Chromosome":"16","Start":"21199880","Stop":"21199880","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":610994,"rule_based_match":true,"evidence_text":"c.1695-2A>G","llm_judgment":"PRESENT","evidence":"c.1695-2A>G","abstract_start":800,"abstract_end":811},{"Name":"NM_001376232.1(ZP2):c.1691_1694dup (p.Cys566fs)","Chromosome":"16","Start":"21201368","Stop":"21201369","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CCCAT","allel_id":610995,"rule_based_match":true,"evidence_text":"c.1691_1694dup (p.C566Wfs*5)","llm_judgment":"PRESENT","evidence":"c.1691_1694dup (p.C566Wfs*5)","abstract_start":817,"abstract_end":845}]}
{"pmid":"30086704","title":"Updated carrier rates for c.35delG (GJB2) associated with hearing loss in Russia and common c.35delG haplotypes in Siberia.","abstract":"BACKGROUND: Mutations in GJB2 gene are a major causes of deafness and their spectrum and prevalence are specific for various populations. The well-known mutation c.35delG is more frequent in populations of Caucasian origin. Data on the c.35delG prevalence in Russia are mainly restricted to the European part of this country. We aimed to estimate the carrier frequency of c.35delG in Western Siberia and thereby update current data on the c.35delG prevalence in Russia. According to a generally accepted hypothesis, c.35delG originated from a common ancestor in the Middle East or the Mediterranean ~ 10,000-14,000 years ago and spread throughout Europe with Neolithic migrations. To test the c.35delG common origin hypothesis, we have reconstructed haplotypes bearing c.35delG and evaluated the approximate age of c.35delG in Siberia.\nMETHODS: The carrier frequency of c.35delG was estimated in 122 unrelated hearing individuals living in Western Siberia. For reconstruction of haplotypes bearing c.35delG, polymorphic D13S141, D13S175, D13S1853 flanking the GJB2 gene, and intragenic rs3751385 were genotyped in deaf patients homozygous for c.35delG (n = 24) and in unrelated healthy individuals negative for c.35delG (n = 67) living in Siberia.\nRESULTS: We present updated carrier rates for c.35delG in Russia complemented by new data on c.35delG carrier frequency in Russians living in Western Siberia (4.1%). Two common D13S141-c.35delG-D13S175-D13S1853 haplotypes, 126-c.35delG-105-202 and 124-c.35delG-105-202, were reconstructed in the c.35delG homozygotes from Siberia. Moreover, identical allelic composition of the two most frequent c.35delG haplotypes restricted by D13S141 and D13S175 was established in geographically remote regions: Siberia and Volga-Ural region (Russia) and Belarus (Eastern Europe).\nCONCLUSIONS: Distribution of the c.35delG carrier frequency in Russia is characterized by pronounced ethno-geographic specificity with a downward trend from west to east. Comparative analysis of the c.35delG haplotypes supports a common origin of c.35delG in some regions of Russia (Volga-Ural region and Siberia) and in Eastern Europe (Belarus). A rough estimation of the c.35delG age in Siberia (about 4800 to 8100 years ago) probably reflects the early formation stages of the modern European population (including the European part of the contemporary territory of Russia) since the settlement of Siberia by Russians started only at the end of sixteenth century.","variants":[{"Name":"NM_004004.6(GJB2):c.35del (p.Gly12fs)","Chromosome":"13","Start":"20189547","Stop":"20189547","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":32043,"rule_based_match":true,"evidence_text":"c.35delG","llm_judgment":"PRESENT","evidence":"c.35delG","abstract_start":162,"abstract_end":170}]}
{"pmid":"32907608","title":"Cloning, expression and enzyme activity delineation of two novel CANT1 mutations: the disappearance of dimerization may indicate the change of protein conformation and even function.","abstract":"BACKGROUND: Desbuquois dysplasia (DBQD) was a rare autosomal recessive skeletal dysplasia. Calcium activated nucleotidase 1 (CANT1) mutation was identified as a common pathogenic change for DBQD type 1 and Kim variant but not for DBQD type 2. To our knowledge, all patients with DBQD type 1 currently found could be explained by mutations in the CANT1 gene, but mutations in the CANT1 gene might not be directly diagnosed as DBQD type 1.\nRESULTS: We have identified two novel CANT1 mutations (mut1: c.594G > A [p.Trp198*], mut2: c.734C > T [p.Pro245Leu]) in three children from a family of Chinese origin for the first time. Two of the three children could be diagnosed as typical DBQD type 1 and one child could not be diagnosed as DBQD type 1 based on the clinical data we had. To further clarify the effect of the two mutations of the CANT1 gene, we studied the CANT1 gene expression and detected the protein secretion and nucleotide enzyme activity through cDNA cloning and expression vectors construction for wild and mutant types. The mut1 was a nonsense mutation which could lead to premature termination and produced the truncated bodies; The CANT1 dimer of mut2 was significantly reduced and even undetectable. The extracellular secretion of mut1 was extremely high while mut2 was significantly reduced compared with the wild type. And mut1 and mut2 also could result in a significant reduction in the activity of CANT1 nucleotidease. From the results we could deduce that the two mutations of the CANT1 gene were the causes of the two cases in this study.\nCONCLUSIONS: Regarding the particularity of the cases reported in this study, the pathogenesis of CANT1 might be more complicated. The genetic and phenotype of three children with the same genetic background need to be further studied. Larger cohort of patients was needed to establish genotype-phenotype correlations in DBQD.","variants":[{"Name":"NM_001159773.2(CANT1):c.734C>T (p.Pro245Leu)","Chromosome":"17","Start":"78995119","Stop":"78995119","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":445906,"rule_based_match":true,"evidence_text":"c.734C>T (p.Pro245Leu)","llm_judgment":"PRESENT","evidence":"p.Pro245Leu","abstract_start":541,"abstract_end":552}]}
{"pmid":"21907016","title":"A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy.","abstract":"Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score ¼ 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].","variants":[{"Name":"NM_206809.4(MOG):c.398C>G (p.Ser133Cys)","Chromosome":"6","Start":"29659628","Stop":"29659628","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":38753,"rule_based_match":true,"evidence_text":"c.398C>G","llm_judgment":"PRESENT","evidence":"c.398C>G","abstract_start":767,"abstract_end":775}]}
{"pmid":"30109272","title":"Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23).","abstract":"Objective: To address the relationship between mutations in the DNA strand break repair protein tyrosyl DNA phosphodiesterase 2 (TDP2) and spinocerebellar ataxia autosomal recessive 23 (SCAR23) and to characterize the cellular phenotype of primary fibroblasts from this disease.\nMethods: We have used exome sequencing, Sanger sequencing, gene editing and cell biology, biochemistry, and subcellular mitochondrial analyses for this study.\nResults: We have identified a patient in the United States with SCAR23 harboring the same homozygous <i>TDP2</i> mutation as previously reported in 3 Irish siblings (c.425+1G>A). The current and Irish patients share the same disease haplotype, but the current patient lacks a homozygous variant present in the Irish siblings in the closely linked gene <i>ZNF193,</i> eliminating this as a contributor to the disease. The current patient also displays symptoms consistent with mitochondrial dysfunction, although levels of mitochondrial function in patient primary skin fibroblasts are normal. However, we demonstrate an inability in patient primary fibroblasts to rapidly repair topoisomerase-induced DNA double-strand breaks (DSBs) in the nucleus and profound hypersensitivity to this type of DNA damage.\nConclusions: These data confirm the <i>TDP2</i> mutation as causative for SCAR23 and highlight the link between defects in nuclear DNA DSB repair, developmental delay, epilepsy, and ataxia.","variants":[{"Name":"NM_016614.3(TDP2):c.425+1G>A","Chromosome":"6","Start":"24658560","Stop":"24658560","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":228225,"rule_based_match":true,"evidence_text":"c.425+1G>A","llm_judgment":"PRESENT","evidence":"c.425+1G>A","abstract_start":604,"abstract_end":614}]}
{"pmid":"26886166","title":"Germline and Somatic DICER1 Mutations in a Well-Differentiated Fetal Adenocarcinoma of the Lung.","abstract":"Germ-line DICER1 mutations predispose to a distinctive tumour predisposition syndrome, the DICER1 syndrome, which is associated with a spectrum of rare mainly childhood-onset tumours. In 2014, a case of well-differentiated fetal adenocarcinoma of the lung (WDFA) was reported in a 16-year-old germ-line DICER1 mutation carrier. Here we report our finding of a characteristic somatic DICER1 RNase IIIb c.5127T>A (p.Asp1709Glu) missense mutation within the WDFA, confirmed using laser capture microscopy. The child has a personal history consistent with the DICER1 syndrome: she developed a multinodular goitre at age 14 years and an ovarian Sertoli-Leydig cell tumour at age 16 years, each of which were found to harbour a somatic DICER1 RNase IIIb missense mutation. The identification of two DICER1 \"hits\" in the WDFA strongly suggests that WDFA is a rare, previously-unrecognised manifestation of DICER1 syndrome.","variants":[{"Name":"NM_177438.3(DICER1):c.5127T>A (p.Asp1709Glu)","Chromosome":"14","Start":"95094125","Stop":"95094125","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":921312,"rule_based_match":true,"evidence_text":"c.5127T>A (p.Asp1709Glu)","llm_judgment":"PRESENT","evidence":"c.5127T>A (p.Asp1709Glu)","abstract_start":401,"abstract_end":425}]}
{"pmid":"28442722","title":"Mutational screening of SLC39A5, LEPREL1 and LRPAP1 in a cohort of 187 high myopia patients.","abstract":"High myopia (HM) is a leading cause of mid-way blindness with a high heritability in East Asia. Although only a few disease genes have been reported, a small proportion of patients could be identified with genetic predispositions. In order to expand the mutation spectrum of the causative genes in Chinese adult population, we investigated three genes, SLC39A5, LEPREL1 and LRPAP1, in a cohort of 187 independent Chinese patients with high myopia. Sanger sequencing was used to find possible pathogenic mutations, which were further screened in normal controls. After a pipeline of database and predictive assessments filtering, we, thereby, identified totally seven heterozygous mutations in the three genes. Among them, three novel missense mutations, c.860C > T, p.Pro287Leu and c.956G > C, p.Arg319Thr in SLC39A5, c.1982A > G, p.Lys661Arg in LEPREL1, were identified as potentially causative mutations. Additionally, the two heterozygous mutations (c.1582G > A, p.Ala528Thr; c.1982A > G, p.Lys661Arg) in one patient in LEPREL1 gene were reported in this study. Our findings will not only augment the mutation spectrum of these three genes, but also provide insights of the contribution of these genes to adult high myopia in Chinese. However, further studies are still needed to address the pathogenicity of each of the mutations reported in this study.","variants":[{"Name":"NM_018192.4(P3H2):c.1982A>G (p.Lys661Arg)","Chromosome":"3","Start":"189964010","Stop":"189964010","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":827782,"rule_based_match":true,"evidence_text":"c.1982A>G, p.Lys661Arg","llm_judgment":"PRESENT","evidence":"c.1982A > G, p.Lys661Arg","abstract_start":818,"abstract_end":842}]}
{"pmid":"18302678","title":"PTCH germline mutations in Chinese nevoid basal cell carcinoma syndrome patients.","abstract":"OBJECTIVES: PTCH, the human homologue of the Drosophila segment polarity gene, patched, has been identified as the gene responsible for nevoid basal cell carcinoma syndrome. The aim of this study was to investigate PTCH gene mutation in Chinese patients with nevoid basal cell carcinoma syndrome.\nMATERIALS AND METHODS: DNA was isolated from both odontogenic keratocyst tissue and peripheral blood of five patients with syndrome and one patient with only multiple odontogenic keratocysts, and mutational analysis of the PTCH gene performed by direct sequencing after amplification of all 23 exons by polymerase chain reaction (PCR).\nRESULTS: A previously reported germline mutation (c.2619C>A) was identified in two familial cases involving the mother and the daughter, with the mother also carrying a novel somatic mutation (c.361_362insGAGC). Three novel germline PTCH mutations (c.1338_1339insGCG, c.331delG and c.1939A>T) were detected in three unrelated patients with syndrome. The patient with multiple odontogenic keratocysts who failed to fulfill the diagnostic criteria of the syndrome also carried a novel germline mutation (c.317T>G).\nCONCLUSION: The frequent germline PTCH mutations detected in our series provide further evidence for the crucial role of PTCH in the pathogenesis of nevoid basal cell carcinoma syndrome in Chinese.","variants":[{"Name":"NM_000264.5(PTCH1):c.317T>G (p.Leu106Arg)","Chromosome":"9","Start":"95506484","Stop":"95506484","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":420497,"rule_based_match":true,"evidence_text":"c.317T>G","llm_judgment":"PRESENT","evidence":"c.317T>G","abstract_start":1135,"abstract_end":1143},{"Name":"NM_000264.5(PTCH1):c.1939A>T (p.Ser647Cys)","Chromosome":"9","Start":"95469062","Stop":"95469062","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1448366,"rule_based_match":true,"evidence_text":"c.1939A>T","llm_judgment":"PRESENT","evidence":"c.1939A>T","abstract_start":915,"abstract_end":924}]}
{"pmid":"31507634","title":"Two Novel","abstract":"Neurofibromatosis type I (NF1) is one of the most common autosomal dominant disorders, since the estimated incidence is one in 3,500 births. In this study, we present bioinformatical and functional characterization of two novel splicing <i>NF1</i> variants, detected in NF1 patients. Patient 1, carrying <i>NF1</i>:c.122A>T, which introduces a new exonic 5' donor splice site, was diagnosed with hormone-positive, Her-2-negative breast cancer at the age of 47. She had an atypical presentation of NF1, with few café-au-lait spots and no Lisch nodules. Patient developed a hemothorax due to subclavian artery rupture, which has previously been described as an extremely rare complication of NF1. Patient 2, carrying <i>NF1</i>:c.7395-17T>G that creates a new intronic 3' acceptor splice site, had quite a typical clinical presentation of NF1: formations on her tongue in the region of her left metacarpal bones and on her left foot, plexiform neurofibroma in her pelvis, several café-au-lait spots, and axillary freckling. She was also diagnosed with cognitive impairment. In the report, we are presenting two novel variants which were successfully classified based on NGS and mRNA analysis. Based on results of mRNA analysis, both variants were classified as likely pathogenic according to ACMG guidelines applying evidence categories PS3, PM2, PP3, and PP1 supporting. By characterizing those two novel <i>NF1</i> splicing variants, we have confirmed the neurofibromatosis type I phenotype in the two probands.","variants":[{"Name":"NM_001042492.3(NF1):c.122A>T (p.Glu41Val)","Chromosome":"17","Start":"31156044","Stop":"31156044","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":578002,"rule_based_match":true,"evidence_text":"NF1:c.122A>T","llm_judgment":"PRESENT","evidence":"c.122A>T","abstract_start":315,"abstract_end":323}]}
{"pmid":"36544182","title":"Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations.","abstract":"OBJECTIVES: We aimed to describe the behavior among Chinese ovarian cancer patients with RAD51D germline mutations at our institution.\nMETHODS: Next-generation sequencing (NGS) was conducted for the entire coding regions and exon/intron boundaries of the RAD51D genes in 781 Chinese ovarian cancer patients treated at our institution from January 1, 2015 to August 1, 2021. Clinicopathological characteristics, treatment modalities, and outcomes were assessed for ovarian cancer patients with RAD51D germline mutations.\nRESULTS: RAD51D germline pathogenic mutations were detected in 1.7% (13/781) of patients in this cohort. RAD51D c. 270_271dup (p. Lys91fs) mutation was the most common mutation which was found in 7 patients (7/13, 53.1%). Patients median age at diagnosis was 58 years (range: 45-69 years). 46.2% (6/13) of them were diagnosed after 60 years. Only 1 patient (1/13, 7.7%) had a family history of ovarian or breast cancer. And 1 patient (1/13, 7.7%) had a personal history of breast cancer. The FIGO 2014 distribution by stage was: stage II in 1 patient (7.7%), stage III in 9 patients (69.2%) and stage IV in 3 patient (23.1%). 92.3% (12/13) patients had high-grade serous carcinoma. 2 patients (2/13, 15.4%) had a primary peritoneal cancer. The majority of patients in the entire cohort were reported to be platinum sensitive (92.3%, 12/13) with a platinum-free interval (PFI) of > 6 months. For patients who received PARPis for 2nd line maintenance treatment (n = 5), 2 patients discontinued PARPis treatment after 33.5 and 8.1 months of duration. Other 3 patients are still on therapy with a duration of 2.4, 13.8 and 30.1 months at the date of data cutoff. 1 patient received PARPi as salvage treatment with a duration of only 1.2 months. Nine patients (9/13, 69.2%) relapsed during follow up and all of them relapsed within 2 years after diagnosis, among which 88.9% (8/9) were classified as platinum-sensitive recurrence (PSR), and only 1 patient was classified as platinum-resistant recurrence (PRR). Median PFS for the entire cohort was 17.3 months. Median PFS for the PSR subgroup was 15.9 months. 2 patients died during follow-up. The OS of these 2 patients was 17.2 and 39.6 months. The 5-year OS rate was 67.5%.\nCONCLUSIONS: RAD51D germline mutations are more frequent in Chinese ovarian cancer patients than other population. Few patients have a family history of ovarian or breast cancer, and personal history of breast cancer. Most patients are diagnosed after 50 years. The sensitivity to PARP inhibitors of patients with RAD51D germline mutations need a further analysis.","variants":[{"Name":"NM_002878.4(RAD51D):c.270_271dup (p.Lys91fs)","Chromosome":"17","Start":"35107439","Stop":"35107440","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TTA","allel_id":242729,"rule_based_match":true,"evidence_text":"RAD51D c. 270_271dup (p. Lys91fs)","llm_judgment":"PRESENT","evidence":"RAD51D c. 270_271dup (p. Lys91fs)","abstract_start":625,"abstract_end":658}]}
{"pmid":"23280318","title":"Screening of SLC26A4 gene in autoimmune thyroid diseases.","abstract":"The Pendred syndrome (PS) gene, SLC26A4, was involved in the genetic susceptibility of autoimmune thyroid disease (AITD) in Tunisian population. Recently, functional assays have shown a differential expression of SLC26A4 gene between Graves' disease (GD) and Hashimoto's thyroiditis (HT). Here, by the mean of DHPLC and HRM, we explored the 21 exons and their flanking intronic sequences of 128 patients affected with GD (n = 64) or HT (n = 64). The pathogenic effect of identified variations on splice was investigated using the web server HSF. Eighteen allelic variations were identified and ranged on missense, sens and splice variations. Nine identified variations (c.-66C>G, c.898A>C, c.1002-9A>C, c.1061T>C, c.1544 + 9G>T, c.1545-5T>G, c.1790T>C, c.1826T>G, c.2139T>G) were previously reported in hearing impairment studies. Forty-seven per cent (30/64) of GD patients and 37,5% (24/64) of HT patients present at least one variant in the explored sequences. Moreover, the analysis of the variant distribution between HT (9 (5'UTR), 12 exonic and 13 intronic) and GD (18 (5'UTR), 13 exonic and 5 intronic) patients showed a significant difference (χ² = 6.54, 2df, P = 0.03). Interestingly, missense changes (I300L, p.M283I, F354S and p.L597S) affected conserved residues of pendrin. On the other hand, the HSF analyses ascertain that some variants identified in HT disease are predicted to have a pathogenic effect on splice. In conclusion, our analysis of SLC26A4 sequence variations suggested a distinct genetics basis between HT and GD patients, which should be confirmed on a large cohort.","variants":[{"Name":"NM_000441.2(SLC26A4):c.898A>C (p.Ile300Leu)","Chromosome":"7","Start":"107683334","Stop":"107683334","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":52739,"rule_based_match":true,"evidence_text":"c.898A>C","llm_judgment":"PRESENT","evidence":"c.898A>C","abstract_start":680,"abstract_end":688},{"Name":"NM_000441.2(SLC26A4):c.1545-5T>G","Chromosome":"7","Start":"107698037","Stop":"107698037","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":52682,"rule_based_match":true,"evidence_text":"c.1545-5T>G","llm_judgment":"PRESENT","evidence":"c.1545-5T>G","abstract_start":729,"abstract_end":740},{"Name":"NM_000441.2(SLC26A4):c.1002-9A>C","Chromosome":"7","Start":"107689044","Stop":"107689044","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":52659,"rule_based_match":true,"evidence_text":"c.1002-9A>C","llm_judgment":"PRESENT","evidence":"c.1002-9A>C","abstract_start":690,"abstract_end":701},{"Name":"NM_000441.2(SLC26A4):c.1061T>C (p.Phe354Ser)","Chromosome":"7","Start":"107689112","Stop":"107689112","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":52662,"rule_based_match":true,"evidence_text":"c.1061T>C","llm_judgment":"PRESENT","evidence":"c.1061T>C","abstract_start":703,"abstract_end":712}]}
{"pmid":"19085939","title":"Fifteen novel mutations in PKLR associated with pyruvate kinase (PK) deficiency: structural implications of amino acid substitutions in PK.","abstract":"Pyruvate kinase (PK) deficiency is a rare disease but an important cause of hereditary nonspherocytic hemolytic anemia. The disease is caused by mutations in the PKLR gene and shows a marked variability in clinical expression. We report on the molecular characterization of 38 PK-deficient patients from 35 unrelated families. Twenty-nine different PKLR mutations were detected, of which 15 are reported here for the first time. Two novel deletions are reported: c.142_159del18 is the largest in-frame deletion described thus far and predicts the loss of six consecutive amino acids (p.Thr48_Thr53del) in the N-terminal domain of red blood cell PK. The other deletion removes nearly 1.5 kb of genomic DNA sequence (c.1618+37_2064del1477) and is one of a few large deletional mutants in PKLR. In addition, 13 novel point mutations were identified: one nonsense mutant, p.Arg488X, and 12 missense mutations, predicting the substitution of a single amino acid: p.Arg40Trp, p.Leu73Pro, p.Ile90Asn, p.Gly111Arg, p.Ala154Thr, p.Arg163Leu, p.Gly165Val, p.Leu272Val, p.Ile310Asn, p.Val320Leu, p.Gly358Glu, and p.Leu374Pro. We used the three-dimensional (3D) structure of recombinant human tetrameric PK to evaluate the protein structural context of the affected residues. In addition, in selected patients red blood cell PK antigen levels were measured by enzyme-linked immunosorbent assay (ELISA). Collectively, the results provided us with a rationale for the observed enzyme deficiency and contribute to both a better understanding of the genotype-to-phenotype correlation in PK deficiency as well as the enzyme's structure and function.","variants":[{"Name":"NM_000298.6(PKLR):c.331G>A (p.Gly111Arg)","Chromosome":"1","Start":"155295709","Stop":"155295709","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":513235,"rule_based_match":false,"evidence_text":"p.Gly111Arg","llm_judgment":"PRESENT","evidence":"p.Gly111Arg","abstract_start":994,"abstract_end":1005},{"Name":"NM_000298.6(PKLR):c.118C>T (p.Arg40Trp)","Chromosome":"1","Start":"155300263","Stop":"155300263","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3539109,"rule_based_match":false,"evidence_text":"c.118C>T (p.Arg40Trp)","llm_judgment":"PRESENT","evidence":"p.Arg40Trp","abstract_start":958,"abstract_end":968}]}
{"pmid":"34860437","title":"Mutational spectrum of congenital long QT syndrome in Turkey; identification of 12 novel mutations across KCNQ1, KCNH2, SCN5A, KCNJ2, CACNA1C, and CALM1.","abstract":"INTRODUCTION: Long QT syndrome (LQTS) is of great importance as it is the most common cause of sudden cardiac death in childhood. The diagnosis is made by the prolongation of the QTc interval on the electrocardiography. However, clinical heterogeneity and nondiagnostic QTc intervals may cause a delay in the diagnosis. In such cases, genetic tests such as next-generation sequencing (NGS) panel analysis enable a definitive diagnosis. We present the first study that aimed to expand the LQTS's mutational spectrum by NGS panel analysis from Turkey.\nMETHODS: Fifty-seven unrelated patients with clinically diagnosed LQTS were investigated using an NGS panel that includes six LQTS-related genes. Clinical aspects, outcome, and molecular analysis results were reviewed.\nRESULTS: Pathogenic (53%)/likely pathogenic (23%)/variant of unknown significance (4%) variants were detected in any of the genes examined in 79% of the patients. Among all detected variants, KCNQ1(71%) was the most common gene, followed by SCN5A (11%), KCNH2 (10%), CALM1 (5%), and CACNA1C (3%). Twelve novel variants were detected. Among the variants in KCNQ1, the c.1097G>A variant was present in 42% of patients. This variant also composed 31% of the variants detected in all of the genes.\nCONCLUSION: Our study expands the spectrum of the variations associated with LQTS with twelve novel variants in five genes. And also it draws attention to the frequency of the KCNQ1 c.1097G>A variant and forms the basis for new studies to determine the possible founder effect in the Turkish population. Furthermore, identifying new variants and clinical findings has importance in elaborating the roles of related genes in pathophysiology and determining the variable expression and incomplete penetration rates in this syndrome.","variants":[{"Name":"NM_000218.3(KCNQ1):c.1097G>A (p.Arg366Gln)","Chromosome":"11","Start":"2585276","Stop":"2585276","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67624,"rule_based_match":true,"evidence_text":"c.1097G>A","llm_judgment":"PRESENT","evidence":"c.1097G>A","abstract_start":1136,"abstract_end":1145}]}
{"pmid":"21835061","title":"Congenital hyperinsulinism in the north-east Netherlands. Clinical features and DNA diagnostics in 22 children","abstract":"OBJECTIVE: To describe the clinical features and relevant genetic mutations in 22 children with congenital hyperinsulinism in the north-east Netherlands.\nDESIGN: Retrospective, descriptive study.\nMETHOD: Children born between June 1988 and June 2009, who were presented at the academic medical centres of Nijmegen and Groningen were included. They were clinically suspected of having congenital hyperinsulinism and DNA diagnostics were carried out. Clinical course, laboratory results, genetic data, interventions, follow-up data and patient demographics were documented.\nRESULTS: A total of 22 children from 20 families were included. Of these 22 children, 5 were born macrosomic. In 16 children the disorder was picked up within the first 4 days of life either through glucose screening of premature children or because they had symptoms. All children were treated with diazoxide; 12 (55%) did not respond to this treatment. Ultimately, 9 children underwent pancreatectomy. Five children had focal type congenital hyperinsulinism. In 15 children 13 different mutations were identified in relevant genes. We found 9 different mutations in the ABCC8-gene, including 2 novel mutations (c.2117-2A>T and c.4076C>G), 1 in the KCNJ11 gene, 1 in the GCK gene, and 2 in the GLUD1 gene. In the villages of Aalten and Silvolde a high prevalence of congenital hyperinsulinism was observed (1 in 6930), probably due to a common ancestor.\nCONCLUSION: The clinical characteristics of Dutch children with congenital hyperinsulinism were comparable with those reported in other study populations. We found two novel mutations in the ABCC8 gene. The mutations in the north-east Netherlands were diverse; no one mutation occurred more frequently than any other.","variants":[{"Name":"NM_000352.6(ABCC8):c.4076C>G (p.Pro1359Arg)","Chromosome":"11","Start":"17396959","Stop":"17396959","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3498706,"rule_based_match":true,"evidence_text":"c.4076C>G","llm_judgment":"PRESENT","evidence":"c.4076C>G","abstract_start":1201,"abstract_end":1210},{"Name":"NM_000352.6(ABCC8):c.2117-2A>T","Chromosome":"11","Start":"17427156","Stop":"17427156","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":959982,"rule_based_match":true,"evidence_text":"c.2117-2A>T","llm_judgment":"PRESENT","evidence":"c.2117-2A>T","abstract_start":1185,"abstract_end":1196}]}
{"pmid":"22981119","title":"A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment.","abstract":"CaBPs are a family of Ca(2+)-binding proteins related to calmodulin and are localized in the brain and sensory organs, including the retina and cochlea. Although their physiological roles are not yet fully elucidated, CaBPs modulate Ca(2+) signaling through effectors such as voltage-gated Ca(v) Ca(2+) channels. In this study, we identified a splice-site mutation (c.637+1G>T) in Ca(2+)-binding protein 2 (CABP2) in three consanguineous Iranian families affected by moderate-to-severe hearing loss. This mutation, most likely a founder mutation, probably leads to skipping of exon 6 and premature truncation of the protein (p.Phe164Serfs(∗)4). Compared with wild-type CaBP2, the truncated CaBP2 showed altered Ca(2+) binding in isothermal titration calorimetry and less potent regulation of Ca(v)1.3 Ca(2+) channels. We show that genetic defects in CABP2 cause moderate-to-severe sensorineural hearing impairment. The mutation might cause a hypofunctional CaBP2 defective in Ca(2+) sensing and effector regulation in the inner ear.","variants":[{"Name":"NM_016366.3(CABP2):c.637+1G>T","Chromosome":"11","Start":"67519792","Stop":"67519792","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":588259,"rule_based_match":true,"evidence_text":"c.637+1G>T","llm_judgment":"PRESENT","evidence":"c.637+1G>T","abstract_start":366,"abstract_end":376}]}
{"pmid":"22275165","title":"SEPT12 mutations cause male infertility with defective sperm annulus.","abstract":"Septins are members of the GTPase superfamily, which has been implicated in diverse cellular functions including cytokinesis and morphogenesis. Septin 12 (SEPT12) is a testis-specific gene critical for the terminal differentiation of male germ cells. We report the identification of two missense SEPT12 mutations, c.266C>T/p.Thr89Met and c.589G>A/p.Asp197Asn, in infertile men. Both mutations are located inside the GTPase domain and may alter the protein structure as suggested by in silico modeling. The p.Thr89Met mutation significantly reduced guanosine-5'-triphosphate (GTP) hydrolytic activity, and the p.Asp197Asn mutation (SEPT12(D197N)) interfered with GTP binding. Both mutant SEPT12 proteins restricted the filament formation of the wild-type SEPT12 in a dose-dependent manner. The patient carrying SEPT12(D197N) presented with oligoasthenozoospermia, whereas the SEPT12(T89M) patient had asthenoteratozoospermia. The characteristic sperm pathology of the SEPT12(D197N) patient included defective annulus with bent tail and loss of SEPT12 from the annulus of abnormal sperm. Our finding suggests loss-of-function mutations in SEPT12 disrupted sperm structural integrity by perturbing septin filament formation.","variants":[{"Name":"NM_144605.5(SEPTIN12):c.266C>T (p.Thr89Met)","Chromosome":"16","Start":"4786006","Stop":"4786006","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45784,"rule_based_match":true,"evidence_text":"c.266C>T/p.Thr89Met","llm_judgment":"PRESENT","evidence":"c.266C>T/p.Thr89Met","abstract_start":314,"abstract_end":333},{"Name":"NM_144605.5(SEPTIN12):c.589G>A (p.Asp197Asn)","Chromosome":"16","Start":"4783690","Stop":"4783690","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45785,"rule_based_match":true,"evidence_text":"c.589G>A/p.Asp197Asn","llm_judgment":"PRESENT","evidence":"c.589G>A/p.Asp197Asn","abstract_start":338,"abstract_end":358}]}
{"pmid":"34899149","title":"Intracranial Calcification Associated with 3-Methylcrotonyl-CoA Carboxylase Deficiency.","abstract":"3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency is the most frequent organic aciduria detected in newborn screening programs. It demonstrates a variable heterogeneous clinical phenotype, ranging from neonatal onset with severe neurological disorders to asymptomatic adult forms. Herein, we report the first 2 related cases of 3-MCC deficiency presenting with intracranial calcification in the literature. A girl and a boy aged 3 years, 9 months and 4 years were included in the study. The main clinical manifestations were acquired microcephaly, global developmental delay, intractable seizures, mild feeding difficulty, and intermittent dystonic contractions. On physical and neurological examinations, their weights, heights, and head circumferences were below the 3rd percentile, they had acquired microcephaly, truncal hypotonia, upper and lower limb spasticity, hyperreflexia, positive bilateral Babinski signs, and clonus. The detailed biochemical and metabolic tests were unremarkable, except blood 3-hydroxyisovalerylcarnitine (C5OH) was slightly increased in case 1. Cranial computed tomography demonstrated mild cerebral and cerebellar atrophy as well as bilateral periventricular and thalamic calcifications in both cases. We identified a homozygous mutation of c.1015G>A (p.V339M) in the <i>MCCC2</i>gene, and the mutation was confirmed by Sanger sequencing. To the best of our knowledge, our cases are the first reported describing intracranial calcification in cases with 3-MCC deficiency. This report expands on the underlying causes of intracranial calcifications and suggests that 3-MCC deficiency may have intracranial calcifications on bilateral thalamus and periventricular white matters. If clinical findings show intracranial calcification, 3-MCC deficiency should also be kept in mind.","variants":[{"Name":"NM_022132.5(MCCC2):c.1015G>A (p.Val339Met)","Chromosome":"5","Start":"71641018","Stop":"71641018","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":200099,"rule_based_match":true,"evidence_text":"c.1015G>A (p.V339M)","llm_judgment":"PRESENT","evidence":"c.1015G>A (p.V339M)","abstract_start":1277,"abstract_end":1296}]}
{"pmid":"23941127","title":"Evaluation of the need for routine clinical testing of PALB2 c.1592delT mutation in BRCA negative Northern Finnish breast cancer families.","abstract":"BACKGROUND: Testing for mutations in the BRCA1 and BRCA2 genes among high-risk breast cancer patients has become a routine practice among clinical geneticists. Unfortunately, however, the genetic background of a majority of the cases coming to the clinics remains currently unexplained, making genetic counseling rather challenging. In recent years it has become evident world-wide that also women carrying a heterozygous germline mutation in PALB2 are at significantly increased risk of getting breast cancer. We have previously studied the clinical as well as biological impact of the PALB2 c.1592delT founder mutation occurring in about 1% of Finnish breast cancer patients unselected for their family history of disease, and our results demonstrated a 40% increased breast cancer risk by age 70 for female mutation carriers. Thus, this relatively common mutation in PALB2 is associated with a high risk of developing breast cancer. The aim of the current study was to analyze whether female index individuals of breast cancer families who had tested negative for germline mutations in BRCA1/BRCA2 as part of genetic counseling services should be offered mutation testing for PALB2 c.1592delT.\nMETHODS: The study cohort consisted of altogether 223 individuals who had contacted the Department of Clinical Genetics at the Oulu University Hospital in Finland between the years 1997 and 2011 for counseling on hereditary breast and/or ovarian cancer risk. 101 of them met our inclusion criteria. Of these, 10 persons were now deceased, but 6 of them had participated in one of our previous studies on PALB2. Seventy (77%) of the remaining 91 persons responded positively to our study invitation. Chart review of updated pedigree data led to the exclusion of 14 further individuals not meeting the selection criteria.\nRESULT: Of the 56 alive affected female individuals screened for PALB2 c.1592delT, altogether two (3.6%) tested positive for this mutation. In addition, of the previously tested but now deceased 6 persons eligible for the current study, one more mutation carrier was observed. Therefore, overall 4.8% (3/62) of the tested individuals belonging to the Northern Finnish 1997-2011 study cohort turned out to be carriers of the PALB2 c.1592delT allele.\nCONCLUSIONS: Given the potential benefits versus harms of this testing, the result of our study suggest that PALB2 c.1592delT should be a routine part of the genetic counseling protocol for Finnish high-risk breast cancer cases tested negative for mutations in BRCA1/BRCA2.","variants":[{"Name":"NM_024675.4(PALB2):c.1592del (p.Leu531fs)","Chromosome":"16","Start":"23634954","Stop":"23634954","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":132119,"rule_based_match":true,"evidence_text":"PALB2 c.1592delT","llm_judgment":"PRESENT","evidence":"PALB2 c.1592delT","abstract_start":587,"abstract_end":603}]}
{"pmid":"27008870","title":"Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.","abstract":"A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10<sup>-8</sup> Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.","variants":[{"Name":"NM_007294.4(BRCA1):c.594-2A>C","Chromosome":"17","Start":"43095924","Stop":"43095924","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":46242,"rule_based_match":true,"evidence_text":"BRCA1 c.594-2A > C (IVS9-2A > C)","llm_judgment":"PRESENT","evidence":"BRCA1 c.594-2A > C (IVS9-2A > C)","abstract_start":107,"abstract_end":139},{"Name":"NM_007294.4(BRCA1):c.641A>G (p.Asp214Gly)","Chromosome":"17","Start":"43095875","Stop":"43095875","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":46245,"rule_based_match":true,"evidence_text":"c.641A>G","llm_judgment":"PRESENT","evidence":"c.641A > G","abstract_start":633,"abstract_end":643}]}
{"pmid":"28488385","title":"The c.797 G>A (p.R266K) cystathionine β-synthase mutation causes homocystinuria by affecting protein stability.","abstract":"Mutations in the cystathionine beta-synthase (CBS) gene are the cause of classical homocystinuria, the most common inborn error in sulfur metabolism. The c.797 G>A (p.R266K) mutation in CBS was originally described in several Norwegian pyridoxine responsive CBS deficient patients, and heterologous gene expression studies have shown that the protein has near wild-type levels of enzyme activity. Here, we characterize a transgenic mouse lacking endogenous Cbs and expressing p.R266K human CBS protein from a zinc inducible metallothionein promoter (Tg-R266K Cbs<sup>-/-</sup> ). Unlike mice expressing other mutant CBS alleles, the Tg-R266K transgene is unable to efficiently rescue neonatal lethality of Cbs<sup>-/-</sup> on a C57BL/6J background. On a C3H/HeJ background, zinc-induced Tg-R266K Cbs<sup>-/-</sup> mice express CBS mRNA, but have very low levels of CBS protein and enzyme activity, resulting in extreme elevations in serum total homocysteine (tHcy). Treatment with pyridoxine did not have any appreciable effect on tHcy, indicating this allele is not pyridoxine responsive in mice. However, treatment with the proteasome inhibitor bortezomib resulted in an 97% reduction in tHcy and a 2381% increase in liver CBS activity. These studies show that the p.R266K mutation causes increased proteasomal degradation in vivo, and that treatments that stabilize the protein can be used to reverse its effect.","variants":[{"Name":"NM_000071.3(CBS):c.797G>A (p.Arg266Lys)","Chromosome":"21","Start":"43063931","Stop":"43063931","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15164,"rule_based_match":true,"evidence_text":"c.797 G>A (p.R266K)","llm_judgment":"PRESENT","evidence":"c.797 G>A (p.R266K)","abstract_start":154,"abstract_end":173}]}
{"pmid":"29536976","title":"Four novel mutations of","abstract":"BACKGROUND: Novel mutations in adenosine deaminase acting on RNA 1 gene (ADAR1) are responsible for dyschromatosis symmetrica hereditaria (DSH). DSH patients display a mixture of hyperpigmented and hypopigmented macules on the dorsal aspects of the extremities, and freckle-like macules on the face.\nAIMS: To provide new evidence for further study of the etiopathogenisis of DSH.\nMETHODS: Genomic DNA was extracted and used as a template for the polymerase chain reaction (PCR) amplification of all 15 coding exons as well as intron-exon boundaries of ADAR1. The PCR products were sequenced directly.\nRESULTS: We identified eight mutations of ADAR1 in four Chinese pedigrees and four individual patients, which were c.2722G>T, p.(Asp908Tyr), c.1657delA, p.(Ser553fs), c.2563_2564delCT, p.(Leu855fs), c.526T>G, p.(Leu176Val) as well as four previously reported mutations c. 3363_3364insT, p.(Lys1122fs), c. 2865_2866delGT, p.(Val955fs), c.1630C>T, p.(Arg544X), and c.2894C>T, p.(Pro965Leu). In silico analysis predicted that all the mutations reported were pathogenic.\nLIMITATIONS: We did not study how ADAR1 played its role in DSH. So, the exact pathogenic mechanism of ADAR1 in DSH patients wasn't clarified in this study.\nCONCLUSION: We found four novel ADAR1 mutations in this study. Our results enlarge the database on ADAR1 mutations associated with DSH.","variants":[{"Name":"NM_001111.5(ADAR):c.2722G>T (p.Asp908Tyr)","Chromosome":"1","Start":"154589409","Stop":"154589409","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":558136,"rule_based_match":true,"evidence_text":"c.2722G>T, p.(Asp908Tyr)","llm_judgment":"PRESENT","evidence":"c.2722G>T, p.(Asp908Tyr)","abstract_start":716,"abstract_end":740},{"Name":"NM_001111.5(ADAR):c.2563_2564del (p.Leu855fs)","Chromosome":"1","Start":"154589861","Stop":"154589862","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":1882065,"rule_based_match":true,"evidence_text":"c.2563_2564delCT, p.(Leu855fs)","llm_judgment":"PRESENT","evidence":"c.2563_2564delCT, p.(Leu855fs)","abstract_start":768,"abstract_end":798},{"Name":"NM_001111.5(ADAR):c.2894C>T (p.Pro965Leu)","Chromosome":"1","Start":"154588250","Stop":"154588250","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1781325,"rule_based_match":true,"evidence_text":"c.2894C>T, p.(Pro965Leu)","llm_judgment":"PRESENT","evidence":"c.2894C>T, p.(Pro965Leu)","abstract_start":964,"abstract_end":988}]}
{"pmid":"31034483","title":"Exploring the hereditary background of renal cancer in Denmark.","abstract":"BACKGROUND: Every year more than 800 patients in Denmark are diagnosed with renal cell carcinoma (RCC) of which 3-5% are expected to be part of a hereditary renal cancer syndrome. We performed genetic screening of causative and putative RCC-genes (VHL, FH, FLCN, MET, SDHB, BAP1, MITF, CDKN2B) in RCC-patients suspected of a genetic predisposition.\nMETHODS: The cohort consisted of forty-eight Danish families or individuals with early onset RCC, a family history of RCC, a family history of RCC and melanoma or both RCC- and melanoma diagnosis in the same individual. DNA was extracted from peripheral blood samples or cancer-free formalin-fixed paraffin-embedded tissue.\nRESULTS: One start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von Hippel-Lindau (VHL). Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC. Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas. No variants were detected in CDKN2B.\nCONCLUSION: Although we did find three VUS's in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark. It is possible that the high prevalence of risk factors such as male gender, smoking and obesity has influenced the development of cancer in the patients of the current study. Further investigations into putative predisposing genes and risk factors of RCC are necessary to enable better prediction of renal cancer risk or presymptomatic testing of relatives in hereditary renal cancer families.","variants":[{"Name":"NM_000551.4(VHL):c.3G>A (p.Met1Ile)","Chromosome":"3","Start":"10141850","Stop":"10141850","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":139145,"rule_based_match":true,"evidence_text":"c.3G>A, p.Met1Ile","llm_judgment":"PRESENT","evidence":"c.3G>A, p.Met1Ile","abstract_start":746,"abstract_end":763},{"Name":"NM_000551.4(VHL):c.631A>C (p.Met211Leu)","Chromosome":"3","Start":"10149954","Stop":"10149954","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":180125,"rule_based_match":true,"evidence_text":"c.631A>C, p.Met211Leu","llm_judgment":"PRESENT","evidence":"c.631A>C, p.Met211Leu","abstract_start":787,"abstract_end":808}]}
{"pmid":"34435740","title":"Deep intronic variant in the ARSB gene as the genetic cause for Maroteaux-Lamy syndrome (MPS VI).","abstract":"Maroteaux-Lamy syndrome (MPS-VI) is a rare autosomal-recessive disorder with a wide spectrum of clinical manifestations, ranging from an attenuated to a rapidly progressive disease. It is caused by variants in ARSB, which encodes the lysosomal arylsulfatase B (ARSB) enzyme, part of the degradation process of glycosaminoglycans in lysosomes. Over 220 variants have been reported so far, with a majority of missense variants. We hereby report two siblings of Bedouin origin with a diagnosis of MPS-VI. Western blots in patient fibroblasts revealed total absence of ARSB protein production. Complete sequencing of the coding region of ARSB did not identify a candidate disease-associated variant. However, deep sequencing of the noncoding region of ARSB by whole genome sequencing (WGS) revealed a c.1142+581A to G variant. The variant is located within intron 5 and fully segregated with the disease in the family. Determination of the genetic cause for these patients enabled targeted treatment by enzyme replacement therapy, along with appropriate genetic counseling and prenatal diagnosis for the family. These results highlight the advantage of WGS as a powerful tool, for improving the diagnostic rate of rare disease-causing variants, and emphasize the importance of studying deep intronic sequence variation as a cause of monogenic disorders.","variants":[{"Name":"NM_000046.5(ARSB):c.1142+581A>G","Chromosome":"5","Start":"78885003","Stop":"78885003","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2847066,"rule_based_match":false,"evidence_text":"c.1142+581A to G","llm_judgment":"PRESENT","evidence":"c.1142+581A to G","abstract_start":797,"abstract_end":813}]}
{"pmid":"15145338","title":"A case of childhood Pompe disease demonstrating phenotypic variability of p.Asp645Asn.","abstract":"A six-year-old child presented at 8 months of age with proximal muscle weakness and mild cardiac hypertrophy. Some alpha-glucosidase activity was detected in muscle but not in fibroblasts. As none of the two pathogenic mutations, [c.1933G>A]+[c.2702T>A] (Asp645Asn/Leu901Gln), led to detectable alpha-glucosidase activity upon expression in COS cells, the phenotype of the patient remained unexplained. A functionally comparable set of mutations, Asp645Asn/insGnt2243, was reported previously to cause classic infantile Pompe disease [Biochem Biophys Res Commun 244 (1998) 921]. We conclude that secondary genetic or environmental factors can be decisive for the phenotypic outcome of classic infantile versus childhood Pompe disease, when the acid alpha-glucosidase activity is extremely low.","variants":[{"Name":"NM_000152.5(GAA):c.1933G>A (p.Asp645Asn)","Chromosome":"17","Start":"80112920","Stop":"80112920","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187010,"rule_based_match":true,"evidence_text":"c.1933G>A","llm_judgment":"PRESENT","evidence":"c.1933G>A","abstract_start":231,"abstract_end":240}]}
{"pmid":"32790509","title":"Macula-predominant retinopathy associated with biallelic variants in","abstract":"PURPOSE: To describe the clinical, electrophysiological, and molecular features of an unusual macula-predominant retinopathy in two unrelated probands with biallelic variants in <i>RDH12</i>.\nMETHODS: Retrospective case series.\nRESULTS: A 29-year-old female presented with visual loss since the age of 14 years. Retinal examination revealed symmetric outer retinal atrophy in the posterior pole with peripapillary sparing. Fundus autofluorescence (AF) showed patchy loss of AF in the posterior pole, with hyper-autofluorescent borders. Optical coherence tomography (OCT) showed loss of the macular outer retinal layers. Pattern electroretinography (PERG) showed macular dysfunction and full-field ERG indicated mild loss of photoreceptor function. Next-generation sequencing (NGS) identified two variants in <i>RDH12</i>: p.(Arg234His) and c.448 + 1 G > A in <i>trans</i>. The second patient was a 10-year-old male with bilateral macular changes and visual loss. Retinal examination showed bilateral macular cloverleaf-like outer retinal changes, with relative foveal sparing. Fundus AF showed bilateral macular hypo-autofluorescent patches with a border of increased signal and preserved foveal AF. OCT showed attenuation of the perifoveal outer retinal layers in the regions of reduced AF signal. PERG showed macular dysfunction, but the full-field ERG was normal. NGS and whole-genome sequencing identified two variants in <i>RDH12</i>: p.(Arg234His) and p.(Cys245_Leu247deI) in <i>trans</i>.\nCONCLUSIONS: Disease-causing variants in <i>RDH12</i> are typically associated with early-onset severe retinal dystrophy with significant macular involvement. Hypomorphic alleles of this gene cause relatively mild retinopathy with predominant macular involvement. This phenotype demonstrates the vulnerability of the macular photoreceptors to certain perturbations of <i>RDH12</i>.","variants":[{"Name":"NM_152443.3(RDH12):c.448+1G>A","Chromosome":"14","Start":"67726156","Stop":"67726156","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":965944,"rule_based_match":true,"evidence_text":"c.448 + 1 G > A","llm_judgment":"PRESENT","evidence":"c.448 + 1 G > A","abstract_start":840,"abstract_end":855},{"Name":"NM_152443.3(RDH12):c.701G>A (p.Arg234His)","Chromosome":"14","Start":"67729233","Stop":"67729233","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":321026,"rule_based_match":false,"evidence_text":"p.(Arg234His)","llm_judgment":"PRESENT","evidence":"p.(Arg234His)","abstract_start":822,"abstract_end":835}]}
{"pmid":"31770251","title":"Repeated and progressive rhabdomyolysis due to a novel carnitine palmitoyltransferase II gene variant in an adult male: A case report.","abstract":"INTRODUCTION: The occurrence of repeated and progressive rhabdomyolysis is rare in clinical settings, particularly in adults. The pathogenesis of rhabdomyolysis is often overlooked due to its rapid recovery. Carnitine palmitoyltransferase (CPT) II deficiency could be a rare etiology of repetitive nontraumatic rhabdomyolysis, and several mutations of CPT II have been reported.\nPATIENT CONCERNS: A 41-year-old man presented with high fever, general malaise, myalgia, dyspnea, and dark-colored urine, and then progressed to anuria. In the past 15 years, he experienced dark-colored urine twice due to exercise and high fever. Physical examination revealed oliguria, suppurated tonsils, poor hemoglobin saturation, alert consciousness, normal neurological signs and reflexes, hypertension, and tachypnea. Laboratory investigations showed positive test results for inflammation, high serum myogenic enzyme levels, and evidence of acute kidney injury (AKI).\nDIAGNOSES: Investigations revealed an extremely high serum myogenic enzyme levels and impaired renal function with serum creatinine level of 510 μmol/L, consistent with the diagnosis of rhabdomyolysis, AKI stage 3, and acute respiratory distress syndrome. High levels of acylcarnitine in the serum confirmed the diagnosis of CPT II deficiency. In addition, whole exome sequencing (WES) was conducted in the patient and his mother.\nINTERVENTIONS: Intubation, ventilator support, and hemodialysis were the major therapeutic interventions at the peak of disease progression. He was then administered valsartan tablets at a dosage of 80 mg per day and L-carnitine supplements.\nOUTCOMES: WES conducted in the patient and his mother revealed 2 novel mutations of CPT II (c.482G>A and c.1493G>T) in this patient. The patient recovered from the severe AKI but the renal function remained impaired at chronic kidney disease stage 3a.\nCONCLUSION: Thus, gene examination can help to understand the etiology of repetitive nontraumatic rhabdomyolysis. Accurate diagnosis can be beneficial for providing an individualized treatment for patients with repeated and progressive rhabdomyolysis.","variants":[{"Name":"NM_000098.3(CPT2):c.482G>A (p.Arg161Gln)","Chromosome":"1","Start":"53210156","Stop":"53210156","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1987043,"rule_based_match":true,"evidence_text":"c.482G>A","llm_judgment":"PRESENT","evidence":"c.482G>A","abstract_start":1720,"abstract_end":1728}]}
{"pmid":"24825797","title":"Novel and atypical splicing mutation in a compound heterozygous UNC13D defect presenting in Familial Hemophagocytic Lymphohistiocytosis triggered by EBV infection.","abstract":"Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL3) is a genetic disorder caused by mutations in UNC13D gene, coding the granule priming factor Munc13-4 that intervenes in NK and T cell cytotoxic function. Here we report the case of a 17-month-old girl with prolonged symptomatic EBV infectious mononucleosis and clinical symptoms of hemophagocytic syndrome. In vitro functional analysis pointed to a degranulation defect. The genetic analysis of UNC13D gene identified initially a heterozygous mutation (c.753+1G>T) in the donor splice-site that resulted in exon 9 skipping (maternal allele). Mutations in other genes were considered, but additional analysis of UNC13D cDNA revealed in the paternal allele a heterozygous transition from G to A (c.2448-13G>A) at the 3' acceptor splice-site in intron 25, generating a new acceptor splice-site that leads to a frameshift and a premature STOP codon. Allele specific amplification of the cDNA confirmed the absence of a functional mRNA from the paternal allele. This case illustrates an atypical compound heterozygous UNC13D mutation affecting the RNA splicing that generates a typical FHL3 phenotype.","variants":[{"Name":"NM_199242.3(UNC13D):c.753+1G>T","Chromosome":"17","Start":"75840506","Stop":"75840506","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":17040,"rule_based_match":true,"evidence_text":"c.753+1G>T","llm_judgment":"PRESENT","evidence":"c.753+1G>T","abstract_start":511,"abstract_end":521},{"Name":"NM_199242.3(UNC13D):c.2448-13G>A","Chromosome":"17","Start":"75831361","Stop":"75831361","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1508873,"rule_based_match":true,"evidence_text":"c.2448-13G>A","llm_judgment":"PRESENT","evidence":"c.2448-13G>A","abstract_start":752,"abstract_end":764}]}
{"pmid":"28602422","title":"Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome.","abstract":"Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10% of affected individuals, the genetic cause of the disease is unknown, suggesting that other loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with no variants in the known MMIHS-associated genes. By performing homozygosity mapping and whole-exome sequencing, we found homozygous variants in myosin light chain kinase (MYLK) in both families. We identified a 7 bp duplication (c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs<sup>∗</sup>51]) in one family and a putative splice-site variant (c.3985+5C>A) in the other. Expression studies and splicing assays indicated that both variants affect normal MYLK expression. Because MYLK encodes an important kinase required for myosin activation and subsequent interaction with actin filaments, it is likely that in its absence, contraction of smooth muscle cells is impaired. The existence of a conditional-Mylk-knockout mouse model with severe gut dysmotility and abnormal function of the bladder supports the involvement of this gene in MMIHS pathogenesis. In aggregate, our findings implicate MYLK as a gene involved in the recessive form of MMIHS, confirming that this disease of the visceral organs is heterogeneous with a myopathic origin.","variants":[{"Name":"NM_053025.4(MYLK):c.3838_3844dup (p.Glu1282fs)","Chromosome":"3","Start":"123664245","Stop":"123664246","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TCGCTTTC","allel_id":259621,"rule_based_match":true,"evidence_text":"c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs<sup>∗</sup>51]","llm_judgment":"PRESENT","evidence":"c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs<sup>∗</sup>51]","abstract_start":736,"abstract_end":789}]}
{"pmid":"20967465","title":"A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome.","abstract":"Warburg Micro syndrome and Martsolf syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, postnatal microcephaly, and developmental delay. The neurodevelopmental and ophthalmological phenotype is more severe in Warburg Micro syndrome in which cerebral malformations and severe motor and mental retardation are common. While biallelic loss-of-function mutations in RAB3GAP1 are present in the majority of patients with Warburg Micro syndrome; a hypomorphic homozygous splicing mutation of RAB3GAP2 has been reported in a single family with Martsolf syndrome. Here, we report a novel homozygous RAB3GAP2 small in-frame deletion, c.499_507delTTCTACACT (p.Phe167_Thr169del) that causes Warburg Micro syndrome in a girl from a consanguineous Turkish family presenting with congenital cataracts, microphthalmia, absent visually evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay. No RAB3GAP2 mutations were detected in ten additional unrelated patients with RAB3GAP1-negative Warburg Micro syndrome, consistent with further genetic heterogeneity. In conclusion, we provide evidence that RAB3GAP2 mutations are not specific to Martsolf syndrome. Rather, our findings suggest that loss-of-function mutations of RAB3GAP1 as well as functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome while hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype. Thus, a phenotypic severity gradient may exist in the RAB3GAP-associated disease continuum (the \"Warburg-Martsolf syndrome\") which is presumably determined by the mutant gene and the nature of the mutation.","variants":[{"Name":"NM_012414.4(RAB3GAP2):c.499_507del (p.Phe167_Thr169del)","Chromosome":"1","Start":"220210804","Stop":"220210812","ReferenceAlleleVCF":"CAGTGTAGAA","AlternateAlleleVCF":"C","allel_id":39739,"rule_based_match":true,"evidence_text":"c.499_507delTTCTACACT (p.Phe167_Thr169del)","llm_judgment":"PRESENT","evidence":"c.499_507delTTCTACACT (p.Phe167_Thr169del)","abstract_start":695,"abstract_end":737}]}
{"pmid":"29721947","title":"Whole-Exome Sequencing Identifies Novel Variants that Co-segregates with Autosomal Recessive Retinal Degeneration in a Pakistani Pedigree.","abstract":"PURPOSE: To identify the molecular basis of inherited retinal degeneration (IRD) in a familial case of Pakistani origin using whole-exome sequencing.\nMETHODS: A thorough ophthalmic examination was completed, and genomic DNA was extracted using standard protocols. Whole exome(s) were captured with Agilent V5 + UTRs probes and sequenced on Illumina HiSeq genome analyzer. The exomeSuite software was used to filter variants, and the candidate causal variants were prioritized, examining their allele frequency and PolyPhen2, SIFT, and MutationTaster predictions. Sanger dideoxy sequencing was performed to confirm the segregation with disease phenotype and absence in ethnicity-matched control chromosomes.\nRESULTS: Ophthalmic examination confirmed retinal degeneration in all affected individuals that segregated as an autosomal recessive trait in the family. Whole-exome sequencing identified two homozygous missense variants: c.1304G > A; p.Arg435Gln in ZNF408 (NM_024741) and c.902G > A; p.Gly301Asp in C1QTNF4 (NM_031909). Both variants segregated with the retinal phenotype in the PKRD320 and were absent in ethnically matched control chromosomes.\nCONCLUSION: Whole-exome sequencing coupled with bioinformatics analysis identified potential novel variants that might be responsible for IRD.","variants":[{"Name":"NM_024741.3(ZNF408):c.1304G>A (p.Arg435Gln)","Chromosome":"11","Start":"46705004","Stop":"46705004","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1047244,"rule_based_match":true,"evidence_text":"c.1304G > A; p.Arg435Gln in ZNF408 (NM_024741)","llm_judgment":"PRESENT","evidence":"c.1304G > A; p.Arg435Gln in ZNF408 (NM_024741)","abstract_start":929,"abstract_end":975}]}
{"pmid":"36926140","title":"Hidrotic ectodermal dysplasia in a Chinese pedigree: A case report.","abstract":"BACKGROUND: We report on a large family of Chinese Han individuals with hidrotic ectodermal dysplasia (HED) with a variation in <i>GJB6</i> (c.31G>A). The patients in the family had a triad of clinical manifestations of varying degrees. Although the same variation locus have been reported, the clinical manifestations of this family were difficult to distinguish from those of congenital thick nail disorder, palmoplantar keratosis, and congenital hypotrichosis.\nCASE SUMMARY: This investigation involved a large Chinese family of 46 members across five generations and included 12 patients with HED. The proband (IV4) was a male patient with normal sweat gland function and dental development, no skeletal dysplasia, no cognitive disability, and no hearing impairments. His parents were not consanguineously married. Physical examination of the proband revealed thinning hair and thickened grayish-yellow nails and toenails with some longitudinal ridges, in addition to mild bilateral palmoplantar hyperkeratosis. <i>GJB6</i>, <i>GJB2</i>, and <i>GJA1</i> have been reported to be the causative genes of HED; therefore, we subjected the patient's samples to Sanger sequencing of these three genes. In this family, the variation locus was at <i>GJB6</i> (c.31G>A, p.Gly11Arg). Overexpression vectors of wild-type <i>GJB6</i> and its variants were established and transfected into HaCaT cell models, and the related mRNA and protein expression changes were determined using real-time reverse transcriptase-polymerase chain reaction and Western blot, respectively.\nCONCLUSION: We report another HED phenotype associated with <i>GJB6</i> variations, which can help clinicians to diagnose HED despite its varying presentations.","variants":[{"Name":"NM_001110219.3(GJB6):c.31G>A (p.Gly11Arg)","Chromosome":"13","Start":"20223450","Stop":"20223450","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20583,"rule_based_match":true,"evidence_text":"c.31G>A (p.Gly11Arg)","llm_judgment":"PRESENT","evidence":"p.Gly11Arg","abstract_start":1265,"abstract_end":1275}]}
{"pmid":"24399866","title":"A novel homozygous mutation at the GAA gene in Mexicans with early-onset Pompe disease.","abstract":"Glycogen-storage disease type II, also named Pompe disease, is caused by the deficiency of the enzyme acid alpha-glucosidase, which originates lysosomal glycogen accumulation leading to progressive neuromuscular damage. Early-onset Pompe disease shows a debilitating and frequently fulminating course. To date, more than 300 mutations have been described; the majority of them are unique to each affected individual. Most early-onset phenotypes are associated with frameshift mutations leading to a truncated alpha-glucosidase protein with loss of function. Founder effects are responsible from many cases from few highprevalence world regions. Herein we described two apparently unrelated cases affected with classical early-onset Pompe disease, both pertaining to a small region from Central Mexico (the State of San Luis Potosí), the same novel homozygous frameshift mutation at gene GAA (c.1987delC) was demonstrated in both cases. This GAA gene deletion implies a change of glutamine to serine at codon 663, and a new reading frame that ends after 33 base pairs, which leads to the translation of a truncated protein. This report contributes to widen the knowledge on the effect of pathogenic mutations in Pompe disease. Here we postulate the existence of a founder effect.","variants":[{"Name":"NM_000152.5(GAA):c.1987del (p.Gln663fs)","Chromosome":"17","Start":"80112972","Stop":"80112972","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":1445068,"rule_based_match":true,"evidence_text":"c.1987delC","llm_judgment":"PRESENT","evidence":"c.1987delC","abstract_start":892,"abstract_end":902}]}
{"pmid":"28724397","title":"Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome.","abstract":"BACKGROUND: The ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings.\nRESULTS: Although clinical panel sequencing of genes implicated in nephrotic syndromes yielded no likely causal mutation, an oligo-SNP microarray identified a ~20-Mb region of homozygosity, with no altered gene dosage, on chromosome 16p13. Intersection of the proband's phenotypes with known disease genes within the homozygous region yielded a single candidate, IFT140, encoding a retrograde intraflagellar transport protein implicated previously in several ciliopathies, including the phenotypically overlapping Mainzer-Saldino syndrome (MZSDS). Sanger sequencing yielded a maternally inherited homozygous c.634G>A; p.Gly212Arg mutation altering the exon 6 splice donor site. Functional studies in cells from the proband showed that the locus produced two transcripts: a majority message containing a mis-splicing event that caused a premature termination codon and a minority message homozygous for the p.Gly212Arg allele. Zebrafish in vivo complementation studies of the latter transcript demonstrated a loss of function effect. Finally, we conducted post-hoc trio-based whole exome sequencing studies to (a) test the possibility of other causal loci in the proband and (b) explain the Mendelian error of segregation for the IFT140 mutation. We show that the proband harbors a chromosome 16 maternal heterodisomy, with segmental isodisomy at 16p13, likely due to a meiosis I error in the maternal gamete.\nCONCLUSIONS: Using clinical phenotyping combined with research-based genetic and functional studies, we have characterized a recurrent IFT140 mutation in the proband; together, these data are consistent with MZSDS. Additionally, we report a rare instance of a uniparental isodisomy unmasking a deleterious mutation to cause a ciliary disorder.","variants":[{"Name":"NM_014714.4(IFT140):c.634G>A (p.Gly212Arg)","Chromosome":"16","Start":"1592176","Stop":"1592176","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40345,"rule_based_match":true,"evidence_text":"c.634G>A; p.Gly212Arg","llm_judgment":"PRESENT","evidence":"c.634G>A; p.Gly212Arg","abstract_start":1186,"abstract_end":1207}]}
{"pmid":"25633036","title":"Low-level constitutional mosaicism of a de novoBRCA1 gene mutation.","abstract":"BACKGROUND: Pathogenic BRCA1 mutations are usually inherited. Constitutional low-level BRCA1 mosaicism has never been reported.\nMETHODS: Next-generation sequencing (NGS) of cancer gene panel of germline and tumour DNA in a patient with early onset, triple-negative breast cancer.\nRESULTS: Constitutional de novo mosaicism (5%) for a pathogenic (c.1953dupG; p.Lys652Glufs*21) BRCA1mutation was detected in leukocytes, buccal tissue and normal breast tissue DNA, with ∼50% mutation in tumorous breast tissue.\nCONCLUSION: This is the first reported case of low-level, multiple tissue, constitutional mosaicism in BRCA1, and highlights the need to consider deep sequencing in affected individuals clinically suspected of having cancer predisposition whose tumours display a BRCA mutation.","variants":[{"Name":"NM_007294.4(BRCA1):c.1953dup (p.Lys652fs)","Chromosome":"17","Start":"43093577","Stop":"43093578","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":69079,"rule_based_match":true,"evidence_text":"c.1953dupG","llm_judgment":"PRESENT","evidence":"c.1953dupG","abstract_start":345,"abstract_end":355}]}
{"pmid":"30805538","title":"Acute respiratory failure and generalized hypotonia secondary to vitamin D dependent rickets type 1A.","abstract":"Vitamin D dependent rickets is a rare autosomal recessive disorder secondary to mutation in 1 α hydroxylase enzyme gene. We are presenting a case of a two-year-old boy with vitamin D dependent rickets type 1A whose diagnosis was missed for a long period and he was treated as nutritional rickets. He suffered with severe hypotonia and regressing milestones. Severe hypotonia with proximal muscle weakness caused respiratory failure which required intensive care admission and mechanical ventilation. DNA analysis revealed previously reported homozygous mutation in CYP27B1 gene (p.Arg429Pro (R429P) at exon c.1286 G > C). Rare genetic disorders of rickets are not considered in early course of disease in regions with high prevalence of vitamin D deficiency. This severe presentation of rickets highlights the need of close monitoring of treatment response and consideration of other differential diagnosis in children who are not responding to vitamin D supplements. There is a high prevalence of genetic disorders particularly autosomal recessive conditions in societies having high rate of inter-family and consanguineous marriages.","variants":[{"Name":"NM_000785.4(CYP27B1):c.1286G>C (p.Arg429Pro)","Chromosome":"12","Start":"57763738","Stop":"57763738","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":260032,"rule_based_match":true,"evidence_text":"c.1286 G > C","llm_judgment":"PRESENT","evidence":"c.1286 G > C","abstract_start":607,"abstract_end":619}]}
{"pmid":"19566901","title":"Novel non-sense GCH1 mutation in a South African family diagnosed with dopa-responsive dystonia.","abstract":"BACKGROUND: Dopa-responsive dystonia (DRD), a movement disorder characterized by onset in early childhood and a dramatic response to low doses of levodopa, has been shown to be caused by a number of different mutations in the GCH1 gene.\nMETHODS: We identified a South African family which presented with DRD in three family members. Polymerase chain reaction (PCR) primers were designed to span all six exons of GCH1 and the PCR products were screened for pathogenic mutations using direct sequencing.\nRESULTS: A novel non-sense mutation (c.233delT; p.I78fsX79) was identified in the DRD patients, which would produce a markedly truncated protein of only 78 amino acids. This mutation was also present in a number of asymptomatic family members.\nCONCLUSIONS: A novel non-sense mutation in the GCH1 gene can be associated with DRD and reduced penetrance in South African patients.","variants":[{"Name":"NM_000161.3(GCH1):c.233del (p.Ile78fs)","Chromosome":"14","Start":"54902431","Stop":"54902431","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1874711,"rule_based_match":true,"evidence_text":"c.233delT; p.I78fsX79","llm_judgment":"PRESENT","evidence":"c.233delT; p.I78fsX79","abstract_start":539,"abstract_end":560}]}
{"pmid":"27286923","title":"Two male sibs with severe micrognathia and a missense variant in MED12.","abstract":"Missense variants in MED12 cause three partially overlapping dysmorphic X-linked intellectual disability (XLID) syndromes: Lujan-Fryns syndrome (also known as Lujan syndrome), FG syndrome (also known as Opitz-Kaveggia syndrome) and X-linked Ohdo syndrome. We report a family with two severely micrognathic male sibs, a 10½ year old boy and a fetus, in which hemizygosity for a previously unreported missense variant in exon 13 of MED12 (NM_005120.2), c.1862G > A, p.(Arg621Gln) was detected by whole exome sequencing. The affected sibs shared no other rare variant with relevance to the phenotype. X-chromosome inactivation in blood was completely skewed (100:0) in the unaffected heterozygous mother, most likely as a result of preferential inactivation of the X-chromosome harbouring the missense variant in MED12. Neither the unaffected brother nor the unaffected maternal grandfather carried the missense variant in MED12. In the 10½ year old boy, upper airway obstruction secondary to Pierre Robin sequence necessitated a tracheostomy for the first 10 months of life. He has mild to moderate intellectual disability and some dysmorphic features seen in MED12-related syndromes. In addition, he has a horizontal gaze paresis, anomalies of the inner ear, and a cervical block vertebra. This report contributes to the expanding phenotypic range associated with MED12-mutations.","variants":[{"Name":"NM_005120.3(MED12):c.1862G>A (p.Arg621Gln)","Chromosome":"X","Start":"71124276","Stop":"71124276","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227160,"rule_based_match":true,"evidence_text":"c.1862G > A, p.(Arg621Gln)","llm_judgment":"PRESENT","evidence":"c.1862G > A, p.(Arg621Gln)","abstract_start":451,"abstract_end":477}]}
{"pmid":"26148721","title":"A splicing mutation in the DMD gene detected by next-generation sequencing and confirmed by mRNA and protein analysis.","abstract":"BACKGROUND: Dystrophinopathies, either the severe Duchenne Muscular Dystrophy (DMD) or the milder Becker Muscular Dystrophy (BMD), are X-linked recessive disorders caused by mutations in the DMD gene. DMD is one of the longest human genes. Large deletions or duplications account for 60-80% of the mutations. Remaining anomalies consist in point mutations or small rearrangements. Routinely, the molecular diagnosis is done by a Multiplex Ligation-dependent Probe Amplification (MLPA) or array Comparative Genome Hybridization (aCGH), followed, if negative, by Sanger sequencing of all exons.\nMETHODS: In this study, massive parallel sequencing (MPS) or next generation sequencing (NGS) was used to make a rapid and costless molecular diagnosis in a young boy suspected of DMD.\nRESULTS: A small deletion: NM_004006.2:c.2803+5_2803+8del was identified. The diagnosis was performed in one single manipulation and within a week. The consequence of this intronic mutation is a skipping of exon 21 confirmed by mRNA and protein analysis.\nCONCLUSIONS: NGS appears to be an efficient new strategy in DMD molecular diagnosis. It highlights the major evolution of the diagnostic strategy towards high throughput technologies, where bioinformatics analysis becomes the real challenge for variations detection. This is the first study reporting in vivo impact of this intronic mutation.","variants":[{"Name":"NM_004006.3(DMD):c.2803+5_2803+8del","Chromosome":"X","Start":"32484911","Stop":"32484914","ReferenceAlleleVCF":"TTTAC","AlternateAlleleVCF":"T","allel_id":1065366,"rule_based_match":true,"evidence_text":"NM_004006.2:c.2803+5_2803+8del","llm_judgment":"PRESENT","evidence":"NM_004006.2:c.2803+5_2803+8del","abstract_start":805,"abstract_end":835}]}
{"pmid":"25031893","title":"A Novel PHEX Gene Mutation in a Patient with Sporadic Hypophosphatemic Rickets.","abstract":"Phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) is a common cause of X-linked hypophosphatemic (XLH) rickets. Diverse PHEX gene mutations have been reported; however, gene mutations in sporadic rickets are less common than in XLH rickets. Herein, we describe a 50-year-old female patient with sporadic hypophosphatemic rickets harboring a novel splicing-site mutation in the PHEX gene (c.663+1G>A) at the exon 5-intron 5 boundary. The patient had recently suffered from right thigh pain and an aggravated waddling gait. She also presented with very short stature, generalized bone pain, and muscle weakness. Despite low serum phosphate levels, her phosphate reabsorption rate was lower than normal. Additionally, her 1,25-dihydroxyvitamin D3 concentration was lower than normal, although FGF23 level was normal. After treatment with alfacalcidol and elemental phosphate, her rachitic symptoms subsided, and callus formation was observed in the fracture site on the right femur.","variants":[{"Name":"NM_000444.6(PHEX):c.663+1G>A","Chromosome":"X","Start":"22077703","Stop":"22077703","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":446612,"rule_based_match":true,"evidence_text":"c.663+1G>A","llm_judgment":"PRESENT","evidence":"c.663+1G>A","abstract_start":425,"abstract_end":435}]}
{"pmid":"34109129","title":"Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review.","abstract":"BACKGROUND: Hemangioblastoma is a benign tumor of the central nervous system and may appear as a component of von Hippel-Lindau (VHL) disease. At present, approximately 40 cases of optic nerve HGBs have been reported in the literature. VHL disease is a rare autosomal-dominant inherited cancer syndrome with different phenotypes caused by variants in the VHL gene. Herein, the authors describe a case of a pediatric patient with VHL disease and with optic nerve HGB, a rare phenotypic expression. The purpose of this study was to explore the genotype-phenotype, clinical features, treatment and follow-up of VHL-associated hemangioblastomas in pediatric patients.\nCASE DESCRIPTION: A 12-year-old boy presented with vision loss, headache and dizziness at our hospital. Magnetic resonance imaging (MRI) revealed a large (19.8 mm*18.5 mm*23.5 mm) irregular mass located in the suprasellar region. The mass was successfully removed after craniotomy and microsurgical treatment. The pathological diagnosis was left optic nerve HGB. Genetic analyses showed p.Pro86Leu (c. 257C>T) heterozygous missense mutations in the VHL gene.\nCONCLUSION: This is the first reported pediatric case of VHL-associated optic nerve HGB. The genotype-phenotype correlation of VHL disease may provide new evidences for predicting tumor penetrance and survival. Gross tumor resection combined with stereotactic radiosurgery might be the most beneficial treatment.","variants":[{"Name":"NM_000551.4(VHL):c.257C>T (p.Pro86Leu)","Chromosome":"3","Start":"10142104","Stop":"10142104","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":180115,"rule_based_match":true,"evidence_text":"c. 257C>T","llm_judgment":"PRESENT","evidence":"c. 257C>T","abstract_start":1063,"abstract_end":1072}]}
{"pmid":"30282619","title":"Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A","abstract":"Objective: Vitamin D dependent rickets type 1A (VDDR1A) is an autosomal recessive disorder caused by mutations in the 1α-hydroxylase gene (<i>CYB27B1</i>). As it may be confused with nutritional rickets and hypophosphatemic rickets, genetic analysis is important for making a correct diagnosis.\nMethods: We analysed genomic DNA from 11 patients from eight different Turkish families. The patients were recruited for our studies if they presented with a diagnosis of VDDR.\nResults: The mean ± standard deviation age at diagnosis was 13.1±7.4 months. Seven patients had mild hypocalcemia at presentation while four patients had normal calcium concentrations. All patients underwent <i>CYP27B1</i> gene analysis. The most prevalent mutation was the c.195 + 2T>G splice donor site mutation, affecting five out of 11 patients with VDDR1A. Two patients from the fourth family were compound heterozygous for c.195 + 2T>G and c.195 + 2 T>A in intron-1. Two patients, from different families, were homozygous for a previously reported duplication mutation in exon 8 (1319_1325dupCCCACCC, Phe443Profs*24). One patient had a homozygous splice site mutation in intron 7 (c.1215 + 2 T>A) and one patient had a homozygous mutation in exon 9 (c.1474 C>T).\nConclusion: Intron-1 mutation was the most common mutation, as previously reported. All patients carrying that mutation were from same city of origin suggesting a “founder” or a “common ancestor” effect. VDDR1A should definitely be considered when a patient with signs of rickets has a normal 25-OHD level or when there is unresponsiveness to vitamin D treatment.","variants":[{"Name":"NM_000785.4(CYP27B1):c.1319_1325dup (p.Phe443fs)","Chromosome":"12","Start":"57763698","Stop":"57763699","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGGGTGGG","allel_id":264701,"rule_based_match":false,"evidence_text":"1319_1325dupCCCACCC, Phe443Profs*24","llm_judgment":"PRESENT","evidence":"1319_1325dupCCCACCC, Phe443Profs*24","abstract_start":1058,"abstract_end":1093}]}
{"pmid":"35840934","title":"LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis.","abstract":"BACKGROUND: Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1.\nCASE PRESENTATION: A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stable imaging findings and the patient is being followed clinically by cardiology, neurology and medical genetics.\nCONCLUSIONS: We identified a novel mutation in the LZTR1 gene, not previously reported in association with NS. This report provides additional evidence to support for the assessment of schwannomatosis in patients with LZTR1-NS and may have overlap with Neurofibromatosis type 1.","variants":[{"Name":"NM_006767.4(LZTR1):c.743G>A (p.Gly248Glu)","Chromosome":"22","Start":"20990477","Stop":"20990477","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1336666,"rule_based_match":true,"evidence_text":"c.743G>A (p.Gly248Glu)","llm_judgment":"PRESENT","evidence":"c.743G>A (p.Gly248Glu)","abstract_start":945,"abstract_end":967}]}
{"pmid":"32818936","title":"A Novel Gain-of-Function KCND3 Variant Associated with Brugada Syndrome.","abstract":"Brugada syndrome (BrS) is a known cause of sudden cardiac death (SCD) characterized by abnormal electrocardiograms and fatal arrhythmias. The variants in KCND3 encoding the KV4.3 potassium-channel (the α-subunit of the Ito) have seldom been reported in BrS. This study aimed to identify novel KCND3 variants associated with BrS and elucidate BrS pathogenesis. High-depth targeted sequencing was performed and the electrophysiological properties of the variants were detected by whole-cell patch-clamp methods in a cultured-cell expressing system. The transcriptional levels of KV4.3 in different genotypes were studied by real-time PCR. Western blot was used to assess channel protein expression. A novel KCND3heterozygous variant, c.1292G>A (Arg431His, R431H), was found in the proband. Whole-cell patch-clamp results revealed a gain-of-function phenotype in the variant, with peak Ito current density increased and faster recovery from inactivation. The expression of mutant Kv4.3 membrane protein increased and the cytoplasmic protein decreased, demonstrating that the membrane/cytoplasm ratio was significantly different. In conclusion, a novel KCND3 heterozygous variant was associated with BrS. The increased Ito current explained the critical role of KCND3 in the pathogenesis of BrS. Genetic screening for KCND3 could be useful for understanding the pathogenesis of BrS and providing effective risk stratification in the clinic.","variants":[{"Name":"NM_001378969.1(KCND3):c.1292G>A (p.Arg431His)","Chromosome":"1","Start":"111780769","Stop":"111780769","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":509066,"rule_based_match":true,"evidence_text":"c.1292G>A (Arg431His, R431H)","llm_judgment":"PRESENT","evidence":"c.1292G>A (Arg431His, R431H)","abstract_start":732,"abstract_end":760}]}
{"pmid":"36410626","title":"Minigene Assay as an Effective Molecular Diagnostic Strategy in Determining the Pathogenicity of Noncanonical Splice-Site Variants in FLCN.","abstract":"Primary spontaneous pneumothorax (PSP) or pulmonary cyst is one of the manifestations of Birt-Hogg-Dubé syndrome, which is caused by pathogenic variants in FLCN gene. Genetic testing in patients with PSP identifies a certain number of missense or intronic variants. These variants are usually considered as variants of uncertain significance, whose functional interpretations pose a challenge in clinical genetics. To improve recognition of pathogenic splice-altering variants in FLCN gene, computational tools are used to prioritize potential splice-altering variants and then a hybrid minigene assay is performed to verify the RNA splicing pattern. Herein, variants in FLCN exon 11 and its flanking sequence are focused. Eight variants detected in 11 patients with PSP are evaluated, and six variants are prioritized by in silico tools as potential splice-altering variants of uncertain significance. Four variants (c.1177-5_1177-3delCTC, c.1292_1300+4del, c.1300+4C>T, and c.1300+5G>A) are demonstrated by minigene assay to alter RNA splicing of FLCN, and the last three of them are novel. RT-PCR of patient-derived RNA gives consistent results. Genotype-phenotype correlation analysis in patients with PSP with these variants demonstrates good concordance. Our results underline the importance of RNA analysis, which could provide molecular evidence for pathogenicity of a variant, and provide essential information for the clinical interpretation of variants. Combining the clinical information, a definitive diagnosis could be made.","variants":[{"Name":"NM_144997.7(FLCN):c.1300+5G>A","Chromosome":"17","Start":"17216375","Stop":"17216375","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":401551,"rule_based_match":true,"evidence_text":"c.1300+5G>A","llm_judgment":"PRESENT","evidence":"c.1300+5G>A","abstract_start":976,"abstract_end":987}]}
{"pmid":"32042919","title":"Deep sequencing of mitochondrial DNA and characterization of a novel","abstract":"OBJECTIVE: To determine the pathogenicity of a novel <i>POLG</i> mutation in a man with late-onset autosomal recessive progressive external ophthalmoplegia using clinical, molecular, and biochemical analyses.\nMETHODS: A multipronged approach with detailed neurologic examinations, muscle biopsy analyses, molecular genetic studies, and in vitro biochemical characterization.\nRESULTS: The patient had slowly progressive bilateral ptosis and severely reduced horizontal and vertical gaze. Muscle biopsy showed slight variability in muscle fiber size, scattered ragged red fibers, and partial cytochrome c oxidase deficiency. Biallelic mutations were identified in the <i>POLG</i> gene encoding the catalytic A subunit of POLγ. One allele carried a novel mutation in the exonuclease domain (c.590T>C; p.F197S), and the other had a previously characterized null mutation in the polymerase domain (c.2740A>C; p.T914P). Biochemical characterization revealed that the novel F197S mutant protein had reduced exonuclease and DNA polymerase activities and confirmed that T914P was inactive. By deep sequencing of mitochondrial DNA (mtDNA) extracted from muscle, multiple large-scale rearrangements were mapped and quantified.\nCONCLUSIONS: The patient's phenotype was caused by biallelic <i>POLG</i> mutations, resulting in one inactive POLγA protein (T914P) and one with decreased polymerase and exonuclease activity (F197S). The reduction in polymerase activity explains the presence of multiple pathogenic large-scale deletions in the patient's mtDNA.","variants":[{"Name":"NM_002693.3(POLG):c.2740A>C (p.Thr914Pro)","Chromosome":"15","Start":"89321007","Stop":"89321007","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":264890,"rule_based_match":true,"evidence_text":"c.2740A>C (p.T914P)","llm_judgment":"PRESENT","evidence":"c.2740A>C","abstract_start":893,"abstract_end":902}]}
{"pmid":"22622956","title":"Glucose transporter-1 (GLUT1) deficiency syndrome: diagnosis and treatment in late childhood.","abstract":"BACKGROUND: Typical cases of glucose transporter-1 deficiency syndrome (GLUT1-DS) present with early-onset epilepsy. We report symptoms, diagnostic results, and effects of therapy in two patients diagnosed with GLUT1-DS at the age of 10 and 15 years, respectively.\nPATIENTS: Patient 1: After four cerebral seizures in the first 2 years of life the patient was seizure-free but showed a complex movement disorder, expressive speech disorder, and mental retardation. Ratio of cerebrospinal fluid (CSF) to blood glucose was 0.41 (reference range 0.65 ± 0.1), molecular genetic testing confirmed GLUT1 deficiency with the novel pathogenic mutation c.1377dupC (p.Phe460LeufsX3) in the SLC2A1 gene. Following 9 months of ketogenic diet started at the age of 10 years, there was distinct improvement of speech and movement disorder. Patient 2 showed pharmacorefractive epilepsy, mental retardation, and a mild movement disorder. At the age of 15 years, extensive intake of food with high fat content was observed. Ratio of CSF to blood glucose was 0.41 (reference range 0.65 ± 0.1). The pathogenic mutation c.634C>T (p.Arg212Cys) was found in the SLC2A1 gene.\nCONCLUSION: Self-induced high-fat diet can be a hint toward GLUT1-DS. Ketogenic diet can be beneficial even when started in late childhood, although it may take several months to achieve a positive effect.","variants":[{"Name":"NM_006516.4(SLC2A1):c.634C>T (p.Arg212Cys)","Chromosome":"1","Start":"42929918","Stop":"42929918","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45874,"rule_based_match":true,"evidence_text":"c.634C>T (p.Arg212Cys)","llm_judgment":"PRESENT","evidence":"c.634C>T (p.Arg212Cys)","abstract_start":1100,"abstract_end":1122}]}
{"pmid":"20018682","title":"Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation.","abstract":"We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139_140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose \"TMCO1 defect syndrome\" as the name of this condition.","variants":[{"Name":"NM_019026.6(TMCO1):c.139_140del (p.Gln46_Ser47insTer)","Chromosome":"1","Start":"165768200","Stop":"165768201","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":404973,"rule_based_match":true,"evidence_text":"c.139_140delAG","llm_judgment":"PRESENT","evidence":"c.139_140delAG","abstract_start":778,"abstract_end":792}]}
{"pmid":"17161971","title":"Mutational analysis of mucopolysaccharidosis type VI patients undergoing a phase II trial of enzyme replacement therapy.","abstract":"Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-4-sulfatase (ARSB) gene. These mutations result in a deficiency of ARSB activity. Ten MPS VI patients were involved in a phase II clinical study of enzyme replacement therapy. Direct sequencing of genomic DNA from these patients was used to identify ARSB mutations. Each individual exon of the ARSB gene was amplified by PCR and subsequently sequenced. Thirteen substitutions (c.215T>G [p.L72R] c.284G>A [p.R95Q], c.305G>A [p.R102H], c.323G>T [p.G108V], c.389C>T [p.P130L], c.511G>A [p.G171S], c.904G>A [p.G302R], c.944G>A [p.R315Q], c.1057T>C [p.W353R], c.1151G>A [p.S384N], c.1178A>C [p.H393P], c.1289A>G [p.H430R] and c.1336G>C [p.G446R]), one deletion (c.238delG), and two intronic mutations (c.1213+5G>A and c.1214-2A>G) were identified. Nine of the 16 mutations identified were novel (R102H, G108V, P130L, G171S, W353R, H430R, G446R, c.1213+5G>A and c.1214-2A>G). The two common polymorphisms c.1072G>A [p.V358M] and c.1126G>A [p.V376M] were identified in some of the patients, along with the silent mutations c.972A>G and c.1191A>G. Cultured fibroblast ARSB mutant protein and residual activity were determined for each patient and, together with genotype information, used to predict the expected clinical severity of each patient.","variants":[{"Name":"NM_000046.5(ARSB):c.1336G>C (p.Gly446Arg)","Chromosome":"5","Start":"78781852","Stop":"78781852","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":550409,"rule_based_match":true,"evidence_text":"c.1336G>C (p.G446R)","llm_judgment":"PRESENT","evidence":"c.1336G>C","abstract_start":766,"abstract_end":775},{"Name":"NM_000046.5(ARSB):c.215T>G (p.Leu72Arg)","Chromosome":"5","Start":"78985034","Stop":"78985034","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":550539,"rule_based_match":true,"evidence_text":"c.215T>G [p.L72R]","llm_judgment":"PRESENT","evidence":"c.215T>G [p.L72R]","abstract_start":522,"abstract_end":539},{"Name":"NM_000046.5(ARSB):c.1289A>G (p.His430Arg)","Chromosome":"5","Start":"78781899","Stop":"78781899","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":550414,"rule_based_match":true,"evidence_text":"c.1289A>G [p.H430R]","llm_judgment":"PRESENT","evidence":"c.1289A>G [p.H430R]","abstract_start":742,"abstract_end":761},{"Name":"NM_000046.5(ARSB):c.1214-2A>G","Chromosome":"5","Start":"78781976","Stop":"78781976","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":550419,"rule_based_match":true,"evidence_text":"c.1214-2A>G","llm_judgment":"PRESENT","evidence":"c.1214-2A>G","abstract_start":858,"abstract_end":869},{"Name":"NM_000046.5(ARSB):c.238del (p.Val80fs)","Chromosome":"5","Start":"78985011","Stop":"78985011","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":15920,"rule_based_match":true,"evidence_text":"c.238delG","llm_judgment":"PRESENT","evidence":"c.238delG","abstract_start":802,"abstract_end":811},{"Name":"NM_000046.5(ARSB):c.284G>A (p.Arg95Gln)","Chromosome":"5","Start":"78984965","Stop":"78984965","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15923,"rule_based_match":true,"evidence_text":"c.284G>A [p.R95Q]","llm_judgment":"PRESENT","evidence":"c.284G>A [p.R95Q]","abstract_start":540,"abstract_end":557},{"Name":"NM_000046.5(ARSB):c.1178A>C (p.His393Pro)","Chromosome":"5","Start":"78839391","Stop":"78839391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":15925,"rule_based_match":true,"evidence_text":"c.1178A>C (p.H393P)","llm_judgment":"PRESENT","evidence":"c.1178A>C","abstract_start":721,"abstract_end":730},{"Name":"NM_000046.5(ARSB):c.904G>A (p.Gly302Arg)","Chromosome":"5","Start":"78885822","Stop":"78885822","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550457,"rule_based_match":true,"evidence_text":"c.904G>A (p.G302R)","llm_judgment":"PRESENT","evidence":"c.904G>A","abstract_start":639,"abstract_end":647},{"Name":"NM_000046.5(ARSB):c.944G>A (p.Arg315Gln)","Chromosome":"5","Start":"78885782","Stop":"78885782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":177363,"rule_based_match":true,"evidence_text":"c.944G>A [p.R315Q]","llm_judgment":"PRESENT","evidence":"c.944G>A [p.R315Q]","abstract_start":659,"abstract_end":677},{"Name":"NM_000046.5(ARSB):c.511G>A (p.Gly171Ser)","Chromosome":"5","Start":"78964595","Stop":"78964595","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550485,"rule_based_match":true,"evidence_text":"c.511G>A [p.G171S]","llm_judgment":"PRESENT","evidence":"c.511G>A [p.G171S]","abstract_start":619,"abstract_end":637},{"Name":"NM_000046.5(ARSB):c.1151G>A (p.Ser384Asn)","Chromosome":"5","Start":"78839418","Stop":"78839418","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":98263,"rule_based_match":true,"evidence_text":"c.1151G>A [p.S384N]","llm_judgment":"PRESENT","evidence":"c.1151G>A [p.S384N]","abstract_start":700,"abstract_end":719},{"Name":"NM_000046.5(ARSB):c.389C>T (p.Pro130Leu)","Chromosome":"5","Start":"78969116","Stop":"78969116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":550502,"rule_based_match":true,"evidence_text":"c.389C>T [p.P130L]","llm_judgment":"PRESENT","evidence":"c.389C>T [p.P130L]","abstract_start":599,"abstract_end":617},{"Name":"NM_000046.5(ARSB):c.323G>T (p.Gly108Val)","Chromosome":"5","Start":"78969182","Stop":"78969182","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":550510,"rule_based_match":true,"evidence_text":"c.323G>T [p.G108V]","llm_judgment":"PRESENT","evidence":"c.323G>T [p.G108V]","abstract_start":579,"abstract_end":597},{"Name":"NM_000046.5(ARSB):c.305G>A (p.Arg102His)","Chromosome":"5","Start":"78984944","Stop":"78984944","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550513,"rule_based_match":true,"evidence_text":"c.305G>A [p.R102H]","llm_judgment":"PRESENT","evidence":"c.305G>A [p.R102H]","abstract_start":559,"abstract_end":577}]}
{"pmid":"26195043","title":"Confirmation of TTC8 as a disease gene for nonsyndromic autosomal recessive retinitis pigmentosa (RP51).","abstract":"Nonsyndromic retinitis pigmentosa (RP) is genetically highly heterogeneous, with >100 disease genes identified. However, mutations in these genes explain only 60% of all RP cases. Blood samples were collected from 12 members of an autosomal recessive RP family. Whole genome homozygosity mapping and haplotype analysis placed the RP locus in this family at chromosome 14q31.3. Whole-exome sequencing (WES) in proband revealed a mutation in TTC8, which was flagged as most likely candidate gene by bioinformatic analysis. TTC8 is mutated in Bardet-Biedl syndrome 8 (BBS8), and once reported previously in a family with nonsyndromic RP. Sequencing of amplified products of exon 13 of TTC8 validated c.1347G>C (p.Gln449His), a novel change that affects the final nucleotide of exon 13 and might deleteriously affect splicing. This mutation segregated completely with the disease in the family and was not observed in 100 ethnically matched controls from same population. This represents second report of a TTC8 mutation in nonsyndromic RP, thus confirming the identity of TTC8 as causative gene for RP51.","variants":[{"Name":"NM_144596.4(TTC8):c.1347G>C (p.Gln449His)","Chromosome":"14","Start":"88872452","Stop":"88872452","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":236865,"rule_based_match":true,"evidence_text":"c.1347G>C (p.Gln449His)","llm_judgment":"PRESENT","evidence":"c.1347G>C (p.Gln449His)","abstract_start":697,"abstract_end":720}]}
{"pmid":"20132997","title":"Three novel mutations in MODY and its phenotype in three different Czech families.","abstract":"AIMS/HYPOTHESIS: MODY (Maturity Onset Diabetes of the Young) is an autosomal dominant inherited type of diabetes with significant genetic heterogeneity. New mutations causing MODY are still being found. A genetically confirmed diagnosis of MODY allows application of individualized treatment based on the underlying concrete genetic dysfunction. Detection of novel MODY mutations helps provide a more complete picture of the possible MODY genotypes.\nMATERIALS AND METHODS: We tested 43 adult Czech patients with clinical characteristics of MODY, using direct sequencing of HNF1A (hepatocyte nuclear factor 1-alpha), HNF4A (hepatocyte nuclear factor 4-alpha) and GCK (glucokinase) genes.\nRESULTS: In three Czech families we identified three novel mutations we believe causing MODY-two missense mutations in HNF1A [F268L (c.802T>C) and P291S (c.871C>T)] and one frame shift mutation in GCK V244fsdelG (c.729delG). Some of the novel HNF1A mutation carriers were successfully transferred from insulin to gliclazide, while some of the novel GCK mutation carriers had a good clinical response when switched from insulin or oral antidiabetic drugs to diet.\nCONCLUSION: We describe three novel MODY mutations in three Czech families. The identification of MODY mutations had a meaningful impact on therapy on the mutation carriers.","variants":[{"Name":"NM_000545.8(HNF1A):c.802T>C (p.Phe268Leu)","Chromosome":"12","Start":"120994252","Stop":"120994252","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1318225,"rule_based_match":true,"evidence_text":"c.802T>C","llm_judgment":"PRESENT","evidence":"c.802T>C","abstract_start":820,"abstract_end":828},{"Name":"NM_000545.8(HNF1A):c.871C>T (p.Pro291Ser)","Chromosome":"12","Start":"120994321","Stop":"120994321","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":441528,"rule_based_match":true,"evidence_text":"c.871C>T","llm_judgment":"PRESENT","evidence":"c.871C>T","abstract_start":841,"abstract_end":849}]}
{"pmid":"22551409","title":"Genotype-phenotype correlations in Bothnia dystrophy caused by RLBP1 gene sequence variations.","abstract":"PURPOSE: To evaluate phenotypes caused by different RLBP1 mutations in autosomal recessive retinitis pigmentosa of Bothnia type.\nMETHODS: Compound heterozygotes for mutations in the RLBP1 gene [c.677T>A]+[c.700C>T] (p.M226K+p.R234W), n = 10, aged 7-84 years, and homozygotes c.677T>A (p.M226K), n = 2, aged 63 and 73 years, were studied using visual acuity (VA), low-contrast VA, visual fields (VFs) and optical coherence tomography (OCT). Retrospective VA and VFs, standardized dark adaptation and full-field electroretinograms (ERGs) were analysed and prolonged dark adaptometry and ERG (at 24 hr) were performed.\nRESULTS: Progressive decline of VA and VF areas was age-dependent. Retinal degenerative maculopathy, peripheral degenerative changes and retinitis punctata albescens (RPA) were present. Early retinal thinning in the central foveal, foveal (Ø 1 mm), and inner ring (Ø 3 mm) in the macular region, with homogenous, high-reflectance RPA changes, was visualized in and adjacent to the retinal pigment epithelium/choriocapillaris using OCT. Reduced dark adaptation and affected ERGs were present in all ages. Prolonged dark adaptation and ERG (at 24 hr), an increase in final threshold, and ERG rod and mixed rod/cone responses were found.\nCONCLUSIONS: The two RLBP1 genotypes presented a phenotypical and electrophysiological expression of progressive retinal disease similar to that previously described in homozygotes for the c.700C>T (p.R234W) RLBP1 mutation. The uniform phenotypical expression of RLBP1 mutations is relevant information for the disease and of importance in planning future treatment strategies.","variants":[{"Name":"NM_000326.5(RLBP1):c.677T>A (p.Met226Lys)","Chromosome":"15","Start":"89211750","Stop":"89211750","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":28140,"rule_based_match":true,"evidence_text":"c.677T>A (p.M226K)","llm_judgment":"PRESENT","evidence":"c.677T>A (p.M226K)","abstract_start":275,"abstract_end":293}]}
{"pmid":"25604815","title":"CRTAP mutation in a patient with Cole-Carpenter syndrome.","abstract":"In 1987, Cole and Carpenter reported two unrelated infants with multiple fractures and deformities of bone, with a skeletal phenotype similar to severe osteogenesis imperfecta. In addition, these patients also had proptosis, blue sclerae, hydrocephalus, and a distinct facial gestalt. They were reported to be of normal intelligence. Radiologically, these patients had characteristic skeletal manifestations including craniosynostosis and deformities similar to severe progressive osteogenesis imperfecta. Since the first description, there have only been a few other reports of patients with a similar phenotype. Collagen studies performed in reported patients have been normal. The molecular basis of this syndrome has not been elucidated and the inheritance pattern is still unknown. We report on a child with Cole-Carpenter syndrome phenotype who has a homozygous c.118G>T mutation in exon 1 of the CRTAP gene. We describe the clinical features and correlate this with her molecular results. This is the first report towards elucidating the molecular basis of Cole-Carpenter syndrome.","variants":[{"Name":"NM_006371.5(CRTAP):c.118G>T (p.Glu40Ter)","Chromosome":"3","Start":"33114195","Stop":"33114195","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":213900,"rule_based_match":true,"evidence_text":"c.118G>T","llm_judgment":"PRESENT","evidence":"c.118G>T","abstract_start":868,"abstract_end":876}]}
{"pmid":"25614306","title":"Expanding the Clinical Spectrum of Mitochondrial Citrate Carrier (SLC25A1) Deficiency: Facial Dysmorphism in Siblings with Epileptic Encephalopathy and Combined D,L-2-Hydroxyglutaric Aciduria.","abstract":"Recessive mutations in SLC25A1 encoding mitochondrial citrate carrier cause a rare inherited metabolic disorder, combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA), characterized by epileptic encephalopathy, respiratory insufficiency, developmental arrest and early death. Here, we describe two siblings compound heterozygotes for null/missense SLC25A1 mutations, c.18_24dup (p.Ala9Profs*82), and c.134C>T (p.Pro45Leu). These children presented with classic clinical features of D,L-2-HGA, but also showed marked facial dysmorphism. Additionally, there was prominent lactic acidosis in one of the siblings. Our observations suggest that facial dysmorphism is a previously unrecognized but an important diagnostic feature of SLC25A1 deficiency and expand the clinical phenotype linked to SLC25A1 mutations.","variants":[{"Name":"NM_005984.5(SLC25A1):c.18_24dup (p.Ala9fs)","Chromosome":"22","Start":"19178649","Stop":"19178650","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CGCGCGGG","allel_id":1709108,"rule_based_match":true,"evidence_text":"c.18_24dup (p.Ala9Profs*82)","llm_judgment":"PRESENT","evidence":"c.18_24dup (p.Ala9Profs*82)","abstract_start":365,"abstract_end":392}]}
{"pmid":"21670405","title":"Novel POLG splice site mutation and optic atrophy.","abstract":"OBJECTIVE: To investigate the molecular etiology of 2 unrelated patients with a multisystem mitochondrial disorder accompanied by optic atrophy in one of them.\nDESIGN: Clinical examination and neurophysiological, radiological, morphological, and molecular analyses.\nSETTING: Tertiary care neuromuscular clinic and molecular genetics laboratory.\nPATIENTS: A 65-year-old man (patient 1) with dyschromatopsia and vision loss since childhood developed progressive external ophthalmoplegia, ptosis, and myopathy in the seventh decade of life and was found to have optic atrophy. A 63-year-old man (patient 2) with a similar phenotype, without visual symptoms, experienced also hearing loss and parkinsonism.\nMAIN OUTCOME MEASURES: Description of the clinical and molecular findings.\nRESULTS: A muscle biopsy specimen showed ragged-red, ragged-blue, and cytochrome c oxidase-negative fibers in both patients. Because optic atrophy in patient 1 suggested an autosomal dominant OPA1-related disorder, the OPA1 gene was first sequenced, the results of which did not detect any mutations. Southern blot and polymerase chain reaction analyses of muscle mitochondrial DNA revealed multiple deletions. Sequencing of POLG detected a novel variant, c.3104 + 3A>T, in both patients. Patient 1 was compound heterozygous for a known p.F749S mutation; patient 2 had p.G848S as the second mutation. Analysis of POLG complementary DNA showed that c.3104 + 3A>T results in skipping of exon 18.\nCONCLUSION: Early-onset dyschromatopsia and optic atrophy can occur not only in OPA1-related but also in POLG-related disorders with significant impact on genetic counseling.","variants":[{"Name":"NM_002693.3(POLG):c.3104+3A>T","Chromosome":"15","Start":"89319225","Stop":"89319225","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":580246,"rule_based_match":true,"evidence_text":"c.3104 + 3A>T","llm_judgment":"PRESENT","evidence":"c.3104 + 3A>T","abstract_start":1234,"abstract_end":1247}]}
{"pmid":"32761583","title":"Identification of a novel variant of COL4A5 gene in a pedigree affected with Alport syndrome","abstract":"OBJECTIVE: To explore the genetic basis for a pedigree affected with Alport syndrome.\nMETHODS: Next generation sequencing and Sanger sequencing was carried out to detect potential variant of the COL4A5 gene among members from the pedigree and 100 unrelated healthy controls.\nRESULTS: A novel missense c.3293G>T (p.Gly1098Val) variant was found in the COL4A5 gene among 6 affected members but not the unaffected members of the pedigree or the 100 healthy controls. According to the American College of Medical Genetics and Genomics standards and guidelines, the c.3293G>T variant was classified as pathogenic (PP1-strong+PM1+PM2+PP3+PP4).\nCONCLUSION: By destructing the Gly-X-Y structure of its protein product, the c.3293G>T variant of the COL4A5 gene probably underlies the Alport syndrome in this pedigree. Above finding has enriched the spectrum of COL4A5 variants.","variants":[{"Name":"NM_033380.3(COL4A5):c.3293G>T (p.Gly1098Val)","Chromosome":"X","Start":"108655377","Stop":"108655377","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3738663,"rule_based_match":true,"evidence_text":"c.3293G>T (p.Gly1098Val)","llm_judgment":"PRESENT","evidence":"c.3293G>T (p.Gly1098Val)","abstract_start":301,"abstract_end":325}]}
{"pmid":"32797665","title":"Recurrent fever of unknown origin: An overlooked symptom of Fabry disease.","abstract":"OBJECTIVE: Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to the absent or deficient activity of lysosomal hydrolase a-galactosidase A (α-Gal A), which leads to the accumulation of its substrates in various organs and tissues. Classic clinical manifestations include angiokeratomas, proteinuria, renal failure, neuropathic pain, and left ventricular hypertrophy. Fever is one of the rare symptoms that may occur during FD.\nMETHODS: Three Chinese Han patients with FD referred to Peking Union Medical College Hospital were reported. The complete medical records were established, and detailed data were collected. Whole-exome sequencing by next-generation sequencing and α-Gal A enzyme activity assay were performed to confirm the diagnosis.\nRESULTS: These three patients all presented with recurrent fever of unknown origin initially, accompanied with arthralgia/arthritis and other symptoms. We identified two known variants in the GLA gene, c.1176_1179delGAAG and c.782G>A (p.G261D), and a novel variant c.440G>A (p.G147E) which is likely pathogenic in our patient.\nCONCLUSIONS: FD should be considered as a rare cause of recurrent fever of unknown origin. The coexistence of gene variants related to systemic autoinflammatory diseases may make the clinical phenotypes of FD more complex and prone to recurrent fever.","variants":[{"Name":"NM_000169.3(GLA):c.782G>A (p.Gly261Asp)","Chromosome":"X","Start":"101398804","Stop":"101398804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":965870,"rule_based_match":true,"evidence_text":"c.782G>A (p.G261D)","llm_judgment":"PRESENT","evidence":"c.782G>A (p.G261D)","abstract_start":988,"abstract_end":1006}]}
{"pmid":"35488210","title":"NGS-based targeted sequencing identified two novel variants in Southwestern Chinese families with oculocutaneous albinism.","abstract":"BACKGROUND: Oculocutaneous albinism (OCA) is a group of heterogeneous genetic diseases characterized by a reduction or complete lack of pigmentation in the hair, skin, and eyes. It is associated with reduced visual acuity, nystagmus, photophobia, and strabismus. OCA type 1 (OCA1) and type 2 (OCA2) are caused by mutations in the tyrosinase (TYR) and OCA2 genes, which are responsible for most cases of OCA. The present study aimed to identify the mutational spectra of 18 southwest Chinese probands with OCA.\nRESULTS: We used a skin disease-targeted panel to sequence more than 400 genes, including 23 genes (TYR, OCA2, AP3B1, BLOC1S3, BLOC1S6, C10orf11, DTNBP1, FRMD7, GPR143, HPS1, HPS3, HPS4, HPS5, HPS6, LYST, MC1R, MITF, MLPH, MYO5A, RAB27A, SLC24A5, SLC45A2, TYRP1) associated with syndromic and non-syndromic albinism. The targeted panel was applied to 18 patients from southwest China, nine (50%) patients were diagnosed with OCA1, and nine (50%) were diagnosed with OCA2. Our data indicate that OCA1 and OCA2, the most common subtypes, probably have the same prevalence in southwest China. In total, we identified 26 variants in TYR and OCA2 from 18 OCA cases using the NGS technology, including 24 variants presented in the Human Gene Mutation Database Professional (HGMD) and two novel variants, c.559_560insCATTATTATGTGTCAAATTATCCCC in TYR and c.1514 T > C in OCA2, which have not been previously reported. According to the American College of Medical Genetics and Genomics (ACMG) classification, c.559_560insCATTATTATGTGTCAAATTATCCCC (p.G190Cfs*12) is classified as a pathogenic variant, and c.1514 T > C (p.F505S) is evaluated as a likely pathogenic variant.\nCONCLUSIONS: Two novel variants were identified which will expand the mutational spectra of TYR and OCA2. The results of the present study may have implications for genetic counseling, carrier screening, and clinical management of the disease.","variants":[{"Name":"NM_000275.3(OCA2):c.1514T>C (p.Phe505Ser)","Chromosome":"15","Start":"27966812","Stop":"27966812","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2967837,"rule_based_match":true,"evidence_text":"c.1514 T > C (p.F505S)","llm_judgment":"PRESENT","evidence":"c.1514 T > C (p.F505S)","abstract_start":1606,"abstract_end":1628}]}
{"pmid":"36457512","title":"Case report: Undifferentiated sarcoma with multiple tumors involved in Lynch syndrome: Unexpected favorable outcome to sintilimab combined with chemotherapy.","abstract":"Background: Patients with Lynch syndrome are at an increased risk of developing simultaneous or metachronous tumors, while sarcomas have been occasionally reported. Sarcomas are generally not considered part of the common Lynch syndrome tumor spectrum. However, more and more studies and case reports suggested that sarcoma could be a rare clinical manifestation of Lynch syndrome, leading to new treatment strategies for sarcoma.\nCase summary: We report the case of a 74-year-old male patient with Lynch syndrome who had rectal mucinous adenocarcinoma and prostate adenocarcinoma and then developed undifferentiated sarcoma of the left neck two years later. Mismatch repair deficiency (dMMR) was confirmed by immunohistochemical staining for the mismatch repair proteins MSH2, MSH6, MLH1 and PMS2. The result of polymerase chain reaction (PCR) microsatellite instability (MSI) testing of sarcoma showed high-level microsatellite instability (MSI-H). Additionally, a pathogenic germline mutation in MSH2 (c.2459-12A>G) was detected by next-generation sequencing (NGS). Taking into account HE morphology, immunohistochemical phenotype, MSI status, NGS result, medical history and germline MSH2 gene mutation, the pathological diagnosis of left neck biopsy tissue was Lynch syndrome related undifferentiated sarcoma with epithelioid morphology. The patient has been receiving immunotherapy (sintilimab) combined with chemotherapy (tegafur, gimeracil and oteracil potassium capsules) and currently has stable disease. We also reviewed the literature to understand the association between sarcoma and Lynch syndrome.\nConclusion: Sarcoma may now be considered a rare clinical manifestation of Lynch syndrome. Attention and awareness about the association between Lynch syndrome and sarcoma need to be increased. Therefore, timely detection of MMR proteins and validation at the gene level for suspicious patients are the keys to avoiding missed or delayed diagnosis and to identifying patients suited for immunotherapy, which may also help to provide appropriate genetic counseling and follow-up management for patients.","variants":[{"Name":"NM_000251.3(MSH2):c.2459-12A>G","Chromosome":"2","Start":"47480684","Stop":"47480684","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":96452,"rule_based_match":true,"evidence_text":"c.2459-12A>G","llm_judgment":"PRESENT","evidence":"c.2459-12A>G","abstract_start":1005,"abstract_end":1017}]}
{"pmid":"36562171","title":"Fatal congenital copper transport defect caused by a homozygous likely pathogenic variant of SLC31A1.","abstract":"Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X-linked spinal muscular atrophy type 3) and ATP7B (Wilson disease). Herein, we report a newborn infant of consanguineous parents with a homozygous pathogenic variant in a highly conserved sequence of SLC31A1, coding for the copper influx transporter 1, CTR1. This missense variant, c.236T > C, was detected by whole exome sequencing. The infant was born with pulmonary hypoplasia and suffered from severe respiratory distress immediately after birth, necessitating aggressive mechanical ventilation. At 2 weeks of age, multifocal brain hemorrhages were diagnosed by cerebral ultrasound and magnetic resonance imaging, together with increased tortuosity of cerebral arteries. Ensuing seizures were only partly controlled by antiepileptic drugs, and the infant became progressively comatose. Laboratory investigations revealed very low serum concentrations of copper and ceruloplasmin. No hair shaft abnormalities were detected by dermatoscopy or light microscopic analyses of embedded hair shafts obtained at 4 weeks of life. The infant died after redirection of care and elective cessation of invasive mechanical ventilation at 1 month of age. This case adds SLC31A1 to the genes implicated in severe hereditary disorders of copper transport in humans.","variants":[{"Name":"NM_001859.4(SLC31A1):c.236T>C (p.Leu79Pro)","Chromosome":"9","Start":"113258727","Stop":"113258727","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1780270,"rule_based_match":true,"evidence_text":"c.236T > C","llm_judgment":"PRESENT","evidence":"c.236T > C","abstract_start":434,"abstract_end":444}]}
{"pmid":"34864681","title":"Late Onset Pompe Disease with Novel Mutations and Atypical Phenotypes.","abstract":"BACKGROUND: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues.\nMATERIALS AND METHODS: We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD.\nRESULTS: The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=).\nCONCLUSION: We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT).","variants":[{"Name":"NM_000152.5(GAA):c.971C>T (p.Pro324Leu)","Chromosome":"17","Start":"80108305","Stop":"80108305","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":426256,"rule_based_match":true,"evidence_text":"c.971C>T (p.Pro324Leu)","llm_judgment":"PRESENT","evidence":"c.971C > T (p.Pro324Leu)","abstract_start":1206,"abstract_end":1230},{"Name":"NM_000152.5(GAA):c.794G>A (p.Ser265Asn)","Chromosome":"17","Start":"80107658","Stop":"80107658","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":489705,"rule_based_match":true,"evidence_text":"c.794G>A (p.Ser265Asn)","llm_judgment":"PRESENT","evidence":"c.794G > A (p.Ser265Asn)","abstract_start":1235,"abstract_end":1259},{"Name":"NM_000152.5(GAA):c.1396dup (p.Val466fs)","Chromosome":"17","Start":"80110008","Stop":"80110009","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":2835909,"rule_based_match":true,"evidence_text":"c.1396dupG (p.Val466GlyfsTer40)","llm_judgment":"PRESENT","evidence":"c.1396dupG (p.Val466GlyfsTer40)","abstract_start":1321,"abstract_end":1352}]}
{"pmid":"32976546","title":"Pathogenic variants of AIPL1, MERTK, GUCY2D, and FOXE3 in Pakistani families with clinically heterogeneous eye diseases.","abstract":"Significant number out of 2.2 billion vision impairments in the world can be attributed to genetics. The current study is aimed to decipher the genetic basis of Leber congenital Amaurosis (LCA), Anterior Segment dysgenesis (ASD), and Retinitis Pigmentosa (RP), segregating in four large consanguineous Pakistani families. The exome sequencing followed by segregation analysis via Sanger sequencing revealed the LCA phenotypes segregating in families GCUF01 and GCUF04 can be attributed to c.465G>T (p.(Gln155His)) missense and novel c.139_140delinsA p.(Pro47Trhfster38) frameshift variant of AIPL1 and GUCY2D, respectively. The c.1843A>T (p.(Lys615*) truncating allele of MERTK is homozygous in all the affected individuals, presumably suffering with RP, of the GCUF02 family. Meanwhile, co-segregation of the ASD phenotype and the c.289A>G (p.(Ile97Val)) variant of FOXE3 was found in the GCUF06 family. All the identified variants were either absent or present in very low frequencies in the control databases. Our in-silico analyses and 3D molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in MERTK, GUCY2D, and FOXE3 were categorized as \"pathogenic\" or \"likely pathogenic\", while the missense variant found in AIPL1 was deemed to have \"uncertain significance\" based upon the variant pathogenicity guidelines from the American College of Medical Genetics and Genomics (ACMG). This paper highlights the genetic diversity of vision disorders in the Pakistani population and reports the identification of four novel mutations in families who segregate clinically heterogeneous eye diseases. Our results give insight into the genotype-phenotype correlations of AIPL1, FOXE3, MERTK, and GUCY2D variants.","variants":[{"Name":"NM_012186.3(FOXE3):c.289A>G (p.Ile97Val)","Chromosome":"1","Start":"47416604","Stop":"47416604","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":971542,"rule_based_match":true,"evidence_text":"c.289A>G (p.(Ile97Val))","llm_judgment":"PRESENT","evidence":"c.289A>G (p.(Ile97Val))","abstract_start":832,"abstract_end":855}]}
{"pmid":"30733730","title":"","abstract":"<b>Background:</b> Limb-girdle muscular dystrophy (LGMD) is an increasingly heterogeneous category of inherited muscle diseases, mainly affecting the muscles of shoulder areas and the hip, segregating in both autosomal recessive and dominant manner. To-date, thirty-one loci have been identified for LGMD including seven autosomal dominant (LGMD type 1) and twenty four autosomal recessive (LGMD type 2) inherited loci. <b>Methodology/Laboratory Examination:</b> The present report describes a consanguineous family segregating LGMD2F in an autosomal recessive pattern. The affected individual is an 11-year-old boy having two brothers and a sister. Direct targeted next generation sequencing was performed for the single affected individual (VI-1) followed by Sanger sequencing. <b>Results:</b> Targeted next generation sequencing revealed a novel homozygous nonsense mutation (c.289C>T; p.Arg97<sup>∗</sup>) in the exon 3 of the delta-sarcoglycan (<i>SGCD</i>) gene, that introduces a premature stop codon (TCA), resulting in a nonsense mediated decay or a truncated protein product. <b>Discussion and Conclusion:</b> This is the first report of LGMD2F caused by an <i>SGCD</i> variant in a Pakistani population. The mutation identified in the present investigation extends the body of evidence implicating the gene <i>SGCD</i> in causing LGMD2F and might help in genetic counseling, which is more important to deliver the risk of carrier or affected in the future pregnancies.","variants":[{"Name":"NM_000337.6(SGCD):c.289C>T (p.Arg97Ter)","Chromosome":"5","Start":"156508697","Stop":"156508697","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1669143,"rule_based_match":true,"evidence_text":"c.289C>T; p.Arg97<sup>∗</sup>","llm_judgment":"PRESENT","evidence":"c.289C>T; p.Arg97<sup>∗</sup>","abstract_start":879,"abstract_end":908}]}
{"pmid":"18035376","title":"Identification of an Arg35X mutation in the PDCD10 gene in a patient with cerebral and multiple spinal cavernous malformations.","abstract":"Although cerebral cavernous malformations (CCMs) are not uncommon, the concurrent finding of cavernous malformations (CMs) both in the brain and spinal cord is quite rare. Furthermore, multiple spinal cord CMs are extremely rare with only a few cases being reported thus far. Recently, we encountered a 33-year-old Korean male with both CCM and multiple spinal intramedullary CMs. The patient complained of seizure and right chest paresthesia. The lesions were located throughout the neuraxis including the cerebral hemisphere, brain stem, and cervical and thoracic spinal cords. Molecular analysis of the KRIT1 (CCM1), CCM2, and PDCD10 (CCM3) genes identified a heterozygous nonsense mutation (c.103C>T; Arg35X) in the PDCD10 gene, which was reported previously in a CCM family. The patient denied a family history, however, his daughter had an identical mutation, but was asymptomatic. Three months later, after identifying the mutation in the father and the daughter, the daughter presented with seizure. To the best of our knowledge, this is the first report of an association between a mutation in the PDCD10 gene and spinal CMs.","variants":[{"Name":"NM_007217.4(PDCD10):c.103C>T (p.Arg35Ter)","Chromosome":"3","Start":"167704889","Stop":"167704889","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":359498,"rule_based_match":true,"evidence_text":"c.103C>T; Arg35X","llm_judgment":"PRESENT","evidence":"c.103C>T; Arg35X","abstract_start":695,"abstract_end":711}]}
{"pmid":"16261627","title":"A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and site-specific vestibular and central oculomotor dysfunction.","abstract":"Mutations within the COCH gene (encoding the cochlin protein) lead to auditory and vestibular impairment in the DFNA9 disorder. In this study, we describe the genetic mapping of progressive autosomal dominant sensorineural hearing loss first affecting high-frequency auditory thresholds within a human pedigree to the long arm of chromosome 14 in band q12. A maximal pairwise LOD score of 7.08 was obtained with marker D14S1021. We identified a c.1625G > T mutation in exon 12 of COCH that co-segregates with auditory dysfunction in the pedigree. The mutation results in a predicted p.C542F substitution at an evolutionarily conserved cysteine residue in the C-terminus of cochlin. The c.1625G > T transversion in COCH exon 12 represents the first reported mutation outside of the LCCL domain which is encoded by exons 4 and 5. The 542F mutant cochlin is translated and secreted by transfected mammalian cells. Western blot analysis under non-reducing and reducing conditions suggests that the 542F mutation alters intramolecular cochlin disulfide bond formation. In the vestibular system, a progressive horizontal canal hypofunction and a probable saccular otolith challenge were detected in family members with the c.1625G > T COCH alteration. Abnormal central oculomotor test results in family members with the c.1625G > T COCH alteration imply a possible central nervous system change not previously noted in DFNA9 pedigrees harboring mutations within the LCCL domain.","variants":[{"Name":"NM_004086.3(COCH):c.1625G>T (p.Cys542Phe)","Chromosome":"14","Start":"30889763","Stop":"30889763","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":21653,"rule_based_match":true,"evidence_text":"c.1625G > T","llm_judgment":"PRESENT","evidence":"c.1625G > T","abstract_start":445,"abstract_end":456}]}
{"pmid":"27879208","title":"Generation of induced pluripotent stem cells (iPSCs) from a retinoblastoma patient carrying a c.2663G>A mutation in RB1 gene.","abstract":"Skin fibroblasts were obtained from a male patient diagnosed with retinoblastoma (RB) carrying a c.2663G>A mutation in the 25 exon of RB1 gene. RB-iPS cells was generated via delivered four reprogramming factors (OCT4, SOX2, NANOG and LIN28) into these skin fibroblasts. The RB-iPS cells retained the RB1 heterozygous mutation resulted in a truncated RB1 mRNA. Characteristic tests proved that the iPSC line presented typical markers of pluripotency and had the capability to form the three germ layers in vitro.","variants":[{"Name":"NM_000321.3(RB1):c.2663G>A (p.Ser888Asn)","Chromosome":"13","Start":"48476843","Stop":"48476843","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":528310,"rule_based_match":true,"evidence_text":"c.2663G>A","llm_judgment":"PRESENT","evidence":"c.2663G>A","abstract_start":97,"abstract_end":106}]}
{"pmid":"20668261","title":"Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations.","abstract":"BACKGROUND: Juvenile amyotrophic lateral sclerosis (ALS) with basophilic inclusions is a form of ALS characterized by protein deposits in motor neurons that are morphologically and tinctorially distinct from those of classic sporadic ALS. The nosologic position of this type of ALS in the molecular pathologic and genetic classification of ALS is unknown.\nMETHODS: We identified neuropathologically 4 patients with juvenile ALS with basophilic inclusions and tested the hypothesis that specific RNA binding protein pathology may define this type of ALS. Immunohistochemical findings prompted us to sequence the fused in sarcoma (FUS) gene.\nRESULTS: Motor symptoms began between ages 17 and 22. Disease progression was rapid without dementia. No family history was identified. Basophilic inclusions were strongly positive for FUS protein but negative for TAR DNA binding protein 43 (TDP-43). Granular and compact FUS deposits were identified in glia and neuronal cytoplasm and nuclei. Ultrastructure of aggregates was in keeping with origin from fragmented rough endoplasmic reticulum. Sequencing of all 15 exons of the FUS gene in 3 patients revealed a novel deletion mutation (c.1554_1557delACAG) in 1 individual and the c.1574C>T (P525L) mutation in 2 others.\nCONCLUSION: Juvenile ALS with basophilic inclusions is a FUS proteinopathy and should be classified as ALS-FUS. The FUS c.1574C>T (P525L) and c.1554_1557delACAG mutations are associated with this distinct phenotype. The molecular genetic relationship with frontotemporal lobar degeneration with FUS pathology remains to be clarified.","variants":[{"Name":"NM_004960.4(FUS):c.1554_1557del (p.Gln519fs)","Chromosome":"16","Start":"31191407","Stop":"31191410","ReferenceAlleleVCF":"CACAG","AlternateAlleleVCF":"C","allel_id":1063634,"rule_based_match":true,"evidence_text":"c.1554_1557delACAG","llm_judgment":"PRESENT","evidence":"c.1554_1557delACAG","abstract_start":1178,"abstract_end":1196},{"Name":"NM_004960.4(FUS):c.1574C>T (p.Pro525Leu)","Chromosome":"16","Start":"31191431","Stop":"31191431","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":264787,"rule_based_match":true,"evidence_text":"c.1574C>T (P525L)","llm_judgment":"PRESENT","evidence":"c.1574C>T (P525L)","abstract_start":1222,"abstract_end":1239}]}
{"pmid":"23669735","title":"Familial hemophagocytic lymphohistiocytosis type 3 diagnosed at school age: a case report.","abstract":"Familial hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by immune hyperactivation and clinical signs of extreme inflammation. We describe a 7-year-old male who presented with fever resistant to antibiotic therapy, pancytopenia, splenomegaly, hypertriglyceridemia, and hyperferritinemia. Bone marrow aspirate showed hemophagocytosis. Epstein-Barr virus genome was positive in blood. Functional screening showed reduced capacity of cytotoxic degranulation. Mutation analysis of the FHL-related genes revealed compound heterozygous for UNC13D mutations: c. 753+1G>T, and the novel c.544C>T (p.P182S). Patients with a clinical presentation of HLH, even if older than typically seen, should be screened for familial HLH by mutation analysis.","variants":[{"Name":"NM_199242.3(UNC13D):c.753+1G>T","Chromosome":"17","Start":"75840506","Stop":"75840506","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":17040,"rule_based_match":true,"evidence_text":"c. 753+1G>T","llm_judgment":"PRESENT","evidence":"c. 753+1G>T","abstract_start":597,"abstract_end":608},{"Name":"NM_199242.3(UNC13D):c.544C>T (p.Pro182Ser)","Chromosome":"17","Start":"75842458","Stop":"75842458","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1050654,"rule_based_match":true,"evidence_text":"c.544C>T (p.P182S)","llm_judgment":"PRESENT","evidence":"c.544C>T (p.P182S)","abstract_start":624,"abstract_end":642}]}
{"pmid":"22887876","title":"The germline TP53 mutation c.722 C>T promotes bone and liver tumorigenesis at a young age.","abstract":"","variants":[{"Name":"NM_000546.6(TP53):c.722C>T (p.Ser241Phe)","Chromosome":"17","Start":"7674241","Stop":"7674241","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27398,"rule_based_match":true,"evidence_text":"c.722 C>T","llm_judgment":"PRESENT","evidence":"c.722 C>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"22968132","title":"14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype.","abstract":"Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in ∼90-95% of classic cases and 40-60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1.","variants":[{"Name":"NM_005249.5(FOXG1):c.256dup (p.Gln86fs)","Chromosome":"14","Start":"28767528","Stop":"28767529","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":187402,"rule_based_match":true,"evidence_text":"c.256dupC, p.Gln86ProfsX35","llm_judgment":"PRESENT","evidence":"c.256dupC, p.Gln86ProfsX35","abstract_start":1175,"abstract_end":1201}]}
{"pmid":"28335037","title":"LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P.","abstract":"Charcot-Marie-Tooth (CMT) disease type 2 is a genetically heterogeneous group of inherited neuropathies characterized by motor and sensory deficits as a result of peripheral axonal degeneration. We recently reported a frameshift (FS) mutation in the Really Interesting New Gene finger (RING) domain of LRSAM1 (c.2121_2122dup, p.Leu708Argfs) that encodes an E3 ubiquitin ligase, as the cause of axonal-type CMT (CMT2P). However, the frequency of LRSAM1 mutations in CMT2 and the functional basis for their association with disease remains unknown. In this study, we evaluated LRSAM1 mutations in two large Dutch cohorts. In the first cohort (n = 107), we sequenced the full LRSAM1 coding exons in an unbiased fashion, and, in the second cohort (n = 468), we specifically sequenced the last, RING-encoding exon in individuals where other CMT-associated genes had been ruled out. We identified a novel LRSAM1 missense mutation (c.2120C > T, p.Pro707Leu) mapping to the RING domain. Based on our genetic analysis, the occurrence of pathogenic LRSAM1 mutations is estimated to be rare. Functional characterization of the FS, the identified missense mutation, as well as of another recently reported pathogenic missense mutation (c.2081G > A, p.Cys694Tyr), revealed that in vitro ubiquitylation activity was largely abrogated. We demonstrate that loss of the E2-E3 interaction that is an essential prerequisite for supporting ubiquitylation of target substrates, underlies this reduced ubiquitylation capacity. In contrast, LRSAM1 dimerization and interaction with the bona fide target TSG101 were not disrupted. In conclusion, our study provides further support for the role of LRSAM1 in CMT and identifies LRSAM1-mediated ubiquitylation as a common determinant of disease-associated LRSAM1 mutations.","variants":[{"Name":"NM_001005373.4(LRSAM1):c.2120C>T (p.Pro707Leu)","Chromosome":"9","Start":"127502847","Stop":"127502847","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":205258,"rule_based_match":true,"evidence_text":"c.2120C > T, p.Pro707Leu","llm_judgment":"PRESENT","evidence":"c.2120C > T, p.Pro707Leu","abstract_start":925,"abstract_end":949}]}
{"pmid":"34347683","title":"Schizophreniform presentation and abrupt neurologic decline in a patient with late-onset mucopolysaccharidosis type IIIB.","abstract":"Due to their low frequency and some atypical presentations, inborn errors of metabolism are frequently misdiagnosed or underdiagnosed, which hinders the correct management of these patients. To illustrate that, here we present a patient that, at early school age, had learning disabilities compared to her classmates, especially for writing. She completed basic education in a regular school and was transferred to a secondary school for students with special needs. At 18 years of age, she presented a first psychiatric abrupt outbreak: she spent a month screaming and without sleeping. Behavioral problems then became apparent, especially hyperactivity, destructive and chaotic behavior, anxiety, and auto-aggressivity and hetero-aggressivity. A diagnosis of schizophreniform disorder was established. Clinical genetic evaluation revealed coarse face, macroglossia, coarse thick hair, and mild hepatomegaly, and the hypothesis of mucopolysaccharidosis-III was raised. Laboratory tests indicated high levels of urinary glycosaminoglycans and almost undetectable NAGLU activity, confirming the diagnosis. Sequencing of the NAGLU gene revealed the c.1318G>C (p.Gly440Arg) and c.1834A>G (p.Ser612Gly) mutations.","variants":[{"Name":"NM_000263.4(NAGLU):c.1318G>C (p.Gly440Arg)","Chromosome":"17","Start":"42543324","Stop":"42543324","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1439383,"rule_based_match":true,"evidence_text":"c.1318G>C (p.Gly440Arg)","llm_judgment":"PRESENT","evidence":"c.1318G>C (p.Gly440Arg)","abstract_start":1147,"abstract_end":1170}]}
{"pmid":"27726050","title":"Mosaicism in ATP1A3-related disorders: not just a theoretical risk.","abstract":"Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes. In AHC, a few familial cases of autosomal dominant inheritance have been reported, along with cases of de novo sporadic mutations. In contrast, autosomal dominant inheritance has frequently been associated with RDP and CAPOS. Here, we report on two unrelated sets of full siblings with ATP1A3 mutations, (c.2116G>A) p. Gly706Arg in the first family, and (c.2266C>T) p. Arg756Cys in the second family, presenting with familial recurrence of the disease. Both families displayed parental germline mosaicism. In the first family, the brother and sister presented with severe intellectual deficiency, early onset pharmacoresistant epilepsy, ataxia, and autistic features. In the second family, both sisters demonstrated severe encephalopathy with ataxia and dystonia following a regression episode during a febrile episode during infancy. To our knowledge, mosaicism has not previously been reported in ATP1A3-related disorders. This report, therefore, provides evidence that germline mosaicism for ATP1A3 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with ATP1A3-related disorders.","variants":[{"Name":"NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)","Chromosome":"19","Start":"41970540","Stop":"41970540","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":413523,"rule_based_match":true,"evidence_text":"c.2266C>T","llm_judgment":"PRESENT","evidence":"c.2266C>T","abstract_start":670,"abstract_end":679},{"Name":"NM_152296.5(ATP1A3):c.2116G>A (p.Gly706Arg)","Chromosome":"19","Start":"41975776","Stop":"41975776","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360446,"rule_based_match":true,"evidence_text":"c.2116G>A","llm_judgment":"PRESENT","evidence":"c.2116G>A","abstract_start":620,"abstract_end":629}]}
{"pmid":"33984517","title":"Whole exome sequencing and functional characterization increase diagnostic yield in siblings with a 46, XY difference of sexual development (DSD).","abstract":"Pathogenic biallelic variants in HSD17B3 result in 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency, variable disruption of testosterone production, and phenotypic diversity among 46, XY individuals with differences of sexual development (DSDs). We performed quad whole exome sequencing (WES) on two male siblings with microphallus, perineal hypospadias, and bifid scrotum and their unaffected parents. Both male siblings were compound heterozygous for a rare pathogenic HSD17B3 variant (c.239 G > A, p.R80Q) previously identified among individuals with 17β-HSD3 deficiency and a HSD17B3 variant (c.641A > G, p.E214 G) of uncertain significance. Following WES, the siblings underwent hCG stimulation testing with measurement of testosterone, androstenedione, and dihydrotestosterone which was non-diagnostic. To confirm pathogenicity of the HSD17B3 variants, we performed transient transfection of HEK-293 cells and measured conversion of radiolabeled androstenedione to testosterone. Both HSD17B3 variants decreased conversion of radiolabeled androstenedione to testosterone. As pathogenic HSD17B3 variants are rare causes of 46, XY DSD and hCG stimulation testing may not be diagnostic for 17β-HSD3 deficiency, WES in 46, XY individuals with DSDs can increase diagnostic yield and identify genomic variants for functional characterization of disruption of testosterone production.","variants":[{"Name":"NM_000197.2(HSD17B3):c.641A>G (p.Glu214Gly)","Chromosome":"9","Start":"96244360","Stop":"96244360","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":902598,"rule_based_match":true,"evidence_text":"c.641A > G, p.E214 G","llm_judgment":"PRESENT","evidence":"c.641A > G, p.E214 G","abstract_start":605,"abstract_end":625}]}
{"pmid":"35770094","title":"Functional Characterization of Two Variants at the Intron 6-Exon 7 Boundary of the KCNQ2 Potassium Channel Gene Causing Distinct Epileptic Phenotypes.","abstract":"Pathogenic variants in KCNQ2 encoding for Kv7.2 potassium channel subunits have been found in patients affected by widely diverging epileptic phenotypes, ranging from Self-Limiting Familial Neonatal Epilepsy (SLFNE) to severe Developmental and Epileptic Encephalopathy (DEE). Thus, understanding the pathogenic molecular mechanisms of KCNQ2 variants and their correlation with clinical phenotypes has a relevant impact on the clinical management of these patients. In the present study, the genetic, biochemical, and functional effects prompted by two variants, each found in a non-familial SLNE or a DEE patient but both affecting nucleotides at the KCNQ2 intron 6-exon 7 boundary, have been investigated to test whether and how they affected the splicing process and to clarify whether such mechanism might play a pathogenetic role in these patients. Analysis of KCNQ2 mRNA splicing in patient-derived lymphoblasts revealed that the SLNE-causing intronic variant (c.928-1G > C) impeded the use of the natural splice site, but lead to a 10-aa Kv7.2 in frame deletion (Kv7.2 p.G310Δ10); by contrast, the DEE-causing exonic variant (c.928G > A) only had subtle effects on the splicing process at this site, thus leading to the synthesis of a full-length subunit carrying the G310S missense variant (Kv7.2 p.G310S). Patch-clamp recordings in transiently-transfected CHO cells and primary neurons revealed that both variants fully impeded Kv7.2 channel function, and exerted strong dominant-negative effects when co-expressed with Kv7.2 and/or Kv7.3 subunits. Notably, Kv7.2 p.G310S, but not Kv7.2 p.G310Δ10, currents were recovered upon overexpression of the PIP<sub>2</sub>-synthesizing enzyme PIP5K, and/or CaM; moreover, currents from heteromeric Kv7.2/Kv7.3 channels incorporating either Kv7.2 mutant subunits were differentially regulated by changes in PIP<sub>2</sub> availability, with Kv7.2/Kv7.2 G310S/Kv7.3 currents showing a greater sensitivity to PIP<sub>2</sub> depletion when compared to those from Kv7.2/Kv7.2 G310Δ10/Kv7.3 channels. Altogether, these results suggest that the two variants investigated differentially affected the splicing process at the intron 6-exon 7 boundary, and led to the synthesis of Kv7.2 subunits showing a differential sensitivity to PIP<sub>2</sub> and CaM regulation; more studies are needed to clarify how such different functional properties contribute to the widely-divergent clinical phenotypes.","variants":[{"Name":"NM_172107.4(KCNQ2):c.928G>A (p.Gly310Ser)","Chromosome":"20","Start":"63438720","Stop":"63438720","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":572967,"rule_based_match":true,"evidence_text":"c.928G > A","llm_judgment":"PRESENT","evidence":"c.928G > A","abstract_start":1132,"abstract_end":1142}]}
{"pmid":"29321515","title":"Nationwide survey on cerebrotendinous xanthomatosis in Japan.","abstract":"Cerebrotendinous xanthomatosis (CTX) is likely to be underdiagnosed and precise epidemiological characteristics of CTX are largely unknown as knowledge on the disorder is based mainly on case reports. We conducted a nationwide survey on CTX to elucidate the frequency, clinical picture, and molecular biological background of Japanese CTX patients. In this first Japanese nationwide survey on CTX, 2541 questionnaires were sent to clinical departments across Japan. A total of 1032 (40.6%) responses were returned completed for further analysis. Forty patients with CTX (50.0% male) were identified between September 2012 and August 2015. The mean age of onset was 24.5 ± 13.6 years, mean age at diagnosis was 41.0 ± 11.6 years, and corresponding mean duration of illness from onset to diagnosis was 16.5 ± 13.5 years. The most common initial symptom was tendon xanthoma, followed next by spastic paraplegia, cognitive dysfunction, cataract, ataxia, and epilepsy. The most predominant mutations in the CYP27A1 gene were c.1214G> A (p.R405Q, 31.6%), c.1421G> A (p.R474Q, 26.3%), and c.435G> T (p.G145=, 15.8%). Therapeutic interventions that included chenodeoxycholic acid, HMG-CoA reductase inhibitor, and LDL apheresis reduced serum cholestanol level in all patients and improved clinical symptoms in 40.5% of patients. Although CTX is a treatable neurodegenerative disorder, our nationwide survey revealed an average 16.5-year diagnostic delay. CTX may be underdiagnosed in Japan, especially during childhood. Early diagnosis and treatment are essential to improve the prognosis of CTX.","variants":[{"Name":"NM_000784.4(CYP27A1):c.1214G>A (p.Arg405Gln)","Chromosome":"2","Start":"218814409","Stop":"218814409","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19299,"rule_based_match":true,"evidence_text":"c.1214G> A (p.R405Q, 31.6%)","llm_judgment":"PRESENT","evidence":"c.1214G> A (p.R405Q, 31.6%)","abstract_start":1020,"abstract_end":1047},{"Name":"NM_000784.4(CYP27A1):c.435G>T (p.Gly145=)","Chromosome":"2","Start":"218809756","Stop":"218809756","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":76777,"rule_based_match":true,"evidence_text":"c.435G> T (p.G145=, 15.8%)","llm_judgment":"PRESENT","evidence":"c.435G> T (p.G145=, 15.8%)","abstract_start":1082,"abstract_end":1108}]}
{"pmid":"33642439","title":"A Resuscitated Case of Acute Myocardial Infarction with both Familial Hypercholesterolemia Phenotype Caused by Possibly Oligogenic Variants of the PCSK9 and ABCG5 Genes and Type I CD36 Deficiency.","abstract":"A 56-year-old postmenopausal woman with out-of-hospital cardiac arrest caused by acute myocardial infraction was successfully resuscitated by intensive treatments and recovered without any neurological disability. She was diagnosed as having familial hypercholesterolemia (FH) based on a markedly elevated low-density lipoprotein cholesterol (LDL-C) level and family history of premature coronary artery disease. Genetic testing in her family members showed that a variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (c.2004C＞A, p.S668R), which had been previously reported as having uncertain significance, was associated with FH, indicating that the variant is a potential candidate for the FH phenotype. Next-generation sequencing analysis for the proband also showed that there was a heterozygous mutation of the ATP-binding cassette sub-family G member 5 ( ABCG5) gene (c.1166G＞A, R389H), which has been reported to increase LDL-C level and the risk of cardiovascular disease. She was also diagnosed as having type 1 CD36 deficiency based on a lack of myocardial uptake of <sup>123</sup>I-labeled 15-(p-iodophenyl)-3-R,S-methyl-pentadecanoic acid in scintigraphy and the absence of CD36 antigen in both monocytes and platelets in flow cytometry. She had a homozygous mutation of the CD36 gene (c.1126-5_1127delTTTAGAT), which occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. To our knowledge, this is the first report of a heterozygous FH phenotype caused by possibly oligogenic variants of the PCSK9 and ABCG5 genes complicated with type I CD36 deficiency caused by a novel homozygous mutation. Both FH phenotype and CD36 deficiency might have caused extensive atherosclerosis, leading to acute myocardial infarction in the present case.","variants":[{"Name":"NM_022436.3(ABCG5):c.1166G>A (p.Arg389His)","Chromosome":"2","Start":"43824071","Stop":"43824071","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20019,"rule_based_match":false,"evidence_text":"c.1166G＞A, R389H","llm_judgment":"PRESENT","evidence":"c.1166G＞A, R389H","abstract_start":897,"abstract_end":913},{"Name":"NM_174936.4(PCSK9):c.2004C>A (p.Ser668Arg)","Chromosome":"1","Start":"55063509","Stop":"55063509","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":389421,"rule_based_match":false,"evidence_text":"c.2004C＞A, p.S668R","llm_judgment":"PRESENT","evidence":"c.2004C＞A, p.S668R","abstract_start":540,"abstract_end":558}]}
{"pmid":"37550668","title":"The East Asian-specific LPL p.Ala288Thr (c.862G > A) missense variant exerts a mild effect on protein function.","abstract":"BACKGROUND: Lipoprotein lipase (LPL) is the key enzyme responsible for the hydrolysis of triglycerides. Loss-of-function variants in the LPL gene are associated with hypertriglyceridemia (HTG) and HTG-related diseases. Unlike nonsense, frameshift and canonical GT-AG splice site variants, a pathogenic role for clinically identified LPL missense variants should generally be confirmed by functional analysis. Herein, we describe the clinical and functional analysis of a rare LPL missense variant.\nMETHODS: Chinese patients with HTG-associated acute pancreatitis (HTG-AP) were screened for rare nonsense, frameshift, missense or canonical GT-AG splice site variants in LPL and four other lipid metabolism-related genes (APOC2, APOA5, GPIHBP1 and LMF1) by Sanger sequencing. The functional consequences of the LPL missense variant of interest were characterized by in vitro expression in HEK-293T and COS-7 cells followed by Western blot and LPL activity assays.\nRESULTS: Five unrelated HTG-AP patients were found to be heterozygous for a rare East Asian-specific LPL missense variant, c.862G > A (p.Ala288Thr). All five patients were adult males, and all were overweight and had a long history of alcohol consumption. Transfection of LPL wild-type and c.862G > A expression vectors into two cell lines followed by Western blot analysis served to exclude the possibility that the p.Ala288Thr missense variant either impaired protein synthesis or increased protein degradation. Contrary to a previous functional study that claimed that p.Ala288Thr had a severe impact on LPL function (reportedly having 36% normal activity), our experiments consistently demonstrated that the variant had a comparatively mild effect on LPL functional activity, which was mediated through its impact upon LPL protein secretion (~ 20% reduced secretion compared to wild-type).\nCONCLUSIONS: In this study, we identified the East Asian-specific LPL c.862G > A (p.Ala288Thr) missense variant in five unrelated HTG-AP patients. We demonstrated that this variant exerted only a relatively mild effect on LPL function in two cell lines. Heterozygosity for this LPL variant may have combined with alcohol consumption to trigger HTG-AP in these patients.","variants":[{"Name":"NM_000237.3(LPL):c.862G>A (p.Ala288Thr)","Chromosome":"8","Start":"19955927","Stop":"19955927","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2905041,"rule_based_match":true,"evidence_text":"c.862G > A (p.Ala288Thr)","llm_judgment":"PRESENT","evidence":"c.862G > A (p.Ala288Thr)","abstract_start":1085,"abstract_end":1109}]}
{"pmid":"30249361","title":"Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis.","abstract":"Charcot-Marie-Tooth (CMT) disease type 1 is an inherited peripheral neuropathy characterized by demyelination and reduced nerve conduction velocities. We present a multi-generational family with peripheral neuropathy in whom clinical CMT panel testing failed to conclude a molecular diagnosis. We found a PMP2 pathogenic variant c.155T > C, p.(Ile52Thr) that segregates with disease suggesting that PMP2 variants should be considered in patients with neuropathy and that it may be prudent to include in clinical CMT gene panels.","variants":[{"Name":"NM_002677.5(PMP2):c.155T>C (p.Ile52Thr)","Chromosome":"8","Start":"81444908","Stop":"81444908","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":590743,"rule_based_match":true,"evidence_text":"c.155T > C, p.(Ile52Thr)","llm_judgment":"PRESENT","evidence":"c.155T > C, p.(Ile52Thr)","abstract_start":329,"abstract_end":353}]}
{"pmid":"18373411","title":"New mutations in the Wilson disease gene, ATP7B: implications for molecular testing.","abstract":"Wilson disease (WND), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. ATP7B encodes a copper transporting P-type ATPase involved in the transport of copper into the plasma protein ceruloplasmin, and for excretion of copper from the liver. Defects in ATP7B lead to copper storage in liver, brain and kidney. Mutation analysis was carried out on 300 WND patients of various origins, and new mutations not previously reported were identified: European white (p.L217X, c.918_931, c.1073delG, c.3082_3085delAAGAinsCG, p.V536A, p.S657R, p.A971V, p.T974M, p.Q1004P, p.D1164N, p.E1173G, p.I1230V, p.M1359I, c.2355+4A>G), Sephardic Jewish (p.Q286X), Filipino (p.G1149A), Lebanese (p.R1228T), Japanese (p.D1267V) and Taiwanese (p.A1328T). All but one missense variant have strong evidence for classification as disease-causing mutations. In the patients reported here, we also identified 20 nucleotide substitutions, six not previously reported, which cause silent amino acid changes or intronic changes. Documentation and characterization of all variants is essential for accurate DNA diagnosis in WND because of the wide range of clinical and biochemical variability.","variants":[{"Name":"NM_000053.4(ATP7B):c.2355+4A>G","Chromosome":"13","Start":"51958307","Stop":"51958307","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":547349,"rule_based_match":true,"evidence_text":"c.2355+4A>G","llm_judgment":"PRESENT","evidence":"c.2355+4A>G","abstract_start":709,"abstract_end":720},{"Name":"NM_000053.4(ATP7B):c.1073del (p.Cys358fs)","Chromosome":"13","Start":"51974147","Stop":"51974147","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":905947,"rule_based_match":true,"evidence_text":"c.1073delG","llm_judgment":"PRESENT","evidence":"c.1073delG","abstract_start":586,"abstract_end":596}]}
{"pmid":"25574057","title":"Abrogation of HMX1 function causes rare oculoauricular syndrome associated with congenital cataract, anterior segment dysgenesis, and retinal dystrophy.","abstract":"PURPOSE: To define the phenotypic manifestation, confirm the genetic basis, and delineate the pathogenic mechanisms underlying an oculoauricular syndrome (OAS).\nMETHODS: Two individuals from a consanguineous family underwent comprehensive clinical phenotyping and electrodiagnostic testing (EDT). Genome-wide microarray analysis and Sanger sequencing of the candidate gene were used to identify the likely causal variant. Protein modelling, Western blotting, and dual luciferase assays were used to assess the pathogenic effect of the variant in vitro.\nRESULTS: Complex developmental ocular abnormalities of congenital cataract, anterior segment dysgenesis, iris coloboma, early-onset retinal dystrophy, and abnormal external ear cartilage presented in the affected family members. Genetic analyses identified a homozygous c.650A>C; p.(Gln217Pro) missense mutation within the highly conserved homeodomain of the H6 family homeobox 1 (HMX1) gene. Protein modelling predicts that the variant may have a detrimental effect on protein folding and/or stability. In vitro analyses were able to demonstrate that the mutation has no effect on protein expression but adversely alters function.\nCONCLUSIONS: Oculoauricular syndrome is an autosomal recessive condition that has a profound effect on the development of the external ear, anterior segment, and retina, leading to significant visual loss at an early age. This study has delineated the phenotype and confirmed HMX1 as the gene causative of OAS, enabling the description of only the second family with the condition. HMX1 is a key player in ocular development, possibly in both the pathway responsible for lens and retina development, and via the gene network integral to optic fissure closure.","variants":[{"Name":"NM_018942.3(HMX1):c.650A>C (p.Gln217Pro)","Chromosome":"4","Start":"8868090","Stop":"8868090","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":190108,"rule_based_match":true,"evidence_text":"c.650A>C; p.(Gln217Pro)","llm_judgment":"PRESENT","evidence":"c.650A>C; p.(Gln217Pro)","abstract_start":823,"abstract_end":846}]}
{"pmid":"29127354","title":"Clinical and Molecular Characterization of PMP22 point mutations in Taiwanese patients with Inherited Neuropathy.","abstract":"Point mutations in the peripheral myelin protein 22 (PMP22) gene have been identified to cause demyelinating Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsy (HNPP). To investigate the mutation spectrum of PMP22 in Han-Chinese population residing in Taiwan, 53 patients with molecularly unassigned demyelinating CMT and 52 patients with HNPP-like neuropathy of unknown genetic causes were screened for PMP22 mutations by Sanger sequencing. Three point mutations were identified in four patients with demyelinating CMT, including c.256 C > T (p.Q86X) in two, and c.310delA (p.I104FfsX7) and c.319 + 1G > A in one each. One PMP22 missense mutation, c.124 T > C (p.C42R), was identified in a patient with HNPP-like neuropathy. The clinical presentations of these mutations vary from mild HNPP-like syndrome to severe infantile-onset demyelinating CMT. In vitro analyses revealed that both PMP22 p.Q86X and p.I104FfsX7 mutations result in truncated PMP22 proteins that are almost totally retained within cytosol, whereas the p.C42R mutation partially impairs cell membrane localization of PMP22 protein. In conclusion, PMP22 point mutations account for 7.5% and 1.9% of demyelinating CMT and HNPP patients with unknown genetic causes, respectively. This study delineates the clinical and molecular features of PMP22 point mutations in Taiwan, and emphasizes their roles in demyelinating CMT or HNPP-like neuropathy.","variants":[{"Name":"NM_000304.4(PMP22):c.256C>T (p.Gln86Ter)","Chromosome":"17","Start":"15239534","Stop":"15239534","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625386,"rule_based_match":true,"evidence_text":"c.256 C > T (p.Q86X)","llm_judgment":"PRESENT","evidence":"c.256 C > T (p.Q86X)","abstract_start":573,"abstract_end":593},{"Name":"NM_000304.4(PMP22):c.124T>C (p.Cys42Arg)","Chromosome":"17","Start":"15259148","Stop":"15259148","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2417807,"rule_based_match":true,"evidence_text":"c.124 T > C (p.C42R)","llm_judgment":"PRESENT","evidence":"c.124 T > C (p.C42R)","abstract_start":691,"abstract_end":711}]}
{"pmid":"27567911","title":"Homozygous KCNMA1 mutation as a cause of cerebellar atrophy, developmental delay and seizures.","abstract":"Dominant gain-of-function mutations of the KCNMA1 gene, encoding the pore-forming subunit of the large conductance voltage- and Ca<sup>2+</sup>-activated K+ channel, have been described in a few patients with the syndrome of epilepsy, paroxysmal dyskinesias and developmental delay. In this report, we describe the loss-of-function phenotype of this newly described disease gene. In two siblings from a consanguineous family with epilepsy, developmental delay and severe cerebellar atrophy, combined exome/autozygome analysis identified a homozygous frameshift duplication in KCNMA1 (c.2026dupT; p. (Tyr676 Leufs<sup>*</sup>7)) in both children. Our report defines a novel autosomal recessive KCNMA1-related epileptic phenotype that encompasses cerebellar atrophy without paroxysmal dyskinesia, and highlights the sensitivity of the developing brain to both increased and decreased activity of the KCNMA1-encoded channels.","variants":[{"Name":"NM_001161352.2(KCNMA1):c.2026dup (p.Tyr676fs)","Chromosome":"10","Start":"77012032","Stop":"77012033","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":431493,"rule_based_match":true,"evidence_text":"c.2026dupT","llm_judgment":"PRESENT","evidence":"c.2026dupT","abstract_start":584,"abstract_end":594}]}
{"pmid":"31298765","title":"SSBP1 mutations in dominant optic atrophy with variable retinal degeneration.","abstract":"OBJECTIVE: Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality.\nMETHODS: Linkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model.\nRESULTS: We defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied.\nINTERPRETATION: SSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019;86:368-383.","variants":[{"Name":"NM_003143.3(SSBP1):c.113G>A (p.Arg38Gln)","Chromosome":"7","Start":"141743588","Stop":"141743588","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":965634,"rule_based_match":true,"evidence_text":"c.113G>A [p.(Arg38Gln)]","llm_judgment":"PRESENT","evidence":"c.113G>A [p.(Arg38Gln)]","abstract_start":739,"abstract_end":762},{"Name":"NM_003143.3(SSBP1):c.320G>A (p.Arg107Gln)","Chromosome":"7","Start":"141745501","Stop":"141745501","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":965635,"rule_based_match":true,"evidence_text":"c.320G>A [p.(Arg107Gln)]","llm_judgment":"PRESENT","evidence":"c.320G>A [p.(Arg107Gln)]","abstract_start":764,"abstract_end":788},{"Name":"NM_003143.3(SSBP1):c.422G>A (p.Ser141Asn)","Chromosome":"7","Start":"141750329","Stop":"141750329","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":965636,"rule_based_match":true,"evidence_text":"c.422G>A [p.(Ser141Asn)]","llm_judgment":"PRESENT","evidence":"c.422G>A [p.(Ser141Asn)]","abstract_start":793,"abstract_end":817}]}
{"pmid":"16415970","title":"The genotype and phenotype studies of 40 Chinese patients with X-linked adrenoleukodystrophy (X-ALD).","abstract":"OBJECTIVE: To elucidate the phenotype and the genotype-phenotype correlations in Chinese patients with X-linked adrenoleukodystrophy (X-ALD).\nMETHODS: Clinical features of 40 Chinese patients with X-ALD were studied and mutation spectrums were investigated by polymerase chain reaction (PCR) and sequencing.\nRESULTS: Among these patients, four were siblings from two unrelated families, the others were unrelated. There were 31 cases with childhood cerebral (CCALD), 8 cases with adolescent cerebral (ACALD) and 1 case with adrenomyeloneuropathy (AMN). Visual impairment, which presented in 12 cases (30%), was the most common initial symptom. Nine (69%) of 13 cases who had hydrocortisone and ACTH measured showed adrenal insufficiency. By follow-up date, 19 cases (47.5%) were dead. The interval from onset to death varied from 1 to 6 years and the average were 3.3 years. The mean age at death was 10.5 years. Eleven cases (27.5%) were in vegetable state. The mean interval from onset to apparently vegetable state was 2.8 years (range from 1 to 6 years). Four cases had progressive neurological disability. Four cases were lost follow-up. One case with CCALD and one case with ACALD progressed slowly. The courses of the disease of these two patients were 5 years and 15 years respectively. Thirty five mutations were identified in 40 cases. Most were located within exon 1-3 (40%, 16/40) and exon 6-8 (42%, 17/40). There is a distinct clustering of missense mutations in exon 6 (17%, 7/40). Five types of mutations were associated with CCALD, three with ACALD and a missense mutation was identified in the patients with AMN. The two patients with long disease courses had a missense mutation c.1559 T>A and a nonsense mutation c.1785 G>A respectively. The siblings with similar manifestations and onset age were observed in two families, whose mutations were c.887 A>G and c.1028 G>T.\nCONCLUSION: The phenotypes, disease severity and rate of neurodegeneration could not be predicted by the nature of mutations.","variants":[{"Name":"NM_000033.4(ABCD1):c.887A>G (p.Tyr296Cys)","Chromosome":"X","Start":"153726153","Stop":"153726153","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":190198,"rule_based_match":true,"evidence_text":"c.887 A>G","llm_judgment":"PRESENT","evidence":"c.887 A>G","abstract_start":1864,"abstract_end":1873}]}
{"pmid":"32396230","title":"What do we learn from dystrophic epidermolysis bullosa, nails only? Idiopathic nail dystrophy may harbor a COL7A1 mutation as the underlying cause.","abstract":"Dystrophic epidermolysis bullosa (DEB) is a genodermatosis caused by mutations in the COL7A1 gene. DEB, nails only (DEB-na), is a rare type of DEB. Patients with DEB-na can be overlooked, and genetic testing is helpful to determine the correct diagnosis. We collected two families with DEB-na. Clinical information was analyzed. Ultrastructural analysis of the skin tissue was performed. Blood samples were obtained. Next-generation sequencing was performed and the results were confirmed by Sanger sequencing. A genetic study revealed two novel heterozygous mutations: COL7A1:c.6742G>A (p.G2248R) in patient 1 and c.7181C>G (p.P2394R) in patient 2. Precise diagnosis was made for every patient based on clinical findings and genetic studies. We summarized the phenotype and COL7A1 mutations related to DEB-na. We report a new phenotype of DEB-na and two novel mutations in COL7A1. In addition, we emphasize the importance of careful clinical examination and genetic testing in the diagnosis of DEB-na.","variants":[{"Name":"NM_000094.4(COL7A1):c.7181C>G (p.Pro2394Arg)","Chromosome":"3","Start":"48570952","Stop":"48570952","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2925931,"rule_based_match":true,"evidence_text":"c.7181C>G (p.P2394R)","llm_judgment":"PRESENT","evidence":"c.7181C>G (p.P2394R)","abstract_start":615,"abstract_end":635}]}
{"pmid":"17469202","title":"Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes.","abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients.","variants":[{"Name":"NM_170707.4(LMNA):c.1968+1G>A","Chromosome":"1","Start":"156138758","Stop":"156138758","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":77776,"rule_based_match":true,"evidence_text":"c.1968+1G>A","llm_judgment":"PRESENT","evidence":"c.1968+1G>A","abstract_start":925,"abstract_end":936},{"Name":"NM_170707.4(LMNA):c.1824C>T (p.Gly608=)","Chromosome":"1","Start":"156138613","Stop":"156138613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29539,"rule_based_match":true,"evidence_text":"c.1824C>T/p.G608G","llm_judgment":"PRESENT","evidence":"c.1824C>T/p.G608G","abstract_start":320,"abstract_end":337},{"Name":"NM_170707.4(LMNA):c.1821G>A (p.Val607=)","Chromosome":"1","Start":"156138610","Stop":"156138610","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29555,"rule_based_match":true,"evidence_text":"c.1821G>A/p.V607V","llm_judgment":"PRESENT","evidence":"c.1821G>A/p.V607V","abstract_start":1015,"abstract_end":1032}]}
{"pmid":"37924809","title":"RAB1A haploinsufficiency phenocopies the 2p14-p15 microdeletion and is associated with impaired neuronal differentiation.","abstract":"Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C>T [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and a mosaic missense mutation (c.83T>C [p.Leu28Pro]), were identified in three individuals with similar neurodevelopmental presentations. In rescue experiments, production of the full-length, but not the truncated, RAB1a rescued Golgi structure and cell proliferation in Rab1-depleted cells. In contrast, the missense-variant RAB1a disrupted Golgi structure despite intact Rab1 expression, suggesting a dominant-negative function of the mosaic missense mutation. Knock-down of RAB1A in cultured human embryonic stem cell-derived neurons resulted in impaired neuronal arborization. Finally, RAB1A is located within the 2p14-p15 microdeletion syndrome locus. The similar clinical presentations of individuals with RAB1A loss-of-function mutations and the 2p14-p15 microdeletion syndrome implicate loss of RAB1A in the pathogenesis of neurodevelopmental manifestations of this microdeletion syndrome. Our study identifies a RAB1A-related neurocognitive disorder with speech and motor delay, demonstrates an essential role for RAB1a in neuronal differentiation, and implicates RAB1A in the etiology of the neurodevelopmental sequelae associated with the 2p14-p15 microdeletion syndrome.","variants":[{"Name":"NM_004161.5(RAB1A):c.523C>T (p.Arg175Ter)","Chromosome":"2","Start":"65088588","Stop":"65088588","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3806232,"rule_based_match":true,"evidence_text":"c.523C>T (p.Arg175Ter)","llm_judgment":"PRESENT","evidence":"p.Arg175Ter","abstract_start":422,"abstract_end":433}]}
{"pmid":"32258229","title":"Diagnosis of Aicardi-Goutières Syndrome in Adults: A Case Series.","abstract":"INTRODUCTION: Aicardi-Goutières syndrome (AGS) is a genetic disease presenting with early-onset encephalopathy, generalized dystonia, spasticity, and cognitive disability. Diagnosis may be difficult in adults, as the clinical course seems static from infancy.\nMETHODS: AGS patients from an adult movement disorders outpatient clinic were retrospectively analyzed.\nRESULTS: A total of 5 patients and 1 asymptomatic carrier from 3 different families were identified. All had a homozygous c.529G>A,p.A177T mutation in exon 7 of the <i>RNASEH2B</i> gene. Two patients had neonatal-onset AGS, 2 had later onset forms, and 1 was slightly symptomatic. All were diagnosed in adulthood after chilblains, and basal ganglia calcifications were identified on computed tomography scans.\nDISCUSSION: AGS patients have marked phenotypic variability regarding psychomotor development and morbidity. The present series included 1 asymptomatic carrier and 1 slightly symptomatic patient, both with homozygous <i>RNASEH2B</i> mutations. Chilblains and basal ganglia calcifications identified on computed tomography scan (but not on magnetic resonance imaging) are important clues for late diagnosis.","variants":[{"Name":"NM_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr)","Chromosome":"13","Start":"50945445","Stop":"50945445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16301,"rule_based_match":true,"evidence_text":"c.529G>A,p.A177T","llm_judgment":"PRESENT","evidence":"c.529G>A,p.A177T","abstract_start":486,"abstract_end":502}]}
{"pmid":"22154191","title":"Screening for VPS35 mutations in Parkinson's disease.","abstract":"Recently 2 groups have independently identified a mutation in the gene 'vacuolar protein sorting 35 homolog' (VPS35 c.1858G>A; p.Asp620Asn) as a possible cause of autosomal dominant Parkinson's disease (PD). In order to assess the frequency of the reported mutation and to search for other possible disease-causing variants in this gene, we sequenced all 17 exons of VPS35 in 96 familial PD cases, and exon 15 (in which the reported mutation is found) in an additional 64 familial PD cases, 175 young-onset PD cases, and 262 sporadic, neuropathologically confirmed PD cases. We identified 1 individual with the p.Asp620Asn mutation and an autosomal dominant family history of PD. Subsequent follow-up of the family confirmed an affected sibling and cousin who also carried the same mutation. No other potentially disease-causing mutations were identified. We conclude that the VPS35 c.1858G>A mutation is an uncommon cause of familial Parkinson's disease in our population.","variants":[{"Name":"NM_018206.6(VPS35):c.1858G>A (p.Asp620Asn)","Chromosome":"16","Start":"46662452","Stop":"46662452","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39152,"rule_based_match":true,"evidence_text":"VPS35 c.1858G>A; p.Asp620Asn","llm_judgment":"PRESENT","evidence":"VPS35 c.1858G>A; p.Asp620Asn","abstract_start":110,"abstract_end":138}]}
{"pmid":"20431721","title":"Mutation analysis of congenital cataract in a Chinese family identified a novel missense mutation in the connexin 46 gene (GJA3).","abstract":"PURPOSE: To identify the genetic defects in a three-generation Chinese family with congenital nuclear cataract.\nMETHODS: Four patients and three healthy members from the family underwent complete physical and ophthalmic examinations. Genomic DNA was extracted from peripheral blood leukocytes of the family members as well as from 100 healthy normal controls. Polymerase chain reaction (PCR) amplification and direct sequencing of all coding exons of candidate genes were performed. The functional consequences of the mutation were analyzed with biology softwares.\nRESULTS: A novel mutation (c.130G>A) was identified in the connexin 46 gene (GJA3), which resulted in the substitution of valine by methionine at the highly conserved codon 44 of connexin 46. This mutation co-segregated among the affected members of the family and was not observed in either unaffected members or the 100 normal controls.\nCONCLUSIONS: This is a novel missense mutation identified in the first extracellular loop of connexin 46; this expands the mutation spectrum of GJA3 in association with congenital cataract.","variants":[{"Name":"NM_021954.4(GJA3):c.130G>A (p.Val44Met)","Chromosome":"13","Start":"20143159","Stop":"20143159","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":641579,"rule_based_match":true,"evidence_text":"c.130G>A","llm_judgment":"PRESENT","evidence":"c.130G>A","abstract_start":592,"abstract_end":600}]}
{"pmid":"30415926","title":"Ketogenic diet as a successful early treatment modality for SCN2A mutation.","abstract":"SCN2A mutations have been described in a very broad spectrum of clinical phenotypes including benign (familial) neonatal/infantile seizures and early infantile epileptic encephalopathies (EIEE) as Ohtahara syndrome (OS), Dravet syndrome (DS), epilepsy of infancy with migrating focal seizures and West syndrome (WS). Treatment modalities for epilepsy caused by SCN2A mutations mainly consist of sodium channel blockers but ketogenic diet (KD) is also considered as an option of treatment for intractible seizures caused by SCN2A mutations. Because of the wide nature of the heterogeneity of mutations related to SCN2A gene, the clinical phenotypes vary in severity and treatment response to KD has been reported to be controversial. We present a patient diagnosed with OS associated with a novel SCN2A mutation (c.408G > A, p.Met136lle; OMIM®: 182390) who had a complete resolution of seizures and EEG abnormalities with KD commenced at 39 days of age. As far as we are aware our case is the youngest patient with SCN2A mutation treated with KD with complete resolution of epilepsy at an early age and has been seizure free of antiepileptic medications for a long duration.","variants":[{"Name":"NM_001040142.2(SCN2A):c.408G>A (p.Met136Ile)","Chromosome":"2","Start":"165307869","Stop":"165307869","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":973252,"rule_based_match":true,"evidence_text":"c.408G > A, p.Met136lle","llm_judgment":"PRESENT","evidence":"c.408G > A, p.Met136lle","abstract_start":812,"abstract_end":835}]}
{"pmid":"22836883","title":"Dysregulated coagulation associated with hypofibrinogenaemia and plasma hypercoagulability: implications for identifying coagulopathic mechanisms in humans.","abstract":"Identifying coagulation abnormalities in patients with combined bleeding and thrombosis history is clinically challenging. Our goal was to probe the complexity of dysregulated coagulation in humans by characterizing pathophysiologic mechanisms in a patient with both bleeding and thrombosis. The patient is a 56-year-old female with a history of haematomas, poor wound healing, and thrombosis (retinal artery occlusion and transient cerebral ischaemia). She had a normal activated partial thromboplastin time, prolonged thrombin and reptilase times, and decreased functional and antigenic fibrinogen levels, and was initially diagnosed with hypodysfibrinogenaemia. This diagnosis was supported by DNA analysis revealing a novel FGB mutation (c.656A>G) predicting a Q189R mutation in the mature chain that was present in the heterozygote state. However, turbidity analysis showed that purified fibrinogen polymerisation and degradation were indistinguishable from normal, and Bβ chain subpopulations appeared normal by two-dimensional difference in-gel electrophoresis, indicating the mutated chain was not secreted. Interestingly, plasma thrombin generation testing revealed the patient's thrombin generation was higher than normal and could be attributed to elevated levels of factor VIII (FVIII, 163-225%). Accordingly, in an arterial injury model, hypofibrinogenaemic mice (Fgn(+/-)) infused with factor VIII demonstrated significantly shorter vessel occlusion times than saline-infused Fgn(+/-) mice. Together, these data associate the complex bleeding and thrombotic presentation with combined hypofibrinogenaemia plus plasma hypercoagulability. These findings suggest previous cases in which fibrinogen abnormalities have been associated with thrombosis may also be complicated by co-existing plasma hypercoagulability and illustrate the importance of \"global\" coagulation testing in patients with compound presentations.","variants":[{"Name":"NM_005141.5(FGB):c.656A>G (p.Gln219Arg)","Chromosome":"4","Start":"154567758","Stop":"154567758","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1152131,"rule_based_match":true,"evidence_text":"c.656A>G","llm_judgment":"PRESENT","evidence":"c.656A>G","abstract_start":742,"abstract_end":750}]}
{"pmid":"21417571","title":"Hb Lynwood [α107(G14) (-T) (α2) HBA2:c.323delT)] in conjunction with the α(3.7) deletion produces a moderately severe α-thalassemia phenotype.","abstract":"We describe a novel frameshift mutation associated with an α-thalassemia (α-thal) phenotype in a patient of Sudanese origin investigated for persistent microcytosis. In addition to the α(3.7) deletion, a novel mutation on the α2 gene was detected: HBA2:c.323delT. This mutation causes a frameshift at codon 107 of the α2 gene. The result is a disturbed amino acid sequence for the following 24 amino acids, and a premature termination codon at position 132.","variants":[{"Name":"NM_000517.6(HBA2):c.323del (p.Val108fs)","Chromosome":"16","Start":"173494","Stop":"173494","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":789590,"rule_based_match":true,"evidence_text":"HBA2:c.323delT","llm_judgment":"PRESENT","evidence":"HBA2:c.323delT","abstract_start":248,"abstract_end":262}]}
{"pmid":"36039580","title":"","abstract":"OBJECTIVES: Congenital hypogonadotropic hypogonadism (CHH) is a rare congenital gonadal dysplasia caused by defects in the synthesis, secretion or signal transduction of hypothalamic gonadotropin releasing hormone. The main manifestations of CHH are delayed or lack puberty, low levels of sex hormones and gonadotropins, and may be accompanied with other clinical phenotypes. Some patients with CHH are also accompanied with anosmia or hyposmia, which is called Kalman syndrome (KS). <i>ANOS1</i>, located on X chromosome, is the first gene associated with CHH in an X-linked recessive manner. This study aims to provide a basis for the genetic diagnosis of CHH by analyzing the gene variant spectrum of <i>ANOS1</i> in CHH and the relationship between clinical phenotype and genotype.\nMETHODS: In this study, whole exome sequencing (WES) was used to screen rare sequencing variants (RSVs) of <i>ANOS1</i> in a Chinese cohort of 165 male CHH patients. Four commonly used <i>in silico</i> tools were used to predict the function of the identified RSVs in coding region, including Polyphen2, Mutation Taster, SIFT, and Combined Annotation Dependent Depletion (CADD). Splice Site Prediction by Neural Network (NNSPLICE) was employed to predict possibilities of intronic RSVs to disrupt splicing. American College of Medical Genetics and Genomics (ACMG) guidelines was used to assess the pathogenicity of the detected RSVs. The <i>ANOS1</i> genetic variant spectrum of CHH patients in Chinese population was established. The relationship between clinical phenotype and genotype was analyzed by collecting detailed clinical data.\nRESULTS: Through WES analysis for 165 CHH patients, <i>ANOS1</i> RSVs were detected in 17 of them, with the frequency of 10.3%. A total of 13 RSVs were detected in the 17 probands, including 5 nonsense variants (p.T76X, p.R191X, p.W257X, p.R262X, and p.W589X), 2 splicing site variants (c.318+3A>C, c.1063-1G>C), and 6 missense variants (p.N402S, p.N155D, p.P504L, p.C157R, p.Q635P, and p.V560I). In these 17 CHH probands with <i>ANOS1</i> RSVs, many were accompanied with other clinical phenotypes. The most common associated phenotype was cryptorchidism (10/17), followed by unilateral renal agenesis (3/17), dental agenesis (3/17), and synkinesia (3/17). Eight RSVs, including p.T76X, p.R191X, p.W257X, p.R262X, p.W589X, c.318+3A>C, c.1063-1G>C, and p.C157R, were predicted to be pathogenic or likely pathogenic <i>ANOS1</i> RSVs by ACMG. Eight CHH patients with pathogenic or likely pathogenic <i>ANOS1</i> variants had additional features. In contrast, only one out of nine CHH patients with non-pathogenic (likely benign or uncertain of significance) <i>ANOS1</i> variants according to ACMG exhibited additional features. And function of the non-pathogenic ANOS1 variants accompanied with other CHH-associated RSVs.\nCONCLUSIONS: The <i>ANOS1</i> genetic spectrum of CHH patients in Chinese population is established. Some of the correlations between clinical phenotype and genotype are also established. Our study indicates that CHH patients with pathogenic or likely pathogenic <i>ANOS1</i> RSVs tend to exhibit additional phenotypes. Although non-pathogenic <i>ANOS1</i> variants only may not be sufficient to cause CHH, they may function together with other CHH-associated RSVs to cause the disease.","variants":[{"Name":"NM_000216.4(ANOS1):c.1063-1G>C","Chromosome":"X","Start":"8568377","Stop":"8568377","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1332925,"rule_based_match":true,"evidence_text":"c.1063-1G>C","llm_judgment":"PRESENT","evidence":"c.1063-1G>C","abstract_start":1924,"abstract_end":1935}]}
{"pmid":"17221859","title":"Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies.","abstract":"Myofibrillar myopathy (MFM) encompasses a genetically heterogeneous group of human diseases caused by mutations in genes coding for structural proteins of muscle. Mutations in the intermediate filament (IF) protein desmin (DES), a major cytoskeletal component of myocytes, lead to severe forms of \"desminopathy,\" which affects cardiac, skeletal, and smooth muscle. Most mutations described reside in the central alpha-helical rod domain of desmin. Here we report three novel mutations--c.1325C>T (p.T442I), c.1360C>T (p.R454W), and c.1379G>T (p.S460I)--located in desmin's non-alpha-helical carboxy-terminal \"tail\" domain. We have investigated the impact of these and four--c.1237G>A (p.E413K), c.1346A>C (p.K449T), c.1353C>G (p.I451M), and c.1405G>A (p.V469M)--previously described \"tail\" mutations on in vitro filament formation and on the generation of ordered cytoskeletal arrays in transfected myoblasts. Although all but two mutants (p.E413K, p.R454W) assembled into IFs in vitro and all except p.E413K were incorporated into IF arrays in transfected C2C12 cells, filament properties differed significantly from wild-type desmin as revealed by viscometric assembly assays. Most notably, when coassembled with wild-type desmin, these mutants revealed a severe disturbance of filament-formation competence and filament-filament interactions, indicating an inherent incompatibility of mutant and wild-type protein to form mixed filaments. The various clinical phenotypes observed may reflect altered interactions of desmin's tail domain with different components of the myoblast cytoskeleton leading to diminished biomechanical properties and/or altered metabolism of the individual myocyte. Our in vitro assembly regimen proved to be a very sensible tool to detect if a particular desmin mutation is able to cause filament abnormalities.","variants":[{"Name":"NM_001927.4(DES):c.1325C>T (p.Thr442Ile)","Chromosome":"2","Start":"219425699","Stop":"219425699","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31873,"rule_based_match":true,"evidence_text":"c.1325C>T (p.T442I)","llm_judgment":"PRESENT","evidence":"c.1325C>T (p.T442I)","abstract_start":486,"abstract_end":505},{"Name":"NM_001927.4(DES):c.1237G>A (p.Glu413Lys)","Chromosome":"2","Start":"219421553","Stop":"219421553","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":77295,"rule_based_match":true,"evidence_text":"c.1237G>A (p.E413K)","llm_judgment":"PRESENT","evidence":"c.1237G>A (p.E413K)","abstract_start":674,"abstract_end":693},{"Name":"NM_001927.4(DES):c.1346A>C (p.Lys449Thr)","Chromosome":"2","Start":"219425720","Stop":"219425720","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":77297,"rule_based_match":true,"evidence_text":"c.1346A>C (p.K449T)","llm_judgment":"PRESENT","evidence":"c.1346A>C (p.K449T)","abstract_start":695,"abstract_end":714},{"Name":"NM_001927.4(DES):c.1360C>T (p.Arg454Trp)","Chromosome":"2","Start":"219425734","Stop":"219425734","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77299,"rule_based_match":true,"evidence_text":"c.1360C>T (p.R454W)","llm_judgment":"PRESENT","evidence":"c.1360C>T (p.R454W)","abstract_start":507,"abstract_end":526}]}
{"pmid":"21145993","title":"Tyrosinemia type II (Richner-Hanhart syndrome): a new mutation in the TAT gene.","abstract":"In the present study we report the clinical features and the molecular genetic investigation of the tyrosine aminotransferase (TAT) gene in a young girl from Croatia with Richner-Hanhart syndrome, mainly suffering from photophobia, hyperkeratosis of the palmes and soles and slight neurological abnormalities. Sequencing analysis of the TAT gene revealed a novel homozygous missense mutation c.1250G>A (p.R417Q) in exon 12, and herewith confirmed the clinical diagnosis. Showing the first symptoms in babyhood, at the age of 8 years it was for the first time clinically diagnosed that the patient suffers from tyrosinemia type II and a therapy with tyrosine and phenylalanine reduced diet has been started successfully. All symptoms disappeared within 2-4 weeks. Since that time, we have been following the girl until today for more than ten years. She is in a good condition, and attends the normal high school program.","variants":[{"Name":"NM_000353.3(TAT):c.1250G>A (p.Arg417Gln)","Chromosome":"16","Start":"71568259","Stop":"71568259","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":548525,"rule_based_match":true,"evidence_text":"c.1250G>A (p.R417Q)","llm_judgment":"PRESENT","evidence":"c.1250G>A (p.R417Q)","abstract_start":392,"abstract_end":411}]}
{"pmid":"34877407","title":"Novel Variations in the","abstract":"BACKGROUND AND OBJECTIVES: To investigate the pathogenicity of 2 novel <i>KDM5C</i> variations, report the clinical and neuroimaging findings, and review the available literature.\nMETHODS: Physical examinations, structural neuroimaging studies, and exome sequence analysis were performed. KDM5C constructs were used to study the effect of the variations in transfected cells.\nRESULTS: We identified 2 novel variations c.2233C>G and c.3392_3393delAG in the <i>KDM5C</i> gene harboring from 2 Chinese families with X-linked intellectual disability (ID). The affected male patients exhibited severe ID, short stature, and facial dysmorphism. The 1 with c.3392_3393delAG additionally had epilepsy and autistic spectrum disorder (ASD). Transiently transfected mutant KDM5C constructs both reduced protein expression and stability and decreased histone demethylase activities in cells. Reviewing the available literature, we found that the associated ASD tended to occur in patients with variations near the C-terminus of KDM5C.\nDISCUSSION: We report the clinical, molecular genetic, and pathologic features in patients with novel variations of <i>KDM5C</i>. The variability of the clinical phenotype in addition to an ID may associate with altered particular parts of KDM5C.","variants":[{"Name":"NM_004187.5(KDM5C):c.3392_3393del (p.Glu1131fs)","Chromosome":"X","Start":"53194976","Stop":"53194977","ReferenceAlleleVCF":"GCT","AlternateAlleleVCF":"G","allel_id":806228,"rule_based_match":true,"evidence_text":"c.3392_3393delAG","llm_judgment":"PRESENT","evidence":"c.3392_3393delAG","abstract_start":432,"abstract_end":448}]}
{"pmid":"21907889","title":"Canavan disease: a novel mutation.","abstract":"Canavan disease, an autosomal recessive inherited leukodystrophy caused by an aspartoacylase deficiency, is common among children of Ashkenazi Jewish descent. We report on a non-Jewish female infant who presented at age 6 months with progressive macrocephaly and developmental delay. A sequence analysis of the aspartoacylase gene revealed compound heterozygosity for a known mutation and for the mutation c.432G>A in exon 2, which has not yet been described in Canavan disease.","variants":[{"Name":"NM_000049.4(ASPA):c.432G>A (p.Lys144=)","Chromosome":"17","Start":"3481798","Stop":"3481798","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":548022,"rule_based_match":true,"evidence_text":"c.432G>A","llm_judgment":"PRESENT","evidence":"c.432G>A","abstract_start":406,"abstract_end":414}]}
{"pmid":"29057815","title":"Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy.","abstract":"We identified herein additional patients with rod-cone dystrophy (RCD) displaying mutations in <i>KIZ</i>, encoding the ciliary centrosomal protein kizuna and performed functional characterization of the respective protein in human fibroblasts and of its mouse ortholog PLK1S1 in the retina. Mutation screening was done by targeted next generation sequencing and subsequent Sanger sequencing validation. <i>KIZ</i> mRNA levels were assessed on blood and serum-deprived human fibroblasts from a control individual and a patient, compound heterozygous for the c.52G>T (p.Glu18*) and c.119_122del (p.Lys40Ilefs*14) mutations in <i>KIZ</i>. KIZ localization, documentation of cilium length and immunoblotting were performed in these two fibroblast cell lines. In addition, PLK1S1 immunolocalization was conducted in mouse retinal cryosections and isolated rod photoreceptors. Analyses of additional RCD patients enabled the identification of two homozygous mutations in <i>KIZ</i>, the known c.226C>T (p.Arg76*) mutation and a novel variant, the c.3G>A (p.Met1?) mutation. Albeit the expression levels of <i>KIZ</i> were three-times lower in the patient than controls in whole blood cells, further analyses in control- and mutant <i>KIZ</i> patient-derived fibroblasts unexpectedly revealed no significant difference between the two genotypes. Furthermore, the averaged monocilia length in the two fibroblast cell lines was similar, consistent with the preserved immunolocalization of KIZ at the basal body of the primary cilia. Analyses in mouse retina and isolated rod photoreceptors showed PLK1S1 localization at the base of the photoreceptor connecting cilium. In conclusion, two additional patients with mutations in <i>KIZ</i> were identified, further supporting that defects in KIZ/PLK1S1, detected at the basal body of the primary cilia in fibroblasts, and the photoreceptor connecting cilium in mouse, respectively, are involved in RCD. However, albeit the mutations were predicted to lead to nonsense mediated mRNA decay, we could not detect changes upon expression levels, protein localization or cilia length in <i>KIZ</i>-mutated fibroblast cells. Together, our findings unveil the limitations of fibroblasts as a cellular model for RCD and call for other models such as induced pluripotent stem cells to shed light on retinal pathogenic mechanisms of <i>KIZ</i> mutations.","variants":[{"Name":"NM_018474.6(KIZ):c.226C>T (p.Arg76Ter)","Chromosome":"20","Start":"21136463","Stop":"21136463","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":133696,"rule_based_match":true,"evidence_text":"c.226C>T (p.Arg76*)","llm_judgment":"PRESENT","evidence":"c.226C>T (p.Arg76*)","abstract_start":988,"abstract_end":1007},{"Name":"NM_018474.6(KIZ):c.52G>T (p.Glu18Ter)","Chromosome":"20","Start":"21126167","Stop":"21126167","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":133697,"rule_based_match":true,"evidence_text":"c.52G>T (p.Glu18*)","llm_judgment":"PRESENT","evidence":"c.52G>T (p.Glu18*)","abstract_start":558,"abstract_end":576},{"Name":"NM_018474.6(KIZ):c.119_122del (p.Lys40fs)","Chromosome":"20","Start":"21132126","Stop":"21132129","ReferenceAlleleVCF":"AAACT","AlternateAlleleVCF":"A","allel_id":133698,"rule_based_match":true,"evidence_text":"c.119_122del (p.Lys40Ilefs*14)","llm_judgment":"PRESENT","evidence":"c.119_122del (p.Lys40Ilefs*14)","abstract_start":581,"abstract_end":611},{"Name":"NM_018474.6(KIZ):c.3G>A (p.Met1Ile)","Chromosome":"20","Start":"21126118","Stop":"21126118","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1365749,"rule_based_match":true,"evidence_text":"c.3G>A (p.Met1?)","llm_judgment":"PRESENT","evidence":"c.3G>A (p.Met1?)","abstract_start":1042,"abstract_end":1058}]}
{"pmid":"31428437","title":"Identification of mutations in","abstract":"G<sub>M2</sub> gangliosides are a group of lysosomal lipid storage disorders that are due to mutations in <i>HEXA</i>, <i>HEXB</i> and <i>GM2A</i>. In our study, 10 patients with these diseases were enrolled, and Sanger sequencing was performed for the <i>HEXA</i> and <i>HEXB</i> genes. The results revealed one known splice site mutation (c.346+1G>A, IVS2+1G>A) and three novel mutations (a large deletion involving exons 6-10; one nucleotide deletion, c.622delG [p.D208Ifsx15]; and a missense mutation, c.919G>A [p.E307K]) in <i>HEXA</i>. In <i>HEXB</i>, one known mutation (c.1597C>T [p.R533C]) and one variant of uncertain significance (c.619A>G [p.I207V]) were identified. Five patients had c.1597C>T in <i>HEXB</i>, indicating a common mutation in south Iran. In this study, a unique large deletion in <i>HEXA</i> was identified as a homozygous state. To predict the cause of the large deletion in <i>HEXA</i>, RepeatMasker was used to investigate the <i>Alu</i> elements. In addition, to identify the breakpoint of this deletion, PCR was performed around these elements. Using Repeat masker, different <i>Alu</i> elements were identified across <i>HEXA</i>, mainly in intron 5 and intron 10 adjacent to the deleted exons. PCR around the <i>Alu</i> elements and Sanger sequencing revealed the start point of a large deletion in <i>Alu</i>Sz6 in the intron 6 and the end of its breakpoint 73 nucleotides downstream of <i>Alu</i>Jo in intron 10. Our study showed that <i>HEXA</i> is an <i>Alu</i>-rich gene that predisposes individuals to disease-associated large deletions due to these elements.","variants":[{"Name":"NM_000520.6(HEXA):c.346+1G>A","Chromosome":"15","Start":"72356524","Stop":"72356524","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":548230,"rule_based_match":true,"evidence_text":"c.346+1G>A","llm_judgment":"PRESENT","evidence":"c.346+1G>A","abstract_start":341,"abstract_end":351}]}
{"pmid":"22560872","title":"A clinical and gene analysis of late-onset combined methylmalonic aciduria and homocystinuria, cblC type, in China.","abstract":"BACKGROUND: Combined methylmalonic aciduria and homocystinuria, cblC type (cblC disease), is the most common inborn disorder of cobalamin metabolism. This disorder is caused by MMACHC gene mutations, and it is usually diagnosed in the early neonatal period. Late-onset cblC is rare and difficult to recognize due to a wide diversity of symptoms.\nMETHODS: Three cases with late-onset combined methylmalonic aciduria and homocystinuria, cblC type, are reported; patients' clinical presentation, imaging and MMACHC gene mutations were analyzed.\nRESULTS: The age of onset in the three patients was 22 years, 40 years and 7 years of age. Two of the patients had MMACHC gene mutations heterozygous for c.609G>A and c.482G>A (case 1 and case 3). The other patient (case 2) presented with gene mutations heterozygous for c.609G>A and c.1A>G. The three patients presented with a heterogeneous clinical picture, including cognitive impairment, epilepsy, ataxia, pyramidal and peripheral nerve symptoms. Cerebral atrophy and bilateral hyperintensity in the deep white matter were visible in MRI scans of the patients' brains; those were significant findings in the three patients with late-onset cblC disease. In contrast with previous reports, bilateral cerebellar cortex abnormalities were also found in one patient (case 2).\nCONCLUSION: Although its occurrence is rare, late-onset combined methylmalonic aciduria and homocystinuria, cblC type, should be considered in making a differential diagnosis in patients who present with neurological symptoms that are not consistent with common neurological diseases, especially when cognition, the pyramidal tract and peripheral nerves are involved.","variants":[{"Name":"NM_015506.3(MMACHC):c.482G>A (p.Arg161Gln)","Chromosome":"1","Start":"45508848","Stop":"45508848","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16464,"rule_based_match":true,"evidence_text":"c.482G>A","llm_judgment":"PRESENT","evidence":"c.482G>A","abstract_start":709,"abstract_end":717}]}
{"pmid":"22151702","title":"Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures.","abstract":"SCN1A is the most relevant epilepsy gene. Mutations of SCN1A generate phenotypes ranging from the extremely severe form of Dravet syndrome (DS) to a mild form of generalized epilepsy with febrile seizures plus (GEFS+). Mosaic SCN1A mutations have been identified in rare familial DS. It is suspected that mosaic mutations of SCN1A may cause other types of familial epilepsies with febrile seizures (FS), which are more common clinically. Thus, we screened SCN1A mutations in 13 families with partial epilepsy with antecedent febrile seizures (PEFS+) using denaturing high-performance liquid chromatography and sequencing. The level of mosaicism was further quantified by pyrosequencing. Two missense SCN1A mutations with mosaic origin were identified in two unrelated families, accounting for 15.4% (2/13) of the PEFS+ families tested. One of the mosaic carriers with ~25.0% mutation of c.5768A>G/p.Q1923R had experienced simple FS; another with ~12.5% mutation of c.4847T>C/p.I1616T was asymptomatic. Their heterozygous children had PEFS+. Recurrent transmission occurred in both families, as noted in most of the families with germline mosaicism reported previously. The two mosaic mutations identified in this study are less destructive missense, compared with the more destructive truncating and splice-site mutations identified in the majority of previous studies. This is the first report of mosaic SCN1A mutations in families with probands that do not exhibit DS, but manifest only a milder phenotype. Therefore, such families with mild cases should be approached with caution in genetic counseling and the possibility of mosaicism origin associated with high recurrence risk should be excluded.","variants":[{"Name":"NM_001165963.4(SCN1A):c.4847T>C (p.Ile1616Thr)","Chromosome":"2","Start":"165994151","Stop":"165994151","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1059023,"rule_based_match":true,"evidence_text":"c.4847T>C/p.I1616T","llm_judgment":"PRESENT","evidence":"c.4847T>C/p.I1616T","abstract_start":965,"abstract_end":983}]}
{"pmid":"22958902","title":"Loss of SUFU function in familial multiple meningioma.","abstract":"Meningiomas are the most common primary tumors of the CNS and account for up to 30% of all CNS tumors. An increased risk of meningiomas has been associated with certain tumor-susceptibility syndromes, especially neurofibromatosis type II, but no gene defects predisposing to isolated familial meningiomas have thus far been identified. Here, we report on a family of five meningioma-affected siblings, four of whom have multiple tumors. No NF2 mutations were identified in the germline or tumors. We combined genome-wide linkage analysis and exome sequencing, and we identified in suppressor of fused homolog (Drosophila), SUFU, a c.367C>T (p.Arg123Cys) mutation segregating with the meningiomas in the family. The variation was not present in healthy controls, and all seven meningiomas analyzed displayed loss of the wild-type allele according to the classic two-hit model for tumor-suppressor genes. In silico modeling predicted the variant to affect the tertiary structure of the protein, and functional analyses showed that the activity of the altered SUFU was significantly reduced and therefore led to dysregulated hedgehog (Hh) signaling. SUFU is a known tumor-suppressor gene previously associated with childhood medulloblastoma predisposition. Our genetic and functional analyses indicate that germline mutations in SUFU also predispose to meningiomas, particularly to multiple meningiomas. It is possible that other genic mutations resulting in aberrant activation of the Hh pathway might underlie meningioma predisposition in families with an unknown etiology.","variants":[{"Name":"NM_016169.4(SUFU):c.367C>T (p.Arg123Cys)","Chromosome":"10","Start":"102550019","Stop":"102550019","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45820,"rule_based_match":true,"evidence_text":"c.367C>T (p.Arg123Cys)","llm_judgment":"PRESENT","evidence":"c.367C>T (p.Arg123Cys)","abstract_start":631,"abstract_end":653}]}
{"pmid":"23457316","title":"Severe short stature due to 3-M syndrome with a novel OBSL1 gene mutation.","abstract":"3-M syndrome is an underdiagnosed autosomal recessive disorder characterized by severe pre- and postnatal growth retardation with minimal dysmorphic features and distinguishing radiological findings. We report a patient who was first admitted at 7.5 years of age. He was born to consanguineous parents with a birth weight of 2250 g. Physical examination revealed a severe short stature (height, 95 cm; SD score -5.64) and minimal dysmorphic features. Biochemistry, endocrine work-up, and karyotype were normal. Reevaluation at 16.5 years of age revealed a height of 128.5 cm (SD score -5.27), prominent forehead, anteverted nasal openings, fleshy nasal tip, full lips, malar hypoplasia, hyperlordosis, prominent heels, testicular volumes 8-10 mL, and pubic hair consistent with Tanner stage II. Growth hormone trial for a year resulted in inadequate height gain (3 cm). The diagnosis of 3-M syndrome was made upon typical findings (thin long bones with diaphyseal narrowing and tall lumbar vertebrae) in a recent skeletal survey. Genetic analysis disclosed a homozygote frame shift mutation in exon 2: c.457_458delinsT resulting in p.Gly153fs.","variants":[{"Name":"NM_015311.3(OBSL1):c.457_458delinsT (p.Gly153fs)","Chromosome":"2","Start":"219570775","Stop":"219570776","ReferenceAlleleVCF":"CC","AlternateAlleleVCF":"A","allel_id":608874,"rule_based_match":true,"evidence_text":"c.457_458delinsT","llm_judgment":"PRESENT","evidence":"c.457_458delinsT","abstract_start":1102,"abstract_end":1118}]}
{"pmid":"25818971","title":"Development of end-stage renal disease at a young age in two cases with Joubert syndrome.","abstract":"Joubert syndrome (JS) is an autosomal recessive genetic disorder. To date, mutations in 20 genes of the genetically heterogeneous JS and JS-related disorders (JSRD) have been reported. Renal involvement occurs in 2-20% of JS cases. Identified renal abnormalities are cystic dysplasia and nephronophthisis. Here we report the clinical course and management of renal failure in early childhood. We present two cases diagnosed with JS that developed end-stage renal disease at young ages. In the genetic studies, a c.5668G>T (p.G1890*) homozygous stop mutation was identified in the CEP290 gene of one of the patients and a c.1303C>G (p.R435G) homozygous mutation in the INPP5E gene of the other. It has been emphasized that it is important to evaluate patients in terms of renal disease when monitoring the progress of Joubert syndrome, a condition that predominantly causes mental and motor development retardation.","variants":[{"Name":"NM_025114.4(CEP290):c.5668G>T (p.Gly1890Ter)","Chromosome":"12","Start":"88077263","Stop":"88077263","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":16372,"rule_based_match":true,"evidence_text":"c.5668G>T (p.G1890*)","llm_judgment":"PRESENT","evidence":"c.5668G>T (p.G1890*)","abstract_start":512,"abstract_end":532}]}
{"pmid":"18760763","title":"C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.","abstract":"All reported mutations in ALAS2, which encodes the rate-regulating enzyme of erythroid heme biosynthesis, cause X-linked sideroblastic anemia. We describe eight families with ALAS2 deletions, either c.1706-1709 delAGTG (p.E569GfsX24) or c.1699-1700 delAT (p.M567EfsX2), resulting in frameshifts that lead to replacement or deletion of the 19-20 C-terminal residues of the enzyme. Prokaryotic expression studies show that both mutations markedly increase ALAS2 activity. These gain-of-function mutations cause a previously unrecognized form of porphyria, X-linked dominant protoporphyria, characterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes, in which a mismatch between protoporphyrin production and the heme requirement of differentiating erythroid cells leads to overproduction of protoporphyrin in amounts sufficient to cause photosensitivity and liver disease.","variants":[{"Name":"NM_000032.5(ALAS2):c.1706_1709del (p.Glu569fs)","Chromosome":"X","Start":"55009235","Stop":"55009238","ReferenceAlleleVCF":"CCACT","AlternateAlleleVCF":"C","allel_id":25521,"rule_based_match":false,"evidence_text":"c.1706-1709 delAGTG (p.E569GfsX24)","llm_judgment":"PRESENT","evidence":"c.1706-1709 delAGTG (p.E569GfsX24)","abstract_start":199,"abstract_end":233},{"Name":"NM_000032.5(ALAS2):c.1699_1700del (p.Met567fs)","Chromosome":"X","Start":"55009244","Stop":"55009245","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":25522,"rule_based_match":false,"evidence_text":"c.1699-1700 delAT (p.M567EfsX2)","llm_judgment":"PRESENT","evidence":"c.1699-1700 delAT (p.M567EfsX2)","abstract_start":237,"abstract_end":268}]}
{"pmid":"15300847","title":"Identification and molecular characterization of alpha-L-iduronidase mutations present in mucopolysaccharidosis type I patients undergoing enzyme replacement therapy.","abstract":"Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase (IDUA). Mutations in the gene are responsible for the enzyme deficiency, which leads to the intralysosomal storage of the partially degraded glycosaminoglycans dermatan sulfate and heparan sulfate. Molecular characterization of MPS I patients has resulted in the identification of over 70 distinct mutations in the IDUA gene. The high degree of molecular heterogeneity reflects the wide clinical variability observed in MPS I patients. Six novel mutations, c.1087C>T (p.R363C), c.1804T>A (p.F602I), c.793G>C, c.712T>A (p.L238Q), c.1727+2T>A, and c.1269C>G (p.S423R), in a total of 14 different mutations, and 13 different polymorphic changes, including the novel c.246C>G (p.H82Q), were identified in a cohort of 10 MPS I patients enrolled in a clinical trial of enzyme-replacement therapy. Five novel amino acid substitutions and c.236C>T (p.A79V) were engineered into the wild-type IDUA cDNA and expressed. A p.G265R read-through mutation, arising from the c.793G>C splice mutation, was also expressed. Each mutation reduced IDUA protein and activity levels to varying degrees with the processing of many of the mutant forms also affected by IDUA. The varied properties of the expressed mutant forms of IDUA reflect the broad range of biochemical and clinical phenotypes of the 10 patients in this study. IDUA kinetic data derived from each patient's cultured fibroblasts, in combination with genotype data, was used to predict disease severity. Finally, residual IDUA protein concentration in cultured fibroblasts showed a weak correlation to the degree of immune response to enzyme-replacement therapy in each patient.","variants":[{"Name":"NM_000203.5(IDUA):c.246C>G (p.His82Gln)","Chromosome":"4","Start":"987896","Stop":"987896","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":98544,"rule_based_match":true,"evidence_text":"c.246C>G (p.H82Q)","llm_judgment":"PRESENT","evidence":"c.246C>G (p.H82Q)","abstract_start":799,"abstract_end":816},{"Name":"NM_000203.5(IDUA):c.236C>T (p.Ala79Val)","Chromosome":"4","Start":"987886","Stop":"987886","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":224720,"rule_based_match":true,"evidence_text":"c.236C>T (p.A79V)","llm_judgment":"PRESENT","evidence":"c.236C>T (p.A79V)","abstract_start":967,"abstract_end":984},{"Name":"NM_000203.5(IDUA):c.1087C>T (p.Arg363Cys)","Chromosome":"4","Start":"1002383","Stop":"1002383","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":543320,"rule_based_match":true,"evidence_text":"c.1087C>T (p.R363C)","llm_judgment":"PRESENT","evidence":"c.1087C>T (p.R363C)","abstract_start":593,"abstract_end":612},{"Name":"NM_000203.5(IDUA):c.793G>C (p.Gly265Arg)","Chromosome":"4","Start":"1001982","Stop":"1001982","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":625880,"rule_based_match":true,"evidence_text":"c.793G>C","llm_judgment":"PRESENT","evidence":"c.793G>C","abstract_start":635,"abstract_end":643}]}
{"pmid":"19636622","title":"Abnormal cochlear potentials from deaf patients with mutations in the otoferlin gene.","abstract":"Otoferlin is involved in neurotransmitter release at the synapse between inner hair cells (IHCs) and auditory nerve fibres, and mutations in the OTOF gene result in severe to profound hearing loss. Abnormal sound-evoked cochlear potentials were recorded with transtympanic electrocochleography from four children with otoferlin (OTOF) mutations to evaluate physiological effects in humans of abnormal neurotransmitter release from IHCs. The subjects were profoundly deaf with absent auditory brainstem responses and preserved otoacoustic emissions consistent with auditory neuropathy. Two children were compound heterozygotes for mutations c.2732_2735dupAGCT and p.Ala964Glu; one subject was homozygous for mutation p.Phe1795Cys, and one was compound heterozygote for two novel mutations c.1609delG in exon 16 and c.1966delC in exon 18. Cochlear potentials evoked by clicks from 60 to 120 dB peak equivalent sound pressure level were compared to recordings obtained from 16 normally hearing children. Cochlear microphonic (CM) was recorded with normal amplitudes from all but one ear. After cancelling CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls. These cochlear potentials were recorded as low as 50-90 dB below behavioural thresholds in contrast to the close correlation in controls between cochlear potentials and behavioural threshold. Summating potential was identified in five out of eight ears with normal latency whilst auditory nerve compound action potentials were either absent or of low amplitude. Stimulation at high rates reduced amplitude and duration of the prolonged potentials, consistent with neural generation. This study suggests that mechano-electrical transduction and cochlear amplification are normal in patients with OTOF mutations. The low-amplitude prolonged negative potentials are consistent with decreased neurotransmitter release resulting in abnormal dendritic activation and impairment of auditory nerve firing.","variants":[{"Name":"NM_194248.3(OTOF):c.5384T>G (p.Phe1795Cys)","Chromosome":"2","Start":"26461845","Stop":"26461845","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":76717,"rule_based_match":false,"evidence_text":"p.Phe1795Cys","llm_judgment":"PRESENT","evidence":"p.Phe1795Cys","abstract_start":716,"abstract_end":728}]}
{"pmid":"35600075","title":"","abstract":"Purpose: To identify novel genetic causes of febrile seizures (FS) and epilepsy with febrile seizures plus (EFS+).\nMethods: We performed whole-exome sequencing in a cohort of 32 families, in which at least two individuals were affected by FS or EFS+. The probands, their parents, and available family members were recruited to ascertain whether the genetic variants were co-segregation. Genes with repetitively identified variants with segregations were selected for further studies to define the gene-disease association.\nResults: We identified two heterozygous <i>ATP6V0C</i> mutations (c.64G > A/p.Ala22Thr and c.361_373del/p.Thr121Profs*7) in two unrelated families with six individuals affected by FS or EFS+. The missense mutation was located in the proteolipid c-ring that cooperated with a-subunit forming the hemichannel for proton transferring. It also affected the hydrogen bonds with surround residues and the protein stability, implying a damaging effect. The frameshift mutation resulted in a loss of function by yielding a premature termination of 28 residues at the C-terminus of the protein. The frequencies of <i>ATP6V0C</i> mutations identified in this cohort were significantly higher than that in the control populations. All the six affected individuals suffered from their first FS at the age of 7-8 months. The two probands later manifested afebrile seizures including myoclonic seizures that responded well to lamotrigine. They all displayed favorable outcomes without intellectual or developmental abnormalities, although afebrile seizures or frequent seizures occurred.\nConclusion: This study suggests that <i>ATP6V0C</i> is potentially a candidate pathogenic gene of FS and EFS+. Screening for <i>ATP6V0C</i> mutations would help differentiating patients with Dravet syndrome caused by <i>SCN1A</i> mutations, which presented similar clinical manifestation but different responses to antiepileptic treatment.","variants":[{"Name":"NM_001694.4(ATP6V0C):c.64G>A (p.Ala22Thr)","Chromosome":"16","Start":"2514167","Stop":"2514167","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2740204,"rule_based_match":true,"evidence_text":"c.64G > A/p.Ala22Thr","llm_judgment":"PRESENT","evidence":"c.64G > A/p.Ala22Thr","abstract_start":589,"abstract_end":609},{"Name":"NM_001694.4(ATP6V0C):c.361_373del (p.Thr121fs)","Chromosome":"16","Start":"2519636","Stop":"2519648","ReferenceAlleleVCF":"GGCACCGCCCAGCA","AlternateAlleleVCF":"G","allel_id":2740205,"rule_based_match":true,"evidence_text":"c.361_373del/p.Thr121Profs*7","llm_judgment":"PRESENT","evidence":"c.361_373del/p.Thr121Profs*7","abstract_start":614,"abstract_end":642}]}
{"pmid":"21519002","title":"Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations.","abstract":"OBJECTIVE: Two unrelated families were ascertained in which sisters had infantile onset of epilepsy and developmental delay. Mutations in the protocadherin 19 (PCDH19) gene cause epilepsy and mental retardation limited to females (EFMR). Despite both sister pairs having a PCDH19 mutation, neither parent in each family was a heterozygous carrier of the mutation. The possibility of parental mosaicism of PCDH19 mutations was investigated.\nMETHODS: Genomic DNA from peripheral blood was obtained and sequenced for PCDH19 mutations. Parentage was confirmed by markers.\nRESULTS: Both sister pairs have a mutation in PCDH19. Sister pair 1 has a missense mutation, c.74T>C, L25P, while sequence analysis indicates both of their parents are negative for the mutation. Diagnostic restriction enzyme analysis detected low-level mosaicism of the mutation in their mother. Sister pair 2 are half-sisters who share a mother and each has the missense PCDH19 mutation c.1019 A>G, N340S. The sequence chromatograph of their mother shows reduced signal for the same mutation. These data indicate maternal somatic and gonadal mosaicism of the PCDH19 mutation in both sister pairs. Phenotyping is suggestive of, and PCDH19 mutation detection is diagnostic for, the disorder EFMR in the affected girls.\nCONCLUSIONS: We show that gonadal mosaicism of a PCDH19 mutation in a parent is an important molecular mechanism associated with the inheritance of EFMR. This should be considered when providing genetic counseling for couples who have one affected daughter as they may risk recurrence of affected daughters and having sons at risk of transmitting EFMR.","variants":[{"Name":"NM_001184880.2(PCDH19):c.74T>C (p.Leu25Pro)","Chromosome":"X","Start":"100408524","Stop":"100408524","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1878326,"rule_based_match":true,"evidence_text":"c.74T>C","llm_judgment":"PRESENT","evidence":"c.74T>C","abstract_start":661,"abstract_end":668},{"Name":"NM_001184880.2(PCDH19):c.1019A>G (p.Asn340Ser)","Chromosome":"X","Start":"100407579","Stop":"100407579","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":203925,"rule_based_match":true,"evidence_text":"c.1019 A>G","llm_judgment":"PRESENT","evidence":"c.1019 A>G","abstract_start":956,"abstract_end":966}]}
{"pmid":"28390064","title":"PGAP3-related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation.","abstract":"BACKGROUND: Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by recessive mutations in genes involved in the glycosylphosphatidylinsitol pathway, including PGAP3.\nMATERIALS AND METHODS: We describe 10 patients from 8 Egyptian families presenting with developmental delay, severe intellectual disability, distinct facial dysmorphism and increased alkaline phosphatase. Sanger sequencing of PGAP3 was performed.\nRESULTS: Eight patients had cleft palate, 4 had postnatal microcephaly and 5 had seizures. Neuro-imaging findings showed thin corpus callosum in 9 patients, mild ventriculomegaly in 3 patients and variable degrees of cerebellar vermis hypoplasia in 4 patients, a finding not previously reported in patients with HPMRS. Additional manifestations included double row teeth, hypogenitalism and congenital heart disease. Biallelic loss of function mutations in the PGAP3 gene were detected in all patients. Nine patients were homozygous for the c.402dupC (p.M135Hfs*28) mutation strongly suggesting a founder effect. On the other hand, 1 patient had a novel mutation, c.817_820delGACT (p.D273Sfs*37).\nCONCLUSION: This is the largest series of patients with HPMRS from same ethnic group. Our results reinforce the distinct clinical and facial features of PGAP3-related HPMRS which are the clue for targeted genetic testing. Moreover, we present additional unreported clinical and neuro-imaging findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.","variants":[{"Name":"NM_033419.5(PGAP3):c.402dup (p.Met135fs)","Chromosome":"17","Start":"39684626","Stop":"39684627","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":226428,"rule_based_match":true,"evidence_text":"c.402dupC (p.M135Hfs*28)","llm_judgment":"PRESENT","evidence":"c.402dupC (p.M135Hfs*28)","abstract_start":971,"abstract_end":995}]}
{"pmid":"27710913","title":"Solving a case of allelic dropout in the GNPTAB gene: implications in the molecular diagnosis of mucolipidosis type III alpha/beta.","abstract":"While being well known that the diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing, not rarely, however, genetic testing needs much perseverance and cunning strategies to identify the causative mutation(s). Here we present a case of a thorny molecular diagnosis of mucolipidosis type III alpha/beta, which is an autosomal recessive lysosomal storage disorder, caused by a defect in the GNPTAB gene that codes for the α/β-subunits of the GlcNAc-1-phosphotransferase. We used both cDNA and gDNA analyses to characterize a mucolipidosis type III alpha/beta patient whose clinical diagnosis was already confirmed biochemically. In a first stage only one causal mutation was identified in heterozygosity, the already described missense mutation c.1196C>T(p.S399F), both at cDNA and gDNA levels. Only after conducting inhibition of nonsense-mediated mRNA decay (NMD) assays and after the utilization of another pair of primers the second mutation, the c.3503_3504delTC deletion, was identified. Our findings illustrate that allelic dropout due to the presence of polymorphisms and/or of mutations that trigger the NMD pathway can cause difficulties in current molecular diagnosis tests.","variants":[{"Name":"NM_024312.5(GNPTAB):c.3503_3504del (p.Leu1168fs)","Chromosome":"12","Start":"101753470","Stop":"101753471","ReferenceAlleleVCF":"TGA","AlternateAlleleVCF":"T","allel_id":17810,"rule_based_match":true,"evidence_text":"c.3503_3504delTC","llm_judgment":"PRESENT","evidence":"c.3503_3504delTC","abstract_start":1010,"abstract_end":1026},{"Name":"NM_024312.5(GNPTAB):c.1196C>T (p.Ser399Phe)","Chromosome":"12","Start":"101770109","Stop":"101770109","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46972,"rule_based_match":true,"evidence_text":"c.1196C>T(p.S399F)","llm_judgment":"PRESENT","evidence":"c.1196C>T(p.S399F)","abstract_start":804,"abstract_end":822}]}
{"pmid":"37715646","title":"Novel MEIOB pathogenic variants including a homozygous non-canonical splicing variant, cause meiotic arrest and human non-obstructive azoospermia.","abstract":"Non-obstructive azoospermia (NOA) is the most severe form of human male infertility, and the genetic causes of NOA with meiotic arrest remain largely unclear. In this study, we identified novel compound heterozygous MEIOB variants (c.814C > T: p.R272X and c.976G > A: p.A326T) and a previously undescribed homozygous non-canonical splicing variant of MEIOB (c.528 + 3A > C) in two NOA-affected individuals from two irrelevant Chinese families. MEIOB missense variant (p.A326T) significantly reduced protein abundance and nonsense variant (p.R272X) produced a truncated protein. Both of two variants impaired the MEIOB-SPATA22 interaction. The MEIOB non-canonical splicing variant resulted in whole Exon 6 skipping by minigene assay, which was predicted to produce a frameshift truncated protein (p.S111Rfs*32). Histological and immunostaining analysis indicated that both patients exhibited a similar phenotype as we previously reported in Meiob mutant mice, that is, absence of spermatids in seminiferous tubules and meiotic arrest. Our study identified three novel pathogenic variants of MEIOB in NOA patients, extending the mutation spectrum of the MEIOB and highlighting the contribution of meiotic recombination related genes in human fertility.","variants":[{"Name":"NM_001163560.3(MEIOB):c.976G>A (p.Ala326Thr)","Chromosome":"16","Start":"1841878","Stop":"1841878","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2852800,"rule_based_match":true,"evidence_text":"c.976G > A: p.A326T","llm_judgment":"PRESENT","evidence":"c.976G > A: p.A326T","abstract_start":256,"abstract_end":275},{"Name":"NM_001163560.3(MEIOB):c.814C>T (p.Arg272Ter)","Chromosome":"16","Start":"1844928","Stop":"1844928","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2099769,"rule_based_match":true,"evidence_text":"c.814C > T: p.R272X","llm_judgment":"PRESENT","evidence":"c.814C > T: p.R272X","abstract_start":232,"abstract_end":251},{"Name":"NM_001163560.3(MEIOB):c.528+3A>C","Chromosome":"16","Start":"1857732","Stop":"1857732","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2852805,"rule_based_match":true,"evidence_text":"c.528 + 3A > C","llm_judgment":"PRESENT","evidence":"c.528 + 3A > C","abstract_start":358,"abstract_end":372}]}
{"pmid":"26249260","title":"A mutation in TRPV4 results in altered chondrocyte calcium signaling in severe metatropic dysplasia.","abstract":"Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is a polymodal modulated non-selective cation channel required for normal development and maintenance of bone and cartilage. Heterozygous mutations of this channel cause a variety of channelopathies, including metatropic dysplasia (MD). We analyzed the effect of a novel TRPV4 mutation c.2398G>A, p.Gly800Asp on intracellular calcium ([Ca(2+) ]i ) regulation in chondrocytes and compared this response to chondrocytes with a frequently observed mutation, c.2396C>T, p.Pro799Leu. We observed temperature-dependent [Ca(2+) ]i oscillations in both intact and MD chondrocytes however, MD mutations exhibited increased peak magnitudes of [Ca(2+) ]i during oscillations. We also found increased baseline [Ca(2+) ]i in MD primary cells, as well as increased [Ca(2+) ]i response to either hypotonic swelling or the TRVP4-specific agonist, GSK1016790A. Oscillations and stimulation responses were blocked with the TRPV4-specific antagonist, GSK205. Analysis of [Ca(2+) ]i response kinetics showed that MD chondrocytes had increased frequency of temperature-sensitive oscillations, and the magnitude and duration of [Ca(2+) ]i responses to given stimuli. Duration of the response of the p.Gly800Asp mutation to stimulation was greater than for the p.Pro799Leu mutation. These experiments show that this region of the channel is essential for proper [Ca(2+) ]i regulation. These studies of primary cells from patients show how both mutant and WT TRPV4 channels regulate cartilage and bone development. © 2015 Wiley Periodicals, Inc.","variants":[{"Name":"NM_021625.5(TRPV4):c.2396C>T (p.Pro799Leu)","Chromosome":"12","Start":"109784378","Stop":"109784378","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20037,"rule_based_match":true,"evidence_text":"c.2396C>T, p.Pro799Leu","llm_judgment":"PRESENT","evidence":"c.2396C>T, p.Pro799Leu","abstract_start":530,"abstract_end":552}]}
{"pmid":"37743782","title":"De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities.","abstract":"The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.","variants":[{"Name":"NM_145166.4(ZBTB47):c.2039A>G (p.Glu680Gly)","Chromosome":"3","Start":"42664393","Stop":"42664393","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2403696,"rule_based_match":true,"evidence_text":"c.2039A>G","llm_judgment":"PRESENT","evidence":"c.2039A>G","abstract_start":719,"abstract_end":728}]}
{"pmid":"31317654","title":"MAP1B related syndrome: Case presentation and review of literature.","abstract":"The microtubule-associated protein 1B (MAP1B) gene serves an important role in axonal growth and brain development. Its expression is known to be elevated in regions that retain high brain plasticity and is regulated by the fragile X mental retardation protein. MAP1B mutations have recently been associated with a phenotype including periventricular nodular heterotopia (PVNH), intellectual disability (ID), seizures, and dysmorphic features. We describe a child presenting with global developmental delays, ID, microcephaly, short stature, seizures, dysmorphic features, and prenatal alcohol exposure with a de novo nonsense MAP1B mutation (c.2035G>T, p.Glu679X) detected on whole exome sequencing (WES). His brain MRI showed PVNH and dysgenesis of the corpus callosum. While significant prenatal alcohol exposure could have modified his phenotype, we believe that this patient presents with features that cannot be explained by fetal alcohol exposure alone. This is the first case report that describes dysmorphic features associated with MAP1B mutations in detail along with supporting pictures and review of previous reported phenotypes. This case not only highlights the value of WES as a screening tool for unrecognized syndromes, but also supports the need for a better description of the phenotype associated with newly detected genetic syndromes by molecular screening.","variants":[{"Name":"NM_005909.5(MAP1B):c.2035G>T (p.Glu679Ter)","Chromosome":"5","Start":"72195390","Stop":"72195390","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":918530,"rule_based_match":true,"evidence_text":"c.2035G>T, p.Glu679X","llm_judgment":"PRESENT","evidence":"c.2035G>T, p.Glu679X","abstract_start":643,"abstract_end":663}]}
{"pmid":"18783408","title":"Confirmation of RAX gene involvement in human anophthalmia.","abstract":"Microphthalmia and anophthalmia are at the severe end of the spectrum of abnormalities in ocular development. Mutations in several genes have been involved in syndromic and non-syndromic anophthalmia. Previously, RAX recessive mutations were implicated in a single patient with right anophthalmia, left microphthalmia and sclerocornea. In this study, we report the findings of novel compound heterozygous RAX mutations in a child with bilateral anophthalmia. Both mutations are located in exon 3. c.664delT is a frameshifting deletion predicted to introduce a premature stop codon (p.Ser222ArgfsX62), and c.909C>G is a nonsense mutation with similar consequences (p.Tyr303X). This is the second report of a patient with anophthalmia caused by RAX mutations. These findings confirm that RAX plays a major role in the early stages of eye development and is involved in human anophthalmia.","variants":[{"Name":"NM_013435.3(RAX):c.664del (p.Ser222fs)","Chromosome":"18","Start":"59269381","Stop":"59269381","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":22676,"rule_based_match":true,"evidence_text":"c.664delT","llm_judgment":"PRESENT","evidence":"c.664delT","abstract_start":497,"abstract_end":506},{"Name":"NM_013435.3(RAX):c.909C>G (p.Tyr303Ter)","Chromosome":"18","Start":"59269136","Stop":"59269136","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":22677,"rule_based_match":true,"evidence_text":"c.909C>G (p.Tyr303X)","llm_judgment":"PRESENT","evidence":"p.Tyr303X","abstract_start":664,"abstract_end":673}]}
{"pmid":"34160414","title":"A germline c.1546dupC MEN1 mutation in an MEN1 family: A case report.","abstract":"RATIONALE: Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome with an autosomal dominant inheritance, and genetic testing for MEN1 gene is important for both affected individuals and their relatives. We present a 2-person family affected by a germline c.1546dupC MEN1 mutation, and one of them had a full-spectrum of MEN-related endocrine tumors.\nPATIENT CONCERNS: A female patient aged 32 years presented with jejunal ulcer perforation due to gastrinoma.\nDIAGNOSES: We conducted genetic analysis and extensive biochemical/radiological evaluation for detecting other endocrine tumors. Multiple pancreatic neuroendocrine tumors (NETs), prolactinoma and primary hyperparathyroidism were diagnosed, and a frame-shift mutation, NM_130799.1:c.1546dupC (p.Arg516Profs∗15), was detected. One daughter of the proband, aged 12 years, had the same mutation for MEN1.\nINTERVENTION: She underwent pancreatic surgery for pancreatic NETs and total parathyroidectomy for primary hyperparathyroidism.\nOUTCOMES: After pancreatic surgery, long-term symptoms of epigastric soreness, acid belching, sweating, and palpitation in fasting were improved. Hypercalcemia was improved after parathyroidectomy and she was supplemented with oral calcium and vitamin D. Her daughter showed normal biochemical surveillance until 15 years of age.\nLESSONS: We report 2 people in a family affected by MEN1 with the heterozygous germline c.1546dupC mutation, a variant that should be surveilled for early development of full-blown MEN1-associated endocrine tumors.","variants":[{"Name":"NM_001370259.2(MEN1):c.1546dup (p.Arg516fs)","Chromosome":"11","Start":"64804620","Stop":"64804621","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":264436,"rule_based_match":true,"evidence_text":"NM_130799.1:c.1546dupC (p.Arg516Profs∗15)","llm_judgment":"PRESENT","evidence":"NM_130799.1:c.1546dupC (p.Arg516Profs∗15)","abstract_start":741,"abstract_end":782}]}
{"pmid":"28620499","title":"Intrauterine death following intraamniotic triiodothyronine and thyroxine therapy for fetal goitrous hypothyroidism associated with polyhydramnios and caused by a thyroglobulin mutation.","abstract":"In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother's second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (<i>TG</i>) mutations which are the likely cause of fetal goitre in the deceased sibling. <i>TG</i> mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases.\nLEARNING POINTS: CH due to biallelic, loss-of-function <i>TG</i> mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.CH due to <i>TG</i> mutations may manifest with variable phenotypes, even within the same kindred.Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.","variants":[{"Name":"NM_003235.5(TG):c.7123G>A (p.Gly2375Arg)","Chromosome":"8","Start":"133029907","Stop":"133029907","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27742,"rule_based_match":true,"evidence_text":"c.7123G > A, p.G2375R","llm_judgment":"PRESENT","evidence":"c.7123G > A, p.G2375R","abstract_start":874,"abstract_end":895}]}
{"pmid":"33014402","title":"Compound heterozygous variants in the","abstract":"Sitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the <i>ABCG8</i> gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.","variants":[{"Name":"NM_022437.3(ABCG8):c.1256_1257delinsAA (p.Ile419Lys)","Chromosome":"2","Start":"43873831","Stop":"43873832","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"AA","allel_id":1294800,"rule_based_match":false,"evidence_text":"c.1256_1257delTCinsAA (p.Ile419Lys)","llm_judgment":"PRESENT","evidence":"c.1256_1257delTCinsAA (p.Ile419Lys)","abstract_start":352,"abstract_end":387}]}
{"pmid":"31149344","title":"A novel missense","abstract":"Phosphatase and tensin homolog (PTEN) plays an important role in tumor suppression. A germline mutation in the <i>PTEN</i> gene induces not only PTEN hamartoma tumor syndrome, including Cowden syndrome, but also macrocephaly/autism syndrome. Here, we describe a boy with macrocephaly/autism syndrome harboring a novel missense heterozygous <i>PTEN</i> mutation, c.959T>C (p.Leu320Ser). Interestingly, a previously reported nonsense mutation resulting in p.Leu320X was found in Cowden syndrome patients. Our case may be suggestive of a genotype-phenotype correlation.","variants":[{"Name":"NM_000314.8(PTEN):c.959T>C (p.Leu320Ser)","Chromosome":"10","Start":"87961051","Stop":"87961051","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1029848,"rule_based_match":true,"evidence_text":"c.959T>C (p.Leu320Ser)","llm_judgment":"PRESENT","evidence":"c.959T>C (p.Leu320Ser)","abstract_start":362,"abstract_end":384}]}
{"pmid":"25132448","title":"Mutations in NOTCH1 cause Adams-Oliver syndrome.","abstract":"Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5' region and three coding variants (c.1285T>C [p.Cys429Arg], c.4487G>A [p.Cys1496Tyr], and c.5965G>A [p.Asp1989Asn]), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743-1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway.","variants":[{"Name":"NM_017617.5(NOTCH1):c.1285T>C (p.Cys429Arg)","Chromosome":"9","Start":"136517908","Stop":"136517908","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":166011,"rule_based_match":true,"evidence_text":"c.1285T>C [p.Cys429Arg]","llm_judgment":"PRESENT","evidence":"c.1285T>C [p.Cys429Arg]","abstract_start":767,"abstract_end":790},{"Name":"NM_017617.5(NOTCH1):c.4487G>A (p.Cys1496Tyr)","Chromosome":"9","Start":"136505409","Stop":"136505409","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":165811,"rule_based_match":true,"evidence_text":"c.4487G>A (p.Cys1496Tyr)","llm_judgment":"PRESENT","evidence":"p.Cys1496Tyr","abstract_start":803,"abstract_end":815},{"Name":"NM_017617.5(NOTCH1):c.5965G>A (p.Asp1989Asn)","Chromosome":"9","Start":"136499229","Stop":"136499229","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":166009,"rule_based_match":true,"evidence_text":"c.5965G>A (p.Asp1989Asn)","llm_judgment":"PRESENT","evidence":"p.Asp1989Asn","abstract_start":833,"abstract_end":845},{"Name":"NM_017617.5(NOTCH1):c.743-1G>T","Chromosome":"9","Start":"136519566","Stop":"136519566","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":166010,"rule_based_match":true,"evidence_text":"c.743-1 G>T","llm_judgment":"PRESENT","evidence":"c.743-1 G>T","abstract_start":982,"abstract_end":993}]}
{"pmid":"33179433","title":"Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.","abstract":"Klippel-Feil syndrome 4 (KFS4; MIM# 616549) is an autosomal recessive disorder caused by biallelic pathogenic variants in MYO18B and comprises, in addition to Klippel-Feil anomaly (KFA), nemaline myopathy, facial dysmorphism, and short stature. We aim to outline the natural history of KFS4 and provide an updated description of its clinical, radiological, laboratory, and molecular findings. We comprehensively analyzed the medical records of 6 Saudi and 1 American patients (including 5 previously unpublished cases) with a molecularly confirmed diagnosis of KFS4. All patients had myopathy of varying severity that followed a slowly progressive or non-progressive course, affecting primarily the proximal musculature of the lower limb although hand involvement with distal arthrogryposis and abnormal interphalangeal creases was also observed. KFA and characteristic dysmorphic features, including ptosis and bulbous nose, were observed in all but two patients. The causal MYO18B variants were a founder NM_032608.5:c.6905C>A; p.(Ser2302*) variant in the Saudi patients (P1-P6) and a novel MYO18B homozygous variant (c.6660_6670del;p.[Arg2220Serfs*74]) in the American Caucasian patient (P7). We report the phenotypic and genetic findings in seven patients with KFS4. We describe the natural history of this disease, confirm myopathy as a universal feature and describe its pattern and progression, and note interesting differences between the phenotypes observed in patients with KFA and those without.","variants":[{"Name":"NM_032608.7(MYO18B):c.6660_6670del (p.Arg2220fs)","Chromosome":"22","Start":"26026633","Stop":"26026643","ReferenceAlleleVCF":"AGATTAGAACCT","AlternateAlleleVCF":"A","allel_id":581234,"rule_based_match":true,"evidence_text":"c.6660_6670del;p.[Arg2220Serfs*74]","llm_judgment":"PRESENT","evidence":"c.6660_6670del;p.[Arg2220Serfs*74]","abstract_start":1120,"abstract_end":1154}]}
{"pmid":"26430231","title":"Peutz-Jeghers syndrome: early clinical expression of a new STK11 gene variant.","abstract":"Genetic heterogeneity has been recognised in Peutz-Jeghers syndrome (PJS) (over 230 STK11 gene mutations reported). We report a rare PJS phenotype with early extensive gastrointestinal (GI) presentation and a new genetic variant. The case presented as haematochezia and mucocutaneous pigmentation (the patient was 3 years of age). Endoscopy showed several polyps throughout the stomach/colon (PJ-type hamartomas); the larger polyps were resected. Small bowel imaging detected multiple jejunum/ileum small polyps. During 8 years of follow-up of this asymptomatic patient, an increasing number of diffusely distributed polyps was observed and polypectomies were performed. Subsequently, the patient failed consultations; when the patient was 13 years of age, emergency surgery was required due to small bowel intussusception (ileal polyp). A STK11 gene study identified two missense variants in heterozygous (yet unknown significance but probably pathogenic): c.854T>A (exon 6) and c.446C>T* (exon 2) (*not previously reported). We report two STK11 gene variants (one not previously described) of yet undetermined causality in a paediatric patient presenting with extensive GI involvement at a very early age, with no family medical history. Structural and functional repercussion of the newly described variants should be further investigated.","variants":[{"Name":"NM_000455.5(STK11):c.446C>T (p.Pro149Leu)","Chromosome":"19","Start":"1219395","Stop":"1219395","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1440101,"rule_based_match":true,"evidence_text":"c.446C>T","llm_judgment":"PRESENT","evidence":"c.446C>T","abstract_start":980,"abstract_end":988}]}
{"pmid":"25047097","title":"Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population.","abstract":"Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita (DC), characterized by cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and severe immunodeficiency in addition to features of DC. Germline mutations in the RTEL1 gene have recently been identified as causative of HH. In this study, the carrier frequency for five RTEL1 mutations that occurred in individuals of Ashkenazi Jewish descent was investigated in order to advise on including them in existing clinical mutation panels for this population. Our screening showed that the carrier frequency for c.3791G>A (p.R1264H) was higher than expected, 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population. Haplotype analyses suggested the presence of a common founder. We recommend that the c.3791G>A RTEL1 mutation be considered for inclusion in carrier screening panels in the Ashkenazi population.","variants":[{"Name":"NM_001283009.1(RTEL1):c.3791G>A (p.Arg1264His)","Chromosome":"20","Start":"63695619","Stop":"63695619","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":51186,"rule_based_match":true,"evidence_text":"c.3791G>A (p.R1264H)","llm_judgment":"PRESENT","evidence":"c.3791G>A (p.R1264H)","abstract_start":614,"abstract_end":634}]}
{"pmid":"26666653","title":"Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness.","abstract":"BACKGROUND: Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations.\nMETHODS: A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification.\nRESULTS: Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response.\nCONCLUSIONS: This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.","variants":[{"Name":"NM_000277.3(PAH):c.500A>T (p.Asn167Ile)","Chromosome":"12","Start":"102866605","Stop":"102866605","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":98650,"rule_based_match":true,"evidence_text":"c.500A > T","llm_judgment":"PRESENT","evidence":"c.500A > T","abstract_start":933,"abstract_end":943},{"Name":"NM_000277.3(PAH):c.434A>T (p.Asp145Val)","Chromosome":"12","Start":"102877469","Stop":"102877469","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":108403,"rule_based_match":true,"evidence_text":"c.434A > T","llm_judgment":"PRESENT","evidence":"c.434A > T","abstract_start":921,"abstract_end":931},{"Name":"NM_000277.3(PAH):c.1196T>C (p.Val399Ala)","Chromosome":"12","Start":"102843649","Stop":"102843649","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":125857,"rule_based_match":true,"evidence_text":"c.1196 T > C","llm_judgment":"PRESENT","evidence":"c.1196 T > C","abstract_start":974,"abstract_end":986},{"Name":"NM_000277.3(PAH):c.529G>C (p.Val177Leu)","Chromosome":"12","Start":"102855313","Stop":"102855313","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":108463,"rule_based_match":true,"evidence_text":"c.529G > C","llm_judgment":"PRESENT","evidence":"c.529G > C","abstract_start":945,"abstract_end":955}]}
{"pmid":"30362618","title":"Zellweger spectrum disorder patient-derived fibroblasts with the PEX1-Gly843Asp allele recover peroxisome functions in response to flavonoids.","abstract":"Zellweger spectrum disorder (ZSD) results from biallelic mutations in PEX genes required for peroxisome biogenesis. PEX1-G843D is a common hypomorphic allele in the patient population that is associated with milder disease. In prior work using a PEX1-G843D/null patient fibroblast line expressing a green fluorescent protein (GFP) reporter with a peroxisome-targeting signal (GFP-PTS1), we demonstrated that treatments with the chemical chaperone betaine and flavonoid acacetin diacetate recovered peroxisome functions. To identify more effective compounds for preclinical investigation, we evaluated 54 flavonoids using this cell-based phenotype assay. Diosmetin showed the most promising combination of potency and efficacy (EC50 2.5 µM). All active 5',7'-dihydroxyflavones showed greater average efficacy than their corresponding flavonols, whereas the corresponding flavanones, isoflavones, and chalcones tested were inactive. Additional treatment with the proteostasis regulator bortezomib increased the percentage of import-rescued cells over treatment with flavonoids alone. Cotreatments of diosmetin and betaine showed the most robust additive effects, as confirmed by three independent functional assays in primary PEX1-G843D patient cells, but neither agent was active alone or in combination in patient cells homozygous for the PEX1 c.2097_2098insT null allele. Moreover, diosmetin treatment increased PEX1, PEX6, and PEX5 protein levels in PEX1-G843D patient cells, but none of these proteins increased in PEX1 null cells. We propose that diosmetin acts as a pharmacological chaperone that improves the stability, conformation, and functions of PEX1/PEX6 exportomer complexes required for peroxisome assembly. We suggest that diosmetin, in clinical use for chronic venous disease, and related flavonoids warrant further preclinical investigation for the treatment of PEX1-G843D-associated ZSD.","variants":[{"Name":"NM_000466.3(PEX1):c.2528G>A (p.Gly843Asp)","Chromosome":"7","Start":"92501562","Stop":"92501562","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22555,"rule_based_match":false,"evidence_text":"PEX1-G843D","llm_judgment":"PRESENT","evidence":"PEX1-G843D","abstract_start":116,"abstract_end":126}]}
{"pmid":"23824750","title":"Low prevalence of germline PALB2 mutations in Australian triple-negative breast cancer.","abstract":"Triple-negative breast cancer (TNBC) is a tumour classification that is defined by oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 receptor negativity. TNBCs share a similar gene expression profile to BRCA-mutated tumours, have been shown to carry a high proportion of BRCA mutations and have a more adverse prognosis compared to other types of breast tumours. PALB2 has been shown to be a moderate-penetrance breast cancer susceptibility gene and is involved in the same DNA damage repair pathway as BRCA1 and BRCA2; this raises the possibility that germline PALB2 mutations may be involved in the pathogenesis of TNBCs. In our study, we sequenced the coding regions of PALB2 (including intron/exon boundaries) in genomic DNA from 347 patients diagnosed with TNBC to determine the prevalence of deleterious mutations in this population. Two novel truncating mutations (c.758dup and c.2390del) and one previously detected truncating mutation (c.3113+5G>C) were found. In addition, five variants predicted to be protein-affecting were also identified. Our study shows that the prevalence of PALB2 germline mutations in individuals with TNBC is ∼1%, similar to the prevalence of PALB2 germline mutation of 1% in familial non-BRCA1/2 breast cancer cohorts.","variants":[{"Name":"NM_024675.4(PALB2):c.3113+5G>C","Chromosome":"16","Start":"23621357","Stop":"23621357","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":235176,"rule_based_match":true,"evidence_text":"c.3113+5G>C","llm_judgment":"PRESENT","evidence":"c.3113+5G>C","abstract_start":982,"abstract_end":993},{"Name":"NM_024675.4(PALB2):c.758dup (p.Ser254fs)","Chromosome":"16","Start":"23635787","Stop":"23635788","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":132279,"rule_based_match":true,"evidence_text":"c.758dup","llm_judgment":"PRESENT","evidence":"c.758dup","abstract_start":909,"abstract_end":917}]}
{"pmid":"38091959","title":"Novel Variants of HPS6 Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of HPS6 Variants.","abstract":"INTRODUCTION: Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of HPS6 variants and their genotype-phenotype correlations.\nMETHODS: Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of family JX. The single coding exon of HPS6 was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of HPS6 reported in the literature were reviewed.\nRESULTS: We identified two different compound heterozygous truncating variants of HPS6 in probands with suspected OA from two independent families. The proband of family JX had c.1674dup and c.503-504del variants, and the other proband from family CZ had a nonsense variant of c.1114C&gt;T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of HPS6 variants and revealed a significant overlap between CpG islands and the variants of HPS6, suggesting a potential link between DNA methylation and HPS6 variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease.\nCONCLUSION: Our research expands the spectrum of HPS6 variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.","variants":[{"Name":"NM_024747.6(HPS6):c.1114C>T (p.Arg372Ter)","Chromosome":"10","Start":"102066588","Stop":"102066588","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1340120,"rule_based_match":false,"evidence_text":"c.1114C>T","llm_judgment":"PRESENT","evidence":"c.1114C>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"25500851","title":"Griscelli syndrome.","abstract":"We report a case of Griscelli Syndrome (GS). Our patient initially presented with a diagnosis of haemophagocytic lymphistiocytosis (HLH). Subsequent microscopic analysis of the patient's hair follicle revealed abnormal distribution of melanosomes in the shaft, which is a hallmark for GS. Analysis of RAB27A gene in this patient revealed a homozygous mutation in exon 6, c.550C>T, p.R184X . This nonsense mutation causes premature truncation of the protein resulting in a dysfunctional RAB27A. Recognition of GS allows appropriate institution of therapy namely chemotherapy for HLH and curative haemotopoeitic stem cell transplantation.","variants":[{"Name":"NM_183235.3(RAB27A):c.550C>T (p.Arg184Ter)","Chromosome":"15","Start":"55205623","Stop":"55205623","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":429705,"rule_based_match":true,"evidence_text":"c.550C>T","llm_judgment":"PRESENT","evidence":"c.550C>T","abstract_start":371,"abstract_end":379}]}
{"pmid":"28575107","title":"Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling.","abstract":"Retinoblastoma (RB) is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA) assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59) while only 42.4% (25/59) of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9%) of tumors screened. There were 3 cases (5.1%) in which no mutations could be detected and germline mutations were detected in 19.5% (8/41) of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59) of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and asymptomatic family members carrying low-penetrance, germline mosaicism or heritable unilateral mutational phenotypes.","variants":[{"Name":"NM_000321.3(RB1):c.607+1G>T","Chromosome":"13","Start":"48349024","Stop":"48349024","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":28132,"rule_based_match":true,"evidence_text":"c.607+1G>T","llm_judgment":"PRESENT","evidence":"c.607+1G>T","abstract_start":1421,"abstract_end":1431},{"Name":"NM_000321.3(RB1):c.1981C>T (p.Arg661Trp)","Chromosome":"13","Start":"48459708","Stop":"48459708","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28126,"rule_based_match":true,"evidence_text":"c.1981C>T","llm_judgment":"PRESENT","evidence":"c.1981C>T","abstract_start":1392,"abstract_end":1401}]}
{"pmid":"26215059","title":"Clinical and genetic analysis of pediatric patients with Wilson disease.","abstract":"BACKGROUND/AIMS: Wilson disease (WD, MIM# 277900) is an autosomal recessive disorder of copper transport resulting from the defective function of a copper transporting P-type ATPase. Detecting mutations and single nucleotide polymorphisms (SNPs) of the ATP7B gene in Turkish pediatric WD patients (n=32) and controls (n=52) is the aim of this research.\nMATERIALS AND METHODS: For screening mutations and SNPs of the ATP7B gene, sequencing was performed.\nRESULTS: Mutations were determined in the ATP7B gene in 23 out of the 32 pediatric patients. The mutation detection rate in the ATP7B gene of the pediatric Turkish WD patients was 71.875%. Fifteen different mutations were determined in the ATP7B gene. These mutations were distributed throughout the ATP7B gene and were as follows: 2 deletion, 1 insertion, 3 nonsense, and 9 missense mutations. Four of these, including c.3111delC (1 deletion) and c.2363C>T, c.3733C>A, and c.3451C>T (3 missense) mutations, were detected in the Turkish WD patients. Eleven polymorphisms were detected in both groups. Among these, c.3727G>A (SNP) was reported in the Wilson Disease Mutation Database by our group. Nine out of the thirty-two pediatric Turkish WD patients had no mutations in the ATP7B gene.\nCONCLUSION: To find the cause of WD in pediatric patients who have no mutation in ATP7B, additional research is necessary.","variants":[{"Name":"NM_000053.4(ATP7B):c.2363C>T (p.Thr788Ile)","Chromosome":"13","Start":"51957600","Stop":"51957600","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":936482,"rule_based_match":true,"evidence_text":"c.2363C>T","llm_judgment":"PRESENT","evidence":"c.2363C>T","abstract_start":902,"abstract_end":911},{"Name":"NM_000053.4(ATP7B):c.3451C>T (p.Arg1151Cys)","Chromosome":"13","Start":"51941186","Stop":"51941186","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186884,"rule_based_match":true,"evidence_text":"c.3451C>T","llm_judgment":"PRESENT","evidence":"c.3451C>T","abstract_start":928,"abstract_end":937}]}
{"pmid":"30651581","title":"Patients with cobalamin G or J defect missed by the current newborn screening program: diagnosis and novel mutations.","abstract":"Cobalamin G (cblG) and cobalamin J (cblJ) defects are rare disorders of cbl metabolism caused by MTR and ABCD4 mutations, respectively. Patients with atypical biochemical features can be missed by current newborn screening using tandem mass spectrometry (MS/MS), in which total homocysteine (tHCY) in dried blood spots (DBS) is not a primary biomarker. Two Chinese patients suspected of cbl defect but missed by newborn screening were studied. Using comprehensive metabolic analyses including MS/MS assay for tHCY in DBS, slightly low methionine in Patient 1, methymalonic aciduria in Patient 2, and homocysteinemia in both patients were detected, and DBS tHCY of two patients were obviously elevated (59.22 μmol/L, 17.75 μmol/L) compared to 140 healthy controls (2.5th-97.5th percentile, 1.05-8.22 μmol/L). Utilizing whole-exome sequencing, we found two novel MTR variants c.871C>T (p.Pro291Ser) and c.1771C>T (p.Arg591*) in Patient 1, and a ABCD4 homozygous variant c.423C>G (p.Asn141Lys) in Patient 2. Our study identified the first cblG patient and cblJ patient in mainland China, and highlighted comprehensive metabolic analyses and genetic tests in patients suspected of cbl defects. It also indicated that supplementary MS/MS assay for tHCY in DBS may be practical for early diagnosis of homocysteinemia, without repeated blood sampling.","variants":[{"Name":"NM_000254.3(MTR):c.871C>T (p.Pro291Ser)","Chromosome":"1","Start":"236825343","Stop":"236825343","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3494861,"rule_based_match":true,"evidence_text":"c.871C>T (p.Pro291Ser)","llm_judgment":"PRESENT","evidence":"c.871C>T (p.Pro291Ser)","abstract_start":874,"abstract_end":896},{"Name":"NM_005050.4(ABCD4):c.423C>G (p.Asn141Lys)","Chromosome":"14","Start":"74297932","Stop":"74297932","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1335298,"rule_based_match":true,"evidence_text":"ABCD4 homozygous variant c.423C>G (p.Asn141Lys)","llm_judgment":"PRESENT","evidence":"ABCD4 homozygous variant c.423C>G (p.Asn141Lys)","abstract_start":943,"abstract_end":990}]}
{"pmid":"25516070","title":"Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders.","abstract":"PURPOSE: Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients.\nMETHODS: Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients.\nRESULTS: Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A>G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G>T, p.W522C and (2) c.2689C>T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection.\nCONCLUSION: Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments.","variants":[{"Name":"NM_000448.3(RAG1):c.1835A>G (p.His612Arg)","Chromosome":"11","Start":"36575139","Stop":"36575139","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":838374,"rule_based_match":false,"evidence_text":"c1835A>G, pH612R","llm_judgment":"PRESENT","evidence":"c1835A>G, pH612R","abstract_start":1112,"abstract_end":1128},{"Name":"NM_000448.3(RAG1):c.256_257del (p.Lys86fs)","Chromosome":"11","Start":"36573560","Stop":"36573561","ReferenceAlleleVCF":"TAA","AlternateAlleleVCF":"T","allel_id":269282,"rule_based_match":false,"evidence_text":"c256_257delAA","llm_judgment":"PRESENT","evidence":"c256_257delAA","abstract_start":1079,"abstract_end":1092},{"Name":"NM_000448.3(RAG1):c.1566G>T (p.Trp522Cys)","Chromosome":"11","Start":"36574870","Stop":"36574870","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":45371,"rule_based_match":true,"evidence_text":"c.1566G>T","llm_judgment":"PRESENT","evidence":"c.1566G>T","abstract_start":1205,"abstract_end":1214},{"Name":"NM_000448.3(RAG1):c.2689C>T (p.Arg897Ter)","Chromosome":"11","Start":"36575993","Stop":"36575993","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":481990,"rule_based_match":true,"evidence_text":"c.2689C>T (p. R897X)","llm_judgment":"PRESENT","evidence":"c.2689C>T","abstract_start":1232,"abstract_end":1241}]}
{"pmid":"36935552","title":"Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.","abstract":"CONTEXT: Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease.\nOBJECTIVE: To investigate for novel genes causing parathyroid cancer.\nMETHODS: We analyzed the germline DNA of 17 patients with \"sporadic\" PC and 3 with atypical parathyroid tumors (APTs) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants.\nRESULTS: We identified germline FLCN variants in 3 unrelated patients with PC. The 2 frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome, while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing; however, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant.\nCONCLUSION: The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy.","variants":[{"Name":"NM_144997.7(FLCN):c.124G>C (p.Gly42Arg)","Chromosome":"17","Start":"17228014","Stop":"17228014","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":645394,"rule_based_match":true,"evidence_text":"c.124G > C (p.G42R)","llm_judgment":"PRESENT","evidence":"c.124G > C (p.G42R)","abstract_start":996,"abstract_end":1015}]}
{"pmid":"23556051","title":"Genetically confirmed Wilson disease in a 9-month old boy with elevations of aminotransferases.","abstract":"Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by alteration of the adenosine triphosphatase 7B gene. It is rare to diagnose WD below the age of three years. Molecular genetic testing is one of the most important diagnostic methods and may confirm the diagnosis in equivocal cases. We report a case of a 9-mo old boy with WD who presented as chronic hepatitis. Genetic analysis showed compound heterozygotes of p.G1186S and c.4006delA.","variants":[{"Name":"NM_000053.4(ATP7B):c.4006del (p.Ile1336fs)","Chromosome":"13","Start":"51937291","Stop":"51937291","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":547591,"rule_based_match":true,"evidence_text":"c.4006delA","llm_judgment":"PRESENT","evidence":"c.4006delA","abstract_start":459,"abstract_end":469}]}
{"pmid":"34821460","title":"Report of two children with global developmental delay in association with de novo TLK2 variant and literature review.","abstract":"We describe clinical details, including novel findings, of two further children with the newly defined TLK2-related disorder. One patient was recruited to the Deciphering Developmental Delay (DDD) Study to identify underlying etiology of global developmental delay. The other was detected on whole-exome sequencing as part of second line investigations following normal microarray. Both patients were found to have de novo heterozygous pathogenic TLK2 variants. A novel c.6del p.(Glu3Lysfs*) loss-of-function frameshift variant was found in Patient 1. A c.1121+1G>A splice-donor variant was detected in Patient 2. TLK2-related neurodevelopmental disorder is a specific syndrome that has been recently described. Global developmental delay, behavioral problems, gastrointestinal disorders, and typical facial dysmorphism are common features. Neuropsychiatric disorders, ophthalmic, musculoskeletal and cranial abnormalities, as well as short stature, have also all been described. The novel findings we describe include sleep disturbance, nondifferentiation of lateral semi-circular canals (where asymmetric semi-circular canals were a feature in the previous cohort), vesico-ureteric reflux, and bilateral periauricular skin tags. Here, we report a novel TLK2 variant and previously undescribed features of TLK2-related disorder, to expand the clinical phenotype and provide further genotype-phenotype correlation.","variants":[{"Name":"NM_006852.6(TLK2):c.1121+1G>A","Chromosome":"17","Start":"62573368","Stop":"62573368","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1691608,"rule_based_match":true,"evidence_text":"c.1121+1G>A","llm_judgment":"PRESENT","evidence":"c.1121+1G>A","abstract_start":554,"abstract_end":565}]}
{"pmid":"31875949","title":"Is BRCA2 involved in early onset colorectal cancer risk?","abstract":"A, Closed symbols indicate patients affected with cancer. Open symbols indicate healthy individuals. The type of cancer and age at presentation are given in brackets. Blue circle represents c.4471_4474del variant and red circle represents the c.9648 + 1G > A. B, RNA was extracted from blood of patient III-3 and his sisters III-1 and III-4. RT-PCR analysis was performed with primers mapping to exons 25 and 27, and PCR products were separated by Bioanalyzer electrophoresis. The sizes of the DNA marker (M) are indicated to the left. LM, lower marker; UM, upper marker. C, Each RT-PCR product from patient III-3 was gel-purified and analyzed by Sanger sequencing. The 297-bp band corresponds to the reference BRCA2 transcript and the 150-bp band corresponds to a BRCA2 transcript lacking exon 26.","variants":[{"Name":"NM_000059.4(BRCA2):c.4471_4474del (p.Leu1491fs)","Chromosome":"13","Start":"32338825","Stop":"32338828","ReferenceAlleleVCF":"TACTG","AlternateAlleleVCF":"T","allel_id":66320,"rule_based_match":true,"evidence_text":"c.4471_4474del","llm_judgment":"PRESENT","evidence":"c.4471_4474del","abstract_start":190,"abstract_end":204},{"Name":"NM_000059.4(BRCA2):c.9648+1G>A","Chromosome":"13","Start":"32397045","Stop":"32397045","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":480476,"rule_based_match":true,"evidence_text":"c.9648 + 1G > A","llm_judgment":"PRESENT","evidence":"c.9648 + 1G > A","abstract_start":243,"abstract_end":258}]}
{"pmid":"33433679","title":"RET compound inheritance in Chinese patients with Hirschsprung disease: lack of penetrance from insufficient gene dysfunction.","abstract":"Hirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of enteric ganglia along variable lengths of the intestine. Genetic defects play a major role in HSCR pathogenesis with nearly 50% of patients having a structural or regulatory deficiency in the major susceptibility gene RET. However, complete molecular defects remain poorly characterized in most patients. Here, we performed detailed genetic, molecular, and populational investigations of rare null mutations and modifiers at the RET locus. We first verified the pathogenicity of three RET splice site mutants (c.1879 + 1G > A, c.2607 + 5G > A and c.2608-3C > G) at the RNA level. We also identified significantly higher risk allele (genotype) frequencies, and their over-transmission, from unaffected parents to affected offspring of three functionally independent enhancer variants (rs2506030, rs7069590 and rs2435357, with odd ratios (OR) of 2.09, 2.71 and 7.59, respectively, P < 0.001). These three common variants are in significant (P < 4.64 × 10<sup>-186</sup>) linkage disequilibrium in the Han Chinese population with ~ 60% of them carrying at least one copy and > 10% with two copies. We show that RET compound inheritance of rare and common variants prevails in 64% (seven out of 11) of Chinese HSCR families. This study supports the idea that common RET variants can modify the penetrance of rare null RET mutations in HSCR, and the combined high susceptibility allele dosage may constitute the unique raised \"risk baseline\" among the Chinese population.","variants":[{"Name":"NM_020975.6(RET):c.2607+5G>A","Chromosome":"10","Start":"43119750","Stop":"43119750","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":359964,"rule_based_match":true,"evidence_text":"c.2607+5G>A","llm_judgment":"PRESENT","evidence":"c.2607 + 5G > A","abstract_start":609,"abstract_end":624},{"Name":"NM_020975.6(RET):c.1879+1G>A","Chromosome":"10","Start":"43113676","Stop":"43113676","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":654156,"rule_based_match":true,"evidence_text":"c.1879+1G>A","llm_judgment":"PRESENT","evidence":"c.1879 + 1G > A","abstract_start":592,"abstract_end":607}]}
{"pmid":"24319098","title":"A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta.","abstract":"We identified a family in which pitted hypomineralized amelogenesis imperfecta (AI) with premature enamel failure segregated in an autosomal recessive fashion. Whole-exome sequencing revealed a missense mutation (c.586C>A, p.P196T) in the I-domain of integrin-β6 (ITGB6), which is consistently predicted to be pathogenic by all available programmes and is the only variant that segregates with the disease phenotype. Furthermore, a recent study revealed that mice lacking a functional allele of Itgb6 display a hypomaturation AI phenotype. Phenotypic characterization of affected human teeth in this study showed areas of abnormal prismatic organization, areas of low mineral density and severe abnormal surface pitting in the tooth's coronal portion. We suggest that the pathogenesis of this form of AI may be due to ineffective ligand binding of ITGB6 resulting in either compromised cell-matrix interaction or compromised ITGB6 activation of transforming growth factor-β (TGF-β) impacting indirectly on ameloblast-ameloblast interactions and proteolytic processing of extracellular matrix proteins via MMP20. This study adds to the list of genes mutated in AI and further highlights the importance of cell-matrix interactions during enamel formation.","variants":[{"Name":"NM_000888.5(ITGB6):c.586C>A (p.Pro196Thr)","Chromosome":"2","Start":"160195376","Stop":"160195376","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":178851,"rule_based_match":true,"evidence_text":"c.586C>A, p.P196T","llm_judgment":"PRESENT","evidence":"c.586C>A, p.P196T","abstract_start":213,"abstract_end":230}]}
{"pmid":"25451950","title":"Molecular and clinical delineation of 12 patients with glycogen storage disease type III in Western Turkey.","abstract":"BACKGROUND: Glycogen storage disease type III (GSD III; MIM #232400) is an autosomal recessive inherited disorder characterized by fasting hypoglycemia, growth retardation, hepatomegaly, progressive myopathy, and cardiomyopathy. GSD III is caused by deficiency in the glycogen debranching enzyme (gene symbol: AGL). Molecular analyses of AGL have indicated heterogeneity depending on ethnic groups. In Turkey we reported 13 different AGL mutations from GSD III patients in the Eastern region; however, the full spectrum of AGL mutations in Turkish population remains unclear. Here we investigated 12 GSD III patients mostly from Western Turkey.\nMETHODS: The full coding exons, their relevant exon-intron boundaries, and the 5'- and 3'-flanking regions of the patients' AGL were sequenced. AGL haplotypes were determined. Splicing mutations were characterized by RNA transcript analysis.\nRESULTS: Twelve different mutations were identified: 7 novel AGL mutations [69-base pair deletion (c.1056_1082+42del69), 21-base par deletion (c.3940_3949+11del21), two small duplications (c.364_365dupCT and c.1497_1500dupAGAG), and 3 splicing mutations (c.1736-11A>G, c.3259+1G>A and c.3588+2T>G)], along with 5 known mutations (c.1019delA, c.958+1G>A, c.4161+5G>A, p.R864X and p.R1218X). Transcripts of splicing mutations (c.1736-11A>G, c.3588+2T>G and c.4161+5G>A) were shown to cause aberrant splicing. AGL haplotype analyses suggested that c.1019delA and c.958+1G>A are founder mutations in Turkish patients, while p.R864X is a recurrent mutation.\nCONCLUSIONS: Our study broadens the spectrum of AGL mutations and demonstrates that mutations in Western Turkey are different from those in the Eastern region.","variants":[{"Name":"NM_000642.3(AGL):c.1497_1500dup (p.Asp501fs)","Chromosome":"1","Start":"99877713","Stop":"99877714","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CAGAG","allel_id":961827,"rule_based_match":true,"evidence_text":"c.1497_1500dupAGAG","llm_judgment":"PRESENT","evidence":"c.1497_1500dupAGAG","abstract_start":1095,"abstract_end":1113},{"Name":"NM_000642.3(AGL):c.3259+1G>A","Chromosome":"1","Start":"99892608","Stop":"99892608","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1355257,"rule_based_match":true,"evidence_text":"c.3259+1G>A","llm_judgment":"PRESENT","evidence":"c.3259+1G>A","abstract_start":1156,"abstract_end":1167},{"Name":"NM_000642.3(AGL):c.4161+5G>A","Chromosome":"1","Start":"99913743","Stop":"99913743","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2898295,"rule_based_match":true,"evidence_text":"c.4161+5G>A","llm_judgment":"PRESENT","evidence":"c.4161+5G>A","abstract_start":1241,"abstract_end":1252},{"Name":"NM_000642.3(AGL):c.958+1G>A","Chromosome":"1","Start":"99870870","Stop":"99870870","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":541439,"rule_based_match":true,"evidence_text":"c.958+1G>A","llm_judgment":"PRESENT","evidence":"c.958+1G>A","abstract_start":1229,"abstract_end":1239}]}
{"pmid":"21393328","title":"An apparently silent nucleotide substitution (c.7056C>T) in the von Willebrand factor gene is responsible for type 1 von Willebrand disease.","abstract":"BACKGROUND: Nucleotide variations not changing protein sequences are considered silent mutations; accumulating data suggest that they can, however, be important in human diseases.\nDESIGN AND METHODS: We report an altered splicing process induced by a silent substitution (c.7056C>T) in the von Willebrand factor gene in a case of type 1 von Willebrand disease originally classified as lacking von Willebrand factor mutations.\nRESULTS: The c.7056C>T synonymous substitution introduces a new donor splice site within exon 41, leading to messenger RNA lacking nucleotides 7055-7081 (c.7055_7081del). The encoded von Willebrand factor protein is predicted to lack amino acids 2352-2360 in the B2 domain. The patient's von Willebrand disease phenotype was characterized by reduced plasma and platelet von Willebrand factor, which was normal in function and multimer structure. In vitro expression studies demonstrated that co-transfection of equimolar c.7055_7081del and wild-type von Willebrand factor (mimicking the patient's heterozygous state) induced a 50% lower von Willebrand factor secretion than the wild type, while almost no von Willebrand factor secretion was seen with the mutated von Willebrand factor alone. The secreted von Willebrand factor was structurally and functionally normal, suggesting that the c.7056C>T substitution behaves like a loss-of-function allele.\nCONCLUSIONS: This is the first report of a synonymous von Willebrand factor substitution being responsible for von Willebrand disease. Our findings suggest the need to reconsider the role of von Willebrand factor polymorphisms in von Willebrand disease.","variants":[{"Name":"NM_000552.5(VWF):c.7056C>T (p.Gly2352=)","Chromosome":"12","Start":"5983175","Stop":"5983175","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620451,"rule_based_match":true,"evidence_text":"c.7056C>T","llm_judgment":"PRESENT","evidence":"c.7056C>T","abstract_start":272,"abstract_end":281}]}
{"pmid":"32846800","title":"Loss-of-function mutation of PCSK9 as a protective factor in the clinical expression of familial hypercholesterolemia: A case report.","abstract":"RATIONALE: Proprotein convertase subtilisin/kexin 9 or PCSK9 is a protein whose main function is to regulate the number of low-density lipoprotein receptors (LDLR) present on the cell surface. Loss-of-function mutations in PCSK9 have been related to low LDL-cholesterol levels and a decrease in the risk of cardiovascular events.\nPATIENT CONCERNS: We present the case of a 27-year-old woman, offspring of a patient with familial homozygous hypercholesterolemia, who presented with mild-moderate hypercholesterolemia.\nDIAGNOSIS: Genetic analysis was performed by next generation sequencing using a customized panel of 198 genes. Sanger sequencing was used to confirm the presence of the variants of interest. The genetic analysis showed a pathogenic heterozygous mutation in LDLR [exon 6:c.902A>G:p(Asp301Gly)], as well as a loss-of-function heterozygous variant in PCSK9 [exon1:c.137 G>T:p.(Arg46Leu)]. The genetic analysis of the index case's mother revealed compound heterozygosity for 2 different mutations in LDLR [c.902A>G:p.(Asp301Gly); c.1646G>T:p.(Gly549Val)] in exon 6 and in exon 11, respectively, and the same loss-of-function variant in PCSK9 that had been found in her daughter [(PCSK9:exon1:c.137G>T:p.(Arg46Leu)]. The maternal grandfather of the index case presented the same genetic variants as his granddaughter.\nINTERVENTIONS: The index case did not receive any specific treatment for hypercholesterolemia. The loss-of-function variant in PCSK9 protected her from higher LDL-cholesterol levels, provided she kept partial activity of the LDLR. In her mother, instead, a PCSK9 inhibitor was tried but failed to achieve lipid control. The reason for this may be the complete absence in LDL receptor activity. LDL apheresis was started afterwards, resulting in adequate lipid level control.\nOUTCOMES: To the date, the index case has achieved to maintain adequate total and LDL-cholesterol levels without any other intervention. She has had no known cardiovascular complication.\nLESSONS: Loss-of-function mutations in PCSK9 could protect from developing more severe forms of hypercholesterolemia. The finding of these mutations (LDLR-PCSK9) in three consecutive generations could imply an adaptive mechanism against the development of hypercholesterolemia.","variants":[{"Name":"NM_000527.5(LDLR):c.902A>G (p.Asp301Gly)","Chromosome":"19","Start":"11107476","Stop":"11107476","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":245847,"rule_based_match":true,"evidence_text":"c.902A>G:p.(Asp301Gly)","llm_judgment":"PRESENT","evidence":"c.902A>G:p.(Asp301Gly)","abstract_start":1019,"abstract_end":1041}]}
{"pmid":"26027496","title":"Homozygosity for frameshift mutations in XYLT2 result in a spondylo-ocular syndrome with bone fragility, cataracts, and hearing defects.","abstract":"Heparan and chondroitin/dermatan sulfated proteoglycans have a wide range of roles in cellular and tissue homeostasis including growth factor function, morphogen gradient formation, and co-receptor activity. Proteoglycan assembly initiates with a xylose monosaccharide covalently attached by either xylosyltransferase I or II. Three individuals from two families were found that exhibited similar phenotypes. The index case subjects were two brothers, individuals 1 and 2, who presented with osteoporosis, cataracts, sensorineural hearing loss, and mild learning defects. Whole exome sequence analyses showed that both individuals had a homozygous c.692dup mutation (GenBank: NM_022167.3) in the xylosyltransferase II locus (XYLT2) (MIM: 608125), causing reduced XYLT2 mRNA and low circulating xylosyltransferase (XylT) activity. In an unrelated boy (individual 3) from the second family, we noted low serum XylT activity. Sanger sequencing of XYLT2 in this individual revealed a c.520del mutation in exon 2 that resulted in a frameshift and premature stop codon (p.Ala174Profs(∗)35). Fibroblasts from individuals 1 and 2 showed a range of defects including reduced XylT activity, GAG incorporation of (35)SO4, and heparan sulfate proteoglycan assembly. These studies demonstrate that human XylT2 deficiency results in vertebral compression fractures, sensorineural hearing loss, eye defects, and heart defects, a phenotype that is similar to the autosomal-recessive disorder spondylo-ocular syndrome of unknown cause. This phenotype is different from what has been reported in individuals with other linker enzyme deficiencies. These studies illustrate that the cells of the lens, retina, heart muscle, inner ear, and bone are dependent on XylT2 for proteoglycan assembly in humans.","variants":[{"Name":"NM_022167.4(XYLT2):c.692dup (p.Val232fs)","Chromosome":"17","Start":"50354465","Stop":"50354466","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":204220,"rule_based_match":true,"evidence_text":"c.692dup","llm_judgment":"PRESENT","evidence":"c.692dup","abstract_start":648,"abstract_end":656},{"Name":"NM_022167.4(XYLT2):c.520del (p.Ala174fs)","Chromosome":"17","Start":"50354013","Stop":"50354013","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":204221,"rule_based_match":true,"evidence_text":"c.520del","llm_judgment":"PRESENT","evidence":"c.520del","abstract_start":980,"abstract_end":988}]}
{"pmid":"37718511","title":"BRCA1 frameshift variants leading to extended incorrect protein C-termini.","abstract":"Carriers of BRCA1 germline pathogenic variants are at substantially higher risk of developing breast and ovarian cancer than the general population. Accurate identification of at-risk individuals is crucial for risk stratification and the implementation of targeted preventive and therapeutic interventions. Despite significant progress in variant classification efforts, a sizable portion of reported BRCA1 variants remain as variants of uncertain clinical significance (VUS). Variants leading to premature protein termination and loss of essential functional domains are typically classified as pathogenic. However, the impact of frameshift variants that result in an extended incorrect terminus (EIT) is not clear. Using validated functional assays, we conducted a systematic functional assessment of 17 previously reported BRCA1 EIT variants and concluded that 16 constitute loss of function variants. This suggests that most EITs are likely to be pathogenic. However, one variant, c.5578dup, displayed protein expression level, affinity to known binding partners, and activity in transcription and homologous recombination assays comparable to the wild-type BRCA1 protein. Twenty-three additional carriers of c.5578dup were identified at a US clinical diagnostic lab and assessed using a family history likelihood model providing, in combination with the functional data, a likely benign interpretation. These results, consistent with family history data in the current study and available data from ClinVar, indicate that most, but not all, BRCA1 variants leading to EIT constitute loss of function variants, and underscore the need for comprehensive assessment of individual variants.","variants":[{"Name":"NM_007294.4(BRCA1):c.5578dup (p.His1860fs)","Chromosome":"17","Start":"43045691","Stop":"43045692","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":46239,"rule_based_match":true,"evidence_text":"c.5578dup","llm_judgment":"PRESENT","evidence":"c.5578dup","abstract_start":986,"abstract_end":995}]}
{"pmid":"36004024","title":"A Rare Case of Pontocerebellar Hypoplasia Type 1B With Literature Review.","abstract":"A full-term female newborn was transferred to our neonatal intensive care unit (NICU) on day two of life for hypotonia. Physical examination was significant for overriding sutures, displaced small anterior fontanelle, axial hypotonia, extremity hypertonia, and slow deep tendon reflexes. She was also noted to have stridor with crying but had unlabored breathing without oxygen requirements and a normal heart examination. A brain magnetic resonance imaging (MRI) showed a large cisterna magna and cerebellar hypoplasia with the majority of the cerebellar vermis present, suggesting a possible Dandy-Walker variant (cerebellar vermis hypoplasia). Head computed tomography showed areas of close approximation of coronal sutures and no synostosis. During the NICU stay, our patient was evaluated by Pediatric Neurology who recommended a chromosomal microarray which returned normal. The patient also had some difficulty feeding initially, but she was able to feed efficiently and gain weight by the time of discharge. After discharge from NICU, her neurological status steadily declined, resulting in poor motor function and poor suck despite regular physical therapy, occupational therapy, and speech therapy. By three months of age, she developed failure to thrive and was admitted to the hospital for evaluation of the cause. Her neurological examination showed worsening of her axial hypotonia with very little movement in the upper extremities and hypertonia in the lower extremities. She had a weak suck with the inability to form a good seal on the nipple. A new heart murmur was noted and an echocardiogram showed a moderate-to-large atrial septal defect. A modified barium swallow study showed severe dysphagia for which she required gastrostomy tube placement for feeding. At follow-up with Neurology, she was noted to have progressive microcephaly, profound hypotonia, areflexia, and nystagmus. A second MRI showed worsening atrophy and increasing ventriculomegaly. By nine months of age, she developed respiratory failure, required a tracheostomy, and remained ventilator-dependent. Genetics was then consulted and recommended a brain malformation genetic panel. The patient was found to be heterozygous for two pathogenic variants in the <i>EXOSC3</i> gene: c.155delC and D132A, which is consistent with a diagnosis of autosomal recessive pontocerebellar hypoplasia (PCH) type 1B. The mother was found to be a heterozygous carrier of the c.155delC pathogenic variant, while the father was a heterozygous carrier for the D132A variant, which confirms that the two variants are present on opposite alleles. PCH describes a rare group of 11 neurodegenerative disorders that are typically seen prenatally or shortly after birth. PCH1 is characterized as a combination of PCH and spinal muscular atrophy, with patients presenting with muscle weakness and global developmental delay. An increased understanding of PCH1 will lead to better care and counseling for patients and families.","variants":[{"Name":"NM_016042.4(EXOSC3):c.155del (p.Pro52fs)","Chromosome":"9","Start":"37784890","Stop":"37784890","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":264333,"rule_based_match":true,"evidence_text":"c.155delC","llm_judgment":"PRESENT","evidence":"c.155delC","abstract_start":2269,"abstract_end":2278}]}
{"pmid":"26402864","title":"Missense Mutations in CRYAB Are Liable for Recessive Congenital Cataracts.","abstract":"PURPOSE: This study was initiated to identify causal mutations responsible for autosomal recessive congenital cataracts in consanguineous familial cases.\nMETHODS: Affected individuals underwent a detailed ophthalmological and clinical examination, and slit-lamp photographs were ascertained for affected individuals who have not yet been operated for the removal of the cataractous lens. Blood samples were obtained, and genomic DNA was extracted from white blood cells. A genome-wide scan was completed with short tandem repeat (STR) markers, and the logarithm of odds (LOD) scores were calculated. Protein coding exons of CRYAB were sequenced, bi-directionally. Evolutionary conservation was investigated by aligning CRYAB orthologues, and the expression of Cryab in embryonic and postnatal mice lens was investigated with TaqMan probe.\nRESULTS: The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis suggested a potential region on chromosome 11q23 harboring CRYAB. DNA sequencing identified a missense variation: c.34C>T (p.R12C) in CRYAB that segregated with the disease phenotype in the family. Subsequent interrogation of our entire cohort of familial cases identified a second familial case localized to chromosome 11q23 harboring a c.31C>T (p.R11C) mutation. In silico analyses suggested that the mutations identified in familial cases, p.R11C and p.R12C will not be tolerated by the three-dimensional structure of CRYAB. Real-time PCR analysis identified the expression of Cryab in mouse lens as early as embryonic day 15 (E15) that increased significantly until postnatal day 6 (P6) with steady level of expression thereafter.\nCONCLUSION: Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.","variants":[{"Name":"NM_001289808.2(CRYAB):c.34C>T (p.Arg12Cys)","Chromosome":"11","Start":"111911691","Stop":"111911691","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1062236,"rule_based_match":true,"evidence_text":"c.34C>T (p.R12C)","llm_judgment":"PRESENT","evidence":"c.34C>T (p.R12C)","abstract_start":1101,"abstract_end":1117},{"Name":"NM_001289808.2(CRYAB):c.31C>T (p.Arg11Cys)","Chromosome":"11","Start":"111911694","Stop":"111911694","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":224412,"rule_based_match":true,"evidence_text":"c.31C>T (p.R11C)","llm_judgment":"PRESENT","evidence":"c.31C>T (p.R11C)","abstract_start":1325,"abstract_end":1341}]}
{"pmid":"29667716","title":"A founder mutation MLC1 c.736delA associated with megalencephalic leukoencephalopathy with subcortical cysts-1 in north Indian kindred.","abstract":"","variants":[{"Name":"NM_015166.4(MLC1):c.736del (p.Ser246fs)","Chromosome":"22","Start":"50070562","Stop":"50070562","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":1683798,"rule_based_match":true,"evidence_text":"MLC1 c.736delA","llm_judgment":"PRESENT","evidence":"MLC1 c.736delA","abstract_start":null,"abstract_end":null}]}
{"pmid":"18682433","title":"Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1.","abstract":"OBJECTIVE: Autoimmune polyglandular syndrome type 1 (APS-1) is characterised by multiple autoimmune diseases. Detection of autoimmune regulator (AIRE) gene mutations facilitates timely and precise diagnosis.\nDESIGN: AIRE mutation detection was performed in a cohort of 11 patients. Two did not meet clinical APS-1 criteria and several started with atypical presentation.\nMETHODS: Sequencing and TaqMan genotyping were used to identify AIRE mutations. Complete AIRE deletion was confirmed and framed by real-time PCR, long-range amplification and analysis of the microsatellite markers.\nRESULTS: Seven different mutations were detected, three were novel: c.892G>A in exon 8, silent mutation c.462A>T in exon 3 most likely affecting splicing, and a complete deletion of a single AIRE allele ((?_68)_(1567-14_?)del). Novel (chronic otitis) and rare (systemic juvenile rheumatoid arthritis, autoimmune bronchiolitis, epilepsy) clinical presentations were observed.\nCONCLUSIONS: AIRE mutation detection was valuable in the diagnostics of APS-1 in patients with atypical presentation. Chronic otitis media possibly broadened the cluster of APS-1 manifestations.","variants":[{"Name":"NM_000383.4(AIRE):c.892G>A (p.Glu298Lys)","Chromosome":"21","Start":"44291107","Stop":"44291107","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":549135,"rule_based_match":true,"evidence_text":"c.892G>A","llm_judgment":"PRESENT","evidence":"c.892G>A","abstract_start":654,"abstract_end":662}]}
{"pmid":"31108500","title":"Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy.","abstract":"The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.","variants":[{"Name":"NM_001085049.3(MRAS):c.203C>T (p.Thr68Ile)","Chromosome":"3","Start":"138397333","Stop":"138397333","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":623613,"rule_based_match":true,"evidence_text":"c.203C > T (p.Thr68Ile)","llm_judgment":"PRESENT","evidence":"c.203C > T (p.Thr68Ile)","abstract_start":600,"abstract_end":623}]}
{"pmid":"28802369","title":"The first sporadic case of DFNA11 identified by next-generation sequencing.","abstract":"We report the first sporadic case of nonsyndromic autosomal dominant hearing loss (DFNA11). The patient was a 5-year-old boy with moderate bilateral hearing loss. Targeted next-generation sequencing analysis of patient DNA identified a known heterozygous DFNA11 mutation, c.689C > T, in MYO7A, encoding p.Ala230Val. The mutation was not detected in the parents of the patient and is considered to be de novo. This mutation is identical to the one reported previously in an Italian family. Accumulation of mutation data increases the feasibility of identifying autosomal dominant mutations in sporadic sensorineural hearing loss.","variants":[{"Name":"NM_000260.4(MYO7A):c.689C>T (p.Ala230Val)","Chromosome":"11","Start":"77156958","Stop":"77156958","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":178258,"rule_based_match":true,"evidence_text":"c.689C > T","llm_judgment":"PRESENT","evidence":"c.689C > T","abstract_start":272,"abstract_end":282}]}
{"pmid":"19766349","title":"Mutations in lipase H cause autosomal recessive hypotrichosis simplex with woolly hair.","abstract":"BACKGROUND: Mutations in lipase H (LIPH) are a rare cause of autosomal recessive hypotrichosis (HT) simplex.\nOBJECTIVE: In this study, we investigated the clinical and molecular basis of HT simplex with woolly hair in 3 nonrelated families.\nMETHODS: Three families of Jewish, Arab Muslim, and Italian origin that presented with HT with woolly hair were studied. The phenotype was confirmed by clinical, microscopic, and histologic examination. Polymorphic microsatellite genotyping and direct automated DNA sequencing of the LIPH gene were used to identify the mutations in our probands.\nRESULTS: All patients had woolly hair since birth. At presentation, scalp hair density was reduced or normal. Sequencing of the LIPH gene revealed two homozygous mutations: a large recurrent 90-base pair duplication mutation in exon 2 in the Jewish and Arab families, and a novel deletion/insertion mutation in exon 4 in the Italian family.\nLIMITATIONS: Only 3 families were studied.\nCONCLUSION: Mutations in LIPH result in variable degrees of HT. Woolly hair is an essential component of the clinical spectrum. A hot spot in the LIPH gene may be c.280_369dup in exon 2.","variants":[{"Name":"NM_139248.3(LIPH):c.280_369dup (p.Lys123_Thr124insGlyLeuLeuSerValGluAspMetAsnValValValValAspTrpAsnArgGlyAlaThrThrLeuIleTyrThrHisAlaSerSerLys)","Chromosome":"3","Start":"185534812","Stop":"185534813","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TCTTACTAGAGGCATGGGTATATATTAAAGTTGTAGCTCCTCGATTCCAATCAACAACAACTACGTTCATGTCTTCAACAGAGAGCAAACC","allel_id":18345,"rule_based_match":true,"evidence_text":"c.280_369dup","llm_judgment":"PRESENT","evidence":"c.280_369dup","abstract_start":1135,"abstract_end":1147}]}
{"pmid":"38579284","title":"Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival.","abstract":"ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.","variants":[{"Name":"NM_000377.3(WAS):c.559+5G>A","Chromosome":"X","Start":"48686139","Stop":"48686139","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360692,"rule_based_match":true,"evidence_text":"c.559+5G>A","llm_judgment":"PRESENT","evidence":"c.559+5G>A","abstract_start":839,"abstract_end":849}]}
{"pmid":"32842620","title":"Novel Mutations in","abstract":"We report the underlying genetic causes of prelingual hearing loss (HL) segregating in eight large consanguineous families, ascertained from the Punjab province of Pakistan. Exome sequencing followed by segregation analysis revealed seven potentially pathogenic variants, including four novel alleles c.257G>A, c.6083A>C, c.89A>G, and c.1249A>G of <i>CLPP</i>, <i>CDH23</i>, <i>COL4A5</i>, and <i>LARS2</i>, respectively. We also identified three previously reported HL-causing variants (c.4528C>T, c.35delG, and c.1219T>C) of <i>MYO15A</i>, <i>GJB2</i>, and <i>TMPRSS3</i> segregating in four families. All identified variants were either absent or had very low frequencies in the control databases. Our in silico analyses and 3-dimensional (3D) molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in <i>MYO15A</i>, <i>GJB2</i>, <i>TMPRSS3</i>, and <i>CDH23</i> were classified as \"pathogenic\" or \"likely pathogenic\", while the variants in <i>CLPP</i> and <i>LARS2</i> fall in the category of \"uncertain significance\" based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant pathogenicity guidelines. This paper highlights the genetic diversity of hearing disorders in the Pakistani population and reports the identification of four novel mutations in four HL families.","variants":[{"Name":"NM_015340.4(LARS2):c.1249A>G (p.Met417Val)","Chromosome":"3","Start":"45491526","Stop":"45491526","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2884459,"rule_based_match":true,"evidence_text":"c.1249A>G","llm_judgment":"PRESENT","evidence":"c.1249A>G","abstract_start":335,"abstract_end":344},{"Name":"NM_022124.6(CDH23):c.6083A>C (p.Asp2028Ala)","Chromosome":"10","Start":"71791165","Stop":"71791165","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":610567,"rule_based_match":true,"evidence_text":"c.6083A>C","llm_judgment":"PRESENT","evidence":"c.6083A>C","abstract_start":311,"abstract_end":320}]}
{"pmid":"31446535","title":"Germline pathogenic variants in BRCA1, BRCA2, PALB2 and RAD51C in breast cancer women from Argentina.","abstract":"PURPOSE: Each year, 17,000 new breast cancer cases are diagnosed in Argentina, and 5400 women die of breast cancer. The contribution of cancer-related mutations to the incidence of breast cancer in Argentina has not yet been explored.\nMETHODS: We sequenced the entire coding regions of BRCA1, BRCA2, PALB2 and RAD51C in 112 unselected Argentinian breast cancer patients.\nRESULTS: A pathogenic genetic variant was found in 12 of 112 (10.7%) patients; two in BRCA1 (1.8%), five in BRCA2 (4.5%), four in PALB2 (3.6%) and one in RAD51C (0.9%). Three of four (75%) PALB2 mutation carriers carried the same variant (c.1653T > A).\nCONCLUSIONS: A founder mutation in PALB2 accounts for up to 4% of breast cancer patients in Argentina. BRCA1, BRCA2, PALB2 and RAD51C should be included in the genetic testing panel of breast cancer patients in Argentina.","variants":[{"Name":"NM_024675.4(PALB2):c.1653T>A (p.Tyr551Ter)","Chromosome":"16","Start":"23634893","Stop":"23634893","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":16282,"rule_based_match":true,"evidence_text":"c.1653T > A","llm_judgment":"PRESENT","evidence":"c.1653T > A","abstract_start":610,"abstract_end":621}]}
{"pmid":"36585006","title":"Diagnosis of a patient with Spinocerebellar ataxia type 29 due to a novel variant of ITPR1 gene","abstract":"OBJECTIVE: To explore the clinical and genetic characteristics of a child with spinocerebellar ataxia type 29 (SCA29) due to novel variant of the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) gene.\nMETHODS: The child was subjected high-throughput sequencing, and candidate variant was verified by Sanger sequencing of his family members.\nRESULTS: The child was found to harbor a c.800C>T (p.T267M) variant of the ITPR1 gene, which was not found in his parents and their fetus. The variant has occurred in a hotspot of the ITPR1 gene variants and was unreported before in China. Based on his clinical and genetic characteristics, the child was diagnosed with SCA29.\nCONCLUSION: The novel heterozygous c.800C>T (p.T267M) of the ITPR1 gene probably underlay the SCA29 in this child.","variants":[{"Name":"NM_001378452.1(ITPR1):c.800C>T (p.Thr267Met)","Chromosome":"3","Start":"4645673","Stop":"4645673","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":205242,"rule_based_match":true,"evidence_text":"c.800C>T (p.T267M)","llm_judgment":"PRESENT","evidence":"c.800C>T (p.T267M)","abstract_start":386,"abstract_end":404}]}
{"pmid":"22964618","title":"Simultaneous detection of Gaucher's disease and renal involvement of non-Hodgkin's lymphoma: the first Asian case report and a review of literature.","abstract":"Gaucher's disease (GD) is a rare autosomal recessive (AR) disorder characterized by a deficiency of glucocerebrosidase (glucosylceramidase, acid β-glucosidase). This enzyme deficiency results in an accumulation of sphingolipids in the cells of GD patients, which may contribute to the dysregulation of the immune system, B-cell dysfunction and expression of specific cytokines such as interleukin (IL) -1, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF). Accumulated substrate may directly affect the patient's immunity and pose a higher risk for cancer, especially hematologic malignancies. However, recent large-scale studies suggest that the relative risks of GD and hematologic malignancies are not statistically significant and, therefore, their association with each other remains controversial. In this report, we present the first Asian GD case where the patient was simultaneously diagnosed with a non-Hodgkin's lymphoma. A renal biopsy confirmed that the patient had diffuse large B-cell lymphoma (DLBCL). A bone marrow study during lymphoma staging revealed Gaucher cells with abundant fibrillary, blue-gray cytoplasm and a wrinkled, tissue paper-like appearance. Subsequently, an acid β-glucosidase (GbA) gene mutation study demonstrating two heterozygote mutations, G202R (c.721G>A; p.G241R), a known pathogenic mutation, and a novel mutation R277C (c.946C>T; p.R316C) prompted the diagnosis of GD. Previous case reports have demonstrated concurrent GD and lymphoma in type 1 GD patients, with 40% of patients diagnosed with GD when a lymphoma is detected during disease evaluation. In Korea, GD cases with the G202R gene mutation have been reported in neuropathic patients with a very low frequency. To our knowledge, this case represents the first observation of the G202R mutation in a type 1 GD patient associated with lymphoma. Furthermore, this report is the first patient with DLBCL with kidney involvement along with GD.","variants":[{"Name":"NM_000157.4(GBA1):c.946C>T (p.Arg316Cys)","Chromosome":"1","Start":"155237394","Stop":"155237394","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":801584,"rule_based_match":true,"evidence_text":"c.946C>T; p.R316C","llm_judgment":"PRESENT","evidence":"c.946C>T; p.R316C","abstract_start":1366,"abstract_end":1383}]}
{"pmid":"25754315","title":"Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss.","abstract":"Novel, single-nucleotide mutations were identified in the mitochondrial methionyl amino-acyl tRNA synthetase gene (MARS2) via whole exome sequencing in two affected siblings with developmental delay, poor growth, and sensorineural hearing loss.We show that compound heterozygous mutations c.550C>T:p.Gln 184* and c.424C>T:p.Arg142Trp in MARS2 lead to decreased MARS2 protein levels in patient lymphoblasts. Analysis of respiratory complex enzyme activities in patient fibroblasts revealed decreased complex I and IV activities. Immunoblotting of patient fibroblast and lymphoblast samples revealed reduced protein levels of NDUFB8 and COXII, representing complex I and IV, respectively. Additionally, overexpression of wild-type MARS2 in patient fibroblasts increased NDUFB8 and COXII protein levels. These findings suggest that recessive single-nucleotide mutations in MARS2 are causative for a new mitochondrial translation deficiency disorder with a primary phenotype including developmental delay and hypotonia. Identification of additional patients with single-nucleotide mutations in MARS2 is necessary to determine if pectus carinatum is also a consistent feature of this syndrome.","variants":[{"Name":"NM_138395.4(MARS2):c.550C>T (p.Gln184Ter)","Chromosome":"2","Start":"197705955","Stop":"197705955","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":190188,"rule_based_match":true,"evidence_text":"c.550C>T:p.Gln 184*","llm_judgment":"PRESENT","evidence":"c.550C>T:p.Gln 184*","abstract_start":289,"abstract_end":308},{"Name":"NM_138395.4(MARS2):c.424C>T (p.Arg142Trp)","Chromosome":"2","Start":"197705829","Stop":"197705829","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":190189,"rule_based_match":true,"evidence_text":"c.424C>T:p.Arg142Trp","llm_judgment":"PRESENT","evidence":"c.424C>T:p.Arg142Trp","abstract_start":313,"abstract_end":333}]}
{"pmid":"16160008","title":"Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).","abstract":"Divalent metal transporter 1 (DMT1) mediates apical iron uptake in duodenal enterocytes and iron transfer from the transferrin receptor endosomal cycle into the cytosol in erythroid cells. Both mk mice and Belgrade rats, which carry an identical DMT1 mutation, exhibit severe microcytic anemia at birth and defective intestinal iron use and erythroid iron use. We report the hematologic phenotype of a child, compound heterozygote for 2 DMT1 mutations, who was affected by severe anemia since birth and showed hepatic iron overload. The novel mutations were a 3-bp deletion in intron 4 (c.310-3_5del CTT) resulting in a splicing abnormality and a C>T transition at nucleotide 1246(p. R416C). A striking reduction of DMT1 protein in peripheral blood mononuclear cells was demonstrated by Western blot analysis. The proband required blood transfusions until erythropoietin treatment allowed transfusion independence when hemoglobin levels between 75 and 95 g/L (7.5 and 9.5 g/dL) were achieved. Hematologic data of this patient at birth and in the first years of life strengthen the essential role of DMT1 in erythropoiesis. The early onset of iron overload indicates that, as in animal models, DMT1 is dispensable for liver iron uptake, whereas its deficiency in the gut is likely bypassed by the up-regulation of other pathways of iron use.","variants":[{"Name":"NM_000617.3(SLC11A2):c.310-5_310-3del","Chromosome":"12","Start":"51004910","Stop":"51004912","ReferenceAlleleVCF":"TAAG","AlternateAlleleVCF":"T","allel_id":24114,"rule_based_match":false,"evidence_text":"c.310-3_5del CTT","llm_judgment":"PRESENT","evidence":"c.310-3_5del CTT","abstract_start":587,"abstract_end":603},{"Name":"NM_000617.3(SLC11A2):c.1246C>T (p.Arg416Cys)","Chromosome":"12","Start":"50992291","Stop":"50992291","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24115,"rule_based_match":false,"evidence_text":"a C>T transition at nucleotide 1246(p. R416C)","llm_judgment":"PRESENT","evidence":"a C>T transition at nucleotide 1246(p. R416C)","abstract_start":645,"abstract_end":690}]}
{"pmid":"28283438","title":"Exome sequencing identified a novel SMAD2 mutation in a Chinese family with early onset aortic aneurysms.","abstract":"Aortic aneurysm remains a devastating disease due to its fatal complications, such as aortic dissection and rupture. A subset of aortic aneurysm is caused by genetic defect and to date more than a dozen of disease-causing genes have been discovered to account for the disease. In this study, by using whole exome sequencing, we identified a novel heterozygous missense mutation (c.833C>T, p.A278V) in the SMAD2 gene in a family with early onset aortic aneurysms. The mutation segregated in this family, was high conserved among species and predicted to be pathogenic by multiple in silico programs. To our knowledge, this is the second report that link the SMAD2 mutations to aortic aneurysm. We recommend that SMAD2 should be included in the expanding panel of genetic testing for patients with unexplained aortic aneurysms, which will facilitate genotype-phenotype correlation of SMAD2 mutations. Given the current wide application of molecular diagnosis in clinical setting, identification of the defected gene allows recognition of additional family members at risk for aortic diseases and gene-based management of the carriers.","variants":[{"Name":"NM_005901.6(SMAD2):c.833C>T (p.Ala278Val)","Chromosome":"18","Start":"47848639","Stop":"47848639","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1318139,"rule_based_match":true,"evidence_text":"c.833C>T, p.A278V","llm_judgment":"PRESENT","evidence":"c.833C>T, p.A278V","abstract_start":379,"abstract_end":396}]}
{"pmid":"24164096","title":"Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy.","abstract":"Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a recently delineated, autosomal recessive condition caused by rare mutations in the N-acylsphingosine amidohydrolase 1 (acid ceramidase) ASAH1 gene. It is characterized by motor neuron disease followed by progressive myoclonic seizures and eventual death due to respiratory insufficiency. Here we report an adolescent female who presented with atonic and absence seizures and myoclonic jerks and was later diagnosed as having myoclonic-absence seizures. An extensive genetic and metabolic work-up was unable to arrive at a molecular diagnosis. Whole exome sequencing (WES) identified two rare, deleterious mutations in the ASAH1 gene: c.850G>T;p.Gly284X and c.456A>C;p.Lys152Asn. These mutations were confirmed by Sanger sequencing in the patient and her parents. Functional studies in cultured fibroblasts showed that acid ceramidase was reduced in both overall amount and enzymatic activity. Ceramide level was doubled in the patient's fibroblasts as compared to control cells. The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness. These findings expand the phenotypic spectrum of SMA-PME caused by novel mutations in ASAH1 and highlight the clinical utility of WES for rare, intractable forms of epilepsy.","variants":[{"Name":"NM_177924.5(ASAH1):c.850G>T (p.Gly284Ter)","Chromosome":"8","Start":"18059639","Stop":"18059639","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":178804,"rule_based_match":true,"evidence_text":"c.850G>T;p.Gly284X","llm_judgment":"PRESENT","evidence":"c.850G>T;p.Gly284X","abstract_start":709,"abstract_end":727},{"Name":"NM_177924.5(ASAH1):c.456A>C (p.Lys152Asn)","Chromosome":"8","Start":"18064458","Stop":"18064458","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":178805,"rule_based_match":true,"evidence_text":"c.456A>C;p.Lys152Asn","llm_judgment":"PRESENT","evidence":"c.456A>C;p.Lys152Asn","abstract_start":732,"abstract_end":752}]}
{"pmid":"29767723","title":"ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins.","abstract":"Multiple mitochondrial dysfunction syndromes (MMDS) comprise a group of severe autosomal recessive diseases characterized by impaired respiration and lipoic acid metabolism, resulting in infantile-onset mitochondrial encephalopathy, non-ketotic hyperglycinemia, myopathy, lactic acidosis and early death. Four different MMDS have been analyzed in detail according to the genes involved in the disease, MMDS1 (NFU1), MMDS2 (BOLA3), MMDS3 (IBA57) and MMDS4 (ISCA2). MMDS5 has recently been described in a clinical case report of patients carrying a mutation in ISCA1, but with no further functional analysis. ISCA1 encodes a mitochondrial protein essential for the assembly of [4Fe-4S] clusters in key metabolic and respiratory enzymes. Here, we describe a patient with a severe early onset leukodystrophy, multiple defects of respiratory complexes and a severe impairment of lipoic acid synthesis. A homozygous missense mutation in ISCA1 (c.29T>G; p.V10G) identified by targeted MitoExome sequencing resulted in dramatic reduction of ISCA1 protein level. The mutation located in the uncleaved presequence severely affected both mitochondrial import and stability of ISCA1. Down-regulation of ISCA1 in HeLa cells by RNAi impaired the biogenesis of mitochondrial [4Fe-4S] proteins, yet could be complemented by expression of wild-type ISCA1. In contrast, the ISCA1 p.V10G mutant protein only partially complemented the defects, closely resembling the biochemical phenotypes observed for ISCA1 patient fibroblasts. Collectively, our comprehensive clinical and biochemical investigations show that the ISCA1 p.V10G mutation functionally impaired mitochondrial [4Fe-4S] protein assembly and hence was causative for the observed clinical defects.","variants":[{"Name":"NM_030940.4(ISCA1):c.29T>G (p.Val10Gly)","Chromosome":"9","Start":"86282430","Stop":"86282430","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":683224,"rule_based_match":true,"evidence_text":"c.29T>G; p.V10G","llm_judgment":"PRESENT","evidence":"c.29T>G; p.V10G","abstract_start":938,"abstract_end":953}]}
{"pmid":"31930989","title":"Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis.","abstract":"BACKGROUND & AIMS: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca<sup>2+</sup>-selective ion channel, in an international cohort of patients and in mice.\nMETHODS: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca<sup>2+</sup> imaging assays. CP was induced by repeated injections of cerulein in TRPV6<sup>mut/mut</sup> mice.\nRESULTS: We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10<sup>-8</sup>). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10<sup>-8</sup>). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10<sup>-9</sup> for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10<sup>-5</sup>). TRPV6<sup>mut/mut</sup> mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis.\nCONCLUSIONS: We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca<sup>2+</sup> balance in pancreatic cells. TRPV6 regulates Ca<sup>2+</sup> homeostasis and pancreatic inflammation.","variants":[{"Name":"NM_018646.6(TRPV6):c.668T>C (p.Ile223Thr)","Chromosome":"7","Start":"142876777","Stop":"142876777","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":581703,"rule_based_match":false,"evidence_text":"c.668T>C (p.Ile223Thr)","llm_judgment":"PRESENT","evidence":"I223T","abstract_start":1738,"abstract_end":1743}]}
{"pmid":"11286507","title":"G76E substitution in type I collagen is the first nonlethal glutamic acid substitution in the alpha1(I) chain and alters folding of the N-terminal end of the helix.","abstract":"The majority of osteogenesis imperfecta (OI) is caused by substitutions for glycine residues in the two alpha chains of type I collagen. Since only 4% of possible nucleotide changes in type I collagen glycine codons would result in a glutamic acid substitution, these are predicted to be infrequent. Only one glutamic acid substitution in type I collagen has been fully reported. We describe here the clinical, biochemical, and molecular characterization of a girl with severe type III OI caused by a G76E substitution in COL1A1. This is the first delineation of a glutamic acid substitution in the alpha1(I) chain causing nonlethal osteogenesis imperfecta. The proband's fibroblast type I collagen chains and cyanogen bromide peptides were electrophoretically normal, while osteoblast collagen was slightly overmodified. This suggested a mutation near the N-terminal end of the collagen helix. A mismatch was detected by RNA:DNA hybrid analysis in cDNA coding for 106 amino acids at the N-terminal end of the helical region. Subclones of both alleles were sequenced and revealed a G --> A (c.761G > A) mutation causing an alpha1(I) G76E substitution in one allele. The presence of the mutation in the proband's leukocyte gDNA, and its absence in parental gDNA, was confirmed by Tsp509I digestion. The glutamic acid substitution alters the folding of the mutant collagen helices. Pericellular processing of type I collagen by the proband's fibroblasts yielded an earlier appearance of the pC-alpha1(I) form and of mature alpha chains as compared to control cell processing. Also, the presence of the glutamic acid substitution apparently exposes the adjacent Arg75 residue in the alpha1 chain. Trypsin digestion of proband fibroblast collagen resulted in shortened alpha1 chains, as confirmed by CNBr analysis. In addition, the Tm for mutant helices from fibroblasts and osteoblasts was decreased 2-4 degrees C versus controls, demonstrating a decrease in helix stability. These findings increase our understanding of the disruptive effect of glutamic acid substitutions in collagen.","variants":[{"Name":"NM_000088.4(COL1A1):c.761G>A (p.Gly254Glu)","Chromosome":"17","Start":"50197053","Stop":"50197053","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32388,"rule_based_match":true,"evidence_text":"c.761G > A","llm_judgment":"PRESENT","evidence":"c.761G > A","abstract_start":1091,"abstract_end":1101}]}
{"pmid":"26316623","title":"Paris-Trousseau thrombocytopenia is phenocopied by the autosomal recessive inheritance of a DNA-binding domain mutation in FLI1.","abstract":"Hemizygous deletion of a variable region on chromosome 11q containing FLI1 causes an inherited platelet-related bleeding disorder in Paris-Trousseau thrombocytopenia and Jacobsen syndrome. These multisystem disorders are also characterized by heart anomalies, changes in facial structure, and intellectual disability. We have identified a consanguineous family with autosomal recessive inheritance of a bleeding disorder that mimics Paris-Trousseau thrombocytopenia but has no other features of the 11q23 deletion syndrome. Affected individuals in this family have moderate thrombocytopenia; absent collagen-induced platelet aggregation; and large, fused α-granules in 1% to 5% of circulating platelets. This phenotype was caused by a FLI1 homozygous c.970C>T-point mutation that predicts an arginine-to-tryptophan substitution in the conserved ETS DNA-binding domain of FLI1. This mutation caused a transcription defect at the promoter of known FLI1 target genes GP6, GP9, and ITGA2B, as measured by luciferase assay in HEK293 cells, and decreased the expression of these target proteins in affected members of the family as measured by Western blotting of platelet lysates. This kindred suggests abnormalities in FLI1 as causative of Paris-Trousseau thrombocytopenia and confirms the important role of FLI1 in normal platelet development.","variants":[{"Name":"NM_002017.5(FLI1):c.970C>T (p.Arg324Trp)","Chromosome":"11","Start":"128810599","Stop":"128810599","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":213674,"rule_based_match":true,"evidence_text":"FLI1 homozygous c.970C>T-point mutation","llm_judgment":"PRESENT","evidence":"FLI1 homozygous c.970C>T-point mutation","abstract_start":735,"abstract_end":774}]}
{"pmid":"20829743","title":"Lack of autofluorescence in fundus albipunctatus associated with mutations in RDH5.","abstract":"PURPOSE: The purpose of this study was to characterize the phenotype of fundus albipunctatus associated with RDH5 mutations.\nMETHODS: Four unrelated patients (patients 1-4) aged 35, 32, 19, and 8 years were examined with full-field electroretinography, multifocal electroretinography, optical coherence tomography, and fundus autofluorescence photography. Molecular genetic investigations included sequencing of RDH5 and RLBP1.\nRESULTS: Patients 1 to 3 harbored homozygous mutations (c.881G>C, c.625C>T, and c.382G>A, respectively) and patient 4 harbored the compound heterozygous mutations (c.95delT and c.712G>T) in RDH5. A large variability in retinal dysfunction caused by RDH5 mutations was found but not fully explained by a simple prediction of reduced enzymatic function. All patients showed lack of autofluorescence of the fundus, indicating a reduced supply of 11-cis retinal to the photoreceptors. The lesions corresponding to the white dots did not autofluoresce and were seen on optical coherence tomography as discrete hyperreflective elements in the outer retina extending from the external limiting membrane to Bruch membrane.\nCONCLUSION: Mutations in RDH5 associated with fundus albipunctatus seem to prevent normal lipofuscin accumulation. A relatively good functional status of 2 of 3 adult patients indicates that interference with 11-cis retinol dehydrogenase function may be a promising strategy for therapeutic intervention in retinal disorders featuring excessive lipofuscin accumulation.","variants":[{"Name":"NM_002905.5(RDH5):c.625C>T (p.Arg209Ter)","Chromosome":"12","Start":"55723941","Stop":"55723941","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":856755,"rule_based_match":true,"evidence_text":"c.625C>T","llm_judgment":"PRESENT","evidence":"c.625C>T","abstract_start":494,"abstract_end":502}]}
{"pmid":"32356190","title":"Myelin bodies in LMX1B-associated nephropathy: potential for misdiagnosis.","abstract":"BACKGROUND: Myelin figures, or zebra bodies, seen on electron microscopy were historically considered pathognomonic of Fabry disease, a rare lysosomal storage disorder caused by alpha-galactosidase A deficiency and associated with X-linked recessive mode of inheritance. More recently, iatrogenic phospholipidosis has emerged as an important alternate cause of myelin figures in the kidney.\nMETHODS: We report two families with autosomal dominant nephropathy presenting with proteinuria and microscopic hematuria, and the kidney biopsies were notable for the presence of myelin figures and zebra bodies.\nRESULTS: Laboratory and genetic work-up for Fabry disease was negative. Genetic testing in both families revealed the same heterozygous missense mutation in LMX1B (C.737G>A, p.Arg246Gln). LMX1B mutations are known to cause nail-patella syndrome, featuring dysplastic nails and patella with or without nephropathy, as well as isolated LMX1B-associated nephropathy in the absence of extrarenal manifestations.\nCONCLUSIONS: LMX1B mutation-associated nephropathy should be considered in hereditary cases of proteinuria and/or hematuria, even in the absence of unique glomerular basement membrane changes indicative of nail-patella syndrome. In addition, LMX1B mutation should be included in the differential diagnosis of myelin figures and zebra bodies on kidney biopsy, so as to avoid a misdiagnosis.","variants":[{"Name":"NM_001174147.2(LMX1B):c.737G>A (p.Arg246Gln)","Chromosome":"9","Start":"126693319","Stop":"126693319","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":490222,"rule_based_match":true,"evidence_text":"C.737G>A, p.Arg246Gln","llm_judgment":"PRESENT","evidence":"C.737G>A, p.Arg246Gln","abstract_start":768,"abstract_end":789}]}
{"pmid":"30200136","title":"Whole exome sequencing detects CHST3 mutation in patient with acute promyelocytic leukemia: A case report.","abstract":"RATIONALE: Acute promyelocytic leukemia (APL) is a kind of acute myeloid leukemia, which was characterized by the presence of PML/RARα fusion gene. Mutations in CHST3 have been previously reported to be associated with a rare phenotype of skeleton dysplasia, known as Spondyloepiphyseal dysplasia. Here we reported 1 patient with APL with CHST3 mutations.\nPATIENT CONCERNS: An 18-year-old girl was referred to the Hematology Department because of a lasting history (10 days) of repeated fever and bleeding on skin. The girl was of short stature for age and with short fingers. Double nail beds were short with anti-nail deformity.\nDIAGNOSES: She was diagnosed with APL according to the 2016 WHO classification after a MICM analysis (bone marrow morphology [M], immunophenotype [I], cytogenetics [C], and molecular biology [M]). Whole exome sequencing revealed complex heterozygous mutations on CHST3. Further confirmation showed that 1 mutation (c.155T>G; p.Leu52Arg) was from her father and the other mutation (c.1414G>A; p.Glu472Lys) was from her mother.\nINTERVENTIONS: The patient received Idarubicin (8 mg/m) injection intravenous drip for 3 days based on all-trans retinoic acid and arsenic trioxide induction therapy.\nOUTCOMES: The patient died from disseminated intravascular coagulation and multiple organ hemorrhage at 9 days after diagnosis.\nLESSONS: This case describes a patient with APL with complex heterozygous mutations on CHST3. Carbohydrate sulfotransferases were found to play an important role in metastatic spread of tumor cells. Whether the mutation status of CHST3 gene has relationship with APL pathogenesis and prognosis is unknown.","variants":[{"Name":"NM_004273.5(CHST3):c.1414G>A (p.Glu472Lys)","Chromosome":"10","Start":"72008445","Stop":"72008445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1412710,"rule_based_match":true,"evidence_text":"c.1414G>A (p.Glu472Lys)","llm_judgment":"PRESENT","evidence":"p.Glu472Lys","abstract_start":1023,"abstract_end":1034}]}
{"pmid":"23479141","title":"Muscle phenotypic variability in limb girdle muscular dystrophy 2 G.","abstract":"Limb girdle muscular dystrophy type 2 G (LGMD2G) is caused by mutations in the telethonin gene. Only few families were described presenting this disease, and they are mainly Brazilians. Here, we identified one additional case carrying the same common c.157C > T mutation in the telethonin gene but with an atypical histopathological muscle pattern. In a female patient with a long duration of symptoms (46 years), muscle biopsy showed, in addition to telethonin deficiency, the presence of nemaline rods, type 1 fiber predominance, nuclear internalization, lobulated fibers, and mitochondrial paracrystalline inclusions. Her first clinical signs were identified at 8 years old, which include tiptoe walking, left lower limb deformity, and frequent falls. Ambulation loss occurred at 41 years old, and now, at 54 years old, she presented pelvic girdle atrophy, winging scapula, foot deformity with incapacity to perform ankle dorsiflexion, and absent tendon reflexes. The presence of nemaline bodies could be a secondary phenomenon, possibly associated with focal Z-line abnormalities of a long-standing disease. However, these new histopathological findings, characteristic of congenital myopathies, expand muscle phenotypic variability of telethoninopathy.","variants":[{"Name":"NM_003673.4(TCAP):c.157C>T (p.Gln53Ter)","Chromosome":"17","Start":"39665762","Stop":"39665762","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20564,"rule_based_match":true,"evidence_text":"c.157C > T","llm_judgment":"PRESENT","evidence":"c.157C > T","abstract_start":251,"abstract_end":261}]}
{"pmid":"28384041","title":"Candidate Gene Analysis Identifies Mutations in CYP1B1 and LTBP2 in Indian Families with Primary Congenital Glaucoma.","abstract":"BACKGROUND: Primary congenital glaucoma (PCG) is a severe ocular disorder that presents early in life. Cytochrome P4501B1 (CYP1B1) and latent transforming growth factor-beta-binding protein 2 (LTBP2) are the most commonly mutated genes in PCG.\nAIM: To investigate the causative genetic mutations in eight Indian families with PCG.\nMATERIALS AND METHODS: Whole-exome sequencing was applied to analyze the genomic DNA samples from PCG probands. Sanger sequencing was utilized to confirm the identified mutations.\nRESULTS: We identified four homozygous missense mutations (c.1405C>T, p.R469W; c.1397G>T, p.G466V; c.1198C>T, p.P400S; and c.1103G>A, p.R368H) in CYP1B1 and one nonsense mutation (c.2421G>A, p.W807X) in LTBP2 in eight Indian families. Among the five mutations identified, G466V in CYP1B1 and W807X in LTBP2 represent novel mutations.\nCONCLUSIONS: Our study expands the mutational spectrum of PCG in the Indian population.","variants":[{"Name":"NM_000104.4(CYP1B1):c.1103G>A (p.Arg368His)","Chromosome":"2","Start":"38071251","Stop":"38071251","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22778,"rule_based_match":true,"evidence_text":"c.1103G>A, p.R368H","llm_judgment":"PRESENT","evidence":"c.1103G>A, p.R368H","abstract_start":634,"abstract_end":652}]}
{"pmid":"37108593","title":"Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series.","abstract":"Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5-15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype-phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the <i>CHD7</i> gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in <i>IL17RD</i> (c.960G>A, p.Met320Ile), <i>FGF17</i> (c.208G>A, p.Gly70Arg), and <i>DUSP6</i> (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the <i>PROK2</i> (c.163del, p.Ile55*), <i>CHD7</i> (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), <i>FLRT3</i> (c.1106C>T, p.Ala369Val), and <i>CCDC103</i> (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, <i>FGF17</i> (p.Gly70Arg), <i>DUSP6</i> (p.Leu145Arg), and <i>CHD7</i> p.(Thr917Met). Except for <i>DUSP6</i>, where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the <i>CHD7</i> gene. The molecular modeling results suggest that the VUS of the <i>DUSP6</i> (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the <i>IL17RD</i> (c.960G>A, p.Met320Ile) and <i>FGF17</i> (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.","variants":[{"Name":"NM_017780.4(CHD7):c.2750C>T (p.Thr917Met)","Chromosome":"8","Start":"60821842","Stop":"60821842","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":969215,"rule_based_match":true,"evidence_text":"c.2750C>T, p.Thr917Met","llm_judgment":"PRESENT","evidence":"c.2750C>T, p.Thr917Met","abstract_start":1369,"abstract_end":1391}]}
{"pmid":"27824480","title":"The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.","abstract":"Familial hypercholesterolemia (FH) is most frequently caused by LDLR or APOB mutations. Therefore, the aim of our study was to examine the genetic background of Slovak patients suspected of FH. Patients with clinical suspicion of FH (235 unrelated probands and 124 family relatives) were recruited throughout Slovakia during the years 2011-2015. The order of DNA analyses in probands was as follows: 1. APOB mutation p.Arg3527Gln by real-time PCR method, 2. direct sequencing of the LDLR gene 3. MLPA analysis of the LDLR gene. We have identified 14 probands and 2 relatives with an APOB mutation p.Arg3527Gln, and 89 probands and 75 relatives with 54 different LDLR mutations. Nine of LDLR mutations were novel (i.e. p.Asp90Glu, c.314-2A>G, p.Asp136Tyr, p.Ser177Pro, p.Lys225_Glu228delinsCysLys, p.Gly478Glu, p.Gly675Trpfs*42, p.Leu680Pro, p.Thr832Argfs*3). This is the first study on molecular genetics of FH in Slovakia encompassing the analysis of whole LDLR gene. Genetic etiology of FH was confirmed in 103 probands (43.8 %). Out of them, 86.4 % of probands carried the LDLR gene mutation and remaining 13.6 % probands carried the p.Arg3527Gln APOB mutation.","variants":[{"Name":"NM_000527.5(LDLR):c.314-2A>G","Chromosome":"19","Start":"11105218","Stop":"11105218","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2905345,"rule_based_match":true,"evidence_text":"c.314-2A>G","llm_judgment":"PRESENT","evidence":"c.314-2A>G","abstract_start":730,"abstract_end":740},{"Name":"NM_000527.5(LDLR):c.2039T>C (p.Leu680Pro)","Chromosome":"19","Start":"11120421","Stop":"11120421","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":434325,"rule_based_match":false,"evidence_text":"p.Leu680Pro","llm_judgment":"PRESENT","evidence":"p.Leu680Pro","abstract_start":828,"abstract_end":839},{"Name":"NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln)","Chromosome":"2","Start":"21006288","Stop":"21006288","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32929,"rule_based_match":false,"evidence_text":"p.Arg3527Gln","llm_judgment":"PRESENT","evidence":"p.Arg3527Gln","abstract_start":417,"abstract_end":429},{"Name":"NM_000527.5(LDLR):c.673_682delinsTGCA (p.Lys225_Glu228delinsCysLys)","Chromosome":"19","Start":"11105579","Stop":"11105588","ReferenceAlleleVCF":"AAATCTGACG","AlternateAlleleVCF":"TGCA","allel_id":2949921,"rule_based_match":false,"evidence_text":"p.Lys225_Glu228delinsCysLys","llm_judgment":"PRESENT","evidence":"p.Lys225_Glu228delinsCysLys","abstract_start":768,"abstract_end":795}]}
{"pmid":"21856450","title":"Biochemical analysis of the G517V POLG variant reveals wild-type like activity.","abstract":"The c.1550g→t mutation in the POLG gene causing the G517V substitution has been reported by many groups to be associated with a variety of mitochondrial diseases, including autosomal dominant and recessive forms of ataxia neuropathy, myopathy and microcephaly, progressive external ophthalmoplegia, diabetes, strokes, hypotonia, and epilepsy. However, the variable disease presentation and age of onset raises suspicion of its pathogenicity. Because of the varied reported associated symptoms and request from physicians to address the consequence of this mutation, we have carried out the biochemical analysis of the purified recombinant human DNA polymerase γ protein harboring the G517V substitution. These analyses revealed that the G517V mutant enzyme retained 80-90% of wild-type DNA polymerase activity, in addition to its functional interaction with the p55 accessory subunit. DNA binding by the mutant was also only slightly lower than the wild-type enzyme. Our data suggest that the G517V mutation by itself in pol γ most likely does not have a role in mitochondrial disorders.","variants":[{"Name":"NM_002693.3(POLG):c.1550G>T (p.Gly517Val)","Chromosome":"15","Start":"89326947","Stop":"89326947","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":76573,"rule_based_match":false,"evidence_text":"c.1550g→t","llm_judgment":"PRESENT","evidence":"c.1550g→t","abstract_start":4,"abstract_end":13}]}
{"pmid":"23936043","title":"Exome sequencing and linkage analysis identified tenascin-C (TNC) as a novel causative gene in nonsyndromic hearing loss.","abstract":"In this study, a five-generation Chinese family (family F013) with progressive autosomal dominant hearing loss was mapped to a critical region spanning 28.54 Mb on chromosome 9q31.3-q34.3 by linkage analysis, which was a novel DFNA locus, assigned as DFNA56. In this interval, there were 398 annotated genes. Then, whole exome sequencing was applied in three patients and one normal individual from this family. Six single nucleotide variants and two indels were found co-segregated with the phenotypes. Then using mass spectrum (Sequenom, Inc.) to rank the eight sites, we found only the TNC gene be co-segregated with hearing loss in 53 subjects of F013. And this missense mutation (c.5317G>A, p.V1773M ) of TNC located exactly in the critical linked interval. Further screening to the coding region of this gene in 587 subjects with nonsyndromic hearing loss (NSHL) found a second missense mutation, c.5368A>T (p. T1796S), co-segregating with phenotype in the other family. These two mutations located in the conserved region of TNC and were absent in the 387 normal hearing individuals of matched geographical ancestry. Functional effects of the two mutations were predicted using SIFT and both mutations were deleterious. All these results supported that TNC may be the causal gene for the hearing loss inherited in these families. TNC encodes tenascin-C, a member of the extracellular matrix (ECM), is present in the basilar membrane (BM), and the osseous spiral lamina of the cochlea. It plays an important role in cochlear development. The up-regulated expression of TNC gene in tissue repair and neural regeneration was seen in human and zebrafish, and in sensory receptor recovery in the vestibular organ after ototoxic injury in birds. Then the absence of normal tenascin-C was supposed to cause irreversible injuries in cochlea and caused hearing loss.","variants":[{"Name":"NM_002160.4(TNC):c.5317G>A (p.Val1773Met)","Chromosome":"9","Start":"115041016","Stop":"115041016","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":102917,"rule_based_match":true,"evidence_text":"c.5317G>A, p.V1773M","llm_judgment":"PRESENT","evidence":"c.5317G>A, p.V1773M","abstract_start":685,"abstract_end":704}]}
{"pmid":"17317524","title":"Late neurological presentations of Wilson disease patients in French population and identification of 8 novel mutations in the ATP7B gene.","abstract":"Wilson disease (WD) is an autosomal recessive disorder of copper biliary excretion caused by an impaired function of ATP7B, a metal-transporting P-type ATPase encoded by WD gene. It results in copper accumulation, mostly in liver and brain tissues. Mutation analysis was carried out on 11 WD French unrelated patients presenting a predominant neurological form of this illness. SSCP and dHPLC analysis followed by sequencing of the 21 exons and their flanking introns were performed. Thirteen different mutations in a total of 17, and, among them, 10 novel variants were evidenced. Two deletions (c.654_655delCC and c.1745_1746delTA), 4 missense mutations (p.F763Y, p.G843R, p.D918A and p.L979Q), 1 nonsense mutation (p.Q1200X), 1 splice site mutation (c.1947-1G>C) and 2 intronic silent substitutions (c.2448-25G>T and c.3412+13T>A) were detected. These data extend the mutational spectrum of the disease, already known to be a very heterogeneous genetic disorder. As compared to hepatic manifestations, the phenotypes associated to these mutations confirm that neurological presentations associated with other mutations than p.H1069Q are also often late in their onset. Most of these neurological forms probably correspond to an attenuated impairment of copper metabolism, as compared to hepatic forms of the disease, mostly diagnosed earlier.","variants":[{"Name":"NM_000053.4(ATP7B):c.1947-1G>C","Chromosome":"13","Start":"51960323","Stop":"51960323","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1492076,"rule_based_match":true,"evidence_text":"c.1947-1G>C","llm_judgment":"PRESENT","evidence":"c.1947-1G>C","abstract_start":753,"abstract_end":764},{"Name":"NM_000053.4(ATP7B):c.1745_1746del (p.Ile582fs)","Chromosome":"13","Start":"51964995","Stop":"51964996","ReferenceAlleleVCF":"CTA","AlternateAlleleVCF":"C","allel_id":186905,"rule_based_match":true,"evidence_text":"c.1745_1746delTA","llm_judgment":"PRESENT","evidence":"c.1745_1746delTA","abstract_start":616,"abstract_end":632}]}
{"pmid":"33999344","title":"Defining the molecular pathology and consequent phenotypes in Egyptian HB patients.","abstract":"BACKGROUND: Hemophilia B (HB) (also known as Christmas disease) is a rare X-linked recessive disorder characterized by spontaneous or prolonged hemorrhages caused by mutations in Factor 9 (F9) gene leading to deficient or defective coagulation F9. Our study aimed at identifying the causative mutations within a sample of HB Egyptian patients. The present study comprised clinical data of eleven HB patients descending from six unrelated families and a seventh family including a carrier mother with a history of deceased HB sibling. Sequencing of F9 gene was performed.\nRESULTS: The study revealed four mutations; two missense NM_000133.3:c.676C>G, (P.Arg226Gly) and NM_000133.3:c.1305T>G, (p.Cys435Trp), and two nonsense mutations NM_000133.3:c.880C>T, (p.Arg294*) and NM_000133.3:c.1150C>T, (p.Arg384*), identified mutations spanned exons 6 and 8 of which a total of three mutations are located in hotspot exon 8 of F9 gene.\nCONCLUSIONS: Reviewing the literature, this is the first molecular analysis of F9 gene in HB Egyptian patients. Consistent genotype/phenotypic severity correlation could be concluded, helping proper genetic counseling and prenatal decision taking.","variants":[{"Name":"NM_000133.4(F9):c.880C>T (p.Arg294Ter)","Chromosome":"X","Start":"139561565","Stop":"139561565","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25626,"rule_based_match":true,"evidence_text":"NM_000133.3:c.880C>T, (p.Arg294*)","llm_judgment":"PRESENT","evidence":"NM_000133.3:c.880C>T, (p.Arg294*)","abstract_start":733,"abstract_end":766}]}
{"pmid":"21534946","title":"Novel TMPRSS3 variants in Pakistani families with autosomal recessive non-syndromic hearing impairment.","abstract":"Mutations in the TMPRSS3 gene are known to cause autosomal recessive non-syndromic hearing impairment (ARNSHI). After undergoing a genome scan, 10 consanguineous Pakistani families with ARNSHI were found to have significant or suggestive evidence of linkage to the TMPRSS3 region. In order to elucidate if the TMPRSS3 gene is responsible for ARNSHI in these families, the gene was sequenced using DNA samples from these families. Six TMPRSS3 variants were found to cosegregate in 10 families. None of these variants were detected in 500 control chromosomes. Four novel variants, three of which are missense [c.310G>A (p.Glu104Lys), c.767C>T (p.Ala256Val) and c.1273T>C (p.Cys425Arg)] and one nonsense [c.310G>T (p.Glu104Stop)], were identified. The pathogenicity of novel missense variants was investigated through bioinformatics analyses. Additionally, the previously reported deletion c.208delC (p.His70ThrfsX19) was identified in one family and the known mutation c.1219T>C (p.Cys407Arg) was found in five families, which makes c.1219T>C (p.Cys407Arg) as the most common TMPRSS3 mutation within the Pakistani population. Identification of these novel variants lends support to the importance of elements within the low-density lipoprotein receptor A (LDLRA) and serine protease domains in structural stability, ligand binding and proteolytic activity for proper TMPRSS3 function within the inner ear.","variants":[{"Name":"NM_001256317.3(TMPRSS3):c.208del (p.His70fs)","Chromosome":"21","Start":"42389043","Stop":"42389043","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":176368,"rule_based_match":true,"evidence_text":"c.208delC (p.His70ThrfsX19)","llm_judgment":"PRESENT","evidence":"c.208delC (p.His70ThrfsX19)","abstract_start":887,"abstract_end":914},{"Name":"NM_001256317.3(TMPRSS3):c.310G>A (p.Glu104Lys)","Chromosome":"21","Start":"42388941","Stop":"42388941","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":497791,"rule_based_match":true,"evidence_text":"c.310G>A (p.Glu104Lys)","llm_judgment":"PRESENT","evidence":"c.310G>A (p.Glu104Lys)","abstract_start":608,"abstract_end":630}]}
{"pmid":"33438142","title":"Novel compound heterozygous variants in the GFPT1 gene leading to rare limb-girdle congenital myasthenic syndrome with rimmed vacuoles.","abstract":"BACKGROUND:  Congenital myasthenic syndrome (CMS) is a heterogeneous group of rare disorders with impaired neuromuscular transmission caused by genetic defects, which is characterized by fatigable muscle weakness.\nCASE PRESENTATION:  Herein, we report a case of limb-girdle CMS (LG-CMS) in a 15-year-old Chinese girl with limb weakness and mild ptosis. The patient presented with well-defined clinical manifestations, muscle imaging, and electrophysiological features associated with CMS. On muscle biopsy, in addition to tubular aggregates identified, an extremely unusual pathological change of rimmed vacuoles in muscle fibers was observed. Whole-exome sequencing disclosed two novel heterozygous variants (c.14 T>A and c.581 T>C) in the human glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene, leading to the substitutions of phenylalanine to tyrosine (p.F5Y) and serine (p.F194S), respectively. Both variants were predicted to be likely pathogenic by SIFT, Polyphen-2, and Mutation Taster. Treatments with pyridostigmine bromide and albuterol produced a dramatic improvement.\nCONCLUSIONS:  Collectively, molecular genetic analysis and muscle biopsy play crucial roles in the diagnosis of GFPT1-related LG-CMS with rimmed vacuoles (a rare phenotype of CMS) and have important implications for treatment decision.","variants":[{"Name":"NM_001244710.2(GFPT1):c.14T>A (p.Phe5Tyr)","Chromosome":"2","Start":"69374107","Stop":"69374107","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":3410621,"rule_based_match":true,"evidence_text":"c.14 T>A","llm_judgment":"PRESENT","evidence":"c.14 T>A","abstract_start":710,"abstract_end":718}]}
{"pmid":"24518553","title":"Three novel mutations in Iranian patients with Tay-Sachs disease.","abstract":"BACKGROUND: Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population.\nMETHODS: In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion.\nRESULTS: Molecular genetics analysis of DNA from 23 patients of TSD revealed mutations that has been previously reported, including four-base duplications c.1274_1277dupTATC in exon 11 and IVS2+1G>A, deletion TTAGGCAAGGGC in exon 10 as well as a few novel mutations, including C331G, which altered Gln>Glu in HEXB, A>G, T>C, and p.R510X in exon 14, which predicted a termination codon or nonsense mutation.\nCONCLUSION: In conclusion, with the discovery of these novel mutations, the genotypic spectrum of Iranian patients with TSD disease has been extended and could facilitate definition of disease-related mutations.","variants":[{"Name":"NM_000520.6(HEXA):c.1274_1277dup (p.Tyr427fs)","Chromosome":"15","Start":"72346579","Stop":"72346580","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGATA","allel_id":18928,"rule_based_match":true,"evidence_text":"c.1274_1277dupTATC","llm_judgment":"PRESENT","evidence":"c.1274_1277dupTATC","abstract_start":613,"abstract_end":631}]}
{"pmid":"30478137","title":"Biallelic disruption of","abstract":"BACKGROUND: During mouse embryonic development the protein kinase domain containing, cytoplasmic (<i>Pkdcc</i>) gene, also known as <i>Vlk,</i> is expressed in several tissues including the ventral midbrain, with particularly strong expression in branchial arches and limb buds. Homozygous <i>Pkdcc</i> knockout mice have dysmorphic features and shortened long bones as the most obvious morphological abnormalities. The human <i>PKDCC</i> gene has currently not been associated with any disorders.\nOBJECTIVE: To use clinical diagnostic exome sequencing (DES) for providing genetic diagnoses to two apparently unrelated patients with similar skeletal abnormalities comprising rhizomelic shortening of limbs and dysmorphic features.\nMETHODS: Patient-parents trio DES was carried out and the identified candidate variants were confirmed by Sanger sequencing.\nRESULTS: Each patient had a homozygous gene disrupting variant in <i>PKDCC</i> considered to explain the skeletal phenotypes shared by both. The first patient was homozygous for the nonsense variant p.(Tyr217*) (NM_1 38 370 c.651C>A) expected to result in nonsense-mediated decay of the mutant transcripts, whereas the second patient was homozygous for the splice donor variant c.639+1G>T predicted to abolish the donor splice site by three in silico splice prediction algorithms.\nCONCLUSIONS: Biallelic gene disrupting variants in <i>PKDCC</i> in humans, just like in mice, cause dysmorphic features and rhizomelic shortening of limbs.","variants":[{"Name":"NM_138370.3(PKDCC):c.639+1G>T","Chromosome":"2","Start":"42048839","Stop":"42048839","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":511422,"rule_based_match":true,"evidence_text":"c.639+1G>T","llm_judgment":"PRESENT","evidence":"c.639+1G>T","abstract_start":1234,"abstract_end":1244},{"Name":"NM_138370.3(PKDCC):c.651C>A (p.Tyr217Ter)","Chromosome":"2","Start":"42053250","Stop":"42053250","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":511423,"rule_based_match":true,"evidence_text":"c.651C>A","llm_judgment":"PRESENT","evidence":"c.651C>A","abstract_start":1080,"abstract_end":1088}]}
{"pmid":"27829685","title":"Late-onset episodic ataxia associated with SLC1A3 mutation.","abstract":"Episodic ataxia type 6 (EA6) is caused by mutations in SLC1A3 that encodes excitatory amino acid transporter 1 (EAAT1), a glial glutamate transporter. EAAT1 regulates the extent and durations of glutamate-mediated signal by the clearance of glutamate after synaptic release. In addition, EAAT1 also has an anion channel activity that prevents additional glutamate release. We identified a missense mutation in SLC1A3 in a family with EA. The proband exhibited typical EA2-like symptoms such as recurrent ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade. Whole-exome sequencing detected a heterozygous c.1177G>A mutation in SLC1A3. This mutation predicted a substitution of isoleucine for a highly conserved valine residue in the seventh transmembrane domain of EAAT1. The mutation was not present in 100 controls, a large panel of in-house genome data and various mutation databases. Most functional prediction scores revealed to be deleterious. Same heterozygous mutation was identified in one clinically affected family member and two asymptomatic members. Our data expand the mutation spectrum of SLC1A3 and the clinical phenotype of EA6.","variants":[{"Name":"NM_004172.5(SLC1A3):c.1177G>A (p.Val393Ile)","Chromosome":"5","Start":"36680477","Stop":"36680477","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1934920,"rule_based_match":true,"evidence_text":"c.1177G>A","llm_judgment":"PRESENT","evidence":"c.1177G>A","abstract_start":700,"abstract_end":709}]}
{"pmid":"38456993","title":"Functional studies associate novel DUOX2 gene variants detected in heterozygosity to Crohn's disease.","abstract":"PURPOSE: Crohn's disease is a chronic gastrointestinal inflammatory disease with possible extraintestinal symptoms. There are predisposing genetic factors and even monogenic variants of the disorder. One of the possible genetic factors are variants of the DUOX2 gene. The protein product of the DUOX2 gene is a dual oxidase enzyme producing H<sub>2</sub>O<sub>2</sub> in the bowel. Reduced H<sub>2</sub>O<sub>2</sub> levels impact mucosal homeostasis and contribute to the development of inflammatory bowel disease. Thus far, only 19 patients with IBD with the DUOX2 variants have been described.\nMETHODS: Here we present a case report of an adolescent female diagnosed at eleven years of age with IBD that was subsequently reclassified as Crohn's disease. She was treated with immunosuppressants and biological therapy but experienced additional complications. Her peripheral blood lymphocyte DNA was studied using massive parallel sequencing. Detected variants were functionally studied.\nRESULTS: Whole exome sequencing found two novel DUOX2 gene variants: a de novo variant c.3646C>T; p.R1216W and a maternally inherited variant c.3391G>A; p.A1131T which were initially classified as variants of unknown significance. However, follow-up functional studies demonstrated that both DUOX2 variants led to impaired H<sub>2</sub>O<sub>2</sub> generation, which led to their reclassification to the likely pathogenic class according to the ACMG.net. Therefore, we conclude that these variants are causative for the disease.\nCONCLUSIONS: Identifying novel variants in patients with Crohn's disease and their families is important for precision medicine approaches and understanding of the pathogenesis of likely \"monogenic\" rare forms of inflammatory bowel disease.","variants":[{"Name":"NM_001363711.2(DUOX2):c.3646C>T (p.Arg1216Trp)","Chromosome":"15","Start":"45097661","Stop":"45097661","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1414486,"rule_based_match":true,"evidence_text":"c.3646C>T; p.R1216W","llm_judgment":"PRESENT","evidence":"c.3646C>T; p.R1216W","abstract_start":1077,"abstract_end":1096}]}
{"pmid":"30642740","title":"A novel MFN2 mutation causes variable clinical severity in a multi-generational CMT2 family.","abstract":"Dominant mutations in MFN2 cause a range of phenotypes, including severe, early-onset axonal neuropathy, \"classical CMT2\", and late-onset axonal neuropathy. We found a novel MFN2 mutation - c.283A>G (p.Arg95Gly) - that results in an axonal neuropathy with variable clinical severity in a multigenerational family. In affected family members, electromyography showed moderate to severe, chronic denervation in distal muscles. Such variable clinical severity highlights the need to do careful assessments of at risk individuals when assessing MFN2 variants.","variants":[{"Name":"NM_014874.4(MFN2):c.283A>G (p.Arg95Gly)","Chromosome":"1","Start":"11992662","Stop":"11992662","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":390815,"rule_based_match":true,"evidence_text":"c.283A>G (p.Arg95Gly)","llm_judgment":"PRESENT","evidence":"c.283A>G (p.Arg95Gly)","abstract_start":190,"abstract_end":211}]}
{"pmid":"26085578","title":"Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy.","abstract":"Multiple symmetric lipomatosis (MSL) is a mitochondrial disorder with impaired brown fat metabolism that has been associated with MERRF mutations in some, but not all, patients. We studied a sibling pair and an unrelated indiviadual who presented with MSL and neuropathy to determine the genetic etiology of this disorder in patients who did not carry the MSL-associated MERRF mutation. Whole-exome sequencing was performed on the siblings, and a rare, shared homozygous mutation in MFN2 (c.2119C>T: p.R707W) was identified. The mutation was not present in their healthy siblings. In silico programs predict it to be pathogenic, and heterozygous carriers of the MFN2 p.R707W substitution are known to have Charcot-Marie-Tooth (CMT) disease. A third, unrelated patient with multiple symmetrical lipomatosis and neuropathy also harbored the same homozygous mutation and had been previously diagnosed with CMT. Functional studies in patient fibroblasts demonstrate that the p.R707W substitution impairs homotypic (MFN2-MFN2) protein interactions required for normal activity and renders mitochondria prone to perinuclear aggregation. These findings show that homozygous mutations at p.R707W in MFN2 are a novel cause of multiple symmetrical lipomatosis.","variants":[{"Name":"NM_014874.4(MFN2):c.2119C>T (p.Arg707Trp)","Chromosome":"1","Start":"12009641","Stop":"12009641","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17319,"rule_based_match":true,"evidence_text":"c.2119C>T: p.R707W","llm_judgment":"PRESENT","evidence":"c.2119C>T: p.R707W","abstract_start":489,"abstract_end":507}]}
{"pmid":"27874200","title":"Two patients with GMPPB mutation: The overlapping phenotypes of limb-girdle myasthenic syndrome and limb-girdle muscular dystrophy dystroglycanopathy.","abstract":"INTRODUCTION: Mutations in the guanosine diphosphate-mannose pyrophosphorylase-B gene (GMPPB) have been identified in congenital muscular dystrophies, limb-girdle muscular dystrophy (LGMD2T), and congenital myasthenic syndromes (CMSs); overall, 41 patients have been described.\nMETHODS: Two patients presented with a myasthenic syndrome (patient 1; 74 years old) and rhabdomyolysis (patient 2; 23 years old). Examinations included repetitive nerve stimulation, muscle biopsy and whole-body MRI (WBMRI); next generation sequencing facilitated diagnosis.\nRESULTS: We identified the following GMPPB mutations: c.79G>C/c.859C>T in the 23-year-old man with LGMD2T-phenotype and c.79G>C homozygosity in the 74-year-old woman with CMS phenotype. WBMRI showed fatty degeneration of paraspinal, thigh adductor, and calf muscles in patient 1 and edematous changes of the soleus muscle in patient 2.\nCONCLUSIONS: This case of c.79G>C homozygosity causing a mild, late-onset CMS phenotype, confirms the mild nature of this common mutation. The descriptions of these 2 new GMPPB cases add to the knowledge regarding this recently discovered, heterogeneous disease. Muscle Nerve 56: 334-340, 2017.","variants":[{"Name":"NM_021971.4(GMPPB):c.859C>T (p.Arg287Trp)","Chromosome":"3","Start":"49722057","Stop":"49722057","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227736,"rule_based_match":true,"evidence_text":"c.859C>T","llm_judgment":"PRESENT","evidence":"c.859C>T","abstract_start":615,"abstract_end":623},{"Name":"NM_021971.4(GMPPB):c.79G>C (p.Asp27His)","Chromosome":"3","Start":"49723648","Stop":"49723648","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":75127,"rule_based_match":true,"evidence_text":"c.79G>C","llm_judgment":"PRESENT","evidence":"c.79G>C","abstract_start":607,"abstract_end":614}]}
{"pmid":"26064711","title":"Ellis-van Creveld Syndrome: Mutations Uncovered in Lebanese Families.","abstract":"Background. Ellis-van Creveld (EvC) syndrome is a rare, autosomal recessive disorder characterized by short stature, short limbs, growth retardation, polydactyly, and ectodermal defects with cardiac anomalies occurring in around 60% of cases. EVC syndrome has been linked to mutations in EVC and EVC2 genes. Case Presentation. We report EvC syndrome in two unrelated Lebanese families both having homozygous mutations in the EVC2 gene, c.2653C>T (p.(Arg885(*))) and c.2012_2015del (p.(Leu671(*))) in exons 15 and 13, respectively, with the latter being reported for the first time. Conclusion. Although EvC has been largely described in the medical literature, clinical features of this syndrome vary. While more research is required to explore other genes involved in EvC, early diagnosis and therapeutic care are important to achieve a better quality of life.","variants":[{"Name":"NM_147127.5(EVC2):c.2653C>T (p.Arg885Ter)","Chromosome":"4","Start":"5618531","Stop":"5618531","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39622,"rule_based_match":true,"evidence_text":"c.2653C>T (p.(Arg885(*)))","llm_judgment":"PRESENT","evidence":"c.2653C>T (p.(Arg885(*)))","abstract_start":436,"abstract_end":461}]}
{"pmid":"31435670","title":"Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease.","abstract":"BCS1L encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Phenotypes reported in association with pathogenic BCS1L variants include growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome), and Björnstad syndrome, characterized by abnormal flattening and twisting of hair shafts (pili torti) and hearing problems. Here we describe two patients harbouring biallelic variants in BCS1L; the first with a heterozygous variant c.166C>T, p.(Arg56*) together with a novel heterozygous variant c.205C>T, p.(Arg69Cys) and a second patient with a novel homozygous c.325C>T, p.(Arg109Trp) variant. The two patients presented with different phenotypes; the first patient presented as an adult with aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties. The second patient was an infant who presented with a classical GRACILE syndrome leading to death at 4 months of age. A decrease in BCS1L protein levels was seen in both patients, and biochemical analysis of Complex III revealed normal respiratory chain enzyme activities in the muscle of both patients. A decrease in Complex III assembly was detected in the adult patient's muscle, whilst the paediatric patient displayed a combined mitochondrial respiratory chain defect in cultured fibroblasts. Yeast complementation studies indicate that the two missense variants, c.205C>T, p.(Arg69Cys) and c.325C>T, p.(Arg109Trp), impair the respiratory capacity of the cell. Together, these data support the pathogenicity of the novel BCS1L variants identified in our patients.","variants":[{"Name":"NM_001079866.2(BCS1L):c.205C>T (p.Arg69Cys)","Chromosome":"2","Start":"218661192","Stop":"218661192","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":210770,"rule_based_match":true,"evidence_text":"c.205C>T, p.(Arg69Cys)","llm_judgment":"PRESENT","evidence":"c.205C>T, p.(Arg69Cys)","abstract_start":649,"abstract_end":671},{"Name":"NM_001079866.2(BCS1L):c.325C>T (p.Arg109Trp)","Chromosome":"2","Start":"218661410","Stop":"218661410","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":210772,"rule_based_match":true,"evidence_text":"c.325C>T, p.(Arg109Trp)","llm_judgment":"PRESENT","evidence":"c.325C>T, p.(Arg109Trp)","abstract_start":717,"abstract_end":740}]}
{"pmid":"21744088","title":"Somatotroph pituitary adenoma with acromegaly and autosomal dominant polycystic kidney disease: SSTR5 polymorphism and PKD1 mutation.","abstract":"A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0-5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48-255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Pathologic, cytogenetic, molecular and in silico analysis was undertaken. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.142C>A (p.L48M, rs4988483) in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subjected to extensive morphological, ultrastructural, cytogenetic and molecular studies. The physical proximity of the PKD1 and SSTR5 genes on chromosome 16 suggests a causal relationship between ADPKD and somatotroph adenoma.","variants":[{"Name":"NM_001009944.3(PKD1):c.5014_5015del (p.Arg1672fs)","Chromosome":"16","Start":"2110152","Stop":"2110153","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":441862,"rule_based_match":false,"evidence_text":"5014_5015delAG","llm_judgment":"PRESENT","evidence":"5014_5015delAG","abstract_start":1033,"abstract_end":1047}]}
{"pmid":"33045405","title":"Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency.","abstract":"Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) is a rare autosomal recessive inborn error of hepatic ketogenesis, caused by mutations in HMGCS2. As its clinical and laboratory manifestations resemble many other metabolic disorders, HMGCS2D definite diagnosis presents a challenge, frequently requiring molecular tests. Only 26 patients with HMGCS2 mutations have been previously described, and this study reports the first two unrelated Thai patients, a 9-month-old male and an 8-month-old female, with HMGCS2D. During acute episodes, steatorrhea and dyslipidemia occurred, both previously unreported. Increased serum levels of triglycerides, very low density lipoproteins (VLDL), and low density lipoproteins (LDL), along with a decreased serum level of HDL were found. Both patients had hypophosphatemic encephalopathy, and the female had metabolic acidosis without hypoglycemia. Trio whole-exome sequencing (WES) revealed that the male harbored two HMGCS2 mutations, a novel c.1480C>T (p.Arg494*) and a previously reported c.1502G>C (p.Arg501Pro), while the female was compound heterozygous for the c.1502G>C (p.Arg501Pro) and a previously reported mutation, c.520T>C (p.Phe174Leu). Interestingly, c.1502G>C (p.Arg501Pro) was not only found in both of our patients but also detected heterozygously in 9 out of 1081 unrelated individuals (allele frequency of 9/2162; 0.42%) in our in-house Thai exome database. Discovery of this common mutation suggests there could be about 14 babies with HMGCS2D within 800,000 newborns in Thailand annually. Therefore, awareness of HMGCS2D among medical personnel in Thailand should be raised.","variants":[{"Name":"NM_005518.4(HMGCS2):c.520T>C (p.Phe174Leu)","Chromosome":"1","Start":"119764211","Stop":"119764211","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":24296,"rule_based_match":true,"evidence_text":"c.520T>C (p.Phe174Leu)","llm_judgment":"PRESENT","evidence":"c.520T>C (p.Phe174Leu)","abstract_start":1192,"abstract_end":1214},{"Name":"NM_005518.4(HMGCS2):c.1502G>C (p.Arg501Pro)","Chromosome":"1","Start":"119750827","Stop":"119750827","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":442601,"rule_based_match":true,"evidence_text":"c.1502G>C (p.Arg501Pro)","llm_judgment":"PRESENT","evidence":"c.1502G>C (p.Arg501Pro)","abstract_start":1056,"abstract_end":1079},{"Name":"NM_005518.4(HMGCS2):c.1480C>T (p.Arg494Ter)","Chromosome":"1","Start":"119750849","Stop":"119750849","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":815883,"rule_based_match":true,"evidence_text":"c.1480C>T (p.Arg494*)","llm_judgment":"PRESENT","evidence":"c.1480C>T (p.Arg494*)","abstract_start":1008,"abstract_end":1029}]}
{"pmid":"20373145","title":"Analysis of mismatch repair gene mutations in Turkish HNPCC patients.","abstract":"Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is caused by the inheritance of a mutant allele of a DNA mismatch repair gene. We aimed to investigate types and frequencies of mismatch repair (MMR) gene mutations in Turkish patients with HNPCC and to identify specific biomarkers for early diagnosis of their non-symptomatic kindred's. The molecular characteristics of 28 Turkish colorectal cancer patients at high-risk for HNPCC were investigated by analysis of microsatellite instability (MSI), immunohistochemistry and methylation-specific PCR in order to select tumors for mutation analysis. Ten cases (35.7%) were classified as MSI (+). Lack of expression of the main MMR proteins was observed in MSI (+) tumors. Hypermethylation of the MLH1 promoter region was observed in one tumor. Nine Lynch syndrome cases showed novel germ-line alterations of the MMR gene: two frame-shifts (MLH1 c.1843dupC and MLH1 c.1743delG) and three missense mutations (MLH1 c.293G>C, MLH1 c.954_955delinsTA and MSH2 c.2210G>A). Unclassified variants were evaluated as likely to be pathogenic by using the in-silico analyses. In addition, the MSH2 c.2210G>A alteration could be considered as a founder mutation for the Turkish population due to its identification in five different Lynch syndrome families and absence in control group. The present study adds new information about MMR gene mutation types and their role in Lynch syndrome. This is the first detailed research on Turkish Lynch syndrome families.","variants":[{"Name":"NM_000251.3(MSH2):c.2210G>A (p.Arg737Lys)","Chromosome":"2","Start":"47476571","Stop":"47476571","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1401177,"rule_based_match":true,"evidence_text":"MSH2 c.2210G>A","llm_judgment":"PRESENT","evidence":"MSH2 c.2210G>A","abstract_start":1016,"abstract_end":1030}]}
{"pmid":"31888296","title":"Next Generation Sequencing Identifies Five Novel Mutations in Lebanese Patients with Bardet-Biedl and Usher Syndromes.","abstract":"AIM: To identify disease-causing mutations in four Lebanese families: three families with Bardet-Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS).\nMETHODS: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis.\nRESULTS: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in <i>BBS9</i>, (M2): c.68T > C; p. (Leu23Pro) in <i>ARL6</i>, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in <i>BBS12</i>. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in <i>BBS5</i>. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in <i>CLRN1</i>. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members.\nCONCLUSION: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.","variants":[{"Name":"NM_198428.3(BBS9):c.2258A>T (p.Glu753Val)","Chromosome":"7","Start":"33505605","Stop":"33505605","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":369720,"rule_based_match":true,"evidence_text":"c.2258A > T, p. (Glu753Val) in <i>BBS9</i>","llm_judgment":"PRESENT","evidence":"c.2258A > T, p. (Glu753Val) in <i>BBS9</i>","abstract_start":725,"abstract_end":767},{"Name":"NM_152618.3(BBS12):c.880T>G (p.Tyr294Asp)","Chromosome":"4","Start":"122742772","Stop":"122742772","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1977766,"rule_based_match":true,"evidence_text":"c.880T > G; p. (Tyr294Asp)","llm_judgment":"PRESENT","evidence":"c.880T > G; p. (Tyr294Asp)","abstract_start":867,"abstract_end":893},{"Name":"NM_152618.3(BBS12):c.265_266del (p.Leu89fs)","Chromosome":"4","Start":"122742155","Stop":"122742156","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":543046,"rule_based_match":true,"evidence_text":"c.265_266delTT; p. (Leu89Valfs*11)","llm_judgment":"PRESENT","evidence":"c.265_266delTT; p. (Leu89Valfs*11)","abstract_start":822,"abstract_end":856}]}
{"pmid":"17968969","title":"MECP2 deletions and genotype-phenotype correlation in Rett syndrome.","abstract":"Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. MECP2 point mutations in exons 2-4 account for about 80% of classic Rett cases and for a lower percentage of variant patients. We investigated the genetic cause in 77 mutation-negative Rett patients (33 classic, 31 variant, and 13 Rett-like cases) by searching missed MECP2 defects. DHPLC analysis of exon 1 and MLPA analysis allowed us to identify the defect in 17 Rett patients: one exon 1 point mutation (c.47_57del) in a classic case and 16 MECP2 large deletions (15/33 classic and 1/31 variant cases). One identical intragenic MECP2 deletion, probably due to gonadal mosaicism, was found in two sisters with discordant phenotype: one classic and one \"highly functioning\" preserved speech variant. This result indicates that other epigenetic or genetic factors, beside MECP2, may contribute to phenotype modulation. Three out of 16 MECP2 deletions extend to the adjacent centromeric IRAK1 gene. A putative involvement of the hemizygosity of this gene in the ossification process is discussed. Finally, results reported here clearly indicate that MECP2 large deletions are a common cause of classic Rett, and MLPA analysis is mandatory in MECP2-negative patients, especially in those more severely affected (P = 0.044).","variants":[{"Name":"NM_001110792.2(MECP2):c.47_57del (p.Gly16fs)","Chromosome":"X","Start":"154097609","Stop":"154097619","ReferenceAlleleVCF":"TCTCCTCCTCGC","AlternateAlleleVCF":"T","allel_id":187561,"rule_based_match":true,"evidence_text":"c.47_57del","llm_judgment":"PRESENT","evidence":"c.47_57del","abstract_start":541,"abstract_end":551}]}
{"pmid":"30787906","title":"Broadening the Spectrum of Adulthood X-Linked Adrenoleukodystrophy: A Report of Two Atypical Cases.","abstract":"X-linked adrenoleukodystrophy (x-ALD) is a rare genetic disorder caused by a mutation in the <i>ABCD1</i> gene, which encodes for a peroxisomal very long chain fatty acid transporter. Clinically, x-ALD can present a wide spectrum of different phenotypes: asymptomatic carriers, Addison only, cerebral x-ALD, and myelopathy with/without evidence of peripheral axonopathy (Adrenomyeloneuropathy). We report on two cases of adult x-ALD, with atypical phenotypes: <b>(Case 1)</b> A 37-years-old male with a 2-years-long history of spastic paraparesis, urinary urgency, and subclinical adrenocortical insufficiency. As an atypical finding, the MRI showed multiple congenital brain development defects. <b>(Case 2)</b> A 63-years-old male with a previous diagnosis of Addison disease, with a 6-years-long history of spastic paraparesis. Two years later, he complained of severe and disabling burning pain in his feet. A nerve conduction study was normal, but a skin biopsy revealed autonomic and somatic small fiber neuropathy. In both cases, genetic testing disclosed hemizygous mutation in <i>ABCD1</i> associated with x-ALD: c.1394-2A > G and p.(Thr254Met), respectively. While case 1 supports the key role of peroxisome functions in brain development, case 2 points to a possible selective and clinically relevant peripheral small fiber degeneration in x-ALD myelopathy.","variants":[{"Name":"NM_000033.4(ABCD1):c.1394-2A>G","Chromosome":"X","Start":"153737155","Stop":"153737155","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2902070,"rule_based_match":true,"evidence_text":"c.1394-2A > G","llm_judgment":"PRESENT","evidence":"c.1394-2A > G","abstract_start":1122,"abstract_end":1135}]}
{"pmid":"32363481","title":"MLH1 intronic variants mapping to + 5 position of splice donor sites lead to deleterious effects on RNA splicing.","abstract":"Germline pathogenic variants in the DNA mismatch repair genes (MMR): MLH1, MSH2, MSH6, and PMS2, are causative of Lynch syndrome (LS). However, many of the variants mapping outside the invariant splice site positions (IVS ± 1, IVS ± 2) are classified as variants of unknown significance (VUS). Three such variants (MLH1 c.588+5G>C, c.588+5G>T and c.677+5G>A) were identified in 8 unrelated LS families from Argentina, Brazil and Chile. Herein, we collected clinical information on these families and performed segregation analysis and RNA splicing studies to assess the implication of these VUS in LS etiology. Pedigrees showed a clear pattern of variant co-segregation with colorectal cancer and/or other LS-associated malignancies. Tumors presented deficient expression of MLH1-PMS2 proteins in 7/7 of the LS families, and MSI-high status in 3/3 cases. Moreover, RNA analyses revealed that c.588+5G>C and c.588+5G>T induce skipping of exon 7 whereas c.677+5G>A causes skipping of exon 8. In sum, we report that the combined clinical findings in the families and the molecular studies provided the evidences needed to demonstrate that the three MLH1 variants are causative of LS and to classify c.588+5G>C and c.677+5G>A as class 5 (pathogenic), and c.588+5G>T as class 4 (likely-pathogenic). Our findings underline the importance of performing clinical and family analyses, as well as RNA splicing assays in order to determine the clinical significance of intronic variants, and contribute to the genetic counseling and clinical management of patients and their relatives.","variants":[{"Name":"NM_000249.4(MLH1):c.677+5G>A","Chromosome":"3","Start":"37012104","Stop":"37012104","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":95791,"rule_based_match":true,"evidence_text":"c.677+5G>A","llm_judgment":"PRESENT","evidence":"c.677+5G>A","abstract_start":347,"abstract_end":357},{"Name":"NM_000249.4(MLH1):c.588+5G>C","Chromosome":"3","Start":"37011867","Stop":"37011867","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":95760,"rule_based_match":true,"evidence_text":"c.588+5G>C","llm_judgment":"PRESENT","evidence":"c.588+5G>C","abstract_start":320,"abstract_end":330},{"Name":"NM_000249.4(MLH1):c.588+5G>T","Chromosome":"3","Start":"37011867","Stop":"37011867","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":850928,"rule_based_match":true,"evidence_text":"c.588+5G>T","llm_judgment":"PRESENT","evidence":"c.588+5G>T","abstract_start":332,"abstract_end":342}]}
{"pmid":"34815942","title":"Congenital hypopituitarism due to novel compound heterozygous","abstract":"Failure to thrive is one of the most common complaints in the endocrinology and genetics clinic. An 8-month-old girl with presentation of motor developmental delay, failure to thrive, and midline facial defects, with history of hypoglycemia at birth and central congenital hypothyroidism (CCH), was brought to our genetic clinic. Hormone test demonstrated combined pituitary hormone deficiency with growth hormone deficiency (GHD), central hypothyroidism, and hypoprolactinemia. Brain magnetic resonance imaging (MRI) showed anterior pituitary hypoplasia (APH), abnormal pituitary stalk, and preserved posterior pituitary lobe. Whole exome sequence (WES) identified a compound heterozygous mutation of the <i>POU1F1</i> gene: c.649C>T (p.Arg217Ter) and c.662T>C (p.Ile221Thr), which are <i>de novo</i> mutation and inherited from mother, respectively. The patient's phenotype was consistent clinically with congenital hypopituitarism due to the <i>POU1F1</i> gene mutation. Based on our literature review, this is the first report of the c.662T>C mutation, to the best of our knowledge. Our study demonstrates the power of WES for early diagnosis of congenital hypopituitarism with its relative phenotype for improving prognosis and preventing irreversible deficit.","variants":[{"Name":"NM_000306.4(POU1F1):c.649C>T (p.Arg217Ter)","Chromosome":"3","Start":"87261289","Stop":"87261289","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":985719,"rule_based_match":true,"evidence_text":"c.649C>T (p.Arg217Ter)","llm_judgment":"PRESENT","evidence":"c.649C>T (p.Arg217Ter)","abstract_start":726,"abstract_end":748}]}
{"pmid":"27178005","title":"Single amino acid loss in the dystrophin protein associated with a mild clinical phenotype.","abstract":"INTRODUCTION: The dystrophinopathies include a spectrum of muscle diseases caused by mutations in the dystrophin (DMD) gene. The clinical phenotype ranges from severe Duchenne muscular dystrophy to a mild phenotype with elevated creatine kinase (CK).\nMETHODS: Clinical and molecular assessment of 7 patients carrying a single amino acid loss in the dystrophin protein (p.His1690del) caused by a c.5068_5070delCAC tri-nucleotide deletion in exon 36 of the DMD gene.\nRESULTS: All patients were asymptomatic or oligosymptomatic and had elevated CK levels. Febrile illness, but not exercise, induced muscle symptoms in some patients. None had evidence of cardiomyopathy. Analysis of the short tandem repeat (STR)45 locus and sequencing of exon 36 of the DMD gene indicates that c.5068_5070delCAC is a founder mutation.\nCONCLUSIONS: The c.5068_5070delCAC locus in the DMD gene is associated with a very mild phenotype. Further study is needed to evaluate disease progression in these patients. Muscle Nerve 55: 46-50, 2017.","variants":[{"Name":"NM_004006.3(DMD):c.5068_5070del (p.His1690del)","Chromosome":"X","Start":"32364666","Stop":"32364668","ReferenceAlleleVCF":"TGTG","AlternateAlleleVCF":"T","allel_id":471856,"rule_based_match":true,"evidence_text":"c.5068_5070delCAC","llm_judgment":"PRESENT","evidence":"c.5068_5070delCAC","abstract_start":395,"abstract_end":412}]}
{"pmid":"26486469","title":"A canine orthologue of the human GFAP c.716G>A (p.Arg239His) variant causes Alexander disease in a Labrador retriever.","abstract":"Alexander disease (AxD) is a fatal neurodegenerative disorder of astrocyte dysfunction in man, for which already a number of causal variants are described, mostly de novo dominant missense variants in the glial fibrillary acidic protein (GFAP). A similar disorder was already phenotypically described in animals but without the identification of causal variants. We diagnosed a Labrador retriever with a juvenile form of AxD based on clinical (tetraparesis with spastic front limbs mimicking 'swimming puppy syndrome') and pathological (the detection of GFAP containing Rosenthal fibers in astrocytes) features. In order to identify a causal variant, the coding sequences of the four detected GFAP transcript variants (orthologues from human transcript variants α, γ, δ/ɛ and κ) were sequenced. From the five detected variants, a heterozygous c.719G>A nucleotide substitution resulting in a p.Arg240His substitution was considered to be causal, because it is orthologous to the heterozygous de novo dominant c.716G>A (p.Arg239His) hotspot variant in man, proven to cause a severe phenotype. In addition, the variant was not found in 50 unrelated healthy Labrador retrievers. Because the condition in dogs is morphologically similar to man, it could be a promising animal model for further elucidating the genotype/phenotype correlation in order to treat or prevent this disease.","variants":[{"Name":"NM_002055.5(GFAP):c.716G>A (p.Arg239His)","Chromosome":"17","Start":"44913333","Stop":"44913333","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31207,"rule_based_match":true,"evidence_text":"c.716G>A (p.Arg239His)","llm_judgment":"PRESENT","evidence":"c.716G>A (p.Arg239His)","abstract_start":1008,"abstract_end":1030}]}
{"pmid":"38066485","title":"Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions.","abstract":"BACKGROUND: TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations.\nMETHODS: In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity.\nRESULTS: We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability.\nCONCLUSIONS: This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.","variants":[{"Name":"NM_138691.3(TMC1):c.1256T>C (p.Phe419Ser)","Chromosome":"9","Start":"72791917","Stop":"72791917","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1952219,"rule_based_match":true,"evidence_text":"c.1256T > C:p.Phe419Ser","llm_judgment":"PRESENT","evidence":"c.1256T > C:p.Phe419Ser","abstract_start":1155,"abstract_end":1178}]}
{"pmid":"20547956","title":"Phenotype associated with mutation in the recently identified autosomal dominant retinitis pigmentosa KLHL7 gene.","abstract":"OBJECTIVE: To characterize the clinical phenotype, with an emphasis on electrophysiologic findings, in a family with autosomal dominant retinitis pigmentosa caused by mutation in the recently identified KLHL7 gene.\nMETHODS: Eleven patients from a single family were selected from the Swedish retinitis pigmentosa register. Four patients had been examined 13 to 17 years earlier and underwent further ophthalmologic examination, including visual acuity, fundus inspection, Goldmann perimetry, full-field electroretinography (ERG), multifocal ERG, and optical coherence tomography. KLHL7 mutation was identified by sequence analysis.\nRESULTS: In most examined family members, the fundus showed minor abnormalities. Full-field ERG demonstrated reduced cone and rod function, but rod responses were preserved in some patients late in life. Follow-up (<or=17 years) demonstrated slowly progressive retinal degeneration. In an adolescent family member, cone and rod function was initially normal, but retinitis pigmentosa was confirmed by electrophysiology 17 years later. Optical coherence tomography and multifocal ERG demonstrated macular abnormalities of varying degree among family members. Genetic analysis revealed a heterozygous exon 6 change (c.458C>T) in 7 family members.\nCONCLUSIONS: Observed in 2 Scandinavian families to date, KLHL7 mutation has recently been associated with autosomal dominant retinitis pigmentosa. Clinical examination with long-term follow-up verified a phenotype with a varying degree of retinal photoreceptor dysfunction and, in some family members, with late onset and preserved rod function until late in life. Clinical Relevance Patients with minor retinal abnormalities and normal ERG findings early in life can harbor an autosomal dominant form of retinitis pigmentosa with a varying degree of visual impediment. Some patients with late onset may retain night vision for many years.","variants":[{"Name":"NM_001031710.3(KLHL7):c.458C>T (p.Ala153Val)","Chromosome":"7","Start":"23140784","Stop":"23140784","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16048,"rule_based_match":true,"evidence_text":"c.458C>T","llm_judgment":"PRESENT","evidence":"c.458C>T","abstract_start":1246,"abstract_end":1254}]}
{"pmid":"26611353","title":"De novo DNM1 mutations in two cases of epileptic encephalopathy.","abstract":"Dynamin 1 (DNM1) is a large guanosine triphosphatase involved in clathrin-mediated endocytosis. In recent studies, de novo mutations in DNM1 have been identified in five individuals with epileptic encephalopathy. In this study, we report two patients with early onset epileptic encephalopathy possessing de novo DNM1 mutations. Using whole exome sequencing, we detected the novel mutation c.127G>A (p.Gly43Ser) in a patient with Lennox-Gastaut syndrome, and a recurrent mutation c.709C>T (p.Arg237Trp) in a patient with West syndrome. Structural consideration of DNM1 mutations revealed that both mutations would destabilize the G domain structure and impair nucleotide binding, dimer formation, and/or GTPase activity of the G domain. These and previous cases of DNM1 mutations were reviewed to verify the phenotypic spectrum. The main clinical features of DNM1 mutations include intractable seizures, intellectual disability, developmental delay, and hypotonia. Most cases showed development delay before the onset of seizures. A patient carrying p.Arg237Trp in this report showed a different developmental status from that of a previously reported case, together with characteristic extrapyramidal movement.","variants":[{"Name":"NM_004408.4(DNM1):c.709C>T (p.Arg237Trp)","Chromosome":"9","Start":"128220201","Stop":"128220201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":264472,"rule_based_match":true,"evidence_text":"c.709C>T (p.Arg237Trp)","llm_judgment":"PRESENT","evidence":"c.709C>T (p.Arg237Trp)","abstract_start":479,"abstract_end":501},{"Name":"NM_004408.4(DNM1):c.127G>A (p.Gly43Ser)","Chromosome":"9","Start":"128203597","Stop":"128203597","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":511793,"rule_based_match":true,"evidence_text":"c.127G>A (p.Gly43Ser)","llm_judgment":"PRESENT","evidence":"c.127G>A (p.Gly43Ser)","abstract_start":389,"abstract_end":410}]}
{"pmid":"18553548","title":"Czech dysplasia: report of a large family and further delineation of the phenotype.","abstract":"Czech dysplasia (OMIM 609162) is a recently delineated COL2A1 disorder characterized by early-onset progressive pseudorheumatoid arthritis, platyspondyly, short third and fourth metatarsals, normal height, and the absence of ophthalmological problems or cleft palate. Czech dysplasia is caused by a specific missense mutation (R275C, c.823C > T) in the triple helical domain of the COL2A1 gene. We report on a large family with 11 patients with typical Czech dysplasia and sensorineural hearing loss. Hearing loss has hitherto not been considered as a major manifestation of Czech dysplasia. Mutation analysis documented the COL2A1 c.823C > T (R275C) mutation in all affected individuals. Thus, Czech dysplasia is possibly caused exclusively by the R275C mutation, which is a unique situation among the COL2A1 disorders. The family provides further evidence for the remarkably uniform manifestation of the clinical and radiological abnormalities and adds hearing loss to the list of major anomalies of Czech dysplasia.","variants":[{"Name":"NM_001844.5(COL2A1):c.823C>T (p.Arg275Cys)","Chromosome":"12","Start":"47994041","Stop":"47994041","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32407,"rule_based_match":true,"evidence_text":"c.823C > T (R275C)","llm_judgment":"PRESENT","evidence":"c.823C > T (R275C)","abstract_start":632,"abstract_end":650}]}
{"pmid":"34130719","title":"Consanguinity-based analysis of exome sequencing yields likely genetic causes in patients with inherited retinal dystrophy.","abstract":"BACKGROUND: Consanguineous families have a relatively high prevalence of genetic disorders caused by bi-allelic mutations in recessive genes. This study aims to evaluate the effectiveness and efficiency of a consanguinity-based exome sequencing approach to capturing genetic mutations in inherited retinal dystrophy families with consanguineous marriages.\nMETHODS: Ten unrelated consanguineous families with a proband affected by inherited retinal dystrophy were recruited in this study. All participants underwent comprehensive ophthalmic examinations. Whole exome sequencing was performed, followed by a homozygote-prior strategy to rapidly filter disease-causing mutations. Bioinformatic prediction of pathogenicity, Sanger sequencing and co-segregation analysis were carried out for further validation.\nRESULTS: In ten consanguineous families, a total of 10 homozygous mutations in 8 IRD genes were identified, including 2 novel mutations, c.1654_1655delAG (p. R552Afs*5) in gene FAM161A in a patient diagnosed with retinitis pigmentosa, and c.830T > C (p.L277P) in gene CEP78 in a patient diagnosed with cone and rod dystrophy.\nCONCLUSION: The genetic etiology in consanguineous families with IRD were successfully identified using consanguinity-based analysis of exome sequencing data, suggesting that this approach could provide complementary insights into genetic diagnoses in consanguineous families with variant genetic disorders.","variants":[{"Name":"NM_001330691.3(CEP78):c.830T>C (p.Leu277Pro)","Chromosome":"9","Start":"78246720","Stop":"78246720","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1502045,"rule_based_match":true,"evidence_text":"c.830T > C (p.L277P)","llm_judgment":"PRESENT","evidence":"c.830T > C (p.L277P)","abstract_start":1046,"abstract_end":1066}]}
{"pmid":"26990772","title":"A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development.","abstract":"Patients with biallelic truncating mutations in PALB2 have a severe form of Fanconi anaemia (FA-N), with a predisposition for developing embryonal-type tumours in infancy. Here we describe two unusual patients from a single family, carrying biallelic PALB2 mutations, one truncating, c.1676_1677delAAinsG;(p.Gln559ArgfsTer2), and the second, c.2586+1G>A; p.Thr839_Lys862del resulting in an in frame skip of exon 6 (24 amino acids). Strikingly, the affected individuals did not exhibit the severe developmental defects typical of FA-N patients and initially presented with B cell non-Hodgkin lymphoma. The expressed p.Thr839_Lys862del mutant PALB2 protein retained the ability to interact with BRCA2, previously unreported in FA-N patients. There was also a large increased chromosomal radiosensitivity following irradiation in G2 and increased sensitivity to mitomycin C. Although patient cells were unable to form Rad51 foci following exposure to either DNA damaging agent, U2OS cells, in which the mutant PALB2 with in frame skip of exon 6 was induced, did show recruitment of Rad51 to foci following damage. We conclude that a very mild form of FA-N exists arising from a hypomorphic PALB2 allele.","variants":[{"Name":"NM_024675.4(PALB2):c.2586+1G>A","Chromosome":"16","Start":"23629203","Stop":"23629203","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1871408,"rule_based_match":true,"evidence_text":"c.2586+1G>A","llm_judgment":"PRESENT","evidence":"c.2586+1G>A","abstract_start":342,"abstract_end":353},{"Name":"NM_024675.4(PALB2):c.1676_1677delinsG (p.Gln559fs)","Chromosome":"16","Start":"23634869","Stop":"23634870","ReferenceAlleleVCF":"TT","AlternateAlleleVCF":"C","allel_id":132124,"rule_based_match":false,"evidence_text":"c.1676_1677delAAinsG;(p.Gln559ArgfsTer2)","llm_judgment":"PRESENT","evidence":"c.1676_1677delAAinsG;(p.Gln559ArgfsTer2)","abstract_start":284,"abstract_end":324}]}
{"pmid":"21763628","title":"RB1 gene mutations in Iranian patients with retinoblastoma: report of four novel mutations.","abstract":"Mutations in the RB1 gene lead to retinoblastoma, which is the most common intraocular tumor in children under the age of 6. In the present survey, the mutations of 18 unrelated Iranian retinoblastoma patients were characterized. Mutation analysis of the RB1 gene was performed in patients by sequencing all coding regions and by multiplex ligation probe-dependent amplification analysis. Clinical signs and symptoms of the retinoblastoma patients were similar to those of previously described patients with retinoblastoma. Eight known mutations and four novel mutations (c.832_833insT, c.1943delC, c.1206C>T, and c.2029delG) were determined. In silico analysis of the c.1206C>T variant showed that exon 12 contained an SC-35 consensus sequence, and this variation disrupted the splicing enhancer element and caused skipping of exon 12. Molecular genetic testing of retinoblastoma patients greatly affects the genetic counseling of the families involved, as well as the management of the disease in patients and at-risk relatives.","variants":[{"Name":"NM_000321.3(RB1):c.1206C>T (p.Ser402=)","Chromosome":"13","Start":"48373483","Stop":"48373483","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":983592,"rule_based_match":true,"evidence_text":"c.1206C>T","llm_judgment":"PRESENT","evidence":"c.1206C>T","abstract_start":599,"abstract_end":608}]}
{"pmid":"20842748","title":"Cerebral arterial stenoses and stroke: novel features of Aicardi-Goutières syndrome caused by the Arg164X mutation in SAMHD1 are associated with altered cytokine expression.","abstract":"Aicardi-Goutières syndrome (AGS) is a rare inborn multisystemic disease, resembling intrauterine viral infection and resulting in psychomotor retardation, spasticity and chilblain-likeskin lesions. Diagnostic criteria include intracerebral calcifications and elevated interferon-alpha and pterin levels in cerebrospinal fluid (CSF). We report on four adult siblings with unknown neurodegenerative disease presenting with cerebrovascular stenoses, stroke and glaucoma in childhood, two of whom died at the age of 40 and 29 years. Genome-wide homozygosity mapping identified 170 candidate genes embedded in a common haplotype of 8Mb on chromosome 20q11-13. Next generation sequencing of the entire region identified the c.490C>T (p.Arg164X) mutationin SAMHD1, a gene most recently described in AGS, on both alleles in all affected siblings.Clinical diagnosis of AGS was then confirmed by demonstrating intracerebral calcifications on cranial computed tomography in all siblings and elevated pterin levels in CSF in three of them. Inpatient fibroblasts, lack of SAMHD1 protein expression was associated with increased basal expression of IL8, while stimulated expression of IFNB1 was reduced. We conclude that cerebrovascular stenoses and stroke associated with the Arg164X mutation in SAMHD1 extend the phenotypic spectrum of AGS. The observed vascular changes most likely reflect a vasculitis caused by dysregulated inflammatory stress response.","variants":[{"Name":"NM_015474.4(SAMHD1):c.490C>T (p.Arg164Ter)","Chromosome":"20","Start":"36935048","Stop":"36935048","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19108,"rule_based_match":true,"evidence_text":"c.490C>T (p.Arg164X)","llm_judgment":"PRESENT","evidence":"c.490C>T (p.Arg164X)","abstract_start":718,"abstract_end":738}]}
{"pmid":"37408354","title":"Odontohypophosphatasia caused by a novel combination of two heterozygous variants: a case report.","abstract":"Hypophosphatasia (HPP) is a rare genetic disorder mainly characterized by skeletal dysplasia that results from a deficiency in tissue-nonspecific alkaline phosphatase (TNSALP), which is encoded by the alkaline phosphatase (<i>ALPL</i>) gene. Odontohypophosphatasia (odonto-HPP) is a mild form of HPP characterized by oral symptoms, such as premature loss of primary teeth. This study was to describe a 4-year-old boy with premature loss of primary teeth who was diagnosed with odonto-HPP. X-ray radiography and laboratory examinations were performed for the diagnosis. Genetic etiology was revealed by whole-exome sequencing. A novel combination of two variants in the <i>ALPL</i> gene was identified in this case; this combination resulted in the odonto-HPP phenotype. c.346G>A (p.Ala116Thr) was inherited from the proband's father, whereas c.1563C>G (p.Ser521Arg) was inherited from the proband's mother. The proband's 8-year-old sister was a heterozygous carrier of c.346G>A (p.Ala116Thr) in the <i>ALPL</i> gene. Thus far, the proband's sister has been asymptomatic. Our findings indicate that c.346G>A is a pathogenic genetic alteration; c.1563C>G might cause a predisposition to the dental phenotype in combination with c.346G>A. It is important for pediatric dentists to consider a diagnosis of odonto-HPP in children with premature loss of primary teeth.","variants":[{"Name":"NM_000478.6(ALPL):c.1563C>G (p.Ser521Arg)","Chromosome":"1","Start":"21577636","Stop":"21577636","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1933872,"rule_based_match":true,"evidence_text":"c.1563C>G (p.Ser521Arg)","llm_judgment":"PRESENT","evidence":"c.1563C>G (p.Ser521Arg)","abstract_start":842,"abstract_end":865}]}
{"pmid":"30796847","title":"MYT1L mutation in a patient causes intellectual disability and early onset of obesity: a case report and review of the literature.","abstract":"Background Obesity has become one of the greatest health risks worldwide. Recently, there was an explosion of information regarding the role of the central nervous system (CNS) in the development of monogenic and syndromic obesity. Case presentation Over the last decade, terminal and interstitial submicroscopic deletions of copy number variants (CNVs) in 2p25.3 and single nucleotide variants (SNVs) in myelin transcription factor 1 like (MYT1L) were detected by genome-wide array analysis and whole exome sequencing (WES) in patients with a nonspecific clinical phenotype that commonly includes intellectual disability (ID), early onset of obesity and speech delay. Here, we report the first Saudi female patient with mild to moderate ID, early onset of obesity and speech delay associated with a de novo pathogenic SNV in the MYT1L gene (c. 1585G>A [Gly529Arg]), which causes an amino acid change from Gly to Arg at position 529 that leads to mental retardation, autosomal dominant 39.","variants":[{"Name":"NM_001303052.2(MYT1L):c.1585G>A (p.Gly529Arg)","Chromosome":"2","Start":"1917238","Stop":"1917238","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":583083,"rule_based_match":true,"evidence_text":"c. 1585G>A [Gly529Arg]","llm_judgment":"PRESENT","evidence":"c. 1585G>A [Gly529Arg]","abstract_start":842,"abstract_end":864}]}
{"pmid":"22391140","title":"The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3.","abstract":"BACKGROUND: Mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene have been recently identified in patients with atypical primary hyperoxaluria (PH). However, it was not clearly established whether these mutations caused disease via loss of function or activation of the gene product.\nMETHODS: Whole-gene sequencing of HOGA1 was conducted in 28 unrelated patients with a high clinical suspicion of PH and in whom Types 1 and 2 had been excluded.\nRESULTS: Fifteen patients were homozygous or compound heterozygous for mutations in HOGA1. In total, seven different mutations were identified including three novel changes: a missense mutation, c.107C > T (p.Ala36Val), and two nonsense mutations c.117C > A (p.Tyr39X) and c.208C > T (p.Arg70X) as well as the previously documented c.860G > T (p.Gly297Val), c.907C > T (p.Arg303Cys) and in-frame c.944_946delAGG (p.Glu315del) mutations. The recurrent c.700 + 5G > T splice site mutation in intron 5 was most common with a frequency of 67%. Expression studies on hepatic messenger RNA demonstrated the pathogenicity of this mutation.\nCONCLUSIONS: The detection of a patient with two novel nonsense mutations within exon 1 of the gene, c.117C > A (p.Tyr39X) and c.208C > T (p.Arg70X), provides definitive proof that PH Type 3 is due to deficiency of the 4-hydroxy-2-oxoglutarate aldolase enzyme.","variants":[{"Name":"NM_138413.4(HOGA1):c.107C>T (p.Ala36Val)","Chromosome":"10","Start":"97584810","Stop":"97584810","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":200652,"rule_based_match":true,"evidence_text":"c.107C > T (p.Ala36Val)","llm_judgment":"PRESENT","evidence":"c.107C > T (p.Ala36Val)","abstract_start":651,"abstract_end":674},{"Name":"NM_138413.4(HOGA1):c.117C>A (p.Tyr39Ter)","Chromosome":"10","Start":"97584820","Stop":"97584820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":200653,"rule_based_match":true,"evidence_text":"c.117C > A (p.Tyr39X)","llm_judgment":"PRESENT","evidence":"c.117C > A (p.Tyr39X)","abstract_start":703,"abstract_end":724},{"Name":"NM_138413.4(HOGA1):c.208C>T (p.Arg70Ter)","Chromosome":"10","Start":"97584911","Stop":"97584911","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":200655,"rule_based_match":true,"evidence_text":"c.208C > T (p.Arg70X)","llm_judgment":"PRESENT","evidence":"c.208C > T (p.Arg70X)","abstract_start":729,"abstract_end":750},{"Name":"NM_138413.4(HOGA1):c.700+5G>T","Chromosome":"10","Start":"97600168","Stop":"97600168","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":200671,"rule_based_match":true,"evidence_text":"c.700 + 5G > T","llm_judgment":"PRESENT","evidence":"c.700 + 5G > T","abstract_start":907,"abstract_end":921},{"Name":"NM_138413.4(HOGA1):c.907C>T (p.Arg303Cys)","Chromosome":"10","Start":"97611582","Stop":"97611582","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":200682,"rule_based_match":true,"evidence_text":"c.907C > T (p.Arg303Cys)","llm_judgment":"PRESENT","evidence":"c.907C > T (p.Arg303Cys)","abstract_start":814,"abstract_end":838}]}
{"pmid":"23709753","title":"Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants.","abstract":"BACKGROUND AND AIM: The majority of mismatch repair (MMR) gene mutations causing Lynch syndrome (LS) occur either in MLH1 or MSH2. However, the relative contribution of PMS2 is less well defined. The aim of this study was to evaluate the role of PMS2 in LS by assessing the pathogenicity of variants of unknown significance (VUS) detected in the mutational analysis of PMS2 in a series of Spanish patients.\nMETHODS: From a cohort of 202 LS suspected patients, 13 patients showing loss of PMS2 expression in tumours were screened for germline mutations in PMS2, using a long range PCR based strategy and multiplex ligation dependent probe amplification (MLPA). Pathogenicity assessment of PMS2 VUS was performed evaluating clinicopathological data, frequency in control population and in silico and in vitro analyses at the RNA and protein level.\nRESULTS: Overall 25 different PMS2 DNA variants were detected. Fourteen were classified as polymorphisms. Nine variants were classified as pathogenic: seven alterations based on their molecular nature and two after demonstrating a functional defect (c.538-3C>G affected mRNA processing and c.137G>T impaired MMR activity). The c.1569C>G variant was classified as likely neutral while the c.384G>A remained as a VUS. We have also shown that the polymorphic variant c.59G>A is MMR proficient.\nCONCLUSIONS: Pathogenic PMS2 mutations were detected in 69% of patients harbouring LS associated tumours with loss of PMS2 expression. In all, PMS2 mutations account for 6% of the LS cases identified. The comprehensive functional analysis shown here has been useful in the classification of PMS2 VUS and contributes to refining the role of PMS2 in LS.","variants":[{"Name":"NM_000535.7(PMS2):c.538-3C>G","Chromosome":"7","Start":"5999278","Stop":"5999278","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":474818,"rule_based_match":true,"evidence_text":"c.538-3C>G","llm_judgment":"PRESENT","evidence":"c.538-3C>G","abstract_start":1096,"abstract_end":1106},{"Name":"NM_000535.7(PMS2):c.137G>T (p.Ser46Ile)","Chromosome":"7","Start":"6005918","Stop":"6005918","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":24284,"rule_based_match":true,"evidence_text":"c.137G>T","llm_judgment":"PRESENT","evidence":"c.137G>T","abstract_start":1136,"abstract_end":1144},{"Name":"NM_000535.7(PMS2):c.59G>A (p.Arg20Gln)","Chromosome":"7","Start":"6005996","Stop":"6005996","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":50155,"rule_based_match":true,"evidence_text":"c.59G>A","llm_judgment":"PRESENT","evidence":"c.59G>A","abstract_start":1310,"abstract_end":1317}]}
{"pmid":"22805550","title":"Prevalence of Fabry disease in a predominantly hypertensive population with left ventricular hypertrophy.","abstract":"BACKGROUND: Patients with Fabry disease (FD) develop progressive left ventricular hypertrophy (LVH). In screening studies in patients with LVH, the prevalence of FD ranges from 0 to 12%. This variability is attributable to different factors like diverging inclusion and exclusion criteria, the evaluation of selected populations and suboptimal screening methods. In this study, we aimed to determine the prevalence of FD in an unselected population of everyday clinical practice presenting LVH, defined as a maximal end-diastolic septal or posterior wall thickness ≥ 13 mm, without exclusion of patients with arterial hypertension or valvular pathology, and using optimal screening methods.\nMETHODS: In adult males, a two-tier approach was used; α-Galactosidase A (aGAL A) activity was measured using a dried bloodspot test (DBS) and diagnosis was confirmed by mutation analysis of the GLA gene. In females, mutation analysis was the primary screening tool.\nRESULTS: 362 men and 178 women were screened. Six patients were diagnosed with a genetic sequence alteration of the GLA gene. One man had a novel mutation, GLA p.Ala5Glu (c.44C>A), presenting as classical FD. Another man and three women had the previously described GLA p.Ala143Thr (c.427G>A) mutation, which generally presents as an attenuated phenotype. One woman had a novel sequence alteration c.639+6A>C, which appeared to be a polymorphism. All true Fabry patients had arterial hypertension (AHT), and one had hypertrophic obstructive cardiomyopathy (HOCM).\nCONCLUSIONS: In a group of unselected patients with LVH, we found a prevalence of Fabry disease of 0.9%. AHT or type of hypertrophy should not be an exclusion criterion for screening for FD.","variants":[{"Name":"NM_000169.3(GLA):c.427G>A (p.Ala143Thr)","Chromosome":"X","Start":"101401752","Stop":"101401752","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25787,"rule_based_match":true,"evidence_text":"c.427G>A","llm_judgment":"PRESENT","evidence":"c.427G>A","abstract_start":1241,"abstract_end":1249},{"Name":"NM_000169.3(GLA):c.639+6A>C","Chromosome":"X","Start":"101400660","Stop":"101400660","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":51627,"rule_based_match":true,"evidence_text":"c.639+6A>C","llm_judgment":"PRESENT","evidence":"c.639+6A>C","abstract_start":1356,"abstract_end":1366}]}
{"pmid":"32839936","title":"A Novel CREBBP in-Frame Deletion Variant in a Chinese Girl with Atypical Rubinstein-Taybi Syndrome Phenotypes.","abstract":"Loss-of-function variants in CREBBP or EP300 result in Rubinstein-Taybi syndrome (RSTS). The previously reported cluster of variants in the last part of exon 30 and the beginning of exon 31 of CREBBP, overlapping with the ZNF2 (zinc finger, ZZ-type; residues 1701 to 1744) and ZNF3 (zinc finger, TAZ-type; residues 1764 to 1853) domains, is associated with atypical RSTS. The main features include developmental delay, short stature, microcephaly, distinctive facial features, autistic behavior, feeding difficulties, recurrent upper airway infections, and hearing impairment. Here, we report a 2-year-7-month-old Chinese girl presenting mild cognitive impairments, developmental delay, short stature, recurrent upper airway infections, and facial dysmorphism that resembled the phenotypes of previously reported atypical RSTS patients. The characteristic facial and limb dysmorphism for RSTS was absent in our patient. In addition, our patient exhibited novel phenotypes including attention deficit hyperactivity disorder (ADHD), sleep problem, and abnormal walking posture. Whole-exome sequencing (WES) identified a novel de novo in-frame deletion variant in the beginning of exon 30 of CREBBP (NM_004380:c.4897_4899delTTC, p.Phe1633del) in the HAT domain where no pathogenic variants have been previously reported to be responsible for atypical RSTS. Our case allows us to more accurately define the borders of the CREBBP coding sequence resulting in atypical RSTS, which are extended to the beginning of exon 30 (residue 1633) at the 5' end of CREBBP in the HAT domain, and reveals novel phenotypes observed in our atypical Chinese RSTS patient.","variants":[{"Name":"NM_004380.3(CREBBP):c.4894TTC[1] (p.Phe1633del)","Chromosome":"16","Start":"3731465","Stop":"3731467","ReferenceAlleleVCF":"CGAA","AlternateAlleleVCF":"C","allel_id":512206,"rule_based_match":false,"evidence_text":"c.4897_4899delTTC, p.Phe1633del","llm_judgment":"PRESENT","evidence":"c.4897_4899delTTC, p.Phe1633del","abstract_start":1207,"abstract_end":1238}]}
{"pmid":"33601267","title":"Intronic variant screening with targeted next-generation sequencing reveals first pseudoexon in LDLR in familial hypercholesterolemia.","abstract":"BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is caused by pathogenic variants in LDLR, APOB, or PCSK9 genes (designated FH+). However, a significant number of clinical FH patients do not carry these variants (designated FH-). Here, we investigated whether variants in intronic regions of LDLR attribute to FH by affecting pre-mRNA splicing.\nMETHODS: LDLR introns are partly covered in routine sequencing of clinical FH patients using next-generation sequencing. Deep intronic variants, >20 bp from intron-exon boundary, were considered of interest once (a) present in FH- patients (n = 909) with LDL-C >7 mmol/L (severe FH-) or after in silico analysis in patients with LDL-C >5 mmol/L (moderate FH-) and b) absent in FH + patients (control group). cDNA analysis and co-segregation analysis were performed to assess pathogenicity of the identified variants.\nRESULTS: Three unique variants were present in the severe FH- group. One of these was the previously described likely pathogenic variant c.2140+103G>T. Three additional variants were selected based on in silico analyses in the moderate FH- group. One of these variants, c.2141-218G>A, was found to result in a pseudo-exon inclusion, producing a premature stop codon. This variant co-segregated with the hypercholesterolemic phenotype.\nCONCLUSIONS: Through a screening approach, we identified a deep intronic variant causal for FH. This finding indicates that filtering intronic variants in FH- patients for the absence in FH + patients might enrich for true FH-causing variants and suggests that intronic regions of LDLR need to be considered for sequencing in FH- patients.","variants":[{"Name":"NM_000527.5(LDLR):c.2141-218G>A","Chromosome":"19","Start":"11122956","Stop":"11122956","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3498414,"rule_based_match":true,"evidence_text":"c.2141-218G>A","llm_judgment":"PRESENT","evidence":"c.2141-218G>A","abstract_start":1139,"abstract_end":1152}]}
{"pmid":"21716161","title":"BRAF, p53 and SOX2 in anaplastic thyroid carcinoma: evidence for multistep carcinogenesis.","abstract":"AIMS: The aim of this study was to genotype a series of papillary thyroid carcinomas (PTCs) and anaplastic thyroid carcinomas (ATCs) for BRAF mutation, and to evaluate p53 and SOX2 expression as factors implicated in tumour progression.\nMETHODS: The study included 17 PTCs and 14 ATCs. Analysis of the exon 15 of BRAF was based on direct sequencing. Immunohistochemistry was used to evaluate p53 and SOX2 expression.\nRESULTS: V600E (c.1799T>A) mutation was observed in 53% (9/17) of PTCs. Two cases of ATCs (2/14; 14%), both with PTC component, harboured BRAF mutation: the classical V600E mutation and an undocumented duplication of codon 599 (c.1795_1797dup; p.Thr599dup). These mutations were present in ATC as well as PTC tumour cells. Overexpression of p53 and SOX2 was depicted respectively in 64% (9/14) and 29% (4/14) of ATCs, and absent in PTCs.\nCONCLUSION: We confirm that V600E mutation is a frequent and specific event in PTC. BRAF-mutated ATCs are associated with a PTC component displaying the same mutation. We describe a new mutation of BRAF, T599dup, in a case of ATC with tall cell PTC component. Moreover, progression from PTC to ATC could be favoured by further TP53 mutation and SOX2 expression.","variants":[{"Name":"NM_004333.6(BRAF):c.1794_1796dup (p.Thr599dup)","Chromosome":"7","Start":"140753338","Stop":"140753339","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGTA","allel_id":176758,"rule_based_match":false,"evidence_text":"c.1795_1797dup; p.Thr599dup","llm_judgment":"PRESENT","evidence":"c.1795_1797dup; p.Thr599dup","abstract_start":645,"abstract_end":672}]}
{"pmid":"24853097","title":"Reversible pulmonary arterial hypertension in cobalamin-dependent cobalamin C disease due to a novel mutation in the MMACHC gene.","abstract":"UNLABELLED: Methylmalonic aciduria and homocystinuria, cobalamin C (CblC) disease (OMIM 277400), is the most frequent inborn error of vitamin B12 (cobalamin, Cbl) metabolism and is caused by an inability of the cell to convert Cbl to its active forms (MeCbl and AdoCbl). More than 75 mutations have been identified in the MMACHC gene which is responsible for CblC disease. We present a case with CblC disease and pulmonary arterial hypertension (PAH) as the main symptom. The patient improved dramatically with parenteral hydroxocobalamin treatment. Most cases of CblC disease have a multisystemic disease with failure to thrive, developmental delay, hypotonia, visual impairment, and hematologic manifestations. This patient had isolated pulmonary hypertension and hyperhomocysteinemia which is thought to be an important factor in the pathogenesis of PAH. Genetic analysis identified a novel homozygous mutation (c.484G > T; p.Gly162Trp) in the MMACHC gene.\nCONCLUSION: CblC disease should be considered in the differential diagnosis of pulmonary hypertension.","variants":[{"Name":"NM_015506.3(MMACHC):c.484G>T (p.Gly162Trp)","Chromosome":"1","Start":"45508850","Stop":"45508850","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2795396,"rule_based_match":true,"evidence_text":"c.484G > T; p.Gly162Trp","llm_judgment":"PRESENT","evidence":"c.484G > T; p.Gly162Trp","abstract_start":915,"abstract_end":938}]}
{"pmid":"22305237","title":"Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review.","abstract":"Glycogen storage disease type IV is a rare autosomal recessive disorder of glycogen metabolism caused by mutations in the GBE1 gene that encodes the 1,4-alpha-glucan-branching enzyme 1. Its clinical presentation is variable, with the most common form presenting in early childhood with primary hepatic involvement. Histologic manifestations in glycogen storage disease type IV typically consist of intracytoplasmic non-membrane-bound inclusions containing abnormally branched glycogen (polyglucosan bodies) within hepatocytes and myocytes. We report a female infant with classic hepatic form of glycogen storage disease type IV who demonstrated diffuse reticuloendothelial system involvement with the spleen, bone marrow, and lymph nodes infiltrated by foamy histiocytes with intracytoplasmic polyglucosan deposits. Sequence analysis of the GBE1 gene revealed compound heterozygosity for a previously described frameshift mutation (c.1239delT) and a novel missense mutation (c.1279G>A) that is predicted to alter a conserved glycine residue. GBE enzyme analysis revealed no detectable activity. A review of the literature for glycogen storage disease type IV patients with characterized molecular defects and deficient enzyme activity reveals most GBE1 mutations to be missense mutations clustering in the catalytic enzyme domain. Individuals with the classic hepatic form of glycogen storage disease type IV tend to be compound heterozygotes for null and missense mutations. Although the extensive reticuloendothelial system involvement that was observed in our patient is not typical of glycogen storage disease type IV, it may be associated with severe enzymatic deficiency and a poor outcome.","variants":[{"Name":"NM_000158.4(GBE1):c.1239del (p.Asp413fs)","Chromosome":"3","Start":"81586188","Stop":"81586188","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":443517,"rule_based_match":true,"evidence_text":"c.1239delT","llm_judgment":"PRESENT","evidence":"c.1239delT","abstract_start":932,"abstract_end":942}]}
{"pmid":"24016420","title":"Tyrosinemia type 1: a rare and forgotten cause of reversible hypertrophic cardiomyopathy in infancy.","abstract":"BACKGROUND: Tyrosinemia type 1 (TT1) is an autosomal recessive disorder caused by deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). TT1 usually presents in infancy with features suggestive of liver disease or with sepsis-like symptoms.\nCASE PRESENTATION: We report two Saudi siblings with TT1. Case 1 was a male infant who presented at 2 months old with fever, vomiting and refusal of feeding. Examination revealed a sick-looking infant with signs of severe dehydration and hypovolemic shock. He was jaundiced, and had hepatomegaly and elevated liver enzymes. Echocardiography was performed in light of a lack of response to inotropes, and revealed biventricular and interventricular septal hypertrophies. The ventricular ejection fraction was 65%. Urine organic acid analysis showed elevated succinylacetone, consistent with a diagnosis of TT1. An FAH gene study identified a c.1 A > G homozygous mutation. This patient responded well to intensive cardiorespiratory therapy, tyrosine-free formula, and oral 2-nitro-4- trifluoromethylbenzyl 1, 3 cyclohexanedione (NTBC). Echocardiographic findings reverted to normal after 4 weeks. Case 2 was the younger brother of Case 1, and was born 6 months after his brother had been confirmed with tyrosinemia. Pregnancy and delivery were uneventful. Serum amino acid and organic acid analyses 4 days after birth confirmed tyrosinemia. DNA analysis identified a c.1 A > G homozygous mutation, as in his brother. Echocardiography was normal. Special formula and NTBC were commenced on day 7 of life. The infant remained asymptomatic after 9 months of follow-up.\nCONCLUSIONS: These cases highlight TT1 as a treatable cause of cardiomyopathy in children. It also supports the idea that early diagnosis and treatment may prevent the development of cardiomyopathy associated with tyrosinemia.","variants":[{"Name":"NM_000137.4(FAH):c.1A>G (p.Met1Val)","Chromosome":"15","Start":"80153055","Stop":"80153055","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":360304,"rule_based_match":true,"evidence_text":"c.1 A > G","llm_judgment":"PRESENT","evidence":"c.1 A > G","abstract_start":889,"abstract_end":898}]}
{"pmid":"27038415","title":"Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families.","abstract":"Fryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations in PIGN were identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency <0.001) donor splice site mutation (c.1674+1G>C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation in PIGN (c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative for PIGN mutations. Mutations in PIGN have been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations in PIGN. Whether PIGN affects other syndromic and non-syndromic forms of CDH warrants investigation.","variants":[{"Name":"NM_176787.5(PIGN):c.1674+1G>C","Chromosome":"18","Start":"62106985","Stop":"62106985","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":259233,"rule_based_match":true,"evidence_text":"c.1674+1G>C","llm_judgment":"PRESENT","evidence":"c.1674+1G>C","abstract_start":711,"abstract_end":722},{"Name":"NM_176787.5(PIGN):c.694A>T (p.Lys232Ter)","Chromosome":"18","Start":"62147082","Stop":"62147082","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":259234,"rule_based_match":true,"evidence_text":"c.694A>T (p.Lys232X)","llm_judgment":"PRESENT","evidence":"p.Lys232X","abstract_start":867,"abstract_end":876}]}
{"pmid":"25197397","title":"Synchronous gastric and sebaceous cancers, a rare manifestation of MLH1-related Muir-Torre syndrome.","abstract":"Muir-Torre syndrome (MTS), a rare variant of the hereditary non polyposis colorectal cancer syndrome, is an autosomal dominant genodermatosis characterised by coincidence of sebaceous gland neoplasms (sebaceous adenoma, epithelioma, or carcinoma) and at least one internal malignancy. The underlying cause of MTS is a germline mutation in DNA mismatch repair genes MSH2, MLH1 and MSH6. We report the case of a 52-year-old caucasian woman with the development of metachronous colon cancer at the age of 38 years, uterine cancer at the age of 43 years, and unique occurrence of synchronous gastric and sebaceous carcinomas related to germline point mutation c. 2194A>T in the last exon of MLH1 gene, resulting in truncated protein in C-terminal region p. Lys732X due to premature stop codon. This mutation, not previously reported in MTS, disrupts the function of MutL complexes presumably by preventing the interaction with PMS1/PMS2 and impairing the endonuclease active site. This case points out the importance of sebaceous neoplasia, especially sebaceous adenocarcinoma, as cutaneous markers of MTS for timely implementation of cancer screening programs.","variants":[{"Name":"NM_000249.4(MLH1):c.2194A>T (p.Lys732Ter)","Chromosome":"3","Start":"37050576","Stop":"37050576","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":95561,"rule_based_match":true,"evidence_text":"c. 2194A>T","llm_judgment":"PRESENT","evidence":"c. 2194A>T","abstract_start":656,"abstract_end":666}]}
{"pmid":"23649928","title":"Functional analysis of a de novo ACTB mutation in a patient with atypical Baraitser-Winter syndrome.","abstract":"Exome sequence analysis can be instrumental in identifying the genetic etiology behind atypical disease. We report a patient presenting with microcephaly, dysmorphic features, and intellectual disability with a tentative diagnosis of Dubowitz syndrome. Exome analysis was performed on the patient and both parents. A de novo missense variant was identified in ACTB, c.349G>A, p.E117K. Recent work in Baraitser-Winter syndrome has identified ACTB and ACTG1 mutations in a cohort of individuals, and we rediagnosed the patient with atypical Baraitser-Winter syndrome. We performed functional characterization of the variant actin and show that it alters cell adhesion and polymer formation supporting its role in disease. We present the clinical findings in the patient, comparison of this patient to other patients with ACTB/ACTG1 mutations, and results from actin functional studies that demonstrate novel functional attributes of this mutant protein.","variants":[{"Name":"NM_001101.5(ACTB):c.349G>A (p.Glu117Lys)","Chromosome":"7","Start":"5529175","Stop":"5529175","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76956,"rule_based_match":true,"evidence_text":"c.349G>A, p.E117K","llm_judgment":"PRESENT","evidence":"c.349G>A, p.E117K","abstract_start":366,"abstract_end":383}]}
{"pmid":"23992033","title":"Broadening the phenotype of LRP2 mutations: a new mutation in LRP2 causes a predominantly ocular phenotype suggestive of Stickler syndrome.","abstract":"Two siblings, from a consanguineous Iraqi family, were investigated to identify the underlying genetic cause of their high myopia, esotropia, vitreous changes and cataract. Subsequent investigation identified low molecular weight proteinuria as part of their syndrome. Exome sequencing of one of the probands revealed a new non-synonymous variant in the LRP2 gene. Sanger sequencing confirmed the mutation and segregation in the family. No mutation was identified in COL9A1/2, COL11A1/2, or COL2A1 genes. The variant (c.11483A>G; p.Asp3828Gly) is predicted to be damaging and is conserved among vertebrate species. Mutations in LRP2 have been shown to cause the Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome, a syndrome associated with facial dysmorphism, ocular anomalies, sensorineural hearing loss, low molecular weight proteinuria, and diaphragmatic hernia and absent corpus callosum, although there is variability in the expression of some features. This family shows a milder phenotype with a predominant eye phenotype similar to the Stickler syndrome and only a few features of the DBS, including microglobulinuria. The presence of microglobulinuria was only detected after molecular results were known. In conclusion, with the identification of a new mutation in LRP2 associated with a predominant eye phenotype similar to the Stickler syndrome, we have broadened the phenotypic spectrum of LRP2 mutations.","variants":[{"Name":"NM_004525.3(LRP2):c.11483A>G (p.Asp3828Gly)","Chromosome":"2","Start":"169169716","Stop":"169169716","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3525977,"rule_based_match":true,"evidence_text":"c.11483A>G; p.Asp3828Gly","llm_judgment":"PRESENT","evidence":"c.11483A>G; p.Asp3828Gly","abstract_start":518,"abstract_end":542}]}
{"pmid":"26101329","title":"Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.","abstract":"BACKGROUND: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus.\nMETHODS: Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu).\nRESULTS: The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site.\nCONCLUSIONS: Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life.","variants":[{"Name":"NM_000207.3(INS):c.187+241G>A","Chromosome":"11","Start":"2160544","Stop":"2160544","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":263780,"rule_based_match":true,"evidence_text":"c.187+241G>A","llm_judgment":"PRESENT","evidence":"c.187+241G>A","abstract_start":308,"abstract_end":320}]}
{"pmid":"23973728","title":"Molecular defects identified by whole exome sequencing in a child with Fanconi anemia.","abstract":"Fanconi anemia is a rare genetic disease characterized by bone marrow failure, multiple congenital malformations, and an increased susceptibility to malignancy. At least 15 genes have been identified that are involved in the pathogenesis of Fanconi anemia. However, it is still a challenge to assign the complementation group and to characterize the molecular defects in patients with Fanconi anemia. In the current study, whole exome sequencing was used to identify the affected gene(s) in a boy with Fanconi anemia. A recurring, non-synonymous mutation was found (c.3971C>T, p.P1324L) as well as a novel frameshift mutation (c.989_995del, p.H330LfsX2) in FANCA gene. Our results indicate that whole exome sequencing may be useful in clinical settings for rapid identification of disease-causing mutations in rare genetic disorders such as Fanconi anemia.","variants":[{"Name":"NM_000135.4(FANCA):c.3971C>T (p.Pro1324Leu)","Chromosome":"16","Start":"89739517","Stop":"89739517","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":422132,"rule_based_match":true,"evidence_text":"c.3971C>T, p.P1324L","llm_judgment":"PRESENT","evidence":"c.3971C>T, p.P1324L","abstract_start":566,"abstract_end":585},{"Name":"NM_000135.4(FANCA):c.989_995del (p.His330fs)","Chromosome":"16","Start":"89795917","Stop":"89795923","ReferenceAlleleVCF":"AGGGCTGT","AlternateAlleleVCF":"A","allel_id":547949,"rule_based_match":true,"evidence_text":"c.989_995del","llm_judgment":"PRESENT","evidence":"c.989_995del","abstract_start":627,"abstract_end":639}]}
{"pmid":"11901181","title":"Deficiency of UDP-galactose:N-acetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId.","abstract":"Deficiency of the Golgi enzyme UDP-Gal:N-acetylglucosamine beta-1,4-galactosyltransferase I (beta4GalT I) (E.C.2.4.1.38) causes a new congenital disorder of glycosylation (CDG), designated type IId (CDG-IId), a severe neurologic disease characterized by a hydrocephalus, myopathy, and blood-clotting defects. Analysis of oligosaccharides from serum transferrin by HPLC, mass spectrometry, and lectin binding revealed the loss of sialic acid and galactose residues. In skin fibroblasts and leukocytes, galactosyltransferase activity was reduced to 5% that of controls. In fibroblasts, a truncated polypeptide was detected that was about 12 kDa smaller in size than wild-type beta4GalT I and that failed to localize to the Golgi apparatus. Sequencing of the beta4GalT I cDNA and gene revealed an insertion of a single nucleotide (1031-1032insC) leading to premature translation stop and loss of the C-terminal 50 amino acids of the enzyme. The patient was homozygous and his parents heterozygous for this mutation. Expression of a corresponding mutant cDNA in COS-7 cells led to the synthesis of a truncated, inactive polypeptide, which localized to the endoplasmic reticulum.","variants":[{"Name":"NM_001497.4(B4GALT1):c.1031dup (p.Arg345fs)","Chromosome":"9","Start":"33113806","Stop":"33113807","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":31268,"rule_based_match":false,"evidence_text":"1031-1032insC","llm_judgment":"PRESENT","evidence":"1031-1032insC","abstract_start":828,"abstract_end":841}]}
{"pmid":"31617442","title":"Heterozygous Missense Pathogenic Variants Within the Second Spectrin Repeat of SPTBN2 Lead to Infantile-Onset Cerebellar Ataxia.","abstract":"The term <i>spinocerebellar ataxia</i> encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of ataxia: autosomal dominant cerebellar ataxias (ADCA, also known as spinocerebellar ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset ataxia, and autosomal recessive spinocerebellar ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar ataxia. Certain ataxia genes, including <i>SPTBN2</i> which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to <i>SPTBN2</i>: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar ataxia, similar to SCAR14. Here, we report a novel <i>de novo</i> heterozygous pathogenic missense variant (c.1310G>A) in <i>SPTBN2</i> in a child with infantile-onset cerebellar ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.","variants":[{"Name":"NM_006946.4(SPTBN2):c.1438C>T (p.Arg480Trp)","Chromosome":"11","Start":"66707731","Stop":"66707731","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":75333,"rule_based_match":true,"evidence_text":"c.1438C>T, p.R480 W","llm_judgment":"PRESENT","evidence":"c.1438C>T, p.R480 W","abstract_start":1193,"abstract_end":1212}]}
{"pmid":"28677912","title":"Analysis of KERA in four families with cornea plana identifies two novel mutations.","abstract":"PURPOSE: To identify the molecular genetic cause in four families of various ethnic backgrounds with cornea plana.\nMETHODS: Detailed ophthalmological examination and direct sequencing of the KERA coding region in five patients of Czech and Turkish origin and their available family members.\nRESULTS: Compound heterozygosity for a novel missense mutation c.209C>T; p.(Pro70Leu) and a novel splice site mutation c.887-1G>A in KERA were detected in two affected siblings of Czech origin. In silico analysis supported the pathogenicity of both variants. The second proband of Czech origin harboured c.835C>T; p.(Arg279*) in a homozygous state. Homozygous mutations c.740A>G; p.(Asn247Ser) and c.674C>T; p.(Ile225Thr) were identified in the Turkish probands, both born out of consanguineous marriages. Observed ocular phenotypes were typical of cornea plana with the exception of one Czech patient who also had marked thinning and protrusion in the superior part of the left cornea (mean keratometry 47.2 D). No corneal endothelial cell pathology was found by specular microscopy in seven eyes, in three eyes visualization of the posterior corneal surface was unsuccessful.\nCONCLUSION: KERA mutation c.740A>G has been identified to date in three different populations, which makes it the most frequently occurring mutation in patients with cornea plana. Marked corneal thinning and ectasia are a very rare finding in this disorder and longitudinal follow-up needs to be performed to determine its potential progressive nature.","variants":[{"Name":"NM_007035.4(KERA):c.209C>T (p.Pro70Leu)","Chromosome":"12","Start":"91056073","Stop":"91056073","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2898917,"rule_based_match":true,"evidence_text":"c.209C>T; p.(Pro70Leu)","llm_judgment":"PRESENT","evidence":"c.209C>T; p.(Pro70Leu)","abstract_start":354,"abstract_end":376},{"Name":"NM_007035.4(KERA):c.740A>G (p.Asn247Ser)","Chromosome":"12","Start":"91055542","Stop":"91055542","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":21558,"rule_based_match":true,"evidence_text":"c.740A>G; p.(Asn247Ser)","llm_judgment":"PRESENT","evidence":"c.740A>G; p.(Asn247Ser)","abstract_start":661,"abstract_end":684}]}
{"pmid":"29620206","title":"Genetic analysis of a congenital split‑hand/split‑foot malformation 4 pedigree.","abstract":"In the present study whole-exome sequencing using the Complete Genomics platform was employed to scan a proband from a split‑hand/split‑foot malformation (SHFM) 4 family. The missense mutation c.728G>A (p.Arg243Gln) in the TP63 gene was revealed to be associated with SHFM. Sanger sequencing confirmed the sequences of the proband and his father. The father was diagnosed with SHFM and harbored a CGG‑to‑CAG mutation in exon 5, which produced a R243Q substitution in the zinc binding site and dimerization site of TP63. The R243Q mutation was predicted to be pathogenic by PolyPhen‑2. The proband, who was diagnosed with four digit SHFM, exhibited a more severe phenotype. X‑ray analysis returned the following results: Absence of third phalange bilaterally and third metacarpus of the left hand; absence of the second toes bilaterally and partial third toes; and partial fusion of the second, third and metatarsal bones of the right side with deformity of the second metatarsal of the right side. Osteochondroma was present in the fourth proximal radial metacarpal of the left hand and the basal and proximal parts of the second metatarsal of the right side. The proband's father had five digits in both feet. These results indicate that the R243Q mutation produces a novel phenotype named SHFM4. The present study revealed that the R243Q mutation in the TP63 gene produced a novel phenotype named SHFM4, thereby demonstrating the mutational overlap between ectrodactyly‑ectodermal dysplasia‑cleft syndrome and SHFM4.","variants":[{"Name":"NM_003722.5(TP63):c.728G>A (p.Arg243Gln)","Chromosome":"3","Start":"189864380","Stop":"189864380","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21567,"rule_based_match":true,"evidence_text":"c.728G>A (p.Arg243Gln)","llm_judgment":"PRESENT","evidence":"c.728G>A (p.Arg243Gln)","abstract_start":193,"abstract_end":215}]}
{"pmid":"28777121","title":"RAF1 variants causing biventricular hypertrophic cardiomyopathy in two preterm infants: further phenotypic delineation and review of literature.","abstract":"Noonan syndrome (NS) is an autosomal dominant disorder characterized by distinctive facial features, short neck, short stature, congenital heart defects, pectus deformities, and variable developmental delays. NS is genetically heterogeneous as pathogenic variants in several genes involved in the Ras/mitogen-activated protein kinase pathway have been associated with a NS phenotype. Overall, 50% of patients harbor pathogenic variants in PTPN11, whereas 3-17% of patients have variants in RAF1. We present two premature neonates with progressive biventricular hypertrophy found to have RAF1 variants in the CR2 domain. Molecular testing in patient 1 revealed a missense variant of a highly conserved residue c.782 C>G (p.P261R). This variant has been reported once with fatal outcome. Patient 2 also had a missense variant in a highly conserved neighboring residue c.770 C>T (p.S257L). This variant has been previously reported, most recently associated with the development of pulmonary arterial hypertension. Both our patients had prenatal findings of polyhydramnios, short long bones, hydrops fetalis, and cardiac anomalies with progressive biventricular hypertrophic cardiomyopathy. Both patients had a lethal outcome. Our findings further support the pathogenicity and lethality of p.P261R, and the need to monitor for pulmonary arterial hypertension in p.S257L. In addition, the second patient was presented with progressive hydrocephalus due to aqueductal stenosis. This could be related to the NS phenotype. More cases with this association are needed to confirm this finding.","variants":[{"Name":"NM_002880.4(RAF1):c.782C>G (p.Pro261Arg)","Chromosome":"3","Start":"12604188","Stop":"12604188","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":49076,"rule_based_match":true,"evidence_text":"c.782 C>G (p.P261R)","llm_judgment":"PRESENT","evidence":"c.782 C>G (p.P261R)","abstract_start":709,"abstract_end":728},{"Name":"NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)","Chromosome":"3","Start":"12604200","Stop":"12604200","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28996,"rule_based_match":true,"evidence_text":"c.770 C>T (p.S257L)","llm_judgment":"PRESENT","evidence":"c.770 C>T (p.S257L)","abstract_start":866,"abstract_end":885}]}
{"pmid":"18499083","title":"Transcription factor FIGLA is mutated in patients with premature ovarian failure.","abstract":"Premature Ovarian Failure (POF) is a genetically heterogenous disorder that leads to hypergonadotropic ovarian failure and infertility. We screened 100 Chinese women with POF for mutations in the oocyte-specific gene FIGLA and identified three variants in four women: missense mutation c.11C --> A (p.A4E) was found in two women; deletion c. 15-36 del (p.G6fsX66), resulting in a frameshift that leads to haploinsufficiency, was found in one woman; and deletion c.419-421 delACA (p.140 delN) was found in one. Functional analyses by the yeast two-hybrid assay demonstrated that the p.140 delN mutation disrupted FIGLA binding to the TCF3 helix-loop-helix (HLH) domain. Our findings show that a subset of Chinese women with sporadic, premature ovarian failure harbor mutations in FIGLA.","variants":[{"Name":"NM_001004311.3(FIGLA):c.15_36del (p.Gly6fs)","Chromosome":"2","Start":"70790603","Stop":"70790624","ReferenceAlleleVCF":"CGGCGCGGGGATCTAGGACGCCG","AlternateAlleleVCF":"C","allel_id":17176,"rule_based_match":false,"evidence_text":"c. 15-36 del (p.G6fsX66)","llm_judgment":"PRESENT","evidence":"c. 15-36 del (p.G6fsX66)","abstract_start":339,"abstract_end":363}]}
{"pmid":"33203140","title":"New Cav1.2 Channelopathy with High-Functioning Autism, Affective Disorder, Severe Dental Enamel Defects, a Short QT Interval, and a Novel","abstract":"Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the <i>CACNA1C</i> gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy.","variants":[{"Name":"NM_000719.7(CACNA1C):c.2399A>C (p.Lys800Thr)","Chromosome":"12","Start":"2585435","Stop":"2585435","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1841558,"rule_based_match":true,"evidence_text":"NM_000719.6: c.2399A > C; p.Lys800Thr","llm_judgment":"PRESENT","evidence":"NM_000719.6: c.2399A > C; p.Lys800Thr","abstract_start":537,"abstract_end":574}]}
{"pmid":"27028212","title":"Analysing the mutational status of adenomatous polyposis coli (APC) gene in breast cancer.","abstract":"BACKGROUND: Breast cancer is a heterogeneous disorder for which the underlying genetic basis remains unclear. We developed a method for identifying adenomatous polyposis coli (APC) mutations and we evaluated the possible association between APC genetic variants and breast cancer susceptibility.\nMETHODS: Genomic DNA was extracted from tumor and matched peripheral blood samples collected from 89 breast cancer patients and from peripheral blood samples collected from 50 controls. All samples were tested for mutations in exons 1-14 and the mutation cluster region of exon 15 by HRM analysis. All mutations were confirmed by direct DNA sequencing.\nRESULTS: We identified a new single nucleotide polymorphism (SNP), c.465A>G (K155K), in exon 4 and seven known SNPs: c.573T>C (Y191Y) in exon 5, c.1005A>G (L335L) in exon 9, c.1458T>C (Y486Y) and c.1488A>T (T496T) in exon 11, c.1635G>A (A545A) in exon 13, and c.4479G>A (T1493T) and c.5465T>A (V1822D) in exon 15. The following alterations were found in 2, 1, 2, and 1 patients, respectively: c.465A>G, c.573T>C, c.1005A>G, and c.1488A>T. There was no observed association between breast cancer risk and any of these APC SNPs.\nCONCLUSIONS: APC mutations occur at a low frequency in Taiwanese breast cancer cases. HRM analysis is a powerful method for the detection of APC mutations in breast.","variants":[{"Name":"NM_000038.6(APC):c.1005A>G (p.Leu335=)","Chromosome":"5","Start":"112819037","Stop":"112819037","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":98250,"rule_based_match":true,"evidence_text":"c.1005A>G (L335L)","llm_judgment":"PRESENT","evidence":"c.1005A>G (L335L)","abstract_start":794,"abstract_end":811}]}
{"pmid":"21620353","title":"Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.","abstract":"Intellectual disability inherited in an autosomal-recessive fashion represents an important fraction of severe cognitive-dysfunction disorders. Yet, the extreme heterogeneity of these conditions markedly hampers gene identification. Here, we report on eight affected individuals who were from three consanguineous families and presented with severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation. Using a combination of autozygosity mapping and either Sanger sequencing of candidate genes or next-generation exome sequencing, we identified one mutation in each of three genes encoding adaptor protein complex 4 (AP4) subunits: a nonsense mutation in AP4S1 (NM_007077.3: c.124C>T, p.Arg42(∗)), a frameshift mutation in AP4B1 (NM_006594.2: c.487_488insTAT, p.Glu163_Ser739delinsVal), and a splice mutation in AP4E1 (NM_007347.3: c.542+1_542+4delGTAA, r.421_542del, p.Glu181Glyfs(∗)20). Adaptor protein complexes (AP1-4) are ubiquitously expressed, evolutionarily conserved heterotetrameric complexes that mediate different types of vesicle formation and the selection of cargo molecules for inclusion into these vesicles. Interestingly, two mutations affecting AP4M1 and AP4E1 have recently been found to cause cerebral palsy associated with severe intellectual disability. Combined with previous observations, these results support the hypothesis that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning and demonstrate the existence of a clinically recognizable syndrome due to deficiency of the AP4 complex.","variants":[{"Name":"NM_001128126.3(AP4S1):c.124C>T (p.Arg42Ter)","Chromosome":"14","Start":"31066320","Stop":"31066320","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39615,"rule_based_match":true,"evidence_text":"NM_007077.3: c.124C>T, p.Arg42(∗)","llm_judgment":"PRESENT","evidence":"NM_007077.3: c.124C>T, p.Arg42(∗)","abstract_start":859,"abstract_end":892}]}
{"pmid":"29510612","title":"PTEN Mutation Identified in Patient Diagnosed with Simultaneous Multiple Cancers.","abstract":"PTEN hamartoma tumor syndrome is a spectrum of disorders characterized by unique phenotypic features including multiple hamartomas caused by mutations of the tumor suppressor gene PTEN. Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are representative diseases, and both have several common clinical features and differences. Because PTEN mutations are associated with an increased risk of malignancy including breast, thyroid, endometrial, and renal cancers, cancer surveillance is an important element of disease management. We report a germline mutation of the PTEN (c.723dupT, exon 7) identified in a young woman with a simultaneous occurrence of breast cancer, dermatofibrosarcoma protuberans, and follicular neoplasm. This case suggests that it is critical for clinicians to recognize the phenotypic features associated with these syndromes to accurately diagnose them and provide preventive care.","variants":[{"Name":"NM_000314.8(PTEN):c.723dup (p.Glu242Ter)","Chromosome":"10","Start":"87957938","Stop":"87957939","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":397704,"rule_based_match":true,"evidence_text":"c.723dupT","llm_judgment":"PRESENT","evidence":"c.723dupT","abstract_start":577,"abstract_end":586}]}
{"pmid":"28074523","title":"Familial gastrointestinal stromal tumors, lentigines, and café-au-lait macules associated with germline c-kit mutation treated with imatinib.","abstract":"BACKGROUND: Familial lentiginosis syndromes are characterized by a wide array of manifestations resulting from activation of molecular pathways which control growth, proliferation, and differentiation of a broad range of tissues. Familial gastrointestinal stromal tumors (GISTs) are often accompanied by additional features like hyperpigmentation, mastocytosis, and dysphagia. They have been described with mutations in c-kit (most commonly), platelet-derived growth factor receptor A, neurofibromatosis-1, and succinate dehydrogenase genes.\nMATERIALS AND METHODS: We report on molecular characterization and tumor histopathology of two siblings in whom lentigines and café-au-lait macules were present along with multifocal GIST. Immuhistochemical analysis of CD34 and CD117 was performed on GIST biopsy samples from both siblings, while c-kit mutational analysis was done by PCR and direct sequencing on DNA from peripheral blood leukocytes of all family members and from paraffin-embedded gastric biopsy specimens of affected siblings.\nRESULTS: Histopathology revealed positive expression of CD117 and CD34. Mutational analysis showed the germline c.1676T>C mutation in c-kit exon 11, (p.(Val559Ala)), in the peripheral blood of both siblings and a second exon 11 mutation, c.1669T>A (p.(Trp557Arg)) in the tumor biopsy of one of them. Initiation of imatinib treatment resulted in striking resolution of their hyperpigmentation and a stable gastrointestinal disease in one of them.\nCONCLUSIONS: A c-kit mutational test in familial GISTs is indicated before initiation of imatinib therapy, as it can help predict tumor response to treatment.","variants":[{"Name":"NM_000222.3(KIT):c.1676T>C (p.Val559Ala)","Chromosome":"4","Start":"54727444","Stop":"54727444","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":28904,"rule_based_match":true,"evidence_text":"c.1676T>C","llm_judgment":"PRESENT","evidence":"c.1676T>C","abstract_start":1151,"abstract_end":1160}]}
{"pmid":"38337354","title":"Natural History of Dilated Cardiomyopathy Due to","abstract":"(1) <b>Introduction</b>: Dilated cardiomyopathy (DCM) mainly affects young individuals and is the main indication of heart transplantation. The variant <i>c.77T>C (p.Val26Ala)</i> of the gene coding for emerin <i>(EMD)</i> in chromosome <i>Xq28</i> has been catalogued as a pathogenic variant for the development of DCM, exhibiting an X-linked inheritance pattern. (2) <b>Methods</b>: A retrospective study was conducted covering the period 2015-2023 in patients with DCM of genetic origin. The primary endpoint was patient age at onset of the first composite major cardiac event, in the form of a first episode of heart failure, malignant ventricular arrhythmia, or end-stage heart failure, according to the presence of truncating variant in titin gene <i>(TTNtv)</i> versus the <i>p.Val26Ala</i> mutation in the <i>EMD</i> protein. (3) <b>Results</b>: A total of 31 and 22 patients were included in the <i>EMD</i> group and <i>TTNtv</i> group, respectively. The primary endpoint was significantly higher in the <i>EMD</i> group, with a hazard ratio of 4.16 (95% confidence interval: 1.83-9.46; <i>p</i> = 0.001). At 55 years of age, all the patients in the <i>EMD</i> group had already presented heart failure, nine presented malignant ventricular arrhythmia (29%), and 13 required heart transplantation (42%). (4) <b>Conclusions</b>: DCM secondary to the <i>c.77T>C (p.Val26Ala)</i> mutation in the <i>EMD</i> gene is associated to an increased risk of major cardiac events compared to patients with DCM due to <i>TTNtv</i>, with a large proportion of transplanted patients in the fifth decade of life.","variants":[{"Name":"NM_000117.3(EMD):c.77T>C (p.Val26Ala)","Chromosome":"X","Start":"154379561","Stop":"154379561","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":178291,"rule_based_match":true,"evidence_text":"c.77T>C (p.Val26Ala)","llm_judgment":"PRESENT","evidence":"c.77T>C (p.Val26Ala)","abstract_start":155,"abstract_end":175}]}
{"pmid":"33321114","title":"A novel mutation in intron 11 donor splice site, responsible of a rare genotype in thyroglobulin gene by altering the pre-mRNA splincing process. Cell expression and bioinformatic analysis.","abstract":"Thyroglobulin (TG) is a homodimeric glycoprotein synthesized by the thyroid gland. To date, two hundred twenty-seven variations of the TG gene have been identified in humans. Thyroid dyshormonogenesis due to TG gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. The purpose of the present study was to identify and characterize new variants in the TG gene. We report an Argentine patient with congenital hypothyroidism, enlarged thyroid gland and low levels of serum TG. Sequencing of DNA, expression of chimeric minigenes as well as bioinformatics analysis were performed. DNA sequencing identified the presence of compound heterozygous mutations in the TG gene: the maternal mutation consists of a c.3001+5G > A, whereas the paternal mutation consists of p.Arg296*. Minigen analysis of the variant c.3001+5A performed in HeLa, CV1 and Hek293T cell lines, showed a total lack of transcript expression. So, in order to validate that the loss of expression was caused by such variation, site-directed mutagenesis was performed on the mutated clone, which previously had a pSPL3 vector change, to give rise to a wild-type clone c.3001+5G, endorsing that the mutation c.3001+5G > A is the cause of the total lack of expression. In conclusion, we demonstrate that the c.3001+5G > A mutation causes a rare genotype, altering the splicing of the pre-mRNA. This work contributes to elucidating the molecular bases of TG defects associated with congenital hypothyroidism and expands our knowledge in relation to the pathologic roles of the position 5 in the donor splice site.","variants":[{"Name":"NM_003235.5(TG):c.3001+5G>A","Chromosome":"8","Start":"132893934","Stop":"132893934","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2947334,"rule_based_match":true,"evidence_text":"c.3001+5G>A","llm_judgment":"PRESENT","evidence":"c.3001+5G > A","abstract_start":810,"abstract_end":823}]}
{"pmid":"36011335","title":"Identification of New Copy Number Variation and the Evaluation of a CNV Detection Tool for NGS Panel Data in Polish Familial Hypercholesterolemia Patients.","abstract":"Familial hypercholesterolemia (FH) is an inherited, autosomal dominant metabolic disorder mostly associated with disease-causing variant in LDLR, APOB or PCSK9. Although the dominant changes are small-scale missense, frameshift and splicing variants, approximately 10% of molecularly defined FH cases are due to copy number variations (CNVs). The first-line strategy is to identify possible pathogenic SNVs (single nucleotide variants) using multiple PCR, Sanger sequencing, or with more comprehensive approaches, such as NGS (next-generation sequencing), WES (whole-exome sequencing) or WGS (whole-genome sequencing). The gold standard for CNV detection in genetic diagnostics are MLPA (multiplex ligation-dependent amplification) or aCGH (array-based comparative genome hybridization). However, faster and simpler analyses are needed. Therefore, it has been proposed that NGS data can be searched to analyze CNV variants. The aim of the study was to identify novel CNV changes in FH patients without detected pathogenic SNVs using targeted sequencing and evaluation of CNV calling tool (DECoN) working on gene panel NGS data; the study also assesses its suitability as a screening step in genetic diagnostics. A group of 136 adult and child patients were recruited for the present study. The inclusion criteria comprised at least “possible FH” according to the Simon Broome diagnostic criteria in children and the DLCN (Dutch Lipid Clinical Network) criteria in adults. NGS analysis revealed potentially pathogenic SNVs in 57 patients. Thirty selected patients without a positive finding from NGS were subjected to MLPA analysis; ten of these revealed possibly pathogenic CNVs. Nine patients were found to harbor exons 4−8 duplication, two harbored exons 6−8 deletion and one demonstrated exon 9−10 deletion in LDLR. To test the DECoN program, the whole study group was referred for bioinformatic analysis. The DECoN program detected duplication of exons 4−8 in the LDLR gene in two patients, whose genetic analysis was stopped after the NGS step. The integration of the two methods proved to be particularly valuable in a five-year-old girl presenting with extreme hypercholesterolemia, with both a pathogenic missense variant (c.1747C>T) and exons 9−10 deletion in LDLR. This is the first report of a heterozygous deletion of exons 9 and 10 co-occurring with SNV. Our results suggest that the NGS-based approach has the potential to identify large-scale variation in the LDLR gene and could be further applied to extend CNV screening in other FH-related genes. Nevertheless, the outcomes from the bioinformatic approach still need to be confirmed by MLPA; hence, the latter remains the reference method for assessing CNV in FH patients.","variants":[{"Name":"NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)","Chromosome":"19","Start":"11116900","Stop":"11116900","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":198015,"rule_based_match":true,"evidence_text":"c.1747C>T","llm_judgment":"PRESENT","evidence":"c.1747C>T","abstract_start":2231,"abstract_end":2240}]}
{"pmid":"31270756","title":"Novel mutations in the GJC2 gene associated with Pelizaeus-Merzbacher-like disease.","abstract":"Inherited white matter disorders of the central nervous system frequently are degenerative and progressive clinical entities. They are classified into myelin disorders, including hypomyelination, dysmyelination, demyelination, and myelin vacuolization, but also astrocytopathies, leuko-axonopathies, microgliopathies, and leuko-vasculopathies. Hypomyelinating leukodystrophy is the main feature of Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD1). PMD- and PMLD1-affected patients display comparable neurological symptoms, including psychomotor developmental delay, spasticity, nystagmus, impairment of cognitive skills, sensorineural hearing loss, and different ophthalmological disabilities. While clinical features overlap, PMD and PMLD1 can be distinguished on the molecular genetic level. PMD is caused by mutations in the gene encoding for the proteolipid protein 1 (PLP1), whereas PMLD1 is associated with mutations in the gene encoding for the gap junction protein gamma 2 (GJC2). Here we present novel compound-heterozygous mutations in the GJC2 gene identified in two, unrelated infantile patients affected with PMLD1. The heterozygous frameshift mutations c.392dupC, p.H132Afs*6 and c.989delC, p.P330Rfs*141 were found in the first patient. The heterozygous nonsense variant c.291C>G, p.Y97*, as well as the heterozygous missense variant c.716T>C, p.V239A were detected in the second patient. All four variants were predicted to be damaging for structure and/or function of the GJC2 protein. Combinations of these genetic variants likely are pathogenic and resulted in the PMLD1-phenotype in the investigated children. In conclusion, our clinical and molecular findings confirmed the genotype-phenotype relationship between mutations in the GJC2 and PMLD1. The novel mutations of GJC2 described herein will help to further understand the pathogenic mechanism underlying PMLD1.","variants":[{"Name":"NM_020435.4(GJC2):c.716T>C (p.Val239Ala)","Chromosome":"1","Start":"228158474","Stop":"228158474","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1707061,"rule_based_match":true,"evidence_text":"c.716T>C, p.V239A","llm_judgment":"PRESENT","evidence":"c.716T>C, p.V239A","abstract_start":1381,"abstract_end":1398}]}
{"pmid":"24633926","title":"Identification of a novel 5' alternative CFTR mRNA isoform in a patient with nasal polyposis and CFTR mutations.","abstract":"Cystic fibrosis may be revealed by nasal polyposis (NP) starting early in life. We performed cystic fibrosis transmembrane conductance regulator (CFTR) DNA and mRNA analyses in the family of a 12-year-old boy presenting with NP and a normal sweat test. Routine DNA analysis only showed the heterozygous c.2551C>T (p.Arg851*) mutation in the child and the father. mRNA analysis showed partial exon skipping due to c.2551C>T and a significant increase in total CFTR mRNA in the patient and the mother, which was attributable to the heterozygous c. -2954G>A variant in the distant promoter region, as demonstrated by in vitro luciferase assays. The 5' rapid amplification of cDNA ends analysis showed the presence of a novel transcript, where the canonical exon 1 was replaced by an alternative exon called 1a-Long. This case report could represent the first description of a CFTR-related disorder associated with the presence of a 5' alternative, probably nonfunctional transcript, similar to those of fetal origin.","variants":[{"Name":"NM_000492.4(CFTR):c.2551C>T (p.Arg851Ter)","Chromosome":"7","Start":"117594990","Stop":"117594990","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22180,"rule_based_match":true,"evidence_text":"c.2551C>T (p.Arg851*)","llm_judgment":"PRESENT","evidence":"c.2551C>T (p.Arg851*)","abstract_start":303,"abstract_end":324}]}
{"pmid":"30881523","title":"A Novel Heterozygous Mutation of the","abstract":"Mutations in the <i>COL4A3</i> gene are frequently reported to be associated with various types of hereditary nephropathy. <i>COL4A3</i> encodes the <i>α</i>3 chain of type IV collagen, which is the main structural protein in the basement membrane. Mutations in this gene are always related to kidney performance, and deafness and ocular lesion have also been reported. In this study, using next-generation sequencing, we investigated the DNA of a family visiting a clinic for hearing loss. A new missense mutation was found in <i>COL4A3</i> of 5 patients, c.3227C>T (p.P1076L). Based on these results, we predict that the mutation is pathogenic and leads to abnormal collagen IV. Here, we report for the first time on this autosomal dominant syndrome, characterized by hearing loss and eye abnormalities, but without renal damage, in all carriers. Since the oldest patient in the trial was less than 50 years old, however, we recommend that renal examination be reviewed regularly. Our results reveal expansion in the mutation spectrum of the <i>COL4A3</i> gene and phenotypic spectrum of collagen IV disease. Our study suggests that next-generation sequencing is an economical and effective method and may help in the accurate diagnosis and treatment of these patients.","variants":[{"Name":"NM_000091.5(COL4A3):c.3227C>T (p.Pro1076Leu)","Chromosome":"2","Start":"227293207","Stop":"227293207","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1302128,"rule_based_match":true,"evidence_text":"c.3227C>T (p.P1076L)","llm_judgment":"PRESENT","evidence":"c.3227C>T (p.P1076L)","abstract_start":557,"abstract_end":577}]}
{"pmid":"35370956","title":"A MEN1 Patient Presenting With Multiple Parathyroid Adenomas and Transient Hypercortisolism: A Case Report and Literature Review.","abstract":"Background: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine syndrome caused by mutations in MEN1 tumor suppressor gene.\nCase Presentation: A 53-year-old Chinese female was admitted to Division of Endocrinology, Tongji Hospital, for hypercalcemic crisis. Increased level of parathyroid hormone (PTH) was confirmed by laboratory tests, and imaging examination showed multiple parathyroid adenomas. Based on gene analysis, the patient was diagnosed as MEN1 associated hyperparathyroidism (HPT) by gene analysis with c.1378C>T (p.Arg460Ter) mutation in MEN1 gene. Her condition was complicated by transient hypercortisolism, mammary mass and uterine leiomyoma. After subtotal parathyroidectomy, PTH and serum calcium levels returned to normal.\nConclusion: HPT with multiple parathyroid adenomas is an indication of MEN1 gene mutation. Serum cortisol and its circadian rhythm can be abnormal in the presence of hypercalcemia and high PTH. These parameters can return to normal after parathyroidectomy.","variants":[{"Name":"NM_001370259.2(MEN1):c.1378C>T (p.Arg460Ter)","Chromosome":"11","Start":"64804789","Stop":"64804789","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31731,"rule_based_match":true,"evidence_text":"c.1378C>T (p.Arg460Ter)","llm_judgment":"PRESENT","evidence":"c.1378C>T (p.Arg460Ter)","abstract_start":534,"abstract_end":557}]}
{"pmid":"25729976","title":"Novel NPHS1 splice site mutations in a Chinese child with congenital nephrotic syndrome.","abstract":"Congenital nephrotic syndrome (CNS) is defined as heavy proteinuria or nephrotic syndrome occurring before 3 months of age. It is characterized by early onset and progresses to end-stage renal disease. Recently, several genes associated with CNS have been identified, including NPHS1 and NPHS2. Mutations in the NPHS1 gene have been identified in patients with CNS in Finland with relatively high frequency. Thus far, only a few case reports about CNS have described an NPHS1 mutation in China. In this study, mutational analyses of NPHS1 and NPHS2 were performed in a Chinese child with CNS. Mutations were analyzed in all exons and exon/intron boundaries of NPHS1 and NPHS2 in the patient and his parents as well as in 50 unrelated controls using polymerase chain reaction and direct sequencing techniques. No mutations were detected in NPHS2. A novel splice site mutation (IVS11+1G>A) within intron 11 and a missense mutation within exon 8 (c.928G>A) in the NPHS1 gene were detected in the child. The child's mother had normal urinalysis and a c.928G>A (D310N) heterozygous mutation, and his father had normal urinalysis and IVS11+1G>A. These were not identified in the 50 unrelated controls. The novel splice site mutation of IVS11+1G>A and a missense mutation at c.928G>A in NPHS1 were found to cause CNS in this Chinese child.","variants":[{"Name":"NM_004646.4(NPHS1):c.928G>A (p.Asp310Asn)","Chromosome":"19","Start":"35849060","Stop":"35849060","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":548766,"rule_based_match":true,"evidence_text":"c.928G>A (D310N)","llm_judgment":"PRESENT","evidence":"c.928G>A (D310N)","abstract_start":1047,"abstract_end":1063}]}
{"pmid":"31953237","title":"A novel SPECC1L mutation causing Teebi hypertelorism syndrome: Expanding phenotypic and genetic spectrum.","abstract":"Only eleven SPECC1L mutations have been reported worldwide which were associated with autosomal dominant oblique facial clefts, Opitz G/BBB Syndrome and Teebi hypertelorism syndrome. In this study, we reported the first Chinese patient with Teebi hypertelorism syndrome. Utilizing whole exome sequencing and Sanger sequencing, we identified a de novo missense mutation NM_015330.3: c.1249A > C, p.(Thr417Pro) in SPECC1L gene. With common manifestations in Teebi hypertelorism syndrome such as special facial appearance, umbilical malformations and congenital heart defects, the patient also had unusual symptoms including recurrent infections, febrile seizures and widely opened anterior fontanelle. Furthermore, all the recorded SPECC1L mutations were analyzed by in silico analysis. Coiled-coil domain 2 was the most frequently mutated domain and positions e and g might be more important than other positions. This paper expanded the phenotypic spectrum of Teebi hypertelorism syndrome and elaborated molecular characteristics of SPECC1L mutations.","variants":[{"Name":"NM_015330.6(SPECC1L):c.1249A>C (p.Thr417Pro)","Chromosome":"22","Start":"24322229","Stop":"24322229","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":590719,"rule_based_match":true,"evidence_text":"NM_015330.3: c.1249A > C, p.(Thr417Pro)","llm_judgment":"PRESENT","evidence":"NM_015330.3: c.1249A > C, p.(Thr417Pro)","abstract_start":369,"abstract_end":408}]}
{"pmid":"28322941","title":"Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP.","abstract":"The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 μg sulfasalazine, 250 μg rosuvastatin, 300 μg glibenclamide, 1200 μg celiprolol, and 600 μg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions.","variants":[{"Name":"NM_004827.3(ABCG2):c.421C>A (p.Gln141Lys)","Chromosome":"4","Start":"88131171","Stop":"88131171","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39346,"rule_based_match":true,"evidence_text":"ABCG2 c.421C>A","llm_judgment":"PRESENT","evidence":"ABCG2 c.421C>A","abstract_start":411,"abstract_end":425}]}
{"pmid":"29713611","title":"Chylomicron Retention Disease: a Description of a New Mutation in a Very Rare Disease.","abstract":"Chylomicron retention disease, also known as Anderson's disease, is a rare hereditary hypocholesterolemic disorder, recessive inherited, characterized by nonspecific symptoms as abdominal distension, steatorrhea, and vomiting associated with failure to thrive. We describe a patient with failure to thrive, chronic diarrhea and steatorrhea who the diagnosis of chylomicron retention disease was established after several months of disease progression. The genetic study confirmed a homozygosity mutation in <i>SAR1B</i> gene, identifying a mutation never previous described [c.83_84delTG(p.Leu28Argfs*7)]. With this case report the authors aim to highlight for this very rare cause of failure to thrive and for the importance of an attempting diagnosis, in order to start adequate management with low fat diet supplemented with fat-soluble vitamins, reverting the state of malnutrition and avoiding possible irreversible and desvantating complications.","variants":[{"Name":"NM_016103.4(SAR1B):c.83_84del (p.Leu28fs)","Chromosome":"5","Start":"134621027","Stop":"134621028","ReferenceAlleleVCF":"CCA","AlternateAlleleVCF":"C","allel_id":1199932,"rule_based_match":true,"evidence_text":"c.83_84delTG(p.Leu28Argfs*7)","llm_judgment":"PRESENT","evidence":"c.83_84delTG(p.Leu28Argfs*7)","abstract_start":575,"abstract_end":603}]}
{"pmid":"16476820","title":"A missense mutation in the coiled-coil domain of the KIF5A gene and late-onset hereditary spastic paraplegia.","abstract":"BACKGROUND: To our knowledge, up to now, only 2 mutations in the KIF5A gene, a member of the kinesin superfamily, have been identified as the molecular cause of early-onset autosomal dominant hereditary spastic paraparesis (ADHSP).\nOBJECTIVE: To assess the genetic defect in a family with late-onset ADHSP.\nPATIENTS AND METHODS: Only the proband agreed to undergo complete neurological testing and mutational analysis. The proband was screened for mutations in the spastin, atlastin, NIPA1, and KIF5A genes, either by denaturing high-performance liquid chromatography or sequence analysis.\nRESULTS: The history of the family was consistent with ADHSP characterized by late onset of the disease. Mutational analysis results were negative for the spastin, atlastin, and NIPA1 genes but identified a missense mutation (c.1082C>T) in the coiled-coil coding region of the KIF5A gene.\nCONCLUSIONS: This finding enlarges the phenotypic spectrum of ADHSP linked to KIF5A and enhances the role of that gene in the epidemiology of this disease. We propose that the KIF5A gene should be routinely analyzed in patients with hereditary spastic paraplegia negative for spastin and atlastin mutations.","variants":[{"Name":"NM_004984.4(KIF5A):c.1082C>T (p.Ala361Val)","Chromosome":"12","Start":"57569648","Stop":"57569648","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21848,"rule_based_match":true,"evidence_text":"c.1082C>T","llm_judgment":"PRESENT","evidence":"c.1082C>T","abstract_start":816,"abstract_end":825}]}
{"pmid":"22038540","title":"Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri.","abstract":"Schwannomatosis is a rare hereditary cancer syndrome in which patients develop multiple non-vestibular schwannomas. The chromatin remodelling gene SMARCB1 (also known as INI1, hSNF5, and BAF47) has been identified as a schwannomatosis predisposing gene, being involved in a subset of sporadic and familial cases. Recent studies have shown that SMARCB1 may also be involved in the development of multiple meningiomas. Previously, we demonstrated that the SMARCB1 exon 2 missense mutation c.143 C > T segregates with the presence of meningiomas in five members of a large family with multiple meningiomas and schwannomas. We extended our genetic analyses by screening 44 additional at-risk family members and identified 13 new carriers. Eleven of these were subjected to magnetic resonance imaging (MRI) of brain and spine. In addition, we analyzed four meningiomas and two schwannomas from family members for the presence of schwannomatosis-specific changes. We found in each tumor retention of the SMARCB1 exon 2 mutation, acquisition of an independent neurofibromatosis type 2 (NF2) gene mutation, and loss of heterozygosity at SMARCB1 and NF2 by loss of the wild-type copy of both genes. The MRI scans revealed one or more falx meningiomas in seven of 11 (64%) newly identified SMARCB1 mutation carriers. We conclude that the SMARCB1 exon 2 missense mutation in this family predisposes to the development of meningiomas as well as schwannomas, occurring via the same genetic pathways, and that this mutation preferentially induces cranial meningiomas located at the falx cerebri.","variants":[{"Name":"NM_003073.5(SMARCB1):c.143C>T (p.Pro48Leu)","Chromosome":"22","Start":"23791805","Stop":"23791805","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39158,"rule_based_match":true,"evidence_text":"c.143 C > T","llm_judgment":"PRESENT","evidence":"c.143 C > T","abstract_start":487,"abstract_end":498}]}
{"pmid":"21922471","title":"Cardioembolic stroke prompting diagnosis of LMNA-associated Emery-Dreifuss muscular dystrophy.","abstract":"The diagnosis of Emery-Dreifuss muscular dystrophy (EDMD) is suggested by the combination of musculoskeletal weakness and wasting, joint contractures, and cardiac disease. Herein we report a patient in whom an ischemic stroke prompted the diagnosis of EDMD. A mutation in the LMNA gene (c.266G>T, p.Arg89Leu) was found. It had been reported previously exclusively with isolated cardiac disease, thus reinforcing the high phenotypic heterogeneity of laminopathies.","variants":[{"Name":"NM_170707.4(LMNA):c.266G>T (p.Arg89Leu)","Chromosome":"1","Start":"156115184","Stop":"156115184","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":77781,"rule_based_match":true,"evidence_text":"c.266G>T, p.Arg89Leu","llm_judgment":"PRESENT","evidence":"c.266G>T, p.Arg89Leu","abstract_start":287,"abstract_end":307}]}
{"pmid":"34915818","title":"A homozygous in-frame duplication within the LRRCT consensus sequence of","abstract":"Ciliopathies are a group of genetic dystrophies causing syndromic and non-syndromic retinal degeneration. We identified <i>CFAP410</i> as the causative gene in a patient with childhood-onset retinal dystrophy without other systemic symptoms at the age of 20. This 20-year-old man presented with cone-rod dystrophy and <i>CFAP410</i> homozygous in-frame duplication variants (c.340_351dup). His clinical features included early subnormal vision, posterior pole staphyloma, and short stature. Unlike the previously reported features of retinal ciliopathy, our patient showed no obvious retinal pigmentation and only a slight hyper-autofluorescent parafoveal ring at the 16-year follow up. This case report aims to characterize the clinical features in a patient with novel, homozygous and likely pathogenic in-frame duplication variants in the <i>CFAP410</i> gene. Ultimately, this report will help contribute to the understanding of <i>CFAP410</i>-associated ciliopathies.","variants":[{"Name":"NM_004928.3(CFAP410):c.340_351dup (p.Thr114_Arg117dup)","Chromosome":"21","Start":"44333054","Stop":"44333055","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGCGCGGCAGGGT","allel_id":1459884,"rule_based_match":true,"evidence_text":"c.340_351dup","llm_judgment":"PRESENT","evidence":"c.340_351dup","abstract_start":375,"abstract_end":387}]}
{"pmid":"28315472","title":"Complex postaxial polydactyly types A and B with camptodactyly, hypoplastic third toe, zygodactyly and other digit anomalies caused by a novel GLI3 mutation.","abstract":"Polydactyly is a phenotypically and genetically highly heterogeneous limb malformation with preaxial and postaxial subtypes and subtypes A and B. Most polydactyly entities are associated with GLI3 mutation. We report on 10 affected individuals from a large Pakistani kindred initially evaluated as a possible new condition. The phenotype is postaxial polydactyly types A and B associated with zygodactyly, postaxial webbing of toes and additional features not previously reported for isolated polydactyly such as camptodactyly, hypoplasia of third toe, and wide space between hallux and second toe. Hypothesizing that the disorder could have resulted from a mutation in a novel gene responsible for polydactyly, we launched a genetic investigation. By linkage mapping and exome sequencing in the most severe case, we identified novel heterozygous frameshift mutation NM_000168.5 (GLI3): c.3635delG (p.(Gly1212Alafs*18)) but did not detect any other possibly deleterious mutation that could explain the unusual features of camptodactyly, hypoplasia of third toe and wide space between first and second toes. Our findings further expand the phenotypic variability of GLI3 polydactyly. We also present a review of GLI3-associated isolated limb anomalies, which indicates that GLI3 mutation leads primarily to two well-established polydactyly types: postaxial types A and B and crossed polydactyly type I. In addition, a variety of other minor digit anomalies generally accompany polydactyly, and there is no straightforward genotype-polydactyly phenotype correlation.","variants":[{"Name":"NM_000168.6(GLI3):c.3635del (p.Gly1212fs)","Chromosome":"7","Start":"41965438","Stop":"41965438","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":380284,"rule_based_match":true,"evidence_text":"NM_000168.5 (GLI3): c.3635delG (p.(Gly1212Alafs*18))","llm_judgment":"PRESENT","evidence":"NM_000168.5 (GLI3): c.3635delG (p.(Gly1212Alafs*18))","abstract_start":867,"abstract_end":919}]}
{"pmid":"33129265","title":"The first case report of Kyphoscoliotic Ehlers-Danlos syndrome of chinese origin with a novel PLOD1 gene mutation.","abstract":"BACKGROUND: Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by progressive kyphoscoliosis, congenital muscular hypotonia, marked joint hypermobility, and severe skin hyperextensibility and fragility. Deficiency of lysyl hydroxylase 1 (LH1) due to mutations of PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) gene has been identified as the pathogenic cause of kEDS (kEDS-PLOD1). Up to now, kEDS-PLOD1 has not been reported among Chinese population.\nCASE PRESENTATION: A 17-year-old Chinese male patient presenting with hypotonia, joint hypermobility and scoliosis was referred to our hospital. After birth, he was found to have severe hypotonia leading to delayed motor development. Subsequently, joint hypermobility, kyphoscoliosis and amblyopia were found. Inguinal hernia was found at age 5 years and closed by surgery. At the same time, he presented with hyperextensible and bruisable velvety skin with widened atrophic scarring after minor trauma. Dislocation of elbow joint was noted at age of 6 years. Orthopedic surgery for correction of kyphoscoliosis was performed at age 10 years. His family history was unremarkable. Physical examination revealed elevated blood pressure. Slight facial dysmorphologies including high palate, epicanthal folds, and down-slanting palpebral fissures were found. He also had blue sclerae with normal hearing. X-rays revealed severe degree of scoliosis and osteopenia. The Echocardiography findings were normal. Laboratory examination revealed a slightly elevated bone turnover. Based on the clinical manifestations presented by our patient, kEDS was suspected. Genetic analysis revealed a novel homozygous missense mutation of PLOD1 (c.1697 G > A, p.C566Y), confirming the diagnosis of kEDS-PLOD1. The patient was treated with alfacalcidol and nifedipine. Improved physical strength and normal blood pressure were reported after 12-month follow-up.\nCONCLUSIONS: This is the first case of kEDS-PLOD1 of Chinese origin. We identified one novel mutation of PLOD1, extending the mutation spectrum of PLOD1. Diagnosis of kEDS-PLOD1 should be considered in patients with congenital hypotonia, progressive kyphoscoliosis, joint hypermobility, and skin hyperextensibility and confirmed by mutation analysis of PLOD1.","variants":[{"Name":"NM_000302.4(PLOD1):c.1697G>A (p.Cys566Tyr)","Chromosome":"1","Start":"11967033","Stop":"11967033","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3762223,"rule_based_match":true,"evidence_text":"c.1697 G > A, p.C566Y","llm_judgment":"PRESENT","evidence":"c.1697 G > A, p.C566Y","abstract_start":1754,"abstract_end":1775}]}
{"pmid":"26029792","title":"Elevated Hb A₂ Levels in a Patient with a Compound Heterozygosity for the (β⁺) -31 (A > G) and (β⁰) Codon 17 (A > T) Mutations Together with a Single α-Globin Gene.","abstract":"We report the molecular and hematological feature of a Thai woman who had clinical diagnosis of β-thalassemia intermedia (β-TI). Hemoglobin (Hb) high performance liquid chromatography (HPLC) analysis identified Hb A (64.4%), Hb F (12.3%) and Hb A2/E (15.9%) with small peaks of Hb Bart's (γ4) and Hb H (β4). She was initially diagnosed as EA Bart's disease, which occurs from combination of Hb H disease and Hb E (HBB: c.79G > A) trait. However, the Hb analysis using capillary electrophoresis (CE) demonstrated no Hb E, 68.5% Hb A, 15.5% Hb F and 16.0% Hb A2. DNA analysis showed a compound heterozygosity for (β(+)) -31 (A > G) (HBB: c.-81A > G) and (β(0)) codon 17 (A > T) (HBB: c.52A > T) mutations and deletional Hb H (- -(SEA)/-α(3.7)). Thus, she was finally diagnosed with a combination of Hb H disease and compound heterozygosity of β(+)/β(0)-thalassemia (β(+)/β(0)-thal). The β-globin mutations could affect not only hematological parameters but also elevate the Hb A2 levels. These effects could not be ameliorated by the coinheritance of Hb H disease. Therefore, a better understanding of the effects of this combination on hematological analysis data will be useful for providing accurate diagnosis, genetic counseling, prevention and control programs of β-thalassemia major (β-TM).","variants":[{"Name":"NM_000518.5(HBB):c.-81A>G","Chromosome":"11","Start":"5227102","Stop":"5227102","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":30505,"rule_based_match":true,"evidence_text":"HBB: c.-81A>G","llm_judgment":"PRESENT","evidence":"HBB: c.-81A > G","abstract_start":631,"abstract_end":646}]}
{"pmid":"23401410","title":"Five novel mutations of GALNS in Korean patients with mucopolysaccharidosis IVA.","abstract":"Mucopolysaccharidosis IVA (MPS IVA; OMIM #253000) is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), a lysosomal enzyme involved in the catabolism of keratan and chondroitin sulfate. In this study, we examined biochemical and genetic data from 6 Korean patients presenting with classic MPS IVA by measuring GALNS activity in peripheral blood leukocytes and skin fibroblasts. We initially identified Korean patients with MPS IVA by clinical, biochemical, and genetic analyses. We performed PCR-direct sequencing to identify molecular defects of the GALNS gene in patients and assessed the mutational statuses of family members as well as 50 healthy unrelated subjects. In silico analyses were performed to check for novel mutations. The mean age of the six female patients was 8.0 ± 5.2 years (range: 2-17 years), and were all found to have severe reductions of GALNS enzyme. A total of 12 mutant alleles were identified, corresponding to 7 different mutations. Five novel mutations were c.218A>G (p.Y73C), c.451C>A (p.P151T), c.725C>G (p.S242C), c.752G>A (p.R251Q), and c.1000C>T (p.Q334X). Two other mutations were c.1156C>T (p.R386C) and c.1243-1G>A. Two mutations, c.451C>A and c.1000C>T, accounted for 58% of all mutations in this sample.","variants":[{"Name":"NM_000512.5(GALNS):c.1243-1G>A","Chromosome":"16","Start":"88822711","Stop":"88822711","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1036160,"rule_based_match":true,"evidence_text":"c.1243-1G>A","llm_judgment":"PRESENT","evidence":"c.1243-1G>A","abstract_start":1171,"abstract_end":1182},{"Name":"NM_000512.5(GALNS):c.218A>G (p.Tyr73Cys)","Chromosome":"16","Start":"88842732","Stop":"88842732","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":99080,"rule_based_match":true,"evidence_text":"c.218A>G (p.Y73C)","llm_judgment":"PRESENT","evidence":"c.218A>G (p.Y73C)","abstract_start":1018,"abstract_end":1035},{"Name":"NM_000512.5(GALNS):c.752G>A (p.Arg251Gln)","Chromosome":"16","Start":"88835731","Stop":"88835731","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1036272,"rule_based_match":true,"evidence_text":"c.752G>A (p.R251Q)","llm_judgment":"PRESENT","evidence":"c.752G>A (p.R251Q)","abstract_start":1077,"abstract_end":1095},{"Name":"NM_000512.5(GALNS):c.725C>G (p.Ser242Cys)","Chromosome":"16","Start":"88835758","Stop":"88835758","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1036274,"rule_based_match":true,"evidence_text":"c.725C>G (p.S242C)","llm_judgment":"PRESENT","evidence":"c.725C>G (p.S242C)","abstract_start":1057,"abstract_end":1075},{"Name":"NM_000512.5(GALNS):c.451C>A (p.Pro151Thr)","Chromosome":"16","Start":"88837737","Stop":"88837737","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":326808,"rule_based_match":true,"evidence_text":"c.451C>A (p.P151T)","llm_judgment":"PRESENT","evidence":"c.451C>A (p.P151T)","abstract_start":1037,"abstract_end":1055},{"Name":"NM_000512.5(GALNS):c.1156C>T (p.Arg386Cys)","Chromosome":"16","Start":"88824853","Stop":"88824853","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15739,"rule_based_match":true,"evidence_text":"c.1156C>T (p.R386C)","llm_judgment":"PRESENT","evidence":"c.1156C>T (p.R386C)","abstract_start":1147,"abstract_end":1166},{"Name":"NM_000512.5(GALNS):c.1000C>T (p.Gln334Ter)","Chromosome":"16","Start":"88832000","Stop":"88832000","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":611356,"rule_based_match":true,"evidence_text":"c.1000C>T (p.Q334X)","llm_judgment":"PRESENT","evidence":"c.1000C>T (p.Q334X)","abstract_start":1101,"abstract_end":1120}]}
{"pmid":"35592512","title":"Inhibition of NR5A1 Phosphorylation Alleviates a Transcriptional Suppression Defect Caused by a Novel","abstract":"Context: Mutations in the <i>NR0B1</i> gene, also well-known as the <i>DAX1</i> gene, are known to cause congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism. The abnormal NR0B1 protein fails to suppress the transcription of promoters of steroidogenic enzymes, which are also targets of NR5A1 protein, also well-known as Ad4BP/SF-1 protein. Since NR5A1 and NR0B1 have antagonistic effects on steroidogenesis, the loss of function due to <i>NR0B1</i> mutations may be compensated by inducing loss of function of NR5A1 protein.\nPatient: A middle-aged man was diagnosed with congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism and genetic analysis revealed him to have a novel <i>NR0B1</i> mutation, c.1222C>T(p.Gln408Ter).\nMethods: NR0B1 activity was evaluated in CLK1/4 inhibitor-treated 293T cells via immunoblotting and luciferase assays of the STAR promoter.\nResults: TG003 treatment suppressed NR5A1 protein function to compensate for the mutant NR0B1 showing inhibited suppression of transcription. Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor.\nConclusion: The specific reduction of NR5A1 phosphorylation by a CLK1/4 inhibitor may alleviate developmental defects in patients with NR0B1 mutations.","variants":[{"Name":"NM_000475.5(NR0B1):c.1222C>T (p.Gln408Ter)","Chromosome":"X","Start":"30304770","Stop":"30304770","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3730717,"rule_based_match":true,"evidence_text":"c.1222C>T(p.Gln408Ter)","llm_judgment":"PRESENT","evidence":"c.1222C>T(p.Gln408Ter)","abstract_start":744,"abstract_end":766}]}
{"pmid":"32619718","title":"Generation of urine-derived iPS cell line via a non-integrative method from a Barth syndrome patient with TAZ gene mutation.","abstract":"Human urine cells from a 6-year-old male X-linked Barth syndrome patient harboring a TAZ frameshift (c.517delG, Xq28) were reprogrammed into the induced pluripotent stem cell (iPSC) line WMUi002-A using non-integration CytoTune®-iPS 2.0 Sendai Virus Reprogramming kit, including four well-known Yamanaka factors SOX2, OCT4, KLF4, and c-MYC. The established patient-derived iPSC expressed endogenous pluripotent markers, had the potential to differentiate into all of the three germ layers, and displayed a normal karyotype.","variants":[{"Name":"NM_000116.5(TAFAZZIN):c.517del (p.Asp173fs)","Chromosome":"X","Start":"154419596","Stop":"154419596","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":1699012,"rule_based_match":true,"evidence_text":"c.517del","llm_judgment":"PRESENT","evidence":"c.517del","abstract_start":101,"abstract_end":109}]}
{"pmid":"30335141","title":"A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation.","abstract":"We report two unrelated families with multigenerational nonsyndromic intellectual disability (ID) segregating with a recurrent de novo missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7). SLC9A7 is located on human X chromosome at Xp11.3 and has not yet been associated with a human phenotype. The gene is widely transcribed, but especially abundant in brain, skeletal muscle and various secretory tissues. Within cells, SLC9A7 resides in the Golgi apparatus, with prominent enrichment in the trans-Golgi network (TGN) and post-Golgi vesicles. In transfected Chinese hamster ovary AP-1 cells, the Leu515Phe mutant protein was correctly targeted to the TGN/post-Golgi vesicles, but its N-linked oligosaccharide maturation as well as that of a co-transfected secretory membrane glycoprotein, vesicular stomatitis virus G (VSVG) glycoprotein, was reduced compared to cells co-expressing SLC9A7 wild-type and VSVG. This correlated with alkalinization of the TGN/post-Golgi compartments, suggestive of a gain-of-function. Membrane trafficking of glycosylation-deficient Leu515Phe and co-transfected VSVG to the cell surface, however, was relatively unaffected. Mass spectrometry analysis of patient sera also revealed an abnormal N-glycosylation profile for transferrin, a clinical diagnostic marker for congenital disorders of glycosylation. These data implicate a crucial role for SLC9A7 in the regulation of TGN/post-Golgi pH homeostasis and glycosylation of exported cargo, which may underlie the cellular pathophysiology and neurodevelopmental deficits associated with this particular nonsyndromic form of X-linked ID.","variants":[{"Name":"NM_001257291.2(SLC9A7):c.1543C>T (p.Leu515Phe)","Chromosome":"X","Start":"46643309","Stop":"46643309","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":539431,"rule_based_match":true,"evidence_text":"c.1543C>T:p.Leu515Phe","llm_judgment":"PRESENT","evidence":"c.1543C>T:p.Leu515Phe","abstract_start":153,"abstract_end":174}]}
{"pmid":"21162090","title":"A novel nonsense mutation in the MPL gene in congenital amegakaryocytic thrombocytopenia.","abstract":"Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive disorder characterized by thrombocytopenia from failure of megakaryopoiesis. CAMT is one of the bone marrow failure syndromes, and the disease progression may involve other lineages leading to pancytopenia. The genetic background of CAMT is mutations in the MPL gene encoding the thrombopoietin receptor. Here, we describe a Korean male with CAMT. Molecular genetic analyses by direct sequencing revealed that he was compound heterozygous for two nonsense mutations in MPL, Tyr63X (c.189C>A), and Arg357X (c.1069C>T), the latter being a novel mutation.","variants":[{"Name":"NM_005373.3(MPL):c.189C>A (p.Tyr63Ter)","Chromosome":"1","Start":"43338208","Stop":"43338208","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":906002,"rule_based_match":true,"evidence_text":"c.189C>A","llm_judgment":"PRESENT","evidence":"c.189C>A","abstract_start":563,"abstract_end":571},{"Name":"NM_005373.3(MPL):c.1069C>T (p.Arg357Ter)","Chromosome":"1","Start":"43346533","Stop":"43346533","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":627884,"rule_based_match":true,"evidence_text":"c.1069C>T","llm_judgment":"PRESENT","evidence":"c.1069C>T","abstract_start":587,"abstract_end":596}]}
{"pmid":"23562982","title":"Genetic analysis of auditory neuropathy spectrum disorder in the Korean population.","abstract":"Auditory neuropathy spectrum disorder (ANSD) is caused by dys-synchronous auditory neural response as a result of impairment of the functions of the auditory nerve or inner hair cells, or synapses between inner hair cells and the auditory nerve. To identify a causative gene causing ANSD in the Korean population, we conducted gene screening of the OTOF, DIAPH3, and PJVK genes in 19 unrelated Korean patients with ANSD. A novel nonsense mutation (p.Y1064X) and a known pathogenic mutation (p.R1939Q) of the OTOF gene were identified in a patient as compound heterozygote. Pedigree analysis for these mutations showed co-segregation of mutation genotype and the disease in the family, and it supported that the p.Y1064X might be a novel genetic cause of autosomal recessive ANSD. A novel missense variant p.K1017R (c.3050A>G) in the DIAPH3 gene was also identified in the heterozygous state. In contrast, no mutation was detected in the PJVK gene. These results indicate that no major causative gene has been reported to date in the Korean population and that pathogenic mutations in undiscovered candidate genes may have an effect on ANSD.","variants":[{"Name":"NM_001042517.2(DIAPH3):c.3050A>G (p.Lys1017Arg)","Chromosome":"13","Start":"59810901","Stop":"59810901","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3853713,"rule_based_match":true,"evidence_text":"c.3050A>G","llm_judgment":"PRESENT","evidence":"c.3050A>G","abstract_start":815,"abstract_end":824}]}
{"pmid":"32886433","title":"First report of a Mexican family with mutation in the CDH1 gene.","abstract":"BACKGROUND: Germline mutations in E-cadherin (CDH1) gene are associated with autosomal-dominantly inherited cancer syndrome characterized by diffuse gastric cancer, lobular breast cancer, and in some families, cleft lip/palate. However, there may be generations in which these neoplasms do not occur at all in a family and later on, one or another carcinoma arises, which makes it difficult for physicians to think about hereditary origin.\nMETHODS: We report the first Mexican family with CDH1 mutation (variant c.377del).\nRESULTS: An asymptomatic young woman underwent a search for mutations in susceptibility genes for breast cancer due to the history of this neoplasm in her mother and maternal aunt. A CDH1 mutation was detected. After an endoscopy, a diffuse gastric carcinoma was found. Later on, three generations of this family were studied. The findings are presented.\nCONCLUSION: Medical communities should be aware of the contribution of this gene in the development of hereditary diffuse gastric carcinoma (HDGC) and breast cancer.","variants":[{"Name":"NM_004360.5(CDH1):c.377del (p.Pro126fs)","Chromosome":"16","Start":"68801878","Stop":"68801878","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":401241,"rule_based_match":true,"evidence_text":"variant c.377del","llm_judgment":"PRESENT","evidence":"variant c.377del","abstract_start":504,"abstract_end":520}]}
{"pmid":"21190393","title":"Senataxin mutations and amyotrophic lateral sclerosis.","abstract":"We studied three patients with mutations in the senataxin gene (SETX). One had juvenile onset of ALS. The second case resembled hereditary motor neuropathy. The third patient had an overlap syndrome of ataxia-tremor and motor neuron disease, phenotypes previously associated with SETX mutations. Our patients were all apparently sporadic, with no other affected relative. Two relatives of patient no. 2 carried the SETX c.4660T > G transversion but did not manifest motor neuron disease, abnormal eye movements, ataxia, or tremor suggesting that genetic or environmental modifiers may influence expression of this SETX polymorphism. Relatives of patients 1 and 3 were not available for examination or SETX mutation screening. Mutations causing ALS4 may be more frequent and heterogeneous than expected. Screening for SETX mutations should be considered in patients with apparently sporadic juvenile-onset ALS, hereditary motor neuropathy, and overlap syndromes with ataxia and motor neuron disease.","variants":[{"Name":"NM_015046.7(SETX):c.4660T>G (p.Cys1554Gly)","Chromosome":"9","Start":"132326938","Stop":"132326938","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":253360,"rule_based_match":true,"evidence_text":"c.4660T > G","llm_judgment":"PRESENT","evidence":"c.4660T > G","abstract_start":420,"abstract_end":431}]}
{"pmid":"24722252","title":"PRKAR1B mutation associated with a new neurodegenerative disorder with unique pathology.","abstract":"Pathological accumulation of intermediate filaments can be observed in neurodegenerative disorders, such as Alzheimer's disease, frontotemporal dementia and Parkinson's disease, and is also characteristic of neuronal intermediate filament inclusion disease. Intermediate filaments type IV include three neurofilament proteins (light, medium and heavy molecular weight neurofilament subunits) and α-internexin. The phosphorylation of intermediate filament proteins contributes to axonal growth, and is regulated by protein kinase A. Here we describe a family with a novel late-onset neurodegenerative disorder presenting with dementia and/or parkinsonism in 12 affected individuals. The disorder is characterized by a unique neuropathological phenotype displaying abundant neuronal inclusions by haematoxylin and eosin staining throughout the brain with immunoreactivity for intermediate filaments. Combining linkage analysis, exome sequencing and proteomics analysis, we identified a heterozygous c.149T>G (p.Leu50Arg) missense mutation in the gene encoding the protein kinase A type I-beta regulatory subunit (PRKAR1B). The pathogenicity of the mutation is supported by segregation in the family, absence in variant databases, and the specific accumulation of PRKAR1B in the inclusions in our cases associated with a specific biochemical pattern of PRKAR1B. Screening of PRKAR1B in 138 patients with Parkinson's disease and 56 patients with frontotemporal dementia did not identify additional novel pathogenic mutations. Our findings link a pathogenic PRKAR1B mutation to a novel hereditary neurodegenerative disorder and suggest an altered protein kinase A function through a reduced binding of the regulatory subunit to the A-kinase anchoring protein and the catalytic subunit of protein kinase A, which might result in subcellular dislocalization of the catalytic subunit and hyperphosphorylation of intermediate filaments.","variants":[{"Name":"NM_001164760.2(PRKAR1B):c.149T>G (p.Leu50Arg)","Chromosome":"7","Start":"711357","Stop":"711357","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":362178,"rule_based_match":true,"evidence_text":"c.149T>G (p.Leu50Arg)","llm_judgment":"PRESENT","evidence":"c.149T>G (p.Leu50Arg)","abstract_start":997,"abstract_end":1018}]}
{"pmid":"33407268","title":"Infantile onset Sandhoff disease: clinical manifestation and a novel common mutation in Thai patients.","abstract":"BACKGROUND: Sandhoff disease (SD) is an autosomal recessive lysosomal storage disorder, resulting in accumulation of GM2 ganglioside, particular in neuronal cells. The disorder is caused by deficiency of β-hexosaminidase B (HEX-B), due to pathogenic variant of human HEXB gene.\nMETHOD: This study describes clinical features, biochemical, and genetic defects among Thai patients with infantile SD during 2008-2019.\nRESULTS: Five unrelated Thai patients presenting with developmental regression, axial hypotonia, seizures, exaggerated startle response to noise, and macular cherry red spot were confirmed to have infantile SD based on deficient HEX enzyme activities and biallelic variants of the HEXB gene. In addition, an uncommon presenting feature, cardiac defect, was observed in one patient. All the patients died in their early childhood. Plasma total HEX and HEX-B activities were severely deficient. Sequencing analysis of HEXB gene identified two variants including c.1652G>A (p.Cys551Tyr) and a novel variant of c.761T>C (p.Leu254Ser), in 90 and 10% of the mutant alleles found, respectively. The results from in silico analysis using multiple bioinformatics tools were in agreement that the p.Cys551Tyr and the p.Leu254Ser are likely pathogenic variants. Molecular modelling suggested that the Cys551Tyr disrupt disulfide bond, leading to protein destabilization while the Leu254Ser resulted in change of secondary structure from helix to coil and disturbing conformation of the active site of the enzyme. Genome-wide SNP array analysis showed no significant relatedness between the five affected individuals. These two variants were not present in control individuals. The prevalence of infantile SD in Thai population is estimated 1 in 1,458,521 and carrier frequency at 1 in 604.\nCONCLUSION: The study suggests that SD likely represents the most common subtype of rare infantile GM2 gangliosidosis identified among Thai patients. We firstly described a potential common variant in HEXB in Thai patients with infantile onset SD. The data can aid a rapid molecular confirmation of infantile SD starting with the hotspot variant and the use of expanded carrier testing.","variants":[{"Name":"NM_000521.4(HEXB):c.761T>C (p.Leu254Ser)","Chromosome":"5","Start":"74705310","Stop":"74705310","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":789251,"rule_based_match":true,"evidence_text":"c.761T>C (p.Leu254Ser)","llm_judgment":"PRESENT","evidence":"c.761T>C (p.Leu254Ser)","abstract_start":1022,"abstract_end":1044},{"Name":"NM_000521.4(HEXB):c.1652G>A (p.Cys551Tyr)","Chromosome":"5","Start":"74721156","Stop":"74721156","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":177100,"rule_based_match":true,"evidence_text":"c.1652G>A (p.Cys551Tyr)","llm_judgment":"PRESENT","evidence":"c.1652G>A (p.Cys551Tyr)","abstract_start":975,"abstract_end":998}]}
{"pmid":"35328834","title":"NKX2-5 Variant in Two Siblings with Thyroid Hemiagenesis.","abstract":"Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis. The aim of the study was to reveal genetic factors responsible for thyroid maldevelopment in two siblings with THA. None of the family members presented with congenital heart defect. The samples were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Enrichment Kit, San Diego, CA 92121, USA). An ultra-rare variant c.839C>T (p.Pro280Leu) in NKX2-5 gene (NM_004387.4) was identified in both affected children and an unaffected father. In the mother, the variant was not present. This variant is reported in population databases with 0.0000655 MAF (GnomAD v3, dbSNP rs761596254). The affected amino acid position is moderately conserved (positive scores in PhyloP: 1.364 and phastCons: 0.398). Functional prediction algorithms showed deleterious impact (dbNSFP v4.1, FATHMM, SIFT) or benign (CADD, PolyPhen-2, Mutation Assessor). According to ACMG criteria, variant is classified as having uncertain clinical significance. For the first time, NKX2-5 gene variants were found in two siblings with THA, providing evidence for its potential contribution to the pathogenesis of this type of thyroid dysgenesis. The presence of the variant in an unaffected parent, carrier of p.Pro280Leu variant, suggests potential contribution of yet unidentified additional factors determining the final penetrance and expression.","variants":[{"Name":"NM_004387.4(NKX2-5):c.839C>T (p.Pro280Leu)","Chromosome":"5","Start":"173232705","Stop":"173232705","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":454836,"rule_based_match":true,"evidence_text":"c.839C>T (p.Pro280Leu)","llm_judgment":"PRESENT","evidence":"c.839C>T (p.Pro280Leu)","abstract_start":436,"abstract_end":458}]}
{"pmid":"26805781","title":"Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.","abstract":"The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.","variants":[{"Name":"NM_152906.7(TANGO2):c.460G>A (p.Gly154Arg)","Chromosome":"22","Start":"20061538","Stop":"20061538","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205385,"rule_based_match":true,"evidence_text":"c.460G>A (p.Gly154Arg)","llm_judgment":"PRESENT","evidence":"c.460G>A (p.Gly154Arg)","abstract_start":468,"abstract_end":490}]}
{"pmid":"29383834","title":"Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.","abstract":"Omodysplasia-2 (OMOD2; OMIM%16475) is a rare autosomal dominant (AD) skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum), and variable degrees of genitourinary anomalies. This clinical phenotype overlaps with that of AD type Robinow syndrome. Recently, a mutation in FZD2 encoding a Frizzled Class Receptor 2 has been identified in a family with AD omodysplasia (an affected girl and her affected mother). Here, we present the second report on a heterozygous novel nonsense FZD2 mutation in OMOD2 or Robinow syndrome-like phenotype. The proband was a 16-year-old boy, who has been followed from infancy to adolescence. He presented with rhizomelic short stature with elbow restriction, mild facial dysmorphism (depressed broad bridge, short nose, anteverted nostrils, long philtrum, and low-set ears), and genital hypoplasia. Radiological examination in infancy showed short, broad humeri with relatively narrow distal ends, mildly broad femora, thick proximal ulnae with hypoplastic, dislocated proximal radii, and short first metacarpals. The abnormal skeletal pattern was persistent in adolescence; however, the humeri and femora became less undermodeled, while the humeri and radii became mildly bowed. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2. The affected codon was next to the previously reported mutation (p.Trp548*). The results indicate that OMOD2 or Robinow syndome-like phenotype can be caused by a heterozygous nonsense FZD2 mutation impairing Wnt signaling. Further molecular studies will permit better clarification of the phenotypic spectrum in patients with OMOD2.","variants":[{"Name":"NM_001466.4(FZD2):c.1640C>A (p.Ser547Ter)","Chromosome":"17","Start":"44559328","Stop":"44559328","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3072902,"rule_based_match":true,"evidence_text":"c.1640C>A, p.S547*","llm_judgment":"PRESENT","evidence":"c.1640C>A, p.S547*","abstract_start":1410,"abstract_end":1428}]}
{"pmid":"27967308","title":"A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis.","abstract":"Context: Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction, characterized by amenorrhea with elevated gonadotropin levels. The disorder presents as absence of normal progression of puberty.\nObjective: To elucidate the cause of ovarian dysfunction in a family with POI.\nDesign: We performed whole-exome sequencing in 2 affected individuals. To evaluate whether DNA double-strand break (DSB) repair activities are altered in biallelic mutation carriers, we applied an enhanced green fluorescent protein-based assay for the detection of specific DSB repair pathways in blood-derived cells.\nSetting: Diagnoses were made at the Pediatric Endocrine Clinic, Clalit Health Services, Sharon-Shomron District, Israel. Genetic counseling and sample collection were performed at the Pediatric Genetics Unit, Schneider Children's Medical Center Israel, Petah Tikva, Israel.\nPatients and Intervention: Two sisters born to consanguineous parents of Israeli Muslim Arab ancestry presented with a lack of normal progression of puberty, high gonadotropin levels, and hypoplastic or absent ovaries on ultrasound. Blood samples for DNA extraction were obtained from all family members.\nMain Outcome Measure: Exome analysis to elucidate the cause of POI in 2 affected sisters.\nResults: Analysis revealed a stop-gain homozygous mutation in the SPIDR gene (KIAA0146) c.839G>A, p.W280*. This mutation altered SPIDR activity in homologous recombination, resulting in the accumulation of 53BP1-labeled DSBs postionizing radiation and γH2AX-labeled damage during unperturbed growth.\nConclusions: SPIDR is important for ovarian function in humans. A biallelic mutation in this gene may be associated with ovarian dysgenesis in cases of autosomal recessive inheritance.","variants":[{"Name":"NM_001080394.4(SPIDR):c.839G>A (p.Trp280Ter)","Chromosome":"8","Start":"47407923","Stop":"47407923","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1319139,"rule_based_match":true,"evidence_text":"c.839G>A, p.W280*","llm_judgment":"PRESENT","evidence":"c.839G>A, p.W280*","abstract_start":1394,"abstract_end":1411}]}
{"pmid":"29653233","title":"Three novel variants (p.Glu178Lys, p.Val245Met, p.Ser250Phe) of the phenylalanine hydroxylase (PAH) gene impair protein expression and function in vitro.","abstract":"Phenylketonuria (PKU) is the most common inherited metabolic disease, an autosomal recessive disorder affecting >10,000 newborns each year globally. It can be caused by over 1000 different naturally occurring mutations in the phenylalanine hydroxylase (PAH) gene. We analyzed three novel naturally occurring PAH gene variants: p.Glu178Lys (c.532G>A), p.Val245Met (c.733G>A) and p.Ser250Phe (c.749C>T). The mutant effect on the PAH enzyme structure and function was predicted by bioinformatics software. Vectors expressing the corresponding PAH variants were generated for expression in E. coli and in HEK293T cells. The RNA expression of the three PAH variants was measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The mutant PAH protein levels were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), western blot and enzyme-linked immunosorbent assay (ELISA). All three variants were predicted to be pathogenic by bioinformatics analysis. The transcription of the three PAH variants was similar to the wild type PAH gene in HEK293T cells. In contrast, the levels of mutant PAH proteins decreased significantly compared to the wild type control, in both E. coli and HEK293T cells. Our results indicate that the three novel PAH gene variants (p.Glu178Lys, p.Val245Met, p.Ser250Phe) impair PAH protein expression and function in prokaryotic and eukaryotic cells.","variants":[{"Name":"NM_000277.3(PAH):c.532G>A (p.Glu178Lys)","Chromosome":"12","Start":"102855310","Stop":"102855310","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":917099,"rule_based_match":true,"evidence_text":"c.532G>A (p.Glu178Lys)","llm_judgment":"PRESENT","evidence":"p.Glu178Lys","abstract_start":327,"abstract_end":338}]}
{"pmid":"33154040","title":"Novel de novo","abstract":"The archain 1 (<i>ARCN1</i>) gene encodes the coatomer subunit delta protein and is a component of the COPI coatomer complex, which is involved in retrograde vesical trafficking from the Golgi complex to the endoplasmic reticulum. Variants in <i>ARCN1</i> have recently been associated with rhizomelic short stature with microcephaly, microretrognathia, and developmental delay. Here we report a 3.5-yr-old boy with microcephaly, global developmental delay, and multiple congenital abnormalities and the <i>ARCN1-</i>related syndrome caused by a novel de novo intronic variant. Whole-exome sequencing of the proband and his parents was utilized to determine the genetic origin of the patient's disorder and identified a de novo variant, NM_001655.5:c.654-15A > G, in the <i>ARCN1</i> gene. Follow-up functional characterization of mRNA from the patient demonstrated that this variant creates a splicing defect of the <i>ARCN1</i> mRNA. <i>ARCN1</i>-related syndrome represents an emerging disorder of developmental delay, and this report represents the sixth described patient. Despite the few instances reported in literature, the phenotype is consistent between our patient and previously reported individuals.","variants":[{"Name":"NM_001655.5(ARCN1):c.654-15A>G","Chromosome":"11","Start":"118584465","Stop":"118584465","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":794216,"rule_based_match":true,"evidence_text":"NM_001655.5:c.654-15A > G","llm_judgment":"PRESENT","evidence":"NM_001655.5:c.654-15A > G","abstract_start":737,"abstract_end":762}]}
{"pmid":"22377713","title":"A synonymous mutation in SPINK5 exon 11 causes Netherton syndrome by altering exonic splicing regulatory elements.","abstract":"Netherton syndrome (NS) is a rare, life-threatening ichthyosiform syndrome caused by recessive loss-of-function mutations in SPINK5 gene encoding lymphoepithelial Kazal-type-related inhibitor (LEKTI), a serine protease inhibitor expressed in the most differentiated epidermal layers and crucial for skin barrier function. We report the functional characterization of a previously unrecognized synonymous variant, c.891C>T (p.Cys297Cys), identified in the SPINK5 exon 11 of an NS patient. We demonstrated that the c.891C>T mutation is associated with abnormal pre-mRNA splicing and residual LEKTI expression in the patient's keratinocytes. Subsequent minigene splicing assays and in silico predictions confirmed the direct role of the synonymous mutation in inhibiting exon 11 inclusion by a mechanism that involves the activity of exonic regulatory sequences, namely splicing enhancer and silencer. However, this deleterious effect was not complete and a residual amount of normal mRNA and LEKTI protein could be detected, correlating with the relatively mild patient's phenotype. Our study represents the first identification of a disease-causing SPINK5 mutation that alters splicing without affecting canonical splice sites.","variants":[{"Name":"NM_006846.4(SPINK5):c.891C>T (p.Cys297=)","Chromosome":"5","Start":"148097875","Stop":"148097875","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360867,"rule_based_match":true,"evidence_text":"c.891C>T (p.Cys297Cys)","llm_judgment":"PRESENT","evidence":"c.891C>T (p.Cys297Cys)","abstract_start":413,"abstract_end":435}]}
{"pmid":"27880784","title":"CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5' Splice Site.","abstract":"Disease-causing germline mutations in CDH1 cause Hereditary Diffuse Gastric Cancer (HDGC). For patients who meet the HDGC screening criteria, the identification and classification of the sequence variants found in CDH1 are critical for risk management of patients. In this report, we describe a germline CDH1 c.1679C>G (p.T560R) variant identified in a 50 year old man who was diagnosed with gastric cancer with a strong family history of gastric cancer (one living brother was diagnosed with gastric cancer at 63 and another brother died of gastric cancer at 45). cDNA analysis, involving fragment analysis and cloning, indicated that the p.T560R mutation created a novel 5' splice donor site, which led to a novel transcript with a 32 nucleotide deletion in exon 11. This abnormal transcript putatively produces a truncated CDH1 protein (E-cadherin) of 575 amino acids instead of 882. We also demonstrated that the variant completely abolishes normal splicing as the mutant allele does not generate any normal transcript. Furthermore, the CDH1 c.1679C>G (p.T560R) variant segregated with gastric cancer in all three family members affected with gastric cancer in this family. These results support the conclusion that CDH1 c.1679C>G (p.T560R) variant is a pathogenic mutation and contributes to HDGC through disruption of normal splicing.","variants":[{"Name":"NM_004360.5(CDH1):c.1679C>G (p.Thr560Arg)","Chromosome":"16","Start":"68819393","Stop":"68819393","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":231976,"rule_based_match":true,"evidence_text":"CDH1 c.1679C>G (p.T560R)","llm_judgment":"PRESENT","evidence":"CDH1 c.1679C>G (p.T560R)","abstract_start":304,"abstract_end":328}]}
{"pmid":"30682496","title":"Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.","abstract":"Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease.","variants":[{"Name":"NM_182476.3(COQ6):c.1058C>A (p.Ala353Asp)","Chromosome":"14","Start":"73961339","Stop":"73961339","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":40280,"rule_based_match":true,"evidence_text":"c.1058C > A [rs397514479]","llm_judgment":"PRESENT","evidence":"c.1058C > A [rs397514479]","abstract_start":777,"abstract_end":802}]}
{"pmid":"22983245","title":"Clinical-genetic analysis of limb-girdle muscular dystrophy 2 type I","abstract":"Seventy four patients with clinical presentation of LGMD and probably autosomal-recessive type of inheritance were examined. Five different mutations of FKRP gene responsible for LGMD2 type I were detected in eight (10.8%) patients. Two of them с.341C>G, c.826C>A were described before and three c.229C>T, с.265C>T, с.1078G>C were found for the first time. The significant clinical polymorphism due to the difference in age of manifestation and severity of clinical presentation was identified.","variants":[{"Name":"NM_024301.5(FKRP):c.229C>T (p.Gln77Ter)","Chromosome":"19","Start":"46755679","Stop":"46755679","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1056587,"rule_based_match":true,"evidence_text":"c.229C>T","llm_judgment":"PRESENT","evidence":"c.229C>T","abstract_start":296,"abstract_end":304},{"Name":"NM_024301.5(FKRP):c.1078G>C (p.Asp360His)","Chromosome":"19","Start":"46756528","Stop":"46756528","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":548924,"rule_based_match":false,"evidence_text":"c.1078G>C","llm_judgment":"PRESENT","evidence":"c.1078G>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"21851503","title":"Aberrant splicing by a mutation, c.403+2T>A, in Korean patients with arthrogryposis-renal-dysfunction-cholestasis syndrome.","abstract":"","variants":[{"Name":"NM_018668.5(VPS33B):c.403+2T>A","Chromosome":"15","Start":"91009799","Stop":"91009799","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":340110,"rule_based_match":true,"evidence_text":"c.403+2T>A","llm_judgment":"PRESENT","evidence":"c.403+2T>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"35998264","title":"A loss-of-function cysteine mutant in fibulin-3 (EFEMP1) forms aberrant extracellular disulfide-linked homodimers and alters extracellular matrix composition.","abstract":"Fibulin-3 (F3 or EFEMP1) is a disulfide-rich, secreted glycoprotein necessary for maintaining extracellular matrix (ECM) and connective tissue integrity. Three studies have identified distinct autosomal recessive F3 mutations in individuals with Marfan Syndrome-like phenotypes. Herein, we characterize how one of these mutations, c.163T>C; p.Cys55Arg (C55R), disrupts F3 secretion, quaternary structure, and function by forming unique extracellular disulfide-linked homodimers. Dual cysteine mutants suggest that the C55R-induced disulfide species forms because of the new availability of Cys70 on adjacent F3 monomers. Surprisingly, mutation of single cysteines located near Cys55 (i.e., Cys29, Cys42, Cys48, Cys61, Cys70, Cys159, and Cys171) also produced similar extracellular disulfide-linked dimers, suggesting that this is not a phenomenon isolated to the C55R mutant. To assess C55R functionality, F3 knockout (KO) retinal pigmented epithelial (RPE) cells were generated, followed by reintroduction of wild-type (WT) or C55R F3. F3 KO cells produced lower levels of the ECM remodeling enzyme, matrix metalloproteinase 2, and reduced formation of collagen VI ECM filaments, both of which were partially rescued by WT F3 overexpression. However, C55R F3 was unable to compensate for these same ECM-related defects. Our results highlight the unique behavior of particular cysteine mutations in F3 and uncover potential routes to restore C55R F3 loss-of-function.","variants":[{"Name":"NM_001039348.3(EFEMP1):c.163T>C (p.Cys55Arg)","Chromosome":"2","Start":"55918019","Stop":"55918019","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":630398,"rule_based_match":true,"evidence_text":"c.163T>C; p.Cys55Arg (C55R)","llm_judgment":"PRESENT","evidence":"c.163T>C; p.Cys55Arg (C55R)","abstract_start":331,"abstract_end":358}]}
{"pmid":"30270081","title":"Novel combined variants of LDLR and LDLRAP1 genes causing severe familial hypercholesterolemia.","abstract":"BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a predominantly autosomal dominant hereditary disorder with significant potential for expansion of coronary artery disease.\nMETHODS: To identify candidate variant/s in FH phenotype implicated genes, next-generation sequencing was performed using a targeted customized gene panel.\nRESULTS: We recognized a 45-year-old Saudi female FH patient with double variants in the LDLR [c.1255 T > G, p.(Y419D)] and LDLRAP1 genes [c.604_605delTCinsA, p.(S202Tfs*2)]. The proband was found to be homozygous for the LDLR variant and heterozygous for the LDLRAP1 variant. Three of the proband's children were found to be double heterozygous for the LDLR/LDLRAP1 gene variant. While her other three children were heterozygous for the same single LDLR variant. Both variants were not previously reported. The variants segregation pattern correlated with the clinical picture and with the patient's lipid profile. FH severity was greater in the proband while her children did not show any clinical manifestations. The missense variant p.(Y419D) was found to be deleterious and clinically significant based on prediction identified by PolyPhen-2 and Proven. Molecular dynamics simulation was used to further analyze the effect of the variant p.(Y419D) on the structure and function of the LDLR protein. The secondary structure was investigated, as well as the solvent accessibility and stabilizing residues. The frameshift variant of the LDLRAP1 gene results in a truncated peptide that could affect the cellular internalization of LDLR/LDL complex.\nCONCLUSIONS: The finding of the combined variants in LDLR/LDLRAP1 genes triggering a severe FH phenotype is essential to elaborate the spectrum of variants causing FH and to understand the genotype-phenotype correlation.","variants":[{"Name":"NM_000527.5(LDLR):c.1255T>G (p.Tyr419Asp)","Chromosome":"19","Start":"11113346","Stop":"11113346","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":354094,"rule_based_match":true,"evidence_text":"c.1255 T > G, p.(Y419D)","llm_judgment":"PRESENT","evidence":"c.1255 T > G, p.(Y419D)","abstract_start":434,"abstract_end":457}]}
{"pmid":"30281152","title":"QRICH1 mutations cause a chondrodysplasia with developmental delay.","abstract":"In many children with short stature, the etiology of the decreased linear growth remains unknown. We sought to identify the underlying genetic etiology in a patient with short stature, irregular growth plates of the proximal phalanges, developmental delay, and mildly dysmorphic facial features. Exome sequencing identified a de novo, heterozygous, nonsense mutation (c.1606C>T:p.R536X) in QRICH1. In vitro studies confirmed that the mutation impaired expression of the QRICH1 protein. SiRNA-mediated knockdown of Qrich1 in primary mouse epiphyseal chondrocytes caused downregulation of gene expression associated with hypertrophic differentiation. We then identified an unrelated individual with another heterozygous de novo nonsense mutation in QRICH1 who had a similar phenotype. A recently published study identified QRICH1 mutations in three patients with developmental delay, one of whom had short stature. Our findings indicate that QRICH1 mutations cause not only developmental delay but also a chondrodysplasia characterized by diminished linear growth and abnormal growth plate morphology due to impaired growth plate chondrocyte hypertrophic differentiation.","variants":[{"Name":"NM_198880.3(QRICH1):c.1606C>T (p.Arg536Ter)","Chromosome":"3","Start":"49046490","Stop":"49046490","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":612052,"rule_based_match":true,"evidence_text":"c.1606C>T:p.R536X","llm_judgment":"PRESENT","evidence":"c.1606C>T:p.R536X","abstract_start":368,"abstract_end":385}]}
{"pmid":"28487885","title":"Novel de novo variant in","abstract":"Pathogenic variants in <i>EBF3</i> were recently described in three back-to-back publications in association with a novel neurodevelopmental disorder characterized by intellectual disability, speech delay, ataxia, and facial dysmorphisms. In this report, we describe an additional patient carrying a de novo missense variant in <i>EBF3</i> (c.487C>T, p.(Arg163Trp)) that falls within a conserved residue in the zinc knuckle motif of the DNA binding domain. Without a solved structure of the DNA binding domain, we generated a homology-based atomic model and performed molecular dynamics simulations for EBF3, which predicted decreased DNA affinity for p.(Arg163Trp) compared with wild-type protein and control variants. These data are in agreement with previous experimental studies of EBF1 showing the paralogous residue is essential for DNA binding. The conservation and experimental evidence existing for EBF1 and in silico modeling and dynamics simulations to validate comparable behavior of multiple variants in <i>EBF3</i> demonstrates strong support for the pathogenicity of p.(Arg163Trp). We show that our patient presents with phenotypes consistent with previously reported patients harboring <i>EBF3</i> variants and expands the phenotypic spectrum of this newly identified disorder with the additional feature of a bicornuate uterus.","variants":[{"Name":"NM_001375380.1(EBF3):c.487C>T (p.Arg163Trp)","Chromosome":"10","Start":"129957325","Stop":"129957325","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":361701,"rule_based_match":true,"evidence_text":"c.487C>T, p.(Arg163Trp)","llm_judgment":"PRESENT","evidence":"c.487C>T, p.(Arg163Trp)","abstract_start":341,"abstract_end":364}]}
{"pmid":"24556927","title":"Genetic, cell biological, and clinical interrogation of the CFTR mutation c.3700 A>G (p.Ile1234Val) informs strategies for future medical intervention.","abstract":"PURPOSE: The purpose of this study was to determine the molecular consequences of the variant c.3700 A>G in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a variant that has been predicted to cause a missense mutation in the CFTR protein (p.Ile1234Val).\nMETHODS: Clinical assays of CFTR function were performed, and genomic DNA from patients homozygous for c.3700 A>G and their family members was sequenced. Total RNA was extracted from epithelial cells of the patients, transcribed into complementary DNA, and sequenced. CFTR complementary DNA clones containing the missense mutation p.Ile1234Val or a truncated exon 19 (p.Ile1234_Arg1239del) were constructed and heterologously expressed to test CFTR protein synthesis and processing.\nRESULTS: In vivo functional measurements revealed that the individuals homozygous for the variant c.3700 A>G exhibited defective CFTR function. We show that this mutation in exon 19 activates a cryptic donor splice site 18 bp upstream of the original donor splice site, resulting in deletion of six amino acids (r.3700_3717del; p.Ile1234_Arg1239del). This deletion, similar to p.Phe508del, causes a primary defect in folding and processing. Importantly, Lumacaftor (VX-809), currently in clinical trial for cystic fibrosis patients with the major cystic fibrosis-causing mutation, p.Phe508del, partially ameliorated the processing defect caused by p.Ile1234_Arg1239del.\nCONCLUSION: These studies highlight the need to verify molecular and clinical consequences of CFTR variants to define possible therapeutic strategies.","variants":[{"Name":"NM_000492.4(CFTR):c.3700A>G (p.Ile1234Val)","Chromosome":"7","Start":"117627753","Stop":"117627753","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":22254,"rule_based_match":true,"evidence_text":"c.3700 A>G (p.Ile1234Val)","llm_judgment":"PRESENT","evidence":"p.Ile1234Val","abstract_start":261,"abstract_end":273}]}
{"pmid":"26879448","title":"Congenital disorder of glycosylphosphatidylinositol (GPI)-anchor biosynthesis--The phenotype of two patients with novel mutations in the PIGN and PGAP2 genes.","abstract":"BACKGROUND: Glycosylphosphatidylinositol (GPI)-anchor deficiencies are a new subclass of congenital disorders of glycosylation. About 26 genes are involved in the GPI-anchor biosynthesis and remodeling pathway, of which mutations in thirteen have been reported to date as causative of a diverse spectrum of intellectual disabilities. Since the clinical phenotype of these disorders varies and the number of described individuals is limited, we present new patients with inherited GPI-anchor deficiency (IGD) caused by mutations in the PGAP2 and PIGN genes.\nPATIENTS AND METHODS: The first girl presented with profound psychomotor retardation, low birth parameters, and chest deformities already existing in neonatal period. The disease course was slowly progressive with severe hypotonia, chronic fever, and respiration insufficiency at the age of 6. The second girl showed profound psychomotor retardation, marked hypotonia, and high birth weight (97 centile). Dysmorphy was mild or absent in both girls. Whole exome sequencing revealed novel variants in the genes PGAP2 (c.2T>G and c.221G>A) and PIGN (c.790G>A and c.932T>G). Impaired GPI binding were was subsequently uncovered, although the hyperactivity of alkaline phosphatase (a GPI-anchored protein) occurred only in first case.\nCONCLUSIONS: Based on our results we can conclude that: 1. GPI-anchor biosynthesis disorders may represent a relatively frequent and overlooked metabolic defect; 2. The utility of GPI binding assessment as a screening test for this group of rare diseases requires further studies.","variants":[{"Name":"NM_176787.5(PIGN):c.932T>G (p.Leu311Trp)","Chromosome":"18","Start":"62143337","Stop":"62143337","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":415608,"rule_based_match":true,"evidence_text":"c.932T>G","llm_judgment":"PRESENT","evidence":"c.932T>G","abstract_start":1117,"abstract_end":1125}]}
{"pmid":"34057271","title":"Biallelic deep intronic variant c.5457+81T>A in TRIP11 causes loss of function and results in achondrogenesis 1A.","abstract":"Biallelic loss of function variants in TRIP11 encoding for the Golgi microtubule-associated protein 210 (GMAP-210) causes the lethal chondrodysplasia achondrogenesis type 1A (ACG1A). Loss of TRIP11 activity has been shown to impair Golgi structure, vesicular transport, and results in loss of IFT20 anchorage to the Golgi that is vital for ciliary trafficking and ciliogenesis. Here, we report four fetuses, two each from two families, who were ascertained antenatally with ACG1A. Affected fetuses in both families are homozygous for the deep intronic TRIP11 variant, c.5457+81T>A, which was found in a shared region of homozygosity. This variant was found to cause aberrant transcript splicing and the retention of 77 base pairs of intron 18. The TRIP11 messenger RNA and protein levels were drastically reduced in fibroblast cells derived from one of the affected fetuses. Using immunofluorescence we also detected highly compacted Golgi apparatus in affected fibroblasts. Further, we observed a significant reduction in the frequency of ciliated cells and in the length of primary cilia in subject-derived cell lines, not reported so far in patient cells with TRIP11 null or hypomorphic variants. Our findings illustrate how pathogenic variants in intronic regions of TRIP11 can impact transcript splicing, expression, and activity, resulting in ACG1A.","variants":[{"Name":"NM_004239.4(TRIP11):c.5457+81T>A","Chromosome":"14","Start":"91975091","Stop":"91975091","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1086973,"rule_based_match":true,"evidence_text":"c.5457+81T>A","llm_judgment":"PRESENT","evidence":"c.5457+81T>A","abstract_start":568,"abstract_end":580}]}
{"pmid":"19705481","title":"Cardiac pathology exceeds skeletal muscle pathology in two cases of limb-girdle muscular dystrophy type 2I.","abstract":"Limb-girdle muscular dystrophy type 2I (LGMD-2I) is caused by mutations in the fukutin-related protein gene (FKRP) that lead to abnormal glycosylation of alpha-dystroglycan in skeletal muscle. Heart involvement in LGMD-2I is common, but little is known about a underlying cardiac pathology. Herein we describe two patients with LGMD-2I (homozygous FKRP mutation c.826C>A, p.Leu276Ile) who developed severe congestive heart failure that required cardiac transplantation. The dystrophic pathology and impairment of alpha-dystroglycan glycosylation were severe in the heart but mild in skeletal muscle, underscoring the lack of correlation between cardiac and skeletal muscle involvement in some LGMD-2I patients.","variants":[{"Name":"NM_024301.5(FKRP):c.826C>A (p.Leu276Ile)","Chromosome":"19","Start":"46756276","Stop":"46756276","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":19260,"rule_based_match":true,"evidence_text":"c.826C>A, p.Leu276Ile","llm_judgment":"PRESENT","evidence":"c.826C>A, p.Leu276Ile","abstract_start":362,"abstract_end":383}]}
{"pmid":"37880421","title":"Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly.","abstract":"Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.","variants":[{"Name":"NM_032982.4(CASP2):c.876+1G>T","Chromosome":"7","Start":"143300052","Stop":"143300052","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2477493,"rule_based_match":true,"evidence_text":"c.876 + 1 G > T","llm_judgment":"PRESENT","evidence":"c.876 + 1 G > T","abstract_start":1032,"abstract_end":1047},{"Name":"NM_032982.4(CASP2):c.1156del (p.Tyr386fs)","Chromosome":"7","Start":"143304712","Stop":"143304712","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":2477445,"rule_based_match":true,"evidence_text":"NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25)","llm_judgment":"PRESENT","evidence":"NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25)","abstract_start":751,"abstract_end":794},{"Name":"NM_032982.4(CASP2):c.1174C>T (p.Gln392Ter)","Chromosome":"7","Start":"143304730","Stop":"143304730","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2477446,"rule_based_match":true,"evidence_text":"c.1174 C > T (p.Gln392Ter)","llm_judgment":"PRESENT","evidence":"c.1174 C > T (p.Gln392Ter)","abstract_start":800,"abstract_end":826},{"Name":"NM_032982.4(CASP2):c.130C>T (p.Arg44Ter)","Chromosome":"7","Start":"143291595","Stop":"143291595","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2477447,"rule_based_match":false,"evidence_text":"c.130 C > T","llm_judgment":"PRESENT","evidence":"c.[130 C > T","abstract_start":864,"abstract_end":876}]}
{"pmid":"27717243","title":"Differences in gene mutations between Chinese and Caucasian cystic fibrosis patients.","abstract":"Cystic fibrosis (CF) is rarely seen in Asian populations. We diagnosed two CF cases. One of them had a novel mutation c.870-1G>C in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. There have been 38 Chinese CF patients reported in literature from 1974 until the present (2016), 25 different mutations were identified. Only one of these mutations (R553X) is in the Caucasian CF screening panel. The mutations identified in Chinese CF patients are very different from the common Caucasian gene mutations. The CFTR gene mutation spectrum for the Chinese population requires further investigation. Pediatr Pulmonol. 2017;52:E11-E14. © 2016 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.","variants":[{"Name":"NM_000492.4(CFTR):c.870-1G>C","Chromosome":"7","Start":"117540099","Stop":"117540099","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":544518,"rule_based_match":true,"evidence_text":"c.870-1G>C","llm_judgment":"PRESENT","evidence":"c.870-1G>C","abstract_start":118,"abstract_end":128}]}
{"pmid":"30710256","title":"Hypotrichosis with cone-rod dystrophy in a patient with cadherin 3 (CDH3) mutation.","abstract":"PURPOSE: To investigate a very rare case of hypotrichosis with cone-rod dystrophy caused by a P-cadherin CDH3 mutation.\nMETHODS: A 16-year-old Syrian girl was examined at age 9 and 14 years with an ophthalmological examination, fundus imaging, OCT and electrophysiological recordings (ERG and PERG). A disease-targeted gene panel sequencing was performed.\nRESULTS: Fundus images showed pigmentations at the posterior eye pole to the mid periphery, as well as vessel tortuosity. OCT images revealed a loss of the outer retinal segments and IS/OS in the central macula. The scotopic and photopic ERGs showed moderately reduced amplitudes at age 9 years that became severely reduced at age of 14 years. The PERG was undetectable at age 9 years. In color vision testing, protan-deutan confusion errors occurred. Gene panel analysis revealed one homozygous mutation in CDH3 (c.1508G>A; p.Arg503His).\nCONCLUSION: This case shows that a CDH3 mutation besides macula dystrophy can cause widespread cone-rod dystrophy with hypotrichosis without any other pathology besides hypoplastic nails. This points to a common pathway of hair growth and photoreceptor development that can be disturbed by a CDH3 mutation (c.1508G>A; p.Arg503His) located in the EC4 repeat region of the gene.","variants":[{"Name":"NM_001793.6(CDH3):c.1508G>A (p.Arg503His)","Chromosome":"16","Start":"68685288","Stop":"68685288","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32678,"rule_based_match":true,"evidence_text":"c.1508G>A; p.Arg503His","llm_judgment":"PRESENT","evidence":"c.1508G>A; p.Arg503His","abstract_start":870,"abstract_end":892}]}
{"pmid":"30120606","title":"Candidate gene sequencing reveals mutations causing hypoplastic amelogenesis imperfecta.","abstract":"OBJECTIVE: Amelogenesis imperfecta (AI) is a rare hereditary disorder affecting the quality and quantity of the tooth enamel. The purpose of this study was to identify the genetic etiology of hypoplastic AI families based on the candidate gene approach.\nMATERIALS AND METHODS: We recruited three Turkish families with hypoplastic AI and performed a candidate gene screening based on the characteristic clinical feature to find the pathogenic genetic etiology.\nRESULTS: The candidate gene sequencing of the LAMB3 gene for family 1 revealed a heterozygous nonsense mutation in the last exon [c.3431C > A, p.(Ser1144*)]. FAM20A gene sequencing for families 2 and 3 identified a homozygous deletion [c.34_35delCT, p.(Leu12Alafs*67)] and a homozygous deletion-insertion (c.1109 + 3_1109 + 7delinsTGGTC) mutation, respectively.\nCONCLUSION: The candidate gene approach can be successfully used to identify the genetic etiology of the AI in some cases with characteristic clinical features.\nCLINICAL RELEVANCE: Identification of the genetic etiology of the AI will help both the family members and dentist understand the nature of the disorder. Characteristic clinical feature can suggest possible genetic causes.","variants":[{"Name":"NM_017565.4(FAM20A):c.1109+3_1109+7delinsTGGTC","Chromosome":"17","Start":"68541978","Stop":"68541982","ReferenceAlleleVCF":"AACTC","AlternateAlleleVCF":"GACCA","allel_id":1683901,"rule_based_match":true,"evidence_text":"c.1109 + 3_1109 + 7delinsTGGTC","llm_judgment":"PRESENT","evidence":"c.1109 + 3_1109 + 7delinsTGGTC","abstract_start":766,"abstract_end":796}]}
{"pmid":"29396028","title":"Cutis laxa, exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG.","abstract":"Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. >100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542T>G (p.L181R) in the X-linked ATP6AP1, an accessory protein of the mammalian vacuolar H<sup>+</sup>-ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures. Proliferation of the patient's fibroblasts was significantly reduced and doubling time prolonged. Additionally, there were alterations in the fibroblasts' amino acid levels and the acylcarnitine composition. Especially, short-chain species were reduced, whereas several medium- to long-chain acylcarnitines (C14-OH to C18) were elevated. Investigation of the main lipid classes revealed that total cholesterol was significantly enriched in the patient's fibroblasts at the expense of phophatidylcholine and phosphatidylethanolamine. Within the minor lipid species, hexosylceramide was reduced, while its immediate precursor ceramide was increased. Since catalase activity and ACOX3 expression in peroxisomes were reduced, we assume an ATP6AP1-dependent impact on the β-oxidation of fatty acids. These results help to understand the complex clinical characteristics of this new patient.","variants":[{"Name":"NM_001183.6(ATP6AP1):c.542T>G (p.Leu181Arg)","Chromosome":"X","Start":"154432444","Stop":"154432444","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":431541,"rule_based_match":true,"evidence_text":"c.542T>G (p.L181R)","llm_judgment":"PRESENT","evidence":"c.542T>G (p.L181R)","abstract_start":350,"abstract_end":368}]}
{"pmid":"29454568","title":"Phenotypic heterogeneity of hereditary diffuse gastric cancer: report of a family with early-onset disease.","abstract":"BACKGROUND AND AIMS: The time course for the development of clinically significant hereditary diffuse gastric cancer (HDGC) is unpredictable. Little is known about the progression from preclinical, indolent lesions to widely invasive, aggressive phenotypes. Gastroendoscopy often fails to detect early lesions, and risk-reducing/prophylactic total gastrectomy (PTG) is the only curative approach. We present an HDGC family with early-onset disease in which clinical and histologic findings provided insight into the understanding of different HDGC phenotypes.\nMETHODS: The proband was diagnosed at age 18 years with widely invasive, metastatic DGC. CDH1 genetic testing identified a pathogenic, germline CDH1 variant (c.1901C>T, p.Ala634Val). Thirty family members were tested, and 15 CDH1 carriers were identified.\nRESULTS: Six family members had PTG, with negative preoperative workup. The proband's 14-year-old sister is the youngest patient, reported to date, to have PTG after negative preoperative biopsy sampling. Intramucosal HDGC foci were detected in all PTG specimens (1-33). In contrast to the \"indolent\" phenotype of these foci, the aggressive DGC from the proband showed pleomorphic cells, absent E-cadherin expression, increased proliferation (Ki-67 index), and activation of oncogenic events (p53, pSrc and pStat3 overexpression). All family members had Helicobacter pylori gastritis. Cag-A-positive strains were detected in all specimens, except in the proband's sister.\nCONCLUSIONS: HDGC is a heterogeneous disease regarding clinical behavior, endoscopic findings, histopathologic features, and immunophenotypic/molecular profile. The presence of bizarre, pleomorphic cells in endoscopic biopsy specimens is suggestive of advanced disease and should prompt clinical intervention. The involvement of a full multidisciplinary team is essential for the management of these patients.","variants":[{"Name":"NM_004360.5(CDH1):c.1901C>T (p.Ala634Val)","Chromosome":"16","Start":"68822190","Stop":"68822190","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27283,"rule_based_match":true,"evidence_text":"c.1901C>T, p.Ala634Val","llm_judgment":"PRESENT","evidence":"c.1901C>T, p.Ala634Val","abstract_start":718,"abstract_end":740}]}
{"pmid":"16838077","title":"Seven cases of Pompe disease from Greece.","abstract":"We present seven cases of Pompe disease (McKusick 232300; glycogen storage disease type II; acid maltase deficiency) from Greece. The onset of symptoms varied from early childhood to late adulthood, and the patients had quite variable duration of disease. All but one of them had muscle weakness and all had mildly to highly elevated serum creatine kinase. The diagnosis in all cases was confirmed by the finding of acid alpha-glucosidase (EC 3.2.1.3/20) deficiency in cultured skin fibroblasts. Thirteen mutant alleles were identified and nine different pathogenic mutations were encountered. Four were new: c.2071_2072insAGCCG leads to frameshift and total loss of function; c.1856G > A (p.Ser619Asn) leads to 90-95% loss of function; and the splice-site mutations c.1552-3C > G and c.2331+4A > G reduce the number of correct splicing events by more than 90%. The splice-site mutation c.-32-13T > G (IVS1-13T > G) was encountered four times and seems equally common among Greek and other caucasians. The other mutations: c.925G > A (p.Gly309Arg), c.[307T > G; 271G > A] (p.Cys103Gly; Asp91Asn), c.271del and c.1655T > C (p.Leu552Pro) have been reported earlier. Our study highlights the heterogeneity of Pompe disease in Greece and provides tools for diagnosis and carrier detection.","variants":[{"Name":"NM_000152.5(GAA):c.1655T>C (p.Leu552Pro)","Chromosome":"17","Start":"80112001","Stop":"80112001","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":265030,"rule_based_match":true,"evidence_text":"c.1655T > C (p.Leu552Pro)","llm_judgment":"PRESENT","evidence":"c.1655T > C (p.Leu552Pro)","abstract_start":1110,"abstract_end":1135},{"Name":"NM_000152.5(GAA):c.1856G>A (p.Ser619Asn)","Chromosome":"17","Start":"80112679","Stop":"80112679","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":358508,"rule_based_match":true,"evidence_text":"c.1856G > A (p.Ser619Asn)","llm_judgment":"PRESENT","evidence":"c.1856G > A (p.Ser619Asn)","abstract_start":677,"abstract_end":702},{"Name":"NM_000152.5(GAA):c.925G>A (p.Gly309Arg)","Chromosome":"17","Start":"80107866","Stop":"80107866","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186997,"rule_based_match":true,"evidence_text":"c.925G > A (p.Gly309Arg)","llm_judgment":"PRESENT","evidence":"c.925G > A (p.Gly309Arg)","abstract_start":1023,"abstract_end":1047},{"Name":"NM_000152.5(GAA):c.1552-3C>G","Chromosome":"17","Start":"80110938","Stop":"80110938","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":410294,"rule_based_match":true,"evidence_text":"c.1552-3C>G","llm_judgment":"PRESENT","evidence":"c.1552-3C > G","abstract_start":767,"abstract_end":780},{"Name":"NM_000152.5(GAA):c.307T>G (p.Cys103Gly)","Chromosome":"17","Start":"80104893","Stop":"80104893","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":98392,"rule_based_match":false,"evidence_text":"c.307T>G","llm_judgment":"PRESENT","evidence":"c.[307T > G","abstract_start":1049,"abstract_end":1060}]}
{"pmid":"31367175","title":"Mutation profile of glaucoma candidate genes in Mauritanian families with primary congenital glaucoma.","abstract":"Purpose: Intraocular pressure leading to glaucoma is a major cause of childhood blindness in developing countries. In this study, we sought to identify gene variants potentially associated with primary congenital glaucoma (PCG) in the Mauritanian population.\nMethods: Using next-generation sequencing (NGS), a panel of PCG candidate genes was screened in a search for DNA mutations in four families with multiple occurrences of PCG.\nResults: Targeted exome sequencing analysis revealed predicted pathogenic mutations in four genes: <i>CYP1B1</i> (c.217_218delTC, p.Ser73Valfs*150), <i>MYOC</i> (878C>A, p.T293K), <i>NTF4</i> (c.601T>G, p.Cys201Gly), and <i>WDR36</i> (c.2078A>G, p.Asn693Ser), each carried by a different family.\nConclusions: Genetic variation associated with PCG in this study reflects the ethnic heterogeneity of the Mauritanian population. However, a larger cohort is needed to identify additional families carrying these mutations and confirm their biologic role.","variants":[{"Name":"NM_000104.4(CYP1B1):c.217_218del (p.Ser73fs)","Chromosome":"2","Start":"38075171","Stop":"38075172","ReferenceAlleleVCF":"CGA","AlternateAlleleVCF":"C","allel_id":1925280,"rule_based_match":true,"evidence_text":"c.217_218delTC","llm_judgment":"PRESENT","evidence":"c.217_218delTC","abstract_start":547,"abstract_end":561}]}
{"pmid":"27164683","title":"Loss of function of PCDH12 underlies recessive microcephaly mimicking intrauterine infection.","abstract":"OBJECTIVE: To identify the genetic basis of a recessive syndrome characterized by prenatal hyperechogenic brain foci, congenital microcephaly, hypothalamic midbrain dysplasia, epilepsy, and profound global developmental disability.\nMETHODS: Identification of the responsible gene by whole exome sequencing and homozygosity mapping.\nRESULTS: Ten patients from 4 consanguineous Palestinian families manifested in utero with hyperechogenic brain foci, microcephaly, and intrauterine growth retardation. Postnatally, patients had progressive severe microcephaly, neonatal seizures, and virtually no developmental milestones. Brain imaging revealed dysplastic elongated masses in the midbrain-hypothalamus-optic tract area. Whole exome sequencing of one affected child revealed only PCDH12 c.2515C>T, p.R839X, to be homozygous in the proband and to cosegregate with the condition in her family. The allele frequency of PCDH12 p.R839X is <0.00001 worldwide. Genotyping PCDH12 p.R839X in 3 other families with affected children yielded perfect cosegregation with the phenotype (probability by chance is 2.0 × 10(-12)). Homozygosity mapping revealed that PCDH12 p.R839X lies in the largest homozygous region (11.7 MB) shared by all affected patients. The mutation reduces transcript expression by 84% (p < 2.4 × 10(-13)). PCDH12 is a vascular endothelial protocadherin that promotes cellular adhesion. Endothelial adhesion disruptions due to mutations in OCLN or JAM3 also cause congenital microcephaly, intracranial calcifications, and profound psychomotor disability.\nCONCLUSIONS: Loss of function of PCDH12 leads to recessive congenital microcephaly with profound developmental disability. The phenotype resembles Aicardi-Goutières syndrome and in utero infections. In cases with similar manifestations but no evidence of infection, our results suggest consideration of an additional, albeit rare, cause of congenital microcephaly.","variants":[{"Name":"NM_016580.4(PCDH12):c.2515C>T (p.Arg839Ter)","Chromosome":"5","Start":"141955337","Stop":"141955337","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":434518,"rule_based_match":true,"evidence_text":"PCDH12 c.2515C>T, p.R839X","llm_judgment":"PRESENT","evidence":"PCDH12 c.2515C>T, p.R839X","abstract_start":778,"abstract_end":803}]}
{"pmid":"27829221","title":"Mutation analysis of a Chinese family with oculocutaneous albinism.","abstract":"Oculocutaneous albinism (OCA) is an autosomal recessive disorder characterized by either complete lack of or a reduction in melanin biosynthesis in the skin, hair, and eyes. OCA1, the most common and severe type, is caused by mutations in the tyrosinase (TYR) gene. In this study, we report a Chinese family with two members affected by OCA. Blood samples were collected from all family members. Genomic DNA was isolated from blood leukocytes, and all coding exons and adjacent intronic sequences of the TYR gene were examined for mutation analysis using polymerase chain reaction (PCR)-based sequencing. A pedigree chart was drawn, and clinical examinations and paraclinical tests were performed. Compound heterozygous mutations in TYR (c.832C>T and c.929_930insC, which resulted in p.Arg278* and p.Arg311Lysfs*7, respectively) were identified in the two patients with milky skin, white hair, photophobia, and reduced visual acuity, while other family members only carried one of two heterozygous mutations. In addition, a homozygous missense mutation c.814G>A (p.Glu272Lys) in the solute carrier family 45 member 2 (SLC45A2) gene was found in both patients and unaffected family members, suggesting that this may not be a causative mutation. The findings of this study expand the mutational spectrum of OCA. Compound heterozygous mutations (c.832C>T and c.929_930insC) in the TYR gene may be responsible for partial clinical manifestations of OCA, while the homozygous missense mutation c.814G>A (p.Glu272Lys) in the SLC45A2 gene may not be associated with OCA.","variants":[{"Name":"NM_000372.5(TYR):c.832C>T (p.Arg278Ter)","Chromosome":"11","Start":"89191214","Stop":"89191214","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105472,"rule_based_match":true,"evidence_text":"c.832C>T","llm_judgment":"PRESENT","evidence":"c.832C>T","abstract_start":738,"abstract_end":746}]}
{"pmid":"27067077","title":"Missed Newborn Screening Case of Carnitine Palmitoyltransferase-II Deficiency.","abstract":"Carnitine palmitoyltransferase-II (CPT-II) deficiency can be detected through newborn screening with tandem mass spectrometry. We report a 4-year-old patient with rhabdomyolysis due to CPT-II deficiency, which was initially missed by newborn screening. The patient presented with a 2-day history of fevers, upper respiratory infection, diffuse myalgia, and tea-colored urine. Her medical history was notable for frequent diffuse myalgia when ill. She was demonstrated to have homozygous mutation c.338C>T, p. S113L in CPT2, which is typically found in the adult-onset, myopathic form of the disease. An unknown number of CPT-II deficient patients with normal newborn screening have not yet presented to medical care with the adult-onset, myopathic form of disease. We conclude that (1) not all cases of CPT-II deficiency are currently detected through newborn screening, even when blood is appropriately collected on day 2 of life and (2) CPT-II deficiency should be kept on the differential for patients presenting with rhabdomyolysis, even if the newborn screening results were normal.","variants":[{"Name":"NM_000098.3(CPT2):c.338C>T (p.Ser113Leu)","Chromosome":"1","Start":"53202427","Stop":"53202427","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23992,"rule_based_match":true,"evidence_text":"c.338C>T, p. S113L","llm_judgment":"PRESENT","evidence":"c.338C>T, p. S113L","abstract_start":496,"abstract_end":514}]}
{"pmid":"21150918","title":"Novel missense mutations in MYO7A underlying postlingual high- or low-frequency non-syndromic hearing impairment in two large families from China.","abstract":"The myosin VIIA (MYO7A) gene encodes a protein classified as an unconventional myosin. Mutations within MYO7A can lead to both syndromic and non-syndromic hearing impairment in humans. Among different mutations reported in MYO7A, only five led to non-syndromic sensorineural deafness autosomal dominant type 11 (DFNA11). Here, we present the clinical, genetic and molecular characteristics of two large Chinese DFNA11 families with either high- or low-frequency hearing loss. Affected individuals of family DX-J033 have a sloping audiogram at young ages with high frequency are most affected. With increasing age, all test frequencies are affected. Affected members of family HB-S037 present with an ascending audiogram affecting low frequencies at young ages, and then all frequencies are involved with increasing age. Genome-wide linkage analysis mapped the disease loci within the DFNA11 interval in both families. DNA sequencing of MYO7A revealed two novel nucleotide variations, c.652G > A (p.D218N) and c.2011G > A (p.G671S), in the two families. It is for the first time that the mutations identified in MYO7A in the present study are being implicated in DFNA11 in a Chinese population. For the first time, we tested electrocochleography (ECochG) in a DFNA11 family with low-frequency hearing loss. We speculate that the low-frequency sensorineural hearing loss in this DFNA11 family was not associated with endolymphatic hydrops.","variants":[{"Name":"NM_000260.4(MYO7A):c.2011G>A (p.Gly671Ser)","Chromosome":"11","Start":"77174831","Stop":"77174831","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38880,"rule_based_match":true,"evidence_text":"c.2011G > A (p.G671S)","llm_judgment":"PRESENT","evidence":"c.2011G > A (p.G671S)","abstract_start":1009,"abstract_end":1030},{"Name":"NM_000260.4(MYO7A):c.652G>A (p.Asp218Asn)","Chromosome":"11","Start":"77156921","Stop":"77156921","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38879,"rule_based_match":true,"evidence_text":"c.652G > A (p.D218N)","llm_judgment":"PRESENT","evidence":"c.652G > A (p.D218N)","abstract_start":984,"abstract_end":1004}]}
{"pmid":"29579189","title":"Cardiac voltage-gated sodium channel mutations associated with left atrial dysfunction and stroke in children.","abstract":"Aims: Cardiac atrial arrhythmias are the most common type of heart rhythm disorders. Its genetic elucidation remains challenging with poor understanding of cellular and molecular processes. These arrhythmias usually affect elderly population but in rare cases, young children may also suffer from such electrical diseases. Severe complications, including stroke, are commonly age related. This study aims to identify a genetic link between electro-mechanic atrial dysfunction and stroke in children.\nMethods and results: In two unrelated boys of 11 and 14 years with both stroke and atrial arrhythmias, the clinical phenotype was determined through a complete physical examination, electrocardiogram (ECG), Holter ECG, and computed tomography. The genetic testing was performed on a large 95 genes panel implicated in myocardial electrical imbalance, using the next generation sequencing method. The panel also includes the genes usually associated with the development of cardiomyopathies. In one child, a left atrial dilation was observed. The 2nd boy suffered from atrial standstill. Both suffered from atrial bradycardia, flutter, and fibrillation. The complete genetic testing revealed the SCN5A c.3823G>A (p.D1275N) mutation in the first family, c.1141-2A>G and c.3157G>A (p.E1053K) mutations in the second family.\nConclusion: Our results strengthen the association between Nav1.5 mutations and the occurrence of stroke in young patients. It emphasizes the need to look for atrial myopathy in the decision process for anticoagulation in young patients with atrial arrhythmic events.","variants":[{"Name":"NM_000335.5(SCN5A):c.1141-2A>G","Chromosome":"3","Start":"38606150","Stop":"38606150","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1343986,"rule_based_match":true,"evidence_text":"c.1141-2A>G","llm_judgment":"PRESENT","evidence":"c.1141-2A>G","abstract_start":1252,"abstract_end":1263},{"Name":"NM_000335.5(SCN5A):c.3157G>A (p.Glu1053Lys)","Chromosome":"3","Start":"38581002","Stop":"38581002","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":24439,"rule_based_match":true,"evidence_text":"c.3157G>A (p.E1053K)","llm_judgment":"PRESENT","evidence":"c.3157G>A (p.E1053K)","abstract_start":1268,"abstract_end":1288}]}
{"pmid":"37777263","title":"Identification of cystic fibrosis transmembrane conductance regulator gene (CFTR) variants: A retrospective study on the western and southern regions of Saudi Arabia.","abstract":"OBJECTIVES: To investigate the geographic distribution of common cystic fibrosis (CF) variants in the western and southern regions of Saudi Arabia.\nMETHODS: A retrospective study was conducted on 69 patients diagnosed with CF at King Faisal Specialist Hospital & Research Center, Jeddah. Patient data were collected retrospectively between June 2000 and November 2021. Various parameters were considered, including patient demographic information, CFTR variants, and respiratory cultures.\nRESULTS: We identified 26 CFTR variants in 69 patients with CF, including one novel variant that had not been reported or published before (1549del G) in 2 patients with CF. The 6 most prevalentvariants were as follows: c.1521_1523delCTT (19%), c.1418delG (10.2%), c.579+1G>T (8.8%), c.2988+1G>A (8.8%), c.3419 T>A (7.2%), and c.4124A>C (5.8%). In addition, respiratory cultures revealed that <i>Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae</i>, and <i>Streptococcus pneumoniae</i> were highly common among patients with CF.\nCONCLUSION: This study highlighted features of patients with CF residing in the Western and Southern regions of Saudi Arabia. Six of the 26 CFTR variants were common in these patients. We also report, for the first time, a novel variant and other CFTR variants that are yet to be reported in Saudi Arabia. These findings could help establish a foundation for cystic fibrosis screening in Saudi Arabia and may assist in clinical diagnosis and prognosis.","variants":[{"Name":"NM_000492.4(CFTR):c.4124A>C (p.His1375Pro)","Chromosome":"7","Start":"117664848","Stop":"117664848","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":68562,"rule_based_match":true,"evidence_text":"c.4124A>C","llm_judgment":"PRESENT","evidence":"c.4124A>C","abstract_start":816,"abstract_end":825}]}
{"pmid":"31030682","title":"A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation.","abstract":"Noonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C &gt; A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C &gt; A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation.","variants":[{"Name":"NM_002880.4(RAF1):c.776C>A (p.Ser259Tyr)","Chromosome":"3","Start":"12604194","Stop":"12604194","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":53800,"rule_based_match":false,"evidence_text":"c.776C > A (p.Ser259Tyr)","llm_judgment":"PRESENT","evidence":"p.Ser259Tyr","abstract_start":644,"abstract_end":655}]}
{"pmid":"26977311","title":"Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS).","abstract":"OBJECTIVE: Mevalonate kinase (MVK) deficiency is a rare autosomal recessive auto-inflammatory disorder characterised by recurring episodes of fever associated with multiple non-specific inflammatory symptoms and caused by mutations in the MVK gene. The phenotypic spectrum is wide and depends mostly on the nature of the mutations. Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a relatively mild presentation and predominantly associated with a c.1129G>A (p.V377I) mutation in the MVK gene. We report cases of two sisters homozygous for this mutation but exhibiting distinct (symptomatic vs asymptomatic) phenotypes.\nMETHODS: Patient history was obtained; physical and clinical examination and laboratory tests were performed; lipopolysaccharide (LPS) response of peripheral blood mononuclear cells was quantified.\nRESULTS: Low MVK enzymatic activity is not necessarily associated with inflammatory symptoms. Increased inflammatory cytokine secretion in response to LPS is associated with symptomatic MVK deficiency.\nCONCLUSIONS: Individuals who are homozygous for the common p.V377I mutation in the MVK gene may not display the characteristic inflammatory episodes diagnostic of MKD and thus may be lost for correct and timely diagnosis.","variants":[{"Name":"NM_000431.4(MVK):c.1129G>A (p.Val377Ile)","Chromosome":"12","Start":"109596515","Stop":"109596515","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26968,"rule_based_match":true,"evidence_text":"c.1129G>A (p.V377I)","llm_judgment":"PRESENT","evidence":"c.1129G>A (p.V377I)","abstract_start":464,"abstract_end":483}]}
{"pmid":"38066485","title":"Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions.","abstract":"BACKGROUND: TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations.\nMETHODS: In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity.\nRESULTS: We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability.\nCONCLUSIONS: This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.","variants":[{"Name":"NM_138691.3(TMC1):c.1256T>C (p.Phe419Ser)","Chromosome":"9","Start":"72791917","Stop":"72791917","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1952219,"rule_based_match":true,"evidence_text":"c.1256T > C:p.Phe419Ser","llm_judgment":"PRESENT","evidence":"c.1256T > C:p.Phe419Ser","abstract_start":1155,"abstract_end":1178}]}
{"pmid":"32299109","title":"Identification of Novel Variants in MEN1: A Study Conducted with Four Multiple Endocrine Neoplasia Type 1 Patients.","abstract":"Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited endocrine tumor syndrome caused by inactivating variants of the <i>MEN1</i> gene. The aim of this study is to explore the clinical and genetic characteristics of four MEN1 patients. We isolated genomic deoxyribonucleic acid from lymphocytes, parathyroid, and thymic tumoral tissue specimens from the MEN1 patients. All exons of the <i>MEN1</i> and <i>CDNK1B</i> genes and adjacent exon-intron sequences were amplified by polymerase chain reaction and subsequently sequenced. Further, the splice alterations were studied by sequencing the amplified RT-PCR products for <i>MEN1</i> cDNA. We identified four heterozygous <i>MEN1</i> germline variants: c.564delC, c.1268G>A, IVS5+5delG, and c.1546_1547insC. Both c.564delC and IVS5+5delG were novel variants. The impact of the <i>MEN1</i> splice variant, IVS5+5delG, was evaluated using bioinformatics and in vitro analyses. The analyses indicated that this variant resulted in skipping of the neighboring exon and was disease-causing. Two novel somatic variants, c.249_252delGTCT and c.313_314insC, were found. Additionally, loss of heterozygosity (LOH) for the <i>MEN1</i> locus (IVS5+5delG and c.564delC) was found in tumor tissue samples from the MEN1 patients, consistent with Knudson's two-hit mechanism. We identified four <i>MEN1</i> germline variants and two novel somatic variants. Early recognition of the phenotype coupled with variant screening of the <i>MEN1</i> gene is the key to diagnosing and treating MEN1 effectively at an early stage.","variants":[{"Name":"NM_001370259.2(MEN1):c.564del (p.Asn189fs)","Chromosome":"11","Start":"64807981","Stop":"64807981","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":3149024,"rule_based_match":true,"evidence_text":"c.564delC","llm_judgment":"PRESENT","evidence":"c.564delC","abstract_start":727,"abstract_end":736},{"Name":"NM_001370259.2(MEN1):c.1268G>A (p.Trp423Ter)","Chromosome":"11","Start":"64805116","Stop":"64805116","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1866590,"rule_based_match":true,"evidence_text":"c.1268G>A","llm_judgment":"PRESENT","evidence":"c.1268G>A","abstract_start":738,"abstract_end":747}]}
{"pmid":"20513136","title":"Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicity.","abstract":"Missense substitutions in high-risk cancer susceptibility genes create clinical uncertainty in the genetic counseling process. Multifactorial likelihood classification approaches and in vitro assays are useful for the classification of exonic sequence variants in BRCA1 and BRCA2, but these currently rely on the assumption that changes in protein function are the major biological mechanism of pathogenicity. This study investigates the potentially pathogenic role of aberrant splicing for exonic variants predicted to encode missense substitutions using patient-derived RNA. No splicing aberrations were identified for BRCA1c.5054C>T and BRCA2c.7336A>G, c.8839G>A, and c.9154C>T. However, RT-PCR analysis identified a major splicing aberration for BRCA1c.4868C>G(p.Ala1623Gly), a variant encoding a missense substitution considered likely to be neutral. Splicing aberrations were also observed for BRCA2c.7988A>T(p.Glu2663Val) and c.8168A>G(p.Asp2723Gly), but both variant and wildtype alleles were shown to be present in full-length mRNA transcripts, suggesting that variant protein may be translated. BRCA2 protein function assays indicated that BRCA2p.Glu2663Val, p.Asp2723Gly and p.Arg3052Trp missense proteins have abrogated function consistent with pathogenicity. Multifactorial likelihood analysis provided evidence for pathogenicity for BRCA1 c.5054C>T(p.Thr1685Ile) and BRCA2c.7988A>T(p.Glu2663Val), c.8168A>G(p.Asp2723Gly) and c.9154C>T(p.Arg3052Trp), supporting experimentally derived evidence. These findings highlight the need for improved bioinformatic prediction of splicing aberrations and to refine multifactorial likelihood models used to assess clinical significance.","variants":[{"Name":"NM_000059.4(BRCA2):c.9154C>T (p.Arg3052Trp)","Chromosome":"13","Start":"32380043","Stop":"32380043","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67431,"rule_based_match":true,"evidence_text":"BRCA2c.9154C>T","llm_judgment":"PRESENT","evidence":"c.9154C>T","abstract_start":671,"abstract_end":680},{"Name":"NM_000059.4(BRCA2):c.8168A>G (p.Asp2723Gly)","Chromosome":"13","Start":"32363370","Stop":"32363370","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":46697,"rule_based_match":true,"evidence_text":"c.8168A>G(p.Asp2723Gly)","llm_judgment":"PRESENT","evidence":"c.8168A>G(p.Asp2723Gly)","abstract_start":933,"abstract_end":956},{"Name":"NM_007294.4(BRCA1):c.5054C>T (p.Thr1685Ile)","Chromosome":"17","Start":"43067628","Stop":"43067628","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70032,"rule_based_match":true,"evidence_text":"BRCA1c.5054C>T","llm_judgment":"PRESENT","evidence":"BRCA1c.5054C>T","abstract_start":621,"abstract_end":635},{"Name":"NM_000059.4(BRCA2):c.7988A>T (p.Glu2663Val)","Chromosome":"13","Start":"32363190","Stop":"32363190","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":67130,"rule_based_match":true,"evidence_text":"BRCA2c.7988A>T(p.Glu2663Val)","llm_judgment":"PRESENT","evidence":"BRCA2c.7988A>T(p.Glu2663Val)","abstract_start":900,"abstract_end":928},{"Name":"NM_007294.4(BRCA1):c.4868C>G (p.Ala1623Gly)","Chromosome":"17","Start":"43071046","Stop":"43071046","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":46170,"rule_based_match":true,"evidence_text":"BRCA1c.4868C>G(p.Ala1623Gly)","llm_judgment":"PRESENT","evidence":"BRCA1c.4868C>G(p.Ala1623Gly)","abstract_start":750,"abstract_end":778}]}
{"pmid":"36222830","title":"An updated counseling framework for moderate-penetrance colorectal cancer susceptibility genes.","abstract":"PURPOSE: With the recent guideline change for individuals at average risk for colorectal cancer (CRC) to initiate colonoscopy at the age of 45 years, there is a need to provide an updated counseling framework for individuals with variants in moderate-penetrance CRC susceptibility genes.\nMETHODS: Population age-specific incidence rates for CRC were obtained from the 2014-2018 US Surveillance, Epidemiology, and End Results Program cancer statistics. Average-risk multipliers derived from a systematic meta-analysis were used to calculate the 5-year and cumulative lifetime risks for specific genetic variants associated with a moderate risk for CRC: NM_007194.4(CHEK2):c.1100del (p.Thr367fs), NM_007194.4(CHEK2):c.470T>C (p.Ile157Thr), NM_000038.6(APC):c.3920T>A (p.Ile1307Lys) and monoallelic MUTYH.\nRESULTS: When an individual at average risk would initiate colonoscopy at age 45 years, a CRC risk of 0.39% is reached. For CHEK2 1100delC, CHEK2 I157T, and APC I1307K heterozygotes, this same level of risk is reached (or nearly reached) by age 40 to 45 years. For individuals with a monoallelic MUTYH variant, the CRC risk is 0.46% by age 45 to 49 years, similar to individuals at average risk.\nCONCLUSION: These updated calculations support recommendations to initiate earlier colonoscopy surveillance for CHEK2 and APC I1307K germline variant heterozygotes. However, earlier surveillance is not indicated for individuals with monoallelic MUTYH germline variants in the absence of family history.","variants":[{"Name":"NM_007194.4(CHEK2):c.1100del (p.Thr367fs)","Chromosome":"22","Start":"28695869","Stop":"28695869","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":133499,"rule_based_match":true,"evidence_text":"NM_007194.4(CHEK2):c.1100del (p.Thr367fs)","llm_judgment":"PRESENT","evidence":"NM_007194.4(CHEK2):c.1100del (p.Thr367fs)","abstract_start":652,"abstract_end":693},{"Name":"NM_007194.4(CHEK2):c.470T>C (p.Ile157Thr)","Chromosome":"22","Start":"28725099","Stop":"28725099","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":20630,"rule_based_match":true,"evidence_text":"NM_007194.4(CHEK2):c.470T>C (p.Ile157Thr)","llm_judgment":"PRESENT","evidence":"NM_007194.4(CHEK2):c.470T>C (p.Ile157Thr)","abstract_start":695,"abstract_end":736}]}
{"pmid":"27924851","title":"Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome.","abstract":"The homeodomain transcription factor distal-less homeobox 3 gene (DLX3) is required for hair, tooth and skeletal development. DLX3 mutations have been found to be responsible for Tricho-Dento-Osseous (TDO) syndrome, characterized by kinky hair, thin-pitted enamel and increased bone density. Here we show that the DLX3 mutation (c.533 A>G; Q178R) attenuates osteogenic potential and senescence of bone mesenchymal stem cells (BMSCs) isolated from a TDO patient, providing a molecular explanation for abnormal increased bone density. Both DLX3 mutations (c.533 A>G and c.571_574delGGGG) delayed cellular senescence when they were introduced into pre-osteoblastic cells MC3T3-E1. Furthermore, the attenuated skeletal aging and bone loss in DLX3 (Q178R) transgenic mice not only reconfirmed that DLX3 mutation (Q178R) delayed cellular senescence, but also prevented aging-mediated bone loss. Taken together, these results indicate that DLX3 mutations act as a loss of function in senescence. The delayed senescence of BMSCs leads to increased bone formation by compensating decreased osteogenic potentials with more generations and extended functional lifespan. Our findings in the rare human genetic disease unravel a novel mechanism of DLX3 involving the senescence regulation of bone formation.","variants":[{"Name":"NM_005220.3(DLX3):c.571_574del (p.Gly191fs)","Chromosome":"17","Start":"49991807","Stop":"49991810","ReferenceAlleleVCF":"TCCCC","AlternateAlleleVCF":"T","allel_id":24111,"rule_based_match":true,"evidence_text":"c.571_574delGGGG","llm_judgment":"PRESENT","evidence":"c.571_574delGGGG","abstract_start":568,"abstract_end":584}]}
{"pmid":"23352578","title":"Hyperglycaemia and β-cell antibodies: is it always pre-type 1 diabetes?","abstract":"We describe 10-year-old girl with mild incidental hyperglycaemia, impaired glucose tolerance and GADA positivity. Family history for mild hyperglycaemia and GADA fluctuation alerted us to a possible MODY diagnosis which was confirmed by detection of GCK mutation c.626C>T; p.T209M. Weak or transient β-cell autoimmunity should not preclude genetic testing for MODY when the clinical features are suggestive.","variants":[{"Name":"NM_000162.5(GCK):c.626C>T (p.Thr209Met)","Chromosome":"7","Start":"44149813","Stop":"44149813","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":793235,"rule_based_match":true,"evidence_text":"c.626C>T; p.T209M","llm_judgment":"PRESENT","evidence":"c.626C>T; p.T209M","abstract_start":263,"abstract_end":280}]}
{"pmid":"22499103","title":"Novel ANO5 mutations causing hyper-CK-emia, limb girdle muscular weakness and Miyoshi type of muscular dystrophy.","abstract":"INTRODUCTION: Mutations in the anoctamin 5 gene (ANO5) have been recently identified.They cause limb girdle muscular dystrophy (LGMD2L) and Miyoshi muscular dystrophy.\nMETHODS: Clinical findings of four unrelated patients are reviewed. Mutation detection was performed by direct sequencing of the ANO5 exons.\nRESULTS: We identified four novel mutations in the ANO5 gene. In one patient, a novel homozygous mutation (c.1965G>C). In three patients, the recurrent heterozygous exon 5 c.191dupA mutation is combined with other variants to form a compound heterozygous state: in two cases, novel splice site mutations in intron 5 (c.295-1G>A) and in intron 14 (c.1407+5G>A), and in one case, a novel missense mutation in exon 4 (c.172C>T).\nCONCLUSIONS: The cases reported here should help to better understand the important role of mutation screening in the ANO5 gene in patients with adult onset muscular dystrophy and very high CK levels.","variants":[{"Name":"NM_213599.3(ANO5):c.172C>T (p.Arg58Trp)","Chromosome":"11","Start":"22218279","Stop":"22218279","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":194563,"rule_based_match":true,"evidence_text":"c.172C>T","llm_judgment":"PRESENT","evidence":"c.172C>T","abstract_start":724,"abstract_end":732},{"Name":"NM_213599.3(ANO5):c.295-1G>A","Chromosome":"11","Start":"22225983","Stop":"22225983","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":567145,"rule_based_match":true,"evidence_text":"c.295-1G>A","llm_judgment":"PRESENT","evidence":"c.295-1G>A","abstract_start":626,"abstract_end":636},{"Name":"NM_213599.3(ANO5):c.1965G>C (p.Trp655Cys)","Chromosome":"11","Start":"22270378","Stop":"22270378","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":514010,"rule_based_match":true,"evidence_text":"c.1965G>C","llm_judgment":"PRESENT","evidence":"c.1965G>C","abstract_start":416,"abstract_end":425}]}
{"pmid":"23824842","title":"Pelger-huet anomaly and a mild skeletal phenotype secondary to mutations in LBR.","abstract":"The Lamin B receptor (LBR) gene has been described to encode a bifunctional protein. Mutations in the LBR gene can affect neutrophil segmentation and sterol reductase activity and have been associated with two different recognized clinical conditions, Pelger-Huet anomaly (PHA) and Greenberg skeletal dysplasia. PHA is a benign autosomal co-dominant laminopathy resulting in bilobed neutrophil nuclei in heterozygotes, and unsegmented (ovoid) neutrophil nuclei in homozygotes. Some putative PHA homozygotes have been reported with minor skeletal malformations. Greenberg skeletal dysplasia is a severe autosomal recessive, perinatal lethal dwarfing disorder in which heterozygous carriers are usually without clinical manifestations. We here report a girl who has bilobed neutrophil nuclei and a mild skeletal dysplasia. Mutation analysis showed two novel mutations in the LBR gene: c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19) and c.1757G > A (p.Arg586His). These mutations were found to be in trans, and, thus, she is a compound heterozygote. Sterol analysis found trace amounts of cholesta-8,14-dien-3beta-ol, which is normally undetected in healthy individuals. This and previously reported cases suggest that mutations in LBR can result in a continuum of phenotypic manifestations.","variants":[{"Name":"NM_002296.4(LBR):c.651_653delinsTGATGAGAAA (p.Ile218fs)","Chromosome":"1","Start":"225418168","Stop":"225418170","ReferenceAlleleVCF":"ATG","AlternateAlleleVCF":"TTTCTCATCA","allel_id":536125,"rule_based_match":true,"evidence_text":"c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19)","llm_judgment":"PRESENT","evidence":"c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19)","abstract_start":883,"abstract_end":928},{"Name":"NM_002296.4(LBR):c.1757G>A (p.Arg586His)","Chromosome":"1","Start":"225403394","Stop":"225403394","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":536126,"rule_based_match":true,"evidence_text":"c.1757G > A (p.Arg586His)","llm_judgment":"PRESENT","evidence":"c.1757G > A (p.Arg586His)","abstract_start":933,"abstract_end":958}]}
{"pmid":"36202930","title":"Clustering of Juvenile Canavan disease in an Indian community due to population bottleneck and isolation: genomic signatures of a founder event.","abstract":"Mild/juvenile Canavan disease (M/JCD) is less frequently reported in the literature and little is known about its pathogenetic mechanisms. We report a comprehensive investigation into the pathogenetic mechanism of a novel NM_000049.4(ASPA):c.526G>A variant in two families. The families belong to Telugu Devanga Chettiar community (TDC) from southern India. TDC has a complex history of migration from their historical origin centuries ago with high endogamy. TDC probably has the highest clustering M/JCD recorded historically (around 24 cases). The pathogenic variant was shown to cause non-classical splicing defect resulting in two different transcripts. The splicing aberration, a loss of function mechanism coupled with a milder missense effect can explain the milder phenotype compared to the infantile-onset CD. The high clustering of an extremely rare form of neurodegenerative disorder with reduced fitness, led us to speculate the possibility of a founder event. Genotyping array of TDC and multiple distinct populations of Indian origin for several population genetic parameters was performed. It yielded robust signatures of a founder event in TDC, such as a high fixation index, increased runs of homozygosity and identity-by-descent in the absence of consanguinity; a large haplotype with high linkage disequilibrium among markers comprising the pathogenic variant; a robust population structure; mutation dating, estimating the age of the potential founder of TDC at around 375 years; possibly a high carrier rate in TDC. This study has not only focused its attention on natural history and pathogenetics but also paves way for carrier screening programs in TDC and future therapeutic studies.","variants":[{"Name":"NM_000049.4(ASPA):c.526G>A (p.Gly176Ser)","Chromosome":"17","Start":"3483592","Stop":"3483592","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1692958,"rule_based_match":true,"evidence_text":"NM_000049.4(ASPA):c.526G>A","llm_judgment":"PRESENT","evidence":"NM_000049.4(ASPA):c.526G>A","abstract_start":222,"abstract_end":248}]}
{"pmid":"19189134","title":"Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.","abstract":"Several studies have suggested that T cell-producing permeability factors might lead to proteinuria in minimal change nephrotic syndrome (MCNS). However, it is still unclear whether T-cell abnormalities cause MCNS. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulation system, which leads to severe autoimmune phenomena including autoimmune enteropathy, atopic dermatitis with high levels of serum immunoglobulin E (IgE), type 1 diabetes mellitus (T1DM), and severe infection such as sepsis, which frequently result in death within the first 2 years of life. This disease is caused by mutations in the FOXP3 gene that result in the defective development of regulatory T (Treg) cells. This report describes a 5-year-old boy with IPEX syndrome with a 3 bp deletion in the FOXP3 gene (c.748-750delAAG, p.250K.del) and a paucity of CD4(+) CD25(+) FOXP3(+) T cells. The boy's condition was complicated by MCNS in addition to many IPEX-related manifestations, such as atopic dermatitis, T1DM, enteropathy, sepsis and hemolytic anemia. This is the first report of IPEX syndrome complicated by MCNS, and our findings imply that Treg cell dysfunction may be crucial for the development of MCNS.","variants":[{"Name":"NM_014009.4(FOXP3):c.748_750del (p.Lys250del)","Chromosome":"X","Start":"49255495","Stop":"49255497","ReferenceAlleleVCF":"CCTT","AlternateAlleleVCF":"C","allel_id":491314,"rule_based_match":false,"evidence_text":"c.748-750delAAG, p.250K.del","llm_judgment":"PRESENT","evidence":"c.748-750delAAG, p.250K.del","abstract_start":852,"abstract_end":879}]}
{"pmid":"35482246","title":"Compound heterozygous mutations of NDUFV1 identified in a child with mitochondrial complex I deficiency.","abstract":"BACKGROUND: Mitochondrial complex I deficiency (MCID) is the most common biochemical defect identified in childhood with mitochondrial diseases, mainly including Leigh syndrome, encephalopathy, macrocephaly with progressive leukodystrophy, hypertrophic cardiomyopathy and myopathy.\nOBJECTIVE: To identify genetic cause in a patient with early onset autosomal recessive MCID.\nMETHODS: Trio whole-exome sequencing was performed and phenotype-related data analyses were conducted. All candidate mutations were confirmed by Sanger sequencing.\nRESULTS: Here we report a child of Leigh syndrome presented with global developmental delay, progressive muscular hypotonia and myocardial damage. A missense mutation c.118C > T (p.Arg40Trp) and a previously reported mutation c.1157G > A (p.Arg386His) in NDUFV1 have been identified as compound heterozygous in the patient. The mutation p.Arg386His is closely associated with the impairment of 4Fe-4S domain and this mutation has been reported pathogenic. The c.118C > T mutation has not been reported in ClinVar and HGMD database. In silico protein analyses showed that p.Arg40 is highly conserved in a wide range of species, and the amino acid substitution p.Trp40 largely decreases the stability of NDUFV1. In addition, the mutation has not been detected in the Asian populations and it was predicted to be deleterious by numerous prediction tools.\nCONCLUSION: This research expands the mutation spectrum of NDUFV1 and substantially provides an early and accurate diagnosis basis of MCID, which would benefit subsequently effective genetic counseling and prenatal diagnosis for future reproduction of the family.","variants":[{"Name":"NM_007103.4(NDUFV1):c.118C>T (p.Arg40Trp)","Chromosome":"11","Start":"67608441","Stop":"67608441","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3139250,"rule_based_match":true,"evidence_text":"c.118C > T (p.Arg40Trp)","llm_judgment":"PRESENT","evidence":"c.118C > T (p.Arg40Trp)","abstract_start":706,"abstract_end":729},{"Name":"NM_007103.4(NDUFV1):c.1157G>A (p.Arg386His)","Chromosome":"11","Start":"67611973","Stop":"67611973","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":488342,"rule_based_match":true,"evidence_text":"c.1157G > A (p.Arg386His)","llm_judgment":"PRESENT","evidence":"c.1157G > A (p.Arg386His)","abstract_start":765,"abstract_end":790}]}
{"pmid":"30689859","title":"Nonsense-mediated mRNA decay efficiency varies in choroideremia providing a target to boost small molecule therapeutics.","abstract":"Choroideremia (CHM) is an x-linked recessive chorioretinal dystrophy, with 30% caused by nonsense mutations in the CHM gene resulting in an in-frame premature termination codon (PTC). Nonsense-mediated mRNA decay (NMD) is the cell's natural surveillance mechanism that detects and destroys PTC-containing transcripts, with UPF1 being the central NMD modulator. NMD efficiency can be variable amongst individuals with some transcripts escaping destruction, leading to the production of a truncated non-functional or partially functional protein. Nonsense suppression drugs, such as ataluren, target these transcripts and read-through the PTC, leading to the production of a full length functional protein. Patients with higher transcript levels are considered to respond better to these drugs, as more substrate is available for read-through. Using Quantitative reverse transcription PCR (RT-qPCR), we show that CHM mRNA expression in blood from nonsense mutation CHM patients is 2.8-fold lower than controls, and varies widely amongst patients, with 40% variation between those carrying the same UGA mutation [c.715 C>T; p.(R239*)]. These results indicate that although NMD machinery is at work, efficiency is highly variable and not wholly dependent on mutation position. No significant difference in CHM mRNA levels was seen between two patients' fibroblasts and their induced pluripotent stem cell-derived retinal pigment epithelium. There was no correlation between CHM mRNA expression and genotype, phenotype or UPF1 transcript levels. NMD inhibition with caffeine was shown to restore CHM mRNA transcripts to near wild-type levels. Baseline mRNA levels may provide a prognostic indicator for response to nonsense suppression therapy, and caffeine may be a useful adjunct to enhance treatment efficacy where indicated.","variants":[{"Name":"NM_000390.4(CHM):c.715C>T (p.Arg239Ter)","Chromosome":"X","Start":"85958965","Stop":"85958965","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":269993,"rule_based_match":true,"evidence_text":"c.715 C>T; p.(R239*)","llm_judgment":"PRESENT","evidence":"c.715 C>T; p.(R239*)","abstract_start":1110,"abstract_end":1130}]}
{"pmid":"31428919","title":"Biallelic INTS1 Mutations Cause a Rare Neurodevelopmental Disorder in Two Chinese Siblings.","abstract":"This study presents two Chinese siblings with a rare neurodevelopmental disorder (NDD) caused by biallelic INTS1 mutations and investigates the clinical features of this disease by means of in silico analysis. Two siblings, an 11-year-old brother and a 5-year-old sister, visited our hospital due to physical retardation and profound intellectual disability. Whole-exome sequencing (WES) was performed for the girl, and Sanger sequencing was used to validate the identified variants. Phenotype correlation analysis and in silico genetic interaction network analysis were performed to investigate genes that could lead to diseases similar to the rare disease in the patients. Growth retardation, distinct intellectual disability, hypertelorism, mild cataract, uneven teeth, abnormal palmar and plantar creases, and dubious genitalia were noted in the sister. No neurological features related to neuropathy were found. The brother showed features and growth delay similar to his sister. Heterozygous novel variants of c.1645A>G,p.Met549Val and c.5881C>T,p.Gln1961* in INTS1 were considered a candidate etiology. Sanger sequencing demonstrated that the variants were inherited from the grandfather and (maternal) grandmother. Phenotype correlation analysis revealed that CTDP1 mutation-induced congenital cataracts-facial dysmorphism-neuropathy (CCFDN) mostly overlapped with the performance of our patients. In silico analysis of the genetic interaction network showed that INTS1 is highly associated with INTS8 and CTDP1. Our study further validated that biallelic INTS1 mutations could bring about the onset of a novel neurodevelopmental disorder.","variants":[{"Name":"NM_001080453.3(INTS1):c.1645A>G (p.Met549Val)","Chromosome":"7","Start":"1496222","Stop":"1496222","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":677202,"rule_based_match":true,"evidence_text":"c.1645A>G,p.Met549Val","llm_judgment":"PRESENT","evidence":"c.1645A>G,p.Met549Val","abstract_start":1016,"abstract_end":1037},{"Name":"NM_001080453.3(INTS1):c.5881C>T (p.Gln1961Ter)","Chromosome":"7","Start":"1473642","Stop":"1473642","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":677203,"rule_based_match":true,"evidence_text":"c.5881C>T,p.Gln1961*","llm_judgment":"PRESENT","evidence":"c.5881C>T,p.Gln1961*","abstract_start":1042,"abstract_end":1062}]}
{"pmid":"32043305","title":"Sequence variant in the CDC42BPB gene is potentially associated with Mullerian duct anomalies.","abstract":"AIM: Mullerian duct anomalies (MDA) are common female genital tract malformations. Genetic and environmental factors are important causes of MDA in women. Although many genes and mutations have been found to be associated with the pathogenesis of MDA, in most cases, the genetic pathogenic factors of MDA are still unknown.\nMETHODS: We first analyzed the three sisters using low coverage whole-genome sequencing. Then whole-exome sequencing was carried out in each patient. The identified sequence variant was confirmed by Sanger sequencing. In silico pathogenicity analysis and conservative analysis of the mutation site were also performed. Protein structural modeling was used to analyze the effect of the mutated amino acid.\nRESULTS: We first analyzed the three sisters with septate uterus using low coverage whole-genome sequencing, but no possible pathogenic copy number variation was found. Then whole-exome sequencing was performed on the three sisters, and a rare homozygous variant, CDC42BPB:c.2012G>A:p.R671Q, was identified. All three patients were found with this variant. Sanger sequencing validated that this variant was segregated within the family. In silico pathogenicity analysis and conservative analysis of the mutation site suggested that the variant might be damaging. Protein structural analysis suggested that R671Q might weaken the electrostatic potential of this region, which may be a significant regulation target or protein interaction surface of CDC42BPB.\nCONCLUSION: We demonstrated that CDC42BPB genetic variant might be potentially associated with the pathogenesis of MDA.","variants":[{"Name":"NM_006035.4(CDC42BPB):c.2012G>A (p.Arg671Gln)","Chromosome":"14","Start":"102968700","Stop":"102968700","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1678944,"rule_based_match":true,"evidence_text":"CDC42BPB:c.2012G>A:p.R671Q","llm_judgment":"PRESENT","evidence":"CDC42BPB:c.2012G>A:p.R671Q","abstract_start":993,"abstract_end":1019}]}
{"pmid":"34298454","title":"PRRT2 variants and effectiveness of various antiepileptic drugs in self-limited familial infantile epilepsy.","abstract":"PURPOSE: Self-limited familial infantile epilepsy (SFIE) is largely associated with variants in proline-rich transmembrane protein 2 (PRRT2). However, the detailed phenotype-genotype correlations are unclear, along with the efficacy of various antiepileptic drugs in the treatment of this epilepsy syndrome. In this study, we analysed the PRRT2 variants associated with SFIE in Chinese patients, and the efficacy of different antiepileptic drugs prescribed during follow-up.\nMETHODS: We retrospectively included 20 patients diagnosed with SFIE and reviewed their clinical characteristics, genetic variants, and treatment responses.\nRESULTS: Eighteen of the 20 (90%) patients harboured the common heterozygous variant of PRRT2 c.649dupC p.(Arg217fs). One patient had two heterozygous variants of PRRT2, c.640G>C p.(Ala214Pro) and c.955G>T p.(Val319Leu), and the other patient harboured a novel c.606delA (p.Pro203Hisfs) variant. Nine patients who had first-line treatment of oxcarbazepine (OXC) became seizure-free. However, initial treatment with levetiracetam (LEV) or sodium valproate (VPA) in eight and three patients, respectively, was not effective even after increasing the dosage, and seizure-free status was only achieved after changing the treatment to OXC. The treatment responses suggested a significant difference (P < 0.001) between OXC and other anti-epileptic drugs.\nCONCLUSION: OXC as a sodium channel blocker may have a better effect than LEV and VPA in the treatment of PRRT2-associated SFIE. PRRT2 variants may be used as a biomarker to help select antiepileptic drugs for SFIE.","variants":[{"Name":"NM_145239.3(PRRT2):c.955G>T (p.Val319Leu)","Chromosome":"16","Start":"29814408","Stop":"29814408","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1394070,"rule_based_match":true,"evidence_text":"c.955G>T p.(Val319Leu)","llm_judgment":"PRESENT","evidence":"c.955G>T p.(Val319Leu)","abstract_start":829,"abstract_end":851}]}
{"pmid":"31323543","title":"Three novel mutations in a group of Chinese patients with X-linked Charcot-Marie-Tooth disease.","abstract":"The X-linked form of Charcot-Marie-Tooth disease type1 (CMTX1) is the second most common hereditary motor and sensory neuropathy caused by mutations in the gap junction beta 1 (GJB1) gene. Here, we report the clinical and genetic features of six unrelated Chinese patients with CMTX1, which were identified by genetic analysis. Among the 6 identified mutations, 3 were previously unknown (c.31A > T, c.42 C > G and c.423 del C). The six patients showed typical signs of CMT with a median age of onset of 16.5 years (range: 13-30). Sensorineural hearing loss was confirmed in the patient with the c.423 del C mutation. White matter lesions on brain magnetic resonance imaging (MRI) were observed in two patients. The three newly identified GJB1 mutations expand the clinical and mutational spectrum of CMTX1.","variants":[{"Name":"NM_000166.6(GJB1):c.42C>G (p.Asn14Lys)","Chromosome":"X","Start":"71223749","Stop":"71223749","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":850241,"rule_based_match":true,"evidence_text":"c.42 C > G","llm_judgment":"PRESENT","evidence":"c.42 C > G","abstract_start":400,"abstract_end":410}]}
{"pmid":"29800053","title":"Olfactory Dysfunction in Patients With CNGB1-Associated Retinitis Pigmentosa.","abstract":"Importance: Co-occurrence of retinitis pigmentosa (RP) and olfactory dysfunction may have a common genetic cause.\nObjective: To report olfactory function and the retinal phenotype in patients with biallelic mutations in CNGB1, a gene coding for a signal transduction channel subunit expressed in rod photoreceptors and olfactory sensory neurons.\nDesign, Setting, and Participants: This case series was conducted from August 2015 through July 2017. The setting was a multicenter study involving 4 tertiary referral centers for inherited retinal dystrophies. Participants were 9 patients with CNGB1-associated RP.\nMain Outcomes and Measures: Results of olfactory testing, ocular phenotyping, and molecular genetic testing using targeted next-generation sequencing.\nResults: Nine patients were included in the study, 3 of whom were female. Their ages ranged between 34 and 79 years. All patients had an early onset of night blindness but were usually not diagnosed as having RP before the fourth decade because of slow retinal degeneration. Retinal features were characteristic of a rod-cone dystrophy. Olfactory testing revealed reduced or absent olfactory function, with all except one patient scoring in the lowest quartile in relation to age-related norms. Brain magnetic resonance imaging and electroencephalography measurements in response to olfactory stimulation were available for 1 patient and revealed no visible olfactory bulbs and reduced responses to odor, respectively. Molecular genetic testing identified 5 novel (c.1312C>T, c.2210G>A, c.2492+1G>A, c.2763C>G, and c.3044_3050delGGAAATC) and 5 previously reported mutations in CNGB1.\nConclusions and Relevance: Mutations in CNGB1 may cause an autosomal recessive RP-olfactory dysfunction syndrome characterized by a slow progression of retinal degeneration and variable anosmia or hyposmia.","variants":[{"Name":"NM_001297.5(CNGB1):c.2210G>A (p.Arg737His)","Chromosome":"16","Start":"57916136","Stop":"57916136","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1484210,"rule_based_match":true,"evidence_text":"c.2210G>A","llm_judgment":"PRESENT","evidence":"c.2210G>A","abstract_start":1539,"abstract_end":1548},{"Name":"NM_001297.5(CNGB1):c.2492+1G>A","Chromosome":"16","Start":"57911752","Stop":"57911752","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1063714,"rule_based_match":true,"evidence_text":"c.2492+1G>A","llm_judgment":"PRESENT","evidence":"c.2492+1G>A","abstract_start":1550,"abstract_end":1561}]}
{"pmid":"30745123","title":"Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr).","abstract":"INTRODUCTION: A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1.\nMETHODS: We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing.\nRESULTS: Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03).\nDISCUSSION: Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a \"mini-population bottleneck\" and subsequent emergence of a rare dominant mutation.","variants":[{"Name":"NM_000021.4(PSEN1):c.1247T>C (p.Ile416Thr)","Chromosome":"14","Start":"73217243","Stop":"73217243","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1167852,"rule_based_match":true,"evidence_text":"NM_000021.3: c.1247T>C p.Ile416Thr","llm_judgment":"PRESENT","evidence":"NM_000021.3: c.1247T>C p.Ile416Thr","abstract_start":411,"abstract_end":445}]}
{"pmid":"22821680","title":"Primary hyperoxaluria type 1 and brachydactyly mental retardation syndrome caused by a novel mutation in AGXT and a terminal deletion of chromosome 2.","abstract":"Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by mutations in the alanine:glyoxylate aminotransferase (AGXT) gene, located on chromosome 2q37. Mutant AGXT leads to excess production and excretion of oxalate, resulting in accumulation of calcium oxalate in the kidney, and progressive loss of renal function. Brachydactyly mental retardation syndrome (BDMR) is an autosomal dominant disorder, caused by haploinsufficiency of histone deacetylase 4 (HDAC4), also on chromosome 2q37. It is characterized by skeletal abnormalities and developmental delay. Here, we report on a girl who had phenotypes of both PH1 and BDMR. PCR-sequencing of the coding regions of AGXT showed a novel missense mutation, c.32C>G (p.Pro11Arg) inherited from her mother. Functional analyses demonstrated that it reduced the enzymatic activity to 31% of the wild-type and redirected some percentage of the enzyme away from the peroxisome. Microsatellite and array-CGH analyses indicated that the proband had a paternal de novo telomeric deletion of chromosome 2q, which included HDAC4. To our knowledge, this is the first report of PH1 and BDMR, with a novel AGXT mutation and a de novo telomeric deletion of chromosome 2q.","variants":[{"Name":"NM_000030.3(AGXT):c.32C>G (p.Pro11Arg)","Chromosome":"2","Start":"240868897","Stop":"240868897","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":200424,"rule_based_match":true,"evidence_text":"c.32C>G (p.Pro11Arg)","llm_judgment":"PRESENT","evidence":"c.32C>G (p.Pro11Arg)","abstract_start":728,"abstract_end":748}]}
{"pmid":"25774885","title":"Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism.","abstract":"CONTEXT: Hypergonadotropic hypogonadism presents in females with delayed or arrested puberty, primary or secondary amenorrhea due to gonadal dysfunction, and is further characterized by elevated gonadotropins and low sex steroids. Chromosomal aberrations and various specific gene defects can lead to hypergonadotropic hypogonadism. Responsible genes include those with roles in gonadal development or maintenance, sex steroid synthesis, or end-organ resistance to gonadotropins. Identification of novel causative genes in this disorder will contribute to our understanding of the regulation of human reproductive function.\nOBJECTIVES: The aim of this study was to identify and report the gene responsible for autosomal-recessive hypergonadotropic hypogonadism in two unrelated families.\nDESIGN AND PARTICIPANTS: Clinical evaluation and whole-exome sequencing were performed in two pairs of sisters with nonsyndromic hypergonadotropic hypogonadism from two unrelated families.\nRESULTS: Exome sequencing analysis revealed two different truncating mutations in the same gene: SOHLH1 c.705delT (p.Pro235fs*4) and SOHLH1 c.27C>G (p.Tyr9stop). Both mutations were unique to the families and segregation was consistent with Mendelian expectations for an autosomal-recessive mode of inheritance.\nCONCLUSIONS: Sohlh1 was known from previous mouse studies to be a transcriptional regulator that functions in the maintenance and survival of primordial ovarian follicles, but loss-of-function mutations in human females have not been reported. Our results provide evidence that homozygous-truncating mutations in SOHLH1 cause female nonsyndromic hypergonadotropic hypogonadism.","variants":[{"Name":"NM_001101677.2(SOHLH1):c.27C>G (p.Tyr9Ter)","Chromosome":"9","Start":"135699441","Stop":"135699441","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":215662,"rule_based_match":true,"evidence_text":"SOHLH1 c.27C>G (p.Tyr9stop)","llm_judgment":"PRESENT","evidence":"SOHLH1 c.27C>G (p.Tyr9stop)","abstract_start":1110,"abstract_end":1137}]}
{"pmid":"35114507","title":"BAP1 germline variants in Finnish patients with malignant mesothelioma.","abstract":"OBJECTIVES: Although asbestos exposure is the most common cause of malignant mesothelioma (MM), an aggressive cancer of the pleura or peritoneum, up to 7% of patients harbor a genetic predisposition to MM. Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause a dominantly inherited tumor predisposition syndrome, BAP1-TPDS, in which MM is the second most common associated cancer. Other frequent cancers in BAP1-TPDS are uveal melanoma (UM), cutaneous melanoma and renal cell carcinoma. Additionally patients can exhibit benign skin lesions, BAP1-inactivated nevi (BIN). Most BINs arise sporadically, but patients with BAP1-TPDS may harbor multiple BINs before other tumors or as the only indication of the syndrome. Our objective was to establish the frequency of pathogenic germline BAP1 variants in Finnish patients with MM.\nMATERIALS AND METHODS: 56 DNA samples archived in the Helsinki Biobank from Finnish patients with MM were sequenced for germline BAP1 variations. Formalin fixed paraffin embedded nevi from a pathogenic variant carrier were subjected to immunohistochemistry and exome sequencing.\nRESULTS: Sanger sequencing identified one patient with Finnish founder mutation c.1780_1781insT, p.(G549Vfs*49) in BAP1. The carrier was diagnosed with MM over fifteen years before the cohorts mean onset age (mean 68, range 27 to 82) although the patient had no asbestos exposure or family history of BAP1-TPDS. However, the patient had three BINs removed prior to the MM. The c.1780_1781insT is now found from five Finnish BAP1-TPDS families with unknown common ancestor.\nCONCLUSION: The frequency of pathogenic germline BAP1 variants in Finnish patients with MM is 1.8 % (95 % CI, 0.04 to 9.2), comparable to the frequency in Finnish patients with UM (1.9 %). The frequency of recurring BINs in patients with BAP1-TPDS should be studied further and genetic testing for BAP1 variants considered if the patient has ≥ 2 BAP1-TPDS core tumors, including BINs.","variants":[{"Name":"NM_004656.4(BAP1):c.1780_1781insT (p.Gly594fs)","Chromosome":"3","Start":"52403247","Stop":"52403248","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":3417387,"rule_based_match":true,"evidence_text":"c.1780_1781insT, p.(G549Vfs*49)","llm_judgment":"PRESENT","evidence":"c.1780_1781insT, p.(G549Vfs*49)","abstract_start":1215,"abstract_end":1246}]}
{"pmid":"20858721","title":"MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families.","abstract":"The variants c.306+5G>A and c.1865T>A (p.Leu622His) of the DNA repair gene MLH1 occur frequently in Spanish Lynch syndrome families. To understand their ancestral history and clinical effect, we performed functional assays and a penetrance analysis and studied their genetic and geographic origins. Detailed family histories were taken from 29 carrier families. Functional analysis included in silico and in vitro assays at the RNA and protein levels. Penetrance was calculated using a modified segregation analysis adjusted for ascertainment. Founder effects were evaluated by haplotype analysis. The identified MLH1 c.306+5G>A and c.1865T>A (p.Leu622His) variants are absent in control populations and segregate with the disease. Tumors from carriers of both variants show microsatellite instability and loss of expression of the MLH1 protein. The c.306+5G>A variant is a pathogenic mutation affecting mRNA processing. The c.1865T>A (p.Leu622His) variant causes defects in MLH1 expression and stability. For both mutations, the estimated penetrance is moderate (age-cumulative colorectal cancer risk by age 70 of 20.1% and 14.1% for c.306+5G>A and of 6.8% and 7.3% for c.1865T>A in men and women carriers, respectively) in the lower range of variability estimated for other pathogenic Spanish MLH1 mutations. A common haplotype was associated with each of the identified mutations, confirming their founder origin. The ages of c.306+5G>A and c.1865T>A mutations were estimated to be 53 to 122 and 12 to 22 generations, respectively. Our results confirm the pathogenicity, moderate penetrance, and founder origin of the MLH1 c.306+5G>A and c.1865T>A mutations. These findings have important implications for genetic counseling and molecular diagnosis of Lynch syndrome.","variants":[{"Name":"NM_000249.4(MLH1):c.1865T>A (p.Leu622His)","Chromosome":"3","Start":"37047652","Stop":"37047652","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":38612,"rule_based_match":true,"evidence_text":"c.1865T>A (p.Leu622His)","llm_judgment":"PRESENT","evidence":"c.1865T>A (p.Leu622His)","abstract_start":28,"abstract_end":51},{"Name":"NM_000249.4(MLH1):c.306+5G>A","Chromosome":"3","Start":"37001058","Stop":"37001058","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":95622,"rule_based_match":true,"evidence_text":"c.306+5G>A","llm_judgment":"PRESENT","evidence":"c.306+5G>A","abstract_start":13,"abstract_end":23}]}
{"pmid":"28211972","title":"TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex.","abstract":"Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder with variable expressivity associated with hamartomatous tumors, abnormalities of the skin, and neurologic problems including seizures, intellectual disability, and autism. TSC is caused by pathogenic variants in either TSC1 or TSC2. In general, TSC2 pathogenic variants are associated with a more severe phenotype than TSC1 pathogenic variants. Here, we report a pathogenic TSC2 variant, c.1864C>T, p.(Arg622Trp), associated with a mild phenotype, with most carriers meeting fewer than two major clinical diagnostic criteria for TSC. This finding has significant implications for counseling patients regarding prognosis. More patient data are required before changing the surveillance recommendations for patients with the reported variant. However, consideration should be given to tailoring surveillance recommendations for all pathogenic TSC1 and TSC2 variants with documented milder clinical sequelae. © 2017 Wiley Periodicals, Inc.","variants":[{"Name":"NM_000548.5(TSC2):c.1864C>T (p.Arg622Trp)","Chromosome":"16","Start":"2071534","Stop":"2071534","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75819,"rule_based_match":true,"evidence_text":"c.1864C>T, p.(Arg622Trp)","llm_judgment":"PRESENT","evidence":"c.1864C>T, p.(Arg622Trp)","abstract_start":468,"abstract_end":492}]}
{"pmid":"24915996","title":"Conradi-Hünermann-Happle syndrome: a novel heterozygous missense mutation, c.204G>T (p.W68C).","abstract":"Conradi-Hünermann-Happle syndrome (X-linked dominant chondrodysplasia punctata, CDPX2 [Online Mendelian Inheritance in Man 302960]) is a rare genodermatosis that presents with blaschkolinear ichthyosis, cicatricial alopecia, chondrodysplasia punctata, asymmetric shortening of the bones, and cataracts. In this case report we describe a child presenting with a patterned alopecia in which supplementary signs and clinical examination of the mother led to the suspicion of Conradi-Hünermann-Happle syndrome. Mutation analysis revealed a heterozygous novel missense mutation, c.204G>T (p.W68C), in exon 2.","variants":[{"Name":"NM_006579.3(EBP):c.204G>T (p.Trp68Cys)","Chromosome":"X","Start":"48523975","Stop":"48523975","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":170115,"rule_based_match":true,"evidence_text":"c.204G>T (p.W68C)","llm_judgment":"PRESENT","evidence":"c.204G>T (p.W68C)","abstract_start":574,"abstract_end":591}]}
{"pmid":"25763508","title":"Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under L-DOPA, 5-HTP and BH4 Trials.","abstract":"UNLABELLED: Objective/context: We describe the second patient presenting the combination of two homoallelic homozygous nonsense mutations in two genes distant from 1.8 Mb in the chromosome 2p13-3, the methylmalonyl-CoA epimerase gene (MCEE) and the sepiapterin reductase gene (SPR).\nCASE REPORT: The patient was born from consanguineous parents. He has presented a moderate but constant methylmalonic acid (MMA) excretion in urine associated with a mental retardation. The first homozygous mutation was identified in the MCEE gene (c.139C>T; p.Arg47*). Progressive dystonia and cataplexy narcolepsy led to diagnose the second homozygous mutation in the SPR gene: c.751A>T; p.Lys251*. Sepiapterin reductase deficiency (SRD) was characterized by a defect in tetrahydrobiopterin (BH4), the cofactor of several hydroxylases needed for the synthesis of neurotransmitters. A treatment with L-DOPA/carbidopa and 5-HTP dramatically improved the dystonic posture, the mood and the hypersomnia, proving that the pathogenesis was due to SRD. A supplementation with BH4 did not induce additional clinical benefit, although HVA and HIAA increased in CSF. The polyunsaturated fatty acids were measured in CSF as the markers of the neuronal stress. We have shown that DHA and its precursor EPA were high before and during the time course of the different treatments.\nIN CONCLUSION: The patient has inherited two copies of the two mutations from his consanguineous parents in the MCEE and SPR genes in the chromosome 2p13-3. DHA and EPA increased in CSF as a response to the neuronal stress induced by the defect in neurotransmitters or the altered metabolism of the odd-chain fatty acids and cholesterol.","variants":[{"Name":"NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)","Chromosome":"2","Start":"71124445","Stop":"71124445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17382,"rule_based_match":true,"evidence_text":"c.139C>T","llm_judgment":"PRESENT","evidence":"c.139C>T","abstract_start":532,"abstract_end":540},{"Name":"NM_003124.5(SPR):c.751A>T (p.Lys251Ter)","Chromosome":"2","Start":"72891502","Stop":"72891502","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":27983,"rule_based_match":true,"evidence_text":"c.751A>T; p.Lys251*","llm_judgment":"PRESENT","evidence":"c.751A>T; p.Lys251*","abstract_start":663,"abstract_end":682}]}
{"pmid":"21990045","title":"Novel FAM20A mutations in hypoplastic amelogenesis imperfecta.","abstract":"Amelogenesis imperfecta (AI) is a genetically and clinically heterogeneous group of inherited dental enamel defects without any other nonoral symptoms. Recently, a disease-causing nonsense mutation (c.406C>T) in a novel gene, FAM20A, was identified in a large consanguineous family affected by AI with gingival hyperplasia. We performed mutational analyses on nine AI families with similar phenotypes and identified three homozygous mutations (c.34_35delCT, c.813-2A>G, c.1175_1179delGGCTC) in three families and a compound heterozygous mutation (c.[590-2A>G] + [c.826C>T]) in one family. An in vitro splicing assay with a minigene confirmed the mutations located in the splicing acceptor site caused the deletion of exons 3 and 6, respectively. Taking into consideration the locations of the nonsense and frameshift mutations, the mutant transcripts are most likely degraded by nonsense-mediated mRNA degradation and it results in a loss of the FAM20A protein. This study confirms the importance of the FAM20A protein in enamel biomineralization as well as tooth eruption.","variants":[{"Name":"NM_017565.4(FAM20A):c.34_35del (p.Leu12fs)","Chromosome":"17","Start":"68600632","Stop":"68600633","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":44147,"rule_based_match":true,"evidence_text":"c.34_35delCT","llm_judgment":"PRESENT","evidence":"c.34_35delCT","abstract_start":444,"abstract_end":456},{"Name":"NM_017565.4(FAM20A):c.813-2A>G","Chromosome":"17","Start":"68542811","Stop":"68542811","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":44148,"rule_based_match":true,"evidence_text":"c.813-2A>G","llm_judgment":"PRESENT","evidence":"c.813-2A>G","abstract_start":458,"abstract_end":468},{"Name":"NM_017565.4(FAM20A):c.1175_1179del (p.Arg392fs)","Chromosome":"17","Start":"68540889","Stop":"68540893","ReferenceAlleleVCF":"GGAGCC","AlternateAlleleVCF":"G","allel_id":44149,"rule_based_match":true,"evidence_text":"c.1175_1179delGGCTC","llm_judgment":"PRESENT","evidence":"c.1175_1179delGGCTC","abstract_start":470,"abstract_end":489},{"Name":"NM_017565.4(FAM20A):c.826C>T (p.Arg276Ter)","Chromosome":"17","Start":"68542796","Stop":"68542796","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44151,"rule_based_match":true,"evidence_text":"c.826C>T","llm_judgment":"PRESENT","evidence":"c.826C>T","abstract_start":563,"abstract_end":571},{"Name":"NM_017565.4(FAM20A):c.406C>T (p.Arg136Ter)","Chromosome":"17","Start":"68555742","Stop":"68555742","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39836,"rule_based_match":true,"evidence_text":"c.406C>T","llm_judgment":"PRESENT","evidence":"c.406C>T","abstract_start":199,"abstract_end":207}]}
{"pmid":"17351744","title":"ATM allelic variants associated to hereditary breast cancer in 94 Chilean women: susceptibility or ethnic influences?","abstract":"Besides BRCA1 and BRCA2, two genes accounting for a small proportion of breast cancer cases, ATM has been widely proposed as a low-penetrance susceptibility gene. Several nucleotide changes have been proposed to be associated with breast cancer, still remaining a high controversy in this sense. We screened the ATM gene in 94 breast cancer patients selected from 78 high-risk families, not presenting a mutation in BRCA1 or BRCA2. We found three novel allelic variants: IVS64 + 51delT and p.L752L, not showing association with hereditary breast cancer, and p.L694L found in one family in two breast cancer patients. Two amino acid substitutions p.S707P and p.F858L, previously reported to be associated with breast cancer, were present in our study in cases and controls, lacking of association with breast cancer. A positive association of c.5557G>A (p.D1853N) was found (OR 2.52, P = 0.008), when analyzed alone and in combination with an intronic variant IVS24-9delT (OR 3.97; P = 0.0003). We postulate that our discrepancies with other reports related to the associated ATM alleles to hereditary breast cancer, as well as discrepancies in the literature between other groups, could be explained by the diversity in the ethnic origins of families gathered in a sole study, and the selection of the control group. In relation to this issue, and based on genetic markers, we found that the Chilean group of breast cancer families in this study has a stronger European genetic component than our control sample selected randomly from the Chilean population.","variants":[{"Name":"NM_000051.4(ATM):c.5557G>A (p.Asp1853Asn)","Chromosome":"11","Start":"108304735","Stop":"108304735","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133907,"rule_based_match":true,"evidence_text":"c.5557G>A (p.D1853N)","llm_judgment":"PRESENT","evidence":"c.5557G>A (p.D1853N)","abstract_start":842,"abstract_end":862}]}
{"pmid":"27196444","title":"Karyomegalic Interstitial Nephritis: A Case Report and Review of the Literature.","abstract":"Karyomegalic interstitial nephritis is a rare cause of hereditary chronic interstitial nephritis, described for the first time over 40 years ago.A 36-year-old woman, of Turkish origin, presented with chronic kidney disease and high blood pressure. She had a history of recurrent upper respiratory tract infections but no familial history of nephropathy. Physical examination was unremarkable. Laboratory tests showed serum creatinine at 2.3 mg/dL with an estimated glomerular filtration rate of 26 mL/min/1.73m, and gamma-glutamyl transpeptidase and alkaline phosphatase at 3 and 1.5 times the upper normal limit. Urinalysis showed 0.8 g/day of nonselective proteinuria, microscopic hematuria, and aseptic leukocyturia. Immunological tests and tests for human immunodeficiency and hepatitis B and C viruses were negative. Complement level and serum proteins electrophoresis were normal. Analysis of the renal biopsy showed severe interstitial fibrosis and tubular atrophy. Numerous tubular cells had nuclear enlargement with irregular outlines, hyperchromatic aspect, and prominent nucleoli. These findings were highly suggestive of karyomegalic interstitial nephritis, which was further confirmed by exome sequencing of FAN1 gene showing an identified homozygous frameshift mutation due to a one-base-pair deletion in exon 12 (c.2616delA).The present case illustrates a rare but severe cause of hereditary interstitial nephritis, sometimes accompanied by subtle extrarenal manifestations. Identification of mutations in FAN1 gene underscores recent insights linking inadequate DNA repair and susceptibility to chronic kidney disease.","variants":[{"Name":"NM_014967.5(FAN1):c.2616del (p.Asp873fs)","Chromosome":"15","Start":"30929226","Stop":"30929226","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":430985,"rule_based_match":true,"evidence_text":"c.2616delA","llm_judgment":"PRESENT","evidence":"c.2616delA","abstract_start":1328,"abstract_end":1338}]}
{"pmid":"31644447","title":"Congenital factor XI deficiency, complete genotype and phenotype of two Iranian families.","abstract":": Congenital factor XI (FXI) deficiency is a mild trauma-related bleeding disorder with estimated worldwide prevalence of one per 1 million. The disorder is less frequent in Iran and a few studies have been performed on Iranian patients. In the current study, we assessed molecular, laboratory and clinical features of two Iranian patients with congenital FXI deficiency and their families. Clinical features and demographic data of the patients were assessed by the physician and a staff member trained specifically to deal with patients with bleeding disorders. FXI activity and antigen assays were performed for seven members of the two families and genotyping was performed by direct sequencing of all F11 gene exons and intron-exon boundaries as well as the untranslated regions. Five members of the two families were affected by FXI deficiency. Both patients experienced prolonged epistaxis, whereas other family members were asymptomatic. Two gene defects were observed in the patients and their families. Two disease-causing mutations were c.943G>A (p.Glu315Lys) missense and the four-nucleotide deletion (g.27849-27852del) in exon 15. The gene deletion was observed in homozygote state in the patient with severe FXI deficiency (FXI activity <1%) and heterozygote state in the parent, whereas the c.943G>A mutation was detected in heterozygote state and was accompanied by epistaxis in the patient. FXI deficiency is a mild bleeding disorder that is caused by heterogeneous molecular defects.","variants":[{"Name":"NM_000128.4(F11):c.943G>A (p.Glu315Lys)","Chromosome":"4","Start":"186280300","Stop":"186280300","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":79095,"rule_based_match":true,"evidence_text":"c.943G>A (p.Glu315Lys)","llm_judgment":"PRESENT","evidence":"c.943G>A (p.Glu315Lys)","abstract_start":1048,"abstract_end":1070}]}
{"pmid":"17536269","title":"Analysis of gene mutations in two patients with tuberous sclerosis complex","abstract":"OBJECTIVE: To analyze the mutation of TSC gene in two sporadic patients with tuberous sclerosis complex (TSC).\nMETHODS: All the coding exons of TSC1 and TSC2 genes of these two patients, unaffected member in the two families, and 100 unrelated population-matched controls were amplified by polymerase chain reaction. The products were analyzed by direct sequencing.\nRESULT: Two TSC2 gene mutations (c. 268C > T, c. 5 227C > T) were identified in two patients, but not in their family members and in 100 unrelated population-matched controls.\nCONCLUSION: These two mutations are the cause of the clinical phenotypes of these two sporadic patients with TSC.","variants":[{"Name":"NM_000548.5(TSC2):c.268C>T (p.Gln90Ter)","Chromosome":"16","Start":"2053384","Stop":"2053384","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":58900,"rule_based_match":true,"evidence_text":"c. 268C > T","llm_judgment":"PRESENT","evidence":"c. 268C > T","abstract_start":399,"abstract_end":410}]}
{"pmid":"36038301","title":"Clinical phenotypes and genotypic spectrum of cystic fibrosis with pancreatic insufficiency in children","abstract":"<b>Objective:</b> To investigate the clinical phenotypes and genotypic spectrum of exocrine pancreatic insufficiency in children with cystic fibrosis. <b>Methods:</b> This was a retrospective analysis of 12 children with cystic fibrosis who presented to Children's Hospital of Fudan University from December 2017 to December 2021. Clinical features, fecal elastase-1 level, genotype, diagnosis and treatment were systematically reviewed. <b>Results:</b> A total of 12 children, 7 males and 5 females, diagnosis aged 5.4 (2.0, 10.6) years, were recruited. Common clinical features included chronic cough in 12 cases, malnutrition in 7 cases, steatorrhea in 7 cases, bronchiectasis in 5 cases and electrolyte disturbance in 4 cases. Exocrine pancreatic insufficiency were diagnosed in 8 cases,the main clinical manifestations were steatorrhea in 7 cases, of which 5 cases started in infancy; 6 cases were complicated with malnutrition, including mild in 1 case, moderate in 2 cases and severe in 3 cases; 3 cases had abdominal distension; 2 cases had intermittent abdominal pain; 4 cases showed fatty infiltration or atrophy of pancreas and 3 cases showed no obvious abnormality by pancreatic magnetic resonance imaging or B-ultrasound. All 8 children were given pancreatic enzyme replacement therapy, follow-up visit of 2.3 (1.2,3.2) years. Diarrhea significantly improved in 6 cases, and 1 case was added omeprazole due to poor efficacy. A total of 20 variations of CFTR were detected in this study, of which 7 were novel (c.1373G>A,c.1810A>C,c.270delA,c.2475_2478dupCGAA,c.2489_c.2490insA, c.884delT and exon 1 deletion). <b>Conclusions:</b> There is a high proportion of exocrine pancreatic insufficiency in Chinese patients with cystic fibrosis. The main clinical manifestations are steatorrhea and malnutrition. Steatorrhea has often started from infancy. Pancreatic enzyme replacement therapy can significantly improve the symptoms of diarrhea and malnutrition.","variants":[{"Name":"NM_000492.4(CFTR):c.1373G>A (p.Gly458Glu)","Chromosome":"7","Start":"117548804","Stop":"117548804","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3410781,"rule_based_match":true,"evidence_text":"c.1373G>A","llm_judgment":"PRESENT","evidence":"c.1373G>A","abstract_start":1523,"abstract_end":1532}]}
{"pmid":"32055014","title":"Smith-Lemli-Opitz syndrome: what is the actual risk for couples carriers of the DHCR7:c.964-1G>C variant?","abstract":"The founder variant DHCR7:c.964-1G>C causing autosomal recessive Smith-Lemli-Opitz (SLOS) was introduced into the Israeli preconception carrier program for Ashkenazi Jews in 2017 because of the high carrier frequency in this population (2.3%). Other disease-causing variants in DHCR7 are relatively rare in Israeli population. Discrepancy between the carrier frequency and disease prevalence raises the question of the actual risks for affected offspring for couples detected by the screening program. We performed a literature review of all relevant publications regarding homozygous DHCR7:c.964-1G>C fetuses/patients. We also collected clinical data about couples identified in the national screening program, including reproductive history. Out of 32 homozygous fetuses, six died in utero, 11 pregnancies were terminated during second trimester, and 15 children were born. All died between first days of life till 3 months of age. Reproductive history of SLOS-at-risk couples showed that after correction for ascertainment bias, out of 61 pregnancies, there was an absence of affected fetuses/children and an excess of miscarriages even if assumed that all the homozygous fetuses were miscarried. Out of these, eight families were Israelis, they had a total of one sick child, 21 healthy children, and 21 miscarriages. Our observations support the previous knowledge that homozygosity for c.964-1G>C in DHCR7 leads to a severe phenotype or early miscarriage. An unexpected observation was the excess of early miscarriages. This phenomenon is unclear and awaits further studies.","variants":[{"Name":"NM_001360.3(DHCR7):c.964-1G>C","Chromosome":"11","Start":"71435840","Stop":"71435840","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":99628,"rule_based_match":true,"evidence_text":"DHCR7:c.964-1G>C","llm_judgment":"PRESENT","evidence":"DHCR7:c.964-1G>C","abstract_start":20,"abstract_end":36}]}
{"pmid":"32993725","title":"Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study.","abstract":"BACKGROUND: Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa.\nRESULTS: A total of 33 patients, aged 5-63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease.\nCONCLUSIONS: In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.","variants":[{"Name":"NM_000512.5(GALNS):c.1171A>G (p.Met391Val)","Chromosome":"16","Start":"88824838","Stop":"88824838","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":99069,"rule_based_match":true,"evidence_text":"NM_000512.5: c.1171A>G, p.Met391Val","llm_judgment":"PRESENT","evidence":"NM_000512.5: c.1171A>G, p.Met391Val","abstract_start":505,"abstract_end":540}]}
{"pmid":"26033879","title":"Clinical aspects of Fanconi anemia individuals with the same mutation of FANCF identified by next generation sequencing.","abstract":"BACKGROUND: Fanconi anemia (FA) is a rare genetic disease characterized by congenital malformations, aplastic anemia and increased risk of developing malignancies. FA is genetically heterogeneous as it is caused by at least 17 different genes. Among these, FANCA, FANCC, and FANCG account for approximately 85% of the patients whereas the remaining genes are mutated in only a small percentage of cases. For this reason, the molecular diagnostic process is complex and not always extended to all the FA genes, preventing the characterization of individuals belonging to rare groups.\nMETHODS: The FA genes were analyzed using a next generation sequencing approach in two unrelated families.\nRESULTS: The analysis identified the same, c.484_485del, homozygous mutation of FANCF in both families. A careful examination of three electively aborted fetuses in one family and one affected girl in the other indicated an association of the FANCF loss-of-function mutation with a severe phenotype characterized by multiple malformations.\nCONCLUSION: The systematic use of next generation sequencing will allow the recognition of individuals from rare complementation groups, a better definition of their clinical phenotypes, and consequently, an appropriate genetic counseling.","variants":[{"Name":"NM_022725.4(FANCF):c.484_485del (p.Leu162fs)","Chromosome":"11","Start":"22625326","Stop":"22625327","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":21382,"rule_based_match":true,"evidence_text":"c.484_485del","llm_judgment":"PRESENT","evidence":"c.484_485del","abstract_start":733,"abstract_end":745}]}
{"pmid":"29582526","title":"Whole-exome sequencing reveals a novel missense mutation in the MARS gene related to a rare Charcot-Marie-Tooth neuropathy type 2U.","abstract":"Charcot-Marie-Tooth (CMT) is a heterogeneous group of progressive disorders, characterized by chronic motor and sensory polyneuropathy. This hereditary disorder is related to numerous genes and varying inheritance patterns. Thus, many patients do not reach a final genetic diagnosis. We describe a 13-year-old girl presenting with progressive bilateral leg weakness and gait instability. Extensive laboratory studies and spinal magnetic resonance imaging scan were normal. Nerve conduction studies revealed severe lower limb peripheral neuropathy with prominent demyelinative component. Following presumptive diagnosis of chronic inflammatory demyelinating polyneuropathy, the patient received treatment with steroids and intravenous immunoglobulins courses for several months, with no apparent improvement. Whole-exome sequencing revealed a novel heterozygous c.2209C>T (p.Arg737Trp) mutation in the MARS gene (OMIM 156560). This gene has recently been related to CMT type 2U. In-silico prediction programs classified this mutation as a probable cause for protein malfunction. Allele frequency data reported this variant in 0.003% of representative Caucasian population. Family segregation analysis study revealed that the patient had inherited the variant from her 60-years old mother, reported as healthy. Neurologic examination of the mother demonstrated decreased tendon reflexes, while nerve conduction studies were consistent with demyelinative and axonal sensory-motor polyneuropathy. Our report highlights the importance of next-generation sequencing approach to facilitate the proper molecular diagnosis of highly heterogeneous neurologic disorders. Amongst other numerous benefits, this approach might prevent unnecessary diagnostic testing and potentially harmful medical treatment.","variants":[{"Name":"NM_004990.4(MARS1):c.2209C>T (p.Arg737Trp)","Chromosome":"12","Start":"57515154","Stop":"57515154","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1172460,"rule_based_match":true,"evidence_text":"c.2209C>T (p.Arg737Trp)","llm_judgment":"PRESENT","evidence":"c.2209C>T (p.Arg737Trp)","abstract_start":861,"abstract_end":884}]}
{"pmid":"32764743","title":"Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia.","abstract":"Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, reduced fertility, and randomization of the left/right body axis. It is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious axonemal defect for pathogenic variants using whole exome capture, next generation sequencing, and bioinformatic analysis assuming an autosomal recessive trait. We identified one subject with an apparently homozygous nonsense variant [(c.1762C>T), p.(Arg588*)] in the uncharacterized CFAP57 gene. Interestingly, the variant results in the skipping of exon 11 (58 amino acids), which may be due to disruption of an exonic splicing enhancer. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Nasal cells from the PCD patient express a shorter, mutant version of CFAP57 and the protein is not incorporated into the axoneme. The missing 58 amino acids include portions of WD repeats that may be important for loading onto the intraflagellar transport (IFT) complexes for transport or docking onto the axoneme. A reduced beat frequency and an alteration in ciliary waveform was observed. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is highly conserved in organisms that assemble motile cilia. CFAP57 is allelic with the BOP2/IDA8/FAP57 gene identified previously in Chlamydomonas reinhardtii. Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass tag (TMT) mass spectroscopy shows that FAP57 is missing, and the \"g\" inner dyneins (DHC7 and DHC3) and the \"d\" inner dynein (DHC2) are reduced, but the FAP57 paralog FBB7 is increased. Together, our data identify a homozygous variant in CFAP57 that causes PCD that is likely due to a defect in the inner dynein arm assembly process.","variants":[{"Name":"NM_001378189.1(CFAP57):c.1762C>T (p.Arg588Ter)","Chromosome":"1","Start":"43209749","Stop":"43209749","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1336511,"rule_based_match":true,"evidence_text":"c.1762C>T","llm_judgment":"PRESENT","evidence":"c.1762C>T","abstract_start":505,"abstract_end":514}]}
{"pmid":"27240426","title":"Hb Tarrant [α126(H9)Asp→Asn; HBA2: c.379G > A (or HBA1)] in a Chinese Family as a Cause of Familial Erythrocytosis.","abstract":"Hb Tarrant [α126(H9)Asp→Asn; HBA2: c.379G > A (or HBA1)], is a rare high oxygen affinity hemoglobin (Hb) variant that causes erythrocytosis, previously described in a few Mexican-American families. Here we report the first Chinese family with this Hb variant presenting with unexplained familial erythrocytosis. No evidence of hemolysis was seen. A locally adapted approach to the diagnostic process in clinical laboratories is discussed. Molecular analysis has an important role in confirmation of the diagnosis. Proper identification of this rare but clinically significant Hb variant is helpful for family counseling and will help to guide appropriate management of absolute erythrocytosis.","variants":[{"Name":"NM_000517.6(HBA2):c.379G>A (p.Asp127Asn)","Chromosome":"16","Start":"173550","Stop":"173550","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":30701,"rule_based_match":true,"evidence_text":"HBA2: c.379G > A","llm_judgment":"PRESENT","evidence":"HBA2: c.379G > A","abstract_start":29,"abstract_end":45}]}
{"pmid":"33451880","title":"Rapid-onset dystonia-parkinsonism with ATP1A3 mutation and left lower limb paroxysmal dystonia.","abstract":"BACKGROUND: Rapid-onset dystonia-parkinsonism (RDP) is a disease characterized by an abrupt onset of dystonia accompanied by signs of parkinsonism and prominent bulbar symptoms.\nCASE REPORT: We describe a case of a female patient, born after normal delivery, but diagnosed with mild intellectual disability at age 7. She presented with an abrupt onset of upper limb dystonia and bradykinesia without tremor in parkinsonism, as well as dysarthria and dysphagia caused by prominent bulbar symptoms, at age 9. She had normal findings on brain magnetic resonance imaging, electroencephalography, and blood examination but was diagnosed with a psychogenic disorder. At age 10, she developed left lower limb paroxysmal stiffness with pain, and at 14, she was hospitalized due to lasting paroxysmal symptoms. Whole-exome sequencing was performed for this index case and her parents, and a de novo missense variant c.829G > A, p.Glu277Lys in ATP1A3 was identified.\nDISCUSSION: This RDP case highlights a rare clinical feature of paroxysmal dystonia that affects the lower left limb and develops after the abrupt onset of permanent dystonia. Currently, there are only three reported RDP cases associated with the same missense mutation, and we summarized the clinical features of all cases including ours, such as onset of age, time for stable, RDP score, relapse and exacerbation. Various symptoms owing to ATP1A3 mutation could develop as ATP1A3-related neurological disorders beyond classical phenotypes such as alternating hemiplegia of childhood (AHC) or RDP. Although RDP is extremely rare during childhood, it is important to understand its clinical characteristics in children.","variants":[{"Name":"NM_152296.5(ATP1A3):c.829G>A (p.Glu277Lys)","Chromosome":"19","Start":"41985082","Stop":"41985082","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27950,"rule_based_match":true,"evidence_text":"c.829G > A, p.Glu277Lys","llm_judgment":"PRESENT","evidence":"c.829G > A, p.Glu277Lys","abstract_start":907,"abstract_end":930}]}
{"pmid":"27490115","title":"NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.","abstract":"PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD).\nMETHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq.\nRESULTS: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed.\nCONCLUSIONS: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad.Genet Med 19 4, 367-376.","variants":[{"Name":"NM_004959.5(NR5A1):c.274C>T (p.Arg92Trp)","Chromosome":"9","Start":"124500686","Stop":"124500686","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260482,"rule_based_match":true,"evidence_text":"c.274C>T p.(Arg92Trp)","llm_judgment":"PRESENT","evidence":"c.274C>T p.(Arg92Trp)","abstract_start":525,"abstract_end":546}]}
{"pmid":"30337194","title":"Two rare variants of the ANXA11 gene identified in Chinese patients with amyotrophic lateral sclerosis.","abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. A recent study has identified mutations in the ANXA11 gene (encoding the calcium-binding protein annexin A11) associated with ALS. Mutation screening of ANXA11 protein-coding exons was performed in a Chinese cohort of 434 patients with sporadic ALS and 50 index patients with familial ALS. Polymerase chain reaction and Sanger sequencing were used for mutation detection. We failed to discover an N-terminal mutation, which was common in the Caucasian cohort. We revealed two rare heterozygous missense variants, c.878C>T (p.A293V) and c.921C>G (p.I307M), which are absent from the population databases and non-neurological controls. They are both located in the conserved annexin domain. The carriers of the mutation exhibited the classical ALS phenotype without cognitive impairment. Our results suggested that further functional studies for these variants are required to support the pathogenicity.","variants":[{"Name":"NM_145868.2(ANXA11):c.921C>G (p.Ile307Met)","Chromosome":"10","Start":"80164081","Stop":"80164081","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3835945,"rule_based_match":true,"evidence_text":"c.921C>G (p.I307M)","llm_judgment":"PRESENT","evidence":"c.921C>G (p.I307M)","abstract_start":611,"abstract_end":629}]}
{"pmid":"19005574","title":"The EPHA2 gene is associated with cataracts linked to chromosome 1p.","abstract":"PURPOSE: Cataracts are a clinically and genetically heterogeneous disorder affecting the ocular lens, and the leading cause of treatable vision loss and blindness worldwide. Here we identify a novel gene linked with a rare autosomal dominant form of childhood cataracts segregating in a four generation pedigree, and further show that this gene is likely associated with much more common forms of age-related cataracts in a case-control cohort.\nMETHODS: Genomic DNA was prepared from blood leukocytes, and genotyping was performed by means of single nucleotide polymorphism (SNP) markers, and short tandem repeat (STR) markers. Linkage analyses were performed with the GeneHunter and MLINK programs, and association analyses were performed with the Haploview and Exemplar programs. Mutation detection was achieved by PCR amplification of exons and di-deoxy cycle-sequencing.\nRESULTS: Genome-wide linkage analysis with SNP markers, identified a likely disease-haplotype interval on chromosome 1p (rs707455-[approximately 10 Mb]-rs477558). Linkage to chromosome 1p was confirmed using STR markers D1S2672 (LOD score [Z]=3.56, recombination distance [theta]=0), and D1S2697 (Z=2.92, theta=0). Mutation profiling of positional-candidate genes detected a heterozygous transversion (c.2842G>T) in exon 17 of the gene coding for Eph-receptor type-A2 (EPHA2) that cosegregated with the disease. This missense change was predicted to result in the non-conservative substitution of a tryptophan residue for a phylogenetically conserved glycine residue at codon 948 (p.G948W), within a conserved cytoplasmic domain of the receptor. Candidate gene association analysis further identified SNPs in the EPHA2 region of chromosome 1p that were suggestively associated with age-related cataracts (p=0.007 for cortical cataracts, and p=0.01 for cortical and/or nuclear cataracts).\nCONCLUSIONS: These data provide the first evidence that EPHA2, which functions in the Eph-ephrin bidirectional signaling pathway of mammalian cells, plays a vital role in maintaining lens transparency.","variants":[{"Name":"NM_004431.5(EPHA2):c.2842G>T (p.Gly948Trp)","Chromosome":"1","Start":"16125304","Stop":"16125304","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":28297,"rule_based_match":true,"evidence_text":"c.2842G>T","llm_judgment":"PRESENT","evidence":"c.2842G>T","abstract_start":1277,"abstract_end":1286}]}
{"pmid":"31852434","title":"Broadening the phenotype of the TWNK gene associated Perrault syndrome.","abstract":"BACKGROUND: Perrault syndrome is a genetically heterogenous, very rare disease, characterized clinically by sensorineural hearing loss, ovarian dysfunction and neurological symptoms. We present the case of a 33 years old female patient with TWNK-associated Perrault syndrome. The TWNK gene is coding the mitochondrial protein Twinkle and currently there are only two reports characterizing the phenotype of TWNK-associated Perrault syndrome. None of these publications reported about special brain MRI alterations and neuropathological changes in the muscle and peripheral nerves.\nCASE PRESENTATION: Our patients with TWNK-dependent Perrault syndrome had severe bilateral hypoacusis, severe ataxia, polyneuropathy, lower limb spastic paraparesis with pyramidal signs, and gonadal dysgenesis. Psychiatric symptoms such as depression and paranoia were present as well. Brain MRI observed progressive cerebellar hyperintensive signs associated with cerebellar, medulla oblongata and cervical spinal cord atrophy. Light microscopy of the muscle biopsy detected severe neurogenic lesions. COX staining was centrally reduced in many muscle fibers. Both muscle and sural nerve electron microscopy detected slightly enlarged mitochondria with abnormal cristae surrounded by lipid vacuoles. In the sural nerve, dystrophic axons had focally uncompacted myelin lamellae present. Genetic investigation revealed multiple mtDNA deletion and compound heterozygous mutations of the TWNK gene (c.1196 A > G, c.1358 G > A).\nCONCLUSION: This study demonstrates that TWNK associated Perrault syndrome has a much broader phenotype as originally published. The coexistence of severe hypoacusis, spastic limb weakness, ataxia, polyneuropathy, gonadal dysgensia, hyperintense signals in the cerebellum and the presence of the mtDNA multiple deletion could indicate the impairment of the TWNK gene. This is the first report about pyramidal tract involvement and cerebellar MRI alteration associated with TWNK-related Perrault syndrome.","variants":[{"Name":"NM_021830.5(TWNK):c.1196A>G (p.Asn399Ser)","Chromosome":"10","Start":"100989406","Stop":"100989406","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":211434,"rule_based_match":true,"evidence_text":"c.1196 A > G","llm_judgment":"PRESENT","evidence":"c.1196 A > G","abstract_start":1477,"abstract_end":1489}]}
{"pmid":"18511281","title":"Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster.","abstract":"Charcot-Marie-Tooth polyneuropathies (CMT) are clinically and genetically heterogeneous. We describe a French-Canadian cluster of 17 recessive CMT cases belonging to 10 families with variable early-onset CMT and scoliosis. The patients demonstrate great intra- and inter-familial variability. Linkage analysis confirmed that all families are linked to CMT4C locus on chromosome 5q32 (multipoint LOD score of 9.06). Haplotype analysis suggests that two SH3TC2 mutations are present in this cohort. The majority of carrier chromosomes, 26 of 34 (76%), carry the c.2860C-->T mutation. Despite extensive sequencing, the other mutation is not yet uncovered. This study demonstrates that the clinical variability observed in CMT4C is due to other factors than the nature of the mutation and that further work is needed to better define the SH3TC2 gene to ensure the identification of all CMT4C mutations.","variants":[{"Name":"NM_024577.4(SH3TC2):c.2860C>T (p.Arg954Ter)","Chromosome":"5","Start":"149026872","Stop":"149026872","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17521,"rule_based_match":false,"evidence_text":"c.2860C-->T","llm_judgment":"PRESENT","evidence":"c.2860C-->T","abstract_start":560,"abstract_end":571}]}
{"pmid":"28432706","title":"Varied pathological and therapeutic response effects associated with CHCHD2 mutant and risk variants.","abstract":"Mutations and polymorphic risk variant of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) have been associated with late-onset Parkinson disease. In vivo pathological evidence of CHCHD2 mutations is currently lacking. Utilizing transgenic Drosophila model, we examined the relative pathophysiologic effect of the pathogenic (c.182C>T, p.Thr61Ile and c.434G>A, p.Arg145Gln) and the risk (c.5C>T, p.Pro2Leu) CHCHD2 variants. All the transgenic models exhibited locomotor dysfunction that could be exacerbated by rotenone exposure, dopaminergic neuron degeneration, reduction in lifespan, mitochondrial dysfunction, oxidative stress, and impairment in synaptic transmission. However, both mutants showed more severe early motor dysfunction, dopaminergic neuronal loss, and higher hydrogen peroxide production compared with the risk variant. p.Thr61Ile (co-segregated in three independent PD families) displayed the most severe phenotype followed by p.Arg145Gln (present only in index patient). We treated the transgenic flies with Ebselen, a mitochondrial hydrogen peroxide scavenger compound; Ebselen appears to be more effective in ameliorating motor function in the mutant than the risk variant models. We provide the first in vivo evidence of the pathological effects associated with CHCHD2 mutations. There was a difference in the pathological and drug response effects between the pathogenic and the risk variants. Ebselen may be a useful neuroprotective drug for carriers of CHCHD2 mutations.","variants":[{"Name":"NM_016139.4(CHCHD2):c.434G>A (p.Arg145Gln)","Chromosome":"7","Start":"56102878","Stop":"56102878","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215640,"rule_based_match":true,"evidence_text":"c.434G>A, p.Arg145Gln","llm_judgment":"PRESENT","evidence":"c.434G>A, p.Arg145Gln","abstract_start":367,"abstract_end":388},{"Name":"NM_016139.4(CHCHD2):c.182C>T (p.Thr61Ile)","Chromosome":"7","Start":"56104344","Stop":"56104344","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":215639,"rule_based_match":true,"evidence_text":"c.182C>T, p.Thr61Ile","llm_judgment":"PRESENT","evidence":"c.182C>T, p.Thr61Ile","abstract_start":342,"abstract_end":362}]}
{"pmid":"32846814","title":"Next-generation sequencing identifies a novel heterozygous I229T mutation on LMNA associated with familial cardiac conduction disease.","abstract":"LMNA gene encodes Lamin A and C (Lamin A/C), which are intermediate filament protein implicating in DNA replication and transcription. Mutations in LMNA are validated to cause cardiac conduction disease (CCD) and cardiomyopathy.In a Chinese family, we identified 5 members harboring the identical heterozygous LMNA (c.686T>C, I229T) disease-causing mutation, which was not found in the 535 healthy controls. In silico analysis, we revealed structural alteration in Lamin A/C I229T mutant. Furthermore, molecular docking identified human polycomb repressive complex 2 and Lamin A/C interact with higher affinity in the presence of I229T, thus may downregulate Nav1.5 channel expression.Our findings expanded the spectrum of mutations associated with CCD and were valuable in the genetic diagnosis and clinical screening for CCD. Molecular docking analysis provided useful information of increased binding affinity between mutant Lamin A/C and polycomb repressive complex 2. However, the concrete mechanism of LMNA mutation (I229T) remains undetermined in our study, future genetics and molecular studies are still needed.","variants":[{"Name":"NM_170707.4(LMNA):c.686T>C (p.Ile229Thr)","Chromosome":"1","Start":"156134851","Stop":"156134851","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":172484,"rule_based_match":true,"evidence_text":"c.686T>C","llm_judgment":"PRESENT","evidence":"c.686T>C","abstract_start":316,"abstract_end":324}]}
{"pmid":"18201569","title":"Origin and evolution of the c.844_845ins68/c.833T>C mutations within the cystathionine beta-synthase gene in great apes.","abstract":"The c.[833C; 844_845ins68] is a common haplotype of the human cystathionine beta-synthase gene among healthy individuals. This polymorphism (5-40% allelic frequency in different populations) consists of the c.844_845ins68 insertion that segregates in cis with the pathogenic c.833T>C substitution (p.I278T). Through genotyping of primates, we have found that gorillas, chimpanzees and bonobos are homozygous for the 68bp insertion, c.844_845ins68. In gorillas and bonobos, the c.844_845ins68 lesion segregates in cis with the wild-type c.833T variant, whilst chimpanzees present the human haplotype. These genetic evidences suggest that the origin of the 68bp insertion might be dated back to 6-8 million years ago, and that the c.833T>C substitution occurred within the allele carrying the insertion. The evolutionary conservation of this peculiar haplotype supports the hypothesis of its protective effects against cardiovascular diseases.","variants":[{"Name":"NM_000071.3(CBS):c.833T>C (p.Ile278Thr)","Chromosome":"21","Start":"43063074","Stop":"43063074","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15159,"rule_based_match":true,"evidence_text":"c.833T>C","llm_judgment":"PRESENT","evidence":"c.833T>C","abstract_start":275,"abstract_end":283}]}
{"pmid":"24939590","title":"Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis.","abstract":"We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea, microphthalmia, hypotonia and developmental delays. Sanger sequencing verified two Peroxidasin (PXDN) mutations in both sibs--a maternally inherited, nonsense mutation, c.1021C>T predicting p.(Arg341*), and a paternally inherited, 23-basepair deletion causing a frameshift and premature protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67). We re-examined exome data from 20 other patients with structural eye defects and identified two additional PXDN mutations in a sporadic male with bilateral microphthalmia, cataracts and anterior segment dysgenesis--a maternally inherited, frameshift mutation, c.1192delT, predicting p.(Tyr398Thrfs*40) and a paternally inherited, missense substitution that was predicted to be deleterious, c.947 A>C, predicting p.(Gln316Pro). Mutations in PXDN were previously reported in three families with congenital cataracts, microcornea, sclerocornea and developmental glaucoma. The gene is expressed in corneal epithelium and is secreted into the extracellular matrix. Defective peroxidasin has been shown to impair sulfilimine bond formation in collagen IV, a constituent of the basement membrane, implying that the eye defects result because of loss of basement membrane integrity in the developing eye. Our finding of a broader phenotype than previously appreciated for PXDN mutations is typical for exome-sequencing studies, which have proven to be highly effective for mutation detection in patients with atypical presentations. We conclude that PXDN sequencing should be considered in microphthalmia with anterior segment dysgenesis.","variants":[{"Name":"NM_012293.3(PXDN):c.1021C>T (p.Arg341Ter)","Chromosome":"2","Start":"1666484","Stop":"1666484","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":150456,"rule_based_match":true,"evidence_text":"c.1021C>T","llm_judgment":"PRESENT","evidence":"c.1021C>T","abstract_start":300,"abstract_end":309},{"Name":"NM_012293.3(PXDN):c.2375_2397del (p.Leu792fs)","Chromosome":"2","Start":"1649383","Stop":"1649405","ReferenceAlleleVCF":"TGGACACCAGGCGCGGCATGGGAA","AlternateAlleleVCF":"T","allel_id":150457,"rule_based_match":true,"evidence_text":"c.2375_2397del23","llm_judgment":"PRESENT","evidence":"c.2375_2397del23","abstract_start":438,"abstract_end":454}]}
{"pmid":"18597679","title":"Novel de novo BRCA2 mutation in a patient with a family history of breast cancer.","abstract":"BACKGROUND: BRCA2 germ-line mutations predispose to breast and ovarian cancer. Mutations are widespread and unclassified splice variants are frequently encountered. We describe the parental origin and functional characterization of a novel de novo BRCA2 splice site mutation found in a patient exhibiting a ductal carcinoma at the age of 40.\nMETHODS: Variations were identified by denaturing high performance liquid chromatography (dHPLC) and sequencing of the BRCA1 and BRCA2 genes. The effect of the mutation on splicing was examined by exon trapping in COS-7 cells and by RT-PCR on RNA isolated from whole blood. The paternity was determined by single nucleotide polymorphism (SNP) microarray analysis. Parental origin of the de novo mutation was determined by establishing mutation-SNP haplotypes by variant specific PCR, while de novo and mosaic status was investigated by sequencing of DNA from leucocytes and carcinoma tissue.\nRESULTS: A novel BRCA2 variant in the splice donor site of exon 21 (nucleotide 8982+1 G-->A/c.8754+1 G-->A) was identified. Exon trapping showed that the mutation activates a cryptic splice site 46 base pairs 3' of exon 21, resulting in the inclusion of a premature stop codon and synthesis of a truncated BRCA2 protein. The aberrant splicing was verified by RT-PCR analysis on RNA isolated from whole blood of the affected patient. The mutation was not found in any of the patient's parents or in the mother's carcinoma, showing it is a de novo mutation. Variant specific PCR indicates that the mutation arose in the male germ-line.\nCONCLUSION: We conclude that the novel BRCA2 splice variant is a de novo mutation introduced in the male spermatozoa that can be classified as a disease causing mutation.","variants":[{"Name":"NM_000059.4(BRCA2):c.8754+1G>A","Chromosome":"13","Start":"32376792","Stop":"32376792","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67335,"rule_based_match":false,"evidence_text":"(nucleotide 8982+1 G-->A/c.8754+1 G-->A)","llm_judgment":"PRESENT","evidence":"(nucleotide 8982+1 G-->A/c.8754+1 G-->A)","abstract_start":1001,"abstract_end":1041}]}
{"pmid":"24102521","title":"Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar.","abstract":"Whole exome sequencing (WES) has greatly facilitated the identification of causal mutations for diverse human genetic disorders. We applied WES as a molecular diagnostic tool to identify disease-causing genes in consanguineous families in Qatar. Seventeen consanguineous families with diverse disorders were recruited. Initial mutation screening of known genes related to the clinical diagnoses did not reveal the causative mutations. Using WES approach, we identified the definitive disease-causing mutations in four families: (i) a novel nonsense homozygous (c.1034C>G) in PHKG2 causing glycogen storage disease type 9C (GSD9C) in a male with initial diagnosis of GSD3; (ii) a novel homozygous 1-bp deletion (c.915del) in NSUN2 in a male proband with Noonan-like syndrome; (iii) a homozygous SNV (c.1598C>G) in exon 11 of IDUA causing Hurler syndrome in a female proband with unknown clinical diagnosis; (iv) a de novo known splicing mutation (c.1645+1G>A) in PHEX in a female proband with initial diagnosis of autosomal recessive hypophosphatemic rickets. Applying WES as a diagnostic tool led to the unambiguous identification of disease-causing mutations in phenotypically complex disorders or correction of the initial clinical diagnosis in ˜25% of our cases.","variants":[{"Name":"NM_000203.5(IDUA):c.1598C>G (p.Pro533Arg)","Chromosome":"4","Start":"1003418","Stop":"1003418","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":26949,"rule_based_match":true,"evidence_text":"c.1598C>G","llm_judgment":"PRESENT","evidence":"c.1598C>G","abstract_start":799,"abstract_end":808},{"Name":"NM_000444.6(PHEX):c.1645+1G>A","Chromosome":"X","Start":"22190503","Stop":"22190503","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":264998,"rule_based_match":true,"evidence_text":"c.1645+1G>A","llm_judgment":"PRESENT","evidence":"c.1645+1G>A","abstract_start":946,"abstract_end":957}]}
{"pmid":"36980948","title":"Novel Variants in the","abstract":"Valosin-containing protein (<i>VCP</i>) gene mutations have been associated with a rare autosomal dominant, adult-onset progressive disease known as multisystem proteinopathy 1 (MSP1), or inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), (IBMPFD), and amyotrophic lateral sclerosis (ALS). We report the clinical and genetic analysis findings in five patients, three from the same family, with novel <i>VCP</i> gene variants: NM_007126.5 <i>c.1106T>C</i> (<i>p.I369T</i>), <i>c.478G>A</i> (<i>p.A160T</i>), and <i>c.760A>T</i> (<i>p.I254F</i>), associated with cardinal MSP1 manifestations including myopathy, PDB, and FTD. Our report adds to the spectrum of heterozygous pathogenic variants found in the <i>VCP</i> gene and the high degree of clinical heterogeneity. This case series prompts increased awareness and early consideration of MSP1 in the differential diagnosis of myopathies and/or PDB, dementia, or ALS to improve the diagnosis and early management of clinical symptoms.","variants":[{"Name":"NM_007126.5(VCP):c.760A>T (p.Ile254Phe)","Chromosome":"9","Start":"35063029","Stop":"35063029","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1774366,"rule_based_match":true,"evidence_text":"NM_007126.5 <i>c.760A>T</i> (<i>p.I254F</i>)","llm_judgment":"PRESENT","evidence":"c.760A>T","abstract_start":556,"abstract_end":564}]}
{"pmid":"23643385","title":"Mutations in SCO2 are associated with autosomal-dominant high-grade myopia.","abstract":"Myopia, or near-sightedness, is an ocular refractive error of unfocused image quality in front of the retinal plane. Individuals with high-grade myopia (dioptric power greater than -6.00) are predisposed to ocular morbidities such as glaucoma, retinal detachment, and myopic maculopathy. Nonsyndromic, high-grade myopia is highly heritable, and to date multiple gene loci have been reported. We performed exome sequencing in 4 individuals from an 11-member family of European descent from the United States. Affected individuals had a mean dioptric spherical equivalent of -22.00 sphere. A premature stop codon mutation c.157C>T (p.Gln53*) cosegregating with disease was discovered within SCO2 that maps to chromosome 22q13.33. Subsequent analyses identified three additional mutations in three highly myopic unrelated individuals (c.341G>A, c.418G>A, and c.776C>T). To determine differential gene expression in a developmental mouse model, we induced myopia by applying a -15.00D lens over one eye. Messenger RNA levels of SCO2 were significantly downregulated in myopic mouse retinae. Immunohistochemistry in mouse eyes confirmed SCO2 protein localization in retina, retinal pigment epithelium, and sclera. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Copper deficiencies have been linked with photoreceptor loss and myopia with increased scleral wall elasticity. Retinal thinning has been reported with an SC02 variant. Human mutation identification with support from an induced myopic animal provides biological insights of myopic development.","variants":[{"Name":"NM_005138.3(SCO2):c.157C>T (p.Gln53Ter)","Chromosome":"22","Start":"50524255","Stop":"50524255","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20717,"rule_based_match":true,"evidence_text":"c.157C>T (p.Gln53*)","llm_judgment":"PRESENT","evidence":"c.157C>T (p.Gln53*)","abstract_start":620,"abstract_end":639}]}
{"pmid":"29783821","title":"Clinical and genetic analysis of eleven pediatric patients with Alagille syndrome","abstract":"<b>Objective:</b> To explore the clinical and molecular genetic features of patients with Alagille syndrome (AS). <b>Methods:</b> The clinical data of eleven pediatric patients, who were suspected to have AS at the Department of Pediatrics in the First Affiliated Hospital of Jinan University from August 2010 to March 2017, were collected and analyzed. Genomic DNA was extracted from peripheral blood leukocytes of the patients and their parents. For 5 patients collected before March 2006, all JAG1 exons and their flanking sequences were directly sequenced. For the remaining 6 patients, high-throughput gene capture technology, chromosomal microarray analysis (CMA) and whole-genome copy-number variant(CNV) analysis were utilized, when necessary, to explore the genetic causes. <b>Results:</b> All patients had cholestasis. However, the γ-glutamyl transpeptidase (GGT) levels in one patient were normal. Nine patients had posterior embryotoxon and facial malformations. Eight patients displayed heart defects. Seven patients presented with vertebral anomalies and among them, 1 patient had sacralization of the cubitus and radius. The condition of nine patients tended to be stabilized on follow-up, but 1 patient died of liver failure in late infancy and 1 got worse. Seven JAG1 variants were detected in 9 out of the 11 AS patients, with c.1977G>A (p.Trp659*) and c.1106_1107delCC (p.Pro369fs) being two novel variants. Two heterozygous interstitial deletions of 3.0 Mb and 9.24 Mb in size, respectively, in chromosome 20 were discovered in the remaining 2 patients. Both deletions involved the entire JAG1 gene. De novo origin was unveiled for the detected variants in 7 patients and interstitial deletions in two. Although the mother of 2 patients carried the relevant variant, she did not demonstrate any clinical features of AS. <b>Conclusions:</b> With cholestasis, posterior embryotoxon, facial malformations, heart defects and vertebral anomalies being the major manifestations, AS demonstrated variable clinical expressivities and incomplete penetrance. This study identified a total of 7 JAG1 variants as well as 2 interstitial deletions involving this gene, and among them, the variants c.1977G>A (p.Trp659* ) and c.1106_1107delCC (p.Pro369fs) as well as the 9.24 Mb chromosomal interstitial deletion had not been reported previously.","variants":[{"Name":"NM_000214.3(JAG1):c.1977G>A (p.Trp659Ter)","Chromosome":"20","Start":"10645993","Stop":"10645993","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":648577,"rule_based_match":true,"evidence_text":"c.1977G>A (p.Trp659*)","llm_judgment":"PRESENT","evidence":"c.1977G>A (p.Trp659*)","abstract_start":1345,"abstract_end":1366}]}
{"pmid":"30927507","title":"p.Ser891Ala RET gene mutations in medullary thyroid cancer: Phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy.","abstract":"Applying genetic screening in medullary thyroid cancer (MTC) patients we identified an unexpectedly high frequency of c.2671T>G, p.Ser891Ala RET mutation carriers. Our aim was to: (a) deeply characterize the clinical expression of this mutation, (b) identify the presence of a founder effect in our region. Genetic analysis was performed in 251 relatives from 28 Ser891Ala kindreds, among 108 p.Ser891Ala asymptomatic carriers, 64 were submitted to thyroidectomy: mean age for 10 subjects presenting C-cells hyperplasia was 30.2 ± 13.7 years, raising to 37.9 ± 10.3 in 14 subjects with micro-MTC and to 55.0 ± 14.7 years in 39 subjects with MTC. Age-related progression across histopathological groups CCH/microMTC and MTC were statistically significant: genetic screening in Ser891Ala families could be safely postponed at the age of 14. To investigate the hypothesis of a common ancestor for Ser891Ala mutation we genotyped for 18 polymorphic microsatellite markers encompassing RET locus all subjects belonging to Ser891Ala families and we identified a founder effect, estimating the age of a common ancestor, dating back to 1493 AD. Ethnographic data collected in historical archives support laboratory results; the high prevalence of this mutation in our region could suggest the hypothesis of a population study to realize a preventive intervention in a rare neoplastic disease.","variants":[{"Name":"NM_020975.6(RET):c.2671T>G (p.Ser891Ala)","Chromosome":"10","Start":"43120144","Stop":"43120144","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":28990,"rule_based_match":true,"evidence_text":"c.2671T>G, p.Ser891Ala","llm_judgment":"PRESENT","evidence":"c.2671T>G, p.Ser891Ala","abstract_start":118,"abstract_end":140}]}
{"pmid":"30859559","title":"Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.","abstract":"Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.","variants":[{"Name":"NM_006767.4(LZTR1):c.406T>C (p.Tyr136His)","Chromosome":"22","Start":"20988015","Stop":"20988015","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":624698,"rule_based_match":false,"evidence_text":"p.Y136H","llm_judgment":"PRESENT","evidence":"p.Y136H","abstract_start":621,"abstract_end":628},{"Name":"NM_006767.4(LZTR1):c.628C>T (p.Arg210Ter)","Chromosome":"22","Start":"20989659","Stop":"20989659","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":590159,"rule_based_match":false,"evidence_text":"c.628C>T (p.Arg210Ter)","llm_judgment":"PRESENT","evidence":"R210*","abstract_start":744,"abstract_end":749},{"Name":"NM_006767.4(LZTR1):c.1149+1G>T","Chromosome":"22","Start":"20992370","Stop":"20992370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2135274,"rule_based_match":true,"evidence_text":"c.1149+1G>T","llm_judgment":"PRESENT","evidence":"c.1149+1G>T","abstract_start":776,"abstract_end":787}]}
{"pmid":"32489792","title":"Xanthomas Can Be Misdiagnosed and Mistreated in Homozygous Familial Hypercholesterolemia Patients: A Call for Increased Awareness Among Dermatologists and Health Care Practitioners.","abstract":"Background: Familial hypercholesterolemia (FH) is an autosomal dominant inherited genetic disorder and results in the development of coronary artery disease (CAD). Clinical diagnosis of homozygous HH patients is usually straightforward because persistent hypercholesterolemia can produce xanthoma and corneal arcus. However, xanthoma may also be misdiagnosed as skin lesions and could therefore be mistreated. The aim of this case study report is to highlight the plight of patients with FH as means of raising awareness of the condition among dermatologists and health care practitioners, also to determine the genotype-phenotype correlation in severely affected homozygous FH proband patients.\nMethods: Genetic screening of FH associated genes was performed by Ion Torrent next-generation sequencing and cascade screening by capillary sequencing.\nResults: We present two clinical cases with prominent skin lesions seen in a dermatology clinic that were referred to plastic surgery for excision. Genetic testing was performed later, and confirmed common single nucleotide deletion variant (c.2027delG) in the <i>LDLR</i> alleles consequent to a frameshift mutation p.(G676Afs*33). In addition to the <i>LDLR</i> variant, two possibly damaging <i>APOB</i> variants p.(L3313I) and p.(L1212M) and three damaging variants p.(R19*), p.(G83Q) and p.(S474*) in <i>APOC3, PON2</i> and <i>LPL</i> genes respectively were identified. The <i>PON2</i> gene variant p.(G83Q) was found to be novel, while others have been previously reported. Both patients were refractory to pharmacological therapies and are currently on lipoprotein apheresis (LA).\nConclusions: The present report indicates the need for increased awareness of FH, among the public and healthcare practitioners and supports the need for diagnostic screening and cascade genetic testing of this high-risk condition, which could ultimately lead to better prevention of CHD in this lethal condition.","variants":[{"Name":"NM_000527.5(LDLR):c.2027del (p.Gly676fs)","Chromosome":"19","Start":"11120408","Stop":"11120408","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":228196,"rule_based_match":true,"evidence_text":"c.2027delG","llm_judgment":"PRESENT","evidence":"c.2027delG","abstract_start":1091,"abstract_end":1101}]}
{"pmid":"30200136","title":"Whole exome sequencing detects CHST3 mutation in patient with acute promyelocytic leukemia: A case report.","abstract":"RATIONALE: Acute promyelocytic leukemia (APL) is a kind of acute myeloid leukemia, which was characterized by the presence of PML/RARα fusion gene. Mutations in CHST3 have been previously reported to be associated with a rare phenotype of skeleton dysplasia, known as Spondyloepiphyseal dysplasia. Here we reported 1 patient with APL with CHST3 mutations.\nPATIENT CONCERNS: An 18-year-old girl was referred to the Hematology Department because of a lasting history (10 days) of repeated fever and bleeding on skin. The girl was of short stature for age and with short fingers. Double nail beds were short with anti-nail deformity.\nDIAGNOSES: She was diagnosed with APL according to the 2016 WHO classification after a MICM analysis (bone marrow morphology [M], immunophenotype [I], cytogenetics [C], and molecular biology [M]). Whole exome sequencing revealed complex heterozygous mutations on CHST3. Further confirmation showed that 1 mutation (c.155T>G; p.Leu52Arg) was from her father and the other mutation (c.1414G>A; p.Glu472Lys) was from her mother.\nINTERVENTIONS: The patient received Idarubicin (8 mg/m) injection intravenous drip for 3 days based on all-trans retinoic acid and arsenic trioxide induction therapy.\nOUTCOMES: The patient died from disseminated intravascular coagulation and multiple organ hemorrhage at 9 days after diagnosis.\nLESSONS: This case describes a patient with APL with complex heterozygous mutations on CHST3. Carbohydrate sulfotransferases were found to play an important role in metastatic spread of tumor cells. Whether the mutation status of CHST3 gene has relationship with APL pathogenesis and prognosis is unknown.","variants":[{"Name":"NM_004273.5(CHST3):c.1414G>A (p.Glu472Lys)","Chromosome":"10","Start":"72008445","Stop":"72008445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1412710,"rule_based_match":true,"evidence_text":"c.1414G>A (p.Glu472Lys)","llm_judgment":"PRESENT","evidence":"p.Glu472Lys","abstract_start":1023,"abstract_end":1034}]}
{"pmid":"33969091","title":"","abstract":"BACKGROUND: <i>Crumbs homolog 2</i> (<i>CRB2</i>) is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes; mutations can directly lead to steroid-resistant nephrotic syndrome (SRNS). However, the characteristics of nephrotic syndrome (NS) caused by <i>CRB2</i> mutations have not been described.\nCASE SUMMARY: We report a novel compound heterozygous mutation of the <i>CRB2</i> gene in two siblings with SRNS. The two siblings had edema, proteinuria, hypoproteinemia and hyperlipidemia. Both their father and mother had normal phenotypes (no history of NS). Whole exon sequencing (WES) of the family showed a novel compound heterozygous mutation, c.2290 (exon 8) C > T and c.3613 (exon 12) G > A. Glucocorticoid therapy (methylprednisolone pulse therapy or oral prednisone) and immunosuppressive agents (tacrolimus) had no effect. During a 3-year follow-up after genetic diagnosis by WES, proteinuria persisted, but the patient was healthy.\nCONCLUSION: <i>CRB2</i> mutations related to SRNS often occur in exons 7, 10, and 12. Clinical manifestations of SRNS caused by <i>CRB2</i> mutations are often less severe than in other forms of SRNS.","variants":[{"Name":"NM_173689.7(CRB2):c.3613G>A (p.Gly1205Ser)","Chromosome":"9","Start":"123375323","Stop":"123375323","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":818263,"rule_based_match":false,"evidence_text":"c.3613 (exon 12) G > A","llm_judgment":"PRESENT","evidence":"c.3613 (exon 12) G > A","abstract_start":722,"abstract_end":744}]}
{"pmid":"28393214","title":"A novel mutation (c.121‑13T>A) in the polypyrimidine tract of the splice acceptor site of intron 2 causes exon 3 skipping in mitochondrial acetoacetyl-CoA thiolase gene.","abstract":"Mitochondrial acetoacetyl-CoA thiolase (T2) (gene symbol: ACAT1) deficiency is an autosomal recessive disorder affecting isoleucine catabolism and ketone body utilization. In this study, mutational analysis of an Indian T2-deficient patient revealed a homozygous mutation (c.121‑13T>A) located at the polypyrimidine tract of the splice acceptor site of intron 2, and exon 3 skipping was identified by cDNA analysis using cycloheximide. We made three mutant constructs (c.121‑13T>A, T>C, and T>G substitutions) followed by making a wild-type minigene construct that included an ACAT1 segment from exon 2 to 4 for a splicing experiment. The minigene splicing experiment demonstrated that exon 3 skipping was induced not only by c.121‑13T>A mutation, but also by the other two substitutions. It was difficult to predict the effect of these mutations on splicing using in silico tools, as predictions of different tools were inconsistent with each other. The minigene splicing experiment remains the most reliable method to unravel splicing abnormalities.","variants":[{"Name":"NM_000019.4(ACAT1):c.121-13T>A","Chromosome":"11","Start":"108133807","Stop":"108133807","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":654081,"rule_based_match":false,"evidence_text":"c.121‑13T>A","llm_judgment":"PRESENT","evidence":"c.121‑13T>A","abstract_start":273,"abstract_end":284}]}
{"pmid":"26137147","title":"Double PALB2 and BRCA1/BRCA2 mutation carriers are rare in breast cancer and breast-ovarian cancer syndrome families from the French Canadian founder population.","abstract":"French Canadian families with breast cancer and breast-ovarian cancer syndrome harbor specific BRCA1, BRCA2 and PALB2 germline mutations, which have been attributed to common founders. Mutations in these genes confer an increased risk to breast and ovarian cancers, and have been identified to play a role in and directly interact with the common homologous recombination DNA repair pathways. Our previous study described the case of a female diagnosed with breast cancer at 45 years old, who harbored the PALB2:c.2323C>T [p.Q775X] and BRCA2:c.9004G>A [p.E3002K] germline mutations, which have been found to recur in the French Canadian cancer families. As the frequency of double heterozygous carriers of breast-ovarian cancer susceptibility alleles is unknown, and due to the possibility that there may be implications for genetic counseling and management for these carriers, the present study investigated the co-occurrence of BRCA1/BRCA2 and PALB2 mutations in the French Canadian cancer families. The PALB2:c.2323C>T [p.Q775X] mutation, which is the only PALB2 mutation to have been identified in French Canadian cancer families, was screened in 214 breast cancer cases and 22 breast-ovarian cancer cases from 114 BRCA1/BRCA2 mutation-positive French Canadian breast cancer (n=61) and breast-ovarian cancer (n=53) families using a tailored polymerase chain reaction-based TaqMan® SNP Genotyping Assay. No additional PALB2:c.2323C>T [p.Q775X] mutation carriers were identified among the BRCA1/BRCA2 mutation carriers. The results suggest that carriers of the PALB2:c.2323C>T [p.Q775X] mutation rarely co-occur in French Canadian breast cancer and breast-ovarian cancer families harboring BRCA1 or BRCA2 mutations.","variants":[{"Name":"NM_000059.4(BRCA2):c.9004G>A (p.Glu3002Lys)","Chromosome":"13","Start":"32379800","Stop":"32379800","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46757,"rule_based_match":true,"evidence_text":"BRCA2:c.9004G>A [p.E3002K]","llm_judgment":"PRESENT","evidence":"BRCA2:c.9004G>A [p.E3002K]","abstract_start":536,"abstract_end":562}]}
{"pmid":"24431331","title":"A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome.","abstract":"INTRODUCTION: Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition.\nMETHODS AND RESULTS: Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells.\nCONCLUSIONS: We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway.","variants":[{"Name":"NM_003491.4(NAA10):c.471+2T>A","Chromosome":"X","Start":"153930761","Stop":"153930761","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":108165,"rule_based_match":false,"evidence_text":"c.471+2T→A","llm_judgment":"PRESENT","evidence":"c.471+2T→A","abstract_start":645,"abstract_end":655}]}
{"pmid":"22699478","title":"Ovarioleukodystrophy: report of a case with the c.338G>A (p.Arg113His) mutation on exon 3 and the c.896G>A (p.Arg299His) mutation on exon 7 of the EIF2B5 gene.","abstract":"The authors present a 28-year-old lady with progressive neurological deterioration beginning in childhood. She had clinical, radiological and genetic features of ovarioleukodystrophy. This is part of the spectrum of vanishing white matter disease and the first such case reported in the UK. The authors also discuss the literature on the disease.","variants":[{"Name":"NM_003907.3(EIF2B5):c.896G>A (p.Arg299His)","Chromosome":"3","Start":"184140470","Stop":"184140470","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":359528,"rule_based_match":true,"evidence_text":"c.896G>A (p.Arg299His)","llm_judgment":"PRESENT","evidence":"c.896G>A (p.Arg299His)","abstract_start":null,"abstract_end":null},{"Name":"NM_003907.3(EIF2B5):c.338G>A (p.Arg113His)","Chromosome":"3","Start":"184137637","Stop":"184137637","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20984,"rule_based_match":true,"evidence_text":"c.338G>A (p.Arg113His)","llm_judgment":"PRESENT","evidence":"c.338G>A (p.Arg113His)","abstract_start":null,"abstract_end":null}]}
{"pmid":"24111644","title":"Description of the phenotypes of 63 heterozygous, homozygous and compound heterozygous patients carrying the Hb Groene Hart [α119(H2)Pro→Ser; HBA1: c.358C>T] variant.","abstract":"We here report the phenotypes and genotypes of 63 patients of North African origin, carriers of Hb Groene Hart [Hb GH, α119(H2)Pro → Ser; HBA1: c.358C>T], an α(+)-thalassemia (α(+)-thal) hemoglobin (Hb) variant. Fifty patients were heterozygous, five were homozygous and eight also carried the common -α(3.7) (rightward) deletion in compound heterozygosity. The expression of the α(GH)-globin chain is increased in the following order: heterozygous, compound heterozygous and homozygous. Parallel significant changes of mean corpuscular Hb (MCH) and mean corpuscular volume (MCV) were also observed. Our large cohort of Hb GH carriers could have been obtained by the systematic realization of globin chain separation by reversed phase liquid chromatography (RP-LC) in our routine Hb testing.","variants":[{"Name":"NM_000558.5(HBA1):c.358C>T (p.Pro120Ser)","Chromosome":"16","Start":"177340","Stop":"177340","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":799854,"rule_based_match":true,"evidence_text":"c.358C>T","llm_judgment":"PRESENT","evidence":"c.358C>T","abstract_start":144,"abstract_end":152}]}
{"pmid":"32572521","title":"A novel de novo heterozygous ALPL nonsense mutation associated with adult hypophosphatasia.","abstract":"Using genetic, clinical, biochemical, and radiographic assessment and bioinformatic approaches, we present an unusual case of adult HPP caused by a novel de novo heterozygous nonsense mutation in the alkaline phosphatase (ALPL).\nINTRODUCTION: Hypophosphatasia (HPP) is caused by genetic alterations of the ALPL gene, encoding the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Here, the purpose was to perform clinical and molecular investigation in a 36-year-old Caucasian woman suspected to present adult HPP.\nMETHODS: Medical and dental histories were obtained for the proposita and family members, including biochemical, radiographic, and dental assessments. ALPL mutational analysis was performed by the Sanger sequencing method, and the functional impact prediction of the identified mutations was assessed by bioinformatic methods.\nRESULTS: We identified a novel heterozygous nonsense mutation in the ALPL gene (NM_000478.6:c.768G>A; W[TGG]>*[TGA]) associated with spontaneous vertebral fracture, severe back pain, musculoskeletal pain, low bone density, and short-rooted permanent teeth loss. Functional prediction analysis revealed that the Trp256Ter mutation led to a complete loss of TNSALP crown domain and extensive loss of other functional domains (calcium-binding domain, active site vicinity, and zinc-binding site) and over 60% loss of homodimer interface residues, suggesting that the mutant TNSALP molecules are nonfunctional and form unstable homodimers. Genotyping of the ALPL in the proposita's parents, sister, and niece revealed that in this case, HPP occurred due to a de novo mutation.\nCONCLUSION: The present study describes a novel genotype-phenotype and structure-function relationship for HPP, contributing to a better molecular comprehension of HPP etiology and pathophysiology.","variants":[{"Name":"NM_000478.6(ALPL):c.768G>A (p.Trp256Ter)","Chromosome":"1","Start":"21568223","Stop":"21568223","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2839338,"rule_based_match":true,"evidence_text":"NM_000478.6:c.768G>A","llm_judgment":"PRESENT","evidence":"NM_000478.6:c.768G>A","abstract_start":933,"abstract_end":953}]}
{"pmid":"27668495","title":"Regressive Retinal Flecks in CRX-Mutated Early-Onset Retinal Dystrophy.","abstract":"PURPOSE: To describe a peculiar flecked-retina phenotype in a young female affected by early-onset retinal dystrophy due to a heterozygous mutation in the cone-rod transcription factor CRX gene.\nCASE REPORT: A 5-year-old girl presented with poor vision and nystagmus from the first month after birth. Opththalmologic examination at baseline revealed an altered foveal reflex, epiretinal membrane, and yellow fleck-like retinal deposits in the mid- and extreme periphery bilaterally that disappeared after 3 years of follow-up. Electoretinogram was non-recordable in both rods and cones components bilaterally. Genomic sequencing identified a heterozygous missense mutation -c.425A > G (Tyr142Cys) in CRX.\nCONCLUSIONS: We identified a novel early-onset retinal dystrophy-related heterozygous CRX mutation associated with early and severe rod and cone dysfunction and regressive flecked-retina appearance on ophthalmoscopy.","variants":[{"Name":"NM_000554.6(CRX):c.425A>G (p.Tyr142Cys)","Chromosome":"19","Start":"47839492","Stop":"47839492","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":105494,"rule_based_match":true,"evidence_text":"c.425A > G (Tyr142Cys)","llm_judgment":"PRESENT","evidence":"c.425A > G (Tyr142Cys)","abstract_start":674,"abstract_end":696}]}
{"pmid":"21172462","title":"SNP-array based whole genome homozygosity mapping: a quick and powerful tool to achieve an accurate diagnosis in LGMD2 patients.","abstract":"A large number of novel disease genes have been identified by homozygosity mapping and the positional candidate approach. In this study we used single nucleotide polymorphism (SNP) array-based, whole genome homozygosity mapping as the first step to a molecular diagnosis in the highly heterogeneous muscle disease, limb girdle muscular dystrophy (LGMD). In a consanguineous family, both affected siblings showed homozygous blocks on chromosome 15 corresponding to the LGMD2A locus. Direct sequencing of CAPN3, encoding calpain-3, identified a homozygous deletion c.483delG (p.Ile162SerfsX17). In a sporadic LGMD patient complete absence of caveolin-3 on Western blot was observed. However, a mutation in CAV3 could not be detected. Homozygosity mapping revealed a large homozygous block at the LGMD2I locus, and direct sequencing of FKRP encoding fukutin-related-protein detected the common homozygous c.826 C>A (p.Leu276Ile) mutation. Subsequent re-examination of this patient's muscle biopsy showed aberrant α-dystroglycan glycosylation. In summary, we show that whole-genome homozygosity mapping using low cost SNP arrays provides a fast and non-invasive method to identify disease-causing mutations in sporadic patients or sibs from consanguineous families in LGMD2. Furthermore, this is the first study describing that in addition to PTRF, encoding polymerase I and transcript release factor, FKRP mutations may cause secondary caveolin-3 deficiency.","variants":[{"Name":"NM_000070.3(CAPN3):c.483del (p.Ile162fs)","Chromosome":"15","Start":"42386268","Stop":"42386268","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":213821,"rule_based_match":true,"evidence_text":"c.483delG (p.Ile162SerfsX17)","llm_judgment":"PRESENT","evidence":"c.483delG (p.Ile162SerfsX17)","abstract_start":563,"abstract_end":591}]}
{"pmid":"29148562","title":"Recurrence of reported CDH23 mutations causing DFNB12 in a special cohort of South Indian hearing impaired assortative mating families - an evaluation.","abstract":"Mutations in CDH23 are known to cause autosomal-recessive nonsyndromic hearing loss (DFNB12). Until now, there was only one study describing its frequency in Indian population. We screened for CDH23 mutations to identify prevalent and recurring mutations among South Indian assortative mating hearing-impaired individuals who were identified as non-DFNB1 (GJB2 and GJB6). Whole-exome sequencing was performed in individuals found to be heterozygous for CDH23 to determine whether there was a second pathogenic allele. In our study, 19 variants including 6 pathogenic missense mutations were identified. The allelic frequency of pathogenic mutations accounts to 4.7% in our cohort, which is higher than that reported previously; three mutations (c.429+4G>A, c.2968G>A, and c.5660C>T) reported in the previous Indian study were found to recur. DFNB12 was found to be the etiology in 3.4% of our cohort, with missense mutation c.2968G>A (p.Asp990Asn) being the most prevalent (2.6%). These results suggest a need to investigate the possibility for higher proportion of CDH23 mutations in the South Indian hearing-impaired population.","variants":[{"Name":"NM_022124.6(CDH23):c.2968G>A (p.Asp990Asn)","Chromosome":"10","Start":"71706911","Stop":"71706911","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":837211,"rule_based_match":true,"evidence_text":"c.2968G>A (p.Asp990Asn)","llm_judgment":"PRESENT","evidence":"c.2968G>A (p.Asp990Asn)","abstract_start":924,"abstract_end":947}]}
{"pmid":"25491159","title":"Histopathological comparison of eyes from patients with autosomal recessive retinitis pigmentosa caused by novel EYS mutations.","abstract":"To evaluate the retinal histopathology in donor eyes from patients with autosomal recessive retinitis pigmentosa (arRP) caused by EYS mutations. Eyes from a 72-year-old female (donor 1, family 1), a 91-year-old female (donor 2, family 2), and her 97-year-old sister (donor 3, family 2) were evaluated with macroscopic, scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT) imaging. Age-similar normal eyes and an eye donated by donor 1's asymptomatic mother (donor 4, family 1) were used as controls. The perifovea and peripheral retina were processed for microscopy and immunocytochemistry with markers for cone and rod photoreceptor cells. DNA analysis revealed EYS mutations c.2259 + 1G > A and c.2620C > T (p.Q874X) in family 1, and c.4350_4356del (p.I1451Pfs*3) and c.2739-?_3244 + ?del in family 2. Imaging studies revealed the presence of bone spicule pigment in arRP donor retinas. Histology of all three affected donor eyes showed very thin retinas with little evidence of stratified nuclear layers in the periphery. In contrast, the perifovea displayed a prominent inner nuclear layer. Immunocytochemistry analysis demonstrated advanced retinal degenerative changes in all eyes, with near-total absence of rod photoreceptors. In addition, we found that the perifoveal cones were more preserved in retinas from the donor with the midsize genomic rearrangement (c.4350_4356del (p.I1451Pfs*3) and c.2739-?_3244 + ?del) than in retinas from the donors with the truncating (c.2259 + 1G > A and c.2620C > T (p.Q874X) mutations. Advanced retinal degenerative changes with near-total absence of rods and preservation of some perifoveal cones are observed in arRP donor retinas with EYS mutations.","variants":[{"Name":"NM_001142800.2(EYS):c.2259+1G>A","Chromosome":"6","Start":"64997581","Stop":"64997581","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":543937,"rule_based_match":true,"evidence_text":"c.2259 + 1G > A","llm_judgment":"PRESENT","evidence":"c.2259 + 1G > A","abstract_start":699,"abstract_end":714},{"Name":"NM_001142800.2(EYS):c.4350_4356del (p.Ile1451fs)","Chromosome":"6","Start":"64591511","Stop":"64591517","ReferenceAlleleVCF":"CAGCTATA","AlternateAlleleVCF":"C","allel_id":193097,"rule_based_match":true,"evidence_text":"c.4350_4356del (p.I1451Pfs*3)","llm_judgment":"PRESENT","evidence":"c.4350_4356del (p.I1451Pfs*3)","abstract_start":758,"abstract_end":787},{"Name":"NM_001142800.2(EYS):c.2620C>T (p.Gln874Ter)","Chromosome":"6","Start":"64912505","Stop":"64912505","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":431711,"rule_based_match":true,"evidence_text":"c.2620C>T (p.Q874X)","llm_judgment":"PRESENT","evidence":"c.2620C > T (p.Q874X)","abstract_start":719,"abstract_end":740}]}
{"pmid":"27815843","title":"COXPD9 an Evolving Multisystem Disease; Congenital Lactic Acidosis, Sensorineural Hearing Loss, Hypertrophic Cardiomyopathy, Cirrhosis and Interstitial Nephritis.","abstract":"We present the second report of combined oxidative phosphorylation deficiency-9. The infant presented in the neonatal period with poor feeding, lactic acidosis and sensorineural hearing loss. He subsequently developed a lethal hypertrophic cardiomyopathy during infancy. Cirrhosis and interstitial nephritis were identified at autopsy. Exome sequencing has detected compound heterozygous mutations in the MRPL3 gene which encodes a large mitochondrial ribosome subunit protein. We identified a known heterozygous variant NM_007208 c.950>G (Pro317Arg) in the MRPL3 gene and a novel heterozygous mutation NM_007208 c.49delC p.(Arg17Aspfs*57). Mutations in MRPL3 have previously been shown to alter ribosome assembly and cause abnormal function of multiple respiratory chain complexes. Our case adds to the evolving knowledge of disorders of mitochondrial translation.","variants":[{"Name":"NM_007208.4(MRPL3):c.950C>G (p.Pro317Arg)","Chromosome":"3","Start":"131462820","Stop":"131462820","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":39600,"rule_based_match":false,"evidence_text":"NM_007208 c.950>G (Pro317Arg)","llm_judgment":"PRESENT","evidence":"NM_007208 c.950>G (Pro317Arg)","abstract_start":521,"abstract_end":550},{"Name":"NM_007208.4(MRPL3):c.49del (p.Arg17fs)","Chromosome":"3","Start":"131502773","Stop":"131502773","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":677003,"rule_based_match":true,"evidence_text":"NM_007208 c.49delC p.(Arg17Aspfs*57)","llm_judgment":"PRESENT","evidence":"NM_007208 c.49delC p.(Arg17Aspfs*57)","abstract_start":603,"abstract_end":639}]}
{"pmid":"32000417","title":"Congenital factor V deficiency from compound heterozygous mutations with a novel variant c.2426del (p.Pro809Hisfs*2) in the F5 gene: A case report.","abstract":"INTRODUCTION: Congenital factor V deficiency (FVD) is a rare bleeding disorder characterized by low or undetectable plasma factor V (FV) levels leading to mild to severe bleeding symptoms. Currently, more than 100 mutations have been reported in F5. We herein report a patient with FVD from mutations in the F5 gene.\nPATIENT CONCERNS: A 52-year-old man with prolonged prothrombin time and activated partial thromboplastin time corrected by mixing test on preoperative screening. His past medical or family history was not remarkable.\nDIAGNOSIS: Factor assays revealed a markedly reduced FV activity at 7%. Other factors were not decreased. DNA sequencing analysis to detect F5 gene mutations showed the patient was compound heterozygous for c.286G>C (p.Asp96His) and c.2426del (p.Pro809Hisfs*2). Asp96His was previously described missense mutation and Pro809Hisfs*2 was a novel deleterious mutation.\nINTERVENTIONS: Fresh-frozen plasma was administered to supplement FV before surgery.\nOUTCOMES: Subsequent factor assays revealed temporarily increased FV activity at 33%.\nCONCLUSION: As was the case in our patient, genotype-phenotype correlations are poor in FVD, and molecular genetic test is necessary to confirm the diagnosis.","variants":[{"Name":"NM_000130.5(F5):c.286G>C (p.Asp96His)","Chromosome":"1","Start":"169572308","Stop":"169572308","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2898359,"rule_based_match":true,"evidence_text":"c.286G>C (p.Asp96His)","llm_judgment":"PRESENT","evidence":"c.286G>C (p.Asp96His)","abstract_start":741,"abstract_end":762}]}
{"pmid":"18830228","title":"Misleading behavioural phenotype with adenylosuccinate lyase deficiency.","abstract":"Adenylosuccinate lyase deficiency is a rare autosomal disorder of de novo purine synthesis, which results in the accumulation of succinylpurines in body fluids. Patients with adenylosuccinate lyase deficiency show a variable combination of mental retardation, epilepsy and autistic features and are usually discovered during screens for unexplained encephalopathy using the Bratton-Marshall assay that reveals the excretion of the succinylaminoimidazolecarboxamide riboside (SAICAr). Here, we report on two sisters aged 11 and 12 years presented with global developmental delay, motor apraxia, severe speech deficits, seizures and behavioural features, which combined excessive laughter, a very happy disposition, hyperactivity, a short attention span, the mouthing of objects, tantrums and stereotyped movements that gave a behavioural profile mimicking Angelman syndrome. Both patients had an increased succinyladenosine/SAICAr ratio of 1.6, and exhibited a novel homozygous missense mutation (c.674T>C; p.Met225Thr) in the exon 6 of the ADSL gene. We suggest that these clinical features might be a new presentation of adenylosuccinate lyase deficiency. On the basis of this observation, although adenylosuccinate lyase deficiency is a rare disorder, this diagnosis should be considered in patients with mental retardation and a behavioural profile suggestive of Angelman syndrome.","variants":[{"Name":"NM_000026.4(ADSL):c.674T>C (p.Met225Thr)","Chromosome":"22","Start":"40359279","Stop":"40359279","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":17507,"rule_based_match":true,"evidence_text":"c.674T>C (p.Met225Thr)","llm_judgment":"PRESENT","evidence":"p.Met225Thr","abstract_start":1006,"abstract_end":1017}]}
{"pmid":"31130285","title":"Germline-Activating RRAS2 Mutations Cause Noonan Syndrome.","abstract":"Noonan syndrome (NS) is characterized by distinctive craniofacial appearance, short stature, and congenital heart disease. Approximately 80% of individuals with NS harbor mutations in genes whose products are involved in the RAS/mitogen-activating protein kinase (MAPK) pathway. However, the underlying genetic causes in nearly 20% of individuals with NS phenotype remain unexplained. Here, we report four de novo RRAS2 variants in three individuals with NS. RRAS2 is a member of the RAS subfamily and is ubiquitously expressed. Three variants, c.70_78dup (p.Gly24_Gly26dup), c.216A>T (p.Gln72His), and c.215A>T (p.Gln72Leu), have been found in cancers; our functional analyses showed that these three changes induced elevated association of RAF1 and that they activated ERK1/2 and ELK1. Notably, prominent activation of ERK1/2 and ELK1 by p.Gln72Leu associates with the severe phenotype of the individual harboring this change. To examine variant pathogenicity in vivo, we generated zebrafish models. Larvae overexpressing c.70_78dup (p.Gly24_Gly26dup) or c.216A>T (p.Gln72His) variants, but not wild-type RRAS2 RNAs, showed craniofacial defects and macrocephaly. The same dose injection of mRNA encoding c.215A>T (p.Gln72Leu) caused severe developmental impairments and low dose overexpression of this variant induced craniofacial defects. In contrast, the RRAS2 c.224T>G (p.Phe75Cys) change, located on the same allele with p.Gln72His in an individual with NS, resulted in no aberrant in vitro or in vivo phenotypes by itself. Together, our findings suggest that activating RRAS2 mutations can cause NS and expand the involvement of RRAS2 proto-oncogene to rare germline disorders.","variants":[{"Name":"NM_012250.6(RRAS2):c.70_78dup (p.Gly24_Gly26dup)","Chromosome":"11","Start":"14358792","Stop":"14358793","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGCCCACGCC","allel_id":615264,"rule_based_match":true,"evidence_text":"c.70_78dup (p.Gly24_Gly26dup)","llm_judgment":"PRESENT","evidence":"c.70_78dup (p.Gly24_Gly26dup)","abstract_start":545,"abstract_end":574},{"Name":"NM_012250.6(RRAS2):c.215A>T (p.Gln72Leu)","Chromosome":"11","Start":"14294844","Stop":"14294844","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":24486,"rule_based_match":true,"evidence_text":"c.215A>T (p.Gln72Leu)","llm_judgment":"PRESENT","evidence":"c.215A>T (p.Gln72Leu)","abstract_start":603,"abstract_end":624}]}
{"pmid":"17584854","title":"Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).","abstract":"We have recently reported a missense mutation in exon 4 of the tubulin alpha 1A (Tuba1a) gene in a hyperactive N-ethyl-N-nitrosourea (ENU) induced mouse mutant with abnormal lamination of the hippocampus. Neuroanatomical similarities between the Tuba1a mutant mouse and mice deficient for Doublecortin (Dcx) and Lis1 genes, and the well-established functional interaction between DCX and microtubules (MTs), led us to hypothesize that mutations in TUBA1A (TUBA3, previous symbol), the human homolog of Tuba1a, might give rise to cortical malformations. This hypothesis was subsequently confirmed by the identification of TUBA1A mutations in two patients with lissencephaly and pachygyria, respectively. Here we report additional TUBA1A mutations identified in six unrelated patients with a large spectrum of brain dysgeneses. The de novo occurrence was shown for all mutations, including one recurrent mutation (c.790C>T, p.R264C) detected in two patients, and two mutations that affect the same amino acid (c.1205G>A, p.R402H; c.1204C>T, p.R402C) detected in two other patients. Retrospective examination of MR images suggests that patients with TUBA1A mutations share not only cortical dysgenesis, but also cerebellar, hippocampal, corpus callosum, and brainstem abnormalities. Interestingly, the specific high level of Tuba1a expression throughout the period of central nervous system (CNS) development, shown by in situ hybridization using mouse embryos, is in accordance with the brain-restricted developmental phenotype caused by TUBA1A mutations. All together, these results, in combination with previously reported data, strengthen the relevance of the known interaction between MTs and DCX, and highlight the importance of the MTs/DCX complex in the neuronal migration process.","variants":[{"Name":"NM_006009.4(TUBA1A):c.1204C>T (p.Arg402Cys)","Chromosome":"12","Start":"49185162","Stop":"49185162","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":168982,"rule_based_match":true,"evidence_text":"c.1204C>T (p.R402C)","llm_judgment":"PRESENT","evidence":"c.1204C>T","abstract_start":1028,"abstract_end":1037},{"Name":"NM_006009.4(TUBA1A):c.790C>T (p.Arg264Cys)","Chromosome":"12","Start":"49185576","Stop":"49185576","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22109,"rule_based_match":true,"evidence_text":"c.790C>T, p.R264C","llm_judgment":"PRESENT","evidence":"c.790C>T, p.R264C","abstract_start":912,"abstract_end":929},{"Name":"NM_006009.4(TUBA1A):c.1205G>A (p.Arg402His)","Chromosome":"12","Start":"49185161","Stop":"49185161","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22110,"rule_based_match":true,"evidence_text":"c.1205G>A, p.R402H","llm_judgment":"PRESENT","evidence":"c.1205G>A, p.R402H","abstract_start":1008,"abstract_end":1026}]}
{"pmid":"30640048","title":"Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders.","abstract":"OBJECTIVES: To describe the clinical and genetic features of a Chinese peroxisome biogenesis disorder 6B patient with PEX10 mutations and review PEX10-related peroxisomal disorders.\nPATIENTS AND METHODS: The proband is a 7-year-old boy with mild mental retardation and gait instability, intention tremor and nystagmus. An extensive clinical and laboratory evaluation including molecular genetic studies was performed. Genomic DNA was extracted from peripheral blood using the standardized phenol/chloroform extraction method, and the coding region of the PEX10 gene was sequenced in three family members.\nRESULTS: Cerebral MRI showed cerebellar atrophy. Magnetic resonance spectroscopy revealed a decreased N-acetyl aspartate peak in the cerebellum. Nerve conduction velocity examination found prolonged motor and sensory nerve potential latencies (proximal obvious), decreased potential amplitude, and slow nerve conduction velocity. Routine blood tests and biochemistries were abnormal. The PEX10 gene test showed compound heterozygous mutations (c.209 G > A, p. G70E and c.830 T > C, p. L277 P). The mutation c.830 T > C, p. L277 P has been previously reported, whereas c.209 G > A, p. G70E is novel.\nCONCLUSION: We identified an ataxia case of peroxisome biogenesis disorder 6B caused by novel compound heterozygous mutations of the PEX10 gene. Peroxisome biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia, especially cases with early onset.","variants":[{"Name":"NM_002617.4(PEX10):c.830T>C (p.Leu277Pro)","Chromosome":"1","Start":"2406566","Stop":"2406566","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":172123,"rule_based_match":true,"evidence_text":"c.830 T > C, p. L277 P","llm_judgment":"PRESENT","evidence":"c.830 T > C, p. L277 P","abstract_start":1074,"abstract_end":1096}]}
{"pmid":"26419326","title":"A novel PIGN mutation and prenatal diagnosis of inherited glycosylphosphatidylinositol deficiency.","abstract":"Glycosylphosphatidylinositol (GPI) anchors tether proteins to the extracellular face of eukaryotic plasma membranes. Defects in the human GPI anchor biosynthetic pathway cause inherited GPI deficiencies (IGDs) characterized by multiple congenital anomalies: dysmorphic faces, developmental delay, hypotonia, and epilepsy. We report the case of a 6-year-old boy with severe psychomotor developmental delay, epilepsy, and decreased granulocyte surface expression of GPI-anchored protein that suggested autosomal recessive GPI deficiency. The case underwent target exome sequencing to screen for IGDs. Target exome sequencing of the proband identified an apparently homozygous c.808T > C (p.Ser270Pro) mutation in PIGN, a gene involved in the GPI anchor biosynthetic pathway. As his parents were expecting another child, genetic carrier screening was conducted for the parents. Direct sequencing of the parents identified a heterozygous c.808T > C PIGN mutation in the father but none in the mother. To identify the mother's mutation, we performed semi-quantitative real-time PCR of the PIGN exons and long PCR, identifying a microdeletion in PIGN (del exons 2-14). The proband had inherited this microdeletion from his mother. Prenatal diagnosis of the fetus revealed that it was a heterozygous carrier of the mother's pathogenic allele. Here, we report a sporadic case of inherited GPI deficiency with a PIGN mutation and the first case of prenatal diagnosis for GPI deficiency.","variants":[{"Name":"NM_176787.5(PIGN):c.808T>C (p.Ser270Pro)","Chromosome":"18","Start":"62146023","Stop":"62146023","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":106812,"rule_based_match":true,"evidence_text":"c.808T > C (p.Ser270Pro)","llm_judgment":"PRESENT","evidence":"c.808T > C (p.Ser270Pro)","abstract_start":674,"abstract_end":698}]}
{"pmid":"24988964","title":"Rigid spine congenital muscular dystrophy produced by SEPN1 mutations (RSMD1)","abstract":"RSMD1 is a rare autosomal recessive disorder. Unlike most congenital muscular dystrophies, early motor improvement and normal CPK are typical, while in contrast to structural myopathies there is no specific muscle morphology. Rigid spine, early scoliosis and joint contractures are characteristic. We diagnosed RSMD1 in a 27-year-old Russian female with previous diagnosis of unspecified myopathy. DNA test detected compound heterozygosity for two SEPN1 mutations: already known missence-mutation c.1397G>A (p.Arg466Gln) and novel frame-shift mutation c.683_689dup7 leading to preterm stop-codon.","variants":[{"Name":"NM_020451.3(SELENON):c.683_689dup (p.Met230fs)","Chromosome":"1","Start":"25808724","Stop":"25808725","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CTGAGCAT","allel_id":405144,"rule_based_match":true,"evidence_text":"c.683_689dup7","llm_judgment":"PRESENT","evidence":"c.683_689dup7","abstract_start":552,"abstract_end":565},{"Name":"NM_020451.3(SELENON):c.1397G>A (p.Arg466Gln)","Chromosome":"1","Start":"25813890","Stop":"25813890","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19531,"rule_based_match":true,"evidence_text":"c.1397G>A (p.Arg466Gln)","llm_judgment":"PRESENT","evidence":"c.1397G>A (p.Arg466Gln)","abstract_start":497,"abstract_end":520}]}
{"pmid":"34660253","title":"Pioneering","abstract":"Research performed in South African (SA) breast, ovarian and prostate cancer patients resulted in the development of a rapid BRCA point-of-care (POC) assay designed as a time- and cost-effective alternative to laboratory-based technologies currently used for first-tier germline DNA testing. In this study the performance of the new assay was evaluated for use on a portable screening device (ParaDNA), with the long-term goal to enable rollout at POC as an inventive step to meet the World Health Organization's sustainable development goals for Africa. DNA samples for germline testing were obtained retrospectively from 50 patients with early-stage hormone receptor-positive breast cancer referred for genomic tumor profiling (MammaPrint). Currently, SA patients with the luminal-type breast cancer are not routinely selected for <i>BRCA1/2</i> testing as is the case for triple-negative disease. An initial evaluation involved the use of multiple control samples representing each of the pathogenic founder/recurrent variants included in the BRCA 1.0 POC Research Assay. Comparison with a validated laboratory-based first-tier real-time polymerase chain reaction (PCR) assay demonstrated 100% concordance. Clinical utility was evident in five patients with the founder <i>BRCA2</i> c.7934delG variant, identified at the 10% (5/50) threshold considered cost-effective for <i>BRCA1/2</i> testing. <i>BRCA2</i> c.7934delG carrier status was associated with a significantly younger age (p=0.03) at diagnosis of breast cancer compared to non-carriers. In three of the <i>BRCA2</i> c.7934delG carriers a high-risk MammaPrint 70-gene profile was noted, indicating a significantly increased risk for both secondary cancers and breast cancer recurrence. Initiating germline DNA testing at the POC for clinical interpretation early in the treatment planning process, will increase access to the most common pathogenic <i>BRCA1/2</i> variants identified in SA and reduce loss to follow-up for timely gene-targeted risk reduction intervention. The ease of using cheek swabs/saliva in future for result generation within approximately one hour assay time, coupled with low cost and a high <i>BRCA1/2</i> founder variant detection rate, will improve access to genomic medicine in Africa. Application of translational pharmacogenomics across ethnic groups, irrespective of age, family history, tumor subtype or recurrence risk profile, is imperative to sustainably implement preventative healthcare and improve clinical outcome in resource-constrained clinical settings.","variants":[{"Name":"NM_000059.4(BRCA2):c.7934del (p.Arg2645fs)","Chromosome":"13","Start":"32362651","Stop":"32362651","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":67108,"rule_based_match":true,"evidence_text":"BRCA2 c.7934delG","llm_judgment":"PRESENT","evidence":"BRCA2</i> c.7934delG","abstract_start":1276,"abstract_end":1296}]}
{"pmid":"29846281","title":"Identification of a Novel Mutation in the SEC23B Gene Associated With Congenital Dyserythropoietic Anemia Type II Through the Use of Next-generation Sequencing Panel in an Undiagnosed Case of Nonimmune Hereditary Hemolytic Anemia.","abstract":"Congenital dyserythropoietic anemias (CDAs) are rare hereditary blood disorders characterized by ineffective erythropoiesis, hemolysis, and erythroblast morphologic abnormalities in the bone marrow. The 3 main types of CDA, I to III, and variant types of CDA, IV-VIII, have been described. The causative genes have been identified as CDAN1, C15ORF41, SEC23B, KIF23, KLF1, and GATA1. CDA type II is the most frequent form. Typical symptoms are jaundice, hepatosplenomegaly, mild-to-severe normocytic anemia, and inadequate reticulocyte response. We report an 18-year-old boy who had chronic mild congenital anemia, jaundice, and splenomegaly mimicking nonautoimmune hemolytic anemia since 18 months of age. Compound heterozygous mutations in SEC23B gene were detected by the use of a gene-targeted next-generation sequencing panel: the already reported missense mutation c.40C>T (p.Arg14Trp), and a new frameshift deletion (c.489_489delG, p.Val164Trpfs*3), confirming the diagnosis of CDA type II. The study underlines the molecular heterogeneity of CDA II and the importance of a precise diagnosis in rare congenital diseases such as CDA II. In consequence, it can be difficult to diagnose because of limited resources, financial constraint, and rarity of disease in the developing country. Advanced laboratories and new molecular approaches may help in diagnosing rare anemias.","variants":[{"Name":"NM_006363.6(SEC23B):c.40C>T (p.Arg14Trp)","Chromosome":"20","Start":"18510875","Stop":"18510875","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16262,"rule_based_match":true,"evidence_text":"c.40C>T (p.Arg14Trp)","llm_judgment":"PRESENT","evidence":"c.40C>T (p.Arg14Trp)","abstract_start":870,"abstract_end":890}]}
{"pmid":"33114497","title":"A New Variant Mutation in","abstract":"Trichohepatoenteric syndrome is an autosomal recessive genetic disease with an estimated prevalence of 1:100,000. The mutation of the disease is placed either in <i>SKIV2L</i> or <i>TTC37</i> genes. The onset of presentation is variable, but symptoms usually start with intractable diarrhea associated with woolly hair abnormality, immune dysfunction, and sometimes hepatic abnormality. This case is of a 10-month-old girl who was born at 37 + 2 weeks due to symmetrical intrauterine growth restriction (IUGR), with a low birth weight (1320 g). It was noticed during her stay in NICU that she had excessive diarrhea on day 8. Gastroenterology suggested starting an extensively-hydrolyzed formula, but no improvement noticed. The multidisciplinary teams decided to order whole-exome sequencing analysis after excluding diarrhea causes. The analysis detected a new variant mutation (<i>c.1297C</i> > <i>T</i>) p. (Arg433Cys). To our knowledge, this is the first time detected in a homozygous state in the <i>SKIV2L</i> gene, as this variant mutation has not been described in any previous literature. Our case was managed mainly by total parenteral nutrition. The patient responded to the treatment appropriately.","variants":[{"Name":"NM_006929.5(SKIC2):c.1297C>T (p.Arg433Cys)","Chromosome":"6","Start":"31962985","Stop":"31962985","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":816461,"rule_based_match":false,"evidence_text":"c.1297C>T (p.Arg433Cys)","llm_judgment":"PRESENT","evidence":"c.1297C>T (p.Arg433Cys)","abstract_start":null,"abstract_end":null}]}
{"pmid":"33662367","title":"Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.","abstract":"BACKGROUND: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency.\nOBJECTIVE: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1.\nMETHODS: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used.\nRESULTS: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain.\nCONCLUSIONS: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.","variants":[{"Name":"NM_005219.5(DIAPH1):c.684+1G>A","Chromosome":"5","Start":"141582311","Stop":"141582311","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3099005,"rule_based_match":true,"evidence_text":"NM_005219:c.684+1G>A","llm_judgment":"PRESENT","evidence":"NM_005219:c.684+1G>A","abstract_start":759,"abstract_end":779}]}
{"pmid":"31347298","title":"Biallelic germline BRCA1 mutations in a patient with early onset breast cancer, mild Fanconi anemia-like phenotype, and no chromosome fragility.","abstract":"BACKGROUND: Biallelic BRCA1 mutations are regarded either embryonically lethal or to cause Fanconi anemia (FA), a genomic instability syndrome characterized by bone marrow failure, developmental abnormalities, and cancer predisposition. We report biallelic BRCA1 mutations c.181T > G (p.Cys61Gly) and c.5096G > A (p.Arg1699Gln) in a woman with breast cancer diagnosed at the age of 30 years. The common European founder mutation p.Cys61Gly confers high cancer risk, whereas the deleterious p.Arg1699Gln is hypomorphic and was suggested to confer intermediate cancer risk.\nMETHODS AND RESULTS: Aside from significant toxicity from chemotherapy, the patient showed mild FA-like features (e.g., short stature, microcephaly, skin hyperpigmentation). Chromosome fragility, a hallmark of FA patient cells, was not present in patient-derived peripheral blood lymphocytes. We demonstrated that the p.Arg1699Gln mutation impairs DNA double-strand break repair, elevates RAD51 foci levels at baseline, and compromises BRCA1 protein function in protecting from replication stress. Although the p.Arg1699Gln mutation compromises BRCA1 function, the residual activity of the p.Arg1699Gln allele likely prevents from chromosome fragility and a more severe FA phenotype.\nCONCLUSION: Our data expand the clinical spectrum associated with biallelic BRCA1 mutations, ranging from embryonic lethality to a mild FA-like phenotype and no chromosome fragility.","variants":[{"Name":"NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln)","Chromosome":"17","Start":"43063930","Stop":"43063930","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46192,"rule_based_match":true,"evidence_text":"c.5096G>A (p.Arg1699Gln)","llm_judgment":"PRESENT","evidence":"c.5096G > A (p.Arg1699Gln)","abstract_start":301,"abstract_end":327},{"Name":"NM_007294.4(BRCA1):c.181T>G (p.Cys61Gly)","Chromosome":"17","Start":"43106487","Stop":"43106487","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":32700,"rule_based_match":true,"evidence_text":"c.181T>G (p.Cys61Gly)","llm_judgment":"PRESENT","evidence":"c.181T > G (p.Cys61Gly)","abstract_start":273,"abstract_end":296}]}
{"pmid":"24503448","title":"Hearing loss associated with an unusual mutation combination in the gap junction beta 2 (GJB2) gene in a Chinese family.","abstract":"OBJECTIVE: To assess the molecular etiology of nonsyndromic sensorineural hearing loss (NSHL) in members of an affected Chinese family.\nMETHODS: Common hearing-related genes including gap junction beta 2 (GJB2), SLC26A4, mitochondrial DNA 12S rRNA, GJB3 and GJB6 were examined in a family consisting of a normal hearing father, an NSHL-affected mother, one normal-hearing child and three NSHL-affected children. Specific primers were used in polymerase chain reactions to amplify the coding regions of the above genes from the peripheral blood DNA from each family member, and the genes were analyzed by direct sequencing. The subjects were evaluated for phenotypic characterization using audiometric testing and radiological examination of the inner ear.\nRESULTS: Pathogenic mutations in the GJB2 gene were identified. The affected mother showed a heterozygous G→A transition at nucleotide 232, resulting in an alanine to threonine substitution at codon 78 (p.A78T), and the normal hearing father had a c.35insG insertion mutation. The three affected children displayed heterozygosity for the GJB2 mutations, showing a previously unreported combination of c.35insG and c.232G>A.\nCONCLUSIONS: The GJB2 mutations account for a significant proportion of NSHL in affected individuals worldwide. Genetic and audiological data analysis of a Chinese family with NSHL revealed a novel c.35insG/c.232G>A compound heterozygous state. Our results highlight the complexity of the GJB2 genotypes and phenotypes.","variants":[{"Name":"NM_004004.6(GJB2):c.232G>A (p.Ala78Thr)","Chromosome":"13","Start":"20189350","Stop":"20189350","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1286866,"rule_based_match":true,"evidence_text":"c.232G>A","llm_judgment":"PRESENT","evidence":"c.232G>A","abstract_start":1170,"abstract_end":1178}]}
{"pmid":"17373699","title":"Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment.","abstract":"In a consanguineous Turkish family, a locus for autosomal recessive nonsyndromic hearing impairment (ARNSHI) was mapped to chromosome 2q31.1-2q33.1. Microsatellite marker analysis in the complete family determined the critical linkage interval that overlapped with DFNB27, for which the causative gene has not yet been identified, and DFNB59, a recently described auditory neuropathy caused by missense mutations in the DFNB59 gene. The 352-amino acid (aa) DFNB59 gene product pejvakin is present in hair cells, supporting cells, spiral ganglion cells, and the first three relays of the afferent auditory pathway. A novel homozygous nonsense mutation (c.499C>T; p.R167X) was detected in the DFNB59 gene, segregating with the deafness in the family. The mRNA derived from the mutant allele was found not to be degraded in lymphocytes, indicating that a truncated pejvakin protein of 166 aa may be present in the affected individuals. Screening of 67 index patients from additional consanguineous Turkish families with autosomal recessive hearing impairment revealed a homozygous missense mutation (c.547C>T; p.R183W) that segregates with the hearing impairment in one family. Furthermore, in a panel of 83 Dutch patients, two additional novel mutations (c.509_512delCACT; p.S170CfsX35 and c.731T>G; p.L244R), which were not present in ethnically matched controls, were found heterozygously. Together, our data indicate that also nonsense mutations in DFNB59 cause nonsyndromic hearing loss, but that mutations in DFNB59 are not a major cause of nonsyndromic hearing impairment in the Turkish and Dutch population.","variants":[{"Name":"NM_001042702.5(PJVK):c.547C>T (p.Arg183Trp)","Chromosome":"2","Start":"178456149","Stop":"178456149","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16336,"rule_based_match":true,"evidence_text":"c.547C>T; p.R183W","llm_judgment":"PRESENT","evidence":"c.547C>T; p.R183W","abstract_start":1097,"abstract_end":1114},{"Name":"NM_001042702.5(PJVK):c.499C>T (p.Arg167Ter)","Chromosome":"2","Start":"178456101","Stop":"178456101","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16339,"rule_based_match":true,"evidence_text":"c.499C>T; p.R167X","llm_judgment":"PRESENT","evidence":"c.499C>T; p.R167X","abstract_start":652,"abstract_end":669}]}
{"pmid":"28089734","title":"Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment.","abstract":"DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.","variants":[{"Name":"NM_001039141.3(TRIOBP):c.3460_3461del (p.Leu1154fs)","Chromosome":"22","Start":"37726012","Stop":"37726013","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":984454,"rule_based_match":true,"evidence_text":"c.3460_3461del (p.Leu1154Alafs*29)","llm_judgment":"PRESENT","evidence":"c.3460_3461del (p.Leu1154Alafs*29)","abstract_start":483,"abstract_end":517},{"Name":"NM_001039141.3(TRIOBP):c.5014G>T (p.Gly1672Ter)","Chromosome":"22","Start":"37735350","Stop":"37735350","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":497767,"rule_based_match":true,"evidence_text":"c.5014G>T (p.Gly1672*)","llm_judgment":"PRESENT","evidence":"c.5014G>T (p.Gly1672*)","abstract_start":395,"abstract_end":417}]}
{"pmid":"26079780","title":"Severe Salt-Losing 3β-Hydroxysteroid Dehydrogenase Deficiency: Treatment and Outcomes of HSD3B2 c.35G>A Homozygotes.","abstract":"CONTEXT: 3-β-hydroxysteroid dehydrogenase (HSD3B2) deficiency accounts for less than 5% of congenital adrenal hyperplasia worldwide, but is relatively common among the Old Order Amish of North America due to a HSD3B2 c.35G>A founder mutation.\nOBJECTIVE: We review clinical presentation, disease course, treatment, and outcomes of a genetically homogenous population of HSD3B2-deficient patients.\nDESIGN AND PARTICIPANTS: This was a retrospective case series: anthropometric, biochemical, and clinical data from 16 (six male) affected subjects (age, 7.2 ± 6.4 y) were compared to reference data from 12 age-matched unaffected siblings.\nSETTING: The setting was the Clinic for Special Children, a nonprofit rural community health center in Lancaster, Pennsylvania.\nMAIN OUTCOME MEASURES: The main outcome measures were growth, skeletal maturation, sexual development, blood pressure, glucocorticoid dose, pituitary-adrenal homeostasis, and long-term morbidity.\nRESULTS: Exogenous glucocorticoid requirement was dichotomous: a standard-dose group (n = 9) required 15.4 ± 4.9 mg/m(2)/d hydrocortisone equivalent, whereas a high-dose group required much larger and more variable doses (hydrocortisone equivalent, 37.8 ± 15.4 mg/m(2)/d) (P < .0001). Despite glucocorticoid doses 2-fold higher than the standard-dose group, high-dose patients: 1) had ACTH, 17-hydroxypregnenolone, and dehydroepiandrosterone levels that were 10-fold, 20-fold, and 20-fold higher, respectively; 2) were exclusively affected by signs of sex steroid excess; and 3) tended to have more iatrogenic complications.\nCONCLUSIONS: Patients with HSD3B2 deficiency and 21-hydroxylase deficiency suffer similar morbid complications from under- and overtreatment, but HSD3B2 deficiency is associated with a distinctive pattern of sex steroid dysmetabolism. Disease- and treatment-related morbidities are almost exclusively observed among subjects who have a high exogenous glucocorticoid requirement.","variants":[{"Name":"NM_000198.4(HSD3B2):c.35G>A (p.Gly12Glu)","Chromosome":"1","Start":"119415454","Stop":"119415454","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1381162,"rule_based_match":true,"evidence_text":"HSD3B2 c.35G>A","llm_judgment":"PRESENT","evidence":"HSD3B2 c.35G>A","abstract_start":210,"abstract_end":224}]}
{"pmid":"36468072","title":"Indentification of novel","abstract":"Misato mitochondrial distribution and morphology regulator 1 (MSTO1) is a nuclear-encoded cytoplasmic protein involved in mitochondrial fusion and distribution. Its disruption causes an extremely rare mitochondrial disorder characterized by early-onset myopathy and cerebellar ataxia. The genotype-phenotype correlation in the <i>MSTO1</i> gene is rarely studied before 2017, and only 25 mutations have been described in the patients. Here, we reported two siblings with progressive cerebellar atrophy and ataxia in a Chinese family. Two compound heterozygous mutations in the <i>MSTO1</i> gene, a novel missense mutation c.571C>T (p.Arg191Trp), and a reported frameshift mutation c.1259delG (p.Gly420ValfsTer2) were identified in the patients by whole exome sequencing. <i>in vitro</i> experiments found both of the mutations lead to reduced protein abundance and link to decreased mtDNA content. Except for ataxia and delayed motor, both of the siblings also have low birth weights, learning difficulties, and dysarthria. Our report enriched the genotype and phenotype spectrums of the <i>MSTO1</i>-related disorder and supported the recessive inheritance of the disease.","variants":[{"Name":"NM_018116.4(MSTO1):c.571C>T (p.Arg191Trp)","Chromosome":"1","Start":"155611993","Stop":"155611993","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":818380,"rule_based_match":true,"evidence_text":"c.571C>T (p.Arg191Trp)","llm_judgment":"PRESENT","evidence":"c.571C>T (p.Arg191Trp)","abstract_start":622,"abstract_end":644}]}
{"pmid":"9792410","title":"Ataxia-telangiectasia in the Japanese population: identification of R1917X, W2491R, R2909G, IVS33+2T-->A, and 7883del5, the latter two being relatively common mutations.","abstract":"We analyzed the data regarding six Japanese ataxia-telangiectasia (A-T) patients from four unrelated families, at the DNA level, to search for possible common mutations in the Japanese population. Among eight mutant alleles in the four families, c. 4612del165 (exon 33 skipping) was identified in two alleles, and c. 5749A to T (R1917X), c. 7471T to C (W2491R), c.7883de15, and c. 8725A to G (R2909G) were identified in one allele each. We found no mutations in the other two alleles. The IVS33 + 2T-->A mutation was identified at the genomic level as the cause of exon 33 skipping. We also identified the IVS33 + 2T-->A mutation in a Japanese patient ATL105 who was previously found to be a homozygote of c. 4612del165. W2491R and R2909G mutations were not detected in more than 100 control Japanese alleles. The latter is located in a highly conserved PI-3 kinase domain and is a completely conserved residue among ATM-related proteins. Taken together with previously documented mutations in five other Japanese A-T patients, IVS33 + 2T-->A and 7883del5 were identified in four and five alleles, respectively, in a total of 18 mutant alleles of Japanese A-T patients. These results suggest that these two mutations are relatively common mutations in the Japanese population.","variants":[{"Name":"NM_000051.4(ATM):c.8725A>G (p.Arg2909Gly)","Chromosome":"11","Start":"108353819","Stop":"108353819","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2898761,"rule_based_match":false,"evidence_text":"c. 8725A to G (R2909G)","llm_judgment":"PRESENT","evidence":"c. 8725A to G (R2909G)","abstract_start":378,"abstract_end":400}]}
{"pmid":"36980931","title":"Identification of Two Homozygous Variants in","abstract":"Mutations in cardiac genes are one of the primary causes of infantile cardiomyopathy. In this study, we report the genetic findings of two siblings carrying variations in the <i>MYBPC3</i> and <i>SMYD1</i> genes. The first patient is a female proband exhibiting hypertrophic cardiomyopathy (HCM) and biventricular heart failure carrying a truncating homozygous <i>MYBPC3</i> variant c.1224-52G>A (IVS13-52G>A) and a novel homozygous variant (c.302A>G; p.Asn101Ser) in the <i>SMYD1</i> gene. The second patient, the proband's sibling, is a male infant diagnosed with hypertrophic cardiomyopathy and carries the same homozygous <i>MYBPC3</i> variant. While this specific <i>MYBPC3</i> variant (c.1224-52G>A, IVS13-52G>A) has been previously reported to be associated with adult-onset hypertrophic cardiomyopathy, this is the first report linking it to infantile cardiomyopathy. In addition, this work describes, for the first time, a novel <i>SMYD1</i> variant (c.302A>G; p.Asn101Ser) that has never been reported. We performed a histopathological evaluation of tissues collected from both probands and show that these variants lead to myofibrillar disarray, reduced and irregular mitochondrial cristae and cardiac fibrosis. Together, these results provide critical insight into the molecular functionality of these genes in human cardiac physiology.","variants":[{"Name":"NM_000256.3(MYBPC3):c.1224-52G>A","Chromosome":"11","Start":"47343314","Stop":"47343314","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186390,"rule_based_match":true,"evidence_text":"c.1224-52G>A (IVS13-52G>A)","llm_judgment":"PRESENT","evidence":"c.1224-52G>A (IVS13-52G>A)","abstract_start":383,"abstract_end":409}]}
{"pmid":"27452334","title":"Whole Exome Sequencing, Familial Genomic Triangulation, and Systems Biology Converge to Identify a Novel Nonsense Mutation in TAB2-encoded TGF-beta Activated Kinase 1 in a Child with Polyvalvular Syndrome.","abstract":"OBJECTIVE: To use whole exome sequencing (WES) of a family trio to identify a genetic cause for polyvalvular syndrome.\nMETHODS AND RESULTS: A male child was born with mild pulmonary valve stenosis and mild aortic root dilatation, and an atrial septal defect, ventricular septal defect, and patent ductus arteriosus that were closed surgically. Subsequently, the phenotype of polyvalvular syndrome with involvement of both semilunar and both atrioventricular valves emerged. His family history was negative for congenital heart disease. Because of hypotonia, myopia, soft pale skin, joint hypermobility, and mild facial dysmorphism, either Noonan syndrome- or William syndrome-spectrum disorders were suspected clinically. However, chromosomal analysis was normal and commercially available Noonan syndrome and William syndrome genetic tests were negative. Whole exome sequencing of the patient and both parents was performed. Variants were analyzed by sporadic and autosomal recessive inheritance models. A sporadic mutation, annotated as c.1491 T > A, in TAB2, resulting in a nonsense mutation, p.Y497X, in the TAB2-encoded TGF-beta activated kinase 1 (TAK1) was identified as the most likely disease-susceptibility gene. This mutation results in elimination of the terminal 197 amino acids, including the C-terminal binding motif critical for interactions with TRAF6 and TAK1.\nCONCLUSIONS: The combination of WES, genomic triangulation, and systems biology has uncovered perturbations in TGF-beta activated kinase 1 signaling as a novel pathogenic substrate for polyvalvular syndrome.","variants":[{"Name":"NM_001292034.3(TAB2):c.1491T>A (p.Tyr497Ter)","Chromosome":"6","Start":"149379406","Stop":"149379406","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":552095,"rule_based_match":true,"evidence_text":"c.1491 T > A","llm_judgment":"PRESENT","evidence":"c.1491 T > A","abstract_start":1039,"abstract_end":1051}]}
{"pmid":"33553065","title":"Novel Compound Heterozygous Mutations in Two Families With Bernard-Soulier Syndrome.","abstract":"<b>Background:</b> Bernard-Soulier Syndrome (BSS) is a rare autosomal recessive bleeding disorder with large platelets and thrombocytopenia. It is caused by homozygous or compound heterozygous mutations in the <i>GP1BA, GP1BB</i>, or <i>GP9</i> genes, which together encode the platelet surface receptor glycoprotein complex GPIb-IX-V. <b>Objectives:</b> We report two novel heterozygous mutations in the <i>GP1BA</i> and the <i>GP9</i> genes, respectively. <b>Patients/Methods:</b> We analyzed the platelet glycoprotein expression by flow cytometry and screened the relevant genes for responsible mutations in two unrelated families. <b>Results:</b> Flow cytometric analyses revealed the absence of CD42a (GPIX) and CD42b (GPIb) on the platelets in the two affected siblings of family 1 and a significantly reduced expression of CD42b (GPIb) in the patient of family 2. In the two siblings, we identified a known frameshift (c.1601_1602delAT) and a novel nonsense mutation (c.1036C>T) in the <i>GP1BA</i> gene that abrogated the production of GP1bα. In the other patient, we found a novel missense mutation (c.112T>C) that was co-inherited with a common one (c.182A>G) in the <i>GP9</i> gene, respectively. All analyzed heterozygous carriers were asymptomatic and had a normal GPIb-IX-V expression. <b>Conclusions:</b> The two novel <i>GP1BA</i> and <i>GP9</i> mutations reported herein increment the number of causative genetic defects in BSS.","variants":[{"Name":"NM_000174.5(GP9):c.182A>G (p.Asn61Ser)","Chromosome":"3","Start":"129061921","Stop":"129061921","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28568,"rule_based_match":true,"evidence_text":"c.182A>G","llm_judgment":"PRESENT","evidence":"c.182A>G","abstract_start":1160,"abstract_end":1168}]}
{"pmid":"34046058","title":"Deep-Phenotyping the Less Severe Spectrum of","abstract":"The two aims of this study were (i) to describe and expand the phenotypic spectrum of <i>PIGT</i> deficiency in affected individuals harboring the c.1582G>A; p.Val528Met or the c.1580A > G; p.Asn527Ser variant in either homozygous or compound heterozygous state, and (ii) to identify potential genotype-phenotype correlations and any differences in disease severity among individuals with and without the <i>PIGT</i> variants. The existing literature was searched to identify individuals with and without the two variants. A detailed phenotypic assessment was performed of 25 individuals (both novel and previously published) with the two <i>PIGT</i> variants. We compared severity of disease between individuals with and without these <i>PIGT</i> variants. Twenty-four individuals carried the <i>PIGT</i> variant Val528Met in either homozygous or compound heterozygous state, and one individual displayed the Asn527Ser variant in a compound heterozygous state. Disease severity in the individual with the Asn527Ser variant was compatible with that in the individuals harboring the Val528Met variant. While individuals without the Asn527Ser or Val528Met variant had focal epilepsy, profound developmental delay (DD), and risk of premature death, those with either of the two variants had moderate to severe DD and later onset of epilepsy with both focal and generalized seizures. Individuals homozygous for the Val528Met variant generally became seizure-free on monotherapy with antiepileptic drugs, compared to other <i>PIGT</i> individuals who were pharmaco-resistant. Two patients were diagnosed with myoclonic-atonic seizures, and a single patient was diagnosed with eyelid myoclonia. Our comprehensive analysis of this large cohort of previously published and novel individuals with <i>PIGT</i> variants broadens the phenotypical spectrum and shows that both Asn527Ser and Val528Met are associated with a milder phenotype and less severe outcome. Our data show that <i>PIGT</i> is a new candidate gene for myoclonic atonic epilepsy. Our genotype-phenotype correlation will be useful for future genetic counseling. Natural history studies of this mild spectrum of <i>PIGT-</i>related disorder may shed light on hitherto unknown aspects of this rare disorder.","variants":[{"Name":"NM_015937.6(PIGT):c.1582G>A (p.Val528Met)","Chromosome":"20","Start":"45425671","Stop":"45425671","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":434678,"rule_based_match":true,"evidence_text":"c.1582G>A; p.Val528Met","llm_judgment":"PRESENT","evidence":"c.1582G>A; p.Val528Met","abstract_start":147,"abstract_end":169}]}
{"pmid":"21654082","title":"Splicing aberrations caused by constitutional RB1 gene mutations in retinoblastoma.","abstract":"Analysis of RB1 mRNA from blood leukocytes of patients with retinoblastoma identified the effects of mutations involving consensus splice site, exonic substitution and whole-exon deletions identified in genomic DNA of these patients. In addition, this study identified mutations in cases in which no mutations were detectable in the genomic DNA. One proband had mutation at the canonical splice site at +5 position of IVS22, and analysis of the transcripts in this family revealed skipping of exon 22 in three members of this family. In one proband, a missense substitution of c.652T greater than G (g.56897T greater than G; Leu218Val) in exon 7 led to splicing aberrations involving deletions of exons 7 and 8, suggesting the formation of a cryptic splice site. In two probands with no detectable changes in the genomic DNA upon screening of RB1 exons and flanking intronic sequences, transcripts were found to have deletions of exon 6 in one, and exons 21 and 22 in another family. In two probands, RNA analysis confirmed genomic deletions involving one or more exons. This study reveals novel effects of RB1 mutations on splicing and suggests the utility of RNA analysis as an adjunct to mutational screening of genomic DNA in retinoblastoma.","variants":[{"Name":"NM_000321.3(RB1):c.652T>G (p.Leu218Val)","Chromosome":"13","Start":"48360061","Stop":"48360061","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":568562,"rule_based_match":false,"evidence_text":"c.652T greater than G (g.56897T greater than G; Leu218Val)","llm_judgment":"PRESENT","evidence":"c.652T greater than G (g.56897T greater than G; Leu218Val)","abstract_start":577,"abstract_end":635}]}
{"pmid":"16493439","title":"Exonic microdeletions in the X-linked PQBP1 gene in mentally retarded patients: a pathogenic mutation and in-frame deletions of uncertain effect.","abstract":"Mutations in PQBP1 were recently identified in families with syndromic and non-syndromic X-linked mental retardation (XLMR). Clinical features frequently associated with MR were microcephaly and/or short stature. The predominant mutations detected so far affect a stretch of six AG dinucleotides in the polar-amino-acid-rich domain (PRD), causing frameshifts in the fourth coding exon. We searched for PQBP1 exon 4 frameshifts in 57 mentally retarded males in whom initial referral description indicated at least one of the following criteria: microcephaly, short stature, spastic paraplegia or family history compatible with XLMR, and in 772 mentally retarded males not selected for specific clinical features or family history. We identified a novel frameshift mutation (23 bp deletion) in two half-brothers with specific clinical features, and performed prenatal diagnosis in this family. We also found two different 21 bp in-frame deletions (c.334-354del(21 bp) and c.393-413del(21 bp)) in four unrelated probands from various ethnic origins, each deleting one of five copies of an imperfect seven amino-acid repeat. Although such deletions have not been detected in 1180 X chromosomes from European controls, the c. 334-354del(21 bp) was subsequently found in two of 477 Xs from Indian controls. We conclude that pathogenic frameshift mutations in PQBP1 are rare in mentally retarded patients lacking specific associated signs and that the 21 bp in-frame deletions may be non-pathogenic, or alternatively could act subtly on PQBP1 function. This touches upon a common dilemma in XLMR, that is, how to distinguish between mutations and variants that may be non-pathogenic or represent risk factors for cognitive impairment.","variants":[{"Name":"NM_001032382.2(PQBP1):c.334_354del (p.Gly113_Arg119del)","Chromosome":"X","Start":"48902257","Stop":"48902277","ReferenceAlleleVCF":"AGCCATGACAAGTCGGACAGGG","AlternateAlleleVCF":"A","allel_id":26023,"rule_based_match":false,"evidence_text":"c.334-354del(21 bp)","llm_judgment":"PRESENT","evidence":"c.334-354del(21 bp)","abstract_start":946,"abstract_end":965}]}
{"pmid":"28336152","title":"Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex.","abstract":"TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1383Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products of TSC1/2 form a complex which at energy limiting states, down-regulates the activity of the regulator of protein synthesis, the mammalian target of rapamycin complex1 (mTORC1). As expected, in contrast to cultured control fibroblasts, starvation of cultured patient fibroblasts obtained from a hypomelanotic macule did not lead to repression of mTORC1, whereas partial repression was observed in patient fibroblasts obtained from non-lesional skin. The findings indicate that the development of hypomelanotic macules is associated with constitutive activated mTORC1, whereas mild deregulation of mTORC1 allows the maintenance of normal skin. Furthermore, the finding establishes the pathogenic effect of the \"silent\" c.4149C>T substitution and emphasizes the need for awareness when interpreting silent substitutions in general.","variants":[{"Name":"NM_000548.5(TSC2):c.4149C>T (p.Ser1383=)","Chromosome":"16","Start":"2084371","Stop":"2084371","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2894988,"rule_based_match":true,"evidence_text":"c.4149C>T","llm_judgment":"PRESENT","evidence":"c.4149C>T","abstract_start":266,"abstract_end":275}]}
{"pmid":"33852188","title":"Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy.","abstract":"Primary hypertrophic osteoarthropathy (PHO) is a rare disease inherited as a recessive or irregular dominant trait and characterized by digital clubbing, pachydermia, and periostosis. Biallelic mutations in HPGD and SLCO2A1, disturbing prostaglandin E<sub>2</sub> (PGE<sub>2</sub> ) catabolism and leading to increased circulating PGE<sub>2</sub> level, cause PHO autosomal recessive 1 (PHOAR1) and PHO autosomal recessive 2 (PHOAR2), respectively. However, no causative genes have been reported for PHO autosomal dominant (PHOAD). Here, we performed Sanger sequencing and whole-genome sequencing (WGS) on DNA samples from seven Chinese PHOAD families; after excluding other single-nucleotide variants (SNVs), structural variations (SVs), and copy number variations (CNVs) in the genomes, we reported six SLCO2A1 monoallelic mutations (c.1660G>A [p.G554R], c.664G>A [p.G222R], c.1106G>A [p.G369D], c.1065dupA [p.Q356TfsX77], c.1293delT [p.S432AfsX48], and c.1807C>T [p.R603X]) in the probands and affected family members. Then, in five other PHO families with probands carrying SLCO2A1 biallelic mutations, we verified that parents with SLCO2A1 monoallelic mutations also displayed PHO manifestations, which further confirmed the pathogenicity of SLCO2A1 monoallelic mutations and illustrated the allelic nature of PHOAD and PHOAR2. Subsequently, through comparison of seven PHOAD probands and 50 PHOAR2 patients, we found onset age in puberty and skewed penetrance rate were similar in both PHO types, but symptoms and signs of PHOAD were milder, including less severe pachydermia (p = .027) and periostosis (p = .005), and less frequent cutis verticis gyrata (p = .011), acne (p = .005), arthralgia (p = .037), and anemia (p = .023). The median urinary PGE<sub>2</sub> level in PHOAD probands was almost half that in PHOAR2 patients (PHOAD 277.58 ng/mmoL creatinine, PHOAR2 473.19 ng/mmoL creatinine; p = .038). Moreover, through the 3-month trial of oral administration of etoricoxib, an effective response similar to that we reported previously in PHOAR2 patients was observed in PHOAD probands. In conclusion, our findings confirm that SLCO2A1 monoallelic mutations are the cause of PHOAD and broaden phenotypic spectrum of PHO. © 2021 American Society for Bone and Mineral Research (ASBMR).","variants":[{"Name":"NM_005630.3(SLCO2A1):c.664G>A (p.Gly222Arg)","Chromosome":"3","Start":"133953723","Stop":"133953723","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":432290,"rule_based_match":true,"evidence_text":"c.664G>A [p.G222R]","llm_judgment":"PRESENT","evidence":"c.664G>A [p.G222R]","abstract_start":857,"abstract_end":875},{"Name":"NM_005630.3(SLCO2A1):c.1807C>T (p.Arg603Ter)","Chromosome":"3","Start":"133935781","Stop":"133935781","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227249,"rule_based_match":true,"evidence_text":"c.1807C>T (p.R603X)","llm_judgment":"PRESENT","evidence":"c.1807C>T","abstract_start":956,"abstract_end":965},{"Name":"NM_005630.3(SLCO2A1):c.1660G>A (p.Gly554Arg)","Chromosome":"3","Start":"133938459","Stop":"133938459","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1163224,"rule_based_match":true,"evidence_text":"c.1660G>A [p.G554R]","llm_judgment":"PRESENT","evidence":"c.1660G>A [p.G554R]","abstract_start":836,"abstract_end":855}]}
{"pmid":"35598269","title":"Variation of COL7A1 gene in dystrophic epidermolysis bullosa pruriginosa","abstract":"OBJECTIVE: To perform gene mutation analysis in a Chinese pedigree with dystrophic epidermolysis bullosa pruriginosa (DEB-Pr), and explore phetotype, genotype, and genotypes-phenotypes relationship of DEB-Pr.\nMETHODS: Potential variants of the COL7A1 gene were detected by skin targeted sequencing panel and verified by Sanger sequencing. The pathogenicity of the variation was analyzed.\nRESULTS: Compound heterozygous variants, c.4128delT and c.8234G>A, were detected in the COL7A1 gene of the two patients. The c.4128delT(p.Pro1376fs) variant was derived from their mother and unreported previously. According to the American College of Medical Genetics and Genomics Standards and Guidelines, it was suggested to be a pathogenic mutation. The c.8234G>A(p.Arg2745Gln) variant was derived from their father, and possibly is a pathogenic variation.\nCONCLUSION: In this study, the compound heterozygous variants of c.4128delT(p.Pro1376fs) and c.8234G>A(p.Arg2745Gln) of the COL7A1 gene probably underlies the disease in this patient and his sister. And our study expands the database on mutations of DEB-Pr.","variants":[{"Name":"NM_000094.4(COL7A1):c.8234G>A (p.Arg2745Gln)","Chromosome":"3","Start":"48566730","Stop":"48566730","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":794091,"rule_based_match":true,"evidence_text":"c.8234G>A(p.Arg2745Gln)","llm_judgment":"PRESENT","evidence":"c.8234G>A(p.Arg2745Gln)","abstract_start":745,"abstract_end":768}]}
{"pmid":"27066538","title":"CHCHD10 variant p.(Gly66Val) causes axonal Charcot-Marie-Tooth disease.","abstract":"OBJECTIVE: We describe the phenotype consistent with axonal Charcot-Marie-Tooth disease type 2 (CMT2) in 4 families with a c.197G>T (p.(Gly66Val)) variant in CHCHD10.\nMETHODS: We sequenced the CHCHD10 gene in a cohort of 107 families with CMT2 of unknown etiology. The patients were characterized by clinical examination and electroneuromyography. Muscle MRI and biopsy of the muscle or nerve were performed in selected cases. Neuropathologic autopsy was performed in 1 case.\nRESULTS: The c.197G>T variant in CHCHD10 was found in 6 families, 4 of which included multiple individuals available for detailed clinical study. Variants in this gene have recently been associated with amyotrophic lateral sclerosis-frontotemporal dementia, mitochondrial myopathy, or spinal muscular atrophy Jokela type (SMAJ), but not with CMT2. Our patients had a late-onset distal axonal neuropathy with motor predominance, progressing to involve sensory nerves. Neurophysiologic and neuropathologic studies confirmed the diagnosis of sensorimotor axonal neuropathy with no loss of anterior horn neurons. Muscle biopsies showed occasional cytochrome c oxidase-negative fibers, combined with small amounts of mitochondrial DNA deletions.\nCONCLUSIONS: CHCHD10 c.197G>T (p.(Gly66Val)) is a cause of sensorimotor axonal neuropathy. This gene should be considered in patients presenting with a pure CMT2 phenotype, particularly when motor symptoms predominate.","variants":[{"Name":"NM_213720.3(CHCHD10):c.197G>T (p.Gly66Val)","Chromosome":"22","Start":"23767438","Stop":"23767438","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":178408,"rule_based_match":true,"evidence_text":"c.197G>T (p.(Gly66Val))","llm_judgment":"PRESENT","evidence":"c.197G>T (p.(Gly66Val))","abstract_start":123,"abstract_end":146}]}
{"pmid":"24528855","title":"X-linked Charcot-Marie-Tooth disease, Arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation.","abstract":"BACKGROUND: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5), Arts syndrome, and non-syndromic sensorineural deafness (DFN2) are allelic syndromes, caused by reduced activity of phosphoribosylpyrophosphate synthetase 1 (PRS-I) due to loss-of-function mutations in PRPS1. As only few families have been described, knowledge about the relation between these syndromes, the phenotypic spectrum in patients and female carriers, and the relation to underlying PRS-I activity is limited.\nMETHODS: We investigated a family with a novel PRPS1 mutation (c.830A > C, p.Gln277Pro) by extensive phenotyping, MRI, and genetic and enzymatic tests.\nRESULTS: The male index subject presented with an overlap of CMTX5 and Arts syndrome features, whereas his sister presented with prelingual DFN2. Both showed mild parietal and cerebellar atrophy on MRI. Enzymatically, PRS-I activity was undetectable in the index subject, reduced in his less affected sister, and normal in his unaffected mother.\nCONCLUSIONS: Our findings demonstrate that CMTX5, Arts syndrome and DFN2 are phenotypic clusters on an intrafamilial continuum, including overlapping phenotypes even within individuals. The respective phenotypic presentation seems to be determined by the exact PRPS1 mutation and the residual enzyme activity, the latter being largely influenced by the degree of skewed X-inactivation. Finally, our findings show that brain atrophy might be more common in PRPS1-disorders than previously thought.","variants":[{"Name":"NM_002764.4(PRPS1):c.830A>C (p.Gln277Pro)","Chromosome":"X","Start":"107647731","Stop":"107647731","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":224827,"rule_based_match":true,"evidence_text":"c.830A > C, p.Gln277Pro","llm_judgment":"PRESENT","evidence":"c.830A > C, p.Gln277Pro","abstract_start":548,"abstract_end":571}]}
{"pmid":"31238300","title":"Familial neurohypophyseal diabetes insipidus in 13 kindreds and 2 novel mutations in the vasopressin gene.","abstract":"BACKGROUND: Autosomal dominant neurohypophyseal diabetes insipidus (adNDI) is caused by arginine vasopressin (AVP) deficiency resulting from mutations in the AVP-NPII gene encoding the AVP preprohormone.\nAIM: To describe the clinical and molecular features of Italian unrelated families with central diabetes insipidus.\nPATIENTS AND METHODS: We analyzed AVP-NPII gene in 13 families in whom diabetes insipidus appeared to be segregating.\nRESULTS: Twenty-two patients were found to carry a pathogenic AVP-NPII gene mutation. Two novel c.173 G>C (p.Cys58Ser) and c.215 C>A (p.Ala72Glu) missense mutations and additional eight different mutations previously described were identified; nine were missense and one non-sense mutation. Most mutations (eight out of ten) occurred in the region encoding for the NPII moiety; two mutations were detected in exon 1. No mutations were found in exon 3. Median age of onset was 32.5 months with a variability within the same mutation (3 to 360 months). No clear genotype-phenotype correlation has been observed, except for the c.55 G>A (p.Ala19Thr) mutation, which led to a later onset of disease (median age 120 months). Brain magnetic resonance imaging (MRI) revealed the absence of posterior pituitary hyperintensity in 8 out of 15 subjects, hypointense signal in 4 and normal signal in 2. Follow-up MRI showed the disappearance of the posterior pituitary hyperintensity after 6 years in one case.\nCONCLUSION: adNDI is a progressive disease with a variable age of onset. Molecular diagnosis and counseling should be provided to avoid unnecessary investigations and to ensure an early and adequate treatment.","variants":[{"Name":"NM_000490.5(AVP):c.55G>A (p.Ala19Thr)","Chromosome":"20","Start":"3084620","Stop":"3084620","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27245,"rule_based_match":true,"evidence_text":"c.55 G>A (p.Ala19Thr)","llm_judgment":"PRESENT","evidence":"c.55 G>A (p.Ala19Thr)","abstract_start":1063,"abstract_end":1084}]}
{"pmid":"30905644","title":"Loss-of-Function Mutations in the CFH Gene Affecting Alternatively Encoded Factor H-like 1 Protein Cause Dominant Early-Onset Macular Drusen.","abstract":"PURPOSE: To characterize the molecular mechanism underpinning early-onset macular drusen (EOMD), a phenotypically severe subtype of age-related macular degeneration (AMD), in a subgroup of patients.\nDESIGN: Multicenter case series, in vitro experimentation, and retrospective analysis of previously reported variants.\nPARTICIPANTS: Seven families with apparently autosomal dominant EOMD.\nMETHODS: Patients underwent a comprehensive ophthalmic assessment. Affected individuals from families A, B, and E underwent whole exome sequencing. The probands from families C, D, F, and G underwent Sanger sequencing analysis of the complement factor H (CFH) gene. Mutant recombinant factor H like-1 (FHL-1) proteins were expressed in HEK293 cells to assess the impact on FHL-1 expression and function. Previously reported EOMD-causing variants in CFH were reviewed.\nMAIN OUTCOME MEASURES: Detailed clinical phenotypes, genomic findings, in vitro characterization of mutation effect on protein function, and postulation of the pathomechanism underpinning EOMD.\nRESULTS: All affected participants demonstrated bilateral drusen. The earliest reported age of onset was 16 years (median, 46 years). Ultra-rare (minor allele frequency [MAF], ≤0.0001) CFH variants were identified as the cause of disease in each family: CFH c.1243del, p.(Ala415ProfsTer39) het; c.350+1G→T het; c.619+1G→A het, c.380G→A, p.(Arg127His) het; c.694C→T p.(Arg232Ter) het (identified in 2 unrelated families in this cohort); and c.1291T→A, p.(Cys431Ser). All mutations affect complement control protein domains 2 through 7, and thus are predicted to impact both FHL-1, the predominant isoform in Bruch's membrane (BrM) of the macula, and factor H (FH). In vitro analysis of recombinant proteins FHL-1<sub>R127H</sub>, FHL-1<sub>A415f/s</sub>, and FHL-1<sub>C431S</sub> demonstrated that they are not secreted, and thus are loss-of-function proteins. Review of 29 previously reported EOMD-causing mutations found that 75.8% (22/29) impact FHL-1 and FH. In total, 86.2% (25/29) of EOMD-associated variants cause haploinsufficiency of FH or FHL-1.\nCONCLUSIONS: Early-onset macular drusen is an underrecognized, phenotypically severe subtype of AMD. We propose that haploinsufficiency of FHL-1, the main regulator of the complement pathway in BrM, where drusen develop, is an important mechanism underpinning the development of EOMD in a number of cases. Understanding the molecular basis of EOMD will shed light on AMD pathogenesis given their pathologic similarities.","variants":[{"Name":"NM_000186.4(CFH):c.1243del (p.Ala415fs)","Chromosome":"1","Start":"196690146","Stop":"196690146","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":1432073,"rule_based_match":true,"evidence_text":"CFH c.1243del, p.(Ala415ProfsTer39)","llm_judgment":"PRESENT","evidence":"CFH c.1243del, p.(Ala415ProfsTer39)","abstract_start":1304,"abstract_end":1339},{"Name":"NM_000186.4(CFH):c.694C>T (p.Arg232Ter)","Chromosome":"1","Start":"196679697","Stop":"196679697","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1151868,"rule_based_match":false,"evidence_text":"c.694C→T p.(Arg232Ter)","llm_judgment":"PRESENT","evidence":"c.694C→T p.(Arg232Ter)","abstract_start":1406,"abstract_end":1428}]}
{"pmid":"30706430","title":"A novel WDR62 missense mutation in microcephaly with abnormal cortical architecture and review of the literature.","abstract":"Autosomal recessive primary microcephaly (MCPH) is a group of rare neurodevelopmental diseases with severe microcephaly at birth. One type of the disorder, MCPH2, is caused by biallelic mutations in the WDR62 gene, which encodes the WD repeat-containing protein 62. Patients with WDR62 mutation may have a wide range of malformations of cortical development in addition to congenital microcephaly. We describe two patients, a boy and a girl, with severe congenital microcephaly, global developmental delay, epilepsy, and failure to thrive. MRI showed hemispherical asymmetry, diffuse pachygyria, thick gray matter, indistinct gray-white matter junction, and corpus callosum and white matter hypoplasia. Whole exome sequencing revealed the same novel homozygous missense mutation, c.668T>C, p.Phe223Ser in exon 6 of the WDR62 gene. The healthy parents were heterozygous for this mutation. The mutation affects a highly conserved region in one of the WD repeats of the WDR62 protein. Haplotype analysis showed genetic relatedness between the families of the patients. Our findings expand the spectrum of mutations randomly distributed in the WDR62 gene. A review is also provided of the brain malformations described in WDR62 mutations in association with congenital microcephaly.","variants":[{"Name":"NM_001083961.2(WDR62):c.668T>C (p.Phe223Ser)","Chromosome":"19","Start":"36067412","Stop":"36067412","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1341067,"rule_based_match":true,"evidence_text":"c.668T>C, p.Phe223Ser","llm_judgment":"PRESENT","evidence":"c.668T>C, p.Phe223Ser","abstract_start":780,"abstract_end":801}]}
{"pmid":"30280194","title":"Compound pathogenic mutation in the USH2A gene in Chinese RP families detected by whole‑exome sequencing.","abstract":"Retinitis pigmentosa (RP) is a common form of inherited retinal degeneration that causes progressive loss of vision or adult blindness, characterized by the impairment of rod and cone photoreceptors. At present, mutations in >60 pathogenic genes have been confirmed to cause RP. The predominant modes of inheritance are autosomal dominant, autosomal recessive and X‑linked. In addition, other modes of inheritance, including digenic or mitochondrial inheritance, have been reported. In previous decades, with the development of sequencing techniques, significant advances in identifying novel RP pathogenic genes and screening mutations have been made. In the present study, whole‑exome sequencing was performed on samples from two Chinese pedigrees diagnosed with RP. A compound heterozygous mutation in the gene usherin 2A (USH2A; c.6,485+5G>A/c.11,156G>A) and a heterozygous X‑linked mutation in the gene retinitis pigmentosa 2 (RP2) ARL3 GTPase‑activating protein (RP2; c.358C>T) were identified by Sanger sequencing and co‑segregation analysis, of which the pathogenic mutation (c.6,485+5G>A) in USH2A has not been previously reported among Chinese patients. The findings of the present study may expand on current knowledge of RP among the Chinese population, providing essential assistance in the molecular diagnosis and screening of RP, and promoting further investigation of the pathogenesis of RP.","variants":[{"Name":"NM_206933.4(USH2A):c.6485+5G>A","Chromosome":"1","Start":"216000398","Stop":"216000398","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":960421,"rule_based_match":false,"evidence_text":"c.6,485+5G>A","llm_judgment":"PRESENT","evidence":"c.6,485+5G>A","abstract_start":833,"abstract_end":845},{"Name":"NM_006915.3(RP2):c.358C>T (p.Arg120Ter)","Chromosome":"X","Start":"46853731","Stop":"46853731","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25590,"rule_based_match":true,"evidence_text":"c.358C>T","llm_judgment":"PRESENT","evidence":"c.358C>T","abstract_start":974,"abstract_end":982}]}
{"pmid":"36291559","title":"Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis.","abstract":"Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant MLH1 and MSH2 alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of AYA-CRC cases remain unexplained. In two teenage siblings with multiple adenomas and CRC, we identified a maternally inherited heterozygous PMS2 exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited POLD1 variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (>100 Mut/Mb) and a large contribution of COSMIC signature SBS20 in both siblings’ CRCs, confirming their predisposition to AYA-CRC results from a high propensity for somatic MMR deficiency (MMRd) compounded by a constitutional Pol δ proofreading defect. COSMIC signature SBS20 as well as SBS26 in the index patient’s CRC were associated with an early mutation burst, suggesting MMRd was an early event in tumorigenesis. The somatic second hits in PMS2 were through loss of heterozygosity (LOH) in both tumors, suggesting PPd-independent acquisition of MMRd. Taken together, these patients represent the first cases of cancer predisposition due to heterozygous variants in PMS2 and POLD1. Analysis of their CRCs supports that POLD1-mutated tumors acquire hypermutation only with concurrent MMRd.","variants":[{"Name":"NM_002691.4(POLD1):c.946G>A (p.Asp316Asn)","Chromosome":"19","Start":"50402717","Stop":"50402717","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":245149,"rule_based_match":false,"evidence_text":"NP_002682.2:p.Asp316Asn","llm_judgment":"PRESENT","evidence":"NP_002682.2:p.Asp316Asn","abstract_start":585,"abstract_end":608}]}
{"pmid":"17473846","title":"Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin.","abstract":"Thirty-two healthy volunteers with different SLCO1B1 genotypes ingested a 20 mg dose of atorvastatin and 10 mg dose of rosuvastatin with a washout period of 1 week. Subjects with the SLCO1B1 c.521CC genotype (n=4) had a 144% (P<0.001) or 61% (P=0.049) greater mean area under the plasma atorvastatin concentration-time curve from 0 to 48 h (AUC(0-48 h)) than those with the c.521TT (n=16) or c.521TC (n=12) genotype, respectively. The AUC(0-48 h) of 2-hydroxyatorvastatin was 100% greater in subjects with the c.521CC genotype than in those with the c.521TT genotype (P=0.018). Rosuvastatin AUC(0-48 h) and peak plasma concentration (Cmax) were 65% (P=0.002) and 79% (P=0.003) higher in subjects with the c.521CC genotype than in those with the c.521TT genotype. These results indicate that, unexpectedly, SLCO1B1 polymorphism has a larger effect on the AUC of atorvastatin than on the more hydrophilic rosuvastatin.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":false,"evidence_text":"c.521T>C","llm_judgment":"PRESENT","evidence":"c.521T>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"25604855","title":"Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease.","abstract":"Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G>A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.","variants":[{"Name":"NM_000484.4(APP):c.2125G>A (p.Gly709Ser)","Chromosome":"21","Start":"25891808","Stop":"25891808","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":626283,"rule_based_match":true,"evidence_text":"c.2125G>A (p.(G709S))","llm_judgment":"PRESENT","evidence":"c.2125G>A (p.(G709S))","abstract_start":1456,"abstract_end":1477}]}
{"pmid":"31230978","title":"The novel synonymous variant in LIPA gene affects splicing and causes lysosomal acid lipase deficiency.","abstract":"Lysosomal acid lipase deficiency (LALD; MIM#278000) is a continuum of autosomal recessive diseases caused by defects in the gene LIPA and historically divided into two phenotypes: severe infantile-onset form called Wolman disease (WD) and childhood/adult-onset form known as cholesteryl ester storage disease (CESD). We report a novel synonymous homozygous variant c.600G > A in LIPA of a patient with LALD. Functional analysis of the patient cDNA and minigene assay revealed this variant as the cause of exonic cryptic splice site activation and 63 b.p. deletion in exon 6. To investigate the impact of this in-frame deletion on protein function, we performed 3D modeling of the human lysosomal acid lipase and showed the alteration of highly conservative region in close proximity to protein active site, which may completely eliminate the enzymatic activity. Using transcript specific real-time quantitative PCR method, we evaluated the relative ratio of the patient's wild type transcript isoform which is significantly reduced and correlates with severe childhood-onset variant of LALD.","variants":[{"Name":"NM_000235.4(LIPA):c.600G>A (p.Leu200=)","Chromosome":"10","Start":"89225167","Stop":"89225167","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":857331,"rule_based_match":true,"evidence_text":"c.600G > A","llm_judgment":"PRESENT","evidence":"c.600G > A","abstract_start":365,"abstract_end":375}]}
{"pmid":"19955557","title":"Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia.","abstract":"BACKGROUND: TOR1A encodes a chaperone-like AAA-ATPase whose Delta GAG (Delta E) mutation is responsible for an early onset, generalised dystonia syndrome. Because of the established role of the TOR1A gene in heritable generalised dystonia (DYT1), a potential genetic contribution of TOR1A to the more prevalent and diverse presentations of late onset, focal dystonia has been suggested.\nRESULTS: A novel TOR1A missense mutation (c.613T-->A, p.F205I) in a patient with late onset, focal dystonia is reported. The mutation occurs in a highly evolutionarily conserved region encoding the AAA-ATPase domain. Expression assays revealed that expression of F205I or Delta E, but not wildtype TOR1A, produced frequent intracellular inclusions.\nCONCLUSIONS: A novel, rare TOR1A variant has been identified in an individual with late onset, focal dystonia and evidence provided that the mutation impairs TOR1A function. Together these findings raise the possibility that this novel TOR1A variant may contribute to the expression of dystonia. In light of these findings, a more comprehensive genetic effort is warranted to identify the role of this and other rare TOR1A variants in the expression of late onset, focal dystonia.","variants":[{"Name":"NM_000113.3(TOR1A):c.613T>A (p.Phe205Ile)","Chromosome":"9","Start":"129818752","Stop":"129818752","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":33477,"rule_based_match":false,"evidence_text":"c.613T-->A, p.F205I","llm_judgment":"PRESENT","evidence":"c.613T-->A, p.F205I","abstract_start":429,"abstract_end":448}]}
{"pmid":"28669108","title":"Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death.","abstract":"Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G>A(p.Arg173Gln)] and BAG3 [BAG3 c.785C>T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood.","variants":[{"Name":"NM_004281.4(BAG3):c.785C>T (p.Ala262Val)","Chromosome":"10","Start":"119672532","Stop":"119672532","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":53956,"rule_based_match":true,"evidence_text":"BAG3 c.785C>T(p.Ala262Val)","llm_judgment":"PRESENT","evidence":"BAG3 c.785C>T(p.Ala262Val)","abstract_start":1242,"abstract_end":1268}]}
{"pmid":"19295179","title":"Clinical and genetic studies in a Chinese family with giant axonal neuropathy.","abstract":"The objective of the study was to investigate a girl with giant axonal neuropathy and detect the mutation of GAN gene in her family. The encoding exons of GAN gene were amplified from genomic DNA of the proband and her parents by polymerase chain reaction and directly sequenced after purification. The proband manifested typical neurological symptoms and pathological abnormalities. The case had 2 heterozygous missense mutations in GAN gene: 1. c. 224 T>A in exon 2, her mother was a heterozygote of this mutation and had normal phenotype; 2. c.1634G>A in exon 10, and her father was a heterozygote of this mutation and had normal phenotype. Both of the mutations caused amino acid changes in the gigaxonin protein. In this family, missense mutation of c.224 T>A and missense mutation of c.1634G>A in GAN gene caused the phenotype of giant axonal neuropathy in the proband. Her parents are heterozygotes of the disease without symptoms.","variants":[{"Name":"NM_022041.4(GAN):c.224T>A (p.Leu75His)","Chromosome":"16","Start":"81351639","Stop":"81351639","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":625326,"rule_based_match":true,"evidence_text":"c. 224 T>A","llm_judgment":"PRESENT","evidence":"c. 224 T>A","abstract_start":447,"abstract_end":457},{"Name":"NM_022041.4(GAN):c.1634G>A (p.Arg545His)","Chromosome":"16","Start":"81377436","Stop":"81377436","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625359,"rule_based_match":true,"evidence_text":"c.1634G>A","llm_judgment":"PRESENT","evidence":"c.1634G>A","abstract_start":545,"abstract_end":554}]}
{"pmid":"24996905","title":"Mutations in HAO1 encoding glycolate oxidase cause isolated glycolic aciduria.","abstract":"BACKGROUND: The primary hyperoxalurias are a group of recessive kidney diseases, characterised by extensive accumulation of calcium oxalate that progressively coalesces into kidney stones. Oxalate overproduction is facilitated by perturbations in the metabolism of glyoxylate, the product of glycolate oxidation, and the immediate precursor of oxalate. Glycolic aciduria associated with hyperoxaluria is regarded as the hallmark of type 1 primary hyperoxaluria. The genetic basis of isolated glycolic aciduria is reported here.\nMETHODS AND RESULTS: Two brothers, born to consanguineous healthy parents of Arab descent, were evaluated for psychomotor delay associated with triple-A-like syndrome (anisocoria, alacrima and achalasia). The proband showed markedly increased urinary glycolic acid excretion with normal excretion of oxalate, citrate and glycerate. Abdominal ultrasound showed normal-sized kidneys with normal echotexture. The genetic nature of triple-A-like syndrome in this kindred was found to be unrelated to this metabolic abnormality. Direct DNA sequencing of glycolate oxidase gene (HAO1) revealed a homozygous c.814-1G>C mutation in the invariant -1 position of intron 5 splice acceptor site. Since HAO1 is a liver-specific enzyme, the effect of this novel mutation on splicing was validated by an in vitro hybrid-minigene approach. We confirmed the appearance of an abnormal splice variant in cells transfected with mutant minigene vector.\nCONCLUSIONS: Our results pinpoint the expression of defective splice variant of glycolate oxidase as the cause of isolated asymptomatic glycolic aciduria. This observation contributes to the development of novel approaches, namely, substrate reduction, for the treatment of primary hyperoxaluria type I.","variants":[{"Name":"NM_017545.3(HAO1):c.814-1G>C","Chromosome":"20","Start":"7885865","Stop":"7885865","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":223743,"rule_based_match":true,"evidence_text":"c.814-1G>C","llm_judgment":"PRESENT","evidence":"c.814-1G>C","abstract_start":1129,"abstract_end":1139}]}
{"pmid":"32977150","title":"Juberg-Hayward syndrome and Roberts syndrome are allelic, caused by mutations in ESCO2.","abstract":"OBJECTIVE: Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, hypoplasia or aplasia of thumbs, short stature, dislocation of radial head, and fusion of humerus and radius leading to elbow restriction. A homozygous mutation in ESCO2 has recently been reported to cause Juberg-Hayward syndrome. Our objective was to investigate the molecular etiology of Juberg-Hayward syndrome in two affected Lisu tribe brothers.\nMATERIALS AND METHODS: Two patients, the unaffected parents, and two unaffected siblings were studied. Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, Western blot analysis, and chromosome testing were performed.\nRESULTS: Two affected brothers had characteristic features of Juberg-Hayward syndrome, except for the absence of microcephaly. The elder brother had bilateral cleft lip and palate, short stature, humeroradial synostosis, and simple partial seizure with secondary generalization. The younger brother had unilateral cleft lip and palate, short stature, and dislocation of radial heads. The homozygous (c.1654C > T; p.Arg552Ter) mutation in ESCO2 was identified in both patients. The other unaffected members of the family were heterozygous for the mutation. The presence of humeroradial synostosis and radial head dislocation in the same family is consistent with both being in the same spectrum of forearm malformations. Chromosome testing of the affected patients showed premature centromere separation. Western blot analysis showed reduced amount of truncated protein.\nCONCLUSION: Our findings confirm that a homozygous mutation in ESCO2 is the underlying cause of Juberg-Hayward syndrome. Microcephaly does not appear to be a consistent feature of the syndrome.","variants":[{"Name":"NM_001017420.3(ESCO2):c.1654C>T (p.Arg552Ter)","Chromosome":"8","Start":"27799697","Stop":"27799697","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1015450,"rule_based_match":true,"evidence_text":"c.1654C > T; p.Arg552Ter","llm_judgment":"PRESENT","evidence":"c.1654C > T; p.Arg552Ter","abstract_start":1161,"abstract_end":1185}]}
{"pmid":"29178637","title":"Allelic spectrum of formiminotransferase-cyclodeaminase gene variants in individuals with formiminoglutamic aciduria.","abstract":"BACKGROUND: Elevated plasma and urine formiminoglutamic acid (FIGLU) levels are commonly indicative of formiminoglutamic aciduria (OMIM #229100), a poorly understood autosomal recessive disorder of histidine and folate metabolism, resulting from formiminotransferase-cyclodeaminase (FTCD) deficiency, a bifunctional enzyme encoded by FTCD.\nMETHODS: In order to further understanding about the molecular alterations that contribute to FIGLU-uria, we sequenced FTCD in 20 individuals with putative FTCD deficiency and varying laboratory findings, including increased FIGLU excretion.\nRESULTS: Individuals tested had biallelic loss-of-function variants in protein-coding regions of FTCD. The FTCD allelic spectrum comprised of 12 distinct variants including 5 missense alterations that replace conserved amino acid residues (c.223A>C, c.266A>G, c.319T>C, c.430G>A, c.514G>T), an in-frame deletion (c.1373_1375delTGG), with the remaining alterations predicted to affect mRNA processing/stability. These included two frameshift variants (c.990dup, c.1366dup) and four nonsense variants (c.337C>T, c.451A>T, c.763C>T, c.1607T>A).\nCONCLUSION: We observed additional FTCD alleles leading to urinary FIGLU elevations, and thus, providing molecular evidence of FTCD deficiency in cases identified by newborn screening or clinical biochemical genetic laboratory testing.","variants":[{"Name":"NM_206965.2(FTCD):c.1373_1375del (p.Val458del)","Chromosome":"21","Start":"46138576","Stop":"46138578","ReferenceAlleleVCF":"GCCA","AlternateAlleleVCF":"G","allel_id":2738496,"rule_based_match":true,"evidence_text":"c.1373_1375delTGG","llm_judgment":"PRESENT","evidence":"c.1373_1375delTGG","abstract_start":895,"abstract_end":912},{"Name":"NM_206965.2(FTCD):c.1607T>A (p.Leu536Ter)","Chromosome":"21","Start":"46137006","Stop":"46137006","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":191558,"rule_based_match":true,"evidence_text":"c.1607T>A","llm_judgment":"PRESENT","evidence":"c.1607T>A","abstract_start":1112,"abstract_end":1121},{"Name":"NM_206965.2(FTCD):c.763C>T (p.Arg255Ter)","Chromosome":"21","Start":"46150399","Stop":"46150399","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620679,"rule_based_match":true,"evidence_text":"c.763C>T","llm_judgment":"PRESENT","evidence":"c.763C>T","abstract_start":1102,"abstract_end":1110},{"Name":"NM_206965.2(FTCD):c.1366dup (p.Glu456fs)","Chromosome":"21","Start":"46138584","Stop":"46138585","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":191241,"rule_based_match":true,"evidence_text":"c.1366dup","llm_judgment":"PRESENT","evidence":"c.1366dup","abstract_start":1043,"abstract_end":1052},{"Name":"NM_206965.2(FTCD):c.266A>G (p.Asp89Gly)","Chromosome":"21","Start":"46153008","Stop":"46153008","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2901706,"rule_based_match":true,"evidence_text":"c.266A>G","llm_judgment":"PRESENT","evidence":"c.266A>G","abstract_start":832,"abstract_end":840},{"Name":"NM_206965.2(FTCD):c.319T>C (p.Cys107Arg)","Chromosome":"21","Start":"46152955","Stop":"46152955","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":649136,"rule_based_match":true,"evidence_text":"c.319T>C","llm_judgment":"PRESENT","evidence":"c.319T>C","abstract_start":842,"abstract_end":850},{"Name":"NM_206965.2(FTCD):c.990dup (p.Pro331fs)","Chromosome":"21","Start":"46145925","Stop":"46145926","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":19058,"rule_based_match":true,"evidence_text":"c.990dup","llm_judgment":"PRESENT","evidence":"c.990dup","abstract_start":1033,"abstract_end":1041},{"Name":"NM_206965.2(FTCD):c.430G>A (p.Gly144Arg)","Chromosome":"21","Start":"46151918","Stop":"46151918","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":266933,"rule_based_match":true,"evidence_text":"c.430G>A","llm_judgment":"PRESENT","evidence":"c.430G>A","abstract_start":852,"abstract_end":860}]}
{"pmid":"19259131","title":"Three independent mutations in the TSC2 gene in a family with tuberous sclerosis.","abstract":"Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by hamartomas and hamartias in multiple organs. TSC is caused by a wide spectrum of mutations within the TSC1 and TSC2 genes. Here, we report a unique family with three independent pathological mutations in TSC2. A c.1322G>A mutation in exon 12 created a stop codon, whereas a second mutation in exon 23 (c.2713C>T) was a missense change. The third mutation was a 4 base pair deletion in intron 20 of TSC2. We showed that this mutation was responsible for abnormal splicing. The three mutations were most likely de novo, as parents of affected patients did not present any features of TSC. In addition, we showed gonadal mosaicism in a branch of the family. To our knowledge, several independent mutations in TSC2 have never been observed in a single family. The probability of finding a family with three different pathological TSC2 mutations is extremely low. We discuss two main hypotheses that may be raised to explain this recurrence: (i) the TSC2 mutation rate is underestimated. In such a case, the likelihood of finding a family with three independent mutations in TSC2 may not be dramatically low; (ii) a heritable defect in a DNA repair gene (eg, mismatch repair gene) segregating in the family that is unlinked to the TSC2 gene might predispose to the occurrence of multiple TSC2 gene mutations, used as a specific target during embryogenesis.","variants":[{"Name":"NM_000548.5(TSC2):c.2713C>T (p.Arg905Trp)","Chromosome":"16","Start":"2076141","Stop":"2076141","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27443,"rule_based_match":true,"evidence_text":"c.2713C>T","llm_judgment":"PRESENT","evidence":"c.2713C>T","abstract_start":390,"abstract_end":399},{"Name":"NM_000548.5(TSC2):c.1322G>A (p.Trp441Ter)","Chromosome":"16","Start":"2062561","Stop":"2062561","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27446,"rule_based_match":true,"evidence_text":"c.1322G>A","llm_judgment":"PRESENT","evidence":"c.1322G>A","abstract_start":300,"abstract_end":309}]}
{"pmid":"29176531","title":"AUTOIMMUNE RETINOPATHY IN A PATIENT WITH A MISSENSE MUTATION IN PITPNM3.","abstract":"PURPOSE: To describe a patient with a PITPNM3 missense mutation who developed late-onset autoimmune retinopathy.\nMETHODS: Case report.\nRESULTS: An 85-year-old man presented with decreased vision, nyctalopia, and photoaversion after an uncomplicated cataract surgery. Multimodal retinal imaging revealed a scalloped pattern of atrophy and a ring of hyperautofluorescence in the perifoveal area on fundus autofluorescence. Spectral domain optical coherence tomography demonstrated loss of the ellipsoid band, along with outer retinal atrophy, sparing the fovea in both eyes. Full field electroretinogram revealed extinguished rod response and severely attenuated cone response. Antiretinal antibodies to 20-kDa and 125-kDa proteins were detected. Whole-exome sequencing revealed a heterozygous variant, c.2579T>C, p.(Ile860Thr) in PITPNM3, predicted to be severely damaging and deleterious to the protein structure and function. Over the course of 3 months, the patient experienced a rapid progression. Neoplastic workup was negative and he was started on immunosuppressive therapy for a presumed diagnosis of nonparaneoplastic autoimmune retinopathy.\nCONCLUSION: To the authors' knowledge, this is the first report of autoimmune retinopathy in a patient with PITPNM3 mutation. PITPNM3 has been previously shown to affect regulatory T cell function.","variants":[{"Name":"NM_031220.4(PITPNM3):c.2579T>C (p.Ile860Thr)","Chromosome":"17","Start":"6457634","Stop":"6457634","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1050513,"rule_based_match":true,"evidence_text":"c.2579T>C, p.(Ile860Thr)","llm_judgment":"PRESENT","evidence":"c.2579T>C, p.(Ile860Thr)","abstract_start":801,"abstract_end":825}]}
{"pmid":"23106651","title":"A novel β(0)-thalassemia frameshift mutation: [HBB:c.216delT].","abstract":"A 33-year-old adult male of Greek ethnicity, with hematological indices suggesting β(0)-thalassemia (β(0)-thal) trait, was investigated for HBB gene mutations in the course of preparation for preimplantation genetic diagnosis (PGD). Application of a routine diagnostic protocol, consisting of sequence analysis of the HBB gene, coupled to multiplex ligation-dependent probe amplification (MLPA), identified a single nucleotide deletion (-T) at codon 72 [HBB: c.216delT], leading to a novel pathogenic frameshift and protein-truncating β(0)-thal mutation (p.Phe72LeufsX18).","variants":[{"Name":"NM_000518.5(HBB):c.216del (p.Phe72fs)","Chromosome":"11","Start":"5226676","Stop":"5226676","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"T","allel_id":857462,"rule_based_match":true,"evidence_text":"HBB: c.216delT","llm_judgment":"PRESENT","evidence":"HBB: c.216delT","abstract_start":454,"abstract_end":468}]}
{"pmid":"30842225","title":"","abstract":"BACKGROUND: A single variant in <i>NAA10</i> (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia.\nMETHODS: Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in <i>NAA10</i> were evaluated using quantitative PCR and RNAseq.\nRESULTS: Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included <i>NAA10</i>. Exome sequencing identified a hemizygous <i>NAA10</i> polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct <i>NAA10</i> PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced <i>NAA10</i> mRNA levels and abnormal 3' UTRs in affected individuals. Targeted sequencing of <i>NAA10</i> in 376 additional affected individuals failed to identify variants in the PAS.\nCONCLUSION: These data show that PAS variants are the most common variant type in <i>NAA10</i>-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that <i>NAA10</i> harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.","variants":[{"Name":"NM_003491.4(NAA10):c.*39A>G","Chromosome":"X","Start":"153929948","Stop":"153929948","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":608811,"rule_based_match":true,"evidence_text":"c.*39A>G","llm_judgment":"PRESENT","evidence":"c.*39A>G","abstract_start":971,"abstract_end":979},{"Name":"NM_003491.4(NAA10):c.*43A>G","Chromosome":"X","Start":"153929944","Stop":"153929944","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":608812,"rule_based_match":true,"evidence_text":"c.*43A>G","llm_judgment":"PRESENT","evidence":"c.*43A>G","abstract_start":796,"abstract_end":804},{"Name":"NM_003491.4(NAA10):c.*40A>G","Chromosome":"X","Start":"153929947","Stop":"153929947","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":608807,"rule_based_match":true,"evidence_text":"c.*40A>G","llm_judgment":"PRESENT","evidence":"c.*40A>G","abstract_start":1007,"abstract_end":1015}]}
{"pmid":"34113375","title":"Whole-Exome Sequencing Reveals a Rare Variant of","abstract":"Non-syndromic hearing loss (NSHL) is one of the most frequent auditory deficits in humans characterized by high clinical and genetic heterogeneity. Very few studies have reported the relationship between <i>OTOF</i> (Locus: DFNB9) and hereditary hearing loss in India. We aimed to decipher the genetic cause of prelingual NSHL in a large affected Muslim consanguineous families using whole-exome sequencing (WES). The study was performed following the guidelines and regulations of the Indian Council of Medical Research (ICMR), New Delhi. The population was identified from Jammu and Kashmir, the Northernmost part of India. Near about 100 individuals were born deaf-mute in the village of 3,000 inhabitants. A total of 103 individuals (with 52 cases and 51 controls) agreed to participate in this study. Our study revealed a rare non-sense homozygous mutation NC_000002.11:g.2:26702224G>A; NM_001287489.2:c.2122C>T; NP_001274418.1:p.(Arg708<sup>∗</sup>) in the 18th exon of the <i>OTOF</i> gene. Our study provides the first insight into this homozygous condition, which has not been previously reported in ExAC, 1,000 Genome and genomAD databases. Furthermore, the variant was confirmed in the population cohort (<i>n</i> = 103) using Sanger sequencing. In addition to the pathogenic <i>OTOF</i> variant, the WES data also revealed novel and recurrent mutations in <i>CDH23, GJB2, MYO15A, OTOG</i>, and <i>SLC26A4</i> genes. The rare pathogenic and the novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions SCV001448680.1, SCV001448682.1 and SCV001448681.1. We conclude that <i>OTOF</i>-related NSHL hearing loss is prevalent in the region due to successive inbreeding in its generations. We recommend premarital genetic testing and genetic counseling strategies to minimize and control the disease risk in future generations.","variants":[{"Name":"NM_194248.3(OTOF):c.2122C>T (p.Arg708Ter)","Chromosome":"2","Start":"26479356","Stop":"26479356","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34683,"rule_based_match":true,"evidence_text":"NM_001287489.2:c.2122C>T; NP_001274418.1:p.(Arg708<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"NM_001287489.2:c.2122C>T; NP_001274418.1:p.(Arg708<sup>∗</sup>)","abstract_start":892,"abstract_end":955}]}
{"pmid":"27965258","title":"A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (","abstract":"OBJECTIVES: Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in <i>NLRP3</i> and <i>NLRC4</i> are linked to hereditary autoinflammatory diseases, whereas polymorphisms in <i>NLRP1</i> are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human <i>NLRP1</i> mutation is associated with autoinflammation remains to be determined.\nMETHODS: To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients.\nRESULTS: We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in <i>NLRP1</i> (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome.\nCONCLUSIONS: We demonstrate the responsibility of human <i>NLRP1</i> in a novel autoinflammatory disorder that we propose to call NAIAD for <i>NLRP1-</i>associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of <i>NLRP1</i> in inflammation and immunity.\nTRIAL REGISTRATION NUMBER: NCT02067962; Results.","variants":[{"Name":"NM_033004.4(NLRP1):c.2176C>T (p.Arg726Trp)","Chromosome":"17","Start":"5558520","Stop":"5558520","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":380164,"rule_based_match":true,"evidence_text":"c.2176C>T; p.Arg726Trp","llm_judgment":"PRESENT","evidence":"c.2176C>T; p.Arg726Trp","abstract_start":1192,"abstract_end":1214},{"Name":"NM_033004.4(NLRP1):c.3641C>G (p.Pro1214Arg)","Chromosome":"17","Start":"5521666","Stop":"5521666","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":380165,"rule_based_match":true,"evidence_text":"c.3641C>G, p.Pro1214Arg","llm_judgment":"PRESENT","evidence":"c.3641C>G, p.Pro1214Arg","abstract_start":1317,"abstract_end":1340}]}
{"pmid":"25234363","title":"Atypical hematologic and renal manifestations in neurofibromatosis type I: coincidence or pathophysiological link?","abstract":"Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors with a birth incidence rate of 1 in 2500-3000. 50% of cases are sporadic. The diagnosis is exclusively based on clinical assessment with clinical diagnostic criteria such as café-au-lait spots, neurofibromas, axillary or groin freckling, Lisch nodules, optic pathway glioma, bony dysplasia and first-degree relative with NF1. We report a family with NF1 in which two members presented atypical clinical features in addition to the classical diagnostic criteria. Three relatives affected by NF1, a father and two of his three sons, are described. The clinical diagnosis was originally worn in all three cases, with the association many spots café-au -lait over the entire body and some axillary freckling as well as first-degree relative. One case presented an Acute Myeloid Leukemia (AML) type 2 at 10 years of age diagnosed before the revelation of bicytopenia associated pallor and isolated asthenia. A second case presented a nephrotic syndrome at 4 years of age due to the association of hydrops with headache and asthenia. Direct sequencing of NF1 led to identify the familial mutation, a previously unreported heterozygous missense mutation c.3443C > A, p.Ala1148Glu in exon 20 which segregated with all three affected patients. The family described in this report confirms the high clinical variability of NF1, even intrafamilial, and raises the question as to whether rare features such as AML and nephrotic syndrome are associated with NF1. Some NF1 patients presenting glomerular diseases or AML have rarely been reported, but due to the small number of cases described the mechanisms underlying these associations are poorly understood. However, it seems important to be aware of the possible occurrence of nephritic syndrome and/or malignant blood diseases in NF1 patients.","variants":[{"Name":"NM_001042492.3(NF1):c.3443C>A (p.Ala1148Glu)","Chromosome":"17","Start":"31232828","Stop":"31232828","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1414945,"rule_based_match":true,"evidence_text":"c.3443C > A, p.Ala1148Glu","llm_judgment":"PRESENT","evidence":"c.3443C > A, p.Ala1148Glu","abstract_start":1309,"abstract_end":1334}]}
{"pmid":"19424285","title":"Mutations in the LMNA gene do not cause axonal CMT in Czech patients.","abstract":"The LMNA gene was sequenced in 98 Czech patients from 94 unrelated families with early-onset axonal Charcot-Marie-Tooth (CMT) disease consistent with both autosomal recessive inheritance and sporadic cases. Biallelic pathogenic mutations were not found in any patient in this group. One patient carried the c.1870C>T mutation that is predicted to result in the amino-acid substitution, p. Arg624Cys, on one allele, but the second causative mutation was not detected. LMNA mutation is not likely to be associated with the disease in this family. To exclude larger deletions/duplications in the LMNA gene not detectable by sequencing, 48 patients from this group were also analyzed with multiplex ligation-dependent probe amplification. No rearrangements in the LMNA gene were detected. We conclude that mutations in the LMNA gene are absent from a large group of Czech patients with axonal autosomal recessive CMT disease. Consequently, LMNA mutation screening does not seem to be relevant for axonal CMT DNA diagnostics. A similar situation may apply to other European populations.","variants":[{"Name":"NM_170707.4(LMNA):c.1870C>T (p.Arg624Cys)","Chromosome":"1","Start":"156138659","Stop":"156138659","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171049,"rule_based_match":true,"evidence_text":"c.1870C>T","llm_judgment":"PRESENT","evidence":"c.1870C>T","abstract_start":307,"abstract_end":316}]}
{"pmid":"33302512","title":"Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the","abstract":"Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the <i>BEST1</i> gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02-1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. <i>BEST1</i>-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.","variants":[{"Name":"NM_004183.4(BEST1):c.199_200del (p.Leu67fs)","Chromosome":"11","Start":"61955151","Stop":"61955152","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":3408544,"rule_based_match":true,"evidence_text":"c.199_200del/p.(Leu67Valfs*164)","llm_judgment":"PRESENT","evidence":"c.199_200del/p.(Leu67Valfs*164)","abstract_start":1361,"abstract_end":1392},{"Name":"NM_004183.4(BEST1):c.524del (p.Ser175fs)","Chromosome":"11","Start":"61956886","Stop":"61956886","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":3120452,"rule_based_match":true,"evidence_text":"c.524del/p.(Ser175Thrfs*19)","llm_judgment":"PRESENT","evidence":"c.524del/p.(Ser175Thrfs*19)","abstract_start":1394,"abstract_end":1421},{"Name":"NM_004183.4(BEST1):c.287_298del (p.Gln96_Asn99del)","Chromosome":"11","Start":"61955752","Stop":"61955763","ReferenceAlleleVCF":"GGAACCAGTACGA","AlternateAlleleVCF":"G","allel_id":431755,"rule_based_match":true,"evidence_text":"c.287_298del/p.(Gln96_Asn99del)","llm_judgment":"PRESENT","evidence":"c.287_298del/p.(Gln96_Asn99del)","abstract_start":1328,"abstract_end":1359},{"Name":"NM_004183.4(BEST1):c.590_615del (p.Leu197fs)","Chromosome":"11","Start":"61956951","Stop":"61956976","ReferenceAlleleVCF":"GCTTGGAGGTCGAATCCGGGACCCTAT","AlternateAlleleVCF":"G","allel_id":3408697,"rule_based_match":true,"evidence_text":"c.590_615del/p.(Leu197Profs*26)","llm_judgment":"PRESENT","evidence":"c.590_615del/p.(Leu197Profs*26)","abstract_start":1423,"abstract_end":1454},{"Name":"NM_004183.4(BEST1):c.454C>T (p.Pro152Ser)","Chromosome":"11","Start":"61955924","Stop":"61955924","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3169470,"rule_based_match":true,"evidence_text":"c.454C>T/p.(Pro152Ser)","llm_judgment":"PRESENT","evidence":"c.454C>T/p.(Pro152Ser)","abstract_start":1280,"abstract_end":1302}]}
{"pmid":"29531337","title":"Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis.","abstract":"Biallelic mutations in NDUFAF6 have been identified as responsible for cases of autosomal recessive Leigh syndrome associated with mitochondrial complex I deficiency. Here we report two siblings and two unrelated subjects with Leigh syndrome, in which we found the same compound heterozygous missense (c.532G>C:p.A178P) and deep intronic (c.420+784C>T) variants in NDUFAF6. We demonstrated that the identified intronic variant creates an alternative splice site, leading to the production of an aberrant transcript. A detailed analysis of whole-exome sequencing data together with the functional validation based on mRNA analysis may reveal pathogenic variants even in non-exonic regions.","variants":[{"Name":"NM_152416.4(NDUFAF6):c.420+784C>T","Chromosome":"8","Start":"95036360","Stop":"95036360","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":917814,"rule_based_match":true,"evidence_text":"c.420+784C>T","llm_judgment":"PRESENT","evidence":"c.420+784C>T","abstract_start":339,"abstract_end":351},{"Name":"NM_152416.4(NDUFAF6):c.532G>C (p.Ala178Pro)","Chromosome":"8","Start":"95045599","Stop":"95045599","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":359159,"rule_based_match":true,"evidence_text":"c.532G>C:p.A178P","llm_judgment":"PRESENT","evidence":"c.532G>C:p.A178P","abstract_start":302,"abstract_end":318}]}
{"pmid":"30950014","title":"Analysis of ACADVL gene variations among nine neonates with very long chain acyl-coA dehydrogenase deficiency","abstract":"OBJECTIVE: To explore the clinical features and variations of ACADVL gene in 9 neonates with very long chain acyl-coenzyme A dehydrogenase deficiency (VLCADD).\nMETHODS: VLCADD was suspected based on the results of neonatal screening by tandem mass spectrometry (MS-MS), with tetradecenoylcarnitine ± tetradecenoylcarnitine/octanoylcarnitine (C14: 1 ± C14: 1/C8) as the mark indexes. Infants with positive outcome were confirmed by sequencing of the ACADVL gene.\nRESULTS: Among 9 VLCADD cases, one case lost during follow-up, the observed phenotypes comprised 2 with severe early-onset form, 1 with hepatic form and 5 with late-onset form. Optimal outcome was acquired for all patients except the 2 early-onset cases. In total 16 ACADVL variations were detected among the 9 infants, which included 8 novel variations (c.96-105del GCCCGGCCCT, c.541C>T, c.863T>G, c.878+1G>C, c.895A>G, c.1238T>C, c.1276G>A, and c.1505T>A) and 11 missense variations. There were 9 genotypic combinations, including 1 homozygote and 8 compound heterozygotes. Except for two patients carrying null variations, all had a good outcome.\nCONCLUSION: VLCADD is relatively rare in southern China, for which late-onset form is common. Carriers of null variations of the ACADVL gene may have relatively poorer clinical outcome. Above results will provide valuable information for the diagnosis and management of VLCADD.","variants":[{"Name":"NM_000018.4(ACADVL):c.1276G>A (p.Ala426Thr)","Chromosome":"17","Start":"7223819","Stop":"7223819","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":646656,"rule_based_match":true,"evidence_text":"c.1276G>A","llm_judgment":"PRESENT","evidence":"c.1276G>A","abstract_start":894,"abstract_end":903},{"Name":"NM_000018.4(ACADVL):c.895A>G (p.Lys299Glu)","Chromosome":"17","Start":"7222683","Stop":"7222683","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1425600,"rule_based_match":true,"evidence_text":"c.895A>G","llm_judgment":"PRESENT","evidence":"c.895A>G","abstract_start":873,"abstract_end":881},{"Name":"NM_000018.4(ACADVL):c.878+1G>C","Chromosome":"17","Start":"7222303","Stop":"7222303","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":940435,"rule_based_match":true,"evidence_text":"c.878+1G>C","llm_judgment":"PRESENT","evidence":"c.878+1G>C","abstract_start":861,"abstract_end":871},{"Name":"NM_000018.4(ACADVL):c.1238T>C (p.Ile413Thr)","Chromosome":"17","Start":"7223699","Stop":"7223699","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2833910,"rule_based_match":true,"evidence_text":"c.1238T>C","llm_judgment":"PRESENT","evidence":"c.1238T>C","abstract_start":883,"abstract_end":892}]}
{"pmid":"20825431","title":"Molecular analysis of Sanfilippo syndrome type C in Spain: seven novel HGSNAT mutations and characterization of the mutant alleles.","abstract":"The Sanfilippo syndrome type C [mucopolysaccharidosis IIIC (MPS IIIC)] is caused by mutations in the HGSNAT gene, encoding an enzyme involved in heparan sulphate degradation. We report the first molecular study on several Spanish Sanfilippo syndrome type C patients. Seven Spanish patients, one Argentinean and three Moroccan patients were analysed. All mutant alleles were identified and comprised nine distinct mutant alleles, seven of which were novel, including four missense mutations (p.A54V, p.L113P, p.G424V and p.L445P) and three splicing mutations due to two point mutations (c.633+1G>A and c.1378-1G>A) and an intronic deletion (c.821-31_821-13del). Furthermore, we found a new single nucleotide polymorphism (SNP) (c.564-98T>C). The two most frequent changes were the previously described c.372-2A>G and c.234+1G>A mutations. All five splicing mutations were experimentally confirmed by studies at the RNA level, and a minigene experiment was carried out in one case for which no fibroblasts were available. Expression assays allowed us to show the pathogenic effect of the four novel missense mutations and to confirm that the already known c.710C>A (p.P237Q) is a non-pathogenic SNP. Haplotype analyses suggested that the two mutations (c.234+1G>A and c.372-2A>G) that were present in more than one patient have a common origin, including one (c.234+1G>A) that was found in Spanish and Moroccan patients.","variants":[{"Name":"NM_152419.3(HGSNAT):c.234+1G>A","Chromosome":"8","Start":"43147064","Stop":"43147064","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39789,"rule_based_match":true,"evidence_text":"c.234+1G>A","llm_judgment":"PRESENT","evidence":"c.234+1G>A","abstract_start":816,"abstract_end":826},{"Name":"NM_152419.3(HGSNAT):c.1378-1G>A","Chromosome":"8","Start":"43193756","Stop":"43193756","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":985616,"rule_based_match":true,"evidence_text":"c.1378-1G>A","llm_judgment":"PRESENT","evidence":"c.1378-1G>A","abstract_start":601,"abstract_end":612},{"Name":"NM_152419.3(HGSNAT):c.372-2A>G","Chromosome":"8","Start":"43158921","Stop":"43158921","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":16275,"rule_based_match":true,"evidence_text":"c.372-2A>G","llm_judgment":"PRESENT","evidence":"c.372-2A>G","abstract_start":801,"abstract_end":811}]}
{"pmid":"21412954","title":"Mutation in ribosomal protein L21 underlies hereditary hypotrichosis simplex.","abstract":"Hereditary hypotrichosis simplex (HHS) is a form of nonsyndromic inherited hair loss disorders without characteristic hair shaft changes, which has marked genetic and clinical heterogeneity. After mapping the locus to 13q12.12-12.3 in a Chinese family with a generalized variant of autosomal dominant HHS (ADHHS), exome sequencing was performed in an affected individual. The cause of the disease in this family was identified as a c.95G>A (p.Arg32Gln) mutation in the RPL21 gene, which encoding the ribosomal protein L21. This mutation cosegregated completely with the disease phenotype and was not observed in unaffected family members, 200 normal controls, the dbSNP database, the YH database or pilot data from the 1000 Genomes Project. Additionally, this mutation was found in two patients from another unrelated Chinese family with HHS. To the best of our knowledge, this is the first report describing the involvement of a ribosomal protein gene mutation in a non-syndromic hair loss disorder.","variants":[{"Name":"NM_000982.4(RPL21):c.95G>A (p.Arg32Gln)","Chromosome":"13","Start":"27254247","Stop":"27254247","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":143259,"rule_based_match":true,"evidence_text":"c.95G>A (p.Arg32Gln)","llm_judgment":"PRESENT","evidence":"c.95G>A (p.Arg32Gln)","abstract_start":432,"abstract_end":452}]}
{"pmid":"22898041","title":"A new β⁰-thalassemia frameshift mutation [β 48 (-T)] in a Uruguayan family.","abstract":"We describe here a new frameshift mutation of β-thalassemia in a Uruguayan family with Italian ancestry [β48 (-T); HBB:c.146delT]. This frameshift results in formation of premature stop codon (TGA) 40 bp downstream and in a short unstable product that is degraded in the cell.","variants":[{"Name":"NM_000518.5(HBB):c.146del (p.Leu49fs)","Chromosome":"11","Start":"5226746","Stop":"5226746","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":857480,"rule_based_match":true,"evidence_text":"HBB:c.146delT","llm_judgment":"PRESENT","evidence":"HBB:c.146delT","abstract_start":115,"abstract_end":128}]}
{"pmid":"27612211","title":"Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A.","abstract":"Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome, is a rare condition with fewer than 40 patients reported in the literature. Characteristic physical findings include neonatal progeroid appearance, sparse scalp hair, prominent scalp veins, and lipoatrophy; in addition, neonatal teeth are often a distinctive finding. The inheritance pattern of this disorder has been postulated to be autosomal recessive, although a specific gene has not been identified. Here we report an infant with the characteristic phenotypic features of Wiedemann-Rautenstrauch syndrome in whom exome sequencing identified two pathogenic variants in POLR3A: c.1909+18G>A; p.(Y637Cfs*23) and c.2617C>T; p.(R873*). Mutations in POLR3A (OMIM #614258) are associated with 4H leukodystrophy syndrome characterized by the triad of hypomyelination, hypodontia, and hypogonadotrophic hypogonadism. The present patient's genotype implies a broader phenotypic range for POLR3A mutations and might expand the clinical spectrum. This proband is notable because she had two null pathogenic variants. Replication in other patients clinically diagnosed with Wiedemann-Rautenstrauch syndrome is needed to further demonstrate this gene-disease association. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_007055.4(POLR3A):c.1909+18G>A","Chromosome":"10","Start":"78009519","Stop":"78009519","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40101,"rule_based_match":true,"evidence_text":"c.1909+18G>A","llm_judgment":"PRESENT","evidence":"c.1909+18G>A","abstract_start":659,"abstract_end":671},{"Name":"NM_007055.4(POLR3A):c.2617C>T (p.Arg873Ter)","Chromosome":"10","Start":"77993367","Stop":"77993367","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":237149,"rule_based_match":true,"evidence_text":"c.2617C>T; p.(R873*)","llm_judgment":"PRESENT","evidence":"c.2617C>T; p.(R873*)","abstract_start":692,"abstract_end":712}]}
{"pmid":"37915296","title":"Genotype and phenotype characterization of primary hypertrophic osteoarthropathy type 2 and chronic enteropathy associated with SLCO2A1: Report of two cases and literature review.","abstract":"Autosomal recessive type 2 primary hypertrophic osteoarthropathy (PHOAR2) and chronic enteropathy associated with SLCO2A1 (CEAS) are two entities caused by pathogenic variants (PVs) in the SLCO2A1 gene that can coexist or occur independently from one another. We report two cases of PHOAR2 in Mexico with concomitant CEAS and conducted a review of the literature of the reported cases of PHOAR2 and/or CEAS to analyze the relationship between their genotype and phenotype presentation. The patients from our Institution with classical PHOAR2 phenotype and CEAS, harbored SLCO2A1 c.547G > A and c.1768del variants. We reviewed 232 cases, of which 86.6% were of Asian origin, and identified 109 different variants in SLCO2A1. Intron 7, exon 13, and exon 4 were predominantly affected. The two most common PVs were c.940 + 1G > A and c.1807C > T. We found a statistically significant association between SLCO2A1 variants located in intron 7, exons 12, and 13 and the development of CEAS. Missense variants were more frequent in isolated PHOAR2, while a greater proportion of protein-truncating variants (PTVs) were found in CEAS. Further investigation is imperative to elucidate the underlying pathophysiological mechanisms associated with CEAS, thereby facilitating the identification of effective therapeutic interventions.","variants":[{"Name":"NM_005630.3(SLCO2A1):c.547G>A (p.Gly183Arg)","Chromosome":"3","Start":"133955044","Stop":"133955044","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":966067,"rule_based_match":true,"evidence_text":"SLCO2A1 c.547G > A","llm_judgment":"PRESENT","evidence":"SLCO2A1 c.547G > A","abstract_start":571,"abstract_end":589},{"Name":"NM_005630.3(SLCO2A1):c.1768del (p.Arg590fs)","Chromosome":"3","Start":"133935820","Stop":"133935820","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":2045062,"rule_based_match":true,"evidence_text":"c.1768del","llm_judgment":"PRESENT","evidence":"c.1768del","abstract_start":594,"abstract_end":603}]}
{"pmid":"18652600","title":"Dystrophin nonsense mutations can generate alternative rescue transcripts in lymphocytes.","abstract":"Secondary alterations in splicing have been reported to produce semi-functional mRNA from several nonsense mutations in the dystrophin gene. Disruptions of exonic splicing enhancers by single nucleotide changes are thought to underlie such alterations. The precise frequencies of such nonsense mutation-dependent splicing alterations, however, remain unknown. Here we analyzed the splicing patterns of dystrophin mRNA in lymphocytes from 38 patients with dystrophinopathies due to nonsense mutations in the dystrophin gene. In seven of the cases (18%), we observed partial skipping of the nonsense-encoding exon. Two of the seven cases, however, exhibited complex activation of a nonsense mutation-created splice site, which resulted in the generation of novel transcripts. Examination of cis-regulatory splicing elements through calculation of splicing probability scores and identification of potential splicing enhancer or silencer sequences failed to disclose a single cause for exon skipping. Remarkably, individual differences in splicing patterns were observed for cells from patients with identical nonsense mutations (C.5899C>T). Although five cases produced semi-functional dystrophin mRNAs, only one of these exhibited a mild clinical course. These results provide important insights about targets for exon skipping induced by candidate antisense oligonucleotides and for ribosomal read-through of nonsense mutations.","variants":[{"Name":"NM_004006.3(DMD):c.5899C>T (p.Arg1967Ter)","Chromosome":"X","Start":"32342123","Stop":"32342123","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26297,"rule_based_match":true,"evidence_text":"C.5899C>T","llm_judgment":"PRESENT","evidence":"C.5899C>T","abstract_start":1127,"abstract_end":1136}]}
{"pmid":"36076925","title":"Altered Expression of","abstract":"Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease caused by heterozygous missense mutations within the gene encoding for the nuclear envelope protein transmembrane protein 43 (TMEM43). The disease is characterized by myocyte loss and fibro-fatty replacement, leading to life-threatening ventricular arrhythmias and sudden cardiac death. However, the role of TMEM43 in the pathogenesis of ACM remains poorly understood. In this study, we generated cardiomyocyte-restricted transgenic zebrafish lines that overexpress eGFP-linked full-length human wild-type (WT) TMEM43 and two genetic variants (c.1073C>T, p.S358L; c.332C>T, p.P111L) using the Tol2-system. Overexpression of WT and p.P111L-mutant TMEM43 was associated with transcriptional activation of the mTOR pathway and ribosome biogenesis, and resulted in enlarged hearts with cardiomyocyte hypertrophy. Intriguingly, mutant p.S358L TMEM43 was found to be unstable and partially redistributed into the cytoplasm in embryonic and adult hearts. Moreover, both TMEM43 variants displayed cardiac morphological defects at juvenile stages and ultrastructural changes within the myocardium, accompanied by dysregulated gene expression profiles in adulthood. Finally, CRISPR/Cas9 mutants demonstrated an age-dependent cardiac phenotype characterized by heart enlargement in adulthood. In conclusion, our findings suggest ultrastructural remodeling and transcriptomic alterations underlying the development of structural and functional cardiac defects in TMEM43-associated cardiomyopathy.","variants":[{"Name":"NM_024334.3(TMEM43):c.332C>T (p.Pro111Leu)","Chromosome":"3","Start":"14131614","Stop":"14131614","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1933090,"rule_based_match":true,"evidence_text":"c.332C>T, p.P111L","llm_judgment":"PRESENT","evidence":"c.332C>T, p.P111L","abstract_start":637,"abstract_end":654}]}
{"pmid":"35782616","title":"Gonadal mosaicism in GNAO1 causing neurodevelopmental disorder with involuntary movements; two additional variants.","abstract":"Background: <i>GNAO1</i> encodes an alpha subunit of the heterotrimeric guanine nucleotide-binding proteins (G proteins). Mutations in <i>GNAO1</i> result in two clinical phenotypes: Early infantile epileptic encephalopathy 17 (EEIE17-OMIM #615473) and Neurodevelopmental disorder with involuntary movements (NEDIM-OMIM #617493). Both are inherited as autosomal dominant disorders and originate mainly as de novo. Only a few are reported as gonadal mosaicism.\nMaterials and methods: We recruited and retrospectively reviewed five patients from two families seen at King Faisal Specialist Hospital and Research Centre in Riyadh (KFSHRC).\nResults: All patients presented with severe neurodevelopmental disorder, followed by progressive dystonia and hyperkinetic movements. In addition, none of the patients had seizures which was consistent with NEDIM phenotype. The specific diagnosis was not clinically entertained and was only found on whole exome sequencing (WES), which identified two variants (c.724-8G > A & c.709G > A). Both variants were previously reported as pathogenic de novo in patients with NEDIM, and one was reported as parental gonadal mosaicism.\nConclusion: We report these variants as additional variants in <i>GNAO1</i> gene that may be inherited as parental gonadal mosaicism. Both variants resulted in NEDIM with no observed clinical differences in the severity than the reported cases. This noticeable reported association between <i>GNAO1</i> gene associated disorders and gonadal mosaicism should be considered in reproductive genetic counselling of affected families. Furthermore, in view of these reports, more studies with prospective data collection to explore the association between <i>GNAO1</i> and gonadal mosaicism and the underlying mechanisms will be necessary.","variants":[{"Name":"NM_020988.3(GNAO1):c.724-8G>A","Chromosome":"16","Start":"56351376","Stop":"56351376","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":415501,"rule_based_match":true,"evidence_text":"c.724-8G > A","llm_judgment":"PRESENT","evidence":"c.724-8G > A","abstract_start":998,"abstract_end":1010}]}
{"pmid":"24473688","title":"Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis.","abstract":"Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is an autosomal recessive disorder caused by a defect in ornithine translocase. This condition leads to variable clinical presentations, including episodic hyperammonaemia, hepatic derangement, and chronic neurological manifestations. Fewer than 100 affected patients have been reported worldwide. Here we report the first two cases in Hong Kong Chinese, who were compound heterozygous siblings for c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile) in the SLC25A15 gene. When the mother refused prenatal diagnosis for the second pregnancy, urgent genetic testing provided the definitive diagnosis within 24 hours to enable specific treatment. Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases.","variants":[{"Name":"NM_014252.4(SLC25A15):c.535C>T (p.Arg179Ter)","Chromosome":"13","Start":"40807376","Stop":"40807376","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21033,"rule_based_match":true,"evidence_text":"c.535C>T (p.Arg179*)","llm_judgment":"PRESENT","evidence":"c.535C>T (p.Arg179*)","abstract_start":461,"abstract_end":481},{"Name":"NM_014252.4(SLC25A15):c.815C>T (p.Thr272Ile)","Chromosome":"13","Start":"40809576","Stop":"40809576","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21038,"rule_based_match":true,"evidence_text":"c.815C>T (p.Thr272Ile)","llm_judgment":"PRESENT","evidence":"c.815C>T (p.Thr272Ile)","abstract_start":486,"abstract_end":508}]}
{"pmid":"25192047","title":"Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy.","abstract":"Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies.","variants":[{"Name":"NM_177402.5(SYT2):c.920A>C (p.Asp307Ala)","Chromosome":"1","Start":"202599351","Stop":"202599351","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":166147,"rule_based_match":true,"evidence_text":"c.920A>C","llm_judgment":"PRESENT","evidence":"c.920A>C","abstract_start":470,"abstract_end":478},{"Name":"NM_177402.5(SYT2):c.923C>T (p.Pro308Leu)","Chromosome":"1","Start":"202599348","Stop":"202599348","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":166148,"rule_based_match":true,"evidence_text":"c.923C>T (p.Pro308Leu)","llm_judgment":"PRESENT","evidence":"p.Pro308Leu","abstract_start":682,"abstract_end":693}]}
{"pmid":"22523156","title":"Primary progressive multiple sclerosis developing in the context of young onset Parkinson's disease.","abstract":"We report a patient with young onset Parkinson's disease (PD) and a heterozygous point mutation in parkin (c.1000C>T; p.Arg334Cys). After 8 years he developed pyramidal signs and reinvestigation demonstrated MRI and laboratory findings supportive of a diagnosis of multiple sclerosis (MS) with a primary progressive (PP) clinical course. This is a previously un-described association of young onset PD with PPMS. Imaging clearly dates the occurrence of each disease as chronologically separate phenomena. There is not currently evidence for shared causation or pathogenesis between the two neurological disorders but we will follow with interest the emerging genetic characterization of parkin in both PD and MS.","variants":[{"Name":"NM_004562.3(PRKN):c.1000C>T (p.Arg334Cys)","Chromosome":"6","Start":"161548937","Stop":"161548937","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":265741,"rule_based_match":true,"evidence_text":"c.1000C>T; p.Arg334Cys","llm_judgment":"PRESENT","evidence":"c.1000C>T; p.Arg334Cys","abstract_start":107,"abstract_end":129}]}
{"pmid":"30586141","title":"Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma.","abstract":"Importance: The protection of telomeres 1 protein (POT1) is a critical component of the shelterin complex, a multiple-protein machine that regulates telomere length and protects telomere ends. Germline variants in POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of cancers including cutaneous T-cell lymphoma (CTCL).\nObjective: To characterize pathogenic variation in POT1 in families with melanoma to inform clinical management.\nDesign, Setting, and Participants: In this case study and pedigree evaluation, analysis of the pedigree of 1 patient with melanoma revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) that was subsequently found in 2 other pedigrees obtained from the GenoMEL Consortium.\nMain Outcomes and Measures: (1) Identification of the POT1 p.I78T variant; (2) evaluation of the clinical features and characteristics of patients with this variant; (3) analysis of 3 pedigrees; (4) genomewide single-nucleotide polymorphism genotyping of germline DNA; and (5) a somatic genetic analysis of available nevi and 1 melanoma lesion.\nResults: The POT1 p.I78T variant was found in 3 melanoma pedigrees, all of persons who self-reported as being of Jewish descent, and was shown to disrupt POT1-telomere binding. A UV mutation signature was associated with nevus and melanoma formation in POT1 variant carriers, and somatic mutations in driver genes such as BRAF, NRAS, and KIT were associated with lesion development in these patients.\nConclusions and Relevance: POT1 p.I78T is a newly identified, likely pathogenic, variant meriting screening for in families with melanoma after more common predisposition genes such as CDKN2A have been excluded. It could also be included as part of gene panel testing.","variants":[{"Name":"NM_015450.3(POT1):c.233T>C (p.Ile78Thr)","Chromosome":"7","Start":"124870933","Stop":"124870933","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":456457,"rule_based_match":true,"evidence_text":"p.I78T, c.233T>C","llm_judgment":"PRESENT","evidence":"p.I78T, c.233T>C","abstract_start":647,"abstract_end":663}]}
{"pmid":"22246954","title":"Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I.","abstract":"We identified a novel missense mutation, c.424G>C (p.Val142Leu) in PRPS1 in a patient with uric acid overproduction without gout but with developmental delay, hypotonia, hearing loss, and recurrent respiratory infections. The uric acid overproduction accompanying this combination of symptoms suggests that the patient presented with phosphoribosylpyrophosphate (PRPP) synthetase superactivity, but recurrent infections have not been associated with superactivity until now. However, recurrent infections are a prominent feature of patients with Arts syndrome, which is caused by PRPS1 loss-of-function mutations, indicating that the patient reported here has an intermediate phenotype. Molecular modeling predicts that the p.Val142Leu change affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss-of-function of PRPP synthetase. This finding is in line with the normal PRPP synthetase activity in fibroblasts and the absence of activity in erythrocytes of the present patient. We postulate that the overall effect of the p.Val142Leu change on protein activity is determined by the cell type, being a gain-of-function in proliferating cells and a loss-of-function in postmitotic cells. Our results show that missense mutations in PRPS1 can cause a continuous spectrum of features ranging from progressive non-syndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites that are affected.","variants":[{"Name":"NM_002764.4(PRPS1):c.424G>C (p.Val142Leu)","Chromosome":"X","Start":"107642384","Stop":"107642384","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":38944,"rule_based_match":true,"evidence_text":"c.424G>C (p.Val142Leu)","llm_judgment":"PRESENT","evidence":"c.424G>C (p.Val142Leu)","abstract_start":41,"abstract_end":63}]}
{"pmid":"21648289","title":"HNF1A mutation presenting with fetal macrosomia and hypoglycemia in childhood prior to onset of overt diabetes.","abstract":"BACKGROUND: HNF1A-MODY (MODY3) is a common subtype of autosomal dominant diabetes. Unlike HNF4-MODY where fetal macrosomia and early postnatal hyperinsulinemic hypoglycemia have been reported, history of transient insulin overproduction has not yet been recognized in individuals with HNF1A-MODY.\nCASE REPORT: Here, we report on a 40-year-old male patient with HNF1A mutation p.Arg272His (c.815G>A) having a history of fetal macrosomia (4750 g, 59 cm), and, at least, one attack of symptomatic hypoglycemia in childhood. Diabetes was subsequently diagnosed at 19 years of age. The proband's daughter who developed diabetes at 16 years carries the same mutation, but her birth weight and length were in the upper normal range, and she never experienced hypoglycemic symptoms.\nCONCLUSION: The observation of fetal macrosomia and hypoglycemia in childhood is indicative of a biphasic impact of the HNF1A mutation on p-cell function over the lifespan, leading from inappropriate insulin oversecretion to final clinical diabetes.","variants":[{"Name":"NM_000545.8(HNF1A):c.815G>A (p.Arg272His)","Chromosome":"12","Start":"120994265","Stop":"120994265","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29970,"rule_based_match":true,"evidence_text":"p.Arg272His (c.815G>A)","llm_judgment":"PRESENT","evidence":"p.Arg272His (c.815G>A)","abstract_start":376,"abstract_end":398}]}
{"pmid":"36410626","title":"Minigene Assay as an Effective Molecular Diagnostic Strategy in Determining the Pathogenicity of Noncanonical Splice-Site Variants in FLCN.","abstract":"Primary spontaneous pneumothorax (PSP) or pulmonary cyst is one of the manifestations of Birt-Hogg-Dubé syndrome, which is caused by pathogenic variants in FLCN gene. Genetic testing in patients with PSP identifies a certain number of missense or intronic variants. These variants are usually considered as variants of uncertain significance, whose functional interpretations pose a challenge in clinical genetics. To improve recognition of pathogenic splice-altering variants in FLCN gene, computational tools are used to prioritize potential splice-altering variants and then a hybrid minigene assay is performed to verify the RNA splicing pattern. Herein, variants in FLCN exon 11 and its flanking sequence are focused. Eight variants detected in 11 patients with PSP are evaluated, and six variants are prioritized by in silico tools as potential splice-altering variants of uncertain significance. Four variants (c.1177-5_1177-3delCTC, c.1292_1300+4del, c.1300+4C>T, and c.1300+5G>A) are demonstrated by minigene assay to alter RNA splicing of FLCN, and the last three of them are novel. RT-PCR of patient-derived RNA gives consistent results. Genotype-phenotype correlation analysis in patients with PSP with these variants demonstrates good concordance. Our results underline the importance of RNA analysis, which could provide molecular evidence for pathogenicity of a variant, and provide essential information for the clinical interpretation of variants. Combining the clinical information, a definitive diagnosis could be made.","variants":[{"Name":"NM_144997.7(FLCN):c.1300+5G>A","Chromosome":"17","Start":"17216375","Stop":"17216375","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":401551,"rule_based_match":true,"evidence_text":"c.1300+5G>A","llm_judgment":"PRESENT","evidence":"c.1300+5G>A","abstract_start":976,"abstract_end":987}]}
{"pmid":"23895425","title":"Functional analysis and in vitro correction of splicing FAH mutations causing tyrosinemia type I.","abstract":"Hereditary tyrosinemia type I (HT1) is a rare disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway, resulting mainly in hepatic alterations due to accumulation of the toxic metabolites fumarylacetoacetate, maleylacetoacetate and succinylacetone. We have characterized using minigenes four splicing mutations affecting exonic or intronic nucleotides of the FAH gene identified in two HT1 patients. Two of the mutations are novel, c.82-1G>A and c.913G>C and the other two have been previously associated with a splicing defect (c.836A>G and c.1062+5G>A). All mutations were confirmed to affect splicing in minigenes, resulting in exon skipping or activation of a cryptic splice site. We have analyzed the effect of different compounds known to modulate splicing (valproic acid, phenyl butyrate, M344, EIPA, and resveratrol) and the overexpression of splice factors of the SR protein family on the transcriptional profile of the mutant minigenes. For the c.836A>G mutation, a partial recovery of the correctly spliced transcript was observed. These results confirm the relevance of performing functional studies for mutations potentially affecting the splicing process and open the possibility of supplementary therapeutic approaches to diseases caused by splicing defects.","variants":[{"Name":"NM_000137.4(FAH):c.1062+5G>A","Chromosome":"15","Start":"80180230","Stop":"80180230","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26909,"rule_based_match":true,"evidence_text":"c.1062+5G>A","llm_judgment":"PRESENT","evidence":"c.1062+5G>A","abstract_start":590,"abstract_end":601}]}
{"pmid":"24755949","title":"Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome.","abstract":"First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C>T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers-Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations.","variants":[{"Name":"NM_007255.3(B4GALT7):c.808C>T (p.Arg270Cys)","Chromosome":"5","Start":"177608994","Stop":"177608994","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20652,"rule_based_match":true,"evidence_text":"NM_007255.2: c.808C>T p.(Arg270Cys)","llm_judgment":"PRESENT","evidence":"NM_007255.2: c.808C>T p.(Arg270Cys)","abstract_start":640,"abstract_end":675}]}
{"pmid":"37288251","title":"Single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with the","abstract":"We present a 55-year-old man with chest tightness and dyspnoea after activity lasting for 2 months who was diagnosed with single coronary artery (SCA) and presented with dilated cardiomyopathy (DCM) with the c.1858C > T mutation in the <i>SCN5A</i> gene. The computed tomography coronary angiogram (CTCA) showed congenital absence of the right coronary artery (RCA), and the right heart was nourished by the left coronary artery branch with no apparent stenosis. Transthoracic echocardiography (TTE) revealed enlargement of the left heart and cardiomyopathy. Cardiac magnetic resonance imaging (CMR) revealed DCM. Genetic testing showed that the c.1858C > T variant of the <i>SCN5A</i> gene could lead to Brugada syndrome and DCM. SCA is a rare congenital anomaly of the coronary anatomy, and this case reported as SCA accompanied by DCM is even rarer. We present a rare case of a 55-year-old man with DCM with the c.1858C > T (p. Arg620Cys)/c.1008G > A (p.(Pro336=) variant of the <i>SCN5A</i> gene, congenital absence of RCA, and c.990_993delAACA (p. Asp332Valfs*5) variant of the <i>APOA5</i> gene. To our knowledge, this is the first report of DCM combined with the <i>SCN5A</i> gene mutation in SCA after searching the PubMed, CNKI and Wanfang databases.","variants":[{"Name":"NM_000335.5(SCN5A):c.1858C>T (p.Arg620Cys)","Chromosome":"3","Start":"38603744","Stop":"38603744","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":78589,"rule_based_match":true,"evidence_text":"c.1858C > T (p. Arg620Cys)","llm_judgment":"PRESENT","evidence":"c.1858C > T (p. Arg620Cys)","abstract_start":915,"abstract_end":941}]}
{"pmid":"27626066","title":"A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia.","abstract":"We describe a child with onset of command auditory hallucinations and behavioral regression at 6 yr of age in the context of longer standing selective mutism, aggression, and mild motor delays. His genetic evaluation included chromosomal microarray analysis and whole-exome sequencing. Sequencing revealed a previously unreported heterozygous de novo mutation c.385G>A in ATP1A3, predicted to result in a p.V129M amino acid change. This gene codes for a neuron-specific isoform of the catalytic α-subunit of the ATP-dependent transmembrane sodium-potassium pump. Heterozygous mutations in this gene have been reported as causing both sporadic and inherited forms of alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism. We discuss the literature on phenotypes associated with known variants in ATP1A3, examine past functional studies of the role of ATP1A3 in neuronal function, and describe a novel clinical presentation associated with mutation of this gene.","variants":[{"Name":"NM_152296.5(ATP1A3):c.385G>A (p.Val129Met)","Chromosome":"19","Start":"41986202","Stop":"41986202","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":262636,"rule_based_match":true,"evidence_text":"c.385G>A","llm_judgment":"PRESENT","evidence":"c.385G>A","abstract_start":360,"abstract_end":368}]}
{"pmid":"31680489","title":"Disease modeling of a mutation in α-actinin 2 guides clinical therapy in hypertrophic cardiomyopathy.","abstract":"Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding α-actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient-derived human-induced pluripotent stem cells (hiPSCs) and show that hiPSC-derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM, such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca<sup>2+</sup> sensitivity, and also prolonged action potential duration and enhanced L-type Ca<sup>2+</sup> current. The L-type Ca<sup>2+</sup> channel blocker diltiazem reduced force amplitude, relaxation, and action potential duration to a greater extent in HCM than in isogenic control. We translated our findings to patient care and showed that diltiazem application ameliorated the prolonged QTc interval in HCM-affected son and sister of the index patient. These data provide evidence for this ACTN2 mutation to be disease-causing in cardiomyocytes, guiding clinical therapy in this HCM family. This study may serve as a proof-of-principle for the use of hiPSC for personalized treatment of cardiomyopathies.","variants":[{"Name":"NM_001103.4(ACTN2):c.740C>T (p.Thr247Met)","Chromosome":"1","Start":"236735677","Stop":"236735677","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":823617,"rule_based_match":true,"evidence_text":"c.740C>T (p.T247M)","llm_judgment":"PRESENT","evidence":"c.740C>T (p.T247M)","abstract_start":139,"abstract_end":157}]}
{"pmid":"26070982","title":"Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73.","abstract":"We describe a novel nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum among 30 children (ages 1.0 to 28 years) from diverse Amish demes. Children with nephrocerebellar syndrome had progressive microcephaly, visual impairment, stagnant psychomotor development, abnormal extrapyramidal movements and nephrosis. Fourteen died between ages 2.7 and 28 years, typically from renal failure. Post-mortem studies revealed (i) micrencephaly without polymicrogyria or heterotopia; (ii) atrophic cerebellar hemispheres with stunted folia, profound granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation; (iii) selective striatal cholinergic interneuron loss; and (iv) optic atrophy with delamination of the lateral geniculate nuclei. Renal tissue showed focal and segmental glomerulosclerosis and extensive effacement and microvillus transformation of podocyte foot processes. Nephrocerebellar syndrome mapped to 700 kb on chromosome 15, which contained a single novel homozygous frameshift variant (WDR73 c.888delT; p.Phe296Leufs*26). WDR73 protein is expressed in human cerebral cortex, hippocampus, and cultured embryonic kidney cells. It is concentrated at mitotic microtubules and interacts with α-, β-, and γ-tubulin, heat shock proteins 70 and 90 (HSP-70; HSP-90), and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase multi-enzyme complex. Recombinant WDR73 p.Phe296Leufs*26 and p.Arg256Profs*18 proteins are truncated, unstable, and show increased interaction with α- and β-tubulin and HSP-70/HSP-90. Fibroblasts from patients homozygous for WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early. Our data suggest that in humans, WDR73 interacts with mitotic microtubules to regulate cell cycle progression, proliferation and survival in brain and kidney. We extend the Galloway-Mowat syndrome spectrum with the first description of diencephalic and striatal neuropathology.","variants":[{"Name":"NM_032856.5(WDR73):c.888del (p.Phe296fs)","Chromosome":"15","Start":"84643719","Stop":"84643719","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":227158,"rule_based_match":true,"evidence_text":"WDR73 c.888delT; p.Phe296Leufs*26","llm_judgment":"PRESENT","evidence":"WDR73 c.888delT; p.Phe296Leufs*26","abstract_start":1034,"abstract_end":1067}]}
{"pmid":"28857146","title":"Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy.","abstract":"Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report 2 patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole-exome sequencing revealed a homozygous mutation in NDUFA2 (c.134A>C, p.Lys45Thr). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole-exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c.134A>C, p.Lys45Thr; c.225del, p.Asn76Metfs*4). Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2.","variants":[{"Name":"NM_002488.5(NDUFA2):c.134A>C (p.Lys45Thr)","Chromosome":"5","Start":"140647330","Stop":"140647330","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":211112,"rule_based_match":true,"evidence_text":"c.134A>C, p.Lys45Thr","llm_judgment":"PRESENT","evidence":"c.134A>C, p.Lys45Thr","abstract_start":756,"abstract_end":776},{"Name":"NM_002488.5(NDUFA2):c.225del (p.Asn76fs)","Chromosome":"5","Start":"140645662","Stop":"140645662","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":211110,"rule_based_match":true,"evidence_text":"c.225del, p.Asn76Metfs*4","llm_judgment":"PRESENT","evidence":"c.225del, p.Asn76Metfs*4","abstract_start":1018,"abstract_end":1042}]}
{"pmid":"30993396","title":"Whole-Exome Sequencing Reveals Novel Genetic Variation for Dilated Cardiomyopathy in Pediatric Chinese Patients.","abstract":"Dilated cardiomyopathy (DCM) is characterized by left or bilateral ventricular dilation and systolic dysfunction without rational conditions, which can lead to progressive heart failure and sudden cardiac death. Most of the pathogenic genes have been reported in adult population by locus mapping in familial cases and animal model studies. However, it still remains challenging to decipher the role of genetics in the etiology of pediatric DCM. We applied whole-exome sequencing (WES) for 30 sporadic pediatric DCM subjects and 100 non-DCM local controls. We identified the pathogenic mutations using bioinformatics tools based on genomic strategies synergistically and confirmed mutations by Sanger sequencing. We identified compound heterozygous nonsense mutations in DSP (c.3799C > T, p.R1267X; c.4444G > T, p.E1482X). In sporadic cases, the two heterozygous mutations in XIRP2 were identified. Then we performed an exome-wide association study with 30 case and 100 control subjects. Interestingly, we could not identify TTN truncating variants in all cases. Collectively, we observed a significant risk signal between carriers of TTN deleterious missense variants and DCM risk (odds ratio 4.0, 95% confidence interval 1.1-22.2, p = 3.12 × 10<sup>-2</sup>). Our observations expanded the spectrum of mutations and were valuable in the pre- and postnatal screening and genetic diagnosis for DCM.","variants":[{"Name":"NM_004415.4(DSP):c.3799C>T (p.Arg1267Ter)","Chromosome":"6","Start":"7579989","Stop":"7579989","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31884,"rule_based_match":true,"evidence_text":"c.3799C > T, p.R1267X","llm_judgment":"PRESENT","evidence":"c.3799C > T, p.R1267X","abstract_start":776,"abstract_end":797}]}
{"pmid":"24961627","title":"Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders.","abstract":"PRPS1 codes for the enzyme phosphoribosyl pyrophosphate synthetase-1 (PRS-1). The spectrum of PRPS1-related disorders associated with reduced activity includes Arts syndrome, Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked non-syndromic sensorineural deafness (DFN2). We describe a novel phenotype associated with decreased PRS-1 function in two affected male siblings. Using whole exome and Sanger sequencing techniques, we identified a novel missense mutation in PRPS1. The clinical phenotype in our patients is characterized by high prenatal maternal α-fetoprotein, intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis. Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus. Exome sequencing of the two affected male siblings identified a shared putative pathogenic mutation c.586C>T p.(Arg196Trp) in the PRPS1 gene that was maternally inherited. Follow-up testing showed normal levels of hypoxanthine in urine samples and uric acid levels in blood serum. The PRS activity was significantly reduced in erythrocytes of the two patients. Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate. This presentation is the most severe form of PRPS1-deficiency syndrome described to date and expands the spectrum of PRPS1-related disorders.","variants":[{"Name":"NM_002764.4(PRPS1):c.586C>T (p.Arg196Trp)","Chromosome":"X","Start":"107645232","Stop":"107645232","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":439509,"rule_based_match":true,"evidence_text":"c.586C>T p.(Arg196Trp)","llm_judgment":"PRESENT","evidence":"c.586C>T p.(Arg196Trp)","abstract_start":929,"abstract_end":951}]}
{"pmid":"30945270","title":"Whole-exome sequencing identified ARL2 as a novel candidate gene for MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome.","abstract":"Adenosine diphosphate (ADP)-ribosylation factor-like 2 (ARL2) protein participates in a broad range of cellular processes and acts as a mediator for mutant ARL2BP in cilium-associated retinitis pigmentosa and for mutant HRG4 in mitochondria-related photoreceptor degeneration. However, mutant ARL2 has not been linked to any human disease so far. Here, we identified a de novo variant in ARL2 (c.44G > T, p.R15L) in a Chinese pedigree with MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome through whole-exome sequencing and co-segregation analysis. Co-immunoprecipitation assay and immunoblotting confirmed that the mutant ARL2 protein showed a 62% lower binding affinity for HRG4 while a merely 18% lower binding affinity for ARL2BP. Immunofluorescence images of ARL2 and HRG4 co-localizing with cytochrome c in HeLa cells described their relationship with mitochondria. Further analyses of the mitochondrial respiratory chain and adenosine triphosphate production showed significant abnormalities under an ARL2-mutant condition. Finally, we generated transgenic mice to test the pathogenicity of this variant and observed retinal degeneration complicated with microcornea and cataract that were similar to those in our patients. In conclusion, we uncover ARL2 as a novel candidate gene for MRCS syndrome and suggest a mitochondria-related mechanism of the first ARL2 variant through site-directed mutagenesis studies.","variants":[{"Name":"NM_001667.4(ARL2):c.44G>T (p.Arg15Leu)","Chromosome":"11","Start":"65014251","Stop":"65014251","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":971568,"rule_based_match":true,"evidence_text":"c.44G > T, p.R15L","llm_judgment":"PRESENT","evidence":"c.44G > T, p.R15L","abstract_start":394,"abstract_end":411}]}
{"pmid":"22448417","title":"Minimal ocular findings in a patient with Best disease caused by the c.653G>A mutation in BEST1","abstract":"PURPOSE: To describe the phenotype in an asymptomatic 64-year-old patient with family history of Best disease and to identify the disease causing variant in the BEST1 gene.\nMETHODS: Detailed ocular examination of the proband including spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography and electrooculography was performed. Direct sequencing approach was used to screen the whole coding sequence of 11 exons of BEST1.\nRESULTS: An early vitelliform stage of Best disease presenting as a small yellowish spot in the macula was observed in the right eye. The fundus appearance in the left eye was normal. SD-OCT of the right macula revealed hypodense space between the retinal pigment epithelium and the neuroretinal layer. Arden ratio was bilaterally mildly reduced; 1.36 in the right and 1.3 in the left eye. Molecular genetic analysis identified a heterozygous change c.653G>A (p.Arg218His) as the disease-causing variant.\nCONCLUSION: Here we report for the first time a phenotype-genotype correlation in a Czech patient with Best disease. SD-OCT is a fast method that may show the presence of small pathological changes. The screening of BEST1 gene enables identification of disease-causing variants in asymptomatic individuals with normal fundus appearance and thus improves counseling to the affected families.","variants":[{"Name":"NM_004183.4(BEST1):c.653G>A (p.Arg218His)","Chromosome":"11","Start":"61957403","Stop":"61957403","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":105625,"rule_based_match":true,"evidence_text":"c.653G>A (p.Arg218His)","llm_judgment":"PRESENT","evidence":"c.653G>A (p.Arg218His)","abstract_start":896,"abstract_end":918}]}
{"pmid":"29652989","title":"Analysis of clinical characteristics and genetic mutation in a pedigree affected with Chediak-Higashi syndrome","abstract":"OBJECTIVE: To explore the genetic basis for a pedigree affected with Chediak-Higashi syndrome (CHS).\nMETHODS: Clinical data of two CHS patients from the pedigree was collected and analyzed. Targeted next generation sequencing and Sanger sequencing were conducted to detect potential mutation of the LYST gene.\nRESULTS: Both patients presented immunodeficiency, oculocutaneous albinism, and acidophilic inclusion body on bone marrow and blood smears. A homozygous c.6077_6078insA (p.Tyr2026Terfs) mutation was detected in the LYST gene in both patients.\nCONCLUSION: Genetic testing can play an important role in the diagnosis of CHS.","variants":[{"Name":"NM_000081.4(LYST):c.6077dup (p.Tyr2026Ter)","Chromosome":"1","Start":"235766122","Stop":"235766123","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":2880860,"rule_based_match":false,"evidence_text":"c.6077_6078insA (p.Tyr2026Terfs)","llm_judgment":"PRESENT","evidence":"c.6077_6078insA (p.Tyr2026Terfs)","abstract_start":463,"abstract_end":495}]}
{"pmid":"27291587","title":"Whole Exome Screening Identifies Novel and Recurrent WISP3 Mutations Causing Progressive Pseudorheumatoid Dysplasia in Jammu and Kashmir-India.","abstract":"We report identification and genetic characterization of a rare skeletal disorder that remained unidentified for decades in a village of Jammu and Kashmir, India. The population residing in this region is highly consanguineous and a lack of understanding of the disorder has hindered clinical management and genetic counseling for the many affected individuals in the region. We collected familial information and identified two large extended multiplex pedigrees displaying apparent autosomal recessive inheritance of an uncharacterized skeletal dysplasia. Whole exome sequencing (WES) in members of one pedigree revealed a rare mutation in WISP3:c.156C > A (NP_003871.1:p.Cys52Ter), that perfectly segregated with the disease in the family. To our surprise, Sanger sequencing the WISP3 gene in the second family identified a distinct, novel splice site mutation c.643 + 1G > A, that perfectly segregated with the disease. Combining our next generation sequencing data with careful clinical documentation (familial histories, genetic data, clinical and radiological findings), we have diagnosed the families with Progressive Pseudorheumatoid Dysplasia (PPD). Our results underscore the utility of WES in arriving at definitive diagnoses for rare skeletal dysplasias. This genetic characterization will aid in genetic counseling and management, critically required to curb this rare disorder in the families.","variants":[{"Name":"NM_198239.2(CCN6):c.156C>A (p.Cys52Ter)","Chromosome":"6","Start":"112061098","Stop":"112061098","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":21420,"rule_based_match":true,"evidence_text":"WISP3:c.156C > A (NP_003871.1:p.Cys52Ter)","llm_judgment":"PRESENT","evidence":"WISP3:c.156C > A (NP_003871.1:p.Cys52Ter)","abstract_start":642,"abstract_end":683}]}
{"pmid":"37901857","title":"Clinical Heterogeneity in Patients with Long QT Syndrome and Segregation of Single Nucleotide Variants and Clinical Symptoms in 17 Affected Families.","abstract":"Introduction: Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram. It increases the risk of ventricular arrhythmias, which can cause syncope or sudden cardiac death. In this study, we study the genotype-phenotype relationships of patients referred to us with suspected arrhythmia syndrome.\nMethods: Seventeen cases and their twenty relatives were evaluated. Next-generation sequencing analysis was performed for 17 LQTS-related genes.\nResults: We detected seventeen single nucleotide variants (SNVs) with potential pathogenic significance in 26 of the 36 subjects analyzed. <i>KCNH2</i> c.172G>A, <i>KCNQ1</i> c.1768G>A, <i>ANK2</i> c.4666A>T, c.1484_1485delCT, <i>KCNH2</i> c.1888G>A were reported as pathogenic or likely pathogenic in HGMD variant classification database.\nConclusion: Current study pointed out that early diagnosis can be life-saving for patients and their families by taking family history and detailed examination. Also, we highlight the clinical heterogeneity of arrhythmia syndrome through a patient with a dual phenotype.","variants":[{"Name":"NM_000238.4(KCNH2):c.1888G>A (p.Val630Ile)","Chromosome":"7","Start":"150951505","Stop":"150951505","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":224342,"rule_based_match":true,"evidence_text":"<i>KCNH2</i> c.1888G>A","llm_judgment":"PRESENT","evidence":"<i>KCNH2</i> c.1888G>A","abstract_start":755,"abstract_end":777}]}
{"pmid":"28679690","title":"","abstract":"Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the <i>SPG20</i> gene, encoding spartin, on Chromosome 13q13. Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability. Targeted exon capture and sequencing showed a homozygous nonsense mutation in the <i>SPG20</i> gene, c.1369C>T (p.Arg457*), in the three affected boys.","variants":[{"Name":"NM_015087.5(SPART):c.1369C>T (p.Arg457Ter)","Chromosome":"13","Start":"36314341","Stop":"36314341","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":373823,"rule_based_match":true,"evidence_text":"c.1369C>T (p.Arg457*)","llm_judgment":"PRESENT","evidence":"c.1369C>T (p.Arg457*)","abstract_start":803,"abstract_end":824}]}
{"pmid":"25447906","title":"Two novel NIPBL gene mutations in Chinese patients with Cornelia de Lange syndrome.","abstract":"Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder characterized by distinctive facial features, mental retardation, and upper limb defects, with the involvement of multiple organs and systems. To date, mutations have been identified in five genes responsible for CdLS: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Here, we present a clinical and molecular characterization of five unrelated Chinese patients whose clinical presentation is consistent with that of CdLS. There were no chromosomal abnormalities in the five children. In three patients, DNA sequencing revealed a previously reported frameshift mutation c.2479delA (p.Arg827GlyfsX20), and two novel mutations including a heterozygous mutation c.6272 G>T (p.Cys2091Phe) and a frameshift mutation c.1672delA (p.Thr558LeufsX7) in NIPBL. For the remaining patients, large deletions and/or duplications within the NIPBL gene were excluded as playing a role in the pathogenesis, by Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. These findings broaden the mutation spectrum of NIPBL and further our understanding of the diverse and variable effects of NIPBL mutations on CdLS.","variants":[{"Name":"NM_133433.4(NIPBL):c.1672del (p.Thr558fs)","Chromosome":"5","Start":"36984851","Stop":"36984851","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"T","allel_id":1491326,"rule_based_match":true,"evidence_text":"c.1672delA (p.Thr558LeufsX7)","llm_judgment":"PRESENT","evidence":"c.1672delA (p.Thr558LeufsX7)","abstract_start":783,"abstract_end":811},{"Name":"NM_133433.4(NIPBL):c.2479del (p.Arg827fs)","Chromosome":"5","Start":"36985659","Stop":"36985659","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":924070,"rule_based_match":true,"evidence_text":"c.2479delA (p.Arg827GlyfsX20)","llm_judgment":"PRESENT","evidence":"c.2479delA (p.Arg827GlyfsX20)","abstract_start":642,"abstract_end":671}]}
{"pmid":"30630233","title":"Clinical and genetic manifestations of immunodeficiency, centromeric instability, and facial anomalies syndrome: a case report and literature review","abstract":"<b>Objective:</b> To analyze the clinical and genetic features of immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome with a case report and literature review. <b>Methods:</b> The clinical data and genetic test of a girl diagnosed with ICF syndrome in the Department of Nephrology and Immunology in Qingdao Women and Children's Hospital in December 2016 were extracted and analyzed. \"ICF syndrome\" \"immunodeficiency, centromeric instability and facial anomalies syndrome\" \"ICF syndrome and DNMT3B\" were used as key words to search Chinese databases and Pubmed for literature until March 2018, and the literature was reviewed. <b>Results:</b> A female patient aged 22 months old with ocular hypertelorism and low-set ears was admitted due to recurrent infection over one year. Laboratory tests showed humoral immune deficiency with IgG<1.34 g/L, IgA<0.060 g/L, and IgM<0.179 g/L, but normal cellular immunity (total T lymphocyte 0.503, hepler T lymphocyte 0.328, cytotoxic T lymphocyte 0.166, natural killer cell 0.184, total B lymphocyte 0.276). Whole-exome sequencing revealed a de novo heterozygous splice site mutation c.922-2A>G in intron 8, and a de novo heterozygous missense mutation c.2477G>A in exon 23 of DNMT3B gene. Chromosome karyotype analysis showed 46, XX, with 64 out of 100 karyotypes showing centromere instability in chromosome 1. Five papers were found which were all in English, with total of 29 patients. Forty-three mutations were reported, including 34 missense, 2 deletion, 1 insertion, 6 splice site mutations. Eleven patients had complex heterozygosis mutations. All patients had centromere instability, humoral immune deficiency and facial dysplasia which were mainly ocular hypertelorism and low-set ears. Most patients had language and motor development delay, and a few were combined with mental retardation. <b>Conclusions:</b> ICF syndrome is a rare autosomal recessive primary immunodeficiency with classic clinical triad manifestations. De novo mutation of DNMT3B gene is one of etiologies according to genetic test.","variants":[{"Name":"NM_006892.4(DNMT3B):c.2477G>A (p.Arg826His)","Chromosome":"20","Start":"32807818","Stop":"32807818","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1014068,"rule_based_match":true,"evidence_text":"c.2477G>A","llm_judgment":"PRESENT","evidence":"c.2477G>A","abstract_start":1218,"abstract_end":1227}]}
{"pmid":"32845056","title":"Hyperphosphatasia with mental retardation syndrome type 4 in three unrelated South African patients.","abstract":"Hyperphosphatasia with mental retardation syndrome (HPMRS) is a rare autosomal recessive disorder caused by pathogenic variants in genes involved in glycosylphosphatidylinositol metabolism that result in a similar phenotype. We describe the first three patients with HPMRS from sub-Saharan Africa. Detection was assisted by Face2Gene phenotype matching and confirmed by the presence of elevated serum alkaline phosphatase. All three patients had severe intellectual disability, absent speech, hypotonia and palatal abnormality (cleft palate in two, very high-arched palate in one), no or minimal brachytelephalangy, and high serum alkaline phosphatase levels. Additional findings included seizures in two, and brain imaging abnormalities in two. In all three patients HPMRS was a top-20 gestalt match using Face2Gene. The overall phenotype is consistent with descriptions in the literature of HPMRS type 4, although not specific to it. Whole exome sequencing in the index patient and his mother detected a candidate variant in a homozygous state in the index patient (PGAP3:c.557G>C, p.Arg186Thr) and heterozygous in the mother. Further variant interpretation indicated pathogenicity. Sanger sequencing of another two patients identified the same homozygous, pathogenic variant, confirming a diagnosis of HPMRS type 4. The shared homozygous variant in apparently unrelated families, and in the absence of consanguinity, suggests the possibility of genetic drift due to a population bottleneck effect, and further research is recommended.","variants":[{"Name":"NM_033419.5(PGAP3):c.557G>C (p.Arg186Thr)","Chromosome":"17","Start":"39673993","Stop":"39673993","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1324468,"rule_based_match":true,"evidence_text":"PGAP3:c.557G>C, p.Arg186Thr","llm_judgment":"PRESENT","evidence":"PGAP3:c.557G>C, p.Arg186Thr","abstract_start":1068,"abstract_end":1095}]}
{"pmid":"21763168","title":"Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.","abstract":"A high prevalence of the sequence variant c.1436C→T in the CPT1A gene has been identified among Alaska Native newborns but the clinical implications of this variant are unknown. We conducted medically supervised fasts in 5 children homozygous for the c.1436C→T variant. Plasma free fatty acids increased normally in these children but their long-chain acylcarnitine and ketone production was significantly blunted. The fast was terminated early in two subjects due to symptoms of hypoglycemia. Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children. Trial registration www.clinical trials.gov NCT00653666 \"Metabolic Consequences of CPT1A Deficiency\"","variants":[{"Name":"NM_001876.4(CPT1A):c.1436C>T (p.Pro479Leu)","Chromosome":"11","Start":"68780662","Stop":"68780662","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76552,"rule_based_match":false,"evidence_text":"c.1436C→T","llm_judgment":"PRESENT","evidence":"c.1436C→T","abstract_start":42,"abstract_end":51}]}
{"pmid":"35085548","title":"Neonatal-Onset Congenital Ectropion Uveae May Be Caused by a Distinct CYP1B1 Pathologic Variant.","abstract":"PURPOSE: To report underlying genetic variants of recently described distinct phenotype of newborn glaucoma: neonatal-onset congenital ectropion uveae (NO-CEU).\nDESIGN: Prospective cohort study.\nMETHODS: Setting: tertiary care teaching institute.\nSUBJECTS: Thirteen children with clinical diagnosis of NO-CEU who had completed 1-year follow-up after glaucoma surgery and had undergone clinical exome sequencing (CES) by selective capture and sequencing of the protein-coding regions of the genes including 19 candidate genes for NO-CEU were assessed. The same criteria were applied for evaluating pathogenicity of variants to all the candidate genes.\nOUTCOME MEASURES: primary-genetic variants found on CES keeping in view the clinical indication of congenital glaucoma; secondary-corneal clarity and intraocular pressure (IOP) at baseline and 1-year follow-up, interventions required to control IOP, and postoperative visual acuity. The genetic variants were correlated with the outcome.\nRESULTS: All 13 patients diagnosed with NO-CEU had onset of glaucoma at birth and severe bilateral disease. Twelve of 13 (92.3%) patients harbored CYP1B1 variants. Nine of these 12 patients (83.3%) were homozygous for [c.1169G>A(p.Arg390His)] in exon-3 of CYP1B, with 5 common homozygous single-nucleotide polymorphisms flanking the pathogenic variant. They had intractable glaucoma and required multiple surgeries. Six patients had persistent corneal opacities, necessitating optical iridectomies. Three patients were compound heterozygous for CYP1B1 variants, showing [c.1169G>A(p.Arg390His)] along with [c.1103G>A(p.Arg368His)], [c.1103G>A (p.Arg368His)] along with [c.1403_1429dup(p.Arg468_Ser476dup)], and [(c.1063C>T(p.Arg355Ter)] along with [c.1325del(p.Pro442GlnfsTer15)]. These patients had better visual outcomes.\nCONCLUSIONS: NO-CEU appears to be a phenotypic marker for specific CYP1B1 genotypes, one of which is [c.1169G>A(p.Arg390His)] in our study population. Phenotype recognition is helpful to characterize the underlying genetic variants.","variants":[{"Name":"NM_000104.4(CYP1B1):c.1169G>A (p.Arg390His)","Chromosome":"2","Start":"38071185","Stop":"38071185","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":583549,"rule_based_match":true,"evidence_text":"[c.1169G>A(p.Arg390His)]","llm_judgment":"PRESENT","evidence":"[c.1169G>A(p.Arg390His)]","abstract_start":1207,"abstract_end":1231}]}
{"pmid":"35070997","title":"Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort.","abstract":"BACKGROUND: Hereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown.\nMETHODS: 1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing.\nRESULTS: A total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. <i>BRCA1</i> and <i>BRCA2</i> mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of <i>BRCA1</i> mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM_007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM_000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing.\nCONCLUSION: This is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies.","variants":[{"Name":"NM_000038.6(APC):c.6665C>A (p.Pro2222His)","Chromosome":"5","Start":"112842259","Stop":"112842259","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1402282,"rule_based_match":true,"evidence_text":"NM_000038.6(APC):c.6665C>A (p.Pro2222His)","llm_judgment":"PRESENT","evidence":"NM_000038.6(APC):c.6665C>A (p.Pro2222His)","abstract_start":1209,"abstract_end":1250}]}
{"pmid":"29518907","title":"Antisense Oligonucleotide-Based Splicing Correction in Individuals with Leber Congenital Amaurosis due to Compound Heterozygosity for the c.2991+1655A>G Mutation in CEP290.","abstract":"Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with <i>CEP290</i> (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing <i>CEP290</i> mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of <i>CEP290</i> transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in <i>CEP290</i>. We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat <i>CEP290</i>-associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant.","variants":[{"Name":"NM_025114.4(CEP290):c.2991+1655A>G","Chromosome":"12","Start":"88101183","Stop":"88101183","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":16376,"rule_based_match":true,"evidence_text":"c.2991+1655A>G","llm_judgment":"PRESENT","evidence":"c.2991+1655A>G","abstract_start":342,"abstract_end":356}]}
{"pmid":"29498494","title":"Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia.","abstract":"We describe a case of twins with sporadic Gorlin syndrome. Both twins had common Gorlin syndrome features including calcification of the falx cerebri, multiple jaw keratocysts, and multiple basal cell carcinomas, but with different expressivity. One brother also had benign testicular mesothelioma. We propose this tumor type as a possible new feature of Gorlin syndrome. Gorlin syndrome is a rare autosomal dominant disorder characterized by both developmental abnormalities and cancer predisposition, with variable expression of various developmental abnormalities and different types of tumors. The syndrome is primarily caused by mutations in the Patched 1 (PTCH1) gene, although rare mutations of Patched 2 (PTCH2) or Suppressor of Fused (SUFU) genes have also been found. Neither founder mutations nor hot spot locations have been described for PTCH1 in Gorlin syndrome patients. Although de novo mutations of the PTCH1 gene occur in almost 50% of Gorlin syndrome cases, there are a few recurrent mutations. Our twin patients were carriers of a de novo mutation in the PTCH1 gene, c.3364_3365delAT (p.Met1122ValfsX22). This is, to our knowledge, the first Gorlin syndrome-causing mutation that has been reported four independent times in distant geographical locations. Therefore, we propose the location of the described mutation as a potential hot spot for mutations in PTCH1.","variants":[{"Name":"NM_000264.5(PTCH1):c.3364_3365del (p.Met1122fs)","Chromosome":"9","Start":"95453562","Stop":"95453563","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":397365,"rule_based_match":true,"evidence_text":"c.3364_3365delAT (p.Met1122ValfsX22)","llm_judgment":"PRESENT","evidence":"c.3364_3365delAT (p.Met1122ValfsX22)","abstract_start":1087,"abstract_end":1123}]}
{"pmid":"34453918","title":"RNA sequencing combining with whole exome sequencing reveals a compound heterozygous variant in ATM in a girl with atypical ataxia-telangiectasia.","abstract":"Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia, oculo-cutaneous telangiectasia, a tendency to malignancies and variable immunodeficiency. Here we described a 5-year-old girl with atypical A-T symptoms. And 2 different ATM variants c.5939_5948del in exon 40 and c.2639-384A > G in intron 17 were detected by whole exome sequencing (WES) combined with RNA sequencing (RNA-seq). The variant spectrum of ATM was expanded. RNA-seq makes up for deficiencies of WES. We proposed a new approach, a dual-omics that combines RNA-seq with WES, for the diagnosis of genetic diseases. Moreover, our study discussed the phenotypic heterogeneity of A-T among family members as well as individuals. For children with recurrent infections and immunodeficiency, we suggested focusing on A-T after the exclusion of other potential diseases.","variants":[{"Name":"NM_000051.4(ATM):c.2639-384A>G","Chromosome":"11","Start":"108268026","Stop":"108268026","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":421073,"rule_based_match":true,"evidence_text":"c.2639-384A>G","llm_judgment":"PRESENT","evidence":"c.2639-384A > G","abstract_start":347,"abstract_end":362}]}
{"pmid":"34871784","title":"Further evidence of affected females with a heterozygous variant in FGF13 causing X-linked developmental and epileptic encephalopathy 90.","abstract":"Developmental and epileptic encephalopathies (DEE) are a genetically heterogeneous group of disorders characterised by early onset epilepsy, epileptiform activity on electroencephalogram and associated developmental delay or neuroregression. With the advent of high throughput sequencing, novel gene-disease associations have been described for DEEs. Voltage activated sodium channels (Na<sub>v</sub>) regulate neuronal excitability. Fibroblast growth factor homologous factors (FHFs) are proteins, which bind to the C terminal cytoplasmic tails of alpha subunits of Na<sub>v</sub> channels and influence their function and surface expression. Gain of function hemizygous or heterozygous variants in FGF13 (also known as FHF2) were recently identified as the cause for X-linked developmental and epileptic encephalopathy 90 (DEE90; MIM# 301058) in seven individuals from five families, which included one female. We report an additional female, providing further evidence for a novel de novo heterozygous missense variant in FGF13, NM_004114.5: c.14T > G p.(Ile5Ser) causing X-linked DEE90. In addition, we review the genotype and phenotype of affected individuals with DEE90.","variants":[{"Name":"NM_004114.5(FGF13):c.14T>G (p.Ile5Ser)","Chromosome":"X","Start":"138710990","Stop":"138710990","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1174233,"rule_based_match":true,"evidence_text":"NM_004114.5: c.14T > G p.(Ile5Ser)","llm_judgment":"PRESENT","evidence":"NM_004114.5: c.14T > G p.(Ile5Ser)","abstract_start":1032,"abstract_end":1066}]}
{"pmid":"24607488","title":"The effect of the common c.2299delG mutation in USH2A on RNA splicing.","abstract":"Recessive variants in the USH2A gene are an important cause of both Usher syndrome and nonsyndromic retinitis pigmentosa. A single base-pair deletion in exon 13 (c.2299delG, p.Glu767Serfs*21) is considered the most frequent mutation of USH2A. It is predicted to generate a premature termination codon and is presumed to lead to nonsense mediated decay. However the effect of this variant on RNA has not been formally investigated. It is not uncommon for exonic sequence alterations to cause aberrant splicing and the aim of the present report is to evaluate the effect of c.2299delG on USH2A transcripts. Nasal cells represent the simplest available tissue to study splicing defects in USH2A. Nasal brushing, RNA extraction from nasal epithelial cells and reverse transcription PCR were performed in five Usher syndrome patients who were homozygous for c.2299delG, two unaffected c.2299delG heterozygotes and seven control individuals. Primers to amplify between exons 12 and 15 and exons 10 and 14 were utilised. Significant variability was observed between different RT-PCR experiments. Importantly, in controls, PCR product of the expected size were amplified on all occasions (13/13 experiments); for patients this was true in only 4/14 experiments (Fisher exact test p = 0.0002). Bioinformatics tools predict the c.2299delG change to disrupt an exonic splicing enhancer and to create an exonic splicing silencer within exon 13. Here, we report an effect of the common c.2299delG mutation on splicing of exons 12 and 13 of USH2A. Future studies are expected to provide important insights into the contribution of this effect on the phenotype.","variants":[{"Name":"NM_206933.4(USH2A):c.2299del (p.Glu767fs)","Chromosome":"1","Start":"216247095","Stop":"216247095","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":17390,"rule_based_match":true,"evidence_text":"c.2299delG","llm_judgment":"PRESENT","evidence":"c.2299delG","abstract_start":162,"abstract_end":172}]}
{"pmid":"36526864","title":"Somatic and germinal mosaicism in a Han Chinese family with laminopathies.","abstract":"\"Laminopathies\" refers to a wide spectrum of myopathies caused by mutations in the LMNA gene. These myopathies include limb girdle muscular dystrophy type 1B (LGMD1B) and dilated cardiomyopathy 1 A (DCM1A), which are both autosomal dominant neurogenetic diseases. There have been few studies on mosaicism in laminopathies. Herein, a Han Chinese family with laminopathies was enrolled in our study. Genetic analysis revealed that the proband carried a novel splice site mutation, c. 1158-3 C > T, in the LMNA gene due to her mother having de novo somatic and gonadal mosaicism. Reverse-transcription polymerase chain reaction (RT-PCR) analysis revealed reduced levels of LMNA mRNA in the proband, which were probably due to nonsense-mediated mRNA decay (NMD). Western blotting revealed reduced lamin A/C protein levels in the skeletal muscle tissue of the proband. In this family, the clinical phenotypes of the proband's mother were normal, and the c. 1158-3 C > T splicing mutation was identified in the blood sample of the proband's mother. Thus, the mutation could be easily considered to be nonpathogenic. Our study emphasizes the importance of mosaicism in the identification of pathogenic variants and genetic counseling.","variants":[{"Name":"NM_170707.4(LMNA):c.1158-3C>T","Chromosome":"1","Start":"156136211","Stop":"156136211","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":172486,"rule_based_match":true,"evidence_text":"c. 1158-3 C > T","llm_judgment":"PRESENT","evidence":"c. 1158-3 C > T","abstract_start":479,"abstract_end":494}]}
{"pmid":"32714376","title":"c.1263+1G>A Is a Latent Hotspot for CYP27A1 Mutations in Chinese Patients With Cerebrotendinous Xanthomatosis.","abstract":"BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis caused by mutations in the CYP27A1 gene. CTX is an underdiagnosed and potentially treatable disease, thus a detailed appreciation of the phenotypic spectrum and genetic characteristics are crucial for early diagnosis and treatment.\nOBJECTIVES AND METHODS: Four CTX families with mutations in the CYP27A1 gene were enrolled in our study. We investigated the clinical characteristics and molecular genetic features of the probands with CTX. Genetic analysis was performed for detecting gene variants. Sanger sequencing and segregation analysis were conducted for haplotype analysis.\nRESULTS: All the four probands were compound heterozygote for two CYP27A1 variants, including one mutation in c.1263+1G>A (intron 7) splice site, two novel likely pathogenic mutations (c.255+1G>T and c.1561dupA) and three pathogenic mutations including c.379C>T, c.1263+1G>A and c.1537C>T previously reported. All of the subjects presented with spastic paraparesis. The other common clinical features included ataxia, childhood-onset diarrhea, cataracts, intellectual disability, tendinous xanthomas and dentate nuclei signal alterations at MRI.\nCONCLUSION: Two novel likely pathogenic mutations (c.255+1G>T and c.1561dupA) were reported in our study. The 1263+1G>A mutation was commonly seen in Chinese reported case series (7/25, 28%) and could be a latent hotspot for Chinese CTX mutations. Our study expanded the mutation spectrum of CYP27A1 gene and provide an insightful view of the phenotypic spectrum and genetic characteristics to help early diagnosis and treatment with to improve neurologic dysfunction.","variants":[{"Name":"NM_000784.4(CYP27A1):c.379C>T (p.Arg127Trp)","Chromosome":"2","Start":"218809700","Stop":"218809700","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76773,"rule_based_match":true,"evidence_text":"c.379C>T","llm_judgment":"PRESENT","evidence":"c.379C>T","abstract_start":941,"abstract_end":949},{"Name":"NM_000784.4(CYP27A1):c.1537C>T (p.Arg513Cys)","Chromosome":"2","Start":"218814971","Stop":"218814971","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":541783,"rule_based_match":true,"evidence_text":"c.1537C>T","llm_judgment":"PRESENT","evidence":"c.1537C>T","abstract_start":967,"abstract_end":976}]}
{"pmid":"23099293","title":"Clinical characterisation of the CABP4-related retinal phenotype.","abstract":"BACKGROUND: Calcium binding protein 4 (CABP4), specifically located in photoreceptor synaptic terminals, has been associated with congenital stationary night blindness based on this clinical diagnosis being made for three individuals from two Swiss families with CABP4 mutations; however, the few reported cases limit phenotype-genotype correlation. We expand the number of reported patients with CABP4 mutations and clinically characterise the CABP4-related phenotype.\nMETHODS: A retrospective case series of 11 individuals (age 2â 26 years; four consanguineous families) with early-onset retinal dysfunction found to harbour CABP4 mutations after a strategy of homozygosity analysis and/or candidate gene testing.\nRESULTS: The 11 patients from four families harboured the same homozygous CABP4 mutation (c.81_82insA; p.Pro28Thrfs*4) and shared a common haplotype. All patients had congenital nystagmus, stable low vision, photophobia and a normal or near-normal fundus appearance. None complained of night blindness when specifically questioned. Eight had hyperopic cycloplegic refractions (≥+ 1.00 dioptre). Electroretinography showed an electronegative waveform response to scotopic bright flash, near-normal to subnormal rod function, and delayed and/or decreased cone responses or was non-recordable. Although these and previously reported families with homozygous mutations were labelled with different clinical diagnoses, all had similar clinical features.\nCONCLUSION: These typical clinical features, which do not include a symptom of night blindness, suggest CABP4 mutations. The phenotype is best uniformly termed congenital cone-rod synaptic disorder. In Saudi Arabia a founder homozygous c.81_82insA CABP4 mutation is a recurrent cause.","variants":[{"Name":"NM_145200.5(CABP4):c.81_82insA (p.Pro28fs)","Chromosome":"11","Start":"67455504","Stop":"67455505","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":188767,"rule_based_match":true,"evidence_text":"c.81_82insA","llm_judgment":"PRESENT","evidence":"c.81_82insA","abstract_start":806,"abstract_end":817}]}
{"pmid":"26194196","title":"A novel OPA1 mutation causing variable age of onset autosomal dominant optic atrophy plus in an Australian family.","abstract":"Pathogenic mutations in the OPA1 gene can be associated with Autosomal Dominant Optic Atrophy (ADOA). In approximately 20 % of patients with OPA1 mutations, a more complex neurodegenerative disorder with extraocular manifestations, known as ADOA Plus, can arise. 12 members of a multigenerational family were assessed clinically and screened for a genetic mutation in OPA1. Eight family members displayed manifestations consistent with ADOA Plus and four did not. Affected members of the oldest available generation displayed the most severe phenotype, which included severe optic atrophy, deafness, ptosis, ophthalmoplegia, proximal myopathy, neuropathy and ataxia. The next generation was less severely affected but several members displayed manifestations only after the fifth decade. Genetic analysis revealed a heterozygous variant in the OPA1 gene (c.1053T>A, p.Asp351Glu) that segregated with disease. The affected family members described here exhibited visual loss later than is typical for OPA1-related disease, as well as later onset of other neurological abnormalities in the fifth or sixth decades of life that progressed to severe neurological disability by the seventh decade. These findings expand the clinical spectrum of OPA1-related disease associated with a novel OPA1 mutation.","variants":[{"Name":"NM_130837.3(OPA1):c.1053T>A (p.Asp351Glu)","Chromosome":"3","Start":"193637969","Stop":"193637969","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3536247,"rule_based_match":true,"evidence_text":"c.1053T>A, p.Asp351Glu","llm_judgment":"PRESENT","evidence":"c.1053T>A, p.Asp351Glu","abstract_start":855,"abstract_end":877}]}
{"pmid":"28207930","title":"Elevation of glycosaminoglycans in the amniotic fluid of a fetus with mucopolysaccharidosis VII.","abstract":"OBJECTIVE: The aim of this study was to quantify glycosaminoglycans (GAGs) in amniotic fluid (AF) from an MPS VII fetus compared with age-matched fetuses obtained from normal pregnancies.\nMETHOD: Disaccharides were measured by liquid chromatography tandem mass spectrometry, compared to age-matched controls. Enzyme assay was performed in AF supernatant or cultured amniocytes. GUSB was analyzed by next generation sequencing using Ion Torrent Personal Genome Machine with a customized panel.\nRESULTS: No activity of β-glucuronidase was detected in fetal cells. The pregnancy was spontaneously terminated in the third trimester. Genetic studies identified a homozygous mutation of p.N379D (c.1135A > G) in the GUSB gene. Liquid chromatography tandem mass spectrometry showed that chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate levels were markedly increased in the MPS VII AF, compared to those in age-matched control AF (dermatan sulfate, heparan sulfate, and chondroitin-6-sulfate more than 10 × than age-matched controls; chondroitin-4-sulfate and keratan sulfate more than 3 times higher).\nCONCLUSION: This is the first report of specific GAG analysis in AF from an MPS VII fetus, indicating that GAG elevation in AF occurs by 21 weeks of gestation and could be an additional tool for prenatal diagnosis of MPS VII and potentially other MPS types. © 2017 John Wiley & Sons, Ltd.","variants":[{"Name":"NM_000181.4(GUSB):c.1135A>G (p.Asn379Asp)","Chromosome":"7","Start":"65974635","Stop":"65974635","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2668807,"rule_based_match":true,"evidence_text":"c.1135A > G","llm_judgment":"PRESENT","evidence":"c.1135A > G","abstract_start":690,"abstract_end":701}]}
{"pmid":"28414188","title":"A case of splenomegaly in CBL syndrome.","abstract":"INTRODUCTION: We present a child with unexplained splenomegaly to highlight this feature as a presenting sign of the RASopathy CBL syndrome and to draw attention to the power and utility of next generation genomic sequencing for providing rapid diagnosis and critical information to guide care in the pediatric clinical setting.\nCLINICAL REPORT: A 7-year-old boy presented with unexplained splenomegaly, attention deficit hyperactivity disorder, mild learning difficulties, easy bruising, mild thrombocytopenia, and subtle dysmorphic features. Extensive haematological testing including a bone marrow biopsy showed mild megaloblastoid erythropoiesis and borderline fibrosis. There were no haematological cytogenetic anomalies or other haematological pathology to explain the splenomegaly. Metabolic testing and chromosomal microarray were unremarkable. Trio whole-exome sequencing (WES) identified a pathogenic de novo heterozygous germline CBL variant (c.1111T > C, p.Y371H), previously reported to cause CBL syndrome and implicated in development of juvenile myelomonocytic leukemia (JMML).\nDISCUSSION: CBL syndrome (more formally known as \"Noonan-syndrome-like disorder with or without juvenile myelomonocytic leukemia\") has overlapping features to Noonan syndrome with significant variability. CBL syndrome and other RASopathy disorders-including Noonan syndrome, neurofibromatosis 1, and Costello syndrome-are important to recognize as these are associated with a cancer-predisposition. CBL syndrome carries a very high risk for JMML, thus accurate diagnosis is of utmost importance. The diagnosis of CBL syndrome in this patient would not have been possible based on clinical features alone. Through WES, a specific genetic diagnosis was made, allowing for an optimized management and surveillance plan, illustrating the power of genomics in clinical practice.","variants":[{"Name":"NM_005188.4(CBL):c.1111T>C (p.Tyr371His)","Chromosome":"11","Start":"119278181","Stop":"119278181","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":28850,"rule_based_match":true,"evidence_text":"c.1111T > C, p.Y371H","llm_judgment":"PRESENT","evidence":"c.1111T > C, p.Y371H","abstract_start":954,"abstract_end":974}]}
{"pmid":"28602030","title":"Variable expressivity of a likely pathogenic variant in KCNQ2 in a three-generation pedigree presenting with intellectual disability with childhood onset seizures.","abstract":"KCNQ2 has been reported as a frequent cause of autosomal dominant benign familial neonatal seizures. De novo likely pathogenic variants in KCNQ2 have been described in neonatal or early infantile onset epileptic encephalopathy patients. Here, we report a three-generation family with six affected patients with a novel likely pathogenic variant (c.628C>T; p.Arg210Cys) in KCNQ2. Four family members, three adults and a child, presented with a childhood seizure onset with variability in the severity of seizures and response to treatment, intellectual disability (ID) as well as behavioral problems. The two youngest affected patients had a variable degree of global developmental delay with no seizures at their current age. This three-generation family with six affected members expands the phenotypic spectrum of KCNQ2 associated encephalopathy to KCNQ2 associated ID and or childhood onset epileptic encephalopathy. We think that KCNQ2 associated epileptic encephalopathy should be included in the differential diagnosis of childhood onset epilepsy and early onset global developmental delay, cognitive dysfunction, or ID. Furthermore, whole exome sequencing in families with ID and history of autosomal dominant inheritance pattern with or without seizures, may further broaden the phenotypic spectrum of KCNQ2 associated epileptic encephalopathy or encephalopathy.","variants":[{"Name":"NM_172107.4(KCNQ2):c.628C>T (p.Arg210Cys)","Chromosome":"20","Start":"63444721","Stop":"63444721","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":203788,"rule_based_match":true,"evidence_text":"c.628C>T; p.Arg210Cys","llm_judgment":"PRESENT","evidence":"c.628C>T; p.Arg210Cys","abstract_start":346,"abstract_end":367}]}
{"pmid":"25978941","title":"Paternal germline mosaicism in collagen VI related myopathies.","abstract":"BACKGROUND: Collagen VI-related disorders are a group of muscular diseases characterized by muscle wasting and weakness, joint contractures, distal laxity, serious respiratory dysfunction and cutaneous alterations, due to mutations in the COL6A1, COL6A2 and COL6A3 genes, encoding for collagen VI, a critical component of the extracellular matrix. The severe Ullrich congenital muscular dystrophy (UCMD) can be due to autosomal recessive mutations in one of the three genes with a related 25% recurrence risk. In the majority of UCMD cases nevertheless, the underlying mutation is thought to arise de novo and the recurrence risk is considered as low.\nMETHODS AND RESULTS: Here we report a family with recurrence of UCMD in two half-sibs. In both, the molecular analysis revealed heterozygosity for the c.896G > A missense mutation in COL6A1 exon 10 (Gly299Glu) and for the COL6A1 c.1823-8G > A variation within COL6A1 intron 29. The intronic variation was inherited from the father and RNA analysis in skin fibroblasts allowed to exclude its role in affecting COL6A1 transcript processing. The Gly299Glu mutation occurred apparently de novo in the two sibs.\nCONCLUSION: The described mutational segregation strongly suggests the occurrence of paternal germline mosaicism. This is the first report of UCMD recurrence due to a germline mosaic COL6 gene mutation. Mosaicism deserves to be considered as possible inheritance pattern in genetic counseling and recurrence risk estimation in collagen VI-related diseases.","variants":[{"Name":"NM_001848.3(COL6A1):c.896G>A (p.Gly299Glu)","Chromosome":"21","Start":"45989645","Stop":"45989645","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":99798,"rule_based_match":true,"evidence_text":"c.896G > A missense mutation in COL6A1 exon 10 (Gly299Glu)","llm_judgment":"PRESENT","evidence":"c.896G > A missense mutation in COL6A1 exon 10 (Gly299Glu)","abstract_start":803,"abstract_end":861}]}
{"pmid":"29423401","title":"Association between Genetic Polymorphism and Risk of von Willebrand Disease in Pakistan.","abstract":"von Willebrand disease (VWD) is an inherited, genetically and clinically heterogeneous hemorrhagic disorder. The most common cause of this disease is mutation in the gene that encodes protein von Willebrand factor (VWF) which is responsible for blood clotting. The current study was designed to investigate the role of genetic polymorphisms with the onset of VWD in population of Pakistan. Three exonic variants (c.3445T>C; c.4975C>T; c.7603C>T) from VWF gene were used for the genotyping purpose. The current study employed a case-control association design involving 43 VWD patients and 100 healthy controls from Pakistani population. The genetic reason of VWD was investigated using the allele specific PCR. The significant (<i>P</i> < 0.05) allelic association was found between all three exonic variants and VWD. The CT genotype of these variants was noticed to be associated with significantly higher risk of VWD [odds ratio (95% CI): 14.7 (4.546-47.98), 26.71 (7.281-97.98), and 21.5 (5.806-80.01) for c.3445T>C, c.4975C>T, and c.7603C>T, resp.] while genotypes CC (c.4975C>T) and TT (c.3445T>C and c.7603C>T) were having protective effect against the disease. However, replicated studies are needed for elaborating the role of these SNPs.","variants":[{"Name":"NM_000552.5(VWF):c.4975C>T (p.Arg1659Ter)","Chromosome":"12","Start":"6018443","Stop":"6018443","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15336,"rule_based_match":true,"evidence_text":"c.4975C>T","llm_judgment":"PRESENT","evidence":"c.4975C>T","abstract_start":424,"abstract_end":433}]}
{"pmid":"33021473","title":"Clinical and molecular epidemiology of erythropoietic protoporphyria in Italy.","abstract":"BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement.\nOBJECTIVE: To provide epidemiological data of EPP in Italy.\nMATERIALS & METHODS: Prospective/retrospective data of EPP patients were collected by an Italian network of porphyria specialist centres (Gruppo Italiano Porfiria, GrIP) over a 20-year period (1996-2017).\nRESULTS: In total, 179 patients (79 females) with a clinical and biochemical diagnosis of EPP were assessed, revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year. Incidence significantly increased after 2009 (due to the availability of alfa-melanotide, which effectively limits skin photosensitivity). Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed ≤10 years old. Gene mutations were assessed in 173 (96.6%) patients; most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP). Only one case of autosomal recessive EPP was observed. Of the 42 different FECH mutations, 15 are novel, three mutations collectively accounted for 45.9% (75/164) of the mutations (c.215dupT [27.2%], c.901_902delTG [11.5%] and c.67 + 5G > A [7.2%]), and frameshift mutations were prevalent (33.3%). A form of light protection was used by 109/179 (60.8%) patients, and 100 (56%) had at least one α-melanotide implant. Three cases of severe acute liver involvement, requiring OLT, were observed.\nCONCLUSION: These data define, for the first time, the clinical and molecular epidemiology of EPP in Italy.","variants":[{"Name":"NM_000140.5(FECH):c.215dup (p.Leu72fs)","Chromosome":"18","Start":"57573344","Stop":"57573345","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":2844654,"rule_based_match":true,"evidence_text":"c.215dupT","llm_judgment":"PRESENT","evidence":"c.215dupT","abstract_start":1325,"abstract_end":1334}]}
{"pmid":"32885477","title":"Severe epidermolysis bullosa simplex phenotype caused by codominant mutations p.Ile377Thr in keratin 14 and p.Gly138Glu in keratin 5.","abstract":"Epidermolysis bullosa simplex (EBS) is a rare skin disease usually inherited in an autosomal dominant pattern. EBS is resulting from mutations in keratin 5 (KRT5) and keratin 14 (KRT14) genes encoding the keratins 5 and 14 proteins expressed in the keratinocytes of the basal layer of the epidermis. To date, seven pathogenic mutations have been reported to be responsible for EBS in the Canadian population from the province of Quebec: p.Pro25Leu, p.Leu150Pro, p.Met327Thr and p.Arg559X in KRT5; p.Arg125Ser, p.Ile377Thr and p.Ile412Phe in KRT14. Here, we present a novel French-Canadian patient diagnosed with EBS confined to the soles but presenting a severe complication form including blisters, hyperkeratosis, skin erosions and toenail abnormalities. Mutation screening was performed by direct sequencing of the entire coding regions of KRT5 and KRT14 genes and revealed the previously reported missense heterozygous mutation c. 1130T > C in KRT14 (p.Ile377Thr). Furthermore, this patient is carrying a second mutation in KRT5, c.413G > A (p.Gly138Glu), which has been linked to an increased risk of basal cell carcinoma in the literature. We suspect an impact of the p.Gly138Glu variant on the EBS phenotype severity of the studied patient. The pathogenicity and consequences of both genetic variations were simulated by in silico tools.","variants":[{"Name":"NM_000526.5(KRT14):c.1130T>C (p.Ile377Thr)","Chromosome":"17","Start":"41583379","Stop":"41583379","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":77200,"rule_based_match":true,"evidence_text":"c. 1130T > C in KRT14 (p.Ile377Thr)","llm_judgment":"PRESENT","evidence":"c. 1130T > C in KRT14 (p.Ile377Thr)","abstract_start":932,"abstract_end":967}]}
{"pmid":"31885218","title":"New clinical characteristics and novel pathogenic variants of patients with hereditary leukodystrophies.","abstract":"AIM: Leukodystrophies are a group of inherited white matter disorders with clinical, genetic, and imaging heterogeneity, which usually pose a diagnostic challenge for physicians. We aimed to identify new clinical characteristics and novel pathogenic variants of hereditary leukodystrophies in this study.\nMETHODS: Whole exome sequencing (WES) was performed in 28 unrelated patients clinically suspected with leukodystrophies. Leukocytes enzyme activity test, electroencephalogram (EEG), electromyography (EMG), and brain MRI were conducted. Functional analysis was performed, and the pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines.\nRESULTS: We made definite diagnosis in 8 probands with 12 pathogenic variants and reported new clinical characteristics and imaging features of these patients. Three novel pathogenic variants were identified, including a microdeletion variant c.2654_2654+3del within CSF1R, a nonsense variant c.1321C>T, and a missense variant c.166G>C within GALC.\nCONCLUSION: Our results have deepened the understanding of clinical, genetic, and imaging heterogeneity of hereditary leukodystrophies, and expanded the spectrum of pathogenic variants and clinical features.","variants":[{"Name":"NM_000153.4(GALC):c.1321C>T (p.Gln441Ter)","Chromosome":"14","Start":"87949862","Stop":"87949862","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1978206,"rule_based_match":true,"evidence_text":"c.1321C>T","llm_judgment":"PRESENT","evidence":"c.1321C>T","abstract_start":1018,"abstract_end":1027}]}
{"pmid":"33231815","title":"Identification and computational analysis of USH1C, and SLC26A4 variants in Pakistani families with prelingual hearing loss.","abstract":"Hearing loss (HL) is clinically and genetically heterogeneous disorder and is the most frequent occurring sensory deficit in humans. This study was conducted to decipher the genetic cause of HL occurring in two large consanguineous Pakistani families (GCNF-01, GCNF-03). Family history and pure tone audiometry of both families suggested prelingual HL, while the affected individuals of GCNF-01 also had low vision and balance problems, consistent with cardinal features of Usher syndrome type I (USH1). Exome sequencing followed by segregating analysis revealed a novel splice site variant (c.877-1G > A) of USH1C occurring with USH1 phenotype in family GCNF01. While the affected individual of family GCNF-03 were homozygous for the c.716 T > A, p.(Val239Asp) previously reported pathogenic variant of SLC26A4. Both variants have very low frequencies in control database. In silico mutagenesis and 3-dimensional simulation analyses revealed that both variants have deleterious impact on the proteins folding and secondary structures. Our study expands the mutation spectrum of the HL genes and emphasizes the utility of exome sequencing coupled with bioinformatics tools for clinical genetic diagnosis, prognosis, and family counseling.","variants":[{"Name":"NM_153676.4(USH1C):c.877-1G>A","Chromosome":"11","Start":"17522927","Stop":"17522927","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":546390,"rule_based_match":true,"evidence_text":"c.877-1G > A","llm_judgment":"PRESENT","evidence":"c.877-1G > A","abstract_start":592,"abstract_end":604}]}
{"pmid":"31063319","title":"Clinical, biochemical and molecular findings of propionic acidemia","abstract":"Propionic acidemia is an infrequent disorder with an autosomal recessive inheritance pattern caused by the deficiency of the mitochondrial enzyme propionyl-CoA carboxylase that converts propionyl-CoA to D-methylmalonyl-CoA. We present the case of a male newborn who showed signs of respiratory distress, vomiting and tiredness during feeding. He presented metabolic acidosis, positive serum and urine ketone bodies, hyperammonemia, anemia, thrombocytopenia and hypoproteinemia. The biochemical study by gas chromatography coupled to mass spectrometry in a urine sample was suggestive of propionic acidemia. The molecular study in the PCCA gene found the mutations c.893A>G (p.K298R) in the father and c.937C> T (p.R313X) in the mother. There is a need to establish the diagnosis of this infrequent entity to implement the therapeutic measures available and provide the appropriate genetic counseling.","variants":[{"Name":"NM_000282.4(PCCA):c.893A>G (p.Lys298Arg)","Chromosome":"13","Start":"100268762","Stop":"100268762","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":445107,"rule_based_match":true,"evidence_text":"c.893A>G (p.K298R)","llm_judgment":"PRESENT","evidence":"c.893A>G (p.K298R)","abstract_start":664,"abstract_end":682}]}
{"pmid":"27820671","title":"Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients.","abstract":"Context: LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism.\nObjective: The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4.\nDesign and Patients: We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants.\nResults: We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant.\nConclusion: This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.","variants":[{"Name":"NM_033343.4(LHX4):c.704G>A (p.Arg235Gln)","Chromosome":"1","Start":"180271932","Stop":"180271932","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":789889,"rule_based_match":false,"evidence_text":"p.Arg235Gln","llm_judgment":"PRESENT","evidence":"p.Arg235Gln","abstract_start":988,"abstract_end":999}]}
{"pmid":"29478781","title":"Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder.","abstract":"ATP synthase, H<sup>+</sup> transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F<sub>1</sub>F<sub>O</sub> ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.","variants":[{"Name":"NM_001687.5(ATP5F1D):c.317T>G (p.Val106Gly)","Chromosome":"19","Start":"1244118","Stop":"1244118","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":482269,"rule_based_match":true,"evidence_text":"c.317T>G (p.Val106Gly)","llm_judgment":"PRESENT","evidence":"c.317T>G (p.Val106Gly)","abstract_start":583,"abstract_end":605},{"Name":"NM_001687.5(ATP5F1D):c.245C>T (p.Pro82Leu)","Chromosome":"19","Start":"1242559","Stop":"1242559","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":446893,"rule_based_match":true,"evidence_text":"c.245C>T (p.Pro82Leu)","llm_judgment":"PRESENT","evidence":"c.245C>T (p.Pro82Leu)","abstract_start":447,"abstract_end":468}]}
{"pmid":"37188672","title":"A novel compound heterozygous of β-thalassemia with HbG-Coushatta: case report of Iran.","abstract":"A 30-year-old male couple from Ardabil city, Iran, were admitted for premarital screening. An abnormal band in HbS/D regions with high levels of HbF and HbA 2 led us to suspect the possibility of a compound heterozygous state of β-thalassemia in our affected proband. Therefore, beta globin chain sequencing of proband discovered a heterozygote combination of the Hb G-Coushatta [b22 (B4) Glu>Ala, HBB: c.68A>C) with HBB: IVS-II-1 (G>A) mutation as a compound heterozygote.","variants":[{"Name":"NM_000518.4(HBB):c.68A>C (p.Glu23Ala)","Chromosome":"11","Start":"5226954","Stop":"5226954","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":30210,"rule_based_match":true,"evidence_text":"HBB: c.68A>C","llm_judgment":"PRESENT","evidence":"HBB: c.68A>C","abstract_start":398,"abstract_end":410}]}
{"pmid":"24814191","title":"Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness.","abstract":"Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes.","variants":[{"Name":"NM_001367561.1(DOCK7):c.2510del (p.Asp837fs)","Chromosome":"1","Start":"62555911","Stop":"62555911","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":143180,"rule_based_match":true,"evidence_text":"c.2510delA [p.Asp837Alafs(∗)48]","llm_judgment":"PRESENT","evidence":"c.2510delA [p.Asp837Alafs(∗)48]","abstract_start":770,"abstract_end":801},{"Name":"NM_001367561.1(DOCK7):c.3709C>T (p.Arg1237Ter)","Chromosome":"1","Start":"62529349","Stop":"62529349","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":143181,"rule_based_match":true,"evidence_text":"c.3709C>T [p.Arg1237(∗)]","llm_judgment":"PRESENT","evidence":"c.3709C>T [p.Arg1237(∗)]","abstract_start":806,"abstract_end":830},{"Name":"NM_001367561.1(DOCK7):c.983C>G (p.Ser328Ter)","Chromosome":"1","Start":"62634825","Stop":"62634825","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":143182,"rule_based_match":true,"evidence_text":"c.983C>G (p.Ser328(∗))","llm_judgment":"PRESENT","evidence":"c.983C>G","abstract_start":987,"abstract_end":995}]}
{"pmid":"17110920","title":"A novel mutation in GJA8 associated with autosomal dominant congenital cataract in a family of Indian origin.","abstract":"PURPOSE: To identify the genetic defect in an autosomal dominant congenital cataract family, having 15 members in three generations, affected with bilateral cataract that gave the appearance of \"full moon\" with Y-sutural opacities.\nMETHODS: A detailed family history and clinical data were recorded. A genome-wide scan by two point linkage analysis using nearly 400 microsatellite markers in combination with multipoint lod score and haplotype analysis was carried out. Mutation screening was performed in the candidate gene by bidirectional sequencing of amplified products.\nRESULTS: A maximum two point lod score of 5.45 at theta=0.00 was obtained with marker D1S534. Haplotype analysis placed the cataract locus to a 14.1 cM region between D1S221 and D1S498, in close proximity to the gene for the gap junction channel protein connexin 50 (GJA8) at 1q21. Mutation screening in GJA8 identified a novel G>C transversion at nucleotide position c.235. This nucleotide change resulted in the substitution of highly conserved valine by leucine at codon 79 (V79L). This nucleotide substitution was neither seen in any unaffected member of the family nor in 180 unrelated control subjects (360 chromosomes) from same ethnic background tested by sequence analysis of GJA8.\nCONCLUSIONS: The present study describes the mapping of a locus for congenital cataract that appeared like \"full moon\" with Y-sutural opacities at 1q21 and identifies a previously unreported mutation in GJA8. These findings thus expand the mutation spectrum of GJA8.","variants":[{"Name":"NM_005267.5(GJA8):c.235G>C (p.Val79Leu)","Chromosome":"1","Start":"147908190","Stop":"147908190","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3412446,"rule_based_match":false,"evidence_text":"c.235G>C","llm_judgment":"PRESENT","evidence":"c.235G>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"20054342","title":"A prevalent mutation with founder effect in xeroderma pigmentosum group C from north Africa.","abstract":"Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder that is associated with an inherited defect of the nucleotide excision repair pathway (NER). In this study, we investigated the involvement of XP genes in 86 XP patients belonging to 66 unrelated families, most of them consanguineous and originating from Maghreb. Sequencing analysis was performed either directly (44 probands) or after having previously characterized the involved XP gene by complementation assay (22 families). XPC and XPA mutations were respectively present in 56/66 and 8/66 probands. Strikingly, we identified the same homozygous frameshift mutation c.1643_1644delTG (p.Val548AlafsX25) in 87% of XP-C patients. Haplotype analysis showed a common founder effect for this mutation in the Mediterranean region, with an estimated age of 50 generations or 1,250 years. Among 7/8 XP-A patients, we found the previously reported nonsense homozygous XPA mutation (p.Arg228X). Six mutations--to our knowledge previously unreported--(five in XPC, one in XPA) were also identified. In conclusion, XPC appears to be the major disease-causing gene concerning xeroderma pigmentosum in North Africa. As the (p.Val548AlafsX25) XPC mutation is responsible for a huge proportion of XP cases, our data imply an obvious simplification of XP molecular diagnosis, at least in North Africa.","variants":[{"Name":"NM_004628.5(XPC):c.1643_1644del (p.Val548fs)","Chromosome":"3","Start":"14158239","Stop":"14158240","ReferenceAlleleVCF":"GCA","AlternateAlleleVCF":"G","allel_id":15301,"rule_based_match":true,"evidence_text":"c.1643_1644delTG (p.Val548AlafsX25)","llm_judgment":"PRESENT","evidence":"c.1643_1644delTG (p.Val548AlafsX25)","abstract_start":638,"abstract_end":673}]}
{"pmid":"36987741","title":"Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature.","abstract":"The TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype-to-phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A > G (N1465S) and c.6244-2A > G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype-to-phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues.","variants":[{"Name":"NM_007118.4(TRIO):c.4394A>G (p.Asn1465Ser)","Chromosome":"5","Start":"14397125","Stop":"14397125","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":964920,"rule_based_match":true,"evidence_text":"c.4394A > G (N1465S)","llm_judgment":"PRESENT","evidence":"c.4394A > G (N1465S)","abstract_start":718,"abstract_end":738}]}
{"pmid":"25678551","title":"Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour.","abstract":"Gastric neuroendocrine tumours (NETs) arise from enterochromaffin-like cells, which are located in oxyntic glands within the stomach. Type I tumours represent 70-80% of gastric NETs and are associated with hypergastrinaemia, chronic atrophic gastritis and achlorhydria. Gastrin is involved in the endocrine regulation of gastric acid production. Most type I gastric NETs are sporadic, have a good prognosis and their genetic basis are unknown. We performed an exome sequencing study in a family with consanguineous parents and 10 children, five of whom were affected by type I gastric NET. Atypical clinical traits included an earlier age of onset (around 30 years), aggressiveness (three had nodal infiltration requiring total gastrectomy and one an adenocarcinoma) and iron-deficiency rather than megaloblastic anaemia. We identified a homozygous missense mutation in the 14th exon of the ATP4A gene (c.2107C>T), which encodes the proton pump responsible for acid secretion by gastric parietal cells. The amino acid p.Arg703Cys is highly conserved across species and originates a change of one of the transmembrane domains that avoids the liberation of protons from cells to stomach. This is consistent with the achlorhydria that was observed in the affected individuals. No germline or somatic mutations in the ATP4A gene were found in sporadic gastric NET patients. Based on the results of this large family, it seems that this atypical form of gastric NET has an earlier age of onset, behaves more aggressively and has atypical clinical traits that differentiated from other studied cases.","variants":[{"Name":"NM_000704.3(ATP4A):c.2107C>T (p.Arg703Cys)","Chromosome":"19","Start":"35555490","Stop":"35555490","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1678492,"rule_based_match":true,"evidence_text":"c.2107C>T","llm_judgment":"PRESENT","evidence":"c.2107C>T","abstract_start":903,"abstract_end":912}]}
{"pmid":"31696758","title":"Novel homozygous in-frame deletion of","abstract":"<b>Background</b>: The <i>GNAT1</i> gene encodes the alpha-subunit of transducin in rod photoreceptors and is an important part of the phototransduction cascade. Defects in <i>GNAT1</i> are very rare but have been identified in autosomal dominant and recessive congenital stationary night blindness (CSNB) and autosomal recessive rod-cone dystrophy. The purpose of this study was to determine the phenotype-genotype relationship in a non-consanguineous Japanese family with a <i>GNAT1</i> mutation.<b>Methods</b>: Detailed ophthalmic examinations were performed on the patients and their family members. Whole exome sequencing (WES) was applied to the DNA obtained from the family members. Sanger sequencing and co-segregation analyses were performed to identify the most likely pathogenic variant.<b>Results</b>: Two female (13- and 11-years) and one male (15-years) patients from a family had night blindness from their childhood. The fundus had a mild golden appearance regardless of the state of light- or dark-adaptation. Electroretinographic (ERG) analyses showed that the scotopic a-wave was extinguished, and the mixed rod-cone responses were severely reduced with an electronegative form in patients. The shapes of the dark-adapted ERGs were similar to those recorded from patients with Oguchi disease. We identified a homozygous in-frame deletion c.818_820delAGA, p.Lys273del in the <i>GNAT1</i> gene. Variants were verified by Sanger sequencing and co-segregated with the disease in five members of the family.<b>Conclusions</b>: Our findings indicate that a recessive <i>GNAT1</i> mutation found in this family could be the cause of the golden appearance of the fundus and negative ERGs with reduced a-waves, and nearly absent b-waves in the mixed rod-cone ERGs.","variants":[{"Name":"NM_144499.3(GNAT1):c.815AGA[1] (p.Lys273del)","Chromosome":"3","Start":"50194607","Stop":"50194609","ReferenceAlleleVCF":"GAGA","AlternateAlleleVCF":"G","allel_id":1427481,"rule_based_match":false,"evidence_text":"c.818_820delAGA, p.Lys273del","llm_judgment":"PRESENT","evidence":"c.818_820delAGA, p.Lys273del","abstract_start":1357,"abstract_end":1385}]}
{"pmid":"19036112","title":"Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene.","abstract":"Familial thrombosis (FT) has been described as a rare autosomal-dominant disorder, mostly caused by activating mutations of the thrombopoietin gene (THPO). Other cases of FT have been linked to one of two different germline mutations in the myeloproliferative leukaemia virus oncogene gene (MPL), which codes for the thrombopoietin receptor MPL. We studied an Arab family with two siblings with severe thrombocytosis by linkage analysis and obtained evidence for linkage to MPL. Sequencing revealed homozygosity for the novel MPL germline mutation p.Pro106Leu (c.317C > T) in the two siblings. Subsequently, homozygosity for p.Pro106Leu was identified in six further FT patients from three other Arab families. Of 18 heterozygous carriers, 14 had normal platelet counts, while four had mild thrombocytosis. Strong support for association of the novel MPL mutation p.Pro106Leu with development of familial thrombocytosis has been obtained. Overall, p.Pro106Leu was absent on 386 alleles of 193 healthy German controls and present on 14 of 426 alleles (3.3%) of 213 unrelated Arabs, which was statistically significantly different (P < 0.001, Fisher's exact test). We assume that p.Pro106Leu is a frequent MPL mutation in the Arab population, leading to severe thrombocytosis in homozygotes and occasionally to mild thrombocytosis in heterozygotes. In the families described the mode of inheritance could be regarded as autosomal-recessive with possible mild heterozygote manifestation rather than autosomal-dominant with high penetrance as usually seen in FT.","variants":[{"Name":"NM_005373.3(MPL):c.317C>T (p.Pro106Leu)","Chromosome":"1","Start":"43338646","Stop":"43338646","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259670,"rule_based_match":true,"evidence_text":"p.Pro106Leu (c.317C > T)","llm_judgment":"PRESENT","evidence":"p.Pro106Leu (c.317C > T)","abstract_start":548,"abstract_end":572}]}
{"pmid":"24388663","title":"Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia.","abstract":"Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurological conditions. Their main pathogenic mechanisms are thought to involve alterations in endomembrane trafficking, mitochondrial function, and lipid metabolism. With a combination of whole-genome mapping and exome sequencing, we identified three mutations in REEP2 in two families with HSP: a missense variant (c.107T>A [p.Val36Glu]) that segregated in the heterozygous state in a family with autosomal-dominant inheritance and a missense change (c.215T>A [p.Phe72Tyr]) that segregated in trans with a splice site mutation (c.105+3G>T) in a family with autosomal-recessive transmission. REEP2 belongs to a family of proteins that shape the endoplasmic reticulum, an organelle that was altered in fibroblasts from an affected subject. In vitro, the p.Val36Glu variant in the autosomal-dominant family had a dominant-negative effect; it inhibited the normal binding of wild-type REEP2 to membranes. The missense substitution p.Phe72Tyr, in the recessive family, decreased the affinity of the mutant protein for membranes that, together with the splice site mutation, is expected to cause complete loss of REEP2 function. Our findings illustrate how dominant and recessive inheritance can be explained by the effects and nature of mutations in the same gene. They have also important implications for genetic diagnosis and counseling in clinical practice because of the association of various modes of inheritance to this new clinico-genetic entity.","variants":[{"Name":"NM_001271803.2(REEP2):c.107T>A (p.Val36Glu)","Chromosome":"5","Start":"138441386","Stop":"138441386","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":102898,"rule_based_match":true,"evidence_text":"c.107T>A (p.Val36Glu)","llm_judgment":"PRESENT","evidence":"p.Val36Glu","abstract_start":411,"abstract_end":421},{"Name":"NM_001271803.2(REEP2):c.215T>A (p.Phe72Tyr)","Chromosome":"5","Start":"138444447","Stop":"138444447","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":102900,"rule_based_match":true,"evidence_text":"c.215T>A (p.Phe72Tyr)","llm_judgment":"PRESENT","evidence":"p.Phe72Tyr","abstract_start":547,"abstract_end":557}]}
{"pmid":"38130397","title":"","abstract":"Context: A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the <i>GCM2</i> [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ).\nObjective: To evaluate the presence of the <i>GCM2</i> p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management.\nMethod: Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the <i>GCM2</i> p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database.\nResults: A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight <i>CASR</i> and two <i>AP2S1</i> mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the <i>GCM2</i> p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the <i>GCM2</i> p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the <i>GCM2</i> p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%.\nConclusion: In contrast to previous observations, the <i>GCM2</i> p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.","variants":[{"Name":"NM_004752.4(GCM2):c.1181A>C (p.Tyr394Ser)","Chromosome":"6","Start":"10874335","Stop":"10874335","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":298705,"rule_based_match":true,"evidence_text":"(NM_ 004752.4) c.1181A> C; p.Tyr394Ser","llm_judgment":"PRESENT","evidence":"(NM_ 004752.4) c.1181A> C; p.Tyr394Ser","abstract_start":159,"abstract_end":197}]}
{"pmid":"33837634","title":"Resolution of sclerotic lesions of dysosteosclerosis due to biallelic SLC29A3 variant in a Turkish girl.","abstract":"Dysosteosclerosis is a group of sclerosing bone dysplasia characterized by short stature, increased bone fragility, osteosclerosis, and platyspondyly. It is a genetically heterogeneous disorder caused by biallelic mutations in the SLC29A3, TNFRSF11A, TCIRG1, and CSF1R genes. To date, four dysosteosclerosis patients with SLC29A3 mutations have been reported. Here, we report biallelic SLC29A3 (c.303_320dupCTACTTTGAGAGCTACCT) variant in a three-year-old girl. She had large anterior fontanelle, fracture history, short stature, camptodactyly, elbow contracture, and melanocytic nevus. Initial skeletal radiographs revealed platyspondyly, dense vertebral endplates (sandwich appearance of the vertebral bodies), diffuse sclerosis of the peripheral side of the pelvic bones, sclerosis of metaphysis and diaphysis of the long bones, metaphyseal widening, and diaphyseal cortical thickening. Mild sclerosis was also present in the skull base, maxilla, rib, scapula, and phalanges. Notably, we observed that sandwich vertebrae appearance significantly resolved and sclerosis of ribs, scapula, pelvis, and long bone metaphysis regressed over a 2.5-year period. However, platyspondyly, metaphyseal widening, and diaphyseal cortical thickening persisted. In conclusion, this study demonstrates spontaneous resolution of osteosclerosis, which was not described previously in patients with dysosteosclerosis.","variants":[{"Name":"NM_018344.6(SLC29A3):c.303_320dup (p.Tyr102_Leu107dup)","Chromosome":"10","Start":"71344210","Stop":"71344211","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ACTACTTTGAGAGCTACCT","allel_id":935150,"rule_based_match":true,"evidence_text":"c.303_320dupCTACTTTGAGAGCTACCT","llm_judgment":"PRESENT","evidence":"c.303_320dupCTACTTTGAGAGCTACCT","abstract_start":395,"abstract_end":425}]}
{"pmid":"22989098","title":"Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management.","abstract":"Systemic primary carnitine deficiency (CDSP) is an autosomal recessive disorder of carnitine transportation. The clinical manifestations of CDSP can vary widely with respect to age of onset, organ involvement, and severity of symptoms, but are typically characterized by episodes of hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia in infants; skeletal myopathy, elevated creatine kinase (CK), and cardiomyopathy in childhood; or cardiomyopathy, arrhythmias, or fatigability in adulthood. The diagnosis can be suspected on newborn screening, but is established by demonstration of low plasma free carnitine concentration (<5 μM, normal 25-50 μM), reduced fibroblast carnitine transport (<10% of controls), and molecular testing of the SLC22A5 gene. The incidence of CDSP varies depending on ethnicity; however the frequency in the United States is estimated to be approximately 1 in 50,000 individuals based on newborn screening data. CDSP is caused by recessive mutations in the SLC22A5 gene. This gene encodes organic cation transporter type 2 (OCTN2) which transport carnitine across cell membranes. Over 100 mutations have been reported in this gene with the c.136C > T (p.P46S) mutation being the most frequent mutation identified. CDSP should be differentiated from secondary causes of carnitine deficiency such as various organic acidemias and fatty acid oxidation defects. CDSP is an autosomal recessive condition; therefore the recurrence risk in each pregnancy is 25%. Carrier screening for at-risk individuals and family members should be obtained by performing targeted mutation analysis of the SLC22A5 gene since plasma carnitine analysis is not a sufficient methodology for determining carrier status. Antenatal diagnosis for pregnancies at increased risk of CDSP is possible by molecular genetic testing of extracted DNA from chorionic villus sampling or amniocentesis if both mutations in SLC22A5 gene are known. Once the diagnosis of CDSP is established in an individual, an echocardiogram, electrocardiogram, CK concentration, liver transaminanses measurement, and pre-prandial blood sugar levels, should be performed for baseline assessment. Primary treatment involves supplementation of oral levocarnitine (L-carnitine) at a dose of 50-400 mg/kg/day divided into three doses. No formal surveillance guidelines for individuals with CDSP have been established to date, however the following screening recommendations are suggested: annual echocardiogram and electrocardiogram, frequent plasma carnitine levels, and CK and liver transaminases measurement can be considered during acute illness. Adult women with CDSP who are planning to or are pregnant should meet with a metabolic or genetic specialist ideally before conception to discuss management of carnitine levels during pregnancy since carnitine levels are typically lower during pregnancy. The prognosis for individuals with CDSP depends on the age, presentation, and severity of symptoms at the time of diagnosis; however the long-term prognosis is favorable as long as individuals remain on carnitine supplementation.","variants":[{"Name":"NM_003060.4(SLC22A5):c.136C>T (p.Pro46Ser)","Chromosome":"5","Start":"132370108","Stop":"132370108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":190414,"rule_based_match":true,"evidence_text":"c.136C > T (p.P46S)","llm_judgment":"PRESENT","evidence":"c.136C > T (p.P46S)","abstract_start":1197,"abstract_end":1216}]}
{"pmid":"21252112","title":"Inherited demyelinating neuropathies with micromutations of peripheral myelin protein 22 gene.","abstract":"The peripheral myelin protein 22 gene (PMP22) encodes an intrinsic membrane protein of compact myelin. Duplication or deletion of PMP22 causes the most common autosomal dominant neuropathies, Charcot-Marie-Tooth disease type 1A or hereditary neuropathy with liability to pressure palsies. Charcot-Marie-Tooth disease type 1A is a hypertrophic de-remyelinating neuropathy manifesting with peroneal muscular atrophy and uniform, marked, slowing of nerve conduction velocities. Hereditary neuropathy with liability to pressure palsies is a recurrent focal neuropathy with sausage-like myelin thickening (tomacula) and non-uniform nerve conduction velocity changes. Missense or nonsense mutations also cause more severe Charcot-Marie-Tooth disease type 1A forms of infancy or hereditary neuropathy with liability to pressure palsies, but they are presumably very rare. We performed a mutational scanning of PMP22 in 229 index patients (46 familial, 183 isolated) referred for suspected inherited neuropathy. The series included 125 cases with hereditary neuropathy with liability to pressure palsies (mean age 42.5 years), 47 cases with Charcot-Marie-Tooth disease type 1A (motor nerve conduction velocities at median nerve below 38 m/s) (mean age 40.7 years) and 57 cases with Charcot-Marie-Tooth with unknown nerve conduction velocities (mean age 43 years). Preliminary molecular studies ruled out PMP22 duplication or deletion or mutations in a comprehensive panel of Charcot-Marie-Tooth genes. Mutational scanning of PMP22 was done by denaturing high performance liquid chromatography and automated nucleotide sequencing. To investigate the molecular basis of phenotype-to-genotype correlations, we performed a transcriptional analysis of PMP22 using reverse-transcriptase polymerase chain reaction and quantitative real-time polymerase chain reaction in two phenotypically divergent nerve biopsies. Ten patients harboured eight micromutations of PMP22 including four novel changes. In six familial and three sporadic cases, detected mutations caused premature or delayed stop codons and were associated with hereditary neuropathy with liability to pressure palsies; the related pathological pictures ranged from classical tomaculous neuropathy to a mild demyelinating neuropathy with atypical non-tomaculous myelin thickenings. In a single family a c.179-2A> G mutation affecting the splice acceptor site of intron 2 cosegregated with a Charcot-Marie-Tooth disease type 1A-like syndrome and a peculiar pathological picture of demyelinating neuropathy without Charcot-Marie-Tooth disease type 1A-like classical onion bulbs or tomacula. Transcriptional analysis of a novel c.174_178 + 7delAAACGGTGAGGC deletion involving exon 2 and intron 2 demonstrated an unstable mutant transcript leading to a p.Asn59GlyfsX12 change; the mutation represented a null allele and caused a typical tomaculous hereditary neuropathy with liability to pressure palsies. The Charcot-Marie-Tooth disease type 1-like c.179-2A > G allele led to a stable transcript with an in-frame deletion of exon 3 (p.Glu60_Ala106del); the predicted shorter protein could exert variable molecular effects. In conclusion, micromutations of PMP22 cause a clinical and pathological continuum of demyelinating neuropathies that may include atypical phenotypes.","variants":[{"Name":"NM_000304.4(PMP22):c.174_178+7del","Chromosome":"17","Start":"15259087","Stop":"15259098","ReferenceAlleleVCF":"AGCCTCACCGTTT","AlternateAlleleVCF":"A","allel_id":625766,"rule_based_match":true,"evidence_text":"c.174_178 + 7delAAACGGTGAGGC","llm_judgment":"PRESENT","evidence":"c.174_178 + 7delAAACGGTGAGGC","abstract_start":2672,"abstract_end":2700}]}
{"pmid":"26543653","title":"Progressive Lower Extremity Weakness and Axonal Sensorimotor Polyneuropathy from a Mutation in KIF5A (c.611G>A;p.Arg204Gln).","abstract":"Introduction. Hereditary Spastic Paraplegia (HSP) is a rare hereditary disorder that primarily involves progressive spasticity of the legs (hamstrings, quadriceps, and calves). Methods. A 27-year-old gentleman was a fast runner and able to play soccer until age 9 when he developed slowly progressive weakness. He was wheelchair-bound by age 25. He was evaluated by laboratory testing, imaging, electrodiagnostics, and molecular genetics. Results. Electrodiagnostic testing revealed an axonal sensorimotor polyneuropathy. Genetic testing for HSP in 2003 was negative; repeat testing in 2013 revealed a mutation in KIF5A (c.611G>A;p.Arg204Gln). Conclusions. A recent advance in neurogenetics has allowed for more genes and mutations to be identified; over 76 different genetic loci for HSP and 59 gene products are currently known. Even though our patient had a sensorimotor polyneuropathy on electrodiagnostic testing and a 2003 HSP genetic panel that was negative, a repeat HSP genetic panel was performed in 2013 due to the advancement in neurogenetics. This revealed a mutation in KIF5A.","variants":[{"Name":"NM_004984.4(KIF5A):c.611G>A (p.Arg204Gln)","Chromosome":"12","Start":"57567515","Stop":"57567515","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45790,"rule_based_match":true,"evidence_text":"c.611G>A;p.Arg204Gln","llm_judgment":"PRESENT","evidence":"c.611G>A;p.Arg204Gln","abstract_start":621,"abstract_end":641}]}
{"pmid":"24342785","title":"Clinical characterization of the Stargardt disease and molecular exploration of the c.2041C>T mutation (ABCA4 gene) in Tunisian patients","abstract":"In order to charaterize the Stargardt disease, the molecular exploration of the c.2041C>T mutation (ABCA4 gene) and genotype phenotype correlation in Tunisian patients, seven unrelated propositi underwent a complete ophthalmological examination. The search for the mutation was performed by a direct sequencing after a specific amplification of exon 14 of the ABCA4 gene. Baseline, the average age of propositi was 20.7 ± 15 years and the sex-ratio was 1.3. The age of the visual impairment perception was 8.1 ± 3.2 years. In all patients, the loss of visual acuity was bilateral and ranged from \"counting fingers\" to 3.2/10. Fundus and retinal fluorescein angiography examination showed advanced stages of the disease. The allele frequency of the c.2041C>T was 28.5% (4/14). We have reported this mutation in two patients. Their average age at onset was 5 and a half years and the disease progression was rapid with a severe visual loss after 1 and 5 years. All patients had a juvenile macular dystrophy with flavimaculatus flecks. To our knowledge, we reported for the first time the homozygous state of the c.2041C>T mutation. Among homozygous patients, the age at onset was early, the loss of visual acuity was important and the prognosis was severe. Due to the severity of the phenotype and the high rate of inbreeding, genetic counseling for healthy heterozygotes is essential.","variants":[{"Name":"NM_000350.3(ABCA4):c.2041C>T (p.Arg681Ter)","Chromosome":"1","Start":"94060656","Stop":"94060656","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":105003,"rule_based_match":true,"evidence_text":"c.2041C>T","llm_judgment":"PRESENT","evidence":"c.2041C>T","abstract_start":80,"abstract_end":89}]}
{"pmid":"33807935","title":"Novel Homozygous Mutations in the Genes","abstract":"BACKGROUND: Ichthyoses are a large group of hereditary cornification disorders, which are both clinically and etiologically heterogeneous and affect mostly all the skin surface of the patients. Ichthyosis has its origin in an ancient Greek word \"ichthys\" meaning fish, this is because the ichthyosis patients have dry, thickened, and scaly skin. There is an excess accumulation of epidermal cells resulting in the appearance of continuous and widespread scales on the body. There are many varieties of ichthyosis with a broad spectrum of intensity, severity, and associated symptoms, most of them are extremely rare. Ichthyosis vulgaris is the most frequently occurring type of ichthyoses.\nMETHOD: The present study consists of four Pakistani ichthyosis families (A, B, C, and D). Whole exome sequencing (WES) approach was used to identify the pathogenic sequence variants in probands. The segregation of these variants in other participants was confirmed by Sanger sequencing.\nRESULTS: Total four variants including, two splice site (<i>TGM1</i>: c.2088 + 1G > A) and (<i>SPINK5</i>: c.882 + 1G > T), a missense (<i>SULT2B1</i>: c.419C > T; p. Ala140Val), and a nonsense (<i>FLG</i>: c.6109C > T; p. Arg2037Ter) variant were identified in families A, C, B, and D, respectively, as causative mutations responsible for ichthyosis in these families.\nCONCLUSION: Our study unravels the molecular etiology of the four Pakistani ichthyosis families and validates the involvement of <i>TGM1, SULT2B1, SPINK5,</i> and <i>FLG</i>, in the etiology of different forms of ichthyosis. In addition, this study also aims to give a detailed clinical report of the studied ichthyosis families.","variants":[{"Name":"NM_002016.2(FLG):c.6109C>T (p.Arg2037Ter)","Chromosome":"1","Start":"152308777","Stop":"152308777","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":263938,"rule_based_match":true,"evidence_text":"FLG: c.6109C > T; p. Arg2037Ter","llm_judgment":"PRESENT","evidence":"p. Arg2037Ter","abstract_start":1198,"abstract_end":1211}]}
{"pmid":"29180823","title":"HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.","abstract":"Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G  >  A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.","variants":[{"Name":"NM_031407.7(HUWE1):c.329G>A (p.Arg110Gln)","Chromosome":"X","Start":"53647390","Stop":"53647390","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":362615,"rule_based_match":true,"evidence_text":"c.329 G  >  A p.Arg110Gln","llm_judgment":"PRESENT","evidence":"c.329 G  >  A p.Arg110Gln","abstract_start":1013,"abstract_end":1038}]}
{"pmid":"29951145","title":"Detection of a new KCNQ1 frameshift mutation associated with Jervell and Lange-Nielsen syndrome in 2 Iranian families.","abstract":"Jervell-Lange Nielsen syndrome (JLNS) with autosomal recessive inheritance is a congenital cardiovascular disorder characterized by prolongation of QT interval on the ECG and deafness. We have performed molecular investigation by haplotype analysis and DNA Sanger sequencing in 2 unrelated Iranian families with a history of syncope. Mutational screening of <i>KCNQ1</i> gene revealed the novel homozygous frameshift mutation c.733-734delGG (p.G245Rfs*39) in 2 obviously unrelated cases of JLNS which is probably a founder mutation in Iran. The novel mutation detected in this study is the first time reported among Iranian population and will be beneficial in the tribe and region-specific cascade screening of LQTS in Iran.","variants":[{"Name":"NM_000218.3(KCNQ1):c.733_734del (p.Gly245fs)","Chromosome":"11","Start":"2572061","Stop":"2572062","ReferenceAlleleVCF":"AGG","AlternateAlleleVCF":"A","allel_id":432231,"rule_based_match":false,"evidence_text":"c.733-734delGG (p.G245Rfs*39)","llm_judgment":"PRESENT","evidence":"c.733-734delGG (p.G245Rfs*39)","abstract_start":426,"abstract_end":455}]}
{"pmid":"33679882","title":"","abstract":"Populations in North Africa (NA) are characterized by a high rate of consanguinity. Consequently, the proportion of founder mutations might be higher than expected and could be a major cause for the high prevalence of recessive genetic disorders like Fanconi anemia (FA). We report clinical, cytogenetic, and molecular characterization of <i>FANCA</i> in 29 North African FA patients from Tunisia, Libya, and Algeria. Cytogenetic tests revealed high rates of spontaneous chromosome breakages for all patients except two of them. <i>FANCA</i> molecular analysis was performed using three different molecular approaches which allowed us to identify causal mutations as homozygous or compound heterozygous forms. It included a nonsense mutation (c.2749C > T; p.Arg917Ter), one reported missense mutation (c.1304G > A; p.Arg435His), a novel missense variant (c.1258G > A; p.Asp409Glu), and the <i>FANCA</i> most common reported mutation (c.3788_3790delTCT; p.Phe1263del). Furthermore, three founder mutations were identified in 86.7% of the 22 Tunisian patients: (1) a deletion of exon 15, in 36.4% patients (8/22); (2), a deletion of exons 4 and 5 in 23% (5/22) and (3) an intronic mutation c.2222 + 166G > A, in 27.3% (6/22). Despite the relatively small number of patients studied, our results depict the mutational landscape of FA among NA populations and it should be taken into consideration for appropriate genetic counseling.","variants":[{"Name":"NM_000135.4(FANCA):c.1304G>A (p.Arg435His)","Chromosome":"16","Start":"89791458","Stop":"89791458","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":401450,"rule_based_match":true,"evidence_text":"c.1304G > A; p.Arg435His","llm_judgment":"PRESENT","evidence":"c.1304G > A; p.Arg435His","abstract_start":802,"abstract_end":826}]}
{"pmid":"37880421","title":"Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly.","abstract":"Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.","variants":[{"Name":"NM_032982.4(CASP2):c.876+1G>T","Chromosome":"7","Start":"143300052","Stop":"143300052","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2477493,"rule_based_match":true,"evidence_text":"c.876+1G>T","llm_judgment":"PRESENT","evidence":"c.876+1G>T","abstract_start":null,"abstract_end":null},{"Name":"NM_032982.4(CASP2):c.1156del (p.Tyr386fs)","Chromosome":"7","Start":"143304712","Stop":"143304712","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":2477445,"rule_based_match":true,"evidence_text":"NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25)","llm_judgment":"PRESENT","evidence":"NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25)","abstract_start":751,"abstract_end":794},{"Name":"NM_032982.4(CASP2):c.1174C>T (p.Gln392Ter)","Chromosome":"7","Start":"143304730","Stop":"143304730","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2477446,"rule_based_match":true,"evidence_text":"c.1174 C > T (p.Gln392Ter)","llm_judgment":"PRESENT","evidence":"c.1174 C > T (p.Gln392Ter)","abstract_start":800,"abstract_end":826},{"Name":"NM_032982.4(CASP2):c.130C>T (p.Arg44Ter)","Chromosome":"7","Start":"143291595","Stop":"143291595","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2477447,"rule_based_match":false,"evidence_text":"c.130 C > T","llm_judgment":"PRESENT","evidence":"c.[130 C > T","abstract_start":864,"abstract_end":876}]}
{"pmid":"22194755","title":"The Novel CFTR Mutation A457P in a Male with a Delayed Diagnosis of Cystic Fibrosis.","abstract":"Cystic fibrosis (CF) is an autosomal recessive disease that may be caused by more than 1000 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We describe the case of a CF patient who was initially diagnosed at 16 years of age after presenting with mild respiratory compromise and pancreatic sufficiency. When genetic testing was first performed using a CF mutation panel, only a single F508del CFTR allele was identified. We subsequently performed testing, which revealed a previously unreported mutation: A457P (p.Ala457Pro, c.1369G>C). The patient's clinical course through adulthood is described, and genotype-phenotype correlation is discussed. The A457P mutation appears to confer a relatively mild phenotype, as is usually observed with CFTR class IV-VI defects. With the advent of more comprehensive and widely available genetic testing techniques, identification of CF genotypes in patients with milder disease variants may help stratify patients for targeted therapy and prevent late complications of the disease.","variants":[{"Name":"NM_000492.4(CFTR):c.1369G>C (p.Ala457Pro)","Chromosome":"7","Start":"117548800","Stop":"117548800","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":544524,"rule_based_match":true,"evidence_text":"c.1369G>C","llm_judgment":"PRESENT","evidence":"c.1369G>C","abstract_start":568,"abstract_end":577}]}
{"pmid":"28253535","title":"Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome.","abstract":"We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1<sup>lew/lew</sup> mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017;81:597-603.","variants":[{"Name":"NM_014231.5(VAMP1):c.51_64del (p.Gly18fs)","Chromosome":"12","Start":"6466290","Stop":"6466303","ReferenceAlleleVCF":"GGGGGACCCCCACCT","AlternateAlleleVCF":"G","allel_id":610400,"rule_based_match":true,"evidence_text":"c.51_64delAGGTGGGGGTCCCC","llm_judgment":"PRESENT","evidence":"c.51_64delAGGTGGGGGTCCCC","abstract_start":184,"abstract_end":208},{"Name":"NM_014231.5(VAMP1):c.146G>C (p.Arg49Pro)","Chromosome":"12","Start":"6465984","Stop":"6465984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":540459,"rule_based_match":true,"evidence_text":"c.146G>C","llm_judgment":"PRESENT","evidence":"c.146G>C","abstract_start":233,"abstract_end":241}]}
{"pmid":"25846081","title":"Novel mutations of low-density lipoprotein receptor gene in China patients with familial hypercholesterolemia.","abstract":"Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder, associated with elevated level of serum low-density lipoprotein-cholesterol (LDL-C), which can lead to premature cardiovascular disease (CVD). Mutations in low density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) have been identified to be the underlying cause of this disease. Genetic research of FH has already been extensively studied all over the world. However, reports of FH mutations in the Chinese population are still limited. In this paper, 20 unrelated FH families were enrolled to detect the candidate gene variants in Chinese FH population by DNA direct sequencing. We identified 12 LDLR variants in 13 FH probands. Importantly, we first reported two unique mutations (c.2000_2000 delG/p.C667LfsX6 and c.605T>C/p.F202S) in LDLR gene. Our discoveries expand the spectrum of LDLR mutations and contribute to the genetic diagnosis and counseling for FH patients.","variants":[{"Name":"NM_000527.5(LDLR):c.2000del (p.Cys667fs)","Chromosome":"19","Start":"11120382","Stop":"11120382","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":246460,"rule_based_match":false,"evidence_text":"c.2000_2000 delG/p.C667LfsX6","llm_judgment":"PRESENT","evidence":"c.2000_2000 delG/p.C667LfsX6","abstract_start":802,"abstract_end":830},{"Name":"NM_000527.5(LDLR):c.605T>C (p.Phe202Ser)","Chromosome":"19","Start":"11105511","Stop":"11105511","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":245655,"rule_based_match":true,"evidence_text":"c.605T>C/p.F202S","llm_judgment":"PRESENT","evidence":"c.605T>C/p.F202S","abstract_start":835,"abstract_end":851}]}
{"pmid":"36174992","title":"Multicenter Surveillance of Cystic Fibrosis in Korean Children.","abstract":"PURPOSE: Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (<i>CFTR</i>) gene, is rare among non-Caucasians. We aimed to identify the clinical features and <i>CFTR</i> mutations in Korean children.\nMETHODS: We included 18 pediatric patients with CF diagnosed using sweat chloride test or genetic analysis for 30 years. HEK293 cells were transfected with wild-type <i>CFTR</i>, ΔF508-<i>CFTR</i>, and L441P-<i>CFTR</i> mutant plasmids for 24 hours and treated with CFTR correctors (VX809 and VX661).\nRESULTS: The median age at diagnosis was 9.2 years. Eleven patients had growth retardation, and 6 had a respiratory failure at diagnosis. Genetic analysis was used for all patients, while sweat testing was for 8 patients. At diagnosis, the median <i>z</i> scores of forced expiratory volume in one second (FEV1), FEV1/forced vital capacity, and forced expiratory flow at 25%-75% of forced vital capacity were -3.61 (-5.78, 1.78), -3.38 (-4.40, -0.60), and -4.45 (-5.78, 0.54), respectively. Two patients were treated with dornase alfa and only one with CFTR modulator. Patients were followed up for 3.7 years as a median. Four patients died at 10.6 years, with 4.2 years of post-diagnosis survival. The most common mutation was exon 16-17b deletion (19.4%). Among 11 single nucleotide variants, c.1322T>C (p.Leu441Pro, L441P) was detected in 4 patients. In the functional assay, L441P-CFTR correction was well restored by CFTR correctors compared with ΔF508.\nCONCLUSIONS: CF is extremely rare in Korean children and is caused by different mutations from those commonly observed in Caucasians. Early diagnosis and treatment availability may improve outcomes. CFTR modulators may be effective for Asian patients with rare <i>CFTR</i> mutations, c.1322T>C (p.Leu441Pro).","variants":[{"Name":"NM_000492.4(CFTR):c.1322T>C (p.Leu441Pro)","Chromosome":"7","Start":"117548753","Stop":"117548753","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":67896,"rule_based_match":true,"evidence_text":"c.1322T>C (p.Leu441Pro)","llm_judgment":"PRESENT","evidence":"c.1322T>C (p.Leu441Pro)","abstract_start":1793,"abstract_end":1816}]}
{"pmid":"32404357","title":"Novel p.G1344E mutation in","abstract":"BACKGROUND: Ectopia lentis refers to dislocation or subluxation of the crystalline lens. Fibrillin-1, encoded by <i>FBN1</i>, is an important microfibrillar structural component that is specifically required for the suspensory ligament of the lens. <i>FBN1</i> mutations may cause abnormal structure of microfibrils and has been associated with a broad spectrum of clinical phenotypes. In this study, we characterised a Chinese dominant family with late-onset isolated ectopia lentis caused by a novel missense <i>FBN1</i> mutation.\nMETHODS: Eight family members, including four patients with suspected isolated ectopia lentis, were recruited from Shanghai. Clinical data and family history of the proband and other affected family members were collected. Ophthalmic examination, systemic examination and echocardiography were performed. Whole exome sequencing and Sanger sequencing were used to detect potential pathogenic variants.\nRESULTS: A novel heterozygous missense mutation c.4031 G>A/p.Gly1344Glu in exon 33 of <i>FBN1</i> was identified. This mutation was detected in all affected family members and led to specific ocular system phenotypes (ectopia lentis, microspherophakia and secondary glaucoma) with minor skeletal involvement (hallux valgus).\nCONCLUSION: The novel c.4031G>A mutation in <i>FBN1</i> is a likely pathogenic mutation for isolated ectopia lentis. Our study expands the spectrum of <i>FBN1</i> mutations and contributes to better comprehension of genotype-phenotype correlations of ectopia lentis disease.","variants":[{"Name":"NM_000138.5(FBN1):c.4031G>A (p.Gly1344Glu)","Chromosome":"15","Start":"48474584","Stop":"48474584","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":528909,"rule_based_match":true,"evidence_text":"c.4031 G>A/p.Gly1344Glu","llm_judgment":"PRESENT","evidence":"c.4031 G>A/p.Gly1344Glu","abstract_start":982,"abstract_end":1005}]}
{"pmid":"29264504","title":"Ethnicity of Patients With Germline","abstract":"CONTEXT: Germline gain-of-function variants in the transcription factor GCM2 were found in 18% of kindreds with familial isolated hyperparathyroidism (FIHP). These variants [c.1136T>A (p.Leu379Gln) and c.1181A>C (p.Tyr394Ser)] were located in a 17-amino acid transcriptional inhibitory domain named C-terminal conserved inhibitory domain (CCID).\nOBJECTIVE: We investigated the ethnicity of individuals with germline variants in the <i>GCM2</i> CCID in our primary hyperparathyroidism (PHPT) patient samples and in the Genome Aggregation Database.\nDESIGN: Ethnicity information was obtained from an in-house clinical database and genetic counseling. Sanger sequencing of blood DNA was used to determine the genotype of the <i>GCM2</i> CCID region. Luciferase reporter assays were performed to determine the functional impact of <i>GCM2</i> variants.\nSETTING AND PATIENTS: National Institute of Diabetes and Digestive and Kidney Diseases endocrine clinic is a service that accepts PHPT referral patients.\nRESULTS: The <i>GCM2</i> p.Tyr394Ser variant was found in 41% [95% confidence interval (CI), 22% to 64%] of Ashkenazi Jewish (AJ) kindreds with FIHP and in 27% (95% CI, 17% to 40%) of AJ patients with sporadic PHPT. The p.Tyr394Ser variant was also found in sporadic PHPT patients of European ancestry, but at a lower prevalence. The p.Leu379Gln variant was found in 8% (95% CI, 1% to 26%) of European kindreds with FIHP and 0.5% (95% CI, 0% to 3.0%) of sporadic PHPT cases of European ancestry. The sporadic PHPT patients with <i>GCM2</i>-activating variants often had multigland involvement or postoperative recurrent or persistent disease.\nCONCLUSIONS: Specific <i>GCM2</i>-activating variants enriched among various ethnic backgrounds could contribute to a large number of cases with FIHP or sporadic PHPT.","variants":[{"Name":"NM_004752.4(GCM2):c.1181A>C (p.Tyr394Ser)","Chromosome":"6","Start":"10874335","Stop":"10874335","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":298705,"rule_based_match":true,"evidence_text":"c.1181A>C (p.Tyr394Ser)","llm_judgment":"PRESENT","evidence":"c.1181A>C (p.Tyr394Ser)","abstract_start":202,"abstract_end":225}]}
{"pmid":"21072067","title":"BEST1-related autosomal dominant vitreoretinochoroidopathy: a degenerative disease with a range of developmental ocular anomalies.","abstract":"PURPOSE: To describe the spectrum of phenotypic characteristics of BEST1-related autosomal dominant vitreoretinochoroidopathy (ADVIRC) in a family with p.V86M mutation.\nMETHODS: A retrospective review of the clinical, psychophysical, and electrophysiological phenotypes of six subjects with ADVIRC. Five family members were sequenced for mutations in the BEST1 gene.\nRESULTS: A heterozygous change, p.V86M (c.256G > A), was identified in the BEST1 gene in the three affected subjects tested, and was shown to segregate with the disease phenotype. The distance visual acuity ranged from ≥ 20/25 to absent perception of light. Clinical features observed included angle closure glaucoma (n = 2), microcornea with shallow anterior chamber (n = 1), iris dysgenesis (n = 2), cataracts (n = 4), classical peripheral concentric band of retinal hyperpigmentation (n = 5), and optic nerve dysplasia (n = 1). Full-field electroretinogram response amplitudes ranged from low normal (two cases; 27 and 32 years) to non-recordable (two cases; 42 and 63 years). Goldmann fields were normal in two (27 and 28 years) but were abnormal in two older subjects. Optical coherence tomography showed macular thinning in the proband, whereas his affected daughter had normal macular thickness. Electro-oculography showed borderline Arden's ratio (1.50) in the lone case tested (27 years).\nCONCLUSION: ADVIRC is a slowly progressive vitreoretinal degeneration that demonstrates marked intra-familial phenotypic variability. Optic nerve dysplasia and iris dysgenesis are novel observations that extend the ocular phenotype of ADVIRC.","variants":[{"Name":"NM_004183.4(BEST1):c.256G>A (p.Val86Met)","Chromosome":"11","Start":"61955726","Stop":"61955726","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17783,"rule_based_match":true,"evidence_text":"c.256G > A","llm_judgment":"PRESENT","evidence":"c.256G > A","abstract_start":407,"abstract_end":417}]}
{"pmid":"18628786","title":"Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe.","abstract":"The triple A syndrome is caused by autosomal recessively inherited mutations in the AAAS gene and is characterized by achalasia, alacrima and adrenal insufficiency as well as progressive neurological impairment. We report on a 14-year-old girl with slowly progressive axonal motor neuropathy with conspicuous muscle wasting of hypothenars and calves as well as alacrima. The mutation analysis of the AAAS gene revealed a compound heterozygous mutation: a c.251G>A mutation in exon 2 that had been reported previously, and a novel c.1288C>T mutation in exon 14. At the transcriptional level, the c.251G>A transition results in an aberrant splicing and decay of this RNA strand so that the particular clinical picture results from the novel c.1288C>T, (p.Leu430Phe, L430F) mutation in a hemizygous form. With transfection experiments, we demonstrate that GFP-ALADIN(L430F) correctly localizes to nuclear pore complexes. Therefore, we conclude that this point mutation impairs ALADIN function at the nuclear pore.","variants":[{"Name":"NM_015665.6(AAAS):c.1288C>T (p.Leu430Phe)","Chromosome":"12","Start":"53308095","Stop":"53308095","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20086,"rule_based_match":true,"evidence_text":"c.1288C>T (p.Leu430Phe, L430F)","llm_judgment":"PRESENT","evidence":"p.Leu430Phe","abstract_start":751,"abstract_end":762}]}
{"pmid":"22180149","title":"Homozygous mutation in MERTK causes severe autosomal recessive retinitis pigmentosa.","abstract":"PURPOSE: Gene identification in retinitis pigmentosa is a prerequisite to future therapies. Accordingly, autosomal recessive retinitis pigmentosa families were genotyped to search for causative mutations.\nMETHODS: Members of a consanguineous Moroccan family had standard ophthalmologic examination, optical coherence tomography-3 scan, autofluorescence testing, and electroretinogram. Their DNA was genotyped with the 250K SNP microchip (Affymetrix) and homozygosity mapping was done. MERTK exons were polymerase chain reaction amplified and sequenced.\nRESULTS: Two sisters and one brother out of 6 siblings had rod cone dystrophy type of retinitis pigmentosa. Salient features were night blindness starting in early infancy, dot-like whitish deposits in fovea and macula with corresponding autofluorescent dots in youngest patients, decreased visual acuity, and cone responses higher than rod responses at electroretinogram. The patients were homozygous in regions from chromosomes 2 and 8, but only that of chromosome 2 was inherited from a common ancestor. Sequencing of the MERTK gene belonging to the chromosome 2 region showed that the 3 affected patients carried a novel homozygous mutation in exon 17, c.2323C>T, leading to p.Arg775X, while their unaffected brothers and sister, parents, and paternal grandfather were heterozygous.\nCONCLUSIONS: MERTK mutations lead to severe retinitis pigmentosa with discrete dot-like autofluorescent deposits at early stages, which are a hallmark of this MERTK-specific dystrophy.","variants":[{"Name":"NM_006343.3(MERTK):c.2323C>T (p.Arg775Ter)","Chromosome":"2","Start":"112021555","Stop":"112021555","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45879,"rule_based_match":true,"evidence_text":"c.2323C>T","llm_judgment":"PRESENT","evidence":"c.2323C>T","abstract_start":1210,"abstract_end":1219}]}
{"pmid":"27321946","title":"Mutations in WNT10B Are Identified in Individuals with Oligodontia.","abstract":"Tooth agenesis is one of the most common developmental anomalies in humans. Oligodontia, a severe form of tooth agenesis, is genetically and phenotypically a heterogeneous condition. Although significant efforts have been made, the genetic etiology of dental agenesis remains largely unknown. In the present study, we performed whole-exome sequencing to identify the causative mutations in Chinese families in whom oligodontia segregates with dominant inheritance. We detected a heterozygous missense mutation (c.632G>A [p.Arg211Gln]) in WNT10B in all affected family members. By Sanger sequencing a cohort of 145 unrelated individuals with non-syndromic oligodontia, we identified three additional mutations (c.569C>G [p.Pro190Arg], c.786G>A [p.Trp262(∗)], and c.851T>G [p.Phe284Cys]). Interestingly, analysis of genotype-phenotype correlations revealed that mutations in WNT10B affect the development of permanent dentition, particularly the lateral incisors. Furthermore, a functional assay demonstrated that each of these mutants could not normally enhance the canonical Wnt signaling in HEPG2 epithelial cells, in which activity of the TOPFlash luciferase reporter was measured. Notably, these mutant WNT10B ligands could not efficiently induce endothelial differentiation of dental pulp stem cells. Our findings provide the identification of autosomal-dominant WNT10B mutations in individuals with oligodontia, which increases the spectrum of congenital tooth agenesis and suggests attenuated Wnt signaling in endothelial differentiation of dental pulp stem cells.","variants":[{"Name":"NM_003394.4(WNT10B):c.632G>A (p.Arg211Gln)","Chromosome":"12","Start":"48968025","Stop":"48968025","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":247468,"rule_based_match":true,"evidence_text":"c.632G>A (p.Arg211Gln)","llm_judgment":"PRESENT","evidence":"p.Arg211Gln","abstract_start":521,"abstract_end":532},{"Name":"NM_003394.4(WNT10B):c.786G>A (p.Trp262Ter)","Chromosome":"12","Start":"48966479","Stop":"48966479","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":247469,"rule_based_match":true,"evidence_text":"c.786G>A (p.Trp262(∗))","llm_judgment":"PRESENT","evidence":"c.786G>A","abstract_start":734,"abstract_end":742}]}
{"pmid":"31788332","title":"Genetic Spectrum and Variability in Chinese Patients with Amyotrophic Lateral Sclerosis.","abstract":"Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by selective impairment of upper and lower motor neurons. We aimed to investigate the genetic spectrum and variability in Chinese patients with ALS. A total of 24 familial ALS (FALS) and 21 early-onset sporadic ALS (SALS) of Chinese ancestry were enrolled. Targeted next-generation sequencing (NGS) was performed in the probands, followed by verification by Sanger sequencing and co-segregation analysis. Clinical features of patients with pathogenic or likely pathogenic variants were present. The mutation frequency of ALS-related genes was then analyzed in Chinese population. In this cohort, 17 known mutations (9 <i>SOD1</i>, 5 <i>FUS</i>, 2 <i>TARDBP</i> and one <i>SETX</i>) were identified in 14 FALS and 6 early-onset SALS. Moreover, 7 novel variants (<i>SOD1</i> c.112G>C, <i>OPTN</i> c.811C>T, <i>ERBB4</i> c.965T>A, <i>DCTN1</i> c.1915C>T, <i>NEFH</i> c.2602G>A, <i>NEK1</i> c.3622G>A, and <i>TAF15</i> c.1535G>A) were identified. In southeastern Chinese FALS, the mutation frequency of <i>SOD1</i>, <i>FUS</i>, and <i>TARDBP</i> was 52.9%, 8.8%, 8.8% respectively. In early-onset SALS, <i>FUS</i> mutations were the most common (22.6%). In Chinese ALS cases, p.H47R is most frequent <i>SOD1</i> mutations, while p.R521 is most common <i>FUS</i> mutation and p.M337V is most common <i>TARDBP</i> mutation. Our results revealed that mutations in <i>SOD1, FUS</i> and <i>TARDBP</i> are the most common cause of Chinese FALS, while <i>FUS</i> mutations are the most common cause of early-onset SALS. The genetic spectrum is different between Chinese ALS and Caucasian ALS.","variants":[{"Name":"NM_001008212.2(OPTN):c.811C>T (p.Arg271Cys)","Chromosome":"10","Start":"13122416","Stop":"13122416","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1029476,"rule_based_match":true,"evidence_text":"OPTN c.811C>T","llm_judgment":"PRESENT","evidence":"OPTN</i> c.811C>T","abstract_start":886,"abstract_end":903},{"Name":"NM_021076.4(NEFH):c.2602G>A (p.Glu868Lys)","Chromosome":"22","Start":"29490242","Stop":"29490242","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1978477,"rule_based_match":true,"evidence_text":"NEFH c.2602G>A","llm_judgment":"PRESENT","evidence":"NEFH</i> c.2602G>A","abstract_start":955,"abstract_end":973},{"Name":"NM_004082.5(DCTN1):c.1915C>T (p.Arg639Trp)","Chromosome":"2","Start":"74368071","Stop":"74368071","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2110861,"rule_based_match":true,"evidence_text":"DCTN1 c.1915C>T","llm_judgment":"PRESENT","evidence":"DCTN1</i> c.1915C>T","abstract_start":931,"abstract_end":950},{"Name":"NM_000454.5(SOD1):c.112G>C (p.Gly38Arg)","Chromosome":"21","Start":"31663829","Stop":"31663829","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":540470,"rule_based_match":true,"evidence_text":"SOD1 c.112G>C","llm_judgment":"PRESENT","evidence":"SOD1</i> c.112G>C","abstract_start":864,"abstract_end":881}]}
{"pmid":"29998021","title":"Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance.","abstract":"Familial adenomatous polyposis (FAP) is an autosomal dominant genetic condition, caused by mutations in the adenomatous polyposis coli <i>(</i>APC<i>)</i> tumor suppressor gene. Desmoid tumors (DTs) are seen in 15% to 20% of FAP patients. Specific location of mutation serves as a guide to predict colonic and extra colonic manifestations and their aggressiveness. A severe FAP-phenotypic family was registered in a genetic counselling high-risk Uruguayan hereditary cancer clinic. Proband's DNA was analysed by NGS, detecting a pathogenic mutation in APC gene. All willing family members were counselled and encouraged to be tested. Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two-base deletion mutation: c.4393_4394delAG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3' end of <i>APC</i> gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients' quality of life.","variants":[{"Name":"NM_000038.6(APC):c.4393_4394del (p.Ser1465fs)","Chromosome":"5","Start":"112839979","Stop":"112839980","ReferenceAlleleVCF":"AAG","AlternateAlleleVCF":"A","allel_id":15850,"rule_based_match":true,"evidence_text":"c.4393_4394delAG in APC gene","llm_judgment":"PRESENT","evidence":"c.4393_4394delAG in APC gene","abstract_start":748,"abstract_end":776}]}
{"pmid":"33999344","title":"Defining the molecular pathology and consequent phenotypes in Egyptian HB patients.","abstract":"BACKGROUND: Hemophilia B (HB) (also known as Christmas disease) is a rare X-linked recessive disorder characterized by spontaneous or prolonged hemorrhages caused by mutations in Factor 9 (F9) gene leading to deficient or defective coagulation F9. Our study aimed at identifying the causative mutations within a sample of HB Egyptian patients. The present study comprised clinical data of eleven HB patients descending from six unrelated families and a seventh family including a carrier mother with a history of deceased HB sibling. Sequencing of F9 gene was performed.\nRESULTS: The study revealed four mutations; two missense NM_000133.3:c.676C>G, (P.Arg226Gly) and NM_000133.3:c.1305T>G, (p.Cys435Trp), and two nonsense mutations NM_000133.3:c.880C>T, (p.Arg294*) and NM_000133.3:c.1150C>T, (p.Arg384*), identified mutations spanned exons 6 and 8 of which a total of three mutations are located in hotspot exon 8 of F9 gene.\nCONCLUSIONS: Reviewing the literature, this is the first molecular analysis of F9 gene in HB Egyptian patients. Consistent genotype/phenotypic severity correlation could be concluded, helping proper genetic counseling and prenatal decision taking.","variants":[{"Name":"NM_000133.4(F9):c.880C>T (p.Arg294Ter)","Chromosome":"X","Start":"139561565","Stop":"139561565","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25626,"rule_based_match":true,"evidence_text":"NM_000133.3:c.880C>T, (p.Arg294*)","llm_judgment":"PRESENT","evidence":"NM_000133.3:c.880C>T, (p.Arg294*)","abstract_start":733,"abstract_end":766}]}
{"pmid":"30928190","title":"Characterization of a p.R76H mutation in Cx50 identified in a Chinese family with congenital nuclear cataract.","abstract":"BACKGROUND/PURPOSE: A three-generation Chinese family with autosomal dominant congenital nuclear cataract was recruited. This study aimed to identify the disease-causing gene for nuclear cataract with functional dissections of the identified mutant.\nMETHODS: Detailed clinical data and family history were recorded. Candidate gene sequencing was performed to identify the disease-causing mutation. Recombinant connexin50 (Cx50) wild type and mutant constructs were synthesized. Triton X-100 solubility and subcellular localization of the recombinant Cx50 proteins were analyzed in HeLa cells. Apoptosis was assayed as the percentage of fragmented nuclei in transfected cells.\nRESULTS: All affected individuals in the family displayed clear phenotypes of dense nuclear cataracts. A c.227 G > A variation was found in the coding region of Cx50, which arginine residue at position 76 was substituted by histidine (p.R76H). This mutation was co-segregated with the disease in the family, and was not observed in 110 unrelated Chinese controls. No statistically significant differences were found in the Triton X-100 solubility and apoptosis rate between wild type and mutant Cx50 in HeLa cells. However, Cx50 mutant was unable to form gap junctional plaques between adjacent cells as the wild type proteins did.\nCONCLUSION: This study identified a novel cataract phenotype caused by the p.R76H mutation in Cx50, providing evidence of further phenotypic heterogeneity associated with this mutation. Functional analysis showed that the mutation affected the formation of gap junction channels and led to opacity in the lens.","variants":[{"Name":"NM_005267.5(GJA8):c.227G>A (p.Arg76His)","Chromosome":"1","Start":"147908182","Stop":"147908182","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1318969,"rule_based_match":true,"evidence_text":"c.227 G > A","llm_judgment":"PRESENT","evidence":"c.227 G > A","abstract_start":781,"abstract_end":792}]}
{"pmid":"35524216","title":"Combined therapy guided by multimodal imaging of fifteen retinal capillary hemangioblastomas in a monocular Von Hippel- Lindau syndrome case report.","abstract":"BACKGROUND: To report the multimodal imaging and treatment of fifteen retinal capillary hemangioblastomas (RCHs) associated with Von Hippel-Lindau syndrome in a monocular patient during a long-term following-up, which supply high-resolution exquisite SS-OCTA images (VG200; SVision Imaging, Ltd., Luoyang, China) and management experience about multiple RCHs.\nCASE PRESENTATION: A 34-year-old monocular male patient complained decreased visual acuity (20/100) without pain and redness in the left eye five years ago. Von Hippel-Lindau syndrome were diagnosed with genetic testing. He, his son and daughter all carried a heterozygosity missense variant c.499C > T (p. Arg167Trp) in the Hg19 gene, a VHL gene located in Chr3:10,191,506. Fifteen RCHs were identified by the application of multimodal imaging, which including fundus photo, fundus autofluorescence (FAF), B-scan ultrasonography (US), fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA) and swept-source optical coherence tomography angiography (SS-OCTA). Transscleral cryotherapy and laser photocoagulation were performed to destroy the largest RCH with the size of 4 PD in diameter. Laser photocoagulation was conducted to seal the middle or tiny RCHs (< 1.5 PD) and their nourishing vessels. The retinal edema and exudative macular detachment were successfully relieved by intraocular injection of bevacizumab for 5 times. The RCHs in the left eye responded well to these treatments and best corrected visual acuity was 20/25 for three years. Three-month recall visits were recommended for him.\nCONCLUSION: For multiple retinal capillary hemangioblastomas in monocular patients, precise combined therapy guided by multimodal imaging has a profound impact on the management of new and recurrent RCHs.","variants":[{"Name":"NM_000551.4(VHL):c.499C>T (p.Arg167Trp)","Chromosome":"3","Start":"10149822","Stop":"10149822","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17257,"rule_based_match":true,"evidence_text":"c.499C > T (p. Arg167Trp)","llm_judgment":"PRESENT","evidence":"c.499C > T (p. Arg167Trp)","abstract_start":652,"abstract_end":677}]}
{"pmid":"29486744","title":"Exome sequencing reveals a novel PLP1 mutation in a Moroccan family with connatal Pelizaeus-Merzbacher disease: a case report.","abstract":"BACKGROUND: Epilepsy regroups a common and diverse set of chronic neurological disorders that are characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Epilepsies have a highly heterogeneous background with a strong genetic contribution and various mode of inheritance. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy. The variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the causal genetic mutation, making diagnosis, genetic counseling and treatment decisions difficult. We report the description of a Moroccan family referred to our genetic department with X-linked epileptic seizures as the only initial diagnosis.\nCASE PRESENTATION: Knowing the new contribution of Next-Generation Sequencing (NGS) for clinical investigation, and given the heterogeneity of this group of disorders we performed a Whole-Exome Sequencing (WES) analysis and co-segregation study in several members of this large family. We detected a novel pathogenic PLP1 missense mutation c.251C > A (p.Ala84Asp) allowing us to make a diagnosis of Pelizaeus-Merzbacher Disease for this family.\nCONCLUSION: This report extends the spectrum of PLP1 mutations and highlights the diagnostic utility of NGS to investigate this group of heterogeneous disorders.","variants":[{"Name":"NM_000533.5(PLP1):c.251C>A (p.Ala84Asp)","Chromosome":"X","Start":"103786524","Stop":"103786524","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3839252,"rule_based_match":true,"evidence_text":"c.251C > A (p.Ala84Asp)","llm_judgment":"PRESENT","evidence":"c.251C > A (p.Ala84Asp)","abstract_start":1077,"abstract_end":1100}]}
{"pmid":"36478253","title":"X-linked hyper-immunoglobulin M syndrome harboring a novel CD40-ligand gene mutation: a case report.","abstract":"The X-linked hyper-IgM syndrome (X-HIGM1) is a rare primary immunodeficiency disorder (PID) caused by mutations in the gene encoding the CD154 protein, also known as CD40 ligand (CD40LG). X-HIGM1 is characterized by normal or elevated serum levels of IgM in association with decreased levels of IgG, IgA, and IgE. The CD40LG protein expressed on activated T cells interacts with its receptor protein, CD40, on B lymphocytes and dendritic cells. Mutations in the CD40LG gene lead to the production of an abnormal CD40L protein that fails to attach to its receptor, CD40 on B cells resulting in failure to produce IgG, IgA, and IgE antibodies. In the present study, we investigated the molecular defects underlying such a PID in a patient presenting with clinical history of pneumonia and acute respiratory distress syndrome (ARDS) at 7 months of age and diagnosed as transient hypogammaglobulinemia with decreased levels of IgG and increased levels of IgM. We have identified a novel and yet to be reported frame shift deletion of a single base pair (c.229delA) in exon 2 (p.Arg77AspfsTer6) of the CD40L gene ensuing the premature truncation of the protein by 6 amino acids by targeted gene sequencing. This frame shift mutation identified as a CD40L variant was found to be pathogenic which was also validated by Sanger sequencing. The in-silico analysis of c.229 del A mutation also predicted the change to be pathological affecting the structure and function of the CD40L (CD40L, CD154) protein and its protein-protein interaction properties.","variants":[{"Name":"NM_000074.3(CD40LG):c.229del (p.Arg77fs)","Chromosome":"X","Start":"136650336","Stop":"136650336","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1860818,"rule_based_match":true,"evidence_text":"c.229delA","llm_judgment":"PRESENT","evidence":"c.229delA","abstract_start":1050,"abstract_end":1059}]}
{"pmid":"29260357","title":"Mutations outside the N-terminal part of RBCK1 may cause polyglucosan body myopathy with immunological dysfunction: expanding the genotype-phenotype spectrum.","abstract":"A subset of patients with polyglucosan body myopathy was found to have underlying mutations in the RBCK1 gene. Affected patients may display diverse symptoms ranging from skeletal muscular weakness, cardiomyopathy to chronic autoinflammation and immunodeficiency. It was suggested that the exact localization of the mutation within the gene might be responsible for the specific phenotype, with N-terminal mutations causing severe immunological dysfunction and mutations in the middle or C-terminal part leading to a myopathy phenotype. We report the clinical, immunological and genetic findings of two unrelated individuals suffering from a childhood-onset RBCK1-asscociated disease caused by the same homozygous truncating mutation (NM_031229.2:c.896_899del, p.Glu299Valfs*46) in the middle part of the RBCK1 gene. Our patients suffered from a myopathy with cardiac involvement, but in contrast to previous reports on mutations in this part of the gene, also displayed signs of autoinflammation and immunodeficiency. Our report suggests that RBCK1 mutations at locations that were previously thought to lack immunological features may also present with immunological dysfunction later in the disease course. This notably broadens the genotype-phenotype correlation of RBCK1-related polyglucosan body myopathy.","variants":[{"Name":"NM_031229.4(RBCK1):c.896_899del (p.Glu299fs)","Chromosome":"20","Start":"421007","Stop":"421010","ReferenceAlleleVCF":"CGTGA","AlternateAlleleVCF":"C","allel_id":150328,"rule_based_match":true,"evidence_text":"NM_031229.2:c.896_899del","llm_judgment":"PRESENT","evidence":"NM_031229.2:c.896_899del","abstract_start":735,"abstract_end":759}]}
{"pmid":"23557332","title":"Mucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfase.","abstract":"BACKGROUND: Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; MPS VI) is an autosomal recessive lysosomal storage disorder in which deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) leads to the storage of glycosaminoglycans (GAGs) in connective tissue. The genotype-phenotype correlation has been addressed in several publications but the picture is not complete. Since 2007, enzyme-replacement therapy (ERT) has been available for patients with MPS VI in the Netherlands. The purpose of our study was to learn more about the genotype-phenotype correlations in MPS VI and the antibody response to ERT with galsulfase (recombinant human arylsulfatase B).\nMETHODS: We identified ARSB mutations in 12 patients and used site-directed mutagenesis to study their effect. Antibody levels to galsulfase were measured using ELISA and a semi-quantitative immunoprecipitation method. We assessed the in vitro inhibitory effect of antibodies on galsulfase uptake and their effect on clinical outcome.\nRESULTS: Five patients had a rapidly progressive phenotype and seven a slowly progressive phenotype. In total 9 pathogenic mutations were identified including 4 novel mutations (N301K, V332G, A237D, and c.1142 + 2 T > C) together composing 8 pathogenic genotypes. Most mutations appeared not to affect the synthesis of ARSB (66 kD precursor), but to hamper its maturation (43 kD ARSB). Disease severity was correlated with urinary GAG excretion. All patients developed antibodies to galsulfase within 26 weeks of treatment. It was demonstrated that these antibodies can inhibit the uptake of galsulfase in vitro.\nCONCLUSIONS: The clinical phenotypes and the observed defects in the biosynthesis of ARSB show that some of the mutations that we identified are clearly more severe than others. Patients receiving galsulfase as enzyme-replacement therapy can develop antibodies towards the therapeutic protein. Though most titers are modest, they can exceed a level at which they potentially affect the clinical outcome of enzyme-replacement therapy.","variants":[{"Name":"NM_000046.5(ARSB):c.1142+2T>C","Chromosome":"5","Start":"78885582","Stop":"78885582","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":550431,"rule_based_match":true,"evidence_text":"c.1142 + 2 T > C","llm_judgment":"PRESENT","evidence":"c.1142 + 2 T > C","abstract_start":1221,"abstract_end":1237}]}
{"pmid":"28443597","title":"A Different SLC2A1 Gene Mutation in Glut 1 Deficiency Syndrome: c.734A>C.","abstract":"BACKGROUND: Glucose transporter type 1 deficiency syndrome is the result of impaired glucose transport into the brain. Patients with glucose transporter type 1 syndrome may present with infantile seizures, developmental delay, acquired microcephaly, spasticity and ataxia.\nCASE REPORT: Here, we report a rare case of glucose transporter type 1 deficiency syndrome caused by a different pathogenic variant in a 10-day-old neonate who presented with intractable seizures and respiratory arrest.\nCONCLUSION: This new pathogenic variant can be seen in glucose transporter type 1 deficiency syndrome.","variants":[{"Name":"NM_006516.4(SLC2A1):c.734A>C (p.Lys245Thr)","Chromosome":"1","Start":"42929726","Stop":"42929726","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2898215,"rule_based_match":true,"evidence_text":"c.734A>C","llm_judgment":"PRESENT","evidence":"c.734A>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"8673113","title":"A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria.","abstract":"Variegate porphyria (VP), a low-penetrant autosomal dominant inherited disorder of haem metabolism, is characterised by photosensitivity (Fig. 1) and a propensity to develop acute neuropsychiatric attacks with abdominal pain, vomiting, constipation, tachycardia, hypertension, psychiatric symptoms and, in the worst cases, quadriplegia. Acute attacks, often precipitated by inappropriate drug therapy, are potentially fatal. While earlier workers thought the distal haem biosynthetic enzyme ferrochelatase may be involved in the genesis of VP, it was shown in the early 1980's, and is now accepted, that VP is associated with decreased protoporphyrinogen oxidase activity (PPO) (E.C.1.3.3.4). VP prevalence is much higher in South Africa than elsewhere; probably due to a founder effect with patients descending from a 17th century Dutch immigrant. PPO cDNAs from Bacillus subtilis, Myxococcus xanthus, human placenta and mouse liver have been cloned, sequenced and expressed. Human and mouse cDNAs consist of open reading frames 1431 nucleotides long, encoding a 477 amino acid protein. The human PPO gene contains thirteen exons, spanning approximately 4.5 kb. We have identified a C to T transition in codon 59 (in exon 3) resulting in an arginine to tryptophan substitution (R59W). A protein expressed from an in vitro-mutagenized PPO construct exhibits substantially less activity than the wild type. The R59W mutation was present in 43 of 45 patients with VP from 26 of 27 South African families investigated, but not in 34 unaffected relatives or 9 unrelated British patients with PPO deficiency. Since at least one of these families is descended from the founder of South African VP, this defect may represent the founder gene defect associated causally with VP in South Africa.","variants":[{"Name":"NM_001122764.3(PPOX):c.175C>T (p.Arg59Trp)","Chromosome":"1","Start":"161167187","Stop":"161167187","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23735,"rule_based_match":false,"evidence_text":"C to T transition in codon 59 (in exon 3) resulting in an arginine to tryptophan substitution (R59W)","llm_judgment":"PRESENT","evidence":"C to T transition in codon 59 (in exon 3) resulting in an arginine to tryptophan substitution (R59W)","abstract_start":1184,"abstract_end":1284}]}
{"pmid":"21046548","title":"A novel mutation in COCH-implications for genotype-phenotype correlations in DFNA9 hearing loss.","abstract":"OBJECTIVES/HYPOTHESIS: To determine the cause of autosomal dominant hearing loss segregating in an American family.\nSTUDY DESIGN: Family study.\nMETHODS: Otologic and audiometric examination was performed on affected family members. Genome wide parametric multipoint linkage mapping using a dominant model was performed with Affymetrix 50K GeneChip data. Direct sequencing was used to confirm the causative mutation.\nRESULTS: In American family 467, segregating autosomal dominant nonsyndromic hearing loss, a novel heterozygous missense mutation (c.362T>C; p.F121S) was identified in the COCH gene. This mutation was also associated with vestibular dysfunction typical of other DFNA9 families. However, affected family members also exhibited memory loss and night blindness.\nCONCLUSIONS: The novel COCH mutation affects the functionally important limulus factor C, Coch-5b2 and Lgl1 domain where most DFNA9 mutations have been localized. The onset of the hearing loss, in the 2nd or 3rd decade of life, is earlier than in most DFNA9 families. The progression of hearing loss and vestibular dysfunction in the American family is typical of other DFNA9 families with mutations in this domain. Memory loss and night blindness have not been previously reported in DFNA9 families.","variants":[{"Name":"NM_004086.3(COCH):c.362T>C (p.Phe121Ser)","Chromosome":"14","Start":"30878933","Stop":"30878933","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2894800,"rule_based_match":true,"evidence_text":"c.362T>C (p.F121S)","llm_judgment":"PRESENT","evidence":"c.362T>C","abstract_start":547,"abstract_end":555}]}
{"pmid":"18521937","title":"Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia.","abstract":"CNGA3 encodes the A-subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel, which is a crucial component of the phototransduction cascade in cone outer segments. Mutations in the CNGA3 gene have been associated with complete and incomplete forms of achromatopsia (ACHR), a congenital, autosomal recessively inherited retinal disorder characterized by lack of color discrimination, reduced visual acuity, nystagmus, and photophobia. Here we report the identification of three novel CNGA3 missense mutations in ACHR patients: c.682G>A (p.E228 K), c.1315C>T (p.R439W), and c.1405G>A (p.A469 T), and the detailed functional analyses of these new as well as five previously reported mutations (R283Q, T291R, F547L, G557R, and E590 K), in conjunction with clinical data of patients carrying these mutations, to establish genotype-phenotype correlations. The functional characterization of mutant CNGA3 channels was performed with calcium imaging and patch clamp recordings in a heterologous HEK293 cell expression system. Results were corroborated by immunostaining and colocalization experiments of the channel protein with the plasma membrane. Several mutations evoked pronounced alterations of the apparent cGMP sensitivity of mutant channels. These functional defects were fully or partially compensated by coexpressing the mutant CNGA3 subunit with the wild-type CNGB3 subunit for channels with the mutations R439W, A469 T, F547L, and E590 K. We could show that several mutant channels with agonist dose-response relationships similar to the wild-type exhibited severely impaired membrane targeting. In addition, this study presents the positive effect of reduced cell culture temperature on surface expression and functional performance of mutant CNG channels with protein folding or trafficking defects.","variants":[{"Name":"NM_001298.3(CNGA3):c.1405G>A (p.Ala469Thr)","Chromosome":"2","Start":"98396575","Stop":"98396575","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":431657,"rule_based_match":true,"evidence_text":"c.1405G>A (p.A469 T)","llm_judgment":"PRESENT","evidence":"c.1405G>A (p.A469 T)","abstract_start":587,"abstract_end":607},{"Name":"NM_001298.3(CNGA3):c.682G>A (p.Glu228Lys)","Chromosome":"2","Start":"98395852","Stop":"98395852","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":288469,"rule_based_match":true,"evidence_text":"c.682G>A (p.E228 K)","llm_judgment":"PRESENT","evidence":"c.682G>A (p.E228 K)","abstract_start":541,"abstract_end":560},{"Name":"NM_001298.3(CNGA3):c.1315C>T (p.Arg439Trp)","Chromosome":"2","Start":"98396485","Stop":"98396485","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":827192,"rule_based_match":true,"evidence_text":"c.1315C>T (p.R439W)","llm_judgment":"PRESENT","evidence":"c.1315C>T (p.R439W)","abstract_start":562,"abstract_end":581}]}
{"pmid":"33325104","title":"Brown-Vialetto-Van Laere and Fazio-Londe syndromes: SLC52A3 mutations with puzzling phenotypes and inheritance.","abstract":"BACKGROUND: Brown-Vialetto-Van Laere syndrome (BVVLS) and Fazio-Londe disease (FLD) are rare neurological disorders presenting with pontobulbar palsy, muscle weakness and respiratory insufficiency. Mutations in SLC52A2 (hRFVT-2) or SLC52A3 (hRFVT-3) genes can be responsible for these disorders with an autosomal recessive pattern of inheritance. The aim of this study was to screen for mutations in SLC52A2 and SLC52A3 among Indian families diagnosed with BVVLS and FLD.\nMETHODS: SLC52A2 and SLC52A3 were screened in one FLD and three BVVLS patients by exon-specific amplification using PCR and sequencing. In silico predictions using bioinformatics tools and confocal imaging using HEK-293 cells were performed to determine the functional impact of identified mutations.\nRESULTS: Genetic analysis of a mother and son with BVVLS was identified with a novel homozygous mutation c.710C>T (p.Ala237Val) in SLC52A3. This variant was found to have an autosomal pseudodominant pattern of inheritance, which was neither listed in the Exome Variant Server or in the 1000 Genomes Project database. In silico analysis and confocal imaging of the p.Ala237Val variant showed higher degree of disorderness in hRFVT-3 that could affect riboflavin transport. Furthermore, a common homozygous mutation c.62A>G (p.Asn21Ser) was identified in other BVVLS and FLD patients. Despite having different clinical phenotypes, both BVVLS and FLD can be attributed to this mutation.\nCONCLUSION: A rare and peculiar pattern of autosomal pseudodominant inheritance is observed for the first time in two genetically related BVVLS cases with Indian origin and a common mutation c.62A>G (p.Asn21Ser) in SLC52A3 can be responsible for both BVVLS and FLD with variable phenotypes.","variants":[{"Name":"NM_033409.4(SLC52A3):c.710C>T (p.Ala237Val)","Chromosome":"20","Start":"763861","Stop":"763861","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1305833,"rule_based_match":true,"evidence_text":"c.710C>T (p.Ala237Val)","llm_judgment":"PRESENT","evidence":"c.710C>T (p.Ala237Val)","abstract_start":878,"abstract_end":900},{"Name":"NM_033409.4(SLC52A3):c.62A>G (p.Asn21Ser)","Chromosome":"20","Start":"765713","Stop":"765713","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":206629,"rule_based_match":true,"evidence_text":"c.62A>G (p.Asn21Ser)","llm_judgment":"PRESENT","evidence":"c.62A>G (p.Asn21Ser)","abstract_start":1287,"abstract_end":1307}]}
{"pmid":"34007417","title":"Prevalence and Molecular Characterization of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency in Females from Previously Malaria Endemic Regions in Northeastern Thailand and Identification of a Novel G6PD Variant.","abstract":"INTRODUCTION: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common X-linked enzymopathy, highly prevalent in the areas where malaria is or has been endemic. Prevalence of G6PD deficiency and characterization of G6PD variants in females from previously malaria-endemic areas of northeastern Thailand remain unstudied.\nMETHODS: Prevalence of G6PD deficiency was determined by a fluorescent spot test (FST), quantitative G6PD activity assay, and multiplex allele-specific (AS)- and restriction fragment length polymorphic (RFLP)-PCR developed for detection of common G6PD variants in the Thai population.\nRESULTS: Prevalence of G6PD deficiency in female samples (n = 355) was 18% by FST, 29.6% by quantitation of G6PD activity, and 28.1% by PCR-based genotyping. The most common variant was G6PD Viangchan (54%), followed by G6PD Canton (11%) and G6PD Union (11%); in addition, a novel heterozygous variant, G6PD Khon Kaen (c.305T>C, p.F102S), was identified. The majority of heterozygotes expressed G6PD activity within the intermediate deficiency range (30-70% median of normal enzyme activity).\nCONCLUSION: High prevalence of G6PD deficiency was present in females from northeastern Thailand, the majority being due to heterozygosity of G6PD variants. The findings will have a bearing on the inclusion of primaquine in antimalarial-based policies for malaria elimination in populations with a high prevalence of G6PD deficiency.","variants":[{"Name":"NM_001360016.2(G6PD):c.305T>C (p.Phe102Ser)","Chromosome":"X","Start":"154535348","Stop":"154535348","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":270373,"rule_based_match":true,"evidence_text":"G6PD Khon Kaen (c.305T>C, p.F102S)","llm_judgment":"PRESENT","evidence":"G6PD Khon Kaen (c.305T>C, p.F102S)","abstract_start":923,"abstract_end":957}]}
{"pmid":"33706081","title":"A novel GPIHBP1 mutation related to familial chylomicronemia syndrome: A series of cases.","abstract":"BACKGROUND AND AIMS: GPIHBP1 is an accessory protein of lipoprotein lipase (LPL) essential for its functioning. Mutations in the GPIHBP1 gene cause a deficit in the action of LPL, leading to severe hypertriglyceridemia and increased risk for acute pancreatitis.\nMETHODS: We describe twelve patients (nine women) with a novel homozygous mutation in intron 2 of the GPIHBP1 gene.\nRESULTS: All patients were from the Northeastern region of Brazil and presented the same homozygous variant located in a highly conserved 3' splicing acceptor site of the GPIHBP1 gene. This new variant was named c.182-1G > T, according to HGVS recommendations. We verified this new GPIHBP1 variant's effect by using the Human Splicing Finder (HSF) tool. This mutation changes the GPIHBP1 pre-mRNA processing and possibly causes the skipping of the exon 3 of the GPIHBP1 gene, affecting almost 50% of the cysteine-rich Lys6 GPIHBP1 domain. Patients presented with severe hypertriglyceridemia (2351 mg/dl [885-20600]) and low HDL (18 mg/dl [5-41). Four patients (33%) had a previous history of acute pancreatitis.\nCONCLUSIONS: We describe a novel GPIHBP1 pathogenic intronic mutation of patients from the Northeast region of Brazil, suggesting the occurrence of a founder effect.","variants":[{"Name":"NM_178172.6(GPIHBP1):c.182-1G>T","Chromosome":"8","Start":"143215012","Stop":"143215012","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1677873,"rule_based_match":true,"evidence_text":"c.182-1G > T","llm_judgment":"PRESENT","evidence":"c.182-1G > T","abstract_start":590,"abstract_end":602}]}
{"pmid":"28276523","title":"Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype.","abstract":"Loss-of-function mutations in the WRN helicase gene cause Werner syndrome- a progeroid syndrome with an elevated risk of cancer and other age-associated diseases. Large numbers of single nucleotide polymorphisms have been identified in WRN. We report here the organismal, cellular, and molecular phenotypes of variant rs3087425 (c. 2500C > T) that results in an arginine to cysteine substitution at residue 834 (R834C) and up to 90% reduction of WRN helicase activity. This variant is present at a high (5%) frequency in Mexico, where we identified 153 heterozygous and three homozygous individuals among 3,130 genotyped subjects. Family studies of probands identified ten additional TT homozygotes. Biochemical analysis of WRN protein purified from TT lymphoblast cell lines confirmed that the R834C substitution strongly and selectively reduces WRN helicase, but not exonuclease activity. Replication track analyses showed reduced replication fork progression in some homozygous cells following DNA replication stress. Among the thirteen TT homozygotes, we identified a previously unreported and statistically significant gender bias in favor of males (p = 0.0016), but none of the clinical findings associated with Werner syndrome. Our results indicate that WRN helicase activity alone is not rate-limiting for the development of clinical WS.","variants":[{"Name":"NM_000553.6(WRN):c.2500C>T (p.Arg834Cys)","Chromosome":"8","Start":"31120294","Stop":"31120294","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":47491,"rule_based_match":true,"evidence_text":"c. 2500C > T","llm_judgment":"PRESENT","evidence":"c. 2500C > T","abstract_start":329,"abstract_end":341}]}
{"pmid":"32047639","title":"A novel nonsense mutation of","abstract":"Xeroderma pigmentosum (XP) group D, a severe disease often typified by extreme sun sensitivity, can be caused by <i>ERCC2</i> mutations. <i>ERCC2</i> encodes an adenosine triphosphate (ATP)-dependent DNA helicase, namely XP group D protein (XPD). The XPD, one of ten subunits of the transcription factor TFIIH, plays a critical role in the nucleotide-excision repair (NER) pathway. Mutations in XPD that affect the NER pathway can lead to neurological degeneration and skin cancer, which are the most common causes of death in XP patients. Here, we present detailed phenotypic information on a Vietnamese family in which four members were affected by XP with extreme sun sensitivity. Genomic analysis revealed a compound heterozygous mutation of <i>ERCC2</i> that affected family members and single heterozygous mutations in unaffected family members. We identified a novel, nonsense mutation in one allele of <i>ERCC2</i> (c.1354C > T, p.Q452X) and a known missense mutation in the other allele (c.2048G > A, p.R683Q). Fibroblasts isolated from the compound heterozygous subject also failed to recover from UV-driven DNA damage, thus recapitulating aspects of XP syndrome in vitro. We describe a novel <i>ERCC2</i> variant that leads to the breakdown of the NER pathway across generations of a family presenting with severe XP.","variants":[{"Name":"NM_000400.4(ERCC2):c.1354C>T (p.Gln452Ter)","Chromosome":"19","Start":"45357497","Stop":"45357497","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1441569,"rule_based_match":true,"evidence_text":"c.1354C > T, p.Q452X","llm_judgment":"PRESENT","evidence":"c.1354C > T, p.Q452X","abstract_start":924,"abstract_end":944},{"Name":"NM_000400.4(ERCC2):c.2048G>A (p.Arg683Gln)","Chromosome":"19","Start":"45352351","Stop":"45352351","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259254,"rule_based_match":true,"evidence_text":"c.2048G > A, p.R683Q","llm_judgment":"PRESENT","evidence":"c.2048G > A, p.R683Q","abstract_start":997,"abstract_end":1017}]}
{"pmid":"17171432","title":"A new infantile case of alpha-N-acetylgalactosaminidase deficiency. Cardiomyopathy as a presenting symptom.","abstract":"alpha-N-Acetylgalactosaminidase deficiency is a lysosomal disorder with clinically very different infantile and adult forms. To date, 12 patients from eight families are known. Neuroaxonal dystrophy or moderate psychomotor retardation, without visceral involvement, have been reported in the infantile form. We describe a new Spanish patient with Schindler disease who presented with hepatomegaly and cardiomyopathy, traits not previously associated with this disease. There was no dysmorphism or neurological involvement in the patient, who died at the age of 8 months. alpha-N-Acetylgalactosaminidase activity was reduced in fibroblasts and liver to 1.6% and 0.57% of controls, respectively. Several lysosomal enzyme activities associated with infantile cardiomyopathy were found in the normal ranges. The patient was a compound heterozygote for the novel mutation p.D217N (c.649G>A) in exon 6 and the already reported mutation p.E325K (c.973G>A) in exon 8. The description of this new case broadens the clinical spectrum of the infantile forms and indicates that Schindler disease should be considered in the diagnosis of metabolic cardiomyopathies.","variants":[{"Name":"NM_000262.3(NAGA):c.973G>A (p.Glu325Lys)","Chromosome":"22","Start":"42061052","Stop":"42061052","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33201,"rule_based_match":true,"evidence_text":"p.E325K (c.973G>A)","llm_judgment":"PRESENT","evidence":"p.E325K (c.973G>A)","abstract_start":930,"abstract_end":948}]}
{"pmid":"28328139","title":"Long term survival of a patient with Perlman syndrome due to novel compound heterozygous missense mutations in RNB domain of DIS3L2.","abstract":"Perlman syndrome is a rare overgrowth syndrome characterized by polyhydramnios, macrosomia, distinctive facial appearance, renal dysplasia, and a predisposition to Wilms' tumor. The syndrome is often associated with a high neonatal mortality rate and there are few reports of long-term survivors. We studied a 6-year-old Japanese female patient, who was diagnosed with Perlman syndrome, with novel compound heterozygous mutations in DIS3L2 (c.[367-2A > G];[1328T > A]), who has survived long term. Most reported DIS3L2 mutations have been the homozygous deletion of exon 6 or exon 9, and these mutations would certainly have caused the loss of both RNA binding and degradation activity. We have identified new compound heterozygous mutations in the DIS3L2 of this long-term survivor of Perlman syndrome. The reason our patient has survived long-term would be a missense mutation (c.1328 T > A, p.Met443Lys) having retained RNA binding in both the cold-shock domains and the S1 domain, and through partial RNA degradation. If partial exonuclease functions remain in at least one allele, long-term survival may be possible. Further studies of Perlman syndrome patients with proven DIS3L2 mutations are needed to clarify genotype-phenotype correlation.","variants":[{"Name":"NM_152383.5(DIS3L2):c.367-2A>G","Chromosome":"2","Start":"232087485","Stop":"232087485","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2894466,"rule_based_match":false,"evidence_text":"c.[367-2A > G]","llm_judgment":"PRESENT","evidence":"c.[367-2A > G]","abstract_start":441,"abstract_end":455}]}
{"pmid":"30414308","title":"Identification of a variant associated with early-onset diabetes in the intron of the insulin gene with exome sequencing.","abstract":"Whole-exome sequencing is a new technology. We used it to explore the gene responsible for early-onset diabetes as a result of impaired insulin secretion in a family. In the INS gene, we identified the heterozygous c.188-31G>A mutation in the proband - a 43-year-old woman. The mutation was also identified in her two daughters with diabetes, but not in her son or her parents, all of whom did not have diabetes. The substitution was located 31 bp proximal to exon 3 in intron 2. It was predicted to create an ectopic splice site leading to inserting 29 nucleotides of intron 2 as an exonic sequence in the transcript. The mutation has been reported in White families, and the present case is the first report in an Asian person. The present results would help in understanding the role of the mutation in developing diabetes.","variants":[{"Name":"NM_000207.3(INS):c.188-31G>A","Chromosome":"11","Start":"2160028","Stop":"2160028","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":207862,"rule_based_match":true,"evidence_text":"c.188-31G>A","llm_judgment":"PRESENT","evidence":"c.188-31G>A","abstract_start":215,"abstract_end":226}]}
{"pmid":"24547928","title":"Advantage of Whole Exome Sequencing over Allele-Specific and Targeted Segment Sequencing in Detection of Novel TULP1 Mutation in Leber Congenital Amaurosis.","abstract":"BACKGROUND: Leber congenital amaurosis (LCA) is a severe form of retinal dystrophy with marked underlying genetic heterogeneity. Until recently, allele-specific assays and Sanger sequencing of targeted segments were the only available approaches for attempted genetic diagnosis in this condition. A broader next-generation sequencing (NGS) strategy, such as whole exome sequencing, provides an improved molecular genetic diagnostic capacity for patients with these conditions.\nMATERIALS AND METHODS: In a child with LCA, an allele-specific assay analyzing 135 known LCA-causing variations, followed by targeted segment sequencing of 61 regions in 14 causative genes was performed. Subsequently, exome sequencing was undertaken in the proband, unaffected consanguineous parents and two unaffected siblings. Bioinformatic analysis used two independent pipelines, BWA-GATK and SOAP, followed by Annovar and SnpEff to annotate the variants.\nRESULTS: No disease-causing variants were found using the allele-specific or targeted segment Sanger sequencing assays. Analysis of variants in the exome sequence data revealed a novel homozygous nonsense mutation (c.1081C > T, p.Arg361*) in TULP1, a gene with roles in photoreceptor function where mutations were previously shown to cause LCA and retinitis pigmentosa. The identified homozygous variant was the top candidate using both bioinformatic pipelines.\nCONCLUSIONS: This study highlights the value of the broad sequencing strategy of exome sequencing for disease gene identification in LCA, over other existing methods. NGS is particularly beneficial in LCA where there are a large number of causative disease genes, few distinguishing clinical features for precise candidate disease gene selection, and few mutation hotspots in any of the known disease genes.","variants":[{"Name":"NM_003322.6(TULP1):c.1081C>T (p.Arg361Ter)","Chromosome":"6","Start":"35505772","Stop":"35505772","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1867847,"rule_based_match":true,"evidence_text":"c.1081C > T, p.Arg361*","llm_judgment":"PRESENT","evidence":"c.1081C > T, p.Arg361*","abstract_start":1152,"abstract_end":1174}]}
{"pmid":"25963545","title":"Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.","abstract":"BACKGROUND: Adams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS.\nMETHODS AND RESULTS: Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway.\nCONCLUSIONS: These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders.","variants":[{"Name":"NM_017617.5(NOTCH1):c.6049_6050del (p.Ser2017fs)","Chromosome":"9","Start":"136499144","Stop":"136499145","ReferenceAlleleVCF":"TGA","AlternateAlleleVCF":"T","allel_id":221062,"rule_based_match":true,"evidence_text":"c.6049_6050delTC","llm_judgment":"PRESENT","evidence":"c.6049_6050delTC","abstract_start":641,"abstract_end":657},{"Name":"NM_017617.5(NOTCH1):c.1649dup (p.Tyr550Ter)","Chromosome":"9","Start":"136516000","Stop":"136516001","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":221067,"rule_based_match":true,"evidence_text":"c.1649dupA","llm_judgment":"PRESENT","evidence":"c.1649dupA","abstract_start":626,"abstract_end":636}]}
{"pmid":"23830518","title":"Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability.","abstract":"Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism.","variants":[{"Name":"NM_021942.6(TRAPPC11):c.2938G>A (p.Gly980Arg)","Chromosome":"4","Start":"183701783","Stop":"183701783","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":75097,"rule_based_match":true,"evidence_text":"c.2938G>A (p.Gly980Arg)","llm_judgment":"PRESENT","evidence":"c.2938G>A (p.Gly980Arg)","abstract_start":649,"abstract_end":672},{"Name":"NM_021942.6(TRAPPC11):c.1287+5G>A","Chromosome":"4","Start":"183684059","Stop":"183684059","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":75098,"rule_based_match":true,"evidence_text":"c.1287+5G>A","llm_judgment":"PRESENT","evidence":"c.1287+5G>A","abstract_start":773,"abstract_end":784}]}
{"pmid":"28554942","title":"MSTO1 is a cytoplasmic pro-mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans.","abstract":"The protein MSTO1 has been localized to mitochondria and linked to mitochondrial morphology, but its specific role has remained unclear. We identified a c.22G > A (p.Val8Met) mutation of MSTO1 in patients with minor physical abnormalities, myopathy, ataxia, and neurodevelopmental impairments. Lactate stress test and myopathological results suggest mitochondrial dysfunction. In patient fibroblasts, MSTO1 mRNA and protein abundance are decreased, mitochondria display fragmentation, aggregation, and decreased network continuity and fusion activity. These characteristics can be reversed by genetic rescue. Short-term silencing of MSTO1 in HeLa cells reproduced the impairment of mitochondrial morphology and dynamics observed in the fibroblasts without damaging bioenergetics. At variance with a previous report, we find MSTO1 to be localized in the cytoplasmic area with limited colocalization with mitochondria. MSTO1 interacts with the fusion machinery as a soluble factor at the cytoplasm-mitochondrial outer membrane interface. After plasma membrane permeabilization, MSTO1 is released from the cells. Thus, an MSTO1 loss-of-function mutation is associated with a human disorder showing mitochondrial involvement. MSTO1 likely has a physiologically relevant role in mitochondrial morphogenesis by supporting mitochondrial fusion.","variants":[{"Name":"NM_018116.4(MSTO1):c.22G>A (p.Val8Met)","Chromosome":"1","Start":"155610270","Stop":"155610270","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432468,"rule_based_match":true,"evidence_text":"c.22G > A (p.Val8Met)","llm_judgment":"PRESENT","evidence":"c.22G > A (p.Val8Met)","abstract_start":153,"abstract_end":174}]}
{"pmid":"26081292","title":"Shwachman-Diamond syndrome (SDS) in a preterm neonate.","abstract":"A preterm neonate at 29-week gestational age was born with intrauterine growth restriction, severe pancytopaenia and gross skeletal dysplasia. Antenatal screening bloods, TORCH/parvovirus tests and karyotype were unremarkable. Postnatally, he had normal microarray comparative genomic hybridization and serum B12/folate levels, and human immunodeficiency virus and cytomegalovirus polymerase chain reaction and antoimmune screening were negative. Targeted gene testing for Shwachman-Diamond syndrome (SDS) revealed the pathognomic mutation (c.183_184delTAinsCT). His postnatal clinical course was complicated by: (i) Ventilator dependency because of a combination of a pathologically compliant chest wall and preterm-associated chronic lung disease. (ii) Progressive bone marrow failure, resulting in transfusion dependence and profound neutropenia associated with recurrent sepsis. (iii) Gastrointestinal failure and TPN dependency. (iv) Poor postnatal growth with weight/length/head circumference all <3rd centile. (v) Prognostication was complicated by the lack of published literature on the presentation of SDS in a preterm infant. However, because of inexorable progression of multiorgan failure, intensive care was withdrawn on day 54 of life. SDS is a rare autosomal recessive disorder characterised by haematological abnormalities, skeletal dysplasia and exocrine pancreatic dysfunction. Neonatal presentation is thought to be extremely rare. However, with the availability of genetic testing, it has now become clear that because of overlap in clinical presentation, term-born infants with skeletal dysplasia and severe respiratory distress may initially be misdiagnosed as asphyxiating thoracic dystrophy. This case report highlights the complexities of preterm birth complicating clinical manifestations of SDS.","variants":[{"Name":"NM_016038.4(SBDS):c.183_184delinsCT (p.Lys62Ter)","Chromosome":"7","Start":"66994286","Stop":"66994287","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"AG","allel_id":18234,"rule_based_match":false,"evidence_text":"c.183_184delTAinsCT","llm_judgment":"PRESENT","evidence":"c.183_184delTAinsCT","abstract_start":541,"abstract_end":560}]}
{"pmid":"35916082","title":"Deep intronic variant in MVK as a cause for mevalonic aciduria initially presenting as non-syndromic retinitis pigmentosa.","abstract":"Non-syndromic retinitis pigmentosa (NSRP) is a clinically and genetically heterogeneous group of disorders characterized by progressive degeneration of the rod and cone photoreceptors, often leading to blindness. The evolving association of syndromic genes to cause NSRP and the increasing role of intronic variants in explaining missing heritability in genetic disorders present challenges in establishing conclusive clinical and genetic diagnoses. This study sought to identify and validate the causative genetic variant(s) in a 13-year-old male initially diagnosed with NSRP. Genome sequencing identified a pathogenic missense variant in MVK [NM_000431.3:c.803T>C (p.Ile268Thr)], in trans with a novel intronic variant predicted to create a new donor splice site (c.768+71C>A). Proband cDNA analysis confirmed the inclusion of the first 68 base pairs of intron 8 that resulted in a frameshift in MVK (r.768_769ins[768+1_768+68]) and significantly reduced the expression of reference transcript (17.6%). Patient re-phenotyping revealed ataxia, cerebellar atrophy, elevated urinary mevalonate and LTE<sub>4</sub> , in keeping with mild mevalonic aciduria and associated syndromic retinitis pigmentosa. Leakage of reference transcript likely explains the milder phenotype observed in our patient. This is the first association of a deep intronic splice variant to cause MVK-related disorder. This report highlights the importance of variant validation and patient re-phenotyping in establishing accurate diagnosis in the era of genome sequencing.","variants":[{"Name":"NM_000431.4(MVK):c.803T>C (p.Ile268Thr)","Chromosome":"12","Start":"109591275","Stop":"109591275","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":26971,"rule_based_match":true,"evidence_text":"NM_000431.3:c.803T>C (p.Ile268Thr)","llm_judgment":"PRESENT","evidence":"NM_000431.3:c.803T>C (p.Ile268Thr)","abstract_start":646,"abstract_end":680}]}
{"pmid":"28083621","title":"Mutation c.256_257delAA in RAG1 Gene in Polish Children with Severe Combined Immunodeficiency: Diversity of Clinical Manifestations.","abstract":"Mutations in RAG1 gene may result in different types of severe combined immunodeficiencies. In this study, we compare clinical symptoms and laboratory findings in four children with identical mutation in RAG1 gene. All of analyzed patients presented symptoms of severe combined immunodeficiencies associated or not with Omenn syndrome (OS) features. In our patients two different types of variants in RAG1 gene were detected. The first of the mutation was the deletion of AA dinucleotide at position c.256_257 (p.Lys86ValfsTer33), the second gene variant was substitution c.2867T>C (p.Ile956Thr). In Patient 1 we detected that compound heterozygous mutations involved both of the mentioned variants. Whereas, in Patients 2, 3 and 4, we confirmed the presence of the dinucleotide deletion but in a homozygous state. In all described patients, sequence analysis of RAG2 gene did not reveal any nucleotide changes. Our data show that mutation c.256_257delAA in RAG1 gene seems to occur quite frequently in the polish patients with severe combined immunodeficiency and may result in classical OS as well as in severe combined immunodeficiency without clinical and laboratory features of OS when occurred in homozygous state. The same mutation but in heterozygous state, in combination with other mutation in RAG1 gene, may result in incomplete OS.","variants":[{"Name":"NM_000448.3(RAG1):c.2867T>C (p.Ile956Thr)","Chromosome":"11","Start":"36576171","Stop":"36576171","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1062328,"rule_based_match":true,"evidence_text":"c.2867T>C (p.Ile956Thr)","llm_judgment":"PRESENT","evidence":"c.2867T>C (p.Ile956Thr)","abstract_start":572,"abstract_end":595}]}
{"pmid":"36633921","title":"Congenital Hypothyroidism in Two Sudanese Families Harboring a Novel Iodotyrosine Deiodinase Mutation (IYD R279C).","abstract":"<b><i>Background:</i></b> Congenital hypothyroidism due to defects in iodotyrosine deiodinase has variable phenotypes and can present as hypothyroid or with normal thyroid testing. <b><i>Methods:</i></b> Whole exome sequencing was performed in individuals from two families originating from different regions of Sudan. Mass spectrometry of urine and serum iodotyrosines was performed on subjects from both families. <b><i>Results:</i></b> A novel iodotyrosine deiodinase (IYD) mutation (c.835C>T; R279C) was identified in individuals from two Sudanese families inherited as autosomal recessive. The mutation was identified by multiple in silica analyses to likely be detrimental. Serum and urine monoiodotyrosine (MIT) and diiodotyrosine (DIT) were markedly elevated in the homozygous subjects. <b><i>Conclusion:</i></b> Measurement of serum and urine DIT and MIT was more sensitive than that of urine iodine or serum thyroid function tests to determine the effect of the IYD mutation.","variants":[{"Name":"NM_203395.3(IYD):c.835C>T (p.Arg279Cys)","Chromosome":"6","Start":"150398202","Stop":"150398202","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2742112,"rule_based_match":true,"evidence_text":"c.835C>T; R279C","llm_judgment":"PRESENT","evidence":"c.835C>T; R279C","abstract_start":487,"abstract_end":502}]}
{"pmid":"23302520","title":"Contribution of the PALB2 c.2323C>T [p.Q775X] founder mutation in well-defined breast and/or ovarian cancer families and unselected ovarian cancer cases of French Canadian descent.","abstract":"BACKGROUND: The PALB2 c.2323C>T [p.Q775X] mutation has been reported in at least three breast cancer families and breast cancer cases of French Canadian descent and this has been attributed to common ancestors. The number of mutation-positive cases reported varied based on criteria of ascertainment of index cases tested. Although inherited PALB2 mutations are associated with increased risks of developing breast cancer, risk to ovarian cancer has not been fully explored in this demographically unique population.\nMETHODS: We screened the PALB2 p.Q775X variant in 71 families with at least three cases of breast cancer (n=48) or breast and ovarian cancers (n=23) that have previously been found negative for at least the most common BRCA1 and BRCA2 mutations reported in the French Canadian population and in 491 women of French Canadian descent who had invasive ovarian cancer and/or low malignant potential tumors of the major histopathological subtypes.\nRESULTS: We identified a PALB2 p.Q775X carrier in a breast cancer family, who had invasive ductal breast carcinomas at 39 and 42 years of age. We also identified a PALB2 p.Q775X carrier who had papillary serous ovarian cystadenocarcinoma at age 58 among the 238 serous subtype ovarian cancer cases investigated, who also had breast cancer at age 52.\nCONCLUSION: Our findings, taken together with previous reports, support adding PALB2 c.2323C>T p.Q775X to the list of cancer susceptibility genes for which founder mutations have been identified in the French Canadian population.","variants":[{"Name":"NM_024675.4(PALB2):c.2323C>T (p.Gln775Ter)","Chromosome":"16","Start":"23629831","Stop":"23629831","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132156,"rule_based_match":true,"evidence_text":"PALB2 c.2323C>T [p.Q775X]","llm_judgment":"PRESENT","evidence":"PALB2 c.2323C>T [p.Q775X]","abstract_start":16,"abstract_end":41}]}
{"pmid":"31181191","title":"A homozygous ABCB4 mutation causing an LPAC syndrome evolves into cholangiocarcinoma.","abstract":"Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. In the present study, we reported a case of a 63-year-old woman, who presented a biliary pain beginning at the age of 30, recurrent after cholecystectomy, along with \"comet-tail shadows\" revealed by ultrasonography thus, fulfilling the diagnosis of LPAC. This disease evolved into a cholangiocarcinoma. To understand the molecular basis of this phenotype, we performed the ABCB4 gene sequencing, followed by in silico analysis and Q-RT-PCR assay. The results displayed a homozygous missense sequence variation (c.140G > A, p.Arg47Gln), predicted as pathogenic according to MutPred. Accordingly, this gave rise to a decreased hepatic ABCB4 mRNA level and structural alterations of the mutated protein. Eventually, we reported, here, the first description of an ABCB4 missense mutation (p.Arg47Gln) at homozygous state in a Tunisian LPAC syndrome. An elucidation of its functional consequences was performed. Besides, this case suggests that the delayed diagnosis of LPAC syndrome and the lack of UDCA treatment may contribute in the development of complications, such as cholangiocarcinoma.","variants":[{"Name":"NM_000443.4(ABCB4):c.140G>A (p.Arg47Gln)","Chromosome":"7","Start":"87462904","Stop":"87462904","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":194305,"rule_based_match":true,"evidence_text":"c.140G > A, p.Arg47Gln","llm_judgment":"PRESENT","evidence":"c.140G > A, p.Arg47Gln","abstract_start":706,"abstract_end":728}]}
{"pmid":"22513797","title":"Homozygous point mutations in platelet glycoprotein ITGA2B gene as cause of Glanzmann thrombasthenia in 2 families.","abstract":"Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex. Physiologically, the integrin GPIIb/IIIa binds Von Willebrand factor and fibrinogen on activated platelets. GT is caused by genetic alterations in ITGA2B or ITGB3 (genes encoding GPIIb and GPIIIa).This study describes 2 siblings diagnosed with GT type I associated with homozygous point mutations in ITGA2B. All patients presented with typical bleeding disorder including moderate hematomas, petechiae, and mucocutaneous bleedings.Both siblings showed severely reduced platelet aggregation especially after stimulation with collagen and adenosine diphosphate. Absence of platelet GPIIb/GPIIIa complex was determined using flow cytometry. Molecular genetic analysis revealed 2 distinct homozygous point mutations in exon 18 of ITGA2B. Family 1 was identified with c.1878G>C and family 2 with c.1787T>C substitution. While the c.1787T>C mutation causes a single amino acid substitution p.I565T, the c.1878G>C mutation (p.Q595H) is predicted to induce a mRNA splicing anomaly.These mutations were identified as cause of GT type I in the described patients. Patients with GT should be documented in a prospective register to verify the correlation between the severity of bleeding symptoms and the pathogenic mutation. This can have effects on therapeutic decisions.","variants":[{"Name":"NM_000419.5(ITGA2B):c.1787T>C (p.Ile596Thr)","Chromosome":"17","Start":"44379780","Stop":"44379780","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":17939,"rule_based_match":true,"evidence_text":"c.1787T>C","llm_judgment":"PRESENT","evidence":"c.1787T>C","abstract_start":978,"abstract_end":987}]}
{"pmid":"26362256","title":"FGFR2 mutation in 46,XY sex reversal with craniosynostosis.","abstract":"Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2-related syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G>C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the 'knock-in' Crouzon mouse model Fgfr2c(C342Y/C342Y) carrying a Cys342Tyr substitution displays XY gonadal sex reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by sex reversal in Fgfr2c(C342Y/-) mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination.","variants":[{"Name":"NM_000141.5(FGFR2):c.1025G>C (p.Cys342Ser)","Chromosome":"10","Start":"121517378","Stop":"121517378","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":361711,"rule_based_match":true,"evidence_text":"c.1025G>C (p.Cys342Ser)","llm_judgment":"PRESENT","evidence":"c.1025G>C (p.Cys342Ser)","abstract_start":702,"abstract_end":725}]}
{"pmid":"31486839","title":"Clinical Characterization of Retinitis Pigmentosa Associated With Variants in SNRNP200.","abstract":"IMPORTANCE: SNRNP200 is a recently identified genetic cause of autosomal dominant retinitis pigmentosa (RP). However, the associated retinal phenotype is not well characterized.\nOBJECTIVE: To describe the retinal phenotype in patients with RP secondary to variants in SNRNP200.\nDESIGN, SETTING, AND PARTICIPANTS: This retrospective, case-series study was performed at 2 tertiary referral centers for inherited retinal diseases. Participants included 9 consecutive patients from 8 families with RP attributed to variants in SNRNP200. Data were collected from August 2017 to March 2018 and analyzed from May to July 2018.\nMAIN OUTCOMES AND MEASURES: Results of clinical evaluation, multimodal retinal imaging, and molecular genetic testing using targeted next-generation sequencing.\nRESULTS: Of the 9 patients included in the analysis (4 female and 5 male; mean [SD] age at presentation, 19 [15] years), each presented with nyctalopia, typically in the first 2 decades of life, although 2 patients experienced symptom onset in middle age. None had any consistent systemic features suggestive of syndromic RP. Retinal imaging studies and electroretinography findings were typical of a rod-predominant dystrophy with later involvement of cone photoreceptors. Phenotypic heterogeneity was typified by 4 unrelated patients with the common c.2041C>T SNRNP200 variant who demonstrated a variable age of disease onset (middle teenage years to the fourth decade of life). Disease progression was slow, with all but 1 patient maintaining visual acuity of better than 20/40 in the better-seeing eye in the fifth and sixth decades of life.\nCONCLUSIONS AND RELEVANCE: These data suggest that variants in SNRNP200 result in nonsyndromic RP with a typical phenotype of a rod-predominant dystrophy. Significant phenotypic heterogeneity and nonpenetrance were noted within some affected families. Symptom onset was typically within the first 2 decades of life, with slow progression and well-preserved visual acuities into the fifth and sixth decades.","variants":[{"Name":"NM_014014.5(SNRNP200):c.2041C>T (p.Arg681Cys)","Chromosome":"2","Start":"96293091","Stop":"96293091","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":623829,"rule_based_match":true,"evidence_text":"c.2041C>T","llm_judgment":"PRESENT","evidence":"c.2041C>T","abstract_start":1333,"abstract_end":1342}]}
{"pmid":"34646230","title":"Case Report: A Novel","abstract":"Diseases of neurodevelopment mostly exhibit neurological and psychiatric symptoms that go from very mild to extremely severe. While the etiology of most cases of neurodevelopmental disease is still unknown, the discovery of underlying genetic causes is rapidly increasing, with hundreds of genes being currently implicated as disease-causing. Here, we report a clinical case of a patient with a previously undiagnosed syndrome comprising severe global developmental delay, intellectual disability, and behavioral disorders (such as attention-deficit/hyperactivity disorder, autism spectrum disorder and recurrent bouts of aggressive behavior). After genetic testing, a pathogenic variant was detected in the <i>GNB1</i> gene, which codes for the G-protein subunit β1. The detected variant (c.217G>A, p.A73T) has not been previously reported in any of the 58 published cases of GNB1 encephalopathy. However, it localizes to the mutational hotspot in exons 6 and 7 in which 88% of all missense mutations occur. An <i>in silico</i> model predicts that this mutation is likely to disrupt the WD40 domain of the GNB1 protein, which is required for its interaction with other G-proteins and, consequently, for downstream signal transduction. In conclusion, we reported an additional GNB1 encephalopathy patient, bearing a novel mutation, taking another step toward a better understanding of its clinical presentation and prospective development of treatments for the disease.","variants":[{"Name":"NM_002074.5(GNB1):c.217G>A (p.Ala73Thr)","Chromosome":"1","Start":"1806525","Stop":"1806525","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1706549,"rule_based_match":true,"evidence_text":"c.217G>A, p.A73T","llm_judgment":"PRESENT","evidence":"c.217G>A, p.A73T","abstract_start":790,"abstract_end":806}]}
{"pmid":"29137425","title":"A fatal case of mitochondrial DNA depletion syndrome with novel compound heterozygous variants in the deoxyguanosine kinase gene.","abstract":"The deoxyguanosine kinase (DGUOK) gene controls mitochondrial DNA (mtDNA) maintenance, and variation in the gene can alter or abolish the anabolism of mitochondrial deoxyribonucleotides. A Chinese female infant, whose symptoms included weight stagnation, jaundice, hypoglycemia, coagulation disorders, abnormal liver function, and multiple abnormal signals in the brain, died at about 10 months old. Genetic testing revealed a compound heterozygote of alleles c.128T>C (p.I43T) and c.313C>T (p.R105<sup>*</sup>) of the DGUOK gene. c.128T>C (p.I43T) is a novel variant located in exon 1 (NM_080916) in the first beta sheet of DGUOK. Her mother was an allele c.313C>T (p.R105<sup>*</sup>) heterozygote, which is located in DGUOK exon 2 (NM_080916) between the third and fourth alpha helixes. c.313C>T (p.R105<sup>*</sup>) is predicted to result in a 173 amino acid residue truncation at the C terminus of DGUOK. There are as many as 112 infantile mtDNA depletion syndrome (MDS) cases in the literature related to DGUOK gene variants. These variants include missense mutations, nucleotide deletion, nucleotide insertion, and nucleotide duplication. Integrated data showed that mutations affected both conserved and non-conserved DGUOK amino acids and are associated with patient deaths.","variants":[{"Name":"NM_080916.3(DGUOK):c.313C>T (p.Arg105Ter)","Chromosome":"2","Start":"73946776","Stop":"73946776","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23193,"rule_based_match":true,"evidence_text":"c.313C>T (p.R105<sup>*</sup>)","llm_judgment":"PRESENT","evidence":"c.313C>T (p.R105<sup>*</sup>)","abstract_start":482,"abstract_end":511}]}
{"pmid":"30736279","title":"Quantifying","abstract":"<i>BRCA1</i> and <i>BRCA2</i> spliceogenic variants are often associated with an elevated risk of breast and ovarian cancers. Analyses of <i>BRCA1</i> and <i>BRCA2</i> splicing patterns have traditionally used technologies that sample a population of cells but do not account for the variation that may be present between individual cells. This novel proof of concept study utilises RNA in situ hybridisation to measure the absolute expression of <i>BRCA1</i> and <i>BRCA2</i> mRNA splicing events in single lymphoblastoid cells containing known spliceogenic variants (<i>BRCA1</i>c.671-2 A>G or <i>BRCA2</i>c.7988 A>T). We observed a large proportion of cells (>42%) in each sample that did not express mRNA for the targeted gene. Increased levels (average mRNA molecules per cell) of <i>BRCA2</i> ∆17_18 were observed in the cells containing the known spliceogenic variant <i>BRCA2</i>c.7988 A>T, but cells containing <i>BRCA1</i>c.671-2 A>G were not found to express significantly increased levels of <i>BRCA1</i> ∆11, as had been shown previously. Instead, we show for each variant carrier sample that a higher proportion of cells expressed the targeted splicing event compared to control cells. These results indicate that <i>BRCA1</i>/<i>2</i> mRNA is expressed stochastically, suggesting that previously reported results using RT-PCR may have been influenced by the number of cells with <i>BRCA1</i>/<i>2</i> mRNA expression and may not represent an elevation of constitutive mRNA expression. Detection of mRNA expression in single cells allows for a more comprehensive understanding of how spliceogenic variants influence the expression of mRNA isoforms. However, further research is required to assess the utility of this technology to measure the expression of predicted spliceogenic <i>BRCA1</i> and <i>BRCA2</i> variants in a diagnostic setting.","variants":[{"Name":"NM_000059.4(BRCA2):c.7988A>T (p.Glu2663Val)","Chromosome":"13","Start":"32363190","Stop":"32363190","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":67130,"rule_based_match":true,"evidence_text":"<i>BRCA2</i>c.7988 A>T","llm_judgment":"PRESENT","evidence":"<i>BRCA2</i>c.7988 A>T","abstract_start":596,"abstract_end":618},{"Name":"NM_007294.4(BRCA1):c.671-2A>G","Chromosome":"17","Start":"43094862","Stop":"43094862","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":262978,"rule_based_match":true,"evidence_text":"<i>BRCA1</i>c.671-2 A>G","llm_judgment":"PRESENT","evidence":"<i>BRCA1</i>c.671-2 A>G","abstract_start":569,"abstract_end":592}]}
{"pmid":"28220263","title":"Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10 years' experience of a medical center in northern Vietnam.","abstract":"Beta-ketothiolase (T2) deficiency is an inherited disease of isoleucine and ketone body metabolism caused by mutations in the ACAT1 gene. Between 2005 and 2016, a total of 41 patients with T2 deficiency were identified at a medical center in northern Vietnam, with an estimated incidence of one in 190,000 newborns. Most patients manifested ketoacidotic episodes of varying severity between 6 and 18 months of age. Remarkably, 28% of patients showed high blood glucose levels (up to 23.3 mmol/L). Ketoacidotic episodes recurred in 43% of patients. The age of onset, frequency of episodes, and identified genotype did not affect patient outcomes that were generally favorable, with the exception of seven cases (five died and two had neurological sequelae). Custom-tailored acute and follow-up management was critical for a positive clinical outcome. Two null mutations, c.622C>T (p.Arg208*) and c.1006-1G>C (p.Val336fs), accounted for 66% and 19% of all identified ACAT1 mutant alleles, respectively. Most patients showed characteristic biochemical abnormalities. A newborn screening program could be expected to have a high yield in Vietnam. Investigation findings of haplotypes linked to the most common ACAT1 mutation (c.622C>T) are consistent with an ancient common founder of mutation-bearing chromosomes belonging to the Kinh ethnic population. The direct management and long-term follow-up of a large number of T2-deficient patients enabled us to study the natural history of this rare disease.","variants":[{"Name":"NM_000019.4(ACAT1):c.1006-1G>C","Chromosome":"11","Start":"108146201","Stop":"108146201","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":421815,"rule_based_match":true,"evidence_text":"c.1006-1G>C (p.Val336fs)","llm_judgment":"PRESENT","evidence":"c.1006-1G>C (p.Val336fs)","abstract_start":895,"abstract_end":919},{"Name":"NM_000019.4(ACAT1):c.622C>T (p.Arg208Ter)","Chromosome":"11","Start":"108140107","Stop":"108140107","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":363710,"rule_based_match":true,"evidence_text":"c.622C>T (p.Arg208*)","llm_judgment":"PRESENT","evidence":"c.622C>T (p.Arg208*)","abstract_start":870,"abstract_end":890}]}
{"pmid":"29422393","title":"A de novo GABRA2 missense mutation in severe early-onset epileptic encephalopathy with a choreiform movement disorder.","abstract":"BACKGROUND: Early-onset epileptic encephalopathy (EOEE) is a severe convulsive disorder with a poor developmental prognosis. Although it has been associated with mutations in a number of genes, the fact that there is a large proportion of patients who remain undiagnosed suggests that there are many more still-unknown genetic causes of EOEE. Achieving a genetic diagnosis is important for understanding the biological basis of the disease, with its implications for treatment and family planning.\nMETHODS: Whole-exome sequencing was performed in a family of Ashkenazi Jewish origin in which a male infant was diagnosed with EOEE. There was no family history of a similar neurologic disease. The patient had extreme hypotonia, neonatal hypothermia, choreiform movements, and vision impairment in addition to the convulsive disorder.\nRESULTS: A de novo heterozygous missense mutation, c.1003A > C, p.Asn335His, was identified in a conserved domain of GABRA2. GABRA2 encodes the α2 subunit of the GABA<sub>A</sub> receptor.\nCONCLUSIONS: In the context of previous reports of an association of de novo mutations in genes encoding different subunits of the GABA<sub>A</sub> receptor (GABRB1, GABRA1, GABRG2, GABRB3) with autosomal dominant epileptic disorders, we conclude that a de novo mutation in GABRA2 is likely to cause autosomal dominant EOEE accompanied by a movement disorder and vision impairment.","variants":[{"Name":"NM_000807.4(GABRA2):c.1003A>C (p.Asn335His)","Chromosome":"4","Start":"46261982","Stop":"46261982","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":609020,"rule_based_match":true,"evidence_text":"c.1003A > C, p.Asn335His","llm_judgment":"PRESENT","evidence":"c.1003A > C, p.Asn335His","abstract_start":884,"abstract_end":908}]}
{"pmid":"17251446","title":"The 208delG mutation in FSCN2 does not associate with retinal degeneration in Chinese individuals.","abstract":"PURPOSE: The 208delG (c.72delG, p.Thr25GlnfsX120) mutation in the FSCN2 gene was reported to cause autosomal dominant retinitis pigmentosa (ADRP) and autosomal dominant macular degeneration (ADMD). The purpose of this study was to detect the 208delG mutation in Chinese individuals, with or without hereditary retinal degeneration.\nMETHODS: DNA fragments encompassing the 208delG mutation were amplified by polymerase chain reaction (PCR). The amplicons were analyzed by sequencing or/and heteroduplex- single-strand conformational polymorphism (SSCP) analysis. An ophthalmic evaluation was conducted in those individuals with the 208delG mutation.\nRESULTS: The 208delG mutation was detected in 8 of 242 unrelated probands: 175 with retinitis pigmentosa (RP), 20 with Leber congenital amaurosis (LCA), and 47 with cone-rod dystrophy (CORD). Of the eight, the retinal diseases were RP in six probands, LCA in one proband, and CORD in one proband. The disease was transmitted as an autosomal dominant (one family), autosomal recessive (two families), or sporadic (five families) trait. The mutation did not cosegregate with retinal degeneration in three families, whereas five normal family members also had the mutation. In addition, this mutation was also detected in 13 of 521 unrelated control subjects.\nCONCLUSIONS: The 208delG mutation in FSCN2 is not associated with hereditary retinal degeneration in the Chinese individuals examined, which contradicts the original report about mutation in FSCN2 as a cause of ADRP and ADMD. This finding reminds us that great care is needed in making mutation-disease associations.","variants":[{"Name":"NM_012418.4(FSCN2):c.72del (p.Thr25fs)","Chromosome":"17","Start":"81528603","Stop":"81528603","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":17984,"rule_based_match":true,"evidence_text":"c.72delG","llm_judgment":"PRESENT","evidence":"c.72delG","abstract_start":22,"abstract_end":30}]}
{"pmid":"21835286","title":"Subclinical echocardiographic abnormalities in phenotype-negative carriers of myosin-binding protein C3 gene mutation for hypertrophic cardiomyopathy.","abstract":"BACKGROUND: Early diastolic myocardial tissue Doppler velocities have reported to be reduced in mutation-positive patients with hypertrophic cardiomyopathy (HCM) in some studies even in the absence of left ventricular hypertrophy (LVH). Strain is a sensitive tool in detecting early systolic abnormalities in patients with HCM. Our goal is to examine novel echocardiographic characteristics of phenotype-negative carriers for a known sarcomeric gene mutation for HCM.\nMETHODS: We evaluated 41 consecutive subjects with a known myosin-binding protein C3 (MYBPC3) mutation (c.3330+2T>G). Subjects who were mutation positive without LVH (G+/LVH-, n = 35) were compared with healthy controls (n = 30) regarding tissue Doppler and segmental longitudinal strain measures.\nRESULTS: The G+/LVH- group was similar to the healthy controls with respect to chamber size, left ventricular mass index, and most diastolic filling parameters, including tissue Doppler-derived early diastolic annular velocities. Global longitudinal strain was similar for both groups (20.3 ± 2.1 vs 19.8 ± 1.8, P = .36), although regional segment analysis showed a notable reduction in the basal septum (16.8 ± 3.1 vs 19.0 ± 4.0%, P = .02) and increase in the basal posterior (22.5 ± 5.2 vs 17.9 ± 5.2, P = .001) as well as mid posterior (21.8 ± 4.7 vs 18.2 ± 3.0, P = .001) walls.\nCONCLUSIONS: In our cohort of phenotype-negative carriers of a specific MYBPC3 mutation, there were minimal differences in conventional 2-dimensional, Doppler, and speckle-tracking-derived parameters of systolic and diastolic function compared with that of healthy subjects. The presence of regional alterations in strain indicative of the presence of underlying subclinical disease requires further validation.","variants":[{"Name":"NM_000256.3(MYBPC3):c.3330+2T>G","Chromosome":"11","Start":"47333192","Stop":"47333192","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":23660,"rule_based_match":true,"evidence_text":"c.3330+2T>G","llm_judgment":"PRESENT","evidence":"c.3330+2T>G","abstract_start":572,"abstract_end":583}]}
{"pmid":"23551881","title":"Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes.","abstract":"Monogenic diabetes due to mutations in the transcription factor genes hepatocyte nuclear factor 1A (HNF1A) and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, HNF1A, and HNF4A. The proband was diagnosed with diabetes at 7 yr of age and treated with insulin for 4 yr. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 yr of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over 2 yr. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 yr of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 yr, respectively. Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.","variants":[{"Name":"NM_000545.8(HNF1A):c.872dup (p.Gly292fs)","Chromosome":"12","Start":"120994314","Stop":"120994315","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":29966,"rule_based_match":true,"evidence_text":"c.872dup","llm_judgment":"PRESENT","evidence":"c.872dup","abstract_start":904,"abstract_end":912}]}
{"pmid":"37537203","title":"Ramifications of POU4F3 variants associated with autosomal dominant hearing loss in various molecular aspects.","abstract":"POU4F3, a member of the POU family of transcription factors, commonly causes autosomal dominant deafness. Exome sequencing was used to identify four novel variants in POU4F3 (NM_002700.2), including c.564dupA: p.Ala189SerfsTer26, c.743T > C:p.Leu248Pro, c.879C > A:p.Phe293Leu, and c.952G > A:p.Val318Met, and diverse aspects of the molecular consequences of their protein expression, stability, subcellular localization, and transcriptional activity were investigated. The expression of three mutant proteins, encoded by missense variants, was reduced compared to the wild-type protein, demonstrating that the mutants were unstable and vulnerable to degradation. Additionally, all the mutant proteins had distinct subcellular localization patterns. A mutant protein carrying p.Ala189SerfsTer26, in which both mono- and bi-partite nuclear localization signals were disrupted, showed abnormal subcellular localization. Resultantly, all the mutant proteins significantly reduced the transcriptional activity required to regulate the downstream target gene expression. Furthermore, we identified the altered expression of 14 downstream target genes associated with inner ear development using patient-derived lymphoblastoid cell lines. There was a significant correlation of the expression profile between patient-derived cells and the cochlear hair cells, which provided a breakthrough for cases where the collection of human cochlear samples for transcriptome studies was unfeasible. This study expanded the genotypic spectrum of POU4F3 in DFNA15, and further refined the molecular mechanisms underlying POU4F3-associated DFNA15.","variants":[{"Name":"NM_002700.3(POU4F3):c.564dup (p.Ala189fs)","Chromosome":"5","Start":"146339989","Stop":"146339990","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":2667969,"rule_based_match":true,"evidence_text":"c.564dupA: p.Ala189SerfsTer26","llm_judgment":"PRESENT","evidence":"c.564dupA: p.Ala189SerfsTer26","abstract_start":199,"abstract_end":228},{"Name":"NM_002700.3(POU4F3):c.743T>C (p.Leu248Pro)","Chromosome":"5","Start":"146340170","Stop":"146340170","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2667970,"rule_based_match":true,"evidence_text":"c.743T > C:p.Leu248Pro","llm_judgment":"PRESENT","evidence":"c.743T > C:p.Leu248Pro","abstract_start":230,"abstract_end":252},{"Name":"NM_002700.3(POU4F3):c.952G>A (p.Val318Met)","Chromosome":"5","Start":"146340379","Stop":"146340379","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1287531,"rule_based_match":true,"evidence_text":"c.952G > A:p.Val318Met","llm_judgment":"PRESENT","evidence":"c.952G > A:p.Val318Met","abstract_start":282,"abstract_end":304},{"Name":"NM_002700.3(POU4F3):c.879C>A (p.Phe293Leu)","Chromosome":"5","Start":"146340306","Stop":"146340306","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3495286,"rule_based_match":true,"evidence_text":"c.879C > A:p.Phe293Leu","llm_judgment":"PRESENT","evidence":"c.879C > A:p.Phe293Leu","abstract_start":254,"abstract_end":276}]}
{"pmid":"31828823","title":"A family with nemaline myopathy type 6 caused by hseterozygous mutation (c.1222C>T) in the KBTBD13 gene in China: A case report.","abstract":"Nemaline myopathy (NEM) is a congenital myopathy that typically presents with proximal muscle weakness and hypotonia. To date, 13 genes have been associated with NEM. The Kelch repeat and BTB domain-containing protein 13 (KBTBD13) gene (KBTBD13)-related NEM is a rarely reported condition, and not a single case has been reported in Asia. Here, we report the case of a mother and daughter in China with NEM caused by a mutation (c.1222C>T) in KBTBD13. Their shared clinical phenotype is symmetrical muscle weakness in the arms and legs with childhood onset. Muscle magnetic resonance imaging showed the unique replacement mode of muscle with fibro-fatty tissue. Histopathological examination revealed the presence of fibers containing rod-shaped structures in the cytoplasm or under the sarcolemma. DNA sequencing analysis detected a heterozygous mutation (c.1222C>T) in KBTBD13 in this family. A founder effect for the variant may exist in the Low Countries of Belgium and the Netherlands, and the mutation may be a hotspot mutation in Europe, as it has not been reported in Asia. Our case study expands the spectrum of KBTBD13-related NEM.","variants":[{"Name":"NM_001101362.3(KBTBD13):c.1222C>T (p.Arg408Cys)","Chromosome":"15","Start":"65078037","Stop":"65078037","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40019,"rule_based_match":true,"evidence_text":"c.1222C>T","llm_judgment":"PRESENT","evidence":"c.1222C>T","abstract_start":429,"abstract_end":438}]}
{"pmid":"26238661","title":"Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome.","abstract":"Klippel-Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported in families with Klippel-Feil. Mutated genes for both dominant (GDF6 and GDF3) and recessive (MEOX1) forms of Klippel-Feil syndrome have been shown to be involved in somite development via transcription regulation and signaling pathways. Heterotaxy arises from defects in proteins that function in the development of left-right asymmetry of the developing embryo. We describe a consanguineous family with a male proband who presents with classical Klippel-Feil syndrome together with heterotaxy (situs inversus totalis). The present patient also had Sprengel's deformity, deformity of the sternum, and a solitary kidney. Using exome sequencing, we identified a homozygous frameshift mutation (c.299delT; p.L100fs) in RIPPLY2, a gene shown to play a crucial role in somitogenesis and participate in the Notch signaling pathway via negatively regulating Tbx6. Our data confirm RIPPLY2 as a novel gene for autosomal recessive Klippel-Feil syndrome, and in addition-from a mechanistic standpoint-suggest the possibility that mutations in RIPPLY2 could also lead to heterotaxy. © 2015 Wiley Periodicals, Inc.","variants":[{"Name":"NM_001009994.3(RIPPLY2):c.299del (p.Leu100fs)","Chromosome":"6","Start":"83857301","Stop":"83857301","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":215009,"rule_based_match":true,"evidence_text":"c.299delT; p.L100fs","llm_judgment":"PRESENT","evidence":"c.299delT; p.L100fs","abstract_start":989,"abstract_end":1008}]}
{"pmid":"18470941","title":"Mutations in CYP1B1 cause primary congenital glaucoma by reduction of either activity or abundance of the enzyme.","abstract":"Primary congenital glaucoma (PCG) is an autosomal recessive disorder caused predominantly by mutations in the CYP1B1 gene. A total of five frequent single nucleotide polymorphisms (SNPs) have been identified in the coding sequence of CYP1B1: rs10012C>G (p.R48G), rs1056827G>T (p.A119S), rs1056836C>G (p.V432L), rs1056837C>T (p.D449D), and rs1800440A>G (p.N453S). We performed a functional characterization of four common CYP1B1 variants presenting different coding SNP haplotypes (RAVDN, GSLDN, RALDS, and RALDN) and five CYP1B1 mutations reported for PCG patients: c.182G>A (p.G61E), c.608A>G (p.N203S), c.1033_1035del (p.L343del), c.241 T>A (p.Y81N), and c.685G>A (p.E229 K). Each mutation was embedded in its corresponding background SNP haplotype. The common variants revealed variation in enzymatic activity; among them, RAVDN showed the highest activity. Mutants p.G61E, p.N203S, and p.L343del each revealed a residual activity (<10%) of their respective haplotype. The microsomal CYP1B1 abundance relative to total protein also showed variation in common variants and a significant reduction in p.L343del, p.Y81N, and p.E229 K. The free energy of folding (DeltaDeltaG) values suggest that the lower stability of the mutants is one key property leading to the experimentally observed lower protein abundance. Our new measure of relative enzymatic activity (U/mg total protein), which combines activity and abundance values, was significantly lower for all five mutations compared to the corresponding background haplotype. We classified p.Y81N and p.E229 K not as mutations but as hypomorphic alleles, since their relative activity values are intermediate between bona fide mutations and the common variant with the lowest activity (RALDS). We propose that CYP1B1 mutations can act by either reducing enzymatic activity (p.G61E and p.N203S), reducing the abundance of the enzyme (p.Y81N and p.E229 K), or both (p.L343del).","variants":[{"Name":"NM_000104.4(CYP1B1):c.182G>A (p.Gly61Glu)","Chromosome":"2","Start":"38075207","Stop":"38075207","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22769,"rule_based_match":true,"evidence_text":"c.182G>A (p.G61E)","llm_judgment":"PRESENT","evidence":"c.182G>A (p.G61E)","abstract_start":566,"abstract_end":583},{"Name":"NM_000104.4(CYP1B1):c.241T>A (p.Tyr81Asn)","Chromosome":"2","Start":"38075148","Stop":"38075148","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":22783,"rule_based_match":true,"evidence_text":"c.241 T>A (p.Y81N)","llm_judgment":"PRESENT","evidence":"c.241 T>A (p.Y81N)","abstract_start":633,"abstract_end":651}]}
{"pmid":"30065612","title":"An","abstract":"BACKGROUND: Auditory Neuropathy Spectrum Disorder (ANSD) is manifested as impairment of auditory nerve activity but preservation of the outer hair cell function.\nOBJECTIVE: This study was to detect the disease-causing gene and variant(s) in a Chinese ANSD family.\nMETHODS: A four-generation consanguineous Chinese ANSD family and 200 unrelated healthy controls were enrolled. Exome sequencing and Sanger sequencing were applied to identify the genetic basis for ANSD in this family.\nRESULTS: Exome sequencing detected a c.1236delC variant of the otoferlin gene in an apparently homozygous state. Sanger sequencing confirmed that the variant co-segregating with the phenotype of hearing impairments in this family. The variant was not detected in 200 healthy controls. The c.1236delC alteration may result in a truncated otoferlin missing the C2C-C2F domains and the C-terminal transmembrane domain, and thus severely damages Ca2+-dependent synaptic vesicle fusion and targeting function of the otoferlin.\nCONCLUSION: Our study suggested that the c.1236delC alteration in the otoferlin gene may be the disease-causing variant in this family, and also shed new light on genetic counseling to this ANSD family.","variants":[{"Name":"NM_194248.3(OTOF):c.1236del (p.Glu413fs)","Chromosome":"2","Start":"26483618","Stop":"26483618","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":76683,"rule_based_match":true,"evidence_text":"c.1236delC","llm_judgment":"PRESENT","evidence":"c.1236delC","abstract_start":520,"abstract_end":530}]}
{"pmid":"24113144","title":"Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.","abstract":"Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms.","variants":[{"Name":"NM_005861.4(STUB1):c.737C>T (p.Thr246Met)","Chromosome":"16","Start":"682232","Stop":"682232","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":132644,"rule_based_match":false,"evidence_text":"NM_005861) c.737C→T, p.Thr246Met","llm_judgment":"PRESENT","evidence":"NM_005861) c.737C→T, p.Thr246Met","abstract_start":435,"abstract_end":467}]}
{"pmid":"32186211","title":"Rare phenotype of ALS4 associated with heterozygous missense mutation c.5842A > G/p.M1948V in helicase domain of","abstract":"","variants":[{"Name":"NM_015046.7(SETX):c.5842A>G (p.Met1948Val)","Chromosome":"9","Start":"132296994","Stop":"132296994","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":904521,"rule_based_match":true,"evidence_text":"c.5842A > G/p.M1948V","llm_judgment":"PRESENT","evidence":"c.5842A > G/p.M1948V","abstract_start":null,"abstract_end":null}]}
{"pmid":"35526386","title":"Generation of an iPSC line (SCTCi014-A) and isogenic control line (SCTCi014-A-1) from an age-related macular degeneration patient carrying the variant c.355G>A in the CFI gene.","abstract":"Age-related macular degeneration (AMD) is a common eye disease among the elderly in the Western world. AMD is a multifactorial disease, with a strong association with genetic variation in the complement system. One of the AMD-associated variants is the c.355G>A (p.Gly119Arg) variant in complement factor I (CFI), a central regulator of complement activation. Here, we report the generation of an iPSC line and its isogenic wildtype control derived from peripheral blood mononuclear cells of a male AMD-affected individual carrying the heterozygous variant c.355G>A (p.Gly119Arg). The line can be utilized to study the effects of this variant in disease-specific cell types.","variants":[{"Name":"NM_000204.5(CFI):c.355G>A (p.Gly119Arg)","Chromosome":"4","Start":"109764664","Stop":"109764664","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76922,"rule_based_match":true,"evidence_text":"c.355G>A (p.Gly119Arg)","llm_judgment":"PRESENT","evidence":"c.355G>A (p.Gly119Arg)","abstract_start":253,"abstract_end":275}]}
{"pmid":"25297583","title":"Analysis of clinical phenotype and genetic mutations of a pedigree of familial hemophagocytic lymphohistiocytosis","abstract":"OBJECTIVE: To analyze mutations in a pedigree of familial hemophagocytic lymphohistiocytosis (FHLH) from Sichuan and provide genetic counseling for the family.\nMETHODS: Clinical data of a case with FHLH diagnosed at West China Second Hospital was retrospectively analyzed. Genomic DNA was extracted from peripheral blood samples of the proband and his family members. Eight candidate genes for primary HLH were amplified with PCR and analyzed by direct sequencing.\nRESULTS: The proband was diagnosed as HLH based on clinical manifestations of recurrent fever for 2 months, hepatosplenomegaly, lymphadenopathy, pancytopenia, hyperferritinemia, and decreased fibrinogen and hemophagocytosis in bone marrow. Genetic testing for primary HLH was carried out considering the relapse of illness after hormone therapy for 8 weeks and the family history. The results of gene sequencing showed that the proband has carried compound heterozygous mutations in PRF1 gene (c.1349C> T in exon 3 and c.445G> A in exon 2). His father has carried a heterozygous mutation (c.445G> A in exon 2) and nonsense mutation (c.900C> T in exon 3), and his mother carried a heterozygous mutation (c.1349C> T in exon 3). Both c.1349C> T and c.445G> A have been previously reported as pathogenic mutations.\nCONCLUSION: The family has been diagnosed as familial HLH type 2 based on clinical and laboratory examinations and molecular genetic testing. Gene sequencing has indicated that is was a recessive type familial HLH.","variants":[{"Name":"NM_001083116.3(PRF1):c.1349C>T (p.Thr450Met)","Chromosome":"10","Start":"70598372","Stop":"70598372","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":460482,"rule_based_match":true,"evidence_text":"c.1349C> T in exon 3","llm_judgment":"PRESENT","evidence":"c.1349C> T in exon 3","abstract_start":959,"abstract_end":979}]}
{"pmid":"15595939","title":"Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex.","abstract":"OBJECTIVE: To find the mutation and polymorphism spectrum of TSC1 and TSC2 genes in patients affected with tuberous sclerosis complex from the Indian population.\nMATERIAL AND METHODS: All coding exons and promoter regions of both TSC genes were screened for mutations and polymorphisms in 24 TSC families using polymerase chain reaction-single strand conformation polymorphism and DNA sequencing techniques.\nRESULTS: A single previously known mutation, c.2111_2112delAT was identified in the TSC1 gene. A total of 11 mutations were identified in the TSC2 gene. Of these, seven mutations, c.137_138delGA, c.2070delC, c.2087_2088insAA, c.3080T>C (p.L1027P), c.648+1G>A, c.3131+1G>A and c.5034C>G were novel. The remaining four mutations, c.4544_4547delACAA, c.1941_1942insT, c.1831C>T (p.R611W) and c.1832G>A (p.R611Q) had been reported previously in other populations. The novel mutation, c.137_138delGA was predicted to result in the production of a very small tuberin protein of 64 amino acids lacking all seven functional domains. In addition, we also detected three and 10 polymorphisms in the TSC1 and TSC2 genes respectively. DNA sequence analysis of promoter regions of both TSC genes in 24 families did not show any variation.\nCONCLUSIONS: This is the first molecular genetic study of TSC in an Indian population. A total of 12 mutations were detected in 24 Indian TSC families in TSC genes. All except one mutation were detected in the TSC2 gene. No variation was found in the promoter regions of either gene. As observed in the western and Japanese populations, the mutations were scattered across the TSC2 gene.","variants":[{"Name":"NM_000548.5(TSC2):c.5034C>G (p.Tyr1678Ter)","Chromosome":"16","Start":"2087907","Stop":"2087907","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":59014,"rule_based_match":true,"evidence_text":"c.5034C>G","llm_judgment":"PRESENT","evidence":"c.5034C>G","abstract_start":684,"abstract_end":693},{"Name":"NM_000548.5(TSC2):c.3080T>C (p.Leu1027Pro)","Chromosome":"16","Start":"2079145","Stop":"2079145","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":59036,"rule_based_match":true,"evidence_text":"c.3080T>C (p.L1027P)","llm_judgment":"PRESENT","evidence":"c.3080T>C (p.L1027P)","abstract_start":634,"abstract_end":654},{"Name":"NM_000548.5(TSC2):c.3131+1G>A","Chromosome":"16","Start":"2079197","Stop":"2079197","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":58406,"rule_based_match":true,"evidence_text":"c.3131+1G>A","llm_judgment":"PRESENT","evidence":"c.3131+1G>A","abstract_start":668,"abstract_end":679},{"Name":"NM_000548.5(TSC2):c.1832G>A (p.Arg611Gln)","Chromosome":"16","Start":"2070571","Stop":"2070571","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27436,"rule_based_match":true,"evidence_text":"c.1832G>A (p.R611Q)","llm_judgment":"PRESENT","evidence":"c.1832G>A (p.R611Q)","abstract_start":797,"abstract_end":816},{"Name":"NM_000548.5(TSC2):c.648+1G>A","Chromosome":"16","Start":"2056245","Stop":"2056245","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":58572,"rule_based_match":true,"evidence_text":"c.648+1G>A","llm_judgment":"PRESENT","evidence":"c.648+1G>A","abstract_start":656,"abstract_end":666},{"Name":"NM_000368.5(TSC1):c.2111_2112del (p.Leu703_Tyr704insTer)","Chromosome":"9","Start":"132903747","Stop":"132903748","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":58067,"rule_based_match":true,"evidence_text":"c.2111_2112delAT","llm_judgment":"PRESENT","evidence":"c.2111_2112delAT","abstract_start":453,"abstract_end":469},{"Name":"NM_000548.5(TSC2):c.4544_4547del (p.Asn1515fs)","Chromosome":"16","Start":"2084998","Stop":"2085001","ReferenceAlleleVCF":"TCAAA","AlternateAlleleVCF":"T","allel_id":58466,"rule_based_match":true,"evidence_text":"c.4544_4547delACAA","llm_judgment":"PRESENT","evidence":"c.4544_4547delACAA","abstract_start":736,"abstract_end":754}]}
{"pmid":"30446579","title":"A newly identified mutation in the","abstract":"Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene (<i>PEX26</i>) in a 19-yr-old female of Ashkenazi Jewish descent who was referred for moderate to severe hearing loss. The proband and three affected siblings are all homozygous for the c.153C>A variant. Skin fibroblasts from this patient show normal morphology in immunostaining of matrix proteins, although the level of catalase was elevated. Import rate of matrix proteins was significantly decreased in the patient-derived fibroblasts. Binding of Pex26-F51L to the AAA ATPase peroxins, Pex1 and Pex6, is severely impaired and affects peroxisome assembly. Moreover, Pex26 in the patient's fibroblasts is reduced to ∼30% of the control, suggesting that Pex26-F51L is unstable in cells. In the patient's fibroblasts, peroxisome-targeting signal 1 (PTS1) proteins, PTS2 protein 3-ketoacyl-CoA thiolase, and catalase are present in a punctate staining pattern at 37°C and in a diffuse pattern at 42°C, suggesting that these matrix proteins are not imported to peroxisomes in a temperature-sensitive manner. Analysis of peroxisomal metabolism in the patient's fibroblasts showed that the level of docosahexaenoic acid (DHA) (C22:6n-3) in ether phospholipids is decreased, whereas other lipid metabolism, including peroxisomal fatty acid β-oxidation, is normal. Collectively, the functional data support the mild phenotype of nonsyndromic hearing loss in patients harboring the F51L variant in <i>PEX26</i>.","variants":[{"Name":"NM_001127649.3(PEX26):c.153C>A (p.Phe51Leu)","Chromosome":"22","Start":"18078529","Stop":"18078529","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":347064,"rule_based_match":true,"evidence_text":"c.153C>A (p.F51L)","llm_judgment":"PRESENT","evidence":"c.153C>A (p.F51L)","abstract_start":93,"abstract_end":110}]}
{"pmid":"27798933","title":"A Pediatric Patient with a CYP24A1 Mutation: Four Years of Clinical, Biochemical, and Imaging Follow-Up.","abstract":"BACKGROUND: A female infant was admitted to hospital due to failure to thrive. She presented hypercalcemia (4.09 mmol/L, normal range: 2.2-2.65 mmol/L), high 25-hydroxyvitamin D (283 nmol/L, normal range: 75-250 nmol/L), 1,25-dihydroxyvitamin D in the upper normal range, and low parathyroid hormone. Vitamin D intoxication was suspected. The patient had received routine rickets prophylaxis.\nMETHODS: Williams-Beuren syndrome was genetically excluded. Sequencing of CYP24A1 showed 2 mutations: c.443T>C and c.1186C>T.\nRESULTS: The patient's clinical status improved after intravenous rehydration, cessation of supplementation, and on a low-calcium diet. 25-Hydroxyvitamin D concentrations normalized within days, while 1,25-dihydroxyvitamin D remained in the upper normal range. We also investigated our patient's bone health.\nCONCLUSION: The patient was hospitalized initially on suspicion of vitamin D intoxication but proved to be a case of compound heterozygosity. Data on the long-term clinical and biochemical evolution of patients with idiopathic infantile hypercalcemia are sparse. Our follow-up showed seasonal variations of vitamin D and calcium parameters, with no influence on kidney function or bone health for the investigated period.","variants":[{"Name":"NM_000782.5(CYP24A1):c.443T>C (p.Leu148Pro)","Chromosome":"20","Start":"54172915","Stop":"54172915","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":620664,"rule_based_match":true,"evidence_text":"c.443T>C","llm_judgment":"PRESENT","evidence":"c.443T>C","abstract_start":495,"abstract_end":503},{"Name":"NM_000782.5(CYP24A1):c.1186C>T (p.Arg396Trp)","Chromosome":"20","Start":"54158136","Stop":"54158136","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38634,"rule_based_match":true,"evidence_text":"c.1186C>T","llm_judgment":"PRESENT","evidence":"c.1186C>T","abstract_start":508,"abstract_end":517}]}
{"pmid":"32109420","title":"De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.","abstract":"Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins. The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function, and conversely, the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect. Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms.","variants":[{"Name":"NM_001007228.2(SPOP):c.362G>A (p.Arg121Gln)","Chromosome":"17","Start":"49619099","Stop":"49619099","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":818727,"rule_based_match":true,"evidence_text":"c.362G>A (p.Arg121Gln)","llm_judgment":"PRESENT","evidence":"c.362G>A (p.Arg121Gln)","abstract_start":872,"abstract_end":894},{"Name":"NM_001007228.2(SPOP):c.430G>A (p.Asp144Asn)","Chromosome":"17","Start":"49619031","Stop":"49619031","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":818728,"rule_based_match":true,"evidence_text":"c. 430G>A (p.Asp144Asn)","llm_judgment":"PRESENT","evidence":"c. 430G>A (p.Asp144Asn)","abstract_start":899,"abstract_end":922},{"Name":"NM_001007228.2(SPOP):c.395G>T (p.Gly132Val)","Chromosome":"17","Start":"49619066","Stop":"49619066","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":818729,"rule_based_match":true,"evidence_text":"c.395G>T (p.Gly132Val)","llm_judgment":"PRESENT","evidence":"c.395G>T (p.Gly132Val)","abstract_start":1062,"abstract_end":1084},{"Name":"NM_001007228.2(SPOP):c.73A>G (p.Thr25Ala)","Chromosome":"17","Start":"49622738","Stop":"49622738","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":818730,"rule_based_match":true,"evidence_text":"c.73A>G (p.Thr25Ala)","llm_judgment":"PRESENT","evidence":"c.73A>G (p.Thr25Ala)","abstract_start":1017,"abstract_end":1037},{"Name":"NM_001007228.2(SPOP):c.412C>T (p.Arg138Cys)","Chromosome":"17","Start":"49619049","Stop":"49619049","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":818731,"rule_based_match":true,"evidence_text":"c.412C>T (p.Arg138Cys)","llm_judgment":"PRESENT","evidence":"c.412C>T (p.Arg138Cys)","abstract_start":1090,"abstract_end":1112},{"Name":"NM_001007228.2(SPOP):c.248A>G (p.Tyr83Cys)","Chromosome":"17","Start":"49619338","Stop":"49619338","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":818732,"rule_based_match":true,"evidence_text":"c.248A>G (p.Tyr83Cys)","llm_judgment":"PRESENT","evidence":"c.248A>G (p.Tyr83Cys)","abstract_start":1039,"abstract_end":1060}]}
{"pmid":"36367610","title":"A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia.","abstract":"PURPOSE: Pathogenic variants (PVs) in BRCA1 and BRCA2 genes are essential biomarkers of an increased breast and ovarian cancer risk and tumor sensitivity to poly ADP ribose polymerase inhibitors. In Russia, eight PVs were thought to be the most common, among which BRCA1 c.5266dup is the most frequently identified one.\nMETHODS: We show the distribution of BRCA1/2 PVs identified with quantitative PCR and targeted next-generation sequencing in 1399 ovarian cancer patients recruited into the study from 72 Russian regions in 2015-2021.\nRESULTS: The most abundant PVs were c.5266dup (41.0%), c.4035del (7.0%), c.1961del (6.3%), c.181 T > G (5.2%), c.3756_3759del (1.8%), c.3700_3704del (1.5%), and c.68_69del (1.5%), all found in BRCA1 and known to be recurrent in Russia. Several other frequent PVs were identified: c.5152 + 1G > T (1.2%), c.1687C > T (1.0%), c.4689C > G (0.9%), c.1510del (0.6%), c.2285_2286del (0.6%) in the BRCA1 gene; and c.5286 T > G (1.2%), c.2808_2811del (0.8%), c.3847_3848del (0.8%), c.658_659del (0.7%), c.7879A > T (0.6%), in the BRCA2 gene. For the most common PV in the BRCA2 gene c.5286 T > G, we suggested that it arose about 700 years ago and is a new founder mutation.\nCONCLUSION: This study extends our knowledge about the BRCA1 and BRCA2 pathogenic variants variability.","variants":[{"Name":"NM_007294.4(BRCA1):c.3700_3704del (p.Val1234fs)","Chromosome":"17","Start":"43091827","Stop":"43091831","ReferenceAlleleVCF":"GTTTAC","AlternateAlleleVCF":"G","allel_id":46098,"rule_based_match":true,"evidence_text":"c.3700_3704del","llm_judgment":"PRESENT","evidence":"c.3700_3704del","abstract_start":671,"abstract_end":685},{"Name":"NM_007294.4(BRCA1):c.1687C>T (p.Gln563Ter)","Chromosome":"17","Start":"43093844","Stop":"43093844","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45982,"rule_based_match":true,"evidence_text":"c.1687C>T","llm_judgment":"PRESENT","evidence":"c.1687C > T","abstract_start":841,"abstract_end":852}]}
{"pmid":"24677762","title":"FKBP14-related Ehlers-Danlos syndrome: expansion of the phenotype to include vascular complications.","abstract":"Biallelic mutations in FKBP14 cause a recessive form of Ehlers-Danlos syndrome (EDS) characterized by progressive kyphoscoliosis, myopathy, and hearing loss. To date, four children and one adult with this condition have been reported. We recently identified a 42-year-old man with severe kyphoscoliosis, restrictive/obstructive lung disease, short stature, mild hearing loss, decreased muscle mass, and a dissection of the celiac artery at age 41. He also had complete occlusion of the superior mesenteric artery with compensatory flow through an enlarged and tortuous inferior mesenteric artery. He was homozygous for a previously identified FKBP14 mutation, c.362dupC, p.(Glu122Argfs*7). He had no mutations in COL3A1, ACTA2, TGFBR1, TGFBR2, or SMAD3. The FKBP14 mutations in our patient occurred on the same haplotype as others with this same mutation. Although one family member in a previous report was thought to have early vascular complications, it could not be confirmed that she had biallelic mutations in FKBP14. This report expands the phenotype of FKBP14-related EDS to include risk for vascular complications and also raises the question of whether the shared haplotype represents a risk allele or founder mutation.","variants":[{"Name":"NM_017946.4(FKBP14):c.362dup (p.Glu122fs)","Chromosome":"7","Start":"30019110","Stop":"30019111","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":264319,"rule_based_match":true,"evidence_text":"c.362dup","llm_judgment":"PRESENT","evidence":"c.362dup","abstract_start":660,"abstract_end":668}]}
{"pmid":"22051731","title":"Phenotypic heterogeneity in Chinese patients with hepatocyte nuclear factor-1β mutations.","abstract":"AIMS/HYPOTHESIS: The aim of this study was to investigate clinical spectrum of hepatocyte nuclear factor-1β (HNF-1β) mutation in Chinese diabetic patients with renal dysfunction and/or structure abnormalities.\nMATERIALS AND METHODS: A total of 104 diabetic patients with renal structural abnormalities and/or non-diabetic renal dysfunction were recruited and HNF-1β mutation was screened by direct sequencing.\nRESULTS: Three heterozygous missense mutations including c.494G>A (p.R165H), c.662A>T (p.D221V) and c.780G>C (p.E260D) were identified. Progression of diabetes and mild decline of renal function were observed in the mutation carriers during the follow-up. The p.R165H mutation carrier had severe β-cell dysfunction and different extrapancreatic phenotypes. Compared with type 2 diabetes and normoglycemics, the p.R165H mutation carrier had a lower basal C-peptide (0.30, 0.61±0.07 and 0.50±0.04 nmol/L for p.R165H, type 2 diabetes and normoglycemics, respectively) and low values of acute C-peptide response to arginine (0.15, 0.48±0.18 and 0.76±0.08 nmol/L for p.R165H, type 2 diabetes and normoglycemics, respectively).\nCONCLUSION: Patients with the HNF-1β mutation in our population can have different pancreatic and extrapancreatic phenotypes. The exact contributions of mutations to the phenotypes await functional confirmation.","variants":[{"Name":"NM_000458.4(HNF1B):c.662A>T (p.Asp221Val)","Chromosome":"17","Start":"37733704","Stop":"37733704","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":623485,"rule_based_match":true,"evidence_text":"c.662A>T (p.D221V)","llm_judgment":"PRESENT","evidence":"c.662A>T (p.D221V)","abstract_start":487,"abstract_end":505},{"Name":"NM_000458.4(HNF1B):c.780G>C (p.Glu260Asp)","Chromosome":"17","Start":"37733586","Stop":"37733586","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":589333,"rule_based_match":true,"evidence_text":"c.780G>C (p.E260D)","llm_judgment":"PRESENT","evidence":"c.780G>C (p.E260D)","abstract_start":510,"abstract_end":528},{"Name":"NM_000458.4(HNF1B):c.494G>A (p.Arg165His)","Chromosome":"17","Start":"37739490","Stop":"37739490","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27686,"rule_based_match":true,"evidence_text":"c.494G>A (p.R165H)","llm_judgment":"PRESENT","evidence":"c.494G>A (p.R165H)","abstract_start":467,"abstract_end":485}]}
{"pmid":"19753316","title":"A novel mutation in GRK1 causes Oguchi disease in a consanguineous Pakistani family.","abstract":"PURPOSE: The purpose of this study was to identify the underlying molecular genetic defect in a large consanguineous Pakistani family with Oguchi disease who had been given a diagnosis of autosomal recessive retinitis pigmentosa.\nMETHODS: The family was genotyped with the Affymetrix 10K single nucleotide polymorphism array. Fine-mapping of a common homozygous region on chromosome 13q was performed using fluorescent microsatellite markers. Mutation analysis was done by direct sequencing of the candidate gene GRK1 located in the region. The segregation of a novel mutation in the family and the frequency of the identified mutation in the Pakistani population were determined by StuI RFLP analysis.\nRESULTS: Genetic mapping supported the diagnosis of typical Oguchi disease in a Pakistani family and also resulted in the identification of a novel nonsense mutation (c.614C>A; p.S205X) in exon 1 of GRK1. This mutation is predicted to result in premature termination of the protein product, thereby affecting the phototransduction cascade. A clinical reappraisal of the family revealed that all patients homozygous for this variant had Oguchi disease.\nCONCLUSIONS: This is the first report to describe a mutation causing typical Oguchi disease in a large consanguineous Pakistani family. This mutation segregated in eight affected members.","variants":[{"Name":"NM_002929.3(GRK1):c.614C>A (p.Ser205Ter)","Chromosome":"13","Start":"113668000","Stop":"113668000","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":858600,"rule_based_match":true,"evidence_text":"c.614C>A; p.S205X","llm_judgment":"PRESENT","evidence":"c.614C>A; p.S205X","abstract_start":870,"abstract_end":887}]}
{"pmid":"29276052","title":"Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population: Genetic and Clinical Aspects.","abstract":"PURPOSE: To analyze the genetic and clinical findings in retinitis pigmentosa (RP) patients of Ashkenazi Jewish (AJ) descent, aiming to identify genotype-phenotype correlations.\nDESIGN: Cohort study.\nPARTICIPANTS: Retinitis pigmentosa patients from 230 families of AJ origin.\nMETHODS: Sanger sequencing was performed to detect specific founder mutations known to be prevalent in the AJ population. Ophthalmologic analysis included a comprehensive clinical examination, visual acuity (VA), visual fields, electroretinography, color vision testing, and retinal imaging by OCT, pseudocolor, and autofluorescence fundus photography.\nMAIN OUTCOME MEASURES: Inheritance pattern and causative mutation; retinal function as assessed by VA, visual fields, and electroretinography results; and retinal structural changes observed on clinical funduscopy as well as by pseudocolor, autofluorescence, and OCT imaging.\nRESULTS: The causative mutation was identified in 37% of families. The most prevalent RP-causing mutations are the Alu insertion (c.1297_8ins353, p.K433Rins31*) in the male germ cell-associated kinase (MAK) gene (39% of families with a known genetic cause for RP) and c.124A>G, p.K42E in dehydrodolichol diphosphate synthase (DHDDS) (33%). Additionally, disease-causing mutations were identified in 11 other genes. Analysis of clinical parameters of patients with mutations in the 2 most common RP-causing genes revealed that MAK patients had better VA and visual fields at relatively older ages in comparison with DHDDS patients. Funduscopic findings of DHDDS patients matched those of MAK patients who were 20 to 30 years older. Patients with DHDDS mutations were referred for electrophysiologic evaluation at earlier ages, and their cone responses became nondetectable at a much younger age than MAK patients.\nCONCLUSIONS: Our AJ cohort of RP patients is the largest reported to date and showed a substantial difference in the genetic causes of RP compared with cohorts of other populations, mainly a high rate of autosomal recessive inheritance and a unique composition of causative genes. The most common RP-causing genes in our cohort, MAK and DHDDS, were not described as major causative genes in other populations. The clinical data show that in general, patients with biallelic MAK mutations had a later age of onset and a milder retinal phenotype compared with patients with biallelic DHDDS mutations.","variants":[{"Name":"NM_205861.3(DHDDS):c.124A>G (p.Lys42Glu)","Chromosome":"1","Start":"26438228","Stop":"26438228","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":39666,"rule_based_match":true,"evidence_text":"c.124A>G, p.K42E","llm_judgment":"PRESENT","evidence":"c.124A>G, p.K42E","abstract_start":1173,"abstract_end":1189}]}
{"pmid":"19906044","title":"CHILD syndrome: the NSDHL gene and its role in CHILD syndrome, a rare hereditary disorder.","abstract":"BACKGROUND: CHILD syndrome, a rare hereditary disorder of keratinization (MIM 308050, 300275), is the acronym proposed by Happle to name a rare entity, characterized by congenital hemidysplasia, icthyosiform nevus and limb defects, ranging from digital hypoplasia to icthyosiform nevus and ipsilateral limb defects, ranging from digital hypoplasia to complete amelia.\nPATIENTS AND METHODS: A 9-month-old female infant presented with skin and limb defects involving the right side of her body. Clinical and laboratory evaluation was performed, including DNA sequence analysis of the NSDHL gene.\nRESULTS: Our patient presented with some of the typical clinical characteristics of CHILD syndrome, i.e. two large erythematous plaques with sharp borders, covered with yellow, wax-like scaling, on the right axilla and on the right groin, dysplastic right hand and alopecia of the right occipital area. The diagnosis was confirmed by DNA screening analysis, that detected a missense mutation c.314C-->T;p-A105V, in the coding region of the NSDHL gene (exon4) of our patient.\nCONCLUSIONS: This is the first report of CHILD syndrome ever reported in Greece. We suggest that the diagnosis of the syndrome is important for patient information and genetic counselling.","variants":[{"Name":"NM_015922.3(NSDHL):c.314C>T (p.Ala105Val)","Chromosome":"X","Start":"152858816","Stop":"152858816","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26465,"rule_based_match":false,"evidence_text":"c.314C-->T;p-A105V","llm_judgment":"PRESENT","evidence":"c.314C-->T;p-A105V","abstract_start":986,"abstract_end":1004}]}
{"pmid":"24899262","title":"Autosomal dominant inheritance of rapidly progressive amyotrophic lateral sclerosis due to a truncation mutation in the fused in sarcoma (FUS) gene.","abstract":"Mutations in the gene encoding the RNA-binding protein fused in sarcoma (FUS) account for 4 - 5% of familial cases of amyotrophic lateral sclerosis (ALS). We describe the identification and in vitro cellular characterization of a genetic mutation in a family in which the index case, and subsequently her two children, each developed rapidly progressive ALS at a young age and died within a year of onset. Exome capture and sequencing revealed a mutation in the FUS gene consisting of a 2-bp deletion, c.1509_1510delAG, resulting in a predicted truncated protein, p.G504Wfs * 12, lacking the nuclear localization signal. Expression of this mutation in HEK293 and NSC-34 cells demonstrated severe cytoplasmic mislocalization of mutant FUS, and colocalization with stress granules when compared to wild-type, R521C and P525L mutant FUS. This study provides further evidence of a broad correlation between clinical severity of FUS-related ALS and mislocalization of the protein to the cytoplasm.","variants":[{"Name":"NM_004960.4(FUS):c.1509_1510del (p.Gly504fs)","Chromosome":"16","Start":"31191076","Stop":"31191077","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":1467921,"rule_based_match":true,"evidence_text":"c.1509_1510delAG","llm_judgment":"PRESENT","evidence":"c.1509_1510delAG","abstract_start":502,"abstract_end":518}]}
{"pmid":"24904850","title":"p.R182C mutation in Korean twin with congenital lipoid adrenal hyperplasia.","abstract":"Congenital lipoid adrenal hyperplasia (CLAH) is the most severe form of congenital adrenal hyperplasia which is caused by mutations in the steroidogenic acute regulatory protein (StAR). The mutations in StAR gene resulted in failure of the transport cholesterol into mitochondria for steroidogenesis in the adrenal gland. Twin sisters (A, B) with normal 46, XX were born at 36+2 gestational week, premature to nonrelated parents. They had symptoms as hyperpigmentation, slightly elevated potassium level and low level of sodium. Laboratory finding revealed normal 17-hydroxyprogesterone level, elevated adrenocorticotropin hormone (A, 4,379.2 pg/mL; B, 11,616.1 pg/mL), and high plasma renin activity (A, 49.02 ng/mL/hr; B, 52.7 ng mL/hr). However, the level of plasma cortisol before treatment was low (1.5 µg/dL) in patient B but normal (8.71 µg/dL) in patient A. Among them, only patient A was presented with adrenal insufficiency symptoms which was suggestive of CLAH and prompted us to order a gene analysis in both twin. The results of gene analysis of StAR in twin revealed same heterozygous conditions for c.544C>T (Arg182Cys) in exon 5 and c.722C>T (Gln258(*)) in exon 7. We report the first case on the mutation of p.R182C in exon 5 of the StAR gene in Korea.","variants":[{"Name":"NM_000349.3(STAR):c.544C>T (p.Arg182Cys)","Chromosome":"8","Start":"38146069","Stop":"38146069","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544414,"rule_based_match":true,"evidence_text":"c.544C>T (Arg182Cys)","llm_judgment":"PRESENT","evidence":"c.544C>T (Arg182Cys)","abstract_start":1114,"abstract_end":1134}]}
{"pmid":"27316387","title":"Intra-familial phenotypic variability in a Moroccan family with hearing loss and palmoplantar keratoderma (PPK).","abstract":"Mutations in the GJB2 gene encoding connexin 26 are the main cause of hereditary hearing impairment. These mutations generate mainly autosomal recessive and rarely autosomal dominant deafness. Dominant mutations in GJB2 can be responsible for isolated deafness as well as syndromic hearing loss associated with various skin abnormalities. Until now few papers discuss dominant mutations in the GJB2 gene. In this work we report a rare case about a Moroccan family with a compound heterozygous mutation (the dominant p.R75Q and the recessive c.35delG alleles) in the GJB2 gene with intra-familial phenotypic variability. This study reinforces the involvement of p.R75Q mutation of GJB2 in syndromic deafness associated with dermatological diseases the palmoplantar keratoderma.","variants":[{"Name":"NM_004004.6(GJB2):c.224G>A (p.Arg75Gln)","Chromosome":"13","Start":"20189358","Stop":"20189358","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32066,"rule_based_match":false,"evidence_text":"p.R75Q","llm_judgment":"PRESENT","evidence":"p.R75Q","abstract_start":516,"abstract_end":522}]}
{"pmid":"33511985","title":"Achondroplasia-First Report from India of a Rare FGFR3 Gene Variant.","abstract":"The clinical manifestations of FGFR3 sequence variations can vary from mild unnoticed short stature to neonatal lethal dwarfism and can be causative of phenotypes including achondroplasia, hypochondroplasia, and thanatophoric dysplasia. Clinical data describe an 11 month old girl with restricted growth and preserved intellect. She had rhizomelic short stature with peculiar facies but no Acanthosis nigricans. In view of the absence of the hotspot mutation c.1138 G>A/G>C (p.Gly380Arg), complete gene sequencing was done that revealed a rare sequence variation, NM_000142.4:c.1043C>G (p.Ser348Cys) in FGFR3. This sequence variation has not been reported from India so far. This report emphasizes the benefit of sequencing the whole gene in individuals who are negative for hotspot mutation of achondroplasia with strong clinical suspicion.","variants":[{"Name":"NM_000142.5(FGFR3):c.1043C>G (p.Ser348Cys)","Chromosome":"4","Start":"1803804","Stop":"1803804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1517670,"rule_based_match":true,"evidence_text":"NM_000142.4:c.1043C>G (p.Ser348Cys)","llm_judgment":"PRESENT","evidence":"NM_000142.4:c.1043C>G (p.Ser348Cys)","abstract_start":564,"abstract_end":599}]}
{"pmid":"33977028","title":"A founder mutation in the","abstract":"Pyridoxine-dependent epilepsy (PDE) is a relatively rare subgroup of epileptic disorders. They generally present in infancy as an early onset epileptic encephalopathy or seizures, refractory to standard treatments, with rapid and variable responses to vitamin B6 treatment. Whole exome sequencing of three unrelated families identified homozygous pathogenic mutation c.370_373del, p.Asp124fs in <i>PLPBP</i> gene in five persons. Haplotype analysis showed a single shared profile for the affected persons and their parents, leading to a hypothesis about founder effect of the mutation in Saguenay-Lac-St-Jean region of French Canadians. All affected probands also shared one single mitochondrial haplotype T2b3 and two rare variations in the mitochondrial genome m.801A>G and m.5166A>G suggesting that a single individual female introduced <i>PLPBP</i> mutation c.370_373del, p.Asp124fs in Quebec. The mutation p.Asp124fs causes a severe disease phenotype with delayed myelination and cortical/subcortical brain atrophy. The most noteworthy radiological finding in this Quebec founder mutation is the presence of the temporal cysts that can be used as a marker of the disease. Also, both patients, who are alive, had a history of prenatal supplements taken by their mothers as antiemetic medication with high doses of pyridoxine. In the context of suspected PDE in patients with neonatal refractory seizures, treatment with pyridoxine and/or Pyridoxal-5-phophate has to be started immediately and continued until the results of genetic analysis received. Even with early appropriate treatment, neurological outcome of our patient is still poor.","variants":[{"Name":"NM_007198.4(PLPBP):c.370_373del (p.Asp124fs)","Chromosome":"8","Start":"37772803","Stop":"37772806","ReferenceAlleleVCF":"GCAGA","AlternateAlleleVCF":"G","allel_id":495361,"rule_based_match":true,"evidence_text":"c.370_373del, p.Asp124fs","llm_judgment":"PRESENT","evidence":"c.370_373del, p.Asp124fs","abstract_start":367,"abstract_end":391}]}
{"pmid":"24664145","title":"Clinical diagnosis, treatment, and ALDH7A1 mutations in pyridoxine-dependent epilepsy in three Chinese infants.","abstract":"Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that causes seizures in neonates and infants. Mutations of the ALDH7A1 gene are now recognized as the molecular basis PDE and help to define this disease. Three Chinese children with PDE were clinically analyzed, followed by treatment and examination of the ALDH7A1 mutations. The seizures of the 3 patients were all resistant to multiple anticonvulsants (2 to 7 types). For case 1, onset of seizures was at the age of 2 months. His seizures were well controlled by intravenous pyridoxine for several days at the age of 3 months 20 days and recurred at intervals of 13, 14 and 38 days after pyridoxine withdrawn for 3 times. At the age of 7 months, symptoms of PDE appeared and uninterrupted oral pyridoxine started. For case 2, her seizures occurred at 8 days after birth. After administration of multiple antiepileptic drugs observed ineffective, high-dose pyridoxine continuous therapy was taken at the age of 10 months and the significant treatment effect induced a diagnostic PDE. Seizure onset in case 3 was at the first day of birth. He experienced inadvertently pyridoxine therapy several times (first time at 2 days after birth) and achieved good therapeutic effect, which was confirmed by physicians until 4 months 10 days. The treatment process in our 3 patients suggested that pyridoxine should be early and purposefully used in patients with early onset seizures. ALDH7A1 gene mutation analysis revealed compound heterozygous mutations in each case: heterozygous c.410G>A (p.G137E) and IVS11+1G>A in case 1, heterozygous c.952G>C (p.A318P) and heterozygous c.965C>T (p.A322V) in case 2, and heterozygous c.902A>T (p.N301I) and IVS11+1G>A in case 3. Only p.N301I was reported previously, all other mutations were novel. This is the first time to report cases of Chinese patients diagnosed with PDE by molecular genetic analysis.","variants":[{"Name":"NM_001182.5(ALDH7A1):c.952G>C (p.Ala318Pro)","Chromosome":"5","Start":"126559296","Stop":"126559296","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":454656,"rule_based_match":true,"evidence_text":"c.952G>C (p.A318P)","llm_judgment":"PRESENT","evidence":"c.952G>C (p.A318P)","abstract_start":1609,"abstract_end":1627},{"Name":"NM_001182.5(ALDH7A1):c.902A>T (p.Asn301Ile)","Chromosome":"5","Start":"126561094","Stop":"126561094","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":33040,"rule_based_match":true,"evidence_text":"c.902A>T (p.N301I)","llm_judgment":"PRESENT","evidence":"c.902A>T (p.N301I)","abstract_start":1692,"abstract_end":1710},{"Name":"NM_001182.5(ALDH7A1):c.965C>T (p.Ala322Val)","Chromosome":"5","Start":"126559283","Stop":"126559283","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1203219,"rule_based_match":true,"evidence_text":"c.965C>T (p.A322V)","llm_judgment":"PRESENT","evidence":"c.965C>T (p.A322V)","abstract_start":1645,"abstract_end":1663}]}
{"pmid":"38162154","title":"A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in","abstract":"Spondylometaphyseal dysplasia Algerian type (MIM no.: 184253) is an uncommon autosomal dominant skeletal dysplasia caused by heterozygous mutations in the <i>COL2A1</i> gene (MIM no.: 120140). In this case based review, we reported a 5-year-old boy with short stature, severe dorsolumbar scoliosis, lumbar hyperlordosis, short trunk, and severe genu valgum <i>.</i> Radiological examination showed platyspondyly, irregular metaphyseal radiolucencies intermingled with radiodensities, and corner fractures. The patient has a c.3275G > A; p.Gly1092Asp mutation in exon 47 of the <i>COL2A1</i> gene and a variant of unknown significance in c.1366-13C > A in intron 21. This latter sequence variant could partially or completely disrupt the natural splice acceptor site of intron 21/exon 22 in the <i>COL2A1</i> gene leading to a potential modification of the phenotypic severity.","variants":[{"Name":"NM_001844.5(COL2A1):c.3275G>A (p.Gly1092Asp)","Chromosome":"12","Start":"47977154","Stop":"47977154","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":194725,"rule_based_match":true,"evidence_text":"c.3275G > A; p.Gly1092Asp","llm_judgment":"PRESENT","evidence":"c.3275G > A; p.Gly1092Asp","abstract_start":524,"abstract_end":549}]}
{"pmid":"29357978","title":"Reccurrent F8 Intronic Deletion Found in Mild Hemophilia A Causes Alu Exonization.","abstract":"Incorporation of distant intronic sequences in mature mRNA is an underappreciated cause of genetic disease. Several disease-causing pseudoexons have been found to contain repetitive elements such as Alu elements. This study describes an original pathological mechanism by which a small intronic deletion leads to Alu exonization. We identified an intronic deletion, c.2113+461_2113+473del, in the F8 intron 13, in two individuals with mild hemophilia A. In vivo and in vitro transcript analysis found an aberrant transcript, with an insertion of a 122-bp intronic fragment (c.2113_2114ins2113+477_2113+598) at the exon 13-14 junction. This out-of-frame insertion is predicted to lead to truncated protein (p.Gly705Aspfs<sup>∗</sup>37). DNA sequencing analysis found that the pseudoexon corresponds to antisense AluY element and the deletion removed a part of the poly(T)-tail from the right arm of these AluY. The heterogenous nuclear riboprotein C1/C2 (hnRNP C) is an important antisense Alu-derived cryptic exon silencer and binds to poly(T)-tracts. Disruption of the hnRNP C binding site in AluY T-tract by mutagenesis or hnRNP C knockdown using siRNA in HeLa cells reproduced the effect of c.2113+461_2113+473del. The screening of 114 unrelated families with mild hemophilia A in whom no genetic event was previously identified found a deletion in the poly(T)-tail of AluY in intron 13 in 54% of case subjects (n = 61/114). In conclusion, this study describes a deletion leading to Alu exonization found in 6.1% of families with mild hemophila A in France.","variants":[{"Name":"NM_000132.4(F8):c.2113+461_2113+473del","Chromosome":"X","Start":"154947225","Stop":"154947237","ReferenceAlleleVCF":"GAAAAAAAAAAAAA","AlternateAlleleVCF":"G","allel_id":494917,"rule_based_match":true,"evidence_text":"c.2113+461_2113+473del","llm_judgment":"PRESENT","evidence":"c.2113+461_2113+473del","abstract_start":366,"abstract_end":388}]}
{"pmid":"21811586","title":"Newborn genetic screening for hearing impairment: a preliminary study at a tertiary center.","abstract":"Universal newborn hearing screening (UNHS) is of paramount importance for early identification and management of hearing impairment in children. However, infants with slight/mild, progressive, or late-onset hearing impairment might be missed in conventional UNHS. To investigate whether genetic screening for common deafness-associated mutations could assist in identifying these infants, 1017 consecutive newborns in a tertiary hospital were subjected to both newborn hearing screening using a two-step distortion-product otoacoustic emissions (DPOAE) screening and newborn genetic screening (NGS) for deafness. The NGS targeted 4 deafness-associated mutations commonly found in the Taiwanese population, including p.V37I (c.109G>A) and c.235delC of the GJB2 gene, c.919-2A>G of the SLC26A4 gene, and mitochondrial m.1555A>G of the 12S rRNA gene. The results of the NGS were then correlated to the results of the NHS. Of the 1017 newborns, 16 (1.6%) had unilateral DPOAE screening failure, and 22 (2.2%) had bilateral DPOAE screening failure. A total of 199 (19.6%) babies were found to have at least 1 mutated allele on the NGS for deafness, 11 (1.1%) of whom were homozygous for GJB2 p.V37I, 6 (0.6%) compound heterozygous for GJB2 p.V37I and c.235delC, and 1 (0.1%) homoplasmic for m.1555A>G, who may potentially have hearing loss. Among them, 3 babies, 5 babies, and 1 baby, respectively, passed the NHS at birth. Comprehensive audiological assessments in the 9 babies at 3 months identified 1 with slight hearing loss and 2 with mild hearing loss. NGS for common deafness-associated mutations may identify infants with slight/mild or potentially progressive hearing impairment, thus compensating for the inherent limitations of the conventional UNHS.","variants":[{"Name":"NC_012920.1(MT-ND1):m.1555A>G","Chromosome":"MT","Start":"1555","Stop":"1555","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":24667,"rule_based_match":true,"evidence_text":"m.1555A>G","llm_judgment":"PRESENT","evidence":"m.1555A>G","abstract_start":816,"abstract_end":825},{"Name":"NM_004004.6(GJB2):c.109G>A (p.Val37Ile)","Chromosome":"13","Start":"20189473","Stop":"20189473","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32062,"rule_based_match":true,"evidence_text":"p.V37I (c.109G>A)","llm_judgment":"PRESENT","evidence":"p.V37I (c.109G>A)","abstract_start":716,"abstract_end":733}]}
{"pmid":"18669544","title":"A novel founder BBS1 mutation explains a unique high prevalence of Bardet-Biedl syndrome in the Faroe Islands.","abstract":"BACKGROUND/AIM: Bardet-Biedl syndrome is a multiorgan disease presenting with retinitis pigmentosa leading to blindness. The aim of the study was to investigate the genetic background of Bardet-Biedl syndrome in the Faroe Island. It was hypothesised that a common genetic background for the syndrome would be found.\nMETHODS: Patients were identified from the files of the Retinitis Pigmentosa Register at the National Eye Clinic, Denmark. The diagnosis of Bardet-Biedl syndrome was verified from medical files. Mutational screening of BBS1, BBS2, BBS4, MKKS and BBS10 was done by denaturing high-performance liquid chromatography.\nRESULTS: Out of 13 prevalent cases in the Faroe Islands, 10 patients from nine families were included. A novel splice site mutation in BBS1, c.1091+3G>C, was identified, and this was predicted to affect protein function by skipping 16 amino acids. Nine patients were homozygous for this mutation, while one patient was compound heterozygous with a recurrent BBS1 mutation, p.Met390Arg. The patients presented with severe ophthalmic phenotypes, while the systemic manifestations of the disease were apparently milder.\nCONCLUSION: A novel BBS1 mutation was identified, most probably a founder mutation, further confirming the Faroe Islands as a genetic isolate. The phenotypic expression of the Faroese patients suggests that different mutations in BBS1 affect various organs differently.","variants":[{"Name":"NM_024649.5(BBS1):c.1169T>G (p.Met390Arg)","Chromosome":"11","Start":"66526181","Stop":"66526181","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":27182,"rule_based_match":false,"evidence_text":"p.Met390Arg","llm_judgment":"PRESENT","evidence":"p.Met390Arg","abstract_start":1004,"abstract_end":1015}]}
{"pmid":"25227139","title":"Desmoplakin mutations with palmoplantar keratoderma, woolly hair and cardiomyopathy.","abstract":"Mutations in genes encoding for desmosomal components are associated with a broad spectrum of phenotypes comprising skin and hair abnormalities and account for 45-50% of cases of arrhythmogenic right ventricular cardiomyopathy. Today, more than 120 dominant and recessive desmoplakin (DSP) gene mutations have been reported to be associated with skin, hair and/or heart defects. Here we report on 3 cases with yet unreported DSP mutations, c.7566_7567delAAinsC, p.R2522Sfs*39, c.7756C>T, p.R2586*, c.2131_2132delAG and c.1067C>A, p.T356K, that were associated with variable woolly hair or hypotrichosis, palmoplantar keratoderma, and cardiac manifestations. In addition, we review and summarise the clinical features and DSP mutations of the patients described in the literature, which illustrates the complexity of this group of disorders and of their genotype-phenotype correlations, which cannot be easily predicted. Early diagnosis is crucial and cardiac examinations have to be performed on a regular basis.","variants":[{"Name":"NM_004415.2(DSP):c.2131_2132delAG","Chromosome":"6","Start":"7574084","Stop":"7574085","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":153685,"rule_based_match":true,"evidence_text":"c.2131_2132delAG","llm_judgment":"PRESENT","evidence":"c.2131_2132delAG","abstract_start":498,"abstract_end":514},{"Name":"NM_004415.4(DSP):c.1067C>A (p.Thr356Lys)","Chromosome":"6","Start":"7567376","Stop":"7567376","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":197036,"rule_based_match":true,"evidence_text":"c.1067C>A, p.T356K","llm_judgment":"PRESENT","evidence":"c.1067C>A, p.T356K","abstract_start":519,"abstract_end":537}]}
{"pmid":"35047857","title":"A recurrent,","abstract":"We report seven affected individuals from six families with a recurrent, <i>de novo</i> variant in the <i>ARPC4</i> gene (c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]). Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex, which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous <i>ARPC4</i> missense variants as a cause of neurodevelopmental disorders and microcephaly.","variants":[{"Name":"NM_005718.5(ARPC4):c.472C>T (p.Arg158Cys)","Chromosome":"3","Start":"9803984","Stop":"9803984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1331025,"rule_based_match":true,"evidence_text":"c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]","llm_judgment":"PRESENT","evidence":"c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]","abstract_start":122,"abstract_end":167}]}
{"pmid":"23477994","title":"Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities.","abstract":"OBJECTIVE: To determine whether individuals with primary ciliary dyskinesia (PCD) from unrelated Amish and Mennonite families harbor a single and unique founder mutation.\nSTUDY DESIGN: Subjects from Amish and Mennonite communities in several states were enrolled in the study. All subjects were clinically characterized, and nasal nitric oxide levels were measured. Nasal epithelial scrapings were collected from several subjects for ciliary ultrastructural analyses. DNA was isolated from patients with PCD and their unaffected first- and second-degree relatives. Genome-wide homozygosity mapping, linkage analyses, targeted mutation analyses, and exome sequencing were performed.\nRESULTS: All subjects from Old-Order Amish communities from Pennsylvania were homozygous for a nonsense mutant DNAH5 allele, c.4348C>T (p.Q1450X). Two affected siblings from an unrelated Mennonite family in Arkansas were homozygous for the same nonsense DNAH5 mutation. Children with PCD from an Amish family from Wisconsin had biallelic DNAH5 mutations, c.4348C>T (p.Q1450X) and c.10815delT (p.P3606HfsX23), and mutations in other genes associated with PCD were also identified in this community.\nCONCLUSION: The Amish and Mennonite subjects from geographically dispersed and socially isolated communities had the same founder DNAH5 mutation, owing to the common heritage of these populations. However, disease-causing mutations in other PCD-associated genes were also found in affected individuals in these communities, illustrating the genetic heterogeneity in this consanguineous population.","variants":[{"Name":"NM_001369.3(DNAH5):c.10815del (p.Pro3606fs)","Chromosome":"5","Start":"13753290","Stop":"13753290","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":76544,"rule_based_match":true,"evidence_text":"c.10815delT (p.P3606HfsX23)","llm_judgment":"PRESENT","evidence":"c.10815delT (p.P3606HfsX23)","abstract_start":1062,"abstract_end":1089},{"Name":"NM_001369.3(DNAH5):c.4348C>T (p.Gln1450Ter)","Chromosome":"5","Start":"13865675","Stop":"13865675","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205552,"rule_based_match":true,"evidence_text":"c.4348C>T (p.Q1450X)","llm_judgment":"PRESENT","evidence":"c.4348C>T (p.Q1450X)","abstract_start":807,"abstract_end":827}]}
{"pmid":"32357925","title":"Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia: a case report.","abstract":"BACKGROUND: Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies.\nCASE PRESENTATION: Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified.\nCONCLUSIONS: We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.","variants":[{"Name":"NM_001369.3(DNAH5):c.7502G>C (p.Arg2501Pro)","Chromosome":"5","Start":"13810166","Stop":"13810166","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":173691,"rule_based_match":true,"evidence_text":"c.7502G > C; p.(R2501P)","llm_judgment":"PRESENT","evidence":"c.7502G > C; p.(R2501P)","abstract_start":994,"abstract_end":1017}]}
{"pmid":"23288994","title":"Novel PRPF31 mutations associated with Chinese autosomal dominant retinitis pigmentosa patients.","abstract":"PURPOSE: To identify the mutations in the pre-mRNA processing factor 31 homolog (PRPF31) gene in Chinese families with autosomal dominant retinitis pigmentosa (adRP) and to characterize the clinical features of those patients who were found to have mutations in the PRPF31 gene.\nMETHODS: Detailed ocular examinations were performed, and genomic DNA was isolated by standard methods for genetic diagnosis. Probands from each family were screened for mutations in the PRPF31 gene that was known to cause adRP. Cosegregation analysis was performed in the available family members. Linkage analysis was performed for one missense mutation to calculate the likelihood of its pathogenicity. Two hundred unrelated, healthy Chinese subjects were screened to exclude nonpathogenic polymorphisms.\nRESULTS: Forty Chinese families with adRP were selected by an analysis of pedigrees. We identified four mutations (c.196_197delAA, c.544_618del75bp, c.615delC, and c.895T>C) in total, and three deletions were novel. Cosegregation analysis of the available family members (20 patients and 17 unaffected family members) revealed that each index patient and all affected family members showed a heterozygous mutation in the PRPF31 gene. In two families, incomplete penetrance was observed. Linkage analysis achieved the maximum LOD score of c.895T>C is 2.09, achieved at θ=0. The four probands with PRPF31 mutations showed classical signs of RP, with relatively preserved central vision and severe visual field constriction.\nCONCLUSIONS: Our studies extended the mutation spectrum of PRPF31, and mutations in PRPF31 were found at a relatively high frequency (10%, 4 of 40 adRP families) in our cohort.","variants":[{"Name":"NM_015629.4(PRPF31):c.895T>C (p.Cys299Arg)","Chromosome":"19","Start":"54126567","Stop":"54126567","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":856939,"rule_based_match":true,"evidence_text":"c.895T>C","llm_judgment":"PRESENT","evidence":"c.895T>C","abstract_start":951,"abstract_end":959}]}
{"pmid":"27905109","title":"A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency.","abstract":"Short-chain enoyl-CoA hydratase (SCEH) is a mitochondrial enzyme involved in the oxidation of fatty acids and the catabolic pathway of valine and, to a lesser extent, isoleucine. Deficiency of this enzyme was recently shown to cause an early childhood Leigh syndrome phenotype. The few reported patients were compound heterozygotes for two missense or missense with truncating variants in ECHS1 that encodes SCEH. We describe two siblings with severe refractory lactic acidosis and death within the first 2 days of life. Following negative clinical whole-exome and whole-genome sequencing, we resorted to autozygome/exome analysis on research basis and identified a homozygous splice site mutation (c.88+5G>A) in the two cases. Analysis of cDNA confirmed complete replacement of the normal transcript with an aberrant transcript (r.88_89ins 88+1_88+11) predicting premature truncation of the protein [p.(Ala31Glufs*23)]. Furthermore, quantitative reverse transcriptase polymerase chain reaction (RTPCR) showed marked reduction in ECHS1, most likely nonsense-mediated decay (NMD)-mediated. This is the first report of homozygosity for a truncating mutation in ECHS1, which may explain the severe phenotype. Our report highlights the need to consider SCEH deficiency in patients with lethal neonatal lactic acidosis, and the potentially limited sensitivity of untargeted genomic sequencing towards non-canonical splicing mutations, which may explain at least some of the 'negative' cases on clinical exome/genome sequencing.","variants":[{"Name":"NM_004092.4(ECHS1):c.88+5G>A","Chromosome":"10","Start":"133373241","Stop":"133373241","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":421784,"rule_based_match":true,"evidence_text":"c.88+5G>A","llm_judgment":"PRESENT","evidence":"c.88+5G>A","abstract_start":699,"abstract_end":708}]}
{"pmid":"27899912","title":"Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects.","abstract":"In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous <i>CLPP</i> frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient's brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the <i>CLPP</i> gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the <i>CLPP</i> gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the <i>CLPP</i> mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounced.","variants":[{"Name":"NM_006012.4(CLPP):c.21del (p.Ala10fs)","Chromosome":"19","Start":"6361595","Stop":"6361595","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"T","allel_id":1868343,"rule_based_match":true,"evidence_text":"c.21delA","llm_judgment":"PRESENT","evidence":"c.21delA","abstract_start":519,"abstract_end":527}]}
{"pmid":"33491095","title":"Porokeratosis Plantaris, Palmaris et Disseminata Caused by Con- genital Pathogenic Variants in the MVD Gene and Loss of Hetero-zygosity in Affected Skin.","abstract":"Porokeratoses are a heterogeneous group of keratinization disorders. For linear porokeratosis and disseminated superficial actinic porokeratosis, a heterozygous pathogenic germline variant in a mevalonate pathway gene and a postzygotic second hit mutation present in affected skin have been shown to be the patho-genetic mechanism for the development of the lesions. However, the molecular mechanism leading to development of porokeratosis plantaris, palmaris et disseminata is not known. This study analysed a cohort of 4 patients with linear porokeratosis and 3 patients with porokeratosis plantaris, palmaris et disseminata, and performed mutation analyses of DNA extracted from blood samples and skin biopsies. All of the study patients carried the heterozygous germline variant c.70+5G>A in the MVD gene. Loss of heterozygosity due to a second hit mutation was found in affected skin of 3 patients with linear porokeratosis and 2 patients with porokeratosis plantaris, palmaris et disseminata. These results suggest that porokeratosis plantaris, palmaris et disseminata shares the same pathogenetic mechanism as other porokeratosis subtypes and belongs to the phenotypic spectrum of MVD-associated porokeratosis.","variants":[{"Name":"NM_002461.3(MVD):c.70+5G>A","Chromosome":"16","Start":"88663006","Stop":"88663006","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1336585,"rule_based_match":true,"evidence_text":"c.70+5G>A","llm_judgment":"PRESENT","evidence":"c.70+5G>A","abstract_start":783,"abstract_end":792}]}
{"pmid":"29934635","title":"Whole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract.","abstract":"PURPOSE: Congenital cataract, opacification of the ocular lens, is clinically and genetically a heterogeneous childhood disease. In this study we aimed to identify the underlying genetic cause of isolated autosomal-dominant lamellar cataract in a multi-generation English family.\nMETHODS: Whole-genome sequencing (WGS) was undertaken in two affected subjects and one unaffected individual. Segregation analysis was performed and a known cataract-causing mutation was identified. Segregation was further validated by sanger sequencing in the entire pedigree.\nRESULTS: A heterozygous mutation c.7 G > T; p.D3Y was identified in an NH<sub>2</sub>-terminal region of the gap junction protein GJA3 and found to co-segregate with disease.\nCONCLUSION: We have identified a recurrent mutation in GJA3 in a large British pedigree causing the novel phenotype of autosomal-dominant congenital lamellar cataract. Previously, p.D3Y was found in a Hispanic family causing pulverulent cataract. WGS proved an efficient method to find the underlying molecular cause in this large family, which could not be mapped due to uninformative markers.","variants":[{"Name":"NM_021954.4(GJA3):c.7G>T (p.Asp3Tyr)","Chromosome":"13","Start":"20143282","Stop":"20143282","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2898987,"rule_based_match":true,"evidence_text":"c.7 G > T; p.D3Y","llm_judgment":"PRESENT","evidence":"c.7 G > T; p.D3Y","abstract_start":591,"abstract_end":607}]}
{"pmid":"36415352","title":"A Novel PACS1 Variant Associated With Schuurs-Hoeijmakers Syndrome Phenotype in an Indigenous Descendant in Brazil: A Case Report.","abstract":"Schuurs-Hoeijmakers syndrome, an autosomal dominant disorder associated with mutations in the PACS1 gene, was initially identified in two unrelated children of European descent from a cohort of individuals with intellectual disabilities. This gene alteration significantly reduced cranial cartilaginous structures, inducing craniofacial alterations predominantly in a dominant-negative fashion. In this paper, we report a novel variant of PACS1 associated with Schuurs-Hoeijmakers syndrome: a boy aged two years and nine months of indigenous descent presenting with motor stereotypies, atypical sensory searches, language delay, and low socio-interactional reciprocity. Whole exome sequencing confirmed the presence of a heterozygous missense mutation c.943C>T p. (Arg315Trp) in the PACS1 gene. The phenotypic profile identified was similar to the other cases of Schuurs-Hoeijmakers syndrome described in the literature. This report highlights the importance of considering the possibility of PACS1 gene alterations and a diagnosis of Schuurs-Hoeijmakers syndrome in patients presenting craniofacial alterations associated with autistic features, psychomotor and language development delay.","variants":[{"Name":"NM_018026.4(PACS1):c.943C>T (p.Arg315Trp)","Chromosome":"11","Start":"66216740","Stop":"66216740","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1963600,"rule_based_match":true,"evidence_text":"c.943C>T p. (Arg315Trp)","llm_judgment":"PRESENT","evidence":"c.943C>T p. (Arg315Trp)","abstract_start":752,"abstract_end":775}]}
{"pmid":"33236446","title":"EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia.","abstract":"OBJECTIVE: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia.\nMETHODS: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients.\nRESULTS: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia.\nINTERPRETATION: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.","variants":[{"Name":"NM_001135651.3(EIF2AK2):c.413G>C (p.Gly138Ala)","Chromosome":"2","Start":"37139734","Stop":"37139734","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1684164,"rule_based_match":true,"evidence_text":"c.413G>C, p.Gly138Ala","llm_judgment":"PRESENT","evidence":"c.413G>C, p.Gly138Ala","abstract_start":837,"abstract_end":858},{"Name":"NM_001135651.3(EIF2AK2):c.388G>A (p.Gly130Arg)","Chromosome":"2","Start":"37141554","Stop":"37141554","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1323638,"rule_based_match":true,"evidence_text":"c.388G>A, p.Gly130Arg","llm_judgment":"PRESENT","evidence":"c.388G>A, p.Gly130Arg","abstract_start":375,"abstract_end":396},{"Name":"NM_001135651.3(EIF2AK2):c.95A>C (p.Asn32Thr)","Chromosome":"2","Start":"37147712","Stop":"37147712","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1323639,"rule_based_match":true,"evidence_text":"c.95A>C (p.Asn32Thr)","llm_judgment":"PRESENT","evidence":"p.Asn32Thr","abstract_start":962,"abstract_end":972}]}
{"pmid":"20226046","title":"Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY).","abstract":"BACKGROUND: Insulin gene (INS) mutations have recently been described as a common cause of permanent neonatal diabetes (PNDM) and a rare cause of diabetes diagnosed in childhood or adulthood.\nMETHODS: INS was sequenced in 116 maturity-onset diabetes of the young (MODYX) patients (n = 48 Danish and n = 68 Czech), 83 patients with gestational diabetes mellitus (GDM), 34 type 1 diabetic patients screened negative for glutamic acid decarboxylase (GAD), and 96 glucose tolerant individuals. The control group was randomly selected from the population-based sampled Inter99 study.\nRESULTS: One novel heterozygous mutation c.17G>A, R6H, was identified in the pre-proinsulin gene (INS) in a Danish MODYX family. The proband was diagnosed at 20 years of age with mild diabetes and treated with diet and oral hypoglycaemic agent. Two other family members who carried the INS R6H were diagnosed with diabetes when 51 years old and with GDM when 27 years old, respectively. A fourth mutation carrier had normal glucose tolerance when 20 years old. Two carriers of INS R6H were also examined twice with an oral glucose tolerance test (OGTT) with 5 years interval. They both had a approximately 30% reduction in beta-cell function measured as insulinogenic index. In a Czech MODYX family a previously described R46Q mutation was found. The proband was diagnosed at 13 years of age and had been treated with insulin since onset of diabetes. Her mother and grandmother were diagnosed at 14 and 35 years of age, respectively, and were treated with oral hypoglycaemic agents and/or insulin.\nCONCLUSION: Mutations in INS can be a rare cause of MODY and we conclude that screening for mutations in INS should be recommended in MODYX patients.","variants":[{"Name":"NM_000207.3(INS):c.17G>A (p.Arg6His)","Chromosome":"11","Start":"2160955","Stop":"2160955","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":79619,"rule_based_match":true,"evidence_text":"c.17G>A","llm_judgment":"PRESENT","evidence":"c.17G>A","abstract_start":620,"abstract_end":627}]}
{"pmid":"33278652","title":"Deep intronic TIMMDC1 variant delays diagnosis of rapidly progressive complex I deficiency.","abstract":"Complex I deficiency is the most common pediatric mitochondrial disease. It can cause a wide range of clinical disorders, including Leigh syndrome. TIMMDC1 encodes an assembly protein of complex I and has been recently associated with early onset mitochondrial disease in three unrelated families. In all three families the same homozygous deep intronic variant was identified leading to inclusion of a new exon resulting in a frameshift and premature stop codon (c.596 + 2146A > G, p.Gly199_Thr200ins5*). Herein, we describe two brothers of Dutch descent, presenting in infancy with hypotonia and respiratory insufficiency and a rapidly progressive and fatal disease course. Laboratory findings and metabolic investigations revealed no specific abnormalities, notably no raised plasma lactate. MRI showed transient lesions in the basal ganglia of brother 1. A muscle biopsy demonstrated complex I deficiency in brother 2. Exome sequencing yielded a novel heterozygous TIMMDC1 variant: c.385C > T, p.(Arg129*). Targeted sequencing revealed the previously published deep intronic variant c.596 + 2146A > G, p.(Gly199_Thr200ins5*) on the second allele which is not detected by exome sequencing. In summary, we present the fourth family with TIMMDC1-related disease, with a novel nonsense variant. This report illustrates the importance of considering mitochondrial disease even when laboratory findings are normal, and the added value of targeted sequencing of introns.","variants":[{"Name":"NM_016589.4(TIMMDC1):c.385C>T (p.Arg129Ter)","Chromosome":"3","Start":"119503556","Stop":"119503556","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":971282,"rule_based_match":true,"evidence_text":"c.385C > T, p.(Arg129*)","llm_judgment":"PRESENT","evidence":"c.385C > T, p.(Arg129*)","abstract_start":986,"abstract_end":1009}]}
{"pmid":"27913194","title":"Genetic screening of THAP1 in primary dystonia patients of India.","abstract":"BACKGROUND: Primary Dystonia is a common movement disorder manifested by dystonic symptoms only. DYT6, a major genetic factor, plays a significant role in primary pure dystonia pathogenesis. In this study we analyzed THAP1 (DYT 6) gene in primary pure dystonia patients, which has been widely studied in other populations but not in Indians.\nMETHODS: The study cohort contained 227 index primary pure dystonia patients with the involvement of cervical region and 254 neurologically control individuals collected from East Indian population. All three exons of THAP1 and their flanking sequences, including exon-intron boundaries, were screened by PCR, DNA sequencing and/or RFLP analysis.\nRESULTS: A total of three nucleotide variants were detected, which include a reported missense mutation (c.427 A>G; p.Met143Val) in a juvenile onset generalized dystonia patient, a novel frameshift deletion mutation (c.208-209 ΔAA; p.K70VfsX15) in a juvenile onset cervical dystonia patient and a rare variant in 3' UTR of THAP1 (c.*157 T>C) in an adult-onset blepharospasm patient. In addition, two SNPs (rs71521601 and rs111989331) were detected both in the patients and controls with the major allele of the latter being significantly over represented in the patients.\nCONCLUSIONS: Our study suggests that the THAP1 is likely to have a causative role in the pathogenesis of Indian primary pure dystonia patients. Though the phenotypic spectrum is extensively diverse, the cervical involvement with dystonic tremor and speech problem is common amongst the patients harboring mutations.","variants":[{"Name":"NM_018105.3(THAP1):c.427A>G (p.Met143Val)","Chromosome":"8","Start":"42838177","Stop":"42838177","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":227322,"rule_based_match":true,"evidence_text":"c.427 A>G; p.Met143Val","llm_judgment":"PRESENT","evidence":"c.427 A>G; p.Met143Val","abstract_start":794,"abstract_end":816}]}
{"pmid":"25208612","title":"Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients.","abstract":"BACKGROUND: Sengers syndrome is an autosomal recessive condition characterized by congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the acylglycerol kinase (AGK) gene have been recently described as the cause of Sengers syndrome in nine families.\nMETHODS: We investigated the clinical and molecular features of Sengers syndrome in seven new families; five families with the severe and two with the milder form.\nRESULTS: Sequence analysis of AGK revealed compound heterozygous or homozygous predicted loss-of-function mutations in all affected individuals. A total of eight different disease alleles were identified, of which six were novel, homozygous c.523_524delAT (p.Ile175Tyrfs*2), c.424-1G > A (splice site), c.409C > T (p.Arg137*) and c.877 + 3G > T (splice site), and compound heterozygous c.871C > T (p.Gln291*) and c.1035dup (p.Ile346Tyrfs*39). All patients displayed perinatal or early-onset cardiomyopathy and cataract, clinical features pathognomonic for Sengers syndrome. Other common findings included blood lactic acidosis and tachydyspnoea while nystagmus, eosinophilia and cervical meningocele were documented in only either one or two cases. Deficiency of the adenine nucleotide translocator was found in heart and skeletal muscle biopsies from two patients associated with respiratory chain complex I deficiency. In contrast to previous findings, mitochondrial DNA content was normal in both tissues.\nCONCLUSION: We compare our findings to those in 21 previously reported AGK mutation-positive Sengers patients, confirming that Sengers syndrome is a clinically recognisable disorder of mitochondrial energy metabolism.","variants":[{"Name":"NM_018238.4(AGK):c.409C>T (p.Arg137Ter)","Chromosome":"7","Start":"141614164","Stop":"141614164","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":205750,"rule_based_match":true,"evidence_text":"c.409C > T (p.Arg137*)","llm_judgment":"PRESENT","evidence":"c.409C > T (p.Arg137*)","abstract_start":766,"abstract_end":788},{"Name":"NM_018238.4(AGK):c.523_524del (p.Ile175fs)","Chromosome":"7","Start":"141621734","Stop":"141621735","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":861593,"rule_based_match":true,"evidence_text":"c.523_524delAT (p.Ile175Tyrfs*2)","llm_judgment":"PRESENT","evidence":"c.523_524delAT (p.Ile175Tyrfs*2)","abstract_start":704,"abstract_end":736},{"Name":"NM_018238.4(AGK):c.1035dup (p.Ile346fs)","Chromosome":"7","Start":"141649319","Stop":"141649320","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":1061022,"rule_based_match":true,"evidence_text":"c.1035dup (p.Ile346Tyrfs*39)","llm_judgment":"PRESENT","evidence":"c.1035dup (p.Ile346Tyrfs*39)","abstract_start":876,"abstract_end":904}]}
{"pmid":"36073783","title":"Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study.","abstract":"Colorectal cancer is the second leading cause of cancer-related deaths in women and men in Algeria. Lynch syndrome (LS) is an autosomal dominant disease caused by heterozygous germline pathogenic variants in mismatch repair genes (MMR) and frequently predisposes to colorectal cancer. However, data about MMR germline pathogenic variants in Algerian patients are limited. This first nationwide study aims to describe clinicopathologic features and germline variants in MMR genes in Algerian families with suspected LS. Sixty-four (64) families with suspected LS were studied. Index cases with LS who fulfilled Amsterdam criteria were screened by PCR-direct sequencing for germline variants in MMR genes: MLH1 (exons 1, 9, 10, 13, 16), MSH2 (exons 5, 6, 7, 12), MSH6 (exons 4 and 8) and PMS2 (exons 6 and 10). We selected these specific risk exons genes since they have a higher probability of harboring pathogenic variants. In addition, two unrelated LS patients were screened by next-generation sequencing using a cancer panel of 30 hereditary cancer genes. Six germline pathogenic variants and one germline likely pathogenic variant were identified in 19 (29.68%) families (4 MLH1, 2 MSH2 and 1 MSH6). Of index cases and relatives who underwent genetic testing (n = 76), 30 (39.47%) had MMR pathogenic gene variants, one (0.13%) had MMR gene likely pathogenic variant and three had MMR variant of uncertain significance, respectively. Two novel germline pathogenic variants in MLH1 (2) and one germline likely pathogenic variant in MSH6 (1) never published in individuals with LS have been detected in the present study. The recurrent MLH1 germline pathogenic variant c.1546C>T has been found in nine LS families, six of them related with two large kindreds, from four North central provinces of Algeria. In addition, the common MSH2 germline pathogenic variant c.942+3A>T has been detected in five unrelated patients with a strong LS family history. The accumulative knowledge about clinicopathological and genetic characteristics of LS in Algerian patients will impact clinical management in the areas of both prevention and treatment.","variants":[{"Name":"NM_000251.3(MSH2):c.942+3A>T","Chromosome":"2","Start":"47414421","Stop":"47414421","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":45242,"rule_based_match":true,"evidence_text":"c.942+3A>T","llm_judgment":"PRESENT","evidence":"c.942+3A>T","abstract_start":1864,"abstract_end":1874}]}
{"pmid":"23155708","title":"Identification of LDLR mutations in two Chinese pedigrees with familial hypercholesterolemia.","abstract":"Familial hypercholesterolemia (FH) is an autosomal dominant, inherited disease (OMIM 143890) characterized by elevated serum cholesterol bound to low-density lipoprotein (LDL). It is mainly caused by mutations of the low-density lipoprotein receptor gene (LDLR). In this study, we investigated two Chinese pedigrees with FH. The probands were a 9-year-old boy and a 1-year-old boy, who had high LDL-C levels. The proband in family A showed skin xanthoma. We sequenced the promoter and all exons and exon-intron boundaries of the LDLR gene to detect potential mutations. Compound heterozygote of c.1747C>T and c.2054C>T was detected in the proband of family A, and a heterozygous indel mutation c.551_553 delGTAinsTT was discovered in the second family. The c.1747C>T and c.2054C>T mutations, which have been reported previously, result in His583Tyr and Pro685Leu substitutions, respectively. The novel c.551_553 delGTAinsTT indel mutation causes a frameshift, which results in a p.Cys184Phe fs21X mutation in the corresponding protein.","variants":[{"Name":"NM_000527.5(LDLR):c.2054C>T (p.Pro685Leu)","Chromosome":"19","Start":"11120436","Stop":"11120436","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18741,"rule_based_match":true,"evidence_text":"c.2054C>T","llm_judgment":"PRESENT","evidence":"c.2054C>T","abstract_start":609,"abstract_end":618},{"Name":"NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)","Chromosome":"19","Start":"11116900","Stop":"11116900","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":198015,"rule_based_match":true,"evidence_text":"c.1747C>T","llm_judgment":"PRESENT","evidence":"c.1747C>T","abstract_start":595,"abstract_end":604}]}
{"pmid":"30626896","title":"A novel homozygous truncating variant of NECAP1 in early infantile epileptic encephalopathy: the second case report of EIEE21.","abstract":"We report the second case of early infantile epileptic encephalopathy (EIEE) arising from a homozygous truncating variant of NECAP1. The boy developed infantile-onset tonic-clonic and tonic seizures, then spasms in clusters. His electroencephalogram (EEG) showed a burst suppression pattern, leading to the diagnosis of Ohtahara syndrome. Whole-exome sequencing revealed the canonical splice-site variant (c.301 + 1 G > A) in NECAP1. In rodents, Necap1 protein is enriched in neuronal clathrin-coated vesicles and modulates synaptic vesicle recycling. cDNA analysis confirmed abnormal splicing that produced early truncating mRNA. There has been only one previous report of a mutation in NECAP1 in a family with EIEE; this was a nonsense mutation (p.R48*) that was cited as EIEE21. Decreased mRNA levels and the loss of the WXXF motif in both the families suggests that loss of NECAP1 function is a common pathomechanism for EIEE21. This study provided additional support that synaptic vesicle recycling plays a key role in epileptogenesis.","variants":[{"Name":"NM_015509.4(NECAP1):c.301+1G>A","Chromosome":"12","Start":"8090300","Stop":"8090300","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":917818,"rule_based_match":true,"evidence_text":"c.301 + 1 G > A","llm_judgment":"PRESENT","evidence":"c.301 + 1 G > A","abstract_start":406,"abstract_end":421}]}
{"pmid":"20552229","title":"Early appearance of hypokalemia in Gitelman syndrome.","abstract":"Inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive co-transporter causes Gitelman syndrome. The main features of this syndrome include normal or low blood pressure, hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and hyperreninemia. These patients are at low risk for preterm birth and do not present with symptoms before school age. As a consequence, the condition is usually diagnosed in late childhood or in adult life. We report on four patients, two pairs of prematurely born twins, in whom hypokalemia was demonstrated early in life. In these children, a tendency towards hypokalemia was first noted during the third week of life. Overt hypokalemia subsequently appeared associated with normal blood pressure, hypochloremia, hyperreninemia, and an inappropriately high fractional excretion of potassium and chloride. Molecular biology studies failed to detect mutations in the SLC12A1, KCNJ1, and CLCNKB genes responsible for the Bartter syndromes type I, II and III, respectively. Compound heterozygous mutations in the SLC12A3 gene were detected in both pairs of twins: a frameshift mutation in exon 10 (c.1196_1202dup7bp), leading to the truncated protein p.Ser402X, and a missense mutation in exon 11, p.Ser475Cys (c.1424C>G) in the first pair; two missense mutations, p.Thr392Ile (c.1175C>T) in exon 9 and p.Ser615Leu in exon 15 (c.1844C>T), in the second pair. In conclusion, the diagnosis of Gitelman syndrome deserves consideration in infants with unexplained hypokalemia.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1424C>G (p.Ser475Cys)","Chromosome":"16","Start":"56879630","Stop":"56879630","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1871433,"rule_based_match":true,"evidence_text":"c.1424C>G","llm_judgment":"PRESENT","evidence":"c.1424C>G","abstract_start":1270,"abstract_end":1279},{"Name":"NM_001126108.2(SLC12A3):c.1175C>T (p.Thr392Ile)","Chromosome":"16","Start":"56878156","Stop":"56878156","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1063694,"rule_based_match":true,"evidence_text":"c.1175C>T (p.Thr392Ile)","llm_judgment":"PRESENT","evidence":"p.Thr392Ile","abstract_start":1324,"abstract_end":1335},{"Name":"NM_001126108.2(SLC12A3):c.1844C>T (p.Ser615Leu)","Chromosome":"16","Start":"56885283","Stop":"56885283","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":553530,"rule_based_match":true,"evidence_text":"c.1844C>T","llm_judgment":"PRESENT","evidence":"c.1844C>T","abstract_start":1386,"abstract_end":1395}]}
{"pmid":"29114388","title":"Epistatic interactions between mutations of TACI (","abstract":"Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, <i>TNFRSF13B</i>) gene. Variants in <i>TNFRSF13B</i>/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the <i>TNFRSF13B</i>/TACI C104R mutation and meets the Ameratunga <i>et al.</i> diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the <i>TNFRSF13B</i>/TACI mutation. Her brother, homozygous for the <i>TNFRSF13B</i>/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a <i>de novo</i> nonsense mutation (T168fsX191) in the Transcription Factor 3 (<i>TCF3</i>) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of <i>TNFRSF13B</i>/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of <i>TCF3</i> impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the <i>TNFRSF13B</i>/TACI and <i>TCF3</i> signalling networks lead to the severe CVID-like disorder and SLE in the proband.","variants":[{"Name":"NM_012452.3(TNFRSF13B):c.310T>C (p.Cys104Arg)","Chromosome":"17","Start":"16948873","Stop":"16948873","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":20341,"rule_based_match":true,"evidence_text":"c.310T>C","llm_judgment":"PRESENT","evidence":"c.310T>C","abstract_start":354,"abstract_end":362}]}
{"pmid":"29684900","title":"Generation of the human induced pluripotent stem cell (hiPSC) line PSMi003-A from a patient affected by an autosomal recessive form of Long QT Syndrome type 1.","abstract":"We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 51years old female patient homozygous for the mutation c.535 G>A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1), not associated with deafness. The hiPSCs, generated using four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC, are pluripotent and can differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs).","variants":[{"Name":"NM_000218.3(KCNQ1):c.535G>A (p.Gly179Ser)","Chromosome":"11","Start":"2570685","Stop":"2570685","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67731,"rule_based_match":true,"evidence_text":"c.535 G>A p.G179S","llm_judgment":"PRESENT","evidence":"c.535 G>A p.G179S","abstract_start":143,"abstract_end":160}]}
{"pmid":"18329934","title":"Lethal hepatopathy and leukodystrophy caused by a novel mutation in MPV17 gene: description of an alternative MPV17 spliced form.","abstract":"It has recently been reported that mutations in MPV17 gene may be causative of mtDNA depletion syndrome (MDS). Patients with this alteration presented with severe liver failure, hypoglycemia, growth retardation and neurological symptoms during the first year of life. We report on the clinical, biochemical and molecular findings of a patient presenting with lethal hepatopathy, polyneuropathy, neurological regression and leukodystrophy associated with mutations in MPV17. Mitochondrial respiratory chain activities were low in liver and within reference values in muscle. However, levels of mtDNA were markedly reduced both in muscle and liver. A novel homozygous mutation in MPV17, c.70+5G>A (IVS1+5G>A), was identified. This intronic change causes the full-length cDNA loss, probably due to loss of strength of the splice donor site of exon 1. Western blot analysis, performed in liver homogenates, further corroborates these results as the amount of patient's protein was highly reduced, or almost absent, compared with that of controls. We also identified an additional alternative spliced form in controls and in the patient, due to exon 2 skipping, that has not previously been reported.","variants":[{"Name":"NM_002437.5(MPV17):c.70+5G>A","Chromosome":"2","Start":"27322443","Stop":"27322443","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46922,"rule_based_match":true,"evidence_text":"c.70+5G>A (IVS1+5G>A)","llm_judgment":"PRESENT","evidence":"c.70+5G>A (IVS1+5G>A)","abstract_start":685,"abstract_end":706}]}
{"pmid":"25173926","title":"Novel α-actinin 2 variant associated with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias: a massively parallel sequencing study.","abstract":"BACKGROUND: Next-generation sequencing might be particularly advantageous in genetically heterogeneous conditions, such as hypertrophic cardiomyopathy (HCM), in which a considerable proportion of patients remain undiagnosed after Sanger. In this study, we present an Italian family with atypical HCM in which a novel disease-causing variant in α-actinin 2 (ACTN2) was identified by next-generation sequencing.\nMETHODS AND RESULTS: A large family spanning 4 generations was examined, exhibiting an autosomal dominant cardiomyopathic trait comprising a variable spectrum of (1) midapical HCM with restrictive evolution with marked biatrial dilatation, (2) early-onset atrial fibrillation and atrioventricular block, and (3) left ventricular noncompaction. In the proband, 48 disease genes for HCM, selected on the basis of published reports, were analyzed by targeted resequencing with a customized enrichment system. After bioinformatics analysis, 4 likely pathogenic variants were identified: TTN c.21977G>A (p.Arg7326Gln); TTN c.8749A>C (p.Thr2917Pro); ACTN2 c.683T>C (p.Met228Thr); and OBSCN c.13475T>G (p.Leu4492Arg). The novel variant ACTN2 c.683T>C (p.Met228Thr), located in the actin-binding domain, proved to be the only mutation fully cosegregating with the cardiomyopathic trait in 18 additional family members (of whom 11 clinically affected). ACTN2 c.683T>C (p.Met228Thr) was absent in 570 alleles of healthy controls and in 1000 Genomes Project and was labeled as Damaging by in silico analysis using polymorphism phenotyping v2, as Deleterious by sorts intolerant from tolerant, and as Disease-Causing by Mutation Taster.\nCONCLUSIONS: A targeted next-generation sequencing approach allowed the identification of a novel ACTN2 variant associated with midapical HCM and juvenile onset of atrial fibrillation, emphasizing the potential of such approach in HCM diagnostic screening.","variants":[{"Name":"NM_001103.4(ACTN2):c.683T>C (p.Met228Thr)","Chromosome":"1","Start":"236731300","Stop":"236731300","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":187396,"rule_based_match":true,"evidence_text":"ACTN2 c.683T>C (p.Met228Thr)","llm_judgment":"PRESENT","evidence":"ACTN2 c.683T>C (p.Met228Thr)","abstract_start":1054,"abstract_end":1082}]}
{"pmid":"26476331","title":"Phenotypic, metabolic, and molecular genetic characterization of six patients with congenital adrenal hyperplasia caused by novel mutations in the CYP11B1 gene.","abstract":"Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited disorder of steroidogenesis. Steroid 11β-hydroxylase deficiency (11β-OHD) due to mutations in the CYP11B1 gene is the second most common form of CAH. In this study, 6 patients suffering from CAH were diagnosed with 11β-OHD using urinary GC-MS steroid metabolomics analysis. The molecular basis of the disorder was investigated by molecular genetic analysis of the CYP11B1 gene, functional characterization of splicing and missense mutations, and analysis of the missense mutations in a computer model of CYP11B1. All patients presented with abnormal clinical signs of hyperandrogenism. Their urinary steroid metabolomes were characterized by excessive excretion rates of metabolites of 11-deoxycortisol as well as metabolites of 11-deoxycorticosterone, and allowed definite diagnosis. Patient 1 carries compound heterozygous mutations consisting of a novel nonsense mutation p.Q102X (c.304C>T) in exon 2 and the known missense mutation p.T318R (c.953C>G) in exon 5. Two siblings (patient 2 and 3) were compound heterozygous carriers of a known splicing mutation c.1200+1G>A in intron 7 and a known missense mutation p.R448H (c.1343G>A) in exon 8. Minigene experiments demonstrated that the c.1200+1G>A mutation caused abnormal pre-mRNA splicing (intron retention). Two further siblings (patient 4 and 5) were compound heterozygous carriers of a novel missense mutation p.R332G (c.994C>G) in exon 6 and the known missense mutation p.R448H (c.1343G>A) in exon 8. A CYP11B1 activity study in COS-1 cells showed that only 11% of the enzyme activity remained in the variant p.R332G. Patient 6 carried a so far not described homozygous deletion g.2470_5320del of 2850 bp corresponding to a loss of the CYP11B1 exons 3-8. The breakpoints of the deletion are embedded into two typical 6 base pair repeats (GCTTCT) upstream and downstream of the gene. Experiments analyzing the influence of mutations on splicing and on enzyme function were applied as complementary procedures to genotyping and provided a rational basis for understanding the clinical phenotype of CAH.","variants":[{"Name":"NM_000497.4(CYP11B1):c.953C>G (p.Thr318Arg)","Chromosome":"8","Start":"142876242","Stop":"142876242","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":544735,"rule_based_match":true,"evidence_text":"c.953C>G","llm_judgment":"PRESENT","evidence":"c.953C>G","abstract_start":1018,"abstract_end":1026},{"Name":"NM_000497.4(CYP11B1):c.304C>T (p.Gln102Ter)","Chromosome":"8","Start":"142879123","Stop":"142879123","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544738,"rule_based_match":true,"evidence_text":"c.304C>T","llm_judgment":"PRESENT","evidence":"c.304C>T","abstract_start":957,"abstract_end":965},{"Name":"NM_000497.4(CYP11B1):c.1200+1G>A","Chromosome":"8","Start":"142875233","Stop":"142875233","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1061227,"rule_based_match":true,"evidence_text":"c.1200+1G>A","llm_judgment":"PRESENT","evidence":"c.1200+1G>A","abstract_start":1135,"abstract_end":1146},{"Name":"NM_000497.4(CYP11B1):c.994C>G (p.Arg332Gly)","Chromosome":"8","Start":"142875839","Stop":"142875839","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":834159,"rule_based_match":true,"evidence_text":"c.994C>G (p.Arg332Gly)","llm_judgment":"PRESENT","evidence":"c.994C>G","abstract_start":1451,"abstract_end":1459}]}
{"pmid":"24718843","title":"Cirrhosis and liver failure: expanding phenotype of Acid sphingomyelinase-deficient niemann-pick disease in adulthood.","abstract":"Acid sphingomyelinase-deficient Niemann-Pick disease (ASMD) includes the severe neuronopathic type A, the non-neuronopathic type B, and rare intermediate cases. Here we report on such an atypical type B patient who died at 31 years of age from liver failure. This male subject was first seen in a paediatric department at the age of 3 years because of significant hepatosplenomegaly. Foam cells in bone marrow, interstitial pneumonitis, a slight facial dysmorphy and normal psychomotor development were additional findings. Acid sphingomyelinase studies in lymphocytes (and later SMPD1 gene studies [c.151_154delGACT; c.1341-21_1341-18delAATG]) established the diagnosis of ASMD. Between the ages 6-27, he developed growth retardation, peripheral neuropathy, kyphoscoliosis, alopecia, and aortic valve insufficiency requiring valve replacement. Surgery for bilateral inguinal hernias was performed twice, when the patient was 10 and 21 years of age, respectively. At the age of 28, he was noted to have hepatosplenomegaly and follow-up investigations revealed ascites and gastric varices. Liver biopsy showed cirrhosis without areas of necrosis (A6 in Child-Pugh classification). He developed haematemesis and worsening encephalopathy leading to his death at age 31. In conclusion, cirrhosis should be considered as a possible complication of ASMD in adult patients, even if hepatic tests are normal.","variants":[{"Name":"NM_000543.5(SMPD1):c.151_154del (p.Asp51fs)","Chromosome":"11","Start":"6390747","Stop":"6390750","ReferenceAlleleVCF":"TCTGA","AlternateAlleleVCF":"T","allel_id":357977,"rule_based_match":true,"evidence_text":"c.151_154delGACT","llm_judgment":"PRESENT","evidence":"c.151_154delGACT","abstract_start":600,"abstract_end":616},{"Name":"NM_000543.5(SMPD1):c.1341-21_1341-18del","Chromosome":"11","Start":"6393873","Stop":"6393876","ReferenceAlleleVCF":"CTGAA","AlternateAlleleVCF":"C","allel_id":2836617,"rule_based_match":true,"evidence_text":"c.1341-21_1341-18delAATG","llm_judgment":"PRESENT","evidence":"c.1341-21_1341-18delAATG","abstract_start":618,"abstract_end":642}]}
{"pmid":"25563800","title":"Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: Report of four Korean cases.","abstract":"We describe detailed clinical, biochemical, neuroimaging and neuropathological features in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), linked to colony-stimulating factor 1 receptor (CSF1R) mutations in four Korean cases. Clinical, biochemical, neuroimaging and neuropathological findings were obtained by direct evaluation and from previous medical records. The genetic analysis of the CSF1R gene was done in two autopsy-confirmed ALSP cases and two cases where ALSP was suspected based on the clinical and neuroimaging characteristics. We identified two known mutations: c.2342C>T (p.A781V) in one autopsy-proven HDLS and clinically ALSP-suspected case and c.2345G>A (p.R782H) in another autopsy-proven POLD case. We also found a novel mutation (c.2296A>G; p.M766V) in a patient presenting with hand tremor, stuttering and hesitant speech, and abnormal behavior whose father died from a possible diagnosis of spinocerebellar ataxia. To the best of our knowledge, this is the first documented ALSP-linked CSF1R mutation in Korea and supports the suggestion that HDLS and POLD, with pathological characteristics that are somewhat different but which are caused by CSF1R mutations, are the same spectrum of disease, ALSP.","variants":[{"Name":"NM_001288705.3(CSF1R):c.2345G>A (p.Arg782His)","Chromosome":"5","Start":"150056316","Stop":"150056316","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46939,"rule_based_match":true,"evidence_text":"c.2345G>A (p.R782H)","llm_judgment":"PRESENT","evidence":"c.2345G>A (p.R782H)","abstract_start":830,"abstract_end":849},{"Name":"NM_001288705.3(CSF1R):c.2342C>T (p.Ala781Val)","Chromosome":"5","Start":"150056319","Stop":"150056319","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171839,"rule_based_match":true,"evidence_text":"c.2342C>T (p.A781V)","llm_judgment":"PRESENT","evidence":"c.2342C>T (p.A781V)","abstract_start":744,"abstract_end":763}]}
{"pmid":"31965066","title":"A newly recognized multiple malformation syndrome with caudal regression associated with a biallelic c.402G>A variant in TBX4.","abstract":"The T-box4 (TBX4) gene (OMIM *601719) belongs to the T-box family of transcription regulators that share a conserved homology domain and are expressed at specific sites during various stages of embryonic development. Tbx4 has been found to be a crucial transcriptional regulator in embryonic hindlimb development in animal models. Monoallelic variants in the TBX4 gene are reported to be associated with skeletal defects of the pelvis and lower limbs. We report here a fetus with a novel multiple malformation syndrome associated with sacrococcygeal agenesis, bilateral lower limb aplasia, hypoplastic left heart, bilateral lung hypoplasia, hydroureteronephrosis, and nonimmune fetal hydrops, found to have a homozygous nonsense variant in the TBX4 gene. We propose that biallelic variants in the TBX4 gene are associated with a severe syndromic phenotype of sacrococcygeal agenesis and lower limb reduction defects.","variants":[{"Name":"NM_001321120.2(TBX4):c.402G>A (p.Trp134Ter)","Chromosome":"17","Start":"61467510","Stop":"61467510","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625980,"rule_based_match":true,"evidence_text":"c.402G>A","llm_judgment":"PRESENT","evidence":"c.402G>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"30705822","title":"Spectrum of mutations underlying Propionic acidemia and further insight into a genotype-phenotype correlation for the common mutation in Saudi Arabia.","abstract":"Propionic acidemia (PA) is an autosomal recessive metabolic disorder. PA is characterized by deficiency of the mitochondrial enzyme propionyl CoA carboxylase (PCC) that results in the accumulation of propionic acid. Alpha and beta subunits of the PCC enzyme are encoded by the <i>PCCA</i> and <i>PCCB</i> genes, respectively. Pathogenic variants in <i>PCCA</i> or <i>PCCB</i> disrupt the function of the PCC enzyme preventing the proper breakdown of certain amino acids and metabolites. To determine the frequency of pathogenic variants in PA in our population, 84 Saudi Arabian patients affected with PA were sequenced for both the <i>PCCA</i> and <i>PCCB</i> genes. We found that variants in <i>PCCA</i> accounted for 81% of our cohort (68 patients), while variants in <i>PCCB</i> only accounted for 19% (16 patients). In total, sixteen different sequence variants were detected in the study, where 7 were found in <i>PCCA</i> and 9 in <i>PCCB</i>. The pathogenic variant (c.425G > A; p.Gly142Asp) in <i>PCCA</i> is the most common cause of PA in our cohort and was found in 59 families (70.2%), followed by the frameshift variant (c.990dupT; p.E331Xfs*1) in <i>PCCB</i> that was found in 7 families (8.3%). The p.Gly142Asp missense variant is likely to be a founder pathogenic variant in patients of Saudi Arabian tribal origin and is associated with a severe phenotype. All variants were inherited in a homozygous state except for one family who was compound heterozygous. A total of 11 novel pathogenic variants were detected in this study thereby increasing the known spectrum of pathogenic variants in the <i>PCCA</i> and <i>PCCB</i> genes.","variants":[{"Name":"NM_000282.4(PCCA):c.425G>A (p.Gly142Asp)","Chromosome":"13","Start":"100157297","Stop":"100157297","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":200253,"rule_based_match":true,"evidence_text":"c.425G > A; p.Gly142Asp","llm_judgment":"PRESENT","evidence":"c.425G > A; p.Gly142Asp","abstract_start":975,"abstract_end":998}]}
{"pmid":"25614308","title":"Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature.","abstract":"BACKGROUND: Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive disease in the mitochondrial transport of long-chain fatty acids. Despite early diagnosis and treatment, the disease still has a high mortality rate.\nMETHODS: Clinical symptoms, long-term follow-up, and biochemical and molecular results of four cases are described and compared with the reviewed literature data of 55 cases.\nRESULTS: Two cases with neonatal onset, carrying in homozygosity the novel variant sequences p.Gly20Asp (c.59G>A) and p.Arg179Gly (c.536A>G), died during an intercurrent infectious process in the first year of life despite adequate dietetic treatment (frequent feeding, high-carbohydrate/low-fat diet, MCT, carnitine). The other two cases, one with infantile onset and the other diagnosed in the newborn period after a previous affected sibling, show excellent development at 4 and 16 years of age under treatment. The review shows that the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. The onset of symptoms is predominantly neonatal in 82% and infantile in 18%. The mortality rate is high (65%), most in the first year of life due to myocardiopathy or sudden death. Outcomes seem to correlate better with the absence of cardiac disease and with a higher long-chain fatty acid oxidation rate in cultured fibroblasts than with residual enzyme activity.\nCONCLUSION: Diagnosis before the occurrence of clinical symptoms by tandem MS-MS and very early therapeutic intervention together with good dietary compliance could lead to a better prognosis, especially in milder clinical cases.","variants":[{"Name":"NM_000387.6(SLC25A20):c.536A>G (p.Asp179Gly)","Chromosome":"3","Start":"48859627","Stop":"48859627","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":587674,"rule_based_match":true,"evidence_text":"c.536A>G","llm_judgment":"PRESENT","evidence":"c.536A>G","abstract_start":552,"abstract_end":560}]}
{"pmid":"23606453","title":"ANO5 gene analysis in a large cohort of patients with anoctaminopathy: confirmation of male prevalence and high occurrence of the common exon 5 gene mutation.","abstract":"Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non-Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%-25% in unselected undiagnosed cases.","variants":[{"Name":"NM_213599.3(ANO5):c.191dup (p.Asn64fs)","Chromosome":"11","Start":"22221100","Stop":"22221101","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":17203,"rule_based_match":true,"evidence_text":"c.191dupA","llm_judgment":"PRESENT","evidence":"c.191dupA","abstract_start":235,"abstract_end":244}]}
{"pmid":"28562391","title":"Pierpont syndrome: report of a new patient.","abstract":"Pierpont syndrome (OMIM #602342) is a rare disorder characterized by developmental delay, characteristic facial gestalt, hearing loss, and abnormal fat distribution in the distal limbs. A specific mutation in TBL1XR1 [c.1337A>G; p.(Tyr446Cys)] has been described recently in six unrelated patients with Pierpont syndrome. We report on a male child with developmental delay, distinctive facial dysmorphic features, dystrophy, and abnormal fat distribution in the feet, in whom we identified the identical TBL1XR1 mutation. This patient also had additional clinical features including microphthalmia, pendular nystagmus, cryptorchidism, dermal sinus, and peripheral joint laxity, which had not been reported previously in association with Pierpont syndrome. This patient corroborates the assumption that Pierpont syndrome is exclusively caused by the specific TBL1XR1 missense mutation p.(Tyr446Cys) and the additional features broaden the phenotypic spectrum of this rare disorder.","variants":[{"Name":"NM_024665.7(TBL1XR1):c.1337A>G (p.Tyr446Cys)","Chromosome":"3","Start":"177033050","Stop":"177033050","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":227687,"rule_based_match":true,"evidence_text":"c.1337A>G; p.(Tyr446Cys)","llm_judgment":"PRESENT","evidence":"c.1337A>G; p.(Tyr446Cys)","abstract_start":218,"abstract_end":242}]}
{"pmid":"31924696","title":"","abstract":"BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.\nOBJECTIVE: Filamin C gene truncations (<i>FLNCtv</i>) have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that <i>FLNCtv</i> could be a novel gene associated with ARVC.\nMETHODS: One hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for <i>FLNC</i> variants. Available family members were tested for cosegregation.\nRESULTS: We identified two unique <i>FLNCtv</i> variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling 'definite' diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.\nCONCLUSION: The identification of <i>FLNCtv</i> as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC <i>non-desmosome</i> disease genes for this disorder. Our findings should prompt inclusion of <i>FLNC</i> genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.","variants":[{"Name":"NM_001458.5(FLNC):c.8107del (p.Asp2703fs)","Chromosome":"7","Start":"128858449","Stop":"128858449","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":564128,"rule_based_match":true,"evidence_text":"c.8107delG, p.Asp2703ThrfsTer69","llm_judgment":"PRESENT","evidence":"c.8107delG, p.Asp2703ThrfsTer69","abstract_start":945,"abstract_end":976},{"Name":"NM_001458.5(FLNC):c.6565G>T (p.Glu2189Ter)","Chromosome":"7","Start":"128854054","Stop":"128854054","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2671561,"rule_based_match":true,"evidence_text":"c.6565 G>T, p.Glu2189Ter","llm_judgment":"PRESENT","evidence":"c.6565 G>T, p.Glu2189Ter","abstract_start":916,"abstract_end":940}]}
{"pmid":"21983716","title":"Clinical and mutation analysis of a Chinese family with muscle eye brain disease","abstract":"OBJECTIVE: To study the clinical feature of a Chinese family with muscle-eye-brain disease (MEB) and the mutation of protein O-linked-mannose beta-1, 2-N-acetylglucosaminyltransferase 1 gene (POMGNT1).\nMETHODS: Clinical data of the proband and his family members were collected. Genomic DNA from the patient and his parents was extracted using standard procedures from the peripheral blood leukocytes. Polymerase chain reaction and DNA direct sequencing were employed to analyze all of the exons to determine the mutation, and the relationship between genotype and phenotype was analyzed.\nRESULTS: The proband was diagnosed as floppy baby, presented with delayed psychomotor development and myopathic face. His serum creatine kinase (CK) level elevated moderately and brain MRI showed cerebral and cerebellar gyrus abnormalities with white matter signal intensity changes, cerebellar cysts and cerebellar and brain stem hypoplasia, consistent with congenital muscular dystrophy with eye brain disorder. Further test with DNA detected a compound heterozygous mutation of c.1896 1 G to C before exon 22 which may induce splicing error, and missense mutation c.1319T to G, p.L440R in exon 16. Both parents had a heterozygous mutation at the mutation sites.\nCONCLUSION: According to our study, the family is diagnosed as MEB. The proband carried compound heterozygous mutations in the POMGNT1 gene, and his parents are heterozygous carriers, which is consistent with autosomal recessive inheritance. The child is definitely diagnosed as having muscle eye brain disease.","variants":[{"Name":"NM_017739.4(POMGNT1):c.1319T>G (p.Leu440Arg)","Chromosome":"1","Start":"46192402","Stop":"46192402","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":71218,"rule_based_match":false,"evidence_text":"c.1319T to G, p.L440R","llm_judgment":"PRESENT","evidence":"c.1319T to G, p.L440R","abstract_start":1156,"abstract_end":1177}]}
{"pmid":"36881552","title":"Novel insights in the pathomechanism of Brugada syndrome and fever-related type 1 ECG changes in a preclinical study using human-induced pluripotent stem cell-derived cardiomyocytes.","abstract":"BACKGROUND: Brugada syndrome (BrS) is causing sudden cardiac death (SCD) mainly at young age. Studying the underlying mechanisms associated with BrS type I electrocardiogram (ECG) changes in the presence of fever and roles of autophagy for BrS remains lacking.\nOBJECTIVES: We sought to study the pathogenic role of an SCN5A gene variant for BrS with fever-induced type 1 ECG phenotype. In addition, we studied the role of inflammation and autophagy in the pathomechanism of BrS.\nMETHODS: Human-induced pluripotent stem cell (hiPSC) lines from a BrS patient harboring a pathogenic variant (c.3148G>A/p. Ala1050Thr) in SCN5A and two healthy donors (non-BrS) and a CRISPR/Cas9 site-corrected cell line (BrS-corr) were differentiated into cardiomyocytes (hiPSC-CMs) for the study.\nRESULTS: Reductions of Na<sub>v</sub> 1.5 expression, peak sodium channel current (I<sub>Na</sub> ) and upstroke velocity (V<sub>max</sub> ) of action potentials with an increase in arrhythmic events were detected in BrS compared to non-BrS and BrS-corr cells. Increasing the cell culture temperature from 37 to 40°C (fever-like state) exacerbated the phenotypic changes in BrS cells. The fever-effects were enhanced by protein kinase A (PKA) inhibitor but reversed by PKA activator. Lipopolysaccharides (LPS) but not increased temperature up to 40°C enhanced the autophagy level in BrS-hiPSC-CMs by increasing reactive oxidative species and inhibiting PI3K/AKT signalling, and hence exacerbated the phenotypic changes. LPS enhanced high temperature-related effect on peak I<sub>Na</sub> shown in BrS hiPSC-CMs. Effects of LPS and high temperature were not detected in non-BrS cells.\nCONCLUSIONS: The study demonstrated that the SCN5A variant (c.3148G>A/p.Ala1050Thr) caused loss-of-function of sodium channels and increased the channel sensitivity to high temperature and LPS challenge in hiPSC-CMs from a BrS cell line with this variant but not in two non-BrS hiPSC-CM lines. The results suggest that LPS may exacerbate BrS phenotype via enhancing autophagy, whereas fever may exacerbate BrS phenotype via inhibiting PKA-signalling in BrS cardiomyocytes with but probably not limited to this variant.","variants":[{"Name":"NM_000335.5(SCN5A):c.3148G>A (p.Ala1050Thr)","Chromosome":"3","Start":"38581011","Stop":"38581011","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":561470,"rule_based_match":true,"evidence_text":"c.3148G>A/p. Ala1050Thr","llm_judgment":"PRESENT","evidence":"c.3148G>A/p. Ala1050Thr","abstract_start":589,"abstract_end":612}]}
{"pmid":"31396399","title":"Primary coenzyme Q10 deficiency-7: expanded phenotypic spectrum and a founder mutation in southern Chinese.","abstract":"Primary coenzyme Q10 deficiency-7 (COQ10D7) is a rare mitochondrial disease caused by biallelic mutations in <i>COQ4</i>. Here we report the largest cohort of COQ10D7 to date, with 11 southern Chinese patients confirmed with biallelic <i>COQ4</i> mutations. Five of them have the classical neonatal-onset encephalo-cardiomyopathy, while the others have infantile onset with more heterogeneous clinical presentations. We also identify a founder mutation <i>COQ4</i> (NM_016035.5): c.370G>A, p.(Gly124Ser) for COQ10D7, suggesting a higher chance of occurrence in the southern Chinese. This study helps improve understanding of the clinical spectrum of this disorder.","variants":[{"Name":"NM_016035.5(COQ4):c.370G>A (p.Gly124Ser)","Chromosome":"9","Start":"128325849","Stop":"128325849","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":458885,"rule_based_match":true,"evidence_text":"NM_016035.5): c.370G>A, p.(Gly124Ser)","llm_judgment":"PRESENT","evidence":"NM_016035.5): c.370G>A, p.(Gly124Ser)","abstract_start":466,"abstract_end":503}]}
{"pmid":"19616983","title":"A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy.","abstract":"A baby-girl with congenital deafness was admitted at the age of 8 weeks for lack of head control, truncal hypotonia and echodense kidneys. At the age of 10 weeks cranial MRI showed a normal brain structure, generalized mild hypomyelination but no lactate peak on (1)H MR spectroscopy. A combined defect of respiratory chain enzyme complexes I, III, IV and V and severe depletion of mitochondrial DNA was found in skeletal muscle tissue. Genetic analysis revealed a novel mutation c.368T>C (p.Phe123Ser) in the RRM2B gene in the expressed maternal allele. The paternal allele was present in genomic DNA, but was not expressed as mature mRNA.","variants":[{"Name":"NM_015713.5(RRM2B):c.368T>C (p.Phe123Ser)","Chromosome":"8","Start":"102224972","Stop":"102224972","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":136335,"rule_based_match":true,"evidence_text":"c.368T>C (p.Phe123Ser)","llm_judgment":"PRESENT","evidence":"c.368T>C (p.Phe123Ser)","abstract_start":480,"abstract_end":502}]}
{"pmid":"29071820","title":"Application of Multigene Panel Sequencing in Patients with Prolonged Rate-corrected QT Interval and No Pathogenic Variants Detected in KCNQ1, KCNH2, and SCN5A.","abstract":"Long QT syndrome (LQTS) is an inherited cardiac disease characterized by a prolonged heart rate-corrected QT (QTc) interval. We investigated the genetic causes in patients with prolonged QTc intervals who were negative for pathogenic variants in three major LQTS-related genes (KCNQ1, KCNH2, and SCN5A). Molecular genetic testing was performed using a panel including 13 LQTS-related genes and 67 additional genes implicated in other cardiac diseases. Overall, putative genetic causes of prolonged QTc interval were identified in three of the 30 patients (10%). Among the LQTS-related genes, we detected a previously reported pathogenic variant, CACNA1C c.1552C>T, responsible for cardiac-only Timothy syndrome. Among the genes related to other cardiac diseases, a likely pathogenic variant, RYR2 c.11995A>G, was identified in a patient with catecholaminergic polymorphic ventricular tachycardia. Another patient who developed dilated cardiomyopathy with prolonged QTc interval was found to carry a likely pathogenic variant, TAZ c.718G>A, associated with infantile dilated cardiomyopathy. Comprehensive screening of genetic variants using multigene panel sequencing enables detection of genetic variants with a possible involvement in QTc interval prolongation, thus uncovering unknown molecular mechanisms underlying LQTS.","variants":[{"Name":"NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys)","Chromosome":"12","Start":"2566465","Stop":"2566465","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":188554,"rule_based_match":true,"evidence_text":"CACNA1C c.1552C>T","llm_judgment":"PRESENT","evidence":"CACNA1C c.1552C>T","abstract_start":646,"abstract_end":663}]}
{"pmid":"21236492","title":"A novel mutation of LAMB2 in a multigenerational mennonite family reveals a new phenotypic variant of Pierson syndrome.","abstract":"PURPOSE: To describe a novel laminin β-2 (LAMB2) mutation associated with nephrotic syndrome and severe retinal disease without microcoria in a large, multigenerational family with Pierson syndrome.\nDESIGN: Retrospective chart review and prospective family examination.\nPARTICIPANTS: An extended consanguineous family of 52 members.\nMETHODS: The eyes, urine, and serum DNA were evaluated in all family members after discovering 2 patients, both younger than 10 years, with bilateral retinal detachments and concurrent renal dysfunction. Linkage analysis was performed in the 9 living affected individuals, 7 using the Illumina Human Hap370 Duo Bead Array (Illumina, San Diego, CA) and 2 using GeneChip 10K (Affymetrix, Santa Clara, CA) mapping arrays.\nMAIN OUTCOME MEASURES: The prevalence and severity of ocular and kidney involvement and genetic findings.\nRESULTS: Eleven affected family members were identified (9 living), all manifesting chronic kidney disease and bilateral chorioretinal pigmentary changes, with or without retinal detachments, but without microcoria or neurodevelopmental deficits, segregating in an autosomal recessive pattern. The causative gene was localized to a 9-Mb region on chromosome 3. Comprehensive gene sequencing revealed a novel LAMB2 variant (c.440A → G; His147R) that was homozygous in the 9 living, affected family members, observed at a frequency of 2.1% in the Old Order Mennonite population, and absent in 91 non-Mennonite controls. The mutation is located in a highly conserved site in the N-terminal domain VI of LAMB2.\nCONCLUSIONS: This study describes a novel mutation of LAMB2 and further expands the spectrum of eye and renal manifestations associated with defects in the laminin β-2 chain.\nFINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.","variants":[{"Name":"NM_002292.4(LAMB2):c.440A>G (p.His147Arg)","Chromosome":"3","Start":"49132135","Stop":"49132135","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":38729,"rule_based_match":false,"evidence_text":"c.440A → G; His147R","llm_judgment":"PRESENT","evidence":"c.440A → G; His147R","abstract_start":1281,"abstract_end":1300}]}
{"pmid":"25546394","title":"Fetal-onset IPEX: report of two families and review of literature.","abstract":"Early-life autoimmunity is an IPEX characteristic, however intrauterine forms had not yet been described. Here, two unrelated families with clear evidence of fetal-onset IPEX are reported. One had 5 miscarriages of males in two generations, and a newborn presenting type-1 diabetes mellitus immediately after birth, diarrhea, thrombocytopenia, eczematous dermatitis, eosinophilia, high IgE levels and autoantibodies to pancreatic islet antigens at 4-days-old. Maternal serology was negative. He presented a FOXP3 mutation, c.1189C>T, p.Arg397Trp, previously described only in another family with IPEX at birth. The second family had several miscarriages of males in three consecutive generations and a novel FOXP3 c.319_320delTC mutation was observed in two miscarried monochorionic twin male fetuses. These twins died at 21weeks of gestation due to hydrops, and CD3+ infiltrating lymphocytes were found in their pancreas. We demonstrate that: i) IPEX may develop in fetal life; and ii) c.1189C>T and c.319_320delTC mutations are associated with early-onset phenotype.","variants":[{"Name":"NM_014009.4(FOXP3):c.1189C>T (p.Arg397Trp)","Chromosome":"X","Start":"49251441","Stop":"49251441","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26446,"rule_based_match":true,"evidence_text":"c.1189C>T","llm_judgment":"PRESENT","evidence":"c.1189C>T","abstract_start":523,"abstract_end":532}]}
{"pmid":"21237447","title":"De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.","abstract":"BACKGROUND: Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting that its disruption represents a common cause of autosomal dominant NSID.\nMETHODS: To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals.\nRESULTS: We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects.\nCONCLUSIONS: We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism.","variants":[{"Name":"NM_006772.3(SYNGAP1):c.2677del (p.Gln893fs)","Chromosome":"6","Start":"33443227","Stop":"33443227","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":49895,"rule_based_match":true,"evidence_text":"c.2677delC/p.Q893RfsX184","llm_judgment":"PRESENT","evidence":"c.2677delC/p.Q893RfsX184","abstract_start":649,"abstract_end":673},{"Name":"NM_006772.3(SYNGAP1):c.2294+1G>A","Chromosome":"6","Start":"33441760","Stop":"33441760","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":49896,"rule_based_match":true,"evidence_text":"c.2294 + 1G>A","llm_judgment":"PRESENT","evidence":"c.2294 + 1G>A","abstract_start":743,"abstract_end":756}]}
{"pmid":"23849777","title":"Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa.","abstract":"Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure. Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66). In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101-1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified. In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified. In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment. Depletion of ARL2BP caused cilia shortening. Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium. This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function.","variants":[{"Name":"NM_012106.4(ARL2BP):c.101-1G>C","Chromosome":"16","Start":"57248536","Stop":"57248536","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":76385,"rule_based_match":true,"evidence_text":"c.101-1G>C","llm_judgment":"PRESENT","evidence":"c.101-1G>C","abstract_start":460,"abstract_end":470},{"Name":"NM_012106.4(ARL2BP):c.134T>G (p.Met45Arg)","Chromosome":"16","Start":"57248570","Stop":"57248570","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":76386,"rule_based_match":true,"evidence_text":"c.134T>G (p.Met45Arg)","llm_judgment":"PRESENT","evidence":"c.134T>G (p.Met45Arg)","abstract_start":575,"abstract_end":596}]}
{"pmid":"28276056","title":"Second family provides further evidence for causation of Steel syndrome by biallelic mutations in COL27A1.","abstract":"Steel syndrome is a rare disorder of the skeleton characterized by facial dysmorphism, short stature, carpal coalition, dislocated radial heads, bilateral hip dislocation and vertical talus. Homozygous variants in COL27A1 were reported in an extending family from Puerto Rico. Here, we report a 5-year-old girl from a non-consanguineous family with facial dysmorphism, short stature, carpal coalition, dislocation of radial heads, bilateral hip dislocation, scoliosis and vertical talus. Exome sequencing identified 2 novel compound heterozygous variants c.521_528del (p.(Cys174Serfs*34)) and c.2119C>T (p.(Arg707*)) in COL27A1 in this child and the parents were heterozygous carriers. We hence report the second molecularly proven case of Steel syndrome and the first case to be reported among non-Puerto Rican population. Our report further validates the role of COL27A1 mutations in causation of Steel syndrome.","variants":[{"Name":"NM_032888.4(COL27A1):c.2119C>T (p.Arg707Ter)","Chromosome":"9","Start":"114196007","Stop":"114196007","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550115,"rule_based_match":true,"evidence_text":"c.2119C>T (p.(Arg707*))","llm_judgment":"PRESENT","evidence":"c.2119C>T (p.(Arg707*))","abstract_start":593,"abstract_end":616},{"Name":"NM_032888.4(COL27A1):c.521_528del (p.Cys174fs)","Chromosome":"9","Start":"114168076","Stop":"114168083","ReferenceAlleleVCF":"TGCGGGCAG","AlternateAlleleVCF":"T","allel_id":550116,"rule_based_match":true,"evidence_text":"c.521_528del (p.(Cys174Serfs*34))","llm_judgment":"PRESENT","evidence":"c.521_528del (p.(Cys174Serfs*34))","abstract_start":555,"abstract_end":588}]}
{"pmid":"24658933","title":"Pyridoxine responsiveness in novel mutations of the PNPO gene.","abstract":"OBJECTIVE: To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations.\nMETHODS: We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria.\nRESULTS: We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5'-phosphate (PLP).\nCONCLUSIONS: This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5'-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug-resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis.","variants":[{"Name":"NM_018129.4(PNPO):c.674G>A (p.Arg225His)","Chromosome":"17","Start":"47946670","Stop":"47946670","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":224877,"rule_based_match":false,"evidence_text":"p.Arg225His","llm_judgment":"PRESENT","evidence":"p.Arg225His","abstract_start":424,"abstract_end":435},{"Name":"NM_018129.4(PNPO):c.421C>T (p.Arg141Cys)","Chromosome":"17","Start":"47945864","Stop":"47945864","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1868218,"rule_based_match":false,"evidence_text":"p.Arg141Cys","llm_judgment":"PRESENT","evidence":"p.Arg141Cys","abstract_start":533,"abstract_end":544}]}
{"pmid":"27531131","title":"Two patients with Canavan disease and structural modeling of a novel mutation.","abstract":"Canavan disease (CD) is a rare fatal childhood neurological autosomal recessive genetic disease caused by mutations in the ASPA gene, which lead to catalytic deficiency of the ASPA enzyme, which catalyzes the hydrolysis of N-acetyl-L-aspartate (NAA) into aspartate and acetate. CD occurs frequently among Ashkenazi Jewish population, however it has been reported in many other ethnic groups with significantly lower frequency. Here, we report on two Egyptian patients diagnosed with CD, the first patient harbors five missense mutations (c.427 A > G; p. I143V, c.502C > T; p. R168C, c.530 T > C; p. I177T, c.557 T > C; p. V186D c.548C > T; p. P183L) and a silent mutation (c.693 C > T; p. Y231Y). The second patient was found to be homozygous for two missense mutations (c.427 A > G; p. I143V and c.557 T > A; p. V186D). Furthermore, molecular modeling of the novel mutation p. P183L provides an instructive explanation of the mutational impact on the protein structure that can affect the function of the ASPA. Here, the clinical, radiological, and biochemical profile of the two patients are reviewed in details.","variants":[{"Name":"NM_000049.4(ASPA):c.502C>T (p.Arg168Cys)","Chromosome":"17","Start":"3483568","Stop":"3483568","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":801731,"rule_based_match":true,"evidence_text":"c.502C > T; p. R168C","llm_judgment":"PRESENT","evidence":"c.502C > T; p. R168C","abstract_start":561,"abstract_end":581},{"Name":"NM_000049.4(ASPA):c.427A>G (p.Ile143Val)","Chromosome":"17","Start":"3481793","Stop":"3481793","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":548311,"rule_based_match":true,"evidence_text":"c.427 A > G; p. I143V","llm_judgment":"PRESENT","evidence":"c.427 A > G; p. I143V","abstract_start":538,"abstract_end":559},{"Name":"NM_000049.4(ASPA):c.548C>T (p.Pro183Leu)","Chromosome":"17","Start":"3489256","Stop":"3489256","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1701497,"rule_based_match":true,"evidence_text":"c.548C > T; p. P183L","llm_judgment":"PRESENT","evidence":"c.548C > T; p. P183L","abstract_start":628,"abstract_end":648},{"Name":"NM_000049.4(ASPA):c.557T>A (p.Val186Asp)","Chromosome":"17","Start":"3489265","Stop":"3489265","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1871483,"rule_based_match":true,"evidence_text":"c.557 T > A; p. V186D","llm_judgment":"PRESENT","evidence":"c.557 T > A; p. V186D","abstract_start":797,"abstract_end":818}]}
{"pmid":"33712684","title":"Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.","abstract":"Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5' splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.","variants":[{"Name":"NM_005198.5(CHKB):c.581G>A (p.Arg194Gln)","Chromosome":"22","Start":"50581420","Stop":"50581420","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":573424,"rule_based_match":true,"evidence_text":"c.581G > A (p.Arg194Gln)","llm_judgment":"PRESENT","evidence":"c.581G > A (p.Arg194Gln)","abstract_start":1156,"abstract_end":1180}]}
{"pmid":"30229577","title":"Genetic Analysis of","abstract":"BACKGROUND: Type II autosomal dominant osteopetrosis (ADO II) is a rare genetically heterogeneous disorder characterized by osteosclerosis and increased bone mass, predominantly involving spine, pelvis, and skull. It is closely related to functional defect of osteoclasts caused by chloride voltage-gated channel 7 (<i>CLCN7</i>) gene mutations. In this study, we aimed to identify the pathogenic mutation in a Korean patient with ADO II using whole exome sequencing.\nMETHODS: We evaluated the clinical, biochemical, and radiographic analysis of a 68-year-old woman with ADO II. We also performed whole exome sequencing to identify pathogenic mutation of a rare genetic disorder of the skeleton. Moreover, a polymorphism phenotyping program, Polymorphism Phenotyping v2 (PolyPhen-2), was used to assess the effect of the identified mutation on protein function.\nRESULTS: Whole exome sequencing using peripheral leukocytes revealed a heterozygous c.296A>G missense mutation in the <i>CLCN7</i> gene. The mutation was also confirmed using Sanger sequencing. The mutation c.296A>G was regarded to have a pathogenic effect by PolyPhen-2 software.\nCONCLUSION: We detect a heterozygous mutation in <i>CLCN7</i> gene of a patient with ADO II, which is the first report in Korea. Our present findings suggest that symptoms and signs of ADO II patient having a c.296A>G mutation in <i>CLCN7</i> may appear at a very late age. The present study would also enrich the database of <i>CLCN7</i> mutations and improve our understanding of ADO II.","variants":[{"Name":"NM_001287.6(CLCN7):c.296A>G (p.Tyr99Cys)","Chromosome":"16","Start":"1461460","Stop":"1461460","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":71503,"rule_based_match":true,"evidence_text":"c.296A>G","llm_judgment":"PRESENT","evidence":"c.296A>G","abstract_start":946,"abstract_end":954}]}
{"pmid":"30819764","title":"Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the","abstract":"Variants in the mitochondrial alanyl-tRNA synthetase 2 gene <i>AARS2</i> (OMIM 612035) are associated with infantile mitochondrial cardiomyopathy or later-onset leukoencephalopathy with premature ovarian insufficiency. Here, we report two newborn siblings who died soon after birth with primary pulmonary hypoplasia without evidence of cardiomyopathy. Whole-exome sequencing detected the same compound heterozygous <i>AARS2</i> variants in both siblings (c.1774C>T, p.Arg592Trp and c.647dup, p.Cys218Leufs*6) that have previously been associated with infantile mitochondrial cardiomyopathy. Segregation analysis in the family confirmed carrier status of the parents and an unaffected sibling. To our knowledge, this is the first report of primary pulmonary hypoplasia in the absence of cardiomyopathy associated with recessive <i>AARS2</i> variants and further defines the phenotypic spectrum associated with this gene.","variants":[{"Name":"NM_020745.4(AARS2):c.647dup (p.Cys218fs)","Chromosome":"6","Start":"44311095","Stop":"44311096","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":152754,"rule_based_match":true,"evidence_text":"c.647dup","llm_judgment":"PRESENT","evidence":"c.647dup","abstract_start":482,"abstract_end":490},{"Name":"NM_020745.4(AARS2):c.1774C>T (p.Arg592Trp)","Chromosome":"6","Start":"44304512","Stop":"44304512","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39897,"rule_based_match":true,"evidence_text":"c.1774C>T, p.Arg592Trp","llm_judgment":"PRESENT","evidence":"c.1774C>T, p.Arg592Trp","abstract_start":455,"abstract_end":477}]}
{"pmid":"27383490","title":"Report - Report on the heterozygosis mutations of c.567dupT, p.(Ile190Tyrfs*13) of MMACHC gene in 1 Child patient with methylmalonic academia.","abstract":"This article reported 1 child patient with early-onset methylmalonic acidemia and proceeded gene detection for the child and his parents. The detecting results showed that there were respectively heterozygosis mutations of c.609G>A,p.(Trp203*) and c.567dupT,p.(Ile190Tyrfs*13) in the MMA CHC gene of child's parents, and all of the diseases were entailed to the child and caused the paroxysm of child. Consequently, the c.567dupT,p.(Ile190Tyrfs*13) was considered as a kind of new gene mutation. After being treated with vitamin B12 and levocamitine, the clinical symptoms and organic acid content of hematuresis of this child patient had taken a turn for the better.","variants":[{"Name":"NM_015506.3(MMACHC):c.609G>A (p.Trp203Ter)","Chromosome":"1","Start":"45508975","Stop":"45508975","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39757,"rule_based_match":true,"evidence_text":"c.609G>A,p.(Trp203*)","llm_judgment":"PRESENT","evidence":"c.609G>A,p.(Trp203*)","abstract_start":223,"abstract_end":243},{"Name":"NM_015506.3(MMACHC):c.567dup (p.Ile190fs)","Chromosome":"1","Start":"45508932","Stop":"45508933","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":541135,"rule_based_match":true,"evidence_text":"c.567dupT,p.(Ile190Tyrfs*13)","llm_judgment":"PRESENT","evidence":"c.567dupT,p.(Ile190Tyrfs*13)","abstract_start":248,"abstract_end":276}]}
{"pmid":"23564332","title":"EXOSC3 mutations in isolated cerebellar hypoplasia and spinal anterior horn involvement.","abstract":"Pontocerebellar hypoplasia (PCH) type 1 is characterized by the co-occurrence of spinal anterior horn involvement and hypoplasia of the cerebellum and pons. EXOSC3 has been recently defined as a major cause of PCH type 1. Three different phenotypes showing variable severity have been reported. We identified a homozygous mutation [c.395A > C/p.D132A] in EXOSC3 in four patients with muscle hypotonia, developmental delay, spinal anterior horn involvement, and prolonged survival, consistent with the \"mild PCH1 phenotype\". Interestingly, isolated cerebellar hypoplasia limited to the hemispheres or involving both hemispheres and vermis was the main neuroradiologic finding, whereas the pontine volume was in the normal range for age. These findings strongly suggest that analysis of the EXOSC3 gene should be recommended also in patients with spinal anterior horn involvement and isolated cerebellar hypoplasia.","variants":[{"Name":"NM_016042.4(EXOSC3):c.395A>C (p.Asp132Ala)","Chromosome":"9","Start":"37783993","Stop":"37783993","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":40348,"rule_based_match":true,"evidence_text":"c.395A > C/p.D132A","llm_judgment":"PRESENT","evidence":"c.395A > C/p.D132A","abstract_start":332,"abstract_end":350}]}
{"pmid":"27535032","title":"Exome sequencing identifies POU4F3 as the causative gene for a large Chinese family with non-syndromic hearing loss.","abstract":"Hearing impairment, or deafness (in its most severe form), is one of the most common human sensory disorders. There have been several reports of autosomal dominant mutations in the POU4F3 gene, which is associated with non-syndromic hearing loss. In this study, we identified a novel heterozygous mutation (c.602delT, p.L201fs) in the gene POU4F3 by taking advantage of whole-exome sequencing, which was validated by Sanger sequencing and completely co-segregated within a large hearing impaired Chinese family. We have focused on this pedigree since 2002, and we have mapped a deafness locus named DFNA42 (which has been renamed DFNA52, OMIM entry 607683) via a genome-wide scan. Furthermore, we analyzed this mutational variant and found that it was located at the beginning of the first functional domain of POU4F3, which could theoretically impair the function of POU4F3. We have identified a novel frameshift mutation in the POU4F3 gene. Further functional studies of variants of this specific gene are needed to illustrate the pathogenic mechanism(s) that underlie hearing impairment.","variants":[{"Name":"NM_002700.3(POU4F3):c.602del (p.Leu201fs)","Chromosome":"5","Start":"146340029","Stop":"146340029","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":3495283,"rule_based_match":true,"evidence_text":"c.602delT","llm_judgment":"PRESENT","evidence":"c.602delT","abstract_start":307,"abstract_end":316}]}
{"pmid":"38128568","title":"Biallelic BORCS8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics.","abstract":"BLOC-one-related complex (BORC) is a multiprotein complex composed of eight subunits named BORCS1-8. BORC associates with the cytosolic face of lysosomes, where it sequentially recruits the small GTPase ARL8 and kinesin-1 and -3 microtubule motors to promote anterograde transport of lysosomes toward the peripheral cytoplasm in non-neuronal cells and the distal axon in neurons. The physiological and pathological importance of BORC in humans, however, remains to be determined. Here, we report the identification of compound heterozygous variants [missense c.85T>C (p.Ser29Pro) and frameshift c.71-75dupTGGCC (p.Asn26Trpfs*51)] and homozygous variants [missense c.196A>C (p.Thr66Pro) and c.124T>C (p.Ser42Pro)] in BORCS8 in five children with a severe early-infantile neurodegenerative disorder from three unrelated families. The children exhibit global developmental delay, severe-to-profound intellectual disability, hypotonia, limb spasticity, muscle wasting, dysmorphic facies, optic atrophy, leuko-axonopathy with hypomyelination, and neurodegenerative features with prevalent supratentorial involvement. Cellular studies using a heterologous transfection system show that the BORCS8 missense variants p.Ser29Pro, p.Ser42Pro and p.Thr66Pro are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution toward the cell periphery. The BORCS8 frameshift variant p.Asn26Trpfs*51, on the other hand, is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution toward the cell periphery. Therefore, all the BORCS8 variants are partial or total loss-of-function alleles and are thus likely pathogenic. Knockout of the orthologous borcs8 in zebrafish causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease. These findings thus identify BORCS8 as a novel genetic locus for an early-infantile neurodegenerative disorder and highlight the critical importance of BORC and lysosome dynamics for the development and function of the central nervous system.","variants":[{"Name":"NM_001145784.2(BORCS8):c.85T>C (p.Ser29Pro)","Chromosome":"19","Start":"19186958","Stop":"19186958","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2401041,"rule_based_match":true,"evidence_text":"c.85T>C (p.Ser29Pro)","llm_judgment":"PRESENT","evidence":"c.85T>C (p.Ser29Pro)","abstract_start":559,"abstract_end":579}]}
{"pmid":"29850532","title":"A Missense Mutation in","abstract":"Hereditary nonsyndromic hearing loss is extremely heterogeneous. Mutations in the POU class 4 transcription factor 3 <i>(POU4F3)</i> are known to cause autosomal dominant nonsyndromic hearing loss linked to the loci of DFNA15. In this study, we describe a pathogenic missense mutation in <i>POU4F3</i> in a four-generation Chinese family (6126) with midfrequency, progressive, and postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining targeted capture of 129 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified <i>POU4F3</i> c.602T>C (p.Leu201Pro) as the disease-causing variant. This variant cosegregated with hearing loss in other family members but was not detected in 580 normal controls or the ExAC database and could be classified as a \"pathogenic variant\" according to the American College of Medical Genetics and Genomics guidelines. We conclude that <i>POU4F3</i> c.602T>C (p.Leu201Pro) is related to midfrequency hearing loss in this family. Routine examination of <i>POU4F3</i> is necessary for the genetic diagnosis of midfrequency hearing loss.","variants":[{"Name":"NM_002700.3(POU4F3):c.602T>C (p.Leu201Pro)","Chromosome":"5","Start":"146340029","Stop":"146340029","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":893201,"rule_based_match":true,"evidence_text":"c.602T>C (p.Leu201Pro)","llm_judgment":"PRESENT","evidence":"c.602T>C (p.Leu201Pro)","abstract_start":591,"abstract_end":613}]}
{"pmid":"23155713","title":"First case report of short-chain acyl-CoA dehydrogenase deficiency in China.","abstract":"Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive inborn error of mitochondrial fatty acid oxidation. It is caused by rare mutations as well as polymorphic susceptibility variants. We describe here the case of a 1-year-old male patient who had growth and mental retardation, seizures, and recurring fever since infancy. Urinary gas chromatography/mass spectrometry (GC/MS) showed elevated levels of ethylmalonic acid. Plasma acylcarnitines on tandem mass spectrometry (MS/MS) and elevations of C4-cartinitine are consistently present. The two polymorphic susceptibility variants of the short-chain acyl-CoA dehydrogenase (SCAD) gene, c.625G>A and c.322G>A, were detected. Because of its highly variable clinical characteristics, there are no related reports in China. This report broadens the phenotype and genotype of SCADD in China and underlines the difficulty of diagnosis.","variants":[{"Name":"NM_000017.4(ACADS):c.322G>A (p.Gly108Ser)","Chromosome":"12","Start":"120737097","Stop":"120737097","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":374625,"rule_based_match":true,"evidence_text":"c.322G>A","llm_judgment":"PRESENT","evidence":"c.322G>A","abstract_start":681,"abstract_end":689}]}
{"pmid":"30652007","title":"A new case of spastic paraplegia type 64 due to a missense mutation in the","abstract":"Spastic paraplegia type 64 (SPG64; OMIM 615683) is a complicated form of hereditary spastic paraplegia (HSP) recently identified in individuals diagnosed with suspected neurodegenerative disease. Affected patients carry homozygous mutations in the ectonucleoside triphosphate diphosphohydrolase 1 gene (<i>ENTPD1</i>). Although they share common characteristics, affected individuals show slight discrepancies in some clinical aspects. At present, only two different cases of SPG64 have been diagnosed. More findings of genetic variation would be helpful to better understand the effect of mutations in the <i>ENTPD1</i> gene on the neurological condition of affected individuals. In this study, we examined a family with an individual diagnosed with suspected HSP based on clinical findings. DNA samples from the proband, her affected sister, and both parents were analyzed using next-generation sequencing. We used an in-house automated pipeline to detect potential neuromuscular disease-causing variants. Variants were confirmed by Sanger sequencing. After cosegregation analysis, the variant NM_001776.5:c.401T>G (p.M134R) of the <i>ENTPD1</i> gene was identified as a novel missense mutation linked to the phenotype of SPG64 in the proband and her sister, who showed similar and distinct clinical features compared with the two cases previously described in the literature.","variants":[{"Name":"NM_001776.6(ENTPD1):c.401T>G (p.Met134Arg)","Chromosome":"10","Start":"95842482","Stop":"95842482","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":552356,"rule_based_match":true,"evidence_text":"NM_001776.5:c.401T>G (p.M134R)","llm_judgment":"PRESENT","evidence":"NM_001776.5:c.401T>G (p.M134R)","abstract_start":1096,"abstract_end":1126}]}
{"pmid":"14974090","title":"A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype.","abstract":"Oculodentodigital dysplasia (ODDD) and Hallermann-Streiff syndrome (HSS) share several clinical characteristics. However, while ODDD is a dominantly inherited disorder due to mutations in the connexin 43 gene GJA1, the inheritance pattern of the HSS syndrome is still debated. Overlapping phenotypes have been described. In one of such cases we found a homozygous change at the very conserved R76 codon (c.227G>A, p.R76H), the clinically normal parents being heterozigous carriers of the same mutation. A different base change at the same codon (p.R76S) leads to a complete dominant ODDD phenotype. A case of full-blown HSS phenotype was also analysed but GJA1 mutations were not found. GJA1 homozygous hypomorphic mutations can result in a phenotype in the HSS/ODDD spectrum.","variants":[{"Name":"NM_000165.5(GJA1):c.227G>A (p.Arg76His)","Chromosome":"6","Start":"121447074","Stop":"121447074","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32035,"rule_based_match":true,"evidence_text":"c.227G>A, p.R76H","llm_judgment":"PRESENT","evidence":"c.227G>A, p.R76H","abstract_start":404,"abstract_end":420}]}
{"pmid":"24373485","title":"Familial hypercholesterolemia mutations in Petrozavodsk: no similarity to St. Petersburg mutation spectrum.","abstract":"BACKGROUND: Familial hypercholesterolemia (FH) is a human monogenic disease induced by a variety of mutations with striking genetic diversity. Despite this variability recurrent mutations occur in each population studied, which allows both elucidating prevalent mutations and developing DNA diagnostic tools for the disease. Recent research of FH in St. Petersburg, Moscow and Novosibirsk (major cities in Russia) demonstrates that each megapolis has its own FH mutation spectrum sharing only small part of mutations with other populations in Russia and Europe. In order to optimize molecular-genetic diagnostic protocols for FH in Russia we studied mutation spectrum in other regions including Petrozavodsk, a smaller town in relatively close proximity to St. Petersburg.\nMETHODS: The principal method was automated detection of single-strand conformation polymorphism followed by direct PCR amplified DNA sequencing.\nRESULTS: Twelve different mutations of the low density lipoprotein (LDL) receptor gene were detected in the Petrozavodsk sample (80 patients). Out of these twelve mutations, seven have never been described before (c.192_201delinsGGACTTCA, c. 195_196insT, c. 618 T > G, c. 1340C > G, c. 1686_1693delinsT, c. 1936C > A, c. 2191delG). Other five mutations (c. 58G > A, c. 925_931del, c. 1194C > T, c. 1532 T > C, c. 1920C > T) were previously characterized elsewhere. All new mutations are considered to be a probable cause of the FH in their carriers. Direct evidence of the neutral character of c.58G > A or p. (Gly20Arg) is provided for the first time. Each pathogenic mutation was a trait of its own unique pedigree and so far has not been found in other patients.\nCONCLUSIONS: Strikingly, out of twelve mutations characterized in the Petrozavodsk sample only one mutation, c. 925_931del, has previously been found in patients from St. Petersburg and Finland (most closely located studied populations), suggesting some common roots in origin of these populations in the past or limited gene exchange between them nowadays. No recurrent mutations were detected.","variants":[{"Name":"NM_000527.5(LDLR):c.1194C>T (p.Ile398=)","Chromosome":"19","Start":"11113285","Stop":"11113285","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":226400,"rule_based_match":true,"evidence_text":"c. 1194C > T","llm_judgment":"PRESENT","evidence":"c. 1194C > T","abstract_start":1300,"abstract_end":1312},{"Name":"NM_000527.5(LDLR):c.1686_1693delinsT (p.Trp562fs)","Chromosome":"19","Start":"11116193","Stop":"11116200","ReferenceAlleleVCF":"GCCCAATG","AlternateAlleleVCF":"T","allel_id":246274,"rule_based_match":true,"evidence_text":"c. 1686_1693delinsT","llm_judgment":"PRESENT","evidence":"c. 1686_1693delinsT","abstract_start":1202,"abstract_end":1221},{"Name":"NM_000527.5(LDLR):c.1920C>T (p.Asn640=)","Chromosome":"19","Start":"11120166","Stop":"11120166","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":243277,"rule_based_match":true,"evidence_text":"c. 1920C > T","llm_judgment":"PRESENT","evidence":"c. 1920C > T","abstract_start":1329,"abstract_end":1341},{"Name":"NM_000527.5(LDLR):c.1936C>A (p.Leu646Ile)","Chromosome":"19","Start":"11120182","Stop":"11120182","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":246414,"rule_based_match":true,"evidence_text":"c. 1936C > A","llm_judgment":"PRESENT","evidence":"c. 1936C > A","abstract_start":1223,"abstract_end":1235},{"Name":"NM_000527.5(LDLR):c.2191del (p.Val731fs)","Chromosome":"19","Start":"11123223","Stop":"11123223","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":246546,"rule_based_match":true,"evidence_text":"c. 2191delG","llm_judgment":"PRESENT","evidence":"c. 2191delG","abstract_start":1237,"abstract_end":1248},{"Name":"NM_000527.5(LDLR):c.1532T>C (p.Leu511Ser)","Chromosome":"19","Start":"11113708","Stop":"11113708","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":246201,"rule_based_match":true,"evidence_text":"c. 1532 T > C","llm_judgment":"PRESENT","evidence":"c. 1532 T > C","abstract_start":1314,"abstract_end":1327},{"Name":"NM_000527.5(LDLR):c.58G>A (p.Gly20Arg)","Chromosome":"19","Start":"11089606","Stop":"11089606","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171195,"rule_based_match":true,"evidence_text":"c.58G>A","llm_judgment":"PRESENT","evidence":"c. 58G > A","abstract_start":1273,"abstract_end":1283},{"Name":"NM_000527.5(LDLR):c.618T>G (p.Ser206Arg)","Chromosome":"19","Start":"11105524","Stop":"11105524","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":245662,"rule_based_match":true,"evidence_text":"c. 618 T > G","llm_judgment":"PRESENT","evidence":"c. 618 T > G","abstract_start":1174,"abstract_end":1186},{"Name":"NM_000527.5(LDLR):c.1340C>G (p.Ser447Cys)","Chromosome":"19","Start":"11113431","Stop":"11113431","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":246111,"rule_based_match":true,"evidence_text":"c. 1340C > G","llm_judgment":"PRESENT","evidence":"c. 1340C > G","abstract_start":1188,"abstract_end":1200}]}
{"pmid":"32358377","title":"A case report and literature review: Identification of a novel AIRE gene mutation associated with Autoimmune Polyendocrine Syndrome Type 1 in East Asians.","abstract":"RATIONALE: Autoimmune polyendocrine syndrome type 1 (APS-1), also referred as the autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED), is a rare autosomal inherited disease predominantly among Caucasians from Northern Europe. This syndrome is very rare in East Asian population.\nPATIENTS CONCERNS: Here, we describe a case of a 15-year-old Chinese boy admitted due to a 1-month history of intermittent fatigue, nausea, vomiting, and diarrhea. His symptom became worse accompanied with chest tightness 4 days before admission. On physical examination, his temperature was 38.5°C, blood pressure was 75/38 mm Hg, and pulse was 98/min. He was a thin boy with mild hyperpigmentation and xanthochromia.\nDIAGNOSIS: After abdominal computed technology and laboratory tests, his diagnosis was APS-1 accompanied with adrenal crisis. Further investigation on whole-exome sequencing revealed a novel homozygous mutation c.47C>G (p.T16R) in exon 1 in the autoimmune regulator (AIRE) gene.\nINTERVENTIONS: This patient underwent replacement therapy of glucocorticoids, corticosteroid, and levothyroxine, as well as calcium and calcitriol supplementation.\nOUTCOMES: He continues to do well 4 years after his hospitalization. During his last follow-up, he had serum thyroid-stimulating hormone level of 3.07 μIU/mL, free triiodothyronine level of 1.92 pg/mL, and free thyroxine level of 13.95 pg/mL. His serum cortisol and ACTH (8 a.m.) levels were 28.53 μg/dL and 69.48 pg/mL, respectively.\nLESSONS: APS-1 is very rare in East Asians and the variable clinical presentations of the disease make the initial diagnosis especially difficult. Autoimmune thyroiditis, type 1 diabetes mellitus, and hepatitis were the three most frequent minor components of APS-1 in East Asian patients with age of onset in late teens and 20s. Sequence analysis of AIRE gene is necessary to verify its diagnostic efficacy in association with clinical findings.","variants":[{"Name":"NM_000383.4(AIRE):c.47C>G (p.Thr16Arg)","Chromosome":"21","Start":"44286053","Stop":"44286053","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3410377,"rule_based_match":true,"evidence_text":"c.47C>G (p.T16R)","llm_judgment":"PRESENT","evidence":"c.47C>G (p.T16R)","abstract_start":929,"abstract_end":945}]}
{"pmid":"22593002","title":"Molecular genetic analysis of MSUD from India reveals mutations causing altered protein truncation affecting the C-termini of E1α and E1β.","abstract":"Maple Syrup Urine Disease is a rare metabolic disorder caused by reduced/absent activity of the branched chain α-Ketoacid dehydrogenase enzyme complex. Mutations in BCKDHA, BCKDHB, and DBT, that encode important subunits of the enzyme complex namely E1α, E1β, and E2, are the primary cause for the disease. We have performed the first molecular genetic analysis of MSUD from India on nine patients exhibiting classical MSUD symptoms. BCKDHA and BCKDHB mutations were identified in four and five patients, respectively including seven novel mutations namely the BCKDHA c.1249delC, c.1312T>C, and c.1561T>A and the BCKDHB c.401T>A, c.548G>A, c.964A>G, and c.1065delT. The BCKDHB c.970C>T (p.R324X) mutation was shown to trigger nonsense mediated decay-based degradation of the transcript. Seven of the total 11 mutations resulted in perturbations in the E1α or E1β C-termini either through altered termination or through an amino acid change; these are expected to result in disruption of E1 enzyme complex assembly. Our study has therefore revealed that BCKDHA and BCKDHB mutations might be primarily responsible for MSUD in the Indian population.","variants":[{"Name":"NM_183050.4(BCKDHB):c.970C>T (p.Arg324Ter)","Chromosome":"6","Start":"80273153","Stop":"80273153","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":102514,"rule_based_match":true,"evidence_text":"BCKDHB c.970C>T (p.R324X)","llm_judgment":"PRESENT","evidence":"BCKDHB c.970C>T (p.R324X)","abstract_start":670,"abstract_end":695},{"Name":"NM_183050.4(BCKDHB):c.548G>A (p.Arg183Gln)","Chromosome":"6","Start":"80168945","Stop":"80168945","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":522228,"rule_based_match":true,"evidence_text":"c.548G>A","llm_judgment":"PRESENT","evidence":"c.548G>A","abstract_start":630,"abstract_end":638},{"Name":"NM_183050.4(BCKDHB):c.964A>G (p.Thr322Ala)","Chromosome":"6","Start":"80273147","Stop":"80273147","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":225788,"rule_based_match":true,"evidence_text":"BCKDHB c.964A>G","llm_judgment":"PRESENT","evidence":"c.964A>G","abstract_start":640,"abstract_end":648}]}
{"pmid":"28778787","title":"Exome sequence identified a c.320A > G ALG13 variant in a female with infantile epileptic encephalopathy with normal glycosylation and random X inactivation: Review of the literature.","abstract":"Congenital Disorders of Glycosylation (CDG) are new and rapidly expanding neurometabolic disorders with multisystem involvements, broad phenotypic manifestations, and variable severity. The majority results from a defect of one of the steps involved with protein or lipid N-glycosylation pathway. Almost all are inherited in autosomal recessive patterns with a few exceptions such as the X-linked ALG13. Mutations of ALG13 are reported, so far in only 10 patients, all were ascertained through exome/genome sequencing. Specifically, the ALG13 c.320A > G (p.Asn107Ser) variant was reported only in females and in all were de novo mutations. These findings may suggest an X-linked dominant inheritance of this mutation with embryonic male lethality. These patients presented with severe infantile epileptic encephalopathy, global developmental delay, and multisystem abnormalities. Only two of these females had glycosylation studies done, and both showed normal pattern of glycosylated serum transferrin isoforms, and none had their X-chromosome inactivation patterns studied. Here, we report on another female patient who is heterozygous for the same ALG13 c.320A > G (p.Asn107Ser) variant. She presented with infantile spasms, epileptic encephalopathy, hypsarrhythmia, hypotonia, developmental delay, intellectual disability, abnormal coagulation profile, feeding problems, hypotonia, and dysmorphic features. The diagnosis of CGD was suspected clinically, but glycosylation studies were done twice and showed normal patterns on both occasions. Her X-inactivation study was also done and, surprisingly, showed a random pattern of X-inactivation, with no evidence of skewness.","variants":[{"Name":"NM_001099922.3(ALG13):c.320A>G (p.Asn107Ser)","Chromosome":"X","Start":"111685040","Stop":"111685040","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":76988,"rule_based_match":true,"evidence_text":"ALG13 c.320A > G (p.Asn107Ser)","llm_judgment":"PRESENT","evidence":"ALG13 c.320A > G (p.Asn107Ser)","abstract_start":537,"abstract_end":567}]}
{"pmid":"33313762","title":"De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.","abstract":"Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.","variants":[{"Name":"NM_005602.6(CLDN11):c.622T>C (p.Ter208Gln)","Chromosome":"3","Start":"170432754","Stop":"170432754","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1108676,"rule_based_match":true,"evidence_text":"c.622T>C","llm_judgment":"PRESENT","evidence":"c.622T>C","abstract_start":605,"abstract_end":613},{"Name":"NM_005602.6(CLDN11):c.622T>G (p.Ter208Glu)","Chromosome":"3","Start":"170432754","Stop":"170432754","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1108677,"rule_based_match":true,"evidence_text":"c.622T>G, p.(*208Gluext*39)","llm_judgment":"PRESENT","evidence":"c.622T>G, p.(*208Gluext*39)","abstract_start":656,"abstract_end":683}]}
{"pmid":"27978560","title":"Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.","abstract":"IMPORTANCE: Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined.\nOBJECTIVE: To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC.\nDESIGN, SETTING, AND PARTICIPANTS: Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing.\nMAIN OUTCOMES AND MEASURES: Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status.\nRESULTS: In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation.\nCONCLUSIONS AND RELEVANCE: Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.","variants":[{"Name":"NM_000038.6(APC):c.3920T>A (p.Ile1307Lys)","Chromosome":"5","Start":"112839514","Stop":"112839514","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":15861,"rule_based_match":true,"evidence_text":"APC c.3920T>A, p.I1307K","llm_judgment":"PRESENT","evidence":"APC c.3920T>A, p.I1307K","abstract_start":1417,"abstract_end":1440}]}
{"pmid":"16965330","title":"Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence.","abstract":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal-recessive autoimmune disease caused by autoimmune regulator gene mutations. The aim of this study was to examine the mutation profile of Polish APECED patients, determine the carrier rate of the most frequent mutation(s) and estimate disease prevalence. While studying 14 unrelated patients, we identified three novel mutations (c.1A>T, affecting the start codon; [IVS1 + 1G>C; IVS1 + 5delG], a complex mutation affecting splice site; c. 908G>C, p.R303P, a missense mutation in plant homeodomain (PHD) and three previously reported mutations (c.769C>T, p.R257X; c.967_979del13bp, C322fsX372; c.931delT, p.C311fsX376). Eleven patients had mutations on both chromosomes, whereas in three patients only a single alteration with proven or likely pathogenic effect was detected. The most frequent was the p.R257X mutation (71% of chromosomes); its carriage rate was assessed in the background population. Analysis of 2008 samples showed eight heterozygotes, indicating the frequency of 0.40% (1:250) and the disease prevalence - 1:129,000 (95% confidence interval: 1:555,000 to 1:30,000). Comparison with an epidemiological estimate (1:619,000, derived for women) suggested that in Poland, APECED is underdiagnosed. Among the patients, no genotype/phenotype correlations were found, but we noted that women had earlier onset of hypoparathyroidism (p < 0.02) and were younger at diagnosis (p < 0.05) than men.","variants":[{"Name":"NM_000383.4(AIRE):c.769C>T (p.Arg257Ter)","Chromosome":"21","Start":"44289773","Stop":"44289773","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18346,"rule_based_match":true,"evidence_text":"c.769C>T, p.R257X","llm_judgment":"PRESENT","evidence":"c.769C>T, p.R257X","abstract_start":631,"abstract_end":648},{"Name":"NM_000383.4(AIRE):c.967_979del (p.Leu323fs)","Chromosome":"21","Start":"44291180","Stop":"44291192","ReferenceAlleleVCF":"TGCCTGTCCCCTCC","AlternateAlleleVCF":"T","allel_id":18348,"rule_based_match":true,"evidence_text":"c.967_979del13bp","llm_judgment":"PRESENT","evidence":"c.967_979del13bp","abstract_start":650,"abstract_end":666},{"Name":"NM_000383.4(AIRE):c.1A>T (p.Met1Leu)","Chromosome":"21","Start":"44286007","Stop":"44286007","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":18353,"rule_based_match":true,"evidence_text":"c.1A>T","llm_judgment":"PRESENT","evidence":"c.1A>T","abstract_start":417,"abstract_end":423}]}
{"pmid":"32669490","title":"Adult-onset Repeat Rhabdomyolysis with a Very Long-chain Acyl-CoA Dehydrogenase Deficiency Due to Compound Heterozygous ACADVL Mutations.","abstract":"Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a genetic disorder of fatty acid beta oxidation that is caused by a defect in ACADVL, which encodes VLCAD. The clinical presentation of VLCAD deficiency is heterogeneous, and either a delayed diagnosis or a misdiagnosis may sometimes occur. We herein describe a difficult-to-diagnose case of the muscle form of adult-onset VLCAD deficiency with compound heterozygous ACADVL mutations including c.790A>G (p.K264E) and c.1246G>A (p.A416T).","variants":[{"Name":"NM_000018.4(ACADVL):c.790A>G (p.Lys264Glu)","Chromosome":"17","Start":"7222214","Stop":"7222214","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":938209,"rule_based_match":true,"evidence_text":"c.790A>G (p.K264E)","llm_judgment":"PRESENT","evidence":"c.790A>G (p.K264E)","abstract_start":455,"abstract_end":473}]}
{"pmid":"37880421","title":"Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly.","abstract":"Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.","variants":[{"Name":"NM_032982.4(CASP2):c.876+1G>T","Chromosome":"7","Start":"143300052","Stop":"143300052","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2477493,"rule_based_match":true,"evidence_text":"c.876 + 1 G > T","llm_judgment":"PRESENT","evidence":"c.876 + 1 G > T","abstract_start":1032,"abstract_end":1047},{"Name":"NM_032982.4(CASP2):c.1156del (p.Tyr386fs)","Chromosome":"7","Start":"143304712","Stop":"143304712","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":2477445,"rule_based_match":true,"evidence_text":"NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25)","llm_judgment":"PRESENT","evidence":"NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25)","abstract_start":751,"abstract_end":794},{"Name":"NM_032982.4(CASP2):c.1174C>T (p.Gln392Ter)","Chromosome":"7","Start":"143304730","Stop":"143304730","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2477446,"rule_based_match":true,"evidence_text":"c.1174 C > T (p.Gln392Ter)","llm_judgment":"PRESENT","evidence":"c.1174 C > T (p.Gln392Ter)","abstract_start":800,"abstract_end":826},{"Name":"NM_032982.4(CASP2):c.130C>T (p.Arg44Ter)","Chromosome":"7","Start":"143291595","Stop":"143291595","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2477447,"rule_based_match":false,"evidence_text":"c.130 C > T","llm_judgment":"PRESENT","evidence":"c.[130 C > T","abstract_start":864,"abstract_end":876}]}
{"pmid":"22339828","title":"Dyskeratosis congenital: clinical features and genotype analysis in two Chinese patients","abstract":"OBJECTIVE: To analysis the clinic and genotype in two Chinese patients with Dyskeratosis congenita (DC).\nMETHODS: The two patients were characterized by mucocutaneous abnormalities (abnormal nails, lacey reticular pigmentation, and oral leukoplakia), bone marrow failure. They were diagnosed with DC. DC genes were amplified by polymerase chain reaction (PCR), including DKC1, TERT, TERC, TINF2, NOP10, NHP2, then DNA sequencing was performed for abnormal exons.\nRESULTS: An abnormal peak was found in exon 6 of TINF2 gene of the two patients. DNA sequencing showed a 845G→A transition in TINF2 gene in the two patients.\nCONCLUSION: We should think about DC if the young patients with mucocutaneous abnormalities and marrow failure. TINF2 c.845G→A(R282H) does exist in the two patients. It is reported in China for the first time.","variants":[{"Name":"NM_001099274.3(TINF2):c.845G>A (p.Arg282His)","Chromosome":"14","Start":"24240635","Stop":"24240635","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20664,"rule_based_match":false,"evidence_text":"TINF2 c.845G→A(R282H)","llm_judgment":"PRESENT","evidence":"TINF2 c.845G→A(R282H)","abstract_start":733,"abstract_end":754}]}
{"pmid":"35418827","title":"An Atypical Presentation of Mevalonate Kinase Deficiency in Response to Colchicine Treatment.","abstract":"Mevalonate kinase deficiency (MKD) is a periodic fever syndrome. Nonsteroidal anti-inflammatory drugs, corticosteroids, and anakinra are the most common treatments. However, colchicine is considered insufficient in disease control. In this case report, we present an 8-month-old infant with an atypical presentation of MKD. She had recurrent fever episodes, diarrhea, and lethargy. Elevated mevalonic acid was not detected in the urine. However, the genetic investigation showed a novel pathogenic heterozygous c.925G>C (p.Gly309Arg) variant and a heterozygous c.1129G>A (p.Val377Ile) mutation in the <i>MVK</i> gene. The patient was treated with colchicine for 8 months. During treatment, no further fever episode had been observed. It should be kept in mind that mevalonic acid excretion may not be present in the urine with mild MKD. Colchicine may be a reasonable option in mild MKD patients for a longer duration of treatment due to favorable adverse event profiles.","variants":[{"Name":"NM_000431.4(MVK):c.1129G>A (p.Val377Ile)","Chromosome":"12","Start":"109596515","Stop":"109596515","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26968,"rule_based_match":true,"evidence_text":"c.1129G>A (p.Val377Ile)","llm_judgment":"PRESENT","evidence":"c.1129G>A (p.Val377Ile)","abstract_start":561,"abstract_end":584}]}
{"pmid":"26377068","title":"Targeted exome sequencing reveals novel USH2A mutations in Chinese patients with simplex Usher syndrome.","abstract":"BACKGROUND: Usher syndrome (USH) is an autosomal recessive disorder characterized by hearing impairment and vision dysfunction due to retinitis pigmentosa. Phenotypic and genetic heterogeneities of this disease make it impractical to obtain a genetic diagnosis by conventional Sanger sequencing.\nMETHODS: In this study, we applied a next-generation sequencing approach to detect genetic abnormalities in patients with USH. Two unrelated Chinese families were recruited, consisting of two USH afflicted patients and four unaffected relatives. We selected 199 genes related to inherited retinal diseases as targets for deep exome sequencing. Through systematic data analysis using an established bioinformatics pipeline, all variants that passed filter criteria were validated by Sanger sequencing and co-segregation analysis.\nRESULTS: A homozygous frameshift mutation (c.4382delA, p.T1462Lfs*2) was revealed in exon20 of gene USH2A in the F1 family. Two compound heterozygous mutations, IVS47 + 1G > A and c.13156A > T (p.I4386F), located in intron 48 and exon 63 respectively, of USH2A, were identified as causative mutations for the F2 family. Of note, the missense mutation c.13156A > T has not been reported so far.\nCONCLUSION: In conclusion, targeted exome sequencing precisely and rapidly identified the genetic defects in two Chinese USH families and this technique can be applied as a routine examination for these disorders with significant clinical and genetic heterogeneity.","variants":[{"Name":"NM_206933.4(USH2A):c.13156A>T (p.Ile4386Phe)","Chromosome":"1","Start":"215674755","Stop":"215674755","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3407990,"rule_based_match":true,"evidence_text":"c.13156A > T (p.I4386F)","llm_judgment":"PRESENT","evidence":"c.13156A > T (p.I4386F)","abstract_start":1005,"abstract_end":1028}]}
{"pmid":"33933153","title":"Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient.","abstract":"We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.","variants":[{"Name":"NM_000465.4(BARD1):c.403G>A (p.Asp135Asn)","Chromosome":"2","Start":"214781471","Stop":"214781471","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":450516,"rule_based_match":true,"evidence_text":"c.403G>A (p.Asp135Asn)","llm_judgment":"PRESENT","evidence":"p.Asp135Asn","abstract_start":70,"abstract_end":81}]}
{"pmid":"15492925","title":"Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.","abstract":"Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.","variants":[{"Name":"NM_001323289.2(CDKL5):c.183del (p.Met63fs)","Chromosome":"X","Start":"18575390","Stop":"18575390","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":153517,"rule_based_match":true,"evidence_text":"c.183delT","llm_judgment":"PRESENT","evidence":"c.183delT","abstract_start":1128,"abstract_end":1137}]}
{"pmid":"32474471","title":"Clinical and Molecular Characterization of a Novel Progranulin Deletion Associated with Different Phenotypes.","abstract":"BACKGROUND: Mutations in the GRN gene are causative for an autosomal dominant form of frontotemporal dementia.\nOBJECTIVE/METHODS: The objective of the present study is to describe clinical and molecular features of three siblings harboring the GRN deletion NM_002087.3:c.295_308delTGCCCACGGGGCTT, p.(Cys99Profs*15) identified with next generation sequencing.\nRESULTS: Our patients demonstrated heterogeneous clinical phenotypes, such as progressive supranuclear palsy-like in the proband and the behavioral variant of frontotemporal dementia in the two affected siblings. Progranulin haploinsufficiency was revealed by both gene expression and protein analyses.\nCONCLUSION: The pathogenicity of the novel GRN deletion c.295_308del TGCCCACGGGGCTT is confirmed by both functional analysis and segregation in three affected siblings.","variants":[{"Name":"NM_002087.4(GRN):c.295_308del (p.Cys99fs)","Chromosome":"17","Start":"44349697","Stop":"44349710","ReferenceAlleleVCF":"CTGCCCACGGGGCTT","AlternateAlleleVCF":"C","allel_id":1871663,"rule_based_match":true,"evidence_text":"NM_002087.3:c.295_308delTGCCCACGGGGCTT, p.(Cys99Profs*15)","llm_judgment":"PRESENT","evidence":"NM_002087.3:c.295_308delTGCCCACGGGGCTT, p.(Cys99Profs*15)","abstract_start":257,"abstract_end":314}]}
{"pmid":"28499369","title":"Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer.","abstract":"BACKGROUND: Renal cell carcinoma is among the most prevalent malignancies. It is generally sporadic. However, genetic studies of rare familial forms have led to the identification of mutations in causative genes such as VHL and FLCN. Mutations in the FLCN gene are the cause of Birt-Hogg-Dubé syndrome, a rare tumor syndrome which is characterized by the combination of renal cell carcinoma, pneumothorax and skin tumors.\nMETHODS: Using Sanger sequencing we identify a heterozygous splice-site mutation in FLCN in lymphocyte DNA of a patient suffering from renal cell carcinoma. Furthermore, both tumor DNA and DNA from a metastasis are analyzed regarding this mutation. The pathogenic effect of the sequence alteration is confirmed by minigene assays and the biochemical consequences on the protein are examined using TALEN-mediated transgenesis in cultured cells.\nRESULTS: Here we describe an FLCN mutation in a 55-year-old patient who presented himself with progressive weight loss, bilateral kidney cysts and renal tumors. He and members of his family had a history of recurrent pneumothorax during the last few decades. Histology after tumor nephrectomy showed a mixed kidney cancer consisting of elements of a chromophobe renal cell carcinoma and dedifferentiated small cell carcinoma component. Subsequent FLCN sequencing identified an intronic c.1177-5_-3delCTC alteration that most likely affected the correct splicing of exon 11 of the FLCN gene. We demonstrate skipping of exon 11 to be the consequence of this mutation leading to a shift in the reading frame and the insertion of a premature stop codon. Interestingly, the truncated protein was still expressed both in cell culture and in tumor tissue, though it was strongly destabilized and its subcellular localization differed from wild-type FLCN. Both, altered protein stability and subcellular localization could be partly reversed by blocking proteasomal and lysosomal degradation.\nCONCLUSIONS: Identification of disease-causing mutations in BHD syndrome requires the analysis of intronic sequences. However, biochemical validation of the consecutive alterations of the resulting protein is especially important in these cases. Functional characterization of the disease-causing mutations in BHD syndrome may guide further research for the development of novel diagnostic and therapeutic strategies.","variants":[{"Name":"NM_144997.7(FLCN):c.1177-5_1177-3del","Chromosome":"17","Start":"17216506","Stop":"17216508","ReferenceAlleleVCF":"TGAG","AlternateAlleleVCF":"T","allel_id":230675,"rule_based_match":false,"evidence_text":"c.1177-5_-3delCTC","llm_judgment":"PRESENT","evidence":"c.1177-5_-3delCTC","abstract_start":1352,"abstract_end":1369}]}
{"pmid":"34545167","title":"Mutation Screening and Functional Study of","abstract":"Objective: Defects in the human solute carrier family 26 member 4 (<i>SLC26A4</i>) gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify <i>SLC26A4</i> mutations in Chinese patients with CH and analyze the function of the mutations.\nMethods: Patients with primary CH were screened for 21 CH candidate genes mutations by targeted next-generation sequencing. All the exons and exon-intron boundaries of <i>SLC26A4</i> were identified and analyzed. The function of six missense mutation in <i>SLC26A4</i> were further investigated <i>in vitro</i>.\nResults: Among 273 patients with CH, seven distinct <i>SLC26A4</i> heterozygous mutations (p.S49R, p.I363L, p.R409H, p.T485M, p.D661E, p.H723R, c.919-2A>G) were identified in 10 patients (3.66%, 10/273). In vitro experiments showed that mutation p.I363L, p.R409H, p.H723R affect the membrane location and ion transport of <i>SLC26A4</i>, while p.S49R did not. Mutation p.T485M and p.D661E only affected ion transport, but had no effect on the membrane location.\nConclusion: The prevalence of <i>SLC26A4</i> mutations was 3.66% in Chinese patients with CH. Five mutations (p.I363L, p.R409H, p.T485M, p.D661E and p.H723R) impaired the membrane location or ion transport function of <i>SLC26A4</i>, suggesting important roles for Ile363, Arg409, Thr485, Asp661, and His723 residues in <i>SLC26A4</i> function. As all variants identified were heterozygous, the pathogenesis of these patients cannot be explained, and the pathogenesis of these patients needs further study.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1454C>T (p.Thr485Met)","Chromosome":"7","Start":"107695949","Stop":"107695949","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":544324,"rule_based_match":false,"evidence_text":"p.T485M","llm_judgment":"PRESENT","evidence":"p.T485M","abstract_start":706,"abstract_end":713}]}
{"pmid":"31046099","title":"A Full Phenotype of Paraganglioma Linked to a Germline SDHB Mosaic Mutation.","abstract":"CONTEXT: Heterozygous germline pathogenic variants found in succinate dehydrogenase (SDH) complex genes predispose to hereditary paraganglioma (PGL) syndromes. No mosaicism has yet been reported in this setting.\nDESIGN AND PARTICIPANT: We describe the clinical history of a case of SDH complex, subunit B (SDHB) mosaicism. A 24-year-old woman who developed a cardiogenic shock during dental surgery was diagnosed with a functional para-aortic PGL, which produced predominantly norepinephrine and its metabolites. The tumor was removed and showed a loss of SDHB expression by immunohistochemistry. Four years after initial laparotomy, the patient had a rapid cardiac decompensation during her second pregnancy, despite negative imaging 10 months before. Two recurrent functional PGLs were found and surgically removed. Initial genetic analysis performed by Sanger sequencing did not reveal any germline pathogenic variant in SDHB, VHL, SDHD, SDHC, SDHAF2, RET, MAX, and TMEM127. Next-generation sequencing performed on tumor- and blood-extracted DNAs highlighted the presence of a mosaic rare variant in SDHB (c.557G>A, p.Cys186Tyr) with an allelic ratio of 15% in the blood DNA.\nCONCLUSIONS: We report the full clinical description of a proband with SDHB mosaicism associated with a functional, recurrent PGL. This case strengthens the necessity to complete the genetic analysis with methodologies able to identify germline mosaicism, especially in the case of early disease onset.","variants":[{"Name":"NM_003000.3(SDHB):c.557G>A (p.Cys186Tyr)","Chromosome":"1","Start":"17024058","Stop":"17024058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1054756,"rule_based_match":true,"evidence_text":"c.557G>A, p.Cys186Tyr","llm_judgment":"PRESENT","evidence":"c.557G>A, p.Cys186Tyr","abstract_start":1109,"abstract_end":1130}]}
{"pmid":"25065913","title":"ELOVL5 mutations cause spinocerebellar ataxia 38.","abstract":"Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.","variants":[{"Name":"NM_021814.5(ELOVL5):c.689G>T (p.Gly230Val)","Chromosome":"6","Start":"53270660","Stop":"53270660","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":153826,"rule_based_match":true,"evidence_text":"c.689G>T (p.Gly230Val)","llm_judgment":"PRESENT","evidence":"p.Gly230Val","abstract_start":345,"abstract_end":356},{"Name":"NM_021814.5(ELOVL5):c.214C>G (p.Leu72Val)","Chromosome":"6","Start":"53291808","Stop":"53291808","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":153827,"rule_based_match":true,"evidence_text":"c.214C>G (p.Leu72Val)","llm_judgment":"PRESENT","evidence":"p.Leu72Val","abstract_start":630,"abstract_end":640}]}
{"pmid":"31942422","title":"Otopalatodigital Syndrome Type I: Novel Characteristics and Prenatal Manifestations in two Siblings.","abstract":"Otopalatodigital spectrum disorder (OPDSD) is rare group of X-linked disorders caused by mutations in the filamin A (<i>FLNA</i>) gene. It is characterized by skeletal dysplasia of variable severity and different extra skeletal manifestations. Its presentation in the fetal period is quite unspecific, so diagnosis is usually made after birth. We present prenatal ultrasonography and postmortem findings that led us to a diagnosis of the mildest form of OPDSD (OPD type I) in two consecutive pregnancies. This is the first report on prenatal diagnosis (PND) of OPD type I. Affected fetuses showed facial dysmorphy (hypertelorism, micrognathia, cleft palate) and digital anomalies, features typical of OPD type I. In addition, microphtalmia and early neonatal death due to severe respiratory distress syndrome are described as a novel characteristics of the disorder. Clinical exome sequencing revealed a hemizygous missense pathogenic variant in the <i>FLNA</i> gene (NM_ 001110556.1: c.620C>T). We suggest that the presence of hypertelorism, micrognathia, digital anomalies on prenatal ultrasound examination should alert suspicion to OPDSD. Detailed clinical examination of mother and other female relatives is of great importance in establishing definitive diagnosis of OPD type I.","variants":[{"Name":"NM_001110556.2(FLNA):c.620C>T (p.Pro207Leu)","Chromosome":"X","Start":"154367844","Stop":"154367844","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26794,"rule_based_match":true,"evidence_text":"NM_ 001110556.1: c.620C>T","llm_judgment":"PRESENT","evidence":"NM_ 001110556.1: c.620C>T","abstract_start":968,"abstract_end":993}]}
{"pmid":"26278556","title":"Atypical Clinical Presentation of Xeroderma Pigmentosum in a Patient Harboring a Novel Missense Mutation in the XPC Gene: The Importance of Clinical Suspicion.","abstract":"BACKGROUND: Xeroderma pigmentosum (XP) is a genodermatosis caused by abnormal DNA repair. XP complementation group C (XPC) is the most frequent type in Mediterranean countries. We describe a case with a novel mutation in the XPC gene.\nCASE: A healthy Caucasian male patient was diagnosed with multiple primary melanomas. Digital follow-up and molecular studies were carried out.\nRESULTS: During digital follow-up 8 more additional melanomas were diagnosed. Molecular studies did not identify mutations in CDKN2A, CDK4 or MITF genes. Two heterozygous mutations in the XPC gene were detected: c.2287delC (p.Leu763Cysfs*4) frameshift and c.2212A>G (p.Thr738Ala) missense mutations.\nCONCLUSION: The p.Thr738Ala missense mutation has not been previously described. Missense mutations in the XPC gene may allow partial functionality that could explain this unusual late onset XP. Atypical clinical presentation of XPC could be misdiagnosed when genetic aberrations allow partial DNA repair capacity.","variants":[{"Name":"NM_004628.5(XPC):c.2287del (p.Leu763fs)","Chromosome":"3","Start":"14148695","Stop":"14148695","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":542803,"rule_based_match":true,"evidence_text":"c.2287delC (p.Leu763Cysfs*4)","llm_judgment":"PRESENT","evidence":"c.2287delC (p.Leu763Cysfs*4)","abstract_start":591,"abstract_end":619}]}
{"pmid":"21160487","title":"Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations.","abstract":"Rett syndrome (RTT) is characterized by a relatively specific clinical phenotype. We screened 152 individuals with RTT phenotype. A total of 22 different known MECP2 mutations were identified in 42 subjects (27.6%). Of the 22 mutations, we identified 7 (31.8%) frameshift-causing deletions, 4 (18.2%) nonsense, 10 (45.5%) missense mutations and one insertion (4.5%). The most frequent pathologic changes were: p.Thr158Met (14.2%) and p.Arg133Cys (11.9%) missense, and p.Arg255Stop (9.5%) and p.Arg294Stop (9.5%) nonsense mutations. We also detected the c.925C >T (p.Arg309Trp) mutation in an affected patient, whose role in RTT pathogenesis is still unknown. Patients without detectable MECP2 defects were screened for mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, responsible for the early-onset variant of RTT. We discovered two novel mutations: c.607G >T resulting in a termination codon at aa203, disrupting the catalytic domain, and c.1708G >T leading to a stop at aa570 of the C terminus. Both patients with CDKL5 mutation presented therapy-resistant epilepsy and a phenotype fitting with the diagnosis of early-onset variant of RTT. No FOXG1 mutation was detected in any of the remaining patients. A total of 110 (72.5%) patients remained without molecular genetic diagnosis that necessitates further search for novel gene mutations in this phenotype. Our results also suggest the need of screening for CDKL5 mutations in patients with Rett phenotype tested negative for MECP2 mutations.","variants":[{"Name":"NM_001323289.2(CDKL5):c.1708G>T (p.Glu570Ter)","Chromosome":"X","Start":"18604632","Stop":"18604632","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":153514,"rule_based_match":true,"evidence_text":"c.1708G >T","llm_judgment":"PRESENT","evidence":"c.1708G >T","abstract_start":950,"abstract_end":960},{"Name":"NM_001323289.2(CDKL5):c.607G>T (p.Glu203Ter)","Chromosome":"X","Start":"18588006","Stop":"18588006","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":153561,"rule_based_match":true,"evidence_text":"c.607G >T","llm_judgment":"PRESENT","evidence":"c.607G >T","abstract_start":860,"abstract_end":869}]}
{"pmid":"32760473","title":"Informing patients about their mutation tests: CDKN2A c.256G>A in melanoma as an example.","abstract":"BACKGROUND: When germline mutations are suspected as causal in cancer, patient DNA may be sequenced to detect variants in relevant genes. If a particular mutation has not been reported in reliable family studies, genetic counselors are facing a dilemma of appropriately informing patients. Many sequencing facilities provide an interpretation of the findings based on the available sequence databases or on prediction tools that are curated from bioinformatics and mechanistic datasets. The counseling dilemma is exacerbated if the pedigree data are not informative but the in silico predictions suggest pathogenicity.\nMETHODS: We present here a real world example of the c.256G > A <i>CDKN2A</i> variant, which was detected in one melanoma patient where two siblings were diagnosed with melanoma in situ. We investigated a detailed family history of the affected siblings in order to survey probability of the cancer risks within the context to this mutation.\nRESULTS: This c.256G > A <i>CDKN2A</i> variant was detected in one of the brothers and in the melanoma-free mother while the other brother in the family tested negative. The variant had been previously described in one patient from a melanoma family. In the family under investigation, the mother's 16 first-and second-degree relatives had survived past the median onset age for melanoma and none presented melanoma. We tested the variant using multiple bioinformatic tools that all predicted deleteriousness of the variant. The genetic counseling report to the melanoma patient stated that the <i>CDKN2A</i> variant was 'likely pathogenic' and the disease was defined as 'likely hereditary melanoma'.\nCONCLUSIONS: The pedigree data showed at the most a low penetrance variant, which, if taken into consideration, might have altered the provided diagnosis. When dealing with 'practically' unknown variants the counselors would be advised to incorporate a detailed family history rather than basing predictions on functionality provided by sequencing facilities.","variants":[{"Name":"NM_000077.5(CDKN2A):c.256G>A (p.Ala86Thr)","Chromosome":"9","Start":"21971103","Stop":"21971103","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3648665,"rule_based_match":true,"evidence_text":"c.256G>A","llm_judgment":"PRESENT","evidence":"c.256G > A","abstract_start":672,"abstract_end":682}]}
{"pmid":"24898207","title":"Structural variation and missense mutation in SBDS associated with Shwachman-Diamond syndrome.","abstract":"BACKGROUND: Shwachman-Diamond syndrome (SDS) is an autosomal recessive ribosomopathy caused mainly by compound heterozygous mutations in SBDS. Structural variation (SV) involving the SBDS locus has been rarely reported in association with the disease. We aimed to determine whether an SV contributed to the pathogenesis of a case lacking biallelic SBDS point mutations.\nCASE PRESENTATION: Whole exome sequencing was performed in a patient with SDS lacking biallelic SBDS point mutations. Array comparative genomic hybridization and Southern blotting were used to seek SVs across the SBDS locus. Locus-specific polymerase chain reaction (PCR) encompassing flanking intronic sequence was also performed to investigate mutation within the locus. RNA expression and Western blotting were performed to analyze allele and protein expression. We found the child harbored a single missense mutation in SBDS (c.98A > C; p.K33T), inherited from the mother, and an SV in the SBDS locus, inherited from the father. The missense allele and SV segregated in accordance with Mendelian expectations for autosomal recessive SDS. Complementary DNA and western blotting analysis and locus specific PCR support the contention that the SV perturbed SBDS protein expression in the father and child.\nCONCLUSION: Our findings implicate genomic rearrangements in the pathogenesis of some cases of SDS and support patients lacking biallelic SBDS point mutations be tested for SV within the SBDS locus.","variants":[{"Name":"NM_016038.4(SBDS):c.98A>C (p.Lys33Thr)","Chromosome":"7","Start":"66995320","Stop":"66995320","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":219162,"rule_based_match":true,"evidence_text":"c.98A > C; p.K33T","llm_judgment":"PRESENT","evidence":"c.98A > C; p.K33T","abstract_start":900,"abstract_end":917}]}
{"pmid":"17905308","title":"Refsum disease due to the splice-site mutation c.135-2A>G before exon 3 of the PHYH gene, diagnosed eight years after detection of retinitis pigmentosa.","abstract":"OBJECTIVES: If Refsum disease (RD) is not considered as a differential at onset of the initial manifestations the diagnosis of RD remains unrecognized for a long time as in the following case.\nCASE REPORT: A 55-y old Caucasian female with hyperextensible joints developed progressive visual impairment due to retinitis pigmentosa and sensorimotor polyneuropathy of the lower limbs since age 32 y. Screening for causes of polyneuropathy at age 40 y revealed markedly elevated serum phytanic acid (PA) with a maximum value of 293.6 microg/ml (n:<6 microg/ml) why RD was diagnosed. Since age 48 y slowly progressive hypacusis was noted. RD was caused by the known transition A135G in exon 3 of the PHYH gene. Additionally, the polymorphism T153C in exon 3 of the PHYH gene was detected. Upon strict adherence to the Chelsea diet PA levels slightly decreased since onset of this therapy.\nCONCLUSION: This case confirms that RD remains unrecognized for a long time if RD is not considered as a differential of retinitis pigmentosa as the initial manifestation of the disease. Early recognition of RD is important since there is the therapeutic option of starting a diet.","variants":[{"Name":"NM_006214.4(PHYH):c.135-2A>G","Chromosome":"10","Start":"13295608","Stop":"13295608","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":22620,"rule_based_match":true,"evidence_text":"c.135-2A>G","llm_judgment":"PRESENT","evidence":"c.135-2A>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"22855677","title":"Novel Mutations of the GNE Gene in Distal Myopathy with Rimmed Vacuoles Presenting with Very Slow Progression.","abstract":"We report novel compound heterozygous mutations of the UDP-N-acetylglucosamine-2-epimerase and N-acetylmannosamine kinase (GNE) gene, c.302G>A (p.R101H) and c.617-4A>G, in a Japanese family with distal myopathy with rimmed vacuoles (DMRV) presenting with slow progression. The three patients could stand and walk even 36, 34, and 39 years after onset, respectively, although affected individuals become wheelchair bound on average 12 years after onset of the disease. The clinical spectrum of DMRV seems to be wider than previously thought in terms of both the clinical course and the severity of the disease.","variants":[{"Name":"NM_005476.7(GNE):c.302G>A (p.Arg101His)","Chromosome":"9","Start":"36246345","Stop":"36246345","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1293412,"rule_based_match":true,"evidence_text":"c.302G>A (p.R101H)","llm_judgment":"PRESENT","evidence":"c.302G>A (p.R101H)","abstract_start":134,"abstract_end":152}]}
{"pmid":"31275356","title":"Whole Exome Sequencing Identified a Novel Biallelic","abstract":"Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. Although biallelic mutations in <i>SMARCAL1</i> gene have been reported to be the genetic etiology of SIOD, its molecular diagnosis has been challenging in a relatively proportion of cases due to the extreme rarity. Here, we made a definitive SIOD diagnosis of a 5-year-old girl with an extremely mild phenotype by applying whole exome sequencing (WES). As a result, a novel maternal mutation (c.2141+5G > A) confirmed to create a novel splice donor site combined with a known paternal mutation (c.1933C > T; p.Arg645Cys) were detected. In addition, previous reported SIOD cases showed excessive enrichment for mutations in the helicase ATP-binding and C-terminal domains of SMARCAL1. Similarly, the novel mutation we identified caused a mutant protein truncated in the SMARCAL1 C-terminus. Interestingly, based on the phenotypic profile, compared to reported cases, the patient in our study exhibited milder symptoms with renal dysfunctions limited to asymptomatic proteinuria, but no neurological signs or recurrent infections. Moreover, we identified 73 <i>SMARCAL1</i>-interacting genes, which formed a significant interconnected interaction network with roles in disease-related pathways such as double-strand break repair via homologous recombination, DNA repair, and replication fork processing. Notably, the top 15 <i>SMARCAL1</i>-interacting genes all showed a similar renal temporal expression pattern. Altogether, to our knowledge, the case in this study is the first case diagnosed originally based on a genetic test via WES rather than a characteristic phenotype. The identification of the novel allelic mutation (c.2141+5G > A) extends the phenotypic spectrum of <i>SMARCAL1</i> mutations and the following bioinformatics analysis presents additional genetic evidence to illustrate the role of <i>SMARCAL1</i> in SIOD.","variants":[{"Name":"NM_014140.4(SMARCAL1):c.2141+5G>A","Chromosome":"2","Start":"216464672","Stop":"216464672","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1420093,"rule_based_match":true,"evidence_text":"c.2141+5G > A","llm_judgment":"PRESENT","evidence":"c.2141+5G > A","abstract_start":496,"abstract_end":509}]}
{"pmid":"26265346","title":"Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score.","abstract":"The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4-5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.","variants":[{"Name":"NM_000110.4(DPYD):c.2846A>T (p.Asp949Val)","Chromosome":"1","Start":"97082391","Stop":"97082391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":94529,"rule_based_match":true,"evidence_text":"c.2846A>T","llm_judgment":"PRESENT","evidence":"c.2846A>T","abstract_start":362,"abstract_end":371}]}
{"pmid":"23141186","title":"Bilateral stenosis of carotid siphon in Hutchinson-Gilford progeria syndrome.","abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease, caused by a de novo mutation of lamin-A gene, LMNA G608G. Accumulation of abnormal lamin-A (progerin) compromises nuclear membrane integrity and results in the accelerated senescence. Affected patients show a typical feature of birdlike face, alopecia, sclerotic skin, loss of subcutaneous fat, and short stature with advancing years. Neonatal scleroderma is the first presentation, although early diagnosis is challenging. The leading cause of death is cardio-/cerebro-vascular accidents associated with atherosclerosis. However, not all findings may recapitulate the aging process. We herein report a 9-year-old Japanese male with HGPS who developed cerebral infarction. The genetic study of peripheral blood-derived DNA determined a heterozygous c.1824C>T mutation, p.G608G. Telomere length of lymphocytes was normal. Bilateral stenosis of carotid siphons was prominent, while systemic arteriosclerosis was unremarkable assessed by the ankle-brachial index, carotid ultrasound imaging and funduscopic study. HGPS patients have marked loss and functional defects in vascular smooth muscle cells, leading to the vulnerability to circulatory stress. Symmetrical stenosis of siphons might occur as a distinctive cerebral vasculopathy of HGPS, rather than simple vascular senescence. Peripheral blood study on LMNA G608G and telomere length could screen progerias in infancy for early therapeutic intervention.","variants":[{"Name":"NM_170707.4(LMNA):c.1824C>T (p.Gly608=)","Chromosome":"1","Start":"156138613","Stop":"156138613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29539,"rule_based_match":true,"evidence_text":"c.1824C>T","llm_judgment":"PRESENT","evidence":"c.1824C>T","abstract_start":828,"abstract_end":837}]}
{"pmid":"32051257","title":"Homozygous mutations in","abstract":"BACKGROUND: Asthenoteratospermia, one of the most common causes for male infertility, often presents with defective sperm heads and/or flagella. Multiple morphological abnormalities of the sperm flagella (MMAF) is one of the common clinical manifestations of asthenoteratospermia. Variants in several genes including <i>DNAH1</i>, <i>CEP135</i>, <i>CATSPER2</i> and <i>SUN5</i> are involved in the genetic pathogenesis of asthenoteratospermia. However, more than half of the asthenoteratospermia cases cannot be explained by the known pathogenic genes.\nMETHODS AND RESULTS: Two asthenoteratospermia-affected men with severe MMAF (absent flagella in >90% spermatozoa) from consanguineous families were subjected to whole-exome sequencing. The first proband had a homozygous missense mutation c.188G>A (p.Arg63Gln) of <i>DZIP1</i> and the second proband had a homozygous stop-gain mutation c.690T>G (p.Tyr230*). Both of the mutations were neither detected in the human population genome data (1000 Genomes Project, Exome Aggregation Consortium) nor in our own data of a cohort of 875 Han Chinese control populations. <i>DZIP1</i> encodes a DAZ (a protein deleted in azoospermia) interacting protein, which was associated with centrosomes in mammalian cells. Immunofluorescence staining of the centriolar protein Centrin1 indicated that the spermatozoa of the proband presented with abnormal centrosomes, including no concentrated centriolar dot or more than two centriolar dots. HEK293T cells transfected with two <i>DZIP1</i>-mutated constructs showed reduced DZIP1 level or truncated DZIP1. The <i>Dzip1</i>-knockout mice, generated by the CRSIPR-Cas9, revealed consistent phenotypes of severe MMAF.\nCONCLUSION: Our study strongly suggests that homozygous <i>DZIP1</i> mutations can induce asthenoteratospermia with severe MMAF. The deficiency of DZIP1 induces sperm centrioles dysfunction and causes the absence of flagella.","variants":[{"Name":"NM_198968.4(DZIP1):c.690T>G (p.Tyr230Ter)","Chromosome":"13","Start":"95630109","Stop":"95630109","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":973089,"rule_based_match":true,"evidence_text":"c.690T>G (p.Tyr230*)","llm_judgment":"PRESENT","evidence":"c.690T>G (p.Tyr230*)","abstract_start":888,"abstract_end":908},{"Name":"NM_198968.4(DZIP1):c.188G>A (p.Arg63Gln)","Chromosome":"13","Start":"95641704","Stop":"95641704","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":973090,"rule_based_match":true,"evidence_text":"c.188G>A (p.Arg63Gln)","llm_judgment":"PRESENT","evidence":"c.188G>A (p.Arg63Gln)","abstract_start":791,"abstract_end":812}]}
{"pmid":"28965849","title":"Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest.","abstract":"Oocyte maturation arrest results in female infertility, but the genetic determinants of human oocyte maturation arrest remain largely unknown. Previously, we identified TUBB8 mutations responsible for human oocyte maturation arrest, indicating the important role of genetic factors in the disorder. However, TUBB8 mutations account for only around 30% of individuals with oocyte maturation arrest; thus, the disorder is likely to involve other genetic factors that are as yet unknown. Here, we initially identified a homozygous nonsense mutation of PATL2 (c.784C>T [p.Arg262<sup>∗</sup>]) in a consanguineous family with a phenotype characterized by human oocyte germinal vesicle (GV) arrest. Subsequent mutation screening of PATL2 in a cohort of 179 individuals identified four additional independent individuals with compound-heterozygous PATL2 mutations with slight phenotypic variability. A genetic burden test further confirmed the genetic contribution of PATL2 to human oocyte maturation arrest. By western blot in HeLa cells, identification of splicing events in affected individuals' granulosa cells, and immunostaining in affected individuals' oocytes, we provide evidence that mutations in PATL2 lead to decreased amounts of protein. These findings suggest an important role for PATL2 mutations in oocyte maturation arrest and expand our understanding of the genetic basis of female infertility.","variants":[{"Name":"NM_001387263.1(PATL2):c.784C>T (p.Arg262Ter)","Chromosome":"15","Start":"44669869","Stop":"44669869","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":437689,"rule_based_match":true,"evidence_text":"c.784C>T (p.Arg262<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"c.784C>T","abstract_start":556,"abstract_end":564}]}
{"pmid":"38091959","title":"Novel Variants of HPS6 Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of HPS6 Variants.","abstract":"INTRODUCTION: Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of HPS6 variants and their genotype-phenotype correlations.\nMETHODS: Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of family JX. The single coding exon of HPS6 was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of HPS6 reported in the literature were reviewed.\nRESULTS: We identified two different compound heterozygous truncating variants of HPS6 in probands with suspected OA from two independent families. The proband of family JX had c.1674dup and c.503-504del variants, and the other proband from family CZ had a nonsense variant of c.1114C&gt;T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of HPS6 variants and revealed a significant overlap between CpG islands and the variants of HPS6, suggesting a potential link between DNA methylation and HPS6 variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease.\nCONCLUSION: Our research expands the spectrum of HPS6 variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.","variants":[{"Name":"NM_024747.6(HPS6):c.1114C>T (p.Arg372Ter)","Chromosome":"10","Start":"102066588","Stop":"102066588","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1340120,"rule_based_match":false,"evidence_text":"c.1114C>T","llm_judgment":"PRESENT","evidence":"c.1114C>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"23264079","title":"Searching for E-cadherin gene mutations in early onset diffuse gastric cancer and hereditary diffuse gastric cancer in Korean patients.","abstract":"The impact of CDH1 gene mutations and large deletions on hereditary diffuse gastric cancer (HDGC) and early onset diffuse gastric cancer (EODGC) has not been determined in Asians. We investigated the mutation status of the CDH1 gene in 25 Korean EODGC patients younger than 50 years and 23 HDGC patients who met the clinical criteria for HDGC. Polymerase chain reaction-direct sequencing was performed, and multiplex ligation-dependent probe amplification (MLPA) was used to evaluate the patients with negative sequencing results. We determined that 2 of 25 (8 %) EODGC patients had CDH1 germline mutations. One was a nonsense mutation (c.1003C>T, p.Arg335*, exon 7) in a 41-year-old female with no family history of cancer. The other was a missense mutation (c.715G>A, p.Gly239Arg, exon 6) in a 28-year-old male with no family history of cancer. One of 23 (4.3 %) HDGC patients had a CDH1 germline mutation (c.1003C>T). The patient's brother and sister died of stomach cancer. The MLPA results revealed no deletion or duplication in any patient. More research is needed to determine additional genetic targets that trigger HDGC. More comprehensive methods such as next-generation sequencing might be a good approach that can be used to identify the genetic causes of pathogenetically unexplained disorders.","variants":[{"Name":"NM_004360.5(CDH1):c.715G>A (p.Gly239Arg)","Chromosome":"16","Start":"68810224","Stop":"68810224","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":136457,"rule_based_match":true,"evidence_text":"c.715G>A (p.Gly239Arg, exon 6)","llm_judgment":"PRESENT","evidence":"p.Gly239Arg","abstract_start":770,"abstract_end":781},{"Name":"NM_004360.5(CDH1):c.1003C>T (p.Arg335Ter)","Chromosome":"16","Start":"68811854","Stop":"68811854","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":139767,"rule_based_match":true,"evidence_text":"c.1003C>T (p.Arg335*, exon 7)","llm_judgment":"PRESENT","evidence":"c.1003C>T","abstract_start":637,"abstract_end":646}]}
{"pmid":"30544479","title":"UGT1A1 genotypes and unconjugated hyperbilirubinemia phenotypes in post-neonatal Chinese children: A retrospective analysis and quantitative correlation.","abstract":"To retrospectively analyze and quantitatively correlate UGT1A1 (bilirubin UDP- glucuronosyltransferase gene) genotypes and unconjugated hyperbilirubinemia (UCH) phenotypes among Chinese children.We retrospectively reviewed UCH patients, quantitatively analyzed genotype-phenotype correlation by comparing with healthy controls. Pfam database, SWISS-model, and Pymol were used for UGT1A1 protein domain analysis and protein modeling for assessing the effect of novel missense variants on protein structure.Seventy four cases, including 21 prolonged unconjugated hyperbilirubinemia (PUCH), 30 Gilbert syndrome (GS), 22 Crigler-Najjar syndrome type II (CNS-II), and 1 Crigler-Najjar syndrome type I (CNS-I) phenotypes were analyzed. Total of 21 variants, including 7 novel variants (c.764T>A/p.L255Q, c.1112C>T/p.T371I, c.1028C>A/p.S343X, c.1047delG/p.I350YfsX16, c.996 + 5G>C/g.6923G>C, c.287G>A/p.G96E, and c.1142G>A/p.S381N) were found. In the multiple regression model, heterozygous A(TA)7TAA, G71R/P364L, and Y486D/other mutations were significantly associated with increased risk of GS, PUCH, and CNS-II, respectively. Total allele number is significantly associated with GS and CNS-II, with each increase in total allele number, the odds ratio (OR) of having GS and CNS-II increased by 1.46 and 4.47 fold, respectively. Having only functional polymorphisms in UGT1A1 gene is associated with increased risk of PUCH, and GS with OR values of 5.67 (95% CI: 1.52-21.13), and 3.88 (95% CI: 1.02-14.78), respectively. Having only mutation is associated with significantly increased risk of having GS phenotype (OR: 34.00, 95% CI: 4.65-248.37), but not CNS-II. Polymorphism plus mutation had the strongest association with CNS-II with OR value of 64.80 (95% CI: 7.68-546.41), followed by GS (OR: 4.53, 95% CI: 1.08-19.08).We detected 7 novel variants, and quantitatively calculated risks of having specific phenotypes using genetic data. Among Chinese children, G71R and P364L is independently associated with PUCH, A(TA)7TAA is associated with GS, and Y486D or other disease-causing mutations were associated with CNS-II. Multiple alleles were associated with more severe phenotypes. Combined variant of G71R+Y486D is a common occurrence among Chinese children with UCH.","variants":[{"Name":"NM_000463.3(UGT1A1):c.287G>A (p.Gly96Glu)","Chromosome":"2","Start":"233760574","Stop":"233760574","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1378677,"rule_based_match":true,"evidence_text":"c.287G>A/p.G96E","llm_judgment":"PRESENT","evidence":"c.287G>A/p.G96E","abstract_start":885,"abstract_end":900},{"Name":"NM_000463.3(UGT1A1):c.1112C>T (p.Thr371Ile)","Chromosome":"2","Start":"233768247","Stop":"233768247","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1890399,"rule_based_match":true,"evidence_text":"c.1112C>T/p.T371I","llm_judgment":"PRESENT","evidence":"c.1112C>T/p.T371I","abstract_start":798,"abstract_end":815}]}
{"pmid":"38105698","title":"Genetic analysis of novel pathogenic gene","abstract":"A 13-year and 6-month-old girl attended the Hunan Children's Hospital due to delayed menarche. The laboratory test results indicated increased follicle-stimulating hormone and luteinizing hormone, decreased anti-Mullerian hormone, and pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries. Her 11-year and 5-month-old younger sister had the same laboratory and imaging findings, and both girls were diagnosed with primary ovarian insufficiency. Whole exome sequencing and Sanger sequencing confirmed that the proband and her sister carried heterozygous variants of <i>HROB</i> gene c.718C>T (p.Arg240*) and c.1351C>T (p.Arg451*), which were inherited from their parents respectively and consistent with autosomal recessive inheritance. Oral estradiol valerate at an initial dose of 0.125 mg/d was given to the proband, and the secondary sexual characteristics began to develop after 6 months.","variants":[{"Name":"NM_001171251.3(HROB):c.718C>T (p.Arg240Ter)","Chromosome":"17","Start":"44148521","Stop":"44148521","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3414236,"rule_based_match":true,"evidence_text":"c.718C>T (p.Arg240*)","llm_judgment":"PRESENT","evidence":"c.718C>T (p.Arg240*)","abstract_start":605,"abstract_end":625},{"Name":"NM_001171251.3(HROB):c.1351C>T (p.Arg451Ter)","Chromosome":"17","Start":"44152679","Stop":"44152679","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3414237,"rule_based_match":true,"evidence_text":"c.1351C>T (p.Arg451*)","llm_judgment":"PRESENT","evidence":"c.1351C>T (p.Arg451*)","abstract_start":630,"abstract_end":651}]}
{"pmid":"27734837","title":"Novel AARS2 gene mutation producing leukodystrophy: a case report.","abstract":"AARS2 gene (NM_020745.3) mutations result in two different phenotypic diseases: infantile mitochondrial cardiomyopathy and late-onset leukoencephalopathy. The patient's first symptoms appeared at the age of 18 years with behavioral changes and psychiatric problems. Some years later, extrapyramidal symptoms, cognitive impairment, nystagmus, dysarthria and pyramidal symptoms also developed. The brain magnetic resonance imaging (MRI) indicated extensive white matter abnormalities. The diagnosis of AARS2 gene mutations causing leukodystrophy was confirmed by genetic testing. Segregation analysis confirmed the compound heterozygous state of the patient. Histological examination of the biopsy did not prove specific pathological alterations. The clinical phenotype of our patient was compared with seven previously described patients suffering from leukoencephalopathy caused by AARS2 mutations. We have documented a new, nonsense AARS2 gene mutation (c.578T>G, p.Leu193*) and a known missense mutation (c.595C>T, p.Arg199Cys) associated with leukoencephalopathy in a male patient. Clinical features, imaging characteristics and genetic testing are presented, and histological data from an AARS2-related leukodystrophy patient are described for the first time.","variants":[{"Name":"NM_020745.4(AARS2):c.595C>T (p.Arg199Cys)","Chromosome":"6","Start":"44311148","Stop":"44311148","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":211239,"rule_based_match":true,"evidence_text":"c.595C>T (p.Arg199Cys)","llm_judgment":"PRESENT","evidence":"p.Arg199Cys","abstract_start":1017,"abstract_end":1028}]}
{"pmid":"26083569","title":"Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations.","abstract":"Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6-8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues.","variants":[{"Name":"NM_020320.5(RARS2):c.1A>G (p.Met1Val)","Chromosome":"6","Start":"87589957","Stop":"87589957","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":226903,"rule_based_match":true,"evidence_text":"c.1A>G, p.?","llm_judgment":"PRESENT","evidence":"c.1A>G, p.?","abstract_start":910,"abstract_end":921},{"Name":"NM_020320.5(RARS2):c.613-3927C>T","Chromosome":"6","Start":"87534869","Stop":"87534869","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1055641,"rule_based_match":true,"evidence_text":"c.613-3927C>T","llm_judgment":"PRESENT","evidence":"c.613-3927C>T","abstract_start":997,"abstract_end":1010}]}
{"pmid":"29907148","title":"A case of Metaplastic atrophic gastritis in immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome.","abstract":"BACKGROUND: Autoimmune metaplastic atrophic gastritis is a chronic progressive inflammatory condition. The clinical spectrum includes pernicious anemia, atrophic gastritis, antibodies to parietal cell antigens and intrinsic factor, achlorhydria, hypergastrinemia and carcinoma. It is rare in paediatric cohorts.\nCASE PRESENTATION: We present the case of a boy with metaplastic atrophic gastritis in whom immune dysregulation, polyendocrinopathy, enteropathy, X-linked(IPEX) syndrome was confirmed by FOXP3 gene mutation. The patient was referred to the hospital at the age of 3 years with recurrent emesis, diarrhoea and malnutrition. His elder brother died at 9 years of age from acute respiratory distress syndrome and renal tubular acidosis. The patient was allergic to cow milk formula and noodles. Oesophagegastroduodenoscopy revealed redness, erosion and edema throughout the stomach; whitish granules in the duodenal bulb; and edema in the second part of the duodenum. Biopsies showed extensive villous atrophy and goblet cell depletion in the duodenum. He was diagnosed with type-1 diabetes mellitus (T1DM) during the treatment of methylprednisolone. Serum antibodies against glutamic acid decarboxylase and pancreatic islets were detected. The patient's FOXP3 gene was sequenced; this identified that the patient was hemizygous for a pathogenic variant [NM_014009.3:c.748_750del (p.Lys250del)].\nCONCLUSION: Metaplastic atrophic gastritis is rarely reported in patients with IPEX. Clinical gastroenterologists should be aware of IPEX syndrome when facing the complex syndromes of metaplastic atrophic gastritis and endocrinopathy.","variants":[{"Name":"NM_014009.4(FOXP3):c.748_750del (p.Lys250del)","Chromosome":"X","Start":"49255495","Stop":"49255497","ReferenceAlleleVCF":"CCTT","AlternateAlleleVCF":"C","allel_id":491314,"rule_based_match":true,"evidence_text":"NM_014009.3:c.748_750del (p.Lys250del)","llm_judgment":"PRESENT","evidence":"NM_014009.3:c.748_750del (p.Lys250del)","abstract_start":1363,"abstract_end":1401}]}
{"pmid":"31228227","title":"Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease.","abstract":"Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe, rare autosomal recessive disorder caused by variants in the heparan-α-glucosaminide N-acetyltransferase (HGSNAT) gene which result in lysosomal accumulation of heparan sulfate. We analyzed clinical presentation, molecular defects and their haplotype context in 78 (27 novel) MPSIIIC cases from 22 countries, the largest group studied so far. We describe for the first time disease-causing variants in the patients from Brazil, Algeria, Azerbaijan, and Iran, and extend their spectrum within Canada, Colombia, Turkey, and the USA. Six variants are novel: two missense, c.773A>T/p.N258I and c.1267G>T/p.G423W, a nonsense c.164T>A/p.L55*, a splice-site mutation c.494-1G>A/p.[P165_L187delinsQSCYVTQAGVRWHHLGSLQALPPGFTPFSYLSLLSSWNC,P165fs], a deletion c.1348delG/p.(D450fs) and an insertion c.1479dupA/p.(Leu494fs). The missense HGSNAT variants lacked lysosomal targeting, enzymatic activity, and likely the correct folding. The haplotype analysis identified founder mutations, p.N258I, c.525dupT, and p.L55* in the Brazilian state of Paraiba, c.493+1G>A in Eastern Canada/Quebec, p.A489E in the USA, p.R384* in Poland, p.R344C and p.S518F in the Netherlands and suggested that variants c.525dupT, c.372-2G>A, and c.234+1G>A present in cis with c.564-98T>C and c.710C>A rare single-nucleotide polymorphisms, have been introduced by Portuguese settlers in Brazil. Altogether, our results provide insights into the origin, migration roots and founder effects of HGSNAT disease-causing variants, and reveal the evolutionary history of MPSIIIC.","variants":[{"Name":"NM_152419.3(HGSNAT):c.494-1G>A","Chromosome":"8","Start":"43161437","Stop":"43161437","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1941516,"rule_based_match":true,"evidence_text":"c.494-1G>A","llm_judgment":"PRESENT","evidence":"c.494-1G>A","abstract_start":714,"abstract_end":724},{"Name":"NM_152419.3(HGSNAT):c.164T>A (p.Leu55Ter)","Chromosome":"8","Start":"43146993","Stop":"43146993","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":637223,"rule_based_match":true,"evidence_text":"c.164T>A/p.L55*","llm_judgment":"PRESENT","evidence":"c.164T>A/p.L55*","abstract_start":674,"abstract_end":689},{"Name":"NM_152419.3(HGSNAT):c.1267G>T (p.Gly423Trp)","Chromosome":"8","Start":"43192320","Stop":"43192320","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":407393,"rule_based_match":true,"evidence_text":"c.1267G>T/p.G423W","llm_judgment":"PRESENT","evidence":"c.1267G>T/p.G423W","abstract_start":644,"abstract_end":661}]}
{"pmid":"29948574","title":"T","abstract":"PURPOSE: All reported patients with hypomorphic X-linked severe combined immunodeficiency (X-SCID) due to c.664C>T (p.R222C) mutations in the gene (IL2RG) encoding the common γ chain (γc) have presented with opportunistic infections within the first year of life, despite the presence of nearly normal NK and T cell numbers. Reporting five children of one extended family with hemizygous mutations in IL2RG, we explore potential diagnostic clues and extend our comprehension of the functional impact of this mutation.\nMETHODS: Whole exome sequencing (WES); detailed immune phenotyping; cytokine-induced STAT phosphorylation; B, T, and NK cell activation; and quantification of sjTRECs in five Arab children with c.664C>T (p.R222C) IL2RG mutation.\nRESULTS: The mean age at clinical presentation with respiratory tract infection or diarrhea was 6.8 (range: 2-12) months. None of the children presented with opportunistic infections. Diagnostic clues were early onset in the first year of life, and a suggestive family history associated with reduced naïve CD4 T cells and absent switched memory B cells. Number and phenotype of NK cells and innate-like lymphocytes were normal. The diagnosis was made by WES and corroborated by absent STAT phosphorylation and reduced functional response after IL-2 and IL-21 stimulation. Four patients underwent successful hematopoietic stem cell transplantation.\nCONCLUSIONS: As early diagnosis and treatment are important, a high index of suspicion in the diagnosis of c.664C>T (p.R222C) X-SCID is needed. This requires prompt genetic testing by next generation sequencing in order to avoid unnecessary delays in the definite diagnosis since immunological work up may not be discriminating. Assays directly testing cytokine signaling or cytokine-dependent functions are helpful in confirming the functional impact of the identified hypomorphic variants.","variants":[{"Name":"NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys)","Chromosome":"X","Start":"71109321","Stop":"71109321","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25066,"rule_based_match":true,"evidence_text":"c.664C>T (p.R222C)","llm_judgment":"PRESENT","evidence":"c.664C>T (p.R222C)","abstract_start":106,"abstract_end":124}]}
{"pmid":"30144375","title":"TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton.","abstract":"Transient receptor potential vanilloid 6 (TRPV6) functions in tetramer form for calcium transport. Until now, TRPV6 has not been linked with skeletal development disorders. An infant with antenatal onset thoracic insufficiency required significant ventilatory support. Skeletal survey showed generalized marked undermineralization, hypoplastic fractured ribs, metaphyseal fractures, and extensive periosteal reaction along femoral, tibial, and humeral diaphyses. Parathyroid hormone (PTH) elevation (53.4-101 pmol/L) initially suggested PTH signaling disorders. Progressively, biochemical normalization with radiological mineralization suggested recovery from in utero pathophysiology. Genomic testing was undertaken and in silico protein modeling of variants. No abnormalities in antenatal CGH array or UPD14 testing. Postnatal molecular genetic analysis found no causative variants in CASR, GNA11, APS21, or a 336 gene skeletal dysplasia panel investigated by whole exome sequencing. Trio exome analysis identified compound heterozygous TRPV6 likely pathogenic variants: novel maternally inherited missense variant, c.1978G > C p.(Gly660Arg), and paternally inherited nonsense variant, c.1528C > T p.(Arg510Ter), confirming recessive inheritance. p.(Gly660Arg) generates a large side chain protruding from the C-terminal hook into the interface with the adjacent TRPV6 subunit. In silico protein modeling suggests steric clashes between interface residues, decreased C-terminal hook, and TRPV6 tetramer stability. The p.(Gly660Arg) variant is predicted to result in profound loss of TRPV6 activity. This first case of a novel dysplasia features severe but improving perinatal abnormalities. The TRPV6 compound heterozygous variants appear likely to interfere with fetoplacental calcium transfer crucial for in utero skeletal development. Astute clinical interpretation of evolving perinatal abnormalities remains valuable in complex calcium and bone pathophysiology and informs exome sequencing interpretation.","variants":[{"Name":"NM_018646.6(TRPV6):c.1978G>C (p.Gly660Arg)","Chromosome":"7","Start":"142872409","Stop":"142872409","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":806433,"rule_based_match":true,"evidence_text":"c.1978G > C p.(Gly660Arg)","llm_judgment":"PRESENT","evidence":"c.1978G > C p.(Gly660Arg)","abstract_start":1118,"abstract_end":1143}]}
{"pmid":"35434101","title":"Short stature associated with a novel mutation in the aggrecan gene: A case report and literature review.","abstract":"BACKGROUND: Mutations in the aggrecan (<i>ACAN</i>) gene are identified in patients with: spondyloepiphyseal dysplasia, Kimberley type; short stature with advanced bone age (BA); in the presence or absence of heterozygous <i>ACAN</i> mutation-induced early-onset osteoarthritis and/or osteochondritis dissecans; and spondyloepimetaphyseal dysplasia, ACAN type. Heterozygous mutations contribute to spondyloepiphyseal dysplasia, Kimberley type (MIM#608361), which is a milder skeletal dysplasia. In contrast, homozygous mutations cause a critical skeletal dysplasia, which is called spondyloepimetaphyseal dysplasia, ACAN type (MIM#612813). Lately, investigations on exome and genome sequencing have shown that <i>ACAN</i> mutations can also lead to idiopathic short stature with or without an advanced BA, in the presence or absence of early-onset osteoarthritis and/or osteochondritis dissecans (MIM#165800). We herein reported a heterozygous defect of <i>ACAN</i> in a family with autosomal dominant short stature, BA acceleration, and premature growth cessation.\nCASE SUMMARY: A 2-year-old male patient visited us due to growth retardation. The patient presented symmetrical short stature (height 79 cm, < -2 SD) without facial features and other congenital abnormalities. Whole-exome sequencing revealed a heterozygous pathogenic variant c. 871C>T (p. Gln291*) of <i>ACAN</i>, which was not yet reported in cases of short stature. This mutation was also detected in his father and paternal grandmother. According to the Human Gene Mutation Database, 67 <i>ACAN</i> mutations are registered. Most of these mutations are genetically inheritable, and very few children with short stature are associated with <i>ACAN</i> mutations. To date, heterozygous <i>ACAN</i> mutations have been reported in approximately 40 families worldwide, including a few individuals with a decelerated BA.\nCONCLUSION: Heterozygous c. 871C>T (p. Gln291*) variation of the <i>ACAN</i> gene was the disease-causing variant in this family. Collectively, our newly discovered mutation expanded the spectrum of <i>ACAN</i> gene mutations.","variants":[{"Name":"NM_001369268.1(ACAN):c.871C>T (p.Gln291Ter)","Chromosome":"15","Start":"88843468","Stop":"88843468","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3011944,"rule_based_match":true,"evidence_text":"c. 871C>T (p. Gln291*)","llm_judgment":"PRESENT","evidence":"c. 871C>T (p. Gln291*)","abstract_start":1342,"abstract_end":1364}]}
{"pmid":"21646290","title":"Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty.","abstract":"BACKGROUND: A limited number of mutations in the GH secretagogue receptor gene (GHSR) have been described in patients with short stature. Objective To analyze GHSR in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients.\nSUBJECTS AND METHODS: The GHSR coding region was directly sequenced in 96 independent patients with ISS, 31 of them with CDGP, in 150 adults, and in 197 children with normal stature. The pharmacological consequences of GHSR non-synonymous variations were established using in vitro cell-based assays.\nRESULTS: Five different heterozygous point variations in GHSR were identified (c.-6 G>C, c.251G>T (p.Ser84Ile), c.505G>A (p.Ala169Thr), c.545 T>C (p.Val182Ala), and c.1072G>A (p.Ala358Thr)), all in patients with CDGP. Neither these allelic variants nor any other mutations were found in 694 alleles from controls. Functional studies revealed that two of these variations (p.Ser84Ile and p.Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. These mutations were identified in two female patients with CDGP (at the age of 13 years, their height SDS were -2.4 and -2.3). Both patients had normal progression of puberty and reached normal adult height (height SDS of -0.7 and -1.4) without treatment.\nCONCLUSION: This is the first report of GHSR mutations in patients with CDGP. Our data raise the intriguing possibility that abnormalities in ghrelin receptor function may influence the phenotype of individuals with CDGP.","variants":[{"Name":"NM_198407.2(GHSR):c.1072G>A (p.Ala358Thr)","Chromosome":"3","Start":"172445190","Stop":"172445190","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1019785,"rule_based_match":true,"evidence_text":"c.1072G>A (p.Ala358Thr)","llm_judgment":"PRESENT","evidence":"c.1072G>A (p.Ala358Thr)","abstract_start":757,"abstract_end":780},{"Name":"NM_198407.2(GHSR):c.545T>C (p.Val182Ala)","Chromosome":"3","Start":"172447869","Stop":"172447869","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1330634,"rule_based_match":true,"evidence_text":"c.545 T>C (p.Val182Ala)","llm_judgment":"PRESENT","evidence":"c.545 T>C (p.Val182Ala)","abstract_start":728,"abstract_end":751}]}
{"pmid":"18700894","title":"LAMA2 gene analysis in a cohort of 26 congenital muscular dystrophy patients.","abstract":"Congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-alpha2. We describe the molecular study of 26 patients with clinical presentation, magnetic resonance imaging and/or laminin-alpha2 expression in muscle, compatible with MDC1A. The combination of full genomic sequencing and complementary DNA analysis led to the particularly high mutation detection rate of 96% (50/52 disease alleles). Besides 22 undocumented polymorphisms, 18 different mutations were identified in the course of this work, 14 of which were novel. In particular, we describe the first fully characterized gross deletion in the LAMA2 gene, encompassing exon 56 (c.7750-1713_7899-2153del), detected in 31% of the patients. The only two missense mutations detected were found in heterozygosity with nonsense or truncating mutations in the two patients with the milder clinical presentation and a partial reduction in muscle laminin-alpha2. Our results corroborate the previous few genotype/phenotype correlations in MDC1A and illustrate the importance of screening for gross rearrangements in the LAMA2 gene, which may be underestimated in the literature.","variants":[{"Name":"NM_000426.4(LAMA2):c.7750-1713_7899-2153del","Chromosome":"6","Start":"129484761","Stop":"129489748","ReferenceAlleleVCF":"GGTAATGATAAACATAAAATCCACATTTGTGGTTACCTCTGAGATGGAGAAGCAAGGAGATGGTATTAGAAAGAAACTCATAAGAGATGCAATGGTATTGTTTCTGAAATTTGGTGGTAGATTTACAGGTATTCATGTTATTATACAGTGTTAACGCAGCTTCATCGTTTACATGTATATCACTCATATTGTGAAGAATATATCAAATAGTCGTAATAAAAATATTTTTGAAGAGTAGAGGGAGAAAAGTGTTATTTTATTTCATTTCTTACTACACATAATAAGCACTAAATAAATATAAAATACAAATGCCCTCGTCAATTTTTTTGTTTATCTTGAAAAATAAACTTTTTTCTCATATTGCAAATGATAAGCTAGTTATAATAAGAATACCAGATCAAATATTCTGAAATAGATTTCCACTAAAGGATACTTGATTCCTTCATCATTGCCAGATATTTAAACACTACCTACTGGCTCCAAATTTCTCCTCTTCAAGATAAAAGAAATGAATGTGAATCACCAGCTTTCAGGATAGTGCTTAAAATAAAACAGATTCCTATTAAAACAATTACAATAAGAAAACACTATGTAGTATAGTATAAAGTAAGTTAAAATGACATTTTAATGTTTTAACATTTTAATAACTCATATCTACTTTATAAAATATCATAGTATATGCTATCTGAAGGAGGAACCAATGTTAAATAGTATAAGTCTGTTAGACATAATTAGATTTAGATTCAGTGCTGGTTAAATTGACAAGTTTTATATTTCAAAGCTAACGGTTTTGATACCCATAGAGTTATTTGTGATTCCTTTCTGCTAAATGGGTTTGATATGGCAAACCATCCATGAGCTAAGGAATTTTTAATTGAGTAGTTTGTGTTTTCCCTTTGACAGATGGTGAGCACTTATCCAGATCCTCAAAATGTTCTGTGGTGGACACGTAACTACATACATGATTTAGTAAATTATTGGAACATGATGATGTTTGATGGAATCTGTCTCTACCACCATAGATGACTCATGGAGAACTGAGCCATCACTGTGTGGCAGGTGCCCCCATACTCCACAAGAAAGGGAGAGCACGTGGCATCAGCTCTAGGGACAAGGACTGCATTCAGGCTCCCTGGGGTTCATGATGGGATATCAAAACCACACTGGTTGCTATAGTAACAGTAGCAAGAAGAAAGCAGGCATGCTTGTGGATGAAAAATTATCTTCCTTCTTTCTAAATGTGGGAGGCAGGTTACATGTTTGTGATAGCGATCTATTCTACCAGCTCAGAGAACAAATTGAAGTCTAAATACTCAGAATGCCACAAGGTTGGGAGTCAGGCCTGATTCTCAGAAGCTAGCTGTCCACTTGTGAATATAAGGGAGAGGGATTTTGTTGACACCCTTTGTCTCCTGATGGGTTTTATAAGTTAGAGGACCAACGCAAGCACAGCTGTTACTTTCAGCATCACAAATCTGCTTTGCAGAGAACTGCTATATTAATATATCCACTTTCCAGATCATCTCACAAGCAAAAATGGTAAATGATTAGAAAGATATTTCCAGCTGTTTTCAAAACCGTTTGAGAAAATAAAGTCTTAATTTCTCAGGTAAGATCTCAGAGCAGACGAACCTGTGGTTCTGCCAGGGAATCTCTAAAGCTAAGCCATAAATGAGACTTCTGTTTAATCTTCAATAACCACTTGCTGTTGCAGGCCTATTATGCAATACTCCTCAACAGGGGCCGTCTGGAAGTGCATCTCTCCACAGGGGCACGAACAATGAGGAAAATTGTGATCAGACCAGAGCCGAATCTGTTTCATGATGGAAGAGAACATTCCGTTCATGTAGAGCGAACTAGAGGGTAACAATAGCACTAAAATATTTATTATTGTAACTCAGGTGAACTTCCTTTGCTAGCATCGGTATCTATCAGTATCTGCCTGAACCTCTGTGTGTGTGGACCTACTATGCATTGCAAAAGGATACCGTAGCTTAATTCCCTCTTCTTTACTTTTCATACTTCGGGAACCTCATTTGCCTCAGCCCTTAGGAGTTCTACCCTTAACATTTTTATTCGTGCAGTTATCTCCACCTTTGGAAAAACCAAATGCATTTTCTGAAGCTATAAATAAGAAAAATCCCTCCCTCTGCCCCTCTTAAATATTACCTCCTCAAATAAGGTATGCACACAGCAAAACTCACAAATCAGCTCCACTGGAGCCAGCAGGCTTTGGCGGTTTCTATCTCATTCAGGTTCCAAAGCAGTTATGGCAGCTGCTTAGCTGTCACAGATACAGAGTGTGGCAGCAGCTGCAGGACCTATTGAGCCTATTAAGTGCATATCTTGTCCCTGTCCCCCTTCCCAAGGTTTGCAGGGTCCCTGCAGAGTGGCTTTCTGAGGGAACAGAATCAAGGGAGGGGAGGAAAATGACTGCTGCCCTGAGCCTGGCCACCTTTTTACAAATCTACCAGAGTGCTTGCCCCAGCCCTGGGCCAGGGAATTGGCTTTACTCATGCACAAACTGATGACTTTCTTTAGAATGCTGCAATACTTTATACTTACTTTATTAGGAAAGTCATCTGTATTTTTCATCAAAATATTGTATGACAACTCAGAGAGATAATTAGTTTAGAAGGACAATTAGAGAAAAAAGAAACAGAAGCCCAGAGACTTCAGGGGTTCAGACCTCCAAGCCAGCAATCCATTTATCAGACTGAAGACATAGAAAAGAACTGGAAATCCAATTTGATGAGGCCTCAAAACACAGAGGATACTTTTAAATGCAACGAGTATGAATATGTAGCAGTAGTTCAGCCAAGCCAATACTATCCTGCAGTGAAAGACCTACATTTACTAATTATCCTCTTGGGGAAAACATTTAGATAAGCAATAAAGATTTCTTACCTTCTAAGTAAACAACAAAGCTTTCCTCAGTTTTTATTATTATTATTATTAGGTAGAGGATTAGGCTGTAGGATGAATTGATACAAAGCGTTCATGCAGAATGGCTACTGAGACGTTTAGAAACCATGATCGAGACAAATGAGGGATCATTTATTTGGACAAACTGAGAACTTTTACTAATCTAACAGCCAGATATTGTAGTCATGGTCTCTGAGGAGAAATGCAAACTGAATGCTCTCATTTGAATCTTAGAATGCTTTAGAATCCTGGTTTCACATGTCTTCTAGATTAGATGTTAGGCCCTTTGACAAACTTTAATCCTTTTCATTGCGGAAAGGACTTTTTAAAAGATTTAAACTTTAGCCGGGCGTGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCCAAGGCAGGTGGATCATGAGGTCAGGAGTTCGAGACCAGCCTGGCCAATATGGTGAAACCCCGTCTCTACTAAAAATGCAAAAACATTAGCCAGACATGGTGGTAGGCGCCTGTAATCACAGCTACTCTGGAGGCTGAGGCAGGAGAAATGCTTAAACCAGGGGGACAGAGGTTTCAGTGAGCCGAGATCGCACCACTGCACTCCAGCCTGGGCAACAGAGCAAGACTCCAACTCGGAAAAAACAAAACAAAACAAAAACATTTAAACTTTAAGGAATTTCAATAAGTAACTGCAGATTTGAGAAATTAGTTTACCGAAATCACTCAAAATGTGTTATTTTGTTGAGAAAGAATTCTGGAATTCCCAAATGCATTACACTATTGTACCACTATGCCACTATGTCCTTTTAACAGGTGCTTCTTCAAGAAGGGCATTTTATTATGCCAACTTCACAGCTGTTGACCATCAATCCAACCTTTATTTGATTAAGCTCAGTATATAGTACATCACTGGAAACCAGTCATTTAGTTAATTGGCCATATAAACGAACAGTTTTGCCATTCATTGTTAATTACAGGATAATATATGACATATTAGTGTGTAGTCACTGAACTCTGTGCCAAAACAGTAATACATTTGCTACCATAATGGCTCATTCGGCACTCTAAGGTTAAAATGCAATCTACTCTATAAGCAAGTGCCACATTAAACTGATTGACCAGAGATCGCAAGTGACCATGAGAACTTCACCCAGAAAAAATTTTTAATGCTTTATATGCCTATTCTATGGCATGATTTGTGTCACATACTAGACAAAGATGATTTGTTTTCATTGTTCTGAATGTATGTGAGATCTGTAATAACATCCTTTCATCACAGATGAGAAAATATTAACTAACCTGCCCAAAATCATGTACTACAAATAACAGGACCAGGTATTAAATGAGATGATATATTTGACTTAAATACCTCCATCTATGCACAGCCAATAGATTATTCTTACATTTTTGTGTGACCATAAAGGTTTATATTACTAAATGTTGATTATGATGTATGATTATTAATTTGGAGATATTTGCATTATCCCAACACTTTTCAGATTTTCAGACTATGCATGTCAGTCATCATTTCTTTTCCTAAAATCCTGGACAAAATGATAGCTTTAATACCGCCTCACAAAATAATTGGATTTTCACCAAACTGGGGGCCAAGCTTCTCAAGAAGCTCCTTCTCCCTTGTCCTCTGCCTCTCTTTACTCCTCCTCCCTCATTCTCTCTCCCTTCCACCCCTTCATCTGGAAAAATCTCCCTTTAGTCACTTTGGTATCTAATTTCTTGGCACTCCAGTGACCTCTGCCTCCTATATCTGCTTTGTCCTCTGATCCTTCTCCTGGCATCCGCCTTGGTGGCCAGCAGTTCTTACTGGACAAAAACATCAAACCCTAAGAGCCTGAAGTAGTTACTTAAGCAAATAGGACAAGCAACTGAACTGAGTTTTTCTTCTGGGAAAGCTTTCTTCACACAGGTACAGAAATAGGCTAAAGGTCAGGAAGTAGGGTGAGATATTTTAGGAGTCATTTGGGGTTTCCAGAATGAGATAAAGATTTTAACACTGAACCCTAAATATTTTCTTTCTTAACATCCAAAGTATGTTCAAACAGAAAAAAGATTAGA","AlternateAlleleVCF":"G","allel_id":29342,"rule_based_match":true,"evidence_text":"c.7750-1713_7899-2153del","llm_judgment":"PRESENT","evidence":"c.7750-1713_7899-2153del","abstract_start":683,"abstract_end":707}]}
{"pmid":"26695873","title":"Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability.","abstract":"Alopecia with mental retardation (APMR) is a very rare disorder. In this study, we report on a consanguineous Pakistani family (AP91) with mild-to-moderate intellectual disability, adolescent alopecia and dentogingival abnormalities. Using homozygosity mapping, linkage analysis and exome sequencing, we identified a novel rare missense variant c.898G>A (p.(Glu300Lys)) in ITGB6, which co-segregates with the phenotype within the family and is predicted to be deleterious. Structural modeling shows that Glu300 lies in the β-propeller domain, and is surrounded by several residues that are important for heterodimerization with α integrin. Previous studies showed that ITGB6 variants can cause amelogenesis imperfecta in humans, but patients from family AP91 who are homozygous for the c.898G>A variant present with neurological and dermatological features, indicating a role for ITGB6 beyond enamel formation. Our study demonstrates that a rare deleterious variant within ITGB6 causes not only dentogingival anomalies but also intellectual disability and alopecia.","variants":[{"Name":"NM_000888.5(ITGB6):c.898G>A (p.Glu300Lys)","Chromosome":"2","Start":"160172592","Stop":"160172592","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":213951,"rule_based_match":true,"evidence_text":"c.898G>A (p.(Glu300Lys))","llm_judgment":"PRESENT","evidence":"c.898G>A (p.(Glu300Lys))","abstract_start":345,"abstract_end":369}]}
{"pmid":"30604644","title":"Compound Heterozygosity for Hb D-Ibadan (HBB: c.263C>A) and Hb C (HBB: c.19G>A).","abstract":"We report an individual with a compound heterozygosity for Hb D-Ibadan (HBB: c.263C>A) and Hb C (HBB: c.19G>A), a hemoglobin (Hb) combination not previously identified. The compound hemoglobinopathy was detected in a young woman during routine prenatal screening. Variant Hbs were identified and confirmed by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE) followed by Sanger DNA sequencing. Hb D-Ibadan was present in significant excess over Hb C (70.3 to 24.4%). A complete blood count (CBC) revealed moderate microcytosis with slight anemia. The history suggests the Hb combination is clinically silent. The findings indicate the compound hemoglobinopathy demonstrates thalassemia minor-like red cell indices with an unequal distribution of the variant Hbs. Comparison with other Hb D-like heterozygous conditions is reviewed.","variants":[{"Name":"NM_000518.4(HBB):c.263C>A (p.Thr88Lys)","Chromosome":"11","Start":"5226629","Stop":"5226629","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":30189,"rule_based_match":true,"evidence_text":"HBB: c.263C>A","llm_judgment":"PRESENT","evidence":"HBB: c.263C>A","abstract_start":72,"abstract_end":85},{"Name":"NM_000518.4(HBB):c.19G>A (p.Glu7Lys)","Chromosome":"11","Start":"5227003","Stop":"5227003","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30165,"rule_based_match":true,"evidence_text":"HBB: c.19G>A","llm_judgment":"PRESENT","evidence":"HBB: c.19G>A","abstract_start":97,"abstract_end":109}]}
{"pmid":"25581745","title":"The c.301_302delAG PROP1 gene mutation in Romanian patients with multiple pituitary hormone deficiency.","abstract":"OBJECTIVE: To establish the frequency of the c.301_302 delAG mutation of the PROP1 gene in Romanian patients with multiple pituitary hormone deficiency (MPHD).\nSUBJECTS AND METHODS: Somatic assessment, hormonal test, bone age, magnetic resonance imaging of the pituitary gland, and molecular diagnosis were performed in 26 patients with MPHD (7 patients with familial form of MPHD and 19 patients with sporadic form of MPHD).\nRESULTS: The c.301_302delAG mutation was detected in the homozygous state in 10 patients belonging to 5 unrelated families (7 patients with familial history of MPHD and 3 patients with sporadic form of MPHD). Those 10 patients presented variable pituitary hormone deficiency and pituitary morphology.\nCONCLUSIONS: The c.301_302delAG homozygous genotype had a high frequency of 38% (10/26), reaching 100% (7/7) in group with familial cases of MPHD and 16% (3/19) in group with sporadic forms of MPHD.","variants":[{"Name":"NM_006261.5(PROP1):c.301_302del (p.Leu102fs)","Chromosome":"5","Start":"177994146","Stop":"177994147","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":23137,"rule_based_match":true,"evidence_text":"c.301_302delAG","llm_judgment":"PRESENT","evidence":"c.301_302delAG","abstract_start":439,"abstract_end":453}]}
{"pmid":"15645653","title":"Identification of two novel missense mutations (p.R1221C and p.R1357W) in the ABCC6 (MRP6) gene in a Japanese patient with pseudoxanthoma elasticum (PXE).","abstract":"Pseudoxanthoma elasticum (PXE) is a rare, inherited, systemic disease of elastic tissue that in particular affects the skin, eyes, and cardiovascular system. Recently, the ABCC6 (MRP6) gene was found to cause PXE. A defective type of ABCC6 gene (16pl3.1) was determined in two Japanese patients with PXE. In order to determine whether these patients have a defect in ABCC6 gene, we examined each of 31 exons and flanking intron sequences by PCR methods (SSCP screening and direct sequencing). We found two novel missense variants in exon 26 and 29 in a compound heterozygous state in the first patient. One is a missense mutation (c.3661C>T; p.R1221C) in exon 26 and the other is a missense mutation (c.4069C>T; p.R1357W) in exon 29. These mutations have not been detected in our control panel of 200 alleles. To our knowledge, this is the first report of mutation identification in the ABCC6 gene in Japanese PXE patients. The second patient was homozygous for 2542_2543delG in ABCC6 gene and heterozygous for 6 kb deletion of LDL-R gene. This case is the first report of a genetically confirmed case of double mutations both in PXE and FH loci.","variants":[{"Name":"NM_001171.6(ABCC6):c.4069C>T (p.Arg1357Trp)","Chromosome":"16","Start":"16154767","Stop":"16154767","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152837,"rule_based_match":true,"evidence_text":"c.4069C>T (p.R1357W)","llm_judgment":"PRESENT","evidence":"c.4069C>T","abstract_start":701,"abstract_end":710},{"Name":"NM_001171.6(ABCC6):c.3661C>T (p.Arg1221Cys)","Chromosome":"16","Start":"16159556","Stop":"16159556","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":426863,"rule_based_match":true,"evidence_text":"c.3661C>T; p.R1221C","llm_judgment":"PRESENT","evidence":"c.3661C>T; p.R1221C","abstract_start":631,"abstract_end":650}]}
{"pmid":"28188379","title":"A novel mutation of laminin β2 (LAMB2) in two siblings with renal failure.","abstract":"This report describes a novel mutation of LAMB2, the gene associated with Pierson syndrome (microcoria-congenital nephrosis syndrome), in two female siblings. The c.970T>C p.(Cys324Arg) mutation in the LAMB2 gene affects one of the eight highly conserved cysteine residues within the first EGF-like module of the laminin β2 protein. These residues form disulfide bonds in order to achieve a correct 3D structure of the protein. The reported phenotype is considered a relatively mild variant of Pierson syndrome and is associated with later-onset (18 months) therapy-resistant nephrotic syndrome leading to renal failure, and ocular abnormalities consisting of high myopia, microcoria, diverse retinal abnormalities, hence a low level of visual acuity. Importantly, the reported LAMB2 mutation was associated with normal neurological development in both siblings.\nCONCLUSION: this report presents the variability of the renal, ocular and neurological phenotypes associated with LAMB2 mutations and underscores the importance of ophthalmologic examination in all children with unexplained renal insufficiency or nephrotic syndrome. What is known • LAMB2 mutations are associated with Pierson syndrome • Pierson syndrome is associated with congenital nephrotic syndrome, microcoria and neurological deficits What is new • A novel mutation in the LAMB2 gene in two female siblings • Genotype and clinical phenotype description of a novel LAMB2 mutation.","variants":[{"Name":"NM_002292.4(LAMB2):c.970T>C (p.Cys324Arg)","Chromosome":"3","Start":"49130806","Stop":"49130806","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":970202,"rule_based_match":true,"evidence_text":"c.970T>C p.(Cys324Arg)","llm_judgment":"PRESENT","evidence":"c.970T>C p.(Cys324Arg)","abstract_start":163,"abstract_end":185}]}
{"pmid":"18458862","title":"Identification of eight novel mutations of the acid alpha-glucosidase gene causing the infantile or juvenile form of glycogen storage disease type II.","abstract":"Glycogen-storage disease type II (GSDII; OMIM #232300), an autosomal recessive disorder caused by a deficiency of the glycogen hydrolysis enzyme acid alpha-glucosidase (acid GAA; acid maltase, EC. 3.2.10.20), results in the accumulation of glycogen in the lysosome. We performed a molecular genetic study on 29 patients with infantile-onset glycogen-storage disease type II (GSDII), 6 with juvenile-onset GSDII and one carrier for GSDII. Seventeen different mutations were identified among them; 8 were novel mutations: c.421C > A (p.L141M), c.872T > C (p.L291P), c.893A > C (p.Y298S), c.1375G > A (p.D459N), c.1437G > C (p.K479N), c.1509_1511del (p.A504del), c.1960T > C (p.S654P), and c.2174G > C (p.R725P). One of the mutations identified, c.2238G > C (p.W746C), which was a sequence change of unknown pathogenic significance causing diminished enzyme activity,was found homozygously in a juvenile-onset patient. We also found a juvenile-onset patient with homozygote c.1935C > A mutation which was frequently found in infantile-onset patients. In addition to mutations, we also identified 14 new polymorphisms in the acid alpha-glucosidase gene. The genotype/phenotype correlations indicated that c.2238G > C (p.W746C) is correlated with juvenile- onset GSDII and that c.872T > C (p.L291P) and c.1411_1414del (p.E471fsX5) are correlated with infantile-onset GSDII. Mutational analysis of GAA is useful in genetic counseling and prenatal diagnosis of the disease.","variants":[{"Name":"NM_000152.5(GAA):c.421C>A (p.Leu141Met)","Chromosome":"17","Start":"80105007","Stop":"80105007","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":548369,"rule_based_match":true,"evidence_text":"c.421C > A (p.L141M)","llm_judgment":"PRESENT","evidence":"c.421C > A (p.L141M)","abstract_start":520,"abstract_end":540},{"Name":"NM_000152.5(GAA):c.1375G>A (p.Asp459Asn)","Chromosome":"17","Start":"80109993","Stop":"80109993","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186557,"rule_based_match":true,"evidence_text":"c.1375G > A (p.D459N)","llm_judgment":"PRESENT","evidence":"c.1375G > A (p.D459N)","abstract_start":586,"abstract_end":607},{"Name":"NM_000152.5(GAA):c.2238G>C (p.Trp746Cys)","Chromosome":"17","Start":"80117016","Stop":"80117016","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":260196,"rule_based_match":true,"evidence_text":"c.2238G > C (p.W746C)","llm_judgment":"PRESENT","evidence":"c.2238G > C (p.W746C)","abstract_start":743,"abstract_end":764},{"Name":"NM_000152.5(GAA):c.1935C>A (p.Asp645Glu)","Chromosome":"17","Start":"80112922","Stop":"80112922","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":19068,"rule_based_match":true,"evidence_text":"c.1935C > A","llm_judgment":"PRESENT","evidence":"c.1935C > A","abstract_start":971,"abstract_end":982}]}
{"pmid":"28008861","title":"Delayed Diagnosis of a 17-Hydroxylase/17,20-Lyase Deficient Patient Presenting as a 46,XY Female: A Low Normal Potassium Level Can Be an Alerting Diagnostic Sign.","abstract":"17-hydroxylase/17,20-lyase deficiency (17-OHD), a rare autosomal recessive defect in adrenal and gonadal steroidogenesis, causes absence of secondary sexual characteristics and frequently associated with hypertension and hypokalemia. Here, we report a 46,XY case who had normal potassium levels and no hypertension. Our patient was a 2.5-year-old female admitted with female external genitalia and inguinal swelling. Pathology of biopsy revealed that this gonad was a testis. Karyotype was 46,XY. She had no hypertension and no hypokalemia. Serum luteinizing hormone and follicle-stimulating hormone levels were high; testosterone, dehydroepiandrosterone sulfate, and androstenedione were low. Human chorionic gonadotrophin stimulation resulted in partial testosterone response. She was initially diagnosed as partial gonadal dysgenesis or testosterone synthesis defect. In her follow-up after noticing low normal potassium levels at age 9 years, progesterone level was measured and detected to be high. Adrenocorticotropic hormone-stimulated steroid measurements were consistent with 17-OHD. Genetic analyses revealed p. R96Q (c.287G>A) homozygous mutation on exon 1 of CYP17A1 gene. In conclusion, evaluation of 46,XY disorder of sex development patients must include serum potassium levels, and near low levels of potassium levels should also suggest 17-OHD despite absence of hypertension or remarkable hypokalemia. Testosterone synthesis defects must be excluded before establishing the diagnosis of partial gonadal dysgenesis.","variants":[{"Name":"NM_000102.4(CYP17A1):c.287G>A (p.Arg96Gln)","Chromosome":"10","Start":"102837075","Stop":"102837075","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16841,"rule_based_match":true,"evidence_text":"c.287G>A","llm_judgment":"PRESENT","evidence":"c.287G>A","abstract_start":1128,"abstract_end":1136}]}
{"pmid":"27450922","title":"Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2.","abstract":"Biallelic mutations in IGHMBP2 cause spinal muscular atrophy with respiratory distress type 1 (SMARD1) or Charcot-Marie-Tooth type 2S (CMT2S). We report three families variably affected by IGHMBP2 mutations. Patient 1, an 8-year-old boy with two homozygous variants: c.2T>C and c.861C>G, was wheelchair bound due to sensorimotor axonal neuropathy and chronic respiratory failure. Patient 2 and his younger sister, Patient 3, had compound heterozygous variants: c.983_987delAAGAA and c.1478C>T. However, clinical phenotypes differed markedly as the elder with sensorimotor axonal neuropathy had still unaffected respiratory function at 4.5 years, whereas the younger presented as infantile spinal muscular atrophy and died from relentless respiratory failure at 11 months. Patient 4, a 6-year-old girl homozygous for IGHMBP2 c.449+1G>T documented to result in two aberrant transcripts, was wheelchair dependent due to axonal polyneuropathy. The clinical presentation in Patients 1 and 3 were consistent with SMARD1, whereas Patients 2 and 4 were in agreement with CMT2S.","variants":[{"Name":"NM_002180.3(IGHMBP2):c.861C>G (p.Ser287Arg)","Chromosome":"11","Start":"68914972","Stop":"68914972","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":511937,"rule_based_match":true,"evidence_text":"c.861C>G","llm_judgment":"PRESENT","evidence":"c.861C>G","abstract_start":278,"abstract_end":286},{"Name":"NM_002180.3(IGHMBP2):c.2T>C (p.Met1Thr)","Chromosome":"11","Start":"68903954","Stop":"68903954","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":214088,"rule_based_match":true,"evidence_text":"c.2T>C","llm_judgment":"PRESENT","evidence":"c.2T>C","abstract_start":267,"abstract_end":273},{"Name":"NM_002180.3(IGHMBP2):c.983_987del (p.Lys328fs)","Chromosome":"11","Start":"68917801","Stop":"68917805","ReferenceAlleleVCF":"TAAGAA","AlternateAlleleVCF":"T","allel_id":214089,"rule_based_match":true,"evidence_text":"c.983_987delAAGAA","llm_judgment":"PRESENT","evidence":"c.983_987delAAGAA","abstract_start":461,"abstract_end":478},{"Name":"NM_002180.3(IGHMBP2):c.1478C>T (p.Thr493Ile)","Chromosome":"11","Start":"68933854","Stop":"68933854","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":214090,"rule_based_match":true,"evidence_text":"c.1478C>T","llm_judgment":"PRESENT","evidence":"c.1478C>T","abstract_start":483,"abstract_end":492},{"Name":"NM_002180.3(IGHMBP2):c.449+1G>T","Chromosome":"11","Start":"68908338","Stop":"68908338","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":200698,"rule_based_match":true,"evidence_text":"c.449+1G>T","llm_judgment":"PRESENT","evidence":"c.449+1G>T","abstract_start":824,"abstract_end":834}]}
{"pmid":"34469883","title":"Nonsyndromic Early-Onset Epileptic Encephalopathies: Two Novel KCTD7 Pathogenic Variants and a Literature Review.","abstract":"Early-onset epileptic encephalopathies (EOEE) affect cognitive, sensory, and motor development. Genetic variations are among the identifiable primary causes of these syndromes. However, some patients have been reported to be affected by EOEE without any other clinical symptoms and signs. We study the genotype and phenotype of patients with nonsyndromic early-onset epileptic encephalopathy (NSEOEE) and report 2 novel patients from Iran. A comprehensive search was conducted in PubMed, John Willy, Springer, Elsevier, and Google Scholar databases to collect related information of all the previously reported cases with KCTD7 mutations. Fifty-four patients (from 40 families) were investigated. Using trio-whole-exome sequencing (trio-WES) and Sanger sequencing, the possible genetic causes of the disorder were checked. The probable impacts of the identified variants on the KCTD7 protein structure and function were predicted. This study provided a detailed overview of all published KCTD7 mutations and 2 de novo ones. We identified 2 novel homozygous variants of uncertain significance, c.458 G > A p. Arg153His and c.529C > T (p.Arg177Cys), in KCTD7 (NM_153033.4) (Chr7(GRCh37)). There is a significant wide distribution of the KCTD7 gene causing NSEOEE among different populations. In conclusion, KCTD7 mutations demonstrate a diverse geographical distribution alongside a wide range of ethnicities. This highlights the importance of careful consideration in the WES data analysis. Mutations of this gene may be a common cause of NSEOEE. Also, this study imprints targeted therapeutic opportunities for potassium channelepsies such as KCTD7-related NSEOEE.","variants":[{"Name":"NM_153033.5(KCTD7):c.529C>T (p.Arg177Cys)","Chromosome":"7","Start":"66638891","Stop":"66638891","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":966193,"rule_based_match":true,"evidence_text":"c.529C>T (p.Arg177Cys)","llm_judgment":"PRESENT","evidence":"c.529C > T (p.Arg177Cys)","abstract_start":1122,"abstract_end":1146},{"Name":"NM_153033.5(KCTD7):c.458G>A (p.Arg153His)","Chromosome":"7","Start":"66638396","Stop":"66638396","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":552118,"rule_based_match":true,"evidence_text":"c.458 G > A p. Arg153His","llm_judgment":"PRESENT","evidence":"c.458 G > A p. Arg153His","abstract_start":1093,"abstract_end":1117}]}
{"pmid":"27578509","title":"PRSS1, SPINK1, CFTR, and CTRC Pathogenic Variants in Korean Patients With Idiopathic Pancreatitis.","abstract":"BACKGROUND: This study aimed to identify pathogenic variants of PRSS1, SPINK1, CFTR, and CTRC genes in Korean patients with idiopathic pancreatitis.\nMETHODS: The study population consisted of 116 Korean subjects (65 males, 51 females; mean age, 30.4 yr, range, 1-88 yr) diagnosed with idiopathic chronic pancreatitis (ICP), idiopathic recurrent acute pancreatitis (IRAP), or idiopathic acute pancreatitis (IAP). We analyzed sequences of targeted regions in the PRSS1, SPINK1, CFTR, and CTRC genes, copy numbers of PRSS1 and SPINK1, and clinical data from medical records.\nRESULTS: We identified three types of pathogenic PRSS1 variants in 11 patients, including p.N29I (n=1), p.R122H (n=1), and p.G208A (n=9). Sixteen patients exhibited heterozygous pathogenic variants of SPINK1, including c.194+2T>C (n=12), p.N34S (n=3), and a novel pathogenic splicing variation c.194+1G>A. A heterozygous CFTR p.Q1352H pathogenic variant was detected in eight patients. One patient carried a heterozygous CTRC p.P249L pathogenic variant, which is a known high-risk variant for pancreatitis. All patients had normal PRSS1 and SPINK1 gene copy numbers. Weight loss occurred more frequently in patients carrying the p.G208A pathogenic variant, while pancreatic duct stones occurred more frequently in patients with the c.194+2T>C pathogenic variant.\nCONCLUSIONS: Pathogenic variants of PRSS1, SPINK1, and CFTR were associated with idiopathic pancreatitis, while pathogenic variants of CTRC were not. Copy number variations of PRSS1 and SPINK1 were not detected.","variants":[{"Name":"NM_002769.5(PRSS1):c.623G>C (p.Gly208Ala)","Chromosome":"7","Start":"142752899","Stop":"142752899","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":252641,"rule_based_match":false,"evidence_text":"p.G208A","llm_judgment":"PRESENT","evidence":"p.G208A","abstract_start":695,"abstract_end":702},{"Name":"NM_002769.5(PRSS1):c.86A>T (p.Asn29Ile)","Chromosome":"7","Start":"142750600","Stop":"142750600","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":26916,"rule_based_match":false,"evidence_text":"p.N29I","llm_judgment":"PRESENT","evidence":"p.N29I","abstract_start":662,"abstract_end":668},{"Name":"NM_001379610.1(SPINK1):c.194+2T>C","Chromosome":"5","Start":"147828020","Stop":"147828020","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":136364,"rule_based_match":true,"evidence_text":"c.194+2T>C (n=12)","llm_judgment":"PRESENT","evidence":"c.194+2T>C (n=12)","abstract_start":791,"abstract_end":808}]}
{"pmid":"21792967","title":"Is the c.3G>C mutation in the succinate dehydrogenase subunit D (SDHD) gene due to a founder effect in Chinese head and neck paraganglioma patients?","abstract":"OBJECTIVES/HYPOTHESIS: Three Chinese patients with head and neck paragangliomas have been reported to carry the c.3G>C mutation in the succinate dehydrogenase subunit D (SDHD) gene. In addition, in our hospital, two further patients were identified who have the same mutation. It is unclear whether the c.3G>C mutation in Chinese patients is a recurrent mutation or if it is due to a founder effect. We conducted haplotype analysis on these patients to answer this question.\nSTUDY DESIGN: Individual case-control study.\nMETHODS: Germ-line mutations were confirmed in the patients and their families examined in this study using direct sequencing. We also constructed and analyzed haplotypes in four Chinese families. Genotype frequencies were compared to the control group.\nRESULTS: Three of four families shared the same haplotype, which rarely occurred in the control group. The last family shared a very short area on the physical map with the other three families.\nCONCLUSIONS: There is a founder effect in Chinese head and neck paraganglioma patients carrying the SDHD c.3G>C mutation.","variants":[{"Name":"NM_003002.4(SDHD):c.3G>C (p.Met1Ile)","Chromosome":"11","Start":"112086910","Stop":"112086910","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":21945,"rule_based_match":true,"evidence_text":"c.3G>C","llm_judgment":"PRESENT","evidence":"c.3G>C","abstract_start":112,"abstract_end":118}]}
{"pmid":"25928877","title":"Variability of systemic and oro-dental phenotype in two families with non-lethal Raine syndrome with FAM20C mutations.","abstract":"BACKGROUND: Raine syndrome (RS) is a rare autosomal recessive bone dysplasia typified by osteosclerosis and dysmorphic facies due to FAM20C mutations. Initially reported as lethal in infancy, survival is possible into adulthood. We describe the molecular analysis and clinical phenotypes of five individuals from two consanguineous Brazilian families with attenuated Raine Syndrome with previously unreported features.\nMETHODS: The medical and dental clinical records were reviewed. Extracted deciduous and permanent teeth as well as oral soft tissues were analysed. Whole exome sequencing was undertaken and FAM20C cDNA sequenced in family 1.\nRESULTS: Family 1 included 3 siblings with hypoplastic Amelogenesis Imperfecta (AI) (inherited abnormal dental enamel formation). Mild facial dysmorphism was noted in the absence of other obvious skeletal or growth abnormalities. A mild hypophosphataemia and soft tissue ectopic mineralization were present. A homozygous FAM20C donor splice site mutation (c.784 + 5 g > c) was identified which led to abnormal cDNA sequence. Family 2 included 2 siblings with hypoplastic AI and tooth dentine abnormalities as part of a more obvious syndrome with facial dysmorphism. There was hypophosphataemia, soft tissue ectopic mineralization, but no osteosclerosis. A homozygous missense mutation in FAM20C (c.1487C > T; p.P496L) was identified.\nCONCLUSIONS: The clinical phenotype of non-lethal Raine Syndrome is more variable, including between affected siblings, than previously described and an adverse impact on bone growth and health may not be a prominent feature. By contrast, a profound failure of dental enamel formation leading to a distinctive hypoplastic AI in all teeth should alert clinicians to the possibility of FAM20C mutations.","variants":[{"Name":"NM_020223.4(FAM20C):c.1487C>T (p.Pro496Leu)","Chromosome":"7","Start":"258687","Stop":"258687","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3529982,"rule_based_match":true,"evidence_text":"c.1487C > T; p.P496L","llm_judgment":"PRESENT","evidence":"c.1487C > T; p.P496L","abstract_start":1340,"abstract_end":1360}]}
{"pmid":"23530176","title":"Mutation in the SLC29A3 gene: a new cause of a monogenic, autoinflammatory condition.","abstract":"Germline mutations in the SLC29A3 gene result in a range of recessive, clinically related syndromes: H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome, Faisalabad histiocytosis, and sinus histiocytosis with massive lymphadenopathy. The main symptoms of these diseases are hyperpigmentation with hypertrichosis, sensorineural deafness, diabetes, short stature, uveitis, and Rosai-Dorfman like histiocytosis. Here, we report the case of an 11-month-old boy with early-onset, recurrent episodes of unprovoked fever lasting 7 to 10 days and associated with pericardial effusion, abdominal pain, diarrhea, and inflammation. Physical examination revealed hyperpigmentation with hypertrichosis, dysmorphic features, and spleen and liver enlargement. Failure to thrive, sensorineural deafness, retarded psychomotor development, and a Rosai-Dorfman like cheek lesion developed subsequently. The febrile episodes did not respond to tumor necrosis factor α antagonists and interleukin-1. Sequencing of the SLC29A3 gene revealed a homozygous missense mutation c.1088G>A (p.Arg363Gln). These observations suggest that a newly identified mutation in the SLC29A3 gene may be associated with an autoinflammatory disorder. Genetic defects in SLC29A3 should be considered in patients with autoinflammatory manifestations, recurrent febrile attacks, and 1 or more of the symptoms found in the broad spectrum of SLC29A3-related disorders (especially hyperpigmentation with hypertrichosis).","variants":[{"Name":"NM_018344.6(SLC29A3):c.1088G>A (p.Arg363Gln)","Chromosome":"10","Start":"71362268","Stop":"71362268","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39905,"rule_based_match":true,"evidence_text":"c.1088G>A (p.Arg363Gln)","llm_judgment":"PRESENT","evidence":"c.1088G>A (p.Arg363Gln)","abstract_start":1085,"abstract_end":1108}]}
{"pmid":"34704396","title":"Clinical and genetic spectrum in Chinese families with Fabry disease: a single-centre case series.","abstract":"AIMS: Fabry disease (FD) is an X-linked genetic disease caused by mutations in the GLA gene that leads to deficient activity of lysosomal enzymes, accumulation of globotriaosylceramide in multi-organ systems, and variant clinical manifestations. We aimed to detail the clinical and genetic spectrum of FD in Chinese families.\nMETHODS AND RESULTS: Five male probands with unexplained left ventricular hypertrophy and their family members were investigated. Genetic screening was available in 11 subjects of the 5 families, 10 of whom proved to be carriers of either GLA gene mutation, including 3 previous reported missense mutations (c.128G > A, c.811G > A, c.950T > C), 1 novel missense mutation (c.37G > C), and 1 novel deletion mutation (c.1241delT). A total of 17 patients were definitely or possibly diagnosed of FD, given their clinical manifestations and hereditary nature of FD. Echocardiography demonstrated normal cardiac structure and function in six female patients. Electrocardiographic pre-excitation occurred in 80% (4/5) of men and 16.7% (1/6) of women. Six patients (6/14, 42.9%) had chronic kidney disease with decreased renal function and all were male (6/7, 85.7%). Six patients presented with acroparesthesia, hypohidrosis, or both. Three female patients and two male patients experienced sudden death, and one male patient with the mutation (c.128G > A) died of progressive heart failure, between 41 and 66 years of age.\nCONCLUSIONS: We reported five unrelated families of FD with different GLA mutations. Clinical manifestations were highly heterogeneous between male and female patients even within the same family. Female patients showed relatively low risks of structural heart disease and renal insufficiency. However, the long-term outcomes might be adverse in both sexes. Our study underlines the importance of molecular screening of the GLA gene for early identification and clinical decision making in patients with FD.","variants":[{"Name":"NM_000169.3(GLA):c.950T>C (p.Ile317Thr)","Chromosome":"X","Start":"101398419","Stop":"101398419","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":849521,"rule_based_match":true,"evidence_text":"c.950T>C","llm_judgment":"PRESENT","evidence":"c.950T > C","abstract_start":658,"abstract_end":668}]}
{"pmid":"18767270","title":"Newborn screening for MCAD deficiency: experience of the first three years in British Columbia, Canada.","abstract":"BACKGROUND: Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency is an autosomal recessive disorder of fatty acid oxidation, with potential fatal outcome. MCAD deficiency is diagnosed by acylcarnitine analysis on newborn screening blood spot cards by tandem mass spectrometry. Early diagnosis of MCAD and presymptomatic treatment can potentially reduce morbidity and mortality.\nOBJECTIVES: To evaluate incidence, clinical outcome, biochemical and molecular phenotype of MCAD cases detected in the first three years of newborn screening in British Columbia (BC).\nMETHODS AND RESULTS: Medium chain length acylcarnitines, octanoylcarnitine (C8) and decanoylcarnitine (C10), were measured on newborn screening blood spot cards. Out of 121,000 live births, 17 newborns had C8 values above the screening cut-off of 0.38 umol/L. Ten newborns had elevated C8 on repeat cards and were investigated further. Both C8 and C8/C10 ratios remained abnormal in all confirmed MCAD cases. Positive predictive value of screening was 58% with no false negative results. Seven patients were homozygous for the common c.985A > G MCAD mutation and three others were compound heterozygous for the c.985A > G and a second mutation. Two novel mutations were identified (c.260T > C and c.382T > A). The estimated incidence of MCAD was approximately 1:12,000 live births. Upon frequent feeding and carnitine supplementation, none of the patients had metabolic crises or adverse outcomes.\nCONCLUSION: Frequency of MCAD in BC is comparable to reports from other newborn screening programs. Persistence of elevated C8 levels and C8/C10 ratios in confirmed MCAD cases suggest that these are sensitive markers for newborn screening. Early detection and treatment have successfully prevented adverse health outcomes in patients with MCAD.","variants":[{"Name":"NM_000016.6(ACADM):c.260T>C (p.Met87Thr)","Chromosome":"1","Start":"75732896","Stop":"75732896","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1454910,"rule_based_match":true,"evidence_text":"c.260T > C","llm_judgment":"PRESENT","evidence":"c.260T > C","abstract_start":1245,"abstract_end":1255}]}
{"pmid":"29619237","title":"Refining the clinical phenotype of Okur-Chung neurodevelopmental syndrome.","abstract":"We describe an 8-year-old Japanese boy with a <i>de novo</i> recurrent missense mutation in <i>CSNK2A1</i>, c.593A>G, that is causative of Okur-Chung neurodevelopmental syndrome. He exhibited distinctive facial features, severe growth retardation with relative macrocephaly, and friendly, hyperactive behavior. His dysmorphic features might suggest a congenital histone modification defect syndrome, such as Kleefstra, Coffin-Siris, or Rubinstein-Taybi syndromes, which are indicative of functional interactions between the casein kinase II, alpha 1 gene and histone modification factors.","variants":[{"Name":"NM_177559.3(CSNK2A1):c.593A>G (p.Lys198Arg)","Chromosome":"20","Start":"492282","Stop":"492282","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":226616,"rule_based_match":true,"evidence_text":"c.593A>G","llm_judgment":"PRESENT","evidence":"c.593A>G","abstract_start":108,"abstract_end":116}]}
{"pmid":"28985901","title":"Systemic Manifestations in Pyridox(am)ine 5'-Phosphate Oxidase Deficiency.","abstract":"OBJECTIVE: Pyridoxine is converted to its biologically active form pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine 5'-phosphate oxidase and serves as a cofactor in nearly 200 reactions in the central nervous system. Pyridox(am)ine 5'-phosphate oxidase deficiency leads to P5P dependent epilepsy, typically a neonatal- or infantile-onset epileptic encephalopathy treatable with P5P or in some cases, pyridoxine. Following identification of retinopathy in a patient with pyridox(am)ine 5'-phosphate oxidase deficiency that was reversible with P5P therapy, we describe the systemic manifestations of pyridox(am)ine 5'-phosphate oxidase deficiency.\nMETHODS: A series of six patients with homozygous mutations of PNPO, the gene coding pyridox(am)ine 5'-phosphate oxidase, were evaluated in our center over the course of two years for phenotyping of neurological and systemic manifestations.\nRESULTS: Five of six were born prematurely, three had anemia and failure to thrive, and two had elevated alkaline phosphatase. A movement disorder was observed in two children, and a reversible retinopathy was observed in the most severely affected infant. All patients had neonatal-onset epilepsy and were on a continuum of developmental delay to profound encephalopathy. Electroencephalographic features included background slowing and disorganization, absent sleep features, and multifocal and generalized epileptiform discharges. All the affected probands carried a homozygous PNPO mutation (c.674 G>T, c.686 G>A and c.352G>A).\nCONCLUSION: In addition to the well-described epileptic encephalopathy, pyridox(am)ine 5'-phosphate oxidase deficiency causes a range of neurological and systemic manifestations. A movement disorder, developmental delay, and encephalopathy, as well as retinopathy, anemia, and failure to thrive add to the broadening clinical spectrum of P5P dependent epilepsy.","variants":[{"Name":"NM_018129.4(PNPO):c.674G>T (p.Arg225Leu)","Chromosome":"17","Start":"47946670","Stop":"47946670","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":203489,"rule_based_match":true,"evidence_text":"c.674 G>T","llm_judgment":"PRESENT","evidence":"c.674 G>T","abstract_start":1491,"abstract_end":1500},{"Name":"NM_018129.4(PNPO):c.686G>A (p.Arg229Gln)","Chromosome":"17","Start":"47946682","Stop":"47946682","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":203490,"rule_based_match":true,"evidence_text":"c.686 G>A","llm_judgment":"PRESENT","evidence":"c.686 G>A","abstract_start":1502,"abstract_end":1511}]}
{"pmid":"26780318","title":"Screening of ABCA4 Gene in a Chinese Cohort With Stargardt Disease or Cone-Rod Dystrophy With a Report on 85 Novel Mutations.","abstract":"PURPOSE: Mutations in the ABCA4 gene are heterogeneous and somewhat ethnic specific and can result in autosomal recessive Stargardt disease (STGD1), cone or cone-rod dystrophy (CRD), and retinitis pigmentosa. The objective of this study was to determine the ABCA4 mutation detection rate and mutation spectrum in a cohort of Chinese patients with STGD1 or CRD and describe the clinical features of the patients with ABCA4 mutations.\nMETHODS: A total of 161 probands were recruited for genetic analysis; these included 96 patients diagnosed with STGD1 and 65 individuals with CRD. All probands underwent ophthalmic examinations. All coding exons and exon-intron boundaries of the ABCA4 gene were screened for mutations by PCR-based DNA sequencing, followed by analyses for pathogenicity by in silico programs.\nRESULTS: We found at least two disease-causing ABCA4 alleles in 102 unrelated patients (63.4%), one disease-causing allele in 16 patients (9.9%), and no disease-causing allele in 43 affected individuals (26.7%), giving an overall mutation detection rate of 73.3% (118/161). In total, 136 disease-causing variants of the ABCA4 gene, including 85 novel ones, were identified. The identified mutations included 77 (57.0%) missense, 19 (14.1%) nonsense, 23 (17.0%) splicing effect, and 16 (11.9%) frameshift small insertion or deletion mutations. The most frequent mutation in this cohort was c.2424C>G p.Y808X, representing 4.7% of all screened alleles (15/322).\nCONCLUSIONS: The mutation spectrum of the ABCA4 gene in Chinese patients is quite different from that for Caucasian patients. The establishment of the mutation profile will facilitate ABCA4 screening and risk evaluation for Chinese patients with STGD1.","variants":[{"Name":"NM_000350.3(ABCA4):c.2424C>G (p.Tyr808Ter)","Chromosome":"1","Start":"94055274","Stop":"94055274","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2831393,"rule_based_match":true,"evidence_text":"c.2424C>G p.Y808X","llm_judgment":"PRESENT","evidence":"c.2424C>G p.Y808X","abstract_start":1398,"abstract_end":1415}]}
{"pmid":"35875466","title":"Distinct NSCLC","abstract":"Introduction: Heritable lung cancer may occur in the context of germline <i>TP53</i> mutations (Li-Fraumeni syndrome). Limited cases of intrafamily tumor genomic characteristics have been reported.\nMain concerns Important Clinical Findings Primary Diagnoses Interventions Outcomes: A 40-year-old woman with no smoking history or known environmental exposure risk was incidentally found to have stage II (T2N1) NSCLC harboring an <i>EGFR</i> exon 19 p.Glu746_Ala750 deletion. Family history was notable for an identical twin sister with colorectal cancer (diagnosed at age 31 y) and a mother with stage I NSCLC harboring an <i>EGFR</i> exon 21 c.2573T>G (p.Leu858Arg) mutation (diagnosed at age 69 y). Genetic testing revealed a germline <i>TP53</i> c.542G>A (p.Arg181His) mutation in the patient, her mother, and her sister, consistent with Li-Fraumeni syndrome. No germline <i>EGFR</i> mutations were detected.\nConclusion: Shared germline <i>TP53</i> mutations may be associated with distinct NSCLC somatic <i>EGFR</i> mutations within families with Li-Fraumeni syndrome. Further understanding of the association between genetic cancer syndromes and lung cancer risk may improve early lung cancer detection in populations not otherwise meeting screening eligibility.","variants":[{"Name":"NM_000546.6(TP53):c.542G>A (p.Arg181His)","Chromosome":"17","Start":"7675070","Stop":"7675070","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152034,"rule_based_match":true,"evidence_text":"c.542G>A (p.Arg181His)","llm_judgment":"PRESENT","evidence":"c.542G>A (p.Arg181His)","abstract_start":749,"abstract_end":771}]}
{"pmid":"17982420","title":"N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population.","abstract":"PURPOSE: The study was conducted to resolve the spectrum of ABCA4 mutations in a cohort of unrelated Danish residents with early-onset macular dystrophy.\nMETHODS: A microarray technique was used to analyze known ABCA4 mutations in genomic DNA from a selected group of 161 unrelated individuals referred to the national low vision clinic. The clinical observation time varied from a single examination to follow-up over 35 years.\nRESULTS: Fifty-nine allegedly disease-associated ABCA4 variants were found in 197 alleles (61.2%) from 124 (77.0%) patients. Two or three mutations were present in 73 (45.3%) patients, and only one mutation was found in 51 (31.7%) patients. The mutation spectrum included 45 missense mutations, five nonsense mutations, two frame shift deletions, and seven splice site mutations. The relative frequency among the mutations varied considerably. Twenty-eight mutations occurred only once among 197 alleles, while the five most abundant mutations were encountered in 50% of the mutation-carrying alleles. The rate of mutation detection, assessed as the fraction of individuals carrying at least one ABCA4 mutation, varied from 27% to 90% among seven phenotypic groups, and a single mutation, p.N965S (c.2894A>G) in the first nucleotide-binding domain accounted for 16.2% of 197 disease-associated alleles. The mutation causes moderate to serious phenotypes and eventually blindness.\nCONCLUSIONS: Our study is the first mutation analysis of Stargardt-related retinopathies in a large cohort of patients from a Scandinavian population. The mutation detection rate, performed with an array-based technique, was comparable to that of other microarray-based ABCA4 studies as well as studies using more laborious techniques involving screening methods followed by sequencing. Four out of five of the most prevalent ABCA4 mutations are reported to be frequent in other Western European populations as well. However, the prevalence of the most common Danish mutation, N965S, significantly deviates from the one found in other studies. This underscores that the ABCA4 mutation spectrum within relatively stable populations might be skewed due to founder effects. The clinical spectrum of patients, who are either homozygous or compound heterozygous for the N965S mutation, indicates that this mutation has an early and profound effect on retinal function.","variants":[{"Name":"NM_000350.3(ABCA4):c.2894A>G (p.Asn965Ser)","Chromosome":"1","Start":"94046943","Stop":"94046943","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":237685,"rule_based_match":true,"evidence_text":"c.2894A>G","llm_judgment":"PRESENT","evidence":"c.2894A>G","abstract_start":1227,"abstract_end":1236}]}
{"pmid":"31497480","title":"Profound vitamin D deficiency in four siblings with Imerslund-Grasbeck syndrome with homozygous CUBN mutation.","abstract":"Imerslund-Grasbeck syndrome (IGS, OMIM 261100) is a rare autosomal recessive disease characterized by vitamin B12 malabsorption resulting in megaloblastic anemia and asymptomatic proteinuria. IGS is caused by bi-allelic mutations in either CUBN or AMN that respectively encode the cubilin and amnionless subunits of the cobalamin-intrinsic factor receptor. We report four siblings (three boys, one girl) of non-consanguineous parents of Jewish background, aged 10 months to 12 years, with homozygous CUBN frameshift c.2614_2615deIGA p.(Asp872LeufisTer3) mutation and typical features of IGS. The two older brothers presented in early infancy with lethargy, mouth ulcerations, eosinophilic enterocolitis, megaloblastic anemia and failure to thrive. Investigations revealed low serum cobalamin levels. Intramuscular hydroxycobalamin supplementation resulted in dramatic resolution of all symptoms including lethargy. A positive impact on their growth curve was seen. Prospective early treatment in the younger siblings prevented these manifestations. Proteinuria with proximal tubulopathy was seen in all patients, plasma protein level and renal function were normal. All children had pronounced vitamin D deficiency and required high doses of oral supplementation. Vitamin B12 treatment could be individually adjusted; requirement decreased with age. Tubulopathy showed improvement over time. Low vitamin D could be explained by cubilin being involved in reabsorption of vitamin carriers.","variants":[{"Name":"NM_001081.4(CUBN):c.2614_2615del (p.Asp872fs)","Chromosome":"10","Start":"17071436","Stop":"17071437","ReferenceAlleleVCF":"ATC","AlternateAlleleVCF":"A","allel_id":70969,"rule_based_match":false,"evidence_text":"c.2614_2615deIGA p.(Asp872LeufisTer3)","llm_judgment":"PRESENT","evidence":"c.2614_2615deIGA p.(Asp872LeufisTer3)","abstract_start":516,"abstract_end":553}]}
{"pmid":"24337409","title":"Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis.","abstract":"Complicated hereditary spastic paraplegias (HSP) are a heterogeneous group of HSP characterized by spasticity associated with a variable combination of neurologic and extra-neurologic signs and symptoms. Among them, HSP with thin corpus callosum and intellectual disability is a frequent subtype, often inherited as a recessive trait (ARHSP-TCC). Within this heterogeneous subgroup, SPG11 and SPG15 represent the most frequent subtypes. We analyzed the mutation frequency of three genes associated with early-onset forms of ARHSP with and without TCC, CYP2U1/SPG56, DDHD2/SPG54 and GBA2/SPG46, in a large population of selected complicated HSP patients by using a combined approach of traditional-based and amplicon-based high-throughput pooled-sequencing. Three families with mutations were identified, one for each of the genes analyzed. Novel homozygous mutations were identified in CYP2U1 (c.1A>C/p.Met1?) and in GBA2 (c.2048G>C/p.Gly683Arg), while the homozygous mutation found in DDHD2 (c.1978G>C/p.Asp660His) had been previously reported in a compound heterozygous state. The phenotypes associated with the CYP2U1 and DDHD2 mutations overlap the SPG56 and the SPG54 subtypes, respectively, with few differences. By contrast, the GBA2 mutated patients show phenotypes combining typical features of both the SPG46 subtype and the recessive ataxia form, with marked intrafamilial variability thereby expanding the spectrum of clinical entities associated with GBA2 mutations. Overall, each of three genes analyzed shows a low mutation frequency in a general population of complicated HSP (<1 % for either CYP2U1 or DDHD2 and approximately 2 % for GBA2). These findings underline once again the genetic heterogeneity of ARHSP-TCC and the clinical overlap between complicated HSP and the recessive ataxia syndromes.","variants":[{"Name":"NM_015214.3(DDHD2):c.1978G>C (p.Asp660His)","Chromosome":"8","Start":"38253642","Stop":"38253642","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":48278,"rule_based_match":true,"evidence_text":"c.1978G>C/p.Asp660His","llm_judgment":"PRESENT","evidence":"c.1978G>C/p.Asp660His","abstract_start":993,"abstract_end":1014}]}
{"pmid":"28679693","title":"Functional validation reveals the novel missense V419L variant in","abstract":"TGF-β-related heritable connective tissue disorders are characterized by a similar pattern of cardiovascular defects, including aortic root dilatation, mitral valve prolapse, vascular aneurysms, and vascular dissections and exhibit incomplete penetrance and variable expressivity. Because of the phenotypic overlap of these disorders, panel-based genetic testing is frequently used to confirm the clinical findings. Unfortunately in many cases, variants of uncertain significance (VUSs) obscure the genetic diagnosis until more information becomes available. Here, we describe and characterize the functional impact of a novel VUS in the <i>TGFBR2</i> kinase domain (c.1255G>T; p.Val419Leu), in a patient with the clinical diagnosis of Marfan syndrome spectrum. We assessed the structural and functional consequence of this VUS using molecular modeling, molecular dynamic simulations, and in vitro cell-based assays. A high-quality homology-based model of TGFBR2 was generated and computational mutagenesis followed by refinement and molecular dynamics simulations were used to assess structural and dynamic changes. Relative to wild type, the V419L induced conformational and dynamic changes that may affect ATP binding, increasing the likelihood of adopting an inactive state, and, we hypothesize, alter canonical signaling. Experimentally, we tested this by measuring the canonical TGF-β signaling pathway activation at two points; V419L significantly delayed SMAD2 phosphorylation by western blot and significantly decreased TGF-β-induced gene transcription by reporter assays consistent with known pathogenic variants in this gene. Thus, our results establish that the V419L variant leads to aberrant TGF-β signaling and confirm the diagnosis of Loeys-Dietz syndrome in this patient.","variants":[{"Name":"NM_003242.6(TGFBR2):c.1255G>T (p.Val419Leu)","Chromosome":"3","Start":"30674105","Stop":"30674105","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":209621,"rule_based_match":true,"evidence_text":"c.1255G>T; p.Val419Leu","llm_judgment":"PRESENT","evidence":"c.1255G>T; p.Val419Leu","abstract_start":667,"abstract_end":689}]}
{"pmid":"25403472","title":"Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with inherited cataract.","abstract":"BACKGROUND: Inherited cataract is a clinically important and genetically heterogeneous cause of visual impairment. Typically, it presents at an early age with or without other ocular/systemic signs and lacks clear phenotype-genotype correlation rendering both clinical classification and molecular diagnosis challenging. Here we have utilized trio-based whole exome sequencing to discover mutations in candidate genes underlying autosomal dominant cataract segregating in three nuclear families.\nRESULTS: In family A, we identified a recurrent heterozygous mutation in exon-2 of the gene encoding γD-crystallin (CRYGD; c.70C > A, p.Pro24Thr) that co-segregated with 'coralliform' lens opacities. Families B and C were found to harbor different novel variants in exon-2 of the gene coding for gap-junction protein α8 (GJA8; c.20T > C, p.Leu7Pro and c.293A > C, p.His98Pro). Each novel variant co-segregated with disease and was predicted in silico to have damaging effects on protein function.\nCONCLUSIONS: Exome sequencing facilitates concurrent mutation-profiling of the burgeoning list of candidate genes for inherited cataract, and the results can provide enhanced clinical diagnosis and genetic counseling for affected families.","variants":[{"Name":"NM_005267.5(GJA8):c.20T>C (p.Leu7Pro)","Chromosome":"1","Start":"147907975","Stop":"147907975","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2898312,"rule_based_match":true,"evidence_text":"c.20T>C (p.Leu7Pro)","llm_judgment":"PRESENT","evidence":"p.Leu7Pro","abstract_start":834,"abstract_end":843},{"Name":"NM_005267.5(GJA8):c.293A>C (p.His98Pro)","Chromosome":"1","Start":"147908248","Stop":"147908248","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3412449,"rule_based_match":true,"evidence_text":"c.293A>C (p.His98Pro)","llm_judgment":"PRESENT","evidence":"p.His98Pro","abstract_start":860,"abstract_end":870},{"Name":"NM_006891.4(CRYGD):c.70C>A (p.Pro24Thr)","Chromosome":"2","Start":"208124294","Stop":"208124294","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":31979,"rule_based_match":true,"evidence_text":"c.70C > A, p.Pro24Thr","llm_judgment":"PRESENT","evidence":"c.70C > A, p.Pro24Thr","abstract_start":619,"abstract_end":640}]}
{"pmid":"27592148","title":"Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion.","abstract":"Mitochondrial DNA (mtDNA) depletion syndrome manifests as diverse early-onset diseases that affect skeletal muscle, brain and liver function. Mutations in several nuclear DNA-encoded genes cause mtDNA depletion. We report on a patient, a 3-month-old boy who presented with hepatic failure, and was found to have severe mtDNA depletion in liver and muscle. Whole-exome sequencing identified a homozygous missense variant (c.544C > T, p.R182W) in the accessory subunit of mitochondrial DNA polymerase gamma (POLG2), which is required for mitochondrial DNA replication. This variant is predicted to disrupt a critical region needed for homodimerization of the POLG2 protein and cause loss of processive DNA synthesis. Both parents were phenotypically normal and heterozygous for this variant. Heterozygous mutations in POLG2 were previously associated with progressive external ophthalmoplegia and mtDNA deletions. This is the first report of a patient with a homozygous mutation in POLG2 and with a clinical presentation of severe hepatic failure and mitochondrial depletion.","variants":[{"Name":"NM_007215.4(POLG2):c.544C>T (p.Arg182Trp)","Chromosome":"17","Start":"64496425","Stop":"64496425","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247359,"rule_based_match":true,"evidence_text":"c.544C > T, p.R182W","llm_judgment":"PRESENT","evidence":"c.544C > T, p.R182W","abstract_start":421,"abstract_end":440}]}
{"pmid":"28826917","title":"Missense mutation in the ITPR1 gene presenting with ataxic cerebral palsy: Description of an affected family and literature review.","abstract":"The inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene on chromosome 3 belongs to a family of genes encoding intracellular calcium channel proteins. Such channels are located primarily within the endoplasmic reticular membrane and release Ca<sup>2+</sup>, an intracellular messenger, which governs numerous intracellular and extracellular functions. We report a family with infantile-onset cerebellar ataxia with delayed motor development and intellectual disability caused by a heterozygous c.805C>T, p.Arg269Trp missense mutation in ITPR1. Both affected family members had postural tremor, hypotonia and dysarthria, but neither had pyramidal signs. Their neuroimaging revealed cerebellar atrophy. Several neurological conditions have been associated with ITPR1 mutations, such as spinocerebellar ataxia type 15 and Gillespie syndrome, and the phenotype may vary according to the location and type of mutations. Spinocerebellar ataxia type 15 is an autosomal dominant disorder, which causes late onset pure cerebellar ataxia. Gillespie syndrome is characterised by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia and cerebellar atrophy. In this report, we provide a detailed phenotypic description of a family with a missense mutation in ITPR1. This mutation has only been reported once before. We also provide a literature review of the various phenotypes associated with ITPR1 gene.","variants":[{"Name":"NM_001378452.1(ITPR1):c.805C>T (p.Arg269Trp)","Chromosome":"3","Start":"4645678","Stop":"4645678","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259766,"rule_based_match":true,"evidence_text":"c.805C>T, p.Arg269Trp","llm_judgment":"PRESENT","evidence":"c.805C>T, p.Arg269Trp","abstract_start":498,"abstract_end":519}]}
{"pmid":"38017116","title":"Identification and characterization of ATM founder mutation in BRCA-negative breast cancer patients of Arab ethnicity.","abstract":"Breast cancer (BC) is the most prevalent malignancy among women worldwide with germline pathogenic variants/likely pathogenic variants (PVs/LPVs) in BRCA1/2 accounting for a large portion of hereditary cases. Recently, heterozygous PVs/LPVs in the ATM serine/threonine kinase or Ataxia-telangiectasia mutated gene (ATM) has been identified as a moderate susceptibility factor for BC in diverse ethnicities. However, the prevalence of ATM PVs/LPVs in BC susceptibility in Arab populations remains largely unexplored. This study investigated the prevalence of ATM PVs/LPVs among BC patients from Saudi Arabia, employing capture-sequencing technology for ATM PVs/LPVs screening in a cohort of 715 unselected BC patients without BRCA1/2 PVs/LPVs. In addition, founder mutation analysis was conducted using the PHASE program. In our entire cohort, four unique PVs/LPVs in the ATM gene were identified in six cases (0.8%). Notably, one recurrent LPV, c.6115G > A:p.Glu2039Lys was identified in three cases, for which haplotype analysis confirmed as a novel putative founder mutation traced back to 13 generations on average. This founder mutation accounted for half of all identified mutant cases and 0.4% of total screened cases. This study further reveals a significant correlation between the presence of ATM mutation and family history of BC (p = 0.0127). These findings underscore an approximate 0.8% prevalence of ATM germline PVs/LPVs in Arab BC patients without BRCA1/2 PVs/LPVs and suggest a founder effect of specific recurrent ATM mutation. These insights can help in the design of a genetic testing strategy tailored to the local population in Saudi Arabia, thereby, enabling more accurate clinical management and risk prediction.","variants":[{"Name":"NM_000051.4(ATM):c.6115G>A (p.Glu2039Lys)","Chromosome":"11","Start":"108316030","Stop":"108316030","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":222097,"rule_based_match":true,"evidence_text":"c.6115G > A:p.Glu2039Lys","llm_judgment":"PRESENT","evidence":"c.6115G > A:p.Glu2039Lys","abstract_start":945,"abstract_end":969}]}
{"pmid":"12089654","title":"Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin.","abstract":"Although fixation of the stapes is usually progressive and secondary to otosclerosis, it may present congenitally, with other skeletal manifestations, as an autosomal dominant syndrome-such as proximal symphalangism (SYM1) or multiple-synostoses syndrome (SYNS1), both of which are caused by mutations in NOG, the gene encoding noggin. We describe a family that was ascertained to have nonsyndromic otosclerosis but was subsequently found to have a congenital stapes ankylosis syndrome that included hyperopia, a hemicylindrical nose, broad thumbs and great toes, and other minor skeletal anomalies but lacked symphalangism. A heterozygous nonsense NOG mutation-c.328C-->T (Q110X), predicted to truncate the latter half of the protein-was identified, and a heterozygous insertion in NOG-c.252-253insC, in which the frameshift is predicted to result in 96 novel amino acids before premature truncation-was identified in a previously described second family with a similar phenotype. In contrast to most NOG mutations that have been reported in kindreds with SYM1 and SYNS1, the mutations observed in these families with stapes ankylosis without symphalangism are predicted to disrupt the cysteine-rich C-terminal domain. These clinical and molecular findings suggest that (1) a broader range of conductive hearing-loss phenotypes are associated with NOG mutations than had previously been recognized, (2) patients with sporadic or familial nonsyndromic otosclerosis should be evaluated for mild features of this syndrome, and (3) NOG alterations should be considered in conductive hearing loss with subtle clinical and skeletal features, even in the absence of symphalangism.","variants":[{"Name":"NM_005450.6(NOG):c.328C>T (p.Gln110Ter)","Chromosome":"17","Start":"56594551","Stop":"56594551","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21743,"rule_based_match":false,"evidence_text":"c.328C-->T (Q110X)","llm_judgment":"PRESENT","evidence":"c.328C-->T (Q110X)","abstract_start":662,"abstract_end":680}]}
{"pmid":"32507413","title":"Characterization of novel progranulin gene variants in Italian patients with neurodegenerative diseases.","abstract":"Loss-of-function mutations in the gene encoding for the protein progranulin (PGRN), GRN, are one of the major genetic abnormalities involved in frontotemporal lobar degeneration. However, genetic variations, mainly missense, in GRN have also been linked to other neurodegenerative diseases. We found 12 different pathogenic/likely pathogenic variants in 21 patients identified in a cohort of Italian patients affected by various neurodegenerative disorders. We detected the p.Thr272SerfsTer10 as the most frequent, followed by the c.1179+3A>G variant. We characterized the clinical phenotype of 12 patients from 3 pedigrees carrying the c.1179+3A>G variant, demonstrated the pathogenicity of this mutation, and detected other rarer variants causing haploinsufficiency (p.Met1?, c.709-2A>T, p.Gly79AspfsTer39). Finally, by applying bioinformatics, neuropathological, and biochemical studies, we characterized 6 missense/synonymous variants (p.Asp94His, p.Gly117Asp, p.Ala266Pro, p.Val279Val, p.Arg298His, p.Ala505Gly), including 4 previously unreported. The designation of variants is crucial for genetic counseling and the enrollment of patients in clinical studies.","variants":[{"Name":"NM_002087.4(GRN):c.1179+3A>G","Chromosome":"17","Start":"44351798","Stop":"44351798","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3086798,"rule_based_match":true,"evidence_text":"c.1179+3A>G","llm_judgment":"PRESENT","evidence":"c.1179+3A>G","abstract_start":531,"abstract_end":542}]}
{"pmid":"22083977","title":"Novel germline CDKN2A mutation associated with head and neck squamous cell carcinomas and melanomas.","abstract":"BACKGROUND: The ability to identify individuals at increased risk of cancer is of immediate clinical relevance. Germline mutations in the CDKN2A locus, encoding the key tumor suppressor proteins p16/INK4A and p14/ARF, are frequently present in kindreds with hereditary cutaneous melanoma but have seldom been reported in families with genetic susceptibility to head and neck squamous cell carcinomas (HNSCC).\nMETHODS: We report the pedigree of a patient with an unusually high incidence of HNSCC and melanomas. CDKN2A mutation analysis was performed with standard capillary sequencing and multiplex ligation-dependent probe amplification.\nRESULTS: A previously unreported germline CDKN2A mutation affecting only the p16/INK4A open reading frame, c.106delG (p.Ala36ArgfsX17), was detected in the proband. This mutation causes a premature termination codon.\nCONCLUSIONS: Our report emphasizes the need to consider germinal CDKN2A mutations in the differential diagnosis of familial HNSCC and the importance of awareness of these tumors in carriers of CDKN2A mutations.","variants":[{"Name":"NM_000077.5(CDKN2A):c.106del (p.Ala36fs)","Chromosome":"9","Start":"21974722","Stop":"21974722","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1160767,"rule_based_match":true,"evidence_text":"c.106delG (p.Ala36ArgfsX17)","llm_judgment":"PRESENT","evidence":"c.106delG (p.Ala36ArgfsX17)","abstract_start":746,"abstract_end":773}]}
{"pmid":"20200614","title":"Recurrent and founder mutations in the Netherlands: Extensive clinical variability in Marfan syndrome patients with a single novel recurrent fibrillin-1 missense mutation.","abstract":"Background/Methods. Marfan syndrome (MFS) is a heritable connective tissue disorder usually caused by a mutation in the fibrillin 1 (FBN1) gene. Typical characteristics of MFS that have been described include dolichostenomelia, ectopia lentis and aortic root dilatation. However, there is great clinical variability in the expression of the syndrome's manifestations, both between and within families. Here we discuss the clinical variability of MFS by describing a large fourgeneration Dutch family with MFS.Results. Nineteen individuals of one family with a single missense FBN1 mutation (c.7916A>G) were identified. The same mutation was found in one unrelated person. Clinical variability was extensive and not all mutation carriers fulfilled the diagnostic criteria for MFS. Some patients only expressed mild skeletal abnormalities, whereas aortic root dilation was present in eight patients, an acute type A aortic dissection was recorded in two other patients, and a mitral valve prolapse was present in eight patients. In some patients cardiac features were not present on initial screening, but did however develop over time.Conclusion. MFS is a clinically highly variable syndrome, which means a meticulous evaluation of suspected cases is crucial. Mutation carriers should be re-evaluated regularly as cardiovascular symptoms may develop over time. (Neth Heart J 2010;18:85-9.).","variants":[{"Name":"NM_000138.5(FBN1):c.7916A>G (p.Tyr2639Cys)","Chromosome":"15","Start":"48415671","Stop":"48415671","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":197590,"rule_based_match":true,"evidence_text":"c.7916A>G","llm_judgment":"PRESENT","evidence":"c.7916A>G","abstract_start":591,"abstract_end":600}]}
{"pmid":"25943031","title":"Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors.","abstract":"PIGT-CDG, an autosomal recessive syndromic intellectual disability disorder of glycosylphosphatidylinositol (GPI) anchors, was recently described in two independent kindreds [Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (OMIM, #615398)]. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of the heteropentameric transamidase complex that facilitates the transfer of GPI to proteins. GPI facilitates attachment (anchoring) of proteins to cell membranes. We describe, at ages 7 and 6 years, two children of non-consanguineous parents; they had hypotonia, severe global developmental delay, and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Exome sequencing revealed that both siblings had compound heterozygous variants in PIGT (NM_015937.5), i.e., c.918dupC, a novel duplication leading to a frameshift, and c.1342C > T encoding a previously described missense variant. Flow cytometry studies showed decreased surface expression of GPI-anchored proteins on granulocytes, consistent with findings in previous cases. These siblings further delineate the clinical spectrum of PIGT-CDG, reemphasize the neuro-ophthalmologic presentation, clarify the endocrine features, and add hypermobility, low CSF albumin quotient, and hearing loss to the phenotypic spectrum. Our results emphasize that GPI anchor-related congenital disorders of glycosylation (CDGs) should be considered in subjects with early onset severe seizure disorders and dysmorphic facial features, even in the presence of a normal carbohydrate-deficient transferrin pattern and N-glycan profiling. Currently available screening for CDGs will not reliably detect this family of disorders, and our case reaffirms that the use of flow cytometry and genetic testing is essential for diagnosis in this group of disorders.","variants":[{"Name":"NM_015937.6(PIGT):c.1342C>T (p.Arg448Trp)","Chromosome":"20","Start":"45424323","Stop":"45424323","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152912,"rule_based_match":true,"evidence_text":"c.1342C > T","llm_judgment":"PRESENT","evidence":"c.1342C > T","abstract_start":900,"abstract_end":911}]}
{"pmid":"18243799","title":"DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA.","abstract":"BACKGROUND: Dystonia and parkinsonism may present as part of the same genetic disorder. Identification of the genetic mutations that underlie these diseases may help to shed light on the aetiological processes involved.\nMETHODS: We identified two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. We did autozygosity mapping and candidate gene sequencing in these families.\nFINDINGS: High-density genome-wide SNP genotyping revealed a disease-segregating region containing 277 homozygous markers identical by state across all affected members from both families. This novel disease locus, designated DYT16, covers 1.2 Mb at chromosome 2q31.2. The crucial interval contains 11 genes or predicted transcripts. Sequence analysis of every exon of all of these transcripts revealed a single disease-segregating mutation, c.665C>T (P222L), in the stress-response gene PRKRA, which encodes the protein kinase, interferon-inducible double-stranded RNA-dependent activator.\nINTERPRETATION: We describe a mutation within the gene PRKRA that segregates with a novel, autosomal recessive, dystonia parkinsonism syndrome. These patients have progressive, generalised, early-onset dystonia with axial muscle involvement, oromandibular (sardonic smile), laryngeal dystonia and, in some cases, parkinsonian features, and do not respond to levodopa therapy.","variants":[{"Name":"NM_003690.5(PRKRA):c.665C>T (p.Pro222Leu)","Chromosome":"2","Start":"178436264","Stop":"178436264","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21385,"rule_based_match":true,"evidence_text":"c.665C>T (P222L)","llm_judgment":"PRESENT","evidence":"c.665C>T (P222L)","abstract_start":899,"abstract_end":915}]}
{"pmid":"22387303","title":"Infantile neuronal ceroid lipofuscinosis: follow-up on a Spanish series.","abstract":"Infantile neuronal ceroid lipofuscinosis (INCL; NCL1, Haltia-Santavuori disease) is caused by mutations in the CLN1/PPT gene which are associated with an early onset INCL phenotype. The most detailed descriptions of INCL have come from Finland and a few series have been reported from southern European countries. Clinical course and follow-up of six Spanish patients with INCL are reported with the aim of assessing the chronological evolution and severity of this disease. The age at disease onset ranged from 8 to 15 months. Delayed motor skills were the initial symptom when the disease began before 12 months of age, and ataxia was the first sign when the disease began later. Cognitive decline, which is described between 12 and 18 months of age, occurred from 16 to 20 months of age. In our series early stage is characterized by motor impairment, cognitive decline and autistic features. Visual failure may appear simultaneously with the neurological symptoms, leading quickly to blindness. As reported, psychomotor regression appeared between 2 and 3 years of age. Myoclonic jerks occurred after 24 months of age and epilepsy was the last symptom of the disease. We report two novel mutations in a patient without epilepsy to date and describe the features of two siblings homozygous for the V181M (c.541G>A) mutation, associated with the most severe INCL phenotype. The clinical evolution might be helpful to identify patients affected by this rare disease. Early diagnosis is essential in order to provide genetic counselling to affected families. Our series may contribute to the study of the genotype-phenotype INCL correlation in the Mediterranean countries.","variants":[{"Name":"NM_000310.4(PPT1):c.541G>A (p.Val181Met)","Chromosome":"1","Start":"40080483","Stop":"40080483","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186623,"rule_based_match":true,"evidence_text":"c.541G>A","llm_judgment":"PRESENT","evidence":"c.541G>A","abstract_start":1308,"abstract_end":1316}]}
{"pmid":"31464095","title":"A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2.","abstract":"Rare coding variants in the triggering receptor expressed on myeloid cells-2 (TREM2) gene have been associated with Alzheimer disease (AD) and homozygous TREM2 loss-of-function variants have been reported in families with monogenic frontotemporal-like dementia with/without bone abnormalities. In a whole-exome sequencing study of a family with probable AD-type dementia without pathogenic variants in known autosomal dominant dementia disease genes and negative for the apolipoprotein E (APOE) ε4 allele, we identified an extremely rare TREM2 coding variant, that is, a glycine-to-tryptophan substitution at amino acid position 145 (NM_018965.3:c.433G>T/p.[Gly145Trp]). This alteration is found in only 1 of 251,150 control alleles in gnomAD. It was present in both severely affected as well as in another putatively affected and one 61 years old as yet unaffected family member suggesting incomplete penetrance and/or a variable age of onset. Gly145 maps to an intrinsically disordered region (IDR) of TREM2 between the immunoglobulin-like and transmembrane domain. Subsequent cellular studies showed that the variant led to IDR shortening and structural changes of the mutant protein resulting in an impairment of cellular responses upon receptor activation. Our results, suggest that a p.(Gly145Trp)-induced structural disturbance and functional impairment of TREM2 may contribute to the pathogenesis of an AD-like form of dementia.","variants":[{"Name":"NM_018965.4(TREM2):c.433G>T (p.Gly145Trp)","Chromosome":"6","Start":"41159841","Stop":"41159841","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1393201,"rule_based_match":true,"evidence_text":"NM_018965.3:c.433G>T/p.[Gly145Trp]","llm_judgment":"PRESENT","evidence":"NM_018965.3:c.433G>T/p.[Gly145Trp]","abstract_start":634,"abstract_end":668}]}
{"pmid":"24712474","title":"Challenges in genetic counseling because of intra-familial phenotypic variation of oral-facial-digital syndrome type 1.","abstract":"Oral-facial-digital syndrome type 1 (OFD1; MIM 311200) is characterized by multiple anomalies of the oral cavity, face and digits. We report a family with OFD1, where two female siblings and their mother shared the same mutation of the responsible gene (OFD1) c.1193_1196delAATC. Phenotypic variability was observed among them; the mother showed minimal features of OFD1, whereas her two daughters showed partial features and the full spectrum of OFD1, respectively. Thus, OFD1 was suspected only after a health check-up during pregnancy of the second patient showing fetal brain anomaly and maternal polycystic kidney. For these reasons, there was a delay in the recognition of OFD1 in this family. Patients with OFD1 show phenotypic variability, which poses challenges for genetic counseling.","variants":[{"Name":"NM_003611.3(OFD1):c.1193_1196del (p.Gln398fs)","Chromosome":"X","Start":"13755208","Stop":"13755211","ReferenceAlleleVCF":"CTCAA","AlternateAlleleVCF":"C","allel_id":49487,"rule_based_match":true,"evidence_text":"c.1193_1196delAATC","llm_judgment":"PRESENT","evidence":"c.1193_1196delAATC","abstract_start":260,"abstract_end":278}]}
{"pmid":"27515321","title":"Duchenne muscular dystrophy caused by a frame-shift mutation in the acceptor splice site of intron 26.","abstract":"BACKGROUND: The dystrophin gene is the one of the largest described in human beings and mutations associated to this gene are responsible for Duchenne or Becker muscular dystrophies.\nCASE PRESENTATION: Here we describe a nucleotide substitution in the acceptor splice site of intron 26 (c.3604-1G > C) carried by a 6-year-old boy who presented with a history of progressive proximal muscle weakness and elevated serum creatine kinase levels. RNA analysis showed that the first two nucleotides of the mutated intron 26 (AC) were not recognized by the splicing machinery and a new splicing site was created within exon 27, generating a premature stop codon and avoiding protein translation.\nCONCLUSIONS: The evaluation of the pathogenic effect of the mutation by mRNA analysis will be useful in the optics of an antisense oligonucleotides (AON)-based therapy.","variants":[{"Name":"NM_004006.3(DMD):c.3604-1G>C","Chromosome":"X","Start":"32448639","Stop":"32448639","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":575401,"rule_based_match":true,"evidence_text":"c.3604-1G > C","llm_judgment":"PRESENT","evidence":"c.3604-1G > C","abstract_start":287,"abstract_end":300}]}
{"pmid":"20555136","title":"Contribution of TARDBP to Alzheimer's disease genetic etiology.","abstract":"The nuclear transactive response (TAR) DNA binding protein-43, TDP-43, is a major constituent of the ubiquitinated neuronal inclusions in patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Missense mutations in TDP-43 have been associated with familial and sporadic ALS. Since TDP-43 immunoreactivity was also frequently observed in Alzheimer's disease (AD) brains and elevated TDP-43 plasma levels were detected in a subset of AD patients, we sequenced the TDP-43 gene, TARDBP, in a well-documented group of AD patients (n=485). We observed one mutation in exon 3 (c.269C>T) predicting a p.Ala90Val substitution in two patients. One extra p.Ala90Val carrier was observed by sequencing exon 3 of an additional set of 254 AD patients. The mutation was absent from 604 control individuals. Allele and haplotype analysis using microsatellite markers suggested that the three patients might share a common founder. However, co-segregation of p.Ala90Val with AD could not be realized leaving its pathogenic unclear at this moment. Also, sequencing in 190 additional AD patients of TARDBP exon 6 in which pathogenic mutations have been reported in FTLD and ALS was negative. Further, genetic association analyses using five single nucleotide polymorphisms did not detect significant differences between AD patients and control individuals. In conclusion, the genetic contribution of TARDBP to AD was restricted to the rare mutation p.Ala90Val (3/739, 0.4%) of unclear pathogenic nature that affects the nuclear localization signal in TDP-43.","variants":[{"Name":"NM_007375.4(TARDBP):c.269C>T (p.Ala90Val)","Chromosome":"1","Start":"11016874","Stop":"11016874","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34333,"rule_based_match":true,"evidence_text":"c.269C>T","llm_judgment":"PRESENT","evidence":"c.269C>T","abstract_start":611,"abstract_end":619}]}
{"pmid":"23143909","title":"Coexistence of KCNV2 associated cone dystrophy with supernormal rod electroretinogram and MFRP related oculopathy in a Turkish family.","abstract":"BACKGROUND AND AIM: To describe the clinical and genetic characteristics of a mother and her son presenting with two distinct and rare forms of retinal degeneration.\nMETHODS: Investigations in both patients comprised spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging, non-contact biometry, ultrasonography, electroretinography (ERG) and analysis of the mutational status of the KCNV2 and MFRP genes in genomic DNA.\nRESULTS: The clinical course and typical ERG pattern indicated a 'cone dystrophy with supernormal rod electroretinogram' in the proband, and SD-OCT demonstrated a subfoveal optical gap with loss of the inner segment/outer segment junction line. The proband was homozygous for a c.782C>A (p.Ala261Asp) mutation in KCNV2. Her son's axial length was shortened with refractive errors of +16.75 dioptres in the right and +14.0 dioptres in the left eye; ERG evidenced a rod-cone dystrophy, OCT showed central macular thickening with cystoid changes and ultrasonography revealed optic disc drusen. MFRP analysis disclosed a 1 bp deletion (c.498delC) that predicts a truncated protein.\nCONCLUSIONS: Two distinct ocular phenotypes with pathogenic mutations in two different genes segregated in this family. The coexistence of two independent autosomal recessive disorders should be considered even when dealing with diseases that bear low carrier frequencies in the general population.","variants":[{"Name":"NM_133497.4(KCNV2):c.782C>A (p.Ala261Asp)","Chromosome":"9","Start":"2718521","Stop":"2718521","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":800549,"rule_based_match":true,"evidence_text":"c.782C>A (p.Ala261Asp)","llm_judgment":"PRESENT","evidence":"c.782C>A (p.Ala261Asp)","abstract_start":730,"abstract_end":752}]}
{"pmid":"25762492","title":"Glutaric Acidemia Type 1-Clinico-Molecular Profile and Novel Mutations in GCDH Gene in Indian Patients.","abstract":"Glutaric acidemia I (GA I, #231670) is one of the treatable, autosomal recessively inherited metabolic disorders. Macrocephaly, acute encephalitis-like crises, dystonia and characteristic frontotemporal atrophy are the hallmarks of this disease. In this communication, we present the clinical, biochemical and molecular profile of seventeen GA I patients from 15 unrelated families from India and report seven novel mutations in GCDH gene (c.281G>A (p.Arg94Gln), c.401A>G (p.Asp134Gly), c.662T>C (p.Leu221Pro), c.881G>C (p.Arg294Pro), c.1173dupG (p.Asn392Glufs*5), c.1238A>G (p.Tyr413Cys) and c.1241A>C (p.Glu414Ala)). Out of these, c.662T>C (p.Leu221Pro) in exon 8 and c.281G>A (p.Arg94Gln) allele in exon 4 were low excretor alleles, whereas c.1241A>C (p.Glu414Ala), c.1173dupG and c.1207C>T (p.His403Tyr) in exon 11 were high excretor alleles. We conclude that c.1204C>T (p.Arg402Trp) is probably the most common mutant allele. Exons 11 and 8 are the hot spot regions of GCDH gene in Indian patients with GA I. An early diagnosis and timely intervention can improve the underlying prognosis. Molecular confirmation is helpful in providing genetic counselling and prenatal diagnosis in subsequent pregnancy.","variants":[{"Name":"NM_000159.4(GCDH):c.881G>C (p.Arg294Pro)","Chromosome":"19","Start":"12896938","Stop":"12896938","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":424376,"rule_based_match":true,"evidence_text":"c.881G>C (p.Arg294Pro)","llm_judgment":"PRESENT","evidence":"c.881G>C (p.Arg294Pro)","abstract_start":511,"abstract_end":533},{"Name":"NM_000159.4(GCDH):c.1173dup (p.Asn392fs)","Chromosome":"19","Start":"12897786","Stop":"12897787","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":549341,"rule_based_match":true,"evidence_text":"c.1173dupG (p.Asn392Glufs*5)","llm_judgment":"PRESENT","evidence":"c.1173dupG (p.Asn392Glufs*5)","abstract_start":535,"abstract_end":563},{"Name":"NM_000159.4(GCDH):c.1204C>T (p.Arg402Trp)","Chromosome":"19","Start":"12897824","Stop":"12897824","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17124,"rule_based_match":true,"evidence_text":"c.1204C>T (p.Arg402Trp)","llm_judgment":"PRESENT","evidence":"c.1204C>T (p.Arg402Trp)","abstract_start":864,"abstract_end":887},{"Name":"NM_000159.4(GCDH):c.281G>A (p.Arg94Gln)","Chromosome":"19","Start":"12892125","Stop":"12892125","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":410475,"rule_based_match":true,"evidence_text":"c.281G>A (p.Arg94Gln)","llm_judgment":"PRESENT","evidence":"c.281G>A (p.Arg94Gln)","abstract_start":440,"abstract_end":461},{"Name":"NM_000159.4(GCDH):c.1238A>G (p.Tyr413Cys)","Chromosome":"19","Start":"12897858","Stop":"12897858","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1868405,"rule_based_match":true,"evidence_text":"c.1238A>G (p.Tyr413Cys)","llm_judgment":"PRESENT","evidence":"c.1238A>G (p.Tyr413Cys)","abstract_start":565,"abstract_end":588}]}
{"pmid":"19287957","title":"Characterization of the c.190T>C missense mutation in BRCA1 codon 64 (Cys64Arg).","abstract":"In the Milan area (Northern Italy), we identified a family characterized by a high prevalence of ovarian and breast cancer cases (5 out of 6 subjects, over 3 generations), and a predominant prevalence of ovarian lesions (4 out of 5 patients). Analysis of BRCA1 and BRCA2 genes allowed the identification of the missense c.190T>C mutation in codon 64 (Cys64Arg) of BRCA1. The aims of the present investigation were to characterize the functional implications of the c.190T>C mutation at the molecular level, and to search whether additional polymorphisms might be linked to the peculiar phenotypic features observed in the Italian pedigree. Molecular modelling studies suggested that substitution of the cysteine 64 with an arginine likely disrupts the architecture of the BRCA1 RING finger domain, responsible for the interaction with BARD1, essential for the tumor-suppressor activity of the BRCA1-BARD1 complex. By splicing site information analysis, exonic splicing enhancer site characterization, and analysis of transcript fragment length and sequence, we showed that the c.190T>C mutation was able to modulate the splicing of exon 5 in a fashion opposite to the c.190T>G transversion, responsible for the functionally-related Cys64Gly amino acid substitution. Genotyping of BRCA1 and BRCA2 in the Italian family revealed the presence of two significant polymorphisms: the cancer-associated c.2612C>T SNP in BRCA1, and the c.-26G>A SNP in the BRCA2 gene, acting as an ovarian cancer risk modifier in carriers of deleterious BRCA1 mutations. Analysis of these SNPs in a genotypically-unrelated Polish family, characterized by prevalent breast neoplasms in carriers of the c.190T>C mutation, revealed a genetic profile consistent with the hypothetic role of both polymorphisms.","variants":[{"Name":"NM_007294.4(BRCA1):c.190T>C (p.Cys64Arg)","Chromosome":"17","Start":"43106478","Stop":"43106478","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":69061,"rule_based_match":true,"evidence_text":"c.190T>C","llm_judgment":"PRESENT","evidence":"c.190T>C","abstract_start":320,"abstract_end":328}]}
{"pmid":"21946453","title":"Early diagnosis of Fabry disease in children","abstract":"Fabry disease, a rare X-linked lysosomal storage disorder, is caused by deficiency of the enzyme α-galactosidase A. The incidence, ranging from one over 40 000 to one over 11 7000 worldwide is probably underestimated due to its unspecific pattern of presentation. The symptoms, including neurological, gastrointestinal, renal, ophthalmological and dermatologic manifestations, start in childhood and adolescence, cause a significant morbidity and are likely to affect the patient's quality of life. Furthermore, Anderson-Fabry disease always progress leading to a multiorgan dysfunction and life-threatening complications with end-stage renal disease, cardiomyopathy and high incidence of stroke. The estimated life in untreated patients is reduced by 15-20 years respectively in men and women. The enzyme replacement therapy, available in Europe from 2001, results in a reduction of major organs failure, morbidity and mortality. We present the case of an 8-year-old male admitted to our Division for overweight with a previous history of acroparesthesias, severe acute pain in hands and feet, abdominal pain, diarrhoea, constipation, bitemporal headache, dyshidrosis, recurrent fever, exercise intolerance and reduced quality of life. The physical examination was within normal limits. The α-galactosidase A activity was deficient in plasma and normal in peripheral leukocytes; the GLA gene showed a nucleotide substitution c.352C>T (p.Arg 118 Cys) in the eson 2 with a residual enzyme activity of the 29% suggesting the diagnosis of Fabry disease. Blood and urine chemistry, the slit-lamp examination and MRI of kidneys, heart and brain excluded any major organ involvement. The enzyme replacement therapy was then started almost three months ago using agasidase alfa at a dose of 0.2 mg/kg infused intravenously every two weeks but, unfortunately, no relief in the symptoms have been reported so far without any severe adverse reactions. This case report aims to point out the importance of an early diagnosis in order to prevent the progression of the disease, the multiorgan failure and to improve the long-term prognosis.","variants":[{"Name":"NM_000169.3(GLA):c.352C>T (p.Arg118Cys)","Chromosome":"X","Start":"101403828","Stop":"101403828","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":51624,"rule_based_match":true,"evidence_text":"c.352C>T (p.Arg 118 Cys)","llm_judgment":"PRESENT","evidence":"c.352C>T (p.Arg 118 Cys)","abstract_start":1426,"abstract_end":1450}]}
{"pmid":"25525168","title":"Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing.","abstract":"PURPOSE: To evaluate variants in the LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 genes in 298 unrelated patients with early-onset high myopia (eoHM).\nMETHODS: Genomic DNA from 298 patients with eoHM was analyzed by whole exome sequencing. Variants in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 genes were selected and analyzed with bioinformatics. Potential candidate variants were confirmed by Sanger sequencing and then validated in available family members and 192 healthy controls.\nRESULTS: A total of nine variants predicted to affect the functional residues were detected. The LRPAP1 gene showed a homozygous frameshift mutation (c.199delC, p.Q67Sfs*8) in a consanguineous family. The ZNF644 gene showed five heterozygous missense mutations (c.1106A>T, p.K369M; c.1648G>A, p.A550T; c.2014A>G, p.S672G; c.2048G>C, p.R683T, and c.2551G>C, p.D851H) in five families, but the c.1106A>T, (p.K369M) and c.1648G>A, (p.A550T) in ZNF644 did not co-segregated with high myopia in the families and should be excluded as causative mutations. The SLC39A5 gene showed a heterozygous missense variant (c.1238G>C, p.G413A) in a sporadic individual. The SCO2 gene showed two heterozygous missense variants (c.334C>T, p.R112W and c.358C>T, p.R120W) in two families. None of the variants was detected in 192 healthy controls and all were predicted to be damaging by both Polyphen-2 and SIFT, except for the previously reported p.S672G mutation in ZNF644, which was predicted to be damaging by SIFT but benign by Polyphen-2. No homozygous or compound heterozygous variants were found in CTSH and LEPREL1.\nCONCLUSIONS: Our results provide additional evidence to support the idea that mutation in LRPAP1 is associated with high myopia. Further studies are expected to evaluate the pathogenicity of the variants in CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2.","variants":[{"Name":"NM_002337.4(LRPAP1):c.199del (p.Gln67fs)","Chromosome":"4","Start":"3532214","Stop":"3532214","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":188059,"rule_based_match":true,"evidence_text":"c.199delC, p.Q67Sfs*8","llm_judgment":"PRESENT","evidence":"c.199delC, p.Q67Sfs*8","abstract_start":647,"abstract_end":668}]}
{"pmid":"32934261","title":"Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients.","abstract":"Pulmonary Arterial Hypertension (PAH) is a rare and fatal disease where knowledge about its genetic basis continues to increase. In this study, we used targeted panel sequencing in a cohort of 624 adult and pediatric patients from the Spanish PAH registry. We identified 11 rare variants in the ATP-binding Cassette subfamily C member 8 (ABCC8) gene, most of them with splicing alteration predictions. One patient also carried another variant in SMAD1 gene (c.27delinsGTAAAG). We performed an ABCC8 in vitro biochemical analyses using hybrid minigenes to confirm the correct mRNA processing of 3 missense variants (c.211C > T p.His71Tyr, c.298G > A p.Glu100Lys and c.1429G > A p.Val477Met) and the skipping of exon 27 in the novel splicing variant c.3394G > A. Finally, we used structural protein information to further assess the pathogenicity of the variants. The results showed 11 novel changes in ABCC8 and 1 in SMAD1 present in PAH patients. After in silico and in vitro biochemical analyses, we classified 2 as pathogenic (c.3288_3289del and c.3394G > A), 6 as likely pathogenic (c.211C > T, c.1429G > A, c.1643C > T, c.2422C > A, c.2694 + 1G > A, c.3976G > A and SMAD1 c.27delinsGTAAAG) and 3 as Variants of Uncertain Significance (c.298G > A, c.2176G > A and c.3238G > A). In all, we show that coupling in silico tools with in vitro biochemical studies can improve the classification of genetic variants.","variants":[{"Name":"NM_000352.6(ABCC8):c.1429G>A (p.Val477Met)","Chromosome":"11","Start":"17443216","Stop":"17443216","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3720058,"rule_based_match":true,"evidence_text":"c.1429G>A p.Val477Met","llm_judgment":"PRESENT","evidence":"c.1429G > A p.Val477Met","abstract_start":665,"abstract_end":688}]}
{"pmid":"35588295","title":"Controversial molecular functions of CBS versus non-CBS domain variants of PRKAG2 in arrhythmia and cardiomyopathy: A case report and literature review.","abstract":"BACKGROUND: PRKAG2 cardiac syndrome is a rare autosomal dominant genetic disorder caused by a PRKAG2 gene variant. There are several major adverse cardiac presentations, including hypertrophic cardiomyopathy (HCM) and life-threatening arrhythmia. Two cases with pathogenic variants in the PRKAG2 gene are reported here who presents different cardiac phenotypes.\nMETHODS: Exome sequencing and variant analysis of PRKAG2 were performed to obtain genetic data, and clinical characteristics were determined.\nRESULTS: The first proband was a 9-month-old female infant (Case 1), and was identified with severe DCM and resistant heart failure. The second proband was a 10-year-old female infant (Case 2), and presented with HCM and ventricular preexcitation. Exome sequencing identified a de novo c.425C > T (p.T142I) heterozygous variant in the PRKAG2 gene for Case 1, and a c.869A > T (p.K290I) for Case 2. The mutated sites in the protein were labeled and identified as p.K290 in the CBS domain and p.T142 in the non-CBS domain. Differences in the molecular functions of CBS and non-CBS domains have not been resolved, and variants might lead to the different cardiomyopathy phenotypes. Single-cell RNA analysis demonstrated similar expression levels of PRKAG2 in cardiomyocytes and conductive tissues. These results suggest that the arrhythmia induced by the PRKAG2 variant was the primary change, and not secondary to cardiomyopathy.\nCONCLUSION: In summary, this is the first case report to describe a DCM phenotype with early onset in patients possessing a PRKAG2 c.425C > T (p.T142I) pathogenic variant. Our results aid in understanding the molecular function of non-CBS variants in terms of the disordered sequence of transcripts. Moreover, we used scRNA-seq to show that electrically conductive cells express a higher level of PRKAG2 than do cardiomyocytes. Therefore, variants in PRKAG2 are expected to also alter the biological function of the conduction system.","variants":[{"Name":"NM_016203.4(PRKAG2):c.425C>T (p.Thr142Ile)","Chromosome":"7","Start":"151781193","Stop":"151781193","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":54882,"rule_based_match":true,"evidence_text":"c.425C > T (p.T142I)","llm_judgment":"PRESENT","evidence":"c.425C > T (p.T142I)","abstract_start":790,"abstract_end":810}]}
{"pmid":"25729264","title":"C596G mutation in FBN1 causes Marfan syndrome with exotropia in a Chinese family.","abstract":"PURPOSE: To screen mutations in the fibrillin-1 (FBN1) gene in a Chinese family with autosomal dominant Marfan syndrome (MFS).\nMETHODS: Patients and unaffected family members were given ophthalmic, cardiovascular, and physical examinations with a 5-year follow-up. Genomic DNA was extracted from the leukocytes of venous blood from all patients and their relatives. The entire coding region of the FBN1gene was screened with an ABI 9700 GeneAmp PCR System. The mutation identified was screened in 100 healthy and ethnically unrelated Chinese individuals.\nRESULTS: Mutation screening in FBN1 identified a T>G transition at position c.1786 in exon 14, leading to substitution of cysteine for glycine at codon 596 (C596G) in this four-generation Chinese family. The C596G mutation was associated with the disease phenotypes in all six patients but not found in 14 unaffected family members or the 100 ethnically unrelated and healthy controls.\nCONCLUSIONS: A C596G mutation in FBN1 was identified in a Chinese family with MFS. Our results expand the spectrum of FBN1 mutations and contribute to the understanding of the role of FBN1 in the pathogenesis of Marfan syndrome.","variants":[{"Name":"NM_000138.5(FBN1):c.1786T>G (p.Cys596Gly)","Chromosome":"15","Start":"48508633","Stop":"48508633","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":363974,"rule_based_match":false,"evidence_text":"c.1786T>G","llm_judgment":"PRESENT","evidence":"c.1786T>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"22565191","title":"A novel splicing mutation in COL1A1 gene caused type I osteogenesis imperfecta in a Chinese family.","abstract":"Osteogenesis imperfect (OI) is a heritable connective tissue disorder with bone fragility as a cardinal manifestation, accompanied by short stature, dentinogenesis imperfecta, hyperlaxity of ligaments and skin, blue sclerae and hearing loss. Dominant form of OI is caused by mutations in the type I procollagen genes, COL1A1/A2. Here we identified a novel splicing mutation c.3207+1G>A (GenBank ID: JQ236861) in the COL1A1 gene that caused type I OI in a Chinese family. RNA splicing analysis proved that this mutation created a new splicing site at c.3200, and then led to frameshift. This result further enriched the mutation spectrum of type I procollagen genes.","variants":[{"Name":"NM_000088.4(COL1A1):c.3207+1G>A","Chromosome":"17","Start":"50188529","Stop":"50188529","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":482137,"rule_based_match":true,"evidence_text":"c.3207+1G>A","llm_judgment":"PRESENT","evidence":"c.3207+1G>A","abstract_start":374,"abstract_end":385}]}
{"pmid":"17212350","title":"A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene.","abstract":"Muscle sodium-channel disorders cover a spectrum of rare myotonic diseases. In a German family with 17 affected individuals in four generations, we identified a heterozygous missense mutation in exon 24 A1481D (c.4442 C>A) of the voltage-gated sodium channel gene (SCN4A) alpha subunit. Phenotypes of 12 family members were characterized by a mild myotonia with cold sensitivity but without paramyotonia. The index patient presented with fluctuating cold- and exercise-induced stiffness of ocular, facial, and distal muscles. The myotonia became more severe at the age of 22 years. His father had had cold- and exercise-induced periodic weakness with fluctuating myotonia since age 10. Later he developed a more severe, purely exercise- and cold-aggravated myotonia of arms, hands, and facial muscles. The father's mother presented with cold-induced myotonia until age 65, when progressive weakness of proximal limb muscles developed. Her muscle biopsies revealed considerable myopathic changes with a variety of fine structural alterations. This study presents a family with cold-aggravated myotonia and progression of myopathic changes in the muscle biopsy with increasing age. In older patients, sodium channelopathies may mimic the phenotypic features of myotonic dystrophy type 2.","variants":[{"Name":"NM_000334.4(SCN4A):c.4442C>A (p.Ala1481Asp)","Chromosome":"17","Start":"63941840","Stop":"63941840","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":569487,"rule_based_match":true,"evidence_text":"c.4442 C>A","llm_judgment":"PRESENT","evidence":"c.4442 C>A","abstract_start":211,"abstract_end":221}]}
{"pmid":"25168863","title":"Prenatal findings in carpenter syndrome and a novel mutation in RAB23.","abstract":"Carpenter syndrome is caused by mutations of the RAB23 gene. To date, 12 distinct mutations have been identified among 34 patients from 26 unrelated families. We report on the prenatal findings in a fetus with Carpenter syndrome with a novel RAB23 mutation. Cystic hygroma, bowed femora, abnormal skull shape and a complex heart defect were seen on ultrasound scan, and Carpenter syndrome was diagnosed at birth. Craniosynostosis and preaxial hexadactyly of the feet were retrospectively detectable on the fetal CT scan. Sequencing of RAB23 identified a homozygous mutation leading to skipping of exon 6 and premature termination codon (c.481G>C; p.Val161Leufs*16). This observation illustrates the difficulty of prenatal ultrasound diagnosis of Carpenter syndrome. To our knowledge, this diagnosis was suggested on ultrasound scan in only one prior patient, although in five other patients abnormal skull shape and variable findings, mainly limb anomalies including bowed femora in one case, were described during the pregnancy. Heart defect and bowed femora are rare postnatal findings. The diagnosis of Carpenter syndrome should therefore be considered on prenatal imaging in cases of bowed femora and/or cardiac defect associated with abnormal skull shape.","variants":[{"Name":"NM_016277.5(RAB23):c.481G>C (p.Val161Leu)","Chromosome":"6","Start":"57194770","Stop":"57194770","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":404641,"rule_based_match":true,"evidence_text":"c.481G>C","llm_judgment":"PRESENT","evidence":"c.481G>C","abstract_start":637,"abstract_end":645}]}
{"pmid":"26586665","title":"BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.","abstract":"BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.\nMETHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.\nRESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.\nCONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.","variants":[{"Name":"NM_000059.4(BRCA2):c.9976A>T (p.Lys3326Ter)","Chromosome":"13","Start":"32398489","Stop":"32398489","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":46822,"rule_based_match":true,"evidence_text":"BRCA2*c.9976A>T; p.Lys3326*","llm_judgment":"PRESENT","evidence":"BRCA2*c.9976A>T; p.Lys3326*","abstract_start":41,"abstract_end":68}]}
{"pmid":"26268155","title":"A start codon mutation of the FRMD7 gene in two Korean families with idiopathic infantile nystagmus.","abstract":"Idiopathic infantile nystagmus (IIN) is the involuntary oscillation of the eyes with onset in the first few months of life. The most common form of inheritance is X-linked, and mutations in FRMD7 gene are a major cause. To identify the FRMD7 gene mutations associated with X-linked IIN, we performed PCR-based DNA direct sequencing in 4 affected subjects from 2 Korean families. We also assessed structural abnormalities of retina and optic nerve head using optical coherence tomography (OCT). Genetic analysis revealed a A>G transversion at nucleotide c.1, the first base of the start codon. This mutation leads to the loss of the primary start codon ATG for methionine, which is replaced by a triplet GTG for valine. The alternative in-frame start codon is not present around a mutation. OCT revealed the morphological changes within the optic nerve head, including shallow cup depth and small cup-to-disc ratio. In summary, we identified a novel start codon mutation within the FRMD7 gene of 2 Korean families. Our data expands the mutation spectrum of FRMD7 causing IIN. We also demonstrated abnormal developments of afferent system in patients with FRMD7 mutations using OCT, which may help to understand the etiological factor in development of nystagmus.","variants":[{"Name":"NM_194277.3(FRMD7):c.1A>G (p.Met1Val)","Chromosome":"X","Start":"132127844","Stop":"132127844","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1491333,"rule_based_match":false,"evidence_text":"c.1A>G","llm_judgment":"PRESENT","evidence":"c.1A>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"18209201","title":"MPZ mutation G123S characterization: evidence for a complex pathogenesis in CMT disease.","abstract":"OBJECTIVES: To characterize the clinical and cellular phenotypes of a novel MPZ mutation identified in a Chinese family with Charcot-Marie-Tooth (CMT) disease type 1B.\nMETHODS: The family was evaluated clinically, electrophysiologically, pathologically, and genetically. The wild-type and mutant P(0) fused with fluorescent proteins were expressed in vitro to monitor their intracellular trafficking. Adhesion assay was also performed to evaluate the adhesiveness of cells.\nRESULTS: The novel MPZ mutation, c.367G>A, is associated with a late-onset demyelinating CMT phenotype with autosomal dominant inheritance. The median motor nerve conduction velocities of patients in this family ranged from 15.7 to 19.6 m/second. The neuropathologic studies from a sural nerve biopsy revealed a severe loss of myelinated fibers, and some onion bulb formation with clusters of regenerative fibers. Fluorescence analysis demonstrated that the mutant protein was retained ectopically in the endoplasmic reticulum and Golgi apparatus. Adhesion assay demonstrated a defective adhesiveness of cells expressing the mutant P(0)G123S protein.\nCONCLUSION: The novel P(0)G123S mutation is associated with typical findings of late-onset demyelinating polyneuropathy in the electrophysiologic and pathologic studies, putatively resulting from aberrant intracellular trafficking of the mutant P(0) protein, which compromises the adhesiveness of the cells.","variants":[{"Name":"NM_000530.8(MPZ):c.367G>A (p.Gly123Ser)","Chromosome":"1","Start":"161306789","Stop":"161306789","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29237,"rule_based_match":true,"evidence_text":"c.367G>A","llm_judgment":"PRESENT","evidence":"c.367G>A","abstract_start":507,"abstract_end":515}]}
{"pmid":"25624737","title":"Novel LIPA mutations in Mexican siblings with lysosomal acid lipase deficiency.","abstract":"Lysosomal acid lipase (LAL) deficiency is an under-recognized lysosomal disease caused by deficient enzymatic activity of LAL. In this report we describe two affected female Mexican siblings with early hepatic complications. At two months of age, the first sibling presented with alternating episodes of diarrhea and constipation, and later with hepatomegaly, elevated transaminases, high levels of total and low-density lipoprotein cholesterol, and low levels of high-density lipoprotein. Portal hypertension and grade 2 esophageal varices were detected at four years of age. The second sibling presented with hepatomegaly, elevated transaminases and mildly elevated low-density lipoprotein and low high-density lipoprotein at six months of age. LAL activity was deficient in both patients. Sequencing of LIPA revealed two previously unreported heterozygous mutations in exon 4: c.253C>A and c.294C>G. These cases highlight the clinical continuum between the so-called Wolman disease and cholesteryl ester storage disease, and underscore that LAL deficiency represents a single disease with a degree of clinical heterogeneity.","variants":[{"Name":"NM_000235.4(LIPA):c.294C>G (p.Asn98Lys)","Chromosome":"10","Start":"89228334","Stop":"89228334","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":492955,"rule_based_match":true,"evidence_text":"c.294C>G","llm_judgment":"PRESENT","evidence":"c.294C>G","abstract_start":893,"abstract_end":901},{"Name":"NM_000235.4(LIPA):c.253C>A (p.Gln85Lys)","Chromosome":"10","Start":"89228375","Stop":"89228375","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":683180,"rule_based_match":true,"evidence_text":"c.253C>A","llm_judgment":"PRESENT","evidence":"c.253C>A","abstract_start":880,"abstract_end":888}]}
{"pmid":"23143338","title":"c.1643_1644delTG XPC mutation is more frequent in Moroccan patients with xeroderma pigmentosum.","abstract":"Xeroderma pigmentosum is a rare autosomal recessive disease characterized by hypersensitivity to UV light which is due to alterations of the nucleotide excision repair pathway. Eight genes (XPA to XPG and XPV) are responsible for the disease. Among them, the XPC gene is known to be the most mutated in Mediterranean patients. The aim of this study was to determine the frequency of the most common XPC mutation and describe the clinical features of Moroccan patients with xeroderma pigmentosum. Twenty four patients belonging to 21 unrelated Moroccan families and 58 healthy subjects were investigated. After clinical examination, the screening for the c.1643_1644delTG (p.Val548AlafsX25) mutation in the XPC gene was performed by PCR and automated sequencing of exon 9 in all patients and controls. The molecular analysis showed that among the 24 patients, 17 were homozygous for the c.1643_1644delTG mutation and all their tested parents were heterozygous, whereas the others (7 patients) did not carry the mutation. The frequency of this mutation was estimated to be 76.19 % (16/21 families). None of the 58 healthy individuals carried this mutation. In addition, clinical investigation showed that the majority of the patients bearing this mutation have the same clinical features. Our results revealed that the p.Val548AlafsX25 mutation is the major cause (76.19 %) of xeroderma pigmentosum in Moroccan families. This would have an important impact on improving management of patients and their relatives.","variants":[{"Name":"NM_004628.5(XPC):c.1643_1644del (p.Val548fs)","Chromosome":"3","Start":"14158239","Stop":"14158240","ReferenceAlleleVCF":"GCA","AlternateAlleleVCF":"G","allel_id":15301,"rule_based_match":true,"evidence_text":"c.1643_1644delTG (p.Val548AlafsX25)","llm_judgment":"PRESENT","evidence":"c.1643_1644delTG (p.Val548AlafsX25)","abstract_start":654,"abstract_end":689}]}
{"pmid":"33531666","title":"A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features.","abstract":"PURPOSE: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10.\nMETHODS: Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry.\nRESULTS: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein.\nCONCLUSION: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.","variants":[{"Name":"NM_206538.4(EMC10):c.287del (p.Gly96fs)","Chromosome":"19","Start":"50479053","Stop":"50479053","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":976525,"rule_based_match":true,"evidence_text":"EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9)","llm_judgment":"PRESENT","evidence":"EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9)","abstract_start":803,"abstract_end":855}]}
{"pmid":"33153448","title":"Novel compound heterozygous TARS2 variants in a Chinese family with mitochondrial encephalomyopathy: a case report.","abstract":"BACKGROUND: Mitochondrial encephalomyopathy caused by bi-allelic deleterious variants in TARS2 is rare. To date, only two pedigrees were reported in the literature and the connection between the gene and disease needs further study.\nCASE PRESENTATION: We report one infant who presented with limb hypertonia, epilepsy, developmental delay, and increased serum lactate from a non-consanguineous Chinese family. Whole-genome sequencing was performed to help to underlie the cause. We identified compound heterozygous variants c.470C > G, p.Thr157Arg and c.2143G > A, p.Glu715Lys in TARS2 and the variants were confirmed by Sanger sequencing. The patient was diagnosed with combined oxidative phosphorylation deficiency 21 according to the Online Mendelian Inheritance in Man (OMIM) database based on the clinical data and the deleterious effect of the two variants in TARS2 predicted by in silico tools.\nCONCLUSIONS: We presented one case diagnosed with combined oxidative phosphorylation deficiency 21 based on clinical characteristics and genetic analysis. This is the first case in China and the fourth case in the world based on our document retrieval. This study facilitates the understanding of combined oxidative phosphorylation deficiency disease and demonstrates that the next-generation sequencing has a high potential to study inherited disease with high phenotypic heterogeneity and genetic heterogeneity including mitochondrial diseases such as combined oxidative phosphorylation deficiency.","variants":[{"Name":"NM_025150.5(TARS2):c.470C>G (p.Thr157Arg)","Chromosome":"1","Start":"150490683","Stop":"150490683","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1333357,"rule_based_match":true,"evidence_text":"c.470C > G, p.Thr157Arg","llm_judgment":"PRESENT","evidence":"c.470C > G, p.Thr157Arg","abstract_start":524,"abstract_end":547},{"Name":"NM_025150.5(TARS2):c.2143G>A (p.Glu715Lys)","Chromosome":"1","Start":"150507050","Stop":"150507050","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1333358,"rule_based_match":true,"evidence_text":"c.2143G > A, p.Glu715Lys","llm_judgment":"PRESENT","evidence":"c.2143G > A, p.Glu715Lys","abstract_start":552,"abstract_end":576}]}
{"pmid":"31782247","title":"Identification of a novel germline BRCA2 variant in a Chinese breast cancer family.","abstract":"Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths in women worldwide. In this study, a large Chinese pedigree with breast cancer including a proband and two female patients was recruited and a familial history of breast cancer was collected by questionnaire. Clinicopathological assessments and neoadjuvant therapy-related information were obtained for the proband. Blood samples were taken, and gDNA was extracted. The BRCA1/2 and PALB2 genes were screened using next-generation sequencing by a targeted gene panel. We have successfully identified a novel, germline heterozygous, missense mutation of the gene BRCA2: c.7007G>T, p.R2336L, which is likely to be pathogenic in the proband and her elder sister who both had breast cancer. Furthermore, the risk factors for developing breast cancer in this family are discussed. Thus, genetic counselling and long-term follow-up should be provided for this family of breast cancer patients as well as carriers carrying a germline variant of BRCA2: c.7007G>T (p.R2336L).","variants":[{"Name":"NM_000059.4(BRCA2):c.7007G>T (p.Arg2336Leu)","Chromosome":"13","Start":"32346896","Stop":"32346896","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":66910,"rule_based_match":true,"evidence_text":"BRCA2: c.7007G>T, p.R2336L","llm_judgment":"PRESENT","evidence":"BRCA2: c.7007G>T, p.R2336L","abstract_start":662,"abstract_end":688}]}
{"pmid":"30402230","title":"Synchronous endometrial and ovarian cancer in Lynch syndrome with a","abstract":"Synchronous endometrial and ovarian cancer (SEOC) is a rare entity among gynecological cancers, which exhibits endometrioid histology in its early stages and generally has a good prognosis. However, diagnosis is difficult and recent reports have demonstrated that most clinically diagnosed cases of SEOC have clonally related cancers, indicating metastatic cancer. The association of SEOC with Lynch syndrome is also not clearly understood. We herein present the case of a 41-year-old SEOC patient with <i>MSH2</i> mutation. The endometrial cancer was an endometrioid adenocarcinoma and the ovarian cancer was mainly endometrioid, but also included a clear cell carcinoma with a borderline clear cell adenofibromatous component, indicating primary ovarian cancer. Both tumors exhibited microsatellite instability (MSI) and loss of expression of MSH2 and MSH6. The patient had a family history of colorectal and gastric cancers. Genetic analysis revealed a germline mutation in exon 6 of <i>MSH2</i> (c.1042C>T, p.Gln348*) and the patient was diagnosed with Lynch syndrome. This <i>MSH2</i> mutation has only been registered in one case in the InSiGHT variant databases and has not been reported in a gynecological tumor or SEOC to date. This case is a rare example of a patient with genetically diagnosed Lynch syndrome who also developed SEOC. This synchronous cancer is not common, but it may be caused by Lynch syndrome. Testing for MSI and immunohistochemistry for mismatch repair deficiency is necessary in cases with suspected SEOC.","variants":[{"Name":"NM_000251.3(MSH2):c.1042C>T (p.Gln348Ter)","Chromosome":"2","Start":"47416395","Stop":"47416395","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":419349,"rule_based_match":true,"evidence_text":"c.1042C>T, p.Gln348*","llm_judgment":"PRESENT","evidence":"c.1042C>T, p.Gln348*","abstract_start":1000,"abstract_end":1020}]}
{"pmid":"18484629","title":"Mutational spectrum of FAM83H: the C-terminal portion is required for tooth enamel calcification.","abstract":"Dental enamel forms through the concerted activities of specialized extracellular matrix proteins, including amelogenin, enamelin, MMP20, and KLK4. Defects in the genes encoding these proteins cause non-syndromic inherited enamel malformations collectively designated as amelogenesis imperfecta (AI). These genes, however, account for only about a quarter of all AI cases. Recently we identified mutations in FAM83H that caused autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI). Unlike other genes that cause AI, FAM83 H does not encode an extracellular matrix protein. Its location inside the cell is completely unknown, as is its function. We here report novel FAM83H mutations in four kindreds with ADHCAI. All are nonsense mutations in the last exon (c.1243G>T, p.E415X; c.891T>A, p.Y297X; c.1380G>A, p.W460X; and c.2029C>T, p.Q677X). These mutations delete between 503 and 883 amino acids from the C-terminus of a protein normally comprised of 1179 residues. The reason these mutations cause such extreme defects in the enamel layer without affecting other parts of the body is not known yet. However it seems evident that the large C-terminal part of the protein is essential for proper enamel calcification.","variants":[{"Name":"NM_198488.5(FAM83H):c.1243G>T (p.Glu415Ter)","Chromosome":"8","Start":"143728218","Stop":"143728218","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":15811,"rule_based_match":true,"evidence_text":"c.1243G>T, p.E415X","llm_judgment":"PRESENT","evidence":"c.1243G>T, p.E415X","abstract_start":771,"abstract_end":789},{"Name":"NM_198488.5(FAM83H):c.891T>A (p.Tyr297Ter)","Chromosome":"8","Start":"143728570","Stop":"143728570","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":15812,"rule_based_match":true,"evidence_text":"c.891T>A, p.Y297X","llm_judgment":"PRESENT","evidence":"c.891T>A, p.Y297X","abstract_start":791,"abstract_end":808},{"Name":"NM_198488.5(FAM83H):c.1380G>A (p.Trp460Ter)","Chromosome":"8","Start":"143728081","Stop":"143728081","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15813,"rule_based_match":true,"evidence_text":"c.1380G>A, p.W460X","llm_judgment":"PRESENT","evidence":"c.1380G>A, p.W460X","abstract_start":810,"abstract_end":828},{"Name":"NM_198488.5(FAM83H):c.2029C>T (p.Gln677Ter)","Chromosome":"8","Start":"143727432","Stop":"143727432","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15814,"rule_based_match":true,"evidence_text":"c.2029C>T (p.Q677X)","llm_judgment":"PRESENT","evidence":"c.2029C>T","abstract_start":834,"abstract_end":843}]}
{"pmid":"38141607","title":"A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.","abstract":"Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAX<sup>Arg60Gln</sup> (Max<sup>∗Arg60Gln</sup>) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAX<sup>Arg60Gln</sup> individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.","variants":[{"Name":"NM_002382.5(MAX):c.179G>A (p.Arg60Gln)","Chromosome":"14","Start":"65078029","Stop":"65078029","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":948631,"rule_based_match":true,"evidence_text":"c.179G>A (p.Arg60Gln)","llm_judgment":"PRESENT","evidence":"c.179G>A (p.Arg60Gln)","abstract_start":318,"abstract_end":339}]}
{"pmid":"23342054","title":"A functional alternative splicing mutation in AIRE gene causes autoimmune polyendocrine syndrome type 1.","abstract":"Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare autosomal recessive disease defined by the presence of two of the three conditions: mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Loss-of-function mutations of the autoimmune regulator (AIRE) gene have been linked to APS-1. Here we report mutational analysis and functional characterization of an AIRE mutation in a consanguineous Chinese family with APS-1. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. We identified a homozygous missense AIRE mutation c.463G>A (p.Gly155Ser) in two siblings with different clinical features of APS-1. In silico splice-site prediction and minigene analysis were carried out to study the potential pathological consequence. Minigene splicing analysis and subsequent cDNA sequencing revealed that the AIRE mutation potentially compromised the recognition of the splice donor of intron 3, causing alternative pre-mRNA splicing by intron 3 retention. Furthermore, the aberrant AIRE transcript was identified in a heterozygous carrier of the c.463G>A mutation. The aberrant intron 3-retaining transcript generated a truncated protein (p.G155fsX203) containing the first 154 AIRE amino acids and followed by 48 aberrant amino acids. Therefore, our study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1.","variants":[{"Name":"NM_000383.4(AIRE):c.463G>A (p.Gly155Ser)","Chromosome":"21","Start":"44287133","Stop":"44287133","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44330,"rule_based_match":true,"evidence_text":"c.463G>A (p.Gly155Ser)","llm_judgment":"PRESENT","evidence":"c.463G>A (p.Gly155Ser)","abstract_start":603,"abstract_end":625}]}
{"pmid":"27616680","title":"Intra-familial variability associated with recessive RYR1 mutation diagnosed prenatally by exome sequencing.","abstract":"OBJECTIVE: To determine the underlying molecular aetiology in a non-consanguineous Irish family who have had three fetal losses because of a primary myopathy characterised by fetal akinesia, arthrogryposis multiplex, bilateral pulmonary hypoplasia and reduced muscle bulk.\nMETHODS: Fetal DNA extracted from amniotic cells was whole genome amplified and subjected to whole exome sequencing.\nRESULTS: Whole exome sequencing identified compound heterozygous variants in RYR1 as the cause of the lethal myopathy in this family. All three fetuses were compound heterozygous for a paternally inherited missense variant (c.2113G > A; p.Gly705Arg) and a novel maternally inherited truncating frameshift deletion (c.8843delC; p.Ser2948Cysfs*58). This family did not have the classic cores and fibre type disproportion typically associated with RYR1 mutation. The RYR1 exome finding was made during the couple's third pregnancy and enabled prenatal genetic testing to be undertaken.\nCONCLUSION: We show that recessive RYR1 mutations can be associated with significant intra-familial variability in clinical presentation which can complicate prediction of clinical outcome. RYR1 mutations can also cause diverse muscle pathologies which thwarts diagnosis. This study demonstrates the impact that exome-based diagnoses can have for families with lethal disorders. © 2016 John Wiley & Sons, Ltd.","variants":[{"Name":"NM_000540.3(RYR1):c.2113G>A (p.Gly705Arg)","Chromosome":"19","Start":"38458238","Stop":"38458238","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1021864,"rule_based_match":true,"evidence_text":"c.2113G > A; p.Gly705Arg","llm_judgment":"PRESENT","evidence":"c.2113G > A; p.Gly705Arg","abstract_start":614,"abstract_end":638},{"Name":"NM_000540.3(RYR1):c.8843del (p.Ser2948fs)","Chromosome":"19","Start":"38507738","Stop":"38507738","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":1064707,"rule_based_match":true,"evidence_text":"c.8843delC; p.Ser2948Cysfs*58","llm_judgment":"PRESENT","evidence":"c.8843delC; p.Ser2948Cysfs*58","abstract_start":705,"abstract_end":734}]}
{"pmid":"23443156","title":"Interstitial lung disease in two brothers with novel compound heterozygous ABCA3 mutations.","abstract":"Mutations in genes critical for surfactant metabolism, including surfactant protein C (SP-C) and ABCA3, are well-recognized causes of interstitial lung disease. Recessive mutations in ABCA3 were first attributed to fatal respiratory failure in full-term neonates, but they are also increasingly being recognized as a cause of respiratory disorders with less severe phenotypes in older children and also adults. Here, we report a 20-month-old boy with interstitial lung disease caused by two distinct ABCA3 mutations. Initial treatment with methylprednisolone was unsuccessful, but the additional administration of hydroxychloroquine was effective. The family history revealed that the patient's older brother had died of idiopathic interstitial lung disease at 6 months of age, suggesting a genetic etiology of the disease. Sequence analyses of SP-C and ABCA3 genes were performed using DNA samples from the patient himself, his parents, and his brother. These analyses revealed novel compound heterozygous mutations in the coding exons of ABCA3 in both the patient and his brother: c.2741A > G, of paternal origin, and c.3715_3716insGGGGGG, of maternal origin. Conclusion Since ABCA3 mutations seem to be a heterogeneous entity with various phenotypes, we recommend genetic testing for mutations in SP-C and ABCA3 genes to be considered in children with unexplained interstitial lung disease.","variants":[{"Name":"NM_001089.3(ABCA3):c.2741A>G (p.Lys914Arg)","Chromosome":"16","Start":"2288289","Stop":"2288289","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2749208,"rule_based_match":true,"evidence_text":"c.2741A > G","llm_judgment":"PRESENT","evidence":"c.2741A > G","abstract_start":1083,"abstract_end":1094}]}
{"pmid":"20631720","title":"Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.","abstract":"The cblC type of combined methylmalonic aciduria (MMA) and homocystinuria (HC) is the most common inborn error of vitamin B(12) metabolism and is caused by mutations in the MMACHC gene. To elucidate the spectrum of mutations that causes combined MMA and HC in Chinese patients, the MMACHC gene was sequenced in 79 unrelated Chinese patients. Sequence analysis identified 98.1% of disease alleles and found that all patients had at least one MMACHC mutation. A total of 24 mutations were identified. Out of the 24 mutations identified, 9 were novel ones, including missense mutations (c.365A>T and c.452A>G), nonsense mutations (c.315C>G and c.615C>A), deletions (c.99delA and c.277-3_c.303del30), duplications (c.248dupT and c.626dupT) and an insertion (c.445_446insA). The c.609G>A, c.658_660delAAG, c.482G>A, c.394C>T and c.80A>G mutations were the most common mutations and accounted for 80% of disease alleles. Haplotype analysis suggests that the spread of the c.80A>G, c.609G>A and c.658_660delAAG mutations in Chinese patients were caused by a founder effect. The results indicate that defects occurring in the MMACHC gene are the major cause of this disease in Chinese patients with combined MMA and HC, and direct mutation analysis can therefore be used as a rapid confirmatory diagnosis among these Chinese patients.","variants":[{"Name":"NM_015506.3(MMACHC):c.80A>G (p.Gln27Arg)","Chromosome":"1","Start":"45500412","Stop":"45500412","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":541098,"rule_based_match":true,"evidence_text":"c.80A>G","llm_judgment":"PRESENT","evidence":"c.80A>G","abstract_start":824,"abstract_end":831},{"Name":"NM_015506.3(MMACHC):c.609G>A (p.Trp203Ter)","Chromosome":"1","Start":"45508975","Stop":"45508975","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39757,"rule_based_match":true,"evidence_text":"c.609G>A","llm_judgment":"PRESENT","evidence":"c.609G>A","abstract_start":774,"abstract_end":782},{"Name":"NM_015506.3(MMACHC):c.394C>T (p.Arg132Ter)","Chromosome":"1","Start":"45508329","Stop":"45508329","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16462,"rule_based_match":true,"evidence_text":"c.394C>T","llm_judgment":"PRESENT","evidence":"c.394C>T","abstract_start":811,"abstract_end":819},{"Name":"NM_015506.3(MMACHC):c.482G>A (p.Arg161Gln)","Chromosome":"1","Start":"45508848","Stop":"45508848","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16464,"rule_based_match":true,"evidence_text":"c.482G>A","llm_judgment":"PRESENT","evidence":"c.482G>A","abstract_start":801,"abstract_end":809},{"Name":"NM_015506.3(MMACHC):c.615C>A (p.Tyr205Ter)","Chromosome":"1","Start":"45508981","Stop":"45508981","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":541138,"rule_based_match":true,"evidence_text":"c.615C>A","llm_judgment":"PRESENT","evidence":"c.615C>A","abstract_start":641,"abstract_end":649},{"Name":"NM_015506.3(MMACHC):c.658_660del (p.Lys220del)","Chromosome":"1","Start":"45509022","Stop":"45509024","ReferenceAlleleVCF":"CAGA","AlternateAlleleVCF":"C","allel_id":101604,"rule_based_match":true,"evidence_text":"c.658_660delAAG","llm_judgment":"PRESENT","evidence":"c.658_660delAAG","abstract_start":784,"abstract_end":799}]}
{"pmid":"23279838","title":"Clinical and molecular characterization of hemoglobin Maputo [beta 47 (CD6) Asp > Tyr HBB: c.142G > T] and G-Ferrara [beta 57 (E1) Asn > Lys HBB: c.174C > A] in a newborn screening in Brazil.","abstract":"","variants":[{"Name":"NM_000518.4(HBB):c.142G>T (p.Asp48Tyr)","Chromosome":"11","Start":"5226750","Stop":"5226750","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":30299,"rule_based_match":true,"evidence_text":"HBB: c.142G > T","llm_judgment":"PRESENT","evidence":"HBB: c.142G > T","abstract_start":null,"abstract_end":null}]}
{"pmid":"15952209","title":"Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome.","abstract":"Autosomal recessive Robinow syndrome is caused by mutations in ROR2 and is characterized by short stature, mesomelic limb shortening, brachydactyly, vertebral abnormalities, and a characteristic \"fetal face\" dysmorphology. We report the clinical and molecular studies on two adults with this condition. Besides typical skeletal and facial features, one patient developed hydronephrosis, nephrocalcinosis, and renal failure. The second patient had characteristic skeletal manifestations including severe spinal involvement and showed endocrinological abnormalities including elevated gonadotropic hormones. The facial phenotype in both patients remained distinctive into adulthood. Analysis of the ROR2 gene revealed a homozygous c.1937_1943delACAAGCT mutation in Patient 1, and compound heterozygosity for c.355C > T (p.R119X). and c.550C > T (p.R184C) in Patient 2.","variants":[{"Name":"NM_004560.4(ROR2):c.1937_1943del (p.Tyr646fs)","Chromosome":"9","Start":"91724551","Stop":"91724557","ReferenceAlleleVCF":"CAGCTTGT","AlternateAlleleVCF":"C","allel_id":22352,"rule_based_match":true,"evidence_text":"c.1937_1943delACAAGCT","llm_judgment":"PRESENT","evidence":"c.1937_1943delACAAGCT","abstract_start":729,"abstract_end":750},{"Name":"NM_004560.4(ROR2):c.355C>T (p.Arg119Ter)","Chromosome":"9","Start":"91757380","Stop":"91757380","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22353,"rule_based_match":true,"evidence_text":"c.355C > T (p.R119X)","llm_judgment":"PRESENT","evidence":"c.355C > T (p.R119X)","abstract_start":806,"abstract_end":826},{"Name":"NM_004560.4(ROR2):c.550C>T (p.Arg184Cys)","Chromosome":"9","Start":"91737463","Stop":"91737463","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22347,"rule_based_match":true,"evidence_text":"c.550C > T (p.R184C)","llm_judgment":"PRESENT","evidence":"c.550C > T (p.R184C)","abstract_start":832,"abstract_end":852}]}
{"pmid":"29732542","title":"Homocarnosinosis: A historical update and findings in the SPG11 gene.","abstract":"OBJECTIVES: A family with homocarnosinosis was reported in the literature in 1976. Three affected siblings had spastic paraplegia, retinitis pigmentosa, mental retardation, and cerebrospinal fluid (CSF) homocarnosine concentrations 20 times higher than in controls. Based on the clinical findings and new genetic techniques, we have been able to establish a precise genetic diagnosis.\nMETHOD: The medical records were re-evaluated, and genetic analyses were performed post-mortem in this original family. SNP array-based whole genome homozygosity mapping and Sanger sequencing of the SPG11 gene were performed. Seven additional Norwegian SPG11 patients and their disease-causing variants and clinical findings were evaluated. Homocarnosine levels in CSF were measured in four of these seven patients.\nRESULTS: A homozygous pathogenic splice-site variant in the SPG11 gene, c.2316 + 1G>A, was found. The clinical findings in the original family correlate with the heterogeneous SPG11 phenotype. The same variant was found in seven other Norwegian SPG11 patients, unrelated to the original family, either as homozygous or compound heterozygous constellation. Normal homocarnosine levels were found in the CSF of all unrelated SPG11 patients.\nCONCLUSIONS: A re-evaluation of the clinical symptoms and findings in the original family correlates with the SPG11 phenotype. The increased levels of homocarnosine do not seem to be a biomarker for SPG11 in our patients. Homocarnosinosis is still a biochemical aberration with unknown clinical significance.","variants":[{"Name":"NM_025137.4(SPG11):c.2316+1G>A","Chromosome":"15","Start":"44622727","Stop":"44622727","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49712,"rule_based_match":true,"evidence_text":"c.2316 + 1G>A","llm_judgment":"PRESENT","evidence":"c.2316 + 1G>A","abstract_start":873,"abstract_end":886}]}
{"pmid":"31165076","title":"","abstract":"The skeletal muscle ryanodine receptor (RyR1), i.e., the Ca<sup>2+</sup> channel of the sarco/endoplasmic reticulum (S/ER), and the voltage-dependent calcium channel Cav1.1 are the principal channels involved in excitation-contraction coupling in skeletal muscle. <i>RYR1</i> gene variants are linked to distinct skeletal muscle disorders, including malignant hyperthermia susceptibility and central core disease (CCD), mainly with autosomal dominant inheritance, and autosomal recessive myopathies with a broad phenotypic and histopathological spectrum. The age at onset of <i>RYR1</i>-related myopathies varies from infancy to adulthood. We report the identification of four <i>RYR1</i> variants in two Italian families: one with myopathy and variants c.4003C>T (p.R1335C) and c.7035C>A (p.S2345R), and another with CCD and variants c.9293G>T (p.S3098I) and c.14771_14772insTAGACAGGGTGTTGCTCTGTTGCCCTTCTT (p.F4924_V4925insRQGVALLPFF). We demonstrate that, in patient-specific lymphoblastoid cells, the c.4003C>T (p.R1335C) variant is not expressed and the in-frame 30-nucleotide insertion variant is expressed at a low level. Moreover, Ca<sup>2+</sup> release in response to the RyR1 agonist 4-chloro-m-cresol and to thapsigargin showed that the c.7035C>A (p.S2345R) variant causes depletion of S/ER Ca<sup>2+</sup> stores and that the compound heterozygosity for variant c.9293G>T (p.S3098I) and the 30-nucleotide insertion increases RyR1-dependent Ca<sup>2+</sup> release without affecting ER Ca<sup>2+</sup> stores. In conclusion, we detected and functionally characterized disease-causing variants of the RyR1 channel in patient-specific lymphoblastoid cells. This paper is dedicated to the memory and contribution of Luigi Del Vecchio.","variants":[{"Name":"NM_000540.3(RYR1):c.4003C>T (p.Arg1335Cys)","Chromosome":"19","Start":"38473614","Stop":"38473614","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":998523,"rule_based_match":true,"evidence_text":"c.4003C>T (p.R1335C)","llm_judgment":"PRESENT","evidence":"c.4003C>T (p.R1335C)","abstract_start":754,"abstract_end":774},{"Name":"NM_000540.3(RYR1):c.9293G>T (p.Ser3098Ile)","Chromosome":"19","Start":"38512304","Stop":"38512304","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3052416,"rule_based_match":true,"evidence_text":"c.9293G>T (p.S3098I)","llm_judgment":"PRESENT","evidence":"c.9293G>T (p.S3098I)","abstract_start":835,"abstract_end":855}]}
{"pmid":"26604000","title":"DNM1L-related mitochondrial fission defect presenting as refractory epilepsy.","abstract":"Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.","variants":[{"Name":"NM_012062.5(DNM1L):c.1085G>A (p.Gly362Asp)","Chromosome":"12","Start":"32731019","Stop":"32731019","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247683,"rule_based_match":true,"evidence_text":"NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp)","llm_judgment":"PRESENT","evidence":"NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp)","abstract_start":1443,"abstract_end":1491}]}
{"pmid":"35272565","title":"Inherited retinal dystrophies in a Kuwaiti tribe.","abstract":"PURPOSE: To evaluate the clinical and genetic spectrum of inherited retinal diseases (IRDs) in a Kuwaiti tribe.\nMETHODS: Forty four patients with IRDs from 28 nuclear families from the tribe, were evaluated for presenting symptoms, visual acuity, fundus examination, OCT, microperimetry, full-field (ff), and multifocal electroretinography (mERG) and genotyping.\nRESULTS: Seventeen patients were diagnosed with autosomal recessive retinitis pigmentosa (arRP) associated with <i>RP1</i> c.606C>A with onset of nictalopia in the third decade, myopia, and macular atrophy by the age of 50; eleven with autosomal recessive cone/rod dystrophy or macular dystrophy associated with <i>RP1</i> c.606C>A (p.Asp202Glu) mutation with color and central vision deterioration in teenage, myopia, paracentral ring scotoma and macular atrophy; eleven were with arRP associated with <i>PDE6B</i> c.992 + 1 G > A mutation with onset around 5 years, myopia, cataract, retained central fixation, and ellipsoid zone and late perimacular atrophy; five-with Leber congenital amaurosis associated with homozygous <i>RPGRIP1</i> for c.1107delA mutation with extinguished ffERG and electrophysiological phenotype of rod and cone; and one patient-with autosomal recessive rod-cone dystrophy associated with homozygous <i>PDE6B</i> c.992 + 1 G > A, who was homozygous <i>ABCA4</i> c.5882 G > A and heterozygous <i>EYS</i>; c.2137 + 1 G > A.\nCONCLUSIONS: This study represents a typical tribe from the Middle East with high rate of consanguinity for many generations that harbors multiple mutated genes associated with IRD. It demonstrates the predominant phenotype and its variability in retinal disorders caused by identical mutations and illustrates the nuances in the clinical presentation and disease progression of patients with pathogenic mutations in more than one gene.","variants":[{"Name":"NM_000283.4(PDE6B):c.992+1G>A","Chromosome":"4","Start":"654889","Stop":"654889","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":857201,"rule_based_match":true,"evidence_text":"c.992 + 1 G > A","llm_judgment":"PRESENT","evidence":"c.992 + 1 G > A","abstract_start":879,"abstract_end":894},{"Name":"NM_006269.2(RP1):c.606C>A (p.Asp202Glu)","Chromosome":"8","Start":"54621572","Stop":"54621572","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":967084,"rule_based_match":true,"evidence_text":"RP1 c.606C>A (p.Asp202Glu)","llm_judgment":"PRESENT","evidence":"RP1</i> c.606C>A (p.Asp202Glu)","abstract_start":678,"abstract_end":708}]}
{"pmid":"31749828","title":"A Pediatric Case of Glioblastoma Multiforme Associated With a Novel Germline p.His112CysfsTer9 Mutation in the","abstract":"Targeted gene panel testing has the power to interrogate hundreds of genes and evaluate the genetic risk for many types of hereditary cancers simultaneously. We screened a 13-year-old male patient diagnosed with glioblastoma multiforme with the aim to get further insights into the biology of his condition. Herein, we applied gene panel sequencing and identified a heterozygous frameshift mutation c.333_334delTC; p.His112CysfsTer9 in the <i>MLH1</i> gene in blood and tumor tissue accompanied by a known heterozygous missense variant of unknown significance c.847C > T; p.Arg283Cys in the <i>TP53</i> gene. Parental screening revealed the presence of the same <i>TP53</i> variant in the father and the same <i>MLH1</i> variant in the mother, who was in fact undergoing treatment for early-stage breast cancer at the time of her son's unfortunate diagnosis. This case reports for the first time the co-occurrence of a genetic mutation in the <i>MLH1</i> gene of the mismatch repair pathway, commonly associated with the Lynch syndrome, accompanied by a rare variant in the <i>TP53</i> gene. This report underlines the need for broad panel gene testing in lieu of single-gene or syndrome-focused gene screening and evaluation of the effects of multiple pathogenic or modifier variants on the phenotypic spectrum of the disease.","variants":[{"Name":"NM_000546.6(TP53):c.847C>T (p.Arg283Cys)","Chromosome":"17","Start":"7673773","Stop":"7673773","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133281,"rule_based_match":true,"evidence_text":"c.847C > T; p.Arg283Cys","llm_judgment":"PRESENT","evidence":"c.847C > T; p.Arg283Cys","abstract_start":560,"abstract_end":583}]}
{"pmid":"33448213","title":"","abstract":"A new syndrome of diabetes, short stature, microcephaly and intellectual disability has been described in association with mutations in the tRNA methyltransferase 10 homologue A (TRMT10A) gene. We report a patient who presented with fasting hyperglycemia, a raised hemoglobin A1c and positive islet cell autoantibodies. Additional clinical features included intellectual disability, hypoplastic kidneys and short stature. In view of the syndromic features coexistant with diabetes, genetic evaluation was carried out, revealing a homozygous mutation in the TRMT10A gene (c.616G>A, p.G206R). The case highlights the importance of genetic evaluation of patients with diabetes with atypical features that can further progress our understanding of the pathophysiology of the rarer subtypes of diabetes.","variants":[{"Name":"NM_001134665.3(TRMT10A):c.616G>A (p.Gly206Arg)","Chromosome":"4","Start":"99553814","Stop":"99553814","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":166023,"rule_based_match":true,"evidence_text":"c.616G>A, p.G206R","llm_judgment":"PRESENT","evidence":"c.616G>A, p.G206R","abstract_start":571,"abstract_end":588}]}
{"pmid":"19304573","title":"Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase.","abstract":"OBJECTIVE: GPIHBP1 is an endothelial cell protein that binds lipoprotein lipase (LPL) and chylomicrons. Because GPIHBP1 deficiency causes chylomicronemia in mice, we sought to determine whether some cases of chylomicronemia in humans could be attributable to defective GPIHBP1 proteins.\nMETHODS AND RESULTS: Patients with severe hypertriglyceridemia (n=60, with plasma triglycerides above the 95th percentile for age and gender) were screened for mutations in GPIHBP1. A homozygous GPIHBP1 mutation (c.344A>C) that changed a highly conserved glutamine at residue 115 to a proline (p.Q115P) was identified in a 33-year-old male with lifelong chylomicronemia. The patient had failure-to-thrive as a child but had no history of pancreatitis. He had no mutations in LPL, APOA5, or APOC2. The Q115P substitution did not affect the ability of GPIHBP1 to reach the cell surface. However, unlike wild-type GPIHBP1, GPIHBP1-Q115P lacked the ability to bind LPL or chylomicrons (d < 1.006 g/mL lipoproteins from Gpihbp1(-/-) mice). Mouse GPIHBP1 with the corresponding mutation (Q114P) also could not bind LPL.\nCONCLUSIONS: A homozygous missense mutation in GPIHBP1 (Q115P) was identified in a patient with chylomicronemia. The mutation eliminated the ability of GPIHBP1 to bind LPL and chylomicrons, strongly suggesting that it caused the patient's chylomicronemia.","variants":[{"Name":"NM_178172.6(GPIHBP1):c.344A>C (p.Gln115Pro)","Chromosome":"8","Start":"143215307","Stop":"143215307","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":153744,"rule_based_match":true,"evidence_text":"c.344A>C","llm_judgment":"PRESENT","evidence":"c.344A>C","abstract_start":500,"abstract_end":508}]}
{"pmid":"27392076","title":"Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.","abstract":"Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.","variants":[{"Name":"NM_013336.4(SEC61A1):c.553A>G (p.Thr185Ala)","Chromosome":"3","Start":"128060598","Stop":"128060598","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":247558,"rule_based_match":true,"evidence_text":"c.553A>G (p.Thr185Ala)","llm_judgment":"PRESENT","evidence":"c.553A>G (p.Thr185Ala)","abstract_start":785,"abstract_end":807},{"Name":"NM_013336.4(SEC61A1):c.200T>G (p.Val67Gly)","Chromosome":"3","Start":"128055731","Stop":"128055731","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":247559,"rule_based_match":true,"evidence_text":"c.200T>G (p.Val67Gly)","llm_judgment":"PRESENT","evidence":"c.200T>G (p.Val67Gly)","abstract_start":812,"abstract_end":833}]}
{"pmid":"28493438","title":"Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.","abstract":"Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity. Whole-exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70%-90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity.","variants":[{"Name":"NM_001605.3(AARS1):c.2067dup (p.Tyr690fs)","Chromosome":"16","Start":"70258142","Stop":"70258143","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":1315642,"rule_based_match":true,"evidence_text":"c.2067dupC (p.Tyr690Leufs*3)","llm_judgment":"PRESENT","evidence":"c.2067dupC (p.Tyr690Leufs*3)","abstract_start":628,"abstract_end":656},{"Name":"NM_001605.3(AARS1):c.2738G>A (p.Gly913Asp)","Chromosome":"16","Start":"70252890","Stop":"70252890","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":244984,"rule_based_match":true,"evidence_text":"c.2738G>A (p.Gly913Asp)","llm_judgment":"PRESENT","evidence":"c.2738G>A (p.Gly913Asp)","abstract_start":661,"abstract_end":684}]}
{"pmid":"34377882","title":"SDHB-Associated Paraganglioma Syndrome in Africa-A Need for Greater Genetic Testing.","abstract":"A germline mutation is identified in almost 40% of pheochromocytoma/paraganglioma (PPGL) syndromes. Genetic testing and counseling are essential for the management of index cases as well as presymptomatic identification and preemptive management of affected family members. Mutations in the genes encoding the mitochondrial enzyme succinate dehydrogenase (SDH) are well described in patients with hereditary PPGL. Among patients of African ancestry, the prevalence, phenotype, germline mutation spectrum, and penetrance of <i>SDH</i> mutations is poorly characterized. We describe a multifocal paraganglioma in a young African male with an underlying missense succinate dehydrogenase subunit B (<i>SDHB</i>) mutation and a history of 3 first-degree relatives who died at young ages from suspected cardiovascular causes. The same <i>SDHB</i> mutation, Class V variant c.724C>A p.(Arg242Ser), was detected in one of his asymptomatic siblings. As there are limited data describing hereditary PPGL syndromes in Africa, this report of an <i>SDHB</i>-associated PPGL is a notable contribution to the literature in this growing field. Due to the noteworthy clinical implications of PPGL mutations, this work highlights the existing need for broader genetic screening among African patients with PPGL despite the limited healthcare resources available in this region.","variants":[{"Name":"NM_003000.3(SDHB):c.724C>A (p.Arg242Ser)","Chromosome":"1","Start":"17022649","Stop":"17022649","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":238171,"rule_based_match":true,"evidence_text":"Class V variant c.724C>A p.(Arg242Ser)","llm_judgment":"PRESENT","evidence":"Class V variant c.724C>A p.(Arg242Ser)","abstract_start":851,"abstract_end":889}]}
{"pmid":"16455195","title":"BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations.","abstract":"We analyzed the mutation spectrum of BRCA1 and BRCA2 genes in 354 Korean breast cancer patients. Overall, 40 patients carried 25 distinct BRCA1/2 mutations including 12 novel mutations. Seven district mutations were found in multiple unrelated patients, with the BRCA2 c.7480C>T mutation detected in eight unrelated patients, accounting for 50% of the mutations detected in BRCA2. The large number (25/40, 62.5%) of recurrent mutations suggests the possibility of developing a simple screening test for these mutations. The frequency of mutations was related to the number and kinds of risk factors, varying from 10.4 to 25% in the five major risk factor groups. The frequency of BRCA mutations in patients with two or more risk factors was markedly higher than that in patients with one risk factor.","variants":[{"Name":"NM_000059.4(BRCA2):c.7480C>T (p.Arg2494Ter)","Chromosome":"13","Start":"32356472","Stop":"32356472","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46655,"rule_based_match":true,"evidence_text":"BRCA2 c.7480C>T","llm_judgment":"PRESENT","evidence":"BRCA2 c.7480C>T","abstract_start":263,"abstract_end":278}]}
{"pmid":"24664533","title":"Mutations in HADHB, which encodes the β-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy.","abstract":"Mitochondrial trifunctional protein (MTP) is a hetero-octamer composed of four α- and four β-subunits that catalyzes the final three steps of mitochondrial β-oxidation of long chain fatty acids. HADHA and HADHB encode the α-subunit and the β-subunit of MTP, respectively. To date, only two cases with MTP deficiency have been reported to be associated with hypoparathyroidism and peripheral polyneuropathy. Here, we report on two siblings with autosomal recessive infantile onset hypoparathyroidism, peripheral polyneuropathy, and rhabdomyolysis. Sequence analysis of HADHA and HADHB in both siblings shows that they were homozygous for a mutation in exon 14 of HADHB (c.1175C>T, [p.A392V]) and the parents were heterozygous for the mutation. Biochemical analysis revealed that the patients had MTP deficiency. Structural analysis indicated that the A392V mutation identified in this study and the N389D mutation previously reported to be associated with hypoparathyroidism are both located near the active site of MTP and affect the conformation of the β-subunit. Thus, the present patients are the second and third cases of MTP deficiency associated with missense HADHB mutation and infantile onset hypoparathyroidism. Since MTP deficiency is a treatable disease, MTP deficiency should be considered when patients have hypoparathyroidism as the initial presenting feature in infancy.","variants":[{"Name":"NM_000183.3(HADHB):c.1175C>T (p.Ala392Val)","Chromosome":"2","Start":"26284908","Stop":"26284908","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":188207,"rule_based_match":true,"evidence_text":"c.1175C>T, [p.A392V]","llm_judgment":"PRESENT","evidence":"c.1175C>T, [p.A392V]","abstract_start":669,"abstract_end":689}]}
{"pmid":"34709441","title":"Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants.","abstract":"Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 (MED1) are two rare skeletal disorders caused by cartilage oligomeric matrix protein (COMP) variants. This study aims to analyze the genotype and phenotype of patients with COMP variants. Clinical information for 14 probands was collected; DNA was extracted from blood for COMP variant detection. Clinical manifestations and radiology scoring systems were established to evaluate the severity of each patient's condition. Serum COMP levels in PSACH patients and healthy subjects were measured. Thirty-nine patients were included, along with 12 PSACH probands and two MED1 probands. Disproportionate short stature, waddling gait, early-onset osteoarthritis and skeletal deformities were the most common features. The height Z-score of PSACH patients correlated negatively with age at evaluation (r =  - 0.603, p = 0.01) and the clinical manifestation score (r =  - 0.556, p = 0.039). Over 50% of the PSACH patients were overweight/obese. The median serum COMP level in PSACH patients was 16.75 ng/ml, which was significantly lower than that in healthy controls (98.53 ng/ml; p < 0.001). The condition of MED1 patients was better than that of PSACH patients. Four novel variants of COMP were detected: c.874T>C, c.1123_1134del, c.1531G>A, and c.1576G>T. Height Z-scores and serum COMP levels were significantly lower in patients carrying mutations located in calmodulin-like domains 6, 7, and 8. As the two phenotypes overlap to different degrees, PSACH and MED1 are suggested to combine to produce \"spondyloepiphyseal dysplasia, COMP type\". Clinical manifestations and radiology scoring systems, serum COMP levels and genotype are important for evaluating patient condition severity.","variants":[{"Name":"NM_000095.3(COMP):c.1123_1134del (p.Ile375_Asp378del)","Chromosome":"19","Start":"18787492","Stop":"18787503","ReferenceAlleleVCF":"GGTCGCCGTCGAT","AlternateAlleleVCF":"G","allel_id":2992429,"rule_based_match":true,"evidence_text":"c.1123_1134del","llm_judgment":"PRESENT","evidence":"c.1123_1134del","abstract_start":1280,"abstract_end":1294}]}
{"pmid":"35656879","title":"Molecular autopsy and clinical family screening in a case of sudden cardiac death reveals ACTN2 mutation related to hypertrophic/dilated cardiomyopathy and a novel LZTR1 variant associated with Noonan syndrome.","abstract":"BACKGROUND: Genetic cardiac diseases are the main trigger of sudden cardiac death (SCD) in young adults. Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiomyopathy and accounts for 0.5 to 1% of SCD cases per year.\nMETHODS: Herein, we report a family with a marked history of SCD focusing on one SCD young adult case and one pediatric case with HCM.\nRESULTS: For the deceased young adult, postmortem whole-exome sequencing (WES) revealed a missense variant in the ACTN2 gene: c.355G > A; p.(Ala119Thr) confirming the mixed hypertrophic/dilated cardiomyopathy phenotype detected in the autopsy. For the pediatric case, WES allowed us the identification of a novel frameshift variant in the LZTR1 gene: c.1745delT; p.(Val582Glyfs*10) which confirms a clinical suspicion of HCM related to Noonan syndrome.\nCONCLUSION: The present study adds further evidence on the pathogenicity of ACTN2: p. Ala119Thr variant in SCD and expands the mutational spectrum of the LZTR1 gene related to Noonan syndrome.","variants":[{"Name":"NM_001103.4(ACTN2):c.355G>A (p.Ala119Thr)","Chromosome":"1","Start":"236719007","Stop":"236719007","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":172928,"rule_based_match":true,"evidence_text":"c.355G > A; p.(Ala119Thr)","llm_judgment":"PRESENT","evidence":"c.355G > A; p.(Ala119Thr)","abstract_start":487,"abstract_end":512}]}
{"pmid":"28339057","title":"GPR143 mutations in Chinese patients with ocular albinism type 1.","abstract":"The aim of the present study was to evaluate mutations of the G protein-coupled receptor 143 (GPR143) gene for ocular albinism type 1 (OA1) in Chinese patients. For the current study, 8 patients with OA1 were selected from the database of ocular genetic diseases. Genomic DNA of OA1 was prepared from venous leukocytes collected from the patients. Cycle sequencing was used to analyze the exons and adjacent introns of GPR143. The variation detected was analyzed by bidirectional DNA sequencing and further evaluated in 96 controls using heteroduplex‑single strand conformational polymorphism analysis. Additionally, slit lamp photography of anterior segment, fundus photography and optical coherence tomography (OCT) were performed to identify the clinical features of OA1. In five patients with OA1, 5 GPR143 gene mutations were identified and four of them there were novel mutations. The screening rate is 62.5%, including c.333G>A (p.W111X), c.353G>A (p.G118E) (known mutation), C.658+2T>G (splice mutation), c.215_216insCGCTGC (p.71‑72insAA) and c.17T>C (p. L6P). These mutations were absent in the 96 normal controls. Only one patient with OA1 in the present study was female. Patients with OA1 often have congenital nystagmus, refractive error, severe decline of visual acuity (from 0.1 to 0.4) and foveal hypoplasia. Different degrees of pigment loss were evident in the patients' iris and retina, whereas macular structure was not identified in the OCT examination. The findings of the present study expanded the gene mutation spectrum of GPR143 and investigated the clinical phenotype of patients with OA1 in the Chinese population. Additional evidence for clinical diagnosis was provided along with differential diagnosis and genetic counseling.","variants":[{"Name":"NM_000273.3(GPR143):c.353G>A (p.Gly118Glu)","Chromosome":"X","Start":"9760724","Stop":"9760724","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":104518,"rule_based_match":true,"evidence_text":"c.353G>A (p.G118E)","llm_judgment":"PRESENT","evidence":"c.353G>A (p.G118E)","abstract_start":946,"abstract_end":964}]}
{"pmid":"31853109","title":"Genetic study of Khyber-Pukhtunkhwa resident Pakistani families presenting primary microcephaly with intellectual disability.","abstract":"OBJECTIVE: To investigate the genetic factor responsible for causing microcephaly and determine allelic heterogeneity of Abnormal spindle microtubule gene.\nMETHODS: The genetic study was conducted at the Kohat University of Science and Technology, Kohat, and Gomal University, D.I.Khan, Pakistan, during 2017-18, and comprised 5 consanguineous families from South Waziristan, Kurram Agency, Karak, Bannu and Dera Ismail Khan regions of the country's Khyber Pakhtukhwa province. Blood samples from all available and cooperative family members (including normal and affected) were obtained, and molecular analysis was carried out through whole genome single nucleotide polymorphisms genotyping, exome sequencing and Sanger sequencing.\nRESULTS: Of the 15 patients, 9(60%) were males and 6(40%) were females. Genetic mapping revealed linkage to the MCPH5 locus which harbours the microcephaly-associated abnormal spindle-like microcephaly gene. Mutation analysis of the gene identified missense mutation c.3978G>A (p.Trp1326*) in families A, B and C, a deletion mutation c.7782_7783delGA (p.(Lys2595Serfs*6)) in family D, and a splice site defect c.2936+5G>A in family E.\nCONCLUSIONS: There was suggestion of strong founder effect of mutation c.3978G>A (p.Trp1326*).","variants":[{"Name":"NM_018136.5(ASPM):c.3978G>A (p.Trp1326Ter)","Chromosome":"1","Start":"197117876","Stop":"197117876","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20000,"rule_based_match":true,"evidence_text":"c.3978G>A (p.Trp1326*)","llm_judgment":"PRESENT","evidence":"c.3978G>A (p.Trp1326*)","abstract_start":1000,"abstract_end":1022},{"Name":"NM_018136.5(ASPM):c.7782_7783del (p.Lys2595fs)","Chromosome":"1","Start":"197101468","Stop":"197101469","ReferenceAlleleVCF":"TTC","AlternateAlleleVCF":"T","allel_id":34458,"rule_based_match":true,"evidence_text":"c.7782_7783delGA (p.(Lys2595Serfs*6))","llm_judgment":"PRESENT","evidence":"c.7782_7783delGA (p.(Lys2595Serfs*6))","abstract_start":1067,"abstract_end":1104}]}
{"pmid":"29035608","title":"F508del CFTR gene mutation in patients with allergic bronchopulmonary aspergillosis.","abstract":"OBJECTIVE: The F508del mutation occurs in approximately 3.5% of Caucasian population of Northern Europe. Heterozygotes have increased risk for asthma and reduced pulmonary function. Allergic bronchopulmonary aspergillosis (ABPA) is more common in patients with cystic fibrosis (CF). We aimed to establish the frequency of F508del mutation in adult patients with ABPA.\nMETHODS: A retrospective matched case-control study of CF genotyped patients with ABPA seen at the National Aspergillosis Centre was undertaken. Key data were collected retrospectively from medical records, including respiratory comorbidities, total IgE, Aspergillus IgG and IgE, and immunoglobulins. Cystic fibrosis transmembrane regulator (CFTR) gene mutation analysis included multiplex PCR and sequencing.\nRESULTS: From a cohort of 189 ABPA patients, 156 were screened for common mutations and variants in the CFTR gene. Eighteen were heterozygous for at least one CFTR mutation; 12 (7.7%) were heterozygous for the F508del, notably; 3 were heterozygous for the intron 8 5T variant; and 1 for an intronic variant of uncertain significance, c.3139 + 18C>T. Eight (67%) had asthma, 7 (58%) had CT-defined bronchiectasis, 4 (33%) hypergammaglobulinemia (>16 g/L), 3 (25%) sinusitis and 1 (8%) chronic pulmonary aspergillosis. Eight (67%) had elevated Aspergillus IgG antibodies (42-98 mg/L), and 8 (67%) had total IgE above 1,000 KIU/L. Two individuals heterozygous for the F508del mutation and the TG12T5 variant were diagnosed with CF, leading to a de novo CF discovery rate of 1.3%.\nCONCLUSIONS: In our ABPA patient cohort, the presence of the delta F508 mutation was higher than that seen in general population. Genetic counseling for CFTR genotyping might be appropriate for these patients.","variants":[{"Name":"NM_000492.4(CFTR):c.3139+18C>T","Chromosome":"7","Start":"117610687","Stop":"117610687","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":44526,"rule_based_match":true,"evidence_text":"c.3139 + 18C>T","llm_judgment":"PRESENT","evidence":"c.3139 + 18C>T","abstract_start":1112,"abstract_end":1126}]}
{"pmid":"33605605","title":"Homozygous missense STRADA mutation in a patient with polyhydramnios, megalencephaly and symptomatic epilepsy syndrome.","abstract":"Homozygous or compound heterozygous mutations in STRADA cause polyhydramnios, megalencephaly and symptomatic epilepsy syndrome (PMSE), with additional features of distinctive facial traits and severe developmental delay or intellectual disability. This syndrome was first defined in 16 Old Order Mennonite patients, carrying a homozygous STRADA deletion of exon 9-13. Five additional PMSE patients have been reported since, each of them with loss-of-function variants. We report a female patient with the typical clinical features of PMSE, homozygous for a novel STRADA missense mutation c.792T>A (p.Ser264Arg) in exon 10. This finding contributes to the further delineation of the phenotype of PMSE.","variants":[{"Name":"NM_001003787.4(STRADA):c.792T>A (p.Ser264Arg)","Chromosome":"17","Start":"63706701","Stop":"63706701","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":361146,"rule_based_match":true,"evidence_text":"c.792T>A (p.Ser264Arg)","llm_judgment":"PRESENT","evidence":"c.792T>A (p.Ser264Arg)","abstract_start":588,"abstract_end":610}]}
{"pmid":"35170221","title":"A novel nonsense variant in TPM4 caused dominant macrothrombocytopenia, mild bleeding tendency and disrupted cytoskeleton remodeling.","abstract":"BACKGROUND: Rare inherited thrombocytopenias are caused by alterations in genes involved in megakaryopoiesis, thrombopoiesis and/or platelet release. Diagnosis is challenging due to poor specificity of platelet laboratory assays, large numbers of culprit genes, and difficult assessment of the pathogenicity of novel variants.\nOBJECTIVES: To characterize the clinical and laboratory phenotype, and identifying the underlying molecular alteration, in a pedigree with thrombocytopenia of uncertain etiology.\nPATIENTS/METHODS: Index case was enrolled in our Spanish multicentric project of inherited platelet disorders due to lifelong thrombocytopenia and bleeding. Bleeding score was recorded by ISTH-BAT. Laboratory phenotyping consisted of blood cells count, blood film, platelet aggregation and flow cytometric analysis. Genotyping was made by whole-exome sequencing (WES). Cytoskeleton proteins were analyzed in resting/spreading platelets by immunofluorescence and immunoblotting.\nRESULTS: Five family members displayed lifelong mild thrombocytopenia with a high number of enlarged platelets in blood film, and mild bleeding tendency. Patient's platelets showed normal aggregation and granule secretion response to several agonists. WES revealed a novel nonsense variant (c.322C>T; p.Gln108*) in TPM4 (NM_003290.3), the gene encoding for tropomyosin-4 (TPM4). This variant led to impairment of platelet spreading capacity after stimulation with TRAP-6 and CRP, delocalization of TPM4 in activated platelets, and significantly reduced TPM4 levels in platelet lysates. Moreover, the index case displayed up-regulation of TPM2 and TPM3 mRNA levels.\nCONCLUSIONS: This study identifies a novel TPM4 nonsense variant segregating with macrothrombocytopenia and impaired platelet cytoskeletal remodeling and spreading. These findings support the relevant role of TPM4 in thrombopoiesis and further expand our knowledge of TPM4-related thrombocytopenia.","variants":[{"Name":"NM_003290.3(TPM4):c.322C>T (p.Gln108Ter)","Chromosome":"19","Start":"16086478","Stop":"16086478","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2742437,"rule_based_match":true,"evidence_text":"c.322C>T; p.Gln108*","llm_judgment":"PRESENT","evidence":"c.322C>T; p.Gln108*","abstract_start":1275,"abstract_end":1294}]}
{"pmid":"36703897","title":"Case report: Two heterozygous pathogenic variants of CYP24A1: A novel cause of hypercalcemia and nephrocalcinosis in adulthood.","abstract":"Background and aims: Vitamin D 24-hydroxylase is an enzyme encoded by the CYP24A1 gene, which inhibits the activation of vitamin D to form inactive metabolites. More than 20 currently described pathogenic variants (usually biallelic) of this gene are responsible for idiopathic infantile hypercalcemia manifested typically in childhood (often in newborns) with hypercalcemia, hypercalciuria, and nephrocalcinosis. However, a few patients (mostly with monoallelic heterozygous pathogenic variants) can develop mild symptoms in adulthood.\nCase description: We present the case of a 43-year-old male patient with hypertension and heterozygous Leiden mutation, with mural thrombi in the common iliac artery, who was sent by a nephrologist to endocrinological examination due to hypoparathyroidism, progressive hypercalcemia, hypercalciuria, and CKDG2A1. Complete laboratory and imaging methods (including PET-CT) excluded PTH-related peptide-mediated hypercalcemia and granulomatosis. Finally, the genetic analysis of the CYP24A1 gene revealed the presence of a novel combination of two heterozygous pathogenic variants: CYP24A1: c. 443T>C p.(Leu148Pro) and c.1186C>T p.(Arg396Trp).\nConclusion: Differential diagnosis of patients with hypercalciuria, nephrocalcinosis, and hypercalcemia related to vitamin D exposure should include the CYP24A1 gene mutation. To the best of our knowledge, this is the first case of the novel combination of two heterozygous pathogenic variants of CYP24A1.","variants":[{"Name":"NM_000782.5(CYP24A1):c.1186C>T (p.Arg396Trp)","Chromosome":"20","Start":"54158136","Stop":"54158136","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38634,"rule_based_match":true,"evidence_text":"c.1186C>T p.(Arg396Trp)","llm_judgment":"PRESENT","evidence":"c.1186C>T p.(Arg396Trp)","abstract_start":1154,"abstract_end":1177}]}
{"pmid":"31781151","title":"Novel","abstract":"Inwardly rectifying K<sup>+</sup> channel 4.1 (Kir4.1), encoded by <i>KCNJ10</i>, is a member of the inwardly rectifying potassium channel family. In the brain, Kir4.1 is predominant in astrocytic glia and accounts for the spatial buffering of K<sup>+</sup> released by neurons during action potential propagation. A number of studies have shown that mutations in <i>KCNJ10</i> are associated with SeSAME/EAST syndrome, which is characterized by seizures, ataxia, sensorineural deafness, and electrolyte imbalance. Herein, we identified two siblings presenting with seizures and motor delays in one outbred kindred. Customized targeted-exome sequencing showed that both affected siblings are compound heterozygous for two <i>KCNJ10</i> missense mutations (NM_002241.4: c.601G > A: p.A201T and c.626T > C: p.I209T). Prediction tools suggested that both amino acid substitutions were deleterious or disease causing. Further functional studies showed that Chinese hamster ovary (CHO) cells expressing either A201T and/or I209T Kir4.1 channels exhibited lower K<sup>+</sup> currents, indicating compromised Kir4.1 biological function. Intriguingly, the A201T but not I209T mutation decreased total and cell surface Kir4.1 levels. Kir4.1 channels with the A201T mutation were unstable and degraded through lysosomal pathway. In conclusion, these data indicated that both A201T and I209T mutations disrupt Kir4.1 activity and are the cause of SeSAME/EAST-like syndrome in the siblings.","variants":[{"Name":"NM_002241.5(KCNJ10):c.626T>C (p.Ile209Thr)","Chromosome":"1","Start":"160041907","Stop":"160041907","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":679958,"rule_based_match":true,"evidence_text":"c.626T > C: p.I209T","llm_judgment":"PRESENT","evidence":"c.626T > C: p.I209T","abstract_start":793,"abstract_end":812},{"Name":"NM_002241.5(KCNJ10):c.601G>A (p.Ala201Thr)","Chromosome":"1","Start":"160041932","Stop":"160041932","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":679959,"rule_based_match":true,"evidence_text":"c.601G > A: p.A201T","llm_judgment":"PRESENT","evidence":"c.601G > A: p.A201T","abstract_start":769,"abstract_end":788}]}
{"pmid":"19223272","title":"Missense mutation of keratin 9 (c.487C>T (p.R163W) in southern Chinese patients with epidermolytic palmoplantar keratoderma.","abstract":"","variants":[{"Name":"NM_000226.4(KRT9):c.487C>T (p.Arg163Trp)","Chromosome":"17","Start":"41571506","Stop":"41571506","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18036,"rule_based_match":true,"evidence_text":"c.487C>T (p.R163W)","llm_judgment":"PRESENT","evidence":"c.487C>T (p.R163W)","abstract_start":null,"abstract_end":null}]}
{"pmid":"35800472","title":"A case report of two siblings with hypertyrosinemia type 1 presenting with hepatic disease with different onset time and severity.","abstract":"Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder caused by a defect in fumarylacetoacetate hydroxylase (FAH) encoded by the <i>FAH</i> gene. Patients with HT1 disorder present with increased blood tyrosine, succinyl acetoacetate, and succinyl acetone levels, and develop clinical manifestations including liver failure, kidney tubular dysfunction, growth failure, rickets, pseudo-porphyric crises, and hepatocellular carcinoma. We encountered two siblings with HT1. Among the siblings, the elder brother developed acute liver failure with coagulopathy at the age of 2 months and was rescued by liver transplantation (LT) following combination therapy with continuous hemodiafiltration and plasma exchange. The younger sister was followed up from the prenatal period for signs of HT1 due to prior history of the condition in her sibling. She was initially considered a carrier of HT1 owing to the lack of overt signs of the disease and negative urine screening for succinyl acetone (SA). She was eventually diagnosed with HT1 because of liver disorder at 9 months of age, associated with a positive urine SA result. Her disease state was controlled by treatment with nitisinone (NTBC). DNA analysis of both siblings identified heterozygous status for a previously reported FAH pathogenic allele (c.782C > T) and a novel likely pathogenic variant (c.688C.G). The siblings have stable lives with no developmental delay or impaired growth. NTBC treatment is effective in preventing the progression of liver and kidney diseases. However, even in cases treated without LT, clinicians should follow up the clinical outcomes over long term, as patients may require LT when developing complications, such as hepatocellular carcinoma.","variants":[{"Name":"NM_000137.4(FAH):c.688C>G (p.Leu230Val)","Chromosome":"15","Start":"80172230","Stop":"80172230","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3534404,"rule_based_match":false,"evidence_text":"c.688C.G","llm_judgment":"PRESENT","evidence":"c.688C.G","abstract_start":1368,"abstract_end":1376},{"Name":"NM_000137.4(FAH):c.782C>T (p.Pro261Leu)","Chromosome":"15","Start":"80173089","Stop":"80173089","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33910,"rule_based_match":true,"evidence_text":"c.782C > T","llm_judgment":"PRESENT","evidence":"c.782C > T","abstract_start":1317,"abstract_end":1327}]}
{"pmid":"20437199","title":"Identification of a novel BRCA1 nucleotide 4803delCC/c.4684delCC mutation and a nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in two Greenlandic Inuit families: implications for genetic screening of Greenlandic Inuit families with high risk for breast and/or ovarian cancer.","abstract":"Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We have recently identified a Greenlandic Inuit BRCA1 nucleotide 234T>G/c.115T>G (p.Cys39Gly) founder mutation, which at that time was the only disease-causing BRCA1/BRCA2 mutation identified in this population. Here, we describe the identification of a novel disease-causing BRCA1 nucleotide 4803delCC/c.4684delCC mutation in a Greenlandic Inuit with ovarian cancer. The mutation introduces a frameshift and a premature stop at codon 1572. We have also identified a BRCA1 nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in another Greenlandic individual with ovarian cancer. This patient share a 1-2 Mb genomic fragment, containing the BRCA1 gene, with four Danish families harbouring the same mutation, suggesting that the 249T>A/c.130T>A (p.Cys44Ser) mutation originates from a Danish ancestor. We conclude that screening of Greenlandic Inuits with high risk of breast or ovarian cancer should include sequencing of the entire BRCA1 gene.","variants":[{"Name":"NM_007294.4(BRCA1):c.130T>A (p.Cys44Ser)","Chromosome":"17","Start":"43115730","Stop":"43115730","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":68858,"rule_based_match":true,"evidence_text":"c.130T>A (p.Cys44Ser)","llm_judgment":"PRESENT","evidence":"c.130T>A (p.Cys44Ser)","abstract_start":602,"abstract_end":623},{"Name":"NM_007294.4(BRCA1):c.115T>G (p.Cys39Gly)","Chromosome":"17","Start":"43115745","Stop":"43115745","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":68820,"rule_based_match":true,"evidence_text":"BRCA1 nucleotide 234T>G/c.115T>G (p.Cys39Gly)","llm_judgment":"PRESENT","evidence":"BRCA1 nucleotide 234T>G/c.115T>G (p.Cys39Gly)","abstract_start":159,"abstract_end":204}]}
{"pmid":"25701870","title":"Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment.","abstract":"There are two known mRNA degradation pathways, 3' to 5' and 5' to 3'. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a splice site variant (c.636+1G>A) that results in an in-frame insertion of 45 nucleotides and a missense variant (c.947C>T; p.Thr316Met). DCPS decaps the cap structure generated by 3' to 5' exonucleolytic degradation of mRNA. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS. In another family, we identified a homozygous mutation (c.161T>C; p.Phe54Ser) in EDC3 in two affected children. EDC3 stimulates DCP2, which decaps mRNAs at the beginning of the 5' to 3' degradation pathway. In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. We show that individuals with biallelic mutations in these genes of seemingly central functions are viable and that these possibly lead to impairment of neurological functions linking mRNA decapping to normal cognition. Our results further affirm an emerging theme linking aberrant mRNA metabolism to neurological defects.","variants":[{"Name":"NM_025083.5(EDC3):c.161T>C (p.Phe54Ser)","Chromosome":"15","Start":"74674964","Stop":"74674964","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":359123,"rule_based_match":true,"evidence_text":"c.161T>C (p.Phe54Ser)","llm_judgment":"PRESENT","evidence":"p.Phe54Ser","abstract_start":701,"abstract_end":711},{"Name":"NM_014026.6(DCPS):c.947C>T (p.Thr316Met)","Chromosome":"11","Start":"126345546","Stop":"126345546","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359140,"rule_based_match":true,"evidence_text":"c.947C>T; p.Thr316Met","llm_judgment":"PRESENT","evidence":"c.947C>T; p.Thr316Met","abstract_start":429,"abstract_end":450},{"Name":"NM_014026.6(DCPS):c.636+1G>A","Chromosome":"11","Start":"126338400","Stop":"126338400","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":359139,"rule_based_match":true,"evidence_text":"c.636+1G>A","llm_judgment":"PRESENT","evidence":"c.636+1G>A","abstract_start":337,"abstract_end":347}]}
{"pmid":"34570399","title":"A bi-allelic loss-of-function SARS1 variant in children with neurodevelopmental delay, deafness, cardiomyopathy, and decompensation during fever.","abstract":"Aminoacyl-tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting aminoacyl-tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl-tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNA<sup>Ser</sup> . SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity. Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.","variants":[{"Name":"NM_006513.4(SARS1):c.638G>T (p.Arg213Leu)","Chromosome":"1","Start":"109231677","Stop":"109231677","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1199566,"rule_based_match":true,"evidence_text":"c.638G>T, p.(Arg213Leu)","llm_judgment":"PRESENT","evidence":"c.638G>T, p.(Arg213Leu)","abstract_start":767,"abstract_end":790}]}
{"pmid":"34102099","title":"De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.","abstract":"Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys<sup>∗</sup>11], c.399_400del [p.Glu133Aspfs<sup>∗</sup>37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.","variants":[{"Name":"NM_001128.6(AP1G1):c.44G>A (p.Arg15Gln)","Chromosome":"16","Start":"71789436","Stop":"71789436","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1289225,"rule_based_match":true,"evidence_text":"c.44G>A [p.Arg15Gln]","llm_judgment":"PRESENT","evidence":"c.44G>A [p.Arg15Gln]","abstract_start":439,"abstract_end":459},{"Name":"NM_001128.6(AP1G1):c.103C>T (p.Arg35Trp)","Chromosome":"16","Start":"71789377","Stop":"71789377","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1289226,"rule_based_match":true,"evidence_text":"c.103C>T (p.Arg35Trp)","llm_judgment":"PRESENT","evidence":"p.Arg35Trp","abstract_start":471,"abstract_end":481},{"Name":"NM_001128.6(AP1G1):c.104G>A (p.Arg35Gln)","Chromosome":"16","Start":"71789376","Stop":"71789376","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1289227,"rule_based_match":true,"evidence_text":"c.104G>A [p.Arg35Gln]","llm_judgment":"PRESENT","evidence":"c.104G>A [p.Arg35Gln]","abstract_start":484,"abstract_end":505}]}
{"pmid":"30235249","title":"Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.","abstract":"During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p.(Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Co-segregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.","variants":[{"Name":"NM_020433.5(JPH2):c.482C>A (p.Thr161Lys)","Chromosome":"20","Start":"44160305","Stop":"44160305","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":165552,"rule_based_match":true,"evidence_text":"JPH2 c.482C>A, p.(Thr161Lys)","llm_judgment":"PRESENT","evidence":"JPH2 c.482C>A, p.(Thr161Lys)","abstract_start":876,"abstract_end":904}]}
{"pmid":"28628109","title":"Truncating mutations in RBM12 are associated with psychosis.","abstract":"Thus far, a handful of highly penetrant mutations conferring risk of psychosis have been discovered. Here we used whole-genome sequencing and long-range phasing to investigate an Icelandic kindred containing ten individuals with psychosis (schizophrenia, schizoaffective disorder or psychotic bipolar disorder). We found that all affected individuals carry RBM12 (RNA-binding-motif protein 12) c.2377G>T (P = 2.2 × 10<sup>-4</sup>), a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif. We replicated the association in a Finnish family in which a second RBM12 truncating mutation (c.2532delT) segregates with psychosis (P = 0.020). c.2377G>T is not fully penetrant for psychosis; however, we found that carriers unaffected by psychosis resemble patients with schizophrenia in their non-psychotic psychiatric disorder and neuropsychological test profile (P = 0.0043) as well as in their life outcomes (including an increased chance of receiving disability benefits, P = 0.011). As RBM12 has not previously been linked to psychosis, this work provides new insight into psychiatric disease.","variants":[{"Name":"NM_006047.6(RBM12):c.2377G>T (p.Gly793Ter)","Chromosome":"20","Start":"35652946","Stop":"35652946","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":426758,"rule_based_match":true,"evidence_text":"c.2377G>T","llm_judgment":"PRESENT","evidence":"c.2377G>T","abstract_start":394,"abstract_end":403},{"Name":"NM_006047.6(RBM12):c.2532del (p.Gly845fs)","Chromosome":"20","Start":"35652791","Stop":"35652791","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":426759,"rule_based_match":true,"evidence_text":"c.2532delT","llm_judgment":"PRESENT","evidence":"c.2532delT","abstract_start":645,"abstract_end":655}]}
{"pmid":"25595571","title":"Autoimmune liver disease in Noonan Syndrome.","abstract":"Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. The syndrome is transmitted as an autosomal dominant trait. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Autoimmune Hepatitis (AIH) is a cryptogenic, chronic and progressive necroinflammatory liver disease. Common features of AIH are hypergammaglobulinemia (IgG), presence of circulating autoantibodies, histological picture of interface hepatitis and response to immunosuppressant drugs. Conventional treatment with Prednisone and Azathioprine is effective in most patients. We describe the case of a 6 years-old girl with Noonan Syndrome and Autoimmune Hepatitis type 1. Molecular analysis of PTPN11 gene showed heterozygous mutation c.923A>G (Asn308Ser) in exon 8. Though association between NS and autoimmune disorders is known, this is the second case of association between Noonan Syndrome and Autoimmune Hepatitis type 1 described in literature. In the management of NS, an accurate clinical evaluation would be recommended. When there is a clinical suspicion of autoimmune phenomena, appropriate laboratory tests should be performed with the aim of clarifying whether the immune system is involved in NS. We think that autoimmunity represents a characteristic of NS, even if the etiopathogenesis is still unknown.","variants":[{"Name":"NM_002834.5(PTPN11):c.923A>G (p.Asn308Ser)","Chromosome":"12","Start":"112477720","Stop":"112477720","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28366,"rule_based_match":true,"evidence_text":"c.923A>G (Asn308Ser)","llm_judgment":"PRESENT","evidence":"c.923A>G (Asn308Ser)","abstract_start":992,"abstract_end":1012}]}
{"pmid":"26658227","title":"Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).","abstract":"Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX±cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90-2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy.","variants":[{"Name":"NM_000110.4(DPYD):c.1129-5923C>G","Chromosome":"1","Start":"97579893","Stop":"97579893","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":623100,"rule_based_match":true,"evidence_text":"c.1129-5923 C>G","llm_judgment":"PRESENT","evidence":"c.1129-5923 C>G","abstract_start":425,"abstract_end":440}]}
{"pmid":"33769317","title":"Novel splicing (c.6529-1G>T) and missense (c.1667G>A) mutations causing factor V deficiency.","abstract":"Congenital factor V deficiency (FVD) is a rare bleeding disorder. In this study, we investigated the genetic basis in an African American patient with factor V activity 3%. Custom sequence capture and targeted next-generation (NGS) sequencing of the F5 gene were undertaken followed by PCR and Sanger sequencing. Two novel variants were identified. In silico analyses correlated clinically with the patient's factor V activity and hemorrhagic tendency. A review of the literature regarding these genomic alterations is presented. We described two novel mutations causing moderate FVD. The first, Chr1:g.169483698C>A with cDNA change (F5):c.6529-1G>T, occurred in a conserved nucleotide at the canonical acceptor splice site of intron 24. The second, Chr1:g.169515775C>T with cDNA change (F5):c.1667G>A, was a missense variant of exon 11, affecting a highly conserved amino acid in the A2 domain. Further research into the mechanisms of F5 mutations leading to FVD and residual factor V expression are needed.","variants":[{"Name":"NM_000130.5(F5):c.1667G>A (p.Ser556Asn)","Chromosome":"1","Start":"169546537","Stop":"169546537","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3176562,"rule_based_match":true,"evidence_text":"c.1667G>A","llm_judgment":"PRESENT","evidence":"c.1667G>A","abstract_start":792,"abstract_end":801}]}
{"pmid":"20833329","title":"Multiple endocrine neoplasia type 1 (MEN1).","abstract":"Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterised by the occurrence of tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene, consists of 10 exons that encode a 610-amino acid protein referred to as Menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division and proliferation. Germ-line mutations usually result in MEN1 or occasionally in an allelic variant referred to as Familial Isolated Hyperparathyroidism (FIHP). MEN1 tumours frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumour suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumours. To date, over 1300 mutations have been reported, and the majority (>70%) of these are predicted to lead to truncated forms of Menin. The mutations are scattered throughout the >9 kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6% and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of Menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation.","variants":[{"Name":"NM_001370259.2(MEN1):c.1378C>T (p.Arg460Ter)","Chromosome":"11","Start":"64804789","Stop":"64804789","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31731,"rule_based_match":true,"evidence_text":"c.1378C>T (Arg460Ter)","llm_judgment":"PRESENT","evidence":"c.1378C>T (Arg460Ter)","abstract_start":1114,"abstract_end":1135},{"Name":"NM_001370259.2(MEN1):c.249_252del (p.Ile85fs)","Chromosome":"11","Start":"64809858","Stop":"64809861","ReferenceAlleleVCF":"TAGAC","AlternateAlleleVCF":"T","allel_id":31732,"rule_based_match":true,"evidence_text":"c.249_252delGTCT","llm_judgment":"PRESENT","evidence":"c.249_252delGTCT","abstract_start":1027,"abstract_end":1043}]}
{"pmid":"20497192","title":"A large cohort study of GJB2 mutations in Japanese hearing loss patients.","abstract":"GJB2 is the gene most frequently associated with hereditary hearing loss, and the GJB2 mutation spectrums vary among different ethnic groups. In this study, the mutation spectrum as well as clinical features of patients with GJB2 mutations as found in more than 1000 Japanese hearing loss families are summarized. The present results show that the frequency of GJB2 mutations in the Japanese population with hearing loss is 14.2% overall and 25.2% in patients with congenital hearing loss. c.235delC was the most frequent allele (49.8%), was associated with a more severe phenotype, and was mainly found in patients who were diagnosed by the age of 3. In contrast, the second most frequent was p.V37I (16.5%), which has a milder phenotype and was mainly found in patients diagnosed at a higher age. Additional clinical features in hearing loss patients with GJB2 mutations in this study were the near absence of tinnitus, vestibular dysfunction and inner ear malformations.","variants":[{"Name":"NM_004004.6(GJB2):c.235del (p.Leu79fs)","Chromosome":"13","Start":"20189347","Stop":"20189347","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":32053,"rule_based_match":true,"evidence_text":"c.235delC","llm_judgment":"PRESENT","evidence":"c.235delC","abstract_start":490,"abstract_end":499}]}
{"pmid":"22991996","title":"Identification of a p.R143Q dominant mutation in the gap junction beta-2 gene in three Chinese patients with different hearing phenotypes.","abstract":"CONCLUSIONS: p.R143Q mutation in GJB2 can cause mild to profound bilateral sensorineural hearing impairment. Although not common in Chinese patients with hearing loss, it is important to identify the specific phenotype and genotype correlations of the dominant mutation in GJB2.\nOBJECTIVE: Mutations in the GJB2 gene are the most common cause of nonsyndromic autosomal recessive sensorineural hearing loss. A few mutations in GJB2 have also been reported to cause dominant nonsyndromic or syndromic hearing loss. However, dominant mutation in GJB2 is not common in Chinese populations.\nMETHODS: Three patients with hearing impairment from Chinese families are reported here. Temporal CT scan, complete physical (including skin and hair) and otoscopic examinations, and an audiological study, including tympanometry, auditory brainstem response (ABR), auditory steady-state response (ASSR), and 40 Hz auditory event-related potential (40 Hz-AERP), were carried out. The two exons of GJB2, the coding exons of SLC26A4, and mitochondrial 12S rRNA were sequenced.\nRESULTS: Sequencing of GJB2 in two patients showed a heterozygous c.428G>A (p.R143Q) mutation, and the third patient was identified with c.299delAT and c.428G>A compound heterozygous mutation. Sequence analysis of the coding exons of SLC26A4 and mitochondrial 12S rRNA was performed but no sequence aberration or deletion was found.","variants":[{"Name":"NM_004004.6(GJB2):c.428G>A (p.Arg143Gln)","Chromosome":"13","Start":"20189154","Stop":"20189154","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32056,"rule_based_match":true,"evidence_text":"c.428G>A (p.R143Q)","llm_judgment":"PRESENT","evidence":"c.428G>A (p.R143Q)","abstract_start":1126,"abstract_end":1144}]}
{"pmid":"31559144","title":"Congenital diarrhea in a newborn infant: A case report.","abstract":"BACKGROUND: Microvillus inclusion disease (MVID) is a rare autosomal recessive cause of severe congenital diarrhea with significant morbidity and mortality. Definitive treatment involves bowel transplant. The diagnosis of this condition can be challenging and a few genetic panels are available for the identification of the most common mutations. We present the case of an infant with MVID due to a mutation not reported in the literature before.\nCASE SUMMARY: We report the case of an infant transferred to our institution with severe diarrhea of unknown etiology, failure to thrive, and significant metabolic derangements. An extensive work-up including stool studies for common gastrointestinal pathogens, abdominal ultrasound, esophagogastroduodenoscopy with duodenal biopsy and flexible sigmoidoscopy failed to reveal a diagnosis. Multiple dietary and formula regimens were introduced but all resulted in voluminous diarrhea. She remained on total parenteral nutrition (TPN) for the duration of her hospital stay. Genetic testing was done and she was subsequently found to have a novel mutation in the <i>MYO5B</i> gene [homozygous mutation for MYO5B c.1462del, p. (Ile488Leufs*93)] giving us the diagnosis of MVID. She remains on TPN while awaiting bowel transplant at the time of the compilation of this case report.\nCONCLUSION: We report a novel mutation involved in MVID and highlight the importance of considering this disease when faced with a newborn presenting with life threatening diarrhea. At the time of this publication, 232 allelic variations of this gene (MIM#606540) exist in National Center for Biotechnology Information's database. Our patient's mutation has not been reported in literature as a cause of MVID.","variants":[{"Name":"NM_001080467.3(MYO5B):c.1462del (p.Ile488fs)","Chromosome":"18","Start":"49962349","Stop":"49962349","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":3414094,"rule_based_match":true,"evidence_text":"MYO5B c.1462del, p. (Ile488Leufs*93)","llm_judgment":"PRESENT","evidence":"MYO5B c.1462del, p. (Ile488Leufs*93)","abstract_start":1151,"abstract_end":1187}]}
{"pmid":"24369075","title":"Deficiency of innate and acquired immunity caused by an IKBKB mutation.","abstract":"BACKGROUND: Severe combined immunodeficiency (SCID) comprises a heterogeneous group of heritable deficiencies of humoral and cell-mediated immunity. Many patients with SCID have lymphocyte-activation defects that remain uncharacterized.\nMETHODS: We performed genetic studies in four patients, from four families of Northern Cree ancestry, who had clinical characteristics of SCID, including early onset of severe viral, bacterial, and fungal infections despite normal B-cell and T-cell counts. Genomewide homozygosity mapping was used to identify a candidate region, which was found on chromosome 8; all genes within this interval were sequenced. Immune-cell populations, signal transduction on activation, and effector functions were studied.\nRESULTS: The patients had hypogammaglobulinemia or agammaglobulinemia, and their peripheral-blood B cells and T cells were almost exclusively of naive phenotype. Regulatory T cells and γδ T cells were absent. All patients carried a homozygous duplication--c.1292dupG in exon 13 of IKBKB, which encodes IκB kinase 2 (IKK2, also known as IKKβ)--leading to loss of expression of IKK2, a component of the IKK-nuclear factor κB (NF-κB) pathway. Immune cells from the patients had impaired responses to stimulation through T-cell receptors, B-cell receptors, toll-like receptors, inflammatory cytokine receptors, and mitogens.\nCONCLUSIONS: A form of human SCID is characterized by normal lymphocyte development despite a loss of IKK2 function. IKK2 deficiency results in an impaired response to activation stimuli in a variety of immune cells, leading to clinically relevant impairment of adaptive and innate immunity. Although Ikk2 deficiency is lethal in mouse embryos, our observations suggest a more restricted, unique role of IKK2-NF-κB signaling in humans. (Funded by the German Federal Ministry of Education and Research and others.).","variants":[{"Name":"NM_001556.3(IKBKB):c.1292dup (p.Gln432fs)","Chromosome":"8","Start":"42318599","Stop":"42318600","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":108187,"rule_based_match":true,"evidence_text":"c.1292dupG in exon 13 of IKBKB","llm_judgment":"PRESENT","evidence":"c.1292dupG in exon 13 of IKBKB","abstract_start":1000,"abstract_end":1030}]}
{"pmid":"34674941","title":"A novel CCDC39 mutation causes multiple morphological abnormalities of the flagella in a primary ciliary dyskinesia patient.","abstract":"RESEARCH QUESTION: Male infertility is a widespread symptom in patients with primary ciliary dyskinesia (PCD). PCD-related male infertility is often caused by asthenozoospermia, with barely normal sperm morphology. Multiple morphological abnormalities of the sperm flagella (MMAF) are a major cause of asthenozoospermia, characterized by various malformed morphologies of sperm flagella. To date, a limited number of genes have been suggested to be involved in the pathogenesis of both PCD and MMAF. What other genes associated with both PCD and MMAF are waiting to be discovered?\nDESIGN: Whole-exome sequencing (WES) was performed to identify the pathogenic mutation associated with MMAF in a PCD patient. Peripheral venous blood and semen samples were collected from the PCD patient. Transmission electron microscopy (TEM), immunofluorescence staining and western blotting were conducted to confirm the pathogenicity of the identified mutation.\nRESULTS: A novel homozygous mutation in CCDC39, c.983 T>C (p. Leu328Pro), was identified in two PCD-affected siblings of a consanguineous family showing a typical PCD phenotype, while the proband was infertile, which is associated with characterized MMAF. Furthermore, TEM revealed the abnormal ultrastructure of the patient's sperm flagella. Moreover, immunofluorescence staining revealed that CCDC39 was almost undetectable in the spermatozoa, which was further confirmed by western blotting. The outcome of intracytoplasmic sperm injection (ICSI) in the patient with the CCDC39 mutation was also favourable.\nCONCLUSION: This study demonstrates that a novel loss-of-function mutation of CCDC39 is involved in the pathogenesis of PCD and MMAF and initially reported that ICSI treatment has a good outcome. Therefore, the novel variant of CCDC39 contributes to the genetic diagnosis, counselling and treatment of male infertility in PCD patients with MMAF phenotype.","variants":[{"Name":"NM_181426.2(CCDC39):c.983T>C (p.Leu328Pro)","Chromosome":"3","Start":"180652214","Stop":"180652214","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2671474,"rule_based_match":true,"evidence_text":"c.983 T>C (p. Leu328Pro)","llm_judgment":"PRESENT","evidence":"c.983 T>C (p. Leu328Pro)","abstract_start":995,"abstract_end":1019}]}
{"pmid":"30569017","title":"Leigh syndrome followed by parkinsonism in an adult with homozygous c.626C>T mutation in","abstract":"OBJECTIVE: To report the clinical, radiologic, biochemical, and molecular characteristics in a 46-year-old participant with adult-onset Leigh syndrome (LS), followed by parkinsonism.\nMETHODS: Case description with diagnostic workup included blood and CSF analysis, skeletal muscle investigations, blue native polyacrylamide gel electrophoresis, whole exome sequencing targeting nuclear genes involved in mitochondrial transcription and translation, cerebral MRI, 123I-FP-CIT brain single-photon emission computed tomography (SPECT), and C-11 raclopride positron emission tomography (PET).\nRESULTS: The participant was found to have a defect in the oxidative phosphorylation caused by a c.626C>T mutation in the gene coding for mitochondrial methionyl-tRNA formyltransferase (<i>MTFMT</i>), which is a pathogenic mutation affecting intramitochondrial protein translation. The proband had a normal concentration of lactate in blood and no abnormal microscopic findings in skeletal muscle. Cerebral MRI showed bilateral lesions in the striatum, mesencephalon, pons, and medial thalamus. Lactate concentration in CSF was increased. FP-CIT SPECT and C-11 raclopride PET demonstrated a defect in the dopaminergic system.\nCONCLUSIONS: We report on a case with adult-onset LS related to a <i>MTFMT</i> mutation. Two years after the onset of symptoms of LS, the proband developed a parkinson-like disease. The c.626C>T mutation is the most common pathogenic mutation found in 22 patients reported earlier in the literature with a defect in <i>MTFMT</i>. The age of the previously reported cases varied between 14 months and 24 years. Our report expands the phenotypical spectrum of <i>MTFMT</i>-related neurologic disease and provides clinical evidence for involvement of <i>MTFMT</i> in extrapyramidal syndromes.","variants":[{"Name":"NM_139242.4(MTFMT):c.626C>T (p.Ser209Leu)","Chromosome":"15","Start":"65021533","Stop":"65021533","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48426,"rule_based_match":true,"evidence_text":"c.626C>T","llm_judgment":"PRESENT","evidence":"c.626C>T","abstract_start":686,"abstract_end":694}]}
{"pmid":"17178739","title":"A cryopyrin-associated periodic syndrome with joint destruction.","abstract":"OBJECTIVE: Describe four generations (11 members) of a family with a cryopyrin-associated periodic syndrome (CAPS), including joint destruction, associated with a CIAS1-gene mutation and good responses to anakinra.\nMETHODS: In addition to detailed questioning and physical examination, six family members underwent haematological, immunological and biochemical testing. Exon 3 of the CIAS1 gene was sequenced in search of a mutation in the 1q44 region.\nRESULTS: During childhood or adolescence, four family members developed different combinations of the following CAPS manifestations: deafness (3/4); arthritis (4/4) with joint destruction for two of them; nervous (cerebral demyelinization, 2/4), cutaneous (livedo and/or urticaria, 3/4) and eye lesions (episcleritis and/or papilloedema, 4/4); IgA hypergammaglobulinaemia (4/4) and inflammatory syndrome (3/4). Sequencing of six family members' CIAS1-gene exon 3 identified a heterozygous mutation, c.1043C > T. Pertinently, this CAPS is distinct from chronic infantile neurological cutaneous and arthritis syndrome/neonatal onset multisystemic inflammatory disease syndrome and Muckle-Wells syndrome (MWS), which also result from exon 3 mutations in this gene. Moreover, this family did not have the usual neurological manifestations, typical morphological features and frequent amyloidosis of MWS.\nCONCLUSIONS: We describe a previously unreported form of CAPS with atypical neurological signs, joint destruction and livedo. This observation extends the clinical spectrum associated with CIAS1 mutations. Anakinra, an interleukin-1-receptor antagonist, prescribed to two family members, was highly effective.","variants":[{"Name":"NM_001243133.2(NLRP3):c.1043C>T (p.Thr348Met)","Chromosome":"1","Start":"247424492","Stop":"247424492","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":103801,"rule_based_match":true,"evidence_text":"c.1043C > T","llm_judgment":"PRESENT","evidence":"c.1043C > T","abstract_start":952,"abstract_end":963}]}
{"pmid":"19672314","title":"Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to type 2 diabetes.","abstract":"BACKGROUND: There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8-10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1-7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8-10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D.\nMETHODOLOGY AND PRINCIPAL FINDINGS: We performed targeted capillary resequencing of HNF1A exons 8-10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (< or =45 years) and/or family history of T2D (> or =1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9-24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rs61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected.\nCONCLUSIONS AND SIGNIFICANCE: We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion.","variants":[{"Name":"NM_000545.8(HNF1A):c.1545G>A (p.Thr515=)","Chromosome":"12","Start":"120999311","Stop":"120999311","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":134678,"rule_based_match":true,"evidence_text":"c.1545G>A, p.T515T","llm_judgment":"PRESENT","evidence":"c.1545G>A, p.T515T","abstract_start":1464,"abstract_end":1482}]}
{"pmid":"26077460","title":"Family with MSH2 mutation presenting with keratoacanthoma and precancerous skin lesions.","abstract":"Muir-Torre syndrome (MTS) is a familial cancer syndrome characterized by a predisposition to keratoacanthoma (KA) and sebaceous tumors. Although MTS and hereditary non-polyposis colorectal cancer (HNPCC) share the same genetic alterations in mismatch repair (MMR) genes, the other skin lesions in MTS or HNPCC have been only rarely reported. We report a family with an MSH2 mutation c.1126_1127delTT (p.Leu376Thrfs*12). A 46-year-old male proband developed KA with sebaceous differentiation, colon cancer and gastric cancer, and fulfilled the diagnostic criteria for MTS. His 80-year-old mother, diagnosed with HNPCC, presented with multiple gastrointestinal tract cancers, Bowen's disease and actinic keratosis. Immunostaining revealed attenuated MSH2 protein expression in KA, as well as in Bowen's disease and actinic keratosis lesions. These findings suggest that MMR gene abnormality is also critical in the development of benign or malignant cutaneous tumors such as actinic keratosis and Bowen's disease in MTS/HNPCC patients.","variants":[{"Name":"NM_000251.3(MSH2):c.1126_1127del (p.Leu376fs)","Chromosome":"2","Start":"47429790","Stop":"47429791","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":1925295,"rule_based_match":true,"evidence_text":"c.1126_1127delTT (p.Leu376Thrfs*12)","llm_judgment":"PRESENT","evidence":"c.1126_1127delTT (p.Leu376Thrfs*12)","abstract_start":383,"abstract_end":418}]}
{"pmid":"32347653","title":"Hydrocephaly associated with compound heterozygous alterations in TRAPPC12.","abstract":"BACKGROUND: Hydrocephalus is characterized by increased cerebrospinal fluid within the brain, a causally heterogeneous disorder estimated to affect 1 per 1,000 live births, with the most severe cases often leading to fetal demise. The large number of known genetic and environmental factors that contribute to hydrocephalus makes the differential diagnosis challenging.\nCASES: Three consecutive pregnancies of an unrelated couple were found by ultrasound to carry fetuses with hydrocephaly. DNA from two affected fetuses and the parents were subjected to whole exome sequencing. Heterozygous alterations in the TRAPPC12 gene were identified in the parents and compound heterozygous alterations were present in the two affected fetuses. The variant from the father (c.954del) leads to a premature termination of the transcript; the variant from the mother (c.1677+5G>A) affects a splice site which leads to aberrant splicing of the TRAPPC12 transcript.\nCONCLUSION: Compound heterozygous variants in TRAPPC12, which encodes a protein involved in Golgi trafficking and mitosis, may disrupt normal brain embryogenesis leading to hydrocephalus and recurrent pregnancy loss.","variants":[{"Name":"NM_016030.6(TRAPPC12):c.1677+5G>A","Chromosome":"2","Start":"3460341","Stop":"3460341","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1708574,"rule_based_match":true,"evidence_text":"c.1677+5G>A","llm_judgment":"PRESENT","evidence":"c.1677+5G>A","abstract_start":856,"abstract_end":867}]}
{"pmid":"28432012","title":"Novel compound heterozygous mutations in the PEX1 gene in two Chinese newborns with Zellweger syndrome based on whole exome sequencing.","abstract":"Peroxisome biogenesis disorders (PBDs) represent a spectrum of human genetic disorders that are characterized by damaged peroxisome assembly. In the newborn period, the characteristics of affected patients include dysmorphic facial features, neonatal hypotonia, seizures, ocular abnormalities, poor feeding, liver cysts with hepatic dysfunction and skeletal defects. These can be caused by a defect in at least 14 different PEX genes. In this study, whole-exome sequencing (WES) was performed on samples from two Chinese newborns with clinical features of Zellweger syndrome. WES identified two novel mutations (c.2416+1G>T and c.2489delT) in patient 1 and another two novel mutations (c.1483+1G>A and c.1727dupG) in patient 2 in the PEX1 gene. All four mutations have a serious influence on the protein function, which also highlights the power of WES, particularly in clinically challenging cases.","variants":[{"Name":"NM_000466.3(PEX1):c.1483+1G>A","Chromosome":"7","Start":"92511579","Stop":"92511579","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":818403,"rule_based_match":true,"evidence_text":"c.1483+1G>A","llm_judgment":"PRESENT","evidence":"c.1483+1G>A","abstract_start":686,"abstract_end":697},{"Name":"NM_000466.3(PEX1):c.1727dup (p.Arg577fs)","Chromosome":"7","Start":"92507069","Stop":"92507070","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":818389,"rule_based_match":true,"evidence_text":"c.1727dupG","llm_judgment":"PRESENT","evidence":"c.1727dupG","abstract_start":702,"abstract_end":712}]}
{"pmid":"32711049","title":"Clinical and GAA gene mutation analysis in 21 Chinese patients with classic infantile pompe disease.","abstract":"Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Early and precise diagnosis can be highly important for the treatment, genetic counselling and prenatal diagnosis of this disease in potential candidates. Considering that Pompe disease studies have not been frequently conduced in China, to better understand the clinical course and molecular defects among this group, our study examined 21 Chinese patients with classic infantile Pompe disease. The median age of symptom onset in the patients was 2.5 months (0-7 months), and the median age of confirmed diagnosis was 5.6 months (2-12 months). GAA gene mutation analysis revealed 17 different mutations, two of which were novel (c.538C>A and c.2096T>C). The most frequent mutation in these patients was c.1935C>A, accounting for 40.5% (17/42 alleles) of the mutations. These results confirm the high prevalence of the c.1935C>A mutation in Chinese patients with classic infantile Pompe disease. Furthermore, identification of the novel alterations in the GAA gene will help to broaden the spectrum of the GAA mutations causing Pompe disease and to better understand the potential pathogenic role of each change.","variants":[{"Name":"NM_000152.5(GAA):c.2096T>C (p.Leu699Pro)","Chromosome":"17","Start":"80113273","Stop":"80113273","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3048363,"rule_based_match":true,"evidence_text":"c.2096T>C","llm_judgment":"PRESENT","evidence":"c.2096T>C","abstract_start":767,"abstract_end":776}]}
{"pmid":"35442417","title":"Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic.","abstract":"Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.","variants":[{"Name":"NM_001289125.3(IFNAR2):c.157T>C (p.Ser53Pro)","Chromosome":"21","Start":"33245010","Stop":"33245010","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":982227,"rule_based_match":true,"evidence_text":"IFNAR2 c.157T>C, p.Ser53Pro","llm_judgment":"PRESENT","evidence":"IFNAR2 c.157T>C, p.Ser53Pro","abstract_start":480,"abstract_end":507}]}
{"pmid":"25173644","title":"Significant expressivity of Wolfram syndrome: phenotypic assessment of two known and one novel mutation in the WFS1 gene in three Iranian families.","abstract":"Wolfram syndrome also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) is a rare neurodegenerative autosomal recessive disorder. There is evidence of variable expressivity both in patients and heterozygous carriers. In this study, we describe three Persian Wolfram syndrome families with differences in the age of onset, signs and symptoms of the disease. We clinically evaluated affected families for verifying WS clinical diagnosis. After linkage analysis via 5 STR markers, molecular analysis for WFS1 was performed by direct sequencing for patients and available family members. Three homozygous mutations were identified including c.1885 C>T, c.2205C>A both in exon 8 and c.460+1G>A in intron 4. The mutation c.2205C>A was found to be novel. We report interesting phenotype-genotype correlations: homozygous c.1885C>T and c.2205C>A variants were correlated with quite different disease severity and onset in the siblings. We report a rare case of WS with homozygous c.1885C>T who is married and has a healthy child. c.460+1G>A showed a possible partial dominant inheritance put forth by a heterozygous parent showing partial WS symptoms while her daughter displayed typical WS symptoms. Due to variable expressivity, detailed clinical examination and molecular diagnostics should be used to confirm WS and a more exact recurrence risk data.","variants":[{"Name":"NM_006005.3(WFS1):c.2205C>A (p.Tyr735Ter)","Chromosome":"4","Start":"6302000","Stop":"6302000","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3859969,"rule_based_match":true,"evidence_text":"c.2205C>A","llm_judgment":"PRESENT","evidence":"c.2205C>A","abstract_start":685,"abstract_end":694},{"Name":"NM_006005.3(WFS1):c.460+1G>A","Chromosome":"4","Start":"6289132","Stop":"6289132","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19554,"rule_based_match":true,"evidence_text":"c.460+1G>A","llm_judgment":"PRESENT","evidence":"c.460+1G>A","abstract_start":714,"abstract_end":724}]}
{"pmid":"37915296","title":"Genotype and phenotype characterization of primary hypertrophic osteoarthropathy type 2 and chronic enteropathy associated with SLCO2A1: Report of two cases and literature review.","abstract":"Autosomal recessive type 2 primary hypertrophic osteoarthropathy (PHOAR2) and chronic enteropathy associated with SLCO2A1 (CEAS) are two entities caused by pathogenic variants (PVs) in the SLCO2A1 gene that can coexist or occur independently from one another. We report two cases of PHOAR2 in Mexico with concomitant CEAS and conducted a review of the literature of the reported cases of PHOAR2 and/or CEAS to analyze the relationship between their genotype and phenotype presentation. The patients from our Institution with classical PHOAR2 phenotype and CEAS, harbored SLCO2A1 c.547G > A and c.1768del variants. We reviewed 232 cases, of which 86.6% were of Asian origin, and identified 109 different variants in SLCO2A1. Intron 7, exon 13, and exon 4 were predominantly affected. The two most common PVs were c.940 + 1G > A and c.1807C > T. We found a statistically significant association between SLCO2A1 variants located in intron 7, exons 12, and 13 and the development of CEAS. Missense variants were more frequent in isolated PHOAR2, while a greater proportion of protein-truncating variants (PTVs) were found in CEAS. Further investigation is imperative to elucidate the underlying pathophysiological mechanisms associated with CEAS, thereby facilitating the identification of effective therapeutic interventions.","variants":[{"Name":"NM_005630.3(SLCO2A1):c.547G>A (p.Gly183Arg)","Chromosome":"3","Start":"133955044","Stop":"133955044","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":966067,"rule_based_match":true,"evidence_text":"SLCO2A1 c.547G > A","llm_judgment":"PRESENT","evidence":"SLCO2A1 c.547G > A","abstract_start":571,"abstract_end":589},{"Name":"NM_005630.3(SLCO2A1):c.1768del (p.Arg590fs)","Chromosome":"3","Start":"133935820","Stop":"133935820","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":2045062,"rule_based_match":true,"evidence_text":"c.1768del","llm_judgment":"PRESENT","evidence":"c.1768del","abstract_start":594,"abstract_end":603}]}
{"pmid":"37962568","title":"A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.","abstract":"Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients' T cells show residual TCR signal transduction and proliferation following anti-CD3/CD28 and phytohemagglutinin (PHA) stimulation. We demonstrate in mouse models that complete (Lck-/-) versus partial (LckP440S/P440S) loss-of-function LCK causes disease with differing phenotypes. While both Lck-/- and LckP440S/P440S mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only LckP440S/P440S mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the LckP440S/P440S mice is prevented by CD4+ T cell depletion or regulatory T cell transfer. These findings demonstrate that P440S LCK spares sufficient T cell function to allow the maturation of some conventional T cells but not regulatory T cells-leading to intestinal inflammation.","variants":[{"Name":"NM_005356.5(LCK):c.1318C>T (p.Pro440Ser)","Chromosome":"1","Start":"32280201","Stop":"32280201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3224419,"rule_based_match":true,"evidence_text":"c.1318C>T","llm_judgment":"PRESENT","evidence":"c.1318C>T","abstract_start":192,"abstract_end":201}]}
{"pmid":"32223457","title":"Novel mutations in a Chinese family with two patients with succinic semialdehyde dehydrogenase deficiency.","abstract":"<b>Background:</b> A considerable proportion of pediatric disease burden is mainly caused by inborn errors of metabolism. Succinic semi-aldehyde dehydrogenase (SSADH) deficiency is an unusual disorder of the gamma-aminobutyric acid metabolism. Till date, very few cases have been reported in China.<b>Case presentation:</b> Trio-WES was used to characterize the <i>ALDH5A1</i> gene in two children of a Chinese family, who presented with seizures, psychomotor delay, development regression, borderline cognition, hypotonia, and harbored the compound heterozygotes NM_001080.3: c.1321G > A (p. Gly441Arg) and c.727_735del (p. Leu243_Ser245del). The former has been reported earlier (rs1041467895), whereas the latter is novel. Amino acid coding at highly conserved amino acid residues was observed to be altered by both mutations. This structural impairment influenced the enzyme structure as indicated by the <i>in silico</i> protein modeling. Cerebral magnetic resonance imaging of the proband and her brother showed excessive gap in the cerebrum and abnormal signals in the bilateral frontal lobe, bilateral basal ganglia, and cerebral foot. Elevated levels of Gamma-hydroxybutyric aciduria were found in their patients on urine organic acid analysis.<b>Conclusion:</b> Our findings contribute to the current knowledge of missense and deletion mutations associated with SSADH deficiency.","variants":[{"Name":"NM_001080.3(ALDH5A1):c.1321G>A (p.Gly441Arg)","Chromosome":"6","Start":"24528144","Stop":"24528144","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1935259,"rule_based_match":true,"evidence_text":"NM_001080.3: c.1321G > A (p. Gly441Arg)","llm_judgment":"PRESENT","evidence":"NM_001080.3: c.1321G > A (p. Gly441Arg)","abstract_start":564,"abstract_end":603}]}
{"pmid":"27014579","title":"Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation.","abstract":"We report a patient with anti-epileptic treatment refractory neonatal seizures responsive to pyridoxine. Biochemical analysis revealed normal markers for antiquitin deficiency and also mutation analysis of the ALDH7A1 (Antiquitin) gene was negative. Mutation analysis of the PNPO gene revealed a novel, homozygous, presumed pathogenic mutation (c.481C > T; p.(Arg161Cys)). Measurements of B6 vitamers in a CSF sample after pyridoxine administration revealed elevated pyridoxamine as the only metabolic marker for PNPO deficiency. With pyridoxine monotherapy the patient is seizure free and neurodevelopmental outcome at the age of 14 months is normal.","variants":[{"Name":"NM_018129.4(PNPO):c.481C>T (p.Arg161Cys)","Chromosome":"17","Start":"47945924","Stop":"47945924","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":203483,"rule_based_match":true,"evidence_text":"c.481C > T; p.(Arg161Cys)","llm_judgment":"PRESENT","evidence":"c.481C > T; p.(Arg161Cys)","abstract_start":345,"abstract_end":370}]}
{"pmid":"27881154","title":"Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients.","abstract":"BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic, hereditary, small vessel disease of the brain causing stroke and vascular dementia in adults. CADASIL has previously been shown to be caused by varying mutations in the NOTCH3 gene. The disorder is often misdiagnosed due to its significant clinical heterogeneic manifestation with familial hemiplegic migraine and several ataxia disorders as well as the location of the currently identified causative mutations. The aim of this study was to develop a new, comprehensive and efficient single assay strategy for complete molecular diagnosis of NOTCH3 mutations through the use of a custom next-generation sequencing (NGS) panel for improved routine clinical molecular diagnostic testing.\nRESULTS: Our custom NGS panel identified nine genetic variants in NOTCH3 (p.D139V, p.C183R, p.R332C, p.Y465C, p.C597W, p.R607H, p.E813E, p.C977G and p.Y1106C). Six mutations were stereotypical CADASIL mutations leading to an odd number of cysteine residues in one of the 34 NOTCH3 gene epidermal growth factor (EGF)-like repeats, including three new typical cysteine mutations identified in exon 11 (p.C597W; c.1791C>G); exon 18 (p.C977G; c.2929T>G) and exon 20 (p.Y1106C; c.3317A>G). Interestingly, a novel missense mutation in the CACNA1A gene was also identified in one CADASIL patient. All variants identified (novel and known) were further investigated using in silico bioinformatic analyses and confirmed through Sanger sequencing.\nCONCLUSIONS: NGS provides an improved and effective methodology for the diagnosis of CADASIL. The NGS approach reduced time and cost for comprehensive genetic diagnosis, placing genetic diagnostic testing within reach of more patients.","variants":[{"Name":"NM_000435.3(NOTCH3):c.1820G>A (p.Arg607His)","Chromosome":"19","Start":"15187125","Stop":"15187125","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3026949,"rule_based_match":false,"evidence_text":"p.R607H","llm_judgment":"PRESENT","evidence":"p.R607H","abstract_start":934,"abstract_end":941},{"Name":"NM_000435.3(NOTCH3):c.1791C>G (p.Cys597Trp)","Chromosome":"19","Start":"15187154","Stop":"15187154","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1862537,"rule_based_match":true,"evidence_text":"c.1791C>G","llm_judgment":"PRESENT","evidence":"c.1791C>G","abstract_start":1224,"abstract_end":1233}]}
{"pmid":"22773173","title":"Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome.","abstract":"Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as 'of uncertain significance'. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic.","variants":[{"Name":"NM_000249.4(MLH1):c.544A>G (p.Arg182Gly)","Chromosome":"3","Start":"37008904","Stop":"37008904","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":95732,"rule_based_match":true,"evidence_text":"c.544A>G (p.Arg182Gly)","llm_judgment":"PRESENT","evidence":"c.544A>G (p.Arg182Gly)","abstract_start":833,"abstract_end":855}]}
{"pmid":"32670577","title":"Novel pathogenic mutations identified in the first Chinese pedigree of complete C6 deficiency.","abstract":"OBJECTIVES: Complete C6 deficiency (C6Q0) is a rare primary immunodeficiency leading to increased susceptibility to recurrent <i>Neisseria</i> infections. Patients with C6Q0 have mostly been reported in individuals of African ancestry previously, but never in Chinese. We identify the first Chinese patients with C6Q0 through family screening of an index case presenting with recurrent <i>Neisseria</i> meningitis with septicaemia and performed extensive clinical, serological and genetic investigations.\nMETHODS: Two variants in <i>C6</i> were identified by next-generation sequencing and confirmed by Sanger sequencing in an index case of C6Q0. Immunological investigations, complement haemolytic assays (CH50/AH50), <i>C6</i> gene sequencing and quantification of serum C6 levels were performed for all available members of his nonconsanguineous family.\nRESULTS: Three C6Q0 patients were identified with near-absent C6 levels, absent CH50/AH50 activity and compound heterozygous for two nonsense mutations in the <i>C6</i> gene: NM_000065.4:c.1786C>T (p.Arg596Ter) and NM_000065.4:c.1816C>T (p.Arg606Ter). Neither mutations have been reported to be pathogenic previously. Two other family members who were heterozygous for either p.Arg596Ter or and p.Arg606Ter had intermediate C6 levels but preserved CH50/AH50 activity. These two loss-of-function mutations showed a strong genotype-phenotype correlation in C6 levels.\nCONCLUSIONS: We report on two compound heterozygous mutations in <i>C6</i>, p.Arg596Ter and p.Arg606Ter inherited in three patients of the first recorded Chinese pedigree of C6Q0. Neither mutations had been reported to be pathogenic previously. We demonstrate that heterozygous family members with subtotal C6 levels had preserved complement haemolytic function and demonstrate a threshold effect of C6 protein level.","variants":[{"Name":"NM_000065.5(C6):c.1816C>T (p.Arg606Ter)","Chromosome":"5","Start":"41159122","Stop":"41159122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3059083,"rule_based_match":true,"evidence_text":"NM_000065.4:c.1816C>T (p.Arg606Ter)","llm_judgment":"PRESENT","evidence":"NM_000065.4:c.1816C>T (p.Arg606Ter)","abstract_start":1072,"abstract_end":1107}]}
{"pmid":"28334867","title":"The silent mutation MLH1 c.543C>T resulting in aberrant splicing can cause Lynch syndrome: a case report.","abstract":"The proband was a 67-year-old man with transverse and sigmoid colon cancer. Microsatellite instability analysis revealed a high frequency of microsatellite instability, and immunohistochemical staining showed the absence of both MLH1 and PMS2 proteins in the sigmoid colon cancer tissue specimens from the patient. DNA sequencing revealed a nucleotide substitution c.543C>T in MLH1, but this variant did not substitute an amino acid. The MLH1 c.543C>T variant was located 3 bases upstream from the end of exon 6 and created a new splice donor site 4 bases upstream from the end of exon 6. Consequently, the last 4 bases of exon 6 were deleted and frameshift occurred. Thus, the MLH1 c.543C>T silent mutation is considered 'pathogenic'.","variants":[{"Name":"NM_000249.4(MLH1):c.543C>T (p.Gly181=)","Chromosome":"3","Start":"37008903","Stop":"37008903","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":621931,"rule_based_match":true,"evidence_text":"c.543C>T","llm_judgment":"PRESENT","evidence":"c.543C>T","abstract_start":365,"abstract_end":373}]}
{"pmid":"17605048","title":"Severe retinitis pigmentosa mapped to 4p15 and associated with a novel mutation in the PROM1 gene.","abstract":"Mutation in the PROM1 gene previously has been identified in one family with retinal degeneration for which neither ERG recordings nor detailed information about visual impairment is available. A large family with multiple individuals affected by retinal degeneration was ascertained in the Punjab province of Pakistan. The visual acuity of all affected patients in the family was severely compromised beginning in early childhood. The retinal disease in this family is a severe form of retinitis pigmentosa (RP) accompanied by macular degeneration. Fundus changes advanced with age. Choriocapillaris atrophy and posterior RPE atrophy were obvious allowing visualization of the large choroidal vessels in patients over 40 years of age. Rod and cone responses on ERG recordings were extinguished in patient's teens. A genome-wide scan mapped the disease to a 34.7 cM region of chromosome 4p14-p16 between D4S1599 and D4S405. A maximum lod score of 3.96 with D4S403 and D4S391 is seen at theta = 0. Sequence analysis of PROM1 located in the linkage interval identified a c.1726C>T homozygous transition in exon 15: resulting in p.Gln576X in the translated protein. This mutation is found in a homozygous state in all six affected individuals and was heterozygous in five of the six unaffected family members examined. The mutation was not detected in 192 chromosomes of unrelated control individuals of the same ethnicity and from the same region. This delineates the phenotypic characteristics of retinopathy caused by mutations in PROM1.","variants":[{"Name":"NM_006017.3(PROM1):c.1726C>T (p.Gln576Ter)","Chromosome":"4","Start":"15994028","Stop":"15994028","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20648,"rule_based_match":true,"evidence_text":"c.1726C>T","llm_judgment":"PRESENT","evidence":"c.1726C>T","abstract_start":1069,"abstract_end":1078}]}
{"pmid":"14974080","title":"The role of cathepsin C in Papillon-Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis.","abstract":"We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon-Lefèvre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early-onset, severe periodontitis. Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations. The possible role of CTSC variants in more common types of non-mendelian, early-onset, severe periodontitis (\"aggressive periodontitis\") has not been investigated. In this study, we have investigated the role of CTSC in all three conditions. We demonstrate that PLS is genetically homogeneous and the mutation spectrum that includes three novel mutations (c.386T>A/p.V129E, c.935A>G/p.Q312R, and c.1235A>G/p.Y412C) in 21 PLS families (including eight from our previous study) provides an insight into structure-function relationships of CTSC. Our data also suggest that a complete loss-of-function appears to be necessary for the manifestation of the phenotype, making it unlikely that weak CTSC mutations are a cause of aggressive periodontitis. This was confirmed by analyses of the CTSC activity in 30 subjects with aggressive periodontitis and age-sex matched controls, which demonstrated that there was no significant difference between these two groups (1,728.7 +/- SD 576.8 micro moles/mg/min vs. 1,678.7 +/- SD 527.2 micro moles/mg/min, respectively, p = 0.73). CTSC mutations were detected in only one of two families with prepubertal periodontitis; these did not form a separate functional class with respect to those observed in classical PLS. The affected individuals in the other prepubertal periodontitis family not only lacked CTSC mutations, but in addition did not share the haplotypes at the CTSC locus. These data suggest that prepubertal periodontitis is a genetically heterogeneous disease that, in some families, just represents a partially penetrant PLS.","variants":[{"Name":"NM_001814.6(CTSC):c.386T>A (p.Val129Glu)","Chromosome":"11","Start":"88312487","Stop":"88312487","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":868931,"rule_based_match":true,"evidence_text":"c.386T>A/p.V129E","llm_judgment":"PRESENT","evidence":"c.386T>A/p.V129E","abstract_start":725,"abstract_end":741},{"Name":"NM_001814.6(CTSC):c.1235A>G (p.Tyr412Cys)","Chromosome":"11","Start":"88294163","Stop":"88294163","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":22339,"rule_based_match":true,"evidence_text":"c.1235A>G/p.Y412C","llm_judgment":"PRESENT","evidence":"c.1235A>G/p.Y412C","abstract_start":765,"abstract_end":782}]}
{"pmid":"32847536","title":"Hereditary hemorrhagic telangiectasia associated with cortical development malformation due to a start loss mutation in ENG.","abstract":"BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare disorder characterized by recurrent epistaxis, telangiectasias and systemic arteriovenous malformations (AVMs). HHT is associated with mutations in genes encoding for proteins involved in endothelial homeostasis such as ENG (endoglin) and ACVRL1 (activin receptor-like kinase-1).\nCASE PRESENTATION: Here we describe a 22-year-old male presenting with a transient episode of slurred speech and left arm paresis. Brain MRI displayed polymicrogyria. A right-to-left shunt in absence of an atrial septum defect was noted. Chest CT revealed multiple pulmonary AVMs, likely causing paradoxical embolism manifesting as a transient ischemic attack. The heterozygous ENG variant, c.3G > A (p.Met1lle), was detected in the patient. This variant was also found in patient's mother and in his younger brother who displayed cortical dysplasia type 2.\nCONCLUSIONS: The detection of cortical development malformations in multiple subjects from the same pedigree may expand the phenotypic features of ENG-related HHT patients. We suggest considering HHT in young patients presenting with acute cerebral ischemic events of unknown origin.","variants":[{"Name":"NM_001114753.3(ENG):c.3G>A (p.Met1Ile)","Chromosome":"9","Start":"127854353","Stop":"127854353","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2901378,"rule_based_match":true,"evidence_text":"c.3G > A (p.Met1lle)","llm_judgment":"PRESENT","evidence":"c.3G > A (p.Met1lle)","abstract_start":780,"abstract_end":800}]}
{"pmid":"30201532","title":"Paradoxical fall in proteinuria during pregnancy in an LCAT-deficient patient-A case report.","abstract":"A 29-year-old lady was diagnosed with lecithin:cholesterol acyltransferase (LCAT) deficiency having presented with bilateral corneal clouding, severely reduced high density lipoproteins cholesterol, and proteinuria. She is a compound heterozygote with two LCAT gene mutations, one of which is novel, c.321C>A in exon 3. Surprisingly, the level of proteinuria significantly improved during pregnancy, despite stopping the angiotensin-converting enzyme inhibitor. However, LCAT concentration and activity remained identical during pregnancy and postpartum. Her pregnancy was complicated by rising triglyceride levels from the second trimester requiring treatment with omega-3 fatty acid and fenofibrate. In the last trimester, a further complication arose when she became hypertensive and proteinuria worsened. She was diagnosed with pre-eclampsia and had an emergency cesarean section at 39 weeks delivering a healthy baby. This case adds to the knowledge of the pathophysiology of LCAT deficiency during pregnancy and will be useful in future patient management.","variants":[{"Name":"NM_000229.2(LCAT):c.321C>A (p.Tyr107Ter)","Chromosome":"16","Start":"67942967","Stop":"67942967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":18710,"rule_based_match":true,"evidence_text":"c.321C>A","llm_judgment":"PRESENT","evidence":"c.321C>A","abstract_start":300,"abstract_end":308}]}
{"pmid":"23849051","title":"Further evidence for germline BAP1 mutations predisposing to melanoma and malignant mesothelioma.","abstract":"We describe a new family with a novel germline BAP1 nonsense mutation, c.723T>G, which leads to a predicted truncated protein, p.Y241*, or nonsense-mediated decay of the BAP1 mRNA. The proband had uveal melanoma (UM), and his paternal family has a remarkable history of multiple cancers. The proband's father had both pleural malignant mesothelioma (MM) and cutaneous melanoma (CM); a paternal uncle had lung cancer, CM, and UM; and a grandmother had CM. The findings in this family provide further support for the existence of a BAP1 cancer syndrome that predisposes to MM, various melanocytic neoplasms, and potentially other cancers. The fact that several members of the family manifested two or more different types of cancer suggests widespread BAP1-related tumor susceptibility targeting tissues of multiple organs. In addition, a review of BAP1 cancer syndrome families reported to date indicates that the location of the BAP1 mutation does not have any bearing on the spectrum of cancer types observed, either for mesothelial or melanocytic tumors.","variants":[{"Name":"NM_004656.4(BAP1):c.723T>G (p.Tyr241Ter)","Chromosome":"3","Start":"52406313","Stop":"52406313","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3417408,"rule_based_match":true,"evidence_text":"c.723T>G","llm_judgment":"PRESENT","evidence":"c.723T>G","abstract_start":71,"abstract_end":79}]}
{"pmid":"36004946","title":"Neurodevelopmental disorder with microcephaly, ataxia, and seizures syndrome: expansion of the clinical spectrum.","abstract":"Neurodevelopmental disorder with microcephaly, ataxia, and seizures (NEDMAS) syndrome is a rare neurodevelopmental disorder characterized by moderate intellectual disability (ID), thin body habitus, microcephaly, seizures, ataxia, muscle weakness, and speech impairment. So far, only two families with NEDMAS have been reported. We report the clinical and molecular characteristics of three unrelated Turkish families with four NEDMAS patients. Whole-exome sequencing was used to search for the disease-causing variant. The main manifestations of the probands are severe developmental delay and ID, thin body habitus, and severe hypotonia. Brain imaging revealed bilateral cerebral and cerebellar diffuse atrophy. Sequencing results showed that both patients carried a novel missense variant c.1196C>T (p.Thr399Met) in the seryl-tRNA synthetase gene. Our findings help expand the variant spectrum of NEDMAS and provide additional information for diagnosing cases with atypical features.","variants":[{"Name":"NM_006513.4(SARS1):c.1196C>T (p.Thr399Met)","Chromosome":"1","Start":"109236487","Stop":"109236487","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2671402,"rule_based_match":true,"evidence_text":"c.1196C>T (p.Thr399Met)","llm_judgment":"PRESENT","evidence":"c.1196C>T (p.Thr399Met)","abstract_start":792,"abstract_end":815}]}
{"pmid":"31009165","title":"A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.","abstract":"A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.","variants":[{"Name":"NM_144670.6(A2ML1):c.4061+1G>C","Chromosome":"12","Start":"8868358","Stop":"8868358","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":608929,"rule_based_match":true,"evidence_text":"c.4061 + 1 G>C","llm_judgment":"PRESENT","evidence":"c.4061 + 1 G>C","abstract_start":766,"abstract_end":780}]}
{"pmid":"28336122","title":"Familial acute necrotizing encephalopathy with RANBP2 mutation: The first report in Northeast Asia.","abstract":"BACKGROUND: Acute necrotizing encephalopathy (ANE) is a rare but rapidly progressing encephalopathy following a febrile illness, commonly a viral infection. It is characterized by the features of acute encephalopathy such as seizure, alteration of consciousness, and symmetric involvement of the bilateral thalamus on neuroimaging tests. Although most ANE cases have occurred sporadically, familial or recurrent ANE has been reported in Caucasian patients, with genetic susceptibility to ANE noted in some patients due to a RANBP2 mutation. We report the cases of two Korean siblings with typical ANE and RANBP2 mutation.\nCASE REPORT: A 2year-old Korean girl presented with prolonged seizures and encephalopathy after two days of febrile illness. Brain computed tomography (CT) showed diffuse brain swelling and low attenuation in the bilateral thalamus. Two months later, her younger sister presented with lethargy and flurries of seizures after a Mycoplasma pneumoniae infection. Brain magnetic resonance imaging scan (MRI) showed a characteristic involvement of the bilateral thalamus, suggesting ANE. Although they received intravenous steroids and immunoglobulin, the older child died; her sister remained in a coma. Both were diagnosed with familial ANE after identifying a common missense mutation in RANBP2 (c.1754C>T: p.Thr585Met) in the younger sister and their father.\nCONCLUSIONS: This report is the first case of familial ANE in Northeast Asia identifying a RANBP2 mutation with poor outcome. Due to rapidly deterioration and recurrent nature of familial ANE, genetic test of RANBP2 mutation should be considered for early diagnosis. Further studies are needed to elucidate the nature of ANE.","variants":[{"Name":"NM_006267.5(RANBP2):c.1754C>T (p.Thr585Met)","Chromosome":"2","Start":"108751993","Stop":"108751993","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23402,"rule_based_match":true,"evidence_text":"c.1754C>T: p.Thr585Met","llm_judgment":"PRESENT","evidence":"c.1754C>T: p.Thr585Met","abstract_start":1316,"abstract_end":1338}]}
{"pmid":"29906059","title":"A Rare Case of Emberger Syndrome Caused By a De Novo Mutation in the GATA2 Gene.","abstract":"Emberger syndrome, or primary lymphedema with myelodysplasia, is a severe rare disease characterized by early primary lymphedema and blood anomalies including acute childhood leukemia. The syndrome is associated with heterozygous mutations in the GATA2 gene. We report on a 13-year-old boy who developed lymphedema of the right lower limb at age 6 years which was accompanied by severe panleukopenia and repeated episodes of erysipelas. The suspicion of Emberger syndrome was confirmed by detection of a new germinal line GATA2 mutation c.414_417del,\np.Ser139Cysfs*78. Clinical treatment included a bone marrow transplant from the father.This case is one of a very limited number of Emberger syndrome cases documented in the literature, and genetic testing proved fundamental\nfor definition of the condition and its association with a de novo mutation in the GATA2 which is reported here for the first time.","variants":[{"Name":"NM_032638.5(GATA2):c.414_417del (p.Ser139fs)","Chromosome":"3","Start":"128486181","Stop":"128486184","ReferenceAlleleVCF":"CAGAG","AlternateAlleleVCF":"C","allel_id":1173936,"rule_based_match":true,"evidence_text":"c.414_417del","llm_judgment":"PRESENT","evidence":"c.414_417del","abstract_start":537,"abstract_end":549}]}
{"pmid":"29051577","title":"De novo mutations of TUBA3D are associated with keratoconus.","abstract":"Keratoconus (KC) is a common degenerative corneal disease, and heredity plays a key role in its development. Although few genes are known to cause KC, a large proportion of disease-causing genes remain to be revealed. Here, we report the identification of TUBA3D as a novel gene linked to KC. Using whole-exome sequencing of a twins pedigree, a novel de novo mutation (c.31 C > T, p.Gln11stop) in TUBA3D gene was identified. A screening performed in 200 additional unrelated patients with KC revealed another two mutations (c.201insTT, p.Val68Leufs*2; c.*2 G > A) in two patients. TUBA3D was expressed highly in the cornea, and the twins had lower TUBA3D expression and higher UPA and MMP1 expressions than the normal parents. Through function prediction and in vitro cell experiment, we further demonstrated that the mutant proteins of TUBA3D were unstable and could lead to human corneal fibroblast cells performing higher MMPs expression and oxidative stress. These changes thus reduce the amount of extracellular matrices within corneas and undoubtedly play a major role in stromal thinning, which is characteristic of KC corneas. Our study showed that TUBA3D is a new gene that causes KC, thus supporting the evidence that this protein has an additional function into the human cornea.","variants":[{"Name":"NM_080386.4(TUBA3D):c.31C>T (p.Gln11Ter)","Chromosome":"2","Start":"131478191","Stop":"131478191","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":508703,"rule_based_match":true,"evidence_text":"c.31 C > T, p.Gln11stop","llm_judgment":"PRESENT","evidence":"c.31 C > T, p.Gln11stop","abstract_start":369,"abstract_end":392}]}
{"pmid":"34621841","title":"Congenital disorder of glycosylation caused by mutation of","abstract":"BACKGROUND: The <i>ATP6AP1</i> gene coding for the accessory protein Ac45 of the vacuolar-type adenosine triphosphatases (V-ATPase) is located on chromosome Xq28. Defects in certain subunits or accessory subunits of the V-ATPase can lead to congenital disorders of glycosylation (CDG). CDG is a group of metabolic disorders in which defective protein and lipid glycosylation processes affect multiple tissues and organs. Therefore, the clinical presentation of patients with <i>ATP6AP1</i>-CDG varies widely. In this report, we present a case of <i>ATP6AP1</i>-CDG in a Chinese infant, with clinical features and genotype.\nCASE SUMMARY: An 8-mo-old boy was admitted to our hospital because unexplained hepatosplenomegaly and elevated transaminases that had been noted while he was being treated for a cough at a local hospital. A post-admission examination at our hospital revealed abnormalities in the infant's liver, brain, and immune system. Trio-based whole exome gene analysis identified a hemizygous pathogenic mutation c.1036G>A (p.E346K) in exon 9 of the <i>ATP6AP1</i> gene. This variant of the <i>ATP6AP1</i> gene has not been reported in East Asian countries until now.\nCONCLUSION: Based on the infant's clinical manifestations and the results of genetic detection, he was clearly diagnosed with <i>ATP6AP1</i>-CDG. The clinical manifestations of children with CDG vary widely. Genetic testing analysis helps in the clinical diagnosis of children with CDG.","variants":[{"Name":"NM_001183.6(ATP6AP1):c.1036G>A (p.Glu346Lys)","Chromosome":"X","Start":"154435338","Stop":"154435338","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":237804,"rule_based_match":true,"evidence_text":"c.1036G>A (p.E346K)","llm_judgment":"PRESENT","evidence":"c.1036G>A (p.E346K)","abstract_start":1026,"abstract_end":1045}]}
{"pmid":"29791652","title":"Inflammatory myopathy in the context of an unusual overlapping laminopathy.","abstract":"Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.","variants":[{"Name":"NM_170707.4(LMNA):c.1634G>A (p.Arg545His)","Chromosome":"1","Start":"156137679","Stop":"156137679","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":172489,"rule_based_match":true,"evidence_text":"c.1634G>A (p.R545H)","llm_judgment":"PRESENT","evidence":"c.1634G>A (p.R545H)","abstract_start":1210,"abstract_end":1229}]}
{"pmid":"28738062","title":"Analysis of novel RUNX2 mutations in Chinese patients with cleidocranial dysplasia.","abstract":"Cleidocranial dysplasia (CCD) is an autosomal dominant inheritable skeletal disorder characterized by cranial dysplasia, clavicle hypoplasia and dental abnormalities. This disease is mainly caused by heterozygous mutations in RUNX2, a gene that encodes an osteoblast-specific transcription factor. In the present study, mutational analyses of RUNX2 gene were performed on four unrelated Chinese patients with CCD. Four different RUNX2 mutations were detected in these patients, including one nonsense mutation (c.199C>T p.Q67X) and three missense mutations (c.338T>G p.L113R, c.557G>C p.R186T and c.673C>T p.R225W). Among them, two mutations (c.199C>T p.Q67X and c.557G>C p.R186T) were novel and the other two had been reported in previous literatures. Except for Q67X mutation located in the Q/A domain, other three mutations were clustered within the highly conserved Runt domain. Green fluorescent protein (GFP) and RUNX2 fusion protein analyses in vitro showed that nuclear accumulation of RUNX2 protein was disturbed by Q67X mutation, while the other two mutations (c.338T>G p.L113R and c.557G>C p.R186T) had no effects on the subcellular distribution of RUNX2. Luciferase reporter assay demonstrated that all the three novel RUNX2 mutations significantly reduced the transactivation activity of RUNX2 on osteocalcin promoter. Our findings enrich the evidence of molecular genetics that the mutations of RUNX2 gene are responsible for CCD.","variants":[{"Name":"NM_001024630.4(RUNX2):c.199C>T (p.Gln67Ter)","Chromosome":"6","Start":"45422733","Stop":"45422733","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2904787,"rule_based_match":true,"evidence_text":"c.199C>T p.Q67X","llm_judgment":"PRESENT","evidence":"c.199C>T p.Q67X","abstract_start":511,"abstract_end":526}]}
{"pmid":"28795768","title":"Hereditary angioedema with a mutation in the plasminogen gene.","abstract":"BACKGROUND: Hereditary angioedema (HAE) with normal C1-INH (HAEnCI) may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or functional mutations in other genes that are still unknown. We sought to identify and characterize a hitherto unknown type of HAE with normal C1-INH and without mutation in the F12 gene.\nMETHODS: The study comprised analysis of whole-exome sequencing, Sanger sequencing, and clinical data of patients.\nRESULTS: We detected a mutation in the plasminogen (PLG) gene in patients with HAEnCI. The mutation c.988A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein. The mutation was identified by next-generation sequencing in 14 patients with HAEnCI belonging to 4 of 7 families. Family studies revealed that this type of HAE was transmitted as an autosomal dominant trait. The PLG gene mutation was present in all studied symptomatic patients and was also found in 9 of 38 index patients from 38 further families with HAEnCI. Most patients had swelling of face/lips (78.3%) and tongue (78.3%). A total of 331 of all 3.795 tongue swellings (8.7%) were associated with dyspnea, voice changes, and imminent asphyxiation. Two women died by asphyxiation due to a tongue swelling.\nCONCLUSIONS: Hereditary angioedema with a mutation in the PLG gene is a novel type of HAE. It is associated with a high risk of tongue swellings.","variants":[{"Name":"NM_000301.5(PLG):c.988A>G (p.Lys330Glu)","Chromosome":"6","Start":"160718730","Stop":"160718730","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":581232,"rule_based_match":true,"evidence_text":"The mutation c.988A>G","llm_judgment":"PRESENT","evidence":"The mutation c.988A>G","abstract_start":548,"abstract_end":569}]}
{"pmid":"38778342","title":"A case report of classic galactosemia with a GALT gene variant and a literature review.","abstract":"BACKGROUND: Galactosemia is an autosomal recessive disorder resulting from an enzyme defect in the galactose metabolic pathway. The most severe manifestation of classic galactosemia is caused by galactose-1-phosphate uridylyltransferase (GALT) deficiency, and this condition can be fatal during infancy if left untreated. It also may result in long-term complications in affected individuals.\nCASE PRESENTATION: This report describes a patient whose initial clinical symptoms were jaundice and liver dysfunction. The patient's liver and coagulation functions did not improve after multiple admissions and treatment with antibiotics, hepatoprotective and choleretic agents and blood transfusion. Genetic analysis revealed the presence of two variants in the GALT gene in the compound heterozygous state: c.377 + 2dup and c.368G > C (p.Arg123Pro). Currently, the variant locus (c.377 + 2dup) in the GALT gene has not been reported in the Human Gene Mutation Database (HGMD), while c.368G > C (p.Arg123Pro) has not been reported in the Genome Aggregation Database (GnomAD) nor the HGMD in East Asian population. We postulated that the two variants may contribute to the development of classical galactosemia.\nCONCLUSIONS: Applications of whole-exome sequencing to detect the two variants can improve the detection and early diagnosis of classical galactosemia and, more specifically, may identify individuals who are compound heterozygous with variants in the GALT gene. Variants in the GALT gene have a potential therapeutic significance for classical galactosemia.","variants":[{"Name":"NM_000155.4(GALT):c.368G>C (p.Arg123Pro)","Chromosome":"9","Start":"34647696","Stop":"34647696","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3540221,"rule_based_match":true,"evidence_text":"c.368G > C (p.Arg123Pro)","llm_judgment":"PRESENT","evidence":"c.368G > C (p.Arg123Pro)","abstract_start":820,"abstract_end":844}]}
{"pmid":"26204956","title":"Longitudinal follow up of a boy affected by Pol III-related leukodystrophy: a detailed phenotype description.","abstract":"BACKGROUND: The 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism) is a newly recognized leukodystrophy. The classical form is characterized by the association of hypomyelination, abnormal dentition, and hypogonadotropic hypogonadism, but the recent identification of two genes (POLR3A and POLR3B) responsible for the syndrome demonstrates that these three main characteristics can be variably combined among \"Pol-III (polymerase III)-related leukodystrophies.\"\nCASE PRESENTATION: We report on the clinical, neuroradiological and endocrinological follow-up of a male affected by 4H syndrome with confirmed POLR3B mutations (c.1568 T > A/p.V523E variant in exon 15 and the novel c.1988C > T/p.T663I mutation in exon 19). Spastic-ataxic gait with worsening of motor performance, progressive moderate intellectual disability and language difficulties were the main neurological findings observed. The first six years of substantial stability of the clinical and imaging features were followed by additional six years that showed a progressive worsening of motor, language and learning disabilities in relation to a progression of the cerebellar involvement. Hypogonadotropic hypogonadism and growth hormone deficiency followed by central hypocortisolism became part of the patient's phenotype. Thyroid function resulted unaffected during follow up.\nCONCLUSIONS: A novel mutation in POLR3B in a patient with an analogue phenotype than those previously described but with more extensive endocrinological features, including hypogonadotropic hypogonadism, growth hormone deficiency and hypocortisolism, was described. These findings permit to better define the clinical spectrum of the disease, to direct specific genetic tests and to tailor clinical management.","variants":[{"Name":"NM_018082.6(POLR3B):c.1568T>A (p.Val523Glu)","Chromosome":"12","Start":"106432421","Stop":"106432421","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":40123,"rule_based_match":true,"evidence_text":"c.1568 T > A/p.V523E","llm_judgment":"PRESENT","evidence":"c.1568 T > A/p.V523E","abstract_start":646,"abstract_end":666}]}
{"pmid":"21063070","title":"Cardiac ion channel gene mutations in Greek long QT syndrome patients.","abstract":"The long QT syndrome (LQTS) is an inherited cardiac arrhythmia that may lead to sudden death in the absence of structural heart disease. Mutations in the cardiac potassium and sodium channel genes can be found in approximately 70 percent of patients with a highly probable clinical diagnosis. In this study, we aimed to genotype and explore the yield of genetic testing of LQTS patients from Greece, for whom there are no collective published data available. We clinically evaluated and genetically screened 17 unrelated patients for mutations in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 cardiac ion channel genes. Genetic testing was positive in 6 out of 8 patients with a highly probable clinical diagnosis of LQTS and negative for all the other patients. Two patients carried KCNQ1 mutations (c.580G>C, c.1022C>T), while 4 patients carried KCNH2 mutations (c.202T>C, c.1714G>A, c.3103delC, c.3136C>T). To the best of our knowledge, the last mentioned mutation (c.3136C>T) is novel. Moreover, 27 single-nucleotide polymorphisms (SNPs) were detected, 5 of which are novel. Our preliminary data indicate a low genetic diversity of the Greek LQTS genetic pool, and are in accordance with international data that genetic testing of the major LQTS genes is efficient in genotyping the majority of patients with a strong clinical diagnosis. Therefore, the transition of an LQTS genetic screening program from research to the diagnostic setting within our ethnic background is feasible.","variants":[{"Name":"NM_000238.4(KCNH2):c.1714G>A (p.Gly572Ser)","Chromosome":"7","Start":"150951679","Stop":"150951679","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":78144,"rule_based_match":true,"evidence_text":"c.1714G>A","llm_judgment":"PRESENT","evidence":"c.1714G>A","abstract_start":871,"abstract_end":880},{"Name":"NM_000238.4(KCNH2):c.3136C>T (p.Gln1046Ter)","Chromosome":"7","Start":"150947344","Stop":"150947344","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1794880,"rule_based_match":true,"evidence_text":"c.3136C>T","llm_judgment":"PRESENT","evidence":"c.3136C>T","abstract_start":894,"abstract_end":903},{"Name":"NM_000218.3(KCNQ1):c.1022C>T (p.Ala341Val)","Chromosome":"11","Start":"2583535","Stop":"2583535","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18160,"rule_based_match":true,"evidence_text":"c.1022C>T","llm_judgment":"PRESENT","evidence":"c.1022C>T","abstract_start":807,"abstract_end":816}]}
{"pmid":"37095481","title":"Clinical and genetic characteristics of children with COX20-associated mitochondrial disorder: case report and literature review.","abstract":"BACKGROUND: The deficiency of cytochrome c oxidase 20 is a rare autosomal recessive mitochondrial disorder characterized by ataxia, dysarthria, dystonia and sensory neuropathy.\nCASE PRESENTATION: In this study, we describe a patient from a non-consanguineous family exhibiting developmental delay, ataxia, hypotonia, dysarthria, strabismus, visual impairment and areflexia. An examination of nerve conduction showed a normal result at first but revealed axonal sensory neuropathy later. This situation has not been reported in any literatures. The whole-exome sequencing analysis revealed that the patient harbored compound heterozygous mutations (c.41 A > G and c.259G > T) of the COX20 gene. By literature review, 5 patients carried the same compound heterozygous mutations.\nCONCLUSION: COX20 might be considered as a potential gene for the early-onset ataxia and the axonal sensory neuropathy. Our patient exhibited strabismus and visual impairment, which expands the clinical presentation of COX20 related mitochondrial disorders caused by the compound heterozygous variants (c.41 A > G and c.259G > T). However, a clear genotype/phenotype correlation has not yet been established. Additional researches and cases are needed to further confirm the correlation.","variants":[{"Name":"NM_198076.6(COX20):c.41A>G (p.Lys14Arg)","Chromosome":"1","Start":"244835755","Stop":"244835755","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":365161,"rule_based_match":true,"evidence_text":"c.41 A > G","llm_judgment":"PRESENT","evidence":"c.41 A > G","abstract_start":648,"abstract_end":658}]}
{"pmid":"33134517","title":"Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by","abstract":"OBJECTIVE: To expand the clinical phenotype of <i>POLR3A</i> mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.\nMETHODS: We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [<sup>1</sup>H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.\nRESULTS: The patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in <i>POLR3A</i>, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant.\nCONCLUSIONS: Mutations in the <i>POLR3A</i> gene cause <i>POLR3A</i>-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of <i>POLR3A</i>-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.","variants":[{"Name":"NM_007055.4(POLR3A):c.1771-6C>G","Chromosome":"10","Start":"78009681","Stop":"78009681","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":964843,"rule_based_match":true,"evidence_text":"c.1771-6C>G","llm_judgment":"PRESENT","evidence":"c.1771-6C>G","abstract_start":799,"abstract_end":810}]}
{"pmid":"23261175","title":"Consequences of partial duplications of the human CFTR gene on cf diagnosis: mutations or ectopic variations.","abstract":"CFTR exon 10 and its flanking regions are duplicated in the human genome. These duplications present mutations compared to the normal exon 10 sequence. Due to the polymorphic sequence of the 3' intron 9 sequence, it may appear difficult to sequence exon 10 and some mutations described in this exon could, in fact, be variations observed in an ectopic duplicated sequence. In our previous work we described a methodology to carry out PCR only of exon 10 and not of ectopic regions. In this work, we analyzed mutations described in the CF data base as being CFTR mutations but also found in ectopic regions: c.1392G>T, c.1338_1339delAT, c.1235delC, and c.1247A>G. We have shown that these mutations appear to be authentic mutations in CFTR exon 10 and not ectopic variations in analyzed patients. These mutations validate the usefulness of our new strategy in the mutation analysis of this region of CFTR.","variants":[{"Name":"NM_000492.4(CFTR):c.1392G>T (p.Lys464Asn)","Chromosome":"7","Start":"117548823","Stop":"117548823","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":67908,"rule_based_match":true,"evidence_text":"c.1392G>T","llm_judgment":"PRESENT","evidence":"c.1392G>T","abstract_start":607,"abstract_end":616},{"Name":"NM_000492.4(CFTR):c.1247A>G (p.Asn416Ser)","Chromosome":"7","Start":"117548678","Stop":"117548678","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":456084,"rule_based_match":true,"evidence_text":"c.1247A>G","llm_judgment":"PRESENT","evidence":"c.1247A>G","abstract_start":652,"abstract_end":661}]}
{"pmid":"23430932","title":"A Novel Mutation in CPT1A Resulting in Hepatic CPT Deficiency.","abstract":"The present work presents a \"from gene defect to clinics\" pathogenesis study of a patient with a hitherto unreported mutation in the CPT1A gene. In early childhood, the patient developed a life-threatening episode (hypoketotic hypoglycemia, liver cytolysis, and hepatomegaly) evocative of a mitochondrial fatty acid oxidation disorder, and presented deficient fibroblast carnitine palmitoyltransferase 1 (CPT1) activity and homozygosity for the c.1783 C > T nucleotide substitution on exon 15 of CPT1A (p.R595W mutant). While confirming CPT1A deficiency, whole blood de novo acylcarnitine synthesis and the levels of carnitine and its esters formally linked intracellular free-carnitine depletion to intracellular carnitine esterification. Sequence alignment and modeling of wild-type and p.*R595W CPT1A proteins indicated that the Arg595 targeted by the mutated codon is phylogenetically well conversed. It contributes to a hydrogen bond network with neighboring residues Cys304 and Met593 but does not participate in the catalysis and carnitine pocket. Its replacement by tryptophan induces steric hindrance with the side chain of Ile480 located in α-helix 12, affecting protein architecture and function. This hindrance with Ile480 is also originally described with tryptophan 304 in the known mutant p.C304W CPT1A, suggesting that the mechanisms that invalidate CPT1A activity and underlie pathogenesis could be common in both the new (p.R595W) and previously described (p.C304W) mutants.","variants":[{"Name":"NM_001876.4(CPT1A):c.1783C>T (p.Arg595Trp)","Chromosome":"11","Start":"68762719","Stop":"68762719","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2898701,"rule_based_match":true,"evidence_text":"c.1783 C > T (p.R595W mutant)","llm_judgment":"PRESENT","evidence":"p.R595W","abstract_start":503,"abstract_end":510}]}
{"pmid":"36756224","title":"A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.","abstract":"ALG6-CDG is a rare, but second most common, type 1 congenital disorder of glycosylation (CDG) caused by a defect in the α-1-3-glucosyltransferase (ALG6) enzyme in the N-glycan assembly pathway. Many mutations have been identified and inherited in an autosomal recessive pattern. There are less than 100 ALG6-CDG cases reported, all sharing the phenotype of hypotonia and developmental delay. The majority (perhaps >70%) have seizures, but a minority have intractable epilepsy or epileptic encephalopathy. We report the clinical course, EEG findings, and neuroimaging of a child found to have compound heterozygous alleles c.257 + 5G > A and c.680G > A (p.G227E) who developed explosive onset of intractable epilepsy and epileptic encephalopathy. Initially, CDG was not suspected due to its rarity and lack of multi-organ system involvement, but rapid whole exam sequence (8-day turnaround) revealed the specific diagnosis quickly.","variants":[{"Name":"NM_013339.4(ALG6):c.680G>A (p.Gly227Glu)","Chromosome":"1","Start":"63411331","Stop":"63411331","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":365439,"rule_based_match":true,"evidence_text":"c.680G > A (p.G227E)","llm_judgment":"PRESENT","evidence":"c.680G > A (p.G227E)","abstract_start":641,"abstract_end":661}]}
{"pmid":"23954390","title":"Co-occurrence of multiple sclerosis and cancer in a BRCA1 positive family.","abstract":"Multiple sclerosis is not known to be a risk factor for subsequent development of cancer. Recently, a multiple sclerosis locus was mapped adjacent to BRCA1 gene. We present a familial case affected by multiple sclerosis and cancer. We identified a c.5266dupC (5382insC) frameshift mutation in a 33-year-old woman with breast cancer, multiple malignant melanomas and multiple sclerosis. The patient's family history shows further cases of multiple sclerosis in BRCA1 mutation carriers. Therefore the presented family may carry a monogenic predisposition for multiple sclerosis nearby to BRCA1.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"c.5266dupC (5382insC)","llm_judgment":"PRESENT","evidence":"c.5266dupC (5382insC)","abstract_start":248,"abstract_end":269}]}
{"pmid":"32142096","title":"Three Mexican Families with β thalassemia intermedia with different molecular basis.","abstract":"Beta thalassemia (β-thal) is a frequent monogenic disease, is clinically and molecularly heterogeneous. This study described molecular and laboratory findings for three Mexican patients with β-thal intermedia phenotype and their relatives. Three Mexican families were studied for presenting β-thal intermedia, ARMS-PCR and Gap-PCR were performed to screen for common mutations, Sanger sequencing for rare or new alleles, and MLPA for identifying deletions and or duplications. In all three families we observed, in heterozygote condition, the mutation c.118C > T (p.Gln39*) also known as codon 39(C > T) in the β globin gene (HBB) associated with a novel molecular defect: a new duplication of the alpha globin gene cluster, a new deletion that includes the loss of exon 3 of HBB and finally a novel mutation in the 3'UTR of HBB (HBB: c.*132C > A). We report three Mexican families with beta thalassemia intermedia due to different molecular basis; a new single nucleotide mutation involving the last nucleotide of the β-globin chain transcript; and two possible new DNA rearrangements, an α cluster duplication, and a partial β gene deletion.","variants":[{"Name":"NM_000518.5(HBB):c.*132C>A","Chromosome":"11","Start":"5225466","Stop":"5225466","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1335191,"rule_based_match":true,"evidence_text":"HBB: c.*132C > A","llm_judgment":"PRESENT","evidence":"HBB: c.*132C > A","abstract_start":830,"abstract_end":846}]}
{"pmid":"20361015","title":"A novel mutation in the major intrinsic protein (MIP) associated with autosomal dominant congenital cataracts in a Chinese family.","abstract":"PURPOSE: To detect the underlying genetic defect in a Chinese family affected with bilateral congenital cataracts.\nMETHODS: A detailed family history and clinical data were recorded. Mutation screening was performed in the nuclear cataract-related gene by bidirectional sequencing of the amplified products. The mutation was verified by denaturing high-performance liquid chromatography (DHPLC).\nRESULTS: Two cataract phenotypes were observed within this family: one eye exhibited Y-suture and nuclear pulverulent opacification of the lens, while the others exhibited complete opacification in the fetal nuclear region. Sequencing of the candidate genes detected a heterozygous c.319G>A change in the coding region of the major intrinsic protein (MIP), resulting in the substitution of a highly conserved Valine by Isoleucine (p.V107I).The mutation was confirmed by DHPLC.\nCONCLUSIONS: This study has identified a novel MIP mutation, p.V107I in a Chinese family with congenital cataracts. To the best of our knowledge, this is the first reported case of cataracts caused by a mutation in the second extracellular loop domain of MIP.","variants":[{"Name":"NM_012064.4(MIP):c.319G>A (p.Val107Ile)","Chromosome":"12","Start":"56454295","Stop":"56454295","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":254635,"rule_based_match":true,"evidence_text":"c.319G>A","llm_judgment":"PRESENT","evidence":"c.319G>A","abstract_start":678,"abstract_end":686}]}
{"pmid":"28670130","title":"Four novel","abstract":"Metachromatic leukodystrophy (MLD) disorder is a rare lysosomal storage disorder that leads to severe neurological symptoms and an early death. MLD occurs due to the deficiency of enzyme arylsulfatase A (ARSA) in leukocytes, and patients with MLD excrete sulfatide in their urine. In this study, the <i>ARSA</i> gene in 12 non-consanguineous MLD patients and 40 healthy individuals was examined using polymerase chain reaction sequencing. Furthermore, the structural and functional effects of new mutations on <i>ARSA</i> were analyzed using SIFT (sorting intolerant from tolerant), I-Mutant 2, and PolyPhen bioinformatics software. Here, 4 new pathogenic homozygous mutations c.585G>T, c.661T>A, c.849C>G, and c.911A>G were detected. The consequence of this study has extended the genotypic spectrum of MLD patients, paving way to a more effective method for carrier detection and genetic counseling.","variants":[{"Name":"NM_000487.6(ARSA):c.585G>T (p.Trp195Cys)","Chromosome":"22","Start":"50626933","Stop":"50626933","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":99032,"rule_based_match":true,"evidence_text":"c.585G>T","llm_judgment":"PRESENT","evidence":"c.585G>T","abstract_start":677,"abstract_end":685}]}
{"pmid":"32695102","title":"Partial Purine Nucleoside Phosphorylase Deficiency Helps Determine Minimal Activity Required for Immune and Neurological Development.","abstract":"<b>Introduction:</b> Complete or near complete absence of the purine nucleoside phosphorylase (PNP) enzyme causes a profound T cell immunodeficiency and neurological abnormalities that are often lethal in infancy and early childhood. We hypothesized that patients with partial PNP deficiency, characterized by a late and mild phenotype due to residual PNP enzyme, would provide important information about the minimal PNP activity needed for normal development. <b>Methods:</b> Three siblings with a homozygous <i>PNP</i> gene mutation (c.769C>G, p.His257Asp) resulting in partial PNP deficiency were investigated. PNP activity was semi-quantitively assayed by the conversion of [14C]inosine in hemolysates, mononuclear cells, and lymphoblastoid B cells. PNP protein expression was determined by Western Blotting in lymphoblastoid B cells. DNA repair was quantified by measuring viability of lymphoblastoid B cells following ionizing irradiation. <b>Results:</b> A 21-year-old female was referred for recurrent sino-pulmonary infections while her older male siblings, aged 25- and 28- years, did not suffer from significant infections. Two of the siblings had moderately reduced numbers of T, B, and NK cells, while the other had near normal lymphocyte subset numbers. T cell proliferations were normal in the two siblings tested. Hypogammaglobulinemia was noted in two siblings, including one that required immunoglobulin replacement. All siblings had typical (normal) neurological development. PNP activity in various cells from two patients were 8-11% of the normal level. All siblings had normal blood uric acid and increased PNP substrates in the urine. PNP protein expression in cells from the two patients examined was similar to that observed in cells from healthy controls. The survival of lymphoblastoid B cells from 2 partial PNP-deficient patients after irradiation was similar to that of PNP-proficient cells and markedly higher than the survival of cells from a patient with absent PNP activity or a patient with ataxia telangiectasia. <b>Conclusions:</b> Patients with partial PNP deficiency can present in the third decade of life with mild-moderate immune abnormalities and typical development. Near-normal immunity might be achieved with relatively low PNP activity.","variants":[{"Name":"NM_000270.4(PNP):c.769C>G (p.His257Asp)","Chromosome":"14","Start":"20476500","Stop":"20476500","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":624472,"rule_based_match":true,"evidence_text":"c.769C>G, p.His257Asp","llm_judgment":"PRESENT","evidence":"c.769C>G, p.His257Asp","abstract_start":537,"abstract_end":558}]}
{"pmid":"24315819","title":"Infantile-onset ascending hereditary spastic paraplegia with bulbar involvement due to the novel ALS2 mutation c.2761C>T.","abstract":"Recessive mutations in the alsin gene cause three clinically distinct motor neuron diseases: juvenile amyotrophic lateral sclerosis (ALS2), juvenile primary lateral sclerosis (JPLS) and infantile-onset ascending hereditary spastic paraplegia (IAHSP). A total of 23 different ALS2 mutations have been described for the three disorders so far. Most of these mutations result in a frameshift leading to a premature truncation of the alsin protein. We report the novel ALS2 truncating mutation c.2761C>T; p.R921X detected by homozygosity mapping and sequencing in two infants affected by IAHSP with bulbar involvement. The mutation c.2761C>T resides in the pleckstrin domain, a characteristic segment of guanine nucleotide exchange factors of the Rho GTPase family, which is involved in the overall neuronal development or maintenance. This study highlights the importance of using homozygosity mapping combined with candidate gene analysis to identify the underlying genetic defect as in this Saudi consanguineous family.","variants":[{"Name":"NM_020919.4(ALS2):c.2761C>T (p.Arg921Ter)","Chromosome":"2","Start":"201728592","Stop":"201728592","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":106525,"rule_based_match":true,"evidence_text":"c.2761C>T","llm_judgment":"PRESENT","evidence":"c.2761C>T","abstract_start":490,"abstract_end":499}]}
{"pmid":"26148547","title":"A novel homozygous variant in the dsp gene underlies the first case of non-syndromic form of alopecia.","abstract":"Autosomal recessive forms of hair loss (alopecia) disorders have previously been associated with variants in at least five different genes including hairless (HR), desmoglein-4 (DSG4), desmocollin-3 (DSC3), lipase-H (LIPH), and lysophosphatidic acid receptor 6 (LPAR6). Here, we report the first familial case of alopecia resulting from a novel homozygous variant in the DSP gene. Since previous reports indicated the presence of heart abnormalities in patients carrying variants in the DSP gene; therefore, the echocardiographic evaluations of all affected members were performed. The results clearly excluded the presence of any form of heart abnormality in patients of the present family. Human genome scan mapped a disease locus on chromosome 6p25.1-p23, harboring DSP gene. Sequence analysis identified a novel homozygous missense variant [c.1493C > T (p.Pro498Leu)] in the DSP gene as the underlying genetic cause of non-syndromic alopecia in the family. The transition alters the completely conserved Pro498 residue in the SH3 domain of plakin that contributes to the stability and rigidity of this subfamily of spectrin repeats (SRs) containing proteins. Our study strengthens the evidence that hereditary hair loss disorders are genetically heterogeneous and imply that isolated form of alopecia is allelic with cardiocutaneous syndromes.","variants":[{"Name":"NM_004415.4(DSP):c.1493C>T (p.Pro498Leu)","Chromosome":"6","Start":"7569259","Stop":"7569259","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":832463,"rule_based_match":true,"evidence_text":"c.1493C > T (p.Pro498Leu)","llm_judgment":"PRESENT","evidence":"c.1493C > T (p.Pro498Leu)","abstract_start":845,"abstract_end":870}]}
{"pmid":"22723944","title":"Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.","abstract":"Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.","variants":[{"Name":"NM_000520.6(HEXA):c.340G>A (p.Glu114Lys)","Chromosome":"15","Start":"72356531","Stop":"72356531","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215043,"rule_based_match":true,"evidence_text":"c.340 G>A (p.E114K)","llm_judgment":"PRESENT","evidence":"c.340 G>A (p.E114K)","abstract_start":1347,"abstract_end":1366},{"Name":"NM_000520.6(HEXA):c.805+1G>C","Chromosome":"15","Start":"72350517","Stop":"72350517","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":362122,"rule_based_match":true,"evidence_text":"c.805+1 G>C","llm_judgment":"PRESENT","evidence":"c.805+1 G>C","abstract_start":1697,"abstract_end":1708},{"Name":"NM_000520.6(HEXA):c.964G>T (p.Asp322Tyr)","Chromosome":"15","Start":"72349101","Stop":"72349101","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":222993,"rule_based_match":true,"evidence_text":"c.964 G>T (p.D322Y)","llm_judgment":"PRESENT","evidence":"c.964 G>T (p.D322Y)","abstract_start":1389,"abstract_end":1408},{"Name":"NM_000520.6(HEXA):c.508C>T (p.Arg170Trp)","Chromosome":"15","Start":"72353130","Stop":"72353130","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18964,"rule_based_match":true,"evidence_text":"c.508C>T (p.R170W)","llm_judgment":"PRESENT","evidence":"c.508C>T (p.R170W)","abstract_start":1538,"abstract_end":1556},{"Name":"NM_000520.6(HEXA):c.1385A>T (p.Glu462Val)","Chromosome":"15","Start":"72346271","Stop":"72346271","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":214781,"rule_based_match":true,"evidence_text":"c.1385A>T (p.E462V)","llm_judgment":"PRESENT","evidence":"c.1385A>T (p.E462V)","abstract_start":1434,"abstract_end":1453}]}
{"pmid":"23656646","title":"WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta.","abstract":"This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T→G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C→A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.","variants":[{"Name":"NM_005430.4(WNT1):c.652T>G (p.Cys218Gly)","Chromosome":"12","Start":"48981179","Stop":"48981179","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":65585,"rule_based_match":false,"evidence_text":"c.652T→G (p.Cys218Gly)","llm_judgment":"PRESENT","evidence":"c.652T→G (p.Cys218Gly)","abstract_start":212,"abstract_end":234},{"Name":"NM_005430.4(WNT1):c.884C>A (p.Ser295Ter)","Chromosome":"12","Start":"48981411","Stop":"48981411","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":59407,"rule_based_match":false,"evidence_text":"c.884C→A, p.Ser295*","llm_judgment":"PRESENT","evidence":"c.884C→A, p.Ser295*","abstract_start":366,"abstract_end":385}]}
{"pmid":"27413738","title":"Diagnosis of Xeroderma Pigmentosum Groups A and C by Detection of Two Prevalent Mutations in West Algerian Population: A Rapid Genotyping Tool for the Frequent XPC Mutation c.1643_1644delTG.","abstract":"Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder. Considering that XP patients have a defect of the nucleotide excision repair (NER) pathway which enables them to repair DNA damage caused by UV light, they have an increased risk of developing skin and eyes cancers. In the present study, we investigated the involvement of the prevalent XPA and XPC genes mutations-nonsense mutation (c.682C>T, p.Arg228X) and a two-base-pair (2 bp) deletion (c.1643_1644delTG or p.Val548Ala fsX25), respectively-in 19 index cases from 19 unrelated families in the West of Algeria. For the genetic diagnosis of XPA gene, we proceeded to PCR-RFLP. For the XPC gene, we validated a routine analysis which includes a specific amplification of a short region surrounding the 2 bp deletion using a fluorescent primer and fragment sizing (GeneScan size) on a sequencing gel. Among the 19 index cases, there were 17 homozygous patients for the 2 bp deletion in the XPC gene and 2 homozygous patients carrying the nonsense XPA mutation. Finally, XPC appears to be the major disease-causing gene concerning xeroderma pigmentosum in North Africa. The use of fragment sizing is the simplest method to analyze this 2 bp deletion for the DNA samples coming from countries where the mutation c.1643_1644delTG of XPC gene is prevalent.","variants":[{"Name":"NM_000380.4(XPA):c.682C>T (p.Arg228Ter)","Chromosome":"9","Start":"97675579","Stop":"97675579","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16034,"rule_based_match":true,"evidence_text":"c.682C>T, p.Arg228X","llm_judgment":"PRESENT","evidence":"c.682C>T, p.Arg228X","abstract_start":401,"abstract_end":420},{"Name":"NM_004628.5(XPC):c.1643_1644del (p.Val548fs)","Chromosome":"3","Start":"14158239","Stop":"14158240","ReferenceAlleleVCF":"GCA","AlternateAlleleVCF":"G","allel_id":15301,"rule_based_match":true,"evidence_text":"c.1643_1644delTG","llm_judgment":"PRESENT","evidence":"c.1643_1644delTG","abstract_start":459,"abstract_end":475}]}
{"pmid":"34215320","title":"PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations.","abstract":"BACKGROUND: The role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported.\nMETHODS: We report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients.\nRESULTS: All patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient's fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients.\nCONCLUSIONS: We provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.","variants":[{"Name":"NM_181697.3(PRDX1):c.515-1G>T","Chromosome":"1","Start":"45511415","Stop":"45511415","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":486708,"rule_based_match":true,"evidence_text":"PRDX1:c.515-1G > T","llm_judgment":"PRESENT","evidence":"PRDX1:c.515-1G > T","abstract_start":1290,"abstract_end":1308}]}
{"pmid":"32612965","title":"Left Bundle Pacing for Left Bundle Branch Block and Intermittent Third-Degree Atrioventricular Block in a","abstract":"Hypertrophic cardiomyopathy (HCM) is a group of myocardial diseases defined by cardiac hypertrophy which cannot be explained by secondary causes with a non-dilated left ventricle and preserved or increased ejection fraction. Sometimes it can be combined with restrictive cardiomyopathy. Here we describe a very rare case of a 12-year-old girl with non-obstructive hypertrophic cardiomyopathy accompanied by restrictive phenotype, complete left bundle branch block and intermittent third-degree atrioventricular block, who presented with recurrent syncope. Her father was also found to have hypertrophic cardiomyopathy and treated with implantable cardioverter defibrillator for ventricular tachycardia. Her younger brother is currently asymptomatic but echocardiogram showed hypertrophic cardiomyopathy. Genetic analysis identified a heterozygous missense mutation (c.2155C>T, p.R719W) of <i>MYH7</i> in the proband girl, her father and her brother. The girl was treated with left bundle pacing and recovered well. The case we present further demonstrates the feasibility of left bundle pacing in children.","variants":[{"Name":"NM_000257.4(MYH7):c.2155C>T (p.Arg719Trp)","Chromosome":"14","Start":"23425971","Stop":"23425971","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29143,"rule_based_match":true,"evidence_text":"c.2155C>T, p.R719W","llm_judgment":"PRESENT","evidence":"c.2155C>T, p.R719W","abstract_start":866,"abstract_end":884}]}
{"pmid":"36190515","title":"Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.","abstract":"Maintaining protein lipoylation is vital for cell metabolism. The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system, intersecting two vital roles for cell survival. Here, we report six patients with biallelic pathogenic variants in GCSH and a broad clinical spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated phenotype of developmental delay, behavioral problems, limited epilepsy and variable movement problems. The mutational spectrum includes one insertion c.293-2_293-1insT, one deletion c.122_(228 + 1_229-1) del, one duplication of exons 4 and 5, one nonsense variant p.Gln76*and four missense p.His57Arg, p.Pro115Leu and p.Thr148Pro and the previously described p.Met1?. Via functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies, we demonstrate for the first time that most variants identified in our cohort produced a hypomorphic effect on both mitochondrial activities, protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affect primarily one function only. The clinical features of the patients reflect the impact of the GCSH changes on any of the two functions analyzed. Our analysis illustrates the complex interplay of functional and clinical impact when pathogenic variants affect a multifunctional protein involved in two metabolic pathways and emphasizes the value of the functional assays to select the treatment and investigate new personalized options.","variants":[{"Name":"NM_004483.5(GCSH):c.293-2_293-1insT","Chromosome":"16","Start":"81084595","Stop":"81084596","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":2671395,"rule_based_match":true,"evidence_text":"c.293-2_293-1insT","llm_judgment":"PRESENT","evidence":"c.293-2_293-1insT","abstract_start":694,"abstract_end":711},{"Name":"NM_004483.5(GCSH):c.170A>G (p.His57Arg)","Chromosome":"16","Start":"81090659","Stop":"81090659","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2671398,"rule_based_match":false,"evidence_text":"c.170A>G (p.His57Arg)","llm_judgment":"PRESENT","evidence":"p.His57Arg","abstract_start":834,"abstract_end":844},{"Name":"NM_004483.5(GCSH):c.344C>T (p.Pro115Leu)","Chromosome":"16","Start":"81084543","Stop":"81084543","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2671401,"rule_based_match":false,"evidence_text":"c.344C>T (p.Pro115Leu)","llm_judgment":"PRESENT","evidence":"p.Pro115Leu","abstract_start":846,"abstract_end":857}]}
{"pmid":"16081310","title":"Phenotypic heterogeneity in the presentation of D-2-hydroxyglutaric aciduria in monozygotic twins.","abstract":"D-2-hydroxyglutaric aciduria (D-2-HGA) is a very rare autosomal recessive metabolic disorder that has recently been associated with mutations in the D-2-hydroxyglutarate dehydrogenase gene. The biochemical phenotype of D-2-HGA is defined by the accumulation of abnormal amounts of D-2-hydroxyglutarate in cerebrospinal fluid, blood, and urine while the clinical phenotype can vary from a severe epileptic encephalopathy to normal. The basis for this phenotypic variation is not well-defined. We report a set of 412-year-old monozygotic (MZ) female twins with D-2-hydroxyglutaric aciduria who are shown to be compound heterozygotes for c.326-327dupTC, p.Glu110ArgfsX19, and c.1123G-->T, p.Asp375Tyr mutations in the D-2-hydroxyglutarate dehydrogenase gene, but who have remarkably different clinical phenotypes. One twin presented with multiple congenital anomalies, severe developmental delay, and abnormal neuroradiological findings, while the other had normal neurocognitive and neuroradiological phenotypes, without concomitant congenital abnormalities. Monozygosity of these twins implies that the differences in the clinical phenotype arise from postzygotic genetic changes, epigenetic differences, or environmental factors that influence the phenotypic response to biochemical perturbation rather than allelic or locus heterogeneity. Though the mechanistic role of these factors in D-2-HGA is far from apparent, the discordance in the phenotypes of these siblings establishes that these factors are at least as important as the nature of the mutant alleles in influencing the progression of the disorder.","variants":[{"Name":"NM_152783.5(D2HGDH):c.1123G>T (p.Asp375Tyr)","Chromosome":"2","Start":"241751371","Stop":"241751371","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":16897,"rule_based_match":false,"evidence_text":"c.1123G-->T, p.Asp375Tyr","llm_judgment":"PRESENT","evidence":"c.1123G-->T, p.Asp375Tyr","abstract_start":673,"abstract_end":697}]}
{"pmid":"30352563","title":"Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report.","abstract":"BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM #611105) is a genetic disease of the central nervous system characterized by lower limb spasticity, cerebellar ataxia and involvement of the dorsal column. The disease is caused by mutations in the DARS2 gene but has never been reported in sub-Saharan Africa so far.\nCASE PRESENTATION: Two siblings, aged 18 years and 15 years, from a consanguineous family presented with pyramidal signs and symptoms since infancy and developmental delay. Whole exome sequencing of the proband identified two compound heterozygous variants (NM_018122.4:c.1762C > G and c.563G > A) in DARS2. Sanger sequencing confirmed the presence of the mutations and their segregation in trans in both patients and in their elder sister (aged 20 years), who showed only brisk reflexes and mild lower limb spasticity. Surprisingly, in contrast to her subtle clinical presentation, the elder sister had abnormal MRI features and serum lactate levels comparable to her ill sisters.\nCONCLUSION: This report illustrates intra-familial phenotypic variation in LBSL and provides an example of a marked dissociation between the clinical and radiological phenotypes of the disease. This may have implications for the detection of mutation carriers in LBSL.","variants":[{"Name":"NM_018122.5(DARS2):c.1762C>G (p.Leu588Val)","Chromosome":"1","Start":"173857529","Stop":"173857529","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":414746,"rule_based_match":true,"evidence_text":"NM_018122.4:c.1762C > G","llm_judgment":"PRESENT","evidence":"NM_018122.4:c.1762C > G","abstract_start":634,"abstract_end":657},{"Name":"NM_018122.5(DARS2):c.563G>A (p.Arg188Gln)","Chromosome":"1","Start":"173833446","Stop":"173833446","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":682589,"rule_based_match":true,"evidence_text":"c.563G > A","llm_judgment":"PRESENT","evidence":"c.563G > A","abstract_start":662,"abstract_end":672}]}
{"pmid":"38503300","title":"Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.","abstract":"Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.","variants":[{"Name":"NM_002801.4(PSMB10):c.601G>A (p.Gly201Arg)","Chromosome":"16","Start":"67934906","Stop":"67934906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3400945,"rule_based_match":true,"evidence_text":"c.601G>A (p.Gly201Arg)","llm_judgment":"PRESENT","evidence":"p.Gly201Arg","abstract_start":1088,"abstract_end":1099},{"Name":"NM_002801.4(PSMB10):c.601G>C (p.Gly201Arg)","Chromosome":"16","Start":"67934906","Stop":"67934906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3400946,"rule_based_match":true,"evidence_text":"c.601G>C (p.Gly201Arg)","llm_judgment":"PRESENT","evidence":"p.Gly201Arg","abstract_start":1088,"abstract_end":1099},{"Name":"NM_002801.4(PSMB10):c.166G>C (p.Asp56His)","Chromosome":"16","Start":"67936291","Stop":"67936291","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3400947,"rule_based_match":true,"evidence_text":"c.166G>C [p.Asp56His]","llm_judgment":"PRESENT","evidence":"c.166G>C [p.Asp56His]","abstract_start":1043,"abstract_end":1064}]}
{"pmid":"24715918","title":"Diabetic Dead-in-Bed Syndrome: A Possible Link to a Cardiac Ion Channelopathy.","abstract":"Sudden unexpected nocturnal death among patients with diabetes occurs approximately ten times more commonly than in the general population. Malignant ventricular arrhythmia due to Brugada syndrome has been postulated as a cause, since a glucose-insulin bolus can unmask the Brugada electrocardiographic signature in genetically predisposed individuals. In this report we present a 16-year-old male with insulin-dependent diabetes who died suddenly at night. His diabetes had been well controlled, without significant hypoglycaemia. At autopsy, he had a full stomach and a glucose level of 7 mmol/L in vitreous humor, excluding hypoglycaemia. Genetic analysis of autopsy DNA revealed a missense mutation, c.370A>G (p.Ile124Val), in the GPD1L gene. A parent carried the same mutation and has QT prolongation. Mutations in this gene have been linked to Brugada syndrome and sudden infant death. The patient may have died from a ventricular arrhythmia, secondary to occult Brugada syndrome, triggered by a full stomach and insulin. The data suggest that molecular autopsies are warranted to investigate other cases of the diabetic dead-in-bed syndrome.","variants":[{"Name":"NM_015141.4(GPD1L):c.370A>G (p.Ile124Val)","Chromosome":"3","Start":"32140231","Stop":"32140231","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15827,"rule_based_match":true,"evidence_text":"c.370A>G (p.Ile124Val)","llm_judgment":"PRESENT","evidence":"c.370A>G (p.Ile124Val)","abstract_start":704,"abstract_end":726}]}
{"pmid":"31568715","title":"Characterization of the renal phenotype in RMND1-related mitochondrial disease.","abstract":"BACKGROUND: The nuclear encoded gene RMND1 (Required for Meiotic Nuclear Division 1 homolog) has recently been linked to RMND1-related mitochondrial disease (RRMD). This autosomal recessive condition characteristically presents with an infantile-onset multisystem disease characterized by severe hypotonia, global developmental delay, failure to thrive, sensorineural hearing loss, and lactic acidosis. Renal disease, however, appears to be one of the more prominent features of RRMD, affecting patients at significantly higher numbers compared to other mitochondrial diseases. We report the clinical, histological, and molecular findings of four RRMD patients across three academic institutions with a focus on the renal manifestations.\nMETHODS: Four patients were identified for the purpose of this study, all of whom had molecular confirmation at the time of inclusion, which included the common pathogenic variant c.713A>G (p.N238S) as well as the three rare variants: c.485delC (p.P162fs), c.533C>T (p.T178M), and c.1317 + 1G>C splice donor variant. Medical history and laboratory findings were collected from the medical records and medical providers.\nRESULTS: In this study, all four patients developed renal disease characterized as tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end-stage renal disease (4/4) necessitating renal transplantation (2/4). Histological evaluation of renal biopsy specimens revealed generalized tubular atrophy and on electron microscopy, abundant mitochondria with pleomorphism and abnormal cristae.\nCONCLUSION: Our experience with RRMD demonstrates a specific pattern of renal disease manifestations and clinical course. Patients are unlikely to respond to traditional chronic kidney disease (CKD) treatments, making early diagnosis and consideration of renal transplantation paramount to the management of RRMD.","variants":[{"Name":"NM_017909.4(RMND1):c.533C>T (p.Thr178Met)","Chromosome":"6","Start":"151436526","Stop":"151436526","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1867951,"rule_based_match":true,"evidence_text":"c.533C>T (p.T178M)","llm_judgment":"PRESENT","evidence":"c.533C>T (p.T178M)","abstract_start":995,"abstract_end":1013},{"Name":"NM_017909.4(RMND1):c.713A>G (p.Asn238Ser)","Chromosome":"6","Start":"151430154","Stop":"151430154","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":171703,"rule_based_match":true,"evidence_text":"c.713A>G (p.N238S)","llm_judgment":"PRESENT","evidence":"c.713A>G (p.N238S)","abstract_start":918,"abstract_end":936}]}
{"pmid":"27133709","title":"Clinical and Genetic Characterization of 26 Tunisian Patients with Allgrove Syndrome.","abstract":"BACKGROUND AND AIMS: Allgrove syndrome is characterized by achalasia, alacrima, and adrenal insufficiency as well as being associated with progressive neurological signs. This is an autosomal recessive disorder due to mutations in the AAAS gene located on chromosome 12q13. The AAAS gene encodes a protein of 546 amino acids, ALADIN. Mutations in this genwere reported in families from North Africa and Europe. Our objective is to conduct a clinical, molecular and genetic study of 26 Tunisian patients with Allgrove syndrome.\nMETHODS: We report 26 Tunisian patients with between two and four clinical features associated with Allgrove syndrome. Blood samples were collected and isolated DNA derived from subjects was amplified. The entire sequence of the AAAS gene was analyzed by PCR and sequencing. PCR-RFLP method was performed to identify the frequent mutations found.\nRESULTS: Sequencing of the AAAS gene revealed a major homozygous mutation (c.1331+1G>A) in 25 patients and R286X mutation in one patient. The presence of a major mutation in several unrelated affected individuals suggests the presence of a founder effect in Tunisia and allows for a fast and targeted molecular diagnosis.\nCONCLUSIONS: We created an easy and rapid molecular enzymatic protocol based on PCR-RFLP using MvaI restriction enzyme that directly targets this major mutation and can be used for prenatal diagnosis and genetic counseling for Tunisian families at risk. To the best of our knowledge, this is the first major series report of Allgrove syndrome in Tunisia.","variants":[{"Name":"NM_015665.6(AAAS):c.1331+1G>A","Chromosome":"12","Start":"53308051","Stop":"53308051","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":260025,"rule_based_match":true,"evidence_text":"c.1331+1G>A","llm_judgment":"PRESENT","evidence":"c.1331+1G>A","abstract_start":949,"abstract_end":960}]}
{"pmid":"32453099","title":"BAG3 Myopathy Presenting With Prominent Neuropathic Phenotype and No Cardiac or Respiratory Involvement: A Case Report and Literature Review.","abstract":"Bcl-2-associated athanogene 3 (BAG3) myopathy is a rare myofibrillar myopathy characterized by toe walking and clumsiness in the first decade with rapid progression to cardiomyopathy and restrictive lung disease in the second decade. Most patients (18 patients) have the c.626C >T (p.Pro209Leu) mutation. We describe BAG3 myopathy due to p.Pro209Leu in a 13-year-old girl with initial prominent neuropathic phenotype and no cardiac or respiratory involvement. Parents reported toe walking and clumsiness since 3 years old. Examination at the age of 13 years showed findings suggestive of Charcot-Marie-Tooth disease. Nerve conduction studies revealed demyelinating polyneuropathy. Next-generation sequencing panel for inherited neuropathies was unrevealing. Whole exome sequencing identified a de novo mutation in BAG3. Muscle biopsy confirmed myofibrillar myopathy. No cardiac involvement or symptoms of respiratory involvement at the age of 14 years. This case emphasizes the phenotypic variability of BAG3 myopathy and the importance of thorough electrophysiological examination and muscle pathology for establishing a precise diagnosis.","variants":[{"Name":"NM_004281.4(BAG3):c.626C>T (p.Pro209Leu)","Chromosome":"10","Start":"119672373","Stop":"119672373","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21020,"rule_based_match":true,"evidence_text":"c.626C >T (p.Pro209Leu)","llm_judgment":"PRESENT","evidence":"c.626C >T (p.Pro209Leu)","abstract_start":271,"abstract_end":294}]}
{"pmid":"31353022","title":"Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies.","abstract":"The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies.","variants":[{"Name":"NM_080476.5(PIGU):c.209T>A (p.Ile70Lys)","Chromosome":"20","Start":"34645321","Stop":"34645321","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":677401,"rule_based_match":true,"evidence_text":"c.209T>A [p.Ile70Lys]","llm_judgment":"PRESENT","evidence":"c.209T>A [p.Ile70Lys]","abstract_start":725,"abstract_end":746},{"Name":"NM_080476.5(PIGU):c.1149C>A (p.Asn383Lys)","Chromosome":"20","Start":"34575149","Stop":"34575149","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":677402,"rule_based_match":true,"evidence_text":"c.1149C>A (p.Asn383Lys)","llm_judgment":"PRESENT","evidence":"p.Asn383Lys","abstract_start":762,"abstract_end":773}]}
{"pmid":"22608501","title":"Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.","abstract":"We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.","variants":[{"Name":"NM_002087.4(GRN):c.813_816del (p.Thr272fs)","Chromosome":"17","Start":"44351139","Stop":"44351142","ReferenceAlleleVCF":"CCTCA","AlternateAlleleVCF":"C","allel_id":31059,"rule_based_match":true,"evidence_text":"c.813_816del (p.Thr272Serfs∗10)","llm_judgment":"PRESENT","evidence":"c.813_816del (p.Thr272Serfs∗10)","abstract_start":313,"abstract_end":344}]}
{"pmid":"24789103","title":"Mutations in the homeodomain of HOXD13 cause syndactyly type 1-c in two Chinese families.","abstract":"BACKGROUND: Syndactyly type 1 (SD1) is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and/or the second and third toes. Its four subtypes (a, b, c, and d) are defined based on variable phenotypes, but the responsible gene is yet to be identified. SD1-a has been mapped to chromosome 3p21.31 and SD1-b to 2q34-q36. SD1-c and SD1-d are very rare and, to our knowledge, no gene loci have been identified.\nMETHODS AND RESULTS: In two Chinese families with SD1-c, linkage and haplotype analyses mapped the disease locus to 2q31-2q32. Copy number variation (CNV) analysis, using array-based comparative genomic hybridization (array CGH), excluded the possibility of microdeletion or microduplication. Sequence analyses of related syndactyly genes in this region identified c.917G>A (p.R306Q) in the homeodomain of HOXD13 in family A. Analysis on family B identified the mutation c.916C>G (p.R306G) and therefore confirmed the genetic homogeneity. Luciferase assays indicated that these two mutations affected the transcriptional activation ability of HOXD13. The spectrum of HOXD13 mutations suggested a close genotype-phenotype correlation between the different types of HOXD13-Syndactyly. Overlaps of the various phenotypes were found both among and within families carrying the HOXD13 mutation.\nCONCLUSIONS: Mutations (p.R306Q and p.R306G) in the homeodomain of HOXD13 cause SD1-c. There are affinities between SD1-c and synpolydactyly. Different limb malformations due to distinct classes of HOXD13 mutations should be considered as a continuum of phenotypes and further classification of syndactyly should be done based on phenotype and genotype.","variants":[{"Name":"NM_000523.4(HOXD13):c.917G>A (p.Arg306Gln)","Chromosome":"2","Start":"176094615","Stop":"176094615","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227488,"rule_based_match":true,"evidence_text":"c.917G>A (p.R306Q)","llm_judgment":"PRESENT","evidence":"c.917G>A (p.R306Q)","abstract_start":864,"abstract_end":882},{"Name":"NM_000523.4(HOXD13):c.916C>G (p.Arg306Gly)","Chromosome":"2","Start":"176094614","Stop":"176094614","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":227492,"rule_based_match":true,"evidence_text":"c.916C>G (p.R306G)","llm_judgment":"PRESENT","evidence":"c.916C>G (p.R306G)","abstract_start":970,"abstract_end":988}]}
{"pmid":"26029709","title":"Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3.","abstract":"Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload.","variants":[{"Name":"NM_003227.4(TFR2):c.2374G>A (p.Gly792Arg)","Chromosome":"7","Start":"100620889","Stop":"100620889","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34226,"rule_based_match":false,"evidence_text":"p.Gly792Arg","llm_judgment":"PRESENT","evidence":"p.Gly792Arg","abstract_start":297,"abstract_end":308}]}
{"pmid":"33014498","title":"Glycogen Storage Disease Type IX due to a Novel Mutation in PHKA2 Gene.","abstract":"We report a case of a 17-month-old male with a history of developmental delay with poor muscle control, hepatomegaly, and transaminitis. Ultrasound of abdomen revealed hepatomegaly with a liver span of 13 cm, homogeneous parenchyma, and normal spleen size. Liver and muscle biopsies were obtained: the liver biopsy revealed distended hepatocytes with excessive glycogen accumulation and fine septate fibrosis. Biopsy of the right vastus lateralis muscle showed focal swollen glycogen containing mitochondria. For the developmental delay, a chromosomal microrarray was ordered. The chromosomal microarray revealed the patient to have 1q21 duplication syndrome and 16p11.2 deletion syndrome. Given the liver and muscle biopsy findings, a glycogen storage disease panel was sent which identified the patient to be hemizygous for a variant of uncertain significance denoted as p.Gly 131Val, c.392G > T in the PHKA2 gene. PKHA2 gene encodes the alpha subunit of hepatic phosphorylase kinase. This change in the PHKA2 gene was in a highly conserved region and had been reported in another patient with decreased enzymatic activity of the phosphorylase kinase and who had symptoms of GSD IX. Based on this, the patient was started on treatment for GSD IX, and his family met with a dietician.","variants":[{"Name":"NM_000292.3(PHKA2):c.392G>T (p.Gly131Val)","Chromosome":"X","Start":"18951166","Stop":"18951166","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3857310,"rule_based_match":true,"evidence_text":"c.392G > T","llm_judgment":"PRESENT","evidence":"c.392G > T","abstract_start":887,"abstract_end":897}]}
{"pmid":"27896095","title":"Residual OCTN2 transporter activity, carnitine levels and symptoms correlate in patients with primary carnitine deficiency.","abstract":"BACKGROUND: The prevalence of primary carnitine deficiency (PCD) in the Faroe Islands is the highest reported in the world (1:300). Serious symptoms related to PCD, e.g. sudden death, have previously only been associated to the c.95A > G/c.95A > G genotype in the Faroe Islands. We report and characterize novel mutations associated with PCD in the Faroese population and report and compare free carnitine levels and OCTN2 transport activities measured in fibroblasts from PCD patients with different genotypes.\nMETHODS: Genetic analyses were used to identify novel mutations, and carnitine uptake analyses in cultured skin fibroblasts from selected patients were used to examine residual OCTN2 transporter activities of the various genotypes.\nRESULTS: Four different mutations, including the unpublished c.131C > T (p.A44V), the novel splice mutation c.825-52G > A and a novel risk-haplotype (RH) were identified in the Faroese population. The two most prevalent genotypes were c.95A > G/RH (1:600) and c.95A > G/c.95A > G (1:1300). Patients homozygous for the c.95A > G mutation had both the significantly (<i>p</i> < 0.01) lowest mean free carnitine level at 2.03 (SD 0.66) μmol/L and lowest residual OCTN2 transporter activity (4% of normal). There was a significant positive correlation between free carnitine levels and residual OCTN2 transporter activities in PCD patients (<i>R</i><sup>2</sup> = 0.430, <i>p</i> < 0.01).\nCONCLUSION: There was a significant positive correlation between carnitine levels and OCTN2 transporter activities. The c.95A > G/c.95A > G genotype had the significantly lowest mean free carnitine level and residual OCTN2 transporter activity.","variants":[{"Name":"NM_003060.4(SLC22A5):c.95A>G (p.Asn32Ser)","Chromosome":"5","Start":"132370067","Stop":"132370067","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":36689,"rule_based_match":true,"evidence_text":"c.95A>G","llm_judgment":"PRESENT","evidence":"c.95A > G","abstract_start":228,"abstract_end":237},{"Name":"NM_003060.4(SLC22A5):c.131C>T (p.Ala44Val)","Chromosome":"5","Start":"132370103","Stop":"132370103","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":562673,"rule_based_match":true,"evidence_text":"c.131C > T (p.A44V)","llm_judgment":"PRESENT","evidence":"c.131C > T (p.A44V)","abstract_start":805,"abstract_end":824}]}
{"pmid":"15523651","title":"Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1.","abstract":"Holoprosencephaly (HPE) is a relatively common brain malformation resulting in an incomplete separation of the two cerebral hemispheres. A number of mutations in different genes have been linked to this malformation, including three missense mutations in the homeodomain of the transcription factor SIX3. In this study, we investigated the functional consequences of these SIX3 mutations with respect to the ability of the protein to interact with and stimulate the transcriptional activity of the nuclear receptor NOR1 (NR4A3). Using glutathione S-transferase fusion protein pull-down assays and transient cotransfections of Neuro-2a cells with expression and reporter vectors, we found that one mutation, c.676C>G (p.L226V), does not alter the properties of SIX3 toward NOR1. Another mutation, c.749T>C (p.V250A), results in the production of a highly unstable protein in Neuro-2a cells. The third mutation, c.770G>C (p.R257P), results in a mutant SIX3 protein that no longer interacts with NOR1 in vivo. These observations suggest that different SIX3 mutations in HPE2 may affect different signaling pathways, and that one of these pathways may involve the nuclear receptor NOR1.","variants":[{"Name":"NM_005413.4(SIX3):c.676C>G (p.Leu226Val)","Chromosome":"2","Start":"44942780","Stop":"44942780","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":21132,"rule_based_match":true,"evidence_text":"c.676C>G (p.L226V)","llm_judgment":"PRESENT","evidence":"c.676C>G (p.L226V)","abstract_start":707,"abstract_end":725},{"Name":"NM_005413.4(SIX3):c.770G>C (p.Arg257Pro)","Chromosome":"2","Start":"44942874","Stop":"44942874","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":21133,"rule_based_match":true,"evidence_text":"c.770G>C (p.R257P)","llm_judgment":"PRESENT","evidence":"c.770G>C (p.R257P)","abstract_start":910,"abstract_end":928},{"Name":"NM_005413.4(SIX3):c.749T>C (p.Val250Ala)","Chromosome":"2","Start":"44942853","Stop":"44942853","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":21134,"rule_based_match":true,"evidence_text":"c.749T>C (p.V250A)","llm_judgment":"PRESENT","evidence":"c.749T>C (p.V250A)","abstract_start":796,"abstract_end":814}]}
{"pmid":"30957593","title":"A case of ocular cystinosis associated with two potentially severe CTNS mutations.","abstract":"BACKGROUND: Ocular cystinosis is a rare autosomal recessive disorder caused by one severe and one mild mutation in the CTNS gene. It is characterised by cystine deposition within the cornea and conjunctiva however, the kidneys are not affected. We report a case of ocular cystinosis caused by two potentially severe CTNS mutations and discuss the possible mechanism of renal sparing.\nMETHODS: This is an observational case report of the proband and her unaffected relatives. All subjects underwent ophthalmic examination, whilst in the proband, In vivo laser scanning confocal microscopy was used to demonstrate cystine crystals within her corneas and conjunctiva. Genetic diagnosis was confirmed by DNA sequencing of the proband and the segregation of the mutations was established in her relatives. RT-PCR of leukocyte RNA was undertaken to determine if aberrant splicing of the CTNS gene was taking place Results: The proband was found to have cystine crystals limited to the anterior corneal stroma and the conjunctiva. Sequencing of the proband's CTNS gene found her to be a compound heterozygote for a 27bp deletion in exon8/intron 8 (c.559_561 + 24del) and a novel c.635C>T variant in exon 9 that is predicted be pathogenic and to result in the substitution of alanine with valine at amino acid position 212 (p.Ala212Val), which is within the 3<sup>rd</sup> transmembrane spanning domain of the CTNS protein. Examination of the proband's leukocyte RNA failed to demonstrate any aberrant CTNS gene splicing.\nCONCLUSION: We present a case of ocular cystinosis caused by two potentially severe CTNS gene mutations. The lack of renal involvement may be due to localised (ocular) aberrant CTNS RNA splicing.","variants":[{"Name":"NM_004937.3(CTNS):c.635C>T (p.Ala212Val)","Chromosome":"17","Start":"3656749","Stop":"3656749","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1012714,"rule_based_match":true,"evidence_text":"c.635C>T (p.Ala212Val)","llm_judgment":"PRESENT","evidence":"p.Ala212Val","abstract_start":1316,"abstract_end":1327}]}
{"pmid":"38311799","title":"Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.","abstract":"OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.\nMETHODS: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant.\nRESULTS: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing.\nINTERPRETATION: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.","variants":[{"Name":"NM_001103.4(ACTN2):c.1516A>G (p.Arg506Gly)","Chromosome":"1","Start":"236749124","Stop":"236749124","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":198055,"rule_based_match":true,"evidence_text":"c.1516A>G (p.Arg506Gly)","llm_judgment":"PRESENT","evidence":"c.1516A>G (p.Arg506Gly)","abstract_start":710,"abstract_end":733}]}
{"pmid":"32655338","title":"Diagnosis of Bloom Syndrome in a Patient with Short Stature, Recurrence of Malignant Lymphoma, and Consanguineous Origin.","abstract":"Bloom syndrome is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin resistance, and a greatly increased risk of early-onset cancer and development of multiple malignancies. Loss-of-function variants of the <i>BLM</i> gene, which codes for a RecQ helicase, cause Bloom syndrome. We report a consanguineous family, with 2 siblings showing clinical signs of suspected chromosome breakage disorder. One of them developed recurrent malignant lymphoma during lifetime. We performed next-generation sequencing analysis, focusing on cancer predisposition syndromes. We identified a homozygous pathogenic nonsense variant c.1642C>T (p.Gln548*) in the <i>BLM</i> gene in the proband, associated with Bloom syndrome. Sanger sequencing validated the presence of a homozygous pathogenic variant in the proband and also in the brother with short stature. In this article, we will focus on the clinical presentation of the syndrome in this particular family as well as the characteristics of malignancies found in the proband.","variants":[{"Name":"NM_000057.4(BLM):c.1642C>T (p.Gln548Ter)","Chromosome":"15","Start":"90761015","Stop":"90761015","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":132935,"rule_based_match":true,"evidence_text":"c.1642C>T (p.Gln548*)","llm_judgment":"PRESENT","evidence":"c.1642C>T (p.Gln548*)","abstract_start":710,"abstract_end":731}]}
{"pmid":"36190515","title":"Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.","abstract":"Maintaining protein lipoylation is vital for cell metabolism. The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system, intersecting two vital roles for cell survival. Here, we report six patients with biallelic pathogenic variants in GCSH and a broad clinical spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated phenotype of developmental delay, behavioral problems, limited epilepsy and variable movement problems. The mutational spectrum includes one insertion c.293-2_293-1insT, one deletion c.122_(228 + 1_229-1) del, one duplication of exons 4 and 5, one nonsense variant p.Gln76*and four missense p.His57Arg, p.Pro115Leu and p.Thr148Pro and the previously described p.Met1?. Via functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies, we demonstrate for the first time that most variants identified in our cohort produced a hypomorphic effect on both mitochondrial activities, protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affect primarily one function only. The clinical features of the patients reflect the impact of the GCSH changes on any of the two functions analyzed. Our analysis illustrates the complex interplay of functional and clinical impact when pathogenic variants affect a multifunctional protein involved in two metabolic pathways and emphasizes the value of the functional assays to select the treatment and investigate new personalized options.","variants":[{"Name":"NM_004483.5(GCSH):c.293-2_293-1insT","Chromosome":"16","Start":"81084595","Stop":"81084596","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":2671395,"rule_based_match":true,"evidence_text":"c.293-2_293-1insT","llm_judgment":"PRESENT","evidence":"c.293-2_293-1insT","abstract_start":694,"abstract_end":711},{"Name":"NM_004483.5(GCSH):c.170A>G (p.His57Arg)","Chromosome":"16","Start":"81090659","Stop":"81090659","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2671398,"rule_based_match":false,"evidence_text":"c.170A>G (p.His57Arg)","llm_judgment":"PRESENT","evidence":"p.His57Arg","abstract_start":834,"abstract_end":844},{"Name":"NM_004483.5(GCSH):c.344C>T (p.Pro115Leu)","Chromosome":"16","Start":"81084543","Stop":"81084543","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2671401,"rule_based_match":false,"evidence_text":"c.344C>T (p.Pro115Leu)","llm_judgment":"PRESENT","evidence":"p.Pro115Leu","abstract_start":846,"abstract_end":857}]}
{"pmid":"29106878","title":"The relationship between the GJB3 c.538C>T variant and hearing phenotype in the Chinese population.","abstract":"BACKGROUND: Mutations in GJB3 were originally shown to underlie an autosomal dominant form of non-syndromic deafness in Chinese patients and the c.538C>T (p.R180*) variants caused high-frequency hearing loss. But after that, few reports have reported this mutation. This study investigated the relationship between the GJB3 c.538C>T variant and hearing phenotype in Chinese to assist with risk assessment and genetic counseling for hearing loss patients and their families.\nMETHOD: The study enrolled 5700 patients with hearing loss and 4600 normal subjects. Deafness gene mutations were distinguished using a gene chip. The GJB3 c.538C>T variant rate was calculated from the results.\nRESULT: Of the 5700 patients, 23 (0.40%) carried a GJB3 c.538C>T heterozygous variant; of these, 11 patients had other gene (GJB2/SLC26A4) mutations simultaneously. Most patients had moderate to profound hearing loss. All 23 patients were sporadic cases and had no family history of deafness. Of the 4600 normal individuals, 11 (0.24%) had GJB3 c.538C>T heterozygous variant. There was no statistical difference in incidence between the two groups.\nCONCLUSIONS: Our results showed that the GJB3 c.538C>T variant has a very low incidence in the Chinese population, and there was no clear evidence to support a role of the GJB3 c.538C>T variant in the autosomal dominant form of non-syndromic deafness. Our findings suggested that GJB3 c.538C>T does not contribute to hearing loss, and this conclusion will assist with genetic counseling and risk prediction for deafness related to the GJB3 c.538C>T variant.","variants":[{"Name":"NM_024009.3(GJB3):c.538C>T (p.Arg180Ter)","Chromosome":"1","Start":"34785300","Stop":"34785300","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21525,"rule_based_match":true,"evidence_text":"GJB3 c.538C>T","llm_judgment":"PRESENT","evidence":"GJB3 c.538C>T","abstract_start":319,"abstract_end":332}]}
{"pmid":"37004249","title":"ACROSIN deficiency causes total fertilization failure in humans by preventing the sperm from penetrating the zona pellucida.","abstract":"STUDY QUESTION: Does a homozygous nonsense mutation in ACR lead to total fertilization failure (TFF) resulting in male infertility in humans?\nSUMMARY ANSWER: A novel homozygous nonsense mutation of ACR (c.167G>A, p.Trp56X) was identified in two infertile brothers and shown to cause human TFF.\nWHAT IS KNOWN ALREADY: ACROSIN, encoded by ACR, is a major acrosomal enzyme expressed only in the acrosome of the sperm head. Inhibition of acrosin prevents sperm penetration of the zona pellucida (ZP) in several species, including humans. Acr-knockout in hamsters causes male infertility with completely blocked fertilization. Of note, there are no reports of ACR mutations associated with TFF in humans.\nSTUDY DESIGN, SIZE, DURATION: Whole-exome sequencing (WES) was used for the identification of pathogenic genes for male factor TFF in eight involved couples.\nPARTICIPANTS/MATERIALS, SETTING, METHODS: Data from eight infertile couples who had experienced TFF during their IVF or ICSI attempts were collected. Functional assays were used to verify the pathogenicity of the potential genetic factors identified by WES. Subzonal insemination (SUZI) and IVF assays were performed to determine the exact pathogenesis of TFF caused by deficiencies in ACROSIN.\nMAIN RESULTS AND THE ROLE OF CHANCE: A novel homozygous nonsense mutation in ACR, c.167G>A, p.Trp56X, was identified in two additional primary infertile brothers whose parents were first cousins. This rare mutation caused ACROSIN deficiency and acrosomal ultrastructural defects in the affected sperm. Spermatozoa lacking ACROSIN were unable to penetrate the ZP, rather than hampering sperm binding, disrupting gamete fusion, or preventing oocyte activation. These findings were supported by the fertilization success of SUZI and ICSI attempts, as well as the normal expression of ACTL7A and PLCζ in the mutant sperm, suggesting that ICSI without remedial assisted oocyte activation is an optimal treatment for ARCOSIN-deficient TFF.\nLIMITATIONS, REASONS FOR CAUTION: The absence of another independent pedigree to support our argument is a limitation of this study.\nWIDER IMPLICATIONS OF THE FINDINGS: The findings expand our understanding of the genes involved in human TFF, providing information for appropriate genetic counseling and fertility guidance for these patients.\nSTUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (grant no. 82201803, 81901541, 82271639, and 32000584), University Synergy Innovation Program of Anhui Province (GXXT-2019-044), and the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences (grant no. 2019PT310002). The authors declare no conflicts of interest.\nTRIAL REGISTRATION NUMBER: N/A.","variants":[{"Name":"NM_001097.3(ACR):c.167G>A (p.Trp56Ter)","Chromosome":"22","Start":"50739360","Stop":"50739360","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2742889,"rule_based_match":true,"evidence_text":"c.167G>A, p.Trp56X","llm_judgment":"PRESENT","evidence":"c.167G>A, p.Trp56X","abstract_start":203,"abstract_end":221}]}
{"pmid":"19237265","title":"New GLUT-1 mutation in a child with treatment-resistant epilepsy.","abstract":"Mutations in the human glucose transporter type I (GLUT-1) gene may result in a phenotype of epilepsy, developmental delay, and movement abnormalities. We present a previously unreported mutation, c.1454 C>T (pPro485Leu) as a likely cause of intractable infantile-onset epilepsy and mild developmental delay in an 11-year-old girl. CSF:serum glucose ratio was 45%. She has had clinical improvement on a modified Atkins diet. Our patient helps further refine the phenotype of Glut-1 deficiency and reveals a new pathologic mutation.","variants":[{"Name":"NM_006516.4(SLC2A1):c.1454C>T (p.Pro485Leu)","Chromosome":"1","Start":"42927066","Stop":"42927066","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":858948,"rule_based_match":true,"evidence_text":"c.1454 C>T (pPro485Leu)","llm_judgment":"PRESENT","evidence":"c.1454 C>T (pPro485Leu)","abstract_start":197,"abstract_end":220}]}
{"pmid":"34133440","title":"DNAH11 compound heterozygous variants cause heterotaxy and congenital heart disease.","abstract":"Heterotaxy (HTX), a condition characterized by internal organs not being arranged as expected relative to each other and to the left-right axis, is often accompanied with congenital heart disease (CHD). The purpose was to detect the pathogenic variants in a Chinese family with HTX and CHD. A non-consanguineous Han Chinese family with HTX and CHD, and 200 unrelated healthy subjects were enlisted. Exome sequencing and Sanger sequencing were applied to identify the genetic basis of the HTX family. Compound heterozygous variants, c.3426-1G>A and c.4306C>T (p.(Arg1436Trp)), in the dynein axonemal heavy chain 11 gene (DNAH11) were identified in the proband via exome sequencing and further confirmed by Sanger sequencing. Neither c.3426-1G>A nor c.4306C>T variant in the DNAH11 gene was detected in 200 healthy controls. The DNAH11 c.3426-1G>A variant was predicted as altering the acceptor splice site and most likely affecting splicing. The DNAH11 c.4306C>T variant was predicted to be damaging, which may reduce the phenotype severity. The compound heterozygous variants, c.3426-1G>A and c.4306C>T, in the DNAH11 gene might be the pathogenic alterations resulting in HTX and CHD in this family. These findings broaden the variant spectrum of the DNAH11 gene and increase knowledge used in genetic counseling for the HTX family.","variants":[{"Name":"NM_001277115.2(DNAH11):c.3426-1G>A","Chromosome":"7","Start":"21601395","Stop":"21601395","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":852074,"rule_based_match":true,"evidence_text":"c.3426-1G>A","llm_judgment":"PRESENT","evidence":"c.3426-1G>A","abstract_start":532,"abstract_end":543}]}
{"pmid":"15131355","title":"Screening for mutations in the GJB3 gene in Brazilian patients with nonsyndromic deafness.","abstract":"Deafness is a complex disorder that is affected by a high number of genes and environmental factors. Recently, enormous progress has been made in nonsyndromic deafness research, with the identification of 90 loci and 33 nuclear and 2 mitochondrial genes involved (http://dnalab-www.uia.ac.be/dnalab/hhh/). Mutations in the GJB3 gene, encoding the gap junction protein connexin 31 (Cx31), have been pathogenically linked to erythrokeratodermia variabilis and nonsyndromic autosomal recessive or dominant hereditary hearing impairment. To determine the contribution of the GJB3 gene to sporadic deafness, we analysed the GJB3 gene in 67 families with nonsyndromic hearing impairment. A single coding exon of the GJB3 gene was amplified from genomic DNA and then sequenced. Here we report on three amino acid changes: Y177D (c.529T > G), 49delK (c.1227C > T), and R32W (c.144-146delGAA). The latter substitution has been previously described, but its involvement in hearing impairment remains uncertain. We hypothesize that mutations in the GJB3 gene are an infrequent cause of nonsyndromic deafness.","variants":[{"Name":"NM_024009.3(GJB3):c.529T>G (p.Tyr177Asp)","Chromosome":"1","Start":"34785291","Stop":"34785291","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":172580,"rule_based_match":true,"evidence_text":"c.529T > G","llm_judgment":"PRESENT","evidence":"c.529T > G","abstract_start":822,"abstract_end":832}]}
{"pmid":"31479177","title":"Novel missense mutation in VPS33B is associated with isolated low gamma-glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome.","abstract":"The typical phenotype of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome involves three cardinal symptoms as the name describes, harboring biallelic mutations on VPS33B or VIPAS39. Except for ARC syndrome, low gamma-glutamyltransferase (GGT) cholestasis often implies hereditary hepatopathy of different severity; however, some remain undiagnosed. Several monogenic defects typically with multiorgan manifestations may only present liver dysfunction at times, such as DGUOK defect and AGL defect. Previously, four VPS33B mutated cases were reported without arthrogryposis, or with less severe symptoms and longer lifespan, indicating the possibility of incomplete ARC phenotype of isolated hepatopathy. So we retrospectively reviewed all patients with confirmed VPS33B/VIPARS39 defect in our center and identified three presenting isolated low-GGT cholestasis with intractable pruritus. Distinguished from others with typical ARC phenotype, these patients did not suffer the other two typical characteristics, survived much longer, and shared a novel missense VPS33B variation c.1726T>C, p.Cys576Arg, causing declined protein expression and abolished interaction with VIPAS39 in-vitro. Serum bile acid profiles of our VPS33B/VIPAS39 mutated patients revealed similar changes to primary defect of bile salt export pump, among which those with isolated cholestasis phenotype had a higher level of total secondary bile acids than that with typical ARC phenotype, indicating the partial residual function of VPS33B.","variants":[{"Name":"NM_018668.5(VPS33B):c.1726T>C (p.Cys576Arg)","Chromosome":"15","Start":"90999725","Stop":"90999725","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":682127,"rule_based_match":true,"evidence_text":"c.1726T>C, p.Cys576Arg","llm_judgment":"PRESENT","evidence":"c.1726T>C, p.Cys576Arg","abstract_start":1095,"abstract_end":1117}]}
{"pmid":"17616415","title":"Glycogen storage disease type II in Spanish patients: high frequency of c.1076-1G>C mutation.","abstract":"Glycogen storage disease type II is an autosomal recessive disorder of glycogen metabolism due to deficiency of lysosomal acid alpha-glucosidase. We present the molecular and enzymatic analyses of 22 Spanish GSD II patients. Molecular analyses revealed nine novel mutations. The most common defects were mutations c.-32-13T>G (25%) and c.1076-1G>C (14%) and we report the first homozygous patient for c.1076-1G>C mutation presenting with an infantile form. Alleles bearing mutation c.-32-13T>G are associated with the same haplotype.","variants":[{"Name":"NM_000152.5(GAA):c.1076-1G>C","Chromosome":"17","Start":"80108488","Stop":"80108488","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1421034,"rule_based_match":true,"evidence_text":"c.1076-1G>C","llm_judgment":"PRESENT","evidence":"c.1076-1G>C","abstract_start":336,"abstract_end":347},{"Name":"NM_000152.5(GAA):c.-32-13T>G","Chromosome":"17","Start":"80104542","Stop":"80104542","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":19066,"rule_based_match":true,"evidence_text":"c.-32-13T>G","llm_judgment":"PRESENT","evidence":"c.-32-13T>G","abstract_start":314,"abstract_end":325}]}
{"pmid":"31104773","title":"A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.","abstract":"The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.","variants":[{"Name":"NM_004068.4(AP2M1):c.508C>T (p.Arg170Trp)","Chromosome":"3","Start":"184180927","Stop":"184180927","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":677400,"rule_based_match":true,"evidence_text":"c.508C>T (p.Arg170Trp)","llm_judgment":"PRESENT","evidence":"c.508C>T (p.Arg170Trp)","abstract_start":494,"abstract_end":516}]}
{"pmid":"33016646","title":"Atypical juvenile hereditary hemochromatosis onset with positive pancreatic islet autoantibodies diabetes caused by novel mutations in HAMP and overall clinical management.","abstract":"BACKGROUND: Atypical clinical symptoms of juvenile hereditary hemochromatosis (JHH) often leads to misdiagnosis and underdiagnosis bringing ominous outcomes, even death.\nMETHODS: The whole exome was sequenced and interpreted. A literature review assisted to analyze and verify the phenotype-genotype relationships. We revealed the entire process of diagnosis, treatments, and outcome of two diabetic onset of JHH families to provide new insights for genotype-phenotype relation with novel compound heterozygous mutations in the hepcidin antimicrobial peptide (HAMP, OMIM: 606464).\nRESULTS: Two probands were diagnosed and treated as type 1 diabetes initially because of specific symptoms and positive islet autoantibodies. Poor control of hyperglycemia and progressive symptoms occurred. Sequencing informed that the compound heterozygous and homozygous mutations c.166C>G and c.223C>T in HAMP caused type 1 diabetic-onset JHH. The two patients accessed irregular phlebotomy treatments, and then, experienced poor prognosis. We summarized the process of overall clinical management of reported 26 cases comparing to our novel atypical diabetic onsets Juvenile Hereditary Hemochromatosis cases.\nCONCLUSION: It was first reported that positive pancreatic islet autoantibodies diabetes onset of JHH resulted from loss-of-function mutations of HAMP, of which the atypical JHH should be differentially diagnosed with type 1 diabetes at the onset. Early administration of phlebotomy and vital organs protection and surveillance might be important for the treatment of atypical JHH.","variants":[{"Name":"NM_021175.4(HAMP):c.223C>T (p.Arg75Ter)","Chromosome":"19","Start":"35285010","Stop":"35285010","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1472936,"rule_based_match":true,"evidence_text":"c.223C>T","llm_judgment":"PRESENT","evidence":"c.223C>T","abstract_start":877,"abstract_end":885}]}
{"pmid":"17410422","title":"Novel mutations found in two genes of thai patients with isolated methylmalonic acidemia.","abstract":"Molecular genetic analysis of three patients diagnosed with isolated methylmalonic acidemia (MMA) revealed that one was mut (0) MMA, with a mutation in the MUT gene encoding the L: -methylmalonyl-CoA mutase (MCM), and two were cblB MMA, with mutations in the MMAB gene required for synthesizing the deoxyadenosylcobalamin cofactor of MCM. The mut (0) patient was homozygous for a novel nonsense mutation in MUT, p.R31X (c.167C --> T), and heterozygous for three previously described polymorphisms, p.K212K (c.712A --> G), p.H532R (c.1671A --> G), and p.V671I (c.2087G --> A). The new MMAB mutation, p.E152X (c.454G --> T), was found to be homozygous in one cblB patient and heterozygous in the other patient, who also had four intron polymorphisms in this gene.","variants":[{"Name":"NM_052845.4(MMAB):c.454G>T (p.Glu152Ter)","Chromosome":"12","Start":"109561485","Stop":"109561485","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":546844,"rule_based_match":false,"evidence_text":"c.454G --> T","llm_judgment":"PRESENT","evidence":"c.454G --> T","abstract_start":608,"abstract_end":620}]}
{"pmid":"26985960","title":"Whole-exome sequencing reveals a novel COL2A1 mutation in a patient with spondylo-epiphyseal dysplasia congenita.","abstract":"Skeletal dysplasia is a group of disorders with more than 450 entities, many of which cannot be differentiated, especially during infancy, but could lead to different clinical courses and prognoses. In this study, we have described a case of a Thai infant with short stature, flat face, pectus carinatum, indirect inguinal hernia, platyspondyly, and generalized delayed endochondral ossification. Using whole-exome sequencing (WES), we successfully identified a de novo heterozygous mutation, c.2024G>A (p.G675D), in the COL2A1 gene, which, to our knowledge, has not been previously reported. These molecular findings helped provide a definite diagnosis of spondyloepiphyseal dysplasia congenita, aiding in proper management of the disease and improved genetic counseling. We demonstrated that WES is an efficient and cost-effective tool for molecular diagnosis for a type II collagenopathy.","variants":[{"Name":"NM_001844.5(COL2A1):c.2024G>A (p.Gly675Asp)","Chromosome":"12","Start":"47983410","Stop":"47983410","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":615941,"rule_based_match":true,"evidence_text":"c.2024G>A (p.G675D)","llm_judgment":"PRESENT","evidence":"c.2024G>A (p.G675D)","abstract_start":493,"abstract_end":512}]}
{"pmid":"24709683","title":"A novel GRN mutation (GRN c.708+6_+9delTGAG) in frontotemporal lobar degeneration with TDP-43-positive inclusions: clinicopathologic report of 6 cases.","abstract":"Understanding of frontotemporal lobar degeneration, the underlying pathology most often linked to the clinical diagnosis of frontotemporal dementia, is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings on 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6_+9delTGAG mutation.","variants":[{"Name":"NM_002087.4(GRN):c.708+6_708+9del","Chromosome":"17","Start":"44350801","Stop":"44350804","ReferenceAlleleVCF":"CGTGA","AlternateAlleleVCF":"C","allel_id":577636,"rule_based_match":false,"evidence_text":"GRN c.708+6_+9delTGAG","llm_judgment":"PRESENT","evidence":"GRN c.708+6_+9delTGAG","abstract_start":847,"abstract_end":868}]}
{"pmid":"26014432","title":"High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing.","abstract":"Screening for founder mutations in BRCA1 and BRCA2 has been discussed as a cost-effective testing strategy in certain populations. In this study, comprehensive BRCA1 and BRCA2 testing was performed in a routine diagnostic setting. The prevalence of the BRCA1 stop mutation c.4183C>T, p.(Gln1395Ter), was determined in unselected breast and ovarian cancer patients from different regions in the Tyrol. Cancer registry data were used to evaluate the impact of this mutation on regional cancer incidence. The mutation c.4183C>T was detected in 30.4% of hereditary BRCA1-associated breast and ovarian cancer patients in our cohort. It was also identified in 4.1% of unselected (26% of unselected triple negative) Tyrolean breast cancer patients and 6.8% of unselected ovarian cancer patients from the Lower Inn Valley (LIV) region. Cancer incidences showed a region-specific increase in age-stratified breast and ovarian cancer risk with standardized incidence ratios of 1.23 and 2.13, respectively. We, thus, report a Tyrolean BRCA1 founder mutation that correlates to a local increase in the breast and ovarian cancer risks. On the basis of its high prevalence, we suggest that targeted genetic analysis should be offered to all women with breast or ovarian cancer and ancestry from the LIV region.","variants":[{"Name":"NM_007294.4(BRCA1):c.4183C>T (p.Gln1395Ter)","Chromosome":"17","Start":"43090946","Stop":"43090946","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":69792,"rule_based_match":true,"evidence_text":"c.4183C>T","llm_judgment":"PRESENT","evidence":"c.4183C>T","abstract_start":273,"abstract_end":282}]}
{"pmid":"24396618","title":"Sporadic Hemiplegic Migraine with ATP1A2 and Prothrombin Gene Mutations.","abstract":"Background. Hemiplegic migraine is a rare type of migraine that may present in children and adolescents. Both familial and sporadic hemiplegic migraines have similar prevalence and clinical characteristics. Patient. We report an adolescent with sporadic hemiplegic migraine who previously had a similar attack in the past and who was initially evaluated for a possible acute ischemic event. Results. Magnetic resonance angiography showed dilatation of the left middle cerebral artery that resolved in a follow-up study. She was also found to have a ATP1A2 (c.2273 G>C) mutation and a heterozygous prothrombin mutation. Conclusions. We suggest that patients with sporadic hemiplegic migraine be tested for both ATP1A2 mutations which in some cases may be pathogenic, and prothrombin mutations which increase the stroke risk for this patient population.","variants":[{"Name":"NM_000702.4(ATP1A2):c.2273G>C (p.Gly758Ala)","Chromosome":"1","Start":"160135591","Stop":"160135591","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":201095,"rule_based_match":true,"evidence_text":"c.2273 G>C","llm_judgment":"PRESENT","evidence":"c.2273 G>C","abstract_start":557,"abstract_end":567}]}
{"pmid":"26174511","title":"Novel KIF7 missense substitutions in two patients presenting with multiple malformations and features of acrocallosal syndrome.","abstract":"We present two children who both had two missense mutations in the Kinesin Family Member 7 (KIF7) gene. A seven year old female with severe developmental delays, failure to thrive and growth retardation, infantile spasms, a cardiac vascular ring and right-sided aortic arch, imperforate anus, hydronephrosis with a right renal cyst, syndactyly and abnormal white matter was a compound heterozygote for c.3365C > G, predicting p.(Ser1122Trp) that was maternally inherited and c.2482G > A, predicting p.(Val828Met) that was paternally inherited. An eight year old female with severe developmental delays, epilepsy, left postaxial polydactyly of the hand and abnormalities of brain development including hydrocephalus, pachygyria and absence of the body and splenium of the corpus callous was a compound heterozygote for c.461G > A, predicting p.(Arg154Gln) and c.2959 G > A, predicting p.(Glu987Lys) that was maternally inherited and her father was unavailable for testing. The presentations in these children include features of acrocallosal syndrome, such as hypoplasia of the corpus callosum, enlarged ventricles, facial dysmorphism with a prominent forehead and broad halluces in the first child, but included atypical findings for individuals previously reported to have truncating mutations in KIF7, including imperforate anus, infantile spasms and severe growth retardation. We conclude that these phenotypes may result from the KIF7 sequence variants and abnormal hedgehog signaling, but that the full spectrum of KIF7-associated features remains to be determined.","variants":[{"Name":"NM_198525.3(KIF7):c.3365C>G (p.Ser1122Trp)","Chromosome":"15","Start":"89629527","Stop":"89629527","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1400422,"rule_based_match":true,"evidence_text":"c.3365C > G, predicting p.(Ser1122Trp)","llm_judgment":"PRESENT","evidence":"c.3365C > G, predicting p.(Ser1122Trp)","abstract_start":402,"abstract_end":440},{"Name":"NM_198525.3(KIF7):c.461G>A (p.Arg154Gln)","Chromosome":"15","Start":"89649809","Stop":"89649809","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":464622,"rule_based_match":true,"evidence_text":"c.461G > A, predicting p.(Arg154Gln)","llm_judgment":"PRESENT","evidence":"c.461G > A, predicting p.(Arg154Gln)","abstract_start":818,"abstract_end":854},{"Name":"NM_198525.3(KIF7):c.2482G>A (p.Val828Met)","Chromosome":"15","Start":"89633796","Stop":"89633796","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":373810,"rule_based_match":true,"evidence_text":"c.2482G > A, predicting p.(Val828Met)","llm_judgment":"PRESENT","evidence":"c.2482G > A, predicting p.(Val828Met)","abstract_start":475,"abstract_end":512},{"Name":"NM_198525.3(KIF7):c.2959G>A (p.Glu987Lys)","Chromosome":"15","Start":"89631647","Stop":"89631647","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":492700,"rule_based_match":true,"evidence_text":"c.2959 G > A, predicting p.(Glu987Lys)","llm_judgment":"PRESENT","evidence":"c.2959 G > A, predicting p.(Glu987Lys)","abstract_start":859,"abstract_end":897}]}
{"pmid":"25565929","title":"A Novel Mutation in the ROGDI Gene in a Patient with Kohlschütter-Tönz Syndrome.","abstract":"Kohlschütter-Tönz Syndrome (KTZS) is an autosomal recessive disorder caused by mutations in the ROGDI gene. This syndrome is characterized by epilepsy, psychomotor regression and amelogenesis imperfecta. In this paper, we report a case of a 13-year-old Malian girl presenting with this rare disease. By genetic analysis, we identified a novel ROGDI homozygous mutation NM_024589.1: c.117+1G>T [Chr16 (GRCh37): g.4852382C>A] which confirmed the diagnosis of Kohlschütter-Tönz syndrome. The mutation abolishes the usual splice donor site of intron 2 which leads to the deletion of exon 2 and in-frame assembly of exon 3. Exon 2 encodes a highly conserved leucine-rich region that is essential for ROGDI protein function. Hence, this deletion may affect the function of the ROGDI protein.","variants":[{"Name":"NM_024589.3(ROGDI):c.117+1G>T","Chromosome":"16","Start":"4802381","Stop":"4802381","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":941137,"rule_based_match":true,"evidence_text":"NM_024589.1: c.117+1G>T","llm_judgment":"PRESENT","evidence":"NM_024589.1: c.117+1G>T","abstract_start":369,"abstract_end":392}]}
{"pmid":"24714551","title":"Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.","abstract":"Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.","variants":[{"Name":"NM_175053.4(KRT74):c.821T>C (p.Phe274Ser)","Chromosome":"12","Start":"52571381","Stop":"52571381","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":102652,"rule_based_match":true,"evidence_text":"c.821T>C variant (p.Phe274Ser)","llm_judgment":"PRESENT","evidence":"c.821T>C variant (p.Phe274Ser)","abstract_start":563,"abstract_end":593}]}
{"pmid":"30245514","title":"Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37.","abstract":"PURPOSE: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family.\nMETHODS: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family.\nRESULTS: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 gene within the DFNA37 locus. Genotyping of all 48 family members confirmed segregation of this variant with the deafness phenotype in the extended family. The c.652-2A>C variant is novel, highly conserved, and confirmed in vitro to alter RNA splicing.\nCONCLUSION: We have identified COL11A1 as the gene responsible for deafness at the DFNA37 locus. Previously, COL11A1 was solely associated with Marshall and Stickler syndromes. This study expands its phenotypic spectrum to include nonsyndromic deafness. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with COL11A1 pathogenic variants.","variants":[{"Name":"NM_001854.4(COL11A1):c.652-2A>C","Chromosome":"1","Start":"103031246","Stop":"103031246","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":653816,"rule_based_match":true,"evidence_text":"c.652-2A>C","llm_judgment":"PRESENT","evidence":"c.652-2A>C","abstract_start":711,"abstract_end":721}]}
{"pmid":"23434467","title":"Familial paraganglioma syndrome: phenotype and relevance of a new SDHB mutation","abstract":"BACKGROUND AND OBJECTIVE: Advances in molecular biology have discovered new genes involved in the development of familial paraganglioma syndrome (PGL) including those encoding mitochondrial succinate dehydrogenase complex (SDH). We describe the diagnosis, clinical expression and genetic counselling in a family diagnosed of PGL due to a new SDHB mutation.\nPATIENTS AND METHOD: Genetic study by PCR-direct sequencing SDHB gene and biochemical determination in blood/urine fractionated catecholamine 24h, metanephrines and conventional (computed tomography/magnetic resonance imaging) and functional imaging ((123)I-MIBG) in all members of a family diagnosed of PGL.\nRESULT: DNA sequencing showed a non-described SDHB heterozygous mutation (c.287-3C>G intron3/exon4) in 5 of the subjects (71%). The estimated penetrance of the mutation's carriers was 40%, with a mean age of 35 years at diagnosis. All patients with active illness required surgical treatment after imaging and laboratory confirmation.\nCONCLUSIONS: We describe the pathogenicity, diagnostic algorithm, genetic counselling and clinical expression of a new SDHB mutation (c.287-3C>G) in a family diagnosed of PGL.","variants":[{"Name":"NM_003000.3(SDHB):c.287-3C>G","Chromosome":"1","Start":"17028739","Stop":"17028739","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":432038,"rule_based_match":true,"evidence_text":"c.287-3C>G","llm_judgment":"PRESENT","evidence":"c.287-3C>G","abstract_start":740,"abstract_end":750}]}
{"pmid":"18637129","title":"Strict sun protection results in minimal skin changes in a patient with xeroderma pigmentosum and a novel c.2009delG mutation in XPD (ERCC2).","abstract":"We examined the clinical, molecular and genetic features of a 16-year-old boy (XP2GO) with xeroderma pigmentosum (XP) and progressive neurological symptoms. The parents are not consanguineous. Increased sun sensitivity led to the diagnosis of XP at 2 years of age and a strict UV protection scheme was implemented. Besides recurrent conjunctivitis and bilateral pterygium, only mild freckling was present on his lips. He shows absent deep tendon reflexes, progressive sensorineural deafness and progressive mental retardation. MRI shows diffuse frontal cerebral atrophy and dilated ventricles. Symptoms of trichothiodystrophy (brittle hair with a tiger-tail banding pattern on polarized microscopy) or Cockayne syndrome (cachectic dwarfism, cataracts, pigmentary retinopathy and spasticity) were absent. XP2GO fibroblasts showed reduced post-UV cell survival (D(37) = 3.8 J/m(2)), reduced nucleotide excision repair, reduced expression of XPD mRNA and an undetectable level of XPD protein. Mutational analysis of the XPD gene in XP2GO revealed two different mutations: a common p.Arg683Trp amino acid change (c.2047C>T) known to be associated with XP and a novel frameshift mutation c.2009delG (p.Gly670Alafs*39). The latter mutation potentially behaves as a null allele. While not preventing neurological degeneration, early diagnosis and rigorous sun protection can result in minimal skin disease without cancer in XP patients.","variants":[{"Name":"NM_000400.4(ERCC2):c.2047C>T (p.Arg683Trp)","Chromosome":"19","Start":"45352352","Stop":"45352352","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31832,"rule_based_match":true,"evidence_text":"c.2047C>T","llm_judgment":"PRESENT","evidence":"c.2047C>T","abstract_start":1109,"abstract_end":1118}]}
{"pmid":"23824842","title":"Pelger-huet anomaly and a mild skeletal phenotype secondary to mutations in LBR.","abstract":"The Lamin B receptor (LBR) gene has been described to encode a bifunctional protein. Mutations in the LBR gene can affect neutrophil segmentation and sterol reductase activity and have been associated with two different recognized clinical conditions, Pelger-Huet anomaly (PHA) and Greenberg skeletal dysplasia. PHA is a benign autosomal co-dominant laminopathy resulting in bilobed neutrophil nuclei in heterozygotes, and unsegmented (ovoid) neutrophil nuclei in homozygotes. Some putative PHA homozygotes have been reported with minor skeletal malformations. Greenberg skeletal dysplasia is a severe autosomal recessive, perinatal lethal dwarfing disorder in which heterozygous carriers are usually without clinical manifestations. We here report a girl who has bilobed neutrophil nuclei and a mild skeletal dysplasia. Mutation analysis showed two novel mutations in the LBR gene: c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19) and c.1757G > A (p.Arg586His). These mutations were found to be in trans, and, thus, she is a compound heterozygote. Sterol analysis found trace amounts of cholesta-8,14-dien-3beta-ol, which is normally undetected in healthy individuals. This and previously reported cases suggest that mutations in LBR can result in a continuum of phenotypic manifestations.","variants":[{"Name":"NM_002296.4(LBR):c.651_653delinsTGATGAGAAA (p.Ile218fs)","Chromosome":"1","Start":"225418168","Stop":"225418170","ReferenceAlleleVCF":"ATG","AlternateAlleleVCF":"TTTCTCATCA","allel_id":536125,"rule_based_match":true,"evidence_text":"c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19)","llm_judgment":"PRESENT","evidence":"c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19)","abstract_start":883,"abstract_end":928},{"Name":"NM_002296.4(LBR):c.1757G>A (p.Arg586His)","Chromosome":"1","Start":"225403394","Stop":"225403394","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":536126,"rule_based_match":true,"evidence_text":"c.1757G > A (p.Arg586His)","llm_judgment":"PRESENT","evidence":"c.1757G > A (p.Arg586His)","abstract_start":933,"abstract_end":958}]}
{"pmid":"15377708","title":"A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect.","abstract":"BACKGROUND: Mutations in a gene encoding a novel protein of unknown function-the ganglioside-induced differentiation-associated protein 1 gene (GDAP1)-are associated with the autosomal recessive Charcot-Marie-Tooth disease type 4A (CMT4A).\nOBJECTIVE: To investigate the role of GDAP1 mutations in causing autosomal recessive neuropathies in an Italian population.\nMETHODS AND RESULTS: 76 patients with severe early onset polyneuropathy and possible autosomal recessive inheritance were screened for mutations. A T>G transversion (c.347 T>G) at codon 116 (M116R) was detected in four affected subjects from three apparently unrelated families. All patients had early onset of disease with pronounced foot deformities and impaired walking. Neurophysiological studies showed an extremely variable expression. Sural nerve biopsies revealed signs of both de-remyelination and axonal impairment, the most prominent feature being a severe loss of larger fibres. Haplotype analysis of the GDAP1 locus demonstrated a common disease haplotype.\nCONCLUSIONS: The association of the mutation with a common haplotype suggested a common ancestor.","variants":[{"Name":"NM_018972.4(GDAP1):c.347T>G (p.Met116Arg)","Chromosome":"8","Start":"74360173","Stop":"74360173","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":46970,"rule_based_match":true,"evidence_text":"c.347 T>G","llm_judgment":"PRESENT","evidence":"c.347 T>G","abstract_start":530,"abstract_end":539}]}
{"pmid":"24225993","title":"A new mutation in the C-SH2 domain of PTPN11 causes Noonan syndrome with multiple giant cell lesions.","abstract":"Noonan syndrome (NS), an autosomal dominant multisystem disorder, is caused by the dysregulation of the RAS-MAPK pathway and is characterized by short stature, heart defects, pectus excavatum, webbed neck, learning problems, cryptorchidism and facial dysmorphism. We here present the clinical and molecular characterization of a family with NS and multiple giant cell lesions (MGCLs). The proband is a 12-year-old girl with NS and MGCL. Her mother shows typical NS without MGCL. Whole-exome sequencing of the girl, her mother and her healthy maternal grand parents revealed a previously unobserved mutation in exon 5 of the PTPN11 gene (c.598 A>T; p.N200Y), transmitted from the mother to the proband. As no other modification in the RAS-MAPK pathway genes as related to Rasopathies was detected in the proband, this report demonstrates for the first time that a unique mutation affecting this, otherwise unaffected signaling route, can cause both NS and NS/MGCL in the same family. This observation further confirms that NS/MGCL is not a distinct entity but rather that MGCL represents a rare complication of NS. Moreover, the localization of the p.N200Y mutation suggests an alternative molecular mechanism for the excessive phosphatase activity of the PTPN11-encoded protein.","variants":[{"Name":"NM_002834.5(PTPN11):c.598A>T (p.Asn200Tyr)","Chromosome":"12","Start":"112454636","Stop":"112454636","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":175541,"rule_based_match":true,"evidence_text":"c.598 A>T; p.N200Y","llm_judgment":"PRESENT","evidence":"c.598 A>T; p.N200Y","abstract_start":637,"abstract_end":655}]}
{"pmid":"21637475","title":"Novel mutations in the TBX5 gene in patients with Holt-Oram Syndrome.","abstract":"The Holt-Oram syndrome (HOS) is an autosomal dominant condition characterized by upper limb and cardiac malformations. Mutations in the TBX5 gene cause HOS and have also been associated with isolated heart and arm defects. Interactions between the TBX5, GATA4 and NKX2.5 proteins have been reported in humans. We screened the TBX5, GATA4, and NKX2.5 genes for mutations, by direct sequencing, in 32 unrelated patients presenting classical (8) or atypical HOS (1), isolated congenital heart defects (16) or isolated upper-limb malformations (7). Pathogenic mutations in the TBX5 gene were found in four HOS patients, including two new mutations (c.374delG; c.678G > T) in typical patients, and the hotspot mutation c.835C > T in two patients, one of them with an atypical HOS phenotype involving lower-limb malformations. Two new mutations in the GATA4 gene were found in association with isolated upper-limb malformations, but their clinical significance remains to be established. A previously described possibly pathogenic mutation in the NKX2.5 gene (c.73C > 7) was detected in a patient with isolated heart malformations and also in his clinically normal father.","variants":[{"Name":"NM_181486.4(TBX5):c.835C>T (p.Arg279Ter)","Chromosome":"12","Start":"114366312","Stop":"114366312","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":210203,"rule_based_match":true,"evidence_text":"c.835C > T","llm_judgment":"PRESENT","evidence":"c.835C > T","abstract_start":714,"abstract_end":724}]}
{"pmid":"38168645","title":"Recessive TMOD1 mutation causes childhood cardiomyopathy.","abstract":"Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1<sup>R189W</sup> and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1<sup>R189W</sup> demonstrated longer thin filaments than GFP-TMOD1<sup>wt</sup>-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1<sup>R189W</sup> showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant's effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.","variants":[{"Name":"NM_003275.4(TMOD1):c.565C>T (p.Arg189Trp)","Chromosome":"9","Start":"97564115","Stop":"97564115","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222256,"rule_based_match":true,"evidence_text":"c.565C>T, p.R189W","llm_judgment":"PRESENT","evidence":"c.565C>T, p.R189W","abstract_start":236,"abstract_end":253}]}
{"pmid":"29130490","title":"Sequence variants in nine different genes underlying rare skin disorders in 10 consanguineous families.","abstract":"BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study.\nMETHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families.\nRESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes.\nCONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.","variants":[{"Name":"NM_000526.5(KRT14):c.92del (p.Ile31fs)","Chromosome":"17","Start":"41586743","Stop":"41586743","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":77282,"rule_based_match":true,"evidence_text":"c.92delT in the KRT14 genes","llm_judgment":"PRESENT","evidence":"c.92delT in the KRT14 genes","abstract_start":752,"abstract_end":779},{"Name":"NM_000094.4(COL7A1):c.5314C>T (p.Arg1772Trp)","Chromosome":"3","Start":"48579271","Stop":"48579271","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620131,"rule_based_match":true,"evidence_text":"c.5314C>T","llm_judgment":"PRESENT","evidence":"c.5314C>T","abstract_start":566,"abstract_end":575},{"Name":"NM_000123.4(ERCC5):c.2453C>T (p.Ala818Val)","Chromosome":"13","Start":"102866765","Stop":"102866765","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":984388,"rule_based_match":true,"evidence_text":"c.2453C>T in ERCC5","llm_judgment":"PRESENT","evidence":"c.2453C>T in ERCC5","abstract_start":546,"abstract_end":564},{"Name":"NM_000382.3(ALDH3A2):c.10G>T (p.Glu4Ter)","Chromosome":"17","Start":"19648981","Stop":"19648981","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":984415,"rule_based_match":true,"evidence_text":"c.10G>T","llm_judgment":"PRESENT","evidence":"c.10G>T","abstract_start":630,"abstract_end":637},{"Name":"NM_001122764.3(PPOX):c.502C>T (p.Arg168Cys)","Chromosome":"1","Start":"161168462","Stop":"161168462","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23733,"rule_based_match":true,"evidence_text":"c.502C>T","llm_judgment":"PRESENT","evidence":"c.502C>T","abstract_start":608,"abstract_end":616},{"Name":"NM_016006.6(ABHD5):c.836del (p.Gln279fs)","Chromosome":"3","Start":"43717733","Stop":"43717733","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":984310,"rule_based_match":true,"evidence_text":"c.836delA in ABHD5","llm_judgment":"PRESENT","evidence":"c.836delA in ABHD5","abstract_start":526,"abstract_end":544},{"Name":"NM_017671.5(FERMT1):c.27del (p.Phe9fs)","Chromosome":"20","Start":"6119528","Stop":"6119528","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":984445,"rule_based_match":true,"evidence_text":"c.27delT in FERMT1","llm_judgment":"PRESENT","evidence":"c.27delT in FERMT1","abstract_start":506,"abstract_end":524},{"Name":"NM_021628.3(ALOXE3):c.1630C>T (p.Gln544Ter)","Chromosome":"17","Start":"8108522","Stop":"8108522","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":445918,"rule_based_match":true,"evidence_text":"c.1630C>T in ALOXE3","llm_judgment":"PRESENT","evidence":"c.1630C>T in ALOXE3","abstract_start":587,"abstract_end":606},{"Name":"NM_002016.2(FLG):c.10459A>T (p.Arg3487Ter)","Chromosome":"1","Start":"152304427","Stop":"152304427","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":984287,"rule_based_match":true,"evidence_text":"c.10459A>T","llm_judgment":"PRESENT","evidence":"c.10459A>T","abstract_start":729,"abstract_end":739}]}
{"pmid":"34354036","title":"First 2 Fabry Cases with Novel Mutation and Their Associated Clusters in Malaysia.","abstract":"BACKGROUND No cases of Fabry disease (FD) have been reported thus far in Malaysia. We aimed to report the demographic characteristics, clinical manifestations, molecular results, and treatment outcomes of 2 FD cases. This study was a retrospective review of 2 family clusters of FD on follow-up in Sarawak, Malaysia. CASE REPORT Two index patients were confirmed to have FD. Index patient 1, who had nephrotic-range proteinuria and cornea verticillata, carried a variant within exon 4 of the GLA gene: c.610 T>C (p.Trp204Arg). Agalsidase beta (Fabrazyme®) enzyme replacement therapy was initiated, with the absence of neutralizing antibody after 24 months. No hypersensitivity or adverse reactions were reported. The patient's proteinuria and renal function remained stable. Other family members who carried the same mutation were asymptomatic. Index patient 2, who had residual activity of alpha-galactosidase A and a normal globotriaosylsphingosine level, carried a novel GLA mutation of c.548-5T>A. He was diagnosed with end-stage renal disease on regular dialysis and had nonspecific headache with 1 episode of seizure a few years prior to FD genetic screening. One brother had chronic neuropathic pain but refused further investigations. Other family members who had the same mutation were asymptomatic. This mutation has never been reported in literature, and its pathogenicity warrants further studies. CONCLUSIONS It is of utmost importance to increase awareness of FD among clinicians, so that appropriate screening may be done to determine its true prevalence and prompt treatment can be initiated early.","variants":[{"Name":"NM_000169.3(GLA):c.548-5T>A","Chromosome":"X","Start":"101400762","Stop":"101400762","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2150569,"rule_based_match":true,"evidence_text":"c.548-5T>A","llm_judgment":"PRESENT","evidence":"c.548-5T>A","abstract_start":990,"abstract_end":1000}]}
{"pmid":"26589685","title":"Correlation of IL36RN mutation with different clinical features of pustular psoriasis in Chinese patients.","abstract":"Different studies have reported various values for the percentage of patients with IL36RN mutations, and it has also been reported that the sites of these mutations differ among different ethnicities. The current study was a cross-sectional study conducted to investigate the risk factors predicting IL36RN mutation in Chinese patients with different clinical features of pustular psoriasis. 57 Han Chinese patients, including 32 with generalized pustular psoriasis, 14 with palmoplantar pustulosis, 9 with plaque-type psoriasis with pustules, and 2 with erythrodermic psoriasis, were enrolled between March 2013 and July 2014. Blood samples were collected, genomic DNA was extracted from leukocytes, and polymerase chain reaction (PCR)-based Sanger sequencing was used to analyze the coding exons and flanking introns of the IL36RN gene. The patients with generalized pustular psoriasis exhibited the highest IL36RN mutation rate (75 %) among the aforementioned patient types, with the subgroup consisting of those patients who had features of acrodermatitis continua of Hallopeau exhibiting the highest c.115+6T>C mutation rate (93.8 %). In addition, early onset, ever generalized pustular psoriasis (more than two attacks), ever acrodermatitis continua of Hallopeau, inverse psoriasis, and a family history of pustular psoriasis were associated with IL36RN mutation. The c.115+6T>C mutation was the most common and the most important variant in all subtypes of pustular psoriasis with IL36RN mutations among our sample of Chinese patients.","variants":[{"Name":"NM_012275.3(IL36RN):c.115+6T>C","Chromosome":"2","Start":"113060943","Stop":"113060943","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":48518,"rule_based_match":true,"evidence_text":"c.115+6T>C","llm_judgment":"PRESENT","evidence":"c.115+6T>C","abstract_start":1105,"abstract_end":1115}]}
{"pmid":"34333724","title":"A founder mutation in the GMPPB gene [c.1000G > A (p.Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients.","abstract":"Twelve patients from seven unrelated South Indian families with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype and recessive inheritance underwent deep clinical phenotyping, electrophysiological evaluation, muscle histopathology, and next-generation sequencing/Sanger sequencing-based identification of the genetic defect. Homozygosity mapping was performed using high-throughput genome-wide genotyping for mapping the mutation and to evaluate the founder effect. The age of disease onset among patients ranged from childhood to 40 years of age. The key clinical manifestations observed were progressive fatigable limb-girdle weakness, muscle hypertrophy/atrophy, and preferential weakness in a dystrophic pattern. The ages at last follow-up ranged from 30 to 64 years; nine were independently ambulant, two required assistance, and one was wheelchair-bound. Lower limb muscle MRI showed varying degrees of fat replacement in the glutei, hamstrings, anterior leg muscles, and medial gastrocnemius. All patients showed significant decrement on repetitive nerve stimulation (RNS). Muscle biopsy in 7 patients revealed varying degrees of dystrophic and neurogenic changes. Treatment with pyridostigmine and/or salbutamol resulted in variable improvement in 10 patients. Genetic analysis showed an identical homozygous GMPPB mutation c.1000G > A (p.Asp334Asn) in all affected patients. A region of homozygosity (6Mbp) was observed flanking the c.1000G > A change in carrier chromosomes. This study identifies c.1000G > A in GMPPB as a common founder mutation in an ethnic community of South Indian descent with milder yet variable degree of clinical presentation of GMPPB-associated LGMD-CMS.","variants":[{"Name":"NM_021971.4(GMPPB):c.1000G>A (p.Asp334Asn)","Chromosome":"3","Start":"49721835","Stop":"49721835","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75121,"rule_based_match":true,"evidence_text":"c.1000G > A (p.Asp334Asn)","llm_judgment":"PRESENT","evidence":"c.1000G > A (p.Asp334Asn)","abstract_start":1368,"abstract_end":1393}]}
{"pmid":"32154999","title":"Novel compound heterozygous stop-gain mutations of LRBA in a Vietnamese patient with Common Variable Immune Deficiency.","abstract":"BACKGROUND: Lipopolysaccharide-responsive and beige-like anchor (LRBA) deficiency is a rare autosomal recessive common variable immunodeficiency (CVID), affecting 1:25,000-1:50,000 people worldwide. Biallelic mutations in the gene LRBA have been implicated in affected individuals.\nMETHODS: We report a 16-year-old Vietnamese, male patient with recurrent CVID symptoms including chronic diarrhea, interstitial pneumonia, cutaneous granulomatous lesions, hepatosplenomegaly, and finger clubbing. Immunological analyses and whole exome sequencing (WES) were performed to investigate phenotypic and genotypic features.\nRESULTS: Immunological analyses revealed hypogammaglobulinemia and low ratios of CD4+/CD8+ T cells. Two novel compound heterozygous stop-gain mutation in LRBA were identified: c.1933C > T (p.R645X) and c.949C > T (p.R317X). Sanger sequencing confirmed the segregation of these variants from the intact parents. The abolished LRBA protein expression was shown by immunoblot analysis. Subsequent treatment potentially saves the child from the same immune thrombocytopenia which led to his brother's untimely death; likely caused by the same LRBA mutations.\nCONCLUSION: This first report of LRBA deficiency in Vietnam expands our knowledge of the diverse phenotypes and genotypes driving CVID. Finally, the utilization of WES shows great promise as an effective diagnostic for CVID in our setting.","variants":[{"Name":"NM_001364905.1(LRBA):c.1933C>T (p.Arg645Ter)","Chromosome":"4","Start":"150897810","Stop":"150897810","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2752052,"rule_based_match":true,"evidence_text":"c.1933C > T (p.R645X)","llm_judgment":"PRESENT","evidence":"c.1933C > T (p.R645X)","abstract_start":792,"abstract_end":813}]}
{"pmid":"24176905","title":"Intronic deletions in the SLC34A3 gene: a cautionary tale for mutation analysis of hereditary hypophosphatemic rickets with hypercalciuria.","abstract":"Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia, variable degrees of rickets/osteomalacia, and hypercalciuria secondary to increased serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels. HHRH is caused by mutations in the SLC34A3 gene, which encodes sodium-phosphate co-transporter type IIc. A 6-1/2-year-old female presented with a history of nephrolithiasis. Her metabolic evaluation revealed increased 24-hour urine calcium excretion with high serum calcium, low intact parathyroid hormone (PTH), and elevated 1,25(OH)2D. In addition, the patient had low to low-normal serum phosphorus with high urine phosphorus. The patient had normal stature; without rachitic or boney deformities or a history of fractures. Genetic analysis of SLC34A3 revealed the patient to be a compound heterozygote for a novel single base pair deletion in exon 12 (c.1304delG) and 30-base pair deletion in intron 6 (g.1440-1469del). The single-base pair mutation causes a frameshift, which results in premature stop codon. The intronic deletion is likely caused by misalignment of the 4-basepair homologous repeats and results in the truncation of an already small intron to 63bp, which would impair proper RNA splicing of the intron. This is the fourth unique intronic deletion identified in patients with HHRH, suggesting the frequent occurrence of sequence misalignments in SLC34A3 and the importance of screening introns in patients with HHRH.","variants":[{"Name":"NM_001177316.2(SLC34A3):c.1304del (p.Ser435fs)","Chromosome":"9","Start":"137234700","Stop":"137234700","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":1020612,"rule_based_match":true,"evidence_text":"c.1304delG","llm_judgment":"PRESENT","evidence":"c.1304delG","abstract_start":919,"abstract_end":929}]}
{"pmid":"22550389","title":"A novel p.F206I mutation in Cx46 associated with autosomal dominant congenital cataract.","abstract":"PURPOSE: To identify the genetic defect in a Chinese family with bilateral congenital cataract.\nMETHODS: A three-generation family was recruited in this study. Detailed family history and clinical data were recorded. Ten candidate genes were screened for causative mutations. Direct sequencing was performed to analyze the cosegregation of the genotype with the disease phenotype.\nRESULTS: Affected individuals presented embryonal nuclear opacities in the lens. Sequencing of the candidate genes showed a heterozygous c. 616T>A variation in the connexin 46 (Cx46) gene, which resulted in the replacement of a highly conserved phenylalanine by isoleucine at codon 206 (p. F206I). This mutation co-segregated with all affected individuals and was not observed in unaffected family members or ethnically matched controls.\nCONCLUSIONS: We report a novel mutation (p.F206I) in the fourth transmembrane domain of connexin 46. These findings thus expand the mutation spectrum of Cx46 in association with congenital cataract.","variants":[{"Name":"NM_021954.4(GJA3):c.616T>A (p.Phe206Ile)","Chromosome":"13","Start":"20142673","Stop":"20142673","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":65607,"rule_based_match":true,"evidence_text":"c. 616T>A","llm_judgment":"PRESENT","evidence":"c. 616T>A","abstract_start":518,"abstract_end":527}]}
{"pmid":"25885670","title":"Familial partial lipodystrophy, Dunnigan variety - challenges for patient care during pregnancy: a case report.","abstract":"BACKGROUND: Familial partial lipodystrophy, Dunnigan variety, is a recognised autosomal dominant disorder which is caused by heterozygous missense mutations in the lamin A/C gene. Dunnigan lipodystrophy is characterised by a variable loss of fat from the extremities and trunk, as well as an excess of subcutaneous fat in the chin and supraclavicular area. The associated metabolic abnormalities include: insulin resistance, diabetes, dyslipidaemia and low leptin levels.\nCASE PRESENTATION: The authors studied the case of a 24-year-old caucasian pregnant woman, with a past medical history of acute pancreatitis, combined dyslipidaemia and diabetes mellitus. At 7 weeks of pregnancy she was referred to the outpatient endocrinology and obstetrics clinic for diabetes care. A physical examination revealed that she presented a loss of fat from the extremities and trunk and also had an excess of subcutaneous fat in the chin. Triglyceride levels were persistently high, and glycaemic control was only achieved through the administration of high doses of insulin (1.8 U/Kg/day). Dunnigan lipodystrophy was suspected and thus a genetic study was requested, which revealed the presence of c.1444C > T (p.Arg482Trp) heterozygote mutation in the lamin A/C gene.\nCONCLUSION: This case is used to illustrate the importance of being able to recognise the clinical signs of this rare lipodystrophic syndrome, which may cause potentially severe consequences, and also the difficulties in treating it during pregnancy.","variants":[{"Name":"NM_170707.4(LMNA):c.1444C>T (p.Arg482Trp)","Chromosome":"1","Start":"156136984","Stop":"156136984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29528,"rule_based_match":true,"evidence_text":"c.1444C > T (p.Arg482Trp)","llm_judgment":"PRESENT","evidence":"c.1444C > T (p.Arg482Trp)","abstract_start":1186,"abstract_end":1211}]}
{"pmid":"32356167","title":"Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family.","abstract":"Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome. Classification and interpretation of intronic variants, especially those outside the consensus ± 1 ~ 2 splice sites are challenging as it is uncertain whether such variants would affect splicing accuracy and efficiency. The assessment of the pathogenicity of splice site variants in MLH1 is further complicated by the various isoforms due to alternative splicing. In this report, we describe a 42-year-old female with Lynch syndrome who carries a germline variant, MLH1 c.678-3T>A, in the splice acceptor site of intron 8. Functional studies and semiquantitative analysis demonstrated that this variant causes a significant increase in the transcripts with exon 9 or exon 9 and 10 deletions, which presumably leads to premature protein truncation or abnormal protein. In addition, we also observed MSI-H and loss of MLH1 by IHC in patient's tumor tissue. This variant also segregated with Lynch Syndrome related cancers in three affected family members. Based on these evidence, the MLH1 c.678-3T>A variant is considered pathogenic.","variants":[{"Name":"NM_000249.4(MLH1):c.678-3T>A","Chromosome":"3","Start":"37014429","Stop":"37014429","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":95799,"rule_based_match":true,"evidence_text":"MLH1 c.678-3T>A","llm_judgment":"PRESENT","evidence":"MLH1 c.678-3T>A","abstract_start":545,"abstract_end":560}]}
{"pmid":"32383243","title":"Constraint and conservation of paired-type homeodomains predicts the clinical outcome of missense variants of uncertain significance.","abstract":"The need to interpret the pathogenicity of novel missense variants of unknown significance identified in the homeodomain of X-chromosome aristaless-related homeobox (ARX) gene prompted us to assess the utility of conservation and constraint across these domains in multiple genes compared to conventional in vitro functional analysis. Pathogenic missense variants clustered in the homeodomain of ARX contribute to intellectual disability (ID) and epilepsy, with and without brain malformation in affected males. Here we report novel c.1112G>A, p.Arg371Gln and c.1150C>T, p.Arg384Cys variants in male patients with ID and severe seizures. The third case of a male patient with a c.1109C>T, p.Ala370Val variant is perhaps the first example of ID and autism spectrum disorder (ASD), without seizures or brain malformation. We compiled data sets of pathogenic variants from ClinVar and presumed benign variation from gnomAD and demonstrated that the high levels of sequence conservation and constraint of benign variation within the homeodomain impacts upon the ability of publicly available in silico prediction tools to accurately discern likely benign from likely pathogenic variants in these data sets. Despite this, considering the inheritance patterns of the genes and disease variants with the conservation and constraint of disease variants affecting the homeodomain in conjunction with current clinical assessments may assist in predicting the pathogenicity of missense variants, particularly for genes with autosomal recessive and X-linked patterns of disease inheritance, such as ARX. In vitro functional analysis demonstrates that the transcriptional activity of all three variants was diminished compared to ARX-Wt. We review the associated phenotypes of the published cases of patients with ARX homeodomain variants and propose expansion of the ARX-related phenotype to include severe ID and ASD without brain malformations or seizures. We propose that the use of the constraint and conservation data in conjunction with consideration of the patient phenotype and inheritance pattern may negate the need for the experimental functional validation currently required to achieve a diagnosis.","variants":[{"Name":"NM_139058.3(ARX):c.1150C>T (p.Arg384Cys)","Chromosome":"X","Start":"25007409","Stop":"25007409","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1890563,"rule_based_match":true,"evidence_text":"c.1150C>T, p.Arg384Cys","llm_judgment":"PRESENT","evidence":"c.1150C>T, p.Arg384Cys","abstract_start":560,"abstract_end":582},{"Name":"NM_139058.3(ARX):c.1112G>A (p.Arg371Gln)","Chromosome":"X","Start":"25010267","Stop":"25010267","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1330941,"rule_based_match":true,"evidence_text":"c.1112G>A, p.Arg371Gln","llm_judgment":"PRESENT","evidence":"c.1112G>A, p.Arg371Gln","abstract_start":533,"abstract_end":555}]}
{"pmid":"33981653","title":"Identification of a Rare Exon 19 Skipping Mutation in ALMS1 Gene in Alström Syndrome Patients From Two Unrelated Saudi Families.","abstract":"<b>Background:</b> Alström syndrome (AS) is a very rare childhood disorder characterized by cardiomyopathy, progressive hearing loss and blindness. Inherited genetic variants of ALMS1 gene are the known molecular cause of this disease. The objective of this study was to characterize the genetic basis and understand the genotype-phenotype relationship in Saudi AS patients. <b>Methods:</b> Clinical phenotyping and whole-exome sequencing (WES) analysis were performed on six AS patients belonging to two unrelated consanguineous Saudi families. Sanger sequencing was performed to determine the mode of inheritance of ALMS1 variant in first-degree family relatives and also to ensure its rare prevalence in 100 healthy population controls. <b>Results:</b> We identified that Alström patients from both the families were sharing a very rare ALMS1, 3'-splice site acceptor (c.11873-2 A>T) variant, which skips entire exon-19 and shortens the protein by 80 amino acids. This disease variant was inherited by AS patients in autosomal recessive mode and is not yet reported in any population-specific genetic databases. AS patients carrying this mutation showed heterogeneity in clinical presentations. Computational analysis of the mutant centroid structure of ALMS1 mRNA revealed that exon-19 skipping enlarges the hairpin loop and decreases the free energy, eventually affecting its folding pattern, stability, and function. Hence, we propose c.11873-2A as an AS causative potential founder mutation in Saudi Arabia because it is found in two families lacking a common lineage. <b>Conclusions:</b> We conclude that WES analysis potentially helps in clinical phenotyping, early diagnosis, and better clinical management of Alström patients showing variable clinical expressivity.","variants":[{"Name":"NM_001378454.1(ALMS1):c.11873-2A>T","Chromosome":"2","Start":"73601193","Stop":"73601193","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":188919,"rule_based_match":true,"evidence_text":"c.11873-2 A>T","llm_judgment":"PRESENT","evidence":"c.11873-2 A>T","abstract_start":872,"abstract_end":885}]}
{"pmid":"34923728","title":"EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma.","abstract":"Juvenile open-angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novel EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co-segregating with disease. Affected variant carriers (N = 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early-onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.","variants":[{"Name":"NM_001039348.3(EFEMP1):c.1480T>C (p.Ter494Gln)","Chromosome":"2","Start":"55867075","Stop":"55867075","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1284212,"rule_based_match":true,"evidence_text":"c.1480T>C, p.Ter494Glnext*29","llm_judgment":"PRESENT","evidence":"c.1480T>C, p.Ter494Glnext*29","abstract_start":247,"abstract_end":275}]}
{"pmid":"28801086","title":"Slowly progressive leukodystrophy in an adolescent male with phosphoglycerate kinase deficiency.","abstract":"We report the case of an 18-year-old man with a phosphoglycerate kinase (PGK) deficiency who had slowly progressive leukodystrophy during adolescence. The patient had a history of severe neonatal jaundice, hemolytic crisis with rhabdomyolysis triggered by febrile viral infections, dysarthria, and intellectual disability during early childhood. Clumsiness in walking and writing became obvious at ∼10years of age. Evaluations performed by us on the 18-year-old patient confirmed the presence of pyramidal tract signs, increased muscle tone, and generalized dystonia. Brain magnetic resonance (MR) imaging revealed leukodystrophy in the periventricular white matter, posterior limbs of the internal capsule, dorsal pons, and middle cerebellar peduncles. Compared to MR images acquired at 9years of age, MR images acquired at 18years of age showed that the white matter atrophy had progressed. The PGK deficiency was diagnosed by identifying a known missense mutation in PGK1 (c.1060G>C) through comprehensive target capture sequencing and by observing low PGK activity in his red blood cells. The patient underwent a ketogenic diet for 2weeks, which we expected would increase adenosine triphosphate levels through sources other than the PGK-associated glycolytic pathway. The diet was not tolerated owing to the unexpected emergence of hemolysis. Hemolytic anemia, neurological dysfunction, and myopathy are often associated with PGK deficiencies. However, leukodystrophy as a symptom of PGK deficiency has not been reported previously. Our case highlights the progressive nature of the neurological complications related to PGK deficiencies. Therefore, long-term follow-up is recommended, even if neurological impairments are not obvious during childhood.","variants":[{"Name":"NM_000291.4(PGK1):c.1060G>C (p.Ala354Pro)","Chromosome":"X","Start":"78124997","Stop":"78124997","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1426925,"rule_based_match":true,"evidence_text":"c.1060G>C","llm_judgment":"PRESENT","evidence":"c.1060G>C","abstract_start":976,"abstract_end":985}]}
{"pmid":"31755339","title":"Asymptomatic adults in a single family with familial exudative vitreoretinopathy and","abstract":"<b>Background</b>: Familial exudative vitreoretinopathy (FEVR) is a disorder of retinal angiogenesis associated with mutations in multiple genes related to the <i>Wnt</i> pathway. The disease is characterized by a spectrum of ophthalmic manifestations that range from asymptomatic to blinding. While FEVR has classically been considered a diagnosis made in the pediatric population, it can be seen in adults and lead to vision loss if unidentified. We present three asymptomatic adults in a single, five-member family with clinical findings and genetic testing supportive of a diagnosis of FEVR.<b>Materials and Methods</b>: Case series. All patients underwent ophthalmologic examination, diagnostic imaging, and genetic testing.<b>Results</b>: A 32-year-old female was referred for evaluation of abnormal retinal vessels. Clinical examination and diagnostic testing revealed retinal vascular dragging, peripheral avascularity, and retinal neovascularization suggestive of a diagnosis of FEVR. Genetic testing was positive for a heterozygous intronic variant (c.149 + 3A>G) in <i>TSPAN12</i>. The same variant was identified in the patient's mother and one adult sister, each showing evidence of early stage FEVR. The patient's father and second adult sister had normal eye exams with negative genetic testing. All patients were asymptomatic with good vision.<b>Conclusions</b>: FEVR can be first diagnosed in asymptomatic adult patients who may require treatment. The disease, therefore, may be incompletely characterized and under diagnosed. The specific variant in <i>TSPAN12</i> identified in this family may be associated with early stage FEVR or disease that manifests later in life. Clinical correlation with exact variants such as this may enhance our understanding of this disease.","variants":[{"Name":"NM_012338.4(TSPAN12):c.149+3A>G","Chromosome":"7","Start":"120840024","Stop":"120840024","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1206057,"rule_based_match":true,"evidence_text":"c.149 + 3A>G","llm_judgment":"PRESENT","evidence":"c.149 + 3A>G","abstract_start":1060,"abstract_end":1072}]}
{"pmid":"21310277","title":"Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease.","abstract":"The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate.","variants":[{"Name":"NM_000791.4(DHFR):c.458A>T (p.Asp153Val)","Chromosome":"5","Start":"80633904","Stop":"80633904","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":38629,"rule_based_match":true,"evidence_text":"c.458A>T (p.Asp153Val)","llm_judgment":"PRESENT","evidence":"c.458A>T (p.Asp153Val)","abstract_start":568,"abstract_end":590}]}
{"pmid":"25556323","title":"Hutchinson-Gilford progeria syndrome caused by an LMNA mutation: a case report.","abstract":"Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year-old boy who was born at full term but presented with scleroderma-like appearance at 1 month of age and gradually developed clinical manifestations of progeria. He had characteristic facial features of prominent eyes, scalp, and leg veins; loss of scalp hair, eyebrows, and eyelashes; stunted growth; scleroderma-like changes of the skin; and a premature aged appearance. Metabolic investigations showed transient methylmalonic aciduria, and genetic testing of the peripheral blood identified the c.1824C>T heterozygous LMNA mutation. The present case is reported because of its rarity.","variants":[{"Name":"NM_170707.4(LMNA):c.1824C>T (p.Gly608=)","Chromosome":"1","Start":"156138613","Stop":"156138613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29539,"rule_based_match":true,"evidence_text":"c.1824C>T","llm_judgment":"PRESENT","evidence":"c.1824C>T","abstract_start":658,"abstract_end":667}]}
{"pmid":"33394956","title":"PERIPHERAL OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN A CHOROIDEREMIA CARRIER.","abstract":"PURPOSE: To describe the peripheral optical coherence tomography findings in a female choroideremia carrier.\nMETHODS: A 56-year-old woman was referred for visual disturbance complaining of some occasional photopsias and increasing difficulty with her vision at night in both eyes. Best-corrected visual acuity was 20/20 in the right eye and 20/150 in the left eye. Fundus examination revealed mildly tilted disks and peripapillary atrophy with subtle retinal pigment epithelial changes in the periphery.\nRESULTS: Macular optical coherence tomography in the right eye appeared unremarkable, but the in the left eye, there was diffuse ellipsoid zone band disruption. Green-light fundus autofluorescence revealed mottled areas of decreased autofluorescence in the mid and far periphery creating an irregular mosaic pattern. Peripheral optical coherence tomography scans revealed more diffuse ellipsoid zone alterations than were apparent on the fundus autofluorescence imaging. Genetic testing revealed a heterozygous pathogenic variant in the CHM gene (c.715C>T, p.Arg239). An additional heterozygous mutation was noted in the CNGB1 gene (c.290+2T>C, splice donor).\nCONCLUSION: Choroideremia carriers may manifest widespread photoreceptor alterations, which may be more extensive than apparent on fundus autofluorescence imaging.","variants":[{"Name":"NM_001297.5(CNGB1):c.290+2T>C","Chromosome":"16","Start":"57964128","Stop":"57964128","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1056336,"rule_based_match":true,"evidence_text":"c.290+2T>C","llm_judgment":"PRESENT","evidence":"c.290+2T>C","abstract_start":1137,"abstract_end":1147},{"Name":"NM_000390.4(CHM):c.715C>T (p.Arg239Ter)","Chromosome":"X","Start":"85958965","Stop":"85958965","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":269993,"rule_based_match":true,"evidence_text":"c.715C>T, p.Arg239","llm_judgment":"PRESENT","evidence":"c.715C>T, p.Arg239","abstract_start":1051,"abstract_end":1069}]}
{"pmid":"32132887","title":"","abstract":"Male breast cancer (MBC) is a rare disease that occurs in ~0.2% of all neoplasms among men. The risk of developing MBC is higher in men with a <i>BRCA2</i> genetic mutation (7%). The aim of this study was to evaluate the association between c.2808_2811del ACAA (p.Ala938Profs) <i>BRCA2</i> mutation in MBC and clinicopathological factors. A 75-year-old patient was admitted to the Genetic Outpatient Clinic with a diagnosis of right breast cancer and with a family history of cancer (two daughters who were diagnosed with breast cancer at ages 46 and 38 years). Postoperative histopathological examination revealed tumor type pT2 N1a Mx, NST NG-3 G-3, Ki-67 (75%), HER2 (+), ER (+++), PR (+++), invasive carcinoma and luminal B subtype. The complete coding sequences of the <i>BRCA1</i> and <i>BRCA2</i> genes were analyzed for genomic DNA material using next generation sequencing on the Ion Torrent platform. The c.2808_2811delACAA (p.Ala938Profs) mutation was observed in the <i>BRCA2</i> gene. The presence of the c.2808_2811delACAA (p.Ala938Profs) mutation in the <i>BRCA2</i> gene was confirmed using the Sanger method. The same <i>BRCA2</i> gene mutation was reported in one of the patient's daughters. The detected mutation causes the frameshift mutation, resulting in the creation of an additional translation termination codon and the synthesis of an abnormal protein. This mutation was associated with a later age of disease, a higher histological degree, a higher mitotic index, a positive steroid receptor status and the luminal B subtype HER2- breast cancer.","variants":[{"Name":"NM_000059.3(BRCA2):c.2808_2811del (p.Ala938Profs)","Chromosome":"13","Start":"32337161","Stop":"32337164","ReferenceAlleleVCF":"TAAAC","AlternateAlleleVCF":"T","allel_id":24361,"rule_based_match":true,"evidence_text":"c.2808_2811delACAA (p.Ala938Profs)","llm_judgment":"PRESENT","evidence":"c.2808_2811delACAA (p.Ala938Profs)","abstract_start":915,"abstract_end":949}]}
{"pmid":"22266148","title":"Novel and recurrent COL7A1 mutation in a Polish population.","abstract":"Dystrophic Epidermolysis Bullosa (DEB) is a rare bullous genodermatosis caused by mutations in COL7A1, which encodes collagen type VII, the main component of anchoring fibrilis. DEB is inherited in an autosomal recessive and dominant manner, depending on the mutation type and localization. The aim of this study was to update the spectrum and frequency of COL7A1 mutations in a cohort of 42 Polish DEB patients. Using direct sequencing strategy we identified 25 different mutations, which gave us a detection rate of about 88%. In total, thirteen novel variants were identified, including three de novo mutations (p.G2680S, p.G2043R and p.Gly2064_Arg2069del). The panel of recessively inherited DEB causing recurrent mutations comprise of five variants: c.425A>G, c.682+1G>A, p.R2069C, p.W796X and, unreported before, c.7154delC, which accounts for about 59% of all mutated alleles in this group. In the dominant type of DEB, only p.G2043R was found to be recurrent and it was identified in 50% patients. Our results give further insight into the pathogenesis and epidemiology of DEB.","variants":[{"Name":"NM_000094.4(COL7A1):c.425A>G (p.Lys142Arg)","Chromosome":"3","Start":"48593538","Stop":"48593538","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":38590,"rule_based_match":true,"evidence_text":"c.425A>G","llm_judgment":"PRESENT","evidence":"c.425A>G","abstract_start":755,"abstract_end":763},{"Name":"NM_000094.4(COL7A1):c.682+1G>A","Chromosome":"3","Start":"48593101","Stop":"48593101","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359487,"rule_based_match":true,"evidence_text":"c.682+1G>A","llm_judgment":"PRESENT","evidence":"c.682+1G>A","abstract_start":765,"abstract_end":775}]}
{"pmid":"38572626","title":"Homozygosity for disease-causing variants in AMT and GLDC in a patient with severe nonketotic hyperglycinemia.","abstract":"Nonketotic hyperglycinemia (NKH) is a relatively well-characterized inborn error of metabolism that results in a combination of lethargy, hypotonia, seizures, developmental arrest, and, in severe cases, death early in life. Three genes encoding components of the glycine cleavage enzyme system-GLDC, AMT, and GCSH-are independently associated with NKH. We report on a patient with severe NKH in whom the homozygous pathogenic variant in AMT (NM_000481.3):c.602_603del (p.Lys201Thrfs*75) and the homozygous likely pathogenic variant in GLDC(NM_000170.2):c.2852C>A (p.Ser951Tyr) were both identified. Our patient demonstrates a novel combination of two homozygous disease-causing variants impacting the glycine cleavage pathway at two different components, and elicits management- and genetic counseling-related challenges for the family.","variants":[{"Name":"NM_000170.3(GLDC):c.2852C>A (p.Ser951Tyr)","Chromosome":"9","Start":"6534775","Stop":"6534775","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":544928,"rule_based_match":true,"evidence_text":"c.2852C>A (p.Ser951Tyr)","llm_judgment":"PRESENT","evidence":"c.2852C>A (p.Ser951Tyr)","abstract_start":553,"abstract_end":576}]}
{"pmid":"28951487","title":"Familial MTC with","abstract":"INTRODUCTION: High prevalence of <i>RET</i> p.Gly533Cys (c.1597G > T) has been found in familial MTC in Greece (exon 8 fMTC). We studied their origin and compared clinical characteristics with non-exon 8 fMTC.\nMETHODS: 102 fMTC (FMTC and MEN2A) patients (31.4% males) were followed for 2.9-37 years (median 6 years). Fifty-one carried the <i>RET</i> exon 8 mutation; the remaining were non-exon 8 fMTC (exons 10, 11, 13, 14). Pre-, post-operative calcitonin, disease extent at diagnosis and follow-up and families' place of origin were recorded.\nRESULTS: Exon 8 fMTC were older (42.3 ± 13.3 vs 30.8 ± 17.8 years, <i>P</i> < 0.001), including index cases (<i>P</i> = 0.016). In index cases, the stage at diagnosis was more favorable in exon 8 fMTC compared to non-exon 8 fMTC (stage I and II: 65% vs 23.8%, stage III: 25% vs 57.1%, stage IV: 10% vs 19%, <i>P</i> = 0.025). More favorable outcome was noted in exon 8 fMTCs (remission: 72.5% vs 45.8%, stable disease: 27.5% vs 41.7%, progression: 0.0% vs 12.5%, <i>P</i> = 0.001). Exon 8 fMTC patients carried more frequently a second malignancy (25.5% vs 6.3%, <i>P</i> = 0.009); 69% of these were PTCs. Exon 8 fMTC patients were significantly older at diagnosis compared to non-exon 8 moderate-risk <i>RET</i> carriers and presented more favorable clinical outcome (remission: 72.5% vs 50%, stable disease: 27.5% vs 41.7%, progression: 0.0% vs 8.3%, <i>P</i> = 0.021). This difference remained when only index cases were analyzed. 'Hot spots' in the origin of exon 8 fMTCs families were recognized. No phenotype or outcome differences were found between the exon 8 families from the various regions.\nCONCLUSIONS: In exon 8 fMTCs' older age, favorable disease stage at diagnosis and favorable outcome suggest slow disease progression compared to non-exon 8 fMTC. Compared with moderate-risk <i>RET</i> mutation carriers, exon 8 fMTC patients have a more favorable clinical outcome. The higher prevalence of second malignancies, especially PTC, not previously reported, merits further investigation. Increased awareness for inherited disease is required for patients with apparently sporadic MTC originating from recognized 'hot spots', as the age at presentation is usually delayed.","variants":[{"Name":"NM_020975.6(RET):c.1597G>T (p.Gly533Cys)","Chromosome":"10","Start":"43112173","Stop":"43112173","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":28989,"rule_based_match":true,"evidence_text":"p.Gly533Cys (c.1597G > T)","llm_judgment":"PRESENT","evidence":"p.Gly533Cys (c.1597G > T)","abstract_start":44,"abstract_end":69}]}
{"pmid":"24603435","title":"Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome.","abstract":"PURPOSE: Treacher Collins syndrome is a mandibulofacial dysostosis caused by mutations in genes involved in ribosome biogenesis and synthesis. TCOF1 mutations are observed in ~80% of the patients and are inherited in an autosomal dominant manner. Recently, two other genes have been reported in <2% of patients--POLR1D in patients with autosomal dominant inheritance, and POLR1C in patients with autosomal recessive inheritance.\nMETHODS: We performed direct sequencing of TCOF1, POLR1C, and POLR1D in two unrelated consanguineous families.\nRESULTS: The four affected children shared the same homozygous mutation in POLR1D (c.163C>G, p.Leu55Val). This mutation is localized in a region encoding the dimerization domain of the RNA polymerase. It is supposed that this mutation impairs RNA polymerase, resulting in a lower amount of mature dimeric ribosomes. A functional analysis of the transcripts of TCOF1 by real-time quantitative reverse transcription-polymerase chain reaction was performed in the first family, demonstrating a 50% reduction in the index case, compatible with this hypothesis.\nCONCLUSION: This is the first report of POLR1D mutation being responsible for an autosomal recessive inherited Treacher Collins syndrome. These results reinforce the concept of genetic heterogeneity of Treacher Collins syndrome and underline the importance of combining clinical expertise and familial molecular analyses for appropriate genetic counseling.","variants":[{"Name":"NM_015972.4(POLR1D):c.163C>G (p.Leu55Val)","Chromosome":"13","Start":"27623011","Stop":"27623011","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":166231,"rule_based_match":true,"evidence_text":"c.163C>G, p.Leu55Val","llm_judgment":"PRESENT","evidence":"c.163C>G, p.Leu55Val","abstract_start":623,"abstract_end":643}]}
{"pmid":"35741760","title":"Identification of New Genetic Determinants in Pediatric Patients with Familial Hypercholesterolemia Using a Custom NGS Panel.","abstract":"The most common form of inherited lipid disorders is familial hypercholesterolemia (FH). It is characterized primarily by high concentrations of the clinical triad of low-density lipoprotein cholesterol, tendon xanthomas and premature CVD. The well-known genetic background are mutations in LDLR, APOB and PCSK9 gene. Causative mutations can be found in 60−80% of definite FH patients and 20−30% of those with possible FH. Their occurrence could be attributed to the activity of minor candidate genes, whose causal mechanism has not been fully discovered. The aim of the conducted study was to identify disease-causing mutations in FH-related and candidate genes in pediatric patients from Poland using next generation sequencing (NGS). An NGS custom panel was designed to cover 21 causative and candidate genes linked to primary dyslipidemia. Recruitment was performed using Simon Broome diagnostic criteria. Targeted next generation sequencing was performed on a MiniSeq sequencer (Illumina, San Diego, CA, USA) using a 2 × 150 bp paired-end read module. Sequencing data analysis revealed pathogenic and possibly pathogenic variants in 33 out of 57 studied children. The affected genes were LDLR, APOB, ABCG5 and LPL. A novel pathogenic 7bp frameshift deletion c.373_379delCAGTTCG in the exon 4 of the LDLR gene was found. Our findings are the first to identify the c.373_379delCAGTTCG mutation in the LDLR gene. Furthermore, the double heterozygous carrier of frameshift insertion c.2416dupG in the LDLR gene and missense variant c.10708C>T in the APOB gene was identified. The c.2416dupG variant was defined as pathogenic, as confirmed by its cosegregation with hypercholesterolemia in the proband’s family. Although the APOB c.10708C>T variant was previously detected in hypercholesterolemic patients, our data seem to demonstrate no clinical impact. Two missense variants in the LPL gene associated with elevated triglyceride plasma level (c.106G>A and c.953A>G) were also identified. The custom NGS panel proved to be an effective research tool for identifying new causative aberrations in a genetically heterogeneous disease as familial hypercholesterolemia (FH). Our findings expand the spectrum of variants associated with the FH loci and will be of value in genetic counseling among patients with the disease.","variants":[{"Name":"NM_000527.5(LDLR):c.2416dup (p.Val806fs)","Chromosome":"19","Start":"11129534","Stop":"11129535","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":246615,"rule_based_match":true,"evidence_text":"c.2416dupG","llm_judgment":"PRESENT","evidence":"c.2416dupG","abstract_start":1484,"abstract_end":1494},{"Name":"NM_000384.3(APOB):c.10708C>T (p.His3570Tyr)","Chromosome":"2","Start":"21006160","Stop":"21006160","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":425464,"rule_based_match":true,"evidence_text":"c.10708C>T","llm_judgment":"PRESENT","evidence":"c.10708C>T","abstract_start":1533,"abstract_end":1543}]}
{"pmid":"27071392","title":"Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation.","abstract":"PURPOSE: To describe the clinical and genetic findings in a patient with autosomal recessive bestrophinopathy (ARB) and his healthy parents.\nMETHODS: The patient and his healthy non-consanguineous parents underwent detailed ophthalmic evaluations including electro-oculography (EOG), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Mutation analysis of the BEST1 gene was performed by Sanger sequencing.\nRESULTS: The FAF images showed multiple spots of increased autofluorescence, and the sites of these spots corresponded to the yellowish deposits detected by ophthalmoscopy. SD-OCT showed cystoid macular changes and a shallow serous macular detachment. The Arden ratio of the EOG was markedly reduced to 1.1 in both eyes. Genetic analysis of the proband detected two sequence variants of the BEST1 gene in the heterozygous state: a novel variant c.717delG, p.V239VfsX2 and an already described c.763C>T, p.R255W variant associated with Best vitelliform macular dystrophy and ARB. The proband's father carried the c.717delG, p.V239VfsX2 variant in the heterozygous state, and the mother carried the c.763C>T, p.R255W variant in the heterozygous state. The parents who were heterozygous for the BEST1 variants had normal visual acuity, EOG, SD-OCT, and FAF images.\nCONCLUSIONS: In a truncating BEST1 mutation, the phenotype associated with ARB is most likely due to a marked decrease in the expression of BEST1 promoted by the nonsense-mediated decay surveillance mechanism, and it may depend on the position of the premature termination of the codon created.","variants":[{"Name":"NM_004183.4(BEST1):c.763C>T (p.Arg255Trp)","Chromosome":"11","Start":"61958194","Stop":"61958194","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152845,"rule_based_match":true,"evidence_text":"c.763C>T, p.R255W","llm_judgment":"PRESENT","evidence":"c.763C>T, p.R255W","abstract_start":947,"abstract_end":964}]}
{"pmid":"25771876","title":"The germline CDH1 c.48 G>C substitution contributes to cancer predisposition through generation of a pro-invasive mutation.","abstract":"Mutation screening of CDH1 is a standard of care for patients who meet criteria for Hereditary Diffuse Gastric Cancer (HDGC). In this setting, the classification of the sequence variants found in CDH1 is a critical step for risk management of patients with HDGC. In this report, we describe a germline CDH1 c.48 G>C variant found in a 21 year old woman and her living great uncle, who were both diagnosed with gastric cancer and belong to a family with high incidence of this type of cancer. This variant occurs at the last nucleotide of exon 1 and presumably results in a Gln-to-His change at codon 16 (Q16H). We used cloning strategies to evaluate the effects on mRNA stability and found that 5/27 and 0/17 clones have the \"C\" mutant allele in patient and her great uncle, respectively. In vitro functional studies revealed that the germline missense mutant (Q16H) had a pro-invasive cell behavior. Both results (functional and clinical) support the conclusion that the CDH1 c.48 G>C (Q16H) variant contributes to HDGC through the generation of a pathogenic missense mutation with loss of anti-invasive function.","variants":[{"Name":"NM_004360.5(CDH1):c.48G>C (p.Gln16His)","Chromosome":"16","Start":"68737463","Stop":"68737463","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1032791,"rule_based_match":true,"evidence_text":"CDH1 c.48 G>C (Q16H)","llm_judgment":"PRESENT","evidence":"CDH1 c.48 G>C (Q16H)","abstract_start":972,"abstract_end":992}]}
{"pmid":"28777931","title":"Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome.","abstract":"The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were identified, including homozygous c.321+1G>T in a subject of Italian ancestry and homozygous c.322-10G>A in affected sibling pairs from two unrelated families of Puerto Rican descent. In addition, compound heterozygous MRPS34 mutations were identified in a proband of French ancestry; a missense (c.37G>A [p.Glu13Lys]) and a nonsense (c.94C>T [p.Gln32<sup>∗</sup>]) variant. We demonstrated that these mutations reduce MRPS34 protein levels and the synthesis of OXPHOS subunits encoded by mtDNA. Examination of the mitoribosome profile and quantitative proteomics showed that the mitochondrial translation defect was caused by destabilization of the small mitoribosomal subunit and impaired monosome assembly. Lentiviral-mediated expression of wild-type MRPS34 rescued the defect in mitochondrial translation observed in skin fibroblasts from affected subjects, confirming the pathogenicity of MRPS34 mutations. Our data establish that MRPS34 is required for normal function of the mitoribosome in humans and furthermore demonstrate the power of quantitative proteomic analysis to identify signatures of defects in specific cellular pathways in fibroblasts from subjects with inherited disease.","variants":[{"Name":"NM_023936.2(MRPS34):c.94C>T (p.Gln32Ter)","Chromosome":"16","Start":"1773026","Stop":"1773026","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432256,"rule_based_match":true,"evidence_text":"c.94C>T (p.Gln32<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"c.94C>T","abstract_start":1033,"abstract_end":1040},{"Name":"NM_023936.1(MRPS34):c.321+1G>T","Chromosome":"16","Start":"1772798","Stop":"1772798","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":423234,"rule_based_match":true,"evidence_text":"c.321+1G>T","llm_judgment":"PRESENT","evidence":"c.321+1G>T","abstract_start":732,"abstract_end":742},{"Name":"NM_023936.2(MRPS34):c.37G>A (p.Glu13Lys)","Chromosome":"16","Start":"1773083","Stop":"1773083","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":423091,"rule_based_match":true,"evidence_text":"c.37G>A [p.Glu13Lys]","llm_judgment":"PRESENT","evidence":"c.37G>A [p.Glu13Lys]","abstract_start":995,"abstract_end":1015},{"Name":"NM_023936.2(MRPS34):c.322-10G>A","Chromosome":"16","Start":"1772656","Stop":"1772656","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":432254,"rule_based_match":true,"evidence_text":"c.322-10G>A","llm_judgment":"PRESENT","evidence":"c.322-10G>A","abstract_start":791,"abstract_end":802}]}
{"pmid":"32881366","title":"TP63-mutation as a cause of prenatal lethal multicystic dysplastic kidneys.","abstract":"BACKGROUND: Ectrodactyly-ectodermal dysplasia-clefting syndrome 3 (EEC) is one of the six overlapping syndromes caused by mutations in the tumor protein p63 gene (TP63). EEC is suspected when patients have cleft hands or feet, polydactyly, and syndactyly, abnormal development of the ectodermally derived structures, and orofacial clefting. Genitourinary (GU) anomalies have been identified in patients with EEC, yet these are often under-recognized and under-reported. The available literature on sonographic prenatal findings is sparse, especially when considering GU anomalies.\nMETHODS: We present the case of a male stillborn fetus, who was found antenatally to have multicystic dysplastic kidneys and anhydramnios. Following the termination of pregnancy, examination and autopsy further revealed unilateral polydactyly and bilateral syndactyly which had not been previously identified on antenatal ultrasound.\nRESULTS: Whole-exome sequencing (WES) revealed a de novo heterozygous pathogenic variant in exon 5 of the TP63 gene: p.His247Arg: c.740A>G (NM_003722.4) which has been reported in the literature. The His247Arg variant has been published as a pathogenic variant in association with EEC, both with and without orofacial clefting.\nCONCLUSION: Our prenatal case expands the phenotypic spectrum of TP63-related disorders in general. In addition, it adds to the phenotype associated with the His247Arg pathogenic variant responsible for EEC. Further, we highlight the importance of WES as a postnatal tool to help clarify unexpected findings, and as a way to add to the spectrum of existing phenotypes of known single-gene disorders.","variants":[{"Name":"NM_003722.5(TP63):c.740A>G (p.His247Arg)","Chromosome":"3","Start":"189864392","Stop":"189864392","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":204424,"rule_based_match":true,"evidence_text":"c.740A>G (NM_003722.4)","llm_judgment":"PRESENT","evidence":"c.740A>G (NM_003722.4)","abstract_start":1045,"abstract_end":1067}]}
{"pmid":"23806170","title":"Constitutional CHEK2 mutations are infrequent in early-onset and familial breast/ovarian cancer patients from Pakistan.","abstract":"BACKGROUND: Less than 20% of Pakistani women with early-onset or familial breast/ovarian cancer harbor germ line mutations in the high-penetrance genes BRCA1, BRCA2 and TP53. Thus, mutations in other genes confer genetic susceptibility to breast cancer, of which CHEK2 is a plausible candidate. CHEK2 encodes a checkpoint kinase, involved in response to DNA damage.\nMETHODS: In the present study we assessed the prevalence of CHEK2 germ line mutations in 145 BRCA1/2-negative early-onset and familial breast/ovarian cancer patients from Pakistan (Group 1). Mutation analysis of the complete CHEK2 coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments.\nRESULTS: Two potentially deleterious missense mutations, c.275C>G (p.P92R) and c.1216C>T, (p.R406C), were identified (1.4%). The c.275C>G mutation is novel and has not been described in other populations. It was detected in a 30-year-old breast cancer patient with a family history of breast and multiple other cancers. The c.1216C>T mutation was found in a 34-year-old ovarian cancer patient from a family with two breast cancer cases. Both mutations were not detected in 229 recently recruited BRCA1/2-negative high risk patients (Group 2).\nCONCLUSION: Our findings suggest that CHEK2 mutations may not contribute significantly to breast/ovarian cancer risk in Pakistani women.","variants":[{"Name":"NM_007194.4(CHEK2):c.275C>G (p.Pro92Arg)","Chromosome":"22","Start":"28734447","Stop":"28734447","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":403907,"rule_based_match":true,"evidence_text":"c.275C>G (p.P92R)","llm_judgment":"PRESENT","evidence":"c.275C>G (p.P92R)","abstract_start":797,"abstract_end":814},{"Name":"NM_007194.4(CHEK2):c.1216C>T (p.Arg406Cys)","Chromosome":"22","Start":"28695753","Stop":"28695753","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152247,"rule_based_match":true,"evidence_text":"c.1216C>T (p.R406C)","llm_judgment":"PRESENT","evidence":"c.1216C>T","abstract_start":819,"abstract_end":828}]}
{"pmid":"27057652","title":"Germline mutations in the VHL gene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family.","abstract":"Von Hippel-Lindau (VHL) disease is a rare autosomal dominant inherited cancer syndrome that is characterized by hemangioblastomas in the central nervous system and retina, renal cell carcinoma and cysts, pancreatic tumors and cysts, and pheochromocytoma. The underlying gene in this disease is the VHL tumor suppressor gene. We characterized a family with 2 affected siblings. The brother and sister displayed VHL type 2B and type 2A features, respectively. Renal lesions in the brother exhibited 3 different phenotypes, including simple renal cysts, multilocular cystic renal cell carcinoma and clear cell renal cell carcinoma. The phenotypes of the 3 concurrent renal lesions were first reported in this study. Mutation detection of the VHL gene revealed 2 recurrent mutations, namely c.256C>T (p.P86S) and c.340 + 5G > C. The former was predicted to be deleterious and to destabilize the hydrophobic core and lead to VHL dysfunction; however, the latter was predicted to be a benign variant. Our findings provided new data for the genotype-phenotype of VHL diseases and elucidated the pathogenic mechanism with in silico analysis.","variants":[{"Name":"NM_000551.4(VHL):c.256C>T (p.Pro86Ser)","Chromosome":"3","Start":"10142103","Stop":"10142103","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":173736,"rule_based_match":true,"evidence_text":"c.256C>T (p.P86S)","llm_judgment":"PRESENT","evidence":"c.256C>T (p.P86S)","abstract_start":787,"abstract_end":804}]}
{"pmid":"32131761","title":"Novel pathogenic VPS13A mutation in Moroccan family with Choreoacanthocytosis: a case report.","abstract":"BACKGROUND: Choreoacanthocytosis (ChAc), is a rare neurodegenerative disease, characterized by movement disorders and acanthocytosis in the peripheral blood smears, and various neurological, neuropsychiatric and neuromuscular signs. It is caused by mutations in VPS13A gene with autosomal recessive pattern of inheritance.\nCASE PRESENTATION: Here we report two patients belonging to a consanguineous Moroccan family who present with movement disorder pathology. They were suspected to have choreoacanthocytosis according to biological, clinical and radiological finding. Thus, whole-exome sequencing was performed for precise diagnosis and identified a homozygous novel nonsense mutation c.337C > T (p.Gln113*) in exon 5 of VPS13A in the two affected siblings.\nCONCLUSION: Here, we report a novel nonsense p.Gln113* mutation in VPS13A identified by whole-exome sequencing, which caused ChAc in a Moroccan family. This is the first description of ChAc in Morocco with genetic confirmation, that expands the mutation diversity of VPS13A and provide clinical, neuroimaging and deep brain stimulation findings.","variants":[{"Name":"NM_033305.3(VPS13A):c.337C>T (p.Gln113Ter)","Chromosome":"9","Start":"77206031","Stop":"77206031","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":800756,"rule_based_match":true,"evidence_text":"c.337C > T (p.Gln113*)","llm_judgment":"PRESENT","evidence":"c.337C > T (p.Gln113*)","abstract_start":688,"abstract_end":710}]}
{"pmid":"23506830","title":"A novel mutation (R122Q) in the cathepsin K gene in a Chinese child with Pyknodysostosis.","abstract":"BACKGROUND: Pyknodysostosis (OMIM 265800) is a rare, autosomal recessive sclerosing skeletal dysplasia as a consequence of the diminished capacity of osteoclasts to degrade organic bone matrix. Pyknodysostosis is caused by mutation in the cathepsin K (CTSK) gene. Up to date, 34 different CTSK mutations have been identified in patients with Pyknodysostosis; however, only one mutation was previously identified in a Chinese patient. The objective of this study was to characterize the clinical manifestations and features of Pyknodysostosis and identify the mutation of the causative gene in a Chinese family with Pyknodysostosis.\nMETHODS: We investigated a non-consanguineous Chinese family in which an 11-year-old child was affected with Pyknodysostosis. Altogether, 203 persons, including the affected individual, his parents and 200 healthy donors, were recruited and genomic DNA was extracted. All 8 exons of the CTSK gene, including the exon-intron boundaries, were amplified and sequenced directly.\nRESULTS: The proband displayed a novel homozygous missense mutation c.365G>A in exon 4 of the CTSK gene. This mutation leads to the substitution of the arginine at position 122 by glutamine (R122Q) in cathepsin K. The parents were heterozygous for this gene mutation, and the mutation was not found in the 200 unrelated controls.\nCONCLUSION: Our study suggests that the novel missense mutation c.365G>A (R122Q) in exon 4 of CTSK gene was responsible for Pyknodysostosis in the Chinese family.","variants":[{"Name":"NM_000396.4(CTSK):c.365G>A (p.Arg122Gln)","Chromosome":"1","Start":"150805895","Stop":"150805895","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":540660,"rule_based_match":true,"evidence_text":"c.365G>A (R122Q)","llm_judgment":"PRESENT","evidence":"c.365G>A (R122Q)","abstract_start":1401,"abstract_end":1417}]}
{"pmid":"33471974","title":"A Population-Based Study of Genes Previously Implicated in Breast Cancer.","abstract":"BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.\nMETHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.\nRESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in <i>BRCA1</i> and <i>BRCA2</i> were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in <i>PALB2</i> were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in <i>BARD1</i>, <i>RAD51C</i>, and <i>RAD51D</i> were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in <i>ATM</i>, <i>CDH1</i>, and <i>CHEK2</i> were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in <i>NBN</i>, were not associated with an increased risk of breast cancer.\nCONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).","variants":[{"Name":"NM_002485.5(NBN):c.657_661del (p.Lys219fs)","Chromosome":"8","Start":"89971214","Stop":"89971218","ReferenceAlleleVCF":"ATTTGT","AlternateAlleleVCF":"A","allel_id":21979,"rule_based_match":true,"evidence_text":"c.657_661del5","llm_judgment":"PRESENT","evidence":"c.657_661del5","abstract_start":1656,"abstract_end":1669}]}
{"pmid":"26114819","title":"Keratopathy in Autoimmune Polyendocrinopathy Syndrome Type 1.","abstract":"PURPOSE: To report the spectrum of phenotypes in patients with autoimmune polyendocrinopathy syndrome type 1 (APS1)-related keratopathy.\nMETHODS: In this retrospective observational case series, 6 patients followed for APS1 were included. Data collected included family history, age at presentation, and systemic and ophthalmic manifestations. The 14 coding exons of the autoimmune regulator (AIRE) gene were sequenced.\nRESULTS: The age at the onset of keratopathy ranged from 4 to 20 years. The ocular symptoms varied from mild photophobia to severe pain, and visual acuity was from light perception to 20/20 Snellen equivalent. Heterogeneous corneal involvement was observed, ranging from minimal superficial punctate staining to severe stromal scarring with deep corneal neovascularization. The severity of ophthalmic findings was uncorrelated to that of systemic manifestations. The genetic analyses identified 2 novel mutations (c.173C>A in exon 2 and c.892G>T in exon 8) and 4 known mutations (c.62C>T in exon 1, c.415C>T in exon 3, c.1096-1G>A in intron 9, and c.1193delC in exon 10) in the AIRE gene. In patients with identical AIRE mutations, including within a sib-pair, heterogeneous phenotypes were observed.\nCONCLUSIONS: Keratopathy can be an early and severe manifestation of APS1, which contributes to the global prognosis of the disease. Its mechanisms remain to be elucidated.","variants":[{"Name":"NM_000383.4(AIRE):c.173C>A (p.Ala58Asp)","Chromosome":"21","Start":"44286597","Stop":"44286597","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":549058,"rule_based_match":true,"evidence_text":"c.173C>A","llm_judgment":"PRESENT","evidence":"c.173C>A","abstract_start":934,"abstract_end":942},{"Name":"NM_000383.4(AIRE):c.1193del (p.Pro398fs)","Chromosome":"21","Start":"44293089","Stop":"44293089","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":549147,"rule_based_match":true,"evidence_text":"c.1193delC in exon 10","llm_judgment":"PRESENT","evidence":"c.1193delC in exon 10","abstract_start":1068,"abstract_end":1089},{"Name":"NM_000383.4(AIRE):c.1096-1G>A","Chromosome":"21","Start":"44292992","Stop":"44292992","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":549068,"rule_based_match":true,"evidence_text":"c.1096-1G>A","llm_judgment":"PRESENT","evidence":"c.1096-1G>A","abstract_start":1039,"abstract_end":1050}]}
{"pmid":"34741542","title":"A defect in molybdenum cofactor binding causes an attenuated form of sulfite oxidase deficiency.","abstract":"Isolated sulfite oxidase deficiency (ISOD) is a rare recessive and infantile lethal metabolic disorder, which is caused by functional loss of sulfite oxidase (SO) due to mutations of the SUOX gene. SO is a mitochondrially localized molybdenum cofactor (Moco)- and heme-dependent enzyme, which catalyzes the vital oxidation of toxic sulfite to sulfate. Accumulation of sulfite and sulfite-related metabolites such as S-sulfocysteine (SSC) are drivers of severe neurodegeneration leading to early childhood death in the majority of ISOD patients. Full functionality of SO is dependent on correct insertion of the heme cofactor and Moco, which is controlled by a highly orchestrated maturation process. This maturation involves the translation in the cytosol, import into the intermembrane space (IMS) of mitochondria, cleavage of the mitochondrial targeting sequence, and insertion of both cofactors. Moco insertion has proven as the crucial step in this maturation process, which enables the correct folding of the homodimer and traps SO in the IMS. Here, we report on a novel ISOD patient presented at 17 months of age carrying the homozygous mutation NM_001032386.2 (SUOX):c.1097G > A, which results in the expression of SO variant R366H. Our studies show that histidine substitution of Arg366, which is involved in coordination of the Moco-phosphate, causes a severe reduction in Moco insertion efficacy in vitro and in vivo. Expression of R366H in HEK SUOX<sup>-/-</sup> cells mimics the phenotype of patient's fibroblasts, representing a loss of SO expression and specific activity. Our studies disclose a general paradigm for a kinetic defect in Moco insertion into SO caused by residues involved in Moco coordination resulting in the case of R366H in an attenuated form of ISOD.","variants":[{"Name":"NM_001032386.2(SUOX):c.1097G>A (p.Arg366His)","Chromosome":"12","Start":"56004486","Stop":"56004486","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":975358,"rule_based_match":true,"evidence_text":"NM_001032386.2 (SUOX):c.1097G > A","llm_judgment":"PRESENT","evidence":"NM_001032386.2 (SUOX):c.1097G > A","abstract_start":1152,"abstract_end":1185}]}
{"pmid":"25946540","title":"Clinical and molecular findings of pachyonychia congenita type 2 (PC-2)","abstract":"Pachyonychia congenita is a group of autosomal dominant inheritance pattern disorders characterized by hypertrophic nail dystrophy There are two main clinical subtypes: type 1 and 2. Pachyonychia congenita type 2 is readily differentiated from type 1 by multiple steatocysts and/or presence of natal teeth and can be confirmed by mutations of KRT6B and KRT17. We report the case of a 33-year-o/d female patient with the missense mutation in KRT17 gene (c.280C> T, p.Arg94Cys) and discuss the several clinical features found with this mutation in the literature.","variants":[{"Name":"NM_000422.3(KRT17):c.280C>T (p.Arg94Cys)","Chromosome":"17","Start":"41624230","Stop":"41624230","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29630,"rule_based_match":true,"evidence_text":"c.280C> T, p.Arg94Cys","llm_judgment":"PRESENT","evidence":"c.280C> T, p.Arg94Cys","abstract_start":453,"abstract_end":474}]}
{"pmid":"34504103","title":"Clinical consequences of BRCA2 hypomorphism.","abstract":"The tumor suppressor FANCD1/BRCA2 is crucial for DNA homologous recombination repair (HRR). BRCA2 biallelic pathogenic variants result in a severe form of Fanconi anemia (FA) syndrome, whereas monoallelic pathogenic variants cause mainly hereditary breast and ovarian cancer predisposition. For decades, the co-occurrence in trans with a clearly pathogenic variant led to assume that the other allele was benign. However, here we show a patient with biallelic BRCA2 (c.1813dup and c.7796 A > G) diagnosed at age 33 with FA after a hypertoxic reaction to chemotherapy during breast cancer treatment. After DNA damage, patient cells displayed intermediate chromosome fragility, reduced survival, cell cycle defects, and significantly decreased RAD51 foci formation. With a newly developed cell-based flow cytometric assay, we measured single BRCA2 allele contributions to HRR, and found that expression of the missense allele in a BRCA2 KO cellular background partially recovered HRR activity. Our data suggest that a hypomorphic BRCA2 allele retaining 37-54% of normal HRR function can prevent FA clinical phenotype, but not the early onset of breast cancer and severe hypersensitivity to chemotherapy.","variants":[{"Name":"NM_000059.4(BRCA2):c.7796A>G (p.Glu2599Gly)","Chromosome":"13","Start":"32357920","Stop":"32357920","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":476859,"rule_based_match":true,"evidence_text":"c.7796 A > G","llm_judgment":"PRESENT","evidence":"c.7796 A > G","abstract_start":481,"abstract_end":493}]}
{"pmid":"17301081","title":"SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness.","abstract":"One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G --> A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1 : 2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.","variants":[{"Name":"NM_003850.3(SUCLA2):c.534+1G>A","Chromosome":"13","Start":"47988540","Stop":"47988540","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21015,"rule_based_match":false,"evidence_text":"c.534 + 1G --> A","llm_judgment":"PRESENT","evidence":"c.534 + 1G --> A","abstract_start":917,"abstract_end":933},{"Name":"NM_003850.3(SUCLA2):c.352G>A (p.Gly118Arg)","Chromosome":"13","Start":"47988901","Stop":"47988901","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21016,"rule_based_match":false,"evidence_text":"p.Gly118Arg","llm_judgment":"PRESENT","evidence":"p.Gly118Arg","abstract_start":891,"abstract_end":902},{"Name":"NM_003850.3(SUCLA2):c.850C>T (p.Arg284Cys)","Chromosome":"13","Start":"47954510","Stop":"47954510","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21017,"rule_based_match":false,"evidence_text":"p.Arg284Cys","llm_judgment":"PRESENT","evidence":"p.Arg284Cys","abstract_start":904,"abstract_end":915}]}
{"pmid":"16088892","title":"Novel PEX1 coding mutations and 5' UTR regulatory polymorphisms.","abstract":"Zellweger syndrome and its milder variants--neonatal adrenoleukodystrophy and infantile Refsum disease--comprise a clinical continuum of diseases referred to as the Zellweger spectrum. Mutations in the PEX1 gene, which consists of 24 exons and encodes a AAA ATPase protein required for peroxisomal protein import, account for approximately two-thirds of the known Zellweger spectrum patient mutations. In this paper, we report on four novel PEX1 mutations and two polymorphisms in an Australasian cohort. Two of the mutations--c.1108_1109insA and c.2391_2392delTC--that lead to the introduction of a premature termination codon in exons 5 and 14, respectively, are associated with the severe Zellweger phenotype. One patient with a milder disease phenotype was a compound heterozygote for two missense mutations (I989T and R998Q), both affecting amino acids in the second, C-terminal AAA domain of the protein. PTS1 protein import levels in cultured skin fibroblasts from this patient were almost 20% of normal control levels. We have also characterized two co-segregating polymorphisms in the 5' UTR of the PEX1 gene. Based on reporter assays, the c.-137T>C polymorphism leads to reduced PEX1 expression, whereas the c.-53C>G polymorphism leads to increased expression. When present together, these regulatory polymorphisms lead to near-normal PEX1 expression. Altered PEX1 expression due to the presence of either the c.-137T>C or the c.-53C>G variant could impact on residual PEX1 function if another co-allelic mutation was present which did not completely abolish PEX1 function. It also follows that the presence of polymorphisms in the PEX1 promoter region could have implications for patients with mutations in other PEX proteins known to interact with PEX1, such as PEX6. Thus, although not deleterious in control individuals, these polymorphisms could contribute to phenotypic heterogeneity among Zellweger spectrum patients.","variants":[{"Name":"NM_000466.3(PEX1):c.1108dup (p.Ile370fs)","Chromosome":"7","Start":"92517406","Stop":"92517407","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AT","allel_id":636452,"rule_based_match":false,"evidence_text":"c.1108_1109insA","llm_judgment":"PRESENT","evidence":"c.1108_1109insA","abstract_start":527,"abstract_end":542}]}
{"pmid":"36292965","title":"Methylome Profiling in Fabry Disease in Clinical Practice: A Proof of Concept.","abstract":"Anderson−Fabry disease (FD) is an X-linked disease caused by a functional deficit of the α-galactosidase A enzyme. FD diagnosis relies on the clinical manifestations and research of GLA gene mutations. However, because of the lack of a clear genotype/phenotype correlation, FD diagnosis can be challenging. Recently, several studies have highlighted the importance of investigating DNA methylation patterns for confirming the correct diagnosis of different rare Mendelian diseases, but to date, no such studies have been reported for FD. Thus, in the present investigation, we analyzed for the first time the genome-wide methylation profile of a well-characterized cohort of patients with Fabry disease. We profiled the methylation status of about 850,000 CpG sites in 5 FD patients, all carrying the same mutation in the GLA gene (exon 6 c.901C>G) and presenting comparable low levels of α-Gal A activity. We found that, although the whole methylome profile did not discriminate the FD group from the unaffected one, several genes were significantly differentially methylated in Fabry patients. Thus, we provide here a proof of concept, to be tested in patients with different mutations and in a larger cohort, that the methylation state of specific genes can potentially identify Fabry patients and possibly predict organ involvement and disease evolution.","variants":[{"Name":"NM_000169.3(GLA):c.901C>G (p.Arg301Gly)","Chromosome":"X","Start":"101398468","Stop":"101398468","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":178286,"rule_based_match":true,"evidence_text":"c.901C>G","llm_judgment":"PRESENT","evidence":"c.901C>G","abstract_start":839,"abstract_end":847}]}
{"pmid":"30946460","title":"Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease.","abstract":"CONTEXT: von Hippel-Lindau (VHL) disease, comprising renal cancer, hemangioblastoma, and/or pheochromocytoma (PHEO), is caused by missense or truncating variants of the VHL tumor-suppressor gene, which is involved in degradation of hypoxia-inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear.\nOBJECTIVE: We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation.\nDESIGN: We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected individuals and evaluated VHL splicing in existing cancer databases.\nRESULTS: We identified a synonymous VHL variant (c.414A>G, p.Pro138Pro) as the driver event in five independent individuals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF-binding domain required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the The Cancer Genome Atlas pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant.\nCONCLUSION: A recurrent synonymous VHL variant (c.414A>G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.","variants":[{"Name":"NM_000551.4(VHL):c.414A>G (p.Pro138=)","Chromosome":"3","Start":"10146587","Stop":"10146587","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":224936,"rule_based_match":true,"evidence_text":"c.414A>G (p.Pro138Pro)","llm_judgment":"PRESENT","evidence":"p.Pro138Pro","abstract_start":722,"abstract_end":733}]}
{"pmid":"33123899","title":"Possible PKHD1 Hot-spot Mutations Related to Early Kidney Function Failure or Hepatofibrosis in Chinese Children with ARPKD: A Retrospective Single Center Cohort Study and Literature Review.","abstract":"PKHD1 mutations are generally considered to cause autosomal recessive polycystic kidney disease (ARPKD). ARPKD is a rare disorder and one of the most severe conditions leading to end-stage renal disease in childhood. With the biallelic deletion mutation, patients have difficulty in surviving the perinatal period, resulting in perinatal or neonatal death. This study retrospectively analyzed patient characteristics, imaging characteristics, laboratory examinations and family surveys from 7 Chinese children with different PKHD1 gene mutations diagnosed by high-throughput sequencing from January 2014 to February 2018. Of the 7 children, there were 3 males and 4 females. Eight missense mutations, two frameshift mutations, two deletion mutations, and two intronic slicing mutations were identified. Six of the mutations have not previously been identified. In the literature search, we identified a total of 29 Chinese children with PKHD1 mutations. The missense mutation c.2507T>C in exon 24 was found in one patient in our study, and five patients with liver fibrosis but normal renal function were reported in the literature. The missense mutation c.5935G>A in exon 37 was found in two patients in our study and three cases in the literature. Four patients had renal failure at an age as young as 1 year of those five patients with the missense mutation c.5935G>A in exon 37. It was concluded that: (1) Kidney length more than 2-3 SDs above the mean and early-onset hypertension might be associated with PKHD1-associated ARPKD; (2) The more enlarged the kidney size is, the lower the renal function is likely to be; (3) c.5935G>A may be a hot spot that leads to early renal failure in Chinese children with PKHD1 mutations; (4) c.2507T>C may be a hot-spot mutation associated with hepatic lesions in Chinese children with PKHD1.","variants":[{"Name":"NM_138694.4(PKHD1):c.2507T>C (p.Val836Ala)","Chromosome":"6","Start":"52046089","Stop":"52046089","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":620237,"rule_based_match":true,"evidence_text":"c.2507T>C","llm_judgment":"PRESENT","evidence":"c.2507T>C","abstract_start":976,"abstract_end":985}]}
{"pmid":"36403339","title":"A novel nonsense mutation in PPP2R5D is associated with neurodevelopmental disorders and shows incomplete penetrance in a Chinese pedigree.","abstract":"BACKGROUND AND PURPOSE: PPP2R5D mutations are known to cause neurodevelopmental disorders in an autosomal-dominant manner. To date, the vast majority of the reported cases in the literature have been sporadic with de novo mutations. There are no data regarding PPP2R5D mutation penetrance. We aimed to unravel the underlying genetic defects in 3 generations of a family affected by intellectual disability, neurodevelopmental delay, and facial dysmorphology.\nMETHODS: We performed detailed clinical examinations and whole-exome sequencing in the family.\nRESULTS: We identified a novel mutation, c.1321 C>T (p.Arg441*), in PPP2R5D. The mutation cosegregated with affected family members I-2 and II-7 but not II-3, who bears the mutation but is phenotypically healthy. Our whole-exome sequencing also excluded the involvement of pathogenic mutations in other genes known to be related to neurodevelopmental disorders. The mutation was predicted to introduce a premature stop codon at position 441, thereby truncating the 162 amino acids at the C-terminus of the encoded protein.\nCONCLUSIONS: We report a familial transmitted PPP2R5D-related neurodevelopmental disorder as well as a novel nonsense pathogenic mutation and its incomplete penetrance. Our study expands the mutational and phenotypic spectra of PPP2R5D-related neurodevelopmental disorders, broadens our understanding of these disorders, and will thus be valuable for mutation-based pre- and postnatal screening and genetic diagnosis of neurodevelopmental disorders.","variants":[{"Name":"NM_006245.4(PPP2R5D):c.1321C>T (p.Arg441Ter)","Chromosome":"6","Start":"43009391","Stop":"43009391","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3013267,"rule_based_match":true,"evidence_text":"c.1321 C>T (p.Arg441*)","llm_judgment":"PRESENT","evidence":"c.1321 C>T (p.Arg441*)","abstract_start":595,"abstract_end":617}]}
{"pmid":"33439489","title":"Adding evidence to the role of NEUROG1 in congenital cranial dysinnervation disorders.","abstract":"Congenital cranial dysinnervation disorders (CCDDs) are a heterogeneous group of neurodevelopmental phenotypes caused by a primary disturbance of innervation due to deficient, absent, or misguided cranial nerves. Although some CCDDs genes are known, several clinical phenotypes and their aetiologies remain to be elucidated. We describe a 12-year-old boy with hypotonia, developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. He had a long expressionless face, severe oromotor dysfunction, bilateral agenesis/severe hypoplasia of the VIII nerve with marked atresia of the internal auditory canals and cochlear labyrinth malformation. Trio-exome sequencing identified a homozygous loss of function variant in the NEUROG1 gene (NM_006161.2: c.202G > T, p.Glu68*). NEUROG1 is considered a causal candidate for CCDDs based on (i) the previous report of a patient with a homozygous gene deletion and developmental delay, deafness due to absent bilateral VIII nerves, and severe oromotor dysfunction; (ii) a second patient with a homozygous NEUROG1 missense variant and corneal opacity, absent corneal reflex and intellectual disability; and (iii) the knockout mouse model phenotype which highly resembles the disorder observed in humans. Our findings support the growing compelling evidence that loss of NEUROG1 leads to a very distinctive disorder of cranial nerves development.","variants":[{"Name":"NM_006161.3(NEUROG1):c.202G>T (p.Glu68Ter)","Chromosome":"5","Start":"135535489","Stop":"135535489","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2740811,"rule_based_match":true,"evidence_text":"NM_006161.2: c.202G > T, p.Glu68*","llm_judgment":"PRESENT","evidence":"NM_006161.2: c.202G > T, p.Glu68*","abstract_start":776,"abstract_end":809}]}
{"pmid":"33565074","title":"Genetic and phenotypic analysis of a patient with phosphogylcerate dehydrogenase deficiency","abstract":"OBJECTIVE: To explore the genetic basis for a child with ocular anomaly, microcephaly, growth retardation and intrauterine growth restriction.\nMETHODS: The patient underwent ophthalmologic examinations including anterior segment photography, fundus color photography, and fundus fluorescein angiography. The patient and her parents were subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis.\nRESULTS: The patient was found to have bilateral persistent pupillary membrane and coloboma of inferior iris, in addition with macular dysplasia and radial pigmentation near the hemal arch of the temporal retina. She was found to have carried compound heterozygous missense variants of the PHGDH gene, namely c.196G>A and c.1177G>A, which were respectively inherited from her father and mother. Bioinformatic analysis suggested both variants to be pathogenic.\nCONCLUSION: The patient was diagnosed with phosphoglycerate dehydrogenase deficiency. Above finding has enriched the phenotypic spectrum of the disease with ocular manifestations.","variants":[{"Name":"NM_006623.4(PHGDH):c.1177G>A (p.Ala393Thr)","Chromosome":"1","Start":"119741865","Stop":"119741865","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1909655,"rule_based_match":true,"evidence_text":"c.1177G>A","llm_judgment":"PRESENT","evidence":"c.1177G>A","abstract_start":778,"abstract_end":787}]}
{"pmid":"20051115","title":"A novel mutation in the glycogen synthase 2 gene in a child with glycogen storage disease type 0.","abstract":"BACKGROUND: Glycogen storage disease type 0 is an autosomal recessive disease presenting in infancy or early childhood and characterized by ketotic hypoglycemia after prolonged fasting and postprandial hyperglycemia and hyperlactatemia. Sixteen different mutations have been identified to date in the gene which encodes hepatic glycogen synthase, resulting in reduction of glycogen storage in the liver.\nCASE PRESENTATION: Biochemical evaluation as well as direct sequencing of exons and exon-intron boundary regions of the GYS2 gene were performed in a patient presenting fasting hypoglycemia and postprandial hyperglycemia and her parents. The patient was found to be compound heterozygous for one previously reported nonsense mutation (c.736 C>T; R243X) and a novel frameshift mutation (966_967delGA/insC) which introduces a stop codon 21 aminoacids downstream from the site of the mutation that presumably leads to loss of 51% of the COOH-terminal part of the protein. The glycemia and lactatemia of the parents after an oral glucose tolerance test were evaluated to investigate a possible impact of the carrier status on the metabolic profile. The mother, who presented a positive family history of type 2 diabetes, was classified as glucose intolerant and the father, who did not exhibit metabolic changes after the glucose overload, had an antecedent history of hypoglycemia after moderate alcohol ingestion.\nCONCLUSION: The current results expand the spectrum of known mutations in GYS2 and suggest that haploinsufficiency could explain metabolic abnormalities in heterozygous carriers in presence of predisposing conditions.","variants":[{"Name":"NM_021957.4(GYS2):c.736C>T (p.Arg246Ter)","Chromosome":"12","Start":"21568952","Stop":"21568952","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31088,"rule_based_match":true,"evidence_text":"c.736 C>T; R243X","llm_judgment":"PRESENT","evidence":"c.736 C>T; R243X","abstract_start":739,"abstract_end":755}]}
{"pmid":"25315659","title":"Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.","abstract":"SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer.","variants":[{"Name":"NM_015278.5(SASH1):c.1849G>A (p.Glu617Lys)","Chromosome":"6","Start":"148533885","Stop":"148533885","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":165961,"rule_based_match":true,"evidence_text":"c.1849G>A; p.Glu617Lys","llm_judgment":"PRESENT","evidence":"c.1849G>A; p.Glu617Lys","abstract_start":693,"abstract_end":715}]}
{"pmid":"29961569","title":"De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features.","abstract":"TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10<sup>-3</sup>) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10<sup>-8</sup>) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.","variants":[{"Name":"NM_032271.3(TRAF7):c.1964G>A (p.Arg655Gln)","Chromosome":"16","Start":"2176350","Stop":"2176350","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":578643,"rule_based_match":true,"evidence_text":"c.1964G>A (p.Arg655Gln)","llm_judgment":"PRESENT","evidence":"c.1964G>A (p.Arg655Gln)","abstract_start":594,"abstract_end":617}]}
{"pmid":"15940697","title":"Generalized arterial calcification of infancy: different clinical courses in two affected siblings.","abstract":"Generalized arterial calcification of infancy (GACI) is a rare autosomal recessive disease caused by mutations in ENPP1. Due to extensive calcification of the arterial media associated with intimal proliferation leading to vascular occlusion, most affected children die within the first 6 months of life. We report on two Taiwanese siblings with an identical genotype, but different clinical course. The male sibling developed heart failure and severe hypertension, and died at the age of 6 weeks despite of treatment with bisphosphonates, ACE inhibitors, and hydralazine. The subsequent female, who was monitored closely pre- and post-natally, is having an uncomplicated clinical course up to the age of 1(1/2) year now. There were similar characteristic sonographic and roentgenographic findings in both siblings in early infancy. In both siblings, the same compound heterozygous mutations (c.1025G > T [p.Gly342Val] and c.1112A > T [Tyr371Phe]) in ENPP1 were identified. Despite the same genotype and similar sonographic and radiographic features in early infancy, the phenotype of GACI can vary to a great extent within one family.","variants":[{"Name":"NM_006208.3(ENPP1):c.1025G>T (p.Gly342Val)","Chromosome":"6","Start":"131861704","Stop":"131861704","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":28630,"rule_based_match":true,"evidence_text":"c.1025G > T [p.Gly342Val]","llm_judgment":"PRESENT","evidence":"c.1025G > T [p.Gly342Val]","abstract_start":893,"abstract_end":918},{"Name":"NM_006208.3(ENPP1):c.1112A>T (p.Tyr371Phe)","Chromosome":"6","Start":"131864886","Stop":"131864886","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":28631,"rule_based_match":true,"evidence_text":"c.1112A > T [Tyr371Phe]","llm_judgment":"PRESENT","evidence":"c.1112A > T [Tyr371Phe]","abstract_start":923,"abstract_end":946}]}
{"pmid":"23430862","title":"Further Delineation of the Phenotype of Congenital Disorder of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping.","abstract":"Congenital disorders of glycosylation (CDG) are an expanding group of genetic diseases affecting protein and lipid glycosylation. These disorders have a variable presentation and are individually rare. DPAGT1-CDG is a protein N-glycosylation disorder with epilepsy, development delay, severe hypotonia, and dysmorphy, reported in a single patient. Here we present the second family with DPAGT1-CDG identified through homozygosity mapping in a large consanguineous family with 18 affected infants. The patients had severe hypotonia, global developmental delay, seizures, and microcephaly but no dysmorphy. In the index case, the brain MRI revealed delayed myelination, and there was fiber type disproportion on muscle biopsy. Homozygosity mapping identified a large block of homozygosity on chromosome 11p15.5-q25 where two known CDG-I causing genes, ALG9 and DPAGT1, are located. Sequencing ALG9 did not reveal any mutations while analysis of DPAGT1 identified a novel homozygous mutation c.902G>A (p.R301H) in two affected infants. The disorder was fatal in all affected cases and mostly in early infancy.","variants":[{"Name":"NM_001382.4(DPAGT1):c.902G>A (p.Arg301His)","Chromosome":"11","Start":"119097870","Stop":"119097870","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1170264,"rule_based_match":true,"evidence_text":"c.902G>A (p.R301H)","llm_judgment":"PRESENT","evidence":"c.902G>A (p.R301H)","abstract_start":989,"abstract_end":1007}]}
{"pmid":"18577048","title":"Richner-Hanhart syndrome detected by expanded newborn screening.","abstract":"Richner-Hanhart syndrome (tyrosinemia type 2) is an inborn error of tyrosine metabolism which is clinically characterized mainly by oculocutaneous symptoms including corneal opacities and keratosis palmoplantaris. Skin symptoms usually develop after the first year of life. We report a neonate in whom already on the third day of life diagnosis of Richner-Hanhart syndrome could be suspected because of elevated tyrosine levels in newborn screening by tandem mass spectrometry. Analysis of the tyrosine aminotransferase gene revealed a homozygous missense mutation p.R433W (c.1297C>T). An 8-year-old brother with persistent plantar hyperkeratotic plaques of the soles of yet unknown origin was subsequently identified to be also affected with Richner-Hanhart syndrome. This demonstrates that early diagnosis of Richner-Hanhart syndrome is possible in neonates by extended newborn screening. Early introduction of dietary treatment is a prerequisite to reduce the risk of clinical symptoms.","variants":[{"Name":"NM_000353.3(TAT):c.1297C>T (p.Arg433Trp)","Chromosome":"16","Start":"71568212","Stop":"71568212","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":547820,"rule_based_match":true,"evidence_text":"c.1297C>T","llm_judgment":"PRESENT","evidence":"c.1297C>T","abstract_start":574,"abstract_end":583}]}
{"pmid":"31469663","title":"A novel missense variant in the BBS7 gene underlying Bardet-Biedl syndrome in a consanguineous Pakistani family.","abstract":"Bardet-Biedl syndrome (BBS) is characterized by six major features: postaxial polydactyly, obesity, learning disabilities, renal anomalies, retinitis pigmentosa and hypogonadism and is inherited in an autosomal recessive manner. BBS is caused by disease causing sequence variants in the 22 BBS genes identified to date. In the present study, a single consanguineous Pakistani Family with BBS was clinically and genetically characterized. After establishing linkage to a BBS gene on chromosome 4q27, Sanger sequencing was performed in all available affected and unaffected members. Sequence analysis of the BBS7 gene revealed novel substitution mutation (c.719G>T; p. Gly240Val). Our findings further extend the body of evidence implicating BBS7 in causing BBS and expand the mutation spectrum.","variants":[{"Name":"NM_176824.3(BBS7):c.719G>T (p.Gly240Val)","Chromosome":"4","Start":"121853086","Stop":"121853086","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1941485,"rule_based_match":true,"evidence_text":"c.719G>T; p. Gly240Val","llm_judgment":"PRESENT","evidence":"c.719G>T; p. Gly240Val","abstract_start":654,"abstract_end":676}]}
{"pmid":"33488593","title":"A Novel Biallelic","abstract":"STING-associated vasculopathy of infantile-onset (SAVI) is one of the newly identified types of interferonopathies. SAVI is caused by heterozygous gain-of-function mutations in the <i>STING1</i>. We herein report for the first time a homozygous variant in the <i>STING1 gene</i> in two siblings that resulted in constitutive activation of <i>STING</i> gene and the SAVI phenotype. Exome sequencing revealed a novel homozygous NM_198282.3: c.841C>T; p.(Arg281Trp) variant in exon 7 of the <i>STING1</i> gene. The variant segregated in the family to be homozygous in all affected and either heterozygous or wild type in all healthy. Computational structural analysis of the mutants revealed changes in the STING protein structure/function. Elevated serum beta-interferon levels were observed in the patients compared to the control family members. Treatment with Janus kinase inhibitor (JAK-I) Ruxolitinib suppressed the inflammatory process, decreased beta-interferon levels, and stopped the progression of the disease.","variants":[{"Name":"NM_198282.4(STING1):c.841C>T (p.Arg281Trp)","Chromosome":"5","Start":"139477434","Stop":"139477434","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":830366,"rule_based_match":true,"evidence_text":"NM_198282.3: c.841C>T; p.(Arg281Trp)","llm_judgment":"PRESENT","evidence":"NM_198282.3: c.841C>T; p.(Arg281Trp)","abstract_start":426,"abstract_end":462}]}
{"pmid":"35034956","title":"MCAD deficiency caused by compound heterozygous pathogenic variants in ACADM.","abstract":"Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is an autosomal recessive disease caused by biallelic pathogenic ACADM variants. We report a case of an asymptomatic Japanese girl with MCAD deficiency caused by compound heterozygous pathogenic variants (NM_000016.5:c.1040G > T (p.Gly347Val) and c.449_452delCTGA (p.Thr150ArgfsTer4)). Because the MCAD residual activity in lymphocytes of the patient was below the limit of quantification, both variants are likely to cause complete loss of MCAD enzymatic activity.","variants":[{"Name":"NM_000016.6(ACADM):c.1040G>T (p.Gly347Val)","Chromosome":"1","Start":"75761216","Stop":"75761216","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2833621,"rule_based_match":true,"evidence_text":"NM_000016.5:c.1040G > T (p.Gly347Val)","llm_judgment":"PRESENT","evidence":"NM_000016.5:c.1040G > T (p.Gly347Val)","abstract_start":266,"abstract_end":303}]}
{"pmid":"25401298","title":"A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.","abstract":"Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.","variants":[{"Name":"NM_001112741.2(KCNC1):c.959G>A (p.Arg320His)","Chromosome":"11","Start":"17772053","Stop":"17772053","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":172192,"rule_based_match":true,"evidence_text":"c.959G>A (p.Arg320His)","llm_judgment":"PRESENT","evidence":"c.959G>A (p.Arg320His)","abstract_start":309,"abstract_end":331}]}
{"pmid":"20002461","title":"Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency.","abstract":"We screened for PDHA1 mutations in 40 patients with biochemically demonstrated PDHc deficiency or strong clinical suspicion, and found changes with probable pathological significance in 20. Five patients presented new mutations: p.A169V, c.932_938del, c.1143_1144 ins24, c.1146_1159dup and c.510-30G> A, this latter is a new undescribed cause of exon 6 skipping. Another four mutations have been found, and previously reported, in our patients: p.H113D, p.P172L, p.Y243del and p.Y369Q. Eleven patients presented seven known mutations: p.R127Q, p.I166I, p.A198T, p.R263G, p.R302C, p.R378C and c.1142_1145dup. The latter three were found in more than one unrelated patient: p.R302C was detected in a heterozygous girl and a mosaic male, p.R378C in two males and finally, c.1142_1145dup in three females; only one in 20 mothers was found to be a carrier (p.R263G). Apart from those 20 patients, the only alteration detected in one girl with clear PDHc and PDH-E1 deficiency was the silent change c.396A> C (p.R132R), and other eight PDHc deficient patients carry combinations of known infrequent polymorphisms that are overrepresented among our 20 unsolved patients. The importance of these changes on PDH activity is unclear. Investigations in the other PDHc genes are in course in order to elucidate the genetic defect in the unresolved patients.","variants":[{"Name":"NM_000284.4(PDHA1):c.1132C>T (p.Arg378Cys)","Chromosome":"X","Start":"19359612","Stop":"19359612","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":212019,"rule_based_match":false,"evidence_text":"p.R378C","llm_judgment":"PRESENT","evidence":"p.R378C","abstract_start":580,"abstract_end":587},{"Name":"NM_000284.4(PDHA1):c.1142_1145dup (p.Trp383fs)","Chromosome":"X","Start":"19359619","Stop":"19359620","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CCAAT","allel_id":25919,"rule_based_match":true,"evidence_text":"c.1142_1145dup","llm_judgment":"PRESENT","evidence":"c.1142_1145dup","abstract_start":592,"abstract_end":606}]}
{"pmid":"25124326","title":"A novel variant in GABRB2 associated with intellectual disability and epilepsy.","abstract":"The γ-aminobutyric acid type A (GABAA ) receptor is one of the three main classes of receptors activated by GABA, the principal inhibitory neurotransmitter in the central nervous system. Mutations in genes encoding various subunits of this receptor (GABRA1, GABRA2, GABRA4, GABRA5, GABRA6, GABRB1, GABRB3, GABRG1, GABRG2, GABRG3, and GABRD) are implicated in a number of neurological and developmental disorders, including epilepsy and autism. To date, no human genetics studies have implicated mutations in GABRB2, encoding the β2 subunit of the GABAA receptor, with neurodevelopmental disorders. Here we present a 12-year-old girl with intellectual disability and epilepsy, who was discovered by whole exome sequencing to have a de novo heterozygous missense variant in exon 4 of GABRB2 (c.236T>C; p.M79T). This variant is likely pathogenic, based on in silico analyses, as well as the fact that it results in the non-conservative substitution of a non-polar amino acid with a polar amino acid at a position that is evolutionarily conserved across multiple species. Our findings underscore the need for further investigation into the mechanisms by which mutations in GABRB2 contribute to neurological and developmental dysfunction.","variants":[{"Name":"NM_001371727.1(GABRB2):c.236T>C (p.Met79Thr)","Chromosome":"5","Start":"161545228","Stop":"161545228","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":171280,"rule_based_match":true,"evidence_text":"c.236T>C; p.M79T","llm_judgment":"PRESENT","evidence":"c.236T>C; p.M79T","abstract_start":790,"abstract_end":806}]}
{"pmid":"26358754","title":"Early-onset encephalopathy with epilepsy associated with a novel splice site mutation in SMC1A.","abstract":"We report on the clinical and molecular characterization of a female patient with early-onset epileptic encephalopathy, who was found to carry a de novo novel splice site mutation in SMC1A. This girl shared some morphologic and anthropometric traits described in patients with clinical diagnosis of Cornelia de Lange syndrome and with SMC1A mutation but also has severe encephalopathy with early-onset epilepsy. In addition, she had midline hand stereotypies and scoliosis leading to the misdiagnosis of a Rett overlap syndrome. Molecular studies found a novel de novo splice site mutation (c.1911 + 1G > T) in SMC1A. This novel splice mutation was associated with an aberrantly processed mRNA that included intron 11 of the gene. Moreover, quantitative approach by RT-PCR showed a severe reduction of the SMC1A transcript suggesting that this aberrant transcript may be unstable and degraded. Taken together, our data suggest that the phenotype may be due to a loss-of-function of SMC1A in this patient. Our findings suggest that loss-of-function mutations of SMC1A may be associated with early-onset encephalopathy with epilepsy.","variants":[{"Name":"NM_006306.4(SMC1A):c.1911+1G>T","Chromosome":"X","Start":"53405492","Stop":"53405492","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":855088,"rule_based_match":true,"evidence_text":"c.1911+1G>T","llm_judgment":"PRESENT","evidence":"c.1911 + 1G > T","abstract_start":591,"abstract_end":606}]}
{"pmid":"34067482","title":"Variants in","abstract":"BACKGROUND: Arrhythmogenic Cardiomyopathy (ACM) is a disease of the cardiac muscle, characterized by frequent ventricular arrhythmias and functional/ structural abnormalities, mainly of the right ventricle. To date, 20 different genes have been associated with ACM and the majority of them encode for desmosomal proteins. In this study, we describe the characterization of two novel variants in <i>MHY7</i> gene, segregating in two ACM families. MYH7 encodes for myosin heavy chain β (MHC-β) isoform, involved in cardiac muscle contractility.\nMETHOD AND RESULTS: In family A, the autopsy revealed ACM with biventricular involvement in both the proband and his father. In family B, the proband had been diagnosed as affected by ACM and implanted with implantable cardioverter defibrillator (ICD), due to ECG evidence of monomorphic ventricular tachycardia after syncope. After clinical evaluation, a molecular diagnosis was performed using a NGS custom panel. The two novel variants identified predicted damaging, located in a highly conserved domain: c. 2630T>C is not described while c.2609G>A has a frequency of 0.00000398. In silico analyses evaluated the docking characteristics between proteins using the Haddock2.2 webserver.\nCONCLUSIONS: Our results reveal two variants in sarcomeric genes to be the molecular cause of ACM, further increasing the genetic heterogeneity of the disease; in fact, sarcomeric variants are usually associated with HCM phenotype. Studies on the role of sarcomere genes in the pathogenesis of ACM are surely recommended in those ACM patients negative for desmosomal mutation screening.","variants":[{"Name":"NM_000257.4(MYH7):c.2609G>A (p.Arg870His)","Chromosome":"14","Start":"23424839","Stop":"23424839","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29159,"rule_based_match":true,"evidence_text":"c.2609G>A","llm_judgment":"PRESENT","evidence":"c.2609G>A","abstract_start":1085,"abstract_end":1094}]}
{"pmid":"16941491","title":"Unique substitution of CHEK2 and TP53 mutations implicated in primary prostate tumors and cancer cell lines.","abstract":"Genetic defects in CHEK2 and TP53 have been implicated in prostate cancer development. However, the interaction of these two genes in prostate cancer tumorigenesis has not been investigated. We previously described 11 CHEK2 mutations in a group of 84 primary prostate tumors. In this report, we screened the same group of tumors for TP53 mutations and revealed nine somatic and two germline mutations. One germline TP53 mutation (c.408A > T/p.Gln136His) and two somatic mutations (c.1022T > G/p.Phe341Cys and c.108-109ins22/p.His37fsX13) are novel to human cancer. More interestingly, CHEK2 and TP53 mutations were observed to be mutually substituted in these tumors. Analysis of five commonly used prostate cancer cell lines revealed that four cell lines harboring TP53 mutations carry no CHEK2 mutation while the only cell line (LNCaP) carrying wild-type TP53 harbors a CHEK2 mutation. The novel CHEK2 mutation (c.1160C>T/p.Thr387Asn) identified in LNCaP cells changes amino acid Thr387 to Asn which has been shown to impair CHEK2 autophosphorylation and activation. Our data suggest that the CHEK2 and TP53 mutations can substitute each other in at least 25% (21/84) of prostate cancers and that DNA damage-signaling pathway plays an important role in prostate cancer tumorigenesis.","variants":[{"Name":"NM_000546.6(TP53):c.408A>T (p.Gln136His)","Chromosome":"17","Start":"7675204","Stop":"7675204","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":479281,"rule_based_match":true,"evidence_text":"c.408A > T/p.Gln136His","llm_judgment":"PRESENT","evidence":"c.408A > T/p.Gln136His","abstract_start":430,"abstract_end":452}]}
{"pmid":"21739173","title":"X-linked adrenal hypoplasia congenita: a novel DAX1 missense mutation and challenges for clinical diagnosis in Africa.","abstract":"Adrenal hypoplasia congenita (AHC) is a rare disease. The X-linked form of AHC is caused by deletions or mutations in DAX1 gene and has a variable clinical presentation. To date, no data on X-linked AHC in central Africa are available. Here, we report a Congolese pedigree with several cases of unexplained deaths of male infants. A careful analysis of the pedigree of this family lead to the recognition of an X-linked inheritance pattern, with subsequent confirmation in a female heterozygous carrier of a DAX1 missense mutation c.1274G>T, (p.Arg425Ile).The diagnosis of this condition remains challenging in a developing country, since the manifestations of AHC overlap with those of the much more frequently occurring infections; darkening of the skin is difficult to evaluate and there is a lack of access to routine endocrinological testing. The diagnosis was eventually made based on the family pedigree, evoking an X-linked inheritance pattern. This illustrates the necessity for medical and clinical genetics to be part of the curriculum of medical school in developing countries.","variants":[{"Name":"NM_000475.5(NR0B1):c.1274G>T (p.Arg425Ile)","Chromosome":"X","Start":"30304718","Stop":"30304718","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":70525,"rule_based_match":true,"evidence_text":"c.1274G>T (p.Arg425Ile)","llm_judgment":"PRESENT","evidence":"p.Arg425Ile","abstract_start":543,"abstract_end":554}]}
{"pmid":"20704743","title":"A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome.","abstract":"BACKGROUND: An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.\nMETHODS: We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.\nRESULTS: The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.\nCONCLUSIONS: We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.","variants":[{"Name":"NM_000249.4(MLH1):c.112A>C (p.Asn38His)","Chromosome":"3","Start":"36993659","Stop":"36993659","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":95119,"rule_based_match":true,"evidence_text":"c.112A > C, p.Asn38His","llm_judgment":"PRESENT","evidence":"c.112A > C, p.Asn38His","abstract_start":69,"abstract_end":91}]}
{"pmid":"34926197","title":"Novel mutations in","abstract":"AIM: To investigate the genetic basis of autosomal recessive retinitis pigmentosa (arRP) in two consanguineous/ endogamous Pakistani families.\nMETHODS: Whole exome sequencing (WES) was performed on genomic DNA samples of patients with arRP to identify disease causing mutations. Sanger sequencing was performed to confirm familial segregation of identified mutations, and potential pathogenicity was determined by predictions of the mutations' functions.\nRESULTS: A novel homozygous frameshift mutation [NM_000440.2:c.1054delG, p. (Gln352Argfs*4); Chr5:g.149286886del (GRCh37)] in the <i>PDE6A</i> gene in an endogamous family and a novel homozygous splice site mutation [NM_033100.3:c.1168-1G>A, Chr10:g.85968484G>A (GRCh37)] in the <i>CDHR1</i> gene in a consanguineous family were identified. The <i>PDE6A</i> variant p. (Gln352Argfs*4) was predicted to be deleterious or pathogenic, whilst the <i>CDHR1</i> variant c.1168-1G>A was predicted to result in potential alteration of splicing.\nCONCLUSION: This study expands the spectrum of genetic variants for arRP in Pakistani families.","variants":[{"Name":"NM_000440.3(PDE6A):c.1054del (p.Gln352fs)","Chromosome":"5","Start":"149907323","Stop":"149907323","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":2419322,"rule_based_match":true,"evidence_text":"NM_000440.2:c.1054delG, p. (Gln352Argfs*4)","llm_judgment":"PRESENT","evidence":"NM_000440.2:c.1054delG, p. (Gln352Argfs*4)","abstract_start":504,"abstract_end":546},{"Name":"NM_033100.4(CDHR1):c.1168-1G>A","Chromosome":"10","Start":"84208728","Stop":"84208728","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2421541,"rule_based_match":true,"evidence_text":"NM_033100.3:c.1168-1G>A","llm_judgment":"PRESENT","evidence":"NM_033100.3:c.1168-1G>A","abstract_start":672,"abstract_end":695}]}
{"pmid":"20574428","title":"Mucopolysaccharidosis IVA mutations in Chinese patients: 16 novel mutations.","abstract":"Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disease caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS) and transmitted as an autosomal recessive trait. This is the first systematic mutation screen in Chinese MPS IVA patients. Mutation detections in 24 unrelated Chinese MPS IVA patients were performed by PCR and direct sequencing of exons or the mRNA of GALNS. A total of 42 mutant alleles were identified, belonging to 27 different mutations. Out of the 27 mutations, 16 were novel, including 2 splicing mutations (c.567-1G>T and c.634-1G>A), 2 nonsense mutations (p.W325X and p.Q422X) and 12 missense mutations (p.T88I, p.H142R, p.P163H, p.G168L, p.H236D, p.N289S, p.T312A, p.G316V, p.A324E, p.L366P, p.Q422K and p.F452L). p.G340D was found to be a common mutation in the Chinese MPS IVA patients, accounting for 16.7% of the total number of mutant alleles. The results show that the mutations in Chinese MPS IVA patients are also family specific but have a different mutation spectrum as compared to those of other populations.","variants":[{"Name":"NM_000512.5(GALNS):c.634-1G>A","Chromosome":"16","Start":"88835850","Stop":"88835850","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1036293,"rule_based_match":true,"evidence_text":"c.634-1G>A","llm_judgment":"PRESENT","evidence":"c.634-1G>A","abstract_start":582,"abstract_end":592},{"Name":"NM_000512.5(GALNS):c.567-1G>T","Chromosome":"16","Start":"88836268","Stop":"88836268","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1036302,"rule_based_match":true,"evidence_text":"c.567-1G>T","llm_judgment":"PRESENT","evidence":"c.567-1G>T","abstract_start":567,"abstract_end":577}]}
{"pmid":"22876111","title":"A nonsense mutation of CRYGC associated with autosomal dominant congenital nuclear cataracts and microcornea in a Chinese pedigree.","abstract":"PURPOSE: To report the identification of a nonsense mutation in γC-crystallin (CRYGC) associated with autosomal dominant congenital nuclear cataracts and microcornea in a Chinese family.\nMETHODS: We investigated four generations of a Chinese family six of whose members were affected by nuclear cataracts and microcornea. The genomic DNA was extracted from peripheral blood leukocytes. All reported nuclear cataract-related candidate genes were screened for causative mutations by direct DNA sequencing. The effects of amino acid changes on the structure and function of proteins were predicted by bioinformatics analysis.\nRESULTS: All affected individuals in this family exhibited nuclear cataracts and microcornea. Direct sequencing of the candidate gene cluster showed a c.471G>A transition in exon 3 of CRYGC, which co-segregated according to family members with cataracts, and was not observed in 100 normal controls. This single nucleotide change was predicted to introduce a translation stop codon at tryptophan 157 (W157X). Bioinformatics analysis showed that the mutation was predicted to affect the function and secondary structure of the CRYGC protein.\nCONCLUSIONS: This study identified a disease-causing mutation c.471G>A in CRYGC in a Chinese family with cataracts, expanding the mutation spectrum of CRYGC causing congenital cataracts.","variants":[{"Name":"NM_020989.4(CRYGC):c.471G>A (p.Trp157Ter)","Chromosome":"2","Start":"208128257","Stop":"208128257","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76977,"rule_based_match":true,"evidence_text":"c.471G>A","llm_judgment":"PRESENT","evidence":"c.471G>A","abstract_start":774,"abstract_end":782}]}
{"pmid":"21876339","title":"A missense mutation in the death domain of EDAR abolishes the interaction with EDARADD and underlies hypohidrotic ectodermal dysplasia.","abstract":"BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a rare condition characterized by hypotrichosis, hypohidrosis and hypodontia. The disease shows X-linked recessive, autosomal-dominant or autosomal-recessive inheritance trait. X-linked form of HED is caused by mutations in the EDA gene, while autosomal forms are caused by mutations in either EDAR or EDARADD genes.\nMETHODS: We analyzed the DNA from a Japanese patient with HED through direct sequencing, and also performed functional studies for the mutation.\nRESULTS: We identified a homozygous missense mutation c.1073G>A (p.R358Q) in the EDAR gene of the patient, which was a nonconservative amino acid substitution within the death domain of EDAR protein. We demonstrated that the p.R358Q mutant EDAR protein lost its affinity to EDARADD, leading to reduced activation of the downstream NF-κB.\nCONCLUSION: Our data further suggest the crucial role of the EDAR signaling in development of hair, teeth, and sweat gland in humans.","variants":[{"Name":"NM_022336.4(EDAR):c.1073G>A (p.Arg358Gln)","Chromosome":"2","Start":"108897181","Stop":"108897181","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259689,"rule_based_match":true,"evidence_text":"c.1073G>A (p.R358Q)","llm_judgment":"PRESENT","evidence":"c.1073G>A (p.R358Q)","abstract_start":571,"abstract_end":590}]}
{"pmid":"15522929","title":"Gonadotroph tumor associated with multiple endocrine neoplasia type 1.","abstract":"Although anterior pituitary tumors constitute a main clinical feature of multiple endocrine neoplasia type 1 (MEN1), and most types of pituitary tumors have been associated with MEN1, gonadotroph tumors have not previously been recognized clinically as part of this syndrome. We report here a woman who presented with ovarian hyperstimulation due to a gonadotroph tumor that was confirmed biochemically and immunohistochemically. She then developed hyperparathyroidism, and she was found to have three hypercellular parathyroid glands. Subsequently, she developed a temporal lobe metastasis of the gonadotroph tumor, demonstrating that it was a gonadotroph carcinoma. The diagnosis of MEN1 was confirmed by finding a deletion mutation (c.307delC) on the second exon of the MEN1 gene that predicts truncation of the resulting menin protein 15 codons downstream from the deletion (p.Leu103fsX15). This case illustrates that gonadotroph tumors, like other pituitary tumors, can be part of MEN1. The clinical implications of this case are that the clinical and biochemical features of gonadotroph tumors should be considered when evaluating patients for MEN1, and MEN1 should be considered in patients who have gonadotroph tumors.","variants":[{"Name":"NM_001370259.2(MEN1):c.307del (p.Leu103fs)","Chromosome":"11","Start":"64809803","Stop":"64809803","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":197559,"rule_based_match":true,"evidence_text":"c.307delC","llm_judgment":"PRESENT","evidence":"c.307delC","abstract_start":736,"abstract_end":745}]}
{"pmid":"27872820","title":"Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación Jiménez Díaz.","abstract":"BACKGROUND: Fundación Jiménez Díaz (FJD) is a reference center for genetic diagnosis of Gaucher disease (GD) in Spain. Genetic analyses of acid β-glucosidase (<i>GBA</i>) gene using different techniques were performed to search for new mutations, in addition to those previously and most frequently found in the Spanish population. Additionally, the study of the chitotriosidase (<i>CHIT1)</i> gene was used to assess the inflammatory status of patients in the follow-up of enzyme replacement therapy (ERT). We present the genetic data gathered during the last nine years at FJD.\nMETHODS: Blood samples from patients with suspected GD were collected for enzymatic and genetic analyses. The genetic analysis was performed on DNA from 124 unrelated suspected cases and 57 relatives from 2007 to 2015, starting with a mutational screening kit, followed by Sanger sequencing of the entire gene and other techniques to look for deletions. <i>CHIT1</i> was also studied to assess the reliability of this biomarker.\nRESULTS: In 46 out of 93 GD patients (49.5%) the two mutant alleles were found. We detected 21 different mutations. The most common mutation was N370S (c.126A > G; p.Asp409Ser current nomenclature) (in 50.5% of patients), followed by L444P (c.1448T > C; p.Leu483Pro current nomenclature) (in 24.7%). The most common heterozygous compound genotype observed (18.3%) was c.1226A > G/c.1448T > C (N370S/L444P). Two novel mutations were found (del. Ex.4-11 and c.1296G > T; pW432C), as well as p.S146L, only once previously reported. Two patients showed the homozygous state for the duplication of <i>CHIT1</i>.\nCONCLUSION: N370S and L444P are the most common mutations and other mutations associated to Parkinson's disease have been observed. This should be taken into account in the genetic counseling of GD patients.","variants":[{"Name":"NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)","Chromosome":"1","Start":"155235843","Stop":"155235843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":19329,"rule_based_match":true,"evidence_text":"c.1226A>G","llm_judgment":"PRESENT","evidence":"c.1226A > G","abstract_start":1377,"abstract_end":1388}]}
{"pmid":"24297685","title":"Detection of a novel mutation in exon 20 of the BRCA1 gene.","abstract":"Hereditary breast cancer constitutes 5-10% of all breast cancer cases. Inherited mutations in the BRCA1 and BRCA2 tumor-suppressor genes account for the majority of hereditary breast cancer cases. The BRCA1 C-terminal region (BRCT) has a functional duplicated globular domain, which helps with DNA damage repair and cell cycle checkpoint protein control. More than 100 distinct BRCA1 missense variants with structural and functional effects have been documented within the BRCT domain. Interpreting the results of mutation screening of tumor-suppressor genes that can have high-risk susceptibility mutations is increasingly important in clinical practice. This study includes a novel mutation, p.His1746 Pro (c.5237A>C), which was found in BRCA1 exon 20 of a breast cancer patient. In silico analysis suggests that this mutation could alter the stability and orientation of the BRCT domain and the differential binding of the BACH1 substrate.","variants":[{"Name":"NM_007294.4(BRCA1):c.5237A>C (p.His1746Pro)","Chromosome":"17","Start":"43057092","Stop":"43057092","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":235937,"rule_based_match":true,"evidence_text":"c.5237A>C","llm_judgment":"PRESENT","evidence":"c.5237A>C","abstract_start":709,"abstract_end":718}]}
{"pmid":"28502589","title":"A case of a novel mutation in HNF1β-related maturity-onset diabetes of the young type 5 with diabetic kidney disease complication in a Chinese family.","abstract":"AIMS: Precise diagnosis of maturity-onset diabetes of the young (MODY) has proven valuable for understanding mechanism of diabetes and selecting optimal therapy. A proband and her mother with diabetic kidney disease (DKD) were studied to investigate potential genes responsible for diabetes and different severity of DKD between the parent and offspring.\nMETHODS: The family with suspected MODY underwent mutational analyses by the whole exome sequencing (WES). Candidate pathogenic variants were validated by Sanger sequencing and tested for co-segregation. The clinical parameters of subjects were collected from medical records.\nRESULTS: A novel missense heterozygous mutation in exon 4 of the hepatocyte nuclear factor 1β (HNF1β), c.1007A > G (p.H336R), was identified in both the proband and her mother. Moreover, comparing the family's WES results, we found that the proband had acquired a KCNQ1 gene mutation from her father and acquired ACE and SORBS1 gene mutations from her mother. These three genes are known susceptibility genes of DKD and may impose additional effects contributing to DKD severity.\nCONCLUSIONS: A novel mutation in HNF1β-MODY was identified in a Chinese family complicated with DKD, and the additional effect of pathogenic variants in susceptibility genes was speculated to contribute to DKD severity.","variants":[{"Name":"NM_000458.4(HNF1B):c.1007A>G (p.His336Arg)","Chromosome":"17","Start":"37731633","Stop":"37731633","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":623436,"rule_based_match":true,"evidence_text":"c.1007A > G (p.H336R)","llm_judgment":"PRESENT","evidence":"c.1007A > G (p.H336R)","abstract_start":735,"abstract_end":756}]}
{"pmid":"27176872","title":"Retinitis pigmentosa and bilateral cystoid macular oedema in a patient heterozygous for the RIM1 mutation previously associated with cone-rod dystrophy 7.","abstract":"BACKGROUND: Autosomal dominant cone-rod dystrophy 7 (CORD7) has been previously associated with the RIM1 c.2459G>A (Arg820His) mutation. Cystoid macular oedema (CMO) is a rare feature of CORD and has not been described in CORD7. We report a patient who was heterozygous for the RIM1 mutation with bilateral CMO and who manifested a retinitis pigmentosa phenotype.\nMATERIALS AND METHODS: The patient's medical notes were retrospectively reviewed over an 18-month period. Genetic testing was performed by next generation sequencing for a panel of 176 genes associated with retinal dystrophy.\nRESULTS: A 34-year-old man presented with a 5-year history of bilateral floaters and blurred vision. Visual acuity was 20/23 and 20/33 in the right and left eyes, respectively. Optical coherence tomography scans revealed bilateral CMO. Goldmann visual field tests detected mid-peripheral ring scotomas. Electrodiagnostic testing was overall consistent with a primary photoreceptor abnormality involving both rods and cones. Subsequent genetic testing identified heterozygosity for the RIM1 c.2459G>A (Arg820His) mutation. Various treatments for CMO were trialled unsuccessfully. However, at his latest clinic appointment the CMO had partially improved following topical brinzolamide therapy. Most recent visual acuity was 20/25 in the right eye and 20/24 in the left eye.\nCONCLUSIONS: This is the first reported case of bilateral CMO in association with the RIM1 mutation. Overall, our findings were more consistent with a phenotype of retinitis pigmentosa. This could imply that the RIM1 mutation causes diverse retinal dystrophies, or that the previously described CORD7 phenotype resulted from a different variant on the same haplotype.","variants":[{"Name":"NM_014989.7(RIMS1):c.2459G>A (p.Arg820His)","Chromosome":"6","Start":"72251007","Stop":"72251007","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19207,"rule_based_match":true,"evidence_text":"RIM1 c.2459G>A (Arg820His)","llm_judgment":"PRESENT","evidence":"RIM1 c.2459G>A (Arg820His)","abstract_start":100,"abstract_end":126}]}
{"pmid":"37357001","title":"Clinical and gene mutation characteristics of patients with hereditary ellipsocytosis: nine cases report and literature review","abstract":"<b>Objective:</b> To report gene mutations in nine patients with hereditary elliptocytosis (HE) and analyze the characteristics of pathogenic gene mutations in HE. <b>Methods:</b> The clinical and gene mutations of nine patients clinically diagnosed with HE at Institute of Hematology & Blood Diseases Hospital from June 2018 to February 2022 were reported and verified by next-generation sequencing to analyze the relationship between gene mutations and clinical phenotypes. <b>Results:</b> Erythrocyte membrane protein gene mutations were detected among nine patients with HE, including six with SPTA1 mutation, one with SPTB mutation, one with EPB41 mutation, and one with chromosome 20 copy deletion. A total of 11 gene mutation sites were involved, including 6 known mutations and 5 novel mutations. The five novel mutations included SPTA1: c.1247A>C (p. K416T) in exon 9, c.1891delG (p. A631fs*17) in exon 15, E6-E12 Del; SPTB: c.154C>T (p. R52W) ; and EPB41: c.1636A>G (p. I546V) . Three of the six patients with the SPTA1 mutation were SPTA1 exon 9 mutation. <b>Conclusion:</b> SPTA1 is the most common mutant gene in patients with HE.","variants":[{"Name":"NM_001355436.2(SPTB):c.154C>T (p.Arg52Trp)","Chromosome":"14","Start":"64805085","Stop":"64805085","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":815868,"rule_based_match":true,"evidence_text":"SPTB: c.154C>T (p. R52W)","llm_judgment":"PRESENT","evidence":"SPTB: c.154C>T (p. R52W)","abstract_start":928,"abstract_end":952}]}
{"pmid":"22435431","title":"Characterization of TGM1 c.984+1G>A mutation identified in a homozygous carrier of lamellar ichthyosis.","abstract":"BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a rare, nonsyndromic, heterogeneous disorder of cornification. It is divided into three clinical subtypes: lamellar ichthyosis (LI); congenital ichthyosiform erythroderma; and harlequin ichthyosis. In the majority of patients, LI is caused by transglutaminase-1 (TGase1) deficiency resulting from mutations in both copies of the transglutaminase 1 (TGM1) gene in chromosome 14.\nCASE REPORT: We report a patient with a severe LI phenotype who has a homozygous putative splicing mutation in the TGM1 gene. Our aim is to assess the pathologic effect of the TGM1 c.984+1G>A by splicing assays and bioinformatic tools.\nRESULTS: c.984+1G>A mutation created two alternative TGM1 mRNA splice variants that included 30 or 32 nucleotides of the 5' of intron 6. At the protein level, the partial in-frame aberrant transcript retaining 30 bp of intron 6 led to the insertion of 10 amino acids (p.Met329_Val330ins10) at the catalytic core domain of TGM1 protein (codons 247-572), whereas the transcript with the insertion of 32 nucleotides is predicted to encode a truncated protein (p.Val330MetfsX12).\nCONCLUSION: Our splicing assay, together with bioinformatic prediction tools, supports the pathological effect of the recently identified c.984+1G>A mutation in the TGM1 gene and unravels the molecular mechanism by which c.984+1G>A acts.","variants":[{"Name":"NM_000359.3(TGM1):c.984+1G>A","Chromosome":"14","Start":"24259703","Stop":"24259703","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1324010,"rule_based_match":true,"evidence_text":"c.984+1G>A","llm_judgment":"PRESENT","evidence":"c.984+1G>A","abstract_start":623,"abstract_end":633}]}
{"pmid":"23742260","title":"Novel membrane frizzled-related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds.","abstract":"PURPOSE: We present a genetic and clinical analysis of two sisters, 3 and 4 years of age, with nanophthalmos and macular folds.\nMETHODS: Ophthalmological examination, general paediatric examination and molecular genetic analysis of the MFRP gene were performed in both affected siblings.\nRESULTS: Clinical analysis showed high hyperopia (+11 D and +12 D), short axial lengths (15 mm) and the presence of macular folds and optic nerve head drusen. Autofluorescence of the retina was generally normal with subtle macular abnormalities. Sequence analysis showed compound heterozygosity for severe MFRP mutations in both sisters: a previously reported p.Asn167fs (c.498dupC) and a novel stop codon mutation p.Gln91X (c.271C>T).\nCONCLUSION: These are the youngest nanophthalmos patients in the literature identified with severe loss of MFRP function, showing already the known structural abnormalities for this disease. Adult patients affected by homozygous or compound heterozygous MFRP mutations generally show signs of retinal dystrophy, with ERG disturbances and RPE abnormalities on autofluorescence imaging. ERG examination could not be performed in these children, but extensive RPE abnormalities were not seen at this young age.","variants":[{"Name":"NM_031433.4(MFRP):c.271C>T (p.Gln91Ter)","Chromosome":"11","Start":"119346046","Stop":"119346046","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":490779,"rule_based_match":true,"evidence_text":"c.271C>T","llm_judgment":"PRESENT","evidence":"c.271C>T","abstract_start":713,"abstract_end":721},{"Name":"NM_031433.4(MFRP):c.498dup (p.Asn167fs)","Chromosome":"11","Start":"119345562","Stop":"119345563","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":19517,"rule_based_match":true,"evidence_text":"c.498dup","llm_judgment":"PRESENT","evidence":"c.498dup","abstract_start":660,"abstract_end":668}]}
{"pmid":"30171085","title":"Spectrum of","abstract":"AIMS: Congenital and cyclical neutropenia are rare inherited diseases that result in recurrent life-threatening bacterial infections due to a deficiency of mature neutrophils. Cyclical neutropenia is usually caused by heterozygous <i>ELANE</i> mutations while congenital neutropenia is genetically heterogeneous with mutations in genes like <i>ELANE, HAX-1, G6PC3</i> and <i>GFI1.</i> The presence of <i>ELANE</i> mutation aids in the establishment of diagnosis and rules out other secondary causes of neutropenia such as autoimmune cytopenia and evolving aplasia. Further, patients with <i>ELANE</i> mutations are also at a high risk of developing myelodysplasia or acute myeloid leukaemia. Hence it is important to screen for these mutations in patients presenting with neutropenia early in life.\nMETHODS: The study included 52 patients who were evaluated for inherited neutropenia. Genomic DNA was extracted from peripheral blood leucocytes and mutation analysis was done by bidirectional Sanger sequencing.\nRESULTS: Ten different missense, frameshift or splice site variants in <i>ELANE</i> gene were identified in 11 patients: c.125C>T (p.Pro42Leu), c.164G>A (p.Cys55Tyr), c.169G>A (p.Ala57Thr), c.179T>C (p.Ile60Thr), c.770C>T (p.Pro257Leu), c.367-8C>A, c.597+1G>A along with three novel mutations c.302T>A (p.Val101Glu), c.468G>T (p.Try156Cys) and c.596delT (Phe199Ser fs*13). Family studies were available for three patients and, in all three instances, the mutation had a de novo origin.\nCONCLUSION: The widespread distribution of mutations suggests the need to screen all the exons in <i>ELANE</i> gene for proper characterisation of the genotype.","variants":[{"Name":"NM_001972.4(ELANE):c.169G>A (p.Ala57Thr)","Chromosome":"19","Start":"852977","Stop":"852977","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1462664,"rule_based_match":true,"evidence_text":"c.169G>A (p.Ala57Thr)","llm_judgment":"PRESENT","evidence":"c.169G>A (p.Ala57Thr)","abstract_start":1178,"abstract_end":1199},{"Name":"NM_001972.4(ELANE):c.367-8C>A","Chromosome":"19","Start":"855556","Stop":"855556","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1476958,"rule_based_match":true,"evidence_text":"c.367-8C>A","llm_judgment":"PRESENT","evidence":"c.367-8C>A","abstract_start":1248,"abstract_end":1258}]}
{"pmid":"28390610","title":"MYO15A splicing mutations in hearing loss: A review literature and report of a novel mutation.","abstract":"Sensorineural hearing loss (SNHL) is the most prevalent genetic sensory defect in humans, affecting about 1 in 1000 newborns around the world. Non-syndromic SNHL accounts for nearly 70% of hereditary hearing loss and 80% of SNHL cases show an autosomal recessive mode of inheritance (ARNSHL). In the present study, we applied targeted-exome sequencing to a family with a single proband affected by congenital sensorineural hearing loss. 127 known genes were sequenced to find the causative mutation. One novel homozygous donor splice site mutation, c.4596 + 1G > A (IVS12 + 1G > A) was found in MYO15A gene. Analysis of this mutation within the family showed that the mutation segregates with hearing loss. New DNA sequencing technologies could lead to identification of the disease causing variants especially in highly heterogeneous disorders such as hearing loss.","variants":[{"Name":"NM_016239.4(MYO15A):c.4596+1G>A","Chromosome":"17","Start":"18135825","Stop":"18135825","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2524567,"rule_based_match":true,"evidence_text":"c.4596 + 1G > A (IVS12 + 1G > A)","llm_judgment":"PRESENT","evidence":"c.4596 + 1G > A (IVS12 + 1G > A)","abstract_start":549,"abstract_end":581}]}
{"pmid":"26370861","title":"A Patient with an Extra-adrenal Pheochromocytoma and Germ-line SDHB Mutation Accompanied by an Atypical Meningioma.","abstract":"The gene succinate dehydrogenase subunit B (SDHB) encodes a protein comprising part of the mitochondrial complex II, which links the Krebs cycle and the electron-transport chain. Heterozygous germ-line SDHB mutations causes familial pheochromocytoma-paraganglioma syndrome and has also been linked to gastrointestinal stromal tumors, as well as renal cell carcinomas. We herein report a patient with a germ-line SDHB mutation who presented with an atypical meningioma that was identified as originating from a somatic SDHB mutation. The 41-year-old man, who had a surgical history of extra-adrenal pheochromocytoma at 23 years of age, recently developed gait disorder and hypertension. At the radiological examination, a tumor was detected in the cervical spinal cord at the C6-7 intervertebral level. The pathological findings of the isolated tumor were atypical meningioma assessed as grade II according to the World Health Organization criteria. Inherited neoplasia syndrome was suspected because of the patient's history of early-onset extra-adrenal pheochromocytoma and the development of meningioma. We therefore performed molecular genetic analyses. A direct sequence analysis revealed a heterozygous germ-line frameshift mutation in SDHB, specifically an 11-nucleotide deletion, c.305-315delCAATGAACATC, in exon 4, resulting in a frameshift p.A102EfsX12. Additionally, the sequence analysis of the tumor DNA revealed only a mutated allele with a frameshift mutation in the germ-line SDHB. Our findings suggest that SDHB plays an important role in the pathogenesis of meningiomas as well as pheochromocytomas. Therefore, a differential diagnosis for metastatic pheochromocytoma and other new onset tumors, including meningioma, particularly in patients with germ-line SDHB mutations and a previous history of pheochromocytoma should be carefully made.","variants":[{"Name":"NM_003000.3(SDHB):c.305_315del (p.Ala102fs)","Chromosome":"1","Start":"17028708","Stop":"17028718","ReferenceAlleleVCF":"TGATGTTCATTG","AlternateAlleleVCF":"T","allel_id":1699065,"rule_based_match":false,"evidence_text":"c.305-315delCAATGAACATC","llm_judgment":"PRESENT","evidence":"c.305-315delCAATGAACATC","abstract_start":1287,"abstract_end":1310}]}
{"pmid":"38009286","title":"Clinical and genetic analysis of infants with pontocerebellar hypoplasia type 6 caused by RARS2 variations.","abstract":"OBJECTIVE: Defects in RARS2 cause cerebellopontine hypoplasia type 6 (pontocerebellar hypoplasia type 6, PCH6, OMIM: #611523), a rare autosomal recessive inherited mitochondrial disease. Here, we report two male patients and their respective family histories.\nMETHODS: We describe the clinical presentation and magnetic resonance imaging (MRI) findings of these patients. Whole-exome sequencing was used to identify the genetic mutations.\nRESULTS: One patient showed hypoglycemia, high lactic acid levels (fluctuating from 6.7 to 14.1 mmol/L), and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and pons. The other patient presented with early infantile developmental and epileptic encephalopathies (EIDEEs) with an initial developmental delay followed by infantile epileptic spasm syndrome (IESS) at 5 months old, with no imaging changes. Whole-exome sequencing identified compound heterozygous RARS2 variants c.25A>G (p.I9V) with c.1261C>T (p.Q421*) and c.1A>G (p.M1V) with c.122A>G (p.D41G) in these two patients. Of these loci, c.1261C>T and c.122A>G have not been previously reported.\nSIGNIFICANCE: Our findings have expanded the RARS2 gene variant spectrum and present EIDEEs and IESS as phenotypes which deepened the association between PCH6 and RARS2.\nPLAIN LANGUAGE SUMMARY: Defects in RARS2 cause cerebellopontine hypoplasia type 6, a rare autosomal recessive inherited mitochondrial disease. Two patients with RARS2 variants were reported in this article. One patient showed hypoglycemia, high lactic acid levels, and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and Page 3 of 21 Epilepsia OpenFor Review Only pons. The other patient presented with an initial developmental delay followed by refractory epilepsy at 5 months old, with no imaging changes. Our findings deepened the association between PCH6 and RARS2.","variants":[{"Name":"NM_020320.5(RARS2):c.1A>G (p.Met1Val)","Chromosome":"6","Start":"87589957","Stop":"87589957","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":226903,"rule_based_match":true,"evidence_text":"c.1A>G (p.M1V)","llm_judgment":"PRESENT","evidence":"c.1A>G (p.M1V)","abstract_start":994,"abstract_end":1008}]}
{"pmid":"27506760","title":"Clinical and endocrine characteristics and genetic analysis of Korean children with McCune-Albright syndrome: a retrospective cohort study.","abstract":"BACKGROUND: McCune-Albright syndrome (MAS) is a rare disease defined by the triad of fibrous dysplasia (FD), café au lait spots, and peripheral precocious puberty (PP). Because of the rarity of this disease, only a few individuals with MAS have been reported in Korea. We describe the various clinical and endocrine manifestations and genetic analysis of 14 patients with MAS in Korea.\nMETHODS: Patients' clinical data-including peripheral PP, FD, and other endocrine problems-were reviewed retrospectively. In addition, treatment experiences of letrozole in five patients with peripheral PP were described. Mutant enrichment with 3'-modified oligonucleotides - polymerase chain reaction (MEMO-PCR) was performed on eight patients to detect mutation in GNAS using blood. MEMO-PCR is a simple and practical method that enables the nondestructive selection and enrichment of minor mutant alleles in blood.\nRESULTS: The median age at diagnosis was 5 years 2 months (range: 18 months to 16 years). Eleven patients were female, and three were male. Thirteen patients showed FD. All female patients showed peripheral PP at onset, and three patients subsequently developed central PP. There was a significant decrease in estradiol levels after two years of letrozole treatment. However, bone age was advanced in four patients. Two patients had clinical hyperthyroidism, and two patients had growth hormone (GH) excess with pituitary microadenoma. c.602G > A (p.Arg201His) in GNAS was detected in two patients in blood, and c.601C > T (p.Arg201Cys) in GNAS was detected in one patient in pituitary adenoma.\nCONCLUSIONS: This study described the various clinical manifestations of 14 patients with MAS in a single center in Korea. This study first applied MEMO-PCR on MAS patients to detect GNAS mutation. Because a broad spectrum of endocrine manifestations could be found in MAS, multiple endocrinopathies should be monitored in MAS patients. Better treatment options for peripheral PP with MAS are needed.","variants":[{"Name":"NM_000516.7(GNAS):c.601C>T (p.Arg201Cys)","Chromosome":"20","Start":"58909365","Stop":"58909365","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30972,"rule_based_match":true,"evidence_text":"c.601C > T (p.Arg201Cys)","llm_judgment":"PRESENT","evidence":"c.601C > T (p.Arg201Cys)","abstract_start":1516,"abstract_end":1540},{"Name":"NM_000516.7(GNAS):c.602G>A (p.Arg201His)","Chromosome":"20","Start":"58909366","Stop":"58909366","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":30973,"rule_based_match":true,"evidence_text":"c.602G > A (p.Arg201His)","llm_judgment":"PRESENT","evidence":"c.602G > A (p.Arg201His)","abstract_start":1440,"abstract_end":1464}]}
{"pmid":"38066485","title":"Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions.","abstract":"BACKGROUND: TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations.\nMETHODS: In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity.\nRESULTS: We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability.\nCONCLUSIONS: This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.","variants":[{"Name":"NM_138691.3(TMC1):c.1256T>C (p.Phe419Ser)","Chromosome":"9","Start":"72791917","Stop":"72791917","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1952219,"rule_based_match":true,"evidence_text":"c.1256T > C:p.Phe419Ser","llm_judgment":"PRESENT","evidence":"c.1256T > C:p.Phe419Ser","abstract_start":1155,"abstract_end":1178}]}
{"pmid":"15024742","title":"Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients.","abstract":"Wilson disease (WD) is a rare inherited autosomal recessive disorder caused by a defect in a metal transporting P-type ATPase, resulting in copper overload in various tissues and cells. The aim was to assess both the phenotype in Brazilian WD patients and the corresponding ATP7B genotype. Sixty subjects belonging to 46 pedigrees diagnosed as WD were included in this study. Direct sequencing of all 21 exons within ATP7B and their flanking introns was performed. Demographic, clinical, laboratory and histopathological data at the time of diagnosis were obtained. We identified twenty-five mutations, twelve of them reported for the first time. The c.3402delC mutation had the highest allelic frequency (30.8%), followed by the c.2123T>C (p.L708P) (16.7%). Exons 8 and 15 were the site of 62.5% of the mutations. The common European mutation c.3207C>A (p.H1069Q) was not present at all. Phenotype varied greatly among individuals with the same ATP7B genotype. Our data confirm the heterogeneity of ATP7B genotype in Brazilian WD patients. The mutational spectrum is compatible with the Brazilian history of Mediterranean immigration; however, new mutations, and different frequencies and phenotype associated with the previously known mutations characterize this population. Exons 8 and 15 should be preferentially screened in WD cases from Brazil. Phenotype variation among subjects with the same ATP7B genotype suggests that modifying factors play an additional role in the pathogenesis of WD.","variants":[{"Name":"NM_000053.4(ATP7B):c.3402del (p.Ala1135fs)","Chromosome":"13","Start":"51942396","Stop":"51942396","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":94515,"rule_based_match":true,"evidence_text":"c.3402delC","llm_judgment":"PRESENT","evidence":"c.3402delC","abstract_start":651,"abstract_end":661},{"Name":"NM_000053.4(ATP7B):c.2123T>C (p.Leu708Pro)","Chromosome":"13","Start":"51958543","Stop":"51958543","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18904,"rule_based_match":true,"evidence_text":"c.2123T>C (p.L708P)","llm_judgment":"PRESENT","evidence":"c.2123T>C (p.L708P)","abstract_start":730,"abstract_end":749}]}
{"pmid":"25967389","title":"Peroxisomal D-bifunctional protein deficiency: First case reports from Slovakia.","abstract":"D-bifunctional protein deficiency (#OMIM 261515) is a rare autosomal recessive hereditary metabolic disorder causing severe clinical and biochemical abnormalities that are usually fatal in the course of the first years of life. This disease is classified as single enzyme peroxisomal disorder affecting the β-oxidation pathway in this compartment. In this paper we present a full overview of the clinical presentation, magnetic resonance imaging, biochemical and molecular data of two Slovak D-bifunctional protein deficient patients. In the clinical presentation of both patients severe generalized hypotonia, depression of neonatal reflexes, craniofacial dysmorphism and seizures dominated starting from the second day of life. In both patients, who died up to two years of life, we found elevated plasma levels of very long chain fatty acids and we identified the presence of causative mutations in the HSD17B4 gene. In the first case, we found the homozygous mutation c.46G>A, which is responsible for a defect in the dehydrogenase domain. In the second patient, the heterozygous mutations c.1369A>G and c.1516C>T were present and functionally they are related to the hydratase domain of the protein. This combination of mutations in the second patient is very rare and has not been reported until now. The presence of mutations was examined in all family members, and the resulting data were successfully utilized for prenatal diagnosis.","variants":[{"Name":"NM_000414.4(HSD17B4):c.46G>A (p.Gly16Ser)","Chromosome":"5","Start":"119452621","Stop":"119452621","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22694,"rule_based_match":true,"evidence_text":"c.46G>A","llm_judgment":"PRESENT","evidence":"c.46G>A","abstract_start":972,"abstract_end":979},{"Name":"NM_000414.4(HSD17B4):c.1369A>G (p.Asn457Asp)","Chromosome":"5","Start":"119509176","Stop":"119509176","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":357373,"rule_based_match":true,"evidence_text":"c.1369A>G","llm_judgment":"PRESENT","evidence":"c.1369A>G","abstract_start":1094,"abstract_end":1103},{"Name":"NM_000414.4(HSD17B4):c.1516C>T (p.Arg506Cys)","Chromosome":"5","Start":"119525228","Stop":"119525228","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":487165,"rule_based_match":true,"evidence_text":"c.1516C>T","llm_judgment":"PRESENT","evidence":"c.1516C>T","abstract_start":1108,"abstract_end":1117}]}
{"pmid":"27090768","title":"Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency.","abstract":"BACKGROUND: ECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh-like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations.\nMETHODS: Clinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed.\nRESULTS: The first sibling is 17 years old and presents with generalized dystonia and severe bilateral pallidal MRI lesions after 1 episode of infantile subacute metabolic encephalopathy (Leigh-like syndrome). In contrast, the younger sibling (15 years old) only suffers from paroxysmal exercise-induced dystonia and has very mild pallidal MRI abnormalities. Both patients carry compound heterozygous ECHS1 mutations: c.232G>T (predicted protein effect: p.Glu78Ter) and c.518C>T (p.Ala173Val). Linkage analysis, exome sequencing, cosegregation, expression studies, and metabolite profiling support the pathogenicity of these mutations. Expression studies in patients' fibroblasts showed mitochondrial localization and severely reduced levels of ECHS1 protein. Increased urinary S-(2-carboxypropyl)cysteine and N-acetyl-S-(2-carboxypropyl)cysteine levels, proposed metabolic markers of this disorder, were documented in both siblings. Sequencing ECHS1 in 30 unrelated patients with paroxysmal dyskinesias revealed no further mutations.\nCONCLUSIONS: The phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. © 2016 International Parkinson and Movement Disorder Society.","variants":[{"Name":"NM_004092.4(ECHS1):c.518C>T (p.Ala173Val)","Chromosome":"10","Start":"133366990","Stop":"133366990","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":364135,"rule_based_match":true,"evidence_text":"c.518C>T (p.Ala173Val)","llm_judgment":"PRESENT","evidence":"c.518C>T (p.Ala173Val)","abstract_start":1024,"abstract_end":1046}]}
{"pmid":"27060313","title":"Clinical features and gene mutations in a patient with multiple aeyl-CoA dehydrogenase deficiency with severe fatty liver","abstract":"OBJECTIVE: To analyze the clinical features and gene mutations in an adolescent patient affected with late-onset multiple aeyl-CoA dehydrogenase deficiency (MADD) with severe fatty liver.\nMETHODS: Potential mutations of the ETFDH gene were detected with polymerase chain reaction (PCR) and DNA sequencing.\nRESULTS: The 13-year-and-10-month girl has presented with weakness without any other special manifestation. Laboratory tests demonstrated an elevation of myocardial enzyme levels, total cholesterol, lactic acid and abnormal serum free fatty acids. H magnetic resonance spectroscopy revealed severe fatty liver. An increase in multiple plasma acyl-carnitines was detected by gas chromatography/mass spectrometry and isobutyrylglycine in urine by screening with tandem mass spectrometry. Genetic analysis demonstrated 2 heterozygous missense mutations c.250G>A (p.Ala84Thr) and c.353G>T (p.Cys118Phe) in the ETFDH gene. The diagnosis of MADD was confirmed. The patient was given large dose of vitamin B2, which resulted in rapid clinical and biochemical improvement.\nCONCLUSION: A common mutation c.250G>A and a novel mutation c.353G>T in the ETFDH gene were identified in the patient. The pathogenic role of c.353G>T (p.Cys118Phe) deserves further study. Early diagnosis of MADD and appropriate therapy is crucial for the prognosis.","variants":[{"Name":"NM_004453.4(ETFDH):c.353G>T (p.Cys118Phe)","Chromosome":"4","Start":"158682372","Stop":"158682372","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":953709,"rule_based_match":true,"evidence_text":"c.353G>T (p.Cys118Phe)","llm_judgment":"PRESENT","evidence":"c.353G>T (p.Cys118Phe)","abstract_start":882,"abstract_end":904}]}
{"pmid":"25865492","title":"Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination.","abstract":"Despite recent advances in understanding the genetic bases of microcephaly, a large number of cases of microcephaly remain unexplained, suggesting that many microcephaly syndromes and associated genes have yet to be identified. Here, we report mutations in PYCR2, which encodes an enzyme in the proline biosynthesis pathway, as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume. Linkage mapping and whole-exome sequencing identified homozygous mutations (c.355C>T [p.Arg119Cys] and c.751C>T [p.Arg251Cys]) in PYCR2 in the affected individuals of two consanguineous families. A lymphoblastoid cell line from one affected individual showed a strong reduction in the amount of PYCR2. When mutant cDNAs were transfected into HEK293FT cells, both variant proteins retained normal mitochondrial localization but had lower amounts than the wild-type protein, suggesting that the variant proteins were less stable. A PYCR2-deficient HEK293FT cell line generated by genome editing with the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system showed that PYCR2 loss of function led to decreased mitochondrial membrane potential and increased susceptibility to apoptosis under oxidative stress. Morpholino-based knockdown of a zebrafish PYCR2 ortholog, pycr1b, recapitulated the human microcephaly phenotype, which was rescued by wild-type human PYCR2 mRNA, but not by mutant mRNAs, further supporting the pathogenicity of the identified variants. Hypomyelination and the absence of lax, wrinkly skin distinguishes this condition from that caused by previously reported mutations in the gene encoding PYCR2's isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development.","variants":[{"Name":"NM_013328.4(PYCR2):c.355C>T (p.Arg119Cys)","Chromosome":"1","Start":"225922043","Stop":"225922043","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":190179,"rule_based_match":true,"evidence_text":"c.355C>T","llm_judgment":"PRESENT","evidence":"c.355C>T","abstract_start":535,"abstract_end":543},{"Name":"NM_013328.4(PYCR2):c.751C>T (p.Arg251Cys)","Chromosome":"1","Start":"225921254","Stop":"225921254","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":190180,"rule_based_match":true,"evidence_text":"c.751C>T (p.Arg251Cys)","llm_judgment":"PRESENT","evidence":"p.Arg251Cys","abstract_start":572,"abstract_end":583}]}
{"pmid":"31394102","title":"Characterization of the cone-rod dystrophy retinal phenotype caused by novel homozygous DRAM2 mutations.","abstract":"Cone-rod dystrophies (CRD) are a group of Inherited Retinal Dystrophies (IRD) characterized by the primary involvement of cone photoreceptors, resulting in the degeneration of the central retina, or macula. Although there are more than 55 CRD genes, a considerable percentage of cases remain unsolved. In this context, the present study aimed to describe and characterize the phenoptype and the genetic cause of 3 CRD families from a cohort of IRD cases. Clinical evaluation in each patient was supported by a complete ophthalmological examination, including visual acuity measurement, fundus retinography, fundus autofluorescence imaging, optical coherence tomography and full-field electroretinography. Molecular diagnoses were performed by whole exome sequencing analyzing a group of 279 IRD genes, and cosegregation of the identified pathogenic variants was confirmed by Sanger sequencing. Three novel homozygous mutations in the autophagy gene DRAM2 were identified as the molecular cause of disease in the three families: c.518-1G>A, c.628_629insAG and c.693+2T>A. Clinical data revealed that the 3 patients presented a shared CRD phenotype with adult-onset macular involvement and later peripheral degeneration, although the age of onset, evolution and severity were variable. In order to characterize the transcription effects of these variants, mRNA expression studies were performed. The results showed alterations in the DRAM2 transcription, including alternative splicing forms and lower levels of mRNA, which correlated with the phenotypic variability observed between patients. For instance, frameshift mutations were related to a less severe phenotype, with circumscribed mid-peripheral involvement, and lower levels of mRNA, suggesting an activation of the nonsense-mediated decay (NMD) pathway; while a more severe and widespread retinal degeneration was associated to the inframe alternative splicing variant reported, possibly due to a malfunctioning or toxicity of the resulting protein. Following these findings, DRAM2 expression was assessed in several human tissues by semi-quantitative RT-PCR and two isoforms were detected ubiquitously, yet with a singular tissue-specific pattern in retina and brain. Altogether, although the unique retinal phenotype described did not correlate with the ubiquitous expression, the retinal-specific expression and the essential role of autophagy in the photoreceptor survival could be key arguments to explain this particular DRAM2 phenotype.","variants":[{"Name":"NM_001349884.2(DRAM2):c.518-1G>A","Chromosome":"1","Start":"111119960","Stop":"111119960","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3859279,"rule_based_match":true,"evidence_text":"c.518-1G>A","llm_judgment":"PRESENT","evidence":"c.518-1G>A","abstract_start":1028,"abstract_end":1038}]}
{"pmid":"23483675","title":"Identification of a GDF5 mutation in a Korean patient with brachydactyly type C without foot involvement.","abstract":"Brachydactyly type C (BDC) is characterized by shortening of the middle phalanges of the index, middle, and little fingers. Hyperphalangy of the index and middle finger and shortening of the first metacarpal can also be observed. BDC is a rare genetic condition associated with the GDF5 gene, and this condition has not been confirmed by genetic analysis so far in the Korean population. Herein, we present a case of a 6-yr-old girl diagnosed with BDC confirmed by molecular genetic analysis. The patient presented with shortening of the second and third digits of both hands. Sequence analysis of the GDF5 gene was performed and the pathogenic mutation, c.1312C>T (p.Arg438Cys), was identified. Interestingly, this mutation was previously described in a patient who presented with the absence of the middle phalanges in the second through fifth toes. However, our patient showed no involvement of the feet. Considering intrafamilial and interfamilial variability, molecular analysis of isolated brachydactyly is warranted to elucidate the genetic origin and establish a diagnosis.","variants":[{"Name":"NM_000557.5(GDF5):c.1312C>T (p.Arg438Cys)","Chromosome":"20","Start":"35434103","Stop":"35434103","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2860940,"rule_based_match":true,"evidence_text":"c.1312C>T (p.Arg438Cys)","llm_judgment":"PRESENT","evidence":"c.1312C>T (p.Arg438Cys)","abstract_start":655,"abstract_end":678}]}
{"pmid":"29395664","title":"Rett-like features and cortical visual impairment in a Japanese patient with HECW2 mutation.","abstract":"Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression. She has no acquired microcephaly, and brain magnetic resonance imaging showed non-specific mild cerebral and cerebellar atrophy without progression over time. Genetic analyses of MECP2, CDKL5, and FOXG1 were negative. Whole-exome sequencing analysis revealed a known de novo mutation (c.3988C > T) in HECW2. The characteristics of her clinical symptoms are severe cortical visual impairment and Rett-like phenotype such as involuntary movements and regression. This is the first report that patients with HECW2 mutation could show Rett-like feature.","variants":[{"Name":"NM_001348768.2(HECW2):c.3988C>T (p.Arg1330Trp)","Chromosome":"2","Start":"196225800","Stop":"196225800","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":243879,"rule_based_match":true,"evidence_text":"c.3988C > T","llm_judgment":"PRESENT","evidence":"c.3988C > T","abstract_start":938,"abstract_end":949}]}
{"pmid":"31709488","title":"A rare frameshift variant in trans with the IVS9-5T allele of CFTR in a Chinese pedigree with congenital aplasia of vas deferens.","abstract":"PURPOSE: Congenital aplasia of vas deferens (CAVD) is an atypical form of cystic fibrosis (CF) and causes obstructive azoospermia and male infertility. Compound heterozygous variants of CFTR are the main cause of CAVD. However, most evidence comes from genetic screening of sporadic cases and little is from pedigree analysis. In this study, we performed analysis in a Chinese pedigree with two CAVD patients in order to determine the genetic cause of this familial disorder.\nMETHODS: In the present study, we performed whole-exome sequencing and co-segregation analysis in a Chinese pedigree involving two patients diagnosed with CAVD.\nRESULTS: We identified a rare frameshift variant (NM_000492.3: c.50dupT;p.S18Qfs*27) and a frequent CBAVD-causing variant (IVS9-TG13-5T) in both patients. The frameshift variant introduced a premature termination codon and was not found in any public databases or reported in the literature. Co-segregation analysis confirmed these two variants were in compound heterozygous state. The other male members, who harbored the frameshift variant and benign IVS9-7T allele, did not have any typical clinical manifestations of CF or CAVD.\nCONCLUSION: Our findings may broaden the mutation spectrum of CFTR in CAVD patients and provide more familial evidence that the combination of a mild variant and a severe variant in trans of CFTR can cause vas deferens malformation.","variants":[{"Name":"NM_000492.4(CFTR):c.50dup (p.Ser18fs)","Chromosome":"7","Start":"117480137","Stop":"117480138","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":68611,"rule_based_match":true,"evidence_text":"NM_000492.3: c.50dupT;p.S18Qfs*27","llm_judgment":"PRESENT","evidence":"NM_000492.3: c.50dupT;p.S18Qfs*27","abstract_start":687,"abstract_end":720}]}
{"pmid":"25620207","title":"Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6.","abstract":"Keppen-Lubinsky syndrome (KPLBS) is a rare disease mainly characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, a narrow nasal bridge, a tented upper lip, a high palate, an open mouth, tightly adherent skin, an aged appearance, and severe generalized lipodystrophy. We sequenced the exomes of three unrelated individuals affected by KPLBS and found de novo heterozygous mutations in KCNJ6 (GIRK2), which encodes an inwardly rectifying potassium channel and maps to the Down syndrome critical region between DIRK1A and DSCR4. In particular, two individuals shared an in-frame heterozygous deletion of three nucleotides (c.455_457del) leading to the loss of one amino acid (p.Thr152del). The third individual was heterozygous for a missense mutation (c.460G>A) which introduces an amino acid change from glycine to serine (p.Gly154Ser). In agreement with animal models, the present data suggest that these mutations severely impair the correct functioning of this potassium channel. Overall, these results establish KPLBS as a channelopathy and suggest that KCNJ6 (GIRK2) could also be a candidate gene for other lipodystrophies. We hope that these results will prompt investigations in this unexplored class of inwardly rectifying K(+) channels.","variants":[{"Name":"NM_002240.5(KCNJ6):c.460G>A (p.Gly154Ser)","Chromosome":"21","Start":"37714697","Stop":"37714697","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187137,"rule_based_match":true,"evidence_text":"c.460G>A","llm_judgment":"PRESENT","evidence":"c.460G>A","abstract_start":804,"abstract_end":812}]}
{"pmid":"25941960","title":"Spinal form cerebrotendinous xanthomatosis patient with long spinal cord lesion.","abstract":"CONTEXT: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited lipid storage disease caused by mutation in the CYP27A1 gene. Spinal form CTX is a rare clinical subgroup of CTX and only 14 patients from 11 families have been reported to date. Here, we report the first Asian patient with spinal form CTX showing characteristic radiological findings.\nFINDINGS: The patient, a 46-year-old Japanese male, developed sensory disturbance of the lower legs at 39 and spastic gait at 46 years of age. Spinal cord magnetic resonance imaging (MRI) revealed a long hyperintense lesion involving lateral corticospinal tracts and gracile tracts in the cervical and thoracic cord on T2-weighted images. Gallium-67 (<sup>67</sup>Ga) scintigraphy revealed abnormal uptake in the Achilles tendons and the serum cholestanol level was elevated. CYP27A1 gene analysis identified homozygous missense mutation, c.1214G>A (p.R405Q). The patient was treated with atorvastatin monotherapy, which reduced serum cholestanol to less than 50% of the pretreatment level.\nCONCLUSION: Spinal form CTX should be considered in the differential diagnosis of cryptogenic myelopathy, especially in patients with a long spinal cord lesion, as treatment with chenodeoxycholic acid and/or competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase reverse the metabolic derangement and prevent the neurologiccal dysfunction.","variants":[{"Name":"NM_000784.4(CYP27A1):c.1214G>A (p.Arg405Gln)","Chromosome":"2","Start":"218814409","Stop":"218814409","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19299,"rule_based_match":true,"evidence_text":"c.1214G>A (p.R405Q)","llm_judgment":"PRESENT","evidence":"c.1214G>A (p.R405Q)","abstract_start":909,"abstract_end":928}]}
{"pmid":"18281469","title":"Mutational analysis of thirty-two double-strand DNA break repair genes in breast and pancreatic cancers.","abstract":"Inactivating mutations in several genes that encode components of the DNA repair machinery have been associated with an increased risk of breast cancer. To assess whether alterations in other DNA repair genes contribute to breast cancer and to further determine the relevance of these genes to pancreatic cancer, we performed mutational analysis of 32 DNA double-strand break repair genes in genomic DNA from 38 breast tumors, 48 pancreatic tumors, and 10 non-BRCA1/BRCA2 hereditary breast cancer patients. A total of 494 coding exons were screened by denatured high-performance liquid chromatography and direct DNA sequencing. Two inactivating mutations were identified in breast tumor samples, a germline single-nucleotide deletion in POLQ (c.3605delT) and a somatic nonsense change in PRKDC (c.2408C>A, p.Ser803X). Two germline-inactivating mutations in RAD50 (c.1875C>G, p.Tyr625X and IVS14+1G>A) were also detected in separate pancreatic tumor samples. In addition, 35 novel nonsynonymous amino acid substitutions, resulting from two in-frame deletions and 33 single nucleotide alterations, were identified. Seven of these were predicted to influence protein function. A separate analysis of the CLSPN c.3839C>T (rs35490896) variant that was observed more frequently in breast tumors than in pancreatic tumors or normal controls failed to detect a significant association with breast cancer risk in a Mayo Clinic breast cancer case-control study. In conclusion, this screen of DNA repair genes implicates PRKDC and POLQ as candidate tumor suppressor genes involved in breast cancer and suggests that inactivating mutations in RAD50 predispose to pancreatic cancer as well as breast cancer.","variants":[{"Name":"NM_005732.4(RAD50):c.1875C>G (p.Tyr625Ter)","Chromosome":"5","Start":"132594950","Stop":"132594950","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":221577,"rule_based_match":true,"evidence_text":"c.1875C>G, p.Tyr625X","llm_judgment":"PRESENT","evidence":"c.1875C>G, p.Tyr625X","abstract_start":864,"abstract_end":884}]}
{"pmid":"35432467","title":"Epidermolysis Bullosa With Congenital Absence of Skin: Congenital Corneal Cloudiness and Esophagogastric Obstruction Including Extended Genotypic Spectrum of","abstract":"Epidermolysis bullosa (EB) is a rare and genetically heterogeneous disorder characterized by skin fragility and blister formation occurring spontaneously or after minor trauma. EB is accompanied by congenital absence of skin (EB with CAS) in some patients. Pathogenic variants of <i>COL7A1</i> are responsible for EB with CAS in the vast majority of cases. Type and subtype diagnosis of EB with CAS generally requires specific immunohistological examinations that are not widely available plus targeted gene analysis. The present study aimed to determine the clinical features of five patients affected by EB with CAS and to identify the underlying genetic defects using whole exome sequencing (WES) followed by focused analysis of the target genes. Four patients had generalized skin involvement and one had localized defects. Two patients exhibited extremely severe skin manifestations and congenital cloudy cornea along with pyloric atresia, and one had partial esophagogastric obstruction and anuria due to vesicoureteric obstruction. In the WES analysis, the average coverage of the target exons was 99.05% (726 of 733 exons), with a range of 96.4-100% for individual genes. We identified four novel and two known pathogenic/likely pathogenic variants of five distinct genes in the examined families: <i>PLEC</i>:c.2536G > T (p.Glu846Ter); <i>LAMC2</i>:c.3385C > T (p.Arg1129Ter); <i>KRT5</i>:c.429G > A (p.Glu477Lys); <i>ITGB4:</i>c.794dupC (p.Ala266SerfsTer5); <i>COL7A1</i>:c.5440C > T (p.Arg1814Cys); and <i>COL7A1</i>:c.6103delG. All alleles were inherited from the parents, except for the <i>KRT5</i> variant as a <i>de novo</i> finding. The findings reveal extremely rare phenotypes found in EB with CAS, namely congenital cloudy cornea, esophagogastric obstruction, and anuria, and extend the genotypic spectrum of EB-related genes. The data confirm that WES provides very high coverage of coding exons/genes and support its use as a reasonable alternative method for diagnosis of EB. The present data from an underrepresented population in Southeast Asia could further broaden the knowledge and research on EB.","variants":[{"Name":"NM_000094.4(COL7A1):c.5440C>T (p.Arg1814Cys)","Chromosome":"3","Start":"48578500","Stop":"48578500","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1035826,"rule_based_match":true,"evidence_text":"COL7A1:c.5440C > T (p.Arg1814Cys)","llm_judgment":"PRESENT","evidence":"p.Arg1814Cys","abstract_start":1495,"abstract_end":1507},{"Name":"NM_005562.3(LAMC2):c.3385C>T (p.Arg1129Ter)","Chromosome":"1","Start":"183243203","Stop":"183243203","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":357027,"rule_based_match":true,"evidence_text":"LAMC2:c.3385C > T (p.Arg1129Ter)","llm_judgment":"PRESENT","evidence":"p.Arg1129Ter","abstract_start":1371,"abstract_end":1383},{"Name":"NM_000213.5(ITGB4):c.794dup (p.Ala266fs)","Chromosome":"17","Start":"75730295","Stop":"75730296","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":1281858,"rule_based_match":true,"evidence_text":"ITGB4:c.794dupC (p.Ala266SerfsTer5)","llm_judgment":"PRESENT","evidence":"p.Ala266Ser","abstract_start":1448,"abstract_end":1459}]}
{"pmid":"30784238","title":"Severe congenital nephrogenic diabetes insipidus in a compound heterozygote with a new large deletion of the AQP2 gene. A case report.","abstract":"BACKGROUND: Congenital nephrogenic diabetes insipidus (NDI) is a rare condition characterized by severe polyuria, due to the inability of the kidneys to concentrate urine in response to arginine vasopressin (AVP). In the majority of the cases, the disease shows an X-linked inherited pattern, although an autosomal recessive inheritance was also observed.\nMETHODS: We report a patient with a severe NDI diagnosed during the neonatal period. Because the patient was female without a family history of congenital NDI, her disease was thought to exhibit an autosomal recessive form.\nRESULTS: A full mutation analysis of AVP receptor 2 (AVPR2; MIM#300538) gene showed no mutations. However, direct Sanger sequencing of the aquaporin 2 (AQP2) revealed an apparently homozygous mutation at nucleotide position NM_000486.5:c.374C>T (p.Thr125Met) in exon 2. Further customized multiplex ligation-dependent probe amplification (MLPA), single-nucleotide polymorphism (SNP) array analysis, and long-range polymerase chain reaction (PCR) followed by Sanger sequencing showed a heterozygous exonic deletion comprising exons 2, 3, and partially 4 of AQP2.\nCONCLUSION: This is the first case of a compound heterozygote patient with a missense mutation involving NM_000486.5:exon2:c.374C>T (p.Thr125Met) and a gross deletion of at least exons 2, 3, and partially 4 on the AQP2 to present with a severe NDI phenotype.","variants":[{"Name":"NM_000486.6(AQP2):c.374C>T (p.Thr125Met)","Chromosome":"12","Start":"49954168","Stop":"49954168","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32876,"rule_based_match":true,"evidence_text":"NM_000486.5:c.374C>T (p.Thr125Met)","llm_judgment":"PRESENT","evidence":"NM_000486.5:c.374C>T (p.Thr125Met)","abstract_start":804,"abstract_end":838}]}
{"pmid":"21967607","title":"Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia.","abstract":"BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder, characterized by recurrent epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVMs) in various visceral organs. Endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1; ALK1), receptors for transforming growth factor-β (TGF-β) superfamily, have been identified as the principal HHT-causing genes.\nMETHODS: Three unrelated Korean HHT patients and their asymptomatic as well as symptomatic family members were genetically diagnosed by sequencing whole exons and their flanking regions of ENG and ACVRL1. Functionality of an aberrant translation start codon, which is created by a substitution mutation at the 5'-untranslated region (UTR) of ENG found in a HHT family, was tested by transient in vitro transfection assay. Decay of the mutant transcripts was also assessed by allele-specific expression analysis.\nRESULTS: Two ENG and one ACVRL1 mutations were identified: a known ENG mutation (c.360+1G > A; p.Gly74_Tyr120del); a novel ENG mutation (c.1-127C > T); and a novel ACVRL1 mutation (c.252_253insC; p.Val85fsX168). We further validated that the 5'-UTR ENG mutation prevents translation of ENG from the biological translation initiation site of the mutant allele, and leads to degradation of the mutant transcripts.\nCONCLUSIONS: This is the first experimental demonstration that a 5'-UTR mutation can prevent translation of ENG among HHT patients, and further supports the previous notion that haploinsufficiency is the primary mechanism of HHT1. Our data also underscore the importance of including exons encoding 5' UTR for HHT mutation screening.","variants":[{"Name":"NM_001114753.3(ENG):c.360+1G>A","Chromosome":"9","Start":"127829686","Stop":"127829686","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259913,"rule_based_match":true,"evidence_text":"c.360+1G > A","llm_judgment":"PRESENT","evidence":"c.360+1G > A","abstract_start":1015,"abstract_end":1027}]}
{"pmid":"30319355","title":"Photoreceptor Guanylate Cyclase (","abstract":"Over 100 mutations in <i>GUCY2D</i> that encodes the photoreceptor guanylate cyclase GC-E are known to cause two major diseases: autosomal recessive Leber congenital amaurosis (arLCA) or autosomal dominant cone-rod dystrophy (adCRD) with a poorly understood mechanism at the molecular level in most cases. Only few mutations were further characterized for their enzymatic and molecular properties. GC-E activity is under control of neuronal Ca<sup>2+</sup>-sensor proteins, which is often a possible route to dysfunction. We investigated five recently-identified GC-E mutants that have been reported in patients suffering from arLCA (one large family) and adCRD/maculopathy (four families). Microsatellite analysis revealed that one of the mutations, c.2538G > C (p.K846N), occurred <i>de novo</i>. To better understand the mechanism by which mutations that are located in different GC-E domains develop different phenotypes, we investigated the molecular consequences of these mutations by expressing wildtype and mutant GC-E variants in HEK293 cells. Analyzing their general enzymatic behavior, their regulation by Ca<sup>2+</sup> sensor proteins and retinal degeneration protein 3 (RD3) dimerization domain mutants (p.E841K and p.K846N) showed a shift in Ca<sup>2+</sup>-sensitive regulation by guanylate cyclase-activating proteins (GCAPs). Mutations in the cyclase catalytic domain led to a loss of enzyme function in the mutant p.P873R, but not in p.V902L. Instead, the p.V902L mutation increased the guanylate cyclase activity more than 20-fold showing a high GCAP independent activity and leading to a constitutively active mutant. This is the first mutation to be described affecting the GC-E catalytic core in a complete opposite way.","variants":[{"Name":"NM_000180.4(GUCY2D):c.2538G>C (p.Lys846Asn)","Chromosome":"17","Start":"8014726","Stop":"8014726","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":800617,"rule_based_match":true,"evidence_text":"c.2538G > C (p.K846N)","llm_judgment":"PRESENT","evidence":"c.2538G > C (p.K846N)","abstract_start":751,"abstract_end":772}]}
{"pmid":"18473191","title":"Identification of two novel aquaporin-2 mutations in a Thai girl with congenital nephrogenic diabetes insipidus.","abstract":"OBJECTIVE: To describe a Thai girl with congenital nephrogenic diabetes insipidus (NDI) and perform mutation analysis of the AQP2 gene.\nDESIGN: Case report.\nPATIENT: A 6-year old girl with a history of failure to thrive, polydipsia and polyuria was studied. Polyuria and polydipsia were observed within the first few months of life. Despite normal serum osmolality and electrolyte, the result of water deprivation test was compatible with a diagnosis of NDI.\nMETHODS: The entire coding regions of the AQP2 gene were assessed by polymerase chain reaction and sequencing analysis. The presence of mutations was also confirmed by restriction enzyme digestion analysis.\nRESULTS: Two heterozygous novel missense mutations were identified. Both were located in exon 1; a guanine-to-thymine substitution at nucleotide position 3 (c.3G-->T) inherited from her mother and a guanine-to-adenine at position 85 (c.85G-->A) inherited from her father, resulting in a methionine to isoleucine at codon 1 (p.M1I) and glycine to serine at codon 29 (p.G29S), respectively. These mutations have never been previously described and were not detected in 100 ethnic-matched unaffected control chromosomes.\nCONCLUSION: We report two novel mutations of the AQP2 gene, p.M1I and p.G29S, associated with autosomal recessive congenital NDI. This study expands the genotypic spectrum of AQP2 mutations and emphasizes an important role of genetic testing for definite diagnosis and genetic counseling.","variants":[{"Name":"NM_000486.6(AQP2):c.85G>A (p.Gly29Ser)","Chromosome":"12","Start":"49950915","Stop":"49950915","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2106912,"rule_based_match":false,"evidence_text":"c.85G-->A","llm_judgment":"PRESENT","evidence":"c.85G-->A","abstract_start":900,"abstract_end":909}]}
{"pmid":"19520594","title":"Fluctuating liver functions in siblings with MPV17 mutations and possible improvement associated with dietary and pharmaceutical treatments targeting respiratory chain complex II.","abstract":"BACKGROUND/AIMS: To describe the clinical and biological findings of two Japanese siblings with novel MPV17 gene mutations (c.451insC/c.509C > T) manifesting hepatic mitochondrial DNA depletion syndrome.\nMETHODS: We observed these brothers and sought to determine the efficacy of treatment targeting respiratory chain complex II for the younger brother.\nRESULTS: A 3-month-old boy had presented with profound liver dysfunction, failure to thrive, and watery diarrhea. Although he was then placed on a carbohydrate-rich diet, his liver function thereafter fluctuated greatly in association with viral infections, and rapidly deteriorated to liver failure. He underwent liver transplantation at 17 months of age but died at 22 months of age. The younger brother, aged 47 months at the time of this writing, presented with liver dysfunction from 8 months of age. His transaminase levels also fluctuated considerably fluctuations in association with viral infections. At 31 months of age, treatment with succinate and ubiquinone was initiated together with a lipid-rich diet using ketone milk. Thereafter, his transaminase levels normalized and never fluctuated, and the liver histology improved.\nCONCLUSIONS: These cases suggested that the clinical courses of patients with MPV17 mutations are greatly influenced by viral infections and that dietary and pharmaceutical treatments targeting the mitochondrial respiratory chain complex II may be beneficial in the clinical management of MPV17 mutant patients.","variants":[{"Name":"NM_002437.5(MPV17):c.509C>T (p.Ser170Phe)","Chromosome":"2","Start":"27309934","Stop":"27309934","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46921,"rule_based_match":true,"evidence_text":"c.509C > T","llm_judgment":"PRESENT","evidence":"c.509C > T","abstract_start":134,"abstract_end":144}]}
{"pmid":"25667652","title":"Five cases of paroxysmal kinesigenic dyskinesia by genetic diagnosis.","abstract":"Paroxysmal kinesigenic dyskinesia (PKD) is an autosomal dominant disorder and PRRT2 is the causative gene of PKD. The aim of this study was to investigate PRRT2 mutations in patients who were clinically diagnosed with PKD. Nine PKD cases, including four familial cases and five sporadic cases, were selected. Peripheral blood was drawn after obtaining informed consent, and genomic DNA was extracted by a standard protocol. Sanger sequencing was performed for the screening of PRRT2 mutations. A total of five cases were detected to harbor PRRT2 mutations. Four familial cases carried a c.649dupC (p.Arg217Profs<sup>*</sup>8) mutation, while one sporadic case and his asymptomatic father carried a c.133-136delCCAG (p.Pro45Argfs<sup>*</sup>44) mutation. PRRT2 mutations were not identified in the remaining cases. The study further confirmed that PRRT2 was a causative gene of PKD and implied that PRRT2 mutation has incomplete penetrance.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC (p.Arg217Profs<sup>*</sup>8)","llm_judgment":"PRESENT","evidence":"c.649dupC (p.Arg217Profs<sup>*</sup>8)","abstract_start":587,"abstract_end":625}]}
{"pmid":"37684520","title":"A population-based survey of FBN1 variants in Iceland reveals underdiagnosis of Marfan syndrome.","abstract":"Marfan syndrome (MFS) is an autosomal dominant condition characterized by aortic aneurysm, skeletal abnormalities, and lens dislocation, and is caused by variants in the FBN1 gene. To explore causes of MFS and the prevalence of the disease in Iceland we collected information from all living individuals with a clinical diagnosis of MFS in Iceland (n = 32) and performed whole-genome sequencing of those who did not have a confirmed genetic diagnosis (27/32). Moreover, to assess a potential underdiagnosis of MFS in Iceland we attempted a genotype-based approach to identify individuals with MFS. We interrogated deCODE genetics' database of 35,712 whole-genome sequenced individuals to search for rare sequence variants in FBN1. Overall, we identified 15 pathogenic or likely pathogenic variants in FBN1 in 44 individuals, only 22 of whom were previously diagnosed with MFS. The most common of these variants, NM_000138.4:c.8038 C > T p.(Arg2680Cys), is present in a multi-generational pedigree, and was found to stem from a single forefather born around 1840. The p.(Arg2680Cys) variant associates with a form of MFS that seems to have an enrichment of abdominal aortic aneurysm, suggesting that this may be a particularly common feature of p.(Arg2680Cys)-associated MFS. Based on these combined genetic and clinical data, we show that MFS prevalence in Iceland could be as high as 1/6,600 in Iceland, compared to 1/10,000 based on clinical diagnosis alone, which indicates underdiagnosis of this actionable genetic disorder.","variants":[{"Name":"NM_000138.5(FBN1):c.8038C>T (p.Arg2680Cys)","Chromosome":"15","Start":"48415549","Stop":"48415549","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":197585,"rule_based_match":true,"evidence_text":"NM_000138.4:c.8038 C > T p.(Arg2680Cys)","llm_judgment":"PRESENT","evidence":"NM_000138.4:c.8038 C > T p.(Arg2680Cys)","abstract_start":912,"abstract_end":951}]}
{"pmid":"20505134","title":"Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency.","abstract":"OBJECTIVE: To describe the current treatment; clinical, biochemical, and molecular findings; and clinical follow-up of patients with aromatic l-amino acid decarboxylase (AADC) deficiency.\nMETHOD: Clinical and biochemical data of 78 patients with AADC deficiency were tabulated in a database of pediatric neurotransmitter disorders (JAKE). A total of 46 patients have been previously reported; 32 patients are described for the first time.\nRESULTS: In 96% of AADC-deficient patients, symptoms (hypotonia 95%, oculogyric crises 86%, and developmental retardation 63%) became clinically evident during infancy or childhood. Laboratory diagnosis is based on typical CSF markers (low homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, and elevated 3-O-methyl-l-dopa, l-dopa, and 5-hydroxytryptophan), absent plasma AADC activity, or elevated urinary vanillactic acid. A total of 24 mutations in the DDC gene were detected in 49 patients (8 reported for the first time: p.L38P, p.Y79C, p.A110Q, p.G123R, p.I42fs, c.876G>A, p.R412W, p.I433fs) with IVS6+ 4A>T being the most common one (allele frequency 45%).\nCONCLUSION: Based on clinical symptoms, CSF neurotransmitters profile is highly indicative for the diagnosis of aromatic l-amino acid decarboxylase deficiency. Treatment options are limited, in many cases not beneficial, and prognosis is uncertain. Only 15 patients with a relatively mild form clearly improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors.","variants":[{"Name":"NM_001082971.2(DDC):c.876G>A (p.Glu292=)","Chromosome":"7","Start":"50499148","Stop":"50499148","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":933896,"rule_based_match":true,"evidence_text":"c.876G>A","llm_judgment":"PRESENT","evidence":"c.876G>A","abstract_start":1041,"abstract_end":1049}]}
{"pmid":"35699517","title":"Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey.","abstract":"Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type-3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype-phenotype relationships in CS/CISS-like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1-associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7-related phenotypes.","variants":[{"Name":"NM_004750.5(CRLF1):c.167T>C (p.Leu56Pro)","Chromosome":"19","Start":"18599795","Stop":"18599795","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1667582,"rule_based_match":true,"evidence_text":"c.167T>C","llm_judgment":"PRESENT","evidence":"c.167T>C","abstract_start":730,"abstract_end":738}]}
{"pmid":"26018198","title":"Adrenal Insufficiency in Mitochondrial Disease: A Rare Case of GFER-Related Mitochondrial Encephalomyopathy and Review of the Literature.","abstract":"GFER-related mitochondrial encephalomyopathy has been previously described only in 3 siblings of a consanguineous Moroccan family. Their phenotype included congenital cataracts, hypotonia, developmental delay, and sensorineural hearing loss. Multiple mitochondrial respiratory chain complex deficiencies were identified on muscle biopsy. We describe a now-19-year-old woman with adrenal insufficiency, lactic acidosis, congenital cataracts, and respiratory insufficiency secondary to mitochondrial disorder, who was reported by North et al (1996) as a toddler. Compound heterozygous GFER mutations c.373C>T (Q125X) and c.581G>A (R194 H) were recently discovered in this patient. The purpose of this report is (1) to expand the phenotype this ultra-rare disorder and (2) to provide a review of the literature describing the unique finding of adrenal insufficiency in patients with molecularly confirmed disorders of mitochondrial metabolism.","variants":[{"Name":"NM_005262.3(GFER):c.373C>T (p.Gln125Ter)","Chromosome":"16","Start":"1984861","Stop":"1984861","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":211704,"rule_based_match":true,"evidence_text":"c.373C>T (Q125X)","llm_judgment":"PRESENT","evidence":"c.373C>T (Q125X)","abstract_start":598,"abstract_end":614},{"Name":"NM_005262.3(GFER):c.581G>A (p.Arg194His)","Chromosome":"16","Start":"1985991","Stop":"1985991","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23730,"rule_based_match":true,"evidence_text":"c.581G>A (R194 H)","llm_judgment":"PRESENT","evidence":"c.581G>A (R194 H)","abstract_start":619,"abstract_end":636}]}
{"pmid":"35090489","title":"Novel bi-allelic MSH4 variants causes meiotic arrest and non-obstructive azoospermia.","abstract":"BACKGROUND: Non-obstructive azoospermia (NOA) is one of the most severe type in male infertility, and the genetic causes of NOA with meiotic arrest remain elusive.\nMETHODS: Four Chinese families with NOA participated in the study. We performed whole-exome sequencing (WES) for the four NOA-affected patients in four pedigrees. The candidate causative gene was further verified by Sanger sequencing. Hematoxylin and eosin staining (H&E) and immunohistochemistry (IHC) were carried out to evaluate the stage of spermatogenesis arrested in the patients with NOA.\nRESULTS: We identified two novel homozygous frameshift mutations of MSH4 and two novel compound heterozygous variants in MSH4 in four pedigrees with NOA. Homozygous loss of function (LoF) variants in MSH4 was identified in the NOA-affected patient (P9359) in a consanguineous Chinese family (NM_002440.4: c.805_812del: p.V269Qfs*15) and one patient with NOA (P21504) in another Chinese family (NM_002440.4: c.2220_2223del:p.K741Rfs*2). Also, compound heterozygous variants in MSH4 were identified in two NOA-affected siblings (P9517 and P9517B) (NM_002440.4: c.G1950A: p.W650X and c.2179delG: p.D727Mfs*11), and the patient with NOA (P9540) (NM_002440.4: c.G244A: p.G82S and c.670delT: p.L224Cfs*3). Histological analysis demonstrated lack of spermatozoa in seminiferous tubules of all patients and IHC showed the spermatogenesis arrested at the meiotic prophase I stage. Consistent with the autosomal recessive mode of inheritance, all of these mutations were inherited from heterozygous parental carriers.\nCONCLUSIONS: We identified that six novel mutations in MSH4 responsible for meiotic arrest and NOA. And these results provide researchers with a new insight to understand the genetic etiology of NOA and to identify new loci for genetic counselling of NOA.","variants":[{"Name":"NM_002440.4(MSH4):c.805_812del (p.Val269fs)","Chromosome":"1","Start":"75815126","Stop":"75815133","ReferenceAlleleVCF":"GGTTCAGTC","AlternateAlleleVCF":"G","allel_id":1685936,"rule_based_match":true,"evidence_text":"NM_002440.4: c.805_812del: p.V269Qfs*15","llm_judgment":"PRESENT","evidence":"NM_002440.4: c.805_812del: p.V269Qfs*15","abstract_start":852,"abstract_end":891},{"Name":"NM_002440.4(MSH4):c.1950G>A (p.Trp650Ter)","Chromosome":"1","Start":"75883664","Stop":"75883664","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1685937,"rule_based_match":false,"evidence_text":"NM_002440.4: c.G1950A: p.W650X","llm_judgment":"PRESENT","evidence":"NM_002440.4: c.G1950A: p.W650X","abstract_start":1106,"abstract_end":1136},{"Name":"NM_002440.4(MSH4):c.2179del (p.Asp727fs)","Chromosome":"1","Start":"75889322","Stop":"75889322","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":1685938,"rule_based_match":true,"evidence_text":"c.2179delG: p.D727Mfs*11","llm_judgment":"PRESENT","evidence":"c.2179delG: p.D727Mfs*11","abstract_start":1141,"abstract_end":1165}]}
{"pmid":"34039421","title":"ZNF445: a homozygous truncating variant in a patient with Temple syndrome and multilocus imprinting disturbance.","abstract":"BACKGROUND: ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus, ZNF445 pathogenic variants are predicted to cause multilocus imprinting disturbances (MLIDs), as do ZFP57 pathogenic variants. In particular, the MEG3/DLK1:IG-DMR would be affected, because the postzygotic methylation imprint of the MEG3/DLK1:IG-DMR is maintained primarily by ZNF445, whereas that of most iDMRs is preserved by both ZFP57 and ZNF445 or primarily by ZFP57.\nRESULTS: We searched for a ZNF445 variant(s) in six patients with various imprinting disorders (IDs) caused by epimutations and MLIDs revealed by pyrosequencing for nine iDMRs, without a selection for the original IDs. Re-analysis of the previously obtained whole exome sequencing data identified a homozygous ZNF445 variant (NM_181489.6:c.2803C>T:p.(Gln935*)) producing a truncated protein missing two of 14 zinc finger domains in a patient with Temple syndrome and MLID. In this patient, array-based genomewide methylation analysis revealed severe hypomethylation of most CpGs at the MEG3:TSS-DMR, moderate hypomethylation of roughly two-thirds of CpGs at the H19/IGF2:IG-DMR, and mild-to-moderate hypomethylation of a few CpGs at the DIRAS3:TSS-DMR, MEST:alt-TSS-DMR, IGF2:Ex9-DMR, IGF2:alt-TSS, and GNAS-AS1:TSS-DMR. Furthermore, bisulfite sequencing analysis for the MEG3/DLK1:IG-DMR delineated a markedly hypomethylated segment (CG-A). The heterozygous parents were clinically normal and had virtually no aberrant methylation pattern.\nCONCLUSIONS: We identified a ZNF445 pathogenic variant for the first time. Since ZNF445 binds to the MEG3/DLK1:IG-DMR and other iDMRs affected in this patient, the development of Temple syndrome and MLID would primarily be explained by the ZNF445 variant. Furthermore, CG-A may be the target site for ZNF445 within the MEG3/DLK1:IG-DMR.","variants":[{"Name":"NM_181489.6(ZNF445):c.2803C>T (p.Gln935Ter)","Chromosome":"3","Start":"44446868","Stop":"44446868","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2417747,"rule_based_match":true,"evidence_text":"NM_181489.6:c.2803C>T:p.(Gln935*)","llm_judgment":"PRESENT","evidence":"NM_181489.6:c.2803C>T:p.(Gln935*)","abstract_start":881,"abstract_end":914}]}
{"pmid":"30487246","title":"De novo mutation in","abstract":"BACKGROUND: Very long-chain fatty acids (VLCFAs) are essential for functioning of biological membranes. ELOVL fatty acid elongase 1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs. We studied two patients with a dominant <i>ELOVL1</i> mutation. Independently, Kutkowska-Kaźmierczak <i>et al.</i> had investigated the same patients and found the same mutation. We extended our study towards additional biochemical, functional, and therapeutic aspects.\nMETHODS: We did mutation screening by whole exome sequencing. RNA-sequencing was performed in patient and control fibroblasts. Ceramide and sphingomyelin levels were measured by LC-MS/MS. ELOVL1 activity was determined by a stable isotope-labelled [<sup>13</sup>C]malonyl-CoA elongation assay. ELOVL1 expression patterns were investigated by immunofluorescence, <i>in situ</i> hybridisation and RT-qPCR. As treatment option, we investigated VLCFA loading of fibroblasts.\nRESULTS: Both patients carried an identical heterozygous <i>de novo ELOVL1</i> mutation (c.494C>T, NM_001256399; p.S165F) not deriving from a founder allele. Patients suffered from epidermal hyperproliferation and increased keratinisation (ichthyosis). Hypomyelination of the central white matter explained spastic paraplegia and central nystagmus, while optic atrophy was causative for reduction of peripheral vision and visual acuity. The mutation abrogated ELOVL1 enzymatic activity and reduced ≥C24 ceramides and sphingomyelins in patient cells. Fibroblast loading with C22:0-VLCFAs increased C24:0-ceramides and sphingomyelins. We found competitive inhibition for ceramide and sphingomyelin synthesis between saturated and monounsaturated VLCFAs. Transcriptome analysis revealed upregulation of modules involved in epidermal development and keratinisation, and downregulation of genes for neurodevelopment, myelination, and synaptogenesis. Many regulated genes carried consensus proliferator-activated receptor (PPAR)α and PPARγ binding motifs in their 5'-regions.\nCONCLUSION: A dominant <i>ELOVL1</i> mutation causes a neuro-ichthyotic disorder possibly amenable to treatment with PPAR-modulating drugs.","variants":[{"Name":"NM_022821.4(ELOVL1):c.494C>T (p.Ser165Phe)","Chromosome":"1","Start":"43364448","Stop":"43364448","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":653802,"rule_based_match":true,"evidence_text":"c.494C>T","llm_judgment":"PRESENT","evidence":"c.494C>T","abstract_start":1032,"abstract_end":1040}]}
{"pmid":"26036578","title":"A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss.","abstract":"Mutation of KCNQ4 has been reported to cause autosomal dominant non-syndromic hearing loss (DFNA2A) that usually presents as progressive hearing loss starting from mild to moderate hearing loss during childhood. Here, we identified a novel KCNQ4 mutation, c.1044_1051del8, in a family with autosomal recessive non-syndromic hearing loss. The proband was homozygous for the mutation and was born to consanguineous parents; she showed severe hearing loss that was either congenital or of early childhood onset. The proband had a sister who was heterozygous for the mutation but showed normal hearing. The mutation caused a frameshift that eliminated most of the cytoplasmic C-terminus, including the A-domain, which has an important role for protein tetramerization, and the B-segment, which is a binding site for calmodulin (CaM) that regulates channel function via Ca ions. The fact that the heterozygote had normal hearing indicates that sufficient tetramerization and CaM binding sites were present to preserve a normal phenotype even when only half the proteins contained an A-domain and B-segment. On the other hand, the severe hearing loss in the homozygote suggests that complete loss of the A-domain and B-segment in the protein caused loss of function due to the failure of tetramer formation and CaM binding. This family suggests that some KCNQ4 mutations can cause autosomal recessive hearing loss with more severe phenotype in addition to autosomal dominant hearing loss with milder phenotype. This genotype-phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype due to deletion of the cytoplasmic C-terminus of the potassium channel.","variants":[{"Name":"NM_004700.4(KCNQ4):c.1044_1051del (p.Ala349Profs)","Chromosome":"1","Start":"40822313","Stop":"40822320","ReferenceAlleleVCF":"AGGCTGCCT","AlternateAlleleVCF":"A","allel_id":204601,"rule_based_match":true,"evidence_text":"c.1044_1051del8","llm_judgment":"PRESENT","evidence":"c.1044_1051del8","abstract_start":256,"abstract_end":271}]}
{"pmid":"25425289","title":"A novel mutation in FGFR2.","abstract":"Craniosynostosis is a congenital anomaly that can occur as an isolated condition or as part of a syndrome. Although several genes are known to cause syndromic craniosynostosis, only 24% can be attributed to known genes. Therefore, it is likely that more mutations and other genes are involved. We present the identification of a novel point mutation in fibroblast growth factor receptor 2 (FGFR2), c.812G>T, p.(Gly271Val) or c.1851G>C, p.(Leu617Phe). Furthermore, we describe a mutation that has been identified just recently, c.812G>T, (p.Gly271Val) or c.1851G>C, (p.Leu617Phe). In addition, we describe findings from a sequence analysis of all coding exons and exon/intron boundaries of FGFR2 performed on 124 patients with syndromic craniosynostosis.","variants":[{"Name":"NM_000141.5(FGFR2):c.812G>T (p.Gly271Val)","Chromosome":"10","Start":"121520106","Stop":"121520106","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":563601,"rule_based_match":true,"evidence_text":"c.812G>T, p.(Gly271Val)","llm_judgment":"PRESENT","evidence":"c.812G>T, p.(Gly271Val)","abstract_start":398,"abstract_end":421}]}
{"pmid":"23046579","title":"Characterization of seven novel mutations on the HEXB gene in French Sandhoff patients.","abstract":"Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by mutations in the HEXB gene encoding the beta subunit of hexosaminidases A and B, two enzymes involved in GM2 ganglioside degradation. Eleven French Sandhoff patients with infantile or juvenile forms of the disease were completely characterized using sequencing of the HEXB gene. A specific procedure was developed to facilitate the detection of the common 5'-end 16kb deletion which was frequent (36% of the alleles) in our study. Eleven other disease-causing mutations were found, among which four have previously been reported (c.850C>T, c.793T>G, c.115del and c.800_817del). Seven mutations were completely novel and were analyzed using molecular modelling. Two deletions (c.176del and c.1058_1060del), a duplication (c.1485_1487dup) and a nonsense mutation (c.552T>G) were predicted to strongly alter the enzyme spatial organization. The splice mutation c.558+5G>A affecting the intron 4 consensus splice site led to a skipping of exon 4 and to a truncated protein (p.191X). Two missense mutations were found among the patients studied. The c.448A>C mutation was probably a severe mutation as it was present in association with the known c.793T>G in an infantile form of Sandhoff disease and as it significantly modified the N-terminal domain structure of the protein. The c.171G>C mutation resulting in a p.W57C amino acid substitution in the N-terminal region is probably less drastic than the other abnormalities as it was present in a juvenile patient in association with the c.176del. Finally, this study reports a rapid detection of the Sandhoff disease-causing alleles facilitating genetic counselling and prenatal diagnosis in at-risk families.","variants":[{"Name":"NM_000521.4(HEXB):c.850C>T (p.Arg284Ter)","Chromosome":"5","Start":"74713584","Stop":"74713584","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18926,"rule_based_match":true,"evidence_text":"c.850C>T","llm_judgment":"PRESENT","evidence":"c.850C>T","abstract_start":614,"abstract_end":622},{"Name":"NM_000521.4(HEXB):c.558+5G>A","Chromosome":"5","Start":"74696744","Stop":"74696744","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":543899,"rule_based_match":true,"evidence_text":"c.558+5G>A","llm_judgment":"PRESENT","evidence":"c.558+5G>A","abstract_start":942,"abstract_end":952}]}
{"pmid":"37377052","title":"Clinical and molecular characterization in a cohort of patients with progressive pseudorheumatoid dysplasia.","abstract":"Progressive pseudorheumatoid dysplasia (PPRD), a rare autosomal recessive syndrome, is a type of skeletal dysplasia associated with pain, stiffness, swelling of multiple joints, and the absence of destructive changes. PPRD occurs due to loss of function pathogenic variants in WISP3 (CCN6) gene, located on chromosome 6q22. In this study, 23 unrelated Egyptian PPRD patients were clinically diagnosed based on medical history, physical and radiological examinations, and laboratory investigations. Sequencing of the whole WISP3 (CCN6) exons and introns boundaries was carried out for all patients. A total of 11 different sequence variations were identified in the WISP3 (CCN6) gene, five of them were new pathogenic variants: the NM_003880.3: c.80T>A (p.L27*), c.161delG (p.C54fs*12), c.737T>C (p.Leu246Pro), c.347-1G>A (IVS3-1G>A), and c.376C>T (p.Q126*). The results of this study expand the spectrum of WISP3 (CCN6) pathogenic variants associated with PPRD. Clinical and genetic analysis is important for proper genetic counseling to curb this rare disorder in the families.","variants":[{"Name":"NM_198239.2(CCN6):c.737T>C (p.Leu246Pro)","Chromosome":"6","Start":"112068352","Stop":"112068352","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3392958,"rule_based_match":true,"evidence_text":"c.737T>C (p.Leu246Pro)","llm_judgment":"PRESENT","evidence":"c.737T>C (p.Leu246Pro)","abstract_start":786,"abstract_end":808}]}
{"pmid":"21394830","title":"A mild neurofibromatosis type 1 phenotype produced by the combination of the benign nature of a leaky NF1-splice mutation and the presence of a complex mosaicism.","abstract":"Here we analyze the genetic and molecular basis responsible for a very benign phenotype observed in an NF1 patient. Quantification of cells carrying the NF1 mutation in different samples derived from the three embryonic layers revealed mosaicism. Furthermore, the construction of a minigene with patient's mutation (c.3198 - 314G>A) confirmed its benign nature due to the leakiness of the splicing mechanism that generated a proportion of correctly spliced transcripts. Hence, we concluded that the mild phenotype observed in this patient is the result of the presence of mosaicism together with the benign nature of a leaky NF1-splice mutation. Finally, with the aim of developing a personalized therapeutic approach for this patient, we demonstrated correction of the splicing defect by using specific antisense morpholino oligomers. Our results provide an example of the molecular complexity behind disease phenotypes and highlight the importance of using comprehensive genetic approaches to better assess phenotype-genotype correlations.","variants":[{"Name":"NM_001042492.3(NF1):c.3198-314G>A","Chromosome":"17","Start":"31231759","Stop":"31231759","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":940397,"rule_based_match":true,"evidence_text":"c.3198 - 314G>A","llm_judgment":"PRESENT","evidence":"c.3198 - 314G>A","abstract_start":316,"abstract_end":331}]}
{"pmid":"23773660","title":"LINS, a modulator of the WNT signaling pathway, is involved in human cognition.","abstract":"BACKGROUND: Inherited intellectual disability (ID) conditions are a group of genetically heterogeneous disorders that lead to variable degrees of cognition deficits. It has been shown that inherited ID can be caused by mutations in over 100 different genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying the defective gene underlying an autosomal recessive ID in two sibs of an Emirati family.\nMETHODS: A combined approach involving homozygosity mapping and whole-exome sequencing was used to identify the causative mutation. RNA analysis was performed to gain further insight into the pathogenic effect of the detected mutation.\nRESULTS: We have identified a homozygous splicing mutation (c.1219_1222+1delAAAGG) in the LINS gene in the affected children. LINS is the human homologue of the Drosophila segment polarity gene lin that encodes an essential regulator of the wingless/Wnt signaling. The identified mutation alters the first consensus nucleotide of the 5' donor splice junction of intron 5 and the 3' end of exon 5. Transcript analysis revealed that this change leads to an exon skipping event resulting in direct splicing of exon 4 to exon 6. Another mutation in LINS has been described very briefly in an Iranian family with autosomal recessive ID and microcephaly.\nCONCLUSION: Our study confirms that LINS, a modulator of the WNT pathway, is an indispensable gene to human cognition and this finding sheds further light on the importance of WNT signaling in human brain development and/or function.","variants":[{"Name":"NM_001040616.3(LINS1):c.1219_1222+1del","Chromosome":"15","Start":"100573650","Stop":"100573654","ReferenceAlleleVCF":"ACCTTT","AlternateAlleleVCF":"A","allel_id":125791,"rule_based_match":true,"evidence_text":"c.1219_1222+1delAAAGG","llm_judgment":"PRESENT","evidence":"c.1219_1222+1delAAAGG","abstract_start":776,"abstract_end":797}]}
{"pmid":"25967385","title":"Whole exome sequencing reveals a novel de novo FOXC1 mutation in a patient with unrecognized Axenfeld-Rieger syndrome and glaucoma.","abstract":"We report the identification of a novel mutation in the fork-head box C1 (FOXC1) gene which occurred de novo in an Italian patient with unrecognized Axenfeld-Rieger syndrome. He was previously diagnosed as having late recognized primary congenital glaucoma at the age of 14 years and was subsequently subjected to multiple surgical interventions due to uncontrolled intraocular pressure and progressive visual field loss. After exclusion of mutations in CYP1B1 and MYOC, trio-whole-exome sequencing revealed de novo in frame deletion in the coding region of the FOXC1 gene (c.407_409delGTC, p.V137del) leading to a deletion of the evolutionary conserved amino acid Valine at position 137 of the protein. Molecular modeling predicted that Val137 deletion impairs FOXC1 DNA-binding capacity and transcriptional activation. Since loss-of-function mutations in FOXC1 are associated with Axenfeld-Rieger syndrome, the genetic findings in combination with re-evaluation of the patient's clinical data resulted in a corrected diagnosis of Axenfeld-Rieger syndrome with developmental glaucoma. We therefore suggest that in addition to CYP1B1 and MYOC, FOXC1 should be included in the genetic analysis of cases with unclear glaucomatous phenotypes to ensure proper diagnosis, adequate treatment and appropriate genetic counseling.","variants":[{"Name":"NM_001453.3(FOXC1):c.409_411del (p.Val137del)","Chromosome":"6","Start":"1610852","Stop":"1610854","ReferenceAlleleVCF":"TTCG","AlternateAlleleVCF":"T","allel_id":486789,"rule_based_match":false,"evidence_text":"c.407_409delGTC, p.V137del","llm_judgment":"PRESENT","evidence":"c.407_409delGTC, p.V137del","abstract_start":574,"abstract_end":600}]}
{"pmid":"35249492","title":"Identification of Novel and Known LDLR Variants Triggering Severe Familial Hypercholesterolemia in Saudi Families.","abstract":"BACKGROUND: Familial hypercholesterolemia (FH) is a common illness mainly caused by variants occurring in the low-density lipoprotein receptor (LDLR) gene. FH is a leading cause of coronary artery disease.\nOBJECTIVE: This study aims to determine genetic defect(s) in homozygous and heterozygous FH index patients and their first-degree blood relatives and understand the genotype-phenotype correlation.\nMETHODS: This study employed the genetic screening of FH-related genes by next-generation sequencing and cascade screening by capillary sequencing.\nRESULTS: We identified the presence of a novel frameshift variant [c.335_336insCGAG, p.(F114Rfs*17)] and three known missense variants [c.622G>A, p.(E208K)], [c.1474G>A, p.(D492N)], [c.1429G>A, p.(D477N)] in the LDLR gene of four unrelated Saudi families with FH. In proband 1, a nonsense variant c.1421C>G, p.(S474*) was also detected at exon 9 of the lipoprotein lipase gene. The segregation arrangement of the identified variants corresponded with the clinical characteristics. In this study, all the detected variants were confined in the ligand-binding domain and epidermal growth factor (EGF)-precursor homology domain of the LDLR protein, which portrayed severe clinical phenotypes of FH. Moreover, these LDLR variants were in a highly conserved residue of the proteins.\nCONCLUSION: In addition to the finding of the novel variant in the LDLR gene that extends the spectrum of variants causing FH, the results of this study also support the need for diagnostic screening and cascade genetic testing of this high-risk condition and to understand the genotype-phenotype correlation, which could lead to better prevention of coronary artery disease.","variants":[{"Name":"NM_000527.5(LDLR):c.622G>A (p.Glu208Lys)","Chromosome":"19","Start":"11105528","Stop":"11105528","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":245665,"rule_based_match":true,"evidence_text":"c.622G>A, p.(E208K)","llm_judgment":"PRESENT","evidence":"c.622G>A, p.(E208K)","abstract_start":687,"abstract_end":706},{"Name":"NM_000527.5(LDLR):c.1429G>A (p.Asp477Asn)","Chromosome":"19","Start":"11113605","Stop":"11113605","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":246152,"rule_based_match":true,"evidence_text":"[c.1429G>A, p.(D477N)]","llm_judgment":"PRESENT","evidence":"[c.1429G>A, p.(D477N)]","abstract_start":733,"abstract_end":755},{"Name":"NM_000527.5(LDLR):c.1474G>A (p.Asp492Asn)","Chromosome":"19","Start":"11113650","Stop":"11113650","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171216,"rule_based_match":true,"evidence_text":"c.1474G>A, p.(D492N)","llm_judgment":"PRESENT","evidence":"c.1474G>A, p.(D492N)","abstract_start":710,"abstract_end":730}]}
{"pmid":"38141607","title":"A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.","abstract":"Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAX<sup>Arg60Gln</sup> (Max<sup>∗Arg60Gln</sup>) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAX<sup>Arg60Gln</sup> individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.","variants":[{"Name":"NM_002382.5(MAX):c.179G>A (p.Arg60Gln)","Chromosome":"14","Start":"65078029","Stop":"65078029","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":948631,"rule_based_match":true,"evidence_text":"c.179G>A (p.Arg60Gln)","llm_judgment":"PRESENT","evidence":"c.179G>A (p.Arg60Gln)","abstract_start":318,"abstract_end":339}]}
{"pmid":"28594066","title":"Novel biallelic mutations in the PNPT1 gene encoding a mitochondrial-RNA-import protein PNPase cause delayed myelination.","abstract":"Recent studies suggest that impaired transcription or mitochondrial translation of small RNAs can cause abnormal myelination. A polynucleotide phosphorylase (PNPase) encoded by PNPT1 facilitates the import of small RNAs into mitochondria. PNPT1 mutations have been reported in patients with neurodevelopmental diseases with mitochondrial dysfunction. We report here 2 siblings with PNPT1 mutations who presented delayed myelination as well as mitochondrial dysfunction. We identified compound heterozygous mutations (c.227G>A; p.Gly76Asp and c.574C>T; p.Arg192*) in PNPT1 by quartet whole-exome sequencing. Analyses of skin fibroblasts from the patient showed that PNPase expression was markedly decreased and that import of the small RNA RNaseP into mitochondria was impaired. Exogenous expression of wild-type PNPT1, but not mutants, rescued ATP production in patient skin fibroblasts, suggesting the pathogenicity of the identified mutations. Our cases expand the phenotypic spectrum of PNPT1 mutations that can cause delayed myelination.","variants":[{"Name":"NM_033109.5(PNPT1):c.574C>T (p.Arg192Ter)","Chromosome":"2","Start":"55679787","Stop":"55679787","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1701728,"rule_based_match":true,"evidence_text":"c.574C>T (p.Arg192*)","llm_judgment":"PRESENT","evidence":"p.Arg192*","abstract_start":552,"abstract_end":561}]}
{"pmid":"23000067","title":"A novel type heterozygous mutation in the glucose-6-phosphatase gene in a Chinese patient with glycogen storage disease Ia.","abstract":"Mutations in the glucose-6-phosphatase (G6Pase) gene are responsible for glycogen storage disease type Ia (GSD Ia). By genotype analysis of the affected pedigree, we identified a novel type mutation in a Chinese patient with GSD Ia. Mutation analysis was performed for the coding region of G6Pase gene using DNA sequencing and TaqMan gene expression assay was used to further confirm the novel mutation. The proband was compound heterozygous for c.311A>T/c.648G>T. Our report expands the spectrum of G6Pase gene mutation in China.","variants":[{"Name":"NM_000151.4(G6PC1):c.311A>T (p.Gln104Leu)","Chromosome":"17","Start":"42904011","Stop":"42904011","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":3495227,"rule_based_match":true,"evidence_text":"c.311A>T","llm_judgment":"PRESENT","evidence":"c.311A>T","abstract_start":446,"abstract_end":454}]}
{"pmid":"18378174","title":"Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community.","abstract":"Maple syrup urine disease (MSUD) is an autosomal recessive disorder, caused by the defective function of the branched-chain alpha-ketoacid dehydrogenase complex (BCKD). BCKD is a mitochondrial complex, encoded by four nuclear genes (BCKDHA, BCKDHB, DBT and DLD), involved in the metabolism of branched-chain amino acids (BCAAs). Since the MSUD mutational spectrum has not been previously assessed in Portugal, in this study we present the molecular characterization of 30 MSUD Portuguese patients. Seventeen putative mutations have been identified (six in BCKDHA, five in BCKDHB and six in DBT); seven of them are here described for the first time. The most common mutation identified was a C deletion in BCKDHA gene (c.117delC; p.R40GfsX23), already reported in the Spanish population. Interestingly, it was found in all patients of a Gypsy community from South of the country, so a founder effect is probably responsible for the high incidence of the disease in this community. Structural models of MSUD missense mutations have been performed to understand their pathogenic effect, in order to elucidate and often to predict the severity of a mutation clinical consequence.","variants":[{"Name":"NM_000709.4(BCKDHA):c.117del (p.Arg40fs)","Chromosome":"19","Start":"41410639","Stop":"41410639","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":99249,"rule_based_match":true,"evidence_text":"c.117delC","llm_judgment":"PRESENT","evidence":"c.117delC","abstract_start":718,"abstract_end":727}]}
{"pmid":"16785853","title":"Novel mutations of the PAX6 gene identified in Chinese patients with aniridia.","abstract":"PURPOSE: Mutations in PAX6 are the major cause of aniridia. Only a few PAX6 mutations in Chinese have been reported. This study is to identify novel mutations in PAX6 of Chinese patients with aniridia.\nMETHODS: Aniridia patients were collected from 11 Chinese families, and genomic DNA was prepared from venous leukocytes. The coding regions of PAX6 were analyzed by direct sequencing of PCR products. Variations detected were further evaluated in available family members as well as in controls by using heteroduplex-SSCP analysis.\nRESULTS: Four novel mutations including c.141+1G>A, c.184-3C>G, c.542C>A (Ser181X), and c.562C>T (Gln188X) and one known mutation c.120C>A (Cys40X) were identified in PAX6 of five unrelated patients with aniridia. All five mutations are expected to generate null alleles of PAX6. Varied ocular phenotypes were observed in different patients within families.\nCONCLUSIONS: We identified four novel mutations and 1 known mutation in the human PAX6 gene. These results expand the mutation spectrum in PAX6 and enrich our knowledge of genotype-phenotype relation due to PAX6 mutations.","variants":[{"Name":"NM_001368894.2(PAX6):c.141+1G>A","Chromosome":"11","Start":"31802703","Stop":"31802703","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":495530,"rule_based_match":true,"evidence_text":"c.141+1G>A","llm_judgment":"PRESENT","evidence":"c.141+1G>A","abstract_start":573,"abstract_end":583}]}
{"pmid":"26294103","title":"C21orf2 is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium.","abstract":"BACKGROUND/AIM: We have noted a phenotype of early-onset retinal dystrophy with macular staphyloma but without high myopia. The aim of this study is to report the underlying genetic mutations and the subcellular localisation of the gene product in the retina.\nMETHODS: Retrospective case series (2012-2015); immunohistochemical analyses of mammalian retina for in situ protein localisation.\nRESULTS: All three probands were first noted to have decreased vision at 3-6 years old which worsened over time. At ages 39, 37 and 12 years old, all had similar retinal findings: dystrophic changes (retinal pigment epithelium mottling, vessel narrowing), macular staphyloma (despite only mild myopia or high hyperopia), and non-recordable electroretinography. All harboured homozygous mutations in C21orf2, a gene recently suggested to be associated with retinal dystrophy but of unknown function. Two had a frameshift deletion c.436_466del (p.Glu146Serfs*6). The third had a missense mutation affecting a highly conserved residue (p.Cys61Tyr) and was short (below the 3rd percentile) and obese (50th percentile for weight despite short stature). Immunohistochemical studies in human, pig and mouse retinas localised C21orf2 protein to the ciliary structures of the photoreceptor cell (the daughter basal body, the centriole adjacent to the basal body, and the connecting cilium).\nCONCLUSIONS: This retinal dystrophy phenotype is caused by recessive mutations in C21orf2 and can be considered a retinal ciliopathy as C21orf2 encodes a protein that localises to photoreceptor ciliary structures. The short stature and obesity noted in the youngest girl suggest that for some patients biallelic C21orf2 mutations may result in syndromic ciliopathy.","variants":[{"Name":"NM_004928.3(CFAP410):c.436_466del (p.Glu146fs)","Chromosome":"21","Start":"44331922","Stop":"44331952","ReferenceAlleleVCF":"TTGGGGCCGCCGTGGCCTGTGCCCTCTCTCTC","AlternateAlleleVCF":"T","allel_id":420010,"rule_based_match":true,"evidence_text":"c.436_466del (p.Glu146Serfs*6)","llm_judgment":"PRESENT","evidence":"c.436_466del (p.Glu146Serfs*6)","abstract_start":920,"abstract_end":950}]}
{"pmid":"16429404","title":"DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population.","abstract":"Hereditary haemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome) is an autosomal dominant disorder characterized by localized angiodysplasia due to mutations in endoglin, ALK-1 gene, and a still unidentified locus. The lack of highly recurrent mutations, locus heterogeneity, and the presence of mutations in almost all coding exons of the two genes makes the screening for mutations time-consuming and costly. In the present study, we developed a DHPLC-based protocol for mutation detection in ALK1 and ENG genes through retrospective analysis of known sequence variants, 20 causative mutations and 11 polymorphisms, and a prospective analysis on 47 probands with unknown mutation. Overall DHPLC analysis identified the causative mutation in 61 out 66 DNA samples (92.4%). We found 31 different mutations in the ALK1 gene, of which 15 are novel, and 20, of which 12 are novel, in the ENG gene, thus providing for the first time the mutational spectrum in a cohort of Italian HHT patients. In addition, we characterized the splicing pattern of ALK1 gene in lymphoblastoid cells, both in normal controls and in two individuals carrying a mutation in the non-invariant -3 position of the acceptor splice site upstream exon 6 (c.626-3C>G). Functional essay demonstrated the existence, also in normal individuals, of a small proportion of ALK1 alternative splicing, due to exon 5 skipping, and the presence of further aberrant splicing isoforms in the individuals carrying the c.626-3C>G mutation.","variants":[{"Name":"NM_000020.3(ACVRL1):c.626-3C>G","Chromosome":"12","Start":"51914436","Stop":"51914436","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":433108,"rule_based_match":true,"evidence_text":"c.626-3C>G","llm_judgment":"PRESENT","evidence":"c.626-3C>G","abstract_start":1234,"abstract_end":1244}]}
{"pmid":"32337609","title":"A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age.","abstract":"Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.","variants":[{"Name":"NM_020223.4(FAM20C):c.1645C>T (p.Arg549Trp)","Chromosome":"7","Start":"259870","Stop":"259870","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16064,"rule_based_match":true,"evidence_text":"c.1645C > T, p.Arg549Trp","llm_judgment":"PRESENT","evidence":"c.1645C > T, p.Arg549Trp","abstract_start":1394,"abstract_end":1418}]}
{"pmid":"27829781","title":"X-linked heterozygous mutations in","abstract":"PURPOSE: To identify genetic mutations in three families with early onset high myopia (eoHM) limited to female members.\nMETHODS: Genomic DNA was collected from participating members of families XF1, XF2, and XF3. Genome-wide linkage scans were performed on the largest family (XF1). Whole exome sequencing was performed on seven samples, including five samples (four affected and one unaffected) from family XF1, as well as the two probands from family XF2 and XF3. Variants were analyzed with multistep bioinformatics analyses. Sanger-dideoxy sequencing was used to verify candidate variations in families and controls.\nRESULTS: The genome-wide linkage scans performed on family XF1 detected a candidate locus on chromosome Xp11.1-Xq13.3 with a maximum logarithm of the odds (LOD) score of 2.48 and 3.01 for markers DXS991 and DXS986, respectively. Parallel whole exome sequencing identified a novel c.893C>A (p.Ala298Asp) mutation in <i>ARR3</i> located on Xq13.1 in family XF1, which was shared by all four affected individuals but not the unaffected individual. Two other novel mutations in <i>ARR3</i>, c.298C>T (p.Arg100*) and c.239T>C (p.Leu80Pro), were detected in families XF2 and XF3, respectively. These mutations were predicted to be damaging and were not present in the normal controls and existing databases. All three mutations cosegregated with eoHM in each of the three families, in which all heterozygous female members are affected whereas all hemizygous male family members are not affected. Transmission of the mutations and eoHM in the three families demonstrates an unusual pattern of X-linked female-limited inheritance.\nCONCLUSIONS: These data suggest that heterozygous mutations in <i>ARR3</i> might be responsible for X-linked female-limited eoHM in the three families, a pattern contrary to the standard X-linked recessive trait. To our knowledge, eoHM is the first human disease associated with mutations in <i>ARR3</i> and the second X-linked female-limited disease identified thus far. Identification of <i>ARR3</i> associated with X-linked female-limited trait provides not only additional evidence of this unusual hereditary pattern but also an additional model for investigating the molecular mechanism responsible for female-limited phenotypes.","variants":[{"Name":"NM_004312.3(ARR3):c.893C>A (p.Ala298Asp)","Chromosome":"X","Start":"70278629","Stop":"70278629","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":472250,"rule_based_match":true,"evidence_text":"c.893C>A (p.Ala298Asp)","llm_judgment":"PRESENT","evidence":"c.893C>A (p.Ala298Asp)","abstract_start":901,"abstract_end":923},{"Name":"NM_004312.3(ARR3):c.298C>T (p.Arg100Ter)","Chromosome":"X","Start":"70276234","Stop":"70276234","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":472251,"rule_based_match":true,"evidence_text":"c.298C>T (p.Arg100*)","llm_judgment":"PRESENT","evidence":"c.298C>T (p.Arg100*)","abstract_start":1108,"abstract_end":1128},{"Name":"NM_004312.3(ARR3):c.239T>C (p.Leu80Pro)","Chromosome":"X","Start":"70276175","Stop":"70276175","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":472252,"rule_based_match":true,"evidence_text":"c.239T>C (p.Leu80Pro)","llm_judgment":"PRESENT","evidence":"c.239T>C (p.Leu80Pro)","abstract_start":1133,"abstract_end":1154}]}
{"pmid":"37277924","title":"Identification of a novel splicing-altering LAMP2 variant in a Chinese family with Danon disease.","abstract":"AIMS: This study aimed to identify a novel splicing-altering LAMP2 variant associated with Danon disease.\nMETHODS AND RESULTS: To identify the potential genetic mutation in a Chinese pedigree, whole-exome sequencing was conducted in the proband, and Sanger sequencing was performed on the proband's parents. To verify the impact of the splice-site variant, a minigene splicing assay was applied. The AlphaFold2 analysis was used to analyse the mutant protein structure. A splice-site variant (NM_013995.2:c.864+5G>A) located at intron 6 of the LAMP2 gene was identified as a potential pathogenic variant. The minigene splicing revealed that this variant causes exon 6 to be skipped, resulting in a truncated protein. The AlphaFold2 analysis showed that the mutation caused a protein twist direction change, leading to conformational abnormality.\nCONCLUSIONS: A novel splice-site variant (NM_013995.2:c.864+5G>A) located at intron 6 of the LAMP2 gene was identified. This discovery may enlarge the LAMP2 variant spectrum, promote accurate genetic counselling, and contribute to the diagnosis of Danon disease.","variants":[{"Name":"NM_002294.3(LAMP2):c.864+5G>A","Chromosome":"X","Start":"120446300","Stop":"120446300","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3410729,"rule_based_match":true,"evidence_text":"NM_013995.2:c.864+5G>A","llm_judgment":"PRESENT","evidence":"NM_013995.2:c.864+5G>A","abstract_start":493,"abstract_end":515}]}
{"pmid":"27026573","title":"ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study.","abstract":"ASAH1 gene encodes for acid ceramidase that is involved in the degradation of ceramide into sphingosine and free fatty acids within lysosomes. ASAH1 variants cause both the severe and early-onset Farber disease and rare cases of spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by childhood onset of proximal muscle weakness and atrophy due to spinal motor neuron degeneration followed by occurrence of severe and intractable myoclonic seizures and death in the teenage years. We studied two subjects, a 30-year-old pregnant woman and her 17-year-old sister, affected with a very slowly progressive non-5q SMA since childhood. No history of seizures or myoclonus has been reported and EEG was unremarkable. The molecular study of ASAH1 gene showed the presence of the homozygote nucleotide variation c.124A>G (r.124a>g) that causes the amino acid substitution p.Thr42Ala. Biochemical evaluation of cultured fibroblasts showed both reduction in ceramidase activity and accumulation of ceramide compared with the normal control. This study describes for the first time the association between ASAH1 variants and an adult SMA phenotype with no myoclonic epilepsy nor death in early age, thus expanding the phenotypic spectrum of ASAH1-related SMA. ASAH1 molecular analysis should be considered in the diagnostic testing of non-5q adult SMA patients.","variants":[{"Name":"NM_177924.5(ASAH1):c.124A>G (p.Thr42Ala)","Chromosome":"8","Start":"18075542","Stop":"18075542","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":552123,"rule_based_match":true,"evidence_text":"c.124A>G (r.124a>g)","llm_judgment":"PRESENT","evidence":"c.124A>G (r.124a>g)","abstract_start":857,"abstract_end":876}]}
{"pmid":"35169782","title":"Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India.","abstract":"Calpainopathy is caused by mutations in the <i>CAPN3</i> . There is only one clinical and genetic study of <i>CAPN3</i> from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5-20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique <i>CAPN3</i> variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051-1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802-9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.","variants":[{"Name":"NM_000070.3(CAPN3):c.802-9G>A","Chromosome":"15","Start":"42389944","Stop":"42389944","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":264570,"rule_based_match":true,"evidence_text":"c.802-9G>A","llm_judgment":"PRESENT","evidence":"c.802-9G > A","abstract_start":1404,"abstract_end":1416}]}
{"pmid":"20454499","title":"Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis.","abstract":"OBJECTIVE: Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far.\nPATIENTS: We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma.\nDESIGN: Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry.\nRESULTS: The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining.\nCONCLUSIONS: Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.","variants":[{"Name":"NM_003977.4(AIP):c.241C>T (p.Arg81Ter)","Chromosome":"11","Start":"67487147","Stop":"67487147","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49589,"rule_based_match":true,"evidence_text":"c.241C>T (R81X)","llm_judgment":"PRESENT","evidence":"c.241C>T (R81X)","abstract_start":809,"abstract_end":824}]}
{"pmid":"36644715","title":"","abstract":"<b>Background</b>  Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including <i>MLH1</i> , <i>MSH2</i> , <i>MSH6,</i> and <i>PMS2</i> (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic <i>PMS2</i> variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. <b>Patients and Methods</b>  The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. <b>Results</b>  The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious <i>PMS2</i> germline heterozygous mutation c.2192_2196delTAACT was detected. <b>Conclusion</b>  Our study supports the notion that LS may be associated with polyps and shows the predisposition of <i>PMS2</i> heterozygous mutation in LS-associated CRC at young age.","variants":[{"Name":"NM_000535.7(PMS2):c.2192_2196del (p.Leu731fs)","Chromosome":"7","Start":"5978675","Stop":"5978679","ReferenceAlleleVCF":"CAGTTA","AlternateAlleleVCF":"C","allel_id":96806,"rule_based_match":true,"evidence_text":"c.2192_2196delTAACT","llm_judgment":"PRESENT","evidence":"c.2192_2196delTAACT","abstract_start":1061,"abstract_end":1080}]}
{"pmid":"38013626","title":"Biallelic variants in the COQ4 gene caused hereditary spastic paraplegia predominant phenotype.","abstract":"INTRODUCTION: Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by progressive degeneration of upper motor neurons. Homozygous or compound heterozygous variants in COQ4 have been reported to cause primary CoQ10 deficiency-7 (COQ10D7), which is a mitochondrial disease.\nAIMS: We aimed to screened COQ4 variants in a cohort of HSP patients.\nMETHODS: A total of 87 genetically unidentified HSP index patients and their available family members were recruited. Whole exome sequencing (WES) was performed in all probands. Functional studies were performed to identify the pathogenicity of those uncertain significance variants.\nRESULTS: In this study, five different COQ4 variants were identified in three Chinese HSP pedigrees and two variants were novel, c.87dupT (p.Arg30*), c.304C>T (p.Arg102Cys). More importantly, we firstly described two early-onset pure HSP caused by COQ4 variants. Functional studies in patient-derived fibroblast lines revealed a reduction cellular CoQ10 levels and the abnormal mitochondrial structure.\nCONCLUSIONS: Our findings revealed that bilateral variants in the COQ4 gene caused HSP predominant phenotype, expanding the phenotypic spectrum of the COQ4-related disorders.","variants":[{"Name":"NM_016035.5(COQ4):c.87dup (p.Arg30Ter)","Chromosome":"9","Start":"128323031","Stop":"128323032","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":2847058,"rule_based_match":true,"evidence_text":"c.87dupT (p.Arg30*)","llm_judgment":"PRESENT","evidence":"c.87dupT (p.Arg30*)","abstract_start":802,"abstract_end":821},{"Name":"NM_016035.5(COQ4):c.304C>T (p.Arg102Cys)","Chromosome":"9","Start":"128325783","Stop":"128325783","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":622394,"rule_based_match":true,"evidence_text":"c.304C>T (p.Arg102Cys)","llm_judgment":"PRESENT","evidence":"c.304C>T (p.Arg102Cys)","abstract_start":823,"abstract_end":845}]}
{"pmid":"21863341","title":"Case seminar: a young female with acute hyponatremia and a sellar mass.","abstract":"In familial cases of combined pituitary hormone deficiency the most common mutations are that of Prophet of Pit 1 (PROP1) gene. PROP1 mutations are associated with deficiencies of growth hormone, thyrotropin, prolactin, and gonadotropins (follicle-stimulating hormone and luteinizing hormone), with evolving adrenocorticotropin (ACTH) deficiency in some cases. On imaging in most patients the pituitary gland is hypoplastic, but occasionally transient pituitary enlargement is found. We report a 22-year-old female initially diagnosed at age 12 with familial hypopituitarism due to PROP1 mutation, who presented with coma and respiratory arrest (acute hyponatremia). She was urgently treated in Intensive Care Unit of Emergency Center with hypertonic saline and stress doses of hydrocortisone, which resulted in the fast increase of plasma osmolality resulting in the osmotic demyelination syndrome. Simultaneously and incidentally on computed tomography scan a large sellar and suprasellar mass were reported as possible Rathke's cleft cyst or craniopharyngioma. Once the patient was stable, ACTH deficiency was documented. She remained replaced with hydrocortisone and subsequently underwent transphenoidal surgery. The removed sellar content revealed no pituitary adenoma or pituitary cells, but only an eosinophilic, colloid-like mass, and necrotic acellular debris. Her sister with hypopituitarism had an empty sella. Genetic testing in both sisters revealed the same homozygous c.150delA mutation in PROP1 gene. Here we report two sisters with the same PROP1 mutation who presented in adulthood with different pituitary morphology, one of them with a large sellar and suprasellar mass, in which transphenoidal surgery provided an extremely rare opportunity for a histopathological analysis of the sellar content. Due to the lack of endocrine care during the transition period hypocortisolism which evolved, a consequence of PROP1 mutation, was not recognized. Empirical use of hydrocortisone in the Intensive Care in our patient with life-threatening acute hyponatremia was appropriate but because glucocorticoid therapy on its own corrects hyponatremia even after stopping hypertonic saline infusion, the risk for over-correction of hyponatremia in ACTH deficiency is high.","variants":[{"Name":"NM_006261.5(PROP1):c.150del (p.Arg53fs)","Chromosome":"5","Start":"177994298","Stop":"177994298","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":23141,"rule_based_match":true,"evidence_text":"c.150delA","llm_judgment":"PRESENT","evidence":"c.150delA","abstract_start":1484,"abstract_end":1493}]}
{"pmid":"31182267","title":"Spinocerebellar ataxia with axonal neuropathy type 1 revisited.","abstract":"Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1; OMIM #607250), an exceedingly rare disorder having been documented in only a single family from Saudi Arabia, is the result of an unusual mutation in the tyrosyl DNA phosphodiesterase 1 gene (TDP1). We performed high-throughput sequencing (whole exome and ataxia gene panel) in two apparently unrelated Omani families segregating sensorimotor neuropathy and ataxia in an autosomal recessive fashion. Following validation by Sanger sequencing, all affected subjects (n = 4) were confirmed to carry the known SCAN1 pathogenic homozygous variant in the TDP1 gene, NM_001008744.1:c.1478A > G (p.His493Arg). In keeping with the initial description, our patients demonstrated progressive ataxia, cerebellar atrophy and disabling axonal sensori-motor neuropathy (n = 4), hypercholesterolemia (n = 2) and elevated serum alpha fetoprotein (n = 3). In addition, our patients also had mild cognitive deficits in multiple domains (n = 3), a feature not previously reported. Our findings independently revalidate the phenotype of TDP1 mutation and expand the clinical spectrum to include mild cognitive deficits. Haplotype sharing, as determined by DNA microarray (CytoScan HD), attests to a possible common founder mutation in the Arab population.","variants":[{"Name":"NM_018319.4(TDP1):c.1478A>G (p.His493Arg)","Chromosome":"14","Start":"89993420","Stop":"89993420","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18463,"rule_based_match":true,"evidence_text":"NM_001008744.1:c.1478A > G (p.His493Arg)","llm_judgment":"PRESENT","evidence":"NM_001008744.1:c.1478A > G (p.His493Arg)","abstract_start":622,"abstract_end":662}]}
{"pmid":"27779714","title":"Whole-exome sequencing identification of novel DNAH5 mutations in a young patient with primary ciliary dyskinesia.","abstract":"Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by structural and/or functional impairment of cilia throughout the whole body. Early diagnosis of PCD is important for the prevention of long‑term sequelae, however early diagnosis is a challenge due to the phenotypic heterogeneity of PCD. In the current study, the patient with PCD was diagnosed at nine years old following several efforts to control intractable airway symptoms. The patient experienced a chronic productive cough beginning in early childhood and had multiple episodes of pneumonia and otitis media with effusion and sinusitis. No situs inversus or other heterotaxias were reported. Serial chest X‑rays exhibited persistent atelectasis and bronchiectasis in the right middle lobe. When the patient was nine years old, electron microscopy of his cilia and genetic analysis were conducted. Electron microscopy of a biopsy specimen from the nasal mucosa indicated loss of the outer dynein arms. Whole‑exome analysis of the genome demonstrated the presence of compound heterozygous mutations in DNAH5: NM_001369.2:c.5983C>T, p.Arg1995X in exon 36 and NM_001369.2:c.9101delG, p.Gly3034ValfsX22 in exon 54; neither of which have been previously reported in the literature in a Japanese patient. Notably, this case is, to the best of our knowledge, the first reported case of PCD caused by the DNAH5 mutation in a Japanese patient.","variants":[{"Name":"NM_001369.3(DNAH5):c.5983C>T (p.Arg1995Ter)","Chromosome":"5","Start":"13830675","Stop":"13830675","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":394759,"rule_based_match":true,"evidence_text":"NM_001369.2:c.5983C>T, p.Arg1995X","llm_judgment":"PRESENT","evidence":"NM_001369.2:c.5983C>T, p.Arg1995X","abstract_start":1083,"abstract_end":1116}]}
{"pmid":"27889058","title":"Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa.","abstract":"Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy.","variants":[{"Name":"NM_138393.4(REEP6):c.404T>C (p.Leu135Pro)","Chromosome":"19","Start":"1496340","Stop":"1496340","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":361897,"rule_based_match":true,"evidence_text":"c.404T>C (p.Leu135Pro)","llm_judgment":"PRESENT","evidence":"p.Leu135Pro","abstract_start":1074,"abstract_end":1085},{"Name":"NM_138393.4(REEP6):c.383C>T (p.Pro128Leu)","Chromosome":"19","Start":"1496319","Stop":"1496319","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":361900,"rule_based_match":true,"evidence_text":"c.383C>T [p.Pro128Leu]","llm_judgment":"PRESENT","evidence":"c.383C>T [p.Pro128Leu]","abstract_start":1037,"abstract_end":1059}]}
{"pmid":"25358429","title":"Autosomal recessive congenital cataract, intellectual disability phenotype linked to STX3 in a consanguineous Tunisian family.","abstract":"The aim of this study is to investigate the genetic basis of autosomal recessive congenital cataract and intellectual disability phenotype in a consanguineous Tunisian family. The whole genome scan of the studied family was performed with single nucleotide polymorphisms (SNPs). The resulted runs of homozygosity (ROH) were analyzed through the integrated Systems Tool for Eye gene discovery (iSyTE) in order to prioritize candidate genes associated with congenital cataract. Selected genes were amplified and sequenced. Bioinformatic analysis was conducted to predict the function of the mutant gene. We identified a new specific lens gene named syntaxin 3 linked to the studied phenotype. The direct sequencing of this gene revealed a novel missense mutation c.122A>G which results in p.E41G. Bioinformatic analysis suggested a deleterious effect of this mutation on protein structure and function. Here, we report for the first time a missense mutation of a novel lens specific gene STX3 in a phenotype associating autosomal recessive congenital cataract and intellectual disability.","variants":[{"Name":"NM_004177.5(STX3):c.122A>G (p.Glu41Gly)","Chromosome":"11","Start":"59787044","Stop":"59787044","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":205602,"rule_based_match":true,"evidence_text":"c.122A>G","llm_judgment":"PRESENT","evidence":"c.122A>G","abstract_start":761,"abstract_end":769}]}
{"pmid":"26307494","title":"Early onset Charcot-Marie-Tooth neuropathy type 2A and severe developmental delay: expanding the clinical phenotype of MFN2-related neuropathy.","abstract":"Charcot-Marie-Tooth (CMT) syndromes are a group of clinically heterogeneous disorders of the peripheral nervous system. Mutations of mitofusin 2 (MFN2) have been recognized to be associated with CMT type 2A (CMT2A). CMT2A is primarily an axonal disorder resulting in motor and sensory neuropathy. We report a male child with psychomotor delay, dysmorphic features, and weakness of lower limbs associated with electrophysiological features of severe, sensory-motor, axonal neuropathy. The patient was diagnosed with early onset CMT2A and severe psychomotor retardation associated with c.310C>T mutation (p.R104W) in MFN2 gene. CMT2A should be considered in patients with both axonal sensory-motor neuropathy and developmental delay.","variants":[{"Name":"NM_014874.4(MFN2):c.310C>T (p.Arg104Trp)","Chromosome":"1","Start":"11992689","Stop":"11992689","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17320,"rule_based_match":true,"evidence_text":"c.310C>T mutation (p.R104W)","llm_judgment":"PRESENT","evidence":"c.310C>T mutation (p.R104W)","abstract_start":584,"abstract_end":611}]}
{"pmid":"1550123","title":"Mucopolysaccharidosis type VI: identification of three mutations in the arylsulfatase B gene of patients with the severe and mild phenotypes provides molecular evidence for genetic heterogeneity.","abstract":"Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy disease) results from the deficient activity of the lysosomal enzyme, arylsulfatase B (ASB; N-acetylgalactosamine-4-sulfatase E.C.3.1.6.1). The enzymatic defect leads to the accumulation of the glycosaminoglycan, dermatan sulfate, primarily in connective tissue and reticuloendothelial cell lysosomes. Although MPS VI patients have normal intelligence and no neurologic abnormalities, the disease is clinically heterogeneous: severely affected individuals expire in childhood or early adolescence while those with the mild or intermediate phenotypes have a slower, milder disease course and a longer life span. The recent isolation of the full-length cDNA-encoding human ASB permitted an investigation of the molecular lesions underlying the phenotypic heterogeneity in MPS VI. The ASB cDNA-coding sequences were determined from two unrelated MPS VI patients with the severe (proband 1) and mild (proband 2) phenotypes. These patients had about 2% and 7% of normal ASB activity in cultured fibroblasts, respectively. Proband 1 was homoallelic for a T-to-C transition in nucleotide (nt) 349, which predicted a cysteine-to-arginine substitution in the ASB polypeptide at residue 117 (C117R). Proband 2 was heteroallelic, having a T-to-C transition in nt 707, which predicted a leucine-to-proline replacement at ASB residue 236 (L236P), and having a G-to-A transition in nt 1214, which predicted a cysteine-to-tyrosine substitution at ASB residue 405 (C405Y). These mutations did not occur in three other unrelated MPS VI patients or in 120 ASB alleles from normal individuals, indicating that they were not polymorphisms. The identification of these three ASB mutations documents the first evidence of molecular heterogeneity in MPS VI and provides an initial basis for genotype/phenotype correlations in this lysosomal storage disease.","variants":[{"Name":"NM_000046.5(ARSB):c.349T>C (p.Cys117Arg)","Chromosome":"5","Start":"78969156","Stop":"78969156","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15917,"rule_based_match":false,"evidence_text":"a T-to-C transition in nucleotide (nt) 349, which predicted a cysteine-to-arginine substitution in the ASB polypeptide at residue 117 (C117R)","llm_judgment":"PRESENT","evidence":"a T-to-C transition in nucleotide (nt) 349, which predicted a cysteine-to-arginine substitution in the ASB polypeptide at residue 117 (C117R)","abstract_start":1101,"abstract_end":1242},{"Name":"NM_000046.5(ARSB):c.707T>C (p.Leu236Pro)","Chromosome":"5","Start":"78955486","Stop":"78955486","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15918,"rule_based_match":false,"evidence_text":"c.707T>C","llm_judgment":"PRESENT","evidence":"c.707T>C","abstract_start":null,"abstract_end":null},{"Name":"NM_000046.5(ARSB):c.1214G>A (p.Cys405Tyr)","Chromosome":"5","Start":"78781974","Stop":"78781974","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15919,"rule_based_match":false,"evidence_text":"c.1214G>A (p.Cys405Tyr)","llm_judgment":"PRESENT","evidence":"C405Y","abstract_start":1503,"abstract_end":1508}]}
{"pmid":"27036314","title":"Tumor progression in DICER1-mutated cystic nephroma-witnessing the genesis of anaplastic sarcoma of the kidney.","abstract":"We report a 7-month-old female infant with a multicystic left renal tumor having histologic features predominantly of a cystic nephroma, but with microscopic cellular foci which contained atypical mitotic figures and anaplastic nuclei. Immunohistochemistry showed strong p53 reactivity in the anaplastic region. DICER1 sequencing confirmed 2 mutations: germ line mutation c.2450delC and c.5438A>G somatic within the tumor. Despite an initial consideration of cystic partially differentiated nephroblastoma, the presence of anaplasia ruled that possibility out, as this is not an acceptable feature for that diagnosis. Moreover, the germ line DICER1 mutation prompted consideration that this case represents a unique \"nascent\" anaplastic sarcoma of kidney, and further immunohistochemical workup demonstrated cytoplasmic, but no nuclear WT-1 reactivity in the cellular foci. The importance of meticulous sampling of cystic lesions is highlighted by this unprecedented case, which lends support to the recent recognition of anaplastic sarcoma of kidney as a DICER1-associated cancer.","variants":[{"Name":"NM_177438.3(DICER1):c.2450del (p.Pro817fs)","Chromosome":"14","Start":"95108080","Stop":"95108080","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":921378,"rule_based_match":true,"evidence_text":"c.2450delC","llm_judgment":"PRESENT","evidence":"c.2450delC","abstract_start":372,"abstract_end":382},{"Name":"NM_177438.3(DICER1):c.5438A>G (p.Glu1813Gly)","Chromosome":"14","Start":"95091292","Stop":"95091292","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":921287,"rule_based_match":true,"evidence_text":"c.5438A>G","llm_judgment":"PRESENT","evidence":"c.5438A>G","abstract_start":387,"abstract_end":396}]}
{"pmid":"22575358","title":"Screening of the TARDBP gene in familial and sporadic amyotrophic lateral sclerosis patients of Chinese origin.","abstract":"TAR DNA-binding protein (TARDBP) mutations have been reported in patients with amyotrophic lateral sclerosis (ALS) in different populations. Only a few studies have screened for TARDBP mutations in Chinese populations. Here, we sequenced the coding region of all five TARDBP exons for mutations in 13 familial ALS (FALS) pedigrees and 312 sporadic ALS (SALS) patients of Chinese origin, as well as 245 healthy control subjects. Two heterozygous missense mutations, c.875G>A (p.S292N) and c.1043G>T (p.G348V), were identified in two and one SALS patients, respectively. One synonymous substitution, c.1098C>G (p.A366A), was identified in two SALS patients. None of the substitutions were found in healthy control subjects. In Chinese populations, the estimated frequency of TARDBP mutations in SALS patients (0.73%) is higher than Japanese and lower than White populations, whereas the estimated mutation frequency in superoxide dismutase 1 (SOD1)-negative FALS patients (15.2%) is higher than both Japanese and White populations. Our findings provide an overview of the occurrence of TARDBP mutations in Chinese ALS patients and highlight the importance of TARDBP mutation screening in Chinese ALS patients.","variants":[{"Name":"NM_007375.4(TARDBP):c.1098C>G (p.Ala366=)","Chromosome":"1","Start":"11022507","Stop":"11022507","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":275852,"rule_based_match":true,"evidence_text":"c.1098C>G (p.A366A)","llm_judgment":"PRESENT","evidence":"c.1098C>G (p.A366A)","abstract_start":598,"abstract_end":617}]}
{"pmid":"25572613","title":"Patient with an SLC26A4 gene mutation who had low-frequency sensorineural hearing loss and endolymphatic hydrops.","abstract":"OBJECTIVE: To report magnetic resonance imaging findings in a patient with an SLC26A4 gene mutation who had low-frequency sensorineural hearing loss.\nCASE REPORT: A 13-year-old girl had bilateral and symmetric low-frequency sensorineural hearing loss. Upon genetic testing, a heterozygous c.1105A > G (p.K369E) mutation of the SLC26A4 gene was detected. Mild endolymphatic hydrops in the right cochlea and marked endolymphatic hydrops in the left vestibulum were seen by magnetic resonance imaging 4 hours after an intravenous gadolinium injection.\nCONCLUSION: This is the first reported case of a patient with the SLC26A4 gene mutation c.1105A > G (p.K369E) who had low-frequency sensorineural hearing loss. Co-occurrence of cochlear and vestibular endolymphatic hydrops suggests an association with that pathology.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1105A>G (p.Lys369Glu)","Chromosome":"7","Start":"107689156","Stop":"107689156","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19861,"rule_based_match":true,"evidence_text":"c.1105A > G (p.K369E)","llm_judgment":"PRESENT","evidence":"c.1105A > G (p.K369E)","abstract_start":289,"abstract_end":310}]}
{"pmid":"31030435","title":"Analysis of FANCA gene mutation in a child with refractory leukocytopenia and thrombocytopenia","abstract":"OBJECTIVE: To explore the genetic basis of a child affected with refractory leukocytopenia and thrombocytopenia.\nMETHODS: Clinical manifestation and auxiliary examination of the child were discussed. Whole exome next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) were used to detected potential mutations of the FANCA gene.\nRESULTS: Repeated blood tests indicated that the child had abnormal WBC count at (2.7-3.98)×10^9;/L, platelet at (33-81) ×10^9;/L and hemoglobin at (100-120) g/L. NGS showed that she and her mother both carried a heterozygous c.3181A>G mutation (non-pathogenic) and a c.3788_3790del mutation of the FANCA gene. MLPA showed that she and her father both had heterozygous deletion of exons 11 to 14 of the FANCA gene.\nCONCLUSION: The compound heterozygous mutations of c.3788_3790del and deletion of exons 11 to 14 of the FANCA gene probably underlie the refractory leukocytopenia and thrombocytopenia in the child.","variants":[{"Name":"NM_000135.4(FANCA):c.3181A>G (p.Ser1061Gly)","Chromosome":"16","Start":"89749788","Stop":"89749788","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":401920,"rule_based_match":true,"evidence_text":"c.3181A>G","llm_judgment":"PRESENT","evidence":"c.3181A>G","abstract_start":592,"abstract_end":601}]}
{"pmid":"33309955","title":"Mild X-linked Alport syndrome due to the COL4A5 G624D variant originating in the Middle Ages is predominant in Central/East Europe and causes kidney failure in midlife.","abstract":"A study of 269 children enrolled into a National Registry for children with persistent glomerular hematuria identified 131 individuals with genetically confirmed X-linked Alport Syndrome. A single variant c.1871G>A p.Gly624Asp (G624D) in COL4A5 was predominant and accounted for 39% of X-linked Alport Syndrome in unrelated Polish families (44 of 113). To evaluate its origins, the genetic variation in a 2.79 Mb segment encompassing the COL4A5 locus on chromosome X was assessed. All G624D alleles were found on the same rare haplotype background, indicating a founder effect dating back to the 12-13th century. The phenotypic data of 131 children with X-linked Alport Syndrome and their 195 affected adult relatives revealed that the G624D variant was associated with a significantly milder clinical course in comparison to other pathogenic COL4A5 variants. Furthermore the clinical course of this genetically uniform cohort was milder than that observed in individuals with other COL4A5 missense mutations. In spite of the benign clinical manifestation throughout childhood and early adulthood, the G624D variant confers significant risk for both kidney failure and deafness in males, albeit 20-30 years later than that observed in individuals with other COL4A5 pathogenic variants (50% cumulative risk of starting dialysis at 54 years (95% confidence interval: 50-62) v. 26 years (95% confidence interval: 22-30)). Thus, males with G624D are candidates for existing and emerging therapies for Alport Syndrome.","variants":[{"Name":"NM_033380.3(COL4A5):c.1871G>A (p.Gly624Asp)","Chromosome":"X","Start":"108598793","Stop":"108598793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":35796,"rule_based_match":true,"evidence_text":"c.1871G>A p.Gly624Asp (G624D)","llm_judgment":"PRESENT","evidence":"c.1871G>A p.Gly624Asp (G624D)","abstract_start":205,"abstract_end":234}]}
{"pmid":"34845217","title":"Recurrent de novo pathogenic variant of WASF1 in a Japanese patient with neurodevelopmental disorder with absent language and variable seizures.","abstract":"A recurrent de novo pathogenic variant of WASF1, NM_003931:c.1516C>T [p.Arg506*], was identified in a 6-year-old female Japanese patient with severe developmental delay, hypotonia, hyperkinetic behavior, and distinctive facial features. The initial report of five adult patients with WASF1 variants was the only previous report regarding variants of this gene; this is the second such report, reaffirming that rare but recurrent truncating variants of WASF1 are associated with severe neurodevelopmental disorders.","variants":[{"Name":"NM_003931.3(WASF1):c.1516C>T (p.Arg506Ter)","Chromosome":"6","Start":"110101594","Stop":"110101594","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":553120,"rule_based_match":true,"evidence_text":"NM_003931:c.1516C>T [p.Arg506*]","llm_judgment":"PRESENT","evidence":"NM_003931:c.1516C>T [p.Arg506*]","abstract_start":49,"abstract_end":80}]}
{"pmid":"25876182","title":"Deleterious mutation in the FYB gene is associated with congenital autosomal recessive small-platelet thrombocytopenia.","abstract":"BACKGROUND: The FYB gene encodes adhesion and degranulation-promoting adaptor protein (ADAP), a hematopoietic-specific protein involved in platelet activation, cell motility and proliferation, and integrin-mediated cell adhesion. No ADAP-related diseases have been described in humans, but ADAP-deficient mice have mild thrombocytopenia and increased rebleeding from tail wounds.\nPATIENTS AND METHODS: We studied a previously reported family of five children from two consanguineous sibships of Arab Christian descent affected with a novel autosomal recessive bleeding disorder with small-platelet thrombocytopenia. Homozygosity mapping and exome sequencing were used to identify the genetic lesion causing the disease phenotype on chromosome 5. Bone-marrow morphology and platelet function were analyzed. Platelets were characterized by scanning electron microscopy.\nRESULTS: We identified a homozygous deleterious nonsense mutation, c.393G>A, in FYB. A reduced percentage of mature megakaryocytes was found in the bone marrow. Patients' platelets showed increased basal expression of P-selectin and PAC-1, and reduced increments of activation markers after stimulation with ADP, as detected by flow cytometry; they also showed reduced pseudopodium formation and the presence of trapped platelets between the fibrin fibers after thrombin addition, as observed on scanning electron microscopy.\nCONCLUSIONS: This is the first report of a disease caused by an FYB defect in humans, manifested by remarkable small-platelet thrombocytopenia and a significant bleeding tendency. The described phenotype shows ADAP to be important for normal platelet production, morphologic changes, and function. It is suggested that mutation analysis of this gene be included in the diagnosis of inherited thrombocytopenia.","variants":[{"Name":"NM_001465.6(FYB1):c.393G>A (p.Trp131Ter)","Chromosome":"5","Start":"39202568","Stop":"39202568","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":404860,"rule_based_match":true,"evidence_text":"c.393G>A","llm_judgment":"PRESENT","evidence":"c.393G>A","abstract_start":935,"abstract_end":943}]}
{"pmid":"27081515","title":"A novel KCNT1 mutation in a Japanese patient with epilepsy of infancy with migrating focal seizures.","abstract":"Epilepsy of infancy with migrating focal seizures (EIFMS) is a rare, early-onset epileptic encephalopathy characterized by polymorphous focal seizures. De novo mutations of KCNT1 have been identified in cases of this disorder. We encountered a sporadic patient with EIFMS, who suffered tonic convulsions at the age of 9 days. Using Sanger sequencing, we identified a de novo missense mutation of the same amino acid affected by a previously identified mutation, c.1420C>T (p.Arg474Cys).","variants":[{"Name":"NM_020822.3(KCNT1):c.1420C>T (p.Arg474Cys)","Chromosome":"9","Start":"135768847","Stop":"135768847","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259918,"rule_based_match":true,"evidence_text":"c.1420C>T (p.Arg474Cys)","llm_judgment":"PRESENT","evidence":"c.1420C>T (p.Arg474Cys)","abstract_start":462,"abstract_end":485}]}
{"pmid":"24329762","title":"Congenital factor XIII deficiency in Pakistan: characterization of seven families and identification of four novel mutations.","abstract":"Deficiency of coagulation factor XIII (FXIII) belongs to the rare bleeding disorders and its incidence is higher in populations with consanguineous marriages. The aims of this study were to characterize patients and relatives from seven families with suspected FXIII deficiency from Pakistan and to identify the underlying mutations. As a first indicator of FXIII deficiency, a 5M urea clot solubility test was used. Plasma FXIII A- and B-subunit antigen levels were determined by ELISA. FXIII activity was measured with an incorporation assay. Sequencing of all exons and intron/exon boundaries of F13A was performed, and a novel splice site defect was confirmed by RT-PCR analysis. Genetic analysis revealed six different mutations in the F13A gene. Two splice site mutations were detected, a novel c.1460+1G>A mutation in the first nucleotide of intron 11 and a previously reported c.2045G>A mutation in the last nucleotide of exon 14. Neither of them was expressed at protein level. A novel nonsense mutation in exon 4, c.567T>A, p.Cys188X, was identified, leading in homozygous form to severe FXIII deficiency. Two novel missense mutations were found in exons 8 and 9, c.1040C>A, p.Ala346Asp and c.1126T>C, p.Trp375Arg, and a previously reported missense mutation in exon 10, c.1241C>T, p.Ser413Leu. All patients homozygous for these missense mutations presented with severe FXIII deficiency. We have analysed a cohort of 27 individuals and reported four novel mutations leading to congenital FXIII deficiency.","variants":[{"Name":"NM_000129.4(F13A1):c.2045G>A (p.Arg682His)","Chromosome":"6","Start":"6151813","Stop":"6151813","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31563,"rule_based_match":true,"evidence_text":"c.2045G>A","llm_judgment":"PRESENT","evidence":"c.2045G>A","abstract_start":885,"abstract_end":894}]}
{"pmid":"32163377","title":"Inherited human IFN-γ deficiency underlies mycobacterial disease.","abstract":"Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by the Bacille Calmette-Guérin (BCG) vaccine and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-γ immunity due to mutations of 15 genes controlling the production of or response to IFN-γ. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-γ receptor 1 (IFN-γR1) and IFN-γR2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN-γ cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN-γ receptor. We describe 2 Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354_357del), causing a frameshift that generates a premature stop codon (p.T119Ifs4*). The mutant allele is loss of expression and loss of function. We also show that the patients' herpesvirus Saimiri-immortalized T lymphocytes did not produce IFN-γ, a phenotype that can be rescued by retrotransduction with WT IFNG cDNA. The blood T and NK lymphocytes from these patients also failed to produce and secrete detectable amounts of IFN-γ. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGR1 or IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGR1 or IFNGR2. This may account for the rarity of patients with autosomal-recessive, complete IFN-γ deficiency relative to patients with complete IFN-γR1 and IFN-γR2 deficiencies.","variants":[{"Name":"NM_000619.3(IFNG):c.354_357del (p.Thr119fs)","Chromosome":"12","Start":"68157922","Stop":"68157925","ReferenceAlleleVCF":"TAGTC","AlternateAlleleVCF":"T","allel_id":962973,"rule_based_match":true,"evidence_text":"c.354_357del","llm_judgment":"PRESENT","evidence":"c.354_357del","abstract_start":875,"abstract_end":887}]}
{"pmid":"36935552","title":"Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.","abstract":"CONTEXT: Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease.\nOBJECTIVE: To investigate for novel genes causing parathyroid cancer.\nMETHODS: We analyzed the germline DNA of 17 patients with \"sporadic\" PC and 3 with atypical parathyroid tumors (APTs) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants.\nRESULTS: We identified germline FLCN variants in 3 unrelated patients with PC. The 2 frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome, while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing; however, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant.\nCONCLUSION: The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy.","variants":[{"Name":"NM_144997.7(FLCN):c.124G>C (p.Gly42Arg)","Chromosome":"17","Start":"17228014","Stop":"17228014","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":645394,"rule_based_match":true,"evidence_text":"c.124G > C (p.G42R)","llm_judgment":"PRESENT","evidence":"c.124G > C (p.G42R)","abstract_start":996,"abstract_end":1015}]}
{"pmid":"15459958","title":"Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G>A (p.G93D) variant with reduced functional activity.","abstract":"Variations of the small heterodimer partner (SHP, NR0B2) gene, an atypical nuclear receptor that inhibits transactivation by hepatocyte nuclear factor (HNF)-4alpha, are associated with obesity among Japanese. The purpose of the study was to evaluate the prevalence of SHP variants among obese Danish men. Using combined SSCP and heteroduplex analysis, we analyzed the entire coding region of SHP for variants in a cohort of 750 Danish men with early-onset obesity and genotyped a cohort of 795 nonobese control subjects using PCR-RFLP. Functional analyses of the identified coding region variants were performed in both MIN6-m9 and HepG2 cell lines. A total of five novel variants, including three missense variants (c.100C>G [p.R34G], c.278G>A [p.G93D], and c.415C>A [p.P139H]) and two silent variants (c.65C>T [p.Y22Y] and c.339G>A [p.P113P]) were identified. Moreover, the previously reported c.512G>C [p.G171A] polymorphism was identified. The 171A allele was not associated with obesity (p = 0.07). The 34G, 93D, and 139H-alleles were rare variants, which were found only among obese subjects. Among the four coding region variants, the 93D-allele showed a reduced in vitro inhibition of the HNF-4alpha transactivation of the HNF-1alpha promoter expression when expressed in MIN6-m9 and HepG2 cell lines (p<0.01). In contrast to reported findings among obese Japanese, functional variants are rare among Danish men. A functional 93D variant of SHP was identified in 1 out of 750 obese and in none of 795 nonobese control subjects. Further large-scale population studies are necessary to assess the clinical impact of this rare variant on obesity risk among European subjects.","variants":[{"Name":"NM_021969.3(NR0B2):c.100C>G (p.Arg34Gly)","Chromosome":"1","Start":"26913841","Stop":"26913841","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2798064,"rule_based_match":true,"evidence_text":"c.100C>G [p.R34G]","llm_judgment":"PRESENT","evidence":"c.100C>G [p.R34G]","abstract_start":717,"abstract_end":734}]}
{"pmid":"21965147","title":"New mutations in the ATM gene and clinical data of 25 AT patients.","abstract":"Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T>C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.","variants":[{"Name":"NM_000051.4(ATM):c.8110T>C (p.Cys2704Arg)","Chromosome":"11","Start":"108335068","Stop":"108335068","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":810679,"rule_based_match":true,"evidence_text":"c.8110T>C (p.Cys2704Arg)","llm_judgment":"PRESENT","evidence":"c.8110T>C (p.Cys2704Arg)","abstract_start":740,"abstract_end":764}]}
{"pmid":"23935176","title":"Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome.","abstract":"OBJECTIVE: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs).\nMETHODS: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing.\nRESULTS: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay.\nCONCLUSIONS: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.","variants":[{"Name":"NM_001371246.1(SCN2A):c.634A>G (p.Asn212Asp)","Chromosome":"2","Start":"165309193","Stop":"165309193","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":481228,"rule_based_match":true,"evidence_text":"c.634A>G","llm_judgment":"PRESENT","evidence":"c.634A>G","abstract_start":767,"abstract_end":775}]}
{"pmid":"26818779","title":"Effective treatment by glycolic acid peeling for cutaneous manifestation of familial generalized acanthosis nigricans caused by FGFR3 mutation.","abstract":"BACKGROUND: Acanthosis nigricans (AN) can occur as a cutaneous manifestation of genetic diseases, one of which is associated with activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3).\nOBJECTIVE: We explored familial AN patients with FGFR3 mutations and examined the effectiveness of glycolic acid (GA) peeling in improving their skin manifestations.\nMETHODS: Sanger sequencing was performed for the genomic DNA extracted from leucocytes of the family members involving familial AN. GA peeling was carried out for the two patients of familial AN once every 2 weeks.\nRESULTS: Heterozygous c.1949A>C (p.K650T) mutation in FGFR3 was identified for the affected family members examined, whereas the wild-type sequence was found for two unaffected individuals. Hyperpigmentation and coarseness of the skin were improved by GA peeling at regular intervals with few adverse effects.\nCONCLUSION: We diagnosed our cases as familial generalized AN caused by heterozygous c.1949A>C (p.K650T) mutation of FGFR3. We propose that GA peeling is a useful and safe therapeutic option to treat familial AN.","variants":[{"Name":"NM_000142.5(FGFR3):c.1949A>C (p.Lys650Thr)","Chromosome":"4","Start":"1806163","Stop":"1806163","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":76763,"rule_based_match":true,"evidence_text":"c.1949A>C (p.K650T)","llm_judgment":"PRESENT","evidence":"c.1949A>C (p.K650T)","abstract_start":611,"abstract_end":630}]}
{"pmid":"20949533","title":"A novel X-linked multiple congenital anomaly syndrome associated with an EBP mutation.","abstract":"Mutations of the gene coding for emopamil binding protein (EBP) can lead to deficient activity of 3-β-hydroxysteroid Δ(8), Δ(7) isomerase and are most commonly identified in. association with the X-linked dominant (male lethal) chondrodysplasia punctata (CDPX2), also known as Conradi-Hunermann syndrome. Our group has identified a hemizygous EBP mutation in males with a phenotype remarkable for Dandy-Walker malformation, cataracts, collodion skin and cryptorchidism. Additional findings of hydrocephalus, dysplasia of the corpus callosum, cardiovascular, craniofacial and skeletal anomalies were regularly seen in affected males and the family histories were supportive of an X-linked -recessive condition. The regularly reproducible constellation of cardinal features aligns very nicely with other disorders of sterol biosynthesis and is further distinguished by an absence of arty clinical manifestations in obligate carrier females. Biochemical analysis of blood from cases demonstrated markedly increased levels of 8(9)-cholestenol, and 8-dehydroeholesterol and a mildly increased level of 7-dehydrocholesterol; a similar pattern to what is seen in CDPX2. Sequence analysis of EJJP revealed a novel hemizygous missense mutation at position 141, predictive of a tryptophan to cysteine substitution (c.141G>T, p.W47C). The unaffected mothers were heterozygous for the c.141G>T mutation arid showed random X-inactivation pattern upon.","variants":[{"Name":"NM_006579.3(EBP):c.141G>T (p.Trp47Cys)","Chromosome":"X","Start":"48523912","Stop":"48523912","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":170113,"rule_based_match":true,"evidence_text":"c.141G>T (p.W47C)","llm_judgment":"PRESENT","evidence":"c.141G>T","abstract_start":1305,"abstract_end":1313}]}
{"pmid":"30498240","title":"Identification of CACNA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance.","abstract":"Sinoatrial node dysfunction and deafness (SANDD) syndrome is rare and characterized by a low heart beat and severe-to-profound deafness. Additional features include fatigue, dizziness, and episodic syncope. The sinoatrial node (SAN) drives heart automaticity and continuously regulates heart rate. The CACNA1D gene encoding the Ca<sub>v</sub>1.3 protein expressed in inner hair cells, atria and SAN, induces loss-of-function in channel activity and underlies SANDD. To date, only one variant c.1208_1209insGGG:p.(G403_V404insG) has been reported for SANDD syndrome. We studied five Pakistani families with SANDD and characterized a new missense variant p.(A376V) in CACNA1D in one family, and further characterized the founder variant p.(G403_V404insG) in four additional pedigrees. We show that affected individuals in the four families which segregate p.(G403_V404insG) share a 1.03 MB haplotype on 3p21.1 suggesting they share a common distant ancestor. In conclusion, we identified new and known variants in CACNA1D in five Pakistani families with SANDD. This study is of clinical importance as the CACNA1D founder variant is only observed in families from the Khyber Pakhtunkhwa (KPK) province, in Pakistan. Therefore, screening patients with congenital deafness for SAN dysfunction in this province could ensure adequate follow-up and prevent cardiac failure associated with SAN.","variants":[{"Name":"NM_000720.4(CACNA1D):c.1208_1209insGGG (p.Gly403dup)","Chromosome":"3","Start":"53673802","Stop":"53673803","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGGG","allel_id":48308,"rule_based_match":true,"evidence_text":"c.1208_1209insGGG:p.(G403_V404insG)","llm_judgment":"PRESENT","evidence":"c.1208_1209insGGG:p.(G403_V404insG)","abstract_start":492,"abstract_end":527}]}
{"pmid":"18758829","title":"Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: identification of six novel alleles.","abstract":"We report the molecular characterization of 12 unrelated Italian patients affected with Sandhoff disease (SD), a recessively inherited disorder caused by mutations in HEXB gene. We identified 11 different mutations of which six are novel: one large deletion of 2,406 nt, (c.299+1471_408del2406), one frameshift mutation c.965delT (p.I322fsX32), one nonsense c.1372C>T (p.Q458X), and three splicing mutations (c.299G>T, c.300-2A>G and c.512-1G>T). One allele was only characterized at the messenger RNA (mRNA) level (r = 1170_1242del). Real-time polymerase chain reaction analysis of the HEXB mRNA from fibroblasts derived from patients carrying the novel point mutations showed that the presence of the premature termination codon in the transcript bearing the mutation c.965delT triggers the nonsense-mediated decay (NMD) pathway, which results in the degradation of the aberrant mRNA. The presence of the c.299G>T mutation leads to the degradation of the mutated mRNA by a mechanism other than NMD, while mutations c.300-2A>G and c.512-1G>T cause the expression of aberrant transcripts. In our group, the most frequent mutation was c.850C>T (p.R284X) representing 29% of the alleles. Haplotype analysis suggested that this mutation did not originate from a single genetic event. Interestingly, the common 16-kb deletion mutation was absent. This work provides valuable information regarding the molecular genetics of SD in Italy and provides new insights into the molecular basis of the disease.","variants":[{"Name":"NM_000521.4(HEXB):c.965del (p.Ile322fs)","Chromosome":"5","Start":"74715573","Stop":"74715573","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":543813,"rule_based_match":true,"evidence_text":"c.965delT (p.I322fsX32)","llm_judgment":"PRESENT","evidence":"c.965delT (p.I322fsX32)","abstract_start":320,"abstract_end":343},{"Name":"NM_000521.4(HEXB):c.512-1G>T","Chromosome":"5","Start":"74696692","Stop":"74696692","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":543894,"rule_based_match":true,"evidence_text":"c.512-1G>T","llm_judgment":"PRESENT","evidence":"c.512-1G>T","abstract_start":434,"abstract_end":444}]}
{"pmid":"31060517","title":"Novel BRCA2 pathogenic variant c.5219 T > G; p.(Leu1740Ter) in a consanguineous Senegalese family with hereditary breast cancer.","abstract":"BACKGROUND: Pathogenic variants associated with hereditary breast cancer have been reported for BRCA1 and BRCA2 (BRCA1/2) genes in patients from multiple ethnicities, but limited information is available from sub-Saharan African populations. We report a BRCA2 pathogenic variant in a Senegalese family with hereditary breast cancer.\nMETHODS: An index case from a consanguineous family and nineteen healthy female relatives were recruited after informed consent. Along with this family, 14 other index cases with family history of breast cancer were also recruited. For the control populations we recruited 48 healthy women with no cancer diagnosis and 48 women diagnosed with sporadic breast cancer without family history. Genomic DNA was extracted from peripheral blood. All BRCA2 exons were amplified by PCR and sequenced. Sequences were compared to the BRCA2 GenBank reference sequence (NM_000059.3) using Alamut Software.\nRESULTS: We identified a novel nonsense pathogenic variant c.5219 T > G; p.(Leu1740Ter) in exon 11 of BRCA2 in the index case. The pathogenic variant was also identified in three sisters and one daughter, but was absent in the controls and unrelated cases.\nCONCLUSIONS: This is the first report of a novel BRCA2 pathogenic variant in a Senegalese family with hereditary breast cancer. This result confirms the diversity of hereditary breast cancer pathogenic variants across populations and extends our knowledge of genetic susceptibility to breast cancer in Africa.","variants":[{"Name":"NM_000059.4(BRCA2):c.5219T>G (p.Leu1740Ter)","Chromosome":"13","Start":"32339574","Stop":"32339574","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":789250,"rule_based_match":true,"evidence_text":"c.5219 T > G; p.(Leu1740Ter)","llm_judgment":"PRESENT","evidence":"c.5219 T > G; p.(Leu1740Ter)","abstract_start":985,"abstract_end":1013}]}
{"pmid":"28419064","title":"The Application of Next-Generation Sequencing for Mutation Detection in Autosomal-Dominant Hereditary Hearing Impairment.","abstract":"OBJECTIVE: Identification of the causative mutation using next-generation sequencing in autosomal-dominant hereditary hearing impairment, as mutation analysis in hereditary hearing impairment by classic genetic methods, is hindered by the high heterogeneity of the disease.\nPATIENTS: Two Swiss families with autosomal-dominant hereditary hearing impairment.\nINTERVENTION: Amplified DNA libraries for next-generation sequencing were constructed from extracted genomic DNA, derived from peripheral blood, and enriched by a custom-made sequence capture library. Validated, pooled libraries were sequenced on an Illumina MiSeq instrument, 300 cycles and paired-end sequencing. Technical data analysis was performed with SeqMonk, variant analysis with GeneTalk or VariantStudio. The detection of mutations in genes related to hearing loss by next-generation sequencing was subsequently confirmed using specific polymerase-chain-reaction and Sanger sequencing.\nMAIN OUTCOME MEASURE: Mutation detection in hearing-loss-related genes.\nRESULTS: The first family harbored the mutation c.5383+5delGTGA in the TECTA-gene. In the second family, a novel mutation c.2614-2625delCATGGCGCCGTG in the WFS1-gene and a second mutation TCOF1-c.1028G>A were identified.\nCONCLUSION: Next-generation sequencing successfully identified the causative mutation in families with autosomal-dominant hereditary hearing impairment. The results helped to clarify the pathogenic role of a known mutation and led to the detection of a novel one. NGS represents a feasible approach with great potential future in the diagnostics of hereditary hearing impairment, even in smaller labs.","variants":[{"Name":"NM_001371623.1(TCOF1):c.1028G>A (p.Ser343Asn)","Chromosome":"5","Start":"150374331","Stop":"150374331","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205576,"rule_based_match":true,"evidence_text":"TCOF1-c.1028G>A","llm_judgment":"PRESENT","evidence":"TCOF1-c.1028G>A","abstract_start":1215,"abstract_end":1230}]}
{"pmid":"24197768","title":"A novel compound mutation of CYP27B1 in a Chinese family with vitamin D-dependent rickets type 1A.","abstract":"OBJECTIVES: Mutations in the CYP27B1 gene, which encodes vitamin D 1α-hydroxylase, are the genetic basis of vitamin D-dependent rickets type 1A (VDDR1A, MIM 264700). The aim of this study was to investigate a novel CYP27B1 mutation and its clinical manifestations.\nMETHODS: VDDR1A was diagnosed based on clinical presentation, a physical examination, bone characteristics on an X-ray, and laboratory results. A molecular model of the CYP27B1 protein was constructed using the SWISS-MODEL server and Swiss-PdbViewer.\nRESULTS: We sequenced the CYP27B1 gene in a 5-year-old male child who presented with growth retardation and a history of frequent hand, leg, and perioral twitching since the age of 12 months. We identified a compound heterozygous mutation consisting of two missense mutations: one in exon 7 (R389C [c.1165C>T]) and one in exon 8 (R459C [c.1375C>T]). We used the wild-type CYP27B1 as a receptor and calcidiol as a ligand to predict the interaction between the R459 site and calcidiol. According to the predicted structure, the wild-type R459 residue localizes to the pocket where CYP27B1 binds to its ligand.\nCONCLUSIONS: According to the Human Gene Mutation Database, the compound heterozygous mutation identified in our patient is novel and has not yet been reported in the literature. This mutation provides a new basis for further research on VDDR1A and for the development of clinical diagnostics.","variants":[{"Name":"NM_000785.4(CYP27B1):c.1165C>T (p.Arg389Cys)","Chromosome":"12","Start":"57764148","Stop":"57764148","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1314481,"rule_based_match":true,"evidence_text":"c.1165C>T","llm_judgment":"PRESENT","evidence":"c.1165C>T","abstract_start":815,"abstract_end":824},{"Name":"NM_000785.4(CYP27B1):c.1375C>T (p.Arg459Cys)","Chromosome":"12","Start":"57763649","Stop":"57763649","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":513614,"rule_based_match":true,"evidence_text":"c.1375C>T","llm_judgment":"PRESENT","evidence":"c.1375C>T","abstract_start":853,"abstract_end":862}]}
{"pmid":"24518553","title":"Three novel mutations in Iranian patients with Tay-Sachs disease.","abstract":"BACKGROUND: Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population.\nMETHODS: In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion.\nRESULTS: Molecular genetics analysis of DNA from 23 patients of TSD revealed mutations that has been previously reported, including four-base duplications c.1274_1277dupTATC in exon 11 and IVS2+1G>A, deletion TTAGGCAAGGGC in exon 10 as well as a few novel mutations, including C331G, which altered Gln>Glu in HEXB, A>G, T>C, and p.R510X in exon 14, which predicted a termination codon or nonsense mutation.\nCONCLUSION: In conclusion, with the discovery of these novel mutations, the genotypic spectrum of Iranian patients with TSD disease has been extended and could facilitate definition of disease-related mutations.","variants":[{"Name":"NM_000520.6(HEXA):c.1274_1277dup (p.Tyr427fs)","Chromosome":"15","Start":"72346579","Stop":"72346580","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGATA","allel_id":18928,"rule_based_match":true,"evidence_text":"c.1274_1277dupTATC","llm_judgment":"PRESENT","evidence":"c.1274_1277dupTATC","abstract_start":613,"abstract_end":631}]}
{"pmid":"15241803","title":"Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients.","abstract":"We examined CMT1A duplication of 17p11.2-p12, mutations of PMP22, MPZ (P0), GJB1 (Cx32), EGR2 and NEFL genes in 57 Korean families with patients diagnosed as having Charcot-Marie-Tooth (CMT) disease. The CMT1A duplication was present in 53.6% of 28 CMT type 1 patients. In the 42 CMT families without CMT1A duplication, 10 pathogenic mutations were found in 9 families. The 10 mutations were not detected in 105 healthy controls. Seven mutations (c.318delT (p.Ala106fs) in PMP22, c.352G>A (p.Asp118Asn), c.449-1G>T (3'-splice site), c.706A>G (p.Lys236Glu) in MPZ, c.407T>C (p.Val136Ala)[corrected], c.502T>C (p.Cys168Arg) in GJB1, and c.1001T>C (p.Leu334Pro) in NEFL) were determined to be novel. The mutation frequencies of PMP22 and MPZ were similar to those found in several European populations, however, it appeared that mutations in GJB1 are less frequent in East Asian CMT patients than in Eur opean patients. We described the identified mutations and phenotype-genotype correlations based on nerve conduction studies.","variants":[{"Name":"NM_000530.8(MPZ):c.706A>G (p.Lys236Glu)","Chromosome":"1","Start":"161305917","Stop":"161305917","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":624996,"rule_based_match":true,"evidence_text":"c.706A>G (p.Lys236Glu)","llm_judgment":"PRESENT","evidence":"c.706A>G (p.Lys236Glu)","abstract_start":533,"abstract_end":555},{"Name":"NM_000166.6(GJB1):c.502T>C (p.Cys168Arg)","Chromosome":"X","Start":"71224209","Stop":"71224209","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":625637,"rule_based_match":true,"evidence_text":"c.502T>C (p.Cys168Arg) in GJB1","llm_judgment":"PRESENT","evidence":"c.502T>C (p.Cys168Arg) in GJB1","abstract_start":599,"abstract_end":629},{"Name":"NM_000530.8(MPZ):c.449-1G>T","Chromosome":"1","Start":"161306465","Stop":"161306465","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":625733,"rule_based_match":true,"evidence_text":"c.449-1G>T (3'-splice site)","llm_judgment":"PRESENT","evidence":"c.449-1G>T (3'-splice site)","abstract_start":504,"abstract_end":531},{"Name":"NM_000166.6(GJB1):c.407T>C (p.Val136Ala)","Chromosome":"X","Start":"71224114","Stop":"71224114","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":25490,"rule_based_match":true,"evidence_text":"c.407T>C (p.Val136Ala)[corrected]","llm_judgment":"PRESENT","evidence":"c.407T>C (p.Val136Ala)[corrected]","abstract_start":564,"abstract_end":597},{"Name":"NM_000530.8(MPZ):c.352G>A (p.Asp118Asn)","Chromosome":"1","Start":"161306804","Stop":"161306804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":625045,"rule_based_match":true,"evidence_text":"c.352G>A (p.Asp118Asn)","llm_judgment":"PRESENT","evidence":"c.352G>A (p.Asp118Asn)","abstract_start":480,"abstract_end":502}]}
{"pmid":"22315187","title":"Occurrence of acute lymphoblastic leukemia and juvenile myelomonocytic leukemia in a patient with Noonan syndrome carrying the germline PTPN11 mutation p.E139D.","abstract":"Noonan syndrome (NS) is a common autosomal dominant condition characterized by short stature, congenital heart defects, and dysmorphic facial features caused in approximately 50% of cases by missense mutations in the PTPN11 gene. NS patients are predisposed to malignancies including myeloproliferative disorders or leukemias. We report a female NS patient carrying a PTPN11 germline mutation c.417 G > C (p.E139D), who developed in her second year of life an acute lymphoblastic leukemia (ALL) and after remission, she developed at 4 years of age a juvenile myelomonocytic leukemia (JMML). Molecular genetic analysis of lymphoblastic blasts at the time of the ALL diagnosis revealed the germline mutation in a heterozygous state, while in the myelomonocytic blasts occurring with JMML diagnosis, the mutation p.E139D was found in a homozygous state due to a uniparental disomy (UPD). These findings lead to the suggestion that the pathogenesis of ALL and JMML in our patient is due to different mechanisms including somatically acquired secondary chromosomal abnormalities.","variants":[{"Name":"NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp)","Chromosome":"12","Start":"112453279","Stop":"112453279","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":48983,"rule_based_match":true,"evidence_text":"c.417 G > C (p.E139D)","llm_judgment":"PRESENT","evidence":"c.417 G > C (p.E139D)","abstract_start":393,"abstract_end":414}]}
{"pmid":"37826942","title":"First report of a patient with homozygous hemoglobin Ernz: Evidence to support a non-pathogenic variant.","abstract":"Hemoglobin Ernz (Hb Ernz) is a missense variant in β-globin caused by a Threonine to Asparagine substitution at the 123rd amino acid position and HBB c.371C > A in gene level. Hb Ernz has been classified as Uncertain Significance (VUS) by ACMG due to limited reports and the absence of any homozygote genotypes. In our study, we found eight cases of Hb Ernz by DNA sequencing of the β-globin gene during >20 years of Thalassemia Screening in individuals with borderline hematological parameters who were possible carriers of thalassemia or their spouses. We also report the first homozygote variant of Hb Ernz. Our findings suggest that the changes in hematological parameters observed in individuals with Hb Ernz are likely due to α-globin gene mutations rather than Hb Ernz itself. These findings support the reclassification of Hb Ernz as a benign variant in variant classification.","variants":[{"Name":"NM_000518.4(HBB):c.371C>A (p.Thr124Asn)","Chromosome":"11","Start":"5225671","Stop":"5225671","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":30623,"rule_based_match":true,"evidence_text":"HBB c.371C > A","llm_judgment":"PRESENT","evidence":"HBB c.371C > A","abstract_start":146,"abstract_end":160}]}
{"pmid":"36825045","title":"Spectrum of Pediatric to Early Adulthood","abstract":"Background: <i>POLR3A</i> pathogenic variants are associated with hypomyelination, hypodontia, hypogonadism, and movement disorders.\nCases: We describe the range of movement disorders seen in six patients (four female, two male) with <i>POLR3A</i> variants [three novel (c.2214del, c.3775G>A, c.3905G>T) and six previously reported (c.760C>T, c.1771-7C>G, c.1909+22G>A, c.2005C>T, c.2422C>T, c.3337-11T>C)]. Patient 1 presented with a neonatal progeroid syndrome and developed parkinsonism, dystonia, ataxia, and spasticity. Patient 2 presented with infant-onset rapidly progressive chorea, and dystonia. Three patients (patients 3, 5, 6) presented predominantly with ataxia in combination with spasticity and dystonia. Patient 4 developed segmental dystonia during adolescence and ataxia in early adulthood. Four patients had vertical gaze impairment. The most common brain MRI abnormality was T2-weighted/FLAIR hyperintensity of the superior cerebellar peduncles and midbrain.\nConclusion: <i>POLR3A</i>-related disorders exhibit significant phenotypic pleomorphism. Vertical gaze dysfunction and T2-weighted/FLAIR hyperintensity of the superior cerebellar peduncles and midbrain may be useful signs suggestive of this condition.","variants":[{"Name":"NM_007055.4(POLR3A):c.3337-11T>C","Chromosome":"10","Start":"77984023","Stop":"77984023","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":540042,"rule_based_match":true,"evidence_text":"c.3337-11T>C","llm_judgment":"PRESENT","evidence":"c.3337-11T>C","abstract_start":392,"abstract_end":404}]}
{"pmid":"34637071","title":"Controversy on the management of patients carrying RET p.V804M mutation.","abstract":"CONTEXT: RET p.V804M is classified as a moderate risk mutation for familial medullary thyroid cancer (FMTC). There is a significant controversy on the management of patients carrying this mutation. We describe a family incidentally discovered to have this mutation and review the literature on RET p.V804M mutation.\nRESULTS: The proband was born to first-degree relative parents. He was noticed to have hypertrophy of some parts of the body and vascular skin changes. Whole-exome sequencing of DNA extracted from a skin biopsy showed a mutation in the PIK3CA (c.3132T>G, p.ASN1044LYS). This variant was not found in DNA extracted from blood. This confirmed the diagnosis of CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis, skeletal or spinal anomalies). Another incidentally found mutation in the skin biopsy and blood sample was RET p.V804M. Although there was no family history of MTC or MEN 2 syndromes, family screening revealed RET p.V804M mutation and FMTC in the proband's father, paternal grandmother, one sister, and one aunt. There was significant interfamilial heterogeneity in the age of presentation and pathology. A review of literature showed that RET p.V804M mutation is a moderate risk mutation associated with late-onset FMTC, usually at middle to old age.\nCONCLUSION: Despite the controversy and the heterogeneous presentation of patients with RET p.V804M mutation, our study and review of the literature suggest that this seemingly \"low\" risk mutation is associated with late-onset but potentially aggressive MTC. This indicates the need for follow-up and timely intervention based on calcitonin level elevation.","variants":[{"Name":"NM_020975.6(RET):c.2410G>A (p.Val804Met)","Chromosome":"10","Start":"43119548","Stop":"43119548","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28984,"rule_based_match":false,"evidence_text":"RET p.V804M","llm_judgment":"PRESENT","evidence":"RET p.V804M","abstract_start":9,"abstract_end":20}]}
{"pmid":"38493358","title":"A loss of function mutation in CLDN25 causing Pelizaeus-Merzbacher-like leukodystrophy.","abstract":"Claudin-25 (CLDN-25), also known as Claudin containing domain 1, is an uncharacterized claudin family member. It has less conserved amino acid sequences when compared to other claudins. It also has a very broad tissue expression profile and there is currently a lack of functional information from murine knockout models. Here, we report a de novo missense heterozygous variant in CLDN25 (c. 745G>C, p. A249P) found in a patient diagnosed with Pelizaeus-Merzbacher-like leukodystrophy and presenting with symptoms such as delayed motor development, several episodes of tonic absent seizures and generalized dystonia. The variant protein does not localize to the cell-cell borders where it would normally be expected to be expressed. Amino acid position 249 is located 4 amino acids from the C-terminal end of the protein where most claudin family members have a conserved binding motif for the key scaffolding protein ZO-1. However, CLDN-25 does not contain this motif. Here, we show that the C-terminal end of CLDN-25 is required for its junctional localization in a ZO-1 independent manner. The A249P mutant protein as well as a deletion mutant lacking its last 5 C-terminal amino acids also failed to localize to the cell-cell border in vitro. Intriguingly, cellular knockout of CLDN25, in vitro, appeared to increase the integrity of the tight junction between 2 contacting cells, while driving highly unusual increased movement of solutes between cells. We propose that the barrier function of CLDN-25 is akin to a decoy claudin, whereby decreasing its expression in \"leaky\" epithelial cells and endothelial cells will drive dynamic changes in the adhesion and interaction capacity of cell-cell contact points. While it remains unclear how this de novo CLDN-25 mutant induces leukodystrophy, our findings strongly suggest that this mutation induces haploinsufficiency of CLDN-25. Elucidating the function of this uncharacterized claudin protein will lead to a better understanding of the role of claudin proteins in health and disease.","variants":[{"Name":"NM_001040181.2(CLDND1):c.745G>C (p.Ala249Pro)","Chromosome":"3","Start":"98516676","Stop":"98516676","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3494613,"rule_based_match":true,"evidence_text":"c. 745G>C, p. A249P","llm_judgment":"PRESENT","evidence":"c. 745G>C, p. A249P","abstract_start":389,"abstract_end":408}]}
{"pmid":"22549407","title":"A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome.","abstract":"Mandibuloacral dysplasia (MAD) is a rare disease resulting from a mutation of LMNA gene encoding lamins A and C. The most common mutation associated with this disease is a homozygous arginine 527 replacement by histidine. Three female patients originating from two unrelated families from Northeast Egypt were examined. Their growth was retarded; they had microcephaly, widened cranial sutures, prominent eyes and cheeks, micrognathia, dental crowding, hypoplastic mandible, acro-osteolysis of distal phalanges, and joint contractures. In addition, they presented some progeroid features, such as pinched nose, premature loss of teeth, loss of hair, scleroderma-like skin atrophy, spine rigidity, and waddling gait. The clinical presentation of the disease varied between the patient originating from Family 1 and patients from Family 2, suggesting that unknown, possibly epigenetic factors, modify the course of the disease. The first symptoms of the disease appeared at the age of 2.5 (a girl from Family 1), 5, and 3 years (girls from Family 2). All patients had the same, novel homozygous c.1580G>T LMNA mutation, resulting in the replacement of arginine 527 by leucine. Computational predictions of such substitution effects suggested that it might alter protein stability and increase the tendency for protein aggregation, and as a result, might influence its interaction with other proteins. In addition, restriction fragment-length polymorphism analysis performed in 178 unrelated individuals showed that up to 1.12% of inhabitants of Northeast Egypt might be heterozygous carriers of this mutation, suggesting the presence of a founder effect in this area.","variants":[{"Name":"NM_170707.4(LMNA):c.1580G>T (p.Arg527Leu)","Chromosome":"1","Start":"156137204","Stop":"156137204","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":906447,"rule_based_match":true,"evidence_text":"c.1580G>T","llm_judgment":"PRESENT","evidence":"c.1580G>T","abstract_start":1093,"abstract_end":1102}]}
{"pmid":"29179439","title":"Next generation sequencing identified novel heterozygous nonsense mutation in","abstract":"Retinitis pigmentosa (RP) is a severe hereditary eye disease characterized by progressive degeneration of photoreceptors and subsequent loss of vision. Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal diseases. Germline mutations of <i>CNGB1</i> is associated with retinitis pigmentosa. We have identified and investigated a 34-year-old Chinese man with markedly have night vision blindness and loss of midperipheral visual field. The proband also lose his far peripheral visual field and also central vision. Proband's retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Target exome capture based next generation sequencing and Sanger sequencing identified novel nonsense mutation, c.1917G>A and a reported mutation, c.2361C>A, in the <i>CNGB1</i> gene. Both the nonsense mutations are predicted to lead to the formation of a premature stop codon which finally results into formation of truncated CNGB1 protein product which finally predicted to be disease causing. According to the variant classification guidelines of ACMG, these two variants are categorized as \"<i>likely pathogenic</i>\" variants. Our findings expand the mutational spectra of <i>CNGB1</i> and are valuable in the mutation-based pre- and post-natal screening and genetic diagnosis for retinitis pigmentosa.","variants":[{"Name":"NM_001297.5(CNGB1):c.2361C>A (p.Tyr787Ter)","Chromosome":"16","Start":"57912938","Stop":"57912938","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":927878,"rule_based_match":true,"evidence_text":"c.2361C>A","llm_judgment":"PRESENT","evidence":"c.2361C>A","abstract_start":857,"abstract_end":866}]}
{"pmid":"31264916","title":"Homozygous and heterozygous retinal phenotypes in families harbouring","abstract":"<b>Introduction</b>: Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (<i>IMPG2</i>) have been shown to underlie recessive childhood-onset rod-cone dystrophy with early macular involvement in several families. In other families, heterozygous <i>IMPG2</i> mutations have been associated with dominant vitelliform macular dystrophy. To date, the retinal phenotype of heterozygotes from families with recessive <i>IMPG2</i>-related retinal dystrophy has not been assessed. This study documents the genotypes and phenotypes observed in both homozygotes and available heterozygotes from additional families with <i>IMPG2</i>-related recessive rod-cone dystrophy. <b>Methods</b>: Retrospective case series (2016-2018). <b>Results</b>: Four families were identified. All were first-cousin marriages and had no known relation to each other. Individuals with biallelic pathogenic variants (7 individuals) had childhood-onset rod-cone dystrophy. Families 1 and 2 harboured the same novel homozygous mutation c.189dup;p.Gln64Thrfs*9 (5 individuals, 4-17 years old). Family 3 harboured the novel homozygous mutation c.533 + 4_533 + 7del;p.? (1 individual, 17 years old), and Family 4 harboured the previously reported homozygous mutation c.3262C>T;p.Arg1088* (1 individual, 45 years old). The 3 available carriers were genetically confirmed (both parents from Family 1 and the father from Family 3) and had macular focal retinal pigment epithelium thickening by optical coherence tomography (OCT). The father from Family 3 also had unilateral sectoral pigmentary retinopathy. <b>Conclusions</b>: Childhood-onset recessive rod-cone dystrophy with early macular involvement should prompt examination of the parents for macular focal retinal pigment epithelium thickening on OCT. If present the possibility of biallelic <i>IMPG2</i> mutations in the proband should be considered. Young affected relatives of the proband can show multimodal imaging abnormalities before they are overtly symptomatic.","variants":[{"Name":"NM_016247.4(IMPG2):c.533+4_533+7del","Chromosome":"3","Start":"101291472","Stop":"101291475","ReferenceAlleleVCF":"ACACT","AlternateAlleleVCF":"A","allel_id":801353,"rule_based_match":true,"evidence_text":"c.533 + 4_533 + 7del","llm_judgment":"PRESENT","evidence":"c.533 + 4_533 + 7del","abstract_start":1119,"abstract_end":1139},{"Name":"NM_016247.4(IMPG2):c.3262C>T (p.Arg1088Ter)","Chromosome":"3","Start":"101231117","Stop":"101231117","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152869,"rule_based_match":true,"evidence_text":"c.3262C>T;p.Arg1088*","llm_judgment":"PRESENT","evidence":"c.3262C>T;p.Arg1088*","abstract_start":1241,"abstract_end":1261},{"Name":"NM_016247.4(IMPG2):c.189dup (p.Gln64fs)","Chromosome":"3","Start":"101319728","Stop":"101319729","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":967077,"rule_based_match":true,"evidence_text":"c.189dup;p.Gln64Thrfs*9","llm_judgment":"PRESENT","evidence":"c.189dup;p.Gln64Thrfs*9","abstract_start":1013,"abstract_end":1036}]}
{"pmid":"26662040","title":"ADIPOR1 Is Mutated in Syndromic Retinitis Pigmentosa.","abstract":"Retinitis pigmentosa (RP) is a genetically heterogeneous retinal disorder. Despite the numerous genes associated with RP already identified, the genetic basis remains unknown in a substantial number of patients and families. In this study, we performed whole-exome sequencing to investigate the molecular basis of a syndromic RP case that cannot be solved by mutations in known disease-causing genes. After applying a series of variant filtering strategies, we identified an apparently homozygous frameshift mutation, c.31delC (p.Q11Rfs*24) in the ADIPOR1 gene. The reported phenotypes of Adipor1-null mice contain retinal dystrophy, obesity, and behavioral abnormalities, which highly mimic those in the syndromic RP patient. We further confirmed ADIPOR1 retina expression by immunohistochemistry. Our results established ADIPOR1 as a novel disease-causing gene for syndromic RP and highlight the importance of fatty acid transport in the retina.","variants":[{"Name":"NM_015999.6(ADIPOR1):c.31del (p.Gln11fs)","Chromosome":"1","Start":"202951040","Stop":"202951040","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":259324,"rule_based_match":true,"evidence_text":"c.31delC (p.Q11Rfs*24)","llm_judgment":"PRESENT","evidence":"c.31delC (p.Q11Rfs*24)","abstract_start":518,"abstract_end":540}]}
{"pmid":"32439808","title":"Mutation in the MICOS subunit gene","abstract":"BACKGROUND: Mitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) complex is known as the 'mitoskeleton' due to its role in maintaining IMM architecture. <i>APOO</i> encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated.\nMETHODS: We have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in <i>APOO</i>. Knockout models in <i>Drosophila melanogaster</i> and <i>Saccharomyces cerevisiae</i> were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.\nRESULTS: A likely pathogenic c.350T>C transition was found in <i>APOO</i> predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and <i>D. melanogaster</i> models.\nCONCLUSION: This is the first case of pathogenic mutation in <i>APOO</i>, causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.","variants":[{"Name":"NM_024122.5(APOO):c.350T>C (p.Ile117Thr)","Chromosome":"X","Start":"23868631","Stop":"23868631","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":964792,"rule_based_match":true,"evidence_text":"c.350T>C","llm_judgment":"PRESENT","evidence":"c.350T>C","abstract_start":1175,"abstract_end":1183}]}
{"pmid":"22973891","title":"Familial amyloid polyneuropathy associated with the novel transthyretin variant Arg34Gly.","abstract":"We report a 57-year-old man with pathognomonic bilateral vitreo-lenticular amyloid opacities (pseudopodia lentis) in whom a novel transthyretin (TTR) mutation was identified. The patient presented due to bilateral floaters. The vitreous cavities of both eyes showed course, fibrilar opacities attached to the posterior lens surface with pseudopodia. There was a history of bilateral carpal tunnel syndrome. Nerve conduction studies showed upper and lower limb axonal polyneuropathy. Magnetic resonance imaging of the brain and spinal cord, renal and cardiac function were normal. Vitreous and conjunctival biopsies confirmed the diagnosis of TTR-related amyloidosis. Genetic analysis of exon 2 of the TTR gene revealed that the patient was heterozygous for a single nucleotide substitution c.160 A>G, resulting in replacement of arginine with glycine at position 34 of the mature protein (Arg34Gly). Five years later the patient developed increasing sensory and motor neuropathy of both lower limbs, and neovascular glaucoma in one eye. We hypothesize that the reason for his neovascular glaucoma was retinal ischaemia secondary to amyloid retinal vasculopathy.","variants":[{"Name":"NM_000371.4(TTR):c.160A>G (p.Arg54Gly)","Chromosome":"18","Start":"31592986","Stop":"31592986","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":647189,"rule_based_match":true,"evidence_text":"c.160 A>G","llm_judgment":"PRESENT","evidence":"c.160 A>G","abstract_start":790,"abstract_end":799}]}
{"pmid":"25218699","title":"Enzymatic diagnosis of homocystinuria by determination of cystathionine-ß-synthase activity in plasma using LC-MS/MS.","abstract":"BACKGROUND: Cystathionine β-synthase (CBS) is released into plasma from organs expressing this enzyme. Decreased plasma CBS activity has been demonstrated in CBS-deficient patients with 16 different genotypes. The aim of this study was to determine plasma CBS activity in patients carrying 11 additional genotypes using two LC-MS/MS methods. Patients and methods CBS activity was measured in EDTA or heparin plasma using either a previously described or a newly developed LC-MS/MS method optimized for analysis of the reaction product, 3,3-(2)H2-cystathionine, as its butyl ester derivative. We analyzed plasma samples from 26 CBS-deficient patients with known genotypes and 57 controls.\nRESULTS: We developed a new LC-MS/MS method for simple and sensitive determination of CBS activity. Plasma CBS activity was low (i.e., 0.001-0.036 of the multiples of median control values, MoM) in patients homozygous for the prevalent Hispanic mutation c.572C>T (p.T191M) but was highly elevated (2.95 MoM) in a single patient homozygous for the c.1330G>A (p.D444N) mutation. Patients with the remaining nine genotypes exhibited decreased activities (0.00-0.22 MoM), which did not overlap with the controls (0.29-2.10 MoM).\nCONCLUSIONS: The determination of CBS activity in plasma is a rapid and non-invasive procedure for detecting a subgroup of CBS-deficient patients with distinct genotypes.","variants":[{"Name":"NM_000071.3(CBS):c.572C>T (p.Thr191Met)","Chromosome":"21","Start":"43065481","Stop":"43065481","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15171,"rule_based_match":true,"evidence_text":"c.572C>T (p.T191M)","llm_judgment":"PRESENT","evidence":"c.572C>T (p.T191M)","abstract_start":942,"abstract_end":960},{"Name":"NM_000071.3(CBS):c.1330G>A (p.Asp444Asn)","Chromosome":"21","Start":"43058862","Stop":"43058862","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15165,"rule_based_match":true,"evidence_text":"c.1330G>A (p.D444N)","llm_judgment":"PRESENT","evidence":"c.1330G>A (p.D444N)","abstract_start":1035,"abstract_end":1054}]}
{"pmid":"32886330","title":"A homozygous nonsense variant in DYM underlies Dyggve-Melchior-Clausen syndrome associated with ectodermal features.","abstract":"Dyggve melchior clausen syndrome (DMC, MIM 223800) is a very rare autosomal recessive form of skeletal dysplasia associated with various degrees of mental retardation. It is characterized by a progressive spondyloepimetaphyseal dysplasia (SEMD) with disproportionate short stature, generalized platyspondyly and lacy iliac crest. Here, we report characterization of large consanguineous family segregating DMC in autosomal recessive manner. Scanning SNP-based human genome identified a 5.3 Mb homozygous region on chromosome 18q21.1-q21.2. Sanger sequencing of the DYM gene, located in the homozygous region, revealed a novel homozygous nonsense variant [c.59 T > A; p.(Leu20*)] in affected members of the family. Analysis of the mRNA, extracted from hair follicles of an affected individual, suggested non-sense mediated decay (NMD) of the truncated transcript. This is the first nonsense and fourth loss of function variant in the DYM gene, causing DMC, reported in the Pakistani population. This study not only extended spectrum of the mutations in the DYM gene but will also facilitate diagnosis of similar other cases in Pakistani population.","variants":[{"Name":"NM_001353214.3(DYM):c.59T>A (p.Leu20Ter)","Chromosome":"18","Start":"49430336","Stop":"49430336","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1313088,"rule_based_match":true,"evidence_text":"c.59 T > A; p.(Leu20*)","llm_judgment":"PRESENT","evidence":"c.59 T > A; p.(Leu20*)","abstract_start":655,"abstract_end":677}]}
{"pmid":"22664151","title":"Pregnancy of a patient with multiple Acyl-CoA dehydrogenation deficiency (MADD).","abstract":"We describe the pregnancy of a patient of French-Canadian descent with multiple Acyl-CoA dehydrogenation deficiency (MADD). The proband was found to harbor a previously reported homozygous missense mutation on EFTDH gene (p.Pro534Leu:c.1601C>T) confirming the biochemical diagnosis of MADD. This mutation was not found in 50 controls from the same ethnic background. The clinical and molecular information of all patients with ETFDH mutations reported in the literature up-to-date are summarized.","variants":[{"Name":"NM_004453.4(ETFDH):c.1601C>T (p.Pro534Leu)","Chromosome":"4","Start":"158706761","Stop":"158706761","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":406420,"rule_based_match":true,"evidence_text":"c.1601C>T","llm_judgment":"PRESENT","evidence":"c.1601C>T","abstract_start":234,"abstract_end":243}]}
{"pmid":"20614188","title":"Functional splicing assay supporting that c.70 + 5G > A mutation in the MPV17 gene is disease causing.","abstract":"Mitochondrial DNA depletion syndrome (MDS) is a group of disorders characterized by a quantitative reduction of the mitochondrial DNA copy number and inherited as autosomal recessive traits. Patients affected by this group of diseases present with a wide variety of symptoms depending on the altered gene. MPV17 is one of the genes causing combined encephalopathy and liver failure and at present there is no treatment for this devastating disease. The gene codes for an inner mitochondrial membrane protein, but its function is still unknown, and therefore, the only way to offer prenatal diagnosis relies on DNA studies. Consequently, mutations have to be well characterized. We previously described a patient homozygous for a novel intronic mutation in the MPV17 gene (c.70 + 5G > A). Here we report the use of a functional splicing assay based on the use of minigenes to support that c.70 + 5G > A mutation is disease causing. We carried out three prenatal diagnoses on three consecutive pregnancies of the previously described family. After two affected fetuses, a healthy baby was born homozygous for the wild-type allele.","variants":[{"Name":"NM_002437.5(MPV17):c.70+5G>A","Chromosome":"2","Start":"27322443","Stop":"27322443","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46922,"rule_based_match":true,"evidence_text":"c.70 + 5G > A","llm_judgment":"PRESENT","evidence":"c.70 + 5G > A","abstract_start":772,"abstract_end":785}]}
{"pmid":"19105189","title":"How much mutant protein is needed to cause a protein aggregate myopathy in vivo? Lessons from an exceptional desminopathy.","abstract":"Myofibrillar myopathies are caused by mutations in desmin, alphaB-crystallin, myotilin, ZASP, and filamin C genes. Since the vast majority of myofibrillar myopathy causing mutations are heterozygous single amino acid substitutions or small in-frame deletions, the pathogenic role of mutant versus wild-type protein cannot be assessed in human skeletal muscle by standard immunodetection techniques. We report on an exceptional desminopathy due to a heterozygous c.735G>C mutation. Immunoblotting detected full-length 53 kDa desmin and a truncated 50 kDa variant in skeletal muscle from three affected patients of two different families. RT-PCR identified three desmin mRNA species encoding for wild-type and two mutant proteins, p.Glu245Asp and p.Asp214_Glu245del. Since previous functional studies on the p.Glu245Asp mutant showed biological properties identical to wild-type desmin, the truncated p.Asp214_Glu245del desmin is the disease-causing mutant. Semiquantitative RT-PCR established a fraction of the truncated desmin mRNA species in a range from 24% to 37%. Initial quantification of corresponding desmin proteins in the muscle biopsy of the index patient of one family indicated a fraction of only 10% of the truncated species. However, serial analyses of different sections from each muscle biopsy revealed a high intra- and interindividual variability of the truncated desmin protein level within a range from 5% to 43%. Desmin assembly studies in vitro have established clear-cut pathogenic ratios of mutant versus wild-type proteins. However, our findings point out a far more complex situation in human skeletal muscle. The heterogeneously distributed mutation load within and between individual specimens, which reflects local differences in the expression and/or turnover of the mutant protein in different areas containing multiple myonuclear domains, renders it impossible to define an exact pathogenic threshold of a specific mutant in vivo.","variants":[{"Name":"NM_001927.4(DES):c.735G>C (p.Glu245Asp)","Chromosome":"2","Start":"219420346","Stop":"219420346","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":77317,"rule_based_match":true,"evidence_text":"c.735G>C","llm_judgment":"PRESENT","evidence":"c.735G>C","abstract_start":462,"abstract_end":470}]}
{"pmid":"21129721","title":"Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.","abstract":"CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development.","variants":[{"Name":"NM_015922.3(NSDHL):c.1098dup (p.Arg367fs)","Chromosome":"X","Start":"152869089","Stop":"152869090","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":34118,"rule_based_match":true,"evidence_text":"c.1098 dup (p.Arg367SerfsX33)","llm_judgment":"PRESENT","evidence":"p.Arg367Ser","abstract_start":638,"abstract_end":649}]}
{"pmid":"24301060","title":"Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene.","abstract":"Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.","variants":[{"Name":"NM_000059.4(BRCA2):c.1845_1846del (p.Asn615fs)","Chromosome":"13","Start":"32333323","Stop":"32333324","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":261106,"rule_based_match":true,"evidence_text":"c.1845_1846delCT","llm_judgment":"PRESENT","evidence":"c.1845_1846delCT","abstract_start":661,"abstract_end":677},{"Name":"NM_000059.4(BRCA2):c.7802A>G (p.Tyr2601Cys)","Chromosome":"13","Start":"32357926","Stop":"32357926","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":183991,"rule_based_match":true,"evidence_text":"c.7802A>G (p.Tyr2601Cys)","llm_judgment":"PRESENT","evidence":"p.Tyr2601Cys","abstract_start":732,"abstract_end":744}]}
{"pmid":"30890130","title":"X-linked inheritances recessive of congenital nystagmus and autosomal dominant inheritances of congenital cataracts coexist in a Chinese family: a case report and literature review.","abstract":"BACKGROUND: Congenital nystagmus (CN) and congenital cataracts are distinct eye diseases and are usually isolated. Cases with CN and congenital cataracts caused by different genes in one family have been rarely reported.\nCASE PRESENTATION: A 27-year-old man presented with CN and congenital cataracts and he underwent cataract extraction 2 weeks after birth. Three years later, he had posterior chamber intraocular lens implantation. The proband's mother was only afflicted by bilateral lens opacities. Lensectomy was performed in both eyes at age 15. The proband's daughter had bilateral central cataracts and no nystagmus. She had undergone cataract extraction when she was two months old. In this family, 8 affected individuals were affected by bilateral cataracts, and three of them presented with CN. The genetic analysis was performed using a specific Hereditary Ophthalmological Disease Gene Panel on proband and his parents (one of which was a patient). PCR and Sanger sequencing verified the presence of these variants in all members of the family. The novel mutation, c.498-3C > T, in FRMD7 explains why X-Linked recessive inheritance of CN was found in a subset of patients. A heterozygous mutation of the GJA8 gene (c.139G > C), was identified in all patients and thus explains the autosomal dominant pattern of inheritance of congenital cataracts within the family.\nCONCLUSIONS: This is the first time that FRMD7 and GJA8 gene mutations have been linked to the pathogenesis of a family with both CN and congenital cataracts. The phenomenon of two different genetic patterns coexisting in one family is rare.","variants":[{"Name":"NM_005267.5(GJA8):c.139G>C (p.Asp47His)","Chromosome":"1","Start":"147908094","Stop":"147908094","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":263944,"rule_based_match":true,"evidence_text":"c.139G > C","llm_judgment":"PRESENT","evidence":"c.139G > C","abstract_start":1228,"abstract_end":1238}]}
{"pmid":"23806041","title":"Coinheritance of a novel mutation on the HBA1 gene: c.187delG (p.W62fsX66) [codon 62 (-G) (α1)] with the α212 patchwork allele and Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T].","abstract":"We describe a novel frameshift mutation on the HBA1 gene (c.187delG), causative of α-thalassemia (α-thal) in a Black Cuban family with multiple sequence variants in the HBA genes and the Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T] mutation. The deletion of the first base of codon 62 resulted in a frameshift at amino acid 62 with a putative premature termination codon (PTC) at amino acid 66 on the same exon (p.W62fsX66), which most likely triggers nonsense mediated decay of the resulting mRNA. This study also presents the first report of the α212 patchwork allele in Latin America and the description of two new sequence variants in the HBA2 region (c.-614G>A in the promoter region and c.95+39 C>T on the first intron).","variants":[{"Name":"NM_000517.6(HBA2):c.95+39C>T","Chromosome":"16","Start":"173046","Stop":"173046","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":432848,"rule_based_match":true,"evidence_text":"c.95+39 C>T","llm_judgment":"PRESENT","evidence":"c.95+39 C>T","abstract_start":692,"abstract_end":703}]}
{"pmid":"25721872","title":"Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young.","abstract":"Mutations in the insulin (INS) gene rarely occur in patients with Maturity-Onset Diabetes of the Young (MODY). We aimed to describe in detail two MODY families with INS mutations. The INS gene was screened by direct sequencing. The probands and their affected relatives underwent a mixed-meal test. Mutation predictions were modeled using I-TASSER and were visualized by Swiss-PdbViewer. A novel heterozygous frameshift mutation p.Gln78fs in the INS gene was found in three generations of patients with clinically distinct diabetes. The single nucleotide deletion (c.233delA) is predicted to change and prolong amino acid sequence, resulting in aberrant proinsulin without native structures of C-peptide and A-chain. In the second family, the heterozygous mutation c.188-31G>A within the terminal intron was detected. The mother and her daughter were misdiagnosed as having type 1 diabetes since the ages of 6 and 2 years, respectively. This result is in contrast to the previously described carrier of the same mutation who was diagnosed with permanent neonatal diabetes. We identified a novel coding frameshift mutation and an intronic mutation in the INS gene leading to childhood-onset diabetes. INS mutations may result in various phenotypes, suggesting that additional mechanisms may be involved in the pathogenesis and clinical manifestation of diabetes.","variants":[{"Name":"NM_000207.3(INS):c.188-31G>A","Chromosome":"11","Start":"2160028","Stop":"2160028","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":207862,"rule_based_match":true,"evidence_text":"c.188-31G>A","llm_judgment":"PRESENT","evidence":"c.188-31G>A","abstract_start":765,"abstract_end":776}]}
{"pmid":"27545674","title":"Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.","abstract":"The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.","variants":[{"Name":"NM_024818.6(UBA5):c.1111G>A (p.Ala371Thr)","Chromosome":"3","Start":"132675903","Stop":"132675903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260377,"rule_based_match":true,"evidence_text":"c.1111G>A (p.Ala371Thr)","llm_judgment":"PRESENT","evidence":"p.Ala371Thr","abstract_start":961,"abstract_end":972},{"Name":"NM_024818.6(UBA5):c.164G>A (p.Arg55His)","Chromosome":"3","Start":"132665825","Stop":"132665825","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260378,"rule_based_match":true,"evidence_text":"c.164G>A","llm_judgment":"PRESENT","evidence":"c.164G>A","abstract_start":1041,"abstract_end":1049}]}
{"pmid":"22290197","title":"Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47) .","abstract":"We recently identified a new locus for spastic paraplegia type 47 (SPG47) in a consanguineous Arabic family with two affected siblings with progressive spastic paraparesis,intellectual disability, seizures, periventricular white matter changes and thin corpus callosum. Using exome sequencing, we now identified a novel AP4B1 frameshift mutation (c.664delC) in this family. This mutation was homozygous in both affected siblings and heterozygous in both parents. The mutant allele was absent in 316 Caucasian and 200 ethnically matched control chromosomes. We propose that AP4B1 mutations cause SPG47 and should be considered in early onset spastic paraplegia with intellectual disability.","variants":[{"Name":"NM_001253852.3(AP4B1):c.664del (p.Leu222fs)","Chromosome":"1","Start":"113900354","Stop":"113900354","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":805148,"rule_based_match":true,"evidence_text":"c.664del","llm_judgment":"PRESENT","evidence":"c.664del","abstract_start":347,"abstract_end":355}]}
{"pmid":"27849156","title":"Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants.","abstract":"AIMS: Acute intermittent porphyria (AIP) is a disorder of the haem biosynthetic pathway caused by mutations in the hydroxymethylbilane synthase (<i>HMBS</i>) gene. Knowledge of the spectrum of mutations present in South Africa is limited. This study presents the molecular profile of 20 South African patients with AIP, and the kinetic analysis of one novel expressed mutated HMBS enzyme and a previously identified mutation at the same position.\nMETHODS: Genomic DNA was isolated from affected probands and selected family members, the <i>HMBS</i> gene amplified and mutations characterised by direct sequencing and restriction enzyme analysis. One of the novel mutations (p.Lys98Glu), a previously characterised mutation at the same position (p.Lys98Arg), and the wild-type enzyme were expressed, purified and subjected to partial kinetic characterisation.\nRESULTS: Four new mutations, p.Lys98Glu, p.Asp230Aspfs<sub>*</sub>20, c.161-1G>A and c.422+3_6delAAGT, are described. Seven previously described mutations were found, while four patients revealed no mutations. Mutation analysis of five offspring of one of the probands carrying the p.Trp283X mutation revealed two asymptomatic carriers. Kinetic analysis showed that the p.Lys98Glu mutation results in loss of substrate affinity, whereas the previously described p.Lys98Arg mutation causes the loss of binding between the enzyme and its dipyrromethane cofactor, rendering the enzyme inactive.\nCONCLUSIONS: This study comprises the most comprehensive characterisation of <i>HMBS</i> gene mutations in patients with AIP in South Africa. The biochemical characterisation of expressed <i>HMBS</i> mutants reveals insight into the mechanism of catalytic activity loss, which may inspire investigation into individualised therapy based on the molecular lesion identified.","variants":[{"Name":"NM_000190.4(HMBS):c.292A>G (p.Lys98Glu)","Chromosome":"11","Start":"119089708","Stop":"119089708","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1436482,"rule_based_match":false,"evidence_text":"p.Lys98Glu","llm_judgment":"PRESENT","evidence":"p.Lys98Glu","abstract_start":674,"abstract_end":684}]}
{"pmid":"30968679","title":"Aromatase Deficiency in Two Siblings with 46,XX Karyotype Raised as Different Genders: A Novel Mutation (p.R115X) in the","abstract":"Aromatase deficiency rarely causes a 46,XX sexual differentiation disorder. The <i>CYP19A1</i> gene encodes the aromatase enzyme which catalyses the conversion of androgens to oestrogens. In cases with 46,XX karyotype, mutations in the <i>CYP19A1</i> gene can lead to disorders of sex development. Clinical findings in aromatase deficiency vary depending on the degree of deficiency. The effect of increased androgens, including acne, cliteromegaly and hirsutism, can be observed in mothers with placental aromatase deficiency. A decrease in maternal virilisation symptoms is observable in the postpartum period. It is rarely reported that there is no virilization in pregnancy. In this study, two 46,XX sibling having the p.R115X (c.343 C>T) novel pathogenic variant in the <i>CYP19A1</i> gene and raised as different genders, with no maternal virilisation during pregnancy, are presented. In conclusion, 46,XX virilised females should be examined in terms of aromatase deficiency once congenital adrenal hyperplasia has been excluded, even if there is no history of maternal virilisation during pregnancy.","variants":[{"Name":"NM_000103.4(CYP19A1):c.343C>T (p.Arg115Ter)","Chromosome":"15","Start":"51227887","Stop":"51227887","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1202851,"rule_based_match":true,"evidence_text":"p.R115X (c.343 C>T)","llm_judgment":"PRESENT","evidence":"p.R115X (c.343 C>T)","abstract_start":723,"abstract_end":742}]}
{"pmid":"29246200","title":"Delayed-onset of progressive pseudorheumatoid dysplasia in a Chinese adult with a novel compound WISP3 mutation: a case report.","abstract":"BACKGROUND: Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive genetic disease that is characterized by pain, stiffness and enlargement of multiple joints with an age of onset between 3 and 8 years old. Mutations in the WISP3 (Wnt1-inducible signal pathway) gene are known to be the cause of PPD.\nCASE PRESENTATION: We present a case of delayed-onset PPD in a Chinese man. The 35-year-old proband presented with an almost 20-year history of pain and limitations in mobility in multiple joints. Based on the clinical manifestations, the patient was diagnosed with PPD; however, there was no specific evidence to confirm this diagnosis. Through mutational analyses, two WIPS3 mutations in exon 4, including a novel frameshift mutation (c.670dupA) in the paternal allele and an already described nonsense mutation (c.756C > A, p.Cys252*) in the maternal allele, were identified in the proband. Thus, the patient was diagnosed with PPD. Furthermore, we found that the proband's son only carried one of the mutations (c.670dupA) and therefore determined that he would not be affected by PPD in the future.\nCONCLUSIONS: In this case, we successfully diagnosed the disease that the proband was affected precisely after the reunion of clinical diagnosis and genetic analysis. These findings demonstrate the clinical utility of genetic analysis to diagnose skeletal dysplasia and guide genetic counseling.","variants":[{"Name":"NM_198239.2(CCN6):c.756C>A (p.Cys252Ter)","Chromosome":"6","Start":"112068371","Stop":"112068371","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2904844,"rule_based_match":true,"evidence_text":"c.756C > A, p.Cys252*","llm_judgment":"PRESENT","evidence":"c.756C > A, p.Cys252*","abstract_start":836,"abstract_end":857}]}
{"pmid":"19793632","title":"Functional deficiencies of sulfite oxidase: Differential diagnoses in neonates presenting with intractable seizures and cystic encephalomalacia.","abstract":"Sulfite oxidase is a mitochondrial enzyme encoded by the SUOX gene and essential for the detoxification of sulfite which results mainly from the catabolism of sulfur-containing amino acids. Decreased activity of this enzyme can either be due to mutations in the SUOX gene or secondary to defects in the synthesis of its cofactor, the molybdenum cofactor. Defects in the synthesis of the molybdenum cofactor are caused by mutations in one of the genes MOCS1, MOCS2, MOCS3 and GEPH and result in combined deficiencies of the enzymes sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase. Although present in many ethnic groups, isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are rare inborn errors of metabolism, which makes awareness of key clinical and laboratory features of affected individuals crucial for early diagnosis. We report clinical, radiologic, biochemical and genetic data on a Brazilian and on a Turkish child with sulfite oxidase deficiency due to the isolated defect and impaired synthesis of the molybdenum cofactor, respectively. Both patients presented with early onset seizures and neurological deterioration. They showed no sulfite oxidase activity in fibroblasts and were homozygous for the mutations c.1136A>G in the SUOX gene and c.667insCGA in the MOCS1 gene, respectively. Widely available routine laboratory tests such as assessment of total homocysteine and uric acid are indicated in children with a clinical presentation resembling that of hypoxic ischemic encephalopathy and may help in obtaining a tentative diagnosis locally, which requires confirmation by specialized laboratories.","variants":[{"Name":"NM_001032386.2(SUOX):c.1136A>G (p.Lys379Arg)","Chromosome":"12","Start":"56004525","Stop":"56004525","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1874505,"rule_based_match":true,"evidence_text":"c.1136A>G","llm_judgment":"PRESENT","evidence":"c.1136A>G","abstract_start":1255,"abstract_end":1264}]}
{"pmid":"23769331","title":"The clinical effect of homozygous ABCA4 alleles in 18 patients.","abstract":"PURPOSE: To describe the phenotypic presentation of a cohort of individuals with homozygous disease-associated ABCA4 variants.\nDESIGN: Retrospective case series.\nPARTICIPANTS: Eighteen affected individuals from 13 families ascertained from a total cohort of 214 families with ABCA4-related retinal disease presenting to a single center.\nMETHODS: A detailed history was obtained, and color fundus photography, autofluorescence (AF) imaging, optical coherence tomography (OCT), and electrophysiologic assessment were performed. Phenotypes based on ophthalmoscopy, AF, and electrophysiology were assigned using previously reported characteristics. ABCA4 mutation detection was performed using the ABCR400 microarray (Asper Biotech, Tartu, Estonia) and high-throughput DNA sequencing, with direct sequencing used to assess segregation.\nMAIN OUTCOME MEASURES: Detailed clinical, electrophysiologic, and molecular genetic findings.\nRESULTS: Eleven disease-associated homozygous ABCA4 alleles were identified, including 1 frame shift, 2 stops, 1 intronic variant causing splice-site alteration, 2 complex missense variants, and 5 missense variants: p.Glu905fsX916, p.Arg1300X, p.Gln2220X, c.4253+4 C>T, p.Leu541Pro and p.Ala1038Val (homozygosity for complex allele), p.Val931Met and p.Arg1705Gln (complex allele), p.Arg212Cys, p.Cys1488Arg, p.Arg1640Trp, p.Gly1961Glu, and p.Leu2027Phe. Eight of these 11 homozygous alleles have not been reported previously. Six of 7 patients with homozygous null alleles had early-onset (<10 years) disease, with all 7 having a severe phenotype. Two patients with homozygous missense variants (p.Leu541Pro and p.Ala1038Val [complex], and p.Arg1640Trp) presented with a severe phenotype. Three patients with homozygous p.Gly1961Glu had adult-onset disease and a mild phenotype. One patient with homozygous p.Leu2027Phe showed a spared fovea and preserved visual acuity.\nCONCLUSIONS: The phenotypes represented in patients identified as homozygous for presumed disease-associated ABCA4 variants gives insight into the effect of individual alleles. Null alleles have severe functional effects, and certain missense variants are similar to nulls, suggesting complete abrogation of protein function. The common alleles identified, p.Gly1961Glu and p. Leu2027Phe, both have a mild structural and functional effect on the adult retina; the latter is associated with relatively retained photoreceptor architecture and function at the fovea.","variants":[{"Name":"NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp)","Chromosome":"1","Start":"94021340","Stop":"94021340","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":105219,"rule_based_match":false,"evidence_text":"p.Arg1640Trp","llm_judgment":"PRESENT","evidence":"p.Arg1640Trp","abstract_start":1334,"abstract_end":1346},{"Name":"NM_000350.3(ABCA4):c.6079C>T (p.Leu2027Phe)","Chromosome":"1","Start":"94005509","Stop":"94005509","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22921,"rule_based_match":false,"evidence_text":"p.Leu2027Phe","llm_judgment":"PRESENT","evidence":"p.Leu2027Phe","abstract_start":1366,"abstract_end":1378},{"Name":"NM_000350.3(ABCA4):c.3898C>T (p.Arg1300Ter)","Chromosome":"1","Start":"94032008","Stop":"94032008","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":105134,"rule_based_match":false,"evidence_text":"p.Arg1300X","llm_judgment":"PRESENT","evidence":"p.Arg1300X","abstract_start":1158,"abstract_end":1168},{"Name":"NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)","Chromosome":"1","Start":"94008251","Stop":"94008251","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22927,"rule_based_match":false,"evidence_text":"p.Gly1961Glu","llm_judgment":"PRESENT","evidence":"p.Gly1961Glu","abstract_start":1348,"abstract_end":1360},{"Name":"NM_000350.3(ABCA4):c.634C>T (p.Arg212Cys)","Chromosome":"1","Start":"94098928","Stop":"94098928","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22937,"rule_based_match":false,"evidence_text":"p.Arg212Cys","llm_judgment":"PRESENT","evidence":"p.Arg212Cys","abstract_start":1307,"abstract_end":1318}]}
{"pmid":"27148590","title":"Discovery of a potentially deleterious variant in TMEM87B in a patient with a hemizygous 2q13 microdeletion suggests a recessive condition characterized by congenital heart disease and restrictive cardiomyopathy.","abstract":"Restrictive cardiomyopathy (RCM) is a rare cause of heart muscle disease with the highest mortality rate among cardiomyopathy types. The etiology of RCM is poorly understood, although genetic causes have been implicated, and syndromic associations have been described. Here, we describe a patient with an atrial septal defect and restrictive cardiomyopathy along with craniofacial anomalies and intellectual disabilities. Initial screening using chromosomal microarray analysis (CMA) identified a maternally inherited 2q13 microdeletion. The patient had many of the features reported in previous cases with the recurrent 2q13 microdeletion syndrome. However, the inheritance of the microdeletion from an unaffected mother combined with the low incidence (10%) and milder forms of cardiac defects in previously reported cases made the clinical significance of the CMA results unclear. Whole-exome sequencing (WES) with trio-based analysis was performed and identified a paternally inherited TMEM87B mutation (c.1366A>G, p.Asn456Asp) in the patient. TMEM87B, a highly conserved, transmembrane protein of currently unknown function, lies within the critical region of the recurrent 2q13 microdeletion syndrome. Furthermore, a recent study had demonstrated that depletion of TMEM87B in zebrafish embryos affected cardiac development and led to cardiac hypoplasia. Thus, by combining CMA and WES, we potentially uncover an autosomal-recessive disorder characterized by a severe cardiac phenotype caused by mutations in TMEM87B. This study expands the spectrum of phenotypes associated with the recurrent 2q13 microdeletion syndrome and also further suggests the role of TMEM87B in its etiology, especially the cardiac pathology.","variants":[{"Name":"NM_032824.3(TMEM87B):c.1366A>G (p.Asn456Asp)","Chromosome":"2","Start":"112098688","Stop":"112098688","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":224817,"rule_based_match":true,"evidence_text":"c.1366A>G, p.Asn456Asp","llm_judgment":"PRESENT","evidence":"c.1366A>G, p.Asn456Asp","abstract_start":1008,"abstract_end":1030}]}
{"pmid":"20524821","title":"Phenotypic expression and origin of the rare beta-thalassemia splice site mutation HBB:c.315 + 1G>T.","abstract":"We present the hematological characteristics of five patients from Surinam and the bordering French Guyana, who are carriers of the rare beta-thalassemia (beta-thal) mutation HBB:c.315+1G>T. Analysis of the phenotype/genotype relationship shows that this allele is a beta(0)-thal variant and illustrates the modulating effect of the alpha-globin gene status on the beta-thal phenotype. The ethnic origin of the five probands, belonging to the so-called Bush Negroes Maroons of Surinam and French Guyana, strongly suggests that this beta-thal mutation has a West African origin and spread in this ethnic group because of a founder effect and/or genetic drift.","variants":[{"Name":"NM_000518.5(HBB):c.315+1G>T","Chromosome":"11","Start":"5226576","Stop":"5226576","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":611304,"rule_based_match":true,"evidence_text":"HBB:c.315+1G>T","llm_judgment":"PRESENT","evidence":"HBB:c.315+1G>T","abstract_start":175,"abstract_end":189}]}
{"pmid":"24100632","title":"A hemizygous GYG2 mutation and Leigh syndrome: a possible link?","abstract":"Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder characterized by unique, bilateral neuropathological findings in brainstem, basal ganglia, cerebellum and spinal cord. LS is genetically heterogeneous, with the majority of the causative genes affecting mitochondrial malfunction, and many cases still remain unsolved. Here, we report male sibs affected with LS showing ketonemia, but no marked elevation of lactate and pyruvate. To identify their genetic cause, we performed whole exome sequencing. Candidate variants were narrowed down based on autosomal recessive and X-linked recessive models. Only one hemizygous missense mutation (c.665G>C, p.W222S) in glycogenin-2 (GYG2) (isoform a: NM_001079855) in both affected sibs and a heterozygous change in their mother were identified, being consistent with the X-linked recessive trait. GYG2 encodes glycogenin-2 (GYG2) protein, which plays an important role in the initiation of glycogen synthesis. Based on the structural modeling, the mutation can destabilize the structure and result in protein malfunctioning. Furthermore, in vitro experiments showed mutant GYG2 was unable to undergo the self-glucosylation, which is observed in wild-type GYG2. This is the first report of GYG2 mutation in human, implying a possible link between GYG2 abnormality and LS.","variants":[{"Name":"NM_001079855.2(GYG2):c.665G>C (p.Trp222Ser)","Chromosome":"X","Start":"2859893","Stop":"2859893","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":166360,"rule_based_match":true,"evidence_text":"c.665G>C (p.W222S)","llm_judgment":"PRESENT","evidence":"c.665G>C","abstract_start":663,"abstract_end":671}]}
{"pmid":"30715675","title":"BRCA1 and BRCA2 Germline Mutation Analysis in Hereditary Breast/Ovarian Cancer Families from the Aures Region (Eastern Algeria): First Report.","abstract":"Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. In this study, we aimed to investigate the mutation spectrum of BRCA1 and BRCA2 genes in hereditary breast/ovarian cancer (HBOC) families from the Aures region (eastern Algeria). High risk breast/ovarian cancer families were selected from overall 1162 consecutive patients collected from cancer registry of anticancer center of Batna. Breast cancers were diagnosed between 2011 and 2015. Recurrent mutations on BRCA1 and BRCA2 previously found in Algerian patients were screened using PCR-direct sequencing in 113 HBOC families. In addition, for the first time in Algeria, HBOC patients were analyzed by NGS using a cancer panel of 30 hereditary cancer genes or BRCA1/2 genetic test. Six distinct deleterious mutations in BRCA1 and BRCA2 and a new VUS in PALB2 were detected in ten patients. Two distinct BRCA2 pathogenic variants c.1813dupA and c.8485C > T detected in two young female triple negative breast cancer (TNBC) patients, respectively, with a family history of male breast cancer, are reported here for the first time in Algerian population. Interestingly, we also detected a BRCA exon 15 deletion in two unrelated young female TNBC patients with strong family history of breast/ovarian cancer. Our study showed differences in the distribution of the mutation spectrum of BRCA genes between the Aures region and the north central region of Algeria. Our results will contribute in the implementation of genetic counseling and testing for patients and families at risk of hereditary breast and ovarian cancer.","variants":[{"Name":"NM_000059.4(BRCA2):c.8485C>T (p.Gln2829Ter)","Chromosome":"13","Start":"32370555","Stop":"32370555","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67268,"rule_based_match":true,"evidence_text":"c.8485C > T","llm_judgment":"PRESENT","evidence":"c.8485C > T","abstract_start":947,"abstract_end":958},{"Name":"NM_000059.4(BRCA2):c.1813dup (p.Ile605fs)","Chromosome":"13","Start":"32333283","Stop":"32333284","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":46318,"rule_based_match":true,"evidence_text":"c.1813dupA","llm_judgment":"PRESENT","evidence":"c.1813dupA","abstract_start":932,"abstract_end":942}]}
{"pmid":"32413971","title":"Molecular Analysis of the","abstract":"<i>ABCA4</i> gene mutations are the cause of a spectrum of <i>ABCA4</i> retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. <i>ABCA4</i> has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of <i>ABCA4</i> variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the <i>ABCA4</i> gene splice-site variants in patients with <i>ABCA4</i> retinopathies. We assessed <i>ABCA4</i> expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length <i>ABCA4</i> transcripts and analyzed <i>ABCA4</i> transcripts from three patients with Stargardt disease carrying different splice-site <i>ABCA4</i> variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of <i>ABCA4</i> variants in patients with <i>ABCA4</i> retinopathies.","variants":[{"Name":"NM_000350.3(ABCA4):c.5312+1G>A","Chromosome":"1","Start":"94015738","Stop":"94015738","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":237652,"rule_based_match":true,"evidence_text":"c.5312+1G>A","llm_judgment":"PRESENT","evidence":"c.5312+1G>A","abstract_start":952,"abstract_end":963},{"Name":"NM_000350.3(ABCA4):c.5836-3C>A","Chromosome":"1","Start":"94008300","Stop":"94008300","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":405252,"rule_based_match":true,"evidence_text":"c.5836-3C>A","llm_judgment":"PRESENT","evidence":"c.5836-3C>A","abstract_start":981,"abstract_end":992}]}
{"pmid":"32252217","title":"Nonclassic congenital lipoid adrenal hyperplasia diagnosed at 17 months in a Korean boy with normal male genitalia: emphasis on pigmentation as a diagnostic clue.","abstract":"Congenital lipoid adrenal hyperplasia (CLAH) is one of the most fatal conditions caused by an abnormality of adrenal and gonadal steroidogenesis. CLAH results from loss-of-function mutations of the steroidogenic acute regulatory (STAR) gene; the disease manifests with electrolyte imbalances and hyperpigmentation in neonates or young infants due to adrenocortical hormone deficiencies, and 46, XY genetic male CLAH patients can be phenotypically female. Meanwhile, some patients with STAR mutations develop hyperpigmentation and mild signs of adrenal insufficiency, such as hypoglycemia, after infancy. These patients are classified as having nonclassic CLAH (NCCLAH) caused by STAR mutations that retain partial activity of STAR. We present the case of a Korean boy with normal genitalia who was diagnosed with NCCLAH. He presented with whole-body hyperpigmentation and electrolyte abnormalities, which were noted at the age of 17 months after an episode of sepsis with peritonitis. The compound heterozygous mutations p.Gly221Ser and c.653C&gt;T in STAR were identified by targeted gene-panel sequencing. Skin hyperpigmentation should be considered an important clue for diagnosing NCCLAH.","variants":[{"Name":"NM_000349.3(STAR):c.661G>A (p.Gly221Ser)","Chromosome":"8","Start":"38145305","Stop":"38145305","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":637195,"rule_based_match":false,"evidence_text":"p.Gly221Ser","llm_judgment":"PRESENT","evidence":"p.Gly221Ser","abstract_start":1021,"abstract_end":1032}]}
{"pmid":"32104752","title":"Use of PCSK9 Inhibitor in a Mexican Boy with Compound Heterozygous Familial Hypercholesterolemia: A Case Report.","abstract":"We report on the case of an 8-year-old Mexican male, with a 3-year-old clinical diagnosis of familial hypercholesterolemia, and the difficulties encountered in his treatment while in our care. His treatment started with a regimen consisting of ezetimibe/simvastatin, cholestyramine, and a dietary plan of 1600 calories, with a limited intake of 200 mg of cholesterol per day. Problems arose when the patient's low-density lipoprotein cholesterol (LDL) levels did not meet ideal targets, which prompted the use of LDL cholesterol apheresis (not available in Mexico) for 6 months. As a last resort, PCSK9 inhibitors were administered but the LDL levels remained in the 600 mg/dL range. AmbryGenetics conducted a genetic test employing the Sanger method. The results suggested that there were 2 different mutations for each allele of the same LDL receptor gene (c.249delTinsGG and p.(Cys109Arg)), located in exons 3 and 4, respectively. We identified compound heterozygous mutations in our index case, with him having both the p.C109R mutation (from the maternal lineage), as well as a c.249delTinsGG mutation (from the paternal lineage). The p.C109R mutation has been previously reported, not only in Mexico, but in European regions (Germany, Czech Republic, Ireland, Italy) as well. Functional studies indicated a residual enzymatic activity of 15% to 30% for heterozygotes. To date, the variant c.249delTinsGG has not been reported. This case study illustrates the fact that in Mexico there are limited options available for treatment in such a scenario. As medical professionals, we are limited by the tools at our disposal.","variants":[{"Name":"NM_000527.5(LDLR):c.325T>C (p.Cys109Arg)","Chromosome":"19","Start":"11105231","Stop":"11105231","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":245493,"rule_based_match":false,"evidence_text":"p.(Cys109Arg)","llm_judgment":"PRESENT","evidence":"p.(Cys109Arg)","abstract_start":878,"abstract_end":891}]}
{"pmid":"23497566","title":"Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.","abstract":"BACKGROUND: Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype.\nMETHODS: Sequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants in 3.500 European control chromosomes and extensive phenotypic investigations of all SACS carriers.\nRESULTS: We identified 11 index patients harbouring 17 novel SACS variants. 9/11 patients harboured two variants of at least probable pathogenicity which were not observed in controls and, in case of missense mutations, were located in highly conserved domains. These 9 patients accounted for at least 11% (9/83) in our series of unexplained early onset ataxia subjects. While most patients (7/9) showed the classical ARSACS triad, the presenting phenotype reached from pure neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth disease) in one subject to the absence of any signs of neuropathy in another. In contrast to its name \"spastic ataxia\", neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) were obligate features. Autonomic features included urine urge incontinence and erectile dysfunction. Apart from the well-established MRI finding of pontine hypointensities, all patients (100%) showed hyperintensities of the lateral pons merging into the (thickened) middle cerebellar peduncles. In addition, 63% exhibited bilateral parietal cerebral atrophy, and 63% a short circumscribed thinning of the posterior midbody of the corpus callosum. In 2 further patients with differences in important clinical features, VUS class 3 variants (c.1373C>T [p.Thr458Ile] and c.2983 G>T [p.Val995Phe]) were identified. These variants were, however, also observed in controls, thus questioning their pathogenic relevance.\nCONCLUSIONS: We here demonstrate that each feature of the classical ARSACS triad (cerebellar ataxia, spasticity and peripheral neuropathy) might be missing in ARSACS. Nevertheless, characteristic MRI features - which also extend to supratentorial regions and involve the cerebral cortex - will help to establish the diagnosis in most cases.","variants":[{"Name":"NM_014363.6(SACS):c.1373C>T (p.Thr458Ile)","Chromosome":"13","Start":"23355239","Stop":"23355239","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":266622,"rule_based_match":true,"evidence_text":"c.1373C>T [p.Thr458Ile]","llm_judgment":"PRESENT","evidence":"c.1373C>T [p.Thr458Ile]","abstract_start":1922,"abstract_end":1945}]}
{"pmid":"11708864","title":"Identification of a novel pancreatitis-associated missense mutation, R116C, in the human cationic trypsinogen gene (PRSS1).","abstract":"Over the past 5 years, several gain-of-function missense mutations in the human cationic trypsinogen gene (PRSS1, OMIM 276000) have been associated with hereditary and/or sporadic pancreatitis. This study reports a new pancreatitis-associated mutation--R116C (CGT > TGT: c.346C > T)--in the gene.","variants":[{"Name":"NM_002769.5(PRSS1):c.346C>T (p.Arg116Cys)","Chromosome":"7","Start":"142751919","Stop":"142751919","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38878,"rule_based_match":true,"evidence_text":"c.346C > T","llm_judgment":"PRESENT","evidence":"c.346C > T","abstract_start":271,"abstract_end":281}]}
{"pmid":"27264805","title":"Analysis of clinical phenotype and ACAT1 gene mutation in a family affected with beta-ketothiolase deficiency","abstract":"OBJECTIVE: To investigate the clinical phenotype and ACAT1 gene mutation in a family affected with beta-ketothiolase deficiency (BKTD).\nMETHODS: Clinical features and laboratory test data were collected. The probands were monozygotic twin brothers. Genomic DNA was isolated from peripheral blood leukocytes obtained from the probands and their family members. Molecular genetic testing of the ACAT1 gene was carried out.\nRESULTS: The probands have presented with fever, vomiting and severe ketoacidosis. By arterial blood gas testing, pH was determined to be 7.164, bicarbonate was 4.0 mmol/L, and urine ketone was ++++. Urinary organic acid gas chromatography-mass spectrometry analysis showed excessive excretion of 3-hydroxybutyric acid, 2-methyl-3-hydroxybutyric acid and tiglylglycine. Increased 3-hydroxybutyrylcarnitine (C4-OH), tiglylcarnitine(C5:1) and 3-hydroxyisovalerylcarnitine (C5-OH) levels. The clinical phenotype of proband's parents were both normal, but an elder sister turned out to be an affected patient. Genetic analysis has identified two heterozygous mutations [c.622C>T(p.R208X) and c.653C>T (p.S218F)] in the proband, which were respectively detected in the mother and father. The c.653C>T (p.S218F) mutation was not found among the 100 healthy controls and has not been included in the Human Gene Mutation Database(HGMD).\nCONCLUSION: The primary clinical manifestations of BKTD is ketoacidosis. Urine organic acid and blood acylcarnitine analyses play an important role in the diagnosis of the disease. The compound heterozygous of ACAT1 gene mutations probably underlie the BKTD in our patient.","variants":[{"Name":"NM_000019.4(ACAT1):c.653C>T (p.Ser218Phe)","Chromosome":"11","Start":"108140138","Stop":"108140138","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":247327,"rule_based_match":true,"evidence_text":"c.653C>T (p.S218F)","llm_judgment":"PRESENT","evidence":"c.653C>T (p.S218F)","abstract_start":1109,"abstract_end":1127}]}
{"pmid":"30863428","title":"Next Generation Sequencing and Animal Models Reveal","abstract":"Age-related hearing loss (ARHL) is the most common sensory impairment in the elderly affecting millions of people worldwide. To shed light on the genetics of ARHL, a large cohort of 464 Italian patients has been deeply characterized at clinical and molecular level. In particular, 46 candidate genes, selected on the basis of genome-wide association studies (GWAS), animal models and literature updates, were analyzed by targeted re-sequencing. After filtering and prioritization steps, <i>SLC9A3R1</i> has been identified as a strong candidate and then validated by \"<i>in vitro\"</i> and <i>\"in vivo\"</i> studies. Briefly, a rare (MAF: 2.886e-5) missense variant c.539G > A, p.(R180Q) was detected in two unrelated male patients affected by ARHL characterized by a severe to profound high-frequency hearing loss. The variant, predicted as damaging, was not present in healthy matched controls. Protein modeling confirmed the pathogenic effect of p.(R180Q) variant on protein's structure leading to a change in the total number of hydrogen bonds. <i>In situ</i> hybridization showed <i>slc9a3r1</i> expression in zebrafish inner ear. A zebrafish knock-in model, generated by CRISPR-Cas9 technology, revealed a reduced auditory response at all frequencies in <i>slc9a3r1</i> <sup>R180Q/R180Q</sup> mutants compared to <i>slc9a3r1</i> <sup>+/+</sup> and <i>slc9a3r1</i> <sup>+/R180Q</sup> animals. Moreover, a significant reduction (5.8%) in the total volume of the saccular otolith (which is responsible for sound detection) was observed in <i>slc9a3r1</i> <sup>R180Q/R180Q</sup> compared to <i>slc9a3r1</i> <sup>+/+</sup> (<i>P</i> = 0.0014), while the utricular otolith, necessary for balance, was not affected in agreement with the human phenotype. Overall, these data strongly support the role of <i>SLC9A3R1</i> gene in the pathogenesis of ARHL opening new perspectives in terms of diagnosis, prevention and treatment.","variants":[{"Name":"NM_004252.5(NHERF1):c.539G>A (p.Arg180Gln)","Chromosome":"17","Start":"74762109","Stop":"74762109","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3043378,"rule_based_match":true,"evidence_text":"c.539G > A, p.(R180Q)","llm_judgment":"PRESENT","evidence":"c.539G > A, p.(R180Q)","abstract_start":664,"abstract_end":685}]}
{"pmid":"32908740","title":"A Novel SPAST/SPG4 Splice-Site Variant in a Family with Dominant Hereditary Spastic Paraplegia.","abstract":"Some causes of spastic paraplegia are treatable and many are not. Diagnostic work-up to determine the etiology can be costly and invasive. Here we report the case of a man with slowly progressive spastic paraparesis. Using a multigene next-generation sequencing (NGS) panel, we identified a novel variant in the consensus splice site of the SPAST gene (exon 13, c.1536G>A, heterozygous), affecting codon 512 of the SPAST mRNA. The observed variant segregated with the disease in four tested family members. In this case, genetic confirmation obviated the need for additional testing such as MRI and lumbar puncture and helped the patient and his family understand his condition and prognosis. We conclude with a brief discussion of the SPG4/SPAST gene and the role of multigene panels in the diagnosis and management of hereditary spastic paraplegia.","variants":[{"Name":"NM_014946.4(SPAST):c.1536G>A (p.Glu512=)","Chromosome":"2","Start":"32141946","Stop":"32141946","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":481652,"rule_based_match":true,"evidence_text":"c.1536G>A","llm_judgment":"PRESENT","evidence":"c.1536G>A","abstract_start":362,"abstract_end":371}]}
{"pmid":"33779092","title":"Ketogenic Diet in Infants with Early-Onset Epileptic Encephalopathy and","abstract":"Research has shown mutations in the voltage-gated sodium channel gene <i>SCN2A</i> to be associated with developmental delays and infantile seizures in patients with early-onset epileptic encephalopathies (EOEEs). Here, we report the case of an infant with a de novo <i>SCN2A</i> mutation with EOEE who had medically refractory seizures that improved with a ketogenic diet (KD) implemented at an age less than 2 months. On the day of his birth, the infant presented with a pattern of convulsions with dozens of episodes per day. An initial video electroencephalogram revealed poor reactivity of background activity, with multiple partial episodes starting from the right temporal region, and abnormal electrical activity in the right hemisphere. The seizures previously were not controlled with successive therapy with phenobarbital, topiramate, and levetiracetam. Genetic testing revealed the presence of a mutation in the <i>SCN2A</i> gene (c.4425C>G, p.Asn1475Lys). The infant's seizures decreased significantly with a combination of KD and medication. The present case exemplifies the potential for personalized genomics in identifying the etiology of an illness. Furthermore, the KD appears to feasible in infants younger than 2 months and might elicit good responses to EOEE associated with <i>SCN2A</i> mutation.","variants":[{"Name":"NM_001040142.2(SCN2A):c.4425C>G (p.Asn1475Lys)","Chromosome":"2","Start":"165380708","Stop":"165380708","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1861550,"rule_based_match":true,"evidence_text":"c.4425C>G, p.Asn1475Lys","llm_judgment":"PRESENT","evidence":"c.4425C>G, p.Asn1475Lys","abstract_start":943,"abstract_end":966}]}
{"pmid":"37723834","title":"Identification of nonfunctional PABPC1L causing oocyte maturation abnormalities and early embryonic arrest in female primary infertility.","abstract":"Oocyte maturation arrest, fertilization failure, and early embryonic arrest are important causes of female infertility, whereas the genetic events that contribute to these processes are largely unknown. Loss-of-function of PABPC1L in mice has been suggested to cause female infertility involved in the absence of mature oocytes or embryos in vivo or in vitro. However, the role of PABPC1L in human female reproduction remains largely elusive. In this study, we identified a homozygous missense mutation (c.536G>A, p.R179Q) and a compound heterozygous mutation (c.793C>T, p.R265W; c.1201C>T, p.Q401*) in PABPC1L in two unrelated infertile females characterized by recurrent oocyte maturation abnormalities and early embryonic arrest. These variants resulted in nonfunctional PABPC1L protein and were associated with impaired chromatin configuration and transcriptional silencing in GV oocytes. Moreover, the binding capacity of mutant PABPC1L to mRNAs related to oocyte maturation and early embryonic development was decreased significantly. Our findings revealed novel PABPC1L mutations causing oocyte maturation abnormalities and early embryonic arrest, confirming the essential role of PABPC1L in human female fertility.","variants":[{"Name":"NM_001372179.1(PABPC1L):c.536G>A (p.Arg179Gln)","Chromosome":"20","Start":"44918938","Stop":"44918938","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3735290,"rule_based_match":true,"evidence_text":"c.536G>A, p.R179Q","llm_judgment":"PRESENT","evidence":"c.536G>A, p.R179Q","abstract_start":504,"abstract_end":521},{"Name":"NM_001372179.1(PABPC1L):c.1201C>T (p.Gln401Ter)","Chromosome":"20","Start":"44930688","Stop":"44930688","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3735292,"rule_based_match":true,"evidence_text":"c.1201C>T (p.Q401*)","llm_judgment":"PRESENT","evidence":"c.1201C>T","abstract_start":580,"abstract_end":589}]}
{"pmid":"26990772","title":"A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development.","abstract":"Patients with biallelic truncating mutations in PALB2 have a severe form of Fanconi anaemia (FA-N), with a predisposition for developing embryonal-type tumours in infancy. Here we describe two unusual patients from a single family, carrying biallelic PALB2 mutations, one truncating, c.1676_1677delAAinsG;(p.Gln559ArgfsTer2), and the second, c.2586+1G>A; p.Thr839_Lys862del resulting in an in frame skip of exon 6 (24 amino acids). Strikingly, the affected individuals did not exhibit the severe developmental defects typical of FA-N patients and initially presented with B cell non-Hodgkin lymphoma. The expressed p.Thr839_Lys862del mutant PALB2 protein retained the ability to interact with BRCA2, previously unreported in FA-N patients. There was also a large increased chromosomal radiosensitivity following irradiation in G2 and increased sensitivity to mitomycin C. Although patient cells were unable to form Rad51 foci following exposure to either DNA damaging agent, U2OS cells, in which the mutant PALB2 with in frame skip of exon 6 was induced, did show recruitment of Rad51 to foci following damage. We conclude that a very mild form of FA-N exists arising from a hypomorphic PALB2 allele.","variants":[{"Name":"NM_024675.4(PALB2):c.2586+1G>A","Chromosome":"16","Start":"23629203","Stop":"23629203","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1871408,"rule_based_match":true,"evidence_text":"c.2586+1G>A","llm_judgment":"PRESENT","evidence":"c.2586+1G>A","abstract_start":342,"abstract_end":353},{"Name":"NM_024675.4(PALB2):c.1676_1677delinsG (p.Gln559fs)","Chromosome":"16","Start":"23634869","Stop":"23634870","ReferenceAlleleVCF":"TT","AlternateAlleleVCF":"C","allel_id":132124,"rule_based_match":false,"evidence_text":"c.1676_1677delAAinsG;(p.Gln559ArgfsTer2)","llm_judgment":"PRESENT","evidence":"c.1676_1677delAAinsG;(p.Gln559ArgfsTer2)","abstract_start":284,"abstract_end":324}]}
{"pmid":"19504431","title":"A new EXT2 mutation in a Chinese family with hereditary multiple exostoses","abstract":"OBJECTIVE: Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by formation of benign cartilage-capped tumors (exostoses), typically located at the juxtaepiphyseal regions of long bones. It is genetically heterogeneous with at least three chromosomal loci: EXT1 on 8q24.1, EXT2 on 11p11, and EXT3 on 19p. EXT1 and EXT2 have been cloned and are responsible for over 80% of cases. A Chinese family with HME has been analyzed in the present study.\nMETHODS: Linkage analysis was firstly performed to determine which of the three EXT genes could be the candidate gene, then mutation screening by PCR and direct sequencing was carried out.\nRESULTS: A novel nonsense mutation (c.1006C>T) in exon 6 of EXT2, which converts the codon CAA (Gln) to the stop codon (TAA) (Gln336X), was identified. Next, prenatal diagnosis was performed and the pregnancy was determined to be normal.\nCONCLUSION: A new EXT2 nonsense mutation was found in a Chinese family with hereditary multipe exostoses. The information was used for a case of prenatal diagnosis.","variants":[{"Name":"NM_207122.2(EXT2):c.1006C>T (p.Gln336Ter)","Chromosome":"11","Start":"44126882","Stop":"44126882","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":935538,"rule_based_match":true,"evidence_text":"c.1006C>T","llm_judgment":"PRESENT","evidence":"c.1006C>T","abstract_start":702,"abstract_end":711}]}
{"pmid":"19230662","title":"Becker muscular dystrophy caused by an intronic mutation reducing the efficiency of the splice donor site of intron 26 of the dystrophin gene.","abstract":"We describe an 11-year-old boy with dystrophinopathy who presented with a history of progressive proximal muscle weakness and elevated serum creatine kinase levels at age 6. Sequence analysis of the dystrophin (DMD) gene did not identify a mutation in the coding regions but revealed a nucleotide substitution in intron 26 (c.3603+3A>T). Since computer algorithms did not conclusively indicate that this sequence variant inactivated the splice site, we analyzed the DMD mRNA from a muscle biopsy of the patient to determine its functional significance. PCR and sequence analysis of the cDNA demonstrated that the mutation reduced the efficiency of the donor splice site and caused activation of a cryptic donor site 113 bp downstream. Activation of the cryptic donor site led to inclusion of 116 bp of intronic sequence containing a stop codon producing a truncated dystrophin protein. Residual wild-type splicing was also detected, which would explain the milder Becker rather than Duchenne phenotype in this patient. We highlight the importance of mRNA analysis for determination of pathogenicity in patients with ambiguous sequence variants in the DMD gene.","variants":[{"Name":"NM_004006.3(DMD):c.3603+3A>T","Chromosome":"X","Start":"32454659","Stop":"32454659","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":404564,"rule_based_match":true,"evidence_text":"c.3603+3A>T","llm_judgment":"PRESENT","evidence":"c.3603+3A>T","abstract_start":324,"abstract_end":335}]}
{"pmid":"34630290","title":"Infantile-Onset Charcot-Marie-Tooth Disease With Pyramidal Features and White Matter Abnormalities Due to a","abstract":"<b>Background:</b> Charcot-Marie-Tooth (CMT) is the most frequent group of inherited neuropathies and includes several heterogeneous phenotypes. Over 80 causative genes have been described so far. Variants in the microrchidia family CW-type zinc finger 2 (<i>MORC2</i>) gene have been described in several axonal polyneuropathy (CMT2) patients with childhood or adult onset. Occasionally more complex phenotypes with delayed milestones, severe hypotonia, intellectual disability, dystonic postures, pyramidal signs, and neuroimaging abnormalities have been reported. <b>Case Presentation:</b> We report on a patient with a <i>de novo MORC2</i> gene variant (c.1181A>G p.Tyr394Cys) with a history of developmental delay, axial hypotonia, progressive gait disorder with dystonic features, and intentional tremor. At the age of 8 years, he showed bilateral pyramidal signs (clonus, increased tendon reflexes, and Babinski sign) and bilateral pes cavus. The first neuroimaging performed at the age of 3 years demonstrated white matter abnormalities in the posterior periventricular zone, in the frontal lobes bilaterally and at the midbrain, stable during childhood and adolescence. Nerve conduction studies (NCS) were negative until the age of 15 years, when a sensory axonal neuropathy appeared. The association between pyramidal signs and neuropathy due to the <i>MORC2</i> gene variant is increasingly being highlighted, although a neuroradiological correlate is evident only in about half of the cases. Longitudinal nerve conduction velocity (NCV) are helpful to identify late-onset features and provide useful information for diagnosis in patients with rare neurogenetic disorders. <b>Conclusions:</b> Characterization of complex neurological disorders is important to delineate the expanding phenotypic spectrum of <i>MORC2</i>-related disease, to confirm if possible the pathogenicity of the variants and to deepen the genotype-phenotype correlation.","variants":[{"Name":"NM_001303256.3(MORC2):c.1181A>G (p.Tyr394Cys)","Chromosome":"22","Start":"30938098","Stop":"30938098","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":426373,"rule_based_match":true,"evidence_text":"c.1181A>G p.Tyr394Cys","llm_judgment":"PRESENT","evidence":"c.1181A>G p.Tyr394Cys","abstract_start":658,"abstract_end":679}]}
{"pmid":"36973888","title":"X-linked myotubular myopathy: a clinical report and a review of the mild phenotype.","abstract":"INTRODUCTION: X-linked myotubular myopathy is a rare centronuclear myopathy that affects approximately 1 in 50,000 male newborns caused by pathogenic variants in the myotubularin 1 gene (MTM1). The clinical severity varies, however the need for ventilatory support occurs almost invariably.\nCASE REPORT: We report the case of a 4-year-old boy presenting mild muscle hypotonia at 12 months-old, expressive language disorder, global developmental delay, and a sensory processing disorder. Clinical exome sequencing identified the hemizygous variant c.722G>A p.(Arg241His) in exon 9 of the myotubularin 1 gene (NM_000252.2). The mother is a heterozygous carrier of the same variant. A diagnosis of a mild form of maternal inherited X-linked myotubular myopathy was established. The child presented significant improvement with speech, occupational, and physical therapies, with no respiratory intercurrences or ventilator dependency.\nCONCLUSION: The presentation of a mild form of this myotubular myopathy, being less commonly reported, added challenge to the diagnosis. The combination of mild hypotonia, feeding difficulties and expressive language disorder should raise suspicion of a neuromuscular disease. There is a lack of verified motor or developmental scores specific to this myopathy to further determine prognosis and need of other therapies. While currently the severity myotubular myopathy is classified according to ventilator dependency, this may be insufficient and unapplicable to milder cases. There is an evident need for a grading system for mild and moderate cases assessing muscle weakness and fatigue, daily life limitations, motor developmental delay, early phenotypical scores, or recurrent respiratory infections.","variants":[{"Name":"NM_000252.3(MTM1):c.722G>A (p.Arg241His)","Chromosome":"X","Start":"150645726","Stop":"150645726","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3494671,"rule_based_match":true,"evidence_text":"c.722G>A p.(Arg241His)","llm_judgment":"PRESENT","evidence":"c.722G>A p.(Arg241His)","abstract_start":547,"abstract_end":569}]}
{"pmid":"18272034","title":"Novel mutation and polymorphism of PRSS1 gene in the Chinese patients with hereditary pancreatitis and chronic pancreatitis.","abstract":"BACKGROUND: Mutations in the cationic trypsinogen gene (PRSS1) have been detected in patients with hereditary pancreatitis (HP). This study investigated the prevalence of the R122H (c.365 G > A), A121T (c.361 G > A) and D162D (c.488 C > T) mutations or polymorphisms in the common, non-hereditary forms of chronic pancreatitis and in an HP family.\nMETHODS: DNA was prepared from blood samples of 54 patients with chronic pancreatitis (35 alcoholic, 17 idiopathic and 2 hereditary) and 120 normal controls. The PRSS1 genes were amplified by polymerase chain reaction (PCR) and their products were analyzed by sequencing and related clinical data were also collected.\nRESULTS: A new polymorphism (c.488 C > T) of PRSS1 was found in 25 patients with chronic pancreatitis (including one affected member of the HP family) and six members of the normal controls. The C/T genotype was significantly increased in chronic pancreatitis (OR: 16.379, 95% CI: 5.7522 - 52.3663), the frequency of c.488 C > T change was in according with the Hardy-Weinberg equilibrium, but it doesn't affect the clinical phenotype. The commonly reported change of R122H (c.365 G > A) was not detected in any of the study subjects. c.361 G > A was found in 2 affected members and one unaffected carrier in an HP family. One of the affected members of an HP family had c.361 G > A mutation and polymorphism (c.488 C > T) in the PRSS1 gene at the same time. The patient's clinical values (C3, C4, CA19-9 and HbA1c) were higher than those of the other patients with chronic pancreatitis. The two patients with HP developed diabetes mellitus and their father died with pancreatic cancer.\nCONCLUSION: A new polymorphism (c.488 C > T) in the PRSS1 gene is associated with chronic pancreatitis, but it did not affect the clinical phenotype while the A121T (c.361 G > A) mutation in the gene shows a significant correlation in the patients with HP.","variants":[{"Name":"NM_002769.5(PRSS1):c.361G>A (p.Ala121Thr)","Chromosome":"7","Start":"142751934","Stop":"142751934","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26924,"rule_based_match":true,"evidence_text":"c.361 G > A","llm_judgment":"PRESENT","evidence":"c.361 G > A","abstract_start":203,"abstract_end":214}]}
{"pmid":"30996589","title":"Seven novel variants expand the spectrum of","abstract":"Purpose: To screen <i>RPE65</i> in 187 families with Leber congenital amaurosis (LCA).\nMethods: Sanger sequencing and/or targeted exome sequencing was employed to identify mutations in the <i>RPE65</i> gene, and intrafamilial cosegregation analysis if DNA was available. In silico analyses and splicing assay were used to evaluate the variants' pathogenicity.\nResults: Genetic analysis revealed 15 mutations in <i>RPE65</i> in 14 pedigrees, including one splice-site mutation, one frameshift mutation, three nonsense mutations, and ten missense mutations. Of the mutations identified in <i>RPE65</i>, seven are novel associated with LCA, including five missense variants (c.124C>T, c.149T>C, c.340A>C, c.425A>G, and c.1399C>G) and two indel (insertions or deletions) variants (c.858+1delG and c.1181_1182insT). In vitro splicing assay was performed to evaluate the functional impact on RNA splicing of novel mutations if two of three in silico analyses were predicated to be non-pathogenic at the protein level. Among these 15 variants, 14 were classified as 'pathogenic variants,' and a variant (c.124C>T) was 'variants with uncertain significance' according to the standards and guidelines of the American College of Medical Genetics and Genomics.\nConclusions: Mutations in <i>RPE65</i> were responsible for 11 of the cohort of 187 Chinese families with LCA, which expands the spectrum of <i>RPE65</i>-related LCA in the Chinese population and potentially facilitates its clinical implementation.","variants":[{"Name":"NM_000329.3(RPE65):c.124C>T (p.Leu42Phe)","Chromosome":"1","Start":"68446831","Stop":"68446831","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":952519,"rule_based_match":true,"evidence_text":"c.124C>T","llm_judgment":"PRESENT","evidence":"c.124C>T","abstract_start":672,"abstract_end":680},{"Name":"NM_000329.3(RPE65):c.1399C>G (p.Pro467Ala)","Chromosome":"1","Start":"68431116","Stop":"68431116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1058809,"rule_based_match":true,"evidence_text":"c.1399C>G","llm_judgment":"PRESENT","evidence":"c.1399C>G","abstract_start":716,"abstract_end":725},{"Name":"NM_000329.3(RPE65):c.1399C>T (p.Pro467Ser)","Chromosome":"1","Start":"68431116","Stop":"68431116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":551518,"rule_based_match":false,"evidence_text":"c.1399C>T","llm_judgment":"PRESENT","evidence":"c.1399C>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"29768383","title":"Treatable massive pericardial effusion and hypertrophic cardiomyopathy in an infant with a novel homozygous ACADVL mutation: A case report.","abstract":"RATIONALE: Infantile-onset hypertrophic cardiomyopathy (HCMP) should be considered a largely genetic condition, although its onset is most often triggered by infection. Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive inborn error of mitochondrial fatty acid β-oxidation that often causes severe cardiomyopathy and/or sudden death during the neonatal period.\nPATIENT CONCERNS: Herein, we report an infant with VLCAD deficiency who presented with severe cardiac manifestations, including massive pericardial effusion and HCMP. The subject's older sister died of unknown causes at three days of age; however, the subject exhibited a normal tandem mass-spectrometry profile during the neonatal period.\nDIAGNOSES: During her later cardiac presentation, the subject's C-14 and C-18 levels became elevated, and she was determined, via the conducted molecular analysis, to harbor a novel homozygous frameshift mutation (c.103_112dup) in ACADVL.\nINTERVENTIONS: After VLCAD deficiency diagnosis, the subject was treated with the administration of a medium chain triglyceride formula and fluid therapy.\nOUTCOMES: The subject's cardiac status was markedly improved by the dietary intervention and fluid therapy.\nLESSONS: This report highlights that genetic mutations should be investigated as possible causes of infantile-onset HCMP, and that early diagnosis and intervention can prevent mortality for patients with VLCAD deficiency.","variants":[{"Name":"NM_000018.4(ACADVL):c.103_112dup (p.Arg38fs)","Chromosome":"17","Start":"7220154","Stop":"7220155","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGCCCGGCCCT","allel_id":1706005,"rule_based_match":true,"evidence_text":"c.103_112dup","llm_judgment":"PRESENT","evidence":"c.103_112dup","abstract_start":952,"abstract_end":964}]}
{"pmid":"29080865","title":"Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats.","abstract":"BACKGROUND: There is increasing interest in the concept of atrial cardiomyopathy, but the underlying molecular and mechanistic determinants remain poorly defined. We identified a family with heritable atrial cardiomyopathy manifesting as progressive atrial-selective electromechanical dysfunction, tachyarrhythmias, and bradyarrhythmias requiring pacemaker implantation. Myosin light-chain 4 (<i>MYL4</i>), encoding the atrial-selective essential myosin light chain, was identified as a candidate gene. We used genetically modified rat models to investigate the role of <i>MYL4</i> in atrial cardiomyopathy.\nMETHODS AND RESULTS: Exome sequencing and systematic bioinformatic analyses identified a rare missense variant of <i>MYL4</i> (c.31G>A [<i>p.E11K</i>]) in a large multiplex atrial cardiomyopathy family pedigree. The mutation cosegregated with atrial standstill (selected as the principal presenting trait) with a logarithm of the odds score of 5.3. The phenotype of rats with <i>MYL4</i> mutation knock-in confirmed the causative role of the mutation. <i>MYL4</i> knockout rats showed a similar atrial cardiomyopathy phenotype, whereas rats with an adjacent 4-amino-acid deletion showed no phenotype. Both <i>MYL4 p.E11K</i> knock-in rats and <i>MYL4</i> knockout rats showed progressive atrial electrophysiological, contractile, and fibrotic abnormalities, similar to affected patients. Biochemical analyses of <i>MYL4 p.E11K</i> mutation rats showed activation of proapoptotic and profibrotic signaling, along with increased atrial-cardiomyocyte terminal deoxynucleotidyl transferase dUTP nick end labeling staining, suggesting enhanced apoptotic cell death, findings that were mimicked by in vitro adenoviral transfer of the mutant gene to neonatal-rat cardiomyocytes.\nCONCLUSIONS: Loss-of-function <i>MYL4</i> gene variants cause progressive atrial cardiomyopathy in humans and rats. Our findings identify <i>MYL4</i> as a key gene required for atrial contractile, electrical and structural integrity. These results improve our understanding of the molecular basis of atrial cardiomyopathy and introduce new models for further mechanistic analysis.","variants":[{"Name":"NM_002476.2(MYL4):c.31G>A (p.Glu11Lys)","Chromosome":"17","Start":"47209453","Stop":"47209453","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":225795,"rule_based_match":true,"evidence_text":"c.31G>A (p.E11K)","llm_judgment":"PRESENT","evidence":"c.31G>A","abstract_start":735,"abstract_end":742}]}
{"pmid":"27829680","title":"Identification of a novel LRRK1 mutation in a family with osteosclerotic metaphyseal dysplasia.","abstract":"Osteosclerotic metaphyseal dysplasia (OSMD) is a rare skeletal dysplasia characterized by osteosclerotic metaphyses with osteopenic diaphyses of the long tubular bones. Our previous study identified a homozygous elongation mutation in leucine-rich repeat kinase 1 gene (LRRK1) in a patient with OSMD and showed that Lrrk1 knockout mice exhibited phenotypic similarity with OSMD. Here we report a second LRRK1 mutation in Indian sibs with OSMD. They had homozygous mutation (c.5971_5972insG) that produces an elongated mutant protein (p.A1991Gfs*31) similar to the first case. The sibs had normal stature, normal intelligence and recurrent fractures. The common radiographic feature was asymmetric and variable sclerosis of vertebral end plates, pelvic margin and metaphyses of tubular bones. One of the sibs had facial dysmorphisms, dentine abnormalities and acro-osteolysis. A comparison between the three OSMD cases with LRRK1 mutations with different ages suggested that the sclerotic lesions resolved with age. Our findings further support that LRRK1 would cause a subset of OSMD cases.","variants":[{"Name":"NM_024652.6(LRRK1):c.5971dup (p.Ala1991fs)","Chromosome":"15","Start":"101068770","Stop":"101068771","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":1318611,"rule_based_match":false,"evidence_text":"c.5971_5972insG","llm_judgment":"PRESENT","evidence":"c.5971_5972insG","abstract_start":474,"abstract_end":489}]}
{"pmid":"30097991","title":"Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties.","abstract":"Lathosterolosis is a rare defect of cholesterol synthesis. Only four previous cases have been reported, two of whom were siblings. We report a fifth patient, with a relatively mild phenotype. He presented at 5 years of age with bilateral posterior cataracts, which were managed with lensectomies and intraocular lens implants. He also had learning difficulties, with a full-scale IQ of 64 at 11 years of age. His head circumference is between the 0.4th and 2nd centiles, and he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes). The diagnosis was established after sequencing a panel of genes associated with cataracts, which revealed compound heterozygous SC5D mutations: c.479C>G p.(Pro160Arg) and c.630C>A p.(Asp210Glu). The plasma lathosterol concentration was markedly raised at 219.8 μmol/L (control range 0.53-16.0), confirming the diagnosis. The c.630C>A p.(Asp210Glu) mutation has been reported in one previous patient, who also had a relatively mild phenotype (Ho et al., JIMD Rep 12:129-134, 2014). The mutation leads to a relatively conservative amino acid substitution, consistent with some residual enzyme activity. Our patient's family did not notice any benefit from treatment with simvastatin. In summary, milder patients with lathosterolosis may present with learning difficulties, cataracts and very subtle dysmorphism. The diagnosis will be missed unless plasma sterols are analysed or relevant genes sequenced.","variants":[{"Name":"NM_006918.5(SC5D):c.630C>A (p.Asp210Glu)","Chromosome":"11","Start":"121307242","Stop":"121307242","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":904265,"rule_based_match":true,"evidence_text":"c.630C>A p.(Asp210Glu)","llm_judgment":"PRESENT","evidence":"c.630C>A p.(Asp210Glu)","abstract_start":776,"abstract_end":798},{"Name":"NM_006918.5(SC5D):c.479C>G (p.Pro160Arg)","Chromosome":"11","Start":"121307091","Stop":"121307091","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":904266,"rule_based_match":true,"evidence_text":"c.479C>G p.(Pro160Arg)","llm_judgment":"PRESENT","evidence":"c.479C>G p.(Pro160Arg)","abstract_start":749,"abstract_end":771}]}
{"pmid":"17054105","title":"Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.","abstract":"Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.","variants":[{"Name":"NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)","Chromosome":"11","Start":"534289","Stop":"534289","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27641,"rule_based_match":true,"evidence_text":"c.34G>A","llm_judgment":"PRESENT","evidence":"c.34G>A","abstract_start":759,"abstract_end":766}]}
{"pmid":"20451171","title":"Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia.","abstract":"We present an autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this clinical entity to chromosome 12q21. In one of the families, three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene, which encodes the aristaless-like homeobox 1 transcription factor. In the second family we identified a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene, providing evidence that complete loss of function of ALX1 protein causes severe disruption of early craniofacial development. Unlike loss of its murine ortholog, loss of human ALX1 does not result in neural-tube defects; however, it does severely affect the orchestrated fusion between frontonasal, nasomedial, nasolateral, and maxillary processes during early-stage embryogenesis. This study further expands the spectrum of the recently recognized autosomal-recessive ALX-related FND phenotype in humans.","variants":[{"Name":"NM_006982.3(ALX1):c.531+1G>A","Chromosome":"12","Start":"85283877","Stop":"85283877","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23150,"rule_based_match":true,"evidence_text":"c.531+1G > A","llm_judgment":"PRESENT","evidence":"c.531+1G > A","abstract_start":726,"abstract_end":738}]}
{"pmid":"22164339","title":"Mutation Analysis of the APC Gene in a Chinese FAP Pedigree with Unusual Phenotype.","abstract":"Background and Aim. Germline mutations of the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP), an autosomal dominant inherited disease mainly characterized by colorectal adenomatous polyposis. Genetic studies of FAP have shown that somatic APC mutations are dependent on the position of the germline APC mutation. However, the molecular mechanism underlying these genotype-phenotype associations for APC in Chinese remain largely unknown. Patients and Methods. In this study, we investigated the APC gene mutation in a Chinese FAP family by systematic screening with multiplex ligation-dependent probe amplification (MLPA), denaturing high-performance liquid chromatography (dHPLC), and DNA sequencing. Promoter methylation was detected by methylation-specific PCR. Results. The identical germline mutation c.1999 C>T (Q667X) of APC was identified in 5 affected members, among which 2 members carried somatic mutations of APC, one with promoter hypermethylation and the other with loss of wild-type allele in their adenomas. The somatic mutations were shown connected with the disease severity, demonstrating a unique genotype-phenotype association in this FAP pedigree. Conclusion. The study revealed the existence of novel pathogenic mutations in Chinese patients with FAP. Somatic mutations are of particular interest because of the unusual phenotypic features shown by patients.","variants":[{"Name":"NM_000038.6(APC):c.1999C>T (p.Gln667Ter)","Chromosome":"5","Start":"112837593","Stop":"112837593","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":233049,"rule_based_match":true,"evidence_text":"c.1999 C>T (Q667X)","llm_judgment":"PRESENT","evidence":"c.1999 C>T (Q667X)","abstract_start":840,"abstract_end":858}]}
{"pmid":"32339256","title":"Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing.","abstract":"BACKGROUND: Partner and localizer BRCA2 (PALB2) is a breast cancer predisposition gene, but the clinical relevance of PALB2 germline mutations in Chinese patients with breast cancer remains unknown. This study attempted to investigate the full prevalence and spectrum of PALB2 germline mutations in China and the associations between PALB2 germline mutations and breast cancer risk.\nMETHODS: A total of 21,216 unselected patients with breast cancer were enrolled from 10 provinces in China, and 5890 Chinese women without cancer were enrolled as healthy controls. PALB2 screening was based on next-generation sequencing.\nRESULTS: A total of 16,501 BRCA1/2-negative patients with breast cancer were analyzed. Deleterious PALB2 mutation carriers accounted for 0.97% (n = 160) in the breast cancer cohort and for 0.19% (n = 11) in the healthy control cohort. Forty-one novel PALB2 germline mutations were identified. A high frequency of PALB2 c.751C>T was detected, and it accounted for 10.63% of the PALB2 germline mutations detected (17 of 160). PALB2 mutations were significantly associated with increased breast cancer risk (odds ratio [OR], 5.23; 95% confidence interval [CI], 2.84-9.65; P < .0001), especially among women 30 years old or younger (OR, 10.09; 95% CI, 3.95-25.79; P < .0001). Clinical characteristics, including a family history, bigger tumor size, triple-negative breast cancer, positive lymph nodes, and bilateral breast cancer, were closely related to PALB2 mutations.\nCONCLUSIONS: This study revealed a comprehensive spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer in China. PALB2 germline mutations confer a moderately increased risk for breast cancer but profoundly increase breast cancer risk for those 30 years old or younger in the Chinese population.","variants":[{"Name":"NM_024675.4(PALB2):c.751C>T (p.Gln251Ter)","Chromosome":"16","Start":"23635795","Stop":"23635795","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132277,"rule_based_match":true,"evidence_text":"PALB2 c.751C>T","llm_judgment":"PRESENT","evidence":"PALB2 c.751C>T","abstract_start":934,"abstract_end":948}]}
{"pmid":"11524739","title":"Identification of four novel RB1 germline mutations in Korean retinoblastoma patients.","abstract":"To elucidate RB1 germline mutations in Korean retinoblastoma patients, DNA samples from 14 children with bilateral (including three familial cases) and 19 children with unilateral retinoblastoma were analyzed. We found germline mutations in three out of 14 bilateral cases and one out of 19 unilateral cases. There were no germline mutations in the three familial cases. PCR-SSCP from each exon showed bandshifts in four patients which, upon sequencing, were shown to be K616E in exon 19 (c.1846A>G), an AA insertion in exon 7 (c.684-685insAA), R500G in exon 16 (c.1498A>G), and an A insertion in exon 23 (c.2391-2392insA), respectively. Hum Mutat 18:252, 2001.","variants":[{"Name":"NM_000321.3(RB1):c.1846A>G (p.Lys616Glu)","Chromosome":"13","Start":"48456235","Stop":"48456235","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3589520,"rule_based_match":true,"evidence_text":"c.1846A>G","llm_judgment":"PRESENT","evidence":"c.1846A>G","abstract_start":489,"abstract_end":498}]}
{"pmid":"34352619","title":"Generation of three induced pluripotent stem cell lines from hypertrophic cardiomyopathy patients carrying MYH7 mutations.","abstract":"MYH7 heterozygous mutations are common genetic causes of hypertrophic cardiomyopathy (HCM). HCM is characterized by hypertrophy of the left ventricle and diastolic dysfunction. We generated three human induced pluripotent stem cell (iPSC) lines from three HCM patients each carrying a single heterozygous mutation in MYH7, c.2167C > T, c.4066G > A, and c.5135G > A, respectively. All lines expressed high levels of pluripotent markers, had normal karyotype, and possessed capability of differentiation into derivatives of the three germ layers, which can serve as valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to MYH7 mutations.","variants":[{"Name":"NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)","Chromosome":"14","Start":"23415651","Stop":"23415651","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45304,"rule_based_match":true,"evidence_text":"c.5135G > A","llm_judgment":"PRESENT","evidence":"c.5135G > A","abstract_start":353,"abstract_end":364}]}
{"pmid":"22087377","title":"A Novel Splice-site Allelic Variant is Responsible for Wilson Disease in an Omani Family.","abstract":"OBJECTIVES: The objective of this study was to characterise Wilson's Disease (WD) [OMIM 277900] genetically and test for allelic variants in the copper transport gene (ATPase, Cu(++) transporting, beta polypeptide, ATP7B) responsible for the disease in an Omani family.\nMETHODS: Three index patients from an Omani family had been previously diagnosed with WD. All three patients suffered neurological symptoms and signs. Forty-six relatives in the family were screened for WD. Eleven more individuals were positive, but asymptomatic.\nRESULTS: Thirteen non-disease-causing allelic gene variants, described previously, were identified in the ATP7B gene from 46 family members. A putative novel disease-causing splice-site variant (c.2866-2A>G), which has not been reported previously, was detected in this family. It is located upstream of exon 13 which encodes part of transmembrane copper channel (Ch/Tm6). Reverse transcription polymerase chain reaction was used to amplify a complementary DNA (cDNA) fragment containing exons 12, 13 and 14. Exon 13 was entirely skipped from the transcript which probably would result in a defective ATP7B protein.\nCONCLUSION: A new ATP7B splice-site allelic variant, found among the 14 WD patients segregated with the disease in a recessive manner, suggests it is a disease-causing variant.","variants":[{"Name":"NM_000053.4(ATP7B):c.2866-2A>G","Chromosome":"13","Start":"51946480","Stop":"51946480","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":612356,"rule_based_match":true,"evidence_text":"c.2866-2A>G","llm_judgment":"PRESENT","evidence":"c.2866-2A>G","abstract_start":729,"abstract_end":740}]}
{"pmid":"33746038","title":"A novel variant in the COX15 gene causing a fatal infantile cardioencephalomyopathy: A case report with clinical and molecular review.","abstract":"The cytochrome c-oxidase (COX) enzyme, also known as mitochondrial complex IV (MT-C4D), is a transmembrane protein complex found in mitochondria. COX deficiency is one of the most frequent causes of electron transport chain defects in humans. Therefore, high energy demand organs and tissues are affected in patients with mutations in the COX15 gene, with variable phenotypic expressiveness. We describe the case of a male newborn with hypertrophic cardiomyopathy and serum and cerebrospinal fluid hyperlacticaemia, whose exome sequencing revealed two variants in a compound heterozygous state: c.232G > A; p.(Gly78Arg), classified as likely pathogenic, and c.452C > G; p.(Ser151Ter), as pathogenic; the former never previously described in the literature.","variants":[{"Name":"NM_078470.6(COX15):c.452C>G (p.Ser151Ter)","Chromosome":"10","Start":"99727098","Stop":"99727098","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":487425,"rule_based_match":true,"evidence_text":"c.452C > G; p.(Ser151Ter)","llm_judgment":"PRESENT","evidence":"c.452C > G; p.(Ser151Ter)","abstract_start":658,"abstract_end":683},{"Name":"NM_078470.6(COX15):c.232G>A (p.Gly78Arg)","Chromosome":"10","Start":"99729593","Stop":"99729593","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1959094,"rule_based_match":true,"evidence_text":"c.232G > A; p.(Gly78Arg)","llm_judgment":"PRESENT","evidence":"c.232G > A; p.(Gly78Arg)","abstract_start":595,"abstract_end":619}]}
{"pmid":"29100092","title":"Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with \"Corner Fractures\".","abstract":"Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of \"corner fractures\" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.","variants":[{"Name":"NM_212482.4(FN1):c.778T>G (p.Cys260Gly)","Chromosome":"2","Start":"215428246","Stop":"215428246","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":411545,"rule_based_match":true,"evidence_text":"c.778T>G","llm_judgment":"PRESENT","evidence":"c.778T>G","abstract_start":1192,"abstract_end":1200},{"Name":"NM_212482.4(FN1):c.718T>G (p.Tyr240Asp)","Chromosome":"2","Start":"215428306","Stop":"215428306","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":411546,"rule_based_match":true,"evidence_text":"c.718T>G","llm_judgment":"PRESENT","evidence":"c.718T>G","abstract_start":1164,"abstract_end":1172},{"Name":"NM_212482.4(FN1):c.260G>T (p.Cys87Phe)","Chromosome":"2","Start":"215434713","Stop":"215434713","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":411549,"rule_based_match":true,"evidence_text":"c.260G>T","llm_judgment":"PRESENT","evidence":"c.260G>T","abstract_start":1140,"abstract_end":1148}]}
{"pmid":"26865426","title":"A novel C8orf37 splice mutation and genotype-phenotype correlation for cone-rod dystrophy.","abstract":"BACKGROUND: To identify the disease-causing mutation in a consanguineous family of Morrocan origin with syndromic autosomal recessive (ar) cone-rod dystrophy (CRD) in two patients and describe genotype-phenotype correlations.\nMATERIALS AND METHODS: Genome-wide homozygosity mapping and direct sequencing of C8orf37, located in a homozygous interval, was performed in the family. mRNA analysis revealed the effect of the newly identified splice-site mutation. For a comparative analysis phenotypic and genetic data of C8orf37 mutations were extracted from published cases.\nRESULTS: The new splice-site mutation c.155+2T>C identified in the family results in a skipping of 82 bp. The CRD phenotypes of our patients were consistent with previous reports. Non-ocular findings in our patients and two previously described patients were postaxial polydactyly present at birth. Both families with additional postaxial polydactyly had splice site mutations affecting intron 1 of C8orf37, one at the slice donor and one at the splice acceptor site.\nCONCLUSIONS: This report extends the genotypic spectrum of C8orf37-associated retinal dystrophies and demonstrates for the first time a genotype-phenotype correlation between an arCRD-polydactyly-association and truncating germline mutations affecting the N-terminal region of the protein. Furthermore, our findings underline the ciliary function of C8orf37 protein.","variants":[{"Name":"NM_177965.4(CFAP418):c.155+2T>C","Chromosome":"8","Start":"95269033","Stop":"95269033","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":404691,"rule_based_match":true,"evidence_text":"c.155+2T>C","llm_judgment":"PRESENT","evidence":"c.155+2T>C","abstract_start":610,"abstract_end":620}]}
{"pmid":"28958982","title":"A Novel Variant in","abstract":"BACKGROUND: Hearing loss is the most common sensory deficit with many genetic and environmental underpinnings. While causative DNA variants have been identified in over 100 genes, most deafness-causing variants are rare, apart from a few exceptions. A single <i>SYNE4</i> variant co-segregating with hearing loss has recently been reported in two Middle-Eastern families.\nCASE REPORT: In this report we present two members of a family with non-syndromic high frequency sensorineural hearing loss who are homozygous for a novel pathogenic <i>SYNE4</i> variant c.129-1G>T.\nCONCLUSION: This case report provides supportive evidence for the causative role of <i>SYNE4</i> variants in hearing loss by presenting an additional family with a novel DNA variant.","variants":[{"Name":"NM_001039876.3(SYNE4):c.129-1G>T","Chromosome":"19","Start":"36008368","Stop":"36008368","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2905443,"rule_based_match":true,"evidence_text":"c.129-1G>T","llm_judgment":"PRESENT","evidence":"c.129-1G>T","abstract_start":559,"abstract_end":569}]}
{"pmid":"31061753","title":"Report of Another Mutation Proven Case of Carbonic Anhydrase II Deficiency.","abstract":"Carbonic anhydrase (CA) II deficiency results in an uncommon type of autosomal recessive sclerosing bone dysplasia with renal tubular acidosis and intracerebral calcification. We report a classic case of CA II-associated osteopetrosis with a previously reported homozygous frameshift mutation. Child was evaluated for short stature and failure to thrive. He was diagnosed as osteopetrosis in view of the presence of hepatosplenomegaly and increased bone density though hematological parameters were normal. Further evaluation showed presence of associated distal renal tubular acidosis raising a possibility of CA II deficiency. Mutation analysis revealed a previously reported homozygous frameshift mutation c.143-146delCTGT (p.Ser48Phefs*9) in <i>CA2.</i> Child has normal growth after initiation of alkali therapy.","variants":[{"Name":"NM_000067.3(CA2):c.143_146del (p.Ser48fs)","Chromosome":"8","Start":"85465376","Stop":"85465379","ReferenceAlleleVCF":"CCTGT","AlternateAlleleVCF":"C","allel_id":620305,"rule_based_match":false,"evidence_text":"c.143-146delCTGT (p.Ser48Phefs*9)","llm_judgment":"PRESENT","evidence":"c.143-146delCTGT (p.Ser48Phefs*9)","abstract_start":709,"abstract_end":742}]}
{"pmid":"22034507","title":"Characterization of a recurrent in-frame UMOD indel mutation causing late-onset autosomal dominant end-stage renal failure.","abstract":"BACKGROUND AND OBJECTIVES: In a single-center renal clinic, we have established routine mutation testing to diagnose UMOD-associated kidney disease (UAKD), an autosomal dominant disorder typically characterized by gout, hyperuricemia, and renal failure in the third to sixth decades.\nDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Four probands and their multigeneration kindreds were assessed by clinical, historical, and biochemical means. Diagnostic UMOD sequencing was performed, and mutant uromodulin was characterized in vitro.\nRESULTS: All available affected members of the four kindreds harbored the same complex indel change in UMOD, which was associated with almost complete absence of gout and a later onset of CKD; the youngest age at ESRD or death was 38 years (range, 38 to 68 years) compared with 3 to 70 years in other reports. Three mutation carriers (all ≤35 years) are currently asymptomatic. The indel sequence (c.278_289del TCTGCCCCGAAGinsCCGCCTCCT; p.V93_G97del/ins AASC) results in the replacement of five amino acids, including one cysteine, by four novel residues, also including a cysteine. Uromodulin staining of the only available patient biopsy suggested disorganized intracellular trafficking with cellular accumulation. Functional characterization of the mutant isoform revealed retarded intracellular trafficking associated with endoplasmic reticulum (ER) retention and reduced secretion into cell culture media, but to a lesser extent than we observed with the previously reported C150S mutation.\nCONCLUSIONS: The indel mutation is associated with a relatively mild clinical UAKD phenotype, consistent with our in vitro analysis. UAKD should be routinely considered as a causative gene for ESRD of unknown cause, especially where there is an associated family history or where biopsy reveals interstitial fibrosis.","variants":[{"Name":"NM_003361.4(UMOD):c.278_289delinsCCGCCTCCT (p.Val93_Gly97delinsAlaAlaSerCys)","Chromosome":"16","Start":"20349012","Stop":"20349023","ReferenceAlleleVCF":"CTTCGGGGCAGA","AlternateAlleleVCF":"AGGAGGCGG","allel_id":243897,"rule_based_match":false,"evidence_text":"c.278_289del TCTGCCCCGAAGinsCCGCCTCCT; p.V93_G97del/ins AASC","llm_judgment":"PRESENT","evidence":"c.278_289del TCTGCCCCGAAGinsCCGCCTCCT; p.V93_G97del/ins AASC","abstract_start":932,"abstract_end":992}]}
{"pmid":"24578718","title":"A novel PRF1 gene mutation in a fatal neonate case with type 2 familial hemophagocytic lymphohistiocytosis.","abstract":"Hemophagocytic lymphohistiocytosis (HLH) occurs in the primary form (genetic or familial) or secondary form (acquired). The familial form of HLH (FHL) is a potentially fatal autosomal recessive disorder that occurs because of constitutional defects in cell-mediated cytotoxicity. Here, we report a fatal neonatal case of type 2 FHL (FHL2) that involved a novel frameshift mutation. Clinically, the newborn presented with severe sepsis-like features and required mechanical ventilation and continuous venovenous hemodiafiltration. Flow cytometry analysis showed marked HLH and complete absence of intracytoplasmic perforin expression in cytotoxic cells; therefore, we performed molecular genetic analyses for PRF1 mutations, which showed that the patient had a compound heterozygous mutation in PRF1, that is, c.65delC (p.Pro22Argfs*2) and c.1090_1091delCT (p.Leu364Glufs*93). Clinical and genetic assessments for FHL are required for neonates with refractory fever and progressive multiple organ failure, particularly when there is no evidence of microbiological or metabolic cause.","variants":[{"Name":"NM_001083116.3(PRF1):c.1090_1091del (p.Leu364fs)","Chromosome":"10","Start":"70598630","Stop":"70598631","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":28760,"rule_based_match":true,"evidence_text":"c.1090_1091delCT (p.Leu364Glufs*93)","llm_judgment":"PRESENT","evidence":"c.1090_1091delCT (p.Leu364Glufs*93)","abstract_start":839,"abstract_end":874}]}
{"pmid":"21537932","title":"A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families.","abstract":"The RAD51C gene has been recently proposed as a high-penetrance breast and ovarian cancer gene. However, early replication studies have failed to confirm the finding. Thus, further studies in larger cohorts should be conducted in order to clarify the role of RAD51C as a cancer susceptibility gene. Here, we describe a high-resolution melting analysis (HRMA)-based method developed for presequence screening of RAD51C sequence variants. We have screened RAD51C sequence variants by HRMA in 492 breast cancer patients with family history of breast and/or ovarian cancer that were previously tested negative for BRCA1/2. All variants were confirmed by direct sequencing. We have detected 12 different RAD51C germ-line sequence variants, including eight transitions, two transversion, and two indels (insA, and delT). All these variants generated melting profiles which differ from wild type homozygous controls. Interestingly, we have identified one clearly pathogenic mutation (c.774delT) in the subset of 101 breast and ovarian cancer families, supporting that RAD51C is a human breast and ovarian cancer susceptibility gene.","variants":[{"Name":"NM_058216.3(RAD51C):c.774del (p.Thr259fs)","Chromosome":"17","Start":"58709927","Stop":"58709927","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":410106,"rule_based_match":true,"evidence_text":"c.774delT","llm_judgment":"PRESENT","evidence":"c.774delT","abstract_start":977,"abstract_end":986}]}
{"pmid":"22341972","title":"Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man.","abstract":"Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs(∗)17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes.","variants":[{"Name":"NM_018713.3(SLC30A10):c.266T>C (p.Leu89Pro)","Chromosome":"1","Start":"219928175","Stop":"219928175","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":39843,"rule_based_match":true,"evidence_text":"c.266T>C (p.Leu89Pro)","llm_judgment":"PRESENT","evidence":"p.Leu89Pro","abstract_start":955,"abstract_end":965},{"Name":"NM_018713.3(SLC30A10):c.585del (p.Thr196fs)","Chromosome":"1","Start":"219927856","Stop":"219927856","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":39844,"rule_based_match":true,"evidence_text":"c.585del (p.Thr196Profs(∗)17)","llm_judgment":"PRESENT","evidence":"p.Thr196Pro","abstract_start":992,"abstract_end":1003}]}
{"pmid":"37288269","title":"Misdiagnosed myocarditis in arrhythmogenic cardiomyopathy induced by a homozygous variant of","abstract":"Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy that is rarely diagnosed in infants or young children. However, some significant homozygous or compound heterozygous variants contribute to more severe clinical manifestations. In addition, inflammation of the myocardium and ventricular arrhythmia might lead to misdiagnosis with myocarditis. Here, we describe an 8-year-old patient who had been misdiagnosed with myocarditis. Timely genetic sequencing helped to identify this case as ACM induced by a homozygous variant of <i>DSG2</i>.\nCase presentation: The proband of this case was an 8-year-old boy who initially presented with chest pain with an increased level of cardiac Troponin I. In addition, the electrocardiogram revealed multiple premature ventricular beats. Cardiac magnetic resonance revealed myocardial edema in the lateral ventricular wall and apex, indicating localized injuries of the myocardium. The patient was primarily suspected to have acute coronary syndrome or viral myocarditis. Whole-exome sequencing confirmed that the proband had a homozygous variation, c.1592T > G, of the <i>DSG2</i> gene. This mutation site was regulated by DNA modification, which induced amino acid sequence changes, protein structure effects, and splice site changes. According to MutationTaster and PolyPhen-2 analyses, the variant was considered a disease-causing mutation. Next, we used SWISS-MODEL to illustrate the mutation site of p.F531C. The ensemble variance of p.F531C indicated the free energy changes after the amino acid change.\nConclusion: In summary, we reported a rare pediatric case initially presenting as myocarditis that transitioned into ACM during follow-up. A homozygous genetic variant of DSG2 was inherited in the proband. This study expanded the clinical feature spectrum of DSG2-associated ACM at an early age. Additionally, the presentation of this case emphasized the difference between homozygous and heterozygous variants of desmosomal genes in disease progression. Genetic sequencing screening could be helpful in distinguishing unexplained myocarditis in children.","variants":[{"Name":"NM_001943.5(DSG2):c.1592T>G (p.Phe531Cys)","Chromosome":"18","Start":"31536370","Stop":"31536370","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":53450,"rule_based_match":true,"evidence_text":"c.1592T > G","llm_judgment":"PRESENT","evidence":"c.1592T > G","abstract_start":1113,"abstract_end":1124}]}
{"pmid":"25512148","title":"A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies.","abstract":"Pulmonary arterial hypertension (PAH) is a pathological condition characterized by a persistent and progressive elevation of pulmonary vascular resistance with devastating consequences if untreated. In the past recent years, several genes have been related to PAH, however, the molecular defect remains unknown in a significant proportion of patients with familial PAH (∼20%). During the past few years, we have observed that PAH shows a particular behavior in Iberian Gypsies, with more aggressive course and frequently affecting multiple members of the same family. We studied five Gypsy families in whom at least one individual from each family developed a severe form of PAH and in whom no mutation had been identified in the common genes. We applied SNP-array-based homozygosity mapping in three families and obtained, among others, one of which included the gene EIF2AK4, recently reported in patients with PAH from group-1' pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). Subsequently, we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks.","variants":[{"Name":"NM_001013703.4(EIF2AK4):c.3344C>T (p.Pro1115Leu)","Chromosome":"15","Start":"40003301","Stop":"40003301","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":414422,"rule_based_match":true,"evidence_text":"c.3344C>T(p.P1115L)","llm_judgment":"PRESENT","evidence":"c.3344C>T(p.P1115L)","abstract_start":1107,"abstract_end":1126}]}
{"pmid":"25180662","title":"Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.","abstract":"INTRODUCTION: Hypophosphatemic rickets (HR) comprises a rare group of inherited diseases. Very recently, mutations in the dentin matrix protein 1 (DMP1) gene were identified in patients with an extremely rare autosomal recessive form of HR (ARHR). To date, very few cases of these mutations were reported.\nMATERIALS AND METHODS: A Lebanese consanguineous family with 2 affected sisters was studied. Patients aged 45 and 47years old presented with short stature, severe genu varum, cranial hyperostosis and a very high bone density that led to a diagnosis of a familial sclerosing bone dysplasia. Molecular analysis of known genes involved in osteopetrosis showed normal results. A combination of genotyping and exome sequencing was performed in order to elucidate the genetic basis of this pathology.\nRESULTS: Biochemical analysis was consistent with normal serum calcium and 1-25(OH)2D levels, low to normal serum phosphorus and elevated PTH values. Serum c-terminal FGF-23 was elevated in one of the two patients. A homozygous mutation disrupting the initiation codon of the DMP1 gene (OMIM 600980), NM_001079911.2: c.1A>G, p.Met1Val, was identified by exome sequencing and confirmed by Sanger sequencing.\nCONCLUSION: We report here a family of ARHR secondary to a DMP1 mutation located in the first coding exon of the gene. Our cases show that some ARHR cases may develop with age an unaccountable increase in bone density and bone overgrowth.","variants":[{"Name":"NM_004407.4(DMP1):c.1A>G (p.Met1Val)","Chromosome":"4","Start":"87656493","Stop":"87656493","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":23614,"rule_based_match":true,"evidence_text":"NM_001079911.2: c.1A>G, p.Met1Val","llm_judgment":"PRESENT","evidence":"NM_001079911.2: c.1A>G, p.Met1Val","abstract_start":1102,"abstract_end":1135}]}
{"pmid":"20363167","title":"Two novel exonic point mutations in HEXA identified in a juvenile Tay-Sachs patient: role of alternative splicing and nonsense-mediated mRNA decay.","abstract":"We have identified three mutations in the beta-hexoseaminidase A (HEXA) gene in a juvenile Tay-Sachs disease (TSD) patient, which exhibited a reduced level of HEXA mRNA. Two mutations are novel, c.814G>A (p.Gly272Arg) and c.1305C>T (p.=), located in exon 8 and in exon 11, respectively. The third mutation, c.1195A>G (p.Asn399Asp) in exon 11, has been previously characterized as a common polymorphism in African-Americans. Hex A activity measured in TSD Glial cells, transfected with HEXA cDNA constructs bearing these mutations, was unaltered from the activity level measured in normal HEXA cDNA. Analysis of RT-PCR products revealed three aberrant transcripts in the patient, one where exon 8 was absent, one where exon 11 was absent and a third lacking both exons 10 and 11. All three novel transcripts contain frameshifts resulting in premature termination codons (PTCs). Transfection of mini-gene constructs carrying the c.814G>A and c.1305C>T mutations proved that the two mutations result in exon skipping. mRNAs that harbor a PTC are detected and degraded by the nonsense-mediated mRNA decay (NMD) pathway to prevent synthesis of abnormal proteins. However, although NMD is functional in the patient's fibroblasts, aberrant transcripts are still present. We suggest that the level of correctly spliced transcripts as well as the efficiency in which NMD degrade the PTC-containing transcripts, apparently plays an important role in the phenotype severity of the unique patient and thus should be considered as a potential target for drug therapy.","variants":[{"Name":"NM_000520.6(HEXA):c.1305C>T (p.Tyr435=)","Chromosome":"15","Start":"72346552","Stop":"72346552","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":106594,"rule_based_match":true,"evidence_text":"c.1305C>T (p.=)","llm_judgment":"PRESENT","evidence":"c.1305C>T (p.=)","abstract_start":222,"abstract_end":237},{"Name":"NM_000520.6(HEXA):c.814G>A (p.Gly272Arg)","Chromosome":"15","Start":"72349251","Stop":"72349251","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2894933,"rule_based_match":true,"evidence_text":"c.814G>A (p.Gly272Arg)","llm_judgment":"PRESENT","evidence":"c.814G>A (p.Gly272Arg)","abstract_start":195,"abstract_end":217},{"Name":"NM_000520.6(HEXA):c.1195A>G (p.Asn399Asp)","Chromosome":"15","Start":"72346662","Stop":"72346662","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":99095,"rule_based_match":true,"evidence_text":"c.1195A>G (p.Asn399Asp)","llm_judgment":"PRESENT","evidence":"c.1195A>G (p.Asn399Asp)","abstract_start":307,"abstract_end":330}]}
{"pmid":"26173784","title":"Two Novel Heterozygous Mutations in ERCC8 Cause Cockayne Syndrome in a Chinese Patient.","abstract":"BACKGROUND: Cockayne syndrome (MIM #133540, Cockayne syndrome B; 216400, Cockayne syndrome A) is a rare autosomal recessive inherited disease in which the characteristic symptoms are premature aging, cachectic dwarfism, lack of subcutaneous fat, neurological alterations, light sensitivity, and failure to thrive. The mutated gene responsible for this syndrome has been identified as usually either CSA (CKN1, ERCC8) or CSB (ERCC6). In this study, we describe the case of a 7-year-old Chinese boy with characteristic symptoms of Cockayne syndrome A and the conduction of mutation screening of the CSA gene.\nMETHODS: The patient was diagnosed with Cockayne syndrome in the pediatrics clinic for growth failure and developmental delay. We collected peripheral blood samples of the patient and his parents and then extracted the genomic DNA. DNA samples from control subjects and the patient were subjected to polymerase chain reaction amplification. All exons and the flanking intron-exon boundaries of CSA were amplified; then, the polymerase chain reaction products were directly sequenced for mutation screening.\nRESULTS: Two novel heterozygous CSA mutations, c.551-2A>C and c.394_398delTTACA, were identified in the patient. The c.551-2A>C mutation originates from his father and changed the splice acceptor site AG to CG, thus possibly causing alternative splicing. The c.394_398delTTACA from his mother caused a frameshift after the amino acid at position 132, thus introducing a premature stop codon in the gene sequence.\nCONCLUSIONS: These mutations extend the mutation spectrum of Cockayne syndrome in the context of Chinese race and provide possibilities of prenatal diagnosis for future offsprings in this family.","variants":[{"Name":"NM_000082.4(ERCC8):c.394_398del (p.Leu132fs)","Chromosome":"5","Start":"60918266","Stop":"60918270","ReferenceAlleleVCF":"TTGTAA","AlternateAlleleVCF":"T","allel_id":543879,"rule_based_match":true,"evidence_text":"c.394_398delTTACA","llm_judgment":"PRESENT","evidence":"c.394_398delTTACA","abstract_start":1176,"abstract_end":1193}]}
{"pmid":"32174975","title":"","abstract":"The RNA polymerase II transcription subunit 12 homolog (<i>MED12</i>) is a member of the mediator complex, which plays a critical role in RNA transcription. Mutations in <i>MED12</i> cause X-linked intellectual disability and other anomalies collectively grouped as <i>MED12</i>-related disorders. While <i>MED12</i> mutations have been most commonly reported in male patients, we present the case of a 1-year-old girl with clinical characteristics similar to <i>MED12-</i>related disorders. To explore the clinical characteristics of the condition and its possible pathogenesis, we analyzed the patient's clinical data; genetic testing by whole-exome sequencing revealed a <i>de novo</i> heterozygous mutation (c.1249-1G > C) in <i>MED12</i>. Further cDNA experiments revealed that the patient had an abnormal splicing at the skipping of exon9, which may have produced a truncated protein. qPCR showed decreased <i>MED12</i> gene expression level in the patient, and an X-chromosome inactivation test confirmed a skewed inactivation of the X-chromosome. The lymphoblast transcription levels of the genes involved in the Gli3-dependent sonic hedgehog (SHH) signaling pathway, namely, <i>CREB5, BMP4</i>, and <i>NEUROG2</i>, were found to be significantly elevated compared with those of her parents and sex- and age-matched controls. Our results support the view that <i>MED12</i> mutations may dysregulate the SHH signaling pathway, which may have accounted for the aberrant craniofacial morphology of our patient.","variants":[{"Name":"NM_005120.3(MED12):c.1249-1G>C","Chromosome":"X","Start":"71122507","Stop":"71122507","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1200232,"rule_based_match":true,"evidence_text":"c.1249-1G > C","llm_judgment":"PRESENT","evidence":"c.1249-1G > C","abstract_start":712,"abstract_end":725}]}
{"pmid":"15278762","title":"Molecular genetic analyses of beta-thalassemia in South India reveals rare mutations in the beta-globin gene.","abstract":"beta-Thalassemia is the most prevalent single-gene disorder. Since no viable forms of treatment are available, the best course is prevention through prenatal diagnosis. In the present study, the prevalence of beta-thalassemia was extensively investigated in the South Indian population, especially from the state of Andhra Pradesh. Screening for causal mutations was carried out on genomic DNA isolated from patient blood samples by using the routine reverse dot blot (RDB) and amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) techniques. DNA sequencing was performed wherever necessary. Among the nine mutations identified, four, including IVS-1-5 (G-C) (IVS1+5G>T), codon 41/42 (-TTCT) (c.124_127delTTCT), codon 15 (G-A) (c.47G>A), and HbS (sickle mutation) (c.20A>T) mutations, accounted for about 98% of the total positive cases. Two mutations viz. codon 8/9 (+G) (c.27_28insG) and HbE (codon 26 G-A) (c.79G>A) exhibited a very low frequency of occurrence, whereas the IVS-1-1 (G-T) (IVS1+1G>T) and the 619 bp deletion (c.366_494del) mutations were absent. We also identified certain rare mutations during the diagnostic evaluation. Gene sequencing confirmed the codon 30 (G-C) (c.92G>C) mutation and the rare codon 5 (-CT) (c.17_18delCT) and IVS-II-837 (T-G) (IVSII-14T>G) mutations. This is the first report of the IVS II 837 mutation in the Indian population. We also report a novel diagnostic application during RDB-based screening for the detection of the (c.92G>C) mutations. Such a comprehensive mutation screening is essential for prenatal diagnosis of beta-thalassemia and control of this highly prevalent monogenic disorder in the Indian population.","variants":[{"Name":"NM_000518.4(HBB):c.92G>C (p.Arg31Thr)","Chromosome":"11","Start":"5226930","Stop":"5226930","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":30273,"rule_based_match":true,"evidence_text":"c.92G>C","llm_judgment":"PRESENT","evidence":"c.92G>C","abstract_start":1212,"abstract_end":1219},{"Name":"NM_000518.5(HBB):c.47G>A (p.Trp16Ter)","Chromosome":"11","Start":"5226975","Stop":"5226975","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30442,"rule_based_match":true,"evidence_text":"c.47G>A","llm_judgment":"PRESENT","evidence":"c.47G>A","abstract_start":753,"abstract_end":760},{"Name":"NM_000518.5(HBB):c.17_18del (p.Pro6fs)","Chromosome":"11","Start":"5227004","Stop":"5227005","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":30461,"rule_based_match":true,"evidence_text":"c.17_18delCT","llm_judgment":"PRESENT","evidence":"c.17_18delCT","abstract_start":1258,"abstract_end":1270}]}
{"pmid":"38387306","title":"The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.","abstract":"Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B<sub>12</sub> metabolism. In cblC, deficient activation of cobalamin results in methylcobalamin and adenosylcobalamin deficiency, elevating methylmalonic acid (MMA) and total plasma homocysteine (tHcy). We retrospectively reviewed the medical files of seven cblC patients: three compound heterozygotes for the MMACHC (NM_015506.3) missense variant c.158T>C p.(Leu53Pro) in trans with the common pathogenic mutation c.271dupA (p.(Arg91Lysfs*14), \"compounds\"), and four c.271dupA homozygotes (\"homozygotes\"). Compounds receiving hydroxocobalamin intramuscular injection monotherapy had age-appropriate psychomotor performance and normal ophthalmological examinations. In contrast, c.271dupA homozygotes showed marked psychomotor retardation, retinopathy and feeding problems despite penta-therapy (hydroxocobalamin, betaine, folinic acid, l-carnitine and acetylsalicylic acid). Pretreatment levels of plasma and urine MMA and tHcy were higher in c.271dupA homozygotes than in compounds. Under treatment, levels of the compounds approached or entered the reference range but not those of c.271dupA homozygotes (tHcy: compounds 9.8-32.9 μM, homozygotes 41.6-106.8 (normal (N) < 14); plasma MMA: compounds 0.14-0.81 μM, homozygotes, 10.4-61 (N < 0.4); urine MMA: compounds 1.75-48 mmol/mol creatinine, homozygotes 143-493 (N < 10)). Patient skin fibroblasts all had low cobalamin uptake, but this was milder in compound cells. Also, the distribution pattern of cobalamin species was qualitatively different between cells from compounds and from homozygotes. Compared to the classic cblC phenotype presented by c.271dupA homozygous patients, c.[158T>C];[271dupA] compounds had mild clinical and biochemical phenotypes and responded strikingly to hydroxocobalamin monotherapy.","variants":[{"Name":"NM_015506.3(MMACHC):c.158T>C (p.Leu53Pro)","Chromosome":"1","Start":"45507432","Stop":"45507432","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":486715,"rule_based_match":true,"evidence_text":"c.158T>C p.(Leu53Pro)","llm_judgment":"PRESENT","evidence":"c.158T>C p.(Leu53Pro)","abstract_start":454,"abstract_end":475}]}
{"pmid":"31160754","title":"Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.","abstract":"PURPOSE: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants.\nMETHODS: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed.\nRESULTS: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants.\nCONCLUSION: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.","variants":[{"Name":"NM_004004.6(GJB2):c.101T>C (p.Met34Thr)","Chromosome":"13","Start":"20189481","Stop":"20189481","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":32039,"rule_based_match":true,"evidence_text":"c.101T>C/p.Met34Thr","llm_judgment":"PRESENT","evidence":"c.101T>C/p.Met34Thr","abstract_start":136,"abstract_end":155},{"Name":"NM_004004.6(GJB2):c.109G>A (p.Val37Ile)","Chromosome":"13","Start":"20189473","Stop":"20189473","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32062,"rule_based_match":true,"evidence_text":"c.109G>A/p.Val37Ile","llm_judgment":"PRESENT","evidence":"c.109G>A/p.Val37Ile","abstract_start":160,"abstract_end":179}]}
{"pmid":"32607581","title":"A Heterozygous Mutation in the Filamin C Gene Causes an Unusual Nemaline Myopathy With Ring Fibers.","abstract":"Autosomal dominant pathogenic variants in the filamin C gene (FLNC) have been associated with myofibrillar myopathies, distal myopathies, and isolated cardiomyopathies. Mutations in different functional domains of FLNC can cause various clinical phenotypes. A novel heterozygous missense variant c.608G>A, p.(Cys203Tyr) in the actin binding domain of FLCN was found to cause an upper limb distal myopathy (MIM #614065). The muscle MRI findings are similar to those observed in FLNC-myofibrillar myopathy (MIM #609524). However, the muscle biopsy revealed >20% of muscle fibers with nemaline bodies, in addition to numerous ring fibers and a predominance of type 1 fibers. Overall, this case shows some unique and rare aspects of FLNC-myopathy constituting a new morphologic phenotype of FLNC-related myopathies.","variants":[{"Name":"NM_001458.5(FLNC):c.608G>A (p.Cys203Tyr)","Chromosome":"7","Start":"128837166","Stop":"128837166","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3392386,"rule_based_match":true,"evidence_text":"c.608G>A, p.(Cys203Tyr)","llm_judgment":"PRESENT","evidence":"c.608G>A, p.(Cys203Tyr)","abstract_start":296,"abstract_end":319}]}
{"pmid":"29653007","title":"Analysis of TGM1 gene mutation in a collodion baby","abstract":"OBJECTIVE: To explore the genetic cause for a Uyghur Chinese child with collodion skin.\nMETHODS: G-banded chromosomal karyotyping was carried out for the child and his parents. High-throughput sequencing for 25 genes related to ichthyosis and ichthyosiform dermatosis was also performed for the child.\nRESULTS: No karyotypic abnormality was found in the child and his parents. High-throughput sequencing has detected in the patient a previously described pathogenic mutation c.919C>T (p.Arg307Trp) and a novel c.856C>T (p.Arg286Trp) mutation in the TGM1 gene. By Sanger sequencing, the child was verified to have carried both mutations. His father was found to be a heterozygous carrier of the c.856C>T (p.Arg286Trp) mutation, while neither mutation was found in the mother.\nCONCLUSION: Congenital ichthyosis associated with the TGM1 gene may show an autosomal recessive inheritance. The collodion condition of the child is probably due to the compound heterozygous mutations of the TGM1 gene.","variants":[{"Name":"NM_000359.3(TGM1):c.856C>T (p.Arg286Trp)","Chromosome":"14","Start":"24259960","Stop":"24259960","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":622241,"rule_based_match":true,"evidence_text":"c.856C>T (p.Arg286Trp)","llm_judgment":"PRESENT","evidence":"c.856C>T (p.Arg286Trp)","abstract_start":510,"abstract_end":532}]}
{"pmid":"30139652","title":"Clinicopathologic Findings of CARS2 Mutation.","abstract":"OBJECTIVES: We describe a 13-year-old girl with a past medical history of epilepsy, intellectual impairment, dysphagia with gastric tube dependence, and autism spectrum disorder who presented with focal status epilepticus.\nMETHODS: Video-electroencephalography revealed left occipital pseudoperiodic epileptiform discharges and frequent seizures originating from the left hemisphere. The seizure was refractory to antiepileptic medications and pharmacologic coma. Subsequently, left occipital lobectomy was done. Extensive evaluation including whole exome sequencing, histopathologic examination of brain and muscle samples, mitochondrial DNA content analysis of tissue sample was completed to detect the etiology.\nRESULTS: Skeletal muscle mitochondrial DNA content (qPCR) analysis showed approximately 37% of the mean value of age and tissue matched control group consistent with a mitochondrial depletion syndrome. Microscopic examination of the brain showed cortical abnormalities that largely consisted of infarct-like pathology in a laminar manner, abnormalities of neuronal distribution, and white matter changes. Compound heterozygous mutations of the CARS2 gene were identified by whole exome sequencing; V52G variant [p.Val52Gly (GTG>GGG):c.155 T>G in exon 1] was inherited from the mother and T188M variant[p.Thr188Met (ACG>ATG): c.563 C>T in exon 5] was inherited from the father.\nCONCLUSION: This is the first detailed clinicopathologic description of the Alpers-Huttenlocher syndrome phenotype from CARS mutations.","variants":[{"Name":"NM_024537.4(CARS2):c.563C>T (p.Thr188Met)","Chromosome":"13","Start":"110687729","Stop":"110687729","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":463464,"rule_based_match":true,"evidence_text":"c.563 C>T in exon 5","llm_judgment":"PRESENT","evidence":"c.563 C>T in exon 5","abstract_start":1340,"abstract_end":1359},{"Name":"NM_024537.4(CARS2):c.155T>G (p.Val52Gly)","Chromosome":"13","Start":"110705939","Stop":"110705939","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":567184,"rule_based_match":true,"evidence_text":"c.155 T>G","llm_judgment":"PRESENT","evidence":"c.155 T>G","abstract_start":1248,"abstract_end":1257}]}
{"pmid":"34544473","title":"Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8.","abstract":"BACKGROUND: Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive metabolic disorder resulting from variants in ACAD8, and is poorly understood, as only dozens of cases have been reported previously. Based on a newborn screening program, we evaluated the incidence, phenotype and genotype of IBDD as well as the prognosis. Moreover, we reviewed the variant spectrum in ACAD8 associated with IBDD.\nMETHODS: Forty unrelated patients with IBDD were retrospectively screened for newborns between Jan 2012 and Dec 2020. Tandem mass spectrometry (MS/MS) was used to determine the concentrations of C4-acylcarnitine, C4/C2 (acetylcarnitine), and C4/C3 (propionylcarnitine). All suspected cases were genetically tested by metabolic genes panel.\nRESULTS: The incidence of IBDD here was 1: 62,599. All patients presented continuously elevated C4-acylcarnitine levels with higher ratios of C4/C2 and C4/C3. Isobutyrylglycine occurred in only 8 patients. During follow-up, four patients had a transient motor delay, and two patients had growth delay. Notably, one case harbored both ACAD8 compound heterozygous variants and a KMT2A de novo variant (c.2739del, p.E914Rfs*35), with IBDD and Wiedemann-Steiner syndrome together, had exact severe global developmental delay. All patients were regularly monitored once they were diagnosed, and each patient gradually had a normal diet after 6 months of age. After 3-108 months of follow-up, most individuals were healthy except the case harboring the KMT2A variant. A total of 16 novel variants in ACAD8, c.4_5delCT, c.109C > T, c.110-2A > T, c.236G > A, c.259G > A, c.381-14G > A, c.413delA, c.473A > G, c.500delG, c.758 T > G, c.842-1G > A, c.911A > T, c.989G > A, c.1150G > C, c.1157A > G and c.1165C > T, were identified. Along with a literature review on 51 ACAD8 variants in 81 IBDD patients, we found that the most common variant was c.286G > A (27.2%), which has been observed solely in the Chinese population to date, followed by c.1000C > T (8.6%), c.1176G > T (3.7%) and c.455 T > C (3.1%).\nCONCLUSION: The concentration of C4-acylcarnitine in NBS plus subsequent genetic testing is necessary for IBDD diagnosis. Both the genotypes and ACAD8 variants in IBDD are highly heterogeneous, and no significant correlations between genotype and phenotype are present here in patients with IBDD. Our IBDD cohort with detaied clinical characteristics, genotypes and long-term prognosis will be helpful for the diagnosis and management of patients with IBDD in the future.","variants":[{"Name":"NM_014384.3(ACAD8):c.473A>G (p.Tyr158Cys)","Chromosome":"11","Start":"134258607","Stop":"134258607","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":372293,"rule_based_match":true,"evidence_text":"c.473A > G","llm_judgment":"PRESENT","evidence":"c.473A > G","abstract_start":1649,"abstract_end":1659},{"Name":"NM_014384.3(ACAD8):c.758T>G (p.Val253Gly)","Chromosome":"11","Start":"134261096","Stop":"134261096","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3222025,"rule_based_match":true,"evidence_text":"c.758 T > G","llm_judgment":"PRESENT","evidence":"c.758 T > G","abstract_start":1672,"abstract_end":1683},{"Name":"NM_014384.3(ACAD8):c.989G>A (p.Arg330Gln)","Chromosome":"11","Start":"134261787","Stop":"134261787","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":935436,"rule_based_match":true,"evidence_text":"c.989G>A","llm_judgment":"PRESENT","evidence":"c.989G > A","abstract_start":1711,"abstract_end":1721}]}
{"pmid":"11748856","title":"Eight novel germline MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer families from Spain.","abstract":"Germline mutations in the MLH1 and MSH2 genes, account for the majority of HNPCC families. We have screened such families from Spain by using DGGE analysis and subsequent direct sequencing techniques. In eight families we identified six novel MLH1 and two novel MSH2 mutations comprising one frame shift mutation (c.1420 del C), two missense mutations (L622H and R687W), two splice site mutations (c.1990-1 G>A and c.453+2 T>C and one nonsense mutation (K329X) in the MLH1 gene as well as two frame shift mutations (c.1979-1980 del AT and c.1704-1705 del AG) in the MSH2 gene. Our analysis contributes to the further characterization of the mutational spectrum of MLH1 and MSH2 genes in HNPCC families.","variants":[{"Name":"NM_000249.4(MLH1):c.1990-1G>A","Chromosome":"3","Start":"37048903","Stop":"37048903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":95459,"rule_based_match":true,"evidence_text":"c.1990-1 G>A","llm_judgment":"PRESENT","evidence":"c.1990-1 G>A","abstract_start":398,"abstract_end":410}]}
{"pmid":"34137732","title":"25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.","abstract":"Vitamin D deficiency remains a major cause of rickets worldwide. Nutritional factors are the major cause and less commonly, inheritance causes. Recently, CYP2R1 has been reported as a major factor for 25-hydroxylation contributing to the inherited forms of vitamin D deficiency. We conducted a prospective cohort study at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, to review cases with 25-hydroxylase deficiency and describe their clinical, biochemical, and molecular genetic features. We analyzed 27 patients from nine different families who presented with low 25-OH vitamin D and not responding to usual treatment. Genetic testing identified two mutations: c.367+1G>A (12/27 patients) and c.768dupT (15/27 patients), where 18 patients were homozygous for their identified mutation and 9 patients were heterozygous. Both groups had similar clinical manifestations ranging in severity, but none of the patients with the heterozygous mutation had hypocalcemic manifestations. Thirteen out of 18 homozygous patients and all the heterozygous patients responded to high doses of vitamin D treatment, but they regressed after decreasing the dose, requiring lifelong therapy. Five out of 18 homozygous patients required calcitriol to improve their biochemical data, whereas none of the heterozygous patients and patients who carried the c.367+1G>A mutation required calcitriol treatment. To date, this is the largest cohort series analyzing CYP2R1-related 25-hydroxylase deficiency worldwide, supporting its major role in 25-hydroxylation of vitamin D. It is suggested that a higher percentage of CYP2R1 mutations might be found in the Saudi population. We believe that our study will help in the diagnosis, treatment, and prevention of similar cases in the future.","variants":[{"Name":"NM_024514.5(CYP2R1):c.367+1G>A","Chromosome":"11","Start":"14885775","Stop":"14885775","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":965315,"rule_based_match":true,"evidence_text":"c.367+1G>A","llm_judgment":"PRESENT","evidence":"c.367+1G>A","abstract_start":689,"abstract_end":699}]}
{"pmid":"28123174","title":"New diagnosis of atypical ataxia-telangiectasia in a 17-year-old boy with T-cell acute lymphoblastic leukemia and a novel ATM mutation.","abstract":"Ataxia-telangiectasia (A-T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM gene. Typically, it presents in early childhood with progressive cerebellar dysfunction along with immunodeficiency and oculocutaneous telangiectasia. An increased risk of malignancy is also associated with the syndrome and, rarely, may be the presenting feature in small children. We describe a 17-year-old boy with slurred speech, mild motor delays and learning disability diagnosed with atypical A-T in the setting of T-cell acute lymphoblastic leukemia. Suspicion for A-T was raised after review of a peripheral blood karyotype demonstrating rearrangements involving chromosomes 7 and/or 14. The diagnosis was confirmed after molecular testing identified a novel homozygous missense variant in ATM (c.5585T>A; p.Leu1862His) that resulted in protein instability and abolished serine/threonine protein kinase activity. To our knowledge, this is the first report of concurrent A-T and lymphoid malignancy diagnoses in an older child or adult with only mild neurological disease. Our experience suggests that screening for the disorder should be considered in any individual with lymphoid malignancy and neurological findings, especially as radiation and certain chemotherapy protocols are contraindicated in A-T.","variants":[{"Name":"NM_000051.4(ATM):c.5585T>A (p.Leu1862His)","Chromosome":"11","Start":"108304763","Stop":"108304763","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":475713,"rule_based_match":true,"evidence_text":"c.5585T>A (p.Leu1862His)","llm_judgment":"PRESENT","evidence":"p.Leu1862His","abstract_start":828,"abstract_end":840}]}
{"pmid":"22569581","title":"Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients.","abstract":"Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures. The long-term follow-up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow-up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A, the c.734G>A/p.R245Q and the c.1406G>A/p.R469H in family B, and the c.721T>A/p.W241R and c.35A>G/p.Q12R in family C. Functional complementation studies in Saccharomyces cerevisiae showed that mutation MSR1-R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1-R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non-fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for RARS2 mutations considering that biochemical abnormalities may be absent in muscle biopsy.","variants":[{"Name":"NM_020320.5(RARS2):c.25A>G (p.Ile9Val)","Chromosome":"6","Start":"87589933","Stop":"87589933","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1863273,"rule_based_match":true,"evidence_text":"c.25A>G/p.I9V","llm_judgment":"PRESENT","evidence":"c.25A>G/p.I9V","abstract_start":1168,"abstract_end":1181},{"Name":"NM_020320.5(RARS2):c.734G>A (p.Arg245Gln)","Chromosome":"6","Start":"87530821","Stop":"87530821","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1867918,"rule_based_match":true,"evidence_text":"c.734G>A/p.R245Q","llm_judgment":"PRESENT","evidence":"c.734G>A/p.R245Q","abstract_start":1219,"abstract_end":1235},{"Name":"NM_020320.5(RARS2):c.1406G>A (p.Arg469His)","Chromosome":"6","Start":"87518639","Stop":"87518639","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":609634,"rule_based_match":true,"evidence_text":"c.1406G>A/p.R469H","llm_judgment":"PRESENT","evidence":"c.1406G>A/p.R469H","abstract_start":1244,"abstract_end":1261},{"Name":"NM_020320.5(RARS2):c.35A>G (p.Gln12Arg)","Chromosome":"6","Start":"87589923","Stop":"87589923","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39869,"rule_based_match":true,"evidence_text":"c.35A>G/p.Q12R","llm_judgment":"PRESENT","evidence":"c.35A>G/p.Q12R","abstract_start":1304,"abstract_end":1318}]}
{"pmid":"18205192","title":"The MLH1 variants p.Arg265Cys and p.Lys618Ala affect protein stability while p.Leu749Gln affects heterodimer formation.","abstract":"Germline mutations in the mismatch repair genes lead to the Lynch syndrome/ HNPCC, and genetic testing is offered to identify individuals at risk of developing this disease. About a third of all genetic alterations detected in the mismatch repair gene MutL homolog 1 (MLH1) are missense variants. The majority of these variants are of equivocal clinical significance. In this report, we investigate the molecular basis of the pathogenicity of three missense variants localized to distinct functional domains. Our results demonstrate that the MLH1 variants p.Arg265Cys (c.793C>T) and p.Lys618Ala (c.1852_1853AA>GC) significantly decrease the stability of the protein, while another missense variant p.Leu749Gln (c.2246T>A) is able to compromise heterodimerization of the MLH1-PMS2 complex.","variants":[{"Name":"NM_000249.4(MLH1):c.1852_1853delinsGC (p.Lys618Ala)","Chromosome":"3","Start":"37047639","Stop":"37047640","ReferenceAlleleVCF":"AA","AlternateAlleleVCF":"GC","allel_id":32128,"rule_based_match":false,"evidence_text":"c.1852_1853AA>GC","llm_judgment":"PRESENT","evidence":"c.1852_1853AA>GC","abstract_start":596,"abstract_end":612},{"Name":"NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)","Chromosome":"3","Start":"37017508","Stop":"37017508","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38609,"rule_based_match":true,"evidence_text":"c.793C>T","llm_judgment":"PRESENT","evidence":"c.793C>T","abstract_start":569,"abstract_end":577}]}
{"pmid":"24115387","title":"Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India.","abstract":"We report a novel missense mutation (c.1040G>A, p.Arg347Gln) in MID2, which encodes ubiquitin ligase E3, as the likely cause of X-linked mental retardation in a large kindred. The mutation was observed in all affected and obligate carriers but not in any unaffected males of the family or in population controls (n = 200). When transiently expressed in HEK293T cell line, the mutation was found to abolish the function of the COS domain in the protein. The GFP-tagged mutant protein accumulated in the cytoplasm instead of binding to the cytoskeleton resulting in its altered subcellular localization. Screening of coding exons of this gene in additional 480 unrelated individuals with idiopathic intellectual disability identified another novel variation p.Asn343Ser. This study highlights the growing role of the ubiquitin pathway in intellectual disability and also, the difference in MID2 determined phenotype observed in this study compared with that of its paralogue MID1 reported in literature.","variants":[{"Name":"NM_012216.4(MID2):c.1040G>A (p.Arg347Gln)","Chromosome":"X","Start":"107905593","Stop":"107905593","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":153582,"rule_based_match":true,"evidence_text":"c.1040G>A, p.Arg347Gln","llm_judgment":"PRESENT","evidence":"c.1040G>A, p.Arg347Gln","abstract_start":37,"abstract_end":59}]}
{"pmid":"31491741","title":"Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients.","abstract":"BACKGROUND AND AIMS: More than 4970 variants in the low-density lipoprotein receptor (LDLR) gene and 350 variants in the proprotein convertase subtilisin/kexin 9 (PCSK9) gene have been reported in familial hypercholesterolemia (FH) patients. However, the effects of these variants on FH pathophysiology have not been fully clarified. We aimed to update the LDLR and PCSK9 variants in Japanese heterozygous FH (HeFH) patients and annotate their clinical significance for the genetic diagnosis of HeFH.\nMETHODS: A genetic analysis of the LDLR and PCSK9 genes was performed in 801 clinically diagnosed HeFH patients. The association of the pathogenic variants with the clinical FH phenotype was examined.\nRESULTS: Pathogenic variants in the LDLR and PCSK9 genes were found in 46% (n = 296) and 7.8% (n = 51) of unrelated FH patients (n = 650), respectively. The prevalence of Achilles tendon thickness was low (44%) in patients harbouring PCSK9 pathogenic variants. Furthermore, 17% of unrelated FH patients harboured one of five frequent LDLR pathogenic variants: c.1845+2T > C, c.1012T > A: p.(Cys338Ser), c.1297G > C: p.(Asp433His), c.1702C > G: p.(Leu568Val), and c.2431A > T: p.(Lys811*). Patients harbouring the c.1845+2T > C and c.1702C > G: p.(Leu568Val) variants had significantly lower serum LDL-cholesterol levels and higher serum HDL-cholesterol levels, respectively, compared with those harbouring the other LDLR pathogenic variants. The proportion of LDLR pathogenic variants was higher in patients with a younger age of coronary artery disease (CAD) onset and significantly decreased as the age of CAD onset increased.\nCONCLUSIONS: This study annotated the clinical significance and characteristics of LDLR and PCSK9 pathogenic variants in Japanese HeFH patients.","variants":[{"Name":"NM_000527.5(LDLR):c.1702C>G (p.Leu568Val)","Chromosome":"19","Start":"11116209","Stop":"11116209","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":246280,"rule_based_match":true,"evidence_text":"c.1702C>G: p.(Leu568Val)","llm_judgment":"PRESENT","evidence":"c.1702C > G: p.(Leu568Val)","abstract_start":1133,"abstract_end":1159},{"Name":"NM_000527.5(LDLR):c.1297G>C (p.Asp433His)","Chromosome":"19","Start":"11113388","Stop":"11113388","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":18771,"rule_based_match":true,"evidence_text":"c.1297G > C: p.(Asp433His)","llm_judgment":"PRESENT","evidence":"c.1297G > C: p.(Asp433His)","abstract_start":1105,"abstract_end":1131},{"Name":"NM_000527.5(LDLR):c.1845+2T>C","Chromosome":"19","Start":"11117000","Stop":"11117000","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":246371,"rule_based_match":true,"evidence_text":"c.1845+2T>C","llm_judgment":"PRESENT","evidence":"c.1845+2T > C","abstract_start":1062,"abstract_end":1075}]}
{"pmid":"22140057","title":"Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations.","abstract":"We report on a boy born to consanguineous parents, who had hypertelorism, a broad nasal bridge, ridge and tip, bifid nasal tip, cleft alae nasi, broad columella, unilateral preauricular tag, shallow labiogingival sulcus, and bilateral large parietal foramina. Cranial MRI revealed a kinked corpus body and small cerebellar vermis. Molecular analysis uncovered a homozygous c.673C > G (p.Q225E) mutation in ALX4 gene. We compare the relatively mild phenotype in the patient to the more marked phenotype described in other patients with homozygous ALX4 mutations, and to the phenotypes in patients with mutations in other ALX genes.","variants":[{"Name":"NM_021926.4(ALX4):c.673C>G (p.Gln225Glu)","Chromosome":"11","Start":"44275452","Stop":"44275452","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":165648,"rule_based_match":true,"evidence_text":"c.673C > G (p.Q225E)","llm_judgment":"PRESENT","evidence":"c.673C > G (p.Q225E)","abstract_start":373,"abstract_end":393}]}
{"pmid":"21990180","title":"Functional characterization of splicing and ligand-binding domain variants in the LDL receptor.","abstract":"Familial hypercholesterolemia (FH) is an autosomal dominant disorder mostly caused by mutations in the LDLR gene. Although the detection of functional mutations in the LDLR gene provides an unequivocal diagnosis of the FH condition, there are many variants whose pathogenicity is still unknown. The aims of this study were to set up a rapid method to determine the effect of LDLR mutations, thereby providing an accurate diagnosis of FH, and to functionally characterize six LDLR mutations detected at high frequency by the LIPOchip(®) platform (Progenika Biopharma, Spain) in the Spanish population. LDLR expression and activity were analyzed by one-single-step flow cytometry assay and confocal microscopy. Splicing effects were determined by sequencing reverse transcription polymerase chain reaction products. The analysis of three heterozygous variants with a single point mutation within the low-density lipoprotein binding domain allowed us to classify the c.806G>A variant as nonpathogenic, and c.862G>A and c.895G>A variants as causative of FH. The results obtained for three variants affecting donor splice sites of the LDLR mRNA, c.313+2dupT, c.1186+5G>A, and c.1845+1G>C, demonstrated that these mutations are pathogenic. These results expand our knowledge of mutations responsible for FH, providing an accurate diagnosis and leading to early treatment to reduce the risk of premature cardiovascular events.","variants":[{"Name":"NM_000527.5(LDLR):c.1845+1G>C","Chromosome":"19","Start":"11116999","Stop":"11116999","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":246368,"rule_based_match":true,"evidence_text":"c.1845+1G>C","llm_judgment":"PRESENT","evidence":"c.1845+1G>C","abstract_start":1171,"abstract_end":1182},{"Name":"NM_000527.5(LDLR):c.806G>A (p.Gly269Asp)","Chromosome":"19","Start":"11106676","Stop":"11106676","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171202,"rule_based_match":true,"evidence_text":"c.806G>A","llm_judgment":"PRESENT","evidence":"c.806G>A","abstract_start":964,"abstract_end":972},{"Name":"NM_000527.5(LDLR):c.862G>A (p.Glu288Lys)","Chromosome":"19","Start":"11107436","Stop":"11107436","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171204,"rule_based_match":true,"evidence_text":"c.862G>A","llm_judgment":"PRESENT","evidence":"c.862G>A","abstract_start":1003,"abstract_end":1011},{"Name":"NM_000527.5(LDLR):c.1186+5G>A","Chromosome":"19","Start":"11111644","Stop":"11111644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":246029,"rule_based_match":true,"evidence_text":"c.1186+5G>A","llm_judgment":"PRESENT","evidence":"c.1186+5G>A","abstract_start":1154,"abstract_end":1165},{"Name":"NM_000527.5(LDLR):c.895G>A (p.Ala299Thr)","Chromosome":"19","Start":"11107469","Stop":"11107469","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":245840,"rule_based_match":true,"evidence_text":"c.895G>A","llm_judgment":"PRESENT","evidence":"c.895G>A","abstract_start":1016,"abstract_end":1024}]}
{"pmid":"24256046","title":"Prevalence of GJB2 mutations in the Silk Road region of China and a report of three novel variants.","abstract":"CONCLUSION: The c.235delC of GJB2 gene is the hotspot mutation of the hearing loss population in the Silk Road region of China. It is high time that some active interventions (such as hearing aids or cochlear implant) are provided to improve their language ability and quality of life.\nOBJECTIVES: The first gene to be identified for humans with nonsyndromic hearing loss was GJB2 gene. We investigated the prevalence of GJB2 mutations in the Silk Road region of China to study the mutation spectrum in this area.\nMETHODS: Bidirectional sequencing was carried out for all PCR products of samples. The statistical analysis was carried out using SAS 9.0.1 software.\nRESULTS: Pathogenic mutations were identified in 243 of 2398 patients, including 168 homozygous mutations and 75 compound heterozygous mutations. Three variants (c.225G>T, c.521G>A, and c.557C>T) are novel mutations.","variants":[{"Name":"NM_004004.6(GJB2):c.557C>T (p.Thr186Met)","Chromosome":"13","Start":"20189025","Stop":"20189025","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":870839,"rule_based_match":true,"evidence_text":"c.557C>T","llm_judgment":"PRESENT","evidence":"c.557C>T","abstract_start":850,"abstract_end":858}]}
{"pmid":"33191723","title":"Congenital chloride diarrhea in patient with SLC26A2 mutation - analysis of the clinical phenotype and differential diagnosis.","abstract":"INTRODUCTION: To analyze the clinical features and SLC26A3 mutation of one patient in our hospital who had congenital loss of chlorine diarrhea (CLD), and to investigate the treatment of the disease and the prognosis.\nMATERIAL AND METHODS: By reviewing the literature, analyzing the clinical features and differential diagnosis and investigating the treatment and prognosis, the patient was diagnosed as CLD.\nRESULTS: Excessive accumulation of amniotic fluid was observed during pregnancy. The patient was born prematurely with normal body weight. The patient was a 4-month old boy admitted for anorexia, watery diarrhea, electrolyte disorders (hyponatremia, hypokalemia and hypochloremia) and metabolic alkalosis. The patient was also considered to be affected by Batter syndrome. After treating with spironolactone, indomethacin and potassium chloride sustained release tablet, the symptom of watery diarrhea was alleviated, the ingested amount of milk increased gradually and the amount of urine became normal; however, electrolyte imbalance persisted and the frequency of bowel movements remained high. Genetic analysis demonstrated that the patient had a SLC26A3 c.269_270dupAA homozygous mutation in exon 3, leading to a frameshift from 91st amino acid Gly and alteration of the SLC26A3 transmembrane protein sequence, thus resulting in a Cl-/HCO3- exchange barrier. The parents of the patient had normal phenotypes and were all heterozygous carriers of the mutation. Moreover, the patient was diagnosed as CLD. Sodium chloride and potassium chloride rather than spironolactone and indomenthacin were given to the patient to correct the dehydration, so the symptom of watery diarrhea alleviated and the blood gas and electrolyte levels returned to the normal range. In addition, the patients morale was good and the ingested amount of milk was moderate.\nCONCLUSIONS: Persistent diarrhea and electrolyte disorder in pediatrics are easy to misdiagnose as CLD. Furthermore, it is difficult to identify Batter syndrome, Gitelman syndrome, renal tubular acidosis and CLD. Blood and stool electrolyte detection and SLC26A3 genetic tests are helpful for diagnosis, and sodium chloride and potassium chloride replacement therapy are critical for the patient prognosis.","variants":[{"Name":"NM_000111.3(SLC26A3):c.269_270dup (p.Gly91fs)","Chromosome":"7","Start":"107793742","Stop":"107793743","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CTT","allel_id":70633,"rule_based_match":true,"evidence_text":"SLC26A3 c.269_270dupAA","llm_judgment":"PRESENT","evidence":"SLC26A3 c.269_270dupAA","abstract_start":1160,"abstract_end":1182}]}
{"pmid":"26522270","title":"NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment.","abstract":"We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family's disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT.","variants":[{"Name":"NM_003491.4(NAA10):c.128A>C (p.Tyr43Ser)","Chromosome":"X","Start":"153933994","Stop":"153933994","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":214759,"rule_based_match":true,"evidence_text":"c.128 A > C; p.Tyr43Ser","llm_judgment":"PRESENT","evidence":"c.128 A > C; p.Tyr43Ser","abstract_start":331,"abstract_end":354}]}
{"pmid":"29872333","title":"Achondrogenesis type 1A: clinical, histologic, molecular, and prenatal ultrasound diagnosis.","abstract":"BACKGROUND: Achondrogenesis type IA (ACG1A) is a rare, lethal autosomal recessive chondrodysplasia affecting endochondral bone ossification and differentiation, causing intrauterine growth restriction, narrow thorax, and short limbs. Mutations in <i>TRIP11</i>, which encodes Golgi microtubule-binding protein 210 in the Golgi apparatus, alter protein transport in tissues.\nCASE PRESENTATION: A 28-week gestation male fetus was diagnosed with ACG1A by clinical, radiological, histologic, and molecular findings.\nRESULTS: Whole exome sequencing was performed on fetal DNA and parental blood. Two fetal heterozygous novel variants of <i>TRIP11</i>, c.2304_2307delTCAA (p.Asn768Lysfs*7) and c.2128_2129delAT (p.lle710Cysfs*19), were inherited from the mother and father, respectively. Both variants created a reading frameshift leading to a premature stop codon and loss of protein function.\nCONCLUSION: To our knowledge, this is the first Latin American report with clinical, radiographic, and molecular diagnosis of ACG1A. Clinical and molecular diagnosis in utero is essential for genotype-phenotype correlation and is useful for providing better genetic counseling.","variants":[{"Name":"NM_004239.4(TRIP11):c.2128_2129del (p.Ile710fs)","Chromosome":"14","Start":"92005847","Stop":"92005848","ReferenceAlleleVCF":"AAT","AlternateAlleleVCF":"A","allel_id":610508,"rule_based_match":true,"evidence_text":"c.2128_2129delAT (p.lle710Cysfs*19)","llm_judgment":"PRESENT","evidence":"c.2128_2129delAT (p.lle710Cysfs*19)","abstract_start":688,"abstract_end":723},{"Name":"NM_004239.4(TRIP11):c.2304_2307del (p.Asn768fs)","Chromosome":"14","Start":"92005669","Stop":"92005672","ReferenceAlleleVCF":"TTTGA","AlternateAlleleVCF":"T","allel_id":610510,"rule_based_match":true,"evidence_text":"c.2304_2307delTCAA (p.Asn768Lysfs*7)","llm_judgment":"PRESENT","evidence":"c.2304_2307delTCAA (p.Asn768Lysfs*7)","abstract_start":647,"abstract_end":683}]}
{"pmid":"24222232","title":"RUNX2 mutations in cleidocranial dysplasia.","abstract":"The runt-related transcription factor 2 gene (RUNX2), which is also known as CBFA1, is a master regulatory gene in bone formation. Mutations in RUNX2 have been identified in cleidocranial dysplasia (CCD) patients. CCD is a rare autosomal dominant skeletal dysplasia that is characterized by delayed closure of cranial sutures, aplastic or hypoplastic clavicle formation, short stature, and dental anomalies, including malocclusion, supernumerary teeth, and delayed eruption of permanent teeth. In this study, we recruited three de novo CCD families and performed mutational analysis of the RUNX2 gene as a candidate gene approach. The mutational study revealed three disease-causing mutations: a missense mutation (c.674G>A, p.Arg225Gln), a frameshift mutation (c.1119delC, p.Arg374Glyfs*), and a nonsense mutation (c.1171C>T, p.Arg391*). Clinical examination revealed a unique dental phenotype (no typical supernumerary teeth, but duplication of anterior teeth) in one patient. We believe that this finding will broaden the understanding of the mechanism of supernumerary teeth formation and CCD-related phenotypes.","variants":[{"Name":"NM_001024630.4(RUNX2):c.1171C>T (p.Arg391Ter)","Chromosome":"6","Start":"45546910","Stop":"45546910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76533,"rule_based_match":true,"evidence_text":"c.1171C>T (p.Arg391*)","llm_judgment":"PRESENT","evidence":"c.1171C>T","abstract_start":816,"abstract_end":825},{"Name":"NM_001024630.4(RUNX2):c.674G>A (p.Arg225Gln)","Chromosome":"6","Start":"45438040","Stop":"45438040","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24341,"rule_based_match":true,"evidence_text":"c.674G>A (p.Arg225Gln)","llm_judgment":"PRESENT","evidence":"p.Arg225Gln","abstract_start":725,"abstract_end":736}]}
{"pmid":"25820994","title":"Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe).","abstract":"Fundus albipunctatus (FA) is a rare, congenital form of night blindness with rod system impairment, characterised by the presence of numerous small, white-yellow retinal lesions. FA belongs to a heterogenous group of so-called flecked retina syndromes. This disorder shows autosomal recessive inheritance and is caused mostly by mutations in the RDH5 gene. This gene encodes the enzyme that is a part of the visual cycle, the 11-cis retinol dehydrogenase. This study is a brief review of the literature on FA and a report of the first molecular evidence for RDH5 gene mutation in a Polish patient with this rare disorder. We present a novel pathogenic RDH5 gene mutation in a 16-year-old female patient with symptoms of night blindness. The patient underwent ophthalmological examinations, including colour vision testing, fundus photography, automated visual field testing, full-field electroretinography (ERG) and spectral optical coherent tomography (SOCT). The patient showed typical FA ERG records, the visual field was constricted and fundus examination revealed numerous characteristic, small, white-yellowish retinal lesions. DNA sequencing of the RDH5 gene coding sequence (exons 2-5) enabled the detection of the homozygous missense substitution c.524A > T (p.Tyr175Phe) in exon 3. This is the first report of RDH5 gene mutation that affects the invariant tyrosine, one of the most conserved amino acid residues in short-chain alcohol dehydrogenases/reductases (SDRs), crucial for these enzymes' activity. The location of this substitution, together with its predicted influence on the protein function, indicate that the p.Tyr175Phe mutation is the cause of FA in our patient.","variants":[{"Name":"NM_002905.5(RDH5):c.524A>T (p.Tyr175Phe)","Chromosome":"12","Start":"55721902","Stop":"55721902","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1416577,"rule_based_match":true,"evidence_text":"c.524A > T (p.Tyr175Phe)","llm_judgment":"PRESENT","evidence":"c.524A > T (p.Tyr175Phe)","abstract_start":1256,"abstract_end":1280}]}
{"pmid":"24498484","title":"Congenital Adrenal Hyperplasia due to 17-alpha-hydoxylase/17,20-lyase Deficiency Presenting with Hypertension and Pseudohermaphroditism: First Case Report from Oman.","abstract":"This is the first report of congenital adrenal hyperplasia (CAH) due to combined 17α-hydroxylase/17,20 lyase deficiency in an Omani patient who was initially treated for many years as a case of hypertension. CAH is an uncommon disorder that results from a defect in steroid hormones biosynthesis in the adrenal cortex. The clinical presentation depends on the site of enzymatic mutations and the types of accumulated steroid precursors. A 22-year-old woman who was diagnosed to have hypertension since the age of 10 years who was treated with anti-hypertensive therapy was referred to the National Diabetes and Endocrine Centre, Royal Hospital, Oman. The patient also had primary amenorrhea and features of sexual infantilism. Full laboratory and radio-imaging investigations were done. Adrenal steroids, pituitary function and karyotyping study were performed and the diagnosis was confirmed by molecular mutation study. Laboratory investigations revealed adrenal steroids and pituitary hormones profile in addition to 46XY karyotype that are consistent with the diagnosis of CAH due to 17α-hydroxylase deficiency. Extensive laboratory workup revealed low levels of serum cortisol (and its precursors 17α-hydroxyprogesterone and 11-deoxycortisol), adrenal androgens (dehydroepiandrosterone sulfate and androstenedione), and estrogen (estradiol); and high levels of mineralocorticoids precursors (11-deoxycorticosterone and corticosterone) with high levels of ACTH, FSH and LH. Mutation analysis revealed CYP17A1-homozygous mutation (c.287G>A p.Arg96Gln) resulting in the complete absence of 17α-hydroxylase/17,20-lyase activity. The patient was treated with dexamethasone and ethinyl estradiol with cessation of anti-hypertensive therapy. A review of the literature was conducted to identify previous studies related to this subtype of CAH. This is the first biochemically and genetically proven case of CAH due to 17α-hydroxylase/17,20-lyase deficiency in Oman and in the Arab World described in the literature.","variants":[{"Name":"NM_000102.4(CYP17A1):c.287G>A (p.Arg96Gln)","Chromosome":"10","Start":"102837075","Stop":"102837075","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16841,"rule_based_match":true,"evidence_text":"c.287G>A p.Arg96Gln","llm_judgment":"PRESENT","evidence":"c.287G>A p.Arg96Gln","abstract_start":1534,"abstract_end":1553}]}
{"pmid":"22145566","title":"Hb H disease with various β hemoglobinopathies: molecular, hematological and diagnostic aspects.","abstract":"We report the molecular, hematological and diagnostic features of three Thai patients with Hb H (β4) disease in combination with different β hemoglobinopathies. The first case was a boy with a hitherto undescribed condition of Hb H-Hb Tak (HBB:c.441_442insAC) syndrome. The second case was an adult male with the Hb H-Hb Hope (HBB:c.410G>A) disease. The last case was a male patient with a combination of Hb H-Hb Constant Spring (Hb CS) (HBA2:c.427T>C) and a high Hbs A(2)/F β(0)-thalassemia (β-thal) trait (the 3.4 kb deletion). In all cases, no Hb H was detected and Hb H inclusion was absent, accurate diagnosis could be obtained after DNA analysis. All of them had mild hypochromic microcytic anemia with hemoglobin (Hb) values ranging from 8.8-10.4 g/dL, PCV 0.31-0.36 L/L and MCV 57.6-66.9 fL and none had ever received a blood transfusion. The levels of Hb Tak (7.8%) and Hb Hope (21.6%), respectively, observed in the first two cases were relatively lower than values found in heterozygotes for these two variants. In the last case, the level of Hb A(2) (4.8%) was within the diagnostic range for a β-thal trait. The Hb F level was not elevated but a small amount of Hb Bart's was observed. Hematological findings and diagnostics using combined Hb and polymerase chain reaction (PCR) analyses are presented and compared with those of the other Thai patients with Hb H-β(0)-thal, Hb H-Hb CS-Hb J-Bangkok (HBB:c.170G>A) and Hb H-Hb CS-Hb Pyrgos (HBB:c.251G>A) previously observed in our series.","variants":[{"Name":"NM_000518.4(HBB):c.410G>A (p.Gly137Asp)","Chromosome":"11","Start":"5225632","Stop":"5225632","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30241,"rule_based_match":true,"evidence_text":"HBB:c.410G>A","llm_judgment":"PRESENT","evidence":"HBB:c.410G>A","abstract_start":327,"abstract_end":339}]}
{"pmid":"28222800","title":"Exome sequencing identifies SLC26A4, GJB2, SCARB2 and DUOX2 mutations in 2 siblings with Pendred syndrome in a Malaysian family.","abstract":"BACKGROUND: Pendred syndrome (PDS, MIM #274600) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss and goiter. In this study, we describing the possible PDS causal mutations in a Malaysian family with 2 daughters diagnosed with bilateral hearing loss and hypothyroidism.\nMETHODS AND RESULTS: Whole exome sequencing was performed on 2 sisters with PDS and their unaffected parents. Our results showed that both sisters inherited monoallelic mutations in the 2 known PDS genes, SLC26A4 (ENST00000265715:c.1343C > T, p.Ser448Leu) and GJB2 (ENST00000382844:c.368C > A, p.Thr123Asn) from their father, as well as another deafness-related gene, SCARB2 (ENST00000264896:c.914C > T, p.Thr305Met) from their mother. We postulated that these three heterozygous mutations in combination may be causative to deafness, and warrants further investigation. Furthermore, we also identified a compound heterozygosity involving the DUOX2 gene (ENST00000603300:c.1588A > T:p.Lys530* and c.3329G > A:p.Arg1110Gln) in both sisters which are inherited from both parents and may be correlated with early onset of goiter. All the candidate mutations were predicted deleterious by in silico tools.\nCONCLUSIONS: In summary, we proposed that PDS in this family could be a polygenic disorder which possibly arises from a combination of heterozygous mutations in SLC26A4, GJB2 and SCARB2 which associated with deafness, as well as compound heterozygous DUOX2 mutations which associated with thyroid dysfunction.","variants":[{"Name":"NM_005506.4(SCARB2):c.914C>T (p.Thr305Met)","Chromosome":"4","Start":"76174224","Stop":"76174224","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":579112,"rule_based_match":true,"evidence_text":"SCARB2 (ENST00000264896:c.914C > T, p.Thr305Met)","llm_judgment":"PRESENT","evidence":"SCARB2 (ENST00000264896:c.914C > T, p.Thr305Met)","abstract_start":678,"abstract_end":726},{"Name":"NM_004004.6(GJB2):c.368C>A (p.Thr123Asn)","Chromosome":"13","Start":"20189214","Stop":"20189214","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":53910,"rule_based_match":true,"evidence_text":"c.368C > A, p.Thr123Asn","llm_judgment":"PRESENT","evidence":"c.368C > A, p.Thr123Asn","abstract_start":592,"abstract_end":615}]}
{"pmid":"32398771","title":"Alternative mRNA splicing can attenuate the pathogenicity of presumed loss-of-function variants in BRCA2.","abstract":"PURPOSE: Current interpretation guidelines for germline variants in high-risk cancer susceptibility genes consider predicted loss-of-function (LoF) variants, such as nonsense variants and variants in the canonical splice site sequences ofBRCA2, to be associated with high cancer risk. However, some variant alleles produce alternative transcripts that encode (partially) functional protein isoforms leading to possible incorrect risk estimations. For accurate classification of variants it is therefore essential that alternative transcripts are identified and functionally characterized.\nMETHODS: We systematically evaluated a large panel of human BRCA2 variants for the production of alternative transcripts and assessed their capacity to exert BRCA2 protein functionality. Evaluated variants included all single-exon deletions, various multiple-exon deletions, intronic variants at the canonical splice donor and acceptor sequences, and variants that previously have been shown to affect messenger RNA (mRNA) splicing in carriers.\nRESULTS: Multiple alternative transcripts encoding (partially) functional protein isoforms were identified (e.g., ∆[E4-E7], ∆[E6-E7], ∆E[6q39_E8], ∆[E10], ∆[E12], ∆E[12-14]). Expression of these transcripts did attenuate the impact of predicted LoF variants such as the canonical splice site variants c.631+2T>G, c.517-2A>G, c.6842-2A>G, c.6937+1G>A, and nonsense variants c.491T>A, c.581G>A, and c.6901G>T.\nCONCLUSION: These results allow refinement of variant interpretation guidelines for BRCA2 by providing insight into the functional consequences of naturally occurring and variant-related alternative splicing events.","variants":[{"Name":"NM_000059.4(BRCA2):c.517-2A>G","Chromosome":"13","Start":"32326497","Stop":"32326497","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":66469,"rule_based_match":true,"evidence_text":"c.517-2A>G","llm_judgment":"PRESENT","evidence":"c.517-2A>G","abstract_start":1347,"abstract_end":1357},{"Name":"NM_000059.4(BRCA2):c.6937+1G>A","Chromosome":"13","Start":"32344654","Stop":"32344654","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":262826,"rule_based_match":true,"evidence_text":"c.6937+1G>A","llm_judgment":"PRESENT","evidence":"c.6937+1G>A","abstract_start":1372,"abstract_end":1383},{"Name":"NM_000059.4(BRCA2):c.631+2T>G","Chromosome":"13","Start":"32326615","Stop":"32326615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":24388,"rule_based_match":true,"evidence_text":"c.631+2T>G","llm_judgment":"PRESENT","evidence":"c.631+2T>G","abstract_start":1335,"abstract_end":1345}]}
{"pmid":"22371642","title":"Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients.","abstract":"AIM: To investigate the protein expression profile of mismatch repair (MMR) genes in suspected cases of Lynch syndrome and to characterize the associated germline mutations.\nMETHODS: Immunohistochemical analysis of tumor samples was performed to determine the protein expression profile of MMR protein. Germline mutation screening was carried out on peripheral blood samples. The entire exon regions of MLH1 and MSH2 genes were amplified by polymerase chain reaction, screened by denaturing high performance liquid chromatography (dHPLC) and analyzed by DNA sequencing to characterize the germline mutations.\nRESULTS: Three out of 34 tissue samples (8.8%) and four out of 34 tissue samples (11.8%) showed loss of nuclear staining by immunohistochemistry, indicating the absence of MLH1 and MSH2 protein expression in carcinoma cells, respectively. dHPLC analysis followed by DNA sequencing showed these samples to have germline mutations of MSH2 gene. However, no deleterious mutations were identified in any of the 19 exons or coding regions of MLH1 gene, but we were able to identify MLH1 promoter polymorphism, -93G > A (rs1800734), in 21 out of 34 patients (61.8%). We identified one novel mutation, transversion mutation c.2005G > C, which resulted in a missense mutation (Gly669Arg), a transversion mutation in exon 1, c.142G > T, which resulted in a nonsense mutation (Glu48Stop) and splice-site mutation, c.2006-6T > C, which was adjacent to exon 13 of MSH2 gene.\nCONCLUSION: Germline mutations were identified in four Malaysian Lynch syndrome patients. Immunohistochemical analysis of tumor tissue proved to be a good pre-screening test before proceeding to germline mutation analysis of DNA MMR genes.","variants":[{"Name":"NM_000251.3(MSH2):c.142G>T (p.Glu48Ter)","Chromosome":"2","Start":"47403333","Stop":"47403333","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":96137,"rule_based_match":true,"evidence_text":"c.142G > T","llm_judgment":"PRESENT","evidence":"c.142G > T","abstract_start":1325,"abstract_end":1335},{"Name":"NM_000251.3(MSH2):c.2005G>C (p.Gly669Arg)","Chromosome":"2","Start":"47475270","Stop":"47475270","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":96319,"rule_based_match":true,"evidence_text":"c.2005G > C","llm_judgment":"PRESENT","evidence":"c.2005G > C","abstract_start":1226,"abstract_end":1237}]}
{"pmid":"27775217","title":"The intronic ABCA4 c.5461-10T>C variant, frequently seen in patients with Stargardt disease, causes splice defects and reduced ABCA4 protein level.","abstract":"PURPOSE: Despite being the third most common ABCA4 variant observed in patients with Stargardt disease, the functional effect of the intronic ABCA4 variant c.5461-10T>C is unknown. The purpose of this study was to investigate the molecular effect of this variant.\nMETHODS: Fibroblast samples from patients carrying the ABCA4 variant c.5461-10T>C were analysed by isolating total RNA, followed by real-time polymerase chain reaction (RT-PCR) using specific primers spanning the variant. For detection of ABCA4 protein, fibroblast samples were lysed and analysed by SDS-PAGE followed by immunoblotting using a monoclonal ABCA4 antibody.\nRESULTS: The ABCA4 variant c.5461-10T>C causes a splicing defect resulting in the reduction of full-length mRNA in fibroblasts from patients and the presence of alternatively spliced mRNAs where exon 39-40 is skipped. A reduced level of full-length ABCA4 protein is observed compared to controls not carrying the variant.\nCONCLUSIONS: This study describes the functional effect and the molecular mechanism of the pathogenic ABCA4 variant c.5461-10T>C. The variant is functionally important as it leads to splicing defects and a reduced level of ABCA4 protein.","variants":[{"Name":"NM_000350.3(ABCA4):c.5461-10T>C","Chromosome":"1","Start":"94011395","Stop":"94011395","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":98777,"rule_based_match":true,"evidence_text":"c.5461-10T>C","llm_judgment":"PRESENT","evidence":"c.5461-10T>C","abstract_start":156,"abstract_end":168}]}
{"pmid":"17893669","title":"Novel mutations of the FRMD7 gene in X-linked congenital motor nystagmus.","abstract":"PURPOSE: Congenital motor nystagmus (CMN) is a relatively common oculomotor disorder characterized by bilateral uncontrollable ocular oscillations. Recently, the FRMD7 gene mutation has been identified as the genetic cause of CMN. The purpose of this study was to identify mutations of the FRMD7 gene in Chinese patients with CMN.\nMETHODS: Clinical data and genomic DNA of three Chinese CMN families were collected after informed consent. Genescan by two-point linkage analysis combined with haplotype analysis was performed and mutation screening of the FRMD7 gene was conducted by direct sequencing.\nRESULTS: Maximum two-point LOD scores of 2.00, 1.76, and 1.16 at theta=0.00 were obtained with markers in proximity to the FRMD7 gene on chromosome Xp26 in the three CMN families. Mutation screening in the FRMD7 gene identified two novel missense mutations (c.781C>G and c.886G>C) and one reported nonsense mutation (c.1003C>T). These nucleotide alterations were not seen in unaffected members of the families or in 100 unrelated control subjects.\nCONCLUSIONS: This study widens the mutation spectrum of the FRMD7 gene.","variants":[{"Name":"NM_194277.3(FRMD7):c.886G>C (p.Gly296Arg)","Chromosome":"X","Start":"132082382","Stop":"132082382","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":860784,"rule_based_match":true,"evidence_text":"c.886G>C","llm_judgment":"PRESENT","evidence":"c.886G>C","abstract_start":873,"abstract_end":881}]}
{"pmid":"30230034","title":"Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer.","abstract":"BRIP1 is a component of the Fanconi Anemia/BRCA pathway responsible for DNA reparation via helicase activity. Some heterozygous variants in BRIP1 could contribute to Hereditary Breast Cancer through a defective DNA repair. The clinical utility of BRIP1 mutations in a familial cancer context is compromised by the conflicting interpretation of \"variants of uncertain significance\" (VUS). Defining the clinical significance of variants identified in genetic tests is a major challenge; therefore, studies that evaluate the biological effect of these variants are definitely necessary. To contribute to this purpose, we have characterized the variant c.550G>T of BRIP1, a missense mutation with little evidence about its pathogenicity. Since Human Splicing Finder<sup>TM</sup> predicts the creation of a new exonic splicing enhancer site we decided to perform cDNA analysis revealing that the c.550G>T mutation located in exon 6 led to an aberrant transcript causing exon 5 skipping. Our results demonstrate that the c.550G>T BRIP1 variant disrupts normal splicing, causing exon 5 skipping. Considering that the exon 5 encodes the helicase domain of BRIP1, it is expected an alteration of the function. This finding enhances the interpretation of this VUS, suggesting a potential pathogenic effect.","variants":[{"Name":"NM_032043.3(BRIP1):c.550G>T (p.Asp184Tyr)","Chromosome":"17","Start":"61847178","Stop":"61847178","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":152735,"rule_based_match":true,"evidence_text":"c.550G>T","llm_judgment":"PRESENT","evidence":"c.550G>T","abstract_start":649,"abstract_end":657}]}
{"pmid":"25498755","title":"A novel mutation in lamin a/c causing familial dilated cardiomyopathy associated with sudden cardiac death.","abstract":"BACKGROUND: Dilated cardiomyopathy (DCM), a cardiac heterogeneous pathology characterized by left ventricular or biventricular dilatation, is a leading cause of heart failure and heart transplantation. The genetic origin of DCM remains unknown in most cases, but >50 genes have been associated with DCM. We sought to identify the genetic implication and perform a genetic analysis in a Spanish family affected by DCM and sudden cardiac death.\nMETHODS AND RESULTS: Clinical assessment and genetic screening were performed in the index case as well as family members. Of all relatives clinically assessed, nine patients showed clinical symptoms related to the pathology. Genetic screening identified 20 family members who carried a novel mutation in LMNA (c.871 G>A, p.E291K). Family segregation analysis indicated that all clinically affected patients carried this novel mutation. Clinical assessment of genetic carriers showed that electrical dysfunction was present previous to mechanical and structural abnormalities.\nCONCLUSIONS: Our results report a novel pathogenic mutation associated with DCM, supporting the benefits of comprehensive genetic studies of families affected by this pathology.","variants":[{"Name":"NM_170707.4(LMNA):c.871G>A (p.Glu291Lys)","Chromosome":"1","Start":"156135247","Stop":"156135247","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":196473,"rule_based_match":true,"evidence_text":"c.871 G>A, p.E291K","llm_judgment":"PRESENT","evidence":"c.871 G>A, p.E291K","abstract_start":754,"abstract_end":772}]}
{"pmid":"38645242","title":"Functional Analysis of G6PD Variants Associated With Low G6PD Activity in the All of Us Research Program.","abstract":"Glucose-6-phosphate dehydrogenase (G6PD) protects red blood cells against oxidative damage through regeneration of NADPH. Individuals with <i>G6PD</i> polymorphisms (variants) that produce an impaired G6PD enzyme are usually asymptomatic, but at risk of hemolytic anemia from oxidative stressors, including certain drugs and foods. Prevention of G6PD deficiency-related hemolytic anemia is achievable through <i>G6PD</i> genetic testing or whole-genome sequencing (WGS) to identify affected individuals who should avoid hemolytic triggers. However, accurately predicting the clinical consequence of <i>G6PD</i> variants is limited by over 800 <i>G6PD</i> variants which remain of uncertain significance. There also remains significant variability in which deficiency-causing variants are included in pharmacogenomic testing arrays across institutions: many panels only include c.202G>A, even though dozens of other variants can also cause G6PD deficiency. Here, we seek to improve <i>G6PD</i> genotype interpretation using data available in the All of Us Research Program and using a yeast functional assay. We confirm that <i>G6PD</i> coding variants are the main contributor to decreased G6PD activity, and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed if only the c.202G>A variant were tested for. We expand clinical interpretation for <i>G6PD</i> variants of uncertain significance; reporting that c.595A>G, known as G6PD Dagua or G6PD Açores, and the newly identified variant c.430C>G, reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that five missense variants of uncertain significance are unlikely to lead to G6PD deficiency, since they were seen in hemi- or homozygous individuals without a reduction in G6PD activity. We also applied the new WHO guidelines and were able to classify two synonymous variants as WHO class C. We anticipate these results will improve the accuracy, and prompt increased use, of <i>G6PD</i> genetic tests through a more complete clinical interpretation of <i>G6PD</i> variants. As the All of Us data increases from 245,000 to 1 million participants, and additional functional assays are carried out, we expect this research to serve as a template to enable complete characterization of G6PD deficiency genotypes. With an increased number of interpreted variants, genetic testing of <i>G6PD</i> will be more informative for preemptively identifying individuals at risk for drug- or food-induced hemolytic anemia.","variants":[{"Name":"NM_001360016.2(G6PD):c.430C>G (p.Pro144Ala)","Chromosome":"X","Start":"154535223","Stop":"154535223","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3498785,"rule_based_match":true,"evidence_text":"c.430C>G","llm_judgment":"PRESENT","evidence":"c.430C>G","abstract_start":1530,"abstract_end":1538},{"Name":"NM_001360016.2(G6PD):c.595A>G (p.Ile199Val)","Chromosome":"X","Start":"154534387","Stop":"154534387","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1780206,"rule_based_match":true,"evidence_text":"c.595A>G","llm_judgment":"PRESENT","evidence":"c.595A>G","abstract_start":1451,"abstract_end":1459}]}
{"pmid":"35065800","title":"Effect of Cis-Compound Variants in MYH7 on Hypertrophic Cardiomyopathy With a Mild Phenotype.","abstract":"Patients with hypertrophic cardiomyopathy (HC) caused by compound variants have severe clinical manifestations, but significant clinical heterogeneity remains. Clinical diversity in these patients may result from different combinations of variants. We analyzed the role of cis-compound variants in a Chinese HC pedigree. Exome sequencing was performed in the proband. Identified variants were detected with bi-directional Sanger sequencing in a pedigree that comprised 3 generations and 28 family members. Follow-up was performed for 16 years. Two missense variants (c.2465T>C, p.Met822Thr; c.4258C>T, p.Arg1420Trp) were identified in the MYH7 gene. These variants were absent in our 761 in-house people without HC and predicted to be pathogenic.Both variants were detected in 11 family members, thus they were believed to inherit cis. In the 11 members, only 5 developed HC, the other 6 were asymptomatic variant carriers with an abnormal electrocardiogram. The HC members had mild hypertrophy with a maximum left ventricular wall thickness of 13 to 21 mm and showed a low incidence of cardiovascular events. In conclusion, the cis-compound variants of Met822Thr and Arg1420Trp in MYH7 are causal but relatively benign, variants associated with familial HC. This finding suggests that different types of compound variants might need to be analyzed for a genotype-phenotype study.","variants":[{"Name":"NM_000257.4(MYH7):c.4258C>T (p.Arg1420Trp)","Chromosome":"14","Start":"23417598","Stop":"23417598","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":52173,"rule_based_match":true,"evidence_text":"c.4258C>T, p.Arg1420Trp","llm_judgment":"PRESENT","evidence":"c.4258C>T, p.Arg1420Trp","abstract_start":591,"abstract_end":614},{"Name":"NM_000257.4(MYH7):c.2465T>C (p.Met822Thr)","Chromosome":"14","Start":"23424983","Stop":"23424983","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1351974,"rule_based_match":true,"evidence_text":"c.2465T>C, p.Met822Thr","llm_judgment":"PRESENT","evidence":"c.2465T>C, p.Met822Thr","abstract_start":567,"abstract_end":589}]}
{"pmid":"25081284","title":"Macular corneal dystrophy and associated corneal thinning.","abstract":"PURPOSE: To identify the molecular genetic cause of macular corneal dystrophy (MCD) in four probands, and characterize phenotypic similarities between MCD and keratoconus.\nMETHODS: We performed ophthalmological examination, Scheimpflug imaging (Pentacam, Oculus Inc.), histopathological examination of excised corneal buttons, and direct sequencing of the CHST6 coding region.\nRESULTS: Pentacam measurements were taken in six eyes of three probands. All showed diffuse corneal thinning with paracentral steepening of the anterior corneal surface that was graded as keratoconus by the integrated software, but without associated ectasia of the posterior corneal surface or regional thinning. Homozygous or compound heterozygous CHST6 mutations were identified in all cases, including two novel mutations, c.13C>T; p.(Arg5Cys) and c.289C>T; p.(Arg97Cys).\nDISCUSSION: Localized elevation of the anterior corneal curvature can occur in MCD in the absence of other features of keratoconus. The identification of a further two Czech probands with the compound allele c.[484C>G; 599T>G] supports the enrichment of this allele in the study population.","variants":[{"Name":"NM_021615.5(CHST6):c.13C>T (p.Arg5Cys)","Chromosome":"16","Start":"75479816","Stop":"75479816","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3525585,"rule_based_match":true,"evidence_text":"c.13C>T; p.(Arg5Cys)","llm_judgment":"PRESENT","evidence":"c.13C>T; p.(Arg5Cys)","abstract_start":804,"abstract_end":824},{"Name":"NM_021615.5(CHST6):c.289C>T (p.Arg97Cys)","Chromosome":"16","Start":"75479540","Stop":"75479540","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3413511,"rule_based_match":true,"evidence_text":"c.289C>T; p.(Arg97Cys)","llm_judgment":"PRESENT","evidence":"c.289C>T; p.(Arg97Cys)","abstract_start":829,"abstract_end":851}]}
{"pmid":"32464486","title":"Novel mutations in the bone morphogenetic protein 6 gene in patients with iron overload and non-homozygous genotype for the HFE p.Cys282Tyr mutation.","abstract":"BACKGROUND: Five main genes are associated with hemochromatosis; however, current studies show that, in addition to these genes, others may be associated with primary iron overload (IO). One of these is the bone morphogenetic protein 6 (BMP6), which encodes a protein that modulates hepcidin synthesis and, consequently, iron homeostasis.\nAIM: To identify BMP6 gene pathogenic variants in patients with IO and non-homozygous genotype for the HFE p.Cys282Tyr mutation.\nMATERIALS AND METHODS: Fifty-three patients with primary IO and non-homozygous genotype for the HFE p.Cys282Tyr were selected. Subsequent bidirectional DNA sequencing of BMP6 exons was performed.\nRESULTS: Two novel variants were found. One at homozygous state p.Gln158Ter (c.472C>T) was pathogenic, the other one at heterozygous state p.Val394Met (c.1180G>A) was of uncertain significance (VUS); the third variant at heterozygous state p.Arg257His (c.770G>A) has already been described and associated with IO. No BMP6 pathogenic variants that would explain iron overload phenotypes were detected in 94% of the studied patients.\nCONCLUSION: Identification of the BMP6 pathogenic variants in Brazilian patients with primary IO might contribute to the genetic understanding of this phenotype.","variants":[{"Name":"NM_001718.6(BMP6):c.472C>T (p.Gln158Ter)","Chromosome":"6","Start":"7727427","Stop":"7727427","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1858505,"rule_based_match":true,"evidence_text":"c.472C>T","llm_judgment":"PRESENT","evidence":"c.472C>T","abstract_start":741,"abstract_end":749},{"Name":"NM_001718.6(BMP6):c.770G>A (p.Arg257His)","Chromosome":"6","Start":"7845245","Stop":"7845245","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1858506,"rule_based_match":true,"evidence_text":"c.770G>A (p.Arg257His)","llm_judgment":"PRESENT","evidence":"p.Arg257His","abstract_start":904,"abstract_end":915}]}
{"pmid":"25433523","title":"Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome.","abstract":"BACKGROUND: Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Recently dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS.\nMETHODS: Here we report the genetic analysis of 5 patients fulfilling the diagnostic criteria of FHS obtained by Sanger sequencing. All of them presented with short stature, speech delay as well as psychomotor delay and typical facial dysmorphism. Three patients showed a good response to growth hormone treatment.\nRESULTS: Two patients demonstrate novel, heterozygous de novo frameshift mutations in exon 34 (c.7396delA and c.7218dupT) leading to premature stop mutations in SRCAP (p.Val2466Tyrfs*9 and p.Gln2407Serfs*36, respectively). In two further patients we found already known SRCAP mutations in exon 34, c.7330C > T and c.7303C > T, respectively, which also lead to premature stop codons: p.Arg2444* and p.Arg2435*. In one patient, we identified a novel de novo stop mutation in exon 33 (c.6985C > T, p.Arg2329*) demonstrating that not all FHS cases are caused by mutations in exon 34 of SRCAP.\nCONCLUSIONS: Our data confirm a mutational hot spot in the final exon of SRCAP in the majority of FHS patients but also show that exon 33 of this gene can be affected.","variants":[{"Name":"NM_006662.3(SRCAP):c.6985C>T (p.Arg2329Ter)","Chromosome":"16","Start":"30736601","Stop":"30736601","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":536905,"rule_based_match":true,"evidence_text":"c.6985C > T, p.Arg2329*","llm_judgment":"PRESENT","evidence":"c.6985C > T, p.Arg2329*","abstract_start":1122,"abstract_end":1145},{"Name":"NM_006662.3(SRCAP):c.7330C>T (p.Arg2444Ter)","Chromosome":"16","Start":"30737370","Stop":"30737370","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39865,"rule_based_match":true,"evidence_text":"c.7330C > T","llm_judgment":"PRESENT","evidence":"c.7330C > T","abstract_start":938,"abstract_end":949},{"Name":"NM_006662.3(SRCAP):c.7303C>T (p.Arg2435Ter)","Chromosome":"16","Start":"30737343","Stop":"30737343","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39866,"rule_based_match":true,"evidence_text":"c.7303C > T","llm_judgment":"PRESENT","evidence":"c.7303C > T","abstract_start":954,"abstract_end":965},{"Name":"NM_006662.3(SRCAP):c.7218dup (p.Gln2407fs)","Chromosome":"16","Start":"30737257","Stop":"30737258","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":1310572,"rule_based_match":true,"evidence_text":"c.7218dupT","llm_judgment":"PRESENT","evidence":"c.7218dupT","abstract_start":750,"abstract_end":760}]}
{"pmid":"26117226","title":"Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: A cross-sectional study.","abstract":"BACKGROUND: Bi-allelic CYP24A1 mutations can cause idiopathic infantile hypercalcemia (IIH), adult-onset nephrocalcinosis, and possibly bone metabolism disturbances. It is currently unclear if heterozygous carriers experience clinical problems or biochemical abnormalities. Our objective is to gain insight in the biochemical profile and health problems in CYP24A1 heterozygotes.\nSTUDY DESIGN: Cross-sectional evaluation of participants. Data of previously reported carriers are reviewed.\nSETTING AND PARTICIPANTS: Outpatient clinic of a tertiary care hospital. Participants were eight family members of an infant with a well-characterized homozygous CYP24A1 mutation c.1186C>T p.(Arg396Trp).\nOUTCOMES: Serum vitamin D metabolites. Symptoms or biochemical signs of hypercalcemia, hypercalciuria or nephrocalcinosis. Bone health in heterozygous as compared to wild type (WT) subjects.\nMEASUREMENTS: Genotyping by Sanger sequencing; vitamin D metabolites by liquid chromatography tandem mass spectrometry; renal, calcium and bone markers by biochemical analyses; presence of nephrocalcinosis by renal ultrasound; bone health by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography.\nRESULTS: Six participants were heterozygous carriers of the mutation. None of the heterozygous subjects had experienced IIH. One had a documented history of nephrolithiasis, two others had complaints compatible with this diagnosis. No major differences between WT and heterozygous subjects were found regarding bone health, serum or urinary calcium or 25OHD/24,25(OH)2D ratio. Literature reports on three out of 33 heterozygous cases suffering from IIH. In all three, the 25OHD/24,25(OH)2D ratio was highly elevated. Nephrocalcinosis was frequently reported in family members of IIH cases.\nLIMITATIONS: Small sample size, lack of a large control group.\nCONCLUSIONS: Our and literature data suggest that most heterozygous CYP24A1 mutation carriers have a normal 25OHD/24,25(OH)2D ratio, are usually asymptomatic and have a normal skeletal status but may possibly be at increased risk of nephrocalcinosis. A review of the available literature suggests that an elevated 25OHD/24,25(OH)2D ratio may be associated with symptoms of IHH, irrespective of carrier status.","variants":[{"Name":"NM_000782.5(CYP24A1):c.1186C>T (p.Arg396Trp)","Chromosome":"20","Start":"54158136","Stop":"54158136","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38634,"rule_based_match":true,"evidence_text":"c.1186C>T p.(Arg396Trp)","llm_judgment":"PRESENT","evidence":"c.1186C>T p.(Arg396Trp)","abstract_start":668,"abstract_end":691}]}
{"pmid":"32555368","title":"Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency.","abstract":"Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.","variants":[{"Name":"NM_032638.5(GATA2):c.1416G>A (p.Pro472=)","Chromosome":"3","Start":"128481046","Stop":"128481046","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":393713,"rule_based_match":true,"evidence_text":"c.1416G>A, p.P472P","llm_judgment":"PRESENT","evidence":"c.1416G>A, p.P472P","abstract_start":635,"abstract_end":653},{"Name":"NM_032638.5(GATA2):c.351C>G (p.Thr117=)","Chromosome":"3","Start":"128486247","Stop":"128486247","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1173940,"rule_based_match":true,"evidence_text":"c.351C>G","llm_judgment":"PRESENT","evidence":"c.351C>G","abstract_start":546,"abstract_end":554},{"Name":"NM_032638.5(GATA2):c.981G>A (p.Gly327=)","Chromosome":"3","Start":"128483896","Stop":"128483896","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1070265,"rule_based_match":true,"evidence_text":"c.981G>A, p.G327G","llm_judgment":"PRESENT","evidence":"c.981G>A, p.G327G","abstract_start":592,"abstract_end":609}]}
{"pmid":"32603808","title":"Neonatal SCN2A encephalopathy: A peculiar recognizable electroclinical sequence.","abstract":"INTRODUCTION: Sodium voltage-gated channel alpha subunit 2 (SCN2A) gene encodes the Nav1.2 subunit of voltage-gated sodium channel in pyramidal neurons. SCN2A gain-of-function mutations are identified more and more often with gene panels and whole exome sequencing. Phenotype ranges from benign neonatal or infantile seizures to severe epileptic encephalopathy. Although large series of patients targeting genetic background point out two main phenotypes with SCN2A encephalopathy, Ohtahara syndrome and malignant migrating partial seizures in infancy (EMPSI), we noticed that in fact, a peculiar clinical and electroencephalogram (EEG) sequence distinct from these syndromes should suggest the diagnosis early.\nPATIENTS AND METHODS: We report three new cases with de novo SCN2A mutations - 166237617C>A p.(Asp1487Glu), c.407T>G p.(Met136Arg), and c.4633A>G p.(Met1545Val) - diagnosed by direct sequencing or genes panel, their follow-up ranging from 4 to 5 years.\nRESULTS: For all three patients, seizures started at two days of life and consisted of apnea and cyanosis with partial clonic or tonic, alternating on both sides with, up to 100/day, evolving to generalized tonic-clonic seizures (GTCS) and epileptic spasms by three months. First EEG showed a discontinuous pattern, evolving to multifocal spikes, by 3 (two patients) and 6 months (one). Seizure frequency decreased progressively by the middle or end of the first year of life. Only less frequent GTCS persisted during the second year of life for two patients. Improvement was observed in two patients with sodium channel blocker (phenytoin) used at age of 1 month for one patient and at 2 years for another one. All patients remained with severe psychomotor delay.\nDISCUSSION: All three infants share a condition different from Ohtahara syndrome in which tonic spasms predominate and suppression-burst pattern is obvious, and from EMPSI, in which partial migrating discharges involve successively the various parts of the brain including occipital regions with oculoclonic seizures, but there is neither discontinuous pattern nor therapeutic response to sodium channel blockers.\nCONCLUSION: Neonatal SCN2A encephalopathy has a recognizable phenotype starting soon after birth with alternating partial motor seizures evolving to infantile spasms and a discontinuous EEG pattern. Seizures improve spontaneously in the first year of life. This electroclinical sequence should indicate the search of SCN2A mutation and suggest the administration of sodium channel blockers.","variants":[{"Name":"NM_001040142.2(SCN2A):c.407T>G (p.Met136Arg)","Chromosome":"2","Start":"165307868","Stop":"165307868","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1984287,"rule_based_match":true,"evidence_text":"c.407T>G p.(Met136Arg)","llm_judgment":"PRESENT","evidence":"c.407T>G p.(Met136Arg)","abstract_start":820,"abstract_end":842}]}
{"pmid":"24140640","title":"Two novel distinct COL1A2 mutations highlight the complexity of genotype-phenotype correlations in osteogenesis imperfecta and related connective tissue disorders.","abstract":"Osteogenesis imperfecta is a heritable connective tissue disorder characterized by variable symptoms including predisposition to fractures. Despite the identification of numerous mutations, a reliable genotype-phenotype correlation has remained notoriously difficult. We now describe two patients with osteogenesis imperfecta and novel, so far undescribed mutations in the COL1A2 gene, further highlighting this complexity. A 3-year-old patient presented with features reminiscent of a connective tissue disorder, with joint hypermobility, Wormian bones, streaky lucencies in the long bones and relative macrocephaly. The patient carried a heterozygous c.1316G > A (p.Gly439Asp) mutation in the COL1A2 gene located in a triple-helix region, in which glycine substitutions have been assumed to cause perinatal lethal OI (Sillence type II). A second family with type I osteogenesis imperfecta carried a heterozygous nonsense mutation c.4060C > T (p.Gln1354X) within the last exon of COL1A2. Whereas other heterozygous nonsense mutations in COL1A2 do not lead to a phenotype, in this case the mRNA is presumed to escape nonsense-mediated decay. Therefore the predicted COL1A2 propeptide lacks the last 13 C-terminal amino acids, suggesting that the OI phenotype results from decelerated assembly and overmodification of the collagen triple helix. The presented COL1A2 mutations exemplify the complexity of COL1A2 genotype-phenotype correlation in genetic counselling in OI.","variants":[{"Name":"NM_000089.4(COL1A2):c.4060C>T (p.Gln1354Ter)","Chromosome":"7","Start":"94430352","Stop":"94430352","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1706690,"rule_based_match":true,"evidence_text":"c.4060C > T (p.Gln1354X)","llm_judgment":"PRESENT","evidence":"c.4060C > T (p.Gln1354X)","abstract_start":932,"abstract_end":956}]}
{"pmid":"20979188","title":"Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene.","abstract":"We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth, who also had Marfan syndrome (MFS; fulfilling the Ghent criteria) with mild skeletal features, dilated aortic bulb, dural ectasia, bilateral subluxation of the lens, and severe myopia in addition to the severe generalized lipodystrophy. She lacked insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. Mutation analysis in the gene encoding fibrillin 1 (FBN1) revealed a novel de novo heterozygous deletion, c.8155_8156del2 in exon 64. The severe generalized lipodystrophy in this patient with progeroid features has not previously been described in other patients with MFS and FBN1 mutations. We did not find a mutation in genes known to be associated with congenital lipodystrophy (APGAT2, BSCL2, CAV1, PTRF-CAVIN, PPARG, LMNB2) or with Hutchinson-Gilford progeria (ZMPSTE24, LMNA/C). Other progeria syndromes were considered unlikely because premature greying, hypogonadism, and scleroderma-like skin disease were not present. Our patient shows striking similarity to two patients who have been published in this journal by O'Neill et al. [O'Neill et al. (2007); Am J Med Genet Part A 143A:1421-1430] with the diagnosis of neonatal progeroid syndrome (NPS). This condition also known as Wiedemann-Rautenstrauch syndrome is a rare disorder characterized by accelerated aging and lipodystrophy from birth, poor postnatal weight gain, and characteristic facial features. The course is usually progressive with early lethality. However this entity seems heterogeneous. We suggest that our patient and the two similar cases described before represent a new entity, a subgroup of MFS with overlapping features to NPS syndrome.","variants":[{"Name":"NM_000138.5(FBN1):c.8155_8156del (p.Lys2719fs)","Chromosome":"15","Start":"48412639","Stop":"48412640","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":48727,"rule_based_match":true,"evidence_text":"c.8155_8156del2","llm_judgment":"PRESENT","evidence":"c.8155_8156del2","abstract_start":540,"abstract_end":555}]}
{"pmid":"26219881","title":"Phenotypic Expansion of Congenital Disorder of Glycosylation Due to SRD5A3 Null Mutation.","abstract":"We present a boy, admitted at 4 months, with facial dysmorphism, hypertrichosis, loose skin, bilateral inguinal hernia, severe hypotonia, psychomotor disability, seizures with hypsarrhythmia (West syndrome), hepatosplenomegaly, increased serum transaminases, iris coloboma, glaucoma, corneal clouding and bilateral dilated lateral ventricles, and extra-axial post-cerebellar space. Serum transferrin isoelectrofocusing (IEF) showed a type 1 pattern. Whole-exome genotyping showed a previously reported homozygous nonsense mutation c.320G>A; p.Trp107X in SRD5A3. Epilepsy and glaucoma have been reported only once in the 19 described SRD5A3-congenital glycosylation defect patients, and corneal clouding not at all.","variants":[{"Name":"NM_024592.5(SRD5A3):c.320G>A (p.Trp107Ter)","Chromosome":"4","Start":"55359444","Stop":"55359444","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":33444,"rule_based_match":true,"evidence_text":"c.320G>A; p.Trp107X","llm_judgment":"PRESENT","evidence":"c.320G>A; p.Trp107X","abstract_start":531,"abstract_end":550}]}
{"pmid":"27927575","title":"Novel mutation in a patient with late onset GLUT1 deficiency syndrome.","abstract":"Glucose transporter 1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism caused by impaired glucose transport through blood brain barrier due to mutation in SLC2A1 gene, encoding transporter protein. Clinical spectrum includes various signs and symptoms, ranging from severe epileptic encephalopathy to movement disorders. The diagnosis of GLUT1-DS requires hypoglycorrhachia in the presence of normoglycaemia with a reduced cerebrospinal fluid (CSF):plasma glucose ratio. The absence of pathogenic mutation in SLC2A1 gene does not exclude the diagnosis. This case report describes a patient with late onset GLUT1-DS with a novel sporadic mutation c.539T>A, p.Met180Lys in exon 5 of the SLC2A1 gene. The dominating clinical features were epilepsy and paroxysmal dyskinesias provoked by infection, emotional stress and fasting. The ictal EEG was characterized by generalized paroxysmal 3-3.5Hz spike-slow wave complexes (absences). Treatment with ketogenic diet showed clinical improvement with the reduction of paroxysmal dyskinesias.","variants":[{"Name":"NM_006516.4(SLC2A1):c.539T>A (p.Met180Lys)","Chromosome":"1","Start":"42930013","Stop":"42930013","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1928394,"rule_based_match":true,"evidence_text":"c.539T>A, p.Met180Lys","llm_judgment":"PRESENT","evidence":"c.539T>A, p.Met180Lys","abstract_start":661,"abstract_end":682}]}
{"pmid":"31074291","title":"Ocular manifestations of intermediate cystinosis: To treat or not to treat?","abstract":"PURPOSE: To report a case of intermediate cystinosis with an atypical presentation in which a delayed non-treatment decision has been proved right over a large period of time.\nMETHODS: This is a unique case report of a patient who underwent full ophthalmologic evaluations including anterior chamber optical coherence tomography on a regular basis during a 7-year follow-up period.\nRESULTS: A 30-year-old woman with photophobia was being studied by the Department of Nephrology with a suspicion of Alport syndrome. Slit-lamp examination showed iridescent deposits throughout the corneal anterior stroma and the inferior tarsal conjunctiva bilaterally. Anterior chamber optical coherence tomography showed stromal hyperreflectivity. <i>CTNS</i> gene was found to be positive for c.416C>T (Ser139Phe) mutation. The patient was offered oral and topical cysteamine which was refused. After a period of 5 years of follow-up, general health status remained stable, corneal disease showed no progression and photophobia complaints diminished. However, the patient was advised to start systemic and topical cysteamine because of the unknown development of the disease.\nCONCLUSION: In this reported case, a delayed non-treatment decision has been proved right contrary to published evidence of active treatment of photophobia. The decision whether to treat or not to treat corneal involvement of the disease is not straightforward. Besides biomicroscopic evaluations, patients' complaints and expectations should be taken into account.","variants":[{"Name":"NM_004937.3(CTNS):c.416C>T (p.Ser139Phe)","Chromosome":"17","Start":"3655307","Stop":"3655307","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19497,"rule_based_match":true,"evidence_text":"c.416C>T (Ser139Phe)","llm_judgment":"PRESENT","evidence":"c.416C>T (Ser139Phe)","abstract_start":778,"abstract_end":798}]}
{"pmid":"26489929","title":"Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome.","abstract":"Axenfeld-Rieger syndrome (ARS) is a disorder affecting the anterior segment of the eye, often leading to secondary glaucoma and several systemic malformations. It is inherited in an autosomal dominant fashion that has been associated with genetic defects in PITX2 and FOXC1. Known genes CYP1b1, PITX2, and FOXC1 were excluded by Sanger sequencing. The purpose of current study is to identify the underlying genetic causes in ARS family by whole exome sequencing (WES). WES was performed for affected proband of family, and variants were prioritized based on in silico analyses. Segregation analysis of candidate variants was performed in family members. A novel heterozygous PRDM5 missense variant (c.877A>G; p.Lys293Glu) was found to segregate with the disease in an autosomal dominant fashion. The novel missense variant was absent from population-matched controls, the Exome Variant Server, and an in-house exome variant database. The Lys293Glu variant is predicted to be pathogenic and affects a lysine residue that is conserved in different species. Variants in the PRDM5 gene were previously identified in anterior segment defects, i.e., autosomal recessive brittle cornea syndrome and keratoconus. The results of this study suggest that genetic variants in PRDM5 can lead to various syndromic and nonsyndromic disorders affecting the anterior segment of the eye.","variants":[{"Name":"NM_018699.4(PRDM5):c.877A>G (p.Lys293Glu)","Chromosome":"4","Start":"120811438","Stop":"120811438","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":223009,"rule_based_match":true,"evidence_text":"c.877A>G; p.Lys293Glu","llm_judgment":"PRESENT","evidence":"c.877A>G; p.Lys293Glu","abstract_start":699,"abstract_end":720}]}
{"pmid":"27939639","title":"Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.","abstract":"Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs<sup>∗</sup>8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency.","variants":[{"Name":"NM_001003694.2(BRPF1):c.1052_1053del (p.Val351fs)","Chromosome":"3","Start":"9739449","Stop":"9739450","ReferenceAlleleVCF":"ATG","AlternateAlleleVCF":"A","allel_id":263800,"rule_based_match":true,"evidence_text":"c.1052_1053del","llm_judgment":"PRESENT","evidence":"c.1052_1053del","abstract_start":414,"abstract_end":428}]}
{"pmid":"21486382","title":"Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans.","abstract":"BACKGROUND:  Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological regulator of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) activity. A number of studies have shown that elevated levels of PAI-1 are related to pathological states such as an increased risk of arterial thrombotic events and a poor prognosis for cancer patients; however, there are few reports about PAI-1 deficiency in humans because the disorder is very rare.\nOBJECTIVE:  To understand the in vivo impact of a complete PAI-1 deficiency, Serpine1(-/-) mice were generated; a number of in vivo studies have been conducted to elucidate the function of PAI-1 using Serpine1(-/-) mice. The phenotypes demonstrated in Serpine1(-/-) mice, however, were quite different from those in humans. Therefore, it is necessary to find out and analyze SERPINE1 deficiency in humans.\nPATIENT AND METHODS:  The patient is a 47-year-old woman who has had multiple episodes of major bleeding. Although most of the patient's blood coagulation factors were functionally normal, her PAI-1 antigen levels were undetectable. Therefore, DNA sequencing of the SERPINE1 gene were analyzed.\nRESULTS:  The proband had a homozygous 1-bp duplication (C) at exon 3 (c.356dupC; p.Ile120AspfsX42). Both wild-type PAI-1 (42.7 kDa) and mutated (Mut) PAI-1 (14.7kDa) were expressed in COS-1 cells, although the level of Mut PAI-1 expressed in the cell lysates was much lower. Wild-type PAI-1 was observed in the culture supernatant, whereas no Mut PAI-1 was detected in the supernatant.\nCONCLUSIONS:  Considering the results of the present study, the translation of mouse studies to humans must be performed with great care.","variants":[{"Name":"NM_000602.5(SERPINE1):c.356dup (p.Ile120fs)","Chromosome":"7","Start":"101130504","Stop":"101130505","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":480748,"rule_based_match":true,"evidence_text":"c.356dupC; p.Ile120AspfsX42","llm_judgment":"PRESENT","evidence":"c.356dupC; p.Ile120AspfsX42","abstract_start":1249,"abstract_end":1276}]}
{"pmid":"24015686","title":"Alopecia and hypotrichosis as characteristic findings in Woodhouse-Sakati syndrome: report of a family with mutation in the C2orf37 gene.","abstract":"Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disorder characterized by alopecia, hypogonadism, diabetes mellitus, intellectual disability, sensorineural deafness, extrapyramidal signs, and low insulinlike growth factor 1 levels. Inter- and intrafamilial phenotypic variability have been reported. Mutations in the C2orf37 gene cause WSS. The present report describes the clinical signs and symptoms of three affected siblings from a consanguineous Bedouin family from Kuwait. Direct sequencing of the C2orf37 gene revealed that the c.436delC (p.Ala147Hisfs*9) mutation was present in a homozygous state in all affected siblings and in a heterozygous state in the parents and a healthy sister. Nine C2orf37 mutations causing WSS have been identified. This family shared the mutation reported earlier in Saudi families and families of Bedouin tribes from Qatar and Israel. No phenotypic or genotypic correlation has been observed. Despite the great phenotypic variability of WSS, hypotrichosis has been observed in all individuals with WSS reported. This condition has not been reported in the dermatologic literature. WSS should be included in the differential diagnosis of syndromic congenital hypotrichosis.","variants":[{"Name":"NM_025000.4(DCAF17):c.436del (p.Ala147fs)","Chromosome":"2","Start":"171448795","Stop":"171448795","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":205728,"rule_based_match":true,"evidence_text":"c.436delC (p.Ala147Hisfs*9)","llm_judgment":"PRESENT","evidence":"c.436delC (p.Ala147Hisfs*9)","abstract_start":549,"abstract_end":576}]}
{"pmid":"35509038","title":"Gitelman syndrome with normocalciuria - a case report.","abstract":"BACKGROUND: Gitelman Syndrome (GS) is a hereditary tubulopathy associated with a biallelic inactivating mutations of the SLC12A3 gene encoding the thiazide-sensitive sodium-chloride cotransporter (NCCT). The typical clinical manifestation is a hypokalemic metabolic alkalosis with significant hypomagnesemia, and low urinary calcium excretion. Hypocalciuria is widely believed to be a hallmark of GS that distinguishes it from Barter's syndrome, presenting as hypercalciuria. The pathomechanism of hypocalciuria in GS is not fully elucidated. Up to date, a clinical course of GS with normocalciuria has been reported only in men, while women have a milder course of the disease with typical hypocalciuria, which is believed as the result of sex hormone. Additionally, there is a growing evidence that calcium channels of the distal nephron could be regulated by a variety of hormones, including aldosterone (Aldo).\nCASE PRESENTATION: We present the case of a 28-year-old Caucasian woman with asymptomatic, chronic hypokalemia, hypomagnesemia, hypochloremic alkalosis and normal urinary calcium excretion. A high renin levels with normal concentration of Aldo in serum have also been found. The values of blood pressure were low. Based on genetic studies, two heterozygous mutations in the trans position were confirmed: c.2186G>T (p.Gly729Val) and c.1247G>C (p.Cys416Ser) in the SLC12A3 gene, which ultimately confirmed the diagnosis of GS.\nCONCLUSIONS: We report here the first case of genetically confirmed GS manifested as normocalciuria in a Caucasian woman. Thus, our result does not confirm a role of sex hormones on the level of calciuria. Based on the results of normal Aldo concentration despite high renin level in our patient, we hypothesized that Aldo may be connecting with the level of urinary calcium excretion in patients with the GS.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.2186G>T (p.Gly729Val)","Chromosome":"16","Start":"56887932","Stop":"56887932","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":983017,"rule_based_match":true,"evidence_text":"c.2186G>T (p.Gly729Val)","llm_judgment":"PRESENT","evidence":"c.2186G>T (p.Gly729Val)","abstract_start":1320,"abstract_end":1343},{"Name":"NM_001126108.2(SLC12A3):c.1247G>C (p.Cys416Ser)","Chromosome":"16","Start":"56879139","Stop":"56879139","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":980379,"rule_based_match":true,"evidence_text":"c.1247G>C (p.Cys416Ser)","llm_judgment":"PRESENT","evidence":"c.1247G>C (p.Cys416Ser)","abstract_start":1348,"abstract_end":1371}]}
{"pmid":"33784018","title":"Deciphering DSC2 arrhythmogenic cardiomyopathy electrical instability: From ion channels to ECG and tailored drug therapy.","abstract":"BACKGROUND: Severe ventricular rhythm disturbances are the hallmark of arrhythmogenic cardiomyopathy (ACM), and are often explained by structural conduction abnormalities. However, comprehensive investigations of ACM cell electrical instability are lacking. This study aimed to elucidate early electrical myogenic signature of ACM.\nMETHODS: We investigated a 41-year-old ACM patient with a missense mutation (c.394C>T) in the DSC2 gene, which encodes desmocollin 2. Pathogenicity of this variant was confirmed using a zebrafish DSC2 model system. Control and DSC2 patient-derived pluripotent stem cells were reprogrammed and differentiated into cardiomyocytes (hiPSC-CM) to examine the specific electromechanical phenotype and its modulation by antiarrhythmic drugs (AADs). Samples of the patient's heart and hiPSC-CM were examined to identify molecular and cellular alterations.\nRESULTS: A shortened action potential duration was associated with reduced Ca<sup>2+</sup> current density and increased K<sup>+</sup> current density. This finding led to the elucidation of previously unknown abnormal repolarization dynamics in ACM patients. Moreover, the Ca<sup>2+</sup> mobilised during transients was decreased, and the Ca<sup>2+</sup> sparks frequency was increased. AAD testing revealed the following: (1) flecainide normalised Ca<sup>2+</sup> transients and significantly decreased Ca<sup>2+</sup> spark occurrence and (2) sotalol significantly lengthened the action potential and normalised the cells' contractile properties.\nCONCLUSIONS: Thorough analysis of hiPSC-CM derived from the DSC2 patient revealed abnormal repolarization dynamics, prompting the discovery of a short QT interval in some ACM patients. Overall, these results confirm a myogenic origin of ACM electrical instability and provide a rationale for prescribing class 1 and 3 AADs in ACM patients with increased ventricular repolarization reserve.","variants":[{"Name":"NM_024422.6(DSC2):c.394C>T (p.Arg132Cys)","Chromosome":"18","Start":"31091108","Stop":"31091108","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":176520,"rule_based_match":true,"evidence_text":"c.394C>T","llm_judgment":"PRESENT","evidence":"c.394C>T","abstract_start":409,"abstract_end":417}]}
{"pmid":"28546763","title":"Mutation analysis of β-thalassemia in East-Western Indian population: a recent molecular approach.","abstract":"BACKGROUND: β-Thalassemia is the most prevalent genetic disorder in India. Its traits and coinheritance vary from mild to severe conditions, resulting in thalassemia minor, intermediate, and major, depending upon many factors.\nPURPOSE: The objective of this study was to identify the incidence of β-thalassemia traits, their coinheritance, and mutations, as well as to support the patients already diagnosed with β-thalassemia in East-Western Indian population for better management.\nPATIENTS AND METHODS: Seventy-five referral cases for β-thalassemia were analyzed for various β-thalassemia traits, heterozygosity, and homozygosity conditions. Blood phenotypic parameters using cell counter and capillary electrophoresis were investigated. Analyses of eight common mutations of thalassemia in India were carried out using polymerase chain reaction-amplification refractory mutation system, end point polymerase chain reaction, and DNA sequencing methods.\nRESULTS: Of these (75) referral cases from East-Western Indian region, 68 were positive for β-thalassemia (90.67%). The majority of case types were of β-thalassemia minor (49, 65.33%), followed by HbE traits (6, 8.0%) and β-thalassemia major, including heterozygous and homozygous (5, 6.66%; 4, 5.33%) types and then HbE homozygous (2, 2.66%), as well as one each of the HbE/β-thalassemia and HbD/β-thalassemia (1, 1.34%) combination. Mutation analysis also revealed that the highest frequency of mutation was c.92+5G>C (41, 60.29%) followed by deletion 619bp (9, 13.23%) and c.79G>A (8, 11.76%) in our study group. Five cases (nos. 24, 27, 33, 58, and 71) exhibited coinheritance between β<sup>0</sup>/β<sup>+</sup> (2), β<sup>0</sup>/β D (1), and c.124_127delTTCT/β<sup>+</sup> or β<sup>0</sup>(2) affecting the Rajasthani and Gujarati populations in our study of the Western region of India.\nCONCLUSION: We strongly recommend these Western populations for genetic screening before adopting reproductive technologies and interracial marital relations.","variants":[{"Name":"NM_000518.5(HBB):c.79G>A (p.Glu27Lys)","Chromosome":"11","Start":"5226943","Stop":"5226943","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30200,"rule_based_match":true,"evidence_text":"c.79G>A","llm_judgment":"PRESENT","evidence":"c.79G>A","abstract_start":1532,"abstract_end":1539}]}
{"pmid":"26167679","title":"Mutation in BMPR2 Promoter: A 'Second Hit' for Manifestation of Pulmonary Arterial Hypertension?","abstract":"BACKGROUND: Hereditary pulmonary arterial hypertension (HPAH) can be caused by autosomal dominant inherited mutations of TGF-β genes, such as the bone morphogenetic protein receptor 2 (BMPR2) and Endoglin (ENG) gene. Additional modifier genes may play a role in disease manifestation and severity. In this study we prospectively assessed two families with known BMPR2 or ENG mutations clinically and genetically and screened for a second mutation in the BMPR2 promoter region.\nMETHODS: We investigated the BMPR2 promoter region by direct sequencing in two index-patients with invasively confirmed diagnosis of HPAH, carrying a mutation in the BMPR2 and ENG gene, respectively. Sixteen family members have been assessed clinically by non-invasive methods and genetically by direct sequencing.\nRESULTS: In both index patients with a primary BMPR2 deletion (exon 2 and 3) and Endoglin missense variant (c.1633G>A, p.(G545S)), respectively, we detected a second mutation (c.-669G>A) in the promoter region of the BMPR2 gene. The index patients with 2 mutations/variants were clinically severely affected at early age, whereas further family members with only one mutation had no manifest HPAH.\nCONCLUSION: The finding of this study supports the hypothesis that additional mutations may lead to an early and severe manifestation of HPAH. This study shows for the first time that in the regulatory region of the BMPR2 gene the promoter may be important for disease penetrance. Further studies are needed to assess the incidence and clinical relevance of mutations of the BMPR2 promoter region in a larger patient cohort.","variants":[{"Name":"NM_001114753.3(ENG):c.1633G>A (p.Gly545Ser)","Chromosome":"9","Start":"127818173","Stop":"127818173","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":240451,"rule_based_match":true,"evidence_text":"c.1633G>A, p.(G545S)","llm_judgment":"PRESENT","evidence":"c.1633G>A, p.(G545S)","abstract_start":900,"abstract_end":920}]}
{"pmid":"28143899","title":"A missense mutation in the","abstract":"BACKGROUND: Autosomal-recessive non-syndromic intellectual disability (ARNS-ID) is an aetiologically heterogeneous disorder. Although little is known about the function of human cereblon (CRBN), its relationship to mild cognitive deficits suggests that it is involved in the basic processes of human memory and learning.\nOBJECTIVES: We aim to identify the genetic cause of intellectual disability and self-mutilation in a consanguineous Saudi family with five affected members.\nMETHODS: Clinical whole-exome sequencing was performed on the proband patient, and Sanger sequencing was done to validate and confirm segregation in other family members.\nRESULTS: A missense variant (c. 1171T>C) in the <i>CRBN</i> gene was identified in five individuals with severe intellectual disability (ID) in a consanguineous Saudi family. The homozygous variant was co-segregating in the family with the phenotype of severe ID, seizures and self-mutilating behaviour. The missense mutation (p.C391R) reported here results in the replacement of a conserved cysteine residue by an arginine in the CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide) domain of CRBN, which contains a zinc-binding site.\nCONCLUSIONS: These findings thus contribute to a growing list of ID disorders caused by <i>CRBN</i> mutations, broaden the spectrum of phenotypes attributable to ARNS-ID and provide new insight into genotype-phenotype correlations between <i>CRBN</i> mutations and the aetiology of ARNS-ID.","variants":[{"Name":"NM_016302.4(CRBN):c.1171T>C (p.Cys391Arg)","Chromosome":"3","Start":"3151023","Stop":"3151023","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":205733,"rule_based_match":true,"evidence_text":"c. 1171T>C","llm_judgment":"PRESENT","evidence":"c. 1171T>C","abstract_start":678,"abstract_end":688}]}
{"pmid":"36709934","title":"Clinical characteristics and genetic analysis of three children with Congenital chlorine diarrhea","abstract":"OBJECTIVE: To explore the clinical characteristics and genetic basis for three children with Congenital chlorine diarrhea (CCD).\nMETHODS: Three children with CCD who attended the Affiliated Children's Hospital of Capital Pediatric Institute from June 2014 to August 2020 were selected as the research subjects. Peripheral blood samples of the three children and their parents were collected for genetic testing. And the results were verified by Sanger sequencing.\nRESULTS: The clinical manifestations of the three children have included recurrent diarrhea, with various degrees of hypochloremia, hypokalemia and refractory metabolic alkalosis. Genetic testing revealed that the three children have all carried variants of the SLC26A3 gene, including homozygous c.1631T>A (p.I544N) variants, c.2063_1G>T and c.1039G>A (p.A347T) compound heterozygous variants, and c.270_271insAA(p.G91kfs*3) and c.2063_1G>T compound heterozygous variants. Sanger sequencing confirmed that all of the variants were inherited from their parents.\nCONCLUSION: The variants of the SLC26A3 gene probably underlay the CCD in these children. Above finding has enriched the spectrum of SLC26A3 gene variants.","variants":[{"Name":"NM_000111.3(SLC26A3):c.1631T>A (p.Ile544Asn)","Chromosome":"7","Start":"107776498","Stop":"107776498","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":70624,"rule_based_match":true,"evidence_text":"c.1631T>A (p.I544N)","llm_judgment":"PRESENT","evidence":"c.1631T>A (p.I544N)","abstract_start":761,"abstract_end":780}]}
{"pmid":"24518840","title":"Novel physiological RECQL4 alternative transcript disclosed by molecular characterisation of Rothmund-Thomson Syndrome sibs with mild phenotype.","abstract":"Rothmund-Thomson syndrome is a rare genodermatosis caused by biallelic mutations of the RECQL4 gene and is characterised by poikiloderma, sparse hair, eyelashes and/or eyebrows, small stature, skeletal and dental abnormalities and cancer predisposition. Mutations predicted to result in the loss of RECQL4 protein have been associated with osteosarcoma risk, but mutation(s)-phenotype correlations are better addressed by combined DNA and RNA analyses. We describe two siblings with a mild phenotype, mainly restricted to the skin, who carry the unreported paternal c.2272C>T alteration in exon 14 and the previously reported maternal exon 15 c.2492_2493delAT, both predicted to result in premature termination codons (p.(Arg758*), p.(His831Argfs*52)). However real-time and transcript analysis showed, in the carrier father and affected daughter, increased levels of a novel RECQL4 physiological alternative transcript with partial in-frame skipping of exon 14, generated by increased usage of a weak cryptic splice site. This alternative transcript is expressed in all controls and tested tissues, its upregulation is specific to the paternal c.2272C>T mutation and depends on the abrogation of the binding motifs for SF2 and SRp55 serine/arginine-rich proteins with bypass of the mutation site located in the skipped exon 14 portion. Moreover, in the proband the increased levels of the alternative transcript, likely encoding a protein isoform with residual activity, may compensate for the dearth of the canonical transcript with the c.2492_2493delAT, accounting for the mild clinical phenotype of the siblings. Our results emphasise the value of RNA analysis to better predict the effects of RECQL4 mutations on the clinical phenotype.","variants":[{"Name":"NM_004260.4(RECQL4):c.2492_2493del (p.His831fs)","Chromosome":"8","Start":"144513109","Stop":"144513110","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":21103,"rule_based_match":true,"evidence_text":"c.2492_2493delAT","llm_judgment":"PRESENT","evidence":"c.2492_2493delAT","abstract_start":643,"abstract_end":659}]}
{"pmid":"28621010","title":"Diversity of renal phenotypes in patients with WDR19 mutations: Two case reports.","abstract":"WDR19 has been reported as a causative gene of nephronophthisis-related ciliopathies. Patients with WDR19 mutations can show various extrarenal manifestations such as skeletal disorders, Caroli disease, and retinal dystrophy, and typically display nephronophthisis as a renal phenotype. However, there is limited information on the renal phenotypes of patients with WDR19 mutations. We report two Japanese infants with Sensenbrenner syndrome caused by WDR19 mutations who demonstrated different features in renal ultrasound and histopathological results, despite several common extrarenal manifestations. Patient 1 had normal sized and hyperechogenic kidneys with several small cysts and histopathological findings compatible with infantile nephronophthisis. Renal ultrasound of Patient 2 showed enlarged kidneys with diffuse microcysts resembling those of autosomal recessive polycystic kidney disease. Her renal histopathology revealed dysplastic kidney with diffuse glomerular cysts. Genetic testing identified compound heterozygous mutations in WDR19 in both patients (Patient 1: c.953delA, c.3533G > A, Patient 2: c.2645 + 1G > T, c.3533G > A). Our patients suggest that WDR19 mutations can cause dysplastic kidney in addition to nephronophthisis pathologically. In addition, differences in pathology of the kidneys from WDR19 mutations may result in heterogeneous features in renal ultrasound findings. Renal phenotypes from WDR19 mutations may thus be more diverse than previously reported. Extrarenal manifestations and genetic testing can therefore help to diagnosis this disease more precisely.","variants":[{"Name":"NM_025132.4(WDR19):c.3533G>A (p.Arg1178Gln)","Chromosome":"4","Start":"39273029","Stop":"39273029","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132656,"rule_based_match":true,"evidence_text":"c.3533G > A","llm_judgment":"PRESENT","evidence":"c.3533G > A","abstract_start":1095,"abstract_end":1106},{"Name":"NM_025132.4(WDR19):c.2645+1G>T","Chromosome":"4","Start":"39244553","Stop":"39244553","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1679038,"rule_based_match":true,"evidence_text":"c.2645 + 1G > T","llm_judgment":"PRESENT","evidence":"c.2645 + 1G > T","abstract_start":1119,"abstract_end":1134}]}
{"pmid":"25687217","title":"Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients.","abstract":"BACKGROUND: To evaluate the prevalence of BAP1 germline mutations in a series of young patients with uveal melanoma (UM), diagnosed before age 30.\nMATERIALS AND METHODS: The study was carried out on 14 young uveal melanoma patients (average age 21.4 years, range 3 months to 29 years). Germline DNA was extracted from peripheral blood. BAP1 sequencing was carried out using direct sequencing of all exons and adjacent intronic sequences. We also tested for germline mutations in additional melanoma-associated candidate genes CDKN2A and CDK4 (exon 4).\nRESULTS: We identified one patient with a pathogenic mutation (c. 1717delC, p.L573fs*3) in BAP1. This patient was diagnosed with UM at age 18 years and had a family history of a father with UM and a paternal grandfather with cancer of unknown origin. One additional patient had an intronic variant of uncertain significance (c.123-48T > G) in BAP1 while the remaining 12 patients had no alteration. None of the patients had CDKN2A or CDK4 (Exon 4) mutations. Family history was positive for a number of additional malignancies in this series, in particular for cutaneous melanoma, prostate, breast and colon cancers. There were no families with a history of mesothelioma or renal cell carcinoma.\nCONCLUSIONS: This study suggests that a small subset of patients with early onset UM has germline mutation in BAP1. While young patients with UM should be screened for germline BAP1 mutations, our results suggest that there is a need to identify other candidate genes which are responsible for UM in young patients.","variants":[{"Name":"NM_004656.4(BAP1):c.1717del (p.Leu573fs)","Chromosome":"3","Start":"52403428","Stop":"52403428","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":222989,"rule_based_match":true,"evidence_text":"c. 1717delC, p.L573fs*3","llm_judgment":"PRESENT","evidence":"c. 1717delC, p.L573fs*3","abstract_start":615,"abstract_end":638}]}
{"pmid":"22061863","title":"A novel splicing mutation in FKBP10 causing osteogenesis imperfecta with a possible mineralization defect.","abstract":"Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by bone fragility and osteopenia, with a broad spectrum of clinical severity. The majority of cases are dominantly inherited and due to mutations in type I collagen genes, whereas recessive forms are less frequent and attributable to mutations in different genes involved in collagen I post translational modifications and folding (prolyl-3-hydroxylase complex, SERPINH1, FKBP10). We report the case of a patient with an initially mild and then progressively severe form of osteogenesis imperfecta due to a novel homozygous splicing mutation in FKBP10 (intron 8 c.1399+1G>A), which results in aberrant mRNA processing and consequent lack of FKBP65 chaperone. Although this mutation does not affect collagen type I post translational modifications in dermal fibroblasts, the histomorphometric pattern of our patient's bone sample showed a mineralization defect possibly due to the mutation in FKBP10.","variants":[{"Name":"NM_021939.4(FKBP10):c.1399+1G>A","Chromosome":"17","Start":"41821090","Stop":"41821090","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2905166,"rule_based_match":true,"evidence_text":"c.1399+1G>A","llm_judgment":"PRESENT","evidence":"c.1399+1G>A","abstract_start":640,"abstract_end":651}]}
{"pmid":"26386245","title":"Novel SMC1A frameshift mutations in children with developmental delay and epilepsy.","abstract":"Cornelia de Lange syndrome (CdLS) is a rare dominantly inherited genetic multisystem developmental condition with considerable phenotypic and allelic heterogeneity. Missense and in-frame deletions within the SMC1A gene can be associated with epilepsy and milder craniofacial features. We report two females who presented with developmental delay and developed isolated medically refractory seizures with unrevealing initial laboratory, imaging and genetic evaluations. Whole exome sequencing (WES) analyses were performed and were instrumental in uncovering the genetic etiology for their conditions. WES identified two novel de novo heterozygous frameshift mutations in the SMC1A gene [c.2853_2856delTCAG (p.Ser951Argfs*12) and c.3549_3552dupGGCC (p.Ile1185Glyfs*23)]. We also observed marked skewing of X-inactivation in one patient. The individual with the p.Ser951Argfs*12 mutation represents an extreme on the CdLS phenotypic spectrum, with prominent neurological involvement of severe developmental delay and refractory epilepsy, with mild craniofacial features. Both individuals eventually had incomplete clinical responses to therapy with valproic acid. We review previous reports of SMC1A mutations with epilepsy. SMC1A should be included in clinical gene panels for early infantile and early childhood epileptic encephalopathy.","variants":[{"Name":"NM_006306.4(SMC1A):c.3549_3552dup (p.Ile1185fs)","Chromosome":"X","Start":"53380685","Stop":"53380686","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TGGCC","allel_id":205197,"rule_based_match":true,"evidence_text":"c.3549_3552dupGGCC (p.Ile1185Glyfs*23)","llm_judgment":"PRESENT","evidence":"c.3549_3552dupGGCC (p.Ile1185Glyfs*23)","abstract_start":729,"abstract_end":767},{"Name":"NM_006306.4(SMC1A):c.2853_2856del (p.Ser951fs)","Chromosome":"X","Start":"53396233","Stop":"53396236","ReferenceAlleleVCF":"CCTGA","AlternateAlleleVCF":"C","allel_id":205198,"rule_based_match":true,"evidence_text":"c.2853_2856delTCAG (p.Ser951Argfs*12)","llm_judgment":"PRESENT","evidence":"c.2853_2856delTCAG (p.Ser951Argfs*12)","abstract_start":687,"abstract_end":724}]}
{"pmid":"21402907","title":"Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke.","abstract":"We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneurysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud's phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-α found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, c.1411-2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Immunoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.","variants":[{"Name":"NM_015474.4(SAMHD1):c.1411-2A>G","Chromosome":"20","Start":"36904251","Stop":"36904251","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":131940,"rule_based_match":true,"evidence_text":"c.1411-2A > G","llm_judgment":"PRESENT","evidence":"c.1411-2A > G","abstract_start":1258,"abstract_end":1271}]}
{"pmid":"25683699","title":"Non-coding VMA21 deletions cause X-linked myopathy with excessive autophagy.","abstract":"X-linked Myopathy with Excessive Autophagy (XMEA) affects proximal muscles of the lower extremities and follows a progressive course reminiscent of muscular dystrophy. It is caused by mutations in VMA21 whose protein product assembles lysosomes' proton pumps. All XMEA mutations to date have been single-nucleotide substitutions that reduce VMA21 expression, which leads to modest lysosomal pH increase, the first step in the disease's pathogenesis. We now report a new class of XMEA mutations. We identified two VMA21 non-coding microdeletions, one intronic (c.54-16_54-8del), the other in the 3'UTR (c.*13_*104del). Both resulted in a relatively more severe (early ambulation loss), diffuse (extra-ocular and upper extremity involvement), and early (neonatal) onset disease compared to previously reported patients. Our cases highlight the importance of including non-coding regions of VMA21 in genetic testing panels of dystrophies and myopathies. Specific diagnosis of XMEA will be particularly important as therapies aimed at correcting the modest rise in lysosomal pH at the root of this disease are developed.","variants":[{"Name":"NM_001017980.4(VMA21):c.*13_*104del","Chromosome":"X","Start":"151405071","Stop":"151405162","ReferenceAlleleVCF":"CCTTTTTATAGCATTAAATTCATTTTTTAAAATGATAAATGCTGGAGGGGGCCATCTGATTTGAATAAAGTTGAAAGAACATGTTAAAGTCAG","AlternateAlleleVCF":"C","allel_id":205366,"rule_based_match":true,"evidence_text":"c.*13_*104del","llm_judgment":"PRESENT","evidence":"c.*13_*104del","abstract_start":602,"abstract_end":615},{"Name":"NM_001017980.4(VMA21):c.54-16_54-8del","Chromosome":"X","Start":"151403611","Stop":"151403619","ReferenceAlleleVCF":"TCTTTGTTTA","AlternateAlleleVCF":"T","allel_id":205367,"rule_based_match":true,"evidence_text":"c.54-16_54-8del","llm_judgment":"PRESENT","evidence":"c.54-16_54-8del","abstract_start":560,"abstract_end":575}]}
{"pmid":"30337205","title":"Neurotransmitter trafficking defect in a patient with clathrin (CLTC) variation presenting with intellectual disability and early-onset parkinsonism.","abstract":"INTRODUCTION: Clathrins play a key role in endocytosis, recycling, and trafficking as well as the generation of presynaptic vesicles. We report a new clinical condition associated with a de novo variant in the CLTC gene, which encodes the clathrin heavy polypeptide.\nCASE REPORT: This 30-year-old woman presented with a developmental disorder during childhood that progressed to mild cognitive decline in late childhood and relapsing-remitting hypokinetic-rigid syndrome with severe achalasia, weight loss, and mood disorder in adulthood. <sup>123</sup>I-Ioflupane SPECT was normal. Blood phenylalanine was slightly increased and PAH sequencing revealed compound heterozygosity for two variants, p.[Asp151Glu]:[Thr380Met]. CSF examination unexpectedly detected a remarkable reduction of homovanillic, 5-hydroxyindolacetic, and 5-methylthetrahydrofolic acids, which could not be ascribed to any alteration of tetrahydrobiopterin and related biogenic amine pathways.\nMETHODS: Trio-based exome sequencing was performed.\nRESULT: A de novo missense variant (c.2669C > T/p.Pro890Leu) was detected in CLTC. Treatment with biogenic amine precursors was ineffective, while the inhibitor of MAO-A selegiline resulted in persistent clinical improvement.\nCONCLUSIONS: We suggest CLTC defect as a new disorder of biogenic amine trafficking, resulting in neurodevelopmental derangement and movement disorder. Neurotransmitter depletion in CSF may be a biomarker of this disease, and selegiline a possible treatment option.","variants":[{"Name":"NM_004859.4(CLTC):c.2669C>T (p.Pro890Leu)","Chromosome":"17","Start":"59677061","Stop":"59677061","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":481274,"rule_based_match":true,"evidence_text":"c.2669C > T/p.Pro890Leu","llm_judgment":"PRESENT","evidence":"c.2669C > T/p.Pro890Leu","abstract_start":1053,"abstract_end":1076}]}
{"pmid":"38105698","title":"Genetic analysis of novel pathogenic gene","abstract":"A 13-year and 6-month old girl attended the Hunan Children's Hospital due to delayed menarche. The laboratory test results indicated an increased follicle-stimulating hormone and luteinizing hormone, decreased anti-Mullerian hormone, and pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries. Her 11-year and 5-month old younger sister had the same laboratory and imaging findings, and both girls were diagnosed as primary ovarian insufficiency. Whole exome sequencing and Sanger sequencing confirmed that the proband and her sister carried heterozygous variants of <i>HROB</i> gene c.718C>T (p.Arg240*) and c.1351C>T (p.Arg451*), which were inherited from their parents respectively and consistent with autosomal recessive inheritance. Oral estradiol valerate at an initial dose of 0.125 mg/d was given to the proband, and the secondary sexual characteristics and uterine development were monitored.","variants":[{"Name":"NM_001171251.3(HROB):c.718C>T (p.Arg240Ter)","Chromosome":"17","Start":"44148521","Stop":"44148521","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3414236,"rule_based_match":true,"evidence_text":"c.718C>T (p.Arg240*)","llm_judgment":"PRESENT","evidence":"c.718C>T (p.Arg240*)","abstract_start":606,"abstract_end":626},{"Name":"NM_001171251.3(HROB):c.1351C>T (p.Arg451Ter)","Chromosome":"17","Start":"44152679","Stop":"44152679","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3414237,"rule_based_match":true,"evidence_text":"c.1351C>T (p.Arg451*)","llm_judgment":"PRESENT","evidence":"c.1351C>T (p.Arg451*)","abstract_start":631,"abstract_end":652}]}
{"pmid":"30068478","title":"A Chinese CARASIL Patient Caused by Novel Compound Heterozygous Mutations in HTRA1.","abstract":"Our objective is to reported a Chinese CARASIL patient caused by novel compound heterozygous mutations in HTRA1. Detailed clinical and neuroimaging examination were conducted in proband and her available family members. Sanger sequencing of NOTCH3 and HTRA1 was used to investigate causative mutations. The patient was born in an outbred family. She experienced recurrent transient ischemic attacks, hair loss, and low back pain. Brain magnetic resonance imaging showed multiple lacunar infarctions, diffuse leukoencephalopathy, and multiple microbleeds of white matter. A compound heterozygous mutation, c.958G > A (p.D320N) and c.1021G > A (p.G341J), were identified in the proband. This report highlights that screening of HTRA1 should be considered in young SVD patient despite from outbred families.","variants":[{"Name":"NM_002775.5(HTRA1):c.958G>A (p.Asp320Asn)","Chromosome":"10","Start":"122506871","Stop":"122506871","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1699062,"rule_based_match":true,"evidence_text":"c.958G > A (p.D320N)","llm_judgment":"PRESENT","evidence":"c.958G > A (p.D320N)","abstract_start":605,"abstract_end":625}]}
{"pmid":"31481313","title":"Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature.","abstract":"ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare disorder caused by a deficiency of dolichol-P-mannose:Man<sub>7</sub>GlcNAc<sub>2</sub>-PP-dolichyl-α-6-mannosyltransferase which presents with intellectual disability, hypotonia, dysmorphic features, low IgG levels with recurrent infections, male genital hypoplasia, and coagulation abnormalities. We report a unique family with three affected individuals, including two older brothers with only cognitive and coagulation defects and a younger brother who died from a severe multisystem disease at age 18 months. The two living brothers are the oldest and mildest cases of ALG12-CDG described thus far. Whole exome sequencing of the older brothers revealed a previously described c.1001delA (p.N334TfsX15) pathogenic variant and a c.671C > T (p.T224 M) variant of uncertain significance in ALG12. Our cases broaden the recognized genetic and phenotypic spectrum of this disorder and suggest a role for other genetic and environmental factors in modulating disease phenotype.","variants":[{"Name":"NM_024105.4(ALG12):c.671C>T (p.Thr224Met)","Chromosome":"22","Start":"49909341","Stop":"49909341","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":471157,"rule_based_match":true,"evidence_text":"c.671C > T (p.T224 M)","llm_judgment":"PRESENT","evidence":"c.671C > T (p.T224 M)","abstract_start":797,"abstract_end":818},{"Name":"NM_024105.4(ALG12):c.1001del (p.Asn334fs)","Chromosome":"22","Start":"49904498","Stop":"49904498","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":243958,"rule_based_match":true,"evidence_text":"c.1001delA (p.N334TfsX15)","llm_judgment":"PRESENT","evidence":"c.1001delA (p.N334TfsX15)","abstract_start":746,"abstract_end":771}]}
{"pmid":"21565171","title":"Identification of CYP4V2 mutation in 21 families and overview of mutation spectrum in Bietti crystalline corneoretinal dystrophy.","abstract":"Bietti crystalline corneoretinal dystrophy (BCD, MIM 210370) is a common form of hereditary retinal degeneration in the Chinese population. BCD is caused by CYP4V2 mutations. Understanding the CYP4V2 mutational spectrum and associated phenotypes is of value for clinical practice. In this study, nine CYP4V2 mutations, including four novel ones (c.215-2A>G, c.761A>G, c.958C>T, and c.1169G>A), were detected in all 21 families with BCD. All patients with CYP4V2 mutations had phenotypes typical for BCD. As of now, 34 CYP4V2 mutations have been identified in 104 of 109 families (95.4%), affecting 204 of the 218 alleles (93.6%). Of the 34 mutations, c.802-8_810del17insGC, c.992A>C, and c.1091-2A>G are the most common mutations, accounting for 62.7%, 7.4%, and 6.4% of the 204 mutant alleles, respectively. The remaining 31 mutations were only detected in 1-6 alleles. Mutations in exons 7, 8, and 9 account for 83.3% of mutant alleles (64.7%, 9.3%, and 10.3%, respectively). Our results expand the mutation spectrum of CYP4V2 and demonstrate an overview of the CYP4V2 mutation spectrum and its frequency in families with BCD. BCD is a clinically and genetically homogenous disease.","variants":[{"Name":"NM_207352.4(CYP4V2):c.761A>G (p.His254Arg)","Chromosome":"4","Start":"186199043","Stop":"186199043","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":47876,"rule_based_match":true,"evidence_text":"c.761A>G","llm_judgment":"PRESENT","evidence":"c.761A>G","abstract_start":358,"abstract_end":366},{"Name":"NM_207352.4(CYP4V2):c.1091-2A>G","Chromosome":"4","Start":"186208863","Stop":"186208863","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":17230,"rule_based_match":true,"evidence_text":"c.1091-2A>G","llm_judgment":"PRESENT","evidence":"c.1091-2A>G","abstract_start":688,"abstract_end":699},{"Name":"NM_207352.4(CYP4V2):c.1169G>A (p.Arg390His)","Chromosome":"4","Start":"186208943","Stop":"186208943","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":47857,"rule_based_match":true,"evidence_text":"c.1169G>A","llm_judgment":"PRESENT","evidence":"c.1169G>A","abstract_start":382,"abstract_end":391}]}
{"pmid":"22713807","title":"A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot.","abstract":"GJA5 gene (MIM no. 121013), localized at 1q21.1, encodes for the cardiac gap junction protein connexin 40. In humans, copy number variants of chromosome 1q21.1 have been associated with variable phenotypes comprising congenital heart disease (CHD), including isolated TOF. In mice, the deletion of Gja5 can cause a variety of complex CHDs, in particular of the cardiac outflow tract, corresponding to TOF in many cases. In the present study, we screened for mutations in the GJA5 gene 178 unrelated probands with isolated TOF. A heterozygous nucleotide change (c.793C>T) in exon 2 of the gene leading to the p.Pro265Ser variant at the carboxyl-terminus of the protein was found in two unrelated sporadic patients, one with classic anatomy and one with pulmonary atresia. This GJA5 missense substitution was not observed in 1568 ethnically-matched control chromosomes. Immunofluorescent staining and confocal microscopy revealed that cells expressing the mutant protein form sparse or no visible gap-junction plaques in the region of cell-cell contact. Moreover, analysis of the transfer of the gap junction permanent tracer lucifer yellow showed that cells expressing the mutant protein have a reduced rate of dye transfer compared with wild-type cells. Finally, use of a zebrafish model revealed that microinjection of the GJA5-p.Pro265Ser mutant disrupts overall morphology of the heart tube in the 37% (22/60) of embryos, compared with the 6% (4/66) of the GJA5 wild-type-injected embryos. These findings implicate GJA5 gene as a novel susceptibility gene for TOF.","variants":[{"Name":"NM_181703.4(GJA5):c.793C>T (p.Pro265Ser)","Chromosome":"1","Start":"147758446","Stop":"147758446","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":626782,"rule_based_match":true,"evidence_text":"c.793C>T","llm_judgment":"PRESENT","evidence":"c.793C>T","abstract_start":561,"abstract_end":569}]}
{"pmid":"35286032","title":"Clinical and molecular findings in 6 Turkish cases with Krabbe disease.","abstract":"BACKGROUND: Krabbe disease is a rare lysosomal storage disorder with a neurodegenerative course that occurs because of the deficiency of the beta-galactocerebrosidase (GALC) enzyme activity. The genetic basis of Krabbe disease consists of biallelic mutations in the GALC gene, but the genetic spectrum in the Turkish population is poorly defined. We aimed to present a Turkish case-series with infantile-onset Krabbe disease, define the clinical and molecular findings and compare the genetic spectrum with the mutations previously reported in the literature.\nMETHODS: Six cases, who were referred to our clinic between 2015-2019, with a definite diagnosis of infantileonset Krabbe disease were included in the study. The family history, clinical information, biochemical and radiological examinations of the patients were screened and evaluated. All encoded exons and exon-intron regions of the GALC gene were sequenced using next generation sequencing technology. Multiplex ligationdependent probe amplification analysis was used for deletion type mutations that could not be detected by sequence analysis.\nRESULTS: GALC gene sequence analysis revealed four known mutations including c.1394C > T (p.Thr465Ile), c.411_413delTAA (p.Lys139del), c.820G > C (p.Glu274Gln), and 30 kilobase deletion mutation among the exons 11-17 (IVS10del30kbp). Moreover, the c.1623G > A (p.Trp541Ter) variant, which was not previously reported in the literature, was detected in two cases.\nCONCLUSIONS: We believe that the demonstration of the genetic spectrum of infantile-onset Krabbe disease in Turkish patients will be an important contribution to the GALC mutation data in our country. More importantly, two novel variants were defined. This knowledge may enable early detection and treatment with the advent of a carrier or newborn screening tests.","variants":[{"Name":"NM_000153.4(GALC):c.411_413del (p.Lys139del)","Chromosome":"14","Start":"87986518","Stop":"87986520","ReferenceAlleleVCF":"CTTA","AlternateAlleleVCF":"C","allel_id":547914,"rule_based_match":true,"evidence_text":"c.411_413delTAA (p.Lys139del)","llm_judgment":"PRESENT","evidence":"c.411_413delTAA (p.Lys139del)","abstract_start":1213,"abstract_end":1242}]}
{"pmid":"32420470","title":"The dynamic landscape of","abstract":"BACKGROUND: Reversion mutations of somatic BRCA mutations are an important source of resistance within ovarian cancer. Furthermore, these reversion mutations are known to change over the course of treatment. Better understanding of the mechanisms leading to reversion mutations and the role of serial ctDNA collection in detecting changes to overall landscape of resistance mutations over time is needed to guide treatment in the metastatic setting.\nMETHODS: Here we study a case of metastatic ovarian cancer undergoing multiple lines of treatment with collection of three serial ctDNA samples. These samples were analyzed by Guardant Health next generation sequencing to detect somatic alterations and their associated mutant allele frequency (MAF) as % cfDNA.\nRESULTS: Analysis of our initial ctDNA collection, taken during PARP-inhibitor therapy, revealed a nonsense BRCA-1 mutation (c. 2563C > T p. Q855∗), consistent with the BRCA 1 somatic mutation detected on tumor tissue analysis. Initial analysis also revealed a reversion mutation (c.2535_2576del) resulting in an in-frame deletion of the somatic BRCA-1 alteration. The second collection, taken while still on PARP-inhibitor therapy, re-demonstrated this indel reversion mutation along with a second indel reversion mutation (c.2546_2587del), again resulting in an in-frame deletion of the somatic BRCA-1 mutation. The final ctDNA, collected upon initiation of immunotherapy, revealed 4 novel SNV reversion mutations (c.2564A > C, c.2564A > T, c.2565G > T, and c.2565G > C). These SNV reversion mutations result in missense amino acid changes rather than insertions or deletions within the BRCA-1 somatic mutation. The previous indel reversion mutations were no longer detected.\nCONCLUSIONS: This study illustrates the role of serial ctDNA analyses in the detection of resistance mutations and the dynamic nature of reversion mutations with multiple lines of treatment. While other studies have described both indels and SNVs that occur in tandem, a change in the types of reversion mutations detected across changing therapies has never before been described. Further studies regarding the unique selective pressures arising from use of multiple types of therapy is needed to fully explain this phenomenon.","variants":[{"Name":"NM_007294.4(BRCA1):c.2563C>T (p.Gln855Ter)","Chromosome":"17","Start":"43092968","Stop":"43092968","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46031,"rule_based_match":true,"evidence_text":"c. 2563C > T p. Q855∗","llm_judgment":"PRESENT","evidence":"c. 2563C > T p. Q855∗","abstract_start":887,"abstract_end":908}]}
{"pmid":"30507656","title":"Short article: Sequence variations of PKHD1 underlie congenital hepatic fibrosis in a Chinese family.","abstract":"OBJECTIVE: Congenital hepatic fibrosis (CHF) is a developmental disorder of the portobiliary system characterized by hepatic fibrosis, portal hypertension, and renal cystic disease. The aim of our study was to identify the disease-causing gene of a Chinese family with CHF.\nPATIENTS AND METHODS: Whole-exome sequencing was performed in the family with CHF and variants were confirmed by Sanger sequencing. Online bioinformatics tools were used to evaluate the pathogenicity of the missense variants. Liver specimens were reviewed to confirm the histopathological diagnosis.\nRESULTS: The compound heterozygous variants c.7994T>C, p.(Leu2665Pro) and c.8518C>T, p.(Arg2840Cys) in PKHD1 were identified in a Chinese family with CHF by whole-exome sequencing. Liver histomorphology was reviewed to confirm the diagnosis of CHF.\nCONCLUSION: We have identified variations in PKHD1 in a Chinese family with CHF. Our study extends the mutation spectrum of CHF and provides information for genetic counseling of patients' family members.","variants":[{"Name":"NM_138694.4(PKHD1):c.7994T>C (p.Leu2665Pro)","Chromosome":"6","Start":"51847888","Stop":"51847888","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1892091,"rule_based_match":true,"evidence_text":"c.7994T>C, p.(Leu2665Pro)","llm_judgment":"PRESENT","evidence":"c.7994T>C, p.(Leu2665Pro)","abstract_start":618,"abstract_end":643},{"Name":"NM_138694.4(PKHD1):c.8518C>T (p.Arg2840Cys)","Chromosome":"6","Start":"51775844","Stop":"51775844","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":624316,"rule_based_match":true,"evidence_text":"c.8518C>T, p.(Arg2840Cys)","llm_judgment":"PRESENT","evidence":"c.8518C>T, p.(Arg2840Cys)","abstract_start":648,"abstract_end":673}]}
{"pmid":"21542062","title":"Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism.","abstract":"Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient-derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS.","variants":[{"Name":"NM_022089.4(ATP13A2):c.3176T>G (p.Leu1059Arg)","Chromosome":"1","Start":"16986864","Stop":"16986864","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1791885,"rule_based_match":true,"evidence_text":"c.3176T>G (p.L1059R)","llm_judgment":"PRESENT","evidence":"c.3176T>G (p.L1059R)","abstract_start":292,"abstract_end":312}]}
{"pmid":"22848008","title":"Medium chain acyl-CoA dehydrogenase deficiency detected among Hispanics by New Jersey newborn screening.","abstract":"In the follow-up of New Jersey newborn screens suggestive of medium chain acyl-CoA dehydrogenase deficiency (MCADD) during a 30-month period, we identified five patients of Hispanic American ethnicity. With information provided by the New Jersey Department of Health and Human Services Newborn Screening program we calculated an overall cumulative incidence of approximately 7.20/100,000 for MCADD; 7.58/100,000 among Hispanic Americans and 7.08/100,000 among non-Hispanic Americans. Among the five Hispanic American infants who screened positive, a common variant (c.443G>A [p.R148K]) was identified which accounted for 30% of the alleles; c.799G>A (p.G267R) and c.985A>G (p.K329E) each accounted for an additional 20%; and a novel variant c.302G>A (p.G101E) was identified in one patient. Although treated prospectively during interim illnesses to prevent unwanted sequelae; till date, none of the patients carrying the c.443G>A variant have been symptomatic.","variants":[{"Name":"NM_000016.6(ACADM):c.443G>A (p.Arg148Lys)","Chromosome":"1","Start":"75734846","Stop":"75734846","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":195186,"rule_based_match":true,"evidence_text":"c.443G>A (p.R148K)","llm_judgment":"PRESENT","evidence":"c.443G>A","abstract_start":566,"abstract_end":574},{"Name":"NM_000016.6(ACADM):c.799G>A (p.Gly267Arg)","Chromosome":"1","Start":"75749509","Stop":"75749509","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18627,"rule_based_match":true,"evidence_text":"c.799G>A (p.G267R)","llm_judgment":"PRESENT","evidence":"c.799G>A (p.G267R)","abstract_start":641,"abstract_end":659}]}
{"pmid":"28777934","title":"Mutations in TRAPPC12 Manifest in Progressive Childhood Encephalopathy and Golgi Dysfunction.","abstract":"Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c.145delG [p.Glu49Argfs<sup>∗</sup>14]) or compound-heterozygous variants (c.360dupC [p.Glu121Argfs<sup>∗</sup>7] and c.1880C>T [p. Ala627Val]). The clinical phenotypes of the three individuals are strikingly similar: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12. Protein transport from the endoplasmic reticulum to and through the Golgi was delayed. TRAPPC12 is a member of the TRAPP protein complex, which functions in membrane trafficking. Variants in several other genes encoding members of the TRAPP complex have been associated with overlapping clinical presentations, indicating shared and distinct functions for each complex member. Detailed understanding of the TRAPP-opathies will illuminate the role of membrane protein transport in human disease.","variants":[{"Name":"NM_016030.6(TRAPPC12):c.145del (p.Glu49fs)","Chromosome":"2","Start":"3387768","Stop":"3387768","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":432365,"rule_based_match":true,"evidence_text":"c.145delG (p.Glu49Argfs<sup>∗</sup>14)","llm_judgment":"PRESENT","evidence":"p.Glu49Arg","abstract_start":613,"abstract_end":623},{"Name":"NM_016030.6(TRAPPC12):c.1880C>T (p.Ala627Val)","Chromosome":"2","Start":"3478848","Stop":"3478848","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":424367,"rule_based_match":true,"evidence_text":"c.1880C>T [p. Ala627Val]","llm_judgment":"PRESENT","evidence":"c.1880C>T [p. Ala627Val]","abstract_start":720,"abstract_end":744}]}
{"pmid":"29163546","title":"Glucose-6-Phosphatase Catalytic Subunit 3 (","abstract":"<i>G6PC3</i> deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients' monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1β and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients' cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses.","variants":[{"Name":"NM_138387.4(G6PC3):c.130C>T (p.Pro44Ser)","Chromosome":"17","Start":"44071095","Stop":"44071095","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187650,"rule_based_match":true,"evidence_text":"c.130 C>T","llm_judgment":"PRESENT","evidence":"c.130 C>T","abstract_start":258,"abstract_end":267}]}
{"pmid":"29910097","title":"A novel compound heterozygous mutation in the POMK gene causing limb-girdle muscular dystrophy-dystroglycanopathy in a sib pair.","abstract":"We describe two Finnish siblings in whom an incidentally detected elevated creatine kinase activity eventually led to a diagnosis of limb-girdle muscular dystrophy-dystroglycanopathy (Type C12; MDDGC12). When diagnosed at age 10 and 13 years, they were mildly affected with a slow or non-progressive disease course. The main symptoms comprised infrequent hip cramps triggered by flexion, neck cramps triggered by yawning, transient growing pains, calf hypertrophy and mild proximal muscle weakness. Their cognitive and motor developments were unremarkable and they were physically active. Whole-exome sequencing revealed compound heterozygous mutations, both of which were novel, in the protein O-mannosyl kinase (POMK) gene in both siblings; a missense mutation, p.Pro322Leu (c.965C > T), and a nonsense mutation, p.Arg46Ter (c.136C > T). The results were confirmed by Sanger sequencing, showing that the parents were heterozygous carriers of one mutation each. This report adds to the literature by providing phenotype and genotype data on this ultra-rare POMK-related dystroglycanopathy.","variants":[{"Name":"NM_032237.5(POMK):c.136C>T (p.Arg46Ter)","Chromosome":"8","Start":"43103684","Stop":"43103684","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":802164,"rule_based_match":true,"evidence_text":"c.136C>T","llm_judgment":"PRESENT","evidence":"c.136C > T","abstract_start":827,"abstract_end":837},{"Name":"NM_032237.5(POMK):c.965C>T (p.Pro322Leu)","Chromosome":"8","Start":"43122789","Stop":"43122789","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":802165,"rule_based_match":true,"evidence_text":"c.965C > T","llm_judgment":"PRESENT","evidence":"c.965C > T","abstract_start":777,"abstract_end":787}]}
{"pmid":"37362409","title":"A novel variant in the","abstract":"Objectives: Patients with Alport syndrome develop progressive kidney function deterioration, sensorineural hearing loss, and ocular abnormalities. This condition is caused by mutations in <i>COL4A5</i> (X-linked inheritance), <i>COL4A3</i> and <i>COL4A4</i> (autosomal dominant or recessive inheritance), and encoding type IV collagen α3, α4, and α5, respectively. If left untreated, clinical symptoms progress from microscopic hematuria to proteinuria, progressive kidney failure, and end-stage kidney disease. At present, kidney transplantation is the only effective approach. Next-generation sequencing is the method of choice for the diagnosis of this condition.\nCase presentation: We report the case of a young man with chronic kidney disease who eventually underwent transplantation. Molecular testing made it possible to determine the etiology of his clinical symptoms and autosomal recessive Alport syndrome type 2. The patient was found to be a compound heterozygote for two missense variants (<i>trans</i> configuration) in the <i>COL4A3</i> gene: A likely pathogenic variant c.4981C>T (p.Arg1661Cys) in exon 52 inherited from the mother (described elsewhere), and another variant of uncertain significance, c.943G>A (p.Gly315Ser), in exon 17 inherited from the father that has not been previously reported in the literature or found in relevant databases.\nConclusions: Following genetic confirmation, genetic counseling was provided to the patient and his direct relatives.","variants":[{"Name":"NM_000091.5(COL4A3):c.4981C>T (p.Arg1661Cys)","Chromosome":"2","Start":"227311838","Stop":"227311838","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":272152,"rule_based_match":true,"evidence_text":"c.4981C>T (p.Arg1661Cys)","llm_judgment":"PRESENT","evidence":"c.4981C>T (p.Arg1661Cys)","abstract_start":1086,"abstract_end":1110}]}
{"pmid":"29706351","title":"Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.","abstract":"Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.","variants":[{"Name":"NM_016306.6(DNAJB11):c.161C>G (p.Pro54Arg)","Chromosome":"3","Start":"186572187","Stop":"186572187","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":540572,"rule_based_match":false,"evidence_text":"p.Pro54Arg","llm_judgment":"PRESENT","evidence":"p.Pro54Arg","abstract_start":529,"abstract_end":539},{"Name":"NM_016306.6(DNAJB11):c.166_167insTT (p.Arg56fs)","Chromosome":"3","Start":"186572192","Stop":"186572193","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CTT","allel_id":540573,"rule_based_match":true,"evidence_text":"c.166_167insTT","llm_judgment":"PRESENT","evidence":"c.166_167insTT","abstract_start":639,"abstract_end":653}]}
{"pmid":"17365003","title":"A novel beta-Thalassemic allele due to a two nucleotide deletion: beta76 (-GC).","abstract":"We have identified and characterized a novel beta-thalassemic mutation in a North African adult. The molecular defect consists of a two nucleotide (nt) deletion in the beta-globin gene at codon 76 [beta76 (-GC), c.229-230delGC]. This frameshift mutation generates a TGA stop codon at position 89. The carrier presented with mild microcytic anemia (Hb 12.8 g/dL, MCV 60 fL), no detectable Hb F, an elevated Hb A2 level (5.5%) with no other mutation in the beta-globin gene and none of the more common known deletions in the alpha-globin cluster. No abnormal hemoglobin (Hb) was present in routine electrophoresis or in high performance liquid chromatography (HPLC) analyses. Pathologic inclusions were absent in both mature red cells and in reticulocytes. This observation reinforces the hypothesis that nonsense and frameshift mutations that result in a premature stop codon in exon 1 or exon 2 inherited in the heterozygous state do not generate dominant beta-thalassemia (thal). This is the first example of a premature stop codon at position 89.","variants":[{"Name":"NM_000518.5(HBB):c.229_230del (p.Ala77fs)","Chromosome":"11","Start":"5226662","Stop":"5226663","ReferenceAlleleVCF":"AGC","AlternateAlleleVCF":"A","allel_id":857460,"rule_based_match":false,"evidence_text":"c.229-230delGC","llm_judgment":"PRESENT","evidence":"c.229-230delGC","abstract_start":212,"abstract_end":226}]}
{"pmid":"36343861","title":"Pathogenicity of Intronic and Synonymous Variants of ATP7B in Wilson Disease.","abstract":"Wilson disease (WD) is a hereditary disorder of copper metabolism, resulting from mutations within ATP7B. Early diagnosis is essential for affected individuals. However, there are still patients with clinically suspected WD who do not have detectable pathogenic variants, which makes diagnosis difficult and delays treatment. This study included such patients from the authors' center and screened for the full-length sequence of ATP7B by next-generation sequencing. Newly identified synonymous and intronic variants were then analyzed with in silico tools. A minigene system was constructed to determine the pathogenicity of these variants in terms of splicing and blood RNA extraction, and RT-PCR experiments were performed on several patients to verify the splicing alterations. The phenotypes of the patients were also analyzed. Fourteen suspected pathogenic variants, including nine synonymous and five intronic variants, were detected in 12 patients with clinically suspected WD. Among them, four synonymous variants (c.1050G>A, c.1122C>G, c.3243G>A, and c.4014T>A) and four intronic variants (c.1543 +40G>A, c.1707+6_1707+16del, c.1870-49A>G, and c.2731-67A>G) resulted in splicing changes in ATP7B. After the above analysis, the diagnosis of WD could be confirmed in eight clinically suspected patients with WD who showed a late age of onset.","variants":[{"Name":"NM_000053.4(ATP7B):c.1870-49A>G","Chromosome":"13","Start":"51961962","Stop":"51961962","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3525954,"rule_based_match":true,"evidence_text":"c.1870-49A>G","llm_judgment":"PRESENT","evidence":"c.1870-49A>G","abstract_start":1136,"abstract_end":1148},{"Name":"NM_000053.4(ATP7B):c.2731-67A>G","Chromosome":"13","Start":"51949863","Stop":"51949863","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3499083,"rule_based_match":true,"evidence_text":"c.2731-67A>G","llm_judgment":"PRESENT","evidence":"c.2731-67A>G","abstract_start":1154,"abstract_end":1166}]}
{"pmid":"23471749","title":"The incidence of PALB2 c.3113G>A in women with a strong family history of breast and ovarian cancer attending familial cancer centres in Australia.","abstract":"The familial aggregation of breast cancer has been well-described with approximately 25% of breast cancers attributable to inherited mutations in currently known breast cancer susceptibility genes. PALB2 c.3113G>A (p.Trp1038*) is a protein-truncating mutation which has been associated with high estimated risk of breast cancer in Australian women (91%; 95% CI = 44-100) to age 70 years. This study screened for PALB2 c.3113G>A in germline DNA representing 871 unrelated individuals from \"high-risk\" breast and/or ovarian cancer families evaluated in the setting of a Familial Cancer Centre in Australia. The PALB2 c.3113G>A mutation was identified in eight of 871 probands (0.92%) from these families. Median age of diagnosis was 42 years. Five of these eight women had contra-lateral breast cancers. Available data suggests that PALB2 c.3113G>A is a rare mutation with estimated breast cancer risks similar in magnitude to that associated with BRCA2 mutations. Although the proportion of high-risk women carrying this PALB2 mutation is low, research efforts should continue in order to effect its translation into clinical genetic testing practice.","variants":[{"Name":"NM_024675.4(PALB2):c.3113G>A (p.Trp1038Ter)","Chromosome":"16","Start":"23621362","Stop":"23621362","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":132221,"rule_based_match":true,"evidence_text":"PALB2 c.3113G>A (p.Trp1038*)","llm_judgment":"PRESENT","evidence":"PALB2 c.3113G>A (p.Trp1038*)","abstract_start":198,"abstract_end":226}]}
{"pmid":"26061264","title":"Residual Hearing in DFNB1 Deafness and Its Clinical Implication in a Korean Population.","abstract":"INTRODUCTION: The contribution of Gap junction beta-2 protein (GJB2) to the genetic load of deafness and its mutation spectra vary among different ethnic groups.\nOBJECTIVE: In this study, the mutation spectrum and audiologic features of patients with GJB2 mutations were evaluated with a specific focus on residual hearing.\nMETHODS: An initial cohort of 588 subjects from 304 families with varying degrees of hearing loss were collected at the otolaryngology clinics of Seoul National University Hospital and Seoul National University Bundang Hospital from September 2010 through January 2014. GJB2 sequencing was carried out for 130 probands with sporadic or autosomal recessive non syndromic hearing loss. The audiograms were evaluated in the GJB2 mutants.\nRESULTS: Of the 130 subjects, 22 (16.9%) were found to carry at least one mutant allele of GJB2. The c.235delC mutation was shown to have the most common allele frequency (39.0%) among GJB2 mutations, followed by p.R143W (26.8%) and p.V37I (9.8%). Among those probands without the p.V37I allele in a trans configuration who showed some degree of residual hearing, the mean air conduction thresholds at 250 and 500 Hz were 57 dB HL and 77.8 dB HL, respectively. The c.235delC mutation showed a particularly wide spectrum of hearing loss, from mild to profound and significantly better hearing thresholds at 250 Hz and 2k Hz than in the non-p.V37I and non-235delC nonsyndromic hearing loss and deafness 1(DFNB1) subjects.\nCONCLUSION: Despite its reputation as the cause of severe to profound deafness, c.235delC, the most frequent DFNB1 mutation in our cohort, caused a wide range of hearing loss with some residual hearing in low frequencies. This finding can be of paramount help for prediction of low frequency hearing thresholds in very young DFNB1 patients and highlights the importance of soft surgery for cochlear implantation in these patients.","variants":[{"Name":"NM_004004.6(GJB2):c.235del (p.Leu79fs)","Chromosome":"13","Start":"20189347","Stop":"20189347","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":32053,"rule_based_match":true,"evidence_text":"c.235delC","llm_judgment":"PRESENT","evidence":"c.235delC","abstract_start":860,"abstract_end":869}]}
{"pmid":"29501320","title":"A novel mutation in the SLC26A4 gene in a Chinese family with non-syndromic hearing loss and enlarged vestibular aqueduct.","abstract":"OBJECTIVES: To identity the genetic causes of hearing loss in a Han Chinese family with enlarged vestibular aqueduct syndrome.\nMETHODS: Multiplex PCR technology combined with Ion Torrent™ next-generation sequencing technology was used to search for pathogenic mutations. A group of 1500 ethnically-matched normal hearing subjects screened for mutations in deafness-related genes using the same method in previously studied were included as a control.\nRESULTS: The proband and his little sister suffered from typical features of sensorineural hearing loss with enlarged vestibular aqueduct (EVA). Both subjects harbored two compound heterozygous mutations in the SLC26A4 gene. A novel mutation named c.2110 G > C (p.Glu704Gln) in exon 19 and another previously reported mutation c.1673 A > T (p.Asn558Ile) were identified. These mutations were carried in the heterozygous state by the parents and therefore co-segregated with the genetic disease. The c.2110 G > C (p.Glu704Gln) mutation was absent in 1500 healthy newborns. Protein alignment indicated high evolutionary conservation of the p.E704 residue, and this mutation was predicted by online tools to be damaging and deleterious.\nCONCLUSION: This study demonstrates that the novel mutation c.2110 G > C (p.Glu704Gln) in compound heterozygosity with c.1673 A > T (p.Asn558Ile) in the SLC26A4 gene corresponds to the EVA in this family. Our study will provide a foundation for elucidating the SLC26A4-related mechanisms of hearing loss.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1673A>T (p.Asn558Ile)","Chromosome":"7","Start":"107700141","Stop":"107700141","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1868059,"rule_based_match":true,"evidence_text":"c.1673 A > T (p.Asn558Ile)","llm_judgment":"PRESENT","evidence":"c.1673 A > T (p.Asn558Ile)","abstract_start":778,"abstract_end":804}]}
{"pmid":"29264471","title":"Pachydermoperiostosis Masquerading as Acromegaly.","abstract":"CONTEXT: Acromegaly usually is suspected on clinical grounds. Biochemical confirmation is required to optimize therapy, but there are other differential diagnoses.\nCASE DESCRIPTION: We describe a 24-year-old Uzbek man who presented with many clinical symptoms and signs of apparent acromegaly. On examination, the patient showed a rugose folding of his scalp, with the formation of tender, painful, rough skin folds in the parietal-occipital region, resembling cerebral gyri (<i>i.e.</i>, cutis verticis gyrate). There was also a thickening and enlargement of the eyelids due to cartilaginous hypertrophy, dystrophic changes of the conjunctiva, and atrophy of the Meibomian glands, with the formation of multiple cysts and granulomas. He perspired excessively. There was thickening of the facial skin, with increased oiliness, increased rugosity, and seborrheic dermatitis. The skin over the hands was thick and apparently fixed to the underlying tissues. However, the patient had a low-normal insulin-like growth factor-1 level. More detailed analysis revealed a family history of relatives with similar problems, and certain features were not in keeping with this diagnosis. The disorder pachydermoperiostosis, or pulmonary hypertrophic osteoarthropathy, was suspected, and next-generation screening confirmed that the patient was homozygous for a pathogenic mutation in the <i>SLCO2A1</i> gene, c.764G>A (p.Gly255Glu).\nCONCLUSION: The condition of pachydermoperiostosis may masquerade as acromegaly but is a genetic disorder, usually autosomal recessive, leading to elevated prostaglandin E2 levels. This is an important, albeit rare, differential diagnosis of acromegaly.","variants":[{"Name":"NM_005630.3(SLCO2A1):c.764G>A (p.Gly255Glu)","Chromosome":"3","Start":"133951305","Stop":"133951305","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39143,"rule_based_match":true,"evidence_text":"c.764G>A (p.Gly255Glu)","llm_judgment":"PRESENT","evidence":"c.764G>A (p.Gly255Glu)","abstract_start":1398,"abstract_end":1420}]}
{"pmid":"31933393","title":"Diagnosis and Prenatal Diagnosis in a Chinese Family Carrying the Rare α-Thalassemia Gene","abstract":"The aim of this study was to identify the rare thalassemia genotype in a family and perform prenatal diagnosis (PND) on the proband's unborn child. Peripheral blood was collected from the family members for hematology analysis and capillary electrophoresis (CE) analysis. Peripheral blood and cord blood were analyzed by gap-polymerase chain reaction (gap-PCR), reverse dot-blot and Sanger sequencing for genotypes of α-thalassemia (α-thal). A heterozygous mutation, <i>HBA2</i>: c.1A>G, was identified in the proband and his father. Two compound heterozygous variants, <i>HBA2</i>: c.1A>G and the - -<sup>SEA</sup> (Southeast Asian) deletion, were revealed in the proband's unborn child. The hemoglobin (Hb) CE result of the fetal cord blood indicated the fetus had Hb H disease. We have identified a rare thalassemia mutation (<i>HBA2</i>: c.1A>G) in a Chinese family and enriched the rare α-thal gene pool in the Chinese population. When the patient's phenotype does not match the genotype detected by thalassemia gene detection kits, further investigation of rare genotypes should be conducted to avoid missed diagnosis or misdiagnosis, which can help guide clinical diagnosis, population screening and genetic counseling.","variants":[{"Name":"NM_000517.6(HBA2):c.1A>G (p.Met1Val)","Chromosome":"16","Start":"172913","Stop":"172913","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":30684,"rule_based_match":true,"evidence_text":"<i>HBA2</i>: c.1A>G","llm_judgment":"PRESENT","evidence":"<i>HBA2</i>: c.1A>G","abstract_start":467,"abstract_end":486}]}
{"pmid":"30160829","title":"Novel phenotype of achondroplasia due to biallelic FGFR3 pathogenic variants.","abstract":"Pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3) gene are responsible for a broad spectrum of skeletal dysplasias, including achondroplasia (ACH). The classic phenotype of ACH is caused by two highly prevalent mutations, c.1138G > A and c.1138G > C (p.Gly380Arg). In the homozygous state, these variant results in a severe skeletal dysplasia, neurologic deficits, and early demise from respiratory insufficiency. Although homozygous biallelic mutations have been reported in patients with ACH in combination with hypochondroplasia or other dominant skeletal dysplasias, thus far, no cases of heterozygous biallelic pathogenic ACH-related variants in FGFR3 have been reported. We describe a novel phenotype of an infant with two ACH-related mutations in FGFR3, p.Gly380Arg and p.Ser344Cys. Discordant features from classic ACH include atypical radiographic findings, severe obstructive sleep apnea, and focal, migrating seizures. We also report the long-term clinical course of her father, who harbors the p.Ser344Cys mutation that has only been reported once previously in a Japanese patient. The phenotype of heterozygous biallelic mutations in FGFR3 associated with ACH is variable, underscoring the importance of recognition and accurate diagnosis to ensure appropriate management.","variants":[{"Name":"NM_000142.5(FGFR3):c.1031C>G (p.Ser344Cys)","Chromosome":"4","Start":"1803792","Stop":"1803792","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1934790,"rule_based_match":false,"evidence_text":"c.1031C>G (p.Ser344Cys)","llm_judgment":"PRESENT","evidence":"p.Ser344Cys","abstract_start":798,"abstract_end":809}]}
{"pmid":"28912863","title":"A novel mutation in the hepatocyte nuclear factor-1β gene in maturity onset diabetes of the young 5 with multiple renal cysts and pancreas hypogenesis: A case report.","abstract":"A 17-year-old Chinese male was hospitalized exhibiting hyperglycemia and increased serum urea nitrogen and creatinine levels in addition to weight loss. The patient was treated with gliclazide. The patient was 150 cm tall, weighed 35 kg and had no family history of diabetes or kidney disease. Physical examination revealed cephalus quadratus, rachitic rosary and a visible toe-out gait. Laboratory examinations revealed that the patient's fasting plasma glucose and glycosylated hemoglobin levels were markedly increased, fasting plasma C-peptide level was slightly increased and no peak 2 h postprandial was observed. Diabetic autoimmune antibodies [islet cell cytoplasmic autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), isulinoma-2-associated autoantibodies (IA2A) and insulin autoantibodies (IAA)] were negative. Levels of serum electrolytes decreased, uric acid and parathyroid hormone increased, mild albuminuria was detected and there was a low proportion of urine. The patient also presented with low bone mass and cataracts. Abdominal computed tomography (CT) revealed a bilateral atrophic kidney with multiple renal cysts, primarily located at the junction of renal cortex and medulla, with a diameter of 0.3-0.7 cm. CT also revealed hypogenesis of the body and tail of the pancreas. In an oral glucose tolerance test, the mother and paternal uncle of the patient were diagnosed with type II diabetes and the patient's sister, maternal uncle and paternal grandpa were diagnosed with glucose tolerance impairment. Genetic testing revealed an unreported amino acid mutation in exon 2 of hepatocyte nuclear factor 1β (c.391C>T), a nonsense mutation of CAA to TAA at codon 131. This mutation was identified in the proband but not in any other family members.","variants":[{"Name":"NM_000458.4(HNF1B):c.391C>T (p.Gln131Ter)","Chromosome":"17","Start":"37739593","Stop":"37739593","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":623520,"rule_based_match":true,"evidence_text":"c.391C>T","llm_judgment":"PRESENT","evidence":"c.391C>T","abstract_start":1650,"abstract_end":1658}]}
{"pmid":"29077258","title":"Whole-exome sequencing identifies a novel mutation of GPD1L (R189X) associated with familial conduction disease and sudden death.","abstract":"Cardiac conduction disease (CCD) is a serious disorder and the leading cause of mortality worldwide. It is characterized by arrhythmia, syncope or even sudden cardiac death caused by the dysfunction of cardiac voltage-gated channel. Previous study has demonstrated that mutations in genes encoding voltage-gated channel and related proteins were the crucial genetic lesion of CCD. In this study, we employed whole-exome sequencing to explore the potential causative genes in a Chinese family with ventricular tachycardia and syncope. A novel nonsense mutation (c.565C>T/p.R189X) of glycerol-3-phosphate dehydrogenase-like (GPD1L) was identified and co-segregated with the affected family members. GPD1L is a crucial interacting protein of SCN5A, a gene encoded sodium channel α-subunit Na<sub>v</sub> 1.5 and mainly associated with Brugada syndrome (BrS). The novel mutation (c.565C>T/p.R189X) may result in a premature stop codon at position 189 in exon 4 of the GPD1L gene and lead to functional haploinsufficiency of GPD1L due to mRNA carrying this mutation will be degraded by nonsense-mediated mRNA decay, which has been confirmed by Western blot in HEK293 cells transfected HIS-GPD1L plasmid. The levels of GPD1L decreasing may disturb the function of Na<sub>v</sub> 1.5 and induce arrhythmia and syncope in the end. In conclusion, our study not only further supported the important role of GPD1L in CCD, but also expanded the spectrum of GPD1L mutations and will contribute to the genetic diagnosis and counselling of families with CCD.","variants":[{"Name":"NM_015141.4(GPD1L):c.565C>T (p.Arg189Ter)","Chromosome":"3","Start":"32146681","Stop":"32146681","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2921913,"rule_based_match":true,"evidence_text":"c.565C>T/p.R189X","llm_judgment":"PRESENT","evidence":"c.565C>T/p.R189X","abstract_start":561,"abstract_end":577}]}
{"pmid":"33977145","title":"Biallelic Pathogenic Variants in","abstract":"OBJECTIVE: Pathogenic variants in <i>TNNT3</i>, the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic <i>TNNT3</i> variants.\nMETHODS: Clinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with <i>TNNT3</i>-related congenital myopathy.\nRESULTS: A homozygous <i>TNNT3</i> variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple <i>in silico</i> prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with <i>TNNT3</i>-related congenital myopathy, were not observed in the patient reported here.\nCONCLUSIONS: This report provides further evidence for the association of biallelic <i>TNNT3</i> variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. <i>TNNT3</i> sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.","variants":[{"Name":"NM_006757.4(TNNT3):c.481-1G>A","Chromosome":"11","Start":"1934545","Stop":"1934545","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":511906,"rule_based_match":true,"evidence_text":"c.481-1G>A","llm_judgment":"PRESENT","evidence":"c.481-1G>A","abstract_start":743,"abstract_end":753}]}
{"pmid":"29971521","title":"R106C TFG variant causes infantile neuroaxonal dystrophy \"plus\" syndrome.","abstract":"TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient's fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking.","variants":[{"Name":"NM_006070.6(TFG):c.316C>T (p.Arg106Cys)","Chromosome":"3","Start":"100728759","Stop":"100728759","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":106771,"rule_based_match":true,"evidence_text":"c.316C > T","llm_judgment":"PRESENT","evidence":"c.316C > T","abstract_start":191,"abstract_end":201}]}
{"pmid":"32161190","title":"Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation.","abstract":"Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.","variants":[{"Name":"NM_001905.4(CTPS1):c.1692-1G>C","Chromosome":"1","Start":"41010160","Stop":"41010160","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":150138,"rule_based_match":true,"evidence_text":"c.1692-1G>C","llm_judgment":"PRESENT","evidence":"c.1692-1G>C","abstract_start":121,"abstract_end":132}]}
{"pmid":"27581592","title":"Primary Carnitine Deficiency - A Rare Treatable Cause of Cardiomyopathy and Massive Hepatomegaly.","abstract":"Systemic primary carnitine deficiency (CDSP) is a rare autosomal recessive disorder caused by a defect in plasma membrane uptake of carnitine due to SLC22A5 gene mutations. A nine-mo-old boy presented with hypertrophic cardiomyopathy, massive hepatomegaly and jaundice. Metabolic testing revealed very low free carnitine levels. Genetic analysis using Sanger sequencing method revealed compound heterozygous mutations in SLC22A5 gene, c. 1354 G > A (p. Glu452Lys, previously reported) and c.231_234del (novel frame-shift). Oral carnitine supplementation resulted in improved clinical outcome with ejection fraction to 75 % and normalization of liver size and enzymes after 3 mo.","variants":[{"Name":"NM_003060.4(SLC22A5):c.1354G>A (p.Glu452Lys)","Chromosome":"5","Start":"132392519","Stop":"132392519","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":36755,"rule_based_match":true,"evidence_text":"c. 1354 G > A (p. Glu452Lys, previously reported)","llm_judgment":"PRESENT","evidence":"c. 1354 G > A (p. Glu452Lys, previously reported)","abstract_start":435,"abstract_end":484}]}
{"pmid":"25595217","title":"Molecular Diagnosis of Hereditary Fructose Intolerance: Founder Mutation in a Community from India.","abstract":"Hereditary fructose intolerance (HFI) is a difficult-to-confirm diagnosis, requiring either invasive liver biopsy-enzyme assay or potentially hazardous fructose challenge test or expensive molecular genetic analysis. Therefore, worldwide there has been a trend towards finding \"common mutations\" in distinct ethnic groups to simplify the process of diagnosis. The nonspecific presentation of the disease often leads to diagnostic confusion with other metabolic liver disorders such as glycogenoses, galactosemia, and tyrosinemia. This leads to much delay in diagnosis with consequent harm to the patient.We report mutations in the ALDOB gene, from eleven Indian patients, seven of whom belong to the Agarwal community. Six patients from the Agarwal community and two non-Agarwal patients harbored one novel mutation, c.324+1G>A (five homozygous and one heterozygous), in the ALDOB gene. Haplotyping performed in families confirmed a founder effect. The community has been known to harbor founder mutations in other genes such as the MLC1, PANK2, and CAPN3 genes, thus providing another evidence for a founder effect in the community in case of HFI. This may pave the path for a simpler and quicker test at least for this community in India. In addition to the founder mutation, we report four other novel mutations, c.112+1delG, c.380-1G>A, c.677G>A, and c.689delA, and a previously reported mutation, c.1013C>T, in the cohort from India.","variants":[{"Name":"NM_000035.4(ALDOB):c.324+1G>A","Chromosome":"9","Start":"101429754","Stop":"101429754","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215108,"rule_based_match":true,"evidence_text":"c.324+1G>A","llm_judgment":"PRESENT","evidence":"c.324+1G>A","abstract_start":817,"abstract_end":827},{"Name":"NM_000035.4(ALDOB):c.380-1G>A","Chromosome":"9","Start":"101427643","Stop":"101427643","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":545031,"rule_based_match":true,"evidence_text":"c.380-1G>A","llm_judgment":"PRESENT","evidence":"c.380-1G>A","abstract_start":1329,"abstract_end":1339},{"Name":"NM_000035.4(ALDOB):c.1013C>T (p.Ala338Val)","Chromosome":"9","Start":"101421891","Stop":"101421891","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186775,"rule_based_match":true,"evidence_text":"c.1013C>T","llm_judgment":"PRESENT","evidence":"c.1013C>T","abstract_start":1402,"abstract_end":1411},{"Name":"NM_000035.4(ALDOB):c.677G>A (p.Gly226Asp)","Chromosome":"9","Start":"101425575","Stop":"101425575","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1054203,"rule_based_match":true,"evidence_text":"c.677G>A","llm_judgment":"PRESENT","evidence":"c.677G>A","abstract_start":1341,"abstract_end":1349}]}
{"pmid":"26004348","title":"Mutation analysis of two families with inherited congenital cataracts.","abstract":"The present study aimed to identify the genetic mutations in two families affected with congenital cataracts. Detailed family histories and clinical data of the family members were recorded. The family members with affected phenotypes were recruited, and candidate gene sequencing was performed to determine the disease‑causing mutation. Bioinformatics analysis was performed to predict the function of the mutant gene. Green fluorescent protein‑tagged human wild‑type CRYAA and GJA8 were sub‑cloned, and the mutants were generated by site‑directed mutagenesis. A novel mutation, c.416T>C (p.L139P), in CRYAA and a known mutation, c.139G>A (p.D47N), in GJA8 were identified. These mutations co‑segregated with all affected individuals in each family and were not observed in the unaffected family members or in unrelated controls. The results of the bioinformatics analysis indicated that the amino acid at position 139 was highly conserved and that the p.L139P mutation was predicted to be damaging, as with p.D47N. Finally, overexpression of the two mutants revealed marked alterations, compared with the wild‑type proteins. These results extend the mutation spectrum of CRYAA and provides further evidence that the p.D47N mutation in GJA8 is a hot-spot mutation.","variants":[{"Name":"NM_005267.5(GJA8):c.139G>A (p.Asp47Asn)","Chromosome":"1","Start":"147908094","Stop":"147908094","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23766,"rule_based_match":true,"evidence_text":"c.139G>A (p.D47N)","llm_judgment":"PRESENT","evidence":"c.139G>A (p.D47N)","abstract_start":631,"abstract_end":648}]}
{"pmid":"25475713","title":"A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations.","abstract":"PURPOSE: To document a distinct vitreo-retinal dystrophy with early-onset cataract as related to recessive KCNJ13 mutations.\nMETHODS: A retrospective case series (two patients from two families) Results: A 12-year-old Saudi Arabian girl with nystagmus since birth was referred because of recent decreased vision. Parents were first cousins and a younger sister had been diagnosed with retinal dystrophy. Examination revealed total white cataract in the right eye. In the left eye, there were posterior cortical lenticular opacities and an unusual retina fundus dystrophic appearance notable for fibrosis over the optic disc and clumped pigmentation. After right eye cataract surgery, the posterior pole of the left eye was seen as similar to that of the right eye and electroretinography revealed severe cone-rod dysfunction, with only subnormal scotopic tracings recordable in both eyes. Next-generation sequencing of retinal dystrophy genes revealed homozygosity for a novel missense mutation in KCNJ13 (c.359T > C; p.Ile120Thr [NM_002242.4]), which co-segregated with the disease. Direct KCNJ13 sequencing for an unrelated 33-year-old Saudi Arabian male with similar clinical findings but early-adult-onset rather than juvenile cataract revealed the same homozygous mutation.\nCONCLUSIONS: Juvenile or early-adult-onset cataract in the setting of a congenital vitreo-retinal dystrophy notable for fibrosis over the disc and clumped pigmentation in the posterior pole is a unique phenotype that suggests recessive KCNJ13 mutations.","variants":[{"Name":"NM_002242.4(KCNJ13):c.359T>C (p.Ile120Thr)","Chromosome":"2","Start":"232771004","Stop":"232771004","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":188958,"rule_based_match":true,"evidence_text":"c.359T > C; p.Ile120Thr [NM_002242.4]","llm_judgment":"PRESENT","evidence":"c.359T > C; p.Ile120Thr [NM_002242.4]","abstract_start":1006,"abstract_end":1043}]}
{"pmid":"29300381","title":"A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans.","abstract":"PURPOSE: We aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome.\nMETHODS: Whole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells.\nRESULTS: We identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y.\nCONCLUSION: Homozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.","variants":[{"Name":"NM_001267727.2(ARSG):c.133G>T (p.Asp45Tyr)","Chromosome":"17","Start":"68307626","Stop":"68307626","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":576301,"rule_based_match":true,"evidence_text":"c.133G>T (p.D45Y)","llm_judgment":"PRESENT","evidence":"c.133G>T (p.D45Y)","abstract_start":500,"abstract_end":517}]}
{"pmid":"25802879","title":"A slowly progressive form of limb-girdle muscular dystrophy type 2C associated with founder mutation in the SGCG gene in Puerto Rican Hispanics.","abstract":"Limb-girdle muscular dystrophy type 2C (LGMD2C) is considered one of the severe forms of childhood-onset muscular dystrophy. The geographical distribution of founder mutations in the SGCG gene has a prominent effect on the prevalence of LGMD2C in certain populations. The aim of this study was to confirm the hypothesis that the c.787G>A (p.E263K) mutation in the SGCG gene is a founder mutation among Puerto Rican Hispanics and to characterize the associated clinical and immunohistochemical phenotype. Genotyping of six polymorphic microsatellite markers internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene was performed on four unrelated Puerto Rican patients with LGMD2C. Preserved ambulation to the second decade of life was observed in at least two subjects. Immunostaining of skeletal muscle demonstrated absence of γ-sarcoglycan in all affected subjects. Two markers, D13S232 and D13S292, were highly informative and confirmed that all four families share the haplotype of the mutant allele. Our findings confirm that the E263K missense mutation in the SGCG gene is a founder mutation in Puerto Rican Hispanics. A slowly progressive disease course with prolonged preservation of ambulation can be seen in association with this mutation, providing evidence for phenotypic variability.","variants":[{"Name":"NM_000231.3(SGCG):c.787G>A (p.Glu263Lys)","Chromosome":"13","Start":"23324452","Stop":"23324452","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17048,"rule_based_match":true,"evidence_text":"c.787G>A (p.E263K)","llm_judgment":"PRESENT","evidence":"c.787G>A (p.E263K)","abstract_start":329,"abstract_end":347}]}
{"pmid":"32005865","title":"Retinitis Pigmentosa Due to Rp1 Biallelic Variants.","abstract":"In the present study, we screened 529 Brazilian individuals affected by inherited retinal disorders. A total of seven unrelated and nonsyndromic patients with RP1 biallelic variants (OMIM # 180100) were diagnosed in our centre and included in the study. They had classic retinitis pigmentosa with diagnosis at the first decade of life. The visual acuities were severely affected at a young age. The fundus aspects were similar among all patients. An atrophic ring was present around the fovea in several cases. All patients had molecular diagnosis, with six different RP1 variants. This study reports two new pathogenic variants - two frameshift duplications (c.1234dupA p.Met412Asnfs*7 and c.1265dupC p.Ala423Cysfs*2) and reinforces other four known pathogenic variants - two frameshift deletions (c.469delG p.Val157Trpfs*16 and c.3843delT p.Pro1282Leufs*12) and two stop gain mutations (c.1186 C > T p.Arg396* and c.1625C > G p.Ser542*). These findings broaden the spectrum of RP1 variants. This study also reviewed the fundus characteristics that clinically could raise the hypothesis of a retinitis pigmentosa due to RP1 gene. It is worthwhile to try to identify the disease-causing variants in each patient since it can provide prognostic information and be useful in genetic consultation and diagnosis in the future.","variants":[{"Name":"NM_006269.2(RP1):c.469del (p.Val157fs)","Chromosome":"8","Start":"54621435","Stop":"54621435","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":1491118,"rule_based_match":true,"evidence_text":"c.469delG p.Val157Trpfs*16","llm_judgment":"PRESENT","evidence":"c.469delG p.Val157Trpfs*16","abstract_start":799,"abstract_end":825},{"Name":"NM_006269.2(RP1):c.1186C>T (p.Arg396Ter)","Chromosome":"8","Start":"54625068","Stop":"54625068","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152852,"rule_based_match":true,"evidence_text":"c.1186 C > T p.Arg396*","llm_judgment":"PRESENT","evidence":"c.1186 C > T p.Arg396*","abstract_start":889,"abstract_end":911},{"Name":"NM_006269.2(RP1):c.1265dup (p.Ala423fs)","Chromosome":"8","Start":"54625146","Stop":"54625147","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":790805,"rule_based_match":true,"evidence_text":"c.1265dupC p.Ala423Cysfs*2","llm_judgment":"PRESENT","evidence":"c.1265dupC p.Ala423Cysfs*2","abstract_start":691,"abstract_end":717},{"Name":"NM_006269.2(RP1):c.3843del (p.Pro1282fs)","Chromosome":"8","Start":"54627719","Stop":"54627719","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":431733,"rule_based_match":true,"evidence_text":"c.3843delT p.Pro1282Leufs*12","llm_judgment":"PRESENT","evidence":"c.3843delT p.Pro1282Leufs*12","abstract_start":830,"abstract_end":858},{"Name":"NM_006269.2(RP1):c.1234dup (p.Met412fs)","Chromosome":"8","Start":"54625113","Stop":"54625114","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":790804,"rule_based_match":true,"evidence_text":"c.1234dupA p.Met412Asnfs*7","llm_judgment":"PRESENT","evidence":"c.1234dupA p.Met412Asnfs*7","abstract_start":660,"abstract_end":686}]}
{"pmid":"22964742","title":"A prevalent and three novel mutations in CYP11B1 gene identified in Chinese patients with 11-beta hydroxylase deficiency.","abstract":"UNLABELLED: 11β-Hydroxylase deficiency (11β-OHD), caused by CYP11B1 mutations, is characterized by hyporeninemic, hypokalemic hypertension and hyperandrogenism. We identified a prevalent and three novel mutations of CYP11B1 gene in nine patients with classic 11β-OHD.\nSUBJECTS AND METHODS: Nine patients with 11β-OHD from unrelated families were recruited. The complications of 11β-OHD occurred in three patients who never received glucocorticoid treatment. CYP11B1 gene was sequenced and 11β-hydroxylase enzymatic activities were assessed in vitro. A haplotype analysis was performed to determine a common ancestor for those subjects who carried the same p.R454C mutation.\nRESULTS: CYP11B1 gene mutations were identified in all patients, with a prevalent (p.R454C) and three novel mutations (p.V148G, IVS7-9C>A, c.1359_1360insG). The p.R141X, p.V148G, c.1359_1360insG and p.R454C mutations retained 4.9%, 3.9%, 3.7%, 4.5% of residual enzymatic activity, respectively. Five of nine patients carried p.R454C mutation, which was only reported in Chinese 11OHD patients. Haplotype analysis showed that this mutation might be inherited from a common ancestor.\nCONCLUSION: The enzymatic activities for p.R141X, p.V148G, c.1359_1360insG and p.R454C mutants were almost completely abolished, which corresponds to classic form of 11β-OHD. The observations of a prevalent mutation and three novel mutations might have potential clinical utility for genetic counseling and prenatal diagnosis in Chinese 11β-OHD patients.","variants":[{"Name":"NM_000497.4(CYP11B1):c.1359dup (p.Arg454fs)","Chromosome":"8","Start":"142874995","Stop":"142874996","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":1675156,"rule_based_match":false,"evidence_text":"c.1359_1360insG","llm_judgment":"PRESENT","evidence":"c.1359_1360insG","abstract_start":813,"abstract_end":828}]}
{"pmid":"23069192","title":"Homozygous SALL1 mutation causes a novel multiple congenital anomaly-mental retardation syndrome.","abstract":"OBJECTIVE: To delineate a novel autosomal recessive multiple congenital anomaly-mental retardation (MCA-MR) syndrome in 2 female siblings of a consanguineous pedigree and to identify the disease-causing mutation.\nSTUDY DESIGN: Both siblings were clinically characterized and homozygosity mapping and sequencing of candidate genes were applied. The contribution of nonsense-mediated messenger RNA (mRNA) decay to the expression of mutant mRNA in fibroblasts of a healthy carrier and a control was studied by pyrosequencing.\nRESULTS: We identified the first homozygous SALL1 mutation, c.3160C > T (p.R1054*), in 2 female siblings presenting with multiple congenital anomalies, central nervous system defects, cortical blindness, and absence of psychomotor development (ie, a novel recognizable, autosomal recessive MCA-MR). The mutant SALL1 transcript partially undergoes nonsense-mediated mRNA decay and is present at 43% of the normal transcript level in the fibroblasts of a healthy carrier.\nCONCLUSION: Previously heterozygous SALL1 mutations and deletions have been associated with dominantly inherited anal-renal-radial-ear developmental anomalies. We identified an allelic recessive SALL1-related MCA-MR. Our findings imply that quantity and quality of SALL1 transcript are important for SALL1 function and determine phenotype, and mode of inheritance, of allelic SALL1-related disorders. This novel MCA-MR emphasizes SALL1 function as critical for normal central nervous system development and warrants a detailed neurologic investigation in all individuals with SALL1 mutations.","variants":[{"Name":"NM_002968.3(SALL1):c.3160C>T (p.Arg1054Ter)","Chromosome":"16","Start":"51139062","Stop":"51139062","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":216957,"rule_based_match":true,"evidence_text":"c.3160C > T (p.R1054*)","llm_judgment":"PRESENT","evidence":"c.3160C > T (p.R1054*)","abstract_start":583,"abstract_end":605}]}
{"pmid":"21738022","title":"Phenotypic variability in a three-generation Northern Irish family with Sotos syndrome.","abstract":"Sotos syndrome is an overgrowth disorder with autosomal dominant inheritance caused by mutations and deletions in the nuclear receptor Set domain-containing protein 1 gene. In general, affected individuals have an advanced bone age, macrocephaly, characteristic facial gestalt and learning difficulties. Genotype-phenotype correlations are unclear. Full penetrance is seen and 95% of cases are de novo. Here, we report a three-generation pedigree, with at least eight affected individuals, shown to harbour the nuclear receptor Set domain-containing protein 1 missense mutation c. 6115C>T. To our knowledge, this is the largest Sotos family reported. The observed phenotype is extremely variable, thus highlighting the clinical heterogeneity that may occur.","variants":[{"Name":"NM_022455.5(NSD1):c.6115C>T (p.Arg2039Cys)","Chromosome":"5","Start":"177283892","Stop":"177283892","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1324150,"rule_based_match":true,"evidence_text":"c. 6115C>T","llm_judgment":"PRESENT","evidence":"c. 6115C>T","abstract_start":578,"abstract_end":588}]}
{"pmid":"16697227","title":"Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria.","abstract":"Methylmalonyl-CoA epimerase (MCE) catalyzes the interconversion of D- and L-methylmalonyl-CoA in the pathway responsible for the degradation of branched chain amino acids, odd chain-length fatty acids, and other metabolites. Despite the occurrence of metabolic disorders in the enzymatic step occurring immediately upstream of MCE (propionyl-CoA carboxylase) and downstream of MCE (adenosylcobalamin-dependent methylmalonyl-CoA mutase), no disease-causing mutations have been described affecting MCE itself. A patient, formerly identified as belonging to the cblA complementation group of vitamin B12 disorders but lacking mutations in the affected gene, MMAA, was tested for mutations in the MCEE gene. The patient's fibroblasts had normal levels of adenosylcobalamin compared to controls, whereas other cblA cell lines typically had reduced levels of the cofactor. As well, this patient had a milder form of methylmalonic aciduria than usually observed in cblA patients. The patient was found to be homozygous for a c.139C>T (p.R47X) mutation in MCEE by sequence analysis that was confirmed by restriction digestion of PCR products. One sibling, also with mild methylmalonic aciduria, was homozygous for the mutation. Both parents and one other sibling were heterozygous. A nearby insertion polymorphism, c.41-160_161insT, heterozygous in both parents, showed the wild-type configuration on the mutant alleles. To assess the impact of isolated MCE deficiency in cultured cells, HeLa cells were transfected with a selectable vector containing MCEE-specific small interfering RNA (siRNA) to suppress gene expression. The reduced level of MCEE mRNA resulted in the reduction of [14C]-propionate incorporation into cellular macromolecules. However, siRNA only led to a small reduction in pathway activity, suggesting that previously postulated non-enzymatic conversion of D- to L-methylmalonyl-CoA may contribute to some flux through the pathway. We conclude that the patient's MCEE defect was responsible for the mild methylmalonic aciduria, confirming a partial requirement for the enzymatic activity in humans.","variants":[{"Name":"NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)","Chromosome":"2","Start":"71124445","Stop":"71124445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17382,"rule_based_match":true,"evidence_text":"c.139C>T (p.R47X)","llm_judgment":"PRESENT","evidence":"c.139C>T (p.R47X)","abstract_start":1018,"abstract_end":1035}]}
{"pmid":"34758064","title":"Hematologic complications with age in Shwachman-Diamond syndrome.","abstract":"Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.","variants":[{"Name":"NM_016038.4(SBDS):c.258+2T>C","Chromosome":"7","Start":"66994210","Stop":"66994210","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18235,"rule_based_match":true,"evidence_text":"The SBDS c.258 + 2T>C variant","llm_judgment":"PRESENT","evidence":"The SBDS c.258 + 2T>C variant","abstract_start":444,"abstract_end":473}]}
{"pmid":"30239107","title":"Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.","abstract":"The ornithine decarboxylase 1 (ODC1) gene plays an important role in physiological and cell developmental processes including embryogenesis, organogenesis, and neoplastic cell growth. Here, we report an 32-month-old Caucasian female with a heterozygous de novo nonsense mutation in the ODC1 gene that leads to a premature abrogation of 14-aa residues at the ODC protein c-terminus. This is the first human case confirming similar symptoms observed in a transgenic ODC1 mouse model first described over 20 years ago. Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss. We here describe for the first time a new pediatric disorder that is directly linked to a de novo pathogenic variant in the ODC1 gene. The ODC1 gene mutation (c.1342 A>T) was identified by whole-exome sequencing and confirmed by Sanger sequencing. Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls. Our autosomal dominant patient who carries this gain-of-function ODC1 mutation may benefit from treatment with α-difluoromethylornithine, a well-tolerated, U.S. Food and Drug Administration (FDA). FDA-approved drug.","variants":[{"Name":"NM_002539.3(ODC1):c.1342A>T (p.Lys448Ter)","Chromosome":"2","Start":"10440768","Stop":"10440768","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":971357,"rule_based_match":true,"evidence_text":"c.1342 A>T","llm_judgment":"PRESENT","evidence":"c.1342 A>T","abstract_start":881,"abstract_end":891}]}
{"pmid":"31765079","title":"Identification of novel variants in the FZD4 gene associated with familial exudative vitreoretinopathy in Chinese families.","abstract":"BACKGROUND: Familial exudative vitreoretinopathy (FEVR, OMIM 133780) is a severe hereditary retinal disease characterized by incomplete retinal vascular development and pathological neovascularization. It has been reported that variants in nine genes are associated with FEVR, but they can only explain approximately 50% of FEVR patients, suggesting that other FEVR-associated variants or genes remain to be discovered.\nMETHODS: Whole-exome sequencing (WES) was carried out to analyse genomic DNA samples from the probands of 68 families with FEVR. Sanger sequencing was used to verify all identified variants. Western blot analysis was utilized to detect the expression of the variant mutant proteins. A luciferase assay was conducted to test the receptor activity of the mutant FZD4 proteins in Norrin-β-catenin signaling.\nRESULTS: Seven heterozygous FZD4 variants were found to cause FEVR in seven families, including six missense variants and one deletion variant: c.182C>T (p.T61I), c.205C>T (p.H69Y), c.217_234del (p.73T_78Qdel), c.264C>A (p.Y88X), c.344G>T (p.G115V), c.678G>A (p.W226X) and c.1310T>C (p.I437T). Among these variants, c.205C>T (p.H69Y) and c.678G>A (p.W226X) are known FEVR-causing variants, while the other five variants are novel pathogenic variants.\nCONCLUSION: Our study revealed the cause of FEVR in seven Chinese families and identified five novel pathogenic variants in FZD4, which expanded the mutation spectrum of FEVR in the Chinese population. These findings also provided further support for using WES in the clinical diagnosis of FEVR.","variants":[{"Name":"NM_012193.4(FZD4):c.205C>T (p.His69Tyr)","Chromosome":"11","Start":"86954881","Stop":"86954881","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152859,"rule_based_match":true,"evidence_text":"c.205C>T (p.H69Y)","llm_judgment":"PRESENT","evidence":"c.205C>T (p.H69Y)","abstract_start":988,"abstract_end":1005},{"Name":"NM_012193.4(FZD4):c.182C>T (p.Thr61Ile)","Chromosome":"11","Start":"86954904","Stop":"86954904","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1890508,"rule_based_match":true,"evidence_text":"c.182C>T (p.T61I)","llm_judgment":"PRESENT","evidence":"c.182C>T (p.T61I)","abstract_start":969,"abstract_end":986}]}
{"pmid":"30445145","title":"Infantile sialidosis: natural history in a preterm infant with two new pathogenic mutations and new ocular findings.","abstract":"Sialidosis is a rare lysosomal storage disease caused by an α-N-acetyl neuraminidase-1 deficiency due to mutations of the NEU1 gene (6p21). Disease severity varies among patients and is linked to the level of residual neuraminidase activity in vivo. At least 40 disease-causing mutations in the NEU1 gene have been reported. Sialidosis occurs in two main clinical variants: type I, the milder form of the disease, and type II, which is subdivided into congenital, infantile, and juvenile forms. We report the clinical, biochemical, and molecular characterization of a patient with infantile sialidosis type II. The abnormal urinary oligosaccharide profile is described for the first time. The genetic characterization of the patient showed two previously unreported missense mutations in the NEU1 gene: p.R78C (c.232C>T) and p.R290Q (c.869G>A).","variants":[{"Name":"NM_000434.4(NEU1):c.869G>A (p.Arg290Gln)","Chromosome":"6","Start":"31860194","Stop":"31860194","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":859504,"rule_based_match":true,"evidence_text":"c.869G>A","llm_judgment":"PRESENT","evidence":"c.869G>A","abstract_start":834,"abstract_end":842}]}
{"pmid":"26996280","title":"Molecularly proven mosaicism in phenotypically normal parent of a girl with Freeman-Sheldon Syndrome caused by a pathogenic MYH3 mutation.","abstract":"We report a case of a female child who has classical Freeman-Sheldon syndrome (FSS) associated with a previously reported recurrent pathogenic heterozygous missense mutation, c.2015G > A, p. (Arg672His), in MYH3 where the phenotypically normal mother is a molecularly confirmed mosaic. To the best of our knowledge, this is the first report in the medical literature of molecularly confirmed parental mosaicism for a MYH3 mutation causing FSS. Since proven somatic mosaicism after having an affected child is consistent with gonadal mosaicism, a significantly increased recurrence risk is advised. Parental testing is thus essential for accurate risk assessment for future pregnancies and the use of new technologies with next generation sequencing (NGS) may improve the detection rate of mosaicism. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_002470.4(MYH3):c.2015G>A (p.Arg672His)","Chromosome":"17","Start":"10641317","Stop":"10641317","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29177,"rule_based_match":true,"evidence_text":"c.2015G > A, p. (Arg672His)","llm_judgment":"PRESENT","evidence":"c.2015G > A, p. (Arg672His)","abstract_start":175,"abstract_end":202}]}
{"pmid":"17893664","title":"Identification of mutations in the myocilin (MYOC) gene in Taiwanese patients with juvenile-onset open-angle glaucoma.","abstract":"PURPOSE: To investigate mutations in the promoter and coding regions of the myocilin (MYOC) gene in Taiwanese patients suffering from juvenile-onset open-angle glaucoma (JOAG).\nMETHODS: MYOC was analyzed for mutations in 48 unrelated Taiwanese probands with JOAG and in 100 healthy control subjects. Genomic DNA was extracted from peripheral blood leukocytes and then subjected to PCR to amplify exons, flanking introns and promoter regions of the MYOC gene. The amplified products were screened for base mutations by autosequence. Data from the two groups were then compared using the chi(2) test. Finally, the levels of MYOC transcripts were predicted by a neural network prediction system to study whether the intron mutations have any effect on the level of mRNA expression.\nRESULTS: The analysis revealed four MYOC mutations and six polymorphisms. The prevalence of MYOC gene mutations in this study was 12.5% (6/48). The mutations included one nonsense mutation (Arg46Stop; 3/6), one missense mutation (Val56Ala; 1/6), one intron mutation (c.604+228A>T; 1/6) as well as one mutation in the 3'-untranslated region (c.1515+73G>C; 1/6). In addition, although c.604+228A>T is an intron mutation and does not alter the content of the amino acid residue, the neural network prediction system revealed that it can potentially create a novel accept splice site during transcription. This mutation might affect the protein structure and consequently the normal function of myocilin.\nCONCLUSIONS: Our results indicate that the c.136C>T (Arg46Stop), c.158T>C (Val56Ala), c.604+228A>T, and c.1515+73G>C mutations of MYOC may be associated with JOAG. In addition, we suggest that the c.136C>T (Arg46Stop) mutation of MYOC is a hot spot in Taiwanese patients with JOAG.","variants":[{"Name":"NM_000261.2(MYOC):c.136C>T (p.Arg46Ter)","Chromosome":"1","Start":"171652476","Stop":"171652476","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22994,"rule_based_match":true,"evidence_text":"c.136C>T (Arg46Stop)","llm_judgment":"PRESENT","evidence":"c.136C>T (Arg46Stop)","abstract_start":1523,"abstract_end":1543}]}
{"pmid":"25124931","title":"Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations.","abstract":"IMPORTANCE: Retinal detachment with avascularity of the peripheral retina, typically associated with familial exudative vitreoretinopathy (FEVR), can result from mutations in KIF11, a gene recently identified to cause microcephaly, lymphedema, and chorioretinal dysplasia (MLCRD) as well as chorioretinal dysplasia, microcephaly, and mental retardation (CDMMR). Ophthalmologists should be aware of the range of presentations for mutations in KIF11 because the phenotypic distinction between FEVR and MLCRD/CDMMR portends management implications in patients with these conditions.\nOBJECTIVE: To identify gene mutations in patients who present with a FEVR phenotype and explore the spectrum of ocular and systemic abnormalities caused by KIF11 mutations in a cohort of patients with FEVR or microcephaly in conjunction with chorioretinopathy or FEVR.\nDESIGN, SETTING, AND PARTICIPANTS: Clinical data and DNA were collected from each participant between 1998 and 2013 from the clinical practices of ophthalmologists and clinical geneticists internationally. Twenty-eight FEVR probands with diagnoses made by the referring physician and without a known FEVR gene mutation, and 3 with microcephaly and chorioretinopathy, were included. At least 1 patient in each pedigree manifested 1 or more of the following: macular dragging, partial retinal detachment, falciform folds, or total retinal detachment.\nEXPOSURES: Whole-exome sequencing was conducted on affected members in multiplex pedigrees, and Sanger sequencing of the 22 exons of the KIF11 gene was performed on singletons. Clinical data and history were collected and reviewed.\nMAIN OUTCOMES AND MEASURES: Identification of mutations in KIF11.\nRESULTS: Four novel heterozygous KIF11 mutations and 1 previously published mutation were identified in probands with FEVR: p.A218Gfs*15, p.E470X, p.R221G, c.790-1G>T, and the previously described heterozygous p.R47X. Documentation of peripheral avascular areas on intravenous fluorescein angiography was possible in 2 probands with fibrovascular proliferation demonstrating phenotypic overlap with FEVR.\nCONCLUSIONS AND RELEVANCE: Mutations in KIF11 cause a broader spectrum of ocular disease than previously reported, including retinal detachment. The KIF11 gene likely plays a role in retinal vascular development and mutations in this gene can lead to clinical overlap with FEVR. Cases of FEVR should be carefully inspected for the presence of microcephaly as a marker for KIF11-related disease to enhance the accuracy of the prognosis and genetic counseling.","variants":[{"Name":"NM_004523.4(KIF11):c.790-1G>T","Chromosome":"10","Start":"92613376","Stop":"92613376","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":190094,"rule_based_match":true,"evidence_text":"c.790-1G>T","llm_judgment":"PRESENT","evidence":"c.790-1G>T","abstract_start":1852,"abstract_end":1862}]}
{"pmid":"32117442","title":"Recurrent NEDD4L Variant in Periventricular Nodular Heterotopia, Polymicrogyria and Syndactyly.","abstract":"NEDD4L encodes an ubiquitin ligase which is expressed in the cortex and ventricular zone of the fetal brain. Missense variants in NEDD4L have been reported in nine patients with periventricular nodular heterotopia (PNH), polymicrogyria, cleft palate, and syndactyly. All reported variants are located in the HECT domain, causing deregulation of signaling pathways, including the AKT/mTOR pathway. Here we describe a first familial case with four affected members with a high degree of intra-familial phenotypic variability. Phenotypic features in the proband consisted of severe neurodevelopmental delay, refractory seizures, bilateral PNH, and perisylvian polymicrogyria. The other family members were less severely affected with mild developmental delay and isolated bilateral PNH. All family members had syndactyly. An unrelated patient presented with severe neurodevelopmental delay, seizures, and hypospadias, expanding the phenotypic spectrum. MRI revealed bilateral PNH and perisylvian polymicrogyria. All tested patients carry the recurrent variant c.623G > A, p.(Arg208Gln) in the WW domain of NEDD4L. The variant in the unrelated patient occurred <i>de novo</i>. This is the first report of a NEDD4L variant located in the WW domain which is probably involved in the recognition of substrates for ligation suggesting a loss of function variant.","variants":[{"Name":"NM_001144967.3(NEDD4L):c.623G>A (p.Arg208Gln)","Chromosome":"18","Start":"58325105","Stop":"58325105","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":855115,"rule_based_match":true,"evidence_text":"c.623G > A, p.(Arg208Gln)","llm_judgment":"PRESENT","evidence":"c.623G > A, p.(Arg208Gln)","abstract_start":1057,"abstract_end":1082}]}
{"pmid":"35991565","title":"Novel","abstract":"<b>Background:</b> Infertility is a global health concern. <i>MEIOB</i> has been found to be associated with premature ovarian insufficiency (POI) and non-obstructive azoospermia (NOA), but its variants have not been reported in Chinese patients. The aim of this study was to identify the genetic aetiology of POI or NOA in three Han Chinese families. <b>Methods:</b> Whole-exome sequencing (WES) was used to identify candidate pathogenic variants in three consanguineous Chinese infertile families with POI or NOA. Sanger sequencing was performed to validate these variants in the proband of family I and her affected family members. <i>In vitro</i> functional analyses were performed to confirm the effects of these variants. <b>Results:</b> Two novel homozygous frameshift variants (c.258_259del and c.1072_1073del) and one novel homozygous nonsense variant (c.814C > T) in the <i>MEIOB</i> gene were identified in three consanguineous Han Chinese families. <i>In vitro</i> functional analyses revealed that these variants produced truncated proteins and affected their function. <b>Conclusion:</b> We identified three novel <i>MEIOB</i> loss-of-function variants in local Chinese patients for the first time and confirmed their pathogenicity using <i>in vitro</i> functional analyses. These results extend the mutation spectrum of the <i>MEIOB</i> gene and have important significance for genetic counselling in these families.","variants":[{"Name":"NM_001163560.3(MEIOB):c.814C>T (p.Arg272Ter)","Chromosome":"16","Start":"1844928","Stop":"1844928","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2099769,"rule_based_match":true,"evidence_text":"c.814C > T","llm_judgment":"PRESENT","evidence":"c.814C > T","abstract_start":862,"abstract_end":872},{"Name":"NM_001163560.3(MEIOB):c.1072_1073del (p.Met358fs)","Chromosome":"16","Start":"1839400","Stop":"1839401","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":2852803,"rule_based_match":true,"evidence_text":"c.1072_1073del","llm_judgment":"PRESENT","evidence":"c.1072_1073del","abstract_start":803,"abstract_end":817}]}
{"pmid":"29434075","title":"A Missense Mutation in GJA8 Encoding Connexin 50 in a Chinese Pedigree with Autosomal Dominant Congenital Cataract.","abstract":"Congenital cataract is leading cause of visual impairment and blindness in children worldwide. Approximately one-third of congenital cataract cases are familial, whose genetic etiology can be distinguished by targeted exome sequencing. Here, a three-generation congenital cataract pedigree was recruited, and physical and ophthalmologic examinations were taken. Targeted exome sequencing of 139 cataract-related genes was performed on the proband III:1. Sanger sequencing was used to validate the presence of variation identified via exome sequencing in family members and 200 controls. Conservative and functional prediction was performed with bioinformatic tools. We, thus, found a heterozygous missense mutation c.10T>A (p.W4R) in gap junction protein alpha 8 (GJA8) in the patients. However, this mutation was not present in normal family members and 200 unrelated controls. The GJA8 gene encodes a gap junction protein, connexin 50 (Cx50), in lens fibers that provide channels for exchange of ions and small molecules between adjacent cells. Conservative and functional prediction suggests that the W-to-R substitution at codon 4 may impair the function of the human Cx50 protein. Accordingly, we analyzed the distribution of Flag-tagged mutant Cx50 protein in HeLa cervical cancer cells. Immunofluorescent staining showed that the W-to-R substitution impaired Cx50 trafficking to the plasma membrane to form the gap junction. In conclusion, c.10T>A (p.W4R) in GJA8 is the newly identified genetic cause of familial congenital cataract. The W-to-R substitution near the amino-terminus may alter the localization of mutant Cx50, thereby impairing gap junction formation, which is the molecular pathogenic mechanism of this mutation.","variants":[{"Name":"NM_005267.5(GJA8):c.10T>A (p.Trp4Arg)","Chromosome":"1","Start":"147907965","Stop":"147907965","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3412493,"rule_based_match":true,"evidence_text":"c.10T>A (p.W4R)","llm_judgment":"PRESENT","evidence":"c.10T>A (p.W4R)","abstract_start":715,"abstract_end":730}]}
{"pmid":"36599939","title":"X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome.","abstract":"Hemolytic-uremic syndrome (HUS), mostly secondary to infectious diseases, is a common cause of acute kidney injury in children. It is characterized by progressive acute kidney failure due to severe thrombotic microangiopathy, associated with nonimmune, Coombs-negative hemolytic anemia and thrombocytopenia. HUS is caused mostly by Shiga toxin-producing E. Coli, and to a lesser extent by Streptococcus pneumonia. In Streptococcus pneumonia HUS (pHUS), bacterial neuraminidase A exposes masked O-glycan sugar residues on erythrocytes, known as the T antigen, triggering a complement cascade causing thrombotic microangiopathy. Atypical HUS (aHUS) is a life-threatening genetic form of the disease, whose molecular mechanism is only partly understood. Through genetic studies, we demonstrate a novel X-linked form of aHUS that is caused by a de-novo missense mutation in C1GALT1C1:c.266 C > T,p.(T89I), encoding a T-synthase chaperone essential for the proper formation and incorporation of the T antigen on erythrocytes. We demonstrate the presence of exposed T antigen on the surface of mutant erythrocytes, causing aHUS in a mechanism similar to that suggested in pHUS. Our findings suggest that both aHUS caused by mutated C1GALT1C1 and pHUS are mediated by the lectin-complement-pathway, not comprehensively studied in aHUS. We thus delineate a shared molecular basis of aHUS and pHUS, highlighting possible therapeutic opportunities.","variants":[{"Name":"NM_001011551.3(C1GALT1C1):c.266C>T (p.Thr89Ile)","Chromosome":"X","Start":"120626901","Stop":"120626901","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2671532,"rule_based_match":true,"evidence_text":"C1GALT1C1:c.266 C > T,p.(T89I)","llm_judgment":"PRESENT","evidence":"C1GALT1C1:c.266 C > T,p.(T89I)","abstract_start":870,"abstract_end":900}]}
{"pmid":"30470562","title":"Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder.","abstract":"Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. The deficiency of this enzyme represents an encephalomyopathic form of mtDNA depletion syndromes. We describe the fatal clinical course of a female patient with a pathogenic mutation in SUCLG1 (c.626C > A, p.Ala209Glu) heterozygous at the genomic DNA level, but homozygous at the transcriptional level. The patient exhibited early-onset neurometabolic abnormality culminating in severe brain atrophy and dystonia leading to death by the age of 3.5 years. Urine and plasma metabolite profiling was consistent with SUCL deficiency which was confirmed by enzyme analysis and lack of mitochondrial substrate-level phosphorylation (mSLP) in skin fibroblasts. Oxygen consumption- but not extracellular acidification rates were altered only when using glutamine as a substrate, and this was associated with mild mtDNA depletion and no changes in ETC activities. Immunoblot analysis revealed no detectable levels of SUCLG1, while SUCLA2 and SUCLG2 protein expressions were largely reduced. Confocal imaging of triple immunocytochemistry of skin fibroblasts showed that SUCLG2 co-localized only partially with the mitochondrial network which otherwise exhibited an increase in fragmentation compared to control cells. Our results outline the catastrophic consequences of the mutated SUCLG1 leading to strongly reduced SUCL activity, mSLP impairment, mislocalization of SUCLG2, morphological alterations in mitochondria and clinically to a severe neurometabolic disease, but in the absence of changes in mtDNA levels or respiratory complex activities.","variants":[{"Name":"NM_003849.4(SUCLG1):c.626C>A (p.Ala209Glu)","Chromosome":"2","Start":"84433399","Stop":"84433399","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":980771,"rule_based_match":true,"evidence_text":"c.626C > A, p.Ala209Glu","llm_judgment":"PRESENT","evidence":"c.626C > A, p.Ala209Glu","abstract_start":430,"abstract_end":453}]}
{"pmid":"19530960","title":"Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment.","abstract":"AIMS: The importance of polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD) for the prediction of severe toxicity in 5-fluorouracil (5-FU)-based chemotherapy is still unclear. This study aims to assess the predictive value of DPYD variation with respect to previously described DPYD variants for 5-FU toxicity. It represents the first analysis of the gene at the haplotype level, also capturing potentially important genetic variation located outside the coding regions of DPYD.\nMATERIALS & METHODS: The entire coding sequence and exon-flanking intronic regions of DPYD were sequenced in 111 cancer patients receiving fluoropyrimidine-based chemotherapy. DPYD haplotypes were inferred and their associations with severe 5-FU toxicity were assessed.\nRESULTS: None of the previously described deleterious variants (IVS14+1G>A, c.2846A>T and c.1679T>G) were detected in 24 patients who experienced severe 5-FU toxicity. A potential association was observed between a haplotype containing three novel intronic polymorphisms (IVS5+18G>A, IVS6+139G>A and IVS9-51T>G) and a synonymous mutation (c.1236G>A), which was observed five- out of eight-times in patients with severe adverse effects.\nCONCLUSION: The association of a haplotype containing no nonsynonymous or splice-site polymorphisms indicates that additional important genetic variation may be located in noncoding gene regions. Furthermore, a comparison with other studies suggests that the relative importance of particular DPYD mutations (IVS14+1G>A and c.2846A>T) for predicting severe 5-FU toxicity differs geographically across Europe.","variants":[{"Name":"NM_000110.4(DPYD):c.1236G>A (p.Glu412=)","Chromosome":"1","Start":"97573863","Stop":"97573863","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105977,"rule_based_match":true,"evidence_text":"c.1236G>A","llm_judgment":"PRESENT","evidence":"c.1236G>A","abstract_start":1101,"abstract_end":1110}]}
{"pmid":"23712021","title":"Prevalence and mutation analysis of short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin.","abstract":"Short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD), also called 2-methylbutyryl CoA dehydrogenase deficiency (2-MBCDD), is a disorder of l-isoleucine metabolism of uncertain clinical significance. SBCADD is inadvertently detected on expanded newborn screening by elevated 2-methylbutyrylcarnitine (C5), which has the same mass to charge (m/s) on tandem mass spectrometry (MS/MS) as isovalerylcarnitine (C5), an analyte that is elevated in isovaleric acidemia (IVA), a disorder in leucine metabolism. SBCADD cases identified in the Hmong-American population have been found in association with the c.1165 A>G mutation in the ACADSB gene. The purposes of this study were to: (a) estimate the prevalence of SBCADD and carrier frequency of the c.1165 A>G mutation in the Hmong ethnic group; (b) determine whether the c.1165 A>G mutation is common to all Hmong newborns screening positive for SBCADD; and (c) evaluate C5 acylcarnitine cut-off values to detect and distinguish between SBCADD and IVA diagnoses. During the first 10years of expanded newborn screening using MS/MS in Wisconsin (2001-2011), 97 infants had elevated C5 values (≥0.44μmol/L), of whom five were Caucasian infants confirmed to have IVA. Of the remaining 92 confirmed SBCADD cases, 90 were of Hmong descent. Mutation analysis was completed on an anonymous, random sample of newborn screening cards (n=1139) from Hmong infants. Fifteen infants, including nine who had screened positive for SBCADD based on a C5 acylcarnitine concentration ≥0.44μmol/L, were homozygous for the c.1165 A>G mutation. This corresponds to a prevalence in this ethnic group of being homozygous for the mutation of 1.3% (95% confidence interval 0.8-2.2%) and of being heterozygous for the mutation of 21.8% (95% confidence interval 19.4-24.3%), which is consistent with the Hardy-Weinberg equilibrium. Detection of homozygous individuals who were not identified on newborn screening suggests that the C5 screening cut-off would need to be as low as 0.20μmol/L to detect all infants homozygous for the ACADSB c.1165 A>G mutation. However, lowering the screening cut-off to 0.20 would also result in five \"false positive\" (non-homozygous) screening results in the Hmong population for every c.1165 A>G homozygote detected. Increasing the cut-off to 0.60μmol/L and requiring elevated C5/C2 (acetylcarnitine) and C5/C3 (propionylcarnitine) ratios to flag a screen as abnormal would reduce the number of infants screening positive, but would still result in an estimated 5 infants with SBCADD per year who would require follow-up and additional biochemical testing to distinguish between SBCADD and IVA diagnoses. Further research is needed to determine the clinical outcomes of SBCADD detected on newborn screening and the c.1165 A>G mutation before knowing whether the optimal screening cut-off would minimize true positives or false negatives for SBCADD associated with this mutation.","variants":[{"Name":"NM_001609.4(ACADSB):c.1165A>G (p.Met389Val)","Chromosome":"10","Start":"123053097","Stop":"123053097","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":638768,"rule_based_match":true,"evidence_text":"c.1165 A>G","llm_judgment":"PRESENT","evidence":"c.1165 A>G","abstract_start":610,"abstract_end":620}]}
{"pmid":"32776440","title":"Whole genome sequence analysis identifies a PAX2 mutation to establish a correct diagnosis for a syndromic form of hyperuricemia.","abstract":"Hereditary hyperuricemia may occur as part of a syndromic disorder or as an isolated nonsyndromic disease, and over 20 causative genes have been identified. Here, we report the use of whole genome sequencing (WGS) to establish a diagnosis in a family in which individuals were affected with gout, hyperuricemia associated with reduced fractional excretion of uric acid, chronic kidney disease (CKD), and secondary hyperparathyroidism, that are consistent with familial juvenile hyperuricemic nephropathy (FJHN). However, single gene testing had not detected mutations in the uromodulin (UMOD) or renin (REN) genes, which cause approximately 30-90% of FJHN. WGS was therefore undertaken, and this identified a heterozygous c.226G>C (p.Gly76Arg) missense variant in the paired box gene 2 (PAX2) gene, which co-segregated with renal tubulopathy in the family. PAX2 mutations are associated with renal coloboma syndrome (RCS), which is characterized by abnormalities in renal structure and function, and anomalies of the optic nerve. Ophthalmological examination in two adult brothers affected with hyperuricemia, gout, and CKD revealed the presence of optic disc pits, consistent with optic nerve coloboma, thereby revising the diagnosis from FJHN to RCS. Thus, our results demonstrate the utility of WGS analysis in establishing the correct diagnosis in disorders with multiple etiologies.","variants":[{"Name":"NM_000278.5(PAX2):c.226G>C (p.Gly76Arg)","Chromosome":"10","Start":"100750707","Stop":"100750707","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":624398,"rule_based_match":true,"evidence_text":"c.226G>C (p.Gly76Arg)","llm_judgment":"PRESENT","evidence":"c.226G>C (p.Gly76Arg)","abstract_start":722,"abstract_end":743}]}
{"pmid":"36774715","title":"MYH2-associated myopathy caused by a novel splice-site variant.","abstract":"MYH2 encodes MyHCIIa, a myosin heavy chain found in fast type 2A fibers. Pathogenic variants in this gene have previously been implicated in dominant and recessive forms of myopathy. Three individuals reported here are part of a family in which four generations of individuals are affected by a slowly progressive, predominantly proximal myopathy in an autosomal dominant inheritance pattern. Affected individuals in this family lacked classic features of an MYH2-associated myopathy such as congenital contractures and ophthalmoplegia. A novel variant, MYH2 c.5673+1G>C, was detected in the proband and subsequently found to segregate with disease in five additional family members. Further studies demonstrated that this variant affects splicing, resulting in novel transcripts. These data and muscle biopsy findings in the proband, indicate that this family's MYH2 variant is causative of their myopathy, adding to our understanding of the clinical and molecular characteristics of the disease.","variants":[{"Name":"NM_017534.6(MYH2):c.5673+1G>C","Chromosome":"17","Start":"10523089","Stop":"10523089","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":624069,"rule_based_match":true,"evidence_text":"MYH2 c.5673+1G>C","llm_judgment":"PRESENT","evidence":"MYH2 c.5673+1G>C","abstract_start":554,"abstract_end":570}]}
{"pmid":"38307397","title":"Evaluating the efficacy of a long-read sequencing-based approach in the clinical diagnosis of neonatal congenital adrenocortical hyperplasia.","abstract":"Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders predominantly characterized by impaired corticosteroid synthesis. Clinical phenotypes include hypoadrenocorticism, electrolyte disturbances, abnormal gonadal development, and short stature, of which severe hyponadrenocorticism and salt wasting can be life-threatening. Genetic analysis can help in the clinical diagnosis of CAH. However, the 21-OHD-causing gene CYP21A2 is arranged in tandem with the highly homologous CYP21A1P pseudogene, making it difficult to determine the exact genotypes using the traditional method of multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing or next-generation sequencing (NGS). We applied a long-read sequencing-based approach termed comprehensive analysis of CAH (CACAH) to 48 newborns with CAH that were diagnosed by clinical features and the traditional MLPA plus Sanger sequencing method for retrospective analysis, to evaluate its efficacy in the clinical diagnosis of neonatal CAH. Compared with the MLPA plus Sanger sequencing method, CACAH showed 100 % consistency in detecting SNV/indel variants located in exons and exon-intron boundary regions of CAH-related genes. It can directly determine the cis-trans relationship without the need to analyze parental genotypes, which reduces the time to diagnosis. Moreover, CACAH was able to distinguish different CYP21A1P/CYP21A2 and TNXA/TNXB chimeras, and detect additional variants (CYP21A2 variants c.-121C > T, c.*13G > A, c.*52C > T, c.*440C > T, c.*443 T > C, and TNXB variants c.12463 + 2 T > C, c.12204 + 5G > A). We also identified the TNXB variant c.11435_11524 + 30del alone instead of as a part of the TNXA/TNXB-CH-1 chimera in two newborns, which might be introduced by gene conversion. All of these characteristics enabled clinicians to better explain the phenotype of subjects and manage them more effectively. CACAH has a great advantage over the traditional MLPA and Sanger sequencing methods, showing substantial potential in the genetic diagnosis and screening of neonatal CAH.","variants":[{"Name":"NM_000500.9(CYP21A2):c.*13G>A","Chromosome":"6","Start":"32041147","Stop":"32041147","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":576926,"rule_based_match":true,"evidence_text":"c.*13G > A","llm_judgment":"PRESENT","evidence":"c.*13G > A","abstract_start":1512,"abstract_end":1522}]}
{"pmid":"30516834","title":"Short-term response to phenytoin sodium in Andersen-Tawil syndrome-1 with a cardiac-dominant phenotype.","abstract":"BACKGROUND: Andersen-Tawil syndrome (ATS) is a rare familial periodic paralysis that typically also affects the heart and skeletal system. Ventricular arrhythmias (VAs) are profound and difficult to control, but minimally symptomatic. In this report, we describe an atypical phenotype of ATS in two related families. We also report our experience with phenytoin sodium for the control of resistant VAs in these patients.\nMETHODS AND RESULTS: Between 2014 and 2018, seven siblings were diagnosed with ATS on the basis of cardiac arrhythmias and genetic evaluation. Heterozygous mutation with c.431G > C (p.G144A) in exon 2 of KCNJ2 gene was observed in all patients. Characteristic cardiac manifestations were noted in all patients but periodic paralysis or objective neurological involvement was distinctly absent. Phenytoin was considered for control of symptomatic VA in three patients. Intake of oral phenytoin (5 mg/kg/day) for 1 month completely suppressed VA (<1% in 24-h Holter monitoring) in two patients, and significantly in the third (8% per 24 h) patient. Phenytoin was well-tolerated in all three patients.\nCONCLUSIONS: We describe a cardiac-predominant phenotype in ATS. ATS should be suspected in patients with typical cardiac manifestations even in the absence of periodic paralysis. Our initial experience with short-term use of phenytoin for control of resistant VAs is encouraging.","variants":[{"Name":"NM_000891.3(KCNJ2):c.431G>C (p.Gly144Ala)","Chromosome":"17","Start":"70175470","Stop":"70175470","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":78471,"rule_based_match":true,"evidence_text":"c.431G > C (p.G144A)","llm_judgment":"PRESENT","evidence":"c.431G > C (p.G144A)","abstract_start":591,"abstract_end":611}]}
{"pmid":"31155284","title":"Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification.","abstract":"Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl<sup>-</sup>/H<sup>+</sup> exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.","variants":[{"Name":"NM_001287.6(CLCN7):c.2144A>G (p.Tyr715Cys)","Chromosome":"16","Start":"1447498","Stop":"1447498","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":360150,"rule_based_match":true,"evidence_text":"c.2144A>G","llm_judgment":"PRESENT","evidence":"c.2144A>G","abstract_start":569,"abstract_end":578}]}
{"pmid":"17072863","title":"Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.","abstract":"Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta-synthase (CBS) gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (q(c.833C) approximately equals 3.3 x 10(-3)), is approximately 20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (q(c.833C) approximately equals 0.18 x 10(-3)), implying clinical underascertainment. Intriguingly, the c.833C mutation is also present in combination with a 68-bp insertion, c.[833C; 844_845ins68], in a substantial proportion of chromosomes from nonhomocystinuric individuals worldwide. We have sought to study the relationship between the pathogenic and nonpathogenic c.833C-bearing chromosomes and to determine whether the pathogenic c.[833C; -] chromosomes are identical-by-descent or instead arose by recurrent mutation. Initial haplotype analysis of 780 randomly selected Czech and sub-Saharan African wild-type chromosomes, employing 12 intragenic markers, revealed 29 distinct CBS haplotypes, of which 10 carried the c.[833C; 844_845ins68] combination; none carried an isolated c.833C or c.844_845ins68 mutation. Subsequent examination of 69 pathogenic c.[833C; -] chromosomes, derived from homocystinuria patients of predominantly European origin, disclosed three unrelated haplotypes that differed from their wild-type counterparts by virtue of the presence of c.833C, thereby indicating that c.833T>C transition has occurred repeatedly and independently in the past. Since c.833T does not reside within an obvious mutational hotspot, we surmise that the three pathogenic and comparatively prevalent c.[833C; -] chromosomes may have originated by recurrent gene conversion employing the common nonpathogenic c.[833C; 844_845ins68] chromosomes as templates.","variants":[{"Name":"NM_000071.3(CBS):c.833T>C (p.Ile278Thr)","Chromosome":"21","Start":"43063074","Stop":"43063074","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15159,"rule_based_match":true,"evidence_text":"c.833T>C","llm_judgment":"PRESENT","evidence":"c.833T>C","abstract_start":48,"abstract_end":56}]}
{"pmid":"30424791","title":"Characterization of two ETFDH mutations in a novel case of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.","abstract":"BACKGROUND: Deficiency of electron transfer flavoprotein dehydrogenase (ETFDH) is associated with multiple acyl-CoA dehydrogenase deficiency (MADD). This disorder is an autosomal recessive lipid storage myopathy (LSM) that exhibits a wide range of clinical features, including myopathy, weakness and multisystem dysfunctions. Many patients with late onset of MADD improve when treated with riboflavin and are also referred to as RR-MADD (riboflavin-responsive multiple Acyl-CoA dehydrogenase disorder).\nMETHODS: In this study, we report the clinical and genetic characterization of a novel RR-MADD patient. Biochemical data were obtained from analysis of muscle and plasma samples. DNA and RNA were extracted from peripheral blood, and sequence analysis and expression study of ETFDH gene were performed. Finally, the impact of mutations on ETFDH folding was evaluated using bioinformatic tools.\nRESULTS: Patient initially presented with vomiting, muscle weakness, and acidosis. Muscle biopsy revealed typical myopathological patterns of lipid storage myopathy and blood acylcarnitine profiles showed a combined elevation of long and medium chain acylcarnitines, supporting the diagnosis of RR-MADD. Molecular analysis of ETFDH gene revealed two heterozygous mutations, a novel splice variation in intron 10, c.1285 + 1G > A, and the previously reported c.560C > T missense mutation. RT-PCR analysis showed an alteration of ETFDH RNA splicing which in turn should lead to the production of a truncated protein. The in silico prediction analysis of ETFDH tridimensional structure demonstrated that the missense mutation resulted in instability and loss of protein activation, while the splice site variation induced a dramatic conformational change of the truncated protein. After MCT diet supplemented with carnitine and riboflavin, the patient showed significant biochemical and clinical improvement, in spite of severe molecular defect.\nCONCLUSION: This case report extends the spectrum of ETFDH mutations in MADD, providing further evidence that patients presenting at least one missense mutation in the FAD-binding domain may respond to either carnitine or riboflavin treatment, due to the recovery of some enzymatic activity.","variants":[{"Name":"NM_004453.4(ETFDH):c.560C>T (p.Ala187Val)","Chromosome":"4","Start":"158685173","Stop":"158685173","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":406419,"rule_based_match":true,"evidence_text":"c.560C > T","llm_judgment":"PRESENT","evidence":"c.560C > T","abstract_start":1354,"abstract_end":1364},{"Name":"NM_004453.4(ETFDH):c.1285+1G>A","Chromosome":"4","Start":"158703592","Stop":"158703592","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":519831,"rule_based_match":true,"evidence_text":"c.1285 + 1G > A","llm_judgment":"PRESENT","evidence":"c.1285 + 1G > A","abstract_start":1309,"abstract_end":1324}]}
{"pmid":"31645653","title":"De novo ZBTB7A variant in a patient with macrocephaly, intellectual disability, and sleep apnea: implications for the phenotypic development in 19p13.3 microdeletions.","abstract":"Interstitial microdeletions at chromosome 19p13.3 are frequently associated with a constellation of clinical features including macrocephaly, characteristic face, intellectual disability, and sleep apnea. Previous studies in 25 patients with 19p13.3 microdeletions have revealed loss of MAP2K2 in 24 patients and that of PIAS4 and ZBTB7A in 23 patients, suggesting that these three adjacent genes are candidate genes for the phenotypic development in 19p13.3 microdeletions. We identified a de novo likely pathogenic heterozygous missense variant of ZBTB7A (NM_015898.3:c.1152C>G, p.(Cys384Trp)) in a Japanese boy with macrocephaly, intellectual disability, and sleep apnea. This variant affects the conserved cysteine residue forming the coordinate bond with Zn<sup>2+</sup> ion at the first zinc finger domain, and is predicted to exert a dominant-negative effect because of the generation of homo- and hetero-dimers with the wild-type and variant ZBTB7A proteins. The results argue for a critical relevance of ZBTB7A to the development of most, but probably not all, of the 19p13.3 microdeletion phenotype.","variants":[{"Name":"NM_015898.4(ZBTB7A):c.1152C>G (p.Cys384Trp)","Chromosome":"19","Start":"4054081","Stop":"4054081","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1334470,"rule_based_match":true,"evidence_text":"NM_015898.3:c.1152C>G, p.(Cys384Trp)","llm_judgment":"PRESENT","evidence":"NM_015898.3:c.1152C>G, p.(Cys384Trp)","abstract_start":558,"abstract_end":594}]}
{"pmid":"23963851","title":"A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).","abstract":"OBJECTIVE: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene were studied in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).\nMETHODS: Exons 1-9 of the HTRA1 gene were amplified and bidirectionally sequenced in a Chinese family with CARASIL. Mutation effects were analysed by three-dimensional modelling of the serine protease HTRA1 protein.\nRESULTS: The proband was found to be homozygous for a novel missense mutation (c.854 C > T) identified in exon 4 of the HTRA1 gene; the parents of the proband were heterozygous for the same missense mutation. This c.854 C > T mutation resulted in a change from proline to leucine (p.P285L) in serine protease HTRA1, and was absent in 260 control chromosomes. Three-dimensional models showed that the change from proline to leucine (p.P285L) could attenuate the hydrogen bond between S284 and S287 residues, which might affect function of serine protease HTRA1.\nCONCLUSION: Discovery of a novel missense mutation (c.854C>T) associated with CARASIL expands the known CARASIL-related mutations in HTRA1.","variants":[{"Name":"NM_002775.5(HTRA1):c.854C>T (p.Pro285Leu)","Chromosome":"10","Start":"122506767","Stop":"122506767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":165896,"rule_based_match":true,"evidence_text":"c.854 C > T","llm_judgment":"PRESENT","evidence":"c.854 C > T","abstract_start":527,"abstract_end":538}]}
{"pmid":"31420593","title":"A novel homozygous FBXO38 variant causes an early-onset distal hereditary motor neuronopathy type IID.","abstract":"Distal hereditary motor neuronopathies (dHMN) are a genetically heterogeneous group of neuromuscular disorders caused by anterior horn cell degeneration and progressive distal muscle weakness. A heterozygous missense variant in FBXO38 has been previously described in two families affected by autosomal-dominant dHMN. In this paper, we describe a homozygous missense variant in FBXO38 (c.1577G>A; p.(Arg526Gln)) in a young Turkish female, offspring of consanguineous parents, with a congenital mild neuronopathy with idiopathic toe walking, normal sensory examination, and hearing loss. This work is the first to describe a novel homozygous variant and a suggested loss of function mechanism in FBXO38, expanding the dHMN type IID phenotype.","variants":[{"Name":"NM_205836.3(FBXO38):c.1577G>A (p.Arg526Gln)","Chromosome":"5","Start":"148417163","Stop":"148417163","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":633588,"rule_based_match":true,"evidence_text":"c.1577G>A; p.(Arg526Gln)","llm_judgment":"PRESENT","evidence":"c.1577G>A; p.(Arg526Gln)","abstract_start":386,"abstract_end":410}]}
{"pmid":"22277643","title":"Criteria to predict carriers of a novel SCN5A mutation in a large Portuguese family affected by the Brugada syndrome.","abstract":"AIMS: Brugada syndrome (BrS) is a life-threatening arrhythmia disorder associated with autosomal-dominant mutations in the SCN5A gene. We aimed to characterize the diagnostic challenges and clinical manifestations of a novel SCN5A mutation associated with BrS.\nMETHODS AND RESULTS: From a novel SCN5A mutation (c.664C>T; p.Arg222X) identified in a proband with the characteristic electrocardiographic pattern and the history of sudden collapse, 122 family members were studied including 40 carriers of the mutation. The electrocardiographic diagnosis of BrS requires type 1 Brugada electrocardiogram (ECG) pattern in >1 right precordial lead (V1-V3), but recently an isolated lead with coved-type ECG was proposed to be enough for the diagnosis. In this family, these proposed criteria (PC) were more sensitive in detecting mutation carriers than the conventional criteria without repercussion on the specificity. Carriers had, on average, longer P-wave duration, PR, and QRS intervals and higher transmural dispersion of repolarization. The prevalence of late potentials was higher in carriers, and individual signal average ECG (SAECG) parameters (QRSf, LAS, and RMS40) also were related to SCN5A gene mutation. Three non-carriers were found to be affected by BrS, two with a spontaneous type 1 ECG with alternative placement of the precordial electrodes, and one only after the pharmacological provocative test, suggesting that other genes may play a role in the pathophysiology of this disease.\nCONCLUSION: The PC for BrS diagnosis should be implemented. Some parameters from the spontaneous ECG and the SAECG are more effective tools than the characteristic repolarization pattern to discriminate between carriers of SCN5A mutations.","variants":[{"Name":"NM_000335.5(SCN5A):c.664C>T (p.Arg222Ter)","Chromosome":"3","Start":"38613782","Stop":"38613782","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":196998,"rule_based_match":true,"evidence_text":"c.664C>T; p.Arg222X","llm_judgment":"PRESENT","evidence":"c.664C>T; p.Arg222X","abstract_start":311,"abstract_end":330}]}
{"pmid":"25983617","title":"Identification of a novel COL1A1 frameshift mutation, c.700delG, in a Chinese osteogenesis imperfecta family.","abstract":"Osteogenesis imperfecta (OI) is a family of genetic disorders associated with bone loss and fragility. Mutations associated with OI have been found in genes encoding the type I collagen chains. People with OI type I often produce insufficient α1-chain type I collagen because of frameshift, nonsense, or splice site mutations in COL1A1 or COL1A2. This report is of a Chinese daughter and mother who had both experienced two bone fractures. Because skeletal fragility is predominantly inherited, we focused on identifying mutations in COL1A1 and COL1A2 genes. A novel mutation in COL1A1, c.700delG, was detected by genomic DNA sequencing in the mother and daughter, but not in their relatives. The identification of this mutation led to the conclusion that they were affected by mild OI type I. Open reading frame analysis indicated that this frameshift mutation would truncate α1-chain type I collagen at residue p263 (p.E234KfsX264), while the wild-type protein would contain 1,464 residues. The clinical data were consistent with the patients' diagnosis of mild OI type I caused by haploinsufficiency of α1-chain type I collagen. Combined with previous reports, identification of the novel mutation COL1A1-c.700delG in these patients suggests that additional genetic and environmental factors may influence the severity of OI.","variants":[{"Name":"NM_000088.3(COL1A1):c.700delG","Chromosome":"17","Start":"50197230","Stop":"50197230","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":1694371,"rule_based_match":true,"evidence_text":"c.700delG","llm_judgment":"PRESENT","evidence":"c.700delG","abstract_start":587,"abstract_end":596}]}
{"pmid":"21386927","title":"Genetic variations in GJA3, GJA8, LIM2, and age-related cataract in the Chinese population: a mutation screening study.","abstract":"PURPOSE: To investigate the role of genetic variations in three known cataract-associated genes, gap junction protein α3 (GJA3), gap junction protein α8 (GJA8), lens intrinsic membrane protein 2 (LIM2), encoding lens fiber cell membrane proteins in the development of age-related cataracts.\nMETHODS: One hundred and forty-five sporadic age-related cataract patients and one hundred and fifty-six unrelated random healthy controls participated in this study. Genomic DNA was extracted from peripheral blood leukocytes. All exons of GJA3, GJA8, and LIM2 were sequenced after being amplified by polymerase chain reaction (PCR). The functional consequences of the mutations were analyzed using PolyPhen.\nRESULTS: We found five novel variations in 145 patients and none of them presented in the 156 controls. There are two variations in GJA3 (c.-39C>G, c. 415G>A); one in GJA8 (c. 823G>A), and two in LIM2 (c.57G>A, c.67A>C). PolyPhen predicted that the LIM2 c.67A>C mutation may have potential pathogenicity.\nCONCLUSIONS: The genetic mutation in GJA3, GJA8, and LIM2 may slightly contribute to the development of age-related cataracts. This study showed a potential relationship between lens fiber cell membrane protein genes and the development of age-related cataracts in the Chinese population.","variants":[{"Name":"NM_001161748.2(LIM2):c.57G>A (p.Leu19=)","Chromosome":"19","Start":"51387387","Stop":"51387387","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":533870,"rule_based_match":true,"evidence_text":"c.57G>A","llm_judgment":"PRESENT","evidence":"c.57G>A","abstract_start":902,"abstract_end":909}]}
{"pmid":"38168645","title":"Recessive TMOD1 mutation causes childhood cardiomyopathy.","abstract":"Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1<sup>R189W</sup> and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1<sup>R189W</sup> demonstrated longer thin filaments than GFP-TMOD1<sup>wt</sup>-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1<sup>R189W</sup> showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant's effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.","variants":[{"Name":"NM_003275.4(TMOD1):c.565C>T (p.Arg189Trp)","Chromosome":"9","Start":"97564115","Stop":"97564115","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222256,"rule_based_match":true,"evidence_text":"c.565C>T, p.R189W","llm_judgment":"PRESENT","evidence":"c.565C>T, p.R189W","abstract_start":236,"abstract_end":253}]}
{"pmid":"24461919","title":"Exome sequencing identifies a novel variant in ACTC1 associated with familial atrial septal defect.","abstract":"BACKGROUND: The genetics of congenital heart disease (CHD) remain incompletely understood. Exome sequencing has been successfully used to identify disease-causing mutations in familial disorders in which candidate gene analyses and linkage mapping have failed.\nMETHODS: We studied a large family characterized by autosomal dominant isolated secundum atrial septal defect (ASD) (MIM No. 612794). Candidate gene resequencing and linkage analysis were uninformative.\nRESULTS: Whole-exome sequencing of 2 affected family members identified 44 rare shared variants, including a nonsynonymous mutation (c.532A>T, p.M178L, NM_005159.4) in alpha-cardiac actin (ACTC1). This mutation was absent from 1834 internal controls as well as from the 1000 Genomes and the Exome Sequencing Project (ESP) databases, but predictions regarding its effect on protein function were divergent. However, p.M178L was the only rare mutation segregating with disease in our family.\nCONCLUSIONS: Our results provide further evidence supporting a causative role for ACTC1 mutations in ASD. Massively parallel sequencing of the exome allows for the detection of novel rare variants causing CHD without the limitations of a candidate gene approach. When mutation prediction algorithms are not helpful, studies of familial disease can help distinguish rare pathologic mutations from benign variants. Consideration of the family history can lead to genetic insights into CHD.","variants":[{"Name":"NM_005159.5(ACTC1):c.532A>T (p.Met178Leu)","Chromosome":"15","Start":"34792492","Stop":"34792492","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":497042,"rule_based_match":true,"evidence_text":"c.532A>T, p.M178L, NM_005159.4","llm_judgment":"PRESENT","evidence":"c.532A>T, p.M178L, NM_005159.4","abstract_start":597,"abstract_end":627}]}
{"pmid":"33428302","title":"Molecular pathophysiology of human MICU1 deficiency.","abstract":"AIMS: MICU1 encodes the gatekeeper of the mitochondrial Ca<sup>2+</sup> uniporter, MICU1 and biallelic loss-of-function mutations cause a complex, neuromuscular disorder in children. Although the role of the protein is well understood, the precise molecular pathophysiology leading to this neuropaediatric phenotype has not been fully elucidated. Here we aimed to obtain novel insights into MICU1 pathophysiology.\nMETHODS: Molecular genetic studies along with proteomic profiling, electron-, light- and Coherent anti-Stokes Raman scattering microscopy and immuno-based studies of protein abundances and Ca<sup>2+</sup> transport studies were employed to examine the pathophysiology of MICU1 deficiency in humans.\nRESULTS: We describe two patients carrying MICU1 mutations, two nonsense (c.52C>T; p.(Arg18*) and c.553C>T; p.(Arg185*)) and an intragenic exon 2-deletion presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception. Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis. Comparative mitochondrial Ca<sup>2+</sup> transport and proteomic studies on lymphoblastoid cells revealed that the [Ca<sup>2+</sup> ] threshold and the cooperative activation of mitochondrial Ca<sup>2+</sup> uptake were lost in MICU1-deficient cells and that 39 proteins were altered in abundance. Several of those proteins are linked to mitochondrial dysfunction and/or perturbed Ca<sup>2+</sup> homeostasis, also impacting on regular cytoskeleton (affecting Spectrin) and Golgi architecture, as well as cellular survival mechanisms.\nCONCLUSIONS: Our findings (i) link dysregulation of mitochondrial Ca<sup>2+</sup> uptake with muscle pathology (including perturbed lipid homeostasis and ER-Golgi morphology), (ii) support the concept of a functional interplay of ER-Golgi and mitochondria in lipid homeostasis and (iii) reveal the vulnerability of the cellular proteome as part of the MICU1-related pathophysiology.","variants":[{"Name":"NM_001195518.2(MICU1):c.52C>T (p.Arg18Ter)","Chromosome":"10","Start":"72566742","Stop":"72566742","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1163343,"rule_based_match":true,"evidence_text":"c.52C>T; p.(Arg18*)","llm_judgment":"PRESENT","evidence":"c.52C>T; p.(Arg18*)","abstract_start":787,"abstract_end":806}]}
{"pmid":"19190165","title":"Rad50 c.687delT does not contribute significantly to familial breast cancer in a French population.","abstract":"Mutations in DNA repair genes are known for their association with hereditary breast cancer. BRCA1 and BRCA2 are the major genes for high-penetrance familial breast and ovarian cancer, whereas mutations in ATM or Chek2 confer more modest cancer risk. Additional genes involved in DNA double-strand break repair have more recently been associated with breast cancer risk: heterozygosity for deleterious mutations in components of the Rad50-Mre11-Nbs1 complex seems to predispose to breast cancer. In particular, the c.687delT mutation in Rad50 conferred an odds ratio of 4.3 for the risk of breast cancer in a study of Finnish breast cancer families. To explore the contribution of this mutation to breast cancer in French families for which no BRCA mutation could be found, we analyzed the relevant exon in 618 familial breast cancer cases and 513 controls with no personal or familial history of breast cancer. Rad50 was analyzed in its entirety for 231 familial cases, with no clearly deleterious mutations detected. These data together suggest that although founder mutations may make Rad50 a significant breast cancer risk factor in certain populations, it is not a factor in others.","variants":[{"Name":"NM_005732.4(RAD50):c.687del (p.Ser229fs)","Chromosome":"5","Start":"132579997","Stop":"132579997","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":182523,"rule_based_match":true,"evidence_text":"c.687delT","llm_judgment":"PRESENT","evidence":"c.687delT","abstract_start":515,"abstract_end":524}]}
{"pmid":"28280076","title":"Identification of Cadherin 2 (","abstract":"BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families.\nMETHODS AND RESULTS: Whole exome sequencing was performed on 2 cousins with ARVC. Validation of 13 heterozygous variants that survived internal quality and frequency filters was performed by Sanger sequencing. These variants were also genotyped in all family members to establish genotype-phenotype cosegregation. High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 (<i>CDH2</i>) gene in unrelated genotype-negative patients with ARVC. In a 3-generation family, we identified by whole exome sequencing a novel mutation in <i>CDH2</i> (c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. The <i>CDH2</i> c.686A>C variant was not present in >200 000 chromosomes available through public databases, which changes a conserved amino acid of cadherin 2 protein and is supported as the causal mutation by parametric linkage analysis. We subsequently screened 73 genotype-negative ARVC probands tested previously for mutations in known ARVC genes and found an additional likely pathogenic variant in <i>CDH2</i> (c.1219G>A, p.Asp407Asn). <i>CDH2</i> encodes cadherin 2 (also known as N-cadherin), a protein that plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis.\nCONCLUSIONS: These data implicate <i>CDH2</i> mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.","variants":[{"Name":"NM_001792.5(CDH2):c.686A>C (p.Gln229Pro)","Chromosome":"18","Start":"28009733","Stop":"28009733","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":917816,"rule_based_match":true,"evidence_text":"NM_001792.5(CDH2):c.686A>C (p.Gln229Pro)","llm_judgment":"PRESENT","evidence":"p.Gln229Pro","abstract_start":930,"abstract_end":941},{"Name":"NM_001792.5(CDH2):c.1219G>A (p.Asp407Asn)","Chromosome":"18","Start":"27992780","Stop":"27992780","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":917817,"rule_based_match":true,"evidence_text":"c.1219G>A, p.Asp407Asn","llm_judgment":"PRESENT","evidence":"c.1219G>A, p.Asp407Asn","abstract_start":1417,"abstract_end":1439}]}
{"pmid":"26161358","title":"Novel Mutation of the GNE Gene Presenting Atypical Mild Clinical Feature: A Korean Case Report.","abstract":"Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy is caused by mutations in GNE, a key enzyme in sialic acid biosynthesis. Here, we reported a case of GNE that presented with atypical mild clinical feature and slow progression. A 48-year-old female had a complaint of left foot drop since the age of 46 years. Electromyography (EMG) and muscle biopsy from left tibialis anterior muscle were compatible with myopathy. Genetic analysis led to the identification of c.1714G>C/c.527A>T compound heterozygous mutation, which is the second most frequent mutation in Japan as far as we know. Previous research has revealed that c.1714G>C/c.527A>T compound heterozygous mutation is a mild mutation as the onset of the disease is much later than the usual age of onset of GNE myopathy and the clinical course is slowly progressive. This was the first case report in Korea of the clinicopathological characteristics of GNE myopathy with GNE (c.1714G>C/c.527A>T compound heterozygous) mutation.","variants":[{"Name":"NM_005476.7(GNE):c.1714G>C (p.Val572Leu)","Chromosome":"9","Start":"36219940","Stop":"36219940","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":21072,"rule_based_match":true,"evidence_text":"c.1714G>C","llm_judgment":"PRESENT","evidence":"c.1714G>C","abstract_start":494,"abstract_end":503}]}
{"pmid":"38214746","title":"An unusual presentation of de novo RAC3 variation in prenatal diagnosis.","abstract":"Pathogenic variants in RAC3 cause a neurodevelopmental disorder with brain malformations and craniofacial dysmorphism, called NEDBAF. This gene encodes a small GTPase, which plays a critical role in neurogenesis and neuronal migration. We report a 31 weeks of gestation fetus with triventricular dilatation, and temporal and perisylvian polymicrogyria, without cerebellar, brainstem, or callosal anomalies. Trio whole exome sequencing identified a RAC3 (NM_005052.3, GRCh38) probably pathogenic de novo variant c.276 T>A p.(Asn92Lys). Eighteen patients harboring 13 different and essentially de novo missense RAC3 variants were previously reported. All the patients presented with corpus callosum malformations. Gyration disorders, ventriculomegaly (VM), and brainstem and cerebellar malformations have frequently been described. The only previous prenatal case associated with RAC3 variant presented with complex brain malformations, mainly consisting of midline and posterior fossa anomalies. We report the second prenatal case of NEDBAF presenting an undescribed pattern of cerebral anomalies, including VM and polymicrogyria, without callosal, cerebellar, or brainstem malformations. All neuroimaging data were reviewed to clarify the spectrum of cerebral malformations.","variants":[{"Name":"NM_005052.3(RAC3):c.276T>A (p.Asn92Lys)","Chromosome":"17","Start":"82032997","Stop":"82032997","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2831264,"rule_based_match":true,"evidence_text":"c.276 T>A p.(Asn92Lys)","llm_judgment":"PRESENT","evidence":"c.276 T>A p.(Asn92Lys)","abstract_start":511,"abstract_end":533}]}
{"pmid":"23073044","title":"Remission and relapse of hemophagocytic lymphohistiocytosis in a patient harboring a PRF1 homozygous mutation: a case report.","abstract":"The aim of this paper was to describe a case of familial hemophagocytic lymphohistiocytosis (HLH) in a pediatric patient with a PRF1 homozygous mutation. An 8-year-old boy diagnosed with HLH was in remission after undergoing nonspecific treatment; however, merely 2 months later, he was presented at our hospital with a relapse of HLH. His genetic analysis showed that he had a homozygous mutation c.1066C>T in the PRF1 gene. Timely distinction of primary HLH from secondary HLH is critical.","variants":[{"Name":"NM_001083116.3(PRF1):c.1066C>T (p.Arg356Trp)","Chromosome":"10","Start":"70598655","Stop":"70598655","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":947019,"rule_based_match":true,"evidence_text":"c.1066C>T","llm_judgment":"PRESENT","evidence":"c.1066C>T","abstract_start":398,"abstract_end":407}]}
{"pmid":"31777199","title":"Spastic paraplegia as the predominant phenotype in a cohort of Chinese patients with adrenoleukodystrophy.","abstract":"BACKGROUND: X-linked adrenoleukodystrophy (ALD) is one of the most common peroxisomal disorders characterized by abnormal accumulation of very long-chain fatty acids (VLCFA) in plasma and tissues and caused by mutations within ABCD1. Clinically, ALD present with various phenotypes, ranging from asymptomatic type to rapidly progressive childhood cerebral form. However, no remarkable abnormality in cerebral white matter usually makes it difficult to distinguish adult ALD from hereditary spastic paraplegia (HSP).\nMETHODS: We analyzed the features of seven Chinese ALD patients who had a primary phenotype of spastic paraplegia. Sequencing was performed in the probands and their familial members. Detailed clinical, VLCFAs test, hormone test, magnetic resonance imaging, and electromyogram are presented.\nRESULTS: We reported seven ALD patients from a Chinese cohort of 142 HSP patients. Genetic investigations revealed five known ABCD1 mutations (c.346G>C, c.521A>G, c.829G>T, c.1415_1416delAG, and c.1849C>T) and two novel mutations (c.454C>G, c.1452_1482del). Further auxiliary testing revealed that they had higher VLCFA and/or adrenal insufficiency.\nCONCLUSIONS: Our findings expand the mutation spectrum of ABCD1 and indicate that ALD represent a significant portion (4.9%, 7/142) of the spastic paraplegia entities. ALD should be considered in male patients with spastic paraplegia, even if there was no positive family history.","variants":[{"Name":"NM_000033.4(ABCD1):c.829G>T (p.Gly277Trp)","Chromosome":"X","Start":"153726095","Stop":"153726095","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1182291,"rule_based_match":true,"evidence_text":"c.829G>T","llm_judgment":"PRESENT","evidence":"c.829G>T","abstract_start":971,"abstract_end":979},{"Name":"NM_000033.4(ABCD1):c.454C>G (p.Arg152Gly)","Chromosome":"X","Start":"153725720","Stop":"153725720","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1475493,"rule_based_match":true,"evidence_text":"c.454C>G","llm_judgment":"PRESENT","evidence":"c.454C>G","abstract_start":1039,"abstract_end":1047}]}
{"pmid":"17964840","title":"An Alu insertion in compound heterozygosity with a microduplication in GNPTAB gene underlies Mucolipidosis II.","abstract":"Mucolipidosis type II (ML II) is a fatal, autosomal recessive, lysosomal storage disorder characterized by severe clinical and radiologic features. ML II results from mutations in alpha and beta subunits, encoded by the GlcNAc-1-phosphotransferase gene (GNPTAB). Most of the 40 different GNPTAB mutations reported so far are insertions and deletions predicting diverse types of aberrant proteins. Alu mobile elements have however never been involved in these events up to now. The Italian ML II patient of our study showed an Alu retrotrasposition in GNPTAB exon 5. The Alu insertion mutation (NM_024312.3:c.555_556insHSU14569) generated a transcript with a skipping of the target exon 5 and a frameshift p.S122fs, causing a premature translation termination codon at position 123. This insertion mutation was found in compound heterozygosity with the frameshift p.S887KfsX33, resulting from a new mono-nucleotide duplication (c.2659dupA) that occurred in GNPTAB exon 13. A possible involvement of cis-splicing elements having an exonic location, such as exon enhancers (ESEs), is discussed as mechanism that led to the production of the aberrant mRNA splicing.","variants":[{"Name":"NM_024312.5(GNPTAB):c.2659dup (p.Ser887fs)","Chromosome":"12","Start":"101764257","Stop":"101764258","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":46979,"rule_based_match":true,"evidence_text":"c.2659dupA","llm_judgment":"PRESENT","evidence":"c.2659dupA","abstract_start":927,"abstract_end":937}]}
{"pmid":"32220196","title":"Phenotype and Genotype Analysis in Two Pedigrees with Hereditary Coagulation Factor Ⅺ Deficiency","abstract":"OBJECTIVE: To analyze the phenotype and genotype in two pedigrees with hereditary coagulation factor Ⅺ (FⅪ) deficiency, and investigate the molecular mechanisms of FⅪ deficiency.\nMETHODS: Two patients with hereditary coagulation FⅪ deficiency were admitted to Chaozhou Central Hospital in Nov 2014 and Jan 2018. The prothrombin time (PT), activated partial thromboplastin time (APTT), FⅪ activity (FⅪ∶C) and FⅪ antigen (FⅪ∶Ag) were tested for phenotypic diagnosis. All the exons and exon-intron boundaries of FⅪ gene of proband were analyzed by PCR and sequencing. The family members were tested for the mutant site of proband. Then the mRNA of FⅪ in the proband was analyzed with RT-PCR.\nRESULTS: The proband-1 was a 7-year-old boy, PT was 10.7 s and APTT was 97.4 s (reference range: 9-12.8 s; 24-40 s), FⅪ∶C (0.6%) and FⅪ∶Ag<1% (reference range: 65%-150%; 72.1%-122.3%). The proband-2 was a 30-year-old female, and showed the PT (11.7 s), APTT (71.3 s), FⅪ∶C (0.7%) and FⅪ∶Ag<1%. FⅧ∶C, FⅨ∶C and FⅫ∶C of two proband were within the normal range. DNA sequencing showed that the proband-1 had a combined mutation of c.326-1G>A and c.1107C>A (p.Tyr351X) in exon 10. His grandmother, mother and brother had a heterozygous splicing mutation of c.326-1G>A, his grandmother and father had a homozygous mutation of c.1107C>A. FXI mRNA was undetected in the proband-1. The proband-2 had a homozygous mutation of c.841C>T (p.Gln263X) in exon 8, and this mutation was also found in her father, mother, daughter and son.\nCONCLUSION: The c.326-1G>A, c.1107C>A(p.Tyr351X) and c.841C>T (p.Gln263X) might be the molecular pathogenesis for two probands with hereditary coagulation factor Ⅺ deficiency.","variants":[{"Name":"NM_000128.4(F11):c.326-1G>A","Chromosome":"4","Start":"186274115","Stop":"186274115","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":357341,"rule_based_match":true,"evidence_text":"c.326-1G>A","llm_judgment":"PRESENT","evidence":"c.326-1G>A","abstract_start":1116,"abstract_end":1126}]}
{"pmid":"23719189","title":"A common and two novel GBA mutations in Thai patients with Gaucher disease.","abstract":"Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the glucocerebrosidase (GBA) gene, leading to a deficiency of lysosomal β-glucosidase and accumulation of glycosphingolipids in macrophages. We studied five Thai families with GD (four with GD type 1 and one with GD type 2). Using long-template PCR, PCR using specific primers for the functional gene, direct sequencing of all coding regions of GBA and restriction enzyme digestions, all 10 mutant alleles were successfully identified. The common c.1448T>C (p.L483P or L444P) mutation was identified in 60% of mutant alleles. Of the two patients homozygous for the p.L483P (L444P) mutation, one died from hepatic failure at age 16 years and the other died from sepsis at age 12 years. This p.L483P (L444P) mutation was found in four different haplotypes, suggesting that it was a recurrent mutation, not caused by a founder effect. Two novel mutations, a missense (c.1204T>C, p.Y402H), and a termination codon mutation (c.1609T>C, p.X537A) were found. Studies to determine the molecular pathomechanism of the p.X537A mutation, the first of its kind in this gene, showed that it decreased the amount of protein being expressed and the enzymatic activity, while it was still correctly localized.","variants":[{"Name":"NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)","Chromosome":"1","Start":"155235252","Stop":"155235252","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19327,"rule_based_match":true,"evidence_text":"c.1448T>C (p.L483P or L444P)","llm_judgment":"PRESENT","evidence":"c.1448T>C (p.L483P or L444P)","abstract_start":526,"abstract_end":554}]}
{"pmid":"31413764","title":"Germline c.1A>C heterozygous pathogenic variant in","abstract":"BACKGROUND: Gastrointestinal stromal tumors (GISTs) represent the most frequent mesenchymal tumor of the gastrointestinal tract. Less than 5% of them seem to be hereditary, being succinate dehydrogenase complex (<i>SDHx</i>) deficient disorders and neurofibromatosis type 1 the more related inherited conditions. Wild type (WT) <i>KIT</i> and <i>PDGFRα</i> GISTs constitute a clue for a hypothetical underlying germline condition.\nCASE PRESENTATION: We present a case of a 20 years old female diagnosed of a gastric WT GIST who developed hepatic metastases during her clinical course. No significant or typical phenotypic features suggestive of a specific syndrome were detected by physical examination. Also, her family history seemed to be irrelevant, since no other cases of GISTs, paragangliomas or pheochromocytomas were reported. Her paternal grandfather died as a consequence of a pituitary adenoma. In light of the age of tumor presentation and somatic features of gastric GIST, we performed genetic testing of <i>SDHx</i> genes. Analysis obtained from peripheral blood sample revealed the presence, in heterozygous state, of the c.1A > C; p.(Met1?) pathogenic variant in the <i>SDHA</i>.\nCONCLUSIONS: To the best of our knowledge, this is the first published report in which the c.1A > C; p.(Met1?) pathogenic variant in the <i>SDHA</i> is associated with a GIST. <i>SDHA</i> pathogenic variants increase the risk of paraganglioma, pheochromocytoma, GIST, pituitary adenoma and renal cancer in an autosomal dominant inherited condition named paraganglioma syndrome type 5. The absence of family history of tumors in <i>SDHA</i> pathogenic variants carriers could be related to its low penetrance. All patients diagnosed with WT GISTs should be referred to a hereditary cancer genetic counseling unit regardless of the age at presentation or the absence of a suspicious family history.","variants":[{"Name":"NM_004168.4(SDHA):c.1A>C (p.Met1Leu)","Chromosome":"5","Start":"218356","Stop":"218356","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":23783,"rule_based_match":true,"evidence_text":"c.1A > C; p.(Met1?)","llm_judgment":"PRESENT","evidence":"c.1A > C; p.(Met1?)","abstract_start":1138,"abstract_end":1157}]}
{"pmid":"24302620","title":"Retinitis pigmentosa mutations of SNRNP200 enhance cryptic splice-site recognition.","abstract":"Mutations in SNRP200 gene cause autosomal-dominant retinal disorder retinitis pigmentosa (RP). The protein product of SNRNP200 is BRR2, a DExD/H box RNA helicase crucial for pre-mRNA splicing. In this study, we prepared p.S1087L and p.R1090L mutations of human BRR2 using bacterial artificial chromosome recombineering and stably expressed them in human cell culture. Mutations in BRR2 did not compromise snRNP assembly and both mutants were incorporated into the spliceosome just as the wild-type (wt) protein. Surprisingly, cells expressing RP mutants exhibited increased splicing efficiency of the LDHA gene. Next, we found that depletion of endogenous BRR2 enhanced usage of a β-globin cryptic splice site while splicing at the correct splice site was inhibited. Proper splicing of optimal and cryptic splice sites was restored in cells expressing BRR2-wt but not in cells expressing RP mutants. Taken together, our data suggest that BRR2 is an important factor in 5'-splice-site recognition and that the RP-linked mutations c.3260C>T (p.S1087L) and c.3269G>T (p.R1090L) affect this BRR2 function.","variants":[{"Name":"NM_014014.5(SNRNP200):c.3269G>T (p.Arg1090Leu)","Chromosome":"2","Start":"96287959","Stop":"96287959","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":48345,"rule_based_match":true,"evidence_text":"c.3269G>T (p.R1090L)","llm_judgment":"PRESENT","evidence":"c.3269G>T (p.R1090L)","abstract_start":1054,"abstract_end":1074},{"Name":"NM_014014.5(SNRNP200):c.3260C>T (p.Ser1087Leu)","Chromosome":"2","Start":"96287968","Stop":"96287968","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22967,"rule_based_match":true,"evidence_text":"c.3260C>T (p.S1087L)","llm_judgment":"PRESENT","evidence":"c.3260C>T (p.S1087L)","abstract_start":1029,"abstract_end":1049}]}
{"pmid":"32820593","title":"Clinical and genetic characteristics of 10 Japanese patients with PROM1-associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population.","abstract":"Variants in the PROM1 gene are associated with cone (-rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10-45)/44.5 (22-73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (-rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p.Gly53Asp). Characteristic features of macular atrophy with generalized cone-dominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G>A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population.","variants":[{"Name":"NM_006017.3(PROM1):c.1117C>T (p.Arg373Cys)","Chromosome":"4","Start":"16013299","Stop":"16013299","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20649,"rule_based_match":false,"evidence_text":"p.Arg373Cys","llm_judgment":"PRESENT","evidence":"p.Arg373Cys","abstract_start":829,"abstract_end":840}]}
{"pmid":"27629384","title":"Combined variants in factor VIII and prostaglandin synthase-1 amplify hemorrhage severity across three generations of descendants.","abstract":"Essentials Co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. We determined pathogenic variants in a three-generational pedigree with excessive bleeding. Bleeding occurred with concurrent variants in prostaglandin synthase-1 (PTGS-1) and factor VIII. The PTGS-1 variant was associated with functional defects in the arachidonic acid pathway.\nSUMMARY: Background Inherited human variants that concurrently cause disorders of primary hemostasis and coagulation are uncommon. Nevertheless, rare cases of co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. Objective We prospectively sought to determine pathogenic variants in a three-generational pedigree with excessive bleeding. Patients/methods Platelet number, size and light transmission aggregometry to multiple agonists were evaluated in pedigree members. Transmission electron microscopy determined platelet morphology and granule content. Thromboxane release studies and light transmission aggregometry in the presence or absence of prostaglandin G<sub>2</sub> assessed specific functional defects in the arachidonic acid pathway. Whole exome sequencing (WES) and targeted nucleotide sequence analysis identified potentially deleterious variants. Results Pedigree members with excessive bleeding had impaired platelet aggregation with arachidonic acid, epinephrine and low-dose ADP, as well as reduced platelet thromboxane B<sub>2</sub> release. Impaired platelet aggregation in response to 2MesADP was rescued with prostaglandin G<sub>2</sub> , a prostaglandin intermediate downstream of prostaglandin synthase-1 (PTGS-1) that aids in the production of thromboxane. WES identified a non-synonymous variant in the signal peptide of PTGS-1 (rs3842787; c.50C>T; p.Pro17Leu) that completely co-segregated with disease phenotype. A variant in the F8 gene causing hemophilia A (rs28935203; c.5096A>T; p.Y1699F) was also identified. Individuals with both variants had more severe bleeding manifestations than characteristic of mild hemophilia A alone. Conclusion We provide the first report of co-existing variants in both F8 and PTGS-1 genes in a three-generation pedigree. The PTGS-1 variant was associated with specific functional defects in the arachidonic acid pathway and more severe hemorrhage.","variants":[{"Name":"NM_000132.4(F8):c.5096A>T (p.Tyr1699Phe)","Chromosome":"X","Start":"154928694","Stop":"154928694","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":25154,"rule_based_match":true,"evidence_text":"c.5096A>T","llm_judgment":"PRESENT","evidence":"c.5096A>T","abstract_start":1928,"abstract_end":1937}]}
{"pmid":"29781741","title":"Slowly progressive retinitis pigmentosa caused by two novel mutations in the MAK gene.","abstract":"BACKGROUND: The growing number of clinical trials currently underway for inherited retinal diseases has highlighted the importance of achieving a molecular diagnosis for all new cases presenting to hospital eye services. The male germ cell-associated kinase (MAK) gene encodes a cilium-associated protein selectively expressed in the retina and testis, and has recently been implicated in autosomal recessive retinitis pigmentosa (RP). Whole exome sequencing has previously identified a homozygous Alu insertion in probands with recessive RP and nonsense and missense mutations have also been reported.\nMATERIALS AND METHODS: Here we describe two novel mutations in different alleles of the MAK gene in a 75-year-old British female, who had a clinical diagnosis of RP () with onset in the fourth decade and no relevant family history. The mutations were established through next generation sequencing of a panel of 111 genes associated with RP and RP-like phenotypes.\nRESULTS: Two novel null mutations were identified within the MAK gene. The first c.1195_1196delAC p.(Thr399fs), was a two base-pair deletion creating a frame-shift in exon 9 predicted to result in nonsense-mediated decay. The second, c.279-2A>G, involved the splice acceptor consensus site upstream of exon 4, predicted to lead to aberrant splicing.\nCONCLUSIONS: The natural history of this individual's RP is consistent with previously described MAK mutations, being significantly milder than that associated with other photoreceptor ciliopathies. We suggest inclusion of MAK as part of wider genetic testing in all individuals presenting with RP.","variants":[{"Name":"NM_001242957.3(MAK):c.1195_1196del (p.Thr399fs)","Chromosome":"6","Start":"10791795","Stop":"10791796","ReferenceAlleleVCF":"AGT","AlternateAlleleVCF":"A","allel_id":859456,"rule_based_match":true,"evidence_text":"c.1195_1196delAC p.(Thr399fs)","llm_judgment":"PRESENT","evidence":"c.1195_1196delAC p.(Thr399fs)","abstract_start":1049,"abstract_end":1078}]}
{"pmid":"34652576","title":"TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.","abstract":"Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.","variants":[{"Name":"NM_006086.4(TUBB3):c.785G>A (p.Arg262His)","Chromosome":"16","Start":"89935236","Stop":"89935236","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":217280,"rule_based_match":true,"evidence_text":"NM_006086.4 (TUBB3):c.785G>A (p.Arg262His)","llm_judgment":"PRESENT","evidence":"NM_006086.4 (TUBB3):c.785G>A (p.Arg262His)","abstract_start":585,"abstract_end":627}]}
{"pmid":"27264810","title":"Mutation analysis of seven patients with Waardenburg syndrome","abstract":"OBJECTIVE: To perform genetic analysis for 7 patients with Waardenburg syndrome.\nMETHODS: Potential mutation of MITF, PAX3, SOX10 and SNAI2 genes was screened by polymerase chain reaction and direct sequencing. Functions of non-synonymous polymorphisms were predicted with PolyPhen2 software.\nRESULTS: Seven mutations, including c.649-651delAGA (p.R217del), c.72delG (p.G24fs), c.185T>C (p.M62T), c.118C>T (p.Q40X), c.422T>C (p.L141P), c.640C>T (p.R214X) and c.28G>T(p.G43V), were detected in the patients. Among these, four mutations of the PAX3 gene (c.72delG, c.185T>C, c.118C>T and c.128G>T) and one SOX10 gene mutation (c.422T>C) were not reported previously. Three non-synonymous SNPs (c.185T>C, c.128G>T and c.422T>C) were predicted as harmful.\nCONCLUSION: Genetic mutations have been detected in all patients with Waardenburg syndrome.","variants":[{"Name":"NM_181458.4(PAX3):c.118C>T (p.Gln40Ter)","Chromosome":"2","Start":"222297181","Stop":"222297181","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1487441,"rule_based_match":true,"evidence_text":"c.118C>T (p.Q40X)","llm_judgment":"PRESENT","evidence":"c.118C>T (p.Q40X)","abstract_start":397,"abstract_end":414}]}
{"pmid":"21426374","title":"Mutations in the LPAR6 and LIPH genes underlie autosomal recessive hypotrichosis/woolly hair in 17 consanguineous families from Pakistan.","abstract":"BACKGROUND: Autosomal recessive hypotrichosis/woolly hair is a rare genetic hair loss disorder characterized by sparse scalp hair/woolly hair, sparse to absent eyebrows and eyelashes, sparse axillary and body hair in affected individuals. This form of hair loss results from mutations in either LPAR6 or LIPH gene.\nAIM: To identify mutations in LPAR6 and LIPH genes in 17 consanguineous Pakistani families showing features of hypotrichosis/woolly hair.\nMETHODS: Genotyping in 17 families was carried out using polymorphic microsatellite markers linked to genes causing autosomal recessive hypotrichosis/woolly hair phenotype. To screen for mutations in LPAR6 and LIPH genes, all of their exons and splice junction sites were amplified by PCR and sequenced using an automated DNA sequencer.\nRESULTS: Genotyping with polymorphic microsatellite markers showed linkage in eight families to LPAR6 and in nine families to LIPH gene. Sequence analysis revealed four recurrent mutations (p.Phe24HisfsX28; p.Asp63Val; p.Gly146Arg; p.Ile188Phe) in LPAR6 and two recurrent mutations (p.Trp108Arg; p.Ile220ArgfsX29) in LIPH gene. Comparison of the haplotypes generated by typing LPAR6 and LIPH genes linked microsatellite markers in different families suggested common founder natures of the two mutations (c.66_69insCATG and c.659_660delTA).\nCONCLUSIONS: Mutations identified in the present study extend the body of evidence implicating LPAR6 and LIPH genes in pathogenesis of human hereditary hair loss.","variants":[{"Name":"NM_001162498.3(LPAR6):c.562A>T (p.Ile188Phe)","Chromosome":"13","Start":"48411862","Stop":"48411862","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":16866,"rule_based_match":false,"evidence_text":"p.Ile188Phe","llm_judgment":"PRESENT","evidence":"p.Ile188Phe","abstract_start":1022,"abstract_end":1033},{"Name":"NM_001162498.3(LPAR6):c.436G>A (p.Gly146Arg)","Chromosome":"13","Start":"48411988","Stop":"48411988","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16867,"rule_based_match":false,"evidence_text":"p.Gly146Arg","llm_judgment":"PRESENT","evidence":"p.Gly146Arg","abstract_start":1009,"abstract_end":1020},{"Name":"NM_139248.3(LIPH):c.659_660del (p.Ile220fs)","Chromosome":"3","Start":"185524129","Stop":"185524130","ReferenceAlleleVCF":"CTA","AlternateAlleleVCF":"C","allel_id":18342,"rule_based_match":true,"evidence_text":"c.659_660delTA","llm_judgment":"PRESENT","evidence":"c.659_660delTA","abstract_start":1314,"abstract_end":1328},{"Name":"NM_001162498.3(LPAR6):c.188A>T (p.Asp63Val)","Chromosome":"13","Start":"48412236","Stop":"48412236","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":214140,"rule_based_match":false,"evidence_text":"c.188A>T (p.Asp63Val)","llm_judgment":"PRESENT","evidence":"p.Asp63Val","abstract_start":997,"abstract_end":1007}]}
{"pmid":"38369462","title":"","abstract":"PURPOSE: This study aims to evaluate the ABCA4 variants in patients diagnosed with Stargardt disease.\nMETHODS: This is a retrospective study designed to investigate variants in the ABCA4 in Stargardt disease and the clinical findings of the cases. Sex, age, age of onset of symptoms, best-corrected visual acuity, color fundus photography, optical coherence tomography, and visual field test of the patients were recorded. Genetic analyses were screened, and patients with at least two variants in the ABCA4 were included in this study.\nRESULTS: Twenty-seven patients diagnosed with Stargardt disease with the ABCA4 variants were included in this study. Twelve of them (44.4%) were female and fifteen (55.5%) were male. The mean age of the cases was 27.44 years (ranging from 8 to 56 years). Thirty different variants were detected in 54 ABCA4 alleles of 27 patients. The two most common pathogenic variants were c.5882 G>A p.(Gly1961Glu) and c.52C>T p.(Arg18Trp) in this cohort. Two novel variants were identified (c.3855_3856dup, c.1554 + 3_1554 + 4del) and the patient with the c.1554 + 3_1554 + 4del variant additionally had a different ABCA4 variant in trans. The other novel variant was homozygous.\nCONCLUSIONS: In this study, two novel variants were described in a Turkish cohort with Stargardt disease. The variant c.52C>T p.(Arg18Trp) was the most common disease-causing variant besides the c.5882 G>A p.(Gly1961Glu) which was identified frequently in the previous studies. A larger sample size is necessary for describing different pathogenic variants and understanding the phenotype-genotype correlations.","variants":[{"Name":"NM_000350.3(ABCA4):c.52C>T (p.Arg18Trp)","Chromosome":"1","Start":"94120994","Stop":"94120994","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22938,"rule_based_match":true,"evidence_text":"c.52C>T p.(Arg18Trp)","llm_judgment":"PRESENT","evidence":"c.52C>T p.(Arg18Trp)","abstract_start":943,"abstract_end":963}]}
{"pmid":"31782247","title":"Identification of a novel germline BRCA2 variant in a Chinese breast cancer family.","abstract":"Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths in women worldwide. In this study, a large Chinese pedigree with breast cancer including a proband and two female patients was recruited and a familial history of breast cancer was collected by questionnaire. Clinicopathological assessments and neoadjuvant therapy-related information were obtained for the proband. Blood samples were taken, and gDNA was extracted. The BRCA1/2 and PALB2 genes were screened using next-generation sequencing by a targeted gene panel. We have successfully identified a novel, germline heterozygous, missense mutation of the gene BRCA2: c.7007G>T, p.R2336L, which is likely to be pathogenic in the proband and her elder sister who both had breast cancer. Furthermore, the risk factors for developing breast cancer in this family are discussed. Thus, genetic counselling and long-term follow-up should be provided for this family of breast cancer patients as well as carriers carrying a germline variant of BRCA2: c.7007G>T (p.R2336L).","variants":[{"Name":"NM_000059.4(BRCA2):c.7007G>T (p.Arg2336Leu)","Chromosome":"13","Start":"32346896","Stop":"32346896","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":66910,"rule_based_match":true,"evidence_text":"BRCA2: c.7007G>T, p.R2336L","llm_judgment":"PRESENT","evidence":"BRCA2: c.7007G>T, p.R2336L","abstract_start":662,"abstract_end":688}]}
{"pmid":"37751738","title":"PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects.","abstract":"Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.","variants":[{"Name":"NM_005032.7(PLS3):c.1497G>C (p.Trp499Cys)","Chromosome":"X","Start":"115646521","Stop":"115646521","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2805401,"rule_based_match":true,"evidence_text":"c.1497G>C (p.Trp499Cys)","llm_judgment":"PRESENT","evidence":"c.1497G>C (p.Trp499Cys)","abstract_start":1082,"abstract_end":1105}]}
{"pmid":"18313027","title":"Human RFT1 deficiency leads to a disorder of N-linked glycosylation.","abstract":"N-linked glycosylation is an essential posttranslational modification of proteins in eukaryotes. The substrate of N-linked glycosylation, dolichol pyrophosphate (DolPP)-GlcNAc(2)Man(9)Glc(3), is assembled through a complex series of ordered reactions requiring the translocation of the intermediate DolPP-GlcNAc(2)Man(5) structure across the endoplasmic-reticulum membrane. A young patient diagnosed with a congenital disorder of glycosylation characterized by an intracellular accumulation of DolPP-GlcNAc(2)Man(5) was found to carry a homozygous point mutation in the RFT1 gene. The c.199C-->T mutation introduced the amino acid substitution p.R67C. The human RFT1 protein shares 22% identity with its yeast ortholog, which is involved in the translocation of DolPP-GlcNAc(2)Man(5) from the cytosolic into the lumenal side of the endoplasmic reticulum. Despite the low sequence similarity between the yeast and the human RFT1 proteins, we demonstrated both their functional orthology and the pathologic effect of the human p.R67C mutation by complementation assay in Deltarft1 yeast cells. The causality of the RFT1 p.R67C mutation was further established by restoration of normal glycosylation profiles in patient-derived fibroblasts after lentiviral expression of a normal RFT1 cDNA. The definition of the RFT1 defect establishes the functional conservation of the DolPP-GlcNAc(2)Man(5) translocation process in eukaryotes. RFT1 deficiency in both yeast and human cells leads to the accumulation of incomplete DolPP-GlcNAc(2)Man(5) and to a profound glycosylation disorder in humans.","variants":[{"Name":"NM_052859.4(RFT1):c.199C>T (p.Arg67Cys)","Chromosome":"3","Start":"53123791","Stop":"53123791","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15824,"rule_based_match":false,"evidence_text":"c.199C-->T","llm_judgment":"PRESENT","evidence":"c.199C-->T","abstract_start":585,"abstract_end":595}]}
{"pmid":"28458902","title":"Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the","abstract":"SUMMARY: <i>HNF4A</i> gene mutations have been reported in cases of transient and persistent hyperinsulinaemic hypoglycaemia of infancy (HHI), particularly in families with adulthood diabetes. The case of a patient with HHI, liver impairment and renal tubulopathy due to a mutation in <i>HNF4A</i> is reported.\nLEARNING POINTS: Urine specimen study in cases of HHI with diazoxide response is necessary to rule out specific metabolic conditions (l-3-hydroxyacyl-coenzyme A dehydrogenase deficiency) or tubular renal involvement.Hyperinsulinaemic hypoglycaemia due to the heterozygous mutation (p.Arg63Trp, c. 187C > T) in the <i>HNF4A</i> gene is associated with renal tubulopathy and liver involvement.Follow-up of patients diagnosed of HHI is mandatory to detect associated conditions.","variants":[{"Name":"NM_175914.5(HNF4A):c.187C>T (p.Arg63Trp)","Chromosome":"20","Start":"44406195","Stop":"44406195","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":165951,"rule_based_match":true,"evidence_text":"c. 187C > T (p.Arg63Trp)","llm_judgment":"PRESENT","evidence":"p.Arg63Trp","abstract_start":593,"abstract_end":603}]}
{"pmid":"27368975","title":"Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.","abstract":"Transient infantile hypertriglyceridemia (HTGT1; OMIM #614480) is a rare autosomal recessive disorder, which manifests in early infancy with transient hypertriglyceridemia, hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis. This rare clinical entity is caused by inactivating mutations in the GPD1 gene, which encodes the cytosolic isoform of glycerol-3-phosphate dehydrogenase. Here we report on four patients from three unrelated families of diverse ethnic origins, who presented with hepatomegaly, liver steatosis, hypertriglyceridemia, with or without fasting ketotic hypoglycemia. Whole exome sequencing revealed the affected individuals to harbor deleterious biallelic mutations in the GPD1 gene, including the previously undescribed c.806G > A (p.Arg269Gln) and c.640T > C (p.Cys214Arg) mutations. The clinical features in three of our patients showed several differences compared to the original reports. One subject presented with recurrent episodes of fasting hypoglycemia along with hepatomegaly, hypetriglyceridemia, and elevated liver enzymes; the second showed a severe liver disease, with intrahepatic cholestasis associated with kidney involvement; finally, the third presented persistent hypertriglyceridemia at the age of 30 years. These findings expand the current knowledge of this rare disorder, both with regard to the phenotype and molecular basis. The enlarged phenotypic spectrum of glycerol-3-phosphate dehydrogenase 1 deficiency can mimic other inborn errors of metabolism with liver involvement and should alert clinicians to recognize this entity by considering GPD1 mutations in appropriate clinical settings.","variants":[{"Name":"NM_005276.4(GPD1):c.806G>A (p.Arg269Gln)","Chromosome":"12","Start":"50107760","Stop":"50107760","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3397858,"rule_based_match":true,"evidence_text":"c.806G > A (p.Arg269Gln)","llm_judgment":"PRESENT","evidence":"c.806G > A (p.Arg269Gln)","abstract_start":772,"abstract_end":796},{"Name":"NM_005276.4(GPD1):c.640T>C (p.Cys214Arg)","Chromosome":"12","Start":"50107594","Stop":"50107594","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3397859,"rule_based_match":true,"evidence_text":"c.640T > C (p.Cys214Arg)","llm_judgment":"PRESENT","evidence":"c.640T > C (p.Cys214Arg)","abstract_start":801,"abstract_end":825}]}
{"pmid":"28181399","title":"Mild achondroplasia/hypochondroplasia with acanthosis nigricans, normal development, and a p.Ser348Cys FGFR3 mutation.","abstract":"Pathogenic allelic variants in the fibroblast growth factor receptor 3 (FGFR3) gene have been associated with a number of phenotypes including achondroplasia, hypochondroplasia, thanatophoric dysplasia, Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome), and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans). Crouzon syndrome with acanthosis nigricans is caused by the pathogenic variant c.1172C>A (p.Ala391Glu) in the FGFR3 gene. The p.Lys650Thr pathogenic variant in FGFR3 has been linked to acanthosis nigricans without significant craniofacial or skeletal abnormalities. Recently, an infant with achondroplasia and a novel p.Ser348Cys FGFR3 mutation was reported. We describe the clinical history of an 8-year-old child with a skeletal dysplasia in the achondroplasia-hypochondroplasia spectrum, acanthosis nigricans, typical development, and the recently described p.Ser348Cys FGFR3 mutation.","variants":[{"Name":"NM_000142.5(FGFR3):c.1043C>G (p.Ser348Cys)","Chromosome":"4","Start":"1803804","Stop":"1803804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1517670,"rule_based_match":false,"evidence_text":"p.Ser348Cys FGFR3 mutation","llm_judgment":"PRESENT","evidence":"p.Ser348Cys FGFR3 mutation","abstract_start":684,"abstract_end":710}]}
{"pmid":"35634501","title":"Case Report: A Chinese Family of Type A Insulin Resistance Syndrome With Diabetes Mellitus, With a Novel Heterozygous Missense Mutation of the Insulin Receptor Gene.","abstract":"Type A Insulin resistance syndrome (TAIRS) is an autosomal dominant or recessive genetic disorder caused by insulin dysfunction resulting from insulin receptor (INSR) gene mutation. The main features of TAIRS include hyperinsulinemia, abnormal glucose metabolism, and changes in acanthosis nigricans. We identified, in China, a TAIRS family with a novel heterozygous missense gene mutation type. One patient from the Chinese Han family exhibited signs and symptoms of TAIRS and was presented for evaluation. Whole-exome sequencing revealed a heterozygous mutation. Both the patient proband and his father were identified with insulin receptor exon 19c.3472C>T(p.Arg1158Trp), which resulted in a missense mutation that led to replace by a base in the amino acid codon. We found that the patient proband and his father exhibited high insulin and C-peptide release after glucose stimulation by insulin and C-peptide release tests. At the same time, we also ruled out the possibility of islet βcell tumor through relevant examinations. These findings indicate that the INSR gene mutation may cause pancreatic β cell functional impairment and contribute to the development of diabetes.","variants":[{"Name":"NM_000208.4(INSR):c.3472C>T (p.Arg1158Trp)","Chromosome":"19","Start":"7122671","Stop":"7122671","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2905337,"rule_based_match":true,"evidence_text":"c.3472C>T(p.Arg1158Trp)","llm_judgment":"PRESENT","evidence":"c.3472C>T(p.Arg1158Trp)","abstract_start":650,"abstract_end":673}]}
{"pmid":"31534215","title":"MNS1 variant associated with situs inversus and male infertility.","abstract":"Ciliopathy disorders due to abnormalities of motile cilia encompass a range of autosomal recessive conditions typified by chronic otosinopulmonary disease, infertility, situs abnormalities and hydrocephalus. Using a combination of genome-wide SNP mapping and whole exome sequencing (WES), we investigated the genetic cause of a form of situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family, assuming that an autosomal recessive founder variant was responsible. This identified a single shared (2.34 Mb) region of autozygosity on chromosome 15q21.3 as the likely disease locus, in which we identified a single candidate biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)]. Genotyping of multiple family members identified randomisation of the laterality defects in other homozygous individuals, with all wild type or MNS1 c.407_410del heterozygous carriers being unaffected, consistent with an autosomal recessive mode of inheritance. This study identifies an MNS1 variant as a cause of laterality defects and male infertility in humans, mirroring findings in Mns1-deficient mice which also display male infertility and randomisation of left-right asymmetry of internal organs, confirming a crucial role for MNS1 in nodal cilia and sperm flagella formation and function.","variants":[{"Name":"NM_018365.4(MNS1):c.407_410del (p.Glu136fs)","Chromosome":"15","Start":"56446887","Stop":"56446890","ReferenceAlleleVCF":"CCTTT","AlternateAlleleVCF":"C","allel_id":622849,"rule_based_match":true,"evidence_text":"NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)","llm_judgment":"PRESENT","evidence":"NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)","abstract_start":704,"abstract_end":749}]}
{"pmid":"22911656","title":"A novel deletion in SMPX causes a rare form of X-linked progressive hearing loss in two families due to a founder effect.","abstract":"X-linked hearing loss is the rarest form of genetic hearing loss contributing to <1% of cases. We identified a multiplex family from Newfoundland (Family 2024) segregating X-linked hearing loss. Haplotyping of the X chromosome and sequencing of positional candidate genes revealed a novel point deletion (c.99delC) in SMPX which encodes a small muscle protein responsible for reducing mechanical stress during muscle contraction. This novel deletion causes a frameshift and a premature stop codon (p.Arg34GlufsX47). We successfully sequenced both SMPX wild-type and mutant alleles from cDNA of a lymphoblastoid cell line, suggesting that the mutant allele may not be degraded via nonsense-mediated mRNA decay. To investigate the role of SMPX in other subpopulations, we fully sequenced SMPX in 229 Canadian probands with hearing loss and identified a second Newfoundland Family (2196) with the same mutation, and a shared haplotype on the X chromosome, suggesting a common ancestor.","variants":[{"Name":"NM_014332.3(SMPX):c.99del (p.Arg34fs)","Chromosome":"X","Start":"21743783","Stop":"21743783","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":48574,"rule_based_match":true,"evidence_text":"c.99delC","llm_judgment":"PRESENT","evidence":"c.99delC","abstract_start":305,"abstract_end":313}]}
{"pmid":"30586397","title":"Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dubé syndrome.","abstract":"Birt-Hogg-Dubé syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, pneumothorax, fibrofolliculomas and renal cell cancer. The diagnosis of BHDS is usually considered if kidney cancer occurs before age 50 years, is multifocal and/or bilateral or of the oncocytoma/hybrid oncocytoma-chromophobe type. Using a sample of 50 BHDS families with a total of 178 patients we analyzed how many kidney cancer patients fulfilled one or more of these criteria. Furthermore, we addressed the question if genotype-phenotype-correlations exist that can be used for risk stratification. Renal cell cancer occurred in 34/178 (19.1%) patients, and the reported male bias was not observed. Furthermore, most kidney malignancies occurred after the age of 50 years. Thus, the majority of tumors did not show the typical hallmarks of BHDS. A below-average tumor frequency (17.2%) was observed for the known mutational hotspot c.1285delC/dupC that was the cause of BHDS in 24% of families. Unexpected was the high tumor frequency (66.7%) associated with mutation c.887C>G within a single family, a finding that merits further exploration.","variants":[{"Name":"NM_144997.7(FLCN):c.887C>G (p.Ser296Ter)","Chromosome":"17","Start":"17219194","Stop":"17219194","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":570802,"rule_based_match":true,"evidence_text":"c.887C>G","llm_judgment":"PRESENT","evidence":"c.887C>G","abstract_start":1060,"abstract_end":1068}]}
{"pmid":"29531775","title":"An unclassified variant of","abstract":"CHARGE syndrome is a rare autosomal dominant disease that is typically caused by heterozygous <i>CHD7</i> mutations. A <i>de novo</i> variant in a <i>CHD7</i> splicing acceptor site (NM_017780.3:c.7165-4A>G) was identified in a Japanese boy with CHARGE syndrome. This variant has been considered to be an \"unclassified variant\" due to its position outside the consensus splicing sites. In this study, abnormal splicing derived from this known variant was confirmed by cDNA sequencing.","variants":[{"Name":"NM_017780.4(CHD7):c.7165-4A>G","Chromosome":"8","Start":"60856441","Stop":"60856441","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":438510,"rule_based_match":true,"evidence_text":"NM_017780.3:c.7165-4A>G","llm_judgment":"PRESENT","evidence":"NM_017780.3:c.7165-4A>G","abstract_start":183,"abstract_end":206}]}
{"pmid":"34157943","title":"Analysis of an NGS retinopathy panel detects chromosome 1 uniparental isodisomy in a patient with","abstract":"<b>Purpose</b>: This study aims to demonstrate the possibility of detecting segmental uniparental isodisomy (iUPD) using a next-generation sequencing gene panel by reporting a Leber congenital amaurosis (LCA) case caused by a homozygous pathogenic variant in <i>RPE65</i> (c.1022 T > C:p.Leu341Ser) inherited exclusively from the proband's mother.<b>Methods</b>: Samples from the trio (proband, mother, and father) were sequenced with a next-generation sequencing (NGS) retinopathy gene panel (224 genes) and the VCF file containing all variants was used in order to determine single nucleotide variant (SNV) counts from each sample across all chromosomes.<b>Results</b>: Trio analysis showed that of 81 Chr1 inherited variants 41 were exclusively maternal, including 21 homozygous. The other 40 variants were common to both parents. On remaining autosomal chromosomes (Chr2-22) 645 inherited variants were found, 147 of them were exclusively maternal and 132 exclusively paternal. Based on these NGS data, it was possible to note that the proband's chromosomes 1 are more similar to his mother's chromosome 1 than his father's, suggesting the pathogenic homozygous variant found in this patient was inherited exclusively from the mother due to uniparental maternal isodisomy.<b>Conclusions</b>: This study presents a secondary analysis pipeline to identify responsible variants for a phenotype and the correct inheritance pattern, which is a critical step to the proper and accurate genetic counseling of all family members. In addition, this approach could be used to determine iUPD in different Mendelian disorders if the sequencing panel identifies variants spread throughout the genome.","variants":[{"Name":"NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser)","Chromosome":"1","Start":"68438293","Stop":"68438293","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28157,"rule_based_match":true,"evidence_text":"c.1022 T > C:p.Leu341Ser","llm_judgment":"PRESENT","evidence":"c.1022 T > C:p.Leu341Ser","abstract_start":273,"abstract_end":297}]}
{"pmid":"19020898","title":"Restrictive dermopathy--a lethal congenital laminopathy. Case report and review of the literature.","abstract":"Restrictive dermopathy (RD) is a rare, fatal, and genetically heterogeneous laminopathy with a predominant autosomal recessive heredity pattern. The phenotype can be caused by mutations in either LMNA (primary laminopathy) or ZMPSTE24 (secondary laminopathy) genes but mostly by homozygous or compound heterozygous ZMPSTE24 mutations. Clinicopathologic findings are unique, allowing a specific diagnosis in most cases. We describe a premature newborn girl of non-consanguineous parents who presented a rigid, translucent and tightly adherent skin, dysmorphic facies, multiple joint contractures and radiological abnormalities. The overall clinical, radiological, histological, and ultrastructural features were typical of restrictive dermopathy. Molecular genetic analysis revealed a homozygous ZMPSTE24 mutation (c.1085_1086insT). Parents and sister were heterozygous asymptomatic carriers. We conclude that RD is a relatively easy and consistent clinical and pathological diagnosis. Despite recent advances in our understanding of RD, the pathogenetic mechanisms of the disease are not entirely clarified. Recognition of RD and molecular genetic diagnosis are important to define the prognosis of an affected child and for recommending genetic counseling to affected families. However, the outcome for a live born patient in the neonatal period is always fatal.","variants":[{"Name":"NM_005857.5(ZMPSTE24):c.1085dup (p.Leu362fs)","Chromosome":"1","Start":"40290870","Stop":"40290871","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":19310,"rule_based_match":false,"evidence_text":"c.1085_1086insT","llm_judgment":"PRESENT","evidence":"c.1085_1086insT","abstract_start":814,"abstract_end":829}]}
{"pmid":"32576142","title":"Two novel compound heterozygous mutations in NGLY1as a cause of congenital disorder of deglycosylation: a case presentation.","abstract":"BACKGROUND: NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) is a multisystemic neurodevelopmental disorder in which affected individuals show developmental delay, epilepsy, intellectual disability, abnormal liver function, and poor growth. This study presents a 10-month-old female infant with elevated liver transaminases, developmental delay, epilepsy (subclinical seizures), and constipation who possesses two compound heterozygous mutations in NGLY1.\nCASE PRESENTATION: The proband was admitted to the Department of Gastroenterology, Children's Hospital of Soochow University, with elevated liver transaminases. She had a history of intrauterine growth retardation and exhibited elevated transaminases, global developmental delay, seizures and light constipation during early infancy. Whole-exome sequencing (WES) and Sanger sequencing revealed two compound heterozygous mutations in NGLY1 that had been inherited in an autosomal recessive manner from her parents. One was a termination mutation, c.1168C > T (p.R390*), and the other was a missense mutation, c.1156G > T (p.D386Y). NGLY1-CDDG is a rare disorder, with a few dozen cases. The two mutations of this proband has not been previously identified.\nCONCLUSIONS: This study investigated a Chinese proband with NGLY1-CDDG born from healthy parents who was studied using WES and Sanger sequencing to identify the causative mutations. We identified two novel compound heterozygous mutations in NGLY1, c.1168C > T (p.R390*)/c.1156G > T (p.D386Y), which are probably causative of disease.","variants":[{"Name":"NM_018297.4(NGLY1):c.1168C>T (p.Arg390Ter)","Chromosome":"3","Start":"25733964","Stop":"25733964","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1477725,"rule_based_match":true,"evidence_text":"c.1168C > T (p.R390*)","llm_judgment":"PRESENT","evidence":"c.1168C > T (p.R390*)","abstract_start":1019,"abstract_end":1040}]}
{"pmid":"21787400","title":"Rare variants in the ATM gene and risk of breast cancer.","abstract":"INTRODUCTION: The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved.\nMETHODS: To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants.\nRESULTS: In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant.\nCONCLUSIONS: The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.","variants":[{"Name":"NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)","Chromosome":"11","Start":"108329202","Stop":"108329202","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18062,"rule_based_match":true,"evidence_text":"c.7271T > G","llm_judgment":"PRESENT","evidence":"c.7271T > G","abstract_start":1017,"abstract_end":1028}]}
{"pmid":"30883759","title":"Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays.","abstract":"Splicing disruption is a common mechanism of gene inactivation associated with germline variants of susceptibility genes. To study the role of BRCA2 mis-splicing in hereditary breast/ovarian cancer (HBOC), we performed a comprehensive analysis of variants from BRCA2 exons 2-9, as well as the initial characterization of the regulatory mechanisms of such exons. A pSAD-based minigene with exons 2-9 was constructed and validated in MCF-7 cells, producing the expected transcript (1016-nt/V1-BRCA2_exons_2-9-V2). DNA variants from mutational databases were analyzed by NNSplice and Human Splicing Finder softwares. To refine ESE-variant prediction, we mapped the regulatory regions through a functional strategy whereby 26 exonic microdeletions were introduced into the minigene and tested in MCF-7 cells. Thus, we identified nine spliceogenic ESE-rich intervals where ESE-variants may be located. Combining bioinformatics and microdeletion assays, 83 variants were selected and genetically engineered in the minigene. Fifty-three changes impaired splicing: 28 variants disrupted the canonical sites, four created new ones, 10 abrogated enhancers, eight created silencers and three caused a double-effect. Notably, nine spliceogenic-ESE variants were located within ESE-containing intervals. Capillary electrophoresis and sequencing revealed more than 23 aberrant transcripts, where exon skipping was the most common event. Interestingly, variant c.67G>A triggered the usage of a noncanonical GC-donor 4-nt upstream. Thirty-six variants that induced severe anomalies (>60% aberrant transcripts) were analyzed according to the ACMG guidelines. Thus, 28 variants were classified as pathogenic, five as likely pathogenic and three as variants of uncertain significance. Interestingly, 13 VUS were reclassified as pathogenic or likely pathogenic variants. In conclusion, a large fraction of BRCA2 variants (∼64%) provoked splicing anomalies lending further support to the high prevalence of this disease-mechanism. The low accuracy of ESE-prediction algorithms may be circumvented by functional ESE-mapping that represents an optimal strategy to identify spliceogenic ESE-variants. Finally, systematic functional assays by minigenes depict a valuable tool for the initial characterization of splicing anomalies and the clinical interpretation of variants. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.","variants":[{"Name":"NM_000059.4(BRCA2):c.67G>A (p.Asp23Asn)","Chromosome":"13","Start":"32316527","Stop":"32316527","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227519,"rule_based_match":true,"evidence_text":"c.67G>A","llm_judgment":"PRESENT","evidence":"c.67G>A","abstract_start":1446,"abstract_end":1453}]}
{"pmid":"22781090","title":"A unique MSH2 exon 8 deletion accounts for a major portion of all mismatch repair gene mutations in Lynch syndrome families of Sardinian origin.","abstract":"Lynch syndrome is an autosomal-dominant hereditary condition predisposing to the development of specific cancers, because of germline mutations in the DNA-mismatch repair (MMR) genes. Large genomic deletions represent a significant fraction of germline mutations, particularly among the MSH2 gene, in which they account for 20% of the mutational spectrum. In this study we analyzed 13 Italian families carrying MSH2 exon 8 deletions, 10 of which of ascertained Sardinian origin. The overrepresentation of Sardinians was unexpected, as families from Sardinia account for a small quota of MMR genes mutation tests performed in our laboratory. The hypothesis that such a result is owing to founder effects in Sardinia was tested by breakpoint junctions sequencing and haplotype analyses. Overall, five different exon eight deletions were identified, two of which recurrent in families, all apparently unrelated, of Sardinian origin (one in eight families, one in two families). The c.1277-1180_1386+2226del3516insCATTCTCTTTGAAAA deletion shares the same haplotype between all families and appears so far restricted to the population of South-West Sardinia, showing the typical features of a founder effect. The three non-Sardinian families showed three different breakpoint junctions and haplotypes, suggesting independent mutational events. This work has useful implications in genetic testing for Lynch syndrome. We developed a quick test for each of the identified deletions: this can be particularly useful in families of Sardinian origin, in which MSH2 exon 8 deletions may represent 50% of the overall mutational spectrum of the four MMR genes causing Lynch syndrome.","variants":[{"Name":"NM_000251.3(MSH2):c.1277-1180_1386+2226delinsCATTCTCTTTGAAAA","Chromosome":"2","Start":"47444368","Stop":"47447883","ReferenceAlleleVCF":"TGCTAAAATTTCTGGAGAAGTTTGGGAACTATTGTTTTGGAGTGAAATGCAGTGTGTTAGATATCACTTGCAGAATTCTTCTAAGGGTATTTATTGGCGATTAGAAAAAAAATCCTTGTGTTATACCAGTAGTAATACAAAGTAATTGTTCAGCTTCTGTTAAGTGTAAAGGACTATACAAGTATTGTGTATAGTTATCTCATTTATTATTTTCTGGGTAGCTATTGTTATTATTACTTCGTACAAAAAGGGAAAAGGAGGCTCAAAGTATCATGCTCCAGATAACAGAGCCAGTAGGTAGCAGAGCTGGGATTGCTACCCAGGTCTCTAGTCCTGCTTTTTCACACTATATACTCATTGCTTCACTTACTCCTTCATACATGATTCCCCAGCATGTACTCTTTTTTTTTTTTTTTTTTTTTTGTTTGAGATAGAATCTCGCTCTCTGTTGCCCAGGCTGGCAGGCAGTAGTGTGATCTTGGGCTAACTGCAACCTCCATCTCCTGCATTCAAGCAGTTCTCCTGCTTCAACCTCCTGAGTAGCTGAGATTATAAGCCTATGCTACCACGCCTGGCTAATTTTTGTATTTTTAGCAGAGATGAGGTTTCGCCTTGTTGGCCAGGCTGGTCTCAAACTCCTGAACTCAAGTGATCTGCCCACCTCAGCCTCCGAAAGTGCTGGGATTATAGGCATGAGCCATCATGTCCGGCCTCCCCATCATGTACCCTTAAATACCATCAAGCACAGTTCCATTGTGTAAAAACTTGGCTTGATTTAACCTGTTAATTGGAACACTGTCATTAATGGAAATTAGGAATATGAGGTAAGCTAGAGGTTTTATTTTAATGACTTTGGGTTATTAAATCTATAAGAAATGAAATTCATTTAGTCATAATTAATGTCATGTTTCTGCATCTATATTACTTGTTGGGTTTACAGACGAGGTAGTGTATTATTAGTGGGAAGCTTTGAGTGCTACATCATCTCCCTTTCTATAAAATAAATTGAGTACGAAACAATTTGAATTAAAACACCTGAGTAAATAGTAACTTTGGAGACCTGCTGTACTATTTGTACCTTTTGGATCAAATGATGCTTGTTTATCTCAGTCAAAATTTTATGATTTGTATTCTGTAAAATGAGATCTTTTTATTTGTTTGTTTTACTACTTTCTTTTAGGAAAACACCAGAAATTATTGTTGGCAGTTTTTGTGACTCCTCTTACTGATCTTCGTTCTGACTTCTCCAAGTTTCAGGAAATGATAGAAACAACTTTAGATATGGATCAGGTATGCAATATACTTTTTAATTTAAGCAGTAGTTATTTTTAAAAAGCAAAGGCCACTTTAAGAAAGTTTGTAGATTTTTCTTTTTAGTATCTAATTGTAGCACCTTTGTGGACAGTGGATGTAATATTAAGTGACAGATGGGAAAAGGATTTTTAAAAAAATAGCAACTGTTTCAGTGGATGAAATAAAGATTATTAGCAGAGAAAATGAATATTGGGCATAACTGTCCTGGTGAAAGACAATCTCATAAATGAACAATTTCATAATTTCGTAAATGCAACTGCATTTTATTTTCAAAGAGAAGGAAAATTATAGTCACTGGAAACGGAAAGAGAAGTTAGAGGTAAACATAGGACACACAAGAAAACTTTCATTTTGTTTATTTTCTTGTTTTTCTTTTGAGACAGGGTTTCCCTCTGTTACCCAGGCTTAAGTGCAGTGACACTATCATAGTTCACTAACCCCTCAAATTCCTGGGTTCAAGTAATCCTCCTGCCTTAGCCTTAGTAGGTGTAAATACAGGTGTGTACCACCATGCCTGGCGAATTTTAAAAAAACTTTTTTATAGAGATGAGCTCTCGCCGTGTTGCCCAAGCTGGTCCTAAAACGCTGGCCTCAAGCTATCCTCCGGCCTCAGTCTTAGCCTCCCAAAATGCTGGGGTTTCAGTAGAAGCCACCATGCCGGGCCACTTCTGTTTCTTTTCCATGTAGAGTTCTTTGCAGGAGGAGGTTAGAATAGGTGTGCATCTCCTAAATAGTTGTCGAATATAACTAAAAAGTTAACCAGGACTCTAAATACTATTTACTTCTAAAATTTGTTAATTGGGAACATTTAGGGTTTAACTGATCTATATCTTATGTCTTTAACAATTTTGAATGATAATTATATGTAAAGTAAGAACAGTTTGTGAAATAGTTGAAAATATCCTTACATGAAAGTGAATTTTAAAGCACAGTTTATGTAATGTTAATGTTTTGTTTTGTATCTGTTAAAAATTTGTTTATATGAACAAGTTTACAGGTTTACTGTGGTGAGCCCGTTGAATATAGTGGGTTTTTTTTGTTTGTTTTGTTTTTGTTTTTGAGATGAAGTCTCACTCTTGTCCCGAGGCTGATGTGCAATGGCGCGATCTTGGCTCACTGCAACCTCTGCCTCCTGGGTTCAAGCGATTCTCCTGCCTTAGCCTCCCGAGTAGCTGGGATTATAGGCACCTGTCACCAAACCCGGCTAAGTTTTGTATTTTTGGTAGAGATGGGATCTCAGCATGTTGGCCAGGCTGGACTCAGGTGATCCGTCTGCCTCGGCCTCCCAAGTGCTGGGATTACAGGTGTGAGCCACCATGCCGAGCCTGAATATAGTGTTTTTAAGTTGCAGGACTTTAAAAATAATATTTTGAAATTTTTCTAAGTTAAATTCCCTGTTAAAATGGTCATGCAGGAATATACGCTTGCATTATTCATATTAGGGTAACTGTTTGGTTTGCTAGTTGTTAGATTCTTTGCATTCCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTGAGACGGAGTTTCACTCTTTTTGACAAGGCTGGAGTGCAATGGCGCTATCTCGGCTCACCTCAACCTCCGCCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGAATTACAGGAATACGCCACCAAGCCCGGCTAATTTTGTATTTTTAGTAGAGATGGGGTTTCTCCATGTTGGTCAGGCTGGTCTCAAACTCCCAGTCTCAGGTGATCAGCCCACCTCGGCCTCCCAAAGTGCTGGGATTACAGGAGTAATCCCCCACCCTTTTAAAAAAATGAGACAGAGTTTTATTCTGTCACCCAGGGTGGAGTGCAGTGGTGCGATCATGGTTCACCGCAGCCTTGAATCTGGGCTCAAGTGATCCTCCCACTTCAGCCTCCCAAGTAGTTGGAACCATAGATGTGCATCACCACACCTGGCTGATTTTTAAATTATTTGTAGAGATGAGGTCTTGCTTGTTGTCTAGGCTGGTCTTAAACTTCTGGGCTTCAGCAGTCCTCCTGCCTCAGCCTCCCAGAGTGCTGAGATGATAGACATGGGCCACTGCCCCTGGCCGCATTTTTCTTTTCTTTTCCTTTCTTTTTTTTTTTTTTTTTTTGAAACGGAGTTTTGCCATTGTCGCCCAGGCTGGAGTGCAGTGGCACGATCTCTGCTCACTGCAACCTCTGCCTCCCGAG","AlternateAlleleVCF":"CATTCTCTTTGAAAA","allel_id":49845,"rule_based_match":false,"evidence_text":"c.1277-1180_1386+2226del3516insCATTCTCTTTGAAAA","llm_judgment":"PRESENT","evidence":"c.1277-1180_1386+2226del3516insCATTCTCTTTGAAAA","abstract_start":979,"abstract_end":1025}]}
{"pmid":"31696227","title":"Atonal homolog 7 (ATOH7) loss-of-function mutations in predominant bilateral optic nerve hypoplasia.","abstract":"Optic nerve hypoplasia (ONH) is a congenital optic nerve abnormality caused by underdevelopment of retinal ganglion cells (RGCs). Despite being a rare disease, ONH is the most common optic disk anomaly in ophthalmological practice. So far, mutations in several genes have been identified as causative; however, many cases of ONH remain without a molecular explanation. The early transcription factor atonal basic-helix-loop-helix (bHLH) transcription factor 7 (ATOH7) is expressed in retinal progenitor cells and has a crucial role in RGC development. Previous studies have identified several mutations in the ATOH7 locus in cases of eye developmental diseases such as non-syndromic congenital retinal non-attachment and persistent hyperplasia of the primary vitreous. Here we present two siblings with a phenotype predominated by bilateral ONH, with additional features of foveal hypoplasia and distinct vascular abnormalities, where whole-exome sequencing identified two compound heterozygous missense mutations affecting a conserved amino acid residue within the bHLH domain of ATOH7 (NM_145178.3:c.175G>A; p.(Ala59Thr) and c.176C>T; p.(Ala59Val)). ATOH7 expression constructs with patient single nucleotide variants were cloned for functional characterization. Protein analyses revealed decreased protein amounts and significantly enhanced degradation in the presence of E47, a putative bHLH dimerization partner. Protein interaction assays revealed decreased heterodimerization and DNA-binding of ATOH7 variants, resulting in total loss of transcriptional activation of luciferase reporter gene expression. These findings strongly support pathogenicity of the two ATOH7 mutations, one of which is novel. Additionally, this report highlights the possible impact of altered ATOH7 dimerization on protein stability and function.","variants":[{"Name":"NM_145178.4(ATOH7):c.176C>T (p.Ala59Val)","Chromosome":"10","Start":"68231502","Stop":"68231502","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":800923,"rule_based_match":true,"evidence_text":"c.176C>T; p.(Ala59Val)","llm_judgment":"PRESENT","evidence":"c.176C>T; p.(Ala59Val)","abstract_start":1127,"abstract_end":1149},{"Name":"NM_145178.4(ATOH7):c.175G>A (p.Ala59Thr)","Chromosome":"10","Start":"68231503","Stop":"68231503","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":800924,"rule_based_match":true,"evidence_text":"NM_145178.3:c.175G>A; p.(Ala59Thr)","llm_judgment":"PRESENT","evidence":"NM_145178.3:c.175G>A; p.(Ala59Thr)","abstract_start":1088,"abstract_end":1122}]}
{"pmid":"35456503","title":"Case Review: Whole-Exome Sequencing Analyses Identify Carriers of a Known Likely Pathogenic Intronic","abstract":"Background: Detecting pathogenic intronic variants resulting in aberrant splicing remains a challenge in routine genetic testing. We describe germline whole-exome sequencing (WES) analyses and apply in silico predictive tools of familial ovarian cancer (OC) cases reported clinically negative for pathogenic BRCA1 and BRCA2 variants. Methods: WES data from 27 familial OC cases reported clinically negative for pathogenic BRCA1 and BRCA2 variants and 53 sporadic early-onset OC cases were analyzed for pathogenic variants in BRCA1 or BRCA2. WES data from carriers of pathogenic BRCA1 or BRCA2 variants were analyzed for pathogenic variants in 10 other OC predisposing genes. Loss of heterozygosity analysis was performed on tumor DNA from variant carriers. Results: BRCA1 c.5407-25T>A intronic variant, identified in two affected sisters and one sporadic OC case, is predicted to create a new splice effecting transcription of BRCA1. WES data from BRCA1 c.5407-25T>A carriers showed no evidence of pathogenic variants in other OC predisposing genes. Sequencing the tumor DNA from the variant carrier showed complete loss of the wild-type allele. Conclusions: The findings support BRCA1 c.5407-25T>A as a likely pathogenic variant and highlight the importance of investigating intronic sequences as causal variants in OC families where the involvement of BRCA1 is highly suggestive.","variants":[{"Name":"NM_007294.4(BRCA1):c.5407-25T>A","Chromosome":"17","Start":"43047728","Stop":"43047728","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":358928,"rule_based_match":true,"evidence_text":"BRCA1 c.5407-25T>A","llm_judgment":"PRESENT","evidence":"BRCA1 c.5407-25T>A","abstract_start":766,"abstract_end":784}]}
{"pmid":"27896094","title":"Concurrent non-ketotic hyperglycinemia and propionic acidemia in an eight year old boy.","abstract":"This is the first reported case of a patient with both non-ketotic hyperglycinemia and propionic acidemia. At 2 years of age, the patient was diagnosed with non-ketotic hyperglycinemia by elevated glycine levels and mutations in the <i>GLDC</i> gene (paternal allele: c.1576_1577insC delT and c.1580delGinsCAA; p.S527Tfs*13, and maternal allele: c.1819G>A; p.G607S). At 8 years of age after having been placed on ketogenic diet, he became lethargic and had severe metabolic acidosis with ketonuria. Urine organic acid analysis and plasma acylcarnitine profile were consistent with propionic acidemia. He was found to have an apparently homozygous mutation in the <i>PCCB</i> gene: c.49C>A; p.Leu17Met. The patient was also treated with natural protein restriction, carnitine, biotin, and thiamine and had subjective and biochemical improvement.","variants":[{"Name":"NM_000170.3(GLDC):c.1819G>A (p.Gly607Ser)","Chromosome":"9","Start":"6587172","Stop":"6587172","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":545578,"rule_based_match":true,"evidence_text":"c.1819G>A","llm_judgment":"PRESENT","evidence":"c.1819G>A","abstract_start":346,"abstract_end":355},{"Name":"NM_000532.5(PCCB):c.49C>A (p.Leu17Met)","Chromosome":"3","Start":"136250424","Stop":"136250424","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":200029,"rule_based_match":true,"evidence_text":"c.49C>A; p.Leu17Met","llm_judgment":"PRESENT","evidence":"c.49C>A; p.Leu17Met","abstract_start":681,"abstract_end":700}]}
{"pmid":"20937258","title":"Unexpected heterogeneity due to recessive and de novo dominant mutations of GJB2 in an Iranian family with nonsyndromic hearing loss: implication for genetic counseling.","abstract":"Mutations in the GJB2 gene are the most common cause of nonsyndromic autosomal recessive sensorineural hearing loss (HL). A few mutations in GJB2 have also been reported to cause dominant nonsyndromic HL. Here we report a large inbred family including two individuals with nonsyndromic sensorineural hearing loss. A dominant GJB2 mutation, c.551G>A (p.R184Q), was detected in the proband, yet his parents were negative for the mutation. The second affected person had heterozygous c.35delG mutation, which was inherited from his father. Large deletions of the GJB6 gene were not detected in this family. This study highlights the importance of mutation analysis in all affected cases within a pedigree.","variants":[{"Name":"NM_004004.6(GJB2):c.551G>A (p.Arg184Gln)","Chromosome":"13","Start":"20189031","Stop":"20189031","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38617,"rule_based_match":true,"evidence_text":"c.551G>A (p.R184Q)","llm_judgment":"PRESENT","evidence":"c.551G>A (p.R184Q)","abstract_start":340,"abstract_end":358}]}
{"pmid":"23200691","title":"PROKR2 mutations in autosomal recessive Kallmann syndrome.","abstract":"OBJECTIVE: To investigate the inheritance pattern of two missense PROKR2 changes within a single family.\nDESIGN: This is a descriptive study.\nSETTING: Tertiary referral center.\nPATIENT(S): The proband and his brother, both with congenital hypogonadotropic hypogonadism and anosmia (Kallmann syndrome).\nINTERVENTION(S): Clinical and biochemical evaluation of Kallmann syndrome. Sequence analysis of the coding exons and exon-intron boundaries of KAL1, FGFR1, FGF8, PROK2, and PROKR2 from polymerase chain reaction (PCR)-amplified genomic DNA. Recombinant human FSH treatment of the proband.\nMAIN OUTCOME MEASURE(S): Phenotypic and genotypic features, and inhibin B response to recombinant human FSH.\nRESULT(S): The proband and his brother were homozygous for two variants in PROKR2; a novel mutation c.701G>A (p.G234D), and a polymorphism c.802C>T (p.R268C). Recombinant human FSH therapy of the proband increased serum inhibin B from <16 to 136 ng/L. The heterozygous parents were fertile and had six children.\nCONCLUSION(S): These findings are consistent with recessive mode of inheritance. PROKR2 signaling does not directly affect Sertoli cell function.","variants":[{"Name":"NM_144773.4(PROKR2):c.802C>T (p.Arg268Cys)","Chromosome":"20","Start":"5302393","Stop":"5302393","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":266582,"rule_based_match":true,"evidence_text":"c.802C>T (p.R268C)","llm_judgment":"PRESENT","evidence":"c.802C>T (p.R268C)","abstract_start":838,"abstract_end":856}]}
{"pmid":"28687525","title":"SMD Kozlowski type caused by p.Arg594His substitution in TRPV4 reveals abnormal ossification and notochordal remnants in discs and vertebrae.","abstract":"Spondylometaphyseal dysplasia Kozlowski type (SMDK) is a monogenic disorder within the TRPV4 dysplasia spectrum and has characteristic spinal and metaphyseal changes. We report skeletal MR imaging in a two-year-old patient who manifested typical clinical and radiographic features of SMDK. The diagnosis was confirmed by molecular analysis which revealed a mutation NM_021625.4:c.1781G > A - p.(Arg594His) in exon 11 of the TRPV4 gene. We have documented abnormalities in endochondral formation of the long and short tubular bones as well as round bones of the wrists and feet. The vertebral bodies had increased thickness of hyaline cartilage which enveloped ossification centers. The vertebrae and discs also had abnormalities in size, shape and structure. These anomalies were most likely the consequence of notochordal remnants presence within the intervertebral discs and in the vertebral bodies. The advantages of MR imaging in bone dysplasias caused by TRPV4 mutations are emphasized in this article.","variants":[{"Name":"NM_021625.5(TRPV4):c.1781G>A (p.Arg594His)","Chromosome":"12","Start":"109792695","Stop":"109792695","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20033,"rule_based_match":true,"evidence_text":"NM_021625.4:c.1781G > A - p.(Arg594His)","llm_judgment":"PRESENT","evidence":"NM_021625.4:c.1781G > A - p.(Arg594His)","abstract_start":366,"abstract_end":405}]}
{"pmid":"28165343","title":"Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.","abstract":"Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism.","variants":[{"Name":"NM_003901.4(SGPL1):c.665G>A (p.Arg222Gln)","Chromosome":"10","Start":"70868394","Stop":"70868394","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":424406,"rule_based_match":true,"evidence_text":"c.665G>A (p.R222Q)","llm_judgment":"PRESENT","evidence":"c.665G>A (p.R222Q)","abstract_start":743,"abstract_end":761},{"Name":"NM_003901.4(SGPL1):c.261+1G>A","Chromosome":"10","Start":"70851211","Stop":"70851211","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":424408,"rule_based_match":true,"evidence_text":"c.261+1G>A (p.S65Rfs*6)","llm_judgment":"PRESENT","evidence":"c.261+1G>A (p.S65Rfs*6)","abstract_start":794,"abstract_end":817}]}
{"pmid":"26911354","title":"Two novel mutations in TMEM38B result in rare autosomal recessive osteogenesis imperfecta.","abstract":"Osteogenesis imperfecta (OI) is a group of clinically and genetically heterogeneous disorders characterized by decreased bone mass and recurrent bone fractures. Transmembrane protein 38B (TMEM38B) gene encodes trimeric intracellular cation channel type B (TRIC-B), mutations of which will lead to the rare form of autosomal recessive OI. Here we detected pathogenic gene mutations in TMEM38B and investigated its phenotypes in three children with OI from two non-consanguineous families of Chinese Han origin. The patients suffered from recurrent fractures, low bone mass, mild bone deformities and growth retardation, but did not have impaired hearing or dentinogenesis imperfecta. Next-generation sequencing and Sanger sequencing revealed a homozygous novel acceptor splice site variant (c.455-7T>G in intron 3, p.R151_G152insVL) in family 1 and a homozygous novel nonsense variant (c.507G>A in exon 4, p.W169X) in family 2. The parents of the probands were all heterozygous carriers of these mutations. We reported the phenotype and novel mutations in TMEM38B of OI for the first time in Chinese population. Our findings of the novel mutations in TMEM38B expand the pathogenic spectrum of OI and strengthen the role of TRIC-B in the pathogenesis of OI.","variants":[{"Name":"NM_018112.3(TMEM38B):c.507G>A (p.Trp169Ter)","Chromosome":"9","Start":"105722586","Stop":"105722586","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1313975,"rule_based_match":true,"evidence_text":"c.507G>A (p.W169X)","llm_judgment":"PRESENT","evidence":"c.507G>A","abstract_start":885,"abstract_end":893}]}
{"pmid":"26026795","title":"Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease.","abstract":"PURPOSE: 3-Hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare disorder of valine metabolism. We present a family with the oldest reported subjects with HIBCH deficiency and provide support that HIBCH deficiency should be included in the differential for elevated hydroxy-C4-carnitine in newborn screening (NBS).\nMETHODS: Whole exome sequencing (WES) was performed on one affected sibling. HIBCH enzymatic activity was measured in patient fibroblasts. Acylcarnitines were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Disease incidence was estimated using a cohort of 61,434 individuals.\nRESULTS: Two siblings presented with infantile-onset, progressive neurodegenerative disease. WES identified a novel homozygous variant in HIBCH c.196C>T; p.Arg66Trp. HIBCH enzymatic activity was significantly reduced in patients' fibroblasts. Acylcarnitine analysis showed elevated hydroxy-C4-carnitine in blood spots of both affected siblings, including in their NBS cards, while plasma acylcarnitines were normal. Estimates show HIBCH deficiency incidence as high as 1 in ~130,000 individuals.\nCONCLUSION: We describe a novel family with HIBCH deficiency at the biochemical, enzymatic and molecular level. Disease incidence estimates indicate HIBCH deficiency may be under-diagnosed. This together with the elevated hydroxy-C4-carnitine found in the retrospective analysis of our patient's NBS cards suggests that this disorder could be screened for by NBS programs and should be added to the differential diagnosis for elevated hydroxy-C4-carnitine which is already measured in most NBS programs using MS/MS.","variants":[{"Name":"NM_014362.4(HIBCH):c.196C>T (p.Arg66Trp)","Chromosome":"2","Start":"190296836","Stop":"190296836","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188107,"rule_based_match":true,"evidence_text":"c.196C>T; p.Arg66Trp","llm_judgment":"PRESENT","evidence":"c.196C>T; p.Arg66Trp","abstract_start":768,"abstract_end":788}]}
{"pmid":"30900330","title":"A novel SAMD9 variant identified in patient with MIRAGE syndrome: Further defining syndromic phenotype and review of previous cases.","abstract":"We present here a case of MIRAGE syndrome due to novel variant (c.2318T>C) in the sterile α motif domain-containing protein 9 (SAMD9) gene. Previous reports have described the clinical phenotype, which includes myelodysplasia, recurrent infections, restriction of growth and development, adrenal insufficiency, genitourinary abnormalities, and enteropathies, often resulting in fatality within the first few years of life. This report illustrates the variability in phenotype by describing an 11-year-old male, diagnosed with MIRAGE at age 9 years when his novel variant was identified through whole exome sequencing. A brief review of previously published cases of MIRAGE syndrome and the genotypic and phenotypic spectrum are presented.","variants":[{"Name":"NM_017654.4(SAMD9):c.2318T>C (p.Ile773Thr)","Chromosome":"7","Start":"93103780","Stop":"93103780","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1903470,"rule_based_match":true,"evidence_text":"c.2318T>C","llm_judgment":"PRESENT","evidence":"c.2318T>C","abstract_start":64,"abstract_end":73}]}
{"pmid":"21321465","title":"Identification of six novel SCN5A mutations in Japanese patients with Brugada syndrome.","abstract":"Mutations in SCN5A are linked to Brugada syndrome in approximately 20% of all cases (BrS1). Several dozen distinct SCN5A mutations in BrS1 have been associated with the increased risk of cardiac arrhythmias. However, the genotype-phenotype relationship remains elusive. The current study analyzed the SCN5A gene to elucidate the potential variability of clinical features in Japanese BrS1 subjects. Subjects of the present study included 30 probands (25 male subjects, 45 ± 15 years of age) with Brugada-pattern ECG. Seven patients had been resuscitated from cardiopulmonary arrest (CPA group). Another 10 patients had a history of syncope (Sy group), and 13 more remain asymptomatic (Asy group). We identified 8 different SCN5A mutations, including 6 novel mutations (CPA group: 1/7, Sy group: 3/10, Asy group: 4/13). An A735E mutation (located at segment (S)1 in domain (D)2) was identified in the CPA group. A novel splice acceptor site mutation (c.393-1c>t), which may produce a prematurely truncated protein, was identified in the Sy group. An E1784K mutation (C-terminus) and a novel mutation V1951M (C-terminus) were also identified in the Sy group. Four novel missense mutations, A586T (D1-D2 linker), R689H (D1-D2 linker), S1553R (S1-S2 in D4), and Q1706H (S5-Pore in D4) were identified in the Asy group. These data may help us understand the genetic heterogeneity of BrS1, which is more prevalent in Japanese than in whites and other ethnic groups.","variants":[{"Name":"NM_000335.5(SCN5A):c.393-1C>T","Chromosome":"3","Start":"38622490","Stop":"38622490","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":496343,"rule_based_match":true,"evidence_text":"c.393-1c>t","llm_judgment":"PRESENT","evidence":"c.393-1c>t","abstract_start":950,"abstract_end":960}]}
{"pmid":"24928221","title":"A new mutation of the PCNT gene in a Colombian patient with microcephalic osteodysplastic primordial dwarfism type II: a case report.","abstract":"INTRODUCTION: Microcephalic osteodysplastic primordial dwarfism is a syndrome characterized by the presence of intrauterine growth restriction, post-natal growth deficiency and microcephaly. Microcephalic osteodysplastic primordial dwarfism type II is the most distinctive syndrome in this group of entities. Individuals affected by this disease present at an adult height of less than 100 cm, a post-pubertal head circumference of 40 cm or less, mild mental retardation, an outgoing personality and bone dysplasia.\nCASE PRESENTATION: We report the first case of a five-year-old Colombian boy of mixed race ancestry (mestizo), with clinical features of microcephaly, prominent and narrow nose, arched palate, amelogenesis imperfecta, short stature, tall and narrow pelvis, disproportionate shortening of fore-arms and legs, and mild coxa vara. Analysis of the PCNT gene by sequencing showed the presence of a nucleotide change in exon 10, c. 1468C>T, evidencing a new mutation not reported in the literature for microcephalic osteodysplastic primordial dwarfism.\nCONCLUSION: The new mutation identified in this case could be associated with the severity of the phenotypic expression of the disease, resulting in the extreme short stature of the patient. Further studies are required to reach an explanation that can justify such findings, and it is vital to emphasize the importance of detection and follow-up by the epidemiological surveillance groups in birth defects and rare diseases.","variants":[{"Name":"NM_006031.6(PCNT):c.1468C>T (p.Gln490Ter)","Chromosome":"21","Start":"46353115","Stop":"46353115","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":169625,"rule_based_match":true,"evidence_text":"c. 1468C>T","llm_judgment":"PRESENT","evidence":"c. 1468C>T","abstract_start":939,"abstract_end":949}]}
{"pmid":"36747105","title":"A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases.","abstract":"U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an indispensable pre-mRNA splicing factor in the early process of splicing. Recently, U2AF2 was reported as a novel candidate gene associated with neurodevelopmental disorders. Herein, we report a patient with a novel presumed heterozygous missense variant in the U2AF2 gene (c.603G>T), who has a similar clinical phenotype as the patient reported before, including epilepsy, intellectual disability, language delay, microcephaly, and hypoplastic corpus callosum. We reviewed the phenotypic and genetic spectrum of patients with U2AF2-related neurological diseases, both newly diagnosed and previously reported. To investigate the possible pathogenesis, EBV-immortalized lymphoblastoid cells were derived from the peripheral blood obtained from the patient and control groups. Furthermore, according to the results of WB, RT-PCR, Q-PCR, and cDNA sequencing of RT-PCR products, the presumed missense variant c.603G>T caused exon 6 skipping in the U2AF2 mRNA transcript and led to a truncated protein (p.E163_E201del). Cell Counting Kit-8 (CCK-8) and cell cycle detection demonstrated that the variant c.603G>T inhibited the proliferation of patient lymphocyte cells compared with the control group. This study is aimed at expanding the phenotypic and genetic spectrum of U2AF2-related neurodevelopmental diseases and investigating the potential effects. This is the first report of the possible pathogenesis of a U2AF2 gene pathogenic variant in a patient with neurodevelopmental diseases and shows that a novel presumed missense variant in the U2AF2 gene causes exon skipping.","variants":[{"Name":"NM_007279.3(U2AF2):c.603G>T (p.Glu201Asp)","Chromosome":"19","Start":"55662618","Stop":"55662618","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2750352,"rule_based_match":true,"evidence_text":"c.603G>T","llm_judgment":"PRESENT","evidence":"c.603G>T","abstract_start":327,"abstract_end":335}]}
{"pmid":"31587467","title":"Novel and lethal case of cardiac involvement in DNM1L mitochondrial encephalopathy.","abstract":"Pathogenic DNM1L mutations cause a mitochondrial disorder with a highly variable clinical phenotype characterized by developmental delay, hypotonia, seizures, microcephaly, poor feeding, ocular abnormalities, and dysarthria. We report the case of an 8-month-old female with autosomal dominant, de novo DNM1L c. 1228G>A (p. E410K) mutation and mitochondrial disorder, septo-optic dysplasia, hypotonia, developmental delay, elevated blood lactate, and severe mitochondrial cardiomyopathy leading to nonischemic congestive heart failure and cardiogenic shock resulting in death. This case suggests that cardiac involvement, previously undescribed, can be a clinically important feature of this syndrome and should be screened for at diagnosis.","variants":[{"Name":"NM_012062.5(DNM1L):c.1228G>A (p.Glu410Lys)","Chromosome":"12","Start":"32731383","Stop":"32731383","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":973843,"rule_based_match":true,"evidence_text":"c. 1228G>A (p. E410K)","llm_judgment":"PRESENT","evidence":"c. 1228G>A (p. E410K)","abstract_start":308,"abstract_end":329}]}
{"pmid":"36299383","title":"The highest frequency of","abstract":"Background: The spectrum of <i>BRCA1</i> and <i>BRCA2</i> mutations varies among populations; however, some mutations may be frequent in particular ethnic groups due to the \"founder\" effect. The c.3700_3704del mutation was previously described as a recurrent <i>BRCA1</i> variant in Eastern European countries. This study aimed to investigate the frequency of c.3700_3704del <i>BRCA1</i> mutation in Albanian breast and ovarian cancer patients from North Macedonia and Kosovo.\nMaterials and methods: A total of 327 patients with invasive breast and/or ovarian cancer (111 Albanian women from North Macedonia and 216 from Kosovo) were screened for 13 recurrent <i>BRCA1/2</i> mutations. Targeted NGS with a panel of 94 cancer-associated genes including <i>BRCA1</i> and <i>BRCA2</i> was performed in a selected group of 118 patients.\nResults: We have identified 21 <i>BRCA1</i>/2 pathogenic variants, 17 (14 <i>BRCA1</i> and 3 <i>BRCA2</i>) in patients from Kosovo (7.9%) and 4 (1 <i>BRCA1</i> and 3 <i>BRCA2</i>) in patients from North Macedonia (3.6%). All <i>BRCA1/2</i> mutations were found in one patient each, except for c.3700_3704del <i>BRCA1</i> mutation which was observed in 14 unrelated families, all except one originating from Kosovo. The c.3700_3704del mutation accounts for 93% of <i>BRCA1</i> mutation positive cases and is present with a frequency of 6% among breast cancer patients from Kosovo.\nConclusions: This is the first report of <i>BRCA1/2</i> mutations among breast and ovarian cancer patients from Kosovo. The finding that <i>BRCA1</i> c.3700_3704del represents a founder mutation in Kosovo with the highest worldwide reported frequency supports the implementation of fast and low-cost screening protocol, regardless of the family history and even a pilot population-based screening in at-risk population.","variants":[{"Name":"NM_007294.4(BRCA1):c.3700_3704del (p.Val1234fs)","Chromosome":"17","Start":"43091827","Stop":"43091831","ReferenceAlleleVCF":"GTTTAC","AlternateAlleleVCF":"G","allel_id":46098,"rule_based_match":true,"evidence_text":"c.3700_3704del","llm_judgment":"PRESENT","evidence":"c.3700_3704del","abstract_start":195,"abstract_end":209}]}
{"pmid":"24361966","title":"Functional characterization of two novel splicing mutations in the OCA2 gene associated with oculocutaneous albinism type II.","abstract":"Oculocutaneous albinism (OCA) is characterized by hypopigmentation of the skin, hair and eye, and by ophthalmologic abnormalities caused by a deficiency in melanin biosynthesis. OCA type II (OCA2) is one of the four commonly-recognized forms of albinism, and is determined by mutation in the OCA2 gene. In the present study, we investigated the molecular basis of OCA2 in two siblings and one unrelated patient. The mutational screening of the OCA2 gene identified two hitherto-unknown putative splicing mutations. The first one (c.1503+5G>A), identified in an Italian proband and her affected sibling, lies in the consensus sequence of the donor splice site of OCA2 intron 14 (IVS14+5G>A), in compound heterozygosity with a frameshift mutation, c.1450_1451insCTGCCCTGACA, which is predicted to determine the premature termination of the polypeptide chain (p.I484Tfs*19). In-silico prediction of the effect of the IVS14+5G>A mutation on splicing showed a score reduction for the mutant splice site and indicated the possible activation of a newly-created deep-intronic acceptor splice site. The second mutation is a synonymous transition (c.2139G>A, p.K713K) involving the last nucleotide of exon 20. This mutation was found in a young African albino patient in compound heterozygosity with a previously-reported OCA2 missense mutation (p.T404M). In-silico analysis predicted that the mutant c.2139G>A allele would result in the abolition of the splice donor site. The effects on splicing of these two novel mutations were investigated using an in-vitro hybrid-minigene approach that led to the demonstration of the causal role of the two mutations and to the identification of aberrant transcript variants.","variants":[{"Name":"NM_000275.3(OCA2):c.1503+5G>A","Chromosome":"15","Start":"27983340","Stop":"27983340","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":208172,"rule_based_match":true,"evidence_text":"c.1503+5G>A","llm_judgment":"PRESENT","evidence":"c.1503+5G>A","abstract_start":530,"abstract_end":541}]}
{"pmid":"30014265","title":"Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals.","abstract":"AIMS/HYPOTHESIS: Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and optic atrophy and is caused by bi-allelic mutations in the WFS1 gene. In a recent sequencing study, an individual with juvenile-onset diabetes was observed to be homozygous for a rare missense variant (c.1672C>T, p.R558C) in the WFS1 gene. The aim of this study was to perform the genetic characterisation of this variant and to determine whether it is causal for young-onset diabetes and Wolfram syndrome.\nMETHODS: We analysed the allele frequency of the missense variant in multiple variant databases. We genotyped the variant in 475 individuals with type 1 diabetes and 2237 control individuals of Ashkenazi Jewish ancestry and analysed the phenotypes of homozygotes. We also investigated the association of this variant with risk for type 2 diabetes using genotype and sequence data for type 2 diabetes cases and controls.\nRESULTS: The missense variant demonstrated an allele frequency of 1.4% in individuals of Ashkenazi Jewish ancestry, 60-fold higher than in other populations. Genotyping of this variant in 475 individuals diagnosed with type 1 diabetes identified eight homozygotes compared with none in 2237 control individuals (genotype relative risk 135.3, p = 3.4 × 10<sup>-15</sup>). The age at diagnosis of diabetes for these eight individuals (17.8 ± 8.3 years) was several times greater than for typical Wolfram syndrome (5 ± 4 years). Further, optic atrophy was observed in only one of the eight individuals, while another individual had the Wolfram syndrome-relevant phenotype of neurogenic bladder. Analysis of sequence and genotype data in two case-control cohorts of Ashkenazi ancestry demonstrated that this variant is also associated with an increased risk of type 2 diabetes in heterozygotes (OR 1.81, p = 0.004).\nCONCLUSIONS/INTERPRETATION: We have identified a low-frequency coding variant in the WFS1 gene that is enriched in Ashkenazi Jewish individuals and causes a mild form of Wolfram syndrome characterised by young-onset diabetes and reduced penetrance for optic atrophy. This variant should be considered for genetic testing in individuals of Ashkenazi ancestry diagnosed with young-onset non-autoimmune diabetes and should be included in Ashkenazi carrier screening panels.","variants":[{"Name":"NM_006005.3(WFS1):c.1672C>T (p.Arg558Cys)","Chromosome":"4","Start":"6301467","Stop":"6301467","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":195995,"rule_based_match":true,"evidence_text":"c.1672C>T, p.R558C","llm_judgment":"PRESENT","evidence":"c.1672C>T, p.R558C","abstract_start":321,"abstract_end":339}]}
{"pmid":"27054699","title":"De novo EDA mutations: Variable expression in two Egyptian families.","abstract":"OBJECTIVE: Mutations in the EDA gene, encoding the epithelial morphogen ectodysplasin-A, can result in different but overlapping phenotypes. Therefore the aim of the study was to search for etiological variations of EDA and other candidate genes in two unrelated Egyptian male children with sporadic non-syndromic tooth agenesis (NTA) and hypohidrotic ectodermal dysplasia (HED).\nDESIGN: Direct sequencing of the coding regions including exon-intron boundaries of EDA, MSX1, PAX9, WNT10A and EDAR was performed in probands and their available family members.\nRESULTS: Two etiological mutations were found in the EDA coding region. The patient with NTA in both deciduous and permanent dentition was a carrier of a novel in-frame deletion situated in the short collagenous domain (c.663-680delTCCTCCTGGTCCTCAAGG, p.222-227delPPGPQG). The second mutation, located outside the minimal furin consensus motif (c.463C>T, p.Arg155Cys, rs132630312), was identified in the patient exhibiting all typical features of HED. The identified EDA mutations were not detected in probands' family members as well as in 188 unrelated control individuals. No pathogenic variants were found in the MSX1, PAX9, WNT10A and EDAR genes.\nCONCLUSION: Our results increase the knowledge of the spectrum of EDA mutations and confirm that this gene is an important candidate gene for two developmental diseases sharing the common feature of the congenital lack of teeth. In addition, these results can support the hypothesis that X-linked HED and EDA-related NTA are the same disease with different degrees of severity.","variants":[{"Name":"NM_001399.5(EDA):c.463C>T (p.Arg155Cys)","Chromosome":"X","Start":"69957093","Stop":"69957093","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26074,"rule_based_match":true,"evidence_text":"c.463C>T (p.Arg155Cys, rs132630312)","llm_judgment":"PRESENT","evidence":"p.Arg155Cys","abstract_start":914,"abstract_end":925}]}
{"pmid":"32617873","title":"Chinese Cases of Metachromatic Leukodystrophy with the Novel Missense Mutations in ARSA Gene.","abstract":"Metachromatic leukodystrophy(MLD) is an autosomal recessive hereditary neurodegenerative lysosomal storage disorder caused by the mutations in arylsulfatase A gene (ARSA), which results in the deficiency of ARSA enzyme. The common clinical characteristics of MLD are abnormal gait, and then gradually appears ataxia, spastic quadriplegia, optic atrophy, cortical blindness, and dementia. We describe two patients in China who were diagnosed with MLD and find that the four ARSA gene mutations (c.1115G>A, c.302G>T, c.893 G> T, and c.302G>T) are associated with MLD, in which c.893 G>T and c.302G>T are novel mutations by gene sequence and clinical manifestations, to further understand the relationship between MLD and ARSA gene.","variants":[{"Name":"NM_000487.6(ARSA):c.1115G>A (p.Arg372Gln)","Chromosome":"22","Start":"50625674","Stop":"50625674","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18121,"rule_based_match":true,"evidence_text":"c.1115G>A","llm_judgment":"PRESENT","evidence":"c.1115G>A","abstract_start":494,"abstract_end":503},{"Name":"NM_000487.6(ARSA):c.893G>T (p.Gly298Val)","Chromosome":"22","Start":"50626240","Stop":"50626240","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3839244,"rule_based_match":true,"evidence_text":"c.893 G>T","llm_judgment":"PRESENT","evidence":"c.893 G>T","abstract_start":575,"abstract_end":584}]}
{"pmid":"25803555","title":"Genotype-phenotype correlation in patients with PRPH2-mutations","abstract":"BACKGROUND: The peripherin-2 (PRPH2) gene encodes a photoreceptor-specific transmembrane-protein called peripherin-2 which is critical for the formation and maintenance of rod and cone outer segments. Over 90 different disease-causing mutations in PRPH2 have been identified which cause a variety of forms of macular degeneration and also retinopathia pigmentosa.\nPATIENTS/MATERIAL AND METHODS: This study is a retrospective observational study of 3 patients ascertained over a 5 month period in the ophthalmogenetic consultation of the university ophthalmic clinic. So far, the patients were followed for 8 months at least. Data examined included clinical history, pedigree analysis, ophthalmological examination, fundus photography, autofluorescence imaging, optical coherence tomography, Arden colour test, Goldmann perimetry and detailed electrophysiological assessment. Blood samples were taken for DNA extraction and mutation analysis of PRPH2 and ABCA4, BEST1, C1QTNF5, CDH3, CNGB3, ELOVL4, FSCN2, PROM1, RDH12, RP1L1, RPGR, TIMP3 was performed.\nRESULTS: All patients had presented with clinically evident maculopathy and visual acuities in the range of 1/50 Metervisus to 0.8 p [dec.]. All had specific electroretinogrammes. All PRPH2 mutations were autosomal dominant. One family was heterozygous for a previously reported missense mutation in the PRPH2 gene c.514C>T, p.R172W. The other patient was heterozygous for a so far non-described PRPH2 deletion and frameshift mutation c.74_77delGGTT, p.W25SfsX12 leading most likely to a truncated, dysfunctional protein. All patients showed a significant, inter-individual phenotypical variability.\nCONCLUSION: The data add to the documented phenotypical variability of PRPH2 mutations and describe the c.74_77delGGTT, p.W25SfsX12 mutation within PRPH2 for the first time. FAF, OCT and electrophysiological exams are helpful tools for diagnosis and evaluation of macular disease due to PRPH2 mutations.","variants":[{"Name":"NM_000322.5(PRPH2):c.514C>T (p.Arg172Trp)","Chromosome":"6","Start":"42721821","Stop":"42721821","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28209,"rule_based_match":true,"evidence_text":"c.514C>T, p.R172W","llm_judgment":"PRESENT","evidence":"c.514C>T, p.R172W","abstract_start":1368,"abstract_end":1385},{"Name":"NM_000322.5(PRPH2):c.74_77del (p.Trp25fs)","Chromosome":"6","Start":"42722258","Stop":"42722261","ReferenceAlleleVCF":"GAACC","AlternateAlleleVCF":"G","allel_id":1164740,"rule_based_match":true,"evidence_text":"c.74_77delGGTT, p.W25SfsX12","llm_judgment":"PRESENT","evidence":"c.74_77delGGTT, p.W25SfsX12","abstract_start":1488,"abstract_end":1515}]}
{"pmid":"30315938","title":"WDR73-related galloway mowat syndrome with collapsing glomerulopathy.","abstract":"Galloway-Mowat syndrome (GAMOS [MIM 251300]) is a rare autosomal recessive disorder that manifests as a combination of nephrotic syndrome, brain abnormalities and developmental delay. It is a clinically and genetically heterogeneous disease. The WDR73 variations are associated with GAMOS1. Here we report two consanguineous families affected by GAMOS1. In the first family, three sisters are affected and in the second family, only one index case is identified. They all show a nephrotic syndrome, a neurological involvement and a collapsing glomerulopathy. The analysis of mutations of WDR73 revealed a new homozygous missense mutation NM_032856.3 c.293T > C; p.(Leu98Pro) in two patients from the first family, and a new homozygous missense mutation NM_032856.3: c.767G > A; p.(Arg256Gln) in the second one. This study extended the clinical and molecular spectrum of GAMOS1 with other cases associated with collapsing glomerulopathy and two novel WDR73 variations that are most likely pathogenic.","variants":[{"Name":"NM_032856.5(WDR73):c.767G>A (p.Arg256Gln)","Chromosome":"15","Start":"84645587","Stop":"84645587","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":623016,"rule_based_match":true,"evidence_text":"NM_032856.3: c.767G > A; p.(Arg256Gln)","llm_judgment":"PRESENT","evidence":"NM_032856.3: c.767G > A; p.(Arg256Gln)","abstract_start":753,"abstract_end":791},{"Name":"NM_032856.5(WDR73):c.293T>C (p.Leu98Pro)","Chromosome":"15","Start":"84647949","Stop":"84647949","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":205481,"rule_based_match":true,"evidence_text":"NM_032856.3 c.293T > C; p.(Leu98Pro)","llm_judgment":"PRESENT","evidence":"NM_032856.3 c.293T > C; p.(Leu98Pro)","abstract_start":638,"abstract_end":674}]}
{"pmid":"15050444","title":"Myelin protein zero gene mutations in Taiwanese patients with Charcot-Marie-Tooth disease type 1.","abstract":"BACKGROUND: Charcot-Marie-Tooth disease type 1 (CMT1) is the most common inherited peripheral neuropathy and represents a genetically heterogeneous condition. In addition to the peripheral myelin protein 22 gene (PMP22) duplication (CMT1A), myelin protein zero gene (MPZ) mutations may account for a certain portion of CMT1 patients (CMT1B).\nOBJECTIVES: The authors analyzed the MPZ mutations in Taiwanese patients who do not have PMP22 duplication. Specifically, their clinical and molecular features were characterized.\nMATERIALS AND METHODS: Twenty-four of 57 unrelated Taiwanese patients with CMT1 were selected after excluding the CMT1A duplication. Subsequent analysis of the coding regions of the MPZ gene was performed with single-strand-conformation polymorphism (SSCP), which was then followed by nucleotide sequencing.\nRESULTS: Four missense mutations and one 4-base pair (bp) deletion, respectively, were identified in five patients, of which one mutation, c.173 T>A, has never been previously reported. Three missense mutations were located in exon 2, the other one in exon 3, and the deletion in exon 6.\nCONCLUSIONS: This study expands the number of CMT1 associated MPZ mutation and suggests that analysis of the coding sequence of MPZ should be performed in all CMT patients without CMT1A duplication to clarify their disease nature.","variants":[{"Name":"NM_000530.8(MPZ):c.173T>A (p.Val58Asp)","Chromosome":"1","Start":"161307319","Stop":"161307319","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":625074,"rule_based_match":true,"evidence_text":"c.173 T>A","llm_judgment":"PRESENT","evidence":"c.173 T>A","abstract_start":969,"abstract_end":978}]}
{"pmid":"24521109","title":"Genetic variants in C5 and poor response to eculizumab.","abstract":"BACKGROUND: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear.\nMETHODS: We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients.\nRESULTS: Of 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G → A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653C → T, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab.\nCONCLUSIONS: The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).","variants":[{"Name":"NM_001735.3(C5):c.2654G>A (p.Arg885His)","Chromosome":"9","Start":"120997683","Stop":"120997683","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":132582,"rule_based_match":false,"evidence_text":"c.2654G → A","llm_judgment":"PRESENT","evidence":"c.2654G → A","abstract_start":692,"abstract_end":703},{"Name":"NM_001735.3(C5):c.2653C>T (p.Arg885Cys)","Chromosome":"9","Start":"120997684","Stop":"120997684","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132583,"rule_based_match":false,"evidence_text":"c.2653C → T","llm_judgment":"PRESENT","evidence":"c.2653C → T","abstract_start":1037,"abstract_end":1048}]}
{"pmid":"19726882","title":"Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.","abstract":"Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance. In 3 branches of a large South African Afrikaner pedigree with an autosomal-dominant form of PFHBI, we identified the mutation c.19G-->A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4) at chromosomal locus 19q13.3. This mutation predicted the amino acid substitution p.E7K in the TRPM4 amino terminus. TRPM4 encodes a Ca2+-activated nonselective cation (CAN) channel that belongs to the transient receptor potential melastatin ion channel family. Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers. Cellular expression studies showed that the c.19G-->A missense mutation attenuated deSUMOylation of the TRPM4 channel. The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface. Our data therefore revealed a gain-of-function mechanism underlying this type of familial heart block.","variants":[{"Name":"NM_017636.4(TRPM4):c.19G>A (p.Glu7Lys)","Chromosome":"19","Start":"49157885","Stop":"49157885","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18809,"rule_based_match":false,"evidence_text":"c.19G-->A","llm_judgment":"PRESENT","evidence":"c.19G-->A","abstract_start":295,"abstract_end":304}]}
{"pmid":"28766502","title":"Transient Neonatal Diabetes due to a Mutation in KCNJ11 in a Child with Klinefelter Syndrome.","abstract":"Klinefelter syndrome is the most frequent chromosomal aneuploidy in males occurring in about 1 in 660 males. Epidemiological studies have demonstrated increased risk of type 1 diabetes and type 2 diabetes in adults with Klinefelter syndrome. There is only one previous report of neonatal diabetes in a patient with Klinefelter syndrome. We report transient neonatal diabetes due to a pathogenic heterozygous variant in KCNJ11 in a male infant with Klinefelter syndrome. A 78-day old male infant was noted to have sustained hyperglycemia with serum glucose ranging between 148 mg/dL (8.2 mmol/L) and 381 mg/dL (21.2 mmol/L) three days after undergoing a complete repair of an atrioventricular defect. Hemoglobin A1c was 6.6%. The patient was born at term with a birth weight of 2.16 kg following a pregnancy complicated by gestational diabetes that was controlled with diet. The patient was initially started on a continuous intravenous insulin drip and subsequently placed on subcutaneous insulin (glargine, human isophane and regular insulin). Insulin was gradually decreased and eventually discontinued at seven months of age. Chromosomal microarray at 11 weeks of age showed XXY and a panel-based, molecular test for neonatal diabetes revealed a pathogenic heterozygous variant c.685G>A (p.Glu229Lys) in KCNJ11. The patient is now 34 months old and continues to have normal fasting and post-prandial glucose and HbA1C levels. The patient will need prospective follow up for assessment of his glycemic status. To our knowledge this is the second reported case of neonatal diabetes in an infant with Klinefelter syndrome and the first due to a mutation in the KCNJ11 in a patient with Klinefelter syndrome.","variants":[{"Name":"NM_000525.4(KCNJ11):c.685G>A (p.Glu229Lys)","Chromosome":"11","Start":"17387407","Stop":"17387407","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":168868,"rule_based_match":true,"evidence_text":"c.685G>A (p.Glu229Lys)","llm_judgment":"PRESENT","evidence":"c.685G>A (p.Glu229Lys)","abstract_start":1281,"abstract_end":1303}]}
{"pmid":"35038048","title":"Whole-exome sequencing analysis to identify novel potential pathogenetic NPC1 mutations in two Chinese families with Niemann-Pick disease type C.","abstract":"BACKGROUND: Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder, affecting the nervous system and the internal organs. It is characterized by the presence of foam cells in bone marrow, liver, and spleen biopsies. Although many mutations in NPC1 have been identified to be related to disease onset, the relationship between genotype and phenotype remains unclear. To elucidate the genetic heterogeneity of NPC, we described the clinical manifestations and possible genetic pathogenesis of two patients from unrelated families with NPC.\nMETHODS: DNA was extracted from the peripheral blood of the two patients and their families and from healthy individuals. Whole-exome sequencing followed by Sanger sequencing was performed to verify the mutations identified in their families.\nRESULTS: We identified four mutations in NPC1 in the two patients from different families: c.1290delC (p.F431Lfs*18)/c.2807G > A(p.G936D) in family A and c.3604_3605insA (p.I1202Nfs*56)/c.881 + 3A > G in family B from their parents. Bioinformatics analysis predicted these mutations to be deleterious, suggesting that mutations in exons are highly conservative. The patient in family A presented with a developmental delay that was different from the typical symptoms of developmental regression in family B.\nCONCLUSION: Our study identified three novel mutations and one known mutation in NPC1 and evaluated their pathogenicity, enriching the NPC1 mutation and phenotype spectrum and providing a new basis for the genetic and prenatal diagnosis of this disease.","variants":[{"Name":"NM_000271.5(NPC1):c.1290del (p.Phe431fs)","Chromosome":"18","Start":"23556279","Stop":"23556279","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":2999755,"rule_based_match":true,"evidence_text":"c.1290delC (p.F431Lfs*18)","llm_judgment":"PRESENT","evidence":"c.1290delC (p.F431Lfs*18)","abstract_start":900,"abstract_end":925}]}
{"pmid":"32817298","title":"Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome is caused by de novo mutations in","abstract":"BACKGROUND: We describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease.\nMETHODS: We performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins.\nRESULTS: We identified two different de novo mutations in <i>protein kinase D1</i> (<i>PRKD1,</i> NM_002742.2): c.1774G>C, p.(Gly592Arg) and c.1808G>A, p.(Arg603His), one in each patient. <i>PRKD1</i> (<i>PKD1</i>, HGNC:9407) encodes a kinase that is a member of the protein kinase D (PKD) family of serine/threonine protein kinases involved in diverse cellular processes such as cell differentiation and proliferation and cell migration as well as vesicle transport and angiogenesis. Functional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G>A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The mutation c.1774G>C, p.(Gly592Arg) in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.\nCONCLUSION: The present cases represent a syndrome, which associates symptoms from several different organ systems: skin, teeth, bones and heart, caused by heterozygous de novo mutations in <i>PRKD1</i> and expands the clinical spectrum of <i>PRKD1</i> mutations, which have hitherto been linked to syndromic congenital heart disease and limb abnormalities.","variants":[{"Name":"NM_002742.3(PRKD1):c.1808G>A (p.Arg603His)","Chromosome":"14","Start":"29624249","Stop":"29624249","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1985820,"rule_based_match":true,"evidence_text":"c.1808G>A, p.(Arg603His)","llm_judgment":"PRESENT","evidence":"c.1808G>A, p.(Arg603His)","abstract_start":448,"abstract_end":472}]}
{"pmid":"28363629","title":"Juvenile hemochromatosis and hepatocellular carcinoma in a patient with a novel mutation in the HJV gene.","abstract":"Juvenile hemochromatosis is a rare but the most severe form of hereditary hemochromatosis which develops due to mutations in the HJV or HAMP genes. It presents in the early adulthood mainly as cardiomyopathy, hypogonadism and liver fibrosis. Unlike hereditary hemochromatosis due to HFE mutation, hepatocellular carcinoma is not known to be associated with juvenile hemochromatosis. Here, we report a patient of Arab ancestry who presented with severe cardiomyopathy. Sequence analysis of the HJV gene followed by homozygosity mapping, identified a previously undescribed homozygous missense variation in exon 3 (c.497A > G; p.H166R) in both the proband and his clinically asymptomatic brother. The former, later developed hepatocellular carcinoma. To the best of our knowledge, neither the mutation identified in our patient, nor a case of juvenile hemochromatosis with hepatocellular carcinoma has been reported before.","variants":[{"Name":"NM_213653.4(HJV):c.497A>G (p.His166Arg)","Chromosome":"1","Start":"146019335","Stop":"146019335","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":535732,"rule_based_match":true,"evidence_text":"c.497A > G; p.H166R","llm_judgment":"PRESENT","evidence":"c.497A > G; p.H166R","abstract_start":613,"abstract_end":632}]}
{"pmid":"37646703","title":"Delineation of molecular characteristics of congenital myasthenic syndromes in Indian families and review of literature.","abstract":"Congenital myasthenic syndromes (CMS) are rare, heterogeneous, and often treatable genetic disorders depending on the underlying molecular defect. We performed a detailed clinical evaluation of seven patients from five unrelated families. Exome sequencing was performed on five index patients. Clinically significant variants were identified in four CMS disease-causing genes: COLQ (3/7), CHRNE (2/7), DOK7 (1/7), and RAPSN (1/7). We identified two novel variants, c.930_933delCATG in DOK7 and c.1016_1032 + 2dup in CHRNE . A common pathogenic variant, c.955-2A>C, has been identified in COLQ -related CMS patients. Homozygosity mapping of this COLQ variant in patients from two unrelated families revealed that it was located in a common homozygous region of 3.2 Mb on chromosome 3 and was likely to be inherited from a common ancestor. Patients with COLQ variants had generalized muscle weakness, those with DOK7 and RAPSN variants had limb-girdle weakness, and those with CHRNE variants had predominant ocular weakness. Patients with COLQ and DOK7 variants showed improvement with salbutamol and CHRNE with pyridostigmine therapy. This study expands the mutational spectrum and adds a small but significant cohort of CMS patients from India. We also reviewed the literature to identify genetic subtypes of CMS in India.","variants":[{"Name":"NM_005677.4(COLQ):c.955-2A>C","Chromosome":"3","Start":"15456581","Stop":"15456581","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2837115,"rule_based_match":true,"evidence_text":"c.955-2A>C","llm_judgment":"PRESENT","evidence":"c.955-2A>C","abstract_start":553,"abstract_end":563}]}
{"pmid":"30606667","title":"Generation of two iPSC lines derived from two unrelated patients with Gaucher disease.","abstract":"Gaucher disease is the most common autosomal recessive lysosomal storage disorder, caused by mutations in the β-glucocerebrosidase gene GBA. Here we describe generation of iPSC from skin-derived fibroblasts from two unrelated individuals with neuronopathic forms of Gaucher disease. The donor for line iPSC-GBA-1, a 21 month old girl, carried the recurring GBA mutation c.1448 T > C, p.Leu483Pro at homozygous state; fibroblasts for line iPS-GBA-2 were obtained from a 4 year old girl compound heterozygous for the GBA mutations c.667 T > C, p.Trp223Arg and c.1226A > G, p.Asn409Ser. iPSCs were developed using integration free episomal vectors (OCT4, KLF4; L-MYC, SOX2 (OSKM) and LIN28). Resource table.","variants":[{"Name":"NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)","Chromosome":"1","Start":"155235843","Stop":"155235843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":19329,"rule_based_match":true,"evidence_text":"c.1226A > G, p.Asn409Ser","llm_judgment":"PRESENT","evidence":"c.1226A > G, p.Asn409Ser","abstract_start":558,"abstract_end":582},{"Name":"NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)","Chromosome":"1","Start":"155235252","Stop":"155235252","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19327,"rule_based_match":true,"evidence_text":"c.1448 T > C, p.Leu483Pro","llm_judgment":"PRESENT","evidence":"c.1448 T > C, p.Leu483Pro","abstract_start":370,"abstract_end":395}]}
{"pmid":"33748949","title":"Third case of Bardet-Biedl syndrome caused by a biallelic variant predicted to affect splicing of IFT74.","abstract":"Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity and renal anomalies with autosomal recessive inheritance. We describe a 6-year-old male with early onset retinal dystrophy, postaxial polydactyly, truncal obesity and motor delays. Exome sequencing revealed a homozygous variant predicted to affect splicing of the IFT74 gene, c.1685-1G > T. This is the third patient with BBS due to variants predicting loss of function in IFT74. All three patients have had retinal dystrophy, polydactyly, obesity, developmental differences, and a notable lack of renal anomalies. We recommend that IFT74 is added to gene panels for the diagnosis of BBS.","variants":[{"Name":"NM_025103.4(IFT74):c.1685-1G>T","Chromosome":"9","Start":"27062617","Stop":"27062617","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":248809,"rule_based_match":true,"evidence_text":"c.1685-1G > T","llm_judgment":"PRESENT","evidence":"c.1685-1G > T","abstract_start":401,"abstract_end":414}]}
{"pmid":"16545979","title":"Clinical, cytogenetic and molecular characterization of a patient with combined succinic semialdehyde dehydrogenase deficiency and incomplete WAGR syndrome with obesity.","abstract":"We describe the clinical course, as well as cytogenetic and molecular findings, of a 3-year-old obese boy with psychomotor retardation who exhibited two rare conditions: succinic semialdehyde dehydrogenase deficiency (SSADH deficiency, MIM 271980), a disorder of gamma-aminobutyric acid metabolism with a heterogeneous clinical spectrum, and partial Wilms' tumor, aniridia, genital abnormalities, and mental retardation (WAGR) syndrome, an association between Wilms' tumor, aniridia, genitourinary malformations, and mental retardation due to mutations involving the short arm of chromosome 11, particularly deletions at the chromosomal region 11p13 (MIM 194072). Diagnosis of SSADH deficiency in our patient was established by demonstration of absent enzyme activity in isolated leucocytes, and was associated with a novel missense mutation (c.587G>A; p.Gly196Asp) in the SSADH coding sequence. We further confirmed an incomplete WAGR syndrome in this boy [karyotype 46, XY, del (11) (p13p14.2)] with a normal WT1 (Wilms' tumor) gene and an absence of pathology in the genitourinary tract, but with obesity (WAGR syndrome with obesity, WAGRO syndrome). The patient also exhibited distinctive cerebral anomalies such as increased signals of the globi pallidi, internal hydrocephalus and cerebellar vermian atrophy. However, treatment options for this patient are limited, including supportive treatment, physiotherapy, special educational training, and vigabatrin. In summary, we report the first patient with the exceptional rare findings of both SSADH deficiency and partial WAGR/WAGRO syndrome.","variants":[{"Name":"NM_001080.3(ALDH5A1):c.587G>A (p.Gly196Asp)","Chromosome":"6","Start":"24503411","Stop":"24503411","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1935219,"rule_based_match":true,"evidence_text":"c.587G>A; p.Gly196Asp","llm_judgment":"PRESENT","evidence":"c.587G>A; p.Gly196Asp","abstract_start":843,"abstract_end":864}]}
{"pmid":"30985648","title":"Clinical features and genetic analysis of childhood sitosterolemia: Two case reports and literature review.","abstract":"RATIONALE: Sitosterolemia is a rare autosomal recessive disorder of dyslipidemia due to mutations of genes ABCG5 and ABCG8, leading to highly elevated plasma levels of plant sterols and expanded body pools of cholesterol.\nPATIENT CONCERNS: We present a 9-year-old and a 7-year-old Chinese boy with hypercholesterolemia and xanthomas of sitosterolemia due to ABCG5 gene mutations. We also make a literature review of another 30 sitosterolemic children cases that have been reported with virulence ABCG5 gene mutations.\nDIAGNOSIS: We took peripheral blood samples from 2 patients and their parents to conduct genetic analysis by next-generation sequencing (NGS) technologies.\nINTERVENTIONS: The 2 patients received dietary modifications without pharmaceuticals treatment.\nOUTCOMES: A c.1166G>A (Arg389His) homozygosis mutation in exon 9 was observed in case 1, whereas a c.751C>T (Gln251*) homozygosis mutation in exon 6 was found in case 2. Literature review found another 30 pediatric cases with sitosterolemia due to ABCG5 gene mutation. The lipid profile was normalized and xanthomas got smaller with combined therapy of a combined low-cholesterol and low-phytosterols diet.\nLESSONS: These suggested that in patients (especially Asian patients) with multiple xanthomas, severe hypercholesterolemia, or elevated low-density lipoprotein-cholesterol, sitosterolemia should be considered in the differential diagnosis. Early diagnosis is important, and restriction of both cholesterol and phytosterols diet should suggested for these patients.","variants":[{"Name":"NM_022436.3(ABCG5):c.751C>T (p.Gln251Ter)","Chromosome":"2","Start":"43826405","Stop":"43826405","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1108866,"rule_based_match":true,"evidence_text":"c.751C>T (Gln251*)","llm_judgment":"PRESENT","evidence":"c.751C>T (Gln251*)","abstract_start":869,"abstract_end":887},{"Name":"NM_022436.3(ABCG5):c.1166G>A (p.Arg389His)","Chromosome":"2","Start":"43824071","Stop":"43824071","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20019,"rule_based_match":true,"evidence_text":"c.1166G>A (Arg389His)","llm_judgment":"PRESENT","evidence":"c.1166G>A (Arg389His)","abstract_start":782,"abstract_end":803}]}
{"pmid":"34888854","title":"Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3 splicing variants.","abstract":"Alport syndrome is a genetic disorder affecting the basement membranes of the kidney, ear and eye, and represents a leading cause of monogenic kidney disease. Alport syndrome is genetically heterogeneous with three key genes involved (COL4A3-5) and several transmission patterns, including monogenic X-linked, autosomal recessive/dominant and digenic. We report a consanguineous family where 13 individuals presented variable features of Alport syndrome including kidney failure on two generations and male-to-male transmission, suggesting autosomal dominant inheritance. COL4A3-5 gene panel analysis surprisingly reveals two distinct, confirmed splice-altering variants in COL4A3 (NM_000091.4: c.1150+5G>A and c.4028-3C>T) present in homozygous or compound heterozygous state in individuals with kidney failure. This adds a further mode of transmission for Alport syndrome where, in a consanguineous family, the independent segregation of two variants at the same locus may create a pseudodominant transmission pattern. These findings highlight the importance of a molecular diagnosis in Alport syndrome for genetic risk counselling, given the variable modes of inheritance, but also the pitfalls of assuming identity by descent in consanguineous families.","variants":[{"Name":"NM_000091.5(COL4A3):c.1150+5G>A","Chromosome":"2","Start":"227261122","Stop":"227261122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3173390,"rule_based_match":true,"evidence_text":"NM_000091.4: c.1150+5G>A","llm_judgment":"PRESENT","evidence":"NM_000091.4: c.1150+5G>A","abstract_start":682,"abstract_end":706}]}
{"pmid":"23479190","title":"Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome.","abstract":"Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1, encoding a receptor for the secreted protein, sonic hedgehog. Recently, a Chinese family with NBCCS carrying a missense mutation in PTCH2, a close homolog of PTCH1, was reported. However, the pathological significance of missense mutations should be discussed cautiously. Here, we report a 13-year-old girl diagnosed with NBCCS based on multiple keratocystic odontogenic tumors and rib anomalies carrying a frameshift mutation in the PTCH2 gene (c.1172_1173delCT). Considering the deleterious nature of the frameshift mutation, our study further confirmed a causative role for the PTCH2 mutation in NBCCS. The absence of typical phenotypes in this case such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism and coarse face, together with previously reported cases, suggested that individuals with NBCCS carrying a PTCH2 mutation may have a milder phenotype than those with a PTCH1 mutation.","variants":[{"Name":"NM_003738.5(PTCH2):c.1172_1173del (p.Phe390_Ser391insTer)","Chromosome":"1","Start":"44829444","Stop":"44829445","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":21184,"rule_based_match":true,"evidence_text":"c.1172_1173delCT","llm_judgment":"PRESENT","evidence":"c.1172_1173delCT","abstract_start":624,"abstract_end":640}]}
{"pmid":"25846194","title":"Clinical, structural, biochemical and X-ray crystallographic correlates of pathogenicity for variants in the C-propeptide region of the COL3A1 gene.","abstract":"Vascular Ehlers-Danlos syndrome (vEDS) is a heritable disorder of connective tissue caused by pathological variants in the COL3A1 gene, which encodes the α1 chain of type III collagen. Type III collagen is a major component of skin, arterial walls, and the gastrointestinal tract. Collagen III protein deficiency manifests as an increased risk of rupture, perforation, and dissection of these structures. The most disruptive gene variants affect the collagen helix via glycine substitutions or splice donor site mutations. The C-propeptide region of COL3A1 includes exons 49-52 and has a crucial role in initiating the C-terminal assembly of procollagen monomers in the early stages of collagen biosynthesis. Nineteen COL3A1 variants have previously been reported in these exons, of which four were associated with a severe vEDS phenotype. We identified two novel C-propeptide missense variants; p.Pro1440Leu, p.Arg1432Leu, and a non-stop mutation, c.4400A > T, p. (*1467Leuext*45). These variants produce variable phenotypes ranging from obvious acrogeria to classical or hypermobile EDS. A previously reported variant p.Lys1313Arg is of unknown clinical significance but likely benign, based on this study. Assigning disease pathogenicity remains complex, clinical phenotyping and crystal structure evidence being crucial. We briefly compare reported phenotypes for patients with missense variants in the C-propeptide domain for other human collagen disorders including COL1A1 and COL1A2 (osteogenesis imperfecta).","variants":[{"Name":"NM_000090.4(COL3A1):c.4295G>T (p.Arg1432Leu)","Chromosome":"2","Start":"189011668","Stop":"189011668","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":392354,"rule_based_match":false,"evidence_text":"c.4295G>T (p.Arg1432Leu)","llm_judgment":"PRESENT","evidence":"p.Arg1432Leu","abstract_start":910,"abstract_end":922},{"Name":"NM_000090.4(COL3A1):c.4319C>T (p.Pro1440Leu)","Chromosome":"2","Start":"189011692","Stop":"189011692","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":517738,"rule_based_match":false,"evidence_text":"c.4319C>T (p.Pro1440Leu)","llm_judgment":"PRESENT","evidence":"p.Pro1440Leu","abstract_start":896,"abstract_end":908}]}
{"pmid":"24372583","title":"Mutation spectrum and prevalence of BRCA1 and BRCA2 genes in patients with familial and early-onset breast/ovarian cancer from Tunisia.","abstract":"The contribution of BRCA1/BRCA2 mutations to hereditary breast cancer in the Tunisian population has not been accurately estimated. The purpose of our study was to estimate the incidence and spectrum of pathogenic mutations in BRCA1/2 genes in early onset and familial breast/ovarian cancer among Tunisian women. To identify predictive factors for BRCA1/2 mutations, we screened the entire coding sequences and intron/exon boundaries of BRCA1/BRCA2 genes in 48 patients by direct sequencing. Twelve pathogenic mutations were detected (25%); three in BRCA1 (c.211dupA in four families, c.5266dupC in three families and c.1504_1508delTTAAA in one family) and two novel mutations in BRCA2 (c.1313dupT in two families and c.7654dupT in two families). We also identified 23 different polymorphisms and unclassified variants. These results indicate that our population has a spectrum of recurrent BRCA mutations.","variants":[{"Name":"NM_007294.4(BRCA1):c.1504_1508del (p.Leu502fs)","Chromosome":"17","Start":"43094023","Stop":"43094027","ReferenceAlleleVCF":"CTTTAA","AlternateAlleleVCF":"C","allel_id":45973,"rule_based_match":true,"evidence_text":"c.1504_1508delTTAAA","llm_judgment":"PRESENT","evidence":"c.1504_1508delTTAAA","abstract_start":618,"abstract_end":637}]}
{"pmid":"22488832","title":"Transmission of the rare HRAS mutation (c. 173C > T; p.T58I) further illustrates its attenuated phenotype.","abstract":"Costello syndrome was delineated based on its distinctive phenotype including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. With exception of two instances of parental mosaicism, one presumed gonadal and the other proven somatic mosaicism for the p.G12S change, all published cases resulted from de novo mutations, typically arising in the paternal germline. More than 90% of these mutations affect the glycine residues in position 12 or 13, and result in a gain-of-function of the altered protein. A rare heterozygous HRAS alteration (c.173C > T; p.T58I) associated with an attenuated phenotype was previously reported in one patient. We identified two additional individuals with this mutation, father and son. Further studies supported origin of the alteration in the grand-paternal germline. Transmission of the mutation underscores its attenuated phenotype compatible with reproduction. We reviewed the phenotype in the newly identified individuals (Patient 1, 2) and include updated information on the first previously reported individual with HRAS p.T58I (Patient 3). Macrocephaly was present in all three. Cardiac findings included hypertrophic cardiomyopathy with double-chambered right ventricle; or mitral valve prolapse in one patient each. While subtle neurologic abnormalities or developmental delay were present in all, only one showed significant cognitive and functional impairment. None developed papillomata or a malignant tumor. Genetic counseling for Costello syndrome needs to take into consideration the particular HRAS mutation.","variants":[{"Name":"NM_005343.4(HRAS):c.173C>T (p.Thr58Ile)","Chromosome":"11","Start":"533883","Stop":"533883","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27649,"rule_based_match":true,"evidence_text":"c.173C > T; p.T58I","llm_judgment":"PRESENT","evidence":"c.173C > T; p.T58I","abstract_start":798,"abstract_end":816}]}
{"pmid":"22341299","title":"Clinical assessment of HNF1A and GCK variants and identification of a novel mutation causing MODY2.","abstract":"A child with impaired fasting glucose was found to be heterozygous for a novel variant at c.659G>A in GCK and a variant at c.1663C>T in HNF1A. Structural modeling and clinical correlation suggests that the GCK variant causes monogenic diabetes while the variant in HNF1A is unlikely to be pathogenic.","variants":[{"Name":"NM_000162.5(GCK):c.659G>A (p.Cys220Tyr)","Chromosome":"7","Start":"44149780","Stop":"44149780","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":44904,"rule_based_match":true,"evidence_text":"c.659G>A","llm_judgment":"PRESENT","evidence":"c.659G>A","abstract_start":90,"abstract_end":98},{"Name":"NM_000545.8(HNF1A):c.1663C>T (p.Leu555Phe)","Chromosome":"12","Start":"120999522","Stop":"120999522","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45469,"rule_based_match":true,"evidence_text":"c.1663C>T","llm_judgment":"PRESENT","evidence":"c.1663C>T","abstract_start":123,"abstract_end":132}]}
{"pmid":"26200108","title":"Influence of the PNPLA3 rs738409 Polymorphism on Non-Alcoholic Fatty Liver Disease and Renal Function among Normal Weight Subjects.","abstract":"In normal weight subjects (body mass index < 25 kg/m2), non-alcoholic fatty liver disease (NAFLD) is likely to coexist with metabolic diseases. The patatin-like phospholipase 3 (PNPLA3) polymorphism rs738409 (c.444C>G) is associated with the risk of NAFLD and/or renal dysfunction; however, the influence of the weight status on the associations remains unknown. We aimed to clarify the associations of the PNPLA3 polymorphism with the risk of NAFLD and/or renal dysfunction, while also paying careful attention to the weight status of the subjects. Cross-sectional and retrospective longitudinal studies with 5.5 ± 1.1 years of follow-up were conducted in 740 and 393 Japanese participants (61.2 ± 10.5 and 67.5 ± 6.0 years), respectively, during a health screening program. Among 591 subjects who did not have a habitual alcohol intake and/or hepatitis B or C virus infections, the PNPLA3 G/G genotype was associated with the risk for NAFLD in normal weight subjects [odds ratio (95% CI): 3.06 (1.11-8.43), P < 0.05]. Among all subjects, carriers of the PNPLA3 G/G genotype with a normal weight had a lower eGFR than those of the C/C genotype [partial regression coefficient (SE): -3.26 (1.48), P < 0.05]. These associations were replicated in the longitudinal analyses. Among the overweight subjects, none of the genotypes were significantly associated in the cross-sectional and longitudinal analyses; however, the power of the analyses was small, especially in the analyses among overweight subjects. The findings of this study suggest that carriers of the PNPLA3 G/G genotype with a normal weight status should nevertheless be carefully monitored for the presence of NAFLD and/or renal dysfunction.","variants":[{"Name":"NM_025225.3(PNPLA3):c.444C>G (p.Ile148Met)","Chromosome":"22","Start":"43928847","Stop":"43928847","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":352627,"rule_based_match":true,"evidence_text":"c.444C>G","llm_judgment":"PRESENT","evidence":"c.444C>G","abstract_start":209,"abstract_end":217}]}
{"pmid":"30451293","title":"POT1 germline mutations but not TERT promoter mutations are implicated in melanoma susceptibility in a large cohort of Spanish melanoma families.","abstract":"BACKGROUND: Germline mutations in telomere-related genes such as POT1 and TERT predispose individuals to familial melanoma.\nOBJECTIVES: To evaluate the prevalence of germline mutations in POT1 and TERT in a large cohort of Spanish melanoma-prone families (at least two affected first- or second-degree relatives).\nMETHODS: Overall, 228 CDKN2A wild-type melanoma-prone families were included in the study. Screening of POT1 was performed in one affected person from each family and TERT was sequenced in one affected patient from 202 families (26 families were excluded owing to DNA exhaustion/degradation). TERT promoter sequencing was extended to an additional 30 families with CDKN2A mutation and 70 patients with sporadic multiple primary melanoma (MPM) with a family history of other cancers.\nRESULTS: We identified four families with potentially pathogenic POT1 germline mutations: a missense variant c.233T>C (p.Ile78Thr); a nonsense variant c.1030G>T (p.Glu344*); and two other variants, c.255G>A (r.125_255del) and c.1792G>A (r.1791_1792insAGTA, p.Asp598Serfs*22), which we confirmed disrupted POT1 mRNA splicing. A TERT promoter variant of unknown significance (c.-125C>A) was detected in a patient with MPM, but no germline mutations were detected in TERT promoter in cases of familial melanoma.\nCONCLUSIONS: Overall, 1·7% of our CDKN2A/CDK4-wild type Spanish melanoma-prone families carry probably damaging mutations in POT1. The frequency of TERT promoter germline mutations in families with melanoma in our population is extremely rare.","variants":[{"Name":"NM_015450.3(POT1):c.233T>C (p.Ile78Thr)","Chromosome":"7","Start":"124870933","Stop":"124870933","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":456457,"rule_based_match":true,"evidence_text":"c.233T>C (p.Ile78Thr)","llm_judgment":"PRESENT","evidence":"c.233T>C (p.Ile78Thr)","abstract_start":906,"abstract_end":927},{"Name":"NM_015450.3(POT1):c.1030G>T (p.Glu344Ter)","Chromosome":"7","Start":"124842940","Stop":"124842940","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1027681,"rule_based_match":true,"evidence_text":"c.1030G>T (p.Glu344*)","llm_judgment":"PRESENT","evidence":"c.1030G>T (p.Glu344*)","abstract_start":948,"abstract_end":969}]}
{"pmid":"33693786","title":"An Asian-specific MPL genetic variant alters JAK-STAT signaling and influences platelet count in the population.","abstract":"Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (β = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.","variants":[{"Name":"NM_005373.3(MPL):c.793C>T (p.Leu265Phe)","Chromosome":"1","Start":"43340066","Stop":"43340066","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":138571,"rule_based_match":true,"evidence_text":"c.793C > T, p.Leu265Phe (L265F)","llm_judgment":"PRESENT","evidence":"c.793C > T, p.Leu265Phe (L265F)","abstract_start":912,"abstract_end":943}]}
{"pmid":"19270816","title":"Clinical features and mutations in the ENG, ACVRL1, and SMAD4 genes in Korean patients with hereditary hemorrhagic telangiectasia.","abstract":"Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that is characterized by abnormal communication between the arteries and veins in the skin, mucosa, and various organs. HHT has been reported to show significant phenotypic variability and genetic heterogeneity with wide ethnic and geographic variations. Although mutations in the endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes have been known to cause HHT for more than 10 yr, little is known about the clinical features or genetic background of Korean patients with HHT. In addition, mutations in mothers against decapentaplegic homolog 4 (SMAD4) are also seen in patients with the combined syndrome of juvenile polyposis and HHT. This study examined five Korean patients with the typical manifestations of HHT such as frequent epistaxis and pulmonary arteriovenous malformations. Direct sequencing of the ENG and ACVRL1 genes revealed one known mutation, ENG c.277C>T, in one patient and two novel mutations, ENG c.992-1G>C and ACVRL1 c.81dupT in two patients, respectively. The remaining two patients with negative results were screened for SMAD4 mutations as well as gross deletions of ENG and ACVRL1 using multiple ligation-dependent probe amplification, but none was detected. Despite the small number of patients investigated, we firstly report Korean patients with genetically confirmed HHT, and show the genetic and allelic heterogeneity underlying HHT.","variants":[{"Name":"NM_001114753.3(ENG):c.277C>T (p.Arg93Ter)","Chromosome":"9","Start":"127829770","Stop":"127829770","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":259914,"rule_based_match":true,"evidence_text":"ENG c.277C>T","llm_judgment":"PRESENT","evidence":"ENG c.277C>T","abstract_start":948,"abstract_end":960}]}
{"pmid":"28402684","title":"A Nonsense ALMS1 Mutation Underlies Alström Syndrome in an Extended Mennonite Kindred Settled in North Mexico.","abstract":"AIM: Alström syndrome (AS) is a rare autosomal recessive multisystem disease caused by biallelic mutations in ALMS1, a gene encoding a widely expressed centrosomal/basal body protein. Although more than 200 pathogenic mutations in ALMS1 have been identified to date in AS patients from various ethnic populations, there are very few reports of ALMS1 founder mutations in isolated populations. Our aim was to describe the molecular characterization of a cohort of AS patients from an extended inbred Mennonite kindred settled in Mexico.\nMETHODS: Genetic study included polymerase chain reaction amplification and direct nucleotide sequencing of the entire ALMS1 gene in DNA from seven related AS patients.\nRESULTS: A homozygous single-nucleotide c.10480C>T substitution in exon 16, predicting a p.Q3494* nonsense mutation, was identified in all affected subjects.\nCONCLUSIONS: To our knowledge, this is the first demonstration of a high prevalence of AS in Mennonites, a population group maintaining high levels of consanguineous marriage in their communities. Our findings provide an example of genetic isolation and consanguinity causing a high prevalence of AS and offer the opportunity for early clinical interventions and for genetic counseling of at-risk couples in this community.","variants":[{"Name":"NM_001378454.1(ALMS1):c.10480C>T (p.Gln3494Ter)","Chromosome":"2","Start":"73572357","Stop":"73572357","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":207024,"rule_based_match":true,"evidence_text":"c.10480C>T","llm_judgment":"PRESENT","evidence":"c.10480C>T","abstract_start":745,"abstract_end":755}]}
{"pmid":"35253374","title":"A de novo heterozygous HOXA11 variant in a patient with mesomelic dysplasia with urogenital abnormalities.","abstract":"Mesomelic dysplasias are a genetically and clinically heterogeneous group of diseases with more than 10 types defined. This article presents an 18-year-old female patient with normal intelligence and a multisystem phenotype including disproportionate short stature, scoliosis, mesomelic limb shortening, radial bowing, short fourth to fifth metacarpals and metatarsals, fusions in the carpal/tarsal bones, operated pes equinovarus, primary amenorrhea, uterine hypoplasia, vesicoureteral reflux, and chronic kidney disease. Whole-exome sequencing revealed a de novo heterozygous c.881T>G (p.Met294Arg) variant in HOXA11 (NM_005523.6) gene. The variant was located in the homeodomain of HOXA11 and predicted to alter DNA-binding ability of the protein. In silico analyses indicated that the variant could promote the alterations in the protein-protein interaction. The possible functional effect of the variant was supposed as dominant-negative. Hoxa11-mutant mice have been reported to exhibit homeotic transformations in the thoracic and sacral vertebrae, zeugopodal phenotype in forelimb and hindlimb, and urogenital abnormalities. Although mice models were reported as mesomelic dysplasia and urogenital abnormalities (MDUGA), this phenotype has not yet been reported in humans. This was the first case with MDUGA putatively related to a de novo variant in HOXA11.","variants":[{"Name":"NM_005523.6(HOXA11):c.881T>G (p.Met294Arg)","Chromosome":"7","Start":"27182857","Stop":"27182857","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2192845,"rule_based_match":true,"evidence_text":"c.881T>G (p.Met294Arg)","llm_judgment":"PRESENT","evidence":"c.881T>G (p.Met294Arg)","abstract_start":578,"abstract_end":600}]}
{"pmid":"16146704","title":"Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency.","abstract":"Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The urine organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/- hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C>A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid. This C12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic acids by mitochondria after their initial shortening by beta-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of urine organic acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorder.","variants":[{"Name":"NM_001876.4(CPT1A):c.1737C>A (p.Tyr579Ter)","Chromosome":"11","Start":"68773268","Stop":"68773268","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":76557,"rule_based_match":true,"evidence_text":"c.1737C>A (Y579X)","llm_judgment":"PRESENT","evidence":"c.1737C>A (Y579X)","abstract_start":532,"abstract_end":549}]}
{"pmid":"28166740","title":"Delineation of cystinuria in Saudi Arabia: A case series.","abstract":"BACKGROUND: Cystinuria is an inherited metabolic disease that is caused by defects in two genes, SLC3A1 and SLC7A9, which result in a renal reabsorptive defect of cystine and other dibasic amino acids, including ornithine, arginine, and lysine. Patients usually present with recurrent renal calculi and may develop renal impairment. Medical management includes high fluid intake and chelating agents. To the best of our knowledge, this is the first study describing cystinuria in Saudi Arabia.\nMETHODS: A retrospective chart review for cystinuria patients from the genetic and nephrology divisions between 2010 to 2015. All patients were investigated, diagnosed and treated at King Abdulaziz Medical City in Saudi Arabia.\nRESULTS: Eight patients were identified from five unrelated families. The age of onset ranged from birth to 14 years. The female to male ratio was 1.7:1. Two new variants in the SLC3A1 and SLC9A7 genes were discovered. All of the detected mutations were missense variants in three different exons, such as c.1711 T > A (p.Cys571Ser) (exon 10), c.1166C > T p.Thr389Met (exon 11) and c.1400 T > A p.Met467Lys (exon 8). Additionally, 37.5% of our patients developed arterial hypertension and 25% had urinary tract infection, but none had renal impairment. No significant clinical differences were detected in this study between type A (SLC3A1 variants) and type B cystinuria (SLC7A9 variant). Two cases were diagnosed based on clinical information, biochemical testing and a positive family history as all of the molecular testing for cystinuria was negative.\nCONCLUSION: Cystinuria has wide genetic heterogeneity with a poor genotype/phenotype correlation. Negative molecular investigations should not rule out the disease if clinical and biochemical investigations support the diagnosis. A larger data registry is essential to better describe the cystinuria genotype/phenotype in Saudi Arabia.","variants":[{"Name":"NM_000341.4(SLC3A1):c.1400T>A (p.Met467Lys)","Chromosome":"2","Start":"44312653","Stop":"44312653","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":33155,"rule_based_match":true,"evidence_text":"c.1400 T>A p.Met467Lys","llm_judgment":"PRESENT","evidence":"c.1400 T > A p.Met467Lys","abstract_start":1104,"abstract_end":1128}]}
{"pmid":"29700987","title":"Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family.","abstract":"BACKGROUND: Haploinsufficiency of TAB2 is known to cause congenital heart defects and cardiomyopathy due to its important roles in cardiovascular tissue, both during development and through adult life. We report a sibling pair displaying adult-onset cardiomyopathy, hypermobility, and mild myopia. Our proband, a 39-year-old male, presents only with the above symptoms, while his 36-year-old sister was also notable for a ventricular septal defect in her infancy.\nMETHODS: Whole-exome sequencing was utilized to identify the molecular basis of the phenotype found in two siblings. A molecular modeling technique that takes advantage of conformational sampling advances (Maxwell's demon molecular dynamics and Monte Carlo) were used to make a model of the mutant variant for comparative analytics to the wild-type.\nRESULTS: Exome sequencing revealed a novel, heterogeneous pathogenic variant in TAB2, c.1039 C>T (p.R347X), that was present in both individuals. This pathogenic variant removes just over half the residues from the TAB2 protein and severely impacts its functional ability, which we describe in detail.\nCONCLUSIONS: Analysis of the proband's family showed a history of cardiomyopathy, but no congenital heart defects or connective tissue disease. We highlight the heterogeneity in phenotype of TAB2 pathogenic variants and confirm the pathogenicity of this new variant through neoteric protein modeling techniques.","variants":[{"Name":"NM_001292034.3(TAB2):c.1039C>T (p.Arg347Ter)","Chromosome":"6","Start":"149378954","Stop":"149378954","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359762,"rule_based_match":true,"evidence_text":"c.1039 C>T (p.R347X)","llm_judgment":"PRESENT","evidence":"c.1039 C>T (p.R347X)","abstract_start":900,"abstract_end":920}]}
{"pmid":"29967133","title":"Novel pathogenic","abstract":"BACKGROUND: Missense variants in <i>SMAD2</i>, encoding a key transcriptional regulator of transforming growth factor beta signalling, were recently reported to cause arterial aneurysmal disease.\nOBJECTIVES: The aims of the study were to identify the genetic disease cause in families with aortic/arterial aneurysmal disease and to further define <i>SMAD2</i> genotype-phenotype correlations.\nMETHODS AND RESULTS: Using gene panel sequencing, we identified a <i>SMAD2</i> nonsense variant and four <i>SMAD2</i> missense variants, all affecting highly conserved amino acids in the MH2 domain. The premature stop codon (c.612dup; p.(Asn205*)) was identified in a marfanoid patient with aortic root dilatation and in his affected father. A p.(Asn318Lys) missense variant was found in a Marfan syndrome (MFS)-like case who presented with aortic root aneurysm and in her affected daughter with marfanoid features and mild aortic dilatation. In a man clinically diagnosed with Loeys-Dietz syndrome (LDS) that presents with aortic root dilatation and marked tortuosity of the neck vessels, another missense variant, p.(Ser397Tyr), was identified. This variant was also found in his affected daughter with hypertelorism and arterial tortuosity, as well as his affected mother. The third missense variant, p.(Asn361Thr), was discovered in a man presenting with coronary artery dissection. Variant genotyping in three unaffected family members confirmed its absence. The last missense variant, p.(Ser467Leu), was identified in a man with significant cardiovascular and connective tissue involvement.\nCONCLUSION: Taken together, our data suggest that heterozygous loss-of-function <i>SMAD2</i> variants can cause a wide spectrum of autosomal dominant aortic and arterial aneurysmal disease, combined with connective tissue findings reminiscent of MFS and LDS.","variants":[{"Name":"NM_005901.6(SMAD2):c.612dup (p.Asn205Ter)","Chromosome":"18","Start":"47868365","Stop":"47868366","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":1318142,"rule_based_match":true,"evidence_text":"c.612dup; p.(Asn205*)","llm_judgment":"PRESENT","evidence":"c.612dup; p.(Asn205*)","abstract_start":618,"abstract_end":639}]}
{"pmid":"31281085","title":"Whole exome sequencing identifies novel variant underlying hereditary spastic paraplegia in consanguineous Pakistani families.","abstract":"Hereditary Spastic paraplegias (HSPs) are heterogeneous group of degenerative disorders characterized by progressive weakness and spasticity of the lower limbs, combined with additional neurological features. This study aimed to identify causative gene variants in two nonrelated consanguineous Pakistani families segregating HSP. Whole exome sequencing (WES) was performed on a total of five individuals from two families including four affected and one phenotypically normal individual. The variants were validated by Sanger sequencing and segregation analysis. In family A, a novel homozygous variant c.604G > A (p.Glu202Lys) was identified in the CYP2U1 gene with clinical symptoms of SPG56 in 3 siblings. Whereas, a previously reported variant c.5769delT (p.Ser1923Argfs*28) in the SPG11 gene was identified in family B manifesting clinical features of SPG11 in 3 affected individuals. Our combined findings add to the clinical and genetic variability associated with CYP2U1 and SPG11 variants highlighting the complexity of HSPs. These findings further emphasize the usefulness of WES as a powerful diagnostic tool.","variants":[{"Name":"NM_025137.4(SPG11):c.5769del (p.Ser1923fs)","Chromosome":"15","Start":"44583911","Stop":"44583911","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"T","allel_id":49751,"rule_based_match":true,"evidence_text":"c.5769delT (p.Ser1923Argfs*28)","llm_judgment":"PRESENT","evidence":"c.5769delT (p.Ser1923Argfs*28)","abstract_start":749,"abstract_end":779}]}
{"pmid":"20399395","title":"Novel mutation in SLC6A19 causing late-onset seizures in Hartnup disorder.","abstract":"Hartnup disorder is caused by an inborn error of neutral amino acid transport in the kidneys and intestines. It is characterized by pellagra-like rash, ataxia, and psychotic behavior. Elevated urinary neutral amino acids are the first indicator of the disorder. SLC6A19 was identified as the causative gene in autosomal-recessive Hartnup disorder, which encodes the amino acid transporter B(0)AT1, mediating neutral amino acid transport from the luminal compartment to the intracellular space. Here, we report on a Korean boy aged 8 years and 5 months with Hartnup disorder, as confirmed by SLC6A19 gene analysis. He manifested seizures, attention-deficit hyperactivity disorder, and mental retardation without pellagra or ataxia. Multiple neutral amino acids were increased in his urine, and genetic analysis of SLC6A19 revealed compound heterozygous mutations, c.908C>T (p.Ser303Leu) and c.1787_1788insG (p.Thr596fsX73), both of which are novel. A novel SLC6A19 gene mutation was associated with late-onset seizures in a Korean patient with Hartnup disorder.","variants":[{"Name":"NM_001003841.3(SLC6A19):c.908C>T (p.Ser303Leu)","Chromosome":"5","Start":"1216578","Stop":"1216578","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":904267,"rule_based_match":true,"evidence_text":"c.908C>T (p.Ser303Leu)","llm_judgment":"PRESENT","evidence":"c.908C>T (p.Ser303Leu)","abstract_start":863,"abstract_end":885}]}
{"pmid":"37958491","title":"The","abstract":"Approximately 30-50% of hereditary breast and ovarian cancer (HBOC) is due to the presence of germline pathogenic variants in the <i>BRCA1</i> (OMIM 113705) and <i>BRCA2</i> (OMIM 600185) onco-suppressor genes, which are involved in DNA damage response. Women who carry pathogenic <i>BRCA1</i> variants are particularly likely to develop breast cancer (BC) and ovarian cancer (OC), with a 45-79 percent and 39-48 percent chance, respectively. The <i>BRCA1</i> c.4096+1G>A variant has been frequently ascertained in Tuscany, Italy, and it has also been detected in other Italian regions and other countries. Its pathogenetic status has been repeatedly changed from a variant of uncertain significance, to pathogenic, to likely pathogenic. In our study, 48 subjects (38 of whom are carriers) from 27 families were genotyped with the Illumina OncoArray Infinium platform (533,531 SNPs); a 20 Mb region (24.6 cM) around <i>BRCA1</i>, including 4130 SNPs (21 inside <i>BRCA1</i>) was selected for haplotype analysis. We used a phylogenetic method to estimate the time to the most recent common ancestor (MRCA) of <i>BRCA1</i> c.4096+1G>A founder pathogenic variant. This analysis suggests that the MRCA lived about 155 generations ago-around 3000 years ago.","variants":[{"Name":"NM_007294.4(BRCA1):c.4096+1G>A","Chromosome":"17","Start":"43091434","Stop":"43091434","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46121,"rule_based_match":true,"evidence_text":"BRCA1 c.4096+1G>A","llm_judgment":"PRESENT","evidence":"BRCA1</i> c.4096+1G>A","abstract_start":450,"abstract_end":471}]}
{"pmid":"23512386","title":"Novel mutations in DAX1 of X-linked adrenal hypoplasia congenita over several generations in one family.","abstract":"OBJECTIVE: X-linked adrenal hypoplasia congenital (AHC) is a rare disorder caused by mutations in DAX1 gene. We report a case of X-linked AHC in a large family to analyze the pathogenesis of this rare disease and to add to our clinical knowledge of it.\nMETHODS: We describe 3-year-old boy's clinical features and laboratory test results, as well as the patient's nuclear family members' clinical symptoms, especially those with features of adrenal insufficiency. Genomic deoxyribonucleic acid (DNA) was extracted from the patient's and the family members' peripheral blood leukocytes, and the coding region and promoter region of DAX1 were directly sequenced.\nRESULTS: A 3-year-old boy who was diagnosed with X-linked AHC presented with atypical symptoms, and his laboratory test results revealed elevated serum adrenocorticotropic hormone levels (ACTH) and decreased serum cortisol levels. Three novel mutations were detected in the DAX1 coding sequence in this family: a missense mutation (c.376G>A, p.Val126Met), a synonymous mutation (c.498G>A, p.Arg166Arg), and a nonsense mutation (c.1225C>T, p. Gln409X).\nCONCLUSIONS: This report describes the familial transmission of AHC over several generations and further expands the number of DAX1 mutations reported in the literature. Early diagnosis and prompt treatment of X-linked AHC are important and may provide a good prognosis.","variants":[{"Name":"NM_000475.5(NR0B1):c.376G>A (p.Val126Met)","Chromosome":"X","Start":"30308988","Stop":"30308988","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227422,"rule_based_match":true,"evidence_text":"c.376G>A (p.Val126Met)","llm_judgment":"PRESENT","evidence":"p.Val126Met","abstract_start":1002,"abstract_end":1013}]}
{"pmid":"36249513","title":"Determination of Cystic Fibrosis Mutation Frequency in Preterm and Term Neonates with Respiratory Tract Problems.","abstract":"Cystic fibrosis (CF) is an autosomal recessive disease. The genetic transition occurs with CF transmembrane conductance regulator (<i>CFTR</i>) gene mutation. We aimed to determine the frequency of CF mutations and also new mutations in the <i>CFTR</i> gene in neonates with respiratory distress. Newborn babies hospitalized due to respiratory distress were included in the patient group. The control group consisted of infants who had no respiratory distress. The <i>CFTR</i> genes of both groups were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. A total of 40 patients (20 in the patient group and 20 in the control group) were evaluated. The <i>CFTR</i> gene analysis was normal in 16 neonates in the patient group, whereas in others: A46D (c.137C>A) (<i>n</i> = 1), D1312G (c.3935A>G) (<i>n</i> = 1), R117H (c.350G>A) (<i>n</i> = 1), S1426P (c.4276T>C) (<i>n</i> = 1) heterozygotes were detected; <i>CFTR</i> gene analysis was normal at 14 neonates in the control group, whereas in others: E1228G (c.3683A>G) (<i>n</i> = 1), E217G (c.650A>G) (<i>n</i> = 1), E632TfsX9 (c1894_1895delAG) (<i>n</i> = 1), I807M (c.2421 A>G) (<i>n</i> = 2), S573F (c.1718C>T) (<i>n</i> = 1) heterozygotes were detected. There was no significant difference in the patient and control groups' <i>CFTR</i> gene analysis (<i>p</i> = 0.340). This study demonstrates the importance of <i>CFTR</i> gene analysis in asymptomatic newborn infants for follow-up and early diagnosis of <i>CFTR</i>-related disorders. In this study, a c.1894_1895delAG (E632TfsX9) heterozygous mutation detected in the <i>CFTR</i> gene in an asymptomatic newborn infant, was first encountered in the literature.","variants":[{"Name":"NM_000492.4(CFTR):c.1718C>T (p.Ser573Phe)","Chromosome":"7","Start":"117590391","Stop":"117590391","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":493936,"rule_based_match":true,"evidence_text":"c.1718C>T","llm_judgment":"PRESENT","evidence":"c.1718C>T","abstract_start":1211,"abstract_end":1220},{"Name":"NM_000492.4(CFTR):c.3935A>G (p.Asp1312Gly)","Chromosome":"7","Start":"117652903","Stop":"117652903","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":68524,"rule_based_match":true,"evidence_text":"c.3935A>G","llm_judgment":"PRESENT","evidence":"c.3935A>G","abstract_start":841,"abstract_end":850},{"Name":"NM_000492.4(CFTR):c.4276T>C (p.Ser1426Pro)","Chromosome":"7","Start":"117666941","Stop":"117666941","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":68604,"rule_based_match":true,"evidence_text":"S1426P (c.4276T>C)","llm_judgment":"PRESENT","evidence":"S1426P (c.4276T>C)","abstract_start":901,"abstract_end":919}]}
{"pmid":"21520339","title":"Identification and functional analyses of CBS alleles in Spanish and Argentinian homocystinuric patients.","abstract":"Homocystinuria due to CBS deficiency is a rare autosomal recessive disorder characterized by elevated plasma levels of homocysteine (Hcy) and methionine (Met). Here we present the analysis of 22 unrelated patients of different geographical origins, mainly Spanish and Argentinian. Twenty-two different mutations were found, 10 of which were novel. Five new mutations were missense and five were deletions of different sizes, including a 794-bp deletion (c.532-37_736 + 438del794) detected by Southern blot analysis. To assess the pathogenicity of these mutations, seven were expressed heterologously in Escherichia coli and their enzyme activities were assayed in vitro, in the absence and presence of the CBS activators PLP and SAM. The presence of the mutant proteins was confirmed by Western blotting. Mutations p.M173del, p.I278S, p.D281N, and p.D321V showed null activity in all conditions tested, whereas mutations p.49L, p.P200L and p.A446S retained different degrees of activity and response to stimulation. Finally, a minigene strategy allowed us to demonstrate the pathogenicity of an 8-bp intronic deletion, which led to the skipping of exon 6. In general, frameshifting deletions correlated with a more severe phenotype, consistent with the concept that missense mutations may recover enzymatic activity under certain conditions.","variants":[{"Name":"NM_000071.3(CBS):c.146C>T (p.Pro49Leu)","Chromosome":"21","Start":"43072048","Stop":"43072048","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":210450,"rule_based_match":false,"evidence_text":"p.49L","llm_judgment":"PRESENT","evidence":"p.49L","abstract_start":921,"abstract_end":926}]}
{"pmid":"26265035","title":"Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio.","abstract":"Despite the growing evidence that dihydropyrimidine dehydrogenase deficiency (DPD, encoded by the DPYD gene) confers a higher risk of developing severe toxicity, most patients are not screened for DPD deficiency before fluoropyrimidine treatment. We report here the genetic and phenotypic analyses of DPD in a family related to a patient who died after a first cycle of 5-fluorouracil and in 15 additional retrospective patients having a partial DPD deficiency (as measured by plasma dihydrouracil/uracil ratio). The patient with lethal toxicity was found to be a compound heterozygote for two DPYD mutations: a novel 8-bp duplication (c.168_175dupGAATAATT, p.Phe59Ter) and c.1679T>G (Ile560Ser). The patient's dihydrouracil/uracil ratio indicates complete DPD deficiency. The novel mutation was found in two members of the patient's family. Deleterious DPYD mutations were identified in 9 out of the 15 patients. The relationship between genotype and dihydrouracil/uracil values in the 22 patients of the present study was significant (P = 0.01).","variants":[{"Name":"NM_000110.4(DPYD):c.1679T>G (p.Ile560Ser)","Chromosome":"1","Start":"97515787","Stop":"97515787","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":94530,"rule_based_match":true,"evidence_text":"c.1679T>G (Ile560Ser)","llm_judgment":"PRESENT","evidence":"c.1679T>G (Ile560Ser)","abstract_start":674,"abstract_end":695}]}
{"pmid":"32672086","title":"Two Novel and Five Rare Mutations in the Non Coding Regions of the β-Globin Gene in the Iranian Population.","abstract":"β-Thalassemia (β-thal) is one of the most frequent genetic disorder in Iran with great mutational diversity. In this study, we describe two novel and five rare mutations in the non coding regions of the β-globin gene; these mutations were identified in the non coding regions of the β-globin gene (<i>HBB</i>) in the heterozygous state. Three alterations were detected in the promoter region, including -9 (C>G) [<i>HBB</i>: c.59C>G (novel mutation)], -54 (G>A) (<i>HBB</i>: c.-104G>A) and -57 (A>T) (<i>HBB</i>: c.-107A>T), three changes in the 5' untranslated region (5'UTR) including +11 (C>G) [<i>HBB</i>: c.-40C>G (novel mutation)], +41 (A>T) (<i>HBB</i>: c.-10A>T) and +43 (C>G) (<i>HBB</i>: c.-8C>G) and one mutation in the 3'UTR 62 (A>G) (<i>HBB</i>: c.*62A>G). Five mutations including -54, -57, +41, +11 and +43 were predicted to be deleterious in all except one <i>in silico</i> prediction tool, and the remaining two mutations were found to be most likely polymorphisms. In conclusion, two novel mutations were reported for the first time worldwide and five rare changes have not been reported previously in any other part of Iran. In the absence of further data, it is not possible to consider them as mutations that determine an ascertained healthy carrier state.","variants":[{"Name":"NM_000518.5(HBB):c.-8C>G","Chromosome":"11","Start":"5227029","Stop":"5227029","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1291613,"rule_based_match":true,"evidence_text":"c.-8C>G","llm_judgment":"PRESENT","evidence":"c.-8C>G","abstract_start":698,"abstract_end":705},{"Name":"NM_000518.5(HBB):c.*62A>G","Chromosome":"11","Start":"5225536","Stop":"5225536","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":487510,"rule_based_match":true,"evidence_text":"c.*62A>G","llm_judgment":"PRESENT","evidence":"c.*62A>G","abstract_start":759,"abstract_end":767},{"Name":"NM_000518.5(HBB):c.-104G>A","Chromosome":"11","Start":"5227125","Stop":"5227125","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1320823,"rule_based_match":true,"evidence_text":"c.-104G>A","llm_judgment":"PRESENT","evidence":"c.-104G>A","abstract_start":475,"abstract_end":484}]}
{"pmid":"29193502","title":"FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.","abstract":"Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause \"immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked\" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.","variants":[{"Name":"NM_014009.4(FOXP3):c.1040G>A (p.Arg347His)","Chromosome":"X","Start":"49253130","Stop":"49253130","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":650102,"rule_based_match":false,"evidence_text":"p.Arg347His","llm_judgment":"PRESENT","evidence":"p.Arg347His","abstract_start":979,"abstract_end":990}]}
{"pmid":"26886902","title":"Cancerous leptomeningitis and familial congenital hypopituitarism.","abstract":"People are at higher risk of cancer as they get older or have a strong family history of cancer. The potential influence of environmental and behavioral factors remains poorly understood. Earlier population and case control studies reported that upper quartile of circulating IGF-I is associated with a higher risk of developing cancer suggesting possible involvement of the growth hormone (GH)/IGF system in initiation or progression of cancer. Since GH therapy increases IGF-1 levels, there have been concerns that GH therapy in hypopituitarism might increase the risk of cancer. We report a 42-year-old female patient who presented with subacute onset of symptoms of meningitis and with the absence of fever which resulted in death 70 days after the onset of symptoms. The patient together with her younger brother was diagnosed at the age of 5 years with familial congenital hypopituitarism, due to homozygous mutation c.150delA in PROP1 gene. Due to evolving hypopituitarism, she was replaced with thyroxine (from age 5), hydrocortisone (from age 13), GH (from age 13 until 17), and sex steroids in adolescence and adulthood. Her consanguineous family has a prominent history of malignant diseases. Six close relatives had malignant disease including her late maternal aunt with breast cancer. BRCA 1 and BRCA 2 mutational analysis in the patient's mother was negative. Histology after autopsy disclosed advanced ovarian cancer with multiple metastases to the brain, leptomeninges, lungs, heart, and adrenals. Low circulating IGF-1 did not seem to protect this patient from cancer initiation and progression in the context of strong family history of malignancies.","variants":[{"Name":"NM_006261.5(PROP1):c.150del (p.Arg53fs)","Chromosome":"5","Start":"177994298","Stop":"177994298","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":23141,"rule_based_match":true,"evidence_text":"c.150del","llm_judgment":"PRESENT","evidence":"c.150del","abstract_start":923,"abstract_end":931}]}
{"pmid":"34096792","title":"Meckel-Gruber Syndrome: Clinical and Molecular Genetic Profiles in Two Fetuses and Review of the Current Literature.","abstract":"<b><i>Background:</i></b> Meckel-Gruber syndrome (MKS; OMIM No. 249000) is a rare, <i>in utero</i> lethal disease characterized by occipital encephalocele, polycystic kidneys, and polydactyly. <b><i>Methodology and Results:</i></b> In this study, two fetuses diagnosed as having MKS in the prenatal period were evaluated on the basis of ultrasonographic findings, postmortem autopsy findings, and molecular genetic analyses. Using exome sequencing analyses a novel homozygous frameshift variant (NM_015631: c.530delA, p.Lys177Argfs*47) was detected at exon 4 of <i>TCTN3</i> gene in case 1, and a novel homozygous synonymous variant (NM_025114: c.180G>A, p Lys60Lys) was detected at exon 3 of <i>CEP290</i> gene in case 2. Case 1 is the first reported case in the literature, which showed the typical MKS clinical feature with a novel frameshift variation in the <i>TCTN3</i> gene. The variant in case 2 is the first reported synonymous variant of <i>CEP290</i> gene in the literature, which has been shown to affect splicing in a functional study at the RNA level. <b><i>Conclusion:</i></b> <i>TCTN3</i> gene variants that were rarely associated with the typical MKS phenotype and all cases with these variations have been discussed in the context of genotype-phenotype. The detection of the first synonymous variant of <i>CEP290</i> gene and the demonstration of its effect on splicing by a functional study are likely to contribute to the molecular etiology of MKS.","variants":[{"Name":"NM_025114.4(CEP290):c.180G>A (p.Lys60=)","Chromosome":"12","Start":"88140956","Stop":"88140956","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1960137,"rule_based_match":true,"evidence_text":"NM_025114: c.180G>A, p Lys60Lys","llm_judgment":"PRESENT","evidence":"NM_025114: c.180G>A, p Lys60Lys","abstract_start":634,"abstract_end":665}]}
{"pmid":"31673062","title":"Reticular Dysgenesis and Mitochondriopathy Induced by Adenylate Kinase 2 Deficiency with Atypical Presentation.","abstract":"Reticular dysgenesis is an autosomal recessive form of severe combined immunodeficiency (SCID) that usually manifests in newborns. It is a unique example of an immune deficiency that is linked to dysfunctional mitochondrial energy metabolism and caused by adenylate kinase 2 (AK2) deficiency. It is characterized by an early differentiation arrest in the myeloid lineage, impaired lymphoid maturation, and sensorineural hearing loss. In this study, a novel AK2 homozygous mutation, c.622 T > C [p.Ser208Pro], was identified in an Old Order Amish patient through whole exome sequencing. Functional studies showed that the patient's cells have no detectable AK2 protein, as well as low oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and proton production rate (PPR). An increased production of reactive oxygen species, mitochondrial membrane permeability, and mitochondrial mass, and decreased ATP production, were also observed. The results confirm the pathogenicity of the AK2 mutation and demonstrate that reticular dysgenesis should be considered in Amish individuals presenting with immune deficiency. We also describe other pathophysiological aspects of AK2 deficiency not previously reported.","variants":[{"Name":"NM_001625.4(AK2):c.622T>C (p.Ser208Pro)","Chromosome":"1","Start":"33013279","Stop":"33013279","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":987481,"rule_based_match":true,"evidence_text":"c.622 T > C [p.Ser208Pro]","llm_judgment":"PRESENT","evidence":"c.622 T > C [p.Ser208Pro]","abstract_start":482,"abstract_end":507}]}
{"pmid":"31226715","title":"EPG5 Variants with Modest Functional Impact Result in an Ameliorated and Primarily Neurological Phenotype in a 3.5-Year-Old Patient with Vici Syndrome.","abstract":"Congenital disorders of autophagy are multisystem disorders with significant neurological involvement. Ectopic p-granules protein 5 (<i>EPG5</i>)-associated Vici syndrome is a prototypical congenital disorder of autophagy and presents with the cardinal features of agenesis of the corpus callosum, cataracts, cardiomyopathy, immunodeficiency, and oculocutaneous hypopigmentation. The majority of <i>EPG5</i> variants leading to Vici syndrome are null alleles with only a few missense variants published to date. Here we report a 3.5-year-old male with compound heterozygous <i>EPG5</i> variants [NM_020964.2: c.772G > T/c.5943-9_5943-5del]. His clinical presentation deviates notably from classic Vici syndrome with a lack of hypopigmentation, cataracts, immunodeficiency, cardiomyopathy, or failure to thrive. Neurological manifestations within the known disease spectrum include early-onset global developmental delay, hypotonia, and postnatal microcephaly. Seizures, hearing loss, or optic nerve atrophy are absent, however. Magnetic resonance imaging demonstrates a thin but fully formed corpus callosum. Based on the ameliorated and primarily neurological phenotype, we hypothesized that the functional impact of the <i>EPG5</i> variants present would be milder with a higher amount of residual <i>EPG</i>5 expression. Analyses of <i>EPG5</i> messenger ribonucleic acid (mRNA) in the patient and his parents were performed to examine expression level and splicing; mRNA from a healthy control and a patient with classic Vici syndrome was also included. Aberrant splicing due to the intronic mutation was detected, but no loss of expression. In contrast, we observed a 50% reduction in mRNA expression in classic Vici syndrome patient fibroblasts. These results support a model of disease severity, which correlates to the dosage of <i>EPG5</i> expression.","variants":[{"Name":"NM_020964.3(EPG5):c.5943-9_5943-5del","Chromosome":"18","Start":"45876347","Stop":"45876351","ReferenceAlleleVCF":"TAAAGA","AlternateAlleleVCF":"T","allel_id":1210522,"rule_based_match":true,"evidence_text":"c.5943-9_5943-5del","llm_judgment":"PRESENT","evidence":"c.5943-9_5943-5del","abstract_start":620,"abstract_end":638}]}
{"pmid":"23218673","title":"Whole exome sequencing in foetal akinesia expands the genotype-phenotype spectrum of GBE1 glycogen storage disease mutations.","abstract":"The clinically and genetically heterogenous foetal akinesias have low rates of genetic diagnosis. Exome sequencing of two siblings with phenotypic lethal multiple pterygium syndrome identified compound heterozygozity for a known splice site mutation (c.691+2T>C) and a novel missense mutation (c.956A>G; p.His319Arg) in glycogen branching enzyme 1 (GBE1). GBE1 mutations cause glycogen storage disease IV (GSD IV), including a severe foetal akinesia sub-phenotype. Re-investigating the muscle pathology identified storage material, consistent with GSD IV, which was confirmed biochemically. This study highlights the power of exome sequencing in genetically heterogeneous diseases and adds multiple pterygium syndrome to the phenotypic spectrum of GBE1 mutation.","variants":[{"Name":"NM_000158.4(GBE1):c.956A>G (p.His319Arg)","Chromosome":"3","Start":"81642817","Stop":"81642817","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":828572,"rule_based_match":true,"evidence_text":"c.956A>G (p.His319Arg)","llm_judgment":"PRESENT","evidence":"p.His319Arg","abstract_start":304,"abstract_end":315},{"Name":"NM_000158.4(GBE1):c.691+2T>C","Chromosome":"3","Start":"81648854","Stop":"81648854","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":205142,"rule_based_match":true,"evidence_text":"c.691+2T>C","llm_judgment":"PRESENT","evidence":"c.691+2T>C","abstract_start":251,"abstract_end":261}]}
{"pmid":"30311141","title":"Case of Neonatal Fatality from Neuromuscular Variant of Glycogen Storage Disease Type IV.","abstract":"Glycogen storage disease type IV (GSD-IV), or Andersen disease, is a rare autosomal recessive disorder that results from the deficiency of glycogen branching enzyme (GBE). This in turn results in accumulation of abnormal glycogen molecules that have longer outer chains and fewer branch points. GSD-IV manifests in a wide spectrum, with variable phenotypes depending on the degree and type of tissues in which this abnormal glycogen accumulates. Typically, GSD-IV presents with rapidly progressive liver cirrhosis and death in early childhood. However, there is a severe congenital neuromuscular variant of GSD-IV that has been reported in the literature, with fewer than 20 patient cases thus far. We report an unusual case of GSD-IV neuromuscular variant in a late preterm female infant who was born to non-consanguineous healthy parents with previously healthy children. Prenatally, our patient was found to have decreased fetal movement and polyhydramnios warranting an early delivery. Postnatally, she had severe hypotonia and respiratory failure, with no hepatic or cardiac involvement. Extensive metabolic and neurological workup revealed no abnormalities. However, molecular analysis by whole-exome sequencing revealed two pathogenic variants in the GBE1 gene. Our patient was thus a compound heterozygote of the two pathogenic variants: one of these was inherited from the mother [p.L490WfsX5 (c.1468delC)], and the other pathogenic variant was a de novo change [p.E449X (c.1245G>T)]. As expected in GSD-IV, diffuse intracytoplasmic periodic acid-Schiff-positive, diastase-resistant inclusions were found in the cardiac myocytes, hepatocytes, and skeletal muscle fibers of our patient.","variants":[{"Name":"NM_000158.4(GBE1):c.1468del (p.Leu490fs)","Chromosome":"3","Start":"81578075","Stop":"81578075","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":443515,"rule_based_match":true,"evidence_text":"c.1468delC","llm_judgment":"PRESENT","evidence":"c.1468delC","abstract_start":1403,"abstract_end":1413}]}
{"pmid":"28604967","title":"Analysis of a multiple osteochondroma case caused by novel splice mutation (c.1164+1G to A) of EXT1 gene","abstract":"OBJECTIVE: To detect potential mutation of EXT1 gene in a pedigree affected with multiple osteochondroma and explore its pathogenic mechanism.\nMETHODS: The coding regions and their flanking sequences of the EXT1/EXT2 genes were subjected to PCR amplification and Sanger sequencing. Suspected mutations were verified by excluding possible single nucleotide polymorphisms and bioinformatics analysis. Transcripts of the EXT1 gene in the proband were analyzed by TA clone-sequencing, with its abundance compared with that of healthy controls.\nRESULTS: DNA sequencing has identified in the proband a novel heterozygous point mutation (c.1164+1G to A) at the 5'splice sites of intron 3 of the EXT1 gene. The same mutation was not found in the healthy controls. Bioinformatics analysis indicated that the mutation is highly conserved and can lead to skipping of exon 3 or aberrant splicing. TA clone-sequencing indicated that the numbers of transcripts with skipping of exon 3 has significantly increased in the proband (< 0.05) compared with the controls.\nCONCLUSION: The c.1164+1G to A mutation has resulted in skipping of exon 3 in a proportion of EXT1 gene transcripts. As the result, the number of transcripts with tumor suppressing function is relatively reduced and has ultimately led to the tumors.","variants":[{"Name":"NM_000127.3(EXT1):c.1164+1G>A","Chromosome":"8","Start":"117835443","Stop":"117835443","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1491210,"rule_based_match":false,"evidence_text":"c.1164+1G to A","llm_judgment":"PRESENT","evidence":"c.1164+1G to A","abstract_start":631,"abstract_end":645}]}
{"pmid":"23113155","title":"Novel Mutations in Sandhoff Disease: A Molecular Analysis among Iranian Cohort of Infantile Patients.","abstract":"BACKGROUND: Sandhoff disease is an autosomal recessive disorder caused by β-hexosaminidase deficiency and accumulation of GM2 ganglioside resulting in progressive motor neuron manifestations and death from respiratory failure and infections in infantiles. Pathogenic mutations in HEXB gene were observed which leads to enzyme activity reduction and interruption of normal metabolic cycle of GM2 ganglioside in sandhoff patients.\nMETHODS: Six infantile index patients with typical biochemical and clinical picture of the disease were studied at the molecular level. After DNA extraction and amplification, probands and their parents, were evaluated by direct sequencing of amplicons.\nRESULTS: We identified 7 different mutations among which 4 were novel. The most prevalent finding (50%) among our population was a 16 kb deletion including the promoter and exons 1-5. The other findings included c.1552delG and c.410G>A, c.362 A>G, c.550delT, c.1597C>T, c.1752delTG.\nCONCLUSION: We conclude that Cys137Tyr and R533C mutations may be pathogenic because of changing amino acid and locating at the conserved region and also they have not been observed in hundred controls. Besides, four mutations including: Cys137Tyr, c.1552delG, c.1597C>T and c.550delT fulfilled almost criteria for pathogenic mutation.","variants":[{"Name":"NM_000521.4(HEXB):c.410G>A (p.Cys137Tyr)","Chromosome":"5","Start":"74689438","Stop":"74689438","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":634009,"rule_based_match":true,"evidence_text":"c.410G>A","llm_judgment":"PRESENT","evidence":"c.410G>A","abstract_start":910,"abstract_end":918},{"Name":"NM_000521.4(HEXB):c.1597C>T (p.Arg533Cys)","Chromosome":"5","Start":"74720731","Stop":"74720731","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":428466,"rule_based_match":true,"evidence_text":"c.1597C>T","llm_judgment":"PRESENT","evidence":"c.1597C>T","abstract_start":942,"abstract_end":951}]}
{"pmid":"24573090","title":"Founder effect confirmation of c.241A>G mutation in the L2HGDH gene and characterization of oxidative stress parameters in six Tunisian families with L-2-hydroxyglutaric aciduria.","abstract":"L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive neurometabolic disorder characterized essentially by the presence of elevated levels of L-2-hydroxyglutaric acid (LGA) in plasma, cerebrospinal fluid and urine. L2HGA is caused by a deficiency in the L2-Hydroxyglutaric dehydrogenase (L2HGDH) enzyme involved in the oxidation of LGA to the alpha 2-ketoglutarate. LGA has been proposed as an endo- and exogenous cytotoxic organic acid that induces free radical formation and generation of reactive oxygen species (ROS). In this report, we analyzed 14 L2HGA patients belonging to six unrelated consanguineous families the south of Tunisia. The patients were diagnosed with L2HGA disease confirmed on the presence of high level of LGA in urine. We analyzed the L2HGDH gene in all probands and identified the same c.241A>G homozygous mutation, which was previously reported in Tunisia. We also used intragenic single nucleotide length polymorphisms (SNPs) and two extragenic microsatellites flanking the L2HGDH gene to confirm the founder effect of c.241A>G mutation in the 14 studied cases. In addition, we carried out the measurement of the oxidative stress parameters in the plasma of L2HGA patients which revealed a significant increase in the malondialdehyde levels (MDA), a biomarker of lipid peroxydation, and the reduced glutathione (GSH). A diminution of the antioxidant enzyme activities including superoxide dismutase (SOD), glutathione peroxidase (GPx), was also observed.","variants":[{"Name":"NM_024884.3(L2HGDH):c.241A>G (p.Lys81Glu)","Chromosome":"14","Start":"50302917","Stop":"50302917","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1874702,"rule_based_match":true,"evidence_text":"c.241A>G","llm_judgment":"PRESENT","evidence":"c.241A>G","abstract_start":822,"abstract_end":830}]}
{"pmid":"33726785","title":"Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia.","abstract":"BACKGROUND: The incidence of breast cancer (BC) and/or ovarian cancer (OC) is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum of BRCA mutations remains little explored in Tunisian patients in particular in the southern region.\nMETHODS: We sequenced the entire coding regions of BRCA1and BRCA2 genes using next generation sequencing (NGS) in 134 selected patients with BC and/or OC.\nRESULTS: Among the 134 patients, 19 (14.17%) carried pathogenic mutations (10 are BRCA1 mutation carriers and 9 are BRCA2 mutation carriers) that are mainly frameshift index (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA in BRCA2 and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 in BRCA1 and 2 in BRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A > T, (K3326*) in BRCA2 exon 27. BRCA carriers correlated significantly with tumor site (p = 0.029) and TNBC cases (p = 0.008). In the groups of patients aged between 31 and 40, and 41-50 years, BRCA1 mutations occurred more frequently in patients with OC than those with BC, and conversely BRCA2 carriers are mostly affected with BC (p = 0.001, and p = 0.044 respectively).\nCONCLUSIONS: The overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast/ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA in BRCA2 gene and the c.5030_5033 delCTAA in BRCA1 gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of BC and/or OC.","variants":[{"Name":"NM_007294.4(BRCA1):c.5030_5033del (p.Thr1677fs)","Chromosome":"17","Start":"43067649","Stop":"43067652","ReferenceAlleleVCF":"ATTAG","AlternateAlleleVCF":"A","allel_id":46179,"rule_based_match":true,"evidence_text":"c.5030_5033 delCTAA","llm_judgment":"PRESENT","evidence":"c.5030_5033 delCTAA","abstract_start":767,"abstract_end":786},{"Name":"NM_000059.4(BRCA2):c.1310_1313del (p.Lys437fs)","Chromosome":"13","Start":"32332779","Stop":"32332782","ReferenceAlleleVCF":"AAAAG","AlternateAlleleVCF":"A","allel_id":46293,"rule_based_match":true,"evidence_text":"c.1310-1313 delAAGA","llm_judgment":"PRESENT","evidence":"c.1310-1313 delAAGA","abstract_start":730,"abstract_end":749}]}
{"pmid":"31696996","title":"Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia.","abstract":"Hereditary spastic paraplegia (HSP) is a group of disorders with predominant symptoms of lower-extremity weakness and spasticity. Despite the delineation of numerous genetic causes of HSP, a significant portion of individuals with HSP remain molecularly undiagnosed. Through exome sequencing, we identified five unrelated families with childhood-onset nonsyndromic HSP, all presenting with progressive spastic gait, leg clonus, and toe walking starting from 7 to 8 years old. A recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense-mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified in this study are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant-negative effect on the normal function of the endosome-specific endosomal sorting complexes required for the transport-I complex.","variants":[{"Name":"NM_016525.5(UBAP1):c.426_427del (p.Lys143fs)","Chromosome":"9","Start":"34241450","Stop":"34241451","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":615907,"rule_based_match":true,"evidence_text":"c.426_427delGA","llm_judgment":"PRESENT","evidence":"c.426_427delGA","abstract_start":512,"abstract_end":526}]}
{"pmid":"16158432","title":"Novel phenotype of craniosynostosis and ocular anterior chamber dysgenesis with a fibroblast growth factor receptor 2 mutation.","abstract":"Fibroblast growth factor receptor 2 (FGFR2) mutations are associated with syndromic and non-syndromic craniosynostoses. More recently it has been recognized that FGFR2 may have a role in the development of the anterior chamber of the eye following the finding of a specific FGFR2 mutation (p.Ser351Cys, c.1231 C --> G) with anterior chamber dysgenesis. Affected patients had a severe craniofacial phenotype and clinical course. A child with a different FGFR2 mutation (p.Ala344Ala, c1032 G --> A heterozygote), premature fusion of the sagittal suture, and an Axenfeld-Rieger anomaly but otherwise normal clinical course is reported. The case provides further evidence that FGFR2 has a role in anterior chamber embryogenesis.","variants":[{"Name":"NM_000141.5(FGFR2):c.1032G>A (p.Ala344=)","Chromosome":"10","Start":"121517371","Stop":"121517371","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28307,"rule_based_match":false,"evidence_text":"c1032 G --> A","llm_judgment":"PRESENT","evidence":"c1032 G --> A","abstract_start":482,"abstract_end":495}]}
{"pmid":"26231217","title":"Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization.","abstract":"Correct morphogenesis and differentiation are critical in development and maintenance of the lens, which is a classic model system for epithelial development and disease. Through germline genomic analyses in patients with lens and eye abnormalities, we discovered functional mutations in the Signal Induced Proliferation Associated 1 Like 3 (SIPA1L3) gene, which encodes a previously uncharacterized member of the Signal Induced Proliferation Associated 1 (SIPA1 or SPA1) family, with a role in Rap1 signalling. Patient 1, with a de novo balanced translocation, 46,XY,t(2;19)(q37.3;q13.1), had lens and ocular anterior segment abnormalities. Breakpoint mapping revealed transection of SIPA1L3 at 19q13.1 and reduced SIPA1L3 expression in patient lymphoblasts. SIPA1L3 downregulation in 3D cell culture revealed morphogenetic and cell polarity abnormalities. Decreased expression of Sipa1l3 in zebrafish and mouse caused severe lens and eye abnormalities. Sipa1l3(-/-) mice showed disrupted epithelial cell organization and polarity and, notably, abnormal epithelial to mesenchymal transition in the lens. Patient 2 with cataracts was heterozygous for a missense variant in SIPA1L3, c.442G>T, p.Asp148Tyr. Examination of the p.Asp148Tyr mutation in an epithelial cell line showed abnormal clustering of actin stress fibres and decreased formation of adherens junctions. Our findings show that abnormalities of SIPA1L3 in human, zebrafish and mouse contribute to lens and eye defects, and we identify a critical role for SIPA1L3 in epithelial cell morphogenesis, polarity, adhesion and cytoskeletal organization.","variants":[{"Name":"NM_015073.3(SIPA1L3):c.442G>T (p.Asp148Tyr)","Chromosome":"19","Start":"38082007","Stop":"38082007","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":222972,"rule_based_match":true,"evidence_text":"c.442G>T, p.Asp148Tyr","llm_judgment":"PRESENT","evidence":"c.442G>T, p.Asp148Tyr","abstract_start":1182,"abstract_end":1203}]}
{"pmid":"29246775","title":"Coronary ectasia in amyloid cardiomyopathy and neuropathy due to the transthyretin mutation c.323A>G.","abstract":"BACKGROUND: atrial fibrillation(AF) is a frequent manifestation of cardiac involvement in genetic and wild-type transthyretin-related familial amyloidosis(TTR-FA). However, ectasia of coronary arteries and ablation for AF have not been reported in TTR-FA.\nMETHODS AND RESULTS: A 65yo male developed progressive sensori-motor polyneuropathy since age 59y. At age 60y bifascicular block and myocardial thickening were recognised. At age 62y heart failure developed and work-up with cardiac MRI suggested amyloidosis but biopsy was non-informative. Coronary angiography revealed ectasias of the coronary arteries. At age 65y AF developed, neither responding to electrical cardioversion nor ablation. Work-up for polyneuropathy revealed the point mutation c.323A>G (p.His108Arg) in the TTR-gene. Tafamidis was started but did not exhibit a beneficial effect after 7 months.\nCONCLUSIONS: TTR-FA may manifest in the coronary arteries with ectasia. Ablation for AF in TTR-FA may be unsuccessful. Tafamidis has been unsuccessful for cardiac or nerve involvement after the first seven months.","variants":[{"Name":"NM_000371.4(TTR):c.323A>G (p.His108Arg)","Chromosome":"18","Start":"31595242","Stop":"31595242","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":846812,"rule_based_match":true,"evidence_text":"c.323A>G (p.His108Arg)","llm_judgment":"PRESENT","evidence":"c.323A>G (p.His108Arg)","abstract_start":752,"abstract_end":774}]}
{"pmid":"31833436","title":"Novel homozygous loss-of-function mutations in","abstract":"<b>Background</b>: Retinitis pigmentosa (RP) is a heterogeneous group of ocular dystrophy. It is challenging to identify the underlying genetic defect in individuals with RP due to huge genetic heterogeneity. This study was designed to delineate the genetic defect(s) underlying RP in extended Saudi families and to describe the possible disease mechanism.<b>Materials and Methods</b>: Fundus photography and a high definition optical coherence tomography (HD-OCT) were performed in order to detect the earlier stages of macular degeneration. Genomic DNA was extracted followed by genome-wide SNP genotyping and whole exome sequencing (WES). Exome data was filtered to identify the genetic variant(s) of interest.<b>Results</b>: Clinical examination showed that affected individuals manifest key features of RP. The fundus exam shows pale optic disc and bone spicules at the periphery. OCT shows macular degeneration as early as at the age of 4 years. Whole genome scan by SNPs identified multiple homozygous regions. WES identified a 10 bps novel insertion mutation (c.3544_3545insAGAAAAGCTG; p.Ala1182fs) in the <i>RP1</i> gene in both affected individuals of family A. Affected individual from family B showed a large insertion of 48 nucleotides in the coding part of the <i>RP1L1</i> gene (c.3955_3956insGGACTAAAGTAATAGAAGGGCTGCAAGAAGAGAGGGTGCAGTTAGAGG; p.Ala1319fs). Sanger sequencing validates the autosomal recessive inheritance of the mutations.<b>Conclusion</b>: The results strongly suggest that the insertion mutations in the <i>RP1</i> and <i>RP1L1</i> genes are responsible for the retinal phenotype in affected individuals from two families. Heterozygous individuals are asymptomatic carriers. We propose that the protective allele in other homozygous regions in heterozygous carriers contribute to the phenotypic variability in asymptomatic individuals.","variants":[{"Name":"NM_178857.6(RP1L1):c.3955_3956insGGACTAAAGTAATAGAAGGGCTGCAAGAAGAGAGGGTGCAGTTAGAGG (p.Glu1318_Ala1319insGlyThrLysValIleGluGlyLeuGlnGluGluArgValGlnLeuGlu)","Chromosome":"8","Start":"10610142","Stop":"10610143","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCCTCTAACTGCACCCTCTCTTCTTGCAGCCCTTCTATTACTTTAGTCC","allel_id":816400,"rule_based_match":true,"evidence_text":"c.3955_3956insGGACTAAAGTAATAGAAGGGCTGCAAGAAGAGAGGGTGCAGTTAGAGG","llm_judgment":"PRESENT","evidence":"c.3955_3956insGGACTAAAGTAATAGAAGGGCTGCAAGAAGAGAGGGTGCAGTTAGAGG","abstract_start":1294,"abstract_end":1356},{"Name":"NM_006269.2(RP1):c.3544_3545insAGAAAAGCTG (p.Ala1182fs)","Chromosome":"8","Start":"54627419","Stop":"54627420","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GAAAGCTGAGA","allel_id":967087,"rule_based_match":true,"evidence_text":"c.3544_3545insAGAAAAGCTG; p.Ala1182fs","llm_judgment":"PRESENT","evidence":"c.3544_3545insAGAAAAGCTG; p.Ala1182fs","abstract_start":1068,"abstract_end":1105}]}
{"pmid":"21500142","title":"High prevalence of short-chain acyl-CoA dehydrogenase deficiency in the Netherlands, but no association with epilepsy of unknown origin in childhood.","abstract":"Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of metabolism, most frequently associated with developmental delay and/or epilepsy. Most SCADD patients carry common SCAD-encoding gene ( ACADS) variants or these variants in combination with a rare ACADS mutation, in the Netherlands predominantly the c.1058C>T. Epilepsy in childhood often remains unexplained and patients with epilepsy related to SCADD may remain undiagnosed because studies for SCADD are often not performed. To test this hypothesis and to further estimate the extent of the Dutch SCADD population, we performed a study on blood spot samples in 131 paediatric patients with epilepsy and 909 anonymous newborns and investigated the presence of the 2 common ACADS variants and the rare c.1058C>T mutation. Overall, the 2 common ACADS variants and the rare c.1058C>T mutation were detected in either homozygous or compound heterozygous forms in 9.2% of the epilepsy and 7.5% of the reference group. A birth prevalence of SCADD with a mutation/variant genotype in the Netherlands as high as >1:1,000 was calculated. This is in contrast with the low number of patients diagnosed clinically and supports the hypothesis that SCADD is clinically irrelevant. Furthermore our study does not support an association between SCADD and epilepsy.","variants":[{"Name":"NM_000017.4(ACADS):c.1058C>T (p.Ser353Leu)","Chromosome":"12","Start":"120739168","Stop":"120739168","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18875,"rule_based_match":true,"evidence_text":"c.1058C>T","llm_judgment":"PRESENT","evidence":"c.1058C>T","abstract_start":345,"abstract_end":354}]}
{"pmid":"18203179","title":"Severe neonatal non-dystrophic myotonia secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) gene.","abstract":"We report on a patient with a severe, rare neonatal form of non-dystrophic myotonia. The patient presented with facial dysmorphism, muscle hypertrophy, severe constipation, psychomotor delay, and frequent cold-induced episodes of myotonia and muscle weakness leading to severe hypoxia and loss of consciousness. Muscle biopsy was non-specific and electromyography revealed intense generalized myotonia. The myotonic episodes improved after introducing oral mexiletine and maintaining room temperature at 28 degrees C. The patient died at 20 months of age following a bronchopulmonary infection. A previously undescribed de novo heterozygous c.3891C > A change, which predicts p.N1297K in the SCN4A gene. Mutations within the voltage-gated sodium channel alpha-subunit gene (SCN4A) have been described in association with several phenotypes including paramyotonia congenita, hyperkalemic or hypokalemic periodic paralysis, and potassium-aggravated myotonias. The cold-sensitive episodes of stiffness followed by weakness suggested the diagnosis of channelopathy in our patient. However, her neonatal onset, the triggering of severe episodes by exposure to modest decreases in temperature, involvement of respiratory muscles with prolonged apnea, early-onset muscle hypertrophy, psychomotor retardation, and fatal outcome are evocative of a distinct clinical subtype. Our observation expands the phenotypic spectrum of sodium channelopathies.","variants":[{"Name":"NM_000334.4(SCN4A):c.3891C>A (p.Asn1297Lys)","Chromosome":"17","Start":"63944694","Stop":"63944694","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":20961,"rule_based_match":true,"evidence_text":"c.3891C > A","llm_judgment":"PRESENT","evidence":"c.3891C > A","abstract_start":641,"abstract_end":652}]}
{"pmid":"28635337","title":"Population-Based Genetic Study of β-Thalassemia Mutations in Mardan Division, Khyber Pakhtunkhwa Province, Pakistan.","abstract":"β-Thalassemia (β-thal) is the most prevalent hereditary blood disorder in Pakistan with a carrier rate of 5.0-8.0%. The homozygous affected children require frequent blood transfusions for their survival. This autosomal recessive disease can only be prevented through awareness programs, carrier screening, mutation detection, genetic counseling and prenatal diagnosis (PND). The present study aimed to determine the prevalence of various mutations causing β-thal and also to detect carriers of these mutations in families living in the Mardan Division, Khyber Pakhtunkhwa (KP) Province, Pakistan. The study was conducted at the Department of Biochemistry, Abdul Wali Khan University Mardan, Pakistan. Blood samples of β-thalassemic families were collected from various transfusion centers in Mardan Division. Using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique, all samples were analyzed for the six most common mutations causing β-thal in this area. Six different mutant primers for the detection of different mutations were used. The most common mutations detected in thalassemic patients were frameshift codons (FSC) 8/9 (+G) (HBB: c.27_28insG), codons 41/42 (-TTCT) (HBB: c.126_129delCTTT), and IVS-I-5 (G>C) (HBB: c.92+5G>C). The predominant mutation for carrying the mutant genes for β-thal were FSC 8/9, IVS-I-5, codons 41/42, IVS-I-1. It was also found that 66.7% of marriages were consanguineous. The FSC 8/9 mutation was found to be the most common β-thal mutation with a frequency of 44.4%. This research project provides a strong incentive for the establishment of large scale mutation detection and PND services in the Mardan Division.","variants":[{"Name":"NM_000518.5(HBB):c.92+5G>C","Chromosome":"11","Start":"5226925","Stop":"5226925","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":30486,"rule_based_match":true,"evidence_text":"IVS-I-5 (G>C) (HBB: c.92+5G>C)","llm_judgment":"PRESENT","evidence":"IVS-I-5 (G>C) (HBB: c.92+5G>C)","abstract_start":1246,"abstract_end":1276}]}
{"pmid":"32884772","title":"An enormous Italian pedigree of Marfan syndrome with a novel mutation in the FBN1 gene.","abstract":"We characterize a large Italian family presenting with Marfan syndrome (MFS), where the same NM_000138.4:c.6872-1G > T splice site mutation in the FBN1 gene was detected in 37 affected individuals with different pathological phenotypes. Further studies on such a large pedigree could identify other genetic factors that influence MFS manifestation.","variants":[{"Name":"NM_000138.5(FBN1):c.6872-1G>T","Chromosome":"15","Start":"48428472","Stop":"48428472","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":672195,"rule_based_match":true,"evidence_text":"NM_000138.4:c.6872-1G > T","llm_judgment":"PRESENT","evidence":"NM_000138.4:c.6872-1G > T","abstract_start":93,"abstract_end":118}]}
{"pmid":"33505695","title":"Novel missense mutation in ligand binding domain of AR gene identified in patient with androgen insensitivity syndrome from Ukraine.","abstract":"To improve diagnostic informativity of AR gene mutation analysis in patients with AIS, we recommend to include novel identified missense mutation c.2507T>G in the list of AIS-causing mutations.","variants":[{"Name":"NM_000044.6(AR):c.2507T>G (p.Ile836Ser)","Chromosome":"X","Start":"67722884","Stop":"67722884","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":963207,"rule_based_match":true,"evidence_text":"c.2507T>G","llm_judgment":"PRESENT","evidence":"c.2507T>G","abstract_start":146,"abstract_end":155}]}
{"pmid":"22739342","title":"Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome.","abstract":"Wagner syndrome (WS) is an autosomal dominant vitreoretinopathy affecting various ocular features and is caused by mutations in the canonical splice sites of the VCAN gene, which encodes the large chondroitin sulfate proteoglycan, versican. We report the identification of novel splice acceptor and donor-site mutations (c.4004-1G>C and c.9265+2T>A) in two large WS families from France and the United Kingdom. To characterize their pathogenic mechanisms we performed qRT-PCR experiments on RNA from patient-derived tissues (venous blood and skin fibroblasts). We also analyzed RNA from the original Swiss family reported by Wagner (who has the previously reported c.9265+1G>A mutation). All three mutations resulted in a quantitative increase of transcript variants lacking exons 7 and/or 8. However, the magnitude of the increase varied between tissues and mutations. We discuss altered balance of VCAN splice variants in combination with reduction in glycosaminoglycan protein modifications as possible pathogenic mechanisms.","variants":[{"Name":"NM_004385.5(VCAN):c.9265+2T>A","Chromosome":"5","Start":"83542270","Stop":"83542270","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":50316,"rule_based_match":true,"evidence_text":"c.9265+2T>A","llm_judgment":"PRESENT","evidence":"c.9265+2T>A","abstract_start":337,"abstract_end":348},{"Name":"NM_004385.5(VCAN):c.4004-1G>C","Chromosome":"5","Start":"83537006","Stop":"83537006","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":50317,"rule_based_match":true,"evidence_text":"c.4004-1G>C","llm_judgment":"PRESENT","evidence":"c.4004-1G>C","abstract_start":321,"abstract_end":332}]}
{"pmid":"18228599","title":"Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding.","abstract":"In a Dutch pedigree suffering from autosomal dominant nonsyndromic hearing impairment (ADNSHI), linkage was found to the locus for DFNA15, with a two-point logarithm of the odds (LOD) score of 5.1. Sequence analysis of the POU4F3 gene that is involved in DFNA15 revealed the presence of a missense mutation (c.865C>T), segregating with the deafness in this family. The mutation is predicted to result in the substitution of a phenylalanine residue for a leucine residue (p.L289F) in the POU homeodomain of the transcription factor POU4F3. Mutation analysis of the POU4F3 gene in 30 patients suffering from dominantly inherited hearing impairment revealed a second novel missense mutation (c.668T>C), resulting in the substitution of a proline for a leucine residue (p.L223P) within the POU-specific DNA-binding domain of the protein. In a computer model describing the structure of the two DNA-binding domains, the alterations are predicted to affect the tertiary structure of these domains. Transient transfection studies showed that whereas the wild-type POU4F3 is located almost exclusively in the nucleus, part of the mutant proteins was also present in the cytoplasm. In addition, both mutant proteins showed greatly reduced capability for binding to DNA as well as transcriptionally activating reporter gene expression. Together, our results describe the identification of the first missense mutations in POU4F3 causing DFNA15. Furthermore, mutations in this gene do not seem to be a rare cause of hearing impairment in the Dutch population, and the POU4F3 gene may thus be suitable for implementation in diagnostic testing.","variants":[{"Name":"NM_002700.3(POU4F3):c.865C>T (p.Leu289Phe)","Chromosome":"5","Start":"146340292","Stop":"146340292","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22118,"rule_based_match":true,"evidence_text":"c.865C>T","llm_judgment":"PRESENT","evidence":"c.865C>T","abstract_start":308,"abstract_end":316},{"Name":"NM_002700.3(POU4F3):c.668T>C (p.Leu223Pro)","Chromosome":"5","Start":"146340095","Stop":"146340095","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":22119,"rule_based_match":true,"evidence_text":"c.668T>C (p.Leu223Pro)","llm_judgment":"PRESENT","evidence":"c.668T>C","abstract_start":689,"abstract_end":697}]}
{"pmid":"32004987","title":"A novel missense mutation in CAV3 gene in an Italian family with persistent hyperCKemia, myalgia and hypercholesterolemia: Double-trouble.","abstract":"Caveolins are essential proteins in caveolae architecture, small plasma membrane invaginations that play a key role in a variety of cellular processes, including vesicular trafficking and signal transduction. Mutations in the gene encoding caveolin-3 (CAV3) cause a broad spectrum of clinical phenotypes, ranging from isolated hyperCKemia to most severe limb girdle muscular dystrophy and cardiomyopathy. We report a novel heterozygous p.Val44Met (c.130G > A) CAV3 mutation in two brothers presenting with persistent elevation of serum creatine kinase, myalgia and hypercholesterolemia. Immunofluorescence study with anticaveolin-3 antibodies on muscle biopsy of the proband confirmed a reduced immuno-reactivity of caveolin-3 on the sarcolemma. This findings support the pathogenic effect of this novel mutation and extend the genotypic and clinical spectrum of Caveolinopathies. Finally, we discuss the hypothesis that the association between CAV3 mutations and hypercholesterolemia may not be coincidental.","variants":[{"Name":"NM_033337.3(CAV3):c.130G>A (p.Val44Met)","Chromosome":"3","Start":"8745541","Stop":"8745541","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":828577,"rule_based_match":true,"evidence_text":"c.130G > A","llm_judgment":"PRESENT","evidence":"c.130G > A","abstract_start":448,"abstract_end":458}]}
{"pmid":"22539873","title":"A novel FBN1 mutation in a Chinese family with isolated ectopia lentis.","abstract":"PURPOSE: To identify the genetic defect in an autosomal dominant isolated ectopia lentis (EL) family.\nMETHODS: Detailed family history and clinical data were collected from the family including sixteen patients with isolated EL. Blood samples of nine patients, one normal person and two unknown children's were collected. Genomic DNA was extracted from leukocytes of peripheral blood. Genotyping was performed by microsatellite markers and logarithm-of-odds (LOD) scores were calculated using the LINKAGE Programs. Mutation screening in the candidate gene, fibrillin-1 (FBN1), was performed by direct sequencing.\nRESULTS: Linkage to the FBN1 locus is verified. Mutation screening in FBN1 identified a C>T transition at nucleotide position c.2920. This nucleotide change results in the cysteine substitution for highly conserved arginine at codon 974 (p.R974C). This mutation is identified in all affected individuals but is not found in 50 control healthy people.\nCONCLUSIONS: A novel mutation of FBN1 results in an arginine to cysteine residue (p.R974C) substitution, which is responsible for the patients with isolated EL in this Chinese family.","variants":[{"Name":"NM_000138.5(FBN1):c.2920C>T (p.Arg974Cys)","Chromosome":"15","Start":"48490013","Stop":"48490013","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48266,"rule_based_match":false,"evidence_text":"c.2920C>T (p.R974C)","llm_judgment":"PRESENT","evidence":"p.R974C","abstract_start":851,"abstract_end":858}]}
{"pmid":"23274434","title":"Congenital chloride diarrhea in Korean children: novel mutations and genetic characteristics.","abstract":"UNLABELLED: Congenital chloride diarrhea (CLD, OMIM#214700) is an autosomal recessive disorder caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene, which encodes an intestinal chloride/bicarbonate exchanger. While more than 50 mutations have been identified throughout the world, there have been no data on the genetic characteristics of the patients of East Asian ethnic origin. In this study, we performed genetic analysis by direct sequencing of the 20 exons and parts of exon-intron boundaries of the SLC26A3 gene in eight patients of Korean origin with non-consanguineous parents. We identified three novel mutations, including two splice-site mutations (c.2063-1G>T in intron 18, c.1047+3 A>C in intron 12) and one missense mutation (p.Ser134Asn in exon 5). One previously identified mutation was also found (p.Pro131Leu in exon 5). The most common mutation was c.2063-1G>T, which was found in at least one allele of all patients.\nCONCLUSION: This is the first report to demonstrate the genetic background of CLD in a single ethnic group of East Asian descent. The c.2063-1G>T mutation could be suggested as a founder mutation in Korean population so that the targeting sequencing for the mutation would be a cost-efficient screening method to confirm a diagnosis of CLD in patients of Korean descent.","variants":[{"Name":"NM_000111.3(SLC26A3):c.2063-1G>T","Chromosome":"7","Start":"107767909","Stop":"107767909","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":70628,"rule_based_match":true,"evidence_text":"c.2063-1G>T","llm_judgment":"PRESENT","evidence":"c.2063-1G>T","abstract_start":684,"abstract_end":695}]}
{"pmid":"30920082","title":"Identification of a p.Trp403* nonsense variant in PHEX causing X-linked hypophosphatemia by inhibiting p38 MAPK signaling.","abstract":"X-linked hypophosphatemia (XLH) is the most common hereditary rickets, caused by mutations in PHEX encoding the phosphate regulating endopeptidase homolog X-linked. Here, we report a nonsense variant in exon 11 of PHEX (c.1209G>A p.Trp403*) cosegregating with XLH in a Chinese family with a LOD score of 2.70. Real-time reverse transcription polymerase chain reaction analysis demonstrated that p.Trp403* variant did not cause nonsense-mediated mRNA decay (NMD), but significantly increased the expression level of FGF23 mRNA in the patients. Interestingly, p.Trp403* significantly reduced phosphorylation of p38 mitogen-activated protein kinase (MAPK) but not ERK1/2. Moreover, overexpression of FGF23 significantly decreased phosphorylation of p38 MAPK, whereas knockdown of FGF23 by siRNA significantly increased phosphorylation of p38 MAPK. These data suggest that p.Trp403* may not function via an NMD mechanism, and instead causes XLH via a novel signaling mechanism involving PHEX, FGF23, and p38 MAPK. This finding provides important insights into genetic and molecular mechanisms for the pathogenesis of XLH.","variants":[{"Name":"NM_000444.6(PHEX):c.1209G>A (p.Trp403Ter)","Chromosome":"X","Start":"22114493","Stop":"22114493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260301,"rule_based_match":true,"evidence_text":"c.1209G>A p.Trp403*","llm_judgment":"PRESENT","evidence":"c.1209G>A p.Trp403*","abstract_start":220,"abstract_end":239}]}
{"pmid":"30508901","title":"Improvement of bone microarchitecture parameters after 12 months of treatment with asfotase alfa in adult patient with hypophosphatasia: Case report.","abstract":"RATIONALE: Hypophosphatasia is an inborn error of metabolism that can appear any time in life, mainly with bone manifestations due to low alkaline phosphatase activity. Asfotase alfa is a specific enzyme reposition treatment that has shown promising results in children; however, there are few reports about the outcomes in adult patients.\nPATIENT CONCERNS: A 36-year-old male presented with an early history of craniosynostosis, short stature, and multiple fractures since the age of 13 years-which needed numerous surgical corrections. He was admitted with a previous diagnosis of osteogenesis imperfecta, taking alendronate, calcium carbonate, cholecalciferol, and calcitriol. Bone mineral density was low (lumbar spine Z-score = -3.0 SD), with impairment of all parameters of high-resolution peripheral quantitative computed tomography (HR-pQCT). Kidney impairment was also observed with reduced creatinine clearance, nephrolithiasis, and nephrocalcinosis.\nDIAGNOSIS: Alkaline phosphatase was unexpectedly low (6 U/L, reference value: 30-120 U/L), with high serum vitamin B6 (260 mcg/L, reference value: 5.2-34.1). Genetic testing showed a homozygous missense mutation in ALPL gene c.443 C>T: p.Thr148Ile.\nINTERVENTION: Asfotase alfa was requested due to important bone deterioration, ambulatory disability, and kidney impairment. It was given subcutaneously 2 mg/kg per dose, 3 times a week, for 12 months before reassessment.\nOUTCOMES: Bone mineral densities of the lumbar spine and whole body, besides almost all HR-pQCT microstructural parameters of the distal tibia, showed improvements and the patient was able to walk without assistant device. Kidney function did not further deteriorate.\nLESSONS: Hypophosphatasia should be considered as a differential diagnosis in young patients with multiple fractures and kidney impairment, since the use of antiresorptive drugs, calcium and vitamin D, commonly used to treat fractures, worsen its symptoms and prognosis. A 12-month asfotase alfa treatment improved bone density and structural parameters even in an adult patient with late diagnosis.","variants":[{"Name":"NM_000478.6(ALPL):c.443C>T (p.Thr148Ile)","Chromosome":"1","Start":"21563255","Stop":"21563255","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2898173,"rule_based_match":true,"evidence_text":"c.443 C>T: p.Thr148Ile","llm_judgment":"PRESENT","evidence":"c.443 C>T: p.Thr148Ile","abstract_start":1186,"abstract_end":1208}]}
{"pmid":"29397530","title":"Childhood Rapid-Onset Ataxia: Expanding the Phenotypic Spectrum of ATP1A3 Mutations.","abstract":"ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in ATP1A3-related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different ATP1A3 variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of ATP1A3 mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of ATP1A3-related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model.","variants":[{"Name":"NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)","Chromosome":"19","Start":"41970540","Stop":"41970540","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":413523,"rule_based_match":true,"evidence_text":"c.2266C>T (p.R756C)","llm_judgment":"PRESENT","evidence":"c.2266C>T (p.R756C)","abstract_start":681,"abstract_end":700}]}
{"pmid":"25190158","title":"Follow up and gene mutation analysis in cases suspected as 3-methylcrotonyl-coenzyme A carboxylase deficiency by neonatal screening","abstract":"OBJECTIVE: 3-Methylcrotonyl-coenzyme A carboxylase deficiency (MCCD) is an autosomal recessive inborn error of leucine catabolism. The cases suspected as MCCD detected by neonatal screening are not rare. The aim of the study was to investigate the clinical outcomes in cases suspected as MCCD by neonatal screening. The second aim was to investigate the mutation spectrum of MCC gene in Chinese population and hotspot mutation.\nMETHOD: Forty-two cases (male 33, female 9) , who had higher blood 3-hydroxy-isovalerylcarnitine (C5-OH) levels(cut-off <0.6 µmol/L) detected by neonatal screening using MS/MS, were recruited to this study during Sept.2011 to Mar.2013. The C5-OH concentrations were [0.84 (0.61-20.15) µmol/L] in 42 cases at the screening recall. Five cases were firstly diagnosed as maternal MCCD, 6 cases as benign MCCD and 31 cases were suspected as MCCD. To follow up the height, weight, mental development, blood C5-OH concentrations and urinary 3-methylcrotonyl-glycine (3-MCG) and 3-hydroxy isovalerate (3-HIVA) in order to investigate the clinical outcome. The MCCC1 and MCCC2 gene mutation were analyzed for some cases. The novel gene variants were evaluated, and the influence of novel missense variants on the protein structure and function were predicted by PolyPhen-2, SIFT, UniProt and PDB software.\nRESULT: (1) Forty-two cases had no symptoms, their physical and mental development were normal in the last visit at the median ages of 29 months, the oldest age of follow up was nearly 9 years. (2) Gene mutation analysis was performed for 29 cases with informed consent signed by parents.Fourteen different mutations were identified in 19 cases. The mutations in MCCC1 gene accounted for 86%, the most common mutation was c.ins1680A, (accounted for 40%). Nine kinds of novel variant were detected including 211AG>CC/p.Q74P, c.295G>A/p.G99S, c.764A>C/p.H255P, c.964G>A/p. E322K, c.1331G>A/p.R444H, c.1124delT, c.39_58del20, c.1518delG, c.639+2T>A.Other 3 kinds of mutation in MCCC1 gene and 2 kinds of mutation in MCCC2 gene have been reported previously; the amino acid of mutant positions of five kinds of novel missense variant are almost highly conserved. These missense variants were predicted to cause change of human MCC protein side chain structure by changing hydrogen bonding, size of amino acid residue and electric charge, and predicted to damage the protein function possibly according to PolyPhen-2 and PDB analysis. So these novel variants may be disease-causing mutations. No mutation were detected in 10 cases. (3) Blood concentrations of C5-OH when screening, recall and end of follow-up in maternal MCCD was 3.50 (1.63-11.43), 1.84 (1.00-9.30), 0.27 (0.26-5.81) µmol/L. There was a significant downward trend.In contrast, benign MCCD group was 8.20 (3.60-9.60), 9.67 (3.88-20.15), 23.0 (5.87-49.10) µmol/L.It showed a rising trend. Children's urinary 3-MCG of benign MCCD group was found abnormally elevated in 4 cases (100%) when they were recalled.\nCONCLUSION: A certain number of cases with MCCD or suspected as MCCD in this study had no symptoms and normal physical and mental development after follow-up to oldest age of nearly 9 years. The mutation in MCCC1 gene is common, nine novel mutations were found, c.ins1680A may be a hotspot mutation in Chinese population. The urinary GC/MS analysis and blood MS/MS analysis for mother should be routinely performed for all cases with high blood C5-OH level detected by neonatal screening.","variants":[{"Name":"NM_020166.5(MCCC1):c.295G>A (p.Gly99Ser)","Chromosome":"3","Start":"183086767","Stop":"183086767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":631106,"rule_based_match":true,"evidence_text":"c.295G>A/p.G99S","llm_judgment":"PRESENT","evidence":"c.295G>A/p.G99S","abstract_start":1849,"abstract_end":1864},{"Name":"NM_020166.5(MCCC1):c.1331G>A (p.Arg444His)","Chromosome":"3","Start":"183039072","Stop":"183039072","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":200045,"rule_based_match":true,"evidence_text":"c.1331G>A/p.R444H","llm_judgment":"PRESENT","evidence":"c.1331G>A/p.R444H","abstract_start":1903,"abstract_end":1920}]}
{"pmid":"22487062","title":"Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity.","abstract":"BACKGROUND: Primary osteoporosis is a rare childhood-onset skeletal condition whose pathogenesis has been largely unknown. We have previously shown that primary osteoporosis can be caused by heterozygous missense mutations in the Low-density lipoprotein receptor-related protein 5 (LRP5) gene, and the role of LRP5 is further investigated here.\nMETHODS: LRP5 was analyzed in 18 otherwise healthy children and adolescents who had evidence of osteoporosis (manifested as reduced bone mineral density i.e. BMD, recurrent peripheral fractures and/or vertebral compression fractures) but who lacked the clinical features of osteogenesis imperfecta (OI) or other known syndromes linked to low BMD. Also 51 controls were analyzed. Methods used in the genetic analyses included direct sequencing and multiplex ligation-dependent probe amplification (MLPA). In vitro studies were performed using luciferase assay and quantitative real-time polymerase chain reaction (qPCR) to examine the effect of two novel and three previously identified mutations on the activity of canonical Wnt signaling and on expression of tryptophan hydroxylase 1 (Tph1) and 5-hydroxytryptamine (5-Htr1b).\nRESULTS: Two novel LRP5 mutations (c.3446 T > A; p.L1149Q and c.3553 G > A; p.G1185R) were identified in two patients and their affected family members. In vitro analyses showed that one of these novel mutations together with two previously reported mutations (p.C913fs, p.R1036Q) significantly reduced the activity of the canonical Wnt signaling pathway. Such reductions may lead to decreased bone formation, and could explain the bone phenotype. Gut-derived Lrp5 has been shown to regulate serotonin synthesis by controlling the production of serotonin rate-limiting enzyme, Tph1. LRP5 mutations did not affect Tph1 expression, and only one mutant (p.L1149Q) reduced expression of serotonin receptor 5-Htr1b (p < 0.002).\nCONCLUSIONS: Our results provide additional information on the role of LRP5 mutations and their effects on the development of juvenile-onset primary osteoporosis, and hence the pathogenesis of the disorder. The mutations causing primary osteoporosis reduce the signaling activity of the canonical Wnt signaling pathway and may therefore result in decreased bone formation. The specific mechanism affecting signaling activity remains to be resolved in future studies.","variants":[{"Name":"NM_002335.4(LRP5):c.3553G>A (p.Gly1185Arg)","Chromosome":"11","Start":"68426103","Stop":"68426103","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":273467,"rule_based_match":true,"evidence_text":"c.3553 G > A; p.G1185R","llm_judgment":"PRESENT","evidence":"c.3553 G > A; p.G1185R","abstract_start":1234,"abstract_end":1256}]}
{"pmid":"12473778","title":"Adult onset glutaric aciduria type I presenting with a leukoencephalopathy.","abstract":"Glutaric aciduria type I usually presents with an acute metabolic crisis during infancy. The authors report a previously healthy 19-year-old woman who presented with recurrent headaches, oculomotor symptoms, and a severe leukoencephalopathy on MRI. The diagnosis was made by urinary organic acid analysis and confirmed by enzyme studies. Genetic analysis revealed compound heterozygosity with a deletion c.219delC in exon 3 and a novel missense mutation R132G in exon 5 of the glutaryl CoA dehydrogenase (GCDH) gene.","variants":[{"Name":"NM_000159.4(GCDH):c.219del (p.Tyr74fs)","Chromosome":"19","Start":"12891921","Stop":"12891921","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":358590,"rule_based_match":true,"evidence_text":"c.219delC","llm_judgment":"PRESENT","evidence":"c.219delC","abstract_start":404,"abstract_end":413}]}
{"pmid":"23151025","title":"Identification of SLC26A4 c.919-2A>G compound heterozygosity in hearing-impaired patients to improve genetic counseling.","abstract":"BACKGROUND: Mutations in the SLC26A4 gene, which encodes the anion transporter, pendrin, are a major cause of autosomal recessive non-syndromic hearing loss (NSHL) in some Asian populations. SLC26A4 c.919-2A>G (IVS7-2A>G) is the most common mutation in East Asian deaf populations. To provide a basis for improving the clinical diagnosis of deaf patients, we evaluated 80 patients with the SLC26A4 c.919-2A>G monoallelic mutation from 1065 hearing-impaired subjects and reported the occurrence of a second mutant allele in these patients.\nMETHODS: The occurrence of a second mutant allele in these 80 patients with a single c.919-2A>G mutation was investigated. Mutation screening was performed by bidirectional sequencing in SLC26A4 exons 2 to 6 and 9 to 21.\nRESULTS: We found that 47/80 patients carried another SLC26A4 c.919-2A>G compound mutation. The five most common mutations were: p.H723R, p.T410M, 15+5G>A (c.1705+5G>A), p.L676Q and p.N392Y. We found a Chinese-specific SLC26A4 mutation spectrum and an associated SLC26A4 contribution to deafness.\nCONCLUSION: Our study illustrates that mutation analysis of other SLC26A4 exons should be undertaken in deaf patients with a single heterozygous SLC26A4 mutation. Moreover, a model of compound heterozygosity may partially explain the disease phenotype.","variants":[{"Name":"NM_000441.2(SLC26A4):c.919-2A>G","Chromosome":"7","Start":"107683453","Stop":"107683453","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19879,"rule_based_match":true,"evidence_text":"SLC26A4 c.919-2A>G (IVS7-2A>G)","llm_judgment":"PRESENT","evidence":"SLC26A4 c.919-2A>G (IVS7-2A>G)","abstract_start":191,"abstract_end":221}]}
{"pmid":"23141577","title":"Analysis of gene mutation in a Chinese family with Norrie disease","abstract":"OBJECTIVE: To detect the pathogenic mutation in a Chinese family with Norrie disease.\nMETHODS: Clinical diagnosis was based on familial history, clinical sign and B ultrasonic examination. Peripheral blood samples were obtained from all available members in a Chinese family with Norrie disease. Genomic DNA was extracted from lymphocytes by the standard SDS-proteinase K-phenol/chloroform method. Two coding exons and all intron-exon boundaries of the NDP gene were PCR amplified using three pairs of primers and subjected to automatic DNA sequence. The causative mutation was confirmed by restriction enzyme analysis and genotyping analysis in all members.\nRESULTS: Sequence analysis of NDP gene revealed a missense mutation c.220C > T (p.Arg74Cys) in the proband and his mother. Further mutation identification by restriction enzyme analysis and genotyping analysis showed that the proband was homozygote of this mutation. His mother and other four unaffected members (III3, IV4, III5 and II2) were carriers of this mutation. The mutant amino acid located in the C-terminal cystine knot-like domain, which was critical motif for the structure and function of NDP.\nCONCLUSION: A NDP missense mutation was identified in a Chinese family with Norrie disease.","variants":[{"Name":"NM_000266.4(NDP):c.220C>T (p.Arg74Cys)","Chromosome":"X","Start":"43949981","Stop":"43949981","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":177444,"rule_based_match":true,"evidence_text":"c.220C > T (p.Arg74Cys)","llm_judgment":"PRESENT","evidence":"c.220C > T (p.Arg74Cys)","abstract_start":727,"abstract_end":750}]}
{"pmid":"31854503","title":"A family affair-Severe fetal and neonatal hemolytic anemia due to novel alpha-spectrin mutations in two siblings.","abstract":"Hereditary spherocytosis (HS) is the most common cause of inherited, nonimmune hemolytic anemia. When inherited in an autosomal dominant fashion, the anemia is typically mild. However, severe, transfusion-dependent anemia is seen in autosomal recessive HS, which is often associated with deficient or absent red blood cell membrane protein alpha-spectrin. We report a 26-year-old para one who was referred to our center at 28 weeks' gestation due to concerns for fetal anemia. Evaluation revealed elevated peak systolic velocity in the middle cerebral artery by Doppler scan and fetal cardiomegaly. Fetal hematocrit obtained by sampling the umbilical vein was 9% confirming severe fetal anemia. Fetal peripheral smear was consistent with hereditary spherocytosis. Genetic analysis of both parents confirmed heterozygosity for the SPTA1 variants (pathogenic variant c.4180del (p.C1394Afs*25), and a variant of uncertain significance, c.1677G>T (p.G449G)) detected by a hemolytic anemia panel in the patient's first child. It is important to consider genetic causes of anemia in patients presenting with severe nonimmune fetal anemia, including autosomal recessive HS. We present a case of autosomal recessive HS with a novel pathogenic variant in the SPTA1 gene which resulted in significant impact on prenatal management.","variants":[{"Name":"NM_003126.4(SPTA1):c.4180del (p.Cys1394fs)","Chromosome":"1","Start":"158645202","Stop":"158645202","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1019201,"rule_based_match":true,"evidence_text":"c.4180del (p.C1394Afs*25)","llm_judgment":"PRESENT","evidence":"c.4180del (p.C1394Afs*25)","abstract_start":865,"abstract_end":890}]}
{"pmid":"30073107","title":"Four Japanese Patients with Congenital Nephrogenic Diabetes Insipidus due to the","abstract":"Almost 90% of nephrogenic diabetes insipidus (NDI) is caused by mutations in the arginine vasopressin receptor 2 gene (<i>AVPR2</i>) on the X chromosome. Herein, we reported clinical and biochemical parameters in four cases of three unrelated Japanese families and analyzed the status of the <i>AVPR2.</i> Two of the four patients had poor weight gain. However, in the male and female sibling cases, neither had poor weight gain while toddlers, but in the male sibling, episodes of recurrent fever, polyuria, and polydipsia led to the diagnosis of NDI at 4 years of age. Analysis of <i>AVPR2</i> identified two nonsense mutations (c.299_300insA; p.K100KfsX91 and c.296G > A; p.W99X) and one missense mutation (c.316C > T; p.R106C). These mutations were previously reported. The patient with c.316C > T; p.R106C had milder symptoms consistent with previous reports. Of the familial cases, the sister was diagnosed as having NDI, but a skewed X-inactivation pattern in her peripheral blood lymphocytes was not identified. In conclusion, our study expands the spectrum of phenotypes and characterized mutations in <i>AVPR2</i> in NDI.","variants":[{"Name":"NM_000054.7(AVPR2):c.316C>T (p.Arg106Cys)","Chromosome":"X","Start":"153905822","Stop":"153905822","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1679484,"rule_based_match":true,"evidence_text":"c.316C > T; p.R106C","llm_judgment":"PRESENT","evidence":"c.316C > T; p.R106C","abstract_start":710,"abstract_end":729}]}
{"pmid":"11412411","title":"Albright hereditary osteodystrophy: identification of a novel mutation in a family","abstract":"Studies to detect mutations in the GNAS1 gene were performed in a male patient with features of Albright hereditary osteodystrophy and resistance of target tissues to parathyroid hormone (Pseudohypoparathyroidism Ia). The same investigations were carried out in the patient's mother who showed somatic features of Albright's hereditary osteodystrophy and brachymetacarpia without resistance to parathyroid hormone (Pseudopseudohypoparathyroidism). A point mutation designated c.794GA (R265H) in exon 10 of GNAS1 was identified in DNA from the patient and his mother. This novel mutation in exon 10 of GNA","variants":[{"Name":"NM_000516.7(GNAS):c.794G>A (p.Arg265His)","Chromosome":"20","Start":"58909759","Stop":"58909759","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1054226,"rule_based_match":false,"evidence_text":"c.794GA (R265H)","llm_judgment":"PRESENT","evidence":"c.794GA (R265H)","abstract_start":476,"abstract_end":491}]}
{"pmid":"32453264","title":"Association of SLCO1B1 c.521T>C (rs4149056) with discontinuation of atorvastatin due to statin-associated muscle symptoms.","abstract":"The most common adverse drug reaction from statins are statin-associated muscle symptoms (SAMS), characterized by myopathy (weakness), myalgia (muscle pain), and commonly elevation in serum creatine kinase. All statins are substrates of the organic anion transporter 1B1 (OATP1B1; gene: SLCO1B1), albeit to different degrees. A genetic polymorphism in SLCO1B1, c.521T>C (rs4149056), markedly decreases OATP1B1 function. The literature is currently unclear as to whether SLCO1B1 c.521T>C is significantly associated with discontinuation of atorvastatin specifically due to SAMS. Our hypothesis was that individuals carrying the SLCO1B1 decreased function 521C allele are more likely to discontinue atorvastatin due to SAMS. This was a retrospective analysis of survey data from 379 Caucasians genotyped for rs4149056 and treated with atorvastatin for at least 12 months. Crude and multivariable logistic regression, adjusted for established risk factors for SAMS, determined the association of SLCO1B1 c.521T>C with discontinuation of atorvastatin due to SAMS (SLCO1B1 521T-homozygotes vs. 521C-carriers). The sample was 51% male, with a mean age of 57 years (SD = 11). Sixty-one percent of participants reported discontinuing atorvastatin due to SAMS, and 32% overall carried the 521C allele. SLCO1B1 521C-carrier status was not a significant predictor of atorvastatin discontinuation in any model: crude OR = 1.07; 95% CI, 0.68-1.66; P = 0.78 and adjusted OR = 1.07; 95% CI, 0.68-1.69; P = 0.76. The results were similar in a sub-group of participants treated with higher doses of atorvastatin (>20 mg). In summary, SLCO1B1 c.521T>C was not significantly associated with discontinuation of atorvastatin therapy due to SAMS.","variants":[{"Name":"NM_006446.5(SLCO1B1):c.521T>C (p.Val174Ala)","Chromosome":"12","Start":"21178615","Stop":"21178615","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40587,"rule_based_match":true,"evidence_text":"SLCO1B1 c.521T>C","llm_judgment":"PRESENT","evidence":"SLCO1B1 c.521T>C","abstract_start":470,"abstract_end":486}]}
{"pmid":"15609246","title":"Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria.","abstract":"d-2-hydroxyglutaric aciduria is a neurometabolic disorder with both a mild and a severe phenotype and with unknown etiology. Recently, a novel enzyme, d-2-hydroxyglutarate dehydrogenase, which converts d-2-hydroxyglutarate into 2-ketoglutarate, and its gene were identified. In the genes of two unrelated patients affected with d-2-hydroxyglutaric aciduria, we identified disease-causing mutations. One patient was homozygous for a missense mutation (c.1331T-->C; p.Val444Ala). The other patient was compound heterozygous for a missense mutation (c.440T-->G; p.Ile147Ser) and a splice-site mutation (IVS1-23A-->G) that resulted in a null allele. Overexpression studies in HEK-293 cells of proteins containing the missense mutations showed a marked reduction of d-2-hydroxyglutarate dehydrogenase activity, proving that mutations in the d-2-hydroxyglutarate dehydrogenase gene cause d-2-hydroxyglutaric aciduria.","variants":[{"Name":"NM_152783.5(D2HGDH):c.1331T>C (p.Val444Ala)","Chromosome":"2","Start":"241767734","Stop":"241767734","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":16891,"rule_based_match":false,"evidence_text":"c.1331T-->C; p.Val444Ala","llm_judgment":"PRESENT","evidence":"c.1331T-->C; p.Val444Ala","abstract_start":451,"abstract_end":475},{"Name":"NM_152783.5(D2HGDH):c.440T>G (p.Ile147Ser)","Chromosome":"2","Start":"241742524","Stop":"241742524","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":16892,"rule_based_match":false,"evidence_text":"c.440T-->G (p.Ile147Ser)","llm_judgment":"PRESENT","evidence":"p.Ile147Ser","abstract_start":559,"abstract_end":570}]}
{"pmid":"32811265","title":"Variants at codon 838 in the","abstract":"BACKGROUND: The <i>GUCY2D</i> gene encodes the photoreceptor guanylate cyclase (GC-E) and different pathogenic variants can lead to Leber congenital amaurosis (LCA) or cone-rod dystrophy (CRD). In this study, we describe three unrelated families who carried different mutations at codon 838 of the <i>GUCY2D</i> gene, and presented different phenotypes of retinal degeneration.\nMATERIALS AND METHODS: Family and personal histories were collected, and the patients underwent best corrected visual acuity (BCVA), fundus photography (FP), electroretinography (ERG), optical coherence tomography (OCT) and fundus autofluorescence (FAF). Venous blood was drawn from patients and family members, and genomic DNA was extracted. Next-generation sequencing of known ocular genes was applied to the proband to find pathogenic variants. Polymerase chain reaction (PCR) and Sanger sequencing were conducted for validation and segregation.\nRESULTS: Six patients from three unrelated families were enrolled. All the patients manifested decreased vision, photophobia and myopia from childhood. ERG recordings demonstrated a significant reduction in cone responses for all patients, while rod responses ranged widely from normal to moderately reduced. All patients were diagnosed with CRD, but the disease severity and progression rates in the three families were significantly different. Three pathogenic variants in the <i>GUCY2D</i> gene (c.2512 C > T (p.R838C), c.2512 C > A (p.R838S) and c.2513 G > A (p.R838H)) were identified.\nCONCLUSIONS: We presented the phenotypes of three Chinese adCRD families carrying different variants at codon 838 of the <i>GUCY2D</i> gene. The R838S variant is a novel genotype associated with <i>GUCY2D</i>-CRD. The R838H variant can cause severe retinal features. Our findings enhance the understanding of <i>GUCY2D</i> phenotypic diversity.","variants":[{"Name":"NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys)","Chromosome":"17","Start":"8014700","Stop":"8014700","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":24394,"rule_based_match":true,"evidence_text":"c.2512 C > T (p.R838C)","llm_judgment":"PRESENT","evidence":"c.2512 C > T (p.R838C)","abstract_start":1426,"abstract_end":1448},{"Name":"NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His)","Chromosome":"17","Start":"8014701","Stop":"8014701","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24396,"rule_based_match":true,"evidence_text":"c.2513 G > A (p.R838H)","llm_judgment":"PRESENT","evidence":"c.2513 G > A (p.R838H)","abstract_start":1477,"abstract_end":1499}]}
{"pmid":"21598002","title":"Malignant fibrous histiocytoma is a rare Lynch syndrome-associated tumor in two German families.","abstract":"Lynch syndrome is characterized by germline mutations of the DNA mismatch repair genes MLH1 and MSH2. The tumor spectrum includes early onset colorectal, urogenital and other cancers. Soft tissue sarcomas have been anecdotally reported in patients with Lynch syndrome, but coincidental manifestation could not be excluded. In this report, we screened a cohort of Lynch syndrome families for tumors outside the established tumor spectrum. We identified two patients with Lynch syndrome and a malignant fibrous histiocytoma (MFH). In both families a causative MSH2 germline mutation (MSH2 c.2038C ≥ T or MSH2 c.942 ± 3A ≥ T) could be detected. Archival tumor material from both resected MFH was analyzed for microsatellite instability expression of MLH1 and MSH2. A mutator phenotype was detected in both MFH with loss of MSH2 protein expression. Subsequently, the causative MSH2 germline mutation was confirmed in both patients. Of note, both tumors were diagnosed at a local advanced stage but could be curatively resected 21 and 11 year ago, respectively. Both patients are alive without local or distant recurrence. In conclusion, our data further support that patients with Lynch syndrome are at increased risk for rare tumors such as MFH. However, the prognosis compared to sporadic MFH seems to be favorable.","variants":[{"Name":"NM_000251.3(MSH2):c.2038C>T (p.Arg680Ter)","Chromosome":"2","Start":"47476399","Stop":"47476399","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45234,"rule_based_match":false,"evidence_text":"MSH2 c.2038C ≥ T","llm_judgment":"PRESENT","evidence":"MSH2 c.2038C ≥ T","abstract_start":582,"abstract_end":598}]}
{"pmid":"24367057","title":"Glycosylphosphatidylinositol (GPI) anchor deficiency caused by mutations in PIGW is associated with West syndrome and hyperphosphatasia with mental retardation syndrome.","abstract":"BACKGROUND: Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors 150 or more kinds of proteins to the human cell surface. There are at least 26 genes involved in the biosynthesis and remodelling of GPI anchored proteins (GPI-APs). Recently, inherited GPI deficiencies (IGDs) were reported which cause intellectual disability often accompanied by epilepsy, coarse facial features and multiple anomalies that vary in severity depending upon the degree of defect and/or step in the pathway of affected gene.\nMETHODS AND RESULTS: A patient born to non-consanguineous parents developed intractable seizures with typical hypsarrhythmic pattern in electroencephalography, and was diagnosed as having West syndrome. Because the patient showed severe developmental delay with dysmorphic facial features and hyperphosphatasia, characteristics often seen in IGDs, the patient was tested for GPI deficiency. The patient had decreased surface expression of GPI-APs on blood granulocytes and was identified to be compound heterozygous for NM_178517:c.211A>C and c.499A>G mutations in PIGW by targeted sequencing.\nCONCLUSION: Here we describe the first patient with deficiency of PIGW, which is involved in the addition of the acyl-chain to inositol in an early step of GPI biosynthesis. Therefore, IGD should be considered in West syndrome and flow cytometric analysis of blood cells is effective in screening IGD.","variants":[{"Name":"NM_001346754.2(PIGW):c.499A>G (p.Met167Val)","Chromosome":"17","Start":"36537600","Stop":"36537600","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":165956,"rule_based_match":true,"evidence_text":"c.499A>G","llm_judgment":"PRESENT","evidence":"c.499A>G","abstract_start":1059,"abstract_end":1067}]}
{"pmid":"25523870","title":"Identification of nondeletional α-thalassemia in a prenatal screening program by reverse dot-blot in southern China.","abstract":"The aim of this study was to demonstrate the performance of nondeletional α-thalassemia (α-thal) prevention using a reverse dot-blot method at a Mainland Chinese hospital. A prenatal control program for nondeletional Hb H disease was performed between January 2009 and December 2013. All couples were screened for α-thal trait, and for couples in which one partner tested positive for α(0)-thal, the other was subjected to screening for Hb Constant Spring (Hb CS, HBA2: c.427T > C) and Hb Quong Sze (Hb QS, HBA2: c.377T > C) mutations by reverse dot-blot assay. Prenatal diagnoses were offered in at-risk pregnancies. During the study period, 51,105 couples were found to be carrying α-thal; among these, 35 (0.07%) couples were found to be at-risk of conceiving an offspring with nondeletional Hb H disease, including 25 couples for Hb H-CS and 10 cases for Hb H-QS. Nine fetuses were diagnosed with nondeletional Hb H disease, and eight of the affected pregnancies were terminated. Detection of nondeletional α-thal is necessary for any prenatal diagnosis (PND) programs in Southeast Asian countries. Reverse dot-blot is a relatively simple method for simultaneous typing of common nondeletional α-thal mutations.","variants":[{"Name":"NM_000517.4(HBA2):c.427T>C (p.Ter143Gln)","Chromosome":"16","Start":"173598","Stop":"173598","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":30663,"rule_based_match":true,"evidence_text":"HBA2: c.427T > C","llm_judgment":"PRESENT","evidence":"HBA2: c.427T > C","abstract_start":464,"abstract_end":480}]}
{"pmid":"29054425","title":"Molecular characterization of congenital myasthenic syndromes in Spain.","abstract":"Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management.","variants":[{"Name":"NM_005055.5(RAPSN):c.264C>A (p.Asn88Lys)","Chromosome":"11","Start":"47448079","Stop":"47448079","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":23085,"rule_based_match":true,"evidence_text":"RAPSN c.264C > A (p.Asn88Lys)","llm_judgment":"PRESENT","evidence":"RAPSN c.264C > A (p.Asn88Lys)","abstract_start":936,"abstract_end":965},{"Name":"NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs)","Chromosome":"4","Start":"3493106","Stop":"3493107","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AGCCT","allel_id":16312,"rule_based_match":true,"evidence_text":"DOK7 c.1124_1127dup (p.Ala378Serfs*30)","llm_judgment":"PRESENT","evidence":"DOK7 c.1124_1127dup (p.Ala378Serfs*30)","abstract_start":1034,"abstract_end":1072},{"Name":"NM_005677.4(COLQ):c.1289A>C (p.Tyr430Ser)","Chromosome":"3","Start":"15453838","Stop":"15453838","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":21693,"rule_based_match":true,"evidence_text":"COLQ c.1289A > C (p.Tyr430Ser)","llm_judgment":"PRESENT","evidence":"COLQ c.1289A > C (p.Tyr430Ser)","abstract_start":1147,"abstract_end":1177}]}
{"pmid":"27861786","title":"Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant.","abstract":"Variants in KCNQ2 encoding for K<sub>v</sub> 7.2 neuronal K<sup>+</sup> channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2-related epilepsy: infantile spasms without prior neonatal seizures associated with a gain-of-function gene variant. With use of an international registry, we identified four unrelated patients with the same de novo heterozygous KCNQ2 c.593G>A, p.Arg198Gln (R198Q) variant. All were born at term and discharged home without seizures or concern of encephalopathy, but developed infantile spasms with hypsarrhythmia (or modified hypsarrhythmia) between the ages of 4 and 6 months. At last follow-up (ages 3-11 years), all patients were seizure-free and had severe developmental delay. In vitro experiments showed that Kv7.2 R198Q subunits shifted current activation gating to hyperpolarized potentials, indicative of gain-of-function; in neurons, K<sub>v</sub> 7.2 and K<sub>v</sub> 7.2 R198Q subunits similarly populated the axon initial segment, suggesting that gating changes rather than altered subcellular distribution contribute to disease molecular pathogenesis. We conclude that KCNQ2 R198Q is a model for a new subclass of KCNQ2 variants causing infantile spasms and encephalopathy, without preceding neonatal seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.","variants":[{"Name":"NM_172107.4(KCNQ2):c.593G>A (p.Arg198Gln)","Chromosome":"20","Start":"63444756","Stop":"63444756","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":203794,"rule_based_match":true,"evidence_text":"KCNQ2 c.593G>A, p.Arg198Gln (R198Q)","llm_judgment":"PRESENT","evidence":"KCNQ2 c.593G>A, p.Arg198Gln (R198Q)","abstract_start":628,"abstract_end":663}]}
{"pmid":"16088911","title":"Mutation spectrum of the APC gene in 83 Korean FAP families.","abstract":"Familial adenomatous polyposis (FAP) is a clinically well-defined hereditary disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP is characterized by polyposis in the large bowel and variable extracolonic manifestations. With an increase of reported APC germline mutations, many reports have investigated genotype-phenotype correlations in FAP patients. Here, we analyzed the APC gene for germline mutations in 83 unrelated Korean FAP patients and investigated genotype-phenotype correlations. We identified germline APC mutations in 59 (71%) of the cases, including 34 frameshift mutations, 19 nonsense mutations, and six splice site mutations. Among 59 patients with the identified germline mutation of the APC gene, 37 had been reported previously and were included in the genotype-phenotype analysis. In the other 22 patients, we identified seven novel mutations: c.1438C>T, c.2232_2233dupCT, c.3426delT, c.3739_3769del31, c.3931_3935delATTGG, c.4332dupA, and c.4722_4725delACTA. Desmoid tumors were identified in six of the examined FAP patients, five of whom had APC germline mutations; these mutations involved codons 849, 864, 1309, 1444 and 1464, respectively (c.2547_2548delTA, c.2592_2593insCT, c.3927_3931delAAAGA, c.4332dupA and c.4391-4394delAGAG). Four of the included FAP patients had papillary thyroid cancers; all were female and had germline APC mutations (c.1863_1865delTTAincCT, c.2805C>A, c.3183_3187delACAAA and c.3927_3931delAAAGA).","variants":[{"Name":"NM_000038.6(APC):c.2805C>A (p.Tyr935Ter)","Chromosome":"5","Start":"112838399","Stop":"112838399","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":15849,"rule_based_match":true,"evidence_text":"c.2805C>A","llm_judgment":"PRESENT","evidence":"c.2805C>A","abstract_start":1434,"abstract_end":1443},{"Name":"NM_000038.6(APC):c.4391_4394del (p.Glu1464fs)","Chromosome":"5","Start":"112839979","Stop":"112839982","ReferenceAlleleVCF":"AAGAG","AlternateAlleleVCF":"A","allel_id":15851,"rule_based_match":false,"evidence_text":"c.4391-4394delAGAG","llm_judgment":"PRESENT","evidence":"c.4391-4394delAGAG","abstract_start":1276,"abstract_end":1294},{"Name":"NM_000038.6(APC):c.3927_3931del (p.Glu1309fs)","Chromosome":"5","Start":"112839515","Stop":"112839519","ReferenceAlleleVCF":"TAAAAG","AlternateAlleleVCF":"T","allel_id":15855,"rule_based_match":true,"evidence_text":"c.3927_3931delAAAGA","llm_judgment":"PRESENT","evidence":"c.3927_3931delAAAGA","abstract_start":1240,"abstract_end":1259}]}
{"pmid":"25760844","title":"A Chinese boy with methylmalonic aciduria cblB type and a novel mutation in the MMAB gene","abstract":"cblB defect is a rare type of methylmalonic aciduria. In this study, a Chinese boy was diagnosed with methylmalonic aciduria cblB type and a novel mutation in the MMAB gene. The clinical presentations, blood acylcarnitines profiles, urine organic acids and genetic features of the patient were reported. The boy presented with fever, feeding difficulty and lethargy at the age of 2 months. Seven days later, he had coma, cold limb, thrombocytopenia, metabolic acidosis and liver damage. His blood propionylcarnitine and urinary methylmalonic acid levels increased significantly, but the plasma total homocysteine level was in the normal range, which supported the diagnosis of isolated methylmalonic aciduria. Gene analysis was performed by direct sequencing. No mutation in the MUT gene was found. However, a reported mutation c.577G>A (p.E193K) and a novel mutation c.562G>A (p.V188M) in the MMAB gene were identified, which confirmed the diagnosis of methylmalonic aciduria cblB type. Progressive clinical and biochemical improvement has been observed after hydroxylcobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine. He is currently 3 years and 11 months old and has a normal development condition. The phenotypes of the patients with cblB defect are nonspecific. Metabolic analysis and MMAB gene analysis are keys for the diagnosis of the disorder.","variants":[{"Name":"NM_052845.4(MMAB):c.562G>A (p.Val188Met)","Chromosome":"12","Start":"109561062","Stop":"109561062","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":546842,"rule_based_match":true,"evidence_text":"c.562G>A (p.V188M)","llm_judgment":"PRESENT","evidence":"c.562G>A (p.V188M)","abstract_start":868,"abstract_end":886},{"Name":"NM_052845.4(MMAB):c.577G>A (p.Glu193Lys)","Chromosome":"12","Start":"109561047","Stop":"109561047","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":546938,"rule_based_match":true,"evidence_text":"c.577G>A (p.E193K)","llm_judgment":"PRESENT","evidence":"c.577G>A (p.E193K)","abstract_start":828,"abstract_end":846}]}
{"pmid":"30818899","title":"Phenotype and genotype of twelve Chinese children with mitochondrial DNA depletion syndromes","abstract":"<b>Objective:</b> To explore the phenotype and genotype of mitochondrial DNA depletion syndromes (MDS) in Chinese children. <b>Methods:</b> The clinical and genetic data of 12 MDS patients (8 were boys and 4 were girls) diagnosed in the Department of Neurology in Beijing Children's Hospital, Capital Medical University from October 2010 to April 2018 were retrospectively collected and analyzed. <b>Results:</b> The developmental milestones were normal or mildly retardated before disease onset. The age of onset ranged from 0 to 2.9-year-old. Most cases developed postnatal or after infection. The most common initial symptoms were feeding difficulty, seizure, muscle weakness, psychomotor regression and hepatic dysfunction. At the last evaluation, all the patients had developmental retardation, failure to thrive, muscle weakness, and dysphagia. Other clinical features were weight loss (9 cases), hearing impairment (7 cases), ptosis (6 cases), seizure (5 cases), dyspnea (4 cases), visual impairment (1 case), hirsutism (1 case), lactic acidosis (7 cases), elevated hepatic enzymes (4 cases) and creatine kinase (2 cases), elevated protein in cerebrospinal fluid (3 cases), abnormalities on screening for inborn error of metabolism (10 cases) and brain magnetic resonance imaging (MRI) (10 cases), abnormal electromyogram (including neurogenic or myogenic injury) (5 cases). Five patients died of infection or multiple organ failure. A total of 18 novel mutations presented below were detected in these patients. Among the 6 cases of encephalomyopathy, there were 3 with SUCLG1 mutation (c. 916G>T, c. 619T>C, c. 980dupT were novel), 2 with SUCLA2 mutation (c. 851G>A, c.971G>A were novel), and one with RRM2B mutation (c.456-2A>G, c.212T>C were novel). All the cases of hepatic encephalopathy all had POLG mutations (c. 3151G>A, c. 2294C>T, c. 2858G>C, c. 680G>A and c. 150_158delGCAGCAGCA were novel). Two cases of infantile-onset spinocerebellar ataxia had TWNK mutations (c. 1163C>T, c. 1319T>C, c. 1388G>A and c. 257_258delAG were novel). One case of myopathy had TK2 mutations (c.557C>G and c.341A>T were novel). <b>Conclusions:</b> The clinical and genetic features of MDS were heterogeneous. Eighteen novel mutations in six MDS related genes were reported, which expanded the genetic spectrum of MDS in Chinese children.","variants":[{"Name":"NM_002693.3(POLG):c.3151G>A (p.Gly1051Arg)","Chromosome":"15","Start":"89319053","Stop":"89319053","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":567328,"rule_based_match":true,"evidence_text":"c. 3151G>A","llm_judgment":"PRESENT","evidence":"c. 3151G>A","abstract_start":1825,"abstract_end":1835},{"Name":"NM_004614.5(TK2):c.557C>G (p.Pro186Arg)","Chromosome":"16","Start":"66517197","Stop":"66517197","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1941671,"rule_based_match":true,"evidence_text":"c.557C>G","llm_judgment":"PRESENT","evidence":"c.557C>G","abstract_start":2091,"abstract_end":2099},{"Name":"NM_021830.5(TWNK):c.1388G>A (p.Arg463Gln)","Chromosome":"10","Start":"100989788","Stop":"100989788","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2844913,"rule_based_match":true,"evidence_text":"c.1388G>A","llm_judgment":"PRESENT","evidence":"c. 1388G>A","abstract_start":2007,"abstract_end":2017},{"Name":"NM_002693.3(POLG):c.2294C>T (p.Pro765Leu)","Chromosome":"15","Start":"89322874","Stop":"89322874","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3062621,"rule_based_match":true,"evidence_text":"c. 2294C>T","llm_judgment":"PRESENT","evidence":"c. 2294C>T","abstract_start":1837,"abstract_end":1847}]}
{"pmid":"32537019","title":"Biallelic mutations in carbamoyl phosphate synthetase 1 induced hyperammonemia in a neonate: A case report.","abstract":"The aim of the present report was to describe the clinical presentation, diagnosis, and treatment of a case of carbamoyl phosphate synthetase 1 (CPS1) deficiency in a neonate, specifically, a 3 day-old female who visited Hunan Provincial People's Hospital due to anorexia and lethargy for 1 day. Physical and laboratory examination, and MRI were undertaken. Whole exome sequencing (WES) was applied for molecular etiology identification. Sanger sequencing was utilized to validate the variants detected by WES. Structural modeling was conducted for pathogenic analysis. Clinical examination revealed increased intracranial pressure, hyperammonemia, reduced citrulline, and increased glutamic acid levels. WES identified compound heterozygosity of c.713G>C, p.Arg238Pro and c.2339G>A, p.Arg780His in <i>CPS1</i> (NCBI reference sequence, NM_001875.4) as candidate pathogenic variants. Sanger sequencing validated these variants. Structural modeling further confirmed the pathogenesis of these mutations. In conclusion, CPS1 deficiency in neonates is a serious condition that may be misdiagnosed due to severe infection. WES can be a helpful tool in facilitating the diagnosis of this disease.","variants":[{"Name":"NM_001875.5(CPS1):c.2339G>A (p.Arg780His)","Chromosome":"2","Start":"210608507","Stop":"210608507","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":359343,"rule_based_match":true,"evidence_text":"c.2339G>A, p.Arg780His","llm_judgment":"PRESENT","evidence":"c.2339G>A, p.Arg780His","abstract_start":773,"abstract_end":795}]}
{"pmid":"21777349","title":"Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population.","abstract":"Germline point or small frameshift mutations of the CDH1 (E-cadherin) gene are known to cause familial gastric cancer (FGC), but the frequency of CDH1 mutations is low in Japanese patients with FGC. Because recent studies have reported germline large genomic deletions of CDH1 in European and Canadian patients with FGC, in the present study we examined DNA samples from 13 Japanese patients with FGC to determine whether similar germline changes were present in CDH1 in this population. Using a sequencing analysis, a 1-bp deletion (c.1212delC), leading to the production of a truncated protein (p.Asn405IlefsX12), was found in an FGC family; immunohistochemical analysis revealed the loss of CDH1 protein expression in the tumors in this family. Using a combination of multiplex ligation-dependent probe amplification (MLPA) and RT-PCR analyses, we also found a large genomic deletion (c.164-?_387+?del), leading to the loss of exon 3 and the production of a truncated protein (p.Val55GlyfsX38), in another FGC family. The functional effects of the detected mutations were examined using a slow aggregation assay. Significant impairment of cell-cell adhesion was detected in CHO-K1 cells expressing Ile405fsX12- and Gly55fsX38-type CDH1 compared with cells expressing wild-type CDH1. Our results suggest that the p.Asn405IlefsX12 and p.Val55GlyfsX38 mutations of the CDH1 gene contribute to carcinogenesis in patients with FGC. This is the first report of CDH1 germline truncating mutations in Japanese patients with FGC. Screening for large germline rearrangements should be included in CDH1 genetic testing for FGC.","variants":[{"Name":"NM_004360.5(CDH1):c.1212del (p.Asn405fs)","Chromosome":"16","Start":"68813383","Stop":"68813383","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":644839,"rule_based_match":true,"evidence_text":"c.1212delC","llm_judgment":"PRESENT","evidence":"c.1212delC","abstract_start":534,"abstract_end":544}]}
{"pmid":"15831990","title":"Two novel mutations in the C7 gene in a Korean patient with complement C7 deficiency.","abstract":"Complement C7 deficiency is an autosomal recessive disorder well known to be associated with increased susceptibility to meningococcal infection and has mostly been reported in Caucasians. In the Korean population, no case of C7 deficiency has been reported to date. Recently we experienced an 11-yr-old girl with meningococcal meningitis who was diagnosed as having C7 deficiency based upon the undetectable serum C7 protein on radial immunodiffusion and the undetectable serum total and C7 hemolytic activities. To identify the genetic basis of the C7 deficiency of the patient, we performed a mutation analysis for the C7 gene and found two novel mutations; a point mutation at the 3' splice acceptor site of intron 4 (c.281-1G>T) and a large deletion mutation encompassing almost the whole C7 gene from exon 1 to exon 17 (c.1-?_2350+?del). A haplotype analysis showed that the large deletion mutation was inherited from the patient's father. To the best of our knowledge, this is the first confirmed case of C7 deficiency in Korea.","variants":[{"Name":"NM_000587.4(C7):c.281-1G>T","Chromosome":"5","Start":"40936337","Stop":"40936337","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":227286,"rule_based_match":true,"evidence_text":"c.281-1G>T","llm_judgment":"PRESENT","evidence":"c.281-1G>T","abstract_start":722,"abstract_end":732}]}
{"pmid":"28056120","title":"Clinical Characterization of CNGB1-Related Autosomal Recessive Retinitis Pigmentosa.","abstract":"IMPORTANCE: There are limited published data on the phenotype of retinitis pigmentosa (RP) related to CNGB1 variants. These data are needed both for prognostic counseling of patients and for understanding potential treatment windows.\nOBJECTIVE: To describe the detailed clinical and molecular genetic findings in a series of patients with RP with likely pathogenic variants in CNGB1.\nDESIGN, SETTING, AND PARTICIPANTS: In this case series, 10 patients from 9 families underwent full ophthalmologic examination. Molecular investigations included whole-exome analysis in 6 patients. The study was conducted from April 17, 2013, to March 3, 2016, with final follow-up completed on March 2, 2016, and data were analyzed from October 27, 2014, to March 29, 2016.\nMAIN OUTCOMES AND MEASURES: Results of ophthalmologic examination and molecular genetic analysis of CNGB1.\nRESULTS: In this case series, 7 women and 3 men from 9 families with a mean (SD) age of 47.4 (13.2) years identified as having CNGB1 variants were included in this study; there was a mean (SD) follow-up length of 3.7 (2.8) years. The first clinical presentation was with nyctalopia in childhood with visual field loss documented later at a mean (SD) age of 33.2 (8.0) years. All patients had preserved best-corrected visual acuity into adulthood, with a mean of 0.1 logMAR (Snellen equivalent, 20/25) in each eye (logMAR range, 0.0 to 0.3 [Snellen 20/20 to 20/40] in the right eye and -0.1 to 0.3 [Snellen 20/16 to 20/40] in the left eye). Fundus examination revealed midperipheral retinal pigment epithelial atrophy and intraretinal pigment migration. Optical coherence tomography of the macula demonstrated complete preservation of the inner segment ellipsoid band in 1 patient, with variable lateral extent in the other patients corresponding to the diameter of a paracentral ring of increased fundus autofluorescence. Electrophysiologic testing in 6 patients confirmed a rod-cone dystrophy phenotype. Molecular investigations identified a previously reported missense variant (p.[N986I]) and 7 variants not previously reported in disease including 4 nonsense (p.[(Q88*], p.[Q222*], p.[Q318*], and p.[R729*]), 2 frameshift (p.[A1048fs*13], p.[L849Afs*3]), and a splice site variant (c.761 + 2T>A).\nCONCLUSIONS AND RELEVANCE: The data from this study suggest that visual acuity and foveal structure in patients with RP are preserved into adult life such that a lengthy window of opportunity should exist for intervention with novel therapies.","variants":[{"Name":"NM_001297.5(CNGB1):c.2957A>T (p.Asn986Ile)","Chromosome":"16","Start":"57901371","Stop":"57901371","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":177287,"rule_based_match":false,"evidence_text":"p.[N986I]","llm_judgment":"PRESENT","evidence":"p.[N986I]","abstract_start":2046,"abstract_end":2055}]}
{"pmid":"22987568","title":"Analysis of the WISP3 gene in Indian families with progressive pseudorheumatoid dysplasia.","abstract":"Progressive pseudorheumatoid dysplasia (PPD) is a progressive skeletal syndrome characterized by stiffness, swelling and pain in multiple joints with associated osteoporosis in affected patients. Radiographically, the predominant features resemble a spondyloepiphyseal dysplasia. Mutations in the WISP3 gene are known to cause this autosomal recessive condition. To date, only a limited number of studies have looked into the spectrum of mutations causing PPD. We report on clinical features and WISP3 mutations in a large series of Indian patients with this rare skeletal dysplasia. Families with at least one member showing clinical and radiologic features of PPD were recruited for the study. Symptoms, signs and radiographic findings were documented in 35 patients from 25 unrelated families. Swelling of small joints of hands and contractures are the most common presenting features. Mutation analysis was carried out by bidirectional sequencing of the WISP3 gene in all 35 patients. We summarize the clinical features of 35 patients with PPD and report on 11 different homozygous mutations and one instance of compound heterozygosity. Eight (c.233G>A, c.340T>C, c.348C>A, c.433T>C, c.682T>C, c.802T>G, c.947_951delAATTT, and c.1010G>A) are novel mutations and three (c.156C>A, c.248G>A, and c.739_740delTG) have been reported previously. One missense mutation (c.1010G>A; p.Cys337Tyr) appears to be the most common in our population being seen in 10 unrelated families. This is the largest cohort of patients with PPD in the literature and the first report from India on mutation analysis of WISP3. We also review all the mutations reported in WISP3 till date.","variants":[{"Name":"NM_198239.2(CCN6):c.1010G>A (p.Cys337Tyr)","Chromosome":"6","Start":"112069565","Stop":"112069565","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":511619,"rule_based_match":true,"evidence_text":"c.1010G>A (p.Cys337Tyr)","llm_judgment":"PRESENT","evidence":"p.Cys337Tyr","abstract_start":1378,"abstract_end":1389},{"Name":"NM_198239.2(CCN6):c.433T>C (p.Cys145Arg)","Chromosome":"6","Start":"112064841","Stop":"112064841","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2904841,"rule_based_match":true,"evidence_text":"c.433T>C","llm_judgment":"PRESENT","evidence":"c.433T>C","abstract_start":1178,"abstract_end":1186},{"Name":"NM_198239.2(CCN6):c.156C>A (p.Cys52Ter)","Chromosome":"6","Start":"112061098","Stop":"112061098","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":21420,"rule_based_match":true,"evidence_text":"c.156C>A","llm_judgment":"PRESENT","evidence":"c.156C>A","abstract_start":1273,"abstract_end":1281},{"Name":"NM_198239.2(CCN6):c.248G>A (p.Gly83Glu)","Chromosome":"6","Start":"112061190","Stop":"112061190","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":626074,"rule_based_match":true,"evidence_text":"c.248G>A","llm_judgment":"PRESENT","evidence":"c.248G>A","abstract_start":1283,"abstract_end":1291},{"Name":"NM_198239.2(CCN6):c.233G>A (p.Cys78Tyr)","Chromosome":"6","Start":"112061175","Stop":"112061175","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620208,"rule_based_match":true,"evidence_text":"c.233G>A","llm_judgment":"PRESENT","evidence":"c.233G>A","abstract_start":1148,"abstract_end":1156}]}
{"pmid":"24100244","title":"Infantile hypophosphatasia without bone deformities presenting with severe pyridoxine-resistant seizures.","abstract":"An infant carrying a heterozygous c.43_46delACTA and a heterozygous c.668 G>A mutation in the ALPL gene with hypophosphatasia in the absence of bone deformities presented with therapy-resistant seizures. Pyridoxal phosphate was extremely high in CSF and plasma. Pyridoxine treatment had only a transient effect and the severe encephalopathy was fatal. Repeated brain MRIs showed progressive cerebral damage. The precise metabolic cause of the seizures remains unknown and pyridoxine treatment apparently does not cure the epilepsy.","variants":[{"Name":"NM_000478.6(ALPL):c.668G>A (p.Arg223Gln)","Chromosome":"1","Start":"21568123","Stop":"21568123","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":364747,"rule_based_match":true,"evidence_text":"c.668 G>A","llm_judgment":"PRESENT","evidence":"c.668 G>A","abstract_start":68,"abstract_end":77}]}
{"pmid":"30872671","title":"Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis.","abstract":"Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease with both autoimmune and autoinflammatory components. Recently, familial cases of systemic-onset JIA have been attributed to mutations in LACC1/FAMIN. We describe three affected siblings from a Moroccan consanguineous family with an early-onset chronic, symmetric and erosive arthritis previously diagnosed as rheumatoid factor (RF)-negative polyarticular JIA. Autozygosity mapping identified four homozygous regions shared by all patients, located in chromosomes 3, 6 (n:2) and 13, containing over 330 genes. Subsequent whole exome sequencing identified two potential candidate variants within these regions (in FARS2 and LACC1/FAMIN). Genotyping of a cohort of healthy Moroccan individuals (n: 352) and bioinformatics analyses finally supported the frameshift c.128_129delGT mutation in the LACC1/FAMIN gene, leading to a truncated protein (p.Cys43Tyrfs*6), as the most probable causative gene defect. Additional targeted sequencing studies performed in patients with systemic-onset JIA (n:23) and RF-negative polyarticular JIA (n: 44) revealed no pathogenic LACC1/FAMIN mutations. Our findings support the homozygous genotype in the LACC1/FAMIN gene as the defect underlying the family here described with a recessively inherited severe inflammatory joint disease. Our evidences provide further support to the involvement of LACC1/FAMIN deficiency in different types of JIA in addition to the initially described systemic-onset JIA.","variants":[{"Name":"NM_153218.4(LACC1):c.128_129del (p.Cys43fs)","Chromosome":"13","Start":"43881112","Stop":"43881113","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":802255,"rule_based_match":true,"evidence_text":"c.128_129delGT","llm_judgment":"PRESENT","evidence":"c.128_129delGT","abstract_start":829,"abstract_end":843}]}
{"pmid":"31630789","title":"RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.","abstract":"Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.","variants":[{"Name":"NM_000977.4(RPL13):c.477+2T>C","Chromosome":"16","Start":"89562393","Stop":"89562393","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":677480,"rule_based_match":true,"evidence_text":"c.477+2 T>C","llm_judgment":"PRESENT","evidence":"c.477+2 T>C","abstract_start":467,"abstract_end":478}]}
{"pmid":"22424600","title":"Mutations in ROGDI Cause Kohlschütter-Tönz Syndrome.","abstract":"Kohlschütter-Tönz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta. The molecular basis has not yet been elucidated. Here, we report that KTS is caused by mutations in ROGDI. Using a combination of autozygosity mapping and exome sequencing, we identified a homozygous frameshift deletion, c.229_230del (p.Leu77Alafs(∗)64), in ROGDI in two affected individuals from a consanguineous family. Molecular studies in two additional KTS-affected individuals from two unrelated Austrian and Swiss families revealed homozygosity for nonsense mutation c.286C>T (p.Gln96(∗)) and compound heterozygosity for the splice-site mutations c.531+5G>C and c.532-2A>T in ROGDI, respectively. The latter mutation was also found to be heterozygous in the mother of the Swiss affected individual in whom KTS was reported for the first time in 1974. ROGDI is highly expressed throughout the brain and other organs, but its function is largely unknown. Possible interactions with DISC1, a protein involved in diverse cytoskeletal functions, have been suggested. Our finding that ROGDI mutations cause KTS indicates that the protein product of this gene plays an important role in neuronal development as well as amelogenesis.","variants":[{"Name":"NM_024589.3(ROGDI):c.229_230del (p.Leu77fs)","Chromosome":"16","Start":"4801292","Stop":"4801293","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":40182,"rule_based_match":true,"evidence_text":"c.229_230del (p.Leu77Alafs(∗)64)","llm_judgment":"PRESENT","evidence":"c.229_230del (p.Leu77Alafs(∗)64)","abstract_start":387,"abstract_end":419},{"Name":"NM_024589.3(ROGDI):c.286C>T (p.Gln96Ter)","Chromosome":"16","Start":"4800548","Stop":"4800548","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40183,"rule_based_match":true,"evidence_text":"c.286C>T (p.Gln96(∗))","llm_judgment":"PRESENT","evidence":"c.286C>T (p.Gln96(∗))","abstract_start":640,"abstract_end":661}]}
{"pmid":"34174466","title":"Severe neurodevelopmental disorder with intractable seizures due to a novel SLC1A4 homozygous variant.","abstract":"INTRODUCTION: Biallelic variants in the SLC1A4 gene have been so far identified as a very rare cause of neurodevelopmental disorders with or without epilepsy and almost exclusively described in the Ashkenazi-Jewish population.\nPATIENTS AND METHODS: Here we present Czech patient with microcephaly, severe global developmental delay and intractable seizures whose condition remained undiagnosed despite access to clinical experience and standard diagnostic methods including examination with an epilepsy targeted NGS gene panel.\nRESULTS: Whole exome sequencing revealed a novel variant NM_003038.4:c.1370G > A p.(Arg457Gln) of the SLC1A4 gene in a homozygous state in the patient, and afterwards Sanger sequencing in both parents confirmed the biallelic origin of the variant. A variant in the same codon, but with a different amino acid exchange, was described previously in a patient that had a very similar phenotype, however, without epilepsy.\nCONCLUSION: Our data suggest that the SLC1A4 gene should be considered in the diagnosis of patients with severe, early onset neurodevelopmental impairment with epilepsy and encourage the analysis of SLC1A4 gene variants via targeted NGS gene panel or whole exome sequencing.","variants":[{"Name":"NM_003038.5(SLC1A4):c.1370G>A (p.Arg457Gln)","Chromosome":"2","Start":"65020917","Stop":"65020917","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1677459,"rule_based_match":true,"evidence_text":"NM_003038.4:c.1370G > A p.(Arg457Gln)","llm_judgment":"PRESENT","evidence":"NM_003038.4:c.1370G > A p.(Arg457Gln)","abstract_start":585,"abstract_end":622}]}
{"pmid":"27573432","title":"Homozygous DNAH1 frameshift mutation causes multiple morphological anomalies of the sperm flagella in Chinese.","abstract":"This study aimed to investigate the genetic pathogeny of multiple morphological anomalies of the flagella (MMAF), which is a genetically heterogeneous disorder leading to male infertility. Nine patients with severe asthenozoospermia caused by MMAF were recruited. Whole genome sequencing and Sanger sequencing were performed, and we found that four of the nine patients were affected by the same homozygous frameshift mutation c.11726_11727delCT (p.[Pro3909ArgfsTer33]) in exon 73 of dynein axonemal heavy chain 1 ( DNAH1 ) gene. The parents and the sibling of proband 1 were all identified as heterozygous carriers. This mutation was distinct from previously reported DNAH1 mutations associated with MMAF and only affected the East Asian group. Furthermore, the variant DNAH1 protein could not be detected in spermatozoa by Western blot or immunofluorescence staining although DNAH1 mRNA was expressed in the spermatozoa. Scanning electron microscopy and transmission electron microscopy analysis showed the anomalies in sperm flagella morphology and ultrastructure in patients carrying this genetic variant. In conclusion, our results add to knowledge of the genetic pathogeny of MMAF and further confirmed the effectiveness of genetic screening in the diagnosis of MMAF.","variants":[{"Name":"NM_015512.5(DNAH1):c.11726_11727del (p.Pro3909fs)","Chromosome":"3","Start":"52396983","Stop":"52396984","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":424405,"rule_based_match":true,"evidence_text":"c.11726_11727delCT (p.[Pro3909ArgfsTer33])","llm_judgment":"PRESENT","evidence":"c.11726_11727delCT (p.[Pro3909ArgfsTer33])","abstract_start":427,"abstract_end":469}]}
{"pmid":"28778788","title":"Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability.","abstract":"In this study we present the first two cases from India of a rare inborn error of metabolism manifesting as dystonia and 3-methylglutaconic aciduria and a Leigh like lesions in the brain MRI associated with SERAC1 gene mutation, a phenotype characteristic of MEGDEL syndrome. A four base pair duplication in exon 15 i.e.NM_032861.3 (SERAC1) c. 1643_1646 dup ATCT (p.(Leu550SerfsX19)) and another with a homozygous missense variation in exon 15 i.e. NM_032861.3 (SERAC1) c.1709 G > A (p.(Gly526Glu)) were detected and both were novel mutations. Hepatopathy was observed in the neonatal period with lactic acidosis in one child and at the age of 5yrs in the other. These cases add to the existing number of patients identified till today and additional mutations in the SERAC1 gene.","variants":[{"Name":"NM_032861.4(SERAC1):c.1643_1646dup (p.Leu550fs)","Chromosome":"6","Start":"158114826","Stop":"158114827","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AAGAT","allel_id":423256,"rule_based_match":true,"evidence_text":"NM_032861.3 (SERAC1) c. 1643_1646 dup ATCT (p.(Leu550SerfsX19))","llm_judgment":"PRESENT","evidence":"NM_032861.3 (SERAC1) c. 1643_1646 dup ATCT (p.(Leu550SerfsX19))","abstract_start":320,"abstract_end":383}]}
{"pmid":"20972686","title":"Neonatal severe hyperparathyroidism: further clinical and molecular delineation.","abstract":"UNLABELLED: We report a newborn female from a consanguineous Sri Lankan family with clinical and biochemical features of neonatal severe hyperparathyroidism (NSHPT). Mutation screening of the calcium-sensing receptor (CASR) gene in genomic DNA revealed a homozygous truncating mutation (c.679C>T, predicting p.R227X), confirming the clinical diagnosis. Other mutations at the R227 position are reported to cause varying degrees of hypercalcemia and hyperparathyroidism, but this nonsense variant is novel and expected to induce unremitting hyperparathyroidism from birth onward. In our patient with NSHPT, early bisphosphonate therapy was crucial in counteracting the marked hypercalcemia and allowed for safe surgical intervention (\"total\" parathyroidectomy, \"thymectomy and hemithyroidectomy\") at 3 months of age.\nCONCLUSION: This report highlights the continuing challenges in diagnosis and management of this life-threatening condition.","variants":[{"Name":"NM_000388.4(CASR):c.679C>T (p.Arg227Ter)","Chromosome":"3","Start":"122261714","Stop":"122261714","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":518951,"rule_based_match":true,"evidence_text":"c.679C>T","llm_judgment":"PRESENT","evidence":"c.679C>T","abstract_start":287,"abstract_end":295}]}
{"pmid":"38369462","title":"","abstract":"PURPOSE: This study aims to evaluate the ABCA4 variants in patients diagnosed with Stargardt disease.\nMETHODS: This is a retrospective study designed to investigate variants in the ABCA4 in Stargardt disease and the clinical findings of the cases. Sex, age, age of onset of symptoms, best-corrected visual acuity, color fundus photography, optical coherence tomography, and visual field test of the patients were recorded. Genetic analyses were screened, and patients with at least two variants in the ABCA4 were included in this study.\nRESULTS: Twenty-seven patients diagnosed with Stargardt disease with the ABCA4 variants were included in this study. Twelve of them (44.4%) were female and fifteen (55.5%) were male. The mean age of the cases was 27.44 years (ranging from 8 to 56 years). Thirty different variants were detected in 54 ABCA4 alleles of 27 patients. The two most common pathogenic variants were c.5882 G>A p.(Gly1961Glu) and c.52C>T p.(Arg18Trp) in this cohort. Two novel variants were identified (c.3855_3856dup, c.1554 + 3_1554 + 4del) and the patient with the c.1554 + 3_1554 + 4del variant additionally had a different ABCA4 variant in trans. The other novel variant was homozygous.\nCONCLUSIONS: In this study, two novel variants were described in a Turkish cohort with Stargardt disease. The variant c.52C>T p.(Arg18Trp) was the most common disease-causing variant besides the c.5882 G>A p.(Gly1961Glu) which was identified frequently in the previous studies. A larger sample size is necessary for describing different pathogenic variants and understanding the phenotype-genotype correlations.","variants":[{"Name":"NM_000350.3(ABCA4):c.52C>T (p.Arg18Trp)","Chromosome":"1","Start":"94120994","Stop":"94120994","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22938,"rule_based_match":true,"evidence_text":"c.52C>T p.(Arg18Trp)","llm_judgment":"PRESENT","evidence":"c.52C>T p.(Arg18Trp)","abstract_start":943,"abstract_end":963}]}
{"pmid":"27882484","title":"Diagnostic challenge of Diamond-Blackfan anemia in mothers and children by whole-exome sequencing.","abstract":"Diamond-Blackfan anemia (DBA) is a pure red cell aplasia that arises from defective ribosomal proteins (RPs). Patients with this rare ribosomopathy present with neonatal anemia and occasional dysmorphism. Clinical heterogeneity and clusters of causative RP genes hamper the diagnosis and perinatal management. We report three mother-and-child pairs of anemia who were finally diagnosed by whole-exome sequencing. Each pair showed distinct disease severity and response to anemia treatment. Only one mother had the diagnostic dysmorphism, including short stature, webbed neck, and thenar hypoplasia. This mother had a frame-shift mutation of RPL11 (exon 3, c.58_59del). Her infant showed transient neonatal anemia, but had no mutations of RP genes. The other mother-child pairs had a missense mutation of RPS19 (exon 4, c.185G>A), and a splicing error of RPS7 (exon 3, c.76-1G>T), respectively. Other than the reported mutations, there were no variants in genes significantly associated with anemia. Our results suggested that whole-exome sequencing (WES) is effective for achieving a prompt and correct diagnosis of human ribosomopathy.","variants":[{"Name":"NM_001011.4(RPS7):c.76-1G>T","Chromosome":"2","Start":"3575816","Stop":"3575816","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":359098,"rule_based_match":true,"evidence_text":"c.76-1G>T","llm_judgment":"PRESENT","evidence":"c.76-1G>T","abstract_start":868,"abstract_end":877},{"Name":"NM_001022.4(RPS19):c.185G>A (p.Arg62Gln)","Chromosome":"19","Start":"41869043","Stop":"41869043","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":468836,"rule_based_match":true,"evidence_text":"c.185G>A","llm_judgment":"PRESENT","evidence":"c.185G>A","abstract_start":819,"abstract_end":827}]}
{"pmid":"34485012","title":"Abnormal VLCADD newborn screening resembling MADD in four neonates with decreased riboflavin levels and VLCAD activity.","abstract":"Early detection of congenital disorders by newborn screening (NBS) programs is essential to prevent or limit disease manifestation in affected neonates. These programs balance between the detection of the highest number of true cases and the lowest number of false-positives. In this case report, we describe four unrelated cases with a false-positive NBS result for very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Three neonates presented with decreased but not deficient VLCAD enzyme activity and two of them carried a single heterozygous <i>ACADVL</i> c.1844G>A mutation. Initial biochemical investigations after positive NBS referral in these infants revealed acylcarnitine and organic acid profiles resembling those seen in multiple acyl-CoA dehydrogenase deficiency (MADD). Genetic analysis did not reveal any pathogenic mutations in the genes encoding the electron transfer flavoprotein (ETF alpha and beta subunits) nor in ETF dehydrogenase. Subsequent further diagnostics revealed decreased levels of riboflavin in the newborns and oral riboflavin administration normalized the MADD-like biochemical profiles. During pregnancy, the mothers followed a vegan, vegetarian or lactose-free diet which probably caused alimentary riboflavin deficiency in the neonates. This report demonstrates that a secondary (alimentary) maternal riboflavin deficiency in combination with reduced VLCAD activity in the newborns can result in an abnormal VLCADD/MADD acylcarnitine profile and can cause false-positive NBS. We hypothesize that maternal riboflavin deficiency contributed to the false-positive VLCADD neonatal screening results.","variants":[{"Name":"NM_000018.4(ACADVL):c.1844G>A (p.Arg615Gln)","Chromosome":"17","Start":"7224973","Stop":"7224973","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":192609,"rule_based_match":true,"evidence_text":"c.1844G>A","llm_judgment":"PRESENT","evidence":"c.1844G>A","abstract_start":567,"abstract_end":576}]}
{"pmid":"35673401","title":"Papillary Thyroid Cancer and a","abstract":"Purpose: About 40% of paragangliomas (PGL) are due to germline mutations in one of several susceptibility genes. These genes rarely predispose to other non-PGL tumors. Here, we describe and functionally characterize a germline <i>SDHB</i> mutation in a patient who developed a <i>BRAF</i> <sup>V600E</sup> mutation-positive papillary thyroid cancer (PTC) and a <i>TERT</i> promotor mutation-positive PGL.\nExperimental design: A 28-year-old asymptomatic man was discovered incidentally to have a large left-sided mid-abdominal PGL and PTC. He underwent resection of the PGL and total thyroidectomy and neck dissection followed by I-131 adjuvant therapy for PTC. The histopathology revealed a high-grade PGL and a tall cell-variant PTC with lymph node metastases (T1b N1b M0). He soon developed PGL spinal metastases that have been rapidly progressing and is currently being treated with Lu<sup>177</sup>-dotatate therapy. Family screening revealed a positive <i>SDHB</i> mutation in the mother, a son, and a brother.\nResults: In addition to the heterozygous <i>SDHB</i> germline mutation (c.688C>T, p.Arg230Cys), molecular analysis revealed a somatic <i>TERT</i> promotor mutation (C228T) in PGL (negative in PTC) and a somatic <i>BRAF</i> <sup>V600E</sup> mutation in PTC (negative in PGL). Functional studies showed a higher proliferation rate in the mutant compared with the wild-type SDHB.\nConclusion: Germline <i>SDHB</i> mutations rarely occur in patients with PTC and may contribute to its aggressiveness. Somatic <i>TERT</i> promotor mutations rarely occur in PGL and contribute to its aggressiveness and metastatic potential.","variants":[{"Name":"NM_003000.3(SDHB):c.688C>T (p.Arg230Cys)","Chromosome":"1","Start":"17022685","Stop":"17022685","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":181608,"rule_based_match":true,"evidence_text":"c.688C>T, p.Arg230Cys","llm_judgment":"PRESENT","evidence":"c.688C>T, p.Arg230Cys","abstract_start":1088,"abstract_end":1109}]}
{"pmid":"12815605","title":"Six novel mutations of the RUNX2 gene in Italian patients with cleidocranial dysplasia.","abstract":"We report clinical and molecular findings in 14 patients with cleidocranial dysplasia (CCD), a well defined skeletal disorder with characteristic clinical findings and autosomal dominant inheritance. We identified ten heterozygous base changes in the RUNX2 gene, including six novel mutations [c.522insA, c.389G>A (W130X), c.662T>G (V221G), IVS2+T>A, c.1111_1129del19, and c.873_874delCA]. We did not establish a clear correlation between clinical features and genotype, the phenotypes of all patients analyzed falling within the range of variation described in CCD without an effect related to the length of the predicted protein. In two cases, however, a limb-girdle myopathy affecting the shoulder muscles was also identified. Our data add new variants to the repertoire of RUNX2 mutations in CCD.","variants":[{"Name":"NM_001024630.4(RUNX2):c.389G>A (p.Trp130Ter)","Chromosome":"6","Start":"45422923","Stop":"45422923","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2904789,"rule_based_match":true,"evidence_text":"c.389G>A (W130X)","llm_judgment":"PRESENT","evidence":"c.389G>A (W130X)","abstract_start":305,"abstract_end":321}]}
{"pmid":"28884940","title":"Variable phenotypic expression in a large Noonan syndrome family segregating a novel SOS1 mutation.","abstract":"Noonan syndrome (NS) is an autosomal dominant multisystem condition with a variable phenotype. The most characteristic features are short stature, congenital heart defects, and recognizable facial features. Mutations in SOS1 are found in 10-20% of patients with NS. Different genotype-phenotype studies mention correlations between SOS1 mutations and some features, such as ectodermal abnormalities and specific facial features. We present a large NS family with a novel pathogenic mutation; SOS1 c.3134C>G, p.Pro1045Arg. Ten family members with NS are included with genetically confirmed mutation and clinical evaluation. The phenotype shows a broad spectrum from only few suggestive features for NS in the older generation to typical features in the youngest generation. We report on a novel pathogenic mutation in the SOS1 gene and a large clinical spectrum in a NS family with ten genetically confirmed affected individuals.","variants":[{"Name":"NM_005633.4(SOS1):c.3134C>G (p.Pro1045Arg)","Chromosome":"2","Start":"38995335","Stop":"38995335","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":921224,"rule_based_match":true,"evidence_text":"SOS1 c.3134C>G, p.Pro1045Arg","llm_judgment":"PRESENT","evidence":"SOS1 c.3134C>G, p.Pro1045Arg","abstract_start":492,"abstract_end":520}]}
{"pmid":"29237421","title":"First-decade patient with colorectal cancer carrying both germline and somatic mutations in APC gene.","abstract":"BACKGROUND: Colorectal carcinoma (CRC) is one of the most common causes of cancer-related deaths. The mean age of patients with CRC ranges from 49 to 60 years. Pediatric CRC is unusual, which often escapes early diagnosis because of a lack of awareness of its occurrence in children. The association between the mutation of APC and the occurrence of CRC in the first decade of life remains unknown.\nCASE PRESENTATION: We report a 10-year-old child with CRC; he was diagnosed with stage IIIB advanced transverse colon cancer without distal metastases. We detected a heterozygous germline mutation at c.5465 T > A in both blood and tissue samples and a heterozygous somatic mutation at c.7397C > T in the tissue sample. Both of these mutations can cause CRC tumorigenesis in the first decade of life.\nCONCLUSIONS: The rare genetic features of this 10-year-old patient might be the predisposing cause of pediatric CRC. Therefore, screening patients with early-onset CRC through clinical and genetic characterizations is suggested.","variants":[{"Name":"NM_000038.6(APC):c.7397C>T (p.Ser2466Phe)","Chromosome":"5","Start":"112842991","Stop":"112842991","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":617252,"rule_based_match":true,"evidence_text":"c.7397C > T","llm_judgment":"PRESENT","evidence":"c.7397C > T","abstract_start":684,"abstract_end":695}]}
{"pmid":"30187681","title":"Protein modeling and clinical description of a novel in-frame GLB1 deletion causing GM1 gangliosidosis type II.","abstract":"BACKGROUND: Beta-galactosidase-1 (GLB1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly GM1 (monosialotetrahexosylganglioside). Pathogenic variants in GLB1 cause two different lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB. In GM1 gangliosidosis, decreased β-galactosidase-1 enzymatic activity leads to the accumulation of GM1 gangliosides, predominantly within the CNS. We present a 22-month-old proband with GM1 gangliosidosis type II (late-infantile form) in whom a novel homozygous in-frame deletion (c.1468_1470delAAC, p.Asn490del) in GLB1 was detected.\nMETHODS: We used an experimental protein structure of β-galactosidase-1 to generate a model of the p.Asn490del mutant and performed molecular dynamic simulations to determine whether this mutation leads to altered ligand positioning compared to the wild-type protein. In addition, residual mutant enzyme activity in patient leukocytes was evaluated using a fluorometric assay.\nRESULTS: Molecular dynamics simulations showed the deletion to alter the catalytic site leading to misalignment of the catalytic residues and loss of collective motion within the model. We predict this misalignment will lead to impaired catalysis of β-galactosidase-1 substrates. Enzyme assays confirmed diminished GLB1 enzymatic activity (~3% of normal activity) in the proband.\nCONCLUSIONS: We have described a novel, pathogenic in-frame deletion of GLB1 in a patient with GM1 gangliosidosis type II.","variants":[{"Name":"NM_000404.4(GLB1):c.1468_1470del (p.Asn490del)","Chromosome":"3","Start":"33016718","Stop":"33016720","ReferenceAlleleVCF":"CGTT","AlternateAlleleVCF":"C","allel_id":827901,"rule_based_match":true,"evidence_text":"c.1468_1470delAAC, p.Asn490del","llm_judgment":"PRESENT","evidence":"c.1468_1470delAAC, p.Asn490del","abstract_start":595,"abstract_end":625}]}
{"pmid":"32789421","title":"Screening for Fabry disease among 619 hemodialysis patients in Saudi Arabia.","abstract":"OBJECTIVES: To determine the prevalence of Fabry disease (FD) among Saudi patients on hemodialysis.\nMETHODS: This prospective study was conducted in 3 major hospitals in the Kingdom of Saudi Arabia (KSA). All adult patients (greater than 18 years old) attending the dialysis unit who have end-stage renal disease (ESRD) and on hemodialysis were included. Known patients with FD and those who refused to participate in the study were excluded. All eligible patients were screened for FD using dry blood spot (DBS) for alpha-galactosidase A (α-Gal A). A positive DBS (enzyme activity less than 40%) was followed by another con rmatory enzyme assay. When the second DBS sample was also positive (enzyme activity less than 40%), a Sanger sequencing of the GLA gene was performed.\nRESULTS: A total of 619 patients with ESRD and on hemodialysis were screened for FD using DBS for α-Gal A enzyme level. Enzymatic activity was below 40% in 11 samples. On retesting, 3 females had less than 20% enzymatic activity suggesting FD. Sanger sequencing of these 3 females showed the variant c.1055C greater than G (p.Ala352Gly) confirming the diagnosis of FD. Family screening of one of these 3 patients revealed one asymptomatic female carrying the same variant.\nCONCLUSION: The prevalence of FD in this cohort was 4.8 per 1000 patients. Screening of Fabry patients with ESRD seems to be a cost-effective strategy. Furthermore, relatives of the patients identified by screening enhances this screening strategy.","variants":[{"Name":"NM_000169.3(GLA):c.1055C>G (p.Ala352Gly)","Chromosome":"X","Start":"101398044","Stop":"101398044","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":214016,"rule_based_match":false,"evidence_text":"c.1055C greater than G (p.Ala352Gly)","llm_judgment":"PRESENT","evidence":"c.1055C greater than G (p.Ala352Gly)","abstract_start":1076,"abstract_end":1112}]}
{"pmid":"36507858","title":"Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient.","abstract":"ARL2BP is a ciliary gene associated with multiple ciliopathy phenotypes. On comprehensive clinical examinations using molecular methods, we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia. Situs inversus and male infertility have never been reported in the same patient with ARL2BP variants; therefore, this a novel ARL2BP-associated phenotypic triad of RP, situs inversus, and male infertility. Moreover, this patient likely had olfactory dysfunction susceptibility and presented with anosmia. We found reduced patient-derived fibroblast proliferation and ciliary length. Our findings expand the genotypic spectrum and reveal abnormal cell proliferation and ciliogenesis in ARL2BP-associated patients.","variants":[{"Name":"NM_012106.4(ARL2BP):c.22_23del (p.Ser8fs)","Chromosome":"16","Start":"57245384","Stop":"57245385","ReferenceAlleleVCF":"GGA","AlternateAlleleVCF":"G","allel_id":3496833,"rule_based_match":true,"evidence_text":"c.22_23delAG (p.S8Lfs*10)","llm_judgment":"PRESENT","evidence":"c.22_23delAG (p.S8Lfs*10)","abstract_start":234,"abstract_end":259}]}
{"pmid":"21752896","title":"SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas.","abstract":"CONTEXT: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA.\nOBJECTIVE: In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations.\nSETTING: This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France).\nMETHODS: We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA.\nRESULTS: Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C → T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C → T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations.\nCONCLUSIONS: Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.","variants":[{"Name":"NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)","Chromosome":"5","Start":"251427","Stop":"251427","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":170202,"rule_based_match":false,"evidence_text":"c.1753C → T (p.Arg585Trp)","llm_judgment":"PRESENT","evidence":"c.1753C → T (p.Arg585Trp)","abstract_start":1137,"abstract_end":1162},{"Name":"NM_004168.4(SDHA):c.91C>T (p.Arg31Ter)","Chromosome":"5","Start":"223509","Stop":"223509","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152315,"rule_based_match":false,"evidence_text":"c.91C → T SDHA gene mutation (p.Arg31X)","llm_judgment":"PRESENT","evidence":"c.91C → T SDHA gene mutation (p.Arg31X)","abstract_start":1026,"abstract_end":1065}]}
{"pmid":"25123644","title":"Seizure recurrence following pyridoxine withdrawal in a patient with pyridoxine-dependent epilepsy.","abstract":"Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive disorder characterized by early onset and recurrent seizures that can be controlled by a high dose of pyridoxine. PDE is caused by mutations in ALDH7A1, which encodes antiquitin. Antiquitin converts α-aminoadipic semialdehyde to α-aminoadipic acid. Seizure recurrence after pyridoxine withdrawal is a criterion for diagnosis, but PDE can be diagnosed conclusively by genetic testing for mutations in the ALDH7A1 gene. In this case study, we report the long-term follow-up of a patient suspected with PDE. She experienced prolonged generalized tonic seizures and was hospitalized in an intensive care unit following pyridoxine withdrawal. Later, we identified a compound heterozygous mutation, c.1216G>A, p.Gly406Arg, and a novel splice donor site mutation, IVS9+5G>A. Confirmation of these mutations would have prevented an unsafe withdrawal test. This case suggests the importance of the genetic determination of PDE to avoid the diagnostic withdrawal of pyridoxine.","variants":[{"Name":"NM_001182.5(ALDH7A1):c.1216G>A (p.Gly406Arg)","Chromosome":"5","Start":"126552122","Stop":"126552122","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1867790,"rule_based_match":true,"evidence_text":"c.1216G>A, p.Gly406Arg","llm_judgment":"PRESENT","evidence":"c.1216G>A, p.Gly406Arg","abstract_start":755,"abstract_end":777}]}
{"pmid":"18160816","title":"SLC40A1 c.1402G-->a results in aberrant splicing, ferroportin truncation after glycine 330, and an autosomal dominant hemochromatosis phenotype.","abstract":"BACKGROUND/AIMS: To determine the molecular basis of a mild hemochromatosis phenotype in a man of Scottish-Irish descent.\nMETHODS: We sequenced genomic DNA to detect mutations of HFE, SLC40A1, TFR2, HAMP, and HFE2. RNA isolated from blood mononuclear cells was used to make cDNA. RT-PCR was performed to amplify ferroportin from cDNA, and amplified products were visualized by electrophoresis and sequenced.\nRESULTS: The proband was heterozygous for the novel mutation c.1402G-->A (predicted G468S) in exon 7 of the ferroportin gene (SLC40A1). Located in the last nucleotide before the splice junction, this mutation results in aberrant splicing to a cryptic upstream splice site located at nt 990 within the same exon. This causes truncation of ferroportin after glycine 330 and the addition of 4 irrelevant amino acids before terminating. The truncated ferroportin protein, missing its C-terminal 241 amino acids, would lack all structural motifs beyond transmembrane region 7. The patient was also heterozygous for the common HFE H63D polymorphism, but did not have coding region mutations in TFR2, HAMP, or HFE2.\nCONCLUSIONS: We conclude that this patient represents a unique example of hemochromatosis due to a single base-pair mutation of SLC40A1 that results in aberrant splicing and truncation of ferroportin.","variants":[{"Name":"NM_014585.6(SLC40A1):c.1402G>A (p.Gly468Ser)","Chromosome":"2","Start":"189563584","Stop":"189563584","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1003571,"rule_based_match":false,"evidence_text":"c.1402G-->A (predicted G468S)","llm_judgment":"PRESENT","evidence":"c.1402G-->A (predicted G468S)","abstract_start":469,"abstract_end":498}]}
{"pmid":"35464846","title":"Case Report: A Novel Mutation Identified in","abstract":"<b>Background:</b> Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare heritable connective tissue disease with various symptoms. The diagnosis of mcEDS is difficult because of the large overlap of clinical symptoms between different EDS subtypes. <b>Methods:</b> We performed karyotype analysis, gene copy number variation detection, whole-exome sequencing, and Sanger sequencing to reveal the underlying genetic etiology of a fetus with structural abnormalities in feet and kidneys. <b>Results:</b> A likely pathogenic mutation [NM_130468.3 c.958C>T (p.Arg320*)] and an uncertain significance mutation [NM_130468.3 c.896A>G (p.Tyr299Cys)] were identified in the carbohydrate sulfotransferase 14 (<i>CHST14</i>) gene by whole-exome sequencing and validated by Sanger sequencing. <b>Conclusion:</b> The two identified mutations appear highly likely to be the genetic causes of the fetal structural abnormalities.","variants":[{"Name":"NM_130468.4(CHST14):c.958C>T (p.Arg320Ter)","Chromosome":"15","Start":"40472171","Stop":"40472171","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":426093,"rule_based_match":true,"evidence_text":"NM_130468.3 c.958C>T (p.Arg320*)","llm_judgment":"PRESENT","evidence":"NM_130468.3 c.958C>T (p.Arg320*)","abstract_start":540,"abstract_end":572}]}
{"pmid":"34565360","title":"Clinical and functional characterization of a novel STUB1 frameshift mutation in autosomal dominant spinocerebellar ataxia type 48 (SCA48).","abstract":"BACKGROUND: Heterozygous pathogenic variants in STUB1 are implicated in autosomal dominant spinocerebellar ataxia type 48 (SCA48), which is a rare familial ataxia disorder. We investigated the clinical, genetic and functional characteristics of STUB1 mutations identified from a Taiwanese ataxia cohort.\nMETHODS: We performed whole genome sequencing in a genetically undiagnosed family with an autosomal dominant ataxia syndrome. Further Sanger sequencing of all exons and intron-exon boundary junctions of STUB1 in 249 unrelated patients with cerebellar ataxia was performed. The pathogenicity of the identified novel STUB1 variant was investigated.\nRESULTS: We identified a novel heterozygous frameshift variant, c.832del (p.Glu278fs), in STUB1 in two patients from the same family. This rare mutation is located in the U-box of the carboxyl terminus of the Hsc70-interacting protein (CHIP) protein, which is encoded by STUB1. Further in vitro experiments demonstrated that this novel heterozygous STUB1 frameshift variant impairs the CHIP protein's activity and its interaction with the E2 ubiquitin ligase, UbE2D1, leading to neuronal accumulation of tau and α-synuclein, caspase-3 activation, and promoting cellular apoptosis through a dominant-negative pathogenic effect. The in vivo study revealed the influence of the CHIP expression level on the differentiation and migration of cerebellar granule neuron progenitors during cerebellar development.\nCONCLUSIONS: Our findings provide clinical, genetic, and a mechanistic insight linking the novel heterozygous STUB1 frameshift mutation at the highly conserved U-box domain of CHIP as the cause of autosomal dominant SCA48. Our results further stress the importance of CHIP activity in neuronal protein homeostasis and cerebellar functions.","variants":[{"Name":"NM_005861.4(STUB1):c.832del (p.Glu278fs)","Chromosome":"16","Start":"682408","Stop":"682408","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":429841,"rule_based_match":true,"evidence_text":"c.832del (p.Glu278fs)","llm_judgment":"PRESENT","evidence":"c.832del (p.Glu278fs)","abstract_start":715,"abstract_end":736}]}
{"pmid":"25847220","title":"Mutation of CHRNA2 in a family with benign familial infantile seizures: Potential role of nicotinic acetylcholine receptor in various phenotypes of epilepsy.","abstract":"Nicotinic acetylcholine receptor genes are involved mainly in nocturnal frontal epilepsy. Despite extensive studies, to date, the α2 subunit did not show a strong association with this peculiar epileptic phenotype. We report CHRNA2 missense mutation in a family with benign familial infantile seizures (BFIS). TrueSeq Custom Amplicon (TSCA) sequencing approach was used to screen 10 ion channel genes in patients with idiopathic epilepsies. TSCA revealed a heterozygous single-nucleotide substitution in CHRNA2 gene (c.1126 C>T; p. Arg376Trp) that segregated in a family with BFIS; based on bio-informatics inspection, the change was predicted to be pathogenic. The investigated family includes parents and their three daughters. In affected individuals, seizures started between 6 and 24 months of age. Seizures were mainly in cluster and well-controlled. Outcome was good in all subjects. Even if nicotinic acetylcholine receptor genes are traditionally associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), this single-family description can open new possibilities in the genetic diagnosis, molecular characterization, and management of CHRNA2-related epilepsy. The pathogenic conversion of arginine 376 to tryptophan alters all of these interactions in the cytoplasmic domain, never reported to be involved in epileptogenic mechanism. Further functional tests will be necessary to strongly relate CHRNA2 mutation with BFIS phenotype.","variants":[{"Name":"NM_000742.4(CHRNA2):c.1126C>T (p.Arg376Trp)","Chromosome":"8","Start":"27463317","Stop":"27463317","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":513195,"rule_based_match":true,"evidence_text":"c.1126 C>T; p. Arg376Trp","llm_judgment":"PRESENT","evidence":"c.1126 C>T; p. Arg376Trp","abstract_start":517,"abstract_end":541}]}
{"pmid":"31960170","title":"Analysis of retinal structure and function in cone dystrophy with supernormal rod response.","abstract":"PURPOSE: To report the clinical and electrophysiological features of cone dystrophy with supernormal rod response (CDSRR).\nMETHODS: Retrospective cohort study of 15 unrelated patients (nine males and six females, median age 16, range 5-47 years) diagnosed with CDSRR by clinical examination, full-field electroretinography (ERG) and genetic testing.\nOBSERVATIONS: History, ophthalmic examination including near vision, color vision and contrast sensitivity assessment, multimodal retinal imaging and ERG. Genetic testing was done for all patients using next-generation sequencing.\nRESULTS: The rate of consanguinity was 86.7%. Color vision was defective in 56.3%. Near vision was defective in all patients (mean 20/160). Contrast sensitivity was affected in all patients at low contrast of 2.5%. A parafoveal ring of increased autofluorescence imaging was seen in most patients (75%). Supernormal mixed maximal response b-wave was seen bilaterally in 63% of patients (and high normal in 37%). Rod dysfunction with prolonged rod b-wave latency was detected in all. The 30-Hz flicker response was more reduced and delayed compared to the single-flash cone response. A novel homozygous missense variant c.530G>C (p.Cys177Ser) in KCNV2 was detected in one patient, the nonsense homozygous mutation c.427G>T (p.Glu143*) was found in 13 patients, and the nonsense c.159C>G (p.Tyr53*) was found in one patient.\nCONCLUSION: This is the largest cohort of CDSRR from a single ethnic background. Rod dysfunction and reduced 30-Hz flicker response were demonstrated in all patients. In contrast to previous descriptions in the literature, a supernormal combined dark-adapted rod-cone ERG was present in the majority of the patients at standard stimulus intensity. Considering the consistent genotype and the demonstration of likely pathogenic genetic variants in all the patients, we argue that the combination of delayed rod b-wave and subnormal flicker response strongly suggests the diagnosis of CDSRR.","variants":[{"Name":"NM_133497.4(KCNV2):c.427G>T (p.Glu143Ter)","Chromosome":"9","Start":"2718166","Stop":"2718166","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":18049,"rule_based_match":true,"evidence_text":"c.427G>T (p.Glu143*)","llm_judgment":"PRESENT","evidence":"c.427G>T (p.Glu143*)","abstract_start":1294,"abstract_end":1314},{"Name":"NM_133497.4(KCNV2):c.530G>C (p.Cys177Ser)","Chromosome":"9","Start":"2718269","Stop":"2718269","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":859750,"rule_based_match":true,"evidence_text":"c.530G>C (p.Cys177Ser)","llm_judgment":"PRESENT","evidence":"c.530G>C (p.Cys177Ser)","abstract_start":1200,"abstract_end":1222}]}
{"pmid":"24715367","title":"Blepharophimosis, short humeri, developmental delay and hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations.","abstract":"We report on two male sibs, a fetus and a newborn, with short humeri and dysmorphic facial features including blepharophimosis. The newborn also had Hirschsprung disease. Goldberg-Shprintzen syndrome and the Say-Barber-Biesecker-Young-Simpson type of Ohdo syndrome were suspected but direct sequencing of KBP and KAT6B failed to identify a mutation. Finally, direct sequencing of MED12, the gene mutated in Opitz-Kaveggia syndrome, Lujan-Fryns syndrome and X-linked Ohdo syndrome identified in the two sibs the missense mutation c.3443G>A (p.Arg1148His) inherited from the mother. This report further expands the phenotypic spectrum of MED12 mutations.","variants":[{"Name":"NM_005120.3(MED12):c.3443G>A (p.Arg1148His)","Chromosome":"X","Start":"71128686","Stop":"71128686","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":59420,"rule_based_match":true,"evidence_text":"c.3443G>A (p.Arg1148His)","llm_judgment":"PRESENT","evidence":"c.3443G>A (p.Arg1148His)","abstract_start":529,"abstract_end":553}]}
{"pmid":"30292630","title":"Targeted exome sequencing identified a novel mutation hotspot and a deletion in Chinese primary hypertrophic osteoarthropathy patients.","abstract":"BACKGROUND: Primary hypertrophic osteoarthropathy (PHO) is a genetically and clinically heterogeneous systematic disorder caused by mutations in genes HPGD and SLCO2A1. The purpose of the present study is to provide useful information for the early and precise diagnosis of PHO and identify causative mutations in Chinese PHO children.\nMETHODS AND RESULTS: The clinical manifestations, radiographic features of seven Chinese pediatric patients were systematically analyzed. Targeted exome sequencing identified a previously reported c.310_311delCT mutation and a novel common splicing site mutation c.324 + 5G > A in the HPGD gene. Relative quantitative real time PCR validated a novel deletion of the exon 4 in the same gene. Neither mutations nor structural variations in the gene SLCO2A1 were detected.\nCONCLUSIONS: In the present study, homozygous or compound heterozygous HPGD mutations were identified in seven Chinese pediatric patients, suggesting an autosomal recessive inheritance. The c.310_311delCT mutation and the splicing site mutation c.324 + 5G > A were likely to be mutational hotspots in Chinese PHO patients. For the first time, a structural variation of the HPGD gene was reported. Homozygous, compound heterozygous mutations or structural variation identified in the HPGD gene proposed that targeted exome sequencing may be a preferable method for pediatric PHO diagnosis and mutation analysis.","variants":[{"Name":"NM_000860.6(HPGD):c.324+5G>A","Chromosome":"4","Start":"174517966","Stop":"174517966","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3521987,"rule_based_match":true,"evidence_text":"c.324 + 5G > A","llm_judgment":"PRESENT","evidence":"c.324 + 5G > A","abstract_start":599,"abstract_end":613}]}
{"pmid":"25008876","title":"STXBP1 gene mutation in newborns with refractory seizures","abstract":"OBJECTIVE: To study the relationship between STXBP1 gene mutations and refractory seizures with unknown causes in newborns.\nMETHODS: The coding region of STXBP1 gene was detected using direct Sanger sequencing in 11 newborns with refractory seizures of unknown causes.\nRESULTS: STXBP1 gene mutation was found in 1 out of 11 patients. It was a missense mutation: c.1439C>T (p.P480L).\nCONCLUSIONS: STXBP1 gene mutation can be found in neonatal refractory seizures of unknown causes, suggesting a new approach of further research of this disease.","variants":[{"Name":"NM_001032221.6(STXBP1):c.1439C>T (p.Pro480Leu)","Chromosome":"9","Start":"127678510","Stop":"127678510","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":202320,"rule_based_match":true,"evidence_text":"c.1439C>T (p.P480L)","llm_judgment":"PRESENT","evidence":"c.1439C>T (p.P480L)","abstract_start":362,"abstract_end":381}]}
{"pmid":"37542277","title":"Genotype, phenotype and treatment outcomes of 17 Malaysian patients with infantile-onset Pompe disease and the identification of 3 novel GAA variants.","abstract":"BACKGROUND: Pompe disease is a rare glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to glycogen deposition in multiple tissues. Infantile-onset Pompe disease (IOPD) patients present within the first year of life with profound hypotonia and hypertrophic cardiomyopathy. Treatment with enzyme replacement therapy (ERT) has significantly improved survival for this otherwise lethal disorder. This study aims to describe the clinical and molecular spectrum of Malaysian IOPD patients, and to analyze their long term treatment outcomes.\nMETHODS: Seventeen patients diagnosed with IOPD between 2000 and 2020 were included in this retrospective cohort study. Clinical and biochemical data were collated and analyzed using descriptive statistics. GAA enzyme levels were performed on dried blood spots. Molecular analysis of the GAA gene was performed by polymerase chain reaction and Sanger sequencing. Structural modelling was used to predict the effect of the novel mutations on enzyme structure.\nRESULTS: Our cohort had a median age of presentation of 3 months and median age of diagnosis of 6 months. Presenting features were hypertrophic cardiomyopathy (100%), respiratory insufficiency (94%), hypotonia (88%), failure to thrive (82%), feeding difficulties (76%), and hepatomegaly (76%). Fourteen different mutations in the GAA gene were identified, with three novel mutations, c.1552-14_1552-1del, exons 2-3 deletion and exons 6-10 deletion. The most common mutation identified was c.1935C > A p.(D645E), with an allele frequency of 33%. Sixteen patients received ERT at the median age of 7 months. Overall survival was 29%. Mean age of death was 17.5 months. Our longest surviving patient has atypical IOPD and is currently 20 years old.\nCONCLUSIONS: This is the first study to analyze the genotype and phenotype of Malaysian IOPD patients, and has identified the c.1935C > A p.(D645E) as the most common mutation. The three novel mutations reported in this study expands the mutation spectrum for IOPD. Our low survival rate underscores the importance of early diagnosis and treatment in achieving better treatment outcomes.","variants":[{"Name":"NM_000152.5(GAA):c.1935C>A (p.Asp645Glu)","Chromosome":"17","Start":"80112922","Stop":"80112922","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":19068,"rule_based_match":true,"evidence_text":"c.1935C > A p.(D645E)","llm_judgment":"PRESENT","evidence":"c.1935C > A p.(D645E)","abstract_start":1541,"abstract_end":1562}]}
{"pmid":"32322264","title":"Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (","abstract":"Mutations in the retinol dehydrogenase 12 (<i>RDH12</i>) gene are primarily associated with Leber congenital amaurosis (LCA) type 13, a severe early onset autosomal recessive retinal dystrophy. Only one family with a heterozygous variant, associated with mild retinitis pigmentosa (RP), has been reported. We report a novel heterozygous variant [(c.759del; p.(Phe254Leufs<sup>∗</sup>24)], resulting in a frameshift and premature termination identified in two unrelated individuals with familial autosomal dominant RP. Both heterozygous variants are associated with a late onset RP phenotype, suggesting a possible genotype-phenotype correlation.","variants":[{"Name":"NM_152443.3(RDH12):c.759del (p.Phe254fs)","Chromosome":"14","Start":"67729287","Stop":"67729287","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":800587,"rule_based_match":true,"evidence_text":"c.759del","llm_judgment":"PRESENT","evidence":"c.759del","abstract_start":347,"abstract_end":355}]}
{"pmid":"26029705","title":"Diversity of the causal genes in hearing impaired Algerian individuals identified by whole exome sequencing.","abstract":"The genetic heterogeneity of congenital hearing disorders makes molecular diagnosis expensive and time-consuming using conventional techniques such as Sanger sequencing of DNA. In order to design an appropriate strategy of molecular diagnosis in the Algerian population, we explored the diversity of the involved mutations by studying 65 families affected by autosomal recessive forms of nonsyndromic hearing impairment (DFNB forms), which are the most prevalent early onset forms. We first carried out a systematic screening for mutations in GJB2 and the recurrent p.(Arg34*) mutation in TMC1, which were found in 31 (47.7%) families and 1 (1.5%) family, respectively. We then performed whole exome sequencing in nine of the remaining families, and identified the causative mutations in all the patients analyzed, either in the homozygous state (eight families) or in the compound heterozygous state (one family): (c.709C>T: p.(Arg237*)) and (c.2122C>T: p.(Arg708*)) in OTOF, (c.1334T>G: p.(Leu445Trp)) in SLC26A4, (c.764T>A: p.(Met255Lys)) in GIPC3, (c.518T>A: p.(Cys173Ser)) in LHFPL5, (c.5336T>C: p.(Leu1779Pro)) in MYO15A, (c.1807G>T: p.(Val603Phe)) in OTOA, (c.6080dup: p.(Asn2027Lys*9)) in PTPRQ, and (c.6017del: p.(Gly2006Alafs*13); c.7188_7189ins14: p.(Val2397Leufs*2)) in GPR98. Notably, 7 of these 10 mutations affecting 8 different genes had not been reported previously. These results highlight for the first time the genetic heterogeneity of the early onset forms of nonsyndromic deafness in Algerian families.","variants":[{"Name":"NM_144672.4(OTOA):c.1807G>T (p.Val603Phe)","Chromosome":"16","Start":"21722905","Stop":"21722905","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":230620,"rule_based_match":true,"evidence_text":"c.1807G>T (p.Val603Phe)","llm_judgment":"PRESENT","evidence":"c.1807G>T","abstract_start":1129,"abstract_end":1138}]}
{"pmid":"31336982","title":"Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases.","abstract":"Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel's aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with <i>FGF3</i> mutations.","variants":[{"Name":"NM_005247.4(FGF3):c.173T>C (p.Leu58Pro)","Chromosome":"11","Start":"69818761","Stop":"69818761","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1941539,"rule_based_match":true,"evidence_text":"c. 173T>C p.L58P","llm_judgment":"PRESENT","evidence":"c. 173T>C p.L58P","abstract_start":435,"abstract_end":451}]}
{"pmid":"15947062","title":"Megadolichobasilar anomaly with thrombosis in a family with Fabry's disease and a novel mutation in the alpha-galactosidase A gene.","abstract":"Fabry's disease is an X-linked lysosomal storage disorder. alpha-Galactosidase deficiency leads to accumulation of globotriaosylceramide mainly in endothelial and smooth muscle cells. Cerebrovascular symptoms with predominant affection of the vertebrobasilar circulation are one of the major sources of morbidity in Fabry's disease. We present a Hungarian family with Fabry's disease caused by a new mutation in the alpha-galactosidase A gene (GLA), and describe a variant expression of the disease. Megadolichobasilar anomaly was diagnosed in two male patients in the family who died of thrombosis. In another female patient who had suffered from disturbance of the vertebrobasilar circulation, a strongly dilated basilar artery without thrombosis was found at autopsy. Another three family members had basilar strokes and large and elongated basilar arteries on MRI. Genetic analysis disclosed a c.47T-->C missense mutation resulting in L16P in the amino acid sequence of the alpha-galactosidase protein. This report suggests that megadolichobasilar anomaly is potentially life-threatening, and that L16P is a disease-causing mutation in patients with Fabry's disease. Early enzyme replacement therapy may prevent the development of these irreversible cerebrovascular complications.","variants":[{"Name":"NM_000169.3(GLA):c.47T>C (p.Leu16Pro)","Chromosome":"X","Start":"101407857","Stop":"101407857","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1805338,"rule_based_match":false,"evidence_text":"c.47T-->C","llm_judgment":"PRESENT","evidence":"c.47T-->C","abstract_start":898,"abstract_end":907}]}
{"pmid":"32944796","title":"Juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia associated with a SMAD4 mutation in a girl.","abstract":"Juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT) are both relatively rare hereditary disorders. Some patients with the SMAD4 gene mutation develop both JPS and HHT, a condition termed JPS-HHT. We herein report a case of childhood-onset JPS-HHT. At nine years old, the patient underwent colonoscopy under suspicion of Crohn's disease, which revealed multiple polyps. A genetic analysis for familial adenomatous polyposis and Peutz-Jeghers syndrome found no mutations. After several years, extraintestinal manifestations, such as repeated epistaxis and several telangiectasias in the upper palate and stomach, were identified, which led to the performance of gene mutation analysis for SMAD4. As a result, a missense mutation in exon 8, codon 361 from arginine to cysteine (c.1081 C>T) was found. Based on this finding, the patient underwent cerebral magnetic resonance angiography, pulmonary perfusion scintigraphy and thoracoabdominal contrast computed tomography. The examination revealed that she had pulmonary arteriovenous fistulas and arteriovenous malformations in both the liver and right mammary gland. Thus, continuous surveillance for vascular lesions and gastrointestinal cancer is scheduled. Making a precise diagnosis of JPS-HHT can lead to the detection of asymptomatic complications and enable appropriate future disease management.","variants":[{"Name":"NM_005359.6(SMAD4):c.1081C>T (p.Arg361Cys)","Chromosome":"18","Start":"51065548","Stop":"51065548","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23582,"rule_based_match":true,"evidence_text":"c.1081 C>T","llm_judgment":"PRESENT","evidence":"c.1081 C>T","abstract_start":805,"abstract_end":815}]}
{"pmid":"29505567","title":"Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3.","abstract":"BACKGROUND: Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed.\nMETHODOLOGY: Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions.\nRESULTS: Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families.\nCONCLUSIONS: This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood.","variants":[{"Name":"NM_001177316.2(SLC34A3):c.1335+2T>A","Chromosome":"9","Start":"137234733","Stop":"137234733","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1055809,"rule_based_match":true,"evidence_text":"c.1335+2T>A","llm_judgment":"PRESENT","evidence":"c.1335+2T>A","abstract_start":1468,"abstract_end":1479},{"Name":"NM_000444.6(PHEX):c.1206del (p.Gln402fs)","Chromosome":"X","Start":"22114489","Stop":"22114489","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1432094,"rule_based_match":true,"evidence_text":"c.1206delA","llm_judgment":"PRESENT","evidence":"c.1206delA","abstract_start":976,"abstract_end":986}]}
{"pmid":"25069792","title":"Von Hippel-Lindau disease type 2 in a Chinese family with a VHL p.W88X truncation.","abstract":"Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the synonymous VHL gene encoding a tumor suppressor. Affected individuals are susceptible to various benign and malignant tumors. Based on the phenotypes, VHL disease is classified as type 1 and type 2. Here, we describe a Chinese family diagnosed as VHL disease type 2, with different metabolic status of tumors on FDG PET-CT. Genetic analysis revealed a germline c.264G>A point mutation, resulting in premature termination at codon 88 (p.W88X). This pedigree represents a rare link between p.W88X nonsense mutation (genotype) and VHL disease type 2 (phenotype), which has not been previously described. This is also the first nonsense mutation to manifest as VHL disease type 2 in ethnic Chinese. We also reviewed the literature and provided an outline of mutations associated with VHL disease in China.","variants":[{"Name":"NM_000551.4(VHL):c.264G>A (p.Trp88Ter)","Chromosome":"3","Start":"10142111","Stop":"10142111","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":931674,"rule_based_match":true,"evidence_text":"c.264G>A","llm_judgment":"PRESENT","evidence":"c.264G>A","abstract_start":463,"abstract_end":471}]}
{"pmid":"31440728","title":"De novo variants in","abstract":"Epilepsy with myoclonic absences is a specific seizure type characterized by bilateral rhythmic clonic jerks with impairment of consciousness. Here, we report an individual with epilepsy with myoclonic absences, mild intellectual disabilities, language disorder, and autism spectrum disorder. His interictal electroencephalogram revealed a spike-and-slow wave complex dominant in the frontal area. His ictal polygraphic and video-electroencephalogram showed a characteristic diffuse synchronous 3-Hz spike-and-wave burst associated with bilateral upper limb myoclonic jerks with impairment of consciousness. Using whole-exome sequencing, we found a novel de novo variant, c.386T>G, p.(Val129Gly), in <i>SETD1B</i> (SET domain containing 1B). We previously reported that two individuals with a de novo <i>SETD1B</i> variant showed intellectual disability, epilepsy, and autism. Of note, one of those individuals and the present case showed epilepsy with myoclonic absences. Therefore, this report supports the indication that <i>SETD1B</i> may be a causative gene for neurodevelopmental disorders and suggests that epilepsy with myoclonic absences may be a characteristic feature of <i>SETD1B</i>-related disorders.","variants":[{"Name":"NM_001353345.2(SETD1B):c.386T>G (p.Val129Gly)","Chromosome":"12","Start":"121805947","Stop":"121805947","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1052702,"rule_based_match":true,"evidence_text":"c.386T>G, p.(Val129Gly)","llm_judgment":"PRESENT","evidence":"c.386T>G, p.(Val129Gly)","abstract_start":672,"abstract_end":695}]}
{"pmid":"29961568","title":"De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.","abstract":"Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.","variants":[{"Name":"NM_003931.3(WASF1):c.1516C>T (p.Arg506Ter)","Chromosome":"6","Start":"110101594","Stop":"110101594","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":553120,"rule_based_match":true,"evidence_text":"c.1516C>T (p.Arg506Ter)","llm_judgment":"PRESENT","evidence":"c.1516C>T (p.Arg506Ter)","abstract_start":612,"abstract_end":635},{"Name":"NM_003931.3(WASF1):c.1482delinsGCCAGG (p.Ile494fs)","Chromosome":"6","Start":"110101628","Stop":"110101628","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"CCTGGC","allel_id":553121,"rule_based_match":true,"evidence_text":"c.1482delinsGCCAGG (p.Ile494MetfsTer23)","llm_judgment":"PRESENT","evidence":"c.1482delinsGCCAGG (p.Ile494MetfsTer23)","abstract_start":711,"abstract_end":750},{"Name":"NM_003931.3(WASF1):c.1558C>T (p.Gln520Ter)","Chromosome":"6","Start":"110100644","Stop":"110100644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":553119,"rule_based_match":true,"evidence_text":"c.1558C>T (p.Gln520Ter)","llm_judgment":"PRESENT","evidence":"c.1558C>T (p.Gln520Ter)","abstract_start":682,"abstract_end":705}]}
{"pmid":"31654490","title":"HSD10 mitochondrial disease: p.Leu122Val variant, mild clinical phenotype, and founder effect in French-Canadian patients from Quebec.","abstract":"BACKGROUND: HSD10 mitochondrial disease (HSD10MD), originally described as a deficiency of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD), is a rare X-linked disorder of a moonlighting protein encoded by the HSD17B10. The diagnosis is usually first suspected on finding elevated isoleucine degradation metabolites in urine, reflecting decreased MHBD activity. However, it is now known that clinical disease pathogenesis reflects other independent functions of the HSD10 protein; particularly its essential role in mitochondrial transcript processing and tRNA maturation. The classical phenotype of HSD10MD in affected males is an infantile-onset progressive neurodegenerative disorder associated with severe mitochondrial dysfunction.\nPATIENTS, METHODS, AND RESULTS: In four unrelated families, we identified index patients with MHBD deficiency, which implied a diagnosis of HSD10MD. Each index patient was independently investigated because of neurological or developmental concerns. All had persistent elevations of urinary 2-methyl-3-hydroxybutyric acid and tiglylglycine. Analysis of HSD17B10 identified a single missense variant, c.364C>G, p.Leu122Val, in each case. This rare variant (1/183336 alleles in gnomAD) was previously reported in one Dutch patient and was described as pathogenic. The geographic origins of our families and results of haplotype analysis together provide evidence of a founder effect for this variant in Quebec. Notably, we identified an asymptomatic hemizygous adult male in one family, while a second independent genetic disorder contributed substantially to the clinical phenotypes observed in probands from two other families.\nCONCLUSION: The phenotype associated with p.Leu122Val in HSD17B10 currently appears to be attenuated and nonprogressive. This report widens the spectrum of phenotypic severity of HSD10MD and contributes to genotype-phenotype correlation. At present, we consider p.Leu122Val a \"variant of uncertain significance.\" Nonetheless, careful follow-up of our patients remains advisable, to assess long-term clinical course and ensure appropriate management. It will also be important to identify other potential patients in our population and to characterize their phenotype.","variants":[{"Name":"NM_004493.3(HSD17B10):c.364C>G (p.Leu122Val)","Chromosome":"X","Start":"53432110","Stop":"53432110","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":26482,"rule_based_match":true,"evidence_text":"c.364C>G, p.Leu122Val","llm_judgment":"PRESENT","evidence":"c.364C>G, p.Leu122Val","abstract_start":1139,"abstract_end":1160}]}
{"pmid":"21892769","title":"SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease.","abstract":"Considerable non-allelic heterogeneity for autosomal recessively inherited Charcot-Marie-Tooth (ARCMT) disease has challenged molecular testing and often requires a large amount of work in terms of DNA sequencing and data interpretation or remains unpractical. This study tested the value of SNP array-based whole-genome homozygosity mapping as a first step in the molecular genetic diagnosis of sporadic or ARCMT in patients from inbred families or outbred populations with the ancestors originating from the same geographic area. Using 10 K 2.0 and 250 K Nsp Affymetrix SNP arrays, 15 (63%) of 24 CMT patients received an accurate genetic diagnosis. We used our Java-based script eHoPASA CMT-easy Homozygosity Profiling of SNP arrays for CMT patients to display the location of homozygous regions and their extent of marker count and base-pairs throughout the whole genome. CMT4C was the most common genetic subtype with mutations detected in SH3TC2, one (p.E632Kfs13X) appearing to be a novel founder mutation. A sporadic patient with severe CMT was homozygous for the c.250G > C (p.G84R) HSPB1 mutation which has previously been reported to cause autosomal dominant dHMN. Two distantly related CMT1 patients with early disease onset were found to carry a novel homozygous mutation in MFN2 (p.N131S). We conclude that SNP array-based homozygosity mapping is a fast, powerful, and economic tool to guide molecular genetic testing in ARCMT and in selected sporadic CMT patients.","variants":[{"Name":"NM_001540.5(HSPB1):c.250G>C (p.Gly84Arg)","Chromosome":"7","Start":"76302962","Stop":"76302962","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":221739,"rule_based_match":true,"evidence_text":"c.250G > C (p.G84R)","llm_judgment":"PRESENT","evidence":"c.250G > C (p.G84R)","abstract_start":1072,"abstract_end":1091}]}
{"pmid":"27989580","title":"The promises and challenges of exome sequencing in familial, non-syndromic congenital heart disease.","abstract":"BACKGROUND: Exome sequencing is an established strategy to identify causal variants in families with two or more members affected by congenital heart disease (CHD). This unbiased approach, in which both rare and common variants are identified, makes it suitable to research complex, heterogeneous diseases such as CHD.\nMETHODS AND RESULTS: Exome sequencing was performed on two affected members of a three generation family with atrial septal defects (ASD), suggesting a dominant inheritance pattern. Variants were filtered using two bioinformatics pipelines and prioritised according to in silico prediction programs. Segregation studies and functional analyses were used to assess co-segregation with disease and effects on protein function, respectively. Following the data and in silico analyses, ten candidate variants were prioritised. Of these, SRPK2 (c.2044C>T[p.Arg682Trp]) and NOTCH1 (c.3835C>T[p.Arg1279Cys]), co-segregated with disease in the family; however, previous functional analyses on SRPK2 make this an unlikely candidate. Functional analyses in the variant (c.3835C>T[p.Arg1279Cys]) of the known CHD gene NOTCH1 demonstrated a non-significant decrease in signalling activity.\nCONCLUSION: This study demonstrates both the potential, as well as the challenges, of applying exome sequencing to complex diseases such as CHD. While in silico evidence and segregation analyses in the NOTCH1 p.Arg1279Cys variant are highly suggestive of pathogenicity, the minimal change in signalling capacity suggests that other variants may be required for CHD development. This study highlights the difficulties of applying exome sequencing in familial, non-syndromic CHD in the clinical environment and a cautionary note in the interpretation of apparently causal abnormalities in silico without supportive functional data.","variants":[{"Name":"NM_017617.5(NOTCH1):c.3835C>T (p.Arg1279Cys)","Chromosome":"9","Start":"136506782","Stop":"136506782","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":240561,"rule_based_match":true,"evidence_text":"NOTCH1 (c.3835C>T[p.Arg1279Cys])","llm_judgment":"PRESENT","evidence":"NOTCH1 (c.3835C>T[p.Arg1279Cys])","abstract_start":887,"abstract_end":919}]}
{"pmid":"16642506","title":"A compound heterozygote harboring novel and recurrent DTDST mutations with intermediate phenotype between atelosteogenesis type II and diastrophic dysplasia.","abstract":"Diastrophic dysplasia sulfate transporter (DTDST) is a sulfate transporter required for the synthesis of sulfated proteoglycans in the cartilage. Over 30 mutations have been described in the DTDST gene, which result in a continuous clinical spectrum of recessively inherited chondrodysplasias, including, in order of increasing severity, a recessive form of multiple epiphyseal dysplasia (rMED), diastrophic dysplasia (DTD), atelosteogenesis type II (AO-II) and achondrogenesis 1B (ACG-1B). Correlation between disease severity and residual sulfate transport activity has been reported. Here we report a patient with DTDST mutations, whose manifestations fell in a range between AO-II and DTD. The patient was a compound heterozygote for the recurrent c.835C>T (p.R279W) and novel c.1987G>A (p.G663R) mutations. Immunocytochemical analysis in HEK293 cells showed that the p.G663R mutation was localized within the cytoplasm, and not to the cell membrane, suggesting p.G663R is a loss-of-function mutation. Our case supports the previously described correlation between the severity of the phenotype and the putative level of residual transport function.","variants":[{"Name":"NM_000112.4(SLC26A2):c.835C>T (p.Arg279Trp)","Chromosome":"5","Start":"149980428","Stop":"149980428","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19128,"rule_based_match":true,"evidence_text":"c.835C>T (p.R279W)","llm_judgment":"PRESENT","evidence":"c.835C>T (p.R279W)","abstract_start":752,"abstract_end":770},{"Name":"NM_000112.4(SLC26A2):c.1987G>A (p.Gly663Arg)","Chromosome":"5","Start":"149981580","Stop":"149981580","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":543810,"rule_based_match":true,"evidence_text":"c.1987G>A (p.G663R)","llm_judgment":"PRESENT","evidence":"c.1987G>A (p.G663R)","abstract_start":781,"abstract_end":800}]}
{"pmid":"23701270","title":"Two novel mutations in apolipoprotein C3 underlie atheroprotective lipid profiles in families.","abstract":"Apolipoprotein C3 (APOC3) mutations carriers typically display high plasma high-density lipoprotein cholesterol (HDL-C) and low triglycerides (TGs). We set out to investigate the prevalence and clinical consequences of APOC3 mutations in individuals with hyperalphalipoproteinemia. Two novel mutations (c.-13-2A>G and c.55+1G>A) and one known mutation (c.127G>A;p.Ala43Thr) were found. Lipid profiles and apoCIII isoform distributions were measured. c.55+1G>A mutation carriers displayed higher HDL-C percentiles (35.6 ± 35.8 vs 99.0 ± 0, p = 0.002) and lower TGs (0.51 (0.37-0.61) vs 1.42 (1.12-1.81) mmol/l, p = 0.007) and apoCIII levels (4.24 ± 1.57 vs 7.33 ± 3.61 mg/dl, p = 0.18). c.-13-2A>G mutation carriers did not display significantly different HDL-C levels (84.0 ± 30.0 vs 63.7 ± 45.7, p = 0.50), a trend towards lower TGs [0.71 (0.54 to 0.78) vs 0.85 (0.85 to -) mmol/l, p = 0.06] and significantly lower apoCIII levels (3.09 ± 1.08 vs 11.45 ± 1.06 mg/dl, p = 0.003). p.Ala43Thr mutation carriers displayed a trend towards higher HDL-C percentiles (91.2 ± 31.8 vs 41.0 ± 29.7 mmol/l, p = 0.06) and significantly lower TGs [0.58 (0.36-0.63) vs 0.95 (0.71-1.20) mmol/l, p = 0.02] and apoCIII levels (4.92 ± 2.33 vs 6.60 ± 1.60, p = 0.25). Heterozygosity for APOC3 mutations results in high HDL-C and low TGs and apoCIII levels. This favourable lipid profile in patients with genetically low apoCIII levels holds promise for current studies investigating the potential of apoCIII inhibition as a novel therapeutic in cardiovascular disease prevention.","variants":[{"Name":"NM_000040.3(APOC3):c.55+1G>A","Chromosome":"11","Start":"116830638","Stop":"116830638","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":143193,"rule_based_match":true,"evidence_text":"c.55+1G>A","llm_judgment":"PRESENT","evidence":"c.55+1G>A","abstract_start":318,"abstract_end":327},{"Name":"NM_000040.3(APOC3):c.127G>A (p.Ala43Thr)","Chromosome":"11","Start":"116830844","Stop":"116830844","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":143194,"rule_based_match":true,"evidence_text":"c.127G>A;p.Ala43Thr","llm_judgment":"PRESENT","evidence":"c.127G>A;p.Ala43Thr","abstract_start":353,"abstract_end":372}]}
{"pmid":"33246395","title":"Exome sequencing of a Pakistani family with spastic paraplegia identified an 18 bp deletion in the cytochrome B5 domain of FA2H.","abstract":"Hereditary spastic paraplegias (HSPs) are a diverse class of neurodegenerative disorders that mainly affect the corticospinal tract of the body and result in various clinical conditions such as lower limb spasticity and muscle weakness in the lower extremities. Worldwide, more than 70 chromosomal loci/genes have been reported to be associated with HSPs, out of which, six genes viz., <i>ATL1, FA2H, GJC2, AP4E1, ALDH18A1</i> and <i>ATP13A2</i> have been mapped in Pakistani families. In the present genetic study, we report on a large consanguineous Pakistani family with a complex form of HSP segregating with a 18 bp deletion in the first exon of the Fatty Acid 2-Hydroxylase (<i>FA2H</i>) gene (NM_024306.5:c.159_176del). The identified in-frame deletion results in loss of six amino acids (p.Arg53_Ile58del) within the cytochrome B5 domain of the protein. FA2H is required for alpha-hydroxylation of free fatty acids to form alpha-hydroxylated sphingolipids. Its cytochrome b5-like heme-binding domain, which spans from residues 15 to 85, imparts the redox activity to FA2H. This mutation has previously been reported in a Pakistani family presenting with a similar form of complex HSP. Together with our findings the pathogenic role of the observed variant is further supported. Mutation studies on additional Pakistani families for <i>FA2H</i> will further elucidate its mutational spectrum, which may help in developing a prenatal diagnostic test for Khyber Pakhtunkhwa resident Pakistani families.","variants":[{"Name":"NM_024306.5(FA2H):c.159_176del (p.Arg53_Ile58del)","Chromosome":"16","Start":"74774580","Stop":"74774597","ReferenceAlleleVCF":"GCTGATGTCCTGGCCCGCC","AlternateAlleleVCF":"G","allel_id":39828,"rule_based_match":true,"evidence_text":"NM_024306.5:c.159_176del","llm_judgment":"PRESENT","evidence":"NM_024306.5:c.159_176del","abstract_start":700,"abstract_end":724}]}
{"pmid":"28105569","title":"The Spectrum of Niemann-Pick Type C Disease in Greece.","abstract":"Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2 genes. We present the clinical, biochemical, and molecular findings in 14 cases diagnosed in Greece during the last 28 years. Age at diagnosis ranged from 2.5 months to 48 years. Systemic manifestations were present in 7/14 patients. All developed neurological manifestations (age of onset 5 months to 42 years). Six patients are still alive (age: 5-50 years). Classical filipin staining pattern was observed in all but four patients (3 NPC1, 1 NPC2). The rate of LDL-induced cholesteryl ester formation was severely reduced in 4/7 and significantly reduced in 3/7 patients studied. Increased chitotriosidase activity was observed in 9/12 patients. Mutation analysis in 11 unrelated patients identified 12 different mutations in the NPC1 gene: eight previously described p.E1089K (c.3265G>A), p.F284Lfs*26 (c.852delT), p.A1132P(c.3394G>C), del promoter region and exons 1-10, p.R1186H (c.3557G>A), p.P1007A (c.3019C>G), p.Q92R(c.275A>G),p.S940L (c.2819C>T), and four novel ones: (p.N701K fs*13 (c.2102-2103insA), p.K1057R (c.3170A>G), IVS23+3insT(c.3591+3insT), p.C1119*(c.3357T>C); and the previously described IVS2+5G>A(c.190+5G>A) mutation in the NPC2 gene. All patients were of Greek origin. Assuming a birth rate of 100,000/year, a rough incidence estimate for NPC disease in Greece would be 0.5/100,000 births.","variants":[{"Name":"NM_000271.5(NPC1):c.275A>G (p.Gln92Arg)","Chromosome":"18","Start":"23572086","Stop":"23572086","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1868293,"rule_based_match":true,"evidence_text":"p.Q92R(c.275A>G)","llm_judgment":"PRESENT","evidence":"p.Q92R(c.275A>G)","abstract_start":1356,"abstract_end":1372},{"Name":"NM_000271.5(NPC1):c.3557G>A (p.Arg1186His)","Chromosome":"18","Start":"23534480","Stop":"23534480","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187022,"rule_based_match":true,"evidence_text":"p.R1186H (c.3557G>A)","llm_judgment":"PRESENT","evidence":"p.R1186H (c.3557G>A)","abstract_start":1312,"abstract_end":1332},{"Name":"NM_000271.5(NPC1):c.3265G>A (p.Glu1089Lys)","Chromosome":"18","Start":"23535681","Stop":"23535681","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":179793,"rule_based_match":true,"evidence_text":"c.3265G>A","llm_judgment":"PRESENT","evidence":"c.3265G>A","abstract_start":1217,"abstract_end":1226},{"Name":"NM_000271.5(NPC1):c.2819C>T (p.Ser940Leu)","Chromosome":"18","Start":"23539447","Stop":"23539447","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187026,"rule_based_match":true,"evidence_text":"p.S940L (c.2819C>T)","llm_judgment":"PRESENT","evidence":"p.S940L (c.2819C>T)","abstract_start":1373,"abstract_end":1392},{"Name":"NM_006432.5(NPC2):c.190+5G>A","Chromosome":"14","Start":"74486324","Stop":"74486324","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23518,"rule_based_match":true,"evidence_text":"IVS2+5G>A(c.190+5G>A)","llm_judgment":"PRESENT","evidence":"IVS2+5G>A(c.190+5G>A)","abstract_start":1548,"abstract_end":1569}]}
{"pmid":"31680794","title":"Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to","abstract":"Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (<i>MTMR2)</i> gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with <i>MTMR2</i> mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in <i>MTMR2</i> (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of <i>MTMR2</i>, suggesting that nonsense <i>MTMR2</i> mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway.","variants":[{"Name":"NM_016156.6(MTMR2):c.1490dup (p.Phe498fs)","Chromosome":"11","Start":"95838196","Stop":"95838197","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":672004,"rule_based_match":true,"evidence_text":"c.1490dupC; p.Phe498IlefsTer2","llm_judgment":"PRESENT","evidence":"c.1490dupC; p.Phe498IlefsTer2","abstract_start":606,"abstract_end":635},{"Name":"NM_016156.6(MTMR2):c.1090C>T (p.Arg364Ter)","Chromosome":"11","Start":"95847803","Stop":"95847803","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":672005,"rule_based_match":true,"evidence_text":"c.1090C>T; p.Arg364Ter","llm_judgment":"PRESENT","evidence":"c.1090C>T; p.Arg364Ter","abstract_start":670,"abstract_end":692},{"Name":"NM_016156.6(MTMR2):c.883C>T (p.Arg295Ter)","Chromosome":"11","Start":"95849784","Stop":"95849784","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":672006,"rule_based_match":true,"evidence_text":"c.883C>T; p.Arg295Ter","llm_judgment":"PRESENT","evidence":"c.883C>T; p.Arg295Ter","abstract_start":704,"abstract_end":725}]}
{"pmid":"30610177","title":"Dysfunction of","abstract":"We have identified a <i>GRAP</i> variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. <i>GRAP</i> encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, <i>Grap</i> is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (<i>drk</i>), the <i>Drosophila</i> homolog of human <i>GRAP</i>, is expressed in Johnston's organ (JO), the fly hearing organ, and the loss of <i>drk</i> in JO causes scolopidium abnormalities. <i>drk</i> mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between <i>GRAP</i> mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.","variants":[{"Name":"NM_006613.4(GRAP):c.311A>T (p.Gln104Leu)","Chromosome":"17","Start":"19024372","Stop":"19024372","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":622031,"rule_based_match":true,"evidence_text":"c.311A>T; p.Gln104Leu","llm_judgment":"PRESENT","evidence":"c.311A>T; p.Gln104Leu","abstract_start":42,"abstract_end":63}]}
{"pmid":"27397503","title":"Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma.","abstract":"Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.","variants":[{"Name":"NM_000137.4(FAH):c.424A>G (p.Arg142Gly)","Chromosome":"15","Start":"80162305","Stop":"80162305","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":917211,"rule_based_match":true,"evidence_text":"NM_000137.2:c.424A > G","llm_judgment":"PRESENT","evidence":"NM_000137.2:c.424A > G","abstract_start":778,"abstract_end":800}]}
{"pmid":"31813911","title":"A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia.","abstract":"Heterozygous mutations in KIF1A have been reported to cause syndromic intellectual disability or pure spastic paraplegia. However, their genotype-phenotype correlations have not been fully elucidated. We herein report a man with autism and hyperactivity along with sensory disturbance and spastic paraplegia, carrying a novel de novo mutation in KIF1A [c.37C>T (p.R13C)]. Autism and hyperactivity have only previously been reported in a patient with c.38 G>A (R13H) mutation. This case suggests that alterations in this arginine at codon 13 might lead to a common clinical spectrum and further expand the genetic and clinical spectra associated with KIF1A mutations.","variants":[{"Name":"NM_001244008.2(KIF1A):c.37C>T (p.Arg13Cys)","Chromosome":"2","Start":"240797716","Stop":"240797716","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":414882,"rule_based_match":true,"evidence_text":"c.37C>T (p.R13C)","llm_judgment":"PRESENT","evidence":"c.37C>T (p.R13C)","abstract_start":353,"abstract_end":369}]}
{"pmid":"22727047","title":"An atypical case of neuronal ceroid lipofuscinosis with co-inheritance of a variably penetrant POLG1 mutation.","abstract":"BACKGROUND: The neuronal ceroid lipofuscinoses (NCLs, or Batten disease) comprise the most common Mendelian form of childhood-onset neurodegeneration, but the functions of the known underlying gene products remain poorly understood. The clinical heterogeneity of these disorders may shed light on genetic interactors that modify disease onset and progression.\nCASE PRESENTATION: We describe a proband with congenital hypotonia and an atypical form of infantile-onset, biopsy-proven NCL. Pathologic and molecular work-up of this patient identified CLN5 mutations as well as a mutation-previously described as incompletely penetrant or a variant of unknown significance-in POLG1, a nuclear gene essential for maintenance of mitochondrial DNA (mtDNA) copy number. The congenital presentation of this patient is far earlier than that described for either CLN5 patients or affected carriers of the POLG1 variant (c.1550 G > T, p.Gly517Val). Assessment of relative mtDNA copy number and mitochondrial membrane potential in the proband and control subjects suggested a pathogenic effect of the POLG1 change as well as a possible functional interaction with CLN5 mutations.\nCONCLUSIONS: These findings suggest that an incompletely penetrant variant in POLG1 may modify the clinical phenotype in a case of CLN5 and are consistent with emerging evidence of interactions between NCL-related genes and mitochondrial physiology.","variants":[{"Name":"NM_002693.3(POLG):c.1550G>T (p.Gly517Val)","Chromosome":"15","Start":"89326947","Stop":"89326947","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":76573,"rule_based_match":true,"evidence_text":"c.1550 G > T, p.Gly517Val","llm_judgment":"PRESENT","evidence":"c.1550 G > T, p.Gly517Val","abstract_start":908,"abstract_end":933}]}
{"pmid":"26124963","title":"Exome Sequencing Identified a Recessive RDH12 Mutation in a Family with Severe Early-Onset Retinitis Pigmentosa.","abstract":"Retinitis pigmentosa (RP) is the most important hereditary retinal disease caused by progressive degeneration of the photoreceptor cells. This study is to identify gene mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in a Chinese family using next-generation sequencing technology. A Chinese family with 7 members including two individuals affected with severe early-onset RP was studied. All patients underwent a complete ophthalmic examination. Exome sequencing was performed on a single RP patient (the proband of this family) and direct Sanger sequencing on other family members and normal controls was followed to confirm the causal mutations. A homozygous mutation c.437T<A (p.V146D) in the retinol dehydrogenase 12 (RDH12) gene, which encodes an NADPH-dependent retinal reductase, was identified as being related to the phenotype of this arRP family. This homozygous mutation was detected in the two affected patients, but not present in other family members and 600 normal controls. Another three normal members in the family were found to carry this heterozygous missense mutation. Our results emphasize the importance of c.437T<A (p.V146D) substitution in RDH12 and provide further support for the causative role of this mutation in the pathogenesis and clinical diagnosis of RP.","variants":[{"Name":"NM_152443.3(RDH12):c.437T>A (p.Val146Asp)","Chromosome":"14","Start":"67726144","Stop":"67726144","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":841682,"rule_based_match":false,"evidence_text":"c.437T<A (p.V146D)","llm_judgment":"PRESENT","evidence":"c.437T<A (p.V146D)","abstract_start":697,"abstract_end":715}]}
{"pmid":"24885015","title":"Clinical and mutational features of Vietnamese children with X-linked agammaglobulinemia.","abstract":"BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immune deficiency characterized by recurrent bacterial infections and profoundly depressed serum immunoglobulin levels and circulating mature B cells. It is caused by mutations of the Bruton tyrosine kinase (BTK) gene and is the most common form of inherited antibody deficiency. To our knowledge, this is the first report of XLA from Vietnam.\nMETHODS: We investigated the BTK gene mutations and clinical features of four unrelated Vietnamese children.\nRESULTS: The mean ages at onset and at diagnosis were 2.5 and 8 years, respectively. All patients had a medical history of otitis media, pneumonia, and septicemia at the time of diagnosis. Other infections reported included sinusitis, bronchiectasis, arthritis, skin infections, meningitis, and recurrent diarrhea. We identified one previously reported mutation (c.441G >A) and three novel mutations: two frameshifts (c.1770delG and c.1742 delG), and one nonsense (c.1249A >T).\nCONCLUSIONS: The delayed diagnosis may be attributable to insufficient awareness of this rare disease on the background of frequent infections even in the immunocompetent pediatric population in Vietnam. Our results further support the importance of molecular genetic testing in diagnosis of XLA.","variants":[{"Name":"NM_000061.3(BTK):c.1249A>T (p.Lys417Ter)","Chromosome":"X","Start":"101356884","Stop":"101356884","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":849517,"rule_based_match":true,"evidence_text":"c.1249A >T","llm_judgment":"PRESENT","evidence":"c.1249A >T","abstract_start":977,"abstract_end":987}]}
{"pmid":"16971895","title":"The congenital \"ant-egg\" cataract phenotype is caused by a missense mutation in connexin46.","abstract":"PURPOSE: \"Ant-egg\" cataract is a rare, distinct variety of congenital/infantile cataract that was reported in a large Danish family in 1967. This cataract phenotype is characterized by ant-egg-like bodies embedded in the lens in a laminar configuration and is inherited as an autosomal dominant trait. We retrieved the family and performed linkage analysis to determine the disease locus and identify the mutated gene.\nMETHODS: The family (CC00103) was identified in a National Register of Hereditary Eye Diseases and updated based on The Danish Civil Register System. Genome wide linkage analysis and haplotyping using STS marker systems were carried out to achieve a LOD score above 3. The disease-causing candidate gene was sequenced and the mutation was identified and verified by restriction enzyme digestion of genomic DNA from all individuals in family CC00103 and 60 healthy controls.\nRESULTS: Linkage analysis resulted in a LOD score of 3.91 for marker D13S1275 located close to the known cataract gene GJA3. A novel missense mutation c.32T > C (L11S), was found by sequencing DNA from two affected members. The mutation was present in all affected individuals and was neither found in unaffected family members nor in 60 healthy individuals by restriction enzyme digests.\nCONCLUSIONS: The congenital \"ant-egg\" cataract phenotype is caused by a L11S mutation in connexin46 (Cx46) located in the signal peptide domain. Further studies are needed to unravel the mechanism leading to the formation of the \"ant-eggs\".","variants":[{"Name":"NM_021954.4(GJA3):c.32T>C (p.Leu11Ser)","Chromosome":"13","Start":"20143257","Stop":"20143257","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3412487,"rule_based_match":true,"evidence_text":"c.32T > C (L11S)","llm_judgment":"PRESENT","evidence":"c.32T > C (L11S)","abstract_start":1044,"abstract_end":1060}]}
{"pmid":"33361639","title":"Reevaluating the pathogenicity of the variations c.439 G>A and c.2132 C>T in the","abstract":"The phospholipase A2 group VI (<i>PLA2G6</i>) gene encodes for a Ca<sup>2+</sup>-independent PLA<sub>2</sub>, which is localized in the cytosol, in the endoplasmic reticulum and in the mitochondrial membrane, plays a major role in phospholipid remodelling. Mutations within this gene have been reported to cause different phenotypes: infantile-onset neuroaxonal dystrophy associated with brain iron accumulation and adult-onset parkinsonian syndrome. In the present study, we analysed the <i>PLA2G6</i> gene sequence in an asymptomatic young woman that was referred to our laboratory by a geneticist for an history of infantile neuroaxonal dystrophy in her little maternal cousin in whom the results of the genetical analysis were not available. We found two variants in the <i>PLA2G6</i> gene (NM_003560.4, c.439 G>A and c.2132 C>T, p.Ala147Thr and p.Pro711Leu) previously reported as pathogenic. These results prompted us to perform a segregation analysis in the parents of this woman and we only found the presence of both variants in the asymptomatic 56-year-old patient's mother. Our molecular genetic testing clearly indicates that the c.439 G>A and c.2132 C>T variations identified in the <i>PLA2G6</i> gene are positioned in cis and are not responsible for infantile neuroaxonal dystrophy which is an autosomal recessive disease.","variants":[{"Name":"NM_003560.4(PLA2G6):c.439G>A (p.Ala147Thr)","Chromosome":"22","Start":"38143275","Stop":"38143275","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":347759,"rule_based_match":true,"evidence_text":"c.439 G>A","llm_judgment":"PRESENT","evidence":"c.439 G>A","abstract_start":808,"abstract_end":817}]}
{"pmid":"26078401","title":"A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.","abstract":"OBJECTIVE: To identify the underlying genetic cause in a consanguineous Chinese family segregating distal hereditary motor neuropathy (dHMN) in an autosomal recessive pattern.\nMETHODS: We used whole-exome sequencing and homozygosity mapping to detect the genetic variant in 2 affected individuals of the consanguineous Chinese family with dHMN. RNA analysis of peripheral blood leukocytes and immunofluorescence and immunoblotting of stable cell lines were performed to support the pathogenicity of the identified mutation.\nRESULTS: We identified 3 shared novel homozygous variants in 3 shared homozygous regions of the affected individuals. Sequencing of these 3 variants in family members revealed the c.151+1G>T mutation in SIGMAR1 gene, which located in homozygous region spanning approximately 5.3 Mb at chromosome 9p13.1-p13.3, segregated with the dHMN phenotype. The mutation causes an alternative splicing event and generates a transcript variant with an in-frame deletion of 60 base pairs in exon 1 (c.92_151del), and results in an internally shortened protein σ1R(31_50del). The proteasomal inhibitor treatment increased the intracellular amount of σ1R(31_50del) and led to the formation of nuclear aggregates. Stable expressing σ1R(31_50del) induced endoplasmic reticulum stress and enhanced apoptosis.\nCONCLUSION: The homozygous c.151+1G>T mutation in SIGMAR1 caused a novel form of autosomal recessive dHMN in a Chinese consanguineous family. Endoplasmic reticulum stress may have a role in the pathogenesis of dHMN.","variants":[{"Name":"NM_005866.4(SIGMAR1):c.151+1G>T","Chromosome":"9","Start":"34637546","Stop":"34637546","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":204390,"rule_based_match":true,"evidence_text":"c.151+1G>T","llm_judgment":"PRESENT","evidence":"c.151+1G>T","abstract_start":704,"abstract_end":714}]}
{"pmid":"37962568","title":"A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.","abstract":"Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients' T cells show residual TCR signal transduction and proliferation following anti-CD3/CD28 and phytohemagglutinin (PHA) stimulation. We demonstrate in mouse models that complete (Lck-/-) versus partial (LckP440S/P440S) loss-of-function LCK causes disease with differing phenotypes. While both Lck-/- and LckP440S/P440S mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only LckP440S/P440S mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the LckP440S/P440S mice is prevented by CD4+ T cell depletion or regulatory T cell transfer. These findings demonstrate that P440S LCK spares sufficient T cell function to allow the maturation of some conventional T cells but not regulatory T cells-leading to intestinal inflammation.","variants":[{"Name":"NM_005356.5(LCK):c.1318C>T (p.Pro440Ser)","Chromosome":"1","Start":"32280201","Stop":"32280201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3224419,"rule_based_match":true,"evidence_text":"c.1318C>T","llm_judgment":"PRESENT","evidence":"c.1318C>T","abstract_start":192,"abstract_end":201}]}
{"pmid":"29581481","title":"Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility.","abstract":"In affected members of a consanguineous family, a syndrome, which is concurrence of set of medical signs, is often observed and commonly assumed to have arisen from pleiotropy, i.e., the phenomenon of a single gene variant affecting multiple traits. We detected six sibs afflicted with a unique combination of digit malformation that includes brachydactyly, symphalangism and zygodactyly plus infertility in males owing to azoospermia, sperm immotility or necrospermia, which we hypothesised to have arisen from a defect in a single gene. We mapped the disease locus and by exome sequencing identified in patients homozygous missense variants bone morphogenetic protein receptor type IB (BMPR1B) c.640C>T (p.(Arg214Cys)) and alpha-2 pyruvate dehydrogenase (PDHA2) c.679A>G (p.(Met227Val)). Structural protein modelling, protein sequence conservation and in silico analysis indicate that both variants affect protein function. BMPR1B is known to be responsible for autosomal dominant brachydactyly and autosomal recessive acromesomelic chondrodysplasia. Our findings show that also recessive complex digit malformation can be caused by BMPR1B variant and not all biallelic BMPR1B variants cause acromesomelic dysplasia. PDHA2 is a novel candidate gene for male infertility; the protein product is a mitochondrial enzyme with highest expression in ejaculated sperm. Our findings are a unique example of two linked variants, ~ 711 Kb apart, in different genes that together manifest as a novel syndrome. They demonstrate that exome sequencing and not candidate gene approach should be employed in disease gene hunt, defining new diseases and genetic testing, to rule out the coincidental presence of two variants contributing together to the phenotype, which may be discerned as a novel disease.","variants":[{"Name":"NM_005390.5(PDHA2):c.679A>G (p.Met227Val)","Chromosome":"4","Start":"95840829","Stop":"95840829","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":439630,"rule_based_match":true,"evidence_text":"c.679A>G (p.(Met227Val))","llm_judgment":"PRESENT","evidence":"c.679A>G (p.(Met227Val))","abstract_start":764,"abstract_end":788}]}
{"pmid":"28574218","title":"A novel mutation in GMPPA in siblings with apparent intellectual disability, epilepsy, dysmorphism, and autonomic dysfunction.","abstract":"GMPPA encodes the GDP-mannose pyrophosphorylase A protein (GMPPA). The function of GMPPA is not well defined, however it is a homolog of GMPPB which catalyzes the reaction that converts mannose-1-phosphate and guanosine-5'-triphosphate to GDP-mannose. Previously, biallelic mutations in GMPPA were reported to cause a disorder characterized by achalasia, alacrima, neurological deficits, and intellectual disability. In this study, we report a female proband with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism. Exome sequencing identified a previously unreported homozygous c.853+1G>A variant in GMPPA in the proband and her affected sister. Their unaffected parents were heterozygous, and unaffected brother homozygous wild type for this variant. Lymphoblast cells from the affected sisters showed complete loss of the GMPPA protein by Western blotting, and increased levels of GDP-mannose in lymphoblasts on high performance liquid chromatography. Based on our findings and the previous report describing patients with an overlapping phenotype, we conclude that this novel variant in GMPPA, identified by exome sequencing in the proband and her affected sister, is the genetic cause of their phenotype and may expand the known phenotype of this recently described glycosylation disorder.","variants":[{"Name":"NM_013335.4(GMPPA):c.853+1G>A","Chromosome":"2","Start":"219505556","Stop":"219505556","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":439637,"rule_based_match":true,"evidence_text":"c.853+1G>A","llm_judgment":"PRESENT","evidence":"c.853+1G>A","abstract_start":661,"abstract_end":671}]}
{"pmid":"22135276","title":"Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.","abstract":"BACKGROUND: Usher syndrome (USH) is an autosomal recessive disorder comprising retinitis pigmentosa, hearing loss and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous with three distinctive clinical types (I-III) and nine Usher genes identified. This study is a comprehensive clinical and genetic analysis of 172 Usher patients and evaluates the contribution of digenic inheritance.\nMETHODS: The genes MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, GPR98, WHRN, CLRN1 and the candidate gene SLC4A7 were sequenced in 172 UK Usher patients, regardless of clinical type.\nRESULTS: No subject had definite mutations (nonsense, frameshift or consensus splice site mutations) in two different USH genes. Novel missense variants were classified UV1-4 (unclassified variant): UV4 is 'probably pathogenic', based on control frequency <0.23%, identification in trans to a pathogenic/probably pathogenic mutation and segregation with USH in only one family; and UV3 ('likely pathogenic') as above, but no information on phase. Overall 79% of identified pathogenic/UV4/UV3 variants were truncating and 21% were missense changes. MYO7A accounted for 53.2%, and USH1C for 14.9% of USH1 families (USH1C:c.496+1G>A being the most common USH1 mutation in the cohort). USH2A was responsible for 79.3% of USH2 families and GPR98 for only 6.6%. No mutations were found in USH1G, WHRN or SLC4A7.\nCONCLUSIONS: One or two pathogenic/likely pathogenic variants were identified in 86% of cases. No convincing cases of digenic inheritance were found. It is concluded that digenic inheritance does not make a significant contribution to Usher syndrome; the observation of multiple variants in different genes is likely to reflect polymorphic variation, rather than digenic effects.","variants":[{"Name":"NM_153676.4(USH1C):c.496+1G>A","Chromosome":"11","Start":"17527222","Stop":"17527222","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":357961,"rule_based_match":true,"evidence_text":"USH1C:c.496+1G>A","llm_judgment":"PRESENT","evidence":"USH1C:c.496+1G>A","abstract_start":1215,"abstract_end":1231}]}
{"pmid":"38099988","title":"Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome.","abstract":"The DNA polymerase δ complex (PolD), comprising catalytic subunit POLD1 and accessory subunits POLD2, POLD3, and POLD4, is essential for DNA synthesis and is central to genome integrity. We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome. The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination. The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years. We performed molecular and functional analysis of the mutant POLD3 and assessed cell cycle progression as well as replication-associated DNA damage. Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components. The cell cycle defect was rescued by transduction with WT POLD3. This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome.","variants":[{"Name":"NM_006591.3(POLD3):c.1118A>C (p.Lys373Thr)","Chromosome":"11","Start":"74634694","Stop":"74634694","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3409160,"rule_based_match":true,"evidence_text":"c.1118A > C; p.K373T","llm_judgment":"PRESENT","evidence":"c.1118A > C; p.K373T","abstract_start":261,"abstract_end":281}]}
{"pmid":"23709754","title":"New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe.","abstract":"BACKGROUND: Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear.\nOBJECTIVE: To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation.\nRESULTS: The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented.\nCONCLUSIONS: The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.","variants":[{"Name":"NM_007315.4(STAT1):c.537C>A (p.Asn179Lys)","Chromosome":"2","Start":"190999630","Stop":"190999630","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":153735,"rule_based_match":true,"evidence_text":"c.537C>A (N179K)","llm_judgment":"PRESENT","evidence":"c.537C>A (N179K)","abstract_start":708,"abstract_end":724},{"Name":"NM_007315.4(STAT1):c.854A>G (p.Gln285Arg)","Chromosome":"2","Start":"190995151","Stop":"190995151","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":153736,"rule_based_match":true,"evidence_text":"c.854 A>G (Q285R)","llm_judgment":"PRESENT","evidence":"c.854 A>G (Q285R)","abstract_start":891,"abstract_end":908},{"Name":"NM_007315.4(STAT1):c.1154C>T (p.Thr385Met)","Chromosome":"2","Start":"190986921","Stop":"190986921","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":153737,"rule_based_match":true,"evidence_text":"c.1154C>T (T385M)","llm_judgment":"PRESENT","evidence":"c.1154C>T (T385M)","abstract_start":977,"abstract_end":994}]}
{"pmid":"31885560","title":"Characterising","abstract":"The 5-alpha-reductase type 2 deficiency (5ARD2) is an autosomal recessive condition associated with impairment in the conversion of testosterone to dihydrotestosterone. This condition leads to undervirilisation in 46,XY individuals. To date, there have been more than 100 variations identified in the gene responsible for 5ARD2 development (steroid 5-alpha-reductase 2, <i>SRD5A2</i>). However, few studies have examined the molecular characterisation of Indonesian 5ARD2 cases. In the current study, we analysed 37 subjects diagnosed with 46,XY DSD (disorders of sex development) with confirmed variations in the <i>SRD5A2</i> gene. We examined results from testosterone/dihydrotestosterone (T/DHT) and urinary etiocholanolone/androsterone (Et/An) ratios, as well as from molecular and clinical analyses. Twelve variants in the <i>SRD5A2</i> gene were identified, and 6 of which were novel, namely, c.34-38delGinsCCAGC, p.Arg50His, p.Tyr136 <sup><i>∗</i></sup> , p.Gly191Arg, p.Phe194Ile, and p.Ile253Val variants. Moreover, we determined that 20 individuals contained harmful mutations, while the remaining 17 variants were benign. Those containing harmful mutations exhibited more severe phenotypes with median external genitalia masculinisation scores (EMS) of 3 (1.5-9) and were more likely to be diagnosed at a later age, reared as female, and virilised at pubertal age. In addition, the respective sensitivities for detecting severe 5ARD2 cases using T/DHT (cutoff: 10) and urinary Et/An ratios (cutoff: 0.95) were 85% and 90%, whereas mild cases were only identified with 64.7% and 47.1% sensitivity, respectively. Although we were unable to identify clear correlations between genotypic and phenotypic characteristics in this study, we clearly showed that individuals who were homozygous or compound heterozygous for any of the harmful mutations were more likely to exhibit classic 5ARD2 phenotypes, lower EMS, female assignment at birth, and virilisation during puberty. These results serve to inform the development of improved clinical and molecular 5ARD2 diagnostic approaches, specifically in Indonesian patients.","variants":[{"Name":"NM_000348.4(SRD5A2):c.571G>A (p.Gly191Arg)","Chromosome":"2","Start":"31529434","Stop":"31529434","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3129217,"rule_based_match":false,"evidence_text":"p.Gly191Arg","llm_judgment":"PRESENT","evidence":"p.Gly191Arg","abstract_start":964,"abstract_end":975}]}
{"pmid":"37246508","title":"Whole-exome sequencing reveals a likely pathogenic LMNA variant causing hypertrophic cardiomyopathy.","abstract":"OBJECTIVE: We studied the clinical and molecular features of a family with hypertrophic cardiomyopathy (HCM).\nBACKGROUND: A very heterogeneous disease affecting the heart muscle, HCM is mostly caused by variants in the proteins of sarcomeres. The detection of HCM pathogenic variants can affect the handling of patients and their families.\nMETHODS: Whole-exome sequencing (WES) was performed to assess the genetic cause(s) of HCM in a consanguineous Iranian family.\nRESULTS: Missense likely pathogenic variant c.1279C>T (p.Arg427Cys) within exon 7 of the LMNA gene (NM_170707) was found. The segregations were confirmed by polymerase chain reaction-based Sanger sequencing.\nCONCLUSIONS: Variant c.1279C>T (p.Arg427Cys) in the LMNA gene seemed to have been the cause of HCM in the family. A few LMNA gene variants related to HCM phenotypes have been recognized so far. Identifying HCM genetic basis confers significant opportunities to understand how the disease can develop and, by extension, how this progression can be arrested. Our study supports WES effectiveness for first-tier variant screening of HCM in a clinical setting.","variants":[{"Name":"NM_170707.4(LMNA):c.1279C>T (p.Arg427Cys)","Chromosome":"1","Start":"156136335","Stop":"156136335","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":196479,"rule_based_match":true,"evidence_text":"c.1279C>T (p.Arg427Cys)","llm_judgment":"PRESENT","evidence":"c.1279C>T (p.Arg427Cys)","abstract_start":510,"abstract_end":533}]}
{"pmid":"28480665","title":"DEND Syndrome with Heterozygous KCNJ11 Mutation Successfully Treated with Sulfonylurea.","abstract":"Permanent neonatal diabetes mellitus (PNDM) is caused by mutations in the ATP-sensitive potassium channel (KATP channel) subunits. Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome is the most severe form of PNDM and is characterized by various neurologic features. We report on a patient with DEND syndrome following initial misdiagnosis with type 1 DM, who was successfully switched from insulin to sulfonylurea therapy. A 50-day-old male presented with fever and seizure, complicated by persistent hyperglycemia. Insulin therapy was initiated. At 10 months of age, the patient was unable to hold his head up and make eye contact with others. At 17.9 years of age, direct sequencing of KCNJ11 identified a heterozygous mutation of c.602G>A (p.R201H). Since then, treatment with gliclazide was initiated and the insulin dose was gradually reduced. Following 3 months, insulin was discontinued with a gliclazide dose of 2.4 mg/kg. The patient continued to have excellent glycemic control with a glycated hemoglobin (HbA1c) level of 5.8% after 5 months. However, the patient's psychomotor retardation did not improve. This study reports the first case of DEND syndrome in Korea caused by a KCNJ11 mutation and emphasizes the necessity to screen mutations in KATP channel genes in patients with neonatal diabetes.","variants":[{"Name":"NM_000525.4(KCNJ11):c.602G>A (p.Arg201His)","Chromosome":"11","Start":"17387490","Stop":"17387490","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23705,"rule_based_match":true,"evidence_text":"c.602G>A (p.R201H)","llm_judgment":"PRESENT","evidence":"c.602G>A (p.R201H)","abstract_start":752,"abstract_end":770}]}
{"pmid":"36164746","title":"Novel compound heterozygous synonymous and missense variants in the MYO7A gene identified by next-generation sequencing in a Chinese family with nonsyndromic hearing loss.","abstract":"BACKGROUND: Variants in the MYO7A gene are increasingly identified among patients suffering from Usher syndrome type 1B (USH1B). However, such mutations are less commonly detected among patients suffering from nonsyndromic hearing loss (NSHL), including autosomal recessive deafness (DFNB2) and autosomal dominant deafness (DFNA11). This research attempts to clarify the genetic base of DFNB2 in a Chinese family and determine the pathogenicity of the identified mutations.\nMETHOD: Targeted next-generation sequencing (TGS) of 127 known deafness genes was performed for the 14-year-old proband. Then, Sanger sequencing was performed on the available family members. A minigene splicing assay was performed to verify the impact of the novel MYO7A synonymous variant. After performing targeted next-generation sequencing (TGS) of 127 existing hearing loss-related genes in a 14-year-old proband, Sanger sequencing was carried out on the available family members. Then, to confirm the influence of the novel MYO7A synonymous variants, a minigene splicing assay was performed.\nRESULTS: Two heteroallelic mutants of MYO7A (NM_000260.3) were identified: a maternally inherited synonymous variant c.2904G > A (p.Glu968=) in exon 23 and a paternally inherited missense variant c.5994G > T (p.Trp1998Cys) in exon 44. The in vitro minigene expression indicated that c.2904G > A may result in skipping of exon 23 resulting in a truncated protein.\nCONCLUSIONS: We reported a novel missense (c.5994G > T) and identified, for the first time, a novel pathogenic synonymous (c.2904G > A) variant within MYO7A in a patient with DFNB2. These findings enrich our understanding of the MYO7A variant spectrum of DFNB2 and can contribute to accurate genetic counseling and diagnosis of NSHL patients.","variants":[{"Name":"NM_000260.4(MYO7A):c.2904G>A (p.Glu968=)","Chromosome":"11","Start":"77181589","Stop":"77181589","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":231385,"rule_based_match":true,"evidence_text":"c.2904G > A (p.Glu968=)","llm_judgment":"PRESENT","evidence":"c.2904G > A (p.Glu968=)","abstract_start":1190,"abstract_end":1213},{"Name":"NM_000260.4(MYO7A):c.5994G>T (p.Trp1998Cys)","Chromosome":"11","Start":"77208746","Stop":"77208746","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1772356,"rule_based_match":true,"evidence_text":"c.5994G > T (p.Trp1998Cys)","llm_judgment":"PRESENT","evidence":"c.5994G > T (p.Trp1998Cys)","abstract_start":1269,"abstract_end":1295}]}
{"pmid":"30942823","title":"Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis.","abstract":"Importance: Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date.\nObjective: To identify genetic mutations associated with linear porokeratosis.\nDesign, Setting, and Participants: Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis.\nInterventions or Exposures: Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions.\nMain Outcomes and Measures: Germline and somatic genomic characteristics of participants with linear porokeratosis.\nResults: Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift).\nConclusions and Relevance: Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.","variants":[{"Name":"NM_002461.3(MVD):c.70+5G>A","Chromosome":"16","Start":"88663006","Stop":"88663006","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1336585,"rule_based_match":true,"evidence_text":"c.70+5G>A","llm_judgment":"PRESENT","evidence":"c.70 + 5G>A","abstract_start":1581,"abstract_end":1592},{"Name":"NM_006556.4(PMVK):c.329G>A (p.Arg110Gln)","Chromosome":"1","Start":"154926467","Stop":"154926467","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1336442,"rule_based_match":true,"evidence_text":"PMVK c.329G>A","llm_judgment":"PRESENT","evidence":"PMVK c.329G>A","abstract_start":1275,"abstract_end":1288},{"Name":"NM_006556.4(PMVK):c.379C>T (p.Gln127Ter)","Chromosome":"1","Start":"154926417","Stop":"154926417","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1336444,"rule_based_match":true,"evidence_text":"PMVK c.379C>T","llm_judgment":"PRESENT","evidence":"PMVK c.379C>T","abstract_start":1462,"abstract_end":1475},{"Name":"NM_002461.3(MVD):c.811_815del (p.Phe271fs)","Chromosome":"16","Start":"88655281","Stop":"88655285","ReferenceAlleleVCF":"CGGGAA","AlternateAlleleVCF":"C","allel_id":1336445,"rule_based_match":true,"evidence_text":"c.811_815del, p.F271Afs*33 frameshift","llm_judgment":"PRESENT","evidence":"c.811_815del, p.F271Afs*33 frameshift","abstract_start":1701,"abstract_end":1738}]}
{"pmid":"34489406","title":"A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing.","abstract":"Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits.","variants":[{"Name":"NM_000535.7(PMS2):c.2002A>G (p.Ile668Val)","Chromosome":"7","Start":"5986763","Stop":"5986763","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":190109,"rule_based_match":true,"evidence_text":"NM_000535.5: c.2002A>G","llm_judgment":"PRESENT","evidence":"NM_000535.5: c.2002A>G","abstract_start":287,"abstract_end":309}]}
{"pmid":"19744229","title":"A novel missense mutation in the EVC gene underlies Ellis-van Creveld syndrome in a Pakistani family.","abstract":"BACKGROUND: Ellis-van Creveld (EVC) syndrome is a rare autosomal recessive disorder characterized by skeletal, ectodermal and cardiac defects. This syndrome is caused by mutations in EVC and EVC2 genes, which are separated by 2.6 kb of genomic sequence on chromosome 4p16.\nMETHODS: In the present study we ascertained a four-generation pedigree of Pakistani origin with features of EVC. Linkage was searched by genotyping microsatellite markers linked to chromosome 4p16. Affected individuals showed homozygosity to the microsatellite markers tightly linked to EVC and EVC2 genes on chromosome 4p16. It was then subjected to direct sequencing of the EVC and EVC2 genes.\nRESULTS: Mutation analysis of the EVC and EVC2 genes identified a novel missense change (c.617G>A; p.S206N) in the EVC gene.\nCONCLUSIONS: We herein report on the first family from Pakistan with a large number of individuals affected by EVC. DNA sequence analysis led to the identification of the fifth missense mutation in the EVC gene.","variants":[{"Name":"NM_153717.3(EVC):c.617G>A (p.Ser206Asn)","Chromosome":"4","Start":"5731657","Stop":"5731657","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":453761,"rule_based_match":true,"evidence_text":"c.617G>A; p.S206N","llm_judgment":"PRESENT","evidence":"c.617G>A; p.S206N","abstract_start":759,"abstract_end":776}]}
{"pmid":"24061862","title":"Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe.","abstract":"Inherited mutations in PALB2 are known to be associated with increased breast cancer risk. We aimed to investigate the prevalence and risk association of a recurrent PALB2 mutation, c.509_510delGA, among 3,924 unselected breast cancer patients from Belarus, Russia or Germany. High-resolution melting analyses and direct sequencing identified the c.509_510delGA allele in 3/1,008 (0.3 %) German breast cancer patients, 2/994 (0.2 %) Russian breast cancer patients and 5/1,922 (0.3 %) Byelorussian breast cancer patients. Breast tumours were mainly estrogen receptor positive and included both ductal and lobular histology. Only one of the ten patients had a first-degree family history of breast cancer. The mutation was not detected in 2,827 healthy females from the same populations, confirming the association of PALB2*c.509_510delGA with breast cancer risk (p = 0.007). These data indicate that the PALB2*c.509_510delGA mutation is prevalent in about 1 in 400 breast cancer patients from Central and Eastern Europe, and the low occurrence of familial clustering is consistent with a moderate penetrance of this mutation.","variants":[{"Name":"NM_024675.4(PALB2):c.509_510del (p.Arg170fs)","Chromosome":"16","Start":"23636036","Stop":"23636037","ReferenceAlleleVCF":"ATC","AlternateAlleleVCF":"A","allel_id":132267,"rule_based_match":true,"evidence_text":"c.509_510delGA","llm_judgment":"PRESENT","evidence":"c.509_510delGA","abstract_start":182,"abstract_end":196}]}
{"pmid":"35531093","title":"Identification of a New Mutation p.P88L in Connexin 50 Associated with Dominant Congenital Cataract.","abstract":"Congenital hereditary cataract is genetically heterogeneous and the leading cause of visual impairment in children. Identification of hereditary causes is critical to genetic counselling and family planning. Here, we examined a four-generation Chinese pedigree with congenital dominant cataract and identified a new mutation in <i>GJA8</i> via targeted exome sequencing. A heterozygous missense mutation c.263C > T, leading to a proline-to-Leucine conversion at the conserved residue 88 in the second transmembrane domain of human connexin 50 (Cx50), was identified in all patients but not in unaffected family members. Functional analyses of the mutation revealed that it disrupted the stability of Cx50 and had a deleterious effect on protein function. Indeed, the mutation compromised normal membrane permeability and gating of ions, and impeded cell migration when overexpressed. Together, our results expand the pathogenic mutation spectrum of Cx50 underlying congenital cataract and lend more support to clinical diagnosis and genetic counseling.","variants":[{"Name":"NM_005267.5(GJA8):c.263C>T (p.Pro88Leu)","Chromosome":"1","Start":"147908218","Stop":"147908218","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1676616,"rule_based_match":true,"evidence_text":"c.263C > T","llm_judgment":"PRESENT","evidence":"c.263C > T","abstract_start":404,"abstract_end":414}]}
{"pmid":"28502515","title":"Lysosomal acid lipase deficiency in all siblings of the same parents.","abstract":"We present 4 normal-weight sibling children with lysosomal acid lipase deficiency (LAL-D). LAL-D was considered in the differential diagnosis based on the absence of secondary causes and primary inherited traits for their marked hyperlipidemia, together with unexplained hepatic transaminase elevation. Residual lysosomal acid lipase activity confirmed the diagnosis. DNA sequencing of LIPA indicated that the siblings were compound heterozygotes (c.894G>A and c.428+1G>A). This case describes the unusual occurrence of all offspring from the same nonconsanguineous mother and father inheriting compound heterozygosity of a recessive trait and the identification of an apparently unique LIPA mutation (c.428+1G>A). It highlights the collaborative effort between a lipidologist and gastroenterologist in developing a differential diagnosis leading to the confirmatory diagnosis of this rare, life-threatening disease. With the availability of an effective enzyme replacement therapy (sebelipase alfa), LAL-D should be entertained in the differential diagnosis of children, adolescents, and young adults with idiopathic hyperlipidemia and unexplained hepatic transaminase elevation.","variants":[{"Name":"NM_000235.4(LIPA):c.428+1G>A","Chromosome":"10","Start":"89228199","Stop":"89228199","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":545310,"rule_based_match":true,"evidence_text":"c.428+1G>A","llm_judgment":"PRESENT","evidence":"c.428+1G>A","abstract_start":461,"abstract_end":471}]}
{"pmid":"30908832","title":"CTSC compound heterozygous mutations in two Chinese patients with Papillon-Lefèvre syndrome.","abstract":"OBJECTIVES: To identify the molecular basis of Papillon-Lefèvre syndrome in two Chinese families.\nMETHODS: Peripheral blood and mouth swab samples were obtained, from which genomic DNA and RNA were isolated. Sanger sequencing was employed to identify the mutations. mRNA expression was tested by real-time quantitative PCR. Evolutionary conservation, pathogenicity prediction and impact of protein structures of the mutations were conducted with bioinformatics tools and homology modelling. HEK293 cells were transfected with plasmids expressing wild-type or mutated CTSC. CTSC protein expression level and enzyme activity were explored.\nRESULTS: Mutation analysis revealed two novel compound heterozygous mutations, the c.190-191insA and c.1211-1212delA in patient 1 and the c.716A>G and c.757+1G>A in patient 2. In both patients, the levels of CTSC mRNA were significantly lower than in their relatives. Homology modelling analysis predicted that the mutations affect the structure and stability of the protein, and in vitro study showed that the CTSC proteins containing the mutations c.190-191insA and c.1211-1212delA, which result in truncated versions of protein, display impaired enzyme activity. The protein containing c.716A>G mutation showed quite similar enzyme activity compared to wild-type CTSC.\nCONCLUSION: Our data support the molecular mechanism of PLS and enlarge the scope of CTSC gene mutations related to PLS.","variants":[{"Name":"NM_001814.6(CTSC):c.716A>G (p.Asn239Ser)","Chromosome":"11","Start":"88300571","Stop":"88300571","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":622829,"rule_based_match":true,"evidence_text":"c.716A>G","llm_judgment":"PRESENT","evidence":"c.716A>G","abstract_start":776,"abstract_end":784}]}
{"pmid":"26833262","title":"A Novel COL4A4 Mutation Identified in a Chinese Family with Thin Basement Membrane Nephropathy.","abstract":"Thin basement membrane nephropathy (TBMN) is often attributable to mutations in the COL4A3 or COL4A4 genes that encode the α3 and α4 chains of type IV collagen, respectively, a major structural protein in the glomerular basement membrane. The aim of this study was to explore a new disease-related genetic mutation associated with the clinical phenotype observed in a Chinese Han family with autosomal dominant TBMN. We conducted a clinical and genetic study comprising seven members of this TBMN family. Mutation screening for COL4A3 and COL4A4 was carried out by direct sequencing. The RNA sequences associated with both proteins were also analyzed with reverse transcription PCR and TA cloning. The result showed that every affected patient had a novel heterozygous splicing mutation in COL4A4 (c.1459 + 1G > A), which led to the elimination of the entire exon 21 from the COL4A4 cDNA and resulted in the direct splicing of exons 20 and 22. This in turn caused a frameshift mutation after exon 20 in the open reading frame of COL4A4. In conclusion, we describe a novel splicing mutation in COL4A4 that results in TBMN. This analysis increases our understanding of TBMN phenotype-genotype correlations, which should facilitate more accurate diagnosis and prenatal diagnosis of TBMN.","variants":[{"Name":"NM_000092.5(COL4A4):c.1459+1G>A","Chromosome":"2","Start":"227089867","Stop":"227089867","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2417958,"rule_based_match":true,"evidence_text":"c.1459 + 1G > A","llm_judgment":"PRESENT","evidence":"c.1459 + 1G > A","abstract_start":798,"abstract_end":813}]}
{"pmid":"29122497","title":"Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases.","abstract":"Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process required to produce various ISC-containing proteins. These ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid, an essential cofactor of respiratory chain complexes. Defects in ISC biogenesis lead to multiple mitochondrial dysfunction syndromes including: ISCA2 with infantile onset leukodystrophy. Recently, a founder mutation, c.229G > A, p.Gly77Ser in ISCA2 was reported to cause Multiple Mitochondrial Dysfunction Syndrome type 4. In a retrospective review of children diagnosed with the ISCA2 defect, we were able to identify ten new patients who were not reported previously with the identical founder mutation. High CSF glycine levels and elevated glycine peaks on MR spectroscopy were demonstrated in all tested probands. All patients were between 3 and 7 months of age with a triad of neurodevelopmental regression, nystagmus and optic atrophy and leukodystrophy. MRI findings were typical in the patients with diffuse, abnormal white matter signal in the cerebrum, cerebellum, brain stem and spinal cord. The patients ended up in a vegetative state, and often premature death due to respiratory infections. We alert clinicians to consider the ISCA2 defect as a differential diagnosis of infantile onset leukodystrophies affecting the brain as well as the spinal cord, especially in the presence of elevated CSF glycine or elevated glycine peaks in MR spectroscopy.","variants":[{"Name":"NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)","Chromosome":"14","Start":"74494329","Stop":"74494329","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":181441,"rule_based_match":true,"evidence_text":"c.229G > A, p.Gly77Ser","llm_judgment":"PRESENT","evidence":"c.229G > A, p.Gly77Ser","abstract_start":453,"abstract_end":475}]}
{"pmid":"29905864","title":"Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly.","abstract":"Central conducting lymphatic anomaly (CCLA) is one of the complex lymphatic anomalies characterized by dilated lymphatic channels, lymphatic channel dysmotility and distal obstruction affecting lymphatic drainage. We performed whole exome sequencing (WES) of DNA from a four-generation pedigree and examined the consequences of the variant by transfection of mammalian cells and morpholino and rescue studies in zebrafish. WES revealed a heterozygous mutation in EPHB4 (RefSeq NM_004444.4; c.2334 + 1G>C) and RNA-Seq demonstrated that the EPHB4 mutation destroys the normal donor site, which leads to the use of a cryptic splice donor that results in retention of the intervening 12-bp intron sequence. Transient co-expression of the wild-type and mutant EPHB4 proteins showed reduced phosphorylation of tyrosine, consistent with a loss-of-function effect. Zebrafish ephb4a morpholino resulted in vessel misbranching and deformities in the lymphatic vessel development, indicative of possible differentiation defects in lymphatic vessels, mimicking the lymphatic presentations of the patients. Immunoblot analysis using zebrafish lysates demonstrated over-activation of mTORC1 as a consequence of reduced EPHB4 signaling. Strikingly, drugs that inhibit mTOR signaling or RAS-MAPK signaling effectively rescued the misbranching phenotype in a comparable manner. Moreover, knock-in of EPHB4 mutation in HEK293T cells also induced mTORC1 activity. Our data demonstrate the pathogenicity of the identified EPHB4 mutation as a novel cause of CCLA and suggesting that ERK inhibitors may have therapeutic benefits in such patients with complex lymphatic anomalies.","variants":[{"Name":"NM_004444.5(EPHB4):c.2334+1G>C","Chromosome":"7","Start":"100807364","Stop":"100807364","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":590224,"rule_based_match":true,"evidence_text":"c.2334 + 1G>C","llm_judgment":"PRESENT","evidence":"c.2334 + 1G>C","abstract_start":490,"abstract_end":503}]}
{"pmid":"21316014","title":"Congenital hypopituitarism due to POU1F1 gene mutation.","abstract":"POU1F1 (Pit-1; Gene ID 5449) is an anterior pituitary transcriptional factor, and POU1F1 mutation is known to cause anterior pituitary hypoplasia, growth hormone and prolactin deficiency and various degree of hypothyroidism. We report here a patient who presented with growth failure and central hypothyroidism since early infancy. However, treatment with thyroxine gave no effect and he subsequently developed calf muscle pseudohypertrophy (Kocher-Debre-Semelaigne syndrome), elevation of creatinine kinase, dilated cardiomyopathy and pericardial effusion. Final diagnosis was made by combined pituitary function test and sequencing analysis that revealed POU1F1 gene C.698T > C (p.F233S) mutation. The rarity of the disease can result in delayed diagnosis and treatment.","variants":[{"Name":"NM_000306.4(POU1F1):c.698T>C (p.Phe233Ser)","Chromosome":"3","Start":"87260072","Stop":"87260072","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2749379,"rule_based_match":true,"evidence_text":"C.698T > C (p.F233S)","llm_judgment":"PRESENT","evidence":"C.698T > C (p.F233S)","abstract_start":669,"abstract_end":689}]}
{"pmid":"28392901","title":"Mutation analysis of connexin 50 gene among Iranian families with autosomal dominant cataracts.","abstract":"OBJECTIVES: Childhood cataract is a genetically heterogeneous eye disorder that results in visual impairment. The aim of this study was to identify the genetic mutations of connexin 50 gene among Iranian families suffered from autosomal dominant congenital cataracts (ADCC).\nMATERIALS AND METHODS: Families, having at least two members with bilateral familial congenital cataract, were selected for the study. Probands were evaluated by detailed ophthalmologist's examination, and the pedigree analysis was performed. PCR amplifications were performed corresponding to coding region and intron-exon boundaries of <i>GJA8</i>, a candidate gene responsible for ADCC. PCR products were subjected to bidirectional sequencing, and the co-segregation of identified mutations was examined and finally, the impact of identified mutations on biological functions of <i>GJA8</i> was predicted by in silico examination.\nRESULTS: Three different genetic alterations, including c.130G>A (p.V44M), c.301G>T (p.R101L) and c.134G>T (p.W45L) in <i>GJA8</i> gene were detected among three probands. Two identified mutations, W45L and V44M have been already reported, while the R101L is a novel mutation and its co-segregation was examined. This mutation was exclusively detected in the ADCC and could not be found among the healthy control group. The result of bioinformatic studies of R101L mutation predicted that this amino acid substitution within <i>GJA8</i> could be a disease-afflicting mutation due to its potential effect on the protein structure and biological function.\nCONCLUSION: Our results suggest that mutations of lens connexin genes such as <i>GJA8</i> gene could be one of the major mechanisms of cataract development, at least in a significant proportion of Iranian patients with ADCC.","variants":[{"Name":"NM_005267.5(GJA8):c.130G>A (p.Val44Met)","Chromosome":"1","Start":"147908085","Stop":"147908085","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1696550,"rule_based_match":true,"evidence_text":"c.130G>A (p.V44M)","llm_judgment":"PRESENT","evidence":"c.130G>A (p.V44M)","abstract_start":965,"abstract_end":982},{"Name":"NM_005267.5(GJA8):c.134G>T (p.Trp45Leu)","Chromosome":"1","Start":"147908089","Stop":"147908089","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":822676,"rule_based_match":true,"evidence_text":"c.134G>T (p.W45L)","llm_judgment":"PRESENT","evidence":"c.134G>T (p.W45L)","abstract_start":1007,"abstract_end":1024}]}
{"pmid":"27930511","title":"Four-year follow-up of a Wilson disease pedigree complicated with epilepsy and hypopituitarism: Case report with a literature review.","abstract":"RATIONALE: Wilson's disease (WD) is an autosomal recessive inherited disorder of copper metabolism with excellent prognosis if treated timely. However, WD is usually prone to neglect and misdiagnosis at an early stage. We reported a rare WD pedigree, and the clinical features, laboratory tests, and gene mutations were analyzed in detail.\nPATIENT CONCERNS: The patient was a 17-year-old and 136-cm-tall girl who presented with limb weakness, combined with multi-organ disorders including blind eye, epilepsy, and hypopituitarism.\nDIAGNOSES: Clinical tests showed a low serum ceruloplasmin level, high urinary copper excretion and Kayser-Fleischer (K-F) rings. She carried a compound heterozygous mutations in ATP7B gene (c.2828G>A and c.3884C>T). Her younger brother, as an asymptomatic patient, manifested with elevation of transaminases but without neurological and hepatic symptoms. They were diagnosed as WD finally.\nINTERVENTIONS: They were treated with sodium dimercaptosulphonate, supplemented with zinc gluconate, vitamin B6, vitamin C, as well as restriction of dietary copper.\nOUTCOMES: The urinary copper excretion and serum transaminase level decreased gradually. The abnormal signals in brainstem and basal ganglia were also remarkably decreased after 4-year of de-copper treatment.\nLESSONS: As to the patients with complicated clinical manifestations, the extrapyramidal symptom and basal ganglia signals should be concerned. The serum ceruloplasmin detection and ATP7B gene mutation screening are necessary.","variants":[{"Name":"NM_000053.4(ATP7B):c.2828G>A (p.Gly943Asp)","Chromosome":"13","Start":"51949699","Stop":"51949699","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":186892,"rule_based_match":true,"evidence_text":"c.2828G>A","llm_judgment":"PRESENT","evidence":"c.2828G>A","abstract_start":722,"abstract_end":731}]}
{"pmid":"26770544","title":"Clinical characteristics and mutation analysis of two Chinese children with 17a-hydroxylase/17,20-lyase deficiency.","abstract":"Combined with the literature, recognize the clinical features and molecular genetic mechanism of the disease. 17a-hydroxylase/17,20-lyase deficiency, a rare form of congenital adrenal hyperplasia, is caused by mutations in the cytochrome P450c17 gene (CYP17A1), and characterized by hypertension, hypokalemia, female sexual infantilism or male pseudohermaphroditism. We presented the clinical and biochemical characterization in two patients (a 13 year-old girl (46, XX) with hypokalemia and lack of pubertal development, a 11 year-old girl (46, XY) with female external genitalia and severe hypertension). CYP17A1 mutations were detected by PCR and direct DNA sequencing in patients and their parents. A homozygous mutation c.985_987delTACinsAA (p.Y329KfsX418) in Exon 6 was found in patient 1, and a homozygous deletion mutation c.1459_1467delGACTCTTTC (p.Asp487_Phe489del) in exon 8 in patient 2. The patients manifested with hypertension, hypokalemia, sexual infantilism should be suspected of having 17a-hydroxylase/17,20-lyase deficiency. Definite diagnosis is depended on mutation analysis. Hydrocortisone treatment in time is crucial to prevent severe hypertension and hypokalemia.","variants":[{"Name":"NM_000102.4(CYP17A1):c.1459_1467del (p.Asp487_Phe489del)","Chromosome":"10","Start":"102830762","Stop":"102830770","ReferenceAlleleVCF":"TGAAAGAGTC","AlternateAlleleVCF":"T","allel_id":620342,"rule_based_match":true,"evidence_text":"c.1459_1467delGACTCTTTC (p.Asp487_Phe489del)","llm_judgment":"PRESENT","evidence":"c.1459_1467delGACTCTTTC (p.Asp487_Phe489del)","abstract_start":831,"abstract_end":875}]}
{"pmid":"21165302","title":"Congenital zinc deficiency from mutations of the SLC39A4 gene as the genetic background of acrodermatitis enteropathica.","abstract":"Acrodermatitis enteropathica (AE) is an autosomal recessive disorder with the clinical triad of acral dermatitis, diarrhea and alopecia. AE is known to be caused by mutations of the SLC39A4 gene on the chromosome band 8q24.3, encoding the zinc transporter in human. An 8-month-old Korean boy presented with eczematous changes on the inguinal area and knees and was diagnosed with AE. Blood tests revealed a markedly decreased level of plasma zinc, and his symptoms improved on oral zinc replacement. To confirm the diagnosis of AE from congenital zinc deficiency, direct sequencing analysis of SLC39A4 was performed and revealed that he was compound heterozygous for a known missense mutation (Arg95Cys) and a novel splicing mutation in the donor site of intron 7 (c.1287+2T>C). Family study showed that his parents were heterozygous carriers of the mutations. To the best of our knowledge, this is the first report of genetically confirmed AE in Korea.","variants":[{"Name":"NM_130849.4(SLC39A4):c.1287+2T>C","Chromosome":"8","Start":"144413956","Stop":"144413956","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1475613,"rule_based_match":true,"evidence_text":"c.1287+2T>C","llm_judgment":"PRESENT","evidence":"c.1287+2T>C","abstract_start":765,"abstract_end":776},{"Name":"NM_130849.4(SLC39A4):c.283C>T (p.Arg95Cys)","Chromosome":"8","Start":"144416001","Stop":"144416001","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18583,"rule_based_match":false,"evidence_text":"Arg95Cys","llm_judgment":"PRESENT","evidence":"Arg95Cys","abstract_start":694,"abstract_end":702}]}
{"pmid":"21337604","title":"Infantile muscular dystrophy in Canadian aboriginals is an αB-crystallinopathy.","abstract":"OBJECTIVE: A recessively transmitted fatal hypertonic infantile muscular dystrophy has been described in Canadian aboriginals. The affected infants present with progressive limb and axial muscle stiffness and develop severe respiratory insufficiency, and most die in the first year of life. We sought to determine the genetic basis of this disease.\nMETHODS: We performed histochemical, immunocytochemical, electron microscopy, and molecular genetic studies in a cohort of 12 patients affected by this disease.\nRESULTS: Conventional histochemical and electron microscopy studies suggested myofibrillar myopathy (MFM). Therefore, we searched for ectopic expression of multiple proteins typical of MFM. Alpha B-crystallin (αBC) expression was absent from all fibers using a monoclonal antibody raised against the entire protein. However, a monoclonal antibody directed against the first 10 residues of αBC immunostained portions of abnormal fibers. Pursuing this clue, we searched for mutations in the gene for αBC (CRYAB) in available DNA samples of 8 patients. All harbored a homozygous deletion, c.60C, predicting a Ser to Ala change at codon 21 and a stop codon after 23 missense residues (p.Ser21AlafsX24). Clinically unaffected parents were heterozygous for this mutation.\nINTERPRETATION: The homozygous c.60delC in CRYAB pinpoints the genetic basis of the fatal infantile hypertonic muscular dystrophy of Canadian aboriginals. MFMs are typically transmitted by dominant inheritance, but in this disease the parental phenotype is rescued by limited expression of the highly truncated nonfunctional mutant gene product. The severe patient phenotype is due to homozygosity for the markedly hypomorphic allele. Ann Neurol, 2011.","variants":[{"Name":"NM_001289808.2(CRYAB):c.60del (p.Ser21fs)","Chromosome":"11","Start":"111911665","Stop":"111911665","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":38624,"rule_based_match":true,"evidence_text":"c.60delC","llm_judgment":"PRESENT","evidence":"c.60delC","abstract_start":1307,"abstract_end":1315}]}
{"pmid":"29959261","title":"Biallelic","abstract":"OBJECTIVE: To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families.\nMETHODS: We used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating <i>SQSTM1</i> mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model.\nRESULTS: We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and c.934_936delinsTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years.\nCONCLUSIONS: This study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in <i>SQSTM1</i> and links this phenotype to defective selective autophagy.","variants":[{"Name":"NM_003900.5(SQSTM1):c.301+2T>A","Chromosome":"5","Start":"179823055","Stop":"179823055","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1325706,"rule_based_match":true,"evidence_text":"c.301+2T>A","llm_judgment":"PRESENT","evidence":"c.301+2T>A","abstract_start":836,"abstract_end":846},{"Name":"NM_003900.5(SQSTM1):c.934_936delinsTGA (p.Arg312Ter)","Chromosome":"5","Start":"179833211","Stop":"179833213","ReferenceAlleleVCF":"AGG","AlternateAlleleVCF":"TGA","allel_id":1325707,"rule_based_match":true,"evidence_text":"c.934_936delinsTGA","llm_judgment":"PRESENT","evidence":"c.934_936delinsTGA","abstract_start":1005,"abstract_end":1023}]}
{"pmid":"30628748","title":"Aberrant RNA splicing is the major pathogenic effect in a knock-in mouse model of the dominantly inherited c.1430A>G human RPE65 mutation.","abstract":"Human RPE65 mutations cause a spectrum of retinal dystrophies that result in blindness. While RPE65 mutations have been almost invariably recessively inherited, a c.1430A>G (p.(D477G)) mutation has been reported to cause autosomal dominant retinitis pigmentosa (adRP). To study the pathogenesis of this human mutation, we have replicated the mutation in a knock-in (KI) mouse model using CRISPR/Cas9-mediated genome editing. Significantly, in contrast to human patients, heterozygous KI mice do not exhibit any phenotypes in visual function tests. When raised in regular vivarium conditions, homozygous KI mice display relatively undisturbed visual functions with minimal retinal structural changes. However, KI/KI mouse retinae are more sensitive to light exposure and exhibit signs of degenerative features when subjected to light stress. We find that instead of merely producing a missense mutant protein, the A>G nucleotide substitution greatly affects appropriate splicing of Rpe65 mRNA by generating an ectopic splice site in comparable context to the canonical one, thereby disrupting RPE65 protein expression. Similar splicing defects were also confirmed for the human RPE65 c.1430G mutant in an in vitro Exontrap assay. Our data demonstrate that a splicing defect is associated with c.1430G pathogenesis, and therefore provide insights in the therapeutic strategy for human patients.","variants":[{"Name":"NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly)","Chromosome":"1","Start":"68431085","Stop":"68431085","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":761008,"rule_based_match":true,"evidence_text":"c.1430A>G (p.(D477G))","llm_judgment":"PRESENT","evidence":"c.1430A>G (p.(D477G))","abstract_start":163,"abstract_end":184}]}
{"pmid":"30349989","title":"Severe Neonatal Manifestations of Infantile Liver Failure Syndrome Type 1 Caused by Cytosolic Leucine-tRNA Synthetase Deficiency.","abstract":"BACKGROUND: Deleterious mutations in cytosolic leucine-tRNA synthetase (LARS) cause infantile liver failure syndrome, type 1 (ILFS1), a recently recognized, rare autosomal recessive disorder (OMIM151350). Only six families with ILFS1 have been reported in the literature. Patients with ILFS1 are typically diagnosed between 5 and 24 months of age with failure to thrive, developmental delays, encephalopathy, microcytic anemia, and chronic liver dysfunction with recurrent exacerbations following childhood illnesses. Neonatal manifestations of this disorder have not been well documented.\nCASE REPORT: We report a premature female newborn with intrauterine growth restriction, failure to thrive, congenital anemia, anasarca, and fulminant liver failure leading to lethal multiple organ failure. Liver failure in this infant was characterized by a disproportionate impairment of liver synthetic function, including severe coagulopathy and hypoalbuminemia without significant defects in liver detoxification or evidence of hepatocellular injury during early phase of the disease. Whole-exome sequencing of child-parent trio identified two inherited missense mutations in LARS in this patient. One, c.1292T>A; p.Val431Asp, has been reported in patients with ILFS1, while the other, c.725C>T; p.Pro242Leu, is novel. Both mutations involve amino acid residues in the highly conserved editing domain of LARS, are predicted to be functionally deleterious, and presumably contribute to the clinical manifestations in this patient.\nCONCLUSION: This is the first case documenting neonatal manifestation of ILFS1, highlighting early, severe, and disproportionate defects in liver synthetic function. Timely diagnosis of ILFS1 is crucial to guide critical clinical management and improve outcomes of this rare and potentially life-threatening disorder.","variants":[{"Name":"NM_020117.11(LARS1):c.1292T>A (p.Val431Asp)","Chromosome":"5","Start":"146151995","Stop":"146151995","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":425624,"rule_based_match":true,"evidence_text":"c.1292T>A; p.Val431Asp","llm_judgment":"PRESENT","evidence":"c.1292T>A; p.Val431Asp","abstract_start":1197,"abstract_end":1219}]}
{"pmid":"32126021","title":"","abstract":"Clinical manifestations of the late-onset adult Pompe disease (glycogen storage disease type II) are heterogeneous. To identify genetic defects of a special patient population with cerebrovascular involvement as the main symptom, we performed whole-genome sequencing (WGS) analysis on a consanguineous Chinese family of total eight members including two Pompe siblings both had cerebral infarction. Two novel compound heterozygous variants were found in GAA gene: c.2238G>C in exon 16 and c.1388_1406del19 in exon 9 in the two patients. We verified the function of the two mutations in leading to defects in GAA protein expression and enzyme activity that are associated with autophagic impairment. We further performed a gut microbiome metagenomics analysis, found that the child's gut microbiome metagenome is very similar to his mother. Our finding enriches the gene mutation spectrum of Pompe disease, and identified the association of the two new mutations with autophagy impairment. Our data also indicates that gut microbiome could be shared within Pompe patient and cohabiting family members, and the abnormal microbiome may affect the blood biochemical index. Our study also highlights the importance of deep DNA sequencing in potential clinical applications.","variants":[{"Name":"NM_000152.5(GAA):c.2238G>C (p.Trp746Cys)","Chromosome":"17","Start":"80117016","Stop":"80117016","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":260196,"rule_based_match":true,"evidence_text":"c.2238G>C","llm_judgment":"PRESENT","evidence":"c.2238G>C","abstract_start":464,"abstract_end":473}]}
{"pmid":"24729269","title":"BRCA1 point mutations in premenopausal breast cancer patients from Central Sudan.","abstract":"Premenopausal breast cancer (BC) is one of the most common cancers of women in rural Africa and part of the disease load may be related to hereditary predisposition, including mutations in the BRCA1 gene. However, the BRCA1 mutations associated with BC in Africa are scarcely characterized. We report here 33 BRCA1 point mutations, among which 2 novel missense variants, found in 59 Central Sudanese premenopausal BC patients. The high fractions of mutations with intercontinental and uniquely African distribution (17/33, 51.5 % and 14/33, 42.4 %, respectively) are in agreement with the high genetic diversity expected in an African population. Overall 24/33 variants (72.7 %) resulted neutral; 8/33 of unknown significance (24.3 %, including the 2 novel missense mutations); 1 (3.0 %) overtly deleterious. Notably, in silico studies predict that the novel C-terminal missense variant c.5090G>A (p.Cys1697Tyr) affects phosphopeptide recognition by the BRCA1 BRCT1 domain and may have a pathogenic impact. Genetic variation and frequency of unique or rare mutations of uncertain clinical relevance pose significant challenges to BRCA1 testing in Sudan, as it might happen in other low-resource rural African contexts.","variants":[{"Name":"NM_007294.4(BRCA1):c.5090G>A (p.Cys1697Tyr)","Chromosome":"17","Start":"43063936","Stop":"43063936","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46191,"rule_based_match":true,"evidence_text":"c.5090G>A (p.Cys1697Tyr)","llm_judgment":"PRESENT","evidence":"c.5090G>A (p.Cys1697Tyr)","abstract_start":887,"abstract_end":911}]}
{"pmid":"23568730","title":"Clinical features and genetic screening of hereditary hemorrhagic telangiectasia","abstract":"OBJECTIVE: To analyze clinical features of 4 families with hereditary hemorrhagic telangiectasia (HHT) and potential mutations of ENG, ACVRL1 and SMAD4 genes.\nMETHODS: Four unrelated HHT patients and their affected family members were analyzed. All exons and flanking regions of ENG, ACVRL1 and SMAD4 genes were analyzed with PCR and direct sequencing and multiplex ligation-dependent probe amplification (MLPA) methods.\nRESULTS: Eleven patients from the 4 families were enrolled in this study. Two ENG and 1 ACVRL1 mutations were identified, among which an ENG mutation (c.207G>A; p.L69L) and an ACVRL1 mutation (c.817C>T; p.L273L) have been previously reported. In addition, a novel ENG mutation (c.1004A>T; p.Q335L) has been found in 3 different families. Similar mutations were not detected in 200 healthy individuals. No mutations of ENG, ACVRL1 and SMAD4 were found in the fourth family.\nCONCLUSION: A novel mutation c.1004A>T (p. Q335L) of ENG has been identified in patients with HHT. And there is significant phenotypic variability and genetic heterogeneity with the disease.","variants":[{"Name":"NM_000020.3(ACVRL1):c.817C>T (p.Leu273=)","Chromosome":"12","Start":"51915269","Stop":"51915269","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":527268,"rule_based_match":true,"evidence_text":"c.817C>T (p.L273L)","llm_judgment":"PRESENT","evidence":"c.817C>T","abstract_start":614,"abstract_end":622}]}
{"pmid":"26963954","title":"Association of Mutations in SLC12A1 Encoding the NKCC2 Cotransporter With Neonatal Primary Hyperparathyroidism.","abstract":"CONTEXT: Primary hyperparathyroidism with hypercalciuria has not been described in the newborn period.\nOBJECTIVE: Our objectives are to identify the genetic basis for neonatal primary hyperparathyroidism in a family with 2 affected children.\nSUBJECTS: An African American boy presenting with mild neonatal primary hyperparathyroidism and hypercalciuria was evaluated at The Children's Hospital of Philadelphia. His older brother with neonatal primary hyperparathyroidism had died in infancy of multiple organ failure.\nMETHODS: We collected clinical and biochemical data and performed exome sequencing analysis on DNA from the patient and his unaffected mother after negative genetic testing for known causes of primary hyperparathyroidism.\nRESULTS: Exome sequencing followed by Sanger sequencing disclosed 2 heterozygous mutations, c.1883C>A, p.(A628D) and c.2786_2787insC, p.(T931fsX10), in the SLC12A1 gene, which was previously implicated in antenatal type 1 Bartter syndrome. Sanger sequencing confirmed the 2 mutations in the proband and his deceased brother; both parents were heterozygous for different mutations and an unaffected sister was homozygous for wild-type alleles.\nCONCLUSIONS: These results demonstrate a previously unrecognized association between neonatal primary hyperparathyroidism and mutation of SLC12A1, the cause of antenatal Bartter syndrome type 1, and suggest that the loss of sodium-potassium-chloride cotransporter-2 cotransporter activity influences parathyroid gland function.","variants":[{"Name":"NM_000338.3(SLC12A1):c.1883C>A (p.Ala628Asp)","Chromosome":"15","Start":"48251711","Stop":"48251711","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":380139,"rule_based_match":true,"evidence_text":"c.1883C>A, p.(A628D)","llm_judgment":"PRESENT","evidence":"c.1883C>A, p.(A628D)","abstract_start":832,"abstract_end":852}]}
{"pmid":"29560582","title":"A family segregating lethal neonatal coenzyme Q","abstract":"Primary CoQ<sub>10</sub> deficiency is a clinically and genetically heterogeneous, autosomal recessive disorder resulting from mutations in genes involved in the synthesis of coenzyme Q<sub>10</sub> (CoQ<sub>10</sub>). To date, mutations in nine proteins required for the biosynthesis of CoQ<sub>10</sub> cause CoQ<sub>10</sub> deficiency with varying clinical presentations. In 2009 the first patient with mutations in COQ9 was reported in an infant with a neonatal-onset, primary CoQ<sub>10</sub> deficiency with multi-system disease. Here we describe four siblings with a previously undiagnosed lethal disorder characterized by oligohydramnios and intrauterine growth restriction, variable cardiomyopathy, anemia, and renal anomalies. The first and third pregnancy resulted in live born babies with abnormal tone who developed severe, treatment unresponsive lactic acidosis after birth and died hours later. Autopsy on one of the siblings demonstrated brain changes suggestive of the subacute necrotizing encephalopathy of Leigh disease. Whole-exome sequencing (WES) revealed the siblings shared compound heterozygous mutations in the COQ9 gene with both variants predicted to affect splicing. RT-PCR on RNA from patient fibroblasts revealed that the c.521 + 2 T > C variant resulted in splicing out of exons 4-5 and the c.711 + 3G > C variant spliced out exon 6, resulting in undetectable levels of COQ9 protein in patient fibroblasts. The biochemical profile of patient fibroblasts demonstrated a drastic reduction in CoQ<sub>10</sub> levels. An additional peak on the chromatogram may represent accumulation of demethoxy coenzyme Q (DMQ), which was shown previously to accumulate as a result of a defect in COQ9. This family expands our understanding of this rare metabolic disease and highlights the prenatal onset, clinical variability, severity, and biochemical profile associated with COQ9-related CoQ<sub>10</sub> deficiencies.","variants":[{"Name":"NM_020312.4(COQ9):c.711+3G>C","Chromosome":"16","Start":"57458353","Stop":"57458353","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3072875,"rule_based_match":true,"evidence_text":"c.711+3G>C","llm_judgment":"PRESENT","evidence":"c.711 + 3G > C","abstract_start":1324,"abstract_end":1338},{"Name":"NM_020312.4(COQ9):c.521+2T>C","Chromosome":"16","Start":"57456648","Stop":"57456648","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3235621,"rule_based_match":true,"evidence_text":"c.521 + 2 T > C","llm_judgment":"PRESENT","evidence":"c.521 + 2 T > C","abstract_start":1254,"abstract_end":1269}]}
{"pmid":"26225579","title":"Novel CDKN2A mutations in Austrian melanoma patients.","abstract":"CDKN2A is the most prominent familial melanoma gene, with mutations occurring in up to 40% of the families. Numerous mutations in the gene are known, several of them representing regional founder mutations. We sought to determine, for the first time, germline mutations in CDKN2A in Austria to identify novel mutations. In total, 700 individuals (136 patients with a positive family history and 164 with at least two primary melanomas as the high-risk groups; 200 with single primary melanomas; and 200 healthy individuals as the control groups) were Sanger sequenced for CDKN2A exon 1α, 1β, and 2. The 136 patients with affected relatives were also sequenced for CDK4 exon 2. We found the disease-associated mutations p.R24P (8×), p.N71T (1×), p.G101W (1×), and p.V126D (1×) in the group with affected relatives and p.R24P (2×) in the group with several primary melanomas. Furthermore, we discovered four mutations of unknown significance, two of which were novel: p.A34V and c.151-4 G>C, respectively. Computational effect prediction suggested p.A34V as conferring a high risk for melanoma, whereas c.151-4 G>C, although being predicted as a splice site mutation by MutationTaster, could not functionally be confirmed to alter splicing. Moreover, computational effect prediction confirmed accumulation of high-penetrance mutations in high-risk groups, whereas mutations of unknown significance were distributed across all groups. p.R24P is the most common high-risk mutation in Austria. In addition, we discovered two new mutations in Austrian melanoma patients, p.A34V and c.151-4 G>C, respectively.","variants":[{"Name":"NM_000077.5(CDKN2A):c.151-4G>C","Chromosome":"9","Start":"21971212","Stop":"21971212","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":151314,"rule_based_match":true,"evidence_text":"c.151-4 G>C","llm_judgment":"PRESENT","evidence":"c.151-4 G>C","abstract_start":977,"abstract_end":988}]}
{"pmid":"22688420","title":"Two novel mutations in the lactase gene in a Japanese infant with congenital lactase deficiency.","abstract":"Intestinal lactase is required for the hydrolysis of lactose that is the most essential carbohydrate in milk and the primary diet source of newborn.  Congenital lactase deficiency [CLD (MIM 223000)] is a severe gastrointestinal disorder and is characterized by watery diarrhea due to an extremely low or the lack of lactase activity in the intestinal wall from birth.  CLD is a rare disease and occurs more frequently in Finland.  Recent studies have shown that mutations in the coding region of the lactase (LCT) gene underlie CLD in patients from Finland and other European countries.  Here, we report two novel mutations in the LCT gene in a Japanese female infant with clinical features consistent with those of CLD.  She suffered from severe watery diarrhea from the age of 2 days on breast milk/lactose containing cow's milk formula.  With the lactose-free hydrolyzed cow's milk formula, diarrhea was stopped, and she has now developed well on a lactose-free diet.  She shows a lactose-intolerance pattern on the lactose challenge test.  Sequence analysis revealed the two mutations in her LCT gene: c.4419C>G (p.Y1473X) in exon 10 transmitted from her mother and c.5387delA (p.D1796fs) in exon 16 transmitted from her father.  Both mutations cause premature truncation of lactase polypeptide and are supposed to be responsible for CLD.  To our knowledge, this is the first report on mutations in the LCT gene in Japan.  We suggest that an increased awareness is required regarding CLD.","variants":[{"Name":"NM_002299.4(LCT):c.4419C>G (p.Tyr1473Ter)","Chromosome":"2","Start":"135804812","Stop":"135804812","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":71028,"rule_based_match":true,"evidence_text":"c.4419C>G (p.Y1473X)","llm_judgment":"PRESENT","evidence":"c.4419C>G (p.Y1473X)","abstract_start":1106,"abstract_end":1126},{"Name":"NM_002299.4(LCT):c.5387del (p.Asp1796fs)","Chromosome":"2","Start":"135789747","Stop":"135789747","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":71031,"rule_based_match":true,"evidence_text":"c.5387delA (p.D1796fs)","llm_judgment":"PRESENT","evidence":"c.5387delA (p.D1796fs)","abstract_start":1170,"abstract_end":1192}]}
{"pmid":"38433265","title":"Heterozygous THBS2 pathogenic variant causes Ehlers-Danlos syndrome with prominent vascular features in humans and mice.","abstract":"Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2<sup>Cys896Arg</sup> KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.","variants":[{"Name":"NM_003247.5(THBS2):c.2686T>C (p.Cys896Arg)","Chromosome":"6","Start":"169225232","Stop":"169225232","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3222252,"rule_based_match":true,"evidence_text":"NM_003247.5:c.2686T>C, p.Cys896Arg","llm_judgment":"PRESENT","evidence":"NM_003247.5:c.2686T>C, p.Cys896Arg","abstract_start":905,"abstract_end":939}]}
{"pmid":"32908725","title":"A Japanese Patient with Genitopatellar Syndrome Transiently Presenting with Cardiac Intramural Cavity during the Neonatal Period.","abstract":"Genitopatellar syndrome (GPS) is a rare autosomal dominant disorder caused by de novo pathogenic variants in the <i>KAT6B</i> gene. It is characterized by genital abnormalities, patellar hypoplasia/agenesis, flexion contractures of the hips and knees, corpus callosum agenesis with microcephaly, and hydronephrosis and/or multiple renal cysts. More than half of patients with GPS have congenital heart defects, mostly atrial and/or ventricular septal defects, patent foramen ovale, and patent ductus arteriosus. We report a case of a Japanese neonate with a de novo heterozygous c.3769_3772delTCTA pathogenic variant in the <i>KAT6B</i> gene who presented with a cardiac intramural cavity of the ventricular septum at birth. The cavity unexpectedly disappeared at 1 month of age, but trabecular septal thinning and flash remained. The features of the cavity were not consistent with those of congenital ventricular diverticulum or aneurysm, and its identity and prognosis are still unclear. Because patients with GPS may exhibit various forms of cardiac malformation, careful cardiac examination and follow-up are required from birth in cases of suspected GPS.","variants":[{"Name":"NM_012330.4(KAT6B):c.3769_3772del (p.Lys1258fs)","Chromosome":"10","Start":"75028589","Stop":"75028592","ReferenceAlleleVCF":"GTCTA","AlternateAlleleVCF":"G","allel_id":39487,"rule_based_match":true,"evidence_text":"c.3769_3772delTCTA","llm_judgment":"PRESENT","evidence":"c.3769_3772delTCTA","abstract_start":579,"abstract_end":597}]}
{"pmid":"27176039","title":"Clinical profile and molecular characterization of Galactosemia in Brazil: identification of seven novel mutations.","abstract":"BACKGROUND: Classical Galactosemia (CG) is an inborn error of galactose metabolism caused by the deficiency of the galactose-1-phosphate uridyltransferase enzyme. It is transmitted as an autosomal recessive disease and is typically characterized by neonatal galactose intolerance, with complications ranging from neonatal jaundice and liver failure to late complications, such as motor and reproductive dysfunctions. Galactosemia is also heterogeneous from a molecular standpoint, with hundreds of different mutations described in the GALT gene, some of them specific to certain populations, reflecting consequence of founder effect.\nMETHODS: This study reviews the main clinical findings and depicts the spectrum of mutations identified in 19 patients with CG, six with Duarte Galactosemia and one with type 2 Galactosemia in Brazil. Some individuals were diagnosed through expanded newborn screening test, which is not available routinely to all newborns.\nRESULTS: The main classical Galactosemia mutations reported to date were identified in this study, as well as the Duarte variant and seven novel mutations - c.2 T > C (p.M1T), c.97C > A (p.R33S), c.217C > T (p.P73S), c.328 + 1G > A (IVS3 + 1G > A), c.377 + 4A > C (IVS4 + 4A > C), c.287_289delACA (p.N97del) and c.506A > C (p.Q169P). This was expected, given the high miscegenation of the Brazilian population.\nCONCLUSIONS: This study expands the mutation spectrum in GALT gene and reinforces the importance of early diagnosis and introduction of dietary treatment, what is possible with the introduction of Galactosemia in neonatal screening programs.","variants":[{"Name":"NM_000155.4(GALT):c.2T>C (p.Met1Thr)","Chromosome":"9","Start":"34646706","Stop":"34646706","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":790904,"rule_based_match":true,"evidence_text":"c.2 T > C (p.M1T)","llm_judgment":"PRESENT","evidence":"c.2 T > C (p.M1T)","abstract_start":1115,"abstract_end":1132}]}
{"pmid":"28361594","title":"An Unusual Hydrops Fetalis Associated with Compound Heterozygosity for Krüppel-like Factor 1 mutations.","abstract":"Hydrops fetalis is commonly due to Hb Bart's (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Krüppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart's disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks' gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks' gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations.","variants":[{"Name":"NM_006563.5(KLF1):c.1012C>A (p.Pro338Thr)","Chromosome":"19","Start":"12884962","Stop":"12884962","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3518129,"rule_based_match":true,"evidence_text":"c.1012C>A, p.Pro338Thr","llm_judgment":"PRESENT","evidence":"c.1012C>A, p.Pro338Thr","abstract_start":1002,"abstract_end":1024}]}
{"pmid":"17661815","title":"Familial CHARGE syndrome because of CHD7 mutation: clinical intra- and interfamilial variability.","abstract":"CHARGE syndrome (OMIM #214800) is a multiple malformation syndrome with distinctive diagnostic criteria, usually because of CHD7 (chromodomain helicase DNA binding 7) haploinsufficiency. Familial occurrence of CHARGE syndrome is rare. We report six patients from two Caucasian families (both with one parent and two children) affected by mild to severe CHARGE syndrome. Direct sequencing of the CHD7 gene was performed in these two unrelated families. A mutation in exon 8 (c.2501C>T - p.S834F) in first chromodomain was found in family A and a nonsense mutation in exon 2 (c.469C>T - p.R157X) in family B. Both mutations are de novo in the parents. In family A, the elder son had bilateral cleft lip and palate, esophageal atresia with fistula, complex heart defect and vertebral abnormalities, while the younger had a posterior coloboma. Their mother had asymptomatic vestibular dysfunction and retinal coloboma, identified after the molecular diagnosis of her children. In family B, both affected children had severe expression of CHARGE syndrome. The father carrying the mutation only had asymmetric anomaly of the pinnae. These familial reports describe the intrafamilial variability of CHARGE syndrome, and underline the presence of CHD7 mutations in patients who do not fit the 'classical clinical criteria' for CHARGE syndrome.","variants":[{"Name":"NM_017780.4(CHD7):c.2501C>T (p.Ser834Phe)","Chromosome":"8","Start":"60816389","Stop":"60816389","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17072,"rule_based_match":true,"evidence_text":"c.2501C>T - p.S834F","llm_judgment":"PRESENT","evidence":"c.2501C>T - p.S834F","abstract_start":474,"abstract_end":493},{"Name":"NM_017780.4(CHD7):c.469C>T (p.Arg157Ter)","Chromosome":"8","Start":"60741901","Stop":"60741901","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":192482,"rule_based_match":true,"evidence_text":"c.469C>T - p.R157X","llm_judgment":"PRESENT","evidence":"c.469C>T - p.R157X","abstract_start":574,"abstract_end":592}]}
{"pmid":"29556724","title":"De novo apparent loss-of-function mutations in PRR12 in three patients with intellectual disability and iris abnormalities.","abstract":"PRR12 encodes a proline-rich protein nuclear factor suspected to be involved in neural development. Its nuclear expression in fetal brains and in the vision system supports its role in brain and eye development more specifically. However, its function and potential role in human disease has not been determined. Recently, a de novo t(10;19) (q22.3;q13.33) translocation disrupting the PRR12 gene was detected in a girl with intellectual disability and neuropsychiatric alterations. Here we report on three unrelated patients with heterozygous de novo apparent loss-of-function mutations in PRR12 detected by clinical whole exome sequencing: c.1918G>T (p.Glu640*), c.4502_4505delTGCC (p.Leu1501Argfs*146) and c.903_909dup (p.Pro304Thrfs*46). All three patients had global developmental delay, intellectual disability, eye and vision abnormalities, dysmorphic features, and neuropsychiatric problems. Eye abnormalities were consistent among the three patients and consisted of stellate iris pattern and iris coloboma. Additional variable clinical features included hypotonia, skeletal abnormalities, sleeping problems, and behavioral issues such as autism and anxiety. In summary, we propose that haploinsufficiency of PRR12 is associated with this novel multisystem neurodevelopmental disorder.","variants":[{"Name":"NM_020719.3(PRR12):c.1918G>T (p.Glu640Ter)","Chromosome":"19","Start":"49596253","Stop":"49596253","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":439633,"rule_based_match":true,"evidence_text":"c.1918G>T (p.Glu640*)","llm_judgment":"PRESENT","evidence":"c.1918G>T (p.Glu640*)","abstract_start":642,"abstract_end":663},{"Name":"NM_020719.3(PRR12):c.4502_4505del (p.Leu1501fs)","Chromosome":"19","Start":"49601646","Stop":"49601649","ReferenceAlleleVCF":"GCTGC","AlternateAlleleVCF":"G","allel_id":439634,"rule_based_match":true,"evidence_text":"c.4502_4505delTGCC (p.Leu1501Argfs*146)","llm_judgment":"PRESENT","evidence":"c.4502_4505delTGCC (p.Leu1501Argfs*146)","abstract_start":665,"abstract_end":704}]}
{"pmid":"35340792","title":"Difficult Journey to Find the Best Treatment for Homozygous Familial Hypercholesterolemia: Case Report.","abstract":"Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal recessive genetic disorder. It is difficult to diagnose and treat it at early stage. We present a nine-year-old boy with HoFH from China. At the beginning, he was misdiagnosed as xanthomatosis in the dermatology department of the local hospital, but the disease did not alleviate after three laser ablation operations. Later, blood lipid monitoring, ultrasound of heart and carotid artery were further added in our hospital, and finally the boy was diagnosed with HoFH by genetic testing. A biallelic mutations was observed in the fourth exon of low density lipoprotein receptor (LDLR): c.418G>A (p.E140K). Our patient achieved a relatively satisfactory therapeutic results after a series of lipid-lowering therapies including atorvastatin monotherapy, lipoprotein apheresis and double-filtration plasma pheresis. We found that LDL-C levels obtained 57% reduction from baseline after atorvastatin combined with double-filtration plasma pheresis (DFPP). It was observed that regression of carotid intima-media thickness (cIMT), valve regurgitation and xanthoma occurred after a series of Intensive lipid-lowering therapy.","variants":[{"Name":"NM_000527.5(LDLR):c.418G>A (p.Glu140Lys)","Chromosome":"19","Start":"11105324","Stop":"11105324","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":245551,"rule_based_match":true,"evidence_text":"c.418G>A (p.E140K)","llm_judgment":"PRESENT","evidence":"c.418G>A (p.E140K)","abstract_start":655,"abstract_end":673}]}
{"pmid":"28943464","title":"The spectrum of Familial Mediterranean Fever gene (MEFV) mutations and genotypes in Iran, and report of a novel missense variant (R204H).","abstract":"BACKGROUND: Familial Mediterranean Fever (FMF) is an autosomal recessive disorder, characterized by recurrent and self-limited episodes of fever, abdominal pain, synovitis and pleuritis. FMF as the most common inherited monogenic autoinflammatory disease mainly affects ethnic groups of the Mediterranean basin, Arab, Jewish, Turkish, Armenian North Africans and Arabic descent.\nMATERIALS AND METHODS: In the present study, we selected 390 unrelated FMF patients according to the Tel-Hashomer criteria, and analyzed all patients for 12 most common mutations of MEFV gene by reverse hybridization assay (FMF strip assay). We also investigated exon 2 and 10 of MEFV gene in 78 patients by Sanger sequencing.\nRESULTS: According to strip assay results, at least one mutation was found in 234 patients (60%), and no mutation was found in other 156 patients (40%). The five most common mutations and allelic frequencies were M694V (13.6%), E148Q (10.4%), M694I (6.5%), V726A (4.1%), and M680I (3.8%). Moreover, we detected a novel missense variant (R204H, c.611 G > A) (SCV000297822) and following rare mutations among sequenced samples; R202Q, P115T, G304R, and E230K.\nCONCLUSION: This study describes the MEFV mutations spectrum and distribution in Iranian population, and shows different mutation patterns among Iranian ethnicities. Moreover, M694V is the most common MEFV mutation in Iran.","variants":[{"Name":"NM_000243.3(MEFV):c.611G>A (p.Arg204His)","Chromosome":"16","Start":"3254457","Stop":"3254457","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":247431,"rule_based_match":true,"evidence_text":"c.611 G > A","llm_judgment":"PRESENT","evidence":"c.611 G > A","abstract_start":1050,"abstract_end":1061}]}
{"pmid":"35600075","title":"","abstract":"Purpose: To identify novel genetic causes of febrile seizures (FS) and epilepsy with febrile seizures plus (EFS+).\nMethods: We performed whole-exome sequencing in a cohort of 32 families, in which at least two individuals were affected by FS or EFS+. The probands, their parents, and available family members were recruited to ascertain whether the genetic variants were co-segregation. Genes with repetitively identified variants with segregations were selected for further studies to define the gene-disease association.\nResults: We identified two heterozygous <i>ATP6V0C</i> mutations (c.64G > A/p.Ala22Thr and c.361_373del/p.Thr121Profs*7) in two unrelated families with six individuals affected by FS or EFS+. The missense mutation was located in the proteolipid c-ring that cooperated with a-subunit forming the hemichannel for proton transferring. It also affected the hydrogen bonds with surround residues and the protein stability, implying a damaging effect. The frameshift mutation resulted in a loss of function by yielding a premature termination of 28 residues at the C-terminus of the protein. The frequencies of <i>ATP6V0C</i> mutations identified in this cohort were significantly higher than that in the control populations. All the six affected individuals suffered from their first FS at the age of 7-8 months. The two probands later manifested afebrile seizures including myoclonic seizures that responded well to lamotrigine. They all displayed favorable outcomes without intellectual or developmental abnormalities, although afebrile seizures or frequent seizures occurred.\nConclusion: This study suggests that <i>ATP6V0C</i> is potentially a candidate pathogenic gene of FS and EFS+. Screening for <i>ATP6V0C</i> mutations would help differentiating patients with Dravet syndrome caused by <i>SCN1A</i> mutations, which presented similar clinical manifestation but different responses to antiepileptic treatment.","variants":[{"Name":"NM_001694.4(ATP6V0C):c.64G>A (p.Ala22Thr)","Chromosome":"16","Start":"2514167","Stop":"2514167","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2740204,"rule_based_match":true,"evidence_text":"c.64G > A/p.Ala22Thr","llm_judgment":"PRESENT","evidence":"c.64G > A/p.Ala22Thr","abstract_start":589,"abstract_end":609},{"Name":"NM_001694.4(ATP6V0C):c.361_373del (p.Thr121fs)","Chromosome":"16","Start":"2519636","Stop":"2519648","ReferenceAlleleVCF":"GGCACCGCCCAGCA","AlternateAlleleVCF":"G","allel_id":2740205,"rule_based_match":true,"evidence_text":"c.361_373del/p.Thr121Profs*7","llm_judgment":"PRESENT","evidence":"c.361_373del/p.Thr121Profs*7","abstract_start":614,"abstract_end":642}]}
{"pmid":"16958054","title":"Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.","abstract":"The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.","variants":[{"Name":"NM_000051.4(ATM):c.1066-6T>G","Chromosome":"11","Start":"108248927","Stop":"108248927","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18077,"rule_based_match":true,"evidence_text":"c.1066-6T>G (IVS10-6T>G)","llm_judgment":"PRESENT","evidence":"c.1066-6T>G (IVS10-6T>G)","abstract_start":264,"abstract_end":288},{"Name":"NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)","Chromosome":"11","Start":"108329202","Stop":"108329202","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18062,"rule_based_match":true,"evidence_text":"c.7271T>G","llm_judgment":"PRESENT","evidence":"c.7271T>G","abstract_start":250,"abstract_end":259}]}
{"pmid":"29037160","title":"\"Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports\".","abstract":"BACKGROUND: Jervell and Lange-Nielsen syndrome (JLNS) isa recessive model of long QT syndrome which might also be related to possible hearing loss. Although the syndrome has been demonstrated to be originated from homozygous or compound heterozygous mutations in either the KCNQ1 or KCNE1 genes, additional mutations in other genetic loci should be considered, particularly in malignant course patients.\nCASE PRESENTATIONS: Three patients were admitted into hospital due to recurrent seizures/syncope, intrauterine and postnatal bradycardia respectively; moreover all three patients had congenital sensorineural hearing-loss. Their electrocardiograms showed markedly prolonged QT interval. Implantable defibrillator was implanted and left cardiac sympathetic denervation was performed due to the progressive disease in case 1. She had countless ventricular fibrillation and appropriate shock while using an implantable defibrillator. The DNA sequencing analysis of the KCNQ1 gene disclosed a homozygous c.728G > A (p.Arg243His) missense mutation in case1. Further targeted next generation sequencing of cardiac panel comprising 68 gene revealed a heterozygous c.1346 T > G (p.Ile449Arg) variant in RYR2 gene and a heterozygous c.809G > A (p.Cys270Tyr) variant in NKX2-5 gene in the same patient. Additional gene alterations in RYR2 and NKX2-5 genes were thought to be responsible for progressive and malignant course of the disease. As a result of DNA sequencing analysis of KCNQ1 and KCNE1 genes, a compound heterozygosity for two mutations had been detected in KCNQ1 gene in case 2: a maternally derived c.477 + 1G > A splice site mutation and a paternally derived c.520C > T (p.Arg174Cys) missense mutation. Sanger sequencing of KCNQ1 and KCNE1 genes displayed a homozygous c.1097G > A (p.Arg366Gln) mutation in KCNQ1 gene in case 3. β-blocker therapy was initiated to all the index subjects.\nCONCLUSIONS: Three families of JLNS who presented with long QT and deafness and who carry homozygous, or compound heterozygous mutation in KCNQ1 gene were presented in this report. It was emphasized that broad targeted cardiac panels may be useful to predict the outcome especially in patients with unexplained phenotype-genotype correlation. Clinical presentations and molecular findings will be discussed further to clarify the phenotype genotype associations.","variants":[{"Name":"NM_000218.3(KCNQ1):c.1097G>A (p.Arg366Gln)","Chromosome":"11","Start":"2585276","Stop":"2585276","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67624,"rule_based_match":true,"evidence_text":"c.1097G > A (p.Arg366Gln)","llm_judgment":"PRESENT","evidence":"c.1097G > A (p.Arg366Gln)","abstract_start":1777,"abstract_end":1802},{"Name":"NM_004387.4(NKX2-5):c.809G>A (p.Cys270Tyr)","Chromosome":"5","Start":"173232735","Stop":"173232735","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":165960,"rule_based_match":true,"evidence_text":"c.809G > A (p.Cys270Tyr)","llm_judgment":"PRESENT","evidence":"c.809G > A (p.Cys270Tyr)","abstract_start":1227,"abstract_end":1251},{"Name":"NM_001035.3(RYR2):c.1346T>G (p.Ile449Arg)","Chromosome":"1","Start":"237454444","Stop":"237454444","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1002632,"rule_based_match":true,"evidence_text":"c.1346 T > G (p.Ile449Arg)","llm_judgment":"PRESENT","evidence":"c.1346 T > G (p.Ile449Arg)","abstract_start":1160,"abstract_end":1186},{"Name":"NM_000218.3(KCNQ1):c.520C>T (p.Arg174Cys)","Chromosome":"11","Start":"2570670","Stop":"2570670","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67726,"rule_based_match":true,"evidence_text":"c.520C > T (p.Arg174Cys)","llm_judgment":"PRESENT","evidence":"c.520C > T (p.Arg174Cys)","abstract_start":1667,"abstract_end":1691},{"Name":"NM_000218.3(KCNQ1):c.728G>A (p.Arg243His)","Chromosome":"11","Start":"2572057","Stop":"2572057","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67760,"rule_based_match":true,"evidence_text":"c.728G > A (p.Arg243His)","llm_judgment":"PRESENT","evidence":"c.728G > A (p.Arg243His)","abstract_start":1003,"abstract_end":1027},{"Name":"NM_000218.3(KCNQ1):c.477+1G>A","Chromosome":"11","Start":"2528019","Stop":"2528019","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":197427,"rule_based_match":true,"evidence_text":"c.477 + 1G > A","llm_judgment":"PRESENT","evidence":"c.477 + 1G > A","abstract_start":1606,"abstract_end":1620}]}
{"pmid":"25585530","title":"Genetic analysis of amyotrophic lateral sclerosis in the Slovenian population.","abstract":"Amyotrophic lateral sclerosis (ALS) is a complex fatal neurodegenerative disease characterized by progressive degeneration and loss of upper motor neurons in the cerebral cortex and lower motor neurons in brainstem and spinal cord. We established the frequencies of mutations in 4 major ALS-associated genes, SOD1, TARDBP, FUS, and C9ORF72 in a representative cohort of 85 Slovenian patients with sporadic form of ALS. Pathogenic massive hexanucleotide repeat expansion mutation in C9ORF72 was detected in 5.9% of patients and was the most common cause of the disease. In the remaining 3 genes, we identified 4 changes in 3 patients, p.Val14Met in SOD1, silent mutation p.Arg522Arg in FUS, and p.Gly93Cys in SOD1 together with a novel synonymous variant c.990A>G (p.Leu330Leu) in TARDBP gene, respectively. This study represents the first genetic screening of major causative genes for ALS in a cohort of sporadic ALS patients from Slovenia and is according to our knowledge the first such study in Slavic population. Overall, we genetically characterized 8.2% sporadic ALS patients.","variants":[{"Name":"NM_004960.4(FUS):c.1566G>A (p.Arg522=)","Chromosome":"16","Start":"31191423","Stop":"31191423","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":529932,"rule_based_match":false,"evidence_text":"silent mutation p.Arg522Arg in FUS","llm_judgment":"PRESENT","evidence":"silent mutation p.Arg522Arg in FUS","abstract_start":654,"abstract_end":688}]}
{"pmid":"30943998","title":"Characteristics of Pompe disease in China: a report from the Pompe registry.","abstract":"BACKGROUND: Pompe disease is a rare, progressive, autosomal recessive lysosomal storage disorder caused by mutations in the acid α-glucosidase gene. This is the first report of Chinese patients from the global Pompe Registry. Chinese patients enrolled in the Registry ( ClinicalTrials.gov , NCT00231400) between Jan 2013 and 2 Sep 2016 with late onset Pompe disease (LOPD; presentation after 12 months of age or presentation at ≤12 months without cardiomyopathy) were included. Data analyses were descriptive.\nRESULTS: Of the 59 Chinese patients included, 86.4% had never received enzyme replacement therapy (ERT). The age at symptom onset and diagnosis was 14.9 (12.35) and 22.1 (10.08) years, which is younger than previous reports of LOPD patients from the rest of the world (28.4 [18.86] and 34.9 [20.03], respectively). The most common diagnosis methods were enzyme assay (79.7%) and/or DNA analysis (61.0%). Of the 36 patients diagnosed using DNA analysis, 31 had standardized variant data and among these patients the most common mutations were c.2238G > C (n = 18, 58.1%) and c.2662G > T (n = 5, 16.1%). Chinese LOPD patients appeared to have worse lung function versus patients from the rest of the world, indicated by lower forced vital capacity (37.2 [14.00]% vs. 63.5 [26.71]%) and maximal expiratory and inspiratory pressure (27.9 [13.54] vs. 51.0 [38.66] cm H<sub>2</sub>O, and 29.4 [12.04] vs. 70.5 [52.78] cm H<sub>2</sub>O).\nCONCLUSIONS: Compared with patients from the rest of the world, Chinese patients with LOPD appeared to have younger age at symptom onset and diagnosis, lower lung function, and the majority had not received ERT. The most common mutations were c.2238G > C and c.2662G > T.","variants":[{"Name":"NM_000152.5(GAA):c.2238G>C (p.Trp746Cys)","Chromosome":"17","Start":"80117016","Stop":"80117016","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":260196,"rule_based_match":true,"evidence_text":"c.2238G > C","llm_judgment":"PRESENT","evidence":"c.2238G > C","abstract_start":1052,"abstract_end":1063}]}
{"pmid":"19359498","title":"Development of genomic reference materials for cystic fibrosis genetic testing.","abstract":"The number of different laboratories that perform genetic testing for cystic fibrosis is increasing. However, there are a limited number of quality control and other reference materials available, none of which cover all of the alleles included in commercially available reagents or platforms. The alleles in many publicly available cell lines that could serve as reference materials have neither been confirmed nor characterized. The Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community as well as Coriell Cell Repositories, have characterized an extended panel of publicly available genomic DNA samples that could serve as reference materials for cystic fibrosis testing. Six cell lines [containing the following mutations: E60X (c.178G>T), 444delA (c.312delA), G178R (c.532G>C), 1812-1G>A (c.1680-1G>A), P574H (c.1721C>A), Y1092X (c.3277C>A), and M1101K (c.3302T>A)] were selected from those existing at Coriell, and seven [containing the following mutations: R75X (c.223C>T), R347H (c.1040G>A), 3876delA (c.3744delA), S549R (c.1646A>C), S549N (c.1647G>A), 3905insT (c.3773_3774insT), and I507V (c.1519A>G)] were created. The alleles in these materials were confirmed by testing in six different volunteer laboratories. These genomic DNA reference materials will be useful for quality assurance, proficiency testing, test development, and research and should help to assure the accuracy of cystic fibrosis genetic testing in the future. The reference materials described in this study are all currently available from Coriell Cell Repositories.","variants":[{"Name":"NM_000492.4(CFTR):c.178G>T (p.Glu60Ter)","Chromosome":"7","Start":"117509047","Stop":"117509047","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":47335,"rule_based_match":true,"evidence_text":"c.178G>T","llm_judgment":"PRESENT","evidence":"c.178G>T","abstract_start":848,"abstract_end":856}]}
{"pmid":"16791849","title":"Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders.","abstract":"Very recently, heterozygous mutations in the genes encoding transforming growth factor beta receptors I (TGFBR1) and II (TGFBR2) have been reported in Loeys-Dietz aortic aneurysm syndrome (LDS). In addition, dominant TGFBR2 mutations have been identified in Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). In the past, mutations of these genes were associated with atherosclerosis and several human cancers. Here, we report a total of nine novel and one known heterozygous sequence variants in the TGFBR1 and TGFBR2 genes in nine of 70 unrelated individuals with MFS-like phenotypes who previously tested negative for mutations in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1). To assess the pathogenic impact of these sequence variants, in silico analyses were performed by the PolyPhen, SIFT, and Fold-X algorithms and by means of a 3D homology model of the TGFBR2 kinase domain. Our results showed that in all but one of the patients the pathogenic effect of at least one sequence variant is highly probable (c.722C > T, c.799A > C, and c.1460G > A in TGFBR1 and c.773T > G, c.1106G > T, c.1159G > A, c.1181G > A, and c.1561T > C in TGFBR2). These deleterious alleles occurred de novo or segregated with the disease in the families, indicating a causative association between the sequence variants and clinical phenotypes. Since TGFBR2 mutations found in patients with MFS-related disorders cannot be distinguished from heterozygous TGFBR2 mutations reported in tumor samples, we emphasize the importance of segregation analysis in affected families. In order to be able to find the mutation that is indeed responsible for a MFS-related phenotype, we also propose that genetic testing for sequence alterations in TGFBR1 and TGFBR2 should be complemented by mutation screening of the FBN1 gene.","variants":[{"Name":"NM_003242.6(TGFBR2):c.1181G>A (p.Cys394Tyr)","Chromosome":"3","Start":"30672364","Stop":"30672364","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":452518,"rule_based_match":true,"evidence_text":"c.1181G > A","llm_judgment":"PRESENT","evidence":"c.1181G > A","abstract_start":1173,"abstract_end":1184},{"Name":"NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)","Chromosome":"9","Start":"99138006","Stop":"99138006","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27563,"rule_based_match":true,"evidence_text":"c.722C > T","llm_judgment":"PRESENT","evidence":"c.722C > T","abstract_start":1081,"abstract_end":1091},{"Name":"NM_004612.4(TGFBR1):c.1460G>A (p.Arg487Gln)","Chromosome":"9","Start":"99149253","Stop":"99149253","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27564,"rule_based_match":true,"evidence_text":"c.1460G > A","llm_judgment":"PRESENT","evidence":"c.1460G > A","abstract_start":1109,"abstract_end":1120},{"Name":"NM_003242.6(TGFBR2):c.1561T>C (p.Trp521Arg)","Chromosome":"3","Start":"30691456","Stop":"30691456","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":799321,"rule_based_match":true,"evidence_text":"c.1561T > C","llm_judgment":"PRESENT","evidence":"c.1561T > C","abstract_start":1190,"abstract_end":1201},{"Name":"NM_003242.6(TGFBR2):c.1159G>A (p.Val387Met)","Chromosome":"3","Start":"30672342","Stop":"30672342","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":53818,"rule_based_match":true,"evidence_text":"c.1159G > A","llm_judgment":"PRESENT","evidence":"c.1159G > A","abstract_start":1160,"abstract_end":1171}]}
{"pmid":"24976573","title":"A newly identified c.1824_1828dupATACG mutation in exon 13 of the GAA gene in infantile-onset glycogen storage disease type II (Pompe disease).","abstract":"Pompe disease or glycogen storage disease type II is a glycogen storage disorder associated with malfunction of the acid α-glucosidase enzyme (GAA; EC.3.2.1.3) leading to intracellular aggregations of glycogenin muscles. The infantile-onset type is the most life-threatening form of this disease, in which most of patients suffer from cardiomyopathy and hypotonia in early infancy. In this study, a typical case of Pompe disease was reported in an Iranian patient using molecular analysis of the GAA gene. Our results revealed a new c.1824_1828dupATACG mutation in exon 13 of the GAA gene. In conclusion, with the finding of this novel mutation, the genotypic spectrum of Iranian patients with Pompe disease has been extended, facilitating the definition of disease-related mutations.","variants":[{"Name":"NM_000152.5(GAA):c.1824_1828dup (p.Ala610fs)","Chromosome":"17","Start":"80112644","Stop":"80112645","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CCGATA","allel_id":358506,"rule_based_match":true,"evidence_text":"c.1824_1828dupATACG","llm_judgment":"PRESENT","evidence":"c.1824_1828dupATACG","abstract_start":533,"abstract_end":552}]}
{"pmid":"30614851","title":"A novel phenotype with splicing mutation identified in a Chinese family with desminopathy.","abstract":"BACKGROUND: Desminopathy, a hereditary myofibrillar myopathy, mainly results from the desmin gene (DES) mutations. Desminopathy involves various phenotypes, mainly including different cardiomyopathies, skeletal myopathy, and arrhythmia. Combined with genotype, it helps us precisely diagnose and treat for desminopathy.\nMETHODS: Sanger sequencing was used to characterize DES variation, and then a minigene assay was used to verify the effect of splice-site mutation on pre-mRNA splicing. Phenotypes were analyzed based on clinical characteristics associated with desminopathy.\nRESULTS: A splicing mutation (c.735+1G>T) in DES was detected in the proband. A minigene assay revealed skipping of the whole exon 3 and transcription of abnormal pre-mRNA lacking 32 codons. Another affected family member who carried the identical mutation, was identified with a novel phenotype of desminopathy, non-compaction of ventricular myocardium. There were 2 different phenotypes varied in cardiomyopathy and skeletal myopathy among the 2 patients, but no significant correlation between genotype and phenotype was identified.\nCONCLUSIONS: We reported a novel phenotype with a splicing mutation in DES, enlarging the spectrum of phenotype in desminopathy. Molecular studies of desminopathy should promote our understanding of its pathogenesis and provide a precise molecular diagnosis of this disorder, facilitating clinical prevention and treatment at an early stage.","variants":[{"Name":"NM_001927.4(DES):c.735+1G>T","Chromosome":"2","Start":"219420347","Stop":"219420347","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":557888,"rule_based_match":true,"evidence_text":"c.735+1G>T","llm_judgment":"PRESENT","evidence":"c.735+1G>T","abstract_start":608,"abstract_end":618}]}
{"pmid":"15940693","title":"PTPN11 mutations play a minor role in isolated congenital heart disease.","abstract":"PTPN11 missense mutations cause approximately 50% of Noonan syndrome, an autosomal dominant disorder presenting with various congenital heart defects, most commonly valvar pulmonary stenosis, and hypertrophic cardiomyopathy. Atrioventricular septal defects and coarctation of the aorta occur in 15% and 9%, respectively. The aim of this study was to determine if PTPN11 mutations exist in non-syndromic patients with these two relevant forms of congenital heart disease. The 15 coding PTPN11 exons and their intron boundaries from subjects with atrioventricular septal defects (n = 24) and coarctation of the aorta (n = 157) were analyzed using denaturing high performance liquid chromatography and sequenced if abnormal. One subject with an atrioventricular septal defect but no other known medical problems had a c.127C > T transition in exon 2, predicting a p.L43F substitution. This mutation affected the phosphotyrosine-binding region in the N-terminal src homology 2 domain and was close to a Noonan syndrome mutation (p.T42A). An otherwise healthy patient with aortic coarctation had a silent c.540C > T change in exon 5 corresponding to p.D180D. Our study showed that PTPN11 mutations are rarely found in two isolated forms of congenital heart disease that commonly occur in Noonan syndrome. The p.L43F mutation belongs to a rare class of PTPN11 mutations altering the phosphotyrosine-binding region. These mutations are not predicted to alter the autoinhibition of the PTPN11 protein product, SHP-2, which is the mechanism for the vast majority of mutations causing Noonan syndrome. Future studies will be directed towards understanding these rare phosphotyrosine binding region mutants.","variants":[{"Name":"NM_002834.5(PTPN11):c.127C>T (p.Leu43Phe)","Chromosome":"12","Start":"112446388","Stop":"112446388","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":552668,"rule_based_match":true,"evidence_text":"c.127C > T","llm_judgment":"PRESENT","evidence":"c.127C > T","abstract_start":815,"abstract_end":825}]}
{"pmid":"24886349","title":"Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome.","abstract":"BACKGROUND: SHORT syndrome is a rare autosomal dominant condition whose name is the acronym of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay (MIM 269880). Additionally, the patients usually present a low birth weight and height, lipodystrophy, delayed bone age, hernias, low body mass index and a progeroid appearance.\nCASE PRESENTATION: In this study, we used whole-exome sequencing approaches in two patients with clinical features of SHORT syndrome. We report the finding of a novel mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8), as well as a recurrent mutation c.1945C > T (p.Arg649Trp) in this gene.\nCONCLUSIONS: We found a novel frameshift mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8) which consists of a deletion right before the site of substrate recognition. As a consequence, the protein lacks the position that interacts with the phosphotyrosine residue of the substrate, resulting in the development of SHORT syndrome.","variants":[{"Name":"NM_181523.3(PIK3R1):c.1945C>T (p.Arg649Trp)","Chromosome":"5","Start":"68296301","Stop":"68296301","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75301,"rule_based_match":true,"evidence_text":"c.1945C > T (p.Arg649Trp)","llm_judgment":"PRESENT","evidence":"c.1945C > T (p.Arg649Trp)","abstract_start":629,"abstract_end":654}]}
{"pmid":"30996034","title":"Brody disease: when myotonia is not myotonia.","abstract":"A 56-year-old man presented with painless impairment of muscle relaxation on vigorous contraction (eg, eyelid closure, hand grip, running). There were no episodes of paralysis, symptom progression, weakness or extramuscular symptoms. Five of his fifteen siblings had similar complaints. His serum creatine kinase was normal. Electromyography showed electrical silence on muscle relaxation, without myotonic discharges. <i>DMPK</i>, <i>ClCN1</i> and <i>SCN4A</i> genetic testing was normal, but he had a homozygous pathogenic variant of <i>ATP2A1</i> (c.1315G>A; pGlu439Lys). Brody disease is a rare autosomal recessive myopathy due to <i>ATP2A1</i> mutations that reduce sarcoplasmic reticulum calcium-ATPase1 activity, hence delaying muscle relaxation.","variants":[{"Name":"NM_004320.6(ATP2A1):c.1315G>A (p.Glu439Lys)","Chromosome":"16","Start":"28894849","Stop":"28894849","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1963750,"rule_based_match":true,"evidence_text":"c.1315G>A; pGlu439Lys","llm_judgment":"PRESENT","evidence":"c.1315G>A; pGlu439Lys","abstract_start":551,"abstract_end":572}]}
{"pmid":"19851887","title":"An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.","abstract":"Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome.","variants":[{"Name":"NM_000179.3(MSH6):c.3984_3987dup (p.Leu1330fs)","Chromosome":"2","Start":"47806630","Stop":"47806631","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"ATCAG","allel_id":94970,"rule_based_match":true,"evidence_text":"c.3984_3987dup","llm_judgment":"PRESENT","evidence":"c.3984_3987dup","abstract_start":493,"abstract_end":507}]}
{"pmid":"22197487","title":"Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy.","abstract":"By using whole-exome sequencing, we identified a homozygous guanine-to-adenine transition at the invariant -1 position of the acceptor site of intron 1 (c.97-1G>A) in solute carrier organic anion transporter family member 2A1 (SLCO2A1), which encodes a prostaglandin transporter protein, as the causative mutation in a single individual with primary hypertrophic osteoarthropathy (PHO) from a consanguineous family. In two other affected individuals with PHO from two unrelated nonconsanguineous families, we identified two different compound heterozygous mutations by using Sanger sequencing. These findings confirm that SLCO2A1 mutations inactivate prostaglandin E(2) (PGE(2)) transport, and they indicate that mutations in SLCO2A1 are the pathogenic cause of PHO. Moreover, this study might also help to explain the cause of secondary hypertrophic osteoarthropathy.","variants":[{"Name":"NM_005630.3(SLCO2A1):c.97-1G>A","Chromosome":"3","Start":"133979619","Stop":"133979619","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39142,"rule_based_match":true,"evidence_text":"c.97-1G>A","llm_judgment":"PRESENT","evidence":"c.97-1G>A","abstract_start":153,"abstract_end":162}]}
{"pmid":"19878916","title":"Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs.","abstract":"Mutations in genes associated with the U4/U6-U5 small nuclear ribonucleoprotein (snRNP) complex of the spliceosome are implicated in autosomal-dominant retinitis pigmentosa (adRP), a group of progressive retinal degenerative disorders leading to visual impairment, loss of visual field, and even blindness. We recently assigned a locus (RP33) for adRP to 2cen-q12.1, a region that harbors the SNRNP200 gene encoding hBrr2, another U4/U6-U5 snRNP component that is required for unwinding of U4/U6 snRNAs during spliceosome activation and for disassembly of the spliceosome. Here, we report the identification of a missense mutation, c.3260C>T (p.S1087L), in exon 25 of the SNRNP200 gene in an RP33-linked family. The c.3260C>T substitution showed complete cosegregation with the retinitis pigmentosa (RP) phenotype over four generations, but was absent in a panel of 400 controls. The p.S1087L mutation and p.R1090L, another adRP-associated allele, reside in the \"ratchet\" helix of the first of two Sec63 domains implicated in the directionality and processivity of nucleic acid unwinding. Indeed, marked defects in U4/U6 unwinding, but not U4/U6-U5 snRNP assembly, were observed in budding yeast for the analogous mutations (N1104L and R1107L) of the corresponding Brr2p residues. The linkage of hBrr2 to adRP suggests that the mechanism of pathogenesis for splicing-factor-related RP may fundamentally derive from a defect in hBrr2-dependent RNA unwinding and a consequent defect in spliceosome activation.","variants":[{"Name":"NM_014014.5(SNRNP200):c.3260C>T (p.Ser1087Leu)","Chromosome":"2","Start":"96287968","Stop":"96287968","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22967,"rule_based_match":true,"evidence_text":"c.3260C>T (p.S1087L)","llm_judgment":"PRESENT","evidence":"c.3260C>T (p.S1087L)","abstract_start":632,"abstract_end":652}]}
{"pmid":"25117416","title":"Sturge Weber-Like Gyral Calcification Seen in Tuberous Sclerosis Complex 1.","abstract":"A 10-year-old girl presented with poorly controlled epilepsy. On evaluation, she had microcephaly, neuro-cutaneous stigmata of tuberous sclerosis complex, profound mental retardation, and spastic hemiparesis. Computed tomography (CT) revealed a calcified subependymal nodule and extensive left gyral calcification of the temporal, parietal, and occipital regions with unilateral cerebral atrophy, radiologic features usually seen in Sturge Weber syndrome. Magnetic resonance imaging (MRI) revealed absence of tubers, enlarged choroid plexus, or leptomeningeal angiomas, thus excluding type 3 Sturge Weber syndrome. The genotype was a heterozygous mutation in exon 18 of the tuberous sclerosis type 1 gene (c.2293C>T p.Q765X). A comparison of previously reported 7 cases of Sturge Weber syndrome and tuberous sclerosis complex was made. This revealed 4 actual double phakomatoses (clinical, radiologic, or genetic phenotypes) and 3 cases with clinical phenotype of tuberous sclerosis and gyral calcifications within tubers simulating the radiologic picture of Sturge Weber syndrome.","variants":[{"Name":"NM_000368.5(TSC1):c.2293C>T (p.Gln765Ter)","Chromosome":"9","Start":"132902703","Stop":"132902703","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":58096,"rule_based_match":true,"evidence_text":"c.2293C>T p.Q765X","llm_judgment":"PRESENT","evidence":"c.2293C>T p.Q765X","abstract_start":706,"abstract_end":723}]}
{"pmid":"38617198","title":"Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic","abstract":"Background and Objectives: Hexokinase 1 (encoded by <i>HK1</i>) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic <i>HK1</i> variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals.\nMethods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic <i>HK1</i> variants and an NDD phenotype.\nResults: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile.\nDiscussion: Genotype-phenotype correlations appear to exist for <i>HK1</i> variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic <i>HK1</i> variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.","variants":[{"Name":"NM_000188.3(HK1):c.1370C>T (p.Thr457Met)","Chromosome":"10","Start":"69382591","Stop":"69382591","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359832,"rule_based_match":true,"evidence_text":"c.1370C>T","llm_judgment":"PRESENT","evidence":"c.1370C>T","abstract_start":611,"abstract_end":620}]}
{"pmid":"25317404","title":"The Study of SLC26A4 Gene Causing Autosomal Recessive Hearing Loss by Linkage Analysis in a Cohort of Iranian Populations.","abstract":"Sensorineural non-syndromic hearing loss is the most common disorder which affects 1 in 500 newborns. Hearing loss is an extremely heterogeneous defect with more than 100 loci identified to date. According to the studies, mutations in GJB2 are estimated to be involved in 50- 80% of autosomal recessive non-syndromic hearing loss cases, but contribution of other loci in this disorder is yet ambiguous. With regard to studies, DFNB4 locus (SLC26A4) can be classified as the second cause of hearing loss. So, this study aimed to determine the contribution of this locus in hearing loss as well as the frequency of SLC26A4 gene mutations in a population in the west of Iran. In this descriptive laboratory study, we included 30 families from the west of Iran with no mutation in GJB2 gene. Linkage analysis was performed by DFNB4 (SLC26A4) molecular markers (STR). The families with hearing loss linked to this locus were further analyzed for mutation detection. SLC26A4 gene exons were amplified and analyzed using direct DNA sequencing. In studied families, 2 families displayed linkage to DFNB4 locus. Identified mutations include mutation in exon 5 (c.416 G>T) and in splicing site of exon 7 (IVS-2 A>G or c.919-2 A>G).","variants":[{"Name":"NM_000441.2(SLC26A4):c.416G>T (p.Gly139Val)","Chromosome":"7","Start":"107674164","Stop":"107674164","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":984330,"rule_based_match":true,"evidence_text":"c.416 G>T","llm_judgment":"PRESENT","evidence":"c.416 G>T","abstract_start":1152,"abstract_end":1161}]}
{"pmid":"21044902","title":"A novel ACVR1 mutation in the glycine/serine-rich domain found in the most benign case of a fibrodysplasia ossificans progressiva variant reported to date.","abstract":"Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant condition, classically characterised by heterotopic ossification beginning in childhood and congenital great toe malformations; occurring in response to a c.617 G > A ACVR1 mutation in the functionally important glycine/serine-rich domain of exon 6. Here we describe a novel c.587 T > C mutation in the glycine/serine-rich domain of ACVR1, associated with delayed onset of heterotopic ossification and an exceptionally mild clinical course. Absence of great toe malformations, the presence of early ossification of the cervical spine facets joints, plus mild bilateral camptodactyly of the 5th fingers, together with a novel ACVR1 mutation, are consistent with the 'FOP-variant' syndrome. The c.587 T > C mutation replaces a conserved leucine with proline at residue 196. Modelling of the mutant protein reveals a steric clash with the kinase domain that will weaken interactions with FKBP12 and induce exposure of the glycine/serine-rich repeat. The mutant receptor is predicted to be hypersensitive to ligand stimulation rather than being constitutively active, consistent with the mild clinical phenotype. This case extends our understanding of the 'FOP-variant' syndrome.","variants":[{"Name":"NM_001111067.4(ACVR1):c.587T>C (p.Leu196Pro)","Chromosome":"2","Start":"157774144","Stop":"157774144","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":205405,"rule_based_match":true,"evidence_text":"c.587 T > C","llm_judgment":"PRESENT","evidence":"c.587 T > C","abstract_start":349,"abstract_end":360}]}
{"pmid":"29464999","title":"Molecular Characteristics of Hb New York [β113(G15)Val→Glu, HBB: c.341T>A] in Thailand.","abstract":"Hb New York or Hb Kaohsiung [β113(G15)Val→Glu (GTG>GAG), HBB: c.341T>A] has been considered a rare β hemoglobin (Hb) variant found originally in an Iranian woman and later in diverse populations but its genetic origin has not been elucidated. Here we report molecular and hematological descriptions of this variant found in the Thai population. Among 5643 subjects referred for hemoglobinopathy investigation during January 2015 to September 2017, 183 (3.2%) were found to carry several Hb variants, including β chain variants (n = 135, 2.4%), α chain variants (n = 33, 0.6%), Hb Lepore-Hollandia (NG_000007.3: g.63290_70702del) and Hb Lepore-Boston-Washington (NG_000007.3: g.63632_71046del) (δβ hybrid Hb) (n = 12, 0.2%) and δ chain variants (n = 3, 0.05%). Of patients with β chain variants, six with normal high performance liquid chromatography (HPLC) patterns, had an abnormal Hb in zone 11 of capillary electrophoresis (CE), the amounts of which ranged from 29.6-45.4% with normal levels of Hb A<sub>2</sub> and Hb F. DNA analysis identified a heterozygous Hb New York mutation in all cases. Further screening of α-thalassemia (α-thal) identified coinheritance of α<sup>+</sup>- and α<sup>0</sup>-thal in two of them who had reduced levels of Hb New York. Haplotype analysis suggested that the Thai Hb New York was likely associated with a single β-globin haplotype [+ - - - - + +], indicating that it was of the same origin. Hematological findings and simple DNA assay based on allele-specific polymerase chain reaction (PCR) for rapid detection of Hb New York are presented.","variants":[{"Name":"NM_000518.5(HBB):c.341T>A (p.Val114Glu)","Chromosome":"11","Start":"5225701","Stop":"5225701","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":30325,"rule_based_match":true,"evidence_text":"HBB: c.341T>A","llm_judgment":"PRESENT","evidence":"HBB: c.341T>A","abstract_start":57,"abstract_end":70}]}
{"pmid":"19165618","title":"Congenital disorder of glycosylation type Ia in a Malaysian family: clinical outcome and description of a novel PMM2 mutation.","abstract":"There are few reports of congenital disorders of glycosylation (CDGs) in the Asian population, although they have been reported worldwide. We identified a Malaysian infant female at 2 days of life with CDG type Ia. The diagnosis was suspected on the basis of inverted nipples and abnormal fat distribution. She had cerebellar hypoplasia and developed coagulopathy, hypothyroidism and severe pericardial effusion and died at 7 months of life. The diagnosis was supported by abnormal serum transferrin isoform pattern that showed elevated levels of the disialotransferrin isoform and trace levels of the asialotransferrin isoform. Enzyme testing of peripheral leukocytes showed decreased level of phosphomannomutase (PMM) activity (0.6 nmol/min per mg protein, normal range 1.6-6.2) and a normal level of phosphomannose isomerase activity (19 nmol/min per mg protein, normal range 12-25), indicating a diagnosis of CDG type Ia. Mutation study of the PMM2 gene showed the patient was heterozygous for both the common p.R141H (c.422T>A) mutation and a novel sequence change in exon 7, c.618C>A. The latter change is predicted to result in the replacement of the highly conserved phenylalanine residue at position 206 with a leucine residue (p.F206L) and occurs in the same codon as the previously reported p.F206S mutation. Analysis of 100 control chromosomes has shown that the p.F206L sequence change is not present, making it highly likely that this change is functionally important. To the best of our knowledge, this is the first report of CDG in the Malay population. Prenatal diagnosis was successfully performed in a subsequent pregnancy for this family.","variants":[{"Name":"NM_000303.3(PMM2):c.618C>A (p.Phe206Leu)","Chromosome":"16","Start":"8813085","Stop":"8813085","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":548120,"rule_based_match":true,"evidence_text":"c.618C>A","llm_judgment":"PRESENT","evidence":"c.618C>A","abstract_start":1081,"abstract_end":1089}]}
{"pmid":"30638982","title":"A PLN nonsense variant causes severe dilated cardiomyopathy in a novel autosomal recessive inheritance mode.","abstract":"BACKGROUND: Pathogenic variants in human phospholamban coding gene (PLN) are known to cause hereditary dilated cardiomyopathy with heart failure in an autosomal dominant mode.\nMETHODS: We performed high-depth targeted next-generation sequencing using a cardiomyopathy-panel containing 80 disease-related genes in 650 unrelated patients with non-ischemic cardiomyopathy to identify potential pathogenic PLN variants. To comprehensively evaluate the genetic cause of the proband and his pedigree, whole-exome sequencing and Sanger sequencing were performed.\nRESULTS: A novel homozygous nonsense variant (p.Glu2Ter, c.4G>T) in PLN was identified in a 36-year-old male suffering from dilated cardiomyopathy with severe heart failure. No more cardiomyopathy-causing variant or likely pathogenic copy number variation was identified. This variant was not detected in 800 unrelated healthy controls. Furthermore, the variant is not in the Exome Aggregation Consortium or the Genome Aggregation databases. Western blots showed that this variant significantly reduced the expression of phospholamban. Furthermore, in pedigree analysis, we found that all five heterozygous PLN-p.Glu2Ter carriers (including four elder relatives) had normal heart size and cardiac function, which revealed a novel autosomal recessive inheritance mode.\nCONCLUSIONS: Our study identified a novel pathogenic variant of PLN, and revealed a novel pathogenic inheritance mode of PLN causing dilated cardiomyopathy with heart failure.","variants":[{"Name":"NM_002667.5(PLN):c.4G>T (p.Glu2Ter)","Chromosome":"6","Start":"118558925","Stop":"118558925","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3839816,"rule_based_match":true,"evidence_text":"c.4G>T","llm_judgment":"PRESENT","evidence":"c.4G>T","abstract_start":613,"abstract_end":619}]}
{"pmid":"33898437","title":"Identification of Novel Mutations in","abstract":"Oocyte maturation and fertilization are fundamental processes for successful human reproduction, and abnormalities in these processes will cause infertility. Recently, we identified biallelic mutations in <i>CDC20</i> that are responsible for human oocyte maturation arrest, fertilization failure, and early embryonic development arrest. In this study, we screened for further <i>CDC20</i> mutations in a new cohort of patients with abnormalities in oocyte maturation, fertilization, and early embryonic development. Through whole-exome sequencing, we identified the four novel mutations c.887G > A (p. Arg296Gln), c.964C > T (p.Arg322<sup>∗</sup>), c.1155G > C (p.Trp385Cys), and c.330 + 1G > A (p. Glu111Ilefs<sup>∗</sup>36) and one previously reported mutation c.965G > A (p.Arg322Gln) in <i>CDC20</i> in four infertile individuals from three independent families. The patients had different phenotypes of oocyte maturation arrest and fertilization failure resulting from the different mutations. This study confirms our previous research and expands the spectrum of known mutations in <i>CDC20</i>, providing new evidence supporting the function of <i>CDC20</i> in the genetic etiology of female infertility characterized by oocyte maturation arrest and fertilization failure.","variants":[{"Name":"NM_001255.3(CDC20):c.964C>T (p.Arg322Ter)","Chromosome":"1","Start":"43360848","Stop":"43360848","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2417660,"rule_based_match":true,"evidence_text":"c.964C > T (p.Arg322<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"c.964C > T (p.Arg322<sup>∗</sup>)","abstract_start":615,"abstract_end":648},{"Name":"NM_001255.3(CDC20):c.330+1G>A","Chromosome":"1","Start":"43359639","Stop":"43359639","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2417661,"rule_based_match":true,"evidence_text":"c.330 + 1G > A (p. Glu111Ilefs<sup>∗</sup>36)","llm_judgment":"PRESENT","evidence":"c.330 + 1G > A (p. Glu111Ilefs<sup>∗</sup>36)","abstract_start":681,"abstract_end":726},{"Name":"NM_001255.3(CDC20):c.965G>A (p.Arg322Gln)","Chromosome":"1","Start":"43360849","Stop":"43360849","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2417654,"rule_based_match":true,"evidence_text":"c.965G > A (p.Arg322Gln)","llm_judgment":"PRESENT","evidence":"c.965G > A (p.Arg322Gln)","abstract_start":764,"abstract_end":788},{"Name":"NM_001255.3(CDC20):c.1155G>C (p.Trp385Cys)","Chromosome":"1","Start":"43361197","Stop":"43361197","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2417662,"rule_based_match":true,"evidence_text":"c.1155G > C (p.Trp385Cys)","llm_judgment":"PRESENT","evidence":"c.1155G > C (p.Trp385Cys)","abstract_start":650,"abstract_end":675}]}
{"pmid":"33966343","title":"Chronic hepatic involvement in the clinical spectrum of A20 haploinsufficiency.","abstract":"BACKGROUND & AIMS: Secondary to tumour necrosis factor-alpha induced protein 3 (TNFAIP3) mutations, A20 haploinsufficiency (HA20) is a recently described autoinflammatory disease with clinical features similar to those of Behçet's and Crohn's diseases but with a constantly expanding clinical spectrum. Here, we describe HA20 liver involvement in three new patients from the same family.\nMETHODS: We retrospectively assessed clinical, biological and/or histological findings for eight patients over three generations of the same family with heterozygous mutations in the TNFAIP3 gene (c.259C > T, p.Arg87*).\nRESULTS: The eight patients exhibited the following: aphthous ulcers (8/8, bipolar in 7), autoimmune features (6/8, including 5 with definitive autoimmune disease diagnoses, ie, type I diabetes, Hashimoto thyroiditis, pernicious anaemia, and/or 5 with antinuclear antibodies ≥320), pustulosis/folliculitis (5/8), abdominal pain (4/8), arthralgia (3/8), enlarged cervical lymph nodes (3/8) and pericarditis (1/8). In addition, three patients (twin sisters and their grandmother aged 23 and 70 years, respectively) exhibited persistent mild hepatic cytolysis associated with splenomegaly (n = 3), hepatomegaly (n = 1) and/or liver atrophy (n = 1) on echography. We could not detect any other causes of chronic liver diseases. Liver biopsies from three patients displayed hepatic fibrosis, hepatocyte injury and/or CD4<sup>+</sup> /CD8<sup>+</sup> T lymphocyte infiltration, and patterns of inflammatory cells and NLRP3 or NF-κB immunostaining differed from the predominant neutrophil infiltration observed in skin or some digestive tract biopsies.\nCONCLUSIONS: This study reinforces the dual involvement of innate and adaptive immunity in HA20 according to both acute and chronic injury and the organ involved and widens its clinical spectrum to include chronic hepatic involvement.","variants":[{"Name":"NM_001270508.2(TNFAIP3):c.259C>T (p.Arg87Ter)","Chromosome":"6","Start":"137871486","Stop":"137871486","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3859318,"rule_based_match":true,"evidence_text":"c.259C > T, p.Arg87*","llm_judgment":"PRESENT","evidence":"c.259C > T, p.Arg87*","abstract_start":585,"abstract_end":605}]}
{"pmid":"27085187","title":"DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology.","abstract":"Mutations in DJ-1 (encoded by PARK7) are a very rare cause of early-onset recessive Parkinson's disease. We describe a patient with early-onset parkinsonism, starting at the age of 22, with poor response to levodopa and additional features in progression (dystonia, pyramidal signs and dementia), who died when he was 49 years old. The neuropathological study showed severe substantia nigra and locus coeruleus neuronal loss, with diffuse Lewy body pathology (Lewy bodies, aberrant neurites, grain-like structures, spheroids and scattered glial pathology). Genetic analysis revealed a novel c.515T > A; p.L172Q mutation in the PARK7 gene. To evaluate the pathogenicity of this new mutation we explored DJ-1 expression levels in vitro showing a massive reduction in DJ-1 protein levels due to a highly unstable and rapidly degraded L172Q mutant. DJ-1 immunohistochemistry of brain tissue revealed no staining in our case. This is the first neuropathological report of a brain from DJ-1-linked parkinsonism that, although based on a single case study, suggests that DJ-1 mutations are causative of α-synucleinopathy. These results can help in the understanding of Parkinson's disease pathophysiology, promote research studies to increase the knowledge on the pathways involved in the neurodegeneration process, and pave the way for new therapeutic interventions.","variants":[{"Name":"NM_007262.5(PARK7):c.515T>A (p.Leu172Gln)","Chromosome":"1","Start":"7984999","Stop":"7984999","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1928346,"rule_based_match":true,"evidence_text":"c.515T > A; p.L172Q","llm_judgment":"PRESENT","evidence":"c.515T > A; p.L172Q","abstract_start":591,"abstract_end":610}]}
{"pmid":"26004201","title":"Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.","abstract":"Arthrogryposis multiplex congenita is defined by the presence of contractures across two or more major joints and results from reduced or absent fetal movement. Here, we present three consanguineous families affected by lethal arthrogryposis multiplex congenita. By whole-exome or targeted exome sequencing, it was shown that the probands each harbored a different homozygous mutation (one missense, one nonsense, and one frameshift mutation) in GPR126. GPR126 encodes G-protein-coupled receptor 126, which has been shown to be essential for myelination of axons in the peripheral nervous system in fish and mice. A previous study reported that Gpr126(-/-) mice have a lethal arthrogryposis phenotype. We have shown that the peripheral nerves in affected individuals from one family lack myelin basic protein, suggesting that this disease in affected individuals is due to defective myelination of the peripheral axons during fetal development. Previous work has suggested that autoproteolytic cleavage is important for activating GPR126 signaling, and our biochemical assays indicated that the missense substitution (p.Val769Glu [c.2306T>A]) impairs autoproteolytic cleavage of GPR126. Our data indicate that GPR126 is critical for myelination of peripheral nerves in humans. This study adds to the literature implicating defective axoglial function as a key cause of severe arthrogryposis multiplex congenita and suggests that GPR126 mutations should be investigated in individuals affected by this disorder.","variants":[{"Name":"NM_198569.3(ADGRG6):c.2306T>A (p.Val769Glu)","Chromosome":"6","Start":"142408187","Stop":"142408187","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":190137,"rule_based_match":true,"evidence_text":"c.2306T>A","llm_judgment":"PRESENT","evidence":"c.2306T>A","abstract_start":1131,"abstract_end":1140}]}
{"pmid":"30858058","title":"Extending the phenotype of Xia-Gibbs syndrome in a two-year-old patient with craniosynostosis with a novel de novo AHDC1 missense mutation.","abstract":"Xia-Gibbs syndrome (Mental retardation, autosomal dominant 25; MRD25) [MIM 615829] is a rare autosomal dominant disease characterized by mental retardation, developmental delay, speech delay, structural brain anomalies, hypotonicity, protuberant eyes, visual problems, laryngomalacia and snoring. Since the first description in 2014, fewer than 50 patients with Xia-Gibbs syndrome have been noticed in the literature. We describe here 2 years 2 months old girl with developmental delay, brain anomalies, laryngomalacia and craniosynostosis. Whole-Exome Sequencing (WES) analyses in patient showed a heterozygous NM_001029882: c.4370 A>G; p. (Asp1457Gly) mutation in AHDC1. Craniosynostosis rarely observed in the patients described to date, and west syndrome-like EEG pattern, constipation and electrolyte imbalance observed for the first time were present in our patient. Further reports and in-vivo/in-vitro works will make possible knowing of the genetic and clinical background of this disease.","variants":[{"Name":"NM_001371928.1(AHDC1):c.4370A>G (p.Asp1457Gly)","Chromosome":"1","Start":"27547746","Stop":"27547746","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":576253,"rule_based_match":true,"evidence_text":"NM_001029882: c.4370 A>G; p. (Asp1457Gly)","llm_judgment":"PRESENT","evidence":"NM_001029882: c.4370 A>G; p. (Asp1457Gly)","abstract_start":612,"abstract_end":653}]}
{"pmid":"30119649","title":"Phenotypic variability of Niemann-Pick disease type C including a case with clinically pure schizophrenia: a case report.","abstract":"BACKGROUND: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with severe prognosis. Disease-specific therapy is crucial to prevent disease progression; however, diagnosing NPC is quite difficult because of remarkably variable clinical presentations. The NPC Suspicion Index (NPC-SI) was developed to overcome this problem. Identifying preclinical cases is important for prevention and therapy. Here, we report three newly diagnosed NPC cases, one typical juvenile-onset case and the cases of two sisters with symptoms neurologically/psychiatrically indistinguishable from dystonia and schizophrenia, respectively.\nCASE PRESENTATION: In Case 1, a 25-year-old man presented with a 14-year history of intellectual disability, clumsiness, spastic ataxia, dysphagia, and frequent falls. Neurological examination revealed vertical supranuclear gaze palsy and involuntary movements. Ultrasonography revealed mild splenomegaly, and filipin staining of skin fibroblasts was positive with a variant staining pattern. NPC1 gene analysis showed compound heterozygous mutations, including c.1421C > T (p.P474L), a known causative mutation, and c.3722 T > C (p.L1241S), a new mutation. In Case 2, a 28-year-old woman, the proband, who had marked splenomegaly in her childhood, survived well, contrary to the expected severe prognosis of infantile NPC. She had minor neuropsychiatric symptoms including auditory hallucinations, nocturnal urination, and sleep paralysis. At the age of 28 years, she presented with a 1-year history of orofacial and oromandibular painful dystonia. The patient's 35-year-old sister (Case 3) was diagnosed with schizophrenia. In both cases, filipin staining of skin fibroblasts was positive with variant staining patterns, as well as elevated levels of urinary bile acids. NPC1 gene analysis showed compound heterozygous mutations including c.3011C > T (p.S1004 L), a known causative mutation, and c.160_161insG (p.D54GfsX4), a new mutation. Their mother, who was under therapy with modafinil for narcolepsy, shared the latter mutation.\nCONCLUSIONS: Marked clinical variability was observed in our three cases. NPC could masquerade as a pure neuropsychiatric disorder such as dystonia or schizophrenia. Abdominal ultrasonography, history evaluation, and neurological examination were quite important in the diagnostic process.","variants":[{"Name":"NM_000271.5(NPC1):c.3011C>T (p.Ser1004Leu)","Chromosome":"18","Start":"23538572","Stop":"23538572","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":341128,"rule_based_match":true,"evidence_text":"c.3011C > T (p.S1004 L)","llm_judgment":"PRESENT","evidence":"c.3011C > T (p.S1004 L)","abstract_start":1872,"abstract_end":1895}]}
{"pmid":"28546535","title":"A novel PRKAG2 mutation in a Chinese family with cardiac hypertrophy and ventricular pre-excitation.","abstract":"PRKAG2 syndrome is a rare autosomal dominant inherited disorder that is characterized by cardiac hypertrophy, ventricular pre-excitation and conduction system abnormalities. There is little knowledge in cardiovascular magnetic resonance (CMR) characteristics of PRKAG2 cardiomyopathy. This study investigated the genetic defect in a three-generation Chinese family with cardiac hypertrophy and ventricular pre-excitation using whole-exome sequencing. A novel missense mutation, c.1006 G > T (p.V336L), was identified in PRKAG2. This mutation had not been identified in the ExAC database, and the prediction result of MutationTaster indicated a deleterious effect. Furthermore, it cosegregated with the disease in the present family and was absent in unrelated 300 healthy controls. cDNA analysis did not detect any splicing defects, although the variant occurred in the first base of exon 9. CMR evaluation in five affected members showed diffuse hypertrophy in a concentric pattern, with markedly increased left ventricular mass above age and gender limits (median 151.3 g/m<sup>2</sup>, range 108.4-233.4 g/m<sup>2</sup>). Two patients in progressive stage and one patient with sudden cardiac death exhibited extensive subendocardial late gadolinium enhancement. In conclusion, molecular screening for PRKAG2 mutations should be considered in patients who exhibit cardiac hypertrophy coexisting with ventricular pre-excitation. CMR offers promising advantages for evaluation of PRKAG2 cardiomyopathy.","variants":[{"Name":"NM_016203.4(PRKAG2):c.1006G>T (p.Val336Leu)","Chromosome":"7","Start":"151572709","Stop":"151572709","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1187215,"rule_based_match":true,"evidence_text":"c.1006 G > T (p.V336L)","llm_judgment":"PRESENT","evidence":"c.1006 G > T (p.V336L)","abstract_start":478,"abstract_end":500}]}
{"pmid":"23592913","title":"A novel connexin 50 gene (gap junction protein, alpha 8) mutation associated with congenital nuclear and zonular pulverulent cataract.","abstract":"PURPOSE: To characterize the disease-causing mutations in four generations of a Chinese family affected with bilateral congenital nuclear and zonular pulverulent cataract.\nMETHODS: Detailed family history and clinical data were recorded. The phenotype was documented using slit-lamp photography. Candidate genes were amplified using PCR and screened for mutations using bidirectional sequencing.\nRESULTS: Affected individuals had nuclear and zonular pulverulent cataract with Y-sutural opacities. Sequencing of the candidate genes revealed a heterozygous c. 139G>C change in the coding sequence of the connexin 50 gene (gap junction protein, alpha 8 [GJA8]), which results in the substitution of a wild-type aspartic acid with a histidine (D47H). This mutation cosegregated with all affected individuals in the family and was not found in unaffected family members or in 100 unrelated controls.\nCONCLUSIONS: Our study has identified a novel connexin 50 gene (GJA8) mutation, resulting in the amino substitution p. D47H in a Chinese family with nuclear and zonular pulverulent congenital cataracts. This mutation is probably the causative lesion for the observed phenotype in this family.","variants":[{"Name":"NM_005267.5(GJA8):c.139G>C (p.Asp47His)","Chromosome":"1","Start":"147908094","Stop":"147908094","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":263944,"rule_based_match":true,"evidence_text":"c. 139G>C","llm_judgment":"PRESENT","evidence":"c. 139G>C","abstract_start":555,"abstract_end":564}]}
{"pmid":"31410651","title":"LMNA-Related Muscular Dystrophy with Clinical Intrafamilial Variability.","abstract":"The LMNA gene is associated to a huge broad of phenotypes, including congenital Emery-Dreifuss muscular dystrophy and late-onset LMNA-related muscular dystrophy. In these forms, muscle weakness, contractures, and cardiac impairment are common. In an autosomal dominant pedigree including 5 affected patients, NGS molecular analysis performed in 6 relatives identifies the heterozygous c.1129C>T p.Arg377Cys variant in the exon 6 of the LMNA gene in three of them. Clinical, laboratorial, imaging investigation of these affected patients showed a significant clinical variability: the father presented subclinical imaging muscular dystrophy masqueraded as radiculopathy. One of his sons presented cardiac arrhythmia, muscular weakness, elbow contractures, and intranuclear pseudoinclusions on muscle biopsy. A second son presented only decreased tendon reflexes. Two other brothers presenting myalgia and cramps were not carriers of the same mutation in the LMNA gene. Early diagnosis, considering these variable phenotype and genotype, is important for genetic counseling, as well as cardiac, and rehabilitation management.","variants":[{"Name":"NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys)","Chromosome":"1","Start":"156136093","Stop":"156136093","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":57195,"rule_based_match":true,"evidence_text":"c.1129C>T p.Arg377Cys","llm_judgment":"PRESENT","evidence":"c.1129C>T p.Arg377Cys","abstract_start":385,"abstract_end":406}]}
{"pmid":"22419169","title":"Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn.","abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C>T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G>A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria.","variants":[{"Name":"NM_170707.4(LMNA):c.1821G>A (p.Val607=)","Chromosome":"1","Start":"156138610","Stop":"156138610","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29555,"rule_based_match":true,"evidence_text":"c.1821G>A","llm_judgment":"PRESENT","evidence":"c.1821G>A","abstract_start":744,"abstract_end":753}]}
{"pmid":"31999076","title":"Two unrelated families with variable expression of Fraser syndrome due to the same pathogenic variant in the FRAS1 gene.","abstract":"We report on two unrelated families of Polish origin with variable expression of Fraser syndrome (FS; MIM#219000) due to homozygosity for the same pathogenic variant, c.6963_6964dup, of FRAS1. In one family, the disorder presented with perinatal and prenatal lethality. One affected female from family 2 who was followed-up for 32 years, represented a relatively favorable long-term outcome. She displayed the typical craniofacial dysmorphism, including right cryptophthalmos, cutaneous syndactyly, abnormalities of the stomathognatic system, bilateral atresia of the external ear canals resulting in conductive hearing loss, and malformations of the larynx, spleen, kidney, and genitourinary tract. Her intellectual capacities were normal. Our observations illustrate that expression and severity of FS, even when caused by the same pathogenic variant, may be quite different ranging from a lethal disorder to a condition with multiple physical malformations but normal psychomotor development. In addition, we propose that the FRAS1 c.6963_6964dup variant may be a founder mutation in the Polish population. Therefore, it would be reasonable to test specifically for this variant first in any FS1 patient of Polish ancestry.","variants":[{"Name":"NM_025074.7(FRAS1):c.6963_6964dup (p.Val2322fs)","Chromosome":"4","Start":"78464515","Stop":"78464516","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CGG","allel_id":17854,"rule_based_match":true,"evidence_text":"c.6963_6964dup","llm_judgment":"PRESENT","evidence":"c.6963_6964dup","abstract_start":167,"abstract_end":181}]}
{"pmid":"26119398","title":"A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia.","abstract":"Persistent elevation of serum creatine kinase (CK) without any symptoms has been called idiopathic hyper CK-emia (IHCK). We examined a four-generation Japanese pedigree of familial IHCK. The multipoint linkage analysis of the pedigree showed seven clear peaks of logarithm of odds (LOD) scores (>1.4). By the exome sequencing followed by multiple filtering processes, we identified one novel heterozygous nonsynonymous single nucleotide variant (SNV), c.7034G>C, p.S2345T in the ryanodine receptor 1 gene, RYR1 cosegregated with IHCK in the pedigree. Mutation Taster predicted this substitution as \"disease causing\" (p=0.999). The PolyPhen-2 and PANTHER subPSEC scores for the substitution are 0.911 (possibly damaging) and -3.56 (probably damaging), respectively. We confirmed the absence of the SNV in 511 healthy Japanese individuals excluding the possibility of a normal variant with a very low frequency. Immunohistochemistry and Western blotting of biopsy samples consistently showed the expression level of RYR1 reduced in the patient. In real-time RT-PCR, the mRNA expression level of RYR1 was also significantly reduced in the patient (p=0.009). These results suggest that the novel nonsynonymous SNV contribute to the vulnerability of the RYR1 protein through the dominant negative effect. We conclude that the SNV in the RYR1 gene is one of the responsible genes of IHCK.","variants":[{"Name":"NM_000540.3(RYR1):c.7034G>C (p.Ser2345Thr)","Chromosome":"19","Start":"38499641","Stop":"38499641","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2905448,"rule_based_match":true,"evidence_text":"c.7034G>C, p.S2345T","llm_judgment":"PRESENT","evidence":"c.7034G>C, p.S2345T","abstract_start":452,"abstract_end":471}]}
{"pmid":"38158857","title":"Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.","abstract":"PURPOSE: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.\nMETHODS: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.\nRESULTS: In 1 family with 2 affected males, we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation.\nCONCLUSION: We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron-containing genes due to germline variation in ZRSR2.","variants":[{"Name":"NM_005089.4(ZRSR2):c.1211_1212del (p.Gly404fs)","Chromosome":"X","Start":"15823001","Stop":"15823002","ReferenceAlleleVCF":"AGG","AlternateAlleleVCF":"A","allel_id":3526376,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1211_1212del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1211_1212del","abstract_start":678,"abstract_end":704},{"Name":"NM_005089.4(ZRSR2):c.1207_1208del (p.Arg403fs)","Chromosome":"X","Start":"15823000","Stop":"15823001","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":966735,"rule_based_match":true,"evidence_text":"NM_005089.4:c.1207_1208del","llm_judgment":"PRESENT","evidence":"NM_005089.4:c.1207_1208del","abstract_start":828,"abstract_end":854}]}
{"pmid":"20493745","title":"Epilepsy caused by CDKL5 mutations.","abstract":"Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype. Subsequently CDKL5 mutations were shown to be associated with more diverse phenotypes including mild epilepsy and autism without epilepsy. Furthermore, CDKL5 mutations were found in patients with Angelman-like phenotype. The severity of epilepsy associated with CDKL5 mutations was recently shown to correlate with the type of CDKL5 mutations and epilepsy was identified to involve three distinct sequential stages. Here, we describe the phenotype of a severe form of neurodevelopmental disease in a female patient with a de novo nonsense mutation of the CDKL5 gene c.175C > T (p.R59X) affecting the catalytic domain of CDKL5 protein. Mutations in the CDKL5 gene are less common in males and can be associated with a genomic deletion as found in our male patient with a deletion of 0.3 Mb at Xp22.13 including the CDKL5 gene. We review phenotypes associated with CDKL5 mutations and examine putative relationships between the clinical epilepsy phenotype and the type of the mutation in the CDKL5 gene.","variants":[{"Name":"NM_001323289.2(CDKL5):c.175C>T (p.Arg59Ter)","Chromosome":"X","Start":"18575383","Stop":"18575383","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":153515,"rule_based_match":true,"evidence_text":"c.175C > T (p.R59X)","llm_judgment":"PRESENT","evidence":"c.175C > T (p.R59X)","abstract_start":767,"abstract_end":786}]}
{"pmid":"28576691","title":"Recurrent elevated liver transaminases and acute liver failure in two siblings with novel bi-allelic mutations of NBAS.","abstract":"BACKGROUND: Acute liver failure (ALF) in children can be life-threatening. Although many causes are known, ALF remains unexplained in about half of the cases. Recently, bi-allelic mutations in NBAS were reported to underlie recurrent episodes of elevated liver transaminases (ELT) and ALF in the context of diverse extrahepatic phenotypes.\nMETHODS AND RESULTS: We here describe two sisters, born to non-consanguineous Portuguese parents, who had short stature and presented with recurrent episodes of severe ELT triggered by febrile respiratory viral infections since early childhood. Patient 1 had mild facial dysmorphism and died during the second ELT crisis at 3-11/12 years of age. Patient 2, currently 9 years old, had multiple episodes of ELT (>30), twice with ALF, often accompanied by extensive urticaria and facial angioedema. Whole-exome and Sanger sequencing revealed that both patients carried previously undescribed compound heterozygous mutations of NBAS (NM_015909.3): c.680A > C (p.His227Pro), affecting an evolutionarily conserved residue, and c.1749G > A (p.Trp583*), causing a premature stop codon. Both mutations are predicted to be highly damaging. The parents and two younger siblings are healthy and heterozygous for one or another mutant allele.\nCONCLUSION: The multiplex kindred reported herein expands the genotypic and phenotypic spectrum of this recently described clinical syndrome due to autosomal recessive NBAS deficiency.","variants":[{"Name":"NM_015909.4(NBAS):c.1749G>A (p.Trp583Ter)","Chromosome":"2","Start":"15468510","Stop":"15468510","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":411605,"rule_based_match":true,"evidence_text":"c.1749G > A (p.Trp583*)","llm_judgment":"PRESENT","evidence":"c.1749G > A (p.Trp583*)","abstract_start":1061,"abstract_end":1084},{"Name":"NM_015909.4(NBAS):c.680A>C (p.His227Pro)","Chromosome":"2","Start":"15534609","Stop":"15534609","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":411606,"rule_based_match":true,"evidence_text":"c.680A > C (p.His227Pro)","llm_judgment":"PRESENT","evidence":"c.680A > C (p.His227Pro)","abstract_start":984,"abstract_end":1008}]}
{"pmid":"21696387","title":"De novo CDH1 mutation in a family presenting with early-onset diffuse gastric cancer.","abstract":"In this report, we describe the first concluded case of a de novo germline mutation in CDH1 in a hereditary diffuse gastric cancer (HDGC) kindred. The incident case was a woman with a personal history of Hodgkin's lymphoma and diffuse gastric cancer, who was then confirmed to have a CDH1 mutation (c.1792 C>T (R598X)). The patient's mother was found to have the same CDH1 germline mutation; however, neither maternal grandparent was found to carry the mutation, thus leading to a conclusion that the proband's mother's mutation is of de novo origin. This case highlights the importance of recognition of the HDGC syndrome and of testing for CDH1 germline mutations in young individuals with diffuse gastric cancer without a family history of the disease.","variants":[{"Name":"NM_004360.5(CDH1):c.1792C>T (p.Arg598Ter)","Chromosome":"16","Start":"68822081","Stop":"68822081","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27280,"rule_based_match":true,"evidence_text":"c.1792 C>T (R598X)","llm_judgment":"PRESENT","evidence":"c.1792 C>T (R598X)","abstract_start":299,"abstract_end":317}]}
{"pmid":"30642748","title":"Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood.","abstract":"AIM: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations.\nMETHOD: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts.\nRESULTS: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival.\nINTERPRETATION: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.","variants":[{"Name":"NM_152416.4(NDUFAF6):c.371T>C (p.Ile124Thr)","Chromosome":"8","Start":"95035527","Stop":"95035527","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":211343,"rule_based_match":true,"evidence_text":"c.371T>C (p.Ile124Thr)","llm_judgment":"PRESENT","evidence":"p.Ile124Thr","abstract_start":789,"abstract_end":800}]}
{"pmid":"27932860","title":"Rebound macular edema following oral acetazolamide therapy for juvenile X-linked retinoschisis in an Italian family.","abstract":"BACKGROUND: Juvenile X-linked retinoschisis (RS1, OMIM: 312700) is a hereditary vitreoretinal dystrophy characterized by bilateral foveal schisis and, in half of the patients, splitting through the nerve fiber layer in the peripheral retina. In the first decade of life, patients usually develop a decrease in visual acuity. Long-term visual outcomes can be poor due to the limited number of known successful treatments.\nPURPOSE: The purposes of this study were to present, for the first time, a p.Arg197Cys missense mutation in the <i>RS1</i> gene (OMIM: 300839) in a four-generation Italian family with RS1 and to examine the clinical response to the treatment with acetazolamide tablets alone or in combination with dorzolamide eye drops as assessed by spectral-domain optical coherence tomography (SD-OCT).\nMETHODS: Eleven individuals, including two brothers with RS1 (patients 1 and 2), underwent a full medical history examination and a comprehensive ocular assessment that involved SD-OCT, fluorescein angiography, electroretinography and DNA analysis. Each RS1 patient received oral acetazolamide (375 mg daily) during the first three months. Thereafter, patient 1 continued only with dorzolamide eyedrops three times a day for a period of three months, while patient 2 spontaneously stopped both medications.\nRESULTS: Sequence analysis of the <i>RS1</i> gene identified a hemizygous c.589C>T (p.Arg197Cys) missense mutation in exon 6, which has not been previously reported in an Italian family. A different response to the medical therapy was observed in the four eyes of the two affected brothers hemizygous for this abnormality. Of note, after acetazolamide interruption, a rebound effect on cystoid macular edema reduced the beneficial effects of the initial therapy for RS1 from p.Arg197Cys mutation. Indeed, a minimal rebound effect on cystoid macular edema, and an improvement in visual acuity, was observed in patient 1 during the six months of treatment. Conversely, in patient 2, an initial improvement in cystoid macular edema was not associated with visual acuity changes, followed by a marked rebound effect.\nCONCLUSION: This study showed that the sequential use of acetazolamide tablets and dorzolamide eye drops should be considered and studied further as a possible treatment for macular edema and visual impairment in patients with RS1 from a hemizygous p.Arg197Cys mutation.","variants":[{"Name":"NM_000330.4(RS1):c.589C>T (p.Arg197Cys)","Chromosome":"X","Start":"18642090","Stop":"18642090","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":104886,"rule_based_match":true,"evidence_text":"c.589C>T (p.Arg197Cys)","llm_judgment":"PRESENT","evidence":"c.589C>T (p.Arg197Cys)","abstract_start":1392,"abstract_end":1414}]}
{"pmid":"30278534","title":"Von Hippel-Lindau with early onset of hemangioblastoma and multiple drop-metastases like spinal lesions: A case report.","abstract":"RATIONALE: Hemangioblastoma is a rare tumor of the central nervous system (CNS). It is usually observed in patients with von-Hippel Lindau (VHL). The peak age for hemangioblastoma is between 20 and 50 years of age with very few cases over 65 or below 18 years of age.\nPATIENT CONCERNS: We report a female with a rare VHL mutation (c.337C>T) who was diagnosed with multifocal CNS hemangioblastoma at a very young age.\nDIAGNOSIS: At 17-years of age, she presented with obstructive hydrocephalus due to large cystic cerebellar mass. Imaging showed multiple lesions resembling drop metastases throughout her spinal cord. Immunohistochemistry of the resected tumor confirmed the pathological diagnosis of hemangioblastoma (World Health Organization Grade 1).\nINTERVENTIONS AND OUTCOME: She was treated with multi-stage resection of her primary and drop- metastasis like disease. She presented six months later with retinal hemangioblastoma while her other lesions were stable. She presented with multiple CNS and eye hemangioblastomas after failing to follow up for 2 years. Subsequently, Everolimus was started to treat her systemic disease.\nLESSONS: The unique feature of our case is the presence of multiple drop-metastases like spinal lesions, which has not been reported in the literature to be associated with hemangioblastoma.","variants":[{"Name":"NM_000551.4(VHL):c.337C>T (p.Arg113Ter)","Chromosome":"3","Start":"10142184","Stop":"10142184","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":221350,"rule_based_match":true,"evidence_text":"c.337C>T","llm_judgment":"PRESENT","evidence":"c.337C>T","abstract_start":331,"abstract_end":339}]}
{"pmid":"34706368","title":"Primary Ovarian Failure in Addition to Classical Clinical Features of Coats Plus Syndrome in a Female Carrying 2 Truncating Variants of CTC1.","abstract":"Coats plus syndrome is an autosomal recessive multisystemic and pleiotropic disorder affecting the eyes, brain, bone, and gastrointestinal tract, usually caused by compound heterozygous variants of the conserved telomere maintenance component 1 gene (CTC1), involved in telomere homeostasis and replication. So far, most reported patients are compound heterozygous for a truncating mutation and a missense variant. The phenotype is believed to result from telomere dysfunction, with accumulation of DNA damage, cellular senescence, and stem cell depletion. Here, we report a 23-year-old female with prenatal and postnatal growth retardation, microcephaly, osteopenia, recurrent fractures, intracranial calcification, leukodystrophy, parenchymal brain cysts, bicuspid aortic valve, and primary ovarian failure. She carries a previously reported maternally inherited pathogenic variant in exon 5 (c.724_727del, p.(Lys242Leufs*41)) and a novel, paternally inherited splice site variant (c.1617+5G>T; p.(Lys480Asnfs*17)) in intron 9. CTC1 transcript analysis showed that the latter resulted in skipping of exon 9. A trace of transcripts was normally spliced resulting in the presence of a low level of wild-type CTC1 transcripts. We speculate that ovarian failure is caused by telomere shortening or chromosome cohesion failure in oocytes and granulosa cells, with early decrease in follicular reserve. This is the first patient carrying 2 truncating CTC1 variants and the first presenting primary ovarian failure.","variants":[{"Name":"NM_025099.6(CTC1):c.724_727del (p.Lys242fs)","Chromosome":"17","Start":"8237440","Stop":"8237443","ReferenceAlleleVCF":"GCTTT","AlternateAlleleVCF":"G","allel_id":39952,"rule_based_match":true,"evidence_text":"c.724_727del, p.(Lys242Leufs*41)","llm_judgment":"PRESENT","evidence":"c.724_727del, p.(Lys242Leufs*41)","abstract_start":895,"abstract_end":927},{"Name":"NM_025099.6(CTC1):c.1617+5G>T","Chromosome":"17","Start":"8234744","Stop":"8234744","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2090668,"rule_based_match":true,"evidence_text":"c.1617+5G>T","llm_judgment":"PRESENT","evidence":"c.1617+5G>T","abstract_start":984,"abstract_end":995}]}
{"pmid":"21044902","title":"A novel ACVR1 mutation in the glycine/serine-rich domain found in the most benign case of a fibrodysplasia ossificans progressiva variant reported to date.","abstract":"Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant condition, classically characterised by heterotopic ossification beginning in childhood and congenital great toe malformations; occurring in response to a c.617 G > A ACVR1 mutation in the functionally important glycine/serine-rich domain of exon 6. Here we describe a novel c.587 T > C mutation in the glycine/serine-rich domain of ACVR1, associated with delayed onset of heterotopic ossification and an exceptionally mild clinical course. Absence of great toe malformations, the presence of early ossification of the cervical spine facets joints, plus mild bilateral camptodactyly of the 5th fingers, together with a novel ACVR1 mutation, are consistent with the 'FOP-variant' syndrome. The c.587 T > C mutation replaces a conserved leucine with proline at residue 196. Modelling of the mutant protein reveals a steric clash with the kinase domain that will weaken interactions with FKBP12 and induce exposure of the glycine/serine-rich repeat. The mutant receptor is predicted to be hypersensitive to ligand stimulation rather than being constitutively active, consistent with the mild clinical phenotype. This case extends our understanding of the 'FOP-variant' syndrome.","variants":[{"Name":"NM_001111067.4(ACVR1):c.587T>C (p.Leu196Pro)","Chromosome":"2","Start":"157774144","Stop":"157774144","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":205405,"rule_based_match":true,"evidence_text":"c.587 T > C","llm_judgment":"PRESENT","evidence":"c.587 T > C","abstract_start":349,"abstract_end":360}]}
{"pmid":"21107780","title":"Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure.","abstract":"Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogenicity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates.","variants":[{"Name":"NM_080916.3(DGUOK):c.3G>A (p.Met1Ile)","Chromosome":"2","Start":"73926913","Stop":"73926913","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1314498,"rule_based_match":true,"evidence_text":"c.3G>A (p.Met1Ile)","llm_judgment":"PRESENT","evidence":"c.3G>A (p.Met1Ile)","abstract_start":539,"abstract_end":557},{"Name":"NM_080916.3(DGUOK):c.494A>T (p.Glu165Val)","Chromosome":"2","Start":"73950635","Stop":"73950635","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":586324,"rule_based_match":true,"evidence_text":"c.494A>T (p.Glu165Val)","llm_judgment":"PRESENT","evidence":"c.494A>T (p.Glu165Val)","abstract_start":559,"abstract_end":581}]}
{"pmid":"26544806","title":"Association between Rare Variants in AP4E1, a Component of Intracellular Trafficking, and Persistent Stuttering.","abstract":"Stuttering is a common, highly heritable neurodevelopmental disorder characterized by deficits in the volitional control of speech. Whole-exome sequencing identified two heterozygous AP4E1 coding variants, c.1549G>A (p.Val517Ile) and c.2401G>A (p.Glu801Lys), that co-segregate with persistent developmental stuttering in a large Cameroonian family, and we observed the same two variants in unrelated Cameroonians with persistent stuttering. We found 23 other rare variants, including predicted loss-of-function variants, in AP4E1 in unrelated stuttering individuals in Cameroon, Pakistan, and North America. The rate of rare variants in AP4E1 was significantly higher in unrelated Pakistani and Cameroonian stuttering individuals than in population-matched control individuals, and coding variants in this gene are exceptionally rare in the general sub-Saharan West African, South Asian, and North American populations. Clinical examination of the Cameroonian family members failed to identify any symptoms previously reported in rare individuals carrying homozygous loss-of-function mutations in this gene. AP4E1 encodes the ε subunit of the heterotetrameric (ε-β4-μ4-σ4) AP-4 complex, involved in protein sorting at the trans-Golgi network. We found that the μ4 subunit of AP-4 interacts with NAGPA, an enzyme involved in the synthesis of the mannose 6-phosphate signal that targets acid hydrolases to the lysosome and the product of a gene previously associated with stuttering. These findings implicate deficits in intracellular trafficking in persistent stuttering.","variants":[{"Name":"NM_007347.5(AP4E1):c.2401G>A (p.Glu801Lys)","Chromosome":"15","Start":"50997380","Stop":"50997380","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":226245,"rule_based_match":true,"evidence_text":"c.2401G>A (p.Glu801Lys)","llm_judgment":"PRESENT","evidence":"c.2401G>A (p.Glu801Lys)","abstract_start":234,"abstract_end":257},{"Name":"NM_007347.5(AP4E1):c.1549G>A (p.Val517Ile)","Chromosome":"15","Start":"50958492","Stop":"50958492","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":226246,"rule_based_match":true,"evidence_text":"c.1549G>A (p.Val517Ile)","llm_judgment":"PRESENT","evidence":"c.1549G>A (p.Val517Ile)","abstract_start":206,"abstract_end":229}]}
{"pmid":"24626099","title":"Endochondral ossification in a case of progressive osseous heteroplasia in a young female child.","abstract":"Progressive osseous heteroplasia (POH) (OMIM 166350) is a rare autosomal dominant condition, characterized by heterotopic ossification of the skin, subcutaneous fat, and deep connective tissue. This condition is distinct from Albright's hereditary osteodystrophy or McCune Albright syndrome (OMIM 103580) and fibrodysplasia ossificans progressiva (OMIM 135100). We present an unusual presentation of POH in a 7-year-old female child. The clinical features included a painful swelling on the left foot, with mechanical complaints. There was no congenital hallux valgus. Family anamnesis was positive in the father. There were subcutaneous ossifications of his left upper arm, right-sided thorax, and lateral side of the right ankle. The father did not allow any radiographs or further examinations. Radiographic examination of the patient revealed ossified subcutaneous plaques on the left foot, lumbar spine, and left scapulae. Additional blood samples were analyzed, revealing no pseudohypoparathyroidism. Sequence analysis of the gene associated with POH, the GNAS1 gene, revealed the heterozygote mutation c.565_568del, previously found in Albright's hereditary osteodystrophy. Histopathological examination of the subcutaneous ossification showed presence of chondrocyte clusters, a feature usually found in fibrodysplasia ossificans progressiva. The combination of the clinical features, the absence of pseudohypoparathyroidism, histology revealing chondrocyte clusters, and the specific GNAS mutation in this patient makes this a truly unusual presentation of POH. The findings in the described case might denote subdivisions of POH. The condition is associated with progressive superficial to deep ossification, progressive restriction of range of motion, and recurrence if excised. We hope to inform pediatricians and orthopedic surgeons to create more awareness of this disorder so that unnecessary treatments can be avoided and proper counseling offered.","variants":[{"Name":"NM_000516.7(GNAS):c.565_568del (p.Asp189fs)","Chromosome":"20","Start":"58909194","Stop":"58909197","ReferenceAlleleVCF":"GCTGA","AlternateAlleleVCF":"G","allel_id":30977,"rule_based_match":true,"evidence_text":"c.565_568del","llm_judgment":"PRESENT","evidence":"c.565_568del","abstract_start":1109,"abstract_end":1121}]}
{"pmid":"30948499","title":"A novel missense mutation in","abstract":"Osteogenesis imperfecta (OI) is a rare heritable bone disorder characterized by low bone mineral density (BMD), recurrent bone fractures, and progressive bone deformities. <i>P4HB</i> encodes protein disulfide isomerase (PDI) and is identified as a novel candidate gene of OI. The purposes of the present study are to detect pathogenic mutation, to evaluate the phenotypes of a Chinese family with mild OI, and to investigate the effects of bisphosphonates on bone of the proband. We detected the pathogenic mutation by next generation sequencing and Sanger sequencing. Laboratory and radiological investigations were conducted to evaluate the phenotypes. The proband was a 12-year-old girl with low BMD, history of recurrent non-traumatic fractures, slight scoliosis, with bluish grey sclera and ligamentous laxity. Her father suffered from one fragility fracture and slight wedge changes of vertebras, with bluish grey sclera. We identified a novel heterozygous missense mutation (c.692A>C, p.His231Pro) in <i>P4HB</i> in the proband and her father. This mutation was predicted to affect the combination of PDI with type I procollagen and lead to the disorder of its triple helix formation. Bisphosphonates were effective in reducing bone resorption and increasing BMD of the proband with well tolerance. In conclusion, we identified a novel mutation in <i>P4HB</i> in a Chinese family with mild OI, which expanded the genotypic and phenotypic spectrum of OI. Bisphosphonates were effective to this extremely rare OI induced by <i>P4HB</i> mutation.","variants":[{"Name":"NM_000918.4(P4HB):c.692A>C (p.His231Pro)","Chromosome":"17","Start":"81847280","Stop":"81847280","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3843433,"rule_based_match":true,"evidence_text":"c.692A>C, p.His231Pro","llm_judgment":"PRESENT","evidence":"c.692A>C, p.His231Pro","abstract_start":983,"abstract_end":1004}]}
{"pmid":"26621368","title":"Novel mutations in EVC cause aberrant splicing in Ellis-van Creveld syndrome.","abstract":"Ellis-van Creveld syndrome (EvC) is a rare autosomal recessive disorder characterized by disproportionate chondrodysplasia, postaxial polydactyly, nail dystrophy, dental abnormalities and in a proportion of patients, congenital cardiac malformations. Weyers acrofacial dysostosis (Weyers) is another dominantly inherited disorder allelic to EvC syndrome but with milder phenotypes. Both disorders can result from loss-of-function mutations in either EVC or EVC2 gene, and phenotypes associated with the two gene mutations are clinically indistinguishable. We present here a clinical and molecular analysis of a Chinese family manifested specific features of EvC syndrome. Sequencing of both EVC and EVC2 identified two novel heterozygous splice site mutations c.384+5G>C in intron 3 and c.1465-1G>A in intron 10 in EVC, which were inherited from mother and father, respectively. In vitro minigene expression assay, RT-PCR and sequencing analysis demonstrated that c.384+5G>C mutation abolished normal splice site and created a new cryptic acceptor site within exon 4, whereas c.1465-1G>A mutation affected consensus splice junction site and resulted in full exon 11 skipping. These two aberrant pre-mRNA splicing processes both produced in-frame abnormal transcripts that possibly led to abolishment of important functional domains. To our knowledge, this is the first report of EVC mutations that cause EvC syndrome in Chinese population. Our data revealed that EVC splice site mutations altered splicing pattern and helped elucidate the pathogenesis of EvC syndrome.","variants":[{"Name":"NM_153717.3(EVC):c.384+5G>C","Chromosome":"4","Start":"5729395","Stop":"5729395","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":543187,"rule_based_match":true,"evidence_text":"c.384+5G>C","llm_judgment":"PRESENT","evidence":"c.384+5G>C","abstract_start":760,"abstract_end":770}]}
{"pmid":"32980423","title":"Combined immunodeficiency caused by a novel homozygous NFKB1 mutation.","abstract":"BACKGROUND: Genetic faults in several components of the nuclear factor-κB pathway cause immunodeficiency. Most defects lead to combined immunodeficiency with a range of severity. Heterozygous mutations in NFKB1 were associated with common variable immunodeficiency, however, homozygous mutations have not been described.\nOBJECTIVE: We studied the molecular basis of combined immunodeficiency in a patient who presented with failure to thrive, persistent EBV viremia and hepatitis, pneumocystis jirovecii pneumonitis, and generalized lymphadenopathy.\nMETHODS: Whole genome and exome sequencing followed by Sanger confirmation were performed to identify the genetic defect. Molecular and cellular techniques were used to assess the variant impact on the nuclear factor-κB pathway and lymphocyte function.\nRESULTS: Genetic analysis revealed a novel homozygous mutation in NFKB1, c.2878G>A, p.Gly960Arg (G960R). This affected p105 phosphorylation and p50 formation on antigen and cytokine stimulation, as well as attenuating nuclear signal transmission. As a result, both T- and B-cell maturation and function were perturbed. The number of memory CD4<sup>+</sup> T cells were reduced, while CD8<sup>+</sup> T cells consisted predominately of expanded differentiated populations. The function of T cells were diminished as shown by reduced responses to mitogens as well as diminished cytokine secretion. B-cell maturation was also affected, with decreased IgD<sup>+</sup>CD27<sup>+</sup> memory B cells while transitional B cells were increased, likely contributing to the reduced ability to produce specific antibodies.\nCONCLUSION: Homozygous G960R mutation in NFKB1 leads to a severe clinical presentation of combined immunodeficiency. This was associated with blockade of nuclear factor-κB pathway signaling, resulting in aberrations in T- and B-cell maturation and function.","variants":[{"Name":"NM_003998.4(NFKB1):c.2878G>A (p.Gly960Arg)","Chromosome":"4","Start":"102616562","Stop":"102616562","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1504002,"rule_based_match":true,"evidence_text":"c.2878G>A, p.Gly960Arg (G960R)","llm_judgment":"PRESENT","evidence":"c.2878G>A, p.Gly960Arg (G960R)","abstract_start":876,"abstract_end":906}]}
{"pmid":"25301372","title":"Rapid and cost-effective molecular diagnosis using exome sequencing of one proband with autosomal dominant congenital cataract.","abstract":"PURPOSE: Due to high genetic heterogeneity, to exclude known mutations and map novel mutations in autosomal dominant congenital cataract (ADCC) using conventional candidate gene screening requires laborious laboratory work. We attempted to use a cost-effective exome sequencing strategy to identify disease-causing mutations in an ADCC pedigree.\nMETHODS: An ADCC pedigree affected by nuclear cataract and 200 unrelated senile cataract controls were recruited and given comprehensive ophthalmic examination. Whole exome of the proband of the family was captured by the Illumina TruSeq Exome Enrichment Kit, followed by sequencing using Illumina HiSeq 2000 sequencer. Validation was performed by direct sequencing.\nRESULTS: The whole exome, including all exons of known ADCC disease-causing genes, was screened for possible disease-causing mutations. A recurrent missense mutation c.773C>T (p.S258F) in exon 2 of the gap junction protein alpha 8 gene (GJA8) was identified in the proband with nuclear cataract. The result was confirmed by direct sequencing. The mutation showed complete co-segregation with the disease phenotype in the family but was not observed in unrelated unaffected controls.\nCONCLUSION: By successfully sequencing whole exome of only one proband and identifying a GJA8 mutation in one ADCC pedigree, the current study demonstrated that exome sequencing could serve as a rapid, robust, and cost-effective approach in clinical diagnosis and disease-causing gene discovery for ADCC.","variants":[{"Name":"NM_005267.5(GJA8):c.773C>T (p.Ser258Phe)","Chromosome":"1","Start":"147908728","Stop":"147908728","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3412461,"rule_based_match":true,"evidence_text":"c.773C>T (p.S258F)","llm_judgment":"PRESENT","evidence":"c.773C>T (p.S258F)","abstract_start":879,"abstract_end":897}]}
{"pmid":"35670385","title":"PERCHING syndrome: Clinical presentation in the first African patient confirmed by clinical whole genome sequencing.","abstract":"PERCHING syndrome is a rare multisystem developmental disorder caused by autosomal recessive (AR) variants (truncating and missense) in the Kelch-like family member 7 gene (KLHL7). We report the first phenotypic and molecular description of PERCHING syndrome in a patient from Central Africa. The patient presented multiple dysmorphic features in addition to neurological, respiratory, gastroenteric, and dysautonomic disorders. Clinical Whole Genome Sequencing in the proband and his mother identified two novel heterozygous variants in the KLHL7 gene, including a maternally inherited intronic variant (NM_001031710.2:c.793 + 5G > C) classified as Variant of Uncertain Significance and a frameshift stop gain variant (NM_001031710.2:c.944delG; p.Ser315ThrfsTer23) of unknown inheritance classified as likely pathogenic. Although the diagnosis was only evoked after genomic testing, the review of published patients suggests that this disease could be clinically recognizable and maybe considered as an encephalopathy. Our report will allow expanding the phenotypic and molecular spectrum of Perching syndrome.","variants":[{"Name":"NM_001031710.3(KLHL7):c.944del (p.Ser315fs)","Chromosome":"7","Start":"23165705","Stop":"23165705","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":1332736,"rule_based_match":true,"evidence_text":"NM_001031710.2:c.944delG; p.Ser315ThrfsTer23","llm_judgment":"PRESENT","evidence":"NM_001031710.2:c.944delG; p.Ser315ThrfsTer23","abstract_start":720,"abstract_end":764},{"Name":"NM_001031710.3(KLHL7):c.793+5G>C","Chromosome":"7","Start":"23144030","Stop":"23144030","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":444113,"rule_based_match":true,"evidence_text":"NM_001031710.2:c.793 + 5G > C","llm_judgment":"PRESENT","evidence":"NM_001031710.2:c.793 + 5G > C","abstract_start":605,"abstract_end":634}]}
{"pmid":"36082568","title":"Genetic analysis of a case with Dubin-Johnson syndrome due to two novel variants of ABCC2 gene","abstract":"OBJECTIVE: To explore the genetic etiology and differential diagnosis for a patient with jaundice.\nMETHODS: Clinical data of the patient and his parents were collected. Genes associated with metabolic liver diseases were subjected to high-throughput sequencing. The pathogenicity of the candidate variants was predicted by using bioinformatics software.\nRESULTS: High-throughput sequencing revealed that the proband has harbored two variants of the ABCC2 gene (NM_000392) including c.3011C>T (p.T1004I) and c.3541C>T (p.R1181X), which were respectively inherited from his father and mother. Both variants have been previously unreported and predicted to be pathogenic by bioinformatics analysis.\nCONCLUSION: The proband was diagnosed with Dubin-Johnson syndrome due to the compound heterozygous variants of the ABCC2 gene. Genetic testing has enabled accurate differential diagnosis of Dubin-Johnson syndrome in this patient.","variants":[{"Name":"NM_000392.5(ABCC2):c.3011C>T (p.Thr1004Ile)","Chromosome":"10","Start":"99831738","Stop":"99831738","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":589427,"rule_based_match":true,"evidence_text":"c.3011C>T (p.T1004I)","llm_judgment":"PRESENT","evidence":"c.3011C>T (p.T1004I)","abstract_start":482,"abstract_end":502}]}
{"pmid":"23633203","title":"Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma.","abstract":"CONTEXT: Reports of the coexistence of pituitary adenomas and pheochromocytoma/paraganglioma are uncommon. Recently germline mutations in 2 of the genes encoding succinate dehydrogenase, SDHC and SDHD, were associated with pituitary tumors.\nOBJECTIVE: Our aim was to determine whether the development of a pituitary adenoma was associated with SDHA mutation.\nPATIENTS: A 46-year-old female presented with carotid body paraganglioma (proband). Subsequently the proband's son was diagnosed with a nonfunctioning pituitary macroadenoma at age 30 years.\nRESULTS: An immunohistochemical analysis of the resected paraganglioma and pituitary adenoma revealed the loss of succinate dehydrogenase subunit B and succinate dehydrogenase subunit A (SDHA) expression in both tumors, with the preservation of staining in nonneoplastic tissue. Mutation analysis showed a novel SDHA mutation (c.1873C>T, p.His625Tyr) in the germline of the proband as well as in the proband's son. In the paraganglioma of the proband, in addition to the germline mutation, a somatic mutation was observed (c.1865G>A, p.Trp622*). In the pituitary adenoma of the proband's son, loss of SDHA immunoreactivity was paradoxically accompanied by loss of the mutant allele.\nCONCLUSIONS: This is the first report of a pituitary adenoma arising in the setting of germline SDHA mutation. The loss of SDHA protein expression in both the paraganglioma (proband) and pituitary adenoma (proband's son) argues strongly for a causative role of SDHA mutation. This report further strengthens the link between pituitary neoplasia and germline SDH mutation. Although pituitary adenomas appear rare among patients carrying SDH subunit mutations, they may have been underrecognized due to the low penetrance of disease and lack of systematic surveillance.","variants":[{"Name":"NM_004168.4(SDHA):c.1873C>T (p.His625Tyr)","Chromosome":"5","Start":"254471","Stop":"254471","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":454980,"rule_based_match":true,"evidence_text":"c.1873C>T, p.His625Tyr","llm_judgment":"PRESENT","evidence":"c.1873C>T, p.His625Tyr","abstract_start":877,"abstract_end":899}]}
{"pmid":"29651865","title":"Compound Heterozygosity for Hb Alperton (HBB: c.407C>T) and IVS-I-5 (G>C) (HBB: c.92+5G>C) Mutations Presenting as a Moderate Anemia in an Indian Family.","abstract":"While knowledge of HBB gene mutations is necessary for offering prenatal diagnosis (PND) of β-thalassemia (β-thal), a genotype-phenotype correlation may not always be available for rare variants. We present for the first time, genotype-phenotype correlation for a compound heterozygous status with IVS-I-5 (G>C) (HBB: c.92+5G>C) and HBB: c.407C>T (Hb Alperton) mutations on the HBB gene in an Indian family. Hb Alperton is a very rare hemoglobin (Hb) variant with scant published information about its clinical presentation, especially when accompanied with another HBB gene mutation. Here we provide biochemical as well as clinical details of this variant.","variants":[{"Name":"NM_000518.5(HBB):c.407C>T (p.Ala136Val)","Chromosome":"11","Start":"5225635","Stop":"5225635","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2843348,"rule_based_match":true,"evidence_text":"HBB: c.407C>T (Hb Alperton)","llm_judgment":"PRESENT","evidence":"HBB: c.407C>T (Hb Alperton)","abstract_start":333,"abstract_end":360}]}
{"pmid":"29855340","title":"TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of α-dystroglycan and muscular dystrophy.","abstract":"BACKGROUND: Transport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb girdle muscular dystrophy and congenital muscular dystrophy. It remains unclear how this protein leads to muscle disease. Furthermore, a role for this protein, or any other membrane trafficking protein, in the etiology of the dystroglycanopathy group of muscular dystrophies has yet to be found. Here, using a multidisciplinary approach including genetics, immunofluorescence, western blotting, and live cell analysis, we implicate both TRAPPC11 and another membrane trafficking protein, GOSR2, in α-dystroglycan hypoglycosylation.\nCASE PRESENTATION: Subject 1 presented with severe epileptic episodes and subsequent developmental deterioration. Upon clinical evaluation she was found to have brain, eye, and liver abnormalities. Her serum aminotransferases and creatine kinase were abnormally high. Subjects 2 and 3 are siblings from a family unrelated to subject 1. Both siblings displayed hypotonia, muscle weakness, low muscle bulk, and elevated creatine kinase levels. Subject 3 also developed a seizure disorder. Muscle biopsies from subjects 1 and 3 were severely dystrophic with abnormal immunofluorescence and western blotting indicative of α-dystroglycan hypoglycosylation. Compound heterozygous mutations in TRAPPC11 were identified in subject 1: c.851A>C and c.965+5G>T. Cellular biological analyses on fibroblasts confirmed abnormal membrane trafficking. Subject 3 was found to have compound heterozygous mutations in GOSR2: c.430G>T and c.2T>G. Cellular biological analyses on fibroblasts from subject 3 using two different model cargo proteins did not reveal defects in protein transport. No mutations were found in any of the genes currently known to cause dystroglycanopathy in either individual.\nCONCLUSION: Recessive mutations in TRAPPC11 and GOSR2 are associated with congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. This is the first report linking membrane trafficking proteins to dystroglycanopathy and suggests that these genes should be considered in the diagnostic evaluation of patients with congenital muscular dystrophy and dystroglycanopathy.","variants":[{"Name":"NM_004287.5(GOSR2):c.430G>T (p.Gly144Trp)","Chromosome":"17","Start":"46935122","Stop":"46935122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39363,"rule_based_match":true,"evidence_text":"c.430G>T","llm_judgment":"PRESENT","evidence":"c.430G>T","abstract_start":1758,"abstract_end":1766},{"Name":"NM_004287.5(GOSR2):c.2T>G (p.Met1Arg)","Chromosome":"17","Start":"46923194","Stop":"46923194","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1314765,"rule_based_match":true,"evidence_text":"c.2T>G","llm_judgment":"PRESENT","evidence":"c.2T>G","abstract_start":1771,"abstract_end":1777},{"Name":"NM_021942.6(TRAPPC11):c.965+5G>T","Chromosome":"4","Start":"183679491","Stop":"183679491","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":453458,"rule_based_match":true,"evidence_text":"c.965+5G>T","llm_judgment":"PRESENT","evidence":"c.965+5G>T","abstract_start":1591,"abstract_end":1601}]}
{"pmid":"15712269","title":"Identification and characterization of five novel MAN2B1 mutations in Italian patients with alpha-mannosidosis.","abstract":"Mutation analysis performed on six Italian families with alpha-mannosidosis type II allowed the identification of five new mutations in the MAN2B1 gene: c.157G>T, c.562C>T, c.599A>T, c.293dupA, c.2402G>A (p.E53X, p.R188X, p.H200L, p.Y99VfsX61, p.G801D). Protein residues G801 and H200 are conserved among the four mammalian alpha-mannosidases cloned to date: human, cattle, cat and mouse. In vitro expression studies demonstrated that both missense mutations expressed no residual alpha-mannosidase activity indicating that they are disease-causing mutations. Modelling into the three-dimensional structure revealed that the p.H200L could involve the catalytic mechanism, whereas p.G801D would affect the correct folding of the enzyme.","variants":[{"Name":"NM_000528.4(MAN2B1):c.599A>T (p.His200Leu)","Chromosome":"19","Start":"12664823","Stop":"12664823","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":204514,"rule_based_match":true,"evidence_text":"c.599A>T","llm_judgment":"PRESENT","evidence":"c.599A>T","abstract_start":173,"abstract_end":181},{"Name":"NM_000528.4(MAN2B1):c.2402G>A (p.Gly801Asp)","Chromosome":"19","Start":"12649170","Stop":"12649170","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":204492,"rule_based_match":true,"evidence_text":"c.2402G>A (p.G801D)","llm_judgment":"PRESENT","evidence":"c.2402G>A","abstract_start":194,"abstract_end":203},{"Name":"NM_000528.4(MAN2B1):c.562C>T (p.Arg188Ter)","Chromosome":"19","Start":"12664860","Stop":"12664860","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":621629,"rule_based_match":true,"evidence_text":"c.562C>T","llm_judgment":"PRESENT","evidence":"c.562C>T","abstract_start":163,"abstract_end":171}]}
{"pmid":"25239229","title":"Identification of a founder mutation for Pendred syndrome in families from northwest Iran.","abstract":"OBJECTIVE: Mutations in the SLC26A4 gene cause both Pendred syndrome and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNB4 locus. The SLC26A4 mutations vary among different communities. Previous studies have shown that mutations in the SLC26A4 gene are responsible for the more common syndromic hereditary hearing loss in Iran. This study assesses the possibility of a founder mutation for Pendred syndrome in northwest Iran.\nMATERIALS AND METHODS: In this study, we performed comprehensive clinical and genetic evaluations in two unrelated families from northwest Iran with nine members affected by hearing loss (HL). After testing short tandem repeat (STR) markers to confirm linkage to the SLC26A4 locus, we screened the SLC26A4 gene by Sanger sequencing of all 21 exons, exon-intron boundaries and the promoter region for any causative mutation. We identified the same causative mutation in these two families as we had detected earlier in two other Azeri families from northwest Iran. To investigate the possibility of a founder effect in these four families, we conducted haplotype analysis, and 14 single nucleotide polymorphisms (SNPs) throughout the SLC26A4 gene were genotyped.\nRESULTS: Patients in the two families showed the phenotype of Pendred syndrome. A known frameshift mutation (c.965insA, p.N322Fs7X) in exon 8 was identified in the two families, which was the same mutation that we detected previously in two other Azeri families. The results of haplotype analysis showed that all 15 patients from four families shared the founder mutation. Common haplotypes were not observed in noncarrier members.\nCONCLUSIONS: Based on the results of our two studies, the c.965insA mutation has only been described in Iranian families from northwest Iran, so there is evidence for a founder mutation originating in this part of Iran.","variants":[{"Name":"NM_000441.2(SLC26A4):c.965dup (p.Asn322fs)","Chromosome":"7","Start":"107683494","Stop":"107683495","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":1170231,"rule_based_match":false,"evidence_text":"c.965insA","llm_judgment":"PRESENT","evidence":"c.965insA","abstract_start":1315,"abstract_end":1324}]}
{"pmid":"12497637","title":"Evaluation of Cx26/GJB2 in German hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and -493del10.","abstract":"Mutations in the connexin 26 gene (GJB2) are responsible for the major part of nonsyndromic autosomal recessive or apparently sporadic prelingual deafness in Caucasians (DFNB1). We screened 228 German hearing-impaired persons for mutations in the GJB2 gene by sequence analysis. Homozygous or compound heterozygous GJB2 mutations were detected in 38/228 (16.7%) of hearing impaired persons. The most frequently occurring mutation was the c.35delG mutation, which was found in 71.1% of the mutated alleles. The next frequent mutation detected in the group of hearing impaired persons was the c.101T>C mutation (9/76 alleles; 11.8%). One new mutation, c.567delA, was observed. We further studied the presence of a 10bp deletion in the 5' UTR of the GJB2 gene (c.-493del10) which was assumed to occur together with the c.101T>C mutation. Ten out of thirteen patients (76.9%) were found to be carriers of both the c.101T>C mutation and the 10bp variant and in 7/14 alleles a linkage disequilibrium between c.101T>C and the 10bp deletion was proven. In 4/14 alleles the linkage was ruled out and for the remaining 3 cases the phase determination was not possible. Seventy one controls were screened for the prevalence of Cx26 mutations and for the c.-493del10 variant. Heterozygosity frequency in the control group was for c.35delG 4.2%, for c.101T>C 1.4% and for c.-493del10 it was 5.6%.","variants":[{"Name":"NM_004004.6(GJB2):c.101T>C (p.Met34Thr)","Chromosome":"13","Start":"20189481","Stop":"20189481","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":32039,"rule_based_match":true,"evidence_text":"c.101T>C","llm_judgment":"PRESENT","evidence":"c.101T>C","abstract_start":591,"abstract_end":599}]}
{"pmid":"23234264","title":"Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.","abstract":"A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.","variants":[{"Name":"NM_000156.6(GAMT):c.577C>T (p.Gln193Ter)","Chromosome":"19","Start":"1397493","Stop":"1397493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2668800,"rule_based_match":true,"evidence_text":"c.577C > T","llm_judgment":"PRESENT","evidence":"c.577C > T","abstract_start":960,"abstract_end":970},{"Name":"NM_000156.6(GAMT):c.289C>T (p.Gln97Ter)","Chromosome":"19","Start":"1399831","Stop":"1399831","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1064665,"rule_based_match":true,"evidence_text":"c.289C > T","llm_judgment":"PRESENT","evidence":"c.289C > T","abstract_start":975,"abstract_end":985}]}
{"pmid":"28139822","title":"Bilateral striatal necrosis caused by ADAR mutations in two siblings with dystonia and freckles-like skin changes that should be differentiated from Leigh syndrome.","abstract":"Pathogenic molecular variants in the ADAR gene are a known cause of rare diseases, autosomal recessive Aicardi- Goutières syndrome type 6, severe infantile encephalopathy with intracranial calcifications and dominant dyschromatosis symmetrica hereditaria, demonstrated mainly in Asian adults. Recently, they have been also found in patients with nonsyndromic bilateral striatal necrosis accompanied by skin changes of the freckles-like type. Here, we present Polish siblings with acute onset and slowly progressive extrapyramidal syndrome with preserved intellectual abilities and basal ganglia changes found in MRI. A Leigh syndrome was considered for a long time as the most frequent cause of such lesions in children. Finally, two molecular variants in non-mitochondria-related ADAR gene c.3202+1G>A (p.?) and c.577C>G (p.Pro193Ala) were revealed by whole exome sequencing. We suggest that bilateral striatal necrosis should be always differentiated from LS to prevent the diagnosis delay. The striatal involvement accompanied by the presence of freckles-like skin changes should direct differential diagnosis to the ADAR gene mutations screening.","variants":[{"Name":"NM_001111.5(ADAR):c.577C>G (p.Pro193Ala)","Chromosome":"1","Start":"154602065","Stop":"154602065","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":131928,"rule_based_match":true,"evidence_text":"c.577C>G (p.Pro193Ala)","llm_judgment":"PRESENT","evidence":"c.577C>G (p.Pro193Ala)","abstract_start":813,"abstract_end":835}]}
{"pmid":"35099838","title":"De novo DYNC1H1 mutation causes infantile developmental and epileptic encephalopathy with brain malformations.","abstract":"BACKGROUND: The human dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene encodes a large subunit of the cytoplasmic dynein complex. DYNC1H1 mutations are associated with various neurological diseases involving both the peripheral and central nervous systems.\nMETHODS: The clinical characteristics and genetic data of an infant carrying the de novo DYNC1H1 variant identified by trio exome sequencing were analyzed. Patients with epilepsy with DYNC1H1 mutations were summarized by reviewing the literature.\nRESULTS: We first identified an infant presenting with epileptic spasms harboring a de novo missense mutation in DYNC1H1 (c.874C>T; p. Arg292Trp), once reported in an adult case, and further summarized another 54 patients with seizures or epilepsy caused by DYNC1H1 pathogenic variants in the literature. Refractory epilepsy, intellectual disability, and cortical developmental malformations are crucial characteristics of patients with developmental and epileptic encephalopathy (DEE) caused by DYNC1H1 variants. Notably, epileptic spasms in this case were resistant to multiple anti-seizure medications, corticosteroids, ketogenic diet, and vagus nerve stimulation treatment. The child also showed cortical gyrus malformation and global developmental delay.\nCONCLUSION: DYNC1H1 variants can cause infantile developmental and epileptic encephalopathy, in which Arg292Trp is a mutation hotspot of the DYNC1H1 gene. Epileptic seizures in this type of DYNC1H1-related DEE are mostly resistant to multiple antiepileptic strategies and need to explore optimized treatments.","variants":[{"Name":"NM_001376.5(DYNC1H1):c.874C>T (p.Arg292Trp)","Chromosome":"14","Start":"101980463","Stop":"101980463","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":789143,"rule_based_match":true,"evidence_text":"c.874C>T; p. Arg292Trp","llm_judgment":"PRESENT","evidence":"c.874C>T; p. Arg292Trp","abstract_start":627,"abstract_end":649}]}
{"pmid":"30886117","title":"From uncertainty to pathogenicity: clinical and functional interrogation of a rare","abstract":"Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by heterozygous germline mutations in the <i>TP53</i> gene. Although more than 200 missense and null <i>TP53</i> mutations are well established as disease-causing, little is known about the pathogenicity and cancer risks associated with small in-frame deletions. This leads to challenges in variant classification and subsequent difficulty making a molecular diagnosis. We report the genetic testing process for a pediatric patient diagnosed with an undifferentiated high-grade brain tumor following his mother's diagnosis of early-onset bilateral breast cancer. Sequential testing revealed that both harbored a heterozygous three-nucleotide deletion in exon 7 of <i>TP53</i> (c.764_766delTCA; I255del), which was classified as a variant of uncertain significance. Because the maternal family history was void of any other LFS spectrum tumors, additional information was needed to effectively classify the variant. Targeted <i>TP53</i> testing of the patient's maternal grandparents confirmed that neither carried the variant; this new de novo data upgraded the variant classification to likely pathogenic. To assess the impact of this mutation on the encoded p53 protein, additional in vitro analyses were performed. Structural modeling predicted that the deletion of isoleucine at codon 255 would disrupt the architecture of the DNA-binding domain, suggesting that it might negatively impact p53 function. Consistent with this notion, the I255del mutant protein exhibited significantly impaired transcriptional activity and greatly reduced growth suppressive properties, similar to more well-characterized LFS-associated p53 mutants. This report illustrates the importance of seeking additional evidence to assign proper pathogenicity classification, which enables optimal genetic counseling and medical management of individuals with LFS and their at-risk relatives.","variants":[{"Name":"NM_000546.6(TP53):c.761TCA[1] (p.Ile255del)","Chromosome":"17","Start":"7674197","Stop":"7674199","ReferenceAlleleVCF":"GTGA","AlternateAlleleVCF":"G","allel_id":410262,"rule_based_match":false,"evidence_text":"c.764_766delTCA; I255del","llm_judgment":"PRESENT","evidence":"c.764_766delTCA; I255del","abstract_start":764,"abstract_end":788}]}
{"pmid":"34642815","title":"WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins.","abstract":"Missense variants located in the N-terminal region of WDR37 were recently identified to cause a multisystemic syndrome affecting neurological, ocular, gastrointestinal, genitourinary, and cardiac development. WDR37 encodes a WD40 repeat-containing protein of unknown function. We identified three novel WDR37 variants, two likely pathogenic de novo alleles and one inherited variant of uncertain significance, in individuals with phenotypes overlapping those previously reported but clustering in a different region of the protein. The novel alleles are C-terminal to the prior variants and located either within the second WD40 motif (c.659A>G p.(Asp220Gly)) or in a disordered protein region connecting the second and third WD40 motifs (c.778G>A p.(Asp260Asn) and c.770C>A p.(Pro257His)). The three novel mutants showed normal cellular localization but lower expression levels in comparison to wild-type WDR37. To investigate the normal interactions of WDR37, we performed co-immunoprecipitation and yeast two-hybrid assays. This revealed the ability of WDR37 to form homodimers and to strongly bind PACS1 and PACS2 phosphofurin acidic cluster sorting proteins; immunocytochemistry confirmed colocalization of WDR37 with PACS1 and PACS2 in human cells. Next, we analyzed previously reported and novel mutants for their ability to dimerize with wild-type WDR37 and bind PACS proteins. Interaction with wild-type WDR37 was not affected for any variant; however, one novel mutant, p.(Asp220Gly), lost its ability to bind PACS1 and PACS2. In summary, this study presents a novel region of WDR37 involved in human disease, identifies PACS1 and PACS2 as major binding partners of WDR37 and provides insight into the functional effects of various WDR37 variants.","variants":[{"Name":"NM_014023.4(WDR37):c.659A>G (p.Asp220Gly)","Chromosome":"10","Start":"1096179","Stop":"1096179","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1269787,"rule_based_match":true,"evidence_text":"c.659A>G p.(Asp220Gly)","llm_judgment":"PRESENT","evidence":"c.659A>G p.(Asp220Gly)","abstract_start":636,"abstract_end":658},{"Name":"NM_014023.4(WDR37):c.778G>A (p.Asp260Asn)","Chromosome":"10","Start":"1103653","Stop":"1103653","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1269788,"rule_based_match":true,"evidence_text":"c.778G>A p.(Asp260Asn)","llm_judgment":"PRESENT","evidence":"c.778G>A p.(Asp260Asn)","abstract_start":739,"abstract_end":761},{"Name":"NM_014023.4(WDR37):c.770C>A (p.Pro257His)","Chromosome":"10","Start":"1103645","Stop":"1103645","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1269789,"rule_based_match":true,"evidence_text":"c.770C>A p.(Pro257His)","llm_judgment":"PRESENT","evidence":"c.770C>A p.(Pro257His)","abstract_start":766,"abstract_end":788}]}
{"pmid":"29409136","title":"Brief Report: Novel UNC13D Intronic Variant Disrupting an NF-κB Enhancer in a Patient With Recurrent Macrophage Activation Syndrome and Systemic Juvenile Idiopathic Arthritis.","abstract":"OBJECTIVE: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (JIA) and has pathologic similarity to hemophagocytic lymphohistiocytosis (HLH). Intronic variants in UNC13D are found in patients with familial HLH type 3 (FHLH3), but the role of noncoding variants in MAS is unknown. The objective of this study was to identify deep intronic UNC13D variants in patients with MAS.\nMETHODS: A custom enrichment library was constructed to sequence a genomic region of ~1 Mb flanking UNC13D in 24 patients with systemic JIA, recurrent MAS, and negative results of prior genetic (exon/coding) testing. The functional consequences of intronic variants were assessed using quantitative polymerase chain reaction in patient-derived peripheral blood mononuclear cells (PBMCs), electromobility shift assay, in vitro transcriptional enhancer assays, and natural killer (NK) cell degranulation assays.\nRESULTS: We evaluated a patient with systemic JIA and recurrent MAS in whom a novel functional intronic variant in UNC13D, c.117+143A>G, was observed. This variant occurred in a proposed regulatory region that drives lymphocyte-specific UNC13D expression and is associated with reduced transcript levels in patient PBMCs. This variant also disrupted NF-κB binding to a functional transcriptional enhancer, leading to reduced enhancer activity in vitro. Partial knockdown of UNC13D expression also led to impaired NK cell degranulation. An additional patient was identified with a previously described UNC13D intronic variant, for a total noncoding variant hit rate of 8.3% (2 of 24).\nCONCLUSION: These findings highlight the notion that intronic variants in key regulatory regions may be associated with MAS in patients with systemic JIA and support deep sequencing approaches when causative coding variants are not identified.","variants":[{"Name":"NM_199242.3(UNC13D):c.117+143A>G","Chromosome":"17","Start":"75844078","Stop":"75844078","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1289365,"rule_based_match":true,"evidence_text":"c.117+143A>G","llm_judgment":"PRESENT","evidence":"c.117+143A>G","abstract_start":1073,"abstract_end":1085}]}
{"pmid":"29756269","title":"Genetic and clinical features of Chinese patients with mitochondrial ataxia identified by targeted next-generation sequencing.","abstract":"AIM: To characterize the mutations in mitochondrial DNA (mtDNA) and mitochondrion-related nuclear genes (nDNA), and clinical features in Chinese patients with mitochondrial ataxia.\nMETHODS: Targeted next-generation sequencing (NGS) technology was performed to screen the whole mtDNA sequence and nDNA genes in a cohort of 33 unrelated ataxia patients.\nRESULTS: A total of 5 pedigrees were finally genetically diagnosed as mitochondrial ataxia, with 3 pathogenic mutations (m.8344A>G, m.9176T>C, and m.9185T>C), one likely pathogenic mutation (m.3995A>G) in mtDNA, and one pathogenic mutation (c.1159_1162dupAAGT, p.Ser388Terfs) in PDHA1. The prevalence of mitochondrial ataxia in our patient cohort is 15.2%. In addition, all 4 patients with mtDNA mutations experienced symptoms of ataxia with age at onset ranging from 12 to 39 years (21 ± 12.2) and developed extrapyramidal symptoms during the disease course. One male patient with pyruvate dehydrogenase deficiency showed an acute intermittent ataxia phenotype.\nCONCLUSIONS: Our results implicate that mitochondrial ataxia might not be as rare in Chinese as previously assumed. This study firstly defines the mutations of mitochondrial ataxia in a Chinese population by targeted NGS, which broadens the clinical spectrum of mtDNA mutations and highlights the importance of screening mtDNA and nDNA mutations among undefined ataxia patients.","variants":[{"Name":"NM_000284.4(PDHA1):c.1159_1162dup (p.Ser388Ter)","Chromosome":"X","Start":"19359637","Stop":"19359638","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TTAAG","allel_id":212021,"rule_based_match":true,"evidence_text":"c.1159_1162dupAAGT, p.Ser388Terfs","llm_judgment":"PRESENT","evidence":"c.1159_1162dupAAGT, p.Ser388Terfs","abstract_start":593,"abstract_end":626}]}
{"pmid":"19220582","title":"The R439C mutation in LMNA causes lamin oligomerization and susceptibility to oxidative stress.","abstract":"Dunnigan-type familial partial lipodystrophy (FPLD) is a laminopathy characterized by an aberrant fat distribution and a metabolic syndrome for which oxidative stress has recently been suggested as one of the disease-causing mechanisms. In a family affected with FPLD, we identified a heterozygous missense mutation c.1315C>T in the LMNA gene leading to the p.R439C substitution. Cultured patient fibroblasts do not show any prelamin A accumulation and reveal honeycomb-like lamin A/C formations in a significant percentage of nuclei. The mutation affects a region in the C-terminal globular domain of lamins A and C, different from the FPLD-related hot spot. Here, the introduction of an extra cysteine allows for the formation of disulphide-mediated lamin A/C oligomers. This oligomerization affects the interaction properties of the C-terminal domain with DNA as shown by gel retardation assays and causes a DNA-interaction pattern that is distinct from the classical R482W FPLD mutant. Particularly, whereas the R482W mutation decreases the binding efficiency of the C-terminal domain to DNA, the R439C mutation increases it. Electron spin resonance spectroscopy studies show significantly higher levels of reactive oxygen species (ROS) upon induction of oxidative stress in R439C patient fibroblasts compared to healthy controls. This increased sensitivity to oxidative stress seems independent of the oligomerization and enhanced DNA binding typical for R439C, as both the R439C and R482W mutants show a similar and significant increase in ROS upon induction of oxidative stress by H2O2.","variants":[{"Name":"NM_170707.4(LMNA):c.1315C>T (p.Arg439Cys)","Chromosome":"1","Start":"156136371","Stop":"156136371","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77701,"rule_based_match":true,"evidence_text":"c.1315C>T","llm_judgment":"PRESENT","evidence":"c.1315C>T","abstract_start":316,"abstract_end":325}]}
{"pmid":"31858365","title":"Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency.","abstract":"BACKGROUND: Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)-like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition.\nMETHODS: A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA.\nRESULTS: Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4<sup>+</sup> T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy.\nCONCLUSIONS: ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.","variants":[{"Name":"NM_012092.4(ICOS):c.356T>C (p.Phe119Ser)","Chromosome":"2","Start":"203955933","Stop":"203955933","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":815894,"rule_based_match":true,"evidence_text":"c.356T>C","llm_judgment":"PRESENT","evidence":"c.356T>C","abstract_start":1035,"abstract_end":1043}]}
{"pmid":"28478914","title":"Late-onset limb-girdle muscular dystrophy caused by GMPPB mutations.","abstract":"Mutations in GMPPB gene have been reported in patients with early-onset disease ranging from severe congenital muscular dystrophies to limb-girdle muscular dystrophy (LGMD) with mental retardation. More recently mutations in GMPPB have been identified with congenital myasthenic syndromes as well as milder phenotypes. We report two unrelated cases with LGMD that underwent clinical, histopathological and genetic studies. In both cases, we found identical compound heterozygous GMPPB mutations c.79G>C p.D27H and c.859C>T p.R287W, leading to a glycosylation defect of alpha-dystroglycan. The onset of muscle weakness was 30-40 years and the progression rate mild to moderate. Case 2 became wheelchair-bound at the age of 60. No cognitive or behavioral symptoms were noted. These cases provide further evidence that GMPPB mutations can also cause late-onset recessive LGMD with milder phenotypes than previously reported, and thus should be considered in the differential diagnosis of patients with adult-onset muscular dystrophies.","variants":[{"Name":"NM_021971.4(GMPPB):c.859C>T (p.Arg287Trp)","Chromosome":"3","Start":"49722057","Stop":"49722057","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227736,"rule_based_match":true,"evidence_text":"c.859C>T p.R287W","llm_judgment":"PRESENT","evidence":"c.859C>T p.R287W","abstract_start":514,"abstract_end":530},{"Name":"NM_021971.4(GMPPB):c.79G>C (p.Asp27His)","Chromosome":"3","Start":"49723648","Stop":"49723648","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":75127,"rule_based_match":true,"evidence_text":"c.79G>C p.D27H","llm_judgment":"PRESENT","evidence":"c.79G>C p.D27H","abstract_start":495,"abstract_end":509}]}
{"pmid":"20145675","title":"The USH2A c.2299delG mutation: dating its common origin in a Southern European population.","abstract":"Usher syndrome type II is the most common form of Usher syndrome. USH2A is the main responsible gene of the three known to be disease causing. It encodes two isoforms of the protein usherin. This protein is part of an interactome that has an essential role in the development and function of inner ear hair cells and photoreceptors. The gene contains 72 exons spanning over a region of 800 kb. Although numerous mutations have been described, the c.2299delG mutation is the most prevalent in several populations. Its ancestral origin was previously suggested after the identification of a common core haplotype restricted to 250 kb in the 5' region that encodes the short usherin isoform. By extending the haplotype analysis over the 800 kb region of the USH2A gene with a total of 14 intragenic single nucleotide polymorphisms, we have been able to define 10 different c.2299delG haplotypes, showing high variability but preserving the previously described core haplotype. An exhaustive c.2299delG/control haplotype study suggests that the major source of variability in the USH2A gene is recombination. Furthermore, we have evidenced twice the amount of recombination hotspots located in the 500 kb region that covers the 3' end of the gene, explaining the higher variability observed in this region when compared with the 250 kb of the 5' region. Our data confirm the common ancestral origin of the c.2299delG mutation.","variants":[{"Name":"NM_206933.4(USH2A):c.2299del (p.Glu767fs)","Chromosome":"1","Start":"216247095","Stop":"216247095","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"T","allel_id":17390,"rule_based_match":true,"evidence_text":"c.2299delG","llm_judgment":"PRESENT","evidence":"c.2299delG","abstract_start":447,"abstract_end":457}]}
{"pmid":"24338230","title":"Prenatal diagnosis of leukocyte adhesion deficiency type-1 (five cases from iran with two new mutations).","abstract":"Leukocyte adhesion deficiency type-1(LAD-1) is one of the immunodeficiency autosomal recessive diseases that results from mutation in integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) ITGB2 gene. The aim of this study was to investigate molecular prenatal diagnosis of LAD-1. Four pregnant women with five fetuses (one pregnancy was twin) with clinical and laboratory diagnosis of LAD-1 in their previous children were studied. The chorionic villus sampling (CVS) was obtained when mothers were in 10-12th weeks of gestation. Mutation analysis of ITGB2 gene for affected children revealed 3 misssense mutations (c.382G>A, a novel mutation, c.2146G>C, and c.715G>A) and one splice site novel mutation (c.1877+2G>A). All of Parents were heterozygous for these mutations. Consideration of affected gene regions for five CVS samples showed two homozygotes and one heterozygote for mutant allele and two homozygotes for normal allele. Interestingly, one of the twin fetuses was affected and another was normal. Briefly, two cases of CVS samples were affected and three cases of remained CVS samples were unaffected.This is the first report of prenatal diagnosis of LAD-1 from Iran with two new mutations that can be used for genetic and prenatal diagnosis for all patients suspected to LAD1 and can be helpful to prevent the birth of affected children with LAD-1. This abstract presented in the second international congress of Immunology, Asthma and Allergy, Tehran, Iran 2013.","variants":[{"Name":"NM_000211.5(ITGB2):c.382G>A (p.Asp128Asn)","Chromosome":"21","Start":"44903482","Stop":"44903482","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":24506,"rule_based_match":true,"evidence_text":"c.382G>A","llm_judgment":"PRESENT","evidence":"c.382G>A","abstract_start":629,"abstract_end":637}]}
{"pmid":"29226947","title":"Phenotype expansion and development in Kosaki overgrowth syndrome.","abstract":"We expand the Kosaki overgrowth syndrome (KOGS) phenotype by over 70% to include 24 unreported KOGS symptoms, in a first male patient, the third overall associated with the PDGFRB c.1751C>G p.(Pro584Arg) mutation. Eighteen of these symptoms are unique to our patient, the remaining six are shared with other patients. Of the 24 unreported features overall, 6 show marked phenotype evolution and varying time of onset. The triangular face detected at 14 months and long palpebral fissures with lateral ectropion at 4 years are present in other members of the cohort. The remaining 4 are unique to Patient 5: pronounced macrocephaly from birth, increasingly triangular anterior skull from 14 months, camptodactyly, emerging at 4 years and worsening joint contractures from 6 years. Compilation of all new symptoms reported here with published clinical data further identifies at least 18 clinical parameters common to all cases to date, encompassing both known KOGS-associated PDGFRB mutations. We therefore propose a set of 18 core KOGS symptoms, with 16 present in early childhood. These results should also impact diagnostic/prognostic scope, intervention and outcome potential for KOGS patients, particularly for developmentally progressive conditions such as scoliosis and myofibroma.","variants":[{"Name":"NM_002609.4(PDGFRB):c.1751C>G (p.Pro584Arg)","Chromosome":"5","Start":"150125501","Stop":"150125501","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":213767,"rule_based_match":true,"evidence_text":"PDGFRB c.1751C>G p.(Pro584Arg)","llm_judgment":"PRESENT","evidence":"PDGFRB c.1751C>G p.(Pro584Arg)","abstract_start":173,"abstract_end":203}]}
{"pmid":"37817461","title":"Novel HPD mutation p.A244V compound with p.T219M causing tyrosinemia type III in a Chinese girl and review of the genotype-phenotype spectrum.","abstract":"BACKGROUND: Hereditary tyrosinemia type III (HT III) is an extremely rare form of tyrosinemia, characterized by autosomal recessive inheritance and biallelic mutations in the HPD gene. The clinical presentation of HT III is variable and poorly understood, with symptoms ranging from developmental delay and intellectual impairment to seizures and intermittent ataxia. This study aimed to provide further insights into the clinical and genetic characteristics of HT III.\nMETHODS: A 3-year-old girl, identified through newborn screening, was diagnosed with HT III using targeted next-generation sequencing. A comprehensive literature review was conducted, and the clinical, biochemical, and genetic findings of previously reported HT III patients were summarized and analyzed.\nRESULTS: The genetic analysis of the proband revealed compound heterozygous mutations in the HPD gene such as c.731C>T (p.A244V) and c.656C>T (p.T219M). Notably, the HPD p.A244V mutation had not been previously documented in public databases or the scientific literature. Bioinformatics analysis classified both variants as pathogenic variants. The patient exhibited persistent tyrosinemia, elevated levels of related metabolite derivatives, confirming the diagnosis of HT III. The review of previously published cases contributed to a better understanding of the clinical and genetic characteristics associated with HT III.\nCONCLUSION: Early diagnosis and prompt treatment in infancy are crucial for managing HT III effectively. Dietary therapy, particularly during childhood, plays a significant role in disease management. The findings from this study enhance our understanding of the genotype-phenotype associations in HT III and emphasize the importance of early intervention for improved patient outcomes.","variants":[{"Name":"NM_002150.3(HPD):c.656C>T (p.Thr219Met)","Chromosome":"12","Start":"121847155","Stop":"121847155","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3544261,"rule_based_match":true,"evidence_text":"c.656C>T (p.T219M)","llm_judgment":"PRESENT","evidence":"c.656C>T (p.T219M)","abstract_start":908,"abstract_end":926}]}
{"pmid":"33000234","title":"Clinical characteristics and gene mutation analysis of an adult patient with ETFDH‑related multiple acyl‑CoA dehydrogenase deficiency.","abstract":"Multiple acyl‑CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive disorder of fatty acid metabolism caused by defects in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH). These defects are mainly classified into the neonatal and late‑onset types, based on their clinical manifestations. ETFDH gene mutations are generally considered to be associated with the late‑onset type. The present study reported an adult woman with late‑onset MADD accompanied with biochemical and muscle biopsy findings indicating metabolic disorders. Gene sequencing analysis showed that the c.1514T>C homozygous mutation in the region of the 12th exon of the ETFDH gene, which led to the amino acid substitution p.I505T (isoleucine > threonine), resulting in defective ETFDH protein function. The results of family verification revealed that the homozygous mutation originated from her parents. The female patient was treated with a large dose of vitamin B2, L‑carnitine and coenzyme Q10, and the symptoms were significantly relieved. The c.1514T>C mutation in the ETFDH gene, was considered as a novel pathogenic mutation that had not been previously reported. Therefore, it was hypothesized that this mutation was responsible for the clinical characteristics of the adult female patient. Overall, this novel mutation could expand the spectrum of the ETFDH gene mutation and provide the basis for the etiological and prenatal diagnosis of MADD.","variants":[{"Name":"NM_004453.4(ETFDH):c.1514T>C (p.Ile505Thr)","Chromosome":"4","Start":"158706674","Stop":"158706674","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1400767,"rule_based_match":true,"evidence_text":"c.1514T>C","llm_judgment":"PRESENT","evidence":"c.1514T>C","abstract_start":626,"abstract_end":635}]}
{"pmid":"14973782","title":"Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I.","abstract":"This study describes the discovery of a new inherited disorder of glycosylation named \"CDG-Ik.\" CDG-Ik (congenital disorder of glycoslyation type Ik) is based on a defect of human mannosyltransferase I (MT-I [MIM 605907]), an enzyme necessary for the elongation of dolichol-linked chitobiose during N-glycan biosynthesis. Mutations in semiconserved regions in the corresponding gene, HMT-1 (yeast homologue, Alg1), in two patients caused drastically reduced enzyme activity, leading to a severe disease with death in early infancy. One patient had a homozygous point mutation (c.773C-->T, S258L), whereas the other patient was compound heterozygous for the mutations c.773C-->T and c.1025A-->C (E342P). Glycosylation and growth of Alg1-deficient PRY56 yeast cells, showing a temperature-sensitive phenotype, could be restored by the human wild-type allele, whereas only slight restoration was observed after transformation with the patients' alleles.","variants":[{"Name":"NM_019109.5(ALG1):c.773C>T (p.Ser258Leu)","Chromosome":"16","Start":"5078789","Stop":"5078789","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19763,"rule_based_match":false,"evidence_text":"c.773C-->T","llm_judgment":"PRESENT","evidence":"c.773C-->T","abstract_start":577,"abstract_end":587}]}
{"pmid":"35533076","title":"Central Visual Function and Genotype-Phenotype Correlations in PDE6A-Associated Retinitis Pigmentosa.","abstract":"Purpose: Autosomal recessive retinitis pigmentosa (arRP) can be caused by mutations in the phosphodiesterase 6A (PDE6A) gene. Here, we describe the natural course of disease progression with respect to central retinal function (i.e., visual acuity, contrast sensitivity, and color vision) and establish a detailed genotype--phenotype correlation.\nMethods: Forty-four patients (26 females; mean age ± SD, 43 ± 13 years) with a confirmed genetic diagnosis of PDE6A-associated arRP underwent comprehensive ophthalmological examinations including best-corrected visual acuity (BCVA) with Early Treatment Diabetic Retinopathy Study charts, contrast sensitivity (CS) with Pelli-Robson charts at distances of 3 m and 1 m, and color vision testing using Roth 28-Hue and Panel D-15 saturated color cups.\nResults: The most frequently observed variants were c.998+1G>A/p.?, c.304C>A/p.R102S, and c.2053G>A/p.V685M. Central retinal function in patients homozygous for variant c.304C>A/p.R102S was better when compared to patients homozygous for variant c.998+1G>A/p.?, although the former were older at baseline. Central retinal function was similar in patients homozygous for variant c.304C>A/p.R102S and patients heterozygous for variants c.304C>A/p.R102S and c.2053G>A/p.V685M, although the latter were younger at baseline. Annual decline rates in central retinal function were small.\nConclusions: We conclude that the severity of the different disease-causing PDE6A mutations in humans with respect to central visual function may be ranked as follows: c.2053G>A/p.V685M in homozygous state (most severe) > c.998+1G>A/p.? in homozygous state > c.304C>A/p.R102S and c.2053G>A/p.V685M in compound-heterozygous state > c.304C>A/p.R102S in homozygous state (mildest). The assessment of treatment efficacy in interventional trials will remain challenging due to small annual decline rates in central retinal function.","variants":[{"Name":"NM_000440.3(PDE6A):c.304C>A (p.Arg102Ser)","Chromosome":"5","Start":"149944370","Stop":"149944370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":190264,"rule_based_match":true,"evidence_text":"c.304C>A/p.R102S","llm_judgment":"PRESENT","evidence":"c.304C>A/p.R102S","abstract_start":863,"abstract_end":879},{"Name":"NM_000440.3(PDE6A):c.998+1G>A","Chromosome":"5","Start":"149914942","Stop":"149914942","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":851268,"rule_based_match":true,"evidence_text":"c.998+1G>A/p.?","llm_judgment":"PRESENT","evidence":"c.998+1G>A/p.?","abstract_start":847,"abstract_end":861},{"Name":"NM_000440.3(PDE6A):c.2053G>A (p.Val685Met)","Chromosome":"5","Start":"149883511","Stop":"149883511","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38829,"rule_based_match":true,"evidence_text":"c.2053G>A/p.V685M","llm_judgment":"PRESENT","evidence":"c.2053G>A/p.V685M","abstract_start":885,"abstract_end":902}]}
{"pmid":"19087158","title":"Autosomal recessive hereditary spastic paraplegia with thin corpus callosum: a novel mutation in the SPG11 gene and further evidence for genetic heterogeneity.","abstract":"BACKGROUND AND PURPOSE: Autosomal Recessive Hereditary Spastic Paraplegia with Thin Corpus Callosum (AR-HSPTCC) is a clinically and genetically heterogeneous complicated form of spastic paraplegia. Two AR-HSPTCC loci have been assigned to chromosome 15q13-15 (SPG11) and chromosome 8p12-p11.21 respectively. Mutations in the SPG11 gene, encoding the spatacsin protein, have been found in the majority of SPG11 families. In this study, involvement of the SPG11 or 8p12-p11.21 loci was investigated in five Italian families, of which four consanguineous.\nMETHODS: Families were tested for linkage to the SPG11 or 8p12-p11.21 loci and the SPG11 gene was screened in all the affected individuals.\nRESULTS: Linkage was excluded in the four consanguineous families. In the only SPG11-linked family the same homozygous haplotype 4.2 cM across the SPG11 locus was shared by all the three affected siblings. A novel c.2608A>G mutation predicted to affect the splicing was found in exon 14 of the SPG11 gene.\nDISCUSSION: This collection of families contributes to highlight the intra and inter locus heterogeneity in AR-HSPTCC, already remarked in previous reports. In particular, it confirms heterogeneity amongst Italian families and reports a new mutation predicted to affect splicing in the spatacsin gene.","variants":[{"Name":"NM_025137.4(SPG11):c.2608A>G (p.Ile870Val)","Chromosome":"15","Start":"44621771","Stop":"44621771","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":49717,"rule_based_match":true,"evidence_text":"c.2608A>G","llm_judgment":"PRESENT","evidence":"c.2608A>G","abstract_start":907,"abstract_end":916}]}
{"pmid":"24458321","title":"Ramsay Hunt syndrome: clinical characterization of progressive myoclonus ataxia caused by GOSR2 mutation.","abstract":"BACKGROUND: Ramsay Hunt syndrome (progressive myoclonus ataxia) is a descriptive diagnosis characterized by myoclonus, ataxia, and infrequent seizures. Often the etiology cannot be determined. Recently, a mutation in the GOSR2 gene (c.430G>T, p.Gly144Trp) was reported in 6 patients with childhood-onset progressive ataxia and myoclonus.\nMETHODS: We evaluated 5 patients with cortical myoclonus, ataxia, and areflexia.\nRESULTS: All 5 patients had the same homozygous mutation in GOSR2. Here we present their clinical and neurophysiological data. Our patients (aged 7-26 years) all originated from the northern Netherlands and showed a remarkably homogeneous phenotype. Myoclonus and ataxia were relentlessly progressive over the years. Electromyography revealed signs of sensory neuronopathy or anterior horn cell involvement, or both, in all patients with absent reflexes.\nCONCLUSIONS: Based on the presented phenotype, we would advise movement disorder specialists to consider mutation analysis of GOSR2 in patients with Ramsay Hunt syndrome, especially when they also have areflexia.","variants":[{"Name":"NM_004287.5(GOSR2):c.430G>T (p.Gly144Trp)","Chromosome":"17","Start":"46935122","Stop":"46935122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39363,"rule_based_match":true,"evidence_text":"c.430G>T (p.Gly144Trp)","llm_judgment":"PRESENT","evidence":"p.Gly144Trp","abstract_start":243,"abstract_end":254}]}
{"pmid":"27896118","title":"Expanding the spectrum of","abstract":"Tay-Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-hexosaminidase-A (EC 3.2.1.52), resulting from the mutation in <i>HEXA</i> gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay-Sachs disease in nine patients confirmed by the deficiency of β-hexosaminidase-A (< 2% of total hexosaminidase activity for infantile patients) in leucocytes. The enzyme activity was assessed by using substrates 4-methylumbelliferyl-N-acetyl-β-d-glucosamine and 4-methylumbelliferyl-N-acetyl-β-d-glucosamine-6-sulfate for total-hexosaminidase and hexosaminidase-A respectively, and heat inactivation method for carrier detection. The exons and exon-intron boundaries of the <i>HEXA</i> gene were bi-directionally sequenced on an automated sequencer. 'In silico' analyses for novel mutations were carried out using SIFT, Polyphen2 and MutationT@ster software programs. The structural study was carried out by UCSF Chimera software using the crystallographic structure of β-hexosaminidase-A (PDB-ID: 2GJX) as the template. Our study identified four novel mutations in three cases. These include a compound heterozygous missense mutation c.524A>C (D175A) and c.805G>C (p.G269R) in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57) and one splice site mutation c.459+4A>C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i) c.532C>T (p.R178C), (ii) c.964G>T (p.D322Y), and (iii) c.1385A>T (p.E462V); two nonsense mutations (i) c.709C>T (p.Q237X) and (ii) c.1528C>T (p.R510X), one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5) and one splice site mutation c.459+5G>A were also identified in six cases. We observe from this study that novel mutations are more frequently observed in Indian patients with Tay-Sachs disease with clustering of ~ 73% of disease causing mutations in exons 5 to 12. This database can be used for a carrier rate screening in the larger population of the country.","variants":[{"Name":"NM_000520.6(HEXA):c.709C>T (p.Gln237Ter)","Chromosome":"15","Start":"72350614","Stop":"72350614","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":358307,"rule_based_match":true,"evidence_text":"c.709C>T (p.Q237X)","llm_judgment":"PRESENT","evidence":"c.709C>T (p.Q237X)","abstract_start":1769,"abstract_end":1787},{"Name":"NM_000520.6(HEXA):c.805G>C (p.Gly269Arg)","Chromosome":"15","Start":"72350518","Stop":"72350518","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":362123,"rule_based_match":true,"evidence_text":"c.805G>C (p.G269R)","llm_judgment":"PRESENT","evidence":"c.805G>C (p.G269R)","abstract_start":1346,"abstract_end":1364},{"Name":"NM_000520.6(HEXA):c.459+5G>A","Chromosome":"15","Start":"72353686","Stop":"72353686","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":361391,"rule_based_match":true,"evidence_text":"c.459+5G>A","llm_judgment":"PRESENT","evidence":"c.459+5G>A","abstract_start":1899,"abstract_end":1909},{"Name":"NM_000520.6(HEXA):c.524A>C (p.Asp175Ala)","Chromosome":"15","Start":"72353114","Stop":"72353114","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":362127,"rule_based_match":true,"evidence_text":"c.524A>C (D175A)","llm_judgment":"PRESENT","evidence":"c.524A>C (D175A)","abstract_start":1325,"abstract_end":1341},{"Name":"NM_000520.6(HEXA):c.459+4A>C","Chromosome":"15","Start":"72353687","Stop":"72353687","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":362129,"rule_based_match":true,"evidence_text":"c.459+4A>C","llm_judgment":"PRESENT","evidence":"c.459+4A>C","abstract_start":1460,"abstract_end":1470},{"Name":"NM_000520.6(HEXA):c.1528C>T (p.Arg510Ter)","Chromosome":"15","Start":"72344139","Stop":"72344139","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186933,"rule_based_match":true,"evidence_text":"c.1528C>T (p.R510X)","llm_judgment":"PRESENT","evidence":"c.1528C>T (p.R510X)","abstract_start":1797,"abstract_end":1816},{"Name":"NM_000520.6(HEXA):c.532C>T (p.Arg178Cys)","Chromosome":"15","Start":"72353106","Stop":"72353106","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18936,"rule_based_match":true,"evidence_text":"c.532C>T (p.R178C)","llm_judgment":"PRESENT","evidence":"c.532C>T (p.R178C)","abstract_start":1666,"abstract_end":1684}]}
{"pmid":"30385752","title":"Clinical Heterogeneity of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A French Multicenter Retrospective Study.","abstract":"OBJECTIVE: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disease caused by mutations in the forkhead box protein 3 gene (FOXP3), which encodes a key regulator of immune tolerance. The aim of this study was to describe the clinical heterogeneity of the disease in a national French cohort.\nMETHODS: Multicenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3.\nRESULTS: Thirty children from 26 families were included. Age at disease onset (median [first to third quartile]) was 1.5 mo [0-84] and at death 3.5 years [0-10.5] (n = 15) indicating a high heterogeneity. Initial presentation was diarrhoea (68%), type 1 diabetes (T1D; 25%), skin lesions (7%) and nephropathy (3%). During the course of the disease the following main symptoms were observed: diarrhoea (100%), skin lesions (85%), T1DM (50%), severe food allergies (39%), haematological disorders (28%), nephropathies (25%), hepatitis (14%) as well as the presence of a variety of autoantibodies. Immunosuppressive mono- or combination therapy led to improvement in eight children. Three boys displayed a stable disease course without any immunosuppressive medication. Overall 10-year survival rate was 43% (42% in transplanted patients and 52% in patients on immunosuppressive therapy). Five out of 22 identified FOXP3 mutations have not been described yet: c.-23 + 1G > A, c.-23 + 5G > A, c.264delC, c.1015C > T and c.1091A > G. The first two produced atypical, attenuated phenotypes. Missense and frameshift mutations affecting the forkhead domain were associated with poor survival (Gehan-Wilcoxon p = 0.002).\nCONCLUSION: The broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.","variants":[{"Name":"NM_014009.4(FOXP3):c.1091A>G (p.Tyr364Cys)","Chromosome":"X","Start":"49251719","Stop":"49251719","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3072955,"rule_based_match":true,"evidence_text":"c.1091A > G","llm_judgment":"PRESENT","evidence":"c.1091A > G","abstract_start":1468,"abstract_end":1479}]}
{"pmid":"31883530","title":"A novel mutation of ABHD5 gene in a Chanarin Dorfman patient with unusual dermatological findings.","abstract":"BACKGROUND: Chanarin Dorfman Syndrome (CDS) is a rare autosomal recessive disorder characterized by the multisytemic accumulation of neutral lipids inside the cytoplasmic lipid droplets. This condition is caused by mutations in the abhydrolase domain containing 5 gene (ABHD5). In CDS the skin involvement is the prevalent and always observed clinical feature, consisting of a non-bullous congenital ichthyosiform erythroderma (NCIE). Moreover, a variable involvement of the liver and neuromuscular system can be also observed. In this report, we aimed to perform the clinical and genetic characterization of a patient affected by CDS with atypical dermatological findings, considering this rare inborn error of neutral lipid metabolism.\nMETHODS: Genomic DNA samples obtained from patient and his parents were used to perform the sequencing of the ABHD5 exons and their intron/exon boundaries. Bioinformatic analyses were performed to investigate the possible effect of the identified mutation on protein structure.\nRESULTS: Here we present the case of a 29-year-old male patient with CDS, who, for long time, has been misdiagnosed as pityriasis rubra pilaris (PRP). He has a history of increasing hyperlipidemia; hepatomegaly associated with hepatosteatosis was also detected. ABHD5 molecular analysis revealed a novel missense mutation, the c.811G > A (p.G271R). Bioinformatic investigations showed that the variant has a deleterious effect on ABHD5 function, probably causing an incorrect folding of the mutant protein.\nCONCLUSIONS: These results highlihts the importance of genetic testing for ABHD5 in unresolved cases of patients presenting unusual skin lesions, that resemble PRP, associated with a history of hyperlipidemia and nonalcoholic fatty liver.","variants":[{"Name":"NM_016006.6(ABHD5):c.811G>A (p.Gly271Arg)","Chromosome":"3","Start":"43717708","Stop":"43717708","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":800846,"rule_based_match":true,"evidence_text":"c.811G > A (p.G271R)","llm_judgment":"PRESENT","evidence":"c.811G > A (p.G271R)","abstract_start":1343,"abstract_end":1363}]}
{"pmid":"29611532","title":"A disease-causing novel missense mutation in the ST14 gene underlies autosomal recessive ichthyosis with hypotrichosis syndrome in a consanguineous family.","abstract":"Autosomal recessive ichthyosis with hypotrichosis (ARIH; MIM 602400) syndrome is characterized by diffused congenital ichthyosis and generalized non-scarring hypotrichosis. The underlying genetic cause of ARIH syndrome has been associated with sequence variants of the gene ST14, encoding type II transmembrane serine protease matriptase, which maps to chromosome 11q24.3. The current report aimed to investigate the clinical features and genetic cause of ARIH syndrome in a large consanguineous family of Pakistani origin. The technique of homozygosity mapping with highly polymorphic microsatellite markers was employed to establish linkage within the family. Sanger sequencing of exons and intron-exon boundaries of ST14 was performed to identify the potential pathogenic sequence variants, followed by structural analysis of the mutated protein. Linkage was established to chromosome 11q24.3, comprising the gene ST14. Sequence analysis led to the identification of a novel homozygous missense variant (c.1315G>A, p.Gly439Ser) in the ST14 gene that co-segregated with the disease phenotype in all affected members. Homology modelling and molecular docking analysis of ST14 with wild-type TMEFF1 protein was performed which revealed that glycine at position 439 is crucial for maintaining normal structural confirmation and interaction with the EGF domain of TMEFF1 protein. Taken together, the data strongly advocate this ST14 variant as the underlying genetic cause of ARIH syndrome in this first reported affected family from Pakistan. Moreover, the present study adds to the spectrum of mutations in the ST14 gene, implicating them in the pathogenesis of ARIH syndrome.","variants":[{"Name":"NM_021978.4(ST14):c.1315G>A (p.Gly439Ser)","Chromosome":"11","Start":"130196661","Stop":"130196661","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":967125,"rule_based_match":true,"evidence_text":"c.1315G>A, p.Gly439Ser","llm_judgment":"PRESENT","evidence":"c.1315G>A, p.Gly439Ser","abstract_start":1007,"abstract_end":1029}]}
{"pmid":"28808920","title":"Prospective Turkish Cohort Study to Investigate the Frequency of Niemann-Pick Disease Type C Mutations in Consanguineous Families with at Least One Homozygous Family Member.","abstract":"BACKGROUND: Niemann-Pick disease Type C (NP-C) is a rare, autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. Diagnosis of NP-C can be challenging and is frequently delayed. Identifying mutations in individuals with NP-C and their relatives enables genetic counseling and prenatal diagnosis and may support earlier diagnosis. Here we report findings from a prospective cohort study in Turkey, using targeted genetic screening of the families of NP-C probands with homozygous NPC1 or NPC2 mutations.\nMETHODS: Probands were selected from a Turkish National Registration Database. Probands had confirmed diagnosis based on NPC1 or NPC2 mutations, with clear indication for consanguineous, homozygous inheritance. Family members were identified from interviews and pedigree analysis. Genetic analysis was performed on DNA from peripheral blood samples from all subjects.\nRESULTS: Four probands and 510 individuals from the four families were included. In these four families, the overall NPC1 or NPC2 heterozygous mutation frequency was 22.7%. A novel mutation was identified in NPC1 (p.T375P; c.1123A>C). A previously described NPC2 mutation (p.E118X; c.352G>T) was also observed in two families from different regions of Turkey. We identified two new patients with NP-C from two families.\nCONCLUSIONS: This is the largest screening study conducted to date in Turkey in the families of patients with NP-C with homozygous inheritance. We have reported heterozygote frequencies, identified a novel mutation, and detected new patients with NP-C. These findings will aid our understanding of NP-C and may lead to improved recognition and more timely diagnosis.","variants":[{"Name":"NM_006432.5(NPC2):c.352G>T (p.Glu118Ter)","Chromosome":"14","Start":"74484426","Stop":"74484426","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":23519,"rule_based_match":true,"evidence_text":"c.352G>T","llm_judgment":"PRESENT","evidence":"c.352G>T","abstract_start":1187,"abstract_end":1195}]}
{"pmid":"28344185","title":"Arthrogryposis as neonatal presentation of Loeys-Dietz syndrome due to a novel TGFBR2 mutation.","abstract":"Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized mainly by cardiovascular, craniofacial and skeletal features. We report on a patient with LDS, whose prenatal examination was compatible with the diagnosis of arthrogryposis multiplex congenita. Neonatal assessment showed craniofacial and cardiovascular findings suggestive of LDS whose diagnosis was confirmed by the detection of a novel mutation (HGVN: NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))) in the TGFBR2 gene. Few prenatal and neonatal cases of LDS have been reported in the literature. We reviewed all cases reported to date with perinatal onset to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome at an early stage to prevent fatal cardiovascular complications. Furthermore we discuss the multidisciplinary follow up required in these patients.","variants":[{"Name":"NM_003242.6(TGFBR2):c.1381T>C (p.Cys461Arg)","Chromosome":"3","Start":"30674231","Stop":"30674231","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":380155,"rule_based_match":true,"evidence_text":"NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))","llm_judgment":"PRESENT","evidence":"NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))","abstract_start":448,"abstract_end":497}]}
{"pmid":"23316014","title":"Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2.","abstract":"Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.","variants":[{"Name":"NM_015884.4(MBTPS2):c.1286G>A (p.Arg429His)","Chromosome":"X","Start":"21880921","Stop":"21880921","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26443,"rule_based_match":true,"evidence_text":"c.1286G>A (p.R429H)","llm_judgment":"PRESENT","evidence":"c.1286G>A (p.R429H)","abstract_start":1008,"abstract_end":1027},{"Name":"NM_015884.4(MBTPS2):c.1523A>G (p.Asn508Ser)","Chromosome":"X","Start":"21882618","Stop":"21882618","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":38911,"rule_based_match":true,"evidence_text":"c.1523A>G (p.N508S)","llm_judgment":"PRESENT","evidence":"c.1523A>G (p.N508S)","abstract_start":1050,"abstract_end":1069}]}
{"pmid":"30811539","title":"Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men.","abstract":"CONTEXT: The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare.\nRESULTS: We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity.\nCONCLUSIONS: Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype.","variants":[{"Name":"NM_013435.3(RAX):c.266del (p.Pro89fs)","Chromosome":"18","Start":"59272941","Stop":"59272941","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":1780689,"rule_based_match":true,"evidence_text":"c.266delC (p.Pro89Argfs*114)","llm_judgment":"PRESENT","evidence":"c.266delC (p.Pro89Argfs*114)","abstract_start":845,"abstract_end":873}]}
{"pmid":"34220820","title":"A Novel Non-Coding Variant in DCLRE1C Results in Deregulated Splicing and Induces SCID Through the Generation of a Truncated ARTEMIS Protein That Fails to Support V(D)J Recombination and DNA Damage Repair.","abstract":"Severe Combined Immune Deficiency (SCID) is a primary deficiency of the immune system in which opportunistic and recurring infections are often fatal during neonatal or infant life. SCID is caused by an increasing number of genetic defects that induce an abrogation of T lymphocyte development or function in which B and NK cells might be affected as well. Because of the increased availability and usage of next-generation sequencing (NGS), many novel variants in SCID genes are being identified and cause a heterogeneous disease spectrum. However, the molecular and functional implications of these new variants, of which some are non-coding, are often not characterized in detail. Using targeted NGS, we identified a novel homozygous c.465-1G>C splice acceptor site variant in the <i>DCLRE1C</i> gene in a T<sup>-</sup>B<sup>-</sup>NK<sup>+</sup> SCID patient and fully characterized the molecular and functional impact. By performing a minigene splicing reporter assay, we revealed deregulated splicing of the <i>DCLRE1C</i> transcript since a cryptic splice acceptor in exon 7 was employed. This induced a frameshift and the generation of a p.Arg155Serfs*15 premature termination codon (PTC) within all <i>DCLRE1C</i> splice variants, resulting in the absence of full-length ARTEMIS protein. Consistently, a V(D)J recombination assay and a G0 micronucleus assay demonstrated the inability of the predicted mutant ARTEMIS protein to perform V(D)J recombination and DNA damage repair, respectively. Together, these experiments molecularly and functionally clarify how a newly identified c.465-1G>C variant in the <i>DCLRE1C</i> gene is responsible for inducing SCID. In a clinical context, this demonstrates how the experimental validation of new gene variants, that are identified by NGS, can facilitate the diagnosis of SCID which can be vital for implementing appropriate therapies.","variants":[{"Name":"NM_001033855.3(DCLRE1C):c.465-1G>C","Chromosome":"10","Start":"14934776","Stop":"14934776","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1359314,"rule_based_match":true,"evidence_text":"c.465-1G>C","llm_judgment":"PRESENT","evidence":"c.465-1G>C","abstract_start":737,"abstract_end":747}]}
{"pmid":"36910710","title":"Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant","abstract":"Stargardt disease type 1 (STGD1) is the most common hereditary form of maculopathy and remains untreatable. STGD1 is caused by biallelic variants in the <i>ABCA4</i> gene, which encodes the ATP-binding cassette (type 4) protein (ABCA4) that clears toxic byproducts of the visual cycle. The c.5461-10T>C p.[Thr1821Aspfs∗6,Thr1821Valfs∗13] variant is the most common severe disease-associated variant, and leads to exon skipping and out-of-frame <i>ABCA4</i> transcripts that prevent translation of functional ABCA4 protein. Homozygous individuals typically display early onset STGD1 and are legally blind by early adulthood. Here, we applied antisense oligonucleotides (AONs) to promote exon inclusion and restore wild-type RNA splicing of <i>ABCA4</i> c.5461-10T>C. The effect of AONs was first investigated <i>in vitro</i> using an <i>ABCA4</i> midigene model. Subsequently, the best performing AONs were administered to homozygous c.5461-10T>C 3D human retinal organoids. Isoform-specific digital polymerase chain reaction revealed a significant increase in correctly spliced transcripts after treatment with the lead AON, QR-1011, up to 53% correct transcripts at a 3 μM dose. Furthermore, western blot and immunohistochemistry analyses identified restoration of ABCA4 protein after treatment. Collectively, we identified QR-1011 as a potent splice-correcting AON and a possible therapeutic intervention for patients harboring the severe <i>ABCA4</i> c.5461-10T>C variant.","variants":[{"Name":"NM_000350.3(ABCA4):c.5461-10T>C","Chromosome":"1","Start":"94011395","Stop":"94011395","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":98777,"rule_based_match":true,"evidence_text":"c.5461-10T>C","llm_judgment":"PRESENT","evidence":"c.5461-10T>C","abstract_start":290,"abstract_end":302}]}
{"pmid":"35782626","title":"Compound heterozygote variants: c.848A > G; p.Glu283Gly and c.890C > T; p.Ala297Val, of Isovaleric acid-CoA dehydrogenase","abstract":"With the execution of expanded newborn screen (NBS) program nationwide, it is uncommon to see severe hyperammonemia associated with isovaleric acidemia (IVA). We present a seven-day-old boy with severe IVA complicated by hyperammonemia. This child was flagged by NBS at 4 days old, but confirmatory testing was delayed due to COVID19 pandemic and parental skepticism. His parents did not adhere to the leucine-restricted diet as recommended. On day 7, the patient presented to the ER with ammonia of 588 μg/dL. Ammonia subsequently rose to >1000 μg/dL. This child received carnitine, 1 dose of Ammonul (sodium benzoate and sodium phenylacetate), arginine, carglumic acid (Carbaglu) and CRRT. Plasma amino acid assay revealed a glutamine level of 256 μmol/L, which is below the lower limit of normal upon arrival to ER and PICU. The hyperammonemia was corrected in 15 h and with the continued use of carglumic acid for 3 days, there was no rebound of hyperammonemia. However, the patient suffered from bone marrow suppression associated with the organic acidemia and required frequent platelet transfusions, as well as G-CSF for neutropenia. The management of this patient provides supporting evidence of the many theoretic metabolic \"facts\" including why Ammonul is not helpful in organic acidemias.","variants":[{"Name":"NM_002225.5(IVD):c.890C>T (p.Ala297Val)","Chromosome":"15","Start":"40415412","Stop":"40415412","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":200289,"rule_based_match":true,"evidence_text":"c.890C>T; p.Ala297Val","llm_judgment":"PRESENT","evidence":"c.890C>T; p.Ala297Val","abstract_start":null,"abstract_end":null},{"Name":"NM_002225.5(IVD):c.848A>G (p.Glu283Gly)","Chromosome":"15","Start":"40414952","Stop":"40414952","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":464753,"rule_based_match":true,"evidence_text":"c.848A > G; p.Glu283Gly","llm_judgment":"PRESENT","evidence":"c.848A > G; p.Glu283Gly","abstract_start":null,"abstract_end":null}]}
{"pmid":"26086840","title":"A homozygous B3GAT3 mutation causes a severe syndrome with multiple fractures, expanding the phenotype of linkeropathy syndromes.","abstract":"Linkeropathies are a group of syndromes characterized by short stature, radio-ulnar synostosis, decreased bone density, congenital contractures and dislocations, joint laxity, broad digits, brachycephaly, small mouth, prominent eyes, short or webbed neck, congenital heart defects and mild developmental delay. Linkeropathies are due to enzymatic defects in the synthesis of the common linker region that joins the core proteins to their glycosaminoglycan (GAG) side chains. The enzyme glucuronyltransferase 1, encoded by B3GAT3, adds the last four saccharides comprising the linker region. Mutations in B3GAT3 have been reported in two unrelated families with the same homozygous mutation (c.830G>A, p.Arg277Gln). We report on a patient with a novel homozygous B3GAT3 (c.667G>A, p.Gly223Ser) mutation and a history of multiple fractures, blue sclerae, and glaucoma. Our patient was a 12-month-old boy born to consanguineous parents and, like previously reported patients, he had bilateral radio-ulnar synostosis, severe osteopenia, an increased gap between first and second toes, bilateral club feet, and atrial and ventricular septal defects. He had the additional features of bilateral glaucoma, hypertelorism, upturned nose with anteverted nares, a small chest, a diaphragmatic hernia, multiple fractures, arachnodactyly, overlapping fingers with ulnar deviation, lymphedema, hypotonia, hearing loss, and perinatal cerebral infarction with bilateral supra- and infratentorial subdural hematomas. We highlight the extended phenotypic range of B3GAT3 mutations and a provide comparative overview of the phenotypic features of the linkeropathies associated with mutations in XYLT1, B4GALT7, B3GALT6, and B3GAT3.","variants":[{"Name":"NM_012200.4(B3GAT3):c.667G>A (p.Gly223Ser)","Chromosome":"11","Start":"62616748","Stop":"62616748","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227735,"rule_based_match":true,"evidence_text":"c.667G>A (p.Gly223Ser)","llm_judgment":"PRESENT","evidence":"p.Gly223Ser","abstract_start":780,"abstract_end":791}]}
{"pmid":"23598963","title":"A novel germline KIT mutation (p.L576P) in a family presenting with juvenile onset of multiple gastrointestinal stromal tumors, skin hyperpigmentations, and esophageal stenosis.","abstract":"Familial gastrointestinal stromal tumor (GIST) syndrome is a rare autosomal dominant genetic disorder. We report on a kindred in which 3 family members carry a germline mutation (c.1727T>C, p.L576P) in exon 11 of the KIT gene. This mutation was not reported so far in familial GISTs. Apart from multiple GISTs in 2 of the mutation carriers, all of them had multiple hyperpigmented skin macules and a history of achalasia-like stenosis of the esophagus in early childhood. In the index patient >100 tumors and a diffuse Cajal cell hyperplasia of the small bowel occurred. Sequencing of DNA extracted from tumor tissue of one of his GISTs revealed the KIT mutation in exon 11 (c.1727T>C). By array comparative genomic hybridization whole chromosomal gains 3, 5, 7, 9, 12, 15, and 18 were detected. In addition, we could identify a gain on chromosome 4, spanning the KIT gene. Together with the family described here, 24 unrelated cases with proven germline mutations in KIT have been reported. In these families the diagnosis was established from the age of 30 years onwards. Because in 1 patient reported here the GIST was a coincidental finding at the age of 15 years, the tumors might occur at a very young age and remain unnoticed until they-either due to increasing size, ulceration, or malignant progression-become symptomatic. Therefore, we propose to start screening patients with known KIT mutations from a younger age.","variants":[{"Name":"NM_000222.3(KIT):c.1727T>C (p.Leu576Pro)","Chromosome":"4","Start":"54727495","Stop":"54727495","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":362798,"rule_based_match":true,"evidence_text":"c.1727T>C","llm_judgment":"PRESENT","evidence":"c.1727T>C","abstract_start":179,"abstract_end":188}]}
{"pmid":"31410132","title":"Metachromatic leukodystrophy: Characterization of two (p.Leu433Val, p.Gly449Arg) arylsulfatase A mutations.","abstract":"Metachromatic leukodystrophy disorder (MLD) is an autosomal recessive lysosomal storage disease. The disease is primarily caused by a deficiency in the enzyme arylsulfatase A (ASA), which is encoded by the ARSA gene. A total of 254 mutations have been reported in different populations. The present study aimed to detect causative gene mutations in an atypical case presenting with attention deficit hyperactivity disorder through whole-exome sequencing. Of note, the patient's mother is from a consanguineous family. Compound heterozygous variants (c.1297C>G) + (c.1345G>A) [(p.Leu433Val) + (p.Gly449Arg)] were identified in exon 8 in the ARSA gene of the pediatric patient. The two missense mutations identified have not been previously reported, to the best of our knowledge. Furthermore, an <i>in silico</i> analysis and multiple phylogenetic tree analyses of ARSA homologs were performed to predict the effects of the two novel mutations. Serial changes were observed in the patient with MLD at follow-up visits over 6 years. However, brain MRI images demonstrated no notable progression and the number of ASA enzymes was stable. Also, the results of neurodevelopmental assessment showed that the patient was diagnose with ADHD. These data may offer a potential explanation of the genotype-phenotype correlation in MLD and enhance the spectrum of mutations associated with the condition.","variants":[{"Name":"NM_000487.6(ARSA):c.1297C>G (p.Leu433Val)","Chromosome":"22","Start":"50625378","Stop":"50625378","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":706022,"rule_based_match":true,"evidence_text":"c.1297C>G","llm_judgment":"PRESENT","evidence":"c.1297C>G","abstract_start":550,"abstract_end":559},{"Name":"NM_000487.6(ARSA):c.1345G>A (p.Gly449Arg)","Chromosome":"22","Start":"50625330","Stop":"50625330","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":758191,"rule_based_match":true,"evidence_text":"c.1345G>A","llm_judgment":"PRESENT","evidence":"c.1345G>A","abstract_start":564,"abstract_end":573}]}
{"pmid":"26374271","title":"Compound heterozygous variants in the LARP7 gene as a cause of Alazami syndrome in a Caucasian female with significant failure to thrive, short stature, and developmental disability.","abstract":"Alazami syndrome is an autosomal recessive disease characterized by primordial dwarfism, distinct dysmorphic features, and severe intellectual disability. Since it was first identified in a large consanguineous Arabic family in 2012, additional cases have not been published in the literature. We present a 2-year-old Northern European/Caucasian female with short stature, failure to thrive, and developmental delay. Whole exome sequencing (WES) identified two novel pathogenic variants in LARP7 (c.213_214dup and c.651_655del), indicating a diagnosis of Alazami syndrome. The case report describes a novel genotypic and phenotypic presentation of Alazami syndrome, contributing to the current knowledge of the condition as well as the expansion of differential diagnoses for growth restriction and intellectual disability.","variants":[{"Name":"NM_016648.4(LARP7):c.213_214dup (p.Ser72fs)","Chromosome":"4","Start":"112646356","Stop":"112646357","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GAT","allel_id":361804,"rule_based_match":true,"evidence_text":"c.213_214dup","llm_judgment":"PRESENT","evidence":"c.213_214dup","abstract_start":497,"abstract_end":509},{"Name":"NM_016648.3(LARP7):c.651_655del","Chromosome":"4","Start":"112647197","Stop":"112647201","ReferenceAlleleVCF":"CAGAAG","AlternateAlleleVCF":"C","allel_id":361805,"rule_based_match":true,"evidence_text":"c.651_655del","llm_judgment":"PRESENT","evidence":"c.651_655del","abstract_start":514,"abstract_end":526}]}
{"pmid":"32023010","title":"New phenotype of DCTN1-related spectrum: early-onset dHMN plus congenital foot deformity.","abstract":"OBJECTIVE: To describe the clinical and genetic features of two patients with different phenotypes due to various Dynactin 1 (DCTN1) gene mutations and further explore the phenotype-genotype relationship.\nMETHODS: Patient 1 is a 23-year-old man with congenital foot deformity and life-long distal muscle weakness and atrophy. Patient 2 is a 48-year-old woman with adult-onset progressive weakness, lower limbs atrophy, and pyramid bundle signs. Electrophysiology test showed normal nerve conduction velocity of both patients and neurogenic changes in needle electromyography. Open sural nerve biopsy for Patient 1 showed slight loss of myelinated nerve fibers. Both patients were performed with whole-exome sequencing followed by functional study of identified variants.\nRESULTS: Two mutations in DCTN1 gene were identified in Patient 1 (c.626dupC) and Patient 2 (c.3823C>T), respectively. In vitro, the wild type mostly located in cytoplasm and colocalized with α-tubulin. However, c.626dupC tended to be trapped into nuclear and the c.3823C>T formed cytoplasmic aggregates, both losing colocalization with α-tubulin. Western blotting showed a truncated mutant with less molecular weight of c.626dupC was expressed.\nINTERPRETATION: We identify two novel DCTN1 mutations causing different phenotypes: (1) early-onset distal hereditary motor neuropathy plus congenital foot malformation and (2) amyotrophic lateral sclerosis, respectively. We provide the initial evidence that foot developmental deficiency probably arises from subcellular localizing abnormality of Dynactin 1, revealing DCTN1-related spectrum is still expanding.","variants":[{"Name":"NM_004082.5(DCTN1):c.3823C>T (p.Arg1275Cys)","Chromosome":"2","Start":"74361513","Stop":"74361513","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1411041,"rule_based_match":true,"evidence_text":"c.3823C>T","llm_judgment":"PRESENT","evidence":"c.3823C>T","abstract_start":864,"abstract_end":873},{"Name":"NM_004082.5(DCTN1):c.626dup (p.Leu210fs)","Chromosome":"2","Start":"74371555","Stop":"74371556","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":1984283,"rule_based_match":true,"evidence_text":"c.626dupC","llm_judgment":"PRESENT","evidence":"c.626dupC","abstract_start":838,"abstract_end":847}]}
{"pmid":"20045868","title":"Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1.","abstract":"Distal arthrogryposis type I (DA1) is a disorder characterized by congenital contractures of the hands and feet for which few genes have been identified. Here we describe a five-generation family with DA1 segregating as an autosomal dominant disorder with complete penetrance. Genome-wide linkage analysis using Affymetrix GeneChip Mapping 10K data from 12 affected members of this family revealed a multipoint LOD(max) of 3.27 on chromosome 12q. Sequencing of the slow-twitch skeletal muscle myosin binding protein C1 (MYBPC1), located within the linkage interval, revealed a missense mutation (c.706T>C) that segregated with disease in this family and causes a W236R amino acid substitution. A second MYBPC1 missense mutation was identified (c.2566T>C)(Y856H) in another family with DA1, accounting for an MYBPC1 mutation frequency of 13% (two of 15). Skeletal muscle biopsies from affected patients showed type I (slow-twitch) fibers were smaller than type II fibers. Expression of a green fluorescent protein (GFP)-tagged MYBPC1 construct containing WT and DA1 mutations in mouse skeletal muscle revealed robust sarcomeric localization. In contrast, a more diffuse localization was seen when non-fused GFP and MYBPC1 proteins containing corresponding MYBPC3 amino acid substitutions (R326Q, E334K) that cause hypertrophic cardiomyopathy were expressed. These findings reveal that the MYBPC1 is a novel gene responsible for DA1, though the mechanism of disease may differ from how some cardiac MYBPC3 mutations cause hypertrophic cardiomyopathy.","variants":[{"Name":"NM_002465.4(MYBPC1):c.706T>C (p.Trp236Arg)","Chromosome":"12","Start":"101642459","Stop":"101642459","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":38755,"rule_based_match":true,"evidence_text":"c.706T>C","llm_judgment":"PRESENT","evidence":"c.706T>C","abstract_start":596,"abstract_end":604},{"Name":"NM_002465.4(MYBPC1):c.2566T>C (p.Tyr856His)","Chromosome":"12","Start":"101670362","Stop":"101670362","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":38756,"rule_based_match":true,"evidence_text":"c.2566T>C","llm_judgment":"PRESENT","evidence":"c.2566T>C","abstract_start":744,"abstract_end":753}]}
{"pmid":"24535794","title":"Mutation in the HTRA1 gene in a patient with degenerated spine as a component of CARASIL syndrome.","abstract":"AIM: To show the mutation in HTRA1 gene in a patient suffering from CARASIL syndrome with degenerated spine as a component of the disease.\nMATERIAL AND METHODS: We identified a family that one of the members had CARASIL syndrome in eastern Turkey and collected venous blood from available persons. The HTRA1 gene sequenced in all family members.\nRESULTS: C to T transition at position 1108 (c.1108 C > T) in exon 6, causing stop codon formation (R370X) was seen in the HTRA1 gene in a homozygous state in the CARASIL patient whereas it was heterozygous in other healthy family members.\nCONCLUSION: We demonstrated homozygous c.1108 C > T mutation in the HTRA1 gene causing a very rare syndrome, especially in the non- Japanese population, called CARASIL. Patients with degenerated spine and progressive clinical symptoms must be evaluated or reevaluated for other central nervous system symptoms and signs to rule out other diseases or syndromes.","variants":[{"Name":"NM_002775.5(HTRA1):c.1108C>T (p.Arg370Ter)","Chromosome":"10","Start":"122508758","Stop":"122508758","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22526,"rule_based_match":true,"evidence_text":"c.1108 C > T","llm_judgment":"PRESENT","evidence":"c.1108 C > T","abstract_start":391,"abstract_end":403}]}
{"pmid":"29754758","title":"Novel valosin-containing protein mutations associated with multisystem proteinopathy.","abstract":"Over fifty missense mutations in the gene coding for valosin-containing protein (VCP) are associated with a unique autosomal dominant adult-onset progressive disease associated with combinations of proximo-distal inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). We report the clinical, histological, and molecular findings in four new patients/families carrying novel VCP mutations: c.474 G > A (p.M158I); c.478 G > C (p.A160P); c.383G > C (p.G128A); and c.382G > T (p.G128C). Clinical features included myopathy, PDB, ALS and Parkinson's disease though frontotemporal dementia was not an associated feature in these families. One of the patients was noted to have severe manifestations of PDB and was suspected of having neoplasia. There were wide inter- and intra-familial variations making genotype-phenotype correlations difficult between the novel mutations and frequency or age of onset of IBM, PDB, FTD, ALS and Parkinson's disease. Increasing awareness of the full spectrum of clinical presentations will improve diagnosis of VCP-related diseases and thus proactively manage or prevent associated clinical features such as PDB.","variants":[{"Name":"NM_007126.5(VCP):c.383G>C (p.Gly128Ala)","Chromosome":"9","Start":"35066737","Stop":"35066737","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":425845,"rule_based_match":true,"evidence_text":"c.383G>C (p.G128A)","llm_judgment":"PRESENT","evidence":"c.383G > C (p.G128A)","abstract_start":514,"abstract_end":534},{"Name":"NM_007126.5(VCP):c.478G>C (p.Ala160Pro)","Chromosome":"9","Start":"35065349","Stop":"35065349","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":524559,"rule_based_match":true,"evidence_text":"c.478 G > C (p.A160P)","llm_judgment":"PRESENT","evidence":"c.478 G > C (p.A160P)","abstract_start":491,"abstract_end":512}]}
{"pmid":"18402384","title":"Early onset Alexander disease: a case report with evidence for manifestation of the disorder in neurohypophyseal pituicytes.","abstract":"We report the first case of Alexander disease diagnosed and published in the region of former Czechoslovakia. The case was characterized by early (late infantile) onset, the absence of megacephaly but with extensive internal hydrocephaly, despite a patent aqueduct. Neuropathology revealed severe depletion ofoligodendroglia and myelin, loss of axons, prominent astrocytosis with massive intracellular, dense globular GFAP aggregates which differed from typical Rosenthal fibers. Additionally, many large aggregates of GFAP were located extracellularly. Globular GFAP aggregates were also identified in neurohypophyseal pituicytes. DNA analysis disclosed a heterozygous mutation c.1117G>A in the GFAP, which is predicted to lead to the amino acid exchange p.Glu-373Lys (E373K) in the C-terminal tail of the GFAP protein. The parents and a healthy sister did not show any variation in GFAP in somatic cells.","variants":[{"Name":"NM_002055.5(GFAP):c.1117G>A (p.Glu373Lys)","Chromosome":"17","Start":"44911246","Stop":"44911246","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77336,"rule_based_match":true,"evidence_text":"c.1117G>A","llm_judgment":"PRESENT","evidence":"c.1117G>A","abstract_start":679,"abstract_end":688}]}
{"pmid":"23775976","title":"HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.","abstract":"Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia.","variants":[{"Name":"NM_006735.4(HOXA2):c.703C>T (p.Gln235Ter)","Chromosome":"7","Start":"27101154","Stop":"27101154","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":94414,"rule_based_match":true,"evidence_text":"c.703C>T, p.Q235*","llm_judgment":"PRESENT","evidence":"c.703C>T, p.Q235*","abstract_start":416,"abstract_end":433}]}
{"pmid":"30661074","title":"Possible Digenic Disease in a Caucasian Family with COL4A3 and COL4A5 Mutations.","abstract":"Microscopic hematuria is a common feature of patients with Alport syndrome, a familial nephropathy due to mutations in COL4A3, COL4A4 or COL4A5. These genes encode for α3, α4, and α5 type IV collagen polypeptide chains (collagen IV α345), crucial for the structural component of the glomerular basement membrane. Even patients with mild phenotype, namely isolated microhematuria (X-linked females with thin basement membrane on electron microscopy or heterozygous carriers of COL4A3 or COL4A4 mutations), can potentially progress to proteinuria and to end-stage renal disease. Recent pedigree analyses provided evidence for digenic inheritance of Alport syndrome by concomitant mutations in COL4A3/COL4A4 or COL4A4/COL4A5. We describe a Caucasian family with concomitant COL4A3 and COL4A5 mutations, consisting of a novel c.4484A>G COL4A3 (p.Gln1495Arg) mutation and a previously reported c.1871G>A COL4A5 (p.Gly624Asp) mutation. Our segregation analysis raises the possibility that Alport syndrome resembles also digenic inheritance by COL4A3/COL4A5.","variants":[{"Name":"NM_000091.5(COL4A3):c.4484A>G (p.Gln1495Arg)","Chromosome":"2","Start":"227308920","Stop":"227308920","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":250651,"rule_based_match":true,"evidence_text":"c.4484A>G COL4A3 (p.Gln1495Arg)","llm_judgment":"PRESENT","evidence":"c.4484A>G COL4A3 (p.Gln1495Arg)","abstract_start":822,"abstract_end":853},{"Name":"NM_033380.3(COL4A5):c.1871G>A (p.Gly624Asp)","Chromosome":"X","Start":"108598793","Stop":"108598793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":35796,"rule_based_match":true,"evidence_text":"c.1871G>A COL4A5 (p.Gly624Asp)","llm_judgment":"PRESENT","evidence":"c.1871G>A COL4A5 (p.Gly624Asp)","abstract_start":889,"abstract_end":919}]}
{"pmid":"27604406","title":"The importance of chilblains as a diagnostic clue for mild Aicardi-Goutières syndrome.","abstract":"Aicardi-Goutières syndrome (AGS) is classically characterized by early-onset encephalopathy. However, in some cases, the presenting symptom of concern may actually be cutaneous rather than neurological, leading to the misdiagnosis of the condition. We report the case of three teenage siblings who presented with a lifetime history of chilblain lesions, only one of whom had notable neurologic deficits. Additional findings included acrocyanosis, Raynaud's phenomenon, low-pitch hoarse voice, headache, and arthritis. They were found to have two pathogenic sequence variants in the SAMHD1 gene: a c.602T>A substitution resulting in p.Ile201Asn protein change, previously reported as a pathogenic mutation, as well as a deletion c.719delT which has not been previously reported but results in a predicted pathogenic frame shift mutation. It is important to consider the diagnosis of AGS in patients and families with chilblain lesions in the presence of unexplained neurologic and rheumatic symptoms. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_015474.4(SAMHD1):c.602T>A (p.Ile201Asn)","Chromosome":"20","Start":"36930783","Stop":"36930783","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":39562,"rule_based_match":true,"evidence_text":"c.602T>A","llm_judgment":"PRESENT","evidence":"c.602T>A","abstract_start":597,"abstract_end":605}]}
{"pmid":"29764576","title":"NIPBL gene mutations in two children with Cornelia de Lange syndrome","abstract":"Both children (one boy and one girl) experienced disease onset in infancy and visited the hospital due to growth retardation. They had unusual facies including thick hair, arched and confluent eyebrows, long and curly eyelashes, short nose, and micrognathia. Patient 1 had congenital heart disease (atrial septal defect and pulmonary stenosis) and special dermatoglyph (a single palmar crease). Patient 2 had cleft palate and moderate-to-severe deafness. Clinical features suggested Cornelia de Lange syndrome in both children. High-throughput sequencing was used to detect the seven known pathogenic genes of Cornelia de Lange syndrome, i.e., the NIPBL, SMC1A, SMC3, HDAC8, RAD21, EP300, and ANKRD11 genes. Sanger sequencing was used to analyze and verify gene mutations. Both patients were found to have novel mutations in the NIPBL gene. One patient had a frameshift mutation in exon 45, c.7834dupA, which caused early termination of translation and produced truncated protein p.R2612fsX20. The other patient had a nonsense mutation, c.505C>T, which caused a premature stop codon and produced truncated protein Q169X. Such mutations were not found in their parents or 50 unrelated healthy individuals.","variants":[{"Name":"NM_133433.4(NIPBL):c.7834dup (p.Arg2612fs)","Chromosome":"5","Start":"37060988","Stop":"37060989","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GA","allel_id":1690244,"rule_based_match":true,"evidence_text":"c.7834dupA","llm_judgment":"PRESENT","evidence":"c.7834dupA","abstract_start":891,"abstract_end":901}]}
{"pmid":"19820004","title":"Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis.","abstract":"CONTEXT: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a metabolic disorder due to homozygous loss-of-function mutations in the SLC34A3 gene encoding the renal type IIc sodium-phosphate cotransporter (NaPi-IIc). The typical presentation is severe rickets and hypophosphatemia, and hypercalciuria is often discovered later or overlooked.\nOBJECTIVE: We sought to determine the genetic basis for severe hypercalciuria and nephrolithiasis/nephrocalcinosis in an adolescent male with elevated serum levels of calcitriol but normal serum levels of calcium and phosphorus.\nDESIGN AND SETTING: We used PCR to analyze the SLC34A3 gene in the proband and members of his family.\nRESULTS: The proband was a compound heterozygote for two SLC34A3 missense mutations, a novel c.544C-->T in exon 6 that results in replacement of arginine at position 182 by tryptophan (R182W) and c.575C-->T in exon 7 that results in replacement of serine at position 192 by leucine (S192L). The R182W and S192L alleles were inherited from the mother and father, respectively, both of whom had hypercalciuria. A clinically unaffected brother was heterozygous for S192L.\nCONCLUSION: We report a novel mutation in the SLC34A3 gene in a patient with an unusual presentation of HHRH. This report emphasizes that moderate and severe hypercalciuria can be manifestations of heterozygous or homozygous loss-of-function mutations in the SLC34A3 gene, respectively, providing further evidence for a gene dosage effect in determining the phenotype. HHRH may be an underdiagnosed condition that can masquerade as idiopathic hypercalciuria or osteopenia.","variants":[{"Name":"NM_001177316.2(SLC34A3):c.544C>T (p.Arg182Trp)","Chromosome":"9","Start":"137233099","Stop":"137233099","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1448529,"rule_based_match":false,"evidence_text":"c.544C-->T","llm_judgment":"PRESENT","evidence":"c.544C-->T","abstract_start":781,"abstract_end":791},{"Name":"NM_001177316.2(SLC34A3):c.575C>T (p.Ser192Leu)","Chromosome":"9","Start":"137233223","Stop":"137233223","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":195771,"rule_based_match":false,"evidence_text":"c.575C-->T in exon 7 that results in replacement of serine at position 192 by leucine (S192L)","llm_judgment":"PRESENT","evidence":"c.575C-->T in exon 7 that results in replacement of serine at position 192 by leucine (S192L)","abstract_start":884,"abstract_end":977}]}
{"pmid":"26197978","title":"Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy.","abstract":"Autosomal recessive cerebellar ataxia (ARCA) is a group of neurological disorders characterized by degeneration or abnormal development of the cerebellum and spinal cord. ARCA is clinically and genetically highly heterogeneous, with over 20 genes involved. Exome sequencing of a girl with ARCA from non-consanguineous Dutch parents revealed two pathogenic variants c.37G>C; p.D13H and c.946A>T; p.K316* in CWF19L1, a gene with an unknown function, recently reported to cause ARCA in a Turkish family. Sanger sequencing showed that the c.37G>C variant was inherited from the father and the c.946A>T variant from the mother. Pathogenicity was based on the damaging effect on protein function as the c.37G>C variant changed the highly conserved, negatively charged aspartic acid to the positively charged histidine and the c.946A>T variant introduced a premature stop codon. In addition, 27 patients with ARCA were tested for pathogenic variants in CWF19L1, however, no pathogenic variants were identified. Our data confirm CWF19L1 as a novel but rare gene causing ARCA.","variants":[{"Name":"NM_018294.6(CWF19L1):c.946A>T (p.Lys316Ter)","Chromosome":"10","Start":"100245817","Stop":"100245817","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":247629,"rule_based_match":true,"evidence_text":"c.946A>T (p.K316*)","llm_judgment":"PRESENT","evidence":"c.946A>T","abstract_start":385,"abstract_end":393}]}
{"pmid":"24086941","title":"Sequence variation data of F8 and F9 genes in functionally validated control individuals: implications on the molecular diagnosis of hemophilia.","abstract":"BACKGROUND: The F8 and F9 genes encode for coagulation factor VIII (FVIII) and FIX, respectively, and mutations in these genes are the genetic basis of hemophilia A/B. To determine whether a sequence variation in F8/F9 is a disease-causing mutation, frequency data from a control population is needed. This study aimed to obtain data on sequence variation in F8/F9 in a set of functionally validated control chromosomes of Korean descent.\nMETHODS: We re-sequenced F8 and F9 from DNA samples of 100 Korean male control individuals with normal PT, aPTT, and FVIII activity. PCR and direct sequencing analyses were performed using primer pairs to cover all coding regions and the flanking intronic sequences.\nRESULTS: Thirteen individuals (13%) were hemizygous for sequence variations in the coding region of F8. Six (6%) had c.3780C>G (p.Asp1260Glu), five (5%) had c.3864A>C (p.Ser1288=). One each individual (1%) had c.4794G>T (p.Glu1598Asp) and c.5069 A>G (p.Glu1690Gly). Asp1260Glu and Ser1288= were known SNPs (rs1800291 and rs1800292, respectively). Glu1598Asp was assigned as a missense mutation in public databases (HGMD and HAMSTeRS), and Glu1690Gly was a novel variation. Based on the normal FVIII activities in control individuals carrying these variations (109% and 148%, respectively), they were considered to be rare SNPs. No variation was observed in F9 of control individuals.\nCONCLUSION: A significant proportion of control individuals carried sequence variations in F8, but not in F9. These results can be used as a reference dataset for molecular diagnosis of hemophilia A and B, particularly in Korea.","variants":[{"Name":"NM_000132.4(F8):c.3780C>G (p.Asp1260Glu)","Chromosome":"X","Start":"154930010","Stop":"154930010","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":49421,"rule_based_match":true,"evidence_text":"c.3780C>G (p.Asp1260Glu)","llm_judgment":"PRESENT","evidence":"c.3780C>G (p.Asp1260Glu)","abstract_start":823,"abstract_end":847},{"Name":"NM_000132.4(F8):c.3864A>C (p.Ser1288=)","Chromosome":"X","Start":"154929926","Stop":"154929926","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":49422,"rule_based_match":true,"evidence_text":"c.3864A>C (p.Ser1288=)","llm_judgment":"PRESENT","evidence":"c.3864A>C (p.Ser1288=)","abstract_start":863,"abstract_end":885}]}
{"pmid":"23093699","title":"MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism.","abstract":"OBJECTIVE: Primary hyperparathyroidism (pHPT) is characterised by an inappropriate over production of parathyroid hormone and it is the most frequent pathological condition of the parathyroid glands. A minority of the cases belong to familial forms, but most of them are sporadic. The genetic alterations underlying the sporadic forms of pHPT remain poorly understood. The main goal of our study is to perform the molecular characterisation of a series of sporadic pHPT cases.\nDESIGN AND METHODS: We have studied matched blood and tumour from 24 patients with pHPT, who went to a medical appointment in Hospital Pedro Hispano. Informed consent was obtained from all individuals. The MEN1, RET and CDKN1B molecular study was carried out in the germline DNA by PCR/SSCP and direct sequencing. Parathyroid tumours were further analysed by the same methods for MEN1, CDKN1B and CTNNB1 genetic alterations. The multiplex ligation-dependent probe amplification technique enabled the evaluation of MEN1 gene deletions. Protein expression for menin, cyclin D1, parafibromin, p27(Kip1), β-catenin and Ki-67 was conducted by immunohistochemistry.\nRESULTS: The study of parathyroid tumours detected two somatic MEN1 mutations (c.249_252delGTCT and c.115_163del49bp) and revealed the presence of MEN1 intragenic deletions in 54% (13/24) of the tumours. In RET and CDKN1B genes only previously described, non-pathogenic variants were found. Cyclin D1 protein was overexpressed in 13% (3/24) of tumours.\nCONCLUSIONS: These results suggest that MEN1 alterations, remarkably intragenic deletions, may represent the most prevalent genetic alteration in sporadic parathyroid tumours.","variants":[{"Name":"NM_001370259.2(MEN1):c.249_252del (p.Ile85fs)","Chromosome":"11","Start":"64809858","Stop":"64809861","ReferenceAlleleVCF":"TAGAC","AlternateAlleleVCF":"T","allel_id":31732,"rule_based_match":true,"evidence_text":"c.249_252delGTCT","llm_judgment":"PRESENT","evidence":"c.249_252delGTCT","abstract_start":1216,"abstract_end":1232}]}
{"pmid":"28043061","title":"FARS2 mutation and epilepsy: Possible link with early-onset epileptic encephalopathy.","abstract":"Early-onset epileptic encephalopathy (EOEE) consists of a heterogeneous group of epilepsy phenotypes. Recent technological advances in molecular biology have also rapidly expanded the genotype of EOEE. Genes involved in diverse molecular pathways, including ion channels, synaptic structure, transcription regulation, and cellular growth, have been implicated in EOEE. Mitochondrial aminoacyl tRNA synthetase, which plays a key role in mitochondrial protein synthesis by attaching 20 different amino acids to the tRNA tail, has been recently linked with the epilepsy phenotype. Here, we report a novel homozygous c.925G>A (G309S) missense mutation in the gene that encodes the human mitochondrial phenylalanyl-tRNA synthetase (FARS2) in four patients from two nonconsanguineous Korean families. All four patients suffered from intractable seizures that started at the age of 3 and 4 months. Seizure types were variable, including infantile spasms and myoclonic seizures, and often prolonged. Although their initial development seemed to be normal, relentless regression after seizure onset occurred in all patients. An etiologic investigation, including brain imaging and metabolic studies, did not reveal a specific etiology. We reviewed the epilepsy phenotypes of six additional FARS2 mutation-positive patients and suggest that FARS2 can be considered one of the genetic causes of EOEE.","variants":[{"Name":"NM_006567.5(FARS2):c.925G>A (p.Gly309Ser)","Chromosome":"6","Start":"5545200","Stop":"5545200","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":578624,"rule_based_match":true,"evidence_text":"c.925G>A (G309S)","llm_judgment":"PRESENT","evidence":"c.925G>A (G309S)","abstract_start":613,"abstract_end":629}]}
{"pmid":"31795264","title":"Contribution of a Novel","abstract":"Anterior segment dysgenesis (ASD) encompasses a spectrum of ocular disorders affecting the structures of the anterior eye chamber. Mutations in several genes, involved in eye development, are implicated in this disorder. ASD is often accompanied by diverse multisystemic symptoms and another genetic cause, such as variants in genes encoding collagen type IV. Thus, a wide spectrum of phenotypes and underlying genetic diversity make fast and proper diagnosis challenging. Here, we used AMELIE, an automatic text mining tool that enriches data with the most up-to-date information from literature, and wANNOVAR, which is based on well-documented databases and incorporates variant filtering strategy to identify genetic variants responsible for severely-manifested ASD in a newborn child. This strategy, applied to trio sequencing data in compliance with ACMG 2015 guidelines, helped us find two compound heterozygous variants of the <i>B3GLCT</i> gene, of which c.660+1G>A (rs80338851) was previously associated with the phenotype of Peters plus syndrome (PPS), while the second, NM_194318.3:c.755delC (p.T252fs), in exon 9 of the same gene was noted for the first time. PPS, a very rare subtype of ASD, is a glycosylation disorder, where the dysfunctional <i>B3GLCT</i> gene product, O-fucose-specific β-1,3-glucosyltransferase, is ineffective in providing a noncanonical quality control system for proper protein folding in cells. Our study expands the mutation spectrum of the <i>B3GLCT</i> gene related to PPS. We suggest that the implementation of automatic text mining tools in combination with careful variant filtering could help translate sequencing results into diagnosis, thus, considerably accelerating the diagnostic process and, thereby, improving patient management.","variants":[{"Name":"NM_194318.4(B3GLCT):c.660+1G>A","Chromosome":"13","Start":"31269278","Stop":"31269278","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16303,"rule_based_match":true,"evidence_text":"c.660+1G>A (rs80338851)","llm_judgment":"PRESENT","evidence":"c.660+1G>A (rs80338851)","abstract_start":963,"abstract_end":986}]}
{"pmid":"14722925","title":"Two novel severe mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) cause familial and/or hereditary pancreatitis.","abstract":"Mutations in the serine protease inhibitor Kazal type 1 gene (SPINK1) encoding pancreatic secretory trypsin inhibitor (PSTI) have recently been found to be associated with chronic pancreatitis. Nevertheless, knowledge of severe mutations is particularly scarce, both in terms of number and in the extent of clinical information. The aim of this study was to expand the known spectrum of such mutations. 46 unrelated families, each including at least two pancreatitis patients and carrying neither cationic trypsinogen (PRSS1) mutations nor the frequent SPINK1 N34S mutation, participated in this study. The four exons and their flanking sequences of the SPINK1 gene were screened by denaturing high performance liquid chromatography analysis (DHPLC); and mutations were identified by direct sequencing. A heterozygous microdeletion mutation (c.27delC), which occurs within a symmetric element, was identified in two families. In one family, c.27delC showed segregation with the disease across two generations, with a penetrance of up to 75%. But in the other family, however, the same mutation manifested as a low-penetrance susceptibility factor. In addition, a novel heterozygous splicing mutation, c.87+1G>A (G>A substitution at nucleotide +1 of intron 2) was found in one family with familial pancreatitis. Our results also helped to resolve the sharply differing views about PSTI's role in pancreatitis.","variants":[{"Name":"NM_001379610.1(SPINK1):c.27del (p.Ser10fs)","Chromosome":"5","Start":"147831551","Stop":"147831551","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":45441,"rule_based_match":true,"evidence_text":"c.27delC","llm_judgment":"PRESENT","evidence":"c.27delC","abstract_start":842,"abstract_end":850}]}
{"pmid":"30055715","title":"Genetic heterogeneity of congenital hearing impairment in Algerians from the Ghardaïa province.","abstract":"BACKGROUND: Consanguinity rate is high in Algeria, and the population is thus at high risk for genetic diseases transmitted on an autosomal recessive mode. Inherited congenital hearing impairment (HI) is a highly heterogeneous disorder, which affects approximately 1 in 800 Algerian newborns. Several hundreds of genes responsible for deafness have been reported among which more than one hundred are responsible for isolated deafness, of which 19 have already been reported to be involved in the Algerian population. This study focuses on patients from the Ghardaïa province, an ethnically and geographically isolated region of Southern Algeria that has the highest consanguinity rate in the country (56%).\nMETHODS: Eleven families, with at least two related members experiencing moderate to profound congenital HI, were recruited and screened for mutations in known HI genes.\nRESULTS: A preliminary screening for common mutations in GJB2 and GJB6 identified the prevalent GJB2:c.35delG mutation in four families. Targeted exome sequencing further identified the causal mutations in the remaining seven families: CIB2:c.97C > T; p.(Arg33*), MYO7A:c.470+1G > A; p.(?), and SLC26A4:c.410C > T; p.(Ser137Leu) biallelic mutations in two families each, and a TECTA:c.2743 A > G; p.(Ile915Val) monoallelic mutation in the only family with autosomal dominant transmission of the HI. Of note, the missense mutations of SLC26A4 and TECTA had not been previously reported.\nCONCLUSION: These results further substantiate the genetic heterogeneity of HI, even in reportedly isolated populations. However, several families may harbor the same mutations as a result of a long history of marriages between relatives. This study has important implications for the HI molecular diagnosis strategy, and to develop genetic counseling for families originating from the Ghardaïa province of Algeria.","variants":[{"Name":"NM_006383.4(CIB2):c.97C>T (p.Arg33Ter)","Chromosome":"15","Start":"78111266","Stop":"78111266","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":805842,"rule_based_match":true,"evidence_text":"CIB2:c.97C > T; p.(Arg33*)","llm_judgment":"PRESENT","evidence":"CIB2:c.97C > T; p.(Arg33*)","abstract_start":1114,"abstract_end":1140}]}
{"pmid":"33613441","title":"Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to","abstract":"<b>Background:</b> As one of the assembly factors of complex I in the mitochondrial respiratory chain, FOXRED1 plays an important role in mitochondrial function. However, only a few patients with mitochondrial encephalopathy due to FOXRED1 defects have been reported. <b>Methods:</b> Two Chinese patients with mitochondrial encephalopathy due to mutations in <i>FOXRED1</i> were identified through trio whole-exome sequencing. The clinical presentation, laboratory data, brain imaging findings, and genetic results were collected and reviewed. All previously reported cases with <i>FOXRED1</i>-related mitochondrial encephalopathy were collected using a PubMed search, and their data were reviewed. <b>Results:</b> Two patients presented with severe neurodevelopmental delay, epilepsy, high lactic acid levels, and remarkable diffuse brain atrophy and polycystic encephalomalacia during early infancy. Trio whole-exome sequencing revealed compound heterozygous variants in both patients: one case harbored a c.606_607delAG frameshift variant and a c.1054C>T (p.R352W) variant. At the same time, the other carried a novel c.352C>T (p.Q118X) variant and a reported c.1054C>T (p.R352W) variant. To date, nine patients have been reported with <i>FOXRED1</i> defects, including our two cases. The most common presentations were neurodevelopment delay (100%), epilepsy (80%), poor feeding (30%), and vision loss (20%). Multisystem involvement comprised cardiovascular dysfunction (30%), abnormal liver function (20%), and hypoglycemia (10%). The neuroimaging results ranged from normal to severe cerebral atrophy and polycystic encephalomalacia in early infancy. Eleven pathogenic variants in FOXRED1 have been reported, comprising six missense variants, two non-sense variants, two frameshift variants, and one splice variant; among these the c.1054C>T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) variants are more common. <b>Conclusion:</b> <i>FOXRED1</i>-related mitochondrial disorders have high clinical and genetic heterogeneity. Our study expanded the clinical and genetic spectrum of <i>FOXRED1</i> defects. Early infantile onset and progressive encephalopathy are the most common clinical presentations, while the variants c.1054C>T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) may be critical founder mutations.","variants":[{"Name":"NM_017547.4(FOXRED1):c.1054C>T (p.Arg352Trp)","Chromosome":"11","Start":"126276476","Stop":"126276476","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40005,"rule_based_match":true,"evidence_text":"c.1054C>T (p.R352W)","llm_judgment":"PRESENT","evidence":"c.1054C>T (p.R352W)","abstract_start":1048,"abstract_end":1067}]}
{"pmid":"22821884","title":"A novel HRAS substitution (c.266C>G; p.S89C) resulting in decreased downstream signaling suggests a new dimension of RAS pathway dysregulation in human development.","abstract":"Costello syndrome is caused by HRAS germline mutations affecting Gly(12) or Gly(13) in >90% of cases and these are associated with a relatively homogeneous phenotype. Rarer mutations in other HRAS codons were reported in patients with an attenuated or mild phenotype. Disease-associated HRAS missense mutations result in constitutive HRAS activation and increased RAF-MEK-ERK and PI3K-AKT signal flow. Here we report on a novel heterozygous HRAS germline alteration, c.266C>G (p.S89C), in a girl presenting with severe fetal hydrops and pleural effusion, followed by a more benign postnatal course. A sibling with the same mutation and fetal polyhydramnios showed a Dandy-Walker malformation; his postnatal course was complicated by severe feeding difficulties. Their apparently asymptomatic father is heterozygous for the c.266C>G change. By functional analyses we identified reduced levels of active HRAS(S89C) and diminished MEK, ERK and AKT phosphorylation in cells overexpressing HRAS(S89C) , which represent novel consequences of disease-associated HRAS mutations. Given our patients' difficult neonatal course and presence of this change in their asymptomatic father, we hypothesize that its harmful consequences may be time limited, with the late fetal stage being most sensitive. Alternatively, the phenotype may develop only in the presence of an additional as-yet-unknown genetic modifier. While the pathogenicity of the HRAS c.266C>G change remains unproven, our data may illustrate wide functional and phenotypic variability of germline HRAS mutations.","variants":[{"Name":"NM_005343.4(HRAS):c.266C>G (p.Ser89Cys)","Chromosome":"11","Start":"533790","Stop":"533790","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":48908,"rule_based_match":true,"evidence_text":"c.266C>G (p.S89C)","llm_judgment":"PRESENT","evidence":"c.266C>G (p.S89C)","abstract_start":467,"abstract_end":484}]}
{"pmid":"31727539","title":"Novel ATAD3A recessive mutation associated to fatal cerebellar hypoplasia with multiorgan involvement and mitochondrial structural abnormalities.","abstract":"Lethal neonatal encephalopathies are heterogeneous congenital disorders that can be caused by mitochondrial dysfunction. Biallelic large deletions in the contiguous ATAD3B and ATAD3A genes, encoding mitochondrial inner membrane ATPases of unknown function, as well as compound heterozygous nonsense and missense mutations in the ATAD3A gene have been recently associated with fatal neonatal cerebellar hypoplasia. In this work, whole exome sequencing (WES) identified the novel homozygous variant c.1217 T > G in ATAD3A, predicting a p.(Leu406Arg) substitution, in four siblings from a consanguineous family presenting with fatal neonatal cerebellar hypoplasia, seizures, axial hypotonia, hypertrophic cardiomyopathy, hepatomegaly, congenital cataract, and dysmorphic facies. Biochemical phenotypes of the patients included hyperlactatemia and hypocholesterolemia. Healthy siblings and parents were heterozygous for this variant, which is predicted to introduce a polar chain within the catalytic domain of ATAD3A that shortens its beta-sheet structure, presumably affecting protein stability. Accordingly, patient's fibroblasts with the homozygous variant displayed a specific reduction in ATAD3A protein levels associated with profound ultrastructural alterations of mitochondrial cristae and morphology. Our findings exclude the causative role of ATAD3B on this severe phenotype, expand the phenotypical spectrum of ATAD3A pathogenic variants and emphasize the vital role of ATAD3A in mitochondrial biogenesis.","variants":[{"Name":"NM_001170535.3(ATAD3A):c.1217T>G (p.Leu406Arg)","Chromosome":"1","Start":"1525242","Stop":"1525242","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":624841,"rule_based_match":true,"evidence_text":"c.1217 T > G","llm_judgment":"PRESENT","evidence":"c.1217 T > G","abstract_start":497,"abstract_end":509}]}
{"pmid":"35355569","title":"Case Report: New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management.","abstract":"Background: The fourth type of multiple endocrine neoplasia (MEN) is known as a rare variant of MEN presenting a MEN1-like phenotype and originating from a germline mutation in CDKN1B. However, due to the small number of cases documented in the literature, the peculiar clinical features of MEN4 are still largely unknown, and clear indications about the clinical management of these patients are currently lacking. In order to widen our knowledge on MEN4 and to better typify the clinical features of this syndrome, we present two more cases of subjects with MEN4, and through a review of the current literature, we provide some possible indications on these patients' management.\nCase Presentation: The first report is about a man who was diagnosed with a metastatic ileal G2-NET at the age of 34. Genetic analysis revealed the mutation p.I119T (c.356T>C) of exon 1 of CDKN1B, a mutation already reported in the literature in association with early-onset pituitary adenomas. The second report is about a 76-year-old woman with a multifocal pancreatic G1-NET. Genetic analysis identified the CDKN1B mutation c.482C>G (p.S161C), described here for the first time in association with MEN4 and currently classified as a variant of uncertain significance. Both patients underwent biochemical and imaging screening for MEN1-related diseases without any pathological findings.\nConclusions: According to the cases reported in the literature, hyperparathyroidism is the most common clinical feature of MEN4, followed by pituitary adenoma and neuroendocrine tumors. However, MEN4 appears to be a variant of MEN with milder clinical features and later onset. Therefore, these patients might need a different and personalized approach in clinical management and a peculiar screening and follow-up strategy.","variants":[{"Name":"NM_004064.5(CDKN1B):c.356T>C (p.Ile119Thr)","Chromosome":"12","Start":"12718195","Stop":"12718195","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":316337,"rule_based_match":true,"evidence_text":"c.356T>C","llm_judgment":"PRESENT","evidence":"c.356T>C","abstract_start":848,"abstract_end":856},{"Name":"NM_004064.5(CDKN1B):c.482C>G (p.Ser161Cys)","Chromosome":"12","Start":"12718831","Stop":"12718831","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":241258,"rule_based_match":true,"evidence_text":"c.482C>G (p.S161C)","llm_judgment":"PRESENT","evidence":"c.482C>G (p.S161C)","abstract_start":1109,"abstract_end":1127}]}
{"pmid":"27668459","title":"A family harboring homozygous FZD4 deletion supports the existence of recessive FZD4-related familial exudative vitreoretinopathy.","abstract":"PURPOSE: To document recessive FZD4-related familial exudative vitreoretinopathy.\nMETHODS: Retrospective case series.\nRESULTS: Two brothers, the only two males among five siblings, had bilateral infantile retinal detachments and were referred for genetic counseling. Next-generation sequencing uncovered a homozygous FZD4 frameshift deletion in both affected brothers (c.40_49delCCCGGGGGCG; p.Pro14Serfs*44). None of the other immediate family members had clinical evidence for retinal disease, including the three family members who underwent confirmatory genetic testing and were found to be heterozygous for the mutation (both parents and one sister).\nCONCLUSIONS: The findings in this family support the concept that some mutated FZD4 alleles can be associated with recessive rather than dominant disease.","variants":[{"Name":"NM_012193.4(FZD4):c.40_49del (p.Pro14fs)","Chromosome":"11","Start":"86955037","Stop":"86955046","ReferenceAlleleVCF":"ACGCCCCCGGG","AlternateAlleleVCF":"A","allel_id":434765,"rule_based_match":true,"evidence_text":"c.40_49delCCCGGGGGCG; p.Pro14Serfs*44","llm_judgment":"PRESENT","evidence":"c.40_49delCCCGGGGGCG; p.Pro14Serfs*44","abstract_start":369,"abstract_end":406}]}
{"pmid":"21603858","title":"Hereditary breast cancer in Middle Eastern and North African (MENA) populations: identification of novel, recurrent and founder BRCA1 mutations in the Tunisian population.","abstract":"Germ-line mutations in BRCA1 breast cancer susceptibility gene account for a large proportion of hereditary breast cancer families and show considerable ethnic and geographical variations. The contribution of BRCA1 mutations to hereditary breast cancer has not yet been thoroughly investigated in Middle Eastern and North African populations. In this study, 16 Tunisian high-risk breast cancer families were screened for germline mutations in the entire BRCA1 coding region and exon-intron boundaries using direct sequencing. Six families were found to carry BRCA1 mutations with a prevalence of 37.5%. Four different deleterious mutations were detected. Three truncating mutations were previously described: c.798_799delTT (916 delTT), c.3331_3334delCAAG (3450 delCAAG), c.5266dupC (5382 insC) and one splice site mutation which seems to be specific to the Tunisian population: c.212 + 2insG (IVS5 + 2insG). We also identified 15 variants of unknown clinical significance. The c.798_799delTT mutation occurred at an 18% frequency and was shared by three apparently unrelated families. Analyzing five microsatellite markers in and flanking the BRCA1 locus showed a common haplotype associated with this mutation. This suggests that the c.798_799delTT mutation is a Tunisian founder mutation. Our findings indicate that the Tunisian population has a spectrum of prevalent BRCA1 mutations, some of which appear as recurrent and founding mutations.","variants":[{"Name":"NM_007294.4(BRCA1):c.798_799del (p.Ser267fs)","Chromosome":"17","Start":"43094732","Stop":"43094733","ReferenceAlleleVCF":"GAA","AlternateAlleleVCF":"G","allel_id":46254,"rule_based_match":true,"evidence_text":"c.798_799delTT","llm_judgment":"PRESENT","evidence":"c.798_799delTT","abstract_start":709,"abstract_end":723},{"Name":"NM_007294.4(BRCA1):c.3331_3334del (p.Gln1111fs)","Chromosome":"17","Start":"43092197","Stop":"43092200","ReferenceAlleleVCF":"TCTTG","AlternateAlleleVCF":"T","allel_id":46079,"rule_based_match":true,"evidence_text":"c.3331_3334delCAAG (3450 delCAAG)","llm_judgment":"PRESENT","evidence":"c.3331_3334delCAAG (3450 delCAAG)","abstract_start":737,"abstract_end":770}]}
{"pmid":"36704080","title":"Mild Neurological Phenotype Associated with Hypomorphic Variants in the Ataxia-Telangiectasia Mutated Gene.","abstract":"Background: Ataxia-telangiectasia (A-T) is a progressive multisystemic neurodegenerative disease. The phenotypic spectrum includes conditions (variant A-T) with mild, late-onset, and atypical clinical presentations characterized by the prevalence of dyskinetic rather than ataxic features.\nCases: We describe the clinical presentations of 3 siblings with early-onset truncal ataxia without obvious neurological deterioration or biological markers of classic A-T phenotype. We performed functional and genetic evaluation of 3 siblings with very mild neurological phenotype. Genetic evaluation with a next-generation sequencing panel for genes causative of cerebellar ataxia detected 2 known ATM gene variants, missense c.9023G>A p.(Arg3008His), and leaky splicing c.1066-6T>G variants. Functional studies showed mildly reduced ATM expression and residual kinase activity in the probands compared with healthy controls.\nConclusions: These results suggest the importance of investigating ATM variants even in the presence of clinical and biological atypical cases to ensure specific therapeutic regimens and oncological surveillance in these patients.","variants":[{"Name":"NM_000051.4(ATM):c.9023G>A (p.Arg3008His)","Chromosome":"11","Start":"108365360","Stop":"108365360","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":151348,"rule_based_match":true,"evidence_text":"c.9023G>A p.(Arg3008His)","llm_judgment":"PRESENT","evidence":"c.9023G>A p.(Arg3008His)","abstract_start":718,"abstract_end":742},{"Name":"NM_000051.4(ATM):c.1066-6T>G","Chromosome":"11","Start":"108248927","Stop":"108248927","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18077,"rule_based_match":true,"evidence_text":"c.1066-6T>G","llm_judgment":"PRESENT","evidence":"c.1066-6T>G","abstract_start":763,"abstract_end":774}]}
{"pmid":"22419169","title":"Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn.","abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C>T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G>A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria.","variants":[{"Name":"NM_170707.4(LMNA):c.1821G>A (p.Val607=)","Chromosome":"1","Start":"156138610","Stop":"156138610","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29555,"rule_based_match":true,"evidence_text":"c.1821G>A","llm_judgment":"PRESENT","evidence":"c.1821G>A","abstract_start":744,"abstract_end":753}]}
{"pmid":"21834907","title":"A mutation in cartilage oligomeric matrix protein (COMP) causes early-onset osteoarthritis in a large kindred study.","abstract":"We performed a genome-wide linkage analysis to identify susceptibility loci in a large six-generation extended family previously reported with early-onset osteoarthritis (OA) DNA sequencing was performed to investigate involvement of the COMP (Cartilage oligomeric matrix protein) gene in this family. The region covering D19S884, D19S226, and D19S414 on chromosome 19p following genome-wide scan from 70 individuals of this kindred showed significant linkage, with a maximum point LOD (logarithm of the odds ratio) score of 2.51 at D19S226. Direct sequencing of the COMP gene, the most plausible candidate gene in the region, identified a c.2152C>T substitution in exon 18 which resulted in a substitution of tryptophan for arginine at position 718 located in the C terminal globular domain of the gene product. A total of 26 individuals were identified with this mutation of which 21 affected individuals had the mutation, and the other five younger individuals (18.6 ± 11.3 years of age) carried the mutation without symptoms. The results indicate that COMP is the disease susceptibility gene and the c.2152C>T mutation in exon 18 could cause early-onset OA phenotypes in this kindred, which is compatible with a previous report that this mutation also causes a mild form of multiple epiphyseal dysplasia (MED).","variants":[{"Name":"NM_000095.3(COMP):c.2152C>T (p.Arg718Trp)","Chromosome":"19","Start":"18783129","Stop":"18783129","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24237,"rule_based_match":true,"evidence_text":"c.2152C>T","llm_judgment":"PRESENT","evidence":"c.2152C>T","abstract_start":640,"abstract_end":649}]}
{"pmid":"31501240","title":"Biallelic mutations in","abstract":"BACKGROUND: Male infertility is a prevalent issue worldwide, mostly due to the impaired sperm motility. Multiple morphological abnormalities of the sperm flagella (MMAF) present aberrant spermatozoa with absent, short, coiled, bent and irregular-calibre flagella resulting in severely decreased motility. Previous studies reported several MMAF-associated genes accounting for approximately half of MMAF cases.\nMETHODS AND RESULT: We conducted genetic analysis using whole-exome sequencing in 88 Han Chinese MMAF probands. <i>CFAP65</i> homozygous mutations were identified in four unrelated consanguineous families, and <i>CFAP65</i> compound heterozygous mutations were found in two unrelated cases with MMAF. All these <i>CFAP65</i> mutations were null, including four frameshift mutations (c.1775delC [p.Pro592Leufs*8], c.3072_3079dup [p.Arg1027Profs*41], c.1946delC [p.Pro649Argfs*5] and c.1580delT [p.Leu527Argfs*31]) and three stop-gain mutations (c.4855C>T [p.Arg1619*], c.5270T>A [p.Leu1757*] and c.5341G>T [p.Glu1781*]). Additionally, two homozygous <i>CFAP65</i> variants likely affecting splicing were identified in two MMAF-affected men of Tunisian and Iranian ancestries, respectively. These biallelic variants of <i>CFAP65</i> were verified by Sanger sequencing and were absent or very rare in large data sets aggregating sequence information from various human populations. <i>CFAP65</i>, encoding the cilia and flagella associated protein 65, is highly and preferentially expressed in the testis. Here we also generated a frameshift mutation in mouse orthologue <i>Cfap65</i> using CRISPR-Cas9 technology. Remarkably, the phenotypes of <i>Cfap65</i>-mutated male mice were consistent with human MMAF.\nCONCLUSIONS: Our experimental observations performed on both human subjects and on <i>Cfap65</i>-mutated mice demonstrate that the presence of biallelic mutations in <i>CFAP65</i> causes the MMAF phenotype and impairs sperm motility.","variants":[{"Name":"NM_194302.4(CFAP65):c.5341G>T (p.Glu1781Ter)","Chromosome":"2","Start":"219004166","Stop":"219004166","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":682585,"rule_based_match":true,"evidence_text":"c.5341G>T (p.Glu1781*)","llm_judgment":"PRESENT","evidence":"p.Glu1781*","abstract_start":1016,"abstract_end":1026}]}
{"pmid":"27558265","title":"Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes.","abstract":"Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis.","variants":[{"Name":"NM_000494.4(COL17A1):c.1873C>T (p.Arg625Ter)","Chromosome":"10","Start":"104053097","Stop":"104053097","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1345799,"rule_based_match":true,"evidence_text":"c.1873C>T, p.R625*","llm_judgment":"PRESENT","evidence":"c.1873C>T, p.R625*","abstract_start":432,"abstract_end":450}]}
{"pmid":"37840311","title":"Re-evaluation of a Fibrillin-1 Gene Variant of Uncertain Significance Using the ClinGen Guidelines.","abstract":"Background: Marfan syndrome (MFS) is caused by fibrillin-1 gene (<i>FBN1</i>) variants. Mutational hotspots and/or well-established critical functional domains of <i>FBN1</i> include cysteine residues, calcium-binding consensus sequences, and amino acids related to interdomain packaging. Previous guidelines for variant interpretation do not reflect the features of genes or related diseases. Using the Clinical Genome Resource (ClinGen) <i>FBN1</i> variant curation expert panel (VCEP), we re-evaluated <i>FBN1</i> germline variants reported as variants of uncertain significance (VUSs).\nMethods: We re-evaluated 26 VUSs in <i>FBN1</i> reported in 161 patients with MFS. We checked the variants in the Human Genome Mutation Database, ClinVar, and VarSome databases and assessed their allele frequencies using the gnomAD database. Patients' clinical information was reviewed.\nResults: Four missense variants affecting cysteines (c.460T>C, c.1006T>C, c.5330G>C, and c.8020T>C) were reclassified as likely pathogenic and were assigned PM1_strong or PM1. Two intronic variants were reclassified as benign by granting BA1 (stand-alone). Four missense variants were reclassified as likely benign. BP5 criteria were applied in cases with an alternate molecular basis for disease, one of which (c.7231G>A) was discovered alongside a pathogenic <i>de novo COL3A1</i> variant (c.1988G>T, p.Gly633Val).\nConclusions: Considering the high penetrance of <i>FBN1</i> variants and clinical variability of MFS, the detection of pathogenic variants is important. The ClinGen <i>FBN1</i> VCEP encompasses mutational hotspots and/or well-established critical functional domains and adjusts the criteria specifically for MFS; therefore, it is beneficial not only for identifying pathogenic <i>FBN1</i> variants but also for distinguishing these variants from those that cause other connective tissue disorders with overlapping clinical features.","variants":[{"Name":"NM_000138.5(FBN1):c.460T>C (p.Cys154Arg)","Chromosome":"15","Start":"48596361","Stop":"48596361","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3732829,"rule_based_match":true,"evidence_text":"c.460T>C","llm_judgment":"PRESENT","evidence":"c.460T>C","abstract_start":930,"abstract_end":938}]}
{"pmid":"25700310","title":"A novel mutation of the HNF1B gene associated with hypoplastic glomerulocystic kidney disease and neonatal renal failure: a case report and mutation update.","abstract":"Hepatocyte nuclear factor 1 beta (HNF1B) plays an important role in embryonic development, namely in the kidney, pancreas, liver, genital tract, and gut. Heterozygous germline mutations of HNF1B are associated with the renal cysts and diabetes syndrome (RCAD). Affected individuals may present a variety of renal developmental abnormalities and/or maturity-onset diabetes of the young (MODY). A Portuguese 19-month-old male infant was evaluated due to hypoplastic glomerulocystic kidney disease and renal dysfunction diagnosed in the neonatal period that progressed to stage 5 chronic renal disease during the first year of life. His mother was diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 chronic renal disease established at age 35, and presented bicornuate uterus, pancreatic atrophy, and gestational diabetes. DNA sequence analysis of HNF1B revealed a novel germline frameshift insertion (c.110_111insC or c.110dupC) in both the child and the mother. A review of the literature revealed a total of 106 different HNF1B mutations, in 236 mutation-positive families, comprising gross deletions (34%), missense mutations (31%), frameshift deletions or insertions (15%), nonsense mutations (11%), and splice-site mutations (8%). The study of this family with an unusual presentation of hypoplastic glomerulocystic kidney disease with neonatal renal dysfunction identified a previously unreported mutation of the HNF1B gene, thereby expanding the spectrum of known mutations associated with renal developmental disorders.","variants":[{"Name":"NM_000458.4(HNF1B):c.110dup (p.Asn38fs)","Chromosome":"17","Start":"37744774","Stop":"37744775","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":623542,"rule_based_match":true,"evidence_text":"c.110dupC","llm_judgment":"PRESENT","evidence":"c.110dupC","abstract_start":951,"abstract_end":960}]}
{"pmid":"31308188","title":"Mitochondrial respiratory chain complex IV deficiency presenting as neonatal respiratory distress syndrome.","abstract":"A term girl infant delivered following foetal distress presented with early respiratory distress syndrome and lactic acidaemia. She subsequently underwent detailed investigation for primary lactic acidaemia and was identified as homozygous for the c.515A>G,p.(Tyr172Cys) missense variant in the <i>LRPPRC</i> gene. Variants in this gene are known to cause French-Canadian type Leigh syndrome. Both parents were confirmed to be heterozygous for this mutation. This is the first case report of mitochondrial respiratory chain complex IV deficiency presenting as foetal distress and neonatal respiratory distress syndrome.","variants":[{"Name":"NM_133259.4(LRPPRC):c.515A>G (p.Tyr172Cys)","Chromosome":"2","Start":"43977231","Stop":"43977231","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1301167,"rule_based_match":true,"evidence_text":"c.515A>G,p.(Tyr172Cys)","llm_judgment":"PRESENT","evidence":"c.515A>G,p.(Tyr172Cys)","abstract_start":248,"abstract_end":270}]}
{"pmid":"30741402","title":"Congenital CLN8 disease of neuronal ceroid lipofuscinosis: a novel phenotype.","abstract":"INTRODUCTION: CLN8 disease is one of the thirteen recognized genetic types of neuronal ceroid lipofuscinosis, a group of neurodegenerative lysosomal storage disorders, most frequent in childhood. A putative 286 amino acids transmembrane CLN8 protein with unknown function is affected. Pathological variants in the CLN8 gene were associated with two different phenotypes: variant late-infantile in individuals from many countries worldwide, and epilepsy progressive with mental retardation, appearing in Finnish and Turkish subjects.\nCASE REPORT: The girl showed psychomotor delay and dementia since birth, tonic-clonic seizures, myoclonus, ataxia with cerebellar atrophy, and early death at 12 years old. Electron microscopy of the skin showed mixed GROD, curvilinear, fingerprint cytosomes and mitochondrial hypertrophy. Two pathological DNA variants in the CLN8 gene (exon 2 c.1A>G; p.?/ exon 3 c.792C>G; p.Asn264Lys) were found confirming a compound heterozygous genotype.\nCONCLUSION: This case is the Latin American index for a new congenital phenotype of the CLN8 disease. The congenital phenotype has to be added to the clinical spectrum of the CLN8 disease. The suspicion of CLN8 disease should be genetically sustained in challenging cases of a neurodegenerative syndrome with psychomotor delay since birth, speech difficulty and seizures. The course includes ataxia, cerebellar atrophy, and early death.","variants":[{"Name":"NM_018941.4(CLN8):c.792C>G (p.Asn264Lys)","Chromosome":"8","Start":"1780498","Stop":"1780498","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":106601,"rule_based_match":true,"evidence_text":"c.792C>G (p.Asn264Lys)","llm_judgment":"PRESENT","evidence":"p.Asn264Lys","abstract_start":907,"abstract_end":918}]}
{"pmid":"28004182","title":"CDK5RAP2 interaction with components of the Hippo signaling pathway may play a role in primary microcephaly.","abstract":"Autosomal recessive primary microcephaly (MCPH) is characterized by a substantial reduction in brain size but with normal architecture. It is often linked to mutations in genes coding for centrosomal proteins; however, their role in brain size regulation is not completely understood. By combining homozygosity mapping and whole-exome sequencing in an MCPH family from Pakistan, we identified a novel mutation (XM_011518861.1; c.4114C > T) in CDK5RAP2, the gene associated with primary microcephaly-3 (MCPH3), leading to a premature stop codon (p.Arg1372*). CDK5RAP2 is a component of the pericentriolar material important for the microtubule-organizing function of the centrosome. Patient-derived primary fibroblasts had strongly decreased CDK5RAP2 amounts, showed centrosomal and nuclear abnormalities and exhibited changes in cell size and migration. We further identified an interaction of CDK5RAP2 with the Hippo pathway components MST1 kinase and the transcriptional regulator TAZ. This finding potentially provides a mechanism through which the Hippo pathway with its roles in the regulation of centrosome number is linked to the centrosome. In the patient fibroblasts, we observed higher levels of TAZ and YAP. However, common target genes of the Hippo pathway were downregulated as compared to the control with the exception of BIRC5 (Survivin), which was significantly upregulated. We propose that the centrosomal deficiencies and the altered cellular properties in the patient fibroblasts can also result from the observed changes in the Hippo pathway components which could thus be relevant for MCPH and play a role in brain size regulation and development.","variants":[{"Name":"NM_018249.6(CDK5RAP2):c.4114C>T (p.Arg1372Ter)","Chromosome":"9","Start":"120419851","Stop":"120419851","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":861595,"rule_based_match":true,"evidence_text":"c.4114C > T","llm_judgment":"PRESENT","evidence":"c.4114C > T","abstract_start":427,"abstract_end":438}]}
{"pmid":"30275004","title":"Biallelic variants in","abstract":"Two male siblings ages 15 and 10 yr old had similar features of intellectual disability, developmental delay, severe speech impairment, microcephaly, prematurity, and transient elevation of liver enzymes in infancy. Exome sequencing revealed one novel (c.65C>A; p.Ala22Asp) and one ultra-rare (c.3214T>C; p.Phe1072Leu) predicted damaging missense variant in <i>trans</i> in the gene encoding cytoplasmic valyl-tRNA synthetase (<i>VARS</i>). Biallelic variants in <i>VARS</i> have previously been associated with a neurodevelopmental disorder characterized by microcephaly, seizures, and cortical atrophy (NDMSCA; MIM #617802). Although our patients have no history of seizures or cortical atrophy, we suggest that the biallelic variants in <i>VARS</i> p.Ala22Asp and p.Phe1072Leu in this family are likely pathogenic and associated with NDMSCA, expanding the clinical phenotype of the condition.","variants":[{"Name":"NM_006295.3(VARS1):c.3214T>C (p.Phe1072Leu)","Chromosome":"6","Start":"31779682","Stop":"31779682","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":550166,"rule_based_match":true,"evidence_text":"c.3214T>C; p.Phe1072Leu","llm_judgment":"PRESENT","evidence":"c.3214T>C; p.Phe1072Leu","abstract_start":294,"abstract_end":317},{"Name":"NM_006295.3(VARS1):c.65C>A (p.Ala22Asp)","Chromosome":"6","Start":"31795153","Stop":"31795153","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":550167,"rule_based_match":true,"evidence_text":"c.65C>A; p.Ala22Asp","llm_judgment":"PRESENT","evidence":"c.65C>A; p.Ala22Asp","abstract_start":253,"abstract_end":272}]}
{"pmid":"38789506","title":"Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.","abstract":"Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.","variants":[{"Name":"NM_000179.3(MSH6):c.3226C>T (p.Arg1076Cys)","Chromosome":"2","Start":"47803473","Stop":"47803473","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":94831,"rule_based_match":true,"evidence_text":"MSH6 c.3226C>T (p.(Arg1076Cys))","llm_judgment":"PRESENT","evidence":"MSH6 c.3226C>T (p.(Arg1076Cys))","abstract_start":499,"abstract_end":530}]}
{"pmid":"18079676","title":"A recurrent FBN1 mutation in an autosomal dominant ectopia lentis family of Indian origin.","abstract":"PURPOSE: To identify the genetic defect in an autosomal dominant ectopia lentis (EL) family having 27 affected members in four generations.\nMETHODS: Detailed family history and clinical data were recorded for 48 family members including 24 persons with isolated ectopia lentis. Candidate gene regions at 5q and 15q known to be linked with ectopia lentis were analyzed using fluorescent labeled microsatellite markers. Mutation screening in the candidate gene, fibrillin-1 (FBN1), at 15q was performed by bidirectional sequencing of the amplified products.\nRESULTS: A maximum LOD score of 5.74 at theta=0.0 was obtained with marker D15S1024 in close proximity to FBN1 at 15q21. Mutation screening in FBN1 identified a C>T transition at nucleotide position c.718. This nucleotide change resulted in the substitution of highly conserved arginine by cysteine at codon 240 (R240C). This nucleotide substitution was not seen in any unaffected member of the family.\nCONCLUSIONS: We report a recurrent R240C mutation in FBN1 in an autosomal dominant ectopia lentis family. This mutation has previously been reported in a family with isolated ectopia lentis, in another family with ectopia lentis and involvement of the skeleton and integument, and in one person with classic Marfan syndrome. This is the largest family with isolated ectopia lentis reported to date. The results of the present study provide convincing evidence for a correlation of R240C and isolated ectopia lentis. In addition, this is the first report of molecular characterization in an ectopia lentis family of Indian origin.","variants":[{"Name":"NM_000138.5(FBN1):c.718C>T (p.Arg240Cys)","Chromosome":"15","Start":"48537629","Stop":"48537629","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31500,"rule_based_match":false,"evidence_text":"c.718C>T","llm_judgment":"PRESENT","evidence":"c.718C>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"21835369","title":"Combined methylmalonic aciduria and homocystinuria cblC type of a Taiwanese infant with c.609G>A and C.567dupT mutations in the MMACHC gene.","abstract":"Combined methylmalonic aciduria and homocystinuria, cobalamin (cbl)C type (cblC disease), the most common inborn error of vitamin B(12), is a rare disorder of intracellular cbl metabolism because of mutations in the MMACHC gene located in chromosome region 1p34.1. It has become possible to establish phenotype-genotype correlations and to observe ethnicity-related trends. This article provides detailed clinical manifestations and outcomes of a Taiwanese infant boy with early-onset cblC disease, heterozygous for c.609G>A and c.567dupT mutations, although there is limited information about cases with c.609G>A or c.567dupT mutation in the literature. He had no significant clinical abnormality during his neonatal period, whereas elevated C3 level was noted at newborn screening. He presented later with life-threatening manifestations and failure to thrive, which resolved through our treatment, although delayed development was still noted at 6 months of age. To date, all reported cblC patients with the c.609G>A mutation have been East Asians. Therefore, we suggest that c.609G>A should be included in the initial mutation screening tests for a cblC patient in East Asian populations.","variants":[{"Name":"NM_015506.3(MMACHC):c.567dup (p.Ile190fs)","Chromosome":"1","Start":"45508932","Stop":"45508933","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":541135,"rule_based_match":true,"evidence_text":"c.567dupT","llm_judgment":"PRESENT","evidence":"c.567dupT","abstract_start":529,"abstract_end":538}]}
{"pmid":"37171638","title":"Repeated intestinal perforations in vascular Ehlers-Danlos syndrome: a case report of a novel mutation in the COL3A1 gene.","abstract":"BACKGROUND: Ehlers-Danlos syndrome is an inherited connective-tissue disorder characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. Intestinal perforation is one of the fatal manifestations of this syndrome, and its management is complicated.\nCASE PRESENTATION: A 58-year-old woman with a familial history of Ehlers-Danlos syndrome visited the emergency department due to a sudden onset of lower abdominal pain. Plain abdominal computed tomography showed abdominal free air. We found a perforated descending colon and subsequently resected this lesion and performed ileostomy. Fifty-one days after this first operation, the patient had transverse colon perforation and thus underwent the Hartmann procedure as the second operation. In addition, she was diagnosed with small bowel perforation 53 days after the first operation and consequently underwent a third operation-partial resection of the jejunum with functional end-to-end anastomosis. Fifty-eight days after the first operation, she complained of acute abdominal pain. Plain abdominal computed tomography showed fluid collection near the jejunojejunal anastomosis. We detected dehiscence at the entry hole of the linear stapler during the operation and thus performed partial resection of the affected jejunum, followed by jejunostomy. The postoperative course of the fourth operation was uneventful. Genetic testing revealed a novel missense mutation (c.2095G>T, p.Gly699Cys) in the COL3A1 gene, which is presumed to be a pathogenic variant of vascular Ehlers-Danlos syndrome.\nCONCLUSION: Vascular Ehlers-Danlos syndrome should be considered in the case of repeated intestinal perforation. The identified missense mutation in the COL3A1 gene (c.2095G>T, p.Gly699Cys) might be a novel pathogenic variation causing vascular Ehlers-Danlos syndrome. Careful postoperative screening and multidisciplinary management are required.","variants":[{"Name":"NM_000090.4(COL3A1):c.2095G>T (p.Gly699Cys)","Chromosome":"2","Start":"188999357","Stop":"188999357","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2805393,"rule_based_match":true,"evidence_text":"c.2095G>T, p.Gly699Cys","llm_judgment":"PRESENT","evidence":"c.2095G>T, p.Gly699Cys","abstract_start":1443,"abstract_end":1465}]}
{"pmid":"18190596","title":"Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population.","abstract":"Mucolipidosis (ML) II (I-cell disease) is a lysosomal storage disorder caused by a deficiency of UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. MLII is an autosomal recessive disease with a carrier rate estimated at 1/39 in Saguenay-Lac-Saint-Jean (SLSJ) (Quebec, Canada), which is the highest frequency documented worldwide. To identify the causing mutation, we sequenced GNPTAB exons in 27 parents of 16 MLII-deceased children from the SLSJ region as obligatory and potential carriers. We also performed a genealogical reconstruction for each parent to evaluate consanguinity levels and genetic contribution of ancestors. Our goal was to identify which parameters could explain the high MLII frequency observed in the SLSJ population. A single mutation (c.3503_3504delTC) was found in all obligatory carriers. In addition, 11 apparent polymorphisms were identified. The mutation was not detected in genomic DNA of 50 unrelated controls. Genealogical data show six founders (three couples) with a higher probability of having introduced the mutation in the population. The frequency of the mutation was increased as a consequence of this founder effect and of the resulting population structure. We suggest that c.3503_3504delTC is the allele causing MLII in the SLSJ population, and its high carrier rate is most likely explained by a founder effect.","variants":[{"Name":"NM_024312.5(GNPTAB):c.3503_3504del (p.Leu1168fs)","Chromosome":"12","Start":"101753470","Stop":"101753471","ReferenceAlleleVCF":"TGA","AlternateAlleleVCF":"T","allel_id":17810,"rule_based_match":true,"evidence_text":"c.3503_3504delTC","llm_judgment":"PRESENT","evidence":"c.3503_3504delTC","abstract_start":792,"abstract_end":808}]}
{"pmid":"33973349","title":"Nonclassic fibrodysplasia ossificans progressiva: A child from Angola with an ACVR1","abstract":"Little is known about FOP in Africa and few cases of nonclassic fibrodysplasia ossificans progressiva (FOP) have been reported on the continent. Here we report a three-year-old girl from Angola with a nonclassic FOP clinical presentation that is characterized by complex malformations of the toes and fingers, reduction defects of the digits, absence of nails, progressive heterotopic ossification, and a confirmed heterozygous ACVR1 variant at c.983G > A. Emerging knowledge of FOP can serve as a catalyst for increasing awareness of FOP in under-represented medical communities by achieving a correct FOP diagnosis, improving access of individuals with FOP to clinical trial recruitment, and enhancing the ability of affected individuals to be part of and interact with the international FOP community.","variants":[{"Name":"NM_001111067.4(ACVR1):c.983G>A (p.Gly328Glu)","Chromosome":"2","Start":"157766004","Stop":"157766004","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38549,"rule_based_match":true,"evidence_text":"c.983G > A","llm_judgment":"PRESENT","evidence":"c.983G > A","abstract_start":445,"abstract_end":455}]}
{"pmid":"21896032","title":"New K103 β3 allele identified in a context of severe neonatal thrombocytopenia.","abstract":"BACKGROUND: A new β3 allele was identified in a severe case of neonatal alloimmune thrombocytopenia (<7 × 10(9) /L).\nSTUDY DESIGN AND METHODS: Diagnosis was done by use of monoclonal antibody-specific immobilization of platelet (PLT) antigen for serologic analyses and polymerase chain reaction (PCR)-sequence-specific primers (SSP) and PCR-restriction fragment length polymorphism (RFLP) for genotyping. Direct sequencing of PCR product was done and mutant αIIbβ3 expressed in HEK-293 cells.\nRESULTS: Serologic analysis revealed in the maternal serum an anti-human PLT alloantigen (HPA)-1a alloantibody associated to an anti-α2β1. Anti-HPA-1a alloimmunization diagnosis was confirmed by genotyping showing maternofetal incompatibility. However, investigation of rare HPA polymorphisms revealed discrepant HPA-16b assignation between PCR-RFLP and PCR-SSP. Sequencing revealed a new c.385C>A mutation in the β3 coding sequence resulting in a false assignation of the HPA-16b allele by PCR-RFLP. This mutation leads to a Q103K substitution in mature β3. The K103-β3 form of the complex was expressed in HEK-293 cells but did not react with the maternal serum.\nCONCLUSION: We have characterized a new rare allele (frequency < 1%) of β3 that yields false HPA-16b genotyping in PCR-RFLP. This new case of false typing assignation emphasizes the necessity to use two genotyping techniques in diagnosis. This particularly applies for rare HPA polymorphisms when PLT phenotyping cannot be used.","variants":[{"Name":"NM_000212.3(ITGB3):c.385C>A (p.Gln129Lys)","Chromosome":"17","Start":"47284466","Stop":"47284466","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2476340,"rule_based_match":true,"evidence_text":"c.385C>A","llm_judgment":"PRESENT","evidence":"c.385C>A","abstract_start":882,"abstract_end":890}]}
{"pmid":"32448126","title":"The mutational spectrum of hunter syndrome reveals correlation between biochemical and clinical profiles in Tunisian patients.","abstract":"BACKGROUND: Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is an X-linked recessive lysosomal storage disorder resulting from deficient activity of iduronate 2-sulfatase (IDS) and the progressive lysosomal accumulation of sulfated glycosaminoglycans (GAGs).\nMETHODS: A diagnosis of MPS II or Hunter syndrome was performed based on the following approach after a clinical and paraclinical suspicion. Two biochemical and molecular tests were carried out separately and according to the availability of the biological material.\nRESULTS: All patients in this cohort presented the most common MPS II clinical features. Electrophoresis of GAGs on a cellulose acetate plate in the presence of a high concentration of heparane sulfate showed an abnormal dermatan sulfate band in the patients compared with that in a control case. Furthermore, leukocyte IDS activity ranged from 0.00 to 0.75 nmol/h/mg of leukocyte protein in patients. Five previously reported mutations were identified in this study patients: one splice site mutation, c.240 + 1G > A; two missense mutations, p.R88P and p.G94D; a large deletion of exon 1 to exon 7; and one nonsense mutation, p.Q396*. In addition, two novel alterations were identified in the MPS II patients: one frame shift mutation, p.D450Nfs*95 and one nonsense mutation, p.Q204*. Additionally, five known IDS polymorphisms were identified in the patients: c.419-16 delT, c.641C > T (p.T214M), c.438 C > T (p.T146T), c.709-87G > A, and c.1006 + 38 T > C.\nCONCLUSIONS: The high level of urine GAGs and the deficiency of iduronate 2-sulfatase activity was associated with the phenotype expression of Hunter syndrome. Molecular testing was useful for the patients' phenotypic classification and the detection of carriers.","variants":[{"Name":"NM_000202.8(IDS):c.240+1G>A","Chromosome":"X","Start":"149504156","Stop":"149504156","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3414871,"rule_based_match":true,"evidence_text":"c.240 + 1G > A","llm_judgment":"PRESENT","evidence":"c.240 + 1G > A","abstract_start":1039,"abstract_end":1053}]}
{"pmid":"21368767","title":"Novel PTCH1 mutations in Japanese Nevoid basal cell carcinoma syndrome patients: two familial and three sporadic cases including the first Japanese patient with medulloblastoma.","abstract":"Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is inherited in an autosomal dominant mode, and is characterized by a combination of developmental abnormalities and predisposition to form a variety of tumors. The hedgehog receptor Patched1 (PTCH1) has been identified as the gene mutated in NBCCS. We analyzed PTCH1 in two familial and three sporadic Japanese NBCCS cases, and identified five germline mutations in PTCH1. Two cases have a nonsense mutation (c.3058C>T and c.2760C>A), one a splice site mutation (c.584+2T>G), one a 1 bp insertion (c.2712_2713insA) and one a 1 bp deletion (c.980Gdel). All mutations induce truncation of the PTCH1 protein or could induce nonsense-mediated mRNA decay. The 11-year-old male patient with splice-site mutation (c.584+2T>G) had medulloblastoma (MB) at the age of 1 year. This is the first NBCCS patient with molecularly defined MB in Japan.","variants":[{"Name":"NM_000264.5(PTCH1):c.3058C>T (p.Gln1020Ter)","Chromosome":"9","Start":"95458123","Stop":"95458123","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1061772,"rule_based_match":true,"evidence_text":"c.3058C>T","llm_judgment":"PRESENT","evidence":"c.3058C>T","abstract_start":487,"abstract_end":496}]}
{"pmid":"30608453","title":"Clinical and genetic analysis of 7 Chinese patients with β-ureidopropionase deficiency.","abstract":"β-Ureidopropionase (βUP) deficiency is an autosomal recessive disease caused by abnormal changes in the pyrimidine-degradation pathway. This study aimed to investigate the mutation of β-ureidopropionase gene (UPB1) gene and clinical features of 7 Chinese patients with βUP deficiency.We reported 7 Chinese patients with βUP deficiency who were admitted at Tianjin Children's Hospital. Urine metabolomics was detected by gas chromatography-mass spectrometry (GC-MS). Then genetic testing of UPB1 was conducted by polymerase chain reaction (PCR) method.The patients presented with developmental delay, seizures, autism, abnormal magnetic resonance imaging, and significantly elevated levels of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid in urine. Subsequent analysis of UPB1 mutation revealed 2 novel missense mutations (c.851G>T and c.853G>A), 3 previously reported mutations including 2 missense mutations (c.977G>A and c.91G>A) and 1 splice site mutation (c.917-1 G>A).The results suggested that the UPB1 mutation may contribute to βUP deficiency. The c.977G>A is the most common mutation in Chinese population.","variants":[{"Name":"NM_016327.3(UPB1):c.917-1G>A","Chromosome":"22","Start":"24523618","Stop":"24523618","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":439218,"rule_based_match":true,"evidence_text":"c.917-1 G>A","llm_judgment":"PRESENT","evidence":"c.917-1 G>A","abstract_start":973,"abstract_end":984}]}
{"pmid":"21945342","title":"Common genetic mutations in the start codon of the SDH subunit D gene among Chinese families with familial head and neck paragangliomas.","abstract":"Head and neck paragangliomas (HNPGLs) are rare, and frequently associated with germline mutations of the succinate dehydrogenase (SDH) genes, especially for familial cases. The purpose of the study is to explore SDH mutations in Chinese families with familial HNPGLs in Taiwan. Four unrelated families with familial HNPGLs were screened for germline mutations in the SDHB, SDHC and SDHD genes by direct sequencing. One hundred healthy subjects without a diagnosis or family history of HNPGLs were screened as normal controls. Immunohistochemistry with SDHB antibody was performed for a carotid body tumor. Two allele variants were identified, including p.Met1Val (c.1A>G) in the SDHD gene in one family and p.Met1Ile (c.3G>C) in the SDHD gene in the other three families. Both variants are considered pathogenic because of the absence of these variants in 100 normal controls, 100% evolutionary conservation of the p.Met1 residue, co-segregation of the variants with the phenotype of HNPGL in pedigrees, and predicted abolishment of the translation start site. The tumor cells obtained from one proband harboring c.3G>C mis-sense mutation were weak diffuse staining in the cytoplasm of tumors cells. This study demonstrates that two mis-sense mutations at the start codon of the SDHD gene, including p.Met1Val (c.1A>G) and p.Met1Ile (c.3G>C), might be mutation hotspots in Chinese patients with familial HNPGLs.","variants":[{"Name":"NM_003002.4(SDHD):c.3G>C (p.Met1Ile)","Chromosome":"11","Start":"112086910","Stop":"112086910","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":21945,"rule_based_match":true,"evidence_text":"c.3G>C","llm_judgment":"PRESENT","evidence":"c.3G>C","abstract_start":718,"abstract_end":724},{"Name":"NM_003002.4(SDHD):c.1A>G (p.Met1Val)","Chromosome":"11","Start":"112086908","Stop":"112086908","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":21950,"rule_based_match":true,"evidence_text":"p.Met1Val (c.1A>G)","llm_judgment":"PRESENT","evidence":"p.Met1Val (c.1A>G)","abstract_start":653,"abstract_end":671}]}
{"pmid":"33712029","title":"Extending the phenotypic spectrum of PRPF8, PRPH2, RP1 and RPGR, and the genotypic spectrum of early-onset severe retinal dystrophy.","abstract":"PURPOSE: To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease.\nMETHODS: Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK).\nRESULTS: The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented.\nCONCLUSIONS: The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.","variants":[{"Name":"NM_006445.4(PRPF8):c.5804G>A (p.Arg1935His)","Chromosome":"17","Start":"1655533","Stop":"1655533","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":537271,"rule_based_match":true,"evidence_text":"c.5804G > A","llm_judgment":"PRESENT","evidence":"c.5804G > A","abstract_start":736,"abstract_end":747}]}
{"pmid":"23417734","title":"Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology.","abstract":"Mutations in SQSTM1 encoding the sequestosome 1/p62 protein have recently been identified in familial and sporadic cases of amyotrophic lateral sclerosis (ALS). p62 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. We sequenced SQSTM1 in 90 French patients with familial ALS (FALS) and 74 autopsied ALS cases with sporadic ALS (SALS). We identified, at the heterozygote state, one missense c.1175C>T, p.Pro392Leu (exon 8) in one of our FALS and one substitution in intron 7 (the c.1165+1G>A, previously called IVS7+1 G-A, A390X) affecting the exon 7 splicing site in one SALS. These mutations that are located in the ubiquitin-associated domain (UBA domain) of the p62 protein have already been described in Paget's disease and ALS patients carrying these mutations had both concomitant Paget's disease. However, we also identified two novel missense mutations in two SALS: the c.259A>G, p.Met87Val in exon 2 and the c.304A>G, p.Lys102Glu in exon 3. These mutations that were not detected in 360 control subjects are possibly pathogenic. Neuropathology analysis of three patients carrying SQSTM1 variants revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed an increased p62 and TDP-43 protein levels in the spinal cord. Our results confirm that SQSTM1 gene mutations could be the cause or genetic susceptibility factor of ALS in some patients.","variants":[{"Name":"NM_003900.5(SQSTM1):c.1175C>T (p.Pro392Leu)","Chromosome":"5","Start":"179836445","Stop":"179836445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23147,"rule_based_match":true,"evidence_text":"c.1175C>T, p.Pro392Leu","llm_judgment":"PRESENT","evidence":"c.1175C>T, p.Pro392Leu","abstract_start":433,"abstract_end":455},{"Name":"NM_003900.5(SQSTM1):c.259A>G (p.Met87Val)","Chromosome":"5","Start":"179823011","Stop":"179823011","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3086268,"rule_based_match":true,"evidence_text":"c.259A>G, p.Met87Val","llm_judgment":"PRESENT","evidence":"c.259A>G, p.Met87Val","abstract_start":921,"abstract_end":941},{"Name":"NM_003900.5(SQSTM1):c.1165+1G>A","Chromosome":"5","Start":"179833783","Stop":"179833783","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23149,"rule_based_match":true,"evidence_text":"c.1165+1G>A","llm_judgment":"PRESENT","evidence":"c.1165+1G>A","abstract_start":522,"abstract_end":533}]}
{"pmid":"28670940","title":"Rare β-Globin Gene Mutations in Pakistan.","abstract":"The aim of this study was to analyze the rare β-thalassemia (β-thal) mutations in the Pakistani population. A total of 8716 unrelated Pakistani individuals having children with transfusion-dependent thalassemia were investigated by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) for the previously reported common and rare β-thal mutations. Genomic sequencing of the β-globin gene and its immediate 5' and 3' flanking regions was done where no known mutation was found. Out of the 8716 individuals studied, 88 (1.0%) were not characterized by ARMS-PCR. Genomic sequencing revealed that 67 (0.82%) individuals had 19 different β-thal mutations including one novel mutation (HBB: c.136delT). The remaining 21 (0.26%) individuals did not show any mutation on the β-globin gene and its immediate flanking regions. The characterized alleles included seven (0.09%) in the 5' untranslated region (5'UTR), 29 (0.35%) in the coding regions, and 31 (0.38%) in the splice junction regions. HBB: c.92+1G>A and HBB: c.113G>A were the most frequently seen rare mutations. The spectrum of β-thal mutations in the Pakistani population is very diverse. In addition to the already reported mutations, another 19 different types of mutations were found. Interestingly, 21 individuals who had children with transfusion-dependent thalassemia and one known β-thal mutation, did not show any mutation on the β-globin gene. HBB: c.92+1G>A and HBB: c.113G>A are the most frequently seen rare mutations in Pakistan.","variants":[{"Name":"NM_000518.5(HBB):c.113G>A (p.Trp38Ter)","Chromosome":"11","Start":"5226779","Stop":"5226779","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":433088,"rule_based_match":true,"evidence_text":"HBB: c.113G>A","llm_judgment":"PRESENT","evidence":"HBB: c.113G>A","abstract_start":1029,"abstract_end":1042}]}
{"pmid":"29382003","title":"Hemoglobin Hornchurch [β43 (CD2) Glu > Lys; HBB: c.130G > A] in a Chinese boy complicated with thrombocytopenia: A case report and literature review.","abstract":"RATIONALE: Hemoglobin Hornchurch is regarded as an asymptomatic hemoglobinopathy with no obvious hematological or clinical abnormalities. Recently, we identified hemoglobin Hornchurch in a 13-year-old Chinese boy complicated with thrombocytopenia, which displayed instability in isopropanol precipitation test.\nPATIENT CONCERNS: In this case report, we reported a Chinese boy with hemoglobin Hornchurch complicated by thrombocytopenia. The patients have been misdiagnosed as aplastic anemia and myelodysplastic syndrome before.\nDIAGNOSES: Hemolysis tests, high-performance liquid chromatography, and HBB gene sequencing identified the E44K (G>A) mutation. Isopropanol precipitation test showed instability in hemoglobin Hornchurch.\nINTERVENTIONS: The patient was given immunosuppressive therapy for 3 months.\nOUTCOMES: His general conditions have improved along with the recovery of the hemogram index.\nLESSONS: Further research is needed to clarify the relation between structural abnormality and functional properties of hemoglobin Hornchurch. This second case of hemoglobin Hornchurch indicates that there might be more hemoglobin variants or their carriers in the Chinese population.","variants":[{"Name":"NM_000518.5(HBB):c.130G>A (p.Glu44Lys)","Chromosome":"11","Start":"5226762","Stop":"5226762","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3731017,"rule_based_match":true,"evidence_text":"HBB: c.130G > A","llm_judgment":"PRESENT","evidence":"HBB: c.130G > A","abstract_start":null,"abstract_end":null}]}
{"pmid":"29597274","title":"Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients.","abstract":"Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mitochondrial HMG-CoA synthase deficiency or mHS deficiency, OMIM #605911) is an inborn error of metabolism that affects ketone body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycemia and dicarboxylic aciduria. The diagnosis is difficult due to the relatively unspecific clinical and biochemical presentation, and fewer than 30 patients have been described. This work describes three new patients with mHS deficiency and two missense mutations c.334C>T (p.R112W) and c.430G>T (p.V144L) previously not reported. We developed a new method to express and measure the activity of the enzyme and in this work the study is extended to ten new missense variants including those of our patients. Enzymatic assays showed that three of the mutant proteins retained some but seven completely lacked activity. The identification of a patient homozygous for a mutation that retains 70% of enzyme activity opens the door to a new interpretation of the disease by demonstrating that a modest impairment of enzyme function can actually produce symptoms. This is also the first study employing molecular dynamics modelling of the enzyme mutations. We show that the correct maintenance of the dimerization surface is crucial for retaining the structure of the active center and therefore the activity of the enzyme.","variants":[{"Name":"NM_005518.4(HMGCS2):c.334C>T (p.Arg112Trp)","Chromosome":"1","Start":"119764397","Stop":"119764397","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2104808,"rule_based_match":true,"evidence_text":"c.334C>T (p.R112W)","llm_judgment":"PRESENT","evidence":"c.334C>T (p.R112W)","abstract_start":540,"abstract_end":558}]}
{"pmid":"36067766","title":"The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability.","abstract":"MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending. MTSS2 is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants in MTSS2 have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygous de novo variant in MTSS2 (GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support that mim is important for appropriate neural function, and that the MTSS2 c.2011C>T variant causes a syndromic form of intellectual disability.","variants":[{"Name":"NM_138383.3(MTSS2):c.2011C>T (p.Arg671Trp)","Chromosome":"16","Start":"70663910","Stop":"70663910","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":965882,"rule_based_match":true,"evidence_text":"c.2011C>T [p.Arg671Trp]","llm_judgment":"PRESENT","evidence":"c.2011C>T [p.Arg671Trp]","abstract_start":402,"abstract_end":425}]}
{"pmid":"29499165","title":"Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4.","abstract":"In a large family of Czech origin, we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12. Whole-genome sequencing identified a unique variant (c.20+544G>T) in this locus, within an intronic regulatory region of GRHL2. Targeted sequencing identified the same variant in three additional previously unsolved PPCD-affected families, including a de novo occurrence that suggests this is a recurrent mutation. Two further unique variants were identified in intron 1 of GRHL2 (c.20+257delT and c.20+133delA) in unrelated PPCD-affected families. GRHL2 is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT) and is a direct transcriptional repressor of ZEB1. ZEB1 mutations leading to haploinsufficiency cause PPCD3. We previously identified promoter mutations in OVOL2, a gene not normally expressed in the corneal endothelium, as the cause of PPCD1. OVOL2 drives mesenchymal-to-epithelial transition (MET) by directly inhibiting EMT-inducing transcription factors, such as ZEB1. Here, we demonstrate that the GRHL2 regulatory variants identified in PPCD4-affected individuals induce increased transcriptional activity in vitro. Furthermore, although GRHL2 is not expressed in corneal endothelial cells in control tissue, we detected GRHL2 in the corneal \"endothelium\" in PPCD4 tissue. These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type. We suggest that mutations inducing MET within the corneal endothelium are a convergent pathogenic mechanism leading to dysfunction of the endothelial barrier and disease.","variants":[{"Name":"NM_024915.4(GRHL2):c.20+544G>T","Chromosome":"8","Start":"101493333","Stop":"101493333","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":482320,"rule_based_match":true,"evidence_text":"c.20+544G>T","llm_judgment":"PRESENT","evidence":"c.20+544G>T","abstract_start":233,"abstract_end":244}]}
{"pmid":"33449224","title":"Double heterozygosity for TP53 and BRCA1 mutations: clinical implications in populations with founder mutations.","abstract":"PURPOSE: The co-occurrence or double heterozygosity of pathogenic/likely pathogenic sequence variants (P/LPSVs) in major cancer susceptibility genes has rarely been reported. Such co-occurrence raises the issues of accurate genetic counseling, preferred recommended surveillance scheme, and the use of preimplantation genetic diagnosis (PGD).\nMETHODS: A clinical report of an Ashkenazi Jewish (AJ) family with co occurrence of two PSVs in BRCA1 and TP53 and a literature search.\nRESULTS: In an AJ family with a substantial history of cancer limited to the maternal side, two siblings co-harbored TP53 (c.733C>A; p.G245S) and the predominant 5266dup BRCA1 mutation, originating from the mother and the father, respectively. PGD is ongoing. Four families were thus far reported as double heterozygotes for both BRCA1/BRCA2 and TP53. Based on the limited available data, it seems that the phenotype in double PSV heterozygotes is not more severe than in single PSV carrier in either gene.\nCONCLUSIONS: This family highlights the need to genotype both parents, especially in populations with founder mutations, when a BRCA1 mutation is detected in an offspring, regardless of family history. The combination of mutations in these two genes presents a challenge for PGD since both genes are located on chromosome 17.","variants":[{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":false,"evidence_text":"5266dup BRCA1","llm_judgment":"PRESENT","evidence":"5266dup BRCA1","abstract_start":641,"abstract_end":654}]}
{"pmid":"19472408","title":"GM1 gangliosidosis and Morquio B disease: expression analysis of missense mutations affecting the catalytic site of acid beta-galactosidase.","abstract":"Alterations in GLB1, the gene coding for acid beta-D-galactosidase (beta-Gal), can result in GM1 gangliosidosis (GM1), a neurodegenerative disorder, or in Morquio B disease (MBD), a phenotype with dysostosis multiplex and normal central nervous system (CNS) function. While most MBD patients carry a common allele, c.817TG>CT (p.W273L), only few of the >100 mutations known in GM1 can be related to a certain phenotype. In 25 multiethnic patients with GM1 or MBD, 11 missense mutations were found as well as one novel insertion and a transversion causing aberrant gene products. Except c.602G>A (p.R201H) and two novel alleles, c.592G>T (p.D198Y) and c.1189C>G (p.P397A), all mutants resulted in significantly reduced beta-Gal activities (<10% of normal) upon expression in COS-1 cells. Although c.997T>C (p.Y333H) expressed 3% of normal activity, the mutant protein was localized in the lysosomal-endosomal compartment. A homozygous case presented with late infantile GM1, while a heterozygous, juvenile case carried p.Y333H together with p.R201H. This allele, recently found in homozygous MBD, gives rise to rough endoplasmic reticulum (RER)-located beta-Gal precursors. Thus, unlike classical MBD, the phenotype of heterozygotes carrying p.R201H may rather be determined by poorly active, properly transported products of the counter allele than by the mislocalized p.R201H precursors.","variants":[{"Name":"NM_000404.4(GLB1):c.602G>A (p.Arg201His)","Chromosome":"3","Start":"33058220","Stop":"33058220","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":195238,"rule_based_match":true,"evidence_text":"c.602G>A (p.R201H)","llm_judgment":"PRESENT","evidence":"c.602G>A (p.R201H)","abstract_start":586,"abstract_end":604}]}
{"pmid":"23977234","title":"A BAP1 mutation in a Danish family predisposes to uveal melanoma and other cancers.","abstract":"Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma. There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers. Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained. Here we describe a Danish family with predominantly uveal melanoma but also a range of other tumor types including lung, neuroendocrine, stomach, and breast cancer; as well as pigmented skin lesions. Whole-exome sequencing identified a BAP1 splice mutation located at c.581-2A>G, which leads to a premature truncation of BAP1 in an individual with uveal melanoma. This mutation was carried by several other family members with melanoma or various cancers. The finding expands on the growing profile of BAP1 as an important uveal and cutaneous melanoma tumor suppressor gene and implicates its involvement in the development of lung, and stomach cancer.","variants":[{"Name":"NM_004656.4(BAP1):c.581-2A>G","Chromosome":"3","Start":"52406909","Stop":"52406909","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1059883,"rule_based_match":true,"evidence_text":"c.581-2A>G","llm_judgment":"PRESENT","evidence":"c.581-2A>G","abstract_start":832,"abstract_end":842}]}
{"pmid":"30805891","title":"Whole exome sequencing identified three ABCC6 variants in two Pakistani families with pseudoxanthoma elasticum phenotype.","abstract":"Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of ectopic mineralization and fragmentation of elastic fibers in skin, eyes, cardiovascular and digestive system. PXE is caused by sequence variants in ABCC6, which encodes multidrug resistance-associated protein 6 (MRP6, also known as the ABCC6 protein). MRP6 is an important regulator of inorganic plasma pyrophosphate that acts as an inhibitor of ectopic mineralization observed in PXE patients with low inorganic plasma pyrophosphate levels. The current study was designed to investigate underlying genetic defect in two unrelated Pakistani families affected with PXE. Whole exome sequencing followed by Sanger sequencing was performed to identify causative variants. A novel homozygous frameshift variant (c.1799_1805dupGTCTGGT) was identified in one family and two previously reported missense variants (c.2294G > A and c.2974G > A) in compound heterozygous form in the other family. We identified ABCC6 variants that are likely cause of the PXE disease in the tested families. Genetic analysis of these families could be useful for pre-symptomatic diagnosis and genetic counselling of the affected families.","variants":[{"Name":"NM_001171.6(ABCC6):c.2974G>A (p.Gly992Arg)","Chromosome":"16","Start":"16169667","Stop":"16169667","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":426902,"rule_based_match":true,"evidence_text":"c.2974G > A","llm_judgment":"PRESENT","evidence":"c.2974G > A","abstract_start":892,"abstract_end":903},{"Name":"NM_001171.6(ABCC6):c.2294G>A (p.Arg765Gln)","Chromosome":"16","Start":"16178919","Stop":"16178919","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39293,"rule_based_match":true,"evidence_text":"c.2294G > A","llm_judgment":"PRESENT","evidence":"c.2294G > A","abstract_start":876,"abstract_end":887}]}
{"pmid":"17531263","title":"A single hERG mutation underlying a spectrum of acquired and congenital long QT syndrome phenotypes.","abstract":"The long QT syndrome (LQTS) is a multi-factorial disorder that predisposes to life-threatening arrhythmias. Both hereditary and acquired subforms have been identified. Here, we present clinical and biophysical evidence that the hERG mutation c.1039 C>T (p.Pro347Ser or P347S) is responsible for both the acquired and the congenital phenotype. In one case the genotype remained silent for years until the administration of several QT-prolonging drugs resulted into a full-blown phenotype, that was reversible upon cessation of these compounds. On the other hand the mutation was responsible for a symptomatic congenital LQTS in a Dutch family, displaying a substantial heterogeneity of the clinical symptoms. Biophysical characterization of the p.Pro347Ser potassium channels using whole-cell patch clamp experiments revealed a novel pathogenic mechanism of reciprocal changes in the inactivation kinetics combined with a dominant-negative reduction of the functional expression in the heterozygous situation, yielding a modest genetic predisposition for LQTS. Our data show that in the context of the multi-factorial aetiology underlying LQTS a modest reduction of the repolarizing power can give rise to a spectrum of phenotypes originating from one mutation. This observation increases the complexity of genotype-phenotype correlations in more lenient manifestations of the disease and underscores the difficulty of predicting the expressivity of the LQTS especially for mutations with a more subtle impact such as p.Pro347Ser.","variants":[{"Name":"NM_000238.4(KCNH2):c.1039C>T (p.Pro347Ser)","Chromosome":"7","Start":"150957380","Stop":"150957380","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":78059,"rule_based_match":true,"evidence_text":"c.1039 C>T (p.Pro347Ser or P347S)","llm_judgment":"PRESENT","evidence":"c.1039 C>T (p.Pro347Ser or P347S)","abstract_start":242,"abstract_end":275}]}
{"pmid":"32633627","title":"Anaplastic Thyroid Cancer Arising from Dyshormonogenetic Goiter: c.3070T>C and Novel c.7070T>C Mutation in the Thyroglobulin Gene.","abstract":"Concomitant thyroid cancer in patients with congenital thyroid dyshormonogenesis (TD) is extremely rare and few cases of differentiated thyroid cancer in patients with TD have been reported thus far. In this study, we describe anaplastic thyroid cancer in a 46-year-old woman with TD who had two germline thyroglobulin (<i>TG</i>) gene mutation, c.3790T>C (p, Cys1264Arg) in exon 17 and a novel c.7070T>C (p.Leu2357Pro) in exon 41 of the <i>TG</i> gene. Two affected younger sisters were also found to have the same <i>TG</i> mutation but not anaplastic thyroid cancer. Any thyroid nodular lesions that develop in patients with TD should be investigated carefully.","variants":[{"Name":"NM_003235.5(TG):c.3790T>C (p.Cys1264Arg)","Chromosome":"8","Start":"132906843","Stop":"132906843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2901251,"rule_based_match":true,"evidence_text":"c.3790T>C (p, Cys1264Arg)","llm_judgment":"PRESENT","evidence":"c.3790T>C (p, Cys1264Arg)","abstract_start":346,"abstract_end":371}]}
{"pmid":"28397226","title":"Analysis of clinical features and GALNS gene mutation in a patient with mucopolysaccharidosis type IV A","abstract":"OBJECTIVE: To detect potential mutation of galactosamine-6-sulfate (GALNS) gene in a Chinese girl affected with mucopolysaccharidosis type IV A (Morquio A syndrome).\nMETHODS: The patient was diagnosed by assaying the activities of mucopolysaccharidosis-related enzymes in leukocytes. Potential mutation in the GALNS gene was detected with PCR and Sanger sequencing.\nRESULTS: The patient was characterized by short stature, skeletal deformities, normal intelligence, and auditory dysfunction. The activities of GALNS enzymes were low. A compound heterozygous missense mutation, c.1094G>T (p.Gly365Val)/c.938C>T (p.Thr313Met), was detected in the GALNS gene. The mutations were respectively inherited from her father and mother. Among them, the c.1094G>T (p.Gly365Val) mutation was not reported previously.\nCONCLUSION: The mutations c.1094G>T (p.Gly365Val)/c.938C>T (p.Thr313Met) probably underlie the pathogenesis of the disease in our patient.","variants":[{"Name":"NM_000512.5(GALNS):c.938C>T (p.Thr313Met)","Chromosome":"16","Start":"88832062","Stop":"88832062","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1036229,"rule_based_match":true,"evidence_text":"c.938C>T (p.Thr313Met)","llm_judgment":"PRESENT","evidence":"c.938C>T (p.Thr313Met)","abstract_start":601,"abstract_end":623},{"Name":"NM_000512.5(GALNS):c.1094G>T (p.Gly365Val)","Chromosome":"16","Start":"88826747","Stop":"88826747","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1036191,"rule_based_match":true,"evidence_text":"c.1094G>T (p.Gly365Val)","llm_judgment":"PRESENT","evidence":"c.1094G>T (p.Gly365Val)","abstract_start":577,"abstract_end":600}]}
{"pmid":"30639582","title":"Genetic analysis of 63 Chinese patients with mucopolysaccharidosis type II: Functional characterization of seven novel IDS variants.","abstract":"Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal storage disorder resulting from the deficiency of the enzyme iduronate-2-sulfatase (IDS).This study described the molecular characteristics of 63 Chinese children with MPS II and investigated functional characterization of seven novel IDS variants. We analyzed mutations in the IDS gene of 63 children with MPS II. Seven novel mutations were further characterized by transient expression studies. 49 different mutations were identified in the IDS gene including 33 previously reported and 16 novel mutations. The mutation p.R443X and c.1122C > T(p.G374G) may be link to attenuated type. The novel missense mutations were predicted damaging in silico. The bioinformatic structural analysis of the novel missense mutations showed that these amino acid replacements would cause a severe impairment of protein structure and function. In vitro functional analysis of the seven novel mutants, showing a very low IDS activity, clearly demonstrated their pathogenic nature. In western blotting analysis of the IDS protein, the examined mutations showed a similar or slightly lower molecular mass of precursor without mature forms being detected. Our study expands the spectrum of genotype of MPS II, provides new insights into the molecular mechanism of MPS II and helps to the future studies of genotype-phenotype correlations to estimate prognosis and develop new therapeutic approach.","variants":[{"Name":"NM_000202.8(IDS):c.1122C>T (p.Gly374=)","Chromosome":"X","Start":"149486983","Stop":"149486983","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25530,"rule_based_match":true,"evidence_text":"c.1122C>T(p.G374G)","llm_judgment":"PRESENT","evidence":"c.1122C > T(p.G374G)","abstract_start":608,"abstract_end":628}]}
{"pmid":"37718511","title":"BRCA1 frameshift variants leading to extended incorrect protein C termini.","abstract":"Carriers of BRCA1 germline pathogenic variants are at substantially higher risk of developing breast and ovarian cancer than the general population. Accurate identification of at-risk individuals is crucial for risk stratification and the implementation of targeted preventive and therapeutic interventions. Despite significant progress in variant classification efforts, a sizable portion of reported BRCA1 variants remain as variants of uncertain clinical significance (VUSs). Variants leading to premature protein termination and loss of essential functional domains are typically classified as pathogenic. However, the impact of frameshift variants that result in an extended incorrect terminus is not clear. Using validated functional assays, we conducted a systematic functional assessment of 17 previously reported BRCA1 extended incorrect terminus variants (EITs) and concluded that 16 constitute loss-of-function variants. This suggests that most EITs are likely to be pathogenic. However, one variant, c.5578dup, displayed a protein expression level, affinity to known binding partners, and activity in transcription and homologous recombination assays comparable to the wild-type BRCA1 protein. Twenty-three additional carriers of c.5578dup were identified at a US clinical diagnostic lab and assessed using a family history likelihood model providing, in combination with the functional data, a likely benign interpretation. These results, consistent with family history data in the current study and available data from ClinVar, indicate that most, but not all, BRCA1 variants leading to an extended incorrect terminus constitute loss-of-function variants and underscore the need for comprehensive assessment of individual variants.","variants":[{"Name":"NM_007294.4(BRCA1):c.5578dup (p.His1860fs)","Chromosome":"17","Start":"43045691","Stop":"43045692","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":46239,"rule_based_match":true,"evidence_text":"c.5578dup","llm_judgment":"PRESENT","evidence":"c.5578dup","abstract_start":1012,"abstract_end":1021}]}
{"pmid":"24926462","title":"A novel de novo mutation within PHEX gene in a young girl with hypophosphatemic rickets and review of literature.","abstract":"X-linked hypophosphatemia (XLH) is the most common form of familial hypophosphatemic rickets and it is caused by loss-of-function mutations in the PHEX gene. Recently, a wide variety of PHEX gene defects in XLH have been revealed; these include missense mutations, nonsense mutations, splice site mutations, insertions, and deletions. Recently, we encountered a 2-year-9-month-old female with sporadic hypophosphatemic rickets. She underwent osteotomy, dental abscess was evident, and there was severe bowing of the legs. A low serum phosphorus level in combination with elevated serum alkaline phosphatase activity and normal serum calcium is suggestive of hypophosphatemic rickets. PHEX gene analysis revealed a splice acceptor site mutation, c.934-1G>T (IVS8(-1)G>T), at the intron8 and exon9 junction. To the best of our knowledge, this mutation is novel and has not been reported. The results of this study expand and improve our understanding of the clinical and molecular characteristics and the global pool of patients with sporadic hypophosphatemic rickets.","variants":[{"Name":"NM_000444.6(PHEX):c.934-1G>T","Chromosome":"X","Start":"22099005","Stop":"22099005","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":792219,"rule_based_match":true,"evidence_text":"c.934-1G>T (IVS8(-1)G>T)","llm_judgment":"PRESENT","evidence":"c.934-1G>T (IVS8(-1)G>T)","abstract_start":745,"abstract_end":769}]}
{"pmid":"32533362","title":"A novel variant in GPAA1, encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various phenotypes.","abstract":"Vascular anomalies (VAs), comprising wide subtypes of tumors and malformations, are often caused by variants in multiple tyrosine kinase (TK) receptor signaling pathways including TIE2, PIK3CA and GNAQ/11. Yet, a portion of individuals with clinical features of VA do not have variants in these genes, suggesting that there are undiscovered pathogenic factors underlying these patients and possibly with overlapping phenotypes. Here, we identified one rare non-synonymous variant (c.968A > G) in the seventh exon of GPAA1 (Glycosylphosphatidylinositol Anchor Attachment Protein 1), shared by the four affected members of a large pedigree with multiple types of VA using whole-exome sequencing. GPAA1 encodes a glycosylphosphatidylinositol (GPI) transamidase complex protein. This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum (ER). We showed such variant led to scarce expression of GPAA1 protein in vascular endothelium and induced a localization change from ER membrane to cytoplasm and nucleus. In addition, expressing wild-type GPAA1 in endothelial cells had an effect to inhibit cell proliferation and migration, while expressing variant GPAA1 led to overgrowth and overmigration, indicating a loss of the quiescent status. Finally, a gpaa1-deficient zebrafish model displayed several types of developmental defects as well as vascular dysplasia, demonstrating that GPAA1 is involved in angiogenesis and vascular remodeling. Altogether, our results indicate that the rare coding variant in GPAA1 (c.968A > G) is causally related to familial forms of VAs.","variants":[{"Name":"NM_003801.4(GPAA1):c.968A>G (p.Asn323Ser)","Chromosome":"8","Start":"144084567","Stop":"144084567","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1434555,"rule_based_match":true,"evidence_text":"c.968A > G","llm_judgment":"PRESENT","evidence":"c.968A > G","abstract_start":481,"abstract_end":491}]}
{"pmid":"31250547","title":"An emerging ribosomopathy affecting the skeleton due to biallelic variations in NEPRO.","abstract":"Cartilage hair hypoplasia (CHH), anauxetic dysplasia 1, and anauxetic dysplasia 2 are rare metaphyseal dysplasias caused by biallelic pathogenic variants in RMRP and POP1, which encode the components of RNAse-MRP endoribonuclease complex (RMRP) in ribosomal biogenesis pathway. Nucleolus and neural progenitor protein (NEPRO), encoded by NEPRO (C3orf17), is known to interact with multiple protein subunits of RMRP. We ascertained a 6-year-old girl with skeletal dysplasia and some features of CHH. RMRP and POP1 did not harbor any causative variant in the proband. Parents-child trio exomes revealed a candidate biallelic variant, c.435G>C, p.(Leu145Phe) in NEPRO. Two families with four affected individuals with skeletal dysplasia and a homozygous missense variant, c.280C>T, p.(Arg94Cys) in NEPRO, were identified from literature and their published phenotype was compared in detail to the phenotype of the child we described. All the five affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. Protein modeling and stability prediction showed that the mutant protein has decreased stability. Both the reported variants are in the same domain of the protein. Our report delineates the clinical and radiological characteristics of an emerging ribosomopathy caused by biallelic variants in NEPRO.","variants":[{"Name":"NM_015412.4(NEPRO):c.435G>C (p.Leu145Phe)","Chromosome":"3","Start":"113013310","Stop":"113013310","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":857997,"rule_based_match":true,"evidence_text":"c.435G>C, p.(Leu145Phe)","llm_judgment":"PRESENT","evidence":"c.435G>C, p.(Leu145Phe)","abstract_start":632,"abstract_end":655}]}
{"pmid":"27783279","title":"Frequency of pathogenic germline mutation in CHEK2, PALB2, MRE11, and RAD50 in patients at high risk for hereditary breast cancer.","abstract":"PURPOSE: This study was performed to evaluate the frequency of mutations in CHEK2, PALB2, MRE11, and RAD50 among Korean patients at high risk for hereditary breast cancer.\nMETHODS: A total of 235 Korean patients with hereditary breast cancer who tested negative for BRCA1/2 mutation were enrolled to this study. Entire coding regions of CHEK2, PALB2, MRE11, and RAD50 were analyzed using massively parallel sequencing (MPS). Sequence variants detected by MPS were confirmed by Sanger sequencing.\nRESULTS: Six patients (2.5 %) were found to have pathogenic variants in CHEK2 (n = 1), PALB2 (n = 2), MRE11 (n = 1), and RAD50 (n = 2). Among the pathogenic variants, PALB2 c.2257C>T was previously reported in other studies, while CHEK2 c.1245dupC, PALB2 c.1048C>T, MRE11 c.1773_1774delAA, RAD50 c.1276C>T, and RAD50 c.3811_3813delGAA were newly identified in this study. A total of 15 missense variants were found in the four genes among 26 patients; 7 patients had a variant in CHEK2, 11 in PALB2, 2 in MRE11, and 6 in RAD50. When in silico analyses were performed to the 15 missense variants, six variants (CHEK2 c.686A>G, PALB2 c.1492G>T, PALB2 c.3054G>C, MRE11 c.140C>T, RAD50 c.1456C>T, and RAD50 c.3790C>T) were predicted to be deleterious.\nCONCLUSIONS: Pathogenic variants in CHEK2, PALB2, MRE11, and RAD50 were detected in a small proportion of Korean patients with features of hereditary breast cancer.","variants":[{"Name":"NM_024675.4(PALB2):c.1492G>T (p.Asp498Tyr)","Chromosome":"16","Start":"23635054","Stop":"23635054","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":180736,"rule_based_match":true,"evidence_text":"PALB2 c.1492G>T","llm_judgment":"PRESENT","evidence":"PALB2 c.1492G>T","abstract_start":1122,"abstract_end":1137},{"Name":"NM_005732.4(RAD50):c.1456C>T (p.Arg486Cys)","Chromosome":"5","Start":"132591227","Stop":"132591227","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":151269,"rule_based_match":true,"evidence_text":"RAD50 c.1456C>T","llm_judgment":"PRESENT","evidence":"RAD50 c.1456C>T","abstract_start":1172,"abstract_end":1187},{"Name":"NM_024675.4(PALB2):c.1048C>T (p.Gln350Ter)","Chromosome":"16","Start":"23635498","Stop":"23635498","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":401810,"rule_based_match":true,"evidence_text":"PALB2 c.1048C>T","llm_judgment":"PRESENT","evidence":"PALB2 c.1048C>T","abstract_start":745,"abstract_end":760},{"Name":"NM_005732.4(RAD50):c.3790C>T (p.Leu1264Phe)","Chromosome":"5","Start":"132642215","Stop":"132642215","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":150644,"rule_based_match":true,"evidence_text":"RAD50 c.3790C>T","llm_judgment":"PRESENT","evidence":"RAD50 c.3790C>T","abstract_start":1193,"abstract_end":1208},{"Name":"NM_024675.4(PALB2):c.2257C>T (p.Arg753Ter)","Chromosome":"16","Start":"23629897","Stop":"23629897","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152117,"rule_based_match":true,"evidence_text":"PALB2 c.2257C>T","llm_judgment":"PRESENT","evidence":"PALB2 c.2257C>T","abstract_start":663,"abstract_end":678},{"Name":"NM_024675.4(PALB2):c.3054G>C (p.Glu1018Asp)","Chromosome":"16","Start":"23621421","Stop":"23621421","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":132218,"rule_based_match":true,"evidence_text":"PALB2 c.3054G>C","llm_judgment":"PRESENT","evidence":"PALB2 c.3054G>C","abstract_start":1139,"abstract_end":1154},{"Name":"NM_005591.4(MRE11):c.140C>T (p.Ala47Val)","Chromosome":"11","Start":"94490846","Stop":"94490846","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":178875,"rule_based_match":true,"evidence_text":"MRE11 c.140C>T","llm_judgment":"PRESENT","evidence":"MRE11 c.140C>T","abstract_start":1156,"abstract_end":1170}]}
{"pmid":"27098783","title":"Mutation Analysis of Gap Junction Protein Beta 1 and Genotype-Phenotype Correlation in X-linked Charcot-Marie-Tooth Disease in Chinese Patients.","abstract":"BACKGROUND: Among patients with Charcot-Marie-Tooth disease (CMT), the X-linked variant (CMTX) caused by gap junction protein beta 1 (GJB1) gene mutation is the second most frequent type, accounting for approximately 90% of all CMTX. More than 400 mutations have been identified in the GJB1 gene that encodes connexin 32 (CX32). CX32 is thought to form gap junctions that promote the diffusion pathway between cells. GJB1 mutations interfere with the formation of the functional channel and impair the maintenance of peripheral myelin, and novel mutations are continually discovered.\nMETHODS: We included 79 unrelated patients clinically diagnosed with CMT at the Department of Neurology of the Chinese People's Liberation Army General Hospital from December 20, 2012, to December 31, 2015. Clinical examination, nerve conduction studies, and molecular and bioinformatics analyses were performed to identify patients with CMTX1.\nRESULTS: Nine GJB1 mutations (c.283G>A, c.77C>T, c.643C>T, c.515C>T, c.191G>A, c.610C>T, c.490C>T, c.491G>A, and c.44G>A) were discovered in nine patients. Median motor nerve conduction velocities of all nine patients were < 38 m/s, resembling CMT Type 1. Three novel mutations, c.643C>T, c.191G>A, and c.610C>T, were revealed and bioinformatics analyses indicated high pathogenicity.\nCONCLUSIONS: The three novel missense mutations within the GJB1 gene broaden the mutational diversity of CMT1X. Molecular analysis of family members and bioinformatics analyses of the afflicted patients confirmed the pathogenicity of these mutations.","variants":[{"Name":"NM_000166.6(GJB1):c.44G>A (p.Arg15Gln)","Chromosome":"X","Start":"71223751","Stop":"71223751","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":213891,"rule_based_match":true,"evidence_text":"c.44G>A","llm_judgment":"PRESENT","evidence":"c.44G>A","abstract_start":1042,"abstract_end":1049},{"Name":"NM_000166.6(GJB1):c.643C>T (p.Arg215Trp)","Chromosome":"X","Start":"71224350","Stop":"71224350","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":245189,"rule_based_match":true,"evidence_text":"c.643C>T","llm_judgment":"PRESENT","evidence":"c.643C>T","abstract_start":978,"abstract_end":986},{"Name":"NM_000166.6(GJB1):c.490C>T (p.Arg164Trp)","Chromosome":"X","Start":"71224197","Stop":"71224197","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":213894,"rule_based_match":true,"evidence_text":"c.490C>T","llm_judgment":"PRESENT","evidence":"c.490C>T","abstract_start":1018,"abstract_end":1026},{"Name":"NM_000166.6(GJB1):c.191G>A (p.Cys64Tyr)","Chromosome":"X","Start":"71223898","Stop":"71223898","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625522,"rule_based_match":true,"evidence_text":"c.191G>A","llm_judgment":"PRESENT","evidence":"c.191G>A","abstract_start":998,"abstract_end":1006},{"Name":"NM_000166.6(GJB1):c.515C>T (p.Pro172Leu)","Chromosome":"X","Start":"71224222","Stop":"71224222","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":471000,"rule_based_match":true,"evidence_text":"c.515C>T","llm_judgment":"PRESENT","evidence":"c.515C>T","abstract_start":988,"abstract_end":996}]}
{"pmid":"32645618","title":"The mutation frequencies of GJB2, GJB3, SLC26A4 and MT-RNR1 of patients with severe to profound sensorineural hearing loss in northwest China.","abstract":"OBJECTIVE: To expose the spectrum and frequency of GJB2, GJB3, SLC26A4 and MT-RNR1 in northwest China and to investigate the underlying causative genes in patients without common mutations.\nMETHODS: We analyzed the mutation screening results of GJB2, GJB3, SLC26A4 and MT-RNR1 in 398 unrelated severe-to-profound probands with bilateral, symmetrical sensorineural hearing loss. Subsequently, we selected 10 probands with a significant family history of inherited hearing loss (HL) that did not have the above four common gene mutations to perform next-generation sequencing (NGS) of 139 known deafness genes, followed by co-segregation analysis of all available family members.\nRESULTS: Among the 398 patients, 69 (17.34%) had the biallelic GJB2 gene mutations, and the most common mutations were c.235delC, c.109G>A and c.299_300delAT, with allele frequencies of 12.31%, 3.38% and 3.89%, respectively. A total of 63 (15.83%) cases with biallelic SLC26A4 mutations were detected, and the most common pathogenic alleles were c.919-2A>G, c.2168A>G and c.1174A>T, with allele frequencies of 9.17%, 2.26% and 0.88%, respectively. Mitochondrial gene mutations were detected in 9 (2.26%) patients, with 5 cases of mitochondrial DNA (mtDNA) m.1555A>G mutation and 4 cases of mtDNA m.1095T>C mutation. In 10 probands with a clear family history of HL, NGS showed two novel pathogenic variants in 2 families, including c.4129C>T/c.3268C>T in LOXHD1, c.334G>A/c.2968G>T in CDH23. Sanger sequencing confirmed that these variants segregated with the HL in each family.\nCONCLUSIONS: Our results showed that GJB2 and SLC26A4 were the two major HL-causing genes in northwest China. The most common mutation alleles in GJB2 were c.235delC, c.109G>A and c.299_300delAT, and those in SLC26A4 were c.919-2A>G, c.2168A>G and c.1174A>T. In addition, both genes and their loci can be used as the first selection of deafness gene screening. Additionally, for patients who did not have mutations of these common genes, NGS provided an efficient diagnosis for increasing known deafness genes.","variants":[{"Name":"NM_001384474.1(LOXHD1):c.4129C>T (p.Arg1377Trp)","Chromosome":"18","Start":"46534418","Stop":"46534418","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2020317,"rule_based_match":true,"evidence_text":"c.4129C>T","llm_judgment":"PRESENT","evidence":"c.4129C>T","abstract_start":1410,"abstract_end":1419}]}
{"pmid":"29131652","title":"Novel Homozygous LRP5 Mutations in Mexican Patients with Osteoporosis-Pseudoglioma Syndrome.","abstract":"AIMS: Osteoporosis-pseudoglioma syndrome (OPPG) is an uncommon autosomal recessive disorder characterized by the rare association of early-onset osteoporosis and severe ocular abnormalities such as persistent fetal vasculature and microphthalmia. Biallelic mutations in the low-density lipoprotein receptor-related protein-5 gene (LRP5) have been associated with OPPG. We present clinical and genetic data from three Mexican OPPG patients, a pair of sibs, and a sporadic case.\nMATERIALS AND METHODS: Three patients underwent clinical examination, including a complete ophthalmic evaluation. Based on the clinical diagnosis of OPPG, the entire coding sequence of LRP5 was polymerase chain reaction-amplified and directly Sanger-sequenced. Genetic testing was extended to the parents of the affected patients.\nRESULTS: Phenotypic variability was observed in the familial case and molecular analysis identified a novel homozygous c.1145C>T, p.(Pro382Leu) variant in both sibs. As expected, their parents were heterozygous carriers. The sporadic patient exhibited a severe osseous phenotype, microphthalmia, and neurological symptoms. In this patient, homozygosity for the c.442C>T, p.(Gln148*) variant was demonstrated, whereas her parents were heterozygous carriers. The p.(Pro382Leu) pathogenic mutation has been previously reported only in a compound heterozygous state in OPPG patients.\nCONCLUSIONS: Two novel homozygous missense and nonsense variants were demonstrated in three OPPG cases from Mexico. Our results expand the spectrum of disease-causing LRP5 mutations. This is the first report of OPPG in our population and our findings may potentially add to a genotype-phenotype correlation.","variants":[{"Name":"NM_002335.4(LRP5):c.1145C>T (p.Pro382Leu)","Chromosome":"11","Start":"68386445","Stop":"68386445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48771,"rule_based_match":true,"evidence_text":"c.1145C>T, p.(Pro382Leu)","llm_judgment":"PRESENT","evidence":"c.1145C>T, p.(Pro382Leu)","abstract_start":927,"abstract_end":951},{"Name":"NM_002335.4(LRP5):c.442C>T (p.Gln148Ter)","Chromosome":"11","Start":"68348197","Stop":"68348197","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":935734,"rule_based_match":true,"evidence_text":"c.442C>T, p.(Gln148*)","llm_judgment":"PRESENT","evidence":"c.442C>T, p.(Gln148*)","abstract_start":1169,"abstract_end":1190}]}
{"pmid":"32627184","title":"De novo missense variants in the RAP1B gene identified in two patients with syndromic thrombocytopenia.","abstract":"We present two independent cases of syndromic thrombocytopenia with multiple malformations, microcephaly, learning difficulties, dysmorphism and other features. Exome sequencing identified two novel de novo heterozygous variants in these patients, c.35G>T p.(Gly12Val) and c.178G>C p.(Gly60Arg), in the RAP1B gene (NM_001010942.2). These variants have not been described previously as germline variants, however functional studies in literature strongly suggest a clinical implication of these two activating hot spot positions. We hypothesize that pathogenic missense variants in the RAP1B gene cause congenital syndromic thrombocytopenia with a spectrum of associated malformations and dysmorphism, possibly through a gain of function mechanism.","variants":[{"Name":"NM_001010942.3(RAP1B):c.35G>T (p.Gly12Val)","Chromosome":"12","Start":"68648759","Stop":"68648759","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2839826,"rule_based_match":true,"evidence_text":"c.35G>T p.(Gly12Val)","llm_judgment":"PRESENT","evidence":"c.35G>T p.(Gly12Val)","abstract_start":248,"abstract_end":268},{"Name":"NM_001010942.3(RAP1B):c.178G>C (p.Gly60Arg)","Chromosome":"12","Start":"68652046","Stop":"68652046","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2839827,"rule_based_match":true,"evidence_text":"c.178G>C p.(Gly60Arg)","llm_judgment":"PRESENT","evidence":"c.178G>C p.(Gly60Arg)","abstract_start":273,"abstract_end":294}]}
{"pmid":"25304119","title":"R368X mutation in MID1 among recurrent mutations in patients with X-linked Opitz G/BBB syndrome.","abstract":"Opitz G/BBB syndrome is a genetically heterogeneous condition, with both autosomal dominant and X-linked forms. The MID1 gene is associated with X-linked Opitz G/BBB syndrome. Most mutations identified are unique, which makes it difficult to assess possible genotype/phenotype correlations. We report on a familial c.1102C>T (p.R368X) mutation in the MID1 gene, previously reported by Cox et al. (Hum Mol Genet 9:2553-2562, 2000), and document it as a recurrent mutation causing Opitz G/BBB syndrome. This mutation may result in various midline defects, including cleft lip/palate, laryngeal cleft, hypertelorism, Dandy-Walker malformation, ventricular septal defect and hypospadias in male patients, with intrafamilial variability. Seven other mutations (c.712G>T, c.829C>T, c.1108A>G, c.1444_1447dupAACA, c.1483C>T, c.1798dupC and entire gene deletions) have been previously reported as recurrent mutations. The presented family with the c.1102C>T mutation provides additional information about the clinical consequences of the nonsense mutation causing premature truncation of the protein at the level of the COS domain.","variants":[{"Name":"NM_000381.4(MID1):c.1102C>T (p.Arg368Ter)","Chromosome":"X","Start":"10474662","Stop":"10474662","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1695251,"rule_based_match":true,"evidence_text":"c.1102C>T (p.R368X)","llm_judgment":"PRESENT","evidence":"c.1102C>T (p.R368X)","abstract_start":315,"abstract_end":334}]}
{"pmid":"30684275","title":"Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights.","abstract":"Lysosomal acid lipase deficiency (LAL-D) is a multi-organ autosomal recessive disease caused by mutations in LIPA. We reviewed data from 681 samples (white blood cells [WBC] n = 625, fibroblasts = 30, liver = 4, amniocytes = 13, chorionic villus = 9) received for analysis of lysosomal acid lipase (LAL) activity over a 15-year period. LIPA sequencing was performed in 49 patients with reduced (n = 26) or deficient (n = 23) LAL activity. The Exome Aggregation Consortium and Genome Aggregation Database dataset were used for LAL-D prevalence calculations. LAL WBC activity was reduced in 67 patients (10.72%) and deficient in 37 (5.92%). The average of LAL activity ± margin of error (CI 95%) was 19.32 ± 0.86 pmol/min/mg for reduced activity patients and 5.90 ± 1.42 pmol/min/mg for deficient patients. The average age at diagnosis for LAL-D was 23.6 years with several patients older than age 30. The correlation between the age at diagnosis and LAL activity showed a significant moderate direct correlation (Pearson's r = 0.46, P < 0.005). Homozygous or compound heterozygous mutations were identified in 9 out of 23 patients with deficient results (detection rate 39.1%). The average LAL activity in molecularly confirmed patients was 4.02 ± 2.02 pmol/min/mg protein, while in molecularly negative patients was 13.886 ± 1.49 pmol/min/mg (P < 0.0001). Twenty-two different mutations were identified including two novel variants (c.309C>A and c.856G>C). A carrier frequency of approximately 1 in 350 was inferred. LAL activity in WBC is a validated tool for LAL-D diagnosis. Higher residual enzymatic activity might result in a milder phenotype leading to diagnosis delay. A cut-off below 12 pmol/min/mg protein might be useful to discriminate patients with LIPA mutations.","variants":[{"Name":"NM_000235.4(LIPA):c.309C>A (p.Ser103Arg)","Chromosome":"10","Start":"89228319","Stop":"89228319","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":545647,"rule_based_match":true,"evidence_text":"c.309C>A","llm_judgment":"PRESENT","evidence":"c.309C>A","abstract_start":1433,"abstract_end":1441}]}
{"pmid":"32571458","title":"Mutations in aminoacyl-tRNA synthetase genes: an analysis of 10 cases","abstract":"OBJECTIVE: To study the clinical features of the diseases associated with aminoacyl-tRNA synthetases (ARS) deficiency.\nMETHODS: A retrospective analysis was performed of the clinical and gene mutation data of 10 children who were diagnosed with ARS gene mutations, based on next-generation sequencing from January 2016 to October 2019.\nRESULTS: The age of onset ranged from 0 to 9 years among the 10 children. Convulsion was the most common initial symptom (7 children). Clinical manifestations included ataxia and normal or mildly retarded intellectual development (with or without epilepsy; n=4) and onset of epilepsy in childhood with developmental regression later (n=2). Some children experienced disease onset in the neonatal period and had severe epileptic encephalopathy, with myoclonus, generalized tonic-clonic seizure, and convulsive seizure (n=4); 3 had severe delayed development, 2 had feeding difficulty, and 1 had hearing impairment. Mutations were found in five genes: 3 had novel mutations in the AARS2 gene (c.331G>C, c.2682+5G>A, c.2164C>T, and c.761G>A), 2 had known mutations in the DARS2 gene (c.228-16C>A and c.536G>A), 1 had novel mutations in the CARS2 gene (c.1036C>T and c.323T>G), 1 had novel mutations in the RARS2 gene (c.1210A>G and c.622C>T), and 3 had novel mutations in the AARS gene (c.1901T>A, c.229C>T, c.244C>T, c.961G>C, c.2248C>T, and Chr16:70298860-70316687del).\nCONCLUSIONS: A high heterogeneity is observed in the clinical phenotypes of the diseases associated with the ARS deficiency. A total of 14 novel mutations in 5 genes are reported in this study, which enriches the clinical phenotypes and genotypes of the diseases associated with ARS deficiency.","variants":[{"Name":"NM_018122.5(DARS2):c.228-16C>A","Chromosome":"1","Start":"173828317","Stop":"173828317","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1170626,"rule_based_match":true,"evidence_text":"c.228-16C>A","llm_judgment":"PRESENT","evidence":"c.228-16C>A","abstract_start":1117,"abstract_end":1128},{"Name":"NM_018122.5(DARS2):c.536G>A (p.Arg179His)","Chromosome":"1","Start":"173833419","Stop":"173833419","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16103,"rule_based_match":true,"evidence_text":"c.536G>A","llm_judgment":"PRESENT","evidence":"c.536G>A","abstract_start":1133,"abstract_end":1141},{"Name":"NM_020320.5(RARS2):c.1210A>G (p.Met404Val)","Chromosome":"6","Start":"87519610","Stop":"87519610","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2833266,"rule_based_match":true,"evidence_text":"c.1210A>G","llm_judgment":"PRESENT","evidence":"c.1210A>G","abstract_start":1251,"abstract_end":1260},{"Name":"NM_024537.4(CARS2):c.1036C>T (p.Arg346Trp)","Chromosome":"13","Start":"110651052","Stop":"110651052","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":936341,"rule_based_match":true,"evidence_text":"c.1036C>T","llm_judgment":"PRESENT","evidence":"c.1036C>T","abstract_start":1185,"abstract_end":1194},{"Name":"NM_024537.4(CARS2):c.323T>G (p.Phe108Cys)","Chromosome":"13","Start":"110701508","Stop":"110701508","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":936347,"rule_based_match":true,"evidence_text":"c.323T>G","llm_judgment":"PRESENT","evidence":"c.323T>G","abstract_start":1199,"abstract_end":1207}]}
{"pmid":"32252659","title":"Case reports: three novel variants in PCCA and PCCB genes in Chinese patients with propionic acidemia.","abstract":"BACKGROUND: Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by the deficiency of the mitochondrial protein propionyl-CoA carboxylase (PCC) and is associated with pathogenic variants in either of the two genes PCCA or PCCB. The present study aimed to identify the genetic cause of three Chinese patients with PA.\nCASE PRESENTATION: Three Chinese PA patients were diagnosed by using gas chromatography-mass spectrometry(GC-MS), tandem mass spectrometry (MS/MS) and molecular diagnostic methods. All patients had onset in the neonatal period. One patient died of infection and metabolic decompensation, and the other two had mild to moderate developmental delay/mental retardation. Mutation analysis of the PCCA gene identified that patient 1 carried the compound heterozygous c.1288C > T(p.R430X) and c.2002G > A(p.G668R), and patient 2 was homozygous for the c.1426C > T(p.R476X) mutation. Mutation analysis of the PCCB gene identified that patient 3 harbored the compound heterozygous mutations c.359_360del AT(p.Y120Cfs*40) and c.1398 + 1G > A. Among these mutations, three (c.1288C > T, c.359_360del AT and c.1398 + 1G > A) are novel.\nCONCLUSIONS: We reported three Chinese PA patients who had PCCA or PCCB mutants. Among them, in the PCCA gene, c.1288C > T(p.R430X) was a nonsense mutation, resulting in a truncated protein. c.359_360del AT was a frameshift mutation, leading to a p.Y120Cfs*40 change in the amino acid sequence in the PCCB protein. c.1398 + 1G > A was a splicing mutation, causing skipping of the exons 13-14. In conclusion, the novel mutations uncovered in this study will expands the mutation spectrum of PA.","variants":[{"Name":"NM_000532.5(PCCB):c.1398+1G>A","Chromosome":"3","Start":"136327733","Stop":"136327733","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3138668,"rule_based_match":true,"evidence_text":"c.1398 + 1G > A","llm_judgment":"PRESENT","evidence":"c.1398 + 1G > A","abstract_start":1057,"abstract_end":1072},{"Name":"NM_000282.4(PCCA):c.1426C>T (p.Arg476Ter)","Chromosome":"13","Start":"100309905","Stop":"100309905","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":214895,"rule_based_match":true,"evidence_text":"c.1426C > T(p.R476X)","llm_judgment":"PRESENT","evidence":"c.1426C > T(p.R476X)","abstract_start":886,"abstract_end":906}]}
{"pmid":"21538323","title":"Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes.","abstract":"OBJECTIVE: To gain insight into the molecular bases of genetically unexplained periodic fever syndromes (PFS) by screening NLRP12, a gene in which only a nonsense and a splice site mutation have so far been identified, and to assess the functional consequences of the identified missense variation.\nMETHODS: NLRP12 was screened for mutations by direct sequencing. Functional assays were performed in HEK 293T cells stably expressing the proapoptotic protein ASC and procaspase 1, in order to determine the effects of normal and mutated NLRP12 proteins on speck formation, caspase 1 signaling, and NF-κB activation.\nRESULTS: A heterozygous NLRP12 missense mutation involving a CpG site (c.1054C>T; p.Arg352Cys) was identified in exon 3, which encodes the nucleotide-binding site (NBS) of the protein, in 2 patients from different countries and carrying different NLRP12 haplotypes. The mutation, which does not alter the inhibitory effect of NLRP12 on NF-κB activation, increases speck formation and activates caspase 1 signaling. To define this new class of PFS, we propose the term NLRP12-associated disorders (NLRP12AD).\nCONCLUSION: Given the rarity of known NLRP12-associated disorders, the identification of this NLRP12 molecular defect contributes to the delineation of the clinical spectrum associated with mutations in this gene and highlights the importance of screening NLRP12 in patients presenting with unexplained PFS. This study also demonstrates, by means of functional assays, the deleterious effect of this recurrent missense mutation; the gain of function for speck formation and caspase 1 signaling associated with this NBS mutation is consistent with the inflammatory phenotype of PFS.","variants":[{"Name":"NM_144687.4(NLRP12):c.1054C>T (p.Arg352Cys)","Chromosome":"19","Start":"53810605","Stop":"53810605","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":514302,"rule_based_match":true,"evidence_text":"c.1054C>T; p.Arg352Cys","llm_judgment":"PRESENT","evidence":"c.1054C>T; p.Arg352Cys","abstract_start":686,"abstract_end":708}]}
{"pmid":"12872256","title":"Evaluation of multiplex capillary heteroduplex analysis: a rapid and sensitive mutation screening technique.","abstract":"Bardet-Biedl syndrome (BBS) is a heterogeneous disease; to date seven loci have been mapped and five identified (BBS1, BBS2, BBS4, BBS6, and BBS7). Inheritance in some families is complex with multiallelic participation making linkage analysis difficult. Previous mutation screens have been carried out by direct sequencing but with an increasing number of patients to be screened for five relatively large genes, a more rapid and cost-effective mutation assay for BBS was required. We have adapted the technique of heteroduplex analysis for use on the MegaBACE 1000, a capillary-based DNA fragment analyser, to improve the resolution and sensitivity of the system. Twelve known alterations (insertions, deletions, missenses, and SNPs) in BBS1, BBS2, BBS4, and BBS6 were used to test the sensitivity of the assay and subsequently used to screen new patients for mutations. We achieved a 100% detection rate while dramatically increasing the sample throughput by virtue of multiplexing up to six PCR products in each capillary. In addition, four novel variants were identified: two in BBS2 [c.522T>A (p.D174E) and c.805-20A>G] and two in BBS4 [c.332+27_28insA and c.1414A>G (p.M472V)]. Compared with sequencing and alternative screening methods, multiplex capillary heteroduplex analysis (MCHA) is extremely cost effective. Hum Mutat 22:151-157, 2003.","variants":[{"Name":"NM_033028.5(BBS4):c.1414A>G (p.Met472Val)","Chromosome":"15","Start":"72736927","Stop":"72736927","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":152879,"rule_based_match":true,"evidence_text":"c.1414A>G (p.M472V)","llm_judgment":"PRESENT","evidence":"c.1414A>G (p.M472V)","abstract_start":1163,"abstract_end":1182}]}
{"pmid":"27225395","title":"Cerebrotendinous xanthomatosis, a metabolic disease with different neurological signs: two case reports.","abstract":"Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive inborn error of bile acids synthesis and lipid accumulation caused by a deficiency of the mitochondrial cytochrome P450 sterol 27-hydroxylase enzyme encoded by CYP27A1. Pathogenic variants in CYP27A1 cause elevated cholestanol levels in the body, which leads to a variable clinical presentation that often includes cataracts, intellectual disability, neurological features, tendon xanthomas, and chronic diarrhea. Herein we describe the cases of two unrelated adult CTX patients. Case 1 is a patient with neurological dysfunction, including moderate intellectual disability, cataract of right eye, and xanthomas; Case 2 is a patient with tendon xanthomas without neurological symptoms. Plasma sterols profile obtained from both cases showed higher levels of cholestanol and cholesterol biosynthetic precursors compared to unaffected subjects. Case 1 and Case 2 were homozygous for the c.1263 + 5G > T (p.Leu396Profs29X) and c.1435C > G (p.Arg479Gly) pathogenic variants, respectively, in the CYP27A1 gene. Interestingly, for the first time, Case 2 variant has been identified in a homozygous state. Our results highlight that the sterol profile and genetic analyses are essential to make the diagnosis of CTX and to exclude other dyslipidemias.","variants":[{"Name":"NM_000784.4(CYP27A1):c.1435C>G (p.Arg479Gly)","Chromosome":"2","Start":"218814716","Stop":"218814716","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":19306,"rule_based_match":true,"evidence_text":"c.1435C > G (p.Arg479Gly)","llm_judgment":"PRESENT","evidence":"c.1435C > G (p.Arg479Gly)","abstract_start":987,"abstract_end":1012}]}
{"pmid":"30953456","title":"A case report of recessive restrictive cardiomyopathy caused by a novel mutation in cardiac troponin I (TNNI3).","abstract":"BACKGROUND: Restrictive cardiomyopathy is a rare cardiac disease, for which several genes including TNNT2, MYPN, FLNC and TNNI3 have been associated with its familial form.\nCASE PRESENTATION: Here we describe a female proband with a severely manifested restrictive phenotype leading to heart transplantation at the age of 41, who was found homozygous for the novel TNNI3 mutation: NM_000363.4:c.586G > C, p.(Asp196His). Her parents were third-degree cousins originating from a small village and although they were found heterozygous for the same variant they displayed no symptoms of the disease. Her older sister who was also found heterozygous was asymptomatic. Her twin sister and her brother who were homozygous for the same variant displayed a restrictive and a hypertrophic phenotype, respectively. Their children are all carriers of the mutation and remain asymptomatic until the age of 21.\nCONCLUSION: These observations point to a recessive mode of inheritance reported for the first time for this combination of gene/disease.","variants":[{"Name":"NM_000363.5(TNNI3):c.586G>C (p.Asp196His)","Chromosome":"19","Start":"55151881","Stop":"55151881","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1899642,"rule_based_match":true,"evidence_text":"NM_000363.4:c.586G > C, p.(Asp196His)","llm_judgment":"PRESENT","evidence":"NM_000363.4:c.586G > C, p.(Asp196His)","abstract_start":381,"abstract_end":418}]}
{"pmid":"26770496","title":"Two novel mutations of FBN1 in Jordanian patients with Marfan syndrome.","abstract":"Marfan syndrome is an autosomal dominant inheritance disorder with a 1/5000-live-birth prevalence. More than 3000 mutations have been characterized thus far in the FBN1 gene. The goal of this study is to facilitate Marfan syndrome diagnosis in Jordanian patients using a molecular genetic testing. All of the 65 coding exons and flanking intronic sequences of the FBN1 gene were amplified using polymerase chain reaction and were subjected to sequencing in five unrelated Jordanian patients suspected of having Marfan syndrome. Four different mutations were identified, including two novel mutations: the c.1553dupG frame-shift (p.Tyr519Ilefs*14) and the c.6650G>A (p.Cys2217Tyr) missense mutations. Two other missense mutations, c.2243G>A (p.Cys748Tyr) and c.2432G>A (p.Cys811Tyr), have been previously detected. Patient number five was heterozygous for the synonymous substitution variant c.1875T>C (p.Asn625Asn; rs#25458). Additionally, eight variants in the intronic sequence of the FBN1 gene were identified, of which the c.2168-46A>G mutation was a new variant. The data provide molecular-based evidence linking Marfan syndrome to pathogenic mutations in the FBN1 gene among Jordanians for the first time. Thus, our results will contribute to the better management of the disease using molecular tools and will help in genetic counseling of the patients' families.","variants":[{"Name":"NM_000138.5(FBN1):c.2243G>A (p.Cys748Tyr)","Chromosome":"15","Start":"48497316","Stop":"48497316","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":409288,"rule_based_match":true,"evidence_text":"c.2243G>A (p.Cys748Tyr)","llm_judgment":"PRESENT","evidence":"c.2243G>A (p.Cys748Tyr)","abstract_start":730,"abstract_end":753},{"Name":"NM_000138.5(FBN1):c.6650G>A (p.Cys2217Tyr)","Chromosome":"15","Start":"48432955","Stop":"48432955","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":197634,"rule_based_match":true,"evidence_text":"c.6650G>A (p.Cys2217Tyr)","llm_judgment":"PRESENT","evidence":"c.6650G>A (p.Cys2217Tyr)","abstract_start":655,"abstract_end":679},{"Name":"NM_000138.5(FBN1):c.2432G>A (p.Cys811Tyr)","Chromosome":"15","Start":"48495576","Stop":"48495576","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":539832,"rule_based_match":true,"evidence_text":"c.2432G>A (p.Cys811Tyr)","llm_judgment":"PRESENT","evidence":"c.2432G>A (p.Cys811Tyr)","abstract_start":758,"abstract_end":781}]}
{"pmid":"33217309","title":"A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl","abstract":"Dysfunction of the endolysosomal system is often associated with neurodegenerative disease because postmitotic neurons are particularly reliant on the elimination of intracellular aggregates. Adequate function of endosomes and lysosomes requires finely tuned luminal ion homeostasis and transmembrane ion fluxes. Endolysosomal CLC Cl<sup>-</sup>/H<sup>+</sup> exchangers function as electric shunts for proton pumping and in luminal Cl<sup>-</sup> accumulation. We now report three unrelated children with severe neurodegenerative disease, who carry the same de novo c.1658A>G (p.Tyr553Cys) mutation in CLCN6, encoding the late endosomal Cl<sup>-</sup>/H<sup>+</sup>-exchanger ClC-6. Whereas Clcn6<sup>-/-</sup> mice have only mild neuronal lysosomal storage abnormalities, the affected individuals displayed severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. The p.Tyr553Cys amino acid substitution strongly slowed ClC-6 gating and increased current amplitudes, particularly at the acidic pH of late endosomes. Transfection of ClC-6<sup>Tyr553Cys</sup>, but not ClC-6<sup>WT</sup>, generated giant LAMP1-positive vacuoles that were poorly acidified. Their generation strictly required ClC-6 ion transport, as shown by transport-deficient double mutants, and depended on Cl<sup>-</sup>/H<sup>+</sup> exchange, as revealed by combination with the uncoupling p.Glu200Ala substitution. Transfection of either ClC-6<sup>Tyr553Cys/Glu200Ala</sup> or ClC-6<sup>Glu200Ala</sup> generated slightly enlarged vesicles, suggesting that p.Glu200Ala, previously associated with infantile spasms and microcephaly, is also pathogenic. Bafilomycin treatment abrogated vacuole generation, indicating that H<sup>+</sup>-driven Cl<sup>-</sup> accumulation osmotically drives vesicle enlargement. Our work establishes mutations in CLCN6 associated with neurological diseases, whose spectrum of clinical features depends on the differential impact of the allele on ClC-6 function.","variants":[{"Name":"NM_001286.5(CLCN6):c.1658A>G (p.Tyr553Cys)","Chromosome":"1","Start":"11834367","Stop":"11834367","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":962913,"rule_based_match":true,"evidence_text":"c.1658A>G (p.Tyr553Cys)","llm_judgment":"PRESENT","evidence":"c.1658A>G (p.Tyr553Cys)","abstract_start":567,"abstract_end":590}]}
{"pmid":"27842159","title":"Mutations in AGBL5, Encoding α-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa.","abstract":"PURPOSE: AGBL5, encoding ATP/GTP binding protein-like 5, was previously proposed as an autosomal recessive retinitis pigmentosa (arRP) candidate gene based on the identification of missense variants in two families. In this study, we performed next-generation sequencing to reveal additional RP cases with AGBL5 variants, including protein-truncating variants.\nMETHODS: Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in three probands. Subsequent Sanger sequencing and segregation analysis were performed in the selected candidate genes. The medical history of individuals carrying AGBL5 variants was reviewed and additional ophthalmic examinations were performed, including fundus photography, fundus autofluorescence imaging, and optical coherence tomography.\nRESULTS: AGBL5 variants were identified in three unrelated arRP families, comprising homozygous variants in family 1 (c.1775G>A:p.(Trp592*)) and family 2 (complex allele: c.[323C>G; 2659T>C]; p.[(Pro108Arg; *887Argext*1)]), and compound heterozygous variants (c.752T>G:p.(Val251Gly) and c.1504dupG:p.(Ala502Glyfs*15)) in family 3. All affected individuals displayed typical RP phenotypes.\nCONCLUSIONS: Our study convincingly shows that variants in AGBL5 are associated with arRP. The identification of AGBL5 and TTLL5, a previously described RP-associated gene encoding the tubulin tyrosine ligase-like family, member 5 protein, highlights the importance of poly- and deglutamylation in retinal homeostasis. Further studies are required to investigate the underlying disease mechanism associated with AGBL5 variants.","variants":[{"Name":"NM_021831.6(AGBL5):c.1775G>A (p.Trp592Ter)","Chromosome":"2","Start":"27058503","Stop":"27058503","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3407495,"rule_based_match":true,"evidence_text":"c.1775G>A:p.(Trp592*)","llm_judgment":"PRESENT","evidence":"c.1775G>A:p.(Trp592*)","abstract_start":909,"abstract_end":930}]}
{"pmid":"27609163","title":"Further evidence for P59L mutation in GJA3 associated with autosomal dominant congenital cataract.","abstract":"CONTEXT: Congenital cataracts are one of the common eye disorders leading to visual impairment or blindness in children worldwide. We found a Chinese family with autosomal dominant pulverulent cataract.\nAIMS: To identify the pathogenic gene mutation in a Chinese family with autosomal dominant inherited pulverulent cataract.\nSUBJECTS AND METHODS: After obtained informed consent, detailed ophthalmic examinations were carried out; genomic DNAs were obtained from seven family members in a three-generation Chinese family with three affected. All exons of candidate genes were amplified by polymerase chain reaction and were sequenced performed by bidirectional sequencing.\nRESULTS: By sequencing the encoding regions of the candidate genes, a missense mutation (c. 176C>T) was detected in gap junction protein alpha 3 genes (GJA3), which resulted in the substitution of highly conserved proline by leucine at codon 59 (p.P59L). The mutation co-segregated with all patients and was absent in 100 normal Chinese controls.\nCONCLUSIONS: The study identified a missense mutation (c. 176C>T) in GJA3 gene associated with autosomal dominant congenital pulverulent cataract in a Chinese family. It gave further evidence of phenotype heterogeneity for P59L mutation in GJA3 associated with congenital cataract.","variants":[{"Name":"NM_021954.4(GJA3):c.176C>T (p.Pro59Leu)","Chromosome":"13","Start":"20143113","Stop":"20143113","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":213992,"rule_based_match":true,"evidence_text":"c. 176C>T","llm_judgment":"PRESENT","evidence":"c. 176C>T","abstract_start":763,"abstract_end":772}]}
{"pmid":"30380558","title":"Results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center.","abstract":"BACKGROUND/AIMS: Fabry disease (FD), a rare x-lined genetic disorder is a cause of renal deterioration. The phenotype of FD is highly variable and nonspecific, and correct diagnosis has always been delayed. We aimed to explore the prevalence and clinical presentation of FD in this high-risk male population in a Northern Taiwan medical center.\nMETHODS: This is the first study to survey the incidence of FD in this high-risk population through the platform of a chronic kidney disease (CKD) education program in Asia. A total of 1,012 male patients with unknown CKD causes were screened using an assay of alpha-galactosidase A activity (α-Gal A) by dried blood spots (DBS). A final GLA gene analysis was also done for those with low enzyme activity.\nRESULTS: We identified two new patients with classic FD and four patients with late-onset FD. One novel GLA mutation with c.413 G>A was found in one classic FD patient (index 5). The prevalence of FD is about 0.59 % (6 in 1,012) in the high-risk population group with CKD. The clinical symptoms of FD patients are nonspecific except in those with various degrees of renal failure. Those patients' correct diagnosis was delayed, taking years and even decades. Three patients received enzyme replacement therapy and one started regular hemodialysis due to persistent renal function deterioration. Another two patients were found from family screening through a new index. In addition, a false negative result occurred in one patient who was proved to have FD by his kidney pathology as determined by this screening.\nCONCLUSION: FD is not such as rare a disease and its prevalence is greater in this high-risk male population. Clinicians need to be aware that FD should be included in the differential diagnosis in CKD with unknown etiology.","variants":[{"Name":"NM_000169.3(GLA):c.413G>A (p.Gly138Glu)","Chromosome":"X","Start":"101401766","Stop":"101401766","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":929533,"rule_based_match":true,"evidence_text":"c.413 G>A","llm_judgment":"PRESENT","evidence":"c.413 G>A","abstract_start":873,"abstract_end":882}]}
{"pmid":"23592912","title":"Mutation in collagen II alpha 1 isoforms delineates Stickler and Wagner syndrome phenotypes.","abstract":"PURPOSE: Stickler syndrome is an arthro-ophthalmopathy with phenotypic overlap with Wagner syndrome. The common Stickler syndrome type I is inherited as an autosomal dominant trait, with causal mutations in collagen type II alpha 1 (COL2A1). Wagner syndrome is associated with mutations in versican (VCAN), which encodes for a chondroitin sulfate proteoglycan. A three-generation Caucasian family variably diagnosed with either syndrome was screened for sequence variants in the COL2A1 and VCAN genes.\nMETHODS: Genomic DNA samples derived from saliva were collected from all family members (six affected and four unaffected individuals). Complete sequencing of COL2A1 and VCAN was performed on two affected individuals. Direct sequencing of remaining family members was conducted if the discovered variants followed segregation.\nRESULTS: A base-pair substitution (c.258C>A) in exon 2 of COL2A1 cosegregated with familial disease status. This known mutation occurs in a highly conserved site that causes a premature stop codon (p.C86X). The mutation was not seen in 1,142 ethnically matched control DNA samples.\nCONCLUSIONS: Premature stop codons in COL2A1 exon 2 lead to a Stickler syndrome type I ocular-only phenotype with few or no systemic manifestations. Mutation screening of COL2A1 exon 2 in families with autosomal dominant vitreoretinopathy is important for accurate clinical diagnosis.","variants":[{"Name":"NM_001844.5(COL2A1):c.258C>A (p.Cys86Ter)","Chromosome":"12","Start":"47999953","Stop":"47999953","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":192309,"rule_based_match":true,"evidence_text":"c.258C>A","llm_judgment":"PRESENT","evidence":"c.258C>A","abstract_start":864,"abstract_end":872}]}
{"pmid":"33484353","title":"Prevalence of mutations in BRCA and MMR genes in patients affected with hereditary endometrial cancer.","abstract":"Endometrial cancer (EC) is the fifth most common cancer in women from developed countries, accounting for 4.8% of new cases and 2.1% of deaths. The genetic basis for the familial risk of endometrial cancer has not been completely defined. Mostly, hereditary EC is part of two syndromes as Lynch syndrome (LS) and Hereditary Breast and Ovarian Cancer syndrome (HBOC). LS is the prototypical hereditary cancer syndrome in EC and accounts for 2-6% of all endometrial cancers. This disease is caused by autosomal dominant mutations in DNA mismatch repair (MMR) genes. Patients carrying a germline mutation in one of the MMR genes have a cumulative lifetime risk to develop EC of 20-70%. HBOC is an autosomal dominantly inherited disease, which mostly predisposes to breast and ovarian cancers, but it can be also associated with other malignancies. HBOC results from germline mutations in BRCA1/2 genes. The aim of this study was to determine the mutational status of a cohort of 40 EC patients, 19 belonging to families with LS and 21 to HBOC. Mutation analysis of MLH1, MSH2, BRCA1 and BRCA2 genes showed pathogenic variants in 17/40 (42.5%) patients. Out of 19 patients belonging to LS families, 8 (42.1%) showed a pathogenic variant. Out of 21 patients belonging to HBOC families, 9 (42.8%) showed a pathogenic variant. 1/21 (4.8%) patient report 1 variant of unknown significance (UV), c.599 C > T (p.T200I), in BRCA2. Moreover, in 1/21 (4.8%) patient we identified a novel missense variant in BRCA2, c.9541A > T (p.Met3181Leu). Mutational analysis was extended to family members, both healthy and cancer affected, of mutated patients; all the tested relatives affected with cancer displayed the pathogenic variant. Our data suggest that patients with hereditary EC have a high percentage of mutations in the LS and HBOC main susceptibility genes; therefore, the surveillance for EC, already indicated in LS patients, should also be recommended for patients with HBOC.","variants":[{"Name":"NM_000059.4(BRCA2):c.599C>T (p.Thr200Ile)","Chromosome":"13","Start":"32326581","Stop":"32326581","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":150680,"rule_based_match":true,"evidence_text":"c.599 C > T (p.T200I)","llm_judgment":"PRESENT","evidence":"c.599 C > T (p.T200I)","abstract_start":1387,"abstract_end":1408}]}
{"pmid":"24604241","title":"Novel and recurrent mutations of STK11 gene in six Chinese cases with Peutz-Jeghers syndrome.","abstract":"BACKGROUND: The serine/threonine kinase 11 (STK11) gene is the main causal gene in Peutz-Jeghers syndrome (PJS). Abnormal STK11 may increase cancer risk of PJS patients via affecting its target proteins such as P53, AMPK, and PTEN. In this study, we investigated the molecular basis of six Chinese PJS patients.\nMATERIALS AND METHODS: Blood samples were collected from four Chinese PJS families and two sporadic patients. The entire coding region of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing. Functions of mutants were assessed by PolyPhen-2, Swiss-Model software, and luciferase reporter assay.\nRESULTS: Novel mutations (c.842_843insC, c.804_805insG, and c.922T>G) and recurrent mutations (c.526G>A, c.180C>G, and c.1062C>G) were identified. Missense mutation c.922T>G and c.526G>A were predicted as probably damaging by PolyPhen-2, while c.1062C>G was benign. Mutation c.108C>G was a nonsense mutation. The 284Ter mutants of c.842_843insC and c.804_805insG significantly diminished the capacity of P53 activity in 293FT cells.\nCONCLUSIONS: Our results support that STK11 gene mutations underlie Chinese patients with PJS. Mutation involving partial kinase domain disrupts normal function of STK11. Our results also enlarge the spectrum of STK11 variants in PJS patients.","variants":[{"Name":"NM_000455.5(STK11):c.526G>A (p.Asp176Asn)","Chromosome":"19","Start":"1220434","Stop":"1220434","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":181057,"rule_based_match":true,"evidence_text":"c.526G>A","llm_judgment":"PRESENT","evidence":"c.526G>A","abstract_start":741,"abstract_end":749},{"Name":"NM_000455.5(STK11):c.180C>G (p.Tyr60Ter)","Chromosome":"19","Start":"1207093","Stop":"1207093","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":420691,"rule_based_match":true,"evidence_text":"c.180C>G","llm_judgment":"PRESENT","evidence":"c.180C>G","abstract_start":751,"abstract_end":759}]}
{"pmid":"32161190","title":"Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation.","abstract":"Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.","variants":[{"Name":"NM_001905.4(CTPS1):c.1692-1G>C","Chromosome":"1","Start":"41010160","Stop":"41010160","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":150138,"rule_based_match":true,"evidence_text":"c.1692-1G>C","llm_judgment":"PRESENT","evidence":"c.1692-1G>C","abstract_start":121,"abstract_end":132}]}
{"pmid":"18798333","title":"Mutation analysis of B3GALTL in Peters Plus syndrome.","abstract":"Peters Plus syndrome comprises ocular anterior segment dysgenesis (most commonly Peters anomaly), short stature, hand anomalies, distinctive facial features, and often other additional defects and is inherited in an autosomal-recessive pattern. Mutations in the beta1,3-glucosyltransferase gene (B3GALTL) were recently reported in 20 out of 20 patients with Peters Plus syndrome. In our study, B3GALTL was examined in four patients with typical Peters Plus syndrome and four patients that demonstrated a phenotypic overlap with this condition. Mutations in B3GALTL were identified in all four patients with typical Peters Plus syndrome, while no mutations were found in the remaining four patients that demonstrated some but not all characteristic features of the syndrome. The previously reported common mutation, c.660 + 1G > A, accounted for 75% of the mutant alleles in our Peters Plus syndrome population. In addition, two new mutant alleles, c.459 + 1G > A and c.230insT, were identified and predicted to result in truncated protein products. These data confirm an important role for B3GALTL in causing typical Peters Plus syndrome, and suggest that this gene may not be implicated in syndromic cases that involve Peters anomaly but lack other classic features of this complex condition.","variants":[{"Name":"NM_194318.4(B3GLCT):c.660+1G>A","Chromosome":"13","Start":"31269278","Stop":"31269278","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16303,"rule_based_match":true,"evidence_text":"c.660 + 1G > A","llm_judgment":"PRESENT","evidence":"c.660 + 1G > A","abstract_start":815,"abstract_end":829},{"Name":"NM_194318.4(B3GLCT):c.459+1G>A","Chromosome":"13","Start":"31247967","Stop":"31247967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":445137,"rule_based_match":true,"evidence_text":"c.459 + 1G > A","llm_judgment":"PRESENT","evidence":"c.459 + 1G > A","abstract_start":948,"abstract_end":962}]}
{"pmid":"34859019","title":"Genetic Variations and Clinical Features of","abstract":"<b>Introduction:</b> Few studies have addressed the genetic spectrum of <i>NPHS1</i> variants in Chinese children with nephrotic syndrome. In this multicenter study, the clinical manifestations and features of <i>NPHS1</i> variants in Chinese children with nephrotic syndrome were researched. <b>Method:</b> Genotypical and phenotypical data from 30 children affected by <i>NPHS1</i> variants were collected from a multicenter registration system in China and analyzed retrospectively. <b>Results:</b> The patients were divided into two groups: congenital nephrotic syndrome (CNS [<i>n</i> = 24]) and non-CNS (early onset nephrotic syndrome [<i>n</i> = 6]). Renal biopsy was performed on four patients in the non-CNS group, revealing minimal change disease in three and focal segmental glomerulosclerosis in one. A total of 61 <i>NPHS</i>1 variants were detected, involving 25 novel variants. The \"recurrent variants\" included c.928G>A(p.Asp310Asn) in eight patients with CNS, followed by c.616C>A(p.Pro206Thr) in four, and c.2207T>C (p.Val736Ala) in three. Steroid treatment was applied in 29.2% (7/24)of the patients in the CNS group and 50% (3/6) of the patients in the non-CNS group. One patient in each group experienced complete remission but relapsed subsequently. Immunosuppressants were administered to three patients in the non-CNS group, eliciting an effective response. In the CNS group, three patients underwent renal transplantation and six died mainly from infection. <b>Conclusion:</b> Variants of <i>NPHS1</i> cause CNS and early childhood-onset nephrotic syndrome. <i>NPHS1</i> variants in Chinese individuals with nephrotic syndrome (NS) were mainly compound heterozygous variants, and c.928G>A(p.Asp310Asn) in exon 8 may act as a recurrent variant in the Chinese population, followed by c.616C>A(p.Pro206Thr) in exon 6. Steroids and immunosuppressants may be effective in selected patients.","variants":[{"Name":"NM_004646.4(NPHS1):c.616C>A (p.Pro206Thr)","Chromosome":"19","Start":"35849646","Stop":"35849646","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2836159,"rule_based_match":true,"evidence_text":"c.616C>A(p.Pro206Thr)","llm_judgment":"PRESENT","evidence":"c.616C>A(p.Pro206Thr)","abstract_start":989,"abstract_end":1010}]}
{"pmid":"29444904","title":"Mutation in an alternative transcript of","abstract":"Infantile-onset epilepsies are a set of severe, heterogeneous disorders for which clinical genetic testing yields causative mutations in ∼20%-50% of affected individuals. We report the case of a boy presenting with intractable seizures at 2 wk of age, for whom gene panel testing was unrevealing. Research-based whole-genome sequencing of the proband and four unaffected family members identified a de novo mutation, NM_001323289.1:c.2828_2829delGA in <i>CDKL5,</i> a gene associated with X-linked early infantile epileptic encephalopathy 2. <i>CDKL5</i> has multiple alternative transcripts, and the mutation lies in an exon in the brain-expressed forms. The mutation was undetected by gene panel sequencing because of its intronic location in the <i>CDKL5</i> transcript typically used to define the exons of this gene for clinical exon-based tests (NM_003159). This is the first report of a patient with a mutation in an alternative transcript of <i>CDKL5</i> This finding suggests that incorporating alternative transcripts into the design and variant interpretation of exon-based tests, including gene panel and exome sequencing, could improve the diagnostic yield.","variants":[{"Name":"NM_001323289.2(CDKL5):c.2828_2829del (p.Arg943fs)","Chromosome":"X","Start":"18628701","Stop":"18628702","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":435196,"rule_based_match":true,"evidence_text":"NM_001323289.1:c.2828_2829delGA","llm_judgment":"PRESENT","evidence":"NM_001323289.1:c.2828_2829delGA","abstract_start":417,"abstract_end":448}]}
{"pmid":"35314380","title":"Spectrum and frequency of CHEK2 variants in breast cancer affected and general population in the Baltic states region, initial results and literature review.","abstract":"BACKGROUND: While BRCA1/2 gene mutational spectrum and clinical features are widely studied, there is limited data on breast cancer-predisposing non-BRCA pathogenic/likely pathogenic variants (PV/LPVs) in the Baltic states region. According to previous studies, CHEK2 is the most frequent moderate-risk breast cancer predisposition gene. The study aimed to analyse the frequency and mutational spectrum of CHEK2 PV/LPVs in the Baltic states region and perform a literature review on the subject.\nMETHODS: The study includes two cohorts - population-based Estonian biobank (EstBB) (N-152 349) and breast cancer affected cases from Latvia (N-105). In the cohort from Latvia, CHEK2, BRCA1, BRCA2, PALB2 testing with next-generation sequencing (NGS) was carried out in selected breast cancer cases. In the EstBB, the full SNP genotyped dataset Global Screening Array (GSA) (N-152 349) was used to screen CHEK2 PV/LPVs and variants c.319+2T > A (p.(?)), c.444+1G>A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*) in CHEK2 are reported from this dataset. In addition, a subset of the EstBB (N-4776) underwent whole-genome sequencing (WGS, N-2420) and whole-exome sequencing (WES, N-2356) and founder variants c.470T > C (p.Ile157Thr), c.444+1G>A (p.(?)), c.1100delC (p.Thr367Metfs*15) in CHEK2 were reported from this dataset. Moreover, a literature overview was performed on April 1, 2021, using the PubMed search of keywords 'CHEK2', 'breast cancer', 'Estonia', 'Lithuania', 'Latvia', 'Poland', 'Belarus' and 'Russia'.\nRESULTS: In the breast cancer affected cohort from Latvia 6 CHEK2 variants, classified as PV/LPVs, were observed (6/105; 5.7%), including recurrent ones c.470T > C (p.Ile157Thr) (1.9%) and del5395(ex9-10del; (p.Met304Leufs*16)) (1.9%), as well as single ones - c.1100delC (p.Thr367Metfs*15) (1%) and c.444+1G>A (p.(?)) (1%). From EstBB NGS data (N-4776) CHEK2 variant c.470T > C (p.Ile157Thr) was detected in 8.6% of cases, c.1100delC (p.Thr367Metfs*15) in 0.6% and c.444+1G>A (p.(?)) in 0.2% of cases. In the EstBB full cohort of SNP array data (N-152 349) CHEK2 variant c.444+1G>A (p.(?)) was detected in 0.02% of cases, c.319+2T > A (p.(?)) in 0.09% of cases, c.433C > T (p.Arg145Trp) in 0.02% of cases and c.283C > T (p.Arg95*) in <0.001% of cases. For the literature review altogether, 49 PubMed articles were found, 23 of which were relevant, representing CHEK2 PV/LPVs in the population of interest. Ten publications are from Poland, eight from Russia, three from Latvia and two from Belarus.\nCONCLUSIONS: This study is the first combined report on complete CHEK2 PV/LPVs screening in selected breast cancer affected cases in Latvia and large-scale population screening in Estonia, providing insight into the CHEK2 mutational spectrum in the Baltic states region. The initial results are in line with other studies that CHEK2 PV/LPVs frequency is around 5-6% of selected breast cancer cases. Here we report three CHEK2 PV/LPV - c.319+2T > A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*), that are novel for the Baltic states region. This is also the first report on c.1100delC (p.Thr367Metfs*15) and c.444+1G>A (p.(?)) from the Baltic states. High population frequency of c.470T > C (p. Ile157Thr) (8.6%) continues to question the variant's pathogenicity in particular populations. Other findings are concordant with previous reports from Latvia and neighbouring populations.","variants":[{"Name":"NM_007194.4(CHEK2):c.319+2T>A","Chromosome":"22","Start":"28734401","Stop":"28734401","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":152066,"rule_based_match":true,"evidence_text":"c.319+2T > A (p.(?))","llm_judgment":"PRESENT","evidence":"c.319+2T > A (p.(?))","abstract_start":927,"abstract_end":947},{"Name":"NM_007194.4(CHEK2):c.433C>T (p.Arg145Trp)","Chromosome":"22","Start":"28725254","Stop":"28725254","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20631,"rule_based_match":true,"evidence_text":"c.433C>T (p.Arg145Trp)","llm_judgment":"PRESENT","evidence":"c.433C > T (p.Arg145Trp)","abstract_start":969,"abstract_end":993}]}
{"pmid":"19839753","title":"Identification of four novel EXT1 and EXT2 mutations in five Chinese pedigrees with hereditary multiple exostoses.","abstract":"Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder most frequently caused by the EXT1 and EXT2 gene mutations resulting in reduction or absence of heparan sulfate (HS) in the exostotic cartilage cap. In this study, we investigated the molecular defects in five Chinese pedigrees with HME by direct sequencing analysis. Two novel EXT1 gene mutations and two novel EXT2 gene mutations were identified in two and three pedigrees, respectively. Of the four mutations identified, the c.651-664delinsTTT and c.680delG mutations in the exon 1 of EXT1 gene would cause frameshift (K218fs and R227fs) and introduce premature stop codon at amino acid site 220 and 251, respectively. The two missense mutations of c.398T > G in exon 2 and c.1016G > A in exon 6 of EXT2 gene result in the Leu133Arg and Cys339Tyr substitution, respectively. As HME is caused by defects in HS synthesis that is a complex process and not fully understood, these naturally occurring EXT mutations may provide important clues to future studies elucidating how EXT proteins contribute to HS biosynthesis.","variants":[{"Name":"NM_207122.2(EXT2):c.1016G>A (p.Cys339Tyr)","Chromosome":"11","Start":"44126892","Stop":"44126892","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":935539,"rule_based_match":true,"evidence_text":"c.1016G > A in exon 6 of EXT2 gene","llm_judgment":"PRESENT","evidence":"c.1016G > A in exon 6 of EXT2 gene","abstract_start":756,"abstract_end":790},{"Name":"NM_000127.3(EXT1):c.651_664delinsTTT (p.Lys218fs)","Chromosome":"8","Start":"118110383","Stop":"118110396","ReferenceAlleleVCF":"TGATGCTGGCTTTG","AlternateAlleleVCF":"AAA","allel_id":955286,"rule_based_match":false,"evidence_text":"c.651-664delinsTTT","llm_judgment":"PRESENT","evidence":"c.651-664delinsTTT","abstract_start":507,"abstract_end":525},{"Name":"NM_207122.2(EXT2):c.398T>G (p.Leu133Arg)","Chromosome":"11","Start":"44108110","Stop":"44108110","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2901599,"rule_based_match":true,"evidence_text":"c.398T > G","llm_judgment":"PRESENT","evidence":"c.398T > G","abstract_start":731,"abstract_end":741}]}
{"pmid":"27432013","title":"Identification of two novel mutations in the COMP gene in six families with pseudoachondroplasia.","abstract":"Pseudoachondroplasia (PSACH; MIM no. 177170) is an autosomal dominant osteochondrodysplasia characterized by short‑limb short stature, brachydactyly and early‑onset osteoarthropathy. Typically, at approximately two years of age, the rate of growth falls below the standard growth curve, causing a moderately severe form of disproportionate short‑limb short stature. The current study described the clinical and radiographic observations of six Chinese patients with PSACH, and identified two de novo novel missense mutations [p.Asp326Asn (c.976G>A) and c.1585A>G (p.Thr529Ala)] in cartilage oligomeric matrix protein (COMP) in the patients. The current study expanded the mutation spectrum of the COMP gene, and contributes to the understanding of phenotype/genotype of COMP‑associated diseases.","variants":[{"Name":"NM_000095.3(COMP):c.976G>A (p.Asp326Asn)","Chromosome":"19","Start":"18787650","Stop":"18787650","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1323540,"rule_based_match":true,"evidence_text":"c.976G>A (p.Asp326Asn)","llm_judgment":"PRESENT","evidence":"p.Asp326Asn","abstract_start":526,"abstract_end":537}]}
{"pmid":"28176296","title":"BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer.","abstract":"BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP-ribose) polymerase (PARP). Despite a number of small-size hospital-based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next-generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population-related without an apparent founder origin. This hot-spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at-risk relatives. Mutation carriers may also benefit from PARP-targeted therapies.","variants":[{"Name":"NM_007294.4(BRCA1):c.4573C>T (p.Gln1525Ter)","Chromosome":"17","Start":"43074433","Stop":"43074433","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":261638,"rule_based_match":true,"evidence_text":"c.4573C > T","llm_judgment":"PRESENT","evidence":"c.4573C > T","abstract_start":904,"abstract_end":915},{"Name":"NM_007294.4(BRCA1):c.283_286del (p.Leu95fs)","Chromosome":"17","Start":"43104883","Stop":"43104886","ReferenceAlleleVCF":"TCAAG","AlternateAlleleVCF":"T","allel_id":574492,"rule_based_match":true,"evidence_text":"c.283_286delCTTG","llm_judgment":"PRESENT","evidence":"c.283_286delCTTG","abstract_start":879,"abstract_end":895}]}
{"pmid":"26388597","title":"X-linked adrenoleukodystrophy in a 6-year-old boy initially presenting with psychiatric symptoms.","abstract":"X-linked adrenoleukodystrophy (ALD) leads to demyelination of the nervous system, adrenal insufficiency and accumulation of long-chain fatty acids. Most young patients with X-linked ALD develop seizures and progressive neurologic deficits, and die within the first two decades of life. We present the case of a 6-year-old with childhood-onset ALD, first presenting with psychiatric symptoms and progressive gait difficulties, slurred speech and cognitive impairment. Genetic testing was performed and a p.R401Q (c.1202G>A) mutation detected in the ABCD1 gene. ALD should be considered in the differential diagnosis of patients presenting with behavior changes and white matter disease in neuroimaging.","variants":[{"Name":"NM_000033.4(ABCD1):c.1202G>A (p.Arg401Gln)","Chromosome":"X","Start":"153736232","Stop":"153736232","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26339,"rule_based_match":true,"evidence_text":"p.R401Q (c.1202G>A)","llm_judgment":"PRESENT","evidence":"p.R401Q (c.1202G>A)","abstract_start":503,"abstract_end":522}]}
{"pmid":"27733563","title":"Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy.","abstract":"OBJECTIVE: To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations.\nMETHODS: A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes.\nRESULTS: The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G>A; p.Arg297Gln) in a girl with EE, ataxia, and tremor.\nCONCLUSIONS: A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders.","variants":[{"Name":"NM_004974.4(KCNA2):c.890G>A (p.Arg297Gln)","Chromosome":"1","Start":"110603893","Stop":"110603893","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":188155,"rule_based_match":true,"evidence_text":"CCDS_827.1: c.890G>A; p.Arg297Gln","llm_judgment":"PRESENT","evidence":"CCDS_827.1: c.890G>A; p.Arg297Gln","abstract_start":1335,"abstract_end":1368},{"Name":"NM_004974.4(KCNA2):c.765_773del (p.Met255_Ile257del)","Chromosome":"1","Start":"110604010","Stop":"110604018","ReferenceAlleleVCF":"AATGATGTTC","AlternateAlleleVCF":"A","allel_id":1058375,"rule_based_match":true,"evidence_text":"CCDS_827.1: c.765_773del; p.255_257del","llm_judgment":"PRESENT","evidence":"CCDS_827.1: c.765_773del; p.255_257del","abstract_start":956,"abstract_end":994}]}
{"pmid":"19372454","title":"Different clinical phenotypes in monozygotic CADASIL twins with a novel NOTCH3 mutation.","abstract":"BACKGROUND AND PURPOSE: CADASIL is a hereditary arteriopathy causing recurrent strokes and cognitive decline. Because monozygotic twins have identical genetic background, differences in their environment and lifestyle could reveal factors that may influence CADASIL patients' clinical course, which is highly variable even within the same family.\nMETHODS: We describe differences in clinical and imaging findings in a pair of monozygotic CADASIL twins.\nRESULTS: Twin B experienced his first-ever stroke 14 years earlier than twin A, and his symptoms, signs, and imaging findings were more severe. Distinguishing factors were twin B's smoking as well as twin A's physical activity and earlier statin treatment. Causative NOTCH3 mutation was a novel c.752G>A -substitution (p.Cys251Tyr).\nCONCLUSIONS: The phenotypic differences in these monozygotic twins suggest influence of environmental and lifestyle factors on the clinical course of CADASIL.","variants":[{"Name":"NM_000435.3(NOTCH3):c.752G>A (p.Cys251Tyr)","Chromosome":"19","Start":"15191795","Stop":"15191795","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":442154,"rule_based_match":true,"evidence_text":"c.752G>A (p.Cys251Tyr)","llm_judgment":"PRESENT","evidence":"p.Cys251Tyr","abstract_start":772,"abstract_end":783}]}
{"pmid":"37164047","title":"Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant.","abstract":"BACKGROUND: Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype.\nOBJECTIVE: The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G.\nMETHODS: Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers. We used in silico predictors and functional studies with peripheral blood and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Isolated RNA was studied by reverse transcription polymerase chain reaction. iPSC-CMs were further characterized at baseline and after nonsense-mediated decay (NMD) inhibition, using quantitative polymerase chain reaction (qPCR), RNA-sequencing, and cellular electrophysiology. American College of Medical Genetics and Genomics (ACMG) criteria were used to adjudicate variant pathogenicity.\nRESULTS: Variant heterozygotes displayed a spectrum of disease phenotypes, spanning from mild ventricular dysfunction with palpitations to severe ventricular arrhythmias requiring device shocks or progressive cardiomyopathy requiring heart transplantation. Consistent with in silico predictors, the c.970-4A>G FLNC variant activated a cryptic splice acceptor site, introducing a 3-bp insertion containing a premature termination codon. NMD inhibition upregulated aberrantly spliced transcripts by qPCR and RNA-sequencing. Patch clamp studies revealed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current in proband-derived iPSC-CMs. These findings fulfilled multiple ACMG criteria for pathogenicity.\nCONCLUSION: Clinical, in silico, and functional evidence support the prediction that the intronic c.970-4A>G VUS disrupts splicing and drives ACM, enabling reclassification from VUS to pathogenic.","variants":[{"Name":"NM_001458.5(FLNC):c.970-4A>G","Chromosome":"7","Start":"128837983","Stop":"128837983","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":425723,"rule_based_match":true,"evidence_text":"c.970-4A>G","llm_judgment":"PRESENT","evidence":"c.970-4A>G","abstract_start":365,"abstract_end":375}]}
{"pmid":"28646019","title":"Functionally Null","abstract":"RAD51D is a key player in DNA repair by homologous recombination (HR), and <i>RAD51D</i> truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating <i>RAD51D</i> variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense <i>RAD51D</i> variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic <i>RAD51D</i> missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense <i>RAD51D</i> variants. <i>Cancer Res; 77(16); 4517-29. ©2017 AACR</i>.","variants":[{"Name":"NM_002878.4(RAD51D):c.620C>T (p.Ser207Leu)","Chromosome":"17","Start":"35103501","Stop":"35103501","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":151816,"rule_based_match":true,"evidence_text":"c.620C>T;p.S207L","llm_judgment":"PRESENT","evidence":"c.620C>T;p.S207L","abstract_start":398,"abstract_end":414}]}
{"pmid":"36468022","title":"Identification of four novel variants in the","abstract":"<b>Background:</b> Hearing loss (HL) is the most common form of sensory disorder in humans. Molecular diagnosis of HL is important for genetic counseling for the affected individuals and their families. <b>Methods:</b> To identify potential genetic causes, we performed whole-exome sequencing and related biomedical informatics for 351 non-syndromic HL patients and their family members. <b>Results:</b> In the present study, we report the identification of four compound heterozygous variants in the <i>CDH23</i> gene from four affected families, including four novel variants (c.995C>A, p.T332K; c.2159G>A, p.R720Q; c.5534A>G, p.N1845S, and c.7055-1G>C) and two frequently reported variants (c.719C>T, p.P240L and c.4762C>T, p.R1588W). <b>Conclusion:</b> Our findings significantly expanded the mutation spectrum of <i>CDH23</i>-associated autosomal recessive hearing loss.","variants":[{"Name":"NM_022124.6(CDH23):c.5534A>G (p.Asn1845Ser)","Chromosome":"10","Start":"71784922","Stop":"71784922","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2838858,"rule_based_match":true,"evidence_text":"c.5534A>G, p.N1845S","llm_judgment":"PRESENT","evidence":"c.5534A>G, p.N1845S","abstract_start":618,"abstract_end":637},{"Name":"NM_022124.6(CDH23):c.2159G>A (p.Arg720Gln)","Chromosome":"10","Start":"71690567","Stop":"71690567","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1053302,"rule_based_match":true,"evidence_text":"c.2159G>A, p.R720Q","llm_judgment":"PRESENT","evidence":"c.2159G>A, p.R720Q","abstract_start":598,"abstract_end":616}]}
{"pmid":"22236406","title":"Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia.","abstract":"Abetalipoproteinemia (ABL) is an inherited disease characterized by the defective assembly and secretion of apolipoprotein B-containing lipoproteins caused by mutations in the microsomal triglyceride transfer protein large subunit (MTP) gene (MTTP). We report here a female patient with an unusual clinical and biochemical ABL phenotype. She presented with severe liver injury, low levels of LDL-cholesterol, and subnormal levels of vitamin E, but only mild fat malabsorption and no retinitis pigmentosa or acanthocytosis. Our objective was to search for MTTP mutations and to determine the relationship between the genotype and this particular phenotype. The subject exhibited compound heterozygosity for two novel MTTP mutations: one missense mutation (p.Leu435His) and an intronic deletion (c.619-5_619-2del). COS-1 cells expressing the missense mutant protein exhibited negligible levels of MTP activity. In contrast, the minigene splicing reporter assay showed an incomplete splicing defect of the intronic deletion, with 26% of the normal splicing being maintained in the transfected HeLa cells. The small amount of MTP activity resulting from the residual normal splicing in the patient explains the atypical phenotype observed. Our investigation provides an example of a functional analysis of unclassified variations, which is an absolute necessity for the molecular diagnosis of atypical ABL cases.","variants":[{"Name":"NM_001386140.1(MTTP):c.1304T>A (p.Leu435His)","Chromosome":"4","Start":"99601674","Stop":"99601674","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":615975,"rule_based_match":false,"evidence_text":"c.1304T>A (p.Leu435His)","llm_judgment":"PRESENT","evidence":"p.Leu435His","abstract_start":755,"abstract_end":766}]}
{"pmid":"14517965","title":"Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic.","abstract":"Congenital Disorder of Glycosylation (CDG) type Ic is caused by mutations in ALG6. This gene encodes an alpha1,3 glucosyltransferase used for synthesis of the lipid linked oligosaccharide (LLO) precursor of the protein N-glycosylation pathway. CDG-Ic patients have moderate to severe psychomotor retardation, seizures, hypotonia, strabismus, and feeding difficulties. We previously identified a typical patient with a heterozygous point mutation, c.391T>C (p.Tyr131His) in ALG6. Using complementation analysis of ALG6-deficient yeast, we show that this alteration is as severe as the most common disease-causing mutation, c998C>T (p. Ala333Val), which occurs in over half of all known CDG-Ic patients. The frequency of c.391T>C (p.Tyr131His) in the US population, is 0.0214, suggesting that homozygotes would occur at a rate of& tilde;1:2,200. We identified one patient with typical CDG-Ic symptoms and a homozygous p.Tyr131His alteration in ALG6. However, in contrast to most CDG patients, her LLO and plasma transferrin glycosylation appeared normal. Thus, it is unclear whether c.391T>C causes CDG-Ic or contributes to the symptoms. Genotyping additional patients with CDG-like symptoms will be required to resolve this issue.","variants":[{"Name":"NM_013339.4(ALG6):c.391T>C (p.Tyr131His)","Chromosome":"1","Start":"63406361","Stop":"63406361","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39379,"rule_based_match":true,"evidence_text":"c.391T>C (p.Tyr131His)","llm_judgment":"PRESENT","evidence":"c.391T>C (p.Tyr131His)","abstract_start":447,"abstract_end":469}]}
{"pmid":"23142638","title":"Scapuloperoneal muscular dystrophy phenotype due to TRIM32-sarcotubular myopathy in South Dakota Hutterite.","abstract":"Scapuloperoneal muscular dystrophy is a group of genetically heterogeneous disorders that share the phenotype of progressive weakness of scapular and anterior distal leg muscles. Recessive mutations in C-terminal domains of TRIM32 result in limb-girdle muscular dystrophy 2H and sarcotubular myopathy, a rare congenital myopathy commonly seen in Hutterites. A scapuloperoneal phenotype has never been reported in sarcotubular myopathy. We here report a 23-year-old Hutterite man with a one-year history of progressive weakness predominantly involving the anterior tibial and left scapular muscles, and hyperCKemia. Biopsy of the anterior tibial muscle showed an active myopathy with non-rimmed vacuoles and mild denervation atrophy associated with reinnervation. The vacuoles are similar to those described in sarcotubular myopathy. TRIM32 sequencing revealed the common c.1459G>A mutation at homozygosity. A search for mutations in TRIM32 should be considered in patients with scapuloperoneal muscular dystrophy, and especially in patients of Hutterite origin or with an atypical vacuolar myopathy.","variants":[{"Name":"NM_012210.4(TRIM32):c.1459G>A (p.Asp487Asn)","Chromosome":"9","Start":"116699201","Stop":"116699201","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22389,"rule_based_match":true,"evidence_text":"c.1459G>A","llm_judgment":"PRESENT","evidence":"c.1459G>A","abstract_start":871,"abstract_end":880}]}
{"pmid":"15580564","title":"Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy.","abstract":"The autosomal recessive spinal muscular atrophy (SMA), a neuromuscular disease and frequent cause of early death in childhood, is caused in 96% of patients by homozygous absence of the survival motor neuron gene (SMN1). The severity of the disease is mainly determined by the copy number of SMN2, a copy gene which predominantly produces exon 7-skipped transcripts and only low amount of full-length transcripts that encode for a protein identical to SMN1. Only about 4% of SMA patients bear one SMN1 copy with an intragenic mutation. A comprehensive molecular genetic analysis of 34 SMA patients who carry one SMN1 gene is presented, including 18 that were previously published. Haplotype analysis with the microsatellite markers Ag1-CA and C212 in these SMA families turned out to be a reliable accessory method in predicting known SMN1 mutations in SMA patients carrying one SMN1 copy. Five novel missense mutations were identified that are localized in: exon 2a c.88G>A (p.D30N) and c.131A>T (p.D44V); exon 3 c.283G>C (p.G95R) and c.332C>G (p.A111G); and exon 6 c.784A>G (p.S262G), respectively. The survival motor neuron (SMN) protein has been shown to be a component of a large complex (termed the SMN complex) that promotes the formation of spliceosomal U small nuclear ribonucleoproteins (snRNPs). Within this complex, SMN forms oligomers and directly interacts via its N-terminus with SMN-interacting protein 1 (SIP1) and via its central Tudor domain with spliceosomal (Sm) proteins. We performed in vitro interaction studies to test whether SMA-causing missense mutations identified in this study interfere with the reported interactions of SMN. Our results show that mutations p.G95R and p.A111G reduce SMN binding to Sm proteins, further confirming the previous finding that the Tudor domain is the essential binding site of SMN to Sm-proteins. However, all mutations, including those in exon 2a, a region shown to be important for the binding of SMN to SIP1, do not disturb the interaction of SMN to SIP1.","variants":[{"Name":"NM_000344.4(SMN1):c.131A>T (p.Asp44Val)","Chromosome":"5","Start":"70938888","Stop":"70938888","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":24211,"rule_based_match":true,"evidence_text":"c.131A>T (p.D44V)","llm_judgment":"PRESENT","evidence":"c.131A>T (p.D44V)","abstract_start":987,"abstract_end":1004},{"Name":"NM_000344.4(SMN1):c.88G>A (p.Asp30Asn)","Chromosome":"5","Start":"70938845","Stop":"70938845","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24214,"rule_based_match":true,"evidence_text":"c.88G>A (p.D30N)","llm_judgment":"PRESENT","evidence":"c.88G>A (p.D30N)","abstract_start":966,"abstract_end":982},{"Name":"NM_000344.4(SMN1):c.283G>C (p.Gly95Arg)","Chromosome":"5","Start":"70942367","Stop":"70942367","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":24215,"rule_based_match":true,"evidence_text":"c.283G>C (p.G95R)","llm_judgment":"PRESENT","evidence":"c.283G>C (p.G95R)","abstract_start":1013,"abstract_end":1030},{"Name":"NM_000344.4(SMN1):c.332C>G (p.Ala111Gly)","Chromosome":"5","Start":"70942416","Stop":"70942416","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":24216,"rule_based_match":true,"evidence_text":"c.332C>G (p.A111G)","llm_judgment":"PRESENT","evidence":"c.332C>G (p.A111G)","abstract_start":1035,"abstract_end":1053},{"Name":"NM_000344.4(SMN1):c.784A>G (p.Ser262Gly)","Chromosome":"5","Start":"70946126","Stop":"70946126","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":24217,"rule_based_match":true,"evidence_text":"c.784A>G (p.S262G)","llm_judgment":"PRESENT","evidence":"c.784A>G (p.S262G)","abstract_start":1066,"abstract_end":1084}]}
{"pmid":"33508233","title":"Homozygous mutations in C14orf39/SIX6OS1 cause non-obstructive azoospermia and premature ovarian insufficiency in humans.","abstract":"Human infertility is a multifactorial disease that affects 8%-12% of reproductive-aged couples worldwide. However, the genetic causes of human infertility are still poorly understood. Synaptonemal complex (SC) is a conserved tripartite structure that holds homologous chromosomes together and plays an indispensable role in the meiotic progression. Here, we identified three homozygous mutations in the SC coding gene C14orf39/SIX6OS1 in infertile individuals from different ethnic populations by whole-exome sequencing (WES). These mutations include a frameshift mutation (c.204_205del [p.His68Glnfs<sup>∗</sup>2]) from a consanguineous Pakistani family with two males suffering from non-obstructive azoospermia (NOA) and one female diagnosed with premature ovarian insufficiency (POI) as well as a nonsense mutation (c.958G>T [p.Glu320<sup>∗</sup>]) and a splicing mutation (c.1180-3C>G) in two unrelated Chinese men (individual P3907 and individual P6032, respectively) with meiotic arrest. Mutations in C14orf39 resulted in truncated proteins that retained SYCE1 binding but exhibited impaired polycomplex formation between C14ORF39 and SYCE1. Further cytological analyses of meiosis in germ cells revealed that the affected familial males with the C14orf39 frameshift mutation displayed complete asynapsis between homologous chromosomes, while the affected Chinese men carrying the nonsense or splicing mutation showed incomplete synapsis. The phenotypes of NOA and POI in affected individuals were well recapitulated by Six6os1 mutant mice carrying an analogous mutation. Collectively, our findings in humans and mice highlight the conserved role of C14ORF39/SIX6OS1 in SC assembly and indicate that the homozygous mutations in C14orf39/SIX6OS1 described here are responsible for infertility of these affected individuals, thus expanding our understanding of the genetic basis of human infertility.","variants":[{"Name":"NM_174978.3(C14orf39):c.958G>T (p.Glu320Ter)","Chromosome":"14","Start":"60465993","Stop":"60465993","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":980760,"rule_based_match":true,"evidence_text":"c.958G>T (p.Glu320<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"c.958G>T","abstract_start":819,"abstract_end":827},{"Name":"NM_174978.3(C14orf39):c.204_205del (p.His68fs)","Chromosome":"14","Start":"60483719","Stop":"60483720","ReferenceAlleleVCF":"CTA","AlternateAlleleVCF":"C","allel_id":980761,"rule_based_match":true,"evidence_text":"c.204_205del [p.His68Glnfs<sup>∗</sup>2]","llm_judgment":"PRESENT","evidence":"c.204_205del [p.His68Glnfs<sup>∗</sup>2]","abstract_start":574,"abstract_end":614},{"Name":"NM_174978.3(C14orf39):c.1180-3C>G","Chromosome":"14","Start":"60457098","Stop":"60457098","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":980759,"rule_based_match":true,"evidence_text":"c.1180-3C>G","llm_judgment":"PRESENT","evidence":"c.1180-3C>G","abstract_start":877,"abstract_end":888}]}
{"pmid":"23018754","title":"Genetic analysis of NR0B1 in congenital adrenal hypoplasia patients: identification of a rare regulatory variant resulting in congenital adrenal hypoplasia and hypogonadal hypogonadism without testicular carcinoma in situ.","abstract":"There have been few testicular histology reports of adult patients with congenital adrenal hypoplasia/hypogonadal hypogonadism (AHC/HH), but Leydig cell hyperplasia has been observed, an indicator of the possibility of malignant transformation. We aimed to define the basis of AHC/HH in 4 pedigrees of different ethnic backgrounds. One patient was elected to have testicular biopsy which was examined for evidence of carcinoma in situ (CIS). NR0B1 mutation analysis was performed by sequence analysis. NR0B1 expression was investigated by RT-PCR. Testicular biopsy sections were stained with HE or immunostained for OCT3/4, an established marker of CIS. We identified NR0B1 variants in the 4 AHC pedigrees: pedigree 1 (United Arab Emirates), c.1130A>G predicting p.(Glu377Gly); pedigree 2 (English Caucasian), c.327C>A predicting p.(Cys109*); pedigree 3 (Oman), a 6-bp deletion of a direct repeat, c.857_862delTGGTGC predicting p.(Leu286_Val287del); pedigree 4 (English Caucasian), c.1168+1G>A, a regulatory variant within the NR0B1 splice donor site. This last male patient, aged 30 years, presented with evidence of HH but incomplete gonadotrophin deficiency, following an earlier diagnosis of Addison's disease at 3 years. Hormonal therapy induced virilisation. Testicular biopsy was performed. The c.1168+1G>A variant abrogated normal splicing of testicular mRNA. Histological examination showed poorly organised testicular architecture and absence of spermatozoa. Morphological analyses and the absence of immunohistochemical staining for OCT3/4 excluded the presence of malignant germ cell cancer and its precursor lesion, CIS. These studies add to the knowledge of the types and ethnic diversity of NR0B1 mutations and their associated phenotypes, and provide insight into the assessment and interpretation of testicular histology in AHC and HH.","variants":[{"Name":"NM_000475.5(NR0B1):c.327C>A (p.Cys109Ter)","Chromosome":"X","Start":"30309037","Stop":"30309037","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":437733,"rule_based_match":true,"evidence_text":"c.327C>A predicting p.(Cys109*)","llm_judgment":"PRESENT","evidence":"c.327C>A predicting p.(Cys109*)","abstract_start":810,"abstract_end":841}]}
{"pmid":"31944481","title":"Protein-elongating mutations in MYH11 are implicated in a dominantly inherited smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease.","abstract":"Gastrointestinal motility disorders include a spectrum of mild to severe clinical phenotypes that are caused by smooth muscle dysfunction. We investigated the genetic etiology of severe esophageal, gastric, and colonic dysmotility in two unrelated families with autosomal dominant disease presentation. Using exome sequencing, we identified a 2 base pair insertion at the end of the myosin heavy chain 11 (MYH11) gene in all affected members of Family 1 [NM_001040113:c.5819_5820insCA(p.Gln1941Asnfs*91)] and a 1 base pair deletion at the same genetic locus in Proband 2 [NM_001040113:c.5819del(p.Pro1940Hisfs*91)]. Both variants are predicted to result in a similarly elongated protein product. Heterozygous dominant negative MYH11 pathogenic variants have been associated with thoracic aortic aneurysm and dissection while biallelic null alleles have been associated with megacystis microcolon intestinal hypoperistalsis syndrome. This report highlights heterozygous protein-elongating MYH11 variants affecting the SM2 isoforms of MYH11 as a cause for severe gastrointestinal dysmotility, and we hypothesize that the mechanistic pathogenesis of this disease, dominant hypercontractile loss-of-function, is distinct from those implicated in other diseases involving MYH11 dysfunction.","variants":[{"Name":"NM_001040113.2(MYH11):c.5819del (p.Pro1940fs)","Chromosome":"16","Start":"15708830","Stop":"15708830","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":616000,"rule_based_match":true,"evidence_text":"NM_001040113:c.5819del(p.Pro1940Hisfs*91)","llm_judgment":"PRESENT","evidence":"NM_001040113:c.5819del(p.Pro1940Hisfs*91)","abstract_start":572,"abstract_end":613},{"Name":"NM_001040113.2(MYH11):c.5819_5820insCA (p.Gln1941fs)","Chromosome":"16","Start":"15708829","Stop":"15708830","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TTG","allel_id":682300,"rule_based_match":true,"evidence_text":"NM_001040113:c.5819_5820insCA(p.Gln1941Asnfs*91)","llm_judgment":"PRESENT","evidence":"NM_001040113:c.5819_5820insCA(p.Gln1941Asnfs*91)","abstract_start":455,"abstract_end":503}]}
{"pmid":"20358613","title":"RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome.","abstract":"We report here on a RAB23 mutation (c.86dupA) present in the homozygote state in four relatives of Comorian origin with Carpenter syndrome. All children presented with acrocephaly and polysyndactyly. However, intrafamilial variability was observed with variable severity of craniosynostosis ranging from cloverleaf skull to predominant involvement of the metopic ridge. All children also presented with a combination of brachydactyly with agenesis of the middle phalanges, syndactyly, broad thumbs, and postaxial polydactyly (2/4) in the hands, and preaxial polydactyly (3) and syndactyly (4) in the toes. Mental development was normal in all four children but the eldest one presented with impaired motor development as a result of orthopedic complications. Brain imaging showed hydrocephalus in 2/4 and additional features included genu valgum (2/4), abnormal genitalia (3/4), corneal anomaly (2/4), umbilical hernia (1/4), severe cyphoscoliosis (1), patent ductus arteriosus (1/4), and accessory spleen (1). In contrast to previous reports, growth was below average except for one patient and the eldest one became moderately overweight with time. We conclude from the report of this large unique family with four affected children that Carpenter syndrome is a genetically homogenous but a clinically variable condition.","variants":[{"Name":"NM_016277.5(RAB23):c.86dup (p.Tyr29Ter)","Chromosome":"6","Start":"57210294","Stop":"57210295","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AT","allel_id":33465,"rule_based_match":true,"evidence_text":"c.86dupA","llm_judgment":"PRESENT","evidence":"c.86dupA","abstract_start":36,"abstract_end":44}]}
{"pmid":"36653541","title":"Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition.","abstract":"CHEK2 is a well-established breast cancer susceptibility gene. The most frequent pathogenic CHEK2 variant is 1100delC, a loss-of-function mutation conferring 2-fold risk for breast cancer. This gene also harbors other rare variants encountered in the clinical gene panels for hereditary cancer. One of these is CHEK2 c.1312 G > T, p.(Asp438Tyr) in the kinase domain of the protein, but due to its rarity its clinical significance for breast cancer predisposition has remained unclear. Here, we tested the prevalence of CHEK2 p.(Asp438Tyr) allele showing enrichment in the Northern Finnish population, in a total of 2284 breast cancer patients from this geographical region. Genotyping was performed for DNA samples extracted from peripheral blood using high-resolution melt analysis. Fourteen CHEK2 p.(Asp438Tyr) carriers were identified (14/2284, 0.6%, P = 0.67): two in the cohort of breast cancer cases with the indication of inherited disease susceptibility (2/281, 0.7%, P = 1.00) and twelve in the breast cancer cohort unselected for the family history of disease and age at disease onset (12/2003, 0.6%, P = 0.66). This frequency did not differ from the frequency in the general population (10/1299, 0.8%). No CHEK2 p.(Asp438Tyr) homozygotes were identified. Our results indicate that CHEK2 p.(Asp438Tyr) carriers do not have an increased risk for breast cancer and the classification of the CHEK2 p.(Asp438Tyr) variant can be changed from the variant of uncertain significance (VUS) to likely benign for breast cancer.","variants":[{"Name":"NM_007194.4(CHEK2):c.1312G>T (p.Asp438Tyr)","Chromosome":"22","Start":"28695190","Stop":"28695190","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":133513,"rule_based_match":true,"evidence_text":"CHEK2 c.1312 G > T, p.(Asp438Tyr)","llm_judgment":"PRESENT","evidence":"CHEK2 c.1312 G > T, p.(Asp438Tyr)","abstract_start":311,"abstract_end":344}]}
{"pmid":"18660473","title":"Expanding the neurologic phenotype of oculodentodigital dysplasia in a 4-generation Hispanic family.","abstract":"We report a 4-generation Hispanic family with oculodentodigital dysplasia whose members were found to have typical phenotypic characteristics of this disorder, as well as a variable expression of neurologic manifestations in multiple generations ranging from a mild spastic gait to moderate to severe spastic tetraparesis/quadriplegia with epilepsy and an abnormal brain and spinal cord magnetic resonance imaging result. Gene testing documented a previously reported missense mutation in GJA1 (connexin 43) exon 2 (c.389T>C;p.I130T). Our evaluation not only expands the phenotypes associated with GJA1 gene mutations but also demonstrates that a great degree of variability in neurological defects can exist within a single family without evidence of genetic anticipation. A genotype-phenotype correlation between the p.I130T mutation and neurologic dysfunction appears more likely with the addition of this report's neurologic and GJA1 gene mutation findings. These findings expand the neurologic phenotype and prognosis and underscore the importance of counseling families with oculodentodigital dysplasia about the possibility of neurologic involvement.","variants":[{"Name":"NM_000165.5(GJA1):c.389T>C (p.Ile130Thr)","Chromosome":"6","Start":"121447236","Stop":"121447236","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":456047,"rule_based_match":true,"evidence_text":"c.389T>C;p.I130T","llm_judgment":"PRESENT","evidence":"c.389T>C;p.I130T","abstract_start":516,"abstract_end":532}]}
{"pmid":"29246599","title":"Manifestations of neurological symptoms and thromboembolism in adults with MTHFR-deficiency.","abstract":"BACKGROUND: Methylenetetrahydrofolate-reductase (MTHFR) deficiency is a rare autosomal recessive disorder affecting intracellular folate metabolism with affection of different organ systems and clinical manifestation usually in childhood.\nOBJECTIVE: We report on four adult members of a family with MTHFR deficiency presenting with neurological and thromboembolic complications in adulthood.\nMETHODS: Extensive diagnostic work-up including genetic testing was performed in four adult members.\nRESULTS: The male siblings aged 42 and 32years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135μmol/L and 231μmol/L. and compound heterozygosity for two novel MTHFR gene mutations in exon 2 (c.202C>G, p.Arg68Gly) and intron 10 (c.1632+2T>G), and the known polymorphic variant MTHFR c.665C>T (p.Ala222Val, MTHFR 677C>T). Their mother was heterozygous for MTHFR c.1632+2T>G and c.665C>T, and a paternal relative was heterozygous for MTHFR c.202.C>G and MTHFR c.665C>T mutation. Both brothers showed partial response to therapy with betaine and multivitamins with clinical improvement. MTHFR activity was determined in fibroblast extracts and was around 4% of the mean control. Cell culture analysis indicated a re-methylation defect due to MTHFR deficiency.\nCONCLUSION: Severe hyperhomocysteinemia due to two mutations of the MTHFR gene resulted in severe neurological symptoms in adulthood. Vitamin and methionine supplementation stabilize tHcy plasma levels. Severity of clinical manifestation varied greatly between the siblings. Damages to the nervous system may be present for years before becoming clinically manifest.","variants":[{"Name":"NM_005957.5(MTHFR):c.202C>G (p.Arg68Gly)","Chromosome":"1","Start":"11802915","Stop":"11802915","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":185794,"rule_based_match":true,"evidence_text":"c.202C>G","llm_judgment":"PRESENT","evidence":"c.202C>G","abstract_start":820,"abstract_end":828}]}
{"pmid":"28874324","title":"Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes.","abstract":"The lamin A/C (LMNA) gene encodes lamins A and C, which have an important role in nuclear cohesion and chromatin organization. Mutations in this gene usually lead to the so-called laminopathies, the primary cardiac manifestations of which are dilated cardiomyopathy and intracardiac conduction defects. Some mutations, associated with lipodystrophy but not cardiomyopathy, have been linked to metabolic abnormalities such as diabetes and severe dyslipidemia. Herein we describe a new phenotype associated with a mutation in exon 11 of the LMNA gene: hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. A 64-year-old woman with hypertrophic cardiomyopathy and a point mutation in exon 11 of the LMNA gene (c.1718C>T, Ser573Leu) presented with severe symptomatic ventricular hypertrophy and left ventricular outflow tract obstruction. She underwent septal alcohol ablation, followed by Morrow myectomy. The patient was also diagnosed with severe dyslipidemia, diabetes and obesity, and fulfilled diagnostic criteria for metabolic syndrome. No other characteristics of LMNA mutation-related phenotypes were identified. The development of type III atrioventricular block with no apparent cause, and mildly depressed systolic function, prompted referral for cardiac resynchronization therapy. In conclusion, the association between LMNA mutations and different phenotypes is complex and not fully understood, and can present with a broad spectrum of severity.","variants":[{"Name":"NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu)","Chromosome":"1","Start":"156138507","Stop":"156138507","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29556,"rule_based_match":true,"evidence_text":"c.1718C>T, Ser573Leu","llm_judgment":"PRESENT","evidence":"c.1718C>T, Ser573Leu","abstract_start":740,"abstract_end":760}]}
{"pmid":"31788662","title":"The first Portuguese family with NEFL-related Charcot-Marie-Tooth type 2 disease.","abstract":"CMT disease caused by <i>NEFL</i> gene mutations is rare. The mode of inheritance can be dominant or recessive and nerve conduction velocities can be normal, reduced (demyelinating) or presenting intermediate values. Two Portuguese adult related members in two successive generations were affected by peripheral neuropathy, one with a chronic ataxic peripheral neuropathy and the other with a classical Charcot-Marie-Tooth phenotype. An axonal sensorimotor peripheral neuropathy was described at neurophysiology. A missense heterozygous mutation, c.794A > G (p.Tyr265Cys), in the <i>NEFL</i> gene was found in both patients. This is the first Portuguese family reported with NEFL-related CMT type 2.","variants":[{"Name":"NM_006158.5(NEFL):c.794A>G (p.Tyr265Cys)","Chromosome":"8","Start":"24955722","Stop":"24955722","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":165494,"rule_based_match":true,"evidence_text":"c.794A > G (p.Tyr265Cys)","llm_judgment":"PRESENT","evidence":"c.794A > G (p.Tyr265Cys)","abstract_start":547,"abstract_end":571}]}
{"pmid":"28538409","title":"A case report of pedigree of a homozygous mutation of the steroidogenic acute regulatory protein causing lipoid congenital adrenal hyperplasia.","abstract":"RATIONALE: Lipoid congenital adrenal hyperplasia (LCAH) is extremely rare, but is the most fatal form of congenital adrenal hyperplasia resulting from mutations in the steroidogenic acute regulatory protein (STAR) gene. LCAH arises from severe defects in the conversion of cholesterol to pregnenolone, the precursor of all steroids.\nPATIENT CONCERNS: A case was reported that an 11-month-old Chinese girl who presented with a sex development disorder and hyponatremia. The clinical and genetic tests were carried out to confirm the diagnosis. The genogram of this case was also explored and analyzed. The girl presented with hyponatremia, decreased cortisol level, elevated adrenocorticotropic hormone level and female vulva despite a 46, XY karyotype. Enlarged adrenal glands and testicular-like tissue in the bilateral inguinal regions were detected with abdominal ultrasound. She was suspected of having LCAH, and definitive diagnosis was made after Sanger sequencing detected a homozygous frameshift variant c.707_708delins CTT (p.Lys236Thrfs*47) on exon 6 of the STAR gene.\nDIAGNOSES: LCAH.\nINTERVENTIONS: She was prescribed hydrocortisone 10 to 12 mg/m2 and 9a- fludrocortisone 100 mg/d.\nOUTCOMES: Her skin hyperpigmentation and vomiting disappeared, and she had normal growth and development without adrenal crisis attacks. Her hormone and electrolyte levels remained normal, except for a persistently elevated ACTH level throughout 2 years of follow-up. At follow-up for 2 years, the patient is now 104.5 cm tall and weighs 23.3 kg at the age of 4 years old. Her plasma sodium and potassium concentration were normal. Her ACTH level is still elevated (1176 pg/mL). Her baseline sex hormone levels are testosterone <0.1 ng/dL and progesterone <0.08 ng/dL. The level of PRA (1.06 ng/mL per h) is within normal range.\nLESSONS: This mutation was in accordance with previously reported gene mutations. The patient's parents were nonconsanguineous; her parents, paternal grandfather, and maternal grandmother were all found to be carriers of a STAR gene mutation. This 46 XY disorders of sex development case presented with adrenal insufficiency and female phenotype initially. The diagnosis was complicated depending on the clinical hormone workup. LCAH was confirmed by genetic tests and genogram of the family.","variants":[{"Name":"NM_000349.3(STAR):c.707_708delinsCTT (p.Lys236fs)","Chromosome":"8","Start":"38145258","Stop":"38145259","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"AAG","allel_id":2151067,"rule_based_match":true,"evidence_text":"c.707_708delins CTT (p.Lys236Thrfs*47)","llm_judgment":"PRESENT","evidence":"c.707_708delins CTT (p.Lys236Thrfs*47)","abstract_start":1012,"abstract_end":1050}]}
{"pmid":"35307828","title":"Genetic analysis reveals novel variants for vascular cognitive impairment.","abstract":"OBJECTIVES: The genetic background of vascular cognitive impairment (VCI) is poorly understood compared to other dementia disorders. The aim of the study was to investigate the genetic background of VCI in a well-characterized Finnish cohort.\nMATERIALS & METHODS: Whole-exome sequencing (WES) was applied in 45 Finnish VCI patients. Copy-number variant (CNV) analysis using a SNP array was performed in 80 VCI patients. This study also examined the prevalence of variants at the miR-29 binding site of COL4A1 in 73 Finnish VCI patients.\nRESULTS: In 40% (18/45) of the cases, WES detected possibly causative variants in genes associated with cerebral small vessel disease (CSVD) or other neurological or stroke-related disorders. These variants included HTRA1:c.847G>A p.(Gly283Arg), TREX1:c.1079A>G, p.(Tyr360Cys), COLGALT1:c.1411C>T, p.(Arg471Trp), PRNP: c.713C>T, p.(Pro238Leu), and MTHFR:c.1061G>C, p.(Gly354Ala). Additionally, screening of variants in the 3'UTR of COL4A1 gene in a sub-cohort of 73 VCI patients identified a novel variant c.*36T>A. CNV analysis showed that pathogenic CNVs are uncommon in VCI.\nCONCLUSIONS: These data support pathogenic roles of variants in HTRA1, TREX1 and in the 3'UTR of COL4A1 in CSVD and VCI, and suggest that vascular pathogenic mechanisms are linked to neurodegeneration, expanding the understanding of the genetic background of VCI.","variants":[{"Name":"NM_001845.6(COL4A1):c.*36T>A","Chromosome":"13","Start":"110150327","Stop":"110150327","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1291808,"rule_based_match":true,"evidence_text":"c.*36T>A","llm_judgment":"PRESENT","evidence":"c.*36T>A","abstract_start":1043,"abstract_end":1051},{"Name":"NM_024656.4(COLGALT1):c.1411C>T (p.Arg471Trp)","Chromosome":"19","Start":"17580715","Stop":"17580715","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1291819,"rule_based_match":true,"evidence_text":"COLGALT1:c.1411C>T, p.(Arg471Trp)","llm_judgment":"PRESENT","evidence":"COLGALT1:c.1411C>T, p.(Arg471Trp)","abstract_start":815,"abstract_end":848},{"Name":"NM_002775.5(HTRA1):c.847G>A (p.Gly283Arg)","Chromosome":"10","Start":"122506760","Stop":"122506760","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1174829,"rule_based_match":true,"evidence_text":"HTRA1:c.847G>A p.(Gly283Arg)","llm_judgment":"PRESENT","evidence":"HTRA1:c.847G>A p.(Gly283Arg)","abstract_start":753,"abstract_end":781},{"Name":"NM_000311.5(PRNP):c.713C>T (p.Pro238Leu)","Chromosome":"20","Start":"4699933","Stop":"4699933","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1291822,"rule_based_match":true,"evidence_text":"PRNP: c.713C>T, p.(Pro238Leu)","llm_judgment":"PRESENT","evidence":"PRNP: c.713C>T, p.(Pro238Leu)","abstract_start":850,"abstract_end":879}]}
{"pmid":"22052681","title":"A novel mutation impairing the tertiary structure and stability of γC-crystallin (CRYGC) leads to cataract formation in humans and zebrafish lens.","abstract":"Congenital cataract is one of the leading causes of human blindness. In this study, we identified a novel, heterozygous c.385G<T mutation in CRYGC that resulted in the substitution of a highly conserved glycine by cysteine at codon 129 (p.Gly129Cys) in a three-generation Chinese family with autosomal dominant congenital nuclear cataract by sequencing candidate genes. Using zebrafish as a model, we demonstrated that γC-crystallin p.Gly129Cys mutant caused the vacuole and the incomplete denucleation of lens, recapitulating the cataract phenotype in human beings. Molecular modeling and spectroscopic studies indicated that the mutation impaired the tertiary structure of the protein by modifying the H-bonding network in the C-terminal domain. The mutation led to a dramatic decrease in the thermal stability of γC-crystallin, and a significant increase in the propensity of aggregation when subject to storage at high concentrations, heat, and UV- irradiation stresses. Taken together, these results indicate that a novel γC-crystallin p.Gly129Cys mutation impaired the tertiary structure of the protein and caused cataract formation, which provides a new insight into how the mutation may affect the γC-crystallin structure, stability, and function. Our study also highlighted zebrafish as a valuable model tool for studying congenital inherited cataract.","variants":[{"Name":"NM_020989.4(CRYGC):c.385G>T (p.Gly129Cys)","Chromosome":"2","Start":"208128343","Stop":"208128343","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":76978,"rule_based_match":false,"evidence_text":"c.385G>T (p.Gly129Cys)","llm_judgment":"PRESENT","evidence":"p.Gly129Cys","abstract_start":237,"abstract_end":248}]}
{"pmid":"21674762","title":"Screening the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK gene mutations in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.","abstract":"BACKGROUND: This study aimed to investigate the prevalence of mutations in the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK in Chinese pediatric patients with EBV-HLH.\nMETHODS: Sixty-seven pediatric patients diagnosed with EBV-HLH in Beijing Children's Hospital were recruited. Nucleotide sequences of all exons and their flanking intronic sequences of PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK were amplified by PCR followed by direct sequencing.\nRESULTS: Eight patients were identified with heterozygous, compound heterozygous, or homozygous mutations in PFR1, UNC13D, and XIAP. Three missense mutations (c.83G>A, c.503G>A, c.632C>T) were found in PRF1 of two males and two females. Compound heterozygous c.93C>G and c.1066C>T were found in PRF1 of a 2.5-year-old female. Four different mutations were found in UNC13D of two patients: compound nonsense heterozygous mutations c.766C>T and c.1215C>G were found in one male and two splicing mutations c.1596+1G>C and c.2709+1G>A were found in another male. A heterozygous mutation c.1099+2T>C in XIAP was found in a 4-year-old male. No detrimental mutations were identified in STX11, SH2D1A, or ITK. NK cell activity did not differ between the eight FHL patients and the remaining patients. There was no statistical difference in clinical features and laboratory data for these two subgroups with biallelic and heterozygous mutations.\nCONCLUSIONS: Seven novel mutations in PRF1, UNC13D, and XIAP were identified in EBV-HLH patients. Only a fraction of the Chinese children with EBV-HLH have genetic defects in PRF1, UNC13D, and XIAP. There were no gene mutations of PRF1/UNC13D/STX11/SH2D1A/XIAP/ITK in the majority of Chinese child patients with EBV-HLH.","variants":[{"Name":"NM_001083116.3(PRF1):c.503G>A (p.Ser168Asn)","Chromosome":"10","Start":"70600400","Stop":"70600400","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1686566,"rule_based_match":true,"evidence_text":"c.503G>A","llm_judgment":"PRESENT","evidence":"c.503G>A","abstract_start":615,"abstract_end":623},{"Name":"NM_001083116.3(PRF1):c.632C>T (p.Ala211Val)","Chromosome":"10","Start":"70599089","Stop":"70599089","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":460488,"rule_based_match":true,"evidence_text":"c.632C>T","llm_judgment":"PRESENT","evidence":"c.632C>T","abstract_start":625,"abstract_end":633},{"Name":"NM_001083116.3(PRF1):c.1066C>T (p.Arg356Trp)","Chromosome":"10","Start":"70598655","Stop":"70598655","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":947019,"rule_based_match":true,"evidence_text":"c.1066C>T","llm_judgment":"PRESENT","evidence":"c.1066C>T","abstract_start":718,"abstract_end":727},{"Name":"NM_001083116.3(PRF1):c.83G>A (p.Arg28His)","Chromosome":"10","Start":"70600820","Stop":"70600820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1029707,"rule_based_match":true,"evidence_text":"c.83G>A","llm_judgment":"PRESENT","evidence":"c.83G>A","abstract_start":606,"abstract_end":613},{"Name":"NM_199242.3(UNC13D):c.766C>T (p.Arg256Ter)","Chromosome":"17","Start":"75840317","Stop":"75840317","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17039,"rule_based_match":true,"evidence_text":"c.766C>T","llm_judgment":"PRESENT","evidence":"c.766C>T","abstract_start":877,"abstract_end":885},{"Name":"NM_199242.3(UNC13D):c.2709+1G>A","Chromosome":"17","Start":"75830577","Stop":"75830577","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":434457,"rule_based_match":true,"evidence_text":"c.2709+1G>A","llm_judgment":"PRESENT","evidence":"c.2709+1G>A","abstract_start":966,"abstract_end":977},{"Name":"NM_001167.4(XIAP):c.1099+2T>C","Chromosome":"X","Start":"123892775","Stop":"123892775","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1056730,"rule_based_match":true,"evidence_text":"c.1099+2T>C","llm_judgment":"PRESENT","evidence":"c.1099+2T>C","abstract_start":1030,"abstract_end":1041}]}
{"pmid":"29424410","title":"Diabetes mellitus caused by a mutation of glucokinase gene. Report of an affected family","abstract":"Maturity-Onset Diabetes of the Young (MODY) refers to a heterogeneous group of monogenic diabetes. Unlike other types of MODY characterized by genetic defects in transcription factors, MODY 2 is triggered by metabolic alterations caused by mutations of glucokinase (GCK), the first enzyme of the glycolytic pathway. We report a three-generation Chilean family with multiple cases affected with this disease. The index case is a patient who presented severe neonatal hyperglycemia (831 mg/dl, without ketosis) requiring continuous infusion of insulin, which was suspended after 48 hours with normalization of blood glucose. Subsequently, continuous glucose monitoring at 4 months of age revealed 47% of tissue glucose levels above 140 mg/dl, with fasting glucose levels between 120 and 166 mg/dl. The genetic analysis revealed a previously reported mutation in heterozygous state of the GCK gene (c.148C>T; p.His50Tyr). This mutation was also identified in more than one affected relative in the last two generations, with a transmission pattern suggestive of dominant inheritance. GCK gene sequencing led to a correct molecular diagnosis of MODY 2 while bioinformatic analysis indicated the possible molecular causes of the enzyme dysfunction. The knowledge of the molecular diagnosis allowed an adequate medical treatment for this disease.","variants":[{"Name":"NM_000162.5(GCK):c.148C>T (p.His50Tyr)","Chromosome":"7","Start":"44153361","Stop":"44153361","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":619858,"rule_based_match":true,"evidence_text":"c.148C>T (p.His50Tyr)","llm_judgment":"PRESENT","evidence":"p.His50Tyr","abstract_start":906,"abstract_end":916}]}
{"pmid":"16269441","title":"Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle.","abstract":"Retinoid dehydrogenases/reductases catalyze key oxidation-reduction reactions in the visual cycle that converts vitamin A to 11-cis retinal, the chromophore of the rod and cone photoreceptors. It has recently been shown that mutations in RDH12, encoding a retinol dehydrogenase, result in severe and early-onset autosomal recessive retinal dystrophy (arRD). In a cohort of 1011 individuals diagnosed with arRD, we have now identified 20 different disease-associated RDH12 mutations, of which 16 are novel, in a total of 22 individuals (2.2%). Haplotype analysis suggested a founder mutation for each of the three common mutations: p.L99I, p.T155I and c.806_810delCCCTG. Patients typically presented with early disease that affected the function of both rods and cones and progressed to legal blindness in early adulthood. Eleven of the missense variants identified in our study exhibited profound loss of catalytic activity when expressed in transiently transfected COS-7 cells and assayed for ability to convert all-trans retinal to all-trans retinol. Loss-of-function appeared to result from decreased protein stability, as expression levels were significantly reduced. For the p.T49M variant, differing activity profiles were associated with each of the alleles of the common p.R161Q RDH12 polymorphism, suggesting that genetic background may act as a modifier of mutation effect. A locus (LCA3) for Leber congenital amaurosis, a severe, early-onset form of arRD, maps close to RDH12 on chromosome 14q24. Haplotype analysis in the family in which LCA3 was mapped excluded RDH12 as the LCA3 gene and thus suggests the presence of a novel arRD gene in this region.","variants":[{"Name":"NM_152443.3(RDH12):c.806_810del (p.Ala269fs)","Chromosome":"14","Start":"67729337","Stop":"67729341","ReferenceAlleleVCF":"CGCCCT","AlternateAlleleVCF":"C","allel_id":17086,"rule_based_match":true,"evidence_text":"c.806_810delCCCTG","llm_judgment":"PRESENT","evidence":"c.806_810delCCCTG","abstract_start":651,"abstract_end":668}]}
{"pmid":"34048777","title":"Novel variants in GUCY2D causing retinopathy and the genotype-phenotype correlation.","abstract":"Leber congenital amaurosis (LCA) is the most severe form of retinopathy and cone/cone-rod dystrophy (CORD) is a common form of inherited retinopathy. Variants in GUCY2D constitute the most common cause of LCA and autosomal dominant CORD (ADCORD). The purpose of this study was to reveal novel variants and document associated phenotypes of patients with GUCY2D-associated retinopathy. Fifty-two potentially pathogenic variants (PPVs), including 12 novel ones (p.Gly144_Ala164del, p.Trp154Glyfs*12, p.Leu186Pro, p.Ala207Pro, p.Ala229Asp, p.Ala353Glu, p.Trp372*, p.Arg528*, p.Arg660Pro, p.Ile682Thr, p.Trp788Cys, and c.1026 + 171_*486del), were identified in 16 families with ADCORD and 34 families with autosomal recessive LCA (ARLCA). The novel variant c.1026 + 171_*486del is a large-scale (16.3 kb) deletion involving exons 4-20 of GUCY2D, and was identified in an ARLCA family in heterozygous status mimicking a homozygous p.Trp788Cys variant. Among the detected 52 PPVs, 32 (61.5%) were missense, seven (13.5%) were splicing, six (11.5%) were nonsense, four (7.7%) were inframe indel, and three (5.8%) were frameshift deletion. The median age of examination in 27 patients with ADCORD was 21.0 years (ranges 3-54) with a median visual acuity (VA) of 0.10 (ranges 0.02-0.90). There were 48.0% of patients with macular atrophy, 86.4% with severe reduced or extinguished cone responses, 77.3% with normal or mildly reduced rod responses, and 60.9% with high myopia. Visual impairment, macular dystrophy, and cone dysfunction deteriorated with age. The median age of examination in 34 patients with ARLCA was 1.1 years (ranges 0.3-25). There were 55.9% of patients with roving nystagmus, 68.2% with VA of worse than hand motion, 59.4% with almost normal fundus, 90.6% with extinguished rod and cone responses, and 50.0% with high hyperopia. In conclusions, twelve novel PPVs in GUCY2D (including a novel large-scale deletion) were identified. Most (32/52, 61.5%) of causative GUCY2D variants were missense. Progressive development of macular atrophy, cone dysfunction, visual impairment, and myopia are four major characteristics of GUCY2D-associated ADCORD. Normal fundus, roving nystagmus, and hypermetropia in early age are common findings specific to GUCY2D-associated ARLCA. The obtained data in this study will be of value in counselling patients and designing future therapeutic approaches.","variants":[{"Name":"NM_000180.4(GUCY2D):c.1582C>T (p.Arg528Ter)","Chromosome":"17","Start":"8007946","Stop":"8007946","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":950351,"rule_based_match":false,"evidence_text":"p.Arg528*","llm_judgment":"PRESENT","evidence":"p.Arg528*","abstract_start":561,"abstract_end":570}]}
{"pmid":"38160741","title":"Clinical and molecular heterogeneity of VPS13D-related neurodevelopmental and movement disorders.","abstract":"BACKGROUND: The VPS13 family of proteins has been implicated in lipid transport and trafficking between endoplasmic reticulum and organelles, to maintain homeostasis of subcellular membranes. Recently, pathogenic variants in each human VPS13S gene, have been linked to distinct human neurodevelopmental or neurodegenerative disorders. Within the VPS13 family of genes, VPS13D is known to be implicated in mitochondria homeostasis and function.\nMETHODS: We investigated a Pakistani sibship affected with neurodevelopmental impairment and severe hyperkinetic (choreoathetoid) movements. Whole exome sequencing (WES) and Sanger sequencing were performed to identify potential candidate variants segregating in the family. We described clinical phenotypes and natural history of the disease during a 3-year clinical follow-up and summarized literature data related to previously identified patients with VPS13D-related neurological disorders.\nRESULTS: We identified by WES an homozygous non-synonymous variant in VPS13D (c.5723 T > C; p.Ile1908Thr) as the potential underlying cause of the disease in our family. Two young siblings developed an early-onset neurological impairment characterized by global developmental delay, with impaired speech and motor milestones, associated to hyperkinetic movement disorders as well as progressive and non-progressive neurological abnormalities.\nCONCLUSION: In this study we delineated the heterogeneity of VPS13D-related clinical phenotypes and described a novel VPS13D homozygous variant associated with severe neurological impairment. Further studies will be pivotal to understand the exact VPS13D function and its impact on mitochondria homeostasis, brain development and regulation of movements, to further clarify genotype-phenotype correlations and provide crucial prognostic information and potential therapeutic implications.","variants":[{"Name":"NM_015378.4(VPS13D):c.5723T>C (p.Ile1908Thr)","Chromosome":"1","Start":"12288311","Stop":"12288311","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3222257,"rule_based_match":true,"evidence_text":"c.5723 T > C; p.Ile1908Thr","llm_judgment":"PRESENT","evidence":"c.5723 T > C; p.Ile1908Thr","abstract_start":1017,"abstract_end":1043}]}
{"pmid":"32193832","title":"Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease.","abstract":"BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder that affects the degradation of branched-chain amino acids and is associated with acute and chronic brain dysfunction. This study presents 11 new patients with MSUD and describes the clinical characteristics and gene mutations reported in Chinese individuals.\nMETHODS: During 2011-2018, 11 pedaitric patients with MSUD from 11 Chinese families were analyzed based on clinical characteristics and mass spectrometry, with confirmation via gene sequencing. Novel mutations affecting protein function were predicted with Mutation-Taster, PolyPhen-2, CADD and SIFT software. 3D models of the mutated proteins were generated by using the SWISS-MODEL online server, and the models were visualized in PyMOL. The characteristics and gene mutations in patients with MSUD were analyzed retrospectively.\nRESULTS: Seventeen mutations in the BCKDHA, BCKDHB and DBT genes were found, 8 of which are novel: c.55C>/T, c.349C>T, c.565C>T, c.808G>A, c.859C>G, and c.1270dupC in BCKDHA; c.275-2A>G in BCKDHB; and c.1291C>T in DBT. Eight patients died. Two patients had severe mental retardation and were physically handicapped. One patient with the intermediate type had relatively good prognosis, with mild psychomotor retardation and adiposity. Four mothers underwent amniocentesis for prenatal diagnosis during their second pregnancy; two fetuses were wild type, and two were carriers of one heterozygous mutation.\nCONCLUSIONS: Eight novel mutations were associated with MSUD in Chinese patients. Prenatal diagnosis was successfully performed by genetic analysis. Mutations in the BCKDHB gene were found in the majority of Chinese patients with MSUD.","variants":[{"Name":"NM_000709.4(BCKDHA):c.859C>G (p.Arg287Gly)","Chromosome":"19","Start":"41422634","Stop":"41422634","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1325030,"rule_based_match":true,"evidence_text":"c.859C>G","llm_judgment":"PRESENT","evidence":"c.859C>G","abstract_start":1021,"abstract_end":1029},{"Name":"NM_001918.5(DBT):c.1291C>T (p.Arg431Ter)","Chromosome":"1","Start":"100196413","Stop":"100196413","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":99893,"rule_based_match":true,"evidence_text":"c.1291C>T in DBT","llm_judgment":"PRESENT","evidence":"c.1291C>T in DBT","abstract_start":1083,"abstract_end":1099},{"Name":"NM_000709.4(BCKDHA):c.55C>T (p.Gln19Ter)","Chromosome":"19","Start":"41397882","Stop":"41397882","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3132854,"rule_based_match":false,"evidence_text":"c.55C>T","llm_judgment":"PRESENT","evidence":"c.55C>T","abstract_start":null,"abstract_end":null},{"Name":"NM_000709.4(BCKDHA):c.565C>T (p.Arg189Cys)","Chromosome":"19","Start":"41419215","Stop":"41419215","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":266487,"rule_based_match":true,"evidence_text":"c.565C>T","llm_judgment":"PRESENT","evidence":"c.565C>T","abstract_start":1001,"abstract_end":1009},{"Name":"NM_000709.4(BCKDHA):c.349C>T (p.Arg117Cys)","Chromosome":"19","Start":"41410983","Stop":"41410983","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":468824,"rule_based_match":true,"evidence_text":"c.349C>T","llm_judgment":"PRESENT","evidence":"c.349C>T","abstract_start":991,"abstract_end":999},{"Name":"NM_000709.4(BCKDHA):c.808G>A (p.Ala270Thr)","Chromosome":"19","Start":"41422325","Stop":"41422325","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1388986,"rule_based_match":true,"evidence_text":"c.808G>A","llm_judgment":"PRESENT","evidence":"c.808G>A","abstract_start":1011,"abstract_end":1019}]}
{"pmid":"18826997","title":"Impact of screening kindreds for SDHD p.Cys11X as a common mutation associated with paraganglioma syndrome type 1.","abstract":"CONTEXT AND OBJECTIVE: Germline mutations of the genes SDHB, SDHC, and SDHD predispose to paraganglioma syndromes. Mutation-specific counseling, risk assessment, and management recommendations ideally should be performed. Here, we provide data for a single common mutation of the SDHD gene.\nMETHODS: The European-American Pheochromocytoma-Paraganglioma Registry served as the source for unrelated index cases affected by pheochromocytoma or paraganglioma. Patients with the SDHD c.33 C-->A (p.Cys11X) germline mutations were reinvestigated by whole-body magnetic resonance imaging and 24-h urinary catecholamine assay. First-degree relatives underwent genetic testing and those testing positive had same clinical investigations. Microsatellite analyses were used to test the hypothesis that all index cases were related and the mutation is a founding one.\nRESULTS: Sixteen index cases with the mutation SDHD p.Cys11X are registered. After testing their relatives, there were a total of 25 mutation carriers. We excluded seven subjects who inherited the mutation from the mother because of maternal imprinting. Thus, 18 mutation carriers were clinically affected. Among these 16 (89%) had head and neck paragangliomas, six (33%) thoracic tumors, six (33%) extraadrenal retroperitoneal, and five (28%) intraadrenal. Of note, 16 (89%) had multiple tumors at first diagnosis, and one (5%) had signs of malignancy during follow-up. Overall penetrance was 100% at age 54. Haplotype analyses revealed evidence for a founder effect.\nCONCLUSIONS: The SDHD p.Cys11X mutation is a founding mutation associated with a high penetrance for paraganglial tumors of the skull base, neck, thorax, and retroperitoneum in the first four decades of life and, rarely, with malignancy.","variants":[{"Name":"NM_003002.4(SDHD):c.33C>A (p.Cys11Ter)","Chromosome":"11","Start":"112086940","Stop":"112086940","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":21954,"rule_based_match":false,"evidence_text":"SDHD c.33 C-->A (p.Cys11X)","llm_judgment":"PRESENT","evidence":"SDHD c.33 C-->A (p.Cys11X)","abstract_start":474,"abstract_end":500}]}
{"pmid":"26043507","title":"A familial case of Coffin-Lowry syndrome caused by RPS6KA3 C.898C>T mutation associated with multiple abnormal brain imaging findings.","abstract":"Coffin-Lowry syndrome (CLS) is a rare X linked mental retardation syndrome characterised by severe psychomotor and growth retardation, distinct facial phenotype, and progressive skeletal malformations. It is caused by mutations in the RPS6KA3 gene located at Xp22.2. In this report we describe a family with CLS consists of three affected males, and two affected females, arising from c.898C>T mutation in RPS6KA3 gene. A 6 year-old, and a 3 year-old boy both had distinct clinical features of Coffin-Lowry syndrome; severe mental and motor retardation, microcephaly, prominent forehead, hypertelorism, large mouth, large ears, large soft hands, puffy tapered fingers, and pectus carinatum. In addition, they had multiple abnormal brain MRI findings. Other siblings presented with a mild and variable phenotype.","variants":[{"Name":"NM_004586.3(RPS6KA3):c.898C>T (p.Arg300Ter)","Chromosome":"X","Start":"20177032","Stop":"20177032","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":806184,"rule_based_match":true,"evidence_text":"c.898C>T","llm_judgment":"PRESENT","evidence":"c.898C>T","abstract_start":385,"abstract_end":393}]}
{"pmid":"35585918","title":"A New Pathogenic Missense Variant in a Consanguineous North-African Family Responsible for a Highly Variable Aceruloplasminemia Phenotype: A Case-Report.","abstract":"Aceruloplasminemia is a rare autosomal recessive inherited disorder. Mutations in the ceruloplasmin gene cause depressed ferroxidase activity leading to iron accumulation. The clinical phenotype is highly variable: anemia, retinopathy, diabetes mellitus, psychiatric disorders, and neurological symptoms including parkinsonian disorders and dementia are the main features of this disease. Characterized by high serum ferritin with low transferrin saturation, aceruloplasminemia uniquely combines brain, liver and systemic iron overload. We report here four new cases of aceruloplasminemia in a consanguineous North-African family. Genetic sequencing revealed a homozygous missense variant c.656T>A in exon 4 of the ceruloplasmin gene, which had been described previously as of \"unknown significance\" in the dbSNP database and never associated with ACP in the HGMD database. Ferroxidase activity was strongly depressed. Clinical manifestations varied among cases. The proband exhibited mild microcytic anemia, diabetes mellitus, psychosis and parkinsonism, whereas the other cases were asymptomatic or mildly anemic, although high serum ferritin and brain iron deposition were documented in all of them. Therapeutic management was complex. The proband started deferoxamine treatment when already symptomatic and he rapidly declined. In the asymptomatic cases, the treatment was associated with poor tolerance and was discontinued due to anemia requiring red blood cell transfusion. Our series illustrates the need for new therapeutic approaches to aceruloplasminemia.","variants":[{"Name":"NM_000096.4(CP):c.656T>A (p.Val219Glu)","Chromosome":"3","Start":"149209336","Stop":"149209336","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":134292,"rule_based_match":true,"evidence_text":"c.656T>A","llm_judgment":"PRESENT","evidence":"c.656T>A","abstract_start":689,"abstract_end":697}]}
{"pmid":"31327192","title":"Gene diagnosis and treatment of hereditary hemorrhagic telangiectasia with epistaxis as its main symptom","abstract":"<b>Objective:</b>The aim of this study is to investigate the gene diagnosis and the treatment of hereditary hemorrhagic telangiectasia (HHT) with epistaxis as the main symptom, and to analyze the mutation of ACVRL1 gene in the family. <b>Method:</b>Detailed pedigree investigation was carried out on the proband.Sixtynine genes related to coagulation disorder were sequenced and analyzed by high throughput sequencing for the father and son of the proband. <b>Result:</b>Four generations of the family consisted of 30 probands, including 11 patients. A pathogenic mutation ACVRL1_ex9 c.1313T > C (p.M438T) was detected in both patient and his father. <b>Conclusion:</b>Recurrent epistaxis is the main manifestation of hereditary hemorrhagic telangiectasia in this family. The mutation of ACVRL1 gene is the pathogenic gene of this family, which can be treated by surgery and medicine.","variants":[{"Name":"NM_000020.3(ACVRL1):c.1313T>C (p.Met438Thr)","Chromosome":"12","Start":"51919051","Stop":"51919051","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":527504,"rule_based_match":true,"evidence_text":"ACVRL1_ex9 c.1313T > C (p.M438T)","llm_judgment":"PRESENT","evidence":"ACVRL1_ex9 c.1313T > C (p.M438T)","abstract_start":574,"abstract_end":606}]}
{"pmid":"37144748","title":"A homozygous Gly470Ala variant in PEX6 causes severe Zellweger spectrum disorder.","abstract":"Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.1409G > C[p.Gly470Ala]). All were of Mixtec ancestry and identified by the California Newborn Screening (NBS) Program to have elevated C26:0-lysophosphatidylcholine but no reportable variants in ABCD1. The clinical and biochemical features of this cohort are described within. Gly470Ala may represent a founder variant in the Mixtec population of Central California. ZSD should be considered in patients who present at birth with severe hypotonia and enlarged fontanelles, especially in the setting of an abnormal NBS, Mixtec ancestry, or family history of infant death. There is a need to further characterize the natural history of ZSD, the Gly470Ala variant, and expand upon possible genotype-phenotype correlations.","variants":[{"Name":"NM_000287.4(PEX6):c.1409G>C (p.Gly470Ala)","Chromosome":"6","Start":"42968944","Stop":"42968944","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":560860,"rule_based_match":true,"evidence_text":"NM_000287.4:c.1409G > C[p.Gly470Ala]","llm_judgment":"PRESENT","evidence":"NM_000287.4:c.1409G > C[p.Gly470Ala]","abstract_start":343,"abstract_end":379}]}
{"pmid":"27678261","title":"Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor.","abstract":"BACKGROUND: Danon disease is an X-linked disorder that leads to fatal cardiomyopathy caused by a deficiency in lysosome-associated membrane protein-2 (LAMP2). In female patients, a later onset and less severe clinical phenotype have been attributed to the random inactivation of the X chromosome carrying the mutant diseased allele. We generated a patient-specific induced pluripotent stem cell (iPSCs)-based model of Danon disease to evaluate the therapeutic potential of Xi-chromosome reactivation using a DNA methylation inhibitor.\nMETHODS: Using whole-exome sequencing, we identified a nonsense mutation (c.520C>T, exon 4) of the LAMP2 gene in a family with Danon disease. We generated iPSC lines from somatic cells derived from the affected mother and her 2 sons, and we then differentiated them into cardiomyocytes (iPSC-CMs) for modeling the histological and functional signatures, including autophagy failure of Danon disease.\nRESULTS: Our iPSC-CM platform provides evidence that random inactivation of the wild-type and mutant LAMP2 alleles on the X chromosome is responsible for the unusual phenotype in female patients with Danon disease. In vitro, iPSC-CMs from these patients reproduced the histological features and autophagy failure of Danon disease. Administration of the DNA demethylating agent 5-aza-2'-deoxycytidine reactivated the silent LAMP2 allele in iPSCs and iPSC-CMs in female patients with Danon disease and ameliorated their autophagy failure, supporting the application of a patient-specific iPSC platform for disease modeling and drug screening.\nCONCLUSIONS: Our iPSC-CM platform provides novel mechanistic and therapeutic insights into the contribution of random X chromosome inactivation to disease phenotype in X-linked Danon disease.","variants":[{"Name":"NM_002294.3(LAMP2):c.520C>T (p.Gln174Ter)","Chromosome":"X","Start":"120449006","Stop":"120449006","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25020,"rule_based_match":true,"evidence_text":"c.520C>T","llm_judgment":"PRESENT","evidence":"c.520C>T","abstract_start":609,"abstract_end":617}]}
{"pmid":"12786840","title":"Cowden's disease: clinical and molecular genetic findings in a patient with a novel PTEN germline mutation.","abstract":"We report a 54-year-old woman with Cowden's disease (CD) who was found to carry a novel germline mutation in the PTEN gene. The mutation (c.334C-->G) introduced a splice donor site within exon 5 that caused the expression of an aberrant transcript lacking 159 nucleotides corresponding to codons 112-164. Clinically, the patient showed multiple benign hamartomatous lesions of the skin, papillomatosis of the lips and oral mucosa, polyposis coli and bilateral fibrocystic disease of the breast. In addition, she developed different types of malignant neoplasms, including bilateral carcinomas of the breast and malignant melanomas of the skin. Molecular genetic analysis of a benign skin hamartoma and an invasive ductal breast carcinoma revealed loss of heterozygosity (LOH) at microsatellite markers on chromosome 10 in the carcinoma but not in the hamartoma. The breast carcinoma additionally carried a somatic TP53 point mutation (c.466C-->G; R156G) that was associated with LOH on 17p and nuclear p53 protein accumulation. Taken together, our findings indicate that benign hamartomas in CD may develop without loss of the second (wild-type) PTEN allele, whereas the pathogenesis of malignant tumours, such as breast carcinomas, appears to require the complete inactivation of Pten as well as further alterations such as the loss of p53-dependent growth control.","variants":[{"Name":"NM_000314.8(PTEN):c.334C>G (p.Leu112Val)","Chromosome":"10","Start":"87933093","Stop":"87933093","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1408329,"rule_based_match":false,"evidence_text":"c.334C-->G","llm_judgment":"PRESENT","evidence":"c.334C-->G","abstract_start":138,"abstract_end":148}]}
{"pmid":"38455531","title":"A novel","abstract":"Objectives: Methylmalonic acidemia (MMA) is a rare inborn genetic disorder that is characterized by increased levels of methylmalonic acid in blood plasma and urine. Isolated methylmalonic acidemia is one of the most common types of MMA and is caused by mutations in the gene encoding methyl-malonyl coenzyme A mutase (<i>MMUT</i>). In this study, we investigated the possible mechanisms underlying the symptoms of isolated MMA in a patient by molecular analysis.\nMethods: PCR amplification and Sanger sequencing analysis was performed to identify variants in the <i>MMUT</i> gene in the proband and his family. Furthermore, minigene constructs were generated to validate the splicing defects in the <i>MMUT</i> gene variant identified in the proband.\nResults: The 3-year-old patient was admitted to the hospital with symptoms of MMA, including fever, convulsions, and vomiting. He showed metabolic acidosis, high levels of methylmalonic acid in blood and urine, and normal blood homocysteine levels. Genetic analysis demonstrated that the patient was a compound heterozygous carrier of two variants in the <i>MMUT</i> gene: a missense c.278G > A variant that has already been reported in a patient with the severe mut⁰ phenotype; and a novel splice site variant c.2125-2A > G. RT-PCR analysis showed that, while the novel variant clearly alters splicing, a minor amount of a full-length transcript is generated, suggesting that a wild-type protein may be produced although at a lower quantitative level. The patient's condition improved after treatment with vitamin B12. Serious complications were not reported during follow-up at age 5.\nConclusions: We identified a novel splice site variant that partially disrupts normal splicing of the <i>MMUT</i> pre-mRNA. Production of a reduced amount of full-length transcript is responsible for the mild clinical phenotype observed in this patient. Functional studies have proven useful in exploring the genotype-phenotype association and in providing guidance for the genetic diagnosis of MMA.","variants":[{"Name":"NM_000255.4(MMUT):c.278G>A (p.Arg93His)","Chromosome":"6","Start":"49459189","Stop":"49459189","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16919,"rule_based_match":true,"evidence_text":"c.278G > A","llm_judgment":"PRESENT","evidence":"c.278G > A","abstract_start":1136,"abstract_end":1146}]}
{"pmid":"23621909","title":"Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism.","abstract":"Neurofibromatosis type 1 (NF1) is caused by loss of function mutations of the NF1 gene, which are de novo in 50% of cases. Although this gene shows one of the highest mutation rates in the human genome, germline mosaicism is very rare in this condition. We describe the molecular analysis of a family in which neurofibromatosis type 1 occurred in two out of four siblings born to unaffected parents. Molecular analysis of the NF1 gene identified in both patients the same splicing mutation c.1392+1G>A, which was absent in parental lymphocytes. Microsatellite analysis showed that the two affected siblings shared the same maternal allele, however a specific PCR-RFLP assay excluded the presence of the NF1 splicing mutation in multiple maternal tissues. Our molecular and clinical findings are consistent with a germline mosaicism for the NF1 splicing mutation. This is the first case of maternal germline mosaicism for a NF1 mutation characterized so far at the molecular level. Our data confirm that germline mosaicism is rare in neurofibromatosis 1, but it has important implications for genetic counseling.","variants":[{"Name":"NM_001042492.3(NF1):c.1392+1G>A","Chromosome":"17","Start":"31206372","Stop":"31206372","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":91294,"rule_based_match":true,"evidence_text":"c.1392+1G>A","llm_judgment":"PRESENT","evidence":"c.1392+1G>A","abstract_start":490,"abstract_end":501}]}
{"pmid":"23373429","title":"Expansion of the clinical ocular spectrum of Wolfram Syndrome in a family carrying a novel WFS1 gene deletion.","abstract":"PURPOSE: To present the results of the clinical and molecular analyses of a familial case of Wolfram Syndrome (WFS) associated with a novel ocular anomaly.\nMETHODS: Full ophthalmologic examination was performed in two WFS siblings. Visante OCT imaging was used for assessing anterior segment anomalies. Genetic analysis included PCR amplification and exon-by-exon nucleotide sequencing of the WFS1 gene.\nRESULTS: Ocular anomalies in both affected siblings included congenital cataract, glaucoma, and optic atrophy. Interestingly, microspherophakia, a feature that has not been previously associated with WFS, was observed in both siblings. Genetic analysis disclosed a novel c.1525_1539 homozygous deletion in exon 8 of WFS1 in DNA from both affected patients.\nCONCLUSIONS: The recognition of microspherophakia in two siblings carrying a novel WFS1 mutation expands the clinical and molecular spectrum of Wolfram syndrome.","variants":[{"Name":"NM_006005.3(WFS1):c.1525_1539del (p.Val509_Tyr513del)","Chromosome":"4","Start":"6301310","Stop":"6301324","ReferenceAlleleVCF":"GCCTGCTCTATGTCTA","AlternateAlleleVCF":"G","allel_id":1451368,"rule_based_match":false,"evidence_text":"c.1525_1539 homozygous deletion","llm_judgment":"PRESENT","evidence":"c.1525_1539 homozygous deletion","abstract_start":675,"abstract_end":706}]}
{"pmid":"30687222","title":"Chorea-Acanthocytosis Presenting as Autosomal Recessive Epilepsy in a Family With a Novel","abstract":"Chorea-acanthocytosis (ChAc) is a rare, adult-onset disease usually characterized by, hence the name, a movement disorder and acanthocytosis in the blood. It is caused by mutations of the <i>VPS13A</i> gene with an autosomal recessive transmission. We report a consanguineous Turkish family with a different and informative clinical and diagnostic course. Three siblings developed seizures and the index patient had been diagnosed with bilateral temporal lobe epilepsy. A key finding, however, was the basal ganglia involvement in neuroimaging although no movement disorder was present. [<sup>18</sup>F]FDG-PET showed a prominent decline in striatal glucose metabolism at 31 years of age and [<sup>123</sup>I]FP-CIT-SPECT revealed a moderate loss of striatal dopamine transporter availability. The family was referred for genetic testing and exome sequencing detected a homozygous novel truncating mutation c.4326 T>A (p.Tyr1442<sup>*</sup>) in <i>VPS13A</i> in all affected siblings. With this case, we present autosomal recessive epilepsy as the predominant phenotype of ChAc with a new homozygous <i>VPS13A</i> mutation and provide pathological structural and molecular neuroimaging findings.","variants":[{"Name":"NM_033305.3(VPS13A):c.4326T>A (p.Tyr1442Ter)","Chromosome":"9","Start":"77314578","Stop":"77314578","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1903485,"rule_based_match":true,"evidence_text":"c.4326 T>A (p.Tyr1442<sup>*</sup>)","llm_judgment":"PRESENT","evidence":"c.4326 T>A (p.Tyr1442<sup>*</sup>)","abstract_start":907,"abstract_end":941}]}
{"pmid":"22683711","title":"Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.","abstract":"Nevus sebaceous is a common congenital cutaneous malformation. Affected individuals may develop benign and malignant secondary tumors in the nevi during life. Schimmelpenning syndrome is characterized by the association of nevus sebaceous with extracutaneous abnormalities. We report that of 65 sebaceous nevi studied, 62 (95%) had mutations in the HRAS gene and 3 (5%) had mutations in the KRAS gene. The HRAS c.37G>C mutation, which results in a p.Gly13Arg substitution, was present in 91% of lesions. Nonlesional tissues from 18 individuals had a wild-type sequence, confirming genetic mosaicism. The HRAS c.37G>C mutation was also found in 8 of 8 associated secondary tumors. Mosaicism for HRAS c.37G>C and KRAS c.35G>A mutations was found in two individuals with Schimmelpenning syndrome. Functional analysis of HRAS c.37G>C mutant cells showed constitutive activation of the MAPK and PI3K-Akt signaling pathways. Our results indicate that nevus sebaceous and Schimmelpenning syndrome are caused by postzygotic HRAS and KRAS mutations. These mutations may predispose individuals to the development of secondary tumors in nevus sebaceous.","variants":[{"Name":"NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)","Chromosome":"12","Start":"25245350","Stop":"25245350","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27621,"rule_based_match":true,"evidence_text":"c.35G>A","llm_judgment":"PRESENT","evidence":"c.35G>A","abstract_start":716,"abstract_end":723},{"Name":"NM_005343.4(HRAS):c.37G>C (p.Gly13Arg)","Chromosome":"11","Start":"534286","Stop":"534286","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":44227,"rule_based_match":true,"evidence_text":"HRAS c.37G>C","llm_judgment":"PRESENT","evidence":"HRAS c.37G>C","abstract_start":406,"abstract_end":418}]}
{"pmid":"27857962","title":"Functional analysis of","abstract":"Malignant hyperthermia manifests as a rapid and sustained rise in temperature in response to pharmacological triggering agents, e.g. inhalational anesthetics and the muscle relaxant suxamethonium. Other clinical signs include an increase in end-tidal CO<sub>2</sub>, increased O<sub>2</sub> consumption, as well as tachycardia, and if untreated a malignant hyperthermia episode can result in death. The metabolic changes are caused by dysregulation of skeletal muscle Ca<sup>2+</sup> homeostasis, resulting from a defective ryanodine receptor Ca<sup>2+</sup> channel, which resides in the sarcoplasmic reticulum and controls the flux of Ca<sup>2+</sup> ions from intracellular stores to the cytoplasm. Most genetic variants associated with susceptibility to malignant hyperthermia occur in the <i>RYR1</i> gene encoding the ryanodine receptor type 1. While malignant hyperthermia susceptibility can be diagnosed by <i>in vitro</i> contracture testing of skeletal muscle biopsy tissue, it is advantageous to use DNA testing. Currently only 35 of over 400 potential variants in <i>RYR1</i> have been classed as functionally causative of malignant hyperthermia and thus can be used for DNA diagnostic tests. Here we describe functional analysis of 2 <i>RYR1</i> variants (c. 7042_7044delCAG, p.ΔGlu2348 and c.641C>T, p.Thr214Met) that occur in the same malignant hyperthermia susceptible family. The p.Glu2348 deletion, causes hypersensitivity to ryanodine receptor agonists using <i>in vitro</i> analysis of cloned human <i>RYR1</i> cDNA expressed in HEK293T cells, while the Thr214Met substitution, does not appear to significantly alter sensitivity to agonist in the same system. We suggest that the c. 7042_7044delCAG, p.ΔGlu2348 <i>RYR1</i> variant could be added to the list of diagnostic mutations for susceptibility to malignant hyperthermia.","variants":[{"Name":"NM_000540.3(RYR1):c.641C>T (p.Thr214Met)","Chromosome":"19","Start":"38446481","Stop":"38446481","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":177297,"rule_based_match":true,"evidence_text":"c.641C>T, p.Thr214Met","llm_judgment":"PRESENT","evidence":"c.641C>T, p.Thr214Met","abstract_start":1304,"abstract_end":1325},{"Name":"NM_000540.3(RYR1):c.7039GAG[1] (p.Glu2348del)","Chromosome":"19","Start":"38499645","Stop":"38499647","ReferenceAlleleVCF":"TGGA","AlternateAlleleVCF":"T","allel_id":136927,"rule_based_match":false,"evidence_text":"c. 7042_7044delCAG, p.ΔGlu2348","llm_judgment":"PRESENT","evidence":"c. 7042_7044delCAG, p.ΔGlu2348","abstract_start":1269,"abstract_end":1299}]}
{"pmid":"21035106","title":"MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes.","abstract":"Distinctive facial features consisting of hypertelorism, telecanthus, blepharophimosis, blepharoptosis, epicanthus inversus, periumbilical defects, and skeletal anomalies are seen in autosomal-recessive Carnevale, Malpuech, Michels, and oculo-skeletal-abdominal (OSA) syndromes. The gene or genes responsible for these syndromes were heretofore unknown. We report on three individuals from two consanguineous Turkish families with findings characteristic of these syndromes, including facial dysmorphism, periumbilical depression, mixed hearing loss, radioulnar synostosis, and coccygeal appendage. Homozygosity mapping yielded an autozygous region on chromosome 3q27 in both families. In one family, whole exome sequencing revealed a missense mutation, MASP1 c.2059G>A (p.G687R), that cosegregated with the phenotype. In the second family, Sanger sequencing of MASP1 revealed a nonsense mutation, MASP1 c.870G>A (p.W290X), that also cosegregated with the phenotype. Neither mutation was found in 192 Turkish controls or 1200 controls of various other ancestries. MASP1 encodes mannan-binding lectin serine protease 1. The two mutations occur in a MASP1 isoform that has been reported to process IGFBP-5, thereby playing a critical role in insulin growth factor availability during craniofacial and muscle development. These results implicate mutations of MASP1 as the cause of a human malformation syndrome and demonstrate the involvement of MASP1 in facial, umbilical, and ear development during the embryonic period.","variants":[{"Name":"NM_139125.4(MASP1):c.2059G>A (p.Gly687Arg)","Chromosome":"3","Start":"187235812","Stop":"187235812","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39032,"rule_based_match":true,"evidence_text":"MASP1 c.2059G>A (p.G687R)","llm_judgment":"PRESENT","evidence":"MASP1 c.2059G>A (p.G687R)","abstract_start":754,"abstract_end":779},{"Name":"NM_139125.4(MASP1):c.870G>A (p.Trp290Ter)","Chromosome":"3","Start":"187253190","Stop":"187253190","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39033,"rule_based_match":true,"evidence_text":"MASP1 c.870G>A (p.W290X)","llm_judgment":"PRESENT","evidence":"MASP1 c.870G>A (p.W290X)","abstract_start":898,"abstract_end":922}]}
{"pmid":"31651202","title":"An Ashkenazi Jewish founder mutation in","abstract":"<b>Background</b>: Mutations in <i>CACNA1F</i> have been mainly associated with X-linked incomplete congenital stationary night blindness (icCSNB). Variable phenotypic expression in females was reported in some families. We report here three non-related Ashkenazi Jewish families originating in Eastern Europe, that included males and a many affected females, initially diagnosed with variable retinal phenotypes.<b>Materials and Methods</b>: Whole exome sequencing (WES), Sanger sequencing and microsatellite haplotyping were used for genetic analysis. Complete ophthalmologic examination was performed including visual acuity, refraction, colour vision, slit-lamp, fundoscopy and electroretinography (ERG).<b>Results</b>: We identified four affected males, showing moderate visual impairment, and seven female carriers, six of them presenting mild to moderate visual impairment. Infantile nystagmus was found in all affected males and in 5/7 females. Nyctalopia and myopia were common in both males and females. Initial clinical differential diagnosis included cone-dystrophy, cone-rod dystrophy, cone-dystrophy with supernormal rod response or CSNB based on ERG results. WES and Sanger sequencing revealed a previously described missense mutation c.2225T>G; p.(F742C) in <i>CACNA1F</i> (NM_001256789.2) in all three families, encompassed by a shared haplotype<b>Conclusions</b>: Our data suggests that p.(F742C) in <i>CACNA1F</i> is an X-linked founder mutation in Ashkenazi Jews originating in Eastern Europe. This mutation causes a mild-to-moderate icCSNB phenotype, expressed in most female carriers. A targeted test for this variant in suspected patients may initiate diagnostic analysis. Our results highlight the relevance of WES in the clinic, allowing fast and accurate diagnosis for unclear and variable clinical phenotype and in pedigrees with multiple possible inheritance patterns.","variants":[{"Name":"NM_001256789.3(CACNA1F):c.2225T>G (p.Phe742Cys)","Chromosome":"X","Start":"49222585","Stop":"49222585","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":800659,"rule_based_match":true,"evidence_text":"c.2225T>G; p.(F742C)","llm_judgment":"PRESENT","evidence":"c.2225T>G; p.(F742C)","abstract_start":1250,"abstract_end":1270}]}
{"pmid":"30888394","title":"Combined Pituitary Hormone Deficiency Caused by a Synonymous HESX1 Gene Mutation.","abstract":"CONTEXT: Mutations in the HESX1 gene can give rise to complex phenotypes that involve variable pituitary hormone deficiencies and other developmental defects.\nCASE DESCRIPTION: A 14-year-old boy presented with short stature and delayed puberty and received a diagnosis of GH deficiency, central hypothyroidism, hypogonadotropic hypogonadism, and secondary adrenal insufficiency. He had anterior pituitary hypoplasia, ectopic posterior pituitary, and an interrupted pituitary stalk. Genetic studies uncovered a heterozygous variant in exon 2 of the HESX1 gene (c.219C>T; p.Ser73Ser). This single base change was predicted to be synonymous at the translational level but was shown to cause skipping of exon 2 in the RNA transcript.\nCONCLUSIONS: This study of a patient with combined pituitary hormone deficiency revealed an unusual synonymous mutation of the HESX1 gene leading to abnormal RNA processing and indicates the importance of investigating silent variants that at first glance appear to be benign.","variants":[{"Name":"NM_003865.3(HESX1):c.219C>T (p.Ser73=)","Chromosome":"3","Start":"57198891","Stop":"57198891","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2137846,"rule_based_match":true,"evidence_text":"c.219C>T (p.Ser73Ser)","llm_judgment":"PRESENT","evidence":"p.Ser73Ser","abstract_start":570,"abstract_end":580}]}
{"pmid":"28881388","title":"Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21.","abstract":"INTRODUCTION: A calpain-3 (CAPN3) gene heterozygous deletion (c.643_663del21) was recently linked to autosomal dominant (AD) limb-girdle muscular dystrophy. However, the possibility of digenic disease was raised. We describe 3 families with AD calpainopathy carrying this isolated mutation.\nMETHODS: Probands heterozygous for CAPN3 c.643_663del21 were identified by targeted next generation or whole exome sequencing. Clinical findings were collected for probands and families. Calpain-3 muscle Western blots were performed in 3 unrelated individuals.\nRESULTS: Probands reported variable weakness in their 40s or 50s, with myalgia, back pain, or hyperlordosis. Pelvic girdle muscles were affected with adductor and hamstring sparing. Creatine kinase was normal to 1,800 U/L, independent of weakness severity. Imaging demonstrated lumbar paraspinal muscle atrophy. Electromyographic findings and muscle biopsies were normal to mildly myopathic. Muscle calpain-3 expression was reduced.\nDISCUSSION: This study provides further evidence for AD calpainopathy associated with CAPN3 c.643_663del21. No pathogenic variants in other genes known to cause myopathy were detected. Muscle Nerve 57: 679-683, 2018.","variants":[{"Name":"NM_000070.2(CAPN3):c.643_663del(p.Ser215_Gly221del)","Chromosome":"15","Start":"42388935","Stop":"42388955","ReferenceAlleleVCF":"TGGTTCCTACGAAGCTCTGAAA","AlternateAlleleVCF":"T","allel_id":213824,"rule_based_match":false,"evidence_text":"c.643_663del21","llm_judgment":"PRESENT","evidence":"c.643_663del21","abstract_start":62,"abstract_end":76}]}
{"pmid":"28202214","title":"Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency.","abstract":"Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.8C>A identified by whole exome sequencing of proband and parents. SCEH deficiency was confirmed with very low SCEH activity in fibroblasts and nearly absent immunoreactivity of SCEH. The patient had a severe neonatal course with elevated blood and cerebrospinal fluid lactate and pyruvate concentrations, high plasma alanine and slightly low plasma cystine. 2-Methyl-2,3-dihydroxybutyric acid was markedly elevated as were metabolites of the three branched-chain α-ketoacids on urine organic acids analysis. These urine metabolites notably decreased when lactic acidosis decreased in blood. Lymphocyte pyruvate dehydrogenase complex (PDC) activity was deficient, but PDC and α-ketoglutarate dehydrogenase complex activities in cultured fibroblasts were normal. Oxidative phosphorylation analysis on intact digitonin-permeabilized fibroblasts was suggestive of slightly reduced PDC activity relative to control range in mitochondria. We reviewed 16 other cases with mutations in ECHS1 where PDC activity was also assayed in order to determine how common and generalized secondary PDC deficiency is associated with primary SCEH deficiency. For reasons that remain unexplained, we find that about half of cases with primary SCEH deficiency also exhibit secondary PDC deficiency. The patient died on day-of-life 39, prior to establishing his diagnosis, highlighting the importance of early and rapid neonatal diagnosis because of possible adverse effects of certain therapeutic interventions, such as administration of ketogenic diet, in this disorder. There is a need for better understanding of the pathogenic mechanisms and phenotypic variability in this relatively recently discovered disorder.","variants":[{"Name":"NM_004092.4(ECHS1):c.8C>A (p.Ala3Asp)","Chromosome":"10","Start":"133373326","Stop":"133373326","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1877945,"rule_based_match":true,"evidence_text":"c.8C>A","llm_judgment":"PRESENT","evidence":"c.8C>A","abstract_start":242,"abstract_end":248},{"Name":"NM_004092.4(ECHS1):c.836T>C (p.Phe279Ser)","Chromosome":"10","Start":"133362905","Stop":"133362905","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":444573,"rule_based_match":true,"evidence_text":"c.836T>C","llm_judgment":"PRESENT","evidence":"c.836T>C","abstract_start":221,"abstract_end":229}]}
{"pmid":"32242460","title":"","abstract":"<i>VRK1</i> encodes a serine/protein kinase possibly involved in pathways related to amyotrophic lateral sclerosis (ALS) pathogenesis. Pathogenic variants in <i>VRK1</i> have been related to different phenotypes. We describe the clinical phenotype of two unrelated Portuguese patients with different <i>VRK1</i> variants. Both patients presented a bilateral distal weakness in lower limbs beginning in childhood slowly progressing to upper limbs, associated with pyramidal signs, without bulbar, respiratory or cognitive involvement, according to probable ALS. Imaging and nerve conduction studies were unremarkable in both patients. Genetic testing in patient 1 identified two <i>VRK1</i> variants in heterozygosity: c.265C > T, p.(Arg89*) and c.769G > A, p.(Gly257Ser), classified as pathogenic and variant of uncertain significance, respectively. In patient 2, two probably pathogenic variants in <i>VRK1</i> were identified in heterozygosity: c.710-14T > C in intron 8 and c.721C > T, p.(Arg241Cys) in exon 9. We report two unrelated patients with different variants in <i>VRK1</i> displaying a similar childhood-onset motor neuron disease/ALS, further expanding the phenotypic spectrum associated to <i>VRK1</i> variants.","variants":[{"Name":"NM_003384.3(VRK1):c.769G>A (p.Gly257Ser)","Chromosome":"14","Start":"96856189","Stop":"96856189","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":413387,"rule_based_match":true,"evidence_text":"c.769G > A, p.(Gly257Ser)","llm_judgment":"PRESENT","evidence":"c.769G > A, p.(Gly257Ser)","abstract_start":745,"abstract_end":770},{"Name":"NM_003384.3(VRK1):c.721C>T (p.Arg241Cys)","Chromosome":"14","Start":"96856141","Stop":"96856141","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":957363,"rule_based_match":true,"evidence_text":"c.721C > T, p.(Arg241Cys)","llm_judgment":"PRESENT","evidence":"c.721C > T, p.(Arg241Cys)","abstract_start":977,"abstract_end":1002}]}
{"pmid":"27087618","title":"A Novel Missense Mutation in the CLPP Gene Causing Perrault Syndrome Type 3 in a Turkish Family.","abstract":"Perrault syndrome (PRLTS) is a heterogeneous group of clinical and genetic disorders characterized by sensory neuronal hearing loss in both sexes and premature ovarian failure or infertility in females. Neurological and hearing loss symptoms appear early in life, but female infertility cannot be detected before puberty. Spastic limbs, muscle weakness, delayed puberty and irregular menstrual cycles have also been observed in PRLTS patients. Mutations in five genes, i.e. HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. Here, we report a milder phenotype of PRLTS in a Turkish family in which two affected patients had no neurological findings. However, both were characterized by sensory neuronal hearing loss and the female sibling had secondary amenorrhea and gonadal dysgenesis. Genome-wide homozygosity mapping using 300K single-nucleotide polymorphism microarray analysis together with iScan platform (Illumina, USA) followed by candidate gene Sanger sequencing with ABI 3500 Genetic Analyzer (Life Technologies, USA) were used for molecular diagnosis. We found a novel missense alteration c.624C>G; p.Ile208Met in exon 5 of the CLPP at chromosome 19p13.3. This study expands the mutation spectrum of CLPP pathogenicity in PRLTS type 3 phenotype.","variants":[{"Name":"NM_006012.4(CLPP):c.624C>G (p.Ile208Met)","Chromosome":"19","Start":"6366326","Stop":"6366326","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":536008,"rule_based_match":true,"evidence_text":"c.624C>G; p.Ile208Met","llm_judgment":"PRESENT","evidence":"c.624C>G; p.Ile208Met","abstract_start":1138,"abstract_end":1159}]}
{"pmid":"36188410","title":"Abnormal decrement on high-frequency repetitive nerve stimulation in congenital myasthenic syndrome with GFPT1 mutations and review of literature.","abstract":"Objectives: Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders characterized by neuromuscular junction defects. Mutations in GFPT1 have been shown to underlie CMS. An increasing number of patients with CMS due to mutations in GFPT1 have been reported. However, a comprehensive review of clinical and genetic analyses of GFPT-related CMS worldwide is lacking, especially, given that the common or hotspot mutations in GFPT1 have not been reported. Here, we described the clinical and genetic findings of three patients with GFPT1 mutations from southwestern China and reviewed the clinical and genetic features of patients with GFPT1-related CMS worldwide.\nMethods: Clinical, laboratory, electrophysiological, myopathological, and genetic analyses of three patients with GFPT1-related CMS from southwestern China were conducted, and a review of previously published or reported cases about congenital myasthenic syndrome with GFPT1 mutations in the PubMed database was made.\nResults: The clinical, laboratory, electrophysiological, and myopathological features by muscle biopsy of three patients with GFPT1-related CMS were consistent with those of previously reported patients with GFPT1 mutations. Additionally, an abnormal decrement in high-frequency RNS was found. Two different homozygous missense mutations (c.331C>T, p.R111C; c.44C>T, p.T15M) were detected by whole-exome sequencing (WES) or targeted neuromuscular disorder gene panels.\nConclusion: A distinct decremental response to high-frequency RNS was found in three patients with GFPT1-related CMS from southwestern China, which has never been reported thus far. In addition, the location and degree of tubular aggregates (TAs) seemed to be associated with the severity of clinical symptoms and serum creatine kinase levels, further expanding the phenotypic spectrum of GFPT1-related CMS. Lastly, some potential hotspot mutations in GFPT1 have been found in GFPT1-CMS worldwide.","variants":[{"Name":"NM_001244710.2(GFPT1):c.44C>T (p.Thr15Met)","Chromosome":"2","Start":"69374077","Stop":"69374077","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1055259,"rule_based_match":true,"evidence_text":"c.44C>T, p.T15M","llm_judgment":"PRESENT","evidence":"c.44C>T, p.T15M","abstract_start":1393,"abstract_end":1408}]}
{"pmid":"24461433","title":"Clinical and pathological heterogeneity of a congenital disorder of glycosylation manifesting as a myasthenic/myopathic syndrome.","abstract":"Congenital disorders of glycosylation are often associated with muscle weakness in apparent isolation or as part of a multi-systemic disorder. We report here the clinical and pathological features resulting from a homozygous mutation of ALG2 in an extended family. Phenotypic heterogeneity is observed among the small cohort of patients reported to date and is highlighted by our study. Linkage analysis, homozygozity mapping and whole exome sequencing followed clinical and pathological characterization of patients who presented with a congenital limb girdle pattern of weakness with no ocular or bulbar involvement. Nerve stimulation studies were consistent with a congenital myasthenic syndrome. Severity and progression of disease was variable. Muscle biopsies showed myopathic features, ragged red fibers and a sub-sarcolemmal accumulation of structurally normal mitochondria. Whole exome sequencing revealed an indel mutation c.214_224delGGGGACTGGCTdelinsAGTCCCCG, p.72_75delGDWLinsSPR in exon 1 of ALG2. Mutation of ALG2 manifested as a limb girdle pattern of muscle weakness with defects at both the neuromuscular junction and sarcomere. In addition the accumulation and distribution of mitochondria in the diseased muscle and the presence of ragged red fibers were supportive of a mitochondrial myopathy. ALG2 mutation results in a heterogeneous phenotype and care should be taken in categorization and treatment of these patients.","variants":[{"Name":"NM_033087.4(ALG2):c.214_224delinsAGTCCCCG (p.Gly72_Leu75delinsSerProArg)","Chromosome":"9","Start":"99221671","Stop":"99221681","ReferenceAlleleVCF":"AGCCAGTCCCC","AlternateAlleleVCF":"CGGGGACT","allel_id":181169,"rule_based_match":false,"evidence_text":"c.214_224delGGGGACTGGCTdelinsAGTCCCCG, p.72_75delGDWLinsSPR","llm_judgment":"PRESENT","evidence":"c.214_224delGGGGACTGGCTdelinsAGTCCCCG, p.72_75delGDWLinsSPR","abstract_start":933,"abstract_end":992}]}
{"pmid":"29737001","title":"Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome.","abstract":"Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which explains the clinical overlap between the two disorders. A narrow spectrum of amino acid substitutions in a restricted region of ZBTB20 encompassing the first and second zinc-finger motifs have been reported thus far. Here, we characterize clinically and functionally the first truncating mutation [(c.1024delC; p.(Gln342Serfs*42)] and a missense change affecting the third zinc-finger motif of the protein [(c.1931C > T; p.(Thr644Ile)]. Our data document that both mutations have dominant negative impact on wild-type ZBTB20, providing further evidence of the specific behavior of PS-causing mutations on ZBTB20 function.","variants":[{"Name":"NM_001348800.3(ZBTB20):c.1024del (p.Gln342fs)","Chromosome":"3","Start":"114351054","Stop":"114351054","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":2417619,"rule_based_match":true,"evidence_text":"c.1024delC; p.(Gln342Serfs*42)","llm_judgment":"PRESENT","evidence":"c.1024delC; p.(Gln342Serfs*42)","abstract_start":794,"abstract_end":824},{"Name":"NM_001348800.3(ZBTB20):c.1931C>T (p.Thr644Ile)","Chromosome":"3","Start":"114339300","Stop":"114339300","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2417620,"rule_based_match":true,"evidence_text":"c.1931C > T; p.(Thr644Ile)","llm_judgment":"PRESENT","evidence":"c.1931C > T; p.(Thr644Ile)","abstract_start":903,"abstract_end":929}]}
{"pmid":"28815871","title":"Clinical and molecular characterization of de novo loss of function variants in HNRNPU.","abstract":"DNA alterations in the 1q43-q44 region are associated with syndromic neurodevelopmental disorders characterized by global developmental delay, intellectual disability, dysmorphic features, microcephaly, seizures, and agenesis of the corpus callosum. HNRNPU is located within the 1q43-q44 region and mutations in the gene have been reported in patients with early infantile epileptic encephalopathy. Here, we report on the clinical presentation of four patients with de novo heterozygous HNRNPU loss-of-function mutations detected by clinical whole exome sequencing: c.651_660del (p.Gly218Alafs*118), c.1089G>A (p.Trp363*), c.1714C>T (p.Arg572*), and c.2270_2271del (p.Pro757Argfs*7). All patients shared similar clinical features as previously reported including seizures, global developmental delay, intellectual disability, variable neurologic regression, behavior issues, and dysmorphic facial features. Features including heart defects and kidney abnormalities were not reported in our patients. These findings expands the clinical spectrum of HNRNPU-related disorder and shows that HNRNPU contributes to a subset of the clinical phenotypes associated with the contiguous 1q43-q44 deletion syndrome.","variants":[{"Name":"NM_031844.3(HNRNPU):c.2270_2271del (p.Pro757fs)","Chromosome":"1","Start":"244855505","Stop":"244855506","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":263008,"rule_based_match":true,"evidence_text":"c.2270_2271del (p.Pro757Argfs*7)","llm_judgment":"PRESENT","evidence":"c.2270_2271del (p.Pro757Argfs*7)","abstract_start":650,"abstract_end":682},{"Name":"NM_031844.3(HNRNPU):c.1714C>T (p.Arg572Ter)","Chromosome":"1","Start":"244856757","Stop":"244856757","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":263009,"rule_based_match":true,"evidence_text":"c.1714C>T (p.Arg572*)","llm_judgment":"PRESENT","evidence":"c.1714C>T (p.Arg572*)","abstract_start":623,"abstract_end":644},{"Name":"NM_031844.3(HNRNPU):c.1089G>A (p.Trp363Ter)","Chromosome":"1","Start":"244859303","Stop":"244859303","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":263010,"rule_based_match":true,"evidence_text":"c.1089G>A (p.Trp363*)","llm_judgment":"PRESENT","evidence":"c.1089G>A (p.Trp363*)","abstract_start":600,"abstract_end":621},{"Name":"NM_031844.3(HNRNPU):c.651_660del (p.Gly218fs)","Chromosome":"1","Start":"244863648","Stop":"244863657","ReferenceAlleleVCF":"CTCCGCCGCCT","AlternateAlleleVCF":"C","allel_id":263011,"rule_based_match":true,"evidence_text":"c.651_660del (p.Gly218Alafs*118)","llm_judgment":"PRESENT","evidence":"c.651_660del (p.Gly218Alafs*118)","abstract_start":566,"abstract_end":598}]}
{"pmid":"35229282","title":"A homozygous frame-shift variant in PROSER1 is associated with developmental delay, hypotonia, genitourinary malformations, and distinctive facial features.","abstract":"We report four children from three related families who presented with a similar phenotype characterized by developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, and genitourinary malformations. They also shared common facial features including arched eyebrows, prominent eyes, broad nasal bridge, low-hanging columella, open mouth, thick lower lip, protruding tongue, large low-set ears, and parietal bossing. Exome sequencing for affected individuals revealed a homozygous frame-shift variant, c.1833del; p.(Thr612Glnfs*22), in PROSER1 which encodes the proline and serine rich protein 1 (PROSER1). PROSER1 has recently been found to be part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer-associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation, consistent with the wide phenotypic spectrum observed in the individuals presented here. The consistent phenotype, the loss-of-function predicted from the frame-shift, the co-segregation of the phenotype in our large pedigree, the vital role of PROSER1 in gene regulation, and the association of related genes with neurodevelopmental disorders argue for the loss of PROSER1 to be the cause for a novel recognizable syndrome.","variants":[{"Name":"NM_025138.5(PROSER1):c.1833del (p.Thr612fs)","Chromosome":"13","Start":"39013419","Stop":"39013419","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":3224476,"rule_based_match":true,"evidence_text":"c.1833del; p.(Thr612Glnfs*22)","llm_judgment":"PRESENT","evidence":"c.1833del; p.(Thr612Glnfs*22)","abstract_start":569,"abstract_end":598}]}
{"pmid":"38433265","title":"Heterozygous THBS2 pathogenic variant causes Ehlers-Danlos syndrome with prominent vascular features in humans and mice.","abstract":"Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2<sup>Cys896Arg</sup> KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.","variants":[{"Name":"NM_003247.5(THBS2):c.2686T>C (p.Cys896Arg)","Chromosome":"6","Start":"169225232","Stop":"169225232","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3222252,"rule_based_match":true,"evidence_text":"NM_003247.5:c.2686T>C, p.Cys896Arg","llm_judgment":"PRESENT","evidence":"NM_003247.5:c.2686T>C, p.Cys896Arg","abstract_start":905,"abstract_end":939}]}
{"pmid":"25709896","title":"Investigation of molybdenum cofactor deficiency due to MOCS2 deficiency in a newborn baby.","abstract":"BACKGROUND: Molybdenum cofactor deficiency (MOCD) is a severe autosomal recessive neonatal metabolic disease that causes seizures and death or severe brain damage. Symptoms, signs and cerebral images can resemble those attributed to intrapartum hypoxia. In humans, molybdenum cofactor (MOCO) has been found to participate in four metabolic reactions: aldehyde dehydrogenase (or oxidase), xanthine oxidoreductase (or oxidase) and sulfite oxidase, and some of the components of molybdenum cofactor synthesis participate in amidoxime reductase. A newborn girl developed refractory seizures, opisthotonus, exaggerated startle reflexes and vomiting on the second day of life. Treatment included intravenous fluid, glucose supplementation, empiric antibiotic therapy and anticonvulsant medication. Her encephalopathy progressed, and she was given palliative care and died aged 1 week. There were no dysmorphic features, including ectopia lentis but ultrasonography revealed a thin corpus callosum.\nOBJECTIVES: The aim of this study is to provide etiology, prognosis and genetic counseling.\nMETHODS: Biochemical analysis of urine, blood, Sanger sequencing of leukocyte DNA, and analysis of the effect of the mutation on protein expression.\nRESULTS: Uric acid level was low in blood, and S-sulfo-L-cysteine and xanthine were elevated in urine. Compound Z was detected in urine. Two MOCS2 gene mutations were identified: c.501 + 2delT, which disrupts a conserved splice site sequence, and c.419C > T (pS140F). Protein expression studies confirmed that the p.S140F substitution was pathogenic. The parents were shown to be heterozygous carriers.\nCONCLUSIONS: Mutation analysis confirmed that the MOCD in this family could not be treated with cPMP infusion, and enabled prenatal diagnosis and termination of a subsequent affected pregnancy.","variants":[{"Name":"NM_004531.5(MOCS2):c.419C>T (p.Ser140Phe)","Chromosome":"5","Start":"53100493","Stop":"53100493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1405579,"rule_based_match":true,"evidence_text":"c.419C > T (pS140F)","llm_judgment":"PRESENT","evidence":"c.419C > T (pS140F)","abstract_start":1480,"abstract_end":1499}]}
{"pmid":"30760879","title":"Novel mutations of AXIN2 identified in a Chinese Congenital Heart Disease Cohort.","abstract":"Congenital heart defects (CHDs), the most common congenital human birth anomalies, involves complex genetic factors. Wnt/β-catenin pathway is critical for cardiogenesis and proved to be associated with numerous congenital heart abnormities. AXIN2 has a unique role in Wnt/β-catenin pathway, as it is not only an important inhibitor but also a direct target of Wnt/β-catenin pathway. However, whether AXIN2 is associated with human CHDs has not been reported. In our present study, we found a differential expression of Axin2 mRNA during the development of mouse heart, indicating its importance in mouse cardiac development. Then using targeted next-generation sequencing, we found two novel case-specific rare mutations [c.28 C > T (p.L10F), c.395 A > G (p.K132R)] in the sequencing region of AXIN2. In vitro functional analysis suggested that L10F might be a loss-of-function mutation and K132R is a gain-of-function mutation. Both mutations disrupted Wnt/β-catenin pathway and failed to rescue CHD phenotype caused by Axin2 knockdown in zebrafish model. Collectively, our study indicates that rare mutations in AXIN2 might contribute to the risk of human CHDs and a balanced canonical Wnt pathway is critical for cardiac development process. To our knowledge, it is the first study of AXIN2 mutations associated with human CHDs, providing new insights into CHD etiology.","variants":[{"Name":"NM_004655.4(AXIN2):c.28C>T (p.Leu10Phe)","Chromosome":"17","Start":"65558593","Stop":"65558593","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1854338,"rule_based_match":true,"evidence_text":"c.28 C > T (p.L10F)","llm_judgment":"PRESENT","evidence":"c.28 C > T (p.L10F)","abstract_start":722,"abstract_end":741},{"Name":"NM_004655.4(AXIN2):c.395A>G (p.Lys132Arg)","Chromosome":"17","Start":"65558226","Stop":"65558226","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":928493,"rule_based_match":true,"evidence_text":"c.395 A > G (p.K132R)","llm_judgment":"PRESENT","evidence":"c.395 A > G (p.K132R)","abstract_start":743,"abstract_end":764}]}
{"pmid":"18450588","title":"Allelic copy number variation in FSCN2 detected using allele-specific genotyping and multiplex real-time PCRs.","abstract":"PURPOSE: Allelic copy number variation (CNV) may alter the functional effects of a heterozygous mutation. The underlying mechanisms and their roles in hereditary diseases, however, are largely unknown. In the present study an FSCN2 mutation was examined that has been reported, not only in patients with retinitis pigmentosa (RP), but also in the normal population.\nMETHODS: Experiments were performed to investigate the gene and allele copy numbers of FSCN2 in patients with RP who have the c.72delG mutation as well as healthy subjects with or without the mutation. A real-time PCR-based genotyping approach was established that used a real-time PCR assay to qualify the copy numbers of both the wild-type and mutant alleles of the FSCN2 gene.\nRESULTS: Three patients with RP and three normal subjects had an equal ratio of the alleles. Of interest, another patient had an asymmetric allele ratio (4:1) of the copy number of the wild-type allele, compared with that of the mutant allele. These findings were further verified using quantitative assays. An allele-specific methylation assay demonstrated a random methylation pattern in the FSCN2 gene.\nCONCLUSIONS: The copy numbers of the FSNC2 gene and of each allele in the mutant samples were quantified. The findings excluded the possibility that allelic CNV was associated with RP, suggesting that the c.72delG variant is not the primary cause of RP. It is not likely that the FSCN2 gene is imprinted differentially. The real-time PCR-based genotyping method developed in this study is useful for investigations of allelic asymmetries within genomic regions with CNVs.","variants":[{"Name":"NM_012418.4(FSCN2):c.72del (p.Thr25fs)","Chromosome":"17","Start":"81528603","Stop":"81528603","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":17984,"rule_based_match":true,"evidence_text":"c.72delG","llm_judgment":"PRESENT","evidence":"c.72delG","abstract_start":492,"abstract_end":500}]}
{"pmid":"20583299","title":"Functional analysis of the HGSNAT gene in patients with mucopolysaccharidosis IIIC (Sanfilippo C Syndrome).","abstract":"Mucopolysaccharidosis (MPS) IIIC is an autosomal recessive lysosomal storage disorder caused by a deficiency in heparan acetyl CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT). The characteristic feature is the deterioration of the central nervous system, but other symptoms may include coarse facies, developmental delay, macrocrania and motor retardation. HGSNAT is localised to the lysosomal membrane and catalyses a transmembrane acetylation in which the terminal glucosamine residue of heparan sulphate acquires an acetyl group, thus forming N-acetylglucosamine. 54 variants of the HGSNAT gene have been identified in MPS IIIC patients thus far, 22 of which are missense mutations. In this study, 20 of the latter were introduced into the cDNA of HGSNAT, and the resultant derivatives were exogenously expressed in cell culture. Transfection of 16 of these resulted in the synthesis of negligible HGSNAT protein and activity. The levels and function of the remaining 4 mutants, however, were similar to those of exogenously expressed wild-type HGSNAT. Interestingly, c.1209G>T (p.W403C), which is present in a variant classified in the former category, has only been sequenced in alleles also possessing c.1843G>A (p.A615T), which independently has a negligible effect on HGSNAT expression. This report suggests that these may function together to abolish HGSNAT activity.","variants":[{"Name":"NM_152419.3(HGSNAT):c.1843G>A (p.Ala615Thr)","Chromosome":"8","Start":"43199504","Stop":"43199504","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205377,"rule_based_match":true,"evidence_text":"c.1843G>A (p.A615T)","llm_judgment":"PRESENT","evidence":"c.1843G>A (p.A615T)","abstract_start":1214,"abstract_end":1233},{"Name":"NM_152419.3(HGSNAT):c.1209G>T (p.Trp403Cys)","Chromosome":"8","Start":"43191554","Stop":"43191554","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":205378,"rule_based_match":true,"evidence_text":"c.1209G>T (p.W403C)","llm_judgment":"PRESENT","evidence":"c.1209G>T (p.W403C)","abstract_start":1077,"abstract_end":1096}]}
{"pmid":"33473340","title":"Genetic characterization of the Albanian Gaucher disease patient population.","abstract":"Gaucher disease (GD) is a recessive metabolic disorder caused by a deficiency of the <i>GBA</i> gene-encoded enzyme β-glucocerebrosidase. We characterized a cohort of 36 Albanian GD patients, 31 with GD type 1 and 5 affected by GD types 2, 3, and an intermediate GD phenotype between type 2 and type 3. Of the 12 different <i>GBA</i> alleles that we detected, the most frequently observed was p.Asn409Ser, followed by p.[Asp448His;His294Gln]. The prevalence of the p.Leu483Pro allele was approximately 10-fold lower than reported in other populations. We identified a novel pathogenic missense variant (c.1129G>A; p.Ala377Thr). All five of our non-type 1 patients had genotypes consisting of the p.[Asp448His;His294Gln] allele in combination with another severe <i>GBA</i> allele. The median Lyso-Gb1 level of treated patients carrying the p.[Asp448His;His294Gln] and no p.Asn409Ser allele was significantly higher than that of treated individuals homozygous or compound heterozygous for the p.Asn409Ser allele. In conclusion, the most important distinguishing features of the Albanian GD patient population are the underrepresentation of the p.Leu483Pro allele and an unusually high number of p.[Asp448His;His294Gln] alleles originating from a common Balkan founder event. The presence of at least one p.Asn409Ser allele is associated with mild disease and low Lyso-Gb1 biomarker levels, while compound heterozygosity involving p.[Asp448His;His294Gln] and no p.Asn409Ser entails severe phenotypes and high Lyso-Gb1 levels.","variants":[{"Name":"NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)","Chromosome":"1","Start":"155235843","Stop":"155235843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":19329,"rule_based_match":false,"evidence_text":"p.Asn409Ser","llm_judgment":"PRESENT","evidence":"p.Asn409Ser","abstract_start":393,"abstract_end":404}]}
{"pmid":"37880421","title":"Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly.","abstract":"Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.","variants":[{"Name":"NM_032982.4(CASP2):c.876+1G>T","Chromosome":"7","Start":"143300052","Stop":"143300052","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2477493,"rule_based_match":true,"evidence_text":"c.876 + 1 G > T","llm_judgment":"PRESENT","evidence":"c.876 + 1 G > T","abstract_start":1032,"abstract_end":1047},{"Name":"NM_032982.4(CASP2):c.1156del (p.Tyr386fs)","Chromosome":"7","Start":"143304712","Stop":"143304712","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":2477445,"rule_based_match":true,"evidence_text":"NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25)","llm_judgment":"PRESENT","evidence":"NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25)","abstract_start":751,"abstract_end":794},{"Name":"NM_032982.4(CASP2):c.1174C>T (p.Gln392Ter)","Chromosome":"7","Start":"143304730","Stop":"143304730","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2477446,"rule_based_match":true,"evidence_text":"c.1174 C > T (p.Gln392Ter)","llm_judgment":"PRESENT","evidence":"c.1174 C > T (p.Gln392Ter)","abstract_start":800,"abstract_end":826},{"Name":"NM_032982.4(CASP2):c.130C>T (p.Arg44Ter)","Chromosome":"7","Start":"143291595","Stop":"143291595","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2477447,"rule_based_match":false,"evidence_text":"c.130 C > T","llm_judgment":"PRESENT","evidence":"c.[130 C > T","abstract_start":864,"abstract_end":876}]}
{"pmid":"28979772","title":"Late-onset Bartter syndrome type II.","abstract":"Mutations in the ROMK1 potassium channel gene (<i>KCNJ1</i>) cause antenatal/neonatal Bartter syndrome type II (aBS II), a renal disorder that begins <i>in utero</i>, accounting for the polyhydramnios and premature delivery that is typical in affected infants, who develop massive renal salt wasting, hypokalaemic metabolic alkalosis, secondary hyperreninaemic hyperaldosteronism, hypercalciuria and nephrocalcinosis. This BS type is believed to represent a disorder of the infancy, but not in adulthood. We herein describe a female patient with a remarkably late-onset and mild clinical manifestation of BS II with compound heterozygous <i>KCNJ1</i> missense mutations, consisting of a novel c.197T > A (p.I66N) and a previously reported c.875G > A (p.R292Q) <i>KCNJ1</i> mutation. We implemented and evaluated the performance of two different bioinformatics-based approaches of targeted massively parallel sequencing [next generation sequencing (NGS)] in defining the molecular diagnosis. Our results demonstrate that aBS II may be suspected in patients with a late-onset phenotype. Our experimental approach of NGS-based mutation screening combined with Sanger sequencing proved to be a reliable molecular approach for defining the clinical diagnosis in our patient, and results in important differential diagnostic and therapeutic implications for patients with BS. Our results could have a significant impact on the diagnosis and methodological approaches of genetic testing in other patients with clinical unclassified phenotypes of nephrocalcinosis and congenital renal electrolyte abnormalities.","variants":[{"Name":"NM_153766.3(KCNJ1):c.197T>A (p.Ile66Asn)","Chromosome":"11","Start":"128840047","Stop":"128840047","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2738328,"rule_based_match":true,"evidence_text":"c.197T > A (p.I66N)","llm_judgment":"PRESENT","evidence":"c.197T > A (p.I66N)","abstract_start":693,"abstract_end":712},{"Name":"NM_153766.3(KCNJ1):c.875G>A (p.Arg292Gln)","Chromosome":"11","Start":"128839369","Stop":"128839369","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1445558,"rule_based_match":true,"evidence_text":"c.875G > A (p.R292Q)","llm_judgment":"PRESENT","evidence":"c.875G > A (p.R292Q)","abstract_start":739,"abstract_end":759}]}
{"pmid":"24376681","title":"Transcriptional defect of an inherited NKX2-5 haplotype comprising a SNP, a nonsynonymous and a synonymous mutation, associated with human congenital heart disease.","abstract":"Germline mutations in cardiac-specific transcription factor genes have been associated with congenital heart disease (CHD) and the homeodomain transcription factor NKX2-5 is an important member of this group. Indeed, more than 40 heterozygous NKX2-5 germline mutations have been observed in individuals with CHD, and these are spread along the coding region, with many shown to impact protein function. In pursuit of understanding causes of CHD, we analyzed n = 49 cardiac biopsies from 28 patients and identified by direct sequencing two nonsynonymous NKX2-5 alterations affecting alanine 119, namely c.356C>A (p.A119E) and c.355G>T, (p.A119S), in patients with AVSD and HLHS, respectively. In functional assays, a significant reduction in transcriptional activities could be determined for the NKX2-5 variants. Importantly, in one family the mother, besides p.A119E, carried a synonymous mutant allele in the homeodomain (c.543G>A, p.Q181), and a synonymous dbSNP (c.63A>G, p.E21) in the transactivation domain of the protein, that were transmitted to the CHD daughter. The presence of these variants in-cis with the p.A119E mutation led to a further reduction in transcriptional activities. Such difference in activity may be in part related to reduced protein expression for the double variant c.356C>A and c.543G>A. We propose changes in mRNA stability and folding, due to a silent mutation and a dbSNP in the NKX2-5 coding region to contribute to the functional defect. Although the clinical significance of the NKX2-5 haplotype identified in the CHD patients remains to be ascertained, we provide evidence of an interaction of a dbSNP, with synonymous and nonsynonymous mutations to negatively impact NKX2-5 transcriptional activity.","variants":[{"Name":"NM_004387.4(NKX2-5):c.543G>A (p.Gln181=)","Chromosome":"5","Start":"173233001","Stop":"173233001","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45320,"rule_based_match":true,"evidence_text":"c.543G>A","llm_judgment":"PRESENT","evidence":"c.543G>A","abstract_start":924,"abstract_end":932},{"Name":"NM_004387.4(NKX2-5):c.356C>A (p.Ala119Glu)","Chromosome":"5","Start":"173233188","Stop":"173233188","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":359686,"rule_based_match":true,"evidence_text":"c.356C>A (p.A119E)","llm_judgment":"PRESENT","evidence":"c.356C>A (p.A119E)","abstract_start":602,"abstract_end":620}]}
{"pmid":"29524613","title":"Whole-exome sequencing identifies rare compound heterozygous mutations in the MYBPC3 gene associated with severe familial hypertrophic cardiomyopathy.","abstract":"Most patients with hypertrophic cardiomyopathy have single-gene autosomal dominant mutations in loci that encode for sarcomeric proteins. The aim of this study was to determine whether pathogenic mutations were present by whole-exome sequencing (WES) in two families with hypertrophic cardiomyopathy (HCM) that presented during adolescence. Blood samples and clinical data were collected from individuals in two families with HCM. DNA was extracted. Mutations were identified using whole-exome sequencing (WES), and the genotypes of family members were identified using Sanger sequencing. Compound heterozygous mutations in the MYBPC3 gene (c.659A > G, p.Tyr220Cys; c.772G > A, p.Glu258Lys,NM_000256, Family 1), (c.873delG, p. Ile292PhefsTer8; c.3G > A, p.Met1?, NM_000256, Family 2) were identified by WES. Patient 1 carried the maternally inherited c.659A > G mutation and the paternally inherited c.772G > A mutation. Patient 2 carried the maternally inherited frameshift mutation c.873delG and the paternally inherited mutation c.3G > A. Two families with HCM presenting during adolescence (age of onset is about 11 years old) demonstrated compound heterozygous mutations in the MYBPC3 gene. These findings suggested an association of MYBPC3 mutations with the early onset of symptoms and worsened prognoses. Our study highlights the importance of genetic screening of all family members in cases of HCM.","variants":[{"Name":"NM_000256.3(MYBPC3):c.3G>A (p.Met1Ile)","Chromosome":"11","Start":"47352645","Stop":"47352645","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1009729,"rule_based_match":true,"evidence_text":"c.3G > A","llm_judgment":"PRESENT","evidence":"c.3G > A","abstract_start":744,"abstract_end":752},{"Name":"NM_000256.3(MYBPC3):c.659A>G (p.Tyr220Cys)","Chromosome":"11","Start":"47348537","Stop":"47348537","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":360028,"rule_based_match":true,"evidence_text":"c.659A > G, p.Tyr220Cys","llm_judgment":"PRESENT","evidence":"c.659A > G, p.Tyr220Cys","abstract_start":641,"abstract_end":664}]}
{"pmid":"29558889","title":"NAA10 dysfunction with normal NatA-complex activity in a girl with non-syndromic ID and a de novo NAA10 p.(V111G) variant - a case report.","abstract":"BACKGROUND: The NAA10-NAA15 (NatA) protein complex is an N-terminal acetyltransferase responsible for acetylating ~ 40% of eukaryotic proteins. In recent years, NAA10 variants have been found in patients with an X-linked developmental disorder called Ogden syndrome in its most severe form and, in other familial or de novo cases, with variable degrees of syndromic intellectual disability (ID) affecting both sexes.\nCASE PRESENTATION: Here we report and functionally characterize a novel and de novo NAA10 (NM_003491.3) c.332 T > G p.(V111G) missense variant, that was detected by trio-based whole exome sequencing in an 11 year old girl with mild/moderate non-syndromic intellectual disability. She had delayed motor and language development, but normal behavior without autistic traits. Her blood leukocyte X-inactivation pattern was within normal range (80/20). Functional characterization of NAA10-V111G by cycloheximide chase experiments suggests that NAA10-V111G has a reduced stability compared to NAA10-WT, and in vitro acetylation assays revealed a reduced enzymatic activity of monomeric NAA10-V111G but not for NAA10-V111G in complex with NAA15 (NatA enzymatic activity).\nCONCLUSIONS: We show that NAA10-V111G has a reduced stability and monomeric catalytic activity, while NatA function remains unaltered. This is the first example of isolated NAA10 dysfunction in a case of ID, suggesting that the syndromic cases may also require a degree of compromised NatA function.","variants":[{"Name":"NM_003491.4(NAA10):c.332T>G (p.Val111Gly)","Chromosome":"X","Start":"153932325","Stop":"153932325","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":511146,"rule_based_match":true,"evidence_text":"c.332 T > G p.(V111G)","llm_judgment":"PRESENT","evidence":"c.332 T > G p.(V111G)","abstract_start":521,"abstract_end":542}]}
{"pmid":"25676728","title":"Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED).","abstract":"Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.","variants":[{"Name":"NM_000494.4(COL17A1):c.2816C>T (p.Thr939Ile)","Chromosome":"10","Start":"104039613","Stop":"104039613","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205532,"rule_based_match":true,"evidence_text":"c.2816C>T, p.T939I","llm_judgment":"PRESENT","evidence":"c.2816C>T, p.T939I","abstract_start":448,"abstract_end":466},{"Name":"NM_000494.4(COL17A1):c.3156C>T (p.Gly1052=)","Chromosome":"10","Start":"104037688","Stop":"104037688","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205533,"rule_based_match":true,"evidence_text":"c.3156C>T","llm_judgment":"PRESENT","evidence":"c.3156C>T","abstract_start":686,"abstract_end":695}]}
{"pmid":"20034086","title":"Various types of LRP5 mutations in four patients with osteoporosis-pseudoglioma syndrome: identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray.","abstract":"Osteoporosis-pseudoglioma syndrome (OPS; OMIM 259770) is an autosomal-recessive genetic disorder characterized by severe osteoporosis and visual disturbance from childhood. Biallelic mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have been frequently detected, while a subset of patients had only one or no detectable mutation. We report on the clinical and molecular findings of four unrelated Japanese patients with the syndrome. The four patients had typical skeletal and ocular phenotypes of OPS, namely severe juvenile osteoporosis and early-onset visual disturbance, with or without mental retardation. We undertook standard PCR-based sequencing for LRP5 and found four missense mutations (p.L145F, p.T244M, p.P382L, and p.T552M), one nonsense mutation (p.R1534X), and one splice site mutation (c.1584+1G>A) among four OPS patients. Although three patients had two heterozygous mutations, one had only one heterozygous splice site mutation. In this patient, RT-PCR from lymphocytic RNA demonstrated splice error resulting in 63-bp insertion between exons 7 and 8. Furthermore, the patient was found to have only mutated RT-PCR fragment, implying that a seemingly normal allele did not express LRP5 mRNA. We then conducted custom- designed oligonucleotide tiling microarray analyses targeted to a 600-kb genome region harboring LRP5 and discovered a 7.2-kb microdeletion encompassing exons 22 and 23 of LRP5. We found various types of LRP5 mutations, including an exon-level deletion that is undetectable by standard PCR-based mutation screening. Oligonucleotide tiling microarray seems to be a powerful tool in identifying cryptic structural mutations.","variants":[{"Name":"NM_002335.4(LRP5):c.1584+1G>A","Chromosome":"11","Start":"68390053","Stop":"68390053","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48774,"rule_based_match":true,"evidence_text":"c.1584+1G>A","llm_judgment":"PRESENT","evidence":"c.1584+1G>A","abstract_start":834,"abstract_end":845}]}
{"pmid":"24634885","title":"R102W mutation in the RS1 gene responsible for retinoschisis and recurrent glaucoma.","abstract":"AIM: To identify the mutations in RS1 gene associated with typical phenotype of X-linked juvenile retinoschisis (XLRS) and a rare condition of concomitant glaucoma.\nMETHODS: Complete ophthalmic examinations were performed in the proband. The coding regions of the RS1 gene that encode retinoschisin were amplified by polymerase chain reaction and directly sequenced.\nRESULTS: The proband showed a typical phenotype of XLRS with large peripheral retinal schisis in both eyes, involving the macula and combined with foveal cystic change, reducing visual acuity. A typical phenotype of recurrent glaucoma with high intraocular pressure (IOP) and reduced visual field was also demonstrated with the patient. Mutation analysis of RS1 gene revealed R102W (c.304C>T) mutations in the affected male, and his mother was proved to be a carrier with the causative mutation and another synonymous polymorphism (c.576C>CT).\nCONCLUSION: We identified the genetic variations of a Chinese family with typical phenotype of XLRS and glaucoma. The severe XLRS phenotypes associated with R102W mutations reveal that the mutation determines a notable alteration in the function of the retinoschisin protein. Identification of the disease-causing mutation is beneficial for future clinical references.","variants":[{"Name":"NM_000330.4(RS1):c.304C>T (p.Arg102Trp)","Chromosome":"X","Start":"18647213","Stop":"18647213","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24926,"rule_based_match":true,"evidence_text":"c.304C>T","llm_judgment":"PRESENT","evidence":"c.304C>T","abstract_start":750,"abstract_end":758}]}
{"pmid":"28548312","title":"Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?","abstract":"Vitamin D requires a two-step activation by hydroxylation: The first step is catalyzed by hepatic 25-hydroxylase (CYP2R1, 11p15.2) and the second one is catalyzed by renal 1α-hydroxylase (CYP27B1, 12q13.1), which produces the active hormonal form of 1,25-(OH)<sub>2</sub> D. Mutations of CYP2R1 have been associated with vitamin D-dependent rickets type 1B (VDDR1B), a very rare condition that has only been reported to affect 4 families to date. We describe 7 patients from 2 unrelated families who presented with homozygous loss-of-function mutations of CYP2R1. Heterozygous mutations were present in their normal parents. We identified a new c.124_138delinsCGG (p.Gly42_Leu46delinsArg) variation and the previously published c.296T>C (p.Leu99Pro) mutation. Functional in vitro studies confirmed loss-of-function enzymatic activity in both cases. We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH)<sub>2</sub> D. Siblings exhibited the three stages of rickets based on biochemical and radiographic findings. Interestingly, adult patients were able to maintain normal mineral metabolism without vitamin D supplementation. One index case presented with a partial improvement with 1alfa-hydroxyvitamin D<sub>3</sub> or alfacalcidol (1α-OH-D<sub>3</sub> ) treatment, and we observed a dramatic increase in the 1,25-(OH)<sub>2</sub> D serum concentration, which indicated the role of accessory 25-hydroxylase enzymes. Lastly, in patients who received calcifediol (25-OH-D<sub>3</sub> ), we documented normal 24-hydroxylase activity (CYP24A1). For the first time, and according to the concept of personalized medicine, we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry). In conclusion, the current study further expands the CYP2R1 mutation spectrum. We note that VDDR1B could be easily mistaken for classical vitamin D deficiency. © 2017 American Society for Bone and Mineral Research.","variants":[{"Name":"NM_024514.5(CYP2R1):c.296T>C (p.Leu99Pro)","Chromosome":"11","Start":"14885847","Stop":"14885847","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":17173,"rule_based_match":true,"evidence_text":"c.296T>C (p.Leu99Pro)","llm_judgment":"PRESENT","evidence":"c.296T>C (p.Leu99Pro)","abstract_start":728,"abstract_end":749}]}
{"pmid":"34034222","title":"Generation of two induced pluripotent stem cell lines from a retinitis pigmentosa patient with compound heterozygous mutations in CRB1.","abstract":"Two human iPSC lines were generated from dermal fibroblasts derived from a patient with retinitis pigmentosa caused by CRB1 mutation using episomal plasmids containing OCT4, SOX2, LIN28, KLF4, L-MYC and mp53DD. These clonal iPSC lines carry compound heterozygous mutations in CRB1 (c.2555 T > C and c.3014A > T). Both lines expressed pluripotency markers, displayed a normal karyotype and demonstrated the ability to differentiate into the three primary germ layers, as well as retinal organoids.","variants":[{"Name":"NM_201253.3(CRB1):c.2555T>C (p.Ile852Thr)","Chromosome":"1","Start":"197427880","Stop":"197427880","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":105772,"rule_based_match":true,"evidence_text":"c.2555 T > C","llm_judgment":"PRESENT","evidence":"c.2555 T > C","abstract_start":282,"abstract_end":294}]}
{"pmid":"36856871","title":"TMEM151A variants associated with paroxysmal kinesigenic dyskinesia.","abstract":"TMEM151A, located at 11q13.2 and encoding transmembrane protein 151A, was recently reported as causative for autosomal dominant paroxysmal kinesigenic dyskinesia (PKD). Here, through comprehensive analysis of sporadic and familial cases, we expand the clinical and mutation spectrum of PKD. In doing so, we clarify the clinical and genetic features of Chinese PKD patients harboring TMEM151A variants and further explore the relationship between TMEM151A mutations and PKD. Whole exome sequencing was performed on 26 sporadic PKD patients and nine familial PKD pedigrees without PRRT2 variants. Quantitative real-time PCR was used to assess the gene expression of frameshift mutant TMEM151A in a PKD patient. TMEM151A variants reported to date were reviewed. Four TMEM151A variants were detected in four unrelated families with 12 individuals, including a frameshift mutation [c.606_607insA (p.Val203fs)], two missense mutations [c.166G > A (p.Gly56Arg) and c.791T > C (p.Val264Ala)], and a non-pathogenic variant [c.994G > A (p.Gly332Arg)]. The monoallelic frameshift mutation [c.606_607insA (p.Val203fs)] may cause TMEM151A mRNA decay, suggesting a potential pathogenic mechanism of haploinsufficiency. Patients with TMEM151A variants had short-duration attacks and presented with dystonia. Our study provides a detailed clinical description of PKD patients with TMEM151A mutations and reports a new disease-causing mutation, expanding the known phenotypes caused by TMEM151A mutations and providing further detail about the pathoetiology of PKD.","variants":[{"Name":"NM_153266.4(TMEM151A):c.606_607insA (p.Val203fs)","Chromosome":"11","Start":"66294852","Stop":"66294853","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":2750242,"rule_based_match":true,"evidence_text":"c.606_607insA (p.Val203fs)","llm_judgment":"PRESENT","evidence":"c.606_607insA (p.Val203fs)","abstract_start":877,"abstract_end":903},{"Name":"NM_153266.4(TMEM151A):c.791T>C (p.Val264Ala)","Chromosome":"11","Start":"66295037","Stop":"66295037","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2750243,"rule_based_match":true,"evidence_text":"c.791T > C (p.Val264Ala)","llm_judgment":"PRESENT","evidence":"c.791T > C (p.Val264Ala)","abstract_start":958,"abstract_end":982}]}
{"pmid":"31432506","title":"Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss.","abstract":"Auditory reception relies on the perception of mechanical stimuli by stereocilia and its conversion to electrochemical signal. Mechanosensory stereocilia are abundant in actin, which provides them with structural conformity necessary for perception of auditory stimuli. Out of three major classes of actin-bundling proteins, plastin 1 encoded by PLS1, is highly expressed in stereocilia and is necessary for their regular maintenance. A missense PLS1 variant associated with autosomal dominant hearing loss (HL) in a small family has recently been reported. Here, we present another PLS1 missense variant, c.805G > A (p.E269K), in a Turkish family with autosomal dominant non-syndromic HL confirming the causative role of PLS1 mutations in HL. We propose that HL due to the p.E269K variant is from the loss of a stable PLS1-ACTB interaction.","variants":[{"Name":"NM_001145319.2(PLS1):c.805G>A (p.Glu269Lys)","Chromosome":"3","Start":"142684312","Stop":"142684312","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":621042,"rule_based_match":true,"evidence_text":"c.805G > A (p.E269K)","llm_judgment":"PRESENT","evidence":"c.805G > A (p.E269K)","abstract_start":606,"abstract_end":626}]}
{"pmid":"34100337","title":"Elevated Hb A","abstract":"Hb A<sub>2</sub> levels are usually high in carriers of β-thalassemia (β-thal). These levels also provide a sensitive marker for the identification of hemoglobin (Hb) variants. In this study, we aimed to examine two patients from two Chinese families who showed elevated Hb A<sub>2</sub> levels but did not show any signs of β-thal. The <i>HBB</i> variants were analyzed using direct sequencing of <i>HBB</i> and <i>in silico</i> prediction analysis. Moreover, the family's genetic history was investigated. We examined two probands from different Chinese families with elevated Hb A<sub>2</sub> levels who were not afflicted with β-thal, although several nucleotide changes were found at codon 81 (CT<i>C</i>>CT<i>A</i>) (<i>HBB</i>: c.246C>A) in Family 1 and a compound heterozygosity for codon 40 (A<i>G</i>G>A<i>A</i>G) (<i>HBB</i>: c.122G>A) and IVS-II-478 (C>A) (<i>HBB</i>: c.316-373C>A) in Family 2. After investigating the genetic history of both families including the β-thal aspect, we found that these mutations were not responsible for the elevated Hb A<sub>2</sub> levels. It is rarely reported that high Hb A<sub>2</sub> level is not indicative of β-thal. In contrast, low or normal Hb A<sub>2</sub> level is always found with β-thal due to other molecular defects that mask their β-thal genotype. Our results highlight the importance of considering the genetic factors related and unrelated to β-thal to improve the accuracy of future genetic counseling.","variants":[{"Name":"NM_000518.5(HBB):c.246C>A (p.Leu82=)","Chromosome":"11","Start":"5226646","Stop":"5226646","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":433087,"rule_based_match":true,"evidence_text":"(HBB: c.246C>A)","llm_judgment":"PRESENT","evidence":"c.246C>A","abstract_start":735,"abstract_end":743}]}
{"pmid":"30763667","title":"Mutational analysis of CFTR in the Ecuadorian population using next-generation sequencing.","abstract":"The frequency distributions of cystic fibrosis variants are heterogeneous in Ecuador because of the genetic admixture of its population. The aim of this study was to identify disease-causing variants among Ecuadorian cystic fibrosis (CF) patients by next-generation sequencing (NGS) of the entire cystic fibrosis transmembrane conductance regulator (CFTR) gene. The results showed an approximation of the frequencies of pathogenic variants in the population under study and an optimal mutation panel for routine first-line CF molecular diagnosis. One hundred and forty-one patients with suspected CF from the 3 largest Ecuadorian cities (Guayaquil, Quito, and Cuenca) were studied. One hundred and seventy mutated alleles were detected in eighty-five individuals. Twenty-eight disease-causing variants were identified, with p.Phe508del and p.His609Arg being the most frequent (both 24.7%) followed by p.Gly85Glu (11.1%), p.Leu15Pro (9.4%), p.Asn1303Lys (4.1%), and p.Gly542* (2.3%). Together, these variants constituted 76.44% of the detected disease-causing variants. The following six novel potentially disease-associated variants were detected: 3 deletions (CFTR_dele10, CFTR_dele12, and c.2672delA), 1 nonsense variant (p.Cys491*), 1 missense variant (p.Trp496Arg), and 1 complex allele (p.[Gly253Arg;Gly451Val]). The remaining mutations occurred in isolation and were present in the databases.","variants":[{"Name":"NM_000492.4(CFTR):c.1826A>G (p.His609Arg)","Chromosome":"7","Start":"117591993","Stop":"117591993","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":68066,"rule_based_match":false,"evidence_text":"p.His609Arg","llm_judgment":"PRESENT","evidence":"p.His609Arg","abstract_start":840,"abstract_end":851}]}
{"pmid":"23000108","title":"Remarkably low fibroblast acid α-glucosidase activity in three adults with Pompe disease.","abstract":"INTRODUCTION: Most adults with Pompe disease are compound heterozygotes in which one acid α-glucosidase (GAA) allele harbors the c.-32-13T>G mutation, causing partial loss of GAA, and the other allele harbors a fully deleterious mutation. The fibroblast GAA activity in these patients is usually between 5% and 25% of the average in healthy individuals. In some adult patients, however, the fibroblast GAA activity is much lower and is in the range that is normally observed in classic-infantile Pompe disease. We investigated the genotype-phenotype correlation in three such adult patients and measured the GAA activity as well as the glycogen content in muscle and fibroblasts in order to better understand the clinical course.\nMETHODS: DNA was sequenced and GAA activity and glycogen content were measured in leukocytes, fibroblasts and muscle. Muscle biopsies were microscopically analyzed and the biosynthesis of GAA in fibroblasts was analyzed by immunoblotting. GAA activity and glycogen content in fibroblasts and muscle tissue in healthy controls, adult patients with Pompe disease and classic-infantile patients were compared with those of the three index patients.\nRESULTS: One patient had genotype c.525delT/c.671G>A (r.0/p.Arg224Gln). Two affected brothers had genotype c.569G>A/c.1447G>A (p.Arg190His/p.Gly483Arg). In all three cases the GAA activity and the glycogen content in fibroblasts were within the same range as in classic-infantile Pompe disease, but the activity and glycogen content in muscle were both within the adult range. In fibroblasts, the first step of GAA synthesis appeared unaffected but lysosomal forms of GAA were not detectable with immunoblotting.\nCONCLUSION: Some adult patients with mutations other than c.-32-13T>G can have very low GAA activity in fibroblasts but express higher activity in muscle and store less glycogen in muscle than patients with classic-infantile Pompe disease. This might explain why these patients have a slowly progressive course of Pompe disease.","variants":[{"Name":"NM_000152.5(GAA):c.569G>A (p.Arg190His)","Chromosome":"17","Start":"80105771","Stop":"80105771","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186992,"rule_based_match":true,"evidence_text":"c.569G>A (p.Arg190His)","llm_judgment":"PRESENT","evidence":"p.Arg190His","abstract_start":1303,"abstract_end":1314},{"Name":"NM_000152.5(GAA):c.1447G>A (p.Gly483Arg)","Chromosome":"17","Start":"80110736","Stop":"80110736","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":269394,"rule_based_match":true,"evidence_text":"c.1447G>A (p.Gly483Arg)","llm_judgment":"PRESENT","evidence":"p.Gly483Arg","abstract_start":1315,"abstract_end":1326},{"Name":"NM_000152.5(GAA):c.671G>A (p.Arg224Gln)","Chromosome":"17","Start":"80105873","Stop":"80105873","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":646875,"rule_based_match":true,"evidence_text":"c.671G>A (p.Arg224Gln)","llm_judgment":"PRESENT","evidence":"p.Arg224Gln","abstract_start":1234,"abstract_end":1245}]}
{"pmid":"33596003","title":"Collagen VI-Related Myopathy Caused by Compound Heterozygous Mutations of COL6A3 in a Consanguineous Kurdish Family.","abstract":"ABSTRACT: Collagen VI-related myopathies are caused by mutations of COL6A1, COL6A2, and COL6A3 and present with a wide phenotypic spectrum ranging from severe Ulrich congenital muscular dystrophy to mild Bethlem myopathy. Here, we report a consanguineous Kurdish family with 3 siblings affected by autosomal-recessive Bethlem myopathy caused by compound heterozygous mutations of COL6A3. We found the previously described missense mutation c.7447A > G/p.(Lys2483Glu) and a novel large deletion encompassing the exon 1-39 of the COL6A3 gene. Apart from the classical clinical symptoms, all patients had keratoconus, which expands the phenotype of the collagen VI-related myopathies.","variants":[{"Name":"NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)","Chromosome":"2","Start":"237344571","Stop":"237344571","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":194138,"rule_based_match":true,"evidence_text":"c.7447A > G/p.(Lys2483Glu)","llm_judgment":"PRESENT","evidence":"c.7447A > G/p.(Lys2483Glu)","abstract_start":440,"abstract_end":466}]}
{"pmid":"27374302","title":"Whole-exome sequencing identifies compound heterozygous mutations in ARSA of two siblings presented with atypical onset of metachromatic leukodystrophy from a Chinese pedigree.","abstract":"BACKGROUND: Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disorder caused mainly by variants in arylsulfatase A (ARSA) gene. MLD can be divided into three major clinical forms according to the age of onset: late infantile, juvenile, and adult. We report two siblings of late infantile MLD presenting with cerebellar ataxia as the only first clinical symptom.\nMETHODS: Because of the unspecific neurological manifestation, whole-exome sequencing (WES) was performed to find disease-causing mutations for molecular diagnosis. Then successive MRI and ARSA activity determination were performed to further confirm the diagnosis. Moreover, the prenatal diagnosis was carried out on the basis of molecular diagnosis.\nRESULTS: The siblings exhibited compound heterozygous variants {[c.302G>T]+[c.1344dupC]} in the ARSA gene, and both of the variants have been reported as disease-causing mutations previously. The results of MRI and low ARSA activity confirmed the diagnosis of MLD. Prenatal diagnosis showed that the fetus was a heterozygous carrier.\nCONCLUSIONS: It is recommended that WES be considered as a first line diagnostic procedure to discover potential disease-causing genetic variants in affected individuals with hereditary traits but without definite clinical diagnosis. However, the final diagnosis should be confirmed by comprehensive evaluations including biochemical, enzymatic or imaging investigations.","variants":[{"Name":"NM_000487.6(ARSA):c.302G>T (p.Gly101Val)","Chromosome":"22","Start":"50627329","Stop":"50627329","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":79020,"rule_based_match":true,"evidence_text":"c.302G>T","llm_judgment":"PRESENT","evidence":"c.302G>T","abstract_start":803,"abstract_end":811},{"Name":"NM_000487.6(ARSA):c.1344dup (p.Gly449fs)","Chromosome":"22","Start":"50625330","Stop":"50625331","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":549113,"rule_based_match":true,"evidence_text":"c.1344dupC","llm_judgment":"PRESENT","evidence":"c.1344dupC","abstract_start":814,"abstract_end":824}]}
{"pmid":"32259399","title":"Expanding the clinical spectrum of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency with Turkish cases harboring novel HMGCS2 gene mutations and literature review.","abstract":"Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) deficiency is a very rare autosomal recessive inborn error of ketone body synthesis and presents with hypoketotic hypoglycemia, metabolic acidosis, lethargy, encephalopathy, and hepatomegaly with fatty liver precipitated by catabolic stress. We report acute presentation of two patients from unrelated two families with novel homozygous c.862C>T and c.725-2A>C mutations, respectively, in HMGCS2 gene. Affected patients had severe hypoketotic hypoglycemia, lethargy, encephalopathy, severe metabolic and lactic acidosis and hepatomegaly after infections. Surprisingly, molecular screening of the second family showed more affected patients without clinical findings. These cases expand the clinic spectrum of this extremely rare disease.","variants":[{"Name":"NM_005518.4(HMGCS2):c.862C>T (p.Arg288Ter)","Chromosome":"1","Start":"119757427","Stop":"119757427","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":263940,"rule_based_match":true,"evidence_text":"c.862C>T","llm_judgment":"PRESENT","evidence":"c.862C>T","abstract_start":397,"abstract_end":405}]}
{"pmid":"21959744","title":"Familial hemophagocytic lymphohistiocytosis in a pediatric patient diagnosed by brain magnetic resonance imaging.","abstract":"Familial hemophagocytic lymphohistiocytosis (fHLH) is an autosomal recessive disorder characterized by proliferation and infiltration of several organs by activated lymphocytes and macrophages. Without allogeneic stem cell transplantation, fHLH is fatal. We describe a previously healthy 11-month-old boy with a rapidly progressive encephalopathy. An older brother died at 8 months following a subacute encephalopathy diagnosed as meningoencephalitis. The family history led to the suspicion of a metabolic disease, but metabolic studies were unrevealing. MRI showed multiple inhomogeneous signal abnormalities in the cortex and white matter, most prominent in the cerebral hemispheres and around the dentate nucleus. Gadolinium-enhanced T1-weighted images showed a multitude of enhancing foci, suggestive of perivascular enhancement. Based on MRI pattern with multiple lesions, perivascular enhancement and family history, fHLH was suspected. DNA analysis showed that the patient was compound-heterozygous for the c.445 G>A (p.Gly149Ser) mutation in exon 1 and the c.757 G>A (p.Glu253Lys) mutation in exon 2 of the perforin 1 gene. The patient was treated according to the international HLH-2004 protocol (dexamethasone, etoposide, cyclosporine, intrathecal methotrexate and prednisolone) followed by allogeneic cord blood transplantation. He showed a significant neurological and radiological improvement. The reported case demonstrates that MRI pattern recognition can lead to early diagnosis of fHLH, with subsequent adequate treatment.","variants":[{"Name":"NM_001083116.3(PRF1):c.445G>A (p.Gly149Ser)","Chromosome":"10","Start":"70600458","Stop":"70600458","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":511872,"rule_based_match":true,"evidence_text":"c.445 G>A (p.Gly149Ser)","llm_judgment":"PRESENT","evidence":"c.445 G>A (p.Gly149Ser)","abstract_start":1015,"abstract_end":1038},{"Name":"NM_001083116.3(PRF1):c.757G>A (p.Glu253Lys)","Chromosome":"10","Start":"70598964","Stop":"70598964","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1372798,"rule_based_match":true,"evidence_text":"c.757 G>A (p.Glu253Lys)","llm_judgment":"PRESENT","evidence":"c.757 G>A (p.Glu253Lys)","abstract_start":1066,"abstract_end":1089}]}
{"pmid":"32319008","title":"Mutations in aARS genes revealed by targeted next-generation sequencing in patients with mitochondrial diseases.","abstract":"Mitochondrial diseases are a clinically heterogeneous group of multisystemic disorders that arise as a result of various mitochondrial dysfunctions. Autosomal recessive aARS deficiencies represent a rapidly growing group of severe rare inherited mitochondrial diseases, involving multiple organs, and currently without curative option. They might be related to defects of mitochondrial aminoacyl t-RNA synthetases (mtARS) that are ubiquitous enzymes involved in mitochondrial aminoacylation and the translation process. Here, using NGS analysis of 281 nuclear genes encoding mitochondrial proteins, we identified 4 variants in different mtARS in three patients from unrelated Tunisian families, with clinical features of mitochondrial disorders. Two homozygous variants were found in KARS (c.683C>T) and AARS2 (c.1150-4C>G), respectively in two patients, while two heterozygous variants in EARS2 (c.486-7C>G) and DARS2 (c.1456C>T) were concomitantly found in the third patient. Bio-informatics investigations predicted their pathogenicity and deleterious effects on pre-mRNA splicing and on protein stability. Thus, our results suggest that mtARS mutations are common in Tunisian patients with mitochondrial diseases.","variants":[{"Name":"NM_020745.4(AARS2):c.1150-4C>G","Chromosome":"6","Start":"44306536","Stop":"44306536","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":369132,"rule_based_match":true,"evidence_text":"c.1150-4C>G","llm_judgment":"PRESENT","evidence":"c.1150-4C>G","abstract_start":811,"abstract_end":822}]}
{"pmid":"26890752","title":"Late-Onset Metachromatic Leukodystrophy with Early Onset Dementia Associated with a Novel Missense Mutation in the Arylsulfatase A Gene.","abstract":"A 48-year-old male patient presented with personality changes and progressive memory loss over 2 years with initially suspected Hashimoto's encephalopathy. Strategy of diagnostic workup of early onset dementia included dementia from neurodegenerative, neuroinflammatory, metabolic/toxic, and psychiatric origin. The patient's neurological exam was normal. MRI revealed a leukencephalopathy, predominantly in the frontal periventricular white matter, without notable changes over 2 years. On neurophysiological examination, prolonged central conduction times and a sensorimotor polyneuropathy were noted. Neuropsychological impairment included disorientation in place and a reduced short time memory. Behavioral alterations were predominated by sudden mood changes and disinhibition. Cerebrospinal fluid was normal. Despite presence of thyroid autoantibodies, glucocorticosteroid treatment did not improve the dementia. A metachromatic leukodystrophy was diagnosed by decreased arylsulfatase-A activity in leucocytes/fibroblasts and identification of a compound heterozygous mutation in the ARSA gene: c.542T>G (exon 3) and the novel mutation c.1013T>C (exon 6). Pathogenic function was suggested by bioinformatic mutation search. In a patient with early onset dementia, strategic diagnostic workup including genetic assessment revealed an adult-onset metachromatic leukodystrophy with a novel mutation in the arylsulfatase A gene.","variants":[{"Name":"NM_000487.6(ARSA):c.542T>G (p.Ile181Ser)","Chromosome":"22","Start":"50626976","Stop":"50626976","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":18096,"rule_based_match":true,"evidence_text":"c.542T>G","llm_judgment":"PRESENT","evidence":"c.542T>G","abstract_start":1101,"abstract_end":1109}]}
{"pmid":"26765483","title":"PCDH19-related epilepsy in two mosaic male patients.","abstract":"PCDH19 gene mutations have been recently associated with an epileptic syndrome characterized by focal and generalized seizures. The PCDH19 gene (Xq22.1) has an unusual X-linked inheritance with a selective involvement for female subjects. A cellular interference mechanism has been hypothesized and male patients can manifest epilepsy only in the case of a mosaicism. So far about 100 female patients, and only one symptomatic male have been described. Using targeted next generation sequencing (NGS) approach we found a PCDH19 point mutation in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. The system allowed us to verify that the two c.1352 C>T; p.(Pro451Leu) and c.918C>G; p.(Tyr306*) variants occurred in mosaic status. Mutations were confirmed by Sanger sequencing and quantified by real-time polymerase chain reaction (PCR). Up to now, the traditional molecular screening for PCDH19-related epilepsy has been targeted to all females with early onset epilepsy with or without cognitive impairment. Male patients were generally excluded. We describe for the first time two mosaic PCDH19 point mutations in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. This finding opens new opportunities for the molecular diagnoses in patients with a peculiar type of epilepsy that remains undiagnosed in male patients.","variants":[{"Name":"NM_001184880.2(PCDH19):c.1352C>T (p.Pro451Leu)","Chromosome":"X","Start":"100407246","Stop":"100407246","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1878325,"rule_based_match":true,"evidence_text":"c.1352 C>T; p.(Pro451Leu)","llm_judgment":"PRESENT","evidence":"c.1352 C>T; p.(Pro451Leu)","abstract_start":672,"abstract_end":697},{"Name":"NM_001184880.2(PCDH19):c.918C>G (p.Tyr306Ter)","Chromosome":"X","Start":"100407680","Stop":"100407680","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":575311,"rule_based_match":true,"evidence_text":"c.918C>G; p.(Tyr306*)","llm_judgment":"PRESENT","evidence":"c.918C>G; p.(Tyr306*)","abstract_start":702,"abstract_end":723}]}
{"pmid":"21293734","title":"Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy.","abstract":"AIMS: To describe genetic and clinical findings in a French family affected by best vitelliform macular dystrophy (BVMD).\nMETHODS: We screened eight at-risk members of a family, including a BVMD-affected proband, by direct sequencing of 11 bestrophin-1 (BEST1) exons. Individuals underwent ophthalmic examination and autofluorescent fundus imaging, indocyanine green angiography, electro-oculogram (EOG), electroretinogram (ERG), multifocal ERG, optical coherence tomography (OCT), and where possible, spectral domain OCT.\nRESULTS: The sequence analysis of the BEST1 gene revealed one previously unknown mutation, c.15C>A (p.Y5X), in two family members and one recently described mutation, c.430A>G (p.S144G), in five family members. Fundus examination and electrophysiological responses provided no evidence of the disease in the patient carrying only the p.Y5X mutation. Three patients with the p.S144G mutation did not show any preclinical sign of BVMD except altered EOGs. Two individuals of the family exhibited a particularly severe phenotype of multifocal BVMD-one individual carrying the p.S144G mutation heterozygously and one individual harboring both BEST1 mutations (p.S144G inherited from his mother and p.Y5X from his father). Both of these family members had multifocal vitelliform autofluorescent lesions combined with abnormal EOG, and the spectral domain OCT displayed a serous retinal detachment. In addition, ERGs demonstrated widespread retinal degeneration and multifocal ERGs showed a reduction in the central retina function, which could be correlated with the decreased visual acuity and visual field scotomas.\nCONCLUSIONS: A thorough clinical evaluation found no pathological phenotype in the patient carrying the isolated p.Y5X mutation. The patients carrying the p.S144G variation in the protein exhibited considerable intrafamilial phenotypic variability. Two young affected patients in this family exhibited an early onset, severe, multifocal BVMD with a diffuse distribution of autofluorescent deposits throughout the retina and rapid evolution toward the loss of central vision. The other genetically affected relatives had only abnormal EOGs and displayed no or extremely slow electrophysiological evolution.","variants":[{"Name":"NM_004183.4(BEST1):c.430A>G (p.Ser144Gly)","Chromosome":"11","Start":"61955900","Stop":"61955900","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3856842,"rule_based_match":true,"evidence_text":"c.430A>G (p.S144G)","llm_judgment":"PRESENT","evidence":"c.430A>G (p.S144G)","abstract_start":690,"abstract_end":708}]}
{"pmid":"21549105","title":"Mucolipidosis in a Chinese family with compound heterozygous mutations at the GNPTAB gene.","abstract":"BACKGROUND: Mucopolysaccharidoses (MPS) are caused by the deficiency in the metabolism of one or more types of mucopolysaccharides or glycosaminoglycans (GAGs). Mucolipidoses (ML) are a group of genetic disorders in which both glycosaminoglycans (GAGs) and sphingolipids build up in the body. Both of MPS and ML belong to lysosomal storage diseases and show similar clinical manifestations. Distinction of these two types of diseases has not been always possible using conventional clinical diagnoses. Genetic test provides a definitive diagnosis for ML and MPS diseases.\nMETHODS: The initial clinical diagnosis had suspected the proband as either MPS or ML. To verify the clinical diagnosis, linkage analysis was performed with a panel of microsatellite markers flanking 10 candidate genetic loci for mucopolysaccharidosis and 2 loci for mucolipidosis. Two-point logarithm of odds (lod) scores was calculated using Linkage Package 5.2 program. Direct DNA sequence analyses of GNPTAB in the family members were performed.\nRESULTS: By using linkage and mutational analyses, we have identified that the family members contain compound heterozygous mutations of p.R364X and c.2715+1G>A in the GNPTAB gene. We determine the family as MLIII based on the DNA-test and clinical diagnoses.\nCONCLUSION: Our study confirms the pathological relationship between the patients' genotype and phenotype in the clinical ML manifestation, and suggests that DNA-based diagnosis serves as a better way to define ML and MPS.","variants":[{"Name":"NM_024312.5(GNPTAB):c.2715+1G>A","Chromosome":"12","Start":"101764201","Stop":"101764201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17807,"rule_based_match":true,"evidence_text":"c.2715+1G>A","llm_judgment":"PRESENT","evidence":"c.2715+1G>A","abstract_start":1171,"abstract_end":1182}]}
{"pmid":"31745726","title":"Novel NAXE variants as a cause for neurometabolic disorder: implications for treatment.","abstract":"Neurometabolic disorders are often inherited and complex disorders that result from abnormalities of enzymes important for development and function of the nervous system. Recently, biallelic mutations in NAXE (APOA1BP) were found in patients with an infantile, lethal, neurometabolic disease. Here, exome sequencing was performed in two affected sisters and their healthy parents. The best candidate, NAXE, was tested for replication in exome sequencing data from 4351 patients with neurodevelopmental disorders. Quantitative RT-PCR, western blot and form factor analysis were performed to assess NAXE expression, protein levels and to analyze mitochondrial morphology in fibroblasts. Vitamin B3 was administered to one patient. Compound heterozygous missense (c.757G>A: p.Gly253Ser) and splicing (c.665-1G>A) variants in NAXE were identified in both affected sisters. In contrast to the previously reported patients with biallelic NAXE variants, our patients showed a milder phenotype with disease onset in early adulthood with psychosis, cognitive impairment, seizures, cerebellar ataxia and spasticity. The symptoms fluctuated. Additional screening of NAXE identified three novel homozygous missense variants (p.Lys245Gln, p.Asp218Asn, p.Ile214Val) in three patients with overlapping phenotype (fluctuating disease course, respiratory insufficiency, movement disorder). Lastly, patients with the c.665-1G>A splicing variant showed a significant reduction of NAXE expression compared to control fibroblasts and undetectable NAXE protein levels compared to control fibroblasts. Based on the metabolic pathway, vitamin B3 and coenzyme Q treatment was introduced in one patient in addition to antiepileptic treatment. This combination and avoidance of triggers was associated with continuous motor and cognitive improvement. The NAXE variants identified in this study suggest a loss-of-function mechanism leading to an insufficient NAD(P)HX repair system. Importantly, symptoms of patients with NAXE variants may improve with vitamin B3/coenzyme Q administration.","variants":[{"Name":"NM_144772.3(NAXE):c.757G>A (p.Gly253Ser)","Chromosome":"1","Start":"156593974","Stop":"156593974","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2046622,"rule_based_match":true,"evidence_text":"c.757G>A: p.Gly253Ser","llm_judgment":"PRESENT","evidence":"c.757G>A: p.Gly253Ser","abstract_start":761,"abstract_end":782}]}
{"pmid":"25073507","title":"Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy.","abstract":"PURPOSE: Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A (OMIM 605000) that results in T-cell lymphopenia and is classified as T(-)B(+)NK(+)severe combined immunodeficiency (SCID). Only two other CORO1A-kindred are known to date, thus the defining characteristics are not well delineated. We identified a unique CORO1A-kindred.\nMETHODS: We captured a 10-year analysis of the immune-clinical phenotypes in two affected siblings from disease debut of age 7 years. Target-specific genetic studies were pursued but unrevealing. Telomere lengths were also assessed. Whole exome sequencing (WES) uncovered the molecular diagnosis and Western blot validated findings.\nRESULTS: We found the compound heterozygous CORO1A variants: c.248_249delCT (p.P83RfsX10) and a novel mutation c.1077delC (p.Q360RfsX44) (NM_007074.3) in two affected non-consanguineous siblings that manifested as absent CD4CD45RA(+) (naïve) T and memory B cells, low NK cells and abnormally increased double-negative (DN) ϒδ T-cells. Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers; the older female sibling also had a disfiguring granulomatous tuberculoid leprosy. Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years. The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations.\nCONCLUSION: We reveal the third CORO1A-mutated kindred, with the immune phenotype of abnormal naïve CD4 and DN T-cells and newfound characteristics of a late/hypomorphic-like SCID of an EV-HPV mucocutaneous syndrome with also B and NK defects and shortened telomeres. Our findings contribute to the elucidation of the CORO1A-SCID-CID spectrum.","variants":[{"Name":"NM_007074.4(CORO1A):c.248_249del (p.Pro83fs)","Chromosome":"16","Start":"30186647","Stop":"30186648","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":49379,"rule_based_match":true,"evidence_text":"c.248_249delCT (p.P83RfsX10)","llm_judgment":"PRESENT","evidence":"c.248_249delCT (p.P83RfsX10)","abstract_start":796,"abstract_end":824}]}
{"pmid":"29656098","title":"A novel PIGA mutation in a Taiwanese family with early-onset epileptic encephalopathy.","abstract":"PURPOSE: We report the first family with PIGA-associated epileptic encephalopathy in Taiwan and hope to elucidate its special phenotype and inheritance pattern.\nMETHOD: We found a Taiwanese family with several members suffered from severe epileptic encephalopathy (ZY07, ZY01, ZY04). To determine the underlying etiology, whole exome sequencing was conducted.\nRESULTS: A single novel variant, NM_002641: c.356G > A, p.Arg119Gln, was identified in the X chromosome PIGA gene in our proband patient (ZY07). The patient's mother (ZY02) and aunt (ZY03) were confirmed as carriers of the hemizygous variant.\nCONCLUSIONS: This paper highlights the highly transmitted features of PIGA and other X-linked EIEEs, raising awareness of rare forms of epileptic encephalopathy.","variants":[{"Name":"NM_002641.4(PIGA):c.356G>A (p.Arg119Gln)","Chromosome":"X","Start":"15331575","Stop":"15331575","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":802044,"rule_based_match":true,"evidence_text":"NM_002641: c.356G > A, p.Arg119Gln","llm_judgment":"PRESENT","evidence":"NM_002641: c.356G > A, p.Arg119Gln","abstract_start":393,"abstract_end":427}]}
{"pmid":"28608624","title":"Four case reports of Chinese cystic fibrosis patients and literature review.","abstract":"AIM: Cystic fibrosis (CF) is an extremely rare disease in Asians. Here, we report four Chinese children with CF and review the literature about Chinese CF patients.\nMETHODS: The cystic fibrosis transmembrane conductance regulator (CFTR) gene testing was performed on four suspected patients for CF screening. We also reviewed the literature about Chinese CF patients from 1970s. The clinical data of all these CF patients were summarized.\nRESULTS: We diagnosed four CF patients who had mutations in the CFTR gene. We identified six different mutations in the four patients. The c.1766+5G>T, c.595C>T, c.2909G>A, and c.4056G>C had been reported already. The two splicing mutations of c.579+1_579+2insACAT and c.1117-1G>C were novel mutations. There have been 46 Chinese CF patients reported in literature from 1974 up to present (2016.12). The clinical manifestations of CF involved several systems. The most common symptom was recurrent pulmonary infections. Thirty-three different mutations were identified; c.1766 + 5G>T was the most common mutation among Chinese CF patients. Only one of these mutations (R553X) was in the Caucasian CF screening panel. The spectrum of CFTR mutations in Chinese was highly different from that of Caucasian.\nCONCLUSIONS: There was a high risk of misdiagnosis or delayed diagnosis of CF even in suspected cases in China. It is necessary to educate Chinese clinicians about the signs, symptoms, and diagnosis of cystic fibrosis and promote the implementation of the sweat chloride test.","variants":[{"Name":"NM_000492.4(CFTR):c.4056G>C (p.Gln1352His)","Chromosome":"7","Start":"117664780","Stop":"117664780","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":22276,"rule_based_match":true,"evidence_text":"c.4056G>C","llm_judgment":"PRESENT","evidence":"c.4056G>C","abstract_start":616,"abstract_end":625},{"Name":"NM_000492.4(CFTR):c.2909G>A (p.Gly970Asp)","Chromosome":"7","Start":"117606674","Stop":"117606674","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44518,"rule_based_match":true,"evidence_text":"c.2909G>A","llm_judgment":"PRESENT","evidence":"c.2909G>A","abstract_start":601,"abstract_end":610},{"Name":"NM_000492.4(CFTR):c.579+1_579+2insACAT","Chromosome":"7","Start":"117534366","Stop":"117534367","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GACAT","allel_id":1490988,"rule_based_match":true,"evidence_text":"c.579+1_579+2insACAT","llm_judgment":"PRESENT","evidence":"c.579+1_579+2insACAT","abstract_start":683,"abstract_end":703},{"Name":"NM_000492.4(CFTR):c.595C>T (p.His199Tyr)","Chromosome":"7","Start":"117535263","Stop":"117535263","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":68685,"rule_based_match":true,"evidence_text":"c.595C>T","llm_judgment":"PRESENT","evidence":"c.595C>T","abstract_start":591,"abstract_end":599}]}
{"pmid":"31347140","title":"Functional analysis of novel RUNX2 mutations identified in patients with cleidocranial dysplasia.","abstract":"RUNX2 (Runt-related transcription factor 2) is a master regulator of osteoblast differentiation, cartilage and bone development. Pathogenic variants in RUNX2 have been linked to the Cleidocranial dysplasia (CCD), which is characterized by hypoplasia or aplasia of clavicles, delayed fontanelle closure, and dental anomalies. Here, we report 11 unrelated Polish patients with CCD caused by pathogenic alterations located in the Runt domain of RUNX2. In total, we identified eight different intragenic variants, including seven missense and one splicing mutation. Three of them are novel: c.407T>A p.(Leu136Gln), c.480C>G p.(Asn160Lys), c.659C>G p.(Thr220Arg), additional three were not functionally tested: c.391C>T p.(Arg131Cys), c.580+1G>T p.(Lys195_Arg229del), c.652A>G p.(Lys218Glu), and the remaining two: c.568C>T p.(Arg190Trp), c.673C>T p.(Arg225Trp) were previously reported and characterized. The performed transactivation and localization studies provide evidence of decreased transcriptional activity of RUNX2 due to mutations targeting the Runt domain and prove that impairment of nuclear localization signal (NLS) affects the subcellular localization of the protein. Presented data show that pathogenic variants discovered in our patients have a detrimental effect on RUNX2, triggering the CCD phenotype.","variants":[{"Name":"NM_001024630.4(RUNX2):c.652A>G (p.Lys218Glu)","Chromosome":"6","Start":"45438018","Stop":"45438018","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1468089,"rule_based_match":true,"evidence_text":"c.652A>G p.(Lys218Glu)","llm_judgment":"PRESENT","evidence":"c.652A>G p.(Lys218Glu)","abstract_start":763,"abstract_end":785}]}
{"pmid":"17068223","title":"A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.","abstract":"The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.","variants":[{"Name":"NM_144701.3(IL23R):c.1142G>A (p.Arg381Gln)","Chromosome":"1","Start":"67240275","Stop":"67240275","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18147,"rule_based_match":true,"evidence_text":"c.1142G>A (p.Arg381Gln)","llm_judgment":"PRESENT","evidence":"p.Arg381Gln","abstract_start":530,"abstract_end":541}]}
{"pmid":"20890276","title":"Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.","abstract":"N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca²(+)-permeable cation channels which are blocked by extracellular Mg²(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg²(+) block and a decrease in Ca²(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.","variants":[{"Name":"NM_001134407.3(GRIN2A):c.1845C>A (p.Asn615Lys)","Chromosome":"16","Start":"9829585","Stop":"9829585","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":38688,"rule_based_match":true,"evidence_text":"c.1845C>A","llm_judgment":"PRESENT","evidence":"c.1845C>A","abstract_start":900,"abstract_end":909}]}
{"pmid":"27785399","title":"Von Hippel-Lindau disease: the clinical manifestations and genetic analysis results of two cases from a single family.","abstract":"von Hippel-Lindau (VHL) disease is an autosomal dominant inherited multi systemic cancer syndrome that is classically associated with neoplasms in multiple organs, and caused by mutations in the <i>VHL</i> gene on chromosome 3p25-p26. Retinal hemangioblastoma (RH) is the most frequent and the earliest clinical sign of the disease, which is seen in 40.0-60.0% of patients. In recent years, studies of patients with VHL tried to put forward the relationship between genotype and phenotype. In this study, two VHL cases in the same family with clinical findings and genetic analysis results are presented. As a consequence of the genetic studies, a heterozygous missense mutation c.202 T>C, p.S68P (Ser68Pro) in exon 1 of the <i>VHL</i> gene that is mapped to chromosome 3p25.3, was found in the patients' DNA sample. The germline mutation of [c.202T>C, p.S68P (Ser68Pro)] that was detected in both cases, has been reported in only two cases in the literature. However, in these reported cases, any systemic involvement except RH, were not reported. Although our cases had the same mutation, we detected renal involve-ment in both cases, and also central nervous system (CNS) involvement in one case, in addition to RH.","variants":[{"Name":"NM_000551.4(VHL):c.202T>C (p.Ser68Pro)","Chromosome":"3","Start":"10142049","Stop":"10142049","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3086223,"rule_based_match":true,"evidence_text":"c.202 T>C, p.S68P (Ser68Pro)","llm_judgment":"PRESENT","evidence":"c.202 T>C, p.S68P (Ser68Pro)","abstract_start":679,"abstract_end":707}]}
{"pmid":"33550051","title":"Generation of an induced pluripotent stem cell line (ZZUi022-A) from a paroxysmal kinesigenic dyskinesia individual carrying the PRRT2 gene mutation.","abstract":"Paroxysmal kinesigenic dyskinesia (PKD), the most common type of paroxysmal movement disorders, is caused by mutations in PRRT2 gene. We identified an unreported PRRT2 c. 535 C > T (p. Q 1 7 9 *) pathogenic mutation in a Chinese Han family with PKD and generated an induced pluripotent stem cell (iPSC) line from a patient in the family by reprogramming fibroblasts with sendai virus. The iPSC line was characterized for genetic uniqueness, genomic integrity, pluripotency, and differentiation ability. This iPSC line will be a powerful tool to to study the molecular mechanisms underlying PKD.","variants":[{"Name":"NM_145239.3(PRRT2):c.535C>T (p.Gln179Ter)","Chromosome":"16","Start":"29813589","Stop":"29813589","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1505970,"rule_based_match":true,"evidence_text":"c. 535 C > T (p. Q 1 7 9 *)","llm_judgment":"PRESENT","evidence":"c. 535 C > T (p. Q 1 7 9 *)","abstract_start":168,"abstract_end":195}]}
{"pmid":"21403111","title":"TUBA1A mutations: from isolated lissencephaly to familial polymicrogyria.","abstract":"BACKGROUND: Mutations in the TUBA1A gene have been reported in patients with lissencephaly and perisylvian pachygyria.\nMETHODS: Twenty-five patients with malformations of cortical development ranging from lissencephaly to polymicrogyria were screened for mutations in TUBA1A.\nRESULTS: Two novel heterozygous missense mutations in TUBA1A were identified: c.629A>G (p.Tyr210Cys) occurring de novo in a boy with lissencephaly, and c.13A>C (p.Ile5Leu) affecting 2 sisters with polymicrogyria whose mother presented somatic mosaicism for the mutation.\nCONCLUSIONS: Mutations in TUBA1A have been described in patients with lissencephaly and pachygyria. We report a mutation in TUBA1A as a cause of polymicrogyria. So far, all mutations in TUBA1A have occurred de novo, resulting in isolated cases. This article describes familial recurrence of TUBA1A mutations due to somatic mosaicism in a parent. These findings broaden the phenotypic spectrum associated with TUBA1A mutations and have implications for genetic counseling.","variants":[{"Name":"NM_006009.4(TUBA1A):c.13A>C (p.Ile5Leu)","Chromosome":"12","Start":"49186824","Stop":"49186824","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":39224,"rule_based_match":true,"evidence_text":"c.13A>C (p.Ile5Leu)","llm_judgment":"PRESENT","evidence":"c.13A>C (p.Ile5Leu)","abstract_start":428,"abstract_end":447},{"Name":"NM_006009.4(TUBA1A):c.629A>G (p.Tyr210Cys)","Chromosome":"12","Start":"49185737","Stop":"49185737","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":613797,"rule_based_match":true,"evidence_text":"c.629A>G (p.Tyr210Cys)","llm_judgment":"PRESENT","evidence":"c.629A>G (p.Tyr210Cys)","abstract_start":354,"abstract_end":376}]}
{"pmid":"17941496","title":"Association of multiple vertebral hemangiomas and severe paraparesis in a patient with a PTEN hamartoma tumor syndrome. Case report.","abstract":"The PTEN hamartoma tumor syndrome, manifestations of which include Cowden disease and Bannayan-Riley-Ruvalcaba syndrome, is caused by various mutations of the PTEN gene located at 10q23. Its major criteria are macrocephaly and a propensity to develop breast and thyroid cancers as well as endometrial carcinoma. Minor diagnostic criteria include hamartomatous intestinal polyps, lipomas, fibrocystic disease of the breasts, and fibromas. Mutations of PTEN can also be found in patients with Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum). The authors report the case of a 17-year-old girl who had a severe cyanotic cardiac malformation for which surgery was not advised and a heterozygous missense mutation (c.406T>C) in exon 5 of PTEN resulting in the substitution of cysteine for arginine (p.Cysl36Arg) in the protein, which was also found in her mother and sister. The patient presented in the pediatric emergency department with severe spastic paraparesis. A magnetic resonance imaging study of the spine showed vertebral hemangiomas at multiple levels, but stenosis and compression were maximal at level T5-6. An emergency T5-6 laminectomy was performed. The decompression was extremely hemorrhagic because the rapid onset of paraparesis necessitated prompt treatment, and there was no time to perform preoperative embolization. The patient's postoperative course was uneventful with gradual recovery. This represents the first report of an association of a PTEN mutation and multiple vertebral angiomas. The authors did not treat the remaining angiomas because surgical treatment was contraindicated without previous embolization, which in itself would present considerable risk in this patient with congenital cyanotic heart disease.","variants":[{"Name":"NM_000314.8(PTEN):c.406T>C (p.Cys136Arg)","Chromosome":"10","Start":"87933165","Stop":"87933165","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":183028,"rule_based_match":true,"evidence_text":"c.406T>C","llm_judgment":"PRESENT","evidence":"c.406T>C","abstract_start":731,"abstract_end":739}]}
{"pmid":"32094424","title":"An autosomal dominant ERLIN2 mutation leads to a pure HSP phenotype distinct from the autosomal recessive ERLIN2 mutations (SPG18).","abstract":"Hereditary spastic paraplegia (HSP) is a heterogeneous inherited disorder that manifests with lower extremity weakness and spasticity. HSP can be inherited by autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have shown that, although rare, mutations in a single gene can lead to multiple patterns of inheritance of HSP. We enrolled the HSP family showing autosomal dominant inheritance and performed genetic study to find the cause of phenotype in this family. We recruited five members of a Korean family as study participants. Four of the five family members had pure HSP. Part of the family members underwent whole-exome sequencing (WES) to identify the causative mutation. As the result of WES and Sanger sequencing analysis, a novel missense mutation (c.452 C > T, p.Ala151Val) of ERLIN2 gene was identified as the cause of the autosomal dominant HSP in the family. Our study suggests that the ERLIN2 gene leads to both autosomal recessive and autosomal dominant patterns of inheritance in HSP. Moreover, autosomal dominant HSP caused by ERLIN2 appears to cause pure HSP in contrast to autosomal recessive ERLIN2 related complicated HSP (SPG18).","variants":[{"Name":"NM_007175.8(ERLIN2):c.452C>T (p.Ala151Val)","Chromosome":"8","Start":"37749586","Stop":"37749586","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":457827,"rule_based_match":true,"evidence_text":"c.452 C > T, p.Ala151Val","llm_judgment":"PRESENT","evidence":"c.452 C > T, p.Ala151Val","abstract_start":799,"abstract_end":823}]}
{"pmid":"22217259","title":"A new β chain hemoglobin variant with increased oxygen affinity: Hb Santa Giusta Sardegna [β93(F9)Cys→Trp; HBB c.282T>G].","abstract":"During a screening program for the identification of β-thalassemia (β-thal) carriers in Sardinia, Italy, we identified two subjects with increased hemoglobin (Hb) levels and an abnormal Hb variant. The same variant was detected in a family member. DNA sequencing revealed a TGT > TGG mutation at codon 93 of the β-globin gene. Structural analysis demonstrated that the cystine residue at position 93 of the β chain was substituted by tryptophan.   Since this amino acid substitution had not yet been reported, we designated this variant Hb Santa Giusta Sardegna for the place of birth of the subjects. This amino acid substitution occurs at the tyrosine pocket of the β chain as well as at the α1β2/α2β1 contact of the quaternary structure of the molecule. The presence of this Hb in the hemolysate causes an increased oxygen affinity, a slightly reduced Bohr effect and a reduced heme-heme interaction (n(50), Hill's constant) in comparison with those of Hb A.","variants":[{"Name":"NM_000518.5(HBB):c.282T>G (p.Cys94Trp)","Chromosome":"11","Start":"5226610","Stop":"5226610","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":983971,"rule_based_match":true,"evidence_text":"HBB c.282T>G","llm_judgment":"PRESENT","evidence":"HBB c.282T>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"14974087","title":"Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue.","abstract":"Germline mutations in mismatch repair (MMR) genes, predominantly in MLH1 and MSH2, are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), a cancer-susceptibility syndrome with high penetrance. In addition, MSH6 mutations have been reported to account for about 10% of all germline mismatch repair (MMR) gene mutations in HNPCC patients, and have been associated with a later age of onset of the disease compared to MLH1 and MSH2 mutations. Here, we report eight novel germline mutations in MSH6. The patients were selected by having developed tumors with loss of MSH6 protein expression. All tumors showed high-level microsatellite instability (MSI-H). Seven mutations resulted in premature stop codons, comprised of two nonsense mutations (c.426G>A [p.W142X], c.2105C>A [p.S702X]), two insertions (c.2611_2614dupATTA [p.I872fsX10], c.3324dupT [p.I1109fsX3]) and three deletions (c.1190_1191delAT [p.Y397fsX3], c.1632_1635delAAAA [p.E544fsX26], c.3513_3514delTA [p.1171fsX5]). In addition, an amino acid substitution of an arginine residue (c.2314C>T [p.R772W]) conserved throughout a wide variety of mutS homologs has been found in a patient not fulfilling the Bethesda criteria for HNPCC. Our results emphasize the suitability of IHC as a pre-selection tool for MSH6 mutation analysis and the high frequency of germline mutation detection in patients with MSH6-deficient tumors. In addition, our findings point towards a broad variability regarding penetrance associated with MSH6 germline mutations.","variants":[{"Name":"NM_000179.3(MSH6):c.3513_3514del (p.Asp1171fs)","Chromosome":"2","Start":"47804983","Stop":"47804984","ReferenceAlleleVCF":"GAT","AlternateAlleleVCF":"G","allel_id":94877,"rule_based_match":true,"evidence_text":"c.3513_3514delTA [p.1171fsX5]","llm_judgment":"PRESENT","evidence":"c.3513_3514delTA [p.1171fsX5]","abstract_start":961,"abstract_end":990},{"Name":"NM_000179.3(MSH6):c.2105C>A (p.Ser702Ter)","Chromosome":"2","Start":"47800088","Stop":"47800088","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1850233,"rule_based_match":true,"evidence_text":"c.2105C>A [p.S702X]","llm_judgment":"PRESENT","evidence":"c.2105C>A [p.S702X]","abstract_start":777,"abstract_end":796},{"Name":"NM_000179.3(MSH6):c.426G>A (p.Trp142Ter)","Chromosome":"2","Start":"47791092","Stop":"47791092","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":94993,"rule_based_match":true,"evidence_text":"c.426G>A [p.W142X]","llm_judgment":"PRESENT","evidence":"c.426G>A [p.W142X]","abstract_start":757,"abstract_end":775},{"Name":"NM_000179.3(MSH6):c.2314C>T (p.Arg772Trp)","Chromosome":"2","Start":"47800297","Stop":"47800297","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":94741,"rule_based_match":true,"evidence_text":"c.2314C>T [p.R772W]","llm_judgment":"PRESENT","evidence":"c.2314C>T [p.R772W]","abstract_start":1057,"abstract_end":1076},{"Name":"NM_000179.3(MSH6):c.2611_2614dup (p.Ile872fs)","Chromosome":"2","Start":"47800592","Stop":"47800593","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AAATT","allel_id":94777,"rule_based_match":true,"evidence_text":"c.2611_2614dupATTA [p.I872fsX10]","llm_judgment":"PRESENT","evidence":"c.2611_2614dupATTA [p.I872fsX10]","abstract_start":815,"abstract_end":847},{"Name":"NM_000179.3(MSH6):c.1190_1191del (p.Tyr397fs)","Chromosome":"2","Start":"47799172","Stop":"47799173","ReferenceAlleleVCF":"CTA","AlternateAlleleVCF":"C","allel_id":94652,"rule_based_match":true,"evidence_text":"c.1190_1191delAT [p.Y397fsX3]","llm_judgment":"PRESENT","evidence":"c.1190_1191delAT [p.Y397fsX3]","abstract_start":896,"abstract_end":925}]}
{"pmid":"23026888","title":"High resolution melting analysis of the MMAA gene in patients with cblA and in those with undiagnosed methylmalonic aciduria.","abstract":"The gene product of MMAA is required for the intracellular metabolism of cobalamin (Cbl). Mutations in this gene lead to the cblA class of disorders, characterized by isolated methylmalonic aciduria. We have been concerned that somatic cell methods of diagnosis may miss patients with mild cellular phenotypes. A high resolution melting analysis (HRMA) assay was developed to rapidly scan the coding exons and flanking intronic regions of the MMAA gene for variants. DNA was scanned by HRMA from 96 unaffected reference individuals, 72 cblA patients confirmed by complementation, and 181 patients with isolated elevated methylmalonic acid, who could not be diagnosed using complementation analysis. Suspected variants were confirmed by Sanger sequencing. In the cblA cohort, HRMA correctly identified all previously known mutations as well as an additional 22 variants, 10 of which had not been previously reported. Novel variants included one duplication (c.551dupG, p.C187LfsX3), one deletion (c.387delC, p.Y129YfsX13), one splice site mutation (c.440-2A>G, splice site), 4 missense mutations (c.748G>A, p.E520K; c.820G>A, p.G274S; c.627G>T, p.R209S; c.826A>G, p.K276E), and 3 nonsense mutations (c.960G>A, p.W320X; c.1075C>T, p.E359X; c.1084C>T, p.Q362X). All novel missense variants affect highly conserved residues and are predicted to be damaging. Scanning of MMAA in the 181 undiagnosed samples revealed a single novel heterozygous missense change (c.821G>A, p.G274D).","variants":[{"Name":"NM_172250.3(MMAA):c.440-2A>G","Chromosome":"4","Start":"145642361","Stop":"145642361","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1934865,"rule_based_match":true,"evidence_text":"c.440-2A>G, splice site","llm_judgment":"PRESENT","evidence":"c.440-2A>G, splice site","abstract_start":1048,"abstract_end":1071}]}
{"pmid":"27738187","title":"Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the","abstract":"BACKGROUND: In 1993, Chitayat <i>et al.</i>, reported a newborn with hyperphalangism, facial anomalies, and bronchomalacia. We identified three additional families with similar findings. Features include bilateral accessory phalanx resulting in shortened index fingers; hallux valgus; distinctive face; respiratory compromise.\nOBJECTIVES: To identify the genetic aetiology of Chitayat syndrome and identify a unifying cause for this specific form of hyperphalangism.\nMETHODS: Through ongoing collaboration, we had collected patients with strikingly-similar phenotype. Trio-based exome sequencing was first performed in Patient 2 through Deciphering Developmental Disorders study. Proband-only exome sequencing had previously been independently performed in Patient 4. Following identification of a candidate gene variant in Patient 2, the same variant was subsequently confirmed from exome data in Patient 4. Sanger sequencing was used to validate this variant in Patients 1, 3; confirm paternal inheritance in Patient 5.\nRESULTS: A recurrent, novel variant NM_006494.2:c.266A>G p.(Tyr89Cys) in <i>ERF</i> was identified in five affected individuals: de novo (patient 1, 2 and 3) and inherited from an affected father (patient 4 and 5). p.Tyr89Cys is an aromatic polar neutral to polar neutral amino acid substitution, at a highly conserved position and lies within the functionally important ETS-domain of the protein. The recurrent <i>ERF</i> c.266A>C p.(Tyr89Cys) variant causes Chitayat syndrome.\nDISCUSSION: <i>ERF</i> variants have previously been associated with complex craniosynostosis. In contrast, none of the patients with the c.266A>G p.(Tyr89Cys) variant have craniosynostosis.\nCONCLUSIONS: We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p.Tyr89Cys substitution in <i>ERF</i>.","variants":[{"Name":"NM_006494.4(ERF):c.266A>G (p.Tyr89Cys)","Chromosome":"19","Start":"42249934","Stop":"42249934","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":262701,"rule_based_match":true,"evidence_text":"NM_006494.2:c.266A>G p.(Tyr89Cys)","llm_judgment":"PRESENT","evidence":"NM_006494.2:c.266A>G p.(Tyr89Cys)","abstract_start":1058,"abstract_end":1091}]}
{"pmid":"24094860","title":"Increasing and persistent DWI changes in a patient with hereditary diffuse leukoencephalopathy with spheroids.","abstract":"We report a case with genetically confirmed hereditary diffuse leukoencephalopathy with spheroids with distinctive MRI features. A 52-year-old woman with a family history of juvenile dementia presented with an 18-month history of progressive cognitive decline. Longitudinal magnetic resonance imaging studies of the brain revealed increasing and persistent white matter hyperintensities on diffusion-weighted images. Linear high intensity signal along axonal fibers arisen from the cerebral cortex was also shown. Finding of subcortical calcifications was noted on brain CT scan. Sequence analysis of CSF1R showed a novel missense mutation c.2467C>T (p.Ala823Val). Persistent and increasing diffusion on magnetic resonance image, presumably reflecting intramyelinic oedema in regions of neurodegeneration, is a distinctive feature observed in this case. The presence of this unique finding can be a diagnostic clue in the early stage of the disease.","variants":[{"Name":"NM_005211.3(CSF1R):c.2467C>T","Chromosome":"5","Start":"150056112","Stop":"150056112","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171835,"rule_based_match":true,"evidence_text":"c.2467C>T","llm_judgment":"PRESENT","evidence":"c.2467C>T","abstract_start":640,"abstract_end":649}]}
{"pmid":"36873630","title":"Steroid-resistant nephrotic syndrome associated with certain","abstract":"Objectives: Steroid-resistant nephrotic syndrome (SRNS) is a clinical syndrome characterized by the lack of response to standard steroid therapy, usually progressing to end-stage renal disease. We reported two cases of female identical twins with SRNS caused by <i>SGPL1</i> variants in one family, reviewed the relevant literature, and summarized their clinical phenotypes, pathological types, and genotypic characteristics.\nMethods: Two cases of nephrotic syndrome caused by <i>SGPL1</i> variants were admitted to Tongji Hospital, affiliated with Tongji Medical College of Huazhong University of Science and Technology. Their clinical data were retrospectively collected, and the peripheral blood genomic DNA was captured and sequenced by whole exome sequencing. Related literature published in PubMed, CNKI, and Wan fang databases was reviewed.\nResults: We described two Chinese identical twin girls with isolated SRNS due to compound heterozygous variants in the <i>SGPL1</i> (intron4 c.261 + 1G > A and intron12 c.1298 + 6T > C). The patients were followed up for 60.0 months and 53.0 months, respectively, having no extra-renal manifestations. They all died due to renal failure. A total of 31 children with <i>SGPL1</i> variants causing nephrotic syndrome (including the reported two cases) were identified through a literature review.\nConclusions: These two female identical twins were the first reported cases of isolated SRNS caused by <i>SGPL1</i> variants. Almost all homozygous and compound heterozygous variants of <i>SGPL1</i> had extra-renal manifestations, but compound heterozygous variants in the intron of <i>SGPL1</i> may have no obvious extra-renal manifestations. Additionally, a negative genetic testing result does not completely rule out genetic SRNS because the Human Gene Mutation Database or ClinVar is constantly being updated.","variants":[{"Name":"NM_003901.4(SGPL1):c.261+1G>A","Chromosome":"10","Start":"70851211","Stop":"70851211","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":424408,"rule_based_match":true,"evidence_text":"c.261 + 1G > A","llm_judgment":"PRESENT","evidence":"c.261 + 1G > A","abstract_start":989,"abstract_end":1003},{"Name":"NM_003901.4(SGPL1):c.1298+6T>C","Chromosome":"10","Start":"70873595","Stop":"70873595","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2742309,"rule_based_match":true,"evidence_text":"c.1298+6T>C","llm_judgment":"PRESENT","evidence":"c.1298 + 6T > C","abstract_start":1017,"abstract_end":1032}]}
{"pmid":"25263169","title":"Identification of TBX5 mutations in a series of 94 patients with Tetralogy of Fallot.","abstract":"Tetralogy of Fallot (TOF) (OMIM #187500) is the most frequent conotruncal congenital heart defect (CHD) with a range of intra- and extracardiac phenotypes. TBX5 is a transcription factor with well-defined roles in heart and forelimb development, and mutations in TBX5 are associated with Holt-Oram syndrome (HOS) (OMIM#142900). Here we report on the screening of 94 TOF patients for mutations in TBX5, NKX2.5 and GATA4 genes. We identified two heterozygous mutations in TBX5. One mutation was detected in a Moroccan patient with TOF, a large ostium secundum atrial septal defect and complete atrioventricular block, and features of HOS including bilateral triphalangeal thumbs and fifth finger clinodactyly. This patient carried a previously described de novo, stop codon mutation (p.R279X) located in exon 8 causing a premature truncated protein. In a second patient from Italy with TOF, ostium secundum atrial septal defect and progressive arrhythmic changes on ECG, we identified a maternally inherited novel mutation in exon 9, which caused a substitution of a serine with a leucine at amino acid position 372 (p.S372L, c.1115C>T). The mother's clinical evaluation demonstrated frequent ventricular extrasystoles and an atrial septal aneurysm. Physical examination and radiographs of the hands showed no apparent skeletal defects in either child or mother. Molecular evaluation of the p.S372L mutation demonstrated a gain-of-function phenotype. We also review the literature on the co-occurrence of TOF and HOS, highlighting its relevance. This is the first systematic screening for TBX5 mutations in TOF patients which detected mutations in two of 94 (2.1%) patients.","variants":[{"Name":"NM_181486.4(TBX5):c.1115C>T (p.Ser372Leu)","Chromosome":"12","Start":"114355974","Stop":"114355974","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":461851,"rule_based_match":true,"evidence_text":"c.1115C>T","llm_judgment":"PRESENT","evidence":"c.1115C>T","abstract_start":1124,"abstract_end":1133}]}
{"pmid":"22906430","title":"Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis.","abstract":"BACKGROUND: Pachydermoperiostosis (PDP) is a rare genetic disorder characterized by 3 major symptoms: pachydermia including cutis verticis gyrata (CVG), periostosis, and finger clubbing. Recently, a homozygous mutation in the gene HPGD, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), was found to be associated with PDP. However, mutations in HPGD have not been identified in Japanese PDP patients.\nOBJECTIVE: We aimed to identify a novel responsible gene for PDP using whole exome sequencing by next-generation DNA sequencer (NGS).\nMETHODS: Five patients, including 2 patient-parent trios were enrolled in this study. Entire coding regions were sequenced by NGS to identify candidate mutations associated with PDP. The candidate mutations were subsequently sequenced using the Sanger method. To determine clinical characteristics, we analyzed histological samples, as well as serum and urinary prostaglandin E2 (PGE2) levels for each of the 5 PDP patients, and 1 additional patient with idiopathic CVG.\nRESULTS: From initial analyses of whole exome sequencing data, we identified mutations in the solute carrier organic anion transporter family, member 2A1 (SLCO2A1) gene, encoding prostaglandin transporter, in 3 of the PDP patients. Follow-up Sanger sequencing showed 5 different SLCO2A1 mutations (c.940+1G>A, p.E427_P430del, p.G104*, p.T347I, p.Q556H) in 4 unrelated PDP patients. In addition, the splice-site mutation c.940+1G>A identified in 3 of 4 PDP patients was determined to be a founder mutation in the Japanese population. Furthermore, it is likely that the combination of these SLCO2A1 mutations in PDP patients is also associated with disease severity.\nCONCLUSION: We found that SLCO2A1 is a novel gene responsible for PDP. Although the SLCO2A1 gene is only the second gene discovered to be associated with PDP, it is likely to be a major cause of PDP in the Japanese population.","variants":[{"Name":"NM_005630.3(SLCO2A1):c.940+1G>A","Chromosome":"3","Start":"133948892","Stop":"133948892","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227251,"rule_based_match":true,"evidence_text":"c.940+1G>A","llm_judgment":"PRESENT","evidence":"c.940+1G>A","abstract_start":1318,"abstract_end":1328}]}
{"pmid":"30927757","title":"Fructose-1,6-bisphosphatase deficiency presented with complex febrile convulsion.","abstract":"Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare inborn error of metabolism affecting gluconeogenesis caused by FBP1 gene mutations. It could be more fatal to infants and children when glycogen reserves are insufficient. A 4-year-old girl was admitted with complex febrile convulsion. Initial laboratory results showed hypoglycemia, metabolic acidosis, and hyperlactatemia. Plasma amino acid and urine organic acid analyses showed increased levels of alanine and tricarboxylic acid cycle intermediates. However, she had similar clinical features, including confusion under severe hypoglycemia, two additional times over 6 months. Correct diagnosis could not be made because of nonspecific symptoms, and mitochondrial disorder was initially suspected. Clinical exome sequencing was performed, and compound heterozygous mutations of c.960_961insG and c.490G>A (p. Ser321ValfsTer13 and p. Gly164Ser) in the FBP1 gene were identified. This is the first Korean pediatric case of FBPase deficiency that initially presented with neurologic clinical features. Despite its very low prevalence in Far-East Asian countries, FBPase deficiency should be considered in children with repeated clinical features of metabolic acidosis with hypoglycemia.","variants":[{"Name":"NM_000507.4(FBP1):c.960_961insG (p.Ser321fs)","Chromosome":"9","Start":"94603437","Stop":"94603438","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":15906,"rule_based_match":true,"evidence_text":"c.960_961insG","llm_judgment":"PRESENT","evidence":"c.960_961insG","abstract_start":840,"abstract_end":853}]}
{"pmid":"36305450","title":"Three Afghani siblings with a novel homozygous variant and further delineation of the clinical features of METTL5 related intellectual disability syndrome.","abstract":"BACKGROUND: METTL5 gene is one of the members of methyltransferase superfamily and biallelic variants cause intellectual disability syndrome (ID) with microcephaly. This article reports three new cases with METTL5 related ID syndrome in a consanguineous family.\nCASE: Afghanistan descent family was affected by a novel homozygous c.362A &gt; G (p.Asp121Gly) METTL5 gene variant. This variant is predicted to be `pathogenic` by multiple in-silico tools. Patients had dysmorphic and neurodevelopmental features including intellectual disability, microcephaly, poor/absent speech, delayed walking, aggressive behavior, large/posteriorly rotated ears, broad nasal base and short stature, which seem to be the cardinal findings of the designated syndrome.\nCONCLUSIONS: While the data reported in these individuals indicate characteristic clinical features of METTL5 related ID syndrome, further investigations and study of additional cases are needed to improve the understanding of disease pathogenesis, and management.","variants":[{"Name":"NM_014168.4(METTL5):c.362A>G (p.Asp121Gly)","Chromosome":"2","Start":"169821136","Stop":"169821136","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":971561,"rule_based_match":false,"evidence_text":"c.362A > G (p.Asp121Gly)","llm_judgment":"PRESENT","evidence":"p.Asp121Gly","abstract_start":345,"abstract_end":356}]}
{"pmid":"29037559","title":"Noninvasive prenatal diagnosis for X-linked disease by maternal plasma sequencing in a family of Hemophilia B.","abstract":"OBJECTIVE: To apply a Hidden Markov Model to test Hemophilia B in a fetus by maternal plasma sequencing only employing proband and maternal haplotypes.\nCASE REPORT: A family at risk for Hemophilia B was recruited in this study. We performed genetic diagnosis on the proband using our targeted capture system (containing F9 gene coding region, highly heterozygous SNPs and a 13-kb chromosome Y specific region), and revealed a causative F9 gene mutation (c.190T>C, p.Cys64Arg). Maternal plasma cell-free DNA obtained at 8 weeks of gestation was targeted-captured and sequenced using the customized system. The fetus inherited the F9 (c.190T>C, p.Cys64Arg) mutation according to the Hidden Markov Model. The mother continued the pregnancy.\nCONCLUSIONS: This study is the first report of a haplotype-based approach in NIPD of Hemophilia B. With further evaluation, this method might be useful for NIPD of Hemophilia B and for other X-linked single-gene disorders.","variants":[{"Name":"NM_000133.4(F9):c.190T>C (p.Cys64Arg)","Chromosome":"X","Start":"139537111","Stop":"139537111","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":800218,"rule_based_match":true,"evidence_text":"c.190T>C (p.Cys64Arg)","llm_judgment":"PRESENT","evidence":"p.Cys64Arg","abstract_start":464,"abstract_end":474}]}
{"pmid":"19863562","title":"MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever.","abstract":"Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder with more than 60 disease-associated mutations in the responsible gene, MEFV. In the present study, we determined 15 MEFV mutations in Iranian Azeri Turkish FMF patients. Five hundred and twenty-four unrelated patients were tested for 15 known mutations in the MEFV gene using amplification refractory mutation system-polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism methods. Thirty-five different genotypes were characterized among the studied patients. Of the alleles investigated, the most common mutation was p.M694V (42.4%), followed by p.V726A (17%), p.E148Q (16.2%), and p.M680I (c.2040G>C) (15.2%). The p.R761H mutation (4.7%) was found to be the most frequent among the rare mutations. The mutations p.M680I (c.2040G>A), p.I692del, p.M694del and p.K695R were not found in this cohort. The remaining mutations account for 7.7% of the identifiable mutations. Five different types of complex alleles were also identified. The results show the diversity and the frequency of the mutations in the Iranian Azeri Turkish FMF patients. The p.R761H mutation is rather prevalent in Azeri Turks; therefore, it should be included in the routine molecular diagnosis of FMF patients from this ethnic group.","variants":[{"Name":"NM_000243.3(MEFV):c.2040G>C (p.Met680Ile)","Chromosome":"16","Start":"3243447","Stop":"3243447","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":45169,"rule_based_match":true,"evidence_text":"p.M680I (c.2040G>C)","llm_judgment":"PRESENT","evidence":"p.M680I (c.2040G>C)","abstract_start":713,"abstract_end":732},{"Name":"NM_000243.3(MEFV):c.2282G>A (p.Arg761His)","Chromosome":"16","Start":"3243205","Stop":"3243205","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17588,"rule_based_match":false,"evidence_text":"p.R761H","llm_judgment":"PRESENT","evidence":"p.R761H","abstract_start":746,"abstract_end":753}]}
{"pmid":"18628482","title":"Penetrance analysis of the PALB2 c.1592delT founder mutation.","abstract":"PURPOSE: PALB2 is a recently identified breast cancer susceptibility gene. We have previously identified in the Finnish population a PALB2 c.1592delT founder truncation mutation that is associated with an increased risk of breast cancer. In the present study, we wanted to assess in more detail the increased risk (hazard ratio, HR) and the age-specific cumulative risk (penetrance) of c.1592delT with regard to susceptibility to breast and other forms of cancer.\nEXPERIMENTAL DESIGN: Modified segregation analyses fitted under maximum likelihood theory were used to estimate age-specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history.\nRESULTS: We found a substantially increased risk of breast cancer [HR, 6.1; 95% confidence interval (95% CI), 2.2-17.2; P = 0.01] equivalent to a 40% (95% CI, 17-77) breast cancer risk by age 70 years, comparable to that for carriers of mutations in BRCA2. We found marginal evidence (P = 0.06) that the HR for breast cancer decreased with age by 4.2% per year (95% CI, 0.2-8.1), from 7.5-fold at age 30 years to 2.0-fold at age 60 years.\nCONCLUSIONS: Our results suggest that it may be appropriate to offer PALB2 c.1592delT mutation testing to Finnish women with breast cancer, especially those with an early age at onset or a family history of breast or related cancers, and to offer carriers the option of participation in extended disease surveillance programs.","variants":[{"Name":"NM_024675.4(PALB2):c.1592del (p.Leu531fs)","Chromosome":"16","Start":"23634954","Stop":"23634954","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":132119,"rule_based_match":true,"evidence_text":"PALB2 c.1592delT","llm_judgment":"PRESENT","evidence":"PALB2 c.1592delT","abstract_start":133,"abstract_end":149}]}
{"pmid":"17686168","title":"A novel DSPP mutation is associated with type II dentinogenesis imperfecta in a Chinese family.","abstract":"BACKGROUND: Hereditary defects of tooth dentin are classified into two main groups: dentin dysplasia (DD) (types I and II) and dentinogenesis imperfecta (DGI) (types I, II, and III). Type II DGI is one of the most common tooth defects with an autosomal dominant mode of inheritance. One disease-causing gene, the dentin sialophosphoprotein (DSPP) gene, has been reported for type II DGI.\nMETHODS: In this study, we characterized a four-generation Chinese family with type II DGI that consists of 18 living family members, including 8 affected individuals. Linkage analysis with polymorphic markers D4S1534 and D4S414 that span the DSPP gene showed that the family is linked to DSPP. All five exons and exon-intron boundaries of DSPP were sequenced in members of type II DGI family.\nRESULTS: Direct DNA sequence analysis identified a novel mutation (c.49C-->T, p.Pro17Ser) in exon 1 of the DSPP gene. The mutation spot, the Pro17 residue, is the second amino acid of the mature DSP protein, and highly conserved during evolution. The mutation was identified in all affected individuals, but not in normal family members and 100 controls.\nCONCLUSION: These results suggest that mutation p.Pro17Ser causes type II DGI in the Chinese family. This study identifies a novel mutation in the DSPP gene, and expands the spectrum of mutations that cause DGI.","variants":[{"Name":"NM_014208.3(DSPP):c.49C>T (p.Pro17Ser)","Chromosome":"4","Start":"87610957","Stop":"87610957","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1491208,"rule_based_match":false,"evidence_text":"c.49C-->T, p.Pro17Ser","llm_judgment":"PRESENT","evidence":"c.49C-->T, p.Pro17Ser","abstract_start":849,"abstract_end":870}]}
{"pmid":"23392294","title":"Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS.","abstract":"Congenital melanocytic nevi (CMN) can be associated with neurological abnormalities and an increased risk of melanoma. Mutations in NRAS, BRAF, and Tp53 have been described in individual CMN samples; however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesized that a single postzygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and nonmelanocytic central nervous system (CNS) lesions. From 15 patients, 55 samples with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12 out of 15 patients, but were absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In 10 patients, the mutation was consistently c.181C>A, p.Q61K, and in 2 patients c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from 5 patients were mutation positive, despite NRAS rarely being reported as mutated in CNS tumors. Loss of heterozygosity was associated with the onset of melanoma in two cases, implying a multistep progression to malignancy. These results suggest that single postzygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases.","variants":[{"Name":"NM_002524.5(NRAS):c.182A>G (p.Gln61Arg)","Chromosome":"1","Start":"114713908","Stop":"114713908","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":28939,"rule_based_match":true,"evidence_text":"c.182A>G, p.Q61R","llm_judgment":"PRESENT","evidence":"c.182A>G, p.Q61R","abstract_start":994,"abstract_end":1010},{"Name":"NM_002524.5(NRAS):c.181C>A (p.Gln61Lys)","Chromosome":"1","Start":"114713909","Stop":"114713909","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":83949,"rule_based_match":true,"evidence_text":"c.181C>A, p.Q61K","llm_judgment":"PRESENT","evidence":"c.181C>A, p.Q61K","abstract_start":958,"abstract_end":974}]}
{"pmid":"35714441","title":"Novel DLX3 variant identified in a family with tricho-dento-osseous syndrome.","abstract":"OBJECTIVES: To identify DLX3 variants in a Chinese family with typical clinical manifestations of tricho-dento-osseous syndrome (TDO).\nDESIGN: Sanger sequencing was performed to detect DLX3 variants in the TDO family. Three-dimensional laser scanning microscopy, bioinformatic and conformational analyses were employed to explore the phenotypic characterization and the functional impact.\nRESULTS: We identified a novel heterozygous variant in the DLX3 gene (c.534G>C; p.Gln178His). Familial co-segregation verified an autosomal dominant inheritance pattern. Bioinformatic prediction demonstrated the deleterious effects of the variant, and DLX3 structure changes suggested the corresponding functional impairments.\nCONCLUSIONS: We identified a variant in the DLX3 gene in an integrated family of Han nationality for the first time. This study expands the variant spectrum of DLX3 and phenotype spectrum of TDO syndrome.","variants":[{"Name":"NM_005220.3(DLX3):c.534G>C (p.Gln178His)","Chromosome":"17","Start":"49991847","Stop":"49991847","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1332570,"rule_based_match":true,"evidence_text":"c.534G>C (p.Gln178His)","llm_judgment":"PRESENT","evidence":"p.Gln178His","abstract_start":469,"abstract_end":480}]}
{"pmid":"24577983","title":"Cobalamin C defect: a patient of late-onset type with homozygous p.R132* mutation.","abstract":"Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is the most frequent inborn error of vitamin B12metabolism. The clinical phenotype includes systemic symptoms and neurological decompensation. Affected patients can be divided into two broad groups, as early-onset and late-onset. We present a Turkish patient who had neurological impairment at the age of four years as presented with late-onset cblC defect. Homozygous c.394C<T; p.R132* mutation in the MMACHC gene was detected. The patient was treated with hydroxocobalamin, betaine and folic acid combination with good clinical and biochemical response.","variants":[{"Name":"NM_015506.3(MMACHC):c.394C>T (p.Arg132Ter)","Chromosome":"1","Start":"45508329","Stop":"45508329","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16462,"rule_based_match":false,"evidence_text":"Homozygous c.394C<T; p.R132* mutation","llm_judgment":"PRESENT","evidence":"Homozygous c.394C<T; p.R132* mutation","abstract_start":426,"abstract_end":463}]}
{"pmid":"25252036","title":"GALNS mutations in Indian patients with mucopolysaccharidosis IVA.","abstract":"Mucopolysaccharidosis IV A (Morquio syndrome A, MPS IVA) is a lysosomal storage disease caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS). The mutation spectrum in this condition is yet to be determined in Indians. We aimed to analyze the mutations in the GALNS gene in Asian Indians with MPS IVA. All the exons and the adjacent intronic regions of the gene were amplified and sequenced in sixty-eight unrelated Indian families. We identified 136 mutant alleles comprising of 40 different mutations. We report twenty-two novel mutations that comprise of seventeen missense (p.Asn32Thr, p.Leu36Arg, p.Pro52Leu, p.Pro77Ser, p.Cys79Arg, p.His142Pro, p.Tyr191Asp, p.Asn204Thr, p.Gly188Ser, p.Phe216Ser, p.Trp230Cys, p.Ala291Ser, p.Gly317Arg, p.His329Pro, p.Arg386Ser, p.Glu450Gly, p.Cys501Ser), three splice-site variants (c.120+1G>C, c.1003-3C>G, c.1139+1G>A), one nonsense mutation (p.Gln414*) and one frameshift mutation (p.Pro420Leufs*440). Eighteen mutations have been reported earlier. Among these p.Ser287Leu (8.82%), p.Phe216Ser (7.35%), p.Asn32Thr (6.61%) and p.Ala291Ser (5.88%) were the most frequent mutations in Indian patients but were rare in the mutational profiles reported in other populations. These results indicate that the Indian patients may have a distinct mutation spectrum compared to those of other populations. Mutant alleles in exon 1, 7 and 8 accounted for 44.8% of the mutations, and sequencing of these exons initially may be a cost-effective approach in Asian Indian patients. This is the largest study on molecular analysis of patients with MPS IVA reported in the literature, and the first report from India.","variants":[{"Name":"NM_000512.5(GALNS):c.647T>C (p.Phe216Ser)","Chromosome":"16","Start":"88835836","Stop":"88835836","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1036290,"rule_based_match":false,"evidence_text":"c.647T>C (p.Phe216Ser)","llm_judgment":"PRESENT","evidence":"p.Phe216Ser","abstract_start":706,"abstract_end":717},{"Name":"NM_000512.5(GALNS):c.235T>C (p.Cys79Arg)","Chromosome":"16","Start":"88842715","Stop":"88842715","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":861191,"rule_based_match":false,"evidence_text":"p.Cys79Arg","llm_judgment":"PRESENT","evidence":"p.Cys79Arg","abstract_start":642,"abstract_end":652},{"Name":"NM_000512.5(GALNS):c.611A>C (p.Asn204Thr)","Chromosome":"16","Start":"88836223","Stop":"88836223","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1036296,"rule_based_match":false,"evidence_text":"p.Asn204Thr","llm_judgment":"PRESENT","evidence":"p.Asn204Thr","abstract_start":680,"abstract_end":691},{"Name":"NM_000512.5(GALNS):c.95A>C (p.Asn32Thr)","Chromosome":"16","Start":"88856783","Stop":"88856783","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1036422,"rule_based_match":false,"evidence_text":"p.Asn32Thr","llm_judgment":"PRESENT","evidence":"p.Asn32Thr","abstract_start":594,"abstract_end":604},{"Name":"NM_000512.5(GALNS):c.571T>G (p.Tyr191Asp)","Chromosome":"16","Start":"88836263","Stop":"88836263","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1036301,"rule_based_match":false,"evidence_text":"p.Tyr191Asp","llm_judgment":"PRESENT","evidence":"p.Tyr191Asp","abstract_start":667,"abstract_end":678},{"Name":"NM_000512.5(GALNS):c.986A>C (p.His329Pro)","Chromosome":"16","Start":"88832014","Stop":"88832014","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1032980,"rule_based_match":false,"evidence_text":"p.His329Pro","llm_judgment":"PRESENT","evidence":"p.His329Pro","abstract_start":758,"abstract_end":769},{"Name":"NM_000512.5(GALNS):c.1156C>A (p.Arg386Ser)","Chromosome":"16","Start":"88824853","Stop":"88824853","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1036181,"rule_based_match":false,"evidence_text":"p.Arg386Ser","llm_judgment":"PRESENT","evidence":"p.Arg386Ser","abstract_start":771,"abstract_end":782},{"Name":"NM_000512.5(GALNS):c.860C>T (p.Ser287Leu)","Chromosome":"16","Start":"88835251","Stop":"88835251","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260136,"rule_based_match":false,"evidence_text":"p.Ser287Leu","llm_judgment":"PRESENT","evidence":"p.Ser287Leu","abstract_start":1020,"abstract_end":1031},{"Name":"NM_000512.5(GALNS):c.1003-3C>G","Chromosome":"16","Start":"88826841","Stop":"88826841","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1036209,"rule_based_match":true,"evidence_text":"c.1003-3C>G","llm_judgment":"PRESENT","evidence":"c.1003-3C>G","abstract_start":851,"abstract_end":862},{"Name":"NM_000512.5(GALNS):c.425A>C (p.His142Pro)","Chromosome":"16","Start":"88837763","Stop":"88837763","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1036339,"rule_based_match":false,"evidence_text":"p.His142Pro","llm_judgment":"PRESENT","evidence":"p.His142Pro","abstract_start":654,"abstract_end":665},{"Name":"NM_000512.5(GALNS):c.120+1G>C","Chromosome":"16","Start":"88856757","Stop":"88856757","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":852679,"rule_based_match":true,"evidence_text":"c.120+1G>C","llm_judgment":"PRESENT","evidence":"c.120+1G>C","abstract_start":839,"abstract_end":849},{"Name":"NM_000512.5(GALNS):c.871G>T (p.Ala291Ser)","Chromosome":"16","Start":"88835240","Stop":"88835240","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":375752,"rule_based_match":false,"evidence_text":"p.Ala291Ser","llm_judgment":"PRESENT","evidence":"p.Ala291Ser","abstract_start":732,"abstract_end":743},{"Name":"NM_000512.5(GALNS):c.107T>G (p.Leu36Arg)","Chromosome":"16","Start":"88856771","Stop":"88856771","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":530388,"rule_based_match":false,"evidence_text":"p.Leu36Arg","llm_judgment":"PRESENT","evidence":"p.Leu36Arg","abstract_start":606,"abstract_end":616},{"Name":"NM_000512.5(GALNS):c.1502G>C (p.Cys501Ser)","Chromosome":"16","Start":"88814506","Stop":"88814506","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1036118,"rule_based_match":false,"evidence_text":"p.Cys501Ser","llm_judgment":"PRESENT","evidence":"p.Cys501Ser","abstract_start":797,"abstract_end":808},{"Name":"NM_000512.5(GALNS):c.1139+1G>A","Chromosome":"16","Start":"88826701","Stop":"88826701","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":940377,"rule_based_match":true,"evidence_text":"c.1139+1G>A","llm_judgment":"PRESENT","evidence":"c.1139+1G>A","abstract_start":864,"abstract_end":875},{"Name":"NM_000512.5(GALNS):c.229C>T (p.Pro77Ser)","Chromosome":"16","Start":"88842721","Stop":"88842721","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1036393,"rule_based_match":false,"evidence_text":"p.Pro77Ser","llm_judgment":"PRESENT","evidence":"p.Pro77Ser","abstract_start":630,"abstract_end":640},{"Name":"NM_000512.5(GALNS):c.1349A>G (p.Glu450Gly)","Chromosome":"16","Start":"88822604","Stop":"88822604","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1036146,"rule_based_match":false,"evidence_text":"p.Glu450Gly","llm_judgment":"PRESENT","evidence":"p.Glu450Gly","abstract_start":784,"abstract_end":795},{"Name":"NM_000512.5(GALNS):c.155C>T (p.Pro52Leu)","Chromosome":"16","Start":"88842795","Stop":"88842795","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1036402,"rule_based_match":false,"evidence_text":"p.Pro52Leu","llm_judgment":"PRESENT","evidence":"p.Pro52Leu","abstract_start":618,"abstract_end":628},{"Name":"NM_000512.5(GALNS):c.690G>T (p.Trp230Cys)","Chromosome":"16","Start":"88835793","Stop":"88835793","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1036283,"rule_based_match":false,"evidence_text":"p.Trp230Cys","llm_judgment":"PRESENT","evidence":"p.Trp230Cys","abstract_start":719,"abstract_end":730}]}
{"pmid":"16786517","title":"A common mutation in the CBS gene explains a high incidence of homocystinuria in the Qatari population.","abstract":"We report the results of a study carried out to delineate genetic and epidemiological aspects of homocystinuria in the Qatari population. Sixty-four patients with homocystinuria (37 males, 27 females, age 1 to 29 years) from 31 nuclear families were ascertained over a period of more than four years. The incidence of homocystinuria in Qatar was calculated to be > or =1:3000, the highest in the world known so far. All patients in whom data were available were vitamin B6-nonresponsive. Molecular studies were performed in all patients. All 53 patients from tribe M and all three patients from tribe K were homozygous for the mutation c.1006C>T (p.R336C) in the CBS gene, with an additional seven patients resulting from mixed marriages between tribe M and tribe K. A single patient from tribe S was homozygous for mutation c.700G>A (p.D234N) in the CBS gene. Both mutations have been previously reported but involve hypermutable CpG dinculeotides and may be recurrent mutations in the Qatari population. The results of this study illustrate a strong founder effect causing a high prevalence of an autosomal recessive disease in a highly consanguineous Arabian population. Molecular neonatal screening may be suitable for early detection of homocystinuria in this population.","variants":[{"Name":"NM_000071.3(CBS):c.700G>A (p.Asp234Asn)","Chromosome":"21","Start":"43065239","Stop":"43065239","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":210429,"rule_based_match":true,"evidence_text":"c.700G>A (p.D234N)","llm_judgment":"PRESENT","evidence":"c.700G>A (p.D234N)","abstract_start":825,"abstract_end":843},{"Name":"NM_000071.3(CBS):c.1006C>T (p.Arg336Cys)","Chromosome":"21","Start":"43062344","Stop":"43062344","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":98334,"rule_based_match":true,"evidence_text":"c.1006C>T (p.R336C)","llm_judgment":"PRESENT","evidence":"c.1006C>T (p.R336C)","abstract_start":636,"abstract_end":655}]}
{"pmid":"26771056","title":"A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency.","abstract":"Primary ovarian insufficiency (POI) results in an early loss of ovarian function, and remains idiopathic in about 80% of cases. Here, we have performed a complete genetic study of a consanguineous family with two POI cases. Linkage analysis and homozygosity mapping identified 12 homozygous regions with linkage, totalling 84 Mb. Whole-exome sequencing of the two patients and a non-affected sister allowed us to detect a homozygous causal variant in the MCM9 gene. The variant c.1483G>T [p.E495*], confirmed using Sanger sequencing, introduced a premature stop codon in coding exon 8 and is expected to lead to the loss of a functional protein. MCM9 belongs to a complex required for DNA repair by homologous recombination, and its impairment in mouse is known to induce meiotic recombination defects and oocyte degeneration. A previous study recently described two consanguineous families in which homozygous mutations of MCM9 were responsible for POI and short stature. Interestingly, the affected sisters in the family described here had a normal height. Altogether, our results provide the confirmation of the implication of MCM9 variants in POI and expand their phenotypic spectrum.","variants":[{"Name":"NM_017696.3(MCM9):c.1483G>T (p.Glu495Ter)","Chromosome":"6","Start":"118829093","Stop":"118829093","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":404862,"rule_based_match":true,"evidence_text":"c.1483G>T [p.E495*]","llm_judgment":"PRESENT","evidence":"c.1483G>T [p.E495*]","abstract_start":478,"abstract_end":497}]}
{"pmid":"33689014","title":"A missense mutation in IFT74, encoding for an essential component for intraflagellar transport of Tubulin, causes asthenozoospermia and male infertility without clinical signs of Bardet-Biedl syndrome.","abstract":"Cilia and flagella are formed around an evolutionary conserved microtubule-based axoneme and are required for fluid and mucus clearance, tissue homeostasis, cell differentiation and movement. The formation and maintenance of cilia and flagella require bidirectional transit of proteins along the axonemal microtubules, a process called intraflagellar transport (IFT). In humans, IFT defects contribute to a large group of systemic diseases, called ciliopathies, which often display overlapping phenotypes. By performing exome sequencing of a cohort of 167 non-syndromic infertile men displaying multiple morphological abnormalities of the sperm flagellum (MMAF) we identified two unrelated patients carrying a homozygous missense variant adjacent to a splice donor consensus site of IFT74 (c.256G > A;p.Gly86Ser). IFT74 encodes for a core component of the IFT machinery that is essential for the anterograde transport of tubulin. We demonstrate that this missense variant affects IFT74 mRNA splicing and induces the production of at least two distinct mutant proteins with abnormal subcellular localization along the sperm flagellum. Importantly, while IFT74 deficiency was previously implicated in two cases of Bardet-Biedl syndrome, a pleiotropic ciliopathy with variable expressivity, our data indicate that this missense mutation only results in primary male infertility due to MMAF, with no other clinical features. Taken together, our data indicate that the nature of the mutation adds a level of complexity to the clinical manifestations of ciliary dysfunction, thus contributing to the expanding phenotypical spectrum of ciliopathies.","variants":[{"Name":"NM_025103.4(IFT74):c.256G>A (p.Gly86Ser)","Chromosome":"9","Start":"26978263","Stop":"26978263","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":984721,"rule_based_match":true,"evidence_text":"c.256G > A;p.Gly86Ser","llm_judgment":"PRESENT","evidence":"c.256G > A;p.Gly86Ser","abstract_start":790,"abstract_end":811}]}
{"pmid":"23395478","title":"Mutations in MED12 cause X-linked Ohdo syndrome.","abstract":"Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome.","variants":[{"Name":"NM_005120.3(MED12):c.3443G>A (p.Arg1148His)","Chromosome":"X","Start":"71128686","Stop":"71128686","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":59420,"rule_based_match":true,"evidence_text":"c.3443G>A [p.Arg1148His]","llm_judgment":"PRESENT","evidence":"c.3443G>A [p.Arg1148His]","abstract_start":568,"abstract_end":592},{"Name":"NM_005120.3(MED12):c.3493T>C (p.Ser1165Pro)","Chromosome":"X","Start":"71129131","Stop":"71129131","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":59421,"rule_based_match":true,"evidence_text":"c.3493T>C (p.Ser1165Pro)","llm_judgment":"PRESENT","evidence":"p.Ser1165Pro","abstract_start":607,"abstract_end":619},{"Name":"NM_005120.3(MED12):c.5185C>A (p.His1729Asn)","Chromosome":"X","Start":"71136440","Stop":"71136440","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":59422,"rule_based_match":true,"evidence_text":"c.5185C>A (p.His1729Asn)","llm_judgment":"PRESENT","evidence":"p.His1729Asn","abstract_start":823,"abstract_end":835}]}
{"pmid":"35368666","title":"Case Report: A Novel ARMC5 Germline Mutation in a Patient with Primary Bilateral Macronodular Adrenal Hyperplasia and Hypogammaglobulinemia.","abstract":"Primary bilateral macronodular adrenal hyperplasia (PBMAH) represents an uncommon cause of endogenous hypercortisolism. Since the first description in 2003 in a French cohort, many papers have been published describing families as well as isolated individuals affected with this condition, who were found to harbor a genetic variants in the armadillo-repeat containing 5 (<i>ARMC5</i>) gene, a tumor-suppressor gene with a still unknown role in the disease pathogenesis. Studies in rat models suggested a possible link between <i>ARMC5</i> damaging variants and the impairment of the cell-mediated immune response, leading to a higher susceptibility to bacterial and viral infections. To our knowledge, we describe the first case of a patient affected by PBMAH with hypogammaglobulinemia and monthly relapsing human herpes simplex viral infections. After the detection of subclinical Cushing's syndrome, a unilateral laparoscopic adrenalectomy was performed. Subsequent genetic analysis of <i>ARMC5</i> performed on genomic DNA extracted both from the adrenal tissue and lymphocytes revealed a novel somatic frameshift variant in exon 1 (c.231_265del:p.A77Afs*13) and a novel germline variant in exon 6 (c.2436del: p. C813Vfs*104). After adrenalectomy, we observed a significant improvement of clinical features concerning both hypercortisolism and relapsing viral infections, thus suggesting a possible adjuvant role of hypercortisolism on a genetic-based derangement of the immune system.","variants":[{"Name":"NM_001105247.2(ARMC5):c.2436del (p.Cys813fs)","Chromosome":"16","Start":"31466513","Stop":"31466513","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":1685962,"rule_based_match":true,"evidence_text":"c.2436del: p. C813Vfs*104","llm_judgment":"PRESENT","evidence":"c.2436del: p. C813Vfs*104","abstract_start":1204,"abstract_end":1229}]}
{"pmid":"24203976","title":"Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm.","abstract":"BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects of the axoneme underlie the disease, which is characterised by chronic respiratory symptoms and obstructive lung disease, infertility and body axis laterality defects. We applied a next-generation sequencing approach to identify the gene responsible for this phenotype in two consanguineous families.\nMETHODS AND RESULTS: Data from whole-exome sequencing in a consanguineous Turkish family, and whole-genome sequencing in the obligate carrier parents of a consanguineous Pakistani family was combined to identify homozygous loss-of-function mutations in ARMC4, segregating in all five affected individuals from both families. Both families carried nonsense mutations within the highly conserved armadillo repeat region of ARMC4: c.2675C>A; pSer892* and c.1972G>T; p.Glu658*. A deficiency of ARMC4 protein was seen in patient's respiratory cilia accompanied by loss of the distal outer dynein arm motors responsible for generating ciliary beating, giving rise to cilia immotility. ARMC4 gene expression is upregulated during ciliogenesis, and we found a predicted interaction with the outer dynein arm protein DNAI2, mutations in which also cause PCD.\nCONCLUSIONS: We report the first use of whole-genome sequencing to identify gene mutations causing PCD. Loss-of-function mutations in ARMC4 cause PCD with situs inversus and cilia immotility, associated with a loss of the distal outer (but not inner) dynein arms. This addition of ARMC4 to the list of genes associated with ciliary outer dynein arm defects expands our understanding of the complexities of PCD genetics.","variants":[{"Name":"NM_018076.5(ODAD2):c.2675C>A (p.Ser892Ter)","Chromosome":"10","Start":"27862558","Stop":"27862558","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":76953,"rule_based_match":true,"evidence_text":"c.2675C>A; pSer892*","llm_judgment":"PRESENT","evidence":"c.2675C>A; pSer892*","abstract_start":902,"abstract_end":921},{"Name":"NM_018076.5(ODAD2):c.1972G>T (p.Glu658Ter)","Chromosome":"10","Start":"27940577","Stop":"27940577","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":106835,"rule_based_match":true,"evidence_text":"c.1972G>T; p.Glu658*","llm_judgment":"PRESENT","evidence":"c.1972G>T; p.Glu658*","abstract_start":926,"abstract_end":946}]}
{"pmid":"32742360","title":"Clinical diagnosis, treatment and screening of the VHL gene in three von Hippel-Lindau disease pedigrees.","abstract":"The present study aimed to investigate the clinical characteristics of von Hippel-Lindau (VHL) disease and the clinical significance of VHL gene detection. The clinical materials of patients with VHL disease were collected from 3 different families between May 1985 and October 2017. A systematic pedigree study and VHL gene detection at the germline level were performed together with a literature review. Of the 22 patients from 3 VHL pedigrees, 10 exhibited VHL gene mutations (3 genotypes) at the germline level. The genotypes of pedigree were VHL-p.R161Q (c.482G>A), VHL-p.N78S (c.233A>G), and VHL-p.R167Q (c.500G>A). During the follow-up period, the symptoms were stable in 10 patients, including 2 cases of central nervous system hemangioblastomas (CNS-HB), 3 cases of bilateral multiple renal cell carcinoma (RCC) and 5 cases of adrenal pheochromocytoma without local recurrence or distant metastasis. Patients with p.R161Q and p.N78S were not associated with CNS-HB, which was different from the clinical phenotype of previously reported families. RCC were Fuhrman II grade, which was consistent with the previous study. The results of the present study indicated that the standardization of early diagnosis and the improvement of long-term efficacy may be achieved by combining clinical screening and VHL gene detection.","variants":[{"Name":"NM_000551.4(VHL):c.233A>G (p.Asn78Ser)","Chromosome":"3","Start":"10142080","Stop":"10142080","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":99233,"rule_based_match":true,"evidence_text":"c.233A>G","llm_judgment":"PRESENT","evidence":"c.233A>G","abstract_start":584,"abstract_end":592}]}
{"pmid":"31978608","title":"Distal motor neuropathy associated with novel EMILIN1 mutation.","abstract":"Elastin microfibril interface-located proteins (EMILINs) are extracellular matrix glycoproteins implicated in elastogenesis and cell proliferation. Recently, a missense mutation in the EMILIN1 gene has been associated with autosomal dominant connective tissue disorder and motor-sensory neuropathy in a single family. We identified by whole exome sequencing a novel heterozygous EMILIN1 mutation c.748C>T [p.R250C] located in the coiled coil forming region of the protein, in four affected members of an autosomal dominant family presenting a distal motor neuropathy phenotype. In affected patient a sensory nerve biopsy showed slight and unspecific changes in the number and morphology of myelinated fibers. Immunofluorescence study of a motor nerve within a muscle biopsy documented the presence of EMILIN-1 in nerve structures. Skin section and skin derived fibroblasts displayed a reduced extracellular deposition of EMILIN-1 protein with a disorganized network of poorly ramified fibers in comparison with controls. Downregulation of emilin1a in zebrafish displayed developmental delay, locomotion defects, and abnormal axonal arborization from spinal cord motor neurons. The phenotype was complemented by wild-type zebrafish emilin1a, and partially the human wild-type EMILIN1 cRNA, but not by the cRNA harboring the novel c.748C>T [p.R250C]. These data suggest a role of EMILIN-1 in the pathogenesis of diseases affecting the peripheral nervous system.","variants":[{"Name":"NM_007046.4(EMILIN1):c.748C>T (p.Arg250Cys)","Chromosome":"2","Start":"27082319","Stop":"27082319","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1709517,"rule_based_match":true,"evidence_text":"c.748C>T [p.R250C]","llm_judgment":"PRESENT","evidence":"c.748C>T [p.R250C]","abstract_start":396,"abstract_end":414}]}
{"pmid":"33937156","title":"Case Report and Review of the Literature: A New and a Recurrent Variant in the","abstract":"Mitochondriopathies represent a wide spectrum of miscellaneous disorders with multisystem involvement, which are caused by various genetic changes. The establishment of the diagnosis of mitochondriopathy is often challenging. Recently, several mutations of the <i>VARS2</i> gene encoding the mitochondrial valyl-tRNA synthetase were associated with early onset encephalomyopathies or encephalocardiomyopathies with major clinical features such as hypotonia, developmental delay, brain MRI changes, epilepsy, hypertrophic cardiomyopathy, and plasma lactate elevation. However, the correlation between genotype and phenotype still remains unclear. In this paper we present a male Caucasian patient with a recurrent c.1168G>A (p.Ala390Thr) and a new missense biallelic variant c.2758T>C (p.Tyr920His) in the <i>VARS2</i> gene which were detected by whole exome sequencing (WES). VARS2 protein was reduced in the patient's muscle. A resulting defect of oxidative phosphorylation (OXPHOS) was proven by enzymatic assay, western blotting and immunohistochemistry from a homogenate of skeletal muscle tissue. Clinical signs of our patient included hyperlactatemia, hypertrophic cardiomyopathy (HCM) and pulmonary hypertension, which led to early death at the age of 47 days without any other known accompanying signs. The finding of novel variants in the <i>VARS2</i> gene expands the spectrum of known mutations and phenotype presentation. Based on our findings we recommend to consider possible mitochondriopathy and to include the analysis of the <i>VARS2</i> gene in the genetic diagnostic algorithm in cases with early manifesting and rapidly progressing HCM with hyperlactatemia.","variants":[{"Name":"NM_020442.6(VARS2):c.1168G>A (p.Ala390Thr)","Chromosome":"6","Start":"30920091","Stop":"30920091","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":513421,"rule_based_match":true,"evidence_text":"c.1168G>A (p.Ala390Thr)","llm_judgment":"PRESENT","evidence":"c.1168G>A (p.Ala390Thr)","abstract_start":713,"abstract_end":736}]}
{"pmid":"26802438","title":"Adult-onset respiratory insufficiency, scoliosis, and distal joint hyperlaxity in patients with multiminicore disease due to novel Megf10 mutations.","abstract":"INTRODUCTION: Multiminicore disease is a congenital myopathy characterized pathologically by the presence of multiple minicore structures in the sarcoplasm. Mutations in the selenoprotein N1-encoding gene (SEPN1) and ryanodine receptor 1-encoding gene (RYR1) are responsible for half of the reported cases. Mutations in multiple epidermal growth factor-like domains 10-encoding gene (MEGF10) have been identified only recently in a few patients with antenatal to infantile-onset myopathy, with and without minicore pathology.\nMETHODS: We report 2 sisters with adult-onset respiratory insufficiency followed by development of limb weakness. Both had scoliosis, distal joint hyperlaxity, and high-arched feet.\nRESULTS: A biopsy of the right triceps muscle in 1 sister showed multiple minicore structures. She had electromyographic changes of myopathy with fibrillation potentials and myotonic discharges. Next generation sequencing identified novel compound heterozygous missense variants in MEGF10 c.230G>A (p.Arg77Gln) and c.1833T>G (p.Cys611Trp) in both sisters.\nCONCLUSIONS: MEGF10 mutations can cause myopathy with adult-onset respiratory insufficiency. Muscle Nerve, 2016 Muscle Nerve 53: 984-988, 2016.","variants":[{"Name":"NM_001256545.2(MEGF10):c.1833T>G (p.Cys611Trp)","Chromosome":"5","Start":"127433502","Stop":"127433502","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":932600,"rule_based_match":true,"evidence_text":"c.1833T>G (p.Cys611Trp)","llm_judgment":"PRESENT","evidence":"c.1833T>G (p.Cys611Trp)","abstract_start":1023,"abstract_end":1046}]}
{"pmid":"30728682","title":"First Report of Association Between Rare α-Thalassemia Mutation (","abstract":"α-Thalassemia is one of the most common monogenic diseases worldwide. The combination of alpha-chain variants with thalassemia mutations may lead to clinical and hematological characteristics, which is of importance for genetic counseling. The present study describes for the first time a rare α1-globin nonsense mutation, codon 99 (<i>HBA1</i>: c.298A>T) associated with a α<sub>2</sub>-chain variant Hb Fontainebleau (<i>HBA2</i>: c.64G>C) in a family from northern Iran. The case is a 23-year-old man with hypochromic microcytic anemia that requested for prenatal diagnosis. The combination of α1-globin mutation and Hb Fontainebleau can cause clinical and hematologic features of thalassemia. This combination also highlights the important heterogeneity of alpha thalassemia in this part of the world.","variants":[{"Name":"NM_000517.6(HBA2):c.64G>C (p.Ala22Pro)","Chromosome":"16","Start":"172976","Stop":"172976","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":789586,"rule_based_match":true,"evidence_text":"HBA2: c.64G>C","llm_judgment":"PRESENT","evidence":"c.64G>C","abstract_start":433,"abstract_end":440}]}
{"pmid":"34626609","title":"Novel mutations associated with carnitine-acylcarnitine translocase and carnitine palmitoyl transferase 2 deficiencies in Malaysia.","abstract":"OBJECTIVE: Carnitine-acylcarnitine Translocase (CACT) deficiency (OMIM 212138) and carnitine palmitoyl transferase 2 (CPT2) deficiency (OMIM 60065050) are rare inherited disorders of mitochondrial long chain fatty acid oxidation. The aim of our study is to review the clinical, biochemical and molecular characteristics in children diagnosed with CACT and CPT2 deficiencies in Malaysia.\nDESIGN AND METHODS: This is a retrospective study. We reviewed medical records of six patients diagnosed with CACT and CPT2 deficiencies. They were identified from a selective high-risk screening of 50,579 patients from January 2010 until Jun 2020.\nRESULTS: All six patients had either elevation of the long chain acylcarnitines and/or an elevated (C16 + C18:1)/C2 acylcarnitine ratio. SLC25A20 gene sequencing of patient 1 and 6 showed a homozygous splice site mutation at c.199-10 T > G in intron 2. Two novel mutations at c.109C > T p. (Arg37*) in exon 2 and at c.706C > T p. (Arg236*) in exon 7 of SLC25A20 gene were found in patient 2. Patient 3 and 4 (siblings) exhibited a compound heterozygous mutation at c.638A > G p. (Asp213Gly) and novel mutation c.1073 T > G p. (Leu358Arg) in exon 4 of CPT2 gene. A significant combined prevalence at 0.01% of CACT and CPT2 deficiencies was found in the symptomatic Malaysian patients.\nCONCLUSIONS: The use of the (C16 + C18:1)/C2 acylcarnitine ratio in dried blood spot in our experience improves the diagnostic specificity for CACT/CPT2 deficiencies over long chain acylcarnitine (C16 and C18:1) alone. DNA sequencing for both genes aids in confirming the diagnosis.","variants":[{"Name":"NM_000387.6(SLC25A20):c.109C>T (p.Arg37Ter)","Chromosome":"3","Start":"48892069","Stop":"48892069","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3172752,"rule_based_match":true,"evidence_text":"c.109C>T p. (Arg37*)","llm_judgment":"PRESENT","evidence":"c.109C > T p. (Arg37*)","abstract_start":912,"abstract_end":934},{"Name":"NM_000387.6(SLC25A20):c.706C>T (p.Arg236Ter)","Chromosome":"3","Start":"48859104","Stop":"48859104","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2838579,"rule_based_match":true,"evidence_text":"c.706C>T p. (Arg236*)","llm_judgment":"PRESENT","evidence":"c.706C > T p. (Arg236*)","abstract_start":952,"abstract_end":975},{"Name":"NM_000098.3(CPT2):c.638A>G (p.Asp213Gly)","Chromosome":"1","Start":"53210312","Stop":"53210312","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":24006,"rule_based_match":true,"evidence_text":"c.638A>G p. (Asp213Gly)","llm_judgment":"PRESENT","evidence":"c.638A > G p. (Asp213Gly)","abstract_start":1101,"abstract_end":1126}]}
{"pmid":"22236406","title":"Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia.","abstract":"Abetalipoproteinemia (ABL) is an inherited disease characterized by the defective assembly and secretion of apolipoprotein B-containing lipoproteins caused by mutations in the microsomal triglyceride transfer protein large subunit (MTP) gene (MTTP). We report here a female patient with an unusual clinical and biochemical ABL phenotype. She presented with severe liver injury, low levels of LDL-cholesterol, and subnormal levels of vitamin E, but only mild fat malabsorption and no retinitis pigmentosa or acanthocytosis. Our objective was to search for MTTP mutations and to determine the relationship between the genotype and this particular phenotype. The subject exhibited compound heterozygosity for two novel MTTP mutations: one missense mutation (p.Leu435His) and an intronic deletion (c.619-5_619-2del). COS-1 cells expressing the missense mutant protein exhibited negligible levels of MTP activity. In contrast, the minigene splicing reporter assay showed an incomplete splicing defect of the intronic deletion, with 26% of the normal splicing being maintained in the transfected HeLa cells. The small amount of MTP activity resulting from the residual normal splicing in the patient explains the atypical phenotype observed. Our investigation provides an example of a functional analysis of unclassified variations, which is an absolute necessity for the molecular diagnosis of atypical ABL cases.","variants":[{"Name":"NM_001386140.1(MTTP):c.1304T>A (p.Leu435His)","Chromosome":"4","Start":"99601674","Stop":"99601674","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":615975,"rule_based_match":false,"evidence_text":"c.1304T>A (p.Leu435His)","llm_judgment":"PRESENT","evidence":"p.Leu435His","abstract_start":755,"abstract_end":766}]}
{"pmid":"36544354","title":"Chronic progressive external ophthalmoplegia plus syndrome due to homozygous missense variant in TOP3A gene.","abstract":"Chronic progressive external ophthalmoplegia (CPEO) plus syndrome due to pathogenic biallelic variants in TOP3A gene has been described in only one single patient. We report two adult siblings with c.614A>G (p.Asp205Gly) homozygous missense variant in the TOP3A gene who had CPEO plus syndrome.","variants":[{"Name":"NM_004618.5(TOP3A):c.614A>G (p.Asp205Gly)","Chromosome":"17","Start":"18302609","Stop":"18302609","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3189215,"rule_based_match":true,"evidence_text":"c.614A>G (p.Asp205Gly)","llm_judgment":"PRESENT","evidence":"c.614A>G (p.Asp205Gly)","abstract_start":198,"abstract_end":220}]}
{"pmid":"33491330","title":"A rare gene variation cap +1 (A>C) (HBB: c. -50A>C) associated with codon 5 (-CT) (HBB: c.17_18delCT) mutation in Syrian family.","abstract":"BACKGROUND: CAP+1 [A>C] (HBB:c.-50A>C) is a rare silent β-thalassemia (β-thal) mutation. Carrier individuals of this mutation show borderline hemoglobin (Hb), mean corpuscular volume (MCV) and Hb A2 levels. This mutation was previously reported in combination with different β-thalassemia mutations, leading to variable phenotypes.\nCASE PRESENTATION: Here, we describe for the first time the combination of silent CAP+1 [A>C] (HBB:c.-50A>C) mutation with β<sup>0</sup> codon 5 [-CT] (HBB:c.17_18delCT) mutation in a Syrian proband, leading to beta thalassemia intermedia (TI).\nCONCLUSIONS: The compound heterozygotes of the silent CAP+1 (A>C) together with another severe beta gene mutation, are phenotypically severe enough to present at an early age and require appropriate therapeutic modalities.","variants":[{"Name":"NM_000518.5(HBB):c.-50A>C","Chromosome":"11","Start":"5227071","Stop":"5227071","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":44956,"rule_based_match":true,"evidence_text":"HBB:c.-50A>C","llm_judgment":"PRESENT","evidence":"HBB:c.-50A>C","abstract_start":25,"abstract_end":37}]}
{"pmid":"23910460","title":"Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia.","abstract":"Many individuals with abnormalities of mitochondrial respiratory chain complex III remain genetically undefined. Here, we report mutations (c.288G>T [p.Trp96Cys] and c.643C>T [p.Leu215Phe]) in CYC1, encoding the cytochrome c1 subunit of complex III, in two unrelated children presenting with recurrent episodes of ketoacidosis and insulin-responsive hyperglycemia. Cytochrome c1, the heme-containing component of complex III, mediates the transfer of electrons from the Rieske iron-sulfur protein to cytochrome c. Cytochrome c1 is present at reduced levels in the skeletal muscle and skin fibroblasts of affected individuals. Moreover, studies on yeast mutants and affected individuals' fibroblasts have shown that exogenous expression of wild-type CYC1 rescues complex III activity, demonstrating the deleterious effect of each mutation on cytochrome c1 stability and complex III activity.","variants":[{"Name":"NM_001916.5(CYC1):c.288G>T (p.Trp96Cys)","Chromosome":"8","Start":"144095991","Stop":"144095991","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":76929,"rule_based_match":true,"evidence_text":"c.288G>T [p.Trp96Cys]","llm_judgment":"PRESENT","evidence":"c.288G>T [p.Trp96Cys]","abstract_start":140,"abstract_end":161},{"Name":"NM_001916.5(CYC1):c.643C>T (p.Leu215Phe)","Chromosome":"8","Start":"144096615","Stop":"144096615","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76930,"rule_based_match":true,"evidence_text":"c.643C>T (p.Leu215Phe)","llm_judgment":"PRESENT","evidence":"p.Leu215Phe","abstract_start":176,"abstract_end":187}]}
{"pmid":"26202387","title":"Retinal histopathology in eyes from patients with autosomal dominant retinitis pigmentosa caused by rhodopsin mutations.","abstract":"PURPOSE: To evaluate the histopathology in donor eyes from patients with autosomal dominant retinitis pigmentosa (ADRP) caused by p.P23H, p.P347T and p.P347L rhodopsin ( RHO ) gene mutations.\nMETHODS: Eyes from a 72-year-old male (donor 1), an 83-year-old female (donor 2), an 80-year-old female (donor 3), and three age-similar normal eyes were examined macroscopically, by scanning laser ophthalmoscopy and optical coherence tomography imaging. Perifoveal and peripheral pieces were processed for microscopy and immunocytochemistry with markers for photoreceptor cells.\nRESULTS: DNA analysis revealed RHO mutations c.68C>A (p.P23H) in donor 1, c.1040C>T (p.P347L) in donor 2 and c.1039C>A (p.P347T) in donor 3. Histology of the ADRP eyes showed retinas with little evidence of stratified nuclear layers in the periphery and a prominent inner nuclear layer present in the perifoveal region in the p.P23H and p.P347T eyes, while it was severely atrophic in the p.P347L eye. The p.P23H and p.P347T mutations cause a profound loss of rods in both the periphery and perifovea, while the p.P347L mutation displays near complete absence of rods in both regions. All three rhodopsin mutations caused a profound loss of cones in the periphery. The p.P23H and p.P347T mutations led to the presence of highly disorganized cones in the perifovea. However, the p.P347L mutation led to near complete absence of cones also in the perifovea.\nCONCLUSIONS: Our results support clinical findings indicating that mutations affecting residue P347 develop more severe phenotypes than those affecting P23. Furthermore, our results indicate a more severe phenotype in the p.P347L retina as compared to the p.P347T retina.","variants":[{"Name":"NM_000539.3(RHO):c.1039C>A (p.Pro347Thr)","Chromosome":"3","Start":"129533710","Stop":"129533710","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1059604,"rule_based_match":true,"evidence_text":"c.1039C>A (p.P347T)","llm_judgment":"PRESENT","evidence":"c.1039C>A (p.P347T)","abstract_start":681,"abstract_end":700},{"Name":"NM_000539.3(RHO):c.68C>A (p.Pro23His)","Chromosome":"3","Start":"129528801","Stop":"129528801","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":28052,"rule_based_match":true,"evidence_text":"c.68C>A (p.P23H)","llm_judgment":"PRESENT","evidence":"c.68C>A (p.P23H)","abstract_start":617,"abstract_end":633},{"Name":"NM_000539.3(RHO):c.1040C>T (p.Pro347Leu)","Chromosome":"3","Start":"129533711","Stop":"129533711","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28053,"rule_based_match":true,"evidence_text":"c.1040C>T (p.P347L)","llm_judgment":"PRESENT","evidence":"c.1040C>T (p.P347L)","abstract_start":646,"abstract_end":665}]}
{"pmid":"28366028","title":"Mutational Profile of Homozygous β-Thalassemia in Rio de Janeiro, Brazil.","abstract":"β-Thalassemia (β-thal) is a hemolytic anemia that is caused by point mutations in most cases. The Brazilian population is highly heterogeneous and knowledge of the mutations that make up the genotypic profile of individuals can contribute information about the formation of the population and clinical condition of patients. In this study, we evaluated the mutations present in homozygous β-thal patients from Rio de Janeiro, Brazil. We analyzed 24 samples of peripheral blood of patients with homozygous β-thal. To identify the mutations, we carried out allele-specific-polymerase chain reaction (AS-PCR) and DNA sequencing. We found 11 different mutations on the β-globin gene. Among the most frequent mutations observed were HBB: c.92 + 6T>C, followed by HBB: c.93-21G>A, HBB: c.118C>T and HBB: c.92 + 1G>A. We also identified the rare mutation HBB: c.75T>A that was reported in an individual carrying Hb S (HBB: c.20A>T)/β-thal (HBB: c.75T>A) but not in Brazilian thalassemic patients, thus, this is the first report of this mutation in Brazilian β-thal patients. For its multiethnic character, Brazil has different mutations that cause β-thal and that are distributed with different frequencies according to the regions of the country. Our findings contribute to the description of the mutational profile of Brazilian thalassemic patients, showing wide heterogeneity and genetic variability.","variants":[{"Name":"NM_000518.5(HBB):c.75T>A (p.Gly25=)","Chromosome":"11","Start":"5226947","Stop":"5226947","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":30498,"rule_based_match":true,"evidence_text":"HBB: c.75T>A","llm_judgment":"PRESENT","evidence":"HBB: c.75T>A","abstract_start":848,"abstract_end":860},{"Name":"NM_000518.5(HBB):c.118C>T (p.Gln40Ter)","Chromosome":"11","Start":"5226774","Stop":"5226774","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":30441,"rule_based_match":true,"evidence_text":"HBB: c.118C>T","llm_judgment":"PRESENT","evidence":"HBB: c.118C>T","abstract_start":775,"abstract_end":788},{"Name":"NM_000518.5(HBB):c.92+1G>A","Chromosome":"11","Start":"5226929","Stop":"5226929","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30475,"rule_based_match":true,"evidence_text":"HBB: c.92 + 1G>A","llm_judgment":"PRESENT","evidence":"HBB: c.92 + 1G>A","abstract_start":793,"abstract_end":809},{"Name":"NM_000518.5(HBB):c.92+6T>C","Chromosome":"11","Start":"5226924","Stop":"5226924","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":30489,"rule_based_match":true,"evidence_text":"HBB: c.92 + 6T>C","llm_judgment":"PRESENT","evidence":"HBB: c.92 + 6T>C","abstract_start":728,"abstract_end":744},{"Name":"NM_000518.5(HBB):c.93-21G>A","Chromosome":"11","Start":"5226820","Stop":"5226820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30493,"rule_based_match":true,"evidence_text":"HBB: c.93-21G>A","llm_judgment":"PRESENT","evidence":"HBB: c.93-21G>A","abstract_start":758,"abstract_end":773}]}
{"pmid":"27852030","title":"A Case of Pol III-related Leukodystrophy with Homozygous Mutation in POLR3A","abstract":"We describe a 27-year-old man with mental retardation, symptomatic epilepsy, myopia, and cerebellar ataxia without spontaneous puberty whose brain magnetic resonance imaging showed hypomyelination. He had child-like facial appearance, with thin facial hair. He had no underarm and pubic hairs, and his penis was small. Laboratory tests showed low levels of luteinizing hormone, follicle-stimulating hormone, and testosterone. Brain MRI showed diffuse hypomyelination, atrophy of the cerebellum and brainstem, and hypoplastic corpus callosum. Ictal N-isopropyl-p-(indone-123)-iodoamphetamine single photon emission computed tomography (<sup>123</sup>I-IMP SPECT) revealed hypoperfusion of bilateral frontal cingulate and temporal lobe and cerebellar hemispheres. Homozygous missense mutation c.2350G>A was found in POLR3A and the patient was diagnosed with Pol III-related leukodystrophy, which is a rare disease. We describe the present case in light of the characteristics of the past reports in Japan. (Received April 5, 2016: Accepted June 30, 2016; Published November 1, 2016).","variants":[{"Name":"NM_007055.4(POLR3A):c.2350G>A (p.Gly784Ser)","Chromosome":"10","Start":"78002206","Stop":"78002206","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1017326,"rule_based_match":true,"evidence_text":"c.2350G>A","llm_judgment":"PRESENT","evidence":"c.2350G>A","abstract_start":791,"abstract_end":800}]}
{"pmid":"22976764","title":"A novel congenital disorder of glycosylation type without central nervous system involvement caused by mutations in the phosphoglucomutase 1 gene.","abstract":"Recent years have seen great advances in our knowledge of congenital disorders of glycosylation (CDG), a clinically and biochemically heterogeneous group of genetic diseases caused by defects in the synthesis (CDG-I) or processing (CDG-II) of glycans that form glycoconjugates. This paper reports a new subtype of non-neurological CDG involving the impaired cytoplasmic biosynthesis of nucleotide sugars needed for glycan biosynthesis. A patient presented with muscle fatigue, elevated creatine kinase, growth hormone deficiency, and first branchial arch syndrome. These findings, together with the abnormal type II plasma transferrin isoform profile detected, was compatible with a CDG. Functional testing and clinical analyses suggested a deficiency in the interconversion of glucose-1-phosphate and glucose-6-phosphate catalyzed by phosphoglucomutase (PGM1), a defect previously described as glycogenosis type XIV (GSDXIV, MIM 612934). PGM1 activity in patient-derived fibroblasts was significantly reduced, as was the quantity of immunoreactive PGM1 protein (Western blot assays). Mutation analysis of PGM1 and subsequent functional analysis investigating transient expression of PGM1 in immortalized patient fibroblasts, followed by ex vivo splicing assays using minigenes, allowed the characterization of two novel pathogenic mutations: c.871G>A (p.Gly291Arg) and c.1144 + 3A>T. The latter represents a severe splicing mutation leading to the out-of-frame skipping of exon 7 and the formation of a truncated protein (p.Arg343fs). MALDI mass spectra of permethylated protein N-glycans from the patient's serum suggested a marked hypoglycosylation defect. The present findings confirm that, in addition to a rare muscular glycolytic defect, PGM1 deficiency causes a non-neurological disorder of glycosylation.","variants":[{"Name":"NM_002633.3(PGM1):c.1144+3A>T","Chromosome":"1","Start":"63638803","Stop":"63638803","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2473119,"rule_based_match":true,"evidence_text":"c.1144+3A>T","llm_judgment":"PRESENT","evidence":"c.1144 + 3A>T","abstract_start":1370,"abstract_end":1383},{"Name":"NM_002633.3(PGM1):c.871G>A (p.Gly291Arg)","Chromosome":"1","Start":"63635017","Stop":"63635017","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1928415,"rule_based_match":true,"evidence_text":"c.871G>A (p.Gly291Arg)","llm_judgment":"PRESENT","evidence":"c.871G>A (p.Gly291Arg)","abstract_start":1343,"abstract_end":1365}]}
{"pmid":"32319736","title":"4H leukodystrophy caused by a homozygous POLR3B mutation: Further delineation of the phenotype.","abstract":"4H leukodystrophy, also known as Pol III-related leukodystrophy, is a rare autosomal recessive neurodegenerative disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. It is caused by biallelic mutations in POLR3A, POL3RB, or POLR1C. So far, only two patients have been described with homozygosity for the common c.1568T>A (p.Val523Glu) POLR3B mutation, both of them showing a remarkably mild clinical course. Here, we report another patient with homozygosity for the same mutation, but with a more severe phenotype including ataxia, developmental delay, and intellectual disability. This information is of importance for clinicians to provide comprehensive counseling to patients with 4H leukodystrophy and their families.","variants":[{"Name":"NM_018082.6(POLR3B):c.1568T>A (p.Val523Glu)","Chromosome":"12","Start":"106432421","Stop":"106432421","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":40123,"rule_based_match":true,"evidence_text":"c.1568T>A (p.Val523Glu)","llm_judgment":"PRESENT","evidence":"c.1568T>A (p.Val523Glu)","abstract_start":348,"abstract_end":371}]}
{"pmid":"37798908","title":"Refining the phenotypic spectrum of CCDC88A-related PEHO-like syndrome.","abstract":"Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and PEHO-like syndromes are very rare infantile disorders characterized by profound intellectual disability, hypotonia, convulsions, optic, and progressive brain atrophy. Many causative genes for PEHO and PEHO-like syndromes have been identified including CCDC88A. So far, only five patients from two unrelated families with biallelic CCDC88A variants have been reported in the literature. Herein, we describe a new family from Egypt with a lethal epileptic encephalopathy. Our patient was the youngest child born to a highly consanguineous couple and had a family history of five deceased sibs with the same condition. She presented with postnatal microcephaly, poor visual responsiveness, and epilepsy. Her brain MRI showed abnormal cortical gyration with failure of opercularization of the insula, hypogenesis of corpus callosum, colpocephaly, reduced white matter, hypoplastic vermis, and brain stem. Whole exome sequencing identified a new homozygous frameshift variant in CCDC88A gene (c.1795_1798delACAA, p.Thr599ValfsTer4). Our study presents the third reported family with this extremely rare disorder. We also reviewed all described cases to better refine the phenotypic spectrum associated with biallelic loss of function variants in the CCDC88A gene.","variants":[{"Name":"NM_001365480.1(CCDC88A):c.1795_1798del (p.Thr599fs)","Chromosome":"2","Start":"55335023","Stop":"55335026","ReferenceAlleleVCF":"CTTGT","AlternateAlleleVCF":"C","allel_id":3535685,"rule_based_match":true,"evidence_text":"c.1795_1798delACAA, p.Thr599ValfsTer4","llm_judgment":"PRESENT","evidence":"c.1795_1798delACAA, p.Thr599ValfsTer4","abstract_start":1072,"abstract_end":1109}]}
{"pmid":"22308153","title":"Prevalence of ATP7B Gene Mutations in Iranian Patients With Wilson Disease.","abstract":"BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder. The WD gene, ATP7B, encodes a copper-transporting ATPase involved in the transport of copper into the plasma protein ceruloplasmin and in excretion of copper from the liver. ATP7B mutations cause copper to accumulate in the liver and brain.\nOBJECTIVES: We examined the ATP7B mutation spectrum in Wilson disease patients in Iran.\nPATIENTS AND METHODS: Genomic DNA was extracted from patients with Wilson disease. The entire coding region of the ATP7B gene was amplified using PCR and analyzed using direct sequencing.\nRESULTS: We identified five novel mutations in 5 Iranian patients with Wilson disease. The first was a transversion, c.2363C > T, which led to an amino acid change from threonine to isoleucine. The second mutation was a deletion, c.2532delA (Val845Ser), which occurred in exon 10. The third mutation was a transition mutation, c.2311C > G (Leu770Leu), which occurred in the TM4 domain of the ATP7B protein. The fourth mutation was a transversion, (c.3061G > A) (Lys1020Lys), in exon 14. Lastly, we identified a transversion, c.3206C > A (His1069Asn) in exon 14 which led to a change in function of the ATP loop domain of the ATP7B protein. The H1069Q mutation was identified as the most common mutation in our study population.\nCONCLUSIONS: Based on our findings, the H1069Q may be a biomarker that can be used in a rapid detection assay for diagnosing WD patients.","variants":[{"Name":"NM_000053.4(ATP7B):c.2363C>T (p.Thr788Ile)","Chromosome":"13","Start":"51957600","Stop":"51957600","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":936482,"rule_based_match":true,"evidence_text":"c.2363C > T","llm_judgment":"PRESENT","evidence":"c.2363C > T","abstract_start":702,"abstract_end":713}]}
{"pmid":"37460425","title":"Identification and 3D architecture analysis of the LIPC gene mutation in a pedigree with familial hypercholesterolemia-like phenotype","abstract":"<b>Objective:</b> To identify and analyze 3D architecture of the mutational sites of susceptible genes in a pedigree with familial hypercholesterolemia-like phenotype (FHLP). <b>Methods:</b> This is a case series study. A pedigree with suspected familial hypercholesterolemia was surveyed. The proband admitted in Beijing Anzhen Hospital in April 2019. Whole-exome sequencing was performed to determine the mutational sites of susceptible genes in the proband. Polymerase chain reaction (PCR) sequencing was used to verify the pathogenic variant on proband's relatives. The structural and functional changes of the proteins were analyzed and predicted by Discovery Studio 4.0 and PyMol 2.0. <b>Results:</b> The patients in the pedigree showed abnormal lipid profiles, especially elevated levels of total cholesterol(TC). The genetic screening detected the c.1330C>T SNP in the exon 8 of lipase C (LIPC) gene, this mutation leads to an amino acid substitution from arginine to cysteine at position 444 (Arg444Cys), in the proband and proband's father and brother. In this family, members with this mutation exhibited elevated TC, whereas lipid profile was normal from the proband's mother without this mutation. This finding indicated that LIPC: c.1330C>T mutation might be the mutational sites of susceptible genes. The analysis showed that Arg444Cys predominantly affected the ligand-binding property of the protein, but had a limited impact on catalytic function. <b>Conclusion:</b> LIPC: c.1330C>T is a new mutational site of susceptible genes in this FHLP pedigree.","variants":[{"Name":"NM_000236.3(LIPC):c.1330C>T (p.Arg444Cys)","Chromosome":"15","Start":"58563665","Stop":"58563665","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1395653,"rule_based_match":true,"evidence_text":"c.1330C>T","llm_judgment":"PRESENT","evidence":"c.1330C>T","abstract_start":856,"abstract_end":865}]}
{"pmid":"37041640","title":"WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome.","abstract":"BACKGROUND: Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review.\nMETHODS: We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review.\nRESULTS: One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7-9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI.\nCONCLUSIONS: We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.","variants":[{"Name":"NM_006005.3(WFS1):c.2051C>T (p.Ala684Val)","Chromosome":"4","Start":"6301846","Stop":"6301846","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39513,"rule_based_match":true,"evidence_text":"c.2051 C > T:p.Ala684Val","llm_judgment":"PRESENT","evidence":"c.2051 C > T:p.Ala684Val","abstract_start":1325,"abstract_end":1349}]}
{"pmid":"32876971","title":"Pilomatricomas and café au lait macules as herald signs of constitutional mismatch repair deficiency (CMMRD) syndrome-A case report.","abstract":"Constitutional mismatch repair deficiency (CMMRD) syndrome results from bi-allelic mutations in DNA mismatch repair genes-MLH1, MSH2, MSH6, or PMS2. We present two siblings with CMMRD having p.Arg802Ter (c.2404C >T) homozygous mutations in PMS2 exon 14 with typical cutaneous features. This case report highlights the role of the dermatologist in early diagnosis of this condition.","variants":[{"Name":"NM_000535.7(PMS2):c.2404C>T (p.Arg802Ter)","Chromosome":"7","Start":"5977629","Stop":"5977629","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24276,"rule_based_match":true,"evidence_text":"p.Arg802Ter (c.2404C >T)","llm_judgment":"PRESENT","evidence":"p.Arg802Ter (c.2404C >T)","abstract_start":191,"abstract_end":215}]}
{"pmid":"26860062","title":"De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia.","abstract":"We report an 8-year-old boy with a complex cerebral malformation, intellectual disability, and complex partial seizures. Whole-exome sequencing revealed a yet unreported de novo variant in the PIK3R2 gene that was recently associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome and bilateral perisylvian polymicrogyria (BPP). Our patient showed cerebral abnormalities (megalencephaly, perisylvian polymicrogyria, and mega corpus callosum) that were consistent with these conditions. Imaging also showed right temporal anomalies suggestive of cortical dysplasia. Until now, only three variants (c.1117G>A (p.(G373R)), c.1126A>G (p.(K376E)) and c.1202T>C (p.(L401P))) affecting the SH2 domain of the PIK3R2 protein have been reported in MPPH and BPP syndromes. In contrast to the variants reported so far, the patient described herein exhibits the c.1669G>C (p.(D557H)) variant that affects a highly conserved residue at the interface with the PI3K catalytic subunit α. The phenotypic spectrum associated with variants in this gene and its pathway are likely to continue to expand as more cases are identified.","variants":[{"Name":"NM_005027.4(PIK3R2):c.1117G>A (p.Gly373Arg)","Chromosome":"19","Start":"18162974","Stop":"18162974","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48407,"rule_based_match":true,"evidence_text":"c.1117G>A (p.(G373R))","llm_judgment":"PRESENT","evidence":"c.1117G>A (p.(G373R))","abstract_start":627,"abstract_end":648}]}
{"pmid":"31331668","title":"Determinants of Riboflavin Responsiveness in Multiple Acyl-CoA Dehydrogenase Deficiency.","abstract":"BACKGROUND: Multiple acyl-CoA dehydrogenase (MADD) deficiency, which is a rare metabolic disorder involving electron transport flavoproteins, has a wide array of clinical phenotypes. In this article, we describe 25 patients with MADD deficiency and present the clinical and laboratory characteristics and diagnostic challenges associated with riboflavin-responsive MADD deficiency.\nMETHODS: Hospital records of patients with biallelic mutations in ETFA, ETFB, or ETFDH genes diagnosed in a single center were analyzed retrospectively. Demographic, clinical, and laboratory characteristics of patients with riboflavin-responsive and riboflavin-unresponsive MADD deficiency were compared using Mann-Whitney U and Fisher's exact tests.\nRESULTS: Respiratory distress and depressed consciousness were significantly more common in patients with riboflavin-unresponsive MADD deficiency (P = 0.015 and P < 0.001), who presented at a younger age (P < 0.001). Patients with riboflavin-responsive MADD deficiency had favorable outcomes but also had life-threatening complications, longer diagnostic delay (median of two years versus 30 days; P < 0.001), and multiple differential diagnoses, resulting in unnecessary investigations and maltreatment. Biopsies showed lipid storage, and complete autopsy was performed in one newborn with riboflavin-unresponsive MADD deficiency, revealing multiple abnormalities. Metabolic profiles were not distinguishable between riboflavin-responsive and riboflavin-unresponsive MADD deficiency (P > 0.05). Four novel variants were detected in ETFDH, one of which (c.1790C>T) may confer riboflavin responsiveness. Siblings with the common myopathic ETFDH c.1130T>C mutation presented with a new phenotype dominated by chronic fatigue without apparent myopathy.\nCONCLUSIONS: Symptoms and outcomes significantly differed between riboflavin-responsive and unresponsive MADD deficiency, but metabolic profiles did not. Functional studies are needed to better characterize the novel ETFDH variants. As treatment is available for riboflavin-responsive MADD deficiency, physicians should maintain a high index of suspicion for MADD deficiency in all age groups.","variants":[{"Name":"NM_004453.4(ETFDH):c.1130T>C (p.Leu377Pro)","Chromosome":"4","Start":"158703436","Stop":"158703436","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":40285,"rule_based_match":true,"evidence_text":"ETFDH c.1130T>C","llm_judgment":"PRESENT","evidence":"ETFDH c.1130T>C","abstract_start":1671,"abstract_end":1686}]}
{"pmid":"28455998","title":"New mutations in GJA8 expand the phenotype to include total sclerocornea.","abstract":"This project expands the disease spectrum for mutations in GJA8 to include total sclerocornea, rudimentary lenses and microphthalmia, in addition to this gene's previously known role in isolated congenital cataracts. Ophthalmic findings revealed bilateral total sclerocornea in 3 probands, with small abnormal lenses in 2 of the cases, and cataracts and microphthalmia in 1 case. Next-generation sequencing revealed de novo heterozygous mutations affecting the same codon of GJA8 : (c.281G>A; p.(Gly94Glu) and c.280G>C; p.(Gly94Arg)) in 2 of the probands, in addition to the c.151G>A; p.(Asp51Asn) mutation we had previously identified in the third case. In silico analysis predicted all of the mutations to be pathogenic. These cases show that deleterious, heterozygous mutations in GJA8 can lead to a severe ocular phenotype of total sclerocornea, abnormal lenses, and/or cataracts with or without microphthalmia, broadening the phenotype associated with this gene. GJA8 should be included when investigating patients with the severe anterior segment abnormality of total sclerocornea.","variants":[{"Name":"NM_005267.5(GJA8):c.280G>C (p.Gly94Arg)","Chromosome":"1","Start":"147908235","Stop":"147908235","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":920589,"rule_based_match":true,"evidence_text":"c.280G>C; p.(Gly94Arg)","llm_judgment":"PRESENT","evidence":"c.280G>C; p.(Gly94Arg)","abstract_start":510,"abstract_end":532},{"Name":"NM_005267.5(GJA8):c.281G>A (p.Gly94Glu)","Chromosome":"1","Start":"147908236","Stop":"147908236","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":920590,"rule_based_match":true,"evidence_text":"c.281G>A; p.(Gly94Glu)","llm_judgment":"PRESENT","evidence":"c.281G>A; p.(Gly94Glu)","abstract_start":483,"abstract_end":505}]}
{"pmid":"34280927","title":"Significance of the p.Phe218Ser and p.Gly304Glu F5 Variants in Hereditary Factor V Deficiency.","abstract":"Hereditary factor V (FV) deficiency is a rare autosomal recessive bleeding disorder caused by F5 gene mutations. The objective of this study was to investigate the p.Phe218Ser and p.Gly304Glu variants found in 2 families with hereditary FV deficiency. The FV activity (FV:C) and FV antigen (FV:Ag) were measured by clotting and ELISA, respectively. The F5 gene and sequence conservation were analyzed by direct sequencing and ClustalX-2.1-win, respectively. One proband carried a homozygous p.Phe218Ser (c.653T>C) mutation, with FV:C and FV:Ag decreased to 11 and 14%, respectively. The other proband carried a heterozygous p.Gly304Glu (c.911G>A) mutation, with FV:C and FV:Ag reduced to 55 and 62%, respectively. Phe218 and Gly304 were highly conserved in the homologous gene in 9 other species. We hypothesized that the p.Phe218Ser and p.Gly304Glu variants are deleterious and responsible for the reduction in FV:C and FV:Ag.","variants":[{"Name":"NM_000130.5(F5):c.911G>A (p.Gly304Glu)","Chromosome":"1","Start":"169556687","Stop":"169556687","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":615288,"rule_based_match":true,"evidence_text":"c.911G>A","llm_judgment":"PRESENT","evidence":"c.911G>A","abstract_start":637,"abstract_end":645},{"Name":"NM_000130.5(F5):c.653T>C (p.Phe218Ser)","Chromosome":"1","Start":"169559230","Stop":"169559230","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2898358,"rule_based_match":true,"evidence_text":"c.653T>C","llm_judgment":"PRESENT","evidence":"c.653T>C","abstract_start":504,"abstract_end":512}]}
{"pmid":"20505086","title":"Targeting of the hair cell proteins cadherin 23, harmonin, myosin XVa, espin, and prestin in an epithelial cell model.","abstract":"We have developed an advantageous epithelial cell transfection model for examining the targeting, interactions, and mutations of hair cell proteins. When expressed in LLC-PK1-CL4 epithelial cells (CL4 cells), the outer hair cell protein prestin showed faithful domain-specific targeting to the basolateral plasma membrane. We examined the consequences of mutations affecting prestin activity and assigned a targeting role to the cytoplasmic tail. The stereociliary link protein cadherin 23 (Cdh23) was targeted to the plasma membrane of CL4 cell microvilli, the topological equivalent of stereocilia. In cells coexpressing the Cdh23 cytoplasmic binding protein harmonin, a large fraction of harmonin became colocalized with Cdh23 in microvilli. Using this assay and in vitro protein binding assays, we formulated an alternative model for Cdh23-harmonin binding, in which the primary interaction is between the harmonin N-domain and a 35-residue internal peptide in the Cdh23 cytoplasmic tail. Contrary to a previous model, we found no role for the Cdh23 C-terminal PDZ (PSD-95/Dlg/ZO-1)-binding motif and observed that Cdh23 bound similar levels of harmonin with or without the exon 68 peptide. We also examined two proteins involved in stereocilium elongation. The stereociliary actin-bundling protein espin was targeted to CL4 cell microvilli and caused microvillar elongation, whereas espin with the c.2469delGTCA or c.1988delAGAG human deafness mutation showed defects in microvillar targeting and elongation. The unconventional myosin motor myosin XVa accumulated at the tips of espin-elongated microvilli, by analogy to its location in stereocilia, whereas myosin XVa with the c.4351G>A or c.4669A>G human deafness mutation did not, revealing functional deficits in motor activity.","variants":[{"Name":"NM_016239.4(MYO15A):c.4351G>A (p.Asp1451Asn)","Chromosome":"17","Start":"18133255","Stop":"18133255","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":857687,"rule_based_match":true,"evidence_text":"myosin XVa with the c.4351G>A","llm_judgment":"PRESENT","evidence":"myosin XVa with the c.4351G>A","abstract_start":1663,"abstract_end":1692}]}
{"pmid":"28436541","title":"PDX1 -MODY and dorsal pancreatic agenesis: New phenotype of a rare disease.","abstract":"Maturity-Onset Diabetes of the Young (MODY) type 4 or PDX1 -MODY is a rare form of monogenic diabetes caused by heterozygous variants in PDX1 . Pancreatic developmental anomalies related to PDX1 are reported only in neonatal diabetes cases. Here, we describe dorsal pancreatic agenesis in 2 patients with PDX1 -MODY. The proband presented with diabetes since 14 years of age and maintained regular glycemic control with low doses of basal insulin and detectable C-peptide levels after 38 years with diabetes. A diagnosis of MODY was suspected. Targeted next-generation sequencing identified a heterozygous variant in PDX1 : c.188delC/p.Pro63Argfs*60. Computed tomography revealed caudal pancreatic agenesis. Low fecal elastase indicated exocrine insufficiency. His son had impaired glucose tolerance, presented similar pancreatic agenesis, and harbored the same allelic variant. The unusual presentation in this Brazilian family enabled expansion upon a rare disease phenotype, demonstrating the possibility of detecting pancreatic malformation even in cases of PDX1 -related diabetes diagnosed after the first year of life. This finding can improve the management of MODY4 patients, leading to precocious investigation of pancreatic dysgenesis and exocrine dysfunction.","variants":[{"Name":"NM_000209.4(PDX1):c.188del (p.Pro63fs)","Chromosome":"13","Start":"27920321","Stop":"27920321","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":33976,"rule_based_match":true,"evidence_text":"c.188delC/p.Pro63Argfs*60","llm_judgment":"PRESENT","evidence":"c.188delC/p.Pro63Argfs*60","abstract_start":624,"abstract_end":649}]}
{"pmid":"23829193","title":"Retrospective study of the medium-chain acyl-CoA dehydrogenase deficiency in Portugal.","abstract":"Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the commonest genetic defect of mitochondrial fatty acid β-oxidation. About 60% of MCADD patients are homozygous for the c.985A>G (p.Lys329Glu) mutation in the ACADM gene (G985 allele). Herein, we present the first report on the molecular and biochemical spectrum of Portuguese MCADD population. From the 109 patients studied, 83 were diagnosed after inclusion of MCADD in the national newborn screening, 8 following the onset of symptoms and 18 through segregation studies. Gypsy ancestry was identified in 85/109 patients. The G985 allele was found in homozygosity in 102/109 patients, in compound heterozygosity in 6/109 and was absent in one patient. Segregation studies in the Gypsy families showed that 93/123 relatives were carriers of the G985 allele, suggesting its high prevalence in this ethnic group. Additionally, three new substitutions-c.218A>G (p.Tyr73Cys), c.503A>T (p.Asp168Val) and c.1205G>T (p.Gly402Val)-were identified. Despite the particularity of the MCADD population investigated, the G985 allele was found in linkage disequilibrium with H1(112) haplotype. Furthermore, two novel haplotypes, H5(212) and H6(122) were revealed.","variants":[{"Name":"NM_000016.6(ACADM):c.1205G>T (p.Gly402Val)","Chromosome":"1","Start":"75762702","Stop":"75762702","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":541303,"rule_based_match":true,"evidence_text":"c.1205G>T (p.Gly402Val)","llm_judgment":"PRESENT","evidence":"c.1205G>T (p.Gly402Val)","abstract_start":959,"abstract_end":982}]}
{"pmid":"33243487","title":"Clinical variations of epileptic syndrome associated with PACS2 variant.","abstract":"BACKGROUND: Recent studies have suggested that two PACS2 pathogenic variants, c.625G > A (p.Glu209Lys) and c.631G > A (p.Glu211Lys), have been causally linked to the characteristic developmental and epileptic encephalopathy, including autistic behaviors, hypotonia, cerebellar dysgenesis and facial dysmorphism. Their seizures appear most difficult to control in neonatal and infant period, but improve after the first year of life. We herein report three patients with the same PACS2 variant, c.625G > A (p.Glu209Lys), showing different characteristics from previous reports.\nCASE REPORT: Case 1, a 2-year-old girl, developed frequent tonic convulsions 2 weeks after birth. Brain magnetic resonance imaging showed a decrease in posterior periventricular white matter volume, an enlargement of the inferior horn of lateral ventricles and old subependymal hemorrhage. Epilepsy is now controlled with antiepileptic drugs. Case 2, a 12-year-old girl, developed generalized tonic convulsions 3 days after birth. Although epilepsy had been controlled since the age of 4, she developed Lennox-Gastaut syndrome at 9 years old. Case 3, a 3-year-old girl, developed tonic convulsions 3 days after birth. She now exhibits normal psychomotor development, and epilepsy is controlled without medicine.\nCONCLUSION: PACS2-related epileptic syndrome presents variable phenotypes than previously reported. We think that our findings expand the clinical spectrum of this disease, and provide important information about the differential diagnosis of neonatal-onset epileptic syndrome.","variants":[{"Name":"NM_001100913.3(PACS2):c.625G>A (p.Glu209Lys)","Chromosome":"14","Start":"105368112","Stop":"105368112","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":486695,"rule_based_match":true,"evidence_text":"c.625G>A (p.Glu209Lys)","llm_judgment":"PRESENT","evidence":"c.625G > A (p.Glu209Lys)","abstract_start":78,"abstract_end":102}]}
{"pmid":"11968094","title":"A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome.","abstract":"Guttmacher syndrome, a dominantly inherited combination of distal limb and genital tract abnormalities, has several features in common with hand-foot-genital syndrome (HFGS), including hypoplastic first digits and hypospadias. The presence of features not seen in HFGS, however, including postaxial polydactyly of the hands and uniphalangeal 2(nd) toes with absent nails, suggests that it represents a distinct entity. HFGS is caused by mutations in the HOXA13 gene. We have therefore re-investigated the original Guttmacher syndrome family, and have found that affected individuals are heterozygous for a novel missense mutation in the HOXA13 homeobox (c.1112A>T; homeodomain residue Q50L), which arose on an allele already carrying a novel 2-bp deletion (-78-79delGC) in the gene's highly conserved promoter region. This deletion produces no detectable abnormalities on its own, but may contribute to the phenotype in the affected individuals. The missense mutation, which alters a key residue in the recognition helix of the homeodomain, is likely to perturb HOXA13's DNA-binding properties, resulting in both a loss and a specific gain of function.","variants":[{"Name":"NM_000522.5(HOXA13):c.1112A>T (p.Gln371Leu)","Chromosome":"7","Start":"27198253","Stop":"27198253","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":29932,"rule_based_match":true,"evidence_text":"c.1112A>T","llm_judgment":"PRESENT","evidence":"c.1112A>T","abstract_start":654,"abstract_end":663}]}
{"pmid":"23768507","title":"Girl with a PRRT2 mutation and infantile focal epilepsy with bilateral spikes.","abstract":"This paper documents the case of a female Japanese patient with infantile focal epilepsy, which was different from benign infantile seizures, and a family history of infantile convulsion and paroxysmal choreoathetosis. The patient developed partial seizures (e.g., psychomotor arrest) at age 14 months. At the time of onset, interictal electroencephalography (EEG) showed bilateral parietotemporal spikes, but the results of neurologic examination and brain magnetic resonance imaging were normal. Her seizures were well controlled with carbamazepine, and she had a normal developmental outcome. EEG abnormalities, however, persisted for more than 6 years, and the spikes moved transiently to the occipital area and began to resemble the rolandic spikes recognized in benign childhood epilepsy. Her father had paroxysmal kinesigenic dyskinesia, with an onset age of 6 years, and her youngest sister had typical benign infantile seizures. Genetic analysis demonstrated that all affected members had a heterozygous mutation of c.649_650insC in the proline-rich transmembrane protein-2 (PRRT2) gene. This case indicates that the phenotypic spectrum of infantile seizures or epilepsy with PRRT2-related pathology may be larger than previously expected, and that genetic investigation of the effect of PRRT2 mutations on idiopathic seizures or epilepsy in childhood may help elucidate the pathological backgrounds of benign childhood epilepsy.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":false,"evidence_text":"c.649_650insC","llm_judgment":"PRESENT","evidence":"c.649_650insC","abstract_start":1025,"abstract_end":1038}]}
{"pmid":"33356342","title":"Novel Mutation in","abstract":"BACKGROUND: Recently, we have reported mutations in LARP7 gene, leading to neurodevelopmental disorders (NDDs), the most frequent cause of disability in children with a broad phenotype spectrum and diverse genetic landscape.\nMETHODS: Here, we present two Iranian patients from consanguineous families with syndromic intellectual disability, facial dysmorphism, and short stature.\nRESULTS: Whole-exome sequencing (WES) revealed a novel homozygous stop-gain (c.C925T, p.R309X) variant and a previously known homozygous acceptor splice-site (c.1669-1_1671del) variant in LARP7 gene, indicating the diagnosis of Alazami syndrome.\nCONCLUSION: These identified variants in patients with Alazami syndrome were consistent with previously reported loss of function variants in LARP7 and provide further evidence that loss of function of LARP7 is the disease mechanism.","variants":[{"Name":"NM_016648.4(LARP7):c.1669-1_1671del","Chromosome":"4","Start":"112657243","Stop":"112657246","ReferenceAlleleVCF":"TTTAG","AlternateAlleleVCF":"T","allel_id":551425,"rule_based_match":true,"evidence_text":"c.1669-1_1671del","llm_judgment":"PRESENT","evidence":"c.1669-1_1671del","abstract_start":539,"abstract_end":555}]}
{"pmid":"16405730","title":"Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma.","abstract":"BACKGROUND: Germline mutations of the SDHD, SDHB and SDHC genes, encoding three of the four subunits of succinate dehydrogenase, are a major cause of hereditary paraganglioma and pheochromocytoma, and demonstrate that these genes are classic tumor suppressors. Succinate dehydrogenase is a heterotetrameric protein complex and a component of both the Krebs cycle and the mitochondrial respiratory chain (succinate:ubiquinone oxidoreductase or complex II).\nMETHODS: Using conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing to analyse genomic DNA from peripheral blood lymphocytes, here we describe the mutation analysis of the SDHB and SDHC genes in 37 patients with sporadic (i.e. no known family history) head and neck paraganglioma and five pheochromocytoma and/or paraganglioma families.\nRESULTS: Two sporadic patients were found to have a SDHB splice site mutation in intron 4, c.423+1G>A, which produces a mis-spliced transcript with a 54 nucleotide deletion, resulting in an 18 amino acid in-frame deletion. A third patient was found to carry the c.214C>T (p.Arg72Cys) missense mutation in exon 4 of SDHC, which is situated in a highly conserved protein motif that constitutes the quinone-binding site of the succinate: ubiquinone oxidoreductase (SQR) complex in E. coli. Together with our previous results, we found 27 germline mutations of SDH genes in 95 cases (28%) of sporadic head and neck paraganglioma. In addition all index patients of five families showing hereditary pheochromocytoma-paraganglioma were found to carry germline mutations of SDHB: four of which were novel, c.343C>T (p.Arg115X), c.141G>A (p.Trp47X), c.281G>A (p.Arg94Lys), and c.653G>C (p.Trp218Ser), and one reported previously, c.136C>T, p.Arg46X.\nCONCLUSION: In conclusion, these data indicate that germline mutations of SDHB and SDHC play a minor role in sporadic head and neck paraganglioma and further underline the importance of germline SDHB mutations in cases of familial pheochromocytoma-paraganglioma.","variants":[{"Name":"NM_003001.5(SDHC):c.214C>T (p.Arg72Cys)","Chromosome":"1","Start":"161340628","Stop":"161340628","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":627041,"rule_based_match":true,"evidence_text":"c.214C>T (p.Arg72Cys)","llm_judgment":"PRESENT","evidence":"c.214C>T (p.Arg72Cys)","abstract_start":1078,"abstract_end":1099},{"Name":"NM_003000.3(SDHB):c.343C>T (p.Arg115Ter)","Chromosome":"1","Start":"17028680","Stop":"17028680","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":194371,"rule_based_match":true,"evidence_text":"c.343C>T (p.Arg115X)","llm_judgment":"PRESENT","evidence":"c.343C>T (p.Arg115X)","abstract_start":1614,"abstract_end":1634},{"Name":"NM_003000.3(SDHB):c.423+1G>A","Chromosome":"1","Start":"17028599","Stop":"17028599","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38851,"rule_based_match":true,"evidence_text":"c.423+1G>A","llm_judgment":"PRESENT","evidence":"c.423+1G>A","abstract_start":907,"abstract_end":917},{"Name":"NM_003000.3(SDHB):c.141G>A (p.Trp47Ter)","Chromosome":"1","Start":"17044820","Stop":"17044820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":390935,"rule_based_match":true,"evidence_text":"c.141G>A (p.Trp47X)","llm_judgment":"PRESENT","evidence":"c.141G>A (p.Trp47X)","abstract_start":1636,"abstract_end":1655},{"Name":"NM_003000.3(SDHB):c.653G>C (p.Trp218Ser)","Chromosome":"1","Start":"17022720","Stop":"17022720","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":472317,"rule_based_match":true,"evidence_text":"c.653G>C (p.Trp218Ser)","llm_judgment":"PRESENT","evidence":"c.653G>C (p.Trp218Ser)","abstract_start":1684,"abstract_end":1706},{"Name":"NM_003000.3(SDHB):c.136C>T (p.Arg46Ter)","Chromosome":"1","Start":"17044825","Stop":"17044825","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152477,"rule_based_match":true,"evidence_text":"c.136C>T, p.Arg46X","llm_judgment":"PRESENT","evidence":"c.136C>T, p.Arg46X","abstract_start":1737,"abstract_end":1755}]}
{"pmid":"16088933","title":"DHPLC analysis of patients with Nevoid Basal Cell Carcinoma Syndrome reveals novel PTCH missense mutations in the sterol-sensing domain.","abstract":"Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is an autosomal dominant disorder characterised by multiple basal cell carcinomas, palmar and plantar pitting, odontogenic keratocysts of the jaws and bilamellar calcification of the falx. Mutations in the PTCH gene are responsible for NBCCS but most studies have found mutations in less than half of the cases tested. We used denaturing high performance liquid chromatography (DHPLC) to screen for PTCH mutations in 28 NBCCS cases, most of whom had been previously evaluated by single stranded conformation polymorphism analysis but found to be negative. Protein truncating (n = 10) and missense or indel (n = 4) mutations were found in 14/28 (50%) cases and one additional case carried an unclassified variant, c.2777G>C. Thirteen of the variants were novel. The mutation frequency was similar in inherited and de novo cases. Three of the missense and indel mutations were in the sterol-sensing domain, and one was in the sixth transmembrane domain.","variants":[{"Name":"NM_000264.5(PTCH1):c.2777G>C (p.Trp926Ser)","Chromosome":"9","Start":"95459710","Stop":"95459710","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1343164,"rule_based_match":true,"evidence_text":"c.2777G>C","llm_judgment":"PRESENT","evidence":"c.2777G>C","abstract_start":758,"abstract_end":767}]}
{"pmid":"32282352","title":"Digital clubbing as the predominant manifestation of hypertrophic osteoarthropathy caused by pathogenic variants in HPGD in three Indian families.","abstract":"15-Hydroxyprostaglandin dehydrogenase is NAD-dependent catalytic enzyme involved in prostaglandin biosynthesis pathway encoded by HPGD. The pathogenic variations in HPGD cause primary hypertrophic osteoarthropathy (PHO). The objective of the present study is to identify the genetic basis in patients with digital clubbing due to PHO. We performed detailed clinical and radiographic evaluation and exome sequencing in patients from three unrelated Indian families with PHO. Exome sequencing revealed two novel, c.34G>A (p.Gly12Ser) and c.313C>T (p.Gln105*) and a known variant, c.418G>C (p.Ala140Pro) in HPGD. Herein, we add three Indian families to HPGD mutation spectrum and review the literature on variants in this gene.","variants":[{"Name":"NM_000860.6(HPGD):c.34G>A (p.Gly12Ser)","Chromosome":"4","Start":"174522418","Stop":"174522418","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":962033,"rule_based_match":true,"evidence_text":"c.34G>A (p.Gly12Ser)","llm_judgment":"PRESENT","evidence":"c.34G>A (p.Gly12Ser)","abstract_start":511,"abstract_end":531},{"Name":"NM_000860.6(HPGD):c.313C>T (p.Gln105Ter)","Chromosome":"4","Start":"174517982","Stop":"174517982","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":962034,"rule_based_match":true,"evidence_text":"c.313C>T (p.Gln105*)","llm_judgment":"PRESENT","evidence":"c.313C>T (p.Gln105*)","abstract_start":536,"abstract_end":556},{"Name":"NM_000860.6(HPGD):c.418G>C (p.Ala140Pro)","Chromosome":"4","Start":"174508699","Stop":"174508699","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":22956,"rule_based_match":true,"evidence_text":"c.418G>C (p.Ala140Pro)","llm_judgment":"PRESENT","evidence":"c.418G>C (p.Ala140Pro)","abstract_start":578,"abstract_end":600}]}
{"pmid":"34952434","title":"Generation of a human induced pluripotent stem cell line YCMi004-A from a patient with dilated cardiomyopathy carrying a protein-truncating mutation of the Titin gene and its differentiation towards cardiomyocytes.","abstract":"Dilated cardiomyopathy (DCM) is a heart muscle disease that causes heart failure and is the leading cause for heart transplantation. It is a heart muscle disease resulted from a variety of genetics, toxic, metabolic, and infectious causes. One of the most prevalent genetic causes of DCM is a protein-truncating variant in the Titin gene (TTNtv). We have generated a human-induced pluripotent stem cell (hiPSC) line from patients who underwent heart transplantation due to DCM carrying a TTNtv mutation (c.70051C > T, p.Arg23351Ter) at the age of 20. The generated hiPSCs showed normal karyotype (46, XY) and expression of pluripotency markers, and were differentiated towards cardiomyocytes successfully.","variants":[{"Name":"NM_001267550.2(TTN):c.70051C>T (p.Arg23351Ter)","Chromosome":"2","Start":"178576081","Stop":"178576081","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":391889,"rule_based_match":true,"evidence_text":"c.70051C > T, p.Arg23351Ter","llm_judgment":"PRESENT","evidence":"c.70051C > T, p.Arg23351Ter","abstract_start":504,"abstract_end":531}]}
{"pmid":"34348960","title":"Homozygous mutations in","abstract":"BACKGROUND: Oligoasthenoteratozoospermia is a typical feature of sperm malformations leading to male infertility. Only a few genes have been clearly identified as pathogenic genes of oligoasthenoteratozoospermia.\nMETHODS AND RESULTS: Here, we identified a homozygous frameshift variant (c.731dup, p.Asn244Lysfs*3) in <i>CCDC34</i>, which is preferentially expressed in the human testis, using whole-exome sequencing in a cohort of 100 Chinese men with multiple morphological abnormalities of the sperm flagella (MMAF). In an additional cohort of 167 MMAF-affected men from North Africa, Iran and France, we identified a second subject harbouring a homozygous <i>CCDC34</i> frameshift variant (c.799_817del, p.Glu267Lysfs*72). Both affected men presented a typical MMAF phenotype with an abnormally low sperm concentration (ie, oligoasthenoteratozoospermia). Transmission electron microscopy analysis of the sperm flagella affected by <i>CCDC34</i> deficiency further revealed dramatic disorganisation of the axoneme. Immunofluorescence assays of the spermatozoa showed that <i>CCDC34</i> deficiency resulted in almost absent staining of CCDC34 and intraflagellar transport-B complex-associated proteins (such as IFT20 and IFT52). Furthermore, we generated a mouse <i>Ccdc34</i> frameshift mutant using CRISPR-Cas9 technology. <i>Ccdc34</i>-mutated (<i>Ccdc34<sup>mut/mut</sup></i> ) male mice were sterile and presented oligoasthenoteratozoospermia with typical MMAF anomalies. Intracytoplasmic sperm injection has good pregnancy outcomes in both humans and mice.\nCONCLUSIONS: Our findings support that <i>CCDC34</i> is crucial to the formation of sperm flagella and that biallelic deleterious mutations in <i>CCDC34</i>/<i>Ccdc34</i> cause male infertility with oligoasthenoteratozoospermia in humans and mice.","variants":[{"Name":"NM_030771.2(CCDC34):c.731dup (p.Asn244fs)","Chromosome":"11","Start":"27341425","Stop":"27341426","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AT","allel_id":1709320,"rule_based_match":true,"evidence_text":"c.731dup","llm_judgment":"PRESENT","evidence":"c.731dup","abstract_start":287,"abstract_end":295},{"Name":"NM_030771.2(CCDC34):c.799_817del (p.Glu267fs)","Chromosome":"11","Start":"27340786","Stop":"27340804","ReferenceAlleleVCF":"TCTGCTATTTCCTTTTTCTC","AlternateAlleleVCF":"T","allel_id":1709321,"rule_based_match":true,"evidence_text":"c.799_817del (p.Glu267Lysfs*72)","llm_judgment":"PRESENT","evidence":"c.799_817del","abstract_start":693,"abstract_end":705}]}
{"pmid":"21834902","title":"Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family.","abstract":"BACKGROUND:   Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by a combination of progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of DAP12 and TREM2, which constitute a receptor/adapter signaling complex expressed on osteoclasts, dendritic cells, macrophages, and microglia. No Japanese patients with TREM2 mutations have been reported previously.\nMETHODS:   We reported three siblings affected with NHD in a Japanese family. Amongst them, two died of NHD during the fourth decade of life. The analysis of genomic DNA, cDNA cloning, and western blot of lymphocyte proteins was performed on samples of the living patient. The transcriptome was studied in the autopsied brain of one patient.\nRESULTS:   We identified a homozygous conversion of a single nucleotide T to C at the second position of intron 3 in the splice-donor consensus site (c.482+2T>C) of the TREM2 gene, resulting in exon 3 skipping and aberrant expression of truncated proteins. We identified 136 upregulated genes involved in inflammatory response and immune cell trafficking and 188 downregulated genes including a battery of GABA receptor subunits and synaptic proteins in the patient's brain.\nCONCLUSIONS:   This is the first report of a Japanese NHD family caused by a splicing mutation of TREM2 that induces both neuroinflammation and neurodegeneration.","variants":[{"Name":"NM_018965.4(TREM2):c.482+2T>C","Chromosome":"6","Start":"41159790","Stop":"41159790","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":71364,"rule_based_match":true,"evidence_text":"c.482+2T>C","llm_judgment":"PRESENT","evidence":"c.482+2T>C","abstract_start":923,"abstract_end":933}]}
{"pmid":"29845260","title":"Two rare missense mutations in the fibrillin‑1 gene associated with atypical cardiovascular manifestations in a Chinese patient affected by Marfan syndrome.","abstract":"The present report aimed to evaluate the results of screen mutations of the fibrillin (FBN) 1 gene and analyze the symptoms in one Chinese patient clinically diagnosed with Marfan syndrome (MFS). Clinical data were collected and FBN1 gene sequencing was performed. Genomic DNA was extracted from the blood sample of the patient. All 65 exons were screened using a polymerase chain reaction assay. The diagnosis of MFS was confirmed via identification of symptoms presenting in the skeletal system (arachnodactyly, walker wrist and thumb signs) and the ocular system (ectopia lentis), in addition to a positive family history. The patient's cardiovascular manifestations (dilatation of the four cardiac chambers, severe mitral valve regurgitation and a large saccular aneurysm of the non‑coronary sinus of Valsalva) were atypical to those that most frequently occur in cases of MFS. Following gene sequencing, two novel heterozygous mutations of the FBN‑1 gene were identified: c.3442C>G in exon 27, proline replaced with alanine (p. Pro1148Ala) and c.6388G>A in exon 52, glutamic acid replaced with lysine (p. Glu2130Lys). The clinical symptoms and family history were important in the diagnosis of MFS, however the atypical signs that presented in the cardiovascular system may be associated with the disease, and may be noted for further cases in the future. Gene sequencing further verified the correct diagnosis of MFS.","variants":[{"Name":"NM_000138.5(FBN1):c.6388G>A (p.Glu2130Lys)","Chromosome":"15","Start":"48437069","Stop":"48437069","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":197650,"rule_based_match":true,"evidence_text":"c.6388G>A (p. Glu2130Lys)","llm_judgment":"PRESENT","evidence":"p. Glu2130Lys","abstract_start":1107,"abstract_end":1120}]}
{"pmid":"29801475","title":"Dyskeratosis congenita with a novel genetic variant in the DKC1 gene: a case report.","abstract":"BACKGROUND: Dyskeratosis congenita (DC) is a rare genetic disorder of bone marrow failure inherited in an X-linked, autosomal dominant or autosomal recessive pattern. It has a wide array of clinical features and patients may be cared for by many medical sub specialties. The typical clinical features consist of lacy reticular skin pigmentation, nail dystrophy and oral leukoplakia. As the disease advances, patients may develop progressive bone marrow failure, pulmonary fibrosis, oesophageal stenosis, urethral stenosis, liver cirrhosis as well as haematological and solid malignancies. Several genes have been implicated in the pathogenesis of dyskeratosis congenita, with the dyskerin pseudouridine synthase 1 (DKC1) gene mutations being the X-linked recessive gene.\nCASE PRESENTATION: Herein, we report a 31-year-old male with history of recurrent febrile episodes who was found to have reticulate skin pigmentation interspersed with hypopigmented macules involving the face, neck and extremities, hyperkeratosis of palms and soles, nail dystrophy, leukoplakia of the tongue, premature graying of hair, watery eyes and dental caries. Several of his male relatives, including two maternal uncles and three maternal cousins were affected with a similar type of disease condition. Pedigree analysis suggested a possible X-linked pattern of inheritance. Genetic testing in the proband showed a novel hemizygous, non-synonymous likely pathogenic variant [NM_001363.4: c.1054A > G: p.Thr352Ala] in the PUA domain of the DKC1 gene. Quantitative polymerase chain reaction for relative telomere length measurements performed in the proband showed that he had very short telomeres [0.38, compared to a control median of 0.71 (range 0.44-1.19)], which is consistent with the DC diagnosis. Co-segregation analysis of the novel mutation and telomere length measurements in the extended family members could not be performed as they were unwilling to provide consent for testing.\nCONCLUSIONS: The novel variant detected in the DKC1 gene adds further to the existing scientific literature on the genotype-phenotype correlation of DC, and has important implications for the clinical and molecular characterization of the disease.","variants":[{"Name":"NM_001363.5(DKC1):c.1054A>G (p.Thr352Ala)","Chromosome":"X","Start":"154773148","Stop":"154773148","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":418962,"rule_based_match":true,"evidence_text":"NM_001363.4: c.1054A > G: p.Thr352Ala","llm_judgment":"PRESENT","evidence":"NM_001363.4: c.1054A > G: p.Thr352Ala","abstract_start":1455,"abstract_end":1492}]}
{"pmid":"31645973","title":"Novel missense variants in the","abstract":"In this report, we present a European family with six individuals affected with Moyamoya disease (MMD). We detected two novel missense variants in the Moyamoya susceptibility gene <i>RNF213</i>, c.12553A>G (p.(Lys4185Glu)) and c.12562G>A (p.(Ala4188Thr)). Cosegregation of the variants with MMD, as well as a previous report of a variant affecting the same amino acid residue in unrelated MMD patients, supports the role of <i>RNF213</i> in the pathogenesis of MMD.","variants":[{"Name":"NM_001256071.3(RNF213):c.12553A>G (p.Lys4185Glu)","Chromosome":"17","Start":"80372536","Stop":"80372536","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":576249,"rule_based_match":true,"evidence_text":"c.12553A>G (p.(Lys4185Glu))","llm_judgment":"PRESENT","evidence":"c.12553A>G (p.(Lys4185Glu))","abstract_start":195,"abstract_end":222},{"Name":"NM_001256071.3(RNF213):c.12562G>A (p.Ala4188Thr)","Chromosome":"17","Start":"80372545","Stop":"80372545","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":576250,"rule_based_match":true,"evidence_text":"c.12562G>A (p.(Ala4188Thr))","llm_judgment":"PRESENT","evidence":"c.12562G>A (p.(Ala4188Thr))","abstract_start":227,"abstract_end":254}]}
{"pmid":"15514099","title":"Liver dysfunction and steatosis in familial hypobetalipoproteinemia.","abstract":"A 32-year-old man presented with increases in serum alanine aminotransferase activity, iron concentration, and transferrin saturation, suggestive of hepatic dysfunction and iron overload. In addition, he had unusually low plasma concentrations of LDL-cholesterol and apolipoprotein (apo) B. Hepatic ultrasonography was consistent with fatty liver. On liver biopsy, marked steatosis and moderate to marked iron deposition were observed. The patient was found to carry the HFE C282Y and H63D mutations, which are associated with hereditary hemochromatosis, and the alpha(1)-antitrypsin PiZ variant. An immunoblot of plasma for apoB showed the presence of a truncated apoB species, indicative of familial hypobetalipoproteinemia. DNA sequence analysis revealed that the patient was heterozygous for the apoB-80.5 (c.11040T>G) mutation. This unique case shows an unusual combination of underlying disorders that could all be contributing to liver dysfunction and fatty liver.","variants":[{"Name":"NM_000384.3(APOB):c.11040T>G (p.Tyr3680Ter)","Chromosome":"2","Start":"21005828","Stop":"21005828","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1313611,"rule_based_match":true,"evidence_text":"c.11040T>G","llm_judgment":"PRESENT","evidence":"c.11040T>G","abstract_start":811,"abstract_end":821}]}
{"pmid":"31222513","title":"Primary creatine deficiency syndrome as a potential missed diagnosis in children with psychomotor delay and seizure: case presentation with two novel variants and literature review.","abstract":"Creatine is the main source of energy for the brain. Primary creatine deficiency syndromes (PCDSs) are inborn error of metabolism of creatine synthesis. Symptoms of central nervous system involvement are the most common clinical manifestations in these disorders. We reviewed medical records of all genetically confirmed patients diagnosed by whole exome sequencing who were referred to Myelin and Neurodegenerative Disorders Clinic, Children's Medical Center, Tehran, Iran, from May 2016 to Dec 2018. A literature review was conducted on clinical and genomic variability of PCDS to compare our patients with previously reported cases. We report two patients with creatine deficiency among a cohort of 550 registered cases out of which 200 patients had a genetically confirmed neurodegenerative disorder diagnosis. The main complain in the first patient with creatine transporter (CRTR) deficiency was seizure and genetic study in this patient identified a novel hemizygote variant of \"c.92 > T; p.Pro31Leu\" in the first exon of SLC6A8 gene. The second patient with guanidinoacetate methyltransferase (GAMT) deficiency had an unknown motor and speech delay as the striking manifestation and molecular assay revealed a novel homozygote variant of \"c.134G > A; p.Trp45*\" in the first exon of GAMT gene. PCDSs usually are associated with nonspecific neurologic symptoms. The first presented case had a mean delayed diagnosis of 5 years. Therefore, in children with unexplained neurologic features including developmental delay and/or regression, mental disability and repeated seizures without any significant findings in metabolic studies, PCDSs can be considered as a differential diagnosis and molecular analysis can be helpful for the precise diagnosis and treatment.","variants":[{"Name":"NM_000156.6(GAMT):c.134G>A (p.Trp45Ter)","Chromosome":"19","Start":"1401343","Stop":"1401343","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1941730,"rule_based_match":true,"evidence_text":"c.134G > A; p.Trp45*","llm_judgment":"PRESENT","evidence":"c.134G > A; p.Trp45*","abstract_start":1247,"abstract_end":1267}]}
{"pmid":"29260190","title":"Novel Mutations in PRPF31 Causing Retinitis Pigmentosa Identified Using Whole-Exome Sequencing.","abstract":"Purpose: The purpose of this study was to investigate the disease-causing mutations for retinitis pigmentosa (RP) patients and function of mutations.\nMethods: We recruited RP families and sporadic RP patients, and performed whole-exome sequencing (WES) to screen for sequence variations. Subsequently, we investigated the expression of green fluorescent protein (GFP) merged expression vectors containing PRPF31 wild type (WT) and its variants. We determined protein stability by cycloheximide (CHX) treatment.\nResults: Two frameshift variants, c.547delG (p.E183fs) and c.804delG (p.L268fs), and one stopgain variant, c.1060C>T (p.R354X), in the pre-mRNA processing factor 31 gene (PRPF31) were identified in three RP families. In comparison with WT, the expressions of GFP-fused PRPF31 (GFP-PRPF31) protein with the mutation c.547delG or c.804delG in HEK293 cells were significantly reduced. However, the expression of GFP-PRPF31 containing the stopgain mutation (GFP-PRPF31sg) was increased. CHX treatment of HEK293 showed the GFP-PRPF31sg protein was more stable than GFP-PRPF31 WT. The WT protein expression was localized in the nuclei, and the mutants in both nuclei and cytoplasm. We screened for PRPF31 mutations in 131 sporadic RP patients by WES and successfully identified three novel mutations: c.G781C (p.G261R), c.A1373T (p.Q458L), and c.C1222T (p.R408W).\nConclusions: Our study revealed novel mutations of PRPF31 in RP. Our results also showed that the two mutations (c.547delG or c.804delG) affect gene expression and GFP-PRPF31sg has increased protein stability.","variants":[{"Name":"NM_015629.4(PRPF31):c.1060C>T (p.Arg354Ter)","Chromosome":"19","Start":"54128187","Stop":"54128187","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":238096,"rule_based_match":true,"evidence_text":"c.1060C>T (p.R354X)","llm_judgment":"PRESENT","evidence":"c.1060C>T (p.R354X)","abstract_start":618,"abstract_end":637}]}
{"pmid":"24986916","title":"A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder.","abstract":"We conducted blinded psychiatric assessments of 26 Amish subjects (52 ± 11 years) from four families with prevalent bipolar spectrum disorder, identified 10 potentially pathogenic alleles by exome sequencing, tested association of these alleles with clinical diagnoses in the larger Amish Study of Major Affective Disorder (ASMAD) cohort, and studied mutant potassium channels in neurons. Fourteen of 26 Amish had bipolar spectrum disorder. The only candidate allele shared among them was rs78247304, a non-synonymous variant of KCNH7 (c.1181G>A, p.Arg394His). KCNH7 c.1181G>A and nine other potentially pathogenic variants were subsequently tested within the ASMAD cohort, which consisted of 340 subjects grouped into controls subjects and affected subjects from overlapping clinical categories (bipolar 1 disorder, bipolar spectrum disorder and any major affective disorder). KCNH7 c.1181G>A had the highest enrichment among individuals with bipolar spectrum disorder (χ(2) = 7.3) and the strongest family-based association with bipolar 1 (P = 0.021), bipolar spectrum (P = 0.031) and any major affective disorder (P = 0.016). In vitro, the p.Arg394His substitution allowed normal expression, trafficking, assembly and localization of HERG3/Kv11.3 channels, but altered the steady-state voltage dependence and kinetics of activation in neuronal cells. Although our genome-wide statistical results do not alone prove association, cumulative evidence from multiple independent sources (parallel genome-wide study cohorts, pharmacological studies of HERG-type potassium channels, electrophysiological data) implicates neuronal HERG3/Kv11.3 potassium channels in the pathophysiology of bipolar spectrum disorder. Such a finding, if corroborated by future studies, has implications for mental health services among the Amish, as well as development of drugs that specifically target HERG3/Kv11.3.","variants":[{"Name":"NM_033272.4(KCNH7):c.1181G>A (p.Arg394His)","Chromosome":"2","Start":"162446391","Stop":"162446391","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":178371,"rule_based_match":true,"evidence_text":"KCNH7 c.1181G>A (p.Arg394His)","llm_judgment":"PRESENT","evidence":"p.Arg394His","abstract_start":547,"abstract_end":558}]}
{"pmid":"27275416","title":"Use of high-throughput targeted exome sequencing in genetic diagnosis of Chinese family with congenital cataract.","abstract":"AIM: To identify disease-causing mutation in a congenital cataract family using enrichment of targeted genes combined with next-generation sequencing.\nMETHODS: A total of 371 known genes related to inherited eye diseases of the proband was selected and captured, followed by high-throughput sequencing. The sequencing data were analyzed by established bioinformatics pipeline. Validation was performed by Sanger sequencing.\nRESULTS: A recurrent heterozygous non-synonymous mutation c.130G>A (p.V44M) in the GJA3 gene was identified in the proband. The result was confirmed by Sanger sequencing. The mutation showed co-segregation with the disease phenotype in the family but was not detected in unaffected controls.\nCONCLUSION: Targeted exome sequencing is a rapid, high-throughput and cost-efficient method for screening known genes and could be applied to the routine gene diagnosis of congenital cataract.","variants":[{"Name":"NM_021954.4(GJA3):c.130G>A (p.Val44Met)","Chromosome":"13","Start":"20143159","Stop":"20143159","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":641579,"rule_based_match":true,"evidence_text":"c.130G>A (p.V44M)","llm_judgment":"PRESENT","evidence":"c.130G>A (p.V44M)","abstract_start":482,"abstract_end":499}]}
{"pmid":"26070314","title":"Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress.","abstract":"BACKGROUND: Familial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, MRAP) or the general steroidogenesis protein (StAR). Recently, nicotinamide nucleotide transhydrogenase (NNT) mutations were found to cause FGD through a postulated mechanism resulting from decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells.\nMETHODS AND RESULTS: In a consanguineous Palestinian family with combined mineralocorticoid and glucocorticoid deficiency, whole-exome sequencing revealed a novel homozygous NNT_c.598 G>A, p.G200S, mutation. Another affected, unrelated Palestinian child was also homozygous for NNT_p.G200S. Haplotype analysis showed this mutation is ancestral; carrier frequency in ethnically matched controls is 1/200. Assessment of patient fibroblasts for ROS production, ATP content and mitochondrial morphology showed that biallelic NNT mutations result in increased levels of ROS, lower ATP content and morphological mitochondrial defects.\nCONCLUSIONS: This report of a novel NNT mutation, p.G200S, expands the phenotype of NNT mutations to include mineralocorticoid deficiency. We provide the first patient-based evidence that NNT mutations can cause oxidative stress and both phenotypic and functional mitochondrial defects. These results directly demonstrate the importance of NNT to mitochondrial function in the setting of adrenocortical insufficiency.","variants":[{"Name":"NM_182977.3(NNT):c.598G>A (p.Gly200Ser)","Chromosome":"5","Start":"43616064","Stop":"43616064","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":260549,"rule_based_match":true,"evidence_text":"NNT_c.598 G>A, p.G200S","llm_judgment":"PRESENT","evidence":"NNT_c.598 G>A, p.G200S","abstract_start":697,"abstract_end":719}]}
{"pmid":"27132592","title":"Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies.","abstract":"Mitochondrial disorders are clinically and genetically diverse, with mutations in mitochondrial or nuclear genes able to cause defects in mitochondrial gene expression. Recently, mutations in several genes encoding factors involved in mt-tRNA processing have been identified to cause mitochondrial disease. Using whole-exome sequencing, we identified mutations in TRMT10C (encoding the mitochondrial RNase P protein 1 [MRPP1]) in two unrelated individuals who presented at birth with lactic acidosis, hypotonia, feeding difficulties, and deafness. Both individuals died at 5 months after respiratory failure. MRPP1, along with MRPP2 and MRPP3, form the mitochondrial ribonuclease P (mt-RNase P) complex that cleaves the 5' ends of mt-tRNAs from polycistronic precursor transcripts. Additionally, a stable complex of MRPP1 and MRPP2 has m(1)R9 methyltransferase activity, which methylates mt-tRNAs at position 9 and is vital for folding mt-tRNAs into their correct tertiary structures. Analyses of fibroblasts from affected individuals harboring TRMT10C missense variants revealed decreased protein levels of MRPP1 and an increase in mt-RNA precursors indicative of impaired mt-RNA processing and defective mitochondrial protein synthesis. The pathogenicity of the detected variants-compound heterozygous c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala) changes in subject 1 and a homozygous c.542G>T (p.Arg181Leu) variant in subject 2-was validated by the functional rescue of mt-RNA processing and mitochondrial protein synthesis defects after lentiviral transduction of wild-type TRMT10C. Our study suggests that these variants affect MRPP1 protein stability and mt-tRNA processing without affecting m(1)R9 methyltransferase activity, identifying mutations in TRMT10C as a cause of mitochondrial disease and highlighting the importance of RNA processing for correct mitochondrial function.","variants":[{"Name":"NM_017819.4(TRMT10C):c.542G>T (p.Arg181Leu)","Chromosome":"3","Start":"101565323","Stop":"101565323","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":226044,"rule_based_match":true,"evidence_text":"c.542G>T (p.Arg181Leu)","llm_judgment":"PRESENT","evidence":"c.542G>T (p.Arg181Leu)","abstract_start":1304,"abstract_end":1326},{"Name":"NM_017819.4(TRMT10C):c.814A>G (p.Thr272Ala)","Chromosome":"3","Start":"101565595","Stop":"101565595","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":226045,"rule_based_match":true,"evidence_text":"c.814A>G (p.Thr272Ala)","llm_judgment":"PRESENT","evidence":"c.814A>G (p.Thr272Ala)","abstract_start":1331,"abstract_end":1353}]}
{"pmid":"29855340","title":"TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of α-dystroglycan and muscular dystrophy.","abstract":"BACKGROUND: Transport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb girdle muscular dystrophy and congenital muscular dystrophy. It remains unclear how this protein leads to muscle disease. Furthermore, a role for this protein, or any other membrane trafficking protein, in the etiology of the dystroglycanopathy group of muscular dystrophies has yet to be found. Here, using a multidisciplinary approach including genetics, immunofluorescence, western blotting, and live cell analysis, we implicate both TRAPPC11 and another membrane trafficking protein, GOSR2, in α-dystroglycan hypoglycosylation.\nCASE PRESENTATION: Subject 1 presented with severe epileptic episodes and subsequent developmental deterioration. Upon clinical evaluation she was found to have brain, eye, and liver abnormalities. Her serum aminotransferases and creatine kinase were abnormally high. Subjects 2 and 3 are siblings from a family unrelated to subject 1. Both siblings displayed hypotonia, muscle weakness, low muscle bulk, and elevated creatine kinase levels. Subject 3 also developed a seizure disorder. Muscle biopsies from subjects 1 and 3 were severely dystrophic with abnormal immunofluorescence and western blotting indicative of α-dystroglycan hypoglycosylation. Compound heterozygous mutations in TRAPPC11 were identified in subject 1: c.851A>C and c.965+5G>T. Cellular biological analyses on fibroblasts confirmed abnormal membrane trafficking. Subject 3 was found to have compound heterozygous mutations in GOSR2: c.430G>T and c.2T>G. Cellular biological analyses on fibroblasts from subject 3 using two different model cargo proteins did not reveal defects in protein transport. No mutations were found in any of the genes currently known to cause dystroglycanopathy in either individual.\nCONCLUSION: Recessive mutations in TRAPPC11 and GOSR2 are associated with congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. This is the first report linking membrane trafficking proteins to dystroglycanopathy and suggests that these genes should be considered in the diagnostic evaluation of patients with congenital muscular dystrophy and dystroglycanopathy.","variants":[{"Name":"NM_004287.5(GOSR2):c.430G>T (p.Gly144Trp)","Chromosome":"17","Start":"46935122","Stop":"46935122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39363,"rule_based_match":true,"evidence_text":"c.430G>T","llm_judgment":"PRESENT","evidence":"c.430G>T","abstract_start":1758,"abstract_end":1766},{"Name":"NM_004287.5(GOSR2):c.2T>G (p.Met1Arg)","Chromosome":"17","Start":"46923194","Stop":"46923194","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1314765,"rule_based_match":true,"evidence_text":"c.2T>G","llm_judgment":"PRESENT","evidence":"c.2T>G","abstract_start":1771,"abstract_end":1777},{"Name":"NM_021942.6(TRAPPC11):c.965+5G>T","Chromosome":"4","Start":"183679491","Stop":"183679491","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":453458,"rule_based_match":true,"evidence_text":"c.965+5G>T","llm_judgment":"PRESENT","evidence":"c.965+5G>T","abstract_start":1591,"abstract_end":1601}]}
{"pmid":"26885414","title":"A Novel Nonsense Mutation of the AGL Gene in a Romanian Patient with Glycogen Storage Disease Type IIIa.","abstract":"Background. Glycogen storage disease type III (GSDIII) is a rare metabolic disorder with autosomal recessive inheritance, caused by deficiency of the glycogen debranching enzyme. There is a high phenotypic variability due to different mutations in the AGL gene. Methods and Results. We describe a 2.3-year-old boy from a nonconsanguineous Romanian family, who presented with severe hepatomegaly with fibrosis, mild muscle weakness, cardiomyopathy, ketotic fasting hypoglycemia, increased transaminases, creatine phosphokinase, and combined hyperlipoproteinemia. GSD type IIIa was suspected. Accordingly, genomic DNA of the index patient was analyzed by next generation sequencing of the AGL gene. For confirmation of the two mutations found, genetic analysis of the parents and grandparents was also performed. The patient was compound heterozygous for the novel mutation c.3235C>T, p.Gln1079(⁎) (exon 24) and the known mutation c.1589C>G, p.Ser530(⁎) (exon 12). c.3235 >T, p.Gln1079(⁎) was inherited from the father, who inherited it from his mother. c.1589C>G, p.Ser530(⁎) was inherited from the mother, who inherited it from her father. Conclusion. We report the first genetically confirmed case of a Romanian patient with GSDIIIa. We detected a compound heterozygous genotype with a novel mutation, in the context of a severe hepatopathy and an early onset of cardiomyopathy.","variants":[{"Name":"NM_000642.3(AGL):c.3235C>T (p.Gln1079Ter)","Chromosome":"1","Start":"99892583","Stop":"99892583","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":541417,"rule_based_match":true,"evidence_text":"c.3235C>T, p.Gln1079(⁎)","llm_judgment":"PRESENT","evidence":"c.3235C>T, p.Gln1079(⁎)","abstract_start":872,"abstract_end":895},{"Name":"NM_000642.3(AGL):c.1589C>G (p.Ser530Ter)","Chromosome":"1","Start":"99877806","Stop":"99877806","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":541442,"rule_based_match":true,"evidence_text":"c.1589C>G, p.Ser530(⁎)","llm_judgment":"PRESENT","evidence":"c.1589C>G, p.Ser530(⁎)","abstract_start":929,"abstract_end":951}]}
{"pmid":"19274735","title":"Mutations in the first MyTH4 domain of MYO15A are a common cause of DFNB3 hearing loss.","abstract":"OBJECTIVES: To use clinical and genetic analyses to determine the mutation causing autosomal recessive nonsyndromic hearing loss (ARNSHL) segregating in two consanguineous Iranian families.\nSTUDY DESIGN: Family study.\nMETHODS: Members of each family received otologic and audiometric examination for the type and extent of hearing loss. Linkage mapping using Affymetrix 50K GeneChips and short tandem repeat (STRP) analysis localized the hearing loss in both families to the DFNB3 locus. Direct sequencing of the MYO15A gene was completed on affected members of both families.\nRESULTS: Family L-3165 segregated a novel homozygous missense mutation (c.6371G>A) that results in a p.R2124Q amino acid substitution in the myosin XVa protein, while family L-896 segregated a novel homozygous missense (c.6555C>T) mutation resulting in a p.P2073S amino acid change.\nCONCLUSIONS: These are the first MYO15A mutations reported to cause DFNB3 sensorineural hearing loss in the Iranian population. Like other mutations located in the myosin tail homology 4 (MyTH4) domain, the p.R2124Q and p.P2073S mutations are predicted to disrupt the function of the myosin XVa protein, which is integral to the mechanosensory activity of hair cells in the inner ear.","variants":[{"Name":"NM_016239.4(MYO15A):c.6371G>A (p.Arg2124Gln)","Chromosome":"17","Start":"18145969","Stop":"18145969","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":928086,"rule_based_match":true,"evidence_text":"c.6371G>A","llm_judgment":"PRESENT","evidence":"c.6371G>A","abstract_start":649,"abstract_end":658}]}
{"pmid":"18489799","title":"Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer.","abstract":"BACKGROUND: The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic) during 1999-2006.\nMETHODS: The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing.\nRESULTS: In 294 unrelated families (29.1% of the 1,010 probands) pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly) and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2) represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A) and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G) were demonstrated to result in aberrant transcripts and are considered as deleterious mutations.\nCONCLUSION: This study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.","variants":[{"Name":"NM_007294.4(BRCA1):c.4185G>A (p.Gln1395=)","Chromosome":"17","Start":"43090944","Stop":"43090944","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":69798,"rule_based_match":true,"evidence_text":"c.4185G>A","llm_judgment":"PRESENT","evidence":"c.4185G>A","abstract_start":1396,"abstract_end":1405},{"Name":"NM_007294.4(BRCA1):c.4675+1G>A","Chromosome":"17","Start":"43074330","Stop":"43074330","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":69923,"rule_based_match":true,"evidence_text":"c.4675+1G>A","llm_judgment":"PRESENT","evidence":"c.4675+1G>A","abstract_start":1410,"abstract_end":1421},{"Name":"NM_000059.4(BRCA2):c.9117+2T>A","Chromosome":"13","Start":"32379915","Stop":"32379915","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":67424,"rule_based_match":true,"evidence_text":"c.9117+2T>A","llm_judgment":"PRESENT","evidence":"c.9117+2T>A","abstract_start":1507,"abstract_end":1518},{"Name":"NM_000059.4(BRCA2):c.9118-2A>G","Chromosome":"13","Start":"32380005","Stop":"32380005","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":67427,"rule_based_match":true,"evidence_text":"c.9118-2A>G","llm_judgment":"PRESENT","evidence":"c.9118-2A>G","abstract_start":1523,"abstract_end":1534},{"Name":"NM_007294.4(BRCA1):c.302-3C>G","Chromosome":"17","Start":"43104264","Stop":"43104264","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":46057,"rule_based_match":true,"evidence_text":"c.302-3C>G","llm_judgment":"PRESENT","evidence":"c.302-3C>G","abstract_start":1384,"abstract_end":1394}]}
{"pmid":"38337174","title":"Oculocutaneous albinism type 4: Novel compound heterozygous mutations in the SLC45A2 gene in a Chinese case.","abstract":"BACKGROUND: Oculocutaneous albinism type 4 (OCA4) is a rare autosomal recessive disorder characterized by a reduction of pigmentation in skin, hair, and eyes, and OCA4 is mainly seen in the SLC45A2 gene variants.\nOBJECTIVE: To report a Chinese patient suspected of oculocutaneous albinism and identify the causing mutation.\nMETHODS: Genomic DNA was extracted from the peripheral blood samples of the patient, his parents, and elder brother. Whole exome sequencing was performed in the family, and Sanger sequencing was then used to verify the mutations.\nRESULTS: Compound heterozygous variants, c.1304C>A (p.S435Y) and c.301C>G (p.R101G) in SLC45A2 gene, were detected in the proband, which were inherited from his father and mother respectively. Based on the ACMG guidelines, we can interpret the c.1304C>A (p.S435Y) variant as a suspected pathogenic variant and the c.301C>G (p.R101G) variant as a clinically significant unspecified variant. The diagnosis of OCA4 is confirmed.\nCONCLUSION: We firstly reported this case of OCA4 with the compound heterozygous variants in the SLC45A2 gene. Our findings further enrich the reservoir of SLC45A2 mutations in OCA4.","variants":[{"Name":"NM_016180.5(SLC45A2):c.1304C>A (p.Ser435Tyr)","Chromosome":"5","Start":"33947227","Stop":"33947227","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3222590,"rule_based_match":true,"evidence_text":"c.1304C>A (p.S435Y)","llm_judgment":"PRESENT","evidence":"c.1304C>A (p.S435Y)","abstract_start":595,"abstract_end":614},{"Name":"NM_016180.5(SLC45A2):c.301C>G (p.Arg101Gly)","Chromosome":"5","Start":"33984283","Stop":"33984283","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3222591,"rule_based_match":true,"evidence_text":"c.301C>G (p.R101G)","llm_judgment":"PRESENT","evidence":"c.301C>G (p.R101G)","abstract_start":619,"abstract_end":637}]}
{"pmid":"23271757","title":"Aspartylglucosaminuria: unusual neonatal presentation in Qatari twins with a novel aspartylglucosaminidase gene mutation and 3 new cases in a Turkish family.","abstract":"Aspartylglucosaminuria is a rare autosomal recessive lysosomal storage disorder leading early to a progressive intellectual disability. Monozygous Qatari twins presented with an unusual perinatal manifestation characterized by severe muscular hypotonia, scarce spontaneous movements, multiple contractures, and respiratory insufficiency. Biochemical investigations suggested aspartylglucosaminuria, and a novel homozygous mutation c.439T>C (p.S147P) was found in the aspartylglucosaminidase gene. However, it cannot be excluded that the unusual neonatal presentation is due to an additional autosomal recessive disease in this multiply consanguineous family. The classical aspartylglucosaminuria phenotype (progressive speech delay, psychomotor retardation, and behavioral abnormalities) was observed in 3 Turkish siblings. Although aspartylglucosaminuria was suspected early, the definite diagnosis was not confirmed until the age of 18 years. A novel homozygous mutation c.346C>T (p.R116W) was found. These 5 cases emphasize that aspartylglucosaminuria is panethnic and may possibly present with prenatal manifestation. Screening for aspartylglucosaminuria should be done in all patients with unexplained psychomotor retardation.","variants":[{"Name":"NM_000027.4(AGA):c.439T>C (p.Ser147Pro)","Chromosome":"4","Start":"177438813","Stop":"177438813","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":70586,"rule_based_match":true,"evidence_text":"c.439T>C (p.S147P)","llm_judgment":"PRESENT","evidence":"c.439T>C (p.S147P)","abstract_start":431,"abstract_end":449},{"Name":"NM_000027.4(AGA):c.346C>T (p.Arg116Trp)","Chromosome":"4","Start":"177439624","Stop":"177439624","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70581,"rule_based_match":true,"evidence_text":"c.346C>T (p.R116W)","llm_judgment":"PRESENT","evidence":"c.346C>T (p.R116W)","abstract_start":973,"abstract_end":991}]}
{"pmid":"29378538","title":"A novel compound heterozygous variant of the SLC12A3 gene in Gitelman syndrome pedigree.","abstract":"BACKGROUND: Gitelman syndrome (GS) is an autosomal recessive disorder caused by genic mutations of SLC12A3 (Solute carrier family 12 member 3), which encodes the Na-Cl cotransporter (NCC), and presents with characteristic metabolic abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. In this study, we report a case of a GS pedigree, including analysis of GS-associated gene mutations.\nMETHODS: We performed next-generation sequencing analysis and Sanger sequencing to explore the SLC12A3 mutations in a GS pedigree that included a 35-year-old female patient with GS and five family members within three generations. Furthermore, we summarized their clinical manifestations and analyzed laboratory parameters related to GS.\nRESULTS: The female proband (the patient with GS) presented with intermittent fatigue and transient periods of tetany, along with significant hypokalemia, hypomagnesemia, and hypocalciuria. All other members of the pedigree had normal laboratory results without obvious GS-related symptoms. Genetic analysis of the SLC12A3 gene identified two novel missense mutations (c.1919A > G, p.N640S in exon 15; c.2522A > G, p.D841G in exon 21) in the patient with GS. Moreover, we demonstrated that her mother, younger maternal uncle, and cousin were carriers of one mutation (c.1919A > G), and her father was the carrier of the other (c.2522A > G).\nCONCLUSION: This is the first report of these two novel pathogenic variants of SLC12A3 and their contribution to GS. Further functional studies are particularly warranted to explore the underlying molecular mechanisms.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1919A>G (p.Asn640Ser)","Chromosome":"16","Start":"56885358","Stop":"56885358","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":260484,"rule_based_match":true,"evidence_text":"c.1919A > G, p.N640S","llm_judgment":"PRESENT","evidence":"c.1919A > G, p.N640S","abstract_start":1135,"abstract_end":1155}]}
{"pmid":"27959436","title":"Novel CC2D2A compound heterozygous mutations cause Joubert syndrome.","abstract":"Joubert syndrome (JS) is an autosomal recessive disorder, which is characterized by hypotonia, ataxia, psychomotor delay, and variable occurrences of oculomotor apraxia and neonatal breathing abnormalities. JS is clinically and genetically heterogeneous. The present study investigated a typical JS family. The 'molar tooth sign' was observed in the proband through magnetic resonance imaging. Other symptoms of JS include cerebellar vermis hypoplasia/dysplasia, oculomotor apraxia and intellectual disability. High‑throughput sequencing revealed that JS was caused by coiled‑coil and C2 domain containing 2A (CC2D2A) compound heterozygous mutations. One CC2D2A allele was affected with a missense mutation, c.2581G>A, which led to a p.Asp861Asn amino acid replacement. The other allele was affected with a c.2848C>T nonsense mutation, which resulted in a truncated CC2D2A protein (p.Arg950Ter). Both of these alterations are novel. Further investigation indicated that the proband's father was the c.2581G>A carrier, whereas the mother was the c.2848C>T carrier. These results indicated that JS in the proband was caused by novel compound heterozygous mutations in CC2D2A, which were inherited from both parents. These findings may be used to establish prenatal molecular diagnostic criteria, which may be beneficial in future pregnancies.","variants":[{"Name":"NM_001378615.1(CC2D2A):c.2848C>T (p.Arg950Ter)","Chromosome":"4","Start":"15559183","Stop":"15559183","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15784,"rule_based_match":true,"evidence_text":"c.2848C>T","llm_judgment":"PRESENT","evidence":"c.2848C>T","abstract_start":807,"abstract_end":816},{"Name":"NM_001378615.1(CC2D2A):c.2581G>A (p.Asp861Asn)","Chromosome":"4","Start":"15555166","Stop":"15555166","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1934824,"rule_based_match":true,"evidence_text":"c.2581G>A","llm_judgment":"PRESENT","evidence":"c.2581G>A","abstract_start":708,"abstract_end":717}]}
{"pmid":"36329616","title":"Acute Intermittent Porphyria: Complete Phenotype in a Patient with p.Arg173Trp Variant in Thailand.","abstract":"BACKGROUND Acute intermittent porphyria (AIP) is a rare genetic disease caused by the deficiency of porphobilinogen deaminase enzyme in the heme synthesis pathway. AIP is passed by autosomal dominant inheritance. Heterozygous pathogenic variants in hydroxymethylbilane synthase (HMBS) are associated with AIP. Multisystemic manifestations of acute neurovisceral features exist, which are quite challenging for diagnosis. Currently, few patients worldwide have been reported with AIP. A small number of reports have been published in Thailand, but none have been confirmed by molecular genetics diagnosis. CASE REPORT A 14-year-old female adolescent presented with severe intermittent abdominal pain, vomiting, seizure, posterior reversible encephalopathy syndrome, syndrome of inappropriate antidiuretic hormone, and muscle weakness, which are all classic phenotypes of an acute AIP attack. The patient received several investigations before AIP was suspected. High levels of urine porphobilinogen, high levels of urine aminolevulinic acid, and a heterozygous known pathogenic variant in HMBS: c.517C>T (p.Arg173Trp) were identified. Therefore, AIP was the definitive diagnosis. Then, Sanger sequencing testing was performed for the patient's family; this variant was found in her father, paternal grandmother, and sister, who were all asymptomatic (latent AIP). After the AIP was confirmed, high carbohydrate loading was given as a standard treatment. She had a full recovery; her clinical course of the attack episode lasted for 8 weeks. CONCLUSIONS An early diagnosis of AIP leads to prompt and specific treatment, which can shorten the duration of attacks, prevent complications, reduce the cost of treatment, and reduce the mortality rate.","variants":[{"Name":"NM_000190.4(HMBS):c.517C>T (p.Arg173Trp)","Chromosome":"11","Start":"119091431","Stop":"119091431","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":639782,"rule_based_match":true,"evidence_text":"c.517C>T (p.Arg173Trp)","llm_judgment":"PRESENT","evidence":"c.517C>T (p.Arg173Trp)","abstract_start":1094,"abstract_end":1116}]}
{"pmid":"23771590","title":"Clinical and polygraphic study of familial paroxysmal kinesigenic dyskinesia with PRRT2 mutation.","abstract":"BACKGROUND: Paroxysmal kinesigenic dyskinesia is a neurological condition characterised by brief attacks of involuntary movements triggered by sudden voluntary movements.\nMETHODS: We describe the clinical, polygraphic, and genetic features of an Italian family with paroxysmal kinesigenic dyskinesia.\nRESULTS: Paroxysmal kinesigenic dyskinesia manifested as brief choreoathetosic-dystonic attacks precipitated by sudden movements, varying in severity and frequency, amongst the four affected family members. The disorder follows an autosomal dominant transmission and affects female members. Mutation of SLC2A1, MR1, CACNA1A, and ATP1A2 genes was excluded by direct sequencing. Mutation analysis of the PRRT2 gene revealed a single nucleotide duplication, c.649dupC, resulting in the frameshift mutation p.Arg217Profs*8 in all affected members.\nCONCLUSION: Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal movement disorder and is often misdiagnosed clinically as epilepsy. We describe a family with paroxysmal kinesigenic dyskinesia associated with PRRT2 gene mutation, mild intrafamilial clinical heterogeneity, and benign course. [Published with video sequences].","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC","llm_judgment":"PRESENT","evidence":"c.649dupC","abstract_start":756,"abstract_end":765}]}
{"pmid":"24014090","title":"Novel mutations in ADAMTSL2 gene underlying geleophysic dysplasia in families from United Arab Emirates.","abstract":"BACKGROUND: Geleophysic dysplasia (GD) is an autosomal recessive disorder characterized by short stature, brachydactyly, stiff joints, thick skin, and cardiac valvular abnormalities that are often responsible for early death. Mutations in ADAMTSL2 and FBN1 genes have been shown to cause GD due to the dysregulation of transforming growth factor-β signaling pathways. Small numbers of mutations in ADAMTSL2 have been reported so far in patients with GD type 1 (GD1).\nMETHODS: In this study, we clinically evaluated two children from two consanguineous Arab families living in the United Arab Emirates with GD1. In addition we have sequenced all the coding exons of ADAMTSL2 gene using Sanger sequencing.\nRESULTS: The two patients exhibited most of the typical features of this rare bone dysplasia. Molecular analysis of the ADAMTSL2 gene revealed two novel homozygous missense mutations (c.938T>C, p.M313T and c.499G>A, p.D167N). The mutations segregated well in the studied families with the parents being heterozygous. In addition, bioinformatics analyses showed that these mutations are affecting conserved amino acids residues and thus strongly support their pathogenicity.\nCONCLUSION: We describe the clinical phenotypes of two patients with GD1 that are caused by two novel homozygous missense mutations in the ADAMTSL2 gene.","variants":[{"Name":"NM_014694.4(ADAMTSL2):c.499G>A (p.Asp167Asn)","Chromosome":"9","Start":"133540684","Stop":"133540684","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":613383,"rule_based_match":true,"evidence_text":"c.499G>A, p.D167N","llm_judgment":"PRESENT","evidence":"c.499G>A, p.D167N","abstract_start":910,"abstract_end":927}]}
{"pmid":"27830107","title":"Congenital Mirror Movements Due to RAD51: Cosegregation with a Nonsense Mutation in a Norwegian Pedigree and Review of the Literature.","abstract":"BACKGROUND: Autosomal dominant congenital mirror movements (CMM) is a neurodevelopmental disorder characterized by early onset involuntary movements of one side of the body that mirror intentional movements on the contralateral side; these persist throughout life in the absence of other neurological symptoms. The main culprit genes responsible for this condition are <i>RAD51</i> and <i>DCC</i>. This condition has only been reported in a few families, and the molecular mechanisms linking <i>RAD51</i> mutations and mirror movements (MM) are poorly understood.\nMETHODS: We collected demographic, clinical, and genetic data of a new family with CMM due to a truncating mutation of <i>RAD51.</i> We reviewed the literature to identify all reported patients with CMM due to <i>RAD51</i> mutations.\nRESULTS: We identified a heterozygous nonsense mutation c.760C>T (p.Arg254*) in eight subjects: four with obvious and disabling MM, and four with a mild phenotype. Including our new family, we identified 32 patients from 6 families with CMM linked to <i>RAD51</i> variants.\nDISCUSSION: Our findings further support the involvement of <i>RAD51</i> in CMM pathogenesis. Possible molecular mechanisms involved in CMM pathogenesis are discussed.","variants":[{"Name":"NM_002875.5(RAD51):c.760C>T (p.Arg254Ter)","Chromosome":"15","Start":"40729620","Stop":"40729620","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38823,"rule_based_match":true,"evidence_text":"c.760C>T (p.Arg254*)","llm_judgment":"PRESENT","evidence":"c.760C>T (p.Arg254*)","abstract_start":854,"abstract_end":874}]}
{"pmid":"33751098","title":"Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy.","abstract":"Sensory neuronopathies are a rare and distinct subgroup of peripheral neuropathies, characterized by degeneration of the dorsal root ganglia neurons. About 50% of sensory neuronopathies are idiopathic and genetic causes remain to be clarified. Through a combination of homozygosity mapping and whole exome sequencing, we linked an autosomal recessive sensory neuronopathy to pathogenic variants in the COX20 gene. We identified eight unrelated families from the eastern Chinese population carrying a founder variant c.41A>G (p.Lys14Arg) within COX20 in either a homozygous or compound heterozygous state. All patients displayed sensory ataxia with a decrease in non-length-dependent sensory potentials. COX20 encodes a key transmembrane protein implicated in the assembly of mitochondrial complex IV. We showed that COX20 variants lead to reduction of COX20 protein in patient's fibroblasts and transfected cell lines, consistent with a loss-of-function mechanism. Knockdown of COX20 expression in ND7/23 sensory neuron cells resulted in complex IV deficiency and perturbed assembly of complex IV, which subsequently compromised cell spare respiratory capacity and reduced cell proliferation under metabolic stress. Consistent with mitochondrial dysfunction in knockdown cells, reduced complex IV assembly, enzyme activity and oxygen consumption rate were also found in patients' fibroblasts. We speculated that the mechanism of COX20 was similar to other causative genes (e.g. SURF1, COX6A1, COA3 and SCO2) for peripheral neuropathies, all of which are functionally important in the structure and assembly of complex IV. Our study identifies a novel causative gene for the autosomal recessive sensory neuronopathy, whose vital function in complex IV and high expression in the proprioceptive sensory neuron further underlines loss of COX20 contributing to mitochondrial bioenergetic dysfunction as a mechanism in peripheral sensory neuron disease.","variants":[{"Name":"NM_198076.6(COX20):c.41A>G (p.Lys14Arg)","Chromosome":"1","Start":"244835755","Stop":"244835755","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":365161,"rule_based_match":true,"evidence_text":"c.41A>G (p.Lys14Arg)","llm_judgment":"PRESENT","evidence":"c.41A>G (p.Lys14Arg)","abstract_start":516,"abstract_end":536}]}
{"pmid":"33520900","title":"Sterol 27-Hydroxylase Deficiency as a Cause of Neonatal Cholestasis: Report of 2 Cases and Review of the Literature.","abstract":"<b>Introduction:</b> Inborn errors of primary bile acid (BA) synthesis are rare autosomal recessive disorders responsible for 1-2% of cases of neonatal cholestasis. Among them, cerebrotendinous xanthomatosis (CTX) is caused by mutations in the <i>CYP27A1</i> gene resulting in the impairment of sterol 27-hydroxylase enzyme activity. <b>Patients and Methods:</b> Here we present the study on two siblings with neonatal cholestasis diagnosed with sterol 27-hydroxylase deficiency. The clinical, biochemical, histological, and molecular presentation at the time of diagnosis and detailed follow-up were described. An extensive overview of the literature regarding patients with sterol 27-hydroxylase deficiency presenting with neonatal cholestasis was also provided. <b>Results:</b> Patient 1 presented with cholestatic jaundice since 10 weeks of age and developed the end-stage liver disease requiring liver transplantation at 8 months of age but finally succumbed 3 years post-transplantation due to autoimmune hemolytic anemia and multiorgan failure development. Next-generation sequencing performed <i>post mortem</i>, revealed him to be homozygous for the known pathogenic splicing variant c.1184+1G>A in the <i>CYP27A1</i> gene. Patient 2 (sibling) presented with cholestatic jaundice since the first day of life. Sanger sequencing of <i>CYP27A1</i> revealed the same results. Chenodeoxycholic acid treatment was introduced just after diagnosis, at 4 months of age. Fourteen patients with sterol 27-hydroxylase deficiency presenting with neonatal cholestasis were reported in the literature, in most of them presenting as a self-limiting disease. <b>Conclusions:</b> An early recognition and treatment initiation in CTX is essential.","variants":[{"Name":"NM_000784.4(CYP27A1):c.1184+1G>A","Chromosome":"2","Start":"218814188","Stop":"218814188","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76741,"rule_based_match":true,"evidence_text":"c.1184+1G>A","llm_judgment":"PRESENT","evidence":"c.1184+1G>A","abstract_start":1193,"abstract_end":1204}]}
{"pmid":"15241803","title":"Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients.","abstract":"We examined CMT1A duplication of 17p11.2-p12, mutations of PMP22, MPZ (P0), GJB1 (Cx32), EGR2 and NEFL genes in 57 Korean families with patients diagnosed as having Charcot-Marie-Tooth (CMT) disease. The CMT1A duplication was present in 53.6% of 28 CMT type 1 patients. In the 42 CMT families without CMT1A duplication, 10 pathogenic mutations were found in 9 families. The 10 mutations were not detected in 105 healthy controls. Seven mutations (c.318delT (p.Ala106fs) in PMP22, c.352G>A (p.Asp118Asn), c.449-1G>T (3'-splice site), c.706A>G (p.Lys236Glu) in MPZ, c.407T>C (p.Val136Ala)[corrected], c.502T>C (p.Cys168Arg) in GJB1, and c.1001T>C (p.Leu334Pro) in NEFL) were determined to be novel. The mutation frequencies of PMP22 and MPZ were similar to those found in several European populations, however, it appeared that mutations in GJB1 are less frequent in East Asian CMT patients than in Eur opean patients. We described the identified mutations and phenotype-genotype correlations based on nerve conduction studies.","variants":[{"Name":"NM_000530.8(MPZ):c.706A>G (p.Lys236Glu)","Chromosome":"1","Start":"161305917","Stop":"161305917","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":624996,"rule_based_match":true,"evidence_text":"c.706A>G (p.Lys236Glu)","llm_judgment":"PRESENT","evidence":"c.706A>G (p.Lys236Glu)","abstract_start":533,"abstract_end":555},{"Name":"NM_000166.6(GJB1):c.502T>C (p.Cys168Arg)","Chromosome":"X","Start":"71224209","Stop":"71224209","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":625637,"rule_based_match":true,"evidence_text":"c.502T>C (p.Cys168Arg)","llm_judgment":"PRESENT","evidence":"c.502T>C (p.Cys168Arg)","abstract_start":599,"abstract_end":621},{"Name":"NM_000530.8(MPZ):c.449-1G>T","Chromosome":"1","Start":"161306465","Stop":"161306465","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":625733,"rule_based_match":true,"evidence_text":"c.449-1G>T (3'-splice site)","llm_judgment":"PRESENT","evidence":"c.449-1G>T (3'-splice site)","abstract_start":504,"abstract_end":531},{"Name":"NM_000166.6(GJB1):c.407T>C (p.Val136Ala)","Chromosome":"X","Start":"71224114","Stop":"71224114","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":25490,"rule_based_match":true,"evidence_text":"c.407T>C (p.Val136Ala)[corrected]","llm_judgment":"PRESENT","evidence":"c.407T>C (p.Val136Ala)[corrected]","abstract_start":564,"abstract_end":597},{"Name":"NM_000530.8(MPZ):c.352G>A (p.Asp118Asn)","Chromosome":"1","Start":"161306804","Stop":"161306804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":625045,"rule_based_match":true,"evidence_text":"c.352G>A (p.Asp118Asn)","llm_judgment":"PRESENT","evidence":"c.352G>A (p.Asp118Asn)","abstract_start":480,"abstract_end":502}]}
{"pmid":"18306019","title":"Malignant hyperthermia susceptibility diagnosed with a family-specific ryanodine receptor gene type 1 mutation.","abstract":"Malignant hyperthermia (MH) is an autosomal dominant disorder of skeletal muscle calcium regulation, and the rate of calcium-induced calcium release (CICR), determined by using skinned fibers of skeletal muscle, has been employed as a diagnostic test for MH susceptibility in Japan. The ryanodine receptor (RYR1), encoding the major calcium-release channel in skeletal muscle sarcoplasmic reticulum, has been shown to be mutated in a number of MH pedigrees. We experienced the detection of accelerated CICR and/or an RYR1 mutation in a patient with an MH episode and his family. Accelerated CICR and an RYR1 mutation (c.14512C>G, p.L4838V) were found in the patient and his father. The MH-causative mutation (c.14512C>G, p.L4838V) was also found in his brother and his son (resulting in the diagnosis of MH without the CICR test), but the mutation was not found in his mother or two daughters. With the detection of the family-specific mutation in other family members, the diagnosis of MH was made without the invasive CICR test.","variants":[{"Name":"NM_000540.3(RYR1):c.14512C>G (p.Leu4838Val)","Chromosome":"19","Start":"38580370","Stop":"38580370","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":136822,"rule_based_match":true,"evidence_text":"c.14512C>G, p.L4838V","llm_judgment":"PRESENT","evidence":"c.14512C>G, p.L4838V","abstract_start":618,"abstract_end":638}]}
{"pmid":"32583627","title":"Genomic profiling of multiple primary cancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1 germline variant.","abstract":"We report a case with a rare combination of synchronous lung adenocarcinoma and bilateral malignant pleural mesotheliomas in a 70-year-old male without asbestos exposure. He metachronously developed peritoneal malignant mesothelioma, intrahepatic cholangiocarcinoma, urothelial carcinoma of the bladder and prostatic adenocarcinoma. Immunohistochemistry revealed complete loss of BAP1 expression in all seven lesions. Targeted next generation sequencing using Todai OncoPanel identified a novel germline variant (c.1565_1566del, p.P522Rfs*14) of BAP1. Additionally, different nonsynonymous somatic mutations of BAP1 were identified in four lesions including lung adenocarcinoma, malignant pleural and peritoneal mesotheliomas, and bladder cancer. The remaining two lesions had different somatic mutations in genes other than BAP1. Multiple BAP1-deficient cancers that developed in a single patient suggest the newly identified germline variant of BAP1 gene to be pathogenic and this case expands the clinical spectrum of BAP1-tumor predisposition syndrome. Screening for BAP1 status is highly recommended in cases with a similar combination of cancers.","variants":[{"Name":"NM_004656.4(BAP1):c.1565_1566del (p.Pro522fs)","Chromosome":"3","Start":"52403579","Stop":"52403580","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":953571,"rule_based_match":true,"evidence_text":"c.1565_1566del","llm_judgment":"PRESENT","evidence":"c.1565_1566del","abstract_start":513,"abstract_end":527}]}
{"pmid":"32365420","title":"VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy.","abstract":"BACKGROUND: Distal motor neuropathies with a genetic origin have a heterogeneous clinical presentation with overlapping features affecting distal nerves and including spinal muscular atrophies and amyotrophic lateral sclerosis. This indicates that their genetic background is heterogeneous.\nPATIENT AND METHODS: In this work, we have identified and characterized the genetic and molecular base of a patient with a distal sensorimotor neuropathy of unknown origin. For this study, we performed whole-exome sequencing, molecular modelling, cloning and expression of mutant gene, and biochemical and cell biology analysis of the mutant protein.\nRESULTS: A novel homozygous recessive mutation in the human VRK1 gene, coding for a chromatin kinase, causing a substitution (c.637T > C; p.Tyr213His) in exon 8, was detected in a patient presenting since childhood a progressive distal sensorimotor neuropathy and spinal muscular atrophy syndrome, with normal intellectual development. Molecular modelling predicted this mutant VRK1 has altered the kinase activation loop by disrupting its interaction with the C-terminal regulatory region. The p.Y213H mutant protein has a reduced kinase activity with different substrates, including histones H3 and H2AX, proteins involved in DNA damage responses, such as p53 and 53BP1, and coilin, the scaffold for Cajal bodies. The mutant VRK1(Y213H) protein is unable to rescue the formation of Cajal bodies assembled on coilin, in the absence of wild-type VRK1.\nCONCLUSION: The VRK1(Y213H) mutant protein alters the activation loop, impairs the kinase activity of VRK1 causing a functional insufficiency that impairs the formation of Cajal bodies assembled on coilin, a protein that regulates SMN1 and Cajal body formation.","variants":[{"Name":"NM_003384.3(VRK1):c.637T>C (p.Tyr213His)","Chromosome":"14","Start":"96855284","Stop":"96855284","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":800787,"rule_based_match":true,"evidence_text":"c.637T>C (p.Tyr213His)","llm_judgment":"PRESENT","evidence":"p.Tyr213His","abstract_start":780,"abstract_end":791}]}
{"pmid":"27110552","title":"Genetic analysis of Iranian family with hereditary cardiac arrhythmias by next generation sequencing.","abstract":"BACKGROUND: Cardiac arrhythmias are responsible for several cases of syncope and sudden cardiac death annually worldwide. Due to overlapping clinical symptoms in some cardiac arrhythmias genetic studies would help to confirm the primary clinical diagnosis made on the basis of solely clinical findings. In addition clinical management of the patient, family screening and provide appropriate counseling and risk assessment for the family members are other advantages of genetic study.\nMATERIALS AND METHODS: Totally nine patients from a family included in this study. The primary diagnosis on the basis of clinical findings was second-degree atrioventricular (AV) block for this family. Mutation in SCN5A gene is frequently reported for second-degree AV block and hence the gene was analyzed using whole gene sequencing but no mutation was detected. Subsequently, the samples were subjected to customized Ampliseq 77 gene panel using next generation sequencing to detect the underlying molecular defects.\nRESULTS: We found c. 5570T>A missense mutation in ANK2 gene for this family. Based on the Online Mendelian Inheritance in Man, ANK2 gene and the mutation detected correspond to long QT syndrome type 4.\nCONCLUSION: This mutation, although already known in other populations, but is reported for the first time in Iranian patients with cardiac arrhythmias. As the case with this family, genetic analysis of patients with cardiac arrhythmias would be helpful in reassessment of clinical diagnosis and therefore would help for patients' management and in some cases re-evaluation of ongoing treatment may be needed.","variants":[{"Name":"NM_001148.6(ANK2):c.5570T>A (p.Val1857Glu)","Chromosome":"4","Start":"113354188","Stop":"113354188","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":393813,"rule_based_match":true,"evidence_text":"c. 5570T>A","llm_judgment":"PRESENT","evidence":"c. 5570T>A","abstract_start":1023,"abstract_end":1033}]}
{"pmid":"34666706","title":"A de novo variant of POLR3B causes demyelinating Charcot-Marie-Tooth disease in a Chinese patient: a case report.","abstract":"BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies, which are subdivided into demyelinating and axonal forms. Biallelic mutations in POLR3B are the well-established cause of hypomyelinating leukodystrophy, which is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. To date, only one study has reported the demyelinating peripheral neuropathy phenotype caused by heterozygous POLR3B variants.\nCASE PRESENTATION: A 19-year-old male patient was referred to our hospital for progressive muscle weakness of the lower extremities. Physical examination showed muscle atrophy, sensory loss and deformities of the extremities. Nerve conduction studies and electromyography tests revealed sensorimotor demyelinating polyneuropathy with secondary axonal loss. Trio whole-exome sequencing revealed a de novo variant in POLR3B (c.3137G > A).\nCONCLUSIONS: In this study, we report the case of a Chinese patient with a de novo variant in POLR3B (c.3137G > A), who manifested demyelinating CMT phenotype without additional neurological or extra-neurological involvement. This work is the second report on POLR3B-related CMT.","variants":[{"Name":"NM_018082.6(POLR3B):c.3137G>A (p.Arg1046His)","Chromosome":"12","Start":"106504119","Stop":"106504119","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1036436,"rule_based_match":true,"evidence_text":"c.3137G > A","llm_judgment":"PRESENT","evidence":"c.3137G > A","abstract_start":889,"abstract_end":900}]}
{"pmid":"24027297","title":"Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy).","abstract":"BACKGROUND: GNE myopathy (also called distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy) is an autosomal recessive myopathy characterised by skeletal muscle atrophy and weakness that preferentially involve the distal muscles. It is caused by mutations in the gene encoding a key enzyme in sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).\nMETHODS: We analysed the GNE gene in 212 Japanese GNE myopathy patients. A retrospective medical record review was carried out to explore genotype-phenotype correlation.\nRESULTS: Sixty-three different mutations including 25 novel mutations were identified: 50 missense mutations, 2 nonsense mutations, 1 insertion, 4 deletions, 5 intronic mutations and 1 single exon deletion. The most frequent mutation in the Japanese population is c.1714G>C (p.Val572Leu), which accounts for 48.3% of total alleles. Homozygosity for this mutation results in more severe phenotypes with earlier onset and faster progression of the disease. In contrast, the second most common mutation, c.527A>T (p.Asp176Val), seems to be a mild mutation as the onset of the disease is much later in the compound heterozygotes with this mutation and c.1714G>C than the patients homozygous for c.1714G>C. Although the allele frequency is 22.4%, there are only three homozygotes for c.527A>T, raising a possibility that a significant number of c.527A>T homozygotes may not develop an apparent disease.\nCONCLUSIONS: Here, we report the mutation profile of the GNE gene in 212 Japanese GNE myopathy patients, which is the largest single-ethnic cohort for this ultra-orphan disease. We confirmed the clinical difference between mutation groups. However, we should note that the statistical summary cannot predict clinical course of every patient.","variants":[{"Name":"NM_005476.7(GNE):c.1714G>C (p.Val572Leu)","Chromosome":"9","Start":"36219940","Stop":"36219940","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":21072,"rule_based_match":true,"evidence_text":"c.1714G>C (p.Val572Leu)","llm_judgment":"PRESENT","evidence":"c.1714G>C (p.Val572Leu)","abstract_start":844,"abstract_end":867},{"Name":"NM_005476.7(GNE):c.527A>T (p.Asp176Val)","Chromosome":"9","Start":"36246120","Stop":"36246120","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":49657,"rule_based_match":true,"evidence_text":"c.527A>T (p.Asp176Val)","llm_judgment":"PRESENT","evidence":"c.527A>T (p.Asp176Val)","abstract_start":1081,"abstract_end":1103}]}
{"pmid":"30703231","title":"Variant analysis for a pedigree affected with limb-girdle muscular dystrophy type 2D","abstract":"OBJECTIVE: To analyze variant of SGCA gene in a Chinese pedigree affected with limb-girdle muscular dystrophy type 2D with whole exome sequencing (WGS).\nMETHODS: Multiplex ligation-dependent probe amplification (MLPA) was employed to detect large fragment deletion or duplication of the DMD gene. FastTarget<sup>TM</sup> next generation sequencing was used to detect variants of the DMD gene, and the result was verified by Sanger sequencing. After excluding the diagnosis of DMD for the proband, WGS was applied to test the proband and his parents. Suspected pathogenic variants were validated by Sanger sequencing.\nRESULTS: No variant, deletion or duplication of the DMD gene was detected. Whole exome sequencing showed that the proband has carried compound heterozygous missense variants c.409G>A (p.Glu137Lys) and c.409G>C (p.Glu137Gln) in exon 5 of the SGCA gene, which were respectively inherited from his mother and father. Neither variant was found in DNA derived from the cord blood sample.\nCONCLUSION: The c.409G>A (p.Glu137Lys) and c.409G>C (p.Glu137Gln) compound heterozygous missense variants probably underlie the disease in the proband. Above finding has facilitated genetic counseling and prenatal diagnosis for the family.","variants":[{"Name":"NM_000023.4(SGCA):c.409G>C (p.Glu137Gln)","Chromosome":"17","Start":"50168397","Stop":"50168397","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":548977,"rule_based_match":true,"evidence_text":"c.409G>C (p.Glu137Gln)","llm_judgment":"PRESENT","evidence":"c.409G>C (p.Glu137Gln)","abstract_start":818,"abstract_end":840}]}
{"pmid":"30843307","title":"POLG mutations presenting as Charcot-Marie-Tooth disease.","abstract":"We report on two patients, with different POLG mutations, in whom axonal neuropathy dominated the clinical picture. One patient presented with late onset sensory axonal neuropathy caused by a homozygous c.2243G>C (p.Trp748Ser) mutation that resulted from uniparental disomy of the long arm of chromosome 15. The other patient had a complex phenotype that included early onset axonal Charcot-Marie-Tooth disease (CMT) caused by compound heterozygous c.926G>A (p.Arg309His) and c.2209G>C (p.Gly737Arg) mutations.","variants":[{"Name":"NM_002693.3(POLG):c.2209G>C (p.Gly737Arg)","Chromosome":"15","Start":"89323460","Stop":"89323460","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":28552,"rule_based_match":true,"evidence_text":"c.2209G>C (p.Gly737Arg)","llm_judgment":"PRESENT","evidence":"c.2209G>C (p.Gly737Arg)","abstract_start":476,"abstract_end":499},{"Name":"NM_002693.3(POLG):c.2243G>C (p.Trp748Ser)","Chromosome":"15","Start":"89323426","Stop":"89323426","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":28546,"rule_based_match":true,"evidence_text":"c.2243G>C (p.Trp748Ser)","llm_judgment":"PRESENT","evidence":"c.2243G>C (p.Trp748Ser)","abstract_start":203,"abstract_end":226},{"Name":"NM_002693.3(POLG):c.926G>A (p.Arg309His)","Chromosome":"15","Start":"89329040","Stop":"89329040","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":374884,"rule_based_match":true,"evidence_text":"c.926G>A (p.Arg309His)","llm_judgment":"PRESENT","evidence":"c.926G>A (p.Arg309His)","abstract_start":449,"abstract_end":471}]}
{"pmid":"27629094","title":"SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome.","abstract":"OBJECTIVE: To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor-1 gene (SIGMAR1) and review the phenotypic spectrum of mutations in this gene.\nMETHODS: We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations.\nRESULTS: In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 of SIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1. No other mutations were identified in 16 additional patients with dHMN.\nCONCLUSIONS: We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies.","variants":[{"Name":"NM_005866.4(SIGMAR1):c.194T>A (p.Leu65Gln)","Chromosome":"9","Start":"34637378","Stop":"34637378","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":563214,"rule_based_match":true,"evidence_text":"c.194T>A (p.Leu65Gln)","llm_judgment":"PRESENT","evidence":"p.Leu65Gln","abstract_start":672,"abstract_end":682}]}
{"pmid":"31932101","title":"POLR3A variants in striatal involvement without diffuse hypomyelination.","abstract":"BACKGROUND: Biallelic variants in POLR3A encoding the largest subunit of RNA polymerase III cause POLR3-related (or 4H) leukodystrophy characterized by neurologic dysfunction, abnormal dentition, endocrine abnormalities and ocular abnormality. Recently, whole-exome sequencing enabled the discovery of POLR3A variants in cases lacking diffuse hypomyelination, the principal MRI phenotype of POLR3-related leukodystrophy. Homozygous c.1771-6C > G variants in POLR3A were recently suggested to cause striatal and red nucleus involvement without white matter involvement.\nCASE REPORT: Here, we report three cases in two families with biallelic POLR3A variants. We identified two sets of compound heterozygous variants in POLR3A, c.1771-6C > G and c.791C > T, p.(Pro264Leu) for family 1 and c.1771-6C > G and c.2671C > T, p.(Arg891*) for family 2. Both families had the c.1771-6C > G variant, which led to aberrant mRNA splicing. Neuropsychiatric regression and severe intellectual disability were identified in three patients. Two cases showed dystonia and oligodontia. Notably, characteristic bilateral symmetric atrophy and abnormal signal of the striatum without diffuse white matter signal change were observed in brain MRI of all three individuals.\nCONCLUSIONS: Striatum abnormalities may be another distinctive MRI finding associated with POLR3A variants, especially in cases including c.1771-6C > G variants and our cases can expand the phenotypic spectrum of POLR3A-related disorders.","variants":[{"Name":"NM_007055.4(POLR3A):c.1771-6C>G","Chromosome":"10","Start":"78009681","Stop":"78009681","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":964843,"rule_based_match":true,"evidence_text":"c.1771-6C>G","llm_judgment":"PRESENT","evidence":"c.1771-6C > G","abstract_start":432,"abstract_end":445},{"Name":"NM_007055.4(POLR3A):c.2671C>T (p.Arg891Ter)","Chromosome":"10","Start":"77993313","Stop":"77993313","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1877901,"rule_based_match":true,"evidence_text":"c.2671C > T, p.(Arg891*)","llm_judgment":"PRESENT","evidence":"c.2671C > T, p.(Arg891*)","abstract_start":805,"abstract_end":829}]}
{"pmid":"27549128","title":"An uncommon inheritance pattern in Niemann-Pick disease type C: identification of probable paternal germline mosaicism in a Mexican family.","abstract":"BACKGROUND: Niemann-Pick disease type C (NP-C) is a fatal lysosomal neurodegenerative and neurovisceral disease. It is caused by defects in intracellular lipid trafficking, which lead to the accumulation of lipids and glycosphingolipids within the endosomes and lysosomes of affected individuals. Pathogenic variants of the NPC1 or NPC2 genes yield highly variable phenotypes with a time course that ranges from fetal onset (i.e., hydrops fetalis) to progressive dementia in adults. NP-C is typically inherited in an autosomal-recessive manner. To our knowledge, no previous report has identified germline mosaicism as an inheritance mechanism in NP-C.\nCASE PRESENTATION: We report the case of a male Mexican patient with \"variant\" filipin staining and a juvenile form of NP-C attributed to compound heterozygosity for two previously reported pathogenic variants of NPC1: c.[1042C>T];[2780C>T] or p.[Arg348*];[Ala927Val]. The proband's mother and healthy sister were heterozygous carriers of the c.2780C > T (exon 18) and c.1042C > T (exon 8) variants, respectively. However, direct sequencing of exons 8 and 18 of NPC1 revealed no mutation in genomic DNA obtained from the father's peripheral blood. DNA profiling ruled out the possibility of non-paternity. We were unable to obtain a sperm sample to demonstrate paternal gonadal mosaicism. NPC1 haplotype analysis using 20 linked single nucleotide variants failed to yield sufficient information to document a p.(Arg348*) NPC1 pathogenic variant-associated haplotype in the family.\nCONCLUSIONS: We propose that this case of NP-C involves paternal germline mosaicism. To the best of our knowledge, this has not previously been reported in NP-C.","variants":[{"Name":"NM_000271.5(NPC1):c.1042C>T (p.Arg348Ter)","Chromosome":"18","Start":"23556527","Stop":"23556527","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1484107,"rule_based_match":true,"evidence_text":"c.1042C>T","llm_judgment":"PRESENT","evidence":"c.[1042C>T","abstract_start":872,"abstract_end":882},{"Name":"NM_000271.5(NPC1):c.2780C>T (p.Ala927Val)","Chromosome":"18","Start":"23539826","Stop":"23539826","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":548540,"rule_based_match":true,"evidence_text":"c.2780C>T (exon 18)","llm_judgment":"PRESENT","evidence":"c.2780C > T (exon 18)","abstract_start":996,"abstract_end":1017}]}
{"pmid":"30417976","title":"Novel mutations identified in patients with tooth agenesis by whole-exome sequencing.","abstract":"OBJECTIVES: To identify potentially pathogenic mutations for tooth agenesis by whole-exome sequencing.\nSUBJECTS AND METHODS: Ten Chinese families including five families with ectodermal dysplasia (syndromic tooth agenesis) and five families with selective tooth agenesis were included. Whole-exome sequencing was performed using genomic DNA. Potentially pathogenic mutations were identified after data filtering and screening. The pathogenicity of novel variants was investigated by segregation analysis, in silico analysis, and functional studies.\nRESULTS: One novel mutation (c.441_442insACTCT) and three reported mutations (c.252delT, c.463C>T, and c.1013C>T) in EDA were identified in families with ectodermal dysplasia. The novel EDA mutation was co-segregated with phenotype. A functional study revealed that NF-κB activation was compromised by the identified mutations. The secretion of active EDA was also compromised detection by western blotting. Novel Wnt10A mutations (c.521T>C and c.653T>G) and EVC2 mutation (c.1472C>T) were identified in families with selective tooth agenesis. The Wnt10A c.521T>C mutation and the EVC2 c.1472C>T mutation were considered as pathogenic for affecting highly conserved amino acids, co-segregated with phenotype and predicted to be disease-causing by SIFT and PolyPhen2. Moreover, several reported mutations in PAX9, Wnt10A, and FGFR3 were also detected.\nCONCLUSIONS: Our study expanded our knowledge on tooth agenesis spectrum by identifying novel variants.","variants":[{"Name":"NM_001399.5(EDA):c.1013C>T (p.Thr338Met)","Chromosome":"X","Start":"70035446","Stop":"70035446","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26087,"rule_based_match":true,"evidence_text":"c.1013C>T","llm_judgment":"PRESENT","evidence":"c.1013C>T","abstract_start":652,"abstract_end":661}]}
{"pmid":"16601870","title":"A single-residue mutation, G203E, causes 3-hydroxy-3-methylglutaric aciduria by occluding the substrate channel in the 3D structural model of HMG-CoA lyase.","abstract":"3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder that affects ketogenesis and leucine metabolism. The disease is caused by mutations in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HL). To date 26 different mutations have been described. A (betaalpha)(8) TIM barrel structure has been proposed for the protein, and almost all missense mutations identified so far localize in the beta sheets that define the inside cavity. We report an Italian patient who bears homozygously a novel HL mutation, c.608G > A (p. G203E) in beta sheet six. A structural model of the mutated protein suggests that glutamic acid 203 impedes catalysis by blocking the entrance to the inner cavity of the enzyme. Loss of functionality has been confirmed in expression studies in E. coli, which demonstrate that the G203E mutation completely abolishes enzyme activity. Beta sheet six and beta sheet two are the two protein regions that accumulate most missense mutations, indicating their importance in enzyme functionality. A model for the mechanism of enzyme function is proposed.","variants":[{"Name":"NM_000191.3(HMGCL):c.608G>A (p.Gly203Glu)","Chromosome":"1","Start":"23808277","Stop":"23808277","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":541004,"rule_based_match":true,"evidence_text":"c.608G > A (p. G203E)","llm_judgment":"PRESENT","evidence":"c.608G > A (p. G203E)","abstract_start":549,"abstract_end":570}]}
{"pmid":"25463447","title":"Identification of two missense mutations of ERCC6 in three Chinese sisters with Cockayne syndrome by whole exome sequencing.","abstract":"Cockayne syndrome (CS) is a rare autosomal recessive disorder, the primary manifestations of which are poor growth and neurologic abnormality. Mutations of the ERCC6 and ERCC8 genes are the predominant cause of Cockayne syndrome, and the ERCC6 gene mutation is present in approximately 65% of cases. The present report describes a case of Cockayne syndrome in a Chinese family, with the patients carrying two missense mutations (c.1595A>G, p.Asp532Gly and c.1607T>G, p.Leu536Trp) in the ERCC6 gene in an apparently compound heterozygote status, especially, p.Asp532Gly has never been reported. The compound heterozygote mutation was found in three patients in the family using whole exome sequencing. The patients' father and mother carried a heterozygous allele at different locations of the ERCC6 gene, which was confirmed by Sanger DNA sequencing. The two mutations are both located in the highly conserved motif I of ATP-binding helicase and are considered \"Damaging,\" \"Probably Damaging,\" \"Disease Causing,\" and \"Conserved\", indicating the role of DNA damage in the pathogenetic process of the disease. The results not only enrich the ERCC6 mutations database, but also indicate that whole exome sequencing will be a powerful tool for discovering the disease causing mutations in clinical diagnosis.","variants":[{"Name":"NM_000124.4(ERCC6):c.1607T>G (p.Leu536Trp)","Chromosome":"10","Start":"49500616","Stop":"49500616","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":836915,"rule_based_match":true,"evidence_text":"c.1607T>G (p.Leu536Trp)","llm_judgment":"PRESENT","evidence":"p.Leu536Trp","abstract_start":467,"abstract_end":478},{"Name":"NM_000124.4(ERCC6):c.1595A>G (p.Asp532Gly)","Chromosome":"10","Start":"49500628","Stop":"49500628","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":545695,"rule_based_match":true,"evidence_text":"c.1595A>G, p.Asp532Gly","llm_judgment":"PRESENT","evidence":"c.1595A>G, p.Asp532Gly","abstract_start":429,"abstract_end":451}]}
{"pmid":"33571483","title":"Identification of novel compound heterozygous variants in SLC19A2 and the genotype-phenotype associations in thiamine-responsive megaloblastic anemia.","abstract":"BACKGROUND AND AIMS: Thiamine-responsive megaloblastic anemia (TRMA), caused by SLC19A2 loss-of-function variants, is characterized by the triad of megaloblastic anemia, progressive sensorineural deafness, and non-type 1 diabetes mellitus. Here, we present the case of a Chinese infant with two novel variants segregating in compound heterozygous form in SLC19A2 and reviewed genotype-phenotype associations (GPAs) in patients with TRMA.\nMATERIALS AND METHODS: Whole-exome sequencing was performed to establish a genetic diagnosis. The clinical manifestations and genetic variants were collected by performing a literature review. The bioinformatics software SIFT, PolyPhen2, and Mutation Taster was applied to predict variant effects and analyze GPAs.\nRESULTS: Two novel variants segregating in compound heterozygous form in SLC19A2 (NM_006996.2: exon2:c.336_363del:p.W112fs; exon2:c.358G>T:p.G120X) was identified. Thiamine supplementation corrected anemia and diabetes mellitus but did not improve the hearing defect. In the literature, 183 patients with TRMA with 74 variants in SLC19A2 have been reported, with high incidence in the Middle East, South Asia, and the northern Mediterranean. Patients with biallelic premature termination codon variants presented with more severe phenotypes, and truncating sites on extracellular domains was a protective factor for the hemoglobin level at diagnosis.\nCONCLUSION: Two novel compound heterozygous variants (NM_006996.2: exon2:c.336_363del:p.W112fs; exon2:c.358G>T:p.G120X) were identified, and GPAs in TRMA indicated the predictability of clinical manifestations.","variants":[{"Name":"NM_006996.3(SLC19A2):c.358G>T (p.Gly120Ter)","Chromosome":"1","Start":"169477604","Stop":"169477604","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2947178,"rule_based_match":true,"evidence_text":"exon2:c.358G>T:p.G120X","llm_judgment":"PRESENT","evidence":"exon2:c.358G>T:p.G120X","abstract_start":877,"abstract_end":899}]}
{"pmid":"26472314","title":"PID in Disguise: Molecular Diagnosis of IRAK-4 Deficiency in an Adult Previously Misdiagnosed With Autosomal Dominant Hyper IgE Syndrome.","abstract":"Autosomal recessive IL-1R-associated kinase 4 (IRAK-4) deficiency is a rare cause of recurrent pyogenic infections with limited inflammatory responses. We describe an adult female patient with severe lung disease who was phenotypically diagnosed as suffering from autosomal dominant Hyper IgE syndrome (AD HIES) because of recurrent skin infections with Staphylococcus aureus, recurrent pneumonia and elevated serum IgE levels. In contrast to findings in AD HIES patients, no abnormalities were found in the Th17 and circulating follicular helper T cell subsets. A panel-based sequencing approach led to the identification of a homozygous IRAK4 stop mutation (c.877C > T, p.Gln293*).","variants":[{"Name":"NM_016123.4(IRAK4):c.877C>T (p.Gln293Ter)","Chromosome":"12","Start":"43778238","Stop":"43778238","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18878,"rule_based_match":true,"evidence_text":"c.877C > T, p.Gln293*","llm_judgment":"PRESENT","evidence":"c.877C > T, p.Gln293*","abstract_start":660,"abstract_end":681}]}
{"pmid":"21267007","title":"A nonsense mutation in FMR1 causing fragile X syndrome.","abstract":"Fragile X syndrome is a common cause of inherited intellectual disability. It is caused by lack of the FMR1 gene product FMRP. The most frequent cause is the expansion of a CGG repeat located in the 5'UTR of FMR1. Alleles with 200 or more repeats become hypermethylated and transcriptionally silent. Only few patients with intragenic point mutations in FMR1 have been reported and, currently, routine analysis of patients referred for fragile X syndrome includes solely analysis for repeat expansion and methylation status. We identified a substitution in exon 2 of FMR1, c.80C>A, causing a nonsense mutation p.Ser27X, in a patient with classical clinical symptoms of fragile X syndrome. The mother who carried the mutation in heterozygous form presented with mild intellectual impairment. We conclude that further studies including western blot and DNA sequence analysis of the FMR1 gene should be performed in patients with typical symptoms of fragile X syndrome in whom no CGG repeat expansion is detected.","variants":[{"Name":"NM_002024.6(FMR1):c.80C>A (p.Ser27Ter)","Chromosome":"X","Start":"147921961","Stop":"147921961","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":38942,"rule_based_match":true,"evidence_text":"c.80C>A","llm_judgment":"PRESENT","evidence":"c.80C>A","abstract_start":572,"abstract_end":579}]}
{"pmid":"28392195","title":"Clinical characteristics of Taiwanese children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency detected by neonatal screening.","abstract":"BACKGROUND/PURPOSE: Neonatal screening for congenital adrenal hyperplasia (CAH) has been conducted in Taiwan since 2000. This study aimed to determine the clinical characteristics of Taiwanese children with CAH due to 21-hydroxylase deficiency (21-OHD) detected by neonatal screening.\nMETHODS: From 2000 to 2015, 26 neonates (14 boys and 12 girls) with classic 21-OHD detected by neonatal screening and confirmed at National Taiwan University Hospital were enrolled. Among them, 22 were diagnosed as salt wasting (SW) type and four as simple virilizing (SV) type. Through a review of medical records, their clinical presentations, laboratory data, and molecular studies were analyzed.\nRESULTS: The most common manifestation was hyperpigmentation. All female neonates regardless of 21-OHD type had atypical genitalia, clitoromegaly, and posterior labial fusion. All of the patients had baseline serum 17-hydroxyprogesterone levels higher than normal. Of the 26 patients, 24 had elevated adrenocorticotropic hormone levels, but only four had low serum cortisol levels. The median baseline adrenocorticotropic hormone, 17-hydroxyprogesterone, and androstenedione levels were significantly higher in patients with SW than in those with SV 21-OHD. All patients with SW 21-OHD had elevated plasma renin activity. The most frequent SW 21-OHD mutations were c.293-13C>G and gene deletion, whereas Ile173Asn and c.293-13C>G were the most frequently detected in SV 21-OHD.\nCONCLUSION: In Taiwan, neonatal screening effectively leads to the early diagnosis of CAH and reduces fatal adrenal crisis in neonates. This study may provide physicians with a better understanding of the clinical findings among children with early-diagnosed CAH, allowing for better care in the future.","variants":[{"Name":"NM_000500.9(CYP21A2):c.293-13C>G","Chromosome":"6","Start":"32039081","Stop":"32039081","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":27194,"rule_based_match":true,"evidence_text":"c.293-13C>G","llm_judgment":"PRESENT","evidence":"c.293-13C>G","abstract_start":1350,"abstract_end":1361}]}
{"pmid":"21567914","title":"A novel mutation in PYCR1 causes an autosomal recessive cutis laxa with premature aging features in a family.","abstract":"The autosomal recessive form of type II cutis laxa (ARCL II) is characterized by the appearance of redundant, inelastic skin with wrinkling, an aged look and additional variable systemic involvement including intrauterine growth retardation, failure to thrive, developmental delay, dysmorphism, osseous abnormality, and CNS manifestations. Several genetic defects have been found in patients and families with the clinical manifestations of ARCL II. Recently, mutations in PYCR1 have been linked to cutis laxa with progeroid features. We ascertained two siblings with of ARCL II born to non-consanguineous parents. Mutation analysis of PYCR1 revealed a novel single-base deletion (c.345delC) in exon 4 leading to frame-shift and premature stop of translation. The effect of this mutation results in a strong reduction of PYCR1 expression in skin fibroblasts from affected siblings. These two cases extend the genotypic spectrum of PYCR1-related ARCL II.","variants":[{"Name":"NM_006907.4(PYCR1):c.345del (p.Arg116fs)","Chromosome":"17","Start":"81935121","Stop":"81935121","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":38819,"rule_based_match":true,"evidence_text":"c.345delC","llm_judgment":"PRESENT","evidence":"c.345delC","abstract_start":681,"abstract_end":690}]}
{"pmid":"28302202","title":"Two novel TSC2 frameshift mutations in tuberous sclerosis complex","abstract":"High-throughput sequencing was performed for the peripheral blood DNA from two probands in the family with tuberous sclerosis complex (TSC) to determine the sequences of TSC-related genes TSC1 and TSC2 and their splicing regions and identify mutation sites. Amplification primers were designed for the mutation sites and polymerase chain reaction and Sanger sequencing were used to verify the sequences of peripheral blood DNA from the probands and their parents. The two probands had c.3981-3982 insA (p.Asp1327AspfsX87) and c.4013-4014 delCA (p.Ser1338Cysfs) heterozygous mutations, respectively, in the TSC2 gene. The parents of proband 1 had no abnormalities at these two loci; the mother of proband 2 had c.4013-4014 delCA heterozygous mutation in the TSC2 gene, while the father and the grandparents of proband 2 had no abnormalities. c.3981-3982 insA mutation may cause early coding termination of amino acid sequence at the 1413th site, and c.4013-4014 delCA mutation may cause early coding termination of amino acid sequence at the 1412th site. These two mutations are the pathogenic mutations for families 1 and 2, respectively, and both of them are novel frameshift mutations, but their association with the disease needs to be further verified by mutant protein function cell model and animal model.","variants":[{"Name":"NM_000548.5(TSC2):c.4013_4014del (p.Ser1338fs)","Chromosome":"16","Start":"2084235","Stop":"2084236","ReferenceAlleleVCF":"TCA","AlternateAlleleVCF":"T","allel_id":1063549,"rule_based_match":false,"evidence_text":"c.4013-4014 delCA (p.Ser1338Cysfs)","llm_judgment":"PRESENT","evidence":"c.4013-4014 delCA (p.Ser1338Cysfs)","abstract_start":526,"abstract_end":560}]}
{"pmid":"22944031","title":"Analysis of CX32 gene mutation and related clinical features in Chinese Han Charcot-Marie-Tooth families","abstract":"OBJECTIVE: To analyze the mutation of CX32 gene and related clinical features in Chinese Han patients with Charcot-Marie-Tooth (CMT) disease.\nMETHODS: Thirty-four CMT families, from 2004 to 2011 at Departments of Neurology, Xiangya Hospital, Third Xiangya Hospital and National Key Laboratory of Medical Genetics, were selected for CX32 mutation screening after the exclusion of the PMP22 duplication and male-to-male transmission. Mutation analysis was carried out by polymerase chain reaction (PCR) plus direct sequencing. Analyses of clinical, electrophysiological and pathological features in 11 patients from 6 CMTX1 families were performed by 2 neurologists.\nRESULTS: Five CX32 gene mutations were detected in 6 CMT families: c.37G > A, c.65G > A, c.246C > G, c.256A > G and c.533A > G. Among them, c.246C > G and c.533A > G were firstly reported. The clinical manifestations included progressive distal muscle atrophy and weakness, areflexia, sensory abnormalities and pes vacus. Nerve conduction velocity ranged from 21.7 to 49.3 m/s. Both demyelination and axonal degeneration were detected in nerve biopsy.\nCONCLUSIONS: CMT1X has a frequency of around 9% in our study. The male patients tend to have more serious clinical features and their electrophysiological and pathological changes are intermediate. CX32 mutation analysis helps to confirm the genetic diagnosis of CMT so as to provide genetic counseling and reproductive guidance and elucidate its pathogenesis.","variants":[{"Name":"NM_000166.6(GJB1):c.37G>A (p.Val13Met)","Chromosome":"X","Start":"71223744","Stop":"71223744","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625457,"rule_based_match":true,"evidence_text":"c.37G > A","llm_judgment":"PRESENT","evidence":"c.37G > A","abstract_start":732,"abstract_end":741},{"Name":"NM_000166.6(GJB1):c.246C>G (p.Ile82Met)","Chromosome":"X","Start":"71223953","Stop":"71223953","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":625545,"rule_based_match":true,"evidence_text":"c.246C > G","llm_judgment":"PRESENT","evidence":"c.246C > G","abstract_start":754,"abstract_end":764}]}
{"pmid":"30085091","title":"Whole-exome sequencing revealed HKDC1 as a candidate gene associated with autosomal-recessive retinitis pigmentosa.","abstract":"Retinitis pigmentosa (RP) is an inheritable retina degenerative disease leading to blindness. Despite the identification of 70 genes associated with RP, the genetic cause of ∼40% of RP patients remains to be elucidated. Whole-exome sequencing was applied on the probands of a RP cohort of 68 unsolved cases to identify candidate genetic mutations. A homozygous missense variant (c.173C > T, p.T58 M) was found in HKDC1 in two unrelated families presenting late-onset retinal degeneration. This variant affects highly conserved amino acid residue and is very rare in several databases and absent in 4000 ethnic-matched controls. Mutant HKDC1 protein partially lost hexokinase activity. Hkdc1 is expressed in the mouse retina and localized to photoreceptor inner segments. To elucidate the in vivo roles of Hkdc1 in the retina, we generated Hkdc1 knockout (KO) mouse models using CRISPR/Cas9 technique. Two independent alleles were identified and backcrossed to C57BL/6 J for 6 generations. Absence of HKDC1 expression in the Hkdc1 KO retina was confirmed by western blot and immunostaning using HKDC1 antibody. Hkdc1 KO mice exhibited reduced scotopic electroretinogram response and thinner outer nuclear layer, similar to some of the human patient phenotypes. Loss of Hkdc1 led to mislocalization of rhodopsin to the inner segments and cell bodies of rods in some regions in the retina. Taken together, our data demonstrated that HKDC1 is associated with autosomal recessively inherited RP.","variants":[{"Name":"NM_025130.4(HKDC1):c.173C>T (p.Thr58Met)","Chromosome":"10","Start":"69227316","Stop":"69227316","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1311497,"rule_based_match":true,"evidence_text":"c.173C > T, p.T58 M","llm_judgment":"PRESENT","evidence":"c.173C > T, p.T58 M","abstract_start":379,"abstract_end":398}]}
{"pmid":"32962506","title":"Next-generation sequencing reveals a novel pathogenic variant in the","abstract":"INTRODUCTION: Ataxia telangiectasia (A-T) is a rare autosomal recessive, multisystemic disease. Patients with the A-T syndrome present a broad spectrum of disease phenotypes. The <i>ATM</i> (ataxia telangiectasia mutated) gene, the only causative gene for A-T.\nMETHOD: A patient of Persian origin presenting with typical A-T was referred to our genetics centre for specialized genetic counselling and testing. Targeted next-generation sequencing (NGS) was applied. Sanger sequencing was used to confirm the candidate variant. Modelling was performed using the SWISS-MODEL server.\nRESULTS: A homozygous stop-gain variant c.829G > T (p.E277*) was found in the <i>ATM</i> gene. This variant was confirmed by Sanger sequencing and modelling of native structure, and truncated structure was performed.\nCONCLUSION: To date, very few pathogenic variants of the <i>ATM</i> gene have been reported from the Iranian population. The finding has implications in molecular diagnostic for A-T in Iran.","variants":[{"Name":"NM_000051.4(ATM):c.829G>T (p.Glu277Ter)","Chromosome":"11","Start":"108244954","Stop":"108244954","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":233941,"rule_based_match":true,"evidence_text":"c.829G > T (p.E277*)","llm_judgment":"PRESENT","evidence":"c.829G > T (p.E277*)","abstract_start":620,"abstract_end":640}]}
{"pmid":"26349194","title":"MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS WITH HOMOZYGOUS MUTATION (C.448DELC, P.LEU150 SER FSX11) ON EXON 6 OF MLC1 GENE.","abstract":"MLC or Van der Knaap disease is a rare entity, a rare and genetically heterogeneous cerebral white matter disease. It is characterized by the presence of macrocephaly, epilepsy and a slowly progressive spastic cerebellar syndrome. It is an autosomal recessive disease caused from mutations of MLC1 gene. In the current case report, a case with MLC who had a homozygous mutation (c.448delC, p.Leul50 ser fsX11) on exon 6 of MLC1 gene is presented.","variants":[{"Name":"NM_015166.4(MLC1):c.448del (p.Leu150fs)","Chromosome":"22","Start":"50077478","Stop":"50077478","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":549442,"rule_based_match":true,"evidence_text":"c.448delC, p.Leul50 ser fsX11","llm_judgment":"PRESENT","evidence":"c.448delC, p.Leul50 ser fsX11","abstract_start":379,"abstract_end":408}]}
{"pmid":"35510366","title":"Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).","abstract":"Nemaline myopathies (NEMs) are genetically and clinically heterogenous. Biallelic or monoallelic variants in TNNT1, encoding slow skeletal troponin T1 (TnT1), cause NEM. We report a 2-year-old patient and his mother carrying the heterozygous TNNT1 variant c.194A>C/p.(Asp65Ala) that occurred de novo in the mother. Both had muscle hypotrophy and muscle weakness. Muscle pathology in the proband's mother revealed slow twitch type 1 fiber hypotrophy and fast twitch type 2 fiber hypertrophy that was confirmed by a reduced ratio of slow skeletal myosin to fast skeletal myosin type 2a. Reverse transcription polymerase chain reaction and immunoblotting data demonstrated increased levels of high-molecular-weight TnT1 isoforms in skeletal muscle of the proband's mother that were also observed in some controls. In an overexpression system, complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was enhanced. The previously reported TnT1-E104V and TnT1-L96P mutants showed reduced or no co-immunoprecipitation with TPM3. Our studies support pathogenicity of the TNNT1 p.(Asp65Ala) variant.","variants":[{"Name":"NM_003283.6(TNNT1):c.194A>C (p.Asp65Ala)","Chromosome":"19","Start":"55141301","Stop":"55141301","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2668687,"rule_based_match":true,"evidence_text":"c.194A>C/p.(Asp65Ala)","llm_judgment":"PRESENT","evidence":"c.194A>C/p.(Asp65Ala)","abstract_start":256,"abstract_end":277}]}
{"pmid":"25638458","title":"A Korean Case of β-Ureidopropionase Deficiency Presenting with Intractable Seizure, Global Developmental Delay, and Microcephaly.","abstract":"β-Ureidopropionase deficiency (OMIM #613161) is a rare autosomal recessive inborn error of metabolism due to mutations in the UPB1 gene, which encodes the third enzyme involved in the pyrimidine degradation pathway. A total of 28 cases have been reported, mainly presenting with seizures, microcephaly, and intellectual disabilities. However, 11 of them were asymptomatic cases (Nakajima et al., J Inherit Metab Dis 37(5):801-812, 2014). We report on a 9-year-old female presenting with intractable epilepsy, microcephaly, and global developmental delay. She was homozygous for p.R326Q (c.977G>A) and heterozygous for p.G31S (c.91G>A) in the UPB1 gene, detected by targeted next-generation sequencing test and subsequently confirmed by biochemical analysis of urine, plasma, and cerebrospinal fluid (CSF) using reversed-phase HPLC, combined with electrospray tandem mass spectrometry. We report a first Korean female case with β-ureidopropionase deficiency.","variants":[{"Name":"NM_016327.3(UPB1):c.91G>A (p.Gly31Ser)","Chromosome":"22","Start":"24495494","Stop":"24495494","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":438924,"rule_based_match":true,"evidence_text":"c.91G>A","llm_judgment":"PRESENT","evidence":"c.91G>A","abstract_start":626,"abstract_end":633}]}
{"pmid":"29593631","title":"Acute Hemorrhagic Encephalitis Responding to Combined Decompressive Craniectomy, Intravenous Immunoglobulin, and Corticosteroid Therapies: Association with Novel","abstract":"BACKGROUND: Acute hemorrhagic encephalomyelitis (AHEM) is considered as a rare form of acute disseminated encephalomyelitis characterized by fulminant encephalopathy with hemorrhagic necrosis and most often fatal outcome.\nOBJECTIVE: To report the association with Ran Binding Protein (<i>RANBP2)</i> gene variant and the response to decompressive craniectomy and high-dose intravenous methylprednisolone (IVMP) in life-threatening AHEM.\nDESIGN: Single case study.\nCASE REPORT: A 6-year-old girl known to have sickle cell disease (SCD) presented an acquired demyelinating syndrome (ADS) with diplopia due to sudden unilateral fourth nerve palsy. She received five pulses of IVMP (30 mg/kg/day). Two weeks after steroid weaning, she developed right hemiplegia and coma. Brain magnetic resonance imaging showed a left frontal necrotico-hemorrhagic lesion and new multifocal areas of demyelination. She underwent decompressive craniotomy and evacuation of an ongoing left frontoparietal hemorrhage. Comprehensive investigations ruled out vascular and infectious process. The neurological deterioration stopped concomitantly with combined neurosurgical drainage of the hematoma, decompressive craniotomy, IVMP, and intravenous immunoglobulins (IVIG). She developed during the following months Crohn disease and sclerosing cholangitis. After 2-year follow-up, there was no new neurological manifestation. The patient still suffered right hemiplegia and aphasia, but was able to walk. Cognitive/behavioral abilities significantly recovered. A heterozygous novel rare missense variant (c.4993A>G, p.Lys1665Glu) was identified in <i>RANBP</i>2, a gene associated with acute necrotizing encephalopathy. RANBP2 is a protein playing an important role in the energy homeostasis of neuronal cells.\nCONCLUSION: In any ADS occurring in the context of SCD and/or autoimmune condition, we recommend to slowly wean steroids and to closely monitor the patient after weaning to quickly treat any recurrence of neurological symptom with IVMP. This case report, in addition to others, stresses the likely efficacy of combined craniotomy, IVIG, and IVMP treatments in AHEM. <i>RANBP2</i> mutations may sensitize the brain to inflammation and predispose to AHEM.","variants":[{"Name":"NM_006267.5(RANBP2):c.4993A>G (p.Lys1665Glu)","Chromosome":"2","Start":"108765532","Stop":"108765532","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1040468,"rule_based_match":true,"evidence_text":"c.4993A>G, p.Lys1665Glu","llm_judgment":"PRESENT","evidence":"c.4993A>G, p.Lys1665Glu","abstract_start":1578,"abstract_end":1601}]}
{"pmid":"34258273","title":"Missense Variant of Endoplasmic Reticulum Region of","abstract":"OBJECTIVE: Genetic variants in the <i>WFS1</i> gene can cause Wolfram syndrome (WS) or autosomal dominant nonsyndromic low-frequency hearing loss (HL). This study is aimed at investigating the molecular basis of HL in an affected Chinese family and the genotype-phenotype correlation of <i>WFS1</i> variants.\nMETHODS: The clinical phenotype of the five-generation Chinese family was characterized using audiological examinations and pedigree analysis. Target exome sequencing of 129 known deafness genes and bioinformatics analysis were performed among six patients and four normal subjects to screen suspected pathogenic variants. We built a complete WFS1 protein model to assess the potential effects of the variant on protein structure.\nRESULTS: A novel heterozygous pathogenic variant NM_006005.3 c.2020G>T (p.Gly674Trp) was identified in the <i>WFS1</i> gene, located in the C-terminal domain of the wolframin protein. We further showed that HL-related <i>WFS1</i> missense variants were mainly concentrated in the endoplasmic reticulum (ER) domain. In contrast, WS-related missense variants are randomly distributed throughout the protein.\nCONCLUSIONS: In this family, we identified a novel variant p.Gly674Trp of <i>WFS1</i> as the primary pathogenic variant causing the low-frequency sensorineural HL, enriching the mutational spectrum of the <i>WFS1</i> gene.","variants":[{"Name":"NM_006005.3(WFS1):c.2020G>T (p.Gly674Trp)","Chromosome":"4","Start":"6301815","Stop":"6301815","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3753253,"rule_based_match":true,"evidence_text":"NM_006005.3 c.2020G>T (p.Gly674Trp)","llm_judgment":"PRESENT","evidence":"NM_006005.3 c.2020G>T (p.Gly674Trp)","abstract_start":789,"abstract_end":824}]}
{"pmid":"21739273","title":"Muscular dystrophy due to mutations in anoctamin 5: clinical and molecular genetic findings","abstract":"Recessive mutations in the anoctamin 5 (ANO5) gene have been recently identified in families with limb girdle muscular dystrophy (LGMD2L) and distal non-dysferlin Miyoshi myopathy. Anoctamin 5 is supposed to be a putative calcium-activated chloride channel. We report five German patients (four index patients) with muscle dystrophy due to mutations in the ANO5 gene. Sequencing of the ANO5 exons 5, 13 and 20 was performed to screen for a common c.191dupA mutation and two other reported mutations (c.1295C>G and p.R758C). The whole coding region of the ANO5 gene was sequenced to identify new mutations. Phenotypically, three patients showed LGMD and one patient Miyoshi type distal myopathy. One sibling had asymptomatic hyperCKemia. The age at onset was 64, 38 and 40 years in patients with LGMD and 23 years in the patient with distal myopathy. The four symptomatic patients showed remarkable asymmetric muscle involvement. There was marked CK elevation (11 to 30 times). Electron microscopy showed multifocal gaps in the sarcolemmal membrane. All patients harboured the common c.191dupA mutation in at least one allele. Two patients with LGMD were homozygous and the third patient and his asymptomatic sister were compound heterozygous for the c.191dupA mutation and a novel p.T548I mutation. The patient with distal myopathy harboured the p.R758C mutation in the second allele. Mutations in the ANO5 gene seem to be a relatively common cause of muscular dystrophy in Germany. Cases with late onset or asymptomatic hyperCKemia can occur. Clinically, asymmetric manifestation is typical.","variants":[{"Name":"NM_213599.3(ANO5):c.191dup (p.Asn64fs)","Chromosome":"11","Start":"22221100","Stop":"22221101","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":17203,"rule_based_match":true,"evidence_text":"c.191dupA","llm_judgment":"PRESENT","evidence":"c.191dupA","abstract_start":447,"abstract_end":456}]}
{"pmid":"16953283","title":"c.301C > T (p.Arg101Cys): a novel mutation in the thrombin-sensitive region of protein S associated with a dysfunctional protein.","abstract":"","variants":[{"Name":"NM_000313.4(PROS1):c.301C>T (p.Arg101Cys)","Chromosome":"3","Start":"93910664","Stop":"93910664","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1943580,"rule_based_match":true,"evidence_text":"c.301C > T (p.Arg101Cys)","llm_judgment":"PRESENT","evidence":"c.301C > T (p.Arg101Cys)","abstract_start":null,"abstract_end":null}]}
{"pmid":"26275698","title":"A Novel de novo Mutation in the G6PD Gene in a Korean Boy with Glucose-6-phosphate Dehydrogenase Deficiency: Case Report.","abstract":"Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive hemolytic anemia caused by a mutation in the G6PD gene on Xq28. Herein, we describe a Korean boy with G6PD deficiency resulting from a novel mutation in G6PD. A 20-month-old boy with hemolytic anemia was referred for molecular diagnosis. He had no relevant family history. The G6PD activity was severely decreased at 0.2 U/g Hb (severe deficiency). Direct sequencing analyses on the G6PD gene revealed that he was hemizygous for a novel missense variant, c.1187C>G (p.Pro396Arg), in exon 10 of G6PD. Family study involving his parents revealed the de novo occurrence of the mutation. This is the first report of genetically confirmed G6PD deficiency in Korea.","variants":[{"Name":"NM_001360016.2(G6PD):c.1187C>G (p.Pro396Arg)","Chromosome":"X","Start":"154532667","Stop":"154532667","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":975606,"rule_based_match":true,"evidence_text":"c.1187C>G (p.Pro396Arg)","llm_judgment":"PRESENT","evidence":"c.1187C>G (p.Pro396Arg)","abstract_start":532,"abstract_end":555}]}
{"pmid":"23859858","title":"Five novel mutations in ARG1 gene in Chinese patients of argininemia.","abstract":"BACKGROUND: Argininemia is an autosomal recessive genetic disorder caused by hepatocyte arginase deficiency. It could be detected by blood amino acids analysis (high arginine) and confirmed by molecular diagnosis. The clinical manifestations in patients are similar to cerebral palsy so the diagnosis is usually much delayed. Reports of argininemia from mainland China are few, and genetic analyses have not been reported.\nPATIENTS AND METHODS: Five Chinese patients with argininemia were investigated. They had progressive spastic tetraplegia, poor physical growth from 1 month to 4 years. When argininemia was found at the ages of 4 to 12 years, four of patients had mental retardation, and three had seizures.\nRESULTS: Elevated blood arginine and significantly decreased erythrocyte arginase activity in five patients confirmed the diagnosis of arginase deficiency. Liver dysfunction was found in four patients, two of whom had mildly elevated blood ammonia levels. Cranial magnetic resonance imaging showed progressive cerebral atrophy in three patients. Six mutations in the ARG1 gene were identified, of which only one (c.703 G>A, p.G235R) in exon 7 has been reported before; c.34 G>T (p.G12X) in exon 1, c.67delG (p.G23fsX31) in exon 2, c.539G>C (p.R180 T) in exon 5, c.374C>T (p.A125 V) in exon 4, and c.646-649del CTCA (p.T215fsX219) in exon 6 were novel mutations.\nCONCLUSIONS: Argininemia is one of the few treatable causes of pediatric spastic paraparesis. Early metabolic investigation is very important to reach a diagnosis and better outcome. Five Chinese patients with late-diagnosed argininemia were reported. The mutation spectrum of ARG1 gene should be different from other populations.","variants":[{"Name":"NM_000045.4(ARG1):c.703G>A (p.Gly235Arg)","Chromosome":"6","Start":"131583392","Stop":"131583392","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":406816,"rule_based_match":true,"evidence_text":"c.703 G>A, p.G235R","llm_judgment":"PRESENT","evidence":"c.703 G>A, p.G235R","abstract_start":1126,"abstract_end":1144},{"Name":"NM_000045.4(ARG1):c.374C>T (p.Ala125Val)","Chromosome":"6","Start":"131581287","Stop":"131581287","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2833255,"rule_based_match":true,"evidence_text":"c.374C>T (p.A125 V)","llm_judgment":"PRESENT","evidence":"c.374C>T (p.A125 V)","abstract_start":1275,"abstract_end":1294}]}
{"pmid":"19131317","title":"A novel mutation in the DSPP gene associated with dentinogenesis imperfecta type II.","abstract":"Hereditary dentin defects are divided into dentinogenesis imperfecta and dentin dysplasia. We identified a family segregating severe dentinogenesis imperfecta. The kindred spanned four generations and showed an autosomal-dominant pattern of inheritance. The proband was a child presenting with a severely affected primary dentition, with wide-open pulp chambers and multiple pulp exposures, resembling a DGI type III (DGI-III) pattern. We hypothesized that a mutation in the DSPP gene is responsible for this severe phenotype. Mutational analyses revealed a novel mutation (c.53T>A, p.V18D) near the intron-exon boundary in the third exon of the DSPP gene. We analyzed the effect of the mutation by means of an in vitro splicing assay, which revealed that the mutation did not affect pre-mRNA splicing. Further studies are needed for a better understanding of the nature of the disease and the development of an appropriate treatment strategy.","variants":[{"Name":"NM_014208.3(DSPP):c.53T>A (p.Val18Asp)","Chromosome":"4","Start":"87612106","Stop":"87612106","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1310444,"rule_based_match":true,"evidence_text":"c.53T>A (p.V18D)","llm_judgment":"PRESENT","evidence":"c.53T>A","abstract_start":574,"abstract_end":581}]}
{"pmid":"25872942","title":"A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy.","abstract":"We studied two monozygotic twins, born to first cousins, affected by a multisystem disease. At birth, they both presented with bilateral cryptorchidism and malformations. Since early adulthood, they developed a slowly progressive neurological syndrome, with cerebellar and pyramidal signs, cognitive impairment, and depression. Dilating cardiomyopathy is also present in both. By whole-exome sequencing, we found a homozygous nucleotide change in XRCC4 (c.673C>T), predicted to introduce a premature stop codon (p.R225*). XRCC4 transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts. XRCC4 plays an important role in non-homologous end joining of DNA double-strand breaks (DSB), a system that is involved in repairing DNA damage from, for example, ionizing radiations. Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair. In contrast with embryonic lethality of the Xrcc4 KO mouse, nonsense mutations in human XRCC4 have recently been associated with primordial dwarfism and, in our cases, with adult-onset neurological impairment, suggesting an important role for DNA repair in the brain. Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients.","variants":[{"Name":"NM_003401.5(XRCC4):c.673C>T (p.Arg225Ter)","Chromosome":"5","Start":"83204849","Stop":"83204849","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":205036,"rule_based_match":true,"evidence_text":"c.673C>T","llm_judgment":"PRESENT","evidence":"c.673C>T","abstract_start":454,"abstract_end":462}]}
{"pmid":"25045523","title":"Recurrent pancreatitis in a patient with familial hypocalciuric hypercalcaemia treated successfully with cinacalcet.","abstract":"UNLABELLED: A 22-year-old female student presented with a history of recurrent pancreatitis. The commonest causes of pancreatitis, including drugs, gallstones, corticosteroids, excess alcohol and hypertriglyceridaemia, were excluded. She was found to have an elevated serum calcium level that was considered to be the cause of her pancreatitis, with a detectable serum parathyroid hormone (PTH). An initial diagnosis of primary hyperparathyroidism was made. However, two neck explorations failed to reveal a parathyroid adenoma. She was referred to our unit three years later as her episodes of pancreatitis were becoming more frequent and her calcium level remained persistently elevated. Her investigations were as follows: elevated adjusted calcium level of 2.79 mmol/l (2.2-2.58), PTH level of 4.2 pmol/l (0.6-6.0), low 24 h urine calcium of 0.3 mmol/l and a urine calcium:creatinine ratio of <0.003. A clinical diagnosis of familial hypocalciuric hypercalcaemia (FHH) was made and confirmed on genetic testing that showed a c.1703 G>A mutation in the calcium-sensing receptor gene. Although the hypercalcaemia of FHH is usually without sequelae due to the generalised changes in calcium sensing, in the presence of this complication she was started on cinacalcet 30 mg daily. She had one further episode of pancreatitis with calcium levels ranging between 2.53 and 2.66 mmol/l. Her cinacalcet was gradually increased to 30 mg three times daily, maintaining her calcium levels in the range of 2.15-2.20 mmol/l. She has not had a further episode of pancreatitis for more than 2 years. FHH is usually a benign condition with minimal complications from hypercalcaemia. Pancreatitis has been reported rarely, and no clear management strategy has been defined in these cases. Cinacalcet was successfully used in treating recurrent pancreatitis in a patient with FHH by maintaining calcium levels in the lower part of the reference range. Whether or not this is an effective long-term treatment remains yet to be seen.\nLEARNING POINTS: FHH is an important differential diagnosis for hypercalcaemia.FHH can rarely cause pancreatitis.No clear strategy is available to help in the management of patients with pancreatitis due to FHH.Cinacalcet was effective in lowering serum calcium levels and reducing the frequency of pancreatitis in our patient with FHH.","variants":[{"Name":"NM_000388.4(CASR):c.1703G>A (p.Cys568Tyr)","Chromosome":"3","Start":"122282207","Stop":"122282207","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1420666,"rule_based_match":true,"evidence_text":"c.1703 G>A","llm_judgment":"PRESENT","evidence":"c.1703 G>A","abstract_start":1029,"abstract_end":1039}]}
{"pmid":"22286118","title":"Lack of any cardiac involvement in a patient with Andersen-Tawil syndrome associated with the c.574A→G mutation in KCNJ2.","abstract":"The Andersen-Tawil syndrome (ATS) is characterized by hypo-normokaliemic muscle periodic paralysis, dysmorphic features and ventricular arrhythmias. Most cases are caused by mutations in KCNJ2, encoding for the potassium inwardly rectifying channel, Kir2.1 (ATS1). Although KCNJ2 mutations show no obvious genotype-phenotype correlations and incomplete penetrance, signs of cardiac involvement are usually present in most ATS1 cases. In contrast, here we describe an Italian ATS1 patient, carrying a c.574A→G mutation in KCNJ2, who had both facial dysmorphisms and muscle periodic paralysis but who did not manifest any cardiac involvement, although the same mutation was originally described in a Japanese kindred, in which all affected individuals manifested a severe cardiac phenotype.","variants":[{"Name":"NM_000891.3(KCNJ2):c.574A>G (p.Thr192Ala)","Chromosome":"17","Start":"70175613","Stop":"70175613","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":78477,"rule_based_match":false,"evidence_text":"c.574A→G","llm_judgment":"PRESENT","evidence":"c.574A→G","abstract_start":500,"abstract_end":508}]}
{"pmid":"35296328","title":"Novel compound heterozygous variants in the PCCB gene causing adult-onset propionic acidemia presenting with neuropsychiatric symptoms: a case report and literature review.","abstract":"BACKGROUND: Propionic acidemia (PA) is a rare autosomal recessive disorder of metabolism caused by mutations in the PCCA or PCCB gene, leading to propionyl CoA carboxylase (PCC) enzyme deficiencies. Most PA patients present variable clinical phenotypes and severity in the neonatal or infant period, with only a few developing symptoms after infancy. This report describes a PA patient with an adult-onset phenotype and a novel compound heterozygous mutation in the PCCB gene. To further explore the genotype-phenotype correlations in late-onset PA, we performed a literature review focusing on and summarizing 11 patients with PCC gene mutations who had the first onset and/or the definite diagnosis after infancy.\nCASE PRESENTATION: A 21-year-old PA patient presented with weakness of four limbs, gait abnormalities, two episodes of seizures, mental and behavior disorders after severe vomiting. Magnetic Resonance Imaging (MRI) demonstrated sustained bilateral caudate head and putamen symmetrical hyperintensity. Biochemical investigations revealed plasma amino and urine values correlating with a PA profile. Genetic analysis confirmed novel compound heterozygous variants in PCCB, with a newly-found pathogenic mutation (c.467T>C) and the c.1316A>G mutation associated with pathogenicity.\nCONCLUSION: We identified a novel compound heterozygous mutation in the PCCB gene causing late-onset PA. Patients carrying mutations in the PCCB gene tend to develop late-onset PA and present neuropsychiatric symptoms and/or signs. Further molecular biological research is needed to explore the genotype-phenotype correlations of PA.","variants":[{"Name":"NM_000532.5(PCCB):c.467T>C (p.Ile156Thr)","Chromosome":"3","Start":"136261989","Stop":"136261989","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":561214,"rule_based_match":true,"evidence_text":"c.467T>C","llm_judgment":"PRESENT","evidence":"c.467T>C","abstract_start":1227,"abstract_end":1235}]}
{"pmid":"29351342","title":"A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux.","abstract":"Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause (40-50%) of chronic kidney disease (CKD) in children. About 40 monogenic causes of CAKUT have so far been discovered. To date less than 20% of CAKUT cases can be explained by mutations in these 40 genes. To identify additional monogenic causes of CAKUT, we performed whole exome sequencing (WES) and homozygosity mapping (HM) in a patient with CAKUT from Indian origin and consanguineous descent. We identified a homozygous missense mutation (c.1336C>T, p.Arg446Cys) in the gene Von Willebrand factor A domain containing 2 (VWA2). With immunohistochemistry studies on kidneys of newborn (P1) mice, we show that Vwa2 and Fraser extracellular matrix complex subunit 1 (Fras1) co-localize in the nephrogenic zone of the renal cortex. We identified a pronounced expression of Vwa2 in the basement membrane of the ureteric bud (UB) and derivatives of the metanephric mesenchyme (MM). By applying in vitro assays, we demonstrate that the Arg446Cys mutation decreases translocation of monomeric VWA2 protein and increases translocation of aggregated VWA2 protein into the extracellular space. This is potentially due to the additional, unpaired cysteine residue in the mutated protein that is used for intermolecular disulfide bond formation. VWA2 is a known, direct interactor of FRAS1 of the Fraser-Complex (FC). FC-encoding genes and interacting proteins have previously been implicated in the pathogenesis of syndromic and/or isolated CAKUT phenotypes in humans. VWA2 therefore constitutes a very strong candidate in the search for novel CAKUT-causing genes. Our results from in vitro experiments indicate a dose-dependent neomorphic effect of the Arg446Cys homozygous mutation in VWA2.","variants":[{"Name":"NM_001272046.2(VWA2):c.1336C>T (p.Arg446Cys)","Chromosome":"10","Start":"114286277","Stop":"114286277","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":672257,"rule_based_match":true,"evidence_text":"c.1336C>T, p.Arg446Cys","llm_judgment":"PRESENT","evidence":"c.1336C>T, p.Arg446Cys","abstract_start":530,"abstract_end":552}]}
{"pmid":"21801158","title":"Herlitz junctional epidermolysis bullosa: diagnostic features, mutational profile, incidence and population carrier frequency in the Netherlands.","abstract":"BACKGROUND: Junctional epidermolysis bullosa, type Herlitz (JEB-H) is a lethal, autosomal recessive blistering disease caused by null mutations in the genes coding for the lamina lucida/densa adhesion protein laminin-332 (LAMB3, LAMA3 and LAMC2).\nOBJECTIVES: To present the diagnostic features and molecular analyses of all 22 patients with JEB-H in the Dutch Epidermolysis Bullosa Registry between 1988 and 2011, and to calculate the disease incidence and carrier frequency in the Netherlands.\nMETHODS: All patients were analysed with immunofluorescence antigen mapping (IF), electron microscopy (EM) and molecular analysis.\nRESULTS: The mean lifespan of our patients with JEB-H was 5·8 months (range 0·5-32·6). IF showed absent (91%) or strongly reduced (9%) staining for laminin-332 with monoclonal antibody GB3. In EM the hemidesmosomes and sub-basal dense plates were hypoplastic or absent. We identified mutations in all 22 patients: in 19 we found LAMB3 mutations, in two LAMA3 mutations, and in one LAMC2 mutations. We found three novel splice site mutations in LAMB3: (i) c.29-2A>G resulting in an out-of-frame skip of exon 3 and a premature termination codon (PTC); (ii) c.1289-2_1296del10 leading to an out-of-frame skip of exon 12 and a PTC; and (iii) c.3228+1G>T leading to an exon 21 skip.\nCONCLUSIONS: All diagnostic tools should be evaluated to clarify the diagnosis of JEB-H. We have identified 11 different mutations in 22 patients with JEB-H, three of them novel. In the Netherlands the incidence rate of JEB-H is 4·0 per one million live births. The carrier frequency of a JEB-H mutation in the Dutch population is 1 in 249.","variants":[{"Name":"NM_000228.3(LAMB3):c.29-2A>G","Chromosome":"1","Start":"209650120","Stop":"209650120","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":186614,"rule_based_match":true,"evidence_text":"c.29-2A>G","llm_judgment":"PRESENT","evidence":"c.29-2A>G","abstract_start":1081,"abstract_end":1090}]}
{"pmid":"23430873","title":"A twelve-year follow-up study on a case of early-onset parkinsonism preceding clinical manifestation of Gaucher disease.","abstract":"Mutations in the glucocerebrosidase gene (GBA1) cause Gaucher disease (GD) and are the most common genetic risk factor for the development of Parkinson's disease (PD). Here, we present a 12-year follow-up study of a male with GD and PD (diagnosed 24years ago), which PD preceded the clinical manifestation of GD by 12years. The patient is a compound heterozygote for mutations c.115+1G>A and c.1226A>G (IVS2 + 1/N370S) in the GBA1 gene. Imiglucerase had a beneficial effect on GD, but not on PD. Treatment with L-dopa and other PD drugs showed temporary efficacy but 2years later significant wearing-off phenomenon and dyskinesias appeared. Unilateral pallidotomy was performed with transient benefit. Cognitive decline appeared later and developed in to akinetic mutism. A lumbar puncture was performed to characterize the biochemical profile of cerebrospinal fluid (CSF). Analyses of monoamine metabolites levels in the CSF, determined by reverse-phase high-performance liquid chromatography, revealed remarkably low levels of all studied monoamine metabolites (HVA, DOPAC, 5-HIAA, MHPG). These data indicate that PD associated with GBA1 mutations may not only affect dopaminergic neurons, but also noradrenergic and serotonergic neurons. Of note, normal levels of P-tau, total tau and β-amyloid (1-42) were detected on ELISA assay. Thus, the cognitive decline, akinetic mutism and moderate cortical atrophy found on the CT scan were not paralleled by any changes of dementia markers in CSF. This single case study extends the follow-up period and adds novel CSF information; however additional data on other patients with both PD and GD may help put our observations in its ultimate proper context.","variants":[{"Name":"NM_000157.4(GBA1):c.115+1G>A","Chromosome":"1","Start":"155240629","Stop":"155240629","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":99352,"rule_based_match":true,"evidence_text":"c.115+1G>A","llm_judgment":"PRESENT","evidence":"c.115+1G>A","abstract_start":377,"abstract_end":387}]}
{"pmid":"30545478","title":"Presence of tau astrogliopathy in frontotemporal dementia caused by a novel Grn nonsense (Trp2*) mutation.","abstract":"Frontotemporal lobar degeneration caused by GRN mutations is mainly associated with a TDP-43 type A proteinopathy. We present a family with autosomal dominant frontotemporal lobar degeneration caused by a novel GRN nonsense mutation (c.5G>A: p.Trp2*) in which the proband's brain also showed prominent glial tauopathy consistent with an aging-related tau astrogliopathy. Astrocytic tauopathy, 4R(+) and 3R(-) immunoreactive, was characterized by thorn-shaped astrocytes present in subpial, subependymal, and perivascular areas, and in gray matter; plus granular or fuzzy tau immunoreactivity in astrocytic processes in gray matter, either solitary or clustered in different regions. Some neurofibrillary tangles and pretangles, both 3R and 4R(+), were present in the medial temporal lobe but did not exhibit the characteristic distribution of Alzheimer's type pathology. This 4R-tau aging-related tau astrogliopathy is likely a co-occurring pathology, although an interaction between progranulin and tau proteins within the neurodegenerative process should not be ruled out.","variants":[{"Name":"NM_002087.4(GRN):c.5G>A (p.Trp2Ter)","Chromosome":"17","Start":"44349169","Stop":"44349169","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3087075,"rule_based_match":true,"evidence_text":"c.5G>A: p.Trp2*","llm_judgment":"PRESENT","evidence":"c.5G>A: p.Trp2*","abstract_start":234,"abstract_end":249}]}
{"pmid":"33884742","title":"Heterozygous missense variant in TRPC6 in a boy with rapidly progressive infantile nephrotic syndrome associated with diffuse mesangial sclerosis.","abstract":"Transient receptor potential channel C6 encoded by TRPC6 is involved in slit diaphragm formation in podocytes, and abnormalities of the TRPC6 protein cause various glomerular diseases. The first identified pathogenic variant of TRPC6 was found to cause steroid-resistant nephrotic syndrome that typically developed in adulthood and then slowly led to end-stage renal disease, along with a renal pathology of focal segmental glomerulosclerosis. Here, we report a patient with rapidly progressing infantile nephrotic syndrome and a heterozygous missense TRPC6 variant. The patient, a 2-year-old Japanese boy, developed steroid-resistant nephrotic syndrome at age 11 months. His renal function deteriorated rapidly, and peritoneal dialysis was introduced at age 1 year and 6 months. His renal pathology, obtained at age 1 year and 1 month, was consistent with diffuse mesangial sclerosis (DMS). Clinical exome analysis and custom panel analysis for hereditary renal diseases revealed a reported heterozygous missense variant in TRPC6 (NM_004621.5:c.523C > T:p.Arg175Trp). This is the first report of a patient with a TRPC6-related renal disorder associated with DMS.","variants":[{"Name":"NM_004621.6(TRPC6):c.523C>T (p.Arg175Trp)","Chromosome":"11","Start":"101504446","Stop":"101504446","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":224411,"rule_based_match":true,"evidence_text":"NM_004621.5:c.523C > T:p.Arg175Trp","llm_judgment":"PRESENT","evidence":"NM_004621.5:c.523C > T:p.Arg175Trp","abstract_start":1032,"abstract_end":1066}]}
{"pmid":"22503135","title":"Hereditary diffuse leukoencephalopathy with axonal spheroids caused by R782H mutation in CSF1R: case report.","abstract":"We report a biopsy-proven and genetically determined case with leukoencephalopathy showing autosomal dominant inheritance and pre-senile dementia. A 51-year old woman gradually developed a decline in cognitive functions with aphasia and epileptic seizures. Four of her family members were diagnosed as having dementia in their forties to sixties. Five years later she became apathetic and bed-ridden. Brain MRI initially showed fronto-temporal dominant cerebral atrophy with multiple small lacunar-like lesions in the deep white matter, but these white matter lesions became diffuse at an advanced stage. Such possibilities as hereditary vascular or fronto-temporal dementia were clinically suspected, but her family members requested a definitive diagnosis. Brain biopsy showed severe loss of myelin and axons in the white matter with relatively preserved cortical structure. The remaining axons disclosed irregular shapes with the formation of many spheroids, and these findings were consistent with a histopathological diagnosis of neuroaxonal dystrophy. DNA analysis disclosed a novel heterozygous c.2345G>A (p.782Arg>His) mutation in exon 18 of the colony stimulating factor 1 receptor gene (CSF1R). Hereditary diffuse leukoencephalopathy with axonal spheroids should be included in the differential diagnosis of familial occurrence of pre-senile dementia.","variants":[{"Name":"NM_001288705.3(CSF1R):c.2345G>A (p.Arg782His)","Chromosome":"5","Start":"150056316","Stop":"150056316","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46939,"rule_based_match":true,"evidence_text":"c.2345G>A (p.782Arg>His)","llm_judgment":"PRESENT","evidence":"c.2345G>A (p.782Arg>His)","abstract_start":1102,"abstract_end":1126}]}
{"pmid":"38423010","title":"Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy.","abstract":"The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux.","variants":[{"Name":"NM_007241.4(SNF8):c.304G>A (p.Val102Ile)","Chromosome":"17","Start":"48937065","Stop":"48937065","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2831936,"rule_based_match":true,"evidence_text":"c.304G>A (p.Val102Ile)","llm_judgment":"PRESENT","evidence":"c.304G>A (p.Val102Ile)","abstract_start":808,"abstract_end":830}]}
{"pmid":"36653541","title":"Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition.","abstract":"CHEK2 is a well-established breast cancer susceptibility gene. The most frequent pathogenic CHEK2 variant is 1100delC, a loss-of-function mutation conferring 2-fold risk for breast cancer. This gene also harbors other rare variants encountered in the clinical gene panels for hereditary cancer. One of these is CHEK2 c.1312 G > T, p.(Asp438Tyr) in the kinase domain of the protein, but due to its rarity its clinical significance for breast cancer predisposition has remained unclear. Here, we tested the prevalence of CHEK2 p.(Asp438Tyr) allele showing enrichment in the Northern Finnish population, in a total of 2284 breast cancer patients from this geographical region. Genotyping was performed for DNA samples extracted from peripheral blood using high-resolution melt analysis. Fourteen CHEK2 p.(Asp438Tyr) carriers were identified (14/2284, 0.6%, P = 0.67): two in the cohort of breast cancer cases with the indication of inherited disease susceptibility (2/281, 0.7%, P = 1.00) and twelve in the breast cancer cohort unselected for the family history of disease and age at disease onset (12/2003, 0.6%, P = 0.66). This frequency did not differ from the frequency in the general population (10/1299, 0.8%). No CHEK2 p.(Asp438Tyr) homozygotes were identified. Our results indicate that CHEK2 p.(Asp438Tyr) carriers do not have an increased risk for breast cancer and the classification of the CHEK2 p.(Asp438Tyr) variant can be changed from the variant of uncertain significance (VUS) to likely benign for breast cancer.","variants":[{"Name":"NM_007194.4(CHEK2):c.1312G>T (p.Asp438Tyr)","Chromosome":"22","Start":"28695190","Stop":"28695190","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":133513,"rule_based_match":true,"evidence_text":"CHEK2 c.1312 G > T, p.(Asp438Tyr)","llm_judgment":"PRESENT","evidence":"CHEK2 c.1312 G > T, p.(Asp438Tyr)","abstract_start":311,"abstract_end":344}]}
{"pmid":"31467430","title":"A CRISPR-based base-editing screen for the functional assessment of BRCA1 variants.","abstract":"Genetic mutations in BRCA1, which is crucial for the process of DNA repair and maintenance of genomic integrity, are known to increase markedly the risk of breast and ovarian cancers. Clinical genetic testing has been used to identify new BRCA1 variants; however, functional assessment and determination of their pathogenicity still poses challenges for clinical management. Here, we describe that CRISPR-mediated cytosine base editor, known as BE3, can be used for the functional analysis of BRCA1 variants. We performed CRISPR-mediated base-editing screening using 745 gRNAs targeting all exons in BRCA1 to identify loss-of-function variants and identified variants whose function has heretofore remained unknown, such as c.-97C>T, c.154C>T, c.3847C>T, c.5056C>T, and c.4986+5G>A. Our results show that CRISPR-mediated base editor is a powerful tool for the reclassification of variants of uncertain significance (VUSs) in BRCA1.","variants":[{"Name":"NM_007294.4(BRCA1):c.5056C>T (p.His1686Tyr)","Chromosome":"17","Start":"43067626","Stop":"43067626","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":531064,"rule_based_match":true,"evidence_text":"c.5056C>T","llm_judgment":"PRESENT","evidence":"c.5056C>T","abstract_start":755,"abstract_end":764}]}
{"pmid":"16056219","title":"Higher prevalence of OCA1 in an ethnic group of eastern India is due to a founder mutation in the tyrosinase gene.","abstract":"PURPOSE: Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders characterized by deficient synthesis of melanin pigment and associated with common developmental abnormalities of the eye. It is one of the major causes of childhood blindness in India. The disease is common among an ethnic group (Tili) of Eastern India, which represents about 12.56% of the Bankura district population (approximately 0.4 million) of West Bengal. The purpose of the study was to investigate the molecular lesions causing OCA within this ethnic group for the unequivocal diagnosis of the carriers and attempt to decipher the cause for the high prevalence of OCA.\nMETHODS: Fourteen OCA-affected Tili families consisting a total of 161 individuals, including 26 patients, were recruited for the study. A lack of tyrosinase (TYR) activity among all the patients was ascertained by the tyrosinase hair bulb assay. Mutation screening in the tyrosinase gene (TYR) was done by single strand conformational polymorphism (SSCP) and DNA sequencing. The restriction fragment length polymorphism (RFLP) assay was carried out to determine the frequency of the pathogenic changes among the normal individuals. Haplotype analysis was performed at the TYR locus using a set of informative microsatellite and SNP markers.\nRESULTS: All the patients were homozygous for a null mutation (c.832C>T, Arg278stop) in TYR exon 2, which might cause a complete loss of enzyme activity. The mutation occurred in the same haplotype background. The frequency of the disease in this ethnic group was estimated to be significantly higher than the world average.\nCONCLUSIONS: OCA1 in the Tili population is due to the occurrence of a founder mutation in the TYR as indicated by haplotype analysis. Higher prevalence of the mutation in the population group is due to marriage within the same community. The diagnostic RFLP assay can be utilized for genetic counseling and thereby will help to reduce the disease load on the population.","variants":[{"Name":"NM_000372.5(TYR):c.832C>T (p.Arg278Ter)","Chromosome":"11","Start":"89191214","Stop":"89191214","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105472,"rule_based_match":true,"evidence_text":"c.832C>T","llm_judgment":"PRESENT","evidence":"c.832C>T","abstract_start":1367,"abstract_end":1375}]}
{"pmid":"29050284","title":"Mutational analysis of a Chinese family with oculocutaneous albinism type 2.","abstract":"Oculocutaneous albinism (OCA) is an autosomal recessive disorder characterized by hypopigmentation of the skin, hair, and eyes accompanied with ophthalmologic abnormalities. Molecular genetic test can confirm the diagnosis of the four subtypes of OCA (OCA1-4). Herein, we report a Chinese family with two patients affected by OCA. Mutations of <i>TYR</i>, <i>OCA2, TYRP1</i>, and <i>SLC45A2</i> were examined by using PCR-sequencing. Large deletions or duplications of <i>TYR</i> and <i>OCA2</i> were examined by Multiplex Ligation-dependent Probe Amplification (MLPA) assay. Compound heterozygous mutations of <i>OCA2</i>, (c.808-3C>G and c.2080-2A>G), were identified in both patients characterized with yellow hair and milky skin, heterochromia iridis, and nystagmus. Several computer-assisted approaches predicted that c.808-3C>G and c.2080-2A>G in <i>OCA2</i> might potentially be pathogenic splicing mutations. No exon rearrangement (deletion/duplication) of <i>TYR</i> and <i>OCA2</i> was observed in the patients by MLPA analysis. This study suggests that compound heterozygous mutations, (c.808-3C>G and c.2080-2A>G), in <i>OCA2</i> may be responsible for partial clinical manifestations of OCA.","variants":[{"Name":"NM_000275.3(OCA2):c.808-3C>G","Chromosome":"15","Start":"28016189","Stop":"28016189","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1701783,"rule_based_match":true,"evidence_text":"c.808-3C>G","llm_judgment":"PRESENT","evidence":"c.808-3C>G","abstract_start":625,"abstract_end":635}]}
{"pmid":"28105082","title":"Genetic diagnosis and treatment of a Chinese ketosis-prone MODY 3 family with depression.","abstract":"BACKGROUND: To analyze the gene mutation and mental disorder of a Chinese ketosis-prone diabetes (KPD) family, and to make a precise diagnosis and give a treatment for them.\nMETHODS: We studied a Chinese family with a clinical diagnosis of maturity-onset diabetes of the young (MODY). The clinical data and the blood samples were collected. The promotor and coding regions inclusive intron exon boundaries of the HNF1A, HNF4A were detected by polymerase chain reaction (PCR) and direct sequencing. The missense mutation was also analyzed by bioinformatics. Genetic counseling was performed twice a month to relieve the mental disorder of the persons.\nRESULTS: The missense mutation c.779 C>T (p.T260M) in exon4 of HNF1A gene was detected, and the symptom heterogenicity among persons in this family were found. All the members were retreated with Gliclazide and stopped to use other medicine, the blood glucose of them were well controlled. We also performed an active genetic counseling to them and the mental disorder of the proband's sister was relieved.\nCONCLUSIONS: A missense mutation of HNF1A gene was first found in Chinese ketosis-prone MODY family with manifestations heterogenicity among the persons. Sulphonylureas medicine and genetic counseling are efficiency ways to treat MODY 3 and its' mental disorder respectively.","variants":[{"Name":"NM_000545.8(HNF1A):c.779C>T (p.Thr260Met)","Chromosome":"12","Start":"120994229","Stop":"120994229","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":260011,"rule_based_match":true,"evidence_text":"c.779 C>T (p.T260M)","llm_judgment":"PRESENT","evidence":"c.779 C>T (p.T260M)","abstract_start":682,"abstract_end":701}]}
{"pmid":"27863619","title":"Identification of SLC26A4 mutations p.L582LfsX4, p.I188T and p.E704K in a Chinese family with large vestibular aqueduct syndrome (LVAS).","abstract":"Large vestibular aqueduct syndrome (LVAS) is a type of hearing loss characterized by an autosomal recessive inheritance. LVAS has been shown to be associated with mutations in SLC26A4 gene. In the present study, we report the clinical, genetic and molecular characterization of a Chinese family with LVAS. By using the targeted sequence capture and next-generation sequencing, we identified heterozygous mutations of SLC26A4 p.I188T (c.563T > C), p.L582LfsX4 (c.1746 delG) and p.E704K (c.2110G > A) in the affected individual of this family, of which SLC26A4 p.E704K is a novel mutation associated with LVAS. By tracing the transmission and functional prediction of these mutations in the pedigree, the heterozygous mutations of p.I188T, p.L582LfsX4 and p.E704K in SLC26A4 gene were responsible for the LVAS of the affected individual. This is the first case of LVAS caused by these mutations.","variants":[{"Name":"NM_000441.2(SLC26A4):c.2110G>A (p.Glu704Lys)","Chromosome":"7","Start":"107710074","Stop":"107710074","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544339,"rule_based_match":true,"evidence_text":"c.2110G>A (p.Glu704Lys)","llm_judgment":"PRESENT","evidence":"c.2110G > A","abstract_start":486,"abstract_end":497},{"Name":"NM_000441.2(SLC26A4):c.563T>C (p.Ile188Thr)","Chromosome":"7","Start":"107674311","Stop":"107674311","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":544395,"rule_based_match":true,"evidence_text":"c.563T>C (p.Ile188Thr)","llm_judgment":"PRESENT","evidence":"c.563T > C","abstract_start":434,"abstract_end":444}]}
{"pmid":"23233793","title":"A novel splice site mutation of CDHR1 in a consanguineous Israeli Christian Arab family segregating autosomal recessive cone-rod dystrophy.","abstract":"PURPOSE: To investigate the genetic basis for autosomal recessive cone-rod dystrophy in a consanguineous Israeli Christian Arab family.\nMETHODS: Patients underwent a detailed ophthalmic examination, including funduscopy, electroretinography (ERG), visual field testing, and optical coherence tomography. Genome-wide homozygosity mapping using a single nucleotide polymorphism array was performed to identify homozygous regions shared between the two affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico analysis was used to predict the effect of the mutation on splicing.\nRESULTS: The family included two affected individuals. Clinical findings included progressive deterioration of visual acuity, photophobia, defective color vision, loss of central visual fields, pigmentary deposits localized mainly in the peripheral retina, a thinned and atrophic macular region, retinal vessel attenuation, absent ERG cone responses, and reduced ERG rod responses. Homozygosity mapping revealed several homozygous intervals shared among the affected individuals. One, a 12Mb interval on chromosome 10, included the CDHR1 gene. Direct sequencing revealed a single base transversion, c.1485+2T>G, located in the conserved donor splice site of Intron 13. This mutation cosegregated with the disease in the family, and was not detected in 208 Israeli Christian Arab control chromosomes. In silico analysis predicted that this mutation eliminates the Intron 13 donor splice site.\nCONCLUSIONS: Only three distinct pathogenic mutations of CDHR1 have been reported to date in patients with autosomal recessive retinal degeneration. Here we report a novel splice site mutation of CDHR1, c.1485+2T>G, underlying autosomal recessive cone-rod dystrophy in a consanguineous Israeli Christian Arab family. This report expands the spectrum of pathogenic mutations of the CDHR1 gene.","variants":[{"Name":"NM_033100.4(CDHR1):c.1485+2T>G","Chromosome":"10","Start":"84211167","Stop":"84211167","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":800693,"rule_based_match":true,"evidence_text":"c.1485+2T>G","llm_judgment":"PRESENT","evidence":"c.1485+2T>G","abstract_start":1230,"abstract_end":1241}]}
{"pmid":"19837936","title":"Six new mutations of the thyroglobulin gene discovered in taiwanese children presenting with thyroid dyshormonogenesis.","abstract":"BACKGROUND: Thyroglobulin (TG) defect is a rare cause of congenital hypothyroidism. Although only 44 mutations of the human TG gene have been identified, we have suspected a TG defect in 38% of Taiwan Chinese children/adolescents presenting with moderate or severe thyroidal dyshormonogenesis.\nSTUDY OBJECTIVE: The aim of the study is to report the discovery of new TG gene mutations and associated clinical manifestations of the defective TG protein.\nPATIENTS AND RESULTS: In seven patients from six families, we detected six new TG gene mutations, including c.1348delT, p.R432X (c.1351C>T), g.IVS3 + 2T>G, c.1712delT, p.Q1765X (c.5350C>T), and c.6047delA. The c.1348delT and p.R432X mutations were the most common, detected in 33 and 25%, respectively, of alleles studied. Haplotype analysis suggested that the c.1348delT and g.IVS3 + 2T>G mutations are due to founder effects, whereas p.R432X is probably due to independently recurrent de novo mutations. mRNA transcript of the g.IVS3 + 2T>G mutant, detected in whole blood by reverse transcription-nested PCR, showed skipping of exon 3 (98-bp deletion) and a frameshift, with a terminal signal after 17 altered amino acid residues.\nCONCLUSIONS: TG defects have an important role in severe thyroidal dyshormonogenesis (pretreatment, or after a 3-wk T(4) withdrawal, plasma T(4) < or = 30 nmol/liter) in Taiwanese. Its genetic characteristics are markedly different from those described in other populations presenting with mutations of the TG gene.","variants":[{"Name":"NM_003235.5(TG):c.1351C>T (p.Arg451Ter)","Chromosome":"8","Start":"132886723","Stop":"132886723","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1020436,"rule_based_match":true,"evidence_text":"p.R432X (c.1351C>T)","llm_judgment":"PRESENT","evidence":"p.R432X (c.1351C>T)","abstract_start":572,"abstract_end":591},{"Name":"NM_003235.5(TG):c.1348del (p.Ser450fs)","Chromosome":"8","Start":"132886720","Stop":"132886720","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":2901249,"rule_based_match":true,"evidence_text":"c.1348delT","llm_judgment":"PRESENT","evidence":"c.1348delT","abstract_start":560,"abstract_end":570}]}
{"pmid":"22104571","title":"Novel mutation in long QT syndrome in a patient with prior diagnosis of epilepsy","abstract":"Congenital long QT syndrome (LQTS) can present as syncope or seizures, secondary to polymorphic ventricular tachycardia, mimicking a primary seizure disorder. In patients treated with an implantable cardioverter-defibrillator (ICD), the recurrence of arrhythmias with subsequent frequent therapeutic shocks may cause adverse reactions, which can be psychogenic. We report the case of a 22-year-old woman with syncope and seizures who was diagnosed in childhood as epileptic and in whom LQTS was diagnosed only in adulthood. Beta-blocker therapy failed and an ICD was implanted. However, as arrhythmias persisted, left cardiac sympathetic denervation was performed. After surgery, three-month follow-up showed a significant reduction in arrhythmias. The genetic study identified a heterozygous mutation, c.1817 C>T p.S606F, on the KCNH2 gene that has not previously been reported in the literature. We also report the rare occurrence of an electrical storm in the course of H1N1 infection. This case illustrates the difficulties in the diagnosis and treatment of LQTS. The possibility of a common genetic basis for arrhythmic diseases and epilepsy is discussed.","variants":[{"Name":"NM_000238.4(KCNH2):c.1817C>T (p.Ser606Phe)","Chromosome":"7","Start":"150951576","Stop":"150951576","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3856594,"rule_based_match":true,"evidence_text":"c.1817 C>T p.S606F","llm_judgment":"PRESENT","evidence":"c.1817 C>T p.S606F","abstract_start":803,"abstract_end":821}]}
{"pmid":"25203534","title":"Whole genome sequencing reveals novel non-synonymous mutation in ectodysplasin A (EDA) associated with non-syndromic X-linked dominant congenital tooth agenesis.","abstract":"Congenital tooth agenesis in human is characterized by failure of tooth development during tooth organogenesis. 300 genes in mouse and 30 genes in human so far have been known to regulate tooth development. However, candidature of only 5 genes viz. PAX9, MSX1, AXIN2, WNT10A and EDA have been experimentally established for congenitally missing teeth like hypodontia and oligodontia. In this study an Indian family with multiple congenital tooth agenesis was identified. Pattern of inheritance was apparently autosomal dominant type with a rare possibility to be X-linked. Whole genome sequencing of two affected individuals was carried out which revealed 119 novel non-synonymous single nucleotide variations (SNVs) distributed among 117 genes. Out of these only one variation (c.956G>T) located at exon 9 of X-linked EDA gene was considered as pathogenic and validated among all the affected and unaffected family members and unrelated controls. This variation leads to p.Ser319Ile change in the TNF homology domain of EDA (transcript variant 1) protein. In silico analysis predicts that this Ser319 is well conserved across different vertebrate species and a part of putative receptor binding site. Structure based homology modeling predicts that this amino acid residue along with four other amino acid residues nearby, those when mutated known to cause selective tooth agenesis, form a cluster that may have functional significance. Taken together these results suggest that c.956G>T (p.Ser319Ile) mutation plausibly reduces the receptor binding activity of EDA leading to distinct tooth agenesis in this family.","variants":[{"Name":"NM_001399.5(EDA):c.956G>T (p.Ser319Ile)","Chromosome":"X","Start":"70035389","Stop":"70035389","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":132579,"rule_based_match":true,"evidence_text":"c.956G>T (p.Ser319Ile)","llm_judgment":"PRESENT","evidence":"c.956G>T (p.Ser319Ile)","abstract_start":1480,"abstract_end":1502}]}
{"pmid":"33363884","title":"A novel KRT1 c.1433A>G p.(Glu478Gly) mutation in a newborn with epidermolytic ichthyosis.","abstract":"Epidermolytic Ichthyosis is a rare genodermatosis related to point mutations affecting the genes encoding for keratin 1 or keratin 10. We report a case of Epidermolytic Ichthyosis in a newborn with a novel mutation (c.1433A>G) of KRT1 gene.","variants":[{"Name":"NM_006121.4(KRT1):c.1433A>G (p.Glu478Gly)","Chromosome":"12","Start":"52676317","Stop":"52676317","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1691331,"rule_based_match":true,"evidence_text":"c.1433A>G","llm_judgment":"PRESENT","evidence":"c.1433A>G","abstract_start":216,"abstract_end":225}]}
{"pmid":"26519721","title":"Novel Mutations in a Patient with Triple A Syndrome.","abstract":"BACKGROUND: Triple A syndrome (Allgrove syndrome), a rare autosomal recessive disorder, is characterized by adrenal insufficiency, achalasia cardia and alacrimia. It is caused by mutations in AAAS gene which encodes a protein called ALADIN.\nCASE CHARACTERISTICS: 8-year-old boy who presented with hypoglycemic seizures, dysphagia, dry eyes and hyperpigmentation. Investigations confirmed achalasia cardia and adrenal insufficiency. Sequencing of AAAS gene revealed two novel mutations in compound heterozygous state (c.1101delG/ c.1310_1311delCT).\nOUTCOME: Patient was managed with hydrocortisone and artificial tears.\nMESSAGE: Sequencing analysis should be done to confirm the diagnosis of clinically suspected Triple A syndrome.","variants":[{"Name":"NM_015665.6(AAAS):c.1310_1311del (p.Pro437fs)","Chromosome":"12","Start":"53308072","Stop":"53308073","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":1313985,"rule_based_match":true,"evidence_text":"c.1310_1311delCT","llm_judgment":"PRESENT","evidence":"c.1310_1311delCT","abstract_start":529,"abstract_end":545}]}
{"pmid":"30745532","title":"Different Clinical Presentation and Tissue Characterization in a Monozygotic Twin Pair with MYH7 Mutation-Related Hypertrophic Cardiomyopathy.","abstract":"This case report demonstrates a pair of monozygotic twins with hypertrophic cardiomyopathy (HCM) carrying the same pathogenic mutation of MYH7 (p.G768R; c.2302G>A), detected by whole exome and Sanger genetic sequencing methods. On multi-modality imaging, they were reported to have similar, but not identical, morphologic expression. Particularly, the clinical presentation and tissue characteristics were not the same. Late gadolinium enhancement (LGE) and T1 mapping of cardiac magnetic resonance showed different extents of myocardial fibrotic characteristics in the twins (twin A: 16.3% LGE and 32.6% extracellular volume [ECV] of the whole left ventricle; twin B: 5.4% LGE and 28.1% ECV of the whole left ventricle). This extraordinary case of HCM provides evidence on the complex pathophysiological mechanisms of HCM and suggests the likely impact of epigenetics and environmental factors on HCM phenotype.","variants":[{"Name":"NM_000257.4(MYH7):c.2302G>A (p.Gly768Arg)","Chromosome":"14","Start":"23425403","Stop":"23425403","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":175624,"rule_based_match":true,"evidence_text":"c.2302G>A","llm_judgment":"PRESENT","evidence":"c.2302G>A","abstract_start":153,"abstract_end":162}]}
{"pmid":"27815844","title":"Incidence and Geographic Distribution of Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency.","abstract":"The incidence of succinic semialdehyde dehydrogenase (SSADH) deficiency, an autosomal recessive inherited disorder of GABA degradation, is unknown. Upon a recent diagnosis of a new family of affected fraternal twins from the Punjabi ethnic group of India, case ascertainment from the literature and our database was done to determine the number of confirmed cases along with their geographic distribution. The probands presented with global developmental delay, infantile onset epilepsy, and a persistent neurodevelopmental disorder upon diagnosis at 10 years of age with intellectual disability, expressive aphasia, and behavioral problems most prominent for hyperactivity. Gamma-hydroxybutyric aciduria and homozygous ALDH5A1 c.608C>T; p.Pro203Leu mutations were confirmed. Identification of all available individual cases with clinical details available including geographic or ethnic origin revealed 182 patients from 40 countries, with the largest number of patients reported from the USA (24%), Turkey (10%), China (7%), Saudi Arabia (6%), and Germany (5%). This study provides an accounting of all published cases of confirmed SSADH deficiency and provides data useful in planning further studies of this rare inborn error of metabolism.","variants":[{"Name":"NM_001080.3(ALDH5A1):c.608C>T (p.Pro203Leu)","Chromosome":"6","Start":"24503432","Stop":"24503432","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1325764,"rule_based_match":true,"evidence_text":"homozygous ALDH5A1 c.608C>T; p.Pro203Leu mutations","llm_judgment":"PRESENT","evidence":"homozygous ALDH5A1 c.608C>T; p.Pro203Leu mutations","abstract_start":709,"abstract_end":759}]}
{"pmid":"23188110","title":"A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55).","abstract":"BACKGROUND: Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy.\nMETHODS: The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control.\nRESULTS: We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV.\nCONCLUSIONS: This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.","variants":[{"Name":"NM_152269.5(MTRFR):c.394C>T (p.Arg132Ter)","Chromosome":"12","Start":"123256924","Stop":"123256924","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48181,"rule_based_match":true,"evidence_text":"c.394C>T, p.R132X","llm_judgment":"PRESENT","evidence":"c.394C>T, p.R132X","abstract_start":1047,"abstract_end":1064}]}
{"pmid":"28122887","title":"Expanding the genetic spectrum of ANOS1 mutations in patients with congenital hypogonadotropic hypogonadism.","abstract":"STUDY QUESTION: What is the prevalence and functional consequence of ANOS1 (KAL1) mutations in a group of men with congenital hypogonadotropic hypogonadism (CHH)?\nSUMMARY ANSWER: Three of forty-two (7.1%) patients presented ANOS1 mutations, including a novel splice site mutation leading to exon skipping and a novel contiguous gene deletion associated with ichthyosis.\nWHAT IS KNOWN ALREADY: CHH is characterized by lack of pubertal development and infertility, due to deficient production, secretion or action of GnRH, and can be associated with anosmia/hyposmia (Kallmann syndrome, KS) or with a normal sense of smell (normosmic CHH). Mutations in the anosmin-1 (ANOS1) gene are responsible for the X-linked recessive form of KS.\nSTUDY DESIGN, SIZE, DURATION: This cross-sectional study included 42 unrelated men with CHH (20 with KS and 22 with normosmic CHH).\nPARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were screened for mutations in the ANOS1 gene by DNA sequencing. Identified mutations were further investigated by RT-PCR analysis and multiplex ligation-dependent probe amplification (MLPA) analysis.\nMAIN RESULTS AND THE ROLE OF CHANCE: Hemizygous mutations were identified in three (7.1%) KS cases: a novel splice acceptor site mutation (c.542-1G>C), leading to skipping of exon 5 in the ANOS1 transcript in a patient with self-reported normosmia (but hyposmic upon testing); a recurrent nonsense mutation (c.571C>T, p.Arg191*); and a novel 4.8 Mb deletion involving ANOS1 and eight other genes (VCX3B, VCX2, PNPLA4, VCX, STS, HDHD1, VCX3A and NLGN4X) in KS associated with ichthyosis.\nLIMITATIONS, REASONS FOR CAUTION: Objective olfactory testing was not performed in all cases of self-reported normosmia and this may have underestimated the olfactory deficits.\nWIDER IMPLICATIONS OF THE FINDINGS: This study further expands the spectrum of known genetic defects associated with CHH and suggests that patients with self-reported normal olfactory function should not be excluded from ANOS1 genetic testing.\nSTUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Portuguese Foundation for Science and Technology. The authors have no conflicts of interest.\nTRIAL REGISTRATION NUMBER: N/A.","variants":[{"Name":"NM_000216.4(ANOS1):c.571C>T (p.Arg191Ter)","Chromosome":"X","Start":"8587949","Stop":"8587949","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1421767,"rule_based_match":true,"evidence_text":"c.571C>T, p.Arg191*","llm_judgment":"PRESENT","evidence":"c.571C>T, p.Arg191*","abstract_start":1425,"abstract_end":1444}]}
{"pmid":"31555371","title":"Novel mutations associated with autosomal-dominant congenital cataract identified in Chinese families.","abstract":"As the leading cause of impaired vision, congenital cataracts, particularly autosomal dominant congenital cataract (ADCC), have been considered as a hereditary disease. The present study aimed to identify genetic defects in Chinese pedigrees with ADCC. A total of 6 Chinese families with ADCC were included, comprising 103 members and 27 patients assessed in total. Genomic DNA samples were extracted from the peripheral blood of probands; mutations were determined using a specific eye disease enrichment panel with next-generation sequencing. Following pathogenicity prediction, sites with notable pathogenicity were screened for further validation. Sanger sequencing was performed in the remaining individuals of the families and 100 normal controls. The pathogenic effects of the mutations, including amino acid substitutions, as well as structural and functional alterations of proteins linked to ADCC, were investigated via bioinformatics analysis. A total of seven mutations in six candidate genes associated with ADCC were identified in the 6 families: Myosin heavy chain 9 (MYH9) c.4150G>C, β-crystallin A4 (CRYBA4) c.169T>C, RPGR-interacting protein 1 (RPGRRIP1) c.2669G>A, wolframin (WFS1) c.1235T>C, CRYBA4 c.26C>T, Ephrin receptor subfamily 2 (EPHA2) c.2663+1G>A and paired box 6 (PAX6) c.11-2A>G. The seven mutations were only detected in affected individuals. Among them, there were three novel mutations (MYH9: c.4150G>C; CRYBA4: c.169T>C; RPGRRIP1: c.2669G>A) and four previously reported ones. Mutations in RPGRIP1 (c.2669G>A) and CRYBA4 (c.26C>T) were predicted to be benign according to bioinformatics analysis. Conversely, other mutations in EPHA2, PAX6, MYH9, CRYBA4 (c.169T>C) and WFS1 were determined to be pathogenic. The present study reported two novel heterozygous mutations (MYH9 c.4150G>C and CRYBA4 c.169T>C) identified by analyzing 6 Chinese families with ADCC, supporting their important roles in the development of the disease.","variants":[{"Name":"NM_001886.3(CRYBA4):c.26C>T (p.Ala9Val)","Chromosome":"22","Start":"26622622","Stop":"26622622","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1014506,"rule_based_match":true,"evidence_text":"CRYBA4 c.26C>T","llm_judgment":"PRESENT","evidence":"CRYBA4 c.26C>T","abstract_start":1212,"abstract_end":1226},{"Name":"NM_020366.4(RPGRIP1):c.2669G>A (p.Arg890Gln)","Chromosome":"14","Start":"21326132","Stop":"21326132","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":926981,"rule_based_match":true,"evidence_text":"RPGRRIP1) c.2669G>A","llm_judgment":"PRESENT","evidence":"RPGRRIP1) c.2669G>A","abstract_start":1163,"abstract_end":1182}]}
{"pmid":"24411048","title":"Detection of a de novo Y278C mutation in FGFR3 in a pregnancy with severe fetal hypochondroplasia: prenatal diagnosis and literature review.","abstract":"OBJECTIVE: We describe a prenatal molecular diagnosis of hypochondroplasia (HCH) in a pregnancy not at risk of HCH and review the literature on prenatal diagnosis of HCH.\nCASE REPORT: A 28-year-old primigravid woman was referred for genetic counseling at 30 weeks of gestation because of short-limbed dwarfism in the fetus. The woman had a body height of 152 cm. Her husband had a body height of 180 cm. Level II ultrasound showed a normal amount of amniotic fluid and a singleton fetus with fetal biometry equivalent to 30 weeks except for short limbs. Fetal biometry measurements were as follows: biparietal diameter = 7.38 cm (30 weeks); head circumference = 28.14 cm (30 weeks); abdominal circumference (AC) = 24.64 cm (30 weeks); femur length (FL) = 3.97 cm (<5th centile); FL/AC ratio = 0.161 (normal > 0.18); humerus = 3.64 cm (<5th centile); radius = 3.49 cm (30 weeks); ulna = 3.76 cm (<5(th) centile); tibia = 3.67 cm (<5th centile); and fibula = 3.72 cm (<5th centile). The digits and craniofacial appearance were normal. A tentative diagnosis of achondroplasia (ACH) was made. DNA testing for the FGFR3 gene and whole-genome array comparative genomic hybridization (aCGH) analysis were performed using cord blood DNA obtained by cordocentesis. FGFR3 mutation analysis revealed a de novo heterozygous c.833A > G, TAC > TGC transversion in exon 7 leading to a p.Tyr278Cys (Y278C) mutation in the FGFR3 protein. aCGH analysis revealed no genomic imbalance in cord blood. After delivery, the fetus had short limbs, a narrow thorax, brachydactyly, and relative macrocephaly. Cytogenetic analysis of cultured placental cells revealed a karyotype of 46,XX.\nCONCLUSION: Prenatal diagnosis of abnormal ultrasound findings suspicious of ACH should include a differential diagnosis of HCH by molecular analysis of FGFR3.","variants":[{"Name":"NM_000142.5(FGFR3):c.833A>G (p.Tyr278Cys)","Chromosome":"4","Start":"1801928","Stop":"1801928","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":31396,"rule_based_match":true,"evidence_text":"c.833A > G","llm_judgment":"PRESENT","evidence":"c.833A > G","abstract_start":1312,"abstract_end":1322}]}
{"pmid":"30425910","title":"Clinical Variability in Two Macedonian Families with Arterial Tortuosity Syndrome.","abstract":"Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder caused by mutations in the solute carrier family 2 member 10 (<i>SLC2A10</i>) gene encoding a glucose/ascorbic acid transporter. The clinical features of ATS are mild-to-severe tortuosity of the large and medium arteries throughout the body, accompanied by dysmorphisms and joint laxity. Vascular changes in different parts of the body lead to stenosis and/or aneurysms requiring difficult surgical procedures. Here we present two new patients with ATS from two unrelated families. Patient 1 presented at 10 years of age with headache and typical physical appearance, delicate skeleton, large visible pulsation of the carotid arteries in the neck, and joint laxity. On computed tomography (CT) angiography she had severe tortuosity of the aortal branches and cerebral arteries, but no significant tortuosity of the pulmonary arteries. Two cousins of the girl carried the same homozygous c.254T>C, p.(Leu85Pro) mutation in <i>SLC2A10</i>, however, they additionally had a severe involvement of the pulmonary vessels. Patient 2 was a 9-year-old girl diagnosed with severe tortuosity and stenosis of the pulmonary arteries and progressive myocardiopathy. Her physical appearance was very similar to Patient 1, except that she also had growth retardation. After long-term follow-up by cardiologists, she underwent cardiac surgery abroad, with an unfavorable outcome. Homozygosity for the c.685C>T, p.(Arg229*) mutation in the <i>SLC2A10</i> gene was detected. Consanguinity was disclosed within both families. Our findings confirm the intrafamilial phenotype variability of ATS. A novel finding is the severe tortuosity of cerebral arteries causing migraine that has not been described before in a child with ATS.","variants":[{"Name":"NM_030777.4(SLC2A10):c.254T>C (p.Leu85Pro)","Chromosome":"20","Start":"46725290","Stop":"46725290","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1001166,"rule_based_match":true,"evidence_text":"c.254T>C, p.(Leu85Pro)","llm_judgment":"PRESENT","evidence":"c.254T>C, p.(Leu85Pro)","abstract_start":961,"abstract_end":983},{"Name":"NM_030777.4(SLC2A10):c.685C>T (p.Arg229Ter)","Chromosome":"20","Start":"46725721","Stop":"46725721","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":170942,"rule_based_match":true,"evidence_text":"c.685C>T, p.(Arg229*)","llm_judgment":"PRESENT","evidence":"c.685C>T, p.(Arg229*)","abstract_start":1458,"abstract_end":1479}]}
{"pmid":"29312905","title":"Atypical Late-Onset Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome with Intractable Diarrhea: A Case Report.","abstract":"Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare life threatening congenital autoimmune disorder caused by mutations in the forkhead box protein 3 (FOXP3) gene. The main typical clinical manifestations of IPEX are enteropathy, type 1 diabetes mellitus, and skin diseases, which usually appear in the first months of life and cause death without treatment. Here, we report a 6-year-old boy with late-onset IPEX syndrome due to a c.1190G>A (p. R397Q) mutation in exon 11 of the FOXP3 gene. The boy had intractable diarrhea, abdominal pain, recurrent infections, and failure to thrive. However, diabetes and skin diseases were not observed in the patient. The patient was received metronidazole, teicoplanin, fluconazole, mycamine, ceftriaxone, azithromycin, and fecal microbiota transplantation for treating infections, methylprednisolone and infliximab for suspicion of Crohn's disease after admission. Finally, the boy was diagnosed as IPEX syndrome by genetic test and received hematopoietic stem cell transplantation (HSCT). Our findings suggests that IPEX should be considered in cases of late-onset, mild forms, and less typical clinical manifestations to avoid diagnostic delay.","variants":[{"Name":"NM_014009.4(FOXP3):c.1190G>A (p.Arg397Gln)","Chromosome":"X","Start":"49251440","Stop":"49251440","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":378413,"rule_based_match":true,"evidence_text":"c.1190G>A (p. R397Q)","llm_judgment":"PRESENT","evidence":"c.1190G>A (p. R397Q)","abstract_start":469,"abstract_end":489}]}
{"pmid":"24743384","title":"The MLH1 c.1852_1853delinsGC (p.K618A) variant in colorectal cancer: genetic association study in 18,723 individuals.","abstract":"Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as \"variants of uncertain significance\", being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.","variants":[{"Name":"NM_000249.4(MLH1):c.1852_1853delinsGC (p.Lys618Ala)","Chromosome":"3","Start":"37047639","Stop":"37047640","ReferenceAlleleVCF":"AA","AlternateAlleleVCF":"GC","allel_id":32128,"rule_based_match":true,"evidence_text":"c.1852_1853delinsGC (p.K618A)","llm_judgment":"PRESENT","evidence":"c.1852_1853delinsGC (p.K618A)","abstract_start":648,"abstract_end":677}]}
{"pmid":"27455011","title":"A novel pathogenic mutation of CRYGD gene in a congenital cataract family","abstract":"OBJECTIVE: To detect the disease-causing mutation in a pedigree affected with autosomal dominant congenital cataract.\nMETHODS: Genomic DNA was extracted and purified from peripheral blood samples from members of the pedigree and 100 healthy controls. Coding regions of 18 candidate genes were screened with PCR and Sanger sequencing. Identified mutations were verified among 100 healthy individuals to exclude single nucleotide polymorphisms.\nRESULTS: A heterozygous nonsense mutation c.471G>A of the CRYGD gene, which resulted in p.Trp157Term, was identified in all three patients. The same mutation was not found in the two normal individuals from the family and 100 healthy controls. The nonsense mutation was predicted to be \"disease causing\" by Mutation t@sting program.\nCONCLUSION: The nonsense mutation c.471G>A of the CRYGD gene probably underlies the congenital cataract in the pedigree.","variants":[{"Name":"NM_006891.4(CRYGD):c.471G>A (p.Trp157Ter)","Chromosome":"2","Start":"208121727","Stop":"208121727","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1455564,"rule_based_match":true,"evidence_text":"c.471G>A","llm_judgment":"PRESENT","evidence":"c.471G>A","abstract_start":485,"abstract_end":493}]}
{"pmid":"25557138","title":"Long-term outcome of loss-of-function mutations in thyrotropin receptor gene.","abstract":"BACKGROUND: Loss-of-function mutations in the thyrotropin receptor (TSHR) gene lead to resistance to TSH (RTSH) presenting with either congenital hypothyroidism (CH) or subclinical hypothyroidism (SCH). Despite several reports of patients with TSHR mutations, data on the long-term outcome of this condition are limited, and no consensus exists on the need for hormone replacement therapy. The aim of the present study was to assess the long-term outcome in children and adolescents with RTSH due to TSHR mutations.\nMETHODS: The TSHR gene was sequenced in 94 subjects (aged 3 days-21 years) with either nonautoimmune SCH or CH with RTSH.\nRESULTS: Twenty-seven subjects (29%) carried mutations in TSHR. Fifteen infants were identified by neonatal screening, and the other 79 patients were detected in the process of testing for various other conditions or because of family occurrence of thyroid test abnormalities. Six different mutations were identified: c.484C>G (p.P162A), c.202C>T (p.P68S), c.790C>T (p.P264S), c.269A>C (p.Q90P), c.1957C>G (p.L653V), and c.1347C>T (p.R450C). Twelve subjects were homozygous, three were compound heterozygous, and 12 were heterozygous. Mean serum TSH levels at diagnosis and at last visit were significantly higher in patients with TSHR mutations than in those without mutations (29.04 vs. 14.15, p=0.002; 31.73 vs. 6.19, p<0.0001, respectively). Homozygous patients had a more severe phenotype (TSH 53.6 vs. 9.24, p<0.0001). Mean serum free thyroxine (fT4) levels at the last visit were significantly lower than at the first visit in the homozygous individuals (p=0.05) for a follow-up period of as long as 11 years. Heterozygous subjects had only mild hyperthyrotropinemia with stable TSH levels. However, homozygous subjects showed a trend toward increased TSH and decreased fT4 with time.\nCONCLUSION: SCH in heterozygotes with TSHR mutations is a stable compensated condition with an appropriately adjusted set point for pituitary-thyroid feedback that does not require replacement therapy. However, homozygous subjects, with incompletely compensated SCH, show reduced fT4 levels over time and may require levothyroxine treatment. Replacement therapy should be considered on an individual basis, and long-term follow up is recommended.","variants":[{"Name":"NM_000369.5(TSHR):c.1957C>G (p.Leu653Val)","Chromosome":"14","Start":"81144015","Stop":"81144015","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2894832,"rule_based_match":true,"evidence_text":"c.1957C>G (p.L653V)","llm_judgment":"PRESENT","evidence":"c.1957C>G (p.L653V)","abstract_start":1034,"abstract_end":1053},{"Name":"NM_000369.5(TSHR):c.269A>C (p.Gln90Pro)","Chromosome":"14","Start":"81068280","Stop":"81068280","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3495105,"rule_based_match":true,"evidence_text":"c.269A>C (p.Q90P)","llm_judgment":"PRESENT","evidence":"c.269A>C (p.Q90P)","abstract_start":1015,"abstract_end":1032},{"Name":"NM_000369.5(TSHR):c.484C>G (p.Pro162Ala)","Chromosome":"14","Start":"81092547","Stop":"81092547","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":21474,"rule_based_match":true,"evidence_text":"c.484C>G (p.P162A)","llm_judgment":"PRESENT","evidence":"c.484C>G (p.P162A)","abstract_start":956,"abstract_end":974},{"Name":"NM_000369.5(TSHR):c.202C>T (p.Pro68Ser)","Chromosome":"14","Start":"81062179","Stop":"81062179","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":429594,"rule_based_match":true,"evidence_text":"c.202C>T (p.P68S)","llm_judgment":"PRESENT","evidence":"c.202C>T (p.P68S)","abstract_start":976,"abstract_end":993}]}
{"pmid":"22113256","title":"BRCA1 c.4987-3C>G is a pathogenic mutation.","abstract":"","variants":[{"Name":"NM_007294.4(BRCA1):c.4987-3C>G","Chromosome":"17","Start":"43067698","Stop":"43067698","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":70013,"rule_based_match":true,"evidence_text":"BRCA1 c.4987-3C>G","llm_judgment":"PRESENT","evidence":"BRCA1 c.4987-3C>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"24997713","title":"Seven Novel Mutations in Bulgarian Patients with Acute Hepatic Porphyrias (AHP).","abstract":"Acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP) are caused by mutations in the hydroxymethylbilane synthase (HMBS), protoporphyrinogen oxidase (PPOX), and coproporphyrinogen oxidase (CPOX) genes, respectively. This study aimed to identify mutations in seven Bulgarian families with AIP, six with VP, and one with HCP. A total of 33 subjects, both symptomatic (n = 21) and asymptomatic (n = 12), were included in this study. The identification of mutations was performed by direct sequencing of all the coding exons of the corresponding enzymes in the probands. The available relatives were screened for the possible mutations. A total of six different mutations in HMBS were detected in all seven families with AIP, three of which were previously described: c.76C>T [p.R26C] in exon 3, c.287C>T [p.S96F] in exon 7, and c.445C>T [p.R149X] in exon 9. The following three novel HMBS mutations were found: c.345-2A>C in intron 7-8, c.279-280insAT in exon 7, and c.887delC in exon 15. A total of three different novel mutations were identified in the PPOX gene in the VP families: c.441-442delCA in exon 5, c.917T>C [p.L306P] in exon 9, and c.1252T>C [p.C418R] in exon 12. A novel nonsense mutation, c.364G>T [p.E122X], in exon 1 of the CPOX gene was identified in the HCP family. This study, which identified mutations in Bulgarian families with AHP for the first time, established seven novel mutation sites. Seven latent carriers were also diagnosed and, therefore, were able to receive crucial counseling to prevent attacks.","variants":[{"Name":"NM_000190.4(HMBS):c.76C>T (p.Arg26Cys)","Chromosome":"11","Start":"119088297","Stop":"119088297","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":639774,"rule_based_match":true,"evidence_text":"c.76C>T [p.R26C]","llm_judgment":"PRESENT","evidence":"c.76C>T [p.R26C]","abstract_start":808,"abstract_end":824}]}
{"pmid":"33400601","title":"Identification of a pathogenic","abstract":"Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. We herein report a large Chinese family presented with phenotypic variability involving thrombocytopenia and/or giant platelets. Whole genome sequencing (WGS) of the proband and one of his affected brothers identified a potentially pathogenic c.952 C > T heterozygous variant in the <i>TUBB1</i> gene. This p.R318W β1-tubulin variant was also identified in three additional siblings and five members of the next generation. These findings were consistent with an autosomal dominant inheritance with incomplete penetrance. Moreover, impaired platelet agglutination in response to ristocetin was detected in the patient's brother. Half of the family members harboring the p.R318W mutation displayed significantly decreased external release of <i>p</i>-selectin by stimulated platelets. The p.R318W β1-tubulin mutation was identified for the first time in a Chinese family with congenital macrothrombocytopenia using WGS as an unbiased sequencing approach. Affected individuals within the family demonstrated impaired platelet aggregation and/or release functions.","variants":[{"Name":"NM_030773.4(TUBB1):c.952C>T (p.Arg318Trp)","Chromosome":"20","Start":"59024379","Stop":"59024379","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15464,"rule_based_match":true,"evidence_text":"c.952 C > T","llm_judgment":"PRESENT","evidence":"c.952 C > T","abstract_start":332,"abstract_end":343}]}
{"pmid":"23443024","title":"Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family.","abstract":"This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.","variants":[{"Name":"NM_000350.3(ABCA4):c.5461-10T>C","Chromosome":"1","Start":"94011395","Stop":"94011395","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":98777,"rule_based_match":true,"evidence_text":"c.5461-10T>C","llm_judgment":"PRESENT","evidence":"c.5461-10T>C","abstract_start":1118,"abstract_end":1130},{"Name":"NM_000350.3(ABCA4):c.4773+3A>G","Chromosome":"1","Start":"94021843","Stop":"94021843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":237659,"rule_based_match":true,"evidence_text":"c.4773+3A>G","llm_judgment":"PRESENT","evidence":"c.4773+3A>G","abstract_start":1221,"abstract_end":1232}]}
{"pmid":"26996949","title":"GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy.","abstract":"The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEβ). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEα and TFIIEβ) as well as decreased phosphorylation of TFIIEα in cells from both children. Interestingly, decreased phosphorylation of TFIIEα was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP.","variants":[{"Name":"NM_002095.6(GTF2E2):c.448G>C (p.Ala150Pro)","Chromosome":"8","Start":"30612400","Stop":"30612400","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":227654,"rule_based_match":true,"evidence_text":"c.448G>C [p.Ala150Pro]","llm_judgment":"PRESENT","evidence":"c.448G>C [p.Ala150Pro]","abstract_start":700,"abstract_end":722},{"Name":"NM_002095.6(GTF2E2):c.559G>T (p.Asp187Tyr)","Chromosome":"8","Start":"30607141","Stop":"30607141","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":227655,"rule_based_match":true,"evidence_text":"c.559G>T (p.Asp187Tyr)","llm_judgment":"PRESENT","evidence":"p.Asp187Tyr","abstract_start":737,"abstract_end":748}]}
{"pmid":"33851480","title":"A next generation sequencing-based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21.","abstract":"BACKGROUND AND PURPOSE: Spinocerebellar ataxia 21 (SCA21) is a rare autosomal dominant neurodegenerative disorder caused by TMEM240 gene mutations. To date, SCA21 has been reported only in a limited number of families worldwide. Here, we describe clinical and molecular findings in five additional SCA21 patients from four unrelated families, diagnosed through a multicentre next generation sequencing-based molecular screening project on a large cohort of patients with degenerative and congenital ataxias.\nMETHODS: A cohort of 393 patients with ataxia of unknown aetiology was selected. Following the identification of heterozygous pathogenic TMEM240 variants using a target resequencing panel, we carried out an in-depth phenotyping of the novel SCA21 patients.\nRESULTS: Five patients from four unrelated families, three of Italian and one of Libyan origin, were identified. These patients were carriers of previously reported TMEM240 mutations. Clinically, our SCA21 cohort includes both adult onset, slowly progressive cerebellar ataxias associated with cognitive impairment resembling cerebellar cognitive affective syndrome and early onset forms associated with cognitive delay, neuropsychiatric features, or evidence of hypomyelination on brain magnetic resonance imaging. None of our patients exhibited signs of extrapyramidal involvement. The so-called \"recurrent\" c.509C>T (p.Pro170Leu) mutation was detected in two of four families, corroborating its role as a hot spot.\nCONCLUSIONS: Our results confirm that SCA21 is present also in Italy, suggesting that it might not be as rare as previously thought. The phenotype of these novel SCA21 patients indicates that slowly progressive cerebellar ataxia, and cognitive and psychiatric symptoms are the most typical clinical features associated with mutations in the TMEM240 gene.","variants":[{"Name":"NM_001114748.2(TMEM240):c.509C>T (p.Pro170Leu)","Chromosome":"1","Start":"1535372","Stop":"1535372","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171039,"rule_based_match":true,"evidence_text":"c.509C>T (p.Pro170Leu)","llm_judgment":"PRESENT","evidence":"c.509C>T (p.Pro170Leu)","abstract_start":1375,"abstract_end":1397}]}
{"pmid":"31379863","title":"Reduced Function and Diversity of T Cell Repertoire and Distinct Clinical Course in Patients With","abstract":"The alpha subunit of IL-7 receptor (IL7R7α) is critical for the differentiation of T cells, specifically for the development and maintenance of γδT cells. Mutations in <i>IL7RA</i> are associated with Severe Combined Immunodeficiency (SCID). Infants with <i>IL7RA</i> deficiency can be identified through newborn screening program. We aimed at defining the immunological and genetic parameters that are directly affected by the <i>IL7RA</i> mutation on the immune system of five unrelated patients which were identified by our newborn screening program for SCID. The patients were found to have a novel identical homozygote mutation in <i>IL7RA</i> (n.c.120 C>G; p.F40L). Both surface expression of IL7Rα and functionality of IL-7 signaling were impaired in patients compared to controls. Structural modeling demonstrated instability of the protein structure due to the mutation. Lastly the <i>TRG</i> immune repertoire of the patients showed reduced diversity, increased clonality and differential CDR3 characteristics. Interestingly, the patients displayed significant different clinical outcome with two displaying severe clinical picture of immunodeficiency and three had spontaneous recovery. Our data supports that the presented <i>IL7RA</i> mutation affects the IL-7 signaling and shaping of the <i>TRG</i> repertoire, reinforcing the role of <i>IL7RA</i> in the immune system, while non-genetic factors may exist that attribute to the ultimate clinical presentation and disease progression.","variants":[{"Name":"NM_002185.5(IL7R):c.120C>G (p.Phe40Leu)","Chromosome":"5","Start":"35860889","Stop":"35860889","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1685903,"rule_based_match":true,"evidence_text":"n.c.120 C>G; p.F40L","llm_judgment":"PRESENT","evidence":"n.c.120 C>G; p.F40L","abstract_start":650,"abstract_end":669}]}
{"pmid":"26574802","title":"A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa.","abstract":"PURPOSE: To identify mutations in FAM161A underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch and Belgian populations and to investigate whether common FAM161A-associated phenotypic features could be identified.\nMETHODS: Homozygosity mapping, amplification-refractory mutation system (ARMS) analysis, and Sanger sequencing were performed to identify mutations in FAM161A. Microsatellite and SNP markers were genotyped for haplotype analysis. Patients with biallelic mutations underwent detailed ophthalmologic examinations, including measuring best-corrected visual acuity, extensive fundus photography with reflectance and autofluorescence imaging, and optical coherence tomography.\nRESULTS: Homozygosity mapping in 230 Dutch individuals with suspected arRP yielded five individuals with a homozygous region harboring FAM161A. Sanger sequencing revealed a homozygous nonsense mutation (c.1309A>T; p.[Arg437*]) in one individual. Subsequent ARMS analysis and Sanger sequencing in Dutch and Belgian arRP patients resulted in the identification of seven additional individuals carrying the p.(Arg437*) mutation, either homozygously or compound heterozygously with another mutation. Haplotype analysis identified a shared haplotype block of 409 kb surrounding the p.(Arg437*) mutation in all patients, suggesting a founder effect. Although the age of onset was variable among patients, all eight developed pronounced outer retinal loss with severe visual field defects and a bull's eye-like maculopathy, followed by loss of central vision within 2 decades after the initial diagnosis in five subjects.\nCONCLUSIONS: A founder mutation in FAM161A p.(Arg437*) underlies approximately 2% of arRP cases in the Dutch and Belgian populations. The age of onset of the retinal dystrophy appears variable, but progression can be steep, with almost complete loss of central vision later in life.","variants":[{"Name":"NM_001201543.2(FAM161A):c.1309A>T (p.Arg437Ter)","Chromosome":"2","Start":"61839695","Stop":"61839695","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":15075,"rule_based_match":true,"evidence_text":"c.1309A>T; p.[Arg437*]","llm_judgment":"PRESENT","evidence":"c.1309A>T; p.[Arg437*]","abstract_start":907,"abstract_end":929}]}
{"pmid":"29688594","title":"Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140.","abstract":"Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases. Using whole-genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27-30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole-exome sequencing. Pathogenicity of the mutation was assessed on the patients' skin fibroblasts. Several hundreds of patients with a ciliopathy phenotype were screened and biallelic mutations were identified in 11 families representing 12 pathogenic variants of which seven are novel. Among those unrelated families especially with a Mainzer-Saldino syndrome, eight carried the same tandem duplication (two at the homozygous state and six at the heterozygous state). In conclusion, we demonstrated the implication of structural variations in IFT140-related diseases expanding its mutation spectrum. We also provide evidences for a unique genomic event mediated by an Alu-Alu recombination occurring on a shared haplotype. We confirm that whole-genome sequencing can be instrumental in the ability to detect structural variants for genomic disorders.","variants":[{"Name":"NM_014714.4(IFT140):c.3454-488_4182+2588dup","Chromosome":"16","Start":"1515627","Stop":"1515628","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CCTCAAGAAATCCTCCCACCTTGGCCTCCCAAAGTGCTGAGATTACAGGCATGAGCCACTGTGCCTGGCCTCAGAATTCTCTATCTGATGAGAACAACCTTGAAGAATACAGGCAAAATAAATACATTTCAGATTAACGAAAAGTAAGAAAATTCATCATCAGGAGATCTGAACTAGAAGAAATGTTAAAGGGAGCTCAGGCTGAAGAGGAGTGATACCACATGCAAATCGGAATCATAGGGAAGAAGTAAGAACACCAGAAATGACGCTTTGGGAGGCCGAGGCAGGCAGATCACCTGAGGTTGGGAGTTTGAGACCAGCCTGACCAACATGGAGAAACCCCATCTCCCCTAAAAATACAAAATTAGCCAGGCGTGGTGGCGCATGCCTGTAATCCCAGCTACTCCGGAGGCTGAGGCAGGAGAATCACTTGAACCTGGAGGGTAGAGGTTGTGGTGAGCTGAGGTTTGTTGCCCACTCCAGCCTGGGCTACAAAGAGCAAAACTCTGTCTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACACCAGAAATGGATGGTAAATATGTAGGTAAATGTAAAAGACTATTTCTTTCCTTTTAATTTCTTCAAAATACATATGACTGTTGAAAGCAACAATTATAACACTATACTGTGTTTATAATACATGTACATGTTACACATACGACAAATACAGGTGGGGACACGGGTGGGAAATGGACCTACCTGCTAACTCTAGTGTGGTAAGTATGTTTATGGTAATCTCCAGGGCAAACACTAGAAATACAATGCAAAGAGGAGTAGAGATAAAAAGCTGATAGCTAAAATGAAATTATAAAAAATAGTCCACTAAGGCCAGGTGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAACACGGTGAAACCCTGTCTCTACTAAAAATACAAAAAAATTATCTGGGCGTGGTGGCGGGCGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGTAGGAGAATGGCGTGAACCCGGGAGGCAGAGCTTGCAGTGAGCCGAGATTGCACCACCGCACTCCAGCCTGGGCGACAGAGCGACACTCTGTCTCAAAAAAAAAAAAAAAAAAAAATCAACTAAAAAGAAGGCAGGAAAAAAGGTTTAAAGTAACAATAATAAAAACTGGTAGAAAAAGTTGACTGGTAGAAAACTGACATGAAAAAGATGGATGGGATTACCATCAGAGTGAGACACTGCAGAAGGAAAGCTGGTAAACTTGAAGCAACAGAAATGGCAAATCCCTAAAATGAAAAACAGAAAAAGTCCTTGGGGGAGAAAAGAAGAGCATCAGTTGAGCTAGGGGATGGTACTGTATATACAAGTCATTGGAATTTCAGAAGCAGAGGAAAAAAGGAATAGAAGGGAACTTCGGCCAGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGTGGAGGCGGGTGGATCACTTGAGGTCACGAGTTCAAGACCAGCCTGGCCAAATGGTGAAACCCCATCTCTACAGGCATGCTGATGCACACCTGTAGTCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATGGCGTGAACCCAGGAGGCGGAGCTTGCAGTGAGCCGAGATCGCGCCACTGCGCTCCAGCCTGGGCAACAGAGTGAGACTCCGTCTCCAAAAAAAAAAAAAAAAAGTACAATAATAAGAAAACCCAATAAAATGATGAGAAGAGACTTGAAGCCTTCACAGAAGGTGTGTAAATGGATAATAAGCACATGAGAAGGAGCTGCACATCACTACTCATCCAGAAAATGTGAATTTAAACCTCAGCAAGGTACTGTTCACCCCCTAGGATGGCTACAGTTCGAAAGAATGATCAAATGTTGGTGGGGATGAGGAAAACGCTAGAACACTGCGGCTGAATAAGTGATTAGCTGGTCACTTTAAAGTGACTACACGCTGTCTCTAAAATTAAAAAATAAGCGACTAAAAAATGGAACACCATTTTCTTTTTTTGTGAAAATCCCTGAAAAAGAAATCGTGGTTATTCAGACTCGGGTACATGCAGACATTTCTTCACAAATAAAGTAAGTCTGTCGCTTTCCTGCGACACTGCTAGTAACAGCCAGTAACAGCGTGAGACTGTTACTTTTTGCTACCGACAGATTTTTTTTTTCTTTTGAGACAGGGTCTCGCTCTGTCACCCAGGCTGGAGTGCAGTGGCGCCATCAGATCTCACTGCAGCCTCAACCTCCTGGGCTCAAGGGATCCTCCCACCTCAGCCTCCCAAGCAGCTGGGACCCCAGGTGTGAGCCACCATGCCTGGCTAATTTTTCCCCTTTTTGTAGAGATGGGGTTTCACCATGTCGCCCAGGCTGCTCTTGAACTCCTGGGCTCAAGTCATTCTCCTGCCTCAGCCTCCCAAAGTGCTGGGATTACAGGAGTGAGCCGCCACACACAGCCTCAGTTTGAGCCGTTAAGCCTTCGTTTCAGGAGCCTTGTGTGGCGGGATGCTGCTAGTGAGCAGCACTCAGGCCTCACCGTCTGGTATTCCTCCTTCCGCACGTAGTGCTCCACCAGGAAGCCATAGACGTCCCCGATGCGGATGGTGCTGTCCAGGTCTGGTTCCTCCAGGAGCAGCTCACACTGCTTGATGGACTCCTTGGGGTCCTCTGTGTACGTCCTGCCGAGAGCAGAGATGAGGCCTGGGCCCCGAAGCCCTGAACACCTACTGCTATCAGAGGTCAGAGGAGACTCTTGGCCTGTAAGAGGAGCTCTCCGGAATGGCAGGAGGAAACTTTCTATGAAGTTAAATTCATTAATTCCTTAATTTGTTCATTCATAAATTAACTCATCCATGTAACATTCTTACTGATCACTTGAATGCTGGGTCCTATGCTTGGACTGAAGACCAAAGACTTCCGACCCCTAGTTCCTGCTCTATGGAACAGTCCAGAGGGGGCTAGAAACCTCTGCACAAAGCGTGACCCAGAGGGGATGTGGTGCATGTGGACAGGGTACACGGAGAGGCGCACGGCACCCCTTGCCCAAGGCCGCTGGGAAGAACCCTCCAAGCAGAGAGGCTGCCCGCACACAGGCTGCGTGTGTGACCTGGCGTGAGGGTCTGTGGCAGAGCAGGGTGTGTGGCCTGTGAGCTGGGGTGACACCAGGGAGGTGAGCCTGCTGGAACACAACATGGTCCAGGGCAGGTGACTGGAGCCGTGTGGAGCTCAGGCTCCCATGTCAGGAGGGTCCAGGGCCCATCTGGCCACCCACTGACTCGGCCATTCCAGACAGGCGCCTGGCCTGCCCTCTGACCCCTGGCCCATAGAAGGTTGCCCACCCTGGCCCTCACACGTCGTCTCCCCTCCACCCACGTCCTGTGCTATCCCTGATGACCAGCTGCTATCGATTCTCCTCCGCTCCTGCCCTGTGGCCTCAGCTCAGCAGACATCTGTGAGACGCTGATACCCCAGAATCGACACGTGCAGGTGGACCGTGCCCTTCCAAGGGGCACCGCTTTGTACGACCTTGTTCAAAGGACTTCTGGAACTCTTGTTTTGGAAAAGGTTCTCCGATAAGGAAAACAGCCCTGCCAGCTGAGACAGAAGCTGGGCCCTGAAGCGCACAGGCGAGTGCCCACCGTGGTGGCCACACAGCAGCTCTCTGAAAAGCTGAGTCACCTGCCCATAATAAAGATGGGGAGGTGTTCAAATAAACTTAGCATCTTGGCCTCTCCTGAAAACCGAGACCATCGGCTGGCTGCCTGGGTCTCCTCTCCACAAGCTTGGAGCTGGTGGCAGTTGACCTGTGGAGAGGCATGAGCCCTCTGGTCACCATGGTCCCCCAACCCCAGGTCACACAGCGGCACTCACTCAGGACTCCCCTGCCCGGCCCCTGCACACCCTCAGCAGGTCTGTGGCTCCCCAGACACACCCTCTCCTGCTCCACATCTGCCTCCTCCTCCCACTCCCCCACCAGGTTTCTCTCTCAGCGTCTCTGGTGTTTCCAGAACACCTTCCCAAGGCTGTGCCCGGGCTCTGAGGGCTCCCAGGAGGAGGTGGGGTGTGTCTTCAGCAGTAGTGCTGTCCCAAGTGAGCTCCCATCTGCTGTCCTGCCCTTTTGCTGGCTGGGGTTTCTCGTGGTCAGCCCCGGCCCTGTAGTCACATCTGCCCTGGCCTGTCCCCGCTGGCCCCGGGGGCACACCTGCGGGCCTGGATGAACCTCTTCACCAGTGCCATCCTGCTCTGCAGCTGCGCCAGCCTGGTCTCCTGGTCCAGGGGGCTCTTGGCCTTGGCCTTGGCCAGGCACTTGTAGGCCTCGGTCAGCGCCCCGTGGGCTTTGTCGTAGTTCTGGTATTCATCAATCTCCACCTGTACAGATGAAACCCGTCAAGACCTGCCGGGCTCCACAGCCCTCCCCGGGGCCCCGCTGGCATGCCAGGGAGGGCCTGCACCTGGGCACAAGCGTCATAAAAGCCAGCCAGGAGGTCCAGGGCCCGCCCCTTGGTGTAGAAGCCGATGATGTTCTTCATGATCTCCGGCTCCTTCCGCCAGTCCAGGGACTGCAGGTAGTTAGCAGCCATGATGTAGATTTCCTTCTGCCTGGACACGCTCGCGAAGAACGTGATTTTCTCCGTGTCTCCGGATTTGAGCAGCGCCCTCATGGCCTAGGCAGAGAGACAGCGGGGCTCAGGCAAGCAGGGGCTGGGCCGGGACAAGCACAAGGGACCCCGAGCAGGAGCTCTCACAAGAAGAGTGGCTCAGGGCTGCCCGGTAGAGAGAGATCTTAGTGGTTGTGCTCTTCCTGGCCAGAAAGGCTCAGCCCTAGCTTGGGGTCATCACGAAGGCAAATGGAGATGCGTGCAGGGGGCCCGCAGCCTAACTGCCTGTGAGGTAGCCGCGGGCTGGGGCCGGGAGAGGCTCACCTTCAGCTTGTTGCCGGCCTGCGTGTACTTCTTGGTGGCCAGGTGGTAGCTGCCCTGGCGCATGCAGCAGTCTGCTATCTGCTCCAGCAGCTCCCGCCGCGACTCCTCAGGCAGGTCCGAGGAGTCCTTGGCCACGGTCATCTTTTCCGCCATCTCCTCGGTGATGCTCATGTTCTGCCCCAGGCACAGCTGCAGGGCTTCCTGATACTGCAAAGGTGCAGAAATGGGACGGGGCTGCCGAGGGGGCCGGGAACTGAAGTGCGCCCCTCATCTGCCACCGCTTCAGAGGAAACCAGGCCCCTCGGCTCAGCGGCGGCTTCTGTCTAGCTGGGGTGGGTATGGAGGGGACAAGGATGTCTCCCCTGCCTCACCAACCTACAATCATTCACGTTACTTTCTCACGCTGTTAACATTCCAGAATGGAACGAAGGAAACAATAGTCTCAAGTGATATATGCTCAAGAGAATATTACGTTTGGGAGAAAAGGAAATTGGTAATTTTCTTCTATAATTCTGAATTTTTAAAGTTAAATTTTTGAGACAGGGTCTCACTCTGTCCCCCAGGCTGGAGTGCAGTGGTGCAGTCACGGCAGCCTCCACCTCCCCAGGGTCAGGTGATCTTCCTACCTCAGTTTTTGTATTTTCAGTAGAGACGGGGTTTTGCAATGTTGCCCAGGCTGGTCTTGAACTCCTGGG","allel_id":513805,"rule_based_match":true,"evidence_text":"c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup)","llm_judgment":"PRESENT","evidence":"c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup)","abstract_start":407,"abstract_end":453}]}
{"pmid":"37718511","title":"BRCA1 frameshift variants leading to extended incorrect protein C termini.","abstract":"Carriers of BRCA1 germline pathogenic variants are at substantially higher risk of developing breast and ovarian cancer than the general population. Accurate identification of at-risk individuals is crucial for risk stratification and the implementation of targeted preventive and therapeutic interventions. Despite significant progress in variant classification efforts, a sizable portion of reported BRCA1 variants remain as variants of uncertain clinical significance (VUSs). Variants leading to premature protein termination and loss of essential functional domains are typically classified as pathogenic. However, the impact of frameshift variants that result in an extended incorrect terminus is not clear. Using validated functional assays, we conducted a systematic functional assessment of 17 previously reported BRCA1 extended incorrect terminus variants (EITs) and concluded that 16 constitute loss-of-function variants. This suggests that most EITs are likely to be pathogenic. However, one variant, c.5578dup, displayed a protein expression level, affinity to known binding partners, and activity in transcription and homologous recombination assays comparable to the wild-type BRCA1 protein. Twenty-three additional carriers of c.5578dup were identified at a US clinical diagnostic lab and assessed using a family history likelihood model providing, in combination with the functional data, a likely benign interpretation. These results, consistent with family history data in the current study and available data from ClinVar, indicate that most, but not all, BRCA1 variants leading to an extended incorrect terminus constitute loss-of-function variants and underscore the need for comprehensive assessment of individual variants.","variants":[{"Name":"NM_007294.4(BRCA1):c.5578dup (p.His1860fs)","Chromosome":"17","Start":"43045691","Stop":"43045692","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":46239,"rule_based_match":true,"evidence_text":"c.5578dup","llm_judgment":"PRESENT","evidence":"c.5578dup","abstract_start":1012,"abstract_end":1021}]}
{"pmid":"23639785","title":"Identification of novel mutations of TP53, ALK and RET gene in metastatic thymic squamous cell carcinoma and its therapeutic implication.","abstract":"Thymic tumors are epithelial tumors of the thymus for which multimodal therapies are often ineffective because of a lack of standardized regimens. Due to the low incidence, the molecular pathology and genomic abnormalities of thymic epithelial tumors are largely unknown. In this study, we report our comprehensively genomic study on a case of metastatic thymic tumor. Using next generation deep DNA sequencing technology, we sequenced 190 segments of 46 cancer genes of the cancer genome to cover 739 COSMIC mutations in 604 loci. Among these sequenced cancer genes, we identified that three low frequency (~10% of cells) mutations in the TP53 gene (c.782+1G>T), ALK gene (c.3551C>T), and RET gene (c.2651A>T). To the best of our knowledge, this is the first study to show those mutations in thymic tumor. Of note, our study further indicates comprehensive molecular analysis may facilitate development of novel diagnostic and therapeutic strategies for thymic tumors.","variants":[{"Name":"NM_000546.6(TP53):c.782+1G>T","Chromosome":"17","Start":"7674180","Stop":"7674180","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":487956,"rule_based_match":true,"evidence_text":"c.782+1G>T","llm_judgment":"PRESENT","evidence":"c.782+1G>T","abstract_start":651,"abstract_end":661}]}
{"pmid":"37455305","title":"Development of High-Resolution Melting Curve Analysis for rapid detection of SEC23B gene mutation causing Congenital Dyserythropoietic Anemia type II in Indian population.","abstract":"BACKGROUND: Congenital dyserythropoietic anemias (CDAs) are a very rare and heterogeneous group of disorders characterized by ineffective erythropoiesis. CDA II is caused by mutations in the SEC23B gene. The most common mutation reported in India is c.1385 A > G, p.Y462C. There is no simple and cost-effective confirmatory diagnostic test available for CDA, and therefore, many patients remain undiagnosed. High-resolution melting curve (HRM) analysis is a polymerase chain reaction (PCR) based technique applied to identify genetic differences and scan nucleic acid sequences. HRM can be used to rapidly screen the common mutation causing CDA II in the Indian population. Thus, we studied the use of High-Resolution Melting Curve Analysis to detect common mutation causing CDA II in the Indian population.\nMETHOD: 11 patients having SEC23B (Y462C) mutation causing CDA II are considered for this study. HRM was used to check the presence of Y462C mutation. To verify the accuracy of the HRM analysis, we compared HRM results with the results of Sanger sequencing. This helped us to confirm the diagnosis.\nRESULTS: We have described the clinical, hematological, and genetic data of eleven patients suffering from CDAII. According to HRM and Sanger sequencing, a homozygous SEC23B (Y462C) mutation was present in all patients, whereas a heterozygous Y462C mutation was present in their parents.\nCONCLUSION: Our data showed that High-Resolution Melting (HRM) analysis could be used to rapidly screen common SEC23B mutation that causes CDA II in the Indian population.","variants":[{"Name":"NM_006363.6(SEC23B):c.1385A>G (p.Tyr462Cys)","Chromosome":"20","Start":"18535723","Stop":"18535723","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1315305,"rule_based_match":true,"evidence_text":"c.1385 A > G, p.Y462C","llm_judgment":"PRESENT","evidence":"c.1385 A > G, p.Y462C","abstract_start":250,"abstract_end":271}]}
{"pmid":"25595958","title":"A novel mutation in GJB1 (c.212T>G) in a Chinese family with X-linked Charcot-Marie-Tooth disease.","abstract":"Gap junction protein beta 1 (GJB1) gene mutations lead to X-linked Charcot-Marie-Tooth (CMTX) disease. We investigated a Chinese family with CMTX and identified a novel GJB1 point mutation. Clinical and electrophysiological features of the pedigree were examined, and sequence alterations of the coding region of GJB1 that encode connexin32 were determined by direct sequencing. Sequence alignment of the mutation site was performed using Clustal W. Mutation effects were analysed using PolyPhen-2, SIFT and Mutation Taster software. The three-dimensional structures of the mutant and wild-type proteins were predicted by modeling with SWISS MODEL online software. The affected family members displayed typical Charcot-Marie-Tooth phenotypes, but phenotypic heterogeneity was observed. Nerve conduction velocities of all affected patients were slow. Sequencing of GJB1 revealed a heterozygous T>G missense mutation at nucleotide 212 in the proband, the proband's mother and the proband's daughter. The affected male sibling of the proband displayed a hemizygous missense mutation with T>G transition at the identical position on the GJB1 gene. This mutation resulted in an amino acid change from isoleucine to serine that was predicted to lead to tertiary structural alterations that would disrupt the function of the GJB1 protein. A novel point mutation in GJB1 was detected, expanding the spectrum of GJB1 mutations known to be associated with CMTX.","variants":[{"Name":"NM_000166.6(GJB1):c.212T>G (p.Ile71Ser)","Chromosome":"X","Start":"71223919","Stop":"71223919","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":625533,"rule_based_match":true,"evidence_text":"c.212T>G","llm_judgment":"PRESENT","evidence":"c.212T>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"27225850","title":"De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux.","abstract":"MEIS2 aberrations are considered to be the cause of intellectual disability, cleft palate and cardiac septal defect, as MEIS2 copy number variation is often observed with these phenotypes. To our knowledge, only one nucleotide-level change-specifically, an in-frame MEIS2 deletion-has so far been reported. Here, we report a female patient with a de novo nonsense mutation (c.611C>G, p.Ser204*) in MEIS2. She showed severe intellectual disability, moderate motor/verbal developmental delay, cleft palate, cardiac septal defect, hypermetropia, severe feeding difficulties with gastro-esophageal reflux and constipation. By reviewing this patient and previous patients with MEIS2 point mutations, we found that feeding difficulty with gastro-esophageal reflux appears to be one of the core clinical features of MEIS2 haploinsufficiency, in addition to intellectual disability, cleft palate and cardiac septal defect.","variants":[{"Name":"NM_170675.5(MEIS2):c.611C>G (p.Ser204Ter)","Chromosome":"15","Start":"37093609","Stop":"37093609","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":415884,"rule_based_match":true,"evidence_text":"c.611C>G, p.Ser204*","llm_judgment":"PRESENT","evidence":"c.611C>G, p.Ser204*","abstract_start":374,"abstract_end":393}]}
{"pmid":"24917129","title":"Identification of novel mutations in the VPS33B gene involved in arthrogryposis, renal dysfunction, and cholestasis syndrome.","abstract":"Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is an autosomal recessive disorder caused by mutations in the VPS33B and VIPAS39. Here, we report novel mutations identified in four patients with ARC syndrome. We analyzed the entire coding regions of the VPS33B and VIPAS39 genes by direct sequencing. To detect novel splice site mutations, mRNA transcripts were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and sequencing. All four patients had compound heterozygous variants in the VPS33B gene. One patient had a previously reported splice site variant with unknown significance, c.239+5G>A, and a novel nonsense mutation, c.621G>A. The other three patients had the c.403+2T>A mutation, and each of them carried one of the splice site variants, c.239+5G>A or c.499-11G>A. c.239+5G>A and c.499-11G>A created novel splice sites which resulted in abnormal transcripts. No significant VIPAS39 mutation was detected in all patients. In patients suspected with ARC syndrome, mutation analysis of the VPS33B gene should be employed as a primary diagnostic test before performing invasive testing procedures such as organ biopsies. Performing mRNA analysis can be useful in predicting the pathogenic phenotype when the mutation seems to affect a normal splicing mechanism.","variants":[{"Name":"NM_018668.5(VPS33B):c.239+5G>A","Chromosome":"15","Start":"91016958","Stop":"91016958","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":491584,"rule_based_match":true,"evidence_text":"c.239+5G>A","llm_judgment":"PRESENT","evidence":"c.239+5G>A","abstract_start":623,"abstract_end":633},{"Name":"NM_018668.5(VPS33B):c.403+2T>A","Chromosome":"15","Start":"91009799","Stop":"91009799","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":340110,"rule_based_match":true,"evidence_text":"c.403+2T>A","llm_judgment":"PRESENT","evidence":"c.403+2T>A","abstract_start":709,"abstract_end":719}]}
{"pmid":"22004070","title":"Phenotypic and mutation spectrums of Thai patients with isovaleric acidemia.","abstract":"BACKGROUND: Isovaleric acidemia (IVA) is an autosomal recessive disorder caused by deficiency of isovaleryl-CoA dehydrogenase (IVD). Clinical features include vomiting, lethargy, metabolic acidosis, and \"sweaty feet\" odor. The pathognomonic metabolite, isovalerylglycine, is detected on urine organic acid analysis. Clinical diagnosis of IVA can be confirmed on mutation analysis of the IVD gene.\nMETHODS: The cases of five unrelated Thai patients with IVA, identified on urine organic acid analysis, are described. Mutation analysis of the IVD gene was performed using polymerase chain reaction sequencing of the entire coding regions.\nRESULTS: Four out of the five IVA patients had an acute neonatal form. The hematologic abnormalities were common and thus could be presenting symptoms in the absence of metabolic acidosis. As for the neurological outcome, only one patient had normal intelligence. Mutation analysis of the IVD gene identified the mutations c.457-3_2CA>GG, c.1199A>G (p.Y371C), c.281C>G (p.A65G), c.358G>A (p.G91R), and c.827T>C (p.L247P). The poor outcome in most patients might be explained by the delayed diagnosis and initial unavailability of the metabolic formulas and medications in Thailand. The c.457-3_2CA>GG mutation was identified in all of the present patients. This suggests that it is the most common mutation in the Thai population. Therefore, it could be a founder mutation in Thai subjects. One of the present Thai IVA patients also had the p.Y371C mutation, which is common in Han Chinese subjects. In addition, two novel mutations, p.A65G and p.L247P, were identified.\nCONCLUSION: The present study provides additional knowledge on the genotype-phenotype of IVA, suggesting that IVD mutations in Asian populations are distinct from these in Western populations.","variants":[{"Name":"NM_002225.5(IVD):c.457-3_457-2delinsGG","Chromosome":"15","Start":"40411257","Stop":"40411258","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"GG","allel_id":186930,"rule_based_match":false,"evidence_text":"c.457-3_2CA>GG","llm_judgment":"PRESENT","evidence":"c.457-3_2CA>GG","abstract_start":960,"abstract_end":974}]}
{"pmid":"30304524","title":"Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease.","abstract":"Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.","variants":[{"Name":"NM_003680.4(YARS1):c.499C>A (p.Pro167Thr)","Chromosome":"1","Start":"32806493","Stop":"32806493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":627763,"rule_based_match":true,"evidence_text":"c.499C > A, p.Pro167Thr","llm_judgment":"PRESENT","evidence":"c.499C > A, p.Pro167Thr","abstract_start":330,"abstract_end":353}]}
{"pmid":"31119281","title":"ADCY10 frameshift variant leading to severe recessive asthenozoospermia and segregating with absorptive hypercalciuria.","abstract":"STUDY QUESTION: Can whole exome sequencing (WES) reveal a novel pathogenic variant in asthenozoospermia in a multiplex family including multiple patients?\nSUMMARY ANSWER: Patients were discovered to be homozygous for a rare 2-bp deletion in the ADCY10 coding region (c.1205_1206del, rs779944215).\nWHAT IS KNOWN ALREADY: ADCY10 encodes for soluble adenylyl cyclase (sAC), which is the predominant adenylate cyclase in sperm. It is already established that proper sAC activity and a constant supply of cAMP are crucial to sperm motility regulation, and knockout mouse models have been reported as severely asthenozoospermic. ADCY10 is a susceptibility gene for dominant absorptive hypercalciuria (OMIM#143870); however, no ADCY10 variations have been confirmed to cause human asthenozoospermia to date.\nSTUDY DESIGN, SIZE, DURATION: This was a retrospective genetics study of a highly consanguineous pedigree of asthenozoospermia. The subject family was recruited in Iran in 2016.\nPARTICIPANTS/MATERIALS, SETTING, METHODS: The two patients were diagnosed as asthenozoospermic through careful clinical investigations. Both patients, respective parents, and an unaffected brother were subjected to WES. The discovered variant was validated by Sanger sequencing and segregated with the phenotype. To confirm the pathogenicity of the variant, sperm samples from both patients, 10 normozoospermic men and 10 asthenozoospermic patients not representing the variation, were treated with a cAMP analogue dissolved in human tubal fluid medium, followed by computer-assisted sperm analysis and statistical analyses.\nMAIN RESULTS AND THE ROLE OF CHANCE: The discovered homozygous variant occurs at 10 amino acids upstream of the ADCY10 nucleotide binding site leading to a premature termination (p.His402Argfs*41). Treatment of the patients' sperm samples with a cell-permeable cAMP analogue resulted in a significant increase in sperm motility, indicating the pathogenic role of the variant. Moreover, absorptive hypercalciuria, segregating within the family, was also associated with the same variant following a dominant inheritance.\nLIMITATIONS, REASONS FOR CAUTION: Though nonsense-mediated decay is highly likely to occur in the mutated transcripts, we were not able to confirm this due to low RNA levels in mature sperm.\nWIDER IMPLICATIONS OF THE FINDINGS: Our finding enlarges the phenotypic spectrum associated with the ADCY10 gene, previously described as a susceptibility gene for dominant absorptive hypercalciuria.\nSTUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Royan Institute, Tehran, Iran, and San Raffaele Hospital, Milan, Italy. The authors have no conflict of interest.\nTRIAL REGISTRATION NUMBER: N/A.","variants":[{"Name":"NM_018417.6(ADCY10):c.1205_1206del (p.His402fs)","Chromosome":"1","Start":"167880125","Stop":"167880126","ReferenceAlleleVCF":"CGT","AlternateAlleleVCF":"C","allel_id":535228,"rule_based_match":true,"evidence_text":"c.1205_1206del","llm_judgment":"PRESENT","evidence":"c.1205_1206del","abstract_start":267,"abstract_end":281}]}
{"pmid":"17893653","title":"Two truncating USH3A mutations, including one novel, in a German family with Usher syndrome.","abstract":"PURPOSE: To identify the genetic defect in a German family with Usher syndrome (USH) and linkage to the USH3A locus.\nMETHODS: DNA samples of five family members (both parents and the three patients) were genotyped with polymorphic microsatellite markers specific for eight USH genes. Three affected family members underwent detailed ocular and audiologic characterization.\nRESULTS: Symptoms in the patients were compatible with Usher syndrome and show intrafamilial variation, for both hearing loss (ranging from severe to profound with non-linear progression) and vision. Genotyping of microsatellite markers for the different USH loci was in line with a defect in the USH3A gene on chromosome 3q25. Sequence analysis of the USH3A gene revealed two truncating mutations; c.149_152delCAGGinsTGTCCAAT, which has been described previously, and a novel mutation, c.502_503insA, segregating with the phenotype.\nCONCLUSIONS: To date, only 11 USH3A mutations have been described. This is the first description of a German family with USH due to USH3A mutations, including one novel. Our findings indicate that also in the Central European population, USH3A mutations should be considered in cases of USH.","variants":[{"Name":"NM_001195794.1(CLRN1):c.149_152delinsTGTCCAAT (p.Ser50fs)","Chromosome":"3","Start":"150972557","Stop":"150972560","ReferenceAlleleVCF":"CCTG","AlternateAlleleVCF":"ATTGGACA","allel_id":186676,"rule_based_match":false,"evidence_text":"c.149_152delCAGGinsTGTCCAAT","llm_judgment":"PRESENT","evidence":"c.149_152delCAGGinsTGTCCAAT","abstract_start":772,"abstract_end":799}]}
{"pmid":"27806333","title":"Novel mutations in CRB1 gene identified in a chinese pedigree with retinitis pigmentosa by targeted capture and next generation sequencing.","abstract":"PURPOSE: To detect the disease-causing gene in a Chinese pedigree with autosomal-recessive retinitis pigmentosa (ARRP).\nMETHODS: All subjects in this family underwent a complete ophthalmic examination. Targeted-capture next generation sequencing (NGS) was performed on the proband to detect variants. All variants were verified in the remaining family members by PCR amplification and Sanger sequencing.\nRESULTS: All the affected subjects in this pedigree were diagnosed with retinitis pigmentosa (RP). The compound heterozygous c.138delA (p.Asp47IlefsX24) and c.1841G>T (p.Gly614Val) mutations in the Crumbs homolog 1 (CRB1) gene were identified in all the affected patients but not in the unaffected individuals in this family. These mutations were inherited from their parents, respectively.\nCONCLUSION: The novel compound heterozygous mutations in CRB1 were identified in a Chinese pedigree with ARRP using targeted-capture next generation sequencing. After evaluating the significant heredity and impaired protein function, the compound heterozygous c.138delA (p.Asp47IlefsX24) and c.1841G>T (p.Gly614Val) mutations are the causal genes of early onset ARRP in this pedigree. To the best of our knowledge, there is no previous report regarding the compound mutations.","variants":[{"Name":"NM_201253.3(CRB1):c.138del (p.Asp47fs)","Chromosome":"1","Start":"197328487","Stop":"197328487","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1928556,"rule_based_match":true,"evidence_text":"c.138delA (p.Asp47IlefsX24)","llm_judgment":"PRESENT","evidence":"c.138delA (p.Asp47IlefsX24)","abstract_start":529,"abstract_end":556},{"Name":"NM_201253.3(CRB1):c.1841G>T (p.Gly614Val)","Chromosome":"1","Start":"197421669","Stop":"197421669","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":930207,"rule_based_match":true,"evidence_text":"c.1841G>T (p.Gly614Val)","llm_judgment":"PRESENT","evidence":"c.1841G>T (p.Gly614Val)","abstract_start":561,"abstract_end":584}]}
{"pmid":"25898808","title":"Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome.","abstract":"Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.Q142*) and c.479_480delTT (p.F160*), in CAV1 in a 7-year-old male and a 3-year-old female of European origin, respectively. Both the patients had generalized fat loss, thin mottled skin and progeroid features at birth. The male patient had cataracts requiring extraction at age 30 months and the female patient had pulmonary arterial hypertension. Dermal fibroblasts of the female patient revealed negligible CAV1 immunofluorescence staining compared to control but there were no differences in the number and morphology of caveolae upon electron microscopy examination. Based upon the similarities in the clinical features of these two patients, previous reports of CAV1 mutations in patients with lipodystrophies and pulmonary hypertension, and similar features seen in CAV1 null mice, we conclude that these variants are the most likely cause of one subtype of neonatal onset generalized lipodystrophy syndrome.","variants":[{"Name":"NM_001753.5(CAV1):c.479_480del (p.Leu159_Phe160insTer)","Chromosome":"7","Start":"116559228","Stop":"116559229","ReferenceAlleleVCF":"CTT","AlternateAlleleVCF":"C","allel_id":205252,"rule_based_match":true,"evidence_text":"c.479_480delTT (p.F160*)","llm_judgment":"PRESENT","evidence":"c.479_480delTT (p.F160*)","abstract_start":491,"abstract_end":515},{"Name":"NM_001753.5(CAV1):c.424C>T (p.Gln142Ter)","Chromosome":"7","Start":"116559174","Stop":"116559174","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":205702,"rule_based_match":true,"evidence_text":"c.424C>T (p.Q142*)","llm_judgment":"PRESENT","evidence":"c.424C>T (p.Q142*)","abstract_start":468,"abstract_end":486}]}
{"pmid":"32805706","title":"First case of fetal goitrous hypothyroidism due to SLC5A5/NIS mutations.","abstract":"BACKGROUND: Among patients with congenital hypothyroidism, 35% have dyshormonogenesis (DH) with thyroid gland in situ with or without goiter. The majority of DH cases are due to mutations in genes involved in thyroid hormone production as TG, TPO, SLC5A5/NIS, SLC26A4/PDS, IYD/DEHAL1, DUOX2, and DUOXA2, and are usually inherited on an autosomal recessive basis. Most previously reported cases of fetal hypothyroidism and goiter were related to TG or TPO mutations and recently DUOXA2.\nPATIENT: In a male patient with antenatal goiter treated with intraamniotic levothyroxine injections, whose long-term follow-up is described in detail, two novel NIS mutations were detected. Mutations of NIS were located in exon 1 (c.52G>A, p.G18R) and exon 13 (c.1546C>T, p.R516X), each mutation was inherited from parents, who are healthy carriers. The p.G18R mutation affecting the first transmembrane domain of the protein can be responsible for deficient iodide uptake. However, the second is a nonsense mutation leading probably to mRNA degradation. In addition, the patient has undergone a thyroidectomy and we have studied the thyroid tissue. The thyroid histology showed heterogeneity with large follicles, epithelial hyperplasia and many areas of fibrosis. Immunohistochemistry with NIS specific antibody showed NIS staining at the basolateral plasma membrane of the thyrocytes.\nCONCLUSIONS: We report the first case of fetal goitrous hypothyroidism due to two novel NIS mutations with access to thyroid tissue of the patient, specific histology studies and long-term follow-up. This case expands our knowledge and provides further insights on molecular causes of fetal goiter in humans.","variants":[{"Name":"NM_000453.3(SLC5A5):c.52G>A (p.Gly18Arg)","Chromosome":"19","Start":"17872371","Stop":"17872371","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3498402,"rule_based_match":true,"evidence_text":"c.52G>A","llm_judgment":"PRESENT","evidence":"c.52G>A","abstract_start":718,"abstract_end":725},{"Name":"NM_000453.3(SLC5A5):c.1546C>T (p.Arg516Ter)","Chromosome":"19","Start":"17888350","Stop":"17888350","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2417879,"rule_based_match":true,"evidence_text":"c.1546C>T (p.R516X)","llm_judgment":"PRESENT","evidence":"c.1546C>T","abstract_start":748,"abstract_end":757}]}
{"pmid":"26451869","title":"Prevalence of type 5 familial hemophagocytic lymphohistiocytosis in Korea and novel mutations in STXBP2.","abstract":"Familial hemophagocytic lymphohistiocytosis (F-HLH or FHL) is a potentially fatal immune dysregulation syndrome with a heterogeneous genetic background. Most recently, STXBP2 has been identified as the causative gene of type 5 FHL (FHL5) with a worldwide distribution. In this study, we investigated the prevalence of FHL5 in Korea. About 50 Korean pediatric patients with HLH who lacked pathogenic mutations in PRF1, UNC13D, or in STX11 from the previous series of 72 patients with HLH were analyzed for STXBP2 mutations by conventional sequencing analyses. As a result, we found one patient with two novel mutations of STXBP2: c.184A>G and c.577A>C. c.184A>G (p.Asn62Asp) was located within a highly conserved region of the STXBP2 protein and predicted to be deleterious. c.577A>C in exon 7 resulted in incomplete splicing mutation with exon 7 skipping concurrent with exon 7-retained transcript with p.Lys193Gln substitution. The frequency of FHL5 was ~1% (1/72) in Korean pediatric patients with HLH. This is the first study on FHL5 in Korea, and the data from a nationwide patient cohort provide another piece of genetic profiles of FHL.","variants":[{"Name":"NM_006949.4(STXBP2):c.184A>G (p.Asn62Asp)","Chromosome":"19","Start":"7639745","Stop":"7639745","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1301186,"rule_based_match":true,"evidence_text":"c.184A>G (p.Asn62Asp)","llm_judgment":"PRESENT","evidence":"c.184A>G (p.Asn62Asp)","abstract_start":652,"abstract_end":673},{"Name":"NM_006949.4(STXBP2):c.577A>C (p.Lys193Gln)","Chromosome":"19","Start":"7641852","Stop":"7641852","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1293550,"rule_based_match":true,"evidence_text":"c.577A>C","llm_judgment":"PRESENT","evidence":"c.577A>C","abstract_start":642,"abstract_end":650}]}
{"pmid":"29174172","title":"Juvenile-onset parkinsonism with pyramidal signs due to compound heterozygous mutations in the F-Box only protein 7 gene.","abstract":"BACKGROUND: Juvenile-onset parkinsonism is often caused by genetic factors. Mutations in several autosomal genes, including the F-box only protein 7 (FBXO7) gene, have been found in patients suffering from juvenile-onset parkinsonism with pyramidal signs. Only five types of FBXO7 mutations have been described. Here, we present a case report about a Chinese patient presenting with juvenile-onset parkinsonism likely caused by FBXO7 mutations.\nMETHODS: The patient was a 32-year-old Chinese male. DNA samples were extracted from the patient and his parents. Exons in parkinsonism-related genes were amplified and sequenced.\nRESULTS: The patient began experiencing a progressive involuntary tremor in his left hand at 16 years of age, which was followed by the development of gait dysfunction, dysarthria, and rapid eye movement sleep behavior disorder. A neurological examination of the patient revealed cogwheel rigidity, bradykinesia, static and postural tremor and bilateral Babinski signs. The patient responded to dopaminergic therapies but was affected by psychiatric side effects. Further genetic analysis of the patient and his parents revealed compound heterozygous mutations of the FBXO7 gene (NM_012179.3) in the patient (a nonsense c.1408G > T (p.E470X) mutation and a missense c.152A > G (p.N51S) mutation coming from the patient's mother and father, respectively).\nCONCLUSIONS: This is the first case harboring FBXO7 mutations that presented with juvenile-onset parkinsonism in the Chinese population.","variants":[{"Name":"NM_012179.4(FBXO7):c.1408G>T (p.Glu470Ter)","Chromosome":"22","Start":"32498369","Stop":"32498369","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3074077,"rule_based_match":true,"evidence_text":"c.1408G > T (p.E470X)","llm_judgment":"PRESENT","evidence":"c.1408G > T (p.E470X)","abstract_start":1245,"abstract_end":1266}]}
{"pmid":"34990597","title":"Clinical and genetic analysis of combined oxidative phosphorylation defificiency-10 caused by MTO1 mutation.","abstract":"The mitochondrial translation optimization factor 1(MTO1) gene mutations had been reported to be linked to combined oxidative phosphorylation defificiency-10 (COXPD10). In this study, we presented the detailed clinical features and genetic analysis of the patient with two variants in MTO1, and reviewed 42 different cases available in publications. Whole exome sequencing and bioinformatics analysis were employed to detect the genetic variants of a 6-month-old boy with metabolic disorder and multiple organ failure; Sanger sequencing was performed to confirm the origin of variants; and clinical data of the patients was retrospectively collected and analyzed. Variant classification was followed to ACMG guidline. The proband was diagnosed with multiple organ failure, severe pneumonia, sepsis, hyperlactatemia, metabolic acidosis, and moderate anemia. Compound heterozygous mutations in the coding region of MTO1 gene (c.1291C > T/p.Arg431Trp and c.1390C > T/p.Arg464Cys) were identified, and the results of family verification experiment showed that the mutations were inherited from the parents, respectively. Combined with clinical symptoms, the patient was diagnosed as COXPD10. In summary, hallmark features of MTO1 mutations were lactic acidosis and hypertrophic cardiomyopathy. Of note, patients with the same genetic mutation may not have the same clinical presentation. Additional MTO1 defificiency cases will help to make genotype-phenotype correlations clearer.","variants":[{"Name":"NM_012123.4(MTO1):c.1390C>T (p.Arg464Cys)","Chromosome":"6","Start":"73482169","Stop":"73482169","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":933454,"rule_based_match":true,"evidence_text":"c.1390C > T/p.Arg464Cys","llm_judgment":"PRESENT","evidence":"c.1390C > T/p.Arg464Cys","abstract_start":952,"abstract_end":975}]}
{"pmid":"30007954","title":"Identification of a LMNA (c.646C>T) variant by whole-exome sequencing in combination with a dilated cardiomyopathy (DCM) related gene filter in a family with familiar DCM.","abstract":"","variants":[{"Name":"NM_170707.4(LMNA):c.646C>T (p.Arg216Cys)","Chromosome":"1","Start":"156134811","Stop":"156134811","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":196467,"rule_based_match":true,"evidence_text":"LMNA (c.646C>T)","llm_judgment":"PRESENT","evidence":"LMNA (c.646C>T)","abstract_start":null,"abstract_end":null}]}
{"pmid":"36928758","title":"Aromatic L-amino acid decarboxylase deficiency in countries in the Middle East: a case series and literature review.","abstract":"Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited neurometabolic disorder that can lead to severe physical and developmental impairment. This report includes 16 patients from the Middle East and is the largest series of patients with confirmed AADC deficiency from this region reported to date. The patients displayed a range of signs and symptoms at presentation and almost all failed to reach major motor milestones. Missed and delayed diagnoses were common leading to the late introduction of targeted treatments. Eight unique variants were identified in the DDC gene, including six missense and two intronic variants. A previously undescribed variant was identified: an intronic variant between exons 13 and 14 (c.1243-10A>G). The patients were mostly treated with currently recommended medications, including dopamine agonists, vitamin B6, and monoamine oxidase inhibitors. One patient responded well, but treatment outcomes were otherwise mostly limited to mild symptomatic improvements. Five patients had died by the time of data collection, confirming that the condition is associated with premature mortality. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age.  Conclusions: Delays in the diagnosis of AADC deficiency are common. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age. What is Known: • Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disorder that can lead to severe physical and developmental impairment. • Currently recommended medications provide mostly mild symptomatic improvements. What is New: • The clinical presentation of sixteen patients with confirmed AADC deficiency varied considerably and almost all failed to reach major motor milestones. • There is an urgent need for earlier diagnosis, given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age.","variants":[{"Name":"NM_001082971.2(DDC):c.1243-10A>G","Chromosome":"7","Start":"50463441","Stop":"50463441","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1889386,"rule_based_match":true,"evidence_text":"c.1243-10A>G","llm_judgment":"PRESENT","evidence":"c.1243-10A>G","abstract_start":740,"abstract_end":752}]}
{"pmid":"26675719","title":"Germline variant FGFR4  p.G388R exposes a membrane-proximal STAT3 binding site.","abstract":"Variant rs351855-G/A is a commonly occurring single-nucleotide polymorphism of coding regions in exon 9 of the fibroblast growth factor receptor FGFR4 (CD334) gene (c.1162G>A). It results in an amino-acid change at codon 388 from glycine to arginine (p.Gly388Arg) in the transmembrane domain of the receptor. Despite compelling genetic evidence for the association of this common variant with cancers of the bone, breast, colon, prostate, skin, lung, head and neck, as well as soft-tissue sarcomas and non-Hodgkin lymphoma, the underlying biological mechanism has remained elusive. Here we show that substitution of the conserved glycine 388 residue to a charged arginine residue alters the transmembrane spanning segment and exposes a membrane-proximal cytoplasmic signal transducer and activator of transcription 3 (STAT3) binding site Y(390)-(P)XXQ(393). We demonstrate that such membrane-proximal STAT3 binding motifs in the germline of type I membrane receptors enhance STAT3 tyrosine phosphorylation by recruiting STAT3 proteins to the inner cell membrane. Remarkably, such germline variants frequently co-localize with somatic mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Using Fgfr4 single nucleotide polymorphism knock-in mice and transgenic mouse models for breast and lung cancers, we validate the enhanced STAT3 signalling induced by the FGFR4 Arg388-variant in vivo. Thus, our findings elucidate the molecular mechanism behind the genetic association of rs351855 with accelerated cancer progression and suggest that germline variants of cell-surface molecules that recruit STAT3 to the inner cell membrane are a significant risk for cancer prognosis and disease progression.","variants":[{"Name":"NM_213647.3(FGFR4):c.1162G>A (p.Gly388Arg)","Chromosome":"5","Start":"177093242","Stop":"177093242","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31365,"rule_based_match":true,"evidence_text":"c.1162G>A (p.Gly388Arg)","llm_judgment":"PRESENT","evidence":"p.Gly388Arg","abstract_start":251,"abstract_end":262}]}
{"pmid":"25879889","title":"Diffuse parenchymal lung disease as first clinical manifestation of GATA-2 deficiency in childhood.","abstract":"BACKGROUND: GATA-2 transcription factor deficiency has recently been described in patients with a propensity towards myeloid malignancy associated with other highly variable phenotypic features: chronic leukocytopenias (dendritic cell-, monocyto-, granulocyto-, lymphocytopenia), increased susceptibility to infections, lymphatic vasculature abnormalities, and sensorineural deafness. Patients often suffer from opportunistic respiratory infections; chronic pulmonary changes have been found in advanced disease.\nCASE PRESENTATION: We present a case of a 17-year-old previously healthy Caucasian male who was admitted to the hospital with fever, malaise, headache, cough and dyspnea. A chest X-ray revealed bilateral interstitial infiltrates and pneumonia was diagnosed. Despite prompt clinical improvement under antibiotic therapy, interstitial changes remained stable. A high resolution computer tomography showed severe diffuse parenchymal lung disease, while the patient's pulmonary function tests were normal and he was asymptomatic. Lung tissue biopsy revealed chronic reparative and resorptive reaction with organizing vasculitis. At the time of the initial presentation to the hospital, serological signs of acute infection with Epstein-Barr virus (EBV) were present; EBV viremia with atypical serological response persisted during two-year follow up. No other infectious agents were found. Marked monocytopenia combined with B-cell lymphopenia led to a suspicion of GATA-2 deficiency. Diagnosis was confirmed by detection of the previously published heterozygous mutation in GATA2 (c.1081 C > T, p.R361C). The patient's brother and father were both carriers of the same genetic defect. The brother had no clinically relevant ailments despite leukocyte changes similar to the index patient. The father suffered from spondylarthritis, and apart from B-cell lymphopenia, no other changes within the leukocyte pool were seen.\nCONCLUSION: We conclude that a diagnosis of GATA-2 deficiency should be considered in all patients with diffuse parenchymal lung disease presenting together with leukocytopenia, namely monocyto-, dendritic cell- and B-lymphopenia, irrespective of severity of the clinical phenotype. Genetic counseling and screening for GATA2 mutations within the patient's family should be provided as the phenotype is highly variable and carriers without apparent immunodeficiency are still in danger of developing myeloid malignancy. A prompt recognition of this rare condition helps to direct clinical treatment strategies and follow-up procedures.","variants":[{"Name":"NM_032638.5(GATA2):c.1081C>T (p.Arg361Cys)","Chromosome":"3","Start":"128481881","Stop":"128481881","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":452064,"rule_based_match":true,"evidence_text":"c.1081 C > T, p.R361C","llm_judgment":"PRESENT","evidence":"c.1081 C > T, p.R361C","abstract_start":1591,"abstract_end":1612}]}
{"pmid":"30680856","title":"A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction.","abstract":"Heterozygous mutations in the inverted formin-2 (INF2) gene provoke focal segmental glomerulosclerosis (FSGS) and intermediate Charcot-Marie-Tooth (CMT) disease with FSGS. Here, we report four patients from a three-generation family with a new cryptic splicing INF2 mutation causing autosomal dominant intermediate CMT with minimal glomerular dysfunction. Three males and one female with a mean age of 51 years (26-87) presented with a slowly progressive sensorimotor polyneuropathy, pes cavus, and kyphoscoliosis. Mean age at CMT disease onset was 11.5 years (3-17), and electrophysiological studies showed demyelinating and axonal features consistent with intermediate CMT. Plasma albumin and creatinine were normal in all four cases, and urine protein was normal in one case and mildly raised in three patients (mean: 0.32 g/L [0.18-0.44], N < 0.14). Genetic analysis found a c.271C > G (p. Arg91Gly) variation in INF2 exon 2, and in vitro splicing assays showed the deletion of the last 120 nucleotides of INF2 exon 2 leading to a 40 amino acids in-frame deletion (p. Arg91_p. Gln130del). This report expands the genetic spectrum of INF2-associated disorders and demonstrates that INF2 mutations may provoke isolated CMT with no clinically relevant kidney involvement. Consequently, INF2 mutation analysis should not be restricted to individuals with coincident neuropathy and renal disease.","variants":[{"Name":"NM_022489.4(INF2):c.271C>G (p.Arg91Gly)","Chromosome":"14","Start":"104701636","Stop":"104701636","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":841097,"rule_based_match":true,"evidence_text":"c.271C > G (p. Arg91Gly)","llm_judgment":"PRESENT","evidence":"c.271C > G (p. Arg91Gly)","abstract_start":879,"abstract_end":903}]}
{"pmid":"20809529","title":"Molecular mechanisms leading to null-protein product from retinoschisin (RS1) signal-sequence mutants in X-linked retinoschisis (XLRS) disease.","abstract":"Retinoschisin (RS1) is a cell-surface adhesion molecule expressed by photoreceptor and bipolar cells of the retina. The 24-kDa protein encodes two conserved sequence motifs: the initial signal sequence targets the protein for secretion while the larger discoidin domain is implicated in cell adhesion. RS1 helps to maintain the structural organization of the retinal cell layers and promotes visual signal transduction. RS1 gene mutations cause X-linked retinoschisis disease (XLRS) in males, characterized by early-onset central vision loss. We analyzed the biochemical consequences of several RS1 signal-sequence mutants (c.1A>T, c.35T>A, c.38T>C, and c.52G>A) found in our subjects. Expression analysis in COS-7 cells demonstrates that these mutations affect RS1 biosynthesis and result in an RS1 null phenotype by several different mechanisms. By comparison, discoidin-domain mutations generally lead to nonfunctional conformational variants that remain trapped inside the cell. XLRS disease has a broad heterogeneity in general, but subjects with the RS1 null-protein signal-sequence mutations are on the more severe end of the clinical phenotype. Results from the signal-sequence mutants are discussed in the context of the discoidin-domain mutations, clinical phenotypes, genotype-phenotype correlations, and implications for RS1 gene replacement therapy.","variants":[{"Name":"NM_000330.4(RS1):c.38T>C (p.Leu13Pro)","Chromosome":"X","Start":"18672031","Stop":"18672031","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":24931,"rule_based_match":true,"evidence_text":"c.38T>C","llm_judgment":"PRESENT","evidence":"c.38T>C","abstract_start":641,"abstract_end":648},{"Name":"NM_000330.4(RS1):c.1A>T (p.Met1Leu)","Chromosome":"X","Start":"18672068","Stop":"18672068","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":482248,"rule_based_match":true,"evidence_text":"c.1A>T","llm_judgment":"PRESENT","evidence":"c.1A>T","abstract_start":624,"abstract_end":630}]}
{"pmid":"18344446","title":"Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP1.","abstract":"PURPOSE: Bothnia dystrophy (BD) is an autosomal recessive retinitis pigmentosa (arRP) associated with the c.700C>T mutation in the RLBP1 gene. Testing of patients with BD has revealed the c.700C>T mutation on one or both alleles. The purpose of this study was to elucidate the underlying genetic mechanisms along with a clinical evaluation of the heterozygous patients with BD.\nMETHODS: Patients with BD heterozygous for the RLBP1 c.700C>T were tested for 848 mutations by arrayed primer-extension technology. Further mutation detection was performed by PCR-restriction fragment length polymorphism (RFLP), sequencing, denaturing (d)HLPC and allelic discrimination. The ophthalmic examinations were performed in all c.700C>T heterozygotes.\nRESULTS: The clinical findings in 10 BD heterozygotes were similar to those in the homozygotes. The presence of a second mutation, c.677T>A, corresponding to p.M226K was detected in all 10 cases. Segregation analysis showed that the mutations were allelic, and the patients were compound heterozygotes [c.677T>A]+[c.700C>T]. One of those patients was also a carrier of the c.40C>T corresponding to the p.R14W change in carbonic anhydrase IV (CAIV) associated with autosomal dominant RP, RP17. His mother, a carrier of the identical change was declared healthy after ophthalmic examination. This sequence variant was found in 6 of 143 tested blood donors.\nCONCLUSIONS: The high frequency of arRP in northern Sweden is due to two mutations in the RLBP1 gene: c.677T>A and c.700C>T. BD is caused by the loss of CRALBP function due to changed physical features and impaired activity of retinoid binding. The CAIV p.R14W sequence variant found in one of the patients with a BD phenotype is a benign polymorphism in a population of northern Sweden.","variants":[{"Name":"NM_000326.5(RLBP1):c.700C>T (p.Arg234Trp)","Chromosome":"15","Start":"89210794","Stop":"89210794","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28139,"rule_based_match":true,"evidence_text":"c.700C>T","llm_judgment":"PRESENT","evidence":"c.700C>T","abstract_start":106,"abstract_end":114},{"Name":"NM_000326.5(RLBP1):c.677T>A (p.Met226Lys)","Chromosome":"15","Start":"89211750","Stop":"89211750","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":28140,"rule_based_match":true,"evidence_text":"c.677T>A","llm_judgment":"PRESENT","evidence":"c.677T>A","abstract_start":871,"abstract_end":879}]}
{"pmid":"12884082","title":"Identification of a novel 2026G-->C mutation of the MRP2 gene in a Japanese patient with Dubin-Johnson syndrome.","abstract":"Dubin-Johnson syndrome is a recessive inherited disorder with conjugated hyperbilirubinemia caused by a dysfunction of multidrug resistance protein 2 (MRP2) on the canalicular membrane of hepatocytes. A mutational analysis of the MRP2 gene was carried out in three Japanese patients and their family members. In two patients, the homozygous mutations c.1901del67 and c,2272del168 were found. In the third patient, a -24C-->T polymorphism and the two mutations c.1901del67 and 2026G-->C were detected. The 2026G-->C mutation was a novel mutation in exon 16 affecting the conversion of Gly(676) to Arg(676) (G676R) in the MRP2 protein, and was not detected in fifty healthy volunteers. The G676R mutation was located in the Walker A motif of the first nucleotide binding domain in the MRP2 protein, and it was suggested that the mutation induced the dysfunction of the MRP2 protein. It was concluded that the compound heterozygosity of the two mutations of the MRP2 gene in the third patient contributed to the induction of hyperbilirubinemia in this case.","variants":[{"Name":"NM_000392.5(ABCC2):c.2026G>C (p.Gly676Arg)","Chromosome":"10","Start":"99813076","Stop":"99813076","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2901489,"rule_based_match":false,"evidence_text":"2026G-->C","llm_judgment":"PRESENT","evidence":"2026G-->C","abstract_start":476,"abstract_end":485}]}
{"pmid":"17068223","title":"A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.","abstract":"The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.","variants":[{"Name":"NM_144701.3(IL23R):c.1142G>A (p.Arg381Gln)","Chromosome":"1","Start":"67240275","Stop":"67240275","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18147,"rule_based_match":true,"evidence_text":"c.1142G>A (p.Arg381Gln)","llm_judgment":"PRESENT","evidence":"p.Arg381Gln","abstract_start":530,"abstract_end":541}]}
{"pmid":"30024541","title":"Two novel TSC2 mutations in pediatric patients with tuberous sclerosis complex: Case report.","abstract":"RATIONALE: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder. The TSC1 and TSC2 genes have been identified as pathogenic genes.\nPATIENT CONCERNS: In this report, we are discussing a novel frameshift mutation and a novel missense mutation in the TSC2 gene.\nDIAGNOSES: The two cases discussed in this study met the latest diagnostic criteria for TSC published by the International Tuberculosis Sclerosis Complex Consensus Conference in 2012.\nINTERVENTIONS: High-throughput sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to examine tuberous sclerosis complex (TSC)-related genes (TSC1 and TSC2) and their splicing regions using peripheral blood DNA from two probands in two families with TSC and to identify the genetic mutation sites. Amplification primers were designed for the mutation sites, and polymerase chain reaction and Sanger sequencing were used to verify the peripheral blood DNA sequences from the probands and their parents.\nOUTCOME: Proband 1 had the c.1228 (exon 12)_c.1229 (exon 12) insG (p.L410RfsX11) heterozygous mutation in the TSC2 gene (chr16), which was a new frameshift mutation. Proband 2 had the c.4925G>A (exon 38) (p.G1642D) heterozygous mutation in the TSC2 gene (chr16), which was a new missense mutation.\nLESSONS: These two novel mutations may be pathogenic mutations for TSC, and their association with the disease needs to be further verified by mutant protein function cell model and animal model.","variants":[{"Name":"NM_000548.5(TSC2):c.4925G>A (p.Gly1642Asp)","Chromosome":"16","Start":"2086807","Stop":"2086807","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":59140,"rule_based_match":true,"evidence_text":"c.4925G>A (exon 38) (p.G1642D)","llm_judgment":"PRESENT","evidence":"c.4925G>A (exon 38) (p.G1642D)","abstract_start":1176,"abstract_end":1206}]}
{"pmid":"36935417","title":"Ribonuclease inhibitor 1 (RNH1) deficiency cause congenital cataracts and global developmental delay with infection-induced psychomotor regression and anemia.","abstract":"Ribonuclease inhibitor 1, also known as angiogenin inhibitor 1, encoded by RNH1, is a ubiquitously expressed leucine-rich repeat protein, which is highly conserved in mammalian species. Inactivation of rnh1 in mice causes an embryonically lethal anemia, but the exact biological function of RNH1 in humans remains unknown and no human genetic disease has so far been associated with RNH1. Here, we describe a family with two out of seven siblings affected by a disease characterized by congenital cataract, global developmental delay, myopathy and psychomotor deterioration, seizures and periodic anemia associated with upper respiratory tract infections. A homozygous splice-site variant (c.615-2A > C) in RNH1 segregated with the disease. Sequencing of RNA derived from patient fibroblasts and cDNA analysis of skeletal muscle mRNA showed aberrant splicing with skipping of exon 7. Western blot analysis revealed a total lack of the RNH1 protein. Functional analysis revealed that patient fibroblasts were more sensitive to RNase A exposure, and this phenotype was reversed by transduction with a lentivirus expressing RNH1 to complement patient cells. Our results demonstrate that loss-of-function of RNH1 in humans is associated with a multiorgan developmental disease with recessive inheritance. It may be speculated that the infection-induced deterioration resulted from an increased susceptibility toward extracellular RNases and/or other inflammatory responses normally kept in place by the RNase inhibitor RNH1.","variants":[{"Name":"NM_203387.3(RNH1):c.615-2A>C","Chromosome":"11","Start":"498935","Stop":"498935","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2740110,"rule_based_match":true,"evidence_text":"c.615-2A > C","llm_judgment":"PRESENT","evidence":"c.615-2A > C","abstract_start":690,"abstract_end":702}]}
{"pmid":"34680903","title":"Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics.","abstract":"Pathogenic variants in the <i>LMNA</i> gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in <i>LMNA</i> have been associated with \"mandibuloacral dysplasia type A\" (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in <i>LMNA</i> exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype-phenotype correlations.","variants":[{"Name":"NM_170707.4(LMNA):c.1580G>A (p.Arg527His)","Chromosome":"1","Start":"156137204","Stop":"156137204","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29538,"rule_based_match":true,"evidence_text":"c.1580G>A-p.Arg527His","llm_judgment":"PRESENT","evidence":"c.1580G>A-p.Arg527His","abstract_start":789,"abstract_end":810},{"Name":"NM_170707.4(LMNA):c.1580G>T (p.Arg527Leu)","Chromosome":"1","Start":"156137204","Stop":"156137204","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":906447,"rule_based_match":true,"evidence_text":"c.1580G>T-p.Arg527Leu","llm_judgment":"PRESENT","evidence":"c.1580G>T-p.Arg527Leu","abstract_start":926,"abstract_end":947}]}
{"pmid":"31395899","title":"ANO5 mutations in the Polish limb girdle muscular dystrophy patients: Effects on the protein structure.","abstract":"LGMD2L is a subtype of limb-girdle muscular dystrophy (LGMD), caused by recessive mutations in ANO5, encoding anoctamin-5 (ANO5). We present the analysis of five patients with skeletal muscle weakness for whom heterozygous mutations within ANO5 were identified by whole exome sequencing (WES). Patients varied in the age of the disease onset (from 22 to 38 years) and severity of the morphological and clinical phenotypes. Out of the nine detected mutations one was novel (missense p.Lys132Met, accompanied by p.His841Asp) and one was not yet characterized in the literature (nonsense, p.Trp401Ter, accompanied by p.Asp81Gly). The p.Asp81Gly mutation was also identified in another patient carrying a p.Arg758Cys mutation as well. Also, a c.191dupA frameshift (p.Asn64LysfsTer15), the first described and common mutation was identified. Mutations were predicted by in silico tools to have damaging effects and are likely pathogenic according to criteria of the American College of Medical Genetics and Genomics (ACMG). Indeed, molecular modeling of mutations revealed substantial changes in ANO5 conformation that could affect the protein structure and function. In addition, variants in other genes associated with muscle pathology were identified, possibly affecting the disease progress. The presented data indicate that the identified ANO5 mutations contribute to the observed muscle pathology and broaden the genetic spectrum of LGMD myopathies.","variants":[{"Name":"NM_213599.3(ANO5):c.242A>G (p.Asp81Gly)","Chromosome":"11","Start":"22221158","Stop":"22221158","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":102572,"rule_based_match":false,"evidence_text":"p.Asp81Gly","llm_judgment":"PRESENT","evidence":"p.Asp81Gly","abstract_start":614,"abstract_end":624}]}
{"pmid":"36692815","title":"Exome Sequencing in Monogenic Forms of Rickets.","abstract":"OBJECTIVE: To understand the phenotypic and genotypic spectrum of genetic forms of rickets in 10 families.\nMETHODS: Detailed clinical, radiographic, and biochemical evaluation of 10 families with phenotypes suggestive of a genetic cause of rickets was performed. Molecular testing using exome sequencing aided in the diagnosis of six different forms of known genetic causes.\nRESULTS: Eleven disease-causing variants including five previously reported variants (CYP27B1:c.1319_1325dup, p.(Phe443Profs*24), VDR:c.1171C>T, p.(Arg391Cys), PHEX: c.1586_1586+1del, PHEX: c.1482+5G>C, PHEX: c.58C>T, p.(Arg20*)) and six novel variants (CYP27B1:c.974C>T, p.(Thr325Met), CYP27B1: c.1376G>A, p.(Arg459His), CYP2R1: c.595C>T, p.(Arg199*), CYP2R1:c.1330G>C, p.(Gly444Arg),SLC34A3:c.1336-11_1336-1del, SLC2A2: c.589G>C, p.(Val197Leu)) in the genes known to cause monogenic rickets were identified.\nCONCLUSION: The authors hereby report a case series of individuals from India with a molecular diagnosis of rickets and provide the literature review which would help in enhancing the clinical and molecular profile for rapid and differential diagnosis of rickets.","variants":[{"Name":"NM_000785.4(CYP27B1):c.1376G>A (p.Arg459His)","Chromosome":"12","Start":"57763648","Stop":"57763648","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":995326,"rule_based_match":true,"evidence_text":"CYP27B1: c.1376G>A, p.(Arg459His)","llm_judgment":"PRESENT","evidence":"CYP27B1: c.1376G>A, p.(Arg459His)","abstract_start":662,"abstract_end":695}]}
{"pmid":"19273793","title":"The spectrum of retinal diseases caused by NR2E3 mutations in Israeli and Palestinian patients.","abstract":"OBJECTIVES: To evaluate the involvement of NR2E3 in inherited retinal degenerative diseases in the Israeli and Palestinian populations and to study phenotypic variability in patients who are homozygous for the same mutation.\nMETHODS: Patients from 35 families underwent clinical evaluation, including a full ophthalmologic examination and electroretinography. Genetic analyses included direct sequencing of polymerase chain reaction products and haplotype reconstruction.\nRESULTS: We recruited 6 consanguineous Muslim families and 2 Jewish families with enhanced S-cone syndrome. Patients from 4 of the Muslim families were homozygous for the same NR2E3 mutation, c.119-2A>C, but showed considerable variability in fundus appearance and retinal function, even among patients of comparable ages. Both Jewish patients were compound heterozygotes for the c.932G>A mutation in combination with c.194-202del9bp or a novel splice-site mutation, c.747+1G>C. Homozygosity analysis in 27 consanguineous families with retinitis pigmentosa revealed a homozygous mutation, c.932G>A, in 2 families. The electroretinographic responses in these patients were compatible with retinitis pigmentosa and did not show the characteristic enhanced S-cone syndrome pattern.\nCONCLUSION: Our results demonstrate the involvement of NR2E3 in enhanced S-cone syndrome and retinitis pigmentosa phenotypes in our populations.\nCLINICAL RELEVANCE: Patients with NR2E3 mutations may manifest variable phenotypes. Moreover, patients who are homozygous for the same NR2E3 mutation have variable expression of retinal disease, suggesting the involvement of modifier genes.","variants":[{"Name":"NM_014249.4(NR2E3):c.119-2A>C","Chromosome":"15","Start":"71811481","Stop":"71811481","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":188865,"rule_based_match":true,"evidence_text":"c.119-2A>C","llm_judgment":"PRESENT","evidence":"c.119-2A>C","abstract_start":664,"abstract_end":674},{"Name":"NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln)","Chromosome":"15","Start":"71813573","Stop":"71813573","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20571,"rule_based_match":true,"evidence_text":"c.932G>A","llm_judgment":"PRESENT","evidence":"c.932G>A","abstract_start":852,"abstract_end":860}]}
{"pmid":"37400730","title":"Molecular insights into hereditary elliptocytosis and pyropoikilocytosis: NGS uncovers multiple potential candidate genes.","abstract":"Hereditary elliptocytosis (HE) and pyropoikilocytosis (HPP) are considered a group of hemolytic anemias (HE/HPP) due to inherited abnormalities of erythrocyte membrane proteins with a worldwide distribution. Most cases are associated with molecular abnormalities linked to spectrin, band 4.1, and ankyrin. The present study aimed to identify significant molecular signatures on a target panel of 8 genes using whole exome sequencing (WES) in 9 Bahraini patients with elliptocytosis. Case selection was based on presence of anemia not associated with iron deficiency or hemoglobinopathy and demonstrating > 50% elliptocytes in blood smears. The c.779 T > C mutation of SPTA1 (Spectrin alpha), which is a known deleterious missense mutation that inhibits normal association of spectrin molecules to form tetramers, was seen in 4 patients in homozygous (n = 1) and heterozygous (n = 3) states. The αLELY abnormality in association with compound heterozygous mutations in SPTA1 was present in 5 patients (2 associated with the SPTA1 c.779 T > C variant; 3 with c.3487 T > G and various other SPTA1 mutations of uncertain/unknown significance). Seven patients had SPTB (Spectrin beta) mutations, predicted as likely benign by in silico analysis. A novel EPB41 (Erythrocyte Membrane Protein Band 4.1) mutation with potential deleterious impact was also seen. Finally, 2 cases showed an InDel (insertion-deletion mutations) abnormality in the gene that codes for the mechanosensitive ion-channel PIEZO (Piezo Type Mechanosensitive Ion Channel Component 1). PIEZO mutations are reported to cause red cell dehydration but have not been previously described in HE/HPP. Results of this study confirm the involvement of previously reported abnormalities in SPTA1 and suggest possible involvement of other candidate genes in a disorder involving polygenic interactions.","variants":[{"Name":"NM_003126.4(SPTA1):c.779T>C (p.Leu260Pro)","Chromosome":"1","Start":"158678434","Stop":"158678434","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":27883,"rule_based_match":true,"evidence_text":"c.779 T > C","llm_judgment":"PRESENT","evidence":"c.779 T > C","abstract_start":644,"abstract_end":655}]}
{"pmid":"29017447","title":"Characterization of a novel KCNJ2 sequence variant detected in Andersen-Tawil syndrome patients.","abstract":"BACKGROUND: Mutations in the KCNJ2 gene encoding the ion channel Kir2.1 have been linked to the Andersen-Tawil syndrome (ATS). Molecular genetic screening performed in a family exhibiting clinical ATS phenotypes unmasked a novel sequence variant (c.434A > G, p.Y145C) in this gene. The aim of this study was to investigate the effect of this variant on Kir2.1 ion channel functionality.\nMETHODS: Mutant as well as wild type GFP tagged Kir2.1 channels were expressed in HEK293 cells. In order to examine the effect of the new variant, electrophysiological measurements were performed using patch clamp technique. Cellular localization of the mutant in comparison to the wild type ion channel was analyzed by confocal laser scanning microscopy.\nRESULTS: The currents of cells expressing only mutant channels or a mixture of wild type and mutant were significantly reduced compared to those expressing wild type (WT) channels (p < 0.01). Whereas WT expressing cells exhibited at -120 mV an averaged current of -4.5 ± 1.9 nA, the mutant generates only a current of -0.17 ± 0.07 nA. A co-expression of mutant and WT channel generates only a partial rescue of the WT current. Confocal laser scanning microscopy indicated that the novel variant is not interfering with synthesis and/or protein trafficking.\nCONCLUSIONS: The detected sequence variant causes loss-of-function of the Kir2.1 channel and explains the clinical phenotypes observed in Andersen-Tawil syndrome patients.","variants":[{"Name":"NM_000891.3(KCNJ2):c.434A>G (p.Tyr145Cys)","Chromosome":"17","Start":"70175473","Stop":"70175473","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":846137,"rule_based_match":true,"evidence_text":"c.434A > G, p.Y145C","llm_judgment":"PRESENT","evidence":"c.434A > G, p.Y145C","abstract_start":247,"abstract_end":266}]}
{"pmid":"31304856","title":"First Description of Hb San Diego (","abstract":"Congenital erythrocytosis is a rare and hereditary disorder of red blood cell (RBC) production that can be caused by high oxygen affinity hemoglobin (Hb) variants. We applied a genetic approach including whole exome sequencing and Sanger sequencing. We identified a heterozygous β-globin gene (Hb San Diego or <i>HBB</i>: c.328G>A) in exon 3 as a causative germline mutation in a Chinese family with congenital erythrocytosis. We concluded that in erythrocytosis with a dominant inheritance and normal or inappropriately high erythropoietin (EPO) levels, the high oxygen affinity Hb variants should be considered. In addition, as a tool for identification of mutations in congenital erythrocytosis, whole exome sequencing improves diagnostic accuracy and provides the opportunity for discovery of novel variants.","variants":[{"Name":"NM_000518.5(HBB):c.328G>A (p.Val110Met)","Chromosome":"11","Start":"5225714","Stop":"5225714","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30381,"rule_based_match":true,"evidence_text":"<i>HBB</i>: c.328G>A","llm_judgment":"PRESENT","evidence":"<i>HBB</i>: c.328G>A","abstract_start":310,"abstract_end":330}]}
{"pmid":"26032230","title":"Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.","abstract":"Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.","variants":[{"Name":"NM_001605.3(AARS1):c.986G>A (p.Arg329His)","Chromosome":"16","Start":"70268356","Stop":"70268356","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23505,"rule_based_match":true,"evidence_text":"c.986G>A, p.(Arg329His)","llm_judgment":"PRESENT","evidence":"c.986G>A, p.(Arg329His)","abstract_start":1522,"abstract_end":1545}]}
{"pmid":"32638197","title":"Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance.","abstract":"PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder that manifests with fever, early-onset vasculitis, strokes, and hematologic dysfunction. This study aimed to identify disease-causing variants by conventional Sanger and whole exome sequencing in two families suspected to have DADA2 and non-confirmatory genotypes. ADA2 enzymatic assay confirmed the clinical diagnosis of DADA2. Molecular diagnosis was important to accurately identify other family members at risk.\nMETHODS: We used a variety of sequencing technologies, ADA2 enzymatic testing, and molecular methods including qRT-PCR and MLPA.\nRESULTS: Exome sequencing identified heterozygosity for the known pathogenic variant ADA2: c.1358A>G, p.Tyr453Cys in a 14-year-old female with a history of ischemic strokes, livedo, and vasculitis. No second pathogenic variant could be identified. ADA2 enzymatic testing in combination with quantitative RT-PCR suggested a loss-of-function allele. Subsequent genome sequencing identified a canonical splice site variant, c.-47+2T>C, within the 5'UTR of ADA2. Two of her unaffected siblings were found to carry the same two pathogenic variants. A homozygous 800-bp duplication comprising exon 7 of ADA2 was identified in a 5-year-old female with features consistent with Diamond-Blackfan anemia (DBA). The duplication was missed by Sanger sequencing of ADA2, chromosomal microarray, and exome sequencing but was detected by MLPA in combination with long-read PCR sequencing. The exon 7 duplication was also identified in her non-symptomatic father and younger sister.\nCONCLUSIONS: ADA2 pathogenic variants may not be detected by conventional sequencing and genetic testing and may require the incorporation of additional diagnostic methods. A definitive molecular diagnosis is crucial for all family members to make informed treatment decisions.","variants":[{"Name":"NM_001282225.2(ADA2):c.-47+2T>C","Chromosome":"22","Start":"17219354","Stop":"17219354","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2523737,"rule_based_match":true,"evidence_text":"c.-47+2T>C","llm_judgment":"PRESENT","evidence":"c.-47+2T>C","abstract_start":1054,"abstract_end":1064}]}
{"pmid":"30165711","title":"Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development.","abstract":"Mutations in <i>SCN2A</i> are associated with a heterogeneous clinical spectrum including epilepsy and autism. Here, we have identified a peculiar phenotype associated with vaccination related exacerbations of ataxia. We report the first family with three individuals affected by <i>SCN2A</i>-associated episodic ataxia (EA) with impaired speech development. The index patient manifested his first episode of subacute cerebellar ataxia at the age of 12 months, 3 weeks after vaccinations for measles, mumps, rubella, and varicella. Cranial magnetic resonance imaging showed a lesion of the left cerebellar hemisphere, which was first considered as a potential cause of the ataxia. The patient fully recovered within 3 weeks, but developed three very similar episodes of transient ataxia within the following 24 months. Whole exome sequencing of the index patient revealed a heterozygous autosomal-dominant mutation in <i>SCN2A</i> (NM_021007, c.4949T > C; p.L1650P), which was confirmed in the likewise affected mother, and was then also identified in the younger brother who developed the first episode of ataxia. We hereby extend the recently described spectrum of <i>SCN2A</i>-associated neurologic disorders, emphasizing that <i>SCN2A</i> mutations should also be considered in familial cases of EA. Coincidental imaging findings or other associated events such as immunizations should not protract genetic investigations.","variants":[{"Name":"NM_001040142.2(SCN2A):c.4949T>C (p.Leu1650Pro)","Chromosome":"2","Start":"165388755","Stop":"165388755","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":859024,"rule_based_match":true,"evidence_text":"NM_021007, c.4949T > C; p.L1650P","llm_judgment":"PRESENT","evidence":"NM_021007, c.4949T > C; p.L1650P","abstract_start":932,"abstract_end":964}]}
{"pmid":"23668869","title":"Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1.","abstract":"Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans. NF1 is caused by mutations of the NF1 gene. Mutation detection is complex owing to the large size of the NF1 gene, the presence of pseudogenes, and the great variety of mutations. Also, few probable genotype-phenotype correlations have been found in NF1. In this study 78 Korean patients from 60 families were screened for NF1 mutations. Mutation analysis of the entire coding region and flanking splice sites was carried out and included the use of a combination of reverse transcription polymerase chain reaction, multiplex ligation probe amplification, or fluorescence in situ hybridization. Mutation spectrum and genotype-phenotype relationship were assessed. Fifty-two distinct NF1 mutations were identified in 60 families. The mutations included 30 single base substitutions (12 missense and 18 nonsense), 11 missplicing mutations, seven small insertion or deletions, and four gross deletions. Sixteen (30.8%) mutations were novel; c.1A>G, c.2033_2034insC, c.2540T>C, c.4537C>T, c.5546G>A, c.6792C>A, and c.6792C>G were recurrently identified. The mutations were evenly distributed across exon 1 through intron 47 of NF1, and no mutational hot spots were found. A genotype-phenotype analysis suggests that there is no clear relationship between specific mutations and clinical features. This analysis revealed a wide spectrum of NF1 mutations in Korean patients. As technologies advance in molecular genetics, the mutation detection rate will increase. Considering that 30.8% of detected mutations were novel, exhaustive mutation analysis of NF1 may be an important tool in early diagnosis and genetic counseling.","variants":[{"Name":"NM_001042492.3(NF1):c.1A>G (p.Met1Val)","Chromosome":"17","Start":"31095310","Stop":"31095310","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":401594,"rule_based_match":true,"evidence_text":"c.1A>G","llm_judgment":"PRESENT","evidence":"c.1A>G","abstract_start":1035,"abstract_end":1041},{"Name":"NM_001042492.3(NF1):c.2540T>C (p.Leu847Pro)","Chromosome":"17","Start":"31229155","Stop":"31229155","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":79214,"rule_based_match":true,"evidence_text":"c.2540T>C","llm_judgment":"PRESENT","evidence":"c.2540T>C","abstract_start":1060,"abstract_end":1069}]}
{"pmid":"32243914","title":"Cellular analysis of a novel mutation p. Ser287Tyr in TOR1A in late-onset isolated dystonia.","abstract":"BACKGROUND: Variations in TOR1A were thought to be associated with early-onset isolated dystonia. The variant S287Y (NM_000113.2: c.860C > A, p. Ser287Tyr, rs766483672) was found in our late-onset isolated dystonia patient. This missense variant is adjacent to R288Q (c.863G > A, p. Arg288Gln), which was reported to be associated with isolated dystonia. The potentially pathogenic role of S287Y is not conclusively known.\nMETHODS: Cytological and molecular biological analyses were performed in vitro to determine whether this variant damages the structure and function of the cell.\nRESULTS: Compared with the SH-SY5Y cells overexpressing wild-type TOR1A, the cells overexpressing the protein with S287Y have an enlarged peri-nuclear space. The same changes in nuclear morphology were also found in the cells overexpressing the pathogenic variants ΔE (NM_000113.2:c.904_906delGAG, p. Glu302del), F205I (NM_000113.2:c.613 T > A, p. Phe205Ile), and R288Q (NM_000113.2:c.863G > A, p. Arg288Gln). Mutated proteins with S287Y presented a higher tendency to form dimers under reducing conditions. The same tendencies were observed in other mutated proteins but not in wild-type torsinA.\nCONCLUSIONS: TorsinA with S287Y damages the structure of the cell nucleus and may be a novel pathogenic mutation that causes isolated dystonia.","variants":[{"Name":"NM_000113.3(TOR1A):c.863G>A (p.Arg288Gln)","Chromosome":"9","Start":"129814108","Stop":"129814108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":172165,"rule_based_match":true,"evidence_text":"c.863G > A, p. Arg288Gln","llm_judgment":"PRESENT","evidence":"c.863G > A, p. Arg288Gln","abstract_start":268,"abstract_end":292}]}
{"pmid":"33453710","title":"Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia","abstract":"Background/aim: Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl- CoA mutase (mut0 or mut– enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort.\nMaterials and methods: The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT, MMAA, MMAB, MMADHC, MCEE genes. Mutation screening identified 30 different types of mutations.\nResults: While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure.\nConclusion: We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.","variants":[{"Name":"NM_172250.3(MMAA):c.1145del (p.His382fs)","Chromosome":"4","Start":"145655322","Stop":"145655322","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":2863448,"rule_based_match":true,"evidence_text":"c.1145delA","llm_judgment":"PRESENT","evidence":"c.1145delA","abstract_start":1314,"abstract_end":1324}]}
{"pmid":"34660840","title":"Novel","abstract":"D-bifunctional protein (DBP) deficiency is a peroxisomal disorder with a high degree of phenotypic heterogeneity. Some patients with DBP deficiency develop progressive leukodystrophy in childhood. We report a 6-year-old boy with moderate hearing loss who presented with developmental regression. Brain magnetic resonance imaging demonstrated progressive leukodystrophy. However, very long chain fatty acids (VLCFAs) in the plasma were at normal levels. Whole-exome sequencing revealed compound heterozygous variants in <i>HSD17B4</i> (NM_000414.3:c.[350A > T];[394C > T], p.[[Asp117Val]];[[Arg132Trp]]). The c.394C > T variant has been identified in patients with DBP deficiency and is classified as likely pathogenic, while the c.350A > T variant was novel and classified as uncertain significance. Although one of the two variants was classified as uncertain significance, an accumulation of phytanic and pristanic acids was identified in the patient, confirming type III DBP deficiency. DBP deficiency should be considered as a diagnosis in children with progressive leukodystrophy and hearing loss even if VLCFAs are within normal levels.","variants":[{"Name":"NM_000414.4(HSD17B4):c.394C>T (p.Arg132Trp)","Chromosome":"5","Start":"119477461","Stop":"119477461","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":543647,"rule_based_match":true,"evidence_text":"c.394C > T","llm_judgment":"PRESENT","evidence":"c.394C > T","abstract_start":608,"abstract_end":618}]}
{"pmid":"36651622","title":"Common pathophysiology for ANXA11 disorders caused by aspartate 40 variants.","abstract":"OBJECTIVE: Mutations in ANXA11 cause amyotrophic lateral sclerosis (ALS) and have recently been identified as a cause of multisystem proteinopathy and adult-onset muscular dystrophy. These conditions are adult-onset diseases and result from the substitution of Aspartate 40 (Asp40) for an apolar residue in the intrinsically disordered domain (IDD) of ANXA11. Some ALS-related variants are known to affect ANXA11 IDD; however, the mechanism by which the myopathy occurs is unknown.\nMETHODS: Genetic analysis was performed using WES-trio. For the study of variant pathogenicity, we used recombinant proteins, muscle biopsy, and fibroblasts.\nRESULTS: Here we describe an individual with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy who carries a new ANXA11 variant at position Asp40 (p.Asp40Ile; c.118_119delGAinsAT). p.Asp40Ile is predicted to enhance the aggregation propensity of ANXA11 to a greater extent than other changes affecting this residue. In vitro studies using recombinant ANXA11<sup>p.Asp40Ile</sup> showed abnormal phase separation and confirmed this variant is more aggregation-prone than the ALS-associated variant ANXA11<sup>p.Asp40Gly</sup> . The study of the patient's fibroblasts revealed defects in stress granules dynamics and clearance, and muscle histopathology showed a myopathic pattern with ANXA11 protein aggregates. Super-resolution imaging showed aggregates expressed as pearl strips or large complex structures in the sarcoplasm, and as layered subsarcolemmal chains probably reflecting ANXA11 multifunctionality.\nINTERPRETATION: We demonstrate common pathophysiology for disorders associated with ANXA11 Asp40 allelic variants. Clinical phenotypes may result from different deleterious impacts of variants upon ANXA11 stability against aggregation, and differential muscle or motor neuron dysfunction expressed as a temporal and tissue-specific continuum.","variants":[{"Name":"NM_145868.2(ANXA11):c.118_119delinsAT (p.Asp40Ile)","Chromosome":"10","Start":"80170852","Stop":"80170853","ReferenceAlleleVCF":"TC","AlternateAlleleVCF":"AT","allel_id":2418185,"rule_based_match":false,"evidence_text":"c.118_119delGAinsAT","llm_judgment":"PRESENT","evidence":"c.118_119delGAinsAT","abstract_start":831,"abstract_end":850}]}
{"pmid":"25274842","title":"HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum.","abstract":"OBJECTIVES: To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies.\nMETHODS: Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization.\nRESULTS: We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population.\nCONCLUSIONS: Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies.","variants":[{"Name":"NM_006736.6(DNAJB2):c.229+1G>A","Chromosome":"2","Start":"219281772","Stop":"219281772","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":181182,"rule_based_match":true,"evidence_text":"c.229+1G>A","llm_judgment":"PRESENT","evidence":"c.229+1G>A","abstract_start":668,"abstract_end":678},{"Name":"NM_006736.6(DNAJB2):c.14A>G (p.Tyr5Cys)","Chromosome":"2","Start":"219279847","Stop":"219279847","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":181183,"rule_based_match":true,"evidence_text":"c.14A>G (p.Tyr5Cys)","llm_judgment":"PRESENT","evidence":"c.14A>G (p.Tyr5Cys)","abstract_start":894,"abstract_end":913}]}
{"pmid":"31173493","title":"A novel mutation in the GARS gene in a Malian family with Charcot-Marie-Tooth disease.","abstract":"BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a very heterogeneous neurological condition with more than 90 reported genetic entities. It is the most common inherited peripheral neuropathy; however, cases are rarely reported in sub-Saharan Africa. In addition, only few families, mostly of Caucasian ancestry, have been reported to have Charcot-Marie-Tooth disease type 2D (CMT2D) mutations. To date no case of CMT2D was reported in Africa. We present here a consanguineous family with CMT phenotype in which a novel mutation in the GARS (glycyl-tRNA synthetase) gene was identified.\nMETHODS: Patients were examined thoroughly and nerve conduction studies (NCS) were performed. DNA from the proband was used for CMT gene panel testing (including 50 genes, PMP22 duplication and mtDNA). Putative mutations were verified in all available family members to check for segregation.\nRESULTS: Two individuals, a male and a female, were found to be affected. Symptoms started in their teenage years with muscle weakness and atrophy in hands. Later, distal involvement of the lower limbs was noticed. Patients complained of minor sensory impairment. NCS showed no response in the upper as well as the lower limbs. Genetic testing surprisingly identified a novel heterozygous missense mutation c.794C>A (p.Ser265Tyr) in the GARS gene associated with CMT2D. This variant segregated with the disease in the family and was also seen in the mother who presented no symptoms.\nCONCLUSION: This is the first report of a genetically confirmed CMT2D case in Africa, expanding its genetic epidemiology. Increasing access to genetic testing may reveal more novel CMT variants or genes in the African population that could be relevant to other populations and further our understanding of their mechanism.","variants":[{"Name":"NM_002047.4(GARS1):c.794C>A (p.Ser265Tyr)","Chromosome":"7","Start":"30609643","Stop":"30609643","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":973006,"rule_based_match":true,"evidence_text":"c.794C>A (p.Ser265Tyr)","llm_judgment":"PRESENT","evidence":"c.794C>A (p.Ser265Tyr)","abstract_start":1287,"abstract_end":1309}]}
{"pmid":"24651309","title":"Mutations in pseudohypoparathyroidism 1a and pseudopseudohypoparathyroidism in ethnic Chinese.","abstract":"An inactivating mutation in the GNAS gene causes either pseudohypoparathyroidism 1a (PHP1A) when it is maternally inherited or pseudopseudohypoparathyroidism (PPHP) when it is paternally inherited. We investigated clinical manifestations and mutations of the GNAS gene in ethnic Chinese patients with PHP1A or PPHP. Seven patients from 5 families including 4 girls and 2 boys with PHP1A and 1 girl with PPHP were studied. All PHP1A patients had mental retardation. They were treated with calcitriol and CaCO3 with regular monitoring of serum Ca levels, urinary Ca/Cr ratios, and renal sonography. Among them, 5 patients also had primary hypothyroidism suggesting TSH resistance. One female patient had a renal stone which was treated with extracorporeal shockwave lithotripsy. She had an increased urinary Ca/Cr ratio of 0.481 mg/mg when the stone was detected. We detected mutations using PCR and sequencing as well as analysed a splice acceptor site mutation using RT-PCR, sequencing, and minigene construct. We detected 5 mutations: c.85C>T (Q29*), c.103C>T (Q35*), c.840-2A>G (R280Sfs*21), c.1027_1028delGA (D343*), and c.1174G>A (E392K). Mutations c.840-2A>G and c.1027_1028delGA were novel. The c.840-2A>G mutation at the splice acceptor site of intron 10 caused retention of intron 10 in the minigene construct but skipping of exon 11 in the peripheral blood cells. The latter was the most probable mechanism which caused a frameshift, changing Arg to Ser at residue 280 and invoking a premature termination of translation at codon 300 (R280Sfs*21). Five GNAS mutations in ethnic Chinese with PHP1A and PPHP were reported. Two of them were novel. Mutation c.840-2A>G destroyed a spice acceptor site and caused exon skipping. Regular monitoring and adjustment in therapy are mandatory to achieve optimal therapeutic effects and avoid nephrolithiasis in patients with PHP1A.","variants":[{"Name":"NM_000516.7(GNAS):c.1174G>A (p.Glu392Lys)","Chromosome":"20","Start":"58910818","Stop":"58910818","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38702,"rule_based_match":true,"evidence_text":"c.1174G>A (E392K)","llm_judgment":"PRESENT","evidence":"c.1174G>A (E392K)","abstract_start":1124,"abstract_end":1141},{"Name":"NM_000516.7(GNAS):c.103C>T (p.Gln35Ter)","Chromosome":"20","Start":"58891829","Stop":"58891829","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":974202,"rule_based_match":true,"evidence_text":"c.103C>T (Q35*)","llm_judgment":"PRESENT","evidence":"c.103C>T (Q35*)","abstract_start":1052,"abstract_end":1067}]}
{"pmid":"35016464","title":"Familial amyotrophic lateral sclerosis induced by gene mutation of SOD1G142A: a case report.","abstract":"Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving both upper and lower motor neurons. The total prevalence of ALS is [2-9]/100,000, with an annual incidence rate of 3/100,000. The disease progresses rapidly and clinically is considered to be progressive degeneration of the upper and lower motor neurons. Although this is a kind of rare disease, the mortality is high once it occurs, which has a great impact on patients and their families. Currently there is no treatment for either the sporadic or familial form. Therefore, it is of great significance to explore the diagnosis and treatment of familial amyotrophic lateral sclerosis (FALS). We report the diagnosis and treatment of a patient with familial ALS caused by mutation of the Cu/Zn superoxide dismutase (SOD1) gene c.425g > C (p.g142a), which is considered rare. We got to know that genetic testing of the patient and his immediate family members assisted in diagnosis and palliative care. Edaravone and Riluzole were used in this case according to the guideline in this case. The progress of the disease was alleviated and the survival experience of patients improved because of this medication administration. The aim of this case report is to provide a reference for the diagnosis and treatment strategy in FALS. What's more, further exploration of treatment using integrated traditional Chinese and Western medicine to delay the disease process has great significance for improved patient outcomes.","variants":[{"Name":"NM_000454.5(SOD1):c.425G>C (p.Gly142Ala)","Chromosome":"21","Start":"31668538","Stop":"31668538","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2408839,"rule_based_match":true,"evidence_text":"c.425g > C (p.g142a)","llm_judgment":"PRESENT","evidence":"c.425g > C (p.g142a)","abstract_start":804,"abstract_end":824}]}
{"pmid":"23504403","title":"Contribution of GJB2 mutations to hearing loss in the Hazara Division of Pakistan.","abstract":"Mutations of GJB2, which encodes connexin 26, are the most common cause of hereditary hearing loss in many human populations. This study was initiated to determine the prevalence of GJB2 mutations in individuals with hearing loss from the Hazara Division in Pakistan. We recruited 70 participants with nonsyndromic deafness segregating as an apparently recessive trait and directly sequenced the GJB2 coding region from their DNA. The homozygous mutations c.71 G → A (p.W24X), c.104 T → G (p.I35S), and c.35delG (p.G12VfsX1) were identified as the cause of hearing loss in three participants (4.28%); in populations from other areas of Pakistan, frequencies of 6-7% have been observed. The mutations c.104 T → G and c.35delG were identified in Pakistan for the first time. These results confirm the low prevalence of GJB2 mutations in Hazara and suggest that mutations in other genes may play a significant role in the etiology of deafness in this population.","variants":[{"Name":"NM_004004.6(GJB2):c.104T>G (p.Ile35Ser)","Chromosome":"13","Start":"20189478","Stop":"20189478","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1177704,"rule_based_match":false,"evidence_text":"c.104 T → G (p.I35S)","llm_judgment":"PRESENT","evidence":"c.104 T → G (p.I35S)","abstract_start":477,"abstract_end":497},{"Name":"NM_004004.6(GJB2):c.71G>A (p.Trp24Ter)","Chromosome":"13","Start":"20189511","Stop":"20189511","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32041,"rule_based_match":false,"evidence_text":"c.71 G → A (p.W24X)","llm_judgment":"PRESENT","evidence":"c.71 G → A (p.W24X)","abstract_start":456,"abstract_end":475}]}
{"pmid":"32894085","title":"Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco.","abstract":"BACKGROUND: To date, the contribution of BRCA1/2 mutations in Moroccan early onset breast cancer patients remains unknown. Here we assess these genetic alterations for the first time in a cohort from North of Morocco.\nMETHODS: Thirty-three patients diagnosed with breast cancer at the age of ≤40 years were recruited irrespective of breast and/or ovarian cancer family history. Coding regions and intron-exon boundaries of BRCA1 and BRCA2 genes were sequenced from peripheral blood DNA using Ion Proton (Thermo Fisher Scientific) next generation sequencing platform.\nRESULTS: Overall, five BRCA germline mutations were identified (15.1%). The frequency of mutations among patients with family history of breast cancer was 16.7%. Three mutations were found in BRCA1 (9%) and two within the BRCA2 gene (6%). These are three frameshift mutations (c.798_799del, c.2125_2126insA, c.5116_5119delAATA), one missense (c.116G > A) and one nonsense mutation (c.289G > T). The mutation c.5116_5119delAATA has a founder effect in North Africa. Moreover, one variant of unknown significance was identified in BRCA2 (c.4090A > G). Most BRCA mutations carriers (80%) had no family history of breast cancer.\nCONCLUSION: Our data do not support the hypothesis that BRCA mutations alone explain the higher frequency of breast cancer in Moroccan young women. The young age (≤40 years) for breast cancer diagnosis seems to be strongly predictive of BRCA mutation status in Moroccan patients. These results will help in decision making with regard to genetic counseling and testing in the national scale.","variants":[{"Name":"NM_007294.4(BRCA1):c.116G>A (p.Cys39Tyr)","Chromosome":"17","Start":"43115744","Stop":"43115744","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45948,"rule_based_match":true,"evidence_text":"c.116G > A","llm_judgment":"PRESENT","evidence":"c.116G > A","abstract_start":910,"abstract_end":920}]}
{"pmid":"16497572","title":"SLOS carrier frequency in Poland as determined by screening for Trp151X and Val326Leu DHCR7 mutations.","abstract":"Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations in the DHCR7 gene. Previous studies estimated the prevalence of SLOS between 1 in 10,000 to 1 in 70,358 based on case frequency surveys. Although panethnic, SLOS appears to be most frequent in Central European populations (Czech Republic 1 in 10,000, Slovakia 1 in 15,000 - 1 in 20,000). In Polish individuals with SLOS two DHCR7 mutations, c.452G>A (p.Trp151X) and c.976G>T (p.Val326Leu), account for 65.2% of all observed DHCR7 mutations. We analyzed 2169 samples for the p.Trp151X mutation and 2087 for the p.Val326Leu mutation. The combined carrier frequency of these two mutations of was 2.40+/-0.32%, yielding a calculated incidence of SLOS in Poland of 2.5 4x10(-4)-4.3 5x10(-4) (1 in 2,300 to 1 in 3,937) placing SLOS among the most common recessive genetic disorders in Poland.","variants":[{"Name":"NM_001360.3(DHCR7):c.452G>A (p.Trp151Ter)","Chromosome":"11","Start":"71441401","Stop":"71441401","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34125,"rule_based_match":true,"evidence_text":"c.452G>A (p.Trp151X)","llm_judgment":"PRESENT","evidence":"c.452G>A (p.Trp151X)","abstract_start":458,"abstract_end":478}]}
{"pmid":"20585803","title":"Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): case report with a new mutation.","abstract":"INTRODUCTION: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystem disorder characterized by severe gastrointestinal dysmotility and leads to cachexia, ptosis, external ophthalmoplegia, peripheral neuropathy, and leukoencephalopathy.\nRESULTS AND DISCUSSION: It is often misdiagnosed as anorexia nervosa or intestinal pseudoobstuctions and are unnecessarily treated with surgery. It has been established that MNGIE is caused by mutations in the gene encoding thymidine phosphorylase, which lead to absolute or nearly complete loss of its catalytic activity, producing systemic accumulations of its substrates, thymidine and deoxyuridine.\nCONCLUSION: We present herein the clinical, neuroimaging, and molecular findings of a patient with MNGIE caused by a novel homozygous TYMP gene mutation (c.112G>T which convert codon 38 from glutamate to a stop codon [p.38E>X]).","variants":[{"Name":"NM_001953.5(TYMP):c.112G>T (p.Glu38Ter)","Chromosome":"22","Start":"50529598","Stop":"50529598","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":224739,"rule_based_match":true,"evidence_text":"c.112G>T","llm_judgment":"PRESENT","evidence":"c.112G>T","abstract_start":842,"abstract_end":850}]}
{"pmid":"23109149","title":"DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy.","abstract":"OBJECTIVE: Congenital disorders of glycosylation (CDG) are a group of metabolic diseases due to defects in protein and lipid glycosylation. We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome. There was clinical evidence of a muscular dystrophy-dystroglycanopathy syndrome, supported by deficient O-mannosylation by muscle immunohistochemistry.\nMETHODS: Biochemical and molecular methods were combined to pinpoint the defect in the glycosylation pathway in the endoplasmic reticulum.\nRESULTS: Metabolic investigations revealed CDG-I, pointing to a defect in protein N-glycosylation in the endoplasmic reticulum. Analysis of lipid-linked oligosaccharides in fibroblasts showed accumulation of Dol-PP-GlcNAc(2) -Man(5) . DNA analysis revealed mutations in DPM2, 1 of the subunits of the dolichol-phosphate-mannose (DPM) synthase; the patient in the first family is compound heterozygous for 2 mutations (c.68A>G, predicting a missense mutation p.Y23C and c.4-1G>C, a splice mutation), whereas the patients in the second family are homozygous for the same missense mutation (c.68A>G, p.Y23C).\nINTERPRETATION: We describe a new CDG, due to a deficiency of DPM2. Hence, mutations have now been described in the genes for the 3 subunits of DPM: DPM1, DPM2, and DPM3, whereby DPM2-CDG links the congenital disorders of glycosylation to the congenital muscular dystrophies.","variants":[{"Name":"NM_003863.4(DPM2):c.68A>G (p.Tyr23Cys)","Chromosome":"9","Start":"127937459","Stop":"127937459","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":48045,"rule_based_match":true,"evidence_text":"c.68A>G","llm_judgment":"PRESENT","evidence":"c.68A>G","abstract_start":1126,"abstract_end":1133}]}
{"pmid":"28540413","title":"A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.","abstract":"Congenital myopathies are a heterogeneous group of muscle disorders that are often genetically determined. Here, we investigated a boy with congenital myopathy, deafness, and neuropathy from a consanguineous Kurdish family by autozygosity mapping and whole exome sequencing. We found a homozygous nonsense mutation in SPTBN4 [c.1597C>T, NM_020971.2; p.(Q533*), NP_066022.2; ClinVar SUB2292235] encoding βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Western blot confirmed the absence of the full-length 288 kDa isoform in muscle and of a specific 72 kDa isoform in fibroblasts. Clinical symptoms of the patient largely corresponded to those described for the quivering mouse, a loss-of-function animal model. Since the human phenotype of βIV-spectrin deficiency included a myopathy with incomplete congenital fiber-type disproportion, we investigated muscle of the quivering (qv4J) mouse and found complete absence of type 1 fibers (fiber-type 2 uniformity). Immunohistology confirmed expression of βIV-spectrin in normal human and mouse muscle at the sarcolemma and its absence in patient and quivering (qv4J) mouse. SPTBN4 mRNA-expression levels in healthy skeletal muscle were found in the range of other regulatory proteins. More patients have to be described to confirm the triad of congenital myopathy, neuropathy and deafness as the defining symptom complex for βIV-spectrin deficiency.","variants":[{"Name":"NM_020971.3(SPTBN4):c.1597C>T (p.Gln533Ter)","Chromosome":"19","Start":"40504064","Stop":"40504064","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":361955,"rule_based_match":true,"evidence_text":"c.1597C>T","llm_judgment":"PRESENT","evidence":"c.1597C>T","abstract_start":326,"abstract_end":335}]}
{"pmid":"22125116","title":"Identification and functional characterization of two novel mutations in the α-helical loop (residues 484-503) of CYBB/gp91(phox)  resulting in the rare X91(+)  variant of chronic granulomatous disease.","abstract":"Chronic granulomatous disease (CGD) is mainly caused by mutations in X-linked CYBB that encodes gp91. We have identified two novel mutations in CYBB resulting in the rare X91(+)-CGD variant, c.1500T>G (p.Asp500Glu) in two male siblings and c.1463C>A (p.Ala488Asp) in an unrelated male. Zymosan and/or PMA (Phorbol 12-myristate 13-acetate)-induced recruitment of p47(phox) and p67(phox) to the membrane fraction was normal for both mutants. Cell-free assays using recombinant wild-type and the mutant proteins revealed that these mutants were not activated by NADPH (nicotinamide adenine dinucleotide phosphate). Interestingly, the Ala488Asp mutant was activated by NADPH in the presence of glutathione. These data suggest that the mutations prevented NADPH from binding to gp91(phox) and the requirement of a negative charge at residue 500 in gp91(phox) for NADPH oxidase assembly, in contrast to a previously described Asp500Gly change. These mutations and the effect of glutathione provide a unique insight into disease pathogenesis and potential therapy in variant X91(+)-CGD.","variants":[{"Name":"NM_000397.4(CYBB):c.1500T>G (p.Asp500Glu)","Chromosome":"X","Start":"37809605","Stop":"37809605","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1878219,"rule_based_match":true,"evidence_text":"c.1500T>G (p.Asp500Glu)","llm_judgment":"PRESENT","evidence":"c.1500T>G (p.Asp500Glu)","abstract_start":191,"abstract_end":214}]}
{"pmid":"32257295","title":"Novel","abstract":"We encountered a patient with mitochondrial trifunctional protein deficiency in whom the corresponding mutations were not identified by a DNA panel for newborn screening for targeted diseases. After diagnosis confirmation by an enzyme assay and immunoblotting using the autopsied liver, the re-evaluation of the panel data indicated a heterozygous deletion of exons 6-9 that was later confirmed at the genomic level. cDNA analysis also identified exonization of the 5' region of intron 9 caused by a deep intronic mutation, c.811 + 82A>G.","variants":[{"Name":"NM_000183.3(HADHB):c.811+82A>G","Chromosome":"2","Start":"26279397","Stop":"26279397","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2834418,"rule_based_match":true,"evidence_text":"c.811 + 82A>G","llm_judgment":"PRESENT","evidence":"c.811 + 82A>G","abstract_start":524,"abstract_end":537}]}
{"pmid":"32618121","title":"A homozygous variant in growth and differentiation factor 2 (GDF2) may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis.","abstract":"The etiology of nonimmune hydrops fetalis is extensive and includes genetic disorders. We describe a term-born female neonate with late onset extensive nonimmune hydrops, that is, polyhydramnios, edema, and congenital bilateral chylothorax. This newborn was successfully treated with repetitive thoracocentesis, total parenteral feeding, octreotide intravenously and finally surgical pleurodesis and corticosteroids. A genetic cause seemed plausible as the maternal history revealed a fatal nonimmune hydrops fetalis. A homozygous truncating variant in GDF2 (c.451C>T, p.(Arg151*)) was detected with exome sequencing. Genetic analysis of tissue obtained from the deceased fetal sibling revealed the same homozygous variant. The parents and two healthy siblings were heterozygous for the GDF2 variant. Skin and lung biopsies in the index patient, as well as the revised lung biopsy of the deceased fetal sibling, showed lymphatic dysplasia and lymphangiectasia. To the best of our knowledge, this is the first report of an association between a homozygous variant in GDF2 with lymphatic dysplasia, hydrothorax and nonimmune hydrops fetalis.","variants":[{"Name":"NM_016204.4(GDF2):c.451C>T (p.Arg151Ter)","Chromosome":"10","Start":"47324945","Stop":"47324945","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2776584,"rule_based_match":true,"evidence_text":"c.451C>T, p.(Arg151*)","llm_judgment":"PRESENT","evidence":"c.451C>T, p.(Arg151*)","abstract_start":559,"abstract_end":580}]}
{"pmid":"33724725","title":"Recessive multiple epiphyseal dysplasia and Stargardt disease in two sisters.","abstract":"BACKGROUND: The rapid spread of genome-wide next-generation sequencing in the molecular diagnosis of rare genetic disorders has produced increasing evidence of multilocus genomic variations in cases with a previously well-characterized molecular diagnosis. Here, we describe two patients with a rare combination of skeletal abnormalities and retinal dystrophy caused by variants in the SLC26A2 and ABCA4 genes, respectively, in a family with parental consanguinity.\nMETHODS: Next-generation sequencing and Sanger sequencing were performed to obtain a molecular diagnosis for the retinal and skeletal phenotypes, respectively.\nRESULTS: Genetic testing revealed that the sisters were homozygous for the p.(Cys653Ser) variant in SLC26A2 and heterozygous for the missense p.(Pro68Leu) and splice donor c.6386+2C>G variants in ABCA4. Segregation analysis confirmed the carrier status of the parents.\nCONCLUSION: Despite low frequency of occurrence, the detection of multilocus genomic variations in a single disease gene-oriented approach can provide accurate diagnosis even in cases with high phenotypic complexity. A targeted sequencing approach can detect relationships between observed phenotypes and underlying genotypes, useful for clinical management.","variants":[{"Name":"NM_000350.3(ABCA4):c.6386+2C>G","Chromosome":"1","Start":"94001000","Stop":"94001000","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":105345,"rule_based_match":true,"evidence_text":"c.6386+2C>G","llm_judgment":"PRESENT","evidence":"c.6386+2C>G","abstract_start":798,"abstract_end":809},{"Name":"NM_000350.3(ABCA4):c.203C>T (p.Pro68Leu)","Chromosome":"1","Start":"94111537","Stop":"94111537","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":105002,"rule_based_match":false,"evidence_text":"c.203C>T (p.Pro68Leu)","llm_judgment":"PRESENT","evidence":"c.203C>T (p.Pro68Leu)","abstract_start":null,"abstract_end":null}]}
{"pmid":"19206176","title":"Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism.","abstract":"Costello syndrome is a rare congenital anomaly syndrome associated with mental retardation and predisposition to benign and malignant tumors, caused by heterozygous missense mutations in the HRAS oncogene. Previously, all molecularly analyzed mutations appeared de novo, and most arose in the paternal germline. A single patient with somatic mosaicism for a Costello syndrome causing HRAS mutation has been reported. Here we describe the first documented transmission of an HRAS mutation from a parent with somatic mosaicism to a child with typical Costello syndrome. Prior to the identification of the underlying gene mutation in Costello syndrome, this family had been identified clinically. The proband was subsequently found to carry a G12S HRAS germline mutation. Testing of the parents for parental origin identified his father as mosaic for the same HRAS mutation. The mother was found not to carry an HRAS mutation. The causative familial mutation is identified as a c.34G > A, which is the most common mutation in the HRAS gene in patients with Costello syndrome. The father carries the mutation in 7-8% of his alleles. This is the second case of mosaicism observed in Costello syndrome and the first direct molecular evidence of father-to-son transmission of the disease-causing mutation. Our observation underlines the importance of parental evaluation, and may have implications for genetic counseling and clinical practice.","variants":[{"Name":"NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)","Chromosome":"11","Start":"534289","Stop":"534289","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27641,"rule_based_match":true,"evidence_text":"c.34G > A","llm_judgment":"PRESENT","evidence":"c.34G > A","abstract_start":975,"abstract_end":984}]}
{"pmid":"32603605","title":"","abstract":"BACKGROUND: Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disease characterized by progressive ventricular enlargement and reduced systolic function. Here, we report genetic and functional analyses implicating the rat sarcoma signaling protein, SOS1 (Son of sevenless homolog 1), in DCM pathogenesis.\nMETHODS: Exome sequencing was performed on 412 probands and family members from our DCM cohort, identifying several <i>SOS1</i> variants with potential disease involvement. As several lines of evidence have implicated dysregulated rat sarcoma signaling in the pathogenesis of DCM, we assessed functional impact of each variant on the activation of ERK (extracellular signal-regulated kinase), AKT (protein kinase B), and JNK (c-Jun N-terminal kinase) pathways. Relative expression levels were determined by Western blot in HEK293T cells transfected with variant or wild-type human <i>SOS1</i> expression constructs.\nRESULTS: A rare <i>SOS1</i> variant [c.571G>A, p.(Glu191Lys)] was found to segregate alongside an A-band <i>TTN</i> truncating variant in a pedigree with aggressive, early-onset DCM. Reduced disease severity in the absence of the <i>SOS1</i> variant suggested its potential involvement as a genetic risk factor for DCM in this family. Exome sequencing identified 5 additional <i>SOS1</i> variants with potential disease involvement in 4 other families [c.1820T>C, p.(Ile607Thr); c.2156G>C, p.(Gly719Ala); c.2230A>G, p.(Arg744Gly); c.2728G>C, p.(Asp910His); c.3601C>T, p.(Arg1201Trp)]. Impacted amino acids occupied a number of functional domains relevant to SOS1 activity, including the N-terminal histone fold, as well as the C-terminal REM (rat sarcoma exchange motif), CDC25 (cell division cycle 25), and PR (proline-rich) tail domains. Increased phosphorylated ERK expression relative to wild-type levels was seen for all 6 <i>SOS1</i> variants, paralleling known disease-relevant <i>SOS1</i> signaling profiles.\nCONCLUSIONS: These data support gain-of-function variation in <i>SOS1</i> as a contributing factor to isolated DCM.","variants":[{"Name":"NM_005633.4(SOS1):c.571G>A (p.Glu191Lys)","Chromosome":"2","Start":"39054763","Stop":"39054763","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49126,"rule_based_match":true,"evidence_text":"c.571G>A, p.(Glu191Lys)","llm_judgment":"PRESENT","evidence":"c.571G>A, p.(Glu191Lys)","abstract_start":976,"abstract_end":999},{"Name":"NM_005633.4(SOS1):c.2230A>G (p.Arg744Gly)","Chromosome":"2","Start":"39012286","Stop":"39012286","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1004039,"rule_based_match":true,"evidence_text":"c.2230A>G, p.(Arg744Gly)","llm_judgment":"PRESENT","evidence":"c.2230A>G, p.(Arg744Gly)","abstract_start":1444,"abstract_end":1468},{"Name":"NM_005633.4(SOS1):c.2156G>C (p.Gly719Ala)","Chromosome":"2","Start":"39013471","Stop":"39013471","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":49168,"rule_based_match":true,"evidence_text":"c.2156G>C, p.(Gly719Ala)","llm_judgment":"PRESENT","evidence":"c.2156G>C, p.(Gly719Ala)","abstract_start":1418,"abstract_end":1442},{"Name":"NM_005633.4(SOS1):c.3601C>T (p.Arg1201Trp)","Chromosome":"2","Start":"38986225","Stop":"38986225","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":552500,"rule_based_match":true,"evidence_text":"c.3601C>T, p.(Arg1201Trp)","llm_judgment":"PRESENT","evidence":"c.3601C>T, p.(Arg1201Trp)","abstract_start":1496,"abstract_end":1521},{"Name":"NM_005633.4(SOS1):c.2728G>C (p.Asp910His)","Chromosome":"2","Start":"39006475","Stop":"39006475","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":274362,"rule_based_match":true,"evidence_text":"c.2728G>C, p.(Asp910His)","llm_judgment":"PRESENT","evidence":"c.2728G>C, p.(Asp910His)","abstract_start":1470,"abstract_end":1494},{"Name":"NM_005633.4(SOS1):c.1820T>C (p.Ile607Thr)","Chromosome":"2","Start":"39022608","Stop":"39022608","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":274364,"rule_based_match":true,"evidence_text":"c.1820T>C, p.(Ile607Thr)","llm_judgment":"PRESENT","evidence":"c.1820T>C, p.(Ile607Thr)","abstract_start":1392,"abstract_end":1416}]}
{"pmid":"24468074","title":"A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.","abstract":"BACKGROUND: We undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome.\nMETHODS: We used whole-exome sequencing to analyze two families affected with CAPOS syndrome, including the original family reported in 1996, and Sanger sequencing to assess familial segregation of rare variants identified in the probands and in a third, apparently unrelated family with CAPOS syndrome.\nRESULTS: We found an identical heterozygous missense mutation, c.2452G > A (p.(Glu818Lys)), in the Na⁺/K⁺ ATPase α₃(ATP1A3) gene in the proband and his affected sister and mother, but not in either unaffected maternal grandparent, in the first family. The same mutation was also identified in the proband and three other affected members of the second family and in all three affected members of the third family. This mutation was not found in more than 3600 chromosomes from unaffected individuals.\nCONCLUSION: Other mutations in ATP1A3 have previously been demonstrated to cause rapid-onset dystonia-parkinsonism (also called dystonia-12) or alternating hemiplegia of childhood. This study shows that an allelic mutation in ATP1A3 produces CAPOS syndrome.","variants":[{"Name":"NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys)","Chromosome":"19","Start":"41970275","Stop":"41970275","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":166024,"rule_based_match":true,"evidence_text":"c.2452G > A (p.(Glu818Lys))","llm_judgment":"PRESENT","evidence":"c.2452G > A (p.(Glu818Lys))","abstract_start":586,"abstract_end":613}]}
{"pmid":"25687216","title":"Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy.","abstract":"BACKGROUND: Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms.\nMATERIALS AND METHODS: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull's eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull's eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed.\nRESULTS: Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation.\nCONCLUSIONS: In summary, a unique case of an adult patient with bull's eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.","variants":[{"Name":"NM_015506.3(MMACHC):c.482G>A (p.Arg161Gln)","Chromosome":"1","Start":"45508848","Stop":"45508848","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16464,"rule_based_match":false,"evidence_text":"c.G482A:p.Arg161Gln","llm_judgment":"PRESENT","evidence":"c.G482A:p.Arg161Gln","abstract_start":1005,"abstract_end":1024}]}
{"pmid":"29390429","title":"New compound heterozygous variants of the cholinergic receptor nicotinic delta subunit gene in a Chinese male with congenital myasthenic syndrome: A case report.","abstract":"INTRODUCTION: Congenital myasthenic syndromes (CMS) are a group of genetic disorders that stem mostly from molecular defects in nicotinic acetylcholine receptors (AChRs). Defects in the cholinergic receptor nicotinic delta subunit (CHRND) gene can cause a series of myasthenic syndromes. Here, we report 2 new compound heterozygous variants of the CHRND gene in a Chinese male with CMS.\nCASE PRESENTATION: A 43-year-old Chinese male presented with progressive muscle weakness, difficulty chewing, and an inability to lift his head from the time he was 8 years old. He was treated with pyridostigmine, which was partially effective. Two weeks prior, he was hospitalized for dyspnea. Upon examination, he was unable to drum his cheeks and exhibited fatigable muscle weakness and facial muscle atrophy. Sequencing of his exome revealed 2 previously unreported mutations in CHRND, c.59G>A (exon2) and c.423G>C (exon5).\nCONCLUSIONS: We identified a new mutational site that contributes to the onset of CMS.","variants":[{"Name":"NM_000751.3(CHRND):c.423G>C (p.Trp141Cys)","Chromosome":"2","Start":"232528570","Stop":"232528570","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2175041,"rule_based_match":true,"evidence_text":"c.423G>C (exon5)","llm_judgment":"PRESENT","evidence":"c.423G>C (exon5)","abstract_start":897,"abstract_end":913},{"Name":"NM_000751.3(CHRND):c.59G>A (p.Trp20Ter)","Chromosome":"2","Start":"232526535","Stop":"232526535","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1903455,"rule_based_match":true,"evidence_text":"c.59G>A","llm_judgment":"PRESENT","evidence":"c.59G>A","abstract_start":877,"abstract_end":884}]}
{"pmid":"30275001","title":"Combination of exome sequencing and immune testing confirms Aicardi-Goutières syndrome type 5 in a challenging pediatric neurology case.","abstract":"Exome sequencing is increasingly being used to help diagnose pediatric neurology cases when clinical presentations are not specific. However, interpretation of equivocal results that include variants of uncertain significance remains a challenge. In those cases, follow-up testing and clinical correlation can help clarify the clinical relevance of the molecular findings. In this report, we describe the diagnostic odyssey of a 4-year-old girl who presented with global developmental delay and seizures, with leukodystrophy seen on MRI. Clinical evaluation, MRI, and comprehensive metabolic testing were performed, followed by whole-exome sequencing (WES), parental testing, follow-up testing, and retrospective detailed clinical evaluation. WES identified two candidate causative pathogenic variants in <i>SAMHD1</i>, a gene associated with the recessive condition Aicardi-Goutières syndrome (AGS) type 5 (OMIM 612952): a previously reported pathogenic variant NM_015474 c.602T>A (p.I201N), maternally inherited, and a rare missense variant of uncertain significance, c.1293A>T(p.L431F). Analysis of type I interferon-related biomarkers demonstrated that the patient has an interferon signature characteristic of AGS. Retrospective detailed clinical evaluation showed that the girl has a phenotype consistent with AGS5, a rare neurological condition. These results further define the phenotypic spectrum associated with specific <i>SAMHD1</i> variants, including heterozygous variants in AGS carriers, and support the idea that autoinflammatory dysregulation is part of the disease pathophysiology. More broadly, this work highlights the issues and methodology involved in ascribing clinical relevance to interpretation of variants detected by WES.","variants":[{"Name":"NM_015474.4(SAMHD1):c.1293A>T (p.Leu431Phe)","Chromosome":"20","Start":"36905481","Stop":"36905481","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":550312,"rule_based_match":true,"evidence_text":"c.1293A>T(p.L431F)","llm_judgment":"PRESENT","evidence":"c.1293A>T(p.L431F)","abstract_start":1070,"abstract_end":1088},{"Name":"NM_015474.4(SAMHD1):c.602T>A (p.Ile201Asn)","Chromosome":"20","Start":"36930783","Stop":"36930783","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":39562,"rule_based_match":true,"evidence_text":"NM_015474 c.602T>A (p.I201N)","llm_judgment":"PRESENT","evidence":"NM_015474 c.602T>A (p.I201N)","abstract_start":963,"abstract_end":991}]}
{"pmid":"19710410","title":"Mutations in ASCC3L1 on 2q11.2 are associated with autosomal dominant retinitis pigmentosa in a Chinese family.","abstract":"PURPOSE: To localize and identify the gene and mutations causing autosomal dominant retinitis pigmentosa in a Chinese Family.\nMETHODS: Families were ascertained and patients underwent complete ophthalmic examinations. Blood samples were collected and DNA was extracted. A linkage scan of genomic regions containing known candidate genes was performed by using 34 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and lod scores were calculated. Candidate genes were sequenced and mutations analyzed.\nRESULTS: A genome-wide scan yielded a lod score of 3.5 at theta = 0 for D2S2333 and 3.46 at theta = 0 for D2S2216. This region harbors the ASCC3L1 gene. Sequencing of ASCC3L1 in an affected family member showed a heterozygous single-base-pair change; c.3269G-->T, predicted to result in an Arg1090Leu amino acid change.\nCONCLUSIONS: The results provide strong evidence that mutations in ASCC3L1 have resulted in autosomal dominant retinitis pigmentosa in this Chinese family.","variants":[{"Name":"NM_014014.5(SNRNP200):c.3269G>T (p.Arg1090Leu)","Chromosome":"2","Start":"96287959","Stop":"96287959","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":48345,"rule_based_match":false,"evidence_text":"c.3269G-->T","llm_judgment":"PRESENT","evidence":"c.3269G-->T","abstract_start":796,"abstract_end":807}]}
{"pmid":"33576469","title":"Genotype variant screening and phenotypic analysis of","abstract":"Isolated ectopia lentis (IEL) can lead to blindness as result of severe complications, such as retinal detachment and secondary glaucoma. Pathogenic variants in the fibrillin 1 (<i>FBN1</i>) gene are a common cause of IEL. The aim of the present study was to investigate the frequency of pathogenic <i>FBN1</i> variants in twelve probands with IEL and to evaluate their associated phenotypes. Systemic clinical examination of the twelve probands indicated that all had bilateral EL with a median age at diagnosis of three years. High myopia was the most common feature among the probands (83.3%; 10/12 cases). No extraocular symptoms (either cardiovascular or skeletal) were observed among these patients. Genomic DNA was extracted from peripheral blood leukocytes from all patients for targeted exome sequencing. Seven heterozygous missense variants in <i>FBN1</i> were identified by bioinformatics analysis and further verified using Sanger sequencing. The seven variants were all classified as pathogenic after segregation analysis on available family members according to the American College of Medical Genetics and Genomics standards and guidelines. Of the seven variants, three were novel, namely c.2179T>C, c.2496T>G and c.3346G>C. The remaining four, namely c.184C>T, c.367T>C, c.1879C>T and c.4096G>A have been reported in previous studies. The seven pathogenic variants were identified in 8/12 (66.7%) probands with IEL. These results expand the variant spectrum of the <i>FBN1</i> gene as well as the understanding of the molecular pathogenesis of IEL.","variants":[{"Name":"NM_000138.5(FBN1):c.2496T>G (p.Cys832Trp)","Chromosome":"15","Start":"48495512","Stop":"48495512","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":51482,"rule_based_match":true,"evidence_text":"c.2496T>G","llm_judgment":"PRESENT","evidence":"c.2496T>G","abstract_start":1215,"abstract_end":1224}]}
{"pmid":"29503925","title":"Atypical presentation of neuronal ceroid lipofuscinosis type 8 in a sibling pair and review of the eye findings and neurological features.","abstract":"PURPOSE: To report atypical presentation of neuronal ceroid lipofuscinoses type 8 (CLN8) to the eye clinic and review clinical features of CLN8.\nOBSERVATIONS: Detailed eye exam by slit lamp exam, indirect ophthalmoscopy, fundus photography, optical coherence tomography, visual fields and electroretinogram (ERG). Molecular genetic testing using Next Generation Sequencing panel (NGS) and array Comparative Genomic Hybridization (aCGH).The siblings in this study presented to the eye clinic with retinitis pigmentosa and cystoid macular edema, and a history of seizures but no severe neurocognitive deficits or regression. Genetic testing identified a c.200C > T (p.A67V) variant in the <i>CLN8</i> gene and a deletion encompassing the entire gene. Electron microscopy of lymphocytes revealed fingerprint inclusions in both siblings.\nCONCLUSIONS: and Importance: Pathogenic variants in <i>CLN8</i> account for the retinitis pigmentosa and seizures in our patients however, currently, they do not have regression or neurocognitive decline. The presentation of NCL can be very diverse and it is important for ophthalmologists to consider this in the differential diagnosis of retinal disorders with seizures or other neurological features. Molecular genetic testing of multiple genes causing isolated and syndromic eye disorders using NGS panels and aCGH along with additional complementary testing may often be required to arrive at a definitive diagnosis.","variants":[{"Name":"NM_018941.4(CLN8):c.200C>T (p.Ala67Val)","Chromosome":"8","Start":"1771254","Stop":"1771254","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":192506,"rule_based_match":true,"evidence_text":"c.200C > T (p.A67V)","llm_judgment":"PRESENT","evidence":"c.200C > T (p.A67V)","abstract_start":652,"abstract_end":671}]}
{"pmid":"28694071","title":"First clinical and genetic description of a family diagnosed with late-onset Pompe disease from Costa Rica.","abstract":"Glycogen storage disease type II, also known as Pompe disease, is an autosomal recessive disorder caused by deficiency of enzymatic activity of acid alpha-glucosidase. The wide phenotypical variation of this disease relates to the amount of residual enzymatic activity depending on the combination of mutations on each allele. We confirmed Pompe disease in a patient that presented with progressive weakness, recurrent episodes of respiratory failure associated with pneumonia, a predominantly demyelinating mixed sensorimotor polyneuropathy and paraspinal complex repetitive discharges. Genetic analysis of the GAA gene from this patient revealed two pathogenic compound heterozygous mutations: c.-32-13T>G (rs386834236, intronic), c.2560C>T (rs121907943, p.Arg854Ter); and one variant of unknown significance: c.1551+42G>A (rs115427918, intronic). We found expected mutations in two siblings and two nieces. Genetic variants reported in this family reflect on the European and African ancestry that we carry in our Costa Rican population.","variants":[{"Name":"NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)","Chromosome":"17","Start":"80118271","Stop":"80118271","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19073,"rule_based_match":true,"evidence_text":"c.2560C>T (rs121907943, p.Arg854Ter)","llm_judgment":"PRESENT","evidence":"c.2560C>T (rs121907943, p.Arg854Ter)","abstract_start":733,"abstract_end":769},{"Name":"NM_000152.5(GAA):c.-32-13T>G","Chromosome":"17","Start":"80104542","Stop":"80104542","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":19066,"rule_based_match":true,"evidence_text":"c.-32-13T>G","llm_judgment":"PRESENT","evidence":"c.-32-13T>G","abstract_start":696,"abstract_end":707}]}
{"pmid":"34440381","title":"Clinical Characterization of Korean Patients with Pseudoxanthoma Elasticum and Angioid Streaks.","abstract":"This study aimed to characterize Korean patients with pseudoxanthoma elasticum (PXE) presenting with angioid streaks. Retinal phenotypes were longitudinally evaluated by multimodal ophthalmic imaging, and targeted gene panel sequencing for inherited retinal diseases was conducted. Seven subjects from unrelated families (median age, 51.2 years) were enrolled and followed for a median of 3.2 years. Four asymptomatic patients were significantly younger than three symptomatic patients with decreased visual acuity at presentation (mean age; 38.1 vs. 61.5 years, <i>p</i> = 0.020). The asymptomatic patients maintained good vision (20/32 or better) and had no choroidal neovascularization (CNV) over the observation period. The symptomatic patients showed additional reduction in visual acuity and bilateral CNV occurrence during the longitudinal follow-up. Pathogenic <i>ABCC6</i> variants were identified in all patients, leading to a diagnosis of PXE. Heterozygous monoallelic variants were identified in four patients and compound heterozygous variants were detected in three patients. Nine <i>ABCC6</i> variants were identified, including one novel variant, c.2035G>T [p.Glu679Ter]. This is the first genetic study of Korean patients with PXE.","variants":[{"Name":"NM_001171.6(ABCC6):c.2035G>T (p.Glu679Ter)","Chromosome":"16","Start":"16182839","Stop":"16182839","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2737522,"rule_based_match":true,"evidence_text":"c.2035G>T [p.Glu679Ter]","llm_judgment":"PRESENT","evidence":"c.2035G>T [p.Glu679Ter]","abstract_start":1163,"abstract_end":1186}]}
{"pmid":"27896549","title":"Embryonal rhabdomyosarcoma in a patient with a heterozygous frameshift variant in the DICER1 gene and additional manifestations of the DICER1 syndrome.","abstract":"Germline mutations in the DICER1 gene are associated with an inherited cancer predisposition syndrome also known as the DICER1-syndrome, which is implicated in a broad range of tumors including pleuropulmonary blastoma, ovarian Sertoli-Leydig cell tumors, ciliary body medulloepithelioma (CBME), pituitary blastoma, embryonal rhabdomyosarcoma (eRMS), anaplastic renal sarcoma as well as ocular, sinonasal tumors ovarian sex-cord tumors, thyroid neoplasia and cystic nephroma. This study describes a novel, heterozygous frameshift DICER1 mutation in a patient, who is affected by different tumors of the DICER1-syndrome, including eRMS, CBME and suspected pleuropulmonary blastoma type I. By whole-exome sequencing of germline material using peripheral blood-derived DNA, we identified a single base pair duplication within the DICER1 gene (c.3405 dupA) that leads to a frameshift and results in a premature stop in exon 21 (p.Gly1136Arg). The metachronous occurrence of two unrelated tumor entities (eRMS and CBME) in a very young child within a short timeframe should have raised the suspicion of an underlying cancer susceptibility syndrome and should be prompt tested for DICER1.","variants":[{"Name":"NM_177438.3(DICER1):c.3405dup (p.Gly1136fs)","Chromosome":"14","Start":"95103990","Stop":"95103991","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":921347,"rule_based_match":true,"evidence_text":"c.3405 dupA","llm_judgment":"PRESENT","evidence":"c.3405 dupA","abstract_start":840,"abstract_end":851}]}
{"pmid":"28696035","title":"Lin-Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders.","abstract":"We report two patients with sagittal craniosynostosis, hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia. The clinical presentation of both patients was initially thought to be suggestive of Lin-Gettig syndrome (LGS), a multiple malformation syndrome associated with craniosynostosis that was initially reported in two brothers in 1990, with a third patient reported in 2003. Our first patient was subsequently found through exome sequencing to have a de novo mutation in KAT6B, c.4572dupT, p.(Thr1525Tyrfs*16). The second patient was ascertained as possible LGS, but KAT6B mutation testing was pursued clinically after the identification of the KAT6B mutation in Patient 1, and identified a de novo mutation, c.4205_4206delCT, p.(Ser1402Cysfs*5). The phenotypic spectrum of KAT6B mutations has been expanding since identification of KAT6B mutations in genitopatellar syndrome (GPS) and Say Barber Biesecker Young Simpson (SBBYS) syndrome patients. We show that craniosynostosis, which has not been previously reported in association with KAT6B mutations, may be part of the genitopatellar/Say Barber Biesecker Young Simpson spectrum. These two patients also further demonstrate the overlapping phenotypes of genitopatellar and SBBYS syndromes recently observed by others. Furthermore, we propose that it is possible that one or more of the previous cases of LGS may have also been due to mutation in KAT6B, and that LGS may actually be a variant within the KAT6B spectrum and not a distinct clinical entity.","variants":[{"Name":"NM_012330.4(KAT6B):c.4205_4206del (p.Ser1402fs)","Chromosome":"10","Start":"75029027","Stop":"75029028","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":47604,"rule_based_match":true,"evidence_text":"c.4205_4206delCT","llm_judgment":"PRESENT","evidence":"c.4205_4206delCT","abstract_start":824,"abstract_end":840}]}
{"pmid":"36352632","title":"Anoctamin-5 Muscular Dystrophy: Report of Two Cases with Different Phenotypes and Genotypes from the Indian Subcontinent.","abstract":"Anoctaminopathies are a group of autosomal recessive skeletal muscle disorders with various clinical phenotypes, caused by anoctamin 5 (ANO5) gene mutations and the abnormal expression of ANO5 protein. Patients with recessive mutations in ANO5 present with variable symptoms ranging from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. Here, we describe the clinical, pathological, and molecular findings of two unrelated patients with ANO5-related muscular dystrophy (MD). Ninety-six histologically identified MD cases were subjected to next-generation sequencing using a customized panel of 54 genes (IIlumina Design Studio). Two patients were diagnosed with ANO5-related MD. One patient had a pathogenic homozygous mutation of c.1406G>A in exon 14, while the other patient had a novel heterozygous mutation of c.2141C>G in exon 19 of ANO5 gene. Both showed two different phenotypes (limb girdle MD and Miyoshi myopathy) and histomorphological patterns. Muscle biopsy of one patient in addition showed amyloid deposit in the walls of interstitial blood vessels. ANO5-related MD is a heterogeneous disease with different clinical phenotypes as well as genotypes. All muscle biopsies with unclassified muscular dystrophies should be subjected to Congo red stain. The results of this study suggest that screening for ANO5 gene should represent an early step in the diagnostic work-up of the patients with undiagnosed MD and persistent asymptomatic hyperCKemia, even when muscle biopsy histomorphology is normal.","variants":[{"Name":"NM_213599.3(ANO5):c.2141C>G (p.Thr714Ser)","Chromosome":"11","Start":"22272895","Stop":"22272895","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":192166,"rule_based_match":true,"evidence_text":"c.2141C>G","llm_judgment":"PRESENT","evidence":"c.2141C>G","abstract_start":862,"abstract_end":871}]}
{"pmid":"22901948","title":"A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia.","abstract":"Achromatopsia (ACHM) is an autosomal-recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus, and severely reduced visual acuity. Its prevalence has been estimated to about 1 in 30,000 individuals. Four genes, GNAT2, PDE6C, CNGA3, and CNGB3, have been implicated in ACHM, and all encode functional components of the phototransduction cascade in cone photoreceptors. Applying a functional-candidate-gene approach that focused on screening additional genes involved in this process in a cohort of 611 index cases with ACHM or other cone photoreceptor disorders, we detected a homozygous single base change (c.35C>G) resulting in a nonsense mutation (p.Ser12(∗)) in PDE6H, encoding the inhibitory γ subunit of the cone photoreceptor cyclic guanosine monophosphate phosphodiesterase. The c.35C>G mutation was present in three individuals from two independent families with a clinical diagnosis of incomplete ACHM and preserved short-wavelength-sensitive cone function. Moreover, we show through immunohistochemical colocalization studies in mouse retina that Pde6h is evenly present in all retinal cone photoreceptors, a fact that had been under debate in the past. These findings add PDE6H to the set of genes involved in autosomal-recessive cone disorders and demonstrate the importance of the inhibitory γ subunit in cone phototransduction.","variants":[{"Name":"NM_006205.3(PDE6H):c.35C>G (p.Ser12Ter)","Chromosome":"12","Start":"14978047","Stop":"14978047","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":45838,"rule_based_match":true,"evidence_text":"c.35C>G","llm_judgment":"PRESENT","evidence":"c.35C>G","abstract_start":634,"abstract_end":641}]}
{"pmid":"32827848","title":"A homozygous variant in the Lamin B receptor gene LBR results in a non-lethal skeletal dysplasia without Pelger-Huët anomaly.","abstract":"Lamin B receptor, a member of the sterol reductase family, is an inner nuclear membrane protein which binds lamin B proteins and is involved in the organization of heterochromatin. Mutations in LBR have been associated with a variety of disorders, such as Pelger-Huët anomaly, a benign abnormality affecting neutrophils, and Greenberg Dysplasia, a lethal condition in the perinatal period. We identified a homozygous LBR missense mutation (NM_002296.4: c.1366C > G, p.(Leu456Val)) in two adult sisters with a Lamin B receptor-related disorder associated with a skeletal dysplasia milder than Greenberg Dysplasia. Individual 1 has short stature with short limbs (mostly rhizomelic for the upper extremities, and mesomelic for the lower extremities), limited elbow extension. She required Achilles tenotomy, and does not have facial dysmorphisms. Individual 2 has similar skeletal features, but also has bowed femurs, osteopenia, spastic paraplegia of the lower limbs, equinovarus feet, a single kidney, neurogenic bladder, obstructive hydronephrosis, scoliosis and syndactyly of the toes. This report provides additional evidence of variability for Lamin B receptor-related disorders associated with a non-lethal skeletal dysplasia without Pelger-Huët anomaly. We describe a novel pathogenic variant that has not been previously associated with disease and demonstrate the effect of this variant on sterol C14-reductase activity.","variants":[{"Name":"NM_002296.4(LBR):c.1366C>G (p.Leu456Val)","Chromosome":"1","Start":"225406781","Stop":"225406781","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":414768,"rule_based_match":true,"evidence_text":"NM_002296.4: c.1366C > G, p.(Leu456Val)","llm_judgment":"PRESENT","evidence":"NM_002296.4: c.1366C > G, p.(Leu456Val)","abstract_start":440,"abstract_end":479}]}
{"pmid":"11461196","title":"A phenylalanine hydroxylase amino acid polymorphism with implications for molecular diagnostics.","abstract":"Mutations in the gene encoding phenylalanine hydroxylase (PAH, EC 1.14.16.1) are associated with various degrees of hyperphenylalaninemia, including classical phenylketonuria (PKU). We examined the PAH gene in a Brazilian PKU family of African origin and identified three missense variants, R252W (c.754C --> T), K274E (c.820A --> G), and I318T (c.953T --> C), the two latter of which were transmitted in cis. Expression analyses in two different in vitro systems showed that I318T is associated with profoundly decreased enzyme activity, whereas the enzyme activity of K274E is indistinguishable from that of the wild-type protein. Detailed kinetic analyses of PAH expressed in E. coli showed that the K274E mutant protein has kinetic properties similar to that of the wild-type protein. Population studies have suggested that the K274E variant occurs on approximately 4% of African-American PAH alleles, whereas the neonatal screening incidence of PKU among African Americans is only 1:100,000. This is to our knowledge the first demonstration of a PAH missense variant with no apparent association to PAH deficiency. Awareness of this common variant may be helpful to laboratories that perform molecular diagnosis of PAH deficiency in populations of African origin.","variants":[{"Name":"NM_000277.3(PAH):c.820A>G (p.Lys274Glu)","Chromosome":"12","Start":"102852837","Stop":"102852837","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":108587,"rule_based_match":false,"evidence_text":"c.820A --> G","llm_judgment":"PRESENT","evidence":"c.820A --> G","abstract_start":320,"abstract_end":332},{"Name":"NM_000277.3(PAH):c.754C>T (p.Arg252Trp)","Chromosome":"12","Start":"102852903","Stop":"102852903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15623,"rule_based_match":false,"evidence_text":"c.754C --> T","llm_judgment":"PRESENT","evidence":"c.754C --> T","abstract_start":298,"abstract_end":310}]}
{"pmid":"25190167","title":"A family with two children diagnosed with aspartylglucosaminuria-case report and literature review","abstract":"OBJECTIVE: The authors sought to investigate the clinical features and characteristics of genetic mutation in patients with aspartylglucosaminuria.\nMETHOD: Clinical data of two pediatric siblings in a family were analyzed retrospectively and relative literature was reviewed in order to study the clinical features, imaging and enzymatic characteristics and genetic mutations.\nRESULT: Case 1, the proband, male, he was hospitalized at 20 months of age because of fever and hepatosplenomegaly for nine days. This child was of moderate nutritional status and normal development. Blood tests showed hemoglobin 78.0 g/L, RBC3.18 × 10¹²/L, WBC 4.06 × 10⁹/L, neutrophils 0.236, lymphocytes 0.631, platelets 34 × 10⁹/L, C-reactive protein 17 mg/L. Blood biochemistry showed alanine aminotransferase 67.1 U/L, aspartate aminotransferase 74.1 U/L, serum albumin 32.8 g/L, direct bilirubin 10.5 µmol/L, lactate dehydrogenase 301.7 U/L. Bone marrow cytology showed reactive morphological changes in bone marrow cells. Atypical lymphocytes could be seen in both peripheral blood and bone marrow smears. Cranial MRI showed poor myelination. Aspartylglucosaminidase activity in peripheral leucocytes of the proband 5.7 nmol/(g × min) vs. normal control>26.6 nmol/(g × min). On his AGA gene and that of his parents, a heterozygous mutation site located in exon 3, c.392C>T (p.S131L), was identified as a novel mutation inherited from his father. The mutation from his mother has not been detected. The proband was not responsive to the anti-infectious medication, nutritional intervention and symptomatic treatment.He died one month after diagnosis.His elder brother, Case 2, showed fever, recurrent respiratory tract infection and progressive psychomotor regression with hepatosplenomegaly from the age of four years. Cranial MRI revealed extensive symmetrical leukodystrophy in bilateral cerebra, cerebellum and brainstem.He died at the age of six years.Related literature was summarized, and no Chinese AGU cases had been reported; 221 foreign cases were collected. The clinical and imaging characteristics were summarized. Delay in language development was one of the clinical symptoms that the majority of parents of AGU children first noted.\nCONCLUSION: Patients with aspartylglucosaminuria lack of specific symptoms.For children with unexplained delayed speech and progressive mental retardation, the possibility of AGU should be considered, and efforts be made for enzymatic and genetic diagnosis. c.392C> T (p.S131L) was identified as a novel mutation of AGA gene.","variants":[{"Name":"NM_000027.4(AGA):c.392C>T (p.Ser131Leu)","Chromosome":"4","Start":"177439578","Stop":"177439578","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1699688,"rule_based_match":true,"evidence_text":"c.392C>T (p.S131L)","llm_judgment":"PRESENT","evidence":"c.392C>T (p.S131L)","abstract_start":1349,"abstract_end":1367}]}
{"pmid":"26555935","title":"DICER1 Mutations and Differentiated Thyroid Carcinoma: Evidence of a Direct Association.","abstract":"CONTEXT: DICER1 germline mutation carriers have an increased predisposition to cancer, such as pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT), and a high prevalence of multinodular goiter (MNG). Although differentiated thyroid carcinoma (DTC) has been reported in some DICER1 mutation carriers with PPB treated with chemotherapy, the association of DTC with DICER1 mutations is not well established.\nCASE DESCRIPTION: We report a family with DICER1 mutation and familial DTC without a history of chemotherapy. A 12-year-old female (patient A) and her 14-year-old sister (patient B) presented with MNG. Family history was notable for a maternal history of DTC and bilateral ovarian SLCT. Both sisters underwent total thyroidectomy. Pathological examination showed nodular hyperplasia and focal papillary thyroid carcinoma within hyperplastic nodules. Subsequently, patient A developed virilization secondary to a unilateral ovarian SLCT. During her evaluation, an incidental cystic nephroma was also found. Three other siblings had MNG on surveillance ultrasound examination; two had thyroidectomies, and one had two microscopic foci of papillary carcinoma. Patient A, her mother, and four affected siblings had a germline heterozygous pathogenic DICER1 mutation c.5441C>T in exon 25, resulting in an amino acid change from p.Ser1814Leu of DICER1. Somatic DICER1 RNase IIIb missense mutations were identified in thyroid nodules from three of the four siblings.\nCONCLUSIONS: This family provides novel insight into an emerging phenotype for DICER1 syndrome, with evidence that germline DICER1 mutations are associated with an increased risk of developing familial DTC, even in the absence of prior treatment with chemotherapy.","variants":[{"Name":"NM_177438.3(DICER1):c.5441C>T (p.Ser1814Leu)","Chromosome":"14","Start":"95091289","Stop":"95091289","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":399958,"rule_based_match":true,"evidence_text":"c.5441C>T","llm_judgment":"PRESENT","evidence":"c.5441C>T","abstract_start":1283,"abstract_end":1292}]}
{"pmid":"30987402","title":"Novel Mutation in GALT Gene in Galactosemia Patient with Group B Streptococcus Meningitis and Acute Liver Failure.","abstract":"Classic galactosemia is an autosomal recessive disorder caused by the deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT) involved in galactose metabolism. Bacterial infections are a known cause of early morbidity and mortality in children with classic galactosemia. The most common agent is <i>Escherichia</i> <i>c</i><i>oli</i><i>,</i> but in rare situations, other bacteria are incriminated. We report a case of a three-week-old female patient with galactosemia, who presented with <i>Group B S</i><i>treptococcus</i> (GBS) meningitis/sepsis. She received treatment with antibiotics, supportive therapy, and erythrocyte transfusion, but after a short period of improvement, she presented acute liver failure with suspicion of an inborn error of metabolism. Rapid nuclear magnetic resonance (NMR) spectroscopy from urine showed highly elevated values of galactose and galactitol. Under intensive treatment for acute liver failure and with a lactose-free diet, her clinical features and laboratory parameters improved considerably. Genetic testing confirmed compound heterozygous status for GALT mutations: c.563 A>G [p.Q188R] and c. 910 C>T, the last mutation being a novel mutation in GALT gene. In countries without an extensive newborn screening program, a high index of suspicion is necessary for early diagnosis and treatment of galactosemia.","variants":[{"Name":"NM_000155.4(GALT):c.910C>T (p.Pro304Ser)","Chromosome":"9","Start":"34649415","Stop":"34649415","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1481800,"rule_based_match":true,"evidence_text":"c. 910 C>T","llm_judgment":"PRESENT","evidence":"c. 910 C>T","abstract_start":1152,"abstract_end":1162}]}
{"pmid":"19656455","title":"Clinical, biochemical and genetic characteristics of Variegate Porphyria in Italy.","abstract":"Variegate Porphyria (VP) is an autosomal dominant disorder found worldwide but is rare in Italy. In this study we provide an overview of clinical, biochemical and genetic background of 33 Italian VP patients diagnosed in the last fifteen years. About 70% of patients had experienced clinical symptoms: 43.4% had photosensivity, 8.7% acute attacks and 47.8% both. Among the 33 patients, 14 different mutations were identified. Of these only 6 defects have been previously described in other countries and 8 are unique having been identified for the first time in Italy. Two of these, the c.851G>T and the c.1013C>G, were found in two and four unrelated families respectively. No mutation has been found in homozygosis and no significant correlation has been observed between specific clinical and biochemical manifestations and the type of mutation. In contrast, normal faecal protoporphyrin excretion was high predictive of silent phenotype. Normal urinary excretion of PBG and ALA, predicted absence of neurovisceral symptoms. This paper represents the first compilation of data on genotype-phenotype relation in Italian patients with VP.","variants":[{"Name":"NM_001122764.3(PPOX):c.851G>T (p.Ser284Ile)","Chromosome":"1","Start":"161169703","Stop":"161169703","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1392708,"rule_based_match":true,"evidence_text":"c.851G>T","llm_judgment":"PRESENT","evidence":"c.851G>T","abstract_start":587,"abstract_end":595}]}
{"pmid":"27438479","title":"Severe defect in mitochondrial complex I assembly with mitochondrial DNA deletions in ACAD9-deficient mild myopathy.","abstract":"INTRODUCTION: Acyl-coenzyme A dehydrogenase 9 (ACAD9) has a role in mitochondrial complex I (CI) assembly. Only a few patients who carry ACAD9 mutations have been reported. They mainly present with severe hypertrophic cardiomyopathy, although a minority have only mild isolated myopathy. Although the secondary factors influencing disease severity have not been elucidated, conservation of CI assembly and residual enzymatic activity have been suggested as explanations for the mild phenotypes associated with ACAD9 mutations.\nMETHODS: We report a novel homozygous ACAD9 mutation (c.1240C>T; p.Arg414Cys) in a 34-year-old woman who presented with non-progressive myopathy.\nRESULTS: We show that this ACAD9 mutation led to a severe defect in CI assembly in the patient's muscle. Furthermore, the impact of CI deficiency is confirmed by accumulation of mitochondrial DNA deletions.\nCONCLUSION: Our data suggest that a major defect of CI assembly is not responsible for a severe phenotype. Muscle Nerve 55: 919-922, 2017.","variants":[{"Name":"NM_014049.5(ACAD9):c.1240C>T (p.Arg414Cys)","Chromosome":"3","Start":"128906211","Stop":"128906211","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":406111,"rule_based_match":true,"evidence_text":"c.1240C>T; p.Arg414Cys","llm_judgment":"PRESENT","evidence":"c.1240C>T; p.Arg414Cys","abstract_start":581,"abstract_end":603}]}
{"pmid":"17511383","title":"Hutchinson-Gilford progeria syndrome: clinical and molecular analysis in an African patient","abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease characterized by an early onset of several clinical features including premature ageing in children. Approximately 80% of HGPS cases are caused by a de novo single-base pair substitution c.1824 C>T (GGC > GGT, p.Gly608Gly) within the exon 11 of the LMNA gene which codes for lamins A and C proteins. This mutation creates an abnormal splice donor site, leading to the formation of a truncated lamin A protein. Only a very few cases of African patients with HGPS have been reported, but none of them has been characterized at the molecular level. We report here a 12 year-old-girl African patient with HGPS, in whom the p.Gly608Gly heterozygous disease-causing mutation was found.","variants":[{"Name":"NM_170707.4(LMNA):c.1824C>T (p.Gly608=)","Chromosome":"1","Start":"156138613","Stop":"156138613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29539,"rule_based_match":true,"evidence_text":"c.1824 C>T (GGC > GGT, p.Gly608Gly)","llm_judgment":"PRESENT","evidence":"c.1824 C>T (GGC > GGT, p.Gly608Gly)","abstract_start":268,"abstract_end":303}]}
{"pmid":"19365571","title":"Macular corneal dystrophy in a Chinese family related with novel mutations of CHST6.","abstract":"PURPOSE: To identify mutations in the carbohydrate sulfotransferase gene (CHST6) for a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes in the affected cornea.\nMETHODS: A corneal button of the proband was obtained by penetrating keratoplasty. The half button and ultrathin sections from the other half button were examined with special stains under a light microscope (LM) and an electron microscope (EM) separately. Genomic DNA was extracted from peripheral blood of 11 family members, and the coding region of CHST6 was amplified by the polymerase chain reaction (PCR) method. The PCR products were analyzed by direct sequencing and restriction enzyme digestion.\nRESULTS: The positive reaction to colloidal iron stain (extracellular blue accumulations in the stroma) was detected under light microscopy. Transmission electron microscopy revealed the enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. The compound heterozygous mutations, c.892C>T and c.1072T>C, were identified in exon 3 of CHST6 in three patients. The two transversions resulted in the substitution of a stop codon for glutamine at codon 298 (p.Q298X) and a missense mutation at codon 358, tyrosine to histidine (p.Y358H). The six unaffected family individuals carried alternative heterozygous mutations. These two mutations were not detected in any of the 100 control subjects.\nCONCLUSIONS: Those novel compound heterozygous mutations were thought to contribute to the loss of CHST6 function, which induced the abnormal metabolism of keratan sulfate (KS) that deposited in the corneal stroma. It could be proved by the observation of a positive stain reaction and the enlarged collagen fibers as well as hyperplastic fibroblasts under microscopes.","variants":[{"Name":"NM_021615.5(CHST6):c.892C>T (p.Gln298Ter)","Chromosome":"16","Start":"75478937","Stop":"75478937","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":344037,"rule_based_match":true,"evidence_text":"c.892C>T","llm_judgment":"PRESENT","evidence":"c.892C>T","abstract_start":1032,"abstract_end":1040}]}
{"pmid":"33134517","title":"Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by","abstract":"OBJECTIVE: To expand the clinical phenotype of <i>POLR3A</i> mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.\nMETHODS: We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [<sup>1</sup>H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.\nRESULTS: The patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in <i>POLR3A</i>, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant.\nCONCLUSIONS: Mutations in the <i>POLR3A</i> gene cause <i>POLR3A</i>-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of <i>POLR3A</i>-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.","variants":[{"Name":"NM_007055.4(POLR3A):c.1771-6C>G","Chromosome":"10","Start":"78009681","Stop":"78009681","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":964843,"rule_based_match":true,"evidence_text":"c.1771-6C>G","llm_judgment":"PRESENT","evidence":"c.1771-6C>G","abstract_start":799,"abstract_end":810}]}
{"pmid":"30111881","title":"Contribution of RAD51D germline mutations in breast and ovarian cancer in Greece.","abstract":"RAD51D gene's protein product is known to be involved in the DNA repair mechanism by homologous recombination. RAD51D germline mutations have been recently associated with ovarian and breast cancer (OC and BC, respectively) predisposition. Our aim was to evaluate the frequency of hereditary RAD51D mutations in Greek patients. To address this, we have screened for RAD51D germline mutations 609 BRCA1- and BRCA2-negative patients diagnosed with OC, unselected for age or family history, and 569 BC patients diagnosed under 55 years and with an additional relative with BC or OC. We identified four pathogenic mutations in four unrelated individuals with family history of BC and/or OC. Three of the RAD51D carriers had developed BC, while the other one was an OC patient, thus accounting for a mutation frequency of 0.16% in the OC cohort and 0.53% in the BC cohort. One of the detected mutations is novel (c.738 + 1G > A), whereas the rest had been detected previously (p.Gln151Ter, p.Arg186Ter, and p.Arg300Ter). It is noteworthy that the 4 carrier families had 13 BC cases and only 4 OC cases. Our data support that RAD51D should be implemented into the comprehensive multigene panel, as mutation carriers may benefit from the administration of PARP inhibitors.","variants":[{"Name":"NM_002878.4(RAD51D):c.738+1G>A","Chromosome":"17","Start":"35103253","Stop":"35103253","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":571079,"rule_based_match":true,"evidence_text":"c.738 + 1G > A","llm_judgment":"PRESENT","evidence":"c.738 + 1G > A","abstract_start":908,"abstract_end":922}]}
{"pmid":"25886484","title":"A novel lamin A/C gene mutation causing spinal muscular atrophy phenotype with cardiac involvement: report of one case.","abstract":"BACKGROUND: Mutations of the lamin A/C gene have been associated with several diseases such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Charcot-Marie-Tooth disease, referred to as laminopathies. Only one report of spinal muscular atrophy and cardiomyopathy phenotype with lamin A/C gene mutations has been published. The concept that lamin A/C gene mutations cause spinal muscular atrophy has not been established.\nCASE PRESENTATION: We report a man aged 65 years who presented with amyotrophy of lower limbs, arrhythmia and cardiac hypofunction. He showed gait disturbance since childhood, and his family showed similar symptoms. Neurological and electrophysiological findings suggested spinal muscular atrophy type 3. Gene analysis of lamin A/C gene showed a novel nonsense mutation p.Q353X (c.1057C > T). Further investigations revealed that he and his family members had cardiac diseases including atrioventricular block.\nCONCLUSIONS: We report the first Japanese case of spinal muscular atrophy phenotype associated with lamin A/C mutation. When a patient presents a spinal muscular atrophy phenotype and unexplained cardiac disease, especially when the family history is positive, gene analysis of lamin A/C gene should be considered.","variants":[{"Name":"NM_170707.4(LMNA):c.1057C>T (p.Gln353Ter)","Chromosome":"1","Start":"156136021","Stop":"156136021","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":196476,"rule_based_match":true,"evidence_text":"c.1057C > T","llm_judgment":"PRESENT","evidence":"c.1057C > T","abstract_start":815,"abstract_end":826}]}
{"pmid":"24709683","title":"A novel GRN mutation (GRN c.708+6_+9delTGAG) in frontotemporal lobar degeneration with TDP-43-positive inclusions: clinicopathologic report of 6 cases.","abstract":"Understanding of frontotemporal lobar degeneration, the underlying pathology most often linked to the clinical diagnosis of frontotemporal dementia, is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings on 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6_+9delTGAG mutation.","variants":[{"Name":"NM_002087.4(GRN):c.708+6_708+9del","Chromosome":"17","Start":"44350801","Stop":"44350804","ReferenceAlleleVCF":"CGTGA","AlternateAlleleVCF":"C","allel_id":577636,"rule_based_match":false,"evidence_text":"GRN c.708+6_+9delTGAG","llm_judgment":"PRESENT","evidence":"GRN c.708+6_+9delTGAG","abstract_start":847,"abstract_end":868}]}
{"pmid":"28427417","title":"Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome.","abstract":"BACKGROUND: Hypertrophic cardiomyopathy (HCM) patients with early repolarization (ER) pattern are at higher risk of ventricular arrhythmia, yet the genetic background of this situation has not been well investigated. Here we report novel trigenic mutations detected in a Chinese family of obstructive HCM with ER and short QT syndrome (SQTS).\nMETHODS: Proband and family members underwent detailed medical assessments. DNAs were extracted from peripheral blood leukocytes for genetic screening with next generation method. The functional characterization of the mutation was conducted in TSA201 cells with patch-clamp experiment.\nRESULTS: The proband was a 52-year-old male who had a ER pattern ECG in inferioral-lateral leads with atrioventricular block and QTc of 356 ms. He also suffered from severe left ventricular hypertrophy and dysfunction. Targeted sequencing revealed trigenic mutations: c.700G>A/p.E234K in DES, c.2966G>A/p.R989H in MYPN, and c.5918G>C/p.R1973P in CACNA1C. All mutations were also detected in his daughter with ER and mild myocardium hypertrophy. The CACNA1C-R1973P mutation caused significant reduction (68.4%) of I<sub>Ca</sub> compared to CACNA1C-WT (n = 14 and 14, P < 0.05). The computer modeling showed that all 3 mutations were highly disease-causing. The proband received the CRT-D (cardiac resynchronizing therapy) implantation, which lowered the left ventricular outflow tract gradient (LVOTG, 124 mmHg pre vs. 27 mmHg post) and restored the LV function (LVEF 40% pre vs. 63% post).\nCONCLUSIONS: The study reveals a novel CACNA1C mutation underlying the unique ER pattern ECGs with SQTS. It also shows the rare trigenic mutations are the pathogenic substrates for the complicated clinical manifestation in HCM patients.","variants":[{"Name":"NM_001927.4(DES):c.700G>A (p.Glu234Lys)","Chromosome":"2","Start":"219420311","Stop":"219420311","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":392379,"rule_based_match":true,"evidence_text":"c.700G>A/p.E234K in DES","llm_judgment":"PRESENT","evidence":"c.700G>A/p.E234K in DES","abstract_start":898,"abstract_end":921}]}
{"pmid":"27316665","title":"Splicing analysis of CYP11B1 mutation in a family affected with 11β-hydroxylase deficiency: case report.","abstract":"BACKGROUND: Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency (11β-OHD) is a rare form of CAH associated with low renin hypertension, hypokalemia, hyperandrogenemia and ambiguous genitalia in affected females. Herein we describe the clinical, hormonal and molecular characteristics of two Uzbekistan siblings with 11β-OHD and analyze the effects of a splicing mutation.\nCASE PRESENTATION: A 46,XX girl presented with genital ambiguity and low renin hypertension; her 46,XY brother presented with precocious puberty. Hormonal studies suggested 11β-OHD. Mutation analysis was performed by PCR followed by Sanger sequencing of the entire coding regions and their flanking introns of the CYP11B1 gene. Mutation analysis showed that both patients were compound heterozygous for IVS7 + 1G > A, and c.421C > T. Although the identified mutations have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. A minigene assay was used to determine the effects of the splicing mutation. The constructs containing either the wild-type or the splice-site mutant CYP11B1 genomic DNA of exons-introns 6-9 were transfected into COS-7 cells; subsequently, RNA splicing was assessed by reversed transcribed-PCR of CYP11B1 complementary DNA. The minigene assay revealed that the IVS7 + 1G > A mutation resulted in two shorter incorrectly spliced products; one skipping the exon 7 and the other skipping the exons 7-8. The c.421C > T mutation leads to the introduction of a premature stop codon at residue 141 (p.R141X). These mutations are expected to code non-functional proteins.\nCONCLUSION: Compound heterozygous mutations (IVS7 + 1G > A and p.R141X) in the CYP11B1 gene were found to cause 11β-OHD. The IVS7 + 1G > A mutation causes aberrant splicing of CYP11B1 leading to exon skipping. This finding could facilitate the future novel therapies targeted on splicing modulation to treat human disease.","variants":[{"Name":"NM_000497.4(CYP11B1):c.421C>T (p.Arg141Ter)","Chromosome":"8","Start":"142877197","Stop":"142877197","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1061231,"rule_based_match":true,"evidence_text":"c.421C > T","llm_judgment":"PRESENT","evidence":"c.421C > T","abstract_start":821,"abstract_end":831}]}
{"pmid":"15714522","title":"cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression.","abstract":"The cblE type of homocystinuria is a rare autosomal recessive disorder caused by impaired reductive activation of methionine synthase. Although earlier biochemical studies proposed that the methionine synthase enzyme might be activated by two different reducing systems, mutations were reported in only the methionine synthase reductase gene (MTRR) in cblE patients. The pathogenicity of MTRR mutations, however, has not yet been tested functionally. We report on nine patients of European origin affected by the cblE type of homocystinuria. They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases. Bone marrow examination performed in seven patients showed megaloblastic changes in all but one of them. All patients exhibited moderate to severe hyperhomocysteinemia (median plasma total homocysteine [Hcy] 92 mumol/L, range 44-169), while clearly reduced methionine was observed only in four cases. Pathogenic mutations were identified in both parental alleles of the MTRR gene in all patients. Five known (c.903+469T>C, c.1361C>T, c.1459G>A, c.1557-4_1557+3del7, and c.1622_1623dupTA) and three novel mutations (c.7A>T, c.1573C>T, and c.1953-6_1953-2del5) were detected. Importantly, transfection of fibroblasts of cblE patients with a wild-type MTRR minigene expression construct resulted in a significant approximately four-fold increase of methionine synthesis, indicating correction of the enzyme defect. Our study shows a link between a milder predominantly hematological presentation and homozygosity for the c.1361C>T mutation, but no other obvious genotype-phenotype correlation. The identification of mutations in the MTRR gene, together with restoration of methionine synthesis following MTRR minigene expression in cblE cells confirms that this disease is caused by defects in the MTRR gene.","variants":[{"Name":"NM_002454.3(MTRR):c.1361C>T (p.Ser454Leu)","Chromosome":"5","Start":"7891405","Stop":"7891405","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22072,"rule_based_match":true,"evidence_text":"c.1361C>T","llm_judgment":"PRESENT","evidence":"c.1361C>T","abstract_start":1150,"abstract_end":1159},{"Name":"NM_002454.3(MTRR):c.903+469T>C","Chromosome":"5","Start":"7883746","Stop":"7883746","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":651340,"rule_based_match":true,"evidence_text":"c.903+469T>C","llm_judgment":"PRESENT","evidence":"c.903+469T>C","abstract_start":1136,"abstract_end":1148},{"Name":"NM_002454.3(MTRR):c.1573C>T (p.Arg525Ter)","Chromosome":"5","Start":"7895749","Stop":"7895749","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259828,"rule_based_match":true,"evidence_text":"c.1573C>T","llm_judgment":"PRESENT","evidence":"c.1573C>T","abstract_start":1250,"abstract_end":1259}]}
{"pmid":"28777491","title":"Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.","abstract":"Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.","variants":[{"Name":"NM_145064.3(STAC3):c.763_766del (p.Leu255fs)","Chromosome":"12","Start":"57244577","Stop":"57244580","ReferenceAlleleVCF":"TAGAG","AlternateAlleleVCF":"T","allel_id":550572,"rule_based_match":true,"evidence_text":"c.763_766delCTCT;p.Leu255IlefsX58","llm_judgment":"PRESENT","evidence":"c.763_766delCTCT;p.Leu255IlefsX58","abstract_start":1259,"abstract_end":1292},{"Name":"NM_145064.3(STAC3):c.851G>C (p.Trp284Ser)","Chromosome":"12","Start":"57244322","Stop":"57244322","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":94325,"rule_based_match":true,"evidence_text":"c.851G>C;p.Trp284Ser","llm_judgment":"PRESENT","evidence":"c.851G>C;p.Trp284Ser","abstract_start":788,"abstract_end":808}]}
{"pmid":"21932610","title":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) due to AIRET16M mutation in a consanguineous Greek girl.","abstract":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) or autoimmune polyendocrine syndrome type 1 (APS-1) is a rare autosomal recessive disease caused by mutations of the AutoImmune REgulator (AIRE) gene, an important mediator of tolerance to self-antigens. It is characterized by two out of three major components: chronic mucocutaneous candidiasis, hypoparathyroidism and Addison's disease. We present an 11-year-old girl suffering from recurrent episodes of mucocutaneous candidiasis and onychomycosis from 1 to 6 years of age, and transient alopecia at the age of 4 years. Hypoparathyroidism and dental enamel hypoplasia were diagnosed at 8 years. Autoantibodies to thyroid and adrenal glands were not detected and all other endocrine functions have remained normal. Genetic analysis revealed that the patient was homozygous for the mutation T16M in exon 1 of the AIRE gene (p.T16M, c.47C>T). This is the first APECED case reported for carrying this mutation in homozygous form. Parents were third cousins and heterozygous carriers of this mutation.","variants":[{"Name":"NM_000383.4(AIRE):c.47C>T (p.Thr16Met)","Chromosome":"21","Start":"44286053","Stop":"44286053","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":79118,"rule_based_match":true,"evidence_text":"c.47C>T","llm_judgment":"PRESENT","evidence":"c.47C>T","abstract_start":914,"abstract_end":921}]}
{"pmid":"29720126","title":"Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?","abstract":"BACKGROUND: 6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life-threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients.\nMETHODS: A total of 105 Chinese pediatric patients with a confirmed diagnosis of ALL were enrolled. We identified the NUDT15 coding variant rs116855232 (c.415C > T), a newly discovered 6-MP toxicity-related locus in Asians, and polymorphisms in TPMT rs1142345 and ITPA rs11273540. Associations between genotypes and 6-MP dose sensitivity, leukopenia, hepatotoxicity, and therapy interruption were evaluated.\nRESULTS: The minor allele frequencies (MAFs) of NUDT15 rs116855232, TPMT rs1142345 and ITPA rs11273540 were 15.7, 2.9, and 18.1%, respectively. NUDT15 and TPMT genetic variants were strongly associated with 6-MP dose intensity. Patients with NUDT15 homogenous genotype (TT) were highly sensitive to 6-MP (dose intensity of 60.27%) compared to these with heterozygous genotype (TC) or wild type (CC), who tolerated an average dose intensity of 83.83 and 94.24%, respectively. The NUDT15 variant was a predictor for leukopenia (OR: 3.62, 95% CI 1.377-9.501, P = 0.009) and early-onset leukopenia (OR: 9.63, 95% CI 2.764-33.514, P = 3.75 × 10<sup>- 4</sup>). No differences were found between 6-MP dose intensity and ITPA polymorphisms.\nCONCLUSION: NUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric ALL patients and may have greatly clinical implications for individualized therapy.","variants":[{"Name":"NM_018283.4(NUDT15):c.415C>T (p.Arg139Cys)","Chromosome":"13","Start":"48045719","Stop":"48045719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227129,"rule_based_match":true,"evidence_text":"c.415C > T","llm_judgment":"PRESENT","evidence":"c.415C > T","abstract_start":708,"abstract_end":718}]}
{"pmid":"24710345","title":"Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease.","abstract":"BACKGROUND: Mutations in PKHD1 cause autosomal recessive Caroli disease, which is a rare congenital disorder involving cystic dilatation of the intrahepatic bile ducts. However, the mutational spectrum of PKHD1 and the phenotype-genotype correlations have not yet been fully established.\nMETHODS: Whole exome sequencing (WES) was performed on one twin sample with Caroli disease from a Chinese family from Shandong province. Routine Sanger sequencing was used to validate the WES and to carry out segregation studies. We also described the PKHD1 mutation associated with the genotype-phenotype of this twin.\nRESULTS: A combination of WES and Sanger sequencing revealed the genetic defect to be a novel compound heterozygous genotype in PKHD1, including the missense mutation c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala), and the nonsense mutation c.2341C>T, which is predicted to result in an arginine to stop codon at codon 781 (c.2341C>T, p.Arg781*). This compound heterozygous genotype co-segregates with the Caroli disease-affected pedigree members, but is absent in 200 normal chromosomes.\nCONCLUSIONS: Our findings indicate exome sequencing can be useful in the diagnosis of Caroli disease patients and associate a compound heterozygous genotype in PKHD1 with Caroli disease, which further increases our understanding of the mutation spectrum of PKHD1 in association with Caroli disease.","variants":[{"Name":"NM_138694.4(PKHD1):c.2341C>T (p.Arg781Ter)","Chromosome":"6","Start":"52048558","Stop":"52048558","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":102281,"rule_based_match":true,"evidence_text":"c.2341C>T (p.Arg781*)","llm_judgment":"PRESENT","evidence":"c.2341C>T","abstract_start":904,"abstract_end":913},{"Name":"NM_138694.4(PKHD1):c.2507T>C (p.Val836Ala)","Chromosome":"6","Start":"52046089","Stop":"52046089","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":620237,"rule_based_match":true,"evidence_text":"c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala)","llm_judgment":"PRESENT","evidence":"c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala)","abstract_start":775,"abstract_end":876}]}
{"pmid":"24195576","title":"Recurrent pulmonary aspergillosis and mycobacterial infection in an unsplenectomized patient with type 1 Gaucher disease.","abstract":"BACKGROUND: The clinical presentation of Gaucher disease (GD), an inherited lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase, is highly variable, and three clinical types are distinguished based upon the presence of neurologic symptoms. Thrombocytopenia, anemia, hepatosplenomegaly, and bone manifestations are the most typical signs of GD type 1 (GD1).\nCASE PRESENTATION: We present the case of an unsplenectomized man suffering from heterozygous GD1 with mutations of c.1226A>G (N370S) and RecNci I (L444P, A456P, and V460V) in the GBA1 gene, who developed recurrent pulmonary aspergillosis caused by Aspergillus fumigatus and a mycobacterial infection caused by Mycobacterium avium. Despite long-lasting therapy of both aspergillosis (including antifungal drugs and surgery), and the mycobacterial infection (triple therapy with rifampicin, ethambutol, and clarithromycin), recurrent positivity for M. avium and A. fumigatus was detected.\nCONCLUSIONS: Symptomatic lung involvement and an increased susceptibility to pulmonary infections are uncommon in GD and, if present, are often associated with more severe disease manifestations. To our knowledge, this is the first published report on the association of GD and pulmonary aspergillosis and mycobacterial infection. It illustrates the increased susceptibility of untreated GD patients to opportunistic pulmonary infections and ineffective eradication of these infections despite adequate therapy.","variants":[{"Name":"NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)","Chromosome":"1","Start":"155235843","Stop":"155235843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":19329,"rule_based_match":true,"evidence_text":"c.1226A>G (N370S)","llm_judgment":"PRESENT","evidence":"c.1226A>G (N370S)","abstract_start":524,"abstract_end":541}]}
{"pmid":"27020652","title":"Report of limb girdle muscular dystrophy type 2a in 6 Iranian patients, one with a novel deletion in CAPN3 gene.","abstract":"Calpain3 is a calcium-dependent intracellular protease involved in an autosomal recessive form of muscular dystrophy known as limb-girdle muscular dystrophy type 2A. Many pathogenic mutations have been identified in calpain3, encoded by the CAPN3 gene, which leads to weakness of the pelvic and shoulder girdle muscles. In the present study, whole exome sequencing was performed on six unrelated Iranian families who presented with progressive muscle weakness, with a strong suspicion of Calpainopathies. Genetic analysis of CAPN3 gene revealed five causative variants which had not been reported in the Iranian population before including a novel 6 bp deletion (c.795_800delCATTGA) and four previously reported mutations (c.1939G > T, c.2243G > A, c.2257delGinsAA, and c.2380 + 2T > G). Our findings indicate that exome sequencing can be a very effective and affordable method to diagnose heterogeneous muscular dystrophies, especially in consanguineous populations such as Iran.","variants":[{"Name":"NM_000070.3(CAPN3):c.795_800del (p.Ile266_Asp267del)","Chromosome":"15","Start":"42389090","Stop":"42389095","ReferenceAlleleVCF":"CCATTGA","AlternateAlleleVCF":"C","allel_id":204177,"rule_based_match":true,"evidence_text":"c.795_800delCATTGA","llm_judgment":"PRESENT","evidence":"c.795_800delCATTGA","abstract_start":663,"abstract_end":681},{"Name":"NM_000070.3(CAPN3):c.2380+2T>G","Chromosome":"15","Start":"42411002","Stop":"42411002","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":620867,"rule_based_match":true,"evidence_text":"c.2380 + 2T > G","llm_judgment":"PRESENT","evidence":"c.2380 + 2T > G","abstract_start":770,"abstract_end":785},{"Name":"NM_000070.3(CAPN3):c.2243G>A (p.Arg748Gln)","Chromosome":"15","Start":"42410646","Stop":"42410646","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":134019,"rule_based_match":true,"evidence_text":"c.2243G > A","llm_judgment":"PRESENT","evidence":"c.2243G > A","abstract_start":736,"abstract_end":747}]}
{"pmid":"25077178","title":"Functional implications of the p.Cys680Arg mutation in the MLH1 mismatch repair protein.","abstract":"In clinical genetic diagnostics, it is difficult to predict whether genetic mutations that do not greatly alter the primary sequence of the encoded protein causing unknown functional effects on cognate proteins lead to development of disease. Here, we report the clinical identification of c.2038 T>C missense mutation in exon 18 of the human MLH1 gene and biochemically characterization of the p.Cys680Arg mutant MLH1 protein to implicate it in the pathogenicity of the Lynch syndrome (LS). We show that the mutation is deficient in DNA mismatch repair and, therefore, contributing to LS in the carriers.","variants":[{"Name":"NM_000249.4(MLH1):c.2038T>C (p.Cys680Arg)","Chromosome":"3","Start":"37048952","Stop":"37048952","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":95480,"rule_based_match":true,"evidence_text":"c.2038 T>C","llm_judgment":"PRESENT","evidence":"c.2038 T>C","abstract_start":290,"abstract_end":300}]}
{"pmid":"19027160","title":"A recessive ryanodine receptor 1 mutation in a CCD patient increases channel activity.","abstract":"Ryanodine receptors plays a crucial role in skeletal muscle excitation-contraction coupling by releasing calcium ions required for muscle contraction from the sarcoplasmic reticulum. At least three phenotypes associated with more than 100 RYR1 mutations have been identified; in order to elucidate possible pathophysiological mechanisms of RYR1 mutations linked to neuromuscular disorders, it is essential to define the mutation class by studying the functional properties of channels harbouring clinically relevant amino acid substitutions. In the present report we investigated the functional effects of the c.7304G>T RYR1 substitution (p.Arg2435Leu) found in a patient affected by central core disease. Both parents were heterozygous for the substitution while the proband was homozygous. We characterized Ca(2+) homeostasis in myoD transduced myotubes from controls, the heterozygous parents and the homozygous proband expressing the endogenous mutation. We also expressed the recombinant mutant channels in heterologous cells and characterized their [(3)H]ryanodine binding and single channel properties. Our results show that the p.Arg2435Leu substitution affects neither the resting [Ca(2+)], nor the sensitivity of the ryanodine receptor to pharmacological activators, but rather reduces the release of Ca(2+) from intracellular stores induced by pharmacological activators as well as by KCl via the voltage sensing dihydropyridine receptor.","variants":[{"Name":"NM_000540.3(RYR1):c.7304G>T (p.Arg2435Leu)","Chromosome":"19","Start":"38499997","Stop":"38499997","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":136943,"rule_based_match":true,"evidence_text":"c.7304G>T RYR1 substitution (p.Arg2435Leu)","llm_judgment":"PRESENT","evidence":"c.7304G>T RYR1 substitution (p.Arg2435Leu)","abstract_start":610,"abstract_end":652}]}
{"pmid":"22584997","title":"Mild iron overload in an African American man with SLC40A1 D270V.","abstract":"We report on a 46-year-old black man who resided in Alabama with normal transferrin saturation, mild hyperferritinemia, chronic hepatitis C, and 3+ iron in hepatocytes and Kupffer cells. Exome sequencing revealed heterozygosity for SLC40A1 D270V (exon 7, c.809A→T), a mutation previously reported only in 1 black patient with iron overload who resided in the Republic of South Africa. The present patient was also heterozygous for: heme transporter FLVCR1 novel allele P542S (exon 10, 1624C→T); FLVCR1 T544M (rs3207090); hemopexin (HPX) R371W (rs75307540); ferritin scavenger receptor (SCARA5) R471H (rs61737287); and transferrin receptor (TFRC) G420S (rs41295879). He had no HFE, TFR2,HJV, or HAMP mutations. D270V was not detected in 19 other African Americans with iron overload who resided in Alabama. The allele frequency of SLC40A1 D270V in 258 African American adults who participated in a health appraisal clinic was 0.0019 (95% confidence interval 0-0.0057). D270V could explain 'classical' ferroportin hemochromatosis phenotypes in some African Americans.","variants":[{"Name":"NM_014053.4(FLVCR1):c.1624C>T (p.Pro542Ser)","Chromosome":"1","Start":"212895246","Stop":"212895246","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":576478,"rule_based_match":false,"evidence_text":"FLVCR1 novel allele P542S (exon 10, 1624C→T)","llm_judgment":"PRESENT","evidence":"FLVCR1 novel allele P542S (exon 10, 1624C→T)","abstract_start":449,"abstract_end":493}]}
{"pmid":"25326109","title":"Common mutation causes cystinosis in the majority of black South African patients.","abstract":"BACKGROUND: The mutations responsible for cystinosis in South African patients are currently unknown. A pertinent question is whether they are similar to those described elsewhere in the world.\nMETHODS: Children who were being managed for cystinosis in the Western Cape Province of South Africa between 2002 and 2013 were studied. All underwent molecular analysis to detect sequence variations in the cystinosis gene.\nRESULTS: This cohort study included 20 patients, 13 of whom were Xhosa-speaking black South Africans and seven were Cape Coloureds (mixed race); none were Caucasian. All had nephropathic infantile-type cystinosis with evidence of proximal tubulopathy, with glycosuria and renal phosphate wasting. Diagnosis was confirmed in 19 cases by demonstrating an elevated cystine concentration in leukocytes. Molecular analysis of the cystinosin gene revealed that 19 patients had a G > A mutation in intron 11 (CTNS-c.971-12G > A p.D324AfsX44) which caused an out-of-frame 10-bp insertion. Of these 19 patients, 16 were homozygous for this mutation, which was the most frequent mutation identified in the alleles of the black South African and Cape Coloured patients (96 and 71 %, respectively).\nCONCLUSION: We recommend that black South African and Cape Coloured patients presenting with cystinosis be tested for CTNS-c.971-12G > A in the first instance, with the possibility of prenatal testing being offered to at-risk families.","variants":[{"Name":"NM_004937.3(CTNS):c.971-12G>A","Chromosome":"17","Start":"3660224","Stop":"3660224","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":531468,"rule_based_match":true,"evidence_text":"CTNS-c.971-12G > A","llm_judgment":"PRESENT","evidence":"CTNS-c.971-12G > A","abstract_start":920,"abstract_end":938}]}
{"pmid":"27439679","title":"FKRP mutations, including a founder mutation, cause phenotype variability in Chinese patients with dystroglycanopathies.","abstract":"Mutations in the fukutin-related protein (FKRP) gene have been associated with dystroglycanopathies, which are common in Europe but rare in Asia. Our study aimed to retrospectively analyze and characterize the clinical, myopathological and genetic features of 12 Chinese patients with FKRP mutations. Three patients were diagnosed with congenital muscular dystrophy type 1C (MDC1C) and nine patients were diagnosed with limb girdle muscular dystrophy type 2I (LGMD2I). Three muscle biopsy specimens had dystrophic changes and reduced glycosylated α-dystroglycan staining, and two showed reduced expression of laminin α2. Two known and 13 novel mutations were identified in our single center cohort. Interestingly, the c.545A>G mutation was found in eight of the nine LGMD2I patients as a founder mutation and this founder mutation in Chinese patients differs from the one seen in European patients. Moreover, patients homozygous for the c.545A>G mutation were clinically asymptomatic, a less severe phenotype than in compound heterozygous patients with the c.545A>G mutation. The 13 novel mutations of FKRP significantly expanded the mutation spectrum of MDC1C and LGMD2I, and the different founder mutations indicate the ethnic difference in FKRP mutations.","variants":[{"Name":"NM_024301.5(FKRP):c.545A>G (p.Tyr182Cys)","Chromosome":"19","Start":"46755995","Stop":"46755995","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":266484,"rule_based_match":true,"evidence_text":"c.545A>G","llm_judgment":"PRESENT","evidence":"c.545A>G","abstract_start":718,"abstract_end":726}]}
{"pmid":"31071452","title":"Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections.","abstract":"Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections. The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86. Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels. Whole exome sequencing (WES) identified a novel heterozygous mutation in RAC2(c.275A > C, p.N92 T). Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP. Cell lines transfected with RAC2 [N92 T] displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA. Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease.","variants":[{"Name":"NM_002872.5(RAC2):c.275A>C (p.Asn92Thr)","Chromosome":"22","Start":"37231945","Stop":"37231945","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":965352,"rule_based_match":true,"evidence_text":"RAC2(c.275A > C, p.N92 T)","llm_judgment":"PRESENT","evidence":"RAC2(c.275A > C, p.N92 T)","abstract_start":571,"abstract_end":596}]}
{"pmid":"34833038","title":"Molecular Analysis of Vietnamese Patients with Mucopolysaccharidosis Type I.","abstract":"Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by deleterious mutations in the α-L-iduronidase (<i>IDUA</i>) gene. Until now, MPS I in Vietnamese has been poorly addressed. Five MPS I patients were studied with direct DNA sequencing using Illumina technology confirming pathogenic variants in the <i>IDUA</i> gene. Clinical characteristics, additional laboratory results, and family history were collected. All patients have presented with the classical characteristic of MPS I, and α-L-iduronidase activity was low with the accumulation of glycosaminoglycans. Three variants in the <i>IDUA</i> gene (c.1190-10C>A (Intronic), c.1046A>G (p.Asp349Gly), c.1862G>C (p.Arg621Pro) were identified. The c.1190-10C>A variant represents six of the ten disease alleles, indicating a founder effect for MPS I in the Vietnamese population. Using biochemical and genetic analyses, the precise incidence of MPS I in this population should accelerate early diagnosis, newborn screening, prognosis, and optimal treatment.","variants":[{"Name":"NM_000203.5(IDUA):c.1046A>G (p.Asp349Gly)","Chromosome":"4","Start":"1002342","Stop":"1002342","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":923376,"rule_based_match":true,"evidence_text":"c.1046A>G (p.Asp349Gly)","llm_judgment":"PRESENT","evidence":"c.1046A>G (p.Asp349Gly)","abstract_start":662,"abstract_end":685}]}
{"pmid":"25370038","title":"Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer.","abstract":"Germline variants affecting the exonuclease domains of POLE and POLD1 predispose to multiple colorectal adenomas and/or colorectal cancer (CRC). The aim of this study was to estimate the prevalence of previously described heterozygous germline variants POLE c.1270C>G, p.(Leu424Val) and POLD1 c.1433G>A, p.(Ser478Asn) in a Dutch series of unexplained familial, early onset CRC and polyposis index cases. We examined 1188 familial CRC and polyposis index patients for POLE p.(Leu424Val) and POLD1 p.(Ser478Asn) variants using competitive allele-specific PCR. In addition, protein expression of the POLE and DNA mismatch repair genes was studied by immunohistochemistry in tumours from POLE carriers. Somatic mutations were screened using semiconductor sequencing. We detected three index patients (0.25%) with a POLE p.(Leu424Val) variant. In one patient, the variant was found to be de-novo. Tumours from three patients from two families were microsatellite instable, and immunohistochemistry showed MSH6/MSH2 deficiency suggestive of Lynch syndrome. Somatic mutations but no germline MSH6 and MSH2 variants were subsequently found, and one tumour displayed a hypermutator phenotype. None of the 1188 patients carried the POLD1 p.(Ser478Asn) variant. POLE germline variant carriers are also associated with a microsatellite instable CRC. POLE DNA analysis now seems warranted in microsatellite instable CRC, especially in the absence of a causative DNA mismatch repair gene germline variant.","variants":[{"Name":"NM_006231.4(POLE):c.1270C>G (p.Leu424Val)","Chromosome":"12","Start":"132673664","Stop":"132673664","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":48560,"rule_based_match":true,"evidence_text":"POLE c.1270C>G, p.(Leu424Val)","llm_judgment":"PRESENT","evidence":"POLE c.1270C>G, p.(Leu424Val)","abstract_start":253,"abstract_end":282}]}
{"pmid":"36039580","title":"","abstract":"OBJECTIVES: Congenital hypogonadotropic hypogonadism (CHH) is a rare congenital gonadal dysplasia caused by defects in the synthesis, secretion or signal transduction of hypothalamic gonadotropin releasing hormone. The main manifestations of CHH are delayed or lack puberty, low levels of sex hormones and gonadotropins, and may be accompanied with other clinical phenotypes. Some patients with CHH are also accompanied with anosmia or hyposmia, which is called Kalman syndrome (KS). <i>ANOS1</i>, located on X chromosome, is the first gene associated with CHH in an X-linked recessive manner. This study aims to provide a basis for the genetic diagnosis of CHH by analyzing the gene variant spectrum of <i>ANOS1</i> in CHH and the relationship between clinical phenotype and genotype.\nMETHODS: In this study, whole exome sequencing (WES) was used to screen rare sequencing variants (RSVs) of <i>ANOS1</i> in a Chinese cohort of 165 male CHH patients. Four commonly used <i>in silico</i> tools were used to predict the function of the identified RSVs in coding region, including Polyphen2, Mutation Taster, SIFT, and Combined Annotation Dependent Depletion (CADD). Splice Site Prediction by Neural Network (NNSPLICE) was employed to predict possibilities of intronic RSVs to disrupt splicing. American College of Medical Genetics and Genomics (ACMG) guidelines was used to assess the pathogenicity of the detected RSVs. The <i>ANOS1</i> genetic variant spectrum of CHH patients in Chinese population was established. The relationship between clinical phenotype and genotype was analyzed by collecting detailed clinical data.\nRESULTS: Through WES analysis for 165 CHH patients, <i>ANOS1</i> RSVs were detected in 17 of them, with the frequency of 10.3%. A total of 13 RSVs were detected in the 17 probands, including 5 nonsense variants (p.T76X, p.R191X, p.W257X, p.R262X, and p.W589X), 2 splicing site variants (c.318+3A>C, c.1063-1G>C), and 6 missense variants (p.N402S, p.N155D, p.P504L, p.C157R, p.Q635P, and p.V560I). In these 17 CHH probands with <i>ANOS1</i> RSVs, many were accompanied with other clinical phenotypes. The most common associated phenotype was cryptorchidism (10/17), followed by unilateral renal agenesis (3/17), dental agenesis (3/17), and synkinesia (3/17). Eight RSVs, including p.T76X, p.R191X, p.W257X, p.R262X, p.W589X, c.318+3A>C, c.1063-1G>C, and p.C157R, were predicted to be pathogenic or likely pathogenic <i>ANOS1</i> RSVs by ACMG. Eight CHH patients with pathogenic or likely pathogenic <i>ANOS1</i> variants had additional features. In contrast, only one out of nine CHH patients with non-pathogenic (likely benign or uncertain of significance) <i>ANOS1</i> variants according to ACMG exhibited additional features. And function of the non-pathogenic ANOS1 variants accompanied with other CHH-associated RSVs.\nCONCLUSIONS: The <i>ANOS1</i> genetic spectrum of CHH patients in Chinese population is established. Some of the correlations between clinical phenotype and genotype are also established. Our study indicates that CHH patients with pathogenic or likely pathogenic <i>ANOS1</i> RSVs tend to exhibit additional phenotypes. Although non-pathogenic <i>ANOS1</i> variants only may not be sufficient to cause CHH, they may function together with other CHH-associated RSVs to cause the disease.","variants":[{"Name":"NM_000216.4(ANOS1):c.1063-1G>C","Chromosome":"X","Start":"8568377","Stop":"8568377","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1332925,"rule_based_match":true,"evidence_text":"c.1063-1G>C","llm_judgment":"PRESENT","evidence":"c.1063-1G>C","abstract_start":1924,"abstract_end":1935}]}
{"pmid":"35114279","title":"Genetic profiles of non-syndromic severe-profound hearing loss in Chinese Hans by whole-exome sequencing.","abstract":"Hereditary hearing loss is highly heterogeneous. Despite over 120 non-syndromic deafness genes have been identified, there are still some of novel genes and variants being explored. In the study, we investigated 105 Chinese Han children with non-syndromic, prelingual, severe-profound hearing loss by whole-exome sequencing on DNA samples. The most common deafness gene was GJB2, mainly in variant c.235delC (p.Leu79CysfsTer3). 14 children were identified with pathogenic mutations in three genes, GJB2, SLC26A4, and OTOF. Two mutations have been identified to be pathogenic and not recorded previously, including c.4691G > A (p.Trp1564Ter) and c.3928_3930dup (p.Lys1310dup) in OTOF. The rare variants c.1349G > A (p.Arg450His) and c.456 T > G (p.Asn152Lys) in GSDME, and c.1595G > T (p.Ser532Ile) in SLC26A4 were detected. The frequency of nonsense variant c.2359G > T (p.Glu787Ter) in OTOA was very high in 17 cases. Four of them were identified to be digenic inheritance, including GJB2 and COL4A4, GJB2 and EYA1, GJB2 and COL4A5, and GJB2 and DFNA5. The findings showed that a novel pathogenic variant and rare variants may be associated with severe and profound hearing loss.","variants":[{"Name":"NM_001127453.2(GSDME):c.1349G>A (p.Arg450His)","Chromosome":"7","Start":"24699168","Stop":"24699168","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":310689,"rule_based_match":true,"evidence_text":"c.1349G > A (p.Arg450His)","llm_judgment":"PRESENT","evidence":"c.1349G > A (p.Arg450His)","abstract_start":702,"abstract_end":727}]}
{"pmid":"22889856","title":"X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face.","abstract":"BACKGROUND: We present a large Dutch family with seven males affected by a novel syndrome of X-linked intellectual disability, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome. Seven female relatives show a much milder expression of the phenotype.\nMETHODS AND RESULTS: We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping, and introduces a premature stop at the beginning of the histone deacetylase catalytic domain. The identified variant completely segregates in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a notably skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated.\nCONCLUSIONS: HDAC8 is a member of the protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The present family provides the first evidence for involvement of HDAC8 in a syndromic form of intellectual disability.","variants":[{"Name":"NM_018486.3(HDAC8):c.164+5G>A","Chromosome":"X","Start":"72572052","Stop":"72572052","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":45845,"rule_based_match":true,"evidence_text":"c.164+5G>A","llm_judgment":"PRESENT","evidence":"c.164+5G>A","abstract_start":553,"abstract_end":563}]}
{"pmid":"29896746","title":"Diagnose of a neonate with X-linked thrombocytopenia by next generation sequencing","abstract":"OBJECTIVE: To explore the genetic basis for a neonate with bloody stool and thrombocytopenia.\nMETHODS: Clinical data of the neonate was collected. Peripheral venous blood samples were extracted from the neonate and his parents. Next generation sequencing through target capturing was carried out to detect potential mutations of genes associated with thrombocytopenia. Suspected mutation was validated by Sanger sequencing.\nRESULTS: The 14-day-old male neonate was admitted to hospital for bloody stool for 8 days, decreased platelet count and reduced platelet volume. His liver function and blood coagulation were both normal. Genetic testing revealed a novel deletional mutation in c.1221delG (G407fsX444) of the WAS gene in the patient, which was inherited from his mother.\nCONCLUSION: The c.1221delG (G407fsX444) mutation of the WAS gene probably underlies the X-linked thrombocytopenia in the proband. Next generation sequencing can facilitate the diagnose and genetic counseling of such diseases.","variants":[{"Name":"NM_000377.3(WAS):c.1221del (p.Asn408fs)","Chromosome":"X","Start":"48688947","Stop":"48688947","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":1888534,"rule_based_match":true,"evidence_text":"c.1221delG (G407fsX444)","llm_judgment":"PRESENT","evidence":"c.1221delG (G407fsX444)","abstract_start":684,"abstract_end":707}]}
{"pmid":"17250666","title":"Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus.","abstract":"In Cyprus, the prevalence of breast cancer associated with BRCA1 and BRCA2 mutations in young women is unknown. In this study, we present the results of mutational analysis of the BRCA1 and BRCA2 genes in 26 Cypriot women diagnosed with breast cancer by the age of 40. The entire coding regions, including splice sites, of the BRCA1 and BRCA2 genes were sequenced using cycle sequencing. We identified four pathogenic mutations: two in BRCA1 [c.1840A>T (K614X), c.5310delG (5429delG)] and two in BRCA2 [c.3531-3534delCAGC (3758del4), c.8755delG (8984delG)] in six of 26 unrelated patients. The BRCA2 mutation c.3531-3534delCAGC (3758del4) is novel and the BRCA1 mutation c.1840A>T (K614X) is reported for the first time in Cypriot patients. The BRCA2 Cypriot founder mutation c.8755delG (8984delG) was detected in three unrelated patients. Additionally, we identified one novel BRCA1 missense mutation, two novel polymorphisms and three novel intronic variants of which BRCA1 c.4185+3A>G (IVS12+3A>G) may be pathogenic. Of the six BRCA1/2 mutation carriers, only four had a family history. These results show that the prevalence of BRCA1 and BRCA2 mutations in Cypriot women diagnosed with early-onset breast cancer is high. We conclude that Cypriot women with early-onset breast cancer should be offered BRCA1/2 testing irrespective of their family history.","variants":[{"Name":"NM_000059.4(BRCA2):c.3531_3534del (p.Asp1177fs)","Chromosome":"13","Start":"32337886","Stop":"32337889","ReferenceAlleleVCF":"ACAGC","AlternateAlleleVCF":"A","allel_id":66150,"rule_based_match":false,"evidence_text":"c.3531-3534delCAGC (3758del4)","llm_judgment":"PRESENT","evidence":"c.3531-3534delCAGC (3758del4)","abstract_start":503,"abstract_end":532},{"Name":"NM_007294.4(BRCA1):c.5310del (p.Phe1772fs)","Chromosome":"17","Start":"43051085","Stop":"43051085","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":70183,"rule_based_match":true,"evidence_text":"c.5310delG (5429delG)","llm_judgment":"PRESENT","evidence":"c.5310delG (5429delG)","abstract_start":462,"abstract_end":483}]}
{"pmid":"32470407","title":"A novel homozygous missense variant in MATN3 causes spondylo-epimetaphyseal dysplasia Matrilin 3 type in a consanguineous family.","abstract":"Spondylo-epimetaphyseal dysplasia Matrilin 3 type (SEMD) is a rare autosomal recessive skeletal dysplasia characterized by short stature, abnormalities in the vertebral bodies and long bones, especially the lower limbs. We enrolled a consanguineous family from Pakistan in which multiple siblings suffered from severe skeletal dysplasia. The six affected subjects ranged in heights from 100 to 136 cm (~-6 standard deviation). Lower limb abnormalities with variable varus and valgus deformities and joint dysplasia were predominant features of the clinical presentation. Whole exome sequencing (WES) followed by Sanger sequencing identified a missense variant, c.542G > A, p.(Arg181Gln) in MATN3 as the genetic cause of the disorder. The variant was homozygous in all affected individuals while the obligate carriers had normal heights with no skeletal symptoms, consistent with a recessive pattern of inheritance. Multiple sequence alignment revealed that MATN3 domain affected by the variant is highly conserved in orthologous proteins. The c.542G > A, p.(Arg181Gln) variant is only the fourth variant in MATN3 causing an autosomal recessive disorder and thus expands the genotypic spectrum.","variants":[{"Name":"NM_002381.5(MATN3):c.542G>A (p.Arg181Gln)","Chromosome":"2","Start":"20005992","Stop":"20005992","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3066762,"rule_based_match":true,"evidence_text":"c.542G > A, p.(Arg181Gln)","llm_judgment":"PRESENT","evidence":"c.542G > A, p.(Arg181Gln)","abstract_start":661,"abstract_end":686}]}
{"pmid":"29352562","title":"CBS mutations are good predictors for B6-responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients.","abstract":"BACKGROUND: Classical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine β-synthase (CβS). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU.\nMETHODS: gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon-intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT-PCR was performed in six patients. Novel missense point mutations were expressed in E. coli by site-directed mutagenesis.\nRESULTS: Parental consanguinity was reported in 16 families, and pyridoxine responsiveness in five (15%) patients. Among individuals from the same family, all presented the same phenotype. Both pathogenic mutations were identified in 29/30 patients. Twenty-one different mutations were detected in nine exons and three introns; being six common mutations. Most prevalent were p.Ile278Thr (18.2%), p.Trp323Ter (11.3%), p.Thr191Met (11.3%), and c.828+1G>A (11.3%). Eight novel mutations were found [c.2T>C, c.209+1delG, c.284T>C, c.329A>T, c.444delG, c.864_868delGAG c.989_991delAGG, and c.1223+5G>T]. Enzyme activity in E. coli-expressed mutations was 1.5% for c.329A>T and 17.5% for c.284T>C. qRT-PCR analysis revealed reduced gene expression in all evaluated genotypes: [c.209+1delG; c.572C>T]; [c.2T>C; c.828+1G>A]; [c.828+1G>A; c.1126G>A]; [c.833T>C; c.989_991delAGG]; [c.1058C>T; c.146C>T]; and [c.444delG; c.444delG]. The expected phenotype according to the genotype (pyridoxine responsiveness) matched in all cases.\nCONCLUSIONS: Most patients studied were pyridoxine nonresponsive and presented early manifestations, suggesting severe phenotypes. Many private mutations were observed, but the four most prevalent mutations together accounted for over 50% of mutated alleles. A good genotype-phenotype relationship was observed within families and for the four most common mutations.","variants":[{"Name":"NM_000071.3(CBS):c.828+1G>A","Chromosome":"21","Start":"43063899","Stop":"43063899","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":549273,"rule_based_match":true,"evidence_text":"c.828+1G>A","llm_judgment":"PRESENT","evidence":"c.828+1G>A","abstract_start":1003,"abstract_end":1013},{"Name":"NM_000071.3(CBS):c.2T>C (p.Met1Thr)","Chromosome":"21","Start":"43072192","Stop":"43072192","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":193365,"rule_based_match":true,"evidence_text":"c.2T>C","llm_judgment":"PRESENT","evidence":"c.2T>C","abstract_start":1057,"abstract_end":1063},{"Name":"NM_000071.3(CBS):c.284T>C (p.Ile95Thr)","Chromosome":"21","Start":"43068541","Stop":"43068541","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":471673,"rule_based_match":true,"evidence_text":"c.284T>C","llm_judgment":"PRESENT","evidence":"c.284T>C","abstract_start":1078,"abstract_end":1086}]}
{"pmid":"30275003","title":"Whole-exome sequencing enables correct diagnosis and surgical management of rare inherited childhood anemia.","abstract":"Correct diagnosis of inherited bone marrow failure syndromes is a challenge because of the significant overlap in clinical presentation of these disorders. Establishing right genetic diagnosis is crucial for patients' optimal clinical management and family counseling. A nondysmorphic infant reported here developed severe transfusion-dependent anemia and met clinical criteria for diagnosis of Diamond-Blackfan anemia (DBA). However, whole-exome sequencing demonstrated that the child was a compound heterozygote for a paternally inherited pathogenic truncating variant (<i>SPTA1</i><sup>c.4975 C>T)</sup> and a novel maternally inherited missense variant of uncertain significance (<i>SPTA1</i><sup>c.5029 G>A</sup>) within the spectrin gene, consistent with hereditary hemolytic anemia due to disruption of red blood cell (RBC) cytoskeleton. Ektacytometry demonstrated abnormal membrane flexibility of the child's RBCs. Scanning electron microscopy revealed morphological aberrations of the patient's RBCs. Both parents were found to have mild hereditary elliptocytosis. Importantly, patients with severe RBC membrane defects may be successfully managed with splenectomy to minimize peripheral destruction of misshapen RBCs, whereas patients with DBA require lifelong transfusions, steroid therapy, or hematopoietic stem cell transplantation. As suggested by the WES findings, splenectomy rendered our patient transfusion-independent, improving the family's quality of life and preventing transfusion-related iron overload. This case illustrates the utility of whole-exome sequencing in clinical care of children with genetic disorders of unclear presentation.","variants":[{"Name":"NM_003126.4(SPTA1):c.4975C>T (p.Arg1659Ter)","Chromosome":"1","Start":"158639587","Stop":"158639587","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":553135,"rule_based_match":true,"evidence_text":"SPTA1<sup>c.4975 C>T)</sup>","llm_judgment":"PRESENT","evidence":"SPTA1<sup>c.4975 C>T)</sup>","abstract_start":null,"abstract_end":null}]}
{"pmid":"27659712","title":"Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype.","abstract":"Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic β-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants.","variants":[{"Name":"NM_000207.3(INS):c.125T>C (p.Val42Ala)","Chromosome":"11","Start":"2160847","Stop":"2160847","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":247779,"rule_based_match":true,"evidence_text":"c.125T > C","llm_judgment":"PRESENT","evidence":"c.125T > C","abstract_start":1063,"abstract_end":1073}]}
{"pmid":"23756445","title":"AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome).","abstract":"MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity.","variants":[{"Name":"NM_001272071.2(AP1S2):c.426+1G>T","Chromosome":"X","Start":"15845378","Stop":"15845378","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":150141,"rule_based_match":true,"evidence_text":"AP1S2 c.426+1 G>T","llm_judgment":"PRESENT","evidence":"AP1S2 c.426+1 G>T","abstract_start":765,"abstract_end":782}]}
{"pmid":"20937241","title":"Expression and processing of the TMEM70 protein.","abstract":"TMEM70 protein represents a novel ancillary factor of mammalian ATP synthase. We have investigated import and processing of this factor in human cells using GFP- and FLAG-tagged forms of TMEM70 and specific antibodies. TMEM70 is synthesized as a 29kDa precursor protein that is processed to a 21kDa mature form. Immunocytochemical detection of TMEM70 showed mitochondrial colocalization with MitoTracker Red and ATP synthase. Western blot of subcellular fractions revealed the highest signal of TMEM70 in isolated mitochondria and mitochondrial location was confirmed by mass spectrometry analysis. Based on analysis of submitochondrial fractions, TMEM70 appears to be located in the inner mitochondrial membrane, in accordance with predicated transmembrane regions in the central part of the TMEM70 sequence. Two-dimensional electrophoretic analysis did not show direct interaction of TMEM70 with assembled ATP synthase but indicated the presence of dimeric form of TMEM70. No TMEM70 protein could be found in cells and isolated mitochondria from patients with ATP synthase deficiency due to TMEM70 c.317-2A>G mutation thus confirming that TMEM70 biosynthesis is prevented in these patients.","variants":[{"Name":"NM_017866.6(TMEM70):c.317-2A>G","Chromosome":"8","Start":"73981153","Stop":"73981153","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15579,"rule_based_match":true,"evidence_text":"TMEM70 c.317-2A>G","llm_judgment":"PRESENT","evidence":"TMEM70 c.317-2A>G","abstract_start":1093,"abstract_end":1110}]}
{"pmid":"17536044","title":"Multitissular involvement in a family with LMNA and EMD mutations: Role of digenic mechanism?","abstract":"BACKGROUND: Mutations in the EMD and LMNA genes, encoding emerin and lamins A and C, are responsible for the X-linked and autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (EDMD). LMNA mutations can also lead to several other disorders, collectively termed laminopathies, involving heart, fat, nerve, bone, and skin tissues, and some premature ageing syndromes.\nMETHODS: Fourteen members of a single family underwent neurologic, electromyographic, and cardiologic assessment. Gene mutation and protein expression analyses were performed for lamins A/C and emerin.\nRESULTS: Clinical investigations showed various phenotypes, including isolated cardiac disease (seven patients), axonal neuropathy (one patient), and a combination of EDMD with axonal neuropathy (two patients), whereas five subjects remained asymptomatic. Genetic analyses identified the coincidence of a previously described homozygous LMNA mutation (c.892C-->T, p. R298C) and a new in-frame EMD deletion (c.110-112delAGA, p. delK37), which segregate independently. Analyses of the contribution of these mutations showed 1) the EMD codon deletion acts in X-linked dominant fashion and was sufficient to induce the cardiac disease, 2) the combination of both the hemizygous EMD and the homozygous LMNA mutations was necessary to induce the EDMD phenotype, 3) emerin was present in reduced amount in EMD-mutated cells, and 4) lamin A/C and emerin expression was most dramatically affected in the doubly mutated fibroblasts.\nCONCLUSIONS: This highlights the crucial role of lamin A/C-emerin interactions, with evidence for synergistic effects of these mutations that lead to Emery-Dreifuss muscular dystrophy as the worsened result of digenic mechanism in this family.","variants":[{"Name":"NM_170707.4(LMNA):c.892C>T (p.Arg298Cys)","Chromosome":"1","Start":"156135268","Stop":"156135268","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29537,"rule_based_match":false,"evidence_text":"c.892C-->T, p. R298C","llm_judgment":"PRESENT","evidence":"c.892C-->T, p. R298C","abstract_start":942,"abstract_end":962}]}
{"pmid":"25501839","title":"High frequency of splice site mutation in 21-hydroxylase deficiency children.","abstract":"PURPOSE: Steroid 21-hydroxylase deficiency (21-OHD) is the common type of congenital adrenal hyperplasia (CAH) caused by defects in the CYP21A2 gene, as an autosomal recessive disease, genetic analysis has a prominent role in its diagnosis. Our objectives were to determine the prevalence of common mutations in a group of Egyptian patients with 21-OHD and their families using rapid methods, and also to detect the rate of deletion, duplication and conversions in CYP21A2 gene.\nMETHODS: Rapid detection methods were used: allele-specific PCR for c.293-13A>G (g.659A>G), c.518T>A (p.I172N) variants and c.332_339del (8-bp deletion in exon 3), and real-time, quantitative PCR assay was used to detect deletion in the CYP21A2 gene. 29 Egyptian patients, 38 family members, and 20 healthy controls were all included in the study.\nRESULTS: The frequency of c.293-13A>G splice mutation was reported in 96.6 % cases, G allele had 2.5-folds higher risk to develop CAH than other alleles. The c.518T>A mutation was reported in 69 % cases, children carrying the mutant allele were 2.1 times more risk. The most frequent combined mutations detected were c.293-13A/C>G/c.518T>A in 58.6 % cases.\nCONCLUSION: The genetic analysis of the splice site mutation c.293-13A>G and c.518T>A variant can be used as good biomarkers for early detection of cases and carriers in 21-OHD CAH Egyptian children, since the methods used have rapid turnaround time.","variants":[{"Name":"NM_000500.9(CYP21A2):c.518T>A (p.Ile173Asn)","Chromosome":"6","Start":"32039426","Stop":"32039426","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":27189,"rule_based_match":true,"evidence_text":"c.518T>A (p.I172N)","llm_judgment":"PRESENT","evidence":"c.518T>A (p.I172N)","abstract_start":571,"abstract_end":589}]}
{"pmid":"24069336","title":"A missense mutation in the alpha-actinin 1 gene (ACTN1) is the cause of autosomal dominant macrothrombocytopenia in a large French family.","abstract":"Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22) with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln) in the alpha-actinin 1 gene (ACTN1) that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes.","variants":[{"Name":"NM_001130004.2(ACTN1):c.137G>A (p.Arg46Gln)","Chromosome":"14","Start":"68925641","Stop":"68925641","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":51196,"rule_based_match":false,"evidence_text":"c.137G>A (p.Arg46Gln)","llm_judgment":"PRESENT","evidence":"p.Arg46Gln","abstract_start":794,"abstract_end":804}]}
{"pmid":"28667000","title":"Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia.","abstract":"Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited β-globin mutation (<i>HBB</i>:c.93-21G>A, IVS-I-110:G>A), a known cause of β-thalassemia minor. As this mutation alone was inconsistent with the severity of the anemia, we performed WES. Although we could not identify any relevant pathogenic single-nucleotide variants (SNVs) or small indels, copy-number variant (CNV) analyses revealed a likely triplication of the entire α-globin cluster, which was subsequently confirmed by multiplex ligation-dependent probe amplification. Treatment and follow-up was redefined according to the diagnosis of β-thalassemia intermedia resulting from a single β-thalassemia mutation in combination with an α-globin cluster triplication. Thus, we describe a case where the typical WES-based analysis of SNVs and small indels was unrevealing, but WES-based CNV analysis resulted in a definitive diagnosis that informed clinical decision-making. More generally, this case illustrates the value of performing CNV analysis when WES is otherwise unable to elucidate a clear genetic diagnosis.","variants":[{"Name":"NM_000518.5(HBB):c.93-21G>A","Chromosome":"11","Start":"5226820","Stop":"5226820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30493,"rule_based_match":true,"evidence_text":"HBB:c.93-21G>A, IVS-I-110:G>A","llm_judgment":"PRESENT","evidence":"c.93-21G>A","abstract_start":504,"abstract_end":514}]}
{"pmid":"31185936","title":"GALC mutations in Chinese patients with late-onset Krabbe disease: a case report.","abstract":"BACKGROUND: Krabbe disease (also known as globoid cell leukodystrophy) cause by a deficiency of the enzyme β-galactocerebrosidase (galactosylceramidase, GALC). The deficiency of GALC leads to accumulation of galactosylceramide and psychosine, the latter GALC substrate having a potential role in triggering demyelination. Typically, the disease has an infantile onset, with rapid deterioration in the first few months, leading to death before the age of 2 years. The late onset forms (late-infantile, juvenile, and adult forms) are rare with variable clinical outcomes, presenting spastic paraplegia as the main symptom.\nCASE PRESENTATION: We recruited a family with two affected individuals. The proband (Patient 1), a 25-year-old male, was presented with slow progressive symptoms, including spastic gait disturbance and vision loss since the 5th year of life. His elder sister (Patient 2), became wheelchair-bound and demented at the age of 22 years. Brain magnetic resonance imaging (MRI) showed increased signal intensity in the white matter along with the involvement of the bilateral corticospinal tracts. GALC deficiency was confirmed by biochemical analysis. DNA sequencing revealed two mutations (c.865G > C: p. G289R and c.136G > T: p. D46Y) in GALC. The clinical characteristics, brain MRI, biochemical and molecular findings led to the diagnosis of Krabbe disease.\nCONCLUSION: Clinical and neuroimaged signs, positive enzymatic analysis and molecular data converged to definite diagnosis in this neurodegenerative disease.","variants":[{"Name":"NM_000153.4(GALC):c.136G>T (p.Asp46Tyr)","Chromosome":"14","Start":"87993029","Stop":"87993029","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":621480,"rule_based_match":true,"evidence_text":"c.136G > T: p. D46Y","llm_judgment":"PRESENT","evidence":"c.136G > T: p. D46Y","abstract_start":1232,"abstract_end":1251}]}
{"pmid":"36942482","title":"A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81.","abstract":"BACKGROUND: Hereditary spastic paraplegia 81 is a recently identified, rare autosomal recessive disease, caused by biallelic pathogenic variants in the SELENOI gene, with only two families reported to date. The features documented in the two previous affected families include sensorineural deafness, blindness, cleft palate, delayed motor development, regression of motor skills, impaired intellectual development, poor speech and language acquisition, spasticity, hyperreflexia, white matter abnormalities and cerebral and cerebellar atrophy.\nMETHODS: In the present study, we performed exome sequencing analysis in a single family with two affected siblings to identify the genetic cause of complicated hereditary spastic paraplegia. The results were further confirmed by Sanger sequencing, cDNA analysis and 3D protein modelling.\nRESULTS: Exome sequencing identified a homozygous, synonymous variant in the SELENOI gene (NM_033505.4:c.126G>A:p.(Lys42Lys)) in both of the siblings. Sanger sequencing confirmed the heterozygous status in both parents consistent with the autosomal recessive inheritance. This variant has been found to disrupt normal splicing and lead to skipping of exon 2, causing in-frame deletion of SELENOI N-terminal 23 amino acids [NM_033505.4:c.57_126del:p.(Tyr20_Lys42del)] and further leading to structural changes in the protein.\nCONCLUSIONS: We report a novel homozygous synonymous variant in the SELENOI gene causing abnormal splicing in two patients affected with hereditary spastic paraplegia 81. This report further expands the phenotypic and genotypic spectrum of hereditary spastic paraplegia 81.","variants":[{"Name":"NM_033505.4(SELENOI):c.126G>A (p.Lys42=)","Chromosome":"2","Start":"26364370","Stop":"26364370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2741432,"rule_based_match":true,"evidence_text":"NM_033505.4:c.126G>A:p.(Lys42Lys)","llm_judgment":"PRESENT","evidence":"NM_033505.4:c.126G>A:p.(Lys42Lys)","abstract_start":925,"abstract_end":958}]}
{"pmid":"26583494","title":"Anticholinesterase Therapy Worsening Head Drop and Limb Weakness Due to a Novel DOK7 Mutation.","abstract":"Dok-7 myasthenia is an autosomal recessive congenital myasthenic syndrome due to DOK7 mutations. Anticholinesterase therapy is ineffective and may worsen the weakness in patients with Dok-7 myasthenia or few other forms of congenital myasthenic syndromes. We describe a 31-year-old man previously diagnosed with seronegative myasthenia gravis. Repetitive stimulation of the right spinal accessory nerve showed 51% decrement. Needle electromyography revealed myopathic changes in clinically affected muscles. Muscle biopsy was normal. The patient was referred to us for worsening weakness after taking pyridostigmine. We searched for DOK7 mutations and identified compound heterozygous mutations of a common c.1124_1127dupTGCC mutation and a novel splice site mutation, c.772+2_+4delinsCCGGGCAGGCGGGCA. Discontinuation of pyridostigmine improved weakness. He further regained strength with oral albuterol therapy and decrement was reduced to 25%. Worsening of symptoms with anticholinesterase therapy in patients with \"seronegative myasthenia gravis\" should prompt clinicians to consider a possibility of congenital myasthenic syndromes to avoid unnecessary use of immunosuppressive therapy. Patients with Dok-7 myasthenia respond well to oral albuterol treatment.","variants":[{"Name":"NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs)","Chromosome":"4","Start":"3493106","Stop":"3493107","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AGCCT","allel_id":16312,"rule_based_match":true,"evidence_text":"c.1124_1127dupTGCC","llm_judgment":"PRESENT","evidence":"c.1124_1127dupTGCC","abstract_start":707,"abstract_end":725}]}
{"pmid":"25644864","title":"Asp58Ala is the predominant mutation of the TTR gene in Korean patients with hereditary transthyretin-related amyloidosis.","abstract":"Hereditary transthyretin (TTR)-related amyloidosis (ATTR) seems to be a rare autosomal-dominant inherited form of systemic amyloidosis. Studies indicate considerable heterogeneity in the disease's presentation and genotype; however, there is little data from Korea, where the prevalence of hereditary ATTR is very low. In this study, we investigated the phenotypic and genotypic spectra of hereditary ATTR in Korea. Direct sequencing analysis was performed to detect TTR gene mutations in amyloidosis patients whose results of TTR immunohistochemical staining were positive or equivocal. Clinical presentation was categorized as exclusively cardiac, exclusively neurologic, or mixed phenotype. Of 12 genetic tests performed, seven were positive for TTR mutations. D58A (c.173A>C) was the most common mutation in this study (57%, 4/7). The majority of those patients with hereditary ATTR had the mixed phenotype (86%, 6/7). The patients with D58A mutation had older ages of disease onset (median, 61 years vs. 42 years; P = 0.08), and a higher incidence of gastrointestinal involvement (75% vs. 0%; P = 0.03) than those with other identified TTR mutations. A significant male predominance was also noted in this study (P = 0.01).","variants":[{"Name":"NM_000371.4(TTR):c.173A>C (p.Asp58Ala)","Chromosome":"18","Start":"31592999","Stop":"31592999","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":647190,"rule_based_match":true,"evidence_text":"c.173A>C","llm_judgment":"PRESENT","evidence":"c.173A>C","abstract_start":770,"abstract_end":778}]}
{"pmid":"29419857","title":"Detection of GCDH mutations in five Chinese patients with glutaric acidemia type I","abstract":"OBJECTIVE To detect potential mutations of GCDH gene in five patients with glutaric acidemia type I (GA-I). METHODS Genomic DNA was extracted from peripheral blood samples from the patients. The 11 exons and their flanking sequences of the GCDH gene were amplified with PCR and subjected to direct sequencing. RESULTS Four mutations of the GCDH gene were identified among the patients, which included c.532G>A (p.G178R), c.533G>A (p.G178E), c.106_107delAC (p.Q37fs*5) and c.1244-2A>C. Among these, c.1244-2A>C was the most common, while c.106_107delAC was a novel mutation, which was predicted to be pathogenic by MutationTaster software. CONCLUSION The diagnosis of GA-I has been confirmed in all of the five patients. Identification of the novel GCDH mutations has enriched the mutational spectrum of the GCDH gene.","variants":[{"Name":"NM_000159.4(GCDH):c.533G>A (p.Gly178Glu)","Chromosome":"19","Start":"12896019","Stop":"12896019","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187040,"rule_based_match":true,"evidence_text":"c.533G>A (p.G178E)","llm_judgment":"PRESENT","evidence":"c.533G>A (p.G178E)","abstract_start":421,"abstract_end":439}]}
{"pmid":"34184482","title":"Autosomal dominant spastic paraplegias","abstract":"OBJECTIVE: To estimate the proportion and spectrum of infrequent autosomal dominant spastic paraplegias in a group of families with DNA-confirmed diagnosis and to investigate their molecular and clinical characteristics.\nMATERIAL AND METHODS: Ten families with 6 AD-SPG: SPG6 (<i>n</i>=1), SPG8 (<i>n</i>=2), SPG9A (<i>n</i>=1), SPG12 (<i>n</i>=1), SPG17 (<i>n</i>=3), SPG31 (<i>n</i>=2) were studied using clinical, genealogical, molecular-genetic (massive parallel sequencing, spastic paraplegia panel, whole-exome sequencing, multiplex ligation-dependent amplification, Sanger sequencing) and bioinformatic methods.\nRESULTS AND CONCLUSION: Nine heterozygous mutations were detected in 6 genes, including the common <i>de novo</i> mutation p.Gly106Arg in <i>NIPA1</i> (SPG6), the earlier reported mutation p.Val626Phe in WASHC5 (SPG8) in isolated case and the novel p.Val695Ala in <i>WASHC5</i> (SPG8) in a family with 4 patients, the novel mutation p.Thr301Arg in <i>RTN2</i> (SPG12) in a family with 2 patients, the novel mutation c.105+4A>G in <i>REEP1</i> (SPG31) in a family with 4 patients and the reported earlier p.Lys101Lys in <i>REEP1</i> (SPG31) in a family with 3 patients, the known <i>de novo</i> mutation p.Arg252Gln in <i>ALDH18A1</i> (SPG9A) in two monozygous twins; the common mutation p.Ser90Leu in <i>BSCL2</i> (SPG17) in a family with 3 patients and in isolated case, reported mutation p.Leu363Pro in a family with 2 patients. SPG6, SPG8, SPG12 and SPG31 presented 'pure' phenotypes, SPG31 had most benign course. Age of onset varied in SPG31 family and was atypically early in SPG6 case. Patients with SPG9A and SPG17 had 'complicated' paraplegias; amyotrophy of hands typical for SPG17 was absent in a child and in an adolescent from 2 families, but may develop later.","variants":[{"Name":"NM_014846.4(WASHC5):c.1876G>T (p.Val626Phe)","Chromosome":"8","Start":"125056817","Stop":"125056817","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":16200,"rule_based_match":false,"evidence_text":"p.Val626Phe in WASHC5 (SPG8)","llm_judgment":"PRESENT","evidence":"p.Val626Phe in WASHC5 (SPG8)","abstract_start":808,"abstract_end":836}]}
{"pmid":"24586645","title":"Clinical, molecular and functional investigation on an infant with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).","abstract":"BACKGROUND AND OBJECTIVE: SLC25A13 analysis has provided reliable evidences for the definitive diagnosis of citrin deficiency (CD) in the past decade. Meanwhile, these studies generated some issues yet to be resolved, including the pathogenicity of SLC25A13 missense mutations and the mRNA product from the mutation c.615+5G>A. This study aims to investigate the effect of a novel missense mutation on the aspartate/glutamate carrier (AGC) function of citrin protein, and to explore the aberrant transcript from c.615+5G>A in the same CD infant.\nMETHODS AND RESULTS: By means of screening for prevalent SLC25A13 mutations and exons sequencing, the patient proved a compound heterozygote of c.615+5G>A and a novel c.1064G>A (p.Arg355Gln) mutation. An aberrant transcript with retention of the entire intron 6, r.[615+1_615+1789ins; 615+5 g>a] (GenBank accession number KJ128074), which was resulted from c.615+5G>A, was detected by RT-PCR and cDNA sequencing. After bioinformatic analyses of the novel missense mutation c.1064G>A, the growth abilities of three agc1Δ yeast strains were tested, which had been transformed with recombinant or empty vectors, respectively. Besides the bioinformatically pathogenic evidences, the growth ability of the agc1Δ strains transformed with mutant recombinant was the same as with empty vector, but significantly lower than that with normal control in functional analysis.\nCONCLUSIONS: A CD infant was definitely diagnosed in this paper by a genetic, transcriptional and functional analysis of SLC25A13 gene. This study provided direct laboratory evidences supporting the splice-site nature of the c.615+5G>A mutation, and the novel c.1064G>A variation, which proved a pathogenic mutation bioinformatically and functionally, enriched the SLC25A13 mutation spectrum.","variants":[{"Name":"NM_014251.3(SLC25A13):c.615+5G>A","Chromosome":"7","Start":"96193032","Stop":"96193032","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34369,"rule_based_match":true,"evidence_text":"c.615+5G>A","llm_judgment":"PRESENT","evidence":"c.615+5G>A","abstract_start":316,"abstract_end":326},{"Name":"NM_014251.3(SLC25A13):c.1064G>A (p.Arg355Gln)","Chromosome":"7","Start":"96184390","Stop":"96184390","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":97542,"rule_based_match":true,"evidence_text":"c.1064G>A (p.Arg355Gln)","llm_judgment":"PRESENT","evidence":"c.1064G>A (p.Arg355Gln)","abstract_start":713,"abstract_end":736}]}
{"pmid":"21820100","title":"Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.","abstract":"Charcot-Marie-Tooth disease is characterized by length-dependent axonal degeneration with distal sensory loss and weakness, deep-tendon-reflex abnormalities, and skeletal deformities. It is caused by mutations in more than 40 genes. We investigated a four-generation family with 23 members affected by the axonal form (type 2), for which the common causes had been excluded by Sanger sequencing. Exome sequencing of three affected individuals separated by eight meioses identified a single shared novel heterozygous variant, c.917A>G, in DYNC1H1, which encodes the cytoplasmic dynein heavy chain 1 (here, novel refers to a variant that has not been seen in dbSNP131or the August 2010 release of the 1000 Genomes project). Testing of six additional affected family members showed cosegregation and a maximum LOD score of 3.6. The shared DYNC1H1 gene variant is a missense substitution, p.His306Arg, at a highly conserved residue within the homodimerization domain. Three mouse models with different mutations within this domain have previously been reported with age-related progressive loss of muscle bulk and locomotor ability. Cytoplasmic dynein is a large multisubunit motor protein complex and has a key role in retrograde axonal transport in neurons. Our results highlight the importance of dynein and retrograde axonal transport in neuronal function in humans.","variants":[{"Name":"NM_001376.5(DYNC1H1):c.917A>G (p.His306Arg)","Chromosome":"14","Start":"101980506","Stop":"101980506","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":38984,"rule_based_match":true,"evidence_text":"c.917A>G","llm_judgment":"PRESENT","evidence":"c.917A>G","abstract_start":525,"abstract_end":533}]}
{"pmid":"34573309","title":"MED12 Mutation in Two Families with X-Linked Ohdo Syndrome.","abstract":"X-linked intellectual deficiency (XLID) is a widely heterogeneous group of genetic disorders that involves more than 100 genes. The mediator of RNA polymerase II subunit 12 (MED12) is involved in the regulation of the majority of RNA polymerase II-dependent genes and has been shown to cause several forms of XLID, including Opitz-Kaveggia syndrome also known as FG syndrome (MIM #305450), Lujan-Fryns syndrome (MIM #309520) and the X-linked Ohdo syndrome (MIM #300895). Here, we report on two first cousins with X-linked Ohdo syndrome with a missense mutation in <i>MED12</i> gene, identified through whole exome sequencing. The probands had facial features typical of X-linked Ohdo syndrome, including blepharophimosis, ptosis, a round face with a characteristic nose and a narrow mouth. Nextera DNA Exome kit (Illumina Inc., San Diego, CA, USA) was used for exome capture. The variant identified was a c.887G > A substitution in exon 7 of the <i>MED12</i> gene leading to the substitution of a glutamine for a highly conserved arginine (p. Arg296Gln). Although the variant described has been previously reported in the literature, our study contributes to the expanding phenotypic spectrum of <i>MED12</i>-related disorders and above all, it demonstrates the phenotypic variability among different affected patients despite harboring identical mutations.","variants":[{"Name":"NM_005120.3(MED12):c.887G>A (p.Arg296Gln)","Chromosome":"X","Start":"71121602","Stop":"71121602","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":512733,"rule_based_match":true,"evidence_text":"c.887G > A","llm_judgment":"PRESENT","evidence":"c.887G > A","abstract_start":905,"abstract_end":915}]}
{"pmid":"17643332","title":"Identification of the molecular defects in Spanish and Argentinian mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) patients, including 9 novel mutations.","abstract":"Maroteaux-Lamy syndrome, or mucopolysaccharidosis VI (MPS VI), is an autosomal recessive lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase or arylsulfatase B (ARSB). We aimed to analyze the spectrum of mutations responsible for the disorder in Spanish and Argentinian patients, not previously studied. We identified all the ARSB mutant alleles, nine of them novel, in 12 Spanish and 4 Argentinian patients. The new changes were as follows: six missense mutations: c.245T>G [p.L82R], c.413A>G [p.Y138C], c.719C>T [p.S240F], c.922G>A [p.G308R], c.1340G>T [p.C447F] and c.1415T>C [p.L472P]; one nonsense mutation: c.966G>A [p.W322X]; and two intronic changes involving splice sites: c.1142+2T>A, in the donor splice site of intron 5, which promotes skipping of exon 5, and c.1143-1G>C, which disrupts the acceptor site of intron 5, resulting in skipping of exon 6. We also report 10 previously described mutations as well as several non-pathogenic polymorphisms. Haplotype analysis indicated a common origin for most of the mutations found more than once. Most of the patients were compound heterozygotes, whereas only four of them were homozygous. These observations confirm the broad allelic heterogeneity of the disease, with 19 different mutations in 16 patients. However, the two most frequent mutations, c.1143-1G>C and c.1143-8T>G, present in both populations, accounted for one-third of the mutant alleles in this group of patients.","variants":[{"Name":"NM_000046.5(ARSB):c.1415T>C (p.Leu472Pro)","Chromosome":"5","Start":"78780584","Stop":"78780584","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":550400,"rule_based_match":true,"evidence_text":"c.1415T>C [p.L472P]","llm_judgment":"PRESENT","evidence":"c.1415T>C [p.L472P]","abstract_start":604,"abstract_end":623},{"Name":"NM_000046.5(ARSB):c.1340G>T (p.Cys447Phe)","Chromosome":"5","Start":"78780659","Stop":"78780659","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":550406,"rule_based_match":true,"evidence_text":"c.1340G>T [p.C447F]","llm_judgment":"PRESENT","evidence":"c.1340G>T [p.C447F]","abstract_start":580,"abstract_end":599},{"Name":"NM_000046.5(ARSB):c.1142+2T>A","Chromosome":"5","Start":"78885582","Stop":"78885582","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":550432,"rule_based_match":true,"evidence_text":"c.1142+2T>A","llm_judgment":"PRESENT","evidence":"c.1142+2T>A","abstract_start":717,"abstract_end":728},{"Name":"NM_000046.5(ARSB):c.245T>G (p.Leu82Arg)","Chromosome":"5","Start":"78985004","Stop":"78985004","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":438563,"rule_based_match":true,"evidence_text":"c.245T>G [p.L82R]","llm_judgment":"PRESENT","evidence":"c.245T>G [p.L82R]","abstract_start":501,"abstract_end":518},{"Name":"NM_000046.5(ARSB):c.966G>A (p.Trp322Ter)","Chromosome":"5","Start":"78885760","Stop":"78885760","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550448,"rule_based_match":true,"evidence_text":"c.966G>A [p.W322X]","llm_judgment":"PRESENT","evidence":"c.966G>A [p.W322X]","abstract_start":648,"abstract_end":666},{"Name":"NM_000046.5(ARSB):c.1143-1G>C","Chromosome":"5","Start":"78839427","Stop":"78839427","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":15926,"rule_based_match":true,"evidence_text":"c.1143-1G>C","llm_judgment":"PRESENT","evidence":"c.1143-1G>C","abstract_start":807,"abstract_end":818},{"Name":"NM_000046.5(ARSB):c.922G>A (p.Gly308Arg)","Chromosome":"5","Start":"78885804","Stop":"78885804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550455,"rule_based_match":true,"evidence_text":"c.922G>A [p.G308R]","llm_judgment":"PRESENT","evidence":"c.922G>A [p.G308R]","abstract_start":560,"abstract_end":578},{"Name":"NM_000046.5(ARSB):c.1143-8T>G","Chromosome":"5","Start":"78839434","Stop":"78839434","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":15927,"rule_based_match":true,"evidence_text":"c.1143-8T>G","llm_judgment":"PRESENT","evidence":"c.1143-8T>G","abstract_start":1360,"abstract_end":1371},{"Name":"NM_000046.5(ARSB):c.719C>T (p.Ser240Phe)","Chromosome":"5","Start":"78955474","Stop":"78955474","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":550471,"rule_based_match":true,"evidence_text":"c.719C>T [p.S240F]","llm_judgment":"PRESENT","evidence":"c.719C>T [p.S240F]","abstract_start":540,"abstract_end":558},{"Name":"NM_000046.5(ARSB):c.413A>G (p.Tyr138Cys)","Chromosome":"5","Start":"78969092","Stop":"78969092","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":550500,"rule_based_match":true,"evidence_text":"c.413A>G [p.Y138C]","llm_judgment":"PRESENT","evidence":"c.413A>G [p.Y138C]","abstract_start":520,"abstract_end":538}]}
{"pmid":"24443915","title":"Mutations in EXPH5 result in autosomal recessive inherited skin fragility.","abstract":"Several different genes have been implicated in the pathophysiology of inherited blistering skin diseases. Recently, autosomal recessive loss-of-function mutations in EXPH5 (encoding exophilin-5, also known as Slac2-b, a protein involved in intracellular vesicle transport) were identified in a new mechanobullous disease resembling a form of epidermolysis bullosa simplex (EBS). Here, we searched for mutations in EXPH5 in a 4-year-old white boy with EBS in whom initial Sanger sequencing of known genes implicated in intraepidermal skin fragility failed to identify pathogenic mutations. Transmission electron microscopy of rubbed nonlesional patient skin revealed disruption of keratinocytes in the lower epidermis with cytolysis and acantholysis, keratin filament clumping and prominent perinuclear cytoplasmic vesicles, and provided the clue to the candidate gene pathology. Sanger sequencing of genomic DNA showed compound heterozygosity for two new mutations in EXPH5, c.1947dupC (p.Pro649fsPro*11) and c.2249C>A (p.Ser750*). Immunofluorescence microscopy of patient skin showed a complete absence of exophilin-5 labelling. This case represents the third pedigree with EXPH5 mutations resulting in inherited skin fragility. The clinical and molecular data expand genotype-phenotype correlation in this new form of EBS and demonstrate the important role of exophilin-5 in keratinocyte cell biology.","variants":[{"Name":"NM_015065.3(EXPH5):c.2249C>A (p.Ser750Ter)","Chromosome":"11","Start":"108513258","Stop":"108513258","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1295245,"rule_based_match":true,"evidence_text":"c.2249C>A (p.Ser750*)","llm_judgment":"PRESENT","evidence":"c.2249C>A (p.Ser750*)","abstract_start":1010,"abstract_end":1031}]}
{"pmid":"25098539","title":"A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function.","abstract":"OBJECTIVE: To describe a novel mutation in TRK-fused gene (TFG) as a new cause of dominant axonal Charcot-Marie-Tooth disease (CMT) identified by exome sequencing and further characterized by in vitro functional studies.\nMETHODS: Exome sequencing and linkage analysis were utilized to investigate a large Taiwanese family with a dominantly inherited adult-onset motor and sensory axonal neuropathy in which mutations in common CMT2-implicated genes had been previously excluded. Functional effects of the mutant gene products were investigated in vitro.\nRESULTS: Exome sequencing of 2 affected individuals in this family revealed a novel heterozygous mutation, c.806G>T (p.Gly269Val), in TFG that perfectly cosegregates with the CMT2 phenotype in all 27 family members. This mutation occurs at an evolutionarily conserved residue and is absent in the 1,140 ethnically matched control chromosomes. Genome-wide linkage study also supported its disease-causative role. Cell transfection studies showed that the TFG p.Gly269Val mutation increased the propensity of TFG proteins to form aggregates, resulting in sequestration of both mutant and wild-type TFG proteins and might thus deplete functional TFG molecules. The secreted Gaussia luciferase reporter assay demonstrated that inhibition of endogenous TFG compromised the protein secretion pathways, which could only be rescued by expressing wild-type TFG but not the p.Gly269Val altered proteins. TFG mutation was not found in 55 additional unrelated patients with CMT2, suggesting its rarity.\nCONCLUSION: This study identifies a new cause of dominant CMT2 and highlights the importance of TFG in the protein secretory pathways that are essential for proper functioning of the human peripheral nervous system.","variants":[{"Name":"NM_006070.6(TFG):c.806G>T (p.Gly269Val)","Chromosome":"3","Start":"100744917","Stop":"100744917","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":166216,"rule_based_match":true,"evidence_text":"c.806G>T (p.Gly269Val)","llm_judgment":"PRESENT","evidence":"c.806G>T (p.Gly269Val)","abstract_start":661,"abstract_end":683}]}
{"pmid":"32303640","title":"Structure-function analyses of the G729R 2-oxoadipate dehydrogenase genetic variant associated with a disorder of l-lysine metabolism.","abstract":"2-Oxoadipate dehydrogenase (E1a, also known as DHTKD1, dehydrogenase E1, and transketolase domain-containing protein 1) is a thiamin diphosphate-dependent enzyme and part of the 2-oxoadipate dehydrogenase complex (OADHc) in l-lysine catabolism. Genetic findings have linked mutations in the <i>DHTKD1</i> gene to several metabolic disorders. These include α-aminoadipic and α-ketoadipic aciduria (AMOXAD), a rare disorder of l-lysine, l-hydroxylysine, and l-tryptophan catabolism, associated with clinical presentations such as developmental delay, mild-to-severe intellectual disability, ataxia, epilepsy, and behavioral disorders that cannot currently be managed by available treatments. A heterozygous missense mutation, c.2185G→A (p.G729R), in <i>DHTKD1</i> has been identified in most AMOXAD cases. Here, we report that the G729R E1a variant when assembled into OADHc <i>in vitro</i> displays a 50-fold decrease in catalytic efficiency for NADH production and a significantly reduced rate of glutaryl-CoA production by dihydrolipoamide succinyl-transferase (E2o). However, the G729R E1a substitution did not affect any of the three side-reactions associated solely with G729R E1a, prompting us to determine the structure-function effects of this mutation. A multipronged systematic analysis of the reaction rates in the OADHc pathway, supplemented with results from chemical cross-linking and hydrogen-deuterium exchange MS, revealed that the c.2185G→A <i>DHTKD1</i> mutation affects E1a-E2o assembly, leading to impaired channeling of OADHc intermediates. Cross-linking between the C-terminal region of both E1a and G729R E1a with the E2o lipoyl and core domains suggested that correct positioning of the C-terminal E1a region is essential for the intermediate channeling. These findings may inform the development of interventions to counter the effects of pathogenic <i>DHTKD1</i> mutations.","variants":[{"Name":"NM_018706.7(DHTKD1):c.2185G>A (p.Gly729Arg)","Chromosome":"10","Start":"12112930","Stop":"12112930","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48163,"rule_based_match":false,"evidence_text":"c.2185G→A (p.G729R)","llm_judgment":"PRESENT","evidence":"c.2185G→A (p.G729R)","abstract_start":724,"abstract_end":743}]}
{"pmid":"18481107","title":"Congenital thrombotic thrombocytopenic purpura associated with unilateral moyamoya disease.","abstract":"Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy disorder associated with congenital or acquired deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. The central nervous system and kidneys are the two major organs of involvement in TTP. Moyamoya (puff of smoke) disease is a cerebral arteriopathy of unknown etiology characterized by narrowing or occlusion of the distal internal carotid or proximal anterior or middle cerebral arteries, which causes the formation of multiple tiny collateral networks. We report here a case of an 11-year-old boy with unilateral moyamoya disease and congenital TTP. The patient had a history of severe neonatal jaundice and thereafter recurrent episodes of hemolytic anemia associated with renal dysfunction and cerebral infarction. The plasma ADAMTS13 activity of the patient <3% of normal, and ADAMTS13 gene analysis revealed an abnormal splicing mutation (c.330+1 G > A) in one allele and a novel missense mutation (p.Ile1217Thr) in the other. This is the first case of a genetically confirmed congenital TTP associated with unilateral moyamoya disease. Although the causal relationship between the two diseases has not been established, TTP may be included as one of the causes of moyamoya syndrome.","variants":[{"Name":"NM_139027.6(ADAMTS13):c.330+1G>A","Chromosome":"9","Start":"133424479","Stop":"133424479","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620810,"rule_based_match":true,"evidence_text":"c.330+1 G > A","llm_judgment":"PRESENT","evidence":"c.330+1 G > A","abstract_start":934,"abstract_end":947}]}
{"pmid":"31055809","title":"Clinical and genetic analysis of a patient with Perrault syndrome and additional neurological features","abstract":"OBJECTIVE: To explore the clinical, neuropathological and genetic characteristics of a patient with Perrault syndrome caused by TWNK mutation.\nMETHODS: Potential variation of the TWNK gene was detected by next-generation sequencing (NGS) and verified by Sanger sequencing.\nRESULTS: The patient has featured primary amenorrhoea and progressive sensorineural hearing loss since childhood. She also had gait anormaly, distal limb atrophy and weakness, and nystagmus. Further study confirmed sensory neuronopathy accompanied with upper and lower motor neuron involvement as well as cerebellum atrophy. NGS has identified two heterozygous variants of the TWNK gene, namely c.794G>A (p.Arg265His) and c.1181G>A (p.Arg394His). Sanger sequencing confirmed that c.1181G>A (p.Arg394His), a known pathogenic variant, was derived from her farther, while c.794G>A(p.Arg265His), a novel variant, was derived from her mother and likely pathogenic according to the ACMG guidelines.\nCONCLUSION: Perrault syndrome is a group of disorders with a high phenotypic heterogeneity. The compound heterozygous variation of c.794G>A (p.Arg265His) and c.1181G>A(p.Arg394His) of the TWNK gene may underlie Perrault syndrome in the patient.","variants":[{"Name":"NM_021830.5(TWNK):c.794G>A (p.Arg265His)","Chromosome":"10","Start":"100989004","Stop":"100989004","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1941528,"rule_based_match":true,"evidence_text":"c.794G>A (p.Arg265His)","llm_judgment":"PRESENT","evidence":"c.794G>A (p.Arg265His)","abstract_start":668,"abstract_end":690}]}
{"pmid":"20506135","title":"Mutations in SOHLH1 gene associate with nonobstructive azoospermia.","abstract":"In a previous study, we found SOHLH1 (spermatogenesis and oogenesis-specific basic helix-loop-helix 1) as the first testis-specific basic helix-loop-helix transcription factor essential for spermatogonial differentiation. SOHLH1 therefore represents an excellent candidate gene for testicular failure such as nonobstructive azoospermia (NOA). We analyzed whether there were mutations in the SOHLH1 gene in 96 Korean patients with NOA. The sequence analysis discovered three novel variations: one intronic variant (c.346-1G>A), and two nonsynonymous exonic variants (c.91T>C and c.529C>A) with known single nucleotide polymorphisms (SNPs), which included six intronic variants, two synonymous, and two nonsynonymous variants. We examined the consequences of mutations in SOHLH1 using in vivo and in vitro assays. Analysis of transcripts from minigenes carrying the c.346-1G>A revealed that splicing site variation leads to the partial deletion at a cryptic splicing site within exon 4. This deletion results in SOHLH1 with a truncated bHLH domain. Transient transfection assay showed that the SOHLH1 mutant with the truncated domain disrupted the transcriptional activity of KIT promoter, whereas two missense mutations harboring either p.Arg37Gln or p.Pro269Ser did not have a significant effect on its transactivation. Our findings indicate that a splice-acceptor site mutation that probably causes a nonfunctional SOHLH1 protein results in nonobstructive azoospermia by the lack of normal spermatogenesis.","variants":[{"Name":"NM_001101677.2(SOHLH1):c.346-1G>A","Chromosome":"9","Start":"135697628","Stop":"135697628","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":551991,"rule_based_match":true,"evidence_text":"c.346-1G>A","llm_judgment":"PRESENT","evidence":"c.346-1G>A","abstract_start":514,"abstract_end":524}]}
{"pmid":"25123707","title":"Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: clinical evidence of crosslink between FGFR and RAS signaling pathways.","abstract":"Dysregulation in the RAS signaling cascade results in a family of malformation syndromes called RASopathies. Meanwhile, alterations in FGFR signaling cascade are responsible for various syndromic forms of craniosynostosis. In general, the phenotypic spectra of RASopathies and craniosynostosis syndromes do not overlap. Recently, however, mutations in ERF, a downstream molecule of the RAS signaling cascade, have been identified as a cause of complex craniosynostosis, suggesting that the RAS and FGFR signaling pathways can interact in the pathogenesis of malformation syndromes. Here, we document a boy with short stature, developmental delay, and severe craniosynostosis involving right coronal, bilateral lambdoid, and sagittal sutures with a de novo mutation in exon1 of SHOC2 (c.4A>G p.Ser2Gly). This observation further supports the existence of a crosslink between the RAS signaling cascade and craniosynostosis. In retrospect, the propositus had physical features suggestive of a dysregulated RAS signaling cascade, such as fetal pleural effusion, fetal hydrops, and atrial tachycardia. In addition to an abnormal cranial shape, which has been reported for this specific mutation, craniosynostosis might be a novel associated phenotype. In conclusion, the phenotypic combination of severe craniosynostosis and RASopathy features observed in the propositus suggests an interaction between the RAS and FGFR signaling cascades. Patients with craniosynostosis in combination with any RASopathy feature may require mutation screening for molecules in the FGFR-RAS signaling cascade.","variants":[{"Name":"NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly)","Chromosome":"10","Start":"110964362","Stop":"110964362","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":21860,"rule_based_match":true,"evidence_text":"c.4A>G p.Ser2Gly","llm_judgment":"PRESENT","evidence":"c.4A>G p.Ser2Gly","abstract_start":784,"abstract_end":800}]}
{"pmid":"27062382","title":"Papillon-Lefèvre syndrome: report of six patients and identification of a novel mutation.","abstract":"Papillon-Lefèvre syndrome is an autosomal recessive genodermatosis typically manifesting with the constellation of palmoplantar keratoderma and progressive early-onset periodontitis. The cutaneous phenotype can be strikingly psoriasiform, possibly posing a diagnostic challenge. This rare disorder is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. We report six patients with Papillon-Lefèvre syndrome from five consanguineous Turkish families, in whom genetic analysis of the CTSC gene revealed four recurrent mutations (c.415G>A; c.1015C>T; c.1019A>G; and c.103-105delCTG) and a novel missense mutation (c.117G>T) in the homozygous state.","variants":[{"Name":"NM_001814.6(CTSC):c.1015C>T (p.Arg339Cys)","Chromosome":"11","Start":"88294383","Stop":"88294383","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1874344,"rule_based_match":true,"evidence_text":"c.1015C>T","llm_judgment":"PRESENT","evidence":"c.1015C>T","abstract_start":567,"abstract_end":576},{"Name":"NM_001814.6(CTSC):c.117G>T (p.Trp39Cys)","Chromosome":"11","Start":"88337556","Stop":"88337556","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3498450,"rule_based_match":true,"evidence_text":"c.117G>T","llm_judgment":"PRESENT","evidence":"c.117G>T","abstract_start":641,"abstract_end":649}]}
{"pmid":"32185794","title":"A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects.","abstract":"Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by defects in the function or structure of motitle cilia. In most cases, causative variants result in axonemal dynein arm anomalies, however, PCD due to radial spoke (RS) and central pair (CP) of microtubules has been rarely reported. To identify the molecular basis of PCD characterized by RS/CP defects, we performed whole exome sequencing in PCD patients with RS/CP defects. We identified a homozygous nonsense variant (c.572G>A; p.Trp191*) in NME5, which encodes a protein component of the RS neck, in one PCD patient with situs solitus. Morpholino knockdown of nme5 in zebrafish embryos resulted in motile cilia defects with phenotypes compatible with ciliopathy. This is the first study to show NME5 as a PCD-causative gene in humans. Our findings indicate that NME5 screening should be considered for PCD patients with RS/CP defects.","variants":[{"Name":"NM_003551.3(NME5):c.572G>A (p.Trp191Ter)","Chromosome":"5","Start":"138115748","Stop":"138115748","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1704178,"rule_based_match":true,"evidence_text":"c.572G>A (p.Trp191*)","llm_judgment":"PRESENT","evidence":"p.Trp191*","abstract_start":520,"abstract_end":529}]}
{"pmid":"33947670","title":"'H-syndrome': a multisystem genetic disorder with cutaneous clues.","abstract":"We present a case of a 25-year-old man who came to our Endocrine Clinic for evaluation of short stature. He had a history of sensorineural hearing loss, hypertrichosis and hyperpigmentation with the thickening of the skin below the hip, gynecomastia and autoimmune haemolytic anaemia. Investigations showed that he had hypergonadotropic hypogonadism. His phenotype was consistent with that of a rare autosomal recessive genodermatosis of 'H-syndrome'. The diagnosis was confirmed by genetic analysis using next-generation sequencing which showed a homozygous mutation in the <i>SLC29A3</i> gene (variant: c.1330G>T (p.Glu444Ter)) which was confirmed by Sanger sequencing. This is a rare syndrome with around 100 cases reported in world literature. Though the skin manifestations are pathognomonic of the H-syndrome, it has myriad presentations like short stature, insulin-dependent diabetes mellitus, hypogonadism, hypothyroidism, dyslipidaemia, cardiac anomalies and sensorineural hearing loss. We report this case to highlight the constellation of features of this rare syndrome and bring awareness among the physicians to be vigilant about this syndrome.","variants":[{"Name":"NM_018344.6(SLC29A3):c.1330G>T (p.Glu444Ter)","Chromosome":"10","Start":"71362510","Stop":"71362510","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":15603,"rule_based_match":true,"evidence_text":"c.1330G>T (p.Glu444Ter)","llm_judgment":"PRESENT","evidence":"c.1330G>T (p.Glu444Ter)","abstract_start":605,"abstract_end":628}]}
{"pmid":"30576981","title":"Severe bleeding due to hypersensitivity to vitamin K antagonist caused by the c.109G>A (p.Ala37Thr) mutation in the F9 gene in a patient with mechanical heart valve prosthesis.","abstract":"","variants":[{"Name":"NM_000133.4(F9):c.109G>A (p.Ala37Thr)","Chromosome":"X","Start":"139537030","Stop":"139537030","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":792126,"rule_based_match":true,"evidence_text":"c.109G>A (p.Ala37Thr)","llm_judgment":"PRESENT","evidence":"c.109G>A (p.Ala37Thr)","abstract_start":null,"abstract_end":null}]}
{"pmid":"29126765","title":"New insights into the phenotype of FARS2 deficiency.","abstract":"Mutations in FARS2 are known to cause dysfunction of mitochondrial translation due to deficient aminoacylation of the mitochondrial phenylalanine tRNA. Here, we report three novel mutations in FARS2 found in two patients in a compound heterozygous state. The missense mutation c.1082C>T (p.Pro361Leu) was detected in both patients. The mutations c.461C>T (p.Ala154Val) and c.521_523delTGG (p.Val174del) were each detected in one patient. We report abnormal in vitro aminoacylation assays as a functional validation of the molecular genetic findings. Based on the phenotypic data of previously reported subjects and the two subjects reported here, we conclude that FARS2 deficiency can be associated with two phenotypes: (i) an epileptic phenotype, and (ii) a spastic paraplegia phenotype.","variants":[{"Name":"NM_006567.5(FARS2):c.461C>T (p.Ala154Val)","Chromosome":"6","Start":"5369031","Stop":"5369031","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":481208,"rule_based_match":true,"evidence_text":"c.461C>T (p.Ala154Val)","llm_judgment":"PRESENT","evidence":"c.461C>T (p.Ala154Val)","abstract_start":346,"abstract_end":368},{"Name":"NM_006567.5(FARS2):c.1082C>T (p.Pro361Leu)","Chromosome":"6","Start":"5613185","Stop":"5613185","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":211259,"rule_based_match":true,"evidence_text":"c.1082C>T (p.Pro361Leu)","llm_judgment":"PRESENT","evidence":"c.1082C>T (p.Pro361Leu)","abstract_start":277,"abstract_end":300}]}
{"pmid":"21466533","title":"Junctional epidermolysis bullosa of late onset explained by mutations in COL17A1.","abstract":"BACKGROUND:   Junctional epidermolysis bullosa of late onset (JEB-lo) is a rare disease characterized by blistering of primarily the hands and feet starting in childhood. The pathogenesis remains unclear.\nOBJECTIVES: To clarify the pathogenesis of JEB-lo.\nMETHODS: Two patients with JEB-lo, a brother and a sister, were examined using electron microscopy (EM), immunofluorescence (IF) antigen mapping and molecular analysis.\nRESULTS: We found subtle changes in IF antigen mapping and EM. The most remarkable changes were loss of the apical-lateral staining of monoclonal antibodies (mAbs) against type XVII collagen (Col17), and a broadened distribution of mAb staining against the ectodomain of Col17, laminin-332 and type VII collagen. Mutation analysis of COL17A1, encoding Col17, showed a compound heterozygosity for a novel mutation c.1992_1995delGGGT and the known mutation c.3908G>A in both patients. The deletion c.1992_1995delGGGT results in a premature termination codon and mRNA decay, leaving the patients functionally hemizygous for the missense mutation c.3908G>A (p.R1303Q) in the noncollagenous 4 domain of Col17.\nCONCLUSIONS: JEB-lo is an autosomal recessive disorder caused by mutations in COL17A1, and subtle aberrations in EM and IF antigen mapping are clues to diagnosis.","variants":[{"Name":"NM_000494.4(COL17A1):c.3908G>A (p.Arg1303Gln)","Chromosome":"10","Start":"104034193","Stop":"104034193","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32689,"rule_based_match":true,"evidence_text":"c.3908G>A (p.R1303Q)","llm_judgment":"PRESENT","evidence":"c.3908G>A (p.R1303Q)","abstract_start":1068,"abstract_end":1088}]}
{"pmid":"36626423","title":"A case report of maturity-onset diabetes of the young (MODY12) in a Chinese Han patient with a novel ABCC8 gene mutation.","abstract":"RATIONALE: Maturity onset diabetes of the young (MODY) is the most common type of monogenic diabetes, characterized by autosomal dominant inheritance, the age of onset is often <25 years old, and the clinical manifestations are atypical. MODY12 is caused by a rare missense mutation of adenosine triphosphate (ATP)-binding cassette transporter subfamily C member 8 (ABCC8) gene and more than 50 ABCC8 variants were associated with MODY12.\nPATIENT CONCERNS: The patient was a 30-year-old Chinese Han man. He was overweight with a poor control of blood glucose.\nDIAGNOSES: The patient was diagnosed with MODY12.\nINTERVENTIONS: The patient was given glimepiride (4 mg/d) with diet and exercise therapy to reduce blood glucose and weight.\nOUTCOMES: The level of fasting blood glucose and C-peptide was improved after 1 year treatment as well as body weight.\nLESSONS: A Chinese Han adult with a heterozygous missense mutation c.3976G > A (p.Glu1326Lys) was diagnosed with MODY12, which was the new pathogenic mutation for the disease. This report expands the spectrum of variants causing MODY12 and reduces misdiagnosis.","variants":[{"Name":"NM_000352.6(ABCC8):c.3976G>A (p.Glu1326Lys)","Chromosome":"11","Start":"17397205","Stop":"17397205","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":272968,"rule_based_match":true,"evidence_text":"c.3976G > A (p.Glu1326Lys)","llm_judgment":"PRESENT","evidence":"c.3976G > A (p.Glu1326Lys)","abstract_start":921,"abstract_end":947}]}
{"pmid":"30061524","title":"Takotsubo as Initial Manifestation of Non-Myopathic Cardiomyopathy Due to the Titin Variant c.1489G > T.","abstract":"<b>Background</b>: Whether patients with subclinical cardiomyopathy (CMP) are more prone to experience Takotsubo syndrome (TTS) than patients without CMP, is unknown. We present a patient with TTS as the initial manifestation of a hitherto unrecognized genetic CMP. <b>Method</b>: case report. <b>Results</b>: At age 55 after the unexpected death of her father, a now 61-year-old female had developed precordial pressure. Work-up revealed moderately reduced systolic function, dyskinesia of the interventricular septum, and indications for a TTS. Coronary angiography was normal but ventriculography showed TTS. Cardiac MRI confirmed reduced systolic function and TTS. TTS resolved without treatment and sequelae. At age 57 atrial fibrillation was recorded. After deterioration of systolic function at age 59 dilated CMP was diagnosed. Despite application of levosimendan, sacubitril, valsartan, and ivabradine, complete remission could not be achieved. Upon genetic work-up by means of a gene panel, the heterozygous mutation c.1489G > T (p. E497X) in exon 9 of the <i>titin</i> gene was detected and made responsible for the phenotype. Neurological work-up precluded involvement of the skeletal muscles. The further course was complicated by ventricular arrhythmias, requiring implantation of an implantable cardioverter defibrillator (ICD).\nCONCLUSIONS: previously subclinical CMP may initially manifest as TTS. Since patients with titin CMP are at risk of developing ventricular arrhythmias and thus to experience sudden cardiac death, appropriate anti-arrhythmic therapy needs to be established.","variants":[{"Name":"NM_001267550.2(TTN):c.1489G>T (p.Glu497Ter)","Chromosome":"2","Start":"178793451","Stop":"178793451","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1024006,"rule_based_match":true,"evidence_text":"c.1489G > T (p. E497X)","llm_judgment":"PRESENT","evidence":"c.1489G > T (p. E497X)","abstract_start":1027,"abstract_end":1049}]}
{"pmid":"19093009","title":"Clinical and genetic findings in Hungarian patients with X-linked juvenile retinoschisis.","abstract":"PURPOSE: To determine clinical phenotypes, examine the age dependency of X-linked juvenile retinoschisis (XLRS), and identify mutations in the retinoschisis1 gene (RS1) in 13 Hungarian (Caucasian) families with this disease.\nMETHODS: This study included 72 members in 13 families. Complete ophthalmological examinations, including optical coherence tomography (OCT) and full-field and multifocal electroretinography (ERG), were performed on 20 affected males, 13 female carriers, and 27 healthy controls. The patients were divided into two age groups (Group I <25 years and Group II >25 years), retrospectively, to assess the possible effects of age. Correlations among genotype, age, best corrected visual acuity (BCVA), OCT, and ERG results were analyzed. A modified classification scheme was done to identify the different phenotypes of the disease. In each of the 72 family members and 100 age-matched male controls, all exons and introns of RS1 were amplified by polymerase chain reaction (PCR) and directly sequenced.\nRESULTS: Foveal retinoschisis was detected in 25 eyes (62.5%) of patients by funduscopy, and in 29 eyes (72.5%) by OCT, while macular lamellar schisis was recognizable only by OCT in 30 eyes (75%) of patients. Foveal thickness (FT) and total macular volume were significantly increased in younger (Group I) patients only. For patients younger than 26 years, large inner nuclear central cysts were observable by OCT, while after 26 years, foveas were atrophic. White flecks and dots, which were like that seen in fundus albipunctatus, were detected in both eyes of one patient. In both patient groups, characteristically decreased b-waves of standard combined ERG were recorded without any significant difference between the patient groups. The BCVA and ERG parameters of all patients and the OCT of younger patients were significantly worse (p<0.05) than those of age-matched controls. A significant difference between the two age groups was found in case FT, total macular volume, and amplitudes of rod b-wave only. Moderate negative correlation (r=-0.54, p<0.001) was detected between age and FT, while only low negative correlation (r=-0.33, p<0.05) was detected between age and standard combined b-wave amplitudes of full-field ERG. BCVA LogMAR did not show any obvious correlation with age (r=-0.14, p=0.39) or with the type of mutation. Nine different mutations were identified in 25 male patients and 31 female carriers of 13 families: six known and one novel missense mutation (c.575C>T, p.Pro192Leu), one insertion mutation (c.579dupC, p.Ile194Hisfs29ext43), and one frameshift, causing splice site mutation (c.78+1G>C) were detected. These mutations were absent in the 100 age-matched male control samples.\nCONCLUSIONS: Foveal cystic schisis was found more often by OCT than by funduscopy (+10%), while flat macular lamellar schisis was recognizable only by OCT. Advancing age inversely influenced the size of cavities (FT), and standard combined b-wave amplitudes of full-field ERG, while BCVA, response density, and implicit times of multifocal electroretinography did not show any obvious correlation with age. The atrophic stage of the disease was observable after 26 years of age. The lesions that appeared to be indicative of fundus albipunctatus were proven to be palisades between the splitted retinal layers. Our modified classification scheme was helpful in assessing the prevalence of disease types. In these Hungarian patients, one novel and eight known mutations were detected. The distribution of mutations in RS1 was different to that reported in the literature, because the greatest number of different mutations was in exon 6 instead of exon 4. Two mutation hot spots were found: between c.418-422 in exon 5 and between c.574-579 in exon 6. Genotype-phenotype correlation was not demonstrable.","variants":[{"Name":"NM_000330.4(RS1):c.575C>T (p.Pro192Leu)","Chromosome":"X","Start":"18642104","Stop":"18642104","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":849868,"rule_based_match":true,"evidence_text":"c.575C>T, p.Pro192Leu","llm_judgment":"PRESENT","evidence":"c.575C>T, p.Pro192Leu","abstract_start":2510,"abstract_end":2531},{"Name":"NM_000330.4(RS1):c.579dup (p.Ile194fs)","Chromosome":"X","Start":"18642099","Stop":"18642100","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":104885,"rule_based_match":true,"evidence_text":"c.579dupC, p.Ile194Hisfs29ext43","llm_judgment":"PRESENT","evidence":"c.579dupC, p.Ile194Hisfs29ext43","abstract_start":2558,"abstract_end":2589}]}
{"pmid":"28774368","title":"Clinical feature and molecular diagnostic analysis of the first non-caucasian child with infantile liver failure syndrome type 1","abstract":"Infantile liver failure syndrome type 1 (ILFS1) is a Mendelian disease due to biallelic mutations in the cytoplasmic leucyl-tRNA synthetase gene (LARS). This study aimed to report the clinical and molecular features of the first non-caucasian ILFS1 patient, providing reliable evidences for the definite diagnosis of ILFS1. The 2 years and 9 months old male patient was referred to the hospital with hepatosplenomegaly over 1 year. At age 17 months, he was found to have hepatosplenomegaly and anemia. Since then, he had been managed in different hospitals. The laboratory tests showed liver dysfunction, hypoproteinemia, coagulopathy and anemia, along with histologically-confirmed cirrhosis and fatty liver; however, the etiology remained undetermined. The subsequent SLC25A13 mutation analysis by means of prevalent mutation screening and Sanger sequencing only revealed a paternally-inherited mutation c.1658G>A, and no aberrant SLC25A13 transcripts could be detected from the maternal allele on cDNA cloning analysis, ruling out the possibility of citrin deficiency. Further target exome high-throughout sequencing of genes relevant to genetic liver diseases detected a paternal c.2133_2135del (p.L712del) and a maternal c.1183G>A (p.D395N) mutation in LARS gene. This finding was then confirmed by Sanger sequencing, and ILFS1 was thus definitely diagnosed. The child has been followed up till age 4 years, and his condition became stabilized.","variants":[{"Name":"NM_020117.11(LARS1):c.1183G>A (p.Asp395Asn)","Chromosome":"5","Start":"146153781","Stop":"146153781","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1294823,"rule_based_match":true,"evidence_text":"c.1183G>A (p.D395N)","llm_judgment":"PRESENT","evidence":"c.1183G>A (p.D395N)","abstract_start":1226,"abstract_end":1245}]}
{"pmid":"38130758","title":"The Effect of Asfotase Alfa on Plasma and Urine Pyrophosphate Levels and Pseudofractures in a Patient With Adult-Onset Hypophosphatasia.","abstract":"Hypophosphatasia (HPP) is an inherited disease caused by variants of the <i>ALPL</i> gene encoding tissue-nonspecific alkaline phosphatase. Adult-onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first-line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64-year-old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the <i>ALPL</i> gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6-minute walk test (525 to 606 m). The EQ-5D-5L index was also improved (0.757 to 0.895). Within a follow-up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the <i>ALPL</i> gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. <i>JBMR Plus</i> published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.","variants":[{"Name":"NM_000478.6(ALPL):c.319G>A (p.Val107Ile)","Chromosome":"1","Start":"21563131","Stop":"21563131","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3394998,"rule_based_match":true,"evidence_text":"c.319G > A; p.Val107Ile","llm_judgment":"PRESENT","evidence":"c.319G > A; p.Val107Ile","abstract_start":780,"abstract_end":803}]}
{"pmid":"17701896","title":"Arts syndrome is caused by loss-of-function mutations in PRPS1.","abstract":"Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Linkage analysis in a Dutch family and an Australian family suggested that the candidate gene maps to Xq22.1-q24. Oligonucleotide microarray expression profiling of fibroblasts from two probands of the Dutch family revealed reduced expression levels of the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1). Subsequent sequencing of PRPS1 led to the identification of two different missense mutations, c.455T-->C (p.L152P) in the Dutch family and c.398A-->C (p.Q133P) in the Australian family. Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients. This is in contrast to the gain-of-function mutations in PRPS1 that were identified previously in PRPS-related gout. The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. To replenish low levels of purines, treatment with S-adenosylmethionine theoretically could have therapeutic efficacy, and a clinical trial involving the two affected Australian brothers is currently underway.","variants":[{"Name":"NM_002764.4(PRPS1):c.398A>C (p.Gln133Pro)","Chromosome":"X","Start":"107640993","Stop":"107640993","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":24976,"rule_based_match":false,"evidence_text":"c.398A-->C (p.Q133P)","llm_judgment":"PRESENT","evidence":"c.398A-->C (p.Q133P)","abstract_start":624,"abstract_end":644},{"Name":"NM_002764.4(PRPS1):c.455T>C (p.Leu152Pro)","Chromosome":"X","Start":"107642415","Stop":"107642415","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":24975,"rule_based_match":false,"evidence_text":"c.455T-->C (p.L152P)","llm_judgment":"PRESENT","evidence":"c.455T-->C (p.L152P)","abstract_start":579,"abstract_end":599}]}
{"pmid":"37751738","title":"PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects.","abstract":"Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.","variants":[{"Name":"NM_005032.7(PLS3):c.1497G>C (p.Trp499Cys)","Chromosome":"X","Start":"115646521","Stop":"115646521","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2805401,"rule_based_match":true,"evidence_text":"c.1497G>C (p.Trp499Cys)","llm_judgment":"PRESENT","evidence":"c.1497G>C (p.Trp499Cys)","abstract_start":1082,"abstract_end":1105}]}
{"pmid":"36209351","title":"PPP2R1A neurodevelopmental disorder is associated with congenital heart defects.","abstract":"Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that regulates numerous biological processes. PPP2R1A encodes the scaffolding \"Aα\" subunit of PP2A. To date, nearly 40 patients have been previously reported with 19 different pathogenic PPP2R1A variants, with phenotypes including intellectual disability, developmental delay, epilepsy, infant agenesis/dysgenesis of the corpus callosum, and dysmorphic features. Apart from a single case, severe congenital heart defects (CHD) have not been described. We report four new unrelated individuals with pathogenic heterozygous PPP2R1A variants and CHD and model the crystal structure of several variants to investigate mechanisms of phenotype disparity. Individuals 1 and 2 have a previously described variant (c.548G>A, p.R183Q) and similar phenotypes with severe ventriculomegaly, agenesis/dysgenesis of the corpus callosum, and severe CHD. Individual 3 also has a recurrent variant (c.544C>T, p.R182W) and presented with agenesis of corpus callosum, ventriculomegaly, mild pulmonic stenosis, and small patent foramen ovale. Individual 4 has a novel variant (c.536C>A, p.P179H), ventriculomegaly, and atrial septal defect. To conclude, we propose expansion of the phenotype of PPP2R1A neurodevelopmental disorder to include CHD. Further, the R183Q variant has now been described in three individuals, all with severe neurologic abnormalities, severe CHD, and early death suggesting that this variant may be particularly deleterious.","variants":[{"Name":"NM_014225.6(PPP2R1A):c.536C>A (p.Pro179His)","Chromosome":"19","Start":"52212718","Stop":"52212718","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1691558,"rule_based_match":true,"evidence_text":"c.536C>A (p.P179H)","llm_judgment":"PRESENT","evidence":"c.536C>A","abstract_start":1135,"abstract_end":1143}]}
{"pmid":"29343526","title":"Mutations in","abstract":"RATIONALE: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated.\nOBJECTIVE: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause.\nMETHODS AND RESULTS: As in dopamine β-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine β-hydroxylase activity, however, was normal, and the <i>DBH</i> gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (<i>CYB561</i>); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of <i>CYB561</i> was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The <i>CYB561</i> gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine β-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 <i>CYB561</i> knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the <i>CYB561</i><sup>(-</sup><sup>/-</sup><sup>)</sup> mice compared with wild-type mice (<i>P</i><0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (<i>P</i><0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine.\nCONCLUSIONS: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in <i>CYB561</i> cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.","variants":[{"Name":"NM_001915.4(CYB561):c.262G>A (p.Gly88Arg)","Chromosome":"17","Start":"63436093","Stop":"63436093","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":581700,"rule_based_match":true,"evidence_text":"c.262G>A, p.Gly88Arg","llm_judgment":"PRESENT","evidence":"c.262G>A, p.Gly88Arg","abstract_start":766,"abstract_end":786},{"Name":"NM_001915.4(CYB561):c.131G>A (p.Trp44Ter)","Chromosome":"17","Start":"63437417","Stop":"63437417","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":581701,"rule_based_match":true,"evidence_text":"c.131G>A, p.Trp44*","llm_judgment":"PRESENT","evidence":"c.131G>A, p.Trp44*","abstract_start":842,"abstract_end":860}]}
{"pmid":"29071585","title":"Expanding the Phenotype of the Founder South Asian Mutation in the Nuclear Encoding Mitochondrial RMND1 Gene.","abstract":"BACKGROUND: Mitochondrial disorders have a wide variability in the phenotype. A 10-mo-old girl presented with a severe phenotype of multisystem involvement due to an uncommon mitochondrial disease. Mutations in the RMND1 gene of nuclear DNA were identified on next generation sequencing. This mutation results in combined oxidative phosphorylation deficiency -11 (OMIM #614922) of the respiratory chain complex. So far in South Asia, patients of this disorder have been reported only from Pakistan and Bangladesh.\nRESULTS: In addition to the features reported in other patients of South Asia with the same mutation at c.1349G>C, index patient from India had hyperaldosteronism, long QT interval but no deafness.\nCONCLUSIONS: Thus, to conclude, this report emphasizes the diagnostic value of FGF21 assay in this disorder. It extends the phenotype associated with the founder mutation in RMND1 gene in patients from South Asia.","variants":[{"Name":"NM_017909.4(RMND1):c.1349G>C (p.Ter450Ser)","Chromosome":"6","Start":"151405236","Stop":"151405236","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":152761,"rule_based_match":true,"evidence_text":"c.1349G>C","llm_judgment":"PRESENT","evidence":"c.1349G>C","abstract_start":618,"abstract_end":627}]}
{"pmid":"38501349","title":"A rare variant c.1802T>C (p. Ile601Thr) associated with severe phenotype among people with cystic fibrosis from south India, and potential genetic admixture in Réunion, France.","abstract":"","variants":[{"Name":"NM_000492.4(CFTR):c.1802T>C (p.Ile601Thr)","Chromosome":"7","Start":"117591969","Stop":"117591969","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":68060,"rule_based_match":true,"evidence_text":"c.1802T>C (p. Ile601Thr)","llm_judgment":"PRESENT","evidence":"c.1802T>C (p. Ile601Thr)","abstract_start":null,"abstract_end":null}]}
{"pmid":"19194555","title":"Two Korean infants with genetically confirmed congenital nephrotic syndrome of Finnish type.","abstract":"Congenital nephrotic syndrome is defined as nephrotic syndrome which manifests in utero or during the first 3 months of life. The prototype of congenital nephrotic syndrome is congenital nephrotic syndrome of Finnish type (CNF, OMIM #602716), which is caused by loss-of-function mutations of the nephrin gene (NPHS1). There have been few clinical case reports of CNF in Korea, but none of which was confirmed by genetic study. Here, we report two children with congenital nephrotic syndrome. Genetic analysis of the NPHS1 gene revealed compound heterozygous frame-shifting mutations (c.2156_2163 delTGCACTGC causing p.L719DfsX4 and c.3250_3251insG causing p.V1084GfsX12) in one patient and a missense mutation (c.1381G>A causing p.R460Q) and a nonsense mutation (c.2442C>G causing p.Y814X) in the other patient. The nonsense mutation was novel. The clinical courses of the patients were typical of CNF. This is the first report of genetically confirmed CNF in Korea to date. The early genetic diagnosis of CNF is important for proper clinical management of the patients and precise genetic counseling of the families.","variants":[{"Name":"NM_004646.4(NPHS1):c.2442C>G (p.Tyr814Ter)","Chromosome":"19","Start":"35842443","Stop":"35842443","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":71113,"rule_based_match":true,"evidence_text":"c.2442C>G (p.Y814X)","llm_judgment":"PRESENT","evidence":"c.2442C>G","abstract_start":763,"abstract_end":772},{"Name":"NM_004646.4(NPHS1):c.2156_2163del (p.Leu719fs)","Chromosome":"19","Start":"35844152","Stop":"35844159","ReferenceAlleleVCF":"GGCAGTGCA","AlternateAlleleVCF":"G","allel_id":71102,"rule_based_match":true,"evidence_text":"c.2156_2163 delTGCACTGC","llm_judgment":"PRESENT","evidence":"c.2156_2163 delTGCACTGC","abstract_start":584,"abstract_end":607}]}
{"pmid":"20052763","title":"Ex vivo splicing assays of mutations at noncanonical positions of splice sites in USHER genes.","abstract":"Molecular diagnosis in Usher syndrome type 1 and 2 patients led to the identification of 21 sequence variations located in noncanonical positions of splice sites in MYO7A, CDH23, USH1C, and USH2A genes. To establish experimentally the splicing pattern of these substitutions, whose impact on splicing is not always predictable by available softwares, ex vivo splicing assays were performed. The branch-point mapping strategy was also used to investigate further a putative branch-point mutation in USH2A intron 43. Aberrant splicing was demonstrated for 16 of the 21 (76.2%) tested sequence variations. The mutations resulted more frequently in activation of a nearby cryptic splice site or use of a de novo splice site than exon skipping (37.5%). This study allowed the reclassification as splicing mutations of one silent (c.7872G>A (p.Glu2624Glu) in CDH23) and four missense mutations (c.2993G>A (p.Arg998Lys) in USH2A, c.592G>A (p.Ala198Thr), c.3503G>C [p.Arg1168Pro], c.5944G>A (p.Gly1982Arg) in MYO7A), whereas it provided clues about a role in structure/function in four other cases: c.802G>A (p.Gly268Arg), c.653T>A (p.Val218Glu) (USH2A), and c.397C>T (p.His133Tyr), c.3502C>T (p.Arg1168Trp) (MYO7A). Our data provide insights into the contribution of splicing mutations in Usher genes and illustrate the need to define accurately their splicing outcome for diagnostic purposes.","variants":[{"Name":"NM_000260.4(MYO7A):c.5944G>A (p.Gly1982Arg)","Chromosome":"11","Start":"77208517","Stop":"77208517","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":491840,"rule_based_match":true,"evidence_text":"c.5944G>A (p.Gly1982Arg)","llm_judgment":"PRESENT","evidence":"c.5944G>A (p.Gly1982Arg)","abstract_start":973,"abstract_end":997},{"Name":"NM_000260.4(MYO7A):c.3502C>T (p.Arg1168Trp)","Chromosome":"11","Start":"77184714","Stop":"77184714","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":546440,"rule_based_match":true,"evidence_text":"c.3502C>T (p.Arg1168Trp)","llm_judgment":"PRESENT","evidence":"c.3502C>T (p.Arg1168Trp)","abstract_start":1175,"abstract_end":1199},{"Name":"NM_022124.6(CDH23):c.7872G>A (p.Glu2624=)","Chromosome":"10","Start":"71803420","Stop":"71803420","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":801689,"rule_based_match":true,"evidence_text":"c.7872G>A (p.Glu2624Glu)","llm_judgment":"PRESENT","evidence":"c.7872G>A (p.Glu2624Glu)","abstract_start":825,"abstract_end":849}]}
{"pmid":"28065684","title":"IGHMBP2-related clinical and genetic features in a cohort of Chinese Charcot-Marie-Tooth disease type 2 patients.","abstract":"IGHMBP2 mutations had been exclusively associated with spinal muscular atrophy with respiratory distress type I. However, increasing AR-CMT2S cases without respiratory failure caused by IGHMBP2 mutations have been reported in the past two years. We detected IGHMBP2 mutations in a cohort of Chinese CMT2 patients using genes panel testing, polymerase chain reaction and Sanger sequencing. We found four families with autosomal recessive IGHMBP2 mutations, and the frequency of IGHMBP2 mutations is 6.5% in CMT2 without dominant inheritance. We detected a homozygous variant c.1235 + 3A > G in Family 1, compound heterozygous variants c.1737C > A and c.2597_2598delAG in Family 2, compound heterozygous variants c.1489G > A and c.2356delG in Family 3, compound heterozygous variants c.1909C > T and c.1061-2A > G in Family 4. According to the standards and guidelines of the American College of Medical Genetics and Genomics, all the above variants were classified as pathogenic. Four mutations, c.1489G > A, c.2356delG, c.2597_2598delAG and c.1061-2A > G, are reported for the first time. The novel splice acceptor site mutation c.1061-2A > G resulted in deletion of 175 bp, and it was predicted to lead to a frameshift after codon 354 with a premature termination at codon 364. In conclusion, mutation screening of IGHMBP2 should be especially considered in AR-CMT2 and sporadic CMT2 patients.","variants":[{"Name":"NM_002180.3(IGHMBP2):c.1909C>T (p.Arg637Cys)","Chromosome":"11","Start":"68936389","Stop":"68936389","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":625251,"rule_based_match":true,"evidence_text":"c.1909C>T","llm_judgment":"PRESENT","evidence":"c.1909C > T","abstract_start":782,"abstract_end":793},{"Name":"NM_002180.3(IGHMBP2):c.2356del (p.Ala786fs)","Chromosome":"11","Start":"68936834","Stop":"68936834","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":625254,"rule_based_match":true,"evidence_text":"c.2356delG","llm_judgment":"PRESENT","evidence":"c.2356delG","abstract_start":727,"abstract_end":737},{"Name":"NM_002180.3(IGHMBP2):c.1489G>A (p.Gly497Arg)","Chromosome":"11","Start":"68933865","Stop":"68933865","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":838953,"rule_based_match":true,"evidence_text":"c.1489G > A","llm_judgment":"PRESENT","evidence":"c.1489G > A","abstract_start":711,"abstract_end":722},{"Name":"NM_002180.3(IGHMBP2):c.1737C>A (p.Phe579Leu)","Chromosome":"11","Start":"68935403","Stop":"68935403","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":244682,"rule_based_match":true,"evidence_text":"c.1737C > A","llm_judgment":"PRESENT","evidence":"c.1737C > A","abstract_start":634,"abstract_end":645},{"Name":"NM_002180.3(IGHMBP2):c.1061-2A>G","Chromosome":"11","Start":"68929181","Stop":"68929181","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1164630,"rule_based_match":true,"evidence_text":"c.1061-2A>G","llm_judgment":"PRESENT","evidence":"c.1061-2A > G","abstract_start":798,"abstract_end":811}]}
{"pmid":"23797725","title":"Identification of succinate dehydrogenase-deficient bladder paragangliomas.","abstract":"A significant number of patients with paragangliomas harbor germline mutations in one of the succinate dehydrogenase (SDH) genes (SDHA, B, C, or D). Tumors with mutations in SDH genes can be identified using immunohistochemistry. Loss of SDHB staining is seen in tumors with a mutation in any one of the SDH genes, whereas loss of both SDHB and SDHA expression is seen only in the context of an SDHA mutation. Identifying an SDH-deficient tumor can be prognostically significant, as tumors with SDHB mutations are more likely to pursue a malignant course. Although the rate of SDH deficiency in paragangliomas in general is known to be approximately 30%, there are only rare reports of SDH-deficient bladder paragangliomas. Therefore, the aim of this study was to determine the rate of SDH deficiency in bladder paragangliomas. Eleven cases of bladder paragangliomas were identified. Hematoxylin and eosin-stained slides of all tumors were reviewed, and immunohistochemical analysis for SDHB and SDHA was performed. For cases with loss of SDHA expression by immunohistochemistry, mutation analysis of the SDHA gene was performed. Loss of SDHB staining was seen in 3 (27%) cases (2 with loss of SDHB only, 1 with loss of SDHB and SDHA). Patients with SDH-deficient tumors were younger than those with tumors with intact SDH expression (mean age at presentation 39 y and 58 y, respectively). Of the 2 patients with SDHB-deficient and SDHA-intact tumors, one was found to have a germline SDHB mutation, and the other had a family history of a malignant paraganglioma. Both patients developed metastatic disease. The one patient with a tumor that was deficient for both SDHB and SDHA had no family history of paragangliomas and no evidence of metastatic disease. Sequencing of this tumor revealed a deleterious heterozygous single-base pair substitution in exon 10 of SDHA (c.1340 A>G; p.His447Arg) in both the tumor and normal tissue, indicative of a germline SDHA mutation, and a deleterious single-base pair substitution in exon 5 of SDHA (c.484 A>T; p.Arg162*) in 1 allele of the tumor only. No patients with intact SDH expression had a family history of paragangliomas; 1 had a synchronous paraganglioma, but none developed metastatic disease. A significant subset of bladder paragangliomas is SDH deficient. It is essential to identify SDH-deficient tumors, as the presence of an SDH mutation has prognostic implications and is important in guiding genetic counseling.","variants":[{"Name":"NM_004168.4(SDHA):c.1340A>G (p.His447Arg)","Chromosome":"5","Start":"236507","Stop":"236507","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":521132,"rule_based_match":true,"evidence_text":"c.1340 A>G; p.His447Arg","llm_judgment":"PRESENT","evidence":"c.1340 A>G; p.His447Arg","abstract_start":1870,"abstract_end":1893}]}
{"pmid":"21532868","title":"DJ-1 Mutations are Rare in a Swedish Parkinson Cohort.","abstract":"Mutations in the PARK7 gene, DJ-1, have been reported to cause early-onset and familial Parkinson's disease (PD). The function of DJ-1 and how it contributes to the development of the disease is not clear today, but several studies report that DJ-1 is responsive to oxidative stress and important for the maintenance of mitochondria. We have screened three coding regions of DJ-1 (exon 2, 5 and 7) in a Swedish Parkinson cohort. The Swedish PD material consisted of 67 patients with a self reported positive family history of PD and 77 patients with early-onset of disease (≤50 years old). We detected two patients with the previously reported synonymous mutation, Ala167Ala (c.501A>G, rs71653621), in exon 7. No Ala167Ala carriers were identified among 213 neurologically healthy Swedish controls. Mechanisms by which the synonymous Ala167Ala mutation can have consequences are unknown. It may affect the mRNA stability, secondary structure of mRNA, synthesis, turnover, protein folding and function. We could show a 1.3% decrease in DJ-1 mRNA folding energy in the A<G substituted sequence compared to the wild type sequence in silico, suggesting a possible small effect of Ala167Ala on DJ-1 gene function. This is the first report on an identified DJ-1 mutation in Swedish PD patients. Our results, in combination with those of previous studies, strengthen the hypothesis that alterations in DJ-1 are not a common cause of familial and early-onset PD world-wide.","variants":[{"Name":"NM_007262.5(PARK7):c.501A>G (p.Ala167=)","Chromosome":"1","Start":"7984985","Stop":"7984985","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":690677,"rule_based_match":true,"evidence_text":"c.501A>G","llm_judgment":"PRESENT","evidence":"c.501A>G","abstract_start":676,"abstract_end":684}]}
{"pmid":"22943132","title":"Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis.","abstract":"BACKGROUND: Vascular elasticity is crucial for maintaining hemodynamics. Molecular mechanisms involved in human elastogenesis are incompletely understood. We describe a syndrome of lethal arteriopathy associated with a novel, identical mutation in the fibulin 4 gene (FBLN4) in a unique cohort of infants from South India.\nMETHODS: Clinical characteristics, cardiovascular findings, outcomes and molecular genetics of twenty-two infants from a distinct population subgroup, presenting with characteristic arterial dilatation and tortuosity during the period August 2004 to June 2011 were studied.\nRESULTS: Patients (11 males, 11 females) presented at median age of 1.5 months, belonging to unrelated families from identical ethno-geographical background; eight had a history of consanguinity. Cardiovascular features included aneurysmal dilatation, elongation, tortuosity and narrowing of the aorta, pulmonary artery and their branches. The phenotype included a variable combination of cutis laxa (52%), long philtrum-thin vermillion (90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%), sagging cheeks (43%), long slender digits (48%), and visible arterial pulsations (38%). Genetic studies revealed an identical c.608A > C (p. Asp203Ala) mutation in exon 7 of the FBLN4 gene in all 22 patients, homozygous in 21, and compound heterozygous in one patient with a p. Arg227Cys mutation in the same conserved cbEGF sequence. Homozygosity was lethal (17/21 died, median age 4 months). Isthmic hypoplasia (n = 9) correlated with early death (≤4 months).\nCONCLUSIONS: A lethal, genetic disorder characterized by severe deformation of elastic arteries, was linked to novel mutations in the FBLN4 gene. While describing a hitherto unreported syndrome in this population subgroup, this study emphasizes the critical role of fibulin-4 in human elastogenesis.","variants":[{"Name":"NM_016938.5(EFEMP2):c.608A>C (p.Asp203Ala)","Chromosome":"11","Start":"65869976","Stop":"65869976","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":47617,"rule_based_match":true,"evidence_text":"c.608A > C (p. Asp203Ala)","llm_judgment":"PRESENT","evidence":"c.608A > C (p. Asp203Ala)","abstract_start":1230,"abstract_end":1255}]}
{"pmid":"28566233","title":"Expanding the genetic cause of multiple sulfatase deficiency: A novel SUMF1 variant in a patient displaying a severe late infantile form of the disease.","abstract":"Multiple sulfatase deficiency (MSD) is a rare inherited metabolic disease caused by defective cellular sulfatases. Activity of sulfatases depends on post-translational modification catalyzed by formylglycine-generating enzyme (FGE), encoded by the SUMF1 gene. SUMF1 pathologic variants cause MSD, a syndrome presenting with a complex phenotype. We describe the first Polish patient with MSD caused by a yet undescribed pathologic variant c.337G>A [p.Glu113Lys] (i.e. p.E113K) in heterozygous combination with the known deletion allele c.519+5_519+8del [p.Ala149_Ala173del]. The clinical picture of the patient initially suggested late infantile metachromatic leukodystrophy, with developmental delay followed by regression of visual, hearing and motor abilities as the most apparent clinical symptoms. Transient signs of ichthyosis and minor dysmorphic features guided the laboratory workup towards MSD. Since MSD is a rare disease and there is a variable clinical spectrum, we thoroughly describe the clinical outcome of our patient. The FGE-E113K variant, expressed in cell culture, correctly localized to the endoplasmic reticulum but was retained intracellularly in contrast to the wild type FGE. Analysis of FGE-mediated activation of steroid sulfatase in immortalized MSD cells revealed that FGE-E113K exhibited only approx. 15% of the activity of wild type FGE. Based on the crystal structure we predict that the exchange of glutamate-113 against lysine should induce a strong destabilization of the secondary structure, possibly affecting the folding for correct disulfide bridging between C235-C346 as well as distortion of the active site groove that could affect both the intracellular stability as well as the activity of FGE. Thus, the novel variant of the SUMF1 gene obviously results in functionally impaired FGE protein leading to a severe late infantile type of MSD.","variants":[{"Name":"NM_182760.4(SUMF1):c.337G>A (p.Glu113Lys)","Chromosome":"3","Start":"4452983","Stop":"4452983","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227720,"rule_based_match":true,"evidence_text":"c.337G>A [p.Glu113Lys]","llm_judgment":"PRESENT","evidence":"c.337G>A [p.Glu113Lys]","abstract_start":438,"abstract_end":460}]}
{"pmid":"17171576","title":"Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy.","abstract":"Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis. We report a patient who presented at 10 months of age with hypotonia and global developmental delay. Subsequently, she developed seizures and choreoathetosis. Magnetic resonance imaging showed high signal bilaterally in the globus pallidus on T2-weighted images. Mitochondrial respiratory chain studies revealed low complex I activity (in muscle 0.052 nmol NADH oxidized per min per unit citrate synthase, controls 0.166 +/- 0.047; in fibroblasts 0.080 nmol NADH oxidized per min per unit citrate synthase, controls 0.197 +/- 0.034). The true diagnosis was suspected at 21 months of age because of persistent low plasma and urine creatinine concentrations. GAMT activity was undetectable in fibroblasts and compound heterozygous mutations were found in the GAMT gene (c.327G>A and c.522G>A). The patient was treated with creatine, dietary arginine restriction and ornithine supplements. Her movement disorder and seizures resolved but she still has severe cognitive impairment and no expressive language. The occurrence of secondary respiratory chain abnormalities in GAMT deficiency may lead to misdiagnosis, particularly as the clinical and radiological features resemble those seen in mitochondrial encephalopathies. It is important to establish the correct diagnosis because specific treatment is available.","variants":[{"Name":"NM_000156.6(GAMT):c.522G>A (p.Trp174Ter)","Chromosome":"19","Start":"1398964","Stop":"1398964","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":203537,"rule_based_match":true,"evidence_text":"c.522G>A","llm_judgment":"PRESENT","evidence":"c.522G>A","abstract_start":876,"abstract_end":884}]}
{"pmid":"25677735","title":"Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy.","abstract":"Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder, caused by mutations in FLVCR2. Hallmarks of the syndrome are glomerular vasculopathy in the central nervous system, severe hydrocephaly, hypokinesia and arthrogryphosis. The disorder is considered prenatally lethal. We report the first patients, a brother and a sister, with Fowler syndrome and survival beyond infancy. The patients present a phenotype of severe intellectual and neurologic disability with seizures, absence of functional movements, and no means of communication. Imaging of the brain showed calcifications, profound ventriculomegaly with only a thin edging of the cerebral cortex and hypoplastic cerebellum. Investigation with whole-exome sequencing (WES) revealed, in both patients, a homozygous pathogenic mutation in FLVCR2, c.1289C>T, compatible with a diagnosis of Fowler syndrome. The results highlight the power of combining WES with a thorough clinical examination in order to identify disease-causing mutations in patients whose clinical presentation differs from previously described cases. Specifically, the findings demonstrate that Fowler syndrome is a diagnosis to consider, not only prenatally but also in severely affected children with gross ventriculomegaly on brain imaging.","variants":[{"Name":"NM_017791.3(FLVCR2):c.1289C>T (p.Thr430Met)","Chromosome":"14","Start":"75641008","Stop":"75641008","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":513724,"rule_based_match":true,"evidence_text":"c.1289C>T","llm_judgment":"PRESENT","evidence":"c.1289C>T","abstract_start":907,"abstract_end":916}]}
{"pmid":"21179243","title":"A novel nonsense mutation in the NDP gene in a Chinese family with Norrie disease.","abstract":"PURPOSE: Norrie disease (ND), a rare X-linked recessive disorder, is characterized by congenital blindness and, occasionally, mental retardation and hearing loss. ND is caused by the Norrie Disease Protein gene (NDP), which codes for norrin, a cysteine-rich protein involved in ocular vascular development. Here, we report a novel mutation of NDP that was identified in a Chinese family in which three members displayed typical ND symptoms and other complex phenotypes, such as cerebellar atrophy, motor disorders, and mental disorders.\nMETHODS: We conducted an extensive clinical examination of the proband and performed a computed tomography (CT) scan of his brain. Additionally, we performed ophthalmic examinations, haplotype analyses, and NDP DNA sequencing for 26 individuals from the proband's extended family.\nRESULTS: The proband's computed tomography scan, in which the fifth ventricle could be observed, indicated cerebellar atrophy. Genome scans and haplotype analyses traced the disease to chromosome Xp21.1-p11.22. Mutation screening of the NDP gene identified a novel nonsense mutation, c.343C>T, in this region.\nCONCLUSIONS: Although recent research has shown that multiple different mutations can be responsible for the ND phenotype, additional research is needed to understand the mechanism responsible for the diverse phenotypes caused by mutations in the NDP gene.","variants":[{"Name":"NM_000266.4(NDP):c.343C>T (p.Arg115Ter)","Chromosome":"X","Start":"43949858","Stop":"43949858","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2901889,"rule_based_match":true,"evidence_text":"c.343C>T","llm_judgment":"PRESENT","evidence":"c.343C>T","abstract_start":1102,"abstract_end":1110}]}
{"pmid":"23815237","title":"Prenatal diagnosis of X-linked recessive Lenz microphthalmia syndrome.","abstract":"Lenz microphthalmia syndrome comprises microphthalmia-anophthalmia with mental retardation, malformed ears and skeletal anomalies, and is inherited in an X-linked recessive pattern. In 2004, it was reported that the missense mutation (BCL-6 co-repressor gene [BCOR] c.254C>T, p.P85L) in a single family with Lenz microphthalmia syndrome co-segregated with the disease phenotype. We report a case of prenatal diagnosis for X-linked recessive Lenz microphthalmia syndrome with the mutation. A 32-year-old gravida 5, para 2 Japanese woman was referred to Nagoya City University Hospital at 15 weeks of gestation. After genetic counseling and informed consent, amniocentesis was performed for fetal karyotyping, which was 46,XY. Using the extracted DNA from cultured amniotic cells, fetal search for BCOR c.254C>T mutation was undertaken. The couple requested medical termination of pregnancy, and the postabortion examination confirmed the diagnosis. This is the third report of a BCOR mutation, associated with X-linked syndromic microphthalmia, and most importantly, it is always the same mutation. The prenatal genetic diagnosis of the Lenz microphthalmia syndrome allowed time for parental counseling and delivery planning.","variants":[{"Name":"NM_001123385.2(BCOR):c.254C>T (p.Pro85Leu)","Chromosome":"X","Start":"40075092","Stop":"40075092","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25950,"rule_based_match":true,"evidence_text":"BCOR c.254C>T","llm_judgment":"PRESENT","evidence":"BCOR c.254C>T","abstract_start":796,"abstract_end":809}]}
{"pmid":"30386727","title":"Fabry disease in a Japanese population-molecular and biochemical characteristics.","abstract":"We had experienced 117 Japanese Fabry patients (72 males and 45 females) from 1977 to 2006, and then we generated an improved Fabry analysis system in 2007 and have found 196 ones (95 males and 101 females) since then. In this study, we summarized the data of the patients and tried to elucidate the molecular and biochemical characteristics of Japanese Fabry patients. Gene analysis revealed various <i>GLA</i> mutations, including missense mutations (56.5%, 48 types); nonsense mutations (15.9%, 13 types); deletions (12.6%, 13 types); splicing defects (10.1%, 6 types); insertions (1.0%, 2 types), and insertions/deletions (0.5%, 1 type), in the patients that were tested. Amino acid substitutions resulting from the missense mutations found in the classic form patients tended to be localized in the core of the GLA protein, and those in the later-onset ones in the peripheral region. The most commonly identified pathogenic mutations are <i>c.888G</i> <i>></i> <i>A (p.M296I)</i>, <i>c.936</i> <i>+</i> <i>919G</i> <i>></i> <i>A</i>, <i>c.679C</i> <i>></i> <i>T (p.R227X)</i>, <i>c.335G</i> <i>></i> <i>A (p.R112H)</i>, <i>c.334C</i> <i>></i> <i>T (p.R112C)</i>, and <i>c.902G</i> <i>></i> <i>A (p.R301Q</i>). Among them, <i>c.888G</i> <i>></i> <i>A (p.M296I)</i> is unique to Japanese Fabry patients. On the other hand, <i>c.936</i> <i>+</i> <i>919G</i> <i>></i> <i>A</i> is a variant that has been frequently detected in Taiwan Chinese Fabry patients, and <i>c.335G</i> <i>></i> <i>A (p.R112H)</i> in various countries. These are found in later-onset patients, and <i>c.679C</i> <i>></i> <i>T (p.R227X)</i> and <i>c.334C</i> <i>></i> <i>T (p.R112C)</i> classic ones. <i>c.902G</i> <i>></i> <i>A (p.R301Q)</i> is found in both classic and later-onset form patients. A possible functional polymorphism, <i>c.196G</i> <i>></i> <i>C (p.E66Q)</i>, was identified in 0.4% of the subjects who underwent high-risk screening. The biochemical findings including leukocyte α-galactosidase A activity, plasma globotriaosylsphingosine level and urinary globotriaosylceramide in the individual phenotypic groups well reflected the phenotypic differences in this disease. The results will be useful for understanding the basis of Fabry disease in Japan.","variants":[{"Name":"NM_000169.3(GLA):c.196G>C (p.Glu66Gln)","Chromosome":"X","Start":"101403984","Stop":"101403984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":25762,"rule_based_match":false,"evidence_text":"c.196G>C (p.E66Q)","llm_judgment":"PRESENT","evidence":"p.E66Q","abstract_start":1837,"abstract_end":1843},{"Name":"NM_000169.3(GLA):c.334C>T (p.Arg112Cys)","Chromosome":"X","Start":"101403846","Stop":"101403846","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38452,"rule_based_match":false,"evidence_text":"c.334C>T (p.R112C)","llm_judgment":"PRESENT","evidence":"p.R112C","abstract_start":1154,"abstract_end":1161},{"Name":"NM_000169.3(GLA):c.335G>A (p.Arg112His)","Chromosome":"X","Start":"101403845","Stop":"101403845","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":192190,"rule_based_match":false,"evidence_text":"c.335G>A (p.R112H)","llm_judgment":"PRESENT","evidence":"p.R112H","abstract_start":1111,"abstract_end":1118}]}
{"pmid":"24115387","title":"Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India.","abstract":"We report a novel missense mutation (c.1040G>A, p.Arg347Gln) in MID2, which encodes ubiquitin ligase E3, as the likely cause of X-linked mental retardation in a large kindred. The mutation was observed in all affected and obligate carriers but not in any unaffected males of the family or in population controls (n = 200). When transiently expressed in HEK293T cell line, the mutation was found to abolish the function of the COS domain in the protein. The GFP-tagged mutant protein accumulated in the cytoplasm instead of binding to the cytoskeleton resulting in its altered subcellular localization. Screening of coding exons of this gene in additional 480 unrelated individuals with idiopathic intellectual disability identified another novel variation p.Asn343Ser. This study highlights the growing role of the ubiquitin pathway in intellectual disability and also, the difference in MID2 determined phenotype observed in this study compared with that of its paralogue MID1 reported in literature.","variants":[{"Name":"NM_012216.4(MID2):c.1040G>A (p.Arg347Gln)","Chromosome":"X","Start":"107905593","Stop":"107905593","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":153582,"rule_based_match":true,"evidence_text":"c.1040G>A, p.Arg347Gln","llm_judgment":"PRESENT","evidence":"c.1040G>A, p.Arg347Gln","abstract_start":37,"abstract_end":59}]}
{"pmid":"35401677","title":"Identification of a","abstract":"Baraitser-Winter cerebrofrontofacial syndrome (BWCFF, OMIM: 243310) is a rare autosomal-dominant developmental disorder associated with variants in the genes <i>ACTB</i> or <i>ACTG1</i>. It is characterized by brain malformations, a distinctive facial appearance, ocular coloboma, and intellectual disability. However, the phenotypes of BWCFF are heterogenous, and its molecular pathogenesis has not been fully elucidated. In the present study, we conducted detailed clinical examinations on a Chinese patient with BWCFF and found novel ocular manifestations including pseudoduplication of the optic disc and nystagmus. Targeted gene panel sequencing and Sanger sequencing identified a <i>de novo</i> heterozygous missense c.478A > G (p.Thr160Ala) variant in <i>ACTB</i>. The mRNA and protein expression of <i>ACTB</i> was assessed by quantitative reverse transcription PCR and Western blots. Furthermore, the functional effects of the pathogenic variant were analyzed by protein structure analysis, which indicated that the variant may affect the active site for ATP hydrolysis by the actin ATPase, resulting in abnormal filamentous actin organization in peripheral blood mononuclear cells. This discovery extends the <i>ACTB</i> variant spectrum, which will improve genetic counseling and diagnosis, and may contribute to understanding the pathogenic mechanisms of actin-related diseases.","variants":[{"Name":"NM_001101.5(ACTB):c.478A>G (p.Thr160Ala)","Chromosome":"7","Start":"5528605","Stop":"5528605","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1241929,"rule_based_match":true,"evidence_text":"c.478A > G (p.Thr160Ala)","llm_judgment":"PRESENT","evidence":"c.478A > G (p.Thr160Ala)","abstract_start":723,"abstract_end":747}]}
{"pmid":"22718341","title":"Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix.","abstract":"Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with ≈10% over-modification. Normal chain incorporation, helix folding, and collagen T(m) support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix.","variants":[{"Name":"NM_021939.4(FKBP10):c.1271_1272delinsA (p.Ala424fs)","Chromosome":"17","Start":"41820961","Stop":"41820962","ReferenceAlleleVCF":"CC","AlternateAlleleVCF":"A","allel_id":49863,"rule_based_match":false,"evidence_text":"c.1271_1272delCCinsA","llm_judgment":"PRESENT","evidence":"c.1271_1272delCCinsA","abstract_start":583,"abstract_end":603}]}
{"pmid":"30931713","title":"Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations two family reports and literature review.","abstract":"OBJECTIVE: To verify the diagnosis of channelopathies in two families and explore the mechanism of the overlap between periodic paralysis (PP) and paramyotonia congenita (PMC).\nMETHODS: We have studied two cases with overlapping symptoms of episodic weakness and stiffness in our clinical center using a series of assessment including detailed medical history, careful physical examination, laboratory analyses, muscle biopsy, electrophysiological evaluation, and genetic analysis.\nRESULTS: The first proband and part of his family with the overlap of PMC and hyperkalemic periodic paralysis (HyperPP) has been identified as c.2111C > T (T704M) substitution of the gene SCN4A. The second proband and part of his family with the overlap of PMC and hypokalemic periodic paralysis type 2 (HypoPP2) has been identified as c.4343G > A (R1448H) substitution of the gene SCN4A. In addition, one member of the second family with overlapping symptoms has been identified as a novel mutation c.2111C > T without the mutation c.4343G > A.\nCONCLUSIONS: SCN4A gene mutations can cause the overlap of PMC and PP (especially the HypoPP2). The clinical symptoms of episodic weakness and stiffness could happen at a different time or temperature. Based on diagnosis assessments such as medical history and muscle biopsy, further evaluations on long-time exercise test, genetic analysis, and patch clamp electrophysiology test need to be done in order to verify the specific subtype of channelopathies. Furthermore, the improvement of one member in the pregnancy period can be used as a reference for the other female in the child-bearing period with T704M.","variants":[{"Name":"NM_000334.4(SCN4A):c.4343G>A (p.Arg1448His)","Chromosome":"17","Start":"63941939","Stop":"63941939","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20938,"rule_based_match":true,"evidence_text":"c.4343G > A (R1448H)","llm_judgment":"PRESENT","evidence":"c.4343G > A (R1448H)","abstract_start":818,"abstract_end":838},{"Name":"NM_000334.4(SCN4A):c.2111C>T (p.Thr704Met)","Chromosome":"17","Start":"63957427","Stop":"63957427","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20935,"rule_based_match":true,"evidence_text":"c.2111C > T (T704M)","llm_judgment":"PRESENT","evidence":"c.2111C > T (T704M)","abstract_start":625,"abstract_end":644}]}
{"pmid":"16274666","title":"Aminoacylase I deficiency: a novel inborn error of metabolism.","abstract":"This is the first report of a patient with aminoacylase I deficiency. High amounts of N-acetylated amino acids were detected by gas chromatography-mass spectrometry in the urine, including the derivatives of serine, glutamic acid, alanine, methionine, glycine, and smaller amounts of threonine, leucine, valine, and isoleucine. NMR spectroscopy confirmed these findings and, in addition, showed the presence of N-acetylglutamine and N-acetylasparagine. In EBV transformed lymphoblasts, aminoacylase I activity was deficient. Loss of activity was due to decreased amounts of aminoacylase I protein. The amount of mRNA for the aminoacylase I was decreased. DNA sequencing of the encoding ACY1 gene showed a homozygous c.1057 C>T transition, predicting a p.Arg353Cys substitution. Both parents were heterozygous for the mutation. The mutation was also detected in 5/161 controls. To exclude the possibility of a genetic polymorphism, protein expression studies were performed showing that the mutant protein had lost catalytic activity.","variants":[{"Name":"NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)","Chromosome":"3","Start":"51988821","Stop":"51988821","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33149,"rule_based_match":true,"evidence_text":"c.1057 C>T","llm_judgment":"PRESENT","evidence":"c.1057 C>T","abstract_start":716,"abstract_end":726}]}
{"pmid":"24842371","title":"Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency.","abstract":"Autosomal recessive mutations in UNC13D, the gene that encodes Munc13-4, are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Munc13-4 expression is obligatory for exocytosis of lytic granules, facilitating cytotoxicity by T cells and natural killer (NK) cells. The mechanisms regulating Munc13-4 expression are unknown. Here, we report that Munc13-4 is highly expressed in differentiated human NK cells and effector CD8(+) T lymphocytes. A UNC13D c.118-308C>T mutation, causative of FHL3, disrupted binding of the ETS family member ELF1 to a conserved intronic sequence. This mutation impairs UNC13D intron 1 recruitment of STAT4 and the chromatin remodeling complex component BRG1, diminishing active histone modifications at the locus. The intronic sequence acted as an overall enhancer of Munc13-4 expression in cytotoxic lymphocytes in addition to representing an alternative promoter encoding a novel Munc13-4 isoform. Mechanistically, T cell receptor engagement facilitated STAT4-dependent Munc13-4 expression in naive CD8(+) T lymphocytes. Collectively, our data demonstrates how chromatin remodeling within an evolutionarily conserved regulatory element in intron 1 of UNC13D regulates the induction of Munc13-4 expression in cytotoxic lymphocytes and suggests that an alternative Munc13-4 isoform is required for lymphocyte cytotoxicity. Thus, mutations associated with primary immunodeficiencies may cause disease by disrupting transcription factor binding.","variants":[{"Name":"NM_199242.3(UNC13D):c.118-308C>T","Chromosome":"17","Start":"75843827","Stop":"75843827","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":531855,"rule_based_match":true,"evidence_text":"UNC13D c.118-308C>T","llm_judgment":"PRESENT","evidence":"UNC13D c.118-308C>T","abstract_start":467,"abstract_end":486}]}
{"pmid":"22521272","title":"Myotonia congenita: novel mutations in CLCN1 gene and functional characterizations in Italian patients.","abstract":"Myotonia congenita is an autosomal dominantly or recessively inherited muscle disorder causing impaired muscle relaxation and variable degrees of permanent muscle weakness, abnormal currents linked to the chloride channel gene (CLCN1) encoding the chloride channel on skeletal muscle membrane. We describe 12 novel mutations: c.1606G>C (p.Val536Leu), c.2533G>A (p.Gly845Ser), c.2434C>T (p.Gln812X), c.1499T>G (p.E500X), c.1012C>T (p.Arg338X), c.2403+1G>A, c.2840T>A (p.Val947Glu), c.1598C>T (p.Thr533Ile), c.1110delC, c.590T>A (p.Ile197Arg), c.2276insA Fs800X, c.490T>C (p.Trp164Arg) in 22 unrelated Italian patients. To further understand the functional outcome of selected missense mutations (p.Trp164Arg, p.Ile197Arg and p.Gly845Ser, and the previously reported p.Gly190Ser) we characterized the biophysical properties of mutant ion channels in tsA cell model. In the physiological range of muscle membrane potential, all the tested mutations, except p.Gly845Ser, reduced the open probability, increased the fast and slow components of deactivation and affected pore properties. This suggests a decrease in macroscopic chloride currents impairing membrane potential repolarization and causing hyperexcitability in muscle membranes. Detailed clinical features are given of the 8 patients characterized by cell electrophysiology. These data expand the spectrum of CLCN1 mutations and may contribute to genotype-phenotype correlations. Furthermore, we provide insights into the fine protein structure of ClC-1 and its physiological role in the maintenance of membrane resting potential.","variants":[{"Name":"NM_000083.3(CLCN1):c.1012C>T (p.Arg338Ter)","Chromosome":"7","Start":"143331264","Stop":"143331264","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":413762,"rule_based_match":true,"evidence_text":"c.1012C>T (p.Arg338X)","llm_judgment":"PRESENT","evidence":"c.1012C>T (p.Arg338X)","abstract_start":420,"abstract_end":441},{"Name":"NM_000083.3(CLCN1):c.1606G>C (p.Val536Leu)","Chromosome":"7","Start":"143341952","Stop":"143341952","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3086306,"rule_based_match":true,"evidence_text":"c.1606G>C (p.Val536Leu)","llm_judgment":"PRESENT","evidence":"c.1606G>C (p.Val536Leu)","abstract_start":326,"abstract_end":349},{"Name":"NM_000083.3(CLCN1):c.2403+1G>A","Chromosome":"7","Start":"143346950","Stop":"143346950","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3086313,"rule_based_match":true,"evidence_text":"c.2403+1G>A","llm_judgment":"PRESENT","evidence":"c.2403+1G>A","abstract_start":443,"abstract_end":454},{"Name":"NM_000083.3(CLCN1):c.2533G>A (p.Gly845Ser)","Chromosome":"7","Start":"143350592","Stop":"143350592","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2738293,"rule_based_match":true,"evidence_text":"c.2533G>A (p.Gly845Ser)","llm_judgment":"PRESENT","evidence":"c.2533G>A (p.Gly845Ser)","abstract_start":351,"abstract_end":374},{"Name":"NM_000083.3(CLCN1):c.490T>C (p.Trp164Arg)","Chromosome":"7","Start":"143321421","Stop":"143321421","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3086300,"rule_based_match":true,"evidence_text":"c.490T>C (p.Trp164Arg)","llm_judgment":"PRESENT","evidence":"c.490T>C (p.Trp164Arg)","abstract_start":561,"abstract_end":583}]}
{"pmid":"28829391","title":"A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290.","abstract":"PURPOSE: To identify the gene defect and to study the clinical characteristics and natural course of disease in a family originally diagnosed with oligocone trichromacy (OT), a rare congenital cone dysfunction syndrome.\nMETHODS: Extensive clinical and ophthalmologic assessment was performed on two siblings with OT and long-term follow up data were analyzed. Subsequently, whole exome sequencing (WES) and Sanger sequence analysis of <i>CEP290</i> was performed in the two siblings. Additionally, the identified <i>CEP290</i> mutations were analyzed in persons with achromatopsia (ACHM) (<i>n</i> = 23) and autosomal recessive or isolated cone dystrophy (CD; <i>n</i> = 145).\nRESULTS: In the first decade of life, the siblings were diagnosed with OT based on low visual acuity, photophobia, nystagmus, and absent cone response on electroretinography , but with normal color discrimination. Over time, the phenotype of OT evolved to a progressive degenerative disease without any <i>CEP290</i>-associated non-ocular features. In both siblings, two nonsense mutations (c.451C>T; p.(Arg151*) and c.4723A>T; p.(Lys1575*)) in <i>CEP290</i> were found. Previously, p.(Arg151*) was demonstrated to induce nonsense-mediated alternative splicing events leading to intact open reading frames of the resulting mRNA products (p.(Leu148_Glu165del) and p.(Leu148_Lys172del)). mRNA analysis for p.(Lys1575*) confirmed a suspected hypomorphic character, as exon 36 skipping was observed in a small fraction of <i>CEP290</i> mRNA, resulting in a 36 aa in-frame deletion (p.(Glu1569_Trp1604del)). No additional cases carrying these variants were identified in the ACHM and CD cohorts.\nCONCLUSIONS: Compound heterozygous hypomorphic mutations in <i>CEP290</i> may lead to a rare form of cone-dominated retinal dystrophy, a novel phenotype belonging to the <i>CEP290</i>-associated spectrum of ciliopathies. These findings provide insight into the effect of <i>CEP290</i> mutations on the clinical phenotype.","variants":[{"Name":"NM_025114.4(CEP290):c.451C>T (p.Arg151Ter)","Chromosome":"12","Start":"88131209","Stop":"88131209","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360113,"rule_based_match":true,"evidence_text":"c.451C>T; p.(Arg151*)","llm_judgment":"PRESENT","evidence":"c.451C>T; p.(Arg151*)","abstract_start":1068,"abstract_end":1089},{"Name":"NM_025114.4(CEP290):c.4723A>T (p.Lys1575Ter)","Chromosome":"12","Start":"88083936","Stop":"88083936","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":16378,"rule_based_match":true,"evidence_text":"c.4723A>T; p.(Lys1575*)","llm_judgment":"PRESENT","evidence":"c.4723A>T; p.(Lys1575*)","abstract_start":1094,"abstract_end":1117}]}
{"pmid":"29215095","title":"Homozygosity for a nonsense variant in AIMP2 is associated with a progressive neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis.","abstract":"We ascertained two unrelated consanguineous families with two affected children each having microcephaly, refractory seizures, intellectual disability, and spastic quadriparesis. Magnetic resonance imaging showed atrophy of cerebrum, cerebellum and spinal cord, prominent cisterna magna, symmetric T2 hypo-intensities in the bilateral basal ganglia and thinning of corpus callosum. Whole-exome sequencing of three affected individuals revealed c.105C>A [p.(Tyr35Ter)] variant in AIMP2. The variant lies in a common homozygous region of 940 kb on chromosome 7 and is likely to have been inherited from a common ancestor. The phenotype noted in our subjects' shares marked similarity with that of hypomyelinating leukodystrophy-3 caused by mutations in closely related gene AIMP1. We hereby report the first human disease associated with deleterious mutations in AIMP2.","variants":[{"Name":"NM_006303.4(AIMP2):c.105C>A (p.Tyr35Ter)","Chromosome":"7","Start":"6009468","Stop":"6009468","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":420147,"rule_based_match":true,"evidence_text":"c.105C>A [p.(Tyr35Ter)]","llm_judgment":"PRESENT","evidence":"c.105C>A [p.(Tyr35Ter)]","abstract_start":444,"abstract_end":467}]}
{"pmid":"26604660","title":"Molecular analysis of the CHST6 gene in Korean patients with macular corneal dystrophy: Identification of three novel mutations.","abstract":"PURPOSE: To identify the underlying genetic defect in Korean patients with macular corneal dystrophy (MCD).\nMETHODS: Genomic DNA was isolated from peripheral blood leukocytes of seven patients from six unrelated families with MCD (three men and four women). Polymerase chain reaction was performed for coding regions of the carbohydrate sulfotransferase (CHST6), gene followed by bidirectional sequencing. Targeted mutational analysis (exons 4, 11-12, 14) of the transforming growth factor, beta-induced (TGFBI) gene was performed for all patients.\nRESULTS: All seven patients were found to have compound heterozygous mutations in the CHST6 gene. In addition to six previously reported mutations, c.95C>A (p.Ser32*), c.521A>G (p.Lys174Arg), c.557C>G (p.Pro186Arg), c.613C>T (p.Arg205Trp), c.820G>A (p.Glu274Lys), and c.1072T>C (p.Tyr358His), three novel mutations were identified in this study, including two missense mutations, c.353C>T (p.Ser118Phe) and c.922C>T (p.His308Tyr), and one frameshift mutation, c.786delC (p.L264Cfs*117). Among the three novel mutations, only the c.353C>T mutation had been reported in the Exon Aggregation Consortium database at an extremely low frequency of 0.00005072. In addition, these three novel mutations were absent from controls in 1,000 genomes, dbSNP, and the TIARA genome database, which is a Korean personal genome database. The most frequent mutation was c.613C>T (p.Arg205Trp), revealed in four unrelated Korean families, which has not previously been reported in other populations. No mutations were detected in the TGFBI gene.\nDISCUSSION: This is the first report on genetic analysis of Korean MCD patients. Three novel and six previously reported disease-causing CHST6 mutations were identified, which expands the mutational spectrum of MCD.","variants":[{"Name":"NM_021615.5(CHST6):c.820G>A (p.Glu274Lys)","Chromosome":"16","Start":"75479009","Stop":"75479009","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3534250,"rule_based_match":true,"evidence_text":"c.820G>A (p.Glu274Lys)","llm_judgment":"PRESENT","evidence":"c.820G>A (p.Glu274Lys)","abstract_start":789,"abstract_end":811},{"Name":"NM_021615.5(CHST6):c.521A>G (p.Lys174Arg)","Chromosome":"16","Start":"75479308","Stop":"75479308","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":20110,"rule_based_match":true,"evidence_text":"c.521A>G (p.Lys174Arg)","llm_judgment":"PRESENT","evidence":"c.521A>G (p.Lys174Arg)","abstract_start":717,"abstract_end":739}]}
{"pmid":"23956117","title":"Redefining the progeroid form of Ehlers-Danlos syndrome: report of the fourth patient with B4GALT7 deficiency and review of the literature.","abstract":"Proteoglycans are a component of the extracellular matrix and are critical for cellular and tissue function. Mutations in proteoglycan components and enzymes involved in proteoglycan synthesis have been implicated in several growth disorders, with common features including short stature and skeletal dysplasia. For example, mutations in B4GALT7, a gene whose protein product catalyzes proteoglycan synthesis, have been associated with the rare progeroid variant of Ehlers-Danlos syndrome. Here, we conducted exome sequencing in a patient with a previously undiagnosed growth disorder and identified compound heterozygous mutations in B4GALT7. This patient is just the fourth individual with genetically confirmed progeroid variant of Ehlers-Danlos syndrome. The mutations include a previously characterized c.808C>T p.Arg270Cys substitution, and a novel c.122T>C p.Leu41Pro substitution. We demonstrate that the novel mutation caused decreased levels of the enzyme, supporting the pathogenicity of the mutation. Our report identifies a novel mutation in B4GALT7 causing the progeroid variant of Ehlers-Danlos syndrome and contributes an extensive phenotypic characterization of a patient with the syndrome. We also reviewed the previous literature in addition to the present patient, and conclude that the key features associated with B4GALT7 deficiency are short stature, developmental anomalies of the forearm bones and elbow, and bowing of the extremities, in addition to the classic features of Ehlers-Danlos syndrome. This report helps define the phenotype of the progeroid variant of Ehlers-Danlos syndrome and furthers our understanding of the effect of proteoglycan defects in growth disorders.","variants":[{"Name":"NM_007255.3(B4GALT7):c.122T>C (p.Leu41Pro)","Chromosome":"5","Start":"177604250","Stop":"177604250","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":227506,"rule_based_match":true,"evidence_text":"c.122T>C p.Leu41Pro","llm_judgment":"PRESENT","evidence":"c.122T>C p.Leu41Pro","abstract_start":855,"abstract_end":874},{"Name":"NM_007255.3(B4GALT7):c.808C>T (p.Arg270Cys)","Chromosome":"5","Start":"177608994","Stop":"177608994","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20652,"rule_based_match":true,"evidence_text":"c.808C>T p.Arg270Cys","llm_judgment":"PRESENT","evidence":"c.808C>T p.Arg270Cys","abstract_start":808,"abstract_end":828}]}
{"pmid":"20046049","title":"Different clinical presentation in siblings with mitochondrial acetoacetyl-CoA thiolase deficiency and identification of two novel mutations.","abstract":"Mitochondrial acetoacetyl-CoA thiolase (T2) catalyzes 2-methylacetoacetyl-CoA cleavage into acetyl-CoA and propionyl-CoA in isoleucine catabolism and interconversion between acetyl-CoA and acetoacetyl-CoA in ketone body metabolism. T2 deficiency is a rare metabolic disease of autosomal recessive inheritance. The disorder is characterized by intermittent ketoacidotic episodes. The onset of clinical symptoms is in the infant or toddler period. The frequency of episodes declines with age, stopping before adolescence. Here we report two siblings with this disorder. The proband (GK65) is a French girl born from non-consanguineous parents. She presented several ketoacidotic episodes with 5 hospitalizations from age 2 to 4 years, the first of them complicated by ketoacidotic coma. Minor episodes, which are generally provoked by infections or high protein intake, still persist at age of 16 years. Molecular analysis of the T2 gene has revealed the compound heterozygosity of c.578T>C (M193T) and IVS8+5g>t. The latter mutation results in skipping of exon 8. In contrast, the younger brother (GK65b) had a unique ketoacidotic crisis at the age of 6 years that is the oldest-age first crisis among T2-deficient patients reported thus far. Despite the mild phenotype, he carried the same T2 gene mutations as his sister (GK65). Furthermore, T2 catalytic activity and T2 protein were not detected in the fibroblasts derived from GK65 and GK65b. In conclusion, the siblings with the same T2 gene mutations present different clinical severity. Diagnostic testing for asymptomatic siblings is important in the management of T2-deficient families.","variants":[{"Name":"NM_000019.4(ACAT1):c.578T>C (p.Met193Thr)","Chromosome":"11","Start":"108139040","Stop":"108139040","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":654044,"rule_based_match":true,"evidence_text":"c.578T>C (M193T)","llm_judgment":"PRESENT","evidence":"c.578T>C (M193T)","abstract_start":980,"abstract_end":996}]}
{"pmid":"15776427","title":"Lysinuric protein intolerance: identification and functional analysis of mutations of the SLC7A7 gene.","abstract":"Lysinuric protein intolerance (LPI) is an inherited hyperdibasic aminoaciduria caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is relatively common in Finland and a few clusters of patients are known in Italy and Japan. The SLC7A7 gene, mutated in LPI patients, encodes the y+LAT-1 protein which is the light subunit of a heterodimeric CAA transporter. We performed the mutation analysis in seven probands from five unrelated LPI families and identified five novel SLC7A7 mutations (p.M50K, p.T188I, p.R333M, p.Y457X, and c.499+?_629-?). By expression studies in X. laevis oocytes or patient's renal tubular cells, the functional analysis of altogether eight SLC7A7 mutations is here reported. Noteworthy, the p.R333M mutation, caused by a G to T transversion of the last nucleotide at 3' end of exon 7, disrupts a functional splicing motif generating misspliced transcripts. Three of the novel mutations were found in patients originating from Greece and Pakistan thus increasing the list of ethnic backgrounds where LPI mutant alleles are present. This reinforces the view that the rarity of LPI outside Finland might be ascribed to misdiagnosis of this disease.","variants":[{"Name":"NM_003982.4(SLC7A7):c.563C>T (p.Thr188Ile)","Chromosome":"14","Start":"22779988","Stop":"22779988","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":71010,"rule_based_match":false,"evidence_text":"c.563C>T (p.Thr188Ile)","llm_judgment":"PRESENT","evidence":"T188I","abstract_start":582,"abstract_end":587}]}
{"pmid":"22734907","title":"A novel EGR2 mutation within a family with a mild demyelinating form of Charcot-Marie-Tooth disease.","abstract":"Mutations of the early growth response 2 (EGR2) gene have been reported in a variety of severe demyelinating neuropathies such as autosomal recessive congenital hypomyelinating neuropathy, autosomal dominant child-onset Dejerine-Sottas neuropathy, and autosomal dominant adult-onset Charcot-Marie-Tooth disease (CMT). Here, we report on a heterozygous mutation in EGR2 (c.1160C>A), which results in threonine at position 387 being changed to asparagine, in a family with a mild demyelinating form of adult-onset CMT. Of note, both the proband and her asymptomatic son exhibited neither pes cavus nor champagne-bottle leg atrophy, suggesting that the heterozygous T387N mutation may result in a relatively mild phenotype of demyelinating CMT.","variants":[{"Name":"NM_000399.5(EGR2):c.1160C>A (p.Thr387Asn)","Chromosome":"10","Start":"62813478","Stop":"62813478","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":49431,"rule_based_match":true,"evidence_text":"c.1160C>A","llm_judgment":"PRESENT","evidence":"c.1160C>A","abstract_start":370,"abstract_end":379}]}
{"pmid":"26385305","title":"Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.","abstract":"Very long chain acyl-coA dehydrogenase deficiency (VLCADD) is an autosomal recessive inborn error of fatty acid oxidation detected by newborn screening (NBS). Follow-up molecular analyses are often required to clarify VLCADD-suggestive NBS results, but to date the outcome of these studies are not well described for the general screen-positive population. In the following study, we report the molecular findings for 693 unrelated patients that sequentially received Sanger sequence analysis of ACADVL as a result of a positive NBS for VLCADD. Highlighting the variable molecular underpinnings of this disorder, we identified 94 different pathogenic ACADVL variants (40 novel), as well as 134 variants of unknown clinical significance (VUSs). Evidence for the pathogenicity of a subset of recurrent VUSs was provided using multiple in silico analyses. Surprisingly, the most frequent finding in our cohort was carrier status, 57% all individuals had a single pathogenic variant or VUS. This result was further supported by follow-up array and/or acylcarnitine analysis that failed to provide evidence of a second pathogenic allele. Notably, exon-targeted array analysis of 131 individuals screen positive for VLCADD failed to identify copy number changes in ACADVL thus suggesting this test has a low yield in the setting of NBS follow-up. While no genotype was common, the c.848T>C (p.V283A) pathogenic variant was clearly the most frequent; at least one copy was found in ~10% of all individuals with a positive NBS. Clinical and biochemical data for seven unrelated patients homozygous for the p.V283A allele suggests that it results in a mild phenotype that responds well to standard treatment, but hypoglycemia can occur. Collectively, our data illustrate the molecular heterogeneity of VLCADD and provide novel insight into the outcomes of NBS for this disorder.","variants":[{"Name":"NM_000018.4(ACADVL):c.848T>C (p.Val283Ala)","Chromosome":"17","Start":"7222272","Stop":"7222272","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":33877,"rule_based_match":true,"evidence_text":"c.848T>C (p.V283A)","llm_judgment":"PRESENT","evidence":"c.848T>C (p.V283A)","abstract_start":1375,"abstract_end":1393}]}
{"pmid":"32925727","title":"Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD) in the ETFDH gene: A case report and a literature review.","abstract":"RATIONALE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting fatty acid, amino acid, and choline metabolism. The clinical manifestation of MADD is heterogeneous, from severe neonatal forms to mild late-onset forms.\nPATIENT CONCERNS: Here, we report a patient who presented with severe hypoglycemia and exercise intolerance suggestive of MADD. Serum tandem mass spectrometry analysis indicated elevated levels of various acyl carnitines at 25 days of age. Exome sequencing of the proband revealed compound heterozygous mutations, c. 413T>G (p.Leu138Arg) and c.1667C > G (p.Pro556Arg), in the ETFDH gene as the probable causative mutations.\nDIAGNOSES: Based on the patient's clinical presentation and test results, the patient was diagnosed with MADD.\nINTERVENTIONS: A high-calorie and reduced-fat diet was given together with oral supplements of L-carnitine (150 mg/day).\nOUTCOMES: He passed away at the age of 4 months because of severe respiratory distress accompanied by muscle weakness.\nLESSONS: He passed away at the age of 4 months because of severe respiratory distress accompanied by muscle weakness. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD and may not only prevent the need for invasive testing but also allow for timely initiation of treatment.","variants":[{"Name":"NM_004453.4(ETFDH):c.413T>G (p.Leu138Arg)","Chromosome":"4","Start":"158684599","Stop":"158684599","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":425603,"rule_based_match":true,"evidence_text":"c. 413T>G (p.Leu138Arg)","llm_judgment":"PRESENT","evidence":"c. 413T>G (p.Leu138Arg)","abstract_start":576,"abstract_end":599}]}
{"pmid":"34535181","title":"A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course.","abstract":"The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca<sup>2+</sup> channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca<sup>2+</sup>-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.","variants":[{"Name":"NM_000540.3(RYR1):c.12083C>T (p.Ser4028Leu)","Chromosome":"19","Start":"38546515","Stop":"38546515","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":198031,"rule_based_match":true,"evidence_text":"c.12083C>T (p.Ser4028Leu)","llm_judgment":"PRESENT","evidence":"c.12083C>T (p.Ser4028Leu)","abstract_start":788,"abstract_end":813}]}
{"pmid":"32282051","title":"An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.","abstract":"CONTEXT: C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type).\nDESIGN: History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant.\nRESULTS: Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B.\nCONCLUSIONS: We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.","variants":[{"Name":"NM_003995.4(NPR2):c.1444_1449del (p.Met482_Leu483del)","Chromosome":"9","Start":"35801646","Stop":"35801651","ReferenceAlleleVCF":"AGCTGAT","AlternateAlleleVCF":"A","allel_id":1290177,"rule_based_match":true,"evidence_text":"c.1444_1449delATGCTG","llm_judgment":"PRESENT","evidence":"c.1444_1449delATGCTG","abstract_start":1076,"abstract_end":1096}]}
{"pmid":"31200524","title":"First Case Report of Primary Carnitine Deficiency Manifested as Intellectual Disability and Autism Spectrum Disorder.","abstract":"Systemic primary carnitine deficiency (PCD) is a genetic disorder caused by decreased or absent organic cation transporter type 2 (OCTN2) carnitine transporter activity, resulting in low serum carnitine levels and decreased carnitine accumulation inside cells. In early life, PCD is usually diagnosed as a metabolic decompensation, presenting as hypoketotic hypoglycemia, Reye syndrome, or sudden infant death; in childhood, PCD presents with skeletal or cardiac myopathy. However, the clinical presentation of PCD characterized by autism spectrum disorder (ASD) with intellectual disability (ID) has seldom been reported in the literature. In this report, we describe the clinical features of a seven-year-old girl diagnosed with PCD who presented atypical features of the disease, including a developmental delay involving language skills, concentration, and attention span, as well as autistic features and brain alterations apparent in magnetic resonance imaging. We aim to highlight the difficulties related to the diagnostic and therapeutic approaches used to diagnose such patients. The case reported here presented typical signs of PCD, including frequent episodes of hypoglycemia, generalized muscle weakness, decreased muscle mass, and physical growth deficits. A molecular genetic study confirmed the definitive diagnosis of the disease (c.1345T>G (p.Y449D)) in gene <i>SLC22A5</i>, located in exon 8. PCD can be accompanied by less common clinical signs, which may delay its diagnosis because the resulting global clinical picture can closely resemble other metabolic disorders. In this case, the patient was prescribed a carnitine-enriched diet, as well as oral carnitine at a dose of 100 mg/kg/day. PCD has a better prognosis if it is diagnosed and treated early; however, a high level of clinical suspicion is required for its timely and accurate diagnosis.","variants":[{"Name":"NM_003060.4(SLC22A5):c.1345T>G (p.Tyr449Asp)","Chromosome":"5","Start":"132392510","Stop":"132392510","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":36754,"rule_based_match":true,"evidence_text":"c.1345T>G (p.Y449D)","llm_judgment":"PRESENT","evidence":"c.1345T>G (p.Y449D)","abstract_start":1349,"abstract_end":1368}]}
{"pmid":"31934206","title":"A novel mutation in a Chinese family with autosomal recessive Alport syndrome: a case report.","abstract":"Alport syndrome (AS) is a familial hereditary nephropathy which is characterized by molecular abnormalities in Collagen IV a345. As more gene mutations are discovered, it has been reported that autosomal recessive disease accounts for a smaller proportion (about 4%) of AS patients than previously recognized. We report here a novel mutation in <i>COL4A4</i> in a Chinese family with autosomal recessive AS. Patient 1 was a 24-year-old Chinese man. He and his brother (patient 2) had a history of proteinuria and hematuria with renal dysfunction and sensorineural deafness. Pathologic findings were consistent with Alport syndrome, and genetic analysis revealed that both patients had two heterozygous mutations, c.1423 G>T (p.Gly475Cys) in EX21/CDS20 and c.735 G>A (p.Pro245Pro) in EX12/CDS11, and that each mutation originated from their mother or father who were carriers for one of these two mutations. Both patients showed similar results by laboratory examination and histopathologic assessment. Patient 1 received ACEI treatment and ran a stable clinical course, whereas patient 2 refused ACEI treatment and had progressive deterioration of renal function. This is the first report of a novel mutation in the collagen domain of <i>COL4A4</i> gene. The results add to the spectrum of mutations in <i>COL4A4</i> of Alport syndrome.","variants":[{"Name":"NM_000092.5(COL4A4):c.735G>A (p.Pro245=)","Chromosome":"2","Start":"227108581","Stop":"227108581","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":590257,"rule_based_match":true,"evidence_text":"c.735 G>A (p.Pro245Pro)","llm_judgment":"PRESENT","evidence":"c.735 G>A (p.Pro245Pro)","abstract_start":756,"abstract_end":779},{"Name":"NM_000092.5(COL4A4):c.1423G>T (p.Gly475Cys)","Chromosome":"2","Start":"227089904","Stop":"227089904","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":553581,"rule_based_match":true,"evidence_text":"c.1423 G>T (p.Gly475Cys)","llm_judgment":"PRESENT","evidence":"c.1423 G>T (p.Gly475Cys)","abstract_start":713,"abstract_end":737}]}
{"pmid":"32938213","title":"A Novel Recurrent","abstract":"OBJECTIVE: While rare variants in the <i>COL5A1</i> gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in <i>COL5A1</i> underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the <i>COL5A1</i> pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The <i>COL5A1</i> c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for <i>COL5A1</i> variants. In this mFMD cohort, <i>COL5A1</i> c.1540G>A and 6 additional relatively rare <i>COL5A1</i> variants predicted to be deleterious in silico were identified and were associated with arterial dissections (<i>P</i>=0.005).\nCONCLUSIONS: <i>COL5A1</i> c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare <i>COL5A1</i> genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for <i>COL5A1</i> should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.","variants":[{"Name":"NM_000093.5(COL5A1):c.1540G>A (p.Gly514Ser)","Chromosome":"9","Start":"134750587","Stop":"134750587","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":240516,"rule_based_match":true,"evidence_text":"c.1540G>A, p.(Gly514Ser)","llm_judgment":"PRESENT","evidence":"c.1540G>A, p.(Gly514Ser)","abstract_start":443,"abstract_end":467}]}
{"pmid":"29021403","title":"Heterozygous mutations affecting the protein kinase domain of","abstract":"INTRODUCTION: Recent evidence has emerged linking mutations in <i>CDK13</i> to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with <i>CDK13</i> mutations.\nMETHODS: Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.\nRESULTS: Our cohort comprised 16 individuals aged 4-16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898-1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.\nCONCLUSIONS: These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the <i>CDK13</i> gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.","variants":[{"Name":"NM_003718.5(CDK13):c.2525A>G (p.Asn842Ser)","Chromosome":"7","Start":"40046007","Stop":"40046007","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":237522,"rule_based_match":false,"evidence_text":"p.(Asn842Ser)","llm_judgment":"PRESENT","evidence":"p.(Asn842Ser)","abstract_start":1014,"abstract_end":1027}]}
{"pmid":"30788684","title":"Generalized Cytokine Increase in the Setting of a Multisystem Clinical Disorder and Carcinoid Syndrome Associated with a Novel NLRP12 Variant.","abstract":"BACKGROUND: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a group of cytoplasmic sensors that survey danger signals released by invading pathogens or damaged tissue. Mutations in the NLRP subfamily affect pro-inflammatory mediators and cause nonspecific systemic symptoms.\nAIMS: We sought to identify a potential genetic etiology of an inflammatory syndrome in a patient that presented with an atypical multisystem illness with carcinoid syndrome as well as atopic and autoimmune features.\nMETHODS: Exome sequencing was performed using the Agilent SureSelect Clinical Research Exome XT kit on an Illumina HiSeq 2500. Longitudinal monitoring of pro-inflammatory cytokines was performed.\nRESULTS: We identified a novel variant (heterozygous c.536C > T [p.Thr179Ile]) in the NLRP12 gene in a 63-year-old woman and her daughter, who presented with an unusual clinical syndrome that differs from autoinflammatory disorders previously reported in association with the NLRP subfamily gene mutations. This NLRP12 variant was predicted to be pathogenic by functional analysis through Hidden Markov Models (FATHMM). Both the mother and the daughter had episodes of abdominal pain, fever, diarrhea, skin rash, hypothyroidism, and elevated urine 5-hydroxyindoleacetic acid (5-HIAA) levels. The proband also had elevated serum levels of pro-inflammatory (IL-1β, IL-6, IL-12, and TNF-α), Th1 (IL-2, IFN-γ), and Th2 (IL-4, IL-5, IL-13) cytokines, but not of Th17 (IL-17) and IL-10.\nCONCLUSION: This report adds to the expanding spectrum of clinical manifestations attributed to the NLRP subfamily gene variants and suggests a role of NLRP12 in the regulation of multiple cytokines.","variants":[{"Name":"NM_144687.4(NLRP12):c.536C>T (p.Thr179Ile)","Chromosome":"19","Start":"53811123","Stop":"53811123","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":471286,"rule_based_match":true,"evidence_text":"c.536C > T (p.Thr179Ile)","llm_judgment":"PRESENT","evidence":"p.Thr179Ile","abstract_start":779,"abstract_end":790}]}
{"pmid":"27143505","title":"H syndrome: First reported paediatric case in Latin America","abstract":"INTRODUCTION: H Syndrome is an extremely rare genetic disease, with a multisystemic character and which can be identified in early childhood, offering the opportunity of specific treatment and genetic counselling.\nOBJECTIVE: To present a clinical case with \"typical\" characteristics of H Syndrome.\nCLINICAL CASE: The case is presented of an 8-year-old male patient who presented with testicular tumours and skin lesions characterised by hyperpigmentation with hypertrichosis, language delay, short stature, and joint deformities. He also presented with bilateral sensorineural hearing loss, anaemia, hypergammaglobulinaemia, and bone disorders. Histopathology studies of the skin and testicular masses reported lymphoplasmacytic infiltration. Sequencing analysis of gene SLC29A3 showed the homozygote mutation c.1087 C>T (p.Arg363Trp; rs387907067).\nCONCLUSIONS: These findings are consistent with H syndrome, and this is the first reported case in Latin America. The key to the diagnosis is the finding of hyperpigmentation with hypertrichosis.","variants":[{"Name":"NM_018344.6(SLC29A3):c.1087C>T (p.Arg363Trp)","Chromosome":"10","Start":"71362267","Stop":"71362267","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39906,"rule_based_match":true,"evidence_text":"c.1087 C>T (p.Arg363Trp; rs387907067)","llm_judgment":"PRESENT","evidence":"c.1087 C>T (p.Arg363Trp; rs387907067)","abstract_start":810,"abstract_end":847}]}
{"pmid":"38025240","title":"Loss-of-Function Homozygous Variant in","abstract":"Introduction: Lipoprotein lipase (LPL) is an important enzyme in lipid metabolism, individuals with <i>LPL</i> gene variants could present type I hyperlipoproteinemia, lipemia retinalis, hepatosplenomegaly, and pancreatitis. To date, there are no reports of renal lipidosis induced by type I hyperlipoproteinemia due to <i>LPL</i> mutation.\nMethods: Renal biopsy was conducted to confirm the etiological factor of nephrotic syndrome in a 44-year-old Chinese man. Lipoprotein electrophoresis, <i>apoE</i> genotype detection, and whole-exome sequencing were performed to confirm the dyslipidemia type and genetic factor. Analysis of the 3-dimensional protein structure and <i>in vitro</i> functional study were conducted to verify variant pathogenicity.\nResults: Renal biopsy revealed numerous CD68 positive foam cells infiltrated in the glomeruli; immunoglobulin and complement staining were negative; and electron microscopy revealed numerous lipid droplets and cholesterol clefts in the cytoplasm of foam cells. Lipoprotein electrophoresis revealed that the patient fulfilled the diagnostic criteria of type I hyperlipoproteinemia. The apoE genotype of the patient was the ε3/ε3 genotype. Whole-exome sequencing revealed an <i>LPL</i> (c.292G > A, p.A98T) homozygous variant with α-helix instability and reduced post-heparin LPL activity but normal lipid uptake capability compared to the wild-type variant.\nConclusion: <i>LPL</i> (c.292G > A, p.A98T) is a pathogenic variant that causes renal lipidosis associated with type I hyperlipoproteinemia. This study provides adequate evidence of the causal relationship between dyslipidemia and renal lesions. However, further research is needed to better understand the pathogenetic mechanism of <i>LPL</i> variant-related renal lesions.","variants":[{"Name":"NM_000237.3(LPL):c.292G>A (p.Ala98Thr)","Chromosome":"8","Start":"19951811","Stop":"19951811","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1194030,"rule_based_match":true,"evidence_text":"LPL (c.292G > A, p.A98T)","llm_judgment":"PRESENT","evidence":"LPL</i> (c.292G > A, p.A98T)","abstract_start":1228,"abstract_end":1256}]}
{"pmid":"28922471","title":"A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN.","abstract":"BACKGROUND: Dowling-Degos disease (DDD), featuring reticulate pigmentation, and familial hidradenitis suppurativa (HS) share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The coexistence of the two disorders was recently found to result from mutations in PSENEN, encoding the γ-secretase subunit protein presenilin enhancer.\nOBJECTIVES: To investigate PSENEN mutations in a series of four unrelated patients who presented with combined DDD and HS.\nMETHODS: Mutation and haplotype analysis of PSENEN by polymerase chain reaction, and cellular assays investigating the Notch signalling pathway.\nRESULTS: Here we report four families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Genes associated with DDD, as well as HS, have been shown to encode important regulators of Notch signalling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in a patient's keratinocytes.\nCONCLUSIONS: The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition.","variants":[{"Name":"NM_172341.4(PSENEN):c.168T>G (p.Tyr56Ter)","Chromosome":"19","Start":"35746709","Stop":"35746709","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1034234,"rule_based_match":true,"evidence_text":"c.168T>G","llm_judgment":"PRESENT","evidence":"c.168T>G","abstract_start":866,"abstract_end":874}]}
{"pmid":"35949226","title":"","abstract":"Background: Variants of the <i>NUS1</i> gene have recently been linked to a spectrum of phenotypes including epilepsy, cerebellar ataxia, cortical myoclonus and intellectual disability (ID), and primary congenital defects of glycosylation.\nCase Report: We report a case of myoclonus epilepsy, mild cerebellar ataxia, and ID due to a new de-novo <i>NUS1</i> missense variant (c.868C>T, p.R290C), and review the current literature of <i>NUS1</i>-associated clinical phenotypes.\nDiscussion: Pathogenic variants of <i>NUS1</i> are found in a rapidly growing number of cases diagnosed with myoclonus epilepsy and/or myoclonus-ataxia syndrome. <i>NUS1</i> should be included in the genetic screening of undiagnosed forms of myoclonus, myoclonus-ataxia, and progressive myoclonus epilepsies.","variants":[{"Name":"NM_138459.5(NUS1):c.868C>T (p.Arg290Cys)","Chromosome":"6","Start":"117707001","Stop":"117707001","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1515666,"rule_based_match":true,"evidence_text":"c.868C>T, p.R290C","llm_judgment":"PRESENT","evidence":"c.868C>T, p.R290C","abstract_start":375,"abstract_end":392}]}
{"pmid":"33326993","title":"NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss.","abstract":"Hearing loss is a frequent sensory impairment in humans and genetic factors account for an elevated fraction of the cases. We have investigated a large family of five generations, with 15 reported individuals presenting non-syndromic, sensorineural, bilateral and progressive hearing loss, segregating as an autosomal dominant condition. Linkage analysis, using SNP-array and selected microsatellites, identified a region of near 13 cM in chromosome 20 as the best candidate to harbour the causative mutation. After exome sequencing and filtering of variants, only one predicted deleterious variant in the NCOA3 gene (NM_181659, c.2810C > G; p.Ser937Cys) fit in with our linkage data. RT-PCR, immunostaining and in situ hybridization showed expression of ncoa3 in the inner ear of mice and zebrafish. We generated a stable homozygous zebrafish mutant line using the CRISPR/Cas9 system. ncoa3-/- did not display any major morphological abnormalities in the ear, however, anterior macular hair cells showed altered orientation. Surprisingly, chondrocytes forming the ear cartilage showed abnormal behaviour in ncoa3-/-, detaching from their location, invading the ear canal and blocking the cristae. Adult mutants displayed accumulation of denser material wrapping the otoliths of ncoa3-/- and increased bone mineral density. Altered zebrafish swimming behaviour corroborates a potential role of ncoa3 in hearing loss. In conclusion, we identified a potential candidate gene to explain hereditary hearing loss, and our functional analyses suggest subtle and abnormal skeletal behaviour as mechanisms involved in the pathogenesis of progressive sensory function impairment.","variants":[{"Name":"NM_181659.3(NCOA3):c.2810C>G (p.Ser937Cys)","Chromosome":"20","Start":"47639679","Stop":"47639679","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1175557,"rule_based_match":true,"evidence_text":"NM_181659, c.2810C > G; p.Ser937Cys","llm_judgment":"PRESENT","evidence":"NM_181659, c.2810C > G; p.Ser937Cys","abstract_start":618,"abstract_end":653}]}
{"pmid":"31125343","title":"Biallelic HEPHL1 variants impair ferroxidase activity and cause an abnormal hair phenotype.","abstract":"Maintenance of the correct redox status of iron is functionally important for critical biological processes. Multicopper ferroxidases play an important role in oxidizing ferrous iron, released from the cells, into ferric iron, which is subsequently distributed by transferrin. Two well-characterized ferroxidases, ceruloplasmin (CP) and hephaestin (HEPH) facilitate this reaction in different tissues. Recently, a novel ferroxidase, Hephaestin like 1 (HEPHL1), also known as zyklopen, was identified. Here we report a child with compound heterozygous mutations in HEPHL1 (NM_001098672) who presented with abnormal hair (pili torti and trichorrhexis nodosa) and cognitive dysfunction. The maternal missense mutation affected mRNA splicing, leading to skipping of exon 5 and causing an in-frame deletion of 85 amino acids (c.809_1063del; p.Leu271_ala355del). The paternal mutation (c.3176T>C; p.Met1059Thr) changed a highly conserved methionine that is part of a typical type I copper binding site in HEPHL1. We demonstrated that HEPHL1 has ferroxidase activity and that the patient's two mutations exhibited loss of this ferroxidase activity. Consistent with these findings, the patient's fibroblasts accumulated intracellular iron and exhibited reduced activity of the copper-dependent enzyme, lysyl oxidase. These results suggest that the patient's biallelic variants are loss-of-function mutations. Hence, we generated a Hephl1 knockout mouse model that was viable and had curly whiskers, consistent with the hair phenotype in our patient. These results enhance our understanding of the function of HEPHL1 and implicate altered ferroxidase activity in hair growth and hair disorders.","variants":[{"Name":"NM_001098672.2(HEPHL1):c.3176T>C (p.Met1059Thr)","Chromosome":"11","Start":"94111033","Stop":"94111033","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":623030,"rule_based_match":true,"evidence_text":"c.3176T>C (p.Met1059Thr)","llm_judgment":"PRESENT","evidence":"p.Met1059Thr","abstract_start":891,"abstract_end":903}]}
{"pmid":"24341803","title":"Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase.","abstract":"BACKGROUND: Synthesis and apoenzyme attachment of lipoic acid have emerged as a new complex metabolic pathway. Mutations in several genes involved in the lipoic acid de novo pathway have recently been described (i.e., LIAS, NFU1, BOLA3, IBA57), but no mutation was found so far in genes involved in the specific process of attachment of lipoic acid to apoenzymes pyruvate dehydrogenase (PDHc), α-ketoglutarate dehydrogenase (α-KGDHc) and branched chain α-keto acid dehydrogenase (BCKDHc) complexes.\nMETHODS: Exome capture was performed in a boy who developed Leigh disease following a gastroenteritis and had combined PDH and α-KGDH deficiency with a unique amino acid profile that partly ressembled E3 subunit (dihydrolipoamide dehydrogenase / DLD) deficiency. Functional studies on patient fibroblasts were performed. Lipoic acid administration was tested on the LIPT1 ortholog lip3 deletion strain yeast and on patient fibroblasts.\nRESULTS: Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene that encodes a mitochondrial lipoyltransferase which is thought to catalyze the attachment of lipoic acid on PDHc, α-KGDHc, and BCKDHc. Anti-lipoic acid antibodies revealed absent expression of PDH E2, BCKDH E2 and α-KGDH E2 subunits. Accordingly, the production of 14CO2 by patient fibroblasts after incubation with 14Cglucose, 14Cbutyrate or 14C3OHbutyrate was very low compared to controls. cDNA transfection experiments on patient fibroblasts rescued PDH and α-KGDH activities and normalized the levels of pyruvate and 3OHbutyrate in cell supernatants. The yeast lip3 deletion strain showed improved growth on ethanol medium after lipoic acid supplementation and incubation of the patient fibroblasts with lipoic acid decreased lactate level in cell supernatants.\nCONCLUSION: We report here a putative case of impaired free or H protein-derived lipoic acid attachment due to LIPT1 mutations as a cause of PDH and α-KGDH deficiencies. Our study calls for renewed efforts to understand the mechanisms of pathology of lipoic acid-related defects and their heterogeneous biochemical expression, in order to devise efficient diagnostic procedures and possible therapies.","variants":[{"Name":"NM_145199.3(LIPT1):c.875C>G (p.Ser292Ter)","Chromosome":"2","Start":"99162832","Stop":"99162832","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":270108,"rule_based_match":true,"evidence_text":"c.875C > G","llm_judgment":"PRESENT","evidence":"c.875C > G","abstract_start":1000,"abstract_end":1010},{"Name":"NM_145199.3(LIPT1):c.535A>G (p.Thr179Ala)","Chromosome":"2","Start":"99162492","Stop":"99162492","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":187694,"rule_based_match":true,"evidence_text":"c.535A > G","llm_judgment":"PRESENT","evidence":"c.535A > G","abstract_start":1015,"abstract_end":1025}]}
{"pmid":"18205010","title":"Occurrence of ocular melanoma thirteen years after skin melanoma: two separate primaries or metastatic disease? A case solved with NRAS and CDKN2A (INK4A-ARF) mutational analysis.","abstract":"The differential diagnosis between primary uveal melanoma and cutaneous melanoma metastasis in the eye may be difficult, both clinically and histologically. We report successful application of combined mutational analysis of the NRAS and the CDKN2A gene to discriminate between these two entities. The patient had a history of a superficial spreading cutaneous melanoma of the left shoulder. Nine years later, she developed a lymph node metastasis in the left axilla, and 13 years later she presented with an atypical, pigmented tumor in the uvea. Histologically, the origin of the uveal melanoma could not be determined with certainty. We performed molecular analysis on the skin melanoma, the lymph node metastasis and the uveal melanoma. We detected an NRAS codon 61 mutation (c.182A>G, p.Gln61Arg) in all three tumor specimens. This mutation was absent in the normal control tissue of the patient, thereby excluding a germline mutation. To confirm a clonal relationship between the tumors, we also performed CDKN2A mutational analysis. We detected a CDKN2A mutation ((p16) c.238C>T, p.Arg80X, (p14) c.404C>T, p.Pro135Leu)) in the tumor samples, but not in the normal control tissue of the patient. We concluded that the uveal melanoma is a metastasis from the cutaneous melanoma removed 13 years before.","variants":[{"Name":"NM_000077.5(CDKN2A):c.238C>T (p.Arg80Ter)","Chromosome":"9","Start":"21971121","Stop":"21971121","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24448,"rule_based_match":true,"evidence_text":"c.238C>T","llm_judgment":"PRESENT","evidence":"c.238C>T","abstract_start":1077,"abstract_end":1085}]}
{"pmid":"25726841","title":"Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes.","abstract":"OBJECTIVE: To test whether mutations in γ-aminobutyric acid type A receptor (GABAA -R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE).\nMETHODS: We performed exome sequencing to compare the frequency of variants in 18 GABAA -R genes in 204 European patients with RE/ARE versus 728 platform-matched controls. Identified GABRG2 variants were functionally assessed for protein stability, trafficking, postsynaptic clustering, and receptor function.\nRESULTS: Of 18 screened GABAA -R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5 of 204, 2.45%) in comparison to controls (1 of 723, 0.14%; odds ratio = 18.07, 95% confidence interval = 2.01-855.07, p = 0.0024, pcorr  = 0.043). We identified a GABRG2 splice variant (c.549-3T>G) in 2 unrelated patients as well as 3 nonsynonymous variations in this gene (p.G257R, p.R323Q, p.I389V). Functional assessment showed reduced surface expression of p.G257R and decreased GABA-evoked currents for p.R323Q. The p.G257R mutation displayed diminished levels of palmitoylation, a post-translational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant γ2 subunit.\nINTERPRETATION: The statistical association and the functional evidence suggest that mutations of the GABRG2 gene may increase the risk of RE/ARE. Restoring the impaired membrane trafficking of some GABRG2 mutations by enhancing palmitoylation might be an interesting therapeutic approach to reverse the pathogenic effect of such mutants.","variants":[{"Name":"NM_198904.4(GABRG2):c.769G>A (p.Gly257Arg)","Chromosome":"5","Start":"162104026","Stop":"162104026","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":426665,"rule_based_match":false,"evidence_text":"p.G257R","llm_judgment":"PRESENT","evidence":"p.G257R","abstract_start":894,"abstract_end":901},{"Name":"NM_198904.4(GABRG2):c.549-3T>G","Chromosome":"5","Start":"162101232","Stop":"162101232","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":201883,"rule_based_match":true,"evidence_text":"c.549-3T>G","llm_judgment":"PRESENT","evidence":"c.549-3T>G","abstract_start":806,"abstract_end":816}]}
{"pmid":"31349801","title":"Characterization of the c.793-1G > A splicing variant in CHEK2 gene as pathogenic: a case report.","abstract":"BACKGROUND: CHEK2 is involved in the DNA damage repair response Fanconi anemia (FA)-BRCA pathway. An increased risk for breast and other cancers has been documented in individuals who carry a single pathogenic CHEK2 variant. As for other genes involved in cancer predisposition, different types of pathogenic variants have been observed, including single nucleotide variations, short insertions/deletions, large genomic rearrangements and splicing variants. Splicing variants occurring in the splicing acceptor or donor site result in alternative mature mRNA produced and can cause intron retention, exon skipping, or creation of alternative 3' and 5' splice site. Thus, the pathogenicity of this type of alterations should always be explored experimentally and their effect in the mRNA and consequently the protein produced, should be defined. The aim of this study was the delineation of the effect of a splicing variant in the CHEK2 gene.\nCASE PRESENTATION: A healthy 28-year-old woman with a family history of breast and ovarian cancer was referred for genetic testing. The variant c.793-1G > A (rs730881687) was identified by Next Generation Sequencing (NGS) using a solution-based capture method, targeting 33 cancer predisposition genes (SeqCap EZ Probe library, Roche NimbleGen). Experimental analysis in patient-derived leukocytes using RT-PCR of mRNA followed by cDNA sequencing revealed the deletion of one base from the alternative transcript created (r.793del). This resulted in a frameshift leading to premature termination codon within exon 7 (p.(Asp265Thrfs*10)).\nCONCLUSIONS: This finding suggests that the CHEK2 splicing variant c.793-1G > A is a deleterious variant. Our case shows that RNA analysis is a valuable tool for uncharacterized splice site variants in individuals referred for testing and facilitates their personalized management.","variants":[{"Name":"NM_007194.4(CHEK2):c.793-1G>A","Chromosome":"22","Start":"28710060","Stop":"28710060","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":181107,"rule_based_match":true,"evidence_text":"c.793-1G > A","llm_judgment":"PRESENT","evidence":"c.793-1G > A","abstract_start":1086,"abstract_end":1098}]}
{"pmid":"30572990","title":"Clinical and genetic features of limb-girdle muscular dystrophy type 1B: a case report","abstract":"This article reports a case of limb-girdle muscular dystrophy type 1B (LGMD1B) caused by a novel splicing heterozygous mutation in the LMNA gene. The proband presented with progressive aggravation of weakness in walking. There was no atrophy of the scapular muscles and the lower-extremity proximal muscles, with normal muscle tension of the extremities, grade 4 muscle strength in the upper and lower extremities, and positive Gower sign. The level of creatine kinase was 779 U/L. Muscle hematoxylin-eosin staining showed muscular dystrophy, and there was no significant reduction in the expression of Lamin A protein. Second-generation sequencing revealed a novel splicing heterozygous mutation, c.810+2T>C, in the LMNA gene, while this locus was normal in his parents. GERP++RS software predicted that the mutation site was highly conservative. Human Splice Finder and Spliceman software predicted that the mutation might be a pathogenic mutation. ExPASy software predicted that the new amino acid sequence became shorter. There were two sequences of mRNA in the patient's muscle: one was the normal sequence, which accounted for 92.2%; the other was partial intron 4 retention, which was the abnormal splice variant accounting for 7.8%. LGMD1B is a type of autosomal dominant inherited myopathy caused by a mutation in the LMNA gene located on the autosomal 1q22. This study extends the mutation spectrum of the LMNA gene and provides help to the diagnosis of LGMD1B.","variants":[{"Name":"NM_170707.4(LMNA):c.810+2T>C","Chromosome":"1","Start":"156134977","Stop":"156134977","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1329329,"rule_based_match":true,"evidence_text":"c.810+2T>C","llm_judgment":"PRESENT","evidence":"c.810+2T>C","abstract_start":698,"abstract_end":708}]}
{"pmid":"35144013","title":"Phenotypic spectrum of autosomal recessive Keratitis-Ichthyosis-Deafness Syndrome (KIDAR) due to mutations in AP1B1.","abstract":"Inborn errors in copper metabolism result in a diverse set of abnormalities such as Wilson disease and MEDNIK syndrome. Homozygous pathogenic variants in AP1B1 lead to KIDAR (Keratitis-Ichthyosis-Deafness Syndrome). The main phenotypic features of KIDAR are ichthyosis, keratitis, erythroderma, and progressive hearing loss accompanied by developmental delay and failure to thrive. Herein, we describe a six-and-a-half-year-old boy with KIDAR caused by a novel pathogenic variant in AP1B1 (NM_001127.4:c.1263C > A, p.Tyr421*). The proband presented with ichthyosis, erythroderma, palmoplantar keratoderma, hearing loss, and corneal scarring. He also had hypotonia, global developmental delay, and photophobia. Lastly, we review all of the previously reported cases and the clinical features associated with KIDAR.","variants":[{"Name":"NM_001127.4(AP1B1):c.1263C>A (p.Tyr421Ter)","Chromosome":"22","Start":"29350043","Stop":"29350043","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1036915,"rule_based_match":true,"evidence_text":"NM_001127.4:c.1263C > A, p.Tyr421*","llm_judgment":"PRESENT","evidence":"NM_001127.4:c.1263C > A, p.Tyr421*","abstract_start":490,"abstract_end":524}]}
{"pmid":"16373086","title":"Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV.","abstract":"Congenital insensitivity to pain with anhidrosis or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is the first human genetic disorder implicated in the neurotrophin signal transduction pathway. HSAN IV is characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, self-mutilating behavior and often mental retardation. Mutations in the neurotrophic tyrosine kinase, receptor, type 1 (NTRK1) are associated with this disorder. Here we report four homozygous mutations, two frameshift (p.Gln626fsX6 and p.Gly181fsX58), one missense (p.Arg761Trp) and one splice site (c.359+5G>T) mutation in four HSAN IV patients. The splice site mutation caused skipping of exons 2 and 3 in patient's mRNA resulting in an in-frame deletion of the second leucine-rich motif. NTRK1 mutations are only rarely reported in the European population. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with HSAN IV.","variants":[{"Name":"NM_002529.4(NTRK1):c.359+5G>T","Chromosome":"1","Start":"156864804","Stop":"156864804","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":625728,"rule_based_match":true,"evidence_text":"c.359+5G>T","llm_judgment":"PRESENT","evidence":"c.359+5G>T","abstract_start":620,"abstract_end":630},{"Name":"NM_002529.4(NTRK1):c.2281C>T (p.Arg761Trp)","Chromosome":"1","Start":"156881532","Stop":"156881532","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":540665,"rule_based_match":false,"evidence_text":"p.Arg761Trp","llm_judgment":"PRESENT","evidence":"p.Arg761Trp","abstract_start":586,"abstract_end":597}]}
{"pmid":"18348261","title":"Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene.","abstract":"Autosomal dominant congenital cutis laxa (ADCL) is genetically heterogeneous and shows clinical variability. Only seven ADCL families with mutations in the elastin gene (ELN) have been described previously. We present morphological and molecular genetic studies in a cutis laxa kindred with a previously undescribed highly variable phenotype caused by a novel ELN mutation c.1621 C > T. The proband presented with severe cutis laxa, severe congenital lung disease previously undescribed in ADCL and pulmonary artery disease, which is often seen in ARCL but rare in ADCL. He also developed infantile spasms (OMIM 308350; West syndrome), which we consider a coincidental association although recessive cutis laxa or even digenic inheritance cannot be excluded. Electron microscopy of the proband's dermis revealed only mild rarefication of elastic fibers (in contrast to most recessive cutis laxa types). Apart from mild elastic fiber fragmentation, dermal morphology of the proband's father was within normal range. Molecular analysis of the ELN gene using genomic DNA from blood and RNA from cultured skin fibroblasts indicated a novel splice site mutation in the proband and his clinically healthy father. Analysis of ELN expression in fibroblasts provided evidence for a dominant-negative effect in the child, while due to an unknown mechanism, the father showed haploinsufficiency which might explain the significant clinical variability.","variants":[{"Name":"NM_000501.4(ELN):c.1621C>T (p.Arg541Ter)","Chromosome":"7","Start":"74060184","Stop":"74060184","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31762,"rule_based_match":true,"evidence_text":"c.1621 C > T","llm_judgment":"PRESENT","evidence":"c.1621 C > T","abstract_start":373,"abstract_end":385}]}
{"pmid":"26197461","title":"Investigation of androgen receptor gene mutations in a series of 21 patients with 46,XY disorders of sex development.","abstract":"AIM: Androgen receptor (AR) gene mutations are the leading cause of 46,XY disorders of sex development (DSD) and are associated with varying degrees of androgen insensitivity. The aim of this study is to investigate AR gene mutations in 46,XY DSD patients with normal testosterone secretion, either normal or high testosterone/dihydrotestosterone (T/DHT) ratio and normal SRD5A2 gene analysis, collectively, suggestive of androgen insensitivity syndrome (AIS).\nMETHODS: We direct sequenced all eight exons of the AR gene in 21 index patients with varying degrees of undervirilization.\nRESULTS: We detected AR gene alterations in five patients. In patients with complete AIS we found p.Val30Met in exon 1 and p.Gly689* in exon 4. One patient with partial AIS had p.Gln712Glu in exon 4. In two patients with partial phenotype, we found common p.Glu213Glu (c.639G>A) SNP, and an additional p.Ile817Ile (c.2451T>C) mutation was found in one of these two patients.\nDISCUSSION: Despite the fact that T/DHT ratio is frequently used in diagnosis of AIS, lack of precisely determined cutoffs compromises correct diagnosis. Hence, depending on clinical and biochemical findings solely may delay correct diagnosis. Direct sequence analysis of the AR is essential for precise diagnosis of AIS.","variants":[{"Name":"NM_000044.6(AR):c.88G>A (p.Val30Met)","Chromosome":"X","Start":"67545234","Stop":"67545234","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3498765,"rule_based_match":false,"evidence_text":"p.Val30Met","llm_judgment":"PRESENT","evidence":"p.Val30Met","abstract_start":683,"abstract_end":693}]}
{"pmid":"30298489","title":"Analysis of GCDH gene mutations in 3 patients from Fujian area with glutaric academia type I","abstract":"OBJECTIVE: To explore clinical features and mutation types in patients from Fujian area with glutaric academia type I(GA I).\nMETHODS: Serum acylcarnitine and urine organic acid of 3 patients were determined with tandem mass spectrometry and gas chromatographic mass spectrometry. The patients also underwent magnetic resonance imaging analysis for the cranial region. Genomic DNA was extracted from peripheral blood samples, and the 12 exons and flanking regions of the GCDH gene were amplified with PCR and subjected to direct DNA sequencing. One hundred healthy newborns were used as controls.\nRESULTS: Mutations of the GCDH gene were identified in all of the 3 patients. Two patients have carried compound heterozygous mutations including c.1244-2A>C and c.1147C>T(p.R383C), c.406G>T(p.G136C) and c.1169G>A(p.G390E), respectively. One has carried homozygous c.1244-2A>C mutation. The same mutations were not detected among the 100 healthy newborns. Only one patient received early intervention and did not develop the disease. The other two had irreversible damagesto their intelligence.\nCONCLUSION: c.1169G>A(p.G390E) is likely pathogenic mutations for GA I patients from Fujianarea. Early screening of neonatal metabolic diseases is crucial for such patients.","variants":[{"Name":"NM_000159.4(GCDH):c.1147C>T (p.Arg383Cys)","Chromosome":"19","Start":"12897767","Stop":"12897767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187043,"rule_based_match":true,"evidence_text":"c.1147C>T(p.R383C)","llm_judgment":"PRESENT","evidence":"c.1147C>T(p.R383C)","abstract_start":758,"abstract_end":776}]}
{"pmid":"24706814","title":"Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.","abstract":"Polycystic livers are seen in the rare inherited disorder isolated polycystic liver disease (PCLD) and are recognized as the most common extrarenal manifestation in autosomal dominant polycystic kidney disease. Hepatic cystogenesis is characterized by progressive proliferation of cholangiocytes, ultimately causing hepatomegaly. Genetically, polycystic liver disease is a heterogeneous disorder with incomplete penetrance and caused by mutations in PRKCSH, SEC63, PKD1, or PKD2. Genome-wide SNP typing and Sanger sequencing revealed no pathogenic variants in hitherto genes in an extended PCLD family. We performed whole-exome sequencing of DNA samples from two members. A heterozygous variant c.3562C > T located at a highly conserved amino acid position (p.R1188W) in the low density lipoprotein receptor-related protein 5 (LRP5) gene segregated with the disease (logarithm of odds score, 4.62) but was not observed in more than 1,000 unaffected individuals. Screening of LRP5 in a PCLD cohort identified three additional mutations in three unrelated families with polycystic livers (p.V454M, p.R1529S, and p.D1551N), again all undetected in controls. All variants were predicted to be damaging with profound structural effects on LRP5 protein domains. Liver cyst tissue and normal hepatic tissue samples from patients and controls showed abundant LRP5 expression by immunohistochemistry. Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation. In conclusion, we demonstrate that germ-line LRP5 missense mutations are associated with hepatic cystogenesis. The findings presented in this study link the pathophysiology of PCLD to deregulation of the canonical wingless signaling pathway.","variants":[{"Name":"NM_002335.4(LRP5):c.3562C>T (p.Arg1188Trp)","Chromosome":"11","Start":"68426112","Stop":"68426112","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":172094,"rule_based_match":true,"evidence_text":"c.3562C > T","llm_judgment":"PRESENT","evidence":"c.3562C > T","abstract_start":695,"abstract_end":706}]}
{"pmid":"29405783","title":"Identification of PITX3 mutations in individuals with various ocular developmental defects.","abstract":"BACKGROUND: Congenital cataract displays large phenotypic (syndromic and isolated cataracts) and genetic heterogeneity. Mutations in several transcription factors involved in eye development, like PITX3, have been associated with congenital cataracts and anterior segment mesenchymal disorders.\nMATERIALS AND METHODS: Targeted sequencing of 187 genes involved in ocular development was performed in 96 patients with mainly anophthalmia and microphthalmia. Additionally, Sanger sequencing analysis of PITX3 was performed on a second cohort of 32 index cases with congenital cataract and Peters anomaly and/or sclereocornea.\nRESULTS: We described five families with four different PITX3 mutations, two of which were novel. In Family 1, the heterozygous recurrent c.640_656dup (p.Gly220Profs*95) mutation cosegregated with eye anomalies ranging from congenital cataract to Peters anomaly. In Family 2, the novel c.669del [p.(Leu225Trpfs*84)] mutation cosegregated with dominantly inherited eye anomalies ranging from posterior embryotoxon to congenital cataract in heterozygous carriers and congenital sclereocornea and cataract in a patient homozygous for this mutation. In Family 3, we identified the recurrent heterozygous c.640_656dup (p.Gly220Profs*95) mutation segregating with congenital cataract. In Family 4, the de novo c.582del [p.(Ile194Metfs*115)] mutation was identified in a patient with congenital cataract, microphthalmia, developmental delay and autism. In Family 5, the c.38G>A (p.Ser13Asn) mutation segregated dominantly in a family with Peters anomaly, which is a novel phenotype associated with the c.38G>A variant compared with the previously reported isolated congenital cataract.\nCONCLUSIONS: Our study unveils different phenotypes associated with known and novel mutations in PITX3, which will improve the genetic counselling of patients and their families.","variants":[{"Name":"NM_005029.4(PITX3):c.640_656dup (p.Gly220fs)","Chromosome":"10","Start":"102230766","Stop":"102230767","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCCCAGGCCCTGCAGGGC","allel_id":459553,"rule_based_match":true,"evidence_text":"c.640_656dup (p.Gly220Profs*95)","llm_judgment":"PRESENT","evidence":"c.640_656dup (p.Gly220Profs*95)","abstract_start":761,"abstract_end":792}]}
{"pmid":"20027113","title":"Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects.","abstract":"BACKGROUND: Systemic primary carnitine deficiency is an autosomal recessive disorder of the carnitine cycle caused by mutations in the SLC22A5 gene that encodes the carnitine transporter, organic cation transporter. Systemic primary carnitine deficiency typically presents in childhood with either metabolic decompensation or cardiomyopathy. We report five families in which low free carnitine levels in the infants' newborn screening have led to the diagnosis of maternal systemic primary carnitine deficiency.\nMETHODS: Blood samples from the infants and /or their family members were used to extract the DNA. The entire coding regions of the SLC22A5 gene were sequenced. The clinical data were obtained from the referring metabolic specialists.\nRESULT: Sequencing the SLC22A5 gene allowed molecular confirmation with identification of three novel mutations: c.1195C>T (p.R399W), c.1324_1325GC>AT (p.A442I), and c.43G>T (p.G15W). All infants were asymptomatic at the time of diagnosis, and one was found to have systemic primary carnitine deficiency. Three mothers are asymptomatic, one had decreased stamina during pregnancy, and one has mild fatigability and developed preeclampsia.\nDISCUSSION: These findings provide further evidence that systemic primary carnitine deficiency presents with a broad clinical spectrum from a metabolic decompensation in infancy to an asymptomatic adult. The maternal systemic primary carnitine deficiency was uncovered by the newborn screening results supporting the previous notion that newborn screening can identify some of the maternal inborn errors of metabolism. It also emphasizes the importance of maternal evaluation after identification of a low free carnitine level in the newborn screening.","variants":[{"Name":"NM_003060.4(SLC22A5):c.1195C>T (p.Arg399Trp)","Chromosome":"5","Start":"132390832","Stop":"132390832","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21466,"rule_based_match":true,"evidence_text":"c.1195C>T (p.R399W)","llm_judgment":"PRESENT","evidence":"c.1195C>T (p.R399W)","abstract_start":860,"abstract_end":879},{"Name":"NM_003060.4(SLC22A5):c.1324_1325delinsAT (p.Ala442Ile)","Chromosome":"5","Start":"132392489","Stop":"132392490","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"AT","allel_id":21467,"rule_based_match":false,"evidence_text":"c.1324_1325GC>AT (p.A442I)","llm_judgment":"PRESENT","evidence":"c.1324_1325GC>AT (p.A442I)","abstract_start":881,"abstract_end":907},{"Name":"NM_003060.4(SLC22A5):c.43G>T (p.Gly15Trp)","Chromosome":"5","Start":"132370015","Stop":"132370015","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":21468,"rule_based_match":true,"evidence_text":"c.43G>T (p.G15W)","llm_judgment":"PRESENT","evidence":"c.43G>T (p.G15W)","abstract_start":913,"abstract_end":929}]}
{"pmid":"15146461","title":"Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and \"modifier\" polymorphisms.","abstract":"Gaucher disease, the most prevalent sphingolipidosis, is caused by the deficient activity of acid beta-glucosidase, mainly due to mutations in the GBA gene. Over 200 mutations have been identified worldwide, more than 25 of which were in Spanish patients. In order to demonstrate causality for Gaucher disease, some of them: c.662C>T (p.P182L), c.680A>G (p.N188S), c.886C>T (p.R257X), c.1054T>C (p.Y313H), c.1093G>A (p.E326K), c.1289C>T (p.P391L), c.1292A>T (p.N392I), c.1322T>C (p.I402T), and the double mutants [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]) and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]), were expressed in Sf9 cells using a baculovirus expression system. Other well-established Gaucher disease mutations, namely c.1226A>G (p.N370S), c.1342G>C (p.D409H), and c.1448T>C (p.L444P), were also expressed for comparison. The levels of residual acid beta-glucosidase activity of the mutant enzymes produced by the cDNAs carrying alleles c.662C>T (p.P182L), c.886C>T (p.R257X), c.1054T>C (p.Y313H), c.1289C>T (p.P391L), and c.1292A>T (p.N392I) were negligible. The c.1226A>G (p.N370S), c.1322T>C (p.I402T), c.1342G>C (p.D409H), c.1448T>C (p.L444P), and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]) alleles produced enzymes with levels ranging from 6 to 14% of the wild-type. The three remaining alleles, c.680A>G (p.N188S), c.1093G>A (p.E326K), and [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]), showed higher activity (66.6, 42.7, and 23.2%, respectively). Expression studies revealed that the c.1093G>A (p.E326K) change, which was never found alone in a Gaucher disease-causing allele, when found in a double mutant such as [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]) and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]), decreases activity compared to the activity found for the other mutation alone. These results suggest that c.1093G>A (p.E326K) should be considered a \"modifier variant\" rather than a neutral polymorphism, as previously considered. Mutation c.680A>G (p.N188S), which produces a mutant enzyme with the highest level of activity, is probably a very mild mutation or another \"modifier variant.\"","variants":[{"Name":"NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)","Chromosome":"1","Start":"155235843","Stop":"155235843","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":19329,"rule_based_match":true,"evidence_text":"c.1226A>G (p.N370S)","llm_judgment":"PRESENT","evidence":"c.1226A>G (p.N370S)","abstract_start":729,"abstract_end":748},{"Name":"NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)","Chromosome":"1","Start":"155235252","Stop":"155235252","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19327,"rule_based_match":true,"evidence_text":"c.1448T>C (p.L444P)","llm_judgment":"PRESENT","evidence":"c.1448T>C (p.L444P)","abstract_start":775,"abstract_end":794}]}
{"pmid":"22947400","title":"A founder mutation causing a severe methylenetetrahydrofolate reductase (MTHFR) deficiency in Bukharian Jews.","abstract":"Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. A novel homozygous MTHFR c.474A>T (p.G158G) mutation was detected in two unrelated children of Jewish Bukharian origin. This mutation generates an abnormal splicing and early termination codon. A carrier frequency of 1:39 (5/196) was determined among unrelated healthy Bukharian Jews. Given the disease severity and allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, or preimplantation diagnosis.","variants":[{"Name":"NM_005957.5(MTHFR):c.474A>T (p.Gly158=)","Chromosome":"1","Start":"11801162","Stop":"11801162","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1054731,"rule_based_match":true,"evidence_text":"c.474A>T (p.G158G)","llm_judgment":"PRESENT","evidence":"c.474A>T (p.G158G)","abstract_start":120,"abstract_end":138}]}
{"pmid":"24844453","title":"Novel point mutations in survival motor neuron 1 gene expand the spectrum of phenotypes observed in spinal muscular atrophy patients.","abstract":"The aim of our study was to identify point mutations in a group of 606 patients diagnosed for spinal muscular atrophy with excluded biallelic loss of the SMN1 gene. Point missense mutations or small deletions in the SMN1 gene were ultimately identified in 18 patients. Six patients were found to have small deletions, the c.429_435del mutation in 3 cases, the c.431delC mutation in 2 and c.722delC in one. Those mutations, not described previously, were characteristic of patients presenting a severe phenotype. The most frequent missense mutation - p.Thr274Ile, was identified in 9 patients presenting a rather mild phenotype. Three other missense mutations, i.e., p.Ser230Leu, p.Ala111Gly and p.Pro244Leu, were identified in a further 3 SMA3 patients. Mutation p.Pro244Leu, not described so far, was identified in a patient with a mild form of SMA and more distal distribution of muscle weakness. Our results suggest a specific point mutation spectrum in the Polish population. The existence of small deletions not identified thus far could suggest a possible founder effect. In patients with preserved one SMN1 allele without common exon 7 deletion, presenting a mild form of SMA, a special consideration should be given to the p.Thr274Ile mutation.","variants":[{"Name":"NM_000344.4(SMN1):c.821C>T (p.Thr274Ile)","Chromosome":"5","Start":"70946163","Stop":"70946163","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":24203,"rule_based_match":false,"evidence_text":"p.Thr274Ile","llm_judgment":"PRESENT","evidence":"p.Thr274Ile","abstract_start":550,"abstract_end":561}]}
{"pmid":"28120589","title":"Identification of a De Novo 3bp Deletion in CRYBA1/A3 Gene in Autosomal Dominant Congenital Cataract.","abstract":"Autosomal dominant congenital cataract (ADCC) is the most common form of inherited cataracts and accounts for one-third of congenital cataracts. Heterozygous null mutations in the crystallin genes are the major cause of the ADCC. This study aims to detect the mutational spectrum of four crystallin genes, CRYBA1/A3, CRYBB1, CRYBB2 and CRYGD in an Iranian family. Genomic DNA was isolated from whole blood cells from theproband and other family members. The coding regions and flanking intronicsequences of crystalline genes were analyzed by Sanger sequencing in aproband with ADCC. The identified mutation was further evaluated in available family members. To predict the potential protein partners of CRYBA1/A3, we also used an in-silico analysis. A de novo heterozygous deletion (c.272-274delGAG, p.G91del) in exon 4 of CRYBA1/A3 gene, leading to a deletion of Glycine at codon 91 was found. This genetic variation did not change the reading frame of CRYBA1 protein. In conclusion, we identified a de novo in-frame 3-bp deletion in the proband with an autosomal dominant congenital cataract, but not in her parents, in an Iranian family. This mutation has occurred de novo on a paternal gamete during spermatogenesis. The in-silico results predicted the interaction of CRYBA1 protein with the other CRY as well as proteins responsible for eye cell signaling.","variants":[{"Name":"NM_005208.5(CRYBA1):c.269GAG[1] (p.Gly91del)","Chromosome":"17","Start":"29252117","Stop":"29252119","ReferenceAlleleVCF":"AGAG","AlternateAlleleVCF":"A","allel_id":413461,"rule_based_match":false,"evidence_text":"c.272-274delGAG, p.G91del","llm_judgment":"PRESENT","evidence":"c.272-274delGAG, p.G91del","abstract_start":783,"abstract_end":808}]}
{"pmid":"31482657","title":"CASQ2 variants in Chinese children with catecholaminergic polymorphic ventricular tachycardia.","abstract":"BACKGROUND: Biallelic variants of the CASQ2 are known to cause the autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease that predisposes young individuals to syncope and sudden cardiac death. To date, only about 24 CASQ2 variants have been reported in association with CPVT pathogenesis; furthermore, studies in Asians, especially in the Chinese population, are relatively rare. The aim of this study was to detect CASQ2 variants in Chinese patients with CPVT.\nMETHODS: We used targeted next-generation sequencing (NGS) to identify CASQ2 variants in Chinese patients with CPVT. A screening process was performed to prioritize rare variants of potential functional significance. Sanger sequencing was conducted to conform the candidate variants and determine the parental origin.\nRESULTS: We identified seven different CASQ2 variants, of which three (c.1074_1075delinsC, c.1175_1178delACAG, and c.838+1G>A) have not been previously reported. The variants exhibited autosomal recessive inheritance, and were detected in four unrelated Chinese families with CPVT. They included a nonsense variant c.97C>T (p.R33*) and a missense variant c.748C>T (p.R250C) in Family 1 with three CPVT patients; two heterozygous frameshift variants, c.1074_1075delinsC (p.G359Afs*12) and c.1175_1178delACAG (p.D392Vfs*84), in Family 2 with one CPVT patient; one pathogenic homozygous variant c.98G>A (p.R33Q) of CASQ2 in the CPVT patient of Family 3; and two heterozygous splicing variants, (c.532+1G>A) and (c.838+1G>A), in Family 4 with one CPVT patient.\nCONCLUSION: To our knowledge, this is the first systematic study of Chinese children with CASQ2 variants. Our work further expands the genetic spectrum of CASQ2-associated CPVT.","variants":[{"Name":"NM_001232.4(CASQ2):c.98G>A (p.Arg33Gln)","Chromosome":"1","Start":"115768444","Stop":"115768444","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":822588,"rule_based_match":true,"evidence_text":"c.98G>A (p.R33Q)","llm_judgment":"PRESENT","evidence":"c.98G>A (p.R33Q)","abstract_start":1429,"abstract_end":1445}]}
{"pmid":"30466290","title":"Is prophylactic gastrectomy indicated for healthy carriers of CDH1 gene mutations associated with hereditary diffuse gastric cancer?","abstract":"INTRODUCTION: hereditary diffuse gastric cancer (HDGC) is a recently reported hereditary cancer syndrome. Patients with suspected HDGC must be under surveillance via endoscopy and multiple biopsies. As an alternative, some studies suggest prophylactic gastrectomy (PG) for disease carriers. The goal of this article was to report our experience with a CDH1 mutation positive family who underwent PG.\nPATIENTS AND METHODS: the index case was a 34-year-old female diagnosed with diffuse gastric adenocarcinoma and massive carcinomatosis. There was a family history of gastric adenocarcinoma in seven family members. A genetic study identified the c.1577G>A mutation, in exon 11 of the CDH1 gene via sequencing analysis.\nRESULTS: this mutation was also present in other six family members, who subsequently underwent prophylactic gastrectomy. The pathology study of resected gastric segments revealed multiple microscopic foci of adenocarcinoma in five of these individuals. These foci were not detected in the multiple endoscopies performed before surgery.\nCONCLUSIONS: we recommend prophylactic gastrectomy for CDH1 mutation carriers even in the absence of lesions during endoscopic screening.","variants":[{"Name":"NM_004360.5(CDH1):c.1577G>A (p.Trp526Ter)","Chromosome":"16","Start":"68819291","Stop":"68819291","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1188398,"rule_based_match":true,"evidence_text":"c.1577G>A","llm_judgment":"PRESENT","evidence":"c.1577G>A","abstract_start":645,"abstract_end":654}]}
{"pmid":"28615295","title":"Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy.","abstract":"BACKGROUND: Hypertrophic cardiomyopathy is a genetically heterogeneous myocardial disease with >1000 causal variants identified. Nonunique variants account for disease in many families. We sought to characterize nonunique variants in Australian families and determine whether they arise from common ancestral mutations or recurrent mutation events.\nMETHODS AND RESULTS: Genetic test results of 467 index patients from apparently unrelated families with hypertrophic cardiomyopathy were evaluated. Causal variants were found in 185 of 467 (40%) families. Nonunique variants accounted for 122 of 185 (66%) families. The most common single genetic cause of hypertrophic cardiomyopathy is the recurrent <i>MYBPC3</i> (myosin-binding protein-C) variant c.1504C>T, p.Arg502Trp, which was found in 13 of 185 (7%) families with a causal variant identified. Thirteen variants in <i>MYBPC3</i> and <i>MYH7</i> (myosin heavy chain 7) were each identified >3 times and accounted for 78 of 185 (42%) hypertrophic cardiomyopathy families with a causal variant. Haplotype analysis of these 13 variants was performed on 126 individuals from 70 Australian families, and 11 variants arose through recurrent mutation events. Two variants, <i>MYBPC3</i> c.1928-2A>G and <i>MYH7</i> c.2681A>G, p.Glu894Gly, were found on 1 haplotype in 6 families each, supportive of a single mutation event inherited from a common ancestor.\nCONCLUSIONS: The majority of families with a causal variant identified have a nonunique variant. Discovery of the genetic origins of human disease forms a fundamental basis for improved understanding of disease pathogenesis and phenotype development.","variants":[{"Name":"NM_000256.3(MYBPC3):c.1928-2A>G","Chromosome":"11","Start":"47339792","Stop":"47339792","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":51755,"rule_based_match":true,"evidence_text":"MYBPC3 c.1928-2A>G","llm_judgment":"PRESENT","evidence":"MYBPC3</i> c.1928-2A>G","abstract_start":1223,"abstract_end":1245},{"Name":"NM_000257.4(MYH7):c.2681A>G (p.Glu894Gly)","Chromosome":"14","Start":"23424148","Stop":"23424148","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":52092,"rule_based_match":true,"evidence_text":"MYH7 c.2681A>G, p.Glu894Gly","llm_judgment":"PRESENT","evidence":"MYH7</i> c.2681A>G, p.Glu894Gly","abstract_start":1253,"abstract_end":1284}]}
{"pmid":"22016686","title":"Identification of compound heterozygous mutation in a Korean patient with alpha 1-antitrypsin deficiency.","abstract":"Alpha 1-antitrypsin (AAT) deficiency is a genetic disorder that primarily affects the lungs and liver. While AAT deficiency is one of the most common genetic disorders in the Caucasian population, it is extremely rare in Asians. Here, we report the case of a 36-year-old Korean woman with AAT deficiency who visited the emergency department of our hospital for the treatment of progressive dyspnea that had begun 10 years ago. She had never smoked. Chest computed tomography revealed panlobular emphysema in both lungs, which suggested AAT deficiency. The serum AAT level was 33 mg/dL (reference interval: 90-200 mg/dL). Four exons of the SERPINA1 gene, which is responsible for AAT deficiency, and their flanking regions were analyzed by PCR-direct sequencing. The patient was found to have 1 missense mutation (c.230C>T, p.Ser77Phe; S(iiyama)) and 1 frameshift mutation (c.1158dupC, p.Glu387ArgfsX14; QO(clayton)). This is the first Korean case of AAT deficiency confirmed by genetic analysis and the second case of a compound heterozygote of S(iiyama) and QO(clayton), the first case of which was reported from Japan.","variants":[{"Name":"NM_001127701.1(SERPINA1):c.230C>T (p.Ser77Phe)","Chromosome":"14","Start":"94383008","Stop":"94383008","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":33031,"rule_based_match":true,"evidence_text":"c.230C>T, p.Ser77Phe; S(iiyama)","llm_judgment":"PRESENT","evidence":"c.230C>T, p.Ser77Phe; S(iiyama)","abstract_start":813,"abstract_end":844},{"Name":"NM_000295.5(SERPINA1):c.1158dup (p.Glu387fs)","Chromosome":"14","Start":"94378547","Stop":"94378548","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":186924,"rule_based_match":true,"evidence_text":"c.1158dupC, p.Glu387ArgfsX14; QO(clayton)","llm_judgment":"PRESENT","evidence":"c.1158dupC, p.Glu387ArgfsX14; QO(clayton)","abstract_start":873,"abstract_end":914}]}
{"pmid":"21834037","title":"Molecular confirmation of HRAS p.G12S in siblings with Costello syndrome.","abstract":"Costello syndrome was first reported based on its characteristic phenotype. Its presentation affects multiple organ systems, including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS have been recognized to cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. Here, we report on the identification of an HRAS mutation c.34G>A, predicting a p.G12S amino acid substitution, in the surviving brother of a previously reported sibling pair, and documentation of the same change in autopsy material from his deceased sister. This represents, to our knowledge, the first molecularly confirmed Costello syndrome in siblings. We did not detect the mutation in a heterozygous state or mosaicism in peripheral white blood cell or cheek swab-derived DNA samples from either parent. Using single nucleotide polymorphic markers and allele-specific amplification, we clearly identified the mutation in the surviving sibling to be of maternal origin. While we cannot exclude two independently occurring de novo mutations, the complete sharing of polymorphic markers around the mutation site in both siblings supports maternal germ cell mosaicism. Recurrence risk counseling for families with apparently de novo occurring autosomal dominant conditions includes discussion of germ cell mosaicism, and this report underscores the applicability of this concern to Costello syndrome.","variants":[{"Name":"NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)","Chromosome":"11","Start":"534289","Stop":"534289","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27641,"rule_based_match":true,"evidence_text":"HRAS mutation c.34G>A","llm_judgment":"PRESENT","evidence":"HRAS mutation c.34G>A","abstract_start":511,"abstract_end":532}]}
{"pmid":"21584334","title":"Multiplex digital PCR: breaking the one target per color barrier of quantitative PCR.","abstract":"Quantitative polymerase chain reactions (qPCR) based on real-time PCR constitute a powerful and sensitive method for the analysis of nucleic acids. However, in qPCR, the ability to multiplex targets using differently colored fluorescent probes is typically limited to 4-fold by the spectral overlap of the fluorophores. Furthermore, multiplexing qPCR assays requires expensive instrumentation and most often lengthy assay development cycles. Digital PCR (dPCR), which is based on the amplification of single target DNA molecules in many separate reactions, is an attractive alternative to qPCR. Here we report a novel and easy method for multiplexing dPCR in picolitre droplets within emulsions-generated and read out in microfluidic devices-that takes advantage of both the very high numbers of reactions possible within emulsions (>10(6)) as well as the high likelihood that the amplification of only a single target DNA molecule will initiate within each droplet. By varying the concentration of different fluorogenic probes of the same color, it is possible to identify the different probes on the basis of fluorescence intensity. Adding multiple colors increases the number of possible reactions geometrically, rather than linearly as with qPCR. Accurate and precise copy numbers of up to sixteen per cell were measured using a model system. A 5-plex assay for spinal muscular atrophy was demonstrated with just two fluorophores to simultaneously measure the copy number of two genes (SMN1 and SMN2) and to genotype a single nucleotide polymorphism (c.815A>G, SMN1). Results of a pilot study with SMA patients are presented.","variants":[{"Name":"NM_000344.4(SMN1):c.815A>G (p.Tyr272Cys)","Chromosome":"5","Start":"70946157","Stop":"70946157","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":24205,"rule_based_match":true,"evidence_text":"c.815A>G","llm_judgment":"PRESENT","evidence":"c.815A>G","abstract_start":1555,"abstract_end":1563}]}
{"pmid":"30002862","title":"Novel variants in","abstract":"We report two female patients with focal segmental glomerulosclerosis and chronic kidney disease. The first patient was found to have a heterozygous, de novo, pathogenic variant in <i>COL4A5</i> (c.141+1G>A, IVS2+1G>A), which is associated with Alport syndrome. The second patient was found to have a heterozygous, likely pathogenic variant in <i>COL4A4</i> (c.2842G>T). Both these variants in <i>COL4A5</i> and <i>COL4A4</i> are novel, and they were detected using whole exome sequencing and gene panel testing, respectively. Additionally, we discuss the complexities of diagnosis in such cases and the benefits of using the abovementioned diagnostic approaches.","variants":[{"Name":"NM_000092.5(COL4A4):c.2842G>T (p.Gly948Ter)","Chromosome":"2","Start":"227054612","Stop":"227054612","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1059217,"rule_based_match":true,"evidence_text":"c.2842G>T","llm_judgment":"PRESENT","evidence":"c.2842G>T","abstract_start":359,"abstract_end":368}]}
{"pmid":"29354166","title":"Adult-onset hypophosphatasia diagnosed following bilateral atypical femoral fractures in a 55-year-old woman.","abstract":"We report the case of a 55-year-old woman who presented to the emergency department having woken from sleep with right sided thigh swelling. Pelvic radiographs revealed bilateral atypical subtrochanteric femoral fractures (ASFFs). In the two years leading up to this admission, the patient had experienced gradually increasing pain and weakness in her legs which had resulted in a decrease in her mobility from fully mobile to bed-bound. During this time a neurologist had organised a magnetic-resonance imaging (MRI) scan of the brain and spine which was normal. There was no history of bisphosphonate (BP) use. Historical and admission blood tests revealed a persistently low serum alkaline phosphatase (ALP), with all other results within normal limits. The patient was treated with intramedullary nailing of both femurs and histological analysis of bone reamings were characteristic of hypophosphatasia (HPP). The patient was independently mobilising with a walking frame on discharge. Subsequent genetic testing revealed bi-allelic pathogenic variants in the TNSALP gene: c.526G>A, p.(Ala176Thr) and c.1171C>T, p.(Arg391Cys). HPP is an inborn error in metabolism caused by mutation in the gene coding for tissue non-specific alkaline phosphatase (TNSALP), resulting in a decrease in serum ALP concentrations. The age at which it presents which can vary from childhood to middle age, with symptoms ranging from perinatal death to late-onset osteomalacia. In those patients who survive to adulthood, there is a predisposition to fractures, including ASFFs. Treatment with asfotase alfa (a bone-targeted, recombinant human TNSALP) has been approved for perinatal, infantile and paediatric-onset hypophosphatasia. This case emphasises the importance of viewing persistent low ALP as a 'red flag' in patients presenting with musculoskeletal symptoms. Timely diagnosis and treatment of HPP can reduce the risk of serious complications, such as those experienced by this patient.","variants":[{"Name":"NM_000478.6(ALPL):c.1171C>T (p.Arg391Cys)","Chromosome":"1","Start":"21575906","Stop":"21575906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":540957,"rule_based_match":true,"evidence_text":"c.1171C>T, p.(Arg391Cys)","llm_judgment":"PRESENT","evidence":"c.1171C>T, p.(Arg391Cys)","abstract_start":1105,"abstract_end":1129}]}
{"pmid":"21542063","title":"A leaky splicing mutation affecting SMN1 exon 7 inclusion explains an unexpected mild case of spinal muscular atrophy.","abstract":"Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder resulting, in most cases, from homozygous deletions of the SMN1 gene or, in rare cases, from SMN1 intragenic mutations. Here we describe the identification and characterization of c.835-3C>T, a novel SMA-causing mutation detected in the intron 6 of the single SMN1 allele of a type IV SMA patient. We demonstrate both ex vivo and in vivo that c.835-3C>T is a deleterious splicing mutation that induces a modest but unequivocal exclusion of exon 7 from the SMN1 transcripts, its \"leakiness\" explaining the exceptionally mild phenotype of this patient. This mutation creates a putative high-affinity binding site for the splicing repressor protein hnRNP A1 overlapping the splice acceptor site of exon 7 (UAG|GGU). Our findings support the current therapeutic strategies aiming at correcting exon 7 splicing in SMA patients, and bring clues about the level of exon 7 inclusion required to achieve a therapeutic effect.","variants":[{"Name":"NM_000344.4(SMN1):c.835-3C>T","Chromosome":"5","Start":"70951938","Stop":"70951938","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":487068,"rule_based_match":true,"evidence_text":"c.835-3C>T","llm_judgment":"PRESENT","evidence":"c.835-3C>T","abstract_start":259,"abstract_end":269}]}
{"pmid":"31376723","title":"Mowat-Wilson syndrome: Generation of two human iPS cell lines (UUIGPi004A and UUIGPi005A) from siblings with a truncating ZEB2 gene variant.","abstract":"Mowat-Wilson syndrome (MWS) is a complex developmental syndrome caused by heterozygous mutations in the Zinc finger E-box-binding homeobox 2 gene (ZEB2). We generated the first human iPSC lines from primary fibroblasts of two siblings with MWS carrying a heterozygous ZEB2 stop mutation (c.1027C > T; p.Arg343*) using the Sendai virus reprogramming system. Both iPSC lines were free from reprogramming vector genes, expressed pluripotency markers and showed potential to differentiate into the three germ layers. Genetic analysis confirmed normal karyotypes and a preserved stop mutation. These iPSC lines will provide a useful resource to study altered neural lineage fate and neuropathophysiology in MWS.","variants":[{"Name":"NM_014795.4(ZEB2):c.1027C>T (p.Arg343Ter)","Chromosome":"2","Start":"144400160","Stop":"144400160","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187166,"rule_based_match":true,"evidence_text":"c.1027C > T; p.Arg343*","llm_judgment":"PRESENT","evidence":"c.1027C > T; p.Arg343*","abstract_start":288,"abstract_end":310}]}
{"pmid":"27930565","title":"A case report with the peculiar concomitance of 2 different genetic syndromes.","abstract":"RATIONALE: Down syndrome (DS) is the most common chromosome disorder in live born infants, affecting several body systems, but usually sparing skeletal muscles. We present the case of a child with coexistence of DS and dystrophinopathy. Only 1 similar case has been reported so far.\nPATIENT CONCERNS: An 8-year-old boy with DS had a history of incidental finding of increased serum creatine kinase levels up to 1775 U/L (normal values 38-174 U/L). He presented no delay in motor development; at the neurological examination, no muscle weakness or fatigability was detected in 2 different evaluations performed over a 6-month period.\nDIAGNOSES: Skeletal muscle biopsy revealed marked dystrophic changes with patchy immunostaining for dystrophin. The Duchenne muscular dystrophy gene was screened for deletions by multiplex polymerase chain reaction, but no mutations were found. Sequence analysis of the Duchenne muscular dystrophy gene revealed a splice-site mutation c.1812+1G>A in intron 15 and confirmed a diagnosis of Becker muscular dystrophy.\nINTERVENTIONS: The patient has started a specific physiotherapy that avoided any deterioration in motor development and muscular wasting.\nOUTCOMES: A multidisciplinary follow-up was initiated. The genetician that followed the patient for DS was supported by the neurologist, the physiotherapist, the pulmonologist, and the cardiologist.\nLESSONS: This peculiar \"double trouble\" case exemplifies the value of careful clinical evaluation and adequate clinical experience to identify the concomitance of 2 different genetic syndromes in the same patient, and it points out the significance of muscular strength assessment in DS patients to make the most correct prognosis, and, consequently, to organize the best long-term care.","variants":[{"Name":"NM_004006.3(DMD):c.1812+1G>A","Chromosome":"X","Start":"32573529","Stop":"32573529","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":172184,"rule_based_match":true,"evidence_text":"c.1812+1G>A","llm_judgment":"PRESENT","evidence":"c.1812+1G>A","abstract_start":968,"abstract_end":979}]}
{"pmid":"38387306","title":"The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.","abstract":"Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B<sub>12</sub> metabolism. In cblC, deficient activation of cobalamin results in methylcobalamin and adenosylcobalamin deficiency, elevating methylmalonic acid (MMA) and total plasma homocysteine (tHcy). We retrospectively reviewed the medical files of seven cblC patients: three compound heterozygotes for the MMACHC (NM_015506.3) missense variant c.158T>C p.(Leu53Pro) in trans with the common pathogenic mutation c.271dupA (p.(Arg91Lysfs*14), \"compounds\"), and four c.271dupA homozygotes (\"homozygotes\"). Compounds receiving hydroxocobalamin intramuscular injection monotherapy had age-appropriate psychomotor performance and normal ophthalmological examinations. In contrast, c.271dupA homozygotes showed marked psychomotor retardation, retinopathy and feeding problems despite penta-therapy (hydroxocobalamin, betaine, folinic acid, l-carnitine and acetylsalicylic acid). Pretreatment levels of plasma and urine MMA and tHcy were higher in c.271dupA homozygotes than in compounds. Under treatment, levels of the compounds approached or entered the reference range but not those of c.271dupA homozygotes (tHcy: compounds 9.8-32.9 μM, homozygotes 41.6-106.8 (normal (N) < 14); plasma MMA: compounds 0.14-0.81 μM, homozygotes, 10.4-61 (N < 0.4); urine MMA: compounds 1.75-48 mmol/mol creatinine, homozygotes 143-493 (N < 10)). Patient skin fibroblasts all had low cobalamin uptake, but this was milder in compound cells. Also, the distribution pattern of cobalamin species was qualitatively different between cells from compounds and from homozygotes. Compared to the classic cblC phenotype presented by c.271dupA homozygous patients, c.[158T>C];[271dupA] compounds had mild clinical and biochemical phenotypes and responded strikingly to hydroxocobalamin monotherapy.","variants":[{"Name":"NM_015506.3(MMACHC):c.158T>C (p.Leu53Pro)","Chromosome":"1","Start":"45507432","Stop":"45507432","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":486715,"rule_based_match":true,"evidence_text":"c.158T>C p.(Leu53Pro)","llm_judgment":"PRESENT","evidence":"c.158T>C p.(Leu53Pro)","abstract_start":454,"abstract_end":475}]}
{"pmid":"30690871","title":"Schuurs-Hoeijmakers syndrome in a patient from India.","abstract":"Schuurs-Hoeijmakers syndrome (SHMS), or Autosomal Dominant Mental Retardation Syndrome type 17 (MRD17) is a rare form of intellectual disability with distinct facial features. A recurrent de novo heterozygous c.607C>T, p.Arg203Trp mutation in the PACS1 gene accounts for all reported cases except for one patient with a de novo heterozygous c.608G>A, p.Arg203Trp mutation. Ethnic background is known to affect the clinical manifestation of dysmorphic syndromes. Here we describe the first Indian patient with Schuurs-Hoeijmakers syndrome (SHMS) with a de novo heterozygous NM_018026.3 (PACS1):c.607C>T (p.Arg203Trp) variant. He is the only child with SHMS with a cleft lip. Thus our report expands the phenotypic spectrum of SHMS and establishes its occurrence across populations.","variants":[{"Name":"NM_018026.4(PACS1):c.607C>T (p.Arg203Trp)","Chromosome":"11","Start":"66211206","Stop":"66211206","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48180,"rule_based_match":true,"evidence_text":"NM_018026.3 (PACS1):c.607C>T (p.Arg203Trp)","llm_judgment":"PRESENT","evidence":"NM_018026.3 (PACS1):c.607C>T (p.Arg203Trp)","abstract_start":573,"abstract_end":615}]}
{"pmid":"30094185","title":"Clinical and molecular characteristics of colombian patients with mucopolysaccharidosis IVA, and description of a new galns gene mutation.","abstract":"A study published in 2012 estimated incidence of MPS IVA, in 0.68 cases per 100, 000 live births in Colombia, and according to the Colombian Fund for High-Cost Diseases, in 2014 there were 15 people diagnosed with MPS IV. To enhance the knowledge of the disease in the country, we aimed to characterize clinical and molecular findings in 12 MPS IVA patients. Twelve patients were included in the study, with most patients of female gender (<i>n</i> = 7, 58,3%), age range 2 to 28 years, average weight 26 kg (17.6-43 kg), average height 97 cm (92-104 cm), average BMI 27.6 kg/m<sup>2</sup> (19.92-47.65 kg/m<sup>2</sup>). Clinical findings were similar to those described in the literature. GALNS gene molecular analysis showed five homozygous missense mutations in exon 11 c.1156C > T or p.R386C, a single nonsense mutation in the heterozygous state c.974G > A p.W325, and heterozygous in exon 9 mutation of exon 3 c.280C > T p.R94C, missense variant reported by Ogawa in 1995 [17]. There was only one patient that presented a homozygous missense mutation in exon 9 c.901G > T p.G301C and four patients showed the heterozygous form. A heterozygous missense mutation in exon 5 c.425A > T p.H142L, which has not been previously reported, was found in a female patient, 2 years 11 months of age. The diagnosis algorithms that include molecular analysis, bioinformatic predictive tools, pharmacogenomics, and proteomics helps to improve the diagnosis, treatment, and prognosis of patients affected by MPS IVA.","variants":[{"Name":"NM_000512.5(GALNS):c.280C>T (p.Arg94Cys)","Chromosome":"16","Start":"88841936","Stop":"88841936","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":645122,"rule_based_match":true,"evidence_text":"c.280C > T p.R94C","llm_judgment":"PRESENT","evidence":"c.280C > T p.R94C","abstract_start":916,"abstract_end":933},{"Name":"NM_000512.5(GALNS):c.901G>T (p.Gly301Cys)","Chromosome":"16","Start":"88832099","Stop":"88832099","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":15747,"rule_based_match":true,"evidence_text":"c.901G > T p.G301C","llm_judgment":"PRESENT","evidence":"c.901G > T p.G301C","abstract_start":1067,"abstract_end":1085},{"Name":"NM_000512.5(GALNS):c.974G>A (p.Trp325Ter)","Chromosome":"16","Start":"88832026","Stop":"88832026","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1036217,"rule_based_match":true,"evidence_text":"c.974G > A p.W325","llm_judgment":"PRESENT","evidence":"c.974G > A p.W325","abstract_start":851,"abstract_end":868},{"Name":"NM_000512.5(GALNS):c.1156C>T (p.Arg386Cys)","Chromosome":"16","Start":"88824853","Stop":"88824853","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15739,"rule_based_match":true,"evidence_text":"c.1156C > T or p.R386C","llm_judgment":"PRESENT","evidence":"c.1156C > T or p.R386C","abstract_start":774,"abstract_end":796},{"Name":"NM_000512.5(GALNS):c.425A>T (p.His142Leu)","Chromosome":"16","Start":"88837763","Stop":"88837763","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":844478,"rule_based_match":true,"evidence_text":"c.425A > T p.H142L","llm_judgment":"PRESENT","evidence":"c.425A > T p.H142L","abstract_start":1177,"abstract_end":1195}]}
{"pmid":"26311697","title":"Analysis of the NDP gene in a Chinese family with X-linked recessive Norrie disease","abstract":"OBJECTIVE: The purpose of the current research was to investigate the NDP (Norrie disease protein) gene in one Chinese family with Norrie disease (ND) and to characterize the related clinical features.\nMETHODS: Clinical data of the proband and his family members were collected. Complete ophthalmic examinations were carried out on the proband. Genomic DNA was extracted from peripheral blood leukocytes of 35 family members. Molecular analysis of the NDP gene was performed by polymerase chain reaction and direct sequencing of all exons and flanking regions.\nRESULTS: A hemizygous NDP missense mutation c.362G > A (p.Arg121Gln) in exon 3 was identified in the affected members, but not in any of the unaffected family individuals.\nCONCLUSIONS: The missense mutation c.362G > A in NDP is responsible for the Norrie disease in this family. This discovery will help provide the family members with accurate and reliable genetic counseling and prenatal diagnosis.","variants":[{"Name":"NM_000266.4(NDP):c.362G>A (p.Arg121Gln)","Chromosome":"X","Start":"43949839","Stop":"43949839","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3407863,"rule_based_match":true,"evidence_text":"c.362G > A (p.Arg121Gln)","llm_judgment":"PRESENT","evidence":"c.362G > A (p.Arg121Gln)","abstract_start":605,"abstract_end":629}]}
{"pmid":"25983621","title":"Novel splice-affecting variants in CYP27A1 gene in two Chilean patients with Cerebrotendinous Xanthomatosis.","abstract":"Cerebrotendinous Xanthomatosis (CTX), a rare lipid storage disorder, is caused by recessive loss-of-function mutations of the 27-sterol hydroxylase (CYP27A1), producing an alteration of the synthesis of bile acids, with an accumulation of cholestanol. Clinical characteristics include juvenile cataracts, diarrhea, tendon xanthomas, cognitive impairment and other neurological manifestations. Early diagnosis is critical, because treatment with chenodeoxycholic acid may prevent neurological damage. We studied the CYP27A1 gene in two Chilean CTX patients by sequencing its nine exons, exon-intron boundaries, and cDNA from peripheral blood mononuclear cells. Patient 1 is a compound heterozygote for the novel substitution c.256-1G > T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the previously-known pathogenic mutation c.1183C > T (p.Arg395Cys). Patient 2 is homozygous for the novel mutation c.1185-1G > A that causes exon 7 skipping and the generation of a premature stop codon in exon 8, leading to the loss of the crucial adrenoxin binding domain of CYP27A1.","variants":[{"Name":"NM_000784.4(CYP27A1):c.256-1G>T","Chromosome":"2","Start":"218809576","Stop":"218809576","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":541767,"rule_based_match":true,"evidence_text":"c.256-1G > T","llm_judgment":"PRESENT","evidence":"c.256-1G > T","abstract_start":724,"abstract_end":736},{"Name":"NM_000784.4(CYP27A1):c.1185-1G>A","Chromosome":"2","Start":"218814379","Stop":"218814379","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":491794,"rule_based_match":true,"evidence_text":"c.1185-1G > A","llm_judgment":"PRESENT","evidence":"c.1185-1G > A","abstract_start":934,"abstract_end":947},{"Name":"NM_000784.4(CYP27A1):c.1183C>T (p.Arg395Cys)","Chromosome":"2","Start":"218814186","Stop":"218814186","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19294,"rule_based_match":true,"evidence_text":"c.1183C > T (p.Arg395Cys)","llm_judgment":"PRESENT","evidence":"c.1183C > T (p.Arg395Cys)","abstract_start":860,"abstract_end":885}]}
{"pmid":"35246562","title":"A comprehensive WGS-based pipeline for the identification of new candidate genes in inherited retinal dystrophies.","abstract":"To enhance the use of Whole Genome Sequencing (WGS) in clinical practice, it is still necessary to standardize data analysis pipelines. Herein, we aimed to define a WGS-based algorithm for the accurate interpretation of variants in inherited retinal dystrophies (IRD). This study comprised 429 phenotyped individuals divided into three cohorts. A comparison of 14 pathogenicity predictors, and the re-definition of its cutoffs, were performed using panel-sequencing curated data from 209 genetically diagnosed individuals with IRD (training cohort). The optimal tool combinations, previously validated in 50 additional IRD individuals, were also tested in patients with hereditary cancer (n = 109), and with neurological diseases (n = 47) to evaluate the translational value of this approach (validation cohort). Then, our workflow was applied for the WGS-data analysis of 14 individuals from genetically undiagnosed IRD families (discovery cohort). The statistical analysis showed that the optimal filtering combination included CADDv1.6, MAPP, Grantham, and SIFT tools. Our pipeline allowed the identification of one homozygous variant in the candidate gene CFAP20 (c.337 C > T; p.Arg113Trp), a conserved ciliary gene, which was abundantly expressed in human retina and was located in the photoreceptors layer. Although further studies are needed, we propose CFAP20 as a candidate gene for autosomal recessive retinitis pigmentosa. Moreover, we offer a translational strategy for accurate WGS-data prioritization, which is essential for the advancement of personalized medicine.","variants":[{"Name":"NM_013242.3(CFAP20):c.337C>T (p.Arg113Trp)","Chromosome":"16","Start":"58115397","Stop":"58115397","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1325366,"rule_based_match":true,"evidence_text":"c.337 C > T; p.Arg113Trp","llm_judgment":"PRESENT","evidence":"c.337 C > T; p.Arg113Trp","abstract_start":1168,"abstract_end":1192}]}
{"pmid":"34980136","title":"Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations.","abstract":"BACKGROUND: Potassium channels are important for the structure and function of the spermatozoa. As a potassium transporter, the mSlo3 is essential for male fertility as Slo3 knockout male mice were infertile with the series of functional defects in sperm cells. However, no pathogenic variant has been detected in human SLO3 to date. Here we reported a human case with homozygous SLO3 mutation. The function of SLO3 in human sperm and the corresponding assisted reproductive strategy are also investigated.\nMETHODS: We performed whole-exome sequencing analysis from a large cohort of 105 patients with asthenoteratozoospermia. The effects of the variant were investigated by quantitative RT-PCR, western blotting, and immunofluorescence assays using the patient spermatozoa. Sperm morphological and ultrastructural studies were conducted using haematoxylin and eosin staining, scanning and transmission electron microscopy.\nRESULTS: We identified a homozygous missense variant (c.1237A > T: p.Ile413Phe) in the sperm-specific SLO3 in one Chinese patient with male infertility. This SLO3 variant was rare in human control populations and predicted to be deleterious by multiple bioinformatic tools. Sperm from the individual harbouring the homozygous SLO3 variant exhibited severe morphological abnormalities, such as acrosome hypoplasia, disruption of the mitochondrial sheath, coiled tails, and motility defects. The levels of SLO3 mRNA and protein in spermatozoa from the affected individual were reduced. Furthermore, the acrosome reaction, mitochondrial membrane potential, and membrane potential during capacitation were also afflicted. The levels of acrosome marker glycoproteins and PLCζ1 as well as the mitochondrial sheath protein HSP60 and SLO3 auxiliary subunit LRRC52, were significantly reduced in the spermatozoa from the affected individual. The affected man was sterile due to acrosome and mitochondrial dysfunction; however, intra-cytoplasmic sperm injection successfully rescued this infertile condition.\nCONCLUSIONS: SLO3 deficiency seriously impact acrosome formation, mitochondrial sheath assembly, and the function of K<sup>+</sup> channels. Our findings provided clinical implications for the genetic and reproductive counselling of affected families.","variants":[{"Name":"NM_001031836.3(KCNU1):c.1237A>T (p.Ile413Phe)","Chromosome":"8","Start":"36834810","Stop":"36834810","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2417449,"rule_based_match":true,"evidence_text":"c.1237A > T: p.Ile413Phe","llm_judgment":"PRESENT","evidence":"c.1237A > T: p.Ile413Phe","abstract_start":978,"abstract_end":1002}]}
{"pmid":"17620124","title":"Two novel connexin32 mutations cause early onset X-linked Charcot-Marie-Tooth disease.","abstract":"BACKGROUND: X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the connexin32 gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions.\nMETHODS: We describe two novel mutations in the connexin32 gene in two Norwegian families.\nRESULTS: Family 1 had a c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247. This probably results in a shorter non-functional protein structure. Affected individuals had an early age at onset usually in the first decade. The symptoms were more severe in men than women. All had severe muscle weakness in the legs. Several abortions were observed in this family. Family 2 had a c.536 G>A (C179Y) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade. Muscle wasting was severe and correlated with muscle weakness in legs. The men and one woman also had symptom from their hands. The neuropathy is demyelinating and the nerve conduction velocities were in the intermediate range (25-49 m/s). Affected individuals had symmetrical clinical findings, while the neurophysiology revealed minor asymmetrical findings in nerve conduction velocity in 6 of 10 affected individuals.\nCONCLUSION: The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode.","variants":[{"Name":"NM_000166.6(GJB1):c.225del (p.Leu76fs)","Chromosome":"X","Start":"71223931","Stop":"71223931","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":33935,"rule_based_match":true,"evidence_text":"c.225delG (R75fsX83)","llm_judgment":"PRESENT","evidence":"c.225delG (R75fsX83)","abstract_start":296,"abstract_end":316}]}
{"pmid":"29969168","title":"Characterization of spliceogenic variants located in regions linked to high levels of alternative splicing: BRCA2 c.7976+5G > T as a case study.","abstract":"Many BRCA1 and BRCA2 (BRCA1/2) genetic variants have been studied at mRNA level and linked to hereditary breast and ovarian cancer due to splicing alteration. In silico tools are reliable when assessing variants located in consensus splice sites, but we may identify variants in complex genomic contexts for which bioinformatics is not precise enough. In this study, we characterize BRCA2 c.7976 + 5G > T variant located in intron 17 which has an atypical donor site (GC). This variant was identified in three unrelated Spanish families and we have detected exon 17 skipping as the predominant transcript occurring in carriers. We have also detected several isoforms (Δ16-18, Δ17,18, Δ18, and ▼17q<sup>224</sup> ) at different expression levels among carriers and controls. This study remarks the challenge of interpreting genetic variants when multiple alternative isoforms are present, and that caution must be taken when using in silico tools to identify potential spliceogenic variants located in GC-AG introns.","variants":[{"Name":"NM_000059.4(BRCA2):c.7976+5G>T","Chromosome":"13","Start":"32362698","Stop":"32362698","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":462843,"rule_based_match":true,"evidence_text":"BRCA2 c.7976+5G>T","llm_judgment":"PRESENT","evidence":"BRCA2 c.7976 + 5G > T","abstract_start":383,"abstract_end":404}]}
{"pmid":"23077026","title":"PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine.","abstract":"OBJECTIVE: To perform a clinical and genetic study of a family with benign familial infantile seizures (BFIS) and, upon finding a PRRT2 gene mutation, to study a cohort of probands with a similar phenotype. We extended the study to all available family members to find out whether PRRT2 mutations cosegregated with additional symptoms.\nMETHODS: We carried out a clinical and genealogic study of a 3-generation family and of 32 additional probands with BFIS (11 families), infantile convulsions and paroxysmal choreoathetosis (ICCA) (9 families), BFIS/generalized epilepsy with febrile seizures plus (5 families), and sporadic benign neonatal or infantile seizures (7 probands/families). We performed a genetic study consisting of linkage analysis and PRRT2 screening of the 33 probands/families.\nRESULTS: We obtained a positive linkage in the 16p11.3-q23.1 chromosomal region in the large BFIS family. Mutation analysis of PRRT2 gene revealed a c.649dupC (p.Arg217Profs*8) in all affected individuals. PRRT2 analysis of the 32 additional probands showed mutations in 10, 8 familial and 2 sporadic, probands. Overall we found PRRT2 mutations in 11 probands with a mutation rate of 11 out of 33 (33%). BFIS co-occurred with migraine and febrile seizures in 2 families, with childhood absence epilepsy in one family and with hemiplegic migraine in one family.\nCONCLUSION: Our results confirm the predominant role of PRRT2 mutations in BFIS and expand the spectrum of PRRT2-associated phenotypes to include febrile seizures, childhood absence seizures, migraine, and hemiplegic migraine.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC (p.Arg217Profs*8)","llm_judgment":"PRESENT","evidence":"c.649dupC (p.Arg217Profs*8)","abstract_start":945,"abstract_end":972}]}
{"pmid":"32518176","title":"","abstract":"BACKGROUND: The nucleotide binding protein-like (<i>NUBPL</i>) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have <i>NUBPL</i> disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families).\nMETHODS: Whole exome sequencing was used to identify patients with compound heterozygous <i>NUBPL</i> variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model (<i>Yarrowia lipolytica</i>) and mitochondrial respiration experiments on patient fibroblasts.\nRESULTS: The previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found <i>in cis</i> with c.815-27T>C, but only two of four families had both variants. The second variant found <i>in trans</i> with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3-18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity.\nCONCLUSION: We report on five new patients with <i>NUBPL</i> disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic <i>NUBPL</i> variants.","variants":[{"Name":"NM_025152.3(NUBPL):c.815-27T>C","Chromosome":"14","Start":"31850092","Stop":"31850092","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":59458,"rule_based_match":true,"evidence_text":"c.815-27T>C","llm_judgment":"PRESENT","evidence":"c.815-27T>C","abstract_start":835,"abstract_end":846},{"Name":"NM_025152.3(NUBPL):c.166G>A (p.Gly56Arg)","Chromosome":"14","Start":"31562125","Stop":"31562125","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15046,"rule_based_match":true,"evidence_text":"c.166G>A [p.G56R]","llm_judgment":"PRESENT","evidence":"c.166G>A [p.G56R]","abstract_start":919,"abstract_end":936},{"Name":"NM_025152.3(NUBPL):c.311T>C (p.Leu104Pro)","Chromosome":"14","Start":"31599308","Stop":"31599308","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":205774,"rule_based_match":true,"evidence_text":"c.311T>C [p.L104P]","llm_judgment":"PRESENT","evidence":"c.311T>C [p.L104P]","abstract_start":1113,"abstract_end":1131},{"Name":"NM_025152.3(NUBPL):c.693+1G>A","Chromosome":"14","Start":"31826715","Stop":"31826715","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":59376,"rule_based_match":true,"evidence_text":"c.693+1G>A","llm_judgment":"PRESENT","evidence":"c.693+1G>A","abstract_start":1151,"abstract_end":1161}]}
{"pmid":"23298237","title":"Three novel germ-line VHL mutations in Hungarian von Hippel-Lindau patients, including a nonsense mutation in a fifteen-year-old boy with renal cell carcinoma.","abstract":"BACKGROUND: Von Hippel-Lindau disease is an autosomal dominantly inherited highly penetrant tumor syndrome predisposing to retinal and central nervous system hemangioblastomas, renal cell carcinoma and phaeochromocytoma among other less frequent complications.\nMETHODS: Molecular genetic testing of the VHL gene was performed in five unrelated families affetced with type I VHL disease, including seven patients and their available family members.\nRESULTS: Molecular genetic investigations detected three novel (c.163 G > T, c.232A > T and c.555C > A causing p.Glu55X, p.Asn78Tyr and p.Tyr185X protein changes, respectively) and two previously described (c.340 + 1 G > A and c.583C > T, resulting in p.Gly114AspfsX6 and p.195GlnX protein changes, respectively) germline point mutations in the VHL gene. Molecular modeling of the VHL-ElonginC-HIF-1alpha complex predicted that the p.Asn78Tyr amino acid exchange remarkably alters the 77-83 loop structure of VHL protein and destabilizes the VHL-HIF-1alpha complex suggesting that the mutation causes type I phenotype and has high risk to associate to renal cell carcinoma. The novel p.55X nonsense mutation associated to bilateral RCC and retinal angioma in a 15-year-old male patient.\nCONCLUSION: We describe the earliest onset renal cell carcinoma in VHL disease reported so far in a 15-year-old boy with a nonsense VHL mutation. Individual tailoring of screening schedule based on molecular genetic status should be considered in order to diagnose serious complications as early as possible. Our observations add to the understanding of genotype-phenotype correlation in VHL disease and can be useful for genetic counseling and follow-up of VHL patients.","variants":[{"Name":"NM_000551.4(VHL):c.232A>T (p.Asn78Tyr)","Chromosome":"3","Start":"10142079","Stop":"10142079","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":224898,"rule_based_match":true,"evidence_text":"c.232A > T","llm_judgment":"PRESENT","evidence":"c.232A > T","abstract_start":525,"abstract_end":535},{"Name":"NM_000551.4(VHL):c.583C>T (p.Gln195Ter)","Chromosome":"3","Start":"10149906","Stop":"10149906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":420456,"rule_based_match":true,"evidence_text":"c.583C>T","llm_judgment":"PRESENT","evidence":"c.583C > T","abstract_start":675,"abstract_end":685},{"Name":"NM_000551.4(VHL):c.555C>A (p.Tyr185Ter)","Chromosome":"3","Start":"10149878","Stop":"10149878","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3086229,"rule_based_match":true,"evidence_text":"c.555C > A causing p.Tyr185X","llm_judgment":"PRESENT","evidence":"c.555C > A","abstract_start":540,"abstract_end":550}]}
{"pmid":"33040083","title":"Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy.","abstract":"Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.","variants":[{"Name":"NM_005033.3(EXOSC9):c.239T>G (p.Leu80Arg)","Chromosome":"4","Start":"121802751","Stop":"121802751","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1679220,"rule_based_match":true,"evidence_text":"c.239T>G (p.Leu80Arg)","llm_judgment":"PRESENT","evidence":"c.239T>G (p.Leu80Arg)","abstract_start":760,"abstract_end":781},{"Name":"NM_005033.3(EXOSC9):c.151G>C (p.Gly51Arg)","Chromosome":"4","Start":"121801911","Stop":"121801911","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1679222,"rule_based_match":true,"evidence_text":"c.151G>C (p.Gly51Arg)","llm_judgment":"PRESENT","evidence":"c.151G>C (p.Gly51Arg)","abstract_start":832,"abstract_end":853}]}
{"pmid":"31347283","title":"Five novel NF1 gene pathogenic variants in 10 different Chinese families with neurofibromatosis type 1.","abstract":"BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with equal sex incidence that is characterized by neurofibromas, café-au-lait macules, axillary freckling, optic pathway tumor, distinctive osseous lesion, and iris Lisch nodules. Inactivating variants in the NF1 gene have been identified to be correlated with NF1. This tumor suppressor gene is located at 17q11.2.\nMETHODS: Ten affected NF1 probands and their available relatives from 10 unrelated Chinese families with neurofibromatosis type 1 were clinically studied. All of these probands mainly complained of osseous lesions. PCR was used to analyze and sequence the variants. We collected both laboratory and radiological information.\nRESULTS: We detected five novel pathogenic variants including two de novo variants in these 10 families: one missense variant, p.Cys709Arg(c.2125T>C), in exon 18 and four frameshift variants: p.Leu1459Profs*2(c.4436dupT) in exon 34; p.Lys99Argfs*4(c.296delA) in exon 4; p.Leu762Cysfs*2(c.2283delA) in exon 19; and p.Leu1522Ilefs*53(c.4562_4563dupAT) in exon 34.\nCONCLUSION: Novel pathogenic variants in the NF1 gene in these families correlated with the phenotype and genotype and explained the clinical manifestations of these patients. The results help us to understand the genetic basis of patients with neurofibromatosis type 1 in China. Our study expands the pathogenic variant spectrum of the NF1 gene and may be helpful in genetic counseling and prenatal genetic diagnosis.","variants":[{"Name":"NM_001042492.3(NF1):c.2125T>C (p.Cys709Arg)","Chromosome":"17","Start":"31226558","Stop":"31226558","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":420783,"rule_based_match":true,"evidence_text":"p.Cys709Arg(c.2125T>C)","llm_judgment":"PRESENT","evidence":"p.Cys709Arg(c.2125T>C)","abstract_start":845,"abstract_end":867}]}
{"pmid":"34828315","title":"A Long Contiguous Stretch of Homozygosity Disclosed a Novel","abstract":"Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years of age. Most cases are apparently sporadic, but about 10-15% have an affected first-degree relative, indicating a genetic etiology. Pathogenic variations in genes involved in development, meiosis and hormonal signaling have been detected in the hereditary form of the disorder. However, most cases of POI remain unsolved even after exhaustive investigation. A 19-year-old Senegalese female affected by non-syndromic POI presented with primary amenorrhoea and answered well to the hormonal induction of puberty. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) was identified on chromosome 7q21.13-q22.1 where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in <i>STAG3</i>. Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as the cause of POI in only eight families and recently as the cause of infertility in a male. The here-identified mutation leads to the truncation of the last 55 amino acids, confirming the important role in meiosis of the <i>STAG3</i> C-terminal domain.","variants":[{"Name":"NM_001282717.2(STAG3):c.3381_3384del (p.Glu1128fs)","Chromosome":"7","Start":"100211152","Stop":"100211155","ReferenceAlleleVCF":"GAAGA","AlternateAlleleVCF":"G","allel_id":1319616,"rule_based_match":true,"evidence_text":"c.3381_3384delAGAA","llm_judgment":"PRESENT","evidence":"c.3381_3384delAGAA","abstract_start":975,"abstract_end":993}]}
{"pmid":"34339548","title":"Spectrum mutations of PRF1, UNC13D, STX11, and STXBP2 genes in Vietnamese patients with hemophagocytic lymphohistiocytosis.","abstract":"INTRODUCTION: The prevalence of gene mutations in hemophagocytic lymphohistiocytosis (HLH) varied between studies. Thus far, data on the genetic background of HLH in Vietnamese patients are limited.\nMETHODS: We recruited 94 HLH patients and analyzed for the 4 genes using Sanger sequencing technology.\nRESULTS: Pathogenic variants were observed in 36 (38.29%) patients, including 27 in UNC13D, 5 in STXBP2, 3 in PRF1, and 2 in STX11 (one patient with digenic variants in both UNC13D and STX11). Monoallelic variants accounted for 77.8% of all cases with mutation. A total of 23 different types of pathogenic variants were documented in the 4 genes tested, including 15 in UNC13D, 3 in PRF1, 3 in STXBP2, and 2 in STX11. Interestingly, the novel splicing variant c.3151G>A in UNC13D was recurrently identified in 8 unrelated patients.\nCONCLUSION: Vietnamese patients with HLH showed a distinct genetic variant spectrum, in which UNC13D is the predominant genetic lesion associated with HLH.","variants":[{"Name":"NM_199242.3(UNC13D):c.3151G>A (p.Gly1051Arg)","Chromosome":"17","Start":"75828787","Stop":"75828787","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":997936,"rule_based_match":true,"evidence_text":"c.3151G>A","llm_judgment":"PRESENT","evidence":"c.3151G>A","abstract_start":762,"abstract_end":771}]}
{"pmid":"31906877","title":"Identification of a compound heterozygote in LYST gene: a case report on Chediak-Higashi syndrome.","abstract":"BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease caused by loss of function of the lysosomal trafficking regulator protein. The causative gene LYST/CHS1 was cloned and identified in 1996, which showed significant homology to other species such as bovine and mouse. To date, 74 pathogenic or likely pathogenic mutations had been reported.\nCASE PRESENTATION: Here we describe a compound heterozygote in LYST gene, which was identified in a 4-year-old female patient. The patient showed skin hypopigmentation, sensitivity to light, mild splenomegaly and reduction of platelets in clinical examination. Giant intracytoplasmic inclusions were observed in the bone marrow examination, suggesting the diagnosis of CHS. Amplicon sequencing was performed to detect pathogenic mutation in LYST gene. The result was confirmed by two-generation pedigree analysis base on sanger sequencing.\nCONCLUSION: A compound heterozygote in LYST gene, consisting of a missense mutation c.5719A > G and an intron mutation c.4863-4G > A, was identified from the patient by using amplicon sequencing. The missense mutation is reported for the first time. Two-generation pedigree analysis showed these two mutations were inherited from the patient's parents, respectively. Our result demonstrated that amplicon sequencing has great potential for accelerating and improving the diagnosis of rare genetic diseases.","variants":[{"Name":"NM_000081.4(LYST):c.5719A>G (p.Ile1907Val)","Chromosome":"1","Start":"235773907","Stop":"235773907","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":553134,"rule_based_match":true,"evidence_text":"c.5719A > G","llm_judgment":"PRESENT","evidence":"c.5719A > G","abstract_start":994,"abstract_end":1005}]}
{"pmid":"30684953","title":"Limb-girdle muscular dystrophy due to GMPPB mutations: A case report and comprehensive literature review.","abstract":"Mutations in the guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) gene are rare. To date, 72 cases with GMPPB gene mutations have been reported. Herein, we reported a case of a 29-year-old Chinese male presenting with limb-girdle muscular dystrophy (LGMD) who was found to have two heterozygous GMPPB mutations. The patient had a progressive limb weakness for 19 years. His parents and elder brother were healthy. On examination he had a waddling gait and absent tendon reflexes in all four limbs. Electromyography showed myogenic damage. Muscle magnetic resonance imaging (MRI) showed fatty degeneration in the bilateral medial thigh muscles. High-throughput gene panel sequencing revealed that the patient carried compound heterozygous mutations in the GMPPB gene, c.553C>T (p.R185C, maternal inheritance) and c.346C>T (p.P116S, paternal inheritance). This case provides additional information regarding the phenotypic spectrum of GMPPB mutations in the Chinese population.","variants":[{"Name":"NM_021971.4(GMPPB):c.553C>T (p.Arg185Cys)","Chromosome":"3","Start":"49722604","Stop":"49722604","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":75124,"rule_based_match":true,"evidence_text":"c.553C>T (p.R185C, maternal inheritance)","llm_judgment":"PRESENT","evidence":"c.553C>T (p.R185C, maternal inheritance)","abstract_start":790,"abstract_end":830}]}
{"pmid":"27173810","title":"Mutation screening of the TPO gene in a cohort of 192 Chinese patients with congenital hypothyroidism.","abstract":"OBJECTIVES: Defects in the human thyroid peroxidase (TPO) gene are reported to be one of the causes of congenital hypothyroidism (CH) due to dyshormonogenesis. The aim of this study was to examine the TPO mutation spectrum and prevalence among patients with CH in the Guangxi Zhuang Autonomous Region of China and to define the relationships between TPO genotypes and clinical phenotypes.\nMETHODS: Blood samples were collected from 192 patients with CH in the Guangxi Zhuang Autonomous Region, China and genomic DNA was extracted from peripheral blood leucocytes. All exons of the 10 common CH-associated genes including TPO together with their exon-intron boundaries were screened by next-generation sequencing (NGS). The effect of the novel TPO mutation was investigated by 'in silico' studies.\nRESULTS: NGS analysis of TPO in 192 patients with CH revealed 3 different variations in 2 individuals (2/192, 1%). Sequencing other CH candidate genes in the patients with TPO variants revealed that patient 1 was homozygous for c.2422delT TPO mutation combined with double heterozygous DUOX2 pathogenic variants (p.R683L/p.L1343F) and patient 2 was triallelic for TPO pathogenic variants (p.R648Q/p.T561M/p.T561M). The present study identified a novel TPO variation c.1682C>T/p.T561M; and four known mutations: c.2422delT/p.C808Afs×24 and c.1943C>T/p.R648Q in TPO, c.2048G>T/p.R683L and c.4027C>T/p.L1343F in DUOX2.\nCONCLUSIONS: Our study indicated that the prevalence of TPO mutations was 1% among studied Chinese patients with CH. More than two variations in one or more CH-associated genes can be found in a single patient, and may, in combination, affect the phenotype of the individual. A novel TPO variation c.1682C>T/p.T561M was found, thereby expanding the mutational spectrum of the gene.","variants":[{"Name":"NM_001206744.2(TPO):c.1682C>T (p.Thr561Met)","Chromosome":"2","Start":"1487905","Stop":"1487905","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2898461,"rule_based_match":true,"evidence_text":"c.1682C>T/p.T561M","llm_judgment":"PRESENT","evidence":"c.1682C>T/p.T561M","abstract_start":1263,"abstract_end":1280}]}
{"pmid":"34747535","title":"Targeted massively parallel sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas: An analysis of 51 individuals in a single-center experience.","abstract":"Constitutional LZTR1 or SMARCB1 pathogenic variants (PVs) have been found in ∼86% of familial and ∼40% of sporadic schwannomatosis cases. Hence, we performed massively parallel sequencing of the entire LZTR1, SMARCB1, and NF2 genomic loci in 35 individuals with schwannomas negative for constitutional first-hit PVs in the LZTR1/SMARCB1/NF2 coding sequences; however, with 22q deletion and/or a different NF2 PV in each tumor, including six cases with only one tumor available. Furthermore, we verified whether any other LZTR1/SMARCB1/NF2 (likely) PVs could be found in 16 cases carrying a SMARCB1 constitutional variant in the 3'-untranslated region (3'-UTR) c.*17C>T, c.*70C>T, or c.*82C>T. As no additional variants were found, functional studies were performed to clarify the effect of these 3'-UTR variants on the transcript. The 3'-UTR variants c.*17C>T and c.*82C>T showed pathogenicity by negatively affecting the SMARCB1 transcript level. Two novel deep intronic SMARCB1 variants, c.500+883T>G and c.500+887G>A, resulting in out-of-frame missplicing of intron 4, were identified in two unrelated individuals. Further resequencing of the entire repeat-masked genomics sequences of chromosome 22q in individuals negative for PVs in the SMARCB1/LZTR1/NF2 coding- and noncoding regions revealed five potential schwannomatosis-predisposing candidate genes, that is, MYO18B, NEFH, SGSM1, SGSM3, and SBF1, pending further verification.","variants":[{"Name":"NM_003073.5(SMARCB1):c.*82C>T","Chromosome":"22","Start":"23834262","Stop":"23834262","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":243654,"rule_based_match":true,"evidence_text":"c.*82C>T","llm_judgment":"PRESENT","evidence":"c.*82C>T","abstract_start":683,"abstract_end":691}]}
{"pmid":"34923510","title":"PREDICTED PROTEIN STRUCTURE VARIATIONS INDICATE THE CLINICAL PRESENTATION OF CYP4V2-RELATED BIETTI CRYSTALLINE DYSTROPHY.","abstract":"PURPOSE: To investigate the relationship between different CYP4V2 disease-causing variants and disease severity in Bietti crystalline dystrophy (BCD).\nMETHODS: Twenty-one subjects from 19 unrelated families with a clinical diagnosis of BCD were enrolled. A novel severity prediction score for BCD based on the predicted molecular impact of CYP4V2 variants was applied for grouping and subsequent analyses. The more severe variants led to less CYP4V2 protein function preservation and a higher severity prediction score.\nRESULTS: All subjects harbored two alleles of CYP4V2 disease-causing variants, of which c.802-8_810del17insGC was the most prevalent (14/21, 66.67%) and c.1507G>C was novel. According to the severity score, the subjects were categorized into severe, moderate, and mild groups with different preservation of central vision (mean logMAR visual acuity 0.95 ± 0.82, 0.89 ± 1.22, and 0.56 ± 0.64, respectively). The patients with a lower severity score had slower disease progression.\nCONCLUSION: This is the first cohort study of BCD in Taiwan, and we established a novel BCD severity index based on the molecular impact of different CYP4V2 variants. More severe impairment of CYP4V2 protein led to a more severe disease course with earlier progression. Our results could be helpful in identifying a therapeutic window for patients with BCD.","variants":[{"Name":"NM_207352.4(CYP4V2):c.1507G>C (p.Gly503Arg)","Chromosome":"4","Start":"186210570","Stop":"186210570","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3169474,"rule_based_match":true,"evidence_text":"c.1507G>C","llm_judgment":"PRESENT","evidence":"c.1507G>C","abstract_start":673,"abstract_end":682}]}
{"pmid":"31470098","title":"Novel missense variant in TTN cosegregating with familial atrioventricular block.","abstract":"BACKGROUND: Cardiovascular diseases are the most common cause of death globally. In which atrioventricular block (AVB) is a common disorder with genetic causes, but the responsible genes have not been fully identified yet. To determine the underlying causative genes involved in cardiac AVB, here we report a three-generation Chinese family with severe autosomal dominant cardiac AVB that has been ruled out as being caused by known genes mutations.\nMETHODS: Whole-exome sequencing was performed in five affected family members across three generations, and co-segregation analysis was validated on other members of this family.\nRESULTS: Whole-exome sequencing and subsequent co-segregation validation identified a novel germline heterozygous point missense mutation, c.49287C > A (p.N16429K), in the titin (TTN, NM_001267550.2) gene in all 5 affected family members but not in the unaffected family members, neither in the large population according to the Genome Aggregation Database (https://gnomad.broadinstitute.org/). The point mutation is predicted to be functionally deleterious by in-silico software tools. Our finding was further supported by the conservative analysis across species.\nCONCLUSION: Based on this study, TTN was identified as a potential novel candidate gene for autosomal dominant AVB; this study expands the mutational spectrum of TTN gene and is the first to implicate TTN mutations as AVB disease causing in a Chinese pedigree.","variants":[{"Name":"NM_001267550.2(TTN):c.49287C>A (p.Asn16429Lys)","Chromosome":"2","Start":"178614110","Stop":"178614110","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":622741,"rule_based_match":true,"evidence_text":"c.49287C > A (p.N16429K)","llm_judgment":"PRESENT","evidence":"c.49287C > A (p.N16429K)","abstract_start":768,"abstract_end":792}]}
{"pmid":"29160035","title":"Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay.","abstract":"Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β-galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.","variants":[{"Name":"NM_000404.4(GLB1):c.75+2dup","Chromosome":"3","Start":"33097008","Stop":"33097009","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":15975,"rule_based_match":true,"evidence_text":"c.75+2dupT","llm_judgment":"PRESENT","evidence":"c.75+2dupT","abstract_start":927,"abstract_end":937}]}
{"pmid":"30622725","title":"Novel neuroblastoma amplified sequence (","abstract":"Biallelic mutations in the neuroblastoma amplified sequence (<i>NBAS</i>) gene have been reported to cause two different clinical spectra: short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome and infantile liver failure syndrome 2 (ILFS2). Here, we describe a case of a 3-year-old Japanese boy who presented with fever-triggered recurrent acute liver failure (ALF). The clinical characteristics were considerable elevation of liver enzymes, severe coagulopathy, and acute renal failure. In addition to the liver phenotype, he had short stature and Pelger-Huët anomaly in the peripheral granulocytes. Whole-exome and Sanger sequencing of the patient and his parents revealed that he carried novel compound heterozygous missense mutations in <i>NBAS</i>, c.1018G>C (p.Gly340Arg) and c.2674 G>T (p.Val892Phe). Both mutations affect evolutionarily conserved amino acid residues and are predicted to be highly damaging. Immunoblot analysis of the patient's skin fibroblasts showed a normal NBAS protein level but a reduced protein level of its interaction partner, p31, involved in Golgi-to-endoplasmic reticulum retrograde vesicular trafficking. We recommend <i>NBAS</i> gene analysis in children with unexplained fever-triggered recurrent ALF or liver dysfunction. Early antipyretic therapy may prevent further episodes of ALF.","variants":[{"Name":"NM_015909.4(NBAS):c.2674G>T (p.Val892Phe)","Chromosome":"2","Start":"15417616","Stop":"15417616","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3494721,"rule_based_match":true,"evidence_text":"c.2674 G>T (p.Val892Phe)","llm_judgment":"PRESENT","evidence":"c.2674 G>T (p.Val892Phe)","abstract_start":807,"abstract_end":831}]}
{"pmid":"20836999","title":"Two inborn errors of metabolism in a newborn: glutaric aciduria type I combined with isobutyrylglycinuria.","abstract":"BACKGROUND: Glutaric aciduria type 1 (GA1) is an inborn error in the metabolism of the amino acids tryptophan, lysine and hydroxylysine due to mutations in the GCDH gene coding for glutaryl-CoA dehydrogenase. Affected individuals often suffer from an encephalopathic crisis in infancy or childhood which results in acute striatal injury leading to a severe dystonic-dyskinetic movement disorder. Isobutyryl-coenzyme dehydrogenase (IBD) is an enzyme encoded by the ACAD8 gene and involved in the catabolism of the branched-chain amino acid valine. Both GA1 and IBD deficiency can be detected by expanded newborn screening using tandem-mass spectrometry, if they are considered screening targets.\nMETHODS: Tandem-mass spectrometry and gas-chromatography with mass-selective detection were used for the assessment of key metabolites in body fluids of a patient with abnormal findings in newborn screening. Mutations were investigated by direct sequencing and by restriction fragment lengths analysis. Valine metabolism was studied in vitro in immortalized lymphocytes.\nRESULTS: Following accumulation of acylcarnitines C5DC and C4, of 3-hydroxyglutaric acid and isobutyrylglycine in body fluids, sequence analysis in the GCDH gene revealed homozygosity for a missense mutation in exon 6, c.482G>A, p.Arg161Gln, which had been reported in GA1 before. In the ACAD8 gene a novel mutation c.841+3G>C was identified, which results in loss of exon 7 and predicts a premature stop of translation. Impaired valine degradation was corroborated by the increased post-load level of acylcarnitine C4 in lymphocytes.\nCONCLUSION: The molecular basis of two inborn errors of metabolism in a newborn was elucidated. The metabolite studies underline the use of urinary C4 acylcarnitine as a sensitive marker of IBD deficiency. A functional test of IBD activity in lymphocytes may replace more invasive fibroblast studies. In view of the combination of two organic acidurias, which may both affect the level of free carnitine, careful follow-up including regular assessment of the carnitine status of the patient appears prudent.","variants":[{"Name":"NM_000159.4(GCDH):c.482G>A (p.Arg161Gln)","Chromosome":"19","Start":"12893630","Stop":"12893630","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187039,"rule_based_match":true,"evidence_text":"c.482G>A, p.Arg161Gln","llm_judgment":"PRESENT","evidence":"c.482G>A, p.Arg161Gln","abstract_start":1285,"abstract_end":1306}]}
{"pmid":"31127728","title":"Late onset CMT2A in a Family with an MFN2 Variant: c.2222T>G (p.Leu741Trp).","abstract":"Mutations in MFN2 cause a range of Charcot-Marie-Tooth disease (CMT) phenotypes with different inheritance patterns and underlying pathogenic mechanisms. Recently, a family with a dominantly inherited CMT harboring c.2222T>G (p.Leu741Trp) mutation in MFN2 has been reported for the first time. Here, we report a second family also with a dominantly inherited CMT harboring the same mutation, thereby confirming the pathogenicity of this mutation. Interestingly, the disease onset of this second family is much later than the previously reported cases.","variants":[{"Name":"NM_014874.4(MFN2):c.2222T>G (p.Leu741Trp)","Chromosome":"1","Start":"12011513","Stop":"12011513","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":447073,"rule_based_match":true,"evidence_text":"c.2222T>G (p.Leu741Trp)","llm_judgment":"PRESENT","evidence":"c.2222T>G (p.Leu741Trp)","abstract_start":215,"abstract_end":238}]}
{"pmid":"23891471","title":"Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia.","abstract":"Primary ciliary dyskinesia (PCD) is a ciliopathy characterized by airway disease, infertility, and laterality defects, often caused by dual loss of the inner dynein arms (IDAs) and outer dynein arms (ODAs), which power cilia and flagella beating. Using whole-exome and candidate-gene Sanger resequencing in PCD-affected families afflicted with combined IDA and ODA defects, we found that 6/38 (16%) carried biallelic mutations in the conserved zinc-finger gene BLU (ZMYND10). ZMYND10 mutations conferred dynein-arm loss seen at the ultrastructural and immunofluorescence level and complete cilia immotility, except in hypomorphic p.Val16Gly (c.47T>G) homozygote individuals, whose cilia retained a stiff and slowed beat. In mice, Zmynd10 mRNA is restricted to regions containing motile cilia. In a Drosophila model of PCD, Zmynd10 is exclusively expressed in cells with motile cilia: chordotonal sensory neurons and sperm. In these cells, P-element-mediated gene silencing caused IDA and ODA defects, proprioception deficits, and sterility due to immotile sperm. Drosophila Zmynd10 with an equivalent c.47T>G (p.Val16Gly) missense change rescued mutant male sterility less than the wild-type did. Tagged Drosophila ZMYND10 is localized primarily to the cytoplasm, and human ZMYND10 interacts with LRRC6, another cytoplasmically localized protein altered in PCD. Using a fly model of PCD, we conclude that ZMYND10 is a cytoplasmic protein required for IDA and ODA assembly and that its variants cause ciliary dysmotility and PCD with laterality defects.","variants":[{"Name":"NM_015896.4(ZMYND10):c.47T>G (p.Val16Gly)","Chromosome":"3","Start":"50345533","Stop":"50345533","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":76931,"rule_based_match":true,"evidence_text":"c.47T>G (p.Val16Gly)","llm_judgment":"PRESENT","evidence":"c.47T>G (p.Val16Gly)","abstract_start":1101,"abstract_end":1121}]}
{"pmid":"31053406","title":"Recessive mutations in proximal I-band of TTN gene cause severe congenital multi-minicore disease without cardiac involvement.","abstract":"Titin, encoded by the gene TTN, is one of the main sarcomere components. It is involved in not only maintaining the structure of cardiac and skeletal muscles, but also in their development, extensibility, elasticity, and signaling events. Congenital titinopathy increasingly appears an important and common form of axial predominant congenital myopathy. The pathophysiological role of TTN in congenital titinopathy and pediatric heart diseases is yet to be explored. Here, we delineate the phenotype of two female siblings who developed severe congenital multi-minicore disease without cardiac involvement. Genetic investigation by whole exome sequencing demonstrated compound heterozygous TTN mutations (c.15496+1G>A, p.5166_5258del; c.18597_18598insC, p.Thr6200Hisfs*15), corresponding to the Ig domain of the proximal I-band. Aberrant splicing causing exon skipping was verified by in vitro minigene analysis. Our results suggest that TTN mutations affecting the Ig domain of the proximal I-band may be a cause of severe congenital defect in skeletal muscles without severe cardiac involvement, thereby providing evidence for the hypothesis that congenital titinopathy patients carrying biallelic N2BA only mutations are at lower cardiac risk than those with other combinations of mutations. Meanwhile, this study confirm the hypothesis on recessive truncating variants of TTN experimentally and thus support earlier reported genotype-phenotype correlations.","variants":[{"Name":"NM_001267550.2(TTN):c.15496+1G>A","Chromosome":"2","Start":"178734327","Stop":"178734327","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":55766,"rule_based_match":true,"evidence_text":"c.15496+1G>A","llm_judgment":"PRESENT","evidence":"c.15496+1G>A","abstract_start":705,"abstract_end":717}]}
{"pmid":"31483760","title":"Whole exome sequencing identified a heterozygous KCNJ2 missense variant underlying autosomal dominant familial hypokalemic periodic paralysis in a Pakistani family.","abstract":"Background Familial hypokalemic periodi9c paralysis (hypoKPP) is a rare autosomal dominant disorder characterized by episodic paralytic attacks caused by fall in blood potassium. CACNA1S, SCN4A or KCNJ2 variants can cause hypoKPP. Case presentation We investigated a Pakistani family affected with autosomal dominant familial hypoKPP through whole exome sequencing (WES). A heterozygous KCNJ2 missense variant c.919A > G was found segregating with the disease phenotype in the family. Conclusions The KCNJ2 missense variant is the likely cause of the disorder in the affected family. The finding should help improve antenatal screening and genetic counselling of this family.","variants":[{"Name":"NM_000891.3(KCNJ2):c.919A>G (p.Met307Val)","Chromosome":"17","Start":"70175958","Stop":"70175958","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":510757,"rule_based_match":true,"evidence_text":"c.919A > G","llm_judgment":"PRESENT","evidence":"c.919A > G","abstract_start":410,"abstract_end":420}]}
{"pmid":"33719663","title":"Novel","abstract":"Hereditary gingival fibromatosis (HGF) is a rare genetic disorder featured by nonsyndromic pathological overgrowth of gingiva. The excessive gingival tissues can cause dental, masticatory, and phonetic problems, which impose severe functional and esthetic burdens on affected individuals. Due to its high recurrent rate, patients with HGF have to undergo repeated surgical procedures of gingival resection, from childhood to adulthood, which significantly compromises their quality of life. Unraveling the genetic etiology and molecular pathogenesis of HGF not only gains insight into gingival physiology and homeostasis but also opens avenues for developing potential therapeutic strategies for this disorder. Recently, mutations in <i>REST</i> (OMIM *600571), encoding a transcription repressor, were reported to cause HGF (GINGF5; OMIM #617626) in 3 Turkish families. However, the functions of REST in gingival homeostasis and pathogenesis of <i>REST</i>-associated HGF remain largely unknown. In this study, we characterized 2 HGF families and identified 2 novel <i>REST</i> mutations, c.2449C>T (p.Arg817*) and c.2771_2793dup (p.Glu932Lysfs*3). All 5 mutations reported to date are nonsenses or frameshifts in the last exon of <i>REST</i> and would presumably truncate the protein. In vitro reporter gene assays demonstrated a partial or complete loss of repressor activity for these truncated RESTs. When coexpressed with the full-length protein, the truncated RESTs impaired the repressive ability of wild-type REST, suggesting a dominant negative effect. Immunofluorescent studies showed nuclear localization of overexpressed wild-type and truncated RESTs in vitro, indicating preservation of the nuclear localization signal in shortened proteins. Immunohistochemistry demonstrated a comparable pattern of ubiquitous REST expression in both epithelium and lamina propria of normal and HGF gingival tissues despite a reduced reactivity in HGF gingiva. Results of this study confirm the pathogenicity of <i>REST</i> truncation mutations occurring in the last exon causing HGF and suggest the pathosis is caused by an antimorphic (dominant negative) disease mechanism.","variants":[{"Name":"NM_005612.5(REST):c.2449C>T (p.Arg817Ter)","Chromosome":"4","Start":"56931307","Stop":"56931307","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1179037,"rule_based_match":true,"evidence_text":"c.2449C>T (p.Arg817*)","llm_judgment":"PRESENT","evidence":"c.2449C>T (p.Arg817*)","abstract_start":1090,"abstract_end":1111}]}
{"pmid":"35218564","title":"Phenotypic spectrum of BLM- and RMI1-related Bloom syndrome.","abstract":"Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative pathogenic variants in all families including three different variants in BLM and one variant in RMI1. The homozygous c.581_582delTT;p.Phe194* and c.3164G>C;p.Cys1055Ser variants in BLM have already been reported in BS patients, while the c.572_573delGA;p.Arg191Lysfs*4 variant is novel. Additionally, we present the detailed clinical characteristics of two cases with BS in which we previously identified the biallelic loss-of-function variant c.1255_1259delAAGAA;p.Lys419Leufs*5 in RMI1. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, skin lesions and upper airway infections were observed only in some of the patients. Overall, patients with pathogenic BLM variants had a more severe BS phenotype compared to patients carrying the pathogenic variants in RMI1, especially in terms of immunodeficiency, which should be considered as one of the most important phenotypic characteristics of BS.","variants":[{"Name":"NM_000057.4(BLM):c.3164G>C (p.Cys1055Ser)","Chromosome":"15","Start":"90794311","Stop":"90794311","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":51244,"rule_based_match":true,"evidence_text":"c.3164G>C;p.Cys1055Ser","llm_judgment":"PRESENT","evidence":"c.3164G>C;p.Cys1055Ser","abstract_start":460,"abstract_end":482}]}
{"pmid":"28757749","title":"Successful treatment of a newborn with congenital hyperinsulinism having a novel heterozygous mutation in the","abstract":"Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in newborns and infants. CHI is characterized by unregulated secretion of insulin from pancreatic β: cells. Here, we reported the case of a large-for-gestational-age, full-term newborn that suffered from CHI and developed severe and persistent hypoglycemia at an early stage of life. The infant was nearly unresponsive to medical treatment, which included continuous intravenous glucagon infusion, oral diazoxide, and nifedipine. After medical treatment had failed, an 18-fluoro L-3,4-dihydroxyphenylalanine positron emission tomography scan of the patient showed a focal lesion at the neck of the pancreas. The patient received subtotal pancreatectomy, and shortly after the procedure, the patient's blood sugar returned to the normal range. The patient was confirmed to have a novel heterozygous mutation at position c.2475+1G>A of the <i>ABCC8</i> gene. This is the first report of a focal form of CHI in a patient in Taiwan, which had preoperatively been confirmed using 18-fluoro L-3,4-dihydroxyphenylalanine positron emission tomography.","variants":[{"Name":"NM_000352.6(ABCC8):c.2475+1G>A","Chromosome":"11","Start":"17413393","Stop":"17413393","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1055995,"rule_based_match":true,"evidence_text":"c.2475+1G>A","llm_judgment":"PRESENT","evidence":"c.2475+1G>A","abstract_start":904,"abstract_end":915}]}
{"pmid":"30528883","title":"Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment in two unrelated patients.","abstract":"CLN6 is a transmembrane protein located in the endoplasmic reticulum that is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis (LINCL), and teenage and adult onset NCL without visual impairment. Here we describe two pediatric patients with LINCL from unrelated families who were evaluated at the National Institutes of Health. Both children exhibited typical phenotypes associated with LINCL except that they lacked the expected visual impairment. Whole exome sequencing identified novel biallelic mutations in CLN6, i.e., c.218-220dupGGT (p.Trp73dup) and c.296A > G (p.Lys99Arg) in Proband 1 and homozygous c.723G > T (p.Met241Ile) in Proband 2. Expression analysis in dermal fibroblasts showed a small increase in CLN6 protein levels. Electron micrographs of these fibroblasts demonstrated large numbers of small membrane-bound vesicles, in addition to lipofuscin deposits. LysoTracker™ Red intensity was increased in fibroblasts from both patients. This study supports a role for CLN6 in lysosomal homeostasis, and highlights the importance of considering CLN6 mutations in the diagnosis of Batten Disease even in patients with normal vision.","variants":[{"Name":"NM_017882.3(CLN6):c.723G>T (p.Met241Ile)","Chromosome":"15","Start":"68208353","Stop":"68208353","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1017967,"rule_based_match":true,"evidence_text":"c.723G > T (p.Met241Ile)","llm_judgment":"PRESENT","evidence":"c.723G > T (p.Met241Ile)","abstract_start":665,"abstract_end":689},{"Name":"NM_017882.3(CLN6):c.218_220dup (p.Trp73dup)","Chromosome":"15","Start":"68214366","Stop":"68214367","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AACC","allel_id":1174643,"rule_based_match":false,"evidence_text":"c.218-220dupGGT (p.Trp73dup)","llm_judgment":"PRESENT","evidence":"c.218-220dupGGT (p.Trp73dup)","abstract_start":580,"abstract_end":608},{"Name":"NM_017882.3(CLN6):c.296A>G (p.Lys99Arg)","Chromosome":"15","Start":"68214291","Stop":"68214291","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1174644,"rule_based_match":true,"evidence_text":"c.296A > G (p.Lys99Arg)","llm_judgment":"PRESENT","evidence":"c.296A > G (p.Lys99Arg)","abstract_start":613,"abstract_end":636}]}
{"pmid":"15108282","title":"Genetic characterization of myeloperoxidase deficiency in Italy.","abstract":"Hereditary myeloperoxidase (MPO) deficiency (MPOD) is the most common neutrophil biochemical defect, and is characterized by a lack of peroxidase activity. In order to extend the epidemiological studies on hereditary MPOD in Italy, a population screening was carried out to detect mutations in the MPO gene. Of approximately 40,000 individuals analyzed, seven partial and eight total MPO-deficient subjects were identified. The genetic characterization of the subjects showed the presence of three already-known mutations (c.752T>C, c.1705C>T, and c.1566_1579del14) and six novel mutations: four missense mutations (c.995C>T, c.1112A>G, c.1715T>G, and c.1927T>C), then a deletion of an adenine within exon 3 (c.325delA) and a mutation within the 3' splice site of intron 11 (c.2031-2A>C). The novel missense mutations cause the substitution of the residues p.A332V, p.D371G, p.L572W, and p.W643R, respectively, and the potential structural changes are discussed. The c.325delA deletion causes a shift of the reading frame with the occurrence of a premature stop codon within the propeptide. Then, considering the difficulty in obtaining bone marrow samples from MPO-deficient subjects to study MPO mRNA splicing in vivo, we set up an eukaryotic expression system to investigate how the c.2031-2A>C mutation alters the MPO pre-mRNA splicing. The activation of a cryptic 3' splice site located 109nt upstream of the authentic 3' splice site was observed. The 109nt-insertion causes a shift in the reading frame that should lead to the generation of an abnormal MPO precursor lacking the enzymatic activity.","variants":[{"Name":"NM_000250.2(MPO):c.1705C>T (p.Arg569Trp)","Chromosome":"17","Start":"58272835","Stop":"58272835","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18665,"rule_based_match":true,"evidence_text":"c.1705C>T","llm_judgment":"PRESENT","evidence":"c.1705C>T","abstract_start":533,"abstract_end":542},{"Name":"NM_000250.2(MPO):c.995C>T (p.Ala332Val)","Chromosome":"17","Start":"58278036","Stop":"58278036","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18669,"rule_based_match":true,"evidence_text":"c.995C>T","llm_judgment":"PRESENT","evidence":"c.995C>T","abstract_start":616,"abstract_end":624},{"Name":"NM_000250.2(MPO):c.1715T>G (p.Leu572Trp)","Chromosome":"17","Start":"58272825","Stop":"58272825","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":18670,"rule_based_match":true,"evidence_text":"c.1715T>G","llm_judgment":"PRESENT","evidence":"c.1715T>G","abstract_start":637,"abstract_end":646},{"Name":"NM_000250.2(MPO):c.2031-2A>C","Chromosome":"17","Start":"58270865","Stop":"58270865","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":18671,"rule_based_match":true,"evidence_text":"c.2031-2A>C","llm_judgment":"PRESENT","evidence":"c.2031-2A>C","abstract_start":775,"abstract_end":786}]}
{"pmid":"32939435","title":"Multisystem Progeroid Syndrome With Lipodystrophy, Cardiomyopathy, and Nephropathy Due to an","abstract":"BACKGROUND: Pathogenic variants in lamin A/C (<i>LMNA</i>) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous <i>LMNA</i> c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome.\nMETHODS: We report 6 new patients with a heterozygous <i>LMNA</i> p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations.\nRESULTS: Of the total 17 patients, all 14 adults with the heterozygous <i>LMNA</i> p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts.\nCONCLUSIONS: The heterozygous <i>LMNA</i> p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.","variants":[{"Name":"NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)","Chromosome":"1","Start":"156136009","Stop":"156136009","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77659,"rule_based_match":true,"evidence_text":"NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)","llm_judgment":"PRESENT","evidence":"c.1045C>T","abstract_start":283,"abstract_end":292}]}
{"pmid":"26946079","title":"Combination of two different homozygote mutations in Pompe disease.","abstract":"Pompe disease (OMIM no 232300) is an autosomal recessive inherited metabolic disorder, caused by glycogen accumulation in the lysosome due to deficiency of the lysosomal acid 03B1-glucosidase enzyme. Here we report the case of an 8-month-old girl of consanguineous Turkish parents, who was diagnosed with the infantile form of Pompe disease. Two different uncommon homozygote mutations (c.32-13 T > G homozygote and c.1856G > A homozygote) were detected. The patient had a more progressive clinical course than expected. We emphasize the rare combination of genetic mutations in this Turkish family with Pompe disease.","variants":[{"Name":"NM_000152.5(GAA):c.1856G>A (p.Ser619Asn)","Chromosome":"17","Start":"80112679","Stop":"80112679","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":358508,"rule_based_match":true,"evidence_text":"c.1856G > A homozygote","llm_judgment":"PRESENT","evidence":"c.1856G > A homozygote","abstract_start":416,"abstract_end":438}]}
{"pmid":"16037974","title":"Mutations in phenotypically mild D-2-hydroxyglutaric aciduria.","abstract":"D-2-hydroxyglutaric aciduria is a neurometabolic disorder with mild and severe phenotypes. Recently, we reported pathogenic mutations in the D-2-hydroxyglutarate dehydrogenase gene as the cause of the severe phenotype of D-2-hydroxyglutaric aciduria in two patients. Here, we report two novel pathogenic mutations in this gene in one patient with a mild presentation and two asymptomatic siblings with D-2-hydroxyglutaric aciduria from two unrelated consanguineous Palestinian families: a splice error (IVS4-2A-->G) and a missense mutation (c.1315A-->G;p.Asn439Asp). Overexpression of this mutant protein showed marked reduction of the enzyme activity.","variants":[{"Name":"NM_152783.5(D2HGDH):c.1315A>G (p.Asn439Asp)","Chromosome":"2","Start":"241767718","Stop":"241767718","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":16895,"rule_based_match":false,"evidence_text":"c.1315A-->G;p.Asn439Asp","llm_judgment":"PRESENT","evidence":"c.1315A-->G;p.Asn439Asp","abstract_start":541,"abstract_end":564}]}
{"pmid":"27908631","title":"Confirmation of the GNB4 gene as causal for Charcot-Marie-Tooth disease by a novel de novo mutation in a Czech patient.","abstract":"The association of GNB4 with Charcot-Marie-Tooth (CMT) has recently been described in a publication by Soong et al. (Soong, et al., 2013). Here we present a patient with CMT in whom whole exome sequencing identified the mutation p.Lys57Glu in the GNB4 gene (NM_021629.3:c.169A>G). The patient, now 41 years old, is a sporadic case in the family. At the age of 35 he presented with severe disability (CMT neuropathy score 29), profound muscle atrophies, pes cavus and scoliosis. Previously, the patient was tested for PMP22 duplications/deletions and later also with 64 CMT gene panel, with no causal variant found. Subsequently, whole exome sequencing was performed. The p.Lys57Glu in the GNB4 gene was identified as the most probable causal variant, the mutation is not present in the patient's parents, neither in his unaffected sister, therefore we assume that the mutation arose de novo. Taken together, these findings support the causal and pathogenic character of the variant. Our report provides important evidence that GNB4 should become an established CMT gene and our findings confirm the original publication by Soong et al. (2013).","variants":[{"Name":"NM_021629.4(GNB4):c.169A>G (p.Lys57Glu)","Chromosome":"3","Start":"179419433","Stop":"179419433","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":827739,"rule_based_match":true,"evidence_text":"NM_021629.3:c.169A>G","llm_judgment":"PRESENT","evidence":"NM_021629.3:c.169A>G","abstract_start":258,"abstract_end":278}]}
{"pmid":"19935827","title":"Modulation of aberrant NF1 pre-mRNA splicing by kinetin treatment.","abstract":"Neurofibromatosis type 1 is one of the most common neurocutaneous autosomal dominant disorders. It is caused by mutations in the neurofibromatosis type 1 (NF1) gene and approximately 30-40% of them affect the correct splicing of NF1 pre-mRNA. In this report, we evaluate the effect of five different drugs, previously found to modify splicing in several genetic disorders, on the splicing of mutated NF1 alleles. For this purpose, cell lines derived from patients bearing 19 different NF1-splicing defects were used. Our results showed that kinetin partially corrects the splicing defect in four of the studied mutations (c.910C>T, c.3113G>A, c.6724C>T and c.6791dupA). Our study is a valuable contribution to the field because it identifies new exon-skipping events that can be reversed by kinetin treatment and provides new information about kinetin splicing modulation. However, owing to the nature of mutations in our patients, kinetin treatment could not be used as a therapeutic agent in these cases.","variants":[{"Name":"NM_001042492.3(NF1):c.910C>T (p.Arg304Ter)","Chromosome":"17","Start":"31200443","Stop":"31200443","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":184531,"rule_based_match":true,"evidence_text":"c.910C>T","llm_judgment":"PRESENT","evidence":"c.910C>T","abstract_start":622,"abstract_end":630}]}
{"pmid":"24772942","title":"Identification of a GJA3 mutation in a Chinese family with congenital nuclear cataract using exome sequencing.","abstract":"Congenital cataract, a clinically and genetically heterogeneous lens disorder is defined as any opacity of the lens presented from birth and is responsible for approximately 10% of worldwide childhood poor vision or blindness. To identify the genetic defect responsible for congenital nuclear cataract in a four-generation Chinese Han family, exome and direct Sanger sequencings were conducted and a missense variant c.139G>A (p.D47N) in the gap junction protein-alpha 3 gene (GJA3) was identified. The variant co-segregated with patients of the family and was not observed in unaffected family members or normal controls. The above findings indicated that the variant was a pathogenic mutation. The mutation p.D47N was found in the first extracellular loop (El) domain of GJA3 protein. Our data suggest that exome sequencing is a powerful tool to discover mutation(s) in cataract, a disorder with high genetic heterogeneity. Our findings may also provide new insights into the cause and diagnosis of congenital nuclear cataract and have implications for genetic counseling.","variants":[{"Name":"NM_021954.4(GJA3):c.139G>A (p.Asp47Asn)","Chromosome":"13","Start":"20143150","Stop":"20143150","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3412471,"rule_based_match":true,"evidence_text":"c.139G>A (p.D47N)","llm_judgment":"PRESENT","evidence":"c.139G>A (p.D47N)","abstract_start":417,"abstract_end":434}]}
{"pmid":"21134364","title":"High resolution melting analysis for the detection of SLC25A13 gene mutations in Taiwan.","abstract":"BACKGROUND: Citrin, encoded by SLC25A13 gene, is a mitochondrial solute transporter with a crucial role in urea, nucleotide and protein synthesis. SLC25A13 mutations cause two phenotypes, adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). This study aimed to develop a high resolution melting (HRM) analysis for SLC25A13 mutation scanning and determine the carrier rate in Taiwan.\nMETHODS: DNAs from healthy subjects (n=479), and patients with hepatocellular carcinoma (HCC, n=100) and NICCD (n=5) were scanned in exons 6, 9, 11, 16, and 17 and parts of introns of SLC25A13 using HRM analysis. All mutations detected by HRM analysis were further confirmed by TaqMan method and/or direct sequencing.\nRESULTS: In healthy subjects, seventeen carriers with mutants c.851_854del (n=10), c.1638_1660dup, c.615+5G>A (n=4), and two novel mutants, c.475C>T and c.1658G>A, were detected. The frequency of carriers was about 1/28. In patients with HCC, there were only 2 carriers with c.851_854del mutant. Patients with NICCD (n=5) diagnosed during 2007 and 2008, harbored compound heterozygous mutations c.851_854del/c.1177+1G>A, c.851_854del/c.1638_1660dup (n=2), c.851_854del/c.615+5G>A, and c.1638_1660dup/c.615+5G>A.\nCONCLUSIONS: HRM analysis is a simple, rapid and robust method for detecting SLC25A13 mutations in clinical laboratories. SLC25A13 mutations may not be a major contributor to the pathogenesis of HCC in Taiwan.","variants":[{"Name":"NM_014251.3(SLC25A13):c.615+5G>A","Chromosome":"7","Start":"96193032","Stop":"96193032","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34369,"rule_based_match":true,"evidence_text":"c.615+5G>A","llm_judgment":"PRESENT","evidence":"c.615+5G>A","abstract_start":856,"abstract_end":866}]}
{"pmid":"38013626","title":"Biallelic variants in the COQ4 gene caused hereditary spastic paraplegia predominant phenotype.","abstract":"INTRODUCTION: Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by progressive degeneration of upper motor neurons. Homozygous or compound heterozygous variants in COQ4 have been reported to cause primary CoQ10 deficiency-7 (COQ10D7), which is a mitochondrial disease.\nAIMS: We aimed to screened COQ4 variants in a cohort of HSP patients.\nMETHODS: A total of 87 genetically unidentified HSP index patients and their available family members were recruited. Whole exome sequencing (WES) was performed in all probands. Functional studies were performed to identify the pathogenicity of those uncertain significance variants.\nRESULTS: In this study, five different COQ4 variants were identified in three Chinese HSP pedigrees and two variants were novel, c.87dupT (p.Arg30*), c.304C>T (p.Arg102Cys). More importantly, we firstly described two early-onset pure HSP caused by COQ4 variants. Functional studies in patient-derived fibroblast lines revealed a reduction cellular CoQ10 levels and the abnormal mitochondrial structure.\nCONCLUSIONS: Our findings revealed that bilateral variants in the COQ4 gene caused HSP predominant phenotype, expanding the phenotypic spectrum of the COQ4-related disorders.","variants":[{"Name":"NM_016035.5(COQ4):c.87dup (p.Arg30Ter)","Chromosome":"9","Start":"128323031","Stop":"128323032","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":2847058,"rule_based_match":true,"evidence_text":"c.87dupT (p.Arg30*)","llm_judgment":"PRESENT","evidence":"c.87dupT (p.Arg30*)","abstract_start":802,"abstract_end":821},{"Name":"NM_016035.5(COQ4):c.304C>T (p.Arg102Cys)","Chromosome":"9","Start":"128325783","Stop":"128325783","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":622394,"rule_based_match":true,"evidence_text":"c.304C>T (p.Arg102Cys)","llm_judgment":"PRESENT","evidence":"c.304C>T (p.Arg102Cys)","abstract_start":823,"abstract_end":845}]}
{"pmid":"27375351","title":"Targeted next-generation sequencing extends the phenotypic and mutational spectrums for EYS mutations.","abstract":"PURPOSE: We aim to determine genetic lesions with a phenotypic correlation in four Chinese families with autosomal recessive retinitis pigmentosa (RP).\nMETHODS: Medical histories were carefully reviewed. All patients received comprehensive ophthalmic evaluations. The next-generation sequencing (NGS) approach targeting a panel of 205 retinal disease-relevant genes and 15 candidate genes was selectively performed on probands from the four recruited families for mutation detection. Online predictive software and crystal structure modeling were also applied to test the potential pathogenic effects of identified mutations.\nRESULTS: Of the four families, two were diagnosed with RP sino pigmento (RPSP). Patients with RPSP claimed to have earlier RP age of onset but slower disease progression. Five mutations in the eyes shut homolog (EYS) gene, involving two novel (c.7228+1G>A and c.9248G>A) and three recurrent mutations (c.4957dupA, c.6416G>A and c.6557G>A), were found as RP causative in the four families. The missense variant c.5093T>C was determined to be a variant of unknown significance (VUS) due to the variant's colocalization in the same allele with the reported pathogenic mutation c.6416G>A. The two novel variants were further confirmed absent in 100 unrelated healthy controls. Online predictive software indicated potential pathogenicity of the three missense mutations. Further, crystal structural modeling suggested generation of two abnormal hydrogen bonds by the missense mutation p.G2186E (c.6557G>A) and elongation of its neighboring β-sheet induced by p.G3083D (c.9248G>A), which could alter the tertiary structure of the eys protein and thus interrupt its physicochemical properties.\nCONCLUSIONS: Taken together, with the targeted NGS approach, we reveal novel EYS mutations and prove the efficiency of targeted NGS in the genetic diagnoses of RP. We also first report the correlation between EYS mutations and RPSP. The genotypic-phenotypic relationship in all Chinese patients carrying mutations in the EYS gene were also reviewed and summarized.","variants":[{"Name":"NM_001142800.2(EYS):c.6416G>A (p.Cys2139Tyr)","Chromosome":"6","Start":"64230600","Stop":"64230600","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187115,"rule_based_match":true,"evidence_text":"c.6416G>A","llm_judgment":"PRESENT","evidence":"c.6416G>A","abstract_start":940,"abstract_end":949},{"Name":"NM_001142800.2(EYS):c.7228+1G>A","Chromosome":"6","Start":"63864185","Stop":"63864185","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":651630,"rule_based_match":true,"evidence_text":"c.7228+1G>A","llm_judgment":"PRESENT","evidence":"c.7228+1G>A","abstract_start":870,"abstract_end":881},{"Name":"NM_001142800.2(EYS):c.9248G>A (p.Gly3083Asp)","Chromosome":"6","Start":"63720783","Stop":"63720783","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2794803,"rule_based_match":true,"evidence_text":"c.9248G>A","llm_judgment":"PRESENT","evidence":"c.9248G>A","abstract_start":886,"abstract_end":895},{"Name":"NM_001142800.2(EYS):c.4957dup (p.Ser1653fs)","Chromosome":"6","Start":"64590909","Stop":"64590910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":152823,"rule_based_match":true,"evidence_text":"c.4957dupA","llm_judgment":"PRESENT","evidence":"c.4957dupA","abstract_start":928,"abstract_end":938},{"Name":"NM_001142800.2(EYS):c.6557G>A (p.Gly2186Glu)","Chromosome":"6","Start":"64081870","Stop":"64081870","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152826,"rule_based_match":true,"evidence_text":"c.6557G>A","llm_judgment":"PRESENT","evidence":"c.6557G>A","abstract_start":954,"abstract_end":963}]}
{"pmid":"15365988","title":"Molecular and functional analysis of SLC25A20 mutations causing carnitine-acylcarnitine translocase deficiency.","abstract":"The enzyme carnitine-acylcarnitine translocase (CACT) is involved in the transport of long-chain fatty acids into mitochondria. CACT deficiency is a life-threatening, recessively inherited disorder of lipid beta-oxidation which manifests in early infancy with hypoketotic hypoglycemia, cardiomyopathy, liver failure, and muscle weakness. We report here the clinical, biochemical, and molecular features of six CACT-deficient patients from Italy, Spain, and North America who exhibited significant clinical heterogeneity. In five patients (Patients 1, 2, 4, 5, and 6) the disease manifested in the neonatal period, while the remaining patient (Patient 3), the younger sibling of an infant who had died with clinical suspicion of fatty acid oxidation defect, has been treated since birth and was clinically asymptomatic at 4.5 years of age. Patients 1 and 4 were deceased within 6 months from the onset of this study, while the remaining four are still alive at 8, 4.5, 3.5, and 2 years, respectively. Sequence analysis of the CACT gene (SLC25A20) disclosed five novel mutations and three previously reported mutations. Three patients were homozygous for the identified mutations. Two of the novel mutations (c.718+1G>C and c.843+4_843+50del) altered the donor splice site of introns 7 and 8, respectively. The 47-nt deletion in intron 8 caused both skipping of exon 8 only and skipping of exons 6-8. Four mutations [[c.159dupT;c.163delA] ([p.Gly54Trp;p.Thr55Ala]) c.397C>T (p.Arg133Trp), c.691G>C (p.Asp231His), and c.842C>T (p.Ala281Val)] resulted in amino acid substitutions affecting evolutionarily conserved regions of the protein. Interestingly, one of these exonic mutations (p.Ala281Val) was associated with a splicing defect also characterized by skipping of exons 6-8. The deleterious effect of the p.Arg133Trp substitution was demonstrated by measuring CACT activity upon expression of the normal and the mutant protein in E. coli and functional reconstitution into liposomes. Combined analysis of clinical, biochemical, and molecular data failed to indicate a correlation between the phenotype and the genotype.","variants":[{"Name":"NM_000387.6(SLC25A20):c.718+1G>C","Chromosome":"3","Start":"48859091","Stop":"48859091","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2894560,"rule_based_match":true,"evidence_text":"c.718+1G>C","llm_judgment":"PRESENT","evidence":"c.718+1G>C","abstract_start":1207,"abstract_end":1217},{"Name":"NM_000387.6(SLC25A20):c.397C>T (p.Arg133Trp)","Chromosome":"3","Start":"48879378","Stop":"48879378","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":920488,"rule_based_match":true,"evidence_text":"c.397C>T (p.Arg133Trp)","llm_judgment":"PRESENT","evidence":"c.397C>T (p.Arg133Trp)","abstract_start":1463,"abstract_end":1485},{"Name":"NM_000387.6(SLC25A20):c.691G>C (p.Asp231His)","Chromosome":"3","Start":"48859119","Stop":"48859119","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":631501,"rule_based_match":true,"evidence_text":"c.691G>C (p.Asp231His)","llm_judgment":"PRESENT","evidence":"c.691G>C (p.Asp231His)","abstract_start":1487,"abstract_end":1509},{"Name":"NM_000387.6(SLC25A20):c.842C>T (p.Ala281Val)","Chromosome":"3","Start":"48858508","Stop":"48858508","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1781300,"rule_based_match":true,"evidence_text":"c.842C>T (p.Ala281Val)","llm_judgment":"PRESENT","evidence":"c.842C>T (p.Ala281Val)","abstract_start":1515,"abstract_end":1537}]}
{"pmid":"29754270","title":"Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction.","abstract":"Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.","variants":[{"Name":"NM_177398.4(LMX1A):c.721G>C (p.Val241Leu)","Chromosome":"1","Start":"165210725","Stop":"165210725","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":800758,"rule_based_match":true,"evidence_text":"c.721G > C (p.Val241Leu)","llm_judgment":"PRESENT","evidence":"c.721G > C (p.Val241Leu)","abstract_start":328,"abstract_end":352},{"Name":"NM_177398.4(LMX1A):c.290G>C (p.Cys97Ser)","Chromosome":"1","Start":"165249614","Stop":"165249614","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":800759,"rule_based_match":true,"evidence_text":"c.290G > C (p.Cys97Ser)","llm_judgment":"PRESENT","evidence":"c.290G > C (p.Cys97Ser)","abstract_start":480,"abstract_end":503}]}
{"pmid":"27629384","title":"Combined variants in factor VIII and prostaglandin synthase-1 amplify hemorrhage severity across three generations of descendants.","abstract":"Essentials Co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. We determined pathogenic variants in a three-generational pedigree with excessive bleeding. Bleeding occurred with concurrent variants in prostaglandin synthase-1 (PTGS-1) and factor VIII. The PTGS-1 variant was associated with functional defects in the arachidonic acid pathway.\nSUMMARY: Background Inherited human variants that concurrently cause disorders of primary hemostasis and coagulation are uncommon. Nevertheless, rare cases of co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. Objective We prospectively sought to determine pathogenic variants in a three-generational pedigree with excessive bleeding. Patients/methods Platelet number, size and light transmission aggregometry to multiple agonists were evaluated in pedigree members. Transmission electron microscopy determined platelet morphology and granule content. Thromboxane release studies and light transmission aggregometry in the presence or absence of prostaglandin G<sub>2</sub> assessed specific functional defects in the arachidonic acid pathway. Whole exome sequencing (WES) and targeted nucleotide sequence analysis identified potentially deleterious variants. Results Pedigree members with excessive bleeding had impaired platelet aggregation with arachidonic acid, epinephrine and low-dose ADP, as well as reduced platelet thromboxane B<sub>2</sub> release. Impaired platelet aggregation in response to 2MesADP was rescued with prostaglandin G<sub>2</sub> , a prostaglandin intermediate downstream of prostaglandin synthase-1 (PTGS-1) that aids in the production of thromboxane. WES identified a non-synonymous variant in the signal peptide of PTGS-1 (rs3842787; c.50C>T; p.Pro17Leu) that completely co-segregated with disease phenotype. A variant in the F8 gene causing hemophilia A (rs28935203; c.5096A>T; p.Y1699F) was also identified. Individuals with both variants had more severe bleeding manifestations than characteristic of mild hemophilia A alone. Conclusion We provide the first report of co-existing variants in both F8 and PTGS-1 genes in a three-generation pedigree. The PTGS-1 variant was associated with specific functional defects in the arachidonic acid pathway and more severe hemorrhage.","variants":[{"Name":"NM_000132.4(F8):c.5096A>T (p.Tyr1699Phe)","Chromosome":"X","Start":"154928694","Stop":"154928694","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":25154,"rule_based_match":true,"evidence_text":"c.5096A>T","llm_judgment":"PRESENT","evidence":"c.5096A>T","abstract_start":1928,"abstract_end":1937}]}
{"pmid":"27886673","title":"In silico, in vitro and case-control analyses as an effective combination for analyzing BRCA1 and BRCA2 unclassified variants in a population-based sample.","abstract":"Ascertaining the clinical consequences of BRCA1 and BRCA2 variants of uncertain significance (VUS) is currently indispensable for providing effective genetic counseling and preventive actions for families with hereditary breast and ovarian cancer (HBOC). To this end, we conducted a combination of in silico prediction and cDNA splicing analyses of 13 BRCA1 and 10 BRCA2 VUS identified in our cohort as well as a case-control analysis in a population-based sample of 10 recurrent VUS. We observed consistent results between the in silico predictions and sequencing analyses for all analyzed VUS. An abnormal cDNA pattern was observed for variants c.212+1G>A and c.5278-1G>A in BRCA1 and c.516+2T>A and c.8168A>G in BRCA2 according to in silico splicing prediction. A case-control study of VUS confirmed the polymorphisms of the c.67+62A>G, c.7008-62A>G and c.8851G>A BRCA2 variants previously published. c.4068G>A in the BRCA2 gene can also be considered a polymorphism due to its occurrence at a frequency greater than 1% in our population. Our study shows that employing population-based analysis and a combination of several in silico methods yields highly accurate information, resulting in a reliable tool for selecting variants for cDNA sequencing analysis in routine cancer genetic counseling units.","variants":[{"Name":"NM_000059.4(BRCA2):c.8168A>G (p.Asp2723Gly)","Chromosome":"13","Start":"32363370","Stop":"32363370","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":46697,"rule_based_match":true,"evidence_text":"c.8168A>G","llm_judgment":"PRESENT","evidence":"c.8168A>G","abstract_start":702,"abstract_end":711},{"Name":"NM_000059.4(BRCA2):c.516+2T>A","Chromosome":"13","Start":"32326284","Stop":"32326284","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":66457,"rule_based_match":true,"evidence_text":"c.516+2T>A","llm_judgment":"PRESENT","evidence":"c.516+2T>A","abstract_start":687,"abstract_end":697}]}
{"pmid":"26851658","title":"Human βA3/A1-crystallin splicing mutation causes cataracts by activating the unfolded protein response and inducing apoptosis in differentiating lens fiber cells.","abstract":"βγ-Crystallins, having a uniquely stable two domain four Greek key structure, are crucial for transparency of the eye lens,. Mutations in lens crystallins have been proposed to cause cataract formation by a variety of mechanisms most of which involve destabilization of the protein fold. The underlying molecular mechanism for autosomal dominant zonular cataracts with sutural opacities in an Indian family caused by a c.215+1G>A splice mutation in the βA3/A1-crystallin gene CRYBA1 was elucidated using three transgenic mice models. This mutation causes a splice defect in which the mutant mRNA escapes nonsense mediated decay by skipping both exons 3 and 4. Skipping these exons results in an in-frame deletion of the mRNA and synthesis of an unstable p.Ile33_Ala119del mutant βA3/A1-crystallin protein. Transgenic expression of mutant βA3/A1-crystallin but not the wild type protein results in toxicity and abnormalities in the maturation and orientation of differentiating lens fibers in c.97_357del CRYBA1 transgenic mice, leading to a small spherical lens, cataract, and often lens capsule rupture. On a cellular level, the lenses accumulated p.Ile33_Ala119del βA3/A1-crystallin with resultant activation of the stress signaling pathway - unfolded protein response (UPR) and inhibition of normal protein synthesis, culminating in apoptosis. This highlights the mechanistic contrast between mild mutations that destabilize crystallins and other proteins, resulting in their being bound by the α-crystallins that buffer lens cells against damage by denatured proteins, and severely misfolded proteins that are not bound by α-crystallin but accumulate and have a direct toxic effect on lens cells, resulting in early onset cataracts.","variants":[{"Name":"NM_005208.5(CRYBA1):c.215+1G>A","Chromosome":"17","Start":"29250301","Stop":"29250301","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":512267,"rule_based_match":true,"evidence_text":"c.215+1G>A","llm_judgment":"PRESENT","evidence":"c.215+1G>A","abstract_start":419,"abstract_end":429}]}
{"pmid":"22521419","title":"Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.","abstract":"Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5× higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-α) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 × 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.","variants":[{"Name":"NM_001366385.1(CARD14):c.349G>A (p.Gly117Ser)","Chromosome":"17","Start":"80182790","Stop":"80182790","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40290,"rule_based_match":true,"evidence_text":"c.349G>A (p.Gly117Ser)","llm_judgment":"PRESENT","evidence":"c.349G>A (p.Gly117Ser)","abstract_start":865,"abstract_end":887},{"Name":"NM_001366385.1(CARD14):c.425A>G (p.Glu142Gly)","Chromosome":"17","Start":"80183988","Stop":"80183988","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":40292,"rule_based_match":true,"evidence_text":"c.425A>G (p.Glu142Gly)","llm_judgment":"PRESENT","evidence":"p.Glu142Gly","abstract_start":707,"abstract_end":718},{"Name":"NM_001366385.1(CARD14):c.424G>A (p.Glu142Lys)","Chromosome":"17","Start":"80183987","Stop":"80183987","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40294,"rule_based_match":true,"evidence_text":"c.424G>A [p.Glu142Lys]","llm_judgment":"PRESENT","evidence":"c.424G>A [p.Glu142Lys]","abstract_start":670,"abstract_end":692},{"Name":"NM_001366385.1(CARD14):c.536G>A (p.Arg179His)","Chromosome":"17","Start":"80184099","Stop":"80184099","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":79675,"rule_based_match":true,"evidence_text":"c.536G>A (p.Arg179His)","llm_judgment":"PRESENT","evidence":"p.Arg179His","abstract_start":1185,"abstract_end":1196}]}
{"pmid":"24022109","title":"Variations of IGHMBP2 gene was not the major cause of Han Chinese patients with non-5q-spinal muscular atrophies.","abstract":"Spinal muscular atrophy with respiratory distress type 1 (SMARD1), a notably common form of non-5q-spinal muscular atrophy, can be confused with infantile spinal muscular atrophy and is characterized by the early onset of diaphragmatic palsy and predominantly distal muscle weakness. The defective gene, immunoglobulin mu-binding protein 2 (IGHMBP2), is located on chromosome 11q13-q21. In this study, we screened the IGHMBP2 gene in 53 unrelated Han Chinese non-5q-spinal muscular atrophy patients and 100 healthy controls. Two novel mutations (c.711+1G>C and c.1817G>A) and 5 nucleotide polymorphisms (c.57T>C, c.1554C>T, c.1914G>A, c.2080C>T, and c.2270G>C) were identified. However, only 1 patient harbored the compound heterozygous mutations (c.711+1G>C, c.1817G>A). Furthermore, the homozygous c.2636C>A (p.T879 K) variation, which has been included as a mutation in the Human Gene Mutation Database, was found both in patients and healthy individuals. In conclusion, the IGHMBP2 gene was not found to be a major causative gene linked to Han Chinese non-5q-spinal muscular atrophy patients.","variants":[{"Name":"NM_002180.3(IGHMBP2):c.1817G>A (p.Arg606His)","Chromosome":"11","Start":"68936297","Stop":"68936297","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":625249,"rule_based_match":true,"evidence_text":"c.1817G>A","llm_judgment":"PRESENT","evidence":"c.1817G>A","abstract_start":561,"abstract_end":570},{"Name":"NM_002180.3(IGHMBP2):c.711+1G>C","Chromosome":"11","Start":"68911604","Stop":"68911604","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":625750,"rule_based_match":true,"evidence_text":"c.711+1G>C","llm_judgment":"PRESENT","evidence":"c.711+1G>C","abstract_start":546,"abstract_end":556}]}
{"pmid":"24129430","title":"Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome.","abstract":"Three different genes of the glycosylphosphatidylinositol anchor synthesis pathway, PIGV, PIGO, and PGAP2, have recently been implicated in hyperphosphatasia-mental retardation syndrome (HPMRS), also known as Mabry syndrome, a rare autosomal recessive form of intellectual disability. The aim of this study was to delineate the PIGV mutation spectrum as well as the associated phenotypic spectrum in a cohort of 16 individuals diagnosed with HPMRS on the basis of intellectual disability and elevated serum alkaline phosphate as minimal diagnostic criteria. All PIGV exons and intronic boundaries were sequenced in 16 individuals. Biallelic PIGV mutations were identified in 8 of 16 unrelated families with HPMRS. The most frequent mutation detected in about 80% of affected families including the cases reported here is the c.1022C>A PIGV mutation, which was found in both the homozygous as well as the heterozygous state. Four further mutations found in this study (c. 176T>G, c.53G>A, c.905T>C, and c.1405C>T) are novel. Our findings in the largest reported cohort to date significantly extend the range of reported manifestations associated with PIGV mutations and demonstrate that the severe end of the clinical spectrum presents as a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations. PIGV mutations are the major cause of HPMRS, which displays a broad clinical variability regarding associated malformations and growth patterns. Severe developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in PIGV-positive individuals.","variants":[{"Name":"NM_017837.4(PIGV):c.1022C>A (p.Ala341Glu)","Chromosome":"1","Start":"26795056","Stop":"26795056","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":16323,"rule_based_match":true,"evidence_text":"c.1022C>A","llm_judgment":"PRESENT","evidence":"c.1022C>A","abstract_start":825,"abstract_end":834},{"Name":"NM_017837.4(PIGV):c.1405C>T (p.Arg469Ter)","Chromosome":"1","Start":"26797767","Stop":"26797767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1423198,"rule_based_match":true,"evidence_text":"c.1405C>T","llm_judgment":"PRESENT","evidence":"c.1405C>T","abstract_start":1002,"abstract_end":1011}]}
{"pmid":"23453665","title":"Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia.","abstract":"Microphthalmia is an important developmental eye disorder. Although mutations in several genes have been linked to this condition, they only account for a minority of cases. We performed autozygome analysis and exome sequencing on a multiplex consanguineous family in which colobomatous microphthalmia is associated with profound global developmental delay, intractable seizures, and corpus callosum abnormalities, and we identified a homozygous truncating mutation in C12orf57 [c.1A>G; p.Met1?]. In a simplex case with a similar phenotype, we identified compound heterozygosity for the same mutation and another missense mutation [c.152T>A; p.Leu51Gln]. Little is known about C12orf57 but we show that it is expressed in several mouse tissues, including the eye and brain. Our data strongly implicate mutations in C12orf57 in the pathogenesis of a clinically distinct autosomal-recessive syndromic form of colobomatous microphthalmia.","variants":[{"Name":"NM_138425.4(C12orf57):c.152T>A (p.Leu51Gln)","Chromosome":"12","Start":"6944575","Stop":"6944575","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":51109,"rule_based_match":true,"evidence_text":"c.152T>A (p.Leu51Gln)","llm_judgment":"PRESENT","evidence":"p.Leu51Gln","abstract_start":642,"abstract_end":652}]}
{"pmid":"21892162","title":"Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia.","abstract":"We report the discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene. We found the same, previously unidentified heterozygous c.1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS-AML in three families and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS family. The resulting alterations reside within the second zinc finger of GATA2, which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counseling, selection of related bone marrow transplant donors and development of therapies.","variants":[{"Name":"NM_032638.5(GATA2):c.1061C>T (p.Thr354Met)","Chromosome":"3","Start":"128481901","Stop":"128481901","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":38666,"rule_based_match":true,"evidence_text":"c.1061C>T (p.Thr354Met)","llm_judgment":"PRESENT","evidence":"c.1061C>T (p.Thr354Met)","abstract_start":179,"abstract_end":202}]}
{"pmid":"34636445","title":"A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia.","abstract":"BACKGROUND: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31.\nOBJECTIVE: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia.\nMETHODS: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the \"GeneMatcher\" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function.\nRESULTS: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility.\nCONCLUSION: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.","variants":[{"Name":"NM_001689.5(ATP5MC3):c.318C>G (p.Asn106Lys)","Chromosome":"2","Start":"175178399","Stop":"175178399","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":964808,"rule_based_match":true,"evidence_text":"c.318C > G; p.Asn106Lys","llm_judgment":"PRESENT","evidence":"c.318C > G; p.Asn106Lys","abstract_start":1045,"abstract_end":1068}]}
{"pmid":"23791648","title":"Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype.","abstract":"Hypophosphatasia (HPP) is an inherited disorder of mineral metabolism caused by mutations in ALPL, encoding tissue non-specific alkaline phosphatase (TNAP). Here, we report the molecular findings from monozygotic twins, clinically diagnosed with tooth-specific odontohypophosphatasia (odonto-HPP). Sequencing of ALPL identified two genetic alterations in the probands, including a heterozygous missense mutation c.454C>T, leading to change of arginine 152 to cysteine (p.R152C), and a novel heterozygous gene deletion c.1318_1320delAAC, leading to the loss of an asparagine residue at codon 440 (p.N440del). Clinical identification of low serum TNAP activity, dental abnormalities, and pedigree data strongly suggests a genotype-phenotype correlation between p.N440del and odonto-HPP in this family. Computational analysis of the p.N440del protein structure revealed an alteration in the tertiary structure affecting the collagen-binding site (loop 422-452), which could potentially impair the mineralization process. Nevertheless, the probands (compound heterozygous: p.[N440del];[R152C]) feature early-onset and severe odonto-HPP phenotype, whereas the father (p.[N440del];[=]) has only moderate symptoms, suggesting p.R152C may contribute or predispose to a more severe dental phenotype in combination with the deletion. These results assist in defining the genotype-phenotype associations for odonto-HPP, and further identify the collagen-binding site as a region of potential structural importance for TNAP function in the biomineralization.","variants":[{"Name":"NM_000478.6(ALPL):c.454C>T (p.Arg152Cys)","Chromosome":"1","Start":"21563266","Stop":"21563266","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1395055,"rule_based_match":true,"evidence_text":"c.454C>T","llm_judgment":"PRESENT","evidence":"c.454C>T","abstract_start":412,"abstract_end":420}]}
{"pmid":"33791913","title":"Clinical and Molecular Features of POLG-Related Sensory Ataxic Neuropathy with Dysarthria and Ophthalmoparesis.","abstract":"Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is a rare mitochondrial disorder associated with mutations in the POLG gene, which encodes the DNA polymerase gamma catalytic subunit. A few POLG-related SANDO cases have been reported, but the genotype-phenotype correlation remains unclear. Here, we report a patient with SANDO carrying two novel missense variants (c.2543G>C, p.G848A and c.452 T>C, p.L151P) in POLG. We also reviewed previously reported cases to systematically evaluate the clinical and genetic features of POLG-related SANDO. A total of 35 distinct variants in the coding region of POLG were identified in 63 patients with SANDO. The most frequent variant was the p.A467T variant, followed by the p.W748S variant. The clinical spectrum of SANDO is heterogeneous. No clear correlation has been observed between the mutation types and clinical phenotypes. Our findings expand the mutational spectrum of POLG and contribute to clinical management and genetic counseling for POLG-related SANDO.","variants":[{"Name":"NM_002693.3(POLG):c.452T>C (p.Leu151Pro)","Chromosome":"15","Start":"89333303","Stop":"89333303","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":333262,"rule_based_match":true,"evidence_text":"c.452 T>C, p.L151P","llm_judgment":"PRESENT","evidence":"c.452 T>C, p.L151P","abstract_start":408,"abstract_end":426}]}
{"pmid":"26829726","title":"Study of in vitro expression of human platelet ITGB3 gene nonsense mutation c.1476G>A","abstract":"OBJECTIVE: To explore the function of a novel nonsense mutation c.1476G>A of ITGB3 gene using an in vitro expression system.\nMETHODS: An eukaryotic expression vector containing ITGB3 c.1476G>A cDNA was generated by site-directed mutagenesis and transformed into E.coli. Plasmid DNA was extracted and sequenced to confirm the target mutations. Wild-type and mutant recombination plasmids were transfected into Chinese hamster ovarian cancer (CHO) cells by nonliposome method, and the stable expression cells were harvested by G418 screening. The ITGB3 gene mRNA transcription and GPIIIa expression level in CHO cells were detected with real-time quantitative PCR, Western blotting and flow cytometry, respectively.\nRESULTS: The eukaryotic expression vectors of wild ITGB3 cDNA and c.1476G>A mutant were successfully constructed. CHO cells with stable expression were obtained after transfection and screening. Compared with the wild-type transfected cells, the amount of CD61 antigen expression was 37% and mRNA transcription level was only 6% in the mutant-transfected cells. Full length GPIIIa protein was found only in the stably wild-type-transfected cells, but not in mutant-transfected cells by Western blotting analysis.\nCONCLUSION: The ITGB3 c.1476G>A mutation can decrease the transcription level and further affect GPIIIa synthesis and CD61 antigen expression.","variants":[{"Name":"NM_000212.3(ITGB3):c.1476G>A (p.Trp492Ter)","Chromosome":"17","Start":"47292354","Stop":"47292354","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2476327,"rule_based_match":true,"evidence_text":"c.1476G>A","llm_judgment":"PRESENT","evidence":"c.1476G>A","abstract_start":64,"abstract_end":73}]}
{"pmid":"20055872","title":"One novel and two recurrent mutations in the keratin 5 gene identified in Chinese patients with epidermolysis bullosa simplex.","abstract":"Epidermolysis bullosa simplex (EBS) is a group of inherited skin diseases, characterized by the formation of intraepidermal blisters. We performed genetic analysis of the keratin 5 (KRT5) gene in two Chinese pedigrees. One novel missense mutation was identified in a patient with sporadic EBS (general, non-Dowling-Meara). Sequence analysis showed a heterozygous T > A transition at nucleotide 1730 of KRT5, changing phenylalanine (Phe) to tyrosine (Tyr) at position 577 of the keratin 5 (K5). In addition, two recurrent mutations c.1649delG (p.Gly550AlafsX77) and c.508G > (p.Glu170Lys) in KRT5 were identified in Chinese patients with mottled pigmentation EBS and localized EBS, respectively. None of the mutations were found in any unaffected family members or in an additional 100 unrelated control samples. These results suggest that these mutations are pathogenic and might be one of the potential causes of EBS in these Chinese patients.","variants":[{"Name":"NM_000424.4(KRT5):c.1649del (p.Gly550fs)","Chromosome":"12","Start":"52515066","Stop":"52515066","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":29694,"rule_based_match":true,"evidence_text":"c.1649delG (p.Gly550AlafsX77)","llm_judgment":"PRESENT","evidence":"c.1649delG (p.Gly550AlafsX77)","abstract_start":531,"abstract_end":560}]}
{"pmid":"35163394","title":"Functional Characterization of","abstract":"The <i>FH</i> gene encodes the fumarate hydratase of the Krebs cycle and functions as a homotetramer to catalyze the hydration of fumarate to malate. Mutations in <i>FH</i> result in uterine leiomyomas, a rare autosomal dominant inherited metabolic disease. However, how <i>FH</i> mutations result in this disease is poorly understood. Here, the <i>FH</i> mutation c.557G>A (p.S186N) was identified in a family with uterine leiomyomas phenotype. A series of studies were performed to confirm the pathogenicity of this mutation. Results showed that the FH mutant exhibited significantly lower fumarase enzyme activity and increased the fumarates level compared with the wildtype, which might be due to the impaired homotetramer formation in the native gel electrophoresis. Interestingly, the immunofluorescence study revealed that the overexpressed FH mutant exhibited puncta structures compared with the evenly expressed FH wildtype in cytoplasm suggesting that the altered amino acid might result in dysfunctional proteins which were accumulated to reduce its cytotoxicity. Importantly, the cells overexpressing the FH mutant exhibited higher proliferation and extracellular acidification rate value (ECAR) which might be caused by the upregulated HIF-1α indicating the tumor phenotype. Notably, phospho-mTOR was significantly increased and autophagy was inhibited in the FH mutant overexpression cells compared with the wildtype. Our work provides new insight into the <i>FH</i> mutation c.557G>A (p.S186N) underlies uterine leiomyomas and important information for accurate genetic counseling and clinical diagnosis of the disease.","variants":[{"Name":"NM_000143.4(FH):c.557G>A (p.Ser186Asn)","Chromosome":"1","Start":"241508784","Stop":"241508784","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152368,"rule_based_match":true,"evidence_text":"c.557G>A (p.S186N)","llm_judgment":"PRESENT","evidence":"c.557G>A (p.S186N)","abstract_start":365,"abstract_end":383}]}
{"pmid":"16211556","title":"Nine mutations including three novel mutations among Russian patients with acute intermittent porphyria.","abstract":"Acute intermittent porphyria (AIP) is a metabolic disease due to a partial deficiency of hydroxymethylbilane synthase (HMBS) in heme biosynthesis. Direct sequencing of genomic DNA samples of 11 unrelated Russian AIP patients, 32 of their relatives and 50 healthy controls from northwestern Russia including Saint Petersburg revealed nine mutations in the HMBS gene. Three novel mutations, c.825+5G>C, c.825+3_825+6del, and c.770T>C, resulted in varying amounts of abnormal transcripts, r.822_825del and [r.770U>C, r.652_771del, r.613_771del]. Six mutations, c.77G>A (p.R26H), c.517C>T (p.R173W), c.583C>T (p.R195C), c.673C>T (p.R225X), c.739T>C (p.C247R), and c.748G>C (p.E250A), have previously been identified in AIP patients from Western and other Eastern European populations. All mutations expressed in COS-1 cells demonstrated low residual activities (0.1-1%). The majority of the mutations were family-specific and also confirmed allelic heterogeneity among Russian AIP patients. The diversity of mutations may reflect the old international history of Saint Petersburg and immigration of people from other parts of Europe.","variants":[{"Name":"NM_000190.4(HMBS):c.77G>A (p.Arg26His)","Chromosome":"11","Start":"119088298","Stop":"119088298","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16482,"rule_based_match":true,"evidence_text":"c.77G>A (p.R26H)","llm_judgment":"PRESENT","evidence":"c.77G>A (p.R26H)","abstract_start":558,"abstract_end":574},{"Name":"NM_000190.4(HMBS):c.517C>T (p.Arg173Trp)","Chromosome":"11","Start":"119091431","Stop":"119091431","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":639782,"rule_based_match":true,"evidence_text":"c.517C>T (p.R173W)","llm_judgment":"PRESENT","evidence":"c.517C>T (p.R173W)","abstract_start":576,"abstract_end":594},{"Name":"NM_000190.4(HMBS):c.673C>T (p.Arg225Ter)","Chromosome":"11","Start":"119092425","Stop":"119092425","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":639787,"rule_based_match":true,"evidence_text":"c.673C>T (p.R225X)","llm_judgment":"PRESENT","evidence":"c.673C>T (p.R225X)","abstract_start":616,"abstract_end":634},{"Name":"NM_000190.4(HMBS):c.583C>T (p.Arg195Cys)","Chromosome":"11","Start":"119091497","Stop":"119091497","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171129,"rule_based_match":true,"evidence_text":"c.583C>T (p.R195C)","llm_judgment":"PRESENT","evidence":"c.583C>T (p.R195C)","abstract_start":596,"abstract_end":614}]}
{"pmid":"31854126","title":"A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases.","abstract":"OBJECTIVE: To identify causative mutations in a patient affected by ataxia and spastic paraplegia.\nMETHODS: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were performed using patient's DNA sample. RT-PCR and cDNA Sanger sequencing were performed on RNA extracted from patient's fibroblasts, as well as western blot.\nRESULTS: A novel missense variant in SPG7 (c.2195T> C; p.Leu732Pro) was first found by whole-exome sequencing (WES), while the second, also unreported, deep intronic variant (c.286 + 853A>G) was identified by whole-genome sequencing (WGS). RT-PCR confirmed the in silico predictions showing that this variant activated a cryptic splice site, inducing the inclusion of a pseudoexon into the mRNA sequence, which encoded a premature stop codon. Western blot showed decreased SPG7 levels in patient's fibroblasts.\nINTERPRETATION: Identification of a deep intronic variant in SPG7, which could only have been detected by performing WGS, led to a diagnosis in this HSP patient. This case challenges the notion of an autosomal dominant inheritance for SPG7, and illustrates the importance of performing WGS subsequently or alternatively to WES to find additional mutations, especially in patients carrying one variant in a gene causing a predominantly autosomal recessive disease.","variants":[{"Name":"NM_003119.4(SPG7):c.2195T>C (p.Leu732Pro)","Chromosome":"16","Start":"89556900","Stop":"89556900","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2523106,"rule_based_match":true,"evidence_text":"c.2195T> C; p.Leu732Pro","llm_judgment":"PRESENT","evidence":"c.2195T> C; p.Leu732Pro","abstract_start":376,"abstract_end":399},{"Name":"NM_003119.4(SPG7):c.286+853A>G","Chromosome":"16","Start":"89511445","Stop":"89511445","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2523107,"rule_based_match":true,"evidence_text":"c.286+853A>G","llm_judgment":"PRESENT","evidence":"c.286 + 853A>G","abstract_start":508,"abstract_end":522}]}
{"pmid":"27648926","title":"Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene.","abstract":"BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases.\nMETHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study.\nRESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series.\nCONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases. Cancer 2017;123:210-218. © 2016 American Cancer Society.","variants":[{"Name":"NM_024675.4(PALB2):c.419del (p.Lys140fs)","Chromosome":"16","Start":"23636127","Stop":"23636127","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":957708,"rule_based_match":true,"evidence_text":"PALB2 c.419delA","llm_judgment":"PRESENT","evidence":"c.419delA","abstract_start":1047,"abstract_end":1056},{"Name":"NM_024675.4(PALB2):c.1984A>T (p.Lys662Ter)","Chromosome":"16","Start":"23630170","Stop":"23630170","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":529895,"rule_based_match":true,"evidence_text":"c.1984A>T","llm_judgment":"PRESENT","evidence":"c.1984A>T","abstract_start":1301,"abstract_end":1310}]}
{"pmid":"34887220","title":"Misdiagnosis of sitosterolemia in a patient as Evans syndrome and familial hypercholesterolemia.","abstract":"Sitosterolemia is a rare form of dyslipidemia that has diverse clinical manifestations, and insufficient knowledge of the disease frequently leads to a delay in diagnosis. We report a case of sitosterolemia in a 26-year-old Chinese woman, characterized by anemia, thrombocytopenia, persistent hypercholesterolemia, premature atherosclerosis, extensive xanthoma, and arthralgia-tenosynovitis. Successive misdiagnoses of Evans syndrome and familial hypercholesterolemia had been made, and the patient had responded minimally to steroid therapy, splenectomy, and statin treatment; therefore, she was referred to our hospital. On admission, a peripheral blood smear revealed the presence of abnormally shaped erythrocytes and giant platelets. Multiple atherosclerotic lesions, sites of tenosynovitis, and carotid sheath xanthomas were identified on ultrasonography. Compound heterozygous mutations of the ABCG5 gene, including a hot variant (c.1,336, exon10 C>T, p.(R446*)) and a novel variant (c.1,325-3(IVS9)_c.1325-2(IVS9)delCA) were separately identified in her parents by pedigree analysis. Plant sterols analysis by high performance liquid chromatography method revealed remarkably elevated plasma plant sterol concentrations after drug withdrawal but reduced rapidly after restarting ezetimibe during follow-up period. After 21 months of treatment with ezetimibe and a low-plant sterol diet, her hematologic abnormalities, tenosynovitis, and hypercholesterolemia had significantly improved; and ultrasonography showed that her skin and carotid sheath xanthomas had resolved or shrunk. This case demonstrates that morphological changes in blood cells on a peripheral blood smear, ultrasonographic findings and ABCG5/ABCG8 gene screening are valuable, and plant sterol analysis in serum is crucial to confirm diagnosis and assess treatment adequacy for sitosterolemia.","variants":[{"Name":"NM_022436.3(ABCG5):c.1336C>T (p.Arg446Ter)","Chromosome":"2","Start":"43822924","Stop":"43822924","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39442,"rule_based_match":false,"evidence_text":"c.1,336, exon10 C>T, p.(R446*)","llm_judgment":"PRESENT","evidence":"c.1,336, exon10 C>T, p.(R446*)","abstract_start":938,"abstract_end":968}]}
{"pmid":"25894957","title":"Clinical and molecular characterization of females affected by X-linked retinoschisis.","abstract":"BACKGROUND: X-linked retinoschisis (XLRS) is a leading cause of juvenile macular degeneration associated with mutations in the RS1 gene. XLRS has a variable expressivity in males and shows no clinical phenotype in carrier females.\nDESIGN: Clinical and molecular characterization of male and female individuals affected with XLRS in a consanguineous family.\nPARTICIPANTS: Consanguineous Eastern European-Australian family\nMETHODS: Four clinically affected and nine unaffected family members were genetically and clinically characterized. Deoxyribonucleic acid (DNA) analysis was conducted by the Australian Inherited Retinal Disease Register and DNA Bank.\nMAIN OUTCOME MEASURES: Clinical and molecular characterization of the causative mutation in a consanguineous family with XLRS.\nRESULTS: By direct sequencing of the RS1 gene, one pathogenic variant, NM_000330.3: c.304C > T, p. R102W, was identified in all clinically diagnosed individuals analysed. The two females were homozygous for the variant, and the males were hemizygous.\nCONCLUSION: Clinical and genetic characterization of affected homozygous females in XLRS affords the rare opportunity to explore the molecular mechanisms of XLRS and the manifestation of these mutations as disease in humans.","variants":[{"Name":"NM_000330.4(RS1):c.304C>T (p.Arg102Trp)","Chromosome":"X","Start":"18647213","Stop":"18647213","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24926,"rule_based_match":true,"evidence_text":"NM_000330.3: c.304C > T, p. R102W","llm_judgment":"PRESENT","evidence":"NM_000330.3: c.304C > T, p. R102W","abstract_start":853,"abstract_end":886}]}
{"pmid":"23385134","title":"Compound heterozygous mutations of SLC26A4 in 4 Chinese families with enlarged vestibular aqueduct.","abstract":"OBJECTIVE: Enlarged vestibular aqueduct is the most common inner ear malformation in individuals with sensorineural hearing loss. Mutations in SLC26A4 can cause non-syndromic EVA. To date, more than 170 SLC26A4 mutations have been described. The aim of the present study was to detect and report genetic causes of four unrelated Chinese families with hearing loss.\nMETHODS: We evaluated 4 families presenting bilateral enlarged vestibular aqueducts and describe the clinical and molecular characteristics of 5 patients.\nRESULTS: The SLC26A4 gene was sequenced in 23 members of these 4 Chinese families with EVA, and the patients were found to carry 4 compound heterozygous mutations, p.G197R and p.S391R, IVS7-2A>G, p.I188T and c.1746 del G, p.V659L and p.T410M, and p.T94I and p.G197R, none of which have been reported previously.\nCONCLUSIONS: These results emphasize the necessity of considering the complete DNA sequencing of the SLC26A4 gene in molecular diagnosis of deafness, especially when phenotypes such as congenital, invariable, and progressive hearing loss with EVA are present.","variants":[{"Name":"NM_000441.2(SLC26A4):c.563T>C (p.Ile188Thr)","Chromosome":"7","Start":"107674311","Stop":"107674311","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":544395,"rule_based_match":false,"evidence_text":"p.I188T","llm_judgment":"PRESENT","evidence":"p.I188T","abstract_start":716,"abstract_end":723},{"Name":"NM_000441.2(SLC26A4):c.589G>A (p.Gly197Arg)","Chromosome":"7","Start":"107674337","Stop":"107674337","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":52731,"rule_based_match":false,"evidence_text":"p.G197R","llm_judgment":"PRESENT","evidence":"p.G197R","abstract_start":684,"abstract_end":691}]}
{"pmid":"28905369","title":"TSGA10 is a novel candidate gene associated with acephalic spermatozoa.","abstract":"Acephalic spermatozoa is a rare teratozoospermia associated with male infertility. However, the pathogenesis of this disorder remains unclear. Here, we report a 27 years old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate. Electron microscopic and immunofluorescence analysis suggested breakage at the midpiece of the patient's sperm cells. Subsequent whole-exome sequencing analysis identified a homozygous deletion within TSGA10 (c.211delG; p.A71Hfs*12), which resulted in the production of truncated TSGA10 protein. TSGA10 is a testis-specific protein that localized to the midpiece in the spermatozoa of a normal control; however, immunostaining failed to detect TSGA10 protein in the patient's sperm. Western blot analysis also showed complete absence of TSGA10 protein in the patient. One cycle of in vitro fertilization-assisted reproduction was conducted, but pregnancy was not achieved after embryo transfer, possibly due to poor embryo quality. Therefore, we speculate that the presence of rare sequence variants within TSGA10 may be associated with acephalic spermatozoa in humans.","variants":[{"Name":"NM_182911.4(TSGA10):c.211del","Chromosome":"2","Start":"99105697","Stop":"99105697","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":513884,"rule_based_match":true,"evidence_text":"c.211delG","llm_judgment":"PRESENT","evidence":"c.211delG","abstract_start":484,"abstract_end":493}]}
{"pmid":"30905398","title":"The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping.","abstract":"Over a relatively short period of time, the clinical geneticist's \"toolbox\" has been expanded by machine-learning algorithms for image analysis, which can be applied to the task of syndrome identification on the basis of facial photographs, but these technologies harbor potential beyond the recognition of established phenotypes. Here, we comprehensively characterized two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p.Ser479Phe), the gene which encodes the nuclear envelope protein LEM domain-containing protein 2 (LEMD2). Despite different ages and ethnic backgrounds, both individuals share a progeria-like facial phenotype and a distinct combination of physical and neurologic anomalies, such as growth retardation; hypoplastic jaws crowded with multiple supernumerary, yet unerupted, teeth; and cerebellar intention tremor. Immunofluorescence analyses of patient fibroblasts revealed mutation-induced disturbance of nuclear architecture, recapitulating previously published data in LEMD2-deficient cell lines, and additional experiments suggested mislocalization of mutant LEMD2 protein within the nuclear lamina. Computational analysis of facial features with two different deep neural networks showed phenotypic proximity to other nuclear envelopathies. One of the algorithms, when trained to recognize syndromic similarity (rather than specific syndromes) in an unsupervised approach, clustered both individuals closely together, providing hypothesis-free hints for a common genetic etiology. We show that a recurrent de novo mutation in LEMD2 causes a nuclear envelopathy whose prognosis in adolescence is relatively good in comparison to that of classical Hutchinson-Gilford progeria syndrome, and we suggest that the application of artificial intelligence to the analysis of patient images can facilitate the discovery of new genetic disorders.","variants":[{"Name":"NM_181336.4(LEMD2):c.1436C>T (p.Ser479Phe)","Chromosome":"6","Start":"33772704","Stop":"33772704","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":905820,"rule_based_match":true,"evidence_text":"c.1436C>T;p.Ser479Phe","llm_judgment":"PRESENT","evidence":"c.1436C>T;p.Ser479Phe","abstract_start":473,"abstract_end":494}]}
{"pmid":"28335750","title":"Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder.","abstract":"BACKGROUND: Many hearing-loss diseases are demonstrated to have Mendelian inheritance caused by mutations in single gene. However, many deaf individuals have diseases that remain genetically unexplained. Auditory neuropathy is a sensorineural deafness in which sounds are able to be transferred into the inner ear normally but the transmission of the signals from inner ear to auditory nerve and brain is injured, also known as auditory neuropathy spectrum disorder (ANSD). The pathogenic mutations of the genes responsible for the Chinese ANSD population remain poorly understood.\nMETHODS: A total of 127 patients with non-syndromic hearing loss (NSHL) were enrolled in Guangxi Zhuang Autonomous Region. A hereditary deafness gene mutation screening was performed to identify the mutation sites in four deafness-related genes (GJB2, GJB3, 12S rRNA, and SLC26A4). In addition, whole-exome sequencing (WES) was applied to explore unappreciated mutation sites in the cases with the singularity of its phenotype.\nRESULTS: Well-characterized mutations were found in only 8.7% (11/127) of the patients. Interestingly, two mutations in the OTOF gene were identified in two affected siblings with ANSD from a Chinese family, including one nonsense mutation c.1273C > T (p.R425X) and one missense mutation c.4994 T > C (p.L1665P). Furthermore, we employed Sanger sequencing to confirm the mutations in each subject. Two compound heterozygous mutations in the OTOF gene were observed in the two affected siblings, whereas the two parents and unaffected sister were heterozygous carriers of c.1273C > T (father and sister) and c.4994 T > C (mother). The nonsense mutation p.R425X, contributes to a premature stop codon, may result in a truncated polypeptide, which strongly suggests its pathogenicity for ANSD. The missense mutation p.L1665P results in a single amino acid substitution in a highly conserved region.\nCONCLUSIONS: Two mutations in the OTOF gene in the Chinese deaf population were recognized for the first time. These findings not only extend the OTOF gene mutation spectrum for ANSD but also indicate that whole-exome sequencing is an effective approach to clarify the genetic characteristics in non-syndromic ANSD patients.","variants":[{"Name":"NM_194248.3(OTOF):c.1273C>T (p.Arg425Ter)","Chromosome":"2","Start":"26483581","Stop":"26483581","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76684,"rule_based_match":true,"evidence_text":"c.1273C > T (p.R425X)","llm_judgment":"PRESENT","evidence":"c.1273C > T (p.R425X)","abstract_start":1250,"abstract_end":1271}]}
{"pmid":"30152556","title":"A p.478I>T KRT1 mutation in a case of annular epidermolytic ichthyosis.","abstract":"Annular epidermolytic ichthyosis (AEI; Online Mendelian Inheritance in Man [OMIM]# 607602) is a rare subtype of epidermolytic ichthyosis that is characterized by polycyclic, migratory erythematous and scaly plaques. It typically results from dominant mutations in the keratin 1 or keratin 10 genes. We present the case of a 5-year-old girl who developed intermittent eruptions of pink, round, scaly, migratory plaques with palmoplantar keratoderma and was originally diagnosed with erythrokeratodermia variabilis et progressiva (EKVP). Genetic analysis revealed a c.1436T>C transition mutation in the keratin 1 gene, and histopathology showed epidermolysis and hyperkeratosis, confirming the diagnosis of AEI.","variants":[{"Name":"NM_006121.4(KRT1):c.1436T>C (p.Ile479Thr)","Chromosome":"12","Start":"52676314","Stop":"52676314","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":30950,"rule_based_match":true,"evidence_text":"c.1436T>C","llm_judgment":"PRESENT","evidence":"c.1436T>C","abstract_start":564,"abstract_end":573}]}
{"pmid":"20964122","title":"Coexistence of neurofibromatosis type 1 and mosaic trisomy 8 in the same patient.","abstract":"We described trisomy 8 mosaicism in a 6-month-old boy with left corneal leukoma, strabismus, posterior urethral valve, tibial bowing and congenital pseudarthrosis of the tibia (CPT) on graphic of left tibia. The patient also had some minor anomalies such as short philtrum, full everted lower lip, microretrognathia, flexion contracture on his left thumb, deep palmar and plantar creases and three cafe-au-lait macules (CALM) larger than 1 cm on the abdomen. Peripheral blood karyotype analysis of the patient showed 46,XY(10%)/47,XY,+8 (90%)). Mosaic trisomy 8 is a rare syndrome characterized by renal, cardiac, ophthalmologic anomalies, dysmorphic facial features and some skeletal manifestations. When re-evaluated at 2 years of age, his gross motor development was delayed and he also had 12 CALM larger than 1 cm, hence the patient fulfilled NIH diagnostic criteria for Neurofibromatosis type 1 (NF 1) based on the CALM and CPT. A truncating mutation was found through comprehensive NF1 mutation analysis, i.e., c.1019_1020delCT (p.Ser340CysfsX12). Here we report a patient with both mosaic trisomy 8 and NF1, which was not described previously.","variants":[{"Name":"NM_001042492.3(NF1):c.1019_1020del (p.Ser340fs)","Chromosome":"17","Start":"31200550","Stop":"31200551","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":538116,"rule_based_match":true,"evidence_text":"c.1019_1020delCT (p.Ser340CysfsX12)","llm_judgment":"PRESENT","evidence":"c.1019_1020delCT (p.Ser340CysfsX12)","abstract_start":1018,"abstract_end":1053}]}
{"pmid":"33125541","title":"SQSTM1 variant in disorders of the frontotemporal dementia-amyotrophic lateral sclerosis spectrum: identification of a novel heterozygous variant and a review of the literature.","abstract":"INTRODUCTION: Accumulating evidence shows that SQSTM1 plays a vital role in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which represent a neurodegenerative disease continuum. Here, we report a novel SQSTM1 variant in a patient presenting with progressive nonfluent aphasia (PNFA) and progressive bulbar palsy (PBP). Relevant literature about FTD and FTD-ALS caused by SQSTM1 mutation was reviewed to better understand its clinical features.\nMETHODS: We collected data from a 66-year-old male patient with a novel heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene who was diagnosed with PNFA and PBP and performed a PubMed literature search using the advanced research criteria: [(\"frontotemporal lobar degeneration\") OR (\"frontotemporal dementia\") OR (\"amyotrophic lateral sclerosis\") OR (\"motor neuron disease\")] AND (\"SQSTM1\"). The clinical features of FTD and FTD-ALS related to SQSTM1 mutation were summarized based on previous cases and our new case.\nRESULTS: The initial symptom of the current patient was progressive verb finding difficulties and effortful speech output, which developed into dysarthria and dysphagia in subsequent months. The results, including tongue atrophy, fasciculations, neurogenic changes, and mild left dominant hypometabolism of 18F-fluorodeoxyglucose PET in the frontal cortex, suggest the possibility of PNFA and PBP. A novel likely pathogenic heterozygous variant (c.995C > G, p.S332X) in the SQSTM1 gene was identified. The literature search revealed a total of 33 FTD and FTD-ALS cases related to the SQSTM1 mutation with detailed clinical information. The mean age of onset (including our patient) was 63.5 ± 9.7 years. bvFTD was the most common clinical phenotype. The missense mutation in the SQSTM1 gene coding region and the UBA domain involvement are its main genetic characteristics.\nCONCLUSION: Although rare, mutations in SQSTM1 can lead to various clinical subtypes of FTD and FTD-ALS, including the rare combination of PNFA and PBP. Exon missense mutation is the main type of mutation, which is common in the UBA domain.","variants":[{"Name":"NM_003900.5(SQSTM1):c.995C>G (p.Ser332Ter)","Chromosome":"5","Start":"179833612","Stop":"179833612","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":633844,"rule_based_match":true,"evidence_text":"c.995C > G, p.S332X","llm_judgment":"PRESENT","evidence":"c.995C > G, p.S332X","abstract_start":582,"abstract_end":601}]}
{"pmid":"28709447","title":"Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death.","abstract":"Neurofilament heavy chain (NEFH) gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc). However, the clinical spectrum of this condition and the physio-pathological pathway remain to be delineated. We report 12 patients from two French families with axonal dominantly inherited form of CMT caused by two new mutations in the NEFH gene. A remarkable feature was the early involvement of proximal muscles of the lower limbs associated with pyramidal signs in some patients. Nerve conduction velocity studies indicated a predominantly motor axonal neuropathy. Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family 2 c.3043_3044del (p.Lys1015Glyfs*47). Both frameshifts lead to 40 additional amino acids translation encoding a cryptic amyloidogenic element. Consistently, we show that these mutations cause protein aggregation which are recognised by the autophagic pathway in motoneurons and triggered caspase 3 activation leading to apoptosis in neuroblastoma cells. Using electroporation of chick embryo spinal cord, we confirm that NEFH mutants form aggregates in vivo and trigger apoptosis of spinal cord neurons. Thus, our results provide a physiological explanation for the overlap between CMT and amyotrophic lateral sclerosis (ALS) clinical features in affected patients.","variants":[{"Name":"NM_021076.4(NEFH):c.3008_3009del (p.Lys1003fs)","Chromosome":"22","Start":"29490645","Stop":"29490646","ReferenceAlleleVCF":"CAA","AlternateAlleleVCF":"C","allel_id":1868583,"rule_based_match":true,"evidence_text":"c.3008_3009del (p.Lys1003Argfs*59)","llm_judgment":"PRESENT","evidence":"c.3008_3009del (p.Lys1003Argfs*59)","abstract_start":731,"abstract_end":765}]}
{"pmid":"25961296","title":"Exome Sequencing Identifies a Mutation in EYA4 as a Novel Cause of Autosomal Dominant Non-Syndromic Hearing Loss.","abstract":"Autosomal dominant non-syndromic hearing loss is highly heterogeneous, and eyes absent 4 (EYA4) is a disease-causing gene. Most EYA4 mutations founded in the Eya-homologous region, however, no deafness causative missense mutation in variable region of EYA4 have previously been found. In this study, we identified a pathogenic missense mutation located in the variable region of the EYA4 gene for the first time in a four-generation Chinese family with 57 members. Whole-exome sequencing (WES) was performed on samples from one unaffected and two affected individuals to systematically search for deafness susceptibility genes, and the candidate mutations and the co-segregation of the phenotype were verified by polymerase chain reaction amplification and by Sanger sequencing in all of the family members. Then, we identified a novel EYA4 mutation in exon 8, c.511G>C; p.G171R, which segregated with postlingual and progressive autosomal dominant sensorineural hearing loss (SNHL). This report is the first to describe a missense mutation in the variable region domain of the EYA4 gene, which is not highly conserved in many species, indicating that the potential unconserved role of 171G>R in human EYA4 function is extremely important.","variants":[{"Name":"NM_004100.5(EYA4):c.511G>C (p.Gly171Arg)","Chromosome":"6","Start":"133462408","Stop":"133462408","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1886366,"rule_based_match":true,"evidence_text":"c.511G>C; p.G171R","llm_judgment":"PRESENT","evidence":"c.511G>C; p.G171R","abstract_start":861,"abstract_end":878}]}
{"pmid":"25756585","title":"Malignant peripheral nerve sheath tumor in cowden syndrome: a first report.","abstract":"Malignant peripheral nerve sheath tumor is a rare malignancy, accounting for 3% to 10% of all soft-tissue sarcomas. We describe a previously healthy 48-year-old man who was diagnosed as having a high-grade malignant neoplasm involving the facial nerve in the right petrous canal after a 4-year history of deafness. The tumor was resected; histologic appearance and immunophenotype, including patchy but strong positivity for S100 protein, indicated a diagnosis of malignant peripheral nerve sheath tumor. A PTEN mutation, c.1003C>T p.(Arg335Ter), was subsequently identified as the cause of Cowden syndrome in another family member (a nephew) with dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease), and genetic testing in the proband's daughter indicated that he was an obligate carrier of the mutation. Sequencing of the tumor showed homozygosity for c.1003C>T, confirming the presence of a germline mutation and implying loss of the second allele. With the exception of Lhermitte-Duclos disease, tumors of the nervous system are not a prominent feature of Cowden syndrome, and this is the first report of malignant peripheral nerve sheath tumor in Cowden syndrome. Sequencing results in the tumor lend evidence to PTEN gene inactivation being implicated in tumorigenesis in this case, suggesting causality rather than chance association.","variants":[{"Name":"NM_000314.8(PTEN):c.1003C>T (p.Arg335Ter)","Chromosome":"10","Start":"87961095","Stop":"87961095","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22872,"rule_based_match":true,"evidence_text":"c.1003C>T p.(Arg335Ter)","llm_judgment":"PRESENT","evidence":"c.1003C>T p.(Arg335Ter)","abstract_start":522,"abstract_end":545}]}
{"pmid":"38168645","title":"Recessive TMOD1 mutation causes childhood cardiomyopathy.","abstract":"Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1<sup>R189W</sup> and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1<sup>R189W</sup> demonstrated longer thin filaments than GFP-TMOD1<sup>wt</sup>-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1<sup>R189W</sup> showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant's effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.","variants":[{"Name":"NM_003275.4(TMOD1):c.565C>T (p.Arg189Trp)","Chromosome":"9","Start":"97564115","Stop":"97564115","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222256,"rule_based_match":true,"evidence_text":"c.565C>T, p.R189W","llm_judgment":"PRESENT","evidence":"c.565C>T, p.R189W","abstract_start":236,"abstract_end":253}]}
{"pmid":"35101151","title":"Heterozygous POLG variant Ser1181Asn co-segregating in a family with autosomal dominant axonal neuropathy, proximal muscle fatigability, ptosis, and ragged red fibers.","abstract":"By whole-exome sequencing, we found the heterozygous POLG variant c.3542G>A; p.Ser1181Asn in a family of four affected individuals, presenting with a mixed neuro-myopathic phenotype. The variant is located within the active site of polymerase gamma, in a cluster region associated with an autosomal dominant inheritance. In adolescence, the index developed distal atrophies and weakness, sensory loss, afferent ataxia, double vision, and bilateral ptosis. One older sister presented with Charcot-Marie-Tooth-like symptoms, while the youngest sister and father reported exercise-induced muscle pain and proximal weakness. In none of the individuals, we observed any involvement of the central nervous system. Muscle biopsies obtained from the father and the older sister showed ragged-red fibers, and electron microscopy confirmed mitochondrial damage. We conclude that this novel POLG variant explains this family's phenotype.","variants":[{"Name":"NM_002693.3(POLG):c.3542G>A (p.Ser1181Asn)","Chromosome":"15","Start":"89317477","Stop":"89317477","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":361412,"rule_based_match":true,"evidence_text":"c.3542G>A; p.Ser1181Asn","llm_judgment":"PRESENT","evidence":"c.3542G>A; p.Ser1181Asn","abstract_start":66,"abstract_end":89}]}
{"pmid":"30262920","title":"Heterozygous LHX3 mutations may lead to a mild phenotype of combined pituitary hormone deficiency.","abstract":"LHX3 is an LIM domain transcription factor involved in the early steps of pituitary ontogenesis. We report here functional studies of three allelic variants, including the first heterozygous variant of LHX3 NM_178138.5(LHX3):c.587T>C (p.(Leu196Pro)) that may be responsible for a milder phenotype of hypopituitarism. Our functional studies showed that NM_178138.5(LHX3):c.587T>C (p.(Leu196Pro)) was not able to activate target promoters in vitro, as it did not bind DNA, and likely affected LHX3 function via a mechanism of haplo-insufficiency. Our study demonstrates the possibility that patients with a heterozygous variant of LHX3 may have pituitary deficiencies, with a milder phenotype than patients with homozygous variants. It is thus of vital to propose an optimal follow-up of such patients, who, until now, were considered as not being at risk of presenting pituitary deficiency. The second variant NM_178138.5(LHX3):c.622C>G (p.(Arg208Gly)), present in a homozygous state, displayed decreased transactivating ability without loss of binding capacity in vitro, concordant with in silico analysis; it should thus be considered to affect LHX3 function. In contrast, the NM_178138.5(LHX3):c.929G>C (p.(Arg310Pro)) variant, in a heterozygous state, also predicted as deleterious in silico, proved functionally active in vitro, and should thus still be classified as a variant of unknown significance. Our study emphasizes the need for functional studies due to the limits of software-based predictions of new variants, and the possible association of a pituitary phenotype to heterozygous LHX3 variants.","variants":[{"Name":"NM_178138.6(LHX3):c.929G>C (p.Arg310Pro)","Chromosome":"9","Start":"136197590","Stop":"136197590","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":195372,"rule_based_match":true,"evidence_text":"NM_178138.5(LHX3):c.929G>C (p.(Arg310Pro))","llm_judgment":"PRESENT","evidence":"NM_178138.5(LHX3):c.929G>C (p.(Arg310Pro))","abstract_start":1178,"abstract_end":1220}]}
{"pmid":"31302911","title":"Diagnosis of two cases from one family with Joubert syndrome caused by novel mutations of TCTN1 gene by whole exome sequencing","abstract":"OBJECTIVE: To explore the pathogenesis of two fetuses from one family affected with Joubert syndrome (JS).\nMETHODS: Whole exome sequencing was employed to screen potential mutations in both fetuses. Suspected mutations were verified by Sanger sequencing. Impact of intronic mutations on DNA transcription was validated by cDNA analysis.\nRESULTS: Two novel TCTN1 mutations, c.342-8A>G and c.1494+1G>A, were identified in exons 2 and 12, respectively.cDNA analysis confirmed the pathogenic nature of both mutations with interference of normal splicing resulting in production of truncated proteins.\nCONCLUSION: The genetic etiology of the family affected with JS has been identified.Above findings have enriched the mutation spectrum of TCTN1gene and facilitated understanding of the genotype-phenotype correlation of JS.","variants":[{"Name":"NM_001082538.3(TCTN1):c.1494+1G>A","Chromosome":"12","Start":"110645130","Stop":"110645130","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1331115,"rule_based_match":true,"evidence_text":"c.1494+1G>A","llm_judgment":"PRESENT","evidence":"c.1494+1G>A","abstract_start":388,"abstract_end":399},{"Name":"NM_001082538.3(TCTN1):c.342-8A>G","Chromosome":"12","Start":"110626354","Stop":"110626354","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3499230,"rule_based_match":true,"evidence_text":"c.342-8A>G","llm_judgment":"PRESENT","evidence":"c.342-8A>G","abstract_start":373,"abstract_end":383}]}
{"pmid":"21340159","title":"Thyroid hormone resistance detected by routine neonatal screening.","abstract":"We report the clinical and laboratory findings, and molecular analysis of a Brazilian patient with resistance to thyroid hormone syndrome (RTH) detected by neonatal screening. The index case was born at term by normal delivery with 2,920 g and 45 cm. TSH of the neonatal screening test performed on the 5(th) day of life was of 13.1 µU/mL (cut-off = 10 µU/mL). In a confirmatory test, serum TSH level was 4.3 µU/mL, total T4 was 19 µg/dL (confirmed in another sample, Total T4 = > 24.0 µg/dL), free T4 was 3.7 ηg/dL, and free T3 was 6.7 pg/mL. Direct sequencing of the beta thyroid hormone receptor gene revealed mutation c.1357C>A (P453T), confirming the diagnosis of RHT. Family study demonstrated the presence of RTH in his 1-year-and-3-month-old sister, in his 35-year-old father, and in his 68-year-old paternal grandfather. All of them had goiter and only his father had received an erroneous diagnosis of hyperthyroidism. The present case shows that clinical evaluation and a judicious interpretation of total T4/free T4 concentrations in a newborn recalled due to slightly altered neonatal TSH can contribute to the diagnosis of RTH.","variants":[{"Name":"NM_001354712.2(THRB):c.1357C>A (p.Pro453Thr)","Chromosome":"3","Start":"24122913","Stop":"24122913","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":27589,"rule_based_match":true,"evidence_text":"c.1357C>A (P453T)","llm_judgment":"PRESENT","evidence":"c.1357C>A (P453T)","abstract_start":622,"abstract_end":639}]}
{"pmid":"33638601","title":"Novel unconventional variants expand the allelic spectrum of OPHN1 gene.","abstract":"Mutations in the OPHN1 gene cause a rare X-linked recessive neurodevelopmental disorder characterized by intellectual disability, variably associated with cerebellar hypoplasia and distinctive facial appearance. In most of cases so far reported, the identified genomic variants involve the region encoding the central RhoGAP domain of the oligophrenin-1 protein, and are predicted to result in a complete loss of function. By using a NGS-based diagnostic approach, we identified three male and a female patients from two unrelated families carrying novel non-disruptive OPHN1 variants (the in-frame c.116_127 deletion and the missense c.2129C>T change, respectively), affecting either the BAR domain or the C-terminus proline-rich domain of the protein. Clinical and neuroimaging findings in the patients recapitulated the main features of OPHN1-related syndrome, including developmental delay, intellectual disability, behavioral disorder, dysmorphic features, seizures, cerebellar hypoplasia, and ventriculomegaly. Yet, we observed a wide variability even among affected siblings, confirming the lack of clear genotype-phenotype correlation. Our results expand the allelic spectrum of OPHN1 and illustrate the challenges for clinical interpretation of non-disruptive variants affecting X-linked genes.","variants":[{"Name":"NM_002547.3(OPHN1):c.116_127del (p.Val39_Asp42del)","Chromosome":"X","Start":"68432894","Stop":"68432905","ReferenceAlleleVCF":"CCGTCTTTGATTA","AlternateAlleleVCF":"C","allel_id":983699,"rule_based_match":true,"evidence_text":"c.116_127 deletion","llm_judgment":"PRESENT","evidence":"c.116_127 deletion","abstract_start":599,"abstract_end":617}]}
{"pmid":"29101065","title":"Targeted sequencing identifies novel GATA6 variants in a large cohort of patients with conotruncal heart defects.","abstract":"Studies have highlighted the critical role of GATA6 in conotruncal heart defects (CTDs). Nevertheless, relationship between GATA6 variants and different CTDs remains largely unknown. Here GATA6 gene was screened in 542 patients with CTDs using targeted sequencing. Variant frequency was 2.0% (11/542). Three novel variants: c.86C>A (p.A29E), c.296T>A (p.V99D) and c.1254delC (p.S418fs) were identified in patients with transposition of the great arteries, double outlet right ventricle and persistent truncus arteriosus, respectively, but in none of the 400 controls. Western blot revealed that A29E and V99D mutant protein had similar expression pattern with wild-type GATA6 protein, but S418fs mutant protein appeared as a truncated doublet. Reporter gene assay demonstrated that A29E and V99D mutant protein retained the ability to activate BNP and ANF promoter, whereas S418fs mutant protein failed to transactivate both of them, compared with wild-type. Subcellular localization of wild-type, A29E and V99D mutant protein were in the nucleus, while S418fs mutant protein was expressed both in the nucleus and cytoplasm. In conclusion, GATA6 variant frequency in sporadic CTDs patients was higher than that in other congenital heart diseases. Variant c.1254delC was a pathogenic variant associated with CTDs, especially PTA, whereas c.86C>A and c.296T>A should be considered as likely pathogenic variants.","variants":[{"Name":"NM_005257.6(GATA6):c.86C>A (p.Ala29Glu)","Chromosome":"18","Start":"22171230","Stop":"22171230","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1454384,"rule_based_match":true,"evidence_text":"c.86C>A (p.A29E)","llm_judgment":"PRESENT","evidence":"c.86C>A (p.A29E)","abstract_start":324,"abstract_end":340}]}
{"pmid":"19650410","title":"A novel loss-of-function mutation in the GNS gene causes Sanfilippo syndrome type D.","abstract":"UNLABELLED: A novel loss-of-function mutation in the GNS gene causes Sanfilippo syndrome type D: Mucopolysaccharidosis type IIID (MIM 252940) is the least common form of the four subtypes of Sanfilippo syndrome. It is an autosomal recessive lysosomal disorder caused by a deficiency of the N-acetylglucosamine-6-sulphatase (GlcNAc-6S sulphatase, GNS), a hydrolase, which is one of the enzymes involved in heparan sulfate catabolism leading to lysosomal storage. The clinical features of this disorder are progressive neurodegeneration with relatively mild somatic symptoms. Twenty patients have been described in the literature and only seven causative mutations in the GNS gene encoding GlcNAc-6S sulphatase have been reported to date. We present the clinical and molecular results of a newly diagnosed Turkish patient with MPS IIID. We identified the novel homozygous single base pair insertion, c.1226GinsG, which leads to a frame-shift and a premature truncation of the GNS protein (p.R409Rfs21X).\nCONCLUSION: This novel mutation provides further evidence that loss-of-function is the underlying pathophysiological mechanism of this rare phenotype.","variants":[{"Name":"NM_002076.4(GNS):c.1226dup (p.Ser410fs)","Chromosome":"12","Start":"64723087","Stop":"64723088","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":17975,"rule_based_match":false,"evidence_text":"c.1226GinsG","llm_judgment":"PRESENT","evidence":"c.1226GinsG","abstract_start":898,"abstract_end":909}]}
{"pmid":"29263050","title":"A Novel Inherited Mutation of","abstract":"Mutations in <i>SCN8A</i>, which codes for the voltage-gated sodium channel Na<sub>V</sub>1.6, have been described in relation to infantile onset epilepsy with developmental delay and cognitive impairment. Here, we report the case of an infant and her father with early onset benign familial infantile epilepsy, but without cognitive or neurological impairment. In this patient, diagnostic exome sequencing (DES) identified a heterozygous mutation (c.4427G>A; p.Gly1476Asp) in the <i>SCN8A</i> gene. This mutation, confirmed by Sanger sequencing, effects a highly conserved amino acid. In-silico analysis predicts that this mutation may be pathogenic. To our knowledge, this is the first clinical report on Korean benign familial infantile epilepsy with a <i>SCN8A</i> mutation. We were able to achieve good seizure control in our patients with sodium channel blockers. This result suggests the application of DES will be valuable for the diagnosis of patients with infantile epilepsy but no cognitive impairment.","variants":[{"Name":"NM_001330260.2(SCN8A):c.4427G>A (p.Gly1476Asp)","Chromosome":"12","Start":"51790405","Stop":"51790405","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1874494,"rule_based_match":true,"evidence_text":"c.4427G>A; p.Gly1476Asp","llm_judgment":"PRESENT","evidence":"c.4427G>A; p.Gly1476Asp","abstract_start":449,"abstract_end":472}]}
{"pmid":"26957898","title":"Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies.","abstract":"PURPOSE: To investigate the efficacy of targeted exome sequencing for mutational screening of Japanese patients with cone dystrophy (CD) or cone-rod dystrophy (CRD).\nMETHODS: DNA samples from 43 Japanese patients with CD or CRD were sequenced using an exome-sequencing panel targeting all 193 known inherited eye disease genes and next-generation sequencing methodologies. Subsequently, candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed using distinct filtering approaches, which included the frequency of the variants in normal populations, in silico prediction tools, and cosegregation.\nRESULTS: Causative mutations were detected in 12 patients with CD or CRD (27.9%). In total, 14 distinct mutations were identified in the genes ABCA4, CDHR1, CRB1, CRX, GUCY2D, KCNV2, PROM1, PRPH2, and RDH5, including four novel mutations, c.3050+1G>A in ABCA4, c.386A>G in CDHR1, c.652+1_652+4del in CRB1, and c.454G>A in KCNV2. Moreover, a putative pathogenic mutation was identified in RGS9BP, a gene recognized as the source of bradyopsia.\nCONCLUSIONS: Targeted exome sequencing effectively identified causative mutations in Japanese patients with CD or CRD. The results confirmed the heterogeneity of the genes responsible for CD and CRD in Japanese populations, as well as the efficacy of targeted exome sequencing-based screening of patients with inherited retinal degeneration.","variants":[{"Name":"NM_033100.4(CDHR1):c.386A>G (p.Asn129Ser)","Chromosome":"10","Start":"84199069","Stop":"84199069","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":947081,"rule_based_match":true,"evidence_text":"c.386A>G in CDHR1","llm_judgment":"PRESENT","evidence":"c.386A>G in CDHR1","abstract_start":912,"abstract_end":929}]}
{"pmid":"21273643","title":"In vitro functional effects of XPC gene rare variants from bladder cancer patients.","abstract":"The XPC gene is involved in repair of bulky DNA adducts formed by carcinogenic metabolites and oxidative DNA damage, both known bladder cancer risk factors. Single nucleotide polymorphisms (SNPs) in XPC have been associated with increased bladder cancer risk. Recently, rarer genetic variants have been identified but it is difficult to ascertain which are of functional importance. During a mutation screen of XPC in DNA from 33 bladder tumour samples and matched blood samples, we identified five novel variants in the patients' germ line DNA. In a case-control study of 771 bladder cancer cases and 800 controls, c.905T>C (Phe302Ser), c.1177C>T (Arg393Trp), c.*156G>A [3' untranslated region (UTR)] and c.2251-37C>A (in an intronic C>G SNP site) were found to be rare variants, with a combined odds ratio of 3.1 (95% confidence interval 1.0-9.8, P=0.048) for carriage of one variant. The fifth variant was a 2% minor allele frequency SNP not associated with bladder cancer. The two non-synonymous coding variants were predicted to have functional effects using analytical algorithms; a reduced recruitment of GFP-tagged XPC plasmids containing either c.905T>C or c.1177C>T to sites of 408 nm wavelength laser-induced oxidative DNA damage was found in vitro. c.*156G>A appeared to be associated with reduced messenger RNA stability in an in vitro plasmid-based assay. Although the laser microbeam assay is relevant to a range of DNA repair genes, our 3' UTR assay based on Green fluorescent protein(GFP) has widespread applicability and could be used to assess any gene. These assays may be useful in determining which rare variants are functional, prior to large genotyping efforts.","variants":[{"Name":"NM_004628.5(XPC):c.*156G>A","Chromosome":"3","Start":"14145785","Stop":"14145785","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":542951,"rule_based_match":true,"evidence_text":"c.*156G>A","llm_judgment":"PRESENT","evidence":"c.*156G>A","abstract_start":661,"abstract_end":670},{"Name":"NM_004628.5(XPC):c.1177C>T (p.Arg393Trp)","Chromosome":"3","Start":"14158706","Stop":"14158706","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":139223,"rule_based_match":true,"evidence_text":"c.1177C>T (Arg393Trp)","llm_judgment":"PRESENT","evidence":"c.1177C>T (Arg393Trp)","abstract_start":638,"abstract_end":659}]}
{"pmid":"25070513","title":"TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment.","abstract":"Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.","variants":[{"Name":"NM_001114748.2(TMEM240):c.489C>G (p.Tyr163Ter)","Chromosome":"1","Start":"1535392","Stop":"1535392","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":171040,"rule_based_match":true,"evidence_text":"c.489C>G/p.Y163*","llm_judgment":"PRESENT","evidence":"c.489C>G/p.Y163*","abstract_start":1175,"abstract_end":1191},{"Name":"NM_001114748.2(TMEM240):c.346C>T (p.Arg116Cys)","Chromosome":"1","Start":"1535616","Stop":"1535616","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171041,"rule_based_match":true,"evidence_text":"c.346C>T/p.R116C","llm_judgment":"PRESENT","evidence":"c.346C>T/p.R116C","abstract_start":1099,"abstract_end":1115},{"Name":"NM_001114748.2(TMEM240):c.239C>T (p.Thr80Met)","Chromosome":"1","Start":"1535723","Stop":"1535723","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171042,"rule_based_match":true,"evidence_text":"c.239C>T/p.T80M","llm_judgment":"PRESENT","evidence":"c.239C>T/p.T80M","abstract_start":1082,"abstract_end":1097},{"Name":"NM_001114748.2(TMEM240):c.511C>T (p.Arg171Trp)","Chromosome":"1","Start":"1535370","Stop":"1535370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171043,"rule_based_match":true,"evidence_text":"c.511C>T/p.R171W","llm_judgment":"PRESENT","evidence":"c.511C>T/p.R171W","abstract_start":1135,"abstract_end":1151},{"Name":"NM_001114748.2(TMEM240):c.509C>T (p.Pro170Leu)","Chromosome":"1","Start":"1535372","Stop":"1535372","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":171039,"rule_based_match":true,"evidence_text":"c.509C>T/p.P170L","llm_judgment":"PRESENT","evidence":"c.509C>T/p.P170L","abstract_start":715,"abstract_end":731}]}
{"pmid":"26963285","title":"Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.","abstract":"PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.\nMETHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.\nRESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.\nCONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.","variants":[{"Name":"NM_002336.3(LRP6):c.3398-2A>C","Chromosome":"12","Start":"12138536","Stop":"12138536","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":227050,"rule_based_match":true,"evidence_text":"c.3398-2A>C","llm_judgment":"PRESENT","evidence":"c.3398-2A>C","abstract_start":683,"abstract_end":694}]}
{"pmid":"38630895","title":"A very rare presentation of mitochondrial elongation factor Tu deficiency-","abstract":"OBJECTIVES: The mitochondrial elongation factor Tu (EF-Tu), encoded by the TUFM gene, is a GTPase, which is part of the mitochondrial protein translation mechanism. If it is activated, it delivers the aminoacyl-tRNAs to the mitochondrial ribosome. Here, a patient was described with a homozygous missense variant in the TUFM [c.1016G>A (p.Arg339Gln)] gene. To date, only six patients have been reported with bi-allelic pathogenic variants in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis, encephalopathy, and cardiomyopathy.\nCASE PRESENTATION: The patient presented here had the phenotypic features of TUFM-related disease, lactic acidosis, hypotonia, liver dysfunction, optic atrophy, and mild encephalopathy.\nCONCLUSIONS: We aimed to expand the clinical spectrum of pathogenic variants of TUFM.","variants":[{"Name":"NM_003321.5(TUFM):c.1016G>A (p.Arg339Gln)","Chromosome":"16","Start":"28844008","Stop":"28844008","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22314,"rule_based_match":true,"evidence_text":"c.1016G>A (p.Arg339Gln)","llm_judgment":"PRESENT","evidence":"c.1016G>A (p.Arg339Gln)","abstract_start":326,"abstract_end":349}]}
{"pmid":"28933964","title":"Identification of novel SPG11 mutations in a cohort of Chinese families with hereditary spastic paraplegia.","abstract":"AIM OF THE STUDY: To investigate the mutation frequency of SPG11, SPG15, SPG5 and SPG7 in China.\nMATERIALS AND METHODS: We have scanned the whole exons of KIAA1840, ZFYVE26, SPG7 and CYP7B1 genes in a group of 36 unrelated Chinese ARHSP families.\nRESULTS: SPG11 mutations were found in 33.33% (12/36) of ARHSP patients in our study, and no mutation was identified in SPG15, SPG5 or SPG7 genes. Among the SPG11 mutations detected, c.1755_1758delAGCA/p. P585PfsX623, c.29832984delTA/p.L934LfsX1010, c.1845_1848delGTCT/p.F617Lfs*5, c.6478+1G>T and c.3662_3665delTCAA/p.I1221RfsX1230 were novel mutations, they all introduced premature termination codons which were predicted to leading to the absence of the spastacsin protein in the patients' cells. All the SPG11 patients in our study presented with spastic paraparesis and/or mental impairment at initial time, and most patients showed thin corpus callosum (TCC) and white matter abnormalities (WMA) in brain MRI. After years' duration, they gradually manifested with dysarthria, dysphagia, peripheral neuropathy, amyotrophy, skeletal deformity, cerebellar signs, ophthalmoplegia, decreased vision, sphincter disturbance and tremor.\nCONCLUSIONS: SPG11 was suspected to be the most common subtype of ARHSP in China, whereas SPG15, SPG5 or SPG7 are rare. The core symptoms of Chinese SPG11 patients showed no difference when compared to SPG11 in western countries, and clinical heterogeneity also existed in our SPG11 patients. We suggested that ARHSP patients with mental impairment, especially combined with TCC, should be excluded SPG11 first in China.","variants":[{"Name":"NM_025137.4(SPG11):c.3662_3665del (p.Ile1221fs)","Chromosome":"15","Start":"44600488","Stop":"44600491","ReferenceAlleleVCF":"CTTGA","AlternateAlleleVCF":"C","allel_id":3072846,"rule_based_match":true,"evidence_text":"c.3662_3665delTCAA/p.I1221RfsX1230","llm_judgment":"PRESENT","evidence":"c.3662_3665delTCAA/p.I1221RfsX1230","abstract_start":545,"abstract_end":579}]}
{"pmid":"21801158","title":"Herlitz junctional epidermolysis bullosa: diagnostic features, mutational profile, incidence and population carrier frequency in the Netherlands.","abstract":"BACKGROUND: Junctional epidermolysis bullosa, type Herlitz (JEB-H) is a lethal, autosomal recessive blistering disease caused by null mutations in the genes coding for the lamina lucida/densa adhesion protein laminin-332 (LAMB3, LAMA3 and LAMC2).\nOBJECTIVES: To present the diagnostic features and molecular analyses of all 22 patients with JEB-H in the Dutch Epidermolysis Bullosa Registry between 1988 and 2011, and to calculate the disease incidence and carrier frequency in the Netherlands.\nMETHODS: All patients were analysed with immunofluorescence antigen mapping (IF), electron microscopy (EM) and molecular analysis.\nRESULTS: The mean lifespan of our patients with JEB-H was 5·8 months (range 0·5-32·6). IF showed absent (91%) or strongly reduced (9%) staining for laminin-332 with monoclonal antibody GB3. In EM the hemidesmosomes and sub-basal dense plates were hypoplastic or absent. We identified mutations in all 22 patients: in 19 we found LAMB3 mutations, in two LAMA3 mutations, and in one LAMC2 mutations. We found three novel splice site mutations in LAMB3: (i) c.29-2A>G resulting in an out-of-frame skip of exon 3 and a premature termination codon (PTC); (ii) c.1289-2_1296del10 leading to an out-of-frame skip of exon 12 and a PTC; and (iii) c.3228+1G>T leading to an exon 21 skip.\nCONCLUSIONS: All diagnostic tools should be evaluated to clarify the diagnosis of JEB-H. We have identified 11 different mutations in 22 patients with JEB-H, three of them novel. In the Netherlands the incidence rate of JEB-H is 4·0 per one million live births. The carrier frequency of a JEB-H mutation in the Dutch population is 1 in 249.","variants":[{"Name":"NM_000228.3(LAMB3):c.29-2A>G","Chromosome":"1","Start":"209650120","Stop":"209650120","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":186614,"rule_based_match":true,"evidence_text":"c.29-2A>G","llm_judgment":"PRESENT","evidence":"c.29-2A>G","abstract_start":1081,"abstract_end":1090}]}
{"pmid":"33462018","title":"Novel SLC12A3 mutation in Gitelman syndrome.","abstract":"Gitelman syndrome (GS) is an autosomal recessive disease characterised by the presence of hypokalaemic metabolic alkalosis with hypomagnesaemia and hypocalciuria. The prevalence of this disease is 1-10/40 000. GS is usually associated with mild and non-specific symptoms and many patients are only diagnosed in adulthood. The disease is caused by mutations in the SLC12A3 gene. We present the case of a 49-year-old man referred to a nephrology appointment due to persistent hypokalaemia and hypomagnesaemia. Complementary evaluation revealed hypokalaemia, hypomagnesaemia, metabolic alkalosis, hyperreninaemia, increased chloride and sodium urinary excretion, and reduced urinary calcium excretion. Renal function, remainder serum and urinary ionogram, and renal ultrasound were normal. A diagnosis of GS was established and confirmed with genetic testing which revealed a novel mutation in SLC12A3 (c.1072del, p.(Ala358Profs*12)). This novel mutation extends the spectrum of known SLC12A3 gene mutations and further supports the allelic heterogeneity of GS.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1072del (p.Ala358fs)","Chromosome":"16","Start":"56872760","Stop":"56872760","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":2944085,"rule_based_match":true,"evidence_text":"c.1072del","llm_judgment":"PRESENT","evidence":"c.1072del","abstract_start":900,"abstract_end":909}]}
{"pmid":"29704304","title":"Loss of function IFT27 variants associated with an unclassified lethal fetal ciliopathy with renal agenesis.","abstract":"Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult-onset disorders. Pathogenic variants in more than 100 ciliary protein-encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT-A) and anterograde transport (IFT-B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT-B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister-Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet-Biedl syndrome to a lethal phenotype.","variants":[{"Name":"NM_001177701.3(IFT27):c.352+1G>T","Chromosome":"22","Start":"36763918","Stop":"36763918","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":576322,"rule_based_match":true,"evidence_text":"c.352 +1G > T","llm_judgment":"PRESENT","evidence":"c.352 +1G > T","abstract_start":665,"abstract_end":678},{"Name":"NM_001177701.3(IFT27):c.118_125del (p.Thr40fs)","Chromosome":"22","Start":"36767355","Stop":"36767362","ReferenceAlleleVCF":"CATTCCTGT","AlternateAlleleVCF":"C","allel_id":3072947,"rule_based_match":true,"evidence_text":"c.118_125del, p.(Thr40Glyfs*11)","llm_judgment":"PRESENT","evidence":"c.118_125del, p.(Thr40Glyfs*11)","abstract_start":627,"abstract_end":658}]}
{"pmid":"34222109","title":"Identification of a Novel WFS1 Mutation Using the Whole Exome Sequencing in an Iranian Pedigree with Autosomal Dominant Hearing Loss.","abstract":"INTRODUCTION: Sensorineural hearing loss is the most frequent type of hearing impairment in the human population. Genetic factors account for over 60% of hearing loss in patients. This is a genetically heterogeneous sensorineural disorder.\nCASE REPORT: We carried out whole exome sequencing (WES) to screen hearing loss candidate genes in a member of an Iranian family with hearing loss. The Sanger process was used to sequencing the variant in the family members. A novel mutation (c. 559C > T) was found in the WFS1 gene (in exon 5) in the patient leading to a heterozygous missense mutation (p.L187F). Furthermore, it co-segregated with HL in the family. All affected individuals in the family had severe-to-profound HL.\nCONCLUSION: This survey is the first to describe WFS1 related HL in the Iranian population. Our data propose that the WFS1-p.L187F mutation is the pathogenic variant for autosomal dominant nonsyndromic hearing loss. Our results extend the range of the WFS1 gene mutations.","variants":[{"Name":"NM_006005.3(WFS1):c.559C>T (p.Leu187Phe)","Chromosome":"4","Start":"6291295","Stop":"6291295","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1929301,"rule_based_match":true,"evidence_text":"c. 559C > T","llm_judgment":"PRESENT","evidence":"c. 559C > T","abstract_start":483,"abstract_end":494}]}
{"pmid":"28018444","title":"Compound heterozygous mutations of","abstract":"Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive mitochondrial disorder of fatty acid β-oxidation, and is associated with mutations in the acyl-CoA dehydrogenase (<i>ACADS</i>) gene. Recent advances in spectrometric screening for inborn errors of metabolism have helped detect several metabolic disorders, including SCADD, without symptoms in the neonate period. This allows immediate initiation of treatment and monitoring, so they remain largely symptomless metabolic disease. Here, we report a 15-month-old asymptomatic male, who was diagnosed with SCADD by newborn screening. Spectrometric screening for inborn errors of metabolism 72 hours after birth revealed an elevated butyrylcarnitine (C4) concentration of 2.25 µmol/L (normal, <0.99 µmol/L). Urinary excretion of ethylmalonic acid was also elevated, as detected by urine organic acid analysis. To confirm the diagnosis of SCADD, direct sequencing analysis of 10 coding exons and the exon-intron boundaries of the <i>ACADS</i> gene were performed. Subsequent sequence analysis revealed compound heterozygous missense mutations c.164C>T (p.Pro55Leu) and c.1031A>G (p.Glu344Gly) on exons 2 and 9, respectively. The patient is now growing up, unretarded by symptoms such as seizure and developmental delay.","variants":[{"Name":"NM_000017.4(ACADS):c.164C>T (p.Pro55Leu)","Chromosome":"12","Start":"120727143","Stop":"120727143","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39568,"rule_based_match":true,"evidence_text":"c.164C>T (p.Pro55Leu)","llm_judgment":"PRESENT","evidence":"c.164C>T (p.Pro55Leu)","abstract_start":1122,"abstract_end":1143}]}
{"pmid":"32754643","title":"Congenital myasthenic syndrome caused by a frameshift insertion mutation in","abstract":"OBJECTIVE: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (<i>GFPT1</i>) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.\nMETHODS: Muscle biopsies, EMG, and whole-exome sequencing were performed.\nRESULTS: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the <i>GFPT1</i> gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology.\nCONCLUSIONS: These results expand on the spectrum of known loss-of-function <i>GFPT1</i> mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.","variants":[{"Name":"NM_001244710.2(GFPT1):c.686dup (p.Ala229_Arg230insTer)","Chromosome":"2","Start":"69354311","Stop":"69354312","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":1059445,"rule_based_match":true,"evidence_text":"NM_001244710.1: c.686dupC; p.Arg230Ter","llm_judgment":"PRESENT","evidence":"NM_001244710.1: c.686dupC; p.Arg230Ter","abstract_start":521,"abstract_end":559}]}
{"pmid":"19629396","title":"The frequency of NBN molecular variants in pediatric astrocytic tumors.","abstract":"Gliomas, particularly those of astrocytic origin, are the most frequent primary central nervous system tumors that develop in children. The majority of them are benign and slow growing, with relatively good prognosis. Several genomic and gene alterations are known to be involved in astrocytoma development, but the precise mechanisms remain poorly understood. The NBN gene, which participates in DNA double-strand break repair and maintenance of genome stability, has been postulated to be a susceptibility factor for a number of cancers. Here we report the results of NBN gene analyses performed in 127 children with various astrocytic tumors. PCR-SSCP analysis followed by DNA sequencing was used for molecular variant screening. Three carriers (2.37%) of different germline mutations on one NBN allele were found. The common Slavic deletion c.657_661del5 (p.K219fsX19) was detected in a patient with pilocytic astrocytoma; a known mutation, c.643C>T (p.R215W), and a new substitution, c.565C>G (p.Q189E), were identified in two patients with primary glioblastoma. The risk of developing astrocytic malignancies is estimated to be 1.33 times higher for c.657_661del5 and 3.2 times higher for c.643C>T than in the general Polish population (P > 0.05). Because of the low frequency of the mutations identified in the studied group, we were unable to determine the exact role of NBN in the development of astrocytoma in children. The presence of two potentially pathogenic NBN molecular variants among 16 glioblastoma cases (12.5%) could be a remarkable finding in our study. We thus cannot exclude a possible role of NBN in the tumorigenesis of a certain type of astrocytic tumors.","variants":[{"Name":"NM_002485.5(NBN):c.643C>T (p.Arg215Trp)","Chromosome":"8","Start":"89971232","Stop":"89971232","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21987,"rule_based_match":true,"evidence_text":"c.643C>T (p.R215W)","llm_judgment":"PRESENT","evidence":"c.643C>T (p.R215W)","abstract_start":945,"abstract_end":963},{"Name":"NM_002485.5(NBN):c.565C>G (p.Gln189Glu)","Chromosome":"8","Start":"89978239","Stop":"89978239","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":809276,"rule_based_match":true,"evidence_text":"c.565C>G (p.Q189E)","llm_judgment":"PRESENT","evidence":"c.565C>G (p.Q189E)","abstract_start":989,"abstract_end":1007}]}
{"pmid":"35150090","title":"Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant.","abstract":"BACKGROUND: The genetic architecture of hearing impairment in Finland is largely unknown. Here, we investigated two Finnish families with autosomal recessive nonsyndromic symmetrical moderate-to-severe hearing impairment.\nMETHODS: Exome and custom capture next-generation sequencing were used to detect the underlying cause of hearing impairment.\nRESULTS: In both Finnish families, we identified a homozygous pathogenic splice site variant c.637+1G>T in CAPB2 that is known to cause autosomal recessive nonsyndromic hearing impairment. Four CABP2 variants have been reported to underlie autosomal recessive nonsyndromic hearing impairment in eight families from Iran, Turkey, Pakistan, Italy, and Denmark. Of these variants, the pathogenic splice site variant c.637+1G>T is the most prevalent. The c.637+1G>T variant is enriched in the Finnish population, which has undergone multiple bottlenecks that can lead to the higher frequency of certain variants including those involved in disease.\nCONCLUSION: We report two Finnish families with hearing impairment due to the CABP2 splice site variant c.637+1G>T.","variants":[{"Name":"NM_016366.3(CABP2):c.637+1G>T","Chromosome":"11","Start":"67519792","Stop":"67519792","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":588259,"rule_based_match":true,"evidence_text":"c.637+1G>T","llm_judgment":"PRESENT","evidence":"c.637+1G>T","abstract_start":440,"abstract_end":450}]}
{"pmid":"28456143","title":"A first case of adrenomyeloneuropathy with mutation Y174S of the adrenoleukodystrophy gene.","abstract":"The patient first noticed spasticity and weakness in his legs. He was diagnosed with chronic myelogenous leukemia (CML); the symptoms were attributed to neuropathy associated with CML. By treatment with dasatinib, he achieved complete hematological remission, but his difficulty in walking was not improved. His neurological symptom worsened together with an increase in body temperature and then disappeared together with a normalized body temperature, which may be attributed to the Uhthoff's phenomenon often observed in multiple sclerosis. He later developed acute fever, vomiting and a high adrenocorticotropic hormone (ACTH) level, which was diagnosed as adrenal insufficiency. Eventually, he was diagnosed with a milder form of adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN) by increased levels of Very Long Chain Fatty Acids (VLCFAs) and genetic testing of the ATP binding cassette subfamily D member 1 (ABCD1) gene. A missense mutation (c.521A>C, p.Tyr174Ser), previously reported to induce severe cerebral ALD, was detected in exon1. Thus, clinical manifestation of ALD is determined by interaction between the primary ABCD1 mutation and modifying genetic and environmental factors. Physicians should be aware of the differing symptoms of AMN and determine the level of VLCFAs in patients having primary adrenal insufficiency, especially those complicated with neurological dysfunction. This is the first report of an AMN patient complicated with CML.","variants":[{"Name":"NM_000033.4(ABCD1):c.521A>C (p.Tyr174Ser)","Chromosome":"X","Start":"153725787","Stop":"153725787","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":677061,"rule_based_match":true,"evidence_text":"c.521A>C, p.Tyr174Ser","llm_judgment":"PRESENT","evidence":"c.521A>C, p.Tyr174Ser","abstract_start":955,"abstract_end":976}]}
{"pmid":"27592010","title":"Early Onset Parkinson's disease due to DJ1 mutations: An Indian study.","abstract":"INTRODUCTION: Early Onset Parkinson's Disease (EOPD) is genetically heterogeneous. PARK2 mutations are the commonest cause of autosomal recessive EOPD followed by PINK1.DJ1 mutations is rare and there is scarce literature on its phenotype and long term outcome.\nOBJECTIVES: We undertook a retrospective study to determine the prevalence of DJ1 mutation(s) in an Indian population and describe the clinical features and long term outcome of EOPD patients with these mutations.\nMETHODS: One hundred EOPD patients and 114 controls were evaluated. All the seven coding exons of DJ1 gene were screened for novel and reported mutations by PCR- Sanger sequencing.\nRESULTS: A novel homozygous missense mutation (c.313 A > T, p. Ile105Phe) in exon 5 was seen in one patient and four unrelated patients had a homozygous missense single nucleotide variant rs71653619 (c.293 G > A, p.Arg98Gln). The clinical phenotype comprised of asymmetrical onset, slowly progressive Parkinsonism with levodopa induced motor restlessness in a patient with the novel mutation (c.313 A > T, p. Ile105Phe) while subjects with c.293 G > A, p.Arg98Gln had early onset levodopa responsive symmetrical Parkinsonism.\nCONCLUSION: DJ1 mutations account for ∼5% of EOPD patients from the Indian population. This study further adds to the clinical spectrum of EOPD with DJ1 mutations.","variants":[{"Name":"NM_007262.5(PARK7):c.293G>A (p.Arg98Gln)","Chromosome":"1","Start":"7970934","Stop":"7970934","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":448380,"rule_based_match":true,"evidence_text":"c.293 G > A, p.Arg98Gln","llm_judgment":"PRESENT","evidence":"c.293 G > A, p.Arg98Gln","abstract_start":857,"abstract_end":880}]}
{"pmid":"38264610","title":"Novel pathogenic variants in Tubulin Tyrosine Like 5 (","abstract":"Purpose: Autosomal recessive cone and cone-rod dystrophies (CD/CRD) are inherited forms of vison loss. Here, we report on and correlate the clinical phenotypes with the underlying genetic mutations.\nMethods: Clinical information was collected from subjects, including a family history with a chart review. They underwent a full ophthalmic examination, including best-corrected visual acuity, direct and indirect ophthalmoscopy, color vision testing, color fundus photography, contrast sensitivity, autofluorescence, and spectral domain-optical coherence tomography (SD-OCT), and full-field electroretinography. Next-generation panel-based genetic testing was used to identify DNA variants in subject buccal swab samples.\nResults: Genetic testing in two patients revealed three novel variants in the <i>TTLL5</i> gene associated with CD/CRD: two missense variants (c.1433G>A;p.(Arg478Gln), c.241C>G;p.(Leu81Val), and one loss-of-function variant (c.2384_2387del;p.(Ala795Valfs*9). Based on <i>in-silico</i> analysis, structural modeling, and comparison to previously reported mutations, these novel variants are very likely to be disease-causing mutations. Combining retinal imaging with SD-OCT analysis, we observed an unusual sheen in the CD/CRD phenotypes.\nConclusion: Based on the protein domain location of novel <i>TTLL5</i> variants and the localization of TTLL5 to the connecting cilium, we conclude that the CD/CRD disease phenotype is characterized as a ciliopathy caused by protein tracking dysfunction. This initially affects cone photoreceptors, where photoreceptor cilia express a high level of TTLL5, but extends to rod photoreceptors over time. Fundus photography correlated with SD-OCT imaging suggests that the macular sheen characteristically seen with <i>TTLL5</i> mutations derives from the photoreceptor's outer segments at the posterior pole.","variants":[{"Name":"NM_015072.5(TTLL5):c.1433G>A (p.Arg478Gln)","Chromosome":"14","Start":"75745527","Stop":"75745527","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":841792,"rule_based_match":true,"evidence_text":"c.1433G>A;p.(Arg478Gln)","llm_judgment":"PRESENT","evidence":"c.1433G>A;p.(Arg478Gln)","abstract_start":864,"abstract_end":887}]}
{"pmid":"23141293","title":"DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria.","abstract":"Abnormalities in metabolite profiles are valuable indicators of underlying pathologic conditions at the molecular level. However, their interpretation relies on detailed knowledge of the pathways, enzymes, and genes involved. Identification and characterization of their physiological function are therefore crucial for our understanding of human disease: they can provide guidance for therapeutic intervention and help us to identify suitable biomarkers for monitoring associated disorders. We studied two individuals with 2-aminoadipic and 2-oxoadipic aciduria, a metabolic condition that is still unresolved at the molecular level. This disorder has been associated with varying neurological symptoms. Exome sequencing of a single affected individual revealed compound heterozygosity for an initiating methionine mutation (c.1A>G) and a missense mutation (c.2185G>A [p.Gly729Arg]) in DHTKD1. This gene codes for dehydrogenase E1 and transketolase domain-containing protein 1, which is part of a 2-oxoglutarate-dehydrogenase-complex-like protein. Sequence analysis of a second individual identified the same missense mutation together with a nonsense mutation (c.1228C>T [p.Arg410(∗)]) in DHTKD1. Increased levels of 2-oxoadipate in individual-derived fibroblasts normalized upon lentiviral expression of the wild-type DHTKD1 mRNA. Moreover, investigation of L-lysine metabolism showed an accumulation of deuterium-labeled 2-oxoadipate only in noncomplemented cells, demonstrating that DHTKD1 codes for the enzyme mediating the last unresolved step in the L-lysine-degradation pathway. All together, our results establish mutations in DHTKD1 as a cause of human 2-aminoadipic and 2-oxoadipic aciduria via impaired turnover of decarboxylation 2-oxoadipate to glutaryl-CoA.","variants":[{"Name":"NM_018706.7(DHTKD1):c.1A>G (p.Met1Val)","Chromosome":"10","Start":"12069034","Stop":"12069034","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":48162,"rule_based_match":true,"evidence_text":"c.1A>G","llm_judgment":"PRESENT","evidence":"c.1A>G","abstract_start":826,"abstract_end":832},{"Name":"NM_018706.7(DHTKD1):c.2185G>A (p.Gly729Arg)","Chromosome":"10","Start":"12112930","Stop":"12112930","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48163,"rule_based_match":true,"evidence_text":"c.2185G>A [p.Gly729Arg]","llm_judgment":"PRESENT","evidence":"c.2185G>A [p.Gly729Arg]","abstract_start":859,"abstract_end":882},{"Name":"NM_018706.7(DHTKD1):c.1228C>T (p.Arg410Ter)","Chromosome":"10","Start":"12094141","Stop":"12094141","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48164,"rule_based_match":true,"evidence_text":"c.1228C>T (p.Arg410(∗))","llm_judgment":"PRESENT","evidence":"c.1228C>T","abstract_start":1163,"abstract_end":1172}]}
{"pmid":"27111165","title":"Familial accumulation of sudden cardiac deaths and the LMNA variant c.868G>A (p.Glu290Lys).","abstract":"","variants":[{"Name":"NM_170707.4(LMNA):c.868G>A (p.Glu290Lys)","Chromosome":"1","Start":"156135244","Stop":"156135244","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":57254,"rule_based_match":true,"evidence_text":"c.868G>A (p.Glu290Lys)","llm_judgment":"PRESENT","evidence":"c.868G>A (p.Glu290Lys)","abstract_start":null,"abstract_end":null}]}
{"pmid":"26893310","title":"Early-Onset Mild Type Leukoencephalopathy Caused by a Homozygous EARS2 Mutation.","abstract":"Childhood leukoencephalopathies are a broad class of diseases, which are extremely rare. The treatment and classification of these disorders are both challenging. Nearly half of children presenting with a leukoencephalopathy remain without a specific diagnosis. Leukoencephalopathy with thalamus and brain stem involvement and high lactate (LTBL) is a newly described childhood leukoencephalopathy caused by mutations in the gene encoding a mitochondrial aminoacyl-tRNA synthetase specific for glutamate, EARS2 Magnetic resonance images show a characteristic leukoencephalopathy with thalamic and brain stem involvement. Here, we report a different clinical course of LTBL supported by typical MRI features in a Turkish patient who presented with a history of failure to walk. The EARS2 gene mutation analysis identified a c.322C>T transition, predicting a p.R108W change. This is the first reported early-onset mild type LTBL caused by a homozygous EARS2 mutation case in the literature.","variants":[{"Name":"NM_001083614.2(EARS2):c.322C>T (p.Arg108Trp)","Chromosome":"16","Start":"23544677","Stop":"23544677","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48386,"rule_based_match":true,"evidence_text":"c.322C>T","llm_judgment":"PRESENT","evidence":"c.322C>T","abstract_start":823,"abstract_end":831}]}
{"pmid":"33916827","title":"Variable Expressivity and Allelic Heterogeneity in Type 2 Familial Partial Lipodystrophy: The p.(Thr528Met) LMNA Variant.","abstract":"Type 2 familial partial lipodystrophy, or Dunnigan disease, is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution. This rare condition results from variants principally affecting exons 8 and 11 of the <i>LMNA</i> gene. In this study, five FPLD2-diagnosed patients carrying the c.1583C>T, p.(Thr528Met) variant in exon 9 of the <i>LMNA</i> gene and with obvious clinical heterogeneity were evaluated. Specific polymorphisms in <i>LMNA</i> and in <i>PPARG</i> were also detected. Exhaustive clinical course, physical examination, biochemical features and family history were recorded, along with the assessment of anthropometric features and body composition by dual-energy X-ray absorptiometry. Preadipocytes obtained from a T528M patient were treated with the classic adipose differentiation medium with pioglitazone. Various adipogenes were evaluated by real-time PCR, and immunofluorescence was used to study intracellular localization of emerin, lamin A and its precursors. As demonstrated with Oil red O staining, the preadipocytes of the T528M patient failed to differentiate, the expression of various adipogenic genes was reduced in the lipodystrophic patient and immunofluorescence studies showed an accumulation of farnesylated prelamin A in T528M cells. We conclude that the T528M variant in <i>LMNA</i> could lead to FPLD2, as the adipogenic machinery is compromised.","variants":[{"Name":"NM_170707.4(LMNA):c.1583C>T (p.Thr528Met)","Chromosome":"1","Start":"156137207","Stop":"156137207","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":77748,"rule_based_match":true,"evidence_text":"c.1583C>T, p.(Thr528Met)","llm_judgment":"PRESENT","evidence":"c.1583C>T, p.(Thr528Met)","abstract_start":314,"abstract_end":338}]}
{"pmid":"36508859","title":"Generation of an induced pluripotent stem cell line (SHCDNi007-A) from a patient with pyruvate carboxylase deficiency carrying compound heterozygous (c.182 T > C/ c.2581G > A) variants in PC.","abstract":"Pyruvate carboxylase (PC) deficiency (PCD), due to biallelic PC variants, is a rare inherited metabolic disease, which is characterized by seizures, global developmental delay, as well as lactic acidosis, and elevated plasma pyruvate and alanine levels in affected individuals. In the present study, a new induced pluripotent stem cell line (SHCDNi007-A) was generated from the peripheral blood mononuclear cells of a 2-month-old male infant with biallelic PC mutations c.(182 T > C;2581G > A), i.e. p.(Ile61Thr;Val861Met). This cell line is expected to facilitate the in vitro modeling of the disease pathophysiology and the development of future therapeutics for PCD.","variants":[{"Name":"NM_001040716.2(PC):c.2581G>A (p.Val861Met)","Chromosome":"11","Start":"66850357","Stop":"66850357","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3534051,"rule_based_match":true,"evidence_text":"c.2581G > A","llm_judgment":"PRESENT","evidence":"c.2581G > A","abstract_start":null,"abstract_end":null}]}
{"pmid":"28716533","title":"Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis.","abstract":"Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot UBQLN2 domain was identified in a sporadic case of ALS. These mutations are conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding with HSP70, and impaired autophagic pathway. Our results confirm the role of PXX repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a SP phenotype, evidence a highly reduced disease penetrance in females carrying UBQLN2 mutations, which is important information for genetic counseling, and underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways.","variants":[{"Name":"NM_013444.4(UBQLN2):c.1481C>T (p.Pro494Leu)","Chromosome":"X","Start":"56565354","Stop":"56565354","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1878278,"rule_based_match":true,"evidence_text":"c.1481C>T, p.Pro494Leu, P494L","llm_judgment":"PRESENT","evidence":"c.1481C>T, p.Pro494Leu, P494L","abstract_start":251,"abstract_end":280}]}
{"pmid":"30244301","title":"MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features.","abstract":"MEDNIK syndrome is an autosomal recessive rare disease as one of the most recently described copper metabolism disorder characterized by intellectual disability, ichthyosis, hearing loss, peripheral neuropathy, enteropathy and keratodermia. Here in, we reported a case presented with ichthyosis and intellectual disability with MEDNIK syndrome that confirmed by mutation analysis in a Turkish child. She was finally diagnosed with MEDNIK syndrome by clinical findings, which were confirmed by molecular genetic testing. Sequencing of AP1S1 gene showed a homozygous insertion c.364dupG (NM_001283.4), which is predicted to cause a frameshift of the reading frame (p.D122Gfs*18). To our knowledge, this is the first case of MEDNIK syndrome from Turkey. Diagnosis of MEDNIK syndrome is still challenging and we hope that this case will contribute to further understanding.","variants":[{"Name":"NM_001283.5(AP1S1):c.364dup (p.Asp122fs)","Chromosome":"7","Start":"101159123","Stop":"101159124","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":495299,"rule_based_match":true,"evidence_text":"c.364dupG (NM_001283.4)","llm_judgment":"PRESENT","evidence":"c.364dupG (NM_001283.4)","abstract_start":575,"abstract_end":598}]}
{"pmid":"16619214","title":"Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression.","abstract":"Germline mutations in the human breast cancer susceptibility genes BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancer. In spite of the large number of sequence variants identified in BRCA1 and BRCA2 mutation analyses, many of these genetic alterations are still classified as variants of unknown significance (VUS). In this study, we evaluated 12 BRCA1/2 intronic variants in order to differentiate their pathogenic or polymorphic effects on the mRNA splicing process. We detected the existence of aberrant splicing in three BRCA1 variants (c.301-2delA/IVS6-2delA, c.441+1G>A/IVS7+1G>A, and c.4986+6T>G/IVS16+6T>G) and two BRCA2 variants (c.8487+1G>A/IVS19+1G>A and c.8632-2A>G/IVS20-2A>G). All but one of the aberrant transcripts arise from mutations affecting the conserved splice acceptor or donor sequences and all would be predicted to result in expression of truncated BRCA1 or BRCA2 proteins. However, we demonstrated that four of these splice-site mutations (i.e., c.301-2delA, c.441+1G>A, c.4986+6T>G, and c.8632-2A>G) with premature termination codons were highly unstable and were unlikely to encode for abundant expression of a mutant protein. Three variants of BRCA1 (c.212+3A>G/IVS5+3A>G, c.593+8A>G/IVS9+8A>G, and c.4986-20A>G/IVS16-20A>G) and four variants of BRCA2 (c.516-19C>T/IVS6-19C>T, c.7976-4_7976_3delTT/IVS17-4delTT, c.8487+19A>G/IVS19+19A>G, and c.9256- 18C>A/IVS24- 18C>A) in our studies show no effects on the normal splicing process, and they are considered to be benign polymorphic alterations. Our studies help to clarify the aberrant splicing in BRCA1 and BRCA2 as well as provide information that can be used clinically to help counsel breast/ovarian cancer prone families.","variants":[{"Name":"NM_007294.4(BRCA1):c.212+3A>G","Chromosome":"17","Start":"43106453","Stop":"43106453","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":69134,"rule_based_match":true,"evidence_text":"c.212+3A>G/IVS5+3A>G","llm_judgment":"PRESENT","evidence":"c.212+3A>G/IVS5+3A>G","abstract_start":1211,"abstract_end":1231},{"Name":"NM_000059.4(BRCA2):c.8487+1G>A","Chromosome":"13","Start":"32370558","Stop":"32370558","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67270,"rule_based_match":true,"evidence_text":"c.8487+1G>A/IVS19+1G>A","llm_judgment":"PRESENT","evidence":"c.8487+1G>A/IVS19+1G>A","abstract_start":669,"abstract_end":691},{"Name":"NM_007294.4(BRCA1):c.441+1G>A","Chromosome":"17","Start":"43104121","Stop":"43104121","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":69862,"rule_based_match":true,"evidence_text":"c.441+1G>A/IVS7+1G>A","llm_judgment":"PRESENT","evidence":"c.441+1G>A/IVS7+1G>A","abstract_start":595,"abstract_end":615},{"Name":"NM_007294.4(BRCA1):c.4986+6T>G","Chromosome":"17","Start":"43070922","Stop":"43070922","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":70011,"rule_based_match":true,"evidence_text":"c.4986+6T>G/IVS16+6T>G","llm_judgment":"PRESENT","evidence":"c.4986+6T>G/IVS16+6T>G","abstract_start":621,"abstract_end":643}]}
{"pmid":"35170635","title":"Early occurrence of primary angle-closure glaucoma in a patient with retinitis pigmentosa and CRB1 gene variations.","abstract":"We describe the case of a 15-year-old girl with decreased visual acuity associated with elevated intraocular pressure in both eyes and angle closure on gonioscopy. She also presented attenuation of retinal vessels and optic disc pallor with large excavation in the left eye. Ultrasound biomicroscopy revealed an anteriorly positioned ciliary body and absence of ciliary sulcus, confirming the plateau iris configuration. Spectral-domain optical coherence tomography revealed a bilateral cystoid macular edema. Genetic screening revealed heterozygous variants of the Crumbs homolog 1 (CRB1) gene (c.2843G>A and c.2506C>A). The patient underwent trabeculectomy for intraocular pressure control and topical treatment for macular edema. This case highlights the importance of performing gonioscopy and evaluating intraocular pressure in patients with a shallow anterior chamber despite young age. In addition, it also shows the importance of genetic screening, when available, in elucidating the diagnosis and providing patients and their families' information on the patient's prognosis and possible therapeutic options.","variants":[{"Name":"NM_201253.3(CRB1):c.2843G>A (p.Cys948Tyr)","Chromosome":"1","Start":"197434706","Stop":"197434706","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48213,"rule_based_match":true,"evidence_text":"c.2843G>A","llm_judgment":"PRESENT","evidence":"c.2843G>A","abstract_start":596,"abstract_end":605}]}
{"pmid":"21340152","title":"Long-term response to sulfonylurea in a patient with diabetes due to mutation in the KCNJ11 gene.","abstract":"OBJECTIVE: To report the long-term (30-month) effect of the switch from insulin to sulfonylurea in a patient carrying the p.G53D (c.158G>A) mutation in KCNJ11 gene.\nSUBJECT AND METHOD: A 29-year-old male patient was diagnosed with diabetes in the third month of life and after identification of a heterozygous p.G53D mutation in the KCNJ11 gene, the therapy was switched from insulin to sulfonylurea.\nRESULTS: Long-term follow-up (30 months) showed that good metabolic control was maintained (HbA1c: 6.6%) and the glibenclamide dose could be reduced.\nCONCLUSION: Long-term therapy with sulfonylureas in patients with neonatal diabetes due to mutation in the KCNJ11 gene is safe and promotes sustained improvement of glycemic control.","variants":[{"Name":"NM_000525.4(KCNJ11):c.158G>A (p.Gly53Asp)","Chromosome":"11","Start":"17387934","Stop":"17387934","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23724,"rule_based_match":true,"evidence_text":"c.158G>A","llm_judgment":"PRESENT","evidence":"c.158G>A","abstract_start":130,"abstract_end":138}]}
{"pmid":"31513304","title":"A founder variant in the South Asian population leads to a high prevalence of FANCL Fanconi anemia cases in India.","abstract":"Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, predisposition to cancer, and congenital abnormalities. FA is caused by pathogenic variants in any of 22 genes involved in the DNA repair pathway responsible for removing interstrand crosslinks. FANCL, an E3 ubiquitin ligase, is an integral component of the pathway, but patients affected by disease-causing FANCL variants are rare, with only nine cases reported worldwide. We report here a FANCL founder variant, anticipated to be synonymous, c.1092G>A;p.K364=, but demonstrated to induce aberrant splicing, c.1021_1092del;p.W341_K364del, that accounts for the onset of FA in 13 cases from South Asia, 12 from India and one from Pakistan. We comprehensively illustrate the pathogenic nature of the variant, provide evidence for a founder effect, and propose including this variant in genetic screening of suspected FA patients in India and Pakistan, as well as those with ancestry from these regions of South Asia.","variants":[{"Name":"NM_018062.4(FANCL):c.1092G>A (p.Lys364=)","Chromosome":"2","Start":"58160108","Stop":"58160108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":918140,"rule_based_match":true,"evidence_text":"c.1092G>A;p.K364=","llm_judgment":"PRESENT","evidence":"c.1092G>A;p.K364=","abstract_start":529,"abstract_end":546}]}
{"pmid":"16386954","title":"Genetic and phenotypic analysis of dilated cardiomyopathy with conduction system disease: demand for strategies in the management of presymptomatic lamin A/C mutant carriers.","abstract":"BACKGROUND: One-third of cases of dilated cardiomyopathy (DCM) is of familial aetiology. Several genes have been reported to cause the autosomal dominant form of DCM.\nAIMS: To analyze the lamin A/C gene (LMNA) in 31 unrelated patients with DCM and conduction system disease (CSD).\nMETHODS: Patients and family members underwent physical examination, ECG/Holter-ECG, echocardiography, and selective coronary angiography. Genetic analysis of all coding exons of LMNA was performed using PCR and sequencing.\nRESULTS: Three different LMNA mutations (Arg377His, c.1397delA, c.424_425ins21nt) were identified in three families with autosomal dominant disease comprised of 39 individuals. 21 individuals were mutation carriers, of whom 12 were symptomatic. We observed a progressive and age-dependent form of DCM with CSD and arrhythmias. First, the patients developed a moderate left ventricular dilatation without symptoms. Later, systolic function declined progressively and the patients became symptomatic resulting in a high mortality due to sudden death and heart failure.\nCONCLUSIONS: Genetic screening leads to the identification of symptomatic and asymptomatic mutant carriers. The latter at a young age should be regarded as \"presymptomatic\" because of the age-dependent disease manifestation. New guidelines are required for the management of these individuals.","variants":[{"Name":"NM_170707.4(LMNA):c.1397del (p.Asn466fs)","Chromosome":"1","Start":"156136936","Stop":"156136936","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":77717,"rule_based_match":true,"evidence_text":"c.1397delA","llm_judgment":"PRESENT","evidence":"c.1397delA","abstract_start":557,"abstract_end":567},{"Name":"NM_170707.4(LMNA):c.1130G>A (p.Arg377His)","Chromosome":"1","Start":"156136094","Stop":"156136094","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29534,"rule_based_match":false,"evidence_text":"Arg377His","llm_judgment":"PRESENT","evidence":"Arg377His","abstract_start":546,"abstract_end":555}]}
{"pmid":"19239046","title":"Recurrent post-infectious rhabdomyolysis in muscle CPT-II deficiency caused by a novel missense mutation.","abstract":"A case is reported of a 39-year-old woman with recurrent rhabdomyolysis caused by minor S. pyogenes tonsillitis. She was diagnosed with the adult form of CPT-II deficiency. Molecular analysis revealed compound heterozygosity for a common c.338C > T (p.Ser113Leu) mutation in exon 3 and a most likely pathogenic c.200C > G (p.Ala67Gly) variant in exon 2. Here we discuss the case, along with a clinical review of rhabdomyolysis and adult CPT-II deficiency. When a patient presents with recurrent episodes of rhabdomyolysis, especially when provoked by minor causes, a thorough work-up for a possible metabolic myopathy is mandatory.","variants":[{"Name":"NM_000098.3(CPT2):c.200C>G (p.Ala67Gly)","Chromosome":"1","Start":"53200766","Stop":"53200766","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":824231,"rule_based_match":true,"evidence_text":"c.200C > G (p.Ala67Gly)","llm_judgment":"PRESENT","evidence":"c.200C > G (p.Ala67Gly)","abstract_start":311,"abstract_end":334}]}
{"pmid":"19261599","title":"Germline mutation in DOK7 associated with fetal akinesia deformation sequence.","abstract":"BACKGROUND: Fetal akinesia deformation sequence syndrome (FADS) is a heterogeneous disorder characterised by fetal akinesia and developmental defects including, in some case, pterygia. Multiple pterygium syndromes (MPS) are traditionally divided into prenatally lethal and non-lethal (such as Escobar) types. Previously, we and others reported that homozygous mutations in the fetal acetylcholine receptor gamma subunit (CHRNG) can cause both lethal and non-lethal MPS, demonstrating that pterygia resulted from fetal akinesia, and that mutations in the acetylcholine receptor subunits CHRNA1, CHRND, and Rapsyn (RAPSN) can also result in a MPS/FADS phenotype.\nMETHODS: We hypothesised that mutations in other acetylcholine receptor related genes may interfere with neurotransmission at the neuromuscular junction and so we analysed 14 cases of lethal MPS/FADS without CHRNG, CHRNA1, CHRNB1, CHRND, or RAPSN mutations for mutations in DOK7.\nRESULTS: A homozygous DOK7 splice site mutation, c.331+1G>T, was identified in a family with three children affected with lethal FADS. Previously DOK7 mutations have been reported to underlie a congenital myaesthenic syndrome with a characteristic \"limb girdle\" pattern of muscle weakness.\nCONCLUSION: This finding is consistent with the hypothesis that whereas incomplete loss of DOK7 function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.","variants":[{"Name":"NM_173660.5(DOK7):c.331+1G>T","Chromosome":"4","Start":"3473637","Stop":"3473637","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":443612,"rule_based_match":true,"evidence_text":"c.331+1G>T","llm_judgment":"PRESENT","evidence":"c.331+1G>T","abstract_start":990,"abstract_end":1000}]}
{"pmid":"34741762","title":"Low genetic confirmation rate in South Indian subjects with a clinical diagnosis of maturity-onset diabetes of the young (MODY) who underwent targeted next-generation sequencing for 13 genes.","abstract":"PURPOSE: To screen for maturity-onset diabetes of the young (MODY) variants in subjects with an early age of onset and positive family history of diabetes mellitus.\nMETHODS: 60 subjects with onset of diabetes between 3 and 30 years of age and parental history (onset < 35 years) of diabetes were recruited after excluding autoimmune, pancreatic and syndromic forms of diabetes. Detailed pedigree chart and clinical data were recorded. MODY genetic testing (MODY 1-13) was performed and variant classification was done adhering to the ACMG guidelines.\nRESULTS: Baseline characteristics of subjects were as follows: mean age of onset of diabetes 19.9 ± 7 years, mean duration of diabetes 6.3 ± 6.8 years, BMI 23.3 ± 3 kg/m<sup>2</sup> and C-peptide 1.56 ± 1.06 nmol/l. Four out of sixty (6.6%) were positive for variants classifiable as pathogenic/likely pathogenic: one patient with HNF4Ac.691C > T, (p.Arg231Trp), two with HNF 1A c.746C > A(p.Ser249Ter) and c.1340C > T(p.Pro447Leu), and one with ABCC8 c.4544C > T (p.Thr1515Met). MODY 1 and MODY 3 variants were documented in the paediatric age group (< 18 years).\nCONCLUSION: A genetic diagnosis of MODY could be confirmed in only 6.6% (4/60) of patients clinically classifiable as MODY. This is less than that reported in clinically diagnosed MODY subjects of European descent. Newly published population data and more stringent criteria for assessment of pathogenicity and younger age of onset of type 2 diabetes in Indians could have contributed to the lower genetic confirmation rate. Apart from variants in the classical genes (HNF1A, HNF4A), a likely pathogenic variant in a non-classical gene (ABCC8) was noted in this study.","variants":[{"Name":"NM_000352.6(ABCC8):c.4544C>T (p.Thr1515Met)","Chromosome":"11","Start":"17394267","Stop":"17394267","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1339911,"rule_based_match":true,"evidence_text":"ABCC8 c.4544C > T (p.Thr1515Met)","llm_judgment":"PRESENT","evidence":"ABCC8 c.4544C > T (p.Thr1515Met)","abstract_start":997,"abstract_end":1029},{"Name":"NM_000545.8(HNF1A):c.1340C>T (p.Pro447Leu)","Chromosome":"12","Start":"120997504","Stop":"120997504","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29967,"rule_based_match":true,"evidence_text":"c.1340C > T(p.Pro447Leu)","llm_judgment":"PRESENT","evidence":"c.1340C > T(p.Pro447Leu)","abstract_start":958,"abstract_end":982}]}
{"pmid":"29437493","title":"Identification of Five Novel Variants in Chinese Oculocutaneous Albinism by Targeted Next-Generation Sequencing.","abstract":"BACKGROUND: The diagnosis of oculocutaneous albinism (OCA) is established using clinical signs and symptoms. OCA is, however, a highly genetically heterogeneous disease with mutations identified in at least nineteen unique genes, many of which produce overlapping phenotypic traits. Thus, differentiating genetic OCA subtypes for diagnoses and genetic counseling is challenging, based on clinical presentation alone, and would benefit from a comprehensive molecular diagnostic.\nAIM: To develop and validate a more comprehensive, targeted, next-generation-sequencing-based diagnostic for the identification of OCA-causing variants.\nMATERIALS AND METHODS: The genomic DNA samples from 28 OCA probands were analyzed by targeted next-generation sequencing (NGS), and the candidate variants were confirmed through Sanger sequencing.\nRESULTS: We observed mutations in the TYR, OCA2, and SLC45A2 genes in 25/28 (89%) patients with OCA. We identified 38 pathogenic variants among these three genes, including 5 novel variants: c.1970G>T (p.Gly657Val), c.1669A>C (p.Thr557Pro), c.2339-2A>C, and c.1349C>G (p.Thr450Arg) in OCA2; c.459_470delTTTTGCTGCCGA (p.Ala155_Phe158del) in SLC45A2.\nCONCLUSION: Our findings expand the mutational spectrum of OCA in the Chinese population, and the assay we developed should be broadly useful as a molecular diagnostic, and as an aid for genetic counseling for OCA patients.","variants":[{"Name":"NM_000275.3(OCA2):c.1970G>T (p.Gly657Val)","Chromosome":"15","Start":"27926236","Stop":"27926236","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3072837,"rule_based_match":true,"evidence_text":"c.1970G>T (p.Gly657Val)","llm_judgment":"PRESENT","evidence":"c.1970G>T (p.Gly657Val)","abstract_start":1019,"abstract_end":1042}]}
{"pmid":"32125366","title":"Recurrent bi-allelic splicing variant c.454+3A>G in TRAPPC4 is associated with progressive encephalopathy and muscle involvement.","abstract":"","variants":[{"Name":"NM_016146.6(TRAPPC4):c.454+3A>G","Chromosome":"11","Start":"119020256","Stop":"119020256","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":373902,"rule_based_match":true,"evidence_text":"c.454+3A>G","llm_judgment":"PRESENT","evidence":"c.454+3A>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"30458859","title":"Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance.","abstract":"BACKGROUND: Deleterious variants in the tumour suppressor BRCA1 are known to cause hereditary breast and ovarian cancer syndrome (HBOC). Missense variants in BRCA1 pose a challenge in clinical care, as their effect on protein functionality often remains unknown. Many of the pathogenic missense variants found in BRCA1 are located in the BRCA1 C-terminal (BRCT) domains, domains that are known to be vital for key functions such as homologous recombination repair, protein-protein interactions and trans-activation (TA). We investigated the TA activity of 12 BRCA1 variants of unknown clinical significance (VUSs) located in the BRCT domains to aid in the classification of these variants.\nRESULTS: Twelve BRCA1 VUSs were investigated using a modified version of the dual luciferase TA activity assay (TA assay) that yielded increased sensitivity and sample throughput. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria using TA assay results and available data. In combining our TA-assay results and available data, in accordance with the ACMG guidelines for variant classification, we proposed the following variant classifications: c.5100A>G, c.5326C>T, c.5348T>C and c.5477A>T as likely benign (class 2) variants. c.5075A>C, c.5116G>A and c.5513T>G were likely pathogenic (class 4), whereas c.5096G>A likely represents a likely pathogenic variant with moderate penetrance. Variants c.5123C>T, c.5125G>A, c.5131A>C and c.5504G>A remained classified as VUSs (class 3).\nCONCLUSIONS: The modified TA assay provides efficient risk assessment of rare missense variants found in the BRCA1 BRCT-domains. We also report that increased post-transfection incubation time yielded a significant increase in TA assay sensitivity.","variants":[{"Name":"NM_007294.4(BRCA1):c.5348T>C (p.Met1783Thr)","Chromosome":"17","Start":"43049179","Stop":"43049179","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":46215,"rule_based_match":true,"evidence_text":"c.5348T>C","llm_judgment":"PRESENT","evidence":"c.5348T>C","abstract_start":1211,"abstract_end":1220},{"Name":"NM_007294.4(BRCA1):c.5326C>T (p.Pro1776Ser)","Chromosome":"17","Start":"43051069","Stop":"43051069","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":402467,"rule_based_match":true,"evidence_text":"c.5326C>T","llm_judgment":"PRESENT","evidence":"c.5326C>T","abstract_start":1200,"abstract_end":1209},{"Name":"NM_007294.4(BRCA1):c.5100A>G (p.Thr1700=)","Chromosome":"17","Start":"43063926","Stop":"43063926","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":184887,"rule_based_match":true,"evidence_text":"c.5100A>G","llm_judgment":"PRESENT","evidence":"c.5100A>G","abstract_start":1189,"abstract_end":1198},{"Name":"NM_007294.4(BRCA1):c.5116G>A (p.Gly1706Arg)","Chromosome":"17","Start":"43063910","Stop":"43063910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":262101,"rule_based_match":true,"evidence_text":"c.5116G>A","llm_judgment":"PRESENT","evidence":"c.5116G>A","abstract_start":1283,"abstract_end":1292},{"Name":"NM_007294.4(BRCA1):c.5513T>G (p.Val1838Gly)","Chromosome":"17","Start":"43045757","Stop":"43045757","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":249180,"rule_based_match":true,"evidence_text":"c.5513T>G","llm_judgment":"PRESENT","evidence":"c.5513T>G","abstract_start":1297,"abstract_end":1306},{"Name":"NM_007294.4(BRCA1):c.5075A>C (p.Asp1692Ala)","Chromosome":"17","Start":"43063951","Stop":"43063951","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":249182,"rule_based_match":true,"evidence_text":"c.5075A>C","llm_judgment":"PRESENT","evidence":"c.5075A>C","abstract_start":1272,"abstract_end":1281},{"Name":"NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln)","Chromosome":"17","Start":"43063930","Stop":"43063930","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":46192,"rule_based_match":true,"evidence_text":"c.5096G>A","llm_judgment":"PRESENT","evidence":"c.5096G>A","abstract_start":1349,"abstract_end":1358}]}
{"pmid":"35842834","title":"A novel splice site variant in the POPDC3 causes autosomal recessive limb-girdle muscular dystrophy type 26.","abstract":"Limb-Girdle muscular dystrophy (LGMD) is a group of muscle disorders with highly heterogeneous genetic patterns and clinical phenotypes, and this group includes multiple subtypes. Different LGMD subtypes have similar phenotypes and clinical overlaps, these subtypes are difficult to distinguish by clinical symptoms alone and can only be accurately diagnosed by analysis in combination with definitive genetic test results. Here, we report a female presenting features of LGMD. After analysis of whole-exome sequencing data, a novel homozygous POPDC3 variant c.486-1G>A (rs113419658) located in the acceptor splice site of intron 2 was identified in the proband. The variant effect on splicing were analyzed by genetic analysis based on cDNA synthesized by the patient's RNA. cDNA analysis indicated that the novel homozygous POPDC3 splice variant disrupted original acceptor splice site, which can cause a frameshift in the mRNA of the POPDC3 gene, thereby producing a truncated POPDC3 protein and ultimately affecting its normal function. POPDC3 variant was recently associated with recessive limb-girdle muscular dystrophy type 26 (LGMDR26). Based on the above results, we hypothesize that this variant is probably a pathogenic variant, and expand the gene variant spectrum of POPDC3.","variants":[{"Name":"NM_022361.5(POPDC3):c.486-1G>A","Chromosome":"6","Start":"105159820","Stop":"105159820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3228469,"rule_based_match":true,"evidence_text":"c.486-1G>A","llm_judgment":"PRESENT","evidence":"c.486-1G>A","abstract_start":559,"abstract_end":569}]}
{"pmid":"22371915","title":"A Korean patient with Morquio B disease with a novel c.13_14insA mutation in the GLB1 gene.","abstract":"Mutations in the GLB1 gene, which encodes acid β-galactosidase, can result in two disease phenotypes: GM1-gangliosidosis (MIM #230500) and Morquio B disease (Mucopolysaccharidosis type IVB, MIM #253010). Morquio B disease occurs much more infrequently than GM1-gangliodosis and is characterized by severe skeletal manifestations (dysostosis multiplex) without central nervous system involvement. Here, we report the first known Korean patient with Morquio B disease. A 7-year-old boy presented with severe progressive skeletal dysplasia including scoliosis, contractures of the elbows, xenu valgum, funnel chest, and trigger thumb requiring surgical intervention. The patient had normal neurological functions and mental status when evaluated by pediatric neurologists. The patient's urinary glycosaminoglycans, measured by the cetylpyridinium chloride (CPC) precipitation test, were 252.8 CPC unit/g creatinine (reference range < 175). Thin layer chromatography of urine showed a keratan sulfate band. Enzyme activity of β-galactosidase in leukocytes was 1.15 nmol/hr/mg protein (reference range 78.1-117.7; 1-1.5% of normal). The patient had compound heterozygous mutations of the GLB1 gene: c.13_14insA (p.L5HfsX29), which was reported in a patient with infantile GM1 gangliosidosis with the near-complete absence of enzyme activity, and c.367G>A (p.G123R), which is a novel frame-shift mutation. In summary, we report the first known Korean patient with Morquio B disease and a novel mutation (c.13_14insA of GLB1).","variants":[{"Name":"NM_000404.4(GLB1):c.367G>A (p.Gly123Arg)","Chromosome":"3","Start":"33068849","Stop":"33068849","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15967,"rule_based_match":true,"evidence_text":"c.367G>A (p.G123R)","llm_judgment":"PRESENT","evidence":"c.367G>A (p.G123R)","abstract_start":1341,"abstract_end":1359}]}
{"pmid":"28886345","title":"RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes.","abstract":"RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.","variants":[{"Name":"NM_006908.5(RAC1):c.218C>T (p.Pro73Leu)","Chromosome":"7","Start":"6392034","Stop":"6392034","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1087055,"rule_based_match":true,"evidence_text":"c.218C>T (p.Pro73Leu)","llm_judgment":"PRESENT","evidence":"c.218C>T (p.Pro73Leu)","abstract_start":468,"abstract_end":489},{"Name":"NM_006908.5(RAC1):c.53G>A (p.Cys18Tyr)","Chromosome":"7","Start":"6387229","Stop":"6387229","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":438552,"rule_based_match":true,"evidence_text":"c.53G>A (p.Cys18Tyr)","llm_judgment":"PRESENT","evidence":"c.53G>A (p.Cys18Tyr)","abstract_start":423,"abstract_end":443},{"Name":"NM_006908.5(RAC1):c.116A>G (p.Asn39Ser)","Chromosome":"7","Start":"6391932","Stop":"6391932","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":438553,"rule_based_match":true,"evidence_text":"c.116A>G (p.Asn39Ser)","llm_judgment":"PRESENT","evidence":"c.116A>G (p.Asn39Ser)","abstract_start":445,"abstract_end":466},{"Name":"NM_006908.5(RAC1):c.470G>A (p.Cys157Tyr)","Chromosome":"7","Start":"6402337","Stop":"6402337","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":438554,"rule_based_match":true,"evidence_text":"c.470G>A (p.Cys157Tyr)","llm_judgment":"PRESENT","evidence":"c.470G>A (p.Cys157Tyr)","abstract_start":495,"abstract_end":517},{"Name":"NM_006908.5(RAC1):c.190T>G (p.Tyr64Asp)","Chromosome":"7","Start":"6392006","Stop":"6392006","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":438555,"rule_based_match":true,"evidence_text":"c.190T>G (p.Tyr64Asp)","llm_judgment":"PRESENT","evidence":"c.190T>G (p.Tyr64Asp)","abstract_start":779,"abstract_end":800},{"Name":"NM_006908.5(RAC1):c.151G>A (p.Val51Met)","Chromosome":"7","Start":"6391967","Stop":"6391967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":438556,"rule_based_match":true,"evidence_text":"c.151G>A (p.Val51Met)","llm_judgment":"PRESENT","evidence":"c.151G>A (p.Val51Met)","abstract_start":630,"abstract_end":651},{"Name":"NM_006908.5(RAC1):c.151G>C (p.Val51Leu)","Chromosome":"7","Start":"6391967","Stop":"6391967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":438557,"rule_based_match":true,"evidence_text":"c.151G>C (p.Val51Leu)","llm_judgment":"PRESENT","evidence":"c.151G>C (p.Val51Leu)","abstract_start":656,"abstract_end":677}]}
{"pmid":"30471091","title":"A HS6ST2 gene variant associated with X-linked intellectual disability and severe myopia in two male twins.","abstract":"X-linked intellectual disability (XLID) refers to a clinically and genetically heterogeneous neurodevelopmental disorder, in which males are more heavily affected than females. Among the syndromic forms of XLID, identified by additional clinical signs as part of the disease spectrum, the association between XLID and severe myopia has been poorly characterized. We used whole exome sequencing (WES) to study two Italian male twins presenting impaired intellectual function and adaptive behavior, in association with severe myopia and mild facial dysmorphisms. WES analysis detected the novel, maternally inherited, mutation c.916G > C (G306R) in the X-linked heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) gene. HS6ST2 transfers sulfate from adenosine 3'-phosphate, 5'-phosphosulfate to the sixth position of the N-sulphoglucosamine residue in heparan sulfate (HS) proteoglycans. Low HS sulfation levels are associated with defective optic disc and stalk morphogenesis during mammalian visual system development. The c.916G>C variant affects the HS6ST2 substrate binding site, and its effect was considered \"deleterious\" by in-silico tools. An in-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity. Taken together, the results suggest that mutant HS6ST2 is possibly involved in the development of myopia and cognitive impairment, characteristics of the probands reported here.","variants":[{"Name":"NM_001394073.1(HS6ST2):c.916G>C (p.Gly306Arg)","Chromosome":"X","Start":"132956839","Stop":"132956839","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":622129,"rule_based_match":true,"evidence_text":"c.916G > C (G306R)","llm_judgment":"PRESENT","evidence":"c.916G > C (G306R)","abstract_start":625,"abstract_end":643}]}
{"pmid":"27069701","title":"Early Infantile Epileptic Encephalopathy in an STXBP1 Patient with Lactic Acidemia and Normal Mitochondrial Respiratory Chain Function.","abstract":"A wide range of clinical findings have been associated with mutations in Syntaxin Binding Protein 1 (STXBP1), including multiple forms of epilepsy, nonsyndromic intellectual disability, and movement disorders. STXBP1 mutations have recently been associated with mitochondrial pathology, although it remains unclear if this phenotype is a part of the core feature for this gene disorder. We report a 7-year-old boy who presented for diagnostic evaluation of intractable epilepsy, episodic ataxia, resting tremor, and speech regression following a period of apparently normal early development. Mild lactic acidemia was detected on one occasion at the time of an intercurrent illness. Due to the concern for mitochondrial disease, ophthalmologic evaluation was performed that revealed bilateral midperiphery pigmentary mottling. Optical coherence tomography (OCT) testing demonstrated a bilaterally thickened ganglion cell layer in the perifovea. Skeletal muscle biopsy analysis showed no mitochondrial abnormalities or respiratory chain dysfunction. Exome sequencing identified a de novo c.1651C>T (p.R551C) mutation in STXBP1. Although mitochondrial dysfunction has been reported in some individuals, our proband had only mild lactic acidemia and no skeletal muscle tissue evidence of mitochondrial disease pathology. Thus, mitochondrial dysfunction is not an obligate feature of STXBP1 disease.","variants":[{"Name":"NM_001032221.6(STXBP1):c.1651C>T (p.Arg551Cys)","Chromosome":"9","Start":"127682509","Stop":"127682509","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":202328,"rule_based_match":true,"evidence_text":"c.1651C>T (p.R551C)","llm_judgment":"PRESENT","evidence":"c.1651C>T (p.R551C)","abstract_start":1087,"abstract_end":1106}]}
{"pmid":"21549337","title":"Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome.","abstract":"Accelerated aging syndromes represent a valuable source of information about the molecular mechanisms involved in normal aging. Here, we describe a progeroid syndrome that partially phenocopies Hutchinson-Gilford progeria syndrome (HGPS) but also exhibits distinctive features, including the absence of cardiovascular deficiencies characteristic of HGPS, the lack of mutations in LMNA and ZMPSTE24, and a relatively long lifespan of affected individuals. Exome sequencing and molecular analysis in two unrelated families allowed us to identify a homozygous mutation in BANF1 (c.34G>A [p.Ala12Thr]), encoding barrier-to-autointegration factor 1 (BAF), as the molecular abnormality responsible for this Mendelian disorder. Functional analysis showed that fibroblasts from both patients have a dramatic reduction in BAF protein levels, indicating that the p.Ala12Thr mutation impairs protein stability. Furthermore, progeroid fibroblasts display profound abnormalities in the nuclear lamina, including blebs and abnormal distribution of emerin, an interaction partner of BAF. These nuclear abnormalities are rescued by ectopic expression of wild-type BANF1, providing evidence for the causal role of this mutation. These data demonstrate the utility of exome sequencing for identifying the cause of rare Mendelian disorders and underscore the importance of nuclear envelope alterations in human aging.","variants":[{"Name":"NM_003860.4(BANF1):c.34G>A (p.Ala12Thr)","Chromosome":"11","Start":"66003284","Stop":"66003284","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39347,"rule_based_match":true,"evidence_text":"c.34G>A [p.Ala12Thr]","llm_judgment":"PRESENT","evidence":"c.34G>A [p.Ala12Thr]","abstract_start":576,"abstract_end":596}]}
{"pmid":"35042684","title":"Novel","abstract":"BACKGROUND: To characterise the phenotype and genetic defects of isolated ectopia lentis (IEL) and to determine the <i>ADAMTSL4</i> gene mutation frequencies in a Chinese congenital ectopia lentis (CEL) cohort.\nMETHODS: In total, 127 Chinese probands with a clinical CEL diagnosis were recruited for this study and underwent ocular and systemic examinations. Whole-exome sequencing was used to detect variants, and Sanger sequencing and bioinformatics analysis verified the pathogenic mutations.\nRESULTS: Overall, biallelic mutations in <i>ADAMTSL4,</i> involving 8 novel <i>ADAMTSL4</i> mutations (c.21-2A>G, c.1174G>C, c.2169C>A, c.2236C>T, c.2263delG, c.2397C>A, c.2488dupC and c.2935T>C) were identified in 5 probands (5/127, 3.94%) with IEL. Additionally, four patients had combined congenital cataracts, and two patients had ectopia lentis et pupillae (ELP). One of eight mutations was a homozygous missense mutation, and the other seven mutations were compound heterozygous. These eight consisted of three missense (37.5%), three frameshift (37.5%), one stop-gain (12.5%) and one spicing mutation (12.5%). These mutations co-segregated with the IEL, and the substitution of amino acids greatly affected conserved residues. Most of the novel mutations were located in the thrombospondin type 1 (TSP1) domain, which ultimately alters the structure of the ADAMTSL4 protein.\nCONCLUSIONS: This study reported five IEL probands with eight novel mutations in the <i>ADAMTSL4</i> gene. The clinical IEL phenotypes caused by these mutations were variable and complex. This study thus establishes the <i>ADAMTSL4</i> gene mutation frequency and expands the gene's mutation spectrum to help recognise <i>ADAMTSL4</i>-related IEL clinical manifestations.","variants":[{"Name":"NM_019032.6(ADAMTSL4):c.2236C>T (p.Arg746Cys)","Chromosome":"1","Start":"150558003","Stop":"150558003","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":862229,"rule_based_match":true,"evidence_text":"c.2236C>T","llm_judgment":"PRESENT","evidence":"c.2236C>T","abstract_start":632,"abstract_end":641}]}
{"pmid":"27620137","title":"In vitro residual activity of phenylalanine hydroxylase variants and correlation with metabolic phenotypes in PKU.","abstract":"Hyperphenylalaninemias (HPAs) are genetic diseases predominantly caused by a wide range of variants in the phenylalanine hydroxylase (PAH) gene. In vitro expression analysis of PAH variants offers the opportunity to elucidate the molecular mechanisms involved in HPAs and to clarify whether a disease-associated variant is genuinely pathogenic, while investigating the severity of a metabolic phenotype, and determining how a variant exerts its deleterious effects on the PAH enzyme. To study the effects of gene variants on PAH activity, we investigated eight variants: c.611A>G (p.Y204C), c.635T>C (p.L212P), c.746T>C (p.L249P), c.745C>T (p.L249F), c.809G>A (p.R270K), c.782G>C (p.R261P), c.587C>A (p.S196Y) and c.1139C>T (p.T380M), associated with different phenotypic groups. Transient expression of mutant full-length cDNAs in COS-7 cells yielded PAH proteins with PAH activity levels between 7% and 51% compared to the wild-type enzyme. With one exception (p.Y204C, which had no significant impact on PAH function), lower PAH activity was associated with a more severe phenotype (e.g. p.L249P with 7% PAH activity, 100% of classic PKU and no BH<sub>4</sub> responsiveness), while higher activity correlated with milder phenotypes (e.g. p.T380M with 28% PAH activity, 97% of mild HPA and 83% of BH<sub>4</sub> responsiveness). The results of the in vitro residual PAH activity have major implications, both for our understanding of genotype-phenotype correlations, and thereby existing inconsistencies, but also for the elucidation of the molecular basis of tetrahydrobiopterin (BH<sub>4</sub>) responsiveness.","variants":[{"Name":"NM_000277.3(PAH):c.809G>A (p.Arg270Lys)","Chromosome":"12","Start":"102852848","Stop":"102852848","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":108582,"rule_based_match":true,"evidence_text":"c.809G>A (p.R270K)","llm_judgment":"PRESENT","evidence":"c.809G>A (p.R270K)","abstract_start":651,"abstract_end":669},{"Name":"NM_000277.3(PAH):c.1139C>T (p.Thr380Met)","Chromosome":"12","Start":"102843706","Stop":"102843706","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15667,"rule_based_match":true,"evidence_text":"c.1139C>T (p.T380M)","llm_judgment":"PRESENT","evidence":"c.1139C>T (p.T380M)","abstract_start":714,"abstract_end":733},{"Name":"NM_000277.3(PAH):c.635T>C (p.Leu212Pro)","Chromosome":"12","Start":"102855207","Stop":"102855207","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":108504,"rule_based_match":true,"evidence_text":"c.635T>C (p.L212P)","llm_judgment":"PRESENT","evidence":"c.635T>C (p.L212P)","abstract_start":591,"abstract_end":609},{"Name":"NM_000277.3(PAH):c.782G>C (p.Arg261Pro)","Chromosome":"12","Start":"102852875","Stop":"102852875","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":108568,"rule_based_match":true,"evidence_text":"c.782G>C (p.R261P)","llm_judgment":"PRESENT","evidence":"c.782G>C (p.R261P)","abstract_start":671,"abstract_end":689}]}
{"pmid":"21575681","title":"A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay.","abstract":"Mutations in the Jumonji AT-rich interactive domain 1C (JARID1C/SMCX/KDM5C) gene, located at Xp11.22, are emerging as frequent causes of X-linked intellectual disability (XLID). KDM5C encodes for a member of an ARID protein family that harbors conserved DNA-binding motifs and acts as a histone H3 lysine 4 demethylase, suggesting a potential role in epigenetic regulation during development, cell growth and differentiation. In this study, we describe clinical and genetic findings of a Brazilian family co-segregating a novel nonsense mutation (c.2172C>A) in exon 15 of KDM5C gene with the intellectual disability phenotype. The transition resulted in replacement of the normal cysteine by a premature termination codon at position 724 of the protein (p.Cys724X), leading to reduced levels of KDM5C transcript probably due to nonsense mediated mRNA decay. The clinical phenotype of the proband, who has two affected brothers and a mild cognitively impaired mother, consisted of short stature, speech delay, hyperactivity, violent behavior and high palate, besides severe mental retardation. Our findings extend the number of KDM5C mutations implicated in XLID and highlight its promise for understanding neural function and unexplained cases of XLID.","variants":[{"Name":"NM_004187.5(KDM5C):c.2172C>A (p.Cys724Ter)","Chromosome":"X","Start":"53199048","Stop":"53199048","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":38951,"rule_based_match":true,"evidence_text":"c.2172C>A","llm_judgment":"PRESENT","evidence":"c.2172C>A","abstract_start":547,"abstract_end":556}]}
{"pmid":"36275728","title":"Phenotypic spectrum in recessive STING-associated vasculopathy with onset in infancy: Four novel cases and analysis of previously reported cases.","abstract":"Gain-of-function variants in the stimulator of interferon response cGAMP interactor 1 (<i>STING1</i>) gene cause STING-Associated Vasculopathy with onset in Infancy (SAVI). Previously, only heterozygous and mostly <i>de novo STING1</i> variants have been reported to cause SAVI. Interestingly, one variant that only leads to SAVI when homozygous, namely c.841C>T p.(Arg281Trp), has recently been described. However, there are no entries in public databases regarding an autosomal recessive pattern of inheritance. Here, we report four additional unrelated SAVI patients carrying c.841C>T in homozygous state. All patients had interstitial lung disease and displayed typical interferon activation patterns. Only one child displayed cutaneous vasculitis, while three other patients presented with a relatively mild SAVI phenotype. Steroid and baricitinib treatment had a mitigating effect on the disease phenotype in two cases, but failed to halt disease progression. Heterozygous c.841C>T carriers in our analysis were healthy and showed normal interferon activation. Literature review identified eight additional cases with autosomal recessive SAVI caused by c.841C>T homozygosity. In summary, we present four novel and eight historic cases of autosomal recessive SAVI. We provide comprehensive clinical data and show treatment regimens and clinical responses. To date, SAVI has been listed as an exclusively autosomal dominant inherited trait in relevant databases. With this report, we aim to raise awareness for autosomal recessive inheritance in this rare, severe disease which may aid in early diagnosis and development of optimized treatment strategies.","variants":[{"Name":"NM_198282.4(STING1):c.841C>T (p.Arg281Trp)","Chromosome":"5","Start":"139477434","Stop":"139477434","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":830366,"rule_based_match":true,"evidence_text":"c.841C>T p.(Arg281Trp)","llm_judgment":"PRESENT","evidence":"c.841C>T p.(Arg281Trp)","abstract_start":354,"abstract_end":376}]}
{"pmid":"30692597","title":"A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency.","abstract":"The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1 (c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows. Magnetic resonance imaging delineated anterior pituitary hypoplasia, ectopic posterior pituitary, invisible pituitary stalk, thinning of the corpus callosum, and hypoplasia of the pons and midbrain. The phenotypically normal parents (first cousins) were heterozygous for the mutation. The results provide further evidence of ROBO1 being involved in the development of the pituitary gland. A recessive mutation of ROBO1 is a potential novel cause of a syndromic disorder associated with combined pituitary hormone deficiency.","variants":[{"Name":"NM_002941.4(ROBO1):c.1342+1G>A","Chromosome":"3","Start":"78685745","Stop":"78685745","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":983744,"rule_based_match":true,"evidence_text":"c.1342+1G>A","llm_judgment":"PRESENT","evidence":"c.1342+1G>A","abstract_start":305,"abstract_end":316}]}
{"pmid":"22711506","title":"Enhanced S-cone syndrome with preserved macular structure and severely depressed retinal function.","abstract":"We present ophthalmic features and genetic analysis findings of a 44-year-old croatian patient with enhanced S-cone syndrome (ESCS). Complete ophthalmic examination, Ishihara colour vision test, dark adaptometry, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging, Goldmann visual field and automated perimetry, full-field electroretinography (ERG), multifocal ERG, S-cone ERG and ON-OFF ERG were performed. Mutation screening of the NR2E3 gene, which encodes a photoreceptor-specific orphan nuclear receptor, was performed with polymerase chain reaction amplification and direct sequencing. The patient has good visual acuity and normal colour vision. Fundus examination showed normal posterior pole and nummular pigment depositions at the level of the retinal pigment epithelium in the mid-periphery of the retina. The SD-OCT images showed normal macular structure and thickness. The ERG showed characteristic findings: photopic and scotopic responses to the same stimulus had a similar waveform and were dominated by short-wavelength-sensitive mechanisms. Mutation analysis revealed the known NR2E3 mutation c.481delA (p.Thr161HisFsX18) and the novel NR2E3 variant c.1120C > T (p.Leu374Phe). To the best of our knowledge, this is the only ESCS patient older than 40 years who phenotypically has preserved macular structure, good central visual acuity and severely depressed full-field ERG as well as the first reported patient with NR2E3 mutation from Croatia.","variants":[{"Name":"NM_014249.4(NR2E3):c.1120C>T (p.Leu374Phe)","Chromosome":"15","Start":"71817571","Stop":"71817571","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3408280,"rule_based_match":true,"evidence_text":"c.1120C > T (p.Leu374Phe)","llm_judgment":"PRESENT","evidence":"c.1120C > T (p.Leu374Phe)","abstract_start":1204,"abstract_end":1229},{"Name":"NM_014249.4(NR2E3):c.481del (p.Thr161fs)","Chromosome":"15","Start":"71812086","Stop":"71812086","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":623884,"rule_based_match":true,"evidence_text":"c.481delA (p.Thr161HisFsX18)","llm_judgment":"PRESENT","evidence":"c.481delA (p.Thr161HisFsX18)","abstract_start":1147,"abstract_end":1175}]}
{"pmid":"21150919","title":"Low prevalence of classical galactosemia in Korean population.","abstract":"This study described the clinical and molecular genetic features of classical galactosemia in Korean population to contribute to the insight in the spectrum of galactosemia in the world, as little is known about the spectrum and incidence of galactosemia in Asia. During the 11-year study period, only three Korean children were identified as having classical galactosemia on the basis of the enzymatic and molecular genetic analysis. Asians have been reported to have mutations distinct from those of Caucasians and African Americans, indicating that galactose-1-phosphate uridyltransferase mutations are ethnically diverse. Our three patients had a total of three mutations (c.252+1G > A, p.Q169H and p.E363K), two of which were novel (p.E363K and c.252+1G > A) mutations. Interestingly, c.252+1G > A, which leads to skipping of exon 2, was observed in all three patients (three of six alleles), indicating that this mutation may be common in Koreans with classical galactosemia. Screening for classical galactosemia in 158,126 Korean newborns identified no patient with classical galactosemia. In conclusion, our findings provide further evidence for the ethnic diversity of classical galactosemia, which may be as rare in Koreans as in other Asian populations.","variants":[{"Name":"NM_000155.4(GALT):c.252+1G>A","Chromosome":"9","Start":"34647259","Stop":"34647259","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":801676,"rule_based_match":true,"evidence_text":"c.252+1G > A","llm_judgment":"PRESENT","evidence":"c.252+1G > A","abstract_start":677,"abstract_end":689}]}
{"pmid":"30872814","title":"Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma.","abstract":"Roma are a socially and culturally distinct isolated population with genetically divergent subisolates, residing mainly across Central, Southern, and Eastern Europe. We evaluated the genetic etiology of hearing impairment (HI) in 15 Hungarian Roma families through exome sequencing. A family with autosomal dominant non-syndromic HI segregating a rare variant in the Calponin-homology 2 domain of PLS1, or Plastin 1 [p.(Leu363Phe)] was identified. Young adult Pls1 knockout mice have progressive HI and show morphological defects to their inner hair cells. There is evidence that PLS1 is important in the preservation of adult stereocilia and normal hearing. Four families segregated the European ancestral variant c.35delG [p.(Gly12fs)] in GJB2, and one family was homozygous for p.(Trp24*), an Indian subcontinent ancestral variant which is common amongst Roma from Slovakia, Czech Republic, and Spain. We also observed variants in known HI genes USH1G, USH2A, MYH9, MYO7A, and a splice site variant in MANBA (c.2158-2A>G) in a family with HI, intellectual disability, behavioral problems, and respiratory inflammation, which was previously reported in a Czech Roma family with similar features. Lastly, using multidimensional scaling and ADMIXTURE analyses, we delineate the degree of Asian/European admixture in the HI families understudy, and show that Roma individuals carrying the GJB2 p.(Trp24*) and MANBA c.2158-2A>G variants have a more pronounced South Asian background, whereas the other hearing-impaired Roma display an ancestral background similar to Europeans. We demonstrate a diverse genetic HI etiology in the Hungarian Roma and identify a new gene PLS1, for autosomal dominant human non-syndromic HI.","variants":[{"Name":"NM_004004.6(GJB2):c.35del (p.Gly12fs)","Chromosome":"13","Start":"20189547","Stop":"20189547","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":32043,"rule_based_match":true,"evidence_text":"c.35delG [p.(Gly12fs)]","llm_judgment":"PRESENT","evidence":"c.35delG [p.(Gly12fs)]","abstract_start":715,"abstract_end":737},{"Name":"NM_001145319.2(PLS1):c.1087C>T (p.Leu363Phe)","Chromosome":"3","Start":"142689723","Stop":"142689723","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":581871,"rule_based_match":false,"evidence_text":"p.(Leu363Phe)","llm_judgment":"PRESENT","evidence":"p.(Leu363Phe)","abstract_start":417,"abstract_end":430},{"Name":"NM_005908.4(MANBA):c.2158-2A>G","Chromosome":"4","Start":"102635047","Stop":"102635047","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":581872,"rule_based_match":true,"evidence_text":"c.2158-2A>G","llm_judgment":"PRESENT","evidence":"c.2158-2A>G","abstract_start":1012,"abstract_end":1023}]}
{"pmid":"26376857","title":"Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria.","abstract":"A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.","variants":[{"Name":"NM_003041.4(SLC5A2):c.265G>A (p.Ala89Thr)","Chromosome":"16","Start":"31484885","Stop":"31484885","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247547,"rule_based_match":true,"evidence_text":"c.265G>A (p.A89T)","llm_judgment":"PRESENT","evidence":"c.265G>A","abstract_start":993,"abstract_end":1001}]}
{"pmid":"23562761","title":"A novel familial case of diffuse leukodystrophy related to NDUFV1 compound heterozygous mutations.","abstract":"NDUFV1 mutations have been related to encephalopathic phenotypes due to mitochondrial energy metabolism disturbances. In this study, we report two siblings affected by a diffuse leukodystrophy, who carry the NDUFV1 c.1156C>T (p.Arg386Cys) missense mutation and a novel 42-bp deletion. Bioinformatic and molecular analysis indicated that this deletion lead to the synthesis of mRNA molecules carrying a premature stop codon, which might be degraded by the nonsense-mediated decay system. Our results add information on the molecular basis and the phenotypic features of mitochondrial disease caused by NDUFV1 mutations.","variants":[{"Name":"NM_007103.4(NDUFV1):c.1156C>T (p.Arg386Cys)","Chromosome":"11","Start":"67611972","Stop":"67611972","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":408448,"rule_based_match":true,"evidence_text":"c.1156C>T (p.Arg386Cys)","llm_judgment":"PRESENT","evidence":"c.1156C>T (p.Arg386Cys)","abstract_start":215,"abstract_end":238}]}
{"pmid":"18435799","title":"Homozygous FGF3 mutations result in congenital deafness with inner ear agenesis, microtia, and microdontia.","abstract":"Homozygous mutations in the fibroblast growth factor 3 (FGF3) gene have recently been discovered in an autosomal recessive form of syndromic deafness characterized by complete labyrinthine aplasia (Michel aplasia), microtia, and microdontia (OMIM 610706 - LAMM). In order to better characterize the phenotypic spectrum associated with FGF3 mutations, we sequenced the FGF3 gene in 10 unrelated families in which probands had congenital deafness associated with various inner ear anomalies, including Michel aplasia, with or without tooth or external ear anomalies. FGF3 sequence changes were not found in eight unrelated probands with isolated inner ear anomalies or with a cochlear malformation along with auricle and tooth anomalies. We identified two new homozygous FGF3 mutations, p.Leu6Pro (c.17T>C) and p. Ile85MetfsX15 (c.254delT), in four subjects from two unrelated families with LAMM. The p.Leu6Pro mutation occurred within the signal site of FGF3 and is predicted to impair its secretion. The c.254delT mutation results in truncation of FGF3. Both mutations completely co-segregated with the phenotype, and heterozygotes did not have any of the phenotypic findings of LAMM. Some affected children had large skin tags on the upper side of the auricles, which is a distinctive clinical component of the syndrome. Enlarged collateral emissary veins associated with stenosis of the jugular foramen were noted on computerized tomographies of most affected subjects with FGF3 mutations. However, similar venous anomalies were also detected in persons with non-syndromic Michel aplasia, suggesting that a direct causative role of impaired FGF3 signaling is unlikely.","variants":[{"Name":"NM_005247.4(FGF3):c.17T>C (p.Leu6Pro)","Chromosome":"11","Start":"69818917","Stop":"69818917","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28880,"rule_based_match":true,"evidence_text":"c.17T>C","llm_judgment":"PRESENT","evidence":"c.17T>C","abstract_start":796,"abstract_end":803}]}
{"pmid":"34624274","title":"The utility of whole-exome sequencing in accurate diagnosis of neuromuscular disorders in consanguineous families in Jordan.","abstract":"BACKGROUND: Neuromuscular disorders (NMDs) encompass a large group of genetic and acquired diseases affecting muscles, leading to progressive muscular weakness. These disorders are frequently inherited in an autosomal-recessive (AR) pattern with extreme heterogeneity and various clinical presentations. Consanguinity increases the likelihood of AR disorders, with high rates of cousin inbreeding in Jordan and other Arab countries. In Jordan, the implementation of genetic diagnosis is limited, with delayed or misdiagnosis of genetic disorders. Thus, the lack of genetic counselling and specialized treatment options is frequently encountered in the country.\nMETHODS: Whole-exome sequencing (WES) was conducted for eleven probands from ten Jordanian families who have been formerly diagnosed with limb-girdle dystrophy (LGMD) and Charcot-Marie-Tooth disease (CMT). The previous diagnoses were established principally on clinical examination in the absence of genetic testing. Additionally, Sanger sequencing and segregation analysis were used to validate the resulted pathogenic variants.\nRESULTS: Multiple variants were identified using WES: For DYSF gene, a missense variant (c. 4076 T > C, p.Leu1359Pro) in exon 38; a nonsense variant (c. 4321C > T, p.Gln1441Ter) in exon 39; a single-nucleotide deletion (c. 5711delG, p.Gly1904AlafsTer101) in exon 51. Other variants included a missense variant (c. 122G > A, p.Arg41Gln) in exon 3 of MPV17 gene, a single-nucleotide deletion (c. 859 delC, p.Lue287Ser fs14*) in exon 6 of SGCB gene, a missense variant (c. 311G > A, p.Gly104Asp) in exon 2 of SLC25A46 gene, a nonsense variant (c. 496C > T, p.Arg166Ter) in exon 5 of SGCG gene, and a nonsense variant (c.3202C > T, p.Gln1068Ter) in exon 13 of SH3TC2 gene.\nCONCLUSION: Utilization of WES is helpful to facilitate rapid and accurate NMDs diagnosis, complementing a thorough clinical evaluation. This approach can be invaluable to aid in the identification of genetic risks among consanguineous couples. Subsequently, well-informed genetic counselling and potential individualized treatment can be provided.","variants":[{"Name":"NM_000232.5(SGCB):c.859del (p.Leu287fs)","Chromosome":"4","Start":"52024055","Stop":"52024055","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":519960,"rule_based_match":true,"evidence_text":"c. 859 delC, p.Lue287Ser fs14*","llm_judgment":"PRESENT","evidence":"c. 859 delC, p.Lue287Ser fs14*","abstract_start":1482,"abstract_end":1512},{"Name":"NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro)","Chromosome":"2","Start":"71611481","Stop":"71611481","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":542183,"rule_based_match":true,"evidence_text":"c. 4076 T > C, p.Leu1359Pro","llm_judgment":"PRESENT","evidence":"c. 4076 T > C, p.Leu1359Pro","abstract_start":1180,"abstract_end":1207}]}
{"pmid":"16152649","title":"Molecular study of WISP3 in nine families originating from the Middle-East and presenting with progressive pseudorheumatoid dysplasia: identification of two novel mutations, and description of a founder effect.","abstract":"Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive syndrome characterized by the presence of spondyloepiphyseal dysplasia associated with pain, stiffness, and swelling of multiple joints, osteoporosis, and the absence of destructive bone changes. The disorder is caused by mutations of the WISP3 gene located on chromosome 6q22. We hereby report the molecular study of the WISP3 gene in nine unrelated consanguineous families originating from the Middle-East: three from Lebanon, five from Syria, and one from Palestinian Bedouin descent, all affected with PPD. Five different sequence variations were identified in the WISP3 gene, two of them being new mutations: the c.589G --> C transversion at codon 197, responsible for a splicing defect (A197fsX201); and the c.536_537delGT deletion (C179fsX), both in exon 3. In all other families, the affected patients were homozygous for a previously described nonsense mutation, namely c.156C --> A (C52X). Interestingly, in the latter families, the C52X mutation was always found associated with a novel c.248G --> A (G83E) variation, suggesting the existence of a founder effect.","variants":[{"Name":"NM_198239.2(CCN6):c.156C>A (p.Cys52Ter)","Chromosome":"6","Start":"112061098","Stop":"112061098","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":21420,"rule_based_match":false,"evidence_text":"c.156C --> A (C52X)","llm_judgment":"PRESENT","evidence":"c.156C --> A (C52X)","abstract_start":954,"abstract_end":973}]}
{"pmid":"27830735","title":"The use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia.","abstract":"Familial hypercholesterolemia (FH) is an autosomal dominant disorder. Although genetic testing is an important tool for detecting FH-causing mutations in patients, diagnostic methods for young patients with severe hypercholesterolemia are understudied. This study compares the target exome sequencing (TES) technique with the DNA resequencing array technique on young patients with severe hypercholesterolemia. A total of 20 unrelated patients (mean age 14.8 years) with total cholesterol > 10 mmol/L were included. 12 patient samples were processed by DNA resequencing array, 14 patient samples were processed by TES, and 6 patient samples were processed by both methods. Functional characterization of novel mutations was performed by flow cytometry. The mutation detection rate (MDR) of DNA resequencing array was 75%, while the MDR of TES was 100%. A total of 27 different mutations in the LDLR were identified, including 3 novel mutations and 8 mutations with previously unknown pathogenicity. Functional characterization of c.673delA, c.1363delC, p.Leu575Phe and p.Leu582Phe variants found that all of them are pathogenic. Additionally, 7 patients were diagnosed with Heterozygous FH (HeFH) in which lipid levels were significantly higher than common HeFH patients. This data indicates that TES is a very efficient tool for genetic diagnosis in young patients with severe hypercholesterolemia.","variants":[{"Name":"NM_000527.5(LDLR):c.1363del (p.Gln455fs)","Chromosome":"19","Start":"11113537","Stop":"11113537","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":246128,"rule_based_match":true,"evidence_text":"c.1363delC","llm_judgment":"PRESENT","evidence":"c.1363delC","abstract_start":1041,"abstract_end":1051},{"Name":"NM_000527.5(LDLR):c.1723C>T (p.Leu575Phe)","Chromosome":"19","Start":"11116876","Stop":"11116876","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":431955,"rule_based_match":false,"evidence_text":"p.Leu575Phe","llm_judgment":"PRESENT","evidence":"p.Leu575Phe","abstract_start":1053,"abstract_end":1064}]}
{"pmid":"31934147","title":"Identification of a novel pre-terminating mutation in human HBB gene as a cause of β","abstract":"Beta (β)-thalassemia (thal) is one of the most common genetic disorders of hemoglobin synthesis worldwide. Most cases of β-thal are caused by point mutations in hemoglobin subunit beta (HBB) gene, and only a minority of cases are caused by missing mutations of HBB gene. In this study, a 31-year-old pregnant woman with a typical thal phenotype was admitted at Fujian Provincial Maternity and Children's Hospital for prenatal diagnosis. Her father also presented with a typical thal phenotype, while the other members in the proband family were normal. Interestingly, Gap-PCR and reverse dot-blot hybridization assays showed that no mutation was found in the human HBA and HBB genes of the proband and her father. Subsequently, Sanger DNA sequencing identified a novel pre-terminating mutation, c.271 G>T [CD90 (GAG>TAG, Glu→stop codon)], in HBB gene from the proband and her father, while the other members in the proband family were normal. This mutation created a stop codon at amino acid 90 in exon 2 coding sequences of HBB gene, and led to a β<sup>0</sup>-thal phenotype. In summary, the present study is, to the best of our knowledge, the first to report a pre-terminating mutation, c.271 G>T [CD90 (GAG>TAG, Glu→stop codon)], in human HBB gene as a cause of β<sup>0</sup>-thal phenotype. This is important for clarifying the molecular mechanism of β<sup>0</sup>-thal and is useful for genetic counseling and prenatal screening.","variants":[{"Name":"NM_000518.5(HBB):c.271G>T (p.Glu91Ter)","Chromosome":"11","Start":"5226621","Stop":"5226621","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":30543,"rule_based_match":true,"evidence_text":"c.271 G>T [CD90 (GAG>TAG, Glu→stop codon)]","llm_judgment":"PRESENT","evidence":"c.271 G>T [CD90 (GAG>TAG, Glu→stop codon)]","abstract_start":795,"abstract_end":837}]}
{"pmid":"28977582","title":"Cardiac paraganglioma with a novel germline mutation of succinate dehydrogenase gene D.","abstract":"A 58-year-old woman with a past medical history of a carotid body tumor, resected 4 months prior to presentation, was admitted to our hospital for treatment of a cardiac tumor that was identified on post-operative echocardiography and chest computed tomography. The cardiac tumor was surgically removed and identified pathologically as a paraganglioma, similarly to the carotid body tumor. Genetic analysis of both tumors identified a non-synonymous mutation in the succinate dehydrogenase (SDH) gene D, Exon4, c.320T>C, p.Leu107Pro showing co-segregation with paternal transmission and maternal imprinting among family members. This novel mutation appears to be the cause of familial paraganglioma in this patient.","variants":[{"Name":"NM_003002.4(SDHD):c.320T>C (p.Leu107Pro)","Chromosome":"11","Start":"112094810","Stop":"112094810","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1785214,"rule_based_match":true,"evidence_text":"c.320T>C, p.Leu107Pro","llm_judgment":"PRESENT","evidence":"c.320T>C, p.Leu107Pro","abstract_start":511,"abstract_end":532}]}
{"pmid":"31730820","title":"28 novel mutations identified from 33 Chinese patients with cilia-related kidney disorders.","abstract":"BACKGROUND: Cilia play an important role in cellular signaling pathways. Defective ciliary function causes a variety of disorders involve retina, skeleton, liver, kidney or others. Cilia-related kidney disorders are characterized by cystic renal disease, nephronophthisis and renal failure in general.\nMETHODS: In this study, we collected 33 families clinically suspected of cilia-related kidney disorders. Capture-based next-generation sequencing (NGS) of 88 related genes, Sanger sequencing, pedigree analysis and functional study were performed to analyze their genetic cause.\nRESULTS: 40 mutations in PKD1, PKD2, PKHD1, DYNC2H1 and TMEM67 genes were identified from 27 of 33 affected families. 70% (28/40) of the mutations were first found in patients. We reported a very early-onset autosomal dominant polycystic kidney disease (ADPKD) family caused by a novel heterozygous PKD1 mutation; another fetus with DYNC2H1 compound heterozygous missense mutations showed mainly kidney dysplasia instead of skeletal abnormalities; and a novel PKD1 mutation, c.12445-3C > G, was confirmed to cause two wrong splicing modes. As for previously reported mutations, such as PKD1, c.6395 T > G (p.F2132C) and c.6868G > T (p.D2290Y), we had new and different findings.\nCONCLUSION: The findings provided new references for genotype-phenotype analyses and broadened the mutation spectrum of detected genes, which were significantly valuable for prenatal diagnosis and genetic counseling.","variants":[{"Name":"NM_001009944.3(PKD1):c.6395T>G (p.Phe2132Cys)","Chromosome":"16","Start":"2108772","Stop":"2108772","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":426161,"rule_based_match":true,"evidence_text":"c.6395 T > G (p.F2132C)","llm_judgment":"PRESENT","evidence":"c.6395 T > G (p.F2132C)","abstract_start":1172,"abstract_end":1195}]}
{"pmid":"35008666","title":"Novel Homozygous Missense Variant in","abstract":"Congenital cataracts (CC) are responsible for approximately one-tenth of childhood blindness cases globally. Here, we report an African American family with a recessively inherited form of CC. The proband demonstrated decreased visual acuity and bilateral cataracts, with nuclear and cortical cataracts in the right and left eye, respectively. Exome sequencing revealed a novel homozygous variant (c.563A > G; p.(Asn188Ser)) in <i>GJA3</i>, which was predicted to be pathogenic by structural analysis. Dominantly inherited variants in <i>GJA3</i> are known to cause numerous types of cataracts in various populations. Our study represents the second case of recessive <i>GJA3</i> allele, and the first report in African Americans. These results validate <i>GJA3</i> as a bona fide gene for recessively inherited CC in humans.","variants":[{"Name":"NM_021954.4(GJA3):c.563A>G (p.Asn188Ser)","Chromosome":"13","Start":"20142726","Stop":"20142726","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1192609,"rule_based_match":true,"evidence_text":"c.563A > G; p.(Asn188Ser)","llm_judgment":"PRESENT","evidence":"c.563A > G; p.(Asn188Ser)","abstract_start":398,"abstract_end":423}]}
{"pmid":"30618027","title":"A Disease-Causing FRMD7 Variant in a Chinese Family with Infantile Nystagmus.","abstract":"In this report, we described a large Han-Chinese family which presents with various phenotypes from unaffected to manifested nystagmus in females. Infantile nystagmus (IN) is characterized by bilateral, involuntary, and periodic eyeball oscillation, occurring at birth or within the first 6 months. The most common inheritance pattern of IN is an X-linked form with incomplete penetrance among females, and the FERM domain containing 7 gene (FRMD7) is a main disease-causing gene. A combination of exome sequencing and Sanger sequencing, as well as detailed clinical examinations were performed on the Chinese IN family. An FRMD7 c.47T>C (p.Phe16Ser) variant was proposed as the disease-causing variant. Incomplete penetrance was found in females with the FRMD7 c.47T>C variant, and hemizygous male affected subjects presented more severe manifestations compared to heterozygous female affected subjects. These findings could enhance genetic counseling and antenatal diagnosis of IN.","variants":[{"Name":"NM_194277.3(FRMD7):c.47T>C (p.Phe16Ser)","Chromosome":"X","Start":"132127798","Stop":"132127798","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1209239,"rule_based_match":true,"evidence_text":"FRMD7 c.47T>C (p.Phe16Ser)","llm_judgment":"PRESENT","evidence":"FRMD7 c.47T>C (p.Phe16Ser)","abstract_start":624,"abstract_end":650}]}
{"pmid":"20565770","title":"The impact of CFNS-causing EFNB1 mutations on ephrin-B1 function.","abstract":"BACKGROUND: Mutations of EFNB1 cause the X-linked malformation syndrome craniofrontonasal syndrome (CFNS). CFNS is characterized by an unusual phenotypic pattern of inheritance, because it affects heterozygous females more severely than hemizygous males. This sex-dependent inheritance has been explained by random X-inactivation in heterozygous females and the consequences of cellular interference of wild type and mutant EFNB1-expressing cell populations. EFNB1 encodes the transmembrane protein ephrin-B1, that forms bi-directional signalling complexes with Eph receptor tyrosine kinases expressed on complementary cells. Here, we studied the effects of patient-derived EFNB1 mutations predicted to give rise to truncated ephrin-B1 protein or to disturb Eph/ephrin-B1 reverse ephrin-B1 signalling. Five mutations are investigated in this work: nonsense mutation c.196C > T/p.R66X, frameshift mutation c.614_615delCT, splice-site mutation c.406 + 2T > C and two missense mutations p.P54L and p.T111I. Both missense mutations are located in the extracellular ephrin domain involved in Eph-ephrin-B1 recognition and higher order complex formation.\nMETHODS: Nonsense mutation c.196C > T/p.R66X, frameshift mutation c.614_615delCT and splice-site mutation c.406+2T > C were detected in the primary patient fibroblasts by direct sequencing of the DNA and were further analysed by RT-PCR and Western blot analyses.The impact of missense mutations p.P54L and p.T111I on cell behaviour and reverse ephrin-B1 cell signalling was analysed in a cell culture model using NIH 3T3 fibroblasts. These cells were transfected with the constructs generated by in vitro site-directed mutagenesis. Investigation of missense mutations was performed using the Western blot analysis and time-lapse microscopy.\nRESULTS AND DISCUSSION: Nonsense mutation c.196C > T/p.R66X and frameshift mutation c.614_615delCT escape nonsense-mediated RNA decay (NMD), splice-site mutation c.406+2T > C results in either retention of intron 2 or activation of a cryptic splice site in exon 2. However, c.614_615delCT and c.406+2T > C mutations were found to be not compatible with production of a soluble ephrin-B1 protein. Protein expression of the p.R66X mutation was predicted unlikely but has not been investigated.Ectopic expression of p.P54L ephrin-B1 resists Eph-receptor mediated cell cluster formation in tissue culture and intracellular ephrin-B1 Tyr324 and Tyr329 phosphorylation. Cells expressing p.T111I protein show similar responses as wild type expressing cells, however, phosphorylation of Tyr324 and Tyr329 is reduced.\nCONCLUSIONS: Pathogenic mechanisms in CFNS manifestation include impaired ephrin-B1 signalling combined with cellular interference.","variants":[{"Name":"NM_004429.5(EFNB1):c.406+2T>C","Chromosome":"X","Start":"68838896","Stop":"68838896","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3413540,"rule_based_match":true,"evidence_text":"c.406+2T>C","llm_judgment":"PRESENT","evidence":"c.406 + 2T > C","abstract_start":942,"abstract_end":956}]}
{"pmid":"24961629","title":"An exome sequencing strategy to diagnose lethal autosomal recessive disorders.","abstract":"Rare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There is often limited fetal DNA available for investigation. We investigated a strategy for diagnosing autosomal recessive lethal disorders in non-consanguineous pedigrees with multiple affected fetuses. Exome sequencing was performed to identify genes where each parent is heterozygous for a rare non-synonymous-coding or splicing variant. Putative pathogenic variants were tested for cosegregation in affected fetuses and unaffected siblings. In eight couples of European ancestry, we found on average 1.75 genes (range 0-4) where both parents were heterozygous for rare potentially deleterious variants. A proof-of-principle study detected heterozygous DYNC2H1 variants in a couple whose five fetuses had short-rib polydactyly. Prospective analysis of two couples with multiple pregnancy terminations for fetal akinesia syndrome was performed and a diagnosis was obtained in both the families. The first couple were each heterozygous for a previously reported GLE1 variant, p.Arg569His or p.Val617Met; both were inherited by their two affected fetuses. The second couple were each heterozygous for a novel RYR1 variant, c.14130-2A>G or p.Ser3074Phe; both were inherited by their three affected fetuses but not by their unaffected child. Biallelic GLE1 and RYR1 disease-causing variants have been described in other cases with fetal akinesia syndrome. We conclude that exome sequencing of parental samples can be an effective tool for diagnosing lethal recessive disorders in outbred couples. This permits early prenatal diagnosis in future pregnancies.","variants":[{"Name":"NM_000540.3(RYR1):c.14130-2A>G","Chromosome":"19","Start":"38575917","Stop":"38575917","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1366897,"rule_based_match":true,"evidence_text":"c.14130-2A>G","llm_judgment":"PRESENT","evidence":"c.14130-2A>G","abstract_start":1339,"abstract_end":1351},{"Name":"NM_001003722.2(GLE1):c.1706G>A (p.Arg569His)","Chromosome":"9","Start":"128536414","Stop":"128536414","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21502,"rule_based_match":false,"evidence_text":"p.Arg569His","llm_judgment":"PRESENT","evidence":"p.Arg569His","abstract_start":1193,"abstract_end":1204},{"Name":"NM_001003722.2(GLE1):c.1849G>A (p.Val617Met)","Chromosome":"9","Start":"128538058","Stop":"128538058","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21503,"rule_based_match":false,"evidence_text":"p.Val617Met","llm_judgment":"PRESENT","evidence":"p.Val617Met","abstract_start":1208,"abstract_end":1219}]}
{"pmid":"28330959","title":"Predominantly myalgic phenotype caused by the c.3466G>A p.A1156T mutation in","abstract":"OBJECTIVE: To characterize the clinical phenotype in patients with p.A1156T sodium channel mutation.\nMETHODS: Twenty-nine Finnish patients identified with the c.3466G>A p.A1156T mutation in the <i>SCN4A</i> gene were extensively examined. In a subsequent study, 63 patients with similar myalgic phenotype and with negative results in myotonic dystrophy type 2 genetic screening (DM2-neg group) and 93 patients diagnosed with fibromyalgia were screened for the mutation. Functional consequences of the p.A1156T mutation were studied in HEK293 cells with whole-cell patch clamp.\nRESULTS: The main clinical manifestation in p.A1156T patients was not myotonia or periodic paralysis but exercise- and cold-induced muscle cramps, muscle stiffness, and myalgia. EMG myotonic discharges were detected in most but not all. Electrophysiologic compound muscle action potentials exercise test showed variable results. The p.A1156T mutation was identified in one patient in the DM2-neg group but not in the fibromyalgia group, making a total of 30 patients so far identified. Functional studies of the p.A1156T mutation showed mild attenuation of channel fast inactivation.\nCONCLUSIONS: The unspecific symptoms of myalgia stiffness and exercise intolerance without clinical myotonia or periodic paralysis in p.A1156T patients make the diagnosis challenging. The symptoms of milder <i>SCN4A</i> mutations may be confused with other similar myalgic syndromes, including fibromyalgia and myotonic dystrophy type 2.","variants":[{"Name":"NM_000334.4(SCN4A):c.3466G>A (p.Ala1156Thr)","Chromosome":"17","Start":"63945614","Stop":"63945614","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20939,"rule_based_match":true,"evidence_text":"c.3466G>A p.A1156T","llm_judgment":"PRESENT","evidence":"c.3466G>A p.A1156T","abstract_start":159,"abstract_end":177}]}
{"pmid":"28174639","title":"A rare CFTR mutation associated with severe disease progression in a 10-year-old Hispanic patient.","abstract":"Cystic fibrosis is a life-shortening multisystem genetic disease. While readily tested, few tests analyze rare gene mutations prevalent among ethnic minorities. This case of a Hispanic child with a rare CF-causing c.233dupT mutation and severe disease emphasizes the need for broad CFTR mutation analyses and genotyping particularly in minority populations.","variants":[{"Name":"NM_000492.4(CFTR):c.233dup (p.Trp79fs)","Chromosome":"7","Start":"117509096","Stop":"117509097","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":68143,"rule_based_match":true,"evidence_text":"c.233dupT","llm_judgment":"PRESENT","evidence":"c.233dupT","abstract_start":214,"abstract_end":223}]}
{"pmid":"30184081","title":"A novel p.(Glu111Val) missense mutation in GUCA1A associated with cone-rod dystrophy leads to impaired calcium sensing and perturbed second messenger homeostasis in photoreceptors.","abstract":"Guanylate Cyclase-Activating Protein 1 (GCAP1) regulates the enzymatic activity of the photoreceptor guanylate cyclases (GC), leading to inhibition or activation of the cyclic guanosine monophosphate (cGMP) synthesis depending on its Ca2+- or Mg2+-loaded state. By genetically screening a family of patients diagnosed with cone-rod dystrophy, we identified a novel missense mutation with autosomal dominant inheritance pattern (c.332A>T; p.(Glu111Val); E111V from now on) in the GUCA1A gene coding for GCAP1. We performed a thorough biochemical and biophysical investigation of wild type (WT) and E111V human GCAP1 by heterologous expression and purification of the recombinant proteins. The E111V substitution disrupts the coordination of the Ca2+ ion in the high-affinity site (EF-hand 3, EF3), thus significantly decreasing the ability of GCAP1 to sense Ca2+ (∼80-fold higher Kdapp compared to WT). Both WT and E111V GCAP1 form dimers independently on the presence of cations, but the E111V Mg2+-bound form is prone to severe aggregation over time. Molecular dynamics simulations suggest a significantly increased flexibility of both the EF3 and EF4 cation binding loops for the Ca2+-bound form of E111V GCAP1, in line with the decreased affinity for Ca2+. In contrast, a more rigid backbone conformation is observed in the Mg2+-bound state compared to the WT, which results in higher thermal stability. Functional assays confirm that E111V GCAP1 interacts with the target GC with a similar apparent affinity (EC50); however, the mutant shifts the GC inhibition out of the physiological [Ca2+] (IC50E111V ∼10 μM), thereby leading to the aberrant constitutive synthesis of cGMP under conditions of dark-adapted photoreceptors.","variants":[{"Name":"NM_001384910.1(GUCA1A):c.332A>T (p.Glu111Val)","Chromosome":"6","Start":"42178410","Stop":"42178410","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":945027,"rule_based_match":true,"evidence_text":"c.332A>T; p.(Glu111Val)","llm_judgment":"PRESENT","evidence":"c.332A>T; p.(Glu111Val)","abstract_start":428,"abstract_end":451}]}
{"pmid":"24036790","title":"Variable expressivity and clinical heterogeneity can complicate the diagnosis and management of Pfeiffer syndrome.","abstract":"We report here a newborn female infant with striking features consistent with severe Pfeiffer syndrome (PS). Pfeiffer syndrome is a rare craniofacial disorder that has an autosomal dominant mode of inheritance (OMIM 101600). Our patient had unexpected differences between her clinical features and those predicted from her genetic tests. The following clinical features were noted: severe exophthalmos, syndactyly, upper extremity contractures, and relative macroglossia. A head computed tomography with three-dimensional reconstruction showed that she did not have craniosynostosis. Genetic tests included a normal 46,XX karyotype and a chromosomal microarray that revealed a copy number gain at 14q23.1 as well as a copy number loss at 16p13.2. FGFR2 sequencing revealed a c.870G>T transversion in exon 8, which is predicted to encode a Trp290Cys substitution.The clinical features of severe exophthalmos and other features typical of PS without craniosynostosis were most consistent with a diagnosis of PS type III. However, her Trp290Cys FGFR2 mutation is reported to be associated with PS type II that includes kleeblatschädel (or \"cloverleaf\") skull anomalies as a cardinal feature. Our patient's lack of craniosynostosis predicted from this mutation is a striking example of variable expressivity. Such discrepancies between the physical findings (phenotype) and the mutation identified (genotype) and the association of different findings with different mutations in the same gene (clinical heterogeneity) can present difficulties in case management. Clinicians should be guided by careful phenotyping rather than by genotypic predictions alone.","variants":[{"Name":"NM_000141.5(FGFR2):c.870G>T (p.Trp290Cys)","Chromosome":"10","Start":"121520048","Stop":"121520048","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":28332,"rule_based_match":true,"evidence_text":"c.870G>T","llm_judgment":"PRESENT","evidence":"c.870G>T","abstract_start":775,"abstract_end":783}]}
{"pmid":"31273342","title":"Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis.","abstract":"PURPOSE: To determine the genetic etiology of deafness in a family (HN-SD01) with autosomal dominant nonsyndromic hearing loss (NSHL).\nMETHODS: Stepwise genetic analysis was performed on family HN-SD01, including hotspot variant screening, exome sequencing, virtual hearing loss gene panel, and genome-wide linkage analysis. Targeted region sequencing was used to screen ABCC1 in additional cases. Cochlear expression of Abcc1 was evaluated by messenger RNA (mRNA) and protein levels. Computational prediction, immunofluorescence, real-time quantitative polymerase chain reaction, and flow cytometry were conducted to uncover functional consequences of candidate variants.\nRESULTS: Stepwise genetic analysis identified a heterozygous missense variant, ABCC1:c.1769A>G (p.Asn590Ser), cosegregating with phenotype in HN-SD01. Screening of ABCC1 in an additional 217 cases identified candidate pathogenic variants c.692G>A (p.Gly231Asp) in a sporadic case and c.887A>T (p.Glu296Val) in a familial proband. Abcc1 expressed in stria vascularis and auditory nerve of mouse cochlea. Immunofluorescence showed p.Asn590Ser distributed in cytomembrane and cytoplasm, while wild type was shown only in cytomembrane. Besides, it generated unstable mRNA and decreased efflux capacity of ABCC1.\nCONCLUSION: Stepwise genetic analysis is efficient to analyze the genetic etiology of NSHL. Variants in ABCC1 are linked with NSHL and suggest an important role of extruding pumps in maintaining cochlea function.","variants":[{"Name":"NM_004996.4(ABCC1):c.1769A>G (p.Asn590Ser)","Chromosome":"16","Start":"16068247","Stop":"16068247","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":917577,"rule_based_match":true,"evidence_text":"ABCC1:c.1769A>G (p.Asn590Ser)","llm_judgment":"PRESENT","evidence":"ABCC1:c.1769A>G (p.Asn590Ser)","abstract_start":752,"abstract_end":781}]}
{"pmid":"27087313","title":"Identification of LCK mutation in a family with atypical epidermodysplasia verruciformis with T-cell defects and virus-induced squamous cell carcinoma.","abstract":"BACKGROUND: Inherited epidermodysplasia verruciformis (EV) is a rare skin disorder characterized by susceptibility to specific types of human papilloma virus (HPV) and is strongly associated with skin carcinomas. Inactivating mutations in EVER1/EVER2 account for most cases of EV. However, more phenotypes related to but distinct from EV have been reported with an immunodeficiency state but without EVER1/EVER2 mutation, and the genetic basis for these atypical EV cases is poorly understood.\nOBJECTIVES: To identify the causative gene responsible for three siblings affected by atypical EV but without EVER1/EVER2 mutation.\nMETHODS: Whole-exome sequencing followed by Sanger sequencing was performed to identify the gene responsible for the patients with atypical EV enrolled in our study.\nRESULTS: A homozygous splicing mutation was detected in LCK (c.188-2A>G). This mutation resulted in an exon 3 deletion T lymphocyte-specific protein tyrosine kinase isoform, which further led to frameshift mutation and subsequent mRNA decay.\nCONCLUSIONS: We demonstrate a novel mutation in LCK in a family affected by atypical EV with T-cell defects, HPV infection and virus-induced malignancy, providing new clues in the understanding of host defences against HPV and better genetic counselling of patients with the EV phenotype.","variants":[{"Name":"NM_005356.5(LCK):c.188-2A>G","Chromosome":"1","Start":"32274991","Stop":"32274991","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3224416,"rule_based_match":true,"evidence_text":"c.188-2A>G","llm_judgment":"PRESENT","evidence":"c.188-2A>G","abstract_start":853,"abstract_end":863}]}
{"pmid":"24116927","title":"Follicular bronchiolitis as phenotype associated with CD25 deficiency.","abstract":"Regulatory T cells [Tregs ; CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+) )] are subsets of T cells involved in the maintenance of peripheral self-tolerance by actively suppressing the activation and expansion of autoreactive T cells. Signalling through the interleukin-2 receptor (IL-2R) contributes to T cell tolerance by controlling three important aspects of regulatory T cell (Treg ) biology. CD25 is the α-chain of the IL-2R that, in concert with the β-chain and γ-chain, constitutes the complete IL-2R. CD25 contributes only to IL-2 binding affinity but not to the recruitment of signalling molecules. However, its importance in the development of a normal immune response is emphasized by the finding that a truncation mutant of CD25 results in an immunodeficiency in humans characterized by an increased susceptibility to viral, bacterial and fungal infections. In 1997, Sharfe et al. described an infant with severe bacterial, viral and fungal infections. Counts of autologous T lymphocytes were moderately low, T cells displayed a weak proliferative response to mitogens in vitro and the patient displayed no rejection of an allogeneic skin graft. However, unlike children with severe combined immunodeficiency (SCID), besides not having circulating T cells, the patient also developed peripheral lymphocytic proliferation and autoimmune primary biliary cirrhosis. We present the first female Argentine patient with mutation in CD25 associated with chronic and severe inflammatory lung disease (follicular bronchiolitis with lymphocyte hyperplasia), eczema and infections. She has no expression of CD25 on CD4(+) T cells and an extremely low amount of Tregs . The molecular study confirmed homozygous missense mutation in the alpha subunit of the IL-2 receptor (CD25αR) (c. 122 a > c; p. Y41S).","variants":[{"Name":"NM_000417.3(IL2RA):c.122A>C (p.Tyr41Ser)","Chromosome":"10","Start":"6025968","Stop":"6025968","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":199918,"rule_based_match":true,"evidence_text":"c. 122 a > c; p. Y41S","llm_judgment":"PRESENT","evidence":"c. 122 a > c; p. Y41S","abstract_start":1784,"abstract_end":1805}]}
{"pmid":"15059150","title":"Ex vivo analysis of aberrant splicing induced by two donor site mutations in PKLR of a patient with severe pyruvate kinase deficiency.","abstract":"Two single-nucleotide substitutions in PKLR constituted the molecular basis underlying pyruvate kinase (PK) deficiency in a patient with severe haemolytic anaemia. One novel mutation, IVS5+1G>A, abolished the intron 5 donor splice site. The other mutation, c.1436G>A, altered the intron 10 donor splice site consensus sequence and, moreover, encoded an R479H substitution. We studied the effects on PKLR pre-mRNA processing, using ex vivo-produced nucleated erythroid cells from the patient. Abolition of the intron 5 splice site initiated two events in the majority of transcripts: skipping of exon 5 or, surprisingly, simultaneous skipping of exon 5 and 6 (Delta5,6). Subcellular localization of transcripts suggested that no functional protein was produced by the IVS5+1A allele. The unusual Delta5,6 transcript suggests that efficient inclusion of exon 6 in wild-type PKLR mRNA depends on the presence of splice-enhancing elements in exon 5. The c.1436G>A mutation caused skipping of exon 10 but was mainly associated with a severe reduction in transcripts although these were, in general, normally processed. Accordingly, low amounts of PK were detected in nucleated erythroid cells of the patient, thus correlating with the patient's PK-deficient phenotype. Finally, several low-abundant transcripts were detected that represent the first examples of \"leaky-splicing\" in PKLR.","variants":[{"Name":"NM_000298.6(PKLR):c.1436G>A (p.Arg479His)","Chromosome":"1","Start":"155293177","Stop":"155293177","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16549,"rule_based_match":true,"evidence_text":"c.1436G>A","llm_judgment":"PRESENT","evidence":"c.1436G>A","abstract_start":257,"abstract_end":266}]}
{"pmid":"33445193","title":"Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency: Cause of Hypoglycemia-Induced Seizure and Death.","abstract":"Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) deficiency (MIM 261680, EC 4.1.1.32, encoded by PCK1) is a rare disorder of gluconeogenesis presenting with recurrent hypoglycemia, hepatic dysfunction, and lactic acidosis. We report on a previously healthy 3-year-old boy who was initially admitted under the suspicion of a febrile seizure during an upper airway infection. Diagnostic workup revealed hypoglycemia as well as a cerebral edema and ruled out an infection. After a complicated course with difficult to treat symptomatic seizures, the child died on the 5th day of admission due to progressive cerebral edema. The metabolic screening showed elevated urinary lactate and Krebs cycle intermediates in line with a primary or secondary energy deficit. Due to the unclear and fatal course, trio exome sequencing was initiated postmortem (\"molecular autopsy\") and revealed the diagnosis of cytosolic PEPCK deficiency based on the compound heterozygosity of a known pathogenic (c.925G > A, p.(Gly309Arg)) and a previously unreported (c.724G > A, p.(Gly242Arg)) variant in <i>PCK1</i> (NM_002591.3). Sanger sequencing ruled out the disease and carrier status in three older brothers. Molecular autopsy was performed due to the unclear and fatal course. The diagnosis of a cytosolic PEPCK deficiency not only helped the family to deal with the grief, but especially took away the fear that the siblings could be affected by an unknown disease in the same manner. In addition, this case increases the genetic and phenotypic spectrum of cytosolic PEPCK deficiency.","variants":[{"Name":"NM_002591.4(PCK1):c.925G>A (p.Gly309Arg)","Chromosome":"20","Start":"57563691","Stop":"57563691","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":335907,"rule_based_match":true,"evidence_text":"c.925G > A, p.(Gly309Arg)","llm_judgment":"PRESENT","evidence":"c.925G > A, p.(Gly309Arg)","abstract_start":985,"abstract_end":1010},{"Name":"NM_002591.4(PCK1):c.724G>A (p.Gly242Arg)","Chromosome":"20","Start":"57563141","Stop":"57563141","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":798766,"rule_based_match":true,"evidence_text":"c.724G > A, p.(Gly242Arg)","llm_judgment":"PRESENT","evidence":"c.724G > A, p.(Gly242Arg)","abstract_start":1041,"abstract_end":1066}]}
{"pmid":"33037779","title":"Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.","abstract":"Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate-to-pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non-single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between \"syndromic\" cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.","variants":[{"Name":"NM_032730.5(RTN4IP1):c.263T>G (p.Val88Gly)","Chromosome":"6","Start":"106628759","Stop":"106628759","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":904239,"rule_based_match":true,"evidence_text":"c.263T>G, p.Val88Gly","llm_judgment":"PRESENT","evidence":"c.263T>G, p.Val88Gly","abstract_start":861,"abstract_end":881}]}
{"pmid":"28061825","title":"New CDH3 mutation in the first Spanish case of hypotrichosis with juvenile macular dystrophy, a case report.","abstract":"BACKGROUND: CDH3 on 16q22.1 is responsible for two rare autosomal recessive disorders with hypotrichosis and progressive macular dystrophy: Hypotrichosis with Juvenile Macular Dystrophy and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy. We present a new case of Hypotrichosis with Juvenile Macular Dystrophy.\nCASE PRESENTATION: A Spanish male born in 1998 from non-consanguineous healthy parents with a suspected diagnosis of Keratosis Follicularis Spinulosa Decalvans and Retinitis Pigmentosa Inversa referred to our Genetics Department (IIS-Fundación Jiménez Díaz). Molecular study of ABCA4 was performed, and a heterozygous missense p.Val2050Leu variant in ABCA4 was found. Clinical revision reclassified this patient as Hypotrichosis with Juvenile Macular Dystrophy. Therefore, further CDH3 sequencing was performed showing a novel maternal missense change p.Val205Met (probably pathogenic by in silico analysis), and a previously reported paternal frameshift c.830del;p.Gly277Alafs*20, thus supporting the clinical diagnosis..\nCONCLUSIONS: This is not only the first Spanish case with this clinical and molecular diagnosis, but a new mutation has been described in CDH3. Moreover, this work reflects the importance of joint assessment of clinical signs and evaluation of pedigree for a correct genetic study approach and diagnostic.","variants":[{"Name":"NM_001793.6(CDH3):c.613G>A (p.Val205Met)","Chromosome":"16","Start":"68678828","Stop":"68678828","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1871450,"rule_based_match":false,"evidence_text":"p.Val205Met","llm_judgment":"PRESENT","evidence":"p.Val205Met","abstract_start":872,"abstract_end":883}]}
{"pmid":"26716871","title":"Identification of Promotor and Exonic Variations, and Functional Characterization of a Splice Site Mutation in Indian Patients with Unconjugated Hyperbilirubinemia.","abstract":"BACKGROUND: Mild unconjugated hyperbilirubinemia (UH), due to reduced activity of the enzyme uridine diphosphoglucuronate-glucuronosyltransferase family, polypeptide 1 (UGT1A1), is a common clinical condition. Most cases are caused by presence in homozygous form of an A(TA)7TAA nucleotide sequence instead of the usual A(TA)6TAA sequence in promoter region of the UGT1A1 gene. In some cases, other genetic variations have been identified which differ between populations. There is need for more data on such genetic variations from India.\nMETHODS: DNA from subjects with unexplained persistent or recurrent UH was tested for the presence of TA promoter insertions. In addition, all five exons and splicing site regions of UGT1A1 gene were sequenced. Several bioinformatics tools were used to determine the biological significance of the observed genetic changes. Functional analysis was done to look for effect of a splice site mutation in UGT1A1.\nRESULTS: Of 71 subjects with UH (68 male; median age [range], 26 [16-63] years; serum bilirubin 56 [26-219] μM/L, predominantly unconjugated) studied, 65 (91.5%) subjects were homozygous for A(TA)7TAA allele, five (7.0%) were heterozygous, and one (1.4%) lacked this change. Fifteen subjects with UH had missense exonic single nucleotide changes (14 heterozygous, 1 homozygous), including one subject with a novel nucleotide change (p.Thr205Asn). Bioinformatics tools predicted some of these variations (p.Arg108Cys, p.Ile159Thr and p.Glu463Val) to be deleterious. Functional characterization of an exonic variation (c.1084G>A) located at a splice site revealed that it results in frameshift deletion of 31 nucleotides and premature truncation of the protein.\nCONCLUSION: Our study revealed several single nucleotide variations in UGT1A1 gene in Indian subjects with UH. Functional characterization of a splice site variation indicated that it leads to disordered splicing. These variations may explain UH in subjects who lacked homozygous A(TA)7TAA promoter alleles.","variants":[{"Name":"NM_000463.3(UGT1A1):c.1084G>A (p.Gly362Ser)","Chromosome":"2","Start":"233767936","Stop":"233767936","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":405663,"rule_based_match":true,"evidence_text":"c.1084G>A","llm_judgment":"PRESENT","evidence":"c.1084G>A","abstract_start":1566,"abstract_end":1575}]}
{"pmid":"36743879","title":"Pulmonary Artery Intimal Sarcoma in a Patient with Lynch Syndrome: Response to an Immune Checkpoint Inhibitor.","abstract":"Intimal sarcoma is an extremely rare mesenchymal tumor arising in the great vessels. To date, intimal sarcoma has not been reported in patients with Lynch syndrome (LS), even though this syndrome lacks DNA mismatch repair ability genetically and is prone to various malignancies. This patient was diagnosed with LS by the Revised Amsterdam Criteria II, and she suffered from intimal sarcoma in the left pulmonary artery. She had a germline missense variant of <i>PMS2</i> (c.1399G>A, pV467I) which is classified as a variant of unknown significance. In her intimal sarcoma, PMS2 expression was decreased. Additionally, it exhibited microsatellite instability and a high tumor mutational burden (69 mutations/Mb) which are features of mismatch repair deficiency, although <i>PMS2</i> (c.1399G>A, pV467I) missense is a variant of unknown significance. The metastatic lesions of intimal sarcoma in this patient responded heterogeneously to pembrolizumab, an immune checkpoint inhibitor. Cytotoxic agents and radiation were also effective for some metastatic lesions, but some lesions, including her liver metastases, were resistant. The hypermutable nature of the LS genotype might acquire resistance to an immune checkpoint inhibitor and other cytotoxic agents such as occurred with her liver metastases.","variants":[{"Name":"NM_000535.7(PMS2):c.1399G>A (p.Val467Ile)","Chromosome":"7","Start":"5987366","Stop":"5987366","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152161,"rule_based_match":true,"evidence_text":"c.1399G>A, pV467I","llm_judgment":"PRESENT","evidence":"c.1399G>A, pV467I","abstract_start":473,"abstract_end":490}]}
{"pmid":"28065824","title":"Variable White Matter Atrophy and Intellectual Development in a Family With X-linked Creatine Transporter Deficiency Despite Genotypic Homogeneity.","abstract":"BACKGROUND: The X-linked creatine transporter deficiency (CRTD) caused by an SLC6A8 mutation represents the second most common cause of X-linked intellectual disability. The clinical phenotype ranges from mild to severe intellectual disability, epilepsy, short stature, poor language skills, and autism spectrum disorders. The objective of this study was to investigate phenotypic variability in the context of genotype, cerebral creatine concentration, and volumetric analysis in a family with CRTD.\nPATIENTS AND METHODS: The clinical phenotype and manifestations of epilepsy were assessed in a Caucasian family with CRTD. DNA sequencing and creatine metabolism analysis confirmed the diagnosis. Cerebral magnetic resonance imaging (cMRI) with voxel-based morphometry and magnetic resonance spectroscopy was performed in all family members.\nRESULTS: An SLC6A8 missense mutation (c.1169C>T; p.Pro390Leu, exon 8) was detected in four of five individuals. Both male siblings were hemizygous, the mother and the affected sister heterozygous for the mutation. Structural cMRI was normal, whereas voxel-based morphometry analysis showed reduced white matter volume below the first percentile of the reference population of 290 subjects in the more severely affected boy compared with family members and controls. Normalized creatine concentration differed significantly between the individuals (P < 0.005).\nCONCLUSIONS: There is a broad phenotypic variability in CRTD even in family members with the same mutation. Differences in mental development could be related to atrophy of the subcortical white matter.","variants":[{"Name":"NM_005629.4(SLC6A8):c.1169C>T (p.Pro390Leu)","Chromosome":"X","Start":"153693932","Stop":"153693932","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1383461,"rule_based_match":true,"evidence_text":"c.1169C>T; p.Pro390Leu","llm_judgment":"PRESENT","evidence":"c.1169C>T; p.Pro390Leu","abstract_start":880,"abstract_end":902}]}
{"pmid":"27683759","title":"A novel platelet-type von Willebrand disease mutation (GP1BA p.Met255Ile) associated with type 2B \"Malmö/New York\" von Willebrand disease.","abstract":"Interaction between von Willebrand factor (VWF) and platelet GPIbα is required for primary haemostasis. Lack or loss-of-function in the ligand-receptor pair results in bleeding complications. Paradoxically, gain-of-function mutations in VWF or GPIbα also result in bleeding complications as observed in type 2B von Willebrand disease (VWD) and platelet-type- (PT-) VWD, respectively. A similar phenotype is observed with increased ristocetin-induced platelet agglutination and disappearance of the highest molecular weight multimers of VWF. We evaluated a patient with a bleeding disorder and a biological presentation compatible with type 2B VWD. VWF and platelet functional assays, sequencing of the VWF and GP1BA genes, and expression studies in HEK cells were performed. Sequencing of the VWF gene in the propositus revealed a heterozygous p.Pro1266Leu mutation previously found in type 2B VWD Malmö/New York. These variants are characterised by a mild phenotype and a normal VWF multimer composition suggesting the presence of a second mutation in our propositus. Sequencing of the GP1BA gene revealed a heterozygous c.765G>A substitution changing Met at position 255 of GPIbα to Ile. This new mutation is located in the β-switch domain where five other gain-of-function mutations have been reported in PT-VWD. Expression of GPIbα Ile255 in HEK GPIb-IX cells resulted in enhanced VWF binding compared to wild-type, similar to known PT-VWD mutations (p.Val249, p.Ser249 and p.Val255) indicating that it contributes to the propositus defects. This first report associating PT- with type 2B VWD illustrates the importance of combining biological assays with genetic testing to better understand the clinical phenotype.","variants":[{"Name":"NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)","Chromosome":"12","Start":"6019621","Stop":"6019621","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15353,"rule_based_match":false,"evidence_text":"c.3797C>T (p.Pro1266Leu)","llm_judgment":"PRESENT","evidence":"p.Pro1266Leu","abstract_start":844,"abstract_end":856}]}
{"pmid":"23402891","title":"Rhodopsin p.N78I dominant mutation causing sectorial retinitis pigmentosa in a pedigree with intrafamilial clinical heterogeneity.","abstract":"OBJECTIVE: The purpose of this study was to determine the molecular basis of retinitis pigmentosa (RP) in a 4 affected sib-family segregating this retinal phenotype.\nMETHODS: Affected sibs underwent complete ophthalmologic examination including funduscopic inspection, electroretinogram, fluorescein angiography, visual field measurement, and optical coherence tomography. Both parents were deceased after their sixties and were reported with no visual handicap. Molecular analysis included direct nucleotide sequencing of the rhodopsin gene (RHO), at chromosome 3q21-q24, in DNA from a total of 4 affected sibs. A total of 200 ethnically matched alleles were included as mutation controls.\nRESULTS: Sector RP was clinically documented in this family. Wide phenotypic variability was observed with visual acuities ranging from 20/20 to 20/200 and variable funduscopic appearance. Molecular analysis disclosed a c.233A>T mutation at RHO exon 1, predicting a missense p.N78I substitution.\nCONCLUSIONS: Even though RP can be caused by mutations in a variety of genes, the RHO gene was chosen to be investigated in this RP family since it has been previously associated to sector disease. This case exemplifies the value of guiding RP molecular analysis based on funduscopic features.","variants":[{"Name":"NM_000539.3(RHO):c.233A>T (p.Asn78Ile)","Chromosome":"3","Start":"129528966","Stop":"129528966","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1934720,"rule_based_match":true,"evidence_text":"c.233A>T","llm_judgment":"PRESENT","evidence":"c.233A>T","abstract_start":911,"abstract_end":919}]}
{"pmid":"24319327","title":"A novel donor splice-site mutation of major intrinsic protein gene associated with congenital cataract in a Chinese family.","abstract":"PURPOSE: To identify the disease-causing gene in a Chinese family with autosomal dominant congenital cataract.\nMETHODS: Clinical and ophthalmologic examinations were performed on all members of a Chinese family with congenital cataract. Nine genes associated with congenital cataract were screened using direct DNA sequencing. Mutations were confirmed using restriction fragment length polymorphism (RFLP) analysis. The mutated multi-intronic plasmid (MIP) minigene, which carries the disease-causing splice-site mutation, and the wild-type (WT) MIP minigene were constructed using the pcDNA3.1 expression vector. Wild-type and mutant MIP minigene constructs were transiently transfected into HeLa cells. After 48 h of incubation at 37 °C, total RNA isolation and reverse transcription (RT)-PCR analysis were performed, and PCR products were separated and confirmed with sequencing.\nRESULTS: Direct DNA sequence analysis identified a novel splice-site mutation in intron 3 (c.606+1 G>A) of the MIP gene. To investigate the manner in which the splice donor mutation could affect mRNA splicing, WT and mutant MIP minigenes were inserted in the pcDNA3.1 (+) vector. Constructs were transfected into HeLa cells. RT-PCR analysis showed that the donor splice site mutation led to deletion of exon 3 in the mRNA encoded by the MIP gene.\nCONCLUSIONS: The present study identified a novel donor splice-site mutation (c.606+1G>A) in the MIP gene in a Chinese family with congenital cataract. In vitro RT-PCR analysis showed that this splice-site mutation resulted in the deletion of exon 3 from mRNA encoded by the MIP gene. This is the first report to show that donor splice-site mutation in MIP genes can cause autosomal dominant congenital cataract.","variants":[{"Name":"NM_012064.4(MIP):c.606+1G>A","Chromosome":"12","Start":"56453071","Stop":"56453071","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1676911,"rule_based_match":true,"evidence_text":"c.606+1 G>A","llm_judgment":"PRESENT","evidence":"c.606+1 G>A","abstract_start":974,"abstract_end":985}]}
{"pmid":"22693542","title":"Exome sequencing identifies compound heterozygous mutations in CYP4V2 in a pedigree with retinitis pigmentosa.","abstract":"Retinitis pigmentosa (RP) is a heterogeneous group of progressive retinal degenerations characterized by pigmentation and atrophy in the mid-periphery of the retina. Twenty two subjects from a four-generation Chinese family with RP and thin cornea, congenital cataract and high myopia is reported in this study. All family members underwent complete ophthalmologic examinations. Patients of the family presented with bone spicule-shaped pigment deposits in retina, retinal vascular attenuation, retinal and choroidal dystrophy, as well as punctate opacity of the lens, reduced cornea thickness and high myopia. Peripheral venous blood was obtained from all patients and their family members for genetic analysis. After mutation analysis in a few known RP candidate genes, exome sequencing was used to analyze the exomes of 3 patients III2, III4, III6 and the unaffected mother II2. A total of 34,693 variations shared by 3 patients were subjected to several filtering steps against existing variation databases. Identified variations were verified in the rest family members by PCR and Sanger sequencing. Compound heterozygous c.802-8_810del17insGC and c.1091-2A>G mutations of the CYP4V2 gene, known as genetic defects for Bietti crystalline corneoretinal dystrophy, were identified as causative mutations for RP of this family.","variants":[{"Name":"NM_207352.4(CYP4V2):c.802-8_810delinsGC","Chromosome":"4","Start":"186201149","Stop":"186201165","ReferenceAlleleVCF":"TCATACAGGTCATCGCT","AlternateAlleleVCF":"GC","allel_id":47877,"rule_based_match":false,"evidence_text":"c.802-8_810del17insGC","llm_judgment":"PRESENT","evidence":"c.802-8_810del17insGC","abstract_start":1127,"abstract_end":1148},{"Name":"NM_207352.4(CYP4V2):c.1091-2A>G","Chromosome":"4","Start":"186208863","Stop":"186208863","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":17230,"rule_based_match":true,"evidence_text":"c.1091-2A>G","llm_judgment":"PRESENT","evidence":"c.1091-2A>G","abstract_start":1153,"abstract_end":1164}]}
{"pmid":"25939784","title":"Novel cystathionine β-synthase gene mutations in a Filipino patient with classic homocystinuria.","abstract":"BACKGROUND: Classic homocystinuria due to cystathionine β-synthase (CBS) deficiency is an autosomal recessive disorder of sulfur metabolism. Clinical manifestations include mental retardation, dislocation of the optic lens (ectopia lentis), skeletal abnormalities and a tendency to thromboembolic episodes. We present the first mutational analysis of CBS in a Filipino patient with classic homocystinuria.\nMETHODS: Genomic DNA was extracted from peripheral blood collected from a diagnosed Filipino patient with classic homocystinuria. The entire coding region of CBS (17 exons) was amplified using polymerase chain reaction and bidirectionally sequenced using standard protocols.\nRESULTS: The patient was found to be compound heterozygous for two novel mutations, g.13995G>A [c.982G>A; p.D328K] and g.15860-15868dupGCAGGAGCT [c.1083-1091dupGCAGGAGCT; p. Q362-L364dupQEL]. Four known single-nucleotide polymorphisms (rs234706, rs1801181, rs706208 and rs706209) were also detected in the present patient's CBS. The patient was heterozygous for all the identified alleles.\nCONCLUSIONS: This is the first mutational analysis of CBS done in a Filipino patient with classic homocystinuria who presented with a novel duplication mutation and a novel missense mutation. Homocystinuria due to CBS deficiency is a heterogeneous disorder at the molecular level.","variants":[{"Name":"NM_000071.3(CBS):c.982G>A (p.Asp328Asn)","Chromosome":"21","Start":"43062368","Stop":"43062368","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":549051,"rule_based_match":true,"evidence_text":"c.982G>A","llm_judgment":"PRESENT","evidence":"c.982G>A","abstract_start":777,"abstract_end":785}]}
{"pmid":"23045948","title":"Mutation analysis of the methylmalonyl-CoA mutase gene in ten Mexican patients with methylmalonic acidemia","abstract":"INTRODUCTION: Methylmalonic acidemia (MMA) is a genetically determined human metabolic disease, characterized by deficient activity of the mitochondrial enzyme, methylmalonyl CoA mutase (MCM). This enzyme catalyzes the isomerization of L-methylmalonyl CoA to succinyl CoA and requires adenosylcobalamin as cofactor. Several mutations have been identified in the unique genetic locus encoding the MCM apoenzyme (mut) which causes MMA.\nAIM: To identify the mutations present in Mexican patients diagnosed with MMA.\nRESULTS: Complete nucleotide sequencing of mut gene exons of 10 Mexican patients with methylmalonic acidemia (MMA) identified one novel mutation and eight mutations previously reported in the methylmalonyl-CoA mutase (mut) gene. The new mutation c.406G > T (p.V136F) was found in one patient combined with the deletion c.1891delG (p.A631QfsX17). The missense mutation c.322C > T (p.R108C) was found in six non-related patients; in addition, the mutations c.ins671-678dupAATTTATG (p.V227NfsX16), c.682C > T (p.R228X), c1022-1023dupA (p. N341KfsX20), c.1846C > T (p.R616C), c.2080C > T (p.R694W), and c.385+3insTAAGGGT (splice) were found. This work reveals that Mexican patients with MMA have new (p.V136F) as well as worldwide and hispanic reported mutations. The mutation R108C is the most frequent change (40% of total alleles) mainly in patients from León, Guanajuato.","variants":[{"Name":"NM_000255.4(MMUT):c.1846C>T (p.Arg616Cys)","Chromosome":"6","Start":"49440316","Stop":"49440316","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544018,"rule_based_match":true,"evidence_text":"c.1846C > T (p.R616C)","llm_judgment":"PRESENT","evidence":"c.1846C > T (p.R616C)","abstract_start":1062,"abstract_end":1083},{"Name":"NM_000255.4(MMUT):c.406G>T (p.Val136Phe)","Chromosome":"6","Start":"49458038","Stop":"49458038","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1060727,"rule_based_match":true,"evidence_text":"c.406G > T (p.V136F)","llm_judgment":"PRESENT","evidence":"c.406G > T (p.V136F)","abstract_start":759,"abstract_end":779},{"Name":"NM_000255.4(MMUT):c.322C>T (p.Arg108Cys)","Chromosome":"6","Start":"49459145","Stop":"49459145","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16926,"rule_based_match":true,"evidence_text":"c.322C > T (p.R108C)","llm_judgment":"PRESENT","evidence":"c.322C > T (p.R108C)","abstract_start":881,"abstract_end":901}]}
{"pmid":"27259050","title":"Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.","abstract":"Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics.","variants":[{"Name":"NM_152703.5(SAMD9L):c.3587G>C (p.Cys1196Ser)","Chromosome":"7","Start":"93132385","Stop":"93132385","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":243920,"rule_based_match":true,"evidence_text":"c.3587G>C (p.Cys1196Ser)","llm_judgment":"PRESENT","evidence":"p.Cys1196Ser","abstract_start":683,"abstract_end":695},{"Name":"NM_152703.5(SAMD9L):c.2640C>A (p.His880Gln)","Chromosome":"7","Start":"93133332","Stop":"93133332","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":243919,"rule_based_match":true,"evidence_text":"c.2640C>A (p.His880Gln)","llm_judgment":"PRESENT","evidence":"p.His880Gln","abstract_start":458,"abstract_end":469}]}
{"pmid":"25402547","title":"Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta.","abstract":"Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal-dominant inheritance, but many autosomal-recessive genes have been reported. We applied whole-exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay.","variants":[{"Name":"NM_006129.5(BMP1):c.808A>G (p.Met270Val)","Chromosome":"8","Start":"22177929","Stop":"22177929","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":188062,"rule_based_match":true,"evidence_text":"c.808A>G","llm_judgment":"PRESENT","evidence":"c.808A>G","abstract_start":695,"abstract_end":703}]}
{"pmid":"17259242","title":"Evaluation of the risk for Tay-Sachs disease in individuals of French Canadian ancestry living in new England.","abstract":"BACKGROUND: The assessment of risk for Tay-Sachs disease (TSD) in individuals of French Canadian background living in New England is an important health issue. In preliminary studies of the enzyme-defined carrier frequency for TSD among Franco-Americans in New England, we found frequencies (1:53) higher than predicted from the incidence of infantile TSD in this region. We have now further evaluated the risk for TSD in the Franco-American population of New England.\nMETHODS: Using a fluorescence-based assay for beta-hexosaminidase activity, we determined the carrier frequencies for TSD in 2783 Franco-Americans. DNA analysis was used to identify mutations causing enzyme deficiency in TSD carriers.\nRESULTS: We determined the enzyme-defined carrier frequency for TSD as 1:65 (95% confidence interval 1:49 to 1:90). DNA-based analysis of 24 of the enzyme-defined carriers revealed 21 with sequence changes: 9 disease-causing, 4 benign, and 8 of unknown significance. Six of the unknowns were identified as c.748G>A p.G250S, a mutation we show by expression analysis to behave similarly to the previously described c.805G>A p.G269S adult-onset TSD mutation. This putative adult-onset TSD c.748G>A p.G250S mutation has a population frequency similar to the common 7.6 kb deletion mutation that occurs in persons of French Canadian ancestry.\nCONCLUSIONS: We estimate the frequency of deleterious TSD alleles in Franco-Americans to be 1:73 (95% confidence interval 1:55 to 1:107). These data provide a more complete data base from which to formulate policy recommendations regarding TSD heterozygosity screening in individuals of French Canadian background.","variants":[{"Name":"NM_000520.6(HEXA):c.748G>A (p.Gly250Ser)","Chromosome":"15","Start":"72350575","Stop":"72350575","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":373669,"rule_based_match":true,"evidence_text":"c.748G>A p.G250S","llm_judgment":"PRESENT","evidence":"c.748G>A p.G250S","abstract_start":1010,"abstract_end":1026}]}
{"pmid":"23946138","title":"A homozygous SLITRK6 nonsense mutation is associated with progressive auditory neuropathy in humans.","abstract":"OBJECTIVES/HYPOTHESIS: SLITRK family proteins control neurite outgrowth and regulate synaptic development. In mice, Slitrk6 plays a role in the survival and innervation of sensory neurons in the inner ear, vestibular apparatus, and retina, and also influences axial eye length. We provide the first detailed description of the auditory phenotype in humans with recessive SLITRK6 deficiency.\nSTUDY DESIGN: Prospective observational case study.\nMETHODS: Nine closely related Amish subjects from an endogamous Amish community of Pennsylvania underwent audiologic and vestibular testing. Single nucleotide polymorphism microarrays were used to map the chromosome locus, and Sanger sequencing or high-resolution melt analysis were used to confirm the allelic variant.\nRESULTS: All nine subjects were homozygous for a novel nonsense variant of SLITRK6 (c.1240C>T, p.Gln414Ter). Adult patients had high myopia. The 4 oldest SLITRK6 c.1240C>T homozygotes had absent ipsilateral middle ear muscle reflexes (MEMRs). Distortion product otoacoustic emissions (DPOAEs) were absent in all ears tested and the cochlear microphonic (CM) was increased in amplitude and duration in young patients and absent in the two oldest subjects. Auditory brainstem responses (ABRs) were dys-synchronised bilaterally with no reproducible waves I, III, or V at high intensities. Hearing loss and speech reception thresholds deteriorated symmetrically with age, which resulted in severe-to-profound hearing impairment by early adulthood. Vestibular evoked myogenic potentials were normal in three ears and absent in one.\nCONCLUSION: Homozygous SLITRK6 c.1240C>T (p.Gln414Ter) nonsense mutations are associated with high myopia, cochlear dysfunction attributed to outer hair cell disease, and progressive auditory neuropathy.","variants":[{"Name":"NM_032229.3(SLITRK6):c.1240C>T (p.Gln414Ter)","Chromosome":"13","Start":"85795269","Stop":"85795269","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":94429,"rule_based_match":true,"evidence_text":"c.1240C>T (p.Gln414Ter)","llm_judgment":"PRESENT","evidence":"c.1240C>T (p.Gln414Ter)","abstract_start":1621,"abstract_end":1644}]}
{"pmid":"25430699","title":"A rare case of unilateral adrenal hyperplasia accompanied by hypokalaemic periodic paralysis caused by a novel dominant mutation in CACNA1S: features and prognosis after adrenalectomy.","abstract":"BACKGROUND: Acute hypokalaemic paralysis is characterised by acute flaccid muscle weakness and has a complex aetiological spectrum. Herein we report, for the first time, a case of unilateral adrenal hyperplasia accompanied by hypokalaemic periodic paralysis type I resulting from a novel dominant mutation in CACNA1S. We present the clinical features and prognosis after adrenalectomy in this case.\nCASE PRESENTATION: A 43-year-old Han Chinese male presented with severe hypokalaemic paralysis that remitted after taking oral potassium. The patient had suffered from periodic attacks of hypokalaemic paralysis for more than 20 years. A computed tomography (CT) scan of the abdomen showed a nodular mass on the left adrenal gland, although laboratory examination revealed the patient had not developed primary aldosteronism. The patient underwent a left adrenalectomy 4 days after admission, and the pathological examination further confirmed a 1.1 cm benign nodule at the periphery of the adrenal gland. Three months after the adrenalectomy, a paralytic attack recurred and the patient asked for assistance from the Department of Medical Genetics. His family history showed that two uncles, one brother, and a nephew also had a history of periodic paralysis, although their symptoms were milder. The patient's CACNA1S and SCN4A genes were sequenced, and a novel missense mutation, c.1582C > T (p.Arg528Cys), in CACNA1S was detected. Detection of the mutation in five adult male family members, including three with periodic paralysis and two with no history of the disease, indicated that this mutation caused hypokalaemic periodic paralysis type I in his family. Follow-up 2 years after adrenalectomy showed that the serum potassium concentration was increased between paralyses and the number and severity of paralytic attacks were significantly decreased.\nCONCLUSION: We identified a novel dominant mutation, c.1582C > T (p.Arg528Cys), in CACNA1S that causes hypokalaemic periodic paralysis. The therapeutic effect of adrenalectomy indicated that unilateral adrenal hyperplasia might make paralytic attacks more serious and more frequent by decreasing serum potassium. This finding suggests that the surgical removal of hyperplastic tissues might relieve the symptoms of patients with severe hypokalaemic paralysis caused by other incurable diseases, even if the adrenal lesion does not cause primary aldosteronism.","variants":[{"Name":"NM_000069.3(CACNA1S):c.1582C>T (p.Arg528Cys)","Chromosome":"1","Start":"201077916","Stop":"201077916","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":823205,"rule_based_match":true,"evidence_text":"c.1582C > T (p.Arg528Cys)","llm_judgment":"PRESENT","evidence":"c.1582C > T (p.Arg528Cys)","abstract_start":1381,"abstract_end":1406}]}
{"pmid":"22504945","title":"A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia.","abstract":"Mutations in the mitochondrial aminoacyl-tRNA synthetases (ARSs) are associated with a strikingly broad range of clinical phenotypes, the molecular basis for which remains obscure. Here, we report a novel missense mutation (c.137G>A, p.Gly46Asp) in the catalytic domain of YARS2, which codes for the mitochondrial tyrosyl-tRNA synthetase, in a subject with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). YARS2 was undetectable by immunoblot analysis in subject myoblasts, resulting in a generalized mitochondrial translation defect. Retroviral expression of a wild-type YARS2 complementary DNA completely rescued the translation defect. We previously demonstrated that the respiratory chain defect in this subject was only present in fully differentiated muscle, and we show here that this likely reflects an increased requirement for YARS2 as muscle cells differentiate. An additional, heterozygous mutation was detected in TRMU/MTU1, a gene encoding the mitochondrial 2-thiouridylase. Although subject myoblasts and myotubes contained half the normal levels of TRMU, thiolation of mitochondrial tRNAs was normal. YARS2 eluted as part of high-molecular-weight complexes of ∼250 kDa and 1 MDa by gel filtration. This study confirms mutations in YARS2 as a cause of MLASA and shows that, like some of the cytoplasmic ARSs, mitochondrial ARSs occur in high-molecular-weight complexes.","variants":[{"Name":"NM_001040436.3(YARS2):c.137G>A (p.Gly46Asp)","Chromosome":"12","Start":"32755738","Stop":"32755738","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":108175,"rule_based_match":true,"evidence_text":"c.137G>A (p.Gly46Asp)","llm_judgment":"PRESENT","evidence":"p.Gly46Asp","abstract_start":234,"abstract_end":244}]}
{"pmid":"32619255","title":"Clinical and genetic analysis of a patient with rare nephronophthisis","abstract":"OBJECTIVE: To explore the genetic basis for a child with clinically suspected nephronophthisis (NPHP).\nMETHODS: Peripheral blood samples of the patient and her parents were collected subjected to high-throughput sequencing. Sanger sequencing was used to verify the gene variants.\nRESULTS: The patient, a 7-year-old girl with congenital blindness, was admitted to a local hospital due to repeated vomiting for 7-8 days and then transferred to author's hospital due to renal failure. Her urine occult bloods (3+) and urine protein (1+) were abnormal. Her blood urea nitrogen and creatinine showed a significant progressive increase. Renal ultrasound showed a mild enlargement in bilateral renal, increased echogenicity, loss of corticomedullary differentiation, and the presence of cysts in both kidneys. No familial genetic history was found in the family of patient and the child was clinically diagnosed with nephronophthisis. The proband was found to harbor compound heterozygous variants of the CEP290 gene, namely c.2587-2A>T and c.2251C>T, which were inherited from her mother and father, respectively. Based on the ACMG guidelines, both variants were predicted to be pathogenic.\nCONCLUSION: The patient was diagnosed with NPHP type 6 due to variants of the CEP290 gene. Above finding has provided new evidence for the genotype-phenotype correlation of this disease.","variants":[{"Name":"NM_025114.4(CEP290):c.2251C>T (p.Arg751Ter)","Chromosome":"12","Start":"88111318","Stop":"88111318","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":576354,"rule_based_match":true,"evidence_text":"c.2251C>T","llm_judgment":"PRESENT","evidence":"c.2251C>T","abstract_start":1034,"abstract_end":1043}]}
{"pmid":"28508084","title":"Clinicopathologic and molecular spectrum of","abstract":"OBJECTIVE: Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (<i>RNASEH1</i>) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations.\nMETHODS: <i>RNASEH1</i> was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA. Clinicopathologic and molecular evaluation of the newly identified and previously reported patients harboring <i>RNASEH1</i> mutations was subsequently undertaken.\nRESULTS: Pathogenic c.424G>A p.Val142Ile <i>RNASEH1</i> mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, <i>RNASEH1</i> genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further <i>RNASEH1</i> mutations were confirmed. <i>RNASEH1</i>-related mitochondrial disease was characterized by PEO (100%), cerebellar ataxia (57%), and dysphagia (50%). The ataxia neuropathy spectrum phenotype was observed in 1 patient. Although the c.424G>A p.Val142Ile mutation underpins all reported <i>RNASEH1</i>-related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families.\nCONCLUSIONS: In our cohort, <i>RNASEH1</i> mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in <i>POLG</i>, <i>RRM2B</i>, and <i>TWNK</i>. <i>RNASEH1</i> genetic analysis should also be considered in all patients with <i>POLG</i>-negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation.","variants":[{"Name":"NM_002936.6(RNASEH1):c.424G>A (p.Val142Ile)","Chromosome":"2","Start":"3550458","Stop":"3550458","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359102,"rule_based_match":true,"evidence_text":"c.424G>A p.Val142Ile","llm_judgment":"PRESENT","evidence":"c.424G>A p.Val142Ile","abstract_start":816,"abstract_end":836}]}
{"pmid":"34060411","title":"Analysis of a Novel Mexican Variant of the","abstract":"We present a study performed on 54 unrelated subjects, with and without thalassemic features. Two primer pairs were proposed to perform Sanger sequencing of the complete <i>HBB</i> gene. The bioinformatic analysis was performed taking advantage of the availability of free online tools. In the sample, we found 11 variants, 10 reported, and one novel. Among the variants found, six are clinically important: three encode a premature stop codon [codon 39 (C>T) (<i>HBB</i>: c.118C>T); IVS-II-1 (G>A) (<i>HBB</i>: c.315+1G>A), and one not reported], a double substitution within the same allele [Hb Borås (<i>HBB</i>: c.266T>G) and Hb Santa Giusta Sardegna (<i>HBB</i>: c.282T>C)], and one whose pathogenicity is not yet defined [Hb Fannin-Lubbock I (<i>HBB</i>: c.359G>A)]. Even though the variants Hb Borås and Hb Santa Giusta Sardegna have been described, there is no report of their combined occurrence on the same allele, which could cause hemolytic anemia. Although the p.Leu88Arg and p.Cys93Trp variants do not alter the final length of the protein, the bioinformatic results suggest that there are differences in the tertiary structure of β-globin genes, mainly affecting helices E and F, being the motifs of interaction with the heme group. The novel variant is a 4 bp insertion that modifies the open reading frame, changing the last amino acid residue and causing a premature stop codon (<i>HBB</i>: c.291-294insGCAC). The variant was associated with β-thalassemia (β-thal). Bioinformatic analysis made it possible to predict the consequences that the new variant of the <i>HBB</i> gene caused on the β-globin tertiary structure.","variants":[{"Name":"NM_000518.5(HBB):c.359G>A (p.Gly120Asp)","Chromosome":"11","Start":"5225683","Stop":"5225683","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38469,"rule_based_match":true,"evidence_text":"Hb Fannin-Lubbock I (HBB: c.359G>A)","llm_judgment":"PRESENT","evidence":"c.359G>A","abstract_start":761,"abstract_end":769}]}
{"pmid":"31973973","title":"Heterozygous type 1 Autosomal Dominant Optic Atrophy (ADOA) with OPA1 c.1936-2A>G genetic variant.","abstract":"","variants":[{"Name":"NM_130837.3(OPA1):c.1936-2A>G","Chromosome":"3","Start":"193648793","Stop":"193648793","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":491924,"rule_based_match":true,"evidence_text":"OPA1 c.1936-2A>G","llm_judgment":"PRESENT","evidence":"OPA1 c.1936-2A>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"29739340","title":"Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects.","abstract":"BACKGROUND: Mutations in the SLC26A4 gene are associated with Pendred syndrome and autosomal recessive non-syndromic deafness (DFNB4). Both disorders have similar audiologic characteristics: bilateral hearing loss, often severe or profound, which may be associated with abnormalities of the inner ear, such as dilatation of the vestibular aqueduct or Mondini dysplasia. But, in Pendred syndrome (OMIM #274600), with autosomal recessive inheritance, besides congenital sensorineural deafness, goiter or thyroid dysfunctions are frequently present. The aim of this study was to determine whether mutations in SLC26A4 are a frequent cause of hereditary deafness in Brazilian patients.\nMETHODS: Microsatellite haplotypes linked to SLC26A4 were investigated in 68 families presenting autosomal recessive non-syndromic deafness. In the probands of the 16 families presenting segregation consistent with linkage to SLC26A4, Sanger sequencing of the 20 coding exons was performed. In an additional sample of 15 individuals with suspected Pendred syndrome, because of the presence of hypothyroidism or cochleovestibular malformations, the SLC26A4 gene coding region was also sequenced.\nRESULTS: In two of the 16 families with indication of linkage to SLC26A4, the probands were found to be compound heterozygotes for probably pathogenic different mutations: three novel (c.1003 T > G (p. F335 V), c.1553G > A (p.W518X), c.2235 + 2 T > C (IVS19 + 2 T > C), and one already described, c.84C > A (p.S28R). Two of the 15 individuals with suspected Pendred syndrome because of hypothyreoidism or cochleovestibular malformations were monoallelic for likely pathogenic mutations: a splice mutation (IVS7 + 2 T > C) and the previously described c.1246A > C (p.T416P). Pathogenic copy number variations were excluded in the monoallelic cases and in those with normal results after Sanger sequencing. Additional mutations in the SLC26A4 gene or other definite molecular cause for deafness were not identified in the monoallelic patients, after exome sequencing.\nCONCLUSIONS: Biallelic pathogenic mutations in SLC26A4 explained ~ 3% of cases selected because of autosomal recessive deafness. Monoallelic mutations were present in ~ 13% of isolated cases of deafness with cochleovestibular malformations or suspected Pendred syndrome. These data reinforce the importance of mutation screening of SLC26A4 in Brazilian subjects and highlight the elevated frequency of monoallelic patients.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1003T>G (p.Phe335Val)","Chromosome":"7","Start":"107689054","Stop":"107689054","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1200160,"rule_based_match":true,"evidence_text":"c.1003 T > G (p. F335 V)","llm_judgment":"PRESENT","evidence":"c.1003 T > G (p. F335 V)","abstract_start":1362,"abstract_end":1386},{"Name":"NM_000441.2(SLC26A4):c.84C>A (p.Ser28Arg)","Chromosome":"7","Start":"107661725","Stop":"107661725","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":186723,"rule_based_match":true,"evidence_text":"c.84C > A (p.S28R)","llm_judgment":"PRESENT","evidence":"c.84C > A (p.S28R)","abstract_start":1474,"abstract_end":1492},{"Name":"NM_000441.2(SLC26A4):c.2235+2T>C","Chromosome":"7","Start":"107710201","Stop":"107710201","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":544453,"rule_based_match":true,"evidence_text":"c.2235+2T>C (IVS19+2T>C)","llm_judgment":"PRESENT","evidence":"c.2235+2T>C (IVS19+2T>C)","abstract_start":null,"abstract_end":null},{"Name":"NM_000441.2(SLC26A4):c.1246A>C (p.Thr416Pro)","Chromosome":"7","Start":"107690220","Stop":"107690220","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":19857,"rule_based_match":true,"evidence_text":"c.1246A>C (p.T416P)","llm_judgment":"PRESENT","evidence":"c.1246A > C (p.T416P)","abstract_start":1728,"abstract_end":1749}]}
{"pmid":"27543438","title":"Intron retention resulting from a silent mutation in the VWF gene that structurally influences the 5' splice site.","abstract":"Disease-associated silent mutations are considered to affect the accurate pre-messenger RNA (mRNA) splicing either by influencing regulatory elements, leading to exon skipping, or by creating a new cryptic splice site. This study describes a new molecular pathological mechanism by which a silent mutation inhibits splicing and leads to intron retention. We identified a heterozygous silent mutation, c.7464C>T, in exon 44 of the von Willebrand factor (VWF) gene in a family with type 1 von Willebrand disease. In vivo and ex vivo transcript analysis revealed an aberrantly spliced transcript, with intron 44 retained in the mRNA, implying disruption of the first catalytic step of splicing at the 5' splice site (5'ss). The abnormal transcript with the retained intronic region coded a truncated protein that lacked the carboxy-terminal end of the VWF protein. Confocal immunofluorescence characterizations of blood outgrowth endothelial cells derived from the patient confirmed the presence of the truncated protein by demonstrating accumulation of VWF in the endoplasmic reticulum. In silico pre-mRNA secondary and tertiary structure analysis revealed that this substitution, despite its distal position from the 5'ss (85 bp downstream), induces cis alterations in pre-mRNA structure that result in the formation of a stable hairpin at the 5'ss. This hairpin sequesters the 5'ss residues involved in U1 small nuclear RNA interactions, thereby inhibiting excision of the pre-mRNA intronic region. This study is the first to show the allosteric-like/far-reaching effect of an exonic variation on pre-mRNA splicing that is mediated by structural changes in the pre-mRNA.","variants":[{"Name":"NM_000552.5(VWF):c.7464C>T (p.Gly2488=)","Chromosome":"12","Start":"5971683","Stop":"5971683","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":611126,"rule_based_match":true,"evidence_text":"c.7464C>T","llm_judgment":"PRESENT","evidence":"c.7464C>T","abstract_start":401,"abstract_end":410}]}
{"pmid":"29381936","title":"Genotype and clinical course in 2 Chinese Han siblings with Wilson disease presenting with isolated disabling premature osteoarthritis: A case report.","abstract":"RATIONALE: Premature osteoarthritis (POA) is a rare condition in Wilson disease (WD). Particularly, when POA is the only complaint of a WD patient for a long time, there would be misdiagnosis or missed diagnosis and then treatment delay.\nPATIENT CONCERNS AND DIAGNOSIS: Two Chinese Han siblings were diagnosed as WD by corneal K-F rings, laboratory test, and mutation analysis. They presented with isolated POA during the first 2 decades or more of their disease course, and were of missed diagnosis during that long time. The older affected sib became disabled due to his severe osteoarthritis when he was as young as 38 years old. Two compound heterozygous pathogenic variants c.2790_2792del and c.2621C>T were revealed in the ATP7B gene through targeted next-generation sequencing (NGS).\nLESSONS: Adolescent-onset POA could be the only complaint of WD individual for at least 2 decades. Long delay in the treatment of WD's POA could lead to disability in early adulthood. Detailed physical examination, special biochemical test, and genotyping through targeted NGS should greatly reduce diagnosis delay in atypical WD patients with isolated POA phenotype.","variants":[{"Name":"NM_000053.4(ATP7B):c.2621C>T (p.Ala874Val)","Chromosome":"13","Start":"51950116","Stop":"51950116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18890,"rule_based_match":true,"evidence_text":"c.2621C>T","llm_judgment":"PRESENT","evidence":"c.2621C>T","abstract_start":698,"abstract_end":707}]}
{"pmid":"25728777","title":"Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features.","abstract":"Through a multi-center collaboration study, we here report six individuals from five unrelated families, with mutations in KAT6A/MOZ detected by whole-exome sequencing. All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A: NM_001099412.1: c.3116_3117 delCT, p.(Ser1039∗); c.3830_3831insTT, p.(Arg1278Serfs∗17); c.3879 dupA, p.(Glu1294Argfs∗19); c.4108G>T p.(Glu1370∗) and c.4292 dupT, p.(Leu1431Phefs∗8). An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome. The common phenotype includes hypotonia, intellectual disability, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, and cardiac defects in combination with subtle facial features such as bitemporal narrowing, broad nasal tip, thin upper lip, posteriorly rotated or low-set ears, and microretrognathia. The identification of human subjects complements previous work from mice and zebrafish where knockouts of Kat6a/kat6a lead to developmental defects.","variants":[{"Name":"NM_006766.5(KAT6A):c.3879dup (p.Glu1294fs)","Chromosome":"8","Start":"41934340","Stop":"41934341","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":178847,"rule_based_match":true,"evidence_text":"c.3879 dupA, p.(Glu1294Argfs∗19)","llm_judgment":"PRESENT","evidence":"c.3879 dupA, p.(Glu1294Argfs∗19)","abstract_start":382,"abstract_end":414},{"Name":"NM_006766.5(KAT6A):c.4108G>T (p.Glu1370Ter)","Chromosome":"8","Start":"41934112","Stop":"41934112","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":171894,"rule_based_match":true,"evidence_text":"c.4108G>T p.(Glu1370∗)","llm_judgment":"PRESENT","evidence":"c.4108G>T p.(Glu1370∗)","abstract_start":416,"abstract_end":438}]}
{"pmid":"27181379","title":"CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.","abstract":"BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.","variants":[{"Name":"NM_000077.5(CDKN2A):c.301G>T (p.Gly101Trp)","Chromosome":"9","Start":"21971058","Stop":"21971058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":24451,"rule_based_match":true,"evidence_text":"c.301G > T, p.Gly101Trp","llm_judgment":"PRESENT","evidence":"c.301G > T, p.Gly101Trp","abstract_start":732,"abstract_end":755},{"Name":"NM_004656.4(BAP1):c.1153C>T (p.Arg385Ter)","Chromosome":"3","Start":"52404550","Stop":"52404550","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":473723,"rule_based_match":true,"evidence_text":"c.1153C > T, p.Arg385*","llm_judgment":"PRESENT","evidence":"c.1153C > T, p.Arg385*","abstract_start":655,"abstract_end":677}]}
{"pmid":"30400067","title":"A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation.","abstract":"Objective The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation. Results Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. Conclusion The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.","variants":[{"Name":"NM_000612.6(IGF2):c.195del (p.Ile66fs)","Chromosome":"11","Start":"2133628","Stop":"2133628","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":905832,"rule_based_match":true,"evidence_text":"a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93))","llm_judgment":"PRESENT","evidence":"a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93))","abstract_start":461,"abstract_end":524}]}
{"pmid":"32974172","title":"","abstract":"Malignant ovarian germ cell tumors (MOGCTs) are neoplasms of the ovary, of which, due to their rarity and heterogeneity, few is reported about genetic background and development. Here, we report a 18-years old patient diagnosed with an ovarian mixed germ cell tumor, without any previous history of malignancies, who has been treated with surgery and chemotherapy and died 4 years later due to peritoneal metastasis complications. Patient's blood DNA was screened for a panel of 52 cancer-related genes in order to identify predisposing aberrations to this rare cancer. The analysis discovered the uncharacterized c.2393G>A variant in <i>RB1</i>, the retinoblastoma gene, leading both to a missense change and a splicing perturbation of the <i>RB1</i> transcript. The variant was found to be hypomorphic, damaging the C-terminal domain with a partially impaired protein function. The variant is inherited from the unaffected mother. Due to an imprinting mechanism, the maternal allele is ~3-fold more expressed than the paternal one. The parent-of-origin effect combined with the hypomorphic impact of the variant determines a rescue of sufficient tumor-suppressor activity to prevent retinoblastoma development but can predispose to other cancers in the adult age. In order to understand the somatic events acting on the germline predisposition we used the NGS-liquid biopsy covering 77 cancer driver genes. Using this approach, we detected deleterious mutations in <i>TP53, SMAD4, FGFR3</i>, and <i>MSH2</i>, indicative of a dis-regulation of cell cycle and DNA repair mechanisms pathways. In conclusion, we have pinpointed for the first time that an <i>RB1</i> leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness.","variants":[{"Name":"NM_000321.3(RB1):c.2393G>A (p.Arg798Gln)","Chromosome":"13","Start":"48465272","Stop":"48465272","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":688175,"rule_based_match":true,"evidence_text":"c.2393G>A","llm_judgment":"PRESENT","evidence":"c.2393G>A","abstract_start":614,"abstract_end":623}]}
{"pmid":"37814107","title":"Novel GPR156 variants confirm its role in moderate sensorineural hearing loss.","abstract":"Hereditary hearing loss (HL) is a genetically heterogeneous disorder affecting people worldwide. The implementation of advanced sequencing technologies has significantly contributed to the identification of novel genes involved in HL. In this study, probands of two Turkish families with non-syndromic moderate HL were subjected to exome sequencing. The data analysis identified the c.600G > A (p.Thr200Thr) and c.1863dupG (p.His622fs) variants in GPR156, which co-segregated with the phenotype as an autosomal recessive trait in the respective families. The in silico predictions and a minigene assay showed that the c.600G > A variant disrupts mRNA splicing. This gene belongs to the family of G protein-coupled receptors whose function is not well established in the inner ear. GPR156 variants have very recently been reported to cause HL in three families. Our study from a different ethnic background confirms GPR156 as a bona fide gene involved in HL in humans. Further investigation towards the understanding of the role of GPCRs in the inner ear is warranted.","variants":[{"Name":"NM_153002.3(GPR156):c.600G>A (p.Thr200=)","Chromosome":"3","Start":"120186658","Stop":"120186658","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2739497,"rule_based_match":true,"evidence_text":"c.600G > A (p.Thr200Thr)","llm_judgment":"PRESENT","evidence":"c.600G > A (p.Thr200Thr)","abstract_start":383,"abstract_end":407},{"Name":"NM_153002.3(GPR156):c.1863dup (p.His622fs)","Chromosome":"3","Start":"120167613","Stop":"120167614","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":2739498,"rule_based_match":true,"evidence_text":"c.1863dupG (p.His622fs)","llm_judgment":"PRESENT","evidence":"c.1863dupG (p.His622fs)","abstract_start":412,"abstract_end":435}]}
{"pmid":"34704412","title":"Screening and follow-up results of fatty acid oxidative metabolism disorders in 608 818 newborns in Jining, Shandong province.","abstract":"To investigate the incidence and gene mutation characteristics of fatty acid oxidative metabolism disorders in Jining area of Shandong province , and to evaluate the therapeutic effect. Blood samples of newborns were collected in Jining of Shandong province between July 14, 2014 and December 31, 2019. Tandem mass spectrometry was used to determine the levels of carnitine and acylcarnitine in the blood to screen for fatty acid oxidative metabolism disorder. For newborns with positive screening result, blood DNA was analyzed by MassARRAY and high-throughput sequencing, then verified by Sanger sequencing. The diagnosed children were given early intervention and treatment, and followed up. Forty-two children with fatty acid oxidative metabolism disorders were screened out of 608 818 newborns, with an incidence rate of 1/14 496. Primary carnitine deficiency (16 cases, 38.10%) and short-chain acyl-CoA dehydrogenase deficiency (16 cases, 38.10%) were the most common, followed by very long-chain acyl-CoA dehydrogenase deficiency (6 cases, 14.29%), medium-chain acyl-CoA dehydrogenase deficiency (4 cases, 9.53%). In children with primary carnitine deficiency, c.1400C>G (p.S467C) and c.51C>G were the most common in mutations; and c.278C>T (p.S93L), c.1049T >C (p.L350P), c.572A>G (p.K191R), c.431T>C (p.L144P) were newly discovered mutations. Ten children with carnitine replacement therapy showed normal development during the follow-up. In 6 children without carnitine replacement treatment, hypoglycemia developed during the neonatal period in 1 case, in whom the creatine kinase was increased, and the intellectual and language development delayed in the later period; the other 5 children developed normally during the follow-up period. The gene mutations c.1031A>G (p.E344G) and c.164C>T (p.P55L) were common in children with short-chain acyl-CoA dehydrogenase deficiency, and the children developed normally during the follow-up. In children with very long-chain acyl-CoA dehydrogenase deficiency, the c.1349G>A was common in gene mutations; and c.488T>A , c.1228G>T (p.D410Y), c.1276G>A (p.A426T), c.1522C>T (p.Q508*), c.1226C>T (p.T409M) were newly discovered mutations. Three children treated with milk powder rich in medium-chain fatty acids had normal development during the follow-up. The other 3 cases with combined carnitine reduction were treated with levocarnitine and milk powder enriched of medium-chain fatty acids, 1 case developed normally during the follow-up, 1 case died of acute illness at the age of and 1 case had acute illness and recovered after treatment, and developed normally during the follow-up. c.449_452del (p.T150Rfs*4) was the most common gene mutation in children with medium-chain acyl-CoA dehydrogenase deficiency, and c. 718A>G (p.M240V) was a newly discovered mutation. All children received low-fat diet, and hunger and fatigue were avoided; 1 child was supplemented with L-carnitine, and the other 3 children were not treated with drugs, and all of them developed normal during the follow-up. Primary carnitine deficiency and short-chain acyl-CoA dehydrogenase deficiency are the most common fatty acid oxidative metabolism disorders in Jining area. There are gene hotspot mutations and new discovered gene mutations in patients. Patients with early diagnosis and treatment through neonatal screening have a good prognosis.","variants":[{"Name":"NM_000018.4(ACADVL):c.1276G>A (p.Ala426Thr)","Chromosome":"17","Start":"7223819","Stop":"7223819","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":646656,"rule_based_match":true,"evidence_text":"c.1276G>A (p.A426T)","llm_judgment":"PRESENT","evidence":"c.1276G>A (p.A426T)","abstract_start":2094,"abstract_end":2113}]}
{"pmid":"32010257","title":"Successful clinical application of pre-implantation genetic diagnosis for infantile neuroaxonal dystrophy.","abstract":"Infantile neuroaxonal dystrophy (INAD) is a rare, lethal, autosomal recessive neurodegenerative disease and leads to progressive impairment of movement and cognition. A couple with a proband child with calcium-independent group VI phospholipase A2 (PLA2G6)-associated INAD and a previous affected pregnancy sought pre-implantation genetic diagnosis (PGD) to bear a healthy child. Intracytoplasmic sperm injection treatment was performed and 15 blastocystic embryos were obtained at days 5 and 6, and these biopsies were amplified. PGD was performed by next-generation sequencing-based linkage analysis in conjunction with aneuploidy screening. Only two embryos were considered for transfer. In the second frozen-thawed embryo transfer cycle, transfer of a mosaic PLA2G6 c.692G>T heterozygous embryo resulted in a singleton ongoing pregnancy. Prenatal diagnosis was performed using amniotic fluid cells, providing results consistent with those of PGD. The aneuploidy screen and karyotype analysis indicated that the chromosomes of the fetus were normal without any mosaicism. The present study reported the first successful PGD for INAD. For parents at risk, this strategy may successfully lead to pregnancies with embryos unlikely to develop INAD, thus providing valuable experience in reproductive management regarding INAD and potentially other single-gene disorders.","variants":[{"Name":"NM_003560.4(PLA2G6):c.692G>T (p.Gly231Val)","Chromosome":"22","Start":"38140087","Stop":"38140087","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2738448,"rule_based_match":true,"evidence_text":"PLA2G6 c.692G>T","llm_judgment":"PRESENT","evidence":"PLA2G6 c.692G>T","abstract_start":763,"abstract_end":778}]}
{"pmid":"17519222","title":"Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene.","abstract":"The melanocortin-4 receptor (MC4R) gene pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for approximately 2% of obesity cases, but its role in common obesity is still elusive. We analyzed the contribution of non-synonymous mutations V103I (rs2229616, c.307G > A) and I251L (no rs, c.751A > C) to obesity in 16 797 individuals of European origin from nine independent case-control, population-based and familial cohorts. We observed a consistent negative association of I251L variant (prevalence ranging 0.41-1.21%) with both childhood and adult class III obesity [odds ratio (OR) ranging from 0.25 to 0.76, 0.001 < P-value < 0.05] and with modulation of body mass index (BMI) in general populations, in eight out of nine studies, whereas only one study showed an association between V103I and BMI. Meta-analyses of previous published data with the current ones provided strong evidence of the protective effect of I251L toward obesity (OR = 0.52, P = 3.58 10-5), together with a modest negative association between V103I and obesity (OR = 0.80, P = 0.002). Taken together, gain-of-function mutations I251L and V103I may be responsible for a preventive fraction of obesity of 2%, which mirrors the prevalence of monogenic obesity due to MC4R haploinsufficiency. These results also emphasize the importance of the MC4R signalling tonus to prevent obesity, even in the context of our current obesogenic environment.","variants":[{"Name":"NM_005912.3(MC4R):c.751A>C (p.Ile251Leu)","Chromosome":"18","Start":"60371599","Stop":"60371599","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":215036,"rule_based_match":true,"evidence_text":"c.751A > C","llm_judgment":"PRESENT","evidence":"c.751A > C","abstract_start":317,"abstract_end":327},{"Name":"NM_005912.3(MC4R):c.307G>A (p.Val103Ile)","Chromosome":"18","Start":"60372043","Stop":"60372043","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215037,"rule_based_match":true,"evidence_text":"c.307G > A","llm_judgment":"PRESENT","evidence":"c.307G > A","abstract_start":287,"abstract_end":297}]}
{"pmid":"30098249","title":"Analysis of clinical manifestation and genetic mutation in a child with X-linked chondrodysplasia punctata 2","abstract":"OBJECTIVE: To analyze clinical manifestations and genetic mutation in a child with severe short stature and other malformations.\nMETHODS: The child has undergone history taking and physical examination. Genome DNA was extracted from peripheral blood samples of the proband and her family members. Candidate genes were captured with Agilent SureSelect and sequenced on an Illumina platform. Suspected mutation was verified by Sanger sequencing.\nRESULTS: The patient, a six-year-and-10-month old girl, presented with non-symmetrical short stature, dysmorphism, abnormalities of limbs and spine, amblyopia of left eye, and cataract of right eye, in addition with frequent respiratory infection and micturition. Laboratory testing suggested 25-hydroxy vitamin D deficiency (18.9 ng/mL). Spine X-ray showed multiple malformations with centrums. Her mother also featured short stature (138 cm). Her aunt had short stature (130 cm) and limb-length discrepancy. Her little brother was 2.5 years old, and his height was 81 cm (-3.4 SD). Exome sequencing revealed a heterozygous mutation c.184C to T (p.Arg62Trp) in the proband and her mother. The same mutation was not found in her father and brother.\nCONCLUSION: The patient was diagnosed with X-linked chondrodysplasia punctata 2. Mutation of the EBP gene probably underlied the disease in this family.","variants":[{"Name":"NM_006579.3(EBP):c.184C>T (p.Arg62Trp)","Chromosome":"X","Start":"48523955","Stop":"48523955","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1513781,"rule_based_match":false,"evidence_text":"c.184C to T (p.Arg62Trp)","llm_judgment":"PRESENT","evidence":"c.184C to T (p.Arg62Trp)","abstract_start":1078,"abstract_end":1102}]}
{"pmid":"28687180","title":"A patient with early myoclonic encephalopathy (EME) with a de novo KCNQ2 mutation.","abstract":"BACKGROUND: The potassium voltage-gated channel subfamily Q member 2 (KCNQ2) gene has been reported to be associated with various types of epilepsy, including benign familial neonatal seizure (BFNS), early infantile epileptic encephalopathy (EIEE), and unclassified early onset encephalopathies. We herein report a patient with early myoclonic encephalopathy (EME) caused by a KCNQ2 mutation.\nCASE REPORT: A male infant started to exhibit erratic myoclonus several days after birth and apnea attacks lasting for seconds with desaturation. One month after birth, his myoclonuses worsened in frequency. Electroencephalogram (EEG) showed a burst and suppression pattern, and myoclonuses occurred in the burst phase with diffuse polyspikes on EEG. At five months, inter-ictal EEG revealed hypsarrhythmia, but his attacks were still only myoclonuses. ACTH treatment was effective and the myoclonus frequency markedly decreased. At one year of age, whole-exome sequencing revealed a heterozygous mutation of the KCNQ2 gene (NM_172107.2): c.601C>T; p.(Arg201Cys), which was confirmed as de novo by Sanger sequencing. This mutation lies within the extracellular portion of the S4 voltage sensor.\nCONCLUSION: Most patients with a KCNQ2 mutation present with seizures starting in the neonatal period with varying severity, ranging from BFNS to Ohtahara syndrome. Furthermore, KCNQ2 appears to be a causative gene for EME.","variants":[{"Name":"NM_172107.4(KCNQ2):c.601C>T (p.Arg201Cys)","Chromosome":"20","Start":"63444748","Stop":"63444748","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":203792,"rule_based_match":true,"evidence_text":"c.601C>T; p.(Arg201Cys)","llm_judgment":"PRESENT","evidence":"c.601C>T; p.(Arg201Cys)","abstract_start":1032,"abstract_end":1055}]}
{"pmid":"31600233","title":"Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types.","abstract":"Hypophosphatasia (HPP) is a rare and intractable metabolic bone disease caused by mutations in the ALPL gene. Here, we undertook a nationwide survey of HPP in Japan, specifically regarding the prominent genetic and dental manifestations of odonto (n = 16 cases) and other (termed \"non-odonto\") (n = 36 cases) types. Mean serum alkaline phosphatase (ALP) values in odonto-type patients were significantly greater than those of non-odonto-type patients (P<0.05). Autosomal dominant and autosomal recessive inheritance patterns were detected, respectively, in 89% of odonto-type and 96% of non-odonto-type patients. The ALPL \"c.1559delT\" mutation, associated with extremely low ALP activity, was found in approximately 70% of cases. Regarding dental manifestations, all patients classified as odonto-type showed early exfoliation of the primary teeth significantly more frequently than patients classified as non-odonto-type (100% vs. 56%; P<0.05). Tooth hypomineralisation was detected in 42% of non-odonto-type patients, but not in any odonto-type patients (0%; P<0.05). Collectively, these results suggest that genetic and dental manifestations of patients with odonto-type and non-odonto-type HPP are significantly different, and these differences should be considered during clinical treatment of patients with HPP.","variants":[{"Name":"NM_000478.6(ALPL):c.1559del (p.Leu520fs)","Chromosome":"1","Start":"21577632","Stop":"21577632","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":28713,"rule_based_match":true,"evidence_text":"c.1559delT","llm_judgment":"PRESENT","evidence":"c.1559delT","abstract_start":623,"abstract_end":633}]}
{"pmid":"18612766","title":"Non-manifesting Refsum heterozygotes carrying the c.135-2A>G PAHX gene transition.","abstract":"So far, subjects heterozygous for PAHX mutations are regarded as non-symptomatic. In the 24-year-old, HIV-negative daughter and the 26-year-old, HIV-negative son of a patient with Refsum disease due to the homozygous c.135-2A>G transition at the splice site before exon 3 of the PAHX gene, slight abnormalities suggestive of the disease became apparent. The daughter reported a single fever cramp in childhood, recurrent, short-lived amaurotic episodes after getting up from supine, short-sightedness, hypoacusis, and restless legs. The son complained about restless legs, hyperhidrosis, hypoacusis, and bulbar oscillations. Though both children carried the same mutation as their mother in the heterozygous form, clinical neurologic examination, nerve conduction studies and serum phytanic acid concentration were normal in both of them, implying that the described abnormalities were not causally related to the PAHX mutation. In the absence of elevated phytanic acid concentrations, clinical neurologic abnormalities in heterozygous relatives of Refsum patients are not attributable to heterozygosity for PAHX mutations.","variants":[{"Name":"NM_006214.4(PHYH):c.135-2A>G","Chromosome":"10","Start":"13295608","Stop":"13295608","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":22620,"rule_based_match":true,"evidence_text":"c.135-2A>G","llm_judgment":"PRESENT","evidence":"c.135-2A>G","abstract_start":217,"abstract_end":227}]}
{"pmid":"34503561","title":"Monogenic mutations in four cases of neonatal-onset watery diarrhea and a mutation review in East Asia.","abstract":"BACKGROUND: Infants with neonatal-onset diarrhea present with intractable diarrhea in the first few weeks of life. A monogenic mutation is one of the disease etiologies and the use of next-generation sequencing (NGS) has made it possible to screen patients for their mutations.\nMAIN BODY: We retrospectively reviewed the clinical data of four children from unrelated families, who presented with neonatal-onset, chronic, watery, non-bloody diarrhea. After genetic whole-exome sequencing, novel mutations were identified in the EPCAM gene of two children. Congenital chloride diarrhea was diagnosed in one case, which was associated with an SLC26A3 mutation, in which the patient presented with watery diarrhea, malnutrition, and hypochloremic alkalosis. Patient 4 was diagnosed with microvillus inclusion disease and possessed novel compound heterozygous mutations in the MYO5B gene. A review of the genetic variants of SLC26A3 reported in East Asia revealed that c.269_270 dupAA (p.G91Kfs*3) is the most frequent SLC26A3 mutation in China, compared with c.2063-1 G > T in Japan and Korea. EPCAM and MYO5B genetic variants were only sporadically reported in East Asia.\nCONCLUSION: This study expands our knowledge of the clinical manifestations and molecular genetics of neonatal-onset watery diarrhea. Early diagnosis could be achieved by genomic analysis in those infants whose histology features are not typical. The discovery of four novel mutations in the EPCAM gene and two novel mutations in the MYO5B gene provides further etiological evidence for the association of genetic mutations with neonatal-onset diarrhea. To date, c.269_270 dupAA is the most frequent SLC26A3 mutation in China.","variants":[{"Name":"NM_000111.3(SLC26A3):c.269_270dup (p.Gly91fs)","Chromosome":"7","Start":"107793742","Stop":"107793743","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CTT","allel_id":70633,"rule_based_match":true,"evidence_text":"c.269_270 dupAA (p.G91Kfs*3)","llm_judgment":"PRESENT","evidence":"c.269_270 dupAA (p.G91Kfs*3)","abstract_start":964,"abstract_end":992}]}
{"pmid":"26867756","title":"Recurrent mutation in the crystallin alpha A gene associated with inherited paediatric cataract.","abstract":"BACKGROUND: Cataract is a major cause of childhood blindness worldwide. The purpose of this study was to determine the genetic cause of paediatric cataract in a South Australian family with a bilateral lamellar paediatric cataract displaying variable phenotypes.\nCASE PRESENTATION: Fifty-one genes implicated in congenital cataract in human or mouse were sequenced in an affected individual from an Australian (Caucasian) family using a custom Ampliseq library on the Ion Torrent Personal Genome Machine. Reads were mapped against the human genome (hg19) and variants called with the Torrent Suite software. Variants were annotated to dbSNP 137 using Ion Reporter (IR 1.6.2) and were prioritised for validation if they were novel or rare and were predicted to be protein changing. We identified a previously reported oligomerization disrupting mutation, c.62G > A (p.R21Q), in the Crystallin alpha A (CRYAA) gene segregating in this three generation family. No other novel or rare coding mutations were detected in the known cataract genes sequenced. Microsatellite markers were used to compare the haplotypes between the family reported here and a previously published family with the same segregating mutation. Haplotype analysis indicated a potential common ancestry between the two South Australian families with this mutation. The work strengthens the genotype-phenotype correlations between this functional mutation in the crystallin alpha A (CRYAA) gene and paediatric cataract.\nCONCLUSION: The p.R21Q mutation is the most likely cause of paediatric cataract in this family. The recurrence of this mutation in paediatric cataract families is likely due to a familial relationship.","variants":[{"Name":"NM_000394.4(CRYAA):c.62G>A (p.Arg21Gln)","Chromosome":"21","Start":"43169161","Stop":"43169161","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":79353,"rule_based_match":true,"evidence_text":"c.62G > A (p.R21Q)","llm_judgment":"PRESENT","evidence":"c.62G > A (p.R21Q)","abstract_start":854,"abstract_end":872}]}
{"pmid":"29907907","title":"Three novel mutations in 20 patients with hereditary spastic paraparesis.","abstract":"Hereditary spastic paraparesis (HSP) constitutes both genetic and clinically heterogeneous group of upper motor neuron diseases. Half of the individuals with autosomal dominant (AD) HSP have mutations in SPAST, ATL1, and REEP1 genes. This study was conducted to elucidate the genetic etiology of patients with the pure type AD-HSP diagnosis. The patient group consisted of 23 individuals from 6 families in Turkey. In the first step of work, Sanger sequencing (SS) was performed in ATL1, SPAST, and REEP1 genes and the second phase whole-exome sequencing (WES) was performed following SS analysis for the patients with no detected mutations in these genes. The results of this study revealed that in ATL1, 6 patients have previously reported c.776C > A mutation and 6 patients have novel c.470 T > C mutation. In SPAST, 3 patients have novel c.1072G > C mutation and 2 patients have novel c.1099-1G > C mutation. WES was performed in three patients, who had no detected mutation in these genes with SS analysis. In this approach, as previously reported c.1859 T > C mutation in KIAA0196 was detected, and it was confirmed with the patient's relatives by SS. In three of patients, no HSP-associated variant could be identified in SS and WES. With this study, the molecular genetic etiology in 20 of 23 (87%) individuals that were included in this study with the utilization of SS and WES was elucidated. Utilization of SS and WES methods have enabled the identification of genetic etiology of HSP further with appropriate genetic counseling that was provided to the patients.","variants":[{"Name":"NM_014946.4(SPAST):c.1099-1G>C","Chromosome":"2","Start":"32126947","Stop":"32126947","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2179573,"rule_based_match":true,"evidence_text":"c.1099-1G > C","llm_judgment":"PRESENT","evidence":"c.1099-1G > C","abstract_start":889,"abstract_end":902},{"Name":"NM_015915.5(ATL1):c.776C>A (p.Ser259Tyr)","Chromosome":"14","Start":"50614425","Stop":"50614425","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":19386,"rule_based_match":true,"evidence_text":"c.776C > A","llm_judgment":"PRESENT","evidence":"c.776C > A","abstract_start":742,"abstract_end":752}]}
{"pmid":"32653833","title":"Detailed Phenotyping and Therapeutic Strategies for Intronic ABCA4 Variants in Stargardt Disease.","abstract":"Stargardt disease is a progressive retinal disorder caused by bi-allelic mutations in the ABCA4 gene that encodes the ATP-binding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease.","variants":[{"Name":"NM_000350.3(ABCA4):c.5196+1137G>A","Chromosome":"1","Start":"94018445","Stop":"94018445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":431618,"rule_based_match":true,"evidence_text":"c.5196+1137G>A","llm_judgment":"PRESENT","evidence":"c.5196+1137G>A","abstract_start":351,"abstract_end":365}]}
{"pmid":"34702576","title":"Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy.","abstract":"BACKGROUND: The type 1 interferonopathy, Aicardi-Goutières syndrome 6 (AGS6), is classically caused by biallelic ADAR mutations whereas dominant ADAR mutations are associated with dyschromatosis symmetrica hereditaria (DSH). The unique dominant ADAR c.3019G>A variant is associated with neurological manifestations which mimic spastic paraplegia and cerebral palsy (CP).\nCASE SUMMARIES: We report three cases of spastic paraplegia or CP diagnosed with AGS6 caused by the ADAR c.3019G>A variant. Two children inherited the variant from an asymptomatic parent, and each child had a different clinical course. The youngest case demonstrated relentless progressive symptoms but responded to immunomodulation using steroids and ruxolitinib.\nCONCLUSION: The ADAR c.3019G>A variant has incomplete penetrance and is a likely underrecognized imitator of spastic paraplegia and dystonic CP. A high level of clinical suspicion is required to diagnose this form of AGS, and disease progression may be ameliorated by immunomodulatory treatment with selective Janus kinase inhibitors.","variants":[{"Name":"NM_001111.5(ADAR):c.3019G>A (p.Gly1007Arg)","Chromosome":"1","Start":"154588125","Stop":"154588125","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48057,"rule_based_match":true,"evidence_text":"ADAR c.3019G>A","llm_judgment":"PRESENT","evidence":"ADAR c.3019G>A","abstract_start":245,"abstract_end":259}]}
{"pmid":"34539727","title":"Oligogenic Inheritance Underlying Incomplete Penetrance of","abstract":"The role of the prokineticin 2 pathway in human reproduction, olfactory bulb morphogenesis, and gonadotropin-releasing hormone secretion is well established. Recent studies have highlighted the implication of di/oligogenic inheritance in this disorder. In the present study, we aimed to identify the genetic mechanisms that could explain incomplete penetrance in hypogonadotropic hypogonadism (HH). This study involved two unrelated Tunisian patients with HH, which was triggered by identifying a homozygous p.(Pro290Ser) mutation in the <i>PROKR2</i> gene in a girl (HH1) with Kallmann syndrome (KS). The functional effect of this variant has previously been well demonstrated. Unexpectedly, her unaffected father (HH1P) and brother (HH1F) also carried this genetic variation at a homozygous state. In the second family, we identified a heterozygous p.(Lys205del) mutation in <i>PROKR2</i>, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a <i>CCDC141</i> variant (c.2803C > T) was involved in 18 pathogenic digenic combinations. The <i>CCDC141</i> variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between <i>DUSP6</i> and <i>SEMA7A</i> genes, predicted as \"dual molecular diagnosis.\" The <i>SEMA7A</i> variant p.(Glu436Lys) is novel and predicted as a VUS by Varsome. Sanger validation revealed the absence of this variant in the healthy mother. We hypothesize that disease expression in HH12 could be induced by the digenic transmission of the <i>SEMA7A</i> and <i>DUSP6</i> variants or a monogenic inheritance involving only the <i>SEMA7A</i> VUS if further functional assays allow its reclassification into pathogenic. Our findings confirm that homozygous loss-of-function genetic variations are insufficient to cause KS, and that oligogenism is most likely the main transmission mode involved in Congenital Hypogonadotropic Hypogonadism.","variants":[{"Name":"NM_144773.4(PROKR2):c.868C>T (p.Pro290Ser)","Chromosome":"20","Start":"5302327","Stop":"5302327","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":886288,"rule_based_match":false,"evidence_text":"p.(Pro290Ser)","llm_judgment":"PRESENT","evidence":"p.(Pro290Ser)","abstract_start":508,"abstract_end":521}]}
{"pmid":"35657619","title":"Phenotype-Based Genetic Analysis Reveals Missing Heritability of ABCA4-Related Retinopathy: Deep Intronic Variants and Copy Number Variations.","abstract":"Purpose: To identify the missing heritability of ABCA4-related retinopathy in a Chinese cohort.\nMethods: We recruited 33 unrelated patients with ABCA4-related retinopathy carrying a monoallelic variant in ABCA4. All patients underwent ophthalmic examinations. Next-generation sequencing of the whole ABCA4 sequence, including coding and noncoding regions, was performed to detect deep intronic variants (DIVs) and copy number variations (CNVs).\nResults: We identified eight missing pathogenic ABCA4 variants in 60.6% of the patients (20/33), which comprised five DIVs and three CNVs. The five DIVs, including four novel (c.1555-816T>G, c.2919-169T>G, c.2919-884G>T, and c.5461-1321A>G) and one reported (c.4539+1100A>G), accounted for the missing alleles in 51.5% of the patients. Minigene assays showed that four novel DIVs activated cryptic splice sites leading to the insertions of pseudoexons. The three novel CNVs consisted of one gross deletion of 1273 bp (exon 2) and two gross duplications covering 25.2 kb (exons 28-43) and 9.4 kb (exons 38-44). The microhomology domains were identified at the breakpoints and revealed the potential mechanisms of CNV formation.\nConclusions: DIVs and CNVs explained approximately two-thirds of the unresolved Chinese cases with ABCA4-related retinopathy. Combining results from phenotypic-directed screening, targeting the whole ABCA4 sequencing and in silico tools can help to identify the missing heritability.","variants":[{"Name":"NM_000350.3(ABCA4):c.4539+1100A>G","Chromosome":"1","Start":"94028345","Stop":"94028345","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3051531,"rule_based_match":true,"evidence_text":"c.4539+1100A>G","llm_judgment":"PRESENT","evidence":"c.4539+1100A>G","abstract_start":704,"abstract_end":718}]}
{"pmid":"26225618","title":"Genetic and Clinical Analyses of Southern Chinese Children with Peutz-Jeghers Syndrome.","abstract":"BACKGROUND: Children with Peutz-Jeghers syndrome (PJS) suffer from the continuous growth of polyps in their gastrointestinal tracts. Limited research on PJS has found that truncating mutations of the serine/threonine kinase 11 (STK11) gene may correlate with early symptoms and a greater number of polyps. Thus, further studies correlating the genetic and clinical characteristics of PJS would increase our understanding of this condition and improve recommendations for treatment.\nAIMS: Our study was designed to characterize the genetic and clinical characteristics of four Chinese PJS children (two girls and two boys) and their affected relatives from Southern China.\nRESULTS: One recurrent missense mutation (c.487G>C) and two novel nonsense (truncation) mutations (c.717G>A and c.871G>T) in the STK11 gene were identified. The two boys with nonsense mutations underwent their first surgeries at younger ages (2 and 4 years) compared to the others. The two girls underwent their first surgeries at similar ages, though the girl with the nonsense mutation underwent more surgeries than the girl with the missense mutation. The children with truncation mutations had medium to high counts of hamartomatous polyps, whereas the girl with the missense mutation had a lower count. The clinical findings were similar among affected individuals within each of the three families.\nCONCLUSIONS: These cases are consistent with previous findings, thus we conclude that children with nonsense mutations in STK11 should be closely monitored for polyp formation.","variants":[{"Name":"NM_000455.5(STK11):c.487G>C (p.Gly163Arg)","Chromosome":"19","Start":"1220395","Stop":"1220395","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":181056,"rule_based_match":true,"evidence_text":"c.487G>C","llm_judgment":"PRESENT","evidence":"c.487G>C","abstract_start":714,"abstract_end":722},{"Name":"NM_000455.5(STK11):c.717G>A (p.Trp239Ter)","Chromosome":"19","Start":"1220700","Stop":"1220700","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":264827,"rule_based_match":true,"evidence_text":"c.717G>A","llm_judgment":"PRESENT","evidence":"c.717G>A","abstract_start":771,"abstract_end":779}]}
{"pmid":"28050600","title":"Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in","abstract":"Variants in <i>NDUFB11,</i> which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in <i>NDUFB11</i> (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in <i>HCCS</i> (which encodes an important mitochondrially targeted protein) and <i>COX7B,</i> which, like <i>NDUFB11,</i> encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that <i>NDUFB11</i> variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related).","variants":[{"Name":"NM_001135998.3(NDUFB11):c.262C>T (p.Arg88Ter)","Chromosome":"X","Start":"47142690","Stop":"47142690","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188131,"rule_based_match":true,"evidence_text":"c.262C > T; p.[Arg88*]","llm_judgment":"PRESENT","evidence":"c.262C > T; p.[Arg88*]","abstract_start":418,"abstract_end":440}]}
{"pmid":"10447258","title":"Identification of a common PEX1 mutation in Zellweger syndrome.","abstract":"The Zellweger spectrum of disease, encompassing Zellweger syndrome and the progressively milder phenotypes of neonatal adrenoleukodystrophy and infantile Refsum disease, is due to a failure to form functional peroxisomes. Cell fusion complementation studies demonstrated that these diseases are genetically heterogeneous, with two-thirds of all patients lying within a single complementation group, CG1. Molecular genetic and cell biology studies have shown that PEX1 is deficient in many CG1 patients. However, previous studies have focused on mildly affected patients and there is still no report of two mutant PEX1 alleles in any Zellweger syndrome patient. Furthermore, mutations in the PMP70 gene have also been identified in two Zellweger syndrome patients from CG1, raising the possibility that CG1 patients may represent a mixture of PEX1-deficient and PMP70-deficient individuals. To address the molecular basis of disease in Zellweger syndrome patients from CG1, we examined all 24 PEX1 exons in four patients, including both patients that have mutations in PMP70. PEX1 mutations were detected in all four patients, including a 1-bp insertion (c.2097insT) in exon 13 that was present in three of the four patients. Subsequent studies demonstrated that this mutation is present in one-half of all CG1 patients and correlates with the Zellweger syndrome phenotype. As this mutation leads to a loss of protein function its frequency makes it the most common cause of Zellweger syndrome, helping to explain the high percentage of patients that belong to CG1.","variants":[{"Name":"NM_000466.3(PEX1):c.2097dup (p.Ile700fs)","Chromosome":"7","Start":"92503169","Stop":"92503170","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":22558,"rule_based_match":false,"evidence_text":"c.2097insT","llm_judgment":"PRESENT","evidence":"c.2097insT","abstract_start":1154,"abstract_end":1164}]}
{"pmid":"32034731","title":"Analysis of 12 cases with methylmalonicacidemia cblA type","abstract":"OBJECTIVE: To explore the clinical feature, genetic variant and clinical outcome of patients with cblA-type methylmalonic acidemia (MMA).\nMETHODS: Clinical manifestations, therapeutic schedule and prognosis of 12 patients with cblA type MMA were analyzed. MMAA gene variants were analyzed for all patients and their parents.\nRESULTS: Vomiting, dyspnea and drowsiness were the major clinical features of cblA-type MMA. Eleven patients were vitamin B12-responsive. After treatment, the blood level of propionylcarnitine, ratio of propionylcarnitine/acetylcarnitine, urine level of methylmalonic acid and methylcitric acid have decreased significantly (P< 0.05). Follow-up study showed that 8 patients (66.7%) had normal development, while the rest (33.3%) remained to have various level of mental or movement delay. Fourteen MMAA gene variants were detected, with c.365T>C (p.L122P) being the most common (29.2%). Six novel variants, including c.54delA (p.A19Hfs*43), c.275G>A (p.G92V), c.456delT (p.G153Vfs*8), c.667dupA (p.T223Nfs*4), c.1114C>T (p.Q372X) and c.1137_1138delCA (p.F379Lfs*27) were found.\nCONCLUSION: The main clinical manifestations of patients with cblA-type of MMA include vomiting, dyspnea and drowsiness. Most patients are vitamin B12-responsive. c.365T>C is a potential hot spot variant of MMAA gene in China.","variants":[{"Name":"NM_172250.3(MMAA):c.1114C>T (p.Gln372Ter)","Chromosome":"4","Start":"145655291","Stop":"145655291","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2947242,"rule_based_match":true,"evidence_text":"c.1114C>T (p.Q372X)","llm_judgment":"PRESENT","evidence":"c.1114C>T (p.Q372X)","abstract_start":1035,"abstract_end":1054}]}
{"pmid":"18270343","title":"The frequency of Muir-Torre syndrome among Lynch syndrome families.","abstract":"Lynch syndrome is the predisposition to visceral malignancies that are associated with deleterious germline mutations in DNA mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2. Muir-Torre syndrome is a variant of Lynch syndrome that includes a predisposition to certain skin tumors. We determined the frequency of Muir-Torre syndrome among 50 Lynch syndrome families that were ascertained from a population-based series of cancer patients who were newly diagnosed with colorectal or endometrial carcinoma. Histories of Muir-Torre syndrome-associated skin tumors were documented during counseling of family members. Muir-Torre syndrome was observed in 14 (28%) of 50 families and in 14 (9.2%) of 152 individuals with Lynch syndrome. Four (44%) of nine families with MLH1 mutations had a member with Muir-Torre syndrome compared with 10 (42%) of 24 families with MSH2 mutations (P = .302). Families who carried the c.942+3A>T MSH2 gene mutation had a higher frequency of Muir-Torre syndrome than families who carried other mutations in the MSH2 gene (75% vs 25%; P = .026). Muir-Torre syndrome was not found in families with mutations in the MSH6 or PMS2 genes. Our results suggest that Muir-Torre syndrome is simply a variant of Lynch syndrome. Screening for Muir-Torre syndrome-associated skin lesions among patients with Lynch syndrome is recommended.","variants":[{"Name":"NM_000251.3(MSH2):c.942+3A>T","Chromosome":"2","Start":"47414421","Stop":"47414421","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":45242,"rule_based_match":true,"evidence_text":"c.942+3A>T","llm_judgment":"PRESENT","evidence":"c.942+3A>T","abstract_start":922,"abstract_end":932}]}
{"pmid":"35188035","title":"Novel biallelic AHR splice site mutation cause isolated foveal hypoplasia in Saudi patient: a case report.","abstract":"CASE DESCRIPTION: A 12-year-old boy with a history of decreased vision and photophobia since he was 1 year old. Comprehensive clinical and molecular approaches were applied to evaluate his condition by which a detailed ophthalmological examination revealed bilateral isolated foveal hypoplasia with the absence of the avascular zone. Novel homozygous aryl hydrocarbon receptor (<i>AHR</i>) splice site mutation NM_001621.4: c.899_908 + 15del (p.?) was identified and segregated within the family members.\nCONCLUSION: This case represents the first report of autosomal recessive isolated foveal hypoplasia without infantile nystagmus in the literature and the second reported <i>AHR</i> mutation with autosomal recessive isolated foveal hypoplasia post the original cloning paper. Our identified novel splice site <i>AHR</i> mutation supports the pathogenicity of the <i>AHR</i> gene and expands its phenotypic spectrum.","variants":[{"Name":"NM_001621.5(AHR):c.899_908+15del","Chromosome":"7","Start":"17334103","Stop":"17334127","ReferenceAlleleVCF":"GTTGTGATGCCAAGTAAGTGAGACTT","AlternateAlleleVCF":"G","allel_id":3499778,"rule_based_match":true,"evidence_text":"NM_001621.4: c.899_908 + 15del","llm_judgment":"PRESENT","evidence":"NM_001621.4: c.899_908 + 15del","abstract_start":411,"abstract_end":441}]}
{"pmid":"30371346","title":"Post-mortem diagnosis of Pompe disease by exome sequencing in a Moroccan family: a case report.","abstract":"BACKGROUND: Pompe disease is an autosomal recessive lysosomal storage disorder characterized by progressive myopathy with proximal muscle weakness, respiratory muscle dysfunction, and cardiomyopathy. Its prevalence ranges between 1/9000 and 1/40,000. It is caused by compound heterozygous or homozygous mutations in the GAA gene, which encodes for the lysosomal enzyme alpha-glucosidase, required for the degrading of lysosomal glycogen.\nCASE PRESENTATION: In this study, we report the case of a Moroccan consanguineous family with hypertrophic cardiomyopathy and sudden cardiac deaths at an early age; our patient was a 7-month-old Moroccan girl. Whole exome sequencing identified the deleterious homozygous mutation c.236_246delCCACACAGTGC (p.Pro79ArgfsX13) of GAA gene leading to a post-mortem diagnosis of Pompe disease.\nCONCLUSION: The identification of the genetic substrate in our patient, the daughter, confirmed the clinical diagnosis of Pompe disease and allowed us to provide appropriate genetic counseling to the family for future pregnancies.","variants":[{"Name":"NM_000152.5(GAA):c.236_246del (p.Pro79fs)","Chromosome":"17","Start":"80104816","Stop":"80104826","ReferenceAlleleVCF":"GCAGTGCCCACA","AlternateAlleleVCF":"G","allel_id":358485,"rule_based_match":true,"evidence_text":"c.236_246delCCACACAGTGC (p.Pro79ArgfsX13)","llm_judgment":"PRESENT","evidence":"c.236_246delCCACACAGTGC (p.Pro79ArgfsX13)","abstract_start":718,"abstract_end":759}]}
{"pmid":"24090759","title":"Novel mutations in ataxia telangiectasia and AOA2 associated with prolonged survival.","abstract":"Ataxia telangiectasia (AT) and ataxia oculomotor apraxia type 2 (AOA2) are autosomal recessive ataxias caused by mutations in genes involved in maintaining DNA integrity. Lifespan in AT is greatly shortened (20s-30s) due to increased susceptibility to malignancies (leukemia/lymphoma). Lifespan in AOA2 is uncertain. We describe a woman with variant AT with two novel mutations in ATM (IVS14+2T>G and 5825C>T, p.A1942V) who died at age 48 with pancreatic adenocarcinoma. Her mutations are associated with an unusually long life for AT and with a cancer rarely associated with that disease. We also describe two siblings with AOA2, heterozygous for two novel mutations in senataxin (3 bp deletion c.343-345 and 1398T>G, p.I466M) who have survived into their 70s, allowing us to characterize the longitudinal course of AOA2. In contrast to AT, we show that persons with AOA2 can experience a prolonged lifespan with considerable motor disability.","variants":[{"Name":"NM_000051.4(ATM):c.5825C>T (p.Ala1942Val)","Chromosome":"11","Start":"108310222","Stop":"108310222","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":180478,"rule_based_match":false,"evidence_text":"5825C>T, p.A1942V","llm_judgment":"PRESENT","evidence":"5825C>T, p.A1942V","abstract_start":401,"abstract_end":418}]}
{"pmid":"30792736","title":"Novel Pathogenic","abstract":"Mutations in the <i>PRSS1</i> (serine protease 1) gene encoding human cationic trypsinogen cause hereditary pancreatitis or may be associated with sporadic chronic pancreatitis. The mutations exert their pathogenic effect either by increasing intra-pancreatic trypsinogen activation (trypsin pathway) or by causing proenzyme misfolding and endoplasmic reticulum stress (misfolding pathway). Here we report a novel heterozygous c.568G>A (p.Glu190Lys) variant identified in a case with chronic pancreatitis. The parents of the index patient had no history of pancreatitis but were unavailable for genetic testing. Functional characterization revealed 2.5-fold increased autoactivation of the mutant trypsinogen relative to wild type. Unlike many other clinically relevant <i>PRSS1</i> mutations, p.Glu190Lys did not alter the chymotrypsin C (CTRC)-dependent degradation of trypsinogen nor did it increase CTRC-mediated processing of the trypsinogen activation peptide. Cellular secretion of the mutant protein was unchanged indicating normal folding behavior. Based on the genetic and functional evidence, we classify the p.Glu190Lys <i>PRSS1</i> variant as likely pathogenic, which stimulates autoactivation of cationic trypsinogen independently of CTRC.","variants":[{"Name":"NM_002769.5(PRSS1):c.568G>A (p.Glu190Lys)","Chromosome":"7","Start":"142752544","Stop":"142752544","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3762323,"rule_based_match":true,"evidence_text":"c.568G>A (p.Glu190Lys)","llm_judgment":"PRESENT","evidence":"c.568G>A (p.Glu190Lys)","abstract_start":427,"abstract_end":449}]}
{"pmid":"33342086","title":"Genomic alterations in the F8 gene correlating with severe hemophilia A in Egyptian patients.","abstract":"BACKGROUND: Hemophilia A (HA) is an inherited X-linked recessive coagulation disorder caused by factor VIII (F8) deficiency. F8 rearrangements involving intron 22 (int22) and intron 1 (int1) account for almost half of severe HA phenotype also a hotspot exon 14 provides numerous mutational patterns. This study aims to identify F8 gene mutations among Egyptian HA patients.\nMETHODS: DNA samples from 60 HA patients were screened for int22 and int1 rearrangements using simplified inverse shifting PCR (IS-PCR) followed by exon 14 sequencing. Also, four uncharacterized patients were studied by targeted exome sequencing.\nRESULTS: In 33.3% of the studied patients, we identified three int22 rearrangements, three exon 14 mutations (two frameshift; one novel (NM_000132.3:c.2734_2735delAA, p.(N912Ffs*6)), a second reported mutation (NM_000132.3:c.3091_3094delAGAA, p.(K1031Lfs*9)), and one nonsense mutation (NM_000132.3:c.2440C>T, p.(R814*)). All identified mutations were detected in patients with severe HA phenotype. Targeted exome sequencing could not detect any known pathogenic variants.\nCONCLUSION: Intron 22 rearrangement and exon 14 mutations correlate with most severe hemophilia A Egyptian patients.","variants":[{"Name":"NM_000132.4(F8):c.3091_3094del (p.Lys1031fs)","Chromosome":"X","Start":"154930696","Stop":"154930699","ReferenceAlleleVCF":"GTCTT","AlternateAlleleVCF":"G","allel_id":353915,"rule_based_match":true,"evidence_text":"NM_000132.3:c.3091_3094delAGAA, p.(K1031Lfs*9)","llm_judgment":"PRESENT","evidence":"NM_000132.3:c.3091_3094delAGAA, p.(K1031Lfs*9)","abstract_start":832,"abstract_end":878}]}
{"pmid":"34295780","title":"Molecular epidemiologic study of citrin deficiency by screening for four reported pathogenic SLC25A13 variants in the Shaanxi and Guangdong provinces, China.","abstract":"BACKGROUND: Citrin deficiency (CD) is an autosomal recessive disease resulting from biallelic mutations of the <i>SLC25A13</i> gene. This study aimed to investigate the molecular epidemiological features of CD in the Guangdong and Shaanxi provinces of China.\nMETHODS: A total of 3,409 peripheral blood samples from Guangdong and 2,746 such samples from Shaanxi province were collected. Four prevalent <i>SLC25A13</i> mutations NG_012247.2 (NM_014251.3): c.852_855del, c.1638_1660dup, c.615+5G>A, and c.1751-5_1751-4ins(2684) were screened by using the conventional polymerase chain reaction (PCR)/PCR-restriction fragment length polymorphism and newly-developed multiplex PCR methods, respectively. The mutated <i>SLC25A13</i> allele frequencies, carrier frequencies, and CD morbidity rates were calculated and then compared with the Chi-square and Fisher's exact tests.\nRESULTS: The mutations were detected in 68 out of 6,818 <i>SLC25A13</i> alleles in Guangdong and 29 out of 5,492 alleles in the Shaanxi population. The carrier frequencies were subsequently calculated to be 1/51 and 1/95, while the CD morbidity rates were 1/10,053 and 1/35,865, in the 2 populations, respectively. When compared with the Shaanxi population, Guangdong exhibited a higher frequency of mutated <i>SLC25A13</i> allele (68/6,818 <i>vs.</i> 29/5,492, χ<sup>2</sup>=8.570, P=0.003) in general, with higher c.852_855del (54/6,818 <i>vs.</i> 13/5,492, χ<sup>2</sup>=17.328, P=0.000) but lower c.1751-5_1751 -4ins(2684) (2/6,818 <i>vs.</i> 9/5,492, P=0.015) allele frequencies. The distribution of c.615+5G>A and c.1638_1660dup between the 2 provinces, as well as all 4 prevalent mutations among different geographic regions within the 2 provinces, did not differed significantly.\nCONCLUSIONS: Our findings depicted the CD molecular epidemiological features in Guangdong and Shaanxi populations, providing preliminary but significant laboratory evidences for the subsequent CD diagnosis and management in the 2 provinces of mainland China.","variants":[{"Name":"NM_014251.3(SLC25A13):c.1638_1660dup (p.Ala554fs)","Chromosome":"7","Start":"96121928","Stop":"96121929","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCCCGGGCAGCCACCTGTAATCTC","allel_id":21042,"rule_based_match":true,"evidence_text":"c.1638_1660dup","llm_judgment":"PRESENT","evidence":"c.1638_1660dup","abstract_start":468,"abstract_end":482}]}
{"pmid":"26232782","title":"A case of early onset rectal cancer of Lynch syndrome with a novel deleterious PMS2 mutation.","abstract":"Heterozygous deleterious mutation of the PMS2 gene is a cause of Lynch syndrome, an autosomal dominant cancer disease. However, the frequency of PMS2 mutation is rare compared with that of the other causative genes; MSH2, MLH1 and MSH6. PMS2 mutation has so far only been reported once from a Japanese facility. Detection of PMS2 mutation is relatively complicated due to the existence of 15 highly homologous pseudogenes, and its gene conversion event with the pseudogene PMS2CL. Therefore, for PMS2 mutation analysis, it is crucial to clearly distinguish PMS2 from its pseudogenes. We report here a novel deleterious 11 bp deletion mutation of exon 11 of PMS2 distinguished from PMS2CL in a 34-year-old Japanese female with rectal cancer. PMS2 mutated at c.1492del11 results in a truncated 500 amino acid protein rather than the wild-type protein of 862 amino acids. This is supported by the fact that, although there is usually concordance between MLH1 and PMS2 expression, cells were immunohistochemically positive for MLH1, whereas PMS2 could not be immunohistochemically stained using an anti-C-terminal PMS2 antibody, or effective PMS2 mRNA degradation with NMD caused by the frameshift mutation.","variants":[{"Name":"NM_000535.7(PMS2):c.1492_1502del (p.Ser498fs)","Chromosome":"7","Start":"5987263","Stop":"5987273","ReferenceAlleleVCF":"CACGGAAGTGCT","AlternateAlleleVCF":"C","allel_id":233518,"rule_based_match":false,"evidence_text":"c.1492del11","llm_judgment":"PRESENT","evidence":"c.1492del11","abstract_start":757,"abstract_end":768}]}
{"pmid":"38061702","title":"Missense Variant c.3301C>T (p.R1101W) in von Willebrand Factor A Sequence in a Patient with Recessive Dystrophic Epidermolysis Bullosa Pruriginosa with Compound Heterozygous","abstract":"Dystrophic epidermolysis bullosa (DEB) pruriginosa is a rare subtype of DEB characterized by multiple, violaceous, and severe pruritic lichenified nodules along with blisters. Here, we report the case of a Korean male who, since the age of 3 years, had multiple pruritic nodules with blisters on both lower extremities. Genetic testing is required to diagnose DEB pruriginosa because its clinical and histologic features are inconclusive. We identified compound heterozygous <i>COL7A1</i> variants of c.5797C>T (p.R1933*) and c.3301C>T (p.R1101W) in the patient, leading to a diagnosis of recessive DEB pruriginosa. Among the variants identified, c.3301C>T is a novel missense variant that has not been reported previously. This variant is in exon 26, which encodes von Willebrand factor A (vWFA) in collagen type VII. vWFA is known to preserve normal dermal structures by interacting with dermal collagens and basement membranes. Considering that this variant contradicts the general concept that autosomal dominant inheritance is more common and that variants typically occur in the triple helical collagenous domain of <i>COL7A1</i> in DEB pruriginosa, we focus on the rarity of this case and the possible pathogenic role of the c.3301C>T (p.R1101W) variant.","variants":[{"Name":"NM_000094.4(COL7A1):c.3301C>T (p.Arg1101Trp)","Chromosome":"3","Start":"48586665","Stop":"48586665","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1435803,"rule_based_match":true,"evidence_text":"c.3301C>T (p.R1101W)","llm_judgment":"PRESENT","evidence":"c.3301C>T (p.R1101W)","abstract_start":526,"abstract_end":546}]}
{"pmid":"29381605","title":"Novel PTCH1 Gene Mutation in Nevoid Basal Cell Carcinoma Syndrome.","abstract":"The purpose of this study was to report clinical characteristics, surgical results, and new PTCH1 gene mutations in nevoid basal cell carcinoma syndrome (NBCCS). Five patients were referred to the Department of Oral and Maxillofacial Surgery from local dental clinics between 2006 and 2016 to treat multiple keratocystic odontogenic tumors (KOTs). The cystic lesions were enucleated and peripheral ostectomy was performed to obtain safety margin. Recurrence and/or de novo development of KOT were assessed. Gene analysis using peripheral blood was performed in all patients to identify the mutation of PTCH1 gene. Three patients showed familial history of first-degree relatives. Of the major criteria, all patients presented KOT but only 1 patient had basal cell carcinoma. Of the minor criteria, 4 of the 5 patients presented macrocephaly and hypertelorism. During follow-up periods, all patients showed recurrence and/or de novo development of KOT in the jaw bone. Mutation analysis of PTCH1 gene showed 3 frameshifts (c.817_818ins(T), c.1226_1227ins(A), and c.2748del(C)), 1 splicing (c.1504-2A>T), and 1 missense (c.385T>C) mutation. Mutations were found in exon 1, 6, 9, 17, and intron 10. Regular follow-up is necessary because recurrence rate of KOT was very high. To help early diagnosis, it is essential to routinely perform genetic testing to detect PTCH1 gene mutations among patients with NBCCS.","variants":[{"Name":"NM_000264.5(PTCH1):c.385T>C (p.Trp129Arg)","Chromosome":"9","Start":"95506416","Stop":"95506416","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1055883,"rule_based_match":true,"evidence_text":"c.385T>C","llm_judgment":"PRESENT","evidence":"c.385T>C","abstract_start":1119,"abstract_end":1127}]}
{"pmid":"27670293","title":"Whole exome sequencing identified novel CRB1 mutations in Chinese and Indian populations with autosomal recessive retinitis pigmentosa.","abstract":"Retinitis pigmentosa (RP) is a leading cause of inherited blindness characterized by progressive degeneration of the retinal photoreceptor cells. This study aims to identify genetic mutations in a Chinese family RP-2236, an Indian family RP-IC-90 and 100 sporadic Indian individuals with autosomal recessive RP (arRP). Whole exome sequencing was performed on the index patients of RP-2236, RP-IC-90 and all of the 100 sporadic Indian patients. Direct Sanger sequencing was used to validate the mutations identified. Four novel mutations and one reported mutation in the crumbs homolog 1 (CRB1) gene, which has been known to cause severe retinal dystrophies, were identified. A novel homozygous splicing mutation c.2129-1G>C was found in the three patients In family RP-2236. A homozygous point mutation p.R664C was found in RP-IC-90. A novel homozygous mutation p.G1310C was identified in patient I-44, while novel compound heterozygous mutations p.N629D and p.A593T were found in patient I-7. All mutations described above were not present in the 1000 normal controls. In conclusion, we identified four novel mutations in CRB1 in a cohort of RP patients from the Chinese and Indian populations. Our data enlarges the CRB1 mutation spectrums and may provide new target loci for RP diagnose and treatment.","variants":[{"Name":"NM_201253.3(CRB1):c.2129-1G>C","Chromosome":"1","Start":"197427453","Stop":"197427453","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":939783,"rule_based_match":true,"evidence_text":"c.2129-1G>C","llm_judgment":"PRESENT","evidence":"c.2129-1G>C","abstract_start":712,"abstract_end":723}]}
{"pmid":"36980135","title":"Frasier Syndrome: A 15-Year-Old Phenotypically Female Adolescent Presenting with Delayed Puberty and Nephropathy.","abstract":"Frasier syndrome (FS) is a rare inherited disorder characterized by gonadal dysgenesis and progressive nephropathy, resulting from mutations in the intron 9 splice donor site of the Wilms tumor 1 (WT1) gene. It is associated with male gonadal dysgenesis (female external genitalia with a 46 XY karyotype), and a high risk of gonadoblastoma during adolescence. Patients with FS present early in childhood with proteinuria that progressively worsens with a high likelihood of end-stage renal disease (ESRD). Herein, we report a 15-year-old female (karyotype 46, XY) patient characterized by delayed puberty and steroid-resistant nephrotic syndrome, in whom whole genome sequencing showed a mutation in intron 9 of the WT1 gene, c.1447 + 4 C>T. This is the first case of FS with delayed puberty as the first complaint with no previous renal symptoms. We consider delayed puberty as an important manifestation of FS and summarize the diagnostic process of delayed puberty in the female phenotype. For clinicians, delayed puberty is a common disorder in pediatrics but requires vigilance for some rare causes. Etiological screening and chromosome karyotype analysis are important for the early diagnosis of FS in patients with delayed puberty.","variants":[{"Name":"NM_024426.6(WT1):c.1447+4C>T","Chromosome":"11","Start":"32391968","Stop":"32391968","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18539,"rule_based_match":true,"evidence_text":"c.1447 + 4 C>T","llm_judgment":"PRESENT","evidence":"c.1447 + 4 C>T","abstract_start":726,"abstract_end":740}]}
{"pmid":"24556926","title":"PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo.","abstract":"PURPOSE: Monoallelic germ-line deleterious mutations of PALB2 (partner and localizer of BRCA2) are associated with breast cancer risk and have been found in several populations, with carrier frequencies of ~1-2%. Initially, these mutations were considered to have moderate penetrance, but accumulating evidence now indicates that they are associated with much higher risk.\nMETHODS: In this study, we sequenced the PALB2 coding regions unlinked to BRCA (breast cancer) genes in 575 probands from Italian breast cancer families recruited in Milan.\nRESULTS: We found 12 carriers (2.1%) of deleterious mutations, and none of the mutations was found in 784 controls collected in Milan. One of these mutations, the c.1027C>T (p.Gln343X), was found to be recurrent in the province of Bergamo in northern Italy, being detected in 6/113 (5.3%) familial breast cancer cases and 2/477 (0.4%) controls recruited in this area (Fisher's exact test: P < 0.01).\nCONCLUSIONS: Our data provide confirmatory findings that, in the Italian population also, deleterious mutations of PALB2 are relatively frequent predisposing factors for breast cancer and may be associated with high risk of the disease.","variants":[{"Name":"NM_024675.4(PALB2):c.1027C>T (p.Gln343Ter)","Chromosome":"16","Start":"23635519","Stop":"23635519","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132093,"rule_based_match":true,"evidence_text":"c.1027C>T (p.Gln343X)","llm_judgment":"PRESENT","evidence":"c.1027C>T (p.Gln343X)","abstract_start":709,"abstract_end":730}]}
{"pmid":"30472657","title":"Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the","abstract":"AIM: Oculocutaneous albinism type 1 (OCA1) is due to <i>TYR</i> mutations. c.1205G>A/p.Arg402Gln (R402Q) is a thermosensitive variant of the <i>TYR</i> gene that has been reported to be responsible for mild forms of OCA1. The aim of our study was to define the phenotype associated with this variant.\nMETHODS: In our retrospective series, among 268 patients diagnosed with OCA1, 122 (45.5%) harboured one pathogenic variant of <i>TYR</i>, and the R402Q variant ensured to be in trans by segregation analysis in 69 patients (25.7%), constituting the 'R402Q-OCA1' group. 146 patients harboured two pathogenic variants of the <i>TYR</i> gene other than R402Q. Clinical records were available for 119 of them, constituting the 'Classical-OCA1' group.\nRESULTS: Most R402Q-OCA1 patients presented with white or yellow-white hair at birth (71.43%), blond hair later (46.97%), a light phototype but with residual pigmentation (69.64%), and blue eyes (76.56%). Their pigmentation was significantly higher than in the classical-OCA1 group. All patients from the R402Q-OCA1 group presented with ocular features of albinism. However the prevalence of photophobia (78.13%) and iris transillumination (83.87%) and the severity scores of iris transillumination, retinal hypopigmentation and foveal hypoplasia were lower in the R402Q-OCA1 group. Visual acuity was higher in the R402Q-OCA1 group (0.38±0.21 logarithm of the minimum angle of resolution vs 0.76±0.24). Investigations concerning a possible additive effect of the c.575C>A/p.Ser192 (S192Y) variant of <i>TYR</i> in cis with R402Q, suggested by others, showed no significant impact on the phenotype.\nCONCLUSION: The R402Q variant leads to variable but generally mild forms of albinism whose less typical presentation may lead to underdiagnosis.","variants":[{"Name":"NM_000372.5(TYR):c.1205G>A (p.Arg402Gln)","Chromosome":"11","Start":"89284793","Stop":"89284793","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18818,"rule_based_match":true,"evidence_text":"c.1205G>A/p.Arg402Gln (R402Q)","llm_judgment":"PRESENT","evidence":"c.1205G>A/p.Arg402Gln (R402Q)","abstract_start":75,"abstract_end":104}]}
{"pmid":"33460826","title":"First evidence of involvement of TBC1D25 in causing human male infertility.","abstract":"Male infertility is a heterogeneous disorder which may result from disruption in molecular and cellular pathways involved in spermatogenesis. Several reports have described abnormal spermatogenesis because of defective autophagy in model organisms. In the present study, we have clinically and genetically characterized a family segregating oligozoospermia in X-linked pattern. Exome sequencing revealed a disease-causing missense variant [NM_002536, c.149 A > C, p.(Glu50Ala)] in TBC1D25, an autophagy gene located on human chromosome Xp11.23. In view of broad expression of the gene in testes and effect of the variant on its interaction with ATG8 homologues, we consider a possible role for the TBC1D25 variant in causing oligozoospermia in the present family. This is the first report describing the involvement of TBC1D25 in causing male infertility.","variants":[{"Name":"NM_002536.4(TBC1D25):c.149A>C (p.Glu50Ala)","Chromosome":"X","Start":"48541358","Stop":"48541358","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1288213,"rule_based_match":true,"evidence_text":"NM_002536, c.149 A > C, p.(Glu50Ala)","llm_judgment":"PRESENT","evidence":"NM_002536, c.149 A > C, p.(Glu50Ala)","abstract_start":440,"abstract_end":476}]}
{"pmid":"26759440","title":"Nystagmus in a newborn: a manifestation of Joubert syndrome in the neonatal period.","abstract":"Joubert syndrome is a rare disorder, usually autosomal recessive, with a prevalence of 1:80,000 to 1:100,000. This disease presents most commonly as breathing irregularities, although the two major clinical criteria are hypotonia and developmental delay, sometimes associated with ocular movement abnormalities. The severity of the presentation varies, ranging from mild cases with normal intelligence to severe developmental delays associated with early death. We report a case of a newborn who presented to the emergency department for absent ocular fixation and torsional nystagmus without other neurological abnormalities. Her cranial MR showed cerebellar vermis agenesis and a molar tooth sign. Her laboratory evaluation, and renal and abdominal ultrasound were normal. An electroretinogram showed mixed retinal dystrophy and an AHI1 homozygous missense c.1981T>C mutation was identified (parents are carriers). Throughout infancy, she has shown mild developmental delay and hypotonia, but no respiratory abnormalities. Owing to variable expressivity, a high level of suspicion is required.","variants":[{"Name":"NM_001134831.2(AHI1):c.1981T>C (p.Ser661Pro)","Chromosome":"6","Start":"135438430","Stop":"135438430","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1406494,"rule_based_match":true,"evidence_text":"AHI1 homozygous missense c.1981T>C mutation","llm_judgment":"PRESENT","evidence":"AHI1 homozygous missense c.1981T>C mutation","abstract_start":834,"abstract_end":877}]}
{"pmid":"33560082","title":"A Novel Intronic Mutation Reduces HAX1 Level and is Associated With Severe Congenital Neutropenia.","abstract":"Severe congenital neutropenia (SCN) is a rare disease. Autosomal recessive forms of SCN are more frequent in countries where consanguineous marriages are common. In this report, we describe a 54-day-old female with neutropenia who presented with ecthyma gangrenosum. Clinical exome sequencing was used to identify the mutation. HAX1 messenger RNA and isoforms were examined by real-time quantitative and conventional polymerase chain reaction. Bone marrow aspiration was stained by hematoxylin and eosin. Granulocytes were tested for apoptosis upon H2O2 exposure. T-cell proliferation was tested by flow cytometry. Clinical exome sequencing revealed a novel homozygous acceptor splice site mutation in intron 3 of HAX1 (c.505-1G>C), which reduced both isoforms A and B of HAX1 messenger RNA. The Western blot studies showed a complete absence of HAX1 protein. The purified neutrophils from the patient showed increased apoptosis upon H2O2 exposure, whereas T-cell proliferative responses to various stimuli were intact. The patient was treated with combined antibiotics, filgrastim, and placed on antibiotics prophylaxis. To the best of our knowledge, our data provide the first experimental evidence for HAX1 deficiency because of a splice site mutation. Although 3 other splice site variants have been deposited in databases, functional studies were missing. This novel variant of HAX1 may explain the SCN and secondary infections in our patients.","variants":[{"Name":"NM_006118.4(HAX1):c.505-1G>C","Chromosome":"1","Start":"154274949","Stop":"154274949","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3062442,"rule_based_match":true,"evidence_text":"c.505-1G>C","llm_judgment":"PRESENT","evidence":"c.505-1G>C","abstract_start":720,"abstract_end":730}]}
{"pmid":"21863277","title":"3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.","abstract":"3-hydroxyisobutyric aciduria is an organic aciduria with a poorly understood biochemical basis. It has previously been assumed that deficiency of 3-hydroxyisobutyrate dehydrogenase (HIBADH) in the valine catabolic pathway is the underlying enzyme defect, but more recent evidence makes it likely that individuals with 3-hydroxyisobutyryic aciduria represent a heterogeneous group with different underlying mechanisms, including respiratory chain defects or deficiency of methylmalonate semialdehyde dehydrogenase. However, to date methylmalonate semialdehyde dehydrogenase deficiency has only been demonstrated at the gene level for a single individual. We present two unrelated patients who presented with developmental delay and increased urinary concentrations of 3-hydroxyisobutyric acid. Both children were products of consanguineous unions and were of European or Pakistani descent. One patient developed a febrile illness and subsequently died from a hepatoencephalopathy at 2 years of age. Further studies were initiated and included tests of the HIBADH enzyme in fibroblast homogenates, which yielded normal activities. Sequencing of the ALDH6A1 gene (encoding methylmalonate semialdehyde dehydrogenase) suggested homozygosity for the missense mutation c.785 C > A (S262Y) in exon 7 which was not found in 210 control alleles. Mutation analysis of the ALDH6A1 gene of the second patient confirmed the presence of a different missense mutation, c.184 C > T (P62S), which was also identified in 1/530 control chromosomes. Both mutations affect highly evolutionarily conserved amino acids of the methylmalonate semialdehyde dehydrogenase protein. Mutation analysis in the ALDH6A1 gene can reveal a cause of 3-hydroxyisobutyric aciduria, which may present with only slightly increased urinary levels of 3-hydroxyisobutyric acid, if a patient is metabolically stable.","variants":[{"Name":"NM_005589.4(ALDH6A1):c.785C>A (p.Ser262Tyr)","Chromosome":"14","Start":"74068927","Stop":"74068927","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":204349,"rule_based_match":true,"evidence_text":"c.785 C > A (S262Y)","llm_judgment":"PRESENT","evidence":"c.785 C > A (S262Y)","abstract_start":1262,"abstract_end":1281},{"Name":"NM_005589.4(ALDH6A1):c.184C>T (p.Pro62Ser)","Chromosome":"14","Start":"74072539","Stop":"74072539","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":204350,"rule_based_match":true,"evidence_text":"c.184 C > T (P62S)","llm_judgment":"PRESENT","evidence":"c.184 C > T (P62S)","abstract_start":1453,"abstract_end":1471}]}
{"pmid":"32354836","title":"Distinct roles of BRCA2 in replication fork protection in response to hydroxyurea and DNA interstrand cross-links.","abstract":"DNA interstrand cross-links (ICLs) are a form of DNA damage that requires the interplay of a number of repair proteins including those of the Fanconi anemia (FA) and the homologous recombination (HR) pathways. Pathogenic variants in the essential gene <i>BRCA2/FANCD1,</i> when monoallelic, predispose to breast and ovarian cancer, and when biallelic, result in a severe subtype of Fanconi anemia. BRCA2 function in the FA pathway is attributed to its role as a mediator of the RAD51 recombinase in HR repair of programmed DNA double-strand breaks (DSB). BRCA2 and RAD51 functions are also required to protect stalled replication forks from nucleolytic degradation during response to hydroxyurea (HU). While RAD51 has been shown to be necessary in the early steps of ICL repair to prevent aberrant nuclease resection, the role of BRCA2 in this process has not been described. Here, based on the analysis of <i>BRCA2</i> DNA-binding domain (DBD) mutants (c.8488-1G>A and c.8524C>T) discovered in FA patients presenting with atypical FA-like phenotypes, we establish that BRCA2 is necessary for the protection of DNA at ICLs. Cells carrying <i>BRCA2</i> DBD mutations are sensitive to ICL-inducing agents but resistant to HU treatment consistent with relatively high HR repair in these cells. BRCA2 function at an ICL protects against DNA2-WRN nuclease-helicase complex and not the MRE11 nuclease that is implicated in the resection of HU-induced stalled replication forks. Our results also indicate that unlike the processing at HU-induced stalled forks, the function of the SNF2 translocases (SMARCAL1, ZRANB3, or HLTF), implicated in fork reversal, are not an integral component of the ICL repair, pointing to a different mechanism of fork protection at different DNA lesions.","variants":[{"Name":"NM_000059.4(BRCA2):c.8488-1G>A","Chromosome":"13","Start":"32370955","Stop":"32370955","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46720,"rule_based_match":true,"evidence_text":"c.8488-1G>A","llm_judgment":"PRESENT","evidence":"c.8488-1G>A","abstract_start":954,"abstract_end":965},{"Name":"NM_000059.4(BRCA2):c.8524C>T (p.Arg2842Cys)","Chromosome":"13","Start":"32370992","Stop":"32370992","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67278,"rule_based_match":true,"evidence_text":"c.8524C>T","llm_judgment":"PRESENT","evidence":"c.8524C>T","abstract_start":970,"abstract_end":979}]}
{"pmid":"25978498","title":"Methionine synthase reductase deficiency (CblE): A report of two patients and a novel mutation.","abstract":"IMPORTANCE: Functional methionine synthase reductase deficiency, also known as cobalamin E disorder, is a rare autosomal recessive inherited disease that results in an impaired remethylation of homocysteine to methionine. It presents with macrocytic anemia, hyperhomocysteinemia, and hypomethioninemia, and may also be accompanied with neurological impairment.\nCLINICAL PRESENTATION: We describe two new cases of unrelated girls with megaloblastic anemia misclassified at first as congenital dyserythropoietic anemia with development of neurologic dysfunction in one of them.\nINTERVENTION: The posterior finding of biochemical features (hyperhomocysteinemia and hypomethioninemia) focused the diagnosis on the inborn errors of intracellular vitamin B12. Subsequent molecular analysis of the methionine synthase reductase (MTRR) gene revealed compound heterozygosity for a transition c.1361C > T (p.Ser454Leu) and another, not yet described in literature, c.1677-1G > A (p.Glu560fs) in one patient, and a single homozygosis mutation, c.1361C > T (p.Ser545Leu) in the other one. These mutations confirmed the diagnosis of cobalamin E deficiency.\nCONCLUSION: Treatment with hydroxocobalamin in combination with betaine appears to be useful for hematological improvement and prevention of brain disabilities in CblE-affected patients. Our study widens the clinical, molecular, metabolic, and cytological knowledge of deficiency MTRR enzyme.","variants":[{"Name":"NM_002454.3(MTRR):c.1677-1G>A","Chromosome":"5","Start":"7896863","Stop":"7896863","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2837890,"rule_based_match":true,"evidence_text":"c.1677-1G > A (p.Glu560fs)","llm_judgment":"PRESENT","evidence":"c.1677-1G > A (p.Glu560fs)","abstract_start":955,"abstract_end":981},{"Name":"NM_002454.3(MTRR):c.1361C>T (p.Ser454Leu)","Chromosome":"5","Start":"7891405","Stop":"7891405","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22072,"rule_based_match":true,"evidence_text":"c.1361C > T (p.Ser454Leu)","llm_judgment":"PRESENT","evidence":"c.1361C > T (p.Ser454Leu)","abstract_start":883,"abstract_end":908}]}
{"pmid":"18427006","title":"A novel SLC26A4 (PDS) deafness mutation retained in the endoplasmic reticulum.","abstract":"OBJECTIVES: To identify mutations in the SLC26A4 gene in individuals with nonsyndromic hearing loss and enlarged vestibular aqueduct, to design a predicted model of the pendrin protein, and to characterize novel mutations by means of localization in mammalian cells and effect of the mutation on the predicted model.\nDESIGN: Validation of the mutation by its exclusion in more than 300 individuals with normal hearing.\nSETTING: A laboratory of genetics of hearing loss research, clinical genetics laboratories, an otolaryngology department at Tel Aviv University, and medical centers in Israel.\nPATIENTS: A patient with nonsyndromic hearing loss and enlarged vestibular aqueduct, 203 deaf probands, and 310 controls with normal hearing.\nINTERVENTIONS: Sequencing the SLC26A4 gene in the patient with nonsyndromic hearing loss and enlarged vestibular aqueduct. Transfection of yellow fluorescent protein (YFP) constructs into mammalian COS7 cells. Designing a computational model of the human SLC26A4 protein.\nMAIN OUTCOME MEASURE: Detection of a novel c.1458_1459insT SLC26A4 mutation.\nRESULTS: A computational model of the human pendrin protein suggests that the novel c.1458_1459insT mutation leads to a prematurely truncated protein, p.Ile487TyrfsX39. Mammalian COS7 cells transfected with the YFP-1458_1459insT construct showed mislocalization of the mutant protein.\nCONCLUSIONS: A novel SLC26A4 mutation was detected in Israel. Because current estimates demonstrate that SLC26A4 mutations are involved in up to 4% of nonsyndromic deafness, our findings emphasize the importance of adding a molecular test for the SLC26A4 gene in the diagnosis of deafness, particularly when bone abnormalities are involved, to the list of genes screened in Israel and elsewhere in the world.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1458dup (p.Ile487fs)","Chromosome":"7","Start":"107695952","Stop":"107695953","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":801644,"rule_based_match":false,"evidence_text":"c.1458_1459insT","llm_judgment":"PRESENT","evidence":"c.1458_1459insT","abstract_start":1052,"abstract_end":1067}]}
{"pmid":"36096209","title":"Analysis of gene mutations of medium-chain acyl-coenzyme a dehydrogenase deficiency (MCADD) by next-generation sequencing in Henan, China.","abstract":"BACKGROUND: Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is a rare inherited metabolic disorder of fatty acid β-oxidation and one of the most common inborn errors of metabolism. The incidence of MCADD varies among regions and ethnic groups. To date, few cases of MCADD have been documented in China.\nOBJECTIVE: The present study aimed to find out the novel genetic pathogenic variants in the Chinese patients and evaluate the detection rate of the disease of high-frequency ACADM pathogenic variants in different regions of China.\nMETHODS: 6 cases of MCADD were screened by tandem mass spectrometric (MS/MS) among 245 054 newborns. We performed next-generation sequencing on 6 families of infants with MCADD. We used the REVEL method to predict the protein function of the detected missense variants and used SPDBV 4.10 to predict the protein 3D structure model. We identified pathogenic variants of ACADM gene in 6 cases of MCADD, and then assessed these variants through Sanger sequencing and association analysis.\nRESULTS: The incidence of neonatal MCADD was 1/40,842 in Henan province. Among the 6 patients, five cases were compound heterozygous variants, one case was homozygous variants. DNA sequencing revealed 4 known (c.449_452del, c.1085G > A, c.1229 T > C, c.589A > G) and 3 novel mutations (c.849 + 5_849 + 8del, c.427A > G, c.1181C > T) in the ACADM gene. Mutation c.1085G > A (p.G362E) was most frequent among Henan people and shows obvious differences between North and South of China.\nCONCLUSION: MCADD is relatively rare in China, and c.1085G > A (p.G362E) is a common mutation in Henan population. Our findings, especially novel variants, will help improve the understanding of the genetic background and have facilitated clinical diagnosis and genetic counseling for the affected families.","variants":[{"Name":"NM_000016.6(ACADM):c.1229T>C (p.Ile410Thr)","Chromosome":"1","Start":"75762726","Stop":"75762726","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1417082,"rule_based_match":true,"evidence_text":"c.1229 T > C","llm_judgment":"PRESENT","evidence":"c.1229 T > C","abstract_start":1271,"abstract_end":1283}]}
{"pmid":"32198973","title":"MAST1 variant causes mega-corpus-callosum syndrome with cortical malformations but without cerebellar hypoplasia.","abstract":"We report the case of a Caucasian Spanish origin female who showed severe psychomotor developmental delay, hypotonia, strabismus, epilepsy, short stature, and poor verbal language development. Brain magnetic resonance imaging scans showed thickened corpus callosum, cortical malformations, and dilated and abnormal configuration of the lateral ventricles without hydrocephalus. Whole-exome sequence uncovered a de novo variant in the microtubule associated serine/threonine kinase 1 gene (MAST1; NM_014975.3:c.1565G>A:p.(Gly522Glu)) that encodes for the MAST1. Only 12 patients have been identified worldwide with 10 different variants in this gene: six patients with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations; two patients with microcephaly and cerebellar hypoplasia; two patients with autism, one patient with diplegia, and one patient with microcephaly and dysmorphism. Our patient shows a new phenotypic subtype defined by mega-corpus-callosum syndrome with cortical malformations without cerebellar hypoplasia. In conclusion, our data expand the phenotypic spectrum associated to MAST1 gene variants.","variants":[{"Name":"NM_014975.3(MAST1):c.1565G>A (p.Gly522Glu)","Chromosome":"19","Start":"12865105","Stop":"12865105","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":797727,"rule_based_match":true,"evidence_text":"NM_014975.3:c.1565G>A:p.(Gly522Glu)","llm_judgment":"PRESENT","evidence":"NM_014975.3:c.1565G>A:p.(Gly522Glu)","abstract_start":496,"abstract_end":531}]}
{"pmid":"23806011","title":"Two complex associations of an HBD mutation and a rare α hemoglobinopathy.","abstract":"We present two case reports in which an HBD mutation is present with a rare α hemoglobinopathy that substantially complicates the associated phenotype. In the first case, a new δ-globin variant, Hb A2-Pierre-Bénite [δ83(EF7)Gly→Arg; HBD: c.250G>C] is associated with Hb Groene Hart [α119(H2)Pro→Ser (α1); HBA1: c.358C>T], an α-thalassemic variant. In the second case, a δ(+)-thalassemic variant, δ4(A1)Thr→Ile; HBD: c.14C>T, is associated with a newly described deletion of the hypersensitive site 40 (HS-40) region on the α-globin gene cluster. In both patients, a δ-globin mutation was suspected because of an abnormally low Hb A2 level, whereas the α hemoglobinopathy was sought to explain the slight microcytosis and hypochromia presented by the probands.","variants":[{"Name":"NM_000519.4(HBD):c.14C>T (p.Thr5Ile)","Chromosome":"11","Start":"5234420","Stop":"5234420","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620405,"rule_based_match":true,"evidence_text":"δ4(A1)Thr→Ile; HBD: c.14C>T","llm_judgment":"PRESENT","evidence":"δ4(A1)Thr→Ile; HBD: c.14C>T","abstract_start":396,"abstract_end":423}]}
{"pmid":"26032558","title":"Minimally symptomatic mcardle disease, expanding the genotype-phenotype spectrum.","abstract":"INTRODUCTION: We report the clinical, biochemical, and molecular findings in a Cypriot family with minimally symptomatic McArdle disease.\nMETHODS: Myophosphorylase in muscle was assessed by histochemistry, quantitative spectrophotometry, and western blot analysis. Mutation identification was performed by PCR amplification of all PYGM exons, followed by bidirectional sequencing. Screening for the new mutation was performed by restriction enzyme analysis.\nRESULTS: We found that a novel c.1151C>T transition in exon 10 of the myophosphorylase gene (PYGM) is associated with minimally symptomatic McArdle disease. Homozygous carriers displayed an ischemic exercise response characterized by a blunted increase in post-exercise blood lactate levels in conjunction with an exaggerated increase in ammonia. Myophosphorylase activity in muscle was 3.75% of normal, whereas the size and abundance of the enzyme were unaffected.\nCONCLUSIONS: These findings expand the genotype-phenotype spectrum of McArdle disease and suggest that enzymatic activity as low as 4% may be sufficient to ameliorate the phenotype.","variants":[{"Name":"NM_005609.4(PYGM):c.1151C>T (p.Ala384Val)","Chromosome":"11","Start":"64753967","Stop":"64753967","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":546769,"rule_based_match":true,"evidence_text":"c.1151C>T","llm_judgment":"PRESENT","evidence":"c.1151C>T","abstract_start":489,"abstract_end":498}]}
{"pmid":"28685844","title":"Genetic characterization of GSD I in Serbian population revealed unexpectedly high incidence of GSD Ib and 3 novel SLC37A4 variants.","abstract":"Glycogen storage disease (GSD) type I is inborn metabolic disease characterized by accumulation of glycogen in multiple organs. We analyzed 38 patients with clinical suspicion of GSD I using Sanger and next-generation sequencing (NGS). We identified 28 GSD Ib and 5 GSD Ia patients. In 5 patients, GSD III, VI, IX, cholesteryl-ester storage disease and Shwachman-Diamond syndrome diagnoses were set using NGS. Incidences for GSD Ia and GSD Ib were estimated at 1:172 746 and 1:60 461 live-births, respectively. Two variants were identified in G6PC gene: c.247C>T (p.Arg83Cys) and c.518T>C (p.Leu173Pro). In SLC37A4 gene, 6 variants were detected. Three previously reported variants c.81T>A (p.Asn27Lys), c.162C>A (p.Ser54Arg) and c.1042_1043delCT (p.Leu348Valfs*53) accounted for 87% of all analyzed alleles. Computational, transcription studies and/or clinical presentation in patients confirmed pathogenic effect of 3 novel variants: c.248G>A (p.Gly83Glu), c.404G>A (p.Gly135Asp) and c.785G>A (p.Ser263Glyfs*33 or p.Gly262Asp). In the cohort, hepatomegaly, hypoglycemia and failure to thrive were the most frequent presenting signs of GSD Ia, while hepatomegaly and recurrent bacterial infections were clinical hallmarks of GSD Ib. All GSD Ib patients developed neutropenia while 20.6% developed inflammatory bowel disease. Our study revealed the highest worldwide incidence of GSD Ib. Furthermore, description of 3 novel variants will facilitate medical genetic practice.","variants":[{"Name":"NM_001164277.2(SLC37A4):c.248G>A (p.Gly83Glu)","Chromosome":"11","Start":"119028327","Stop":"119028327","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1055988,"rule_based_match":true,"evidence_text":"c.248G>A (p.Gly83Glu)","llm_judgment":"PRESENT","evidence":"c.248G>A (p.Gly83Glu)","abstract_start":936,"abstract_end":957},{"Name":"NM_001164277.2(SLC37A4):c.81T>A (p.Asn27Lys)","Chromosome":"11","Start":"119029289","Stop":"119029289","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":79181,"rule_based_match":true,"evidence_text":"c.81T>A (p.Asn27Lys)","llm_judgment":"PRESENT","evidence":"c.81T>A (p.Asn27Lys)","abstract_start":682,"abstract_end":702}]}
{"pmid":"31552204","title":"A","abstract":"Among neonatal epileptic syndromes, benign familial neonatal seizures (BFNS) are often due to autosomal-dominant mutations of the KCNQ2 gene. Seizures are usually characterized by asymmetric tonic posturing with apnea with onset in the first 7 days of life; they may even occur more than 10 times per day or evolve into status epilepticus. The delivery course of our patient was uneventful and family history was negative; on the second day of life the baby became pale, rigid, and apnoic during breastfeeding and appeared jittery and irritable when stimulated or examined. At age 3 days, she experienced clusters of generalized tonic seizures with pallor, desaturation, bradycardia, and partial response to intravenous phenobarbital; during her 4th and 5th days of life, three episodes of tonic seizures were noticed. At age 6 days, the patient experienced about 10 episodes of tonic seizures involving both sides of the body, which gradually responded to intravenous phenytoin. Electroencephalograms revealed abnormalities but brain MRI was normal. The patient is seizure-free since postnatal day 21; she is now 12 months old with cognitive development within normal limits at Bayley III Scale and mild motor delay. The patient is on maintenance therapy with phenobarbital since she was 7 months old. A <i>de novo</i> heterozygous mutation (c.853C>T/p.P285S) in the KCNQ2 gene was identified. We therefore describe a case of <i>de novo</i> KCNQ2-related neonatal convulsions with necessity of multiple anticonvulsants for the control of seizures, mutation occurring in the pore channel of the voltage-gated potassium channel subfamily Q member 2 associated with a likely benign course; furthermore, the same mutation of the KCNQ2 gene and a similar one (c.854C>A/p.P285H) have already been described in association with Ohtahara syndrome. Probably acquired environmental, perinatal and genetic risk factors are very important in determining the different phenotype; we hope that the rapid progress of analysis tools in molecular diagnosis can also be used in the search of an individualized therapeutic approach for these patients.","variants":[{"Name":"NM_172107.4(KCNQ2):c.853C>T (p.Pro285Ser)","Chromosome":"20","Start":"63439672","Stop":"63439672","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":964540,"rule_based_match":true,"evidence_text":"c.853C>T/p.P285S","llm_judgment":"PRESENT","evidence":"c.853C>T/p.P285S","abstract_start":1343,"abstract_end":1359}]}
{"pmid":"28881388","title":"Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21.","abstract":"INTRODUCTION: A calpain-3 (CAPN3) gene heterozygous deletion (c.643_663del21) was recently linked to autosomal dominant (AD) limb-girdle muscular dystrophy. However, the possibility of digenic disease was raised. We describe 3 families with AD calpainopathy carrying this isolated mutation.\nMETHODS: Probands heterozygous for CAPN3 c.643_663del21 were identified by targeted next generation or whole exome sequencing. Clinical findings were collected for probands and families. Calpain-3 muscle Western blots were performed in 3 unrelated individuals.\nRESULTS: Probands reported variable weakness in their 40s or 50s, with myalgia, back pain, or hyperlordosis. Pelvic girdle muscles were affected with adductor and hamstring sparing. Creatine kinase was normal to 1,800 U/L, independent of weakness severity. Imaging demonstrated lumbar paraspinal muscle atrophy. Electromyographic findings and muscle biopsies were normal to mildly myopathic. Muscle calpain-3 expression was reduced.\nDISCUSSION: This study provides further evidence for AD calpainopathy associated with CAPN3 c.643_663del21. No pathogenic variants in other genes known to cause myopathy were detected. Muscle Nerve 57: 679-683, 2018.","variants":[{"Name":"NM_000070.2(CAPN3):c.643_663del(p.Ser215_Gly221del)","Chromosome":"15","Start":"42388935","Stop":"42388955","ReferenceAlleleVCF":"TGGTTCCTACGAAGCTCTGAAA","AlternateAlleleVCF":"T","allel_id":213824,"rule_based_match":false,"evidence_text":"c.643_663del21","llm_judgment":"PRESENT","evidence":"c.643_663del21","abstract_start":62,"abstract_end":76}]}
{"pmid":"19863546","title":"Novel PORCN mutations in focal dermal hypoplasia.","abstract":"Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes.","variants":[{"Name":"NM_203475.3(PORCN):c.1094G>A (p.Arg365Gln)","Chromosome":"X","Start":"48516067","Stop":"48516067","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":975661,"rule_based_match":true,"evidence_text":"c.1094G>A (p.R365Q)","llm_judgment":"PRESENT","evidence":"c.1094G>A (p.R365Q)","abstract_start":729,"abstract_end":748}]}
{"pmid":"23889802","title":"Clinical and molecular characterization of Hb Hofu in eastern India.","abstract":"INTRODUCTION: Hb Hofu (HBB:c. 380T>A) is a rare inherited hemoglobin abnormality with few case reports in the world literature.\nMETHODS: Screening for the sickle cell gene mutation and other hemoglobinopathies was carried out using the sickle slide test, Hb electrophoresis, and HPLC under an ongoing central government project.\nRESULTS: We detected twelve Hb Hofu heterozygotes and three sickle Hb Hofu compound heterozygotes. The heterozygotes were asymptomatic except for one individual who had chronic kidney disease and moderate anemia. Only one HbS-Hofu case was symptomatic and presented with intermittent attacks of painful crisis. In the carrier state, the Hb Hofu eluted as a hump at the beginning of the HbA(0) window. But in HbS-Hofu cases, Hb Hofu eluted as a single peak in the HbA(0) window, with the HbA(2) levels being >4% consistently.\nCONCLUSION: HbS-Hofu has a variable clinical presentation. The retention time of Hb Hofu on HPLC is very close to that of HbA(0) and often elutes in the A0 window. Thus, there is every possibility of the HbS-Hofu chromatogram to be misinterpreted as that of a sickle cell trait/transfused sickle cell-beta-thalassemia case. This is the first time where Hb Hofu has been detected by HPLC, which is the widely accepted screening technique for hemoglobinopathies around the world.","variants":[{"Name":"NM_000518.5(HBB):c.380T>A (p.Val127Glu)","Chromosome":"11","Start":"5225662","Stop":"5225662","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":30240,"rule_based_match":true,"evidence_text":"HBB:c. 380T>A","llm_judgment":"PRESENT","evidence":"HBB:c. 380T>A","abstract_start":23,"abstract_end":36}]}
{"pmid":"15459954","title":"Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations.","abstract":"A subtype of phenylalanine hydroxylase (PAH) deficiency that responds to cofactor (tetrahydrobiopterin, BH4) supplementation has been associated with phenylketonuria (PKU) mutations. The underlying molecular mechanism of this responsiveness is as yet unknown and requires a detailed in vitro expression analysis of the associated mutations. With this aim, we optimized the analysis of the kinetic and cofactor binding properties in recombinant human PAH and in seven mild PKU mutations, i.e., c.194T>C (p.I65T), c.204A>T (p.R68S), c.731C>T (p.P244L), c.782G>A (p.R261Q), c.926C>T (p.A309V), c.1162G>A (p.V388M), and c.1162G>A (p.Y414C) expressed in E. coli. For p.I65T, p.R68S, and p.R261Q, we could in addition study the equilibrium binding of BH4 to the tetrameric forms by isothermal titration calorimetry (ITC). All the mutations resulted in catalytic defects, and p.I65T, p.R68S, p.P244L, and most probably p.A309V, showed reduced binding affinity for BH4. The possible stabilizing effect of the cofactor was explored using a cell-free in vitro synthesis assay combined with pulse-chase methodology. BH4 prevents the degradation of the proteins of folding variants p.A309V, p.V388M, and p.Y414C, acting as a chemical chaperone. In addition, for wild-type PAH and all mild PKU mutants analyzed in this study, BH4 increases the PAH activity of the synthesized protein and protects from the rapid inactivation observed in vitro. Catalase and superoxide dismutase partially mimic this protection. All together, our results indicate that the response to BH4 substitution therapy by PKU mutations may have a multifactorial basis. Both effects of BH4 on PAH, i.e., the chemical chaperone effect preventing protein misfolding and the protection from inactivation, may be relevant mechanisms of the responsive phenotype.","variants":[{"Name":"NM_000277.3(PAH):c.194T>C (p.Ile65Thr)","Chromosome":"12","Start":"102894893","Stop":"102894893","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15675,"rule_based_match":true,"evidence_text":"c.194T>C (p.I65T)","llm_judgment":"PRESENT","evidence":"c.194T>C (p.I65T)","abstract_start":493,"abstract_end":510},{"Name":"NM_000277.3(PAH):c.926C>T (p.Ala309Val)","Chromosome":"12","Start":"102846938","Stop":"102846938","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":98660,"rule_based_match":true,"evidence_text":"c.926C>T (p.A309V)","llm_judgment":"PRESENT","evidence":"c.926C>T (p.A309V)","abstract_start":571,"abstract_end":589}]}
{"pmid":"15915086","title":"Genotypic differences of MCAD deficiency in the Asian population: novel genotype and clinical symptoms preceding newborn screening notification.","abstract":"PURPOSE: In contrast to its high prevalence in Caucasians, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is reported to be an extremely rare metabolic disorder in the Asian population. The common MCAD gene (ACADM) mutation 985A>G (p.K329E), accounting for the majority of cases in Caucasians, has not been detected in this ethnic group, and the spectrum of ACADM mutations has remained unknown.\nMETHOD: Biochemical genetic testing including plasma acylcarnitine and urine acylglycine analyses, as well as sequencing of ACADM was performed in a Korean family with a newborn who had an elevated octanoyl (C8) carnitine concentration by newborn screening (NBS). Genotyping of 50 Korean newborns with normal NBS results was performed.\nRESULT: We report the identification of the first Korean patient with MCAD deficiency, caused by a novel missense mutation in ACADM, 843A>T (R281S), and a 4-bp deletion, c.449_452delCTGA. The patient became symptomatic before notification of the abnormal NBS result. Both the father and a brother who were identified as carriers for the 4-bp deletion had mildly elevated plasma C8 and C10:1 carnitine concentrations, whereas the acylcarnitine profile was normal in the mother who carries the missense mutation.\nCONCLUSION: The 4-bp deletion may represent a common Asian ACADM mutation, considering that it recently has also been found in two of the three Japanese patients in whom genotyping was performed. Greater availability of MCAD mutation analysis is likely to unravel the molecular basis of MCAD deficiency in the Asian population that might differ from Caucasians.","variants":[{"Name":"NM_000016.6(ACADM):c.843A>T (p.Arg281Ser)","Chromosome":"1","Start":"75749553","Stop":"75749553","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":541324,"rule_based_match":false,"evidence_text":"c.843A>T (R281S)","llm_judgment":"PRESENT","evidence":"R281S","abstract_start":880,"abstract_end":885},{"Name":"NM_000016.6(ACADM):c.449_452del (p.Thr150fs)","Chromosome":"1","Start":"75734849","Stop":"75734852","ReferenceAlleleVCF":"ATGAC","AlternateAlleleVCF":"A","allel_id":186630,"rule_based_match":true,"evidence_text":"c.449_452delCTGA","llm_judgment":"PRESENT","evidence":"c.449_452delCTGA","abstract_start":909,"abstract_end":925}]}
{"pmid":"19267246","title":"The silent mutation nucleotide 744 G --> A, Lys172Lys, in exon 6 of BRCA2 results in exon skipping.","abstract":"Germ-line mutations in BRCA2 predispose to breast and ovarian cancer. Mutations are widespread throughout the gene and include disease-causing mutations as frameshift, nonsense, splicing mutations and large genomic rearrangements. However a large number of mutations, including missense, silent and intron variants are of unknown significance. Here, we describe the functional characterization of a silent mutation (nucleotide 744 G --> A/c.516 G --> A, Lys172Lys) in exon 6 of BRCA2 in a Danish family with breast and ovarian cancer. Exon trapping analysis showed that the mutation results in skipping of exon 6 and/or both exon 5 and 6, which was verified by RT-PCR analysis on RNA isolated from whole blood of the affected patient. We therefore conclude that the BRCA2 silent mutation Lys172Lys is a disease-causing mutation.","variants":[{"Name":"NM_000059.4(BRCA2):c.516G>A (p.Lys172=)","Chromosome":"13","Start":"32326282","Stop":"32326282","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":66463,"rule_based_match":false,"evidence_text":"c.516 G --> A","llm_judgment":"PRESENT","evidence":"c.516 G --> A","abstract_start":439,"abstract_end":452}]}
{"pmid":"28401488","title":"A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family.","abstract":"PURPOSE: The purpose of this study was to identify mutations that cause non-syndromic male infertility using whole exome sequencing of family cases.\nMETHODS: We recruited a consanguineous Turkish family comprising nine siblings with male triplets; two of the triplets were infertile as well as one younger infertile brother. Whole exome sequencing (WES) performed on two azoospermic brothers identified a mutation in the melanoma antigen family B4 (MAGEB4) gene which was confirmed via Sanger sequencing and then screened for on control groups and unrelated infertile subjects. The effect of the mutation on messenger RNA (mRNA) and protein levels was tested after in vitro cell transfection. Structural features of MAGEB4 were predicted throughout the conserved MAGE domain.\nRESULTS: The novel single-base substitution (c.1041A>T) in the X-linked MAGEB4 gene was identified as a no-stop mutation. The mutation is predicted to add 24 amino acids to the C-terminus of MAGEB4. Our functional studies were unable to detect any effect either on mRNA stability, intracellular localization of the protein, or the ability to homodimerize/heterodimerize with other MAGE proteins. We thus hypothesize that these additional amino acids may affect the proper protein interactions with MAGEB4 partners.\nCONCLUSION: The whole exome analysis of a consanguineous Turkish family revealed MAGEB4 as a possible new X-linked cause of inherited male infertility. This study provides the first clue to the physiological function of a MAGE protein.","variants":[{"Name":"NM_002367.4(MAGEB4):c.1041A>T (p.Ter347Cys)","Chromosome":"X","Start":"30243176","Stop":"30243176","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1330011,"rule_based_match":true,"evidence_text":"c.1041A>T","llm_judgment":"PRESENT","evidence":"c.1041A>T","abstract_start":821,"abstract_end":830}]}
{"pmid":"29177700","title":"Novel Mutations in PLOD2 Cause Rare Bruck Syndrome.","abstract":"Bruck syndrome is a rare autosomal recessive form of osteogenesis imperfecta (OI), which is mainly characterized by joint contractures and recurrent fragility fractures. Mutations in FKBP10 and PLOD2 were identified as the underlying genetic defects of Bruck syndrome. Here we investigated the phenotypes and the pathogenic mutations of three unrelated Chinese patients with Bruck syndrome. Clinical fractures, bone mineral density (BMD), bone turnover biomarkers, and skeletal images were evaluated in detail. The pathogenic mutations were identified by targeted next-generation sequencing and subsequently confirmed by Sanger sequencing and cosegregation analysis. We also evaluated the effects of zoledronic acid on bone fracture incidence and BMD of the patients. Three patients had congenital joint contractures, recurrent fragility fractures, camptodactyly, clubfoot, scoliosis, but without dentinogenesis imperfecta and hearing loss. Five novel heterozygous mutations were detected in PLOD2, including three heterozygous missense mutations (c.1138C>T, p.Arg380Cys; c.1153T>C, p.Cys385Arg; and c.1982G>A, p.Gly661Asp), one heterozygous nonsense mutation (c.2038C>T, p.Arg680X), and one heterozygous splice-site mutation (c.503-2A>G). Their parents were all heterozygous carriers of these mutations in PLOD2. No clear genotype-phenotype correlations were found in these patients with PLOD2 mutations. Z-score of BMD was significantly increased, but scoliosis progressed and new bone fractures occurred during the treatment of zoledronic acid. Our findings expanded the spectrum of gene mutations of Bruck syndrome.","variants":[{"Name":"NM_182943.3(PLOD2):c.1982G>A (p.Gly661Asp)","Chromosome":"3","Start":"146071290","Stop":"146071290","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1399010,"rule_based_match":true,"evidence_text":"c.1982G>A, p.Gly661Asp","llm_judgment":"PRESENT","evidence":"c.1982G>A, p.Gly661Asp","abstract_start":1100,"abstract_end":1122},{"Name":"NM_182943.3(PLOD2):c.1138C>T (p.Arg380Cys)","Chromosome":"3","Start":"146085263","Stop":"146085263","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1319754,"rule_based_match":true,"evidence_text":"c.1138C>T, p.Arg380Cys","llm_judgment":"PRESENT","evidence":"c.1138C>T, p.Arg380Cys","abstract_start":1048,"abstract_end":1070},{"Name":"NM_182943.3(PLOD2):c.2038C>T (p.Arg680Ter)","Chromosome":"3","Start":"146071125","Stop":"146071125","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":360847,"rule_based_match":true,"evidence_text":"c.2038C>T, p.Arg680X","llm_judgment":"PRESENT","evidence":"c.2038C>T, p.Arg680X","abstract_start":1161,"abstract_end":1181}]}
{"pmid":"27033541","title":"AIP mutations in young patients with acromegaly and the Tampico Giant: the Mexican experience.","abstract":"Although aryl hydrocarbon receptor-interacting protein (AIP) mutations are rare in sporadic acromegaly, their prevalence among young patients is nonnegligible. The objectives of this study were to evaluate the frequency of AIP mutations in a cohort of Mexican patients with acromegaly with disease onset before the age of 30 and to search for molecular abnormalities in the AIP gene in teeth obtained from the \"Tampico Giant\". Peripheral blood DNA from 71 patients with acromegaly (51 females) with disease onset <30 years was analysed (median age of disease onset of 23 years) and correlated with clinical, biochemical and imaging characteristics. Sequencing was also carried out in DNA extracted from teeth of the Tampico Giant. Five patients (7 %) harboured heterozygous, germline mutations of the AIP gene. In two of them (a 9-year-old girl with gigantism and a young man with symptoms of GH excess since age 14) the c.910C>T (p.Arg304Ter), well-known truncating mutation was identified; in one of these two cases and her identical twin sister, the mutation proved to be a de novo event, since neither of their parents were found to be carriers. In the remaining three patients, new mutations were identified: a frameshift mutation (c.976_977insC, p.Gly326AfsTer), an in-frame deletion (c.872_877del, p.Val291_Leu292del) and a nonsense mutation (c.868A > T, p.Lys290Ter), which are predicted to be pathogenic based on in silico analysis. Patients with AIP mutations tended to have an earlier onset of acromegaly and harboured larger and more invasive tumours. A previously described genetic variant of unknown significance (c.869C > T, p.Ala299Val) was identified in DNA from the Tampico Giant. The prevalence of AIP mutations in young Mexican patients with acromegaly is similar to that of European cohorts. Our results support the need for genetic evaluation of patients with early onset acromegaly.","variants":[{"Name":"NM_003977.4(AIP):c.976_977insC (p.Gly326fs)","Chromosome":"11","Start":"67490976","Stop":"67490977","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":1347873,"rule_based_match":true,"evidence_text":"c.976_977insC, p.Gly326AfsTer","llm_judgment":"PRESENT","evidence":"c.976_977insC, p.Gly326AfsTer","abstract_start":1237,"abstract_end":1266},{"Name":"NM_003977.4(AIP):c.910C>T (p.Arg304Ter)","Chromosome":"11","Start":"67490910","Stop":"67490910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19927,"rule_based_match":true,"evidence_text":"c.910C>T (p.Arg304Ter)","llm_judgment":"PRESENT","evidence":"c.910C>T (p.Arg304Ter)","abstract_start":921,"abstract_end":943}]}
{"pmid":"32257295","title":"Novel","abstract":"We encountered a patient with mitochondrial trifunctional protein deficiency in whom the corresponding mutations were not identified by a DNA panel for newborn screening for targeted diseases. After diagnosis confirmation by an enzyme assay and immunoblotting using the autopsied liver, the re-evaluation of the panel data indicated a heterozygous deletion of exons 6-9 that was later confirmed at the genomic level. cDNA analysis also identified exonization of the 5' region of intron 9 caused by a deep intronic mutation, c.811 + 82A>G.","variants":[{"Name":"NM_000183.3(HADHB):c.811+82A>G","Chromosome":"2","Start":"26279397","Stop":"26279397","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2834418,"rule_based_match":true,"evidence_text":"c.811 + 82A>G","llm_judgment":"PRESENT","evidence":"c.811 + 82A>G","abstract_start":524,"abstract_end":537}]}
{"pmid":"16570191","title":"Novel mutations in CLN8 in Italian variant late infantile neuronal ceroid lipofuscinosis: Another genetic hit in the Mediterranean.","abstract":"Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive neurodegenerative disorders typically characterized by the accumulation of autofluorescent material in tissues. On the basis of clinical features, age at onset, and molecular genetic defects, it is possible to distinguish at least nine forms. The CLN8 form was first described in Finland, where all the patients are homozygous for a p.Arg24Gly mutation in CLN8. More recently, it has been found that a subset of a Turkish variant of late infantile NCL (v-LINCL) is also associated with CLN8 mutations. To identify the molecular defect in Italian patients with v-LINCL, the CLN8 gene was directly sequenced in 10 patients. Controls were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Five fluorescent-labeled microsatellite markers covering 1 cM around the gene were used for haplotype analysis. In three Italian v-LINCL patients, identified in a small area in southern Italy, we detected four new mutations in CLN8: c.66delG (p.Gly22fs), c.88G>C (p.Ala30Pro), c.473A>G (p.Tyr158Cys), and c.581A>G (p.Gln194Arg). The single-base deletion was found in two unrelated patients. The novel missense mutations were not identified in ethnically matched control chromosomes. Our findings expand the number of CLN8 variants and corroborate the notion that CLN8 patients are not confined to the Finnish population.","variants":[{"Name":"NM_018941.4(CLN8):c.88G>C (p.Ala30Pro)","Chromosome":"8","Start":"1771142","Stop":"1771142","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":17845,"rule_based_match":true,"evidence_text":"c.88G>C (p.Ala30Pro)","llm_judgment":"PRESENT","evidence":"c.88G>C (p.Ala30Pro)","abstract_start":1053,"abstract_end":1073},{"Name":"NM_018941.4(CLN8):c.473A>G (p.Tyr158Cys)","Chromosome":"8","Start":"1771527","Stop":"1771527","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":71349,"rule_based_match":true,"evidence_text":"c.473A>G (p.Tyr158Cys)","llm_judgment":"PRESENT","evidence":"c.473A>G (p.Tyr158Cys)","abstract_start":1075,"abstract_end":1097}]}
{"pmid":"32172615","title":"A novel mutation in","abstract":"Ataxia telangiectasia is a hereditary multisystem disorder with a wide range of symptoms and signs. It is inherited in an autosomal recessive manner due to a mutation in the ataxia telangiectasia mutated (<i>ATM</i>) gene, which encodes a protein kinase with a domain related to a phosphatidylinositol 3-kinase (PI-3 kinase) proteins that respond to DNA damage by phosphorylating key substrates involved in DNA repair and/or cell cycle control. The characteristics of the disease include progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctiva, immunodeficiency with frequent infections, and an increased risk for malignancy. In this article, we report a novel homozygous missense variant c.1516G > T, p.(Gly506Cys) in the <i>ATM</i> gene causing ataxia telangiectasia in a Saudi female. This variant led to the development of a later onset disease (at the age of 14 years) and the classical neurodegenerative process both clinically and on imaging. However, no immune system dysfunction or endocrine abnormalities were present. This is the second novel mutation in this gene so far reported from Saudi Arabia. The novel mutation described in the present study widened the genetic spectrum of <i>ATM</i>-associated diseases, which will benefit studies addressing this disease in the future.","variants":[{"Name":"NM_000051.4(ATM):c.1516G>T (p.Gly506Cys)","Chromosome":"11","Start":"108250981","Stop":"108250981","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":132796,"rule_based_match":true,"evidence_text":"c.1516G > T, p.(Gly506Cys)","llm_judgment":"PRESENT","evidence":"c.1516G > T, p.(Gly506Cys)","abstract_start":778,"abstract_end":804}]}
{"pmid":"30617279","title":"A novel mutation in VRK1 associated with distal spinal muscular atrophy.","abstract":"Distal spinal muscular atrophy (dSMA) is a rare clinically and genetically heterogeneous group of inherited disorders characterized by progressive distal muscle weakness and wasting. So far, more than 65% of patients with dSMA have undiscovered genetic mutations. Recently, compound heterozygous mutations in the vaccinia-related kinase 1 (VRK1) gene have been identified for the first time in two siblings with adult-onset dSMA from an Ashkenazi Jewish family. Here, we also report two affected siblings with adult-onset dSMA in a Chinese family. Whole exome sequencing and subsequent Sanger sequencing identified a novel nonsense mutation (c.1124G >A, p.W375*) in exon 12 of the VRK1 gene, co-segregating with the dSMA phenotype in an autosomal recessive pattern. In conclusion, our findings identify a novel nonsense mutation p.W375* in the VRK1 gene in a Chinese family with autosomal recessive dSMA and broaden the genetic spectrum of VRK1-associated dSMA.","variants":[{"Name":"NM_003384.3(VRK1):c.1124G>A (p.Trp375Ter)","Chromosome":"14","Start":"96876085","Stop":"96876085","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1428713,"rule_based_match":true,"evidence_text":"c.1124G>A (p.W375*)","llm_judgment":"PRESENT","evidence":"c.1124G >A","abstract_start":642,"abstract_end":652}]}
{"pmid":"25228067","title":"Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.","abstract":"OBJECTIVES: Our aim was to determine the molecular cause of autosomal dominant familial retinal arteriolar tortuosity (FRAT) in a family with three affected subjects.\nMATERIAL AND METHODS: Ophthalmologic evaluation included determination of best-corrected visual acuity (BCVA), slit-lamp and dilated fundus inspection, applanation tonometry, fundus photography, and fluorescein retinal angiography (FA). Molecular methods included whole exome sequencing analysis and Sanger sequencing validation of putative causal mutation in DNA from affected individuals.\nRESULTS: Typical signs of familial retinal arteriolar tortuosity were observed in all three patients. Exome sequencing identified a heterozygous c.1528G > A (p. Gly510Arg) mutation in COL4A1. Sanger sequencing confirmed that all three patients harbored the same pathogenetic mutation in COL4A1. The p. Gly510Arg variant in COL4A1 was absent in DNA from an available unaffected daughter, from a set of control alleles, and from publicly available databases.\nCONCLUSIONS: The molecular basis of familial retinal arteriolar tortuosity was identified for the first time, thus expanding the human phenotypes linked to COL4A1 mutations. Interestingly, the COL4A1 p.Gly510Arg mutation has been previously identified in a family with HANAC (Hereditary Angiopathy with Nephropathy, Aneurysm and Cramps), a multisystemic disease featuring retinal arteriolar tortuosity. No cerebral, neurologic, renal, cardiac or vascular anomalies were recognized in the pedigree described here. These data indicate that identical mutations in COL4A1 can originate both eye-restricted and systemic phenotypes.","variants":[{"Name":"NM_001845.6(COL4A1):c.1528G>A (p.Gly510Arg)","Chromosome":"13","Start":"110192222","Stop":"110192222","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33502,"rule_based_match":true,"evidence_text":"c.1528G > A (p. Gly510Arg)","llm_judgment":"PRESENT","evidence":"c.1528G > A (p. Gly510Arg)","abstract_start":703,"abstract_end":729}]}
{"pmid":"22129472","title":"The Arabic allele: a single base pair substitution activates a 10-base downstream cryptic splice acceptor site in exon 12 of LDLR and severely decreases LDLR expression in two unrelated Arab families with familial hypercholesterolemia.","abstract":"Familial hypercholesterolemia (FH) is a monogenic autosomal dominant disorder caused by defects in LDLR. Few reports describe FH mutations among Arabs. We describe a mutation in LDLR of two unrelated Arab families. We investigated 19 patients using DNA sequencing, RFLP, and real-time (RT) PCR. DNA sequencing showed a base pair substitution (c.1706-2 A>T) in the splice acceptor site of LDLR intron 11. Our results were confirmed by RFLP on 2% agarose gel. In silico analysis predicted a new cryptic splice site downstream of the original position generating a 10-base deletion from the beginning of exon 12; (c.1706-1715del.ATCTCCTCAG). cDNA sequencing of exon 12 confirmed the computational analysis. The deletion was visualized on 4% agarose gel. The deletion generates a frameshift and a premature termination codon (c.1991-1993; p.(Asp569Valfs*93). RT-PCR revealed that LDLR mRNA is 9.3%±6.5 and 17.9%±8.0 for FH homozygote and heterozygote individuals respectively, compared to a healthy family control. We predict a class II LDLR mutation that leads to a truncated receptor missing exons 14-18. We called this mutation \"the Arabic allele\". We expect a significant contribution of this mutation to the prevalence of FH among Arabs. Also, we propose that the severe down regulation of LDLR mRNA expression is due to nonsense-mediated-decay.","variants":[{"Name":"NM_000527.5(LDLR):c.1706-2A>T","Chromosome":"19","Start":"11116857","Stop":"11116857","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":243274,"rule_based_match":true,"evidence_text":"c.1706-2 A>T","llm_judgment":"PRESENT","evidence":"c.1706-2 A>T","abstract_start":343,"abstract_end":355}]}
{"pmid":"23044053","title":"Congenital disorder of glycosylation type Ic: report of a Japanese case.","abstract":"Congenital disorders of glycosylation (CDG) are inherited metabolic diseases affecting N-linked glycosylation pathways with variable clinical presentations characterized by psychomotor retardation, seizures, ataxia and hypotonia. CDG-Ic is caused by mutation in the ALG6 gene encoding alpha-1,3-glucosyltransferase. We present a 9-year-old girl diagnosed as having CDG-Ic. She developed severe psychomotor retardation, epileptic seizures, muscle hypotonia, strabismus and some dysmorphic features without inverted nipples or fat pads. She showed a fluctuating serum transaminase level with or without some infection, and a characteristically low level of antithrombin III. MR imaging of the brain at age 2years demonstrated the lower limit of normal myelination, mild atrophy of the cerebrum, and mild hypoplasia of the brainstem and cerebellum. The patient exhibited a CDG type I pattern of serum transferrin on isoelectric focusing and mass spectrometric profiling. Sequence analysis of the ALG6 gene showed two heterozygous mutations, c.998C>T (A333V) and c.1061C>T (P354L). The patient was diagnosed as having CDG-Ic with a novel mutation, making her the first Japanese case. It was suggested that the severe psychomotor retardation in the patient was due to the existence of multiple mutant ALG6 alleles.","variants":[{"Name":"NM_013339.4(ALG6):c.998C>T (p.Ala333Val)","Chromosome":"1","Start":"63419380","Stop":"63419380","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20536,"rule_based_match":true,"evidence_text":"c.998C>T (A333V)","llm_judgment":"PRESENT","evidence":"c.998C>T (A333V)","abstract_start":1038,"abstract_end":1054}]}
{"pmid":"22665969","title":"Identification of recurrent and novel mutations in TULP1 in Pakistani families with early-onset retinitis pigmentosa.","abstract":"PURPOSE: To identify the genetic defects underlying retinitis pigmentosa (RP) in Pakistani families.\nMETHODS: Genome-wide high-density single-nucleotide-polymorphism microarray analysis was performed using the DNA of nine affected individuals from two large families with multiple consanguineous marriages. Data were analyzed to identify homozygous regions that are shared by affected sibs in each family. Sanger sequencing was performed for genes previously implicated in autosomal recessive RP and allied retinal dystrophies that resided in the identified homozygous regions. Probands from both families underwent fundus examination and electroretinogram measurements.\nRESULTS: The tubby-like protein 1 gene (TULP1) was present in the largest homozygous region in both families. Sequence analysis identified a previously reported mutation (c.1138A>G; p.Thr380Ala) in one family and a novel pathogenic variant (c.1445G>A; p.Arg482Gln) in the other family. Both variants were found to be present in a homozygous state in all affected individuals, were heterozygous present in the unaffected parents, and heterozygous present or absent in normal individuals. Affected individuals of both families showed an early-onset form of RP.\nCONCLUSIONS: Homozygosity mapping, combined with candidate-gene analysis, successfully identified genetic defects in TULP1 in two large Pakistani families with early-onset retinitis pigmentosa.","variants":[{"Name":"NM_003322.6(TULP1):c.1445G>A (p.Arg482Gln)","Chromosome":"6","Start":"35500031","Stop":"35500031","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":966097,"rule_based_match":true,"evidence_text":"c.1445G>A (p.Arg482Gln)","llm_judgment":"PRESENT","evidence":"p.Arg482Gln","abstract_start":923,"abstract_end":934}]}
{"pmid":"29896733","title":"Analysis of KIT mutations in five patients from two Han Chinese pedigrees affected with Piebaldism","abstract":"OBJECTIVE: To screen for KIT gene mutations in two Han Chinese pedigrees affected with Piebaldism.\nMETHODS: Clinical data of the pedigrees was collected. Genomic DNA was extracted from blood samples collected from the pedigrees and 120 unrelated healthy controls. All coding exons of the KIT gene were subjected to PCR amplification and direct sequencing.\nRESULTS: Two missense mutations, c.1861G>A(p.Ala621Thr) and c.1872G>A(p.Met624Ile), were identified respectively in the two pedigrees. Neither mutation was found among healthy members from the respective pedigree and the 120 unrelated healthy controls. c.1872G>A is a novel mutation.\nCONCLUSION: Mutations of the KIT gene may affect the structure and function of the transmembrane receptor KIT, which lead to the disease.","variants":[{"Name":"NM_000222.3(KIT):c.1861G>A (p.Ala621Thr)","Chromosome":"4","Start":"54727909","Stop":"54727909","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":559932,"rule_based_match":true,"evidence_text":"c.1861G>A(p.Ala621Thr)","llm_judgment":"PRESENT","evidence":"c.1861G>A(p.Ala621Thr)","abstract_start":389,"abstract_end":411}]}
{"pmid":"35712814","title":"Early cardiomyopathy without severe metabolic dysregulation in a patient with cblB-type methylmalonic acidemia.","abstract":"BACKGROUND: Cardiomyopathy is a known complication of organic acidemias but generally thought to be secondary to poor metabolic control.\nMETHODS: Our patient was found through biochemical testing and Sanger sequencing to harbor an Icelandic founder mutation: NM_052845.4(MMAB):c.571C > T(p.Arg191Trp), leading to an early presentation (4 h after birth) of cblB-type methylmalonic acidemia (MMA). Biochemical testing of this patient suggested B-12-responsiveness and thus the patient was treated with cyanocobalamin throughout life. Informed parental consent was obtained for this report.\nRESULTS: Our patient had three metabolic decompensations in her life (at birth, at 1 month, and at 5 months). The first decompensation was probably linked to stress of delivery, second to rhinovirus infection, and third by co-infection of norovirus and enterovirus. At 3 months, the patient was noted to be tachypneic, although this was attributed to her underlying metabolic acidosis. At 5 months and 10 days, the patient was admitted with minor flu-like symptoms but developed severe diarrhea in hospital and upon rehydration had cardiac decompensation and was found to have undiagnosed dilated cardiomyopathy. Although, patient was treated aggressively with dextrose, hemodialysis, levocarnitine, and vasoactive agents, there was limited response to medications to treat cardiac failure, and eventually the patient passed away before turning 6 months old.\nCONCLUSIONS: Other than these three mild decompensations, patient had very good metabolic control, thus demonstrating that even without frequent metabolic decompensation, cardiomyopathy can be an observed phenotype in cblB-type MMA even very early in life, suggesting that this phenotype may be independent of metabolic control.","variants":[{"Name":"NM_052845.4(MMAB):c.571C>T (p.Arg191Trp)","Chromosome":"12","Start":"109561053","Stop":"109561053","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":215031,"rule_based_match":true,"evidence_text":"NM_052845.4(MMAB):c.571C > T(p.Arg191Trp)","llm_judgment":"PRESENT","evidence":"NM_052845.4(MMAB):c.571C > T(p.Arg191Trp)","abstract_start":259,"abstract_end":300}]}
{"pmid":"18207370","title":"Genotype-phenotype correlation in non-Hallopeau-Siemens recessive dystrophic epidermolysis bullosa: the splice site mutation c.6216+5G > T in the COL7A1 gene results in aberrant and normal splicings.","abstract":"","variants":[{"Name":"NM_000094.4(COL7A1):c.6216+5G>T","Chromosome":"3","Start":"48575202","Stop":"48575202","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1481399,"rule_based_match":true,"evidence_text":"c.6216+5G > T","llm_judgment":"PRESENT","evidence":"c.6216+5G > T","abstract_start":null,"abstract_end":null}]}
{"pmid":"17679936","title":"A family with autosomal dominant primary congenital cataract associated with a CRYGC mutation: evidence of clinical heterogeneity.","abstract":"PURPOSE: To describe a family with primary congenital cataract associated with a CRYGC mutation.\nMETHODS: One family with several affected members with primary congenital cataract and 170 healthy controls were examined. DNA from leukocytes was isolated to analyze the CRYGA-D gene cluster.\nRESULTS: DNA sequencing analysis of the CRYGA-D gene cluster of the affected members showed the heterozygous missense mutation c.502C>T in the CRYGC gene. This transition mutation resulted in the substitution of Arg at position 168 by Trp. Analysis of the healthy members of the family and 170 unrelated controls showed a normal sequence of the CRYGA-D gene cluster.\nCONCLUSIONS: In the present study, we described a family with nuclear congenital cataract that segregated the CRYGC missense mutation c.502C>T. This mutation has been associated with the phenotype of lamellar cataract but is also considered a single nucleotide polymorphism (SNP) in the NCBI database. Our data and previous report support that R168W is the actual disease-causing mutation and should no longer be considered a SNP. This is the first case of phenotypic heterogeneity in the primary congenital cataract specifically associated with the R168W mutation in the CRYGC gene.","variants":[{"Name":"NM_020989.4(CRYGC):c.502C>T (p.Arg168Trp)","Chromosome":"2","Start":"208128226","Stop":"208128226","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31984,"rule_based_match":true,"evidence_text":"c.502C>T","llm_judgment":"PRESENT","evidence":"c.502C>T","abstract_start":417,"abstract_end":425}]}
{"pmid":"16685652","title":"Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia.","abstract":"DNA polymerase gamma (pol gamma ) is required to maintain the genetic integrity of the 16,569-bp human mitochondrial genome (mtDNA). Mutation of the nuclear gene for the catalytic subunit of pol gamma (POLG) has been linked to a wide range of mitochondrial diseases involving mutation, deletion, and depletion of mtDNA. We describe a heterozygous dominant mutation (c.1352G-->A/p.G451E) in POLG2, the gene encoding the p55 accessory subunit of pol gamma , that causes progressive external ophthalmoplegia with multiple mtDNA deletions and cytochrome c oxidase (COX)-deficient muscle fibers. Biochemical characterization of purified, recombinant G451E-substituted p55 protein in vitro revealed incomplete stimulation of the catalytic subunit due to compromised subunit interaction. Although G451E p55 retains a wild-type ability to bind DNA, it fails to enhance the DNA-binding strength of the p140-p55 complex. In vivo, the disease most likely arises through haplotype insufficiency or heterodimerization of the mutated and wild-type proteins, which promote mtDNA deletions by stalling the DNA replication fork. The progressive accumulation of mtDNA deletions causes COX deficiency in muscle fibers and results in the clinical phenotype.","variants":[{"Name":"NM_007215.4(POLG2):c.1352G>A (p.Gly451Glu)","Chromosome":"17","Start":"64477929","Stop":"64477929","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20315,"rule_based_match":false,"evidence_text":"c.1352G-->A/p.G451E","llm_judgment":"PRESENT","evidence":"c.1352G-->A/p.G451E","abstract_start":366,"abstract_end":385}]}
{"pmid":"24384324","title":"Novel GAA sequence variant c.1211 A>G reduces enzyme activity but not protein expression in infantile and adult onset Pompe disease.","abstract":"Pompe disease is a clinically and genetically heterogeneous autosomal recessive disorder caused by lysosomal acid α-glucosidase (GAA) deficiency. We report on two affected members of a non-consanguineous Caucasian family, including a classical infantile-onset patient with severe cardiomyopathy (IO) and his paternal grandmother with the adult-onset (AO) form. Two compound heterozygous sequence variants of the GAA gene were identified in each patient by mutation analyses (IO=c.1211A>G and c.1798C>T; AO=c.1211A>G and c.692+5G>T). For this study, the biochemical phenotype resulting from the missense mutation c.1211A>G in exon 8, which converts a highly conserved aspartate to glycine (p.Asp404Gly), was of specific interest because it had not been reported previously. Western blotting revealed a robust expression of all GAA isoforms in quadriceps muscle of both patients (fully CRIM positive), while enzymatic activity was 3.6% (IO) and 6.6% (AO) of normal controls. To further validate these findings, the c.1211A>G sequence variant was introduced in wild type GAA cDNA and over-expressed in HEK293T cells. Site-directed mutagenesis analyses confirmed that the mutation does not affect processing or expression of GAA protein, but rather impairs enzyme function. Similar results were reported for c.1798C>T (p.Arg600Cys), which further supports the biochemical phenotype observed in IO. The third mutation (c.692+5G>T, in intron 3) was predicted to affect normal splicing of the GAA mRNA, and qPCR indeed verified a 4-fold lower mRNA expression in AO. It is concluded that the novel sequence variant c.1211A>G results in full CRIM but significantly lower GAA activity, which in combination with c.1798C>T leads to infantile-onset Pompe disease. We surmise that the difference in disease severity between the two family members in this study is due to a milder effect of the intronic mutation c.692+5G>T (vs. c.1798C>T) on phenotype, partially preserving GAA activity and delaying onset in the proband (paternal grandmother).","variants":[{"Name":"NM_000152.5(GAA):c.1211A>G (p.Asp404Gly)","Chromosome":"17","Start":"80108713","Stop":"80108713","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":950360,"rule_based_match":true,"evidence_text":"c.1211A>G (p.Asp404Gly)","llm_judgment":"PRESENT","evidence":"p.Asp404Gly","abstract_start":689,"abstract_end":700},{"Name":"NM_000152.5(GAA):c.1798C>T (p.Arg600Cys)","Chromosome":"17","Start":"80112621","Stop":"80112621","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":646900,"rule_based_match":true,"evidence_text":"c.1798C>T (p.Arg600Cys)","llm_judgment":"PRESENT","evidence":"c.1798C>T (p.Arg600Cys)","abstract_start":1304,"abstract_end":1327},{"Name":"NM_000152.5(GAA):c.692+5G>T","Chromosome":"17","Start":"80105899","Stop":"80105899","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":531967,"rule_based_match":true,"evidence_text":"c.692+5G>T","llm_judgment":"PRESENT","evidence":"c.692+5G>T","abstract_start":520,"abstract_end":530}]}
{"pmid":"32392611","title":"Optic Atrophy and Generalized Chorea in a Patient Harboring an OPA10/RTN4IP1 Pathogenic Variant.","abstract":"<i>RTN4IP1</i> pathogenic variants (OPA10 syndrome) have been described in patients with early-onset recessive optic neuropathy and recently associated with a broader clinical spectrum, from isolated optic neuropathy to severe encephalopathies with epilepsy. Here we present a case of a patient with a complex clinical picture characterized by bilateral optic nerve atrophy, horizontal nystagmus, myopia, mild intellectual disability, generalized chorea, isolated small subependymal heterotopia, and asynchronous self-resolving midbrain MRI (magnetic resonance imaging) lesions. By using massive gene sequencing, we identified in this patient the c.308G > A (p.Arg103His) homozygous pathogenic variant in the <i>RTN4IP1</i> gene. Complex movement disorders and relapsing-remitting neuroradiological lesions have not been previously reported in this condition. Our case expands the clinical spectrum of OPA10 syndrome and opens new opportunities for the molecular diagnosis.","variants":[{"Name":"NM_032730.5(RTN4IP1):c.308G>A (p.Arg103His)","Chromosome":"6","Start":"106622936","Stop":"106622936","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215758,"rule_based_match":true,"evidence_text":"c.308G > A (p.Arg103His)","llm_judgment":"PRESENT","evidence":"c.308G > A (p.Arg103His)","abstract_start":647,"abstract_end":671}]}
{"pmid":"30950025","title":"Analysis of clinical phenotype and TGM1 gene mutation in a child with neonatal congenital ichthyosis","abstract":"OBJECTIVE: To explore the genetic cause for a child with congenital ichthyosis.\nMETHODS: The child was subjected to next generation sequencing using a specific gene panel. Suspected mutation was validated by Sanger sequencing.\nRESULTS: The proband was found to harbor compound heterozygous mutations c.327delG (p.Met109Ilefs*2) and c.791G>A (p.Arg264Gln) of the TGM1 gene, which were respectively inherited from his mother and father. The same mutations were not found among 101 healthy controls. c.327delG was not reported previously. By bioinformatic analysis, both mutations are likely to impair the function of TGase-1 protein.\nCONCLUSION: The compound heterozygous mutations of c.327delG and c.791G> A of the TGM1 gene probably underlie the ichthyosis in the proband. The result has facilitated prenatal diagnosis for this pedigree.","variants":[{"Name":"NM_000359.3(TGM1):c.327del (p.Met109fs)","Chromosome":"14","Start":"24261876","Stop":"24261876","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1451211,"rule_based_match":true,"evidence_text":"c.327delG (p.Met109Ilefs*2)","llm_judgment":"PRESENT","evidence":"c.327delG (p.Met109Ilefs*2)","abstract_start":300,"abstract_end":327},{"Name":"NM_000359.3(TGM1):c.791G>A (p.Arg264Gln)","Chromosome":"14","Start":"24260025","Stop":"24260025","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":329126,"rule_based_match":true,"evidence_text":"c.791G>A (p.Arg264Gln)","llm_judgment":"PRESENT","evidence":"c.791G>A (p.Arg264Gln)","abstract_start":332,"abstract_end":354}]}
{"pmid":"25708704","title":"A new compound heterozygous mutation in GJB2 causes nonsyndromic hearing loss in a consanguineous Iranian family.","abstract":"OBJECTIVE: To investigate mutations in GJB2 in a consanguineous Iranian family with multiple members affected by non-syndromic hearing loss.\nMETHODS: DNA was extracted from blood samples and the coding region of the conexin 26 gene was amplified using PCR. Bidirectional sequencing was carried out on PCR products.\nRESULTS: Direct sequencing of the PCR products led to the identification of a novel compound heterozygous mutation of c.551G>C/c.397T>G (p.R184P/p.W133G) and a previously reported homozygous mutation c.551G>C (R184P/R184P). Compound heterozygous mutation was identified in the father and his daughter and homozygous mutation was identified in his affected son. In silico analysis of p.W133G predicted mutation has deleterious effect on protein structure.\nCONCLUSION: These results show the usefulness of GJB2 mutation screening and bioinformatic analysis for genetic diagnosis and counseling of non-syndromic hearing loss.","variants":[{"Name":"NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)","Chromosome":"13","Start":"20189031","Stop":"20189031","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":32046,"rule_based_match":true,"evidence_text":"c.551G>C","llm_judgment":"PRESENT","evidence":"c.551G>C","abstract_start":433,"abstract_end":441}]}
{"pmid":"27309958","title":"Whole Exome Sequencing and Segregation Analysis Confirms That a Mutation in COL17A1 Is the Cause of Epithelial Recurrent Erosion Dystrophy in a Large Dominant Pedigree Previously Mapped to Chromosome 10q23-q24.","abstract":"PURPOSE: To report identification of a COL17A1 mutation in a family with a corneal dystrophy previously mapped to chromosome 10q23-q24.\nMETHODS: Whole-exome sequencing was performed on DNA samples from five affected family members and two unrelated, unaffected individuals. Identified variants were filtered for those that were: located in the linked interval on chromosome 10q23-q24; novel or rare (minor allele frequency ≤0.01); heterozygous; present in all affected individuals and not in controls; and present in genes that encode proteins expressed in human corneal epithelial cells (reads per kilobase per million ≥1). Sanger sequencing of identified variants (SNVs) was performed in additional family members. In silico analysis was used to predict the functional impact of non-synonymous variants.\nRESULTS: Three SNVs located in two genes were identified that met the filtering criteria: one rare synonymous c.3156C>T variant in the collagen, type XVII, alpha I (COL17A1) gene; and two rare variants, one synonymous and one missense, in the dynamin binding protein (DNMBP) gene. Sanger sequencing of additional family members determined that only the COL17A1 variant segregates with the affected phenotype. In silico analysis predicts that the missense variant in DNMBP would be tolerated.\nCONCLUSIONS: The corneal dystrophy mapped to chromosome 10q23-q24 is associated with the c.3156C>T variant in COL17A1. As this variant has recently been identified in five other families with early onset recurrent corneal erosions, and has been shown in vitro to introduce a cryptic splice donor site, this dystrophy is likely caused by aberrant splicing of COL17A1 and should be classified as epithelial recurrent erosion dystrophy.","variants":[{"Name":"NM_000494.4(COL17A1):c.3156C>T (p.Gly1052=)","Chromosome":"10","Start":"104037688","Stop":"104037688","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205533,"rule_based_match":true,"evidence_text":"c.3156C>T","llm_judgment":"PRESENT","evidence":"c.3156C>T","abstract_start":916,"abstract_end":925}]}
{"pmid":"27796263","title":"Uniparental Isodisomy of Chromosome 1 Unmasking an Autosomal Recessive 3-Beta Hydroxysteroid Dehydrogenase Type II-Related Congenital Adrenal Hyperplasia.","abstract":"Steroid 3-beta hydroxysteroid dehydrogenase type II (3β-HSD2) deficiency is a rare autosomal recessive form of congenital adrenal hyperplasia (CAH). We report the genetic basis of 3β-HSD2 deficiency arising from uniparental isodisomy (UPD) of chromosome 1. We describe a term undervirilized male whose newborn screen indicated borderline CAH. The patient presented on the 7<sup>th</sup> day of life in salt-wasting adrenal crisis. Steroid hormone testing revealed a complex pattern suggestive of 3β-HSD deficiency. Chromosomal microarray and single nucleotide polymorphism analysis revealed complete UPD of chromosome 1. Sanger sequencing of <i>HSD3B2</i> revealed a previously described missense mutation, c.424G>A (p.E142K) in homozygous state, thus confirming the diagnosis of 3β-HSD2 deficiency. We provide evidence of the existence of an uncommon mechanism for <i>HSD3B2</i> gene-related CAH arising from UPD of chromosome 1.","variants":[{"Name":"NM_000198.4(HSD3B2):c.424G>A (p.Glu142Lys)","Chromosome":"1","Start":"119421925","Stop":"119421925","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27229,"rule_based_match":true,"evidence_text":"c.424G>A (p.E142K)","llm_judgment":"PRESENT","evidence":"c.424G>A (p.E142K)","abstract_start":707,"abstract_end":725}]}
{"pmid":"26250584","title":"Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency.","abstract":"Severe protein C-deficiency is a rare heritable thrombophilia of the newborn. Infants with biallelic PROC mutations present purpura fulminans and intracranial thromboembolism, while the prenatal onset of mutated heterozygotes remains unclear. We herewith present the first case of fetal ventriculomegaly and neonatal stroke associated with heterozygous PROC mutation. The infant was born to a healthy mother at 38 gestational weeks. The fetal growth had been normal, but the routine ultrasound screening had indicated mild hydrocephalus at 28 weeks of gestation. He developed convulsions two days after birth. Computed tomography of the brain revealed multiple hemorrhagic infarctions and ventriculomegaly. Dissociated levels of the plasma activity between protein C (21%) and protein S (42%) reached to determine the heterozygote of PROC c.574_576delAAG, a common thrombophilic predisposition in Asian ancestries. PC-mutant heterozygotes may have a limited high risk of cerebral thromboembolism during the perinatal course.","variants":[{"Name":"NM_000312.4(PROC):c.574AAG[1] (p.Lys193del)","Chromosome":"2","Start":"127426121","Stop":"127426123","ReferenceAlleleVCF":"GAGA","AlternateAlleleVCF":"G","allel_id":227218,"rule_based_match":false,"evidence_text":"PROC c.574_576delAAG","llm_judgment":"PRESENT","evidence":"PROC c.574_576delAAG","abstract_start":834,"abstract_end":854}]}
{"pmid":"17963004","title":"Mutational screening of the APC gene in Chilean families with familial adenomatous polyposis: nine novel truncating mutations.","abstract":"PURPOSE: Familial adenomatous polyposis is characterized by the development of hundreds of adenomatous polyps located mainly in the colon and rectum. Patients with familial adenomatous polyposis who do not receive treatment will develop cancer before aged 40 years. This disease is caused by germline mutations in the adenomatous polyposis coli gene. Different studies have shown a correlation between the location of the mutation and the clinical phenotype, such as the grade of severity and/or the presence of extracolonic manifestations, such as desmoid tumors. This study was designed to identify germline mutation in the adenomatous polyposis coli gene in Chilean families with familial adenomatous polyposis.\nMETHODS: We examined the adenomatous polyposis coli gene in 24 Chilean families with familial adenomatous polyposis. The adenomatous polyposis coli gene was screened for mutations combining single strand conformation polymorphism technique, protein truncation test, and DNA sequencing.\nRESULTS: We detected 17 different truncating mutations in 21 of 24 families (87.5 percent); 9 of these were novel. Fourteen mutations were detected in exon 15, being the most frequent c.3,927_3,931delAAAGA, found in 3 of 21 families (14 percent). Eight families (33 percent) showed at least one patient affected with desmoid tumors, presenting mutations between codons 849 and 1,533. Interestingly, two mutations, c.3,632dupA and c.3,783_3,784delTT, leading into a truncating protein at codons 1,216 and 1,274, were associated with almost 100 percent penetrance for desmoid tumors among relatives.\nCONCLUSIONS: We achieved 87 percent mutation detection rate in adenomatous polyposis coli gene; more than 50 percent of them were novel. The high percentage of novel mutations found may be because of the genetic composition of the Chilean population, which is an admixture of Amerindian and Spaniards, and the scarce information in the literature about similar populations.","variants":[{"Name":"NM_000038.6(APC):c.3927_3931del (p.Glu1309fs)","Chromosome":"5","Start":"112839515","Stop":"112839519","ReferenceAlleleVCF":"TAAAAG","AlternateAlleleVCF":"T","allel_id":15855,"rule_based_match":false,"evidence_text":"c.3,927_3,931delAAAGA","llm_judgment":"PRESENT","evidence":"c.3,927_3,931delAAAGA","abstract_start":1185,"abstract_end":1206}]}
{"pmid":"26721930","title":"Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP.","abstract":"In mammals, sperm-oocyte fusion initiates Ca(2+) oscillations leading to a series of events called oocyte activation, which is the first stage of embryo development. Ca(2+) signaling is elicited by the delivery of an oocyte-activating factor by the sperm. A sperm-specific phospholipase C (PLCZ1) has emerged as the likely candidate to induce oocyte activation. Recently, PAWP, a sperm-born tryptophan domain-binding protein coded by WBP2NL, was proposed to serve the same purpose. Here, we studied two infertile brothers exhibiting normal sperm morphology but complete fertilization failure after intracytoplasmic sperm injection. Whole exomic sequencing evidenced a missense homozygous mutation in PLCZ1, c.1465A>T; p.Ile489Phe, converting Ile 489 into Phe. We showed the mutation is deleterious, leading to the absence of the protein in sperm, mislocalization of the protein when injected in mouse GV and MII oocytes, highly abnormal Ca(2+) transients and early embryonic arrest. Altogether these alterations are consistent with our patients' sperm inability to induce oocyte activation and initiate embryo development. In contrast, no deleterious variants were identified in WBP2NL and PAWP presented normal expression and localization. Overall we demonstrate in humans, the absence of PLCZ1 alone is sufficient to prevent oocyte activation irrespective of the presence of PAWP. Additionally, it is the first mutation located in the C2 domain of PLCZ1, a domain involved in targeting proteins to cell membranes. This opens the door to structure-function studies to identify the conserved amino acids of the C2 domain that regulate the targeting of PLCZ1 and its selectivity for its lipid substrate(s).","variants":[{"Name":"NM_033123.4(PLCZ1):c.1465A>T (p.Ile489Phe)","Chromosome":"12","Start":"18688215","Stop":"18688215","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":263832,"rule_based_match":true,"evidence_text":"c.1465A>T; p.Ile489Phe","llm_judgment":"PRESENT","evidence":"c.1465A>T; p.Ile489Phe","abstract_start":707,"abstract_end":729}]}
{"pmid":"22781098","title":"Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies.","abstract":"Identification of mutations in the HOGA1 gene as the cause of autosomal recessive primary hyperoxaluria (PH) type III has revitalized research in the field of PH and related stone disease. In contrast to the well-characterized entities of PH type I and type II, the pathophysiology and prevalence of type III is largely unknown. In this study, we analyzed a large cohort of subjects previously tested negative for type I/II by complete HOGA1 sequencing. Seven distinct mutations, among them four novel, were found in 15 patients. In patients of non-consanguineous European descent the previously reported c.700+5G>T splice-site mutation was predominant and represents a potential founder mutation, while in consanguineous families private homozygous mutations were identified throughout the gene. Furthermore, we identified a family where a homozygous mutation in HOGA1 (p.P190L) segregated in two siblings with an additional AGXT mutation (p.D201E). The two girls exhibiting triallelic inheritance presented a more severe phenotype than their only mildly affected p.P190L homozygous father. In silico analysis of five mutations reveals that HOGA1 deficiency is causing type III, yet reduced HOGA1 expression or aberrant subcellular protein targeting is unlikely to be the responsible pathomechanism. Our results strongly suggest HOGA1 as a major cause of PH, indicate a greater genetic heterogeneity of hyperoxaluria, and point to a favorable outcome of type III in the context of PH despite incomplete or absent biochemical remission. Multiallelic inheritance could have implications for genetic testing strategies and might represent an unrecognized mechanism for phenotype variability in PH.","variants":[{"Name":"NM_138413.4(HOGA1):c.700+5G>T","Chromosome":"10","Start":"97600168","Stop":"97600168","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":200671,"rule_based_match":true,"evidence_text":"c.700+5G>T","llm_judgment":"PRESENT","evidence":"c.700+5G>T","abstract_start":605,"abstract_end":615}]}
{"pmid":"16835863","title":"Paternal bias in parental origin of HRAS mutations in Costello syndrome.","abstract":"Costello syndrome (CS) is a rare congenital condition caused by heterozygous de novo missense mutations affecting the codon for glycine 12 or 13 of the HRAS gene. We have identified 39 CS patients harboring the p.Gly12Ser mutation (NM_005343.2:c.34 G > A), two patients with c.35G > C mutations resulting in p.Gly12Ala substitutions, and one patient carrying the p.Gly13Cys substitution (c.37G > A). We analyzed the region flanking the mutated sites in 42 probands and 59 parents, and used four polymorphic markers to trace the parental origin of the germline mutations: one highly polymorphic hexanucleotide (GGGCCT) repeat region, defining three alleles with different numbers of repeat units (two, three, or four), and three SNPs. One of the SNPs, rs12628 (c.81T > C), was found in strong linkage disequilibrium with the hexanucleotide repeat region. Out of a total of 24 probands with polymorphic markers, 16 informative families were tested and the paternal origin of the germline mutation was found in 14 CS probands; a distribution that is neither consistent with an equal likelihood of mutations arising in either parent (P = 0.0018), nor with exclusive paternal origin.","variants":[{"Name":"NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)","Chromosome":"11","Start":"534289","Stop":"534289","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27641,"rule_based_match":true,"evidence_text":"p.Gly12Ser mutation (NM_005343.2:c.34 G > A)","llm_judgment":"PRESENT","evidence":"p.Gly12Ser mutation (NM_005343.2:c.34 G > A)","abstract_start":211,"abstract_end":255},{"Name":"NM_005343.4(HRAS):c.35G>C (p.Gly12Ala)","Chromosome":"11","Start":"534288","Stop":"534288","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":27642,"rule_based_match":true,"evidence_text":"c.35G > C","llm_judgment":"PRESENT","evidence":"c.35G > C","abstract_start":275,"abstract_end":284}]}
{"pmid":"34913263","title":"A novel missense variant of SCN4A co-segregates with congenital essential tremor in a consanguineous Kurdish family.","abstract":"Essential tremor (ET) is a neurological disorder characterized by bilateral and symmetric postural, isometric, and kinetic tremors of forelimbs produced during voluntary movements. To date, only a single SCN4A variant has been suggested to cause ET. In continuation of the previous report on the association between SCN4A and ET in a family from Spain, we validated the pathogenicity of a novel SCN4A variant and its involvement in ET in a second family affected by this disease. We recruited a Kurdish family with four affected members manifesting congenital tremor. Using whole-exome sequencing, we identified a novel missense variant in SCN4A, NM_000334.4:c.4679C>T; p.(Pro1560Leu), thus corroborating SCN4A's role in ET. The residue is highly conserved across vertebrates and the substitution is predicted to be pathogenic by various in silico tools. Western blotting and immunocytochemistry performed in cells derived from one of the patients showed reduced immunoreactivity of SCN4A as compared to control cells. The study provides supportive evidence for the role of SCN4A in the etiology of ET and expands the phenotypic spectrum of channelopathies to this neurological disorder.","variants":[{"Name":"NM_000334.4(SCN4A):c.4679C>T (p.Pro1560Leu)","Chromosome":"17","Start":"63941603","Stop":"63941603","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1290432,"rule_based_match":true,"evidence_text":"NM_000334.4:c.4679C>T; p.(Pro1560Leu)","llm_judgment":"PRESENT","evidence":"NM_000334.4:c.4679C>T; p.(Pro1560Leu)","abstract_start":647,"abstract_end":684}]}
{"pmid":"32392875","title":"Whole Exome Sequencing with Comprehensive Gene Set Analysis Identified a Biparental-Origin Homozygous c.509G>A Mutation in","abstract":"Skeletal dysplasia (SD) is a complex group of bone and cartilage disorders often detectable by fetal ultrasound, but the definitive diagnosis remains challenging because the phenotypes are highly variable and often overlap among different disorders. The molecular mechanisms underlying this condition are also diverse. Hundreds of genes are involved in the pathogenesis of SD, but most of them are yet to be elucidated, rendering genotyping almost infeasible except those most common such as fibroblast growth factor receptor 3 (<i>FGFR3</i>), collagen type I alpha 1 chain (<i>COL1A1</i>), collagen type I alpha 2 chain (<i>COL1A2</i>), diastrophic dysplasia sulfate transporter (<i>DTDST</i>), and SRY-box 9 (<i>SOX9</i>). Here, we report the use of trio-based whole exome sequencing (trio-WES) with comprehensive gene set analysis in two Taiwanese non-consanguineous families with fetal SD at autopsy. A biparental-origin homozygous c.509G>A(p.G170D) mutation in peptidylprolyl isomerase B (<i>PPIB</i>) gene was identified. The results support a diagnosis of a rare form of autosomal recessive SD, osteogenesis imperfecta type IX (OI IX), and confirm that the use of a trio-WES study is helpful to uncover a genetic explanation for observed fetal anomalies (e.g., SD), especially in cases suggesting autosomal recessive inheritance. Moreover, the finding of an identical <i>PPIB</i> mutation in two non-consanguineous families highlights the possibility of the founder effect, which deserves future investigations in the Taiwanese population.","variants":[{"Name":"NM_000942.5(PPIB):c.509G>A (p.Gly170Asp)","Chromosome":"15","Start":"64156744","Stop":"64156744","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1402946,"rule_based_match":true,"evidence_text":"c.509G>A(p.G170D)","llm_judgment":"PRESENT","evidence":"c.509G>A(p.G170D)","abstract_start":936,"abstract_end":953}]}
{"pmid":"36571463","title":"OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis.","abstract":"PURPOSE: Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.\nMETHODS: Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.\nRESULTS: Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ<sup>2</sup> = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca<sup>2+</sup> uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca<sup>2+</sup> uptake, demonstrating loss of function.\nCONCLUSION: Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.","variants":[{"Name":"NM_001346194.2(OXGR1):c.371T>G (p.Leu124Arg)","Chromosome":"13","Start":"96987389","Stop":"96987389","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2534356,"rule_based_match":true,"evidence_text":"c.371T>G, p.L124R","llm_judgment":"PRESENT","evidence":"c.371T>G, p.L124R","abstract_start":691,"abstract_end":708}]}
{"pmid":"36758444","title":"Broadening the phenotypic spectrum of the presumably epilepsy-related SV2A gene variants.","abstract":"Missense variants in the synaptic vesicle glycoprotein SV2A gene have been previously found in a few individuals with epilepsy. Adverse reaction to levetiracetam in individuals with various variants of this gene has recently been described. Here, we report on a family with several members affected by epilepsy. In affected members of this family, we identified a variant in the SV2A gene (NM_014849.5: c.1978 G>A, p.(Gly660Arg). This family case further supports the role of the SV2A gene in autosomal dominant epilepsy. It provides new information on the course of epilepsy in people with variants in the SV2A gene who have never been treated with SV2A agonists and specific neurodevelopmental features of this syndrome.","variants":[{"Name":"NM_014849.5(SV2A):c.1978G>A (p.Gly660Arg)","Chromosome":"1","Start":"149905947","Stop":"149905947","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3481976,"rule_based_match":true,"evidence_text":"NM_014849.5: c.1978 G>A, p.(Gly660Arg)","llm_judgment":"PRESENT","evidence":"NM_014849.5: c.1978 G>A, p.(Gly660Arg)","abstract_start":390,"abstract_end":428}]}
{"pmid":"30804983","title":"","abstract":"Mitochondrial DNA depletion syndromes (MTDPS) are a group of rare genetic disorders caused by defects in multiple genes involved in mitochondrial DNA (mtDNA) maintenance. Among those, <i>FBXL4</i> mutations result in the encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13; OMIM #615471), which commonly presents as a combination of failure to thrive, neurodevelopmental delays, encephalopathy, hypotonia, and persistent lactic acidosis. We report here the case of a Lebanese infant presenting to us with profound neurodevelopmental delays, generalized hypotonia, facial dysmorphic features, and extreme emaciation. Whole-exome sequencing (WES) showed the girl as having MTDPS13 with an underlying <i>FBXL4</i> missense mutation that has been previously reported only twice in unrelated individuals (c.1303C > T). Comprehensive literature search marked our patient as being the 94th case of MTDPS13 reported to date worldwide, and the first from Lebanon. We include at the end of this report a comprehensive mutation review table of all the pathological <i>FBXL4</i> mutations reported in the literature, using it to highlight, for the first time, a possible founder effect of Arab origins to the disorder, being most prevalent in patients of Arab descent as shown in our mutation table. Finally, we provide a direct comparison of the disorder's clinical manifestations across two unrelated patients harboring the same disease-causing mutation as our patient, emphasizing the remarkable variability in genotype-to-phenotype correlation characteristic of the disease.","variants":[{"Name":"NM_001278716.2(FBXL4):c.1303C>T (p.Arg435Ter)","Chromosome":"6","Start":"98899282","Stop":"98899282","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76993,"rule_based_match":true,"evidence_text":"c.1303C > T","llm_judgment":"PRESENT","evidence":"c.1303C > T","abstract_start":804,"abstract_end":815}]}
{"pmid":"31403263","title":"Longitudinal MRI findings in patient with SLC25A12 pathogenic variants inform disease progression and classification.","abstract":"Aspartate-glutamate carrier 1 (AGC1) is one of two exchangers within the malate-aspartate shuttle. AGC1 is encoded by the SLC25A12 gene. Three patients with pathogenic variants in SLC25A12 have been reported in the literature. These patients were clinically characterized by neurodevelopmental delay, epilepsy, hypotonia, cerebral atrophy, and hypomyelination; however, there has been discussion in the literature as to whether this hypomyelination is primary or secondary to a neuronal defect. Here we report a 12-year-old patient with variants in SLC25A12 and magnetic resonance imaging (MRI) at multiple ages. Novel compound heterozygous, recessive variants in SLC25A12 were identified: c.1295C>T (p.A432V) and c.1447-2_1447-1delAG. Clinical presentation is characterized by severe intellectual disability, nonambulatory, nonverbal status, hypotonia, epilepsy, spastic quadriplegia, and a happy disposition. The serial neuroimaging findings are notable for cerebral atrophy with white matter involvement, namely, early hypomyelination yet subsequent progression of myelination. The longitudinal MRI findings are most consistent with a leukodystrophy of the leuko-axonopathy category, that is, white matter abnormalities that are most suggestive of mechanisms that result from primary neuronal defects. We present here the first case of a patient with compound heterozygous variants in SLC25A12, including brain MRI findings, in the oldest individual reported to date with this neurogenetic condition.","variants":[{"Name":"NM_003705.5(SLC25A12):c.1295C>T (p.Ala432Val)","Chromosome":"2","Start":"171809616","Stop":"171809616","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1720819,"rule_based_match":true,"evidence_text":"c.1295C>T (p.A432V)","llm_judgment":"PRESENT","evidence":"c.1295C>T (p.A432V)","abstract_start":690,"abstract_end":709},{"Name":"NM_003705.5(SLC25A12):c.1447-2_1447-1del","Chromosome":"2","Start":"171791590","Stop":"171791591","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":1720820,"rule_based_match":true,"evidence_text":"c.1447-2_1447-1delAG","llm_judgment":"PRESENT","evidence":"c.1447-2_1447-1delAG","abstract_start":714,"abstract_end":734}]}
{"pmid":"24385578","title":"Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia.","abstract":"BACKGROUND: Congenital diaphragmatic hernia (CDH) is a common birth defect affecting 1 in 3000 births. It is characterised by herniation of abdominal viscera through an incompletely formed diaphragm. Although chromosomal anomalies and mutations in several genes have been implicated, the cause for most patients is unknown.\nMETHODS: We used whole exome sequencing in two families with CDH and congenital heart disease, and identified mutations in GATA6 in both.\nRESULTS: In the first family, we identified a de novo missense mutation (c.1366C>T, p.R456C) in a sporadic CDH patient with tetralogy of Fallot. In the second, a nonsense mutation (c.712G>T, p.G238*) was identified in two siblings with CDH and a large ventricular septal defect. The G238* mutation was inherited from their mother, who was clinically affected with congenital absence of the pericardium, patent ductus arteriosus and intestinal malrotation. Deep sequencing of blood and saliva-derived DNA from the mother suggested somatic mosaicism as an explanation for her milder phenotype, with only approximately 15% mutant alleles. To determine the frequency of GATA6 mutations in CDH, we sequenced the gene in 378 patients with CDH. We identified one additional de novo mutation (c.1071delG, p.V358Cfs34*).\nCONCLUSIONS: Mutations in GATA6 have been previously associated with pancreatic agenesis and congenital heart disease. We conclude that, in addition to the heart and the pancreas, GATA6 is involved in development of two additional organs, the diaphragm and the pericardium. In addition, we have shown that de novo mutations can contribute to the development of CDH, a common birth defect.","variants":[{"Name":"NM_005257.6(GATA6):c.1366C>T (p.Arg456Cys)","Chromosome":"18","Start":"22181516","Stop":"22181516","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39169,"rule_based_match":true,"evidence_text":"c.1366C>T, p.R456C","llm_judgment":"PRESENT","evidence":"c.1366C>T, p.R456C","abstract_start":535,"abstract_end":553},{"Name":"NM_005257.6(GATA6):c.712G>T (p.Gly238Ter)","Chromosome":"18","Start":"22171856","Stop":"22171856","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":165814,"rule_based_match":true,"evidence_text":"c.712G>T (p.G238*)","llm_judgment":"PRESENT","evidence":"c.712G>T","abstract_start":643,"abstract_end":651}]}
{"pmid":"35150090","title":"Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant.","abstract":"BACKGROUND: The genetic architecture of hearing impairment in Finland is largely unknown. Here, we investigated two Finnish families with autosomal recessive nonsyndromic symmetrical moderate-to-severe hearing impairment.\nMETHODS: Exome and custom capture next-generation sequencing were used to detect the underlying cause of hearing impairment.\nRESULTS: In both Finnish families, we identified a homozygous pathogenic splice site variant c.637+1G>T in CAPB2 that is known to cause autosomal recessive nonsyndromic hearing impairment. Four CABP2 variants have been reported to underlie autosomal recessive nonsyndromic hearing impairment in eight families from Iran, Turkey, Pakistan, Italy, and Denmark. Of these variants, the pathogenic splice site variant c.637+1G>T is the most prevalent. The c.637+1G>T variant is enriched in the Finnish population, which has undergone multiple bottlenecks that can lead to the higher frequency of certain variants including those involved in disease.\nCONCLUSION: We report two Finnish families with hearing impairment due to the CABP2 splice site variant c.637+1G>T.","variants":[{"Name":"NM_016366.3(CABP2):c.637+1G>T","Chromosome":"11","Start":"67519792","Stop":"67519792","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":588259,"rule_based_match":true,"evidence_text":"c.637+1G>T","llm_judgment":"PRESENT","evidence":"c.637+1G>T","abstract_start":440,"abstract_end":450}]}
{"pmid":"11297621","title":"Somatic mutation and germline variants of MINPP1, a phosphatase gene located in proximity to PTEN on 10q23.3, in follicular thyroid carcinomas.","abstract":"Various genes have been identified to play a role in the pathogenesis of follicular thyroid tumors. Cowden syndrome is the only known familial syndrome with an increased risk of both follicular thyroid adenoma (FA) and carcinoma (FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to 10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of markers within 10q22-24 occurs in about 25%. Recently, another phosphatase gene, MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove 3-phosphate from inositol phosphate substrates, a function that overlaps that of PTEN. Because of this overlapping function with PTEN and the physical location of MINPP1 to a region with frequent LOH in follicular thyroid tumors, we considered it to be an excellent candidate gene that could contribute to the pathogenesis of follicular thyroid tumors. We analyzed DNA from tumor and corresponding normal tissue from 23 patients with FA and 15 patients with FTC for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant and three benign tumors. One of these FTCs with LOH was found to harbor a somatic c.122C > T or S41L mutation. We also found two germline sequence variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was found in only one patient with FA but not in patients with FTC or normal controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases and normal controls but not in patients with FTC. These results suggest a role for MINPP1 in the pathogenesis of at least a subset of malignant follicular thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele for FTC.","variants":[{"Name":"NM_004897.5(MINPP1):c.122C>T (p.Ser41Leu)","Chromosome":"10","Start":"87505037","Stop":"87505037","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20060,"rule_based_match":true,"evidence_text":"c.122C > T","llm_judgment":"PRESENT","evidence":"c.122C > T","abstract_start":1392,"abstract_end":1402}]}
{"pmid":"35839600","title":"Missense variant c.1460 T > C (p.L487P) enhances protein degradation of ER mannosyltransferase ALG9 in two new ALG9-CDG patients presenting with West syndrome and review of the literature.","abstract":"ALG9-CDG is a CDG-I defect within the group of Congenital Disorders of Glycosylation (CDG). We here describe the clinical symptoms of two new and unrelated ALG9-CDG patients, both carrying the novel homozygous missense variant c.1460 T > C (p.L487P) in the ALG9 gene which led to global developmental delay, psychomotor disability, facial dysmorphisms, brain and heart defects, hearing loss, hypotonia, as well as feeding problems. New clinical symptoms comprised West syndrome with hypsarrhythmia. Quantitative RT-PCR analysis revealed a significantly enhanced ALG9 mRNA transcript level, whereas the protein amount in fibroblasts was significantly reduced. This could be ascribed to a stronger degradation of the mutated ALG9 protein in patient fibroblasts. Lipid-linked oligosaccharide analysis showed an ALG9-CDG characteristic accumulation of Man<sub>6</sub>GlcNAc<sub>2</sub>-PP-dolichol and Man<sub>8</sub>GlcNAc<sub>2</sub>-PP-dolichol in patient cells. The clinical findings of our patients and of all previously published ALG9-CDG patients are brought together to further expand the knowledge about this rare N-glycosylation disorder. SYNOPSIS: Homozygosity for p.L487P in ALG9 causes protein degradation and leads to West syndrome.","variants":[{"Name":"NM_024740.2(ALG9):c.1460T>C (p.Leu487Pro)","Chromosome":"11","Start":"111837480","Stop":"111837480","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1691079,"rule_based_match":true,"evidence_text":"c.1460 T > C (p.L487P)","llm_judgment":"PRESENT","evidence":"c.1460 T > C (p.L487P)","abstract_start":227,"abstract_end":249}]}
{"pmid":"27052445","title":"Association between SCO2 mutation and extreme myopia in Japanese patients.","abstract":"PURPOSE: To investigate the role of SCO2 in extreme myopia of Japanese patients.\nMETHODS: In total, 101 Japanese patients with extreme myopia (axial length of ≥30 mm) OU at the Kyoto University Hospital were included in this study. Exon 2 of SCO2 was sequenced by conventional Sanger sequencing. The detected variants were assessed using in silico prediction programs: SIFT, PolyPhen-2 and MutationTaster. To determine the frequency of the mutations in normal subjects, we referred to the 1000 Genomes Project data and the Human Genetic Variation Database (HGVD) in the Human Genetic Variation Browser.\nRESULTS: The average age of the participants was 62.9 ± 12.7 years. There were 31 males (30.7 %) and 70 females. Axial lengths were 31.76 ± 1.17 mm OD and 31.40 ± 1.07 mm OS, and 176 eyes (87.6 %) out of 201 eyes had myopic maculopathy of grade 2 or more. Among the 101 extremely myopic patients, one mutation (c.290 C > T;p.Ala97Val) in SCO2 was detected. This mutation was not found in the 1000 Genomes Project data or HGVD data. Variant type of the mutation was nonsynonymous. Although the SIFT prediction score was 0.350, the PolyPhen-2 probability was 0.846, thus predicting its pathogenicity to be possibly damaging. MutationTaster PhyloP was 1.268, suggesting that the mutation is conserved.\nCONCLUSIONS: We identified one novel possibility of an extreme myopia-causing mutation in SCO2. No other disease-causing mutation was found in 101 extremely myopic Japanese patients, suggesting that SCO2 plays a limited role in Japanese extreme myopia. Further investigation is required for better understanding of extreme myopia.","variants":[{"Name":"NM_005138.3(SCO2):c.290C>T (p.Ala97Val)","Chromosome":"22","Start":"50524122","Stop":"50524122","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1452408,"rule_based_match":true,"evidence_text":"c.290 C > T;p.Ala97Val","llm_judgment":"PRESENT","evidence":"c.290 C > T;p.Ala97Val","abstract_start":914,"abstract_end":936}]}
{"pmid":"29769798","title":"Novel variants identified with next-generation sequencing in Polish patients with cone-rod dystrophy.","abstract":"Purpose: The aim of this study was to identify the molecular genetic basis of cone-rod dystrophy in 18 unrelated families of Polish origin. Cone-rod dystrophy is one of the inherited retinal dystrophies, which constitute a highly heterogeneous group of disorders characterized by progressive dysfunction of photoreceptors and retinal pigment epithelium (RPE) cells.\nMethods: The study group was composed of four groups of patients representing different Mendelian inheritance of the disease: autosomal dominant (AD), autosomal recessive (AR), X-linked recessive (XL), and autosomal recessive or X-linked recessive (AR/XL). The combined molecular strategy included Sanger sequencing of the <i>RPGR-ORF15</i> gene (three families with XL and three families with the AR/XL mode of inheritance), mutation-specific microarray analysis of the <i>ABCA4</i> gene (five families with the AR mode of inheritance and two families with the AR/XL mode of inheritance), targeted next-generation sequencing (NGS) of inherited retinal disease-associated (IRD) genes (seven families with the AD mode of inheritance and five families with the AR mode of inheritance), and whole exome sequencing, performed in select families who had been mutation-negative in the analysis with the targeted NGS panel (one family with the AD mode of inheritance, one family with the AR mode of inheritance, and two families with the AR/XL mode of inheritance).\nResults: Based on this combined strategy, we managed to identify potentially causative variants in seven out of 18 families with CRD. Five of these variants are novel: c.3142_3143dupAA, p.(Glu1049Argfs*41) in the <i>RPGR-ORF15</i> gene, two variants: c.1612delT, p.(Trp538Glyfs*15) and c.2389dupG, p.(Ile798Hisfs*20) in the <i>PROM1</i> gene in one family, c.592A>C, p.(Ser198Arg) in the <i>PRPH2</i> gene and the variant c.1691A>G, p.(Asp564Gly) in the <i>ATF6</i> gene that we have already reported to be pathogenic. NGS on the IRD panel allowed the molecular basis of CRD to be identified in four out of 14 families with a total detection rate of 38%. WES allowed identification of the molecular genetic basis of CRD in one family.\nConclusions: This is the first report on the spectrum of disease genes and pathogenic variants causing CRD in the Polish population. The study presents five novel variants identified in four genes and therefore, broadens the spectrum of probable pathogenic variants associated with CRD.","variants":[{"Name":"NM_006017.3(PROM1):c.1612del (p.Trp538fs)","Chromosome":"4","Start":"15998455","Stop":"15998455","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":3407993,"rule_based_match":true,"evidence_text":"c.1612delT, p.(Trp538Glyfs*15)","llm_judgment":"PRESENT","evidence":"c.1612delT, p.(Trp538Glyfs*15)","abstract_start":1676,"abstract_end":1706},{"Name":"NM_000322.5(PRPH2):c.592A>C (p.Ser198Arg)","Chromosome":"6","Start":"42704601","Stop":"42704601","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1164697,"rule_based_match":true,"evidence_text":"c.592A>C, p.(Ser198Arg)","llm_judgment":"PRESENT","evidence":"c.592A>C, p.(Ser198Arg)","abstract_start":1782,"abstract_end":1805}]}
{"pmid":"17719863","title":"Delayed transport of tissue-nonspecific alkaline phosphatase with missense mutations causing hypophosphatasia.","abstract":"Hypophosphatasia is a rare genetic disease characterized by diminished bone and tooth mineralization due to deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). The disease is clinically heterogeneous due to different mutations in the TNSALP gene. In order to determine whether mutated TNSALP proteins may be sequestered, degraded, or subjected to delay in their transport to the cell membrane, we built a plasmid expressing a YFP-TNSALP fluorescent fusion protein allowing the observation of cellular localization in live cells by fluorescence confocal microscopy at different time points after transfection. We studied five mutants (c. 571G>A, c. 653T>C, c. 746G>T, c. 1363G>A and c. 1468A>T) exhibiting various levels of in vitro residual enzymatic activity. While the wild-type protein reached the membrane within the first 24h after transfection, the mutants reached the membrane with delays of 24, 48 or 72 h. For all of the tested mutations, accumulation of the mutated proteins, mainly in the Golgi apparatus, was observed. We concluded that reduced ALP activity of these TNSALP mutants results from structural disturbances and delay in membrane anchoring, and not from compromised catalytic activity.","variants":[{"Name":"NM_000478.6(ALPL):c.571G>A (p.Glu191Lys)","Chromosome":"1","Start":"21564139","Stop":"21564139","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28709,"rule_based_match":true,"evidence_text":"c. 571G>A","llm_judgment":"PRESENT","evidence":"c. 571G>A","abstract_start":654,"abstract_end":663},{"Name":"NM_000478.6(ALPL):c.653T>C (p.Ile218Thr)","Chromosome":"1","Start":"21568108","Stop":"21568108","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3849990,"rule_based_match":true,"evidence_text":"c. 653T>C","llm_judgment":"PRESENT","evidence":"c. 653T>C","abstract_start":665,"abstract_end":674},{"Name":"NM_000478.6(ALPL):c.1363G>A (p.Gly455Ser)","Chromosome":"1","Start":"21577436","Stop":"21577436","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":357070,"rule_based_match":true,"evidence_text":"c. 1363G>A","llm_judgment":"PRESENT","evidence":"c. 1363G>A","abstract_start":687,"abstract_end":697},{"Name":"NM_000478.6(ALPL):c.1468A>T (p.Ile490Phe)","Chromosome":"1","Start":"21577541","Stop":"21577541","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2898190,"rule_based_match":true,"evidence_text":"c. 1468A>T","llm_judgment":"PRESENT","evidence":"c. 1468A>T","abstract_start":702,"abstract_end":712}]}
{"pmid":"22209761","title":"Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression.","abstract":"BACKGROUND: Paroxysmal dyskinesias (PDs), a clinically and genetically heterogeneous group of episodic movement disorders, include kinesigenic PD (PKD), exercise-induced PD (PED) and non-kinesigenic PD (PNKD). These disorders are all transmitted as autosomal dominant traits with incomplete penetrance. Several PD-related genetic disorders, including PKD and familial infantile convulsions with paroxysmal choreoathetosis (ICCA), mapped to the same region on chromosome 16. Independent genetic studies have recently revealed that PKD can be caused by loss-of-function mutations in the proline-rich transmembrane protein 2 gene (PRRT2). We tested the hypothesis that other forms of PDs are also due to PRRT2 mutations.\nMETHODS/RESULTS: The whole genomic region of PRRT2 was sequenced in six Han Chinese families and 15 sporadic cases of PD-related phenotypes. The previously reported mutation, c.649dupC (p.R217Pfs*7), was found in two families with PKD, one family with ICCA, one family with PNKD-like phenotype, and two sporadic cases with PED. In an additional ICCA family, a novel frameshift mutation, c.904dupG (p.D302Gfs*38), was identified. A missense mutation, c.913G→A (p.G305R), and a synonymous substitution, c.1011C→T (p.G337G), were also detected in two sporadic PKD cases.\nCONCLUSION: This study shows that PKD, ICCA and some other PD-related phenotypes are part of the same phenotypic spectrum, caused by mutations in PRRT2. This underscores the complexity of the phenotypic consequences of PRRT2 mutations.","variants":[{"Name":"NM_145239.3(PRRT2):c.1011C>T (p.Gly337=)","Chromosome":"16","Start":"29814464","Stop":"29814464","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360388,"rule_based_match":false,"evidence_text":"c.1011C→T (p.G337G)","llm_judgment":"PRESENT","evidence":"c.1011C→T (p.G337G)","abstract_start":1219,"abstract_end":1238},{"Name":"NM_145239.3(PRRT2):c.913G>A (p.Gly305Arg)","Chromosome":"16","Start":"29814366","Stop":"29814366","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":491156,"rule_based_match":false,"evidence_text":"c.913G→A (p.G305R)","llm_judgment":"PRESENT","evidence":"c.913G→A (p.G305R)","abstract_start":1168,"abstract_end":1186},{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC (p.R217Pfs*7)","llm_judgment":"PRESENT","evidence":"c.649dupC (p.R217Pfs*7)","abstract_start":893,"abstract_end":916}]}
{"pmid":"12971424","title":"CblE type of homocystinuria: mild clinical phenotype in two patients homozygous for a novel mutation in the MTRR gene.","abstract":"Patients with the cblE type of homocystinuria usually present with megaloblastic anaemia, feeding difficulties, developmental delay and cerebral atrophy. We present a 14-year-old Spanish girl (patient 1) and a 10-year-old Portuguese boy (patient 2) with cblE disease and mild clinical phenotype. The main clinical feature in both patients was persistent megaloblastic anaemia observed at 3 years and at 2 months of age, respectively. Diagnosis was made at the ages of 9 and 7 years, respectively, owing to persistent macrocytosis despite cobalamin treatment. Plasma total homocysteine values at diagnosis were 91 micromol/L and 44 micromol/L, respectively, in the absence of methylmalonic aciduria. Neurological and neurophysiological examinations were normal except for two small lesions on brain MRI suggestive of ischaemia and slight abnormalities in somatosensitive evoked potentials. Enzymatic analysis, complementation studies and clearly reduced production of methylcobalamin from 57Co-labelled cyanocobalamin indicated functional methionine synthase reductase deficiency due to the cblE defect. Genetic analysis confirmed that both patients are homozygous for a novel mutation c.1361C>T in the methionine synthase reductase gene leading to a replacement of serine by leucine (S454L) in a highly conserved FAD-binding domain. We propose that homozygosity for this novel mutation may be associated with a mild phenotype, although its long-term deleterious neurological consequences remain possible. Furthermore, we propose that even in the absence of apparent neurological involvement, total homocysteine should be investigated in patients with resistant megaloblastic anaemia to detect possible mild forms of the cblE type of homocystinuria.","variants":[{"Name":"NM_002454.3(MTRR):c.1361C>T (p.Ser454Leu)","Chromosome":"5","Start":"7891405","Stop":"7891405","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22072,"rule_based_match":true,"evidence_text":"c.1361C>T","llm_judgment":"PRESENT","evidence":"c.1361C>T","abstract_start":1185,"abstract_end":1194}]}
{"pmid":"34392356","title":"Whole-exome sequencing of consanguineous families with infertile men and women identifies homologous mutations in SPATA22 and MEIOB.","abstract":"STUDY QUESTION: Can whole-exome sequencing (WES) reveal pathogenic mutations in two consanguineous Pakistani families with infertile patients?\nSUMMARY ANSWER: A homozygous spermatogenesis associated 22 (SPATA22) frameshift mutation (c.203del), which disrupts the interaction with meiosis specific with OB-fold (MEIOB), and a MEIOB splicing mutation (c.683-1G>A) that led to loss of MEIOB protein cause familial infertility.\nWHAT IS KNOWN ALREADY: MEIOB and SPATA22, direct binding partners and functional collaborators, form a meiosis-specific heterodimer that regulates meiotic recombination. The protein stability and the axial localization of MEIOB and SPATA22 depend on each other. Meiob and Spata22 knockout mice have the same phenotypes: mutant spermatocytes can initiate meiotic recombination but are unable to complete DSB repair, leading to crossover formation failure, meiotic prophase arrest, and sterility.\nSTUDY DESIGN, SIZE, DURATION: We performed WES for the patients and controls in two consanguineous Pakistani families to screen for mutations. The pathogenicity of the identified mutations was assessed by in vitro assay and mutant mouse model.\nPARTICIPANTS/MATERIALS, SETTING, METHODS: Two consanguineous Pakistani families with four patients (three men and one woman) suffering from primary infertility were recruited. SPATA22 and MEIOB mutations were screened from the WES data, followed by functional verification in cultured cells and mice.\nMAIN RESULTS AND THE ROLE OF CHANCE: A homozygous SPATA22 frameshift mutation (c.203del) was identified in a patient with non-obstructive azoospermia (NOA) from a consanguineous Pakistani family and a homozygous MEIOB splicing mutation (c.683-1G>A) was identified in two patients with NOA and one infertile woman from another consanguineous Pakistani family. The SPATA22 mutation destroyed the interaction with MEIOB. The MEIOB splicing mutation induced Exon 9 skipping, which causes a 32aa deletion in the oligonucleotide-binding domain without affecting the interaction between MEIOB and SPATA22. Furthermore, analyses of the Meiob mutant mice modelling the patients' mutation revealed that the MEIOB splicing mutation leads to loss of MEIOB proteins, abolished SPATA22 recruitment on chromosome axes, and meiotic arrest due to meiotic recombination failure. Thus, our study suggests that SPATA22 and MEIOB may both be causative genes for human infertility.\nLIMITATIONS, REASONS FOR CAUTION: As SPATA22 and MEIOB are interdependent and essential for meiotic recombination, screening for mutations of SPATA22 and MEIOB in both infertile men and women in larger cohorts is important to further reveal the role of the SPATA22 and MEIOB heterodimer in human fertility.\nWIDER IMPLICATIONS OF THE FINDINGS: These findings provide direct clinical and functional evidence that mutations in SPATA22 and MEIOB can cause meiotic recombination failure, supporting a role for these mutations in human infertility and their potential use as targets for genetic diagnosis of human infertility.\nSTUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research and Developmental Program of China (2018YFC1003900, 2018YFC1003700, and 2019YFA0802600), the National Natural Science Foundation of China (31890780, 31630050, 32061143006, 82071709, and 31871514), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000). The authors declare no conflicts of interest.\nTRIAL REGISTRATION NUMBER: N/A.","variants":[{"Name":"NM_001163560.3(MEIOB):c.683-1G>A","Chromosome":"16","Start":"1853135","Stop":"1853135","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2852802,"rule_based_match":true,"evidence_text":"c.683-1G>A","llm_judgment":"PRESENT","evidence":"c.683-1G>A","abstract_start":350,"abstract_end":360}]}
{"pmid":"28779003","title":"Novel idiopathic DCM-related","abstract":"BACKGROUND: Variants of <i>SCN5A</i>, encoding cardiac sodium channel, have been linked to the development of dilated cardiomyopathy (DCM). We aimed to explore novel <i>SCN5A</i> variants in patients with idiopathic DCM (iDCM) and to identify the distribute characteristics and pathological mechanisms as well as clinical phenotypes associated with the variants in patients with iDCM.\nMETHODS: <i>SCN5A</i> exons sequencing was performed inpatients with iDCM (n=90) and two control cohorts (arrhythmias group, n=90, and healthy group, n=195). Clinical characteristics were compared between carriers and non-carriers. We then generated a novel heterozygous knock-in (KI) mouse by homologous recombination. Cardiac function, electrical parameters and histological characteristics were examined at basal or stimulating condition.\nRESULTS: We found three novel non-synonymous <i>SCN5A</i> variants associated with iDCM, including c.674G>A, c.677C>T, and c.4340T>A. The newly defined iDCM-related variants mainly located in the S4 segment of domain I (DI-S4). Incidence of atrioventricular block was significantly higher in mutant patients with iDCM than in non-carriers. Structural injuries were absent at both basal and stress condition in KI mice carrying c.674G>A (R225Q); however, this variant significantly prolonged PR intervals at baseline without affecting other ECG parameters, which was linked to decreased peak sodium current density in KI cardiomyocytes. Histological analysis of the atrioventricular node did not show any evidences of cell damages.\nCONCLUSION: Our results suggest that the iDCM-related <i>SCN5A</i> variants in the DI-S4 could predispose electrical disorders by reducing peak sodium current density.","variants":[{"Name":"NM_000335.5(SCN5A):c.674G>A (p.Arg225Gln)","Chromosome":"3","Start":"38613772","Stop":"38613772","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":78925,"rule_based_match":true,"evidence_text":"c.674G>A","llm_judgment":"PRESENT","evidence":"c.674G>A","abstract_start":926,"abstract_end":934}]}
{"pmid":"22738334","title":"The αIIb p.Leu841Met (Cab3(a+) ) polymorphism results in a new human platelet alloantigen involved in neonatal alloimmune thrombocytopenia.","abstract":"BACKGROUND: Fetal-neonatal alloimmune thrombocytopenia (FNAIT) diagnosis relies on maternofetal incompatibility and alloantibody identification. Genotyping for rare platelet (PLT) polymorphisms allowed the identification of three families with suspected or confirmed maternofetal incompatibility for the αIIb-c.2614C>A mutation (Halle et al., Transfusion 2008;48:14-15).\nSTUDY DESIGN AND METHODS: A polymerase chain reaction-sequence-specific primers amplification assay was designed to genotype the αIIb-c.2614C>A mutation. HEK293 cells expressing αIIb-Leu841 or αIIb-Met841 αIIbβ3 forms were used to probe the reactivity of maternal sera from these families and to study the effects of the substitution on αIIbβ3 expression and functions.\nRESULTS: Tested by flow cytometry (FCM), one serum sample specifically reacted with αIIb-Met841 but not with αIIb-Leu841 αIIbβ3. This specificity revealed the αIIb-Leu841 polymorphism as a new alloantigen named Cab3(a+) . Cross-match testing using FCM also showed the Cab3(a+) antigen to be expressed at the PLT surface. As for anti-human PLT alloantigen (HPA)-3a (or -3b) and anti-HPA-9bw, detection of anti-Cab3(a+) alloantibodies appeared difficult and required whole PLT assays when classical monoclonal antibody-specific immobilization of PLT antigen test failed. In our FNAIT set, the immune response to Cab3(a+) maternofetal incompatibility could induce severe thrombocytopenias and life-threatening hemorrhages. The p.Leu841Met substitution has limited effects, if any, on local αIIb structure, preserving both αIIbβ3 expression and functions.\nCONCLUSION: The Cab3(a+) polymorphism is a new rare alloantigen (allelic frequency <1%) carried by αIIb that might result in severe life-threatening thrombocytopenias. In Sub-Saharan African populations, higher Cab3(a+) gene frequencies (up to 8.2%; Halle et al., Transfusion 2008;48:14-15) and homozygous people are observed.","variants":[{"Name":"NM_000419.5(ITGA2B):c.2614C>A (p.Leu872Met)","Chromosome":"17","Start":"44375704","Stop":"44375704","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":346140,"rule_based_match":true,"evidence_text":"αIIb-c.2614C>A","llm_judgment":"PRESENT","evidence":"αIIb-c.2614C>A","abstract_start":304,"abstract_end":318}]}
{"pmid":"16714133","title":"Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.","abstract":"Methylmalonic aciduria and homocystinuria, cblC type (MIM 277400), is the most frequent inborn error of vitamin B12 (cobalamin, Cbl) metabolism, caused by an inability of the cell to convert Cbl to both of its active forms (MeCbl, AdoCbl). Although considered a disease of infancy, some patients develop symptoms in childhood, adolescence, or adulthood. The gene responsible for cblC, MMACHC, was recently identified. We studied phenotype-genotype correlations in 37 patients from published case-reports, representing most of the landmark descriptions of this disease. 25/37 had early-onset disease, presenting in the first 6 months of life: 17/25 were found to be either homozygous for the c.271dupA mutation (n=9) or for the c.331C>T mutation (n=3), or compound heterozygotes for these 2 mutations (n=5). 9/12 late-onset cases presented with acute neurological symptoms: 4/9 were homozygous for the c.394C>T mutation, 2/9 were compound heterozygotes for the c.271dupA and c.394C>T mutations, and 3/9, for the c.271dupA mutation and a missense mutation. Several observations on ethnic origins were noted: the c.331C>T mutation is seen in Cajun and French-Canadian patients and the c.394C>T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. The recognition of phenotype-genotype correlations and the association of mutations with specific ethnicities will be useful for identification of disease-causing mutations in cblC patients, for carrier detection and prenatal diagnosis in families where mutations are known, and in setting up initial screening programs in molecular diagnostic laboratories. Further study into disease mechanism of specific mutations will help to understand phenotypic presentations and the overall pathogenesis in cblC patients.","variants":[{"Name":"NM_015506.3(MMACHC):c.271dup (p.Arg91fs)","Chromosome":"1","Start":"45507544","Stop":"45507545","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":16460,"rule_based_match":true,"evidence_text":"c.271dupA","llm_judgment":"PRESENT","evidence":"c.271dupA","abstract_start":691,"abstract_end":700},{"Name":"NM_015506.3(MMACHC):c.394C>T (p.Arg132Ter)","Chromosome":"1","Start":"45508329","Stop":"45508329","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16462,"rule_based_match":true,"evidence_text":"c.394C>T","llm_judgment":"PRESENT","evidence":"c.394C>T","abstract_start":901,"abstract_end":909},{"Name":"NM_015506.3(MMACHC):c.331C>T (p.Arg111Ter)","Chromosome":"1","Start":"45508266","Stop":"45508266","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16463,"rule_based_match":true,"evidence_text":"c.331C>T","llm_judgment":"PRESENT","evidence":"c.331C>T","abstract_start":727,"abstract_end":735}]}
{"pmid":"32591292","title":"The first Japanese cases of familial hypercholesterolemia due to a known pathogenic APOB gene variant, c.10580 G>A: p.(Arg3527Gln).","abstract":"BACKGROUND: We previously showed that patients without pathogenic variants in the LDLR and PCSK9 genes comprised approximately 40% of familial hypercholesterolemia (FH) cases.\nOBJECTIVE: Our aim was to identify novel causative variants in Japanese patients with FH.\nMETHODS: Whole-exome sequencing was performed in 216 family members from 123 families without pathogenic variants in the LDLR and PCSK9 genes. Clinical and biochemical data were gathered from the family members.\nRESULTS: The known p.(Arg3527Gln) variant in the APOB gene was identified in one Japanese family. The other pathogenic variants in the APOB gene were not identified. The p.(Arg3527Gln) variant was not identified in the other 113 index cases without pathogenic variants in the LDLR and PCSK9 genes. The allele frequency of the p.(Arg3527Gln) variant was 0.0001 in the general Japanese population.\nCONCLUSION: This is the first report of Japanese cases of FH caused by a known pathogenic APOB variant, p.(Arg3527Gln).","variants":[{"Name":"NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln)","Chromosome":"2","Start":"21006288","Stop":"21006288","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32929,"rule_based_match":true,"evidence_text":"c.10580 G>A: p.(Arg3527Gln)","llm_judgment":"PRESENT","evidence":"c.10580 G>A: p.(Arg3527Gln)","abstract_start":null,"abstract_end":null}]}
{"pmid":"36860576","title":"Novel compound heterozygous mutations of LAMA2-limb-girdle muscular dystrophy: A case report and literature review.","abstract":"The laminin α2 (LAMA2) gene pathogenic variants can lead to limb-girdle muscular dystrophy (known as LGMDR23), which is rarely reported and characterized by proximal weakness in the limbs. We present the case of a 52-year-old woman who gradually developed weakness in both lower extremities since the age of 32 years. Magnetic resonance imaging (MRI) brain showed symmetrical sphenoid wings-like white matter demyelination in bilateral lateral ventricles. Electromyography showed quadriceps muscle damage on the bilateral lower extremity. Next-generation sequencing (NGS) found two loci variations in the LAMA2 gene, i.e., c.2749 + 2dup and c.8689C>T. This case highlights the importance of considering LGMDR23 in patients presenting with weakness and white matter demyelination on MRI brain and further expands the gene variants spectrum of LGMDR23.","variants":[{"Name":"NM_000426.4(LAMA2):c.2749+2dup","Chromosome":"6","Start":"129288059","Stop":"129288060","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":543814,"rule_based_match":true,"evidence_text":"c.2749 + 2dup","llm_judgment":"PRESENT","evidence":"c.2749 + 2dup","abstract_start":623,"abstract_end":636}]}
{"pmid":"24684036","title":"X-linked hypophosphatemic rickets: case report.","abstract":"INTRODUCTION: X-linked hypophosphatemic rickets (XLHR) is a dominant inherited disease caused by isolated renal phosphate wasting and impairment of vitamin D activation. We present a girl with X-linked hypophosphatemic rickets (XLHR) as a consequence of de novo mutation in the PHEX gene.\nCASE OUTLINE: A 2.2-year-old girl presented with prominent lower limb rachitic deformity, waddling gait and disproportionate short stature (79 cm, < P5; -1,85 SD). On the basis of hypophosphatemia, hyperphosphaturia, high serum level of alkaline phosphatase, normal calcemia, 25(OH)D and PTH, as well as characteristic clinical and X-ray findings, diagnosis of hypophosphatemic rickets (HR) was made. Normal calciuria and absence of other renal tubular disorders indicated HR as a consequence of isolated hyperphosphaturia. The treatment (phosphate 55 mg/kg and calcitriol 35 ng/kg per day), introduced 15 month ago, resulted in a stable normalization of alkaline phosphatase and phosphorus serum levels (with intact calcemia and calciuria), disappearance of X-ray signs of the active rickets and improvement of the child's longitudinal growth (0.6 cm per month). Subsequently, by detection of already known mutation in the PHEX gene: c.1735G>A (p.G579R) (exon 17), XLHR was diagnosed. Analysis of the parental PHEX gene did not show the abnormality, which indicated that the child's XLHR was caused by de novo mutation of this gene.\nCONCLUSION: Identification of genetic defects is exceptionally significant for diagnosis and differential diagnosis of hereditary HR.","variants":[{"Name":"NM_000444.6(PHEX):c.1735G>A (p.Gly579Arg)","Chromosome":"X","Start":"22219070","Stop":"22219070","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227925,"rule_based_match":true,"evidence_text":"c.1735G>A (p.G579R)","llm_judgment":"PRESENT","evidence":"c.1735G>A (p.G579R)","abstract_start":1224,"abstract_end":1243}]}
{"pmid":"19586842","title":"The genotype-phenotype correlation of the MYH7 gene c.1273G > a mutation in familial hypertrophic cardiomyopathy","abstract":"To investigate the genotype-phenotype correlation in Chinese familial hypertrophic cardiomyopathy (HCM), peripheral blood samples were collected from 7 members of a Chinese HCM family, and 120 normal subjects were recruited as control. The full encoding exons and flanking sequences of the cardiac troponin T (TNNT2) gene, beta-myosin heavy chain (MYH7) gene and myosin binding protein C (MYBPC3) gene were amplified and the products were sequenced directly to detect the mutations. A missense mutation, c.1273G>A, was identified in exon 14 of the MYH7 gene in 4 members of the Chinese HCM family, which resulted a glycine (Gly) to arginine (Arg) exchange at amino acid residue 425. The 425th glycine amino acid residue is highly conservative across the different species. The clinical phenotypes among the family members who carried this mutation presented significant individual differences. The c.1273G>A mutation of the MYH7 gene might be the causal mutation of the familial HCM. The heterogeneity of phenotypes suggested that multiple factors may be involved in the pathogenesis of HCM.","variants":[{"Name":"NM_000257.4(MYH7):c.1273G>A (p.Gly425Arg)","Chromosome":"14","Start":"23429089","Stop":"23429089","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":52004,"rule_based_match":true,"evidence_text":"c.1273G>A","llm_judgment":"PRESENT","evidence":"c.1273G>A","abstract_start":504,"abstract_end":513}]}
{"pmid":"26376857","title":"Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria.","abstract":"A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.","variants":[{"Name":"NM_003041.4(SLC5A2):c.265G>A (p.Ala89Thr)","Chromosome":"16","Start":"31484885","Stop":"31484885","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247547,"rule_based_match":true,"evidence_text":"c.265G>A (p.A89T)","llm_judgment":"PRESENT","evidence":"c.265G>A","abstract_start":993,"abstract_end":1001}]}
{"pmid":"23401503","title":"Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup.","abstract":"Mutations of both nuclear and mitochondrial DNA (mtDNA)-encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.523delC, p.Q175RfsX38), which codes for the heart-muscle isoform of the adenine nucleotide translocator-1. Ten homozygous null (adenine nucleotide translocator-1(-/-)) patients monitored over a median of 6 years had a phenotype of progressive myocardial thickening, hyperalaninemia, lactic acidosis, exercise intolerance, and persistent adrenergic activation. Electrocardiography and echocardiography with velocity vector imaging revealed abnormal contractile mechanics, myocardial repolarization abnormalities, and impaired left ventricular relaxation. End-stage heart disease was characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. Substantial variability in the progression and severity of heart disease segregated with maternal lineage, and sequencing of mtDNA from five maternal lineages revealed two major European haplogroups, U and H. Patients with the haplogroup U mtDNAs had more rapid and severe cardiomyopathy than those with haplogroup H.","variants":[{"Name":"NM_001151.4(SLC25A4):c.523del (p.Gln175fs)","Chromosome":"4","Start":"185145174","Stop":"185145174","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":211024,"rule_based_match":true,"evidence_text":"c.523delC","llm_judgment":"PRESENT","evidence":"c.523delC","abstract_start":405,"abstract_end":414}]}
{"pmid":"24781758","title":"An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome.","abstract":"The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non-consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome.","variants":[{"Name":"NM_001253852.3(AP4B1):c.1160_1161del (p.Thr387fs)","Chromosome":"1","Start":"113898755","Stop":"113898756","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":166193,"rule_based_match":true,"evidence_text":"c.1160_1161delCA (p.(Thr387Argfs*30))","llm_judgment":"PRESENT","evidence":"c.1160_1161delCA (p.(Thr387Argfs*30))","abstract_start":778,"abstract_end":815}]}
{"pmid":"28611678","title":"A Fourth","abstract":"\"Amelogenesis imperfecta\" (AI) describes a group of genetic conditions that result in defects in tooth enamel formation. Mutations in many genes are known to cause AI, including the gene encoding the serine protease, kallikrein related peptidase 4 (<i>KLK4</i>), expressed during the maturation stage of amelogenesis. In this study we report the fourth <i>KLK4</i> mutation to be identified in autosomal recessively-inherited hypomaturation type AI, c.632delT, p.(L211Rfs<sup>*</sup>37) (NM_004917.4, NP_004908.4). This homozygous variant was identified in five Pakistani AI families and is predicted to result in a transcript with a premature stop codon that escapes nonsense mediated decay. However, the protein may misfold, as three of six disulphide bonds would be disrupted, and may be degraded or non-functional as a result. Primary teeth were obtained from one affected individual. The enamel phenotype was characterized using high-resolution computerized X-ray tomography (CT), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and microhardness testing (MH). Enamel from the affected individual (referred to as KLK4 enamel) was hypomineralised in comparison with matched control enamel. Furthermore, KLK4 inner enamel was hypomineralised compared with KLK4 outer enamel. SEM showed a clear structural demarcation between KLK4 inner and outer enamel, although enamel structure was similar to control tissue overall. EDX showed that KLK4 inner enamel contained less calcium and phosphorus and more nitrogen than control inner enamel and KLK4 outer enamel. MH testing showed that KLK4 inner enamel was significantly softer than KLK4 outer enamel (<i>p</i> < 0.001). However, the hardness of control inner enamel was not significantly different to that of control outer enamel. Overall, these findings suggest that the <i>KLK4</i> c.632delT mutation may be a common cause of autosomal recessive AI in the Pakistani population. The phenotype data obtained mirror findings in the <i>Klk4</i><sup>-/-</sup> mouse and suggest that KLK4 is required for the hardening and mineralization of the inner enamel layer but is less essential for hardening and mineralization of the outer enamel layer.","variants":[{"Name":"NM_004917.5(KLK4):c.632del (p.Leu211fs)","Chromosome":"19","Start":"50907067","Stop":"50907067","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":272347,"rule_based_match":true,"evidence_text":"c.632delT, p.(L211Rfs<sup>*</sup>37) (NM_004917.4, NP_004908.4)","llm_judgment":"PRESENT","evidence":"c.632delT, p.(L211Rfs<sup>*</sup>37) (NM_004917.4, NP_004908.4)","abstract_start":450,"abstract_end":513}]}
{"pmid":"29914921","title":"Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells.","abstract":"BACKGROUND: The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic \"healthy\" individuals. A VUS is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded, and thus cannot be definitively annotated. VUS, therefore, pose critical clinical interpretation and risk-assessment challenges, and new methods are urgently needed to better characterize their pathogenicity.\nMETHODS: To address this challenge and showcase the uncertainty surrounding genomic variant interpretation, we recruited a \"healthy\" asymptomatic individual, lacking cardiac-disease clinical history, carrying a hypertrophic cardiomyopathy (HCM)-associated genetic variant (NM_000258.2:c.170C>A, NP_000249.1:p.Ala57Asp) in the sarcomeric gene MYL3, reported by the ClinVar database to be \"likely pathogenic.\" Human-induced pluripotent stem cells (iPSCs) were derived from the heterozygous VUS MYL3<sub>(170C>A)</sub> carrier, and their genome was edited using CRISPR/Cas9 to generate 4 isogenic iPSC lines: (1) corrected \"healthy\" control; (2) homozygous VUS MYL3<sub>(170C>A</sub><sub>)</sub>; (3) heterozygous frameshift mutation MYL3<sup>(170C>A/fs</sup><sup>)</sup>; and (4) known heterozygous MYL3 pathogenic mutation (NM_000258.2:c.170C>G), at the same nucleotide position as VUS MYL3<sub>(170C>A)</sub>, lines. Extensive assays including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic iPSC-derived cardiomyocytes (iPSC-CMs).\nRESULTS: The heterozygous VUS MYL3<sub>(170C>A)</sub>-iPSC-CMs did not show an HCM phenotype at the gene expression, morphology, or functional levels. Furthermore, genome-edited homozygous VUS MYL3<sub>(170C>A)</sub>- and frameshift mutation MYL3<sup>(170C>A/fs)</sup>-iPSC-CMs lines were also asymptomatic, supporting a benign assessment for this particular MYL3 variant. Further assessment of the pathogenic nature of a genome-edited isogenic line carrying a known pathogenic MYL3 mutation, MYL3<sub>(170C>G)</sub>, and a carrier-specific iPSC-CMs line, carrying a MYBPC3<sub>(961G>A)</sub> HCM variant, demonstrated the ability of this combined platform to provide both pathogenic and benign assessments.\nCONCLUSIONS: Our study illustrates the ability of clustered regularly interspaced short palindromic repeats/Cas9 genome-editing of carrier-specific iPSCs to elucidate both benign and pathogenic HCM functional phenotypes in a carrier-specific manner in a dish. As such, this platform represents a promising VUS risk-assessment tool that can be used for assessing HCM-associated VUS specifically, and VUS in general, and thus significantly contribute to the arsenal of precision medicine tools available in this emerging field.","variants":[{"Name":"NM_000258.3(MYL3):c.170C>G (p.Ala57Gly)","Chromosome":"3","Start":"46860813","Stop":"46860813","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":40440,"rule_based_match":true,"evidence_text":"NM_000258.2:c.170C>G","llm_judgment":"PRESENT","evidence":"NM_000258.2:c.170C>G","abstract_start":1357,"abstract_end":1377},{"Name":"NM_000258.3(MYL3):c.170C>A (p.Ala57Asp)","Chromosome":"3","Start":"46860813","Stop":"46860813","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":52291,"rule_based_match":true,"evidence_text":"NM_000258.2:c.170C>A, NP_000249.1:p.Ala57Asp","llm_judgment":"PRESENT","evidence":"NM_000258.2:c.170C>A, NP_000249.1:p.Ala57Asp","abstract_start":807,"abstract_end":851}]}
{"pmid":"31105016","title":"Prevalence and clinicoradiological features of spinocerebellar ataxia type 34 in a Japanese ataxia cohort.","abstract":"INTRODUCTION: Spinocerebellar ataxia (SCA) type 34, a form of autosomal dominantly inherited ataxia, has recently been associated with mutations in the ELOVL4 gene. However, a genetic study of the prevalence of SCA34 in an ataxia cohort has never been reported.\nMETHODS: We performed a mutation screening of ELOVL4 in a cohort of 153 undiagnosed index ataxia patients, selected after excluding for common SCA types, in a series of 506 Japanese index ataxia patients.\nRESULTS: Heterozygous mutation c.698C > T (p.T233M) was detected in an index patient with multisystem neurodegeneration including ataxia and erythrokeratodermia skin lesions, an archetypal skin phenotype in SCA34. The patient's father also presented with ataxia but not skin lesions. Although this mutation has been recently reported in a single English-Canadian patient, the present study confirms its cosegregation with the ataxia phenotype in the Japanese kindred. Brain magnetic resonance imaging (MRI) of the patient and his father revealed marked pontine and cerebellar atrophy as well as the hot cross bun sign, that is common in cerebellar type of multiple system atrophy and was also described in SCA34 patients harboring two other mutations: p.L168F and p.W246G.\nCONCLUSION: This represents the first genetic study of the prevalence of SCA34 in an ataxia cohort and demonstrates its low prevalence (0.2%) in ataxia patients. The broad SCA34 clinical spectrum suggests variable multisystem neurodegeneration. Clinicians should be aware of this rare disease entity, particularly if erythrokeratodermia or the hot cross bun sign in MRI are present in undiagnosed degenerative ataxia patients.","variants":[{"Name":"NM_022726.4(ELOVL4):c.698C>T (p.Thr233Met)","Chromosome":"6","Start":"79916855","Stop":"79916855","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":537497,"rule_based_match":true,"evidence_text":"c.698C > T (p.T233M)","llm_judgment":"PRESENT","evidence":"c.698C > T (p.T233M)","abstract_start":498,"abstract_end":518}]}
{"pmid":"36973888","title":"X-linked myotubular myopathy: a clinical report and a review of the mild phenotype.","abstract":"INTRODUCTION: X-linked myotubular myopathy is a rare centronuclear myopathy that affects approximately 1 in 50,000 male newborns caused by pathogenic variants in the myotubularin 1 gene (MTM1). The clinical severity varies, however the need for ventilatory support occurs almost invariably.\nCASE REPORT: We report the case of a 4-year-old boy presenting mild muscle hypotonia at 12 months-old, expressive language disorder, global developmental delay, and a sensory processing disorder. Clinical exome sequencing identified the hemizygous variant c.722G>A p.(Arg241His) in exon 9 of the myotubularin 1 gene (NM_000252.2). The mother is a heterozygous carrier of the same variant. A diagnosis of a mild form of maternal inherited X-linked myotubular myopathy was established. The child presented significant improvement with speech, occupational, and physical therapies, with no respiratory intercurrences or ventilator dependency.\nCONCLUSION: The presentation of a mild form of this myotubular myopathy, being less commonly reported, added challenge to the diagnosis. The combination of mild hypotonia, feeding difficulties and expressive language disorder should raise suspicion of a neuromuscular disease. There is a lack of verified motor or developmental scores specific to this myopathy to further determine prognosis and need of other therapies. While currently the severity myotubular myopathy is classified according to ventilator dependency, this may be insufficient and unapplicable to milder cases. There is an evident need for a grading system for mild and moderate cases assessing muscle weakness and fatigue, daily life limitations, motor developmental delay, early phenotypical scores, or recurrent respiratory infections.","variants":[{"Name":"NM_000252.3(MTM1):c.722G>A (p.Arg241His)","Chromosome":"X","Start":"150645726","Stop":"150645726","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3494671,"rule_based_match":true,"evidence_text":"c.722G>A p.(Arg241His)","llm_judgment":"PRESENT","evidence":"c.722G>A p.(Arg241His)","abstract_start":547,"abstract_end":569}]}
{"pmid":"31343737","title":"Syndromic chorioretinal coloboma associated with heterozygous de novo RARA mutation affecting an amino acid critical for retinoic acid interaction.","abstract":"Retinoid acid receptors (RAR) are transcription factors that bind retinoic acid (RA), a metabolite of vitamin A. RARs are composed of three subunits encoded by RARA, RARB and RARG. In humans, RARB defects cause syndromic microphthalmia. So far, no germline pathogenic variants have been identified in RARA or RARG. We describe a girl with a de novo mutation NM_000964 c.826C > T (p.Arg276Trp) in RARA with symptoms overlapping those described in RARB patients (coloboma, muscular hypotonia, dilated pulmonary artery, ectopic kidney). RARA Arg276 residue is functionally important, as it was previously shown that its substitution for Ala or Gln causes a 50- or 21-fold impairment of RA binding, respectively. Moreover, in leukemic cells, the p.Arg611Trp mutation in a chimeric PML/RARA gene (corresponding to the RARA p.Arg276Trp detected in our patient) conferred resistance to therapy by decreasing binding of all-trans RA. The functional effect of RARA p.Arg276Trp was further confirmed by in silico modeling which showed that binding of RA by the Trp276 variant was similarly defective as in the deleterious model Ala276 mutant. We propose that RARA p.Arg276Trp causes the disease by affecting RA interaction with the RARA receptor.","variants":[{"Name":"NM_000964.4(RARA):c.826C>T (p.Arg276Trp)","Chromosome":"17","Start":"40354320","Stop":"40354320","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":189152,"rule_based_match":true,"evidence_text":"NM_000964 c.826C > T (p.Arg276Trp)","llm_judgment":"PRESENT","evidence":"NM_000964 c.826C > T (p.Arg276Trp)","abstract_start":358,"abstract_end":392}]}
{"pmid":"20151204","title":"Fructose 1,6-bisphosphatase deficiency: enzyme and mutation analysis performed on calcitriol-stimulated monocytes with a note on long-term prognosis.","abstract":"Fructose 1,6-bisphosphatase (FBPase) deficiency is an inborn error of metabolism in the gluconeogenetic pathway. During periods of low food intake or infections, a defect in FBPase can result in hypoglycemia, ketonuria and metabolic acidosis. We established a diagnostic system for FBPase deficiency consisting of enzyme activity measurement and mutation detection in calcitriol-stimulated monocytes. In healthy individuals, we showed that FBPase activity is present in monocytes but not in other leukocytes. We describe the clinical course of four individuals from two Swedish families with FBPase deficiency. Family 1: patient 1 died at the age of 6 months after a severe episode with hypoglycemia and acidosis; patients 2 and 3 were followed for >30 years and were found to have a very favorable long-term prognosis. Their FBPase activity from jejunum (residual activity 15-25% of healthy controls), mixed leukocytes (low or normal levels), and calcitriol-stimulated monocytes (no detectable activity) was compared. Mutation analysis showed they were heterozygous for two genetic alterations (c.778G>A; c.881G>A), predicting amino acid exchanges at position p.G260R and p.G294E, originating from their parents. Family 2: patient 4 had no detectable levels of FBPase in stimulated monocytes. A mutation (c.648C>G) predicting a premature stop codon at position p.Y216X was found in one allele and a large deletion of about 300 kb, where the genes FBP2, FBP1 and a part of ONPEP are located, in the other. In conclusion, we present a reliable diagnostic system to verify an FBPase deficiency and find the genetic aberration.","variants":[{"Name":"NM_000507.4(FBP1):c.778G>A (p.Gly260Arg)","Chromosome":"9","Start":"94605504","Stop":"94605504","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":553126,"rule_based_match":true,"evidence_text":"c.778G>A","llm_judgment":"PRESENT","evidence":"c.778G>A","abstract_start":1096,"abstract_end":1104}]}
{"pmid":"28163940","title":"Asymptomatic Congenital Hyperinsulinism due to a Glucokinase-Activating Mutation, Treated as Adrenal Insufficiency for Twelve Years.","abstract":"Congenital hyperinsulinism (CHI) caused by a glucokinase- (GCK-) activating mutation shows autosomal dominant inheritance, and its severity ranges from mild to severe. A 43-year-old female with asymptomatic hypoglycemia (47 mg/dL) was diagnosed as partial adrenal insufficiency and the administration of hydrocortisone (10 mg/day) was initiated. Twelve years later, her 8-month-old grandchild was diagnosed with CHI. Heterozygosity of exon 6 c.590T>C (p.M197T) was identified in a gene analysis of GCK, which was also detected in her son and herself. The identification of GCK-activating mutations in hyperinsulinemic hypoglycemia patients may be useful for a deeper understanding of the pathophysiology involved and preventing unnecessary glucocorticoid therapy.","variants":[{"Name":"NM_000162.5(GCK):c.590T>C (p.Met197Thr)","Chromosome":"7","Start":"44149849","Stop":"44149849","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":441111,"rule_based_match":true,"evidence_text":"c.590T>C (p.M197T)","llm_judgment":"PRESENT","evidence":"c.590T>C (p.M197T)","abstract_start":442,"abstract_end":460}]}
{"pmid":"18445140","title":"A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations.","abstract":"CONTEXT: Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome (OMIM 160980). About 70% of cases are familiar; most have mutations of the PRKAR1A gene on chromosome 17q22-24. There is little phenotype-genotype correlation known to date.\nOBJECTIVE: To study the genotype-phenotype correlation in a family with newly diagnosed CNC and three generations of subjects bearing the same PRKAR1A mutation. The proband was diagnosed with hepatocellular carcinoma, a tumour that appears to be associated with CNC.\nDESIGN: The study consisted of clinical and genetic analysis of a total of 10 individuals belonging to a large Italian family.\nPATIENTS: The index case was referred for PRKAR1A gene mutation analysis because he met the diagnostic criteria for a clinical diagnosis of CNC.\nRESULTS: The PRKAR1A-inactivating mutation c.502 +1G > A in the intron 5 splice-donor site was detected after bidirectional sequencing of germline DNA. The mutation causes a frameshift in the transcribed sequence and a nonsense mRNA that was shown to be degraded; this leads to PRKAR1A haploinsufficiency in all tissues. All available relatives were screened first by DNA testing and, if the latter was positive, by clinical, biochemical and imaging means.\nCONCLUSIONS: A novel PRKAR1A mutation with an apparently low penetrance and variable expression is reported; the same mutation is also associated with a hepatocellular carcinoma. This is the first time a PRKAR1A mutation is reported in individuals who were diagnosed with CNC after retrospective family screening and following the identification of a proband; the finding has implications for genetic counselling on PRKAR1A and/or CNC.","variants":[{"Name":"NM_002734.5(PRKAR1A):c.502+1G>A","Chromosome":"17","Start":"68524078","Stop":"68524078","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":468302,"rule_based_match":true,"evidence_text":"c.502 +1G > A","llm_judgment":"PRESENT","evidence":"c.502 +1G > A","abstract_start":849,"abstract_end":862}]}
{"pmid":"30072168","title":"Clinical and genetic profiles of patients with X-linked agammaglobulinemia from southeast Turkey: Novel mutations in BTK gene.","abstract":"BACKGROUND: X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels, and clinically by extracellular bacterial infections which mainly compromise the respiratory tract. We aimed to analyze the clinical, immunological and genetic characteristics of 22 male children with XLA.\nMETHODS: Twenty-two children with XLA from 12 unrelated families were enrolled in this study. Clinical and demographic features of patients, serum immunoglobulin levels, percentage of B cells and BTK gene mutations were reviewed retrospectively.\nRESULTS: We identified 12 different mutations in 22 patients from 12 unrelated families. The most frequent type of mutation was premature stop codon (33.3%). Ten mutations had been reported previously including three missense mutations (c.1774T>C, c.1684C>T, c.83G>T), three premature stop codons (c.1558C>T, c.1573C>T, c.753G>A), two splice-site (c.683-1G>A, c.1567-12_1567-9delTTTG) and two small nucleotide deletions (c.902-904_delAAG, c.179_181delAGA). Two novel mutations of the BTK gene were also presented and included one splice-site mutation (c.391+1G>C) and one premature stop codon mutation (c.1243_1243delG). Six out of 12 mutations of the BTK gene were located in the SH1 domain, two in the PH domain, two in the SH3 domain and two in the SH2 domain. Three patients had a history of severe infection before diagnosis. We did not identify any correlation between severity of clinical symptoms and the genotype.\nCONCLUSIONS: Our results show that mutations in southeast Turkey could be different from those in the rest of the world and molecular genetic tests are an important tool for early confirmed diagnosis of XLA.","variants":[{"Name":"NM_000061.3(BTK):c.1558C>T (p.Arg520Ter)","Chromosome":"X","Start":"101356060","Stop":"101356060","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26416,"rule_based_match":true,"evidence_text":"c.1558C>T","llm_judgment":"PRESENT","evidence":"c.1558C>T","abstract_start":895,"abstract_end":904}]}
{"pmid":"24327139","title":"Clinical investigation and mutation analysis of a child with citrin deficiency complicated with purpura, convulsive seizures and methioninemia","abstract":"OBJECTIVE: To analyze the clinical features and SLC25A13 gene mutations of a child with citrin deficiency complicated with purpura, convulsive seizures and methioninemia.\nMETHODS: The patient was subjected to physical examination and routine laboratory tests. Blood amino acids and acylcarnitines, and urine organic acids and galactose were analyzed respectively with tandem mass spectrometry and gas chromatographic mass spectrometry. SLC25A13 gene mutation screening was conducted by high resolution melt (HRM) analysis.\nRESULTS: The petechiae on the patient's face and platelet count (27×10(9)/L, reference range 100×10(9)/L-300×10(9)/L) supported the diagnosis of immunologic thrombocytopenic purpura (ITP). Laboratory tests found that the patient have abnormal coagulation, cardiac enzyme, liver function and liver enzymes dysfunction. Tandem mass spectrometry also found methionine to be increased (286 μmol/L, reference ranges 8-35 μmol/L). The patient did not manifest any galactosemia, citrullinemia and tyrosinemia. Analysis of SLC25A13 gene mutation found that the patient has carried IVS16ins3kb, in addition with abnormal HRM result for exon 6. Direct sequencing of exon 6 revealed a novel mutation c.495delA. The same mutation was not detected in 100 unrelated healthy controls. Further analysis of her family has confirmed that the c.495delA mutation has derived from her farther, and that the IVS16ins3kb was derived from her mother.\nCONCLUSION: The clinical features and metabolic spectrum of citrin deficiency can be variable. The poor prognosis and severity of clinical symptoms of the patient may be attributed to the novel c.495delA mutation.","variants":[{"Name":"NM_014251.3(SLC25A13):c.495del (p.Ala166fs)","Chromosome":"7","Start":"96193157","Stop":"96193157","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":247326,"rule_based_match":true,"evidence_text":"c.495delA","llm_judgment":"PRESENT","evidence":"c.495delA","abstract_start":1212,"abstract_end":1221}]}
{"pmid":"20648714","title":"Molecular analysis of the AGL gene: identification of 25 novel mutations and evidence of genetic heterogeneity in patients with Glycogen Storage Disease Type III.","abstract":"PURPOSE: Glycogen Storage Disease Type III (limit dextrinosis; Cori or Forbes disease) is an autosomal recessive disorder of glycogen metabolism caused by deficient activity of glycogen debranching enzyme in liver and muscle (Glycogen Storage Disease Type IIIa) or liver only (Glycogen Storage Disease Type IIIb). These two clinically distinct phenotypes are caused by mutations in the same gene (amylo-1,6-glucosidase or AGL). Although most patients with Glycogen Storage Disease Type III have private mutations, common mutations have been identified in some populations, and two specific mutations in exon 3, c.18_19delGA (p.Gln6HisfsX20) and c.16C>T (p.Gln6X), are associated with the Glycogen Storage Disease Type IIIb phenotype.\nMETHODS: To further examine the heterogeneity found in Glycogen Storage Disease Type III patients, we have sequenced the AGL gene in 34 patients with a clinically and/or biochemically confirmed diagnosis of Glycogen Storage Disease Type III.\nRESULTS: We have identified 38 different mutations (25 novel and 13 previously reported) and have compiled a list of all mutations previously reported in the literature.\nDISCUSSION: We conclude that Glycogen Storage Disease Type III is a highly heterogeneous disorder usually requiring full gene sequencing to identify both pathogenic mutations. The finding of at least one of the two exon 3 mutations in all of the Glycogen Storage Disease Type IIIb patients tested allows for diagnosis of this subtype without the need for a muscle biopsy.","variants":[{"Name":"NM_000642.3(AGL):c.18_19del (p.Gln6fs)","Chromosome":"1","Start":"99851059","Stop":"99851060","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":192258,"rule_based_match":true,"evidence_text":"c.18_19delGA (p.Gln6HisfsX20)","llm_judgment":"PRESENT","evidence":"c.18_19delGA (p.Gln6HisfsX20)","abstract_start":611,"abstract_end":640},{"Name":"NM_000642.3(AGL):c.16C>T (p.Gln6Ter)","Chromosome":"1","Start":"99851058","Stop":"99851058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16134,"rule_based_match":true,"evidence_text":"c.16C>T (p.Gln6X)","llm_judgment":"PRESENT","evidence":"c.16C>T (p.Gln6X)","abstract_start":645,"abstract_end":662}]}
{"pmid":"34513534","title":"Primary Ciliary Dyskinesia: Ancestral Haplotypes Analysis of the RSPH4A Founder Mutation in Puerto Rico.","abstract":"Genetic mutations in >50 genes, including <i>RSPH4A,</i> can lead to primary ciliary dyskinesia (PCD). <i>RSPH4A</i> mutations affect radial spokes, which alter the configuration of the ciliary ultrastructure and lead to chronic oto-sinopulmonary disease. The <i>RSPH4A</i> [c.921+3_6delAAGT] founder mutation was described as one cause of PCD without laterality defects in Puerto Rico. The average Puerto Rican genetic composition includes 64% European, 21% African ancestral, and 15% Native-American or Taino, a native tribe in the Caribbean at the start of the European colonization, genes. Due to the relatively elevated Taino ancestry on the island, it might have contributed to the endemicity of the <i>RSPH4A</i> [c.921+3_6delAAGT] splice site mutation. However, the ancestry of this mutation is still not confirmed. This article describes the two pediatric PCD cases with the Puerto Rican foundermutationand reports an ancestral haplotype analysis of the <i>RSPH4A</i> [c.921+3_6delAAGT] splice site mutation. A median-joining haplotype network was constructed with the genome sequence data from 104 Puerto Rican subjects in the 1000 Genomes Project (1000GP). This study found that the <i>RSPH4A</i> [c.921+3_6delAAGT] splice site mutation was carried to Puerto Rico from Europe by conquistadors or shortly after the conquest and that it gained frequency on the island through genetic drift fueled by a subsequent population expansion.","variants":[{"Name":"NM_001010892.3(RSPH4A):c.921+3_921+6del","Chromosome":"6","Start":"116623002","Stop":"116623005","ReferenceAlleleVCF":"TAGTA","AlternateAlleleVCF":"T","allel_id":94432,"rule_based_match":false,"evidence_text":"c.921+3_6delAAGT","llm_judgment":"PRESENT","evidence":"c.921+3_6delAAGT","abstract_start":275,"abstract_end":291}]}
{"pmid":"29533536","title":"Mutation spectra and founder effect of TMC1 in patients with non-syndromic deafness in Xiamen area, China.","abstract":"To analyze the spectrum and founder effect of TMC1 mutations in patients with non-syndromic deafness in the Xiamen area. Sporadic pedigrees were detected by targeted next-generation sequencing, and 110 unrelated patients from Xiamen Special Education School were analyzed through Sanger sequencing for the TMC1 gene. In total, 53 SNPs were designed to analyze the haplotypes of the TMC1 c.2050G>C mutation. The probands of three families were found to be homozygous for TMC1 c.2050G>C, and their parents were all heterozygous for the TMC1 c.2050G>C mutation. In 110 unrelated patients from Xiamen Special Education School, four were found to carry compound heterozygotes of TMC1 c.2050G>C, which were compound heterozygotes of c.804G>A, c.1127T>C, c.1165C>T, and c.1396_1398delAAC, respectively. Three types of TMC1 polymorphisms (c.45C>T, c.1713C>T, c.2208+49C>T) and two heterozygotes of novel variants (c.1764-4C>A, c.2073G>A[p.K691K]) were found in the remaining 100 patients. In total, four novel variants were detected in this study. These mutations and variants were not detected in 100 normal samples. The haplotypes of the probands of families with TMC1 c.2050G>C were identical. There were unique hotspots and spectra of TMC1 mutations in the Xiamen deaf population. Haplotype analysis is useful to understand the founder effect of the hot spot mutation.","variants":[{"Name":"NM_138691.3(TMC1):c.804G>A (p.Trp268Ter)","Chromosome":"9","Start":"72772475","Stop":"72772475","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3075523,"rule_based_match":true,"evidence_text":"c.804G>A","llm_judgment":"PRESENT","evidence":"c.804G>A","abstract_start":727,"abstract_end":735},{"Name":"NM_138691.3(TMC1):c.2050G>C (p.Asp684His)","Chromosome":"9","Start":"72826915","Stop":"72826915","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2797700,"rule_based_match":true,"evidence_text":"TMC1 c.2050G>C","llm_judgment":"PRESENT","evidence":"TMC1 c.2050G>C","abstract_start":382,"abstract_end":396},{"Name":"NM_138691.3(TMC1):c.1165C>T (p.Arg389Ter)","Chromosome":"9","Start":"72789258","Stop":"72789258","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":57020,"rule_based_match":true,"evidence_text":"c.1165C>T","llm_judgment":"PRESENT","evidence":"c.1165C>T","abstract_start":748,"abstract_end":757}]}
{"pmid":"25327599","title":"Pro731Ser mutation in the β-myosin heavy chain and hypertrophic cardiomyopathy in a Chinese pedigree","abstract":"OBJECTIVE: To identify the casual mutation of a Chinese pedigree with hypertrophic cardiomyopathy (HCM), and to analyze the genotype-phenotype relationship.\nMETHODS: The coding exons of 26 reported disease genes were sequenced by targeted resequencing in the proband and the identified mutation were detected with bi-directional Sanger sequencing in all family members and 307 healthy controls. The genotype-phenotype correlation was analyzed in the family.\nRESULTS: A missense mutation (c.2191C > T, p. Pro731Ser) in the 20th exon of MYH7 gene was identified. This mutation was absent in 307 healthy controls and predicted to be pathogenic by PolyPhen-HCM. Totally 13 family members carried this mutation, including 10 patients with HCM and 3 asymptomatic mutation carriers. The proband manifested severe congestive heart failure and 8 patients expressed various clinical manifestations of heart failure, including dyspnea, palpitations, chest pain, amaurosis or syncope. Five patients were diagnosed as HCM at the age of 16 or younger. One family member suffered sudden cardiac death.\nCONCLUSIONS: The Pro731Ser of MYH7 gene mutation is a causal and malignant mutation linked with familiar HCM.","variants":[{"Name":"NM_000257.4(MYH7):c.2191C>T (p.Pro731Ser)","Chromosome":"14","Start":"23425790","Stop":"23425790","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":179623,"rule_based_match":true,"evidence_text":"c.2191C > T, p. Pro731Ser","llm_judgment":"PRESENT","evidence":"c.2191C > T, p. Pro731Ser","abstract_start":488,"abstract_end":513}]}
{"pmid":"31130376","title":"Recessive MYH7-related myopathy in two families.","abstract":"Myopathies due to recessive MYH7 mutations are exceedingly rare, reported in only two families to date. We describe three patients from two families (from Australia and the UK) with a myopathy caused by recessive mutations in MYH7. The Australian family was homozygous for a c.5134C > T, p.Arg1712Trp mutation, whilst the UK patient was compound heterozygous for a truncating (c.4699C > T; p.Gln1567*) and a missense variant (c.4664A > G; p.Glu1555Gly). All three patients shared key clinical features, including infancy/childhood onset, pronounced axial/proximal weakness, spinal rigidity, severe scoliosis, and normal cardiac function. There was progressive respiratory impairment necessitating non-invasive ventilation despite preserved ambulation, a combination of features often seen in SEPN1- or NEB-related myopathies. On biopsy, the Australian proband showed classical myosin storage myopathy features, while the UK patient showed multi-minicore like areas. To establish pathogenicity of the Arg1712Trp mutation, we expressed mutant MYH7 protein in COS-7 cells, observing abnormal mutant myosin aggregation compared to wild-type. We describe skinned myofiber studies of patient muscle and hypertrophy of type II myofibers, which may be a compensatory mechanism. In summary, we have expanded the phenotype of ultra-rare recessive MYH7 disease, and provide novel insights into associated changes in muscle physiology.","variants":[{"Name":"NM_000257.4(MYH7):c.5134C>T (p.Arg1712Trp)","Chromosome":"14","Start":"23415652","Stop":"23415652","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29157,"rule_based_match":true,"evidence_text":"c.5134C > T, p.Arg1712Trp","llm_judgment":"PRESENT","evidence":"c.5134C > T, p.Arg1712Trp","abstract_start":275,"abstract_end":300},{"Name":"NM_000257.4(MYH7):c.4699C>T (p.Gln1567Ter)","Chromosome":"14","Start":"23416258","Stop":"23416258","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":841262,"rule_based_match":true,"evidence_text":"c.4699C > T; p.Gln1567*","llm_judgment":"PRESENT","evidence":"c.4699C > T; p.Gln1567*","abstract_start":377,"abstract_end":400},{"Name":"NM_000257.4(MYH7):c.4664A>G (p.Glu1555Gly)","Chromosome":"14","Start":"23416293","Stop":"23416293","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":179504,"rule_based_match":true,"evidence_text":"c.4664A>G (p.Glu1555Gly)","llm_judgment":"PRESENT","evidence":"p.Glu1555Gly","abstract_start":439,"abstract_end":451}]}
{"pmid":"36092934","title":"Twelve exonic variants in the","abstract":"<b>Background:</b> Bartter syndrome (BS) is a rare renal tubular disease caused by gene variants in <i>SLC12A1</i>, <i>KCNJ1</i>, <i>CLCNKA</i>, <i>CLCNKB</i>, <i>BSND</i> or <i>MAGED2</i> genes. There is growing evidence that many exonic mutations can affect the pre-mRNA normal splicing and induce exon skipping by altering various splicing regulatory signals. Therefore, the aim of this study was to gain new insights into the consequences of exonic mutations associated with BS on pre-mRNA splicing. <b>Methods:</b> We analyzed all the missense, nonsense and synonymous variants described in six pathogenic genes by bioinformatics programs and identified candidate mutations that may promote exon skipping through a minigene system. <b>Results:</b> Results of the study showed that 12 of 14 candidate variants distributed in <i>SLC12A1</i> (c.728G>A, C.735C>G, c.904C>T, c.905G>A, c.1304C>T, c.1493C>T, c.2221A>T) and <i>CLCNKB</i> (c.226C>T, c.228A>C, c.229G>A, c.229G>C, c.1979C>A) were identified to induce splicing alterations. These variants may not only disrupt exonic splicing enhancers (ESEs) but also generate new exonic splicing silencers (ESSs), or disturb the classic splicing sites. <b>Conclusion:</b> To our knowledge, this is a comprehensive study regarding alterations in pre-mRNA of exonic variants in BS pathogenic genes. Our results reinforce the necessity of assessing the consequences of exonic variants at the mRNA level.","variants":[{"Name":"NM_000338.3(SLC12A1):c.1493C>T (p.Ala498Val)","Chromosome":"15","Start":"48246949","Stop":"48246949","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1871280,"rule_based_match":true,"evidence_text":"c.1493C>T","llm_judgment":"PRESENT","evidence":"c.1493C>T","abstract_start":896,"abstract_end":905},{"Name":"NM_000338.3(SLC12A1):c.905G>A (p.Arg302Gln)","Chromosome":"15","Start":"48230433","Stop":"48230433","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":270124,"rule_based_match":true,"evidence_text":"c.905G>A","llm_judgment":"PRESENT","evidence":"c.905G>A","abstract_start":875,"abstract_end":883}]}
{"pmid":"33097395","title":"Biallelic variants in two complex I genes cause abnormal splicing defects in probands with mild Leigh syndrome.","abstract":"Leigh syndrome is a genetically heterogeneous disorder resulting from deficient oxidative energy biogenesis. The syndrome is characterized by subacute episodic decompensations, transiently elevated lactate, and necrotizing brain lesions most often in the striatum and brainstem. Acute decompensation is often triggered by viral infections. Sequalae from repeated episodes leads to progressive neurological deterioration and death. The severity of Leigh syndrome varies widely, from a rapid demise in childhood to rare adult presentations. Although the causes of Leigh syndrome include genes affecting a variety of different pathways, more than 75 of them are nuclear or mitochondrial encoded genes involved in the assembly and catalytic activity of mitochondrial respiratory complex I. Here we report the detailed clinical and molecular phenotype of two adults with mild presentations of NDUFS3 and NDUFAF6-related Leigh Syndrome. Mitochondrial assays revealed slightly reduced complex I activity in one proband and normal complex I activity in the other. The proband with NDUFS3-related Leigh syndrome was mildly affected and lived into adulthood with novel biallelic variants causing aberrant mRNA splicing (NM_004551.2:c.419G > A; p.Arg140Gln; NM_004551.2:c.381 + 6 T > C). The proband with NDUFAF6-related Leigh syndrome had biallelic variants that cause defects in mRNA splicing (NM_152416.3:c.371 T > C; p.Ile124Thr; NM_152416.3:c.420 + 2_420 + 3insTA). The mild phenotypes of these two individuals may be attributed to some residual production of normal NDUFS3 and NDUFAF6 proteins by NDUFS3 and NDUFAF6 mRNA isoforms alongside mutant transcripts. Taken together, these cases reported herein suggest that splice-regulatory variants to complex I proteins could result in milder phenotypes.","variants":[{"Name":"NM_004551.3(NDUFS3):c.381+6T>C","Chromosome":"11","Start":"47580990","Stop":"47580990","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":320904,"rule_based_match":true,"evidence_text":"NM_004551.2:c.381 + 6 T > C","llm_judgment":"PRESENT","evidence":"NM_004551.2:c.381 + 6 T > C","abstract_start":1247,"abstract_end":1274},{"Name":"NM_152416.4(NDUFAF6):c.420+2_420+3insTA","Chromosome":"8","Start":"95035578","Stop":"95035579","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TTA","allel_id":1052779,"rule_based_match":true,"evidence_text":"NM_152416.3:c.420 + 2_420 + 3insTA","llm_judgment":"PRESENT","evidence":"NM_152416.3:c.420 + 2_420 + 3insTA","abstract_start":1423,"abstract_end":1457},{"Name":"NM_004551.3(NDUFS3):c.419G>A (p.Arg140Gln)","Chromosome":"11","Start":"47582125","Stop":"47582125","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1052776,"rule_based_match":true,"evidence_text":"NM_004551.2:c.419G > A; p.Arg140Gln","llm_judgment":"PRESENT","evidence":"NM_004551.2:c.419G > A; p.Arg140Gln","abstract_start":1210,"abstract_end":1245},{"Name":"NM_152416.4(NDUFAF6):c.371T>C (p.Ile124Thr)","Chromosome":"8","Start":"95035527","Stop":"95035527","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":211343,"rule_based_match":true,"evidence_text":"NM_152416.3:c.371 T > C; p.Ile124Thr","llm_judgment":"PRESENT","evidence":"NM_152416.3:c.371 T > C; p.Ile124Thr","abstract_start":1385,"abstract_end":1421}]}
{"pmid":"24444888","title":"Development of a feasible assay for the detection of GAA mutations in patients with Pompe disease.","abstract":"BACKGROUND: Pompe disease is an inherited autosomal recessive deficiency of acid α-glucosidase (GAA) and is due to pathogenic sequence variants in the corresponding GAA gene. While the analysis of enzyme activity remains the diagnostic test of choice for individuals with Pompe disease, mutation analysis remains for establishing a definitive diagnosis.\nMETHODS: High resolution melting (HRM) analysis was performed to screen GAA mutations. Genomic DNA was extracted from peripheral blood samples of the two patients with Pompe disease and 250 normal controls. Exons 2 through 20 of the GAA gene were screened by the HRM analysis. The results were subsequently confirmed by direct sequencing.\nRESULTS: This assay proved to be feasible in detecting seven known (c.2T>C, c.1726G>A, c.1845G>A, c.1935C>A, c.1958C>A, c.2238G>C, and c.2815_2816del) GAA mutations. Each mutation could be readily and accurately identified in the difference plot curves. We estimated the carrier frequency of the most common mutation, c.1935G>A (p.D645E), in the Taiwanese population to be 0.2%.\nCONCLUSIONS: In clinical practice, we suggest that HRM analysis is assumed as a fast and reliable method for screening GAA gene mutations especially the most common mutations which are responsible for Pompe disease among the Taiwanese populations.","variants":[{"Name":"NM_000152.5(GAA):c.2238G>C (p.Trp746Cys)","Chromosome":"17","Start":"80117016","Stop":"80117016","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":260196,"rule_based_match":true,"evidence_text":"c.2238G>C","llm_judgment":"PRESENT","evidence":"c.2238G>C","abstract_start":813,"abstract_end":822}]}
{"pmid":"31624069","title":"Biallelic loss of","abstract":"Genome sequencing was performed on matched normal and tumor tissue from a 6.5-yr-old boy with a diagnosis of recurrent medulloblastoma. A pathogenic heterozygous c.432+1G>A canonical splice donor site variant in <i>GNAS</i> was detected on analysis of blood DNA. Analysis of tumor DNA showed the same splice variant along with copy-neutral loss of heterozygosity on Chromosome 20 encompassing <i>GNAS</i>, consistent with predicted biallelic loss of <i>GNAS</i> in the tumor specimen. This case strengthens the evidence implicating <i>GNAS</i> as a tumor-suppressor gene in medulloblastoma and highlights a scenario in which therapeutics targeting the cAMP pathway may be of great utility.","variants":[{"Name":"NM_000516.7(GNAS):c.432+1G>A","Chromosome":"20","Start":"58903792","Stop":"58903792","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":440007,"rule_based_match":true,"evidence_text":"c.432+1G>A","llm_judgment":"PRESENT","evidence":"c.432+1G>A","abstract_start":162,"abstract_end":172}]}
{"pmid":"33712029","title":"Extending the phenotypic spectrum of PRPF8, PRPH2, RP1 and RPGR, and the genotypic spectrum of early-onset severe retinal dystrophy.","abstract":"PURPOSE: To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease.\nMETHODS: Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK).\nRESULTS: The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented.\nCONCLUSIONS: The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.","variants":[{"Name":"NM_006445.4(PRPF8):c.5804G>A (p.Arg1935His)","Chromosome":"17","Start":"1655533","Stop":"1655533","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":537271,"rule_based_match":true,"evidence_text":"c.5804G > A","llm_judgment":"PRESENT","evidence":"c.5804G > A","abstract_start":736,"abstract_end":747}]}
{"pmid":"30168660","title":"STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.","abstract":"SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca<sup>2+</sup> release. Co-immunoprecipitation of STAC3 with Ca<sub>V</sub> 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and Ca<sub>V</sub> 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of Ca<sub>V</sub> 1.1 sarcolemma mislocalization or impaired STAC3-Ca<sub>V</sub> 1.1 interaction.","variants":[{"Name":"NM_145064.3(STAC3):c.997-1G>T","Chromosome":"12","Start":"57243911","Stop":"57243911","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":678969,"rule_based_match":true,"evidence_text":"c.997-1G>T","llm_judgment":"PRESENT","evidence":"c.997-1G > T","abstract_start":399,"abstract_end":411},{"Name":"NM_145064.3(STAC3):c.851G>C (p.Trp284Ser)","Chromosome":"12","Start":"57244322","Stop":"57244322","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":94325,"rule_based_match":false,"evidence_text":"p.(Trp284Ser)","llm_judgment":"PRESENT","evidence":"p.(Trp284Ser)","abstract_start":270,"abstract_end":283}]}
{"pmid":"32629717","title":"Intestinal lymphangiectasia in a 3-month-old girl: A case report of Hennekam syndrome caused by CCBE1 mutation.","abstract":"RATIONAL: Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation and rupture of intestinal lymphatic channels leading to protein-losing enteropathy. IL is classified as primary and secondary types.\nPATIENT CONCERNS: A 3-month-old girl born at term from vaginal delivery with an APGAR score of 10/10 and birth weight of 4.310 g (>97° percentile) was admitted to our hospital because of increasing abdominal tenderness and diarrhea. At first examination, she presented an abdominal circumference of 60 cm, edema of the lower extremities and vulva, and facial dysmorphisms (hypertelorism, flat nasal bridge, flat mid-face).\nDIAGNOSIS: Once admitted, ultrasonography showed a large amount of ascites, while blood laboratory investigations revealed severe hypoproteinemia, hypoalbuminemia and hypogammaglobulinemia. Lymphoscintigraphy with 99m-Tc-nanocolloid demonstrated abnormal leakage of the tracer in the abdomen as evidence of IL. To detect a possible secondary, exams were performed and demonstrated positive antibody titres for CMV-IgM and IgG in blood and CMV-DNA positivity in blood, urine, saliva, maternal milk, and gastric and duodenal biopsies. Genetic investigations identified the genomic variant c.472C>T of the CCBE1 gene, coding for a protein variant (p.Arg158Cys), in homozygosity.\nINTERVENTIONS: Total parenteral nutrition was started and continued for a total of 18 days, then gradually bridged by enteral nutrition with a special formula. In addition, antiviral therapy for CMV infection was added first with intravenous ganciclovir for 14 days, resulting in the disappearance of blood viral load after 7 days of therapy and then with valganciclovir per os for another 30 days.\nOUTCOMES: The clinical course of the child gradually improved. A few days after starting treatments, lower extremities and vulvar edema disappeared, and abdominal circumference gradually decreased to a stable value of 38 cm, without any ultrasonographic signs of ascites left. Moreover, serum albumin and IgG rose to normal values after 3 months (4.3 g/dL and 501 mg/dL, respectively).\nLESSONS: This case suggests that in presence of IL both primary and secondary causes should be evaluated. On the other hand, genetic diagnosis is crucial not only for diagnosis but also for prognosis in HS. Life expectancy and quality could deeply vary among different gene mutations and protein variants of the same gene. Further studies and case reports are needed to better understand the clinical meaning of these genetic results and the role of CMV as trigger of IL.","variants":[{"Name":"NM_133459.4(CCBE1):c.472C>T (p.Arg158Cys)","Chromosome":"18","Start":"59466820","Stop":"59466820","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15488,"rule_based_match":true,"evidence_text":"c.472C>T","llm_judgment":"PRESENT","evidence":"c.472C>T","abstract_start":1232,"abstract_end":1240}]}
{"pmid":"22118538","title":"Novel mechanism of a CDH1 splicing mutation in a Korean patient with signet ring cell carcinoma.","abstract":"We report a novel mechanism of a CDH1 splicing mutation in a patient with signet ring cell carcinoma of the stomach. A 27-year-old man complaining of aggravated dyspepsia was diagnosed with signet ring cell carcinoma. Both his father and uncle had died of stomach cancer at a young age. DNA sequencing analysis of the CDH1 gene revealed a splice site mutation(c.833-2A>G). By RNA/cDNA sequencing analysis, CDH1 c.833-2A>G generated a new acceptor site within intron 6, causing the insertion of a 79-bp intronic sequence between exon 6 and 7 (r.833-79_833-1ins), and resulting in a frame shift. E-cadherin immunohistochemical staining revealed a loss of CDH1 expression. This study reveals the disease-causing mechanism of this splicing mutation, and emphasizes the need for functional studies using RNA samples for the accurate interpretation of detected splicing variant. This is the first reported case of a CDH1 mutation in a Korean patient.","variants":[{"Name":"NM_004360.5(CDH1):c.833-2A>G","Chromosome":"16","Start":"68811682","Stop":"68811682","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":432884,"rule_based_match":true,"evidence_text":"c.833-2A>G","llm_judgment":"PRESENT","evidence":"c.833-2A>G","abstract_start":360,"abstract_end":370}]}
{"pmid":"29889250","title":"Prevalence and molecular characteristics of defective mismatch repair epithelial ovarian cancer in a Japanese hospital-based population.","abstract":"BACKGROUND: The prevalence and molecular characteristics of defective mismatch repair epithelial ovarian cancers in the Japanese population have scarcely been investigated.\nMETHODS: Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary epithelial ovarian cancers in patients who underwent oophorectomy at our institution between April 2005 and September 2014. Genetic and/or epigenetic alterations of the mismatch repair genes were investigated in patients with loss of any mismatch repair proteins in the tumor.\nRESULTS: There were 305 patients with a median age of 54 years (range, 18-83 years). Loss of expression in the ovarian tumor of one or more mismatch repair proteins was observed in 3 of the 305 patients (0.98%): 2 patients MLH1/PMS2 loss and 1 patient showed MSH2/MSH6 loss. Genetic testing of these three patients failed to reveal any pathogenic germline mutations of MLH1 or MSH2. One patient with MLH1/PMS2 loss showed hypermethylation of the promoter region of MLH1. Somatic mutations were found in each of the alleles of MLH1 (c.545dupG and deletion of exons 2-19) in the other patient with MLH1/PMS2 loss. In the patient with MSH2/MSH6 loss, two somatic mutations were detected in MSH2 (c.229_230delAG and c.1861C>T), although we could not determine whether these mutations were biallelic or not.\nCONCLUSIONS: The prevalence of defective mismatch repair epithelial ovarian cancer in the Japanese hospital-based population was extremely low. Molecular mechanism involved in such defective mismatch repair ovarian cancers seems to be epigenetic events through MLH1 promotor hypermethylation or somatically mutated mismatch repair genes without germline mismatch repair mutation.","variants":[{"Name":"NM_000251.3(MSH2):c.1861C>T (p.Arg621Ter)","Chromosome":"2","Start":"47475126","Stop":"47475126","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":96279,"rule_based_match":true,"evidence_text":"c.1861C>T","llm_judgment":"PRESENT","evidence":"c.1861C>T","abstract_start":1339,"abstract_end":1348}]}
{"pmid":"26987331","title":"Frequency of Rare Alpha-1 Antitrypsin Variants in Polish Patients with Chronic Respiratory Disorders.","abstract":"The SERPINA1 gene encoding the alpha-1 antitrypsin (A1AT) protein is highly polymorphic. It is known that, apart from the most prevalent PI*S and PI*Z A1AT deficiency variants, other so-called rare variants also predispose individuals to severe chronic respiratory disorders such as emphysema and chronic obstructive pulmonary disease. Our aim was to assess the frequencies of common and rare SERPINA1 mutations in a group of 1033 Polish patients referred for A1AT deficiency diagnostics due to chronic respiratory disorders in the period of January 2014-September 2015. All blood samples were analyzed according to the routine diagnostic protocol, including A1AT serum concentration assessment by nephelometry and immune isoelectric focusing, followed by PCR genotyping and direct sequencing when necessary. A total of 890 out of the 1033 samples (86 %) carried the normal PI*MM genotype, whereas, in 143 samples (14 %), at least one A1AT deficiency variant was detected. In 132 subjects, PI*S (2.1 %) and PI*Z (10.8 %) common deficiency alleles were identified, yielding frequencies of 0.011 and 0.062, respectively. Rare SERPINA1 variants were detected in nine patients: PI*F (c.739C>T) (n = 5) and PI*I (c.187C>T) (n = 4). Samples from the patients with an A1AT serum concentration below 120 mg/dl and presenting a PI*MM-like phenotypic pattern were retrospectively analyzed by direct sequencing for rare SERPINA1 mutations, revealing a PI*M2Obernburg (c.514G>T) mutation in one patient and a non-pathogenic mutation (c.922G>T) in another. We conclude that the deficiency PI*Z A1AT allele is considerably more common in patients with chronic respiratory disorders than in the general Polish population. The prevalence of the PI*F allele seems higher than in other European studies.","variants":[{"Name":"NM_001127701.1(SERPINA1):c.739C>T (p.Arg247Cys)","Chromosome":"14","Start":"94381049","Stop":"94381049","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":33000,"rule_based_match":true,"evidence_text":"c.739C>T","llm_judgment":"PRESENT","evidence":"c.739C>T","abstract_start":1180,"abstract_end":1188}]}
{"pmid":"34734492","title":"More autosomal dominant SPG18 cases than recessive? The first AD-SPG18 pedigree in Chinese and literature review.","abstract":"OBJECTIVE: Hereditary spastic paraplegia (HSP) due to ERLIN2 gene mutations was designated as spastic paraplegia 18 (SPG18). To date, SPG18 families/cases are still rarely reported. All early reported cases shared the autosomal recessive (AR) inheritance pattern. Over the past 3 years, autosomal dominant (AD) or sporadic SPG18 cases had been continuously reported. Here, we reported the clinical and genetic features of the first autosomal dominant SPG18 pedigree in Chinese.\nMETHODS: We conducted detailed medical history inquiry, neurological examinations of the proband and his family members, and charted the family tree. The proband underwent brain and cervical magnetic resonance imaging (MRI), electromyography (EMG), and whole exome sequencing. Sanger sequencing was performed to verify the genetic variation in the proband and some family members. A literature review of all reported SPG18 families/cases was carried out to summarize the clinical-genetic characteristics of SPG18 under different inheritance patterns.\nRESULTS: Four patients were clinically diagnosed as chronic spastic paraplegia in three consecutive generations with the autosomal dominant inheritance model. All the patients presented juvenile-adolescent onset and gradually worsening pure HSP phenotype. Clinical phenotypes were consistent within the family. Whole exome sequencing in the proband identified a previously reported heterozygous c.502G > A (p.V168M) mutation in exon 8 of ERLIN2 gene. This mutation was cosegregated with the phenotype in the family and was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. To date, eight AR-SPG18 families, five AD-SPG18 families, and three sporadic cases had been reported. Clinical phenotype of AD-SPG18 was juvenile-adolescent onset pure HSP, while the phenotype of AR-SPG18 was mostly complicated HSP with earlier onset and more severe conditions. In rare cases, the initial spastic paraplegia could evolve to rapidly progressive amyotrophic lateral sclerosis (ALS).\nCONCLUSIONS: We reported the first autosomal dominant SPG18 pedigree in Chinese Han population, which added more pathogenic evidence for V168M mutation. As more SPG18 cases reported, the essentials of SPG18 need to be updated in clinical practice. Special attentions should be given in gene test for upper motor neuron disorders in case of missing heterozygous mutations in ERLIN2.","variants":[{"Name":"NM_007175.8(ERLIN2):c.502G>A (p.Val168Met)","Chromosome":"8","Start":"37749797","Stop":"37749797","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":946059,"rule_based_match":true,"evidence_text":"c.502G > A (p.V168M)","llm_judgment":"PRESENT","evidence":"c.502G > A (p.V168M)","abstract_start":1424,"abstract_end":1444}]}
{"pmid":"31602195","title":"Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.","abstract":"Basel-Vanagaite-Smirin-Yosef syndrome (OMIM 616449) is a rare autosomal recessive genetic disorder characterized by severe developmental delay and variable craniofacial, neurological, cardiac, and ocular anomalies in the presence of variants in the <i>MED25</i> gene. So far, only a handful of patients have been reported with this condition globally. Here, we report an additional Lebanese family with 2 affected siblings presenting with severely delayed psychomotor and language development as well as craniofacial anomalies. By whole-exome sequencing (WES), a homozygous variant was found in the <i>MED25</i> gene, c.518T>C, predicted to result in a p.Ile173Thr change in the MED25 protein. This change has recently been reported in another Lebanese family. Review of the literature, the importance of this mutation in the Lebanese population, and the possibility that this condition may be underdiagnosed and only effectively detected using molecular techniques such as WES are discussed.","variants":[{"Name":"NM_030973.4(MED25):c.518T>C (p.Ile173Thr)","Chromosome":"19","Start":"49829083","Stop":"49829083","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":920956,"rule_based_match":true,"evidence_text":"c.518T>C","llm_judgment":"PRESENT","evidence":"c.518T>C","abstract_start":618,"abstract_end":626}]}
{"pmid":"18781329","title":"LRRK2 R1628P increases risk of Parkinson's disease: replication evidence.","abstract":"We showed that the frequency of a LRRK2 variant (c.4883G > C, R1628P) was higher in Parkinson's disease (PD) compared to controls (8.4 vs. 3.4%, P = 0.046, OR 2.5, 95% CI 1.1-5.6). In the multivariate logistic regression (with adjustments made for the effect of age, age of onset, and gender), the heterozygous R1628P genotype was associated with an increased risk of PD compared to controls (OR 3.3, 95% CI 1.4- 7.9, P = 0.007). We provided an independent confirmation that the R1628P variant increases the risk of PD among Chinese.","variants":[{"Name":"NM_198578.4(LRRK2):c.4883G>C (p.Arg1628Pro)","Chromosome":"12","Start":"40320043","Stop":"40320043","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":47804,"rule_based_match":true,"evidence_text":"c.4883G > C","llm_judgment":"PRESENT","evidence":"c.4883G > C","abstract_start":49,"abstract_end":60}]}
{"pmid":"33208113","title":"Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees.","abstract":"BACKGROUND: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods.\nMETHODS: This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families.\nRESULTS: The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects.\nCONCLUSION: In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.","variants":[{"Name":"NM_016239.4(MYO15A):c.6442T>A (p.Trp2148Arg)","Chromosome":"17","Start":"18146040","Stop":"18146040","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1292226,"rule_based_match":false,"evidence_text":"c.T6442A:p.W2148R","llm_judgment":"PRESENT","evidence":"c.T6442A:p.W2148R","abstract_start":868,"abstract_end":885}]}
{"pmid":"25564561","title":"The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.","abstract":"BACKGROUND: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.\nMETHODS AND RESULTS: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F.\nCONCLUSIONS: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.","variants":[{"Name":"NM_016343.4(CENPF):c.1744G>T (p.Glu582Ter)","Chromosome":"1","Start":"214640082","Stop":"214640082","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":188212,"rule_based_match":true,"evidence_text":"c.1744G>T, p.E582X","llm_judgment":"PRESENT","evidence":"c.1744G>T, p.E582X","abstract_start":832,"abstract_end":850},{"Name":"NM_016343.4(CENPF):c.8692C>T (p.Arg2898Ter)","Chromosome":"1","Start":"214657139","Stop":"214657139","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":188214,"rule_based_match":true,"evidence_text":"c.8692 C>T, p.R2898X","llm_judgment":"PRESENT","evidence":"c.8692 C>T, p.R2898X","abstract_start":963,"abstract_end":983}]}
{"pmid":"32422350","title":"Acute liver failure in a male patient with NGLY1-congenital disorder of deglycosylation.","abstract":"Congenital disorder of N-linked deglycosylation (CDDG, MIM 615273) is a very rare autosomal recessive disorder caused by pathogenic variants in the NGLY1 gene. Transient transaminitis is the typical hepatic dysfunction described in these patients, but also included neonatal jaundice, hepatomegaly, splenomegaly, and steatosis. Microscopically, intrahepatic cytoplasmic inclusions and fibrosis are seen. We report a five-year-old male patient who presented a severe episode of acute liver failure (ALF). Exome sequencing identified compound heterozygous pathogenic/likely pathogenic variants in the NGLY1 gene: NM_018297.3:c.1891del, p.(Gln631Serfs*7) in exon 12 and NM_018297.3:c.531dup, p.(Asn178Glnfs*9) in exon 4. Serology for the most frequent viral hepatitis infections, autoimmune panel, and investigations for metabolic or toxic causes were also normal or negative. Hepatic disease resolved favorably after 46 days. Liver function tests and elastography remains normal after a 2-year follow-up. This is the first report of a reversible ALF among patients with NGLY1-CDDG. Although its definitive cause remains unknown, we suggest a direct relation between liver disease and mitochondrial respiratory chain damage in the context of impaired NGLY1 gene function. Further reports are required in order to know the long-term prognosis of ALF in patients with NGLY1-CDDG.","variants":[{"Name":"NM_018297.4(NGLY1):c.531dup (p.Asn178fs)","Chromosome":"3","Start":"25751224","Stop":"25751225","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":3032522,"rule_based_match":true,"evidence_text":"NM_018297.3:c.531dup, p.(Asn178Glnfs*9)","llm_judgment":"PRESENT","evidence":"NM_018297.3:c.531dup, p.(Asn178Glnfs*9)","abstract_start":667,"abstract_end":706},{"Name":"NM_018297.4(NGLY1):c.1891del (p.Gln631fs)","Chromosome":"3","Start":"25719534","Stop":"25719534","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":65631,"rule_based_match":true,"evidence_text":"NM_018297.3:c.1891del, p.(Gln631Serfs*7)","llm_judgment":"PRESENT","evidence":"NM_018297.3:c.1891del, p.(Gln631Serfs*7)","abstract_start":611,"abstract_end":651}]}
{"pmid":"19419416","title":"Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene.","abstract":"This multicenter study evaluated the mutation spectrum and frequencies of the MLH1 and MSH2 genes and determined the occurrence of large genomic deletions in 93 unrelated Taiwanese families that fulfilled the Amsterdam criteria II by denaturing high-performance liquid chromatography analysis, DNA sequencing for aberrant chromatograms, and multiplex ligation-dependent probe amplification analysis. In total, 38 pathogenic mutations (10 large deletions and 28 point mutations or small deletion/insertions) in the MSH2 or MLH1 gene were identified in 61 of the 93 families (66%). Three of the 10 large deletions and 14 of the 28 point mutations or small insertions/deletions have not been reported elsewhere. Three mutations in the MLH1 gene, the MLH1c.1846_1848delAAG (5 families), deletion exons 11-15 (4 unrelated families), and MLH1c.793C>T (13 unrelated families), accounted for 35% of all cases with pathogenic mutations. Haplotype analysis indicated that mutant c.793C>T alleles were derived from two distinct common founders that might be inherited from a single ancestor of presumably Chinese origin. As a mutation detection strategy for Taiwanese Lynch syndrome patients, we recommend that diagnosis starts with screening for large genomic deletions and continues by screening for common mutations in exons 10 and 16 of the MLH1 gene prior to searching for small mutations in the remaining exons.","variants":[{"Name":"NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)","Chromosome":"3","Start":"37017508","Stop":"37017508","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38609,"rule_based_match":true,"evidence_text":"MLH1c.793C>T","llm_judgment":"PRESENT","evidence":"MLH1c.793C>T","abstract_start":832,"abstract_end":844},{"Name":"NM_000249.4(MLH1):c.1846AAG[2] (p.Lys618del)","Chromosome":"3","Start":"37047632","Stop":"37047634","ReferenceAlleleVCF":"TGAA","AlternateAlleleVCF":"T","allel_id":32119,"rule_based_match":false,"evidence_text":"MLH1c.1846_1848delAAG","llm_judgment":"PRESENT","evidence":"MLH1c.1846_1848delAAG","abstract_start":747,"abstract_end":768}]}
{"pmid":"32240488","title":"Molecular and biochemical study of glutaric aciduria type 1 in 49 Russian families: nine novel mutations in the GCDH gene.","abstract":"Glutaric aciduria type 1 (GA1, deficiency of glutaryl CoA dehydrogenase, glutaric acidemia type 1) (ICD-10 code: E72.3; MIM 231670) is an autosomal recessive disease caused by mutations in the gene encoding the enzyme glutaryl CoA dehydrogenase (GCDH). Herein, we present the biochemical and molecular genetic characteristics of 51 patients diagnosed with GA1 from 49 unrelated families in Russia. We identified a total of 21 variants, 9 of which were novel: c.127 + 1G > T, с.471_473delCGA, c.161 T > C (p.Leu54Pro), c.531C > A (р.Phe177Leu), c.647C > T (p.Ser216Leu), c.705G > A (р.Gly235Asp), c.898 G > A (р.Gly300Ser), c.1205G > C (р.Arg402Pro), c.1178G > A (р.Gly393Glu). The most commonly detected missense variants were c.1204C > T (p.Arg402Trp) and с.1262C > T (р.Ala421Val), which were identified in 56.38% and 11.7% of mutated alleles. A heterozygous microdeletion of the short arm (p) of chromosome 19 from position 12,994,984-13,003,217 (8233 b.p.) and from position 12,991,506-13,003,217 (11,711 b.p.) were detected in two patients. Genes located in the area of imbalance were KLF1, DNASE2, and GCDH. Patients presented typical GA1 biochemical changes in the biological fluids, except one patient with the homozygous mutation p.Val400Met. No correlation was found between the GCDH genotype and glutaric acid (GA) concentration in the cohort of our patients.","variants":[{"Name":"NM_000159.4(GCDH):c.1262C>T (p.Ala421Val)","Chromosome":"19","Start":"12899486","Stop":"12899486","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17121,"rule_based_match":false,"evidence_text":"с.1262C > T (р.Ala421Val)","llm_judgment":"PRESENT","evidence":"с.1262C > T (р.Ala421Val)","abstract_start":757,"abstract_end":782},{"Name":"NM_000159.4(GCDH):c.471_473del (p.Ser157_Glu158delinsArg)","Chromosome":"19","Start":"12893619","Stop":"12893621","ReferenceAlleleVCF":"GCGA","AlternateAlleleVCF":"G","allel_id":3817378,"rule_based_match":false,"evidence_text":"c.471_473delCGA","llm_judgment":"PRESENT","evidence":"c.471_473delCGA","abstract_start":null,"abstract_end":null},{"Name":"NM_000159.4(GCDH):c.127+1G>T","Chromosome":"19","Start":"12891523","Stop":"12891523","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2150467,"rule_based_match":true,"evidence_text":"c.127 + 1G > T","llm_judgment":"PRESENT","evidence":"c.127 + 1G > T","abstract_start":459,"abstract_end":473},{"Name":"NM_000159.4(GCDH):c.647C>T (p.Ser216Leu)","Chromosome":"19","Start":"12896216","Stop":"12896216","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1192107,"rule_based_match":true,"evidence_text":"c.647C > T (p.Ser216Leu)","llm_judgment":"PRESENT","evidence":"c.647C > T (p.Ser216Leu)","abstract_start":544,"abstract_end":568},{"Name":"NM_000159.4(GCDH):c.1205G>C (p.Arg402Pro)","Chromosome":"19","Start":"12897825","Stop":"12897825","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3392911,"rule_based_match":true,"evidence_text":"c.1205G > C (р.Arg402Pro)","llm_judgment":"PRESENT","evidence":"c.1205G > C (р.Arg402Pro)","abstract_start":623,"abstract_end":648},{"Name":"NM_000159.4(GCDH):c.531C>A (p.Phe177Leu)","Chromosome":"19","Start":"12896017","Stop":"12896017","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2805044,"rule_based_match":true,"evidence_text":"c.531C > A (р.Phe177Leu)","llm_judgment":"PRESENT","evidence":"c.531C > A (р.Phe177Leu)","abstract_start":518,"abstract_end":542}]}
{"pmid":"10205265","title":"Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling.","abstract":"Problems with diagnosis and genetic counseling occur for patients with autosomal recessive proximal spinal muscular atrophy (SMA) who do not show the most common mutation: homozygous absence of at least exon 7 of the telomeric survival motor neuron gene (SMN1). Here we present molecular genetic data for 42 independent nondeleted SMA patients. A nonradioactive quantitative PCR test showed one SMN1 copy in 19 patients (45%). By sequencing cloned reverse-transcription (RT) PCR products or genomic fragments of SMN1, we identified nine different mutations in 18 of the 19 patients, six described for the first time: three missense mutations (Y272C, T274I, S262I), three frameshift mutations in exons 2a, 2b, and 4 (124insT, 241-242ins4, 591delA), one nonsense mutation in exon 1 (Q15X), one Alu-mediated deletion from intron 4 to intron 6, and one donor splice site mutation in intron 7 (c.922+6T-->G). The most frequent mutation, Y272C, was found in 6 (33%) of 18 patients. Each intragenic mutation found in at least two patients occurred on the same haplotype background, indicating founder mutations. Genotype-phenotype correlation allowed inference of the effect of each mutation on the function of the SMN1 protein and the role of the SMN2 copy number in modulating the SMA phenotype. In 14 of 23 SMA patients with two SMN1 copies, at least one intact SMN1 copy was sequenced, which excludes a 5q-SMA and suggests the existence of further gene(s) responsible for approximately 4%-5% of phenotypes indistinguishable from SMA. We determined the validity of the test, and we discuss its practical implications and limitations.","variants":[{"Name":"NM_000344.4(SMN1):c.815A>G (p.Tyr272Cys)","Chromosome":"5","Start":"70946157","Stop":"70946157","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":24205,"rule_based_match":false,"evidence_text":"Y272C","llm_judgment":"PRESENT","evidence":"Y272C","abstract_start":643,"abstract_end":648}]}
{"pmid":"30967788","title":"Investigating the Complex Arrhythmic Phenotype Caused by the Gain-of-Function Mutation KCNQ1-G229D.","abstract":"The congenital long QT syndrome (LQTS) is a cardiac electrophysiological disorder that can cause sudden cardiac death. LQT1 is a subtype of LQTS caused by mutations in KCNQ1, affecting the slow delayed-rectifier potassium current (<i>I</i> <sub>Ks</sub>), which is essential for cardiac repolarization. Paradoxically, gain-of-function mutations in KCNQ1 have been reported to cause borderline QT prolongation, atrial fibrillation (AF), sinus bradycardia, and sudden death, however, the mechanisms are not well understood. The goal of the study is to investigate the ionic, cellular and tissue mechanisms underlying the complex phenotype of a gain-of-function mutation in KCNQ1, c.686G > A (p.G229D) using computer modeling and simulations informed by <i>in vitro</i> measurements. Previous studies have shown this mutation to cause AF and borderline QT prolongation. We report a clinical description of a family that carry this mutation and that a member of the family died suddenly during sleep at 21 years old. Using patch-clamp experiments, we confirm that KCNQ1-G229D causes a significant gain in channel function. We introduce the effect of the mutation in populations of atrial, ventricular and sinus node (SN) cell models to investigate mechanisms underlying phenotypic variability. In a population of human atrial and ventricular cell models and tissue, the presence of KCNQ1-G229D predominantly shortens atrial action potential duration (APD). However, in a subset of models, KCNQ1-G229D can act to prolong ventricular APD by up to 7% (19 ms) and underlie depolarization abnormalities, which could promote QT prolongation and conduction delays. Interestingly, APD prolongations were predominantly seen at slow pacing cycle lengths (CL > 1,000 ms), which suggests a greater arrhythmic risk during bradycardia, and is consistent with the observed sudden death during sleep. In a population of human SN cell models, the KCNQ1-G229D mutation results in slow/abnormal sinus rhythm, and we identify that a stronger L-type calcium current enables the SN to be more robust to the mutation. In conclusion, our computational modeling experiments provide novel mechanistic explanations for the observed borderline QT prolongation, and predict that KCNQ1-G229D could underlie SN dysfunction and conduction delays. The mechanisms revealed in the study can potentially inform management and treatment of KCNQ1 gain-of-function mutation carriers.","variants":[{"Name":"NM_000218.3(KCNQ1):c.686G>A (p.Gly229Asp)","Chromosome":"11","Start":"2572015","Stop":"2572015","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67753,"rule_based_match":true,"evidence_text":"c.686G > A (p.G229D)","llm_judgment":"PRESENT","evidence":"c.686G > A (p.G229D)","abstract_start":678,"abstract_end":698}]}
{"pmid":"29178624","title":"Clinical and genetic characteristics of xeroderma pigmentosum in Nepal.","abstract":"BACKGROUND: Little is known about xeroderma pigmentosum (XP) in Himalayan countries.\nOBJECTIVE: To describe clinical characteristics of XP in Nepal and investigate its genetic bases.\nMETHODS: This study was carried out on all consecutive patients referred for XP to a Nepalese tertiary referral centre in 2014-2015. Clinical data were collected using a standardized questionnaire. DNA was extracted from salivary samples, and next-generation sequencing (NGS) was conducted using a panel covering all 8 known XP genes (classical XP (XP-A to XP-G) and XP variant) and a skin cancer modifier gene, the melanocortin 1 receptor gene (MC1R).\nRESULTS: Seventeen patients (median age: 15 years; range: 1-32) were included. Twelve had skin cancers (including a total of 8 squamous cell carcinomas, 60 basal cell carcinomas, ocular carcinomas requiring an orbital exenteration in 3 patients, but no melanoma). Fifteen patients carried the same homozygous non-sense XPC mutation c.1243C>T, p.R415X. A homozygous non-sense XPA mutation (p.W235X) was found in the only patient with a history of early severe sunburn reaction and associated neurological symptoms. Associated genetic alterations included heterozygous missense variants in XPD/ERCC2 gene and the presence of MC1R variant R163Q in 5 and 9 patients, respectively.\nCONCLUSION: Although not previously reported, XP seems frequent in Nepal. Patients often presented with a very severe phenotype after a long history of excessive sun exposure without knowledge of the disease. Fifteen of 17 had the same p.R415X XPC mutation, which seems very specific of XP in Nepal, suggesting a founder effect. NGS analyses frequently revealed associated genetic alterations which could play a modifier role in the clinical expression of the disease.","variants":[{"Name":"NM_004628.5(XPC):c.1243C>T (p.Arg415Ter)","Chromosome":"3","Start":"14158640","Stop":"14158640","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432247,"rule_based_match":true,"evidence_text":"c.1243C>T, p.R415X","llm_judgment":"PRESENT","evidence":"c.1243C>T, p.R415X","abstract_start":968,"abstract_end":986}]}
{"pmid":"23958592","title":"Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India.","abstract":"Beta-ketothiolase deficiency, or mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is a rare autosomal recessive disorder affecting isoleucine catabolism and ketone body metabolism. A patient from South India presented with acute ketoacidosis at 11 months of age. During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated and large amounts of 2-methyl-3-hydroxybutyrate, tiglylglycine, and 2-methylacetoacetate were excreted. Brain CT showed bilateral basal ganglia lesions. Potassium ion-activated acetoacetyl-CoA thiolase activity was deficient in the patient's fibroblasts. The patient is a homozygote for a novel c.578T>G (M193R) mutation. This is the first report of T2 deficiency confirmed by enzyme and molecular analysis from India.","variants":[{"Name":"NM_000019.4(ACAT1):c.578T>G (p.Met193Arg)","Chromosome":"11","Start":"108139040","Stop":"108139040","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":654045,"rule_based_match":true,"evidence_text":"c.578T>G (M193R)","llm_judgment":"PRESENT","evidence":"c.578T>G (M193R)","abstract_start":678,"abstract_end":694}]}
{"pmid":"26472200","title":"Japanese recurrent mutation c.6216+5G>T in COL7A1 leads to a mild phenotype of dystrophic epidermolysis bullosa.","abstract":"","variants":[{"Name":"NM_000094.4(COL7A1):c.6216+5G>T","Chromosome":"3","Start":"48575202","Stop":"48575202","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1481399,"rule_based_match":true,"evidence_text":"c.6216+5G>T","llm_judgment":"PRESENT","evidence":"c.6216+5G>T","abstract_start":null,"abstract_end":null}]}
{"pmid":"23568436","title":"Recurrent and founder mutations in the Netherlands-Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy.","abstract":"BACKGROUND: Recently, we showed that the c.40_42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10-15 % of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death.\nMETHODS: Our goal was to evaluate the geographical distribution and the origin of this specific mutation in the Netherlands and to get an estimation of the prevalence in a Dutch population cohort. Therefore, we investigated the postal codes of the places of residence of PLN p.Arg14del mutation carriers and places of birth of their ancestors. In addition, a large population-based cohort (PREVEND) was screened for the presence of this mutation.\nRESULTS: By April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. A total of 358 family members were also found to carry this mutation, resulting in a total of 459 mutation carriers. The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents' places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07 %).\nCONCLUSION: The p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. The mutation that arose 575-825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands.","variants":[{"Name":"NM_002667.5(PLN):c.37AGA[1] (p.Arg14del)","Chromosome":"6","Start":"118558957","Stop":"118558959","ReferenceAlleleVCF":"TAAG","AlternateAlleleVCF":"T","allel_id":53747,"rule_based_match":false,"evidence_text":"c.40_42delAGA (p.Arg14del)","llm_judgment":"PRESENT","evidence":"c.40_42delAGA (p.Arg14del)","abstract_start":41,"abstract_end":67}]}
{"pmid":"19807737","title":"Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis.","abstract":"The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited lysosomal storage diseases and the prototype of childhood onset neurodegenerative disorders. To date, 10 NCL entities (CLN1-CLN10) are known and characterized by accumulation of autofluorescent storage material, age of onset and clinical symptoms. CLN8 was first identified as the causative gene for a late-onset form with progressive epilepsy and mental retardation in Finnish patients. In addition, CLN8 phenotypes were described in Turkish, Israeli and Italian patients with a more rapid progression of visual loss, epilepsy, ataxia and mental decline. Here, we report the first mutations in German (c.611G>T) and Pakistani (c.709G>A) patients. Our findings confirm previous assumptions that the CLN8 variant can occur in many ethnic groups. So far, large CLN gene deletions are only known for the CLN3 gene. Here, we also describe a novel, large CLN8 gene deletion c.544-2566_590del2613 in a Turkish family with a slightly more severe phenotype. Our data indicate that patients with clinical signs of late infantile NCL and characteristic ultrastructural inclusions should also be screened for CLN8 mutations independent of their ethnic origin.","variants":[{"Name":"NM_018941.4(CLN8):c.709G>A (p.Gly237Arg)","Chromosome":"8","Start":"1780415","Stop":"1780415","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186761,"rule_based_match":true,"evidence_text":"c.709G>A","llm_judgment":"PRESENT","evidence":"c.709G>A","abstract_start":695,"abstract_end":703},{"Name":"NM_018941.4(CLN8):c.611G>T (p.Arg204Leu)","Chromosome":"8","Start":"1780317","Stop":"1780317","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":71354,"rule_based_match":true,"evidence_text":"c.611G>T","llm_judgment":"PRESENT","evidence":"c.611G>T","abstract_start":670,"abstract_end":678}]}
{"pmid":"24027063","title":"Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects.","abstract":"PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts) is a recently described autosomal-recessive neurodegenerative disease caused by mutations in the α-β-hydrolase domain-containing 12 gene (ABHD12). Only five homozygous ABHD12 mutations have been reported and the pathogenesis of PHARC remains unclear. We evaluated a woman who manifested short stature as well as the typical features of PHARC. Sequence analysis of ABHD12 revealed a novel heterozygous c.1129A>T (p.Lys377*) mutation. Targeted comparative genomic hybridization detected a 59-kb deletion that encompasses exon 1 of ABHD12 and exons 1-4 of an adjacent gene, GINS1, and includes the promoters of both genes. The heterozygous deletion was also carried by the patient's asymptomatic mother. Quantitative reverse transcription-PCR demonstrated ∼50% decreased expression of ABHD12 RNA in lymphoblastoid cell lines from both individuals. Activity-based protein profiling of serine hydrolases revealed absence of ABHD12 hydrolase activity in the patient and 50% reduction in her mother. This is the first report of compound heterozygosity in PHARC and the first study to describe how a mutation might affect ABHD12 expression and function. The possible involvement of haploinsufficiency for GINS1, a DNA replication complex protein, in the short stature of the patient and her mother requires further studies.","variants":[{"Name":"NM_001042472.3(ABHD12):c.1129A>T (p.Lys377Ter)","Chromosome":"20","Start":"25302247","Stop":"25302247","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2905527,"rule_based_match":true,"evidence_text":"c.1129A>T (p.Lys377*)","llm_judgment":"PRESENT","evidence":"c.1129A>T (p.Lys377*)","abstract_start":483,"abstract_end":504}]}
{"pmid":"25863075","title":"Mutations of phenylalanine hydroxylase gene detected in 20 patients with phenylketonuria from Yunnan Province","abstract":"OBJECTIVE: To investigate the mutations of phenylalanine hydroxylase (PAH) gene in 20 phenylketonuria (PKU) patients from Yunnan.\nMETHODS: The 13 exons and the splicing regions of 12 introns of the PAH gene were sequenced to detect mutations in 20 unrelated PKU patients.\nRESULTS: PAH gene sequencing has revealed 15 types of mutations, in which the most frequently mutation was p.R243Q (30.0%), followed by p.Y356X(10.0%), p.R111X (7.5%), IVS4+2T>A (7.5%) and p.V399V (7.5%). Exons 7, 11, 3 and introns 4, 11 were most frequently involved. Six novel mutations, including c.59A>C, c.60G>C, c.690_691insG, c.1119_1120insT, c.441+2T>A, c.842+4A>T and c.1200+1T>G were detected.\nCONCLUSION: PAH gene mutations identified in Yunnan are more similar to those of northern China, with R243R being the most common, though there are still certain characteristics for the type and frequency of mutations.","variants":[{"Name":"NM_000277.3(PAH):c.842+4A>T","Chromosome":"12","Start":"102852811","Stop":"102852811","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":794126,"rule_based_match":true,"evidence_text":"c.842+4A>T","llm_judgment":"PRESENT","evidence":"c.842+4A>T","abstract_start":634,"abstract_end":644}]}
{"pmid":"29383847","title":"Growth pattern of Rahman syndrome.","abstract":"Recently, in a cohort study with \"overgrowth syndrome with intellectual disability,\" five subjects were reported to have de novo heterozygous truncating variants in HIST1H1E, which encodes linker histone H 1.4. However, their growth pattern appeared complex that four out of five patients had a decreasing height percentile over time, and three of these patients began with above-average heights but exhibited reductions to average heights or below when they were older. Herein, we report a female patient with intellectual disability and distinctive facial features including a wide nasal bridge and prominent cheek bones. She did not exhibit skeletal overgrowth, but she had a short stature at 21 years of age. An exome analysis identified a de novo heterozygous 1-bp duplication in HIST1H1E, that is, c.433dup p.(Ala145Glyfs*51). The physical features of the proposita were essentially the same as those observed in patients with the aforementioned HIST1H1E-related overgrowth syndrome. Our review of the growth trajectories in seven patients showed that five of seven patients did not exhibit skeletal overgrowth. This \"lack of overgrowth in overgrowth syndrome\" is reminiscent of a subset of patients with a short stature who have Sotos syndrome, a prototypic overgrowth syndrome. Considering this complexity in growth, this newly identified condition should be referred to as Rahman syndrome.","variants":[{"Name":"NM_005321.3(H1-4):c.433dup (p.Ala145fs)","Chromosome":"6","Start":"26156821","Stop":"26156822","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":495307,"rule_based_match":true,"evidence_text":"c.433dup p.(Ala145Glyfs*51)","llm_judgment":"PRESENT","evidence":"c.433dup p.(Ala145Glyfs*51)","abstract_start":804,"abstract_end":831}]}
{"pmid":"29343710","title":"Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation.","abstract":"Limited data is available on phenotypic variations with the same genotype in hypertrophic cardiomyopathy (HCM). The present study aims to explore the relationship between genotype and phenotype characterized by cardiovascular magnetic resonance (CMR) in a large Chinese family. A proband diagnosed with HCM from a multigenerational family underwent next-generation sequencing based on a custom sureSelect panel, including 117 candidate pathogenic genes associated with cardiomyopathies. All genetic results were confirmed by the Sanger sequencing method. All confirmed mutation carriers underwent CMR exam and myocardial tissue characterization using T1 mapping and late gadolinium enhancement (LGE) on a 3T scanner (Siemens Trio, Gemany). After clinical and genetic screening of 36 (including the proband) members of a large Chinese family, nineteen family members are determined to carry the single p.T1377M (c.4130C>T) mutation in the MYH7 gene. Of these 19 mutation carriers, eight are diagnosed with HCM, one was considered as borderline affected and ten are not clinically or phenotypically affected. Different HCM phenotypes are present in the nine affected individuals in this family. In addition, we have found different tissue characteristics assessed by T1 mapping and LGE in these individuals. We describe a family that demonstrates the diverse HCM phenotypes associated with a single MYH7 mutation.","variants":[{"Name":"NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met)","Chromosome":"14","Start":"23418249","Stop":"23418249","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":52162,"rule_based_match":true,"evidence_text":"c.4130C>T","llm_judgment":"PRESENT","evidence":"c.4130C>T","abstract_start":911,"abstract_end":920}]}
{"pmid":"31433872","title":"Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.","abstract":"BACKGROUND: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA.\nOBJECTIVES: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients.\nMETHODS: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction.\nRESULTS: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001).\nCONCLUSIONS: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.","variants":[{"Name":"NM_003119.4(SPG7):c.1529C>T (p.Ala510Val)","Chromosome":"16","Start":"89546737","Stop":"89546737","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":51184,"rule_based_match":true,"evidence_text":"c.1529C>T (p.Ala510Val)","llm_judgment":"PRESENT","evidence":"c.1529C>T (p.Ala510Val)","abstract_start":1148,"abstract_end":1171}]}
{"pmid":"33600035","title":"Re-evaluating the pathogenicity of the c.783+2T>C BAP1 germline variant.","abstract":"BAP1 germline pathogenic sequence variants (PSVs) underlie a unique tumor predisposition syndrome (BAP1-TPDS) associated with an increased lifetime risk for developing primarily pleural and peritoneal mesothelioma and uveal and cutaneous melanoma. Overwhelmingly, BAP1 PSVs are unique, family-specific inactivating variants. We identified seven families, six of Jewish Iraqi origin, harboring an identical BAP1 splice variant (c.783+2T>C), currently assigned a \"likely pathogenic\" status. Given a nonclassical BAP1-TPDS tumor type clustering and low penetrance in these families, the pathogenicity of this variant was re-evaluated by a combined approach including literature analysis, revised bioinformatics analysis, allelic loss, effect on the transcript, and tumor protein expression patterns. None of the three available tumors showed an allelic loss, there was no discernable effect on alternative splicing based on reverse-transcription polymerase chain reaction, and there was no decrease or loss of somatic protein expression in 2/3 analyzed tumors. This led to assigning a Benign Strong (BS) criteria, BS4, supporting BS3 criteria, and weakening the Pathogenic Supporting (PP) criteria PP5. Combined, these data suggest that this sequence variant should be reclassified as a variant of unknown significance by American College of Medical Genetics (ACMG) criteria.","variants":[{"Name":"NM_004656.4(BAP1):c.783+2T>C","Chromosome":"3","Start":"52406251","Stop":"52406251","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":406345,"rule_based_match":true,"evidence_text":"c.783+2T>C","llm_judgment":"PRESENT","evidence":"c.783+2T>C","abstract_start":427,"abstract_end":437}]}
{"pmid":"21907011","title":"Translation initiator EIF4G1 mutations in familial Parkinson disease.","abstract":"Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.","variants":[{"Name":"NM_198241.3(EIF4G1):c.3614G>A (p.Arg1205His)","Chromosome":"3","Start":"184327401","Stop":"184327401","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39027,"rule_based_match":true,"evidence_text":"c.3614G>A (p.Arg1205His)","llm_judgment":"PRESENT","evidence":"c.3614G>A (p.Arg1205His)","abstract_start":208,"abstract_end":232},{"Name":"NM_198241.3(EIF4G1):c.1505C>T (p.Ala502Val)","Chromosome":"3","Start":"184322089","Stop":"184322089","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39028,"rule_based_match":true,"evidence_text":"EIF4G1 c.1505C>T (p.Ala502Val)","llm_judgment":"PRESENT","evidence":"EIF4G1 c.1505C>T (p.Ala502Val)","abstract_start":348,"abstract_end":378}]}
{"pmid":"16435223","title":"Mutational spectrum in ten Italian patients affected by methylmalonyl-CoA mutase deficiency.","abstract":"We report seven novel mutations, including three amino acids substitutions (p.Glu286Lys, p.Cys560Tyr, p.Pro615Leu), two nonsense mutations (p.Arg31X, p.Glu 451X), one splicing defect (c.2125-1G >A), one small deletion (c.1758-1759delA) and nine previously described mutations identified in 10 unrelated Italian patients affected by mut MMA.","variants":[{"Name":"NM_000255.4(MMUT):c.1844C>T (p.Pro615Leu)","Chromosome":"6","Start":"49440318","Stop":"49440318","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1406395,"rule_based_match":false,"evidence_text":"p.Pro615Leu","llm_judgment":"PRESENT","evidence":"p.Pro615Leu","abstract_start":102,"abstract_end":113}]}
{"pmid":"31352694","title":"Phosphate matters when investigating hypercalcemia: a mutation in SLC34A3 causing HHRH","abstract":"Summary: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, autosomal recessive disorder caused by mutations in the SLC34A3 gene that encodes the renal sodium-dependent phosphate cotransporter 2c (NaPi-IIc). It may present as intermittent mild hypercalcemia which may attract initial diagnostic attention but appreciation of concomitant hypophosphatemia is critical for consideration of the necessary diagnostic approach. A 21-year-old woman was assessed by adult endocrinology for low bone mass. She initially presented age two with short stature, nephrocalcinosis and mild intermittent hypercalcemia with hypercalciuria. She had no evidence of medullary sponge kidney or Fanconi syndrome and no bone deformities, pain or fractures. She had recurrent episodes of nephrolithiasis. In childhood, she was treated with hydrochlorothiazide to reduce urinary calcium. Upon review of prior investigations, she had persistent hypophosphatemia with phosphaturia, low PTH and a high-normal calcitriol. A diagnosis of HHRH was suspected and genetic testing confirmed a homozygous c.1483G>A (p.G495R) missense mutation of the SLC34A3 gene. She was started on oral phosphate replacement which normalized her serum phosphate, serum calcium and urine calcium levels over the subsequent 5 years. HHRH is an autosomal recessive condition that causes decreased renal reabsorption of phosphate, leading to hyperphosphaturia, hypophosphatemia and PTH-independent hypercalcemia due to the physiologic increase in calcitriol which also promotes hypercalciuria. Classically, patients present in childhood with bone pain, vitamin D-independent rickets and growth delay. This case of a SLC34A3 mutation illustrates the importance of investigating chronic hypophosphatemia even in the presence of other more common electrolyte abnormalities.\nLearning Points: Hypophosphatemia is an important diagnostic clue that should not be ignored, even in the face of more common electrolyte disorders.\n\nHHRH is a cause of PTH-independent hypophosphatemia that may also show hypercalcemia.\n\nHHRH is a cause of hypophosphatemic nephrocalcinosis that should not be treated with calcitriol, unlike other congenital phosphate wasting syndromes.\n\nSome congenital phosphate wasting disorders may not present until adolescence or early adulthood.","variants":[{"Name":"NM_001177316.2(SLC34A3):c.1483G>A (p.Gly495Arg)","Chromosome":"9","Start":"137236099","Stop":"137236099","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1941525,"rule_based_match":true,"evidence_text":"c.1483G>A (p.G495R)","llm_judgment":"PRESENT","evidence":"c.1483G>A (p.G495R)","abstract_start":1093,"abstract_end":1112}]}
{"pmid":"25059010","title":"Werner syndrome: clinical evaluation of two cases and a novel mutation.","abstract":"Werner syndrome (WS) is a premature aging disorder, inherited in an autosomal recessive pattern and caused by the mutation in the WRN gene. In this report we describe two male patients with negative family history who demonstrate characteristic findings of WS, with different mutations, including one novel mutation. The first case was a 47-year-old man who had been suffering from large, ischemic ulcers on both legs for 7 years. Physical examination revealed a thin and short man with severe wasting of all extremities. He had a high-pitched voice, hoarseness, a characteristic bird-like facies, bilateral cataracts, generalized osteoporosis, hypotrichosis, atrophic and poikilodermic skin, flexion contractures of hands, feet and knees, and soft tissue calcifications. Laboratory investigations revealed anemia, high erythrocyte sedimentation rate, low creatinine clearance, and high liver enzymes. Genetic analysis showed a homozygous novel 1bp-deletion in exon 19 of WRN, 2426/27delG, causing frameshift and protein truncation R809SfsX2, which has not been described before. The second case was a 23-year-old man who was referred for large callosities on both feet, present for 7 years. He complained of weakness, weight loss, wasting of muscles, and early graying of hair. The entire skin was thin, wrinkled and dry. Generalized hypotrichosis, scattered ephelid-like macules, sclerotic fingers, calcinosis cutis on ears, hyperpigmentation on elbows were the other alterations of skin. Skeletal survey revealed osteoporosis. Genetic analysis showed a homozygous known pathogenic splice site mutation c.3460-2A>G, causing skipping of Exon 30 in WRN.","variants":[{"Name":"NM_000553.6(WRN):c.3460-2A>G","Chromosome":"8","Start":"31147362","Stop":"31147362","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1516873,"rule_based_match":true,"evidence_text":"c.3460-2A>G","llm_judgment":"PRESENT","evidence":"c.3460-2A>G","abstract_start":1605,"abstract_end":1616},{"Name":"NM_000553.6(WRN):c.2427del (p.Arg809fs)","Chromosome":"8","Start":"31116506","Stop":"31116506","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":1440546,"rule_based_match":false,"evidence_text":"2426/27delG","llm_judgment":"PRESENT","evidence":"2426/27delG","abstract_start":977,"abstract_end":988}]}
{"pmid":"25066811","title":"Genetic and clinical analysis of ABCA4-associated disease in African American patients.","abstract":"Autosomal recessive Stargardt disease (STGD1) is caused by hundreds of mutations in the ABCA4 gene, which are often specific to racial and ethnic groups. Here, we investigated the ABCA4 variation and their phenotypic expression in a cohort of 44 patients of African American descent, a previously under-characterized racial group. Patients were screened for mutations in ABCA4 by next-generation sequencing and array-comparative genomic hybridization (aCGH), followed by analyses for pathogenicity by in silico programs. Thorough ophthalmic examination was performed on all patients. At least two (expected) disease-causing alleles in the ABCA4 gene were identified in 27 (61.4%) patients, one allele in 11 (25%) patients, and no ABCA4 mutations were found in six (13.6%) patients. Altogether, 39 different disease-causing ABCA4 variants, including seven new, were identified on 65 (74%) chromosomes, most of which were unique for this racial group. The most frequent ABCA4 mutation in this cohort was c.6320G>A (p.(R2107H)), representing 19.3% of all disease-associated alleles. No large copy number variants were identified in any patient. Most patients reported later onset of symptoms. In summary, the ABCA4 mutation spectrum in patients of West African descent differs significantly from that in patients of European descent, resulting in a later onset and \"milder\" disease.","variants":[{"Name":"NM_000350.3(ABCA4):c.6320G>A (p.Arg2107His)","Chromosome":"1","Start":"94001068","Stop":"94001068","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105337,"rule_based_match":true,"evidence_text":"c.6320G>A (p.(R2107H))","llm_judgment":"PRESENT","evidence":"c.6320G>A (p.(R2107H))","abstract_start":1002,"abstract_end":1024}]}
{"pmid":"31390136","title":"Confirmation and further delineation of the SMG9-deficiency syndrome, a rare and severe developmental disorder.","abstract":"INTRODUCTION: SMG9 deficiency is an extremely rare autosomal recessive condition originally described in three patients from two families harboring homozygous truncating SMG9 variants in a context of severe syndromic developmental disorder. To our knowledge, no additional patient has been described since this first report.\nMETHODS: We performed exome sequencing in a patient exhibiting a syndromic developmental delay and in her unaffected parents and report the phenotypic features.\nRESULTS: Our patient presented with a syndromic association of severe global developmental delay and diverse malformations, including cleft lip and palate, facial dysmorphic features, brain abnormalities, heart defect, growth retardation, and severe infections. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous.\nCONCLUSIONS: We confirm that bi-allelic truncating SMG9 variants cause a severe developmental syndrome including brain and heart malformations associated with facial dysmorphic features, severe growth and developmental delay with or without ophthalmological abnormalities, severe feeding difficulties, and life-threatening infections.","variants":[{"Name":"NM_019108.4(SMG9):c.1177C>T (p.Gln393Ter)","Chromosome":"19","Start":"43733659","Stop":"43733659","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":972693,"rule_based_match":true,"evidence_text":"NM_019108.3:c.1177C>T, p.(Gln393*)","llm_judgment":"PRESENT","evidence":"NM_019108.3:c.1177C>T, p.(Gln393*)","abstract_start":792,"abstract_end":826}]}
{"pmid":"19370764","title":"Identification and molecular characterization of six novel mutations in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTG) gene in patients with mucolipidosis III gamma.","abstract":"Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense (p.T286M) and nonsense (p.W111X) mutations and a transition in the obligate AG-dinucleotide of the intron 8 acceptor splice site (c.610-2A>G). Three microdeletions were also identified, two of which (c.611delG and c.640_667del28) were located within the coding region whereas one (c.609+28_610-16del) was located entirely within intron 8. RT-PCR analysis of the c.610-2A>G transition demonstrated that the change altered splicing, leading to the production of two distinct aberrantly spliced forms, viz. the skipping of exon 9 (p.G204_K247del) or the retention of introns 8 and 9 (p.G204VfsX28). RT-PCR analysis, performed on a patient homozygous for the intronic deletion (c.609+28_610-16del), failed to detect any GNPTG RNA transcripts. To determine whether c.609+28_610-16del allele-derived transcripts were subject to nonsense-mediated mRNA decay (NMD), patient fibroblasts were incubated with the protein synthesis inhibitor anisomycin. An RT-PCR fragment retaining 43 bp of intron 8 was consistently detected suggesting that the 33-bp genomic deletion had elicited NMD. Quantitative real-time PCR and GNPTG western blot analysis confirmed that the homozygous microdeletion p.G204VfsX17 had elicited NMD resulting in failure to synthesize GNPTG protein. Analysis of the sequences surrounding the microdeletion breakpoints revealed either intrinsic repetitivity of the deleted region or short direct repeats adjacent to the breakpoint junctions. This is consistent with these repeats having mediated the microdeletions via replication slippage and supports the view that the mutational spectrum of the GNPTG gene is strongly influenced by the properties of the local DNA sequence environment.","variants":[{"Name":"NM_032520.5(GNPTG):c.609+28_610-16del","Chromosome":"16","Start":"1362562","Stop":"1362595","ReferenceAlleleVCF":"GGTGGGCCTGGCTGGGAGCTGGGTGCTGCCCCTGC","AlternateAlleleVCF":"G","allel_id":34571,"rule_based_match":true,"evidence_text":"c.609+28_610-16del","llm_judgment":"PRESENT","evidence":"c.609+28_610-16del","abstract_start":568,"abstract_end":586},{"Name":"NM_032520.5(GNPTG):c.610-2A>G","Chromosome":"16","Start":"1362609","Stop":"1362609","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":34573,"rule_based_match":true,"evidence_text":"c.610-2A>G","llm_judgment":"PRESENT","evidence":"c.610-2A>G","abstract_start":417,"abstract_end":427},{"Name":"NM_032520.4(GNPTG):c.611delG","Chromosome":"16","Start":"1362610","Stop":"1362610","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":17834,"rule_based_match":true,"evidence_text":"c.611delG","llm_judgment":"PRESENT","evidence":"c.611delG","abstract_start":487,"abstract_end":496}]}
{"pmid":"34900253","title":"Congenital nephrotic syndrome in a Hispanic Guatemalan newborn associated with a","abstract":"Congenital nephrotic syndrome (CNS) is an autosomal recessive disorder usually detected in the first 3 months of life when the syndromes effects manifest, including edema and a failure to gain weight. A baby boy was admitted to the Neonatal Intensive Care Unit for prematurity (35 weeks) with unremarkable maternal prenatal laboratory tests. The patient had persistent systemic hypertension, hypoproteinemia, hypoalbuminemia and nephrotic range proteinuria. CNS was diagnosed, and genetic testing showed a homozygous variant, c.3024A>G (AGA>AGG) in exon 22 of the nephrin locus. Bioinformatics analysis suggested the genetic condition was likely a result of malfunctional DNA binding sites of transcription factors FOXL1 and FOXC1.","variants":[{"Name":"NM_004646.4(NPHS1):c.3024A>G (p.Arg1008=)","Chromosome":"19","Start":"35839322","Stop":"35839322","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":422260,"rule_based_match":true,"evidence_text":"c.3024A>G (AGA>AGG)","llm_judgment":"PRESENT","evidence":"c.3024A>G (AGA>AGG)","abstract_start":526,"abstract_end":545}]}
{"pmid":"30940775","title":"Identifying a","abstract":"Breast cancer (BC) is the most common female cancer found worldwide. It is responsible for 25% of all cancer patients in females. Hereditary BC accounts for about 5-10% of all BC cases. The breast cancer 1 gene (<i>BRCA1</i>) and the breast cancer 2 gene (<i>BRCA2</i>) are the two most-studied BC susceptibility genes. Genetic testing for disease-causing mutations in <i>BRCA1, BRCA2</i>, and other BC susceptibility genes is strongly recommended for members of families having a BC family history. The present study found a heterozygous c.5722_5723del mutation in the <i>BRCA2</i> exon 11 of a large Han-Chinese BC family using whole exome sequencing and Sanger sequencing. It may cause DNA double-strand breaks repair dysfunction by disturbing homologous recombination, further resulting in BC. The study findings may help supplement and further improve genetic testing strategies and BC risk estimation methodologies in China.","variants":[{"Name":"NM_000059.4(BRCA2):c.5722_5723del (p.Leu1908fs)","Chromosome":"13","Start":"32340073","Stop":"32340074","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":24359,"rule_based_match":true,"evidence_text":"c.5722_5723del","llm_judgment":"PRESENT","evidence":"c.5722_5723del","abstract_start":539,"abstract_end":553}]}
{"pmid":"17253930","title":"Characterization of missense mutations and large deletions in the ALPL gene by sequencing and quantitative multiplex PCR of short fragments.","abstract":"Hypophosphatasia is a rare inherited bone disorder characterized by defective bone and dental mineralization and deficiency of serum and liver/bone/kidney alkaline phosphatase activity. The disease is due to mutations in the alkaline phosphatase liver-type (ALPL) gene. Gross deletions or insertions have not previously been reported in this gene. We report here the characterization of nine novel ALPL gene mutations in a series of 8 patients affected by various forms of hypophosphatasia. The newly discovered mutations included five missense mutations (c.368C --> A, c.814C--> T, c.1196C--> T, c.1199C--> T, c.1283G--> C), two small deletions (c.797_802del, c.1044_1055del), and two large deletions. The large deletions were detected by quantitative multiplex polymerase chain reaction (PCR) of short fluorescent fragments (QMPSF). We conclude that QMPSF slightly reduces the proportion of undetected mutations in hypophosphatasia and improves genetic counselling in the affected families.","variants":[{"Name":"NM_000478.6(ALPL):c.368C>A (p.Ala123Asp)","Chromosome":"1","Start":"21563180","Stop":"21563180","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":540808,"rule_based_match":false,"evidence_text":"c.368C --> A","llm_judgment":"PRESENT","evidence":"c.368C --> A","abstract_start":556,"abstract_end":568},{"Name":"NM_000478.6(ALPL):c.814C>T (p.Arg272Cys)","Chromosome":"1","Start":"21570326","Stop":"21570326","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28723,"rule_based_match":false,"evidence_text":"c.814C--> T","llm_judgment":"PRESENT","evidence":"c.814C--> T","abstract_start":570,"abstract_end":581},{"Name":"NM_000478.6(ALPL):c.1283G>C (p.Arg428Pro)","Chromosome":"1","Start":"21576615","Stop":"21576615","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":980301,"rule_based_match":false,"evidence_text":"c.1283G--> C","llm_judgment":"PRESENT","evidence":"c.1283G--> C","abstract_start":611,"abstract_end":623}]}
{"pmid":"29491734","title":"Identification of a Missense Mutation in the α-galactosidase A Gene in a Chinese Family with Fabry Disease.","abstract":"INTRODUCTION: Fabry Disease (FD), the second most common lysosomal storage disorder after Gaucher disease, is characterized by variable clinical manifestations, including angiokeratoma, corneal dystrophy, recurrent episodes of extremity pain, renal impairment, cardiac complications and cerebrovascular manifestations. It is caused by mutations in the α-galactosidase A gene (gene symbol GLA) on chromosome Xq22, which leads to deficiency of lysosomal α-galactosidase A (α-Gal A), and subsequent accumulation of glycosphingolipids in various tissues and organs. The aim of this study is to identify the disease-causing mutation in a five-generation Chinese family with FD. A c.782G>T transversion (p.G261V) in the GLA gene was identified in four patients and two asymptomatic carriers by direct sequencing, and it co-segregated with the disease in the family. The variant is predicted to be disease-causing mutation and result in seriously abnormal function of α-Gal A. Four patients in this family present with classic phenotype of FD, including acroparesthesias, hypohidrosis, angiokeratomas and intermittent burning pain in extremity.\nCONCLUSION: The disease severity is similar among male and female patients. Our study extends the genotype-phenotype relationship between mutations in the GLA gene and clinical findings of FD, which may be helpful in the genetic counseling of patients with FD.","variants":[{"Name":"NM_000169.3(GLA):c.782G>T (p.Gly261Val)","Chromosome":"X","Start":"101398804","Stop":"101398804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":223932,"rule_based_match":true,"evidence_text":"c.782G>T transversion (p.G261V)","llm_judgment":"PRESENT","evidence":"c.782G>T transversion (p.G261V)","abstract_start":675,"abstract_end":706}]}
{"pmid":"26395884","title":"Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations.","abstract":"Mutations in the KCNA1 gene are known to cause episodic ataxia/myokymia syndrome type 1 (EA1). Here, we describe two families with unique presentations who were enrolled in an IRB-approved study, extensively phenotyped, and whole exome sequencing (WES) performed. Family 1 had a diagnosis of isolated cataplexy triggered by sudden physical exertion in multiple affected individuals with heterogeneous neurological findings. All enrolled affected members carried a KCNA1 c.941T>C (p.I314T) mutation. Family 2 had an 8-year-old patient with muscle spasms with rigidity for whom WES revealed a previously reported heterozygous missense mutation in KCNA1 c.677C>G (p.T226R), confirming the diagnosis of EA1 without ataxia. WES identified variants in KCNA1 that explain both phenotypes expanding the phenotypic spectrum of diseases associated with mutations of this gene. KCNA1 mutations should be considered in patients of all ages with episodic neurological phenotypes, even when ataxia is not present. This is an example of the power of genomic approaches to identify pathogenic mutations in unsuspected genes responsible for heterogeneous diseases.","variants":[{"Name":"NM_000217.3(KCNA1):c.941T>C (p.Ile314Thr)","Chromosome":"12","Start":"4912319","Stop":"4912319","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":415337,"rule_based_match":true,"evidence_text":"KCNA1 c.941T>C (p.I314T)","llm_judgment":"PRESENT","evidence":"KCNA1 c.941T>C (p.I314T)","abstract_start":464,"abstract_end":488},{"Name":"NM_000217.3(KCNA1):c.677C>G (p.Thr226Arg)","Chromosome":"12","Start":"4912055","Stop":"4912055","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":28531,"rule_based_match":true,"evidence_text":"KCNA1 c.677C>G (p.T226R)","llm_judgment":"PRESENT","evidence":"KCNA1 c.677C>G (p.T226R)","abstract_start":645,"abstract_end":669}]}
{"pmid":"15300860","title":"Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11).","abstract":"Both myosin 7A (MYO7A) and calmodulin (CaM) are required for transduction and adaptation processes in inner ear hair cells. We identified a novel heterozygous missense mutation (c.2557C>T; p.R853C) in a family with autosomal dominant non-syndromic hearing loss that changes an evolutionarily invariant residue of the fifth IQ motif (IQ5), a putative calmodulin (CaM) binding domain, of MYO7A. Functional effects of the p.R853C mutation were investigated in a physiological cellular environment by expressing MYO7A IQ5-containing peptides in smooth muscle cells of microarteries, in which overexpression of wildtype IQ5 (with intact calmodulin binding) would be expected to compete with myosin light chain kinase (MLCK) for CaM binding. Indeed, analysis of calmodulin-dependent vasoconstriction suggests constitutive binding of CaM to the wildtype, but not the p.R853C-mutated IQ5 motif at all physiologically relevant Ca2+ concentrations. Thus our data suggest a disturbed CaM/MYO7A binding of the p.R853C mutant, this amino acid change may result in impaired adaptation to environmental stimuli and progressive deterioration of hearing transduction in heterozygotes. A defect in CaM/MYO7A interaction represents a novel pathomechanism for genetic hearing loss. It provides an attractive molecular target for therapeutic interventions aimed to delay or prevent the onset of hearing loss in families with mutations in myosin IQ domains.","variants":[{"Name":"NM_000260.4(MYO7A):c.2557C>T (p.Arg853Cys)","Chromosome":"11","Start":"77179924","Stop":"77179924","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1324336,"rule_based_match":true,"evidence_text":"c.2557C>T; p.R853C","llm_judgment":"PRESENT","evidence":"c.2557C>T; p.R853C","abstract_start":178,"abstract_end":196}]}
{"pmid":"16868655","title":"Is autosomal recessive deafness associated with oculocutaneous albinism a \"coincidence syndrome\"?","abstract":"Hearing impairment is frequently found associated with pigmentary disorders in many syndromes. However, total oculocutaneous albinism (OCA) associated with deafness has been described only once, by Ziprkowski and Adam (Arch Dermatol 89:151-155, 1964) in an inbred family. A syndrome associating deafness and OCA was suggested by the authors, but two separate recessive genes segregating in this inbred group were also proposed later by Fraser (OMIM # 220900). Combined deafness and total OCA were also observed by us in a family originally reported to be nonconsanguineous but in which haplotyping showed evidence of a common ancestry: the proband was affected by both diseases, one of his sisters had only OCA and another sister had only deafness. Both the proband and his deaf sister were found to be homozygotes for the 35delG mutation (GJB2 gene), the most frequent cause of hereditary deafness. Linkage analysis with markers close to the four known OCA loci excluded linkage to OCA1, OCA2, and OCA3, and homozygosity in markers near OCA4 locus was observed. Sequencing of the corresponding gene (MATP) revealed a c.1121delT mutation, which leads to a stop codon at position 397 (L374fsX397). Clearly, the combined occurrence of deafness and albinism in this pedigree was due to mutations in two different genes, showing autosomal recessive inheritance. We speculate that the putative syndrome reported by Ziprkowski and Adam might have resulted from the co-occurrence of autosomal recessive deafness and albinism in the same pedigree, as suggested by Fraser.","variants":[{"Name":"NM_016180.5(SLC45A2):c.1121del (p.Leu374fs)","Chromosome":"5","Start":"33951589","Stop":"33951589","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":19545,"rule_based_match":true,"evidence_text":"c.1121delT","llm_judgment":"PRESENT","evidence":"c.1121delT","abstract_start":1118,"abstract_end":1128}]}
{"pmid":"26715087","title":"The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation.","abstract":"INTRODUCTION: CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles. The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model.\nRESULTS: We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. This finding was the basis for developing the 'NOTCH3 score', a quantitative measure for the NOTCH3 accumulation load. This score proved to be a robust and sensitive method to assess the progression of NOTCH3 accumulation, and a feasible biomarker for pre-clinical therapeutic testing.\nCONCLUSIONS: This novel, translational CADASIL mouse model is a suitable model for pre-clinical testing of therapeutic strategies aimed at delaying or reversing NOTCH3 accumulation, using the NOTCH3 score as a biomarker.","variants":[{"Name":"NM_000435.3(NOTCH3):c.544C>T (p.Arg182Cys)","Chromosome":"19","Start":"15192095","Stop":"15192095","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24259,"rule_based_match":true,"evidence_text":"c.544C > T, p.Arg182Cys","llm_judgment":"PRESENT","evidence":"c.544C > T, p.Arg182Cys","abstract_start":879,"abstract_end":902}]}
{"pmid":"23462331","title":"Four novel GALC gene mutations in two Chinese patients with Krabbe disease.","abstract":"Krabbe disease (OMIM #245200) is a rare autosomal recessive leukodystrophy caused by deficiency of galactocerebrosidase (GALC) activity. We identified four novel mutations of the GALC gene in two unrelated Chinese families with Krabbe disease: one insertion mutation, c.1836_1837insT, and one nonsense mutation, c.599C>A (p.S200X), in an infantile patient, and one deletion mutation, c.1911+1_1911+5delGTAAG, and one missense mutation, c.2041G>A, in an adult late-onset patient. This is the first identification of GALC mutations in the Chinese population.","variants":[{"Name":"NM_000153.4(GALC):c.599C>A (p.Ser200Ter)","Chromosome":"14","Start":"87982227","Stop":"87982227","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":186921,"rule_based_match":true,"evidence_text":"c.599C>A (p.S200X)","llm_judgment":"PRESENT","evidence":"c.599C>A (p.S200X)","abstract_start":312,"abstract_end":330},{"Name":"NM_000153.4(GALC):c.1911+1_1911+5del","Chromosome":"14","Start":"87939900","Stop":"87939904","ReferenceAlleleVCF":"ACTTAC","AlternateAlleleVCF":"A","allel_id":547600,"rule_based_match":true,"evidence_text":"c.1911+1_1911+5delGTAAG","llm_judgment":"PRESENT","evidence":"c.1911+1_1911+5delGTAAG","abstract_start":384,"abstract_end":407},{"Name":"NM_000153.4(GALC):c.2041G>A (p.Val681Met)","Chromosome":"14","Start":"87934749","Stop":"87934749","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":204567,"rule_based_match":true,"evidence_text":"c.2041G>A","llm_judgment":"PRESENT","evidence":"c.2041G>A","abstract_start":436,"abstract_end":445}]}
{"pmid":"25557349","title":"Early-onset epileptic encephalopathy with hearing loss in two siblings with TBC1D24 recessive mutations.","abstract":"BACKGROUND: Recent studies have shown that recessive mutations in the TBC1D24 gene cause a variety of epilepsy syndromes, DOORS syndrome and nonsyndromic deafness.\nMETHODS/RESULTS: We report on two siblings with hypotonia, early-onset epileptic encephalopathy, and severe developmental delay. The patients presented with clonic and myoclonic jerks within 1 h after birth. The seizures were resistant to treatment. Audiologic examination showed bilateral sensorineural hearing loss in both siblings. Genetic analysis revealed compound heterozygous mutations in the TBC1D24 gene: a novel missense mutation c.32A > G (p.Asp11Gly) in exon 2 and a frameshift mutation c.1008delT (p.His336Glnfs*12) in exon 4.\nCONCLUSION: This report supports previous observations that mutations in TBC1D24 cause diverse phenotypes. In fact, early-onset epileptic encephalopathy with sensorineural hearing loss is an additional phenotype observed in patients with recessive TBC1D24 mutations.","variants":[{"Name":"NM_001199107.2(TBC1D24):c.1008del (p.His336fs)","Chromosome":"16","Start":"2498262","Stop":"2498262","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":96874,"rule_based_match":true,"evidence_text":"c.1008delT (p.His336Glnfs*12)","llm_judgment":"PRESENT","evidence":"c.1008delT (p.His336Glnfs*12)","abstract_start":663,"abstract_end":692}]}
{"pmid":"29761599","title":"Analysis of the exome aggregation consortium (ExAC) database suggests that the BAP1-tumor predisposition syndrome is underreported in cancer patients.","abstract":"The BAP1-tumor predisposition syndrome (BAP1-TPDS) has been recently identified to predispose patients to a variety of cancers and preneoplastic lesions. About 130 unrelated probands have been identified worldwide; however, the impact of the syndrome is suspected to be much larger given the diversity of the cancer phenotype. To evaluate the frequency of germline BAP1 mutations in the general and cancer populations, we analyzed the Exome Aggregation Consortium (ExAC), a database that contains 53105 exomes of unrelated individuals unaffected by cancer (general population) and exomes of 7601 unrelated individuals affected by cancer provided by the Cancer Genome Atlas (TCGA, cancer subjects). BAP1 null variants were seen at much higher frequency in the cancer subjects (0.0526%) compared to the general population (0.00188%) with a relative risk of 27.93 and (P = 0.0011, [95% CI: 3.122-249.883], Fisher's exact test). We also studied a reported BAP1 null variant, c.1203T > G, p.T401* (rs200156887), observed commonly in the general population. Sequencing and restriction fragment polymorphism of the RT-4 cell line that contains this variant revealed that it is in fact a 3bp deletion/insertion, c.1201_1203delinsGAG, a likely benign missense alteration p.Y401E explaining the relative high frequency of this variant in the general population. In conclusion, germline null mutations in BAP1 have a significantly higher frequency in cancer patients than the general population. Given the low frequency of reported families with BAP1-TPDS, our results suggest that the syndrome is underreported especially in patients with cancer.","variants":[{"Name":"NM_004656.4(BAP1):c.1203T>G (p.Tyr401Ter)","Chromosome":"3","Start":"52404500","Stop":"52404500","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":575710,"rule_based_match":true,"evidence_text":"c.1203T > G, p.T401*","llm_judgment":"PRESENT","evidence":"c.1203T > G, p.T401*","abstract_start":971,"abstract_end":991}]}
{"pmid":"22759192","title":"Two novel mutations of the NCSTN gene in Chinese familial acne inverse.","abstract":"BACKGROUND: Acne inversa (AI; MIM 142690), or hidradenitis suppurativa (HS), is a type of autosomal-dominant genodermatosis caused by mutations in γ-secretase. The complex of γ-secretase is a transmembrane protease that catalyses the cleavage of a set of membrane proteins and is comprised of four subunits encoded by four genes, including PSEN1, PSENEN, NCSTN and APH1. However, mutations associated with AI vary significantly, and it is important to define the specific mutation with a particular AI patient.\nOBJECTIVE: To determine specific mutations in the γ-secretase gene associated with two Chinese AI families.\nMETHODS: Two families of three generations with apparent AI symptoms were examined through proband analysis. Genomic DNAs of the family members and a cohort of 100 healthy individuals were isolated and subjected to polymerase chain reaction (PCR) and direct DNA sequencing.\nRESULTS: Two heterozygous missense mutations, c.647A>C (p.Q216P) in the exon 6, and c.223G>A (p.V75I) in the exon 3 of the NCSTN gene, were identified in the two families respectively. No mutations were found in 100 healthy individuals.\nCONCLUSIONS: We have identified two novel mutations within the NCSTN gene associated with AI.","variants":[{"Name":"NM_015331.3(NCSTN):c.223G>A (p.Val75Ile)","Chromosome":"1","Start":"160349031","Stop":"160349031","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1386137,"rule_based_match":true,"evidence_text":"c.223G>A (p.V75I)","llm_judgment":"PRESENT","evidence":"c.223G>A (p.V75I)","abstract_start":977,"abstract_end":994}]}
{"pmid":"33465333","title":"Variable expressivity in patients with autosomal recessive retinitis pigmentosa associated with the gene","abstract":"PURPOSE: In a cohort of eight families (11 patients) with autosomal recessive retinitis pigmentosa (arRP), we clinically characterized disease associated with mutations in <i>CNGB1</i>.\nMETHODS: Visual function was determined by measuring the patients' visual acuity, dark- and light-adapted perimetry, and by full-field electroretinography. Retinal structure was evaluated with spectral-domain optical coherence tomography, fundus imaging, and autofluorescence imaging.\nRESULTS: Age of onset ranged from 4 to 49 years (mean [SD] 26 [17], median 27 years). The age at visit was 27-54 years, mean 37 (17). The range of visual acuity was logMAR -0.1 to 1.3 (Snellen 20/16 to 20/400) in the right eye and -0.1 to 0.9 (Snellen 20/16 to 20/160) in the left eye. Electrophysiological testing in five patients showed an absence of the rod response. Cone responses ranged from normal to severely reduced. The patients exhibited loss of rod vision more severe than cone vision. Funduscopic images showed widespread retinal degeneration with pigment clumping, optic disk pallor, arteriole attenuation, and a peri-foveal ring of hyper autofluorescence. Three families were tested for olfactory dysfunction and results indicated mild to complete anosmia in individuals with mutations in <i>CNGB1</i>. Genetic analysis revealed 6 novel variants, c.2127 C > G, p.Phe709Leu; c.1431 C > A, p.Cys477*; c.2034 G > A, p.Trp678*; c.2092 T > C, p.Cys698Arg; and c.583 + 2 T > C, c.2305-34 G > A and 3 variants that have been previously described, c.2957A>T, p.Asn986Ile; c.2544dup, p.Leu849Alafs*3; and c.2492 + 1 G > A.\nDISCUSSION: This is the first report for six novel <i>CNGB1</i> variants associated with arRP. Two families had olfactory dysfunction in patients with arRP and family members who were heterozygous for a <i>CNGB1</i> mutation. Additionally, findings demonstrated variable penetrance and expressivity of disease in these patients.","variants":[{"Name":"NM_001297.5(CNGB1):c.2127C>G (p.Phe709Leu)","Chromosome":"16","Start":"57917307","Stop":"57917307","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":856856,"rule_based_match":true,"evidence_text":"c.2127 C > G, p.Phe709Leu","llm_judgment":"PRESENT","evidence":"c.2127 C > G, p.Phe709Leu","abstract_start":1333,"abstract_end":1358},{"Name":"NM_001297.5(CNGB1):c.583+2T>C","Chromosome":"16","Start":"57960480","Stop":"57960480","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1056335,"rule_based_match":true,"evidence_text":"c.583 + 2 T > C","llm_judgment":"PRESENT","evidence":"c.583 + 2 T > C","abstract_start":1441,"abstract_end":1456}]}
{"pmid":"17896316","title":"An unusual presentation of macular corneal dystrophy associated with uniparental isodisomy and a novel Leu173Pro mutation.","abstract":"PURPOSE: To report an unusual phenotype of macular corneal dystrophy (MCDC1) associated with a novel CHST6 mutation transmitted via maternal isodisomy.\nMETHODS: Slit lamp examination of the patient and his parents was performed. DNA was collected from each individual for amplification and sequencing of the CHST6 coding region, as well as exons 4 and 12 of TGFBI. Serum antigenic keratan sulfate (AgKS) levels were measured for confirmation of the diagnosis and subtyping of MCDC1. Quantitative real-time PCR (qPCR) was performed to differentiate between homozygous and hemizygous sequence variants. Genotyping at 12 single nucleotide polymorphisms (SNPs) within and surrounding CHST6 was performed to determine the pattern of inheritance of mutations identified in CHST6.\nRESULTS: Examination of the proband revealed bilateral, discrete, axially distributed, gray-white deposits at the level of Bowman's layer, with diffuse fine corneal stromal haze. Screening of TGFBI exons 4 and 12 in the proband did not reveal any allelic variants. However, screening of CHST6 in the proband demonstrated a novel homozygous missense mutation involving a highly conserved amino acid (c.518T > C; Leu173Pro) and undetectable serum AgKS levels in the proband confirmed the diagnosis of type I MCDC1. Quantitative PCR confirmed that both copies of CHST6 were present in the patient, excluding the possibility that the mutation was present in the hemizygous state. The results of genotyping were consistent with maternal isodisomy, as the patient was homozygous for an allele possessed by his mother at each SNP, two of which were informative and demonstrated nonpaternal inheritance.\nCONCLUSION: A phenotypically unusual variant of MCDC1 was found to be associated with the novel Leu173Pro mutation in CHST6, transmitted via uniparental isodisomy, a previously unreported pattern of inheritance in the corneal dystrophies.","variants":[{"Name":"NM_021615.5(CHST6):c.518T>C (p.Leu173Pro)","Chromosome":"16","Start":"75479311","Stop":"75479311","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1049857,"rule_based_match":true,"evidence_text":"c.518T > C; Leu173Pro","llm_judgment":"PRESENT","evidence":"c.518T > C; Leu173Pro","abstract_start":1173,"abstract_end":1194}]}
{"pmid":"30302839","title":"Compound heterozygous missense mutations p.Leu207Pro and p.Tyr544Cys in TGM1 cause a severe form of lamellar ichthyosis.","abstract":"TGM1 is the most common gene responsible for lamellar ichthyosis. Previous studies have suggested that patients with lamellar ichthyosis carrying two missense mutations in TGM1 show significantly less severe phenotypes than those with at least one truncating mutation in TGM1. Here, we report a patient with severe lamellar ichthyosis who was compound heterozygous for TGM1 missense mutations, including a novel one. A 22-year-old Japanese man presented with large, dark brown, plate-like scales on the extremities and small adherent scales on the face and trunk. His other clinical findings included ectropion, hair loss, hypohidrosis, hyperthermia in summer, palmoplantar keratoderma and constriction of the fingers. Dermoscopy revealed accentuated sulci cutis with numerous large keratotic plugs in the cristae cutis. Histologically, orthohyperkeratosis and mild acanthosis were noted. Electron microscopy showed reduced cornified envelope thickness and numerous lipid droplets in the stratum corneum. Mutation analysis revealed the patient to be compound heterozygous for missense mutations, c.620T>C (p.Leu207Pro) and c.1631A>G (p.Tyr544Cys), in TGM1. Furthermore, we showed that TGM1 enzymatic activity was largely absent in his epidermis. These findings led us to diagnose him as having lamellar ichthyosis. This study has two important notions. First, even two missense mutations in TGM1 can cause severe lamellar ichthyosis. Second, this is the first report of dermoscopic findings of lamellar ichthyosis, implicating the obstruction of sweat glands by keratotic plugs in the pathogenesis of hypohidrosis in the disease. In conclusion, this study provides further insights into genotype-phenotype correlations and pathogenesis in lamellar ichthyosis.","variants":[{"Name":"NM_000359.3(TGM1):c.1631A>G (p.Tyr544Cys)","Chromosome":"14","Start":"24255378","Stop":"24255378","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":547806,"rule_based_match":true,"evidence_text":"c.1631A>G (p.Tyr544Cys)","llm_judgment":"PRESENT","evidence":"c.1631A>G (p.Tyr544Cys)","abstract_start":1123,"abstract_end":1146}]}
{"pmid":"27214836","title":"Further characterisation of the recently described SLC26A4 c.918+2T>C mutation and reporting of a novel variant predicted to be damaging.","abstract":"Pendred syndrome (PS) is the second most common type of autosomal recessive syndromic hearing loss (HL). It is characterised by sensorineural HL and goiter with occasional hypothyroidism. These features are generally accompanied by malformations of the inner ear, as enlarged vestibular aqueduct (EVA). In about 50% of probands, mutations in the SLC26A4 gene are the cause of the disease. Here we report the case of a Portuguese female, aged 47, presenting with severe to profound HL and hypothyroidism. Her mother and sister, both deceased, had suffered from HL and goiter. By MRI and CT, an enlarged vestibular aqueduct and endolymphatic sac were observed. Molecular study of the patient included screening for GJB2 coding mutations and GJB6 common deletions followed by screening of all SLC26A4 exons, as well as intronic regions 8 and 14. Mutation c.918+2T>C was found for the first time in homozygosity in the intronic region 7 of the SLC26A4 gene. Whilst sequencing the control samples, a novel mutation c.821C>G was found in heterozygosity in the exon 7 of SLC26A4 gene and was predicted to be damaging. This study thus led to the finding of two novel SLC26A4 genotypes and provides new insight on the phenotypic features associated with PS.","variants":[{"Name":"NM_000441.2(SLC26A4):c.918+2T>C","Chromosome":"7","Start":"107683356","Stop":"107683356","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":357535,"rule_based_match":true,"evidence_text":"c.918+2T>C","llm_judgment":"PRESENT","evidence":"c.918+2T>C","abstract_start":852,"abstract_end":862}]}
{"pmid":"34747535","title":"Targeted massively parallel sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas: An analysis of 51 individuals in a single-center experience.","abstract":"Constitutional LZTR1 or SMARCB1 pathogenic variants (PVs) have been found in ∼86% of familial and ∼40% of sporadic schwannomatosis cases. Hence, we performed massively parallel sequencing of the entire LZTR1, SMARCB1, and NF2 genomic loci in 35 individuals with schwannomas negative for constitutional first-hit PVs in the LZTR1/SMARCB1/NF2 coding sequences; however, with 22q deletion and/or a different NF2 PV in each tumor, including six cases with only one tumor available. Furthermore, we verified whether any other LZTR1/SMARCB1/NF2 (likely) PVs could be found in 16 cases carrying a SMARCB1 constitutional variant in the 3'-untranslated region (3'-UTR) c.*17C>T, c.*70C>T, or c.*82C>T. As no additional variants were found, functional studies were performed to clarify the effect of these 3'-UTR variants on the transcript. The 3'-UTR variants c.*17C>T and c.*82C>T showed pathogenicity by negatively affecting the SMARCB1 transcript level. Two novel deep intronic SMARCB1 variants, c.500+883T>G and c.500+887G>A, resulting in out-of-frame missplicing of intron 4, were identified in two unrelated individuals. Further resequencing of the entire repeat-masked genomics sequences of chromosome 22q in individuals negative for PVs in the SMARCB1/LZTR1/NF2 coding- and noncoding regions revealed five potential schwannomatosis-predisposing candidate genes, that is, MYO18B, NEFH, SGSM1, SGSM3, and SBF1, pending further verification.","variants":[{"Name":"NM_003073.5(SMARCB1):c.*82C>T","Chromosome":"22","Start":"23834262","Stop":"23834262","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":243654,"rule_based_match":true,"evidence_text":"c.*82C>T","llm_judgment":"PRESENT","evidence":"c.*82C>T","abstract_start":683,"abstract_end":691}]}
{"pmid":"31006083","title":"A case of X-linked retinoschisis with atypical fundus appearance.","abstract":"PURPOSE: Mutations in the RS1 gene are known to cause retinoschisis, an X-linked hereditary retinal degeneration. Here, we present a case of atypical retinoschisis with clinical findings of retinoschisis and retinitis pigmentosa.\nMETHODS: This report is an observational case report. The detailed ophthalmological examinations included visual field determination, multimodal imaging and electrophysiological recordings. Targeted next-generation sequencing of a retinal disease gene panel was performed.\nRESULTS: The 55-year-old male, highly hyperopic patient, presented with a best-corrected Snellen visual acuity of 20/100 in the right eye and 20/400 in the left eye. In the kinetic visual field, there was a superior scotoma, as well as a ring scotoma in the inferior hemisphere in the right eye and a concentric visual field constriction to 10° in the left eye. Funduscopy revealed marked pigmentary changes (i.e. bone spicules) in the mid-periphery bilaterally and symmetrically, as well as two small intra-retinal haemorrhages in the left eye. Full-field electroretinography recordings showed extinguished rod and cone responses. Diagnostic-genetic testing revealed a hemizygous missense mutation in the RS1 gene (c.305G > A; p.Arg102Gln) was identified.\nCONCLUSION: We present a case of atypical retinoschisis with clinical findings of retinitis pigmentosa.","variants":[{"Name":"NM_000330.4(RS1):c.305G>A (p.Arg102Gln)","Chromosome":"X","Start":"18647212","Stop":"18647212","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":24935,"rule_based_match":true,"evidence_text":"c.305G > A; p.Arg102Gln","llm_judgment":"PRESENT","evidence":"c.305G > A; p.Arg102Gln","abstract_start":1219,"abstract_end":1242}]}
{"pmid":"30025130","title":"Phenotype Variations Caused by Mutations in the RP1L1 Gene in a Large Mainly German Cohort.","abstract":"Purpose: Mutations in the retinitis pigmentosa-1-like-1 (RP1L1) gene are the major cause of autosomal dominant occult macular dystrophy (OCMD), while recessive mutations have been linked to autosomal recessive retinitis pigmentosa (arRP). We present the clinical phenotype of a large German OCMD cohort, as well as four RP patients.\nMethods: A total of 42 OCMD patients (27 families) and 4 arRP patients (3 families) with genetically confirmed mutations in RP1L1 were included. Genomic DNA was analyzed by targeted analysis of the c.133C>T;p.R45W mutation for all RP or macular dystrophy-related genes. All patients underwent ophthalmologic examination including psychophysical tests, electrophysiology, fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT). Follow-up time was up to 12 years.\nResults: In 25 OCMD index patients genomic testing revealed the heterozygous mutation c.133C>T;p.R45W in RP1L1; one patient was homozygous for the mutation. Two OCMD patients displayed the variants c.3599G>A;p.G1200D and c.2849G>A;p.R950H, respectively, in a heterozygous state. All OCMD patients showed characteristic clinical findings and typical microstructural photoreceptor changes. Two arRP patients displayed the novel homozygous mutations c.3022C>T;p.Q1008* and c.1107G>A;p.W369*, respectively, while two RP-siblings carried the two heterozygous mutations c.455G>A;p.R152Q and c.5959C>T;p.Q1987*, the first also being novel. All arRP cases were mild with disease onset ≈30 years and preserved ERG-responses.\nConclusions: OCMD phenotype showed consistent clinical findings including classical microstructural changes on SD-OCT. An important hallmark of RP1L1-related OCMD is the dominant family history with reduced penetrance. Furthermore, novel mutations in association with arRP were identified, outlining the complexity of the protein.","variants":[{"Name":"NM_178857.6(RP1L1):c.133C>T (p.Arg45Trp)","Chromosome":"8","Start":"10623069","Stop":"10623069","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17232,"rule_based_match":true,"evidence_text":"c.133C>T;p.R45W","llm_judgment":"PRESENT","evidence":"c.133C>T;p.R45W","abstract_start":531,"abstract_end":546},{"Name":"NM_178857.6(RP1L1):c.455G>A (p.Arg152Gln)","Chromosome":"8","Start":"10622747","Stop":"10622747","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1201905,"rule_based_match":true,"evidence_text":"c.455G>A;p.R152Q","llm_judgment":"PRESENT","evidence":"c.455G>A;p.R152Q","abstract_start":1393,"abstract_end":1409},{"Name":"NM_178857.6(RP1L1):c.3022C>T (p.Gln1008Ter)","Chromosome":"8","Start":"10611076","Stop":"10611076","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":612797,"rule_based_match":true,"evidence_text":"c.3022C>T;p.Q1008*","llm_judgment":"PRESENT","evidence":"c.3022C>T;p.Q1008*","abstract_start":1276,"abstract_end":1294}]}
{"pmid":"27120018","title":"Gain-of-Function Mutations in RARB Cause Intellectual Disability with Progressive Motor Impairment.","abstract":"Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.","variants":[{"Name":"NM_000965.5(RARB):c.638T>C (p.Leu213Pro)","Chromosome":"3","Start":"25580574","Stop":"25580574","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":215046,"rule_based_match":true,"evidence_text":"c.638T>C (p.Leu213Pro)","llm_judgment":"PRESENT","evidence":"c.638T>C (p.Leu213Pro)","abstract_start":592,"abstract_end":614},{"Name":"NM_000965.5(RARB):c.1159C>T (p.Arg387Cys)","Chromosome":"3","Start":"25596428","Stop":"25596428","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":94343,"rule_based_match":true,"evidence_text":"c.1159C>T (p.Arg387Cys)","llm_judgment":"PRESENT","evidence":"c.1159C>T (p.Arg387Cys)","abstract_start":161,"abstract_end":184}]}
{"pmid":"20051841","title":"Identification and functional characterization of a novel nonsense mutation in FGA accounting for congenital afibrinogenemia in six Egyptian patients.","abstract":"Congenital afibrinogenemia is a rare coagulation disorder attributed to over forty mutations found either in homozygosity or in compound heterozygosity, the majority localized in FGA encoding the fibrinogen Aalpha-chain. Despite the number of genetic analyses performed the study of additional patients still allows the identification of novel mutations and a better understanding of fibrinogen structure and function. Here we report the identification and functional analysis of a novel nonsense mutation in FGA exon 5: c.718C>T (CAG>TAG) p.Q240X (Q221X in the mature chain lacking the signal peptide), accounting for fibrinogen deficiency in six Egyptian patients. Expression of the mutant Aalpha-chain cDNA in combination with wild-type Bbeta-chain and gamma-chain cDNAs demonstrated that although the mutant chain could be detected in the cell media of transfected COS-7 cells it was less secreted in comparison to the wild-type Aalpha-chain. Our patients were all homozygous for p.Q240X(Q221X) yet their clinical spectrum varied considerably in their onset of presentation or severity, with bleeding ranging from moderate mucous membrane bleeds in adolescence to life threatening intracranial hemorrhage in infancy.","variants":[{"Name":"NM_021871.4(FGA):c.718C>T (p.Gln240Ter)","Chromosome":"4","Start":"154586711","Stop":"154586711","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1669131,"rule_based_match":true,"evidence_text":"c.718C>T (CAG>TAG) p.Q240X","llm_judgment":"PRESENT","evidence":"c.718C>T (CAG>TAG) p.Q240X","abstract_start":521,"abstract_end":547}]}
{"pmid":"20683989","title":"A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder.","abstract":"Peroxisomal biogenesis disorders (PBD) are groups of inherited neurometabolic disorders caused by defects in PEX genes. We report on a female infant, born to a consanguineous parents (first degree cousins), who presented with inactivity, poor sucking, and hypotonia early in the neonatal period. She had subtle dysmorphic features. Liver function tests were impaired with raised liver enzymes, conjugated and unconjugated hyperbilirubinemia. CT of the brain showed diffuse bilateral changes. She developed seizures with an abnormal EEG. Plasma very long chain fatty acid analysis showed high C26:0 levels and increasedC26:0/C22:0 and C24:0/C22:0 ratios, which is consistent with a PBD. Studies in fibroblasts including plasmalogen biosynthesis, peroxisomal fatty acid alfa and beta oxidation confirmed the diagnosis of PBD. Immunofluoresence microscopy revealed the absence of peroxisomes in fibroblasts. The patient was assigned to the PEX19 complementation group. Subsequent mutation analysis of the PEX19 gene revealed homozygosity for a c.320delA frameshift mutation. The patient had a stormy course with multiple admissions to the pediatric intensive care unit with pneumonia, liver impairment, sepsis, and epilepsy. At 1 year of age she developed metabolic acidosis with normal anion gap, proteinuria, aminoaciduria, and glucosuria consistent with a renal tubular defect. Abdominal ultrasound showed multiple gallstones. Other causes of gallstones like haemoglobinopathy were excluded. So far, only two siblings had been reported with mutations in the PEX19 gene. Our patient showed a previously unrecognized association of gallstones and a renal tubular defect with a PBD.","variants":[{"Name":"NM_002857.4(PEX19):c.320del (p.Lys107fs)","Chromosome":"1","Start":"160282970","Stop":"160282970","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":39017,"rule_based_match":true,"evidence_text":"c.320delA","llm_judgment":"PRESENT","evidence":"c.320delA","abstract_start":1041,"abstract_end":1050}]}
{"pmid":"30542963","title":"Clinical and genetic characterization of an Italian family with slow-channel syndrome.","abstract":"INTRODUCTION: The slow-channel congenital myasthenic syndrome (SCCMS) is a postsynaptic form of congenital myasthenic syndromes (CMSs), a clinically heterogeneous group of disorders caused by genetic defects leading to an abnormal signal transmission at the endplate.\nMETHODS: We report clinical and molecular data of a multigenerational family in which the presentation of a progressive proximal-distal weakness with ocular involvement led to a number of different clinical diagnoses.\nRESULTS: A comprehensive genetic study which included whole-genome linkage analysis and whole-exome sequencing identified a heterozygous missense substitution (c.721C>T, p.L241F) in the ε subunit of the acetylcholine receptor (CHRNE) that was consistent with clinical weakness in all patients.\nDISCUSSION: SCCMS is characterized by a broad and heterogeneous clinical phenotype in which disease onset, symptoms, severity, and progression can be highly variable even between family members. The identification of a CHRNE mutation allowed to make the definitive diagnosis of CMS in this family and contributed to define the clinical spectrum of this disease.","variants":[{"Name":"NM_000080.4(CHRNE):c.721C>T (p.Leu241Phe)","Chromosome":"17","Start":"4901071","Stop":"4901071","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":33391,"rule_based_match":true,"evidence_text":"c.721C>T, p.L241F","llm_judgment":"PRESENT","evidence":"c.721C>T, p.L241F","abstract_start":646,"abstract_end":663}]}
{"pmid":"24637349","title":"A novel HSF4 gene mutation causes autosomal-dominant cataracts in a Chinese family.","abstract":"Congenital cataracts are a significant cause of visual impairment or blindness in children. One-third of cases estimated to have a genetic cause. We carried out gene analysis and bioinformatics analysis to map the locus and to identify the underlying genetic defect in a 12-member, four-generation Chinese family affected with bilateral congenital cataracts. We screened individuals of the family and discovered a distinct missense mutation in HSF4 (a gene at this locus that encodes teat-shock transcription factor 4). Bioinformatics analysis was used to determine possible changes in the protein structure that could affect the phenotype. Sequencing of the candidate genes showed a heterozygous c.69 G→T change in the heat shock transcription factor 4 (HSF4) gene, which resulted in the substitution of a lysine with an asparagine (p. K23N). This mutation cosegregated with all affected individuals and was not observed in unaffected family members. Bioinformatics analysis indicated that the p. K23N mutation was predicted to be disease causing. This is the first report of the novel missense mutation, c.69 G→T (p. K23N), in exon 3 of the HSF4 locus on 16q21-q22 associated with bilateral congenital cataracts in a Chinese family. This novel mutation could enable propergenetic diagnostics and counseling in affected families and could lead to a better understanding of the structure and function of HSF4 in health and disease.","variants":[{"Name":"NM_001374675.1(HSF4):c.69G>T (p.Lys23Asn)","Chromosome":"16","Start":"67164880","Stop":"67164880","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1871446,"rule_based_match":false,"evidence_text":"c.69 G→T (p. K23N)","llm_judgment":"PRESENT","evidence":"c.69 G→T (p. K23N)","abstract_start":1106,"abstract_end":1124}]}
{"pmid":"24842371","title":"Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency.","abstract":"Autosomal recessive mutations in UNC13D, the gene that encodes Munc13-4, are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Munc13-4 expression is obligatory for exocytosis of lytic granules, facilitating cytotoxicity by T cells and natural killer (NK) cells. The mechanisms regulating Munc13-4 expression are unknown. Here, we report that Munc13-4 is highly expressed in differentiated human NK cells and effector CD8(+) T lymphocytes. A UNC13D c.118-308C>T mutation, causative of FHL3, disrupted binding of the ETS family member ELF1 to a conserved intronic sequence. This mutation impairs UNC13D intron 1 recruitment of STAT4 and the chromatin remodeling complex component BRG1, diminishing active histone modifications at the locus. The intronic sequence acted as an overall enhancer of Munc13-4 expression in cytotoxic lymphocytes in addition to representing an alternative promoter encoding a novel Munc13-4 isoform. Mechanistically, T cell receptor engagement facilitated STAT4-dependent Munc13-4 expression in naive CD8(+) T lymphocytes. Collectively, our data demonstrates how chromatin remodeling within an evolutionarily conserved regulatory element in intron 1 of UNC13D regulates the induction of Munc13-4 expression in cytotoxic lymphocytes and suggests that an alternative Munc13-4 isoform is required for lymphocyte cytotoxicity. Thus, mutations associated with primary immunodeficiencies may cause disease by disrupting transcription factor binding.","variants":[{"Name":"NM_199242.3(UNC13D):c.118-308C>T","Chromosome":"17","Start":"75843827","Stop":"75843827","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":531855,"rule_based_match":true,"evidence_text":"UNC13D c.118-308C>T","llm_judgment":"PRESENT","evidence":"UNC13D c.118-308C>T","abstract_start":467,"abstract_end":486}]}
{"pmid":"29991546","title":"A novel mutation in Wiskott-Aldrich gene manifesting as macrothrombocytopenia and neutropenia.","abstract":"Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder, described as a clinical triad of microthrombocytopenia, eczema and recurrent infections. Different mutations in WAS gene have been identified, resulting in various phenotypes and a broad range of disease severity, ranging from classic WAS to X-linked thrombocytopenia and X-linked neutropenia. WAS in some cases can be fatal without haematopoietic stem cell transplantation early in life. In this particular case, we present a novel mutation with a unique presentation. An 18-year-old man incidentally found to have macrothrombocytopenia and neutropenia at 16 years of age later found to be hemizygous for c. 869T>C (p.Ile290Thr) mutation in WAS gene. The late presentation, absence of other manifestations of WAS and presence of macrothrombocytopenia, rather than microthrombocytopenia, which is usually a characteristic finding in WAS, misled the initial diagnosis. On review of literature, this mutation has not been reported as causing WAS.","variants":[{"Name":"NM_000377.3(WAS):c.869T>C (p.Ile290Thr)","Chromosome":"X","Start":"48688391","Stop":"48688391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":980208,"rule_based_match":true,"evidence_text":"c. 869T>C (p.Ile290Thr)","llm_judgment":"PRESENT","evidence":"c. 869T>C (p.Ile290Thr)","abstract_start":666,"abstract_end":689}]}
{"pmid":"28164329","title":"Charcot-Marie-Tooth disease type 1C: Clinical and electrophysiological findings for the c.334G>a (p.Gly112Ser) Litaf/Simple mutation.","abstract":"INTRODUCTION: Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare, dominantly inherited neuropathy caused by mutations in the lipopolysaccharide-induced tumor necrosis factor (LITAF) or small integral membrane protein of the lysosome/late endosome (SIMPLE) gene.\nMETHODS: We present a case series comprised of 10 patients in whom CMT1C is caused by a Gly112Ser substitution in the encoded protein. We focus on clinical presentation, electrodiagnostic analyses, and our findings in the context of previously described cases.\nRESULTS: The Gly112Ser mutation causing CMT1C is a mild form of CMT, as patients walked on time, had less weakness than those with Charcot-Marie-Tooth disease type 1A (CMT1A), had a CMT neuropathy score (CMTNS) indicative of mild disease, and had faster ulnar and median motor nerve conduction velocities compared to those with CMT1A.\nDISCUSSION: The G112S mutation in LITAF seems to be clinically indistinguishable from a mild presentation of CMT1A. Muscle Nerve 56: 1092-1095, 2017.","variants":[{"Name":"NM_001136472.2(LITAF):c.334G>A (p.Gly112Ser)","Chromosome":"16","Start":"11553576","Stop":"11553576","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21096,"rule_based_match":true,"evidence_text":"c.334G>a (p.Gly112Ser)","llm_judgment":"PRESENT","evidence":"G112S","abstract_start":877,"abstract_end":882}]}
{"pmid":"34354232","title":"OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype.","abstract":"Biallelic pathogenic variants of OTUD6B have recently been described to cause intellectual disability (ID) with seizures. Here, we report the clinical and molecular characterization of five additional patients (from two unrelated Egyptian families) with ID due to homozygous OTUD6B variants. In Family I, the two affected brothers had additional retinal degeneration, a symptom not yet reported in OTUD6B-related ID. Whole-exome sequencing (WES) identified a novel nonsense variant in OTUD6B (c.271C>T, p.(Gln91Ter)), but also a nonsense variant in RP1L1 (c.5959C>T, p.(Gln1987Ter)), all in homozygous state. Biallelic pathogenic variants in RP1L1 cause autosomal recessive retinitis pigmentosa type 88 (RP88). Thus, RP1L1 dysfunction likely accounts for the visual phenotype in this family with two simultaneous autosomal recessive disorders. In Family II, targeted sequencing revealed a novel homozygous missense variant (c.767G>T, p.(Gly256Val)), confirming the clinically suspected OTUD6B-related ID. Consistent with the clinical variability in previously reported OTUD6B patients, our patients showed inter- and intrafamilial differences with regard to the clinical and brain imaging findings. Interestingly, various orodental features were present including macrodontia, dental crowding, abnormally shaped teeth, and thick alveolar ridges. Broad distal phalanges (especially the thumbs and halluces) with prominent interphalangeal joints and fetal pads were recognized in all patients and hence considered pathognomonic. Our study extends the spectrum of the OTUD6B-associated phenotype. Retinal degeneration, albeit present in both patients from Family I, was shown to be unrelated to OTUD6B, demonstrating the need for in-depth analysis of WES data in consanguineous families to uncover simultaneous autosomal recessive disorders.","variants":[{"Name":"NM_178857.6(RP1L1):c.5959C>T (p.Gln1987Ter)","Chromosome":"8","Start":"10608139","Stop":"10608139","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":413765,"rule_based_match":true,"evidence_text":"c.5959C>T, p.(Gln1987Ter)","llm_judgment":"PRESENT","evidence":"c.5959C>T, p.(Gln1987Ter)","abstract_start":556,"abstract_end":581}]}
{"pmid":"31672125","title":"A de novo SCN8A heterozygous mutation in a child with epileptic encephalopathy: a case report.","abstract":"BACKGROUND: Epilepsy is a complex disorder caused by various factors, including genetic aberrance. Recent studies have identified an essential role of the sodium channel Nav1.6, encoded by the gene SCN8A, in epileptic encephalopathy.\nCASE PRESENTATION: Using parent-offspring trio targeted-exome sequencing, we identified a de novo heterozygous missense mutation c.3953A > G (p.N1318S) in SCN8A in a 3-year-and-9-month Chinese female patient with early infantile epileptic encephalopathy and a normal magnetic resonance imaging of the brain.\nCONCLUSIONS: This de novo mutation was only detected in the patient but not in her parents. Bioinformatic analysis indicates the pathogenicity of this mutation. Administration of the sodium channel blocker well controlled seizures in the patient. Therefore, we recommend trio targeted-exome sequencing as a routine method for pathogenic variant screening in patients with intractable epilepsy and a normal MRI.","variants":[{"Name":"NM_001330260.2(SCN8A):c.3953A>G (p.Asn1318Ser)","Chromosome":"12","Start":"51786552","Stop":"51786552","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":682181,"rule_based_match":true,"evidence_text":"c.3953A > G (p.N1318S)","llm_judgment":"PRESENT","evidence":"c.3953A > G (p.N1318S)","abstract_start":363,"abstract_end":385}]}
{"pmid":"15714519","title":"Validation of dye-binding/high-resolution thermal denaturation for the identification of mutations in the SLC22A5 gene.","abstract":"Primary carnitine deficiency is an autosomal recessive disorder of fatty acid oxidation resulting from defective carnitine transport. This disease is caused by mutations in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. Here we validate dye-binding/high-resolution thermal denaturation as a screening procedure to identify novel mutations in this gene. This procedure is based on the amplification of DNA by PCR in capillaries with the dsDNA binding dye LCGreen I. The PCR reaction is then analyzed in the same capillary by high-resolution thermal denaturation. Samples with abnormal melting profiles are sequenced. This technique correctly identified all known patients who were compound heterozygotes for different mutations in the carnitine transporter gene and about 30% of homozygous patients. The remaining 70% of homozygous patients were identified by a second amplification, in which the patient's DNA was mixed with the DNA of a normal control. This screening system correctly identified eight novel mutations and both abnormal alleles in six new families with primary carnitine deficiency. The causative role of the missense mutations identified (c.3G>T/p.M1I, c.695C>T/p.T232M, and c.1403 C>G/p.T468R) was confirmed by expression in Chinese hamster ovary (CHO) cells. These results expand the mutational spectrum in primary carnitine deficiency and indicate dye-binding/high-resolution thermal denaturation as an ideal system to screen for mutations in diseases with no prevalent molecular alteration.","variants":[{"Name":"NM_003060.4(SLC22A5):c.695C>T (p.Thr232Met)","Chromosome":"5","Start":"132385370","Stop":"132385370","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":36720,"rule_based_match":true,"evidence_text":"c.695C>T/p.T232M","llm_judgment":"PRESENT","evidence":"c.695C>T/p.T232M","abstract_start":1185,"abstract_end":1201},{"Name":"NM_003060.4(SLC22A5):c.1403C>G (p.Thr468Arg)","Chromosome":"5","Start":"132392568","Stop":"132392568","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":36758,"rule_based_match":true,"evidence_text":"c.1403 C>G/p.T468R","llm_judgment":"PRESENT","evidence":"c.1403 C>G/p.T468R","abstract_start":1207,"abstract_end":1225},{"Name":"NM_003060.4(SLC22A5):c.3G>T (p.Met1Ile)","Chromosome":"5","Start":"132369975","Stop":"132369975","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":21464,"rule_based_match":true,"evidence_text":"c.3G>T/p.M1I","llm_judgment":"PRESENT","evidence":"c.3G>T/p.M1I","abstract_start":1171,"abstract_end":1183}]}
{"pmid":"32978031","title":"Congenital myasthenic syndromes in the Thai population: Clinical findings and novel mutations.","abstract":"Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of genetic disorders of the neuromuscular junction. Next generation sequencing has been increasingly used for molecular diagnosis in CMS patients. This study aimed to identify the disease-causing variants in Thai patients. We recruited patients with a diagnosis of CMS based on clinical and electrophysiologic findings, and whole exome sequencing was performed. Thirteen patients aged from 2 to 54 years (median: 8 years) from 12 families were enrolled. Variants were identified in 9 of 13 patients (69%). Five novel variants and two previously reported variant were found in the COLQ, RAPSN and CHRND gene. The previously reported c.393+1G>A splice site variant in the COLQ gene was found in a majority of patients. Five patients harbor the homozygous splice site c.393+1G>A variant, and two patients carry compound heterozygous c.393+1G>A, c.718-1G>T, and c.393+1G>A, c.865G>T (p.Gly289Ter) variants. The novel variants were also found in RAPSN (p.Cys251del, p.Arg282Cys) and CHRND (p.Met481del). Molecular diagnosis in CMS patients can guide treatment decisions and may be life changing, especially in patients with COLQ mutations.","variants":[{"Name":"NM_005677.4(COLQ):c.393+1G>A","Chromosome":"3","Start":"15478976","Stop":"15478976","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":414915,"rule_based_match":true,"evidence_text":"c.393+1G>A","llm_judgment":"PRESENT","evidence":"c.393+1G>A","abstract_start":701,"abstract_end":711}]}
{"pmid":"33136338","title":"Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot-Marie-Tooth disease.","abstract":"OBJECTIVE: To identify and characterize the pathogenicity of novel variants in Chinese patients with Charcot-Marie-Tooth disease.\nMETHODS: Multiplex ligation-dependent probe amplification (MLPA) and whole-exome sequencing (WES) were performed in 30 unrelated CMT patients. Minigene assay was used to verify the effect of a novel splicing variant (c.694+1G>A) on pre-mRNA. Primary fibroblast cell lines were established from skin biopsies to characterize the biological effects of the novel variants p.L26R and p.S169fs. The mitochondrial structure was observed by an electron microscope. The expression level of protein was analyzed by Western Blotting. Mitochondrial dynamics and mitochondrial membrane potential (MMP, Δψm) were analyzed via immunofluorescence study. Mitochondrial ATP levels were analyzed via bioluminescence assay. The rate of oxygen consumption was measured with a Seahorse Bioscience XF-96 extracellular flux analyzer.\nRESULTS: We identified 10 pathogenic variants in three known CMT related genes, including three novel variants (p.L26R, p.S169fs, c.694+1G>A) and one known pathogenic variant (p.R120W) in GDAP1. Further, we described the clinical features of patients carrying pathogenic variants in GDAP1 and found that almost all Chinese CMT patients with GDAP1 variants present axonal type. The effect of c.694+1G>A on pre-mRNA was verified via minigene splice assay. Cellular biological effects showed ultrastructure damage of mitochondrial, reduced protein levels, different patterns of mitochondrial dynamics, decreased mitochondrial membrane potential (Δψm), ATP content, and defects in respiratory capacity in the patient carrying p.L26R and p.S169fs in GDAP1.\nINTERPRETATION: Our results broaden the genetic spectrum of GDAP1 and provided functional evidence for mitochondrial pathways in the pathogenesis of GDAP1 variants.","variants":[{"Name":"NM_018972.4(GDAP1):c.694+1G>A","Chromosome":"8","Start":"74363054","Stop":"74363054","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":565224,"rule_based_match":true,"evidence_text":"c.694+1G>A","llm_judgment":"PRESENT","evidence":"c.694+1G>A","abstract_start":347,"abstract_end":357}]}
{"pmid":"37324257","title":"The pathogenic p.Gln319Ter variant is not causing congenital adrenal hyperplasia when inherited in one of the duplicated CYP21A2 genes.","abstract":"Objective: The study aimed to identify the pathogenic status of p.Gln319Ter (NM_000500.7: c.955C>T) variant when inherited in a single <i>CYP21A2</i> gene (bimodular RCCX haplotype) and to discriminate between a non-causing congenital adrenal hyperplasia (CAH) allele when inherited in a duplicated and functional <i>CYP21A2</i> gene context (trimodular RCCX haplotype).\nMethods: 38 females and 8 males with hyperandrogenemia, previously screened by sequencing and identified as carriers for the pathogenic p.Gln319Ter, were herein tested by multiplex ligation-dependent probe amplification (MLPA) and a real-time PCR Copy number Variation (CNV) assay.\nResults: Both MLPA and real-time PCR CNV analyses confirmed a bimodular and pathogenic RCCX haplotype with a single <i>CYP21A2</i> in 19/46 (41.30%) p.Gln319Ter carriers and who in parallel all shared elevated 17-OHP levels. The remaining 27 individuals that also carried the p.Gln319Ter exhibited low 17-OHP levels as a result of their carriership of a duplicated <i>CYP21A2</i> with a trimodular RCCX haplotype. Interestingly, all of these individuals also carried in linkage disequilibrium with p.Gln319Ter two single nucleotide polymorphisms, the c.293-79G>A (<i>rs114414746</i>) in intron 2 and the c.*12C>T (<i>rs150697472</i>) in the 3'-UTR. Therefore, these variants can be used to distinguish between pathogenic and non-pathogenic genomic contexts of the c.955T (p.Gln319) in the genetic diagnosis of congenital adrenal hyperplasia (CAH).\nConclusion: The employed methodologies identified a considerable number of individuals with non-pathogenic p.Gln319Ter from the individuals that typically carry the pathogenic p.Gln319Ter in a single <i>CYP21A2</i>. Therefore, it is extremely important the detection of such haplotypes for the prenatal diagnosis, treatment and genetic counseling in patients with CAH.","variants":[{"Name":"NM_000500.9(CYP21A2):c.*12C>T","Chromosome":"6","Start":"32041146","Stop":"32041146","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":576925,"rule_based_match":true,"evidence_text":"c.*12C>T (rs150697472)","llm_judgment":"PRESENT","evidence":"c.*12C>T","abstract_start":1257,"abstract_end":1265}]}
{"pmid":"32924121","title":"Gene variant analysis of a fetus with autosomal recessive polycystic kidney disease","abstract":"OBJECTIVE: To explore the genetic basis for a fetus with autosomal recessive polycystic kidney disease (ARPKD).\nMETHODS: Fetal tissue and peripheral blood samples were respectively obtained from the abortus and the couple. Following extraction of genomic DNA, genetic testing was carried out.\nRESULTS: The fetus was found to carry compound heterozygous variants of the PKHD1 gene, namely c.5336A>T (p.N1779I) and c.9455delA (p.N3152Tfs*10), which were respectively inherited from the husband and wife.\nCONCLUSION: The c.5336A>T and c.9455delA variants of the PKHD1 gene probably account for the ARPKD in the fetus. Above results have enabled genetic counseling and prenatal diagnosis for the couple.","variants":[{"Name":"NM_138694.4(PKHD1):c.5336A>T (p.Asn1779Ile)","Chromosome":"6","Start":"52022845","Stop":"52022845","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3393046,"rule_based_match":true,"evidence_text":"c.5336A>T (p.N1779I)","llm_judgment":"PRESENT","evidence":"c.5336A>T (p.N1779I)","abstract_start":388,"abstract_end":408}]}
{"pmid":"24239060","title":"Novel TPM3 mutation in a family with cap myopathy and review of the literature.","abstract":"Cap myopathy is a rare congenital myopathy characterized by the presence of caps within muscle fibres and caused by mutations in ACTA1, TPM2 or TPM3. Thus far, only three cases with TPM3-related cap myopathy have been described. Here, we report on the first autosomal dominant family with cap myopathy in three-generations, caused by a novel heterozygous mutation in the alpha-tropomyosin-slow-encoding gene (TPM3; exon 4; c.445C>A; p.Leu149Ile). The three patients experienced first symptoms of muscle weakness in childhood and followed a slowly progressive course. They presented generalized hypotrophy and mild muscle weakness, elongated face, high arched palate, micrognathia, scoliosis and respiratory involvement. Intrafamilial variability of skeletal deformities, respiratory involvement and mild cardiac abnormalities was noted. Muscle MRI revealed a recognizable pattern of fatty muscle infiltration and masseter muscle hypertrophy. Subsarcolemmal caps were present in 6-10% of the fibres and immunoreactive with anti-tropomyosin antibodies. We conclude that the MRI-pattern of muscle involvement and the presence of masseter muscle hypertrophy in cap myopathy may guide molecular genetic diagnosis towards a mutation in TPM3. Regular respiratory examinations are important, even if patients have no anamnestic clues. We compare our findings to all cases of cap myopathy with identified mutations (n=11), thus far reported in the literature.","variants":[{"Name":"NM_152263.4(TPM3):c.445C>A (p.Leu149Ile)","Chromosome":"1","Start":"154173134","Stop":"154173134","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2417679,"rule_based_match":true,"evidence_text":"c.445C>A (p.Leu149Ile)","llm_judgment":"PRESENT","evidence":"p.Leu149Ile","abstract_start":433,"abstract_end":444}]}
{"pmid":"25170858","title":"RDH5 retinopathy (fundus albipunctatus) with preserved rod function.","abstract":"PURPOSE: The aim of this study is to characterize the clinical features of four unrelated Chinese patients with retinal dehydrogenase 5 (RDH5) retinopathy (fundus albipunctatus) and to identify the genetic defects underlying this disorder.\nMETHODS: Complete ophthalmic examinations, including slit-lamp biomicroscopy, dilated indirect ophthalmoscopy, spectral domain optical coherence tomography, and full-field electroretinography were performed. Genomic DNA was prepared from peripheral venous leukocytes. Polymerase chain reaction and direct sequencing were used to screen the coding exons and exon/intron boundaries of the RDH5 gene (11-cis-retinol dehydrogenase).\nRESULTS: Four patients with RDH5 retinopathy, including two 6-year-old boys, from 4 unrelated Chinese families were recruited in this study. A novel c.832C>T (p.Arg278Ter) nonsense mutation of the RDH5 gene was identified in one 6-year-old boy, who has a compound heterozygous mutation with c.928delC/InsGAAG (p.Leu310GluVal). Homozygous Leu310GluVal mutations were identified in 2 male patients including the other 6-year-old boy. The other patient was a 29-year-old woman in whom compound heterozygous changes c.500G>A (p.Arg167His) and Leu310GluVal in RDH5 were identified. All patients manifested the fundus phenotype of fundus albipunctatus. Electroretinograms recorded in 1 boy (Case 3) showed scotopic waveforms within normal range under standard conditions and no change after prolonged dark adaptation. Scotopic waveforms were within the normal range for Case 4 while higher amplitudes (30% increase) were recorded after prolonged dark adaptation. The two adult patients had depressed scotopic electroretinogram responses under standard conditions. Optical coherence tomography showed discrete highly reflective lesions extending from the retinal pigment epithelium to the level of the external limiting membrane.\nCONCLUSION: A novel c.832C>T (p.Arg278Ter) nonsense mutation in RDH5 was identified. A specific mutation, Leu310GluVal, was seen in the homozygous state in one adult male and one boy and in the heterozygous state in one female adult and one boy with RDH5 retinopathy, suggesting a common mutation. Preserved rod function was observed in one young subject in this study.","variants":[{"Name":"NM_002905.5(RDH5):c.500G>A (p.Arg167His)","Chromosome":"12","Start":"55721878","Stop":"55721878","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":332166,"rule_based_match":true,"evidence_text":"c.500G>A (p.Arg167His)","llm_judgment":"PRESENT","evidence":"c.500G>A (p.Arg167His)","abstract_start":1181,"abstract_end":1203}]}
{"pmid":"30688039","title":"Identification of a pathogenic mutation in ATP2A1 via in silico analysis of exome data for cryptic aberrant splice sites.","abstract":"BACKGROUND: Pathogenic mutations causing aberrant splicing are often difficult to detect. Standard variant analysis of next-generation sequence (NGS) data focuses on canonical splice sites. Noncanonical splice sites are more difficult to ascertain.\nMETHODS: We developed a bioinformatics pipeline that screens existing NGS data for potentially aberrant novel essential splice sites (PANESS) and performed a pilot study on a family with a myotonic disorder. Further analyses were performed via qRT-PCR, immunoblotting, and immunohistochemistry. RNAi knockdown studies were performed in Drosophila to model the gene deficiency.\nRESULTS: The PANESS pipeline identified a homozygous ATP2A1 variant (NC_000016.9:g.28905928G>A; NM_004320.4:c.1287G>A:p.(Glu429=)) that was predicted to cause the omission of exon 11. Aberrant splicing of ATP2A1 was confirmed via qRT-PCR, and abnormal expression of the protein product sarcoplasmic/endoplasmic reticulum Ca<sup>++</sup> ATPase 1 (SERCA1) was demonstrated in quadriceps femoris tissue from the proband. Ubiquitous knockdown of SERCA led to lethality in Drosophila, as did knockdown targeting differentiating or fusing myoblasts.\nCONCLUSIONS: This study confirms the potential of novel in silico algorithms to detect cryptic mutations in existing NGS data; expands the phenotypic spectrum of ATP2A1 mutations beyond classic Brody myopathy; and suggests that genetic testing of ATP2A1 should be considered in patients with clinical myotonia.","variants":[{"Name":"NM_004320.6(ATP2A1):c.1287G>A (p.Glu429=)","Chromosome":"16","Start":"28894607","Stop":"28894607","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":536902,"rule_based_match":true,"evidence_text":"NM_004320.4:c.1287G>A:p.(Glu429=)","llm_judgment":"PRESENT","evidence":"NM_004320.4:c.1287G>A:p.(Glu429=)","abstract_start":722,"abstract_end":755}]}
{"pmid":"18186571","title":"Detection of hMSH2 and hMLH1 mutations in Chinese hereditary non-polyposis colorectal cancer kindreds.","abstract":"AIM: To establish and validate the mutation testing for identification and characterization of hereditary non-polyposis colorectal cancer (HNPCC) in suspected Chinese patients.\nMETHODS: Five independent Chinese kindreds with HNPCC fulfilling the classical Amsterdam criteria were collected. Genomic DNA was extracted after informed consent was obtained. The coding region of hMSH2 and hMLH1 genes was detected by polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC). Mutations identified in the proband by DHPLC were directly sequenced using a 377 DNA sequencer, analyzed with a basic local alignment tool (BLAST), and tested in the corresponding family members by direct DNA sequencing.\nRESULTS: Mutations were identified in two Chinese HNPCC kindreds. One was the missense mutation of hMSH2 c.1808A-->G resulting in Asp 603 Gly identified in the proband of the fifth HNPCC (HNPCC5) kindred. In the HNP5 kindred, three family members were found to have this mutation and two of them had colorectal cancer. The other mutation of hMLH1 c.1882A-->G was identified in the HNP2 kindred's proband, which might be the nonsense mutation analyzed by BLAST.\nCONCLUSION: Pedigree investigation and mutation testing of hMSH2 and hMLH1 are the practical methods to identify high-risk HNPCC patients in China.","variants":[{"Name":"NM_000251.3(MSH2):c.1808A>G (p.Asp603Gly)","Chromosome":"2","Start":"47475073","Stop":"47475073","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":96266,"rule_based_match":false,"evidence_text":"c.1808A-->G","llm_judgment":"PRESENT","evidence":"c.1808A-->G","abstract_start":834,"abstract_end":845}]}
{"pmid":"21278745","title":"A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease.","abstract":"Susceptibility to Crohn's disease, a complex inflammatory disease, is influenced by common variants at many loci. The common exonic synonymous SNP (c.313C>T) in IRGM, found in strong linkage disequilibrium with a deletion polymorphism, has been classified as non-causative because of the absence of an alteration in the IRGM protein sequence or splice sites. Here we show that a family of microRNAs (miRNAs), miR-196, is overexpressed in the inflammatory intestinal epithelia of individuals with Crohn's disease and downregulates the IRGM protective variant (c.313C) but not the risk-associated allele (c.313T). Subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of Crohn's disease-associated adherent invasive Escherichia coli by autophagy. These results suggest that the association of IRGM with Crohn's disease arises from a miRNA-based alteration in IRGM regulation that affects the efficacy of autophagy, thereby implicating a synonymous polymorphism as a likely causal variant.","variants":[{"Name":"NM_001145805.2(IRGM):c.313C>T (p.Leu105=)","Chromosome":"5","Start":"150848436","Stop":"150848436","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39673,"rule_based_match":true,"evidence_text":"c.313C>T","llm_judgment":"PRESENT","evidence":"c.313C>T","abstract_start":148,"abstract_end":156}]}
{"pmid":"32857947","title":"Bartter syndrome with long-term follow-up: a case report.","abstract":"Bartter syndrome is a rare inherited disease caused by <i>CLCNKB</i> mutation, which results in inactivation of the chloride channel Kb protein. Bartter syndrome is characterized by extreme hypokalemia, hypochloremia, metabolic alkalosis, hyperrenin-induced angiotensinemia, hyperaldosteronemia, and normal blood pressure. We herein report a case of Bartter syndrome that manifested as vomiting, hypokalemia, metabolic alkalosis, normal blood pressure, and significant hyperrenin-induced angiotensinemia. The patient, a 5-month-old girl, carried two known heterozygous pathogenic mutations: c.88C > T (p.Arg30*), which she had inherited from her father, and c.1313G > A (p.Arg438His), which she had inherited from her mother. Treatment with indomethacin, a nonsteroidal anti-inflammatory drug, led to rapid improvement of the hypokalemia, and treatment was continued for 14 years. The indomethacin also induced a sustainable reduction in the hypokalemia and metabolic alkalosis.","variants":[{"Name":"NM_000085.5(CLCNKB):c.1313G>A (p.Arg438His)","Chromosome":"1","Start":"16051725","Stop":"16051725","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2116053,"rule_based_match":true,"evidence_text":"c.1313G > A (p.Arg438His)","llm_judgment":"PRESENT","evidence":"c.1313G > A (p.Arg438His)","abstract_start":658,"abstract_end":683}]}
{"pmid":"33833410","title":"Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain.","abstract":"PURPOSE: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).\nMETHODS: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.\nRESULTS: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.\nCONCLUSION: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.","variants":[{"Name":"NM_001164760.2(PRKAR1B):c.1003C>T (p.Arg335Trp)","Chromosome":"7","Start":"550573","Stop":"550573","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1161645,"rule_based_match":true,"evidence_text":"c.1003C>T (p.Arg335Trp; NM_001164760)","llm_judgment":"PRESENT","evidence":"c.1003C>T (p.Arg335Trp; NM_001164760)","abstract_start":912,"abstract_end":949}]}
{"pmid":"25814778","title":"BRCA genetic screening in Middle Eastern and North African: mutational spectrum and founder BRCA1 mutation (c.798_799delTT) in North African.","abstract":"BACKGROUND: The contribution of BRCA1 mutations to both hereditary and sporadic breast and ovarian cancer (HBOC) has not yet been thoroughly investigated in MENA.\nMETHODS: To establish the knowledge about BRCA1 mutations and their correlation with the clinical aspect in diagnosed cases of HBOC in MENA populations. A systematic review of studies examining BRCA1 in BC women in Cyprus, Jordan, Egypt, Lebanon, Morocco, Algeria, and Tunisia was conducted.\nRESULTS: Thirteen relevant references were identified, including ten studies which performed DNA sequencing of all BRCA1 exons. For the latter, 31 mutations were detected in 57 of the 547 patients ascertained. Familial history of BC was present in 388 (71%) patients, of whom 50 were mutation carriers. c.798_799delTT was identified in 11 North African families, accounting for 22% of total identified BRCA1 mutations, suggesting a founder allele. A broad spectrum of other mutations including c.68_69delAG, c.181T>G, c.5095C>T, and c.5266dupC, as well as sequence of unclassified variants and polymorphisms, was also detected.\nCONCLUSION: The knowledge of genetic structure of BRCA1 in MENA should contribute to the assessment of the necessity of preventive programs for mutation carriers and clinical management. The high prevalence of BC and the presence of frequent mutations of the BRCA1 gene emphasize the need for improving screening programs and individual testing/counseling.","variants":[{"Name":"NM_007294.4(BRCA1):c.798_799del (p.Ser267fs)","Chromosome":"17","Start":"43094732","Stop":"43094733","ReferenceAlleleVCF":"GAA","AlternateAlleleVCF":"G","allel_id":46254,"rule_based_match":true,"evidence_text":"c.798_799delTT","llm_judgment":"PRESENT","evidence":"c.798_799delTT","abstract_start":758,"abstract_end":772}]}
{"pmid":"24793765","title":"Two unrelated patients with rare Crigler-Najjar syndrome type I: two novel mutations and a patient with loss of heterozygosity of UGT1A1 gene.","abstract":"Crigler-Najjar syndrome type I (CN-I) is the most severe type of hereditary unconjugated hyperbilirubinemia. It is caused by homozygous or compound heterozygous mutations of the UDP-glycuronosyltransferase gene (UGT1A1) on chromosome 2q37. Two patients clinically diagnosed with CN-I were examined in this paper. We sequenced five exons and their flanking sequences, specifically the promoter region of UGT1A1, of the two patients and their parents. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the UGT1A1 gene copy number of one patient. In patient A, two mutations, c.239_245delCTGTGCC (p.Pro80HisfsX6; had not been reported previously) and c.1156G>T (p.Val386Phe), were identified. In patient B, we found that this patient had lost heterozygosity of the UGT1A1 gene by inheriting a deletion of one allele, and had a novel mutation c.1253delT (p.Met418ArgfsX5) in the other allele. In summary, we detected three UGT1A1 mutations in two CN-I patients: c.239_245delCTGTGCC (p.Pro80HisfsX6), c.1253delT (p.Met418ArgfsX5), and c.1156G>T (p.Val386Phe). The former two mutations are pathogenic; however, the pathogenic mechanism of c.1156G>T (p.Val386Phe) is unknown.","variants":[{"Name":"NM_000463.3(UGT1A1):c.1156G>T (p.Val386Phe)","Chromosome":"2","Start":"233768291","Stop":"233768291","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2667945,"rule_based_match":true,"evidence_text":"c.1156G>T (p.Val386Phe)","llm_judgment":"PRESENT","evidence":"c.1156G>T (p.Val386Phe)","abstract_start":679,"abstract_end":702}]}
{"pmid":"22447252","title":"Mutation screening of the EYA1, SIX1, and SIX5 genes in an East Asian cohort with branchio-oto-renal syndrome.","abstract":"OBJECTIVES/HYPOTHESIS: To explore the genetic characteristics of branchio-oto-renal (BOR) syndrome in an East Asian population.\nSTUDY DESIGN: Prospective clinical genetic study.\nMETHODS: Twelve families (total of 18 patients) who fulfilled the criteria for BOR syndrome were enrolled in this study. Mutation screening of the EYA1, SIX1, and SIX5 genes was performed by direct sequencing and quantitative polymerase chain reaction, and genotype-phenotype correlation was investigated.\nRESULTS: Two novel EYA1 variants, c.466C>T (p.Q156X) and c.1735delG (p.D579fs), were identified in two multiplex families. The c.466C>T variant resulted in a truncated EYA1 protein, whereas the c.1735delG variant was predicted to encode an EYA1 protein with an abnormal C terminal. Neither variant was identified in a panel of 100 normal controls, and both were cosegregated with the BOR phenotype in the pedigrees, indicating that they were pathogenic mutations. No SIX1 and SIX5 mutations were detected in members of the remaining 10 families. Analysis of the genotype-phenotype correlation revealed a high phenotypic variability between and within BOR families.\nCONCLUSIONS: Two novel EYA1 mutations (c.466C>T and c.1735delG) were identified in two families with BOR syndrome. SIX1 and SIX5 mutations were not detected in the present study. Further investigation is warranted regarding the contribution of SIX1 and SIX5 mutations to BOR syndrome in East Asian populations.","variants":[{"Name":"NM_000503.6(EYA1):c.466C>T (p.Gln156Ter)","Chromosome":"8","Start":"71317642","Stop":"71317642","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":946176,"rule_based_match":true,"evidence_text":"c.466C>T (p.Q156X)","llm_judgment":"PRESENT","evidence":"c.466C>T (p.Q156X)","abstract_start":518,"abstract_end":536}]}
{"pmid":"23017645","title":"The contribution of the SPINK1 c.194+2T>C mutation to the clinical course of idiopathic chronic pancreatitis in Chinese patients.","abstract":"BACKGROUND: Recent data suggest that the serine protease inhibitor Kazal type 1 (SPINK1) gene mutation is associated with idiopathic chronic pancreatitis. However, few studies have focused on the serine protease inhibitor Kazal type 1 c.194+2T>C mutation. Therefore, our goal was to study the prevalence and impact of serine protease inhibitor Kazal type 1 mutations on the clinical profile of idiopathic chronic pancreatitis patients in China.\nMETHODS: A retrospective-cohort study of 118 Chinese patients with idiopathic chronic pancreatitis was performed, and genetic tests were carried out to detect SPINK1 mutations. Subjects without pancreatitis were used as controls. In total, 118 idiopathic chronic pancreatitis patients and 100 control subjects were evaluated.\nRESULTS: The serine protease inhibitor Kazal type 1 c.194+2T>C variant was present in 44.9% of patients with idiopathic chronic pancreatitis. The frequency of diabetes in idiopathic chronic pancreatitis patients with the serine protease inhibitor Kazal type 1 c.194+2T>C mutation (39.6%) was higher than that of patients without the mutation (9.2%). The time to occurrence of diabetes mellitus after idiopathic chronic pancreatitis symptom onset is significantly influenced by the c.194+2T>C mutation (p<0.001). In addition, the mean age of diabetes onset in patients with the serine protease inhibitor Kazal type 1 c.194+2T>C mutation (38.33 ± 9.50) was significantly younger than that of patients without this mutation (49.67 ± 6.74).\nCONCLUSIONS: The presence of the serine protease inhibitor Kazal type 1 c.194+2T>C mutation seems to be associated with idiopathic chronic pancreatitis and could predispose individuals to pancreatic diabetes onset at an earlier age.","variants":[{"Name":"NM_001379610.1(SPINK1):c.194+2T>C","Chromosome":"5","Start":"147828020","Stop":"147828020","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":136364,"rule_based_match":true,"evidence_text":"c.194+2T>C","llm_judgment":"PRESENT","evidence":"c.194+2T>C","abstract_start":235,"abstract_end":245}]}
{"pmid":"31650731","title":"Clinical Validity of Next-Generation Sequencing Multi-Gene Panel Testing for Detecting Pathogenic Variants in Patients With Hereditary Breast-Ovarian Cancer Syndrome.","abstract":"BACKGROUND: Hereditary breast and ovarian cancer syndrome (HBOC) is caused by pathogenic variants in <i>BRCA</i> and other cancer-related genes. We analyzed variants in <i>BRCA</i> gene and other cancer-related genes in HBOC patients to evaluate the clinical validity of next-generation sequencing (NGS) multi-gene panel testing.\nMETHODS: The <i>BRCA1/2</i> NGS testing was conducted for 262 HBOC patients. Multiplex ligation-dependent probe amplification and direct Sanger sequencing were performed for confirmation. Multi-gene panel testing was conducted for 120 patients who did not possess <i>BRCA1/2</i> pathogenic variants but met the National Comprehensive Cancer Network criteria.\nRESULTS: Pathogenic variants in <i>BRCA1/2</i> were detected in 30 HBOC patients (11.5%). Additionally, four out of the 120 patients possessed pathogenic variants by multi-gene panel testing (3.3%): <i>MSH2</i> (c.256G>T, p.Glu86*), <i>PMS2</i> (c.1687C>T, p.Arg563*), <i>CHEK2</i> (c.546C>A, p.Tyr182*), and <i>PALB2</i> (c.3351-1G>C). All the four patients had a family history of cancer.\nCONCLUSIONS: Multi-gene panel testing could be a significant screening tool for HBOC patients, especially for those with a family history of cancer.","variants":[{"Name":"NM_024675.4(PALB2):c.3351-1G>C","Chromosome":"16","Start":"23603670","Stop":"23603670","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":815622,"rule_based_match":true,"evidence_text":"PALB2 (c.3351-1G>C)","llm_judgment":"PRESENT","evidence":"PALB2</i> (c.3351-1G>C)","abstract_start":1001,"abstract_end":1024},{"Name":"NM_000251.3(MSH2):c.256G>T (p.Glu86Ter)","Chromosome":"2","Start":"47408445","Stop":"47408445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1848745,"rule_based_match":true,"evidence_text":"c.256G>T","llm_judgment":"PRESENT","evidence":"c.256G>T","abstract_start":901,"abstract_end":909},{"Name":"NM_000535.7(PMS2):c.1687C>T (p.Arg563Ter)","Chromosome":"7","Start":"5987078","Stop":"5987078","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":138806,"rule_based_match":true,"evidence_text":"c.1687C>T, p.Arg563*","llm_judgment":"PRESENT","evidence":"c.1687C>T, p.Arg563*","abstract_start":935,"abstract_end":955}]}
{"pmid":"22355252","title":"Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290.","abstract":"PURPOSE: This study investigated the centrosomal protein, 290-KD (CEP290) associated genotype and ocular and extra-ocular phenotype in 18 patients with Leber congenital amaurosis (LCA).\nMETHODS: Eighteen patients with LCA from 14 families with mutations in the CEP290 gene were identified with sequencing or with heteroduplex analysis. Ophthalmic examinations were performed on all patients. Scans of the central nervous system were reassessed in three patients and obtained in two. Renal function was evaluated in all patients. Ultrasonography of the kidneys was performed in six patients.\nRESULTS: Eight patients (from five families) carried the c.2991+1655A>G mutation homozygously. Nine solitary patients carried this variant combined with a nonsense, frameshift, or splice site mutation on the second allele. One new nonsense mutation was identified: c.1078C>T. Fourteen patients (from 12 families) had been completely blind from birth or had light perception. The best-recorded visual acuity was 20/200. Peripheral fundus changes appeared to be progressive with a relatively preserved posterior pole. Novel ophthalmic features for the CEP290 phenotype were Coats-like exudative vasculopathy in two patients, a small chorioretinal coloboma in one patient, and well defined, small, atrophic spots at the level of the retinal pigment epithelium causing a dot-like appearance in five patients. Some CEP290 patients exhibited systemic abnormalities. We found abnormal proprioception in two patients and mild mental retardation in one. One patient was infertile due to immobile spermatozoa. No renal abnormalities were detected.\nCONCLUSIONS: CEP290-associated LCA has a severe, progressive, and clinically identifiable phenotype. Distinct extra-ocular findings were noted, which may be attributed to ciliary dysfunction.","variants":[{"Name":"NM_025114.4(CEP290):c.1078C>T (p.Arg360Ter)","Chromosome":"12","Start":"88125357","Stop":"88125357","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":527675,"rule_based_match":true,"evidence_text":"c.1078C>T","llm_judgment":"PRESENT","evidence":"c.1078C>T","abstract_start":856,"abstract_end":865}]}
{"pmid":"25457557","title":"De novo FUS mutations in 2 Korean patients with sporadic amyotrophic lateral sclerosis.","abstract":"Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder. Approximately 5% of ALS patients are familial (fALS) cases, and the remaining 95% are apparently sporadic (sALS) cases. To date, a number of genes have been discovered as associated with ALS, but the genetic background of sALS is not yet fully understood. The occurrence of de novo mutations in ALS genes might be an explanation for sALS, but reduced penetrance could be an alternative theory. Previously, we screened mutations in 5 ALS genes including SOD1 and FUS in 9 fALS and 249 sALS patients and found a total of 15 patients with either SOD1 (7 fALS and 3 sALS) or FUS (1 fALS and 4 sALS) mutations. Interestingly, only 1 fALS patient had the FUS mutation, whereas 4 sALS patients had mutations in this gene. To determine if the FUS mutations in sALS were de novo, we performed genetic analysis on 2 sALS patients with living parents. Genetic analysis confirmed that 2 FUS mutations, including the c.1483C>T (p.Arg495*) and the c.1509_1510delAG (p.Gly504Trpfs*12) mutations, were found only in the patients and not in their parents, confirming the de novo occurrence of these mutations. These findings support the notion that de novo mutations are responsible for a certain proportion of sALS.","variants":[{"Name":"NM_004960.4(FUS):c.1509_1510del (p.Gly504fs)","Chromosome":"16","Start":"31191076","Stop":"31191077","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":1467921,"rule_based_match":true,"evidence_text":"c.1509_1510delAG (p.Gly504Trpfs*12)","llm_judgment":"PRESENT","evidence":"c.1509_1510delAG (p.Gly504Trpfs*12)","abstract_start":1016,"abstract_end":1051},{"Name":"NM_004960.4(FUS):c.1483C>T (p.Arg495Ter)","Chromosome":"16","Start":"31191052","Stop":"31191052","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":38662,"rule_based_match":true,"evidence_text":"c.1483C>T (p.Arg495*)","llm_judgment":"PRESENT","evidence":"c.1483C>T (p.Arg495*)","abstract_start":986,"abstract_end":1007}]}
{"pmid":"34504686","title":"Ehlers-Danlos syndrome kyphoscoliotic type 2 caused by mutations in the FKBP14 gene: an analysis of five cases.","abstract":"<b>Background.</b> This study deals with a rare (orphan) monogenic connective tissue disorder - Ehlers-Danlos syndrome kyphoscoliotic type 2 (EDSKS2). Kyphoscoliotic type 2 Ehlers-Danlos syndrome is an autosomal recessive disorder caused by mutations in the FKBP14 gene (7p14.3), which encodes the FKBP22 protein. According to the 2017 classification, this type is in group seven - collagen spatial structure and cross-linking defects. We present results of clinical examination and molecular genetic analysis for five patients with age varying from two to fifteen years.  <b>Methods.</b> Five patients were examined using clinical and laboratory methods. DNA samples used for the analysis were extracted from whole blood samples using a Wizard® Genomic DNA Purification Kit (Promega, USA) according to the manufacturer's protocol.  <b>Results.</b> The major clinical findings were kyphoscoliosis, early motor development delay, muscular weakness, hypotonia and hearing loss. Molecular genetic analysis detected a homozygous c.362dupC duplication in exon 3 of the FKBP14 gene in all five patients. This mutation is common in various countries. Differential diagnostics were carried out to exclude other Ehlers-Danlos syndrome types and myopathies.  <b>Conclusions.</b> Literature analysis and examination of five EDSKS2 patients demonstrated the involvement of major organs and systems, such as joints, spine, muscles, cardiovascular system, respiratory system, hearing, and vision, into the pathological process. Kidney mobility increases and nephroptosis seems to be secondary caused by muscular weakness. During molecular genetic analysis, to verify EDSKS2 it is recommended to initially search for the c.362dupC duplication, which appears to be common in European countries, including Russia.","variants":[{"Name":"NM_017946.4(FKBP14):c.362dup (p.Glu122fs)","Chromosome":"7","Start":"30019110","Stop":"30019111","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":264319,"rule_based_match":true,"evidence_text":"c.362dupC","llm_judgment":"PRESENT","evidence":"c.362dupC","abstract_start":1025,"abstract_end":1034}]}
{"pmid":"15880721","title":"ATM mutations, haplotype analysis, and immunological status of Russian patients with ataxia telangiectasia.","abstract":"Mutations in the ATM gene are responsible for the autosomal recessive disorder, ataxia telangiectasia (A-T). Mutations in different ethnic groups are distributed along the entire length of the large, 66 exon ATM gene. In this study, A-T patients from 16 Russian families were assessed for immunological status and ATM haplotype analysis, and screened for ATM mutations. Haplotype analysis was performed to enhance the efficiency of mutation detection. Mutations predicted to cause disease were identified in 19 of 32 alleles (59%), including a truncating mutation (c.5932G>T) that was identified in 8/32 (25%) alleles both by haplotype analysis and mutation screening. This mutation has been found in low abundance in other European A-T cohorts suggesting that this founder-effect mutation may be of Russian origin. The abundance of this mutation may allow for large-scale screening of cancer patients to help clarify the role of ATM in breast and other cancers. Nine of the remaining mutations were previously unreported, and add to the multitude of unique mutations found throughout the gene.","variants":[{"Name":"NM_000051.4(ATM):c.5932G>T (p.Glu1978Ter)","Chromosome":"11","Start":"108312424","Stop":"108312424","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":132871,"rule_based_match":true,"evidence_text":"c.5932G>T","llm_judgment":"PRESENT","evidence":"c.5932G>T","abstract_start":565,"abstract_end":574}]}
{"pmid":"23430832","title":"Two Cases of Pulmonary Hypertension Associated with Type III Glycogen Storage Disease.","abstract":"Glycogen storage diseases (GSDs) comprise a large, heterogeneous group of disorders characterized by abnormal glycogen deposition. Multiple cases in the literature have demonstrated an association between GSD type I and pulmonary arterial hypertension (PAH). We now also report on two patients with GSD type III and PAH, a novel association. The first patient was a 16-year-old girl of Nicaraguan descent with a history of hepatomegaly and growth retardation. Molecular testing identified a homozygous 17delAG mutation in AGL consistent with GSD type IIIb. At the age of 16, she was found to have PAH and was started on medical therapy. Two years later, she developed acute chest pain and died shortly thereafter. The second patient is a 13-year-old girl of Colombian descent homozygous for the c.3911dupA mutation consistent with GSD IIIa. An echocardiogram at age 2 showed left ventricular hypertrophy, which resolved following the institution of a high protein, moderate carbohydrate diet during the day and continuous gastric-tube feeding overnight. At the age of 12, she was found to have pulmonary hypertension. She was started on sildenafil, and her clinical status has shown marked improvement including normalization of her elevated transaminases. PAH may be a rare association in patients with GSD IIIa and IIIb and should be evaluated with screening echocardiograms for cardiac hypertrophy or if they present with symptoms of right-sided heart failure such as shortness of breath, chest pain, cyanosis, fatigue, dizziness, syncope, or edema. Early diagnosis of PAH is important as increasingly effective treatments are now available.","variants":[{"Name":"NM_000642.3(AGL):c.3911dup (p.Asn1304fs)","Chromosome":"1","Start":"99912471","Stop":"99912472","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":357222,"rule_based_match":true,"evidence_text":"c.3911dupA","llm_judgment":"PRESENT","evidence":"c.3911dupA","abstract_start":795,"abstract_end":805}]}
{"pmid":"21852022","title":"Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS.","abstract":"Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. About 10% of ALS cases are familial (FALS) and the genetic defect is known only in approximately 20%-30% of these cases. The most common genetic cause of ALS is SOD1 (superoxide dismutase 1) mutation. Very recently, mutations of the optineurin gene (OPTN), which is involved in open-angle glaucoma, were identified in 3 Japanese patients/families with ALS, and subsequently in a few FALS patients of European descent. We found a heterozygous nonsense mutation (c.493C>T, p.Gln165X, exon 6) in the OPTN gene in a Danish patient with ALS, and the mutation segregated from his affected father. The p.Gln165X mutation could not be detected in 1070 healthy Danish controls, in 1000 Danish individuals with metabolic phenotypes or in 64 sporadic ALS (SALS) cases. The p.Gln165X mutation described in this study is the first mutation reported in a Danish family and is likely involved in disease pathogenesis. Until now, only few OPTN mutations have been associated with ALS. As the underlying genetic defect is known only in approximately 20%-30% of FALS families, further screening of these cases is necessary for establishing the contribution of OPTN mutations in disease pathogenesis.","variants":[{"Name":"NM_001008212.2(OPTN):c.493C>T (p.Gln165Ter)","Chromosome":"10","Start":"13112576","Stop":"13112576","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1858882,"rule_based_match":true,"evidence_text":"c.493C>T, p.Gln165X","llm_judgment":"PRESENT","evidence":"c.493C>T, p.Gln165X","abstract_start":542,"abstract_end":561}]}
{"pmid":"31111429","title":"Spinocerebellar Ataxia Type 28-Phenotypic and Molecular Characterization of a Family with Heterozygous and Compound-Heterozygous Mutations in AFG3L2.","abstract":"While heterozygous mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia 28 (SCA28), homozygous mutations in the same gene can cause spastic ataxia 5 (SPAX5). AFG3L2 encodes a mitochondrial ATP-dependent metalloprotease. We here report a SCA28 patient with biallelic AFG3L2 variants and his heterozygous mother. The patient and his mother underwent a detailed neurological examination and fibroblast lines were established. The effect of the two missense variants on mitochondria was assessed by form factor analysis and quantification of mitochondrial proteins (TOMM70, complex V). The 39-year-old index patient presented with a slowly progressive cerebellar gait disorder for 19 years, bilateral ptosis, and dysarthria. A cranial MRI showed mild cerebellar atrophy. He carried two compound-heterozygous, rare, missense variants (c.1847A>G [p.Y616C], c.2167G>A [p.V723M]) in AFG3L2, while his mother was heterozygous for the first change that had previously been described in SPAX5. Altered mitochondrial morphology and interconnectivity, together with reduced protein levels of TOMM70 and complex V (ATPase), suggest mitochondrial structural defects in the patient's fibroblasts. No significant abnormalities were found in his mother's fibroblast cultures albeit all measurements were slightly below the control level. We here present a SCA28 patient with compound-heterozygous AFG3L2 variants and demonstrate mitochondrial abnormalities in skin fibroblast cultures from this patient. Thus, AFG3L2 variants should be considered in both slowly progressive ataxias and phenotypes with clinical features reminiscent of mitochondrial disease. Of note, ptosis was present in both mutation carriers and may serve as a red flag in the diagnosis of SCA28.","variants":[{"Name":"NM_006796.3(AFG3L2):c.1847A>G (p.Tyr616Cys)","Chromosome":"18","Start":"12340334","Stop":"12340334","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39384,"rule_based_match":true,"evidence_text":"c.1847A>G [p.Y616C]","llm_judgment":"PRESENT","evidence":"c.1847A>G [p.Y616C]","abstract_start":849,"abstract_end":868},{"Name":"NM_006796.3(AFG3L2):c.2167G>A (p.Val723Met)","Chromosome":"18","Start":"12337349","Stop":"12337349","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":211843,"rule_based_match":true,"evidence_text":"c.2167G>A (p.V723M)","llm_judgment":"PRESENT","evidence":"c.2167G>A","abstract_start":870,"abstract_end":879}]}
{"pmid":"35586535","title":"Spastic Paraplegia Type 7 and Movement Disorders: Beyond the Spastic Paraplegia.","abstract":"Background: Spastic paraplegia type 7 (SPG7) mutations can present either as a pure form or a complex phenotype with movement disorders.\nObjective: Describe the main features of subjects with SPG7 mutations associated with movement disorders.\nMethods: We analyzed the clinical and paraclinical information of subjects with SPG7 mutations associated with movement disorders.\nResults: Sixteen affected subjects from 11 families were identified. Male sex predominated (10 of 16) and the mean age at onset was 41.25 ± 16.1 years. A cerebellar syndrome was the most frequent clinical movement disorder phenotype (7 of 16); however, parkinsonism (2 of 16), dystonia (1 of 16), and mixed phenotypes between them were also seen. The \"ears of the lynx\" sign was found in four subjects. A total of nine SPG7 variants were found, of which the most frequent was the c.1529C > T (p.Ala510Val).\nConclusion: This case series expands the motor phenotype associated with SPG7 mutations. Clinicians must consider this entity in single or familial cases with combined movement disorders.","variants":[{"Name":"NM_003119.4(SPG7):c.1529C>T (p.Ala510Val)","Chromosome":"16","Start":"89546737","Stop":"89546737","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":51184,"rule_based_match":true,"evidence_text":"c.1529C > T (p.Ala510Val)","llm_judgment":"PRESENT","evidence":"c.1529C > T (p.Ala510Val)","abstract_start":854,"abstract_end":879}]}
{"pmid":"14722927","title":"The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria.","abstract":"The molecular basis of cystathionine beta-synthase (CBS) deficiency has been studied in 536 patient alleles with 130 different mutations described. To date, no study has reported on the incidence of any of the reported mutations in patients from the UK and the US. We developed a new antisense oligonucleotide (ASO) PCR/hybridization method to screen for 12 of the most frequent CBS mutations in 14 unrelated patients from the UK and 38 unrelated patients from the US, a total of 104 independent alleles. We determined 16/28 (57%) and 28/76 (37%) of the affected alleles in the UK and US patients, respectively. Four different mutations were identified in the UK patients (c.374G>A, R125Q; c.430G>A, E144K; c.833T>C, I278T; c.919G>A, G307S) and 8 mutations identified in the patients from the US (c.341C>T, A114V; c.374G>A, R125Q; c.785C>T, T262M; c.797G>A, R266K; c.833T>C, I278T; c.919G>A, G307S; g.13217A>C (del ex 12); c.1330G>A, D444N). The I278T was the predominant mutation in both populations, present in 8 (29%) of 28 independent alleles from the UK and in 14 (18%) of 76 independent alleles from the US. The incidence of the G307S mutation was 21% in the UK patients and 8% in the US patients. The spectrum of mutations observed in the patients from the UK and US is closer to that which is observed in Northern Europe and bears less resemblance to that observed in Ireland.","variants":[{"Name":"NM_000071.3(CBS):c.374G>A (p.Arg125Gln)","Chromosome":"21","Start":"43066320","Stop":"43066320","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":194786,"rule_based_match":true,"evidence_text":"c.374G>A","llm_judgment":"PRESENT","evidence":"c.374G>A","abstract_start":673,"abstract_end":681},{"Name":"NM_000071.3(CBS):c.919G>A (p.Gly307Ser)","Chromosome":"21","Start":"43062988","Stop":"43062988","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15156,"rule_based_match":true,"evidence_text":"c.919G>A, G307S","llm_judgment":"PRESENT","evidence":"c.919G>A, G307S","abstract_start":724,"abstract_end":739},{"Name":"NM_000071.3(CBS):c.341C>T (p.Ala114Val)","Chromosome":"21","Start":"43066353","Stop":"43066353","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15158,"rule_based_match":true,"evidence_text":"c.341C>T, A114V","llm_judgment":"PRESENT","evidence":"c.341C>T, A114V","abstract_start":797,"abstract_end":812},{"Name":"NM_000071.3(CBS):c.833T>C (p.Ile278Thr)","Chromosome":"21","Start":"43063074","Stop":"43063074","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15159,"rule_based_match":true,"evidence_text":"c.833T>C, I278T","llm_judgment":"PRESENT","evidence":"c.833T>C, I278T","abstract_start":707,"abstract_end":722},{"Name":"NM_000071.3(CBS):c.785C>T (p.Thr262Met)","Chromosome":"21","Start":"43063943","Stop":"43063943","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":196148,"rule_based_match":true,"evidence_text":"c.785C>T, T262M","llm_judgment":"PRESENT","evidence":"c.785C>T, T262M","abstract_start":831,"abstract_end":846},{"Name":"NM_000071.3(CBS):c.430G>A (p.Glu144Lys)","Chromosome":"21","Start":"43066264","Stop":"43066264","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15161,"rule_based_match":true,"evidence_text":"c.430G>A, E144K","llm_judgment":"PRESENT","evidence":"c.430G>A, E144K","abstract_start":690,"abstract_end":705},{"Name":"NM_000071.3(CBS):c.797G>A (p.Arg266Lys)","Chromosome":"21","Start":"43063931","Stop":"43063931","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15164,"rule_based_match":true,"evidence_text":"c.797G>A, R266K","llm_judgment":"PRESENT","evidence":"c.797G>A, R266K","abstract_start":848,"abstract_end":863},{"Name":"NM_000071.3(CBS):c.1330G>A (p.Asp444Asn)","Chromosome":"21","Start":"43058862","Stop":"43058862","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15165,"rule_based_match":true,"evidence_text":"c.1330G>A, D444N","llm_judgment":"PRESENT","evidence":"c.1330G>A, D444N","abstract_start":923,"abstract_end":939}]}
{"pmid":"35582950","title":"Whole-exome sequencing identified novel variants in CPLANE1 that causes oral-facial-digital syndrome Ⅵ by inducing primary cilia abnormality.","abstract":"Oral-facial-digital syndrome (OFDS) is a multisystemic ciliopathic disorder with an autosomal recessive mode of inheritance. OFDS usually manifests with typical craniofacial anomalies and variable occurrence of polydactyly. Germline variants in CPLANE1 cause OFDS VI. In this study, we investigated a 26-year-old Chinese female patient who was 23<sup>+1</sup>  weeks pregnant. She had a history of adverse pregnancy outcomes with multiple foetal malformations. We performed ultrasonography and identified the foetus as having a posterior fossa Blake cyst and postaxial polydactyly. The patient decided to terminate her pregnancy, and further genetic molecular analysis was performed. We identified the aborted foetus as having postaxial polydactyly. Whole-exome sequencing identified a missense variant (c.3599C>T, p.A1200V) in exon 20 and a c.834+1G>T variant in exon 7 of CPLANE1 (NM_023073.3) in the foetus. Sanger sequencing confirmed that these variants came from the parents of the foetus. In this study, we investigated a family with OFDS VI through genetic testing and bioinformatics analysis, which provided powerful help for prenatal diagnosis. Then, we demonstrated that the cell migration rate and the number of cilia were decreased after interference with CPLANE1 expression in NIH/3T3 cells. After CPLANE1 knockdown, the Hh signalling pathway was inhibited, and the Hh pathway activator SAG reversed the inhibitory effect. This is the first report of a family with OFDS VI in the Chinese population.","variants":[{"Name":"NM_001384732.1(CPLANE1):c.3599C>T (p.Ala1200Val)","Chromosome":"5","Start":"37198775","Stop":"37198775","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":214213,"rule_based_match":true,"evidence_text":"c.3599C>T, p.A1200V","llm_judgment":"PRESENT","evidence":"c.3599C>T, p.A1200V","abstract_start":804,"abstract_end":823}]}
{"pmid":"30457648","title":"Clinical Course of Autosomal Recessive Bestrophinopathy Complicated by Choroidal Neovascularization.","abstract":"The authors report the clinical course of two cases of autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization (CNV). One patient presenting with a novel BEST1 mutation (c.658 C>T, p.Gln220*) underwent anti-vascular endothelial growth factor therapy. Response to treatment was documented on optical coherence tomography angiography (OCTA). Despite initial response to treatment, recurrent CNV exudation with progressive subretinal fibrosis was observed. In the second patient, the CNV was not treated and spontaneous regression was observed. This report indicates that the clinical course of CNV in ARB may vary considerably, ranging from spontaneous regression to progressive subretinal fibrosis despite intervention. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:888-892.].","variants":[{"Name":"NM_004183.4(BEST1):c.658C>T (p.Gln220Ter)","Chromosome":"11","Start":"61957408","Stop":"61957408","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":408395,"rule_based_match":true,"evidence_text":"c.658 C>T, p.Gln220*","llm_judgment":"PRESENT","evidence":"c.658 C>T, p.Gln220*","abstract_start":201,"abstract_end":221}]}
{"pmid":"21311890","title":"RET-protooncogene variants in patients with sporadic neoplasms of the digestive tract and the central nervous system.","abstract":"PURPOSE: The RET protooncogene plays a crucial role in neural crest development; accordingly, mutations of RET cause MEN2A and familial medullary thyroid carcinoma, while the expression deregulation of RET is involved in the pathophysiology of glioblastoma multiforme (GBM) and pancreatic cancer (PDAC). The aim of this study was to evaluate if germline variants of the RET protooncogene are associated with GBM, pancreatic cancer and gastric cancer (GC).\nMETHODS: Genomic DNA from peripheral blood was isolated from 100 patients with GBM, 65 patients with GC and 54 patients with PDAC. The coding sequence of RET promoter, exon 2 and exon 13 was amplified. Sequence variations at -5 and -1 in the promotor and in exon 2 were determined through a LightCycler assay, and analysis of exon 13 was carried out by genomic sequencing.\nRESULTS: There was no significant association of the RET-promoter or exon 2 genotypes with the phenotype in the different populations, although there was an increase of the GG genotype of the -5G>A variant in all cancers compared to controls. Sequencing of exon 13 identified mutation c.2372A>T in codon 791 (Y791F) in heterozygous state in one of 100 GBM patients, in two of 65 patients with gastric cancer, in two of 54 PDAC patients and in none of the controls.\nCONCLUSIONS: Although our data did not reach significance in our small cohorts, we cannot rule out the involvement of the -5G promoter allele and the c.2372A>T mutation in the development of the aforementioned tumours.","variants":[{"Name":"NM_020975.6(RET):c.2372A>T (p.Tyr791Phe)","Chromosome":"10","Start":"43118460","Stop":"43118460","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":28975,"rule_based_match":true,"evidence_text":"c.2372A>T","llm_judgment":"PRESENT","evidence":"c.2372A>T","abstract_start":1114,"abstract_end":1123}]}
{"pmid":"32591345","title":"Novel form of rhizomelic skeletal dysplasia associated with a homozygous variant in","abstract":"BACKGROUND: Studies exploring molecular mechanisms underlying congenital skeletal disorders have revealed novel regulators of skeletal homeostasis and shown protein glycosylation to play an important role.\nOBJECTIVE: To identify the genetic cause of rhizomelic skeletal dysplasia in a consanguineous Pakistani family.\nMETHODS: Clinical investigations were carried out for four affected individuals in the recruited family. Whole genome sequencing (WGS) was completed using DNA from two affected and two unaffected individuals from the family. Sequencing data were processed, filtered and analysed. In silico analyses were performed to predict the effects of the candidate variant on the protein structure and function. Small interfering RNAs (siRNAs) were used to study the effect of <i>Gnpnat1</i> gene knockdown in primary rat chondrocytes.\nRESULTS: The patients presented with short stature due to extreme shortening of the proximal segments of the limbs. Radiographs of one individual showed hip dysplasia and severe platyspondyly. WGS data analyses identified a homozygous missense variant c.226G>A; p.(Glu76Lys) in <i>GNPNAT1</i>, segregating with the disease. Glucosamine 6-phosphate N-acetyltransferase, encoded by the highly conserved gene <i>GNPNAT1</i>, is one of the enzymes required for synthesis of uridine diphosphate N-acetylglucosamine, which participates in protein glycosylation. Knockdown of <i>Gnpnat1</i> by siRNAs decreased cellular proliferation and expression of chondrocyte differentiation markers collagen type 2 and alkaline phosphatase, indicating that <i>Gnpnat1</i> is important for growth plate chondrocyte proliferation and differentiation.\nCONCLUSIONS: This study describes a novel severe skeletal dysplasia associated with a biallelic, variant in <i>GNPNAT1</i>. Our data suggest that GNPNAT1 is important for growth plate chondrogenesis.","variants":[{"Name":"NM_198066.4(GNPNAT1):c.226G>A (p.Glu76Lys)","Chromosome":"14","Start":"52781903","Stop":"52781903","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1292306,"rule_based_match":true,"evidence_text":"c.226G>A; p.(Glu76Lys)","llm_judgment":"PRESENT","evidence":"c.226G>A; p.(Glu76Lys)","abstract_start":1095,"abstract_end":1117}]}
{"pmid":"31810733","title":"Adult-Diagnosed Nonsyndromic Nephronophthisis in Australian Families Caused by Biallelic NPHP4 Variants.","abstract":"There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults. We identified 2 families with presumed adult-diagnosed nonsyndromic NPHP and negative diagnostic genetic testing results from our Renal Genetics Clinic. Both had 2 affected siblings without extrarenal phenotypes. After informed consent, research whole-genome sequencing was undertaken. Biallelic NPHP4 variants were identified in trans and clinically confirmed in all 4 affected individuals, confirming a genetic diagnosis. Participant 1 of the first family (F1P1) had kidney failure diagnosed at 19 years of age. An affected younger sibling (F1P2) reached kidney failure at age 15 years after kidney biopsy suggested NPHP. Pathogenic variants detected in NPHP4 in this family were NM_015102.4:c.3766C>T (p.Gln1256*) and a 31-kb deletion affecting exons 12 to 16. In the second family, F2P3 reached kidney failure at age 27 years having undergone kidney biopsy suggesting NPHP. An affected younger sibling (F2P4) has chronic kidney disease stage 4 at age 39 years. The NPHP4 variants detected were NM_015102.4:c.1998_1999del (p.Tyr667Phefs*23) and c.3646G>T (p.Asp1216Tyr). The latter variant was initially missed in diagnostic sequencing due to inadequate NPHP4 coverage (94.3% exonic coverage). With these reports, we identify NPHP4 as an appreciable genetic cause for adult-diagnosed nonsyndromic NPHP that should be considered by adult nephrologists.","variants":[{"Name":"NM_015102.5(NPHP4):c.3766C>T (p.Gln1256Ter)","Chromosome":"1","Start":"5865152","Stop":"5865152","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":818171,"rule_based_match":true,"evidence_text":"NM_015102.4:c.3766C>T (p.Gln1256*)","llm_judgment":"PRESENT","evidence":"NM_015102.4:c.3766C>T (p.Gln1256*)","abstract_start":851,"abstract_end":885}]}
{"pmid":"34164522","title":"Six","abstract":"BACKGROUND: Hypophosphatasia (HPP) is a rare hereditary disorder characterized by defective bone and tooth mineralization caused by mutations in the alkaline phosphatase (<i>ALPL</i>) gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Here we performed clinical and molecular studies on 5 HPP children to investigate the pathogenic mechanisms of the <i>ALPL</i> gene variants.\nMETHODS: Clinical and genetic analyses were performed on 5 HPP children, and the loci where <i>ALPL</i> variants were identified. Plasmids containing the relevant loci were constructed. The molecular and cellular mechanisms of the pathogenic <i>ALPL</i> variants were investigated by cellular immunofluorescence, enzyme activity assay, and protein expression assay.\nRESULTS: A total of 6 <i>ALPL</i> variants were identified in 5 HPP children: proband 1: c.346G>A (p.A116T); proband 2: c.346G>A (p.A116T)/deletions from c.1097 to c.1099 CCT (p.T366_S367deli) compound heterozygous variant; proband 3: insertion of G from c.1014 to c.1015 (p.H338fs)/c.1446C>A (p.H482Q) compound heterozygous variant; proband 4: c.920C>T (p.P307L); and proband 5: c.883A>G (p.M295V). Twenty-four hours after the HEK-293T was transfected with different variant plasmids, its alkaline phosphatase activity and enzyme protein content were reduced compared with the wild type, and there were differences among different variants. Except for 1014-G-1015+C1446A, the degree of reduction in enzyme activity was negatively correlated with the severity of clinical manifestations. Immunofluorescence revealed that the variants (especially c.883A>G and c.920C>T) caused a decrease in alkaline phosphatase expression in the cellular membrane.\nCONCLUSIONS: In total, 3 novel variants were identified in these 5 HPP children, the discovery of which will enrich the human <i>ALPL</i> gene mutation database. Different variants in the <i>ALPL</i> gene can downregulate the activity of TNSALP enzyme (and thus affect its function) by affecting protein expression and translational modifications. The same variant may cause clinical manifestations of different severities in different individuals due to the presence of dominant negative effects, alterations in noncoding sequences, blind area of intron regulatory region sequencing, and variations in environmental and individual factors. The molecular mechanisms via which the <i>ALPL</i> gene exerts its expression effect <i>in vivo</i> are highly variable and warrant further investigation.","variants":[{"Name":"NM_000478.6(ALPL):c.1446C>A (p.His482Gln)","Chromosome":"1","Start":"21577519","Stop":"21577519","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2749206,"rule_based_match":true,"evidence_text":"c.1446C>A (p.H482Q)","llm_judgment":"PRESENT","evidence":"c.1446C>A (p.H482Q)","abstract_start":1039,"abstract_end":1058}]}
{"pmid":"38041679","title":"Recurrent de novo","abstract":"BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific <i>SPTLC1</i> variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in <i>SPTLC2</i> c.778G>A [p.Glu260Lys] manifesting with juvenile ALS.\nMETHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed.\nRESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that <i>SPTLC2</i> variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing <i>SPTLC2</i> variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported <i>SPTLC1</i> ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in <i>SPTLC1</i> and <i>SPTCL2</i>-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS.\nCONCLUSIONS: <i>SPTLC2</i> is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further.","variants":[{"Name":"NM_004863.4(SPTLC2):c.778G>A (p.Glu260Lys)","Chromosome":"14","Start":"77562468","Stop":"77562468","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":936755,"rule_based_match":true,"evidence_text":"c.778G>A [p.Glu260Lys]","llm_judgment":"PRESENT","evidence":"c.778G>A [p.Glu260Lys]","abstract_start":506,"abstract_end":528}]}
{"pmid":"31156707","title":"Two Infants With Beta-Ketothiolase Deficiency Identified by Newborn Screening in China.","abstract":"Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disease caused by a defect of mitochondrial acetoacetyl-CoA thiolase. Beginning in 2014, we carried out newborn screening by tandem mass spectrometry (MS/MS) followed by next-generation sequencing (NGS) and identified two infants with BKTD among 203,750 newborns born in Jiangsu Province, China. Both infants showed the characteristic chemical abnormalities of BKTD. We used NGS to confirm variants in the <i>ACAT1</i>. Patient 1 had the compound heterozygous variants c.721dupA and c.928G > C. Patient 2 had compound heterozygosity for the c.238+1G > A and c.1163G > T variants. c.721dupA, c.928G > C and c.1163G > T were suspected to be likely pathogenic, whereas c.238+1G > A was determined to be pathogenic. None of the four variants have been reported in the literature. Patient 1 presented with onset of metabolic acidosis and neonatal hypoglycemia 8 days after birth, whereas patient 2 was detected through neonatal disease screening but had no clinical manifestations. These findings contribute to our understanding of the clinical characteristics and genetic basis of BKTD.","variants":[{"Name":"NM_000019.4(ACAT1):c.721dup (p.Thr241fs)","Chromosome":"11","Start":"108140205","Stop":"108140206","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":1941543,"rule_based_match":true,"evidence_text":"c.721dupA","llm_judgment":"PRESENT","evidence":"c.721dupA","abstract_start":531,"abstract_end":540}]}
{"pmid":"22892508","title":"A novel SACS mutation in an atypical case with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).","abstract":"Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disorder with symptoms of spastic ataxia, neuropathy, pyramidal sign, finger and foot deformities, and hypermyelination of retinal nerve fibers. SACS is mutated in ARSACS. The clinical diversity of ARSACS is recognized, which sometimes makes its diagnosis difficult. By using homozygosity mapping, we identified a novel homozygous c.12020C > T missense mutation in a consanguineous Japanese family with atypical clinical features. In addition to the absence of spasticity and hypermyelinated retinal nerve fibers, the present case had urinary dysfunction, impotence, and severe constipation, indicating the possibility of autonomic dysfunction. Furthermore, we showed the diagnostic usefulness of MRI even for the case of atypical clinical features. It had been considered that cases without obvious spasticity were very rare, however recent reports on atypical cases as well as our case indicate that ARSACS cases without obvious spasticity might be more frequent than previously thought. We should be aware of atypical features of ARSACS for the correct diagnosis.","variants":[{"Name":"NM_014363.6(SACS):c.12020C>T (p.Ser4007Phe)","Chromosome":"13","Start":"23331856","Stop":"23331856","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":547382,"rule_based_match":true,"evidence_text":"c.12020C > T","llm_judgment":"PRESENT","evidence":"c.12020C > T","abstract_start":432,"abstract_end":444}]}
{"pmid":"25502464","title":"Identification of a Premature Termination Mutation in the Proline-Rich Transmembrane Protein 2 Gene in a Chinese Family with Febrile Seizures.","abstract":"Febrile seizures (FS), the most frequent type of seizures in children, occur in neurologically normal infants and children between the ages of 3 months and 5 years with genetic predisposition. The aim of this study was to identify the responsible gene in a four-generation Chinese Han pedigree with autosomal dominant FS. Seven family members (three affected and four unaffected) were enrolled in this study. Exome sequencing was conducted and a duplication mutation c.649dupC (p.R217Pfs*8) in the proline-rich transmembrane protein 2 gene (PRRT2) was identified. The mutation co-segregated with the disorder and was absent in normal controls. To our knowledge, this is the first report of a pedigree with complete penetrance of FS, which is caused by mutation in the PRRT2 gene. FS is a novel phenotype of the c.649dupC (p.R217Pfs*8) mutation. Our discovery broadens the spectrum of genetic causes of FS and the spectrum of phenotypes linked to mutation in the PRRT2 gene.","variants":[{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC (p.R217Pfs*8)","llm_judgment":"PRESENT","evidence":"c.649dupC (p.R217Pfs*8)","abstract_start":467,"abstract_end":490}]}
{"pmid":"23181747","title":"Hb Iberia [α104(G11)Cys → Arg,TGC>CGC (α2) (HBA2:c.313T>C)], a new α-thalassemic hemoglobin variant found in the Iberian Peninsula: report of six cases.","abstract":"We report a new structural defect of the α2-globin chain presenting with moderate microcytic hypochromic anemia, in six individuals from three unrelated families, living in Portugal and Spain. α-Globin gene deletions were ruled out by gap-polymerase chain reaction (gap-PCR) and multiplex ligation-dependent probe amplification (MLPA). Direct sequencing of the α2-globin gene revealed a substitution of codon 104 [α104(G11)Cys→Arg, TGC>CGC (α2) (HBA2:c.313T>C)]. This new variant, not detectable by high performance liquid chromatography (HPLC) or electrophoresis, was called Hb Iberia, as it was observed for the first time in families from the Iberian Peninsula.   Although the mutant allele is transcribed, as indicated by the balanced mRNA α/β ratio, the abnormal α2 chain could not form a stable tetramer as the cysteine and arginine residues, located at the α1β1 contact, differ in size, charge and hydrophobicity.   Hb Iberia is the third mutation described at codon 104 on the α-globin genes, namely, Hb Sallanches (α2, TGC>TAC) and Hb Oegstgeest (α1, TGC>AGC), also characterized as unstable hemoglobins (Hbs), present on an α-thalassemic phenotype.","variants":[{"Name":"NM_000517.6(HBA2):c.313T>C (p.Cys105Arg)","Chromosome":"16","Start":"173484","Stop":"173484","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":792575,"rule_based_match":true,"evidence_text":"HBA2:c.313T>C","llm_judgment":"PRESENT","evidence":"HBA2:c.313T>C","abstract_start":446,"abstract_end":459}]}
{"pmid":"33028645","title":"Helicase-inactivating","abstract":"Fanconi anemia is a genetically and phenotypically heterogeneous disorder characterized by congenital anomalies, bone marrow failure, cancer, and sensitivity of chromosomes to DNA cross-linking agents. One of the 22 genes responsible for Fanconi anemia is <i>BRIP1</i>, in which biallelic truncating mutations lead to Fanconi anemia group J and monoallelic truncating mutations predispose to certain cancers. However, of the more than 1000 reported missense mutations in <i>BRIP1</i>, very few have been functionally characterized. We evaluated the functional consequence of BRIP1 p.R848H (c.2543G > A), which was homozygous in two cousins with low birth weight, microcephaly, upper limb abnormalities, and imperforate anus and for whom chromosome breakage analysis of patient cells revealed increased mitomycin C sensitivity. BRIP1 p.R848H alters a highly conserved residue in the catalytic DNA helicase domain. We show that BRIP1 p.R848H leads to a defect in helicase activity. Heterozygosity at this missense has been reported in multiple cancer patients but, in the absence of functional studies, classified as of unknown significance. Our results support that this mutation is pathogenic for Fanconi anemia in homozygotes and for increased cancer susceptibility in heterozygous carriers.","variants":[{"Name":"NM_032043.3(BRIP1):c.2543G>A (p.Arg848His)","Chromosome":"17","Start":"61693462","Stop":"61693462","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":151213,"rule_based_match":true,"evidence_text":"BRIP1 p.R848H (c.2543G > A)","llm_judgment":"PRESENT","evidence":"BRIP1 p.R848H (c.2543G > A)","abstract_start":575,"abstract_end":602}]}
{"pmid":"34361012","title":"Rare Gain-of-Function","abstract":"Loss-of-function mutations in the K<sub>V</sub>4.3 channel-encoding <i>KCND3</i> gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain the potential pathogenic role of <i>KCND3</i> variant in iron accumulation-related cerebellar ataxia. We presented a patient with slowly progressive cerebellar ataxia, parkinsonism, cognitive impairment, and iron accumulation in the basal ganglia and the cerebellum. Whole exome sequencing analyses identified in the patient a heterozygous <i>KCND3</i> c.1256G>A (p.R419H) variant predicted to be disease-causing by multiple bioinformatic analyses. In vitro biochemical and immunofluorescence examinations revealed that, compared to the human K<sub>V</sub>4.3 wild-type channel, the p.R419H variant exhibited normal protein abundance and subcellular localization pattern. Electrophysiological investigation, however, demonstrated that the K<sub>V</sub>4.3 p.R419H variant was associated with a dominant increase in potassium current amplitudes, as well as notable changes in voltage-dependent gating properties leading to enhanced potassium window current. These observations indicate that, in direct contrast with the loss-of-function <i>KCND3</i> mutations previously reported in cerebellar ataxia patients, we identified a rare gain-of-function <i>KCND3</i> variant that may expand the clinical and molecular spectra of neurodegenerative cerebellar disorders associated with brain iron accumulation.","variants":[{"Name":"NM_001378969.1(KCND3):c.1256G>A (p.Arg419His)","Chromosome":"1","Start":"111786957","Stop":"111786957","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":364361,"rule_based_match":true,"evidence_text":"c.1256G>A (p.R419H)","llm_judgment":"PRESENT","evidence":"c.1256G>A (p.R419H)","abstract_start":697,"abstract_end":716}]}
{"pmid":"24269976","title":"Clinical and molecular genetic study of infantile-onset Pompe disease in Chinese patients: identification of 6 novel mutations.","abstract":"Pompe disease is an autosomal recessive disorder and is caused by a deficiency in acid alpha-glucosidase (GAA). A broad range of studies have been performed on Pompe patients from different countries. However, the clinical course and molecular basis of the disease in Mainland China have not been well defined. In the present study, we examined a total of 18 Chinese children with infantile-onset Pompe disease to better understand the clinical and genetic features in this population. The median age at symptom onset was 3.6 months (range: 1.7-6.8 months) and 6.3 months at diagnosis (range: 2.5-9.3 months). All but 1 patient died at a median age of 8.2 months (range: 4.7-18.7 months). Molecular analysis revealed 20 different mutations, 6 of which are novel (c.1356delC, c.378G>A, c.1827C>G, c.859-2 A>T, c.1551+2T>G, and c.1465G>T). The most common mutation in the study was c.1935C>A, accounting for 25% (9/36 alleles) of the mutations. Our study provides the first comprehensive examination of the clinical course of infantile-onset Pompe disease and mutations of the GAA gene for patients in Mainland China. Our results confirm the high prevalence of the c.1935C>A mutation, previously reported for other populations, in Mainland Chinese patients with infantile-onset Pompe disease. Furthermore, six novel mutations in the GAA gene are reported for the first time.","variants":[{"Name":"NM_000152.5(GAA):c.378G>A (p.Trp126Ter)","Chromosome":"17","Start":"80104964","Stop":"80104964","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":938284,"rule_based_match":true,"evidence_text":"c.378G>A","llm_judgment":"PRESENT","evidence":"c.378G>A","abstract_start":775,"abstract_end":783},{"Name":"NM_000152.5(GAA):c.1827C>G (p.Tyr609Ter)","Chromosome":"17","Start":"80112650","Stop":"80112650","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1868272,"rule_based_match":true,"evidence_text":"c.1827C>G","llm_judgment":"PRESENT","evidence":"c.1827C>G","abstract_start":785,"abstract_end":794},{"Name":"NM_000152.5(GAA):c.1935C>A (p.Asp645Glu)","Chromosome":"17","Start":"80112922","Stop":"80112922","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":19068,"rule_based_match":true,"evidence_text":"c.1935C>A","llm_judgment":"PRESENT","evidence":"c.1935C>A","abstract_start":880,"abstract_end":889}]}
{"pmid":"18283468","title":"Atypical CLN2 with later onset and prolonged course: a neuropathologic study showing different sensitivity of neuronal subpopulations to TPP1 deficiency.","abstract":"This is the first neuropathology report of a male patient (born 1960-died 1975) with an extremely rare, atypical variant of CLN2 that has been diagnosed only in five families so far. The clinical history started during his preschool years with relatively mild motor and psychological difficulties, but with normal intellect and vision. Since age six there were progressive cerebellar and extrapyramidal symptomatology, amaurosis, and mental deterioration. Epileptic seizures were absent. The child died aged 15 years in extreme cachexy. Neuropathology revealed neurolysosomal storage of autofluorescent, curvilinear and subunit c of mitochondrial ATP synthase (SCMAS) rich material. The neuronal storage led to laminar neuronal depopulation in the cerebral cortex and to a practically total eradication of the cerebellar cortical neurons. The other areas of the central nervous system including hippocampus, which are usually heavily affected in classical forms of CLN2, displayed either a lesser degree or absence of neuronal storage, or storage without significant neuronal loss. Transformation of the stored material to the spheroid like perikaryal inclusions was rudimentary. The follow-up, after 30 years, showed heterozygous values of TPP1 (tripeptidylpeptidase 1) activity in the white blood cells of both parents and the sister. DNA analysis of CLN2 gene identified a paternal frequent null mutation c.622C > T (p.Arg208 X) in the 6th exon and a maternal novel mutation c.1439 T > G in exon 12 (p.Val480Gly). TPP1 immunohistochemistry using a specific antibody gave negative results in the brain and other organs. Our report supports the notion that the spectrum of CLN2 phenotypes may be surprisingly broad. The study revealed variable sensitivities in neuronal subpopulations to the metabolic defect which may be responsible for the variant's serious course.","variants":[{"Name":"NM_000391.4(TPP1):c.1439T>G (p.Val480Gly)","Chromosome":"11","Start":"6614978","Stop":"6614978","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":859889,"rule_based_match":true,"evidence_text":"c.1439 T > G in exon 12 (p.Val480Gly)","llm_judgment":"PRESENT","evidence":"c.1439 T > G in exon 12 (p.Val480Gly)","abstract_start":1478,"abstract_end":1515},{"Name":"NM_000391.4(TPP1):c.622C>T (p.Arg208Ter)","Chromosome":"11","Start":"6617040","Stop":"6617040","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17682,"rule_based_match":true,"evidence_text":"c.622C > T (p.Arg208 X)","llm_judgment":"PRESENT","evidence":"c.622C > T (p.Arg208 X)","abstract_start":1408,"abstract_end":1431}]}
{"pmid":"24140114","title":"Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency.","abstract":"Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by antibody deficiency, poor humoral response to antigens, and recurrent infections. To investigate the molecular cause of CVID, we carried out exome sequence analysis of a family diagnosed with CVID and identified a heterozygous frameshift mutation, c.2564delA (p.Lys855Serfs(∗)7), in NFKB2 affecting the C terminus of NF-κB2 (also known as p100/p52 or p100/p49). Subsequent screening of NFKB2 in 33 unrelated CVID-affected individuals uncovered a second heterozygous nonsense mutation, c.2557C>T (p.Arg853(∗)), in one simplex case. Affected individuals in both families presented with an unusual combination of childhood-onset hypogammaglobulinemia with recurrent infections, autoimmune features, and adrenal insufficiency. NF-κB2 is the principal protein involved in the noncanonical NF-κB pathway, is evolutionarily conserved, and functions in peripheral lymphoid organ development, B cell development, and antibody production. In addition, Nfkb2 mouse models demonstrate a CVID-like phenotype with hypogammaglobulinemia and poor humoral response to antigens. Immunoblot analysis and immunofluorescence microscopy of transformed B cells from affected individuals show that the NFKB2 mutations affect phosphorylation and proteasomal processing of p100 and, ultimately, p52 nuclear translocation. These findings describe germline mutations in NFKB2 and establish the noncanonical NF-κB signaling pathway as a genetic etiology for this primary immunodeficiency syndrome.","variants":[{"Name":"NM_001322934.2(NFKB2):c.2564del (p.Lys855fs)","Chromosome":"10","Start":"102402144","Stop":"102402144","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":76320,"rule_based_match":true,"evidence_text":"c.2564delA (p.Lys855Serfs(∗)7)","llm_judgment":"PRESENT","evidence":"c.2564delA (p.Lys855Serfs(∗)7)","abstract_start":333,"abstract_end":363},{"Name":"NM_001322934.2(NFKB2):c.2557C>T (p.Arg853Ter)","Chromosome":"10","Start":"102402138","Stop":"102402138","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76319,"rule_based_match":true,"evidence_text":"c.2557C>T (p.Arg853(∗))","llm_judgment":"PRESENT","evidence":"c.2557C>T (p.Arg853(∗))","abstract_start":570,"abstract_end":593}]}
{"pmid":"23510391","title":"Case report: long-term survival of an infant syndromic patient affected by atypical teratoid-rhabdoid tumor.","abstract":"BACKGROUND: Atypical teratoid rhabdoid tumor (ATRT) patients display a dismal median overall survival of less than 1 year. A consistent fraction of cases carries de-novo SMARCB1/INI1 constitutional mutations in the setting of the \"rhabdoid tumor predisposition syndrome\" and the outcome is worst in infant syndromic ATRT patients.\nCASE PRESENTATION: We here describe a patient affected by mosaic Klinefelter syndrome and by rhabdoid tumor predisposition syndrome caused by constitutional SMARCB1/INI1 heterozygous mutation c.118C>T (Arg40X). Patient's ATRT primary tumor occurred at 2 years of age concurrent with metastatic lesions. The patient was rendered without evidence of disease by combined surgery, high-dose poli-chemotherapy and craniospinal irradiation, followed by autologous hematopoietic stem cell transplantation. At the onset of a spinal lesion 5.5 years later, both tumors were pathologically and molecularly evaluated at the national central pathology review board and defined as ATRT in a syndromic patient, with strong evidence of a clonal origin of the two lesions. The patient was then treated according to SIOP guidelines and is now alive without evidence of disease 24 months after the detection of metastatic disease and 90 months after the original diagnosis.\nCONCLUSION: The report underscores the current utility of multiple comprehensive approaches for the correct diagnosis and clinical management of patients affected by rare and atypical brain neoplasms. Successful local control of disease and achievement of long-term survival is possible in ATRT patients even in the setting of rhabdoid tumor predisposition syndrome, infant age at diagnosis and metastatic spread of disease, thus justifying the efforts for the management of this severe condition.","variants":[{"Name":"NM_003073.5(SMARCB1):c.118C>T (p.Arg40Ter)","Chromosome":"22","Start":"23791780","Stop":"23791780","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":403820,"rule_based_match":true,"evidence_text":"c.118C>T (Arg40X)","llm_judgment":"PRESENT","evidence":"c.118C>T (Arg40X)","abstract_start":523,"abstract_end":540}]}
{"pmid":"29625443","title":"Comprehensive Molecular Screening in Chinese Usher Syndrome Patients.","abstract":"Purpose: Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese patients with USH and to describe the clinical features of the patients with mutations.\nMethods: A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations.\nResults: We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles.\nConclusions: Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future.","variants":[{"Name":"NM_206933.4(USH2A):c.8559-2A>G","Chromosome":"1","Start":"215877882","Stop":"215877882","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":57766,"rule_based_match":true,"evidence_text":"c.8559-2A>G","llm_judgment":"PRESENT","evidence":"c.8559-2A>G","abstract_start":1316,"abstract_end":1327}]}
{"pmid":"25330800","title":"Congenital Visual Impairment and Progressive Microcephaly Due to Lysyl-Transfer Ribonucleic Acid (RNA) Synthetase (KARS) Mutations: The Expanding Phenotype of Aminoacyl-Transfer RNA Synthetase Mutations in Human Disease.","abstract":"Aminoacyl-transfer ribonucleic acid (RNA) synthetases (ARSs) are a group of enzymes required for the first step of protein translation. Each aminoacyl-transfer RNA synthetase links a specific amino acid to its corresponding transfer RNA component within the cytoplasm, mitochondria, or both. Mutations in ARSs have been linked to a growing number of diseases. Lysyl-transfer RNA synthetase (KARS) links the amino acid lysine to its cognate transfer RNA. We report 2 siblings with severe infantile visual loss, progressive microcephaly, developmental delay, seizures, and abnormal subcortical white matter. Exome sequencing identified mutations within the KARS gene (NM_005548.2):c.1312C>T; p.Arg438Trp and c.1573G>A; p.Glu525Lys occurring within a highly conserved region of the catalytic domain. Our patients' phenotype is remarkably similar to a phenotype recently reported in glutaminyl-transfer RNA synthetase (QARS), another bifunctional ARS gene. This finding expands the phenotypic spectrum associated with mutations in KARS and draws attention to aminoacyl-transfer RNA synthetase as a group of enzymes that are increasingly being implicated in human disease.","variants":[{"Name":"NM_005548.3(KARS1):c.1312C>T (p.Arg438Trp)","Chromosome":"16","Start":"75631194","Stop":"75631194","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":985696,"rule_based_match":true,"evidence_text":"c.1312C>T; p.Arg438Trp","llm_judgment":"PRESENT","evidence":"c.1312C>T; p.Arg438Trp","abstract_start":679,"abstract_end":701},{"Name":"NM_005548.3(KARS1):c.1573G>A (p.Glu525Lys)","Chromosome":"16","Start":"75628691","Stop":"75628691","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":985697,"rule_based_match":true,"evidence_text":"c.1573G>A; p.Glu525Lys","llm_judgment":"PRESENT","evidence":"c.1573G>A; p.Glu525Lys","abstract_start":706,"abstract_end":728}]}
{"pmid":"20729507","title":"Genotype-phenotype correlations in a group of 15 SCN1A-mutated Italian patients with GEFS+ spectrum (seizures plus, classical and borderline severe myoclonic epilepsy of infancy).","abstract":"Mutations in SCN1A gene have been associated with the spectrum of generalized/genetic epilepsy with febrile seizures plus. Recently, databases reporting SCN1A mutations and clinical details of patients have been created to facilitate genotype- phenotype correlations, actually not completely defined, particularly if a specific mutation underlies phenotypes. We report on a group of 15 patients with clinical features of GEFS+ (3), classical (7), or borderline severe myoclonic epilepsy of infancy (5), in whom genetic analysis of patients and parents and follow-up period were performed to establish genotype-phenotype correlations, to enrich literature and databases data. We found 11 pathogenic mutations (5 novel: c.80 G>C exon 1; c.187 T>C exon 1; c.3061 G>T exon 16; c.4297 G>A exon 22; c.5579 delA ins TCTCC exon 26) and 4 novel nucleotidic variants (IVS5+38 C>T intron 5; IVS8-19 C>T intron 18; c.4945 C>T exon 25; c.5127 C>A exon 26). Paternal inheritance was observed in 4/4 cases.","variants":[{"Name":"NM_001165963.4(SCN1A):c.187T>C (p.Phe63Leu)","Chromosome":"2","Start":"166073435","Stop":"166073435","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":79405,"rule_based_match":true,"evidence_text":"c.187 T>C exon 1","llm_judgment":"PRESENT","evidence":"c.187 T>C exon 1","abstract_start":735,"abstract_end":751}]}
{"pmid":"28488341","title":"Next-generation sequencing targeted disease panel in rod-cone retinal dystrophies in Māori and Polynesian reveals novel changes and a common founder mutation.","abstract":"IMPORTANCE: This study identifies unique genetic variation observed in a cohort of Māori and Polynesian patients with rod-cone retinal dystrophies using a targeted next-generation sequencing retinal disease gene panel.\nBACKGROUND: With over 250 retinal disease genes identified, genetic diagnosis is still only possible in 60-70% of individuals and even less within unique ethnic groups.\nDESIGN: Prospective genetic testing in patients with rod-cone retinal dystrophies identified from the New Zealand Inherited Retinal Disease Database, PARTICIPANTS: Sixteen patients of Māori and Polynesian ancestry.\nMETHODS: Next-generation sequencing of a targeted retinal gene panel. Sanger sequencing for a novel PDE6B mutation in subsequent Māori patients.\nMAIN OUTCOME MEASURES: Genetic diagnosis, genotype-phenotype correlation.\nRESULTS: Thirteen unique pathogenic variants were identified in 9 of 16 (56.25%) patients in 10 different genes. A definitive genetic diagnosis was made in 7/16 patients (43.7%). Six changes were novel and not in public databases of human variation. In four patients, a homozygous, novel pathogenic variant (c.2197G > C, p.(Ala 733Pro)) in PDE6B was identified and also present in a further five similarly affected Māori patients.\nCONCLUSIONS AND RELEVANCE: Over half of the Māori and Polynesian patients with inherited rod-cone diseases have no pathogenic variant(s) detected with a targeted retinal next-generation sequencing strategy, which is supportive of novel genetic mechanisms in this population. A novel PDE6B founder variant is likely to account for 16% of recessive inherited retinal dystrophy in Māori. Careful characterization of the clinical presentation permits identification of further Māori patients with a similar phenotype and simplifies the diagnostic algorithm.","variants":[{"Name":"NM_000283.4(PDE6B):c.2197G>C (p.Ala733Pro)","Chromosome":"4","Start":"665258","Stop":"665258","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1400544,"rule_based_match":true,"evidence_text":"c.2197G > C, p.(Ala 733Pro)","llm_judgment":"PRESENT","evidence":"c.2197G > C, p.(Ala 733Pro)","abstract_start":1130,"abstract_end":1157}]}
{"pmid":"25681615","title":"Genetic analysis in Factor XI deficient patients from central China: identification of one novel and seven recurrent mutations.","abstract":"Factor XI (FXI) deficiency is a rare bleeding disorder with a range of manifestations from asymptomatic to trauma related bleeding. To identify mutations in FXI-deficient patients and characterize the phenotype-genotype relationship, we studied six patients and their 18 family members in central China. Five patients were identified by presurgical or routine laboratory screening but had no bleeding symptoms. Only one patient exhibited excessive injury- and surgical-related bleeding. Eight mutations were detected, including five nonsense mutations (p.Tyr369*, p.Arg72*, p.Gln281*, p.Trp519*, and p.Trp246*), two missense mutations (p.Thr40Ile and p.Ala430Thr), and a 4-bp deletion in a splice site (c.1136-4delGTTG); one mutation was novel (p.Thr40Ile). In vitro, the p.Thr40Ile mutant protein exhibited impaired secretion and function. Five of the patients were homozygous or compound heterozygous, but only one nonsense mutation was found in Patient 2. In these patients, bleeding tendency was not correlated with FXI levels or with a single heterozygous mutation. Thrombin generation tests could not distinguish the bleeder from non-bleeders. In conclusion, we reported 8 mutations in the FXI gene (F11) leading to FXI deficiency. Moreover, the functional consequences of a novel mutation leading to FXI deficiency have been elucidated. More cases are needed to find any signature of founder effect in the Chinese population and its potential relationship with other Asian population.","variants":[{"Name":"NM_000128.4(F11):c.1288G>A (p.Ala430Thr)","Chromosome":"4","Start":"186284244","Stop":"186284244","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":275318,"rule_based_match":false,"evidence_text":"p.Ala430Thr","llm_judgment":"PRESENT","evidence":"p.Ala430Thr","abstract_start":651,"abstract_end":662},{"Name":"NM_000128.4(F11):c.841C>T (p.Gln281Ter)","Chromosome":"4","Start":"186280097","Stop":"186280097","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":443610,"rule_based_match":false,"evidence_text":"p.Gln281*","llm_judgment":"PRESENT","evidence":"p.Gln281*","abstract_start":574,"abstract_end":583}]}
{"pmid":"22479329","title":"Screening of MAMLD1 mutations in 70 children with 46,XY DSD: identification and functional analysis of two new mutations.","abstract":"More than 50% of children with severe 46,XY disorders of sex development (DSD) do not have a definitive etiological diagnosis. Besides gonadal dysgenesis, defects in androgen biosynthesis, and abnormalities in androgen sensitivity, the Mastermind-like domain containing 1 (MAMLD1) gene, which was identified as critical for the development of male genitalia, may be implicated. The present study investigated whether MAMLD1 is implicated in cases of severe 46,XY DSD and whether routine sequencing of MAMLD1 should be performed in these patients.Seventy children with severe non-syndromic 46,XY DSD of unknown etiology were studied. One hundred and fifty healthy individuals were included as controls. Direct sequencing of the MAMLD1, AR, SRD5A2 and NR5A1 genes was performed. The transactivation function of the variant MAMLD1 proteins was quantified by the luciferase method.TWO NEW MUTATIONS WERE IDENTIFIED: p.S143X (c.428C>A) in a patient with scrotal hypospadias with microphallus and p.P384L (c.1151C>T) in a patient with penile hypospadias with microphallus. The in vitro functional study confirmed no residual transactivating function of the p.S143X mutant and a significantly reduced transactivation function of the p.P384L protein (p = 0.0032). The p.P359S, p.N662S and p.H347Q variants are also reported with particularly high frequency of the p.359T- p.662G haplotype in the DSD patients.Severe undervirilization in XY newborns can reveal mutations of MAMLD1. MAMLD1 should be routinely sequenced in these patients with otherwise normal AR, SRD5A2 and NR5A1genes.","variants":[{"Name":"NM_005491.5(MAMLD1):c.1151C>T (p.Pro384Leu)","Chromosome":"X","Start":"150470724","Stop":"150470724","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1455746,"rule_based_match":true,"evidence_text":"p.P384L (c.1151C>T)","llm_judgment":"PRESENT","evidence":"p.P384L (c.1151C>T)","abstract_start":991,"abstract_end":1010}]}
{"pmid":"30591955","title":"Central Hypothyroidism and Novel Clinical Phenotypes in Hemizygous Truncation of","abstract":"Transducin <i>β</i>-like 1 X-linked (<i>TBL1X</i>) gene encodes a subunit of the nuclear corepressor-silencing mediator for retinoid and thyroid hormone receptor complex (NCoR-SMRT) involved in repression of thyroid hormone action in the pituitary and hypothalamus. <i>TBL1X</i> defects were recently associated with central hypothyroidism and hearing loss. The current study aims to describe the clinical and genetic characterization of a male diagnosed with central hypothyroidism through thyroid hormone profiling, TRH test, brain MRI, audiometry, and psychological evaluation. Next-generation sequencing of known genes involved in thyroid disorders was implemented. The 6-year-old boy was diagnosed with central hypothyroidism [free T4: 10.42 pmol/L (normal: 12 to 22 pmol/L); TSH: 1.57 mIU/L (normal: 0.7 to 5.7 mIU/L)], with a mildly reduced TSH response to TRH. He was further diagnosed with attention-deficit/hyperactivity disorder (ADHD) at 7 years, alternating episodes of encopresis and constipation, and frequent headaches. MRI showed a normal pituitary but detected a Chiari malformation type I (CMI). At 10 years, audiometry identified poor hearing threshold at high frequencies. Sequencing revealed a nonsense hemizygous mutation in <i>TBL1X</i> [c.1015C>T; p.(Arg339Ter)] largely truncating its WD-40 repeat domain involved in nuclear protein-protein interactions. In conclusion, to our knowledge, we identified the first severely truncating <i>TBL1X</i> mutation in a patient with central hypothyroidism, hypoacusia, and novel clinical features like ADHD, gastrointestinal dysmotility, and CMI. Given the relevance of TBL1X and NCoR-SMRT for the regulation of transcriptional programs at different tissues (pituitary, cochlea, brain, fossa posterior, and cerebellum), severe mutations in <i>TBL1X</i> may lead to a distinct syndrome with a phenotypic spectrum wider than previously reported.","variants":[{"Name":"NM_005647.4(TBL1X):c.1015C>T (p.Arg339Ter)","Chromosome":"X","Start":"9693381","Stop":"9693381","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":679177,"rule_based_match":true,"evidence_text":"c.1015C>T; p.(Arg339Ter)","llm_judgment":"PRESENT","evidence":"c.1015C>T; p.(Arg339Ter)","abstract_start":1262,"abstract_end":1286}]}
{"pmid":"28488682","title":"Exome sequencing revealed a splice site variant in the IQCE gene underlying post-axial polydactyly type A restricted to lower limb.","abstract":"Polydactyly is characterized by an extra supernumerary digit/toe with or without bony element. To date variants in four genes GLI3, ZNF141, MIPOL1 and PITX1 have been implicated in developing non-syndromic form of polydactyly. The present study involved characterization of large consanguineous family of Pakistani origin segregating post-axial polydactyly type A, restricted to lower limb, in autosomal recessive pattern. DNA of two affected members in the family was subjected to exome sequencing. Sanger sequencing was then followed to validate segregation of the variants in the family members. A homozygous splice acceptor site variant (c.395-1G>A) was identified in the IQCE gene, which completely co-segregated with post-axial polydactyly phenotype within the family. The homozygous variant was absent in different public variant databases, 7000 in-house exomes, 130 exomes from unrelated Pakistani individuals and 215 ethnically matched controls. Mini-gene splicing assay was used to test effect of the variant on function of the gene. The assay revealed loss of first nucleotide of exon 6, producing a -1 frameshift and a premature stop codon 22 bases downstream of the variant (p.Gly132Valfs*22). The study provided the first evidence of involvement of the IQCE gene in limbs development in humans.","variants":[{"Name":"NM_152558.5(IQCE):c.395-1G>A","Chromosome":"7","Start":"2573417","Stop":"2573417","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":431409,"rule_based_match":true,"evidence_text":"c.395-1G>A","llm_judgment":"PRESENT","evidence":"c.395-1G>A","abstract_start":642,"abstract_end":652}]}
{"pmid":"16189708","title":"A type II collagen mutation also results in oto-spondylo-megaepiphyseal dysplasia.","abstract":"Oto-spondylo-megaepiphyseal dysplasia (OSMED) is a skeletal dysplasia characterized by severe sensorineural hearing loss, enlarged epiphyses and early onset of osteoarthritis. COL11A2 has been reported as a causative gene for OSMED. We have identified a novel COL2A1 mutation at a splice-acceptor site within intron 10 (c.709-2A>G) in an OSMED patient. This mutation caused the skipping of exon 11, and of exons 11 and 13. These exon-skipping events are presumed to cause an in-frame deletion of the triple helical region of the COL2A1 product. Thus, our findings highlight the genetic heterogeneity of OSMED and extend the phenotypic spectrum of type II collagenopathy, as well as confirming the overlap between type II and type XI collagenopathies.","variants":[{"Name":"NM_001844.5(COL2A1):c.709-2A>G","Chromosome":"12","Start":"47995310","Stop":"47995310","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":32437,"rule_based_match":true,"evidence_text":"c.709-2A>G","llm_judgment":"PRESENT","evidence":"c.709-2A>G","abstract_start":320,"abstract_end":330}]}
{"pmid":"24526388","title":"Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation [corrected].","abstract":"β-ureidopropionase (βUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-β-amino aciduria. To date, only 16 genetically confirmed patients with βUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese βUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant βUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, βUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human βUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that βUP deficiency is not as rare as generally considered and screening for βUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.","variants":[{"Name":"NM_016327.3(UPB1):c.977G>A (p.Arg326Gln)","Chromosome":"22","Start":"24523679","Stop":"24523679","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227414,"rule_based_match":true,"evidence_text":"c.977G > A (p.R326Q)","llm_judgment":"PRESENT","evidence":"p.R326Q","abstract_start":435,"abstract_end":442}]}
{"pmid":"35572607","title":"Variants Disrupting CD40L Transmembrane Domain and Atypical X-Linked Hyper-IgM Syndrome: A Case Report With Leishmaniasis and Review of the Literature.","abstract":"X-linked hyper-IgM (XHIGM) syndrome is caused by mutations of the CD40LG gene, encoding the CD40L protein. The clinical presentation is characterized by early-onset infections, with profound hypogammaglobulinemia and often elevated IgM, susceptibility to opportunistic infections, such as <i>Pneumocystis jirovecii</i> pneumonia, biliary tract disease due to <i>Cryptosporidium parvum</i>, and malignancy. We report a 41-year-old male presenting with recurrent leishmaniasis, hypogammaglobulinemia, and myopathy. Whole-exome sequencing (WES) identified a missense variant in the CD40LG gene (c.107T>A, p.M36K), involving the transmembrane domain of the protein and a missense variant in the carnitine palmitoyl-transferase II (CPT2; c.593C>G; p.S198C) gene, leading to the diagnosis of hypomorphic XHIGM and CPT2 deficiency stress-induced myopathy. A review of all the previously reported cases of XHIGM with variants in the transmembrane domain showcased that these patients could present with atypical clinical features. Variants in the transmembrane domain of CD40LG act as hypomorphic generating a protein with a lower surface expression. Unlike large deletions or extracellular domain variants, they do not abolish the interaction with CD40, therefore preserving some biological activity.","variants":[{"Name":"NM_000074.3(CD40LG):c.107T>A (p.Met36Lys)","Chromosome":"X","Start":"136648355","Stop":"136648355","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":411134,"rule_based_match":true,"evidence_text":"c.107T>A, p.M36K","llm_judgment":"PRESENT","evidence":"c.107T>A, p.M36K","abstract_start":592,"abstract_end":608}]}
{"pmid":"20683152","title":"BRCA1 and BRCA2 germline mutations screening in Algerian breast/ovarian cancer families.","abstract":"BACKGROUND: Breast cancer is the leading cause of cancer death in women in Algeria. The contribution of BRCA1 and BRCA2 mutations to hereditary breast/ovarian cancer in Algerian population is largely unknown. Here, we describe analysis of BRCA1 and BRCA2 genes in 86 individuals from 70 families from an Algerian cohort with a personal and family history suggestive of genetic predisposition to breast cancer.\nMETHODS: The approach used is based on BRCA1 and BRCA2 mutations screening by High-Resolution Melting (HRM) curve analysis followed by direct sequencing. All samples for which no pathogenic mutation was found were analyzed by MLPA for large deletions or duplications.\nRESULTS: Three distinct pathogenic mutations c.83_84delTG, c.181T>G, c.798_799delTT and two large rearrangements involving deletion of exon 2 and exon 8 respectively, were detected in BRCA1 gene. Moreover 17 unclassified variants and polymorphisms were detected in BRCA1 gene (6 described for the first time). Two pathogenic mutations, c.1310_1313delAAGA and c.5722_5723delCT and 40 unclassified variants and polymorphisms (14 never described before) were identified in BRCA2 gene.\nCONCLUSIONS: For the first time, we used HRM and MLPA to identify BRCA1 and BRCA2 mutations in Algerian patients with a personal and family history suggestive of genetic predisposition to breast cancer. The implications of these new findings in regard to genetic testing and counseling are substantial for the Algerian population.","variants":[{"Name":"NM_007294.4(BRCA1):c.83_84del (p.Leu28fs)","Chromosome":"17","Start":"43115776","Stop":"43115777","ReferenceAlleleVCF":"CCA","AlternateAlleleVCF":"C","allel_id":70400,"rule_based_match":true,"evidence_text":"c.83_84delTG","llm_judgment":"PRESENT","evidence":"c.83_84delTG","abstract_start":723,"abstract_end":735},{"Name":"NM_007294.4(BRCA1):c.798_799del (p.Ser267fs)","Chromosome":"17","Start":"43094732","Stop":"43094733","ReferenceAlleleVCF":"GAA","AlternateAlleleVCF":"G","allel_id":46254,"rule_based_match":true,"evidence_text":"c.798_799delTT","llm_judgment":"PRESENT","evidence":"c.798_799delTT","abstract_start":747,"abstract_end":761},{"Name":"NM_007294.4(BRCA1):c.181T>G (p.Cys61Gly)","Chromosome":"17","Start":"43106487","Stop":"43106487","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":32700,"rule_based_match":true,"evidence_text":"c.181T>G","llm_judgment":"PRESENT","evidence":"c.181T>G","abstract_start":737,"abstract_end":745}]}
{"pmid":"29769041","title":"Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report.","abstract":"BACKGROUND: Blended phenotypes or co-occurrence of independent phenotypically distinct conditions are extremely rare and are due to coincidence of multiple pathogenic mutations, especially due to consanguinity. Hereditary fibrinogen deficiencies result from mutations in the genes FGA, FGB, and FGG, encoding the three different polypeptide chains that comprise fibrinogen. Neurodevelopmental abnormalities have not been associated with fibrinogen deficiencies. In this study, we report an unusual patient with a combination of two independently inherited genetic conditions; fibrinogen deficiency and early onset cortical atrophy.\nCASE PRESENTATION: The study describes a male child from consanguineous family presented with hypofibrinogenemia, diffuse cortical atrophy, microcephaly, hypertonia and axonal motor neuropathy. Through a combination of homozygosity mapping and exome sequencing, we identified bi-allelic pathogenic mutations in two genes: a homozygous novel truncating mutation in FGG (c.554del; p.Lys185Argfs*14) and a homozygous missense mutation in TBCD (c.1423G > A;p.Ala475Thr). Loss of function mutations in FGG have been associated with fibrinogen deficiency, while the c.1423G > A mutation in TBCD causes a novel syndrome of neurodegeneration and early onset encephalopathy.\nCONCLUSIONS: Our study highlights the importance of homozygosity mapping and exome sequencing in molecular prenatal diagnosis, especially when multiple gene mutations are responsible for the phenotype.","variants":[{"Name":"NM_005993.5(TBCD):c.1423G>A (p.Ala475Thr)","Chromosome":"17","Start":"82870328","Stop":"82870328","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":264891,"rule_based_match":true,"evidence_text":"c.1423G > A;p.Ala475Thr","llm_judgment":"PRESENT","evidence":"c.1423G > A;p.Ala475Thr","abstract_start":1073,"abstract_end":1096}]}
{"pmid":"17707409","title":"A novel point mutation in PMP22 gene in an Italian family with hereditary neuropathy with liability to pressure palsies.","abstract":"Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant inherited disorder characterized by recurrent sensory or motor dysfunction. In 85% of HNPP cases the genetic defect is a 1.4 Mb deletion on chromosome 17p11.2, encompassing the PMP22 gene. Point mutations in the PMP22 gene responsible for HNPP phenotypes are rare. We investigated a 17-years-old girl who led to our detecting a novel mutation in PMP22 gene. The mutation was also detected in her father and corresponded to a deletion of one tymidine at position 11 in exon2 (c.11delT). This novel mutation creates a shift on the reading frame starting at codon 4 and leads to the introduction of a premature stop at codon 6.","variants":[{"Name":"NM_000304.4(PMP22):c.11del (p.Leu4fs)","Chromosome":"17","Start":"15260717","Stop":"15260717","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":625407,"rule_based_match":true,"evidence_text":"c.11delT","llm_judgment":"PRESENT","evidence":"c.11delT","abstract_start":564,"abstract_end":572}]}
{"pmid":"28815995","title":"Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease.","abstract":"In this study, we describe a Japanese family with progressive hearing loss and macrothrombocytopenia. Using next-generation and Sanger sequencing analyses, we identified a heterozygous variant in exon 27 of the DIAPH1 gene (NM_005219), c.3637C>T, p.R1213X. All patients in the family had sensorineural hearing loss and macrothrombocytopenia. None of the patients exhibited a tendency to bleed. No pathogenic variants were found in the MYH9 gene. Hearing loss began with high-frequency loss during early childhood and progressed to severe hearing loss involving all frequencies. Analyses of the mean platelet volume and platelet distribution width indicated that the macrothrombocytopenia is progressive in patients with DIAPH1 related disease.There are no reports describing progressive macrothrombocytopenia in patients with pathogenic variants of DIAPH1. Thus, progressive macrothrombocytopenia may be a novel feature of deafness patients with pathogenic variants in DIAPH1.","variants":[{"Name":"NM_005219.5(DIAPH1):c.3637C>T (p.Arg1213Ter)","Chromosome":"5","Start":"141524167","Stop":"141524167","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":229284,"rule_based_match":true,"evidence_text":"c.3637C>T, p.R1213X","llm_judgment":"PRESENT","evidence":"c.3637C>T, p.R1213X","abstract_start":236,"abstract_end":255}]}
{"pmid":"30668579","title":"Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia.","abstract":"Phenylalanine hydroxylase (PAH) deficiency is responsible for most cases of phenylketonuria (PKU). Furthermore, numerous studies on BH4-sensitive PAH deficiency have been conducted. To date, BH4, a cofactor of PAH, has not been used to treat PKU in Russia.Genotype data of patients with PKU can be used to predict their sensitivity to BH4 therapy. A cohort of 2579 patients with PKU from Russia was analyzed for 25 common PAH gene mutations using custom allele-specific multiplex ligation-dependent probe amplification-based technology. A mutation detection rate of 84.1% chromosomes was accomplished. Both pathogenic alleles were identified in 73.1% of patients. The most frequent pathogenic variants were p.Arg408Trp (50.9%), p.Arg261Gln (5.3%), p.Pro281Leu (3.5%), IVS12+1G>A (3.1%), IVS10-11G>A (2.6%), and p.Arg158Leu (2.4%). The exact boundaries of a PAH exon 5 deletion were defined as EX5del4154ins268 (c.442-2913_509+1173del4154ins268). Severe phenotypes prevailed in the cohort, and classical PKU was observed in 71.8% cases. Due to the genotype-based prediction, 55.9% of the probands were non-responders to the BH4-treatment, and 20.2% were potential responders. Analysis of genotype data is useful to predict BH4 response in PKU patients. The high rate of non-responders among Russian patients was due to the high allele frequency of severe PAH mutations.","variants":[{"Name":"NM_000277.3(PAH):c.1222C>T (p.Arg408Trp)","Chromosome":"12","Start":"102840493","Stop":"102840493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15616,"rule_based_match":false,"evidence_text":"p.Arg408Trp","llm_judgment":"PRESENT","evidence":"p.Arg408Trp","abstract_start":707,"abstract_end":718}]}
{"pmid":"30945686","title":"Novel mutation in","abstract":"This study evaluates a family with two siblings having severe growth retardation and facial dysmorphism, born to consanguineous normal healthy parents. Affymetrix CytoScan 750K microarray showed a 34-Mb pericentric homozygous region on chromosome 6 for both siblings. <i>CUL7</i> was one of the 141 genes present in this region. Sanger sequencing of <i>CUL7</i> gene detected a 2-bp novel deletion in the 15th exon (c.2943_2944delCT of the cDNA). This deletion leads to a frameshift and a premature termination signal much upstream of the wild-type termination signal, leading to a nonsense mediated decay of the mRNA. CUL7 protein plays an important role in formation of 3M complex, ubiquitination, microtubule dynamics and cell cycle regulation. Mutations in <i>CUL7</i> gene is known to cause a rare 3M syndrome. Information about the novel mutation has been accepted in the ClinVar database with rs1064792895.","variants":[{"Name":"NM_014780.5(CUL7):c.2943_2944del (p.Cys982fs)","Chromosome":"6","Start":"43045321","Stop":"43045322","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":413879,"rule_based_match":true,"evidence_text":"c.2943_2944delCT","llm_judgment":"PRESENT","evidence":"c.2943_2944delCT","abstract_start":416,"abstract_end":432}]}
{"pmid":"30584653","title":"Pair analysis and custom array CGH can detect a small copy number variation in COQ6 gene.","abstract":"BACKGROUND: Recently, comprehensive genetic approaches for steroid-resistant nephrotic syndrome (SRNS) using next-generation sequencing (NGS) have been established, but causative gene mutations could not be detected in almost 70% of SRNS patients. Main reason for the low variant detection rate is that most of them are SRNS caused not by genetic but by immunological factors. But some of them are probably because of the difficulty of detecting copy number variations (CNVs) in causative genes by NGS.\nMETHODS: In this study, we performed two analytical methods of NGS data-dependent pair analysis and custom array comparative genomic hybridization (aCGH) in addition to NGS analysis in an infantile nephrotic syndrome case.\nRESULTS: We detected only one known pathogenic heterozygous missense mutation in exon 7 of COQ6 c.782C > T, p.(Pro261Leu) by NGS. With pair analysis, heterozygous exon 1-2 deletion was suspected and was confirmed by custom aCGH. As a result, a small CNV was successfully detected in the COQ6 gene. Because we could detect variants in COQ6 and could start treatment by coenzyme Q10 (CoQ10) in his very early stage of SRNS, the patient achieved complete remission.\nCONCLUSIONS: These relatively novel methods should be adopted in cases with negative results in gene tests by NGS analysis. Especially, in cases with CoQ10 deficiency, it is possible to delay initiating dialysis by starting treatment at their early stages.","variants":[{"Name":"NM_182476.3(COQ6):c.782C>T (p.Pro261Leu)","Chromosome":"14","Start":"73959223","Stop":"73959223","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":798678,"rule_based_match":true,"evidence_text":"c.782C > T, p.(Pro261Leu)","llm_judgment":"PRESENT","evidence":"c.782C > T, p.(Pro261Leu)","abstract_start":822,"abstract_end":847}]}
{"pmid":"29188604","title":"Analysis of 12 patients with novel mutations of Dystrophin gene","abstract":"OBJECTIVE: To study the characteristics, location, and amino acid changes of novel mutations of the Dystrophin gene.\nMETHODS: Twelve patients in whom no deletion or duplication of the Dystrophin gene was detected were analyzed with next-generation sequencing. Fifty healthy adult males were recruited as the controls.\nRESULTS: All patients were detected with mutations of the Dystrophin gene, which included c.33C>G, c.583C>T, c.1333C>T, c.2593C>T, c.5731A>T, c.7288G>T, c.2803+1G>T, c.10034G>A, c.4289A>G, c.1905_906delAG, c.5017delC, c.5768_5771delAAGA, and c.6261_6262insA. No similar mutations were found among the controls.\nCONCLUSION: Our data has enriched the mutation spectrum of the Dystrophin gene and may provide an important basis for genetic diagnosis.","variants":[{"Name":"NM_004006.3(DMD):c.10034G>A (p.Arg3345Gln)","Chromosome":"X","Start":"31180422","Stop":"31180422","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1861773,"rule_based_match":true,"evidence_text":"c.10034G>A","llm_judgment":"PRESENT","evidence":"c.10034G>A","abstract_start":484,"abstract_end":494}]}
{"pmid":"19006214","title":"Paternal somatic mosaicism of a TGFBR2 mutation transmitting to an affected son with Loeys-Dietz syndrome.","abstract":"We report on somatic mosaicism of a TGFBR2 missense mutation, c.1336G>A (D446N). The affected son with the heterozygous mutation was previously reported [Sakai et al. (2006); Am J Med Genet A 140A:1719-1725]. Further evaluation indicates his clinical condition is Loeys-Dietz syndrome. Parental blood samples were studied to confirm whether the propositus' mutation was a de novo change, and suggested a trace of the mutation in the father. DNAs extracted from blood leukocytes, buccal cells, hair root cells, and nails in the father indicated 52%, 25%, 0%, and 35% of cells harbored the mutation, respectively. This is the first detailed report of somatic mosaicism of a TGFBR2 mutation.","variants":[{"Name":"NM_003242.6(TGFBR2):c.1336G>A (p.Asp446Asn)","Chromosome":"3","Start":"30674186","Stop":"30674186","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":259758,"rule_based_match":true,"evidence_text":"c.1336G>A (D446N)","llm_judgment":"PRESENT","evidence":"c.1336G>A (D446N)","abstract_start":62,"abstract_end":79}]}
{"pmid":"34496286","title":"Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature.","abstract":"INTRODUCTION: Aminoacyl transfer RNA (tRNA) synthetases are associated with diseases when mutations occur in their encoding genes. Pulmonary alveolar proteinosis can be caused by mutation in the methionyl-tRNA synthetase (MARS) gene while mutations in the leucine-tRNA synthetase (LARS) gene lead to infantile liver failure syndrome type 1. We report the case of a patient with LARS1 pathogenics variants and two patients with MARS1 pathogenics variants. The aim of this study was to analyze the phenotypes of our three patients in detail and classify cases in the literature using Human Phenotype Ontology (HPO) terms.\nRESULTS: The first patient has two previously undescribed heterozygous variants in LARS1 (c.1818dup and c.463A>G). The other two patients' MARS1 variants (c.1177G>A and c.1700C>T) have already been described in the literature. All three patients had anemia, hepatomegaly, feeding difficulties, failure to thrive and hypoalbuminemia. Including ours, 65 patients are described in total, for whom 117 phenotypic abnormalities have been described at least once, 41.9% of which both in patients with LARS1 and MARS1 mutations.\nCONCLUSION: Patients with LARS1 and MARS1 mutations seem to share a common phenotype but further deep phenotyping studies are required to clarify the details of these complex pathologies.","variants":[{"Name":"NM_004990.4(MARS1):c.1177G>A (p.Ala393Thr)","Chromosome":"12","Start":"57500406","Stop":"57500406","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187252,"rule_based_match":true,"evidence_text":"c.1177G>A","llm_judgment":"PRESENT","evidence":"c.1177G>A","abstract_start":775,"abstract_end":784}]}
{"pmid":"28192073","title":"Recurrent and novel mutations in the NTRK1 gene lead to rare congenital insensitivity to pain with anhidrosis in two Chinese patients.","abstract":"BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive autonomic and sensory neuropathy. CIPA is associated with various mutations in NTRK1.\nCASES: Two unrelated Chinese patients presented separately with symptoms of insensitivity to pain, inability to sweat, repeated painless fractures, and Charcot arthropathy were recruited. Both of them were clinically diagnosed with CIPA. Increased serum bone resorption marker (β-CTX) levels and decreased BMD were observed in both patients. X-ray films revealed enlarged bony calli in the fracture sites, Charcot arthropathy, and bilateral lower limb osteomyelitis. Sanger sequencing demonstrated compound heterozygous mutations in NTRK1 for proband 1 (IVS7-33T>A in intron 7 and c. 2281C>T in exon 17) and for proband 2 (IVS7-33T>A in intron 7 and c.1652delA in exon 14), of which the variation in exon 14 in NTRK1 was a novel mutation.\nCONCLUSIONS: We report the detailed phenotypes, as well as both recurrent and novel mutations in NTRK1 in 2 Chinese patients with CIPA. The genetic findings of our study expand the gene mutation spectrum of CIPA.","variants":[{"Name":"NM_002529.4(NTRK1):c.2281C>T (p.Arg761Trp)","Chromosome":"1","Start":"156881532","Stop":"156881532","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":540665,"rule_based_match":true,"evidence_text":"c. 2281C>T in exon 17","llm_judgment":"PRESENT","evidence":"c. 2281C>T in exon 17","abstract_start":776,"abstract_end":797}]}
{"pmid":"19394258","title":"The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome.","abstract":"Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.","variants":[{"Name":"NM_080916.3(DGUOK):c.444-62C>A","Chromosome":"2","Start":"73950523","Stop":"73950523","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1467042,"rule_based_match":true,"evidence_text":"c.444-62C>A","llm_judgment":"PRESENT","evidence":"c.444-62C>A","abstract_start":318,"abstract_end":329}]}
{"pmid":"22646272","title":"NLRP7 mutation analysis in sporadic hydatidiform moles in Tunisian patients: NLRP7 and sporadic mole.","abstract":"CONTEXT: Hydatidiform mole, an aberrant human pregnancy, is commonly a nonrecurrent disease. Recently, a rare autosomal recessive form of familial and/or recurrent molar pregnancies was associated with mutations in the NLRP7 gene.\nOBJECTIVE: To investigate whether NLRP7 mutations exist in Tunisian women with sporadic hydatidiform moles.\nDESIGN: Genomic DNA from 38 unrelated Tunisian patients with sporadic hydatidiform moles were screened by sequencing all NLRP7 exons. A high-resolution melting curve analysis was performed on 170 DNA controls to analyze new sequence variants.\nRESULTS: More than 13% of these patients were heterozygous for NLRP7 mutations. We found 2 novel missense mutations in the heterozygous state, c.544G>A (p.Val182Met) in 1 patient and c.1480G>A (p.Ala494Thr) in 2 patients, and 2 already reported mutations, c.1532A>G (p.Lys511Arg) and c.2156C>T (p.Ala719Val), in 2 patients. None of these mutations were identified in 170 controls except for 1 woman who was heterozygous for p.Val182Met.\nCONCLUSION: As homozygous NLRP7 mutations are associated with recurrent hydatidiform mole or conception loss, the heterozygous state could represent a risk factor for nonrecurrent mole.","variants":[{"Name":"NM_001127255.2(NLRP7):c.1532A>G (p.Lys511Arg)","Chromosome":"19","Start":"54939287","Stop":"54939287","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":271712,"rule_based_match":true,"evidence_text":"c.1532A>G (p.Lys511Arg)","llm_judgment":"PRESENT","evidence":"c.1532A>G (p.Lys511Arg)","abstract_start":838,"abstract_end":861},{"Name":"NM_001127255.2(NLRP7):c.2156C>T (p.Ala719Val)","Chromosome":"19","Start":"54936405","Stop":"54936405","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":103639,"rule_based_match":true,"evidence_text":"c.2156C>T (p.Ala719Val)","llm_judgment":"PRESENT","evidence":"c.2156C>T (p.Ala719Val)","abstract_start":866,"abstract_end":889}]}
{"pmid":"30090657","title":"The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia.","abstract":"Our study aimed to identify the underlying causes in patients with early onset dementia by clinical and genetic exploration. We recruited a group of 38 patients with early-onset dementia. Firstly, hexanucleotide repeat expansions in <i>C9ORF72</i> gene were screened in all subjects to exclude the possibility of copy number variation. Then, the whole exome sequencing (WES) was conducted, and the data were analyzed focusing on 89 dementia-related causing and susceptible genes. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. There were no pathogenic expansions in <i>C9ORF72</i> detected. According to the ACMG standards and guidelines, we identified five known pathogenic mutations, <i>PSEN1</i> P284L, <i>PSEN1</i>c.857-1G>A, <i>PSEN1</i> I143T, <i>PSEN1</i> G209E and <i>MAPT</i> G389R, and one novel pathogenic mutation <i>APP</i> K687N. All these mutations caused dementia with the mean onset age of 38.3 (range from 27 to 51) and rapid progression. Eleven variants with uncertain significance were also detected and needed further verification. The clinical phenotypes of dementia are heterogeneous, with both onset ages and clinical features being influenced by mutation position as well as the causative gene. WES can serve as efficient diagnostic tools for different heterogeneous dementia.","variants":[{"Name":"NM_000021.4(PSEN1):c.428T>C (p.Ile143Thr)","Chromosome":"14","Start":"73173655","Stop":"73173655","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":103918,"rule_based_match":false,"evidence_text":"PSEN1 I143T","llm_judgment":"PRESENT","evidence":"PSEN1</i> I143T","abstract_start":837,"abstract_end":852}]}
{"pmid":"29244146","title":"Ezh2 Mutations Found in the Weaver Overgrowth Syndrome Cause a Partial Loss of H3K27 Histone Methyltransferase Activity.","abstract":"Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for histone H3 at lysine 27 (H3K27) trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome.\nObjective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome cause either a gain of function or a partial loss of function.\nDesign: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos.\nResults: A de novo missense EZH2 mutation [c.1876G>A (p.Val626Met)] was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality, whereas heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation.\nConclusion: We generated a mouse model with the same mutation as our patient, found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.","variants":[{"Name":"NM_004456.5(EZH2):c.1876G>A (p.Val626Met)","Chromosome":"7","Start":"148811696","Stop":"148811696","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":168576,"rule_based_match":true,"evidence_text":"c.1876G>A (p.Val626Met)","llm_judgment":"PRESENT","evidence":"c.1876G>A (p.Val626Met)","abstract_start":997,"abstract_end":1020}]}
{"pmid":"24029078","title":"A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy.","abstract":"We performed analysis of KCNT1 in two unrelated patients with malignant migrating partial seizures in infancy. Both patients had intractable focal seizures since two months of age. Their seizures were characterized by a shift of epileptic focus during a single seizure and were resistant to most antiepileptic drugs but responded to vagus nerve stimulation in one and clorazepate in the other. Bidirectional sequencing for KCNT1 was analyzed by standard Sanger sequencing method. A de novo c.862G>A (p.Gly288Ser) missense mutation was identified at the pore region of KCNT1 channel in both patients, whereas all KCNT1 mutations in the previous reports were identified mostly in the intracellular C-terminal region. Computational analysis suggested possible changes in the molecular structure and the ion channel property induced by the Gly288Ser mutation. Because the G-to-A transition was located at CG dinucleotide sequences as previously reported for KCNT1 mutations, the recurrent occurrence of de novo KCNT1 mutations indicated the hot spots of these locations.","variants":[{"Name":"NM_020822.3(KCNT1):c.862G>A (p.Gly288Ser)","Chromosome":"9","Start":"135759686","Stop":"135759686","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":131953,"rule_based_match":true,"evidence_text":"c.862G>A (p.Gly288Ser)","llm_judgment":"PRESENT","evidence":"c.862G>A (p.Gly288Ser)","abstract_start":490,"abstract_end":512}]}
{"pmid":"19753312","title":"Mutations that are a common cause of Leber congenital amaurosis in northern America are rare in southern India.","abstract":"PURPOSE: To test patients from southern India for the presence of mutations that most commonly cause Leber congenital amaurosis (LCA) in northern America.\nMETHODS: A review of the literature identified 177 unique LCA causing mutations in eight different genes: aryl hydrocarbon receptor interacting protein-like 1 (AIPL1), crumbs homolog 1 (CRB1), cone-rod homeobox (CRX), guanylate cyclase 2D (GUCY2D), nephronophthisis 6 (NPHP6), retinol dehydrogenase 12 (RDH12), retinal pigment epithelium-specific protein 65 kDa (RPE65), and retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1). Allele-specific ligation assay and bidirectional sequencing were used to test 38 unrelated LCA patients from southern India for 104 of these mutations, which contribute to more than 30% of the LCA cases in a northern American population.\nRESULTS: Only one participant was found to harbor one of the 104 mutations in the allele-specific assay (homozygous RPE65 Tyr368His). A mutation that was not part of the assay (homozygous RPE65 Tyr143Asp) was incidentally detected in a second patient when an equivocal signal from one allele on the assay was followed up with automated DNA sequencing.\nCONCLUSIONS: Mutations that contribute to 30% of the LCA cases in northern America were detected in only 2.6% of LCA cases in our cohort from southern India. There were no instances of IVS26 c.2991+1655 A>G in NPHP6, the most commonly detected mutation in LCA. These data suggest that LCA in India is caused primarily by a different set of mutations in the same genes associated with disease in northern America, or by mutations in other genes that have not yet been discovered. Therefore, mutation-specific assays developed for European and northern American cohorts may not be suited for testing LCA patients from India or other ethnically distinct populations.","variants":[{"Name":"NM_000329.3(RPE65):c.1102T>C (p.Tyr368His)","Chromosome":"1","Start":"68438213","Stop":"68438213","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":38825,"rule_based_match":false,"evidence_text":"homozygous RPE65 Tyr368His","llm_judgment":"PRESENT","evidence":"homozygous RPE65 Tyr368His","abstract_start":944,"abstract_end":970}]}
{"pmid":"29753094","title":"Sequence variations in TENM3 gene causing eye anomalies with intellectual disability: Expanding the phenotypic spectrum.","abstract":"Microphthalmia, anophthalmia are the malformations of the eye, referring to a congenital absence, and a reduced size of the eyeball. Coloboma of iris is associated with many of the cases. Here, we report a propositus with eye anomalies and intellectual disability associated with TENM3 pathogenic variations identified by exome sequencing and confirms intellectual disability as a phenotype associated with TENM3 variations. This child was compound heterozygote [NM_001080477.3(TENM3):c.4046C > G; p.(Ala1349Gly) and NM_001080477.3(TENM3): c.7687C > T; p.(Arg2563Trp)] for the missense likely pathogenic sequence variations in TENM3 gene. To our knowledge only three patients till now have been reported to have TENM3 pathogenic variations in association with microphthalmia, two siblings without developmental delay and third with developmental delay. This report supports the association of TENM3 variations with colobomatous microphthalmia and expands the phenotypic spectrum associated with pathogenic variations in this gene.","variants":[{"Name":"NM_001080477.4(TENM3):c.7687C>T (p.Arg2563Trp)","Chromosome":"4","Start":"182799938","Stop":"182799938","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":480538,"rule_based_match":true,"evidence_text":"NM_001080477.3(TENM3): c.7687C > T; p.(Arg2563Trp)","llm_judgment":"PRESENT","evidence":"NM_001080477.3(TENM3): c.7687C > T; p.(Arg2563Trp)","abstract_start":517,"abstract_end":567},{"Name":"NM_001080477.4(TENM3):c.4046C>G (p.Ala1349Gly)","Chromosome":"4","Start":"182754413","Stop":"182754413","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":480539,"rule_based_match":true,"evidence_text":"NM_001080477.3(TENM3):c.4046C > G; p.(Ala1349Gly)","llm_judgment":"PRESENT","evidence":"NM_001080477.3(TENM3):c.4046C > G; p.(Ala1349Gly)","abstract_start":463,"abstract_end":512}]}
{"pmid":"26138499","title":"SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum.","abstract":"Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole-exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi-Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.","variants":[{"Name":"NM_003038.5(SLC1A4):c.766G>A (p.Glu256Lys)","Chromosome":"2","Start":"65010729","Stop":"65010729","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":259742,"rule_based_match":true,"evidence_text":"c.766G>A, p.(E256K)","llm_judgment":"PRESENT","evidence":"c.766G>A, p.(E256K)","abstract_start":537,"abstract_end":556}]}
{"pmid":"27884763","title":"ACOX2 deficiency: An inborn error of bile acid synthesis identified in an adolescent with persistent hypertransaminasemia.","abstract":"BACKGROUND & AIMS: Acyl-CoA oxidase (ACOX2) is involved in the shortening of C27 cholesterol derivatives to generate C24 bile acids. Inborn errors affecting the rest of peroxisomal enzymes involved in bile acid biosynthesis have been described. Here we aimed at investigating the case of an adolescent boy with persistent hypertransaminasemia of unknown origin and suspected dysfunction in bile acid metabolism.\nMETHODS: Serum and urine samples were taken from the patient, his sister and parents and underwent HPLC-MS/MS and HPLC-TOF analyses. Coding exons in genes of interest were amplified by high-fidelity PCR and sequenced. Wild-type or mutated (mutACOX2) variants were overexpressed in human hepatoblastoma HepG2 cells to determine ACOX2 enzymatic activity, expression and subcellular location.\nRESULTS: The patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates, mainly tauroconjugated trihydroxycholestanoic acid (THCA). Genetic analysis of enzymes potentially involved revealed a homozygous missense mutation (c.673C>T; R225W) in ACOX2. His only sister was also homozygous for this mutation and exhibited similar alterations in bile acid profiles. Both parents were heterozygous and presented normal C24 and C27 bile acid levels. Immunofluorescence studies showed similar protein size and peroxisomal localization for both normal and mutated variants. THCA biotransformation into cholic acid was enhanced in cells overexpressing ACOX2, but not in those overexpressing mutACOX2. Both cell types showed similar sensitivity to oxidative stress caused by C24 bile acids. In contrast, THCA-induced oxidative stress and cell death were reduced by overexpressing ACOX2, but not mutACOX2.\nCONCLUSION: ACOX2 deficiency, a condition characterized by accumulation of toxic C27 bile acid intermediates, is a novel cause of isolated persistent hypertransaminasemia.\nLAY SUMMARY: Elevation of serum transaminases is a biochemical sign of liver damage due to multiplicity of causes (viruses, toxins, autoimmunity, metabolic disorders). In rare cases the origin of this alteration remains unknown. We have identified by the first time in a young patient and his only sister a familiar genetic defect of an enzyme called ACOX2, which participates in the transformation of cholesterol into bile acids as a cause of increased serum transaminases in the absence of any other symptomatology. This treatable condition should be considered in the diagnosis of those patients where the cause of elevated transaminases remains obscure.","variants":[{"Name":"NM_003500.4(ACOX2):c.673C>T (p.Arg225Trp)","Chromosome":"3","Start":"58531723","Stop":"58531723","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":362581,"rule_based_match":true,"evidence_text":"c.673C>T","llm_judgment":"PRESENT","evidence":"c.673C>T","abstract_start":1078,"abstract_end":1086}]}
{"pmid":"27903347","title":"Clinical, genetic and pathological features of neuronal ceroid lipofuscinosis in 5 Chinese patients","abstract":"<b>Objective:</b> To report the clinical, genetic and ultrastructural pathological features of neuronal ceroid lipofuscinosis (NCLs) in 5 Chinese patients. <b>Methods:</b> A total of 5 patients with NCLs were collected from 2013 to 2015 diagnosed by the department of pediatrics of Beijing Tian Tan Hospital. Their clinical, electrophysiological and neuroimaging data of the patients were reviewed.A total of 9 underlying genes of NCLs were tested in 4 cases and their parents.Ultrastructural pathology by skin biopsy was performed in 3 cases respectively. <b>Results:</b> We identified two novel homozygous mutations and one novel heterozygous pathogenic mutation in 3 patients. The confirmed mutations included c. 1153G >C (p.Gly385Arg) MFSD8 homozygous mutation, c 321-1G >A CLN5 intron splice site homozygous mutation and c 407G >A (p.Arg136His)CLN6 heterozygous mutation, which had never been reported before. While no gene mutation was detected in the rest 1 case. Among the 3 cases received electron microscope testing of skin biopsy, 2 presented with fingerprint inclusions mixed with granular osmiophilic deposits, rectilinear profiles mixed with granular osmiophilic deposits were noted in another case. <b>Conclusions:</b> The patients of NCLs caused by the mutations of MFSD8, CLN5 and CLN6 genes in Chinese population were firstly reported in this study. There are some relevence between genotype, pathomorphology and clinical presentation of NCLs. The pathomorphology is still a gold standard for the diagnosis of NCLs.","variants":[{"Name":"NM_017882.3(CLN6):c.407G>A (p.Arg136His)","Chromosome":"15","Start":"68211754","Stop":"68211754","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":389162,"rule_based_match":false,"evidence_text":"c 407G >A (p.Arg136His)CLN6 heterozygous mutation","llm_judgment":"PRESENT","evidence":"c 407G >A (p.Arg136His)CLN6 heterozygous mutation","abstract_start":826,"abstract_end":875}]}
{"pmid":"29016355","title":"Genetic analysis of fructose-1,6-bisphosphatase (FBPase) deficiency in nine consanguineous Pakistani families.","abstract":"BACKGROUND: Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare inherited metabolic disorder characterized by recurrent episodes of hypoglycemia, ketosis and lactic acidosis. FBPase is encoded by FBP1 gene and catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate in the last step of gluconeogenesis. We report here FBP1 mutations in nine consanguineous Pakistani families affected with FBPase deficiency.\nMETHODS: Nine families having one or two individuals affected with FBPase deficiency were enrolled over a period of 3 years. All FBP1 exonic regions including splicing sites were PCR-amplified and sequenced bidirectionally. Familial cosegregation of mutations with disease was confirmed by direct sequencing and PCR-RFLP analysis.\nRESULTS: Three different FBP1 mutations were identified. Each of two previously reported mutations (c.472C>T (p.Arg158Trp) and c.841G>A (p.Glu281Lys)) was carried by four different families. The ninth family carried a novel 4-bp deletion (c.609_612delAAAA), which is predicted to result in frameshift (p.Lys204Argfs*72) and loss of FBPase function. The novel variant was not detected in any of 120 chromosomes from normal ethnically matched individuals.\nCONCLUSIONS: FBPase deficiency is often fatal in the infancy and early childhood. Early diagnosis and prompt treatment is therefore crucial to preventing early mortality. We recommend the use of c.472C>T and c.841G>A mutations as first choice genetic markers for molecular diagnosis of FBPase deficiency in Pakistan.","variants":[{"Name":"NM_000507.4(FBP1):c.472C>T (p.Arg158Trp)","Chromosome":"9","Start":"94610016","Stop":"94610016","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":553128,"rule_based_match":true,"evidence_text":"c.472C>T (p.Arg158Trp)","llm_judgment":"PRESENT","evidence":"c.472C>T (p.Arg158Trp)","abstract_start":867,"abstract_end":889},{"Name":"NM_000507.4(FBP1):c.841G>A (p.Glu281Lys)","Chromosome":"9","Start":"94603557","Stop":"94603557","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":370993,"rule_based_match":true,"evidence_text":"c.841G>A (p.Glu281Lys)","llm_judgment":"PRESENT","evidence":"c.841G>A (p.Glu281Lys)","abstract_start":894,"abstract_end":916}]}
{"pmid":"25376329","title":"A novel ERCC6 splicing variant associated with a mild Cockayne syndrome phenotype.","abstract":"BACKGROUND: Cockayne syndrome is an autosomal recessive, heterogeneous syndrome with classical features, including short stature, microcephaly, developmental delay, neuropathy, and photosensitivity. New genomic approaches offer improved molecular diagnostic potential.\nMETHODS: Whole-exome sequencing was employed to study a consanguineous extended family with severe short stature and variable presentations of peripheral neuropathy, lipoatrophy, photosensitivity, webbed neck, and hirsutism.\nRESULTS: We identified a novel homozygous ERCC6 variant at the donor splice site of intron 9 (c.1992 + 3A>G), which was predicted to only slightly perturb splicing efficiencies. Assessment of primary fibroblast-derived mRNAs, however, revealed a dominant splicing species that utilized an unsuspected putative donor splice site within exon 9, resulting in predicted early protein termination (p.Arg637Serfs*34).\nCONCLUSIONS: We describe a new splicing ERCC6 defect causal of Cockayne syndrome. The application of exome sequence analysis was integral to diagnosis, given the complexity of phenotypic presentation in the affected family members. The novel splicing defect, furthermore, illustrates how a seemingly minor change in the relative strength of a splice site can have significant biological consequences.","variants":[{"Name":"NM_000124.4(ERCC6):c.1992+3A>G","Chromosome":"10","Start":"49483343","Stop":"49483343","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1481214,"rule_based_match":true,"evidence_text":"c.1992 + 3A>G","llm_judgment":"PRESENT","evidence":"c.1992 + 3A>G","abstract_start":588,"abstract_end":601}]}
{"pmid":"23579484","title":"Exome sequencing reveals CCDC111 mutation associated with high myopia.","abstract":"Myopia is a refractive error of the eye that is prevalent worldwide. The most extreme form, high myopia, is usually associated with other ocular disorders such as retinal detachment, macular degeneration, cataract, and glaucoma, and is one of leading causes of blindness. The etiology is complex and has not been fully elucidated. In this study, we identified a novel missense variant of the CCDC111 gene (NM_152683.2: c.265T > G; p.Y89D) in a high myopia family by exome sequencing. The variant was identified in 4 patients from an additional 270 sporadic high myopia patients, but not found in 270 controls. The amino acid is highly conserved across species, and variants giving rise to amino acid substitutions are predicted to be functionally damaging. The CCDC111 gene was ubiquitously expressed in primary cell cultures from human eye tissue, including corneal epithelial cells, choroidal melanoma cells, scleral fibroblasts, retinal epithelial cells, retinal Müller cells, and lens capsule epithelial cells. In summary, our results suggested that the CCDC111 may be a susceptibility gene for high myopia.","variants":[{"Name":"NM_152683.4(PRIMPOL):c.265T>G (p.Tyr89Asp)","Chromosome":"4","Start":"184659424","Stop":"184659424","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":76354,"rule_based_match":true,"evidence_text":"NM_152683.2: c.265T > G; p.Y89D","llm_judgment":"PRESENT","evidence":"NM_152683.2: c.265T > G; p.Y89D","abstract_start":406,"abstract_end":437}]}
{"pmid":"27935012","title":"Mutational Analysis of Agxt in Tunisian Population with Primary Hyperoxaluria Type 1.","abstract":"BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive metabolic disorder caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine:glyoxylate aminotransferase (AGT). PH1 is a clinically and genetically heterogeneous disorder. The aim of our study was to analyze and characterize the mutational spectrum of PH1 in Tunisian patients.\nMATERIALS AND METHODS: Molecular studies of 146 Tunisian patients suspected with PH were performed by PCR/Restriction fragment length polymorphism (RFLP) to detect seven mutations described as the most common. Direct sequencing for the 11 exons was performed in patients in whom any mutation was not identified.\nRESULTS: The genetic diagnosis of PH1 was confirmed in 62.3% of patients. The first molecular approach based on PCR/restriction enzyme test was positive in 37.6% of patients, whereas the second molecular approach based on whole gene sequencing was successful in 24% of cases. Twelve pathogenic mutations were detected in our cohort. Two mutations were novel, and five were detected for the first time in Tunisians. The three most frequent mutations were p.Ile244Thr, p.Gly190Arg, and c.33dupC, with a frequency of 43.4%, 21.4%, and 13.1%, respectively.\nCONCLUSION: The two novel mutations detected in our study extend the spectrum of known AGXT gene mutations. The screen for the mutations identified in this study can provide a useful, cost-effective, and first-line investigation in Tunisian PH1 patients.","variants":[{"Name":"NM_000030.3(AGXT):c.568G>A (p.Gly190Arg)","Chromosome":"2","Start":"240873022","Stop":"240873022","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186657,"rule_based_match":false,"evidence_text":"p.Gly190Arg","llm_judgment":"PRESENT","evidence":"p.Gly190Arg","abstract_start":1154,"abstract_end":1165}]}
{"pmid":"15657175","title":"A common Fanconi anemia mutation in black populations of sub-Saharan Africa.","abstract":"Fanconi anemia (FA) is a genetically heterogeneous chromosomal instability syndrome associated with multiple congenital abnormalities, aplastic anemia, and cancer. We report that a deletion mutation in the FANCG gene (c.637_643delTACCGCC) was present in 82% of FA patients in the black populations of Southern Africa. These patients originated from South Africa, Swaziland, Mozambique, and Malawi. The mutation was found on the same haplotype and was present in 1% of controls from the black South African population. These data indicate that the birth incidence of FA in this population is higher than 1 in 40 000, which is much higher than previously supposed, and suggest that the FANCG deletion is an ancient founder mutation in Bantu-speaking populations of sub-Saharan Africa. Diagnostic screening is now possible by means of a simple DNA test.","variants":[{"Name":"NM_004629.2(FANCG):c.637_643del (p.Tyr213fs)","Chromosome":"9","Start":"35077267","Stop":"35077273","ReferenceAlleleVCF":"TGGCGGTA","AlternateAlleleVCF":"T","allel_id":21758,"rule_based_match":true,"evidence_text":"c.637_643delTACCGCC","llm_judgment":"PRESENT","evidence":"c.637_643delTACCGCC","abstract_start":218,"abstract_end":237}]}
{"pmid":"22522645","title":"A novel intronic mutation and a missense mutation of MEN1 identified in two Chinese families with multiple endocrine neoplasia type 1.","abstract":"BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) caused by MEN1 mutation is widely recognized. To date, 14 novel mutations were reported in Chinese and intronic mutations are getting more attention.\nAIM: To explore clinical features and MEN1 mutations in two Chinese families suffering from MEN1.\nMETHODS: Nineteen individuals (10 males and 9 females) from two unrelated families with MEN1 were studied. Mutations of MEN1 were analyzed by direct sequencing of PCR products. In vitro splicing analysis was also performed with minigenes containing both wildtype and novel mutant fragments. Through the RNAstructure program, we analyzed the secondary structure of the wild type MEN1 pre-mRNA and then introduced T>G mutation at +2 donor splice site of intron 7.\nRESULTS: Clinical features of 3 patients in two families were described, and 5 individuals were proven to be carriers of MEN1 mutation without apparent symptoms. A novel splicing site mutation of the intron 7 (IVS7+2 T→G) was identified in the first family. In vitro analysis also verified this mutation caused the aberrant splicing of MEN1 mRNA. With the RNAstructure program, we could figure out that the global secondary structure as well as the number of stems and loops of pre-mRNA greatly changed after this mutation. The mutation c. 1227 C>A (C409X) was identified in another family, which also caused the truncation of menin.\nCONCLUSION: We reported a novel intronic mutation and a missense mutations in two Chinese families suffering from MEN1.","variants":[{"Name":"NM_001370259.2(MEN1):c.1227C>A (p.Cys409Ter)","Chromosome":"11","Start":"64805157","Stop":"64805157","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2898659,"rule_based_match":true,"evidence_text":"c. 1227 C>A (C409X)","llm_judgment":"PRESENT","evidence":"c. 1227 C>A (C409X)","abstract_start":1302,"abstract_end":1321}]}
{"pmid":"35910211","title":"The Prevalence and Genetic Spectrum of Familial Hypercholesterolemia in Qatar Based on Whole Genome Sequencing of 14,000 Subjects.","abstract":"Familial hypercholesterolemia (FH) is an inherited disease characterized by reduced efficiency of low-density lipoprotein-cholesterol (LDL-C) removal from the blood and, consequently, an increased risk of life-threatening early cardiovascular complications. In Qatar, the prevalence of FH has not been determined and the disease, as in many countries, is largely underdiagnosed. In this study, we combined whole-genome sequencing data from the Qatar Genome Program with deep phenotype data from Qatar Biobank for 14,056 subjects to determine the genetic spectrum and estimate the prevalence of FH in Qatar. We used the Dutch Lipid Clinic Network (DLCN) as a diagnostic tool and scrutinized 11 FH-related genes for known <i>pathogenic</i> and <i>possibly pathogenic</i> mutations. Results revealed an estimated prevalence of 0.8% (1:125) for definite/probable cases of FH in the Qatari population. We detected 16 known <i>pathogenic/likely pathogenic</i> mutations in <i>LDLR</i> and one in <i>PCSK9;</i> all in a heterozygous state with high penetrance. The most common mutation was rs1064793799 (c.313+3A >C) followed by rs771019366 (p.Asp90Gly); both in <i>LDLR</i>. In addition, we identified 18 highly penetrant <i>possibly pathogenic</i> variants, of which 5 were Qatari-specific, in <i>LDLR</i>, <i>APOB</i>, <i>PCSK9</i> and <i>APOE</i>, which are predicted to be among the top 1% most deleterious mutations in the human genome but further validations are required to confirm their pathogenicity. We did not detect any homozygous FH or autosomal recessive mutations in our study cohort. This pioneering study provides a reliable estimate of FH prevalence in Qatar based on a significantly large population-based cohort, whilst uncovering the spectrum of genetic variants associated with FH.","variants":[{"Name":"NM_000527.5(LDLR):c.313+3A>C","Chromosome":"19","Start":"11102789","Stop":"11102789","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":410432,"rule_based_match":true,"evidence_text":"c.313+3A >C","llm_judgment":"PRESENT","evidence":"c.313+3A >C","abstract_start":1097,"abstract_end":1108}]}
{"pmid":"26449400","title":"Molecular, biochemical, and structural analysis of a novel mutation in patients with methylmalonyl-CoA mutase deficiency.","abstract":"BACKGROUND: Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting from genetic defects in methylmalonyl-CoA mutase (MCM). This enzyme is encoded by the MUT gene and is required for the degradation of odd-chain fatty acids, the amino acids valine, isoleucine, methionine, and threonine, and cholesterol.\nMETHOD: Three unrelated affected patients with isolated MMA and their parents were studied. The MUT gene was analyzed by PCR and sequencing of its entire coding region and the highly conserved exon-intron splice junctions. The homology modeling of the novel mutation found in the MUT gene was performed using the online Swiss-Prot server for automated modeling and then analyzed with special bioinformatics software to better study the structural effects caused by the mutation.\nRESULT: We found one homozygous nucleotide change in intron 12 of the MUT gene (c.2125-3 C>G). The variant is located near the highly conserved acceptor splice site of intron 12. A region at the C-terminus of the protein from ASP709 to GLN748 has been deleted by the alteration of c.2125-3 C>G in intron 12 of the MUT gene. Further studies of the novel mutation in the MUT gene by means of homology modeling revealed abnormalities in the protein's structure, which causes the protein to act malfunctioning and also the mRNA expression analysis of MUT gene confirmed these results.\nCONCLUSION: We report this novel mutation, including its clinical and biochemical features and genetic defects, in the MUT gene of three patients affected with isolated MMA. Structural analyses of the mutated protein identified changes in the energy and stereochemical features of the protein that unfortunately altered the protein's functionalities. Therefore, we demonstrate that a novel splice site mutation in intron 12 of the MUT gene is a potential highly pathogenic allele via inhibition of alternative splicing.","variants":[{"Name":"NM_000255.4(MMUT):c.2125-3C>G","Chromosome":"6","Start":"49431859","Stop":"49431859","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":651561,"rule_based_match":true,"evidence_text":"c.2125-3 C>G","llm_judgment":"PRESENT","evidence":"c.2125-3 C>G","abstract_start":880,"abstract_end":892}]}
{"pmid":"19852576","title":"Characterization of CTNS mutations in Arab patients with cystinosis.","abstract":"BACKGROUND: Cystinosis is an autosomal recessive disease characterized by impaired transport of free cystine out of lysosomes with resulting renal and ophthalmic manifestations. Mutations in CTNS, encoding cystinosin, are the only known cause of this autosomal recessive disorder with more than 85 different mutations described so far.\nPURPOSE: To identify CTNS mutations in Arab cystinosis patients.\nMETHODS: In this study, we have analyzed the mutational spectrum of CTNS in a population of 21 patients from 13 families of Arab origin. The entire coding region and flanking intronic regions of CTNS were analyzed by direct sequencing.\nRESULTS: Eight mutations were identified, four of which are novel (c.530A>G, c.681G>A, 1013T>G, and c.1018_1041del).\nCONCLUSION: These alleles will provide the basis for routine molecular diagnosis of cystinosis in the region.","variants":[{"Name":"NM_004937.3(CTNS):c.681G>A (p.Glu227=)","Chromosome":"17","Start":"3656795","Stop":"3656795","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":548117,"rule_based_match":true,"evidence_text":"c.681G>A","llm_judgment":"PRESENT","evidence":"c.681G>A","abstract_start":714,"abstract_end":722}]}
{"pmid":"28577564","title":"High frequency of the recurrent c.1310_1313delAAGA BRCA2 mutation in the North-East of Morocco and implication for hereditary breast-ovarian cancer prevention and control.","abstract":"BACKGROUND: To date, a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer in the Moroccan population. Less than 20 different mutations of these two genes have been identified in Moroccan patients, and recently we reported a further BRCA2 mutation (c.1310_1313delAAGA; p.Lys437IlefsX22) in three unrelated patients, all from the North-East of the country. We aimed in this study to evaluate the frequency and geographic distribution of this BRCA2 frameshift mutation, in order to access its use as the first-line BRCA genetic testing strategy for Moroccan patients. We enrolled in this study 122 patients from different regions of Morocco, with suggestive inherited predisposition to breast and ovarian cancers. All subjects gave written informed consent to BRCA1/2 genetic testing. According to available resources of our lab and enrolled families, 51 patients were analyzed by the conventional individual exon-by-exon Sanger sequencing, 23 patients were able to benefit from a BRCA next generation sequencing and a target screening for exon 10 of BRCA2 gene was performed in 48 patients.\nRESULTS: Overall, and among the 122 patients analyzed for at least the exon 10 of the BRCA2 gene, the c.1310_1313delAAGA frameshift mutation was found in 14 patients. Genealogic investigation revealed that all carriers of this mutation shared the same geographic origin and were descendants of the North-East of Morocco.\nDISCUSSION: In this study, we highlighted that c.1310_1313delAAGA mutation of BRCA2 gene is recurrent with high frequency in patients from the North-East region of Morocco. Therefore, we propose to use, in public health strategies, the detection of this mutation as the first-line screening tests in patients with breast and ovarian cancer originated from this region.","variants":[{"Name":"NM_000059.4(BRCA2):c.1310_1313del (p.Lys437fs)","Chromosome":"13","Start":"32332779","Stop":"32332782","ReferenceAlleleVCF":"AAAAG","AlternateAlleleVCF":"A","allel_id":46293,"rule_based_match":true,"evidence_text":"c.1310_1313delAAGA","llm_judgment":"PRESENT","evidence":"c.1310_1313delAAGA","abstract_start":304,"abstract_end":322}]}
{"pmid":"36139699","title":"Splicing Analysis of 16","abstract":"PALB2 loss-of-function variants are associated with significant increased risk of breast cancer as well as other types of tumors. Likewise, splicing disruptions are a common mechanism of disease susceptibility. Indeed, we previously showed, by minigene assays, that 35 out of 42 PALB2 variants impaired splicing. Taking advantage of one of these constructs (mgPALB2_ex1-3), we proceeded to analyze other variants at exons 1 to 3 reported at the ClinVar database. Thirty-one variants were bioinformatically analyzed with MaxEntScan and SpliceAI. Then, 16 variants were selected for subsequent RNA assays. We identified a total of 12 spliceogenic variants, 11 of which did not produce any trace of the expected minigene full-length transcript. Interestingly, variant c.49-1G > A mimicked previous outcomes in patient RNA (transcript ∆(E2p6)), supporting the reproducibility of the minigene approach. A total of eight variant-induced transcripts were characterized, three of which (∆(E1q17), ∆(E3p11), and ∆(E3)) were predicted to introduce a premature termination codon and to undergo nonsense-mediated decay, and five (▼(E1q9), ∆(E2p6), ∆(E2), ▼(E3q48)-a, and ▼(E3q48)-b) maintained the reading frame. According to an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme, which integrates mgPALB2 data, six PALB2 variants were classified as pathogenic/likely pathogenic, five as VUS, and five as likely benign. Furthermore, five ±1,2 variants were catalogued as VUS because they produced significant proportions of in-frame transcripts of unknown impact on protein function.","variants":[{"Name":"NM_024675.4(PALB2):c.49-1G>A","Chromosome":"16","Start":"23638130","Stop":"23638130","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":575602,"rule_based_match":true,"evidence_text":"c.49-1G > A","llm_judgment":"PRESENT","evidence":"c.49-1G > A","abstract_start":765,"abstract_end":776}]}
{"pmid":"27840894","title":"Seven novel and six de novo PHEX gene mutations in patients with hypophosphatemic rickets.","abstract":"Inactivating mutations in phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) have been identified as a cause of X-linked hypophosphatemic rickets (XLH; OMIM 307800). In the present study, we enrolled 43 patients from 18 unrelated families clinically diagnosed with hypophosphatemic rickets and 250 healthy controls. For each available individual, all 22 exons with their exon-intron boundaries of the PHEX gene were directly sequenced. The levels of serum fibroblast growth factor 23 (FGF23) were measured as well. Sequencing analysis detected 17 different PHEX gene mutations, and 7 of these were identified as novel: 3 missense mutations, including c.304G>A (p.Gly102Arg) in exon 3, c.229T>C (p.Cys77Arg) in exon 3 and c.824T>C (p.Leu275Pro) in exon 7; 2 deletion mutations, including c.528delT (p.Glu177LysfsX44) in exon 5 and c.1234delA (p.Ser412ValfsX12) in exon 11; and 2 alternative splicing mutations, including c.436_436+1delAG in intron 4 at splicing donor sites and c.1483-1G>C in intron 13 at splicing acceptor sites. Moreover, 6 mutations were proven to be de novo in 6 sporadic cases and the probands were all females. No mutations were found in the 250 healthy controls. The serum levels of FGF23 varied widely among the patients with XLH, and no significant difference was found when compared with those of the healthy controls. On the whole, the findings of this study provide new insight into the spectrum of PHEX mutations and provide potential evidence of a critical domain in PHEX protein. In addition, the finding of an overlap of the serum FGF23 levels between the patients with XLH and the healthy controls indicates its limited diagnostic value in XLH.","variants":[{"Name":"NM_000444.6(PHEX):c.304G>A (p.Gly102Arg)","Chromosome":"X","Start":"22047166","Stop":"22047166","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":849888,"rule_based_match":true,"evidence_text":"c.304G>A (p.Gly102Arg)","llm_judgment":"PRESENT","evidence":"c.304G>A (p.Gly102Arg)","abstract_start":686,"abstract_end":708},{"Name":"NM_000444.6(PHEX):c.1483-1G>C","Chromosome":"X","Start":"22178272","Stop":"22178272","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":960981,"rule_based_match":true,"evidence_text":"c.1483-1G>C","llm_judgment":"PRESENT","evidence":"c.1483-1G>C","abstract_start":1012,"abstract_end":1023},{"Name":"NM_000444.6(PHEX):c.824T>C (p.Leu275Pro)","Chromosome":"X","Start":"22094074","Stop":"22094074","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1056764,"rule_based_match":true,"evidence_text":"c.824T>C (p.Leu275Pro)","llm_judgment":"PRESENT","evidence":"c.824T>C (p.Leu275Pro)","abstract_start":756,"abstract_end":778}]}
{"pmid":"24655110","title":"BCS1L gene mutation causing GRACILE syndrome: case report.","abstract":"GRACILE syndrome is a rare autosomal recessive disease characterized by fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload, profound lactic acidosis, and early death. It is caused by homozygosity for a missense mutation in the BCS1L gene. The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III. Here we report that a homozygous mutation c.296C > T (p.P99L), in the first exon of BCS1L gene found in an affected 2-month-old boy of asymptomatic consanguineous parents results in GRACILE syndrome. This genotype is associated with a severe clinical presentation. So far no available treatments have changed the fatal course of the disease, and the metabolic disturbance responsible is still not clearly identified. Therefore, providing prenatal diagnosis in families with previous affected infants is of major importance. Mitochondrial disorders are an extremely heterogeneous group of diseases sharing, in common, the fact that they all ultimately impair the function of the mitochondrial respiratory chain. A clinical picture with fetal growth restriction, postnatal lactacidosis, aminoaciduria, hypoglycemia, coagulopathy, elevated liver enzymes, and cholestasis should direct investigations on mitochondrial disorder.","variants":[{"Name":"NM_001079866.2(BCS1L):c.296C>T (p.Pro99Leu)","Chromosome":"2","Start":"218661283","Stop":"218661283","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21203,"rule_based_match":true,"evidence_text":"c.296C > T (p.P99L)","llm_judgment":"PRESENT","evidence":"c.296C > T (p.P99L)","abstract_start":405,"abstract_end":424}]}
{"pmid":"24583439","title":"Antithrombin-p.Ala416Pro: the second reported case in Japan.","abstract":"A 42-year-old man was referred to our department due to recurrent deep venous thrombosis. He, his father and his aunt had low antithrombin (AT) heparin cofactor activity and progressive AT activity levels with normal AT antigen levels. A single nucleotide substitution of G to C was found at nucleotide position c.1246 in exon 7 of the patient's AT gene, resulting in a p.Ala416Pro mutation of AT. The same mutation was identified in his father and aunt, but not his sister, who had a normal AT level. These results show that the AT-p.Ala416Pro mutation was responsible for type IIa AT deficiency in this family.","variants":[{"Name":"NM_000488.4(SERPINC1):c.1246G>C (p.Ala416Pro)","Chromosome":"1","Start":"173904038","Stop":"173904038","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":33046,"rule_based_match":false,"evidence_text":"c.1246G>C (p.Ala416Pro)","llm_judgment":"PRESENT","evidence":"p.Ala416Pro","abstract_start":370,"abstract_end":381}]}
{"pmid":"30388038","title":"Characterization of MDPL Fibroblasts Carrying the Recurrent p.Ser605del Mutation in POLD1 Gene.","abstract":"Mandibular hypoplasia, deafness, and progeroid features, with concomitant lipodystrophy, define a multisystem disorder named MDPL syndrome. MDPL has been associated with heterozygous mutations in POLD1 gene resulting in loss of DNA polymerase δ activity. In this study, we report clinical, genetic, and cellular studies of a 13-year-old Pakistani girl, presenting growth retardation, sensorineural deafness, altered distribution of subcutaneous adipose tissue, and insulin resistance. We performed Sanger sequencing of POLD1 gene in the proband and the healthy parents. Fibroblasts obtained from dermal biopsy were evaluated for the specific hallmarks of cellular senescence and for their response to the DNA-induced damage. Patient carried the recurrent heterozygous de novo in frame deletion (c.1812_1814delCTC, p.Ser605del ) within POLD1 gene, previously detected in 16 MDPL patients. In patient's fibroblasts we observed severe nuclear envelope anomalies, presence of micronuclei, accumulation of prelamin A, altered cell growth, and cellular senescence. In addition, we observed a persistence of DNA damage after cisplatin exposure, compared to control cells. In conclusion, the MDPL nuclear and cellular findings resemble features observed in other progeroid syndromes and familial lipodystrophies. Although further investigations will be necessary, these information could be used to establish targeted therapeutic approaches.","variants":[{"Name":"NM_002691.4(POLD1):c.1809CTC[1] (p.Ser605del)","Chromosome":"19","Start":"50408818","Stop":"50408820","ReferenceAlleleVCF":"TCTC","AlternateAlleleVCF":"T","allel_id":75314,"rule_based_match":false,"evidence_text":"c.1812_1814delCTC, p.Ser605del","llm_judgment":"PRESENT","evidence":"c.1812_1814delCTC, p.Ser605del","abstract_start":795,"abstract_end":825}]}
{"pmid":"35729508","title":"The GALNS p.P77R variant is a probable Gujarati-Indian founder mutation causing Mucopolysaccharidosis IVA syndrome.","abstract":"BACKGROUND: Mucopolysaccharidosis IVA (Morquio syndrome A, MPS IVA) is an autosomal recessive lysosomal storage disorder caused due to biallelic variants in the N-acetylgalactoseamine-6-sulfate sulfatase (GALNS) gene. The mutation spectrum in this condition is determined amongst sub-populations belonging to the north, south and east India geography, however, sub-populations of west Indian origin, especially Gujarati-Indians, are yet to be studied. We aimed to analyse the variants present in the GLANS gene amongst the population of Gujarat by sequencing all exons and exon-intron boundaries of the GALNS gene in patients from 23 unrelated families.\nRESULTS: We report 11 variants that include eight missense variants: (p.L36R, p.D39G, p.P77R, p.C79R, pP125L, p.P151L, p.G255A and p.L350P), one splice site variant: (c.121-7C > G), one small insertion: (c.1241_1242insA, p.I416HfsTer2) and one small deletion: (c.839_841delACA). Of these, three missense variants (p.D39G, p.G255A and p.L350P), one splice site and the two indels mentioned above are novel. Interestingly, we observed a higher than anticipated prevalence of p.P77R variant in our cohort (n = 14/25, 56%). Haplotype analysis in cases with p.P77R variant and 63 ethnicity matched healthy population controls suggested a 4 SNP haplotype block present in cases compared to controls (likelihood ratio test p-value = 1.16 × 10<sup>-13</sup>), thereby suggesting p.P77R variant as a founder variant in the Gujarati-Indian population. Furthermore, age of mutation analysis suggested the variant to have arisen approximately 450 years ago in the population.\nCONCLUSION: p.P77R variant in the GLANS gene is likely to be a founder variant in MPS IVA patients of Gujarati-Indian ancestry and appeared approximately 450 years ago in the population. To our knowledge, this is the first variant to be posited as a founder variant in the GLANS gene in patients with MPS IVA syndrome.","variants":[{"Name":"NM_000512.5(GALNS):c.121-7C>G","Chromosome":"16","Start":"88842836","Stop":"88842836","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":904966,"rule_based_match":true,"evidence_text":"c.121-7C > G","llm_judgment":"PRESENT","evidence":"c.121-7C > G","abstract_start":821,"abstract_end":833},{"Name":"NM_000512.5(GALNS):c.230C>G (p.Pro77Arg)","Chromosome":"16","Start":"88842720","Stop":"88842720","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":844479,"rule_based_match":false,"evidence_text":"p.P77R","llm_judgment":"PRESENT","evidence":"p.P77R","abstract_start":740,"abstract_end":746}]}
{"pmid":"37804054","title":"LRRC23 deficiency causes male infertility with idiopathic asthenozoospermia by disrupting the assembly of radial spokes.","abstract":"Asthenozoospermia (AZS) is the primary cause of infertility in males. The radial spoke (RS) is an axonemal structure, connecting the peripheral doublet microtubules with the central pair of microtubules. This T-shaped multiprotein complex functions as a mechanochemical sensor to promote sperm motility. LRRC23 is a novel subunit of the RS complex that is necessary for flagellar assembly and movement in mice. However, the importance of LRRC23 in modulating RS formation in humans remains unclear. Here, we identified a homozygous nonsense mutation in LRRC23 (c.376C>T:p. Arg126X) in an infertile AZS patient whose parents were consanguineous. We verified the adversity of this novel mutation because of its ability to disrupt LRRC23 synthesis and impair RSs integrity. Furthermore, we demonstrated an interaction between LRRC23 and RSPH3 in vitro, indicating that LCCR23 is associated with RS in humans. Meanwhile, the LRRC23-mutant patient had a good prognosis following intracytoplasmic sperm injection. This study provides strong preliminary evidence that LRRC23 defects are potential causative factors of AZS in humans, which expands our knowledge for improved genetic counseling and better reproductive recommendations for patients with AZS.","variants":[{"Name":"NM_001135217.2(LRRC23):c.376C>T (p.Arg126Ter)","Chromosome":"12","Start":"6906548","Stop":"6906548","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3396496,"rule_based_match":true,"evidence_text":"c.376C>T:p. Arg126X","llm_judgment":"PRESENT","evidence":"c.376C>T:p. Arg126X","abstract_start":561,"abstract_end":580}]}
{"pmid":"21071250","title":"Novel mutations in the human MCCA and MCCB gene causing methylcrotonylglycinuria.","abstract":"Methylcrotonylglycinuria (MCG) is an inborn error of leucine catabolism and has a recessive pattern of inheritance that results from the deficiency of 3-methylcrotonyl-CoA carboxylase (MCC). The clinical phenotypes are highly variable ranging from neonatal onset with severe neurological involvement to asymptomatic adults. Here we identified two novel MCCA (exon 3: c.137G>A; p.46G>E), (IVS7-1G>A splice site mutation), and four novel MCCB (exon 11: c.1065A>T; p.355L>F), (exon 15: c.1430A>G; p.477Q>R), (exon 16: c.1549G>A; p.517G>R), (exon 16: c.1559A>C; p.520Y>S) mutant alleles from five MCC-deficient patients.","variants":[{"Name":"NM_022132.5(MCCC2):c.1549G>A (p.Gly517Arg)","Chromosome":"5","Start":"71652729","Stop":"71652729","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1055521,"rule_based_match":true,"evidence_text":"c.1549G>A (p.517G>R)","llm_judgment":"PRESENT","evidence":"c.1549G>A","abstract_start":515,"abstract_end":524},{"Name":"NM_022132.5(MCCC2):c.1065A>T (p.Leu355Phe)","Chromosome":"5","Start":"71641068","Stop":"71641068","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":200100,"rule_based_match":true,"evidence_text":"c.1065A>T","llm_judgment":"PRESENT","evidence":"c.1065A>T","abstract_start":451,"abstract_end":460},{"Name":"NM_022132.5(MCCC2):c.1430A>G (p.Gln477Arg)","Chromosome":"5","Start":"71650125","Stop":"71650125","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1446724,"rule_based_match":true,"evidence_text":"c.1430A>G (p.477Q>R)","llm_judgment":"PRESENT","evidence":"c.1430A>G","abstract_start":483,"abstract_end":492},{"Name":"NM_020166.5(MCCC1):c.137G>A (p.Gly46Glu)","Chromosome":"3","Start":"183092545","Stop":"183092545","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":200050,"rule_based_match":true,"evidence_text":"c.137G>A","llm_judgment":"PRESENT","evidence":"c.137G>A","abstract_start":367,"abstract_end":375},{"Name":"NM_022132.5(MCCC2):c.1559A>C (p.Tyr520Ser)","Chromosome":"5","Start":"71652739","Stop":"71652739","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":455958,"rule_based_match":true,"evidence_text":"c.1559A>C (p.520Y>S)","llm_judgment":"PRESENT","evidence":"c.1559A>C","abstract_start":547,"abstract_end":556}]}
{"pmid":"33642439","title":"A Resuscitated Case of Acute Myocardial Infarction with both Familial Hypercholesterolemia Phenotype Caused by Possibly Oligogenic Variants of the PCSK9 and ABCG5 Genes and Type I CD36 Deficiency.","abstract":"A 56-year-old postmenopausal woman with out-of-hospital cardiac arrest caused by acute myocardial infraction was successfully resuscitated by intensive treatments and recovered without any neurological disability. She was diagnosed as having familial hypercholesterolemia (FH) based on a markedly elevated low-density lipoprotein cholesterol (LDL-C) level and family history of premature coronary artery disease. Genetic testing in her family members showed that a variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (c.2004C＞A, p.S668R), which had been previously reported as having uncertain significance, was associated with FH, indicating that the variant is a potential candidate for the FH phenotype. Next-generation sequencing analysis for the proband also showed that there was a heterozygous mutation of the ATP-binding cassette sub-family G member 5 ( ABCG5) gene (c.1166G＞A, R389H), which has been reported to increase LDL-C level and the risk of cardiovascular disease. She was also diagnosed as having type 1 CD36 deficiency based on a lack of myocardial uptake of <sup>123</sup>I-labeled 15-(p-iodophenyl)-3-R,S-methyl-pentadecanoic acid in scintigraphy and the absence of CD36 antigen in both monocytes and platelets in flow cytometry. She had a homozygous mutation of the CD36 gene (c.1126-5_1127delTTTAGAT), which occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. To our knowledge, this is the first report of a heterozygous FH phenotype caused by possibly oligogenic variants of the PCSK9 and ABCG5 genes complicated with type I CD36 deficiency caused by a novel homozygous mutation. Both FH phenotype and CD36 deficiency might have caused extensive atherosclerosis, leading to acute myocardial infarction in the present case.","variants":[{"Name":"NM_022436.3(ABCG5):c.1166G>A (p.Arg389His)","Chromosome":"2","Start":"43824071","Stop":"43824071","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20019,"rule_based_match":false,"evidence_text":"c.1166G＞A, R389H","llm_judgment":"PRESENT","evidence":"c.1166G＞A, R389H","abstract_start":897,"abstract_end":913},{"Name":"NM_174936.4(PCSK9):c.2004C>A (p.Ser668Arg)","Chromosome":"1","Start":"55063509","Stop":"55063509","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":389421,"rule_based_match":false,"evidence_text":"c.2004C＞A, p.S668R","llm_judgment":"PRESENT","evidence":"c.2004C＞A, p.S668R","abstract_start":540,"abstract_end":558}]}
{"pmid":"18604903","title":"A newborn infant with hyperventilation","abstract":"Respiratory alkalosis is an early sign of urea cycle disorder. A high level of plasma ammonia will strengthen this suspicion. It is of great importance to transfer the infant as soon as possible to a unit capable of giving specific treatment with Na-benzoate, Na-phenylbutyrate, argininchloride and carglumic acid. The early treatment may also include haemodialysis, which is preferred over peritoneal dialysis or exchange transfusion. We here describe an infant with respiratory alkalosis within the first two days of life and a high plasma level of ammonia (> 700 micromol/L). He did not respond to conventional therapy and died 48 hours after birth in spite of specific treatment. DNA-analysis showed a gene defect in the OTC gene, c.67C >T (p.R23X), a known mutation leading to urea cycle disorder (OTC). It is important to detect carriers among older siblings and to inform the parents of the possibility of prenatal diagnostics.","variants":[{"Name":"NM_000531.6(OTC):c.67C>T (p.Arg23Ter)","Chromosome":"X","Start":"38352763","Stop":"38352763","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":103184,"rule_based_match":true,"evidence_text":"c.67C >T (p.R23X)","llm_judgment":"PRESENT","evidence":"c.67C >T (p.R23X)","abstract_start":735,"abstract_end":752}]}
{"pmid":"26085992","title":"Novel CYP4V2 mutations associated with Bietti crystalline corneoretinal dystrophy in Chinese patients.","abstract":"AIM: To analyze the CYP4V2 mutations in five unrelated Chinese patients with Bietti crystalline corneoretinal dystrophy (BCD) and to provide clinical features of these patients. BCD is a rare monogenic autosomal recessively inherited disorder characterized by the presence of crystals in the retina and retinal pigment epithelium atrophy. Mutations in the CYP4V2 gene have been found to be causative for BCD.\nMETHODS: Ophthalmic examinations were carried out in the affected individuals. Peripheral blood samples were collected and genomic DNA was extracted. All exons and flanking intronic regions of the CYP4V2 gene were amplified with polymerase chain reaction and screened for mutations by direct DNA sequencing. One hundred control chromosomes were also screened to exclude nonpathogenic polymorphisms.\nRESULTS: Fundus examination revealed the presence of tiny yellowish-sparkling crystals at the posterior pole of the fundus and atrophy of the retinal pigment epithelium in all patients. Choroid neovascularization was noted in one patient. Five different CYP4V2 mutations were identified, including two missense mutations (p.F73L, p.R400H), two splice site mutations (c.802-8_810del17insGC, c.1091-2A>G), and one single base-pair deletion (p.T479TfsX7 or c.1437delC). The two splice site mutations were identified in three of the patients with BCD. Mutation p.T479TfsX7 was a novel mutation not observed in any of 100 ethnically matched control chromosomes.\nCONCLUSION: Mutation c.802-8_810del17insGC and c.1091-2A>G are common mutations in Chinese patients with BCD. Our results expand the allelic heterogeneity of BCD.","variants":[{"Name":"NM_207352.4(CYP4V2):c.802-8_810delinsGC","Chromosome":"4","Start":"186201149","Stop":"186201165","ReferenceAlleleVCF":"TCATACAGGTCATCGCT","AlternateAlleleVCF":"GC","allel_id":47877,"rule_based_match":false,"evidence_text":"c.802-8_810del17insGC","llm_judgment":"PRESENT","evidence":"c.802-8_810del17insGC","abstract_start":1175,"abstract_end":1196}]}
{"pmid":"29245273","title":"A delayed diagnosis of X-linked hyper IgM syndrome complicated with toxoplasmic encephalitis in a child: A case report and literature review.","abstract":"INTRODUCTION: The X-linked hyper-immunoglobulin M syndrome (XHIGM) is an uncommon primary combined immunodeficiency disease caused by CD40L gene mutations. A delayed or missed diagnosis of XHIGM is common and concerning, owing to atypical immunoglobulin profile and phenotype of some patients, low recognition, and limited knowledge of clinicians on XHIGM in some underdeveloped areas. Opportunistic infections are a prominent clinical feature of XHIGM. However, toxoplasma encephalitis occurs sporadically and is extremely rare in patients with XHIGM.\nDIAGNOSTIC AND THERAPEUTIC PROCEDURE: A 2 years and 10 months' old male suffered from 3 times of serious infection since 1 year and 4 months of age. Although with history of recurrent respiratory infections, protracted diarrhea, persistent or intermittent neutropenia companioned with oral ulcer, and a typical immunoglobulin profile during his second disease attack, the consideration of XHIGM was still completely ignored because of our low recognition and limited knowledge of this disorder. The diagnosis of XHIGM was ultimately confirmed by detection of elevated serum IgM concentration, decreased serum IgG and IgE concentration, and identification of a mutation c.654C>A (p.C218X) in CD40L gene. Given clinical manifestation of lethargy, uncontrollable somnolence and ataxia, a cat/dog exposure history, positive serum Toxoplasma gondii (T gondii) IgM, positive cerebrospinal fluid T gondii PCR results, and typical characteristics of brain magnetic resonance imaging as multiple rings liked nodules lesions in bilateral cerebral hemisphere cortex, bilateral basal ganglia, and dorsal thalamus, the diagnosis of toxoplasmic encephalitis was considered during his third disease attack. Thereafter, oral administration of sulfadiazine and azithromycin, intravenous immunoglobulin, and subcutaneous injection of G-CSF were initiated. Regrettably, the patient abandoned the treatment because of economic factor and died 3 months after discharge.\nCONCLUSIONS: A more thorough clinical history and some features like recurrent respiratory infections, protracted diarrhea, and persistent or intermittent neutropenia companioned with oral ulcer could increase clinical suspicion of XHIGM. Cerebral toxoplasmosis is rare in patients with XHIGM, but still should be considered. The present study firstly reported a delayed diagnosed case of XHIGM with CD40L gene c.654C>A (p.C218X) mutant complicated with toxoplasma encephalitis in Chinese population, which highlighted the importance of CD40-CD40L interaction in cell-mediated immunity against T gondii.","variants":[{"Name":"NM_000074.3(CD40LG):c.654C>A (p.Cys218Ter)","Chromosome":"X","Start":"136659283","Stop":"136659283","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2405123,"rule_based_match":true,"evidence_text":"c.654C>A (p.C218X)","llm_judgment":"PRESENT","evidence":"c.654C>A (p.C218X)","abstract_start":1222,"abstract_end":1240}]}
{"pmid":"32745242","title":"Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore.","abstract":"Identification of ancestry-specific pathogenic variants is imperative for diagnostic, treatment, management and prevention strategies, and to understand penetrance/modifiers on risk. Our study aimed to determine the clinical significance of a recurrent BRCA1 c.442-22_442-13del variant of unknown significance identified among 13 carriers from six Chinese families, all with a significant history of breast and/or ovarian cancer. We further aimed to establish whether this was due to a founder effect and explore its origins. Haplotype analysis, using nine microsatellite markers encompassing 2.5 megabase pairs around the BRCA1 locus, identified a common haploblock specific to the variant carriers, confirming a founder effect. Variant age was estimated to date back 77.9 generations to 69 bc using the Gamma approach. On principal component analysis using single nucleotide polymorphisms merged with 1000 Genomes dataset, variant carriers were observed to overlap predominantly with the southern Han Chinese population. To determine pathogenicity of the variant, we assessed the functional effect on RAD51 foci formation as well as replication fork stability upon induction of DNA damage and observed an impaired DNA repair response associated with the variant. In summary, we identified an ancient Chinese founder mutation dating back 77.9 generations, possibly common among individuals of southern Han Chinese descent. Using evidence from phenotypic/family history studies, segregation analysis and functional characterization, the BRCA1 variant was reclassified from uncertain significance to pathogenic.","variants":[{"Name":"NM_007294.4(BRCA1):c.442-22_442-13del","Chromosome":"17","Start":"43099893","Stop":"43099902","ReferenceAlleleVCF":"GGTAAAGAACA","AlternateAlleleVCF":"G","allel_id":245054,"rule_based_match":true,"evidence_text":"BRCA1 c.442-22_442-13del","llm_judgment":"PRESENT","evidence":"BRCA1 c.442-22_442-13del","abstract_start":253,"abstract_end":277}]}
{"pmid":"28055140","title":"EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.","abstract":"Impairment of translation initiation and its regulation within the integrated stress response (ISR) and related unfolded-protein response has been identified as a cause of several multisystemic syndromes. Here, we link MEHMO syndrome, whose genetic etiology was unknown, to this group of disorders. MEHMO is a rare X-linked syndrome characterized by profound intellectual disability, epilepsy, hypogonadism and hypogenitalism, microcephaly, and obesity. We have identified a C-terminal frameshift mutation (Ile465Serfs) in the EIF2S3 gene in three families with MEHMO syndrome and a novel maternally inherited missense EIF2S3 variant (c.324T>A; p.Ser108Arg) in another male patient with less severe clinical symptoms. The EIF2S3 gene encodes the γ subunit of eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the ISR. Studies in patient fibroblasts confirm increased ISR activation due to the Ile465Serfs mutation and functional assays in yeast demonstrate that the Ile465Serfs mutation impairs eIF2γ function to a greater extent than tested missense mutations, consistent with the more severe clinical phenotype of the Ile465Serfs male mutation carriers. Thus, we propose that more severe EIF2S3 mutations cause the full MEHMO phenotype, while less deleterious mutations cause a milder form of the syndrome with only a subset of the symptoms.","variants":[{"Name":"NM_001415.4(EIF2S3):c.324T>A (p.Ser108Arg)","Chromosome":"X","Start":"24057695","Stop":"24057695","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":260480,"rule_based_match":true,"evidence_text":"c.324T>A (p.Ser108Arg)","llm_judgment":"PRESENT","evidence":"p.Ser108Arg","abstract_start":645,"abstract_end":656}]}
{"pmid":"23838601","title":"Large copy number variations in combination with point mutations in the TYMP and SCO2 genes found in two patients with mitochondrial disorders.","abstract":"Mitochondrial disorders are caused by defects in mitochondrial or nuclear DNA. Although the existence of large deletions in mitochondrial DNA (mtDNA) is well known, deletions affecting whole genes are not commonly described in patients with mitochondrial disorders. Based on the results of whole-genome analyses, copy number variations (CNVs) occur frequently in the human genome and may overlap with many genes associated with clinical phenotypes. We report the discovery of two large heterozygous CNVs on 22q13.33 in two patients with mitochondrial disorders. The first patient harboured a novel point mutation c.667G>A (p.D223N) in the SCO2 gene in combination with a paternally inherited 87-kb deletion. As hypertrophic cardiomyopathy (HCMP) was not documented in the patient, this observation prompted us to compare his clinical features with all 44 reported SCO2 patients in the literature. Surprisingly, the review shows that HCMP was present in only about 50% of the SCO2 patients with non-neonatal onset. In the second patient, who had mitochondrial neurogastrointestinal encephalopathy (MNGIE), a maternally inherited 175-kb deletion and the paternally inherited point mutation c.261G>T (p.E87D) in the TYMP gene were identified.","variants":[{"Name":"NM_005138.3(SCO2):c.667G>A (p.Asp223Asn)","Chromosome":"22","Start":"50523745","Stop":"50523745","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3762566,"rule_based_match":true,"evidence_text":"c.667G>A (p.D223N)","llm_judgment":"PRESENT","evidence":"c.667G>A (p.D223N)","abstract_start":613,"abstract_end":631}]}
{"pmid":"36980996","title":"","abstract":"Multiple synostoses syndrome (OMIM: #186500, #610017, #612961, #617898) is a genetically heterogeneous group of autosomal dominant diseases characterized by abnormal bone unions. The joint fusions frequently involve the hands, feet, elbows or vertebrae. Pathogenic variants in <i>FGF9</i> have been associated with multiple synostoses syndrome type 3 (SYNS3). So far, only five different missense variants in <i>FGF9</i> that cause SYNS3 have been reported in 18 affected individuals. Unlike other multiple synostoses syndromes, conductive hearing loss has not been reported in SYNS3. In this report, we describe the clinical and selected radiological findings in a large multigenerational family with a novel missense variant in <i>FGF9</i>: c.430T>C, p.(Trp144Arg). We extend the phenotypic spectrum of SYNS3 by suggesting that cleft palate and conductive hearing loss are part of the syndrome and highlight the high degree of intrafamilial phenotypic variability. These findings should be considered when counseling affected individuals.","variants":[{"Name":"NM_002010.3(FGF9):c.430T>C (p.Trp144Arg)","Chromosome":"13","Start":"21701238","Stop":"21701238","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2401916,"rule_based_match":true,"evidence_text":"c.430T>C, p.(Trp144Arg)","llm_judgment":"PRESENT","evidence":"c.430T>C, p.(Trp144Arg)","abstract_start":743,"abstract_end":766}]}
{"pmid":"35641352","title":"Distal spinal muscular atrophy featured by predominant calf muscle involvement in VRK1 associated disease - Case series and review.","abstract":"We describe the shared clinical, biochemical, radiological and myopathological characteristics of four patients with distal spinal muscular atrophy (dSMA) caused by vaccinia-related kinase 1 (VRK1) variants and provide a review of the literature on phenotype-genotype correlations in VRK1-related disease. The clinical phenotype was characterized by adult-onset dSMA with predominant calf muscle involvement and mildly elevated serum creatinine kinase (CK) levels. Muscle imaging showed predominant atrophy and fatty replacement of calf muscles. We identified the novel compound heterozygous variants c.607C>T (p.Arg203Trp) and c.858G>T (p.Met286Ile) in two siblings with adult-onset dSMA. Additionally, two unrelated patients both carried the known c.583T>G (p.Leu195Val) VRK1 variant, with either c.197C>G (p.Ala66Gly) or c.701A>G (p.Asn234Ser) as a second variant. We conclude that compound heterozygous VRK1 variants cause distal spinal muscular atrophy with predominant posterior leg muscle involvement.","variants":[{"Name":"NM_003384.3(VRK1):c.858G>T (p.Met286Ile)","Chromosome":"14","Start":"96856555","Stop":"96856555","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":136176,"rule_based_match":true,"evidence_text":"c.858G>T (p.Met286Ile)","llm_judgment":"PRESENT","evidence":"c.858G>T (p.Met286Ile)","abstract_start":628,"abstract_end":650},{"Name":"NM_003384.3(VRK1):c.583T>G (p.Leu195Val)","Chromosome":"14","Start":"96855230","Stop":"96855230","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1048807,"rule_based_match":true,"evidence_text":"c.583T>G (p.Leu195Val)","llm_judgment":"PRESENT","evidence":"c.583T>G (p.Leu195Val)","abstract_start":750,"abstract_end":772}]}
{"pmid":"24346070","title":"Prevalence of the 35delG mutation in the GJB2 gene in two samples of non-syndromic deaf subjects from Chile.","abstract":"Hearing loss is the most common inherited sensorial deficiency in humans; about 1 in 1000 children suffer from severe or profound hearing loss at birth. Mutations in the GJB2 gene are the most common cause of prelingual, non-syndromic autosomal recessive deafness in many populations; the c.35delG mutation is the most common in Caucasian populations. The frequency of the c.35delG mutation was estimated in two samples of deaf patients from Santiago, Chile. Unrelated non-syndromic sensorioneural deaf patients were examined: Group 1 consisted of 47 unrelated individuals with neurosensory deafness referred to the Chilean Cochlear Implant Program; Group 2 included 66 school children with prelingual deafness attending special education institutions for deaf people. Individuals with profound to moderate isolated neurosensory hearing loss with unknown etiology were included. The presence of the c.35delG mutation was evaluated by the allele-specific polymerase chain reaction method (PCR), and in some cases it was confirmed by direct DNA sequencing of the coding region of the GJB2 gene. Deaf relatives were present in 20.3% of the cases. We found 19.5% (22/113) patients with the c.35delG mutation, 6 of them homozygous; these rates are similar to frequencies found in other Latin American countries.","variants":[{"Name":"NM_004004.6(GJB2):c.35del (p.Gly12fs)","Chromosome":"13","Start":"20189547","Stop":"20189547","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":32043,"rule_based_match":true,"evidence_text":"c.35delG","llm_judgment":"PRESENT","evidence":"c.35delG","abstract_start":289,"abstract_end":297}]}
{"pmid":"27263053","title":"The molecular characterization of Beta globin gene in thalassemia patients reveals rare and a novel mutations in Pakistani population.","abstract":"INTRODUCTION: A multicentre study (including four cities in Pakistan) aimed to investigate the frequency and spectrum of alpha and beta thalassemia genetic mutations and XmnI polymorphism of the Gamma Globin gene.\nMETHODS: One hundred and sixty one beta thalassemia patients, identified on the ground of haematological parameters, were screened for mutations of the Alpha (HBA2 and HBA1) and Beta (HBB) Globin genes as well as Gamma (HBG2) Globin gene, -158 Gγ XmnI polymorphism, using a combination of multiplex GAP polymerase chain reaction (PCR), Sanger sequencing and restriction fragment length polymerase (RFLP) based PCR.\nRESULTS: Mutations of at least one HBB gene was identified in 157 of 161 patients screened. Among 16 identified mutations in the beta gene, HBB:c.27_28insG (p. Ser10Valfs*14) was the most prevalent. α(-3.7) and α(-4.2) deletions were co-inherited with beta thalassemia mutations. Rare mutations such as HBB:c.-138C > T and HBB:c.315 + 1G > A were also identified. One novel variant (HBB:c.-148T > A), two rare mutations [HBB:c.332T > C (p.Leu111Pro); HBB:c.92G > C (p.Arg31Thr] and a novel association, HBB:c.[92G > C (p.Arg31Thr)] and [-92C > G], were reported for the first time in our study. HBG2:c.-211C > T base-pair substitution (historically described as -158 GγXmnI polymorphism) was present in 36% of the patients.\nCONCLUSION: Heterogeneity in clinical and haematological parameters in TM, show that monogenic disorders can present with a wide spectrum of disease severity. Our studies identified rare and novel mutations that will be useful in the prevention of highly prevalent disease of thalassemia in Pakistan following nationwide awareness campaign.","variants":[{"Name":"NM_000518.5(HBB):c.315+1G>A","Chromosome":"11","Start":"5226576","Stop":"5226576","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30477,"rule_based_match":true,"evidence_text":"HBB:c.315+1G>A","llm_judgment":"PRESENT","evidence":"HBB:c.315 + 1G > A","abstract_start":952,"abstract_end":970},{"Name":"NM_000518.4(HBB):c.332T>C (p.Leu111Pro)","Chromosome":"11","Start":"5225710","Stop":"5225710","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":30391,"rule_based_match":true,"evidence_text":"HBB:c.332T>C (p.Leu111Pro)","llm_judgment":"PRESENT","evidence":"HBB:c.332T > C (p.Leu111Pro)","abstract_start":1050,"abstract_end":1078},{"Name":"NM_000518.4(HBB):c.92G>C (p.Arg31Thr)","Chromosome":"11","Start":"5226930","Stop":"5226930","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":30273,"rule_based_match":true,"evidence_text":"HBB:c.92G > C (p.Arg31Thr)","llm_judgment":"PRESENT","evidence":"HBB:c.[92G > C (p.Arg31Thr)","abstract_start":1132,"abstract_end":1159}]}
{"pmid":"26954065","title":"A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.","abstract":"Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome.","variants":[{"Name":"NM_031263.4(HNRNPK):c.931_932insTT (p.Pro311fs)","Chromosome":"9","Start":"83971903","Stop":"83971904","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GAA","allel_id":222923,"rule_based_match":true,"evidence_text":"c.931_932insTT","llm_judgment":"PRESENT","evidence":"c.931_932insTT","abstract_start":499,"abstract_end":513}]}
{"pmid":"33232902","title":"Generation of a human iPSC line from an epileptic encephalopathy patient with electrical status epilepticus during sleep carrying KCNA2 (p.P405L) mutation.","abstract":"Mutations in KCNA2 gene, encoding for the voltage-gated K+ channel Kv1.2, has been reported to be associated with epilepsy disorders. This channel is mainly expressed in the central nervous system and plays an important role in neuronal excitability and neurotransmitter release. Herein, we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells of an eight-year-old girl with epileptic encephalopathy and electrical status epilepticus during sleep carrying a mutation (c.1214C > T, p.Pro405Leu) in KCNA2. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro.","variants":[{"Name":"NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu)","Chromosome":"1","Start":"110603569","Stop":"110603569","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":188152,"rule_based_match":true,"evidence_text":"c.1214C > T, p.Pro405Leu","llm_judgment":"PRESENT","evidence":"c.1214C > T, p.Pro405Leu","abstract_start":514,"abstract_end":538}]}
{"pmid":"28576516","title":"A novel missense mutation in the SLC26A4 gene causes nonsyndromic hearing loss and enlarged vestibular aqueduct.","abstract":"OBJECTIVES: We aimed to investigate the genetic causes of hearing loss in a Chinese proband with nonsyndromic hearing loss and enlarged vestibular aqueduct syndrome.\nMETHODS: We conducted clinical and genetic evaluations in a deaf proband and his normal-hearing parents. Multiplex PCR technology combined with Ion Torrent™ next-generation sequencing technology was used to detect the pathogenic mutations. As a control, a group of 1500 previously studied healthy newborns from the same ethnic background were subjected to deafness gene screening using the same method as in our previous study.\nRESULTS: The proband harbored two mutations in the SLC26A4 gene in the form of compound heterozygosity. He was found to be heterozygous for a novel mutation named c.1742 G > T (p.Arg581Met) in exon 13 and for the known mutation c.589 G > A (p.Gly197Arg). These variants were carried in the heterozygous state by the parents and therefore co-segregated with the genetic disease. The c.1742 G > T (p.Arg581Met) mutation was absent in 1500 healthy newborns. Protein alignment indicated high evolutionary conservation of the p.R581 residue, and this mutation was predicted by PolyPhen-2 and other online tools to be damaging.\nCONCLUSION: This study demonstrates that the novel mutation c.1742 G > T (p.Arg581Met) in compound heterozygosity with c.589 G > A in the SLC26A4 gene is the main cause of deafness in a family clinically diagnosed with enlarged vestibular aqueduct (EVA). Our study will provide a basic foundation for further investigations to elucidate the SLC26A4-related mechanisms of hearing loss.","variants":[{"Name":"NM_000441.2(SLC26A4):c.589G>A (p.Gly197Arg)","Chromosome":"7","Start":"107674337","Stop":"107674337","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":52731,"rule_based_match":true,"evidence_text":"c.589 G > A (p.Gly197Arg)","llm_judgment":"PRESENT","evidence":"c.589 G > A (p.Gly197Arg)","abstract_start":822,"abstract_end":847}]}
{"pmid":"26677014","title":"Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation.","abstract":"OBJECTIVE: Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination-known as infantile convulsions and paroxysmal choreoathetosis (ICCA)-are related autosomal dominant diseases. PRRT2 (proline-rich transmembrane protein 2 gene) has been identified as the major gene in all 3 conditions, found to be mutated in 80 to 90% of familial and 30 to 35% of sporadic cases.\nMETHODS: We searched for the genetic defect in PRRT2-negative, unrelated families with BFIS or ICCA using whole exome or targeted gene panel sequencing, and performed a detailed cliniconeurophysiological workup.\nRESULTS: In 3 families with a total of 16 affected members, we identified the same, cosegregating heterozygous missense mutation (c.4447G>A; p.E1483K) in SCN8A, encoding a voltage-gated sodium channel. A founder effect was excluded by linkage analysis. All individuals except 1 had normal cognitive and motor milestones, neuroimaging, and interictal neurological status. Fifteen affected members presented with afebrile focal or generalized tonic-clonic seizures during the first to second year of life; 5 of them experienced single unprovoked seizures later on. One patient had seizures only at school age. All patients stayed otherwise seizure-free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or \"shivering\" attacks, triggered by stretching, motor initiation, or emotional stimuli. In 1 case, we recorded typical PKD spells by video-EEG-polygraphy, documenting a cortical involvement.\nINTERPRETATION: Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical-genetic spectrum of combined epileptic and dyskinetic syndromes.","variants":[{"Name":"NM_001330260.2(SCN8A):c.4447G>A (p.Glu1483Lys)","Chromosome":"12","Start":"51790425","Stop":"51790425","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247612,"rule_based_match":true,"evidence_text":"c.4447G>A; p.E1483K","llm_judgment":"PRESENT","evidence":"c.4447G>A; p.E1483K","abstract_start":756,"abstract_end":775}]}
{"pmid":"31152388","title":"Genetic testing and PGD for unexplained recurrent fetal malformations with MAGEL2 gene mutation.","abstract":"Birth defects are caused by multiple factors, such as chromosome abnormality, environmental factors, and maternal factors. In this study, we focused on exploring the genetic causes of a non-consanguineous couple who suffered from four times of unsuccessful pregnancy due to unexplained recurrent fetal malformations with similar symptoms and normal chromosome copy number variations. Using trio-whole exome sequencing (trio-WES) for this couple and one of the affected fetuses, we found a mutation, c.1996delC on the maternal imprinted gene MAGEL2 that was carried by the affected fetus and husband, leading to Schaaf-Yang syndrome. To screen this mutation, we further performed preimplantation genetic diagnosis (PGD) strategy followed by a gene pedigree validation and pathogenicity analysis. After the transfer of a PGD-screened embryo, a normal newborn without previous abnormal symptoms was born (February 15, 2019). We present the first data that identified a pathogenic gene (MAGEL2 c.1996delC) in a fetus with Schaaf-Yang syndrome in the EAS (East Asian) database and overcame this genetic defect by using processed PGD for this couple based on the WES results.","variants":[{"Name":"NM_019066.5(MAGEL2):c.1996del (p.Gln666fs)","Chromosome":"15","Start":"23645747","Stop":"23645747","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":434101,"rule_based_match":true,"evidence_text":"c.1996delC","llm_judgment":"PRESENT","evidence":"c.1996delC","abstract_start":499,"abstract_end":509}]}
{"pmid":"24044590","title":"Imerslund-Gräsbeck syndrome in a 25-month-old Italian girl caused by a homozygous mutation in AMN.","abstract":"Imerslund-Gräsbeck syndrome is a rare autosomal recessive disorder, characterized by vitamin B12 deficiency due to selective malabsorption of the vitamin and usually results in megaloblastic anemia appearing in childhood. It is responsive to parenteral vitamin B12 therapy.The estimated prevalence (calculated based on Scandinavian data) is less than 6:1,000,000. However, many cases may be misdiagnosed.When there is reasonable evidence to suspect that a patient suffers from IGS, a new and straightforward approach to diagnosis is mutational analysis of the appropriate genes. We report for the first time the case of a girl of Italian ancestry with IGS genetically confirmed by the detection of a homozygous missense mutation in the AMN gene (c.208-2 A > G).","variants":[{"Name":"NM_030943.4(AMN):c.208-2A>G","Chromosome":"14","Start":"102928424","Stop":"102928424","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":71390,"rule_based_match":true,"evidence_text":"c.208-2 A > G","llm_judgment":"PRESENT","evidence":"c.208-2 A > G","abstract_start":746,"abstract_end":759}]}
{"pmid":"19824023","title":"Werner syndrome gene variants in human sarcomas.","abstract":"Werner syndrome is an autosomal inherited disease that is characterized by premature aging. The gene mutated in Werner syndrome (WS), WRN, encodes both a 3' --> 5' DNA helicase and a 3' --> 5' DNA exonuclease. Among the WS phenotypes is an exceptionally high incidence of sarcomas. We asked whether spontaneous sarcomas, not known to be associated with WS, also harbor mutations or unreported single nucleotide polymorphisms (SNPs) in WRN. We analyzed RNA or DNA sequences within the helicase and exonuclease domains from 51 and 69 matched sarcoma and adjacent normal tissues, respectively. Among a total of 13 nucleotide variants detected, we identified three novel nonsynonymous substitutions: c.611C>T, c.809_810insT, and c.1882C>G. We further characterized one, c.611C>T, which results in substitution of an evolutionarily conserved proline at amino acid 204 in the exonuclease domain with leucine. We show that P204L WRN exhibits a reduction of WRN exonuclease activity; the specific activity is approximately 10-fold lower than that of wild-type WRN. In contrast, the helicase activity of P204L WRN is reduced less than twofold.","variants":[{"Name":"NM_000553.6(WRN):c.611C>T (p.Pro204Leu)","Chromosome":"8","Start":"31067139","Stop":"31067139","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":562293,"rule_based_match":true,"evidence_text":"c.611C>T","llm_judgment":"PRESENT","evidence":"c.611C>T","abstract_start":696,"abstract_end":704}]}
{"pmid":"32646389","title":"Pathogenic role of the vitreous in angle-closure glaucoma with autosomal recessive bestrophinopathy: a case report.","abstract":"BACKGROUND: Autosomal recessive bestrophinopathy (ARB) is caused by homozygous or compound heterozygous mutations in the BEST1 gene and always accompanied with refractory angle-closure glaucoma (ACG). The exact mechanism for the pan-ocular abnormalities in ARB is still unknown and the management of ACG in these cases is challenging.\nCASE PRESENTATION: A 26-year-old patient with a novel autosomal-recessively inherited c.1 A > G variant in BEST1 diagnosed as ARB and ACG, presented as widespread vitelliform deposits in the posterior pole, retinoschisis in the macula, vitreoretinal interface abnormalities, shallow anterior chamber depth (ACD) and angle closure with uncontrolled intraocular pressure (IOP). Combined phacoemulsification, intraocular lens implantation and goniosynechialysis did not improve any clinical presentation. However, low dose transscleral cyclophotocoagulation with subsequent vitreous liquefaction effectively lowered IOP, deepened ACD, and rehabilitated retinoschisis in both eyes.\nCONCLUSIONS: This case implied vitreous condition may play a pathogenic role in formation of retinoschisis and ACG in the patients with ARB. Treatments that induce vitreous liquefaction could be used to treat young ACG patients with ARB or other kinds of ACG to avoid vision-threatening post-operative complications.","variants":[{"Name":"NM_004183.4(BEST1):c.1A>G (p.Met1Val)","Chromosome":"11","Start":"61951807","Stop":"61951807","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2154029,"rule_based_match":true,"evidence_text":"c.1 A > G","llm_judgment":"PRESENT","evidence":"c.1 A > G","abstract_start":421,"abstract_end":430}]}
{"pmid":"24413997","title":"Identification of recurrent c.742G>T nonsense mutation in ECM1 in Pakistani families suffering from lipoid proteinosis.","abstract":"Lipoid proteinosis (LP) is one of the rare, recessive autosomal disorders clinically characterized by widespread deposition of hyaline-like material in the skin, mucosa and viscera. Classical features include beaded eyelid papules, laryngeal infiltration and hoarseness of voice caused by pathogenic mutations in the ECM1 gene located on 1q21.2. In present study ethnically different, three consanguineous Pakistani families with typical cutaneous features of LP were analysed to investigate the underlying molecular basis. PCR based linkage analysis using microsatellite markers localized the families to locus 1q21.2, harboring ECM1 gene. To identify the mutation in the candidate gene (ECM1), Sanger sequencing was carried out. All the families were found to carry c.742 G>T nonsense mutation in exon 7 of the ECM1 gene that resulted in a truncated ECM1 protein containing 247 amino acids instead of 540 (p.E248X). To further investigate the impact and importance of mutation in LP pathogenesis we applied different bioinformatics tools. In silico studies has predicted lack of functional domains and 65 % shorter ECM1 mutant protein. It is the first report of recurrence mutation from Pakistan as c.742G>T nonsense mutation was found in three ethnically different Pakistani families with LP. Study strengthens the conclusion that c.742G>T mutation is the pathological cause of LP. Furthermore, data also support the fact that exon 7 is one of the most common hot spots of pathological mutations in ECM1. The absence of functional domains and truncated sequence most likely contribute to the lack of ECM1 function and thereby influence several aspects of dermal homeostasis that leads to LP pathogenesis.","variants":[{"Name":"NM_004425.4(ECM1):c.742G>T (p.Glu248Ter)","Chromosome":"1","Start":"150511490","Stop":"150511490","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1174232,"rule_based_match":true,"evidence_text":"c.742 G>T nonsense mutation in exon 7 of the ECM1 gene","llm_judgment":"PRESENT","evidence":"c.742 G>T nonsense mutation in exon 7 of the ECM1 gene","abstract_start":768,"abstract_end":822}]}
{"pmid":"26166723","title":"Glycogen Storage Disease Type IV: A Case With Histopathologic Findings in First-Trimester Placental Tissue.","abstract":"A 30-yr-old woman presented with 2 consecutive miscarriages within 7 mo. Histopathologic examination of the placental tissue showed intracytoplasmic inclusion vacuoles with a strong reaction in Periodic acid-Schiff staining and a slightly pallor reaction in alcian blue staining. Additional molecular genetic analyses confirmed glycogen storage disease Type IV with the finding of compound heterozygosity for 2 mutations (c.691+2T>C and c.1570C>T, p.R524X) in the GBE1 gene. We conclude that glycogen storage disease Type IV can cause early miscarriage and that diagnosis can initially be made on histopathologic examination. Genetic analysis is required to confirm the diagnosis and to offer prenatal genetic testing in future pregnancies.","variants":[{"Name":"NM_000158.4(GBE1):c.1570C>T (p.Arg524Ter)","Chromosome":"3","Start":"81577973","Stop":"81577973","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17820,"rule_based_match":true,"evidence_text":"c.1570C>T (p.R524X)","llm_judgment":"PRESENT","evidence":"c.1570C>T","abstract_start":437,"abstract_end":446},{"Name":"NM_000158.4(GBE1):c.691+2T>C","Chromosome":"3","Start":"81648854","Stop":"81648854","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":205142,"rule_based_match":true,"evidence_text":"c.691+2T>C","llm_judgment":"PRESENT","evidence":"c.691+2T>C","abstract_start":422,"abstract_end":432}]}
{"pmid":"30788324","title":"Investigating of variations in BRCA1 gene in Iranian families with breast cancer.","abstract":"<b>Background:</b> Breast cancer is one of the most common cancers among Iranian women whose relationship with mutation status in BRCA1 is previously approved. Therefore, screening of the most mutated exons in BRCA1 in hereditary breast cancer patients provides beneficial information about the main disease-causing reason. <b>Methods:</b> A total of 14 Iranian hereditary breast cancer patients participated in this case series study. DNA was extracted from patients' blood samples for PCR assay. The quality of PCR products was determined using horizontal electrophoresis. Then, sequencing and analysis of the sequencing results were performed to investigate variation status in the sequences. <b>Results:</b> Five variants in 4 patients were found, including 1 pathogenic variant in exon 16 (H1686Q, NM_007294.3:c.5058T>A) and 4 novel intronic variants of uncertain significance (NC_000017.11:41228314G>T, NC_000017.11:41228309C>T, NC_000017.11:41228317G>T, and NC_000017.11:41203042G>A) in BRCA1. This study was the first to report 1 rare pathogenic variant in BRCA1 (H1686Q, NM_007294.3: c.5058T>A) in an Iranian family as the main disease-causing reason. Another interesting finding was non-existence of variations in almost all globally-reported and mutated exons in BRCA1. <b>Conclusion:</b> Investigation of these exons in BRCA1 showed the uniqueness of mutation pattern in Iranian breast cancer patients compared to other world regions. Due to the existence of other BRCA1 exons and also other predisposing genes in breast cancer, the main cause of cancer development in other participants might have been put in those exons and genes. We concluded that the most mutated exons in BRCA1 in Iranian population may not be the same as those found in other parts of the world.","variants":[{"Name":"NM_007294.4(BRCA1):c.5058T>A (p.His1686Gln)","Chromosome":"17","Start":"43067624","Stop":"43067624","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":70033,"rule_based_match":true,"evidence_text":"NM_007294.3:c.5058T>A","llm_judgment":"PRESENT","evidence":"NM_007294.3:c.5058T>A","abstract_start":803,"abstract_end":824}]}
{"pmid":"30693673","title":"Mutation analysis of common deafness genes among 1,201 patients with non-syndromic hearing loss in Shanxi Province.","abstract":"BACKGROUND: Hearing impairment is one of most frequent birth defects, which affects nearly 1 in every 1,000 live births. However, the molecular etiology of non-syndromic deafness in China is not well studied. Here, we have investigated the presence of mutations in three genes commonly mutated in non-syndromic deafness patients in Shanxi Province, which has the highest frequency of birth defects in China.\nMETHODS: In total, 1,201 unrelated non-syndromic deafness patients and 300 healthy individuals were enrolled. The hearing ability was confirmed by audiologic evaluation. Three major deafness-related genes (GJB2, SLC26A4 (PDS), and mtDNA 12S rRNA) of all individuals enrolled were analyzed by Sanger sequencing.\nRESULTS: The results showed that GJB2 mutations accounted for 21.23% (255/1,201) in the patient group, with c.235delC, a hotspot mutation, accounting for 10.99% (132/1,201). Moreover, 11 new GJB2 mutations were identified. SLC26A4 mutations accounted for 9.33% (112/1,201) in the patient group, with IVS7-2A>G as the most prevalent mutation accounting for 4.75% (57/1,201). In addition, 15 patients (1.25%) were found to carry mtDNA 12S rRNA c.1555A>G mutation, while only two cases had the mtDNA 12S rRNA c.1494C>T.\nCONCLUSION: In our research, it was found that c.235delC in GJB2 and c.919-2A>G (IVS7-2A>G) in SLC26A4 were the highest frequency pathogenic variants in Shanxi Province. Taken together, our data will enrich the database of deafness mutations and will help clinical diagnosis, treatment, and genetic counseling of hearing impairment.","variants":[{"Name":"NM_004004.6(GJB2):c.235del (p.Leu79fs)","Chromosome":"13","Start":"20189347","Stop":"20189347","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":32053,"rule_based_match":true,"evidence_text":"c.235delC","llm_judgment":"PRESENT","evidence":"c.235delC","abstract_start":827,"abstract_end":836}]}
{"pmid":"16630736","title":"When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients.","abstract":"Mucolipidosis II (ML II) and Mucolipidosis type III (ML III) are autosomal recessive disorders of lysosomal hydrolases trafficking due to the deficiency of the multimeric enzyme, UDP-N-acetylglucosamine-1-phosphotransferase. The alpha/beta subunits encoded by the GNPTA gene is the catalytic subunit of the enzyme while the gamma recognition subunit is encoded by the GNPTAG gene. We report the molecular analysis of GNPTA in 21 families with ML II and 3 families with ML III. The ML II mutant genotypes included three splice-site mutations [IVS1-2A>G; IVS17+1G>A; IVS18+1G>A] in seven Palestinian, Israeli Arab-Muslims, and Turkish patients; a two base pair deletion [c.3503_4delTC] [corrected] in 11 patients from Israel, Turkey, and Ireland; two nonsense mutations [c.2533C>T (Q845X); c.3613C>T (R1205X)], in a Turkish and an Arab-Muslim patient from the Nablus area, respectively, and an insertion mutation [c.2916insT] in a patient from Nablus. The ML III mutant genotypes included a splice-site mutation [IVS17+6T>G] in two patients from Irish/Scottish origin who were compound heterozygous for a nonsense mutation [c.3565C>T (R1189X)] and the deletion mutation [c.3503_4delTC] [corrected] respectively. The third ML III patient from France was compound heterozygous for a missense mutation [c.1196C>T] and the same deletion [c.3503_4delTC] [corrected] found homozygous in 11 ML II patients. The 21 ML II patients were homozygous while the three ML III patients were compound heterozygous for mutations in GNPTA. The results of this study confirm that ML II or ML III phenotype is not due to the localization of the mutations, but rather to the severity of the mutations, ML II and ML III might be allelic, and ML III is genetically heterogeneous. We suggest that the diseases due to mutations in GNPTA represent a clinical continuum between ML III and ML II, and the classification of these diseases should be based on the age of onset, clinical symptoms, and severity.","variants":[{"Name":"NM_024312.5(GNPTAB):c.2533C>T (p.Gln845Ter)","Chromosome":"12","Start":"101764384","Stop":"101764384","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46978,"rule_based_match":true,"evidence_text":"c.2533C>T (Q845X)","llm_judgment":"PRESENT","evidence":"c.2533C>T (Q845X)","abstract_start":769,"abstract_end":786},{"Name":"NM_024312.5(GNPTAB):c.3503_3504del (p.Leu1168fs)","Chromosome":"12","Start":"101753470","Stop":"101753471","ReferenceAlleleVCF":"TGA","AlternateAlleleVCF":"T","allel_id":17810,"rule_based_match":false,"evidence_text":"c.3503_4delTC","llm_judgment":"PRESENT","evidence":"c.3503_4delTC","abstract_start":669,"abstract_end":682}]}
{"pmid":"30339652","title":"Fanconi Anemia and Ataxia Telangiectasia in Siblings who Inherited Unique Combinations of Novel FANCA and ATM Null Mutations.","abstract":"A unique consanguineous family with 2 genomic instability disorders, Fanconi anemia and ataxia telangiectasia, revealed exceptional combinations of null mutations in the FANCA and ATM genes. Two siblings with Fanconi anemia had novel homozygous consecutive microdeletions (c.1361-1370delCCTCCTTTGG, c.1374delC) adjoined to upstream 65 nucleotide direct tandem repeats and deletion hotspot motifs in the FANCA gene. The sibling with ataxia telangiectasia revealed a homozygous p.Arg2993Stop (c.8977C>T) null mutation in the ATM gene. All patients were also heterozygous for the opposite mutations without any additional clinical or laboratory manifestations. Double heterozygote parents did not present any clinical symptoms suggestive of the 2 disorders.","variants":[{"Name":"NM_000051.4(ATM):c.8977C>T (p.Arg2993Ter)","Chromosome":"11","Start":"108365208","Stop":"108365208","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":183467,"rule_based_match":true,"evidence_text":"p.Arg2993Stop (c.8977C>T)","llm_judgment":"PRESENT","evidence":"p.Arg2993Stop (c.8977C>T)","abstract_start":476,"abstract_end":501}]}
{"pmid":"28396750","title":"Dominant deafness-onychodystrophy syndrome caused by an","abstract":"Our report clarifies the role of <i>ATP6V1B2</i> in patients with deafness and onycho-osteodystrophy and confirms that a recurring <i>ATP6V1B2</i> c.1516C>T [p.(Arg506*)], variant causes dominant deafness-onychodystrophy (DDOD) syndrome.","variants":[{"Name":"NM_001693.4(ATP6V1B2):c.1516C>T (p.Arg506Ter)","Chromosome":"8","Start":"20220382","Stop":"20220382","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":199855,"rule_based_match":true,"evidence_text":"ATP6V1B2 c.1516C>T [p.(Arg506*)]","llm_judgment":"PRESENT","evidence":"ATP6V1B2</i> c.1516C>T [p.(Arg506*)]","abstract_start":134,"abstract_end":170}]}
{"pmid":"35446965","title":"Analysis of clinical phenotypes and ATP7B gene variants in 75 children patients with Wilson' s disease","abstract":"OBJECTIVE: To analyze the clinical phenotypes and ATP7B gene variants among children patients with Wilson' s disease from Northwestern China.\nMETHODS: The clinical features and variants of the ATP7B gene among 75 children with hepatic Wilson' s disease were retrospectively analyzed.\nRESULTS: Among the 75 cases, 4 were presymptomatic, 59 had isolated transaminase elevation, 12 had acute and/or chronic liver diseases. Nine children were found to harbor homozygous variants, 64 harbored compound heterozygous variants, and two only had heterozygous variants of the ATP7B gene. In total 49 variants were detected, with common variants including c.2333G>T (p.Arg778Leu), c.2621C>T (p.Ala874Val) and c.2975C>T (Pro992Leu), which yielded allelic frequencies of 28.7%, 12.7% and 9.3%, respectively. Six novel variants were detected, which included c.1908dupC (p.Asn637Glnfs*118), c.4179_4180insC (p.Pro1394Profs*15), c.1604A>G (p.Glu535Gly), c.2278C>T (p.Pro760Ser), c.3008C>A (p.Ala1003Glu) and c.3532A>C (p.Thr1178Pro). Except for c.1604A>G (p.Glu535Gly), the remainder five were all predicted to be likely pathogenic. No significant correlation was found between genotype and phenotype among the patients.\nCONCLUSION: The common mutation types of the ATP7B gene among patients with hepatic Wilson disease in Northwestern China are c.2333G>T (p.Arg778Leu), c.2621C>T (p.Ala874Val) and c.2975C>T (p.Pro992Leu), there is no significant correlation between their genotypes and phenotypes.","variants":[{"Name":"NM_000053.4(ATP7B):c.3532A>C (p.Thr1178Pro)","Chromosome":"13","Start":"51941105","Stop":"51941105","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2958002,"rule_based_match":true,"evidence_text":"c.3532A>C (p.Thr1178Pro)","llm_judgment":"PRESENT","evidence":"c.3532A>C (p.Thr1178Pro)","abstract_start":992,"abstract_end":1016},{"Name":"NM_000053.4(ATP7B):c.2333G>T (p.Arg778Leu)","Chromosome":"13","Start":"51958333","Stop":"51958333","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":18891,"rule_based_match":true,"evidence_text":"c.2333G>T (p.Arg778Leu)","llm_judgment":"PRESENT","evidence":"c.2333G>T (p.Arg778Leu)","abstract_start":645,"abstract_end":668}]}
{"pmid":"27701732","title":"Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome.","abstract":"Tatton-Brown-Rahman syndrome (TBRS) was recently described in 13 isolated cases with de novo mutations in the DNMT3A gene. This autosomal dominant condition is characterized by tall stature, intellectual disability and a distinctive facial appearance. Here, we report six cases of inherited TBRS caused by novel DNMT3A germline mutations. The affected individuals belong to two sib-ships: four from an Old Order Amish family in America and two from a French Canadian family in Canada. All of them presented with characteristic features of TBRS, including dysmorphic facial features, increased height, intellectual disability, and variable additional features. We performed clinical exome sequencing and identified two mutations in the DNMT3A gene, a c.2312G>A (p.Arg771Gln) missense mutation in the Amish family and a c.2296_2297delAA (p.Lys766Glufs*15) small deletion in the French Canadian family. Parental DNA analysis by Sanger sequencing revealed that the Amish mutation was inherited from the healthy mosaic father. This study reflects the first cases with inherited TBRS and expands the phenotypic spectrum of TBRS.","variants":[{"Name":"NM_022552.5(DNMT3A):c.2312G>A (p.Arg771Gln)","Chromosome":"2","Start":"25240312","Stop":"25240312","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":431903,"rule_based_match":true,"evidence_text":"c.2312G>A (p.Arg771Gln)","llm_judgment":"PRESENT","evidence":"c.2312G>A (p.Arg771Gln)","abstract_start":750,"abstract_end":773}]}
{"pmid":"33099109","title":"Generation of an iPSC line (AKOSi006-A) from fibroblasts of an NPC1 patient, carrying the homozygous mutation p.I1061T (c.3182 T > C) and a control iPSC line (AKOSi007-A) using a non-integrating Sendai virus system.","abstract":"Niemann-Pick disease type C1 (NPC1) is a rare inherited lipid storage disorder caused by mutations in the NPC1 gene. Mutations lead to impaired lipid trafficking and subsequently to accumulation of cholesterol and sphingolipids. NPC1-patients present variable multisystemic symptoms, including neurological deficits. Here, we describe the generation of human iPSC lines obtained from fibroblasts of a male individual, carrying the homozygous mutation p.I1061T, and an unrelated and healthy male individual. A non-integrating Sendai virus system, containing KLF4, OCT3/4, SOX2 and C-MYC, was used for reprogramming. These cell lines provide a valuable resource for studying the pathophysiology of multisystemic NPC1-disease.","variants":[{"Name":"NM_000271.5(NPC1):c.3182T>C (p.Ile1061Thr)","Chromosome":"18","Start":"23536736","Stop":"23536736","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18006,"rule_based_match":true,"evidence_text":"c.3182 T > C","llm_judgment":"PRESENT","evidence":"c.3182 T > C","abstract_start":null,"abstract_end":null}]}
{"pmid":"31001908","title":"A novel CDKN2A variant (p16","abstract":"Germline mutations in CDKN2A (p16) are commonly found in patients with family history of melanoma or personal history of multiple primary melanomas. The p16 tumor suppressor gene regulates cell cycle progression and senescence through binding of cyclin-dependent kinases (CDK) and also regulates cellular oxidative stress independently of cell cycle control. We identified a germline missense (c.350T>C, p.Leu117Pro) CDKN2A mutation in a patient who had history of four primary melanomas, numerous nevi, and self-reported family history of melanoma. This particular CDKN2A mutation has not been previously reported in prior large studies of melanoma kindreds or patients with multiple primary melanomas. Compared with wild-type p16, the p16<sup>L117P</sup> mutant largely retained binding capacity for CDK4 and CDK6 but exhibited impaired capacity for repressing cell cycle progression and inducing senescence, while retaining its ability to reduce mitochondrial reactive oxygen species. Structural modeling predicted that the Leu117Pro mutation disrupts a putative adenosine monophosphate (AMP) binding pocket involving residue 117 in the fourth ankyrin domain. Identification of this new likely pathogenic variant extends our understanding of CDKN2A in melanoma susceptibility and implicates AMP as a potential regulator of p16.","variants":[{"Name":"NM_000077.5(CDKN2A):c.350T>C (p.Leu117Pro)","Chromosome":"9","Start":"21971009","Stop":"21971009","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":822022,"rule_based_match":true,"evidence_text":"c.350T>C, p.Leu117Pro","llm_judgment":"PRESENT","evidence":"c.350T>C, p.Leu117Pro","abstract_start":394,"abstract_end":415}]}
{"pmid":"35008666","title":"Novel Homozygous Missense Variant in","abstract":"Congenital cataracts (CC) are responsible for approximately one-tenth of childhood blindness cases globally. Here, we report an African American family with a recessively inherited form of CC. The proband demonstrated decreased visual acuity and bilateral cataracts, with nuclear and cortical cataracts in the right and left eye, respectively. Exome sequencing revealed a novel homozygous variant (c.563A > G; p.(Asn188Ser)) in <i>GJA3</i>, which was predicted to be pathogenic by structural analysis. Dominantly inherited variants in <i>GJA3</i> are known to cause numerous types of cataracts in various populations. Our study represents the second case of recessive <i>GJA3</i> allele, and the first report in African Americans. These results validate <i>GJA3</i> as a bona fide gene for recessively inherited CC in humans.","variants":[{"Name":"NM_021954.4(GJA3):c.563A>G (p.Asn188Ser)","Chromosome":"13","Start":"20142726","Stop":"20142726","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1192609,"rule_based_match":true,"evidence_text":"c.563A > G; p.(Asn188Ser)","llm_judgment":"PRESENT","evidence":"c.563A > G; p.(Asn188Ser)","abstract_start":398,"abstract_end":423}]}
{"pmid":"33420188","title":"Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant.","abstract":"We describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.","variants":[{"Name":"NM_000539.3(RHO):c.404G>C (p.Arg135Pro)","Chromosome":"3","Start":"129530918","Stop":"129530918","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1464526,"rule_based_match":true,"evidence_text":"RHO variant c.404G > C p.(Arg135Pro)","llm_judgment":"PRESENT","evidence":"RHO variant c.404G > C p.(Arg135Pro)","abstract_start":1099,"abstract_end":1135}]}
{"pmid":"19842205","title":"Three novel mutations of the IRF6 gene with one associated with an unusual feature in Van der Woude syndrome.","abstract":"Van der Woude syndrome (VWS) is a dominantly inherited disorder characterized by cleft lip with or without cleft palate and lip pits. It remains the most common syndromic form of oral clefts. Mutations in the interferon regulatory factor 6 (IRF6) gene have been identified in patients with VWS. We reported three unrelated families with lower lip anomalies. Two had lower lip pits, a cardinal sign of VWS, but the other had a heart-shaped mass on lower lip without pits, oral clefts, or hypodontia. This isolated anomaly has not been previously observed in VWS. We performed mutation analysis by PCR-sequencing the entire coding region of the IRF6 gene. Three potentially pathogenic mutations, c.145C>T (p.Q49X), c.171T>G (p.F57L), and 1306C>G (p.L436V) were successfully identified. All the missense mutations were not detected in 100 unaffected ethnic-matched control chromosomes and have never been previously reported. The p.Q49X and p.F57L mutations were located in the highly conserved DNA binding domain while the p.L436V was located at the carboxy-terminal region. This study reported an undescribed clinical feature of VWS and three novel mutations, expanding the phenotypic spectrum of VWS and mutational spectrum of IRF6.","variants":[{"Name":"NM_006147.4(IRF6):c.145C>T (p.Gln49Ter)","Chromosome":"1","Start":"209801269","Stop":"209801269","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":48590,"rule_based_match":true,"evidence_text":"c.145C>T (p.Q49X)","llm_judgment":"PRESENT","evidence":"c.145C>T (p.Q49X)","abstract_start":694,"abstract_end":711}]}
{"pmid":"27121329","title":"Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.","abstract":"Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.","variants":[{"Name":"NM_000277.3(PAH):c.443G>T (p.Gly148Val)","Chromosome":"12","Start":"102866662","Stop":"102866662","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":546821,"rule_based_match":false,"evidence_text":"c.443G>T (p.Gly148Val)","llm_judgment":"PRESENT","evidence":"p.Gly148Val","abstract_start":1037,"abstract_end":1048},{"Name":"NM_000277.3(PAH):c.847A>G (p.Ile283Val)","Chromosome":"12","Start":"102851752","Stop":"102851752","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1053675,"rule_based_match":false,"evidence_text":"c.847A>G (p.Ile283Val)","llm_judgment":"PRESENT","evidence":"p.Ile283Val","abstract_start":1021,"abstract_end":1032}]}
{"pmid":"27994174","title":"Evidence of digenic inheritance in autoinflammation-associated genes.","abstract":"Familial Mediterranean fever (FMF) has traditionally been considered as a monogenic autosomal recessive disorder caused by mutations in the MEFV gene with highest incidence among Mediterranean populations. In a considerable number of patients with typical FMF, only one MEFV mutation was identified and the possibility that more than one autoinflammatory gene may be responsible for their disease was investigated. In the present study, an extensive search for possible mutations in three hereditary recurrent fever (HRF) genes was performed in 128 MEFV heterozygous Greek-Cypriots clinically diagnosed based on their phenotype with FMF-like disease from a previous study. Sequence analysis was performed for MVK, TNFRSF1A and NLRP3 genes which is also known to cause HRFs. In total, three patients were identified with heterozygous mutations and a second mutation in an autoinflammatory gene. Two patients carried a MEFV mutation and a NLRP3 mutation, and an additional third carried a MEFV mutation and a TNFRSF1A mutation. Patient 1 carried MEFV p.[Val726Ala] (NM_000243.2:c.2177T>C) and NLRP3 p.[Val198Met] (NM_001243133.1:c.592G>A) variants and patient 2 carried MEFV p.[Glu148Gln] (NM_000243.2:c.442G>C) variant which is of uncertain significance and NLRP3 p.[Arg176Trp] (NM_001243133.1:c.526C>T). Lastly, patient 3 was identified to carry MEFV p.[Met694Val] (NM_000243.2:c.2080A>G) and TNFRSF1A p.[Arg121Gln] (NM_001065.3:c.362G>A) variants. The results from this study indicate that screening of genes known to cause HRFs in patients already identified with a single MEFV mutation, can reveal quite rare but potentially causative mutational combinations at different loci. Such interaction provide further evidence for possible locus-locus interactions and phenotypes resulting from digenic inheritance.","variants":[{"Name":"NM_001243133.2(NLRP3):c.592G>A (p.Val198Met)","Chromosome":"1","Start":"247424041","Stop":"247424041","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19410,"rule_based_match":true,"evidence_text":"NLRP3 p.[Val198Met] (NM_001243133.1:c.592G>A)","llm_judgment":"PRESENT","evidence":"NLRP3 p.[Val198Met] (NM_001243133.1:c.592G>A)","abstract_start":1091,"abstract_end":1136},{"Name":"NM_000243.3(MEFV):c.2177T>C (p.Val726Ala)","Chromosome":"16","Start":"3243310","Stop":"3243310","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":17579,"rule_based_match":true,"evidence_text":"MEFV p.[Val726Ala] (NM_000243.2:c.2177T>C)","llm_judgment":"PRESENT","evidence":"MEFV p.[Val726Ala] (NM_000243.2:c.2177T>C)","abstract_start":1044,"abstract_end":1086},{"Name":"NM_000243.3(MEFV):c.442G>C (p.Glu148Gln)","Chromosome":"16","Start":"3254626","Stop":"3254626","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":17581,"rule_based_match":true,"evidence_text":"NM_000243.2:c.442G>C","llm_judgment":"PRESENT","evidence":"NM_000243.2:c.442G>C","abstract_start":1188,"abstract_end":1208},{"Name":"NM_001243133.2(NLRP3):c.526C>T (p.Arg176Trp)","Chromosome":"1","Start":"247423975","Stop":"247423975","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1294178,"rule_based_match":true,"evidence_text":"NLRP3 p.[Arg176Trp] (NM_001243133.1:c.526C>T)","llm_judgment":"PRESENT","evidence":"NLRP3 p.[Arg176Trp] (NM_001243133.1:c.526C>T)","abstract_start":1257,"abstract_end":1302}]}
{"pmid":"36915884","title":"Prevalence of germline mutations in cancer susceptibility genes in Chinese patients with renal cell carcinoma.","abstract":"Background: Germline pathogenic variants are estimated to affect 3-5% of patients with renal cell carcinoma (RCC). The identification of patients with hereditary RCC is important for cancer screening and treatment guidance.\nMethods: Whole-exome sequencing (WES) (n=69) or gene panel sequencing containing 139 genes (n=54) related to germline cancer predisposition was used to analyze germline mutations in 123 patients with RCC admitted to Department of Urology, The Third Medical Center of Chinese PLA General Hospital. Chi-square test (χ<sup>2</sup>) was used to analyze relationship between clinicopathologic parameters and germline mutations.\nResults: A total of 13 (10.57%) patients carried pathogenic or likely pathogenic germline mutations in 10 cancer predisposition genes, including <i>VHL, FH, FLCN, SDHB, MUTYH, RAD51C, NBN, RAD50, FANCI</i>, and <i>FANCM</i>. A total of 6 of these 10 cancer predisposition genes were associated with maintenance of genomic stability and DNA repair. Patients harboring pathogenic germline mutations tended to have an earlier RCC onset. The prevalence of deleterious mutations was higher in patients with bilateral or multifocal RCC compared to patients without bilateral or multifocal RCC. Patients with non-clear cell RCC (nccRCC) were significantly more likely to have RCC-associated gene mutations.\nConclusions: To our knowledge, this is the first report of pathogenic germline mutations in the <i>FANCI</i> and <i>FANCM</i> genes and heterozygous germline missense mutation in exon 5 of the <i>FH</i> gene c.563A>T:p.N188I in RCC. Young RCC patients, patients with bilateral or multifocal RCC, or patients with nccRCC are more likely to have pathogenic/potentially pathogenic germline mutations.","variants":[{"Name":"NM_000143.4(FH):c.563A>T (p.Asn188Ile)","Chromosome":"1","Start":"241508778","Stop":"241508778","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1054825,"rule_based_match":true,"evidence_text":"c.563A>T:p.N188I","llm_judgment":"PRESENT","evidence":"c.563A>T:p.N188I","abstract_start":1555,"abstract_end":1571}]}
{"pmid":"18307025","title":"A Japanese patient with Li-Fraumeni syndrome who had nine primary malignancies associated with a germline mutation of the p53 tumor-suppressor gene.","abstract":"We describe a patient who had nine primary malignant tumors and a germline mutation in the p53 tumor-suppressor gene, characteristically found in the Li-Fraumeni syndrome (LFS). A 15-year-old girl with no family history of cancer was referred to our hospital because of pain and swelling of the right knee. Osteosarcoma was diagnosed. The patient received chemotherapy followed by surgery and had a remission. After the age of 28 years, nine primary malignant tumors developed successively, including right breast cancer, colon cancer, malignant fibrous histiocytoma (MFH) of the abdominal wall, right lung double cancers, bilateral breast cancers, and MFH of the left thigh. This is the second highest number of types of primary malignant tumors to be reported in LFS. All tumors were treated by a multidisciplinary approach, including surgery. Genetic analysis revealed a germline missense mutation in the p53 gene (c.659 A > G), resulting in Y220C, which has been reported in three families with LFS. The patient died of lung metastasis from MFH at the age of 37 years. Despite the multiple tumors, repeated induction of remissions resulted in long survival. Our findings suggest that a multidisciplinary approach to treatment, including surgery, is beneficial in patients with LFS.","variants":[{"Name":"NM_000546.6(TP53):c.659A>G (p.Tyr220Cys)","Chromosome":"17","Start":"7674872","Stop":"7674872","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":133276,"rule_based_match":true,"evidence_text":"c.659 A > G","llm_judgment":"PRESENT","evidence":"c.659 A > G","abstract_start":918,"abstract_end":929}]}
{"pmid":"34925852","title":"Classification and genetic counselling for a novel splicing mutation of the","abstract":"BACKGROUND: Lynch-syndrome-associated cancer is caused by germline pathogenic mutations in mismatch repair genes. The major challenge to Lynch-syndrome screening is the interpretation of variants found by diagnostic testing. This study aimed to classify the <i>MLH1</i> c.1989 + 5G>A mutation, which was previously reported as a variant of uncertain significance, to describe its clinical phenotypes and characteristics, to enable detailed genetic counselling.\nMETHODS: We reviewed the database of patients with Lynch-syndrome gene detection in our hospital. A novel variant of <i>MLH1</i> c.1989 + 5G>A identified by next-generation sequencing was further investigated in this study. Immunohistochemical staining was carried out to assess the expression of MLH1 and PMS2 protein in tumour tissue. <i>In silico</i> analysis by Alamut software was used to predict the <i>MLH1</i> c.1989 + 5G>A variant function. Reverse transcription-polymerase chain reaction and sequencing of RNA from whole blood were used to analyse the functional significance of this mutation.\nRESULTS: Among affected family members in the suspected Lynch-syndrome pedigree, the patient suffered from late-stage colorectal cancer but had a good prognosis. We found the <i>MLH1</i> c.1989 + 5G>A variant, which led to aberrant splicing and loss of MLH1 and PMS2 protein in the nuclei of tumour cells. An aberrant transcript was detectable and skipping of <i>MLH1</i> exon 17 in carriers of <i>MLH1</i> c.1989 + 5G>A was confirmed.\nCONCLUSIONS: <i>MLH1</i> c.1989 + 5G>A was detected in a cancer family pedigree and identified as a pathological variant in patients with Lynch syndrome. The mutation spectrum of Lynch syndrome was enriched through enhanced genetic testing and close surveillance might help future patients who are suspected of having Lynch syndrome to obtain a definitive early diagnosis.","variants":[{"Name":"NM_000249.4(MLH1):c.1989+5G>A","Chromosome":"3","Start":"37048614","Stop":"37048614","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":561436,"rule_based_match":true,"evidence_text":"MLH1 c.1989 + 5G>A","llm_judgment":"PRESENT","evidence":"MLH1</i> c.1989 + 5G>A","abstract_start":261,"abstract_end":283}]}
{"pmid":"29748569","title":"A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy.","abstract":"The NAA10-NAA15 complex (NatA) is an N-terminal acetyltransferase that catalyzes N-terminal acetylation of ~40% of all human proteins. N-terminal acetylation has several different roles in the cell, including altering protein stability and degradation, protein localization and protein-protein interactions. In recent years several X-linked NAA10 variants have been associated with genetic disorders. We have identified a previously undescribed NAA10 c.215T>C p.(Ile72Thr) variant in three boys from two unrelated families with a milder phenotypic spectrum in comparison to most of the previously described patients with NAA10 variants. These boys have development delay, intellectual disability, and cardiac abnormalities as overlapping phenotypes. Functional studies reveal that NAA10 Ile72Thr is destabilized, while binding to NAA15 most likely is intact. Surprisingly, the NatA activity of NAA10 Ile72Thr appears normal while its monomeric activity is decreased. This study further broadens the phenotypic spectrum associated with NAA10 deficiency, and adds to the evidence that genotype-phenotype correlations for NAA10 variants are much more complex than initially anticipated.","variants":[{"Name":"NM_003491.4(NAA10):c.215T>C (p.Ile72Thr)","Chromosome":"X","Start":"153932549","Stop":"153932549","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":362166,"rule_based_match":true,"evidence_text":"NAA10 c.215T>C p.(Ile72Thr)","llm_judgment":"PRESENT","evidence":"NAA10 c.215T>C p.(Ile72Thr)","abstract_start":445,"abstract_end":472}]}
{"pmid":"32853479","title":"Report of a germline double heterozygote in MSH2 and PALB2.","abstract":"BACKGROUND: Carriers with pathogenic variants in MSH2 have increased risk to develop colorectal, endometrium, ovarian, and other types of cancer. The PALB2 is associated with breast, ovarian, pancreatic, and prostate cancer. We describe the case of a 42-year-old female diagnosed with endometrial cancer at the age of 42 years with a strong family history of colorectal cancer, which was referred to our private diagnostic laboratory for genetic testing.\nMETHODS: In this study, we performed next-generation sequencing (NGS) using an amplicon based 26 genes panel. The presence of multi-exonic copy number variations (CNVs) was investigated by computational analysis and Multiplex Ligation-dependent Probe Amplification (MLPA).\nRESULTS: A gross deletion of the genomic region encompassing exons 11-16 of the MSH2 and the loss-of-function variant c.757_758delCT, p.(Leu253Ilefs*3) in the PALB2 were identified in the proband.\nCONCLUSIONS: Multigene analysis using NGS technology allows the identification of pathogenic variants in genes that would normally not be tested based on the patient diagnosis. In our case these results explained not only the personal and/or family history of cancer but also allowed the surveillance for prevention of other cancer types. Moreover, the detection of large genomic rearrangements should be routinely included in hereditary cancer testing.","variants":[{"Name":"NM_024675.4(PALB2):c.757_758del (p.Leu253fs)","Chromosome":"16","Start":"23635788","Stop":"23635789","ReferenceAlleleVCF":"TAG","AlternateAlleleVCF":"T","allel_id":132278,"rule_based_match":true,"evidence_text":"c.757_758delCT, p.(Leu253Ilefs*3)","llm_judgment":"PRESENT","evidence":"c.757_758delCT, p.(Leu253Ilefs*3)","abstract_start":846,"abstract_end":879}]}
{"pmid":"29444762","title":"Hemimegalencephaly with Bannayan-Riley-Ruvalcaba syndrome.","abstract":"Hemimegalencephaly is known to occur in Proteus syndrome, but has not been reported, to our knowledge, in the other PTEN mutation-related syndrome of Bannayan-Riley-Ruvalcaba. Here, we report a patient with Bannayan-Riley-Ruvalcaba syndrome who also had hemimegalencephaly and in whom the hemimegalencephaly was evident well before presentation of the characteristic manifestations of Bannayan-Riley-Ruvalcaba syndrome. An 11-year-old boy developed drug-resistant focal seizures on the fifth day of life. MRI revealed left hemimegalencephaly. He later showed macrocephaly, developmental delay, athetotic quadriplegic cerebral palsy, and neuromuscular scoliosis. Freckling of the penis, which is characteristic of Bannayan-Riley-Ruvalcaba syndrome, was not present at birth but was observed at 9 years of age. Gene analysis revealed a c.510 T>G PTEN mutation. This patient and his other affected family members, his father and two siblings, were started on the tumour screening procedures recommended for patients with PTEN mutations. This case highlights the importance of early screening for PTEN mutations in cases of hemimegalencephaly not otherwise explained by another disorder, even in the absence of signs of Proteus syndrome or the full manifestations of Bannayan-Riley Ruvalcaba syndrome.","variants":[{"Name":"NM_000314.8(PTEN):c.510T>G (p.Ser170Arg)","Chromosome":"10","Start":"87952135","Stop":"87952135","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":810100,"rule_based_match":true,"evidence_text":"c.510 T>G PTEN mutation","llm_judgment":"PRESENT","evidence":"c.510 T>G PTEN mutation","abstract_start":834,"abstract_end":857}]}
{"pmid":"26813946","title":"Against all odds: blended phenotypes of three single-gene defects.","abstract":"Whole-exome sequencing allows for an unbiased and comprehensive mutation screening. Although successfully used to facilitate the diagnosis of single-gene disorders, the genetic cause(s) of a substantial proportion of presumed monogenic diseases remain to be identified. We used whole-exome sequencing to examine offspring from a consanguineous marriage featuring a novel combination of congenital hypothyroidism, hypomagnesemia and hypercholesterolemia. Rather than identifying one causative variant, we report the first instance in which three independent autosomal-recessive single-gene disorders were identified in one patient. Together, the causal variants give rise to a blended and seemingly novel phenotype: we experimentally characterized a novel splice variant in the thyroglobulin gene (c.638+5G>A), resulting in skipping of exon 5, and detected a pathogenic splice variant in the magnesium transporter gene TRPM6 (c.2667+1G>A), causing familial hypomagnesemia. Based on the third variant, a stop variant in ABCG5 (p.(Arg446*)), we established a diagnosis of sitosterolemia, confirmed by elevated blood plant sterol levels and successfully initiated targeted lipid-lowering treatment. We propose that blended phenotypes resulting from several concomitant single-gene disorders in the same patient likely account for a proportion of presumed monogenic disorders of currently unknown cause and contribute to variable genotype-phenotype correlations.","variants":[{"Name":"NM_003235.5(TG):c.638+5G>A","Chromosome":"8","Start":"132873226","Stop":"132873226","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":214869,"rule_based_match":true,"evidence_text":"c.638+5G>A","llm_judgment":"PRESENT","evidence":"c.638+5G>A","abstract_start":797,"abstract_end":807},{"Name":"NM_017662.5(TRPM6):c.2667+1G>A","Chromosome":"9","Start":"74788613","Stop":"74788613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":214870,"rule_based_match":true,"evidence_text":"c.2667+1G>A","llm_judgment":"PRESENT","evidence":"c.2667+1G>A","abstract_start":925,"abstract_end":936}]}
{"pmid":"37239474","title":"Biallelic Variants in Seven Different Genes Associated with Clinically Suspected Bardet-Biedl Syndrome.","abstract":"Bardet-Biedl syndrome (BBS) is a rare clinically and genetically heterogeneous autosomal recessive multi-systemic disorder with 22 known genes. The primary clinical and diagnostic features include six different hallmarks, such as rod-cone dystrophy, learning difficulties, renal abnormalities, male hypogonadism, post-axial polydactyly, and obesity. Here, we report nine consanguineous families and a non-consanguineous family with several affected individuals presenting typical clinical features of BBS. In the present study, 10 BBS Pakistani families were subjected to whole exome sequencing (WES), which revealed novel/recurrent gene variants, including a homozygous nonsense mutation (c.94C>T; p.Gln32Ter) in the <i>IFT27</i> (NM_006860.5) gene in family A, a homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the <i>BBIP1</i> (NM_001195306.1) gene in family B, a homozygous nonsense variant (c.720C>A; p.Cys240Ter) in the <i>WDPCP</i> (NM_015910.7) in family C, a homozygous nonsense variant (c.505A>T; p.Lys169Ter) in the <i>LZTFL1</i> (NM_020347.4) in family D, pathogenic homozygous 1 bp deletion (c.775delA; p.Thr259Leufs*21) in the <i>MKKS</i>/<i>BBS5</i> (NM_170784.3) gene in family E, a pathogenic homozygous missense variant (c.1339G>A; p.Ala447Thr) in <i>BBS1</i> (NM_024649.4) in families F and G, a pathogenic homozygous donor splice site variant (c.951+1G>A; p?) in <i>BBS1</i> (NM_024649.4) in family H, a pathogenic bi-allelic nonsense variant in <i>MKKS</i> (NM_170784.3) (c.119C>G; p.Ser40*) in family I, and homozygous pathogenic frameshift variants (c.196delA; p.Arg66Glufs*12) in <i>BBS5</i> (NM_152384.3) in family J. Our findings extend the mutation and phenotypic spectrum of four different types of ciliopathies causing BBS and also support the importance of these genes in the development of multi-systemic human genetic disorders.","variants":[{"Name":"NM_020347.4(LZTFL1):c.505A>T (p.Lys169Ter)","Chromosome":"3","Start":"45831090","Stop":"45831090","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":3393132,"rule_based_match":true,"evidence_text":"c.505A>T (p.Lys169Ter)","llm_judgment":"PRESENT","evidence":"p.Lys169Ter","abstract_start":1014,"abstract_end":1025},{"Name":"NM_015910.7(WDPCP):c.720C>A (p.Cys240Ter)","Chromosome":"2","Start":"63433850","Stop":"63433850","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3393134,"rule_based_match":true,"evidence_text":"c.720C>A (p.Cys240Ter)","llm_judgment":"PRESENT","evidence":"p.Cys240Ter","abstract_start":913,"abstract_end":924}]}
{"pmid":"30889162","title":"Charcot-Marie-Tooth disease with pyramidal features due to a new mutation of EGR2 gene.","abstract":"BACKGROUND AND AIM OF THE WORK: Childhood-onset peripheral neuropathies are often of genetic origin. Charcot-Marie-Tooth (CMT), is considered the commonest neuromuscular disorder. Due to its high clinical heterogeneity, especially in the pediatric age, the co-existence of central and peripheral symptoms and signs does not necessarily rule out a diagnosis of hereditary peripheral neuropathy.\nMETHODS: We describe the clinical, neurophysiological and genetic findings in a teen-age patient evaluated for acquired toe-walking and progressive difficulties in walking since the age of 5. Genetic testing was carried out with a targeted NGS panel. Identified variants are analyzed using Variant Studio program (Illumina). Rare variants and variants considered as pathogenic were analyzed by Sanger direct sequencing.\nRESULTS: The coexistence of peripheral and pyramidal signs in the lower limbs, the absence of a significant pre/perinatal history, the unremarkable brain and spine MRI, together with the presence of a sensory-motor polyneuropathy in all four limbs, prompted the execution of genetic investigations with an NGS panel covering hereditary spastic paraplegias, motor neuron disease and Charcot-Marie-Tooth. We identified a previously undescribed variant (c.1142G>T, p.Arg381Leu) in the EGR2 gene.\nCONCLUSIONS: ERG2 gene has been described as a cause of various phenotypes, including a rare autosomal dominant form of CMT (CMT type 1D) representing approximately 1% of all CMT subgroups. We describe a novel pathogenic variant in EGR2 gene leading to the development of a complex association of peripheral and central neurological signs, underscoring the genetic and clinical heterogeneity of hereditary neuropathies of pediatric onset.","variants":[{"Name":"NM_000399.5(EGR2):c.1142G>T (p.Arg381Leu)","Chromosome":"10","Start":"62813496","Stop":"62813496","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1061937,"rule_based_match":true,"evidence_text":"c.1142G>T, p.Arg381Leu","llm_judgment":"PRESENT","evidence":"c.1142G>T, p.Arg381Leu","abstract_start":1265,"abstract_end":1287}]}
{"pmid":"35741767","title":"Biallelic Optic Atrophy 1 (","abstract":"Dominant optic atrophy (DOA), MIM # 605290, is the most common hereditary optic neuropathy inherited in an autosomal dominant pattern. Clinically, it presents a progressive decrease in vision, central visual field defects, and retinal ganglion cell loss. A biallelic mode of inheritance causes syndromic DOA or Behr phenotype, MIM # 605290. This case report details a family with Biallelic Optic Atrophy 1 (OPA1). The proband is a child with a severe phenotype and two variants in the OPA1 gene. He presented with congenital nystagmus, progressive vision loss, and optic atrophy, as well as progressive ataxia, and was found to have two likely pathogenic variants in his OPA1 gene: c.2287del (p.Ser763Valfs*15) maternally inherited and c.1311A>G (p.lIle437Met) paternally inherited. The first variant is predicted to be pathogenic and likely to cause DOA. In contrast, the second is considered asymptomatic by itself but has been reported in patients with DOA phenotype and is presumed to act as a phenotypic modifier. On follow-up, he developed profound vision impairment, intractable seizures, and metabolic strokes. A literature review of reported biallelic OPA1-related Behr syndrome was performed. Twenty-one cases have been previously reported. All share an early-onset, severe ocular phenotype and systemic features, which seem to be the hallmark of the disease.","variants":[{"Name":"NM_130837.3(OPA1):c.1311A>G (p.Ile437Met)","Chromosome":"3","Start":"193643378","Stop":"193643378","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":59852,"rule_based_match":true,"evidence_text":"c.1311A>G (p.lIle437Met)","llm_judgment":"PRESENT","evidence":"c.1311A>G (p.lIle437Met)","abstract_start":736,"abstract_end":760}]}
{"pmid":"25370867","title":"Molecular characterization of a β-thalassemia intermedia patient presenting inferior vena cava thrombosis: interaction of the β-globin erythroid Krüppel-like factor binding site mutation with Hb E and α(+)-thalassemia.","abstract":"The molecular basis and hematological phenotype of adult Thai β-thalassemia intermedia (β-TI) patients encountered with inferior vena cava (IVC) thrombosis were investigated. Hematological and molecular analysis revealed a trait previously not described. The disease was caused by interaction of the β(+)-thalassemia (β(+)-thal) gene with the -90 (C > T) (HBB: c.-140C > T) transition within the erythroid Krüppel-like factor (EKLF) binding site of the β-globin gene promoter with Hb E (HBB: c.79G > A) and α(+)-thalassemia (α(+)-thal). Hematological data of the patient were compared with those of heterozygous forms of these defects found in his family members and different genotype-phenotype interactions are illustrated. Globin gene haplotype analysis indicates an independent origin of this Thai β(+)-thal gene. Accurate diagnoses as well as knowledge of genotype-phenotype relationships were required for providing appropriate management of such cases.","variants":[{"Name":"NM_000518.5(HBB):c.79G>A (p.Glu27Lys)","Chromosome":"11","Start":"5226943","Stop":"5226943","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30200,"rule_based_match":true,"evidence_text":"Hb E (HBB: c.79G > A)","llm_judgment":"PRESENT","evidence":"Hb E (HBB: c.79G > A)","abstract_start":481,"abstract_end":502},{"Name":"NM_000518.5(HBB):c.-140C>T","Chromosome":"11","Start":"5227161","Stop":"5227161","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":30553,"rule_based_match":true,"evidence_text":"HBB: c.-140C > T","llm_judgment":"PRESENT","evidence":"HBB: c.-140C > T","abstract_start":356,"abstract_end":372}]}
{"pmid":"24228726","title":"Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation.","abstract":"BACKGROUND: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disease with severe microcephaly at birth due to a pronounced reduction in brain volume and intellectual disability. Biallelic mutations in the WD repeat-containing protein 62 gene WDR62 are the genetic cause of MCPH2. However, the exact underlying pathomechanism of MCPH2 remains to be clarified.\nMETHODS/RESULTS: We characterized the clinical, radiological, and cellular features that add to the human MCPH2 phenotype. Exome sequencing followed by Sanger sequencing in a German family with two affected daughters with primary microcephaly revealed in the index patient the compound heterozygous mutations c.1313G>A (p.R438H) / c.2864-2867delACAG (p.D955Afs*112) of WDR62, the second of which is novel. Radiological examination displayed small frontal lobes, corpus callosum hypoplasia, simplified hippocampal gyration, and cerebellar hypoplasia. We investigated the cellular phenotype in patient-derived lymphoblastoid cells and compared it with that of healthy female controls. WDR62 expression in the patient's immortalized lymphocytes was deranged, and mitotic spindle defects as well as abnormal centrosomal protein localization were apparent.\nCONCLUSION: We propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2.","variants":[{"Name":"NM_001083961.2(WDR62):c.1313G>A (p.Arg438His)","Chromosome":"19","Start":"36081512","Stop":"36081512","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39992,"rule_based_match":true,"evidence_text":"c.1313G>A (p.R438H)","llm_judgment":"PRESENT","evidence":"c.1313G>A (p.R438H)","abstract_start":696,"abstract_end":715},{"Name":"NM_001083961.2(WDR62):c.2864_2867del (p.Asp955fs)","Chromosome":"19","Start":"36100867","Stop":"36100870","ReferenceAlleleVCF":"GGACA","AlternateAlleleVCF":"G","allel_id":1373411,"rule_based_match":false,"evidence_text":"c.2864-2867delACAG (p.D955Afs*112)","llm_judgment":"PRESENT","evidence":"c.2864-2867delACAG (p.D955Afs*112)","abstract_start":718,"abstract_end":752}]}
{"pmid":"31944864","title":"Compound heterozygous mutations in the","abstract":"<b>Purpose:</b> Sjögren-Larsson syndrome is a rare, autosomal, recessive neurocutaneous disorder caused by mutations in the <i>ALDH3A2</i> gene, which encodes the fatty aldehyde dehydrogenase enzyme. Deficiency in fatty aldehyde dehydrogenase results in an abnormal accumulation of toxic fatty aldehydes in the brain and skin, which cause spasticity, intellectual disability, ichthyosis, and other clinical manifestations. We present the clinical features and mutation analyses of a case of SLS.<b>Materials and Methods:</b> The family history and clinical data of the patient were collected. Genomic DNA was extracted from peripheral blood samples of the patient and her parents, and next-generation sequencing was performed. The candidate mutation sites that required further validation were then sequenced by Sanger sequencing. Bioinformatics software PSIPRED and RaptorX were used to predict the secondary and tertiary structures of proteins.<b>Results:</b> The patient, a five-year-old girl with complaints of cough for three days and intermittent convulsions for seven hours, was admitted to the hospital. Other clinical manifestations included spastic paraplegia, mental retardation, tooth defects, and ichthyosis. Brain magnetic resonance imaging showed periventricular leukomalacia. Genetic screening revealed compound heterozygous mutations in the ALDH3A2 gene: a frameshift mutation c.779delA (p.K260Rfs*6) and a missense mutation c.1157A > G (p.N386S). Neither of the ALDH3A2 alleles in the compound heterozygote patient were able to generate normal fatty aldehyde dehydrogenase, which were likely responsible for her phenotype of Sjögren-Larsson syndrome.<b>Conclusion:</b> The compound heterozygous mutations found in the <i>ALDH3A2</i> gene support the diagnosis of Sjögren-Larsson syndrome in the patient and expand the genotype spectrum of the gene.","variants":[{"Name":"NM_000382.3(ALDH3A2):c.779del (p.Lys260fs)","Chromosome":"17","Start":"19657842","Stop":"19657842","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":3132788,"rule_based_match":true,"evidence_text":"c.779delA (p.K260Rfs*6)","llm_judgment":"PRESENT","evidence":"c.779delA (p.K260Rfs*6)","abstract_start":1394,"abstract_end":1417}]}
{"pmid":"36454683","title":"Homozygous COQ7 mutation: a new cause of potentially treatable distal hereditary motor neuropathy.","abstract":"Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G>T (p.1Met?) was identified in the COQ7 gene. This gene encodes a protein required for coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood samples and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G>T (p.1Met?) in the COQ7 gene and the effect of coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient's fibroblasts, resulting in a decrease in coenzyme Q10 production and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient's plasma. Normal coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing the COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair the mitochondrial respiratory chain. Seahorse experiments showed that the patient's cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by coenzyme Q10 supplementation of the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients.","variants":[{"Name":"NM_016138.5(COQ7):c.3G>T (p.Met1Ile)","Chromosome":"16","Start":"19067667","Stop":"19067667","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1511532,"rule_based_match":true,"evidence_text":"c.3G>T (p.1Met?)","llm_judgment":"PRESENT","evidence":"c.3G>T (p.1Met?)","abstract_start":238,"abstract_end":254}]}
{"pmid":"23430799","title":"MNGIE Syndrome: Liver Cirrhosis Should Be Ruled Out Prior to Bone Marrow Transplantation.","abstract":"Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive mitochondriopathy caused by loss-of-function mutations in the thymidine phosphorylase gene. The disease leads to premature death and is characterized by gastrointestinal dysmotility and cachexia, external ophthalmoplegia, a sensorimotor neuropathy, and leukoencephalopathy. Bone marrow transplantation (BMT) is the only potentially curative treatment that can achieve a sustained biochemical correction of the metabolic imbalances.We report a 23-year-old male homozygous for the c.866A > C, p.Glu289Ala mutation of the TYMP gene, who presented with fatty liver and cachexia. Laboratory examinations were unremarkable except for increased transaminase activities. Grade II fibrosis and steatosis was found in an initial and a follow-up liver biopsy 4 years later. Myeloablative conditioning and BMT was performed 10 years after initial presentation due to the progressive weight loss and polyneuropathy. Pre-transplant liver staging was normal except for an elevated transient elastography of 31.6 kPa. Severe ascites developed after transplantation and liver function deteriorated progressively to liver failure. Despite engraftment on day +15, the patient died on day +18 from liver failure. Autopsy revealed micronodular liver cirrhosis, and postmortem diagnosis of acute-on-chronic liver failure was done.This case illustrates the difficulties and importance of diagnosing liver cirrhosis in MNGIE. Before BMT, patients must be carefully evaluated by transient elastography, liver biopsy, or assessment of hepatic venous pressure gradient. In patients with liver cirrhosis, further studies should evaluate if liver transplantation may be an alternative to BMT. Considerable amounts of thymidine phosphorylase are expressed in liver tissue which may prevent accumulation of toxic metabolites.","variants":[{"Name":"NM_001953.5(TYMP):c.866A>C (p.Glu289Ala)","Chromosome":"22","Start":"50526638","Stop":"50526638","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":31692,"rule_based_match":true,"evidence_text":"c.866A > C, p.Glu289Ala","llm_judgment":"PRESENT","evidence":"c.866A > C, p.Glu289Ala","abstract_start":564,"abstract_end":587}]}
{"pmid":"28528517","title":"Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6.","abstract":"Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. High microsatellite instability (MSI-H) and loss of MMR protein expression in tumours reflecting a defective MMR are indicators for LS, as well as a positive family history of early onset CRC. MSH2 and MSH6 form a major functional heterodimer, and MSH3 is an alternative binding partner for MSH2. So far, the role of germline MSH3 variants remains unclear, as to our knowledge heterozygous truncating variants are not regarded causative for LS, but were detected in patients with CRC, and recently biallelic MSH3 defects have been identified in two patients with adenomatous polyposis. By gene screening we investigated the role of MSH3 in 11 LS patients with truncating MSH6 germline variants and an unexplained MSH2 protein loss in their corresponding MSI-H tumours. We report the first two LS patients harbouring heterozygous germline variants c.1035del and c.2732T>G in MSH3 coincidentally with truncating variants in MSH6. In the patient with truncating germline variants in MSH3 and MSH6, two additional somatic second hits in both genes abrogate all binding partners for the MSH2 protein which might subsequently be degraded. The clinical relevance of MSH3 germline variants is currently under re-evaluation, and heterozygous MSH3 defects alone do not seem to induce a LS phenotype, but might aggravate the MSH6 phenotype in affected family members.","variants":[{"Name":"NM_002439.5(MSH3):c.1035del (p.Pro346_Leu347insTer)","Chromosome":"5","Start":"80674990","Stop":"80674990","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":795725,"rule_based_match":true,"evidence_text":"c.1035del","llm_judgment":"PRESENT","evidence":"c.1035del","abstract_start":1067,"abstract_end":1076}]}
{"pmid":"35837780","title":"Aromatase deficiency caused by mutation of","abstract":"Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (<i>CYP19A1</i>), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. <i>CYP19A1</i> gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.","variants":[{"Name":"NM_000103.4(CYP19A1):c.1093C>T (p.Arg365Trp)","Chromosome":"15","Start":"51212490","Stop":"51212490","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2671024,"rule_based_match":true,"evidence_text":"c.1093C>T, p.R365W","llm_judgment":"PRESENT","evidence":"c.1093C>T, p.R365W","abstract_start":760,"abstract_end":778}]}
{"pmid":"38358893","title":"Clinical, immunohistochemical, and genetic characterization of splice-altering biallelic DES variants: Therapeutic implications.","abstract":"Pathogenic variants in the DES gene clinically manifest as progressive skeletal muscle weakness, cardiomyopathy with associated severe arrhythmias, and respiratory insufficiency, and are collectively known as desminopathies. While most DES pathogenic variants act via a dominant mechanism, recessively acting variants have also been reported. Currently, there are no effective therapeutic interventions for desminopathies of any type. Here, we report an affected individual with rapidly progressive dilated cardiomyopathy, requiring heart transplantation at age 13 years, in the setting of childhood-onset skeletal muscle weakness. We identified biallelic DES variants (c.640-13 T>A and c.1288+1 G>A) and show aberrant DES gene splicing in the affected individual's muscle. Through the generation of an inducible lentiviral system, we transdifferentiated fibroblast cultures derived from the affected individual into myoblasts and validated this system using RNA sequencing. We tested rationally designed, custom antisense oligonucleotides to screen for splice correction in these transdifferentiated cells and a functional minigene splicing assay. However, rather than correctly redirecting splicing, we found them to induce undesired exon skipping. Our results indicate that, while an individual precision-based molecular therapeutic approach to splice-altering pathogenic variants is promising, careful preclinical testing is imperative for each novel variant to test the feasibility of this type of approach for translation.","variants":[{"Name":"NM_001927.4(DES):c.1288+1G>A","Chromosome":"2","Start":"219423821","Stop":"219423821","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":650939,"rule_based_match":true,"evidence_text":"c.1288+1 G>A","llm_judgment":"PRESENT","evidence":"c.1288+1 G>A","abstract_start":687,"abstract_end":699}]}
{"pmid":"34979989","title":"CUBN gene mutations may cause focal segmental glomerulosclerosis (FSGS) in children.","abstract":"BACKGROUND: Imerslund-Gräsbeck Syndrome (IGS) is mainly caused by CUBN gene biallelic mutations. Proteinuria accompanies IGS specific symptoms in about half of the patients, isolated proteinuria is rarely reported. Here we present 3 patients with isolated proteinuria and focal segmental glomerulosclerosis (FSGS) caused by CUBN gene biallelic pathogenic variants.\nMETHOD: Whole exome sequencing was performed on three children with isolated proteinuria. CUBN gene biallelic pathogenic variants were found and then verified by sanger sequencing. Their clinical, pathological and molecular genetic characteristics were analyzed and correlated accordingly.\nRESULTS: All three children presented with isolated proteinuria, no megaloblastic anemia. Their urine levels of β2 microglobulin were normal or slightly higher. Renal biopsies showed focal segmental glomerulosclerosis with mild glomerular mesangial hypercellularity, partial effacement of foot processes and podocyte microvillation. Two of them were found to carry compound heterozygous mutations and one homozygous mutation of CUBN gene. Totally four CUBN gene biallelic pathogenic variants were identified, including c.9287 T > C (p.L3096P), c.122 + 1G > A, c.7906C > T (p.R2636*), c.10233G > A (p.W3411*). Except for intron splice-site mutation, all other variants are located in highly conserved sites of CUB domain for binding to albumin.\nCONCLUSION: The results demonstrate that CUBN gene mutations may cause isolated proteinuria pathologically presented as FSGS. Our cases extend the spectrum of renal manifestation and genotype of CUBN gene mutations.","variants":[{"Name":"NM_001081.4(CUBN):c.7906C>T (p.Arg2636Ter)","Chromosome":"10","Start":"16906209","Stop":"16906209","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":569558,"rule_based_match":true,"evidence_text":"c.7906C>T (p.R2636*)","llm_judgment":"PRESENT","evidence":"c.7906C > T (p.R2636*)","abstract_start":1215,"abstract_end":1237},{"Name":"NM_001081.4(CUBN):c.10233G>A (p.Trp3411Ter)","Chromosome":"10","Start":"16835143","Stop":"16835143","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1312491,"rule_based_match":true,"evidence_text":"c.10233G>A (p.W3411*)","llm_judgment":"PRESENT","evidence":"c.10233G > A (p.W3411*)","abstract_start":1239,"abstract_end":1262}]}
{"pmid":"15701167","title":"Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia.","abstract":"BACKGROUND: Familial hypercholesterolemia is a human monogenic disease caused by population-specific mutations in the low density lipoprotein (LDL) receptor gene. Despite thirteen different mutations of the LDL receptor gene were reported from Russia prior to 2003, the whole spectrum of disease-causing gene alterations in this country is poorly known and requires further investigation provided by the current study.\nMETHODS: Forty-five patients with clinical diagnosis of FH were tested for the apolipoprotein B (apoB) mutation R3500Q by restriction fragment length analysis. After exclusion of R3500Q mutation high-sensitive fluorescent single-strand conformation polymorphism (SSCP) analysis and automatic DNA sequencing were used to search for mutations in the LDL receptor gene.\nRESULTS: We found twenty one rare sequence variations of the LDL receptor gene. Nineteen were probably pathogenic mutations, and two (P518P, T705I) were considered as neutral ones. Among the mutations likely to be pathogenic, eight were novel (c.670-671insG, C249X, c.936-940del5, c.1291-1331del41, W422X, c.1855-1856insA, D601N, C646S), and eleven (Q12X, IVS3+1G>A, c.651-653del3, E207X, c.925-931del7, C308Y, L380H, c.1302delG, IVS9+1G>A, V776M, V806I) have already been described in other populations. None of the patients had the R3500Q mutation in the apoB gene.\nCONCLUSIONS: Nineteen pathogenic mutations in the LDL receptor gene in 23 probands were identified. Two mutations c.925-931del7 and L380H are shared by St.-Petersburg population with neighbouring Finland and several other mutations with Norway, Sweden or Denmark, i.e. countries from the Baltic Sea region. Only four mutations (c.313+1G>A, c.651-653del3, C308Y and W422X) were recurrent as all those were found in two unrelated families. By this study the number of known mutations in the LDL receptor gene in St.-Petersburg area was increased nearly threefold. Analysis of all 34 low density lipoprotein receptor gene mutations found in St.-Petersburg argues against strong founder effect in Russian familial hypercholesterolemia.","variants":[{"Name":"NM_000527.5(LDLR):c.925_931del (p.Pro309fs)","Chromosome":"19","Start":"11107498","Stop":"11107504","ReferenceAlleleVCF":"AACCCATC","AlternateAlleleVCF":"A","allel_id":18768,"rule_based_match":false,"evidence_text":"c.925-931del7","llm_judgment":"PRESENT","evidence":"c.925-931del7","abstract_start":1175,"abstract_end":1188}]}
{"pmid":"23551881","title":"Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes.","abstract":"Monogenic diabetes due to mutations in the transcription factor genes hepatocyte nuclear factor 1A (HNF1A) and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, HNF1A, and HNF4A. The proband was diagnosed with diabetes at 7 yr of age and treated with insulin for 4 yr. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 yr of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over 2 yr. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 yr of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 yr, respectively. Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.","variants":[{"Name":"NM_000545.8(HNF1A):c.872dup (p.Gly292fs)","Chromosome":"12","Start":"120994314","Stop":"120994315","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":29966,"rule_based_match":true,"evidence_text":"c.872dup","llm_judgment":"PRESENT","evidence":"c.872dup","abstract_start":904,"abstract_end":912}]}
{"pmid":"35145552","title":"Case Report: Biallelic Loss of Function ATM due to Pathogenic Synonymous and Novel Deep Intronic Variant c.1803-270T > G Identified by Genome Sequencing in a Child With Ataxia-Telangiectasia.","abstract":"Ataxia-telangiectasia (AT) is a complex neurodegenerative disease with an increased risk for bone marrow failure and malignancy. AT is caused by biallelic loss of function variants in <i>ATM</i>, which encodes a phosphatidylinositol 3-kinase that responds to DNA damage. Herein, we report a child with progressive ataxia, chorea, and genome instability, highly suggestive of AT. The clinical ataxia gene panel identified a maternal heterozygous synonymous variant (NM_000051.3: c.2250G > A), previously described to result in exon 14 skipping. Subsequently, trio genome sequencing led to the identification of a novel deep intronic variant [NG_009830.1(NM_000051.3): c.1803-270T > G] inherited from the father. Transcript analyses revealed that c.1803-270T > G results in aberrant inclusion of 56 base pairs of intron 11. <i>In silico</i> tests predicted a premature stop codon as a consequence, suggesting non-functional ATM; and DNA repair analyses confirmed functional loss of ATM. Our findings highlight the power of genome sequencing, considering deep intronic variants in undiagnosed rare disease patients.","variants":[{"Name":"NM_000051.4(ATM):c.2250G>A (p.Lys750=)","Chromosome":"11","Start":"108256340","Stop":"108256340","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18083,"rule_based_match":true,"evidence_text":"NM_000051.3: c.2250G > A","llm_judgment":"PRESENT","evidence":"NM_000051.3: c.2250G > A","abstract_start":465,"abstract_end":489},{"Name":"NM_000051.4(ATM):c.1803-270T>G","Chromosome":"11","Start":"108252547","Stop":"108252547","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1860803,"rule_based_match":true,"evidence_text":"c.1803-270T > G","llm_judgment":"PRESENT","evidence":"c.1803-270T > G","abstract_start":667,"abstract_end":682}]}
{"pmid":"30254413","title":"Infant cholestasis patient with a novel missense mutation in the","abstract":"Steroid 5β-reductase [aldo-keto reductase family 1 member D1 (<i>AKR1D1</i>)] is essential for bile acid biosynthesis. Bile acid deficiency caused by genetic defects in <i>AKR1D1</i> leads to life-threatening neonatal hepatitis and cholestasis. There is still limited experience regarding the treatment of this disease. We describe an infant who presented with hyperbilirubinemia and coagulopathy but normal bile acid and γ-glutamyltransferase. Gene analysis was performed using genomic DNA from peripheral lymphocytes from the patient, his parents, and his elder brother. The patient was compound heterozygous for c.919C>T in exon 8 and exhibited a loss of heterozygosity of the <i>AKR1D1</i> gene, which led to an amino acid substitution of arginine by cysteine at amino acid position 307 (p.R307C). Based on these mutations, the patient was confirmed to have primary 5β-reductase deficiency. Ursodeoxycholic acid (UDCA) treatment did not have any effect on the patient. However, when we changed to chenodeoxycholic acid (CDCA) treatment, his symptoms and laboratory tests gradually improved. It is therefore crucial to supplement with an adequate dose of CDCA early to improve clinical symptoms and to normalize laboratory tests.","variants":[{"Name":"NM_005989.4(AKR1D1):c.919C>T (p.Arg307Cys)","Chromosome":"7","Start":"138113753","Stop":"138113753","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3075513,"rule_based_match":true,"evidence_text":"c.919C>T","llm_judgment":"PRESENT","evidence":"c.919C>T","abstract_start":615,"abstract_end":623}]}
{"pmid":"24450158","title":"MFN2 gene analysis in patients with hereditary motor and sensory neuropathy from Bashkortostan Republic","abstract":"Hereditary motor and sensory neuropathy (HMSN) type IIA is caused by mutations in the mitofusin type-2 (MFN2) gene and represents one of the most common axonal forms of HMSN. We determined the spectrum and frequency of MFN2 gene mutations in patients from the Bashkortostan Republic (BR). Four different mutations were revealed in 5 out of 170 unrelated patients, i.e., c.2113G>A (p.Val705Ile) (1.2% among all types of H MSN in the total sample of patients and 2% among patients of Tatar ethnicity). This mutation was described previously; c.775C>T (p.Arg259Cys) (0.6%, in the total sample of patients and 2% among the patients of Tatar ethnicity); c.776G>A (p.Arg259His) (0.6% in the total sample of patients and 1.5% among the patients of Russians ethnicity); and c.2171T>C (p.Leu724Pro) (1.2% in the total sample of patients and 7.4% among the patients of Bashkirs ethnicity). These are new mutations that were not observed among healthy family members and in control samples of healthy subjects. Five identified nucleotide substitutions represent single nucleotide polymorphisms of the gene, including c.892G>A (p.Gly298Arg), c.957C>T (Gly319Gly), and c1039-222t>c, which were described previously, while c.175+28c>t and c.2204+15t>c represent new nucleotide substitutions in the intron regions of the gene.","variants":[{"Name":"NM_014874.4(MFN2):c.776G>A (p.Arg259His)","Chromosome":"1","Start":"11999055","Stop":"11999055","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":556905,"rule_based_match":true,"evidence_text":"c.776G>A (p.Arg259His)","llm_judgment":"PRESENT","evidence":"c.776G>A (p.Arg259His)","abstract_start":649,"abstract_end":671},{"Name":"NM_014874.4(MFN2):c.775C>T (p.Arg259Cys)","Chromosome":"1","Start":"11999054","Stop":"11999054","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":165484,"rule_based_match":true,"evidence_text":"c.775C>T (p.Arg259Cys)","llm_judgment":"PRESENT","evidence":"c.775C>T (p.Arg259Cys)","abstract_start":540,"abstract_end":562},{"Name":"NM_014874.4(MFN2):c.2171T>C (p.Leu724Pro)","Chromosome":"1","Start":"12009693","Stop":"12009693","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":558098,"rule_based_match":true,"evidence_text":"c.2171T>C (p.Leu724Pro)","llm_judgment":"PRESENT","evidence":"c.2171T>C (p.Leu724Pro)","abstract_start":766,"abstract_end":789},{"Name":"NM_014874.4(MFN2):c.957C>T (p.Gly319=)","Chromosome":"1","Start":"12001541","Stop":"12001541","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":141915,"rule_based_match":true,"evidence_text":"c.957C>T (Gly319Gly)","llm_judgment":"PRESENT","evidence":"c.957C>T (Gly319Gly)","abstract_start":1130,"abstract_end":1150}]}
{"pmid":"30978478","title":"Molecular diagnosis of asparagine synthetase (ASNS) deficiency in two Indian families and literature review of 29 ASNS deficient cases.","abstract":"In the current study, we report three cases of Asparagine Synthetase (ASNS) Deficiency from two consanguineous families. Family 1 had two early neonatal deaths due to a novel mutation in the ASNS gene c.788C > T (p.S263F) and both the children presented with microcephaly and one of them had severe intracranial haemorrhage. The proband from the second family was homozygous for c.146G > A (p.R49Q) and manifested myoclonic seizures, developmental delay, coarse hair and diffuse cortical atrophy. Molecular docking studies of both the mutations revealed alteration in the ligand binding site. Till date, 26 mutations were reported in ASNS gene in 29 affected children indicating high degree of genetic heterogeneity and high mortality. Although asparagine depletion is not of diagnostic utility, multiple linear regression model suggested that asparagine levels vary to the extent of 20.6% based on glutamine and aspartate levels and ASNS deficiency results in depletion of asparagine synthesis. ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy.","variants":[{"Name":"NM_001673.5(ASNS):c.146G>A (p.Arg49Gln)","Chromosome":"7","Start":"97869011","Stop":"97869011","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":369679,"rule_based_match":true,"evidence_text":"c.146G > A (p.R49Q)","llm_judgment":"PRESENT","evidence":"c.146G > A (p.R49Q)","abstract_start":379,"abstract_end":398}]}
{"pmid":"12938095","title":"Molecular analysis in Fabry disease in Spain: fifteen novel GLA mutations and identification of a homozygous female.","abstract":"Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A gene (GLA). Here we report molecular studies in 22 unrelated Spanish patients with Fabry disease ( 20 males and two females). Fifteen novel mutations were identified. In addition 7 previously described mutations and two previously reported polymorphisms were detected. The 15 novel mutations comprise: eight missense E48K (c.142G>A), W81S (c.242G>C), D170H (c.508G>C), W226C (c.678G>T), Q279R (c.836A>G), C382Y (c.1145G>A), I407K (c.1220T>A), L414S (c.1241T>C); one nonsense W95X (c.284G>A); one insertion Y216fsX15 (c.646_647insT); two small deletions G346fsX1 (c.1037delG), K426fsX23 (c.1277_1278delAA); one gross deletion comprising exons 5, 6, 7; one complex mutation (insertion and deletion) A368fsX24 (c.1102delGinsTTATAC), and one splice-site mutation IVS4+1G>A (c.639+1G>A). One of the females was found homozygous for Q279R mutation and she presented with the classic phenotype since the age of 8 years, this case extending into women the severe phenotype observed in classically affected males. Mutation analysis provided precise identification for 30 heterozygotes among female relatives and detection of a de novo mutation. The molecular studies on Spanish Fabry patients here reported further contribute to the identification of new mutations in this disease, and allow reliable detection of heterozygotes which has consequences for genetic counselling and for treatment.","variants":[{"Name":"NM_000169.3(GLA):c.242G>C (p.Trp81Ser)","Chromosome":"X","Start":"101403938","Stop":"101403938","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1015385,"rule_based_match":true,"evidence_text":"W81S (c.242G>C)","llm_judgment":"PRESENT","evidence":"W81S (c.242G>C)","abstract_start":459,"abstract_end":474}]}
{"pmid":"34627237","title":"Retinitis pigmentosa and molar tooth sign caused by novel AHI1 compound heterozygote pathogenic variants.","abstract":"BACKGROUND: Joubert syndrome (JS) is a group of rare congenital disorders characterized by cerebellar vermis dysplasia, developmental delay, and retina dysfunctions. Herein, we reported a Chinese patient carrying a new variant in the AHI1 gene with mild JS, and the 3D structure of the affected Jouberin protein was also predicted.\nCASE PRESENTATION: The patient was a 31-year-old male, who presented difficulty at finding toys at the age of 2 years, night blindness from age of 5 years, intention tremor and walking imbalance from 29 years of age. Tubular visual field and retina pigmentation were observed on ophthalmology examinations, as well as molar tooth sign on brain magnetic resonance imaging (MRI). Whole exome sequence revealed two compound heterozygous variants at c.2105C>T (p.T702M) and c.1330A>T (p.I444F) in AHI1 gene. The latter one was a novel mutation. The 3D protein structure was predicted using I-TASSER and PyMOL, showing structural changes from functional β-sheet and α-helix to non-functional D-loop, respectively.\nCONCLUSIONS: Mild JS due to novel variants at T702M and I444F in the AHI1 gene was reported. The 3D-structural changes in Jouberin protein might underlie the pathogenesis of JS.","variants":[{"Name":"NM_001134831.2(AHI1):c.2105C>T (p.Thr702Met)","Chromosome":"6","Start":"135433188","Stop":"135433188","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":565442,"rule_based_match":true,"evidence_text":"c.2105C>T (p.T702M)","llm_judgment":"PRESENT","evidence":"c.2105C>T (p.T702M)","abstract_start":778,"abstract_end":797}]}
{"pmid":"23636107","title":"A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT.","abstract":"PURPOSE: To delineate the molecular basis for a novel autosomal recessive syndrome, characterised by distinct facial features, intellectual disability, hypotonia and seizures, in combination with abnormal skeletal, endocrine, and ophthalmologic findings.\nMETHODS: We examined four patients from a consanguineous kindred with a strikingly similar phenotype, by using whole exome sequencing (WES). Functional validation of the initial results were performed by flow cytometry determining surface expression of glycosylphosphatidylinositol (GPI) and GPI anchored proteins and, in addition, by in vivo assays on zebrafish embryos.\nRESULTS: The results from WES identified a homozygous mutation, c.547A>C (p.Thr183Pro), in PIGT; Sanger sequencing of additional family members confirmed segregation with the disease. PIGT encodes phosphatidylinositol-glycan biosynthesis class T (PIG-T) protein, which is a subunit of the transamidase complex that catalyses the attachment of proteins to GPI. By flow cytometry, we found that granulocytes from the patients had reduced levels of the GPI anchored protein CD16b, supporting pathogenicity of the mutation. Further functional in vivo validation via morpholino mediated knockdown of the PIGT ortholog in zebrafish (pigt) showed that, unlike human wild-type PIGT mRNA, the p.Thr183Pro encoding mRNA failed to rescue gastrulation defects induced by the suppression of pigt.\nCONCLUSIONS: We identified mutations in PIGT as the cause of a novel autosomal recessive intellectual disability syndrome. Our results demonstrate a new pathogenic mechanism in the GPI anchor pathway and expand the clinical spectrum of disorders belonging to the group of GPI anchor deficiencies.","variants":[{"Name":"NM_015937.6(PIGT):c.547A>C (p.Thr183Pro)","Chromosome":"20","Start":"45419348","Stop":"45419348","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":75603,"rule_based_match":true,"evidence_text":"c.547A>C (p.Thr183Pro)","llm_judgment":"PRESENT","evidence":"c.547A>C (p.Thr183Pro)","abstract_start":691,"abstract_end":713}]}
{"pmid":"15725586","title":"Characterization of MTM1 mutations in 31 Japanese families with myotubular myopathy, including a patient carrying 240 kb deletion in Xq28 without male hypogenitalism.","abstract":"X-linked myotubular myopathy is a congenital muscle disorder due to MTM1 mutation, and is characterized clinically by generalized muscle weakness and hypotonia at birth usually resulting in early death. We newly identified 26 unrelated Japanese patients with MTM1 mutations by genomic DNA and transcript analysis, including 12 novel mutations. Among 31 patients, including our previously reported five patients, the c.1261-10A>G splice site mutation was the most frequent mutation. Three mutations, one missense and two splice site, were associated with milder phenotype. Of particular interest, one boy had a 240 kb deletion in Xq28 encompassing CXorf6 (formerly F18), MTM1 and MTMR1 but was not accompanied by hypogenitalism. CXorf6, which have been implicated in male sexual development, was not entirely deleted in this boy, resulting in the fusion with the MTMR1 gene. A chimeric fusion transcript was detected in patient's muscle by RT-PCR, suggesting this fusion gene product avoids the phenotype. This deletion led us to refine the critical region of CXorf6 for the development of male genitalia.","variants":[{"Name":"NM_000252.3(MTM1):c.1261-10A>G","Chromosome":"X","Start":"150659654","Stop":"150659654","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":26097,"rule_based_match":true,"evidence_text":"c.1261-10A>G","llm_judgment":"PRESENT","evidence":"c.1261-10A>G","abstract_start":416,"abstract_end":428}]}
{"pmid":"26915939","title":"Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient?","abstract":"BACKGROUND: Germline pathogenic mutations in cancer susceptibility genes result in inherited cancer syndromes. In the Afrikaner population of South Africa (SA), three founder mutations in the BRCA genes that lead to hereditary breast and ovarian cancer syndrome (HBOCS) have been identified.\nOBJECTIVES: To investigate the uptake and type of molecular testing performed on patients for HBOCS, to determine the prevalence of the three Afrikaner founder BRCA mutations as well as non-founder BRCA mutations in the study population, and to analyse the utility of two mutation prediction models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and Manchester scoring method) in assisting with the decision for the most cost-effective testing option.\nMETHODS: A retrospective file review was performed on counsellees of self-reported Afrikaner ancestry from Johannesburg, SA (2001 - 2014), with a personal or family history of breast and/or ovarian cancer. Demographic and family history information was recorded and Manchester and BOADICEA scores were calculated for each patient.\nRESULTS: Of 86 unrelated counsellees whose files were reviewed, 54 (62.8%) underwent BRCA genetic testing; 18 (33.3%) tested positive for a mutation, and 14 of these (77.8%) for an Afrikaner founder mutation. Twelve counsellees had the BRCA2 c.7934delG mutation. Four non-founder mutations were identified. BOADICEA scores were significantly higher in counsellees who tested positive for a mutation than in those who tested negative.\nCONCLUSIONS: Founder mutation testing should be performed as a first-line option. BOADICEA is very useful in identifying counsellees at high risk for a BRCA mutation and also assists with the decision to pursue further testing following a negative founder mutation result. These findings assist in guiding an informed genetic counselling service for at-risk individuals with an Afrikaner background.","variants":[{"Name":"NM_000059.4(BRCA2):c.7934del (p.Arg2645fs)","Chromosome":"13","Start":"32362651","Stop":"32362651","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":67108,"rule_based_match":true,"evidence_text":"BRCA2 c.7934delG mutation","llm_judgment":"PRESENT","evidence":"BRCA2 c.7934delG mutation","abstract_start":1358,"abstract_end":1383}]}
{"pmid":"28972032","title":"Diverse phenotype of hypokalaemic periodic paralysis within a family.","abstract":"Hypokalaemic periodic paralysis typically presents with intermittent mild-to-moderate weakness lasting hours to days. We report a case with an uncommon phenotype of late-onset myopathy without episodic paralytic attacks. Initial work-up including muscle biopsy was inconclusive. A subsequent review of the right deltoid biopsy, long exercise testing and repeated family history was helpful, followed by appropriate genetic testing. We identified a heterozygous pathogenic mutation in calcium ion channel (<i>CACNA1S</i>:c.1583G>A p.Arg528His) causing hypokalaemic periodic paralysis. Myopathy can present without episodic paralysis and the frequency of paralytic episodes does not correlate well with the development and progression of a fixed myopathy. Our report also highlights the intrafamilial phenotypic variation of hypokalaemic periodic paralysis secondary to a <i>CACNA1S</i> gene mutation.","variants":[{"Name":"NM_000069.3(CACNA1S):c.1583G>A (p.Arg528His)","Chromosome":"1","Start":"201077915","Stop":"201077915","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32664,"rule_based_match":true,"evidence_text":"CACNA1S:c.1583G>A p.Arg528His","llm_judgment":"PRESENT","evidence":"p.Arg528His","abstract_start":530,"abstract_end":541}]}
{"pmid":"15580560","title":"The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations.","abstract":"Limb girdle muscular dystrophy (LGMD) is common in the Hutterite population of North America. We previously identified a mutation in the TRIM32 gene in chromosome region 9q32, causing LGMD2H in approximately two-thirds of the 60 Hutterite LGMD patients studied to date. A genomewide scan was undertaken in five families who did not show linkage to the LGMD2H locus on chromosome 9. A second LGMD locus, LGMD2I, was identified in chromosome region 19q13.3, and the causative mutation was identified as c.826C>A (L276I), a missense mutation in the FKRP gene. A comparison of the clinical characteristics of the two LGMD patient groups in this population reveals some differences. LGMD2I patients generally have an earlier age at diagnosis, a more severe course, and higher serum creatine kinase (CK) levels. In addition, some of these patients show calf hypertrophy, cardiac symptoms, and severe reactions to general anesthesia. None of these features are present among LGMD2H patients. A single common haplotype surrounding the FKRP gene was identified in the Hutterite LGMD2I patients. An identical core haplotype was also identified in 19 other non-Hutterite LGMD2I patients from Europe, Canada, and Brazil. The occurrence of this mutation on a common core haplotype suggests that L276I is a founder mutation that is dispersed among populations of European origin.","variants":[{"Name":"NM_024301.5(FKRP):c.826C>A (p.Leu276Ile)","Chromosome":"19","Start":"46756276","Stop":"46756276","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":19260,"rule_based_match":true,"evidence_text":"c.826C>A (L276I)","llm_judgment":"PRESENT","evidence":"c.826C>A (L276I)","abstract_start":501,"abstract_end":517}]}
{"pmid":"22456618","title":"The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression.","abstract":"CONTEXT: Anecdotal evidence suggests a high incidence in Trentino, Italy, of head and neck paragangliomas (HNPGL), a rare autosomal dominant disease called paraganglioma type 1 syndrome and caused by germ-line mutations of the SDHD gene.\nOBJECTIVE: The aim of this study was to investigate the origin, spread, and clinical expression of the disease in this geographic region.\nDESIGN, SETTING, AND PARTICIPANTS: Trentino natives with HNPGL were recruited for establishing clinical expression of the disease, presence of a founder effect, and age of common ancestor. A large sample of the local population was recruited for determination of mutation prevalence and spread.\nMAIN OUTCOME MEASURES: SDHD genetic testing was offered to first-degree relatives, and clinical surveillance was offered to at-risk carriers. The hypothesis of a founder effect was explored by haplotype analysis, and time to the most recent common ancestor was estimated by decay of haplotype sharing over time.\nRESULTS: A total of 287 of the 540 recruited individuals from 95 kindreds carried the SDHD c.341A>G p.Tyr114Cys mutation. The prevalent phenotype was bilateral or multiple HNPGL, with low prevalence of pheochromocytoma and malignant forms. Penetrance was high. A common ancestor was dated between the 14th and 15th century, with the mutation spreading from the Mocheni Valley, a geographic, cultural and, presumably, a genetic isolate to 1.5% of the region's population.\nCONCLUSIONS: A combination of particular demographic, geographical, and historical conditions has resulted in the oldest and largest SDHD founder effect so far characterized and has transformed a rare disease into an endemic disease with major public health implications.","variants":[{"Name":"NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys)","Chromosome":"11","Start":"112094831","Stop":"112094831","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":21939,"rule_based_match":true,"evidence_text":"SDHD c.341A>G p.Tyr114Cys","llm_judgment":"PRESENT","evidence":"SDHD c.341A>G p.Tyr114Cys","abstract_start":1069,"abstract_end":1094}]}
{"pmid":"18426830","title":"Autoimmune polyendocrine syndrome type I in Slovakia: relevance of screening patients with autoimmune Addison's disease.","abstract":"BACKGROUND: Autoimmune polyendocrine syndrome type I (APS I) is a monogenic disease affecting endocrine glands and other organs due to mutations of the autoimmune regulator (AIRE) gene. There is a wide variability in clinical phenotypes in patients with APS I, which makes the diagnosis a challenge.\nOBJECTIVE: To screen for APS I among Slovakian patients with sporadic Addison's disease and clinical features that raised the suspicion of APS I.\nMETHODS: All 14 exons and exon-intron boundaries of the AIRE gene were sequenced. In addition, autoantibodies specific for Addison's disease and polyendocrine syndromes were assayed.\nRESULTS: Using clinical criteria we identified four patients with APS I in three families. Two patients had a novel missense mutation in exon 2 (c.274C>T, p.R92W) and either the Finnish major mutation (c.769C>T) or the common 13 bp deletion (c.967-979del13bp). APS I was diagnosed in a brother of the latter after his death due to an adrenal crisis. A fourth patient had primary adrenal failure and hypoparathyroidism without AIRE mutations or APS-I specific autoantibodies.\nCONCLUSIONS: Four patients with APS I were found in a Slovakian cohort of Addison patients, although the lack of detectable AIRE mutations and APS I-specific autoantibodies raises uncertainty regarding the pathogenesis in one of the patients. This study demonstrates the merits of screening patients with phenotypic features or autoantibody findings that could indicate APS I, even in adult patients. It is necessary to identify APS I patients in order to provide appropriate treatment and follow-up of the various components of APS I.","variants":[{"Name":"NM_000383.4(AIRE):c.967_979del (p.Leu323fs)","Chromosome":"21","Start":"44291180","Stop":"44291192","ReferenceAlleleVCF":"TGCCTGTCCCCTCC","AlternateAlleleVCF":"T","allel_id":18348,"rule_based_match":false,"evidence_text":"c.967-979del13bp","llm_judgment":"PRESENT","evidence":"c.967-979del13bp","abstract_start":871,"abstract_end":887},{"Name":"NM_000383.4(AIRE):c.274C>T (p.Arg92Trp)","Chromosome":"21","Start":"44286698","Stop":"44286698","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":378471,"rule_based_match":true,"evidence_text":"c.274C>T","llm_judgment":"PRESENT","evidence":"c.274C>T","abstract_start":774,"abstract_end":782}]}
{"pmid":"23878505","title":"Novel mutations in RPE65 identified in consanguineous Pakistani families with retinal dystrophy.","abstract":"PURPOSE: To identify pathogenic mutations responsible for retinal dystrophy in three consanguineous Pakistani families.\nMETHODS: A thorough ophthalmic examination including fundus examination and electroretinography was performed, and blood samples were collected from all participating members. Genomic DNA was extracted, and genome-wide linkage and/or exclusion analyses were completed with fluorescently labeled short tandem repeat microsatellite markers. Two-point Lod scores were calculated, and coding exons along with exon-intron boundaries of RPE65 gene were sequenced, bidirectionally.\nRESULTS: Ophthalmic examinations of the patients affected in all three families suggested retinal dystrophy with an early, most probably congenital, onset. Genome-wide linkage and/or exclusion analyses localized the critical interval in all three families to chromosome 1p31 harboring RPE65. Bidirectional sequencing of RPE65 identified a splice acceptor site variation in intron 2: c.95-1G>A, a single base substitution in exon 3: c.179T>C, and a single base deletion in exon 5: c.361delT in the three families, respectively. All three variations segregated with the disease phenotype in their respective families and were absent from ethnically matched control chromosomes.\nCONCLUSIONS: These results strongly suggest that causal mutations in RPE65 are responsible for retinal dystrophy in the affected individuals of these consanguineous Pakistani families.","variants":[{"Name":"NM_000329.3(RPE65):c.361del (p.Ser121fs)","Chromosome":"1","Start":"68444665","Stop":"68444665","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1366928,"rule_based_match":true,"evidence_text":"c.361delT","llm_judgment":"PRESENT","evidence":"c.361delT","abstract_start":1075,"abstract_end":1084},{"Name":"NM_000329.3(RPE65):c.179T>C (p.Leu60Pro)","Chromosome":"1","Start":"68446776","Stop":"68446776","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3762504,"rule_based_match":true,"evidence_text":"c.179T>C","llm_judgment":"PRESENT","evidence":"c.179T>C","abstract_start":1027,"abstract_end":1035}]}
{"pmid":"32425388","title":"Molecular Characterization of G6PD Deficiency: Report of Three Novel G6PD Variants.","abstract":"G6PD deficiency is a monogenic, X-linked genetic defect with a worldwide prevalence of around 400 million people and an overall prevalence of 8.5% in India. Hemolytic anemia is encountered in only a small proportion of patients with G6PD variants and is usually triggered by some exogenous agent. Although G6PD deficiency was reported in India more than 50 years ago, there are very few studies on molecular characterization and phenotypic correlation in G6PD deficient patients. We aimed to study the epidemiology and correlate the phenotypic expression with molecular genotypes in symptomatic G6PD deficient patients. All symptomatic hemolytic anaemia patients with a possible etiology of G6PD deficiency based on the clinical, hematological and biochemical parameters and reduced G6PD enzyme levels were included in this study. Molecular analysis of the G6PD gene was done by direct Sanger sequencing. From a total of 38 patients with hemolytic anemia suspected for G6PD deficiency, 24 patients had reduced G6PD enzyme levels and were included for the molecular analysis and mutations in the <i>G6PD</i> gene were identified in 21 of them (83.3%). The different mutations identified in our study include 6 patients with c.131C > G (G6PD Orissa), 3 patients with c.563C > T (G6PD Mediterranean), two patients with c.825G > T (G6PD Bangkok), one patient each with c.208T > C (G6PD Namouru), c.487G > A (G6PD Mahidol), c.949G > A (G6PD Kerala-Kalyan), c.100 G > A (G6PD Chatham), c.1178C > G (G6PD Nashville), c.1361 G > A (G6PD Andalus) and 4 patients with novel mutations (2 patients with c.1186C > T and 1 patient each with c.1288-2A > T and c.1372C > T. No disease causing genetic variants were identified in the other three cases. Co-inheritance of other red cell and hemoglobin disorders can modify the clinical phenotype of G6PD patients and the diagnostic accuracy can be improved by molecular characterization of the variant.","variants":[{"Name":"NM_001360016.2(G6PD):c.1288-2A>T","Chromosome":"X","Start":"154532464","Stop":"154532464","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1780197,"rule_based_match":true,"evidence_text":"c.1288-2A>T","llm_judgment":"PRESENT","evidence":"c.1288-2A > T","abstract_start":1627,"abstract_end":1640},{"Name":"NM_001360016.2(G6PD):c.1372C>T (p.Leu458Phe)","Chromosome":"X","Start":"154532273","Stop":"154532273","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1780146,"rule_based_match":true,"evidence_text":"c.1372C>T","llm_judgment":"PRESENT","evidence":"c.1372C > T","abstract_start":1645,"abstract_end":1656}]}
{"pmid":"28449119","title":"Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.","abstract":"CblX (MIM309541) is an X-linked recessive disorder characterized by defects in cobalamin (vitamin B12) metabolism and other developmental defects. Mutations in HCFC1, a transcriptional co-regulator which interacts with multiple transcription factors, have been associated with cblX. HCFC1 regulates cobalamin metabolism via the regulation of MMACHC expression through its interaction with THAP11, a THAP domain-containing transcription factor. The HCFC1/THAP11 complex potentially regulates genes involved in diverse cellular functions including cell cycle, proliferation, and transcription. Thus, it is likely that mutation of THAP11 also results in biochemical and other phenotypes similar to those observed in patients with cblX. We report a patient who presented with clinical and biochemical phenotypic features that overlap cblX, but who does not have any mutations in either MMACHC or HCFC1. We sequenced THAP11 by Sanger sequencing and discovered a potentially pathogenic, homozygous variant, c.240C > G (p.Phe80Leu). Functional analysis in the developing zebrafish embryo demonstrated that both THAP11 and HCFC1 regulate the proliferation and differentiation of neural precursors, suggesting important roles in normal brain development. The loss of THAP11 in zebrafish embryos results in craniofacial abnormalities including the complete loss of Meckel's cartilage, the ceratohyal, and all of the ceratobranchial cartilages. These data are consistent with our previous work that demonstrated a role for HCFC1 in vertebrate craniofacial development. High throughput RNA-sequencing analysis reveals several overlapping gene targets of HCFC1 and THAP11. Thus, both HCFC1 and THAP11 play important roles in the regulation of cobalamin metabolism as well as other pathways involved in early vertebrate development.","variants":[{"Name":"NM_020457.3(THAP11):c.240C>G (p.Phe80Leu)","Chromosome":"16","Start":"67842794","Stop":"67842794","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":380161,"rule_based_match":true,"evidence_text":"c.240C > G (p.Phe80Leu)","llm_judgment":"PRESENT","evidence":"c.240C > G (p.Phe80Leu)","abstract_start":1001,"abstract_end":1024}]}
{"pmid":"15241802","title":"Characterization of three myotonia-associated mutations of the CLCN1 chloride channel gene via heterologous expression.","abstract":"Two novel mutations of the human CLCN1 chloride channel gene, c.592C>G (p.L198V) and c.2255A>G (p.K752R), are described, occurring coincidentally in the one myotonic patient. These individual mutations and a construct with both mutations in the one cDNA were transcribed and expressed in Xenopus oocytes where channel gating parameters were extracted from chloride currents recorded under voltage clamp. We found that the p.L198V mutation has its major effects on the common (or slow) gate of the chloride channel, as do other dominant ClC-1 mutations, and may therefore be causative of the patient's symptoms (when co-expressed with wild-type human ClC-1, the p.L198V mutation exerts a dominant negative effect on common gating) but the p.K752R mutation appears to be innocuous and may be a benign polymorphism. A third mutant, the recently described c.2795C>T (p.P932L), was expressed in HEK 293 cells. Despite the severity of the disease associated with this mutation, chloride currents in cells expressing p.P932L were not significantly different from those of cells expressing wild-type ClC-1.","variants":[{"Name":"NM_000083.3(CLCN1):c.2255A>G (p.Lys752Arg)","Chromosome":"7","Start":"143346222","Stop":"143346222","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1401376,"rule_based_match":true,"evidence_text":"c.2255A>G (p.K752R)","llm_judgment":"PRESENT","evidence":"c.2255A>G (p.K752R)","abstract_start":85,"abstract_end":104},{"Name":"NM_000083.3(CLCN1):c.592C>G (p.Leu198Val)","Chromosome":"7","Start":"143321744","Stop":"143321744","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":33898,"rule_based_match":true,"evidence_text":"c.592C>G (p.L198V)","llm_judgment":"PRESENT","evidence":"c.592C>G (p.L198V)","abstract_start":62,"abstract_end":80},{"Name":"NM_000083.3(CLCN1):c.2795C>T (p.Pro932Leu)","Chromosome":"7","Start":"143351793","Stop":"143351793","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32572,"rule_based_match":true,"evidence_text":"c.2795C>T (p.P932L)","llm_judgment":"PRESENT","evidence":"c.2795C>T (p.P932L)","abstract_start":852,"abstract_end":871}]}
{"pmid":"25527630","title":"Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family.","abstract":"BACKGROUND: Intellectual disability (ID) is a highly heterogeneous condition affecting 2% of the population worldwide. In a field study conducted in a highly inbred area of Northeastern Brazil, we investigated a consanguineous family in which seven adults presented syndromic ID.\nMETHODS: Genome-Wide Human SNP Array 6.0 (Affymetrix) microarray was used to determine regions of homozygosity-by-descent and whole exome sequencing (WES) was performed in one affected individual using Extended Nextera Rapid-Capture Exome and Illumina HiSeq2500.\nRESULTS: We found two regions with an logarithm of the odds (LOD) score of 3.234: a region spanning 4.0 Mb in 19q13.32-q13.33 and a pericentromeric 20 Mb area in chromosome 2 (2p12-q11.2). WES disclosed in the critical region of chromosome 19 a homozygous variant (c.418C>T, p.Arg140Trp) in Mediator complex subunit 25 (MED25), predicted as deleterious by PolyPhen-2, Provean, Mutation Taster and Sorting Intolerant From Tolerant (SIFT). MED25 is a component of the Mediator complex, involved in regulation of transcription of nearly all RNA polymerase II-dependent genes. Deleterious mutations in MED12, MED17 and MED23 have already been associated with ID.\nCONCLUSIONS: These findings demonstrate that the combination of field investigation of families in highly inbred regions with modern technologies is an effective way for identifying new genes associated with ID.","variants":[{"Name":"NM_030973.4(MED25):c.418C>T (p.Arg140Trp)","Chromosome":"19","Start":"49828983","Stop":"49828983","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":181570,"rule_based_match":true,"evidence_text":"c.418C>T, p.Arg140Trp","llm_judgment":"PRESENT","evidence":"c.418C>T, p.Arg140Trp","abstract_start":808,"abstract_end":829}]}
{"pmid":"23278966","title":"cDNA analysis of the BRCA1 unclassified variant c.5194-12G>A.","abstract":"","variants":[{"Name":"NM_007294.4(BRCA1):c.5194-12G>A","Chromosome":"17","Start":"43057147","Stop":"43057147","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70118,"rule_based_match":true,"evidence_text":"c.5194-12G>A","llm_judgment":"PRESENT","evidence":"c.5194-12G>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"32800039","title":"Dyspnea and ventilator dependence after birth in a full-term female infant","abstract":"A female infant, aged 43 days, had shortness of breath, cyanosis, groan, and dyspnea since birth. Physical examination showed cyanosis of lips and three-concave sign, and multiple lung imaging examinations showed diffuse ground-glass opacities in both lungs. The girl was given anti-infective therapy and continuous mechanical ventilation but there were no significant improvements in symptoms. Gene testing confirmed a compound heterozygous mutation, c.1890C>A(p.Tyr630Ter)+c.3208G>A(p.Ala1070Thr), in the ABCA3 gene, with the former from her father and the latter from her mother. Pathological examination of the lungs indicated pulmonary interstitial disease. The girl was diagnosed with infantile diffuse pulmonary interstitial disease caused by mutations in the ABCA3 gene. When full-term neonates experience shortness of breath and dyspnea after birth, pulmonary imaging suggests diffuse ground-glass changes, and conventional treatment is not effective (ventilator-dependent), congenital pulmonary surfactant metabolism defects needs to be considered. Gene testing, which can provide a basis for early intervention, prognostic evaluation, and genetic counseling, should be performed as early as possible.","variants":[{"Name":"NM_001089.3(ABCA3):c.3208G>A (p.Ala1070Thr)","Chromosome":"16","Start":"2286764","Stop":"2286764","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2895000,"rule_based_match":true,"evidence_text":"c.3208G>A(p.Ala1070Thr)","llm_judgment":"PRESENT","evidence":"c.3208G>A(p.Ala1070Thr)","abstract_start":475,"abstract_end":498},{"Name":"NM_001089.3(ABCA3):c.1890C>A (p.Tyr630Ter)","Chromosome":"16","Start":"2298392","Stop":"2298392","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2944064,"rule_based_match":true,"evidence_text":"c.1890C>A(p.Tyr630Ter)","llm_judgment":"PRESENT","evidence":"c.1890C>A(p.Tyr630Ter)","abstract_start":452,"abstract_end":474}]}
{"pmid":"29482514","title":"Expansion of phenotypic spectrum of MYO15A pathogenic variants to include postlingual onset of progressive partial deafness.","abstract":"BACKGROUND: MYO15A variants, except those in the N-terminal domain, have been shown to be associated with congenital or pre-lingual severe-to-profound hearing loss (DFNB3), which ultimately requires cochlear implantation in early childhood. Recently, such variants have also been shown to possibly cause moderate-to-severe hearing loss. Herein, we also demonstrate that some MYO15A mutant alleles can cause postlingual onset of progressive partial deafness.\nMETHODS: Two multiplex Korean families (SB246 and SB224), manifesting postlingual, progressive, partial deafness in an autosomal recessive fashion, were recruited. Molecular genetics testing was performed in two different pipelines, in a parallel fashion, for the SB246 family: targeted exome sequencing (TES) of 129 known deafness genes from the proband and whole exome sequencing (WES) of all affected subjects. Only the former pipeline was performed for the SB224 family. Rigorous bioinformatics analyses encompassing structural variations were executed to investigate any causative variants.\nRESULTS: In the SB246 family, two different molecular diagnostic pipelines provided exactly the same candidate variants: c.5504G > A (p.R1835H) in the motor domain and c.10245_10247delCTC (p.S3417del) in the FERM domain of MYO15A. In the SB224 family, c.9790C > T (p.Q3264X) and c.10263C > G (p.I3421M) in the FERM domain were detected as candidate variants.\nCONCLUSIONS: Some recessive MYO15A variants can cause postlingual onset of progressive partial deafness. The phenotypic spectrum of DFNB3 should be extended to include such partial deafness. The mechanism for a milder phenotype could be due to the milder pathogenic potential from hypomorphic alleles of MYO15A or the presence of modifier genes. This merits further investigation.","variants":[{"Name":"NM_016239.4(MYO15A):c.10263C>G (p.Ile3421Met)","Chromosome":"17","Start":"18172203","Stop":"18172203","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1293440,"rule_based_match":true,"evidence_text":"c.10263C > G (p.I3421M)","llm_judgment":"PRESENT","evidence":"c.10263C > G (p.I3421M)","abstract_start":1333,"abstract_end":1356},{"Name":"NM_016239.4(MYO15A):c.5504G>A (p.Arg1835His)","Chromosome":"17","Start":"18141116","Stop":"18141116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2896844,"rule_based_match":true,"evidence_text":"c.5504G > A (p.R1835H)","llm_judgment":"PRESENT","evidence":"c.5504G > A (p.R1835H)","abstract_start":1175,"abstract_end":1197},{"Name":"NM_016239.4(MYO15A):c.10247CCT[1] (p.Ser3417del)","Chromosome":"17","Start":"18172185","Stop":"18172187","ReferenceAlleleVCF":"GCTC","AlternateAlleleVCF":"G","allel_id":857691,"rule_based_match":false,"evidence_text":"c.10245_10247delCTC (p.S3417del)","llm_judgment":"PRESENT","evidence":"c.10245_10247delCTC (p.S3417del)","abstract_start":1222,"abstract_end":1254}]}
{"pmid":"25678555","title":"Biallelic mutations in CAD, impair de novo pyrimidine biosynthesis and decrease glycosylation precursors.","abstract":"In mitochondria, carbamoyl-phosphate synthetase 1 activity produces carbamoyl phosphate for urea synthesis, and deficiency results in hyperammonemia. Cytoplasmic carbamoyl-phosphate synthetase 2, however, is part of a tri-functional enzyme encoded by CAD; no human disease has been attributed to this gene. The tri-functional enzyme contains carbamoyl-phosphate synthetase 2 (CPS2), aspartate transcarbamylase (ATCase) and dihydroorotase (DHOase) activities, which comprise the first three of six reactions required for de novo pyrimidine biosynthesis. Here we characterize an individual who is compound heterozygous for mutations in different domains of CAD. One mutation, c.1843-1G>A, results in an in-frame deletion of exon 13. The other, c.6071G>A, causes a missense mutation (p.Arg2024Gln) in a highly conserved residue that is essential for carbamoyl-phosphate binding. Metabolic flux studies showed impaired aspartate incorporation into RNA and DNA through the de novo synthesis pathway. In addition, CTP, UTP and nearly all UDP-activated sugars that serve as donors for glycosylation were decreased. Uridine supplementation rescued these abnormalities, suggesting a potential therapy for this new glycosylation disorder.","variants":[{"Name":"NM_004341.5(CAD):c.1843-1G>A","Chromosome":"2","Start":"27226130","Stop":"27226130","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":199876,"rule_based_match":true,"evidence_text":"c.1843-1G>A","llm_judgment":"PRESENT","evidence":"c.1843-1G>A","abstract_start":674,"abstract_end":685},{"Name":"NM_004341.5(CAD):c.6071G>A (p.Arg2024Gln)","Chromosome":"2","Start":"27242098","Stop":"27242098","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":199877,"rule_based_match":true,"evidence_text":"c.6071G>A (p.Arg2024Gln)","llm_judgment":"PRESENT","evidence":"p.Arg2024Gln","abstract_start":781,"abstract_end":793}]}
{"pmid":"33649541","title":"Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.","abstract":"Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.","variants":[{"Name":"NM_006009.4(TUBA1A):c.1193T>G (p.Met398Arg)","Chromosome":"12","Start":"49185173","Stop":"49185173","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":976512,"rule_based_match":true,"evidence_text":"c.1193T>G, p.(Met398Arg)","llm_judgment":"PRESENT","evidence":"c.1193T>G, p.(Met398Arg)","abstract_start":670,"abstract_end":694},{"Name":"NM_006009.4(TUBA1A):c.467G>A (p.Arg156His)","Chromosome":"12","Start":"49185899","Stop":"49185899","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":976513,"rule_based_match":true,"evidence_text":"c.467G>A, p.(Arg156His)","llm_judgment":"PRESENT","evidence":"c.467G>A, p.(Arg156His)","abstract_start":641,"abstract_end":664},{"Name":"NM_006009.4(TUBA1A):c.1216C>G (p.His406Asp)","Chromosome":"12","Start":"49185150","Stop":"49185150","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":976511,"rule_based_match":true,"evidence_text":"c.1216C>G, p.(His406Asp)","llm_judgment":"PRESENT","evidence":"c.1216C>G, p.(His406Asp)","abstract_start":615,"abstract_end":639}]}
{"pmid":"36118280","title":"","abstract":"Purpose: To present a case of unilateral <i>IMPG2</i>-associated adult onset vitelliform macular dystrophy (AVMD).\nObservations: A 68 year-old female presented with best corrected visual acuity (BCVA) of 20/20 and 20/40 for the right and left eye respectively. The patient had a left subfoveal yellow lesion on dilated fundus examination. Optical coherence tomography showed hyper-reflective material accumulation below the fovea in the left eye only. The patient was followed for 10 years with stable BCVA, and evolution of the subretinal vitelliform lesion to a \"vitelliruptive\" stage. The right eye did not develop vitelliform lesion. Genetic testing identified a heterozygous likely disease-causing variant in <i>IMPG2</i>; c.3423-7_3423-4del.\nConclusions and importance: This is the first report of unilateral AVMD associated with <i>IMPG2</i>, expanding the phenotypic spectrum of <i>IMPG2</i> retinopathy. We provide further evidence that <i>IMPG2</i> variants can cause both autosomal recessive rod-cone dystrophy and autosomal dominant AVMD, with implications for patient counselling.","variants":[{"Name":"NM_016247.4(IMPG2):c.3423-7_3423-4del","Chromosome":"3","Start":"101229594","Stop":"101229597","ReferenceAlleleVCF":"AAAAG","AlternateAlleleVCF":"A","allel_id":191931,"rule_based_match":true,"evidence_text":"c.3423-7_3423-4del","llm_judgment":"PRESENT","evidence":"c.3423-7_3423-4del","abstract_start":728,"abstract_end":746}]}
{"pmid":"22620673","title":"A novel CaSR mutation presenting as a severe case of neonatal familial hypocalciuric hypercalcemia.","abstract":"BACKGROUND: Familial Hypocalciuric Hypercalcemia (FHH) is a generally benign disorder caused by heterozygous inactivating mutations in the Calcium-Sensing Receptor (CaSR) gene resulting in altered calcium metabolism.\nOBJECTIVE: We report a case of unusually severe neonatal FHH due to a novel CaSR gene mutation that presented with perinatal fractures and moderate hypercalcemia. CASE OVERVIEW: A female infant was admitted at 2 weeks of age for suspected non-accidental trauma (NAT). Laboratory testing revealed hypercalcemia (3.08 mmol/L), elevated iPTH (20.4 pmol/L) and low urinary calcium clearance (0.0004). Radiographs demonstrated multiple healing metaphyseal and rib fractures and bilateral femoral bowing. The femoral deformity and stage of healing were consistent with prenatal injuries rather than non-accidental trauma (NAT). Treatment was initiated with cholecalciferol, 400 IU/day, and by 6 weeks of age, iPTH levels had decreased into the high-normal range. Follow up radiographs demonstrated marked improvement of bone lesions by 3 months. A CaSR gene mutation study showed heterozygosity for a T>C nucleotide substitution at c.1664 in exon 6, resulting in amino acid change I555T in the extracellular domain consistent with a missense mutation. Her mother does not carry the mutation and the father is unknown. At 18 months of age, the child continues to have relative hyperparathyroidism and moderate hypercalcemia but is otherwise normal.\nCONCLUSION: This neonate with intrauterine fractures and demineralization, moderate hypercalcemia and hyperparathyroidism was found to have a novel inactivating missense mutation of the CaSR not detected in her mother. Resolution of bone lesions and reduction of hyperparathyroidism was likely attributable to the natural evolution of the disorder in infancy as well as the mitigating effect of cholecalciferol treatment.","variants":[{"Name":"NM_000388.4(CASR):c.1664T>C (p.Ile555Thr)","Chromosome":"3","Start":"122282168","Stop":"122282168","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":792992,"rule_based_match":false,"evidence_text":"T>C nucleotide substitution at c.1664","llm_judgment":"PRESENT","evidence":"T>C nucleotide substitution at c.1664","abstract_start":1112,"abstract_end":1149}]}
{"pmid":"38193604","title":"Expanding the phenotypic spectrum for CDK8-related disease: A case report.","abstract":"BACKGROUND: Cyclin-dependent kinase 8 (CDK8) is part of a regulatory kinase module that regulates the activity of the Mediator complex. The Mediator, a large conformationally flexible protein complex, goes on to regulate RNA polymerase II activity, consequently affecting transcriptional regulation. Thus, inactivating mutations of the genes within the kinase module cause aberrant transcriptional regulation and disease, namely, CDK8-related intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA).\nCASE PRESENTATION: We describe, for the first time, a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother. The clinical presentation of the child and mother is within the described clinical spectrum for IDDHBA; however, undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child. This phenotype was not found in the mother, highlighting a heterogenous presentation for the same variant within the same family. Furthermore, the described clinical presentation may further support the notion of a module- or Mediator-related syndrome with varying clinical presentation.\nCONCLUSION: This case report documents the first inherited case of IDDHBA and expands the phenotypic spectrum for CDK8-related disease to include undocumented progressive contractures of the hips and knees as well as scoliosis, which may support the notion of a module- or Mediator-related syndrome with varying clinical presentation.","variants":[{"Name":"NM_001260.3(CDK8):c.599G>A (p.Arg200Gln)","Chromosome":"13","Start":"26385295","Stop":"26385295","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":860055,"rule_based_match":true,"evidence_text":"CDK8 variant c.599G>A, p.(Arg200Gln)","llm_judgment":"PRESENT","evidence":"CDK8 variant c.599G>A, p.(Arg200Gln)","abstract_start":618,"abstract_end":654}]}
{"pmid":"17068223","title":"A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.","abstract":"The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.","variants":[{"Name":"NM_144701.3(IL23R):c.1142G>A (p.Arg381Gln)","Chromosome":"1","Start":"67240275","Stop":"67240275","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18147,"rule_based_match":true,"evidence_text":"c.1142G>A (p.Arg381Gln)","llm_judgment":"PRESENT","evidence":"p.Arg381Gln","abstract_start":530,"abstract_end":541}]}
{"pmid":"26110311","title":"Long-Term Observations in an Affected Family with Neurogenic Scapuloperoneal Syndrome Caused by Mutation R269C in the TRPV4 Gene.","abstract":"Mutations in the TRPV4 gene, encoding a polymodal Ca(2+) permeable channel, are causative for several human diseases, affecting the skeletal and the peripheral nervous system with highly variable phenotypes. We report on a family with two affected individuals. The father clinically suffered from a classical scapuloperoneal syndrome, while the son presented with a severe neonatal onset with congenital respiratory distress, feeding problems and arthrogryposis multiplex. Multi-Gene Panel sequencing by next generation sequencing revealed the heterozygous mutation c.805C>T (p.R269C) in the TRPV4 gene. Long-term observation over two decades showed no relevant disease progression in the father and, after a dramatic neonatal period, a significant improvement in the son who became ambulant with orthoses at the age of 5 years, suggesting a reasonably good prognosis even in cases with severe neonatal onset. Long-term findings in muscle ultrasound correlated with the clinical course, showing stable or even slightly improved findings. Neurography revealed a late-onset sensory neuropathy in the father, which was so far not described in TRPV4 neuropathies.","variants":[{"Name":"NM_021625.5(TRPV4):c.805C>T (p.Arg269Cys)","Chromosome":"12","Start":"109800666","Stop":"109800666","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20041,"rule_based_match":true,"evidence_text":"c.805C>T (p.R269C)","llm_judgment":"PRESENT","evidence":"c.805C>T (p.R269C)","abstract_start":566,"abstract_end":584}]}
{"pmid":"17420068","title":"Angiokeratoma corporis diffusum in human beta-mannosidosis: Report of a new case and a novel mutation.","abstract":"BACKGROUND: Human beta-mannosidosis, a rare disorder of oligosaccharide catabolism, results from a deficiency of beta-mannosidase activity. So far, mutational analysis has been performed in only seven families and revealed 11 mutations in the MANBA gene which encodes the enzyme beta-mannosidase.\nOBJECTIVES: We report here a 36-year-old Arab female with beta-mannosidosis who presented with mental retardation and multiple angiokeratomas. We describe in this patient a novel null mutation and review the previously reported MANBA gene mutations and their clinical correlations.\nMETHODS: Histopathology, ultrastructural analysis, and enzyme assays were performed. Sequencing of cDNA and genomic DNA analysis was conducted in a search for a mutation in the MANBA gene.\nRESULTS: Histopathology of a skin biopsy specimen from the patient showed the characteristic findings of angiokeratoma. Electron microscopy showed cytoplasmic vacuolation. Enzymatic activity of beta-mannosidase in the patient's serum, leukocytes, and fibroblasts was less than 1% of control values. Sequencing of the MANBA cDNA revealed a G-->A transition in exon 6 at nucleotide position c.693, resulting in the formation of a stop codon (W231X).\nLIMITATIONS: Only one family was studied.\nCONCLUSIONS: A new case of human beta-mannosidosis is presented and the first MANBA gene mutation from Arab ancestry is reported. Reviewing the reported MANBA gene mutations does not reveal a clear genotype-phenotype correlation. The importance of angiokeratoma corporis diffusum as the clue to the diagnosis of beta-mannosidosis and other lysosomal storage diseases is emphasized.","variants":[{"Name":"NM_005908.4(MANBA):c.693G>A (p.Trp231Ter)","Chromosome":"4","Start":"102690752","Stop":"102690752","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":621166,"rule_based_match":false,"evidence_text":"c.693G>A (p.Trp231Ter)","llm_judgment":"PRESENT","evidence":"c.693G>A (p.Trp231Ter)","abstract_start":null,"abstract_end":null}]}
{"pmid":"24007330","title":"Correlation between genotype and phenotype in patients with bi-allelic SLC26A4 mutations.","abstract":"Mutation of SLC26A4 is the most common cause of prelingual hearing loss in East Asia. Patients with SLC26A4 mutations have variable phenotypes ranging from non-syndromic hearing loss to Pendred syndrome. Here, we analyzed the correlation between genotype and various inner ear phenotypes and found a possible underlying mechanism. This study included 111 patients with bi-allelic SLC26A4 mutations who had bilateral enlarged vestibular aqueduct (EVA) and hearing loss. p.H723R (61%), c.919-2A>G (24%), and p.T410M (4%) were the most common mutations in Korean patients with EVAs. Residual hearing in patients with c.919-2A>G or p.T410M mutations was better than that of patients with p.H723R homozygous mutations. Interestingly, quantitative polymerase chain reaction showed normal pendrin transcript (6-17% of normal levels) was produced from patients with c.919-2A>G homozygous mutations. Surface expression ratio of pendrin and residual anion exchange activity were higher in cells transfected with p.T410M in comparison to cells transfected with p.H723R. These results suggest that there is a correlation between degree of residual hearing and the SLC26A4 genotype commonly found in the East Asian population.","variants":[{"Name":"NM_000441.2(SLC26A4):c.919-2A>G","Chromosome":"7","Start":"107683453","Stop":"107683453","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19879,"rule_based_match":true,"evidence_text":"c.919-2A>G","llm_judgment":"PRESENT","evidence":"c.919-2A>G","abstract_start":484,"abstract_end":494}]}
{"pmid":"34421504","title":"Clinical Exome Sequencing Enables Congenital Sialidosis Type II Diagnosis in Two Siblings Presenting with Unreported Clinical Features from a Rare Homozygous Sequence Variant p.(Tyr370Cys) in","abstract":"Sialidosis is a rare autosomal recessive disease that presents with progressive lysosomal storage of sialylated glycopeptides and oligosaccharides caused by homozygous or compound heterozygous sequence variants in the neuraminidase 1 (<i>NEU1</i>) gene. These sequence variants can lead to sialidosis type I and II; the latter is the most severe and presents prenatally or at early age. However, sialidosis diagnosis is challenging, especially in those health systems with limited resources of developing countries. Consequently, it is necessary to dip into high-throughput molecular diagnostic tools to allow for an accurate diagnosis with better cost-effectiveness and turnaround time. We report a 4-member pedigree segregating an ultrarare missense variant, c.1109A>G; p.Tyr370Cys, in <i>NEU1</i> as detected by whole-exome sequencing. Two short-lived siblings, who presented with previously unreported clinical features from such a homozygous sequence variant, were diagnosed with sialidosis type II. Additionally, we present a novel molecular model exhibiting the consequences of the variant in the sialidase-1 tridimensional structure. This study allowed us to provide a definitive diagnosis for our patients, increase our understanding of this pathogenic variant, and improve genetic counseling.","variants":[{"Name":"NM_000434.4(NEU1):c.1109A>G (p.Tyr370Cys)","Chromosome":"6","Start":"31859858","Stop":"31859858","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":974883,"rule_based_match":true,"evidence_text":"c.1109A>G; p.Tyr370Cys","llm_judgment":"PRESENT","evidence":"c.1109A>G; p.Tyr370Cys","abstract_start":761,"abstract_end":783}]}
{"pmid":"27236923","title":"BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia.","abstract":"Spondyloepimetaphyseal dysplasias (SEMDs) comprise a heterogeneous group of autosomal-dominant and autosomal-recessive disorders. An apparent X-linked recessive (XLR) form of SEMD in a single Italian family was previously reported. We have been able to restudy this family together with a second family from Korea by segregating a severe SEMD in an X-linked pattern. Exome sequencing showed missense mutations in BGN c.439A>G (p.Lys147Glu) in the Korean family and c.776G>T (p.Gly259Val) in the Italian family; the c.439A>G (p.Lys147Glu) mutation was also identified in a further simplex SEMD case from India. Biglycan is an extracellular matrix proteoglycan that can bind transforming growth factor beta (TGF-β) and thus regulate its free concentration. In 3-dimensional simulation, both altered residues localized to the concave arc of leucine-rich repeat domains of biglycan that interact with TGF-β. The observation of recurrent BGN mutations in XLR SEMD individuals from different ethnic backgrounds allows us to define \"XLR SEMD, BGN type\" as a nosologic entity.","variants":[{"Name":"NM_001711.6(BGN):c.439A>G (p.Lys147Glu)","Chromosome":"X","Start":"153505950","Stop":"153505950","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":244173,"rule_based_match":true,"evidence_text":"c.439A>G (p.Lys147Glu)","llm_judgment":"PRESENT","evidence":"c.439A>G (p.Lys147Glu)","abstract_start":417,"abstract_end":439},{"Name":"NM_001711.6(BGN):c.776G>T (p.Gly259Val)","Chromosome":"X","Start":"153507052","Stop":"153507052","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":244174,"rule_based_match":true,"evidence_text":"c.776G>T (p.Gly259Val)","llm_judgment":"PRESENT","evidence":"c.776G>T (p.Gly259Val)","abstract_start":465,"abstract_end":487}]}
{"pmid":"30903679","title":"PADDAS syndrome associated with hair dysplasia caused by a de novo missense variant of PUM1.","abstract":"PUM1 has been very recently reported as responsible for a new form of developmental disorder named PADDAS syndrome. We describe here an additional patient with early onset developmental delay, epilepsy, microcephaly, and hair dysplasia, with a de novo heterozygous missense variant of PUM1: c.3439C > T, p.(Arg1147Trp). This variant was absent from databases and predicted deleterious by multiple softwares. The same missense variant has been reported by Gennarino et al., in a girl with much more severe epilepsy. Our report is in favor of a variable expressivity of PADDAS syndrome, and broadens the phenotypic spectrum with the description of hair dysplasia.","variants":[{"Name":"NM_001020658.2(PUM1):c.3439C>T (p.Arg1147Trp)","Chromosome":"1","Start":"30933339","Stop":"30933339","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":609302,"rule_based_match":true,"evidence_text":"c.3439C > T, p.(Arg1147Trp)","llm_judgment":"PRESENT","evidence":"c.3439C > T, p.(Arg1147Trp)","abstract_start":291,"abstract_end":318}]}
{"pmid":"33398081","title":"A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing.","abstract":"Nonsyndromic hearing loss is genetically heterogeneous. Despite comprehensive genetic testing, many cases remain unsolved because the clinical significance of identified variants is uncertain or because biallelic pathogenic variants are not identified for presumed autosomal recessive cases. Common synonymous variants are often disregarded. Determining the pathogenicity of synonymous variants may improve genetic diagnosis. We report a synonymous variant c.9861 C > T/p.(Gly3287=) in MYO15A in homozygosity or compound heterozygosity with another pathogenic or likely pathogenic MYO15A variant in 10 unrelated families with nonsyndromic sensorineural hearing loss. Biallelic variants in MYO15A were identified in 21 affected and were absent in 22 unaffected siblings. A mini-gene assay confirms that the synonymous variant leads to abnormal splicing. The variant is enriched in the Ashkenazi Jewish population. Individuals carrying biallelic variants involving c.9861 C > T often exhibit progressive post-lingual hearing loss distinct from the congenital profound deafness typically associated with biallelic loss-of-function MYO15A variants. This study establishes the pathogenicity of the c.9861 C > T variant in MYO15A and expands the phenotypic spectrum of MYO15A-related hearing loss. Our work also highlights the importance of multicenter collaboration and data sharing to establish the pathogenicity of a relatively common synonymous variant for improved diagnosis and management of hearing loss.","variants":[{"Name":"NM_016239.4(MYO15A):c.9861C>T (p.Gly3287=)","Chromosome":"17","Start":"18166434","Stop":"18166434","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":54942,"rule_based_match":true,"evidence_text":"c.9861 C > T/p.(Gly3287=)","llm_judgment":"PRESENT","evidence":"c.9861 C > T/p.(Gly3287=)","abstract_start":457,"abstract_end":482}]}
{"pmid":"30820142","title":"Variable reduction in Norrin signaling activity caused by novel mutations in","abstract":"Purpose: To identify novel mutations in <i>FZD4</i> and to investigate their pathogenicity in a cohort of Chinese patients with familial exudative vitreoretinopathy (FEVR).\nMethods: Next-generation sequencing was performed in patients with a clinical diagnosis of FEVR. Wide-field angiography was performed in probands and family members if available. Clinical data were collected from patient charts. The effect of the mutations in <i>FZD4</i> on its biologic activity in the Norrin/β-catenin signaling pathway was analyzed with the luciferase reporter assay.\nResults: Four novel mutations in <i>FZD4</i> (c.1188_1192del/p.F396fs, c.1220delC/p.A407Vfs*24, c.905G>A/p.C302Y, c.1325T>A/p.V442E) were identified in four unrelated families. The mutations were not detected in 200 healthy individuals. The variability of the ocular phenotypes was not only observed in the probands and parents harboring the same mutation but also between two eyes in one individual. All four novel mutations introduced reduction in luciferase activity. Compared with the wild-type, the FZD4 level of the four mutants also decreased variably.\nConclusions: Four novel mutations in <i>FZD4</i> were identified in Chinese patients with FEVR. No correlation in the reduced luciferase activity and the ocular phenotype was observed in this study. This study further emphasized the complexity of the FEVR-causing machinery.","variants":[{"Name":"NM_012193.4(FZD4):c.1188_1192del (p.Phe396fs)","Chromosome":"11","Start":"86951564","Stop":"86951568","ReferenceAlleleVCF":"TAAGTA","AlternateAlleleVCF":"T","allel_id":1903505,"rule_based_match":true,"evidence_text":"c.1188_1192del/p.F396fs","llm_judgment":"PRESENT","evidence":"c.1188_1192del/p.F396fs","abstract_start":607,"abstract_end":630}]}
{"pmid":"30576819","title":"Detection of Germline Mutations of the SMARCB1 Gene in a Chinese Family with Intraspinal Schwannomatosis.","abstract":"BACKGROUND: Schwannomatosis is the third subtype of neurofibromatosis. Because the tumor is multiple and prone to recurrence, it often brings challenges to clinical diagnosis and treatment. In the past decade, researchers have come to realize the relationship between the SMARCB1 gene and schwannomatosis, which is expected to improve the current level of diagnosis and treatment.\nCASE DESCRIPTION: We collected the clinical data of intraspinal schwannomatosis in the same family, which is rare, and carried out the genetic tests on 3 generations of family members (N = 25). We found that 8 family members had germline mutations of the SMARCB1 gene, manifested as mutation at the splice site between SMARCB1 gene exon 8 and 9 (c.1118 + 1G > A).\nCONCLUSIONS: The structural and functional abnormalities of proteins caused by the mutations of the SMARCB1 gene may be the molecular basis for the pathogenesis of schwannomatosis in this family. This study may provide clues for the study of schwannomatosis in the future.","variants":[{"Name":"NM_003073.5(SMARCB1):c.1118+1G>A","Chromosome":"22","Start":"23833704","Stop":"23833704","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":469984,"rule_based_match":true,"evidence_text":"c.1118+1G>A","llm_judgment":"PRESENT","evidence":"c.1118 + 1G > A","abstract_start":727,"abstract_end":742}]}
{"pmid":"35853885","title":"Functional assessment of missense variants of uncertain significance in the cancer susceptibility gene PALB2.","abstract":"Germline PALB2 pathogenic variants are associated with an increased lifetime risk for breast, pancreatic, and ovarian cancer. However, the interpretation of the pathogenicity of numerous PALB2 missense variants of uncertain significance (VUSs) identified in germline genetic testing remains a challenge. Here we selected ten potentially pathogenic PALB2 VUSs identified in 2279 Chinese patients with breast cancer and evaluated their impacts on PALB2 function by systematic functional assays. We showed that three PALB2 VUSs p.K16M [c.47 A > T], p.L24F [c.72 G > C], and p.L35F [c.103 C > T] in the coiled-coil domain impaired PALB2-mediated homologous recombination. The p.L24F and p.L35F variants partially disrupted BRCA1-PALB2 interactions, reduced RAD51 foci formation in response to DNA damage, abrogated ionizing radiation-induced G2/M checkpoint maintenance, and conferred increased sensitivity to olaparib and cisplatin. The p.K16M variant presented mild effects on BRCA1-PALB2 interactions and RAD51 foci formation. Altogether, we identify two novel PALB2 VUSs, p.L24F and p.L35F, that compromise PALB2 function and may increase cancer risk. These two variants display marked olaparib and cisplatin sensitivity and may help predict response to targeted therapy in the clinical treatment of patients with these variants.","variants":[{"Name":"NM_024675.4(PALB2):c.72G>C (p.Leu24Phe)","Chromosome":"16","Start":"23638106","Stop":"23638106","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":151469,"rule_based_match":true,"evidence_text":"c.72 G > C","llm_judgment":"PRESENT","evidence":"c.72 G > C","abstract_start":554,"abstract_end":564}]}
{"pmid":"37070599","title":"A de novo TINF2, R282C Mutation in a Case of Dyskeratosis Congenital Founded by Next-Generation Sequencing.","abstract":"Background: Dyskeratosis congenita (DC), an inherited and rare disease prevalent in males, is clinically manifested by reticulate hyperpigmentation, nail dystrophy, and leukoplakia. DC is associated with the increased risk of malignancy and other potentially lethal complications such as bone marrow failure, as well as lung and liver diseases. Mutations in 19 genes were found to be correlated with DC. Herein, we report a 12-year-old boy carrying a de novo mutation in TINF2 gene.\nMethods: Whole exome sequencing (WES) was performed on DNA sample of the proband, and the variant was investigated in the family by Sanger sequencing. Population and bioinformatics analysis were performed.\nResults: The NM_ 001099274.3(TINF2): c.844C>T (p.Arg282Cys) mutation was found by WES.\nConclusion: There was no history of the disease in the family, and the variant was classified as a de novo mutation.","variants":[{"Name":"NM_001099274.3(TINF2):c.844C>T (p.Arg282Cys)","Chromosome":"14","Start":"24240636","Stop":"24240636","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20666,"rule_based_match":true,"evidence_text":"NM_ 001099274.3(TINF2): c.844C>T (p.Arg282Cys)","llm_judgment":"PRESENT","evidence":"NM_ 001099274.3(TINF2): c.844C>T (p.Arg282Cys)","abstract_start":702,"abstract_end":748}]}
{"pmid":"33064266","title":"Clinical, biochemical and molecular findings of 24 Brazilian patients with glutaric acidemia type 1: 4 novel mutations in the GCDH gene.","abstract":"Glutaric aciduria type 1 (GA-1) is a rare but treatable inherited disease caused by deficiency of glutaryl-CoA dehydrogenase activity due to GCDH gene mutations. In this study, we report 24 symptomatic GA-1 Brazilian patients, and present their clinical, biochemical, and molecular findings. Patients were diagnosed by high levels of glutaric and/or 3-hydroxyglutaric and glutarylcarnitine. Diagnosis was confirmed by genetic analysis. Most patients had the early-onset severe form of the disease and the main features were neurological deterioration, seizures and dystonia, usually following an episode of metabolic decompensation. Despite the early symptomatology, diagnosis took a long time for most patients. We identified 13 variants in the GCDH gene, four of them were novel: c.91 + 5G > A, c.167T > G, c.257C > T, and c.10A > T. The most common mutation was c.1204C > T (p.R402W). Surprisingly, the second most frequent mutation was the new mutation c.91 + 5G > A (IVS1 ds G-A + 5). Our results allowed a complete characterization of the GA-1 Brazilian patients. Besides, they expand the mutational spectrum of GA-1, with the description of four new mutations. This work reinforces the importance of awareness of GA-1 among doctors in order to allow early diagnosis and treatment in countries like Brazil where the disease has not been included in newborn screening programs.","variants":[{"Name":"NM_000159.4(GCDH):c.91+5G>A","Chromosome":"19","Start":"12891400","Stop":"12891400","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":653601,"rule_based_match":true,"evidence_text":"c.91 + 5G > A","llm_judgment":"PRESENT","evidence":"c.91 + 5G > A","abstract_start":782,"abstract_end":795},{"Name":"NM_000159.4(GCDH):c.167T>G (p.Leu56Arg)","Chromosome":"19","Start":"12891870","Stop":"12891870","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3817377,"rule_based_match":true,"evidence_text":"c.167T>G","llm_judgment":"PRESENT","evidence":"c.167T > G","abstract_start":797,"abstract_end":807}]}
{"pmid":"28710804","title":"Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study.","abstract":"AIM: To characterize clinical features and mutation spectrum in Chinese patients with CADASIL.\nMETHODS: We collected 261 clinically suspected Chinese CADASIL patients from three hospitals located in different regions of China. Sanger sequencing is performed to screen the exons 2 to 24 of NOTCH3 gene. Clinical and genetic data were retrospectively studied. Haplotype analyses were performed in patients carrying p.Arg544Cys and p.Arg607Cys, respectively.\nRESULTS: A total of 214 patients were finally genetically diagnosed as CADASIL, with 45 known NOTCH3 mutations and a novel c.1817G>T mutation. We found that patients carrying p.Arg607Cys or p.Arg544Cys mutation located in exon 11 occupied nearly 35% in our mutation spectrum. In retrospectively study of clinical data, we found a higher number of patients having cognitive impairment and a lower number of patients having migraine with aura. Furthermore, we identified that patients carrying mutations in exon 11 seemed to experience a later disease onset (p=6.8×10<sup>-5</sup> ). Additionally, a common haplotype was found in patients from eastern China carrying p.Arg607Cys, and the patients from Fujian carrying p.Arg544Cys shared the same haplotype with patients from Taiwan carrying p.Arg544Cys.\nCONCLUSIONS: These findings broaden the mutational and clinical spectrum of CADASIL and provide additional evidences for the existence of founder effect in CADASIL patients.","variants":[{"Name":"NM_000435.3(NOTCH3):c.1819C>T (p.Arg607Cys)","Chromosome":"19","Start":"15187126","Stop":"15187126","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":361523,"rule_based_match":false,"evidence_text":"p.Arg607Cys","llm_judgment":"PRESENT","evidence":"p.Arg607Cys","abstract_start":429,"abstract_end":440}]}
{"pmid":"18629883","title":"Clinical phenotype correlates to glycoprotein phenotype in a sib pair with CDG-Ia.","abstract":"Congenital disorder of glycosylation (CDG) type Ia (PMM2 mutations) is the most common genetic disorder of protein N-glycosylation. The wide clinical spectrum with mild to severe impairment of neurological function and extensive allelic heterogeneity hamper phenotype-genotype comparison. We report on two male adult siblings with the PMM2 mutations c. 385G > A (p.V129M) and c. 422G > A (p.R141H) and partially different clinical phenotype. Patient 2 has a more severe degree of neurological and systemic involvement and a more pronounced decrease in levels of serum glycoproteins. MALDI-TOF mass spectrometry of serum transferrin and alpha-1-antitrypsin shows more pronounced glycosylation defects in the more severely affected patient. Glycoproteomic analysis may reveal differences in CDG-Ia patients with different disease severity and might endorse clinical characterization of CDG-Ia patients.","variants":[{"Name":"NM_000303.3(PMM2):c.385G>A (p.Val129Met)","Chromosome":"16","Start":"8811116","Stop":"8811116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22747,"rule_based_match":true,"evidence_text":"c. 385G > A (p.V129M)","llm_judgment":"PRESENT","evidence":"c. 385G > A (p.V129M)","abstract_start":350,"abstract_end":371}]}
{"pmid":"38247840","title":"","abstract":"Besides visceral heterotaxia, <i>Pkd1l1</i> null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in <i>PKD1L1</i> exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of <i>PKD1L1</i> in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in <i>PKD1L1</i> in two of the five case-parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants' impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of <i>Pkd1l1</i> mutant mouse embryos revealed about 20% of <i>Pkd1l1<sup>-/-</sup></i> embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in <i>Pkd1l1<sup>-/-</sup></i> embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of <i>PKD1L1</i> in congenital lymphatic anomalies, including CCTs.","variants":[{"Name":"NM_138295.5(PKD1L1):c.1543G>A (p.Gly515Arg)","Chromosome":"7","Start":"47905305","Stop":"47905305","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3222588,"rule_based_match":true,"evidence_text":"c.1543G>A(p.Gly515Arg)","llm_judgment":"PRESENT","evidence":"c.1543G>A(p.Gly515Arg)","abstract_start":639,"abstract_end":661},{"Name":"NM_138295.5(PKD1L1):c.6549G>T (p.Gln2183His)","Chromosome":"7","Start":"47830049","Stop":"47830049","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3222589,"rule_based_match":true,"evidence_text":"c.6549G>T(p.Gln2183His)","llm_judgment":"PRESENT","evidence":"c.6549G>T(p.Gln2183His)","abstract_start":840,"abstract_end":863},{"Name":"NM_138295.5(PKD1L1):c.3845T>A (p.Val1282Glu)","Chromosome":"7","Start":"47873950","Stop":"47873950","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1275006,"rule_based_match":true,"evidence_text":"c.3845T>A(p.Val1282Glu)","llm_judgment":"PRESENT","evidence":"c.3845T>A(p.Val1282Glu)","abstract_start":666,"abstract_end":689}]}
{"pmid":"25443471","title":"The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes.","abstract":"Examination of genotype-phenotype correlations along with functional evaluation of CFTR mutations may not be straightforward. The c.1865G>A, p.Gly622Asp (G622D), located at the NBD1 C terminus of the CFTR protein, was initially reported in patients with male infertility. However, the substitution of Gly622 by an aspartic acid in vitro would perturb the local structure or even affect the CFTR folding itself. In order to determine whether p.Gly622Asp affects the risk of developing a CFTR-Related disorder (CFTR-RD) or cystic fibrosis (CF), we analyzed the phenotype of subjects bearing the p.Gly622Asp mutation. We report molecular and clinical analyses in eleven unrelated patients with CF or CFTR-RD with compound heterozygosity for the p.Gly622Asp mutation. On the basis of the clinical features presented by the eleven patients, we postulate that the p.Gly622Asp might be associated with a wide spectrum of phenotypes including classical cystic fibrosis.","variants":[{"Name":"NM_000492.4(CFTR):c.1865G>A (p.Gly622Asp)","Chromosome":"7","Start":"117592032","Stop":"117592032","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44497,"rule_based_match":true,"evidence_text":"c.1865G>A, p.Gly622Asp (G622D)","llm_judgment":"PRESENT","evidence":"c.1865G>A, p.Gly622Asp (G622D)","abstract_start":130,"abstract_end":160}]}
{"pmid":"29277593","title":"Oculoleptomeningeal Amyloidosis Secondary to the Rare Transthyretin c.381T>G (p.Ile127Met) Mutation.","abstract":"BACKGROUND: Oculoleptomeningeal amyloidosis (OLMA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal leptomeninges along with ocular involvement. Of >100 TTR mutations identified, few have been associated with OLMA. Herein we describe the first report of leptomeningeal amyloidosis associated with the c.381T>G (p.Ile127Met) TTR mutation, linking this variant to the OLMA phenotype.\nCASE DESCRIPTION: A 53 year-old man presented with a 2-year history of progressive symptoms including upper and lower limb weakness, ataxia, and peripheral and autonomic neuropathy. Neuroimaging, including gadolinium-enhanced magnetic resonance imaging of the brain and spinal axis, identified diffuse leptomeningeal enhancement along the brainstem and spinal cord plus evidence of hemosiderosis. Pathologic and genetic analyses of biopsy material from enhancing intradural extramedullary tissue at the thoracolumbar junction was diagnostic of amyloidosis of a transthyretin type secondary to a TTR c.381T>G (p.Ile127Met) mutation.\nCONCLUSIONS: OLMA represents a rare subtype of heritable transthyretin amyloidosis that may present with progressive neurological decline secondary to central nervous system leptomeningeal amyloid deposition. This case identifies the c.381T>G (p.Ile127Met) TTR mutation variant as being implicated in the OLMA phenotype.","variants":[{"Name":"NM_000371.4(TTR):c.381T>G (p.Ile127Met)","Chromosome":"18","Start":"31598612","Stop":"31598612","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1064528,"rule_based_match":true,"evidence_text":"c.381T>G (p.Ile127Met)","llm_judgment":"PRESENT","evidence":"c.381T>G (p.Ile127Met)","abstract_start":384,"abstract_end":406}]}
{"pmid":"30230192","title":"Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype.","abstract":"BACKGROUND & AIMS: Wilson's disease (WD) is an autosomal recessive disorder associated with disease-causing alterations across the ATP7B gene, with highly variable symptoms and age of onset. We aimed to assess whether the clinical variability of WD relates to modifier genes.\nMETHODS: A total of 248 WD patients were included, of whom 148 were diagnosed after age of 17. Human exome libraries were constructed using AmpliSeq technology and sequenced using the IonProton platform.\nRESULTS: ATP7B p.His1069Gln mutation was present in 215 patients, with 112 homozygotes and 103 heterozygotes. Three other mutations: p.Gln1351Ter, p.Trp779Ter and c.3402delC were identified in >10 patients. Among patients, 117 had a homozygous mutation, 101 were compound heterozygotes, 27 had one heterozygous mutation, and 3 other patients had no identifiable pathogenic variant of ATP7B. Sixteen mutations were novel, found as part of a compound mutation or as a sole, homozygous mutation. For disease phenotype prediction, age at diagnosis was a deciding factor, while frameshift allelic variants of ATP7B and being male increased the odds of developing a neurological phenotype. Rare allelic variants in ESD and INO80 increased and decreased chances for the neurological phenotype, respectively, while rare variants in APOE and MBD6 decreased the chances of WD early manifestation. Compound mutations contributed to earlier age of onset.\nCONCLUSIONS: In a Polish population, genetic screening for WD may help genotype for four variants (p.His1069Gln, p.Gln1351Ter, p.Trp779Ter and c.3402delC), with direct sequencing of all ATP7B amplicons as a second diagnostic step. We also identified some allelic variants that may modify a WD phenotype.","variants":[{"Name":"NM_000053.4(ATP7B):c.3402del (p.Ala1135fs)","Chromosome":"13","Start":"51942396","Stop":"51942396","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":94515,"rule_based_match":true,"evidence_text":"c.3402delC","llm_judgment":"PRESENT","evidence":"c.3402delC","abstract_start":643,"abstract_end":653}]}
{"pmid":"23112574","title":"Membrane frizzled-related protein gene-related ophthalmological syndrome: 30-month follow-up of a sporadic case and review of genotype-phenotype correlation in the literature.","abstract":"PURPOSE: To report a new sporadic case of membrane frizzled-related protein gene (MFRP)-related syndrome with a 30-month follow-up, and to review the literature for genotype-phenotype correlation in MFRP mutations.\nMETHODS: A complete ophthalmological evaluation was performed at presentation and 30 months later, including best-corrected visual acuity test, slit lamp examination, fundoscopy, kinetic perimetry, electroretinography, fundus imaging (color, red-free, and autofluorescence), and morphologic-biometric analysis of the eye structures with an optical biometer, anterior-segment optical coherence tomography, retinal optical coherence tomography, and a confocal scanning laser for optic nerve head study. Polymerase chain reaction amplification of DNA obtained from peripheral blood lymphocytes and nucleotide sequencing of the complete MFRP gene were performed. The literature on cases of posterior microphthalmos and retinitis pigmentosa associated with MFRP mutations was reviewed.\nRESULTS: A 33-year-old female patient presented with posterior microphthalmos, retinitis pigmentosa with patches of retinal pigmented epithelium atrophy and scarce pigment mobilization, foveoschisis, and optic nerve drusen. After 30 months, progression of rod-cone retinal degeneration was detected. One obligate carrier showed a normal eye phenotype. A homozygote mutation in the MFRP gene (c.492delC), predicting a truncated protein (P166fsX190), was identified with genetic analysis. To our knowledge, 17 cases of MFRP-related syndrome have been reported in the literature, including the patient described herein. The phenotype of the syndrome, expressivity, and age of onset varied among and within the affected families. However, all patients sharing homozygous mutation c.492delC (alternatively named c.498delC) showed a complete phenotype (including foveoschisis and optic nerve head drusen), and similar fundus characteristics.\nCONCLUSIONS: A new sporadic case of MFRP-related syndrome is reported. Review of the literature showed variability in the phenotype, but initial elements of genotype-phenotype correlation have been identified in patients sharing the mutation of the present case.","variants":[{"Name":"NM_031433.4(MFRP):c.498del (p.Asn167fs)","Chromosome":"11","Start":"119345563","Stop":"119345563","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":19515,"rule_based_match":true,"evidence_text":"c.492delC (alternatively named c.498delC)","llm_judgment":"PRESENT","evidence":"c.492delC (alternatively named c.498delC)","abstract_start":1772,"abstract_end":1813}]}
{"pmid":"26270344","title":"R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL.","abstract":"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.","variants":[{"Name":"NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys)","Chromosome":"19","Start":"15197537","Stop":"15197537","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":442187,"rule_based_match":true,"evidence_text":"c.160C>T (p.Arg54Cys)","llm_judgment":"PRESENT","evidence":"p.Arg54Cys","abstract_start":305,"abstract_end":315}]}
{"pmid":"30680869","title":"A case of early-onset epileptic encephalopathy with a homozygous TBC1D24 variant caused by uniparental isodisomy.","abstract":"TBC1D24-related disorders are rare neurodevelopmental disorders that show a broad range of neuropsychiatric deficits and are mostly inherited in an autosomal recessive manner. Here we describe a case with early-onset epileptic encephalopathy, in whom exome sequencing detected a novel pathogenic homozygous c.442G>A, p.(Glu148Lys) variant in TBC1D24. She showed severe developmental delay, congenital sensorineural hearing loss and seizures, but the combination of a high dose phenobarbital and potassium bromide was very effective for the seizures. Sanger sequencing revealed that her mother was a heterozygous carrier of the TBC1D24 variant, but her father showed only wild-type alleles. Homozygosity mapping analysis using exome data showed loss of the heterozygosity region at 16p13.3-p13.13 encompassing TBC1D24. Genotyping analysis using rare variants within loss of the heterozygosity region indicated that the patient has a homozygous haplotype inherited from her mother, indicating maternal segmental uniparental isodisomy (UPiD). These data clearly show that exome sequencing is a powerful tool to perform comprehensive genetic analysis.","variants":[{"Name":"NM_001199107.2(TBC1D24):c.442G>A (p.Glu148Lys)","Chromosome":"16","Start":"2496590","Stop":"2496590","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":797290,"rule_based_match":true,"evidence_text":"c.442G>A, p.(Glu148Lys)","llm_judgment":"PRESENT","evidence":"c.442G>A, p.(Glu148Lys)","abstract_start":307,"abstract_end":330}]}
{"pmid":"24938629","title":"Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype.","abstract":"AIMS: Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype-phenotype correlations in patients carrying a novel DSP c.1339C>T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations.\nMETHODS AND RESULTS: Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC (n = 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n = 23) (aged 40 ± 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C>T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C>T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging.\nCONCLUSION: DSP c.1339C>T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly.","variants":[{"Name":"NM_004415.4(DSP):c.1339C>T (p.Gln447Ter)","Chromosome":"6","Start":"7568509","Stop":"7568509","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1060861,"rule_based_match":true,"evidence_text":"DSP c.1339C>T","llm_judgment":"PRESENT","evidence":"DSP c.1339C>T","abstract_start":328,"abstract_end":341}]}
{"pmid":"16287143","title":"Four novel TMC1 (DFNB7/DFNB11) mutations in Turkish patients with congenital autosomal recessive nonsyndromic hearing loss.","abstract":"Mutations in the transmembrane channel-like gene 1 (TMC1) cause prelingual autosomal recessive (DFNB7/11) and postlingual progressive autosomal dominant (DFNA36) nonsyndromic hearing loss. To determine the genetic causes of autosomal recessive nonsyndromic hearing loss (ARNSHL) in the northeast and east of Turkey, 65 unrelated families without mutations in the protein coding region of the GJB2 (GJB2-negative) were analyzed. A genomewide scan for homozygosity and linkage analysis in one of these families revealed a 13.2 cM critical region between D9S273 and D9S153 at chromosome 9p13.2-q21.31 with a maximum two-point lod score of 4.00 at theta=0.0 for marker D9S175. TMC1 is in this critical region. Homozygosity screening with intragenic markers for TMC1 in the remaining 64 families suggested involvement of this gene in three additional families. Subsequent sequencing of TMC1 in these four families revealed four novel homozygous mutations, c.776A>G [p.Tyr259Cys], c.821C>T [p.Pro274Leu], c.1334G>A [p.Arg445His], and c.1083_1087delCAGAT [p.Arg362ProfrX6]. Our results indicate that TMC1 mutations account for at least 6% (4/65) of ARNSHL in GJB2-negative Turkish families from the northeast and east of Turkey.","variants":[{"Name":"NM_138691.3(TMC1):c.821C>T (p.Pro274Leu)","Chromosome":"9","Start":"72772492","Stop":"72772492","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1161817,"rule_based_match":true,"evidence_text":"c.821C>T [p.Pro274Leu]","llm_judgment":"PRESENT","evidence":"c.821C>T [p.Pro274Leu]","abstract_start":975,"abstract_end":997},{"Name":"NM_138691.3(TMC1):c.1334G>A (p.Arg445His)","Chromosome":"9","Start":"72791995","Stop":"72791995","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1318805,"rule_based_match":true,"evidence_text":"c.1334G>A [p.Arg445His]","llm_judgment":"PRESENT","evidence":"c.1334G>A [p.Arg445His]","abstract_start":999,"abstract_end":1022}]}
{"pmid":"26826406","title":"Neonatal multiorgan failure due to ACAD9 mutation and complex I deficiency with mitochondrial hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules.","abstract":"Complex I deficiency causes Leigh syndrome, fatal infant lactic acidosis, and neonatal cardiomyopathy. Mutations in more than 100 nuclear DNA and mitochondrial DNA genes miscode for complex I subunits or assembly factors. ACAD9 is an acyl-CoA dehydrogenase with a novel function in assembly of complex I; biallelic mutations cause progressive encephalomyopathy, recurrent Reye syndrome, and fatal cardiomyopathy. We describe the first autopsy in fatal neonatal lethal lactic acidosis due to mutations in ACAD9 that reduced complex I activity. We identified mitochondrial hyperplasia in cardiac myocytes, diaphragm muscle, and liver and renal tubules in formalin-fixed, paraffin-embedded tissue using immunohistochemistry for mitochondrial antigens. Whole-exome sequencing revealed compound heterozygous variants in the ACAD9 gene: c.187G>T (p.E63*) and c.941T>C (p.L314P). The nonsense mutation causes late infantile lethality; the missense variant is novel. Autopsy-derived fibroblasts had reduced complex I activity (53% of control) with normal activity in complexes II to IV, similar to reported cases of ACAD9 deficiency.","variants":[{"Name":"NM_014049.5(ACAD9):c.187G>T (p.Glu63Ter)","Chromosome":"3","Start":"128884689","Stop":"128884689","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1458188,"rule_based_match":true,"evidence_text":"c.187G>T (p.E63*)","llm_judgment":"PRESENT","evidence":"c.187G>T (p.E63*)","abstract_start":831,"abstract_end":848}]}
{"pmid":"19151366","title":"Variable expression of a novel PLP1 mutation in members of a family with Pelizaeus-Merzbacher disease.","abstract":"Pelizaeus-Merzbacher disease is a rare X-linked disorder caused by mutations of the proteolipid protein 1 gene that encodes a structural component of myelin. It is characterized by progressive psychomotor delay, nystagmus, spastic quadriplegia, and cerebellar ataxia. Variable clinical expression was seen in 5 members of a family bearing a novel missense mutation in proteolipid protein 1, c.619T>C. Symptomatic patients included a 6-year-old girl, her younger brother, and their maternal uncle, a 29-year-old college graduate initially diagnosed with cerebral palsy; their brain magnetic resonance imaging studies showed diffuse dysmyelination. The mother had a history of delayed walking, achieved independently by age 3; she and the maternal grandmother were asymptomatic on presentation. Review of clinical information and family history led to consideration of Pelizaeus-Merzbacher disease. Subsequent identification of the causal mutation enabled preimplantation genetic diagnosis and the birth of an unaffected child.","variants":[{"Name":"NM_000533.5(PLP1):c.619T>C (p.Tyr207His)","Chromosome":"X","Start":"103787963","Stop":"103787963","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3414203,"rule_based_match":true,"evidence_text":"c.619T>C","llm_judgment":"PRESENT","evidence":"c.619T>C","abstract_start":391,"abstract_end":399}]}
{"pmid":"36282599","title":"Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.","abstract":"Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features.","variants":[{"Name":"NM_019059.5(TOMM7):c.86C>T (p.Pro29Leu)","Chromosome":"7","Start":"22822694","Stop":"22822694","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2795823,"rule_based_match":true,"evidence_text":"c.86C>T; p.Pro29Leu","llm_judgment":"PRESENT","evidence":"c.86C>T; p.Pro29Leu","abstract_start":470,"abstract_end":489}]}
{"pmid":"33232506","title":"Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy.","abstract":"Fluoropyrimidines (FPs), mainly 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Cap), remain the backbone of the treatment of many different solid tumors. Despite their broad use in clinical routine, 10&ndash;40% of patients experience severe, and in rare cases (0.2&ndash;0.5%) even lethal, FP-related toxicity in early chemotherapy cycles. Today, there is a plethora of evidence that genetic variants in the gene encoding for the 5-FU catabolising enzyme dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) are predictive of severe FP-related toxicities, and international clinical practice recommendations for DPYD genotype-guided FP dosing and therapeutic drug monitoring (TDM) are available. In spite of this strong evidence and DPYD genotyping becoming standard practice in other countries, it is has not been widely adopted in Switzerland to date. Here, we discuss current guidelines on genotype-guided FP dosing and TDM, and propose recommendations tailored to the situation in Switzerland to facilitate their clinical uptake for the further individualisation of FP chemotherapy. We recommend preemptive testing of four DPYD variants (c.1905+1G&gt;A (rs3918290), c.1679T&gt;G (rs55886062), c.2846A&gt;T (rs67376798) and c.1129-5923C&gt;G (rs75017182, c.1236G&gt;A/HapB3)) in patients with an indication for FP-based chemotherapy, with the costs reimbursed through the compulsory health insurance in Switzerland. Carriers of these variants (6.5% in the Swiss population) have a 40&ndash;50% risk of developing severe early-onset toxicity when treated with standard FP doses. In these patients, we therefore recommend the use of a reduced starting dose, based on a dose adjustment scheme provided herein. Furthermore, we recommend the use of infusional 5-FU in patients with a DPYD risk genotype in order to enable TDM-based dose escalation. Only if the use of an infusional 5-FU regimen is not feasible should a slow titration of Cap, starting with the recommended reduced dose and basing further doses on monitoring of toxicity, be considered. Given that several studies have shown that TDM in 5-FU treatment improves not only the therapy&rsquo;s safety, but potentially also its efficacy, we also include detailed TDM-based dosing guidelines and discuss the pre-analytical aspects of 5-FU TDM.","variants":[{"Name":"NM_000110.4(DPYD):c.2846A>T (p.Asp949Val)","Chromosome":"1","Start":"97082391","Stop":"97082391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":94529,"rule_based_match":false,"evidence_text":"c.2846A>T (rs67376798)","llm_judgment":"PRESENT","evidence":"c.2846A>T (rs67376798)","abstract_start":null,"abstract_end":null},{"Name":"NM_000110.4(DPYD):c.1679T>G (p.Ile560Ser)","Chromosome":"1","Start":"97515787","Stop":"97515787","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":94530,"rule_based_match":false,"evidence_text":"c.1679T>G (rs55886062)","llm_judgment":"PRESENT","evidence":"c.1679T>G (rs55886062)","abstract_start":null,"abstract_end":null}]}
{"pmid":"21981781","title":"Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder.","abstract":"Persons with neurodevelopmental disorders or autism spectrum disorder (ASD) often harbor chromosomal microdeletions, yet the individual genetic contributors within these regions have not been systematically evaluated. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosomal region 2q23.1 and acquired 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints; aligned microdeletions to determine the critical region; assessed effects on mRNA expression; and examined medical records, photos, and clinical evaluations. We identified a single gene, methyl-CpG-binding domain 5 (MBD5), as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression, intellectual disability, epilepsy, and autistic features. Fourteen alterations, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening, disrupted MBD5 alone. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. No copy-number alterations of MBD5 were observed in 7878 controls, suggesting MBD5 alterations are highly penetrant. We surveyed MBD5 coding variations among 747 ASD subjects compared to 2043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG-binding domain missense variant, p.79Gly>Glu (c.236G>A) (p = 0.012). These results suggest that genetic alterations of MBD5 cause features of 2q23.1 microdeletion syndrome and that this epigenetic regulator significantly contributes to ASD risk, warranting further consideration in research and clinical diagnostic screening and highlighting the importance of chromatin remodeling in the etiology of these complex disorders.","variants":[{"Name":"NM_001378120.1(MBD5):c.236G>A (p.Gly79Glu)","Chromosome":"2","Start":"148463758","Stop":"148463758","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":196051,"rule_based_match":true,"evidence_text":"c.236G>A (p = 0.012)","llm_judgment":"PRESENT","evidence":"c.236G>A","abstract_start":1593,"abstract_end":1601}]}
{"pmid":"32509318","title":"Novel","abstract":"Comprehensive genomic analysis was performed in a patient with mild psychomotor developmental delay, elevated creatine kinase, and white matter abnormalities. The results revealed biallelic pathogenic variants in the gene related to merosin-deficient congenital muscular dystrophy, NM_000426.3(LAMA2):c.1338_1339del [p.Gly447Phefs*7] and c.2749 + 2dup, which consist of compound heterozygous involvement with predicted loss-of-function and splicing abnormalities.","variants":[{"Name":"NM_000426.4(LAMA2):c.2749+2dup","Chromosome":"6","Start":"129288059","Stop":"129288060","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":543814,"rule_based_match":true,"evidence_text":"c.2749 + 2dup","llm_judgment":"PRESENT","evidence":"c.2749 + 2dup","abstract_start":338,"abstract_end":351}]}
{"pmid":"28733338","title":"Early and lethal neurodegeneration with myasthenic and myopathic features: A new","abstract":"OBJECTIVE: To describe the presentation and identify the cause of a new clinical phenotype, characterized by early severe neurodegeneration with myopathic and myasthenic features.\nMETHODS: This case study of 5 patients from 3 families includes clinical phenotype, serial MRI, electrophysiologic testing, muscle biopsy, and full autopsy. Genetic workup included whole exome sequencing and segregation analysis of the likely causal mutation.\nRESULTS: All 5 patients showed severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy. Three patients had congenital contractures. All patients died during their first year of life. In 2 of our patients, electrophysiologic testing showed abnormal decrement, but treatment with pyridostigmine led only to temporary improvement. Causative mutations in <i>ALG14</i> were identified in all patients. The mutation c.220 G>A (p.Asp74Asn) was homozygous in 2 patients and heterozygous in the other 3 patients. Additional heterozygous mutations were c.422T>G (p.Val141Gly) and c.326G>A (p.Arg109Gln). In all cases, parents were found to be heterozygous carriers. None of the identified variants has been described previously.\nCONCLUSIONS: We report a genetic syndrome combining myasthenic features and severe neurodegeneration with therapy-refractory epilepsy. The underlying cause is a glycosylation defect due to mutations in <i>ALG14</i>. These cases broaden the phenotypic spectrum associated with <i>ALG14</i> congenital disorders of glycosylation as previously only isolated myasthenia has been described.","variants":[{"Name":"NM_144988.4(ALG14):c.326G>A (p.Arg109Gln)","Chromosome":"1","Start":"95027223","Stop":"95027223","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":365560,"rule_based_match":true,"evidence_text":"c.326G>A (p.Arg109Gln)","llm_judgment":"PRESENT","evidence":"c.326G>A (p.Arg109Gln)","abstract_start":1043,"abstract_end":1065},{"Name":"NM_144988.4(ALG14):c.220G>A (p.Asp74Asn)","Chromosome":"1","Start":"95064934","Stop":"95064934","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":365258,"rule_based_match":true,"evidence_text":"c.220 G>A (p.Asp74Asn)","llm_judgment":"PRESENT","evidence":"c.220 G>A (p.Asp74Asn)","abstract_start":883,"abstract_end":905},{"Name":"NM_144988.4(ALG14):c.422T>G (p.Val141Gly)","Chromosome":"1","Start":"94983305","Stop":"94983305","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":628286,"rule_based_match":true,"evidence_text":"c.422T>G (p.Val141Gly)","llm_judgment":"PRESENT","evidence":"c.422T>G (p.Val141Gly)","abstract_start":1016,"abstract_end":1038}]}
{"pmid":"35464678","title":"Rare occult macular dystrophy with a pathogenic variant in the RP1L1 gene in a patient of Swiss descent.","abstract":"Purpose: We report a first case of bilateral occult macular dystrophy (OMD) with a c.133C>T (p.Arg45Trp) pathogenic variant in the retinitis pigmentosa 1-like 1 (<i>RP1L1</i>) gene in a patient of Caucasian Swiss decent.\nObservations: A 34-year-old man presented with decreased visual acuity known since childhood. Fundus examination of both eyes revealed no pathology other than mildly increased granularity of the foveal retinal pigment epithelium. The full-field electroretinogram (ffERG) presented with normal findings while the multifocal electroretinogram (mfERG) showed severely reduced amplitudes of the foveal response. Optical coherence tomography (OCT) showed foveal outer retinal atrophy. Fundus autofluorescence (FAF) imaging demonstrated near-normal findings with minimal mottling at the posterior pole. The genetic analysis revealed a heterozygous pathogenic variant (c.133C>T, p.Arg45Trp) in the <i>RP1L1</i> gene.\nConclusion and importance: Our present case suggests that OMD shows a wide range of clinical presentations with a variety of ophthalmological findings, age of disease onset, visual acuity, and genetic diversity.","variants":[{"Name":"NM_178857.6(RP1L1):c.133C>T (p.Arg45Trp)","Chromosome":"8","Start":"10623069","Stop":"10623069","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17232,"rule_based_match":true,"evidence_text":"c.133C>T (p.Arg45Trp)","llm_judgment":"PRESENT","evidence":"c.133C>T (p.Arg45Trp)","abstract_start":83,"abstract_end":104}]}
{"pmid":"26757782","title":"Fetal Anemia and Hydrops Fetalis Associated with Homozygous Hb Constant Spring (HBA2: c.427T > C).","abstract":"Hb Constant Spring (Hb CS, HBA2: c.427T > C) is a common nondeletional α-thalassemia (α-thal) that results from a nucleotide substitution at the termination codon of the α2-globin gene. Homozygosity for Hb CS (α(CS)α/α(CS)α) is relatively rare, and generally characterized with mild hemolytic anemia, jaundice, and splenomegaly. In this report we present a fetus with cardiomegaly, pericardial effusion, enlarged placenta and increased middle cerebral artery-peak systolic velocity (MCA-PSV) at 24 weeks' gestation. Fetal blood sampling revealed the severe anemia [hemoglobin (Hb) level being 4.8 g/dL] and Hb H (β4) disease-like hematological findings with Hb Bart's (γ4) level of 17.9%. DNA sequencing of the α-globin genes found that both partners were Hb CS carriers and the fetus was an Hb CS homozygote. Therefore, this was a rare case of homozygous Hb CS which demonstrated an unusual and serious anemia and hydrops fetalis in utero.","variants":[{"Name":"NM_000517.4(HBA2):c.427T>C (p.Ter143Gln)","Chromosome":"16","Start":"173598","Stop":"173598","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":30663,"rule_based_match":true,"evidence_text":"HBA2: c.427T > C","llm_judgment":"PRESENT","evidence":"HBA2: c.427T > C","abstract_start":27,"abstract_end":43}]}
{"pmid":"29531774","title":"A novel","abstract":"Biallelic mutations in the post-GPI attachment to proteins 3 (<i>PGAP3</i>) gene cause hyperphosphatasia with mental retardation syndrome 4 (HPMRS4), which is characterized by elevated serum alkaline phosphatase, severe psychomotor developmental delay, seizures, and facial dysmorphism. To date, 15 <i>PGAP3</i> mutations have been reported in humans. Here we report a novel homozygous <i>PGAP3</i> mutation (c.314C>A, p.Pro105Gln) in a Croatian patient and fully describe the clinical features.","variants":[{"Name":"NM_033419.5(PGAP3):c.314C>A (p.Pro105Gln)","Chromosome":"17","Start":"39684715","Stop":"39684715","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1701506,"rule_based_match":true,"evidence_text":"c.314C>A, p.Pro105Gln","llm_judgment":"PRESENT","evidence":"c.314C>A, p.Pro105Gln","abstract_start":409,"abstract_end":430}]}
{"pmid":"29625835","title":"A MYH3 mutation identified for the first time in a Chinese family with Sheldon-Hall syndrome (DA2B).","abstract":"Sheldon-Hall syndrome is the most common type of distal arthrogryposis syndromes, also known as distal arthrogryposis 2B (DA2B). Sheldon-Hall syndrome is caused by mutations in the TPM2, TNNI2, TNNT3 or MYH3 gene and characterized by ulnar deviation, camptodactyly, overlapping fingers and scoliosis from birth. We investigated a Chinese family with multiple members who clinically presented with distal arthrogryposis of the hands. In total, 261 subjects including one proband and ten family members from the non-consanguineous Chinese family and 250 healthy volunteers were included and had their genomic DNA extracted. A novel missense mutation in exon 13 of the MYH3 gene, c.1160A > G (p.Tyr387Cys), was identified in the proband and his father through whole-exome sequencing. The proband and six affected family members were confirmed to carry this mutation by Sanger sequencing, although the mutation was not detected in the four unaffected individuals or 250 volunteers. This is the first report of a novel MYH3 mutation being identified as the cause of DA2B in a Chinese family. Our findings confirm that MYH3 gene mutations can be a pathogenic cause of DA2B in Asian patients. This study increases the mutational spectrum in MYH3 and aids genetic counseling and prenatal diagnosis.","variants":[{"Name":"NM_002470.4(MYH3):c.1160A>G (p.Tyr387Cys)","Chromosome":"17","Start":"10644684","Stop":"10644684","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":619825,"rule_based_match":true,"evidence_text":"c.1160A > G (p.Tyr387Cys)","llm_judgment":"PRESENT","evidence":"c.1160A > G (p.Tyr387Cys)","abstract_start":677,"abstract_end":702}]}
{"pmid":"20101687","title":"Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literature.","abstract":"Restrictive dermopathy (RD) is a rare, severe, lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence. To date, about 60 cases of RD were described. The signs of the disease are very characteristic and include intrauterine growth retardation, thin, tightly adherent translucent skin, superficial vessels, typical facial dysmorphism as well as generalized joint contractures. The syndrome is caused in most cases by ZMPSTE24 autosomal recessive mutations, or, less frequently, by LMNA autosomal dominant mutations. We report on two brothers affected with RD, who died in the neonatal period. Molecular analyses were performed in the second child, for whom biological material was available, and both parents. Compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene. The autosomal recessive inheritance was confirmed by the parents' genomic analysis. Besides, a review of the mutations causing RD is made.","variants":[{"Name":"NM_005857.5(ZMPSTE24):c.50del (p.Lys17fs)","Chromosome":"1","Start":"40258320","Stop":"40258320","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":49843,"rule_based_match":true,"evidence_text":"c.50delA","llm_judgment":"PRESENT","evidence":"c.50delA","abstract_start":836,"abstract_end":844},{"Name":"NM_005857.5(ZMPSTE24):c.584_585del (p.Tyr195fs)","Chromosome":"1","Start":"40270083","Stop":"40270084","ReferenceAlleleVCF":"CTA","AlternateAlleleVCF":"C","allel_id":49844,"rule_based_match":true,"evidence_text":"c.584_585delAT","llm_judgment":"PRESENT","evidence":"c.584_585delAT","abstract_start":858,"abstract_end":872}]}
{"pmid":"27761313","title":"Comparative functional characterization of novel non-syndromic","abstract":"We characterized a novel <i>GJB2</i> missense variant, c.133G>A, p.Gly45Arg, and compared it with the only other variant at the same amino acid position of the connexin 26 protein (Cx26) reported to date: c.134G>A, p.Gly45Glu. Whereas both variants are associated with hearing loss and are dominantly inherited, p.Gly45Glu has been implicated in the rare fatal keratitis-ichthyosis-deafness (KID) syndrome, which results in cutaneous infections and septicemia with premature demise in the first year of life. In contrast, p.Gly45Arg appears to be non-syndromic. Subcellular localization experiments in transiently co-transfected HeLa cells demonstrated that Cx26-WT (wild-type) and p.Gly45Arg form gap junctions, whereas Cx26-WT with p.Gly45Glu protein does not. The substitution of a nonpolar amino acid glycine in wildtype Cx26 at position 45 with a negatively charged glutamic acid (acidic) has previously been shown to interfere with Ca<sup>2+</sup> regulation of hemichannel gating and to inhibit the formation of gap junctions, resulting in cell death. The novel variant p.Gly45Arg, however, changes this glycine to a positively charged arginine (basic), resulting in the formation of dysfunctional gap junctions that selectively affect the permeation of negatively charged inositol 1,4,5-trisphosphate (IP<sub>3</sub>) and contribute to hearing loss. Cx26 p.Gly45Arg transfected cells, unlike cells transfected with p.Gly45Glu, thrived at physiologic Ca<sup>2+</sup> concentrations, suggesting that Ca<sup>2+</sup> regulation of hemichannel gating is unaffected in Cx26 p.Gly45Arg transfected cells. Thus, the two oppositely charged amino acids that replace the highly conserved uncharged glycine in p.Gly45Glu and p.Gly45Arg, respectively, produce strikingly different effects on the structure and function of the Cx26 protein.","variants":[{"Name":"NM_004004.6(GJB2):c.134G>A (p.Gly45Glu)","Chromosome":"13","Start":"20189448","Stop":"20189448","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32072,"rule_based_match":true,"evidence_text":"c.134G>A, p.Gly45Glu","llm_judgment":"PRESENT","evidence":"c.134G>A, p.Gly45Glu","abstract_start":205,"abstract_end":225},{"Name":"NM_004004.6(GJB2):c.133G>A (p.Gly45Arg)","Chromosome":"13","Start":"20189449","Stop":"20189449","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":546941,"rule_based_match":true,"evidence_text":"c.133G>A, p.Gly45Arg","llm_judgment":"PRESENT","evidence":"c.133G>A, p.Gly45Arg","abstract_start":55,"abstract_end":75}]}
{"pmid":"30315757","title":"Additional molecular and clinical evidence open the way to definitive IARC classification of the BRCA1 c.5332G > A (p.Asp1778Asn) variant.","abstract":"OBJECTIVES: In silico splicing analysis, a mini-gene assay and splicing data, obtained using RNA from blood samples, have shown that the BRCA1 c.5332G > A variant induces exon 21 skipping. However, despite these evidences, up to date, this variant is unclassified. The aim of this study is to provide further molecular and clinical evidence for the BRCA1 c.5332G > A variant in a patient with high grade serous ovarian carcinoma (HGSOC) to allow a definitive classification of this variant.\nDESIGN AND METHOD: The effect of the BRCA1 c.5332G > A variant on RNA splicing was evaluated by amplifying regions of BRCA1 from the cDNA of the patient. Loss of heterozygosity (LOH) in tumor tissue was also investigated.\nRESULTS: The c.5332G > A allele causes significantly aberrant splicing of the BRCA1 exon 21. Evaluation of the c.5332A allele in tumor tissue highlights a possible loss of heterozygosity, supporting her pathogenic effect.\nCONCLUSIONS: Our results regarding the c.5332G > A variant confirm that it contributed to predisposition and onset of ovarian carcinoma in the patient. We propose to classify this variant as 'likely-pathogenic' (class IV).","variants":[{"Name":"NM_007294.4(BRCA1):c.5332G>A (p.Asp1778Asn)","Chromosome":"17","Start":"43051063","Stop":"43051063","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70197,"rule_based_match":true,"evidence_text":"BRCA1 c.5332G > A (p.Asp1778Asn)","llm_judgment":"PRESENT","evidence":"c.5332G > A","abstract_start":143,"abstract_end":154}]}
{"pmid":"32849781","title":"Identification and Computational Analysis of Novel","abstract":"Non-syndromic oculocutaneous albinism (nsOCA) is an inherited disorder of melanin biosynthesis with autosomal recessive mode of inheritance, presenting either hypopigmented or depigmented skin, hair, and eyes. It is genetically heterogeneous with seven loci (OCA1-OCA7) reported to date. In the present study, we have reported three consanguineous families (A, B, C) presenting identical nsOCA phenotypes. Sanger sequencing revealed a novel [NM_000372.5: c.826 T > C, p.(Cys276Arg)] and a recurrent variant [NM_000372.5: c.832C > T, p.(Arg278<sup>∗</sup>)] in tyrosinase (<i>TYR</i>) in families A and B, respectively. Microsatellite marker-based homozygosity mapping linked family C to OCA4. Sequence analysis identified a novel insertion variant (NM_016180.5: c.1331_1332insA) in the <i>SLC45A2</i>. Further, <i>in silico</i> mutagenesis and dynamic simulation approaches revealed that a novel Cys276Arg variant abolished the cysteine bridge and might contribute toward decreased stability of the TYR protein. Our study expands the mutation spectrum of the <i>TYR</i> and <i>SLC45A2</i> genes and emphasizes that molecular investigations are essential for accurate disease diagnosis.","variants":[{"Name":"NM_000372.5(TYR):c.832C>T (p.Arg278Ter)","Chromosome":"11","Start":"89191214","Stop":"89191214","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105472,"rule_based_match":true,"evidence_text":"NM_000372.5: c.832C > T, p.(Arg278<sup>∗</sup>)","llm_judgment":"PRESENT","evidence":"NM_000372.5: c.832C > T, p.(Arg278<sup>∗</sup>)","abstract_start":508,"abstract_end":555},{"Name":"NM_000372.5(TYR):c.826T>C (p.Cys276Arg)","Chromosome":"11","Start":"89191208","Stop":"89191208","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2742177,"rule_based_match":true,"evidence_text":"NM_000372.5: c.826 T > C, p.(Cys276Arg)","llm_judgment":"PRESENT","evidence":"NM_000372.5: c.826 T > C, p.(Cys276Arg)","abstract_start":442,"abstract_end":481}]}
{"pmid":"31322236","title":"Identification of CRB1 mutations in two Chinese consanguineous families exhibiting autosomal recessive retinitis pigmentosa.","abstract":"Retinitis pigmentosa (RP) is a leading cause of inherited blindness characterized by progressive loss of retinal photoreceptor cells. The present study aimed to identify the causative gene mutations in two Chinese families with autosomal recessive retinitis pigmentosa (arRP). Two Chinese consanguineous arRP families (RP‑2284 and RP‑2360) were recruited in this study, involving totally three affected and 25 unaffected members. All the affected members underwent a complete ophthalmic examination, including fundus photography, multifocal electroretinography (ERG) and full field ERG. Exome sequencing was performed on the three RP patients in the two families, followed by direct Sanger sequencing in all the family members and in 1,260 unrelated controls for validation of the mutations identified. Two homozygous missense mutations in the crumbs homolog 1 (CRB1) gene, which is known to cause severe retinal dystrophies, were found to be related to the phenotype of the two arRP families. The homozygous missense mutation c.1997 T>A in CRB1 was detected in two patients in the RP‑2284 family. The proband in the RP‑2360 family was the only RP patient and was found to carry the novel homozygous missense mutation c.2426 A>C in CRB1. The two mutations were heterozygous or absent in the other healthy family members, and they were absent in the 1,260 controls. The amino acid changes in the CRB1 protein affected by the two mutations were predicted to be damaging by Polyohen‑2. Our study reported two CRB1 mutations causing arRP in two Chinese families, which expands the CRB1 mutation spectrum of RP in the Chinese population and emphasizes the causative role of CRB1 in RP.","variants":[{"Name":"NM_201253.3(CRB1):c.1997T>A (p.Val666Asp)","Chromosome":"1","Start":"197421825","Stop":"197421825","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1471410,"rule_based_match":true,"evidence_text":"c.1997 T>A","llm_judgment":"PRESENT","evidence":"c.1997 T>A","abstract_start":1027,"abstract_end":1037}]}
{"pmid":"16883537","title":"CHEK2 c.1100delC may not contribute to genetic background of hereditary breast cancer from Shanghai of China","abstract":"OBJECTIVE: To investigate the prevalence of CHEK2 c.1100delC mutation among non-BRCA1/BRCA2 familial/early-onset breast cancer patients in Shanghai.\nMETHODS: One hundred and fourteen non-BRCA1/BRCA2 hereditary breast cancer patients were analyzed, among whom 76 cases had at least one first-degree relative affected with breast cancer and 38 cases were diagnosed as breast cancer below the age of 40 years without family history. The mutation genotyping of CHEK2 c.1100delC were carried out through long-range PCR amplifying of exons 10-14, and followed by amplification of exon 10 and then DNA direct sequencing.\nRESULTS: No c.1100delC frame-shift mutation was identified in our studied population. One novel missense mutation 1111C>T (p.His371Tyr), located in kinase catalytic domain, was found in 3 familial breast cancer cases but no one in control group.\nCONCLUSION: CHEK2 c.1100delC is rare variant for Chinese population and may not contribute to predisposition for hereditary breast cancer in Shanghai. Novel variant -1111C>T could be in association with genetic susceptibility to breast cancer. A further study is needed to confirm the results.","variants":[{"Name":"NM_007194.4(CHEK2):c.1111C>T (p.His371Tyr)","Chromosome":"22","Start":"28695858","Stop":"28695858","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":133501,"rule_based_match":false,"evidence_text":"1111C>T (p.His371Tyr)","llm_judgment":"PRESENT","evidence":"1111C>T (p.His371Tyr)","abstract_start":728,"abstract_end":749}]}
{"pmid":"29896790","title":"De novo mutations of STXBP1 in Chinese children with early onset epileptic encephalopathy.","abstract":"To detect syntaxin-binding protein 1 (STXBP1) mutations in Chinese patients with early onset epileptic encephalopathy (EOEE) of unknown etiology. Targeted next-generation sequencing was used to identify STXBP1 mutations in 143 Chinese patients with EOEE of unknown etiology. A filtering process was applied to prioritize rare variants of potential functional significance. Then Sanger sequencing was employed to validate the parental origin of the variants. Detailed clinical and genetic data were collected for 9 STXBP1-positive patients. Eight de novo heterozygous STXBP1 mutations were identified in 9 patients; 5 were novel mutations (c.1155delC, c.1030-1G>A, c.217G>C, c.268G>C, c.1480_1481 insT) and 3 were previously reported (c.1216C> T, c.1217G>A [2 cases], c.875G>A). Two patients had Ohtahara syndrome and 1 had West syndrome at onset, whereas the other 6 presented with EOEE that did not fit a specific recognized epilepsy syndrome. Six of these patients later evolved to West syndrome. All but 2 cases were prescribed more than 2 antiepileptic drugs (AEDs) plus other regimens. Four subjects showed good responses to levetiracetam (LEV) alone or in combination with other AEDs, and one case (1/3) achieved complete freedom from seizures with a ketogenic diet (KD). All patients exhibited severe to profound global developmental delay. Five novel heterozygous de novo STXBP1 mutations were discovered in patients with EOEE from China. STXBP1 mutational analysis should be performed in cases of EOEE of unknown etiology. LEV as monotherapy or adjunctive therapy with other regimens, as well as KD should be considered for management of this patient group.","variants":[{"Name":"NM_001032221.6(STXBP1):c.268G>C (p.Asp90His)","Chromosome":"9","Start":"127660051","Stop":"127660051","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":925363,"rule_based_match":true,"evidence_text":"c.268G>C","llm_judgment":"PRESENT","evidence":"c.268G>C","abstract_start":674,"abstract_end":682}]}
{"pmid":"22866093","title":"Genetic testing and first presymptomatic diagnosis in Moroccan families at high risk for breast/ovarian cancer.","abstract":"Germline mutations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancers and are responsible for a substantial proportion of familial breast and ovarian cancers. No female individuals from families from Morocco affected by breast cancer with mutations of these genes have previously been reported, and clinicians in Morocco are unaccustomed to dealing with healthy female individuals carrying mutations in the BRCA genes. This study aimed to report the initial experience of a group of Moroccan investigators carrying out predictive genetic testing to detect a known familial mutation in healthy Moroccan females with a high risk of developing breast cancer and to introduce supervision of these asymptomatic female carriers as a new approach in the prevention and early diagnosis of breast and ovarian cancers in Morocco. Presymptomatic diagnosis was carried out using DNA genetic testing in 5 healthy Moroccan female individuals from three families with an elevated risk of developing breast cancer. These are the first Moroccan families reported to be affected by breast cancers associated with BRCA mutations. Presymptomatic diagnosis was carried out for breast cancer in 5 female individuals from three Moroccan families with BRCA mutations. Two of the families are the first reported incidence of the founder mutation Ashkenazi BRCA1-185_186delAG in Moroccan patients. The third family carried the known BRCA2 mutation c.5073dupA/p.trp1692metfsX3. We tested the presence of these mutations in 5 asymptomatic healthy females from the three families. Two sisters from family 1 carried the BRCA1-185_186delAG mutation, whereas the third female individual from family 2 carried the c.5073dupA/p.trp1692metfsX3 mutation. However, one healthy female individual and her mother from family 3 did not carry the familial mutation of the BRCA1 gene. This study found BRCA mutations in three asymptomatic subjects, suggesting that this is the first step towards the development of persistent medical monitoring of females from families with a history of breast and ovarian cancers. Consequently, it is crucial for oncologists in Morocco to initiate the supervision of healthy female individuals with genetic defects which may lead to hereditary cancers.","variants":[{"Name":"NM_000059.4(BRCA2):c.5073dup (p.Trp1692fs)","Chromosome":"13","Start":"32339421","Stop":"32339422","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":46499,"rule_based_match":true,"evidence_text":"c.5073dupA/p.trp1692metfsX3","llm_judgment":"PRESENT","evidence":"c.5073dupA/p.trp1692metfsX3","abstract_start":1448,"abstract_end":1475}]}
{"pmid":"29240602","title":"Unclassified Variants of BRCA1 and BRCA2 in Korean Patients With Ovarian Cancer.","abstract":"OBJECTIVE: The aim of the present study was to investigate unclassified variants (UVs) in BRCA1 and 2 of Korean patients with ovarian cancer.\nMETHODS: We retrospectively analyzed 138 patients diagnosed with ovarian/fallopian tubal/peritoneal cancer between January 2013 and January 2016, whose BRCA genetic test results and clinical characteristics were available for review. Patient peripheral blood lymphocyte specimens were assessed for BRCA mutations and variations by direct sequencing. Identified UVs were classified according to several algorithms.\nRESULTS: The results of genetic testing revealed 31 (22.5%, 31/138) pathogenic BRCA mutations (24 BRCA1, 7 BRCA2 mutations). The BRCA1 c.390C>A mutation was observed in 4 patients (12.9%, 4/31). Thirty-four (24.6%, 34/138) BRCA UVs were identified in 33 patients. Of these, the BRCA1 c.4883T>C and BRCA2 c.8187G>T variants were each detected in 4 patients (4/34, 11.8%). According to the used algorithms and cosegregation test, the BRCA1 c.5339T>C and BRCA2 c.8437_8439delGGA variants were both predicted to be likely pathogenic.\nCONCLUSIONS: The 2 identified likely pathogenic UVs require further verification with clinical evidence. Clarifying the clinical significance of UVs is an increasingly important step for cancer treatment in the current era of precision medicine.","variants":[{"Name":"NM_007294.4(BRCA1):c.5339T>C (p.Leu1780Pro)","Chromosome":"17","Start":"43049188","Stop":"43049188","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":70208,"rule_based_match":true,"evidence_text":"BRCA1 c.5339T>C","llm_judgment":"PRESENT","evidence":"BRCA1 c.5339T>C","abstract_start":988,"abstract_end":1003},{"Name":"NM_007294.4(BRCA1):c.390C>A (p.Tyr130Ter)","Chromosome":"17","Start":"43104173","Stop":"43104173","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":69713,"rule_based_match":true,"evidence_text":"BRCA1 c.390C>A","llm_judgment":"PRESENT","evidence":"BRCA1 c.390C>A","abstract_start":685,"abstract_end":699}]}
{"pmid":"17113806","title":"Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations.","abstract":"Isolated methylmalonic acidurias (MMA-urias) comprise a group of rare autosomal recessively inherited disorders characterised by accumulation of MMA in urine and other body fluids, resulting from deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MCM). Isolated MMA-uria results from either MCM apoenzyme defects (mut(0) and mut(-)) or defects in synthesis of its cofactor 5-deoxyadenosylcobalamin, i.e. cblA, cblB and cblD-variant 2. To date various studies have identified 171 disease-causing mutations in the MCM gene (MUT). We report mutation analysis in 32 probands with mut MMA-uria including 13 probands with a mut(-) defect. Sixty two of 64 possible mutant alleles were identified, seven of which were novel missense alleles. We found three novel mutations (c.427C>T/p.H143Y; c.862T>C/p.S288P; c.1361G>A/p.G454E) among 19 probands with a mut(0) defect and four novel mutations (c.299A>G/p.Y100C; c.1031C>T/p.S344F; c.1097A>G/p.N366S; c.2081G>T/p.R694L) among 13 probands with a mut(-) defect. Our study provides evidence that the p.Y100C, p.R108H, p.N366S, p.V633G, p.R694W, p.R694L and p.M700K mutations are associated with a mut(-) phenotype.","variants":[{"Name":"NM_000255.4(MMUT):c.1097A>G (p.Asn366Ser)","Chromosome":"6","Start":"49451701","Stop":"49451701","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":216046,"rule_based_match":true,"evidence_text":"c.1097A>G/p.N366S","llm_judgment":"PRESENT","evidence":"c.1097A>G/p.N366S","abstract_start":945,"abstract_end":962},{"Name":"NM_000255.4(MMUT):c.299A>G (p.Tyr100Cys)","Chromosome":"6","Start":"49459168","Stop":"49459168","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":216052,"rule_based_match":true,"evidence_text":"c.299A>G/p.Y100C","llm_judgment":"PRESENT","evidence":"c.299A>G/p.Y100C","abstract_start":908,"abstract_end":924}]}
{"pmid":"27240500","title":"Identification of a novel mutation in SLC26A4 gene in a Chinese family with enlarged vestibular aqueduct syndrome.","abstract":"OBJECTIVE: To investigate the genetic causes of hearing loss in a two generation Chinese family with enlarged vestibular aqueduct syndrome (EVAS).\nMETHODS: Clinical and genetic evaluations were conducted in a deaf proband and her normal-hearing parents. Sanger sequencing analysis of all the 21 exons, the exon-intron boundaries and the promoter in SLC26A4 gene was performed to detect the pathogenic mutations. PCR-restricted fragment length polymorphism (PCR-RFLP) was used to further identify the mutation. Phylogenetic analysis was carried out with multiple sequence alignment using BioEdit software. Three-dimensional (3D) modeling of the human wild-type and mutant SLC26A4 (NP_000432.1) was carried out using I-TASSER (http://zhanglab.ccmb.med.umich.edu/).\nRESULTS: Clinical examinations showed that the proband suffered from typical features of sensorineural hearing loss with enlarged vestibular aqueduct. A novel nonsense mutation c.2118C>A (p.C706X) in exon 19 was identified in compound heterozygosity with the splice-site mutation c.919-2A>G in the proband by using Sanger sequencing. The mother was a heterozygous carrier of c.919-2A>G in intron 7, while the father was a heterozygous carrier of c.2118C>A. The mutation c.2118C>A was not found in 200 unrelated controls using Sanger sequencing. PCR-RFLP showed the PCR product of the proband was not digested at 2110 by Fau I because of the c.2118C>A mutation. 3D-structure modeling indicated that the mutation c.2118C>A resulted in a truncate Pendrin protein. Protein alignment indicated high conservation of p.C706 residue in healthy Homo, Nomascus, Pan, Macaca, Canis, Sus, Mus, Rattus, Cricetulus and Xenopus.\nCONCLUSIONS: This study revealed a novel heterozygous mutation c.2118C>A (p.C706X) compound with c.919-2A>G in SLC26A4 gene in a patient with EVAS.","variants":[{"Name":"NM_000441.2(SLC26A4):c.2118C>A (p.Cys706Ter)","Chromosome":"7","Start":"107710082","Stop":"107710082","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":544449,"rule_based_match":true,"evidence_text":"c.2118C>A (p.C706X)","llm_judgment":"PRESENT","evidence":"c.2118C>A (p.C706X)","abstract_start":940,"abstract_end":959}]}
{"pmid":"28445022","title":"Novel Mutation (c.8725T>C) in Two Siblings With Late-Onset LAMA2-Related Muscular Dystrophy.","abstract":"","variants":[{"Name":"NM_000426.4(LAMA2):c.8725T>C (p.Cys2909Arg)","Chromosome":"6","Start":"129507510","Stop":"129507510","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2904864,"rule_based_match":true,"evidence_text":"c.8725T>C","llm_judgment":"PRESENT","evidence":"c.8725T>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"31291907","title":"CLCN2-related leukoencephalopathy: a case report and review of the literature.","abstract":"BACKGROUND: Loss-of-function mutations in the CLCN2 gene were recently discovered to be a cause of a type of leukodystrophy named CLCN2-related leukoencephalopathy (CC2L), which is characterized by intramyelinic edema. Herein, we report a novel mutation in CLCN2 in an individual with leukodystrophy.\nCASE PRESENTATION: A 38-year-old woman presented with mild hand tremor, scanning speech, nystagmus, cerebellar ataxia in the upper limbs, memory decline, tinnitus, and dizziness. An ophthalmologic examination indicated macular atrophy, pigment epithelium atrophy and choroidal capillary atrophy. Brain magnetic resonance imaging (MRI) showed the diffuse white matter involvement of specific white matter tracts. Decreased diffusion anisotropy was detected in various brain regions of the patient. Diffusion tensor tractography (DTT) showed obviously thinner tracts of interest than in the controls, with a decreased fiber number (FN), increased radial diffusivity (RD) and unchanged axial diffusivity (AD). A novel homozygous c.2257C > T (p.Arg753Ter) mutation in exon 20 of the CLCN2 gene was identified.\nCONCLUSION: CC2L is a rare condition characterized by diffuse edema involving specific fiber tracts that pass through the brainstem. The distinct MRI patterns could be a strong indication for CLCN2 gene analysis. The findings of our study may facilitate the understanding of the pathophysiology and clinical symptoms of this disease.","variants":[{"Name":"NM_004366.6(CLCN2):c.2257C>T (p.Arg753Ter)","Chromosome":"3","Start":"184352457","Stop":"184352457","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1941473,"rule_based_match":true,"evidence_text":"c.2257C > T (p.Arg753Ter)","llm_judgment":"PRESENT","evidence":"c.2257C > T (p.Arg753Ter)","abstract_start":1027,"abstract_end":1052}]}
{"pmid":"35499143","title":"COASY related pontocerebellar hypoplasia type 12: A common Indian mutation with expansion of the phenotypic spectrum.","abstract":"Pontocerebellar hypoplasia (PCH) type 12 is a rare, perinatal lethal neurodegenerative genetic disorder caused by biallelic mutations in the COASY gene. Herein, we describe the clinical and neuroradiological profile of nine affected fetuses/neonates from five families identified with a common COASY: c.1486-3C>G biallelic variant. Four of the five families were identified after data reanalysis of unresolved, severe PCH like phenotype and the fifth family through collaboration. The common antenatal phenotype was cerebellar hypoplasia. Microcephaly, arthrogryposis, and intrauterine growth restriction were the shared postnatal findings. The neurological manifestations included seizures, poor sucking, and spasticity. Novel findings of corpus callosum agenesis, simplified gyral pattern, normal sized pons, optic neuropathy, and a small thorax are reported in this series. The allele frequency of the COASY: c.1486-3C>G variant was 0.62% in the available Asian Indian database. We describe this as a possible common Indian origin variant. To the best of our knowledge, this is the largest PCH12 series reported.","variants":[{"Name":"NM_025233.7(COASY):c.1486-3C>G","Chromosome":"17","Start":"42565656","Stop":"42565656","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":590638,"rule_based_match":true,"evidence_text":"COASY: c.1486-3C>G","llm_judgment":"PRESENT","evidence":"COASY: c.1486-3C>G","abstract_start":294,"abstract_end":312}]}
{"pmid":"28503092","title":"Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the","abstract":"BACKGROUND: Evaluation of the pathogenicity of a gene variant of unknown significance (VUS) is crucial for molecular diagnosis and genetic counseling, but can be challenging. This is especially so in phenotypically variable diseases, such as von Hippel-Lindau disease (vHL). vHL is caused by germline mutations in the VHL gene, which predispose to the development of multiple tumors such as central nervous system hemangioblastomas and renal cell carcinoma (RCC).\nOBJECTIVE: We propose a method for the evaluation of VUS pathogenicity through our experience with the VHL missense mutation c.241C>T (p.P81S).\nMETHOD: 1) Clinical evaluation of known variant carriers: We evaluated a family of five VHL p.P81S carriers, as well as the clinical characteristics of all the p.P81S carriers reported in the literature; 2) Evaluation of tumor tissue via genetic analysis, histology, and immunohistochemistry (IHC); 3) Assessment of the variant's impact on protein structure and function, using multiple databases, in silico algorithms, and reports of functional studies.\nRESULTS: Only one family member had clinical signs of vHL with early-onset RCC. IHC analysis showed no VHL protein expressed in the tumor, consistent with biallelic VHL inactivation. The majority of in silico algorithms reported p.P81S as possibly pathogenic in relation to vHL or RCC, but there were discrepancies. Functional studies suggest that p.P81S impairs the VHL protein's function.\nCONCLUSION: The VHL p.P81S mutation is most likely a low-penetrant pathogenic variant predisposing to RCC development. We suggest the above-mentioned method for VUS evaluation with use of different methods, especially a variety of in silico methods and tumor tissue analysis.","variants":[{"Name":"NM_000551.4(VHL):c.241C>T (p.Pro81Ser)","Chromosome":"3","Start":"10142088","Stop":"10142088","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17272,"rule_based_match":true,"evidence_text":"c.241C>T (p.P81S)","llm_judgment":"PRESENT","evidence":"c.241C>T (p.P81S)","abstract_start":589,"abstract_end":606}]}
{"pmid":"33354762","title":"Biallelic loss-of-function HACD1 variants are a bona fide cause of congenital myopathy.","abstract":"Congenital myopathies include a wide range of genetically determined disorders characterized by muscle weakness that usually manifest shortly after birth. To date, two different homozygous loss-of-function variants in the HACD1 gene have been reported to cause congenital myopathy. We identified three patients manifesting with neonatal-onset generalized muscle weakness and motor delay that carried three novel homozygous likely pathogenic HACD1 variants. The two of these changes (c.373_375+2delGAGGT and c.785-1G>T) were predicted to introduce splice site alterations, while one is a nonsense change (c.458G>A). The clinical presentation of our and the previously reported patients was comparable, including the temporally progressive improvement that seems to be characteristic of HACD1-related myopathy. Our findings conclusively confirm the implication of HACD1 in the pathogenesis of congenital myopathies, corroborate the main phenotypic features, and further define the genotypic spectrum of this genetic form of myopathy. Importantly, the genetic diagnosis of HACD1-related myopathy bears impactful prognostic value.","variants":[{"Name":"NM_014241.4(HACD1):c.373_375+2del","Chromosome":"10","Start":"17603928","Stop":"17603932","ReferenceAlleleVCF":"TACCTC","AlternateAlleleVCF":"T","allel_id":1407122,"rule_based_match":true,"evidence_text":"c.373_375+2delGAGGT","llm_judgment":"PRESENT","evidence":"c.373_375+2delGAGGT","abstract_start":483,"abstract_end":502},{"Name":"NM_014241.4(HACD1):c.458G>A (p.Trp153Ter)","Chromosome":"10","Start":"17603585","Stop":"17603585","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1690787,"rule_based_match":true,"evidence_text":"c.458G>A","llm_judgment":"PRESENT","evidence":"c.458G>A","abstract_start":604,"abstract_end":612},{"Name":"NM_014241.4(HACD1):c.785-1G>T","Chromosome":"10","Start":"17590447","Stop":"17590447","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1690788,"rule_based_match":true,"evidence_text":"c.785-1G>T","llm_judgment":"PRESENT","evidence":"c.785-1G>T","abstract_start":507,"abstract_end":517}]}
{"pmid":"27111571","title":"The discovery of LRRK2 p.R1441S, a novel mutation for Parkinson's disease, adds to the complexity of a mutational hotspot.","abstract":"Mutations in the LRRK2 gene result in autosomal dominant, late onset Parkinson's disease (PD). Three such mutations (p.R1441C, p.R1441G, and p.R1441H) are known to occur within codon 1441, and haplotype analyses indicate that each one has arisen independently on multiple occasions. We sequenced the entire coding region of 18 casual genes for PD or other parkinsonian neurodegenerative disorders in the proband of a family with autosomal dominant PD. We discovered a new missense mutation in the LRRK2 gene, c.4321C>A (p.R1441S). The mutation was predicted to be highly deleterious in silico (Combined Annotation Dependent Depletion score of 25.5) and segregated with disease in the pedigree. The clinical characteristics of affected family members were similar to those described in PD families with other mutations in LRRK2 codon 1441 and included resting tremor, rigidity, bradykinesia, unilateral onset, and a good response to levodopa. Age at onset ranged from 41 to 76. Two of the affected members of the pedigree underwent detailed, longitudinal neuropsychological testing, and both displayed evidence of mild cognitive deficits at or slightly preceding the onset of motor symptoms. LRRK2 p.R1441S represents the fourth pathogenic mutation observed within codon 1441 and its discovery adds to the remarkable complexity of a mutational hotspot within the ROC domain of the LRRK2 protein. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_198578.4(LRRK2):c.4321C>A (p.Arg1441Ser)","Chromosome":"12","Start":"40310434","Stop":"40310434","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":227175,"rule_based_match":true,"evidence_text":"c.4321C>A (p.R1441S)","llm_judgment":"PRESENT","evidence":"c.4321C>A (p.R1441S)","abstract_start":509,"abstract_end":529}]}
{"pmid":"30887539","title":"Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study.","abstract":"Phosphoglycerate kinase (PGK) deficiency is a rare X-linked metabolic disorder caused by mutations in the PGK1 gene. Patients usually develop various combinations of nonspherocytic hemolytic anemia (NSHA), myopathy, and central nervous system disorders. In this national multicenter observational retrospective study, we recorded all known French patients with PGK deficiency, and 3 unrelated patients were identified. Case 1 was a 32-year-old patient with severe chronic axonal sensorimotor polyneuropathy resembling Charcot-Marie-Tooth (CMT) disease, mental retardation, microcephaly, ophthalmoplegia, pes cavus, and the new c.323G > A PGK1 hemizygous mutation. Case 2 was a 71-year-old patient with recurrent exertional rhabdomyolysis, and a c.943G > A PGK1 hemizygous mutation. Case 3 was a 48-year-old patient with NSHA, retinitis pigmentosa, mental retardation, seizures, stroke, parkinsonism, and a c.491A > T PGK1 hemizygous mutation. This study confirms that PGK deficiency is an extremely rare disorder with a wide phenotypic spectrum, and demonstrates for the first time that PGK deficiency may affect the peripheral nervous system and present as a CMT-like disorder.","variants":[{"Name":"NM_000291.4(PGK1):c.943G>A (p.Asp315Asn)","Chromosome":"X","Start":"78124880","Stop":"78124880","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1426915,"rule_based_match":true,"evidence_text":"c.943G > A PGK1 hemizygous mutation","llm_judgment":"PRESENT","evidence":"c.943G > A PGK1 hemizygous mutation","abstract_start":745,"abstract_end":780}]}
{"pmid":"24923815","title":"Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity.","abstract":"We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30-6.09, p = 2 × 10(-5)) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.1129-5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p = 5 × 10(-6)), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129-5923C>G/hapB3 variant is a major contributor to severe early-onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.1679T>G and c.2846A>T). Pre-therapeutic DPYD testing may prevent 20-30% of life-threatening or lethal episodes of FP toxicity in Caucasian patients.","variants":[{"Name":"NM_000110.4(DPYD):c.1905+1G>A","Chromosome":"1","Start":"97450058","Stop":"97450058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15471,"rule_based_match":true,"evidence_text":"c.1905+1G>A","llm_judgment":"PRESENT","evidence":"c.1905+1G>A","abstract_start":1160,"abstract_end":1171},{"Name":"NM_000110.4(DPYD):c.1129-5923C>G","Chromosome":"1","Start":"97579893","Stop":"97579893","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":623100,"rule_based_match":true,"evidence_text":"c.1129-5923C>G","llm_judgment":"PRESENT","evidence":"c.1129-5923C>G","abstract_start":260,"abstract_end":274}]}
{"pmid":"24668659","title":"Skeletal dysplasia, global developmental delay, and multiple congenital anomalies in a 5-year-old boy-report of the second family with B3GAT3 mutation and expansion of the phenotype.","abstract":"As a major component of the extracellular matrix, proteoglycans influence the mechanical properties of connective tissue and play an important role in cell-cell and cell-matrix interactions. Genetic defects of proteoglycan biosynthesis lead to multi-system disorders, often most prominently affecting the skeletal system and skin. Specific deficiencies in the enzymes involved in the biosynthesis of the linkage region between the core of the proteoglycan protein and its glycosaminoglycan side chains are known as linkeropathies. We report on a patient from a second family with a homozygous c.830G>A (p.Arg277Gln) mutation in the B3GAT3 gene. The clinical features expand the previously reported phenotype of B3GAT3 mutations and of linkeropathies in general. This patient has short stature, facial dysmorphisms, skeletal findings, joint laxity, and cardiac manifestations similar to those previously associated with B3GAT3 mutations. However, he also has developmental delay, a refractive errors, dental defects, pectus carinatum, and skin abnormalities that have only been associated with linkeropathies caused by mutations in B4GALT6 and B4GALT7. He has bilateral inguinal hernias and atlanto-axial as well as atlanto-occipital instability that have not been previously associated with B3GAT3 mutations. We provide a detailed clinical report and a comparative overview of the phenotypic features of the linkeropathies caused by mutations in B3GAT3, B4GALT6, and B4GALT7.","variants":[{"Name":"NM_012200.4(B3GAT3):c.830G>A (p.Arg277Gln)","Chromosome":"11","Start":"62616585","Stop":"62616585","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39530,"rule_based_match":true,"evidence_text":"c.830G>A (p.Arg277Gln)","llm_judgment":"PRESENT","evidence":"c.830G>A (p.Arg277Gln)","abstract_start":593,"abstract_end":615}]}
{"pmid":"29675035","title":"Trio Clinical Exome Sequencing in a Patient With Multicentric Carpotarsal Osteolysis Syndrome: First Case Report in the Balkans.","abstract":"Exome sequencing can interrogate thousands of genes simultaneously and it is becoming a first line diagnostic tool in genomic medicine. Herein, we applied trio clinical exome sequencing (CES) in a patient presenting with undiagnosed skeletal disorder, minor facial abnormalities, and kidney hypoplasia; her parents were asymptomatic. Testing the proband and her parents led to the identification of a <i>de novo</i> mutation c.188C>T (p.Pro63Leu) in the <i>MAFB</i> gene, which is known to cause multicentric carpotarsal osteolysis syndrome (MCTO). The c.188C>T mutation lies in a hotspot amino acid stretch within the transactivation domain of MAFB, which is a negative regulator of RANKL-induced osteoclastogenesis. MCTO is an extremely rare autosomal dominant (AD) disorder that typically arises spontaneously and causes carpotarsal osteolysis, often followed by nephropathy. To the best of our knowledge, this is the first study reporting genetically diagnosed MCTO in the Balkans.","variants":[{"Name":"NM_005461.5(MAFB):c.188C>T (p.Pro63Leu)","Chromosome":"20","Start":"40688663","Stop":"40688663","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2797565,"rule_based_match":true,"evidence_text":"c.188C>T (p.Pro63Leu)","llm_judgment":"PRESENT","evidence":"c.188C>T (p.Pro63Leu)","abstract_start":425,"abstract_end":446}]}
{"pmid":"33294763","title":"Monogenic Diabetes in a Child with Cystic Fibrosis: A Case Report and Review of the Literature.","abstract":"Cystic fibrosis-related diabetes (CFRD) is associated with worsening pulmonary function, lower body mass index, increased infection frequency, and earlier mortality. While the incidence of CFRD is rising, its development in patients under the age of 10 years is uncommon. We present a 9-year-old girl with cystic fibrosis (CF) who presented with a 5-year history of nonprogressive hyperglycemia, demonstrated by abnormal oral glucose tolerance tests, glycated hemoglobin A1c (HbA1c) levels consistently >6.5%, and negative pancreatic autoantibodies. Subsequent genetic testing revealed a pathogenic heterozygous recessive mutation in the <i>GCK</i> gene at c.667G>A (p.Gly223Ser), consistent with a diagnosis of GCK-MODY. Significant dysglycemia in young children with CF should raise suspicion for alternative etiologies of diabetes and warrants further investigation. The clinical impact of underlying monogenic diabetes in patients with CF is unclear, and close follow-up is warranted. This case also offers unique insight on the impact of hyperglycemia in the absence of insulin deficiency on CF-specific outcomes.","variants":[{"Name":"NM_000162.5(GCK):c.667G>A (p.Gly223Ser)","Chromosome":"7","Start":"44149772","Stop":"44149772","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":428730,"rule_based_match":true,"evidence_text":"c.667G>A (p.Gly223Ser)","llm_judgment":"PRESENT","evidence":"c.667G>A (p.Gly223Ser)","abstract_start":657,"abstract_end":679}]}
{"pmid":"23244118","title":"Colon cancer prevention by detection of APC gene mutation in a family with attenuated familial adenomatous polyposis.","abstract":"BACKGROUND: Genetic mutation is a significant factor in colon CA pathogenesis. Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary disease characterized by multiple colorectal adenomatous polyps affecting a number of cases in the family. This report focuses on a family with attenuated familial adenomatous polyposis (AFAP) with exon 4 mutation, c.481C>T p.Q161X of the APC gene.\nMETHODS: We analyzed 20 members of a family with AFAP. Clinical and endoscopic data were collected for phenotype determination. Genetic analysis was also performed by direct sequencing of the APC gene.\nRESULT: Five patients with a phenotype of AFAP were found. Endoscopic polyposis was demonstrated among the second generation with genotype mutation of the disease (age > 50 years) consistent with delayed phenotypic adenomatous polyposis in AFAP. APC gene mutation was identified in exon 4 of the APC gene, with mutation points of c.481C>T p.Q161X. Laparoscopic subtotal colectomy was performed to prevent carcinogenesis.\nCONCLUSION: A family with attenuated familial adenomatous polyposis of APC related to exon 4 mutation, c.481C>T p.Q161X, was reported and the phenotypic finding was confirmed by endoscopic examination. Genetic mutation analysis might be advantageous in AFAP for long term colon cancer prevention and management due to subtle or asymptomatic phenotype presentation in early adulthood.","variants":[{"Name":"NM_000038.6(APC):c.481C>T (p.Gln161Ter)","Chromosome":"5","Start":"112775687","Stop":"112775687","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":232995,"rule_based_match":true,"evidence_text":"c.481C>T p.Q161X","llm_judgment":"PRESENT","evidence":"c.481C>T p.Q161X","abstract_start":367,"abstract_end":383}]}
{"pmid":"36680912","title":"Novel LIAS variants in a patient with epilepsy and profound developmental disabilities.","abstract":"Multiple mitochondrial enzymes employ lipoic acid as a coenzyme. Pathogenic variants in LIAS, encoding lipoic acid synthase (LIAS), are associated with autosomal recessive LIAS-related disorder (OMIM# 614462). This disorder is characterized by infantile-onset hypotonia, profound psychomotor delay, epileptic encephalopathy, nonketotic hyperglycinemia, and lactic acidosis. We present the case of a 20-year-old female who experienced developmental deficits at the age of 6 months and began to have seizures at 3 years of age. Exome sequencing revealed compound heterozygous novel variants in LIAS, designated c.277delC (p.Leu93Ter) and c.542A > T (p.Asp181Val). The p.Leu93Ter variant is predicted to cause loss of function due to the severe truncation of the encoded protein. To examine the p.Asp181Val variant, functional analysis was performed using Baker's yeast (Saccharomyces cerevisiae) lacking LIP5, the homologue of human LIAS. Wild-type LIAS promoted oxidative growth of the lip5∆ yeast strain. In contrast, lip5∆ yeast expressing p.Asp181Val exhibited poor growth, similar to known pathogenic variants, p.Asp215Glu and p.Met310Thr. Our work has expanded the phenotypic and genotypic spectrum of LIAS-related disorder and established the use of the yeast model as a system for functional study of novel missense variants in LIAS.","variants":[{"Name":"NM_006859.4(LIAS):c.542A>T (p.Asp181Val)","Chromosome":"4","Start":"39465194","Stop":"39465194","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":201772,"rule_based_match":true,"evidence_text":"c.542A > T (p.Asp181Val)","llm_judgment":"PRESENT","evidence":"c.542A > T (p.Asp181Val)","abstract_start":636,"abstract_end":660}]}
{"pmid":"27227689","title":"Seventeen Novel Mutations in PCCA and PCCB Genes in Indian Propionic Acidemia Patients, and Their Outcomes.","abstract":"AIMS: The goal of this study was to identify mutations in the propionyl-CoA carboxylase alpha subunit (PCCA) and propionyl-CoA carboxylase beta subunit (PCCB) genes, and to assess their effects on propionic academia (PA) patients.\nMETHODOLOGY: Twenty-five Indian children with PA were enrolled in this study. Bidirectional Sanger sequencing was performed on both the coding and flanking regions of the PCCA and PCCB genes and the chromatograms were analyzed. Bioinformatic tools were used to classify novel variations into pathogenic or benign.\nRESULTS: The majority of the cases (19/25, 76%) were of the early-onset (<90 days of age) type and 5 were of the late-onset type. The majority of patients had mutations in the PCCA gene (18/25). A total of 26 mutations were noted: 20 in the PCCA gene and 6 in PCCB gene. Seventeen mutations were novel (14 in PCCA and 3 in PCCB). The SNP c.937C>T (p.Arg313Ter), was noted in 9/36 (25%) alleles in the PCCA gene. All of the children were symptomatic and only three survived who are doing well with no major disabilities.\nCONCLUSION: The spectrum of mutations in the PCCA and PCCB genes among Indians is distinct from other populations. The absence of a common mutation signifies the heterogeneity and admixture of various subpopulations. These findings also suggest that individuals of Indian origin may not benefit from the mutation-based \"carrier screening panels\" offered by many genetic laboratories.","variants":[{"Name":"NM_000282.4(PCCA):c.937C>T (p.Arg313Ter)","Chromosome":"13","Start":"100273218","Stop":"100273218","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":47475,"rule_based_match":true,"evidence_text":"c.937C>T (p.Arg313Ter)","llm_judgment":"PRESENT","evidence":"c.937C>T (p.Arg313Ter)","abstract_start":883,"abstract_end":905}]}
{"pmid":"20213768","title":"Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive hypotrichosis.","abstract":"Autosomal recessive hypotrichosis (ARH) is characterized by sparse hair on the scalp without other abnormalities. Three genes, DSG4, LIPH, and LPAR6 (P2RY5), have been reported to underlie ARH. We performed a mutation search for the three candidate genes in five independent Japanese ARH families and identified two LIPH mutations: c.736T>A (p.Cys246Ser) in all five families, and c.742C>A (p.His248Asn) in four of the five families. Out of 200 unrelated control alleles, we detected c.736T>A in three alleles and c.742C>A in one allele. Haplotype analysis revealed each of the two mutant alleles is derived from a respective founder. These results suggest the LIPH mutations are prevalent founder mutations for ARH in the Japanese population. LIPH encodes PA-PLA(1)alpha (LIPH), a membrane-associated phosphatidic acid-preferring phospholipase A(1)alpha. Two residues, altered by these mutations, are conserved among PA-PLA(1)alpha of diverse species. Cys(246) forms intramolecular disulfide bonds on the lid domain, a crucial structure for substrate recognition, and His(248) is one amino acid of the catalytic triad. Both p.Cys246Ser- and p.His248Asn-PA-PLA(1)alpha mutants showed complete abolition of hydrolytic activity and had no P2Y5 activation ability. These results suggest defective activation of P2Y5 due to reduced 2-acyl lysophosphatidic acid production by the mutant PA-PLA(1)alpha is involved in the pathogenesis of ARH.","variants":[{"Name":"NM_139248.3(LIPH):c.736T>A (p.Cys246Ser)","Chromosome":"3","Start":"185519292","Stop":"185519292","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":227256,"rule_based_match":true,"evidence_text":"c.736T>A (p.Cys246Ser)","llm_judgment":"PRESENT","evidence":"c.736T>A (p.Cys246Ser)","abstract_start":332,"abstract_end":354}]}
{"pmid":"17891434","title":"The effect of p.Arg25Cys alteration in NKX2-5 on conotruncal heart anomalies: mutation or polymorphism?","abstract":"Heterozygous mutations in the NKX2-5 gene of patients with various congenital heart defects have been reported. Most of the congenital heart defects associated with the mutations in the NKX2-5 gene are conotruncal heart anomalies, primarily the tetralogy of Fallot. In this study, the authors screened 72 Turkish children with conotruncal heart anomalies and 185 healthy control subjects to find the NKX2-5 alterations. They found one previously documented NKX2-5 missense alteration, heterozygous c.73C>T (p.Arg25Cys), in a 10-year-old boy with tetralogy of Fallot. The same heterozygous alteration was found also in the patient's healthy father and in two unrelated persons in the healthy control group. The current study shows for the first time the presence of p.Arg25Cys in healthy control subjects other than African Americans. These results show that no genetic support exists for the pathogenecity of this alteration, although a previous in vitro study and theoretical predictions suggest a structural/functional difference in the altered protein region.","variants":[{"Name":"NM_004387.4(NKX2-5):c.73C>T (p.Arg25Cys)","Chromosome":"5","Start":"173235011","Stop":"173235011","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24047,"rule_based_match":true,"evidence_text":"c.73C>T (p.Arg25Cys)","llm_judgment":"PRESENT","evidence":"c.73C>T (p.Arg25Cys)","abstract_start":498,"abstract_end":518}]}
{"pmid":"31056671","title":"Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies.","abstract":"We performed next generation sequencing on 1696 patients with epilepsy and intellectual disability using a gene panel with 480 epilepsy-related genes including all GABAA receptor subunit genes (GABRs), and we identified six de novo GABR mutations, two novel GABRA5 mutations (c.880G>T, p.V294F and c.1238C>T, p.S413F), two novel GABRA1 mutations (c.778C>T, p.P260S and c.887T>C, p.L296S/c.944G>T, p.W315L) and two known GABRA1 mutations (c.335G>A, p.R112Q and c.343A>G, p.N115D) in six patients with intractable early onset epileptic encephalopathy. The α5(V294F and S413F) and α1(P260S and L296S/W315L) subunit residue substitutions were all in transmembrane domains, while the α1(R112Q and N115R) subunit residue substitutions were in the N-terminal GABA binding domain. Using multidisciplinary approaches, we compared effects of mutant GABAA receptor α5 and α1 subunits on the properties of recombinant α5β3γ2 and α1β3γ2 GABAA receptors in both neuronal and non-neuronal cells and characterized their effects on receptor clustering, biogenesis and channel function. GABAA receptors containing mutant α5 and α1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABAA receptor function and decreased GABA binding potency. Our study identified GABRA5 as a causative gene for early onset epileptic encephalopathy and expands the mutant GABRA1 phenotypic spectrum, supporting growing evidence that defects in GABAergic neurotransmission contribute to early onset epileptic encephalopathy phenotypes.","variants":[{"Name":"NM_000810.4(GABRA5):c.880G>T (p.Val294Phe)","Chromosome":"15","Start":"26943217","Stop":"26943217","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":676984,"rule_based_match":true,"evidence_text":"c.880G>T, p.V294F","llm_judgment":"PRESENT","evidence":"c.880G>T, p.V294F","abstract_start":276,"abstract_end":293},{"Name":"NM_000810.4(GABRA5):c.1238C>T (p.Ser413Phe)","Chromosome":"15","Start":"26948082","Stop":"26948082","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":676985,"rule_based_match":true,"evidence_text":"c.1238C>T, p.S413F","llm_judgment":"PRESENT","evidence":"c.1238C>T, p.S413F","abstract_start":298,"abstract_end":316}]}
{"pmid":"21051746","title":"Recurrent deep intronic mutations in the SLC12A3 gene responsible for Gitelman's syndrome.","abstract":"BACKGROUND AND OBJECTIVES: Gitelman's syndrome (GS) is an autosomal recessive renal tubular disorder caused by mutations in the SLC12A3 gene encoding the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC). Despite meticulous sequencing of genomic DNA, approximately one-third of GS patients are negative or heterozygotes for the known mutations.\nDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Because blood leukocytes express NCC mRNA, we evaluate whether deep intronic mutations contribute to GS patients with uniallelic or undetectable SLC12A3 mutations. Twenty-nine patients with GS (men/women = 16/13), including eight negative and 21 uniallelic SLC12A3 mutations from 19 unrelated families, and normal controls were enrolled in an academic medical center. Analysis of cDNA from blood leukocytes, sequencing of the corresponding introns of genomic DNA for abnormal transcript, and analysis of NCC protein expression from renal biopsy were performed.\nRESULTS: We identified nine Taiwan aboriginal patients carrying c.1670-191C→T mutations in intron 13 and 10 nonaboriginal patients carrying c.2548+253C→T mutations in intron 21 from 14 families (14/19). These two mutations undetected in 100 healthy subjects created pseudoexons containing new premature termination codons. Haplotype analysis with markers flanking SLC12A3 revealed that both mutations did not have founder effects. Apical NCC expression in the DCT of renal tissue was markedly diminished in two patients carrying deep intronic mutations.\nCONCLUSIONS: Deep intronic mutations in SLC12A3 causing defective NCC expression can be identified with the RNA-based approach in patients with GS. c.1670-191C→T and c.2548+253C→T are hot spot mutations that can be screened in GS patients with uniallelic or negative SLC12A3 mutations.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1670-191C>T","Chromosome":"16","Start":"56883858","Stop":"56883858","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":652576,"rule_based_match":false,"evidence_text":"c.1670-191C→T","llm_judgment":"PRESENT","evidence":"c.1670-191C→T","abstract_start":1018,"abstract_end":1031}]}
{"pmid":"11857743","title":"Identification and in vitro expression of novel CDH23 mutations of patients with Usher syndrome type 1D.","abstract":"Usher syndrome (USH) is a group of autosomal recessive sensory disorders characterized by progressive retinitis pigmentosa (RP) and sensorineural hearing impairment. Usher syndrome type 1 (USH1), with additional vestibular dysfunction, represents the most severe form and shows extensive allelic and non-allelic heterogeneity. At least six USH1 loci exist (USH1A-F), and four of the underlying genes have been identified. Recently, a novel gene, cadherin 23 (CDH23), was shown to be mutated in USH1D. We performed mutation screening by single strand conformation polymorphism (SSCP) analysis and direct sequencing on 33 USH1 patients previously excluded for USH1B and USH1C. On eight disease alleles of four patients, four different mutations were identified, three of them novel (c.6933delT, c.5712G-->A, and IVS45-9G-->A). Exon trapping experiments were performed with two mutations. In the case of a c.5712G-->A transition of the last base of exon 42, that is an apparently synonymous mutation, skipping of exon 42 was observed. By the mutation IVS45-9G-->A, a novel splice acceptor site was created and the insertion of 7 intronic bp was observed. Two mutations, IVS45-9G-->A and the previously described IVS51+5G-->A, were each found in more than one patient. Haplotype analysis by SNPs within CDH23 suggests common ancestors for each of the mutations. Among the total of 52 USH1 cases studied by us, CDH23 mutations account for about 10% of all disease alleles. Our results further suggest that in patients with a typical USH1D phenotype, a significant portion of CDH23 mutations leads to premature termination of translation or loss of numerous amino acid residues, with a high frequency of changes causing aberrant splicing of CDH23 mRNA.","variants":[{"Name":"NM_022124.6(CDH23):c.6933del (p.Thr2313fs)","Chromosome":"10","Start":"71798457","Stop":"71798457","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":1393512,"rule_based_match":true,"evidence_text":"c.6933delT","llm_judgment":"PRESENT","evidence":"c.6933delT","abstract_start":781,"abstract_end":791},{"Name":"NM_022124.6(CDH23):c.5712G>A (p.Thr1904=)","Chromosome":"10","Start":"71785100","Stop":"71785100","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":55154,"rule_based_match":false,"evidence_text":"c.5712G-->A","llm_judgment":"PRESENT","evidence":"c.5712G-->A","abstract_start":793,"abstract_end":804}]}
{"pmid":"30560021","title":"Ataxia with ocular apraxia type 2 not responding to 4-aminopyridine: A rare mutation in the","abstract":"Ataxia with ocular apraxia type 2 is an autosomal recessive disorder caused by a mutation in the senataxin (<i>SETX</i>) gene. The disease is characterized by early onset cerebellar ataxia, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and increased levels of α-fetoprotein. Reported here is a rare homozygous frameshift deletion c.5308_5311del, p.(Glu1770Ilefs*15) in the <i>SETX</i> gene in a Saudi family. Ataxia with ocular apraxia type 2 was diagnosed based on the patient's history, an examination, and genetic testing. Genetic testing remains the only definitive method with which to identify the gene responsible. This is the third case report of this rare mutation in the literature. Ataxia with ocular apraxia type 2 continues to be a challenging disease to manage with no therapeutic options available to date. In the current case, the medication 4-aminopyridine was inefficacious in improving walking or balance. Further research is needed to identify potential treatments for this challenging condition.","variants":[{"Name":"NM_015046.7(SETX):c.5308_5311del (p.Glu1770fs)","Chromosome":"9","Start":"132311820","Stop":"132311823","ReferenceAlleleVCF":"TTCTC","AlternateAlleleVCF":"T","allel_id":441283,"rule_based_match":true,"evidence_text":"c.5308_5311del, p.(Glu1770Ilefs*15)","llm_judgment":"PRESENT","evidence":"c.5308_5311del, p.(Glu1770Ilefs*15)","abstract_start":356,"abstract_end":391}]}
{"pmid":"23838279","title":"Novel GJB1 mutation causing adult-onset Charcot-Marie-Tooth disease in a female patient.","abstract":"Charcot-Marie-Tooth disease (CMT), which is the eponym for hereditary motor and sensory neuropathy (HMSN), affects ∼1 in 2500 individuals. The most common subtype of X-linked CMT, CMTX1, is caused by mutations in GJB1, the gene encoding connexin 32, a gap junction protein in myelinated Schwann cells. We report a woman, who presented at the age of 56 years with gait unsteadiness and tingling in her feet. Clinical investigation revealed impaired sensation to pinprick, light touch and vibration in her distal lower limbs. Ankle reflexes were bilaterally absent. Sequencing revealed a novel heterozygous c.712C>T (p.R238C) mutation in the GJB1 gene. This mutation is predicted to result in the loss of disulfide bonds and thus in abnormal protein structure. In this woman, the reported novel GJB1 mutation resulted in sensory abnormalities, slowly progressive loss of distal lower limb strength, and notable loss of balance, with onset of symptoms late in adult age.","variants":[{"Name":"NM_000166.6(GJB1):c.712C>T (p.Arg238Cys)","Chromosome":"X","Start":"71224419","Stop":"71224419","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":471001,"rule_based_match":true,"evidence_text":"c.712C>T (p.R238C)","llm_judgment":"PRESENT","evidence":"c.712C>T (p.R238C)","abstract_start":605,"abstract_end":623}]}
{"pmid":"21221996","title":"Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia.","abstract":"Sclerosteosis and Van Buchem disease are related recessive sclerosing bone dysplasias caused by alterations in the SOST gene. We tested the hypothesis that craniodiaphyseal dysplasia (CDD) (MIM 122860), an extremely rare sclerosing bone dysplasia resulting facial distortion referred to as \"leontiasis ossea\", could also be caused by SOST mutations. We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD. As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST. We conclude that CDD, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST. Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism.","variants":[{"Name":"NM_025237.3(SOST):c.61G>A (p.Val21Met)","Chromosome":"17","Start":"43758681","Stop":"43758681","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40277,"rule_based_match":true,"evidence_text":"c.61G>A (Val21Met)","llm_judgment":"PRESENT","evidence":"c.61G>A (Val21Met)","abstract_start":374,"abstract_end":392},{"Name":"NM_025237.3(SOST):c.61G>T (p.Val21Leu)","Chromosome":"17","Start":"43758681","Stop":"43758681","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":40278,"rule_based_match":true,"evidence_text":"c.61G>T (Val21Leu)","llm_judgment":"PRESENT","evidence":"c.61G>T (Val21Leu)","abstract_start":397,"abstract_end":415}]}
{"pmid":"31448886","title":"A Novel Missense Mutation in Human Receptor Roundabout-1","abstract":"Pituitary stalk interruption syndrome (PSIS) is characterized by the association of an absent or thin pituitary stalk, an absent or hypoplastic anterior pituitary lobe and an ectopic posterior pituitary (EPP) lobe. The causes of this anatomical defect include both genetic and environmental factors. Molecular genetic defects have been indentified in a small number of patients with PSIS. A 4-year-old boy presented with hypoglycemia and hyponatremia associated with growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone deficiencies. The patient had right sided strabismus. magnetic resonance imaging images showed pituitary hypoplasia, EPP and absent pituitary stalk. A novel Receptor Roundabout-1 <i>(ROBO1)</i> missense mutation (c.1690C>T, p.Pro564Ser) that may contribute to the disorder was found in this patient and his mother, who also exhibited pituitary abnormalities.","variants":[{"Name":"NM_002941.4(ROBO1):c.1690C>T (p.Pro564Ser)","Chromosome":"3","Start":"78668243","Stop":"78668243","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":983679,"rule_based_match":true,"evidence_text":"c.1690C>T, p.Pro564Ser","llm_judgment":"PRESENT","evidence":"c.1690C>T, p.Pro564Ser","abstract_start":757,"abstract_end":779}]}
{"pmid":"38617198","title":"Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic","abstract":"Background and Objectives: Hexokinase 1 (encoded by <i>HK1</i>) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic <i>HK1</i> variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals.\nMethods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic <i>HK1</i> variants and an NDD phenotype.\nResults: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile.\nDiscussion: Genotype-phenotype correlations appear to exist for <i>HK1</i> variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic <i>HK1</i> variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.","variants":[{"Name":"NM_000188.3(HK1):c.1370C>T (p.Thr457Met)","Chromosome":"10","Start":"69382591","Stop":"69382591","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359832,"rule_based_match":true,"evidence_text":"c.1370C>T","llm_judgment":"PRESENT","evidence":"c.1370C>T","abstract_start":611,"abstract_end":620}]}
{"pmid":"24390236","title":"Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin.","abstract":"CHEK2 encodes a serine/threonine-protein kinase which plays a critical role in DNA damage signaling pathways. CHEK2 directly phosphorylates and regulates the functions of p53 and BRCA1. Most women with breast and/or ovarian cancer are not carriers of mutant BRCA1 or BRCA2. Multiple studies have shown that a CHEK2*1100delC confers about a two-fold increased risk of breast cancer in unselected females and a tenfold increase in males. Moreover, studies have shown that first-degree relatives of bilateral breast cancer cases who carried the CHEK2*1100delC allele had an eight-fold increased risk of breast cancer. It has been suggested that CHEK2 functions as a low-penetrance susceptibility gene for cancers and multiplies the risks associated with other gene(s) to increase cancer risk. The main goal of this study was to evaluate and to compare the role of truncating mutations, splice junction mutations and rare missense substitutions in breast cancer susceptibility gene CHEK2. Present study was performed on 140 individuals including 70 breast cancer patients both with and without family history and 70 normal individuals. Written consent was obtained and 3 ml intravenous blood was drawn from all the subjects. DNA was extracted from all the samples through inorganic method published already. Primers were synthesized for all the 14 exons of CHEK2 gene. Coding and adjacent intronic sequences of CHEK2 gene were amplified and sequenced. Two genetic variants (p.H371Y, p.D438Y) were found in exon 10 and exon 11 of gene CHEK2 which were not found in any of the 70 control individuals from same geographical area and ethnic group. The genetic variant c.1312G>T (p.D438Y) identified in a patient with a family history of breast cancer. To our knowledge, this is first mutation scanning study of gene CHEK2 from Balochistan population.","variants":[{"Name":"NM_007194.4(CHEK2):c.1312G>T (p.Asp438Tyr)","Chromosome":"22","Start":"28695190","Stop":"28695190","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":133513,"rule_based_match":true,"evidence_text":"c.1312G>T (p.D438Y)","llm_judgment":"PRESENT","evidence":"c.1312G>T (p.D438Y)","abstract_start":1660,"abstract_end":1679}]}
{"pmid":"18355452","title":"A novel splice site mutation of the LDL receptor gene in a Tunisian hypercholesterolemic family.","abstract":"BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease caused by mutations in either the low-density lipoprotein receptor, the apolipoprotein B or the proprotein convertase subtilisin/kexin type 9 genes. It is characterized by a high concentration of low-density lipoprotein (LDL), which frequently gives rise to premature coronary disease. In this study, we report a novel splice site mutation of the LDL receptor gene in a Tunisian family.\nMETHODS: Seven patients from the family were screened for mutations in the LDLR gene and the apoB gene, using direct sequencing. RT-PCR and study on cultured skin fibroblast were realised to characterize the effect of novel mutation.\nRESULTS: Direct sequencing of the promoter and 18 exons reveals a G>A substitution in the splice site junction of intron 8 (c.1186+1 G>A). Study on cultured skin fibroblasts showed a residual activity of 10% of the LDL receptor. Reverse transcription, amplification and direct sequencing of RNA from patient's lymphocytes reveal a deletion of the final 51 bp of exon 8 preserving the reading frame.\nCONCLUSIONS: The study identified a novel splice mutation c.1186+1 G>A in the LDL receptor gene. It causes the utilization of a new cryptic donor splice site 51 bp downstream from the normal site.","variants":[{"Name":"NM_000527.5(LDLR):c.1186+1G>A","Chromosome":"19","Start":"11111640","Stop":"11111640","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":246028,"rule_based_match":true,"evidence_text":"c.1186+1 G>A","llm_judgment":"PRESENT","evidence":"c.1186+1 G>A","abstract_start":835,"abstract_end":847}]}
{"pmid":"27060300","title":"Identification of two novel mutations of MUT gene in a Chinese family affected with isolated methylmalonic acidemia","abstract":"OBJECTIVE: To explore the molecular etiology for a Chinese family affected with isolated methylmalonic acidemia (MMA).\nMETHODS: Potential mutations of MUT, MMAA and MMAB genes in the proband were screened by PCR and Sanger sequencing. The pathogenicity of identified mutations was analyzed using Polyphen2, SIFT, HSF, DNAMAN 6.0 and Swiss-PdbViewer4.1.0 software.\nRESULTS: Two novel mutations of the MUT gene, including c.581C>T (p.P194L) and c.1219A>T (p.N407Y), were discovered in the proband, which were inherited respectively from his mother and father. Bioinformatics analysis suggested that both mutations were damaging. The affected codons P194 and N407, both located in the (beta, alpha) 8 barrel domain and to which the substrate methylmalonyl-CoA is bound, are highly conserved across various species. Both mutations can disrupt the space conformation of its protein product, affecting the function of the MCM protein.\nCONCLUSION: The novel mutations of MUT gene probably underlie the isolated MMA in this family.","variants":[{"Name":"NM_000255.4(MMUT):c.1219A>T (p.Asn407Tyr)","Chromosome":"6","Start":"49451579","Stop":"49451579","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":543707,"rule_based_match":true,"evidence_text":"c.1219A>T (p.N407Y)","llm_judgment":"PRESENT","evidence":"c.1219A>T (p.N407Y)","abstract_start":443,"abstract_end":462},{"Name":"NM_000255.4(MMUT):c.581C>T (p.Pro194Leu)","Chromosome":"6","Start":"49457863","Stop":"49457863","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1060725,"rule_based_match":true,"evidence_text":"c.581C>T (p.P194L)","llm_judgment":"PRESENT","evidence":"c.581C>T (p.P194L)","abstract_start":420,"abstract_end":438}]}
{"pmid":"21900944","title":"Genome-wide association study identifies genetic variants in GOT1 determining serum aspartate aminotransferase levels.","abstract":"We carried out a genome-wide association study of serum aspartate aminotransferase (AST) activity in 866 Amish participants of the Heredity and Phenotype Intervention Heart Study and identified significant association of AST activity with a cluster of single nucleotide polymorphisms located on chromosome 10q24.1 (peak association was rs17109512; P=2.80E-14), in the vicinity of GOT1, the gene encoding cytosolic AST (cAST). Sequencing of GOT1 revealed an in-frame deletion of three nucleic acids encoding asparagine at position 389 c.1165_1167delAAC (p.Asn389del) in the gene. Deletion carriers had significantly lower AST activity levels compared with homozygotes for the common allele (mean±s.d.: 10.0±2.8 versus 18.8±5.2 U l(-1); P=2.80E-14). Further genotyping of the deletion in other Amish samples (n=1932) identified an additional 20 carriers (minor allele frequency (MAF)=0.0052). The deletion was not detected in 647 outbred Caucasians. Asn at codon 389 is conserved among known mammalian cASTs. In vitro transient transfection of wild-type and mutant cAST indicated that mutant cAST protein was barely detectable in the cells. Furthermore, even after correction for cAST expression, mutant cAST had markedly diminished enzymatic activity. Remarkably, we did not find any association between the deletion and metabolic traits including serum fasting glucose or insulin, fasting and post-meal lipids, inflammatory markers, or sub-clinical markers of cardiovascular disease. In conclusion, we discovered a rare in-frame deletion in GOT1 gene, which inactivates cAST enzyme in the Old Order Amish. This finding will help us to understand structure and function of the enzyme and would be useful for predicting serum AST levels.","variants":[{"Name":"NM_002079.3(GOT1):c.1165_1167del (p.Asn389del)","Chromosome":"10","Start":"99397622","Stop":"99397624","ReferenceAlleleVCF":"CGTT","AlternateAlleleVCF":"C","allel_id":38679,"rule_based_match":true,"evidence_text":"c.1165_1167delAAC (p.Asn389del)","llm_judgment":"PRESENT","evidence":"c.1165_1167delAAC (p.Asn389del)","abstract_start":534,"abstract_end":565}]}
{"pmid":"25052314","title":"Functional correction by antisense therapy of a splicing mutation in the GALT gene.","abstract":"In recent years, antisense therapy has emerged as an increasingly important therapeutic approach to tackle several genetic disorders, including inborn errors of metabolism. Intronic mutations activating cryptic splice sites are particularly amenable to antisense therapy, as the canonical splice sites remain intact, thus retaining the potential for restoring constitutive splicing. Mutational analysis of Portuguese galactosemic patients revealed the intronic variation c.820+13A>G as the second most prevalent mutation, strongly suggesting its pathogenicity. The aim of this study was to functionally characterize this intronic variation, to elucidate its pathogenic molecular mechanism(s) and, ultimately, to correct it by antisense therapy. Minigene splicing assays in two distinct cell lines and patients' transcript analyses showed that the mutation activates a cryptic donor splice site, inducing an aberrant splicing of the GALT pre-mRNA, which in turn leads to a frameshift with inclusion of a premature stop codon (p.D274Gfs*17). Functional-structural studies of the recombinant wild-type and truncated GALT showed that the latter is devoid of enzymatic activity and prone to aggregation. Finally, two locked nucleic acid oligonucleotides, designed to specifically recognize the mutation, successfully restored the constitutive splicing, thus establishing a proof of concept for the application of antisense therapy as an alternative strategy for the clearly insufficient dietary treatment in classic galactosemia.","variants":[{"Name":"NM_000155.4(GALT):c.820+13A>G","Chromosome":"9","Start":"34648907","Stop":"34648907","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":36603,"rule_based_match":true,"evidence_text":"c.820+13A>G","llm_judgment":"PRESENT","evidence":"c.820+13A>G","abstract_start":471,"abstract_end":482}]}
{"pmid":"26379196","title":"Frame shift mutations of the ZMPSTE24 gene in two siblings with restrictive dermopathy.","abstract":"Restrictive dermopathy (RD) is a rare lethal autosomal recessive genodermatosis, characterized by abnormally rigid skin with prominent superficial vasculature, erosions and epidermal hyperkeratosis, dysplastic clavicles, joint contractures, mouth fixed in the 'O' position, small pinched nose, and neonatal death. Mutations of ZMPSTE24 and LMNA genes are reported as the causes of RD, with those of ZMPSTE24 being more prevalent. Here, we report on a familial c.50delA (p.Lys17Serfs*21) mutation of the ZMPSTE24 gene, causing RD in two siblings.","variants":[{"Name":"NM_005857.5(ZMPSTE24):c.50del (p.Lys17fs)","Chromosome":"1","Start":"40258320","Stop":"40258320","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":49843,"rule_based_match":true,"evidence_text":"c.50delA (p.Lys17Serfs*21)","llm_judgment":"PRESENT","evidence":"c.50delA (p.Lys17Serfs*21)","abstract_start":460,"abstract_end":486}]}
{"pmid":"29599744","title":"Myopathy With","abstract":"OBJECTIVE: The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies.\nPATIENTS AND METHODS: Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy.\nRESULTS: Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in <i>SQSTM1</i> (c.1175C>T, p.Pro392Leu) and a heterozygous variant in <i>TIA1</i> (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness.\nCONCLUSION: The findings indicate that all the affected individuals have a myopathy associated with both variants in <i>SQSTM1</i> and <i>TIA1</i>, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the <i>TIA1</i> variant is a modifier of the <i>SQSTM1</i> mutation. We identify the combination of <i>SQSTM1</i> and <i>TIA1</i> variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the digenic nature of the disease.","variants":[{"Name":"NM_003900.5(SQSTM1):c.1175C>T (p.Pro392Leu)","Chromosome":"5","Start":"179836445","Stop":"179836445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23147,"rule_based_match":true,"evidence_text":"c.1175C>T, p.Pro392Leu","llm_judgment":"PRESENT","evidence":"c.1175C>T, p.Pro392Leu","abstract_start":929,"abstract_end":951}]}
{"pmid":"32571898","title":"Clinical spectrum and genetic variations of","abstract":"BACKGROUND: <i>LMNA</i>-related muscular dystrophy is caused by mutations in <i>LMNA</i> gene. We aimed to identify genetic variations and clinical features in a large cohort of Chinese patients with <i>LMNA</i> mutations in an attempt to establish genotype-phenotype correlation.\nMETHODS: The clinical presentations of patients with <i>LMNA</i>-related muscular dystrophy were recorded using retrospective and prospective cohort study. <i>LMNA</i> mutation analysis was performed by Sanger sequencing or next-generation sequencing. Mosaicism was detected by personal genome machine amplicon deep sequencing for mosaicism.\nRESULTS: Eighty-four patients were identified to harbour <i>LMNA</i> mutations. Forty-one of those were diagnosed with <i>LMNA</i>-related congenital muscular dystrophy (L-CMD), 32 with Emery-Dreifuss muscular dystrophy (EDMD) and 11 with limb-girdle muscular dystrophy type 1B (LGMD1B). We identified 21 novel and 29 known <i>LMNA</i> mutations. Two frequent mutations were identified: c.745C>T and c.1357C>T. A correlation between the location of mutation and the clinical phenotype was observed: mutations affecting the head and coil 2A domains mainly occurred in L-CMD, while the coil 2B and Ig-like domains mainly related to EDMD and LGMD1B. We found somatic mosaicism in one parent of four probands. Muscle biopsies revealed 11 of 20 biopsied L-CMD exhibited inflammatory changes, and muscle cell ultrastructure showed abnormal nuclear morphology.\nCONCLUSIONS: Our detailed clinical and genetic analysis of 84 patients with <i>LMNA</i>-related muscular dystrophy expands clinical spectrum and broadens genetic variations caused by <i>LMNA</i> mutations. We identified 21 novel and 29 known <i>LMNA</i> mutations and found two frequent mutations. A correlation between the location of mutation and the clinical severity was observed. Preliminary data suggested that low-dose corticosteroid treatment may be effective.","variants":[{"Name":"NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp)","Chromosome":"1","Start":"156136413","Stop":"156136413","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29517,"rule_based_match":true,"evidence_text":"c.1357C>T","llm_judgment":"PRESENT","evidence":"c.1357C>T","abstract_start":1023,"abstract_end":1032},{"Name":"NM_170707.4(LMNA):c.745C>T (p.Arg249Trp)","Chromosome":"1","Start":"156134910","Stop":"156134910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29563,"rule_based_match":true,"evidence_text":"c.745C>T","llm_judgment":"PRESENT","evidence":"c.745C>T","abstract_start":1010,"abstract_end":1018}]}
{"pmid":"26216793","title":"DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy.","abstract":"Mutations in the DEPDC5 (DEP domain-containing protein 5) gene are a major cause of familial focal epilepsy with variable foci (FFEVF) and are predicted to account for 12-37% of families with inherited focal epilepsies. To assess the clinical impact of DEPDC5 mutations in familial temporal lobe epilepsy, we screened a collection of Italian families with either autosomal dominant lateral temporal epilepsy (ADLTE) or familial mesial temporal lobe epilepsy (FMTLE). The probands of 28 families classified as ADLTE and 17 families as FMTLE were screened for DEPDC5 mutations by whole exome or targeted massive parallel sequencing. Putative mutations were validated by Sanger sequencing. We identified a DEPDC5 nonsense mutation (c.918C>G; p.Tyr306*) in a family with two affected members, clinically classified as FMTLE. The proband had temporal lobe seizures with prominent psychic symptoms (déjà vu, derealization, and forced thoughts); her mother had temporal lobe seizures, mainly featuring visceral epigastric auras and anxiety. In total, we found a single DEPDC5 mutation in one of (2.2%) 45 families with genetic temporal lobe epilepsy, a proportion much lower than that reported in other inherited focal epilepsies.","variants":[{"Name":"NM_001242896.3(DEPDC5):c.918C>G (p.Tyr306Ter)","Chromosome":"22","Start":"31798628","Stop":"31798628","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":259347,"rule_based_match":true,"evidence_text":"c.918C>G; p.Tyr306*","llm_judgment":"PRESENT","evidence":"c.918C>G; p.Tyr306*","abstract_start":729,"abstract_end":748}]}
{"pmid":"32761997","title":"Pseudo-Bartter syndrome in Chinese children with cystic fibrosis: Clinical features and genotypic findings.","abstract":"OBJECTIVES: To characterize the clinical and genotypic features of cystic fibrosis-associated pseudo-Bartter syndrome (CF-PBS) in Chinese children.\nMETHODS: We recruited and characterized the clinical manifestations of 12 Chinese children with CF-PBS. Sweat test, blood and urinary analysis, sputum culture, chest and sinus computed tomography, and abdominal ultrasonography were obtained. Whole-exome sequencing, bioinformatics analysis, and Sanger sequencing validation were performed to define the genotypes.\nRESULTS: CF-PBS was accompanied by recurrent and/or persistent pneumonia (91.7%), pancreatitis (83.3%), vomiting and/or diarrhea (66.7%), failure to thrive and liver disease (58.3% respectively), among our patients. The predominant organisms found in the airways were Pseudomonas aeruginosa (83.3%) and Staphylococcus aureus (75.0%). The mean concentrations of blood gas and electrolytes were pH 7.58, bicarbonate 40.8 mmol/L, sodium 125.9 mmol/L, chloride 77.5 mmol/L, and potassium 2.6 mmol/L. A high recurrence rate (50.0%) of CF-PBS was observed despite continued electrolyte supplementation during follow-up. In all, 19 different variants of CFTR gene were identified, and 10 of these were found to be novel observations (c.262_266delTTATA[p.L88FfsX21], c.579+2insACAT, c.1210-3C>G, c.1733T>C[p.L578P], c.2236_2246delGAGGCGATACTinsAAAAATC[p.E746KfsX8], c.3068T>G [p.I1023R], c.3635delT[p.V1212AfsX16], c.3859delG[p.G1287EfsX2], c.3964-7A>G and ΔE23 [c.3718-?_3873+?del]). The c.2909G>A[p.G970D] was the most common variant, with an allele frequency of 16.6%. A homozygous genotype of c.1521_1523delCTT[p.F508del] was discovered for the first time in patients of Chinese origin.\nCONCLUSIONS: In China, CF-PBS usually presents early and recurs frequently in infancy, accompanied by multiple comorbidities. Recurrence of CF-PBS in school-going patients does occur but is rare. The p.G970D is the most frequent variant, with a significant ethnic tendency of Chinese origin.","variants":[{"Name":"NM_000492.3(CFTR):c.1521_1523del (p.Phe508del)","Chromosome":"7","Start":"117559591","Stop":"117559593","ReferenceAlleleVCF":"ATCT","AlternateAlleleVCF":"A","allel_id":22144,"rule_based_match":true,"evidence_text":"c.1521_1523delCTT[p.F508del]","llm_judgment":"PRESENT","evidence":"c.1521_1523delCTT[p.F508del]","abstract_start":1601,"abstract_end":1629},{"Name":"NM_000492.4(CFTR):c.1733T>C (p.Leu578Pro)","Chromosome":"7","Start":"117590406","Stop":"117590406","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2157657,"rule_based_match":true,"evidence_text":"c.1733T>C[p.L578P]","llm_judgment":"PRESENT","evidence":"c.1733T>C[p.L578P]","abstract_start":1300,"abstract_end":1318}]}
{"pmid":"24129431","title":"Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.","abstract":"Acromesomelic chondrodysplasias (ACDs) are characterized by disproportionate shortening of the appendicular skeleton, predominantly affecting the middle (forearms and forelegs) and distal segments (hands and feet). Here, we present two consanguineous families with missense (c.157T>C, p.(C53R)) or nonsense (c.657G>A, p.(W219*)) mutations in BMPR1B. Homozygous affected individuals show clinical and radiographic findings consistent with ACD-type Grebe. Functional analysis of the missense mutation C53R revealed that the mutated receptor was partially located at the cell membrane. In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay. Further, overexpression of the C53R mutation in an in vitro chondrogenesis assay showed no effect on cell differentiation, indicating a loss of function. The nonsense mutation (c.657G>A, p.(W219*)) introduces a premature stop codon, which is predicted to be subject to nonsense-mediated mRNA decay, causing reduced protein translation of the mutant allele. A loss-of-function effect of both mutations causing recessive ACD-type Grebe is further supported by the mild brachydactyly or even non-penetrance of these mutations observed in the heterozygous parents. In contrast, dominant-negative BMPR1B mutations described previously are associated with autosomal-dominant brachydactyly-type A2.","variants":[{"Name":"NM_001203.3(BMPR1B):c.157T>C (p.Cys53Arg)","Chromosome":"4","Start":"95114733","Stop":"95114733","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":213897,"rule_based_match":true,"evidence_text":"c.157T>C, p.(C53R)","llm_judgment":"PRESENT","evidence":"c.157T>C, p.(C53R)","abstract_start":275,"abstract_end":293},{"Name":"NM_001203.3(BMPR1B):c.657G>A (p.Trp219Ter)","Chromosome":"4","Start":"95129933","Stop":"95129933","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":213898,"rule_based_match":true,"evidence_text":"c.657G>A (p.(W219*))","llm_judgment":"PRESENT","evidence":"c.657G>A","abstract_start":308,"abstract_end":316}]}
{"pmid":"33890291","title":"Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia.","abstract":"The glycine cleavage system H protein (GCSH) is an integral part of the glycine cleavage system with its additional involvement in the synthesis and transport of lipoic acid. We hypothesize that pathogenic variants in GCSH can cause variant nonketotic hyperglycinemia (NKH), a heterogeneous group of disorders with findings resembling a combination of severe NKH (elevated levels of glycine in plasma and CSF, progressive lethargy, seizures, severe hypotonia, no developmental progress, early death) and mitochondriopathies (lactic acidosis, leukoencephalopathy and Leigh-like lesions on MRI). We herein report three individuals from two unrelated Indian families with clinical, biochemical, and radiological findings of variant NKH, harboring a biallelic start loss variant, c.1A > G in GCSH.","variants":[{"Name":"NM_004483.5(GCSH):c.1A>G (p.Met1Val)","Chromosome":"16","Start":"81096278","Stop":"81096278","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":260129,"rule_based_match":true,"evidence_text":"c.1A > G","llm_judgment":"PRESENT","evidence":"c.1A > G","abstract_start":776,"abstract_end":784}]}
{"pmid":"22415235","title":"Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families.","abstract":"BACKGROUND: Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer. We studied ovarian and breast cancer families having at least one woman affected by ovarian carcinoma, to assess the importance of RAD51D mutations in such families.\nMETHODS: The coding region of the RAD51D gene was analysed in 175 BRCA1/2-negative families with family histories of both ovarian and breast cancer ascertained from two Canadian and two Belgian institutions.\nRESULTS: We identified one previously reported deleterious mutation, p.Arg186(*) (c.556C>T), and two novel variants; missense substitution p.Cys119Arg and an intronic variant c.83-26A>G. p.Arg186(*) segregated with the disease in the family and two ovarian carcinomas available for analysis showed loss of the wild-type allele, but the novel variants are likely neutral.\nCONCLUSION: RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. We show that mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer, and we feel testing should be preferentially offered to affected women from such families.","variants":[{"Name":"NM_002878.4(RAD51D):c.355T>C (p.Cys119Arg)","Chromosome":"17","Start":"35107113","Stop":"35107113","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":180806,"rule_based_match":false,"evidence_text":"p.Cys119Arg","llm_judgment":"PRESENT","evidence":"p.Cys119Arg","abstract_start":702,"abstract_end":713},{"Name":"NM_002878.4(RAD51D):c.556C>T (p.Arg186Ter)","Chromosome":"17","Start":"35106406","Stop":"35106406","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39241,"rule_based_match":true,"evidence_text":"c.556C>T","llm_judgment":"PRESENT","evidence":"c.556C>T","abstract_start":645,"abstract_end":653}]}
{"pmid":"23417386","title":"Spinal neurofibromatosis associated with classical neurofibromatosis type 1: genetic characterisation of an atypical case.","abstract":"Spinal tumours are observed in about 40% of neurofibromatosis type 1 (NF1) patients and occur within two subgroups: (1) NF1 patients carrying classical diagnostic criteria and only one or few spinal tumours and (2) patients with few NF1 stigmata but multiple bilateral spinal tumours, an entity called spinal neurofibromatosis. We report a young patient whose classical NF1 stigmata and numerous spinal neurofibromas matched both groups. He carried a single base deletion, c.389delA in exon 4a, which creates a premature termination at codon 164. This case illustrates the possibility of variant phenotypes and a novel NF1 mutation associated with spinal neurofibromatosis.","variants":[{"Name":"NM_001042492.3(NF1):c.389del (p.His130fs)","Chromosome":"17","Start":"31163286","Stop":"31163286","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1406460,"rule_based_match":true,"evidence_text":"c.389delA","llm_judgment":"PRESENT","evidence":"c.389delA","abstract_start":473,"abstract_end":482}]}
{"pmid":"36933359","title":"Generation of induced pluripotent stem cells (IBMSi027-A) from a patient with hearing loss carrying WFS1 c.2051C > T (p.Ala684Val) variant.","abstract":"Pathogenic variants of the WFS1 gene can cause recessive-inherited Wolfram syndrome or dominant-inherited Wolfram-like syndrome with optic atrophy and hearing impairment. Using the Sendai virus delivery system, we generated induced pluripotent stem cells from the peripheral blood mononuclear cells of a female patient with the WFS1 pathogenic variant c.2051C > T (p.Ala684Val). The resulting induced pluripotent stem cells exhibited a normal karyotype and pluripotency, as confirmed using immunofluorescence staining, and differentiated into three germ layers in vivo. This cellular model provides a useful platform for investigating the pathogenic mechanisms of both blindness and deafness related to WFS1 variants.","variants":[{"Name":"NM_006005.3(WFS1):c.2051C>T (p.Ala684Val)","Chromosome":"4","Start":"6301846","Stop":"6301846","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39513,"rule_based_match":true,"evidence_text":"WFS1 c.2051C > T (p.Ala684Val)","llm_judgment":"PRESENT","evidence":"c.2051C > T","abstract_start":352,"abstract_end":363}]}
{"pmid":"17377962","title":"Heterozygous nonsense mutation SATB2 associated with cleft palate, osteoporosis, and cognitive defects.","abstract":"Studies of human chromosomal aberrations and knockout (KO) mice have suggested SATB2 as a candidate gene for a human malformation syndrome of craniofacial patterning and brain development. Of 59 unrelated patients with craniofacial dysmorphism, with or without mental retardation, one 36-year-old man had a nonsynonymous mutation in SATB2. The affected individual exhibited craniofacial dysmorphisms including cleft palate, generalized osteoporosis, profound mental retardation, epilepsy and a jovial personality. He carries a de novo germline nonsense mutation (c.715C>T, p.R239X) in the exon 6 of SATB2. Expression studies showed that the mutant RNA was stable, expected to produce a truncated protein predicted to retain its dimerization domain and exert a dominant negative effect. This new syndrome is the first determined to result from mutation of a gene within the family that encodes nuclear matrix-attachment region (MAR) proteins.","variants":[{"Name":"NM_001172509.2(SATB2):c.715C>T (p.Arg239Ter)","Chromosome":"2","Start":"199349159","Stop":"199349159","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17558,"rule_based_match":true,"evidence_text":"c.715C>T, p.R239X","llm_judgment":"PRESENT","evidence":"c.715C>T, p.R239X","abstract_start":563,"abstract_end":580}]}
{"pmid":"38464914","title":"L-2 hydroxyglutaric aciduria: report of a Mexican-Mayan patient with the mutation c.569C>T and response to vitamin supplements and levocarnitine.","abstract":"Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by pathogenic variants in the <i>L2HGDH</i> gene which encodes mitochondrial 2-hydroxyglutarate dehydrogenase. Here, we report a case of L2HGA in a Mexican-Mayan patient with a homozygous mutation at <i>L2HGDH</i> gene and clinical response to vitamin supplements and levocarnitine.\nCase report: A 17-year-old, right-handed female patient with long-term history of seizures, developmental delay and ataxia was referred to a movement disorders specialist for the evaluation of tremor. Her brain MRI showed typical findings of L2HGA. The diagnosis was corroborated with elevated levels of 2-hydroxyglutaric acid in urine and genetic test which revealed a homozygous genetic known variant c.569C>T in exon 5 of <i>L2HGDH</i> gene. She was treated with levocarnitine and vitamin supplements, showing improvement in tremor and gait.\nDiscussion: To our knowledge this is the first report of a Mexican patient with L2HGA. This case adds information about a rare condition in a different ethnic group and supports the findings of other authors which encountered symptomatic improvement with the use of flavin adenine dinucleotide (and its precursor riboflavin), and levocarnitine.\nHighlights: We report the first case of Mexican-Mayan patient with L2HGA showing a missense homozygous mutation in <i>L2HGDH</i> gene, and improvement of symptoms with vitamin supplements and levocarnitine.","variants":[{"Name":"NM_024884.3(L2HGDH):c.569C>T (p.Thr190Ile)","Chromosome":"14","Start":"50284005","Stop":"50284005","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3228522,"rule_based_match":true,"evidence_text":"c.569C>T","llm_judgment":"PRESENT","evidence":"c.569C>T","abstract_start":806,"abstract_end":814}]}
{"pmid":"19488752","title":"A novel beta-globin mutation (HBB:c.107A>G; or codon 35 beta (A-->G)) at alpha-beta chain interfaces.","abstract":"","variants":[{"Name":"NM_000518.5(HBB):c.107A>G (p.Tyr36Cys)","Chromosome":"11","Start":"5226785","Stop":"5226785","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":857492,"rule_based_match":true,"evidence_text":"HBB:c.107A>G","llm_judgment":"PRESENT","evidence":"HBB:c.107A>G","abstract_start":null,"abstract_end":null}]}
{"pmid":"30759959","title":"A Case of Autosomal Dominant Osteopetrosis Type 2 with a","abstract":"Osteopetrosis is a rare genetic disease characterized by increased bone density and bone fractures due to defective osteoclast function. Autosomal dominant osteopetrosis type 2 (ADO-2), Albers-Schonberg disease, is characterized by the sclerosis of bones, predominantly involving the spine, pelvis and the base of the skull. Here, we report a typical case of osteopetrosis in a 17.7-year-old male who carries a heterozygous c.746C>T mutation in exon 9 in the <i>chloride voltage-gated channel 7 (CLCN7)</i> gene. The patient’s spine showed multiple sclerotic changes including sandwich vertebra. His father had the same mutation but his skeletal radiographs were normal. This is the first reported case of ADO-2, confirmed by genetic testing in a Korean patient.","variants":[{"Name":"NM_001287.6(CLCN7):c.746C>T (p.Pro249Leu)","Chromosome":"16","Start":"1457330","Stop":"1457330","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1451456,"rule_based_match":true,"evidence_text":"c.746C>T","llm_judgment":"PRESENT","evidence":"c.746C>T","abstract_start":424,"abstract_end":432}]}
{"pmid":"36466854","title":"RIPK1 mutations causing infantile-onset IBD with inflammatory and fistulizing features.","abstract":"Purpose: Receptor-interacting serine/threonine-protein kinase 1 <i>(</i>RIPK1) is an important regulator of necroptosis and inflammatory responses. We present the clinical features, genetic analysis and immune work-up of two patients with infantile-onset inflammatory bowel disease (IBD) resulting from <i>RIPK1 </i>mutations.\nMethods: Whole exome and Sanger sequencing was performed in two IBD patients. Mass cytometry time of flight (CyTOF) was conducted for in-depth immunophenotyping on one of the patient's peripheral blood mononuclear cells, and compared to control subjects and patients with Crohn's disease.\nResults: The patients presented with severe colitis and perianal fistulas in the first months of life, without severe/atypical infections. Genetic studies identified pathogenic genetic variants in <i>RIPK1</i> (Patient 1, A c.1934C>T missense mutation in Exon 11; Patient 2, c.580G>A missense mutation residing in Exon 4). Protein modeling demonstrated that the mutation in Patient 1 displaces a water molecule, potentially disrupting the local environment, and the mutation in Patient 2 may lead to disruption of the packing and conformation of the kinase domain. Immunofluorescence RIPK1 staining in rectal biopsies demonstrated no expression for Patient 1 and minimal expression for Patient 2, compared to controls and patients with active Crohn's disease. Using CyTOF unbiased clustering analysis, we identified peripheral immune dysregulation in one of these patients, characterized by an increase in IFNγ CD8<sup>+</sup> T cells along with a decrease in monocytes, dendritic cells and B cells. Moreover, RIPK1-deficient patient's immune cells exhibited decreased IL-6 production in response to lipopolysaccharide (LPS) across multiple cell types including T cells, B cells and innate immune cells.\nConclusions: Mutations in <i>RIPK1</i> should be considered in very young patients presenting with colitis and perianal fistulas. Given RIPK1's role in inflammasome activation, but also in epithelial cells, it is unclear whether IL1 blockade or allogeneic hematopoietic stem cell transplantation can suppress or cure the hyper-inflammatory response in these patients. Additional studies in humans are required to better define the role of RIPK1 in regulating intestinal immune responses, and how treatment can be optimized for patients with RIPK1 deficiency.","variants":[{"Name":"NM_001354930.2(RIPK1):c.1934C>T (p.Thr645Met)","Chromosome":"6","Start":"3113257","Stop":"3113257","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":589851,"rule_based_match":true,"evidence_text":"c.1934C>T","llm_judgment":"PRESENT","evidence":"c.1934C>T","abstract_start":840,"abstract_end":849}]}
{"pmid":"23141461","title":"Late onset of symptoms in an atypical patient with the cblJ inborn error of vitamin B12 metabolism: diagnosis and novel mutation revealed by exome sequencing.","abstract":"Inborn errors of vitamin B(12) (cobalamin) metabolism are characterized by decreased production of active cobalamin cofactors and subsequent deficiencies in the activities of methionine synthase and methylmalonyl-CoA mutase. With the recent discovery of the cblJ defect in two patients with phenotypes mimicking the cblF defect, there are nine genes known to be involved in cobalamin metabolism. The new defect is caused by mutations in the ABCD4 gene, encoding an ABC transporter. At the moment, there is no clear distinction between the cblJ and cblF defects either clinically or biochemically, and both defects result in blocks in the transport of cobalamin from the lysosome to the cytoplasm. A patient was diagnosed with hyperhomocysteinemia and methylmalonic aciduria at the age of 8 years. Incorporations of both [(14)C]propionate and [(14)C]methyltetrahydrofolate in cultured fibroblasts were within reference ranges and thus too high to allow for complementation analysis. We observed decreased synthesis of both adenosylcobalamin and methylcobalamin and accumulation of unmetabolized cyanocobalamin. Exome sequencing was performed to identify causative mutation(s) and Sanger re-sequencing was performed to validate segregation of mutation in the family. By this approach, a homozygous mutation, c.423C>G, in the ABCD4 gene was identified. Here, we report the successful application of exome sequencing for diagnosis of a rare inborn error of vitamin B(12) metabolism in a patient whose unusual presentation precluded diagnosis using standard biochemical and genetic approaches. The patient represents only the third known patient with the cblJ disorder.","variants":[{"Name":"NM_005050.4(ABCD4):c.423C>G (p.Asn141Lys)","Chromosome":"14","Start":"74297932","Stop":"74297932","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1335298,"rule_based_match":true,"evidence_text":"c.423C>G","llm_judgment":"PRESENT","evidence":"c.423C>G","abstract_start":1306,"abstract_end":1314}]}
{"pmid":"31444901","title":"Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.","abstract":"Generalized arterial calcifications of infancy (GACI) is caused by mutations in ENPP1. Other ENPP1-related phenotypes include pseudoxanthoma elasticum, hypophosphatemic rickets, and Cole disease. We studied four children from two Bedouin consanguineous families who presented with severe clinical phenotype including thrombocytopenia, hypoglycemia, hepatic, and neurologic manifestations. Initial working diagnosis included congenital infection; however, patients remained without a definitive diagnosis despite extensive workup. Consequently, we investigated a potential genetic etiology. Whole exome sequencing (WES) was performed for affected children and their parents. Following the identification of a novel mutation in the ENPP1 gene, we characterized this novel multisystemic presentation and revised relevant imaging studies. Using WES, we identified a novel homozygous mutation (c.556G > C; p.Gly186Arg) in ENPP1 which affects a highly conserved protein domain (somatomedin B2). ENPP1-associated genetic diseases exhibit phenotypic heterogeneity depending on mutation type and location. Follow-up clinical characterization of these families allowed us to revise and detect new features of systemic calcifications, which established the diagnosis of GACI, expanding the phenotypic spectrum associated with ENPP1 mutations. Our findings demonstrate that this novel ENPP1 founder mutation can cause a fatal multisystemic phenotype, mimicking severe congenital infection. This also represents the first reported mutation affecting the SMB2 domain, associated with GACI.","variants":[{"Name":"NM_006208.3(ENPP1):c.556G>C (p.Gly186Arg)","Chromosome":"6","Start":"131851267","Stop":"131851267","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":976532,"rule_based_match":true,"evidence_text":"c.556G > C; p.Gly186Arg","llm_judgment":"PRESENT","evidence":"c.556G > C; p.Gly186Arg","abstract_start":889,"abstract_end":912}]}
{"pmid":"23205931","title":"Electroclinical presentation and genotype-phenotype relationships in patients with Unverricht-Lundborg disease carrying compound heterozygous CSTB point and indel mutations.","abstract":"PURPOSE: Unverricht-Lundborg disease (EPM1A) is frequently due to an unstable expansion of a dodecamer repeat in the CSTB gene, whereas other types of mutations are rare. EPM1A due to homozygous expansion has a rather stereotyped presentation with prominent action myoclonus. We describe eight patients with five different compound heterozygous CSTB point or indel mutations in order to highlight their particular phenotypical presentations and evaluate their genotype-phenotype relationships.\nMETHODS: We screened CSTB mutations by means of Southern blotting and the sequencing of the genomic DNA of each proband. CSTB messenger RNA (mRNA) aberrations were characterized by sequencing the complementary DNA (cDNA) of lymphoblastoid cells, and assessing the protein concentrations in the lymphoblasts. The patient evaluations included the use of a simplified myoclonus severity rating scale, multiple neurophysiologic tests, and electroencephalography (EEG)-polygraphic recordings. To highlight the particular clinical features and disease time-course in compound heterozygous patients, we compared some of their characteristics with those observed in a series of 40 patients carrying the common homozygous expansion mutation observed at the C. Besta Foundation, Milan, Italy.\nKEY FINDINGS: The eight compound heterozygous patients belong to six EPM1A families (out of 52; 11.5%) diagnosed at the Laboratory of Genetics of the Galliera Hospitals in Genoa, Italy. They segregated five different heterozygous point or indel mutations in association with the common dodecamer expansion. Four patients from three families had previously reported CSTB mutations (c.67-1G>C and c.168+1_18del); one had a novel nonsense mutation at the first exon (c.133C>T) leading to a premature stop codon predicting a short peptide; the other three patients from two families had a complex novel indel mutation involving the donor splice site of intron 2 (c.168+2_169+21delinsAA) and leading to an aberrant transcript with a partially retained intron. The protein dose (cystatin B/β-actin) in our heterozygous patients was 0.24 ± 0.02, which is not different from that assessed in patients bearing the homozygous dodecamer expansion. The compound heterozygous patients had a significantly earlier disease onset (7.4 ± 1.7 years) than the homozygous patients, and their disease presentations included frequent myoclonic seizures and absences, often occurring in clusters throughout the course of the disease. The seizures were resistant to the pharmacologic treatments that usually lead to complete seizure control in homozygous patients. EEG-polygraphy allowed repeated seizures to be recorded. Action myoclonus progressively worsened and all of the heterozygous patients older than 30 years were in wheelchairs. Most of the patients showed moderate to severe cognitive impairment, and six had psychiatric symptoms.\nSIGNIFICANCE: EPM1A due to compound heterozygous CSTB mutations presents with variable but often markedly severe and particular phenotypes. Most of our patients presented with the electroclinical features of severe epilepsy, which is unexpected in homozygous patients, and showed frequent seizures resistant to pharmacologic treatment. The presence of variable phenotypes (even in siblings) suggests interactions with other genetic factors influencing the final disease presentation.","variants":[{"Name":"NM_000100.4(CSTB):c.67-1G>C","Chromosome":"21","Start":"43774760","Stop":"43774760","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":23434,"rule_based_match":true,"evidence_text":"c.67-1G>C","llm_judgment":"PRESENT","evidence":"c.67-1G>C","abstract_start":1658,"abstract_end":1667}]}
{"pmid":"23029027","title":"A novel missense SNRNP200 mutation associated with autosomal dominant retinitis pigmentosa in a Chinese family.","abstract":"The SNRNP200 gene encodes hBrr2, a helicase essential for pre-mRNA splicing. Six mutations in SNRNP200 have recently been discovered to be associated with autosomal dominant retinitis pigmentosa (adRP). In this work, we analyzed a Chinese family with adRP and identified a novel missense mutation in SNRNP200. To identify the genetic defect in this family, exome of the proband was captured and sequencing analysis was performed to exclude known genetic defects and find possible pathogenic mutations. Subsequently, candidate mutations were validated in affected family members using Sanger sequencing. A novel missense mutation, c.2653C>G transition (p.Q885E), in exon 20 of SNRNP200 was identified. The mutation co-segregated with the disease phenotype over four generations and was absent in 100 normal unaffected individuals. This mutation occurs at highly conserved position in hBrr2 and is predicted to have a functional impact, suggesting that hBrr2-dependent small nuclear riboproteins (snRNPs) unwinding and spliceosome activation is important in the pathogenesis of some variants of RP.","variants":[{"Name":"NM_014014.5(SNRNP200):c.2653C>G (p.Gln885Glu)","Chromosome":"2","Start":"96290415","Stop":"96290415","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":48346,"rule_based_match":true,"evidence_text":"c.2653C>G transition (p.Q885E)","llm_judgment":"PRESENT","evidence":"c.2653C>G transition (p.Q885E)","abstract_start":630,"abstract_end":660}]}
{"pmid":"29127544","title":"A Brazilian family with inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia linked to the VCP pGly97Glu mutation.","abstract":"The objective of this study is to report a Brazilian patient and his family with inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). A systematic review of the literature on the valosin-containing protein (VCP) mutation was also performed. The proband (patient) was initially treated as a case of possible refractory polymyositis with Paget's disease and later as an inclusion body myopathy. However, after admission to our service, and considering his personal and familial antecedents, whole exome sequencing was performed revealing valosin-containing protein (VCP) c.290G>A (p.Gly97Glu) mutation in the patient and his nine family members. The clinical presentation of the patient and his family was characterized by different degrees and evaluations of IBMPFD. According to the literature, only one family (Chinese) has this same VCP mutation concomitantly with different IBMPFD phenotype manifestations. The present study shows that IBMPFD should be considered as a differential diagnosis in patients with inflammatory myopathies associated to bone disease and/or cognitive impairment. Moreover, the study expands the genotypic spectrum of missense mutations of VCP gene in a Brazilian family with variable phenotypes.","variants":[{"Name":"NM_007126.5(VCP):c.290G>A (p.Gly97Glu)","Chromosome":"9","Start":"35067903","Stop":"35067903","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215002,"rule_based_match":true,"evidence_text":"VCP c.290G>A (p.Gly97Glu)","llm_judgment":"PRESENT","evidence":"p.Gly97Glu","abstract_start":628,"abstract_end":638}]}
{"pmid":"26992473","title":"A case of Canavan disease with microcephaly.","abstract":"BACKGROUND: Canavan disease is an autosomal recessive disorder with spongy degeneration of white matter of the brain. It presents with developmental delay, visual problems and macrocephaly.\nPATIENT DESCRIPTION: We report a ten-month old boy with Canavan disease who presented with global developmental delay, seizures, abnormal eye movements and microcephaly.\nRESULTS: MRI brain revealed diffuse involvement of the supra tentorial white matter, globus pallidi, thalami, dentate nuclei and brainstem with sparing of the corpus callosum. The genetic testing revealed homozygous mutation of aspartoacylase gene [c.859 G>A (p.Ala287Thr)] in Exon 6.\nCONCLUSION: Possibility of Canavan disease should be considered even in the presence of microcephaly.","variants":[{"Name":"NM_000049.4(ASPA):c.859G>A (p.Ala287Thr)","Chromosome":"17","Start":"3499005","Stop":"3499005","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186967,"rule_based_match":true,"evidence_text":"c.859 G>A (p.Ala287Thr)","llm_judgment":"PRESENT","evidence":"c.859 G>A (p.Ala287Thr)","abstract_start":609,"abstract_end":632}]}
{"pmid":"28473773","title":"Analyses of","abstract":"Amelogenesis imperfecta is a group of rare inherited disorders that affect tooth enamel formation, quantitatively and/or qualitatively. The aim of this study was to identify the genetic etiologies of two families presenting with hypomaturation amelogenesis imperfecta. DNA was isolated from peripheral blood samples obtained from participating family members. Whole exome sequencing was performed using DNA samples from the two probands. Sequencing data was aligned to the NCBI human reference genome (NCBI build 37.2, hg19) and sequence variations were annotated with the dbSNP build 138. Mutations in <i>MMP20</i> were identified in both probands. A homozygous missense mutation (c.678T>A; p.His226Gln) was identified in the consanguineous Family 1. Compound heterozygous <i>MMP20</i> mutations (c.540T>A, p.Tyr180<sup>*</sup> and c.389C>T, p.Thr130Ile) were identified in the non-consanguineous Family 2. Affected persons in Family 1 showed hypomaturation AI with dark brown discoloration, which is similar to the clinical phenotype in a previous report with the same mutation. However, the dentition of the Family 2 proband exhibited slight yellowish discoloration with reduced transparency. Functional analysis showed that the p.Thr130Ile mutant protein had reduced activity of MMP20, while there was no functional MMP20 in the Family 1 proband. These results expand the mutational spectrum of the <i>MMP20</i> and broaden our understanding of genotype-phenotype correlations in amelogenesis imperfecta.","variants":[{"Name":"NM_004771.4(MMP20):c.389C>T (p.Thr130Ile)","Chromosome":"11","Start":"102611889","Stop":"102611889","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":620376,"rule_based_match":true,"evidence_text":"c.389C>T (p.Thr130Ile)","llm_judgment":"PRESENT","evidence":"p.Thr130Ile","abstract_start":843,"abstract_end":854}]}
{"pmid":"24300783","title":"Exome sequencing identifies Laing distal myopathy MYH7 mutation in a Roma family previously diagnosed with distal neuronopathy.","abstract":"We describe a Hungarian Roma family, originally investigated for autosomal dominant distal muscular atrophy. The mother started toe walking at 3 years and lost ambulation at age 27. Her three daughters presented with early steppage gait and showed variable progression. Muscle biopsies were nonspecific showing myogenic lesions in the mother and lesions resembling neurogenic atrophy in the two siblings. To identify the causative abnormality whole exome sequencing was performed in two affected girls and their unaffected father, unexpectedly revealing the MYH7 mutation c.4849_4851delAAG (p.K1617del) in both girls, reported to be causative for Laing distal myopathy. Sanger sequencing confirmed the mutation in the affected mother and third affected daughter. In line with variable severity in Laing distal myopathy our patients presented a more severe phenotype. Our case is the first demonstration of Laing distal myopathy in the Roma and the successful use of whole exome sequencing in obtaining a definitive diagnosis in ambiguous cases.","variants":[{"Name":"NM_000257.4(MYH7):c.4844AGA[2] (p.Lys1617del)","Chromosome":"14","Start":"23416105","Stop":"23416107","ReferenceAlleleVCF":"ATCT","AlternateAlleleVCF":"A","allel_id":188231,"rule_based_match":false,"evidence_text":"c.4849_4851delAAG (p.K1617del)","llm_judgment":"PRESENT","evidence":"c.4849_4851delAAG (p.K1617del)","abstract_start":572,"abstract_end":602}]}
{"pmid":"17068223","title":"A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.","abstract":"The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.","variants":[{"Name":"NM_144701.3(IL23R):c.1142G>A (p.Arg381Gln)","Chromosome":"1","Start":"67240275","Stop":"67240275","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18147,"rule_based_match":true,"evidence_text":"c.1142G>A (p.Arg381Gln)","llm_judgment":"PRESENT","evidence":"p.Arg381Gln","abstract_start":530,"abstract_end":541}]}
{"pmid":"27734835","title":"Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation.","abstract":"Pathogenic germline mutations in the folliculin (FLCN) tumor suppressor gene predispose to Birt-Hogg-Dubé (BHD) syndrome, a rare disease characterized by the development of cutaneous hamartomas (fibrofolliculomas), multiple lung cysts, spontaneous pneumothoraces and renal cell cancer. In this study, we report the identification of 13 variants and three polymorphisms in the FLCN gene in 143 Danish patients or families with suspected BHD syndrome. Functional mini-gene splicing analysis revealed that two intronic variants (c.1062+2T>G and c.1177-5_1177-3del) introduced splicing aberrations. Eleven families exhibited the c.1062+2T>G mutation. Combined single nucleotide polymorphism array-haplotype analysis showed that these families share a 3-Mb genomic fragment containing the FLCN gene, revealing that the c.1062+2T>G mutation is a Danish founder mutation. On the basis of in silico prediction and functional splicing assays, we classify the 16 identified variants in the FLCN gene as follows: nine as pathogenic, one as likely pathogenic, three as likely benign and three as polymorphisms. In conclusion, the study describes the FLCN mutation spectrum in Danish BHD patients, and contributes to a better understanding of BHD syndrome and management of BHD patients.","variants":[{"Name":"NM_144997.7(FLCN):c.1177-5_1177-3del","Chromosome":"17","Start":"17216506","Stop":"17216508","ReferenceAlleleVCF":"TGAG","AlternateAlleleVCF":"T","allel_id":230675,"rule_based_match":true,"evidence_text":"c.1177-5_1177-3del","llm_judgment":"PRESENT","evidence":"c.1177-5_1177-3del","abstract_start":542,"abstract_end":560},{"Name":"NM_144997.7(FLCN):c.1062+2T>G","Chromosome":"17","Start":"17219017","Stop":"17219017","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":260154,"rule_based_match":true,"evidence_text":"c.1062+2T>G","llm_judgment":"PRESENT","evidence":"c.1062+2T>G","abstract_start":526,"abstract_end":537}]}
{"pmid":"38445235","title":"Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency.","abstract":"Background: Hereditary angioedema (HAE) is a potentially life-threatening disorder characterized by recurrent episodes of subcutaneous or submucosal swelling. HAE with normal C1 inhibitor (HAE-nC1-INH) is an underdiagnosed condition. Although the association with genetic variants has been identified for some families, the genetic causes in many patients with HAE-nC1-INH remain unknown. The role of genes associated with bradykinin catabolism is not fully understood.\nObjective: We sought to investigate the biological parameters and the genes related to kallikrein-kinin system in families with a clinical phenotype of HAE-nC1-INH and presenting with a carboxypeptidase N (CPN) deficiency.\nMethods: This study includes 4 families presenting with HAE-nC1-INH and CPN deficiency. Patients' clinical records were examined, biological parameters of kallikrein-kinin system were measured, and genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictive algorithms (Human Splicing Finder, Sorting Intolerant From Tolerant, Polymorphism Phenotyping v2, MutationTaster, and ClinPred) were used to classify variants as affecting splicing, as benign to deleterious, or as disease-causing.\nResults: Patients presented with angioedema and urticaria, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Affected patients displayed low CPN activity-30% to 50% of median value in plasma. We identified 3 variants of the <i>CPN1</i> gene encoding the catalytic 55-kDa subunit of CPN: c.533G>A, c.582A>G, and c.734C>T. CPN deficiency associated with genetic variants segregated with HAE-nC1-INH symptoms in affected family members.\nConclusions: <i>CPN1</i> gene variants are associated with CPN deficiency and HAE-nC1-INH symptoms in 4 unrelated families. Genetic CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, with synergistic effects in angioedema and urticarial symptoms.","variants":[{"Name":"NM_001308.3(CPN1):c.734C>T (p.Thr245Met)","Chromosome":"10","Start":"100065213","Stop":"100065213","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3499780,"rule_based_match":true,"evidence_text":"c.734C>T","llm_judgment":"PRESENT","evidence":"c.734C>T","abstract_start":1542,"abstract_end":1550},{"Name":"NM_001308.3(CPN1):c.533G>A (p.Gly178Asp)","Chromosome":"10","Start":"100069757","Stop":"100069757","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":21662,"rule_based_match":true,"evidence_text":"c.533G>A","llm_judgment":"PRESENT","evidence":"c.533G>A","abstract_start":1518,"abstract_end":1526}]}
{"pmid":"28290784","title":"The Familial Hypercholesterolemia Caused by a Novel Human Low Density Lipoprotein Receptor Gene Mutation c.1327 T>C (p.W433R)","abstract":"During investigation of molecular nature of familial hypercholesterolemia (FH) in Petrozavodsk (Russia) cohort of patients a novel low density lipoprotein (LDL) receptor gene mutation was found. This mutation designated c.1327 T>C (W443R [W422R]) was predicted to cause substitution of arginine for tryptophan residue in the very conservative -propeller domain of the LDL receptor. Inheritance of the new mutation was traced in four generations and its cosegregation with hypercholesterolemia phenotype was observed. Despite the predicted pathogenic effect of the mutation, ischemic heart disease in the pedigree was mild or absent. We consider identification of this mutation in the pedigree extremely helpful to start preventive medical treatment in affected patients.","variants":[{"Name":"NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg)","Chromosome":"19","Start":"11113418","Stop":"11113418","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":985783,"rule_based_match":true,"evidence_text":"c.1327 T>C (W443R [W422R])","llm_judgment":"PRESENT","evidence":"c.1327 T>C (W443R [W422R])","abstract_start":220,"abstract_end":246}]}
{"pmid":"20361012","title":"A mutation in the FOXE3 gene causes congenital primary aphakia in an autosomal recessive consanguineous Pakistani family.","abstract":"PURPOSE: Aphakia is the complete absence of any lens in the eye, either due to surgical removal of the lens as a result of a perforating wound or ulcer, or due to a congenital anomaly. The purpose of this study was to elucidate the molecular genetics for a large consanguineous Pakistani family with a clear aphakia phenotype.\nMETHODS: The initial homozygosity screening of the family was extended to all the known autosomal recessive cataract loci in order to exclude the possibility of surgical cataract removal leading to aphakia. The screening was performed using polymorphic nucleotide repeat markers, followed by DNA sequencing of a possible candidate gene, the forkhead box protein E3 gene (FOXE3). The identified mutation was counter-checked by a diagnostic restriction enzyme digest of all the family members, and an analysis of the normal population.\nRESULTS: The initial homozygosity screening of 13 known autosomal recessive loci resulted in negative LOD (logarithm of odds) scores. The aphakia phenotype suggested a mutation in FOXE3 close to the AR-locus 1p34.3-p32.2, and sequence analyses revealed the nonsense mutation c.720C>A, changing cysteine 240 to a stop codon. Segregation in the family was shown by diagnostic restriction enzyme digest, and marker analysis of another aphakia family from Madagascar carrying the same mutation excluded the presence of a founder mutation. Clinical re-examination of the family was not possible due to the escalating security concerns and internal displacement of the population in this region of Pakistan which has prevailed for many months.\nCONCLUSIONS: FOXE3 is responsible for the early developmental arrest of the lens placode, and the complete loss of a functional FOXE3 protein results in primary aphakia. It can also be deduced that this mutation is quite primitive in origin since the same mutation is responsible for the same phenotypic outcome in two families of geographically different descent.","variants":[{"Name":"NM_012186.3(FOXE3):c.720C>A (p.Cys240Ter)","Chromosome":"1","Start":"47417035","Stop":"47417035","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":23487,"rule_based_match":true,"evidence_text":"c.720C>A","llm_judgment":"PRESENT","evidence":"c.720C>A","abstract_start":1136,"abstract_end":1144}]}
{"pmid":"23644456","title":"Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits.","abstract":"Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.","variants":[{"Name":"NM_018490.5(LGR4):c.376C>T (p.Arg126Ter)","Chromosome":"11","Start":"27391119","Stop":"27391119","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70564,"rule_based_match":true,"evidence_text":"c.376C>T","llm_judgment":"PRESENT","evidence":"c.376C>T","abstract_start":629,"abstract_end":637}]}
{"pmid":"18850119","title":"A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis.","abstract":"Neuronal ceroid lipofuscinoses (NCL) are lysosomal storage disorders and constitute the most common group of progressive neurodegenerative diseases in childhood. Most NCLs are inherited in a recessive manner and are clinically characterised by a variable age at onset, epileptic seizures, psychomotor decline, visual impairment and premature death. To date, eight causative genes have been identified to underlie various clinical forms of NCL. We performed a genome-wide linkage analysis followed by sequencing the recently described NCL gene MFSD8 in three affected and three unaffected members of a consanguineous Egyptian family with an autosomal recessively inherited progressive neurodegenerative disorder. The clinical picture of the patients was compatible with a late infantile NCL (LINCL); however, impairment of the visual system was not a cardinal symptom in the respective family. By linkage analysis, we identified two putative loci on chromosome 1p36.11-p35.1 and 4q28.1-q28.2. The latter locus (4q28.1-q28.2) contained the MFSD8 gene, comprising a novel homozygous missense mutation in exon 5 (c.362a>g /p.Tyr121Cys), which segregated with the disease in the three affected sibs. We describe a novel mutation in the previously identified MFSD8 gene in a family with a common phenotype of LINCL, but no clinical report of vision loss. Our results enlarge the mutational and perhaps the nosological spectrum of one of the recently identified subtypes of NCL, called CLN7.","variants":[{"Name":"NM_001371596.2(MFSD8):c.362A>G (p.Tyr121Cys)","Chromosome":"4","Start":"127943829","Stop":"127943829","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":16043,"rule_based_match":true,"evidence_text":"c.362a>g /p.Tyr121Cys","llm_judgment":"PRESENT","evidence":"c.362a>g /p.Tyr121Cys","abstract_start":1109,"abstract_end":1130}]}
{"pmid":"24594238","title":"Novel SOST gene mutation in a sclerosteosis patient from Morocco: a case report.","abstract":"Sclerosteosis (OMIM 269500) is a rare autosomal recessive condition characterized by increased bone density associated with syndactyly. It is linked to a genetic defect in the SOST gene coding for sclerostin. So far, seven different loss-of-function mutations in SOST have been reported in patients with sclerosteosis. Recently, two mutations in LRP4 gene underlying sclerosteosis were identified, reflecting the genetic heterogeneity of this disease. We report here a 30-years-old Moroccan man presented with typical clinical and radiological features of sclerosteosis who carries a novel homozygous mutation in the SOST gene, characterized as a nonsense mutation (c.79C > T; p.Gln27∗) in exon 1 of the SOST gene. This is to our knowledge the first case of sclerosteosis reported from Morocco and North Africa.","variants":[{"Name":"NM_025237.3(SOST):c.79C>T (p.Gln27Ter)","Chromosome":"17","Start":"43758663","Stop":"43758663","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1334638,"rule_based_match":true,"evidence_text":"c.79C > T; p.Gln27∗","llm_judgment":"PRESENT","evidence":"c.79C > T; p.Gln27∗","abstract_start":666,"abstract_end":685}]}
{"pmid":"30665929","title":"Novel intronic","abstract":"Pleuropulmonary blastomas (PPB) are rare aggressive paediatric lung malignancies associated with <i>DICER1</i> variants. We present two cases, a 2-year-old girl with upper respiratory tract symptoms as well as a 6-month-old girl sibling undergoing screening due to family history of malignancy. Imaging of the 2-year-old girl revealed a large mass filling the right hemithorax which was determined to be a type II PPB after pathological examination. Imaging of the 6-month-old sibling demonstrated a small cystic lesion in the posterior basal segment of the right lower lobe which was determined to be a type 1r PPB after pathological examination. The 2-year-old girl received adjuvant chemotherapy while the baby sister underwent resection alone and both are alive and well at 12 months and 7 months, respectively. Sequence analysis in both cases confirmed the same <i>DICER1</i> variation, c.2437-2A>G (likely pathogenic), which has not been previously described in the literature.","variants":[{"Name":"NM_177438.3(DICER1):c.2437-2A>G","Chromosome":"14","Start":"95108095","Stop":"95108095","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":400720,"rule_based_match":true,"evidence_text":"c.2437-2A>G","llm_judgment":"PRESENT","evidence":"c.2437-2A>G","abstract_start":892,"abstract_end":903}]}
{"pmid":"16835894","title":"Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE).","abstract":"Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently, ABCC6 mutations were identified as causing PXE. In this follow-up study we report the investigation of 61 German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the complete ABCC6 gene. In addition, we characterized the proximal ABCC6 promoter of PXE patients according to mutation. In this study we identified 32 disease-causing ABCC6 variants, which had been described previously by us and others, and 10 novel mutations (eight missense mutations and two splice site alterations). The mutation detection rate among index patients was 87.7%. Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G > T. In the ABCC6 promoter we found the polymorphisms c.-127C > T, c.-132C > T, and c.-219A > C. The difference in the c.-219A > C frequencies between PXE patients and controls were determined as statistically significant. Interestingly, c.-219A > C is located in a transcriptional activator sequence of the ABCC6 promoter and occurred in a binding site for a transcriptional repressor, predominantly found in genes that participate in lipid metabolism. Obtaining these genetic data signifies our contribution to elucidating the pathogenetics of PXE.","variants":[{"Name":"NM_001171.6(ABCC6):c.2787+1G>T","Chromosome":"16","Start":"16173283","Stop":"16173283","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":21599,"rule_based_match":true,"evidence_text":"c.2787+1G > T","llm_judgment":"PRESENT","evidence":"c.2787+1G > T","abstract_start":822,"abstract_end":835}]}
{"pmid":"30022420","title":"Autozygosity mapping of methylmalonic acidemia associated genes by short tandem repeat markers facilitates the identification of five novel mutations in an Iranian patient cohort.","abstract":"Isolated Methylmalonic acidemia/aciduria (MMA) is a group of inborn errors of metabolism disease which is caused by defect in methylmalonyl-CoA mutase (MCM) enzyme. The enzyme has a key function in the catabolism of branched chain amino acids (BCAA, isoleucine, and valine), methionine, and threonine. MCM is encoded by a single gene named \"MUT\". Other subtypes of MMA are caused by mutations in cblA (encoded by MMAA) and cblB (encoded by MMAB), which is involved in the synthesis of methylmalonyl-coenzyme A cofactor. Different types of mutations have been identified as the cause of MMA. However, the mutation spectrum of MMA in Iran has not been studied so far. Here, we aimed to investigate the MMA causative mutations in the Iranian population. Using STR (Short Tandem Repeat) markers, we performed autozygosity mapping to identify the potential pathogenic variants in 11 patients with clinical diagnosis of MMA. Nineteen STR markers which are linked to the MUT, MMAA and MMAB genes (the genes with known causative mutations in MMA) were selected for PCR-amplification using two recently designed multiplex PCR panels. Next, the families that were diagnosed with homozygous haplotypes for the candidate genes were directly sequenced. Five novel mutations (c.805delG, c.693delC, c.223A > T, c.668A > G and c.976A > G in MUT) were identified beside other 4 recurrent mutations (c.361insT in MUT, c.571C > T and c.197-1 G > T in MMAB and c.1075C > T in MMAA). In silico analyses were also performed to predict the pathogenicity of the identified variants. The mutation c.571C > T in MMAB was the most common mutation in our study.","variants":[{"Name":"NM_052845.4(MMAB):c.571C>T (p.Arg191Trp)","Chromosome":"12","Start":"109561053","Stop":"109561053","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":215031,"rule_based_match":true,"evidence_text":"c.571C > T","llm_judgment":"PRESENT","evidence":"c.571C > T","abstract_start":1400,"abstract_end":1410}]}
{"pmid":"35597529","title":"An exceptional biallelic N-terminal frame shift mutation in ZMPSTE24 leads to non-lethal progeria due to possible utilization of a downstream alternative start codon.","abstract":"Biallelic mutations in ZMPSTE24 are known to be associated with autosomal recessive mandibuloacral dysplasia with type B lipodystrophy (MADB) and lethal restrictive dermopathy (RD), respectively. Disease manifestation is depending on the remaining enzyme activity of the mutated ZMPSTE24 protein. To date, complete loss of function has exclusively been reported in RD cases. In this study, we identified a novel N-terminal homozygous frameshift mutation (c.28_29insA) in a consanguineous family segregating with MADB. An in-depth analysis of the mutated sequence revealed, that the one base pair insertion creates a novel downstream in-frame start codon, which supposedly serves as an alternative translation initiation site (TIS). This possible rescue mechanism would explain the relatively mild clinical outcome in the studied individuals. Our findings demonstrate the necessity for careful interpretation of N-terminal variants potentially effecting translation initiation.","variants":[{"Name":"NM_005857.5(ZMPSTE24):c.28_29insA (p.Leu10fs)","Chromosome":"1","Start":"40258299","Stop":"40258300","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":2878746,"rule_based_match":true,"evidence_text":"c.28_29insA","llm_judgment":"PRESENT","evidence":"c.28_29insA","abstract_start":455,"abstract_end":466}]}
{"pmid":"25288723","title":"Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer.","abstract":"Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.","variants":[{"Name":"NM_020937.4(FANCM):c.5101C>T (p.Gln1701Ter)","Chromosome":"14","Start":"45189123","Stop":"45189123","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":400207,"rule_based_match":true,"evidence_text":"c.5101C>T (p.Q1701X)","llm_judgment":"PRESENT","evidence":"c.5101C>T (p.Q1701X)","abstract_start":887,"abstract_end":907}]}
{"pmid":"36579105","title":"Pseudoileus caused by primary visceral myopathy in a Han Chinese patient with a rare","abstract":"BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a syndrome of intestinal motor dysfunction caused by intestinal nerve, muscle, and/or Cajal stromal cell lesions. CIPO is a serious category of gastrointestinal dynamic dysfunction, which can eventually lead to the death of patients with intestinal failure. Due to considerable phenotypic heterogeneity, the estimated incidence of CIPO is 1/476190 and 1/416666 in men and women, respectively. According to the etiology, CIPO can be divided into idiopathic and secondary, of which the latter is the most common, often secondary to tumor, virus infection, connective tissue disease, neurological diseases, and endocrine diseases. Idiopathic CIPO in the intestinal tract is divided into visceral myopathy, neuropathy, and stromal cell lesions according to the location. Surgery is usually not recommended for CIPO, because it often does not benefit patients with CIPO, and postoperative intestinal obstruction is likely to occur, which may even worsen the condition.\nCASE SUMMARY: Here, we describe the case of a 43-year-old male Han Chinese patient with a 15-year history of recurrent abdominal distention with no clear cause. The results of physical, biochemical, and other relevant examinations showed no clear abnormalities. Contrast-enhanced computed tomography (CT) indicated a large duodenum, clear expansion of the intestinal lumen, and CIPO. Whole exome sequencing (WES) of the patient and his mother confirmed the diagnosis of primary familial visceral myopathy type 2 chronic pseudoileus with a rare heterozygous gene mutation in <i>MYH11</i>. This is the second reported case of CIPO with a heterozygous <i>MYH11</i> [NM_001040113.1: c.5819delC (p.Pro1940Hisfs*91)] mutation.\nCONCLUSION: This case report indicates that physicians can perform routine clinical examinations, CT, and WES to achieve a diagnosis and treatment of CIPO in early disease stages.","variants":[{"Name":"NM_001040113.2(MYH11):c.5819del (p.Pro1940fs)","Chromosome":"16","Start":"15708830","Stop":"15708830","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":616000,"rule_based_match":true,"evidence_text":"NM_001040113.1: c.5819delC (p.Pro1940Hisfs*91)","llm_judgment":"PRESENT","evidence":"NM_001040113.1: c.5819delC (p.Pro1940Hisfs*91)","abstract_start":1687,"abstract_end":1733}]}
{"pmid":"33643967","title":"Whole Exome Sequencing Identifies Three Novel Mutations in the","abstract":"Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental defect that is characterized by reduced head circumference at birth along with non-progressive intellectual disability. Till date, 25 genes related to MCPH have been reported so far in humans. The <i>ASPM</i> (abnormal spindle-like, microcephaly-associated) gene is among the most frequently mutated MCPH gene. We studied three different families having primary microcephaly from different regions of Saudi Arabia. Whole exome sequencing (WES) and Sanger sequencing were done to identify the genetic defect. Collectively, three novel variants were identified in the <i>ASPM</i> gene from three different primary microcephaly families. Family 1, showed a deletion mutation leading to a frameshift mutation c.1003del. (p.Val335<sup>*</sup>) in exon 3 of the <i>ASPM</i> gene and family 2, also showed deletion mutation leading to frameshift mutation c.1047del (p.Gln349Hisfs<sup>*</sup>18), while in family 3, we identified a missense mutation c.5623A>G leading to a change in protein (p.Lys1875Glu) in exon 18 of the <i>ASPM</i> gene underlying the disorder. The identified respective mutations were ruled out in 100 healthy control samples. In conclusion, we found three novel mutations in the <i>ASPM</i> gene in Saudi families that will help to establish a disease database for specified mutations in Saudi population and will further help to identify strategies to tackle primary microcephaly in the kingdom.","variants":[{"Name":"NM_018136.5(ASPM):c.5623A>G (p.Lys1875Glu)","Chromosome":"1","Start":"197103628","Stop":"197103628","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1952145,"rule_based_match":true,"evidence_text":"c.5623A>G","llm_judgment":"PRESENT","evidence":"c.5623A>G","abstract_start":1014,"abstract_end":1023}]}
{"pmid":"36067420","title":"A DOUBLE HYPERAUTOFLUORESCENT RING IN A 33-YEAR-OLD-FEMALE PATIENT.","abstract":"PURPOSE: To describe the clinical phenotype and molecular diagnosis of a patient with atypical presentation of enhanced S-cone syndrome.\nMETHODS: This is a case report of a patient who underwent best-corrected visual acuity, slit-lamp exam, fundus examination, autofluorescence, optical coherence tomography, kinetic perimetry, and full-field electroretinography. Genetic testing was performed via next-generation sequencing.\nRESULTS: A 33-year-old female patient presented with mild nyctalopia, but normal rod function measured by electroretinogram and foveoschisis on optical coherence tomography. She also presented a double hyperautofluorescent ring on autofluorescence. Genetic testing found a pathogenic variant c.925C>G (p.Arg309Gly) and a likely pathogenic variant c.299C>T (p.Arg77Trp) in NR2E3 gene.\nCONCLUSION: Enhanced S-cone syndrome may present without the pathognomonic findings of decreased rod function on electroretinogram, suggesting the importance of genetic testing in retinal diseases for diagnosis.","variants":[{"Name":"NM_014249.4(NR2E3):c.925C>G (p.Arg309Gly)","Chromosome":"15","Start":"71813566","Stop":"71813566","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1056257,"rule_based_match":true,"evidence_text":"c.925C>G (p.Arg309Gly)","llm_judgment":"PRESENT","evidence":"c.925C>G (p.Arg309Gly)","abstract_start":718,"abstract_end":740}]}
{"pmid":"36788019","title":"Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome.","abstract":"BACKGROUND: Joubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the 'molar tooth sign'. Over 40 JS-associated genes are known, accounting for two-thirds of cases.\nMETHODS: While most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known 'founder variants' in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in ~550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of ~600 JS probands from the USA.\nRESULTS: All variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant (<i>TMEM216</i> c.218G>T) was significantly enriched in American compared with European patients with JS, while <i>MKS1</i> c.1476T>G was about 10 times more frequent among European JS. Frequencies of other variants were comparable in the two cohorts. Genotyping of several markers identified four novel European founder haplotypes.Two recurrent variants (<i>MKS1</i> c.1476T>G and <i>KIAA0586</i> c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. However, while fibroblasts from a <i>MKS1</i> c.1476T>G healthy homozygote showed impaired ability to form primary cilia and mildly reduced ciliary length, ciliary parameters were normal in cells from a <i>KIAA0586</i> c.428delG healthy homozygote.\nCONCLUSION: This study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants.","variants":[{"Name":"NM_001173990.3(TMEM216):c.218G>T (p.Arg73Leu)","Chromosome":"11","Start":"61393965","Stop":"61393965","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":15236,"rule_based_match":true,"evidence_text":"TMEM216 c.218G>T","llm_judgment":"PRESENT","evidence":"TMEM216</i> c.218G>T","abstract_start":819,"abstract_end":839}]}
{"pmid":"33588035","title":"TGM6 might not be a specific causative gene for spinocerebellar ataxia resulting from genetic analysis and functional study.","abstract":"OBJECTIVE: To investigate whether TGM6 is a specific causative gene for spinocerebellar ataxia type 35 (SCA35).\nMATERIALS AND METHODS: The next-generation sequencing (NGS) data consisted of 47 SCA, 762 non-SCA patients and 2827 normal controls were analyzed. The allele frequencies of low frequent and deleterious TGM6 variants were compared. Functional studies were performed in five widely distributed variants (V314M, R342Q, P347L, V391M, L517W).\nRESULTS: Two TGM6 detrimental variants were identified in one SCA patient, 14 in non-SCA patients and 43 in normal controls, the allele frequencies of TGM6 variants did not differ among the SCA and other controls. Seven reported pathogenic variants (c.7 + 1G > T, c.331C > T, c.1171G > A, c.1478C > T, c.1528G > C, c.1550 T > G and c.1722_1724delAGA) were identified in patients with various neurologic diseases or normal controls. All the 5 widely distributed variants led to destabilization and significantly reduction of enzymatic activity of TG6 as the reported pathogenic mutations.\nCONCLUSIONS: TGM6 might not be a specific causative gene for SCA35, the relevant clinical consult or diagnostic should be pay more attention.","variants":[{"Name":"NM_198994.3(TGM6):c.1171G>A (p.Val391Met)","Chromosome":"20","Start":"2403658","Stop":"2403658","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":350759,"rule_based_match":true,"evidence_text":"c.1171G>A","llm_judgment":"PRESENT","evidence":"c.1171G > A","abstract_start":726,"abstract_end":737}]}
{"pmid":"30976112","title":"Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay.","abstract":"The transforming growth factor-beta (TGFβ) signaling pathway is essential for palatogenesis and retinal development. Glycoprotein A repetitions predominant (GARP), encoded by LRRC32, is a TGFβ cell surface receptor that has been studied primarily in the context of cellular immunity. We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T; p.(Arg544Ter)) in two families with developmental delay, cleft palate, and proliferative retinopathy. Garp-null mice have palate defects and die within 24 h after birth. Our study establishes LRRC32 as a candidate disease-associated gene in humans and lends further support to the role of the TGFβ pathway in palatogenesis and retinal development.","variants":[{"Name":"NM_001128922.2(LRRC32):c.1630C>T (p.Arg544Ter)","Chromosome":"11","Start":"76659963","Stop":"76659963","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":536136,"rule_based_match":true,"evidence_text":"c.1630C>T; p.(Arg544Ter)","llm_judgment":"PRESENT","evidence":"c.1630C>T; p.(Arg544Ter)","abstract_start":340,"abstract_end":364}]}
{"pmid":"22291433","title":"Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds.","abstract":"Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.","variants":[{"Name":"NM_004064.5(CDKN1B):c.356T>C (p.Ile119Thr)","Chromosome":"12","Start":"12718195","Stop":"12718195","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":316337,"rule_based_match":true,"evidence_text":"c.356T>C (p.I119T)","llm_judgment":"PRESENT","evidence":"c.356T>C (p.I119T)","abstract_start":724,"abstract_end":742}]}
{"pmid":"26526666","title":"Hodgkin lymphoma as a novel presentation of familial DICER1 syndrome.","abstract":"UNLABELLED: DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly presenting with pleuropulmonary blastoma (PPB), ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. We describe the occurrence of a Hodgkin lymphoma (HL) of the T cell phenotype in a family with DICER1 syndrome. The patient presented with PPB Type I and HL. Immunohistochemical staining of the Hodgkin and Reed-Sternberg cells revealed CD30, TGP, CD2, CD3, CD15, and IRF4 positivity and weekly positivity of PAX5. T cell receptor repertoire analysis suggested HL of T cell origin, which is in contrast to common B cell-derived HL. The mother had been diagnosed with thyroid cysts, one sister had died from a primitive neuroectodermal tumor, and a brother had died from PPB Type III. Two mutational events were revealed in all affected family members; a single bp deletion, c.5299delC, leading to a frameshift and premature stop in exon 24 and a heterozygous variant (c.4616C>T; p.Thr1539Met) located in exon 23 of the DICER1 gene. This variant is predicted to be benign by in silico analysis.\nCONCLUSION: Future studies looking for DICER1 mutations in HL cases of the T cell phenotype will be important to confirm its association with constitutional DICER1 syndrome.\nWHAT IS KNOWN: • DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly pleuropulmonary blastoma, ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. • Hodgkin lymphoma is one of the most frequent types of malignant lymphomas and typically arises sporadically. T cell-derived Hodgkin lymphomas are exceptionally rare. What is New: • DICER1 syndrome may have an even broader phenotypic spectrum and seems to be associated with rare forms of T cell Hodgkin lymphoma.","variants":[{"Name":"NM_177438.3(DICER1):c.4616C>T (p.Thr1539Met)","Chromosome":"14","Start":"95096304","Stop":"95096304","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":241922,"rule_based_match":true,"evidence_text":"c.4616C>T; p.Thr1539Met","llm_judgment":"PRESENT","evidence":"c.4616C>T; p.Thr1539Met","abstract_start":985,"abstract_end":1008},{"Name":"NM_177438.3(DICER1):c.5299del (p.His1767fs)","Chromosome":"14","Start":"95093953","Stop":"95093953","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":248819,"rule_based_match":true,"evidence_text":"c.5299delC","llm_judgment":"PRESENT","evidence":"c.5299delC","abstract_start":891,"abstract_end":901}]}
{"pmid":"37907725","title":"Distal hereditary motor neuronopathy as a new phenotype associated with variants in BAG3.","abstract":"OBJECTIVE: To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy.\nMETHODS: This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3.\nRESULTS: Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novel heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members.\nCONCLUSIONS: We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adult-onset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies.","variants":[{"Name":"NM_004281.4(BAG3):c.1513_1514insGGAC (p.Val505fs)","Chromosome":"10","Start":"119677067","Stop":"119677068","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGGAC","allel_id":3735976,"rule_based_match":true,"evidence_text":"c.1513_1514insGGAC (p.Val505GlyfsTer6)","llm_judgment":"PRESENT","evidence":"c.1513_1514insGGAC (p.Val505GlyfsTer6)","abstract_start":1138,"abstract_end":1176}]}
{"pmid":"18821982","title":"Mutations in the EDA gene are responsible for X-linked hypohidrotic ectodermal dysplasia and hypodontia in Chinese kindreds.","abstract":"X-linked hypohidrotic ectodermal dysplasia (XLHED, OMIM 305100) is a rare congenital disorder that results in the defective development of teeth, hair, nails, and eccrine sweat glands. Previous studies found that mutations in the ectodysplasin A (EDA) gene are associated with XLHED. In the present study, we investigated four Chinese families suffering from classical XLHED and investigated two additional families segregating hypodontia in an X-linked recessive manner. Mutations were characterized respectively in the EDA gene in all families, and five of these mutations were found to be novel. Among these mutations, five were missense (c.200A>T, c.463C>T, c.758T>C, c.926T>G, and c.491A>C) and located in the functional domain of EDA, and one was a splice donor site mutation in intron 5 (c.IVS5 + 1G>A), which may result in an alternative transcript derived from a new cryptic splice site. Our data further confirm that EDA mutations could cause both XLHED and isolated hypodontia and provide evidence that EDA is a strong candidate gene for tooth genesis.","variants":[{"Name":"NM_001399.5(EDA):c.463C>T (p.Arg155Cys)","Chromosome":"X","Start":"69957093","Stop":"69957093","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26074,"rule_based_match":true,"evidence_text":"c.463C>T","llm_judgment":"PRESENT","evidence":"c.463C>T","abstract_start":652,"abstract_end":660},{"Name":"NM_001399.5(EDA):c.491A>C (p.Glu164Ala)","Chromosome":"X","Start":"69957121","Stop":"69957121","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":53362,"rule_based_match":true,"evidence_text":"c.491A>C","llm_judgment":"PRESENT","evidence":"c.491A>C","abstract_start":686,"abstract_end":694}]}
{"pmid":"27084214","title":"Late-onset spastic paraplegia type 10 (SPG10) family presenting with bulbar symptoms and fasciculations mimicking amyotrophic lateral sclerosis.","abstract":"Pathogenic mutations in the KIF5A-SPG10 gene, encoding the kinesin HC5A, can be associated with autosomal dominant hereditary spastic paraplegia (ADHSP). It accounts for about 10% of the complicated forms of ADHSP. Peripheral neuropathy, distal upper limb amyotrophy, and cognitive decline are the most common additional clinical features. We examined a 66-year-old Japanese woman manifesting gait disturbance and spastic dysarthria for 6years with positive family history. She showed evidence of upper and lower motor neuron involvement and fasciculations, thus mimicking amyotrophic lateral sclerosis (ALS). Genetic analysis revealed a heterozygous variant in KIF5A (c.484C>T, p.Arg162Trp) in 2 symptomatic members. The mutation was also identified in 4 asymptomatic members, including 2 elderly members aged over 78years. Electromyography in the 2 symptomatic members revealed evidence of lower motor neuron involvement and fasciculation potentials in distal muscles. This report describes the first known Asian family with a KIF5A mutation and broadens the clinical and electrophysiological spectrum associated with KIF5A-SPG10 mutations. Given that our cases showed pseudobulbar palsy, fasciculation and altered penetrance, KIF5A-SPG10 might well be considered as a differential diagnosis of sporadic ALS.","variants":[{"Name":"NM_004984.4(KIF5A):c.484C>T (p.Arg162Trp)","Chromosome":"12","Start":"57564956","Stop":"57564956","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":926692,"rule_based_match":true,"evidence_text":"c.484C>T, p.Arg162Trp","llm_judgment":"PRESENT","evidence":"c.484C>T, p.Arg162Trp","abstract_start":669,"abstract_end":690}]}
{"pmid":"23227268","title":"Novel PAX9 and COL1A2 missense mutations causing tooth agenesis and OI/DGI without skeletal abnormalities.","abstract":"Inherited dentin defects are classified into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia (DD). The genetic etiology of DD-I is unknown. Defects in dentin sialophosphoprotein (DSPP) cause DD type II and DGI types II and III. DGI type I is the oral manifestation of osteogenesis imperfecta (OI), a systemic disease typically caused by defects in COL1A1 or COL1A2. Mutations in MSX1, PAX9, AXIN2, EDA and WNT10A can cause non-syndromic familial tooth agenesis. In this study a simplex pattern of clinical dentinogenesis imperfecta juxtaposed with a dominant pattern of hypodontia (mild tooth agenesis) was evaluated, and available family members were recruited. Mutational analyses of the candidate genes for DGI and hypodontia were performed and the results validated. A spontaneous novel mutation in COL1A2 (c.1171G>A; p.Gly391Ser) causing only dentin defects and a novel mutation in PAX9 (c.43T>A; p.Phe15Ile) causing hypodontia were identified and correlated with the phenotypic presentations in the family. Bone radiographs of the proband's dominant leg and foot were within normal limits. We conclude that when no DSPP mutation is identified in clinically determined isolated DGI cases, COL1A1 and COL1A2 should be considered as candidate genes. PAX9 mutation p.Phe15Ile within the N-terminal β-hairpin structure of the PAX9 paired domain causes tooth agenesis.","variants":[{"Name":"NM_000089.4(COL1A2):c.1171G>A (p.Gly391Ser)","Chromosome":"7","Start":"94410501","Stop":"94410501","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":413957,"rule_based_match":true,"evidence_text":"COL1A2 (c.1171G>A; p.Gly391Ser)","llm_judgment":"PRESENT","evidence":"COL1A2 (c.1171G>A; p.Gly391Ser)","abstract_start":836,"abstract_end":867}]}
{"pmid":"19296131","title":"Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3).","abstract":"Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3-1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered.","variants":[{"Name":"NM_000110.4(DPYD):c.299_302del (p.Phe100fs)","Chromosome":"1","Start":"97740411","Stop":"97740414","ReferenceAlleleVCF":"GATGA","AlternateAlleleVCF":"G","allel_id":486871,"rule_based_match":true,"evidence_text":"c.299_302delTCAT","llm_judgment":"PRESENT","evidence":"c.299_302delTCAT","abstract_start":674,"abstract_end":690}]}
{"pmid":"38253347","title":"Neuronal ceroid lipofuscinosis type 11 diagnosed patient with bi-allelic variants in","abstract":"OBJECTIVES: Neuronal ceroid lipofuscinosis type 11 (NCL11) is a rare disease that presents with progressive cognitive decline, epilepsy, visual impairment, retinal atrophy, cerebellar ataxia and cerebellar atrophy. We present herein a case of NCL11 in a patient diagnosed with neuromotor developmental delay, epilepsy, bronchiolitis obliterans and hypothyroidism.\nCASE PRESENTATION: A 4-year-old male patient was admitted to our clinic with global developmental delay and a medical history that included recurrent hospitalizations for pneumonia at the age of 17 days, and in months 4, 5 and 7. Family history revealed a brother with similar clinical findings (recurrent pneumonia, hypothyroidism, hypotonicity, swallowing dysfunction and neuromotor delay) who died from pneumonia at the age of 22 months. Computed tomography of the thorax was consistent with bronchiolitis obliterans, while epileptic discharges were identified on electroencephalogram with a high incidence of bilateral fronto-centro-temporal and generalized spike-wave activity but no photoparoxysmal response. Cranial MRI revealed T2 hyperintense areas in the occipital periventricular white matter and volume loss in the white matter, a thin corpus callosum and vermis atrophy. A whole-exome sequencing molecular analysis revealed compound heterozygous c.430G>A (p.Asp144Asn) and c.415T>C (p.Cys139Arg) variants in the GRN gene.\nCONCLUSIONS: The presented case indicates that NCL11 should be taken into account in patients with epilepsy and neurodegenerative diseases.","variants":[{"Name":"NM_002087.4(GRN):c.415T>C (p.Cys139Arg)","Chromosome":"17","Start":"44350293","Stop":"44350293","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":580336,"rule_based_match":true,"evidence_text":"c.415T>C (p.Cys139Arg)","llm_judgment":"PRESENT","evidence":"c.415T>C (p.Cys139Arg)","abstract_start":1350,"abstract_end":1372}]}
{"pmid":"30689892","title":"CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection.","abstract":"High myopia is a severe form of nearsightedness, which can result in blindness due to its associated complications. While both genetic and environmental factors can cause high myopia, early-onset high myopia (eoHM), which is defined as high myopia that occurs before school age, is considered to be caused mainly by genetic variations, with minimal environmental involvement. Here we report six rare heterozygous loss-of-function (LoF) variants in CPSF1 that were identified in six of 623 probands with eoHM but none of 2657 probands with other forms of genetic eye diseases; this difference was statistically significant (P = 4.60 × 10-5, Fisher's exact test). The six variants, which were confirmed by Sanger sequencing, were c.3862_3871dup (p.F1291*), c.2823_2824del (p.V943Lfs*65), c.1858C>T (p.Q620*), c.15C>G (p.Y5*), c.3823G>T (p.D1275Y) and c.4146-2A>G. Five of these six variants were absent in existing databases, including gnomAD, 1000G and EVS. The remaining variant, c.4146-2A>G, was present in gnomAD with a frequency of 1/229918. Clinical data demonstrated eoHM in the six probands with these mutations. Knockdown of cpsf1 by morpholino oligonucleotide (MO) injection in zebrafish eggs resulted in small eye size in 84.38% of the injected larvae, and this phenotype was rescued in 61.39% of the zebrafish eggs when the cpsf1 MO and the cpsf1 mRNA were co-injected. The projection of retinal ganglion cell (RGC) towards the tectum was abnormal in cpsf1 morphants. Thus, we demonstrated that heterozygous LoF mutations in CPSF1 are associated with eoHM and that CPSF1 may play an important role in the development of RGC axon projection.","variants":[{"Name":"NM_013291.3(CPSF1):c.4146-2A>G","Chromosome":"8","Start":"144393592","Stop":"144393592","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":818123,"rule_based_match":true,"evidence_text":"c.4146-2A>G","llm_judgment":"PRESENT","evidence":"c.4146-2A>G","abstract_start":849,"abstract_end":860},{"Name":"NM_013291.3(CPSF1):c.3823G>T (p.Asp1275Tyr)","Chromosome":"8","Start":"144394149","Stop":"144394149","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":818124,"rule_based_match":true,"evidence_text":"c.3823G>T (p.D1275Y)","llm_judgment":"PRESENT","evidence":"c.3823G>T (p.D1275Y)","abstract_start":824,"abstract_end":844},{"Name":"NM_013291.3(CPSF1):c.1858C>T (p.Gln620Ter)","Chromosome":"8","Start":"144398338","Stop":"144398338","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":818125,"rule_based_match":true,"evidence_text":"c.1858C>T (p.Q620*)","llm_judgment":"PRESENT","evidence":"c.1858C>T (p.Q620*)","abstract_start":786,"abstract_end":805},{"Name":"NM_013291.3(CPSF1):c.2823_2824del (p.Val943fs)","Chromosome":"8","Start":"144396600","Stop":"144396601","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":818126,"rule_based_match":true,"evidence_text":"c.2823_2824del (p.V943Lfs*65)","llm_judgment":"PRESENT","evidence":"c.2823_2824del (p.V943Lfs*65)","abstract_start":755,"abstract_end":784}]}
{"pmid":"34946930","title":"Genotype-Specific Lesion Growth Rates in Stargardt Disease.","abstract":"Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed biallelic <i>ABCA4</i> mutations from five genotype groups: c.6079C>T, c.[2588G>C;5603A>T], c.3113C>T, c.5882G>A and c.5603A>T. Fundus autofluorescence (AF) 30° × 30° images were manually segmented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean ± SD age 45 ± 19 years; range 21-86) were recruited. Patients with c.3113C>T or c.6079C>T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; <i>p</i> < 0.001 and 0.14 to 0.21; <i>p</i> < 0.001) respectively, as compared to those patients harbouring c.5882G>A at 0.06 mm/year (95% CI 0.03-0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset.","variants":[{"Name":"NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)","Chromosome":"1","Start":"94010911","Stop":"94010911","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":105279,"rule_based_match":true,"evidence_text":"c.5603A>T","llm_judgment":"PRESENT","evidence":"c.5603A>T","abstract_start":298,"abstract_end":307},{"Name":"NM_000350.3(ABCA4):c.6079C>T (p.Leu2027Phe)","Chromosome":"1","Start":"94005509","Stop":"94005509","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22921,"rule_based_match":true,"evidence_text":"c.6079C>T","llm_judgment":"PRESENT","evidence":"c.6079C>T","abstract_start":241,"abstract_end":250},{"Name":"NM_000350.3(ABCA4):c.3113C>T (p.Ala1038Val)","Chromosome":"1","Start":"94043413","Stop":"94043413","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22933,"rule_based_match":true,"evidence_text":"c.3113C>T","llm_judgment":"PRESENT","evidence":"c.3113C>T","abstract_start":273,"abstract_end":282},{"Name":"NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)","Chromosome":"1","Start":"94008251","Stop":"94008251","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22927,"rule_based_match":true,"evidence_text":"c.5882G>A","llm_judgment":"PRESENT","evidence":"c.5882G>A","abstract_start":284,"abstract_end":293}]}
{"pmid":"24782640","title":"ARC syndrome with high GGT cholestasis caused by VPS33B mutations.","abstract":"Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085) is an autosomal recessive disorder that is caused by mutations in 2 interacting genes VPS33B and VIPAS39. Mutations in VPS33B gene account for most cases of ARC. As low or normal gamma-glutamyl transpeptidase (GGT) activity has been described in all patients with ARC syndrome identified so far, ARC syndrome is a possible diagnosis for low GGT cholestasis. Here we describe a Chinese patient with neonatal cholestasis and a high GGT level in three consecutive tests. She had other typical manifestations of ARC syndrome, including arthrogryposis multiplex congenita, renal involvement and ichthyosis. Genetic study of the VPS33B gene further confirmed the diagnosis by identification of compound heterozygosity of two known disease-causing mutations, c.403+2T > A and c.1509-1510insG. The mechanism of high GGT in this patient is unclear. Nevertheless, this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found.","variants":[{"Name":"NM_018668.5(VPS33B):c.403+2T>A","Chromosome":"15","Start":"91009799","Stop":"91009799","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":340110,"rule_based_match":true,"evidence_text":"c.403+2T > A","llm_judgment":"PRESENT","evidence":"c.403+2T > A","abstract_start":831,"abstract_end":843}]}
{"pmid":"30630810","title":"A Novel Nonsense Mutation of","abstract":"Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked disease caused by <i>PHF6</i> mutations. Classic BFLS has been associated with intellectual disability (ID), developmental delay (DD), obesity, epilepsy, typical facial features and anomalies of fingers and toes. Endocrinological phenotypes and outcome of treatment in this condition remain to be delineated. Here we report a patient who exhibited complete growth hormone deficiency who responded to hormonal treatment but with adverse effects. Horseshoe kidney was present in this patient, which is also atypical in BFLS. A heterozygous nonsense mutation c.673C>T (p.R225X) of <i>PHF6</i> gene was identified in the patient, inherited from her unaffected mother. Both the patient and her mother showed highly skewed X-inactivation. We reviewed the phenotypes of all reported BFLS cases, and summarized their endocrine presentations. This first report of an Asian patient with BFLS further delineated the genetic and phenotypic spectrum of the syndrome. The adverse effect experienced by the patient suggests caution in the use of growth hormone treatment in this condition.","variants":[{"Name":"NM_001015877.2(PHF6):c.673C>T (p.Arg225Ter)","Chromosome":"X","Start":"134413910","Stop":"134413910","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":481264,"rule_based_match":true,"evidence_text":"c.673C>T (p.R225X)","llm_judgment":"PRESENT","evidence":"c.673C>T (p.R225X)","abstract_start":617,"abstract_end":635}]}
{"pmid":"25354131","title":"An intriguing high performance liquid chromatogram of a double heterozygosity for Hb Q-India/Hb D-Punjab.","abstract":"Cation exchange high performance liquid chromatography (HPLC) is commonly utilized as the first method of screening for thalassemias and hemoglobinopathies worldwide. This method of diagnosis requires knowledge of the clinical background and complete blood counts as well as skill and experience in interpreting the sometimes complex results produced. An asymptomatic 27-year-old pregnant North Indian woman was found to have a highly unusual chromatographic pattern with multiple unexpected peaks during routine antenatal screening. Most concerning was a C-window peak as Hb C (HBB: c.19G>A) is rare in ethnic Asian Indian populations. Cellulose acetate electrophoresis at alkaline pH (8.6) and parental screening were performed. These revealed the correct diagnosis to be a double heterozygosity for Hb Q-India (HBA1: c.193G>C) (an uncommon asymptomatic α-globin chain variant) plus Hb D-Punjab (HBB: c.364G>C) (a β-globin chain variant that is common in this region and is asymptomatic in the heterozygous state). The unexpected C-window peak was the hybrid of the abnormal α-Q-India and β-D-Punjab globin chains. Another small peak was explained as a variant Hb A2 formed by the combination of α-Q-India and δ-globin chains. Hematopathologists should be cognizant of the complex pattern resulting from coinheritance of both α- and β-globin structural variants. Second-line testing and parental testing are invaluable in resolving unknown peaks, especially if rare or unexpected variants are being considered. Although both Hb Q-India and Hb D-Punjab are relatively common in northwestern India, to the best of our knowledge, only two recent reports describe a total of three cases of such diagnostically puzzling coinheritance.","variants":[{"Name":"NM_000558.3(HBA1):c.193G>C (p.Asp65His)","Chromosome":"16","Start":"177026","Stop":"177026","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":30842,"rule_based_match":true,"evidence_text":"HBA1: c.193G>C","llm_judgment":"PRESENT","evidence":"HBA1: c.193G>C","abstract_start":814,"abstract_end":828}]}
{"pmid":"19428252","title":"Molecular analysis in a family presenting with a mild form of late-onset autosomal dominant chronic progressive external ophthalmoplegia.","abstract":"Nuclear genes affecting mitochondrial genome stability were screened in an Italian family presenting with autosomal dominant progressive external ophthalmoplegia (adPEO) associated with multiple mitochondrial DNA (mtDNA) deletions. We report on a heterozygous c.907C>T (p.R303W) mutation found in the N-terminal domain of the human mitochondrial DNA helicase, Twinkle protein, in six members of a family, in which two individuals manifested late-onset PEO and morphological and molecular signs of mitochondrial dysfunction along with two carriers who are presently free of disease manifestation. We also investigated if the p.R303W mutation in PEO1 gene affected the relative copy number of mitochondrial DNA genomes.","variants":[{"Name":"NM_021830.5(TWNK):c.907C>T (p.Arg303Trp)","Chromosome":"10","Start":"100989117","Stop":"100989117","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1200824,"rule_based_match":true,"evidence_text":"c.907C>T (p.R303W)","llm_judgment":"PRESENT","evidence":"c.907C>T (p.R303W)","abstract_start":260,"abstract_end":278}]}
{"pmid":"32088909","title":"Small adrenal incidentaloma becoming an aggressive adrenocortical carcinoma in a patient carrying a germline APC variant.","abstract":"PURPOSE: Recent guidelines on adrenal incidentalomas suggested in patients with an indeterminate adrenal mass and no significant hormone excess that follow up with a repeat noncontrast CT or MRI after 6-12 months may be an option.\nMETHODS: We report the case of a 32-year-old woman who presented with a 2.9 × 1.9 cm left adrenal incidentaloma that was stable in size for 4 years. Ten years later the left adrenal mass was a stage IV adrenocortical carcinoma (ACC).\nRESULTS: In 2006, a 32-year-old French Canadian woman was referred to endocrinology for a left 2.9 × 1.9 cm incidentally discovered adrenal mass (31 HU). She had normal hormonal investigation. The patient was followed with adrenal imaging and hormonal investigation yearly for 4 years and the lesion stayed stable in size over the 4 years. Ten years later, in 2016, the patient presented with renal colic. Urological CT unexpectedly revealed that the left adrenal mass was now measuring 9 × 8.2 cm and 2 new hepatic lesions were found. Biochemical workup demonstrated hypercorticism and hyperandrogenemia: plasma cortisol after 1 mg overnight DST of 476 nmol/L and DHEA-S of 14.0 μmol/L (N 0.9-6.5). Twenty-four hour urine steroid profiling was consistent with an adrenocortical carcinoma (ACC) co-secreting cortisol, androgens and glucocorticoid precursors. The diagnosis of ACC with hepatic ACC metastases was confirmed at histology. Following genetic analysis, germline heterozygous variant of uncertain significance (VUS) was identified in the exon 16 of the APC gene (c.2414G > A, p.Arg805Gln). Immunohistochemical staining's of the ACC was positive for IGF-2 and cytoplasmic/nuclear β-catenin staining.\nCONCLUSIONS: This case illustrates that (1) small adrenal incidentaloma stable in size may evolve to ACC and (2) better genetic characterization of these patients may eventually give clues on this unusual evolution.","variants":[{"Name":"NM_000038.6(APC):c.2414G>A (p.Arg805Gln)","Chromosome":"5","Start":"112838008","Stop":"112838008","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":394289,"rule_based_match":true,"evidence_text":"c.2414G > A, p.Arg805Gln","llm_judgment":"PRESENT","evidence":"c.2414G > A, p.Arg805Gln","abstract_start":1538,"abstract_end":1562}]}
{"pmid":"30771478","title":"Whole exome sequencing revealed mutations in FBXL4, UNC80, and ADK in Thai patients with severe intellectual disabilities.","abstract":"Intellectual disabilities (ID) are etiologically heterogeneous. Advanced molecular techniques could be helpful in identification of the underlying genetic defects. We aimed to characterize clinical and molecular features of three Thai patients with ID. Patient 1 had ID, hypotonia and lactic acidosis. Patient 2 had ID and growth failure. Patient 3 had ID, seizure, diarrhea and hypoglycemia. Whole exome sequencing found that Patient 1 was homozygous for a nonsense, c.1303C>T (p.Arg435Ter), mutation in FBXL4, a gene responsible for encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13). Patient 2 was compound heterozygous for two novel mutations, c.3226C>T (p.Arg1076Ter) and c.3205C>T (p.Arg1069Ter), in UNC80, a known gene of infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2). Patient 3 was homozygous for a novel missense, c.427T>C (p.Cys143Arg), mutation in ADK, a known gene of adenosine kinase deficiency leading to hypermethioninemia. This study expands the mutational spectra of ID genes.","variants":[{"Name":"NM_001278716.2(FBXL4):c.1303C>T (p.Arg435Ter)","Chromosome":"6","Start":"98899282","Stop":"98899282","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76993,"rule_based_match":true,"evidence_text":"c.1303C>T (p.Arg435Ter)","llm_judgment":"PRESENT","evidence":"c.1303C>T (p.Arg435Ter)","abstract_start":468,"abstract_end":491},{"Name":"NM_001371986.1(UNC80):c.3226C>T (p.Arg1076Ter)","Chromosome":"2","Start":"209839406","Stop":"209839406","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3043298,"rule_based_match":true,"evidence_text":"c.3226C>T (p.Arg1076Ter)","llm_judgment":"PRESENT","evidence":"c.3226C>T (p.Arg1076Ter)","abstract_start":666,"abstract_end":690}]}
{"pmid":"19303004","title":"Clinical and genetic features of TGFBI-linked corneal dystrophies in Mexican population: description of novel mutations and novel genotype-phenotype correlations.","abstract":"Corneal dystrophies (CDS) are inherited disorders characterized by an altered corneal transparency and refractive index which may be caused by a progressive accumulation of deposits within the different corneal layers. Most CDs are inherited in an autosomal dominant fashion and mutations in the TGFBI gene at chromosome 5q31 cause the majority of CDs affecting the stromal layer. A genotype-phenotype correlation has been identified in most analyzed populations as specific amino acid changes in TGFBI protein cause specific stromal phenotypes. However, analysis of additional populations will help to broaden the mutational spectrum ultimately allowing a better clinical-molecular classification of patients with this group of diseases. In this work, eighteen unrelated Mexican probands suffering from stromal CDs were clinically assessed and their TGFBI gene status investigated. Complete ophthalmologic evaluation, including biomicroscopic inspection and dilated fundus examination, was performed. In addition, detailed genealogical analyses as well as automated DNA sequencing of the entire TGFBI gene were done in all probands. Mutation-carrying exons were examined in 50 first and second degree relatives. Phenotypic analysis disclosed the occurrence of 6 cases of lattice CD, 6 of granular CD, 2 of granular type 2 (Avellino CD), 2 of polymorphic corneal amyloidosis, 1 of Reis-Bucklers CD, and 1 of an unclassifiable phenotype. TGFBI mutations were identified in all 18 probands. A total of six different mutations were observed: p.V113I, p.M502V, p.A546D, p.L550P, p.R555W, and p.H626R. Of these, mutations p.L550P (originated by the change c.1649T>C at exon 12), p.M502V (c.1504A>G, at exon 11), and p.V113I (c.337G>A, at exon 4), are novel TGFBI mutations. All subjects with lattice CD in our sample carried the p.H626R mutation. No instances of defects at codon 124, one of the two most frequently mutated sites in TGFBI-linked CDs, were detected. A distinct TGFBI mutational pattern was identified in Mexican patients with stromal CDs. Novel TGFBI mutations and new genotype-phenotype correlations were also recognized. This study stresses the importance of performing TGFBI genetic analysis in distinct CD populations.","variants":[{"Name":"NM_000358.3(TGFBI):c.1504A>G (p.Met502Val)","Chromosome":"5","Start":"136055773","Stop":"136055773","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":721224,"rule_based_match":true,"evidence_text":"c.1504A>G","llm_judgment":"PRESENT","evidence":"c.1504A>G","abstract_start":1683,"abstract_end":1692},{"Name":"NM_000358.3(TGFBI):c.337G>A (p.Val113Ile)","Chromosome":"5","Start":"136046373","Stop":"136046373","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1483788,"rule_based_match":true,"evidence_text":"c.337G>A","llm_judgment":"PRESENT","evidence":"c.337G>A","abstract_start":1720,"abstract_end":1728}]}
{"pmid":"26728349","title":"Two Novel Missense Mutations and a 5bp Deletion in the Erythroid-Specific Promoter of the PKLR Gene in Two Unrelated Patients With Pyruvate Kinase Deficient Transfusion-Dependent Chronic Nonspherocytic Hemolytic Anemia.","abstract":"We report two children with severe chronic hemolytic anemia, the cause of which was difficult to establish because of transfusion dependency. Reduced erythrocyte pyruvate kinase activity in their asymptomatic parents provided the diagnostic clues for mutation screening of the PKLR gene and revealed that one child was a compound heterozygote of a novel paternally derived 5-bp deletion in the promoter region (c.-88_-84delTCTCT) and a maternally derived missense mutation in exon nine (c.1174G>A; p.Ala392Thr). The second child was a compound heterozygote of two novel missense mutations, namely a paternally derived exon ten c.1381G>A (p.Glu461Lys) and a maternally derived exon seven c.907-908delCC (p.Pro303GlyfsX12) variant.","variants":[{"Name":"NM_000298.6(PKLR):c.1174G>A (p.Ala392Thr)","Chromosome":"1","Start":"155293533","Stop":"155293533","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1151812,"rule_based_match":true,"evidence_text":"c.1174G>A (p.Ala392Thr)","llm_judgment":"PRESENT","evidence":"p.Ala392Thr","abstract_start":498,"abstract_end":509}]}
{"pmid":"7833921","title":"Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase).","abstract":"Essential fructosuria is one of the oldest known inborn errors of metabolism. It is a benign condition which is believed to result from deficiency of hepatic fructokinase (ketohexokinase, KHK, E.C.2.7.1.3). This enzyme catalyses the first step of metabolism of dietary fructose, conversion of fructose to fructose-1-phosphate. Despite the early recognition of this disorder, the primary structure of human KHK and the molecular basis of essential fructosuria have not been previously defined. In this report, the isolation and sequencing of full-length cDNA clones encoding human ketohexokinase are described. Alternative mRNA species and alternative KHK isozymes are produced by alternative polyadenylation and splicing of the KHK gene. The KHK proteins show a high level of sequence conservation relative to rat KHK. Direct evidence that mutation of the KHK structural gene is the cause of essential fructosuria was also obtained. In a well-characterized family, in which three of eight siblings have fructosuria, all affected individuals are compound heterozygotes for two mutations Gly40Arg and Ala43Thr. Both mutations result from G-->A transitions, and each alters the same conserved region of the KHK protein. Neither mutation was seen in a sample of 52 unrelated control individuals. An additional conservative amino acid change (Val49IIe) was present on the KHK allele bearing Ala43Thr.","variants":[{"Name":"NM_006488.3(KHK):c.118G>A (p.Gly40Arg)","Chromosome":"2","Start":"27092357","Stop":"27092357","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27070,"rule_based_match":false,"evidence_text":"Gly40Arg","llm_judgment":"PRESENT","evidence":"Gly40Arg","abstract_start":1086,"abstract_end":1094},{"Name":"NM_006488.3(KHK):c.127G>A (p.Ala43Thr)","Chromosome":"2","Start":"27092366","Stop":"27092366","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27071,"rule_based_match":false,"evidence_text":"Ala43Thr","llm_judgment":"PRESENT","evidence":"Ala43Thr","abstract_start":1099,"abstract_end":1107}]}
{"pmid":"31471722","title":"GPT2 mutations in autosomal recessive developmental disability: extending the clinical phenotype and population prevalence estimates.","abstract":"The glutamate pyruvate transaminase 2 (GPT2) gene produces a nuclear-encoded mitochondrial enzyme that catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. Recessive mutations in GPT2 have been recently identified in a new syndrome involving intellectual and developmental disability (IDD), postnatal microcephaly, and spastic paraplegia. We have identified additional families with recessive GPT2 mutations and expanded the phenotype to include small stature. GPT2 loss-of-function mutations were identified in four families, nine patients total, including: a homozygous mutation in one child [c.775T>C (p.C259R)]; compound heterozygous mutations in two siblings [c.812A>C (p.N271T)/c.1432_1433delGT (p.V478Rfs*73)]; a novel homozygous, putative splicing mutation [c.1035C>T (p.G345=)]; and finally, a recurrent mutation, previously identified in a distinct family [c.1210C>T (p.R404*)]. All patients were diagnosed with IDD. A majority of patients had remarkably small stature throughout development, many < 1st percentile for height and weight. Given the potential biological function of GPT2 in cellular growth, this phenotype is strongly suggestive of a newly identified clinical susceptibility. Further, homozygous GPT2 mutations manifested in at least 2 of 176 families with IDD (approximately 1.1%) in a Pakistani cohort, thereby representing a relatively common cause of recessive IDD in this population, with recurrence of the p.R404* mutation in this population. Based on variants in the ExAC database, we estimated that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2.","variants":[{"Name":"NM_133443.4(GPT2):c.812A>C (p.Asn271Thr)","Chromosome":"16","Start":"46909919","Stop":"46909919","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":971609,"rule_based_match":true,"evidence_text":"c.812A>C (p.N271T)","llm_judgment":"PRESENT","evidence":"c.812A>C (p.N271T)","abstract_start":736,"abstract_end":754},{"Name":"NM_133443.4(GPT2):c.775T>C (p.Cys259Arg)","Chromosome":"16","Start":"46909882","Stop":"46909882","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":971610,"rule_based_match":true,"evidence_text":"c.775T>C (p.C259R)","llm_judgment":"PRESENT","evidence":"c.775T>C (p.C259R)","abstract_start":666,"abstract_end":684},{"Name":"NM_133443.4(GPT2):c.1210C>T (p.Arg404Ter)","Chromosome":"16","Start":"46922414","Stop":"46922414","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":249203,"rule_based_match":true,"evidence_text":"c.1210C>T (p.R404*)","llm_judgment":"PRESENT","evidence":"c.1210C>T (p.R404*)","abstract_start":938,"abstract_end":957}]}
{"pmid":"21779199","title":"Heterogeneous spectrum of CFTR gene mutations in Korean patients with cystic fibrosis.","abstract":"BACKGROUND: Cystic fibrosis (CF) is one of the most common hereditary disorders among Caucasians. The most common mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been well established among Caucasian populations. In Koreans, however, there are very few cases of genetically confirmed CF thus far, and the spectrum of mutations seems quite different from that observed in Caucasians.\nMETHODS: In the present study, we describe the cases of 2 Korean CF patients, present sequencing results identifying mutations in their CFTR gene, and summarize the results of CFTR mutational spectrum from previously reported Korean CF patients. The mutations described were identified by performing direct sequencing analysis of the complete coding regions and flanking intronic sequences of the CFTR gene, followed by multiplex ligation-dependent probe amplification (MLPA) analysis in order to detect gene deletions or duplications that could not be identified by a direct sequencing method.\nRESULTS: Three CFTR mutations were identified in the 2 patients, including p.Q98R, c.2052delA, and c.579+5G>A. In an analysis of 9 Korean CF patients that included the 2 patients presented in this study, p.Q98R mutation was the only recurrently observed mutation with a frequency of 18.8% (3/16 alleles). Furthermore, only one of the mutations (c.3272-26A>G) was found among the 32 common mutations in the screening panel for Caucasians from the Cystic Fibrosis Mutation Database.\nCONCLUSIONS: Sequencing of the entire CFTR gene followed by MLPA analysis, rather than using the targeted sequencing-based screening panel for mutations commonly found in Caucasian populations, is recommended for genetic analysis of Korean CF patients.","variants":[{"Name":"NM_000492.4(CFTR):c.579+5G>A","Chromosome":"7","Start":"117534370","Stop":"117534370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":68679,"rule_based_match":true,"evidence_text":"c.579+5G>A","llm_judgment":"PRESENT","evidence":"c.579+5G>A","abstract_start":1115,"abstract_end":1125},{"Name":"NM_000492.4(CFTR):c.2052del (p.Lys684fs)","Chromosome":"7","Start":"117592213","Stop":"117592213","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":47057,"rule_based_match":true,"evidence_text":"c.2052delA","llm_judgment":"PRESENT","evidence":"c.2052delA","abstract_start":1099,"abstract_end":1109}]}
{"pmid":"21541994","title":"Camurati-Engelmann disease: unique variant featuring a novel mutation in TGFβ1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand.","abstract":"We report a 32-year-old man and his 59-year-old mother with a unique and extensive variant of Camurati-Engelmann disease (CED) featuring histopathological changes of osteomalacia and alterations within TGFβ1 and TNFSF11 encoding TGFβ1 and RANKL, respectively. He suffered leg pain and weakness since childhood and reportedly grew until his late 20s, reaching 7 feet in height. He had deafness, perforated nasal septum, torus palatinus, disproportionately long limbs with knock-knees, low muscle mass, and pseudoclubbing. Radiographs revealed generalized skeletal abnormalities, including wide bones and cortical and trabecular bone thickening in keeping with CED, except that long bone ends were also affected. Lumbar spine and hip BMD Z-scores were + 7.7 and + 4.4, respectively. Biochemical markers of bone turnover were elevated. Hypocalciuria accompanied low serum 25-hydroxyvitamin D (25[OH]D) levels. Pituitary hypogonadism and low serum insulin-like growth factor (IGF)-1 were present. Karyotype was normal. Despite vitamin D repletion, iliac crest histology revealed severe osteomalacia. Exon 1 of TNFRSF11A (RANK), exons 2, 3, and 4 of LRP5, and all coding exons and adjacent mRNA splice junctions of TNFRSF11B (OPG), SQSTM1 (sequestosome 1), and TNSALP (tissue nonspecific alkaline phosphatase) were intact. His asymptomatic and less dysmorphic 5'11″ mother, also with low serum 25(OH)D, had milder clinical, radiological, biochemical, and histopathological findings. Both individuals were heterozygous for a novel 12-bp duplication (c.27_38dup, p.L10_L13dup) in exon 1 of TGFβ1, predicting four additional leucine residues in the latency-associated-peptide segment of TGFβ1, consistent with CED. The son was also homozygous for a single base transversion in TNFSF11, predicting a nonconservative amino acid change (c.107C > G, p.Pro36Arg) in the intracellular domain of RANKL that was heterozygous in his nonconsanguineous parents. This TNFSF11 variant was not found in the SNP Database, nor in published TNFSF11 association studies, but it occurred in four of the 134 TNFSF11 alleles (3.0%) we tested randomly among individuals without CED. Perhaps the unique phenotype of this CED family is conditioned by altered RANKL activity.","variants":[{"Name":"NM_003701.4(TNFSF11):c.107C>G (p.Pro36Arg)","Chromosome":"13","Start":"42574410","Stop":"42574410","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":328404,"rule_based_match":true,"evidence_text":"c.107C > G (p.Pro36Arg)","llm_judgment":"PRESENT","evidence":"c.107C > G","abstract_start":1826,"abstract_end":1836}]}
{"pmid":"23846910","title":"A Japanese adult case of guanidinoacetate methyltransferase deficiency.","abstract":"Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis resulting in cerebral creatine depletion. We present a 38-year-old patient, the first Japanese case of GAMT deficiency. Developmental delay started after a few months of age with a marked delay in language, which resulted in severe intellectual deficit. She showed hyperactivity and trichotillomania from childhood. Epileptic seizures appeared at 18 months and she had multiple types of seizures including epileptic spasms, brief tonic seizures, atypical absences, complex partial seizures with secondary generalization, and \"drop\" seizures. They have been refractory to multiple antiepileptic drugs. Although there have been no involuntary movements, magnetic resonance imaging revealed T2 hyperintense lesions in bilateral globus pallidi. Motor regression started around 30 years of age and the patient is now able to walk for only short periods. Very low serum creatinine levels measured by enzymatic method raised a suspicion of GAMT deficiency, which was confirmed by proton magnetic resonance spectroscopy and urinary guanidinoacetate assay. GAMT gene analysis revealed that the patient is a compound heterozygote of c.578A>G, p.Gln193Arg and splice site mutation, c.391G>C, p.Gly131Arg, neither of which have been reported in the literature. We also identified two aberrant splice products from the patient's cDNA analysis. The patient was recently started on supplementation of high-dose creatine and ornithine, the effects of which are currently under evaluation. Although rare, patients with developmental delay, epilepsy, behavioral problems, and movement disorders should be vigorously screened for GAMT deficiency, as it is a treatable disorder.","variants":[{"Name":"NM_000156.6(GAMT):c.578A>G (p.Gln193Arg)","Chromosome":"19","Start":"1397492","Stop":"1397492","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1319665,"rule_based_match":true,"evidence_text":"c.578A>G, p.Gln193Arg","llm_judgment":"PRESENT","evidence":"c.578A>G, p.Gln193Arg","abstract_start":1217,"abstract_end":1238},{"Name":"NM_000156.6(GAMT):c.391G>C (p.Gly131Arg)","Chromosome":"19","Start":"1399524","Stop":"1399524","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2421588,"rule_based_match":true,"evidence_text":"c.391G>C, p.Gly131Arg","llm_judgment":"PRESENT","evidence":"c.391G>C, p.Gly131Arg","abstract_start":1265,"abstract_end":1286}]}
{"pmid":"31614793","title":"NGS Analysis for Molecular Diagnosis of Retinitis Pigmentosa (RP): Detection of a Novel Variant in","abstract":"This work describes the application of NGS for molecular diagnosis of RP in a family with a history of severe hypovision. In particular, the proband received a clinical diagnosis of RP on the basis of medical, instrumental examinations and his family history. The proband was subjected to NGS, utilizing a customized panel including 24 genes associated with RP and other retinal dystrophies. The NGS analysis revealed a novel missense variant (c.668T > A, I223N) in <i>PRPH2</i> gene, which was investigated by segregation and bioinformatic analysis. The variant is located in the D2 loop domain of PRPH2, which is critical for protein activity. Bioinformatic analysis described the c.668T > A as a likely pathogenic variant. Moreover, a 3D model prediction was performed to better characterize the impact of the variant on the protein, reporting a disruption of the α-helical structures. As a result, the variant protein showed a substantially different conformation with respect to the wild-type PRPH2. The identified variant may therefore affect the oligomerization ability of the D2 loop and, ultimately, hamper PRPH2 proper functioning and localization. In conclusion, <i>PRPH2</i>_c.668T > A provided a molecular explanation of RP symptomatology, highlighting the clinical utility of NGS panels to facilitate genotype-phenotype correlations.","variants":[{"Name":"NM_000322.5(PRPH2):c.668T>A (p.Ile223Asn)","Chromosome":"6","Start":"42704525","Stop":"42704525","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1164679,"rule_based_match":true,"evidence_text":"c.668T > A","llm_judgment":"PRESENT","evidence":"c.668T > A","abstract_start":444,"abstract_end":454}]}
{"pmid":"33659639","title":"New recessive mutations in","abstract":"OBJECTIVE: To report the identification of 2 new homozygous recessive mutations in the synaptotagmin 2 (<i>SYT2</i>) gene as the genetic cause of severe and early presynaptic forms of congenital myasthenic syndromes (CMSs).\nMETHODS: Next-generation sequencing identified new homozygous intronic and frameshift mutations in the <i>SYT2</i> gene as a likely cause of presynaptic CMS. We describe the clinical and electromyographic patient phenotypes, perform ex vivo splicing analyses to characterize the effect of the intronic mutation on exon splicing, and analyze the functional impact of this variation at the neuromuscular junction (NMJ).\nRESULTS: The 2 infants presented a similar clinical phenotype evoking first a congenital myopathy characterized by muscle weakness and hypotonia. Next-generation sequencing allowed to the identification of 1 homozygous intronic mutation c.465+1G>A in patient 1 and another homozygous frameshift mutation c.328_331dup in patient 2, located respectively in the 5' splice donor site of <i>SYT2</i> intron 4 and in exon 3. Functional studies of the intronic mutation validated the abolition of the splice donor site of exon 4 leading to its skipping. In-frame skipping of exon 4 that encodes part of the C2A calcium-binding domain of SYT2 is associated with a loss-of-function effect resulting in a decrease of neurotransmitter release and severe pre- and postsynaptic NMJ defects.\nCONCLUSIONS: This study identifies new homozygous recessive <i>SYT2</i> mutations as the underlying cause of severe and early presynaptic form of CMS expanding the genetic spectrum of recessive <i>SYT2</i>-related CMS associated with defects in neurotransmitter release.","variants":[{"Name":"NM_177402.5(SYT2):c.465+1G>A","Chromosome":"1","Start":"202602998","Stop":"202602998","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1182325,"rule_based_match":true,"evidence_text":"c.465+1G>A","llm_judgment":"PRESENT","evidence":"c.465+1G>A","abstract_start":879,"abstract_end":889}]}
{"pmid":"30950137","title":"Functional and structural analysis of rare SLC2A2 variants associated with Fanconi-Bickel syndrome and metabolic traits.","abstract":"Deleterious variants in SLC2A2 cause Fanconi-Bickel Syndrome (FBS), a glycogen storage disorder, whereas less common variants in SLC2A2 associate with numerous metabolic diseases. Phenotypic heterogeneity in FBS has been observed, but its causes remain unknown. Our goal was to functionally characterize rare SLC2A2 variants found in FBS and metabolic disease-associated variants to understand the impact of these variants on GLUT2 activity and expression and establish genotype-phenotype correlations. Complementary RNA-injected Xenopus laevis oocytes were used to study mutant transporter activity and membrane expression. GLUT2 homology models were constructed for mutation analysis using GLUT1, GLUT3, and XylE as templates. Seventeen FBS variants were characterized. Only c.457_462delCTTATA (p.Leu153_Ile154del) exhibited residual glucose uptake. Functional characterization revealed that only half of the variants were expressed on the plasma membrane. Most less common variants (except c.593 C>A (p.Thr198Lys) and c.1087 G>T (p.Ala363Ser)) exhibited similar GLUT2 transport activity as the wild type. Structural analysis of GLUT2 revealed that variants affect substrate-binding, steric hindrance, or overall transporter structure. The mutant transporter that is associated with a milder FBS phenotype, p.Leu153_Ile154del, retained transport activity. These results improve our overall understanding of the underlying causes of FBS and impact of GLUT2 function on various clinical phenotypes ranging from rare to common disease.","variants":[{"Name":"NM_000340.2(SLC2A2):c.457_462del (p.Leu153_Ile154del)","Chromosome":"3","Start":"171009992","Stop":"171009997","ReferenceAlleleVCF":"TTATAAG","AlternateAlleleVCF":"T","allel_id":1463748,"rule_based_match":true,"evidence_text":"c.457_462delCTTATA (p.Leu153_Ile154del)","llm_judgment":"PRESENT","evidence":"c.457_462delCTTATA (p.Leu153_Ile154del)","abstract_start":777,"abstract_end":816}]}
{"pmid":"24372464","title":"Genotype-phenotype analysis of Jervell and Lange-Nielsen syndrome in six families from Saudi Arabia.","abstract":"We sought to explore the genotype-phenotype of Jervell and Lange-Nielsen syndrome (JLNS) patients in Saudi Arabia. We have also assessed the plausible effect of consanguinity into the pathology of JLNS. Six families with at least one JLNS-affected member attended our clinic between 2011 and 2013. Retrospective and prospective clinical data were collected and genetic investigation was performed. Pathogenic mutations in the KCNQ1 gene were detected in all JLNS patients. The homozygous mutations detected were Leu273Phe, Asp202Asn, Ile567Thr, and c.1486_1487delCT and compound heterozygous mutations were c.820_ 830del and c.1251+1G>T. All living JLNS patients except one had a QTc of >500 ms and a history of recurrent syncope. β-Blockers abolished the cardiac-related events in all patients except two siblings with homozygous Ile567Thr mutation. Four of the six mutations were originally reported in autosomal dominant long QT syndrome (LQTS) patients. Eighty percent of the heterozygote mutation carriers showed prolongation of QTc, but majority of these reported no symptoms attributable to arrhythmias. Mutations detected in this study will be advantageous in tribe and region-specific cascade screening of LQTS in Saudi Arabia.","variants":[{"Name":"NM_000218.3(KCNQ1):c.604G>A (p.Asp202Asn)","Chromosome":"11","Start":"2570754","Stop":"2570754","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67745,"rule_based_match":false,"evidence_text":"Asp202Asn","llm_judgment":"PRESENT","evidence":"Asp202Asn","abstract_start":523,"abstract_end":532},{"Name":"NM_000218.3(KCNQ1):c.1486_1487del (p.Leu496fs)","Chromosome":"11","Start":"2662051","Stop":"2662052","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":67651,"rule_based_match":true,"evidence_text":"c.1486_1487delCT","llm_judgment":"PRESENT","evidence":"c.1486_1487delCT","abstract_start":549,"abstract_end":565},{"Name":"NM_000218.3(KCNQ1):c.817C>T (p.Leu273Phe)","Chromosome":"11","Start":"2572882","Stop":"2572882","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18158,"rule_based_match":false,"evidence_text":"Leu273Phe","llm_judgment":"PRESENT","evidence":"Leu273Phe","abstract_start":512,"abstract_end":521},{"Name":"NM_000218.3(KCNQ1):c.1700T>C (p.Ile567Thr)","Chromosome":"11","Start":"2777000","Stop":"2777000","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":67675,"rule_based_match":false,"evidence_text":"Ile567Thr","llm_judgment":"PRESENT","evidence":"Ile567Thr","abstract_start":534,"abstract_end":543}]}
{"pmid":"25545163","title":"A de novo ADCY5 mutation causes early-onset autosomal dominant chorea and dystonia.","abstract":"IMPORTANCE: Apart from Huntington's disease, little is known of the genetics of autosomal dominant chorea associated with dystonia. Here we identify adenylate cyclase 5 (ADCY5) as a likely new causal gene for early-onset chorea and dystonia.\nOBSERVATIONS: Whole exome sequencing in a three-generation family affected with autosomal dominant chorea associated with dystonia identified a single de novo mutation—c.2088+1G>A in a 5' donor splice-site of ADCY5—segregating with the disease. This mutation seeming leads to RNA instability and therefore ADCY5 haploinsufficiency.\nCONCLUSIONS AND RELEVANCE: Our finding confirms the genetic/clinical heterogeneity of the disorder; corroborated by previous identification of ADCY5 mutations in one family with dyskinesia-facial myokymia and in two unrelated sporadic cases of paxoysmal choreic/dystonia-facial myokymia; ADCY5's high expression in the striatum and movement disorders in ADCY5-deficient mice. Hence ADCY5 genetic analyses may be relevant in the diagnostic workup of unexplained early-onset hyperkinetic movement disorders.","variants":[{"Name":"NM_183357.3(ADCY5):c.2088+1G>A","Chromosome":"3","Start":"123325321","Stop":"123325321","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215062,"rule_based_match":true,"evidence_text":"c.2088+1G>A","llm_judgment":"PRESENT","evidence":"c.2088+1G>A","abstract_start":410,"abstract_end":421}]}
{"pmid":"21953331","title":"Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity.","abstract":"OBJECTIVE: Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome) is an autoinflammatory syndrome recently described in children. We undertook this study to investigate the clinical phenotype, genetic cause, and immune dysregulation in 9 CANDLE syndrome patients.\nMETHODS: Genomic DNA from all patients was screened for mutations in PSMB8 (proteasome subunit β type 8). Cytokine levels were measured in sera from 3 patients. Skin biopsy samples were evaluated by immunohistochemistry, and blood microarray profile and STAT-1 phosphorylation were assessed in 4 patients and 3 patients, respectively.\nRESULTS: One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A), suggesting a protein truncation; 4 patients were homozygous and 2 were heterozygous for a previously reported missense mutation (c.224C>T); and 1 patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the 4 patients with the same mutation, only 2 shared the same haplotype, indicating a mutational hot spot. PSMB8 mutation-positive and -negative patients expressed high levels of interferon-γ (IFNγ)-inducible protein 10. Levels of monocyte chemotactic protein 1, interleukin-6 (IL-6), and IL-1 receptor antagonist were moderately elevated. Microarray profiles and monocyte STAT-1 activation suggested a unique IFN signaling signature, unlike in other autoinflammatory disorders.\nCONCLUSION: CANDLE syndrome is caused by mutations in PSMB8, a gene recently reported to cause \"JMP\" syndrome (joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced childhood-onset lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8-associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target.","variants":[{"Name":"NM_148919.4(PSMB8):c.405C>A (p.Cys135Ter)","Chromosome":"6","Start":"32842674","Stop":"32842674","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":38817,"rule_based_match":true,"evidence_text":"c.405C>A","llm_judgment":"PRESENT","evidence":"c.405C>A","abstract_start":723,"abstract_end":731},{"Name":"NM_148919.4(PSMB8):c.224C>T (p.Thr75Met)","Chromosome":"6","Start":"32843013","Stop":"32843013","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":634822,"rule_based_match":true,"evidence_text":"c.224C>T","llm_judgment":"PRESENT","evidence":"c.224C>T","abstract_start":863,"abstract_end":871}]}
{"pmid":"33785574","title":"Impact of a frequent nearsplice","abstract":"OBJECTIVE: Mutations in superoxide dismutase 1 gene (<i>SOD1)</i>, encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in <i>SOD1</i> non-coding sequences, is pathogenic.\nMETHODS: We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.\nRESULTS: We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358-10T>G nearsplice <i>SOD1</i> variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.\nCONCLUSIONS: Our results highlighted nearsplice/intronic mutations in <i>SOD1</i> are responsible for a significant portion of French fALS and suggested the systematic analysis of the <i>SOD1</i> mRNA sequence could become the method of choice for <i>SOD1</i> screening, not to miss these specific cases.","variants":[{"Name":"NM_000454.5(SOD1):c.358-10T>G","Chromosome":"21","Start":"31668461","Stop":"31668461","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":29809,"rule_based_match":true,"evidence_text":"c.358-10T>G","llm_judgment":"PRESENT","evidence":"c.358-10T>G","abstract_start":1073,"abstract_end":1084}]}
{"pmid":"26896187","title":"The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population.","abstract":"BACKGROUND: Congenital hearing loss (CHL) is diagnosed in 1 - 2 newborns in 1000, genetic factors contribute to two thirds of CHL cases in industrialised countries. Mutations of the GJB2 gene located in the DFNB1 locus (13q11-12) are a major cause of CHL worldwide. The aim of this cross-sectional study was to assess the contribution of the DFNB1 locus containing the GJB2 and GJB6 genes in the development of early onset hearing loss in the affected group of participants, to determine the population-specific mutational profile and DFNB1-related HL burden in Lithuanian population.\nMETHODS: Clinical data were obtained from a collection of 158 affected participants (146 unrelated probands) with early onset non-syndromic HL. GJB2 and GJB6 gene sequencing and GJB6 gene deletion testing were performed. The data of GJB2 and GJB6 gene sequencing in 98 participants in group of self-reported healthy Lithuanian inhabitants were analysed. Statistic summary, homogeneity tests, and logistic regression analysis were used for the assessment of genotype-phenotype correlation.\nRESULTS: Our findings show 57.5% of affected participants with two pathogenic GJB2 gene mutations identified. The most prevalent GJB2 mutations were c.35delG, p. (Gly12Valfs*2) (rs80338939) and c.313_326del14, p. (Lys105Glyfs*5) (rs111033253) with allele frequencies 64.7% and 28.3% respectively. GJB6 gene mutations were not identified in the affected group of participants. The statistical analysis revealed significant differences between GJB2(-) and GJB2(+) groups in disease severity (p = 0.001), and family history (p = 0.01). The probability of identification of GJB2 mutations in patients with various HL characteristics was estimated. The carrier rate of GJB2 gene mutations - 7.1% (~1 in 14) was identified in the group of healthy participants and a high frequency of GJB2-related hearing loss was estimated in our population.\nDISCUSSION: The results show a very high proportion of GJB2-positive individuals in the research group affected with sensorineural HL. The allele frequency of c.35delG mutation (64.7 %) is consistent with many previously published studies in groups of affected individuals of Caucasian populations. The high frequency of the c.313_326del14 (28.3 % of pathogenic alleles) mutation in affected group of participants was an unexpected finding in our study suggesting not only a high frequency of carriers of this mutation in our population but also its possible origin in Lithuanian ancestors. The high frequency of carriers of the c.313_326del14 mutation in the entire Lithuanian population is supported by it being identified twice in the ethnic Lithuanian group of healthy participants (a frequency 2.0 % of carriers in the study group).\nCONCLUSION: Analysis of the allele frequency of GJB2 gene mutations revealed a high proportion of c. 313_326del14 (rs111033253) mutations in the GJB2-positive group suggesting its possible origin in Lithuanian forebears. The high frequency of carriers of GJB2 gene mutations in the group of healthy participants corresponds to the substantial frequency of GJB2-associated HL in Lithuania. The observations of the study indicate the significant contribution of GJB2 gene mutations to the pathogenesis of the disorder in the Lithuanian population and will contribute to introducing principles to predict the characteristics of the disease in patients.","variants":[{"Name":"NM_004004.6(GJB2):c.313_326del (p.Lys105fs)","Chromosome":"13","Start":"20189256","Stop":"20189269","ReferenceAlleleVCF":"CCCCTTGATGAACTT","AlternateAlleleVCF":"C","allel_id":53904,"rule_based_match":true,"evidence_text":"c.313_326del14","llm_judgment":"PRESENT","evidence":"c.313_326del14","abstract_start":1268,"abstract_end":1282}]}
{"pmid":"33599434","title":"Characterisation of LDL receptor gene mutations in a North Indian cohort of children with homozygous familial hypercholesterolaemia.","abstract":"INTRODUCTION: Homozygous familial hypercholesterolaemia (HoFH) carries a grave prognosis but is often underdiagnosed and undertreated. Confirmation of molecular diagnosis helps in planning effective management and determining prognosis accurately. Aim of the study: To determine the spectrum of mutations in the LDLR gene in a cohort of children with a clinical diagnosis of HoFH.\nMATERIAL AND METHODS: Genomic DNA was extracted from peripheral blood samples of 8 patients, who were children of either sex, aged under 16 years, and diagnosed clinically with HoFH using the Simon Broome criteria. The potential variants in the LDLR gene were analysed by Sanger sequencing.\nRESULTS: Fifty variations were found in the 8 patients; 39 (78%) were single nucleotide variations while 8 (16%) and 3 (6%) were deletions and insertions, respectively. The pathogenic variants in the LDLR gene were detected in four patients; three showed duplication in exon 17 (c.2416dupG) creating an amino acid change at position 806 (p.Val806GlyfsTer11) while one had a missense variant in the exon 9 at position c.1285G>A resulting in a change in amino acid at position 429 (p.Val429Met). The variants were found in heterozygous state in the parents or siblings of probands who showed pathogenic variants.\nCONCLUSIONS: The frequency of disease-causing variants in the LDLR gene in our patients with HoFH was 50%. Further studies to characterise mutations in genes for apolipoprotein B, proprotein convertase subtilisin/kexin type 9, or LDL adaptor protein are suggested in all children with a clinical diagnosis of HoFH.","variants":[{"Name":"NM_000527.5(LDLR):c.2416dup (p.Val806fs)","Chromosome":"19","Start":"11129534","Stop":"11129535","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":246615,"rule_based_match":true,"evidence_text":"c.2416dupG","llm_judgment":"PRESENT","evidence":"c.2416dupG","abstract_start":951,"abstract_end":961}]}
{"pmid":"35537890","title":"Novel Dental Anomaly-associated Mutations in WNT10A Protein Binding Sites.","abstract":"OBJECTIVE: WNT/β-catenin signaling is initiated by binding of a WNT protein to a Frizzled (FZD) receptor and a co-receptor, low-density lipoprotein (LDL) receptor-related protein 5 or 6 (LRP5/6). The objective of this study was to find the genetic variants responsible for dental anomalies found in 4 families.\nMETHODS: Clinical and radiographic examination and whole exome sequencing were performed on 5 patients affected with dental anomalies and the mutant proteins modeled.\nRESULTS: Five patients were heterozygous for the WNT10A variants, including c.877C>T; p.Arg293Cys, c.874A>G; p.Ser292Gly, c.1042C>T; p.Arg348Cys, and c.1039G>T; p.347GluX. The p.Arg293Cys and p.Ser292Gly mutations are located in the WNT10A N-terminal domain region with binding sites for FZD receptor, porcupine, WNTLESS, and extracellular binding proteins, so they are likely to have adverse effects on binding these proteins. The p.Arg348Cys mutation, which is located in the binding site of LRP5/6 co-receptors, is postulated to result in impaired binding to these co-receptors. The nonsense mutation p.347GluX is predicted to result in the truncation of most of the C-terminal domain, which is likely to disrupt the binding of WNT10A to WNTLESS, the membrane protein that binds lipid-acylated WNT proteins to carry them from the endoplasmic reticulum to the cell surface and FZD.\nCONCLUSIONS: Four novel mutations in WNT10A were identified in patients with isolated tooth agenesis. The mutations in the N-terminal domain and the interface between the N- and C-terminal domains of WNT10A in our patients are likely to disrupt its binding with FZD, LRP5/6, and various other proteins involved in WNT10A processing and transport, impair WNT and SHH signaling, and subsequently result in tooth agenesis, microdontia, and root maldevelopment.","variants":[{"Name":"NM_025216.3(WNT10A):c.877C>T (p.Arg293Cys)","Chromosome":"2","Start":"218892894","Stop":"218892894","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1683899,"rule_based_match":true,"evidence_text":"c.877C>T; p.Arg293Cys","llm_judgment":"PRESENT","evidence":"c.877C>T; p.Arg293Cys","abstract_start":554,"abstract_end":575},{"Name":"NM_025216.3(WNT10A):c.1042C>T (p.Arg348Cys)","Chromosome":"2","Start":"218893059","Stop":"218893059","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1683900,"rule_based_match":true,"evidence_text":"c.1042C>T; p.Arg348Cys","llm_judgment":"PRESENT","evidence":"c.1042C>T; p.Arg348Cys","abstract_start":600,"abstract_end":622}]}
{"pmid":"18580441","title":"SPINK1 and PRSS1 mutations in benign pancreatic hyperenzymemia.","abstract":"UNLABELLED: The aim of this study was to determine whether mutations in SPINK1/PRSS1 genes are associated with benign pancreatic hyperenzymemia (BPH).\nMETHODS: Sixty-eight subjects with BPH (including 13 familial cases) were studied. In all, we sequenced germline DNA for all the exons and intro-exon boundaries of PRSS1 and SPINK1.\nRESULTS: Nine (13.2%) of the 68 subjects harbored PRSS1 or SPINK1 mutations. As to PRSS1, no hereditary pancreatitis-associated variant was detected, whereas previously undescribed mutations (p.Ala148Val and c.40+1G>A) were respectively found in 2 subjects (2.9%). SPINK1 mutations were detected in 7 subjects (10.3%). Five of them exhibited known mutations (3 p.Asn34Ser, 1 p.Pro55Ser, and 1 c.88-23A>T), whereas 2 had a newly found variant (p.Arg67Gly and c.*32C>T, respectively). Only 2 familial BPH, belonging to 2 different families, were found to carry a mutation (1 with p.Ala148Val for PRSS1 and 1 with p.Asn34Ser for SPINK1).\nCONCLUSIONS: No known mutations of PRSS1 have been found in BPH, whereas the frequency of known SPINK1 variants is similar to that reported in the general population. No segregation of PRSS1/SPINK1 variants occurs in BPH families. Benign pancreatic hyperenzymemia cannot be explained by mutations in genes whose variants are known to be associated with pancreatitis or by mutations in other PRSS1/SPINK1 genes.","variants":[{"Name":"NM_002769.5(PRSS1):c.443C>T (p.Ala148Val)","Chromosome":"7","Start":"142752016","Stop":"142752016","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1685161,"rule_based_match":false,"evidence_text":"p.Ala148Val","llm_judgment":"PRESENT","evidence":"p.Ala148Val","abstract_start":525,"abstract_end":536},{"Name":"NM_002769.5(PRSS1):c.40+1G>A","Chromosome":"7","Start":"142749525","Stop":"142749525","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1027845,"rule_based_match":true,"evidence_text":"c.40+1G>A","llm_judgment":"PRESENT","evidence":"c.40+1G>A","abstract_start":541,"abstract_end":550}]}
{"pmid":"34535384","title":"Characterization of variants of uncertain significance in isovaleryl-CoA dehydrogenase identified through newborn screening: An approach for faster analysis.","abstract":"INTRODUCTION: Clinical standard of care for newborn screening (NBS) is acylcarnitine metabolites quantitation by tandem mass spectrometry (MS/MS) from dried blood spots. Follow up sequencing often results in identification of one or more variants of uncertain significance (VUS). Isovaleric acidemia (IVA) is an autosomal recessive inborn error of metabolism caused by deficiency of isovaleryl-CoA dehydrogenase (IVDH) in the Leu catabolism pathway. Many IVD mutations are characterized as VUS complicating IVA clinical diagnoses and treatment. We present a testing platform approach to confirm the functional implication of VUS identified in newborns with IVA applicable to multiple inborn errors of metabolism identified by NBS.\nMETHODS: An IVD null HEK293T cell culture model was generated by using a dual sgRNA CRISPR/Cas9 genome-editing strategy targeting IVD exons 2-3. Clonal cell lines were confirmed by a combination of genomic breakpoint sequencing and droplet digital PCR. The IVD null model had no IVDH antigen signal and 96% reduction in IVDH enzyme activity. The IVD null model was transfected with vectors containing control or variant IVD and functional assays were performed to determine variant pathogenicity.\nRESULTS: c.149G > C (p.Arg50Pro; precursor numbering), c.986T > C (p.Met329Thr), and c.1010G > A (p.Arg337Gln), c.1179del394 f. mutant proteins had reduced IVDH protein and activity. c.932C > T (p.Ala311Val), c.707C > T (p.Thr236Ile), and c.1232G > A (p.Arg411Gln) had stable IVDH protein, but no enzyme activity. c.521T > G (p.Val174Gly) had normal IVDH protein and activity. IVD variant transfection results confirmed results from IVA fibroblasts containing the same variants.\nCONCLUSIONS: We have developed an IVD null HEK293T cell line to rapidly allow determination of VUS pathogenicity following identification of novel alleles by clinical sequencing following positive NBS results for suspected IVA. We suggest similar models can be generated via genome-editing for high throughput assessment of VUS function for a multitude of inborn errors of metabolism and can ideally supplement NBS programs.","variants":[{"Name":"NM_002225.5(IVD):c.707C>T (p.Thr236Ile)","Chromosome":"15","Start":"40413010","Stop":"40413010","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":264619,"rule_based_match":true,"evidence_text":"c.707C > T (p.Thr236Ile)","llm_judgment":"PRESENT","evidence":"c.707C > T (p.Thr236Ile)","abstract_start":1437,"abstract_end":1461},{"Name":"NM_002225.5(IVD):c.1232G>A (p.Arg411Gln)","Chromosome":"15","Start":"40418223","Stop":"40418223","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":445310,"rule_based_match":true,"evidence_text":"c.1232G > A (p.Arg411Gln)","llm_judgment":"PRESENT","evidence":"c.1232G > A (p.Arg411Gln)","abstract_start":1467,"abstract_end":1492}]}
{"pmid":"22627569","title":"Report on the p.Ser489X (p.Ser489*) CFTR mutation, a variant with severe associated phenotype and high prevalence in a Quebec French-Canadian cystic fibrosis patient population.","abstract":"PURPOSE: This study reports on the phenotype of cystic fibrosis patients identified to be carriers of the p.Ser489X (p.Ser489*; c.1466C>A) cystic fibrosis transmembrane conductance regulator (CFTR) mutation, a variant rarely described in the cystic fibrosis literature, as well as on its allelic frequency in a French-Canadian cystic fibrosis patient cohort.\nMETHODS: Reported phenotypes and allelic frequency of this variant were collected based on the data from a large French-Canadian cystic fibrosis patient cohort.\nRESULTS: Cystic fibrosis patients found to carry the p.Ser489X variant generally presented with classic gastrointestinal manifestations of this condition in infancy. The allelic frequency of this variant was calculated to be 0.7% for this population.\nCONCLUSION: The p.Ser489X CFTR variant is a severe disease-causing CFTR allele that is relatively frequent in the French-Canadian cystic fibrosis patient population, warranting its inclusion into CFTR molecular testing panel for this population.","variants":[{"Name":"NM_000492.4(CFTR):c.1466C>A (p.Ser489Ter)","Chromosome":"7","Start":"117559537","Stop":"117559537","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":67927,"rule_based_match":true,"evidence_text":"p.Ser489X (p.Ser489*; c.1466C>A)","llm_judgment":"PRESENT","evidence":"p.Ser489X (p.Ser489*; c.1466C>A)","abstract_start":106,"abstract_end":138}]}
{"pmid":"30733662","title":"A Novel Mutation of","abstract":"Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR; OMIM 152950) is a rare autosomal dominantly inherited syndrome. Mutations in the kinesin family member 11 (<i>KIF11</i>) gene have been associated with this condition. Here, we report a de novo novel heterozygous missense mutation in exon 12 of the <i>KIF11</i> gene [c.1402T>G; p.(Leu468Val)] in a boy with 22q11.2 microdeletion syndrome. His major features were microcephaly, ventricular septal defect, congenital lymphedema of the feet, and distinct facial appearance including upslanting palpebral fissures, a broad nose with rounded tip, anteverted nares, long philtrum with a thin upper lip, pointed chin, and prominent ears. His right eye was enucleated due to subretinal hemorrhage and retinal detachment at age 3 months. Lacunae of chorioretinal atrophy and the pale optic disc were present in the left eye. He also had a de novo 1.6-Mb microdeletion in the Di George/VCFS region of chromosome 22q11.2 in SNP array, which was confirmed by FISH analysis. In this study, for the first time, we describe the co-occurrence of a <i>KIF11</i> mutation and 22q11.2 deletion syndrome in a patient with MCLMR.","variants":[{"Name":"NM_004523.4(KIF11):c.1402T>G (p.Leu468Val)","Chromosome":"10","Start":"92630272","Stop":"92630272","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":994119,"rule_based_match":true,"evidence_text":"c.1402T>G; p.(Leu468Val)","llm_judgment":"PRESENT","evidence":"c.1402T>G; p.(Leu468Val)","abstract_start":358,"abstract_end":382}]}
{"pmid":"23534974","title":"Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome.","abstract":"BACKGROUND: Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers.\nOBJECTIVE: We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.\nMETHODS: We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations.\nRESULTS: We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation.\nCONCLUSIONS: Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.","variants":[{"Name":"NM_007315.4(STAT1):c.1154C>T (p.Thr385Met)","Chromosome":"2","Start":"190986921","Stop":"190986921","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":153737,"rule_based_match":true,"evidence_text":"c.1154C>T, T385M","llm_judgment":"PRESENT","evidence":"c.1154C>T, T385M","abstract_start":1304,"abstract_end":1320}]}
{"pmid":"21935284","title":"Dopa-responsive dystonia with a novel initiation codon mutation in the GCH1 gene misdiagnosed as cerebral palsy.","abstract":"Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic response to relatively low doses of levodopa. However, patients with DRD can be misdiagnosed as cerebral palsy or spastic diplegia due to phenotypic variation. Here we report a young woman with DRD who were severely disabled and misdiagnosed as cerebral palsy for over 10 yr. A small dose of levodopa restored wheelchair-bound state to normality. However, thoracolumbar scoliosis has remained as a sequel due to late detection of DRD. Genetic analysis by using PCR-direct sequencing revealed a novel initiation codon mutation (c.1A>T; p.Met1Leu) in GTP cyclohydrolase 1 (GCH1) gene. Although it is known that DRD can be misdiagnosed as cerebral palsy, this case reinforces the importance of differential diagnosis of DRD from cerebral palsy.","variants":[{"Name":"NM_000161.3(GCH1):c.1A>T (p.Met1Leu)","Chromosome":"14","Start":"54902663","Stop":"54902663","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":464177,"rule_based_match":true,"evidence_text":"c.1A>T (p.Met1Leu)","llm_judgment":"PRESENT","evidence":"p.Met1Leu","abstract_start":646,"abstract_end":655}]}
{"pmid":"22197488","title":"Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus.","abstract":"Pterygium syndromes are complex congenital disorders that encompass several distinct clinical conditions characterized by multiple skin webs affecting the flexural surfaces often accompanied by craniofacial anomalies. In severe forms, such as in the autosomal-recessive Bartsocas-Papas syndrome, early lethality is common, complicating the identification of causative mutations. Using exome sequencing in a consanguineous family, we identified the homozygous mutation c.1127C>A in exon 7 of RIPK4 that resulted in the introduction of the nonsense mutation p.Ser376X into the encoded ankyrin repeat-containing kinase, a protein that is essential for keratinocyte differentiation. Subsequently, we identified a second mutation in exon 2 of RIPK4 (c.242T>A) that resulted in the missense variant p.Ile81Asn in the kinase domain of the protein. We have further demonstrated that RIPK4 is a direct transcriptional target of the protein p63, a master regulator of stratified epithelial development, which acts as a nodal point in the cascade of molecular events that prevent pterygium syndromes.","variants":[{"Name":"NM_020639.3(RIPK4):c.1127C>A (p.Ser376Ter)","Chromosome":"21","Start":"41743950","Stop":"41743950","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":39468,"rule_based_match":true,"evidence_text":"c.1127C>A","llm_judgment":"PRESENT","evidence":"c.1127C>A","abstract_start":468,"abstract_end":477},{"Name":"NM_020639.3(RIPK4):c.242T>A (p.Ile81Asn)","Chromosome":"21","Start":"41756757","Stop":"41756757","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":39469,"rule_based_match":true,"evidence_text":"c.242T>A","llm_judgment":"PRESENT","evidence":"c.242T>A","abstract_start":745,"abstract_end":753}]}
{"pmid":"22885111","title":"RAPADILINO RECQL4 mutant protein lacks helicase and ATPase activity.","abstract":"The RecQ family of helicases has been shown to play an important role in maintaining genomic stability. In humans, this family has five members and mutations in three of these helicases, BLM, WRN and RECQL4, are associated with disease. Alterations in RECQL4 are associated with three diseases, Rothmund-Thomson syndrome, Baller-Gerold syndrome, and RAPADILINO syndrome. One of the more common mutations found in RECQL4 is the RAPADILINO mutation, c.1390+2delT which is a splice-site mutation leading to an in-frame skipping of exon 7 resulting in 44 amino acids being deleted from the protein (p.Ala420-Ala463del). In order to characterize the RAPADILINO RECQL4 mutant protein, it was expressed in bacteria and purified using an established protocol. Strand annealing, helicase, and ATPase assays were conducted to characterize the protein's activities relative to WT RECQL4. Here we show that strand annealing activity in the absence of ATP is unchanged from that of WT RECQL4. However, the RAPADILINO protein variant lacks helicase and ssDNA-stimulated ATPase activity. These observations help explain the underlying molecular etiology of the disease and our findings provide insight into the genotype and phenotype association among RECQL4 syndromes.","variants":[{"Name":"NM_004260.4(RECQL4):c.1390+2del","Chromosome":"8","Start":"144515324","Stop":"144515324","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":71037,"rule_based_match":true,"evidence_text":"c.1390+2delT","llm_judgment":"PRESENT","evidence":"c.1390+2delT","abstract_start":448,"abstract_end":460}]}
{"pmid":"32595021","title":"A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay.","abstract":"INTRODUCTION: Hypomyelinating leukodystrophies (HLDs) are genetically heterogeneous syndromes, presenting abnormalities in myelin development in the central nervous system. Recently, a recurrent de novo mutation in TMEM106B was identified to be responsible for five cases of HLD. We report the first Japanese case of TMEM106B gene mutation.\nCASE STUDY: A 3-year-old patient presented with nystagmus and muscle hypotonia in his neonatal period, followed by delayed psychomotor development. Brain magnetic resonance images showed delayed myelination. Wave III and subsequent components were not presented by his auditory brainstem response. These features were similar to those observed in Pelizaeus-Merzbacher disease (PMD).\nMETHODS: Proteolipid protein 1 (PLP1) gene screening, Mendelian disease panel exome, and whole-exome sequencing (WES) were sequentially performed.\nRESULTS: After excluding mutations in either PLP1 or other known HLD genes, WES identified a mutation c.754G > A, p.(Asp252Asn) in TMEM106B, which appeared to occur de novo, as shown by Sanger sequencing and SalI restriction enzyme digestion of PCR products.\nDISCUSSION: This is the sixth case of HLD with a TMEM106B mutation. All six cases harbored the same variant. This specific TMEM106B mutation should be investigated when a patient shows PMD-like features without PLP1 mutation. Our PCR-SalI digestion assay may serve as a tool for rapid HLD diagnosis.","variants":[{"Name":"NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn)","Chromosome":"7","Start":"12231904","Stop":"12231904","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":513887,"rule_based_match":true,"evidence_text":"c.754G > A, p.(Asp252Asn)","llm_judgment":"PRESENT","evidence":"c.754G > A, p.(Asp252Asn)","abstract_start":973,"abstract_end":998}]}
{"pmid":"31957987","title":"A Turkish patient with novel AHCY variants and presumed diagnosis of S-adenosylhomocysteine hydrolase deficiency.","abstract":"S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive neurometabolic disorder affecting the muscles, liver, and nervous system. The disease occurs by pathogenic variants of AHCY gene encoding S-adenosylhomocysteine hydrolase (AHCY) enzyme. This article reports a patient with presumed AHCY deficiency who was diagnosed by whole exome sequencing due to compound heterozygosity of novel p.T57I (c.170C>T) and p.V217M (c.649G>A) variants of AHCY gene. The patient had diffuse edema, coagulopathy, central nervous system abnormalities, and hypotonia. She died in 3 months due to cardiovascular collapse. Clinical findings of the present case were compatible with previously reported AHCY deficiency patients and the novel variants we found are considered to be the cause of the symptoms. This article also compiles the previous reports and expands clinical spectrum of AHCY deficiency by adding new features.","variants":[{"Name":"NM_000687.4(AHCY):c.170C>T (p.Thr57Ile)","Chromosome":"20","Start":"34295444","Stop":"34295444","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2853381,"rule_based_match":true,"evidence_text":"c.170C>T","llm_judgment":"PRESENT","evidence":"c.170C>T","abstract_start":409,"abstract_end":417},{"Name":"NM_000687.4(AHCY):c.649G>A (p.Val217Met)","Chromosome":"20","Start":"34290848","Stop":"34290848","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2853382,"rule_based_match":true,"evidence_text":"c.649G>A","llm_judgment":"PRESENT","evidence":"c.649G>A","abstract_start":432,"abstract_end":440}]}
{"pmid":"26277102","title":"Novel mutations and polymorphisms in the CFTR gene associated with three subtypes of congenital absence of vas deferens.","abstract":"OBJECTIVE: To study the new genotypes in congenital absence of vas deferens (CAVD) and the correlation with different phenotypes, and to investigate the pathogenesis of the disease based on bioinformatics analysis.\nDESIGN: Case-control study.\nSETTING: University-affiliated tertiary teaching hospital.\nPATIENT(S): Nineteen patients with CAVD and azoospermia. The time period of the study was from May 2013 to April 2014.\nINTERVENTION(S): None.\nMAIN OUTCOME MEASURE(S): Sanger sequencing was performed in the coding regions and intron-exon boundaries of the cystic fibrosis transmembrane regulator CFTR gene on the polymerase chain reaction (PCR) products. Mutations/variations were identified and compared with the control subjects, and bioinformatics analysis searched in the dbSNP and 1000 Genomes Project. Functional effects of the novel mutations were predicted. Structural modeling of the wild and mutant proteins was also performed.\nRESULT(S): A total of 8 mutations were identified in 12 patients, 4 of which were novel (c.4433C>G, c.3469-3C>A, c.1357delT, and c.3407C>T). The mutation c.4433C>G occurred in the PSD-95/DLG/ZO-1 (PDZ)-binding motif in the CFTR protein, which was predicted to disrupt the interaction between CFTR and CFTR-associated ligand (CAL). Another missense mutation, c.3407C>T, was predicted to damage and destroy the transmembrane adenosine triphosphate (ATP)-binding cassette domain. The splicing mutation, c.3469-3C>A, was predicted to truncate exon 22 by Human Splicing Finder. The frameshift mutation, c.1357delT, was predicted to introduce a premature stop codon at position 453 and lead to 1,012 amino acids truncation at the carboxyl terminus of the CFTR protein.\nCONCLUSION(S): This study illustrates the significance of whole exon sequencing of the CFTR gene in patients with CAVD. It is essential for determining the pathogenesis of novel mutations using bioinformatics analysis and to identify correlation between new genotypes and phenotypes.","variants":[{"Name":"NM_000492.4(CFTR):c.3407C>T (p.Ala1136Val)","Chromosome":"7","Start":"117614652","Stop":"117614652","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":587027,"rule_based_match":true,"evidence_text":"c.3407C>T","llm_judgment":"PRESENT","evidence":".3407C>T)","abstract_start":1068,"abstract_end":1077},{"Name":"NM_000492.4(CFTR):c.4433C>G (p.Thr1478Arg)","Chromosome":"7","Start":"117667098","Stop":"117667098","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":808872,"rule_based_match":true,"evidence_text":"c.4433C>G","llm_judgment":"PRESENT","evidence":".4433C>G,","abstract_start":1028,"abstract_end":1037},{"Name":"NM_000492.4(CFTR):c.3469-3C>A","Chromosome":"7","Start":"117627519","Stop":"117627519","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1792609,"rule_based_match":true,"evidence_text":"c.3469-3C>A","llm_judgment":"PRESENT","evidence":".3469-3C>A,","abstract_start":1039,"abstract_end":1050}]}
{"pmid":"23629877","title":"Novel and recurrent mutations in the EXT1 and EXT2 genes in Chinese kindreds with multiple osteochondromas.","abstract":"Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder caused by heterozygous germline mutations in the exostonsin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we screened mutations in the EXT1/EXT2 genes in four Chinese MO kindreds by direct sequencing. Three point mutations were detected, including a nonsense mutation in the EXT2 gene (c.544C > T) and two splice site mutations in the EXT1 and EXT2 genes, respectively (EXT1: c.1883 + 1G > A and EXT2: c.1173 + 1G > T). Although splice site mutations constitute at least 10% of all mutations that cause MO, there has been limited research on their pathogenic effect on RNA processing due to poor availability of patient RNA samples. In this study, ex vivo and in vivo splicing assays were used to investigate the effect of EXT1 and EXT2 mutations on aberrant splicing at the mRNA level. Our results indicate that identified splice site mutations can cause either cryptic splice site usage or exon skipping.","variants":[{"Name":"NM_207122.2(EXT2):c.544C>T (p.Arg182Ter)","Chromosome":"11","Start":"44109201","Stop":"44109201","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259984,"rule_based_match":true,"evidence_text":"c.544C > T","llm_judgment":"PRESENT","evidence":"c.544C > T","abstract_start":368,"abstract_end":378},{"Name":"NM_000127.3(EXT1):c.1883+1G>A","Chromosome":"8","Start":"117807216","Stop":"117807216","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":851670,"rule_based_match":true,"evidence_text":"c.1883 + 1G > A","llm_judgment":"PRESENT","evidence":"c.1883 + 1G > A","abstract_start":458,"abstract_end":473}]}
{"pmid":"37005154","title":"A novel homozygous nonsense variant of LMF1 in pregnancy-induced hypertriglyceridemia with acute pancreatitis.","abstract":"Hypertriglyceridemia (HTG)-induced pancreatitis during pregnancy could lead to maternal and fetal death. However, its genetic bases are not fully understood, and its treatment strategies are yet to be established. Here we report a case with a novel homozygous nonsense variant of LMF1 in pregnancy-associated HTG with acute pancreatitis. Our patient had childhood-onset severe HTG that had been well-controlled by dietary management in the non-pregnant period with plasma triglyceride (TG) levels at around 200 mg/dL. Milky plasma was noted at the first-trimester pregnancy checkup, followed by a severe increase in plasma TG (10,500 mg/dL) that resulted in pancreatitis in the last trimester. The implementation of strict dietary fat restriction (less than 4 grams per day) reduced plasma TG levels and led to successful delivery. Exome sequencing revealed a novel homozygous nonsense variant in LMF1 (c.697C>T, p.Arg233Ter). The activities of lipoprotein lipase (LPL) and hepatic lipase in post-heparin plasma were not abolished but reduced. The use of pemafibrate decreased plasma TG levels with a concomitant increase in LPL activity. HTG in childhood or early pregnancy is commonly assumed to be polygenic in origin but should be regarded as a feature suggestive of monogenic hyperchylomicronemia. Adequate TG monitoring and dietary fat restriction should be implemented to prevent potentially lethal events of pancreatitis.","variants":[{"Name":"NM_022773.4(LMF1):c.697C>T (p.Arg233Ter)","Chromosome":"16","Start":"893039","Stop":"893039","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1669571,"rule_based_match":true,"evidence_text":"c.697C>T, p.Arg233Ter","llm_judgment":"PRESENT","evidence":"c.697C>T, p.Arg233Ter","abstract_start":903,"abstract_end":924}]}
{"pmid":"25114813","title":"Novel Mutation in the PKHD1 Gene Diagnosed Prenatally in a Fetus with Autosomal Recessive Polycystic Kidney Disease.","abstract":"We report a 29-year-old gravida 2, para 0100, who presented at 19 weeks and 4 days of gestation for ultrasound to assess fetal anatomy. Routine midtrimester fetal anatomy ultrasound revealed enlarged, hyperechoic fetal kidneys and normal amniotic fluid index. Follow-up ultrasound at 23 weeks and 5 days revealed persistently enlarged, hyperechoic fetal kidneys. Progressive oligohydramnios was not evident until 29 weeks of gestation, with anhydramnios noted by 35 weeks of gestation. Amniocentesis was performed for karyotype and to search for mutations in the PKHD1 for the presumptive diagnosis of autosomal recessive polycystic kidney disease (ARPKD). In our patient, a maternally inherited, previously reported pathogenic missense mutation in the PKHD1 gene, c.10444C>T, was identified. A second, previously unreported de novo mutation, c.5909-2delA, was also identified. This mutation affects the canonical splice site and is most likely pathogenic. Our case highlights PKHD1 allelic heterogeneity and the importance of genetic testing in the prenatal setting where many other genetic etiologies can phenocopy ARPKD.","variants":[{"Name":"NM_138694.4(PKHD1):c.10444C>T (p.Arg3482Cys)","Chromosome":"6","Start":"51659682","Stop":"51659682","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":186706,"rule_based_match":true,"evidence_text":"c.10444C>T","llm_judgment":"PRESENT","evidence":"c.10444C>T","abstract_start":765,"abstract_end":775}]}
{"pmid":"21917543","title":"Association of the congenital neuromuscular form of glycogen storage disease type IV with a large deletion and recurrent frameshift mutation.","abstract":"Anderson disease, also known as glycogen storage disease type IV (MIM 232500), is a rare autosomal recessive disorder caused by a deficiency of glycogen branching enzyme. Glycogen storage disease type IV has a broad clinical spectrum ranging from a perinatal lethal form to a nonprogressive later-onset disease in adults. Here, we report 2 unrelated infants who were born small for their gestational age and who had profound hypotonia at birth and thus needed mechanical ventilation. Both of these patients shared the same frameshift mutation (c.288delA, pGly97GlufsX46) in the GBE1 gene. In addition, both of these patients were found to have 2 different large deletions in the GBE1 gene; exon 7 and exons 2 to 7, respectively, on the other alleles. This case report also highlights the need for a more comprehensive search for large deletion mutations associated with glycogen storage disease type IV, especially if routine GBE1 gene sequencing results are equivocal.","variants":[{"Name":"NM_000158.4(GBE1):c.288del (p.Gly97fs)","Chromosome":"3","Start":"81705469","Stop":"81705469","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":357326,"rule_based_match":true,"evidence_text":"c.288delA, pGly97GlufsX46","llm_judgment":"PRESENT","evidence":"c.288delA, pGly97GlufsX46","abstract_start":544,"abstract_end":569}]}
{"pmid":"30498080","title":"Loss of human ICOSL results in combined immunodeficiency.","abstract":"Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (<i>ICOSLG</i>; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSL<sup>N219K</sup> mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSL<sup>N219K</sup> diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSL<sup>N219K</sup> also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human <i>ICOSLG</i> deficiency as a novel cause of a combined immunodeficiency.","variants":[{"Name":"NM_015259.6(ICOSLG):c.657C>G (p.Asn219Lys)","Chromosome":"21","Start":"44235312","Stop":"44235312","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3401219,"rule_based_match":true,"evidence_text":"c.657C>G","llm_judgment":"PRESENT","evidence":"c.657C>G","abstract_start":491,"abstract_end":499}]}
{"pmid":"31132167","title":"Genetic basis of unexplained erythrocytosis in Indian patients.","abstract":"OBJECTIVE: To evaluate the spectrum of genetic defects in Indian patients with unexplained erythrocytosis.\nMETHODS: Fifteen families (18 patients) with unexplained erythrocytosis were enrolled after excluding polycythemia vera and secondary erythrocytosis. Focused Sanger sequencing from genomic DNA was performed for EPOR (exon 8), VHL (exons 2-3), EGLN1 (exons 2-5), EPAS1 (exon 12), and all exons of HBB, HBA1, and HBA2 genes.\nRESULTS: Eleven of the 18 patients (including two pairs of brothers) had Chuvash polycythemia, that is, homozygosity for VHL:c.598C > T (p.Arg200Trp). Three patients (two of whom were brothers) had HBB mutations associated with increased oxygen-affinity hemoglobin-one had a heterozygous Hb McKees Rocks HBB:c.438T > A (p.Tyr146*), and two brothers showed heterozygous Hb Rainier HBB:c.437A > G (p.Tyr146Cys). No pathogenic variants were found in the remaining four cases.\nCONCLUSION: A gene-by-gene Sanger sequencing approach could determine a genetic basis for erythrocytosis in 11 of the 15 (73%) Indian families, with homozygous VHL:c.598C > T (p.Arg200Trp) being the commonest pathogenic variant. This first study from the Indian subcontinent provides a rationale for analyzing this variant in patients with suspected congenital erythrocytosis from this region. Rare first occurrences of Hb McKees Rocks and Hb Rainier in Indians are also being reported.","variants":[{"Name":"NM_000518.5(HBB):c.437A>G (p.Tyr146Cys)","Chromosome":"11","Start":"5225605","Stop":"5225605","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":30361,"rule_based_match":true,"evidence_text":"HBB:c.437A > G (p.Tyr146Cys)","llm_judgment":"PRESENT","evidence":"HBB:c.437A > G (p.Tyr146Cys)","abstract_start":810,"abstract_end":838},{"Name":"NM_000551.4(VHL):c.598C>T (p.Arg200Trp)","Chromosome":"3","Start":"10149921","Stop":"10149921","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17271,"rule_based_match":true,"evidence_text":"VHL:c.598C > T (p.Arg200Trp)","llm_judgment":"PRESENT","evidence":"VHL:c.598C > T (p.Arg200Trp)","abstract_start":551,"abstract_end":579}]}
{"pmid":"36036427","title":"MERTK missense variants in three patients with retinitis pigmentosa.","abstract":"BACKGROUND: <i>MERTK (MER proto-oncogene, tyrosine kinase)</i> is a transmembrane protein essential in regulating photoreceptor outer segment phagocytosis. Biallelic mutations in <i>MERTK</i> cause retinal degeneration. Here we present the retinal phenotype of three patients with missense variants in <i>MERTK</i>.\nMATERIALS AND METHODS: All patients underwent a full clinical examination, fundus photography, short-wavelength fundus autofluorescence and optical coherence tomography imaging. Two patients also underwent Goldmann visual field testing and electroretinography was undertaken for the third patient. Molecular genetic testing was undertaken using next generation or whole-exome sequencing with all variants confirmed by Sanger sequencing.\nRESULTS: The first patient was a 29-year-old female heterozygous for a missense variant (c.1133C>T, p.Thr378 Met) and a nonsense variant (c.1744_1751delinsT, p.Ile582Ter) in <i>MERTK</i>. The second patient was a 26-year-old male homozygous for a c.2163T>A, p.His721Gln variant in <i>MERTK</i>. The third patient was an 11-year-old female heterozygous for a deletion of exons 5-19 and a missense variant (c.1866 G>C, p.Lys622Asn) in <i>MERTK</i>. Reduced night vision was the initial symptom in all patients. Fundoscopy revealed typical signs of retinitis pigmentosa (RP) with early-onset macular atrophy. All three <i>MERTK</i> missense variants affect highly conserved residues within functional domains, have low population frequencies and are predicted to be pathogenic <i>in silico</i>.\nCONCLUSIONS: We report three missense variants in <i>MERTK</i> and present the associated phenotypic data, which are supportive of non-syndromic RP. <i>MERTK</i> is a promising candidate for viral-mediated gene replacement therapy. Moreover, one variant represents a single nucleotide transition, which is theoretically targetable with CRISPR-Cas9 base-editing.","variants":[{"Name":"NM_006343.3(MERTK):c.1133C>T (p.Thr378Met)","Chromosome":"2","Start":"111975461","Stop":"111975461","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1003162,"rule_based_match":true,"evidence_text":"c.1133C>T, p.Thr378 Met","llm_judgment":"PRESENT","evidence":"c.1133C>T, p.Thr378 Met","abstract_start":842,"abstract_end":865},{"Name":"NM_006343.3(MERTK):c.2163T>A (p.His721Gln)","Chromosome":"2","Start":"112019496","Stop":"112019496","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":856140,"rule_based_match":true,"evidence_text":"c.2163T>A, p.His721Gln","llm_judgment":"PRESENT","evidence":"c.2163T>A, p.His721Gln","abstract_start":1000,"abstract_end":1022}]}
{"pmid":"25045380","title":"Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia.","abstract":"BACKGROUND AND PURPOSE: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively.\nMETHODS: Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes.\nRESULTS: Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected.\nCONCLUSIONS: We conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.","variants":[{"Name":"NM_014946.4(SPAST):c.131C>A (p.Ser44Ter)","Chromosome":"2","Start":"32063962","Stop":"32063962","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3859712,"rule_based_match":true,"evidence_text":"c.131C>A","llm_judgment":"PRESENT","evidence":"c.131C>A","abstract_start":927,"abstract_end":935},{"Name":"NM_014946.4(SPAST):c.1372A>C (p.Ser458Arg)","Chromosome":"2","Start":"32136927","Stop":"32136927","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1925273,"rule_based_match":true,"evidence_text":"c.1372A>C","llm_judgment":"PRESENT","evidence":"c.1372A>C","abstract_start":987,"abstract_end":996}]}
{"pmid":"27666198","title":"Nagashima-type palmoplantar keratosis in a Chinese Han population.","abstract":"Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive form of palmoplantar keratoderma (PPK), which is caused by mutations in the SERPINB7 gene. NPPK has only been reported in Japanese and Chinese populations. The present study was conducted on 12 unrelated Chinese patients who were clinically predicted to suffer from NPPK. Mutation screening was performed by direct sequencing of the entire coding regions of SERPINB7, SLURP1, AQP5, CSTA, KRT1 and KRT9 genes. Direct sequencing of SERPINB7 revealed five homozygous founder mutations (c.796C>T) and four compound heterozygous mutations in nine patients, including one novel mutation (c.122_127delTGGTCC). Nine out of the 12 patients were diagnosed with NPPK due to SERPINB7 pathogenic mutations, and the results expanded the known mutation spectrum of NPPK. Taking the other seven reported Chinese patients, who had been definitively diagnosed with NPPK by genetic testing, into account, the present study further demonstrated that NPPK is a common entity in Mainland China, and c.796C>T is the most prevalent mutation and exerts a founder effect. Furthermore, the NPPK cases described in the current study presented a consistently mild phenotype, as compared with the degrees of phenotypic variability associated with other types of relatively severe PPK, including Mal de Meleda and Olmsted syndrome.","variants":[{"Name":"NM_003784.4(SERPINB7):c.796C>T (p.Arg266Ter)","Chromosome":"18","Start":"63804288","Stop":"63804288","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":108188,"rule_based_match":true,"evidence_text":"c.796C>T","llm_judgment":"PRESENT","evidence":"c.796C>T","abstract_start":554,"abstract_end":562}]}
{"pmid":"19123044","title":"Haplotype and quantitative transcript analyses of Portuguese breast/ovarian cancer families with the BRCA1 R71G founder mutation of Galician origin.","abstract":"We investigated the functional effect of the missense variant c.211A>G (R71G) localized at position -2 of exon 5 donor splice site in the BRCA1 gene and evaluated whether Portuguese and Galician families with this mutation share a common ancestry. Three unrelated Portuguese breast/ovarian cancer families carrying this variant were studied through qualitative and quantitative transcript analyses. We also evaluated the presence of loss of heterozigosity and the histopathologic characteristics of the carcinomas in those families. Informative families (two from Portugal and one from Galicia) were genotyped for polymorphic microsatellite markers flanking BRCA1 to reconstruct haplotypes. Qualitative RNA analysis revealed the presence of two alternative transcripts both in carriers of the BRCA1 R71G variant and in controls. Semi-quantitative fragment analysis and real-time RT-PCR showed a significant increase of the transcript with an out of frame deletion of the last 22nt of exon 5 (BRCA1-Delta22ntex5) and a decrease of the full-length transcript (BRCA1-ex5FL) in patients carrying the R71G mutation as compared to controls, whereas no significant differences were found for the transcript with in frame skipping of exon 5 (BRCA1-Deltaex5). One haplotype was found to segregate in the two informative Portuguese families and in the Galician family. We demonstrate that disruption of alternative transcript ratios is the mechanism causing hereditary breast/ovarian cancer associated with the BRCA1 R71G mutation. Furthermore, our findings indicate a common ancestry of the Portuguese and Galician families sharing this mutation.","variants":[{"Name":"NM_007294.4(BRCA1):c.211A>G (p.Arg71Gly)","Chromosome":"17","Start":"43106457","Stop":"43106457","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":32732,"rule_based_match":true,"evidence_text":"c.211A>G (R71G)","llm_judgment":"PRESENT","evidence":"c.211A>G (R71G)","abstract_start":62,"abstract_end":77}]}
{"pmid":"21880801","title":"GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1.","abstract":"CONTEXT: KISS1 is a candidate gene for GnRH deficiency.\nOBJECTIVE: Our objective was to identify deleterious mutations in KISS1.\nPATIENTS AND METHODS: DNA sequencing and assessment of the effects of rare sequence variants (RSV) were conducted in 1025 probands with GnRH-deficient conditions.\nRESULTS: Fifteen probands harbored 10 heterozygous RSV in KISS1 seen in less than 1% of control subjects. Of the variants that reside within the mature kisspeptin peptide, p.F117L (but not p.S77I, p.Q82K, p.H90D, or p.P110T) reduces inositol phosphate generation. Of the variants that lie within the coding region but outside the mature peptide, p.G35S and p.C53R (but not p.A129V) are predicted in silico to be deleterious. Of the variants that lie outside the coding region, one (g.1-3659C→T) impairs transcription in vitro, and another (c.1-7C→T) lies within the consensus Kozak sequence. Of five probands tested, four had abnormal baseline LH pulse patterns. In mice, testosterone decreases with heterozygous loss of Kiss1 and Kiss1r alleles (wild-type, 274 ± 99, to double heterozygotes, 69 ± 16 ng/dl; r(2) = 0.13; P = 0.03). Kiss1/Kiss1r double-heterozygote males have shorter anogenital distances (13.0 ± 0.2 vs. 15.6 ± 0.2 mm at P34, P < 0.001), females have longer estrous cycles (7.4 ± 0.2 vs. 5.6 ± 0.2 d, P < 0.01), and mating pairs have decreased litter frequency (0.59 ± 0.09 vs. 0.71 ± 0.06 litters/month, P < 0.04) and size (3.5 ± 0.2 vs. 5.4 ± 0.3 pups/litter, P < 0.001) compared with wild-type mice.\nCONCLUSIONS: Deleterious, heterozygous RSV in KISS1 exist at a low frequency in GnRH-deficient patients as well as in the general population in presumably normal individuals. As in Kiss1(+/-)/Kiss1r(+/-) mice, heterozygous KISS1 variants in humans may work with other genetic and/or environmental factors to cause abnormal reproductive function.","variants":[{"Name":"NM_002256.4(KISS1):c.349T>C (p.Phe117Leu)","Chromosome":"1","Start":"204190552","Stop":"204190552","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1293370,"rule_based_match":false,"evidence_text":"p.F117L","llm_judgment":"PRESENT","evidence":"p.F117L","abstract_start":464,"abstract_end":471}]}
{"pmid":"23085272","title":"MODY 2: mutation identification and molecular ancestry in a Brazilian family.","abstract":"Maturity Onset Diabetes of the Young (MODY) is a heterogeneous group of genetic diseases characterized by a primary defect in insulin secretion and hyperglycemia, non-ketotic disease, monogenic autosomal dominant mode of inheritance, age at onset less than 25 years, and lack of auto-antibodies. It accounts for 2-5% of all cases of non-type 1 diabetes. MODY subtype 2 is caused by mutations in the glucokinase (GCK) gene. In this study, we sequenced the GCK gene of two volunteers with clinical diagnosis for MODY2 and we were able to identify four mutations including one for a premature stop codon (c.76C>T). Based on these results, we have developed a specific PCR-RFLP assay to detect this mutation and tested 122 related volunteers from the same family. This mutation in the GCK gene was detected in 21 additional subjects who also had the clinical features of this genetic disease. In conclusion, we identified new GCK gene mutations in a Brazilian family of Italian descendance, with one due to a premature stop codon located in the second exon of the gene. We also developed a specific assay that is fast, cheap and reliable to detect this mutation. Finally, we built a molecular ancestry model based on our results for the migration of individuals carrying this genetic mutation from Northern Italy to Brazil.","variants":[{"Name":"NM_000162.5(GCK):c.76C>T (p.Gln26Ter)","Chromosome":"7","Start":"44153433","Stop":"44153433","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44920,"rule_based_match":true,"evidence_text":"c.76C>T","llm_judgment":"PRESENT","evidence":"c.76C>T","abstract_start":602,"abstract_end":609}]}
{"pmid":"33159016","title":"Identification of novel","abstract":"Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons. More than 30 genes have been linked to ALS to date, including <i>FUS</i> and <i>TARDBP</i>, which exhibit similar roles in RNA metabolism. This study explored the use of high-resolution melting (HRM) analysis to screen for <i>FUS</i> and <i>TARDBP</i> mutation hotspot regions in 146 Chinese ALS patients, which achieved 100% detection. Two <i>FUS</i> mutations were observed in two different familial ALS probands, a missense mutation (p.R521H) and a novel splicing mutation (c.1541+1G>A). Five <i>TARDBP</i> mutations were identified in six ALS patients, including a novel 3'UTR mutation (c.*731A>G) and four missense mutations (p.G294V, p.M337V, p.G348V, and p.I383V). We found that <i>FUS</i> mutations were present in 1.4% of Chinese ALS patients, whereas <i>TARDBP</i> mutations were responsible for 4.1% of Chinese ALS cases. Here, we describe the accuracy of using highly sensitive HRM analysis to identify two novel <i>FUS</i> and <i>TARDBP</i> mutations in Chinese sporadic and familial ALS cases. Our study contributes to the further understanding of the genetic and phenotypic diversity of ALS.","variants":[{"Name":"NM_004960.4(FUS):c.1541+1G>A","Chromosome":"16","Start":"31191111","Stop":"31191111","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":851669,"rule_based_match":true,"evidence_text":"c.1541+1G>A","llm_judgment":"PRESENT","evidence":"c.1541+1G>A","abstract_start":596,"abstract_end":607}]}
{"pmid":"34846068","title":"Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants.","abstract":"PALB2 loss-of-function variants confer high risk of developing breast cancer. Here we present a systematic functional analysis of PALB2 splice-site variants detected in approximately 113,000 women in the large-scale sequencing project Breast Cancer After Diagnostic Gene Sequencing (BRIDGES; https://bridges-research.eu/). Eighty-two PALB2 variants at the intron-exon boundaries were analyzed with MaxEntScan. Forty-two variants were selected for the subsequent splicing functional assays. For this purpose, three splicing reporter minigenes comprising exons 1-12 were constructed. The 42 potential spliceogenic variants were introduced into the minigenes by site-directed mutagenesis and assayed in MCF-7/MDA-MB-231 cells. Splicing anomalies were observed in 35 variants, 23 of which showed no traces or minimal amounts of the expected full-length transcripts of each minigene. More than 30 different variant-induced transcripts were characterized, 23 of which were predicted to truncate the PALB2 protein. The pathogenicity of all variants was interpreted according to an in-house adaptation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) variant classification scheme. Up to 23 variants were classified as pathogenic/likely pathogenic. Remarkably, three ±1,2 variants (c.49-2A>T, c.108+2T>C, and c.211+1G>A) were classified as variants of unknown significance, as they produced significant amounts of either in-frame transcripts of unknown impact on the PALB2 protein function or the minigene full-length transcripts. In conclusion, we have significantly contributed to the ongoing effort of identifying spliceogenic variants in the clinically relevant PALB2 cancer susceptibility gene. Moreover, we suggest some approaches to classify the findings in accordance with the ACMG-AMP rationale. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.","variants":[{"Name":"NM_024675.4(PALB2):c.211+1G>A","Chromosome":"16","Start":"23637849","Stop":"23637849","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":484691,"rule_based_match":true,"evidence_text":"c.211+1G>A","llm_judgment":"PRESENT","evidence":"c.211+1G>A","abstract_start":1364,"abstract_end":1374},{"Name":"NM_024675.4(PALB2):c.49-2A>T","Chromosome":"16","Start":"23638131","Stop":"23638131","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":184302,"rule_based_match":true,"evidence_text":"c.49-2A>T","llm_judgment":"PRESENT","evidence":"c.49-2A>T","abstract_start":1337,"abstract_end":1346}]}
{"pmid":"32748564","title":"Severe reaction to radiotherapy provoked by hypomorphic germline mutations in ATM (ataxia-telangiectasia mutated gene).","abstract":"BACKGROUND: A minority of breast cancer (BC) patients suffer from severe reaction to adjuvant radiotherapy (RT). Although deficient DNA double-strand break repair is considered the main basis for the reactions, pretreatment identification of high-risk patients has been challenging.\nMETHODS: To retrospectively determine the etiology of severe local reaction to RT in a 39-year-old woman with BC, we performed next-generation sequencing followed by further clinical and functional studies.\nRESULTS: We found a -4 intronic variant (c.2251-4A>G) in trans with a synonymous (c.3576G>A) variant affecting the ATM DNA-repair gene (NG_009830.1, NM_000051.3) which is linked to autosomal recessive ataxia-telangiectasia (A-T). We verified abnormal transcripts resulting from both variants, next to a minor wild-type transcript leading to a residual ATM kinase activity and genomic instability. Follow-up examination of the patient revealed no classic sign of A-T but previously unnoticed head dystonia and mild dysarthria, a family history of BC and late-onset ataxia segregating with the variants. Additionally, her serum level of alpha-fetoprotein (AFP) was elevated similar to A-T patients.\nCONCLUSION: Considering the variable presentations of A-T and devastating impact of severe reactions to RT, we suggest a routine measurement of AFP in RT-candidate BC patients followed by next-generation sequencing with special attention to non-canonical splice site and synonymous variants in ATM.","variants":[{"Name":"NM_000051.4(ATM):c.3576G>A (p.Lys1192=)","Chromosome":"11","Start":"108281168","Stop":"108281168","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18074,"rule_based_match":true,"evidence_text":"c.3576G>A","llm_judgment":"PRESENT","evidence":"c.3576G>A","abstract_start":572,"abstract_end":581},{"Name":"NM_000051.4(ATM):c.2251-4A>G","Chromosome":"11","Start":"108257477","Stop":"108257477","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":183183,"rule_based_match":true,"evidence_text":"c.2251-4A>G","llm_judgment":"PRESENT","evidence":"c.2251-4A>G","abstract_start":531,"abstract_end":542}]}
{"pmid":"29949513","title":"Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR): clinical heterogeneity and long-term efficacious management of eight patients from four unrelated Arab families with a loss of function VDR mutation.","abstract":"BACKGROUND: Vitamin D regulates the concentrations of calcium and phosphate in blood and promotes the growth and remodeling of bones. The circulating active form of vitamin D, 1,25-dihydroxyvitamin D, binds to the vitamin D receptor (VDR), which heterodimerizes with the retinoid X receptor to regulate the expression of target genes. Inactivating mutations in the VDR gene cause hereditary vitamin D-resistant rickets (HVDRR), a rare disorder characterized by an early onset of rickets, growth retardation, skeletal deformities, hypocalcemia, hypophosphatemia and secondary hyperparathyroidism, and in some cases alopecia.\nMETHODS: We describe eight new HVDRR patients from four unrelated consanguineous families. The VDR gene was sequenced to identify mutations. The management of patients over a period of up to 11 years following the initial diagnosis is assessed.\nRESULTS: Although all patients exhibit main features of HVDRR and carry the same c.885C>A (p.Y295*) loss of function mutation in the VDR gene, there was heterogeneity of the manifestations of HVDRR-associated phenotypes and developmental milestones. These eight patients were successfully treated over a period of 11 years. All clinical symptoms were improved except alopecia.\nCONCLUSIONS: The study concludes that VDR sequencing and laboratory tests are essential to confirm HVDRR and to assess the effectiveness of the treatment.","variants":[{"Name":"NM_000376.3(VDR):c.885C>A (p.Tyr295Ter)","Chromosome":"12","Start":"47846679","Stop":"47846679","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":22786,"rule_based_match":true,"evidence_text":"c.885C>A (p.Y295*)","llm_judgment":"PRESENT","evidence":"c.885C>A (p.Y295*)","abstract_start":950,"abstract_end":968}]}
{"pmid":"29706633","title":"A pathogenic role for germline PTEN variants which accumulate into the nucleus.","abstract":"The PTEN gene encodes a master regulator protein that exerts essential functions both in the cytoplasm and in the nucleus. PTEN is mutated in the germline of both patients with heterogeneous tumor syndromic diseases, categorized as PTEN hamartoma tumor syndrome (PHTS), and a group affected with autism spectrum disorders (ASD). Previous studies have unveiled the functional heterogeneity of PTEN variants found in both patient cohorts, making functional studies necessary to provide mechanistic insights related to their pathogenicity. Here, we have functionally characterized a PTEN missense variant [c.49C>G; p.(Gln17Glu); Q17E] associated to both PHTS and ASD patients. The PTEN Q17E variant displayed partially reduced PIP3-catalytic activity and normal stability in cells, as shown using S. cerevisiae and mammalian cell experimental models. Remarkably, PTEN Q17E accumulated in the nucleus, in a process involving the PTEN N-terminal nuclear localization sequence. The analysis of additional germline-associated PTEN N-terminal variants illustrated the existence of a PTEN N-terminal region whose targeting in disease causes PTEN nuclear accumulation, in parallel with defects in PIP3-catalytic activity in cells. Our findings highlight the frequent occurrence of PTEN gene mutations targeting PTEN N-terminus whose pathogenicity may be related, at least in part, with the retention of PTEN in the nucleus. This could be important for the implementation of precision therapies for patients with alterations in the PTEN pathway.","variants":[{"Name":"NM_000314.8(PTEN):c.49C>G (p.Gln17Glu)","Chromosome":"10","Start":"87864518","Stop":"87864518","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":475447,"rule_based_match":true,"evidence_text":"c.49C>G; p.(Gln17Glu); Q17E","llm_judgment":"PRESENT","evidence":"c.49C>G; p.(Gln17Glu); Q17E","abstract_start":603,"abstract_end":630}]}
{"pmid":"31566927","title":"Renal globotriaosylceramide deposits for Fabry disease linked to uncertain pathogenicity gene variant c.352C>T/p.Arg118Cys: A family study.","abstract":"BACKGROUND: Fabry disease (FD) has an extensive phenotypic expression associated with GLA gene variants. The GLA gene variant c.352C>T/p.Arg118Cys was considered with uncertain pathogenicity because of the finding of high residual alpha-galactosidase A (α-Gal A) enzyme activity, the absence of Mendelian segregation with an FD phenotype with many individuals remaining asymptomatic at old ages and the lack of globotriaosylceramide (Gb3) deposits in tissues. Gb3 deposits are found in kidneys before the progression to overt microalbuminuria and decreased glomerular filtration.\nMETHODS: We describe a family with c.352C>T/p.Arg118Cys variant and pathognomonic signs of FD renal damage in masculine children.\nRESULTS: The proband died of end-stage renal failure and we analyzed GLA gene in his offspring and found the variant in all daughters and five of seven grandchildren. In patients who we measure plasma and urinary Gb3, α-Gal A enzyme activity, and plasma globotriaosylsphingosine (Lyso-Gb3), these were normal or almost normal. A kidney biopsy was performed in two boys and one girl with normal renal function and characteristic signs of FD as enlarged and vacuolated epithelial cells, myelin figures, myelin-like figures, lamellated structures in podocytes and endothelial cells, were found in boys. These boys received agalsidase beta 1 mg/kg IV infusion every other week to prevent further renal damage.\nCONCLUSION: This is the first report that shows a link between FD renal Gb3 deposits and c.352C>T/p.Arg118Cys variant, supporting pathogenicity of a variant considered until now with uncertain pathogenicity.","variants":[{"Name":"NM_000169.3(GLA):c.352C>T (p.Arg118Cys)","Chromosome":"X","Start":"101403828","Stop":"101403828","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":51624,"rule_based_match":true,"evidence_text":"c.352C>T/p.Arg118Cys","llm_judgment":"PRESENT","evidence":"c.352C>T/p.Arg118Cys","abstract_start":126,"abstract_end":146}]}
{"pmid":"19306328","title":"Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract.","abstract":"Congenital cataracts (CCs) are clinically and genetically heterogeneous. Mutations in the same gene may lead to CCs differing in inheritance, morphology and severity. Loci for autosomal dominant posterior polar CC and total CC have both been mapped to the chromosomal 1p36 region harboring the EPHA2 receptor tyrosine kinase gene. Here, we report mutations of EPHA2 in three CC families from different ancestral groups. In a Chinese family with posterior polar CC, we identified a missense mutation, c.2819C>T (p.T940I), replacing a critical amino acid that functions at the receptor oligomerization interface. In a British family with posterior polar CC and an Australian family with total CC, we found a frameshift mutation (c.2915_2916delTG) and a splicing mutation (c.2826-9G>A), respectively. These two mutations are predicted to produce novel C-terminal polypeptides with 39 identical amino acids. Yeast two-hybrid analysis showed stronger interaction between the total CC-associated mutant EPHA2 and low molecular weight protein-tyrosine phosphatase, a negative regulator of EPHA2 signaling. Our results implicate the Eph-ephrin signaling system in development of human cataract and provide a novel insight into the molecular mechanism underlying the pathogenesis of human CCs.","variants":[{"Name":"NM_004431.5(EPHA2):c.2819C>T (p.Thr940Ile)","Chromosome":"1","Start":"16129440","Stop":"16129440","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28298,"rule_based_match":true,"evidence_text":"c.2819C>T (p.T940I)","llm_judgment":"PRESENT","evidence":"c.2819C>T (p.T940I)","abstract_start":500,"abstract_end":519},{"Name":"NM_004431.5(EPHA2):c.2826-9G>A","Chromosome":"1","Start":"16125329","Stop":"16125329","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":263955,"rule_based_match":true,"evidence_text":"c.2826-9G>A","llm_judgment":"PRESENT","evidence":"c.2826-9G>A","abstract_start":770,"abstract_end":781},{"Name":"NM_004431.5(EPHA2):c.2915_2916del (p.Val972fs)","Chromosome":"1","Start":"16125230","Stop":"16125231","ReferenceAlleleVCF":"CCA","AlternateAlleleVCF":"C","allel_id":822930,"rule_based_match":true,"evidence_text":"c.2915_2916delTG","llm_judgment":"PRESENT","evidence":"c.2915_2916delTG","abstract_start":727,"abstract_end":743}]}
{"pmid":"24808020","title":"Expanding sialidosis spectrum by genome-wide screening: NEU1 mutations in adult-onset myoclonus.","abstract":"OBJECTIVE: To identify the genetic cause of a familial form of late-onset action myoclonus in 2 unrelated patients. Both probands had 2 siblings displaying a similar disorder. Extensive laboratory examinations, including biochemical assessment for urine sialic acid in the 2 probands, were negative.\nMETHODS: Exome sequencing was performed in the probands using an Illumina platform. Segregation analysis of putative mutations was performed in all family members by standard Sanger sequencing protocols.\nRESULTS: NEU1 mutations were detected in 3 siblings of each family with prominent cortical myoclonus presenting in the third decade of life and having a mild and slowly progressive course. They did not have macular cherry-red spot and their urinary sialic acid excretion was within normal values. Genetic analysis demonstrated a homozygous mutation in family 1 (c.200G>T, p.S67I) and 2 compound heterozygous mutations in family 2 (c.679G>A, p.G227R; c.913C>T, p.R305C).\nCONCLUSIONS: Our observation indicates that sialidosis should be suspected and the NEU1 gene analyzed in patients with isolated action myoclonus presenting in adulthood in the absence of other typical clinical and laboratory findings.","variants":[{"Name":"NM_000434.4(NEU1):c.913C>T (p.Arg305Cys)","Chromosome":"6","Start":"31860150","Stop":"31860150","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2904746,"rule_based_match":true,"evidence_text":"c.913C>T, p.R305C","llm_judgment":"PRESENT","evidence":"c.913C>T, p.R305C","abstract_start":954,"abstract_end":971},{"Name":"NM_000434.4(NEU1):c.679G>A (p.Gly227Arg)","Chromosome":"6","Start":"31860558","Stop":"31860558","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":421583,"rule_based_match":true,"evidence_text":"c.679G>A","llm_judgment":"PRESENT","evidence":"c.679G>A","abstract_start":935,"abstract_end":943}]}
{"pmid":"35621276","title":"A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families.","abstract":"Mitochondrial complex V plays an important role in oxidative phosphorylation by catalyzing the generation of ATP. Most complex V subunits are nuclear encoded and not yet associated with recognized Mendelian disorders. Using exome sequencing, we identified a rare homozygous splice variant (c.87+3A>G) in ATP5PO, the complex V subunit which encodes the oligomycin sensitivity conferring protein, in three individuals from two unrelated families, with clinical suspicion of a mitochondrial disorder. These individuals had a similar, severe infantile and often lethal multi-systemic disorder that included hypotonia, developmental delay, hypertrophic cardiomyopathy, progressive epileptic encephalopathy, progressive cerebral atrophy, and white matter abnormalities on brain MRI consistent with Leigh syndrome. cDNA studies showed a predominant shortened transcript with skipping of exon 2 and low levels of the normal full-length transcript. Fibroblasts from the affected individuals demonstrated decreased ATP5PO protein, defective assembly of complex V with markedly reduced amounts of peripheral stalk proteins, and complex V hydrolytic activity. Further, expression of human ATP5PO cDNA without exon 2 (hATP5PO-∆ex2) in yeast cells deleted for yATP5 (ATP5PO homolog) was unable to rescue growth on media which requires oxidative phosphorylation when compared to the wild type construct (hATP5PO-WT), indicating that exon 2 deletion leads to a non-functional protein. Collectively, our findings support the pathogenicity of the ATP5PO c.87+3A>G variant, which significantly reduces but does not eliminate complex V activity. These data along with the recent report of an affected individual with ATP5PO variants, add to the evidence that rare biallelic variants in ATP5PO result in defective complex V assembly, function and are associated with Leigh syndrome.","variants":[{"Name":"NM_001697.3(ATP5PO):c.87+3A>G","Chromosome":"21","Start":"33914447","Stop":"33914447","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":965916,"rule_based_match":true,"evidence_text":"c.87+3A>G","llm_judgment":"PRESENT","evidence":"c.87+3A>G","abstract_start":290,"abstract_end":299}]}
{"pmid":"16291504","title":"Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations.","abstract":"The fatty acid oxidation disorder most commonly identified by tandem mass spectrometry newborn screening is the potentially fatal medium-chain acyl-CoA dehydrogenase deficiency (MCAD). In clinically presenting cases, 80% are homozygous for the common mutation, c.985A > G and 18% heterozygous. We screened 592,785 babies and identified 34 with MCAD, 17 homozygous for c.985A > G, 14 with one copy, and 3 with no copy. We sequenced the exons of 19 patients, the 17 carrying one or no copy of c.985A > G, and two with marginal findings, and examined correlations between groups of mutations and biochemical markers. We found two known or putative pathogenic mutations in 18 of the 19 patients. Two mutations appeared more than once: c.199T > C, not recorded in clinically presenting cases (n = 4), and c.583G > A (n = 2). Patients homozygous for c.985A > G had the highest levels of neonatal octanoylcarnitine, plasma octanoylcarnitine when asymptomatic, and urinary acylglycines. Compound heterozygotes of c.985A > G and other mutations had intermediate levels, and those without c.985A > G, or heterozygous for that and c.199T > C had the lowest levels of these analytes. There was overlap in all values. The c.985A > G and c.583G > A mutations appear to have functional effects towards the severe end of the spectrum, and the c.199T > C mutation a smaller effect, as has been previously postulated. If these results are confirmed and extended, this could influence the advice given to parents of babies with MCAD detected by newborn screening, and make management more specific. In the meantime, all MCAD patients identified by newborn screening have, by definition, a functional defect and require careful clinical management.","variants":[{"Name":"NM_000016.6(ACADM):c.985A>G (p.Lys329Glu)","Chromosome":"1","Start":"75761161","Stop":"75761161","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18625,"rule_based_match":true,"evidence_text":"c.985A > G","llm_judgment":"PRESENT","evidence":"c.985A > G","abstract_start":261,"abstract_end":271},{"Name":"NM_000016.6(ACADM):c.583G>A (p.Gly195Arg)","Chromosome":"1","Start":"75740094","Stop":"75740094","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18633,"rule_based_match":true,"evidence_text":"c.583G > A (n = 2)","llm_judgment":"PRESENT","evidence":"c.583G > A (n = 2)","abstract_start":800,"abstract_end":818},{"Name":"NM_000016.6(ACADM):c.199T>C (p.Tyr67His)","Chromosome":"1","Start":"75732724","Stop":"75732724","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":18636,"rule_based_match":true,"evidence_text":"c.199T > C","llm_judgment":"PRESENT","evidence":"c.199T > C","abstract_start":731,"abstract_end":741}]}
{"pmid":"24675553","title":"Ribosomal protein mutations in Korean patients with Diamond-Blackfan anemia.","abstract":"Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by hypoproliferative anemia, associated physical malformations and a predisposition to cancer. DBA has been associated with mutations and deletions in the large and small ribosomal protein genes, and genetic aberrations have been detected in ∼50-60% of patients. In this study, nine Korean DBA patients were screened for mutations in eight known DBA genes (RPS19, RPS24, RPS17, RPS10, RPS26, RPL35A, RPL5 and RPL11) using the direct sequencing method. Mutations in RPS19, RPS26 and RPS17 were detected in four, two and one patient, respectively. Among the mutations detected in RPS19, two mutations were novel (c.26T>A, c.357-2A>G). For the mutation-negative cases, array-CGH analysis was performed to identify copy-number variations, and no deletions involving the known DBA gene regions were identified. The relative mRNA expression of RPS19 estimated using real-time quantitative PCR analysis revealed two- to fourfold reductions in RPS19 mRNA expression in three patients with RPS19 mutations, and p53 protein expression analysis by immunohistochemistry showed variable but significant nuclear staining in the DBA patients. In conclusion, heterozygous mutations in the known DBA genes RPS19, RPS26 and RPS17 were detected in seven out of nine Korean DBA patients. Among these patients, RPS19 was the most frequently mutated gene. In addition, decreased RPS19 mRNA expression and p53 overexpression were observed in the Korean DBA patients, which supports the hypothesis that haploinsufficiency and p53 hyperactivation represent a central pathway underlying the pathogenesis of DBA.","variants":[{"Name":"NM_001022.4(RPS19):c.357-2A>G","Chromosome":"19","Start":"41869697","Stop":"41869697","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2905469,"rule_based_match":true,"evidence_text":"c.357-2A>G","llm_judgment":"PRESENT","evidence":"c.357-2A>G","abstract_start":709,"abstract_end":719}]}
{"pmid":"28830375","title":"A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome.","abstract":"BACKGROUND: Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically.\nCASE PRESENTATION: We reported a consanguineous family (two affected sisters) with Perrault syndrome. The proband had the characteristics of Perrault syndrome: ovarian dysgenesis, bilateral hearing loss and obvious neurological signs. Target genetic sequencing and triplet repeat primed PCR (TP-PCR) plus capillary electrophoresis was conducted to detect causative mutations in the proband. The detected variant was further confirmed in the proband and tested in other family members by Sanger sequencing. Both the proband and her sister were found homozygous for the novel variant HSD17B4 c.298G > T (p.A100S) with their parents heterozygous. Detected by western blot, the protein expression of HSD17B4 mutant was much lower than that of the wild type in SH-SY5Y cells transfected by HSD17B4 wild type or mutant plasmid, which indicated the pathogenicity of the HSD17B4 mutation.\nCONCLUSIONS: Our findings supported that HSD17B4 was one of the genes contributing to Perrault syndrome with the likely pathogenic variant c.298G > T (p.A100S). Special manifestations of cerebellar impairment were found in cases caused by HSD17B4 mutations. Besides, attention should be paid to distinguish Perrault syndrome from D-bifunctional protein deficiency and hereditary ataxia.","variants":[{"Name":"NM_000414.4(HSD17B4):c.298G>T (p.Ala100Ser)","Chromosome":"5","Start":"119475723","Stop":"119475723","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":543645,"rule_based_match":true,"evidence_text":"c.298G > T (p.A100S)","llm_judgment":"PRESENT","evidence":"c.298G > T (p.A100S)","abstract_start":848,"abstract_end":868}]}
{"pmid":"21712857","title":"Identification of a Gypsy SHOX mutation (p.A170P) in Léri-Weill dyschondrosteosis and Langer mesomelic dysplasia.","abstract":"We report the clinical and molecular characteristics of 12 Spanish families with multiple members affected with Léri-Weill dyschondrosteosis (LWD) or Langer mesomelic dysplasia (LMD), who present the SHOX (short stature homeobox gene) mutation p.A170P (c.508G>C) in heterozygosity or homozygosity, respectively. In all studied families, the A170P mutation co-segregated with the fully penetrant phenotype of mesomelic limb shortening and Madelung deformity. A shared haplotype around SHOX was observed by microsatellite analysis, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the families were of this ethnic group. Mutation screening in 359 Eastern-European Gypsies failed to identify any carriers. For the first time, we have shown SHOX expression in the human growth plate of a 22-week LMD fetus, homozygous for the A170P mutation. Although the mutant SHOX protein was expressed in all zones of the growth plate, the chondrocyte columns in the proliferative zone were disorganized with the chondrocytes occurring in smaller columnal clusters. We have also identified a novel mutation at the same residue, c. 509C>A (p.A170D), in two unrelated Spanish LWD families, which similar to A170P mutation impedes nuclear localization of SHOX. In conclusion, we have identified A170P as the first frequent SHOX mutation in Gypsy LWD and LMD individuals.","variants":[{"Name":"NM_000451.4(SHOX):c.508G>C (p.Ala170Pro)","Chromosome":"X","Start":"640842","Stop":"640842","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":38949,"rule_based_match":true,"evidence_text":"c.508G>C (p.Ala170Pro)","llm_judgment":"PRESENT","evidence":"c.508G>C","abstract_start":253,"abstract_end":261},{"Name":"NM_000451.4(SHOX):c.509C>A (p.Ala170Asp)","Chromosome":"X","Start":"640843","Stop":"640843","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":38950,"rule_based_match":true,"evidence_text":"c. 509C>A (p.A170D)","llm_judgment":"PRESENT","evidence":"c. 509C>A (p.A170D)","abstract_start":1143,"abstract_end":1162}]}
{"pmid":"23667851","title":"A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer.","abstract":"Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various early-onset tumors. Since the introduction of classic LFS criteria, various criteria have been proposed to include patients with incomplete LFS features, which make up Li-Fraumeni-like syndromes (LFL). Germline missense mutations of TP53 are the primary cause of LFS and LFL. Mutations mostly reside in the DNA-binding domain of the gene and have a dominant-negative effect (DNE) over alternate wild-type alleles. Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V) and has been reported in a case of multiple primary colon tumors. Herein we report a second case of the same mutation in a breast cancer patient, who has familial history of late-onset malignancies. Due to the relatively late onset of malignancies, neither case fulfils previously defined criteria for the syndrome. Mutational analysis for breast tissue in this patient showed a loss of heterozygosity. These clinical features may suggest a relatively weak DNE of A189V compared to other TP53 mutations, and in silico predictions and in vitro findings of the function of A189V mutant protein are conflicting. Considering the increased risk of malignancies and the therapeutic implications for patients who have a TP53 mutation, care must be taken when treating those who are suspected of possessing cancer-prone traits due to TP53 mutation, especially when there is a family history of late-onset cancer with low penetrance.","variants":[{"Name":"NM_000546.6(TP53):c.566C>T (p.Ala189Val)","Chromosome":"17","Start":"7674965","Stop":"7674965","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27421,"rule_based_match":true,"evidence_text":"Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V)","llm_judgment":"PRESENT","evidence":"Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V)","abstract_start":513,"abstract_end":621}]}
{"pmid":"26647175","title":"Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?","abstract":"We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism. In an 8-year old female with an early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy, a previously unreported de novo missense mutation was identified in SCN8A (c.5615G>A; p.Arg1872Gln), affecting a highly conserved residue located in the C-terminal of the Nav1.6 protein. Aside from decreased homovanillic acid and 5-hydroxyindoleacetic acid, 5-methyltetrahydrofolate was also found to be low. We hypothesize that these channelopathies cause abnormal synaptic mono-amine metabolite secretion/uptake via impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures. Treatment with oral 5-hydroxytryptophan, l-Dopa/Carbidopa, and a dopa agonist resulted in mild improvement of seizure control in the male case, most likely via dopamine and serotonin receptor activated signal transduction and modulation of glutamatergic, GABA-ergic and glycinergic neurotransmission. Neurotransmitter analysis in other sodium channelopathy patients will help validate our findings, potentially yielding novel treatment opportunities.","variants":[{"Name":"NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln)","Chromosome":"12","Start":"51807101","Stop":"51807101","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247729,"rule_based_match":true,"evidence_text":"c.5615G>A; p.Arg1872Gln","llm_judgment":"PRESENT","evidence":"c.5615G>A; p.Arg1872Gln","abstract_start":933,"abstract_end":956}]}
{"pmid":"19438932","title":"Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.","abstract":"Mutations in the LEMD3 gene were recently incriminated in Buschke-Ollendorff syndrome (BOS) and osteopoikilosis, with or without melorheostosis. The relationship of this gene with isolated sporadic melorheostosis is less clear. We investigated LEMD3 in a two-generation BOS family showing an extremely variable expression of the disease, in a sporadic patient with skin features of BOS, and in an additional subject with isolated melorheostosis. We identified two different mutations, both resulting in a premature stop codon, in the two cases of BOS. The mutation (c.2564G>A) reported in the familial case is novel, while that observed in the sporadic case (c.1963C>T) has been previously reported in an American woman with osteopoikilosis and melorheostosis who had a family history of isolated osteopoikilosis. The search for mutations in DNA extracted from the peripheral blood, as well as skin and bone biopsies of the patient with melorheostosis failed to identify any pathogenic change. Our results further expand the LEMD3 mutation repertoire, corroborate the extreme interfamilial and intrafamilial clinical variability of LEMD3 mutations, and underline the lack of a clear phenotype-genotype correlation in BOS. The present study supports the general conclusion that LEMD3 mutations do not contribute to isolated sporadic melorheostosis. The genetic or epigenetic influences that are responsible for the development of melorheostosis require further investigation.","variants":[{"Name":"NM_014319.5(LEMD3):c.2564G>A (p.Trp855Ter)","Chromosome":"12","Start":"65245931","Stop":"65245931","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17797,"rule_based_match":true,"evidence_text":"c.2564G>A","llm_judgment":"PRESENT","evidence":"c.2564G>A","abstract_start":566,"abstract_end":575},{"Name":"NM_014319.5(LEMD3):c.1963C>T (p.Arg655Ter)","Chromosome":"12","Start":"65239970","Stop":"65239970","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17798,"rule_based_match":true,"evidence_text":"c.1963C>T","llm_judgment":"PRESENT","evidence":"c.1963C>T","abstract_start":659,"abstract_end":668}]}
{"pmid":"30729724","title":"Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders.","abstract":"BACKGROUND: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood.\nMETHODS: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations.\nRESULTS: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain.\nCONCLUSIONS: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.","variants":[{"Name":"NM_005120.3(MED12):c.3884G>A (p.Arg1295His)","Chromosome":"X","Start":"71130051","Stop":"71130051","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":512737,"rule_based_match":true,"evidence_text":"c.3884G>A; p.R1295H","llm_judgment":"PRESENT","evidence":"c.3884G>A; p.R1295H","abstract_start":923,"abstract_end":942},{"Name":"NM_005120.3(MED12):c.2692A>G (p.Asn898Asp)","Chromosome":"X","Start":"71126975","Stop":"71126975","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1200237,"rule_based_match":true,"evidence_text":"c.2692A>G; p.N898D","llm_judgment":"PRESENT","evidence":"c.2692A>G; p.N898D","abstract_start":878,"abstract_end":896},{"Name":"NM_005120.3(MED12):c.3640C>T (p.Arg1214Cys)","Chromosome":"X","Start":"71129378","Stop":"71129378","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":964630,"rule_based_match":true,"evidence_text":"c.3640C>T; p.R1214C","llm_judgment":"PRESENT","evidence":"c.3640C>T; p.R1214C","abstract_start":898,"abstract_end":917}]}
{"pmid":"18549403","title":"Founder effect and estimation of the age of the c.892C>T (p.Arg298Cys) mutation in LMNA associated to Charcot-Marie-Tooth subtype CMT2B1 in families from North Western Africa.","abstract":"CMT2B1, an axonal subtype (MIM 605588) of the Charcot-Marie-Tooth disease, is an autosomal recessive motor and sensory neuropathy characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness. The genetic defect associated with the disease is, to date, a unique homozygous missense mutation, p.Arg298Cys (c.892C>T), in the LMNA gene. So far, this mutation has only been found in affected individuals originating from a restricted region of North Western Africa (northwest of Algeria and east of Morocco), strongly suggesting a founder effect. In order to address this hypothesis, genotyping of both STRs and intragenic SNPs was performed at the LMNA locus, at chromosome 1q21.2-q21.3, in 42 individuals affected with CMT2B1 from 25 Algerian families. Our results indicate that the affected individuals share a common ancestral haplotype in a region of about 1.0 Mb (1 cM) and that the most recent common ancestor would have lived about 800-900 years ago (95% confidence interval: 550 to 1300 years).","variants":[{"Name":"NM_170707.4(LMNA):c.892C>T (p.Arg298Cys)","Chromosome":"1","Start":"156135268","Stop":"156135268","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29537,"rule_based_match":true,"evidence_text":"p.Arg298Cys (c.892C>T)","llm_judgment":"PRESENT","evidence":"p.Arg298Cys (c.892C>T)","abstract_start":340,"abstract_end":362}]}
{"pmid":"15671102","title":"Childhood hypophosphatasia due to a de novo missense mutation in the tissue-nonspecific alkaline phosphatase gene.","abstract":"Hypophosphatasia is an inherited disorder due to mutations in the bone alkaline phosphatase (ALPL) gene. We report here a patient with childhood hypophosphatasia diagnosed at 1.4 yr because of pectus excavatum, large anterior fontanel, rachitic skeletal changes, and low serum alkaline phosphatase. Sequencing of the ALPL gene produced evidence of two distinct missense mutations, E174K (c.571G>A), of maternal origin, and a de novo mutation, M45I (c.186G>C). The study of various microsatellite polymorphisms ruled out false paternity and therefore confirmed that M45I occurred de novo in the paternal germline or in the early development of the patient. Site-directed mutagenesis showed that M45I results in the absence of in vitro alkaline phosphatase activity, suggesting that the mutation is a severe allele. In conclusion, childhood hypophosphatasia in this patient is the result of compound heterozygosity for the moderate mutation E174K and a novel severe de novo mutation M45I.","variants":[{"Name":"NM_000478.6(ALPL):c.571G>A (p.Glu191Lys)","Chromosome":"1","Start":"21564139","Stop":"21564139","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28709,"rule_based_match":true,"evidence_text":"c.571G>A","llm_judgment":"PRESENT","evidence":"c.571G>A","abstract_start":388,"abstract_end":396}]}
{"pmid":"27345729","title":"Expanding the genotypic spectrum of CCBE1 mutations in Hennekam syndrome.","abstract":"Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder, with 25% of patients having mutations in CCBE1. We identified a family with two brothers presenting with primary lymphedema, and performed exome sequencing to determine the cause of their disease. Analysis of four family members showed that both affected brothers had the same rare compound heterozygous mutations in CCBE1. The presumed paternally inherited NM_133459.3:c.310G>A; p.(Asp104Asn), lies adjacent to other known pathogenic CCBE1 mutations, while the maternally inherited NM_133459.3:c.80T>C; p.(Leu27Pro) lies in the CCBE1 signal peptide, which has not previously been associated with disease. Functional analysis in a zebrafish model of lymphatic disease showed that both mutations lead to CCBE1 loss of function, confirming the pathogenicity of these variants and expanding the genotypic spectrum of lymphatic disorders. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_133459.4(CCBE1):c.310G>A (p.Asp104Asn)","Chromosome":"18","Start":"59469563","Stop":"59469563","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1336209,"rule_based_match":true,"evidence_text":"NM_133459.3:c.310G>A; p.(Asp104Asn)","llm_judgment":"PRESENT","evidence":"NM_133459.3:c.310G>A; p.(Asp104Asn)","abstract_start":440,"abstract_end":475}]}
{"pmid":"31155284","title":"Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification.","abstract":"Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl<sup>-</sup>/H<sup>+</sup> exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.","variants":[{"Name":"NM_001287.6(CLCN7):c.2144A>G (p.Tyr715Cys)","Chromosome":"16","Start":"1447498","Stop":"1447498","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":360150,"rule_based_match":true,"evidence_text":"c.2144A>G","llm_judgment":"PRESENT","evidence":"c.2144A>G","abstract_start":569,"abstract_end":578}]}
{"pmid":"34585832","title":"Bi-allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families.","abstract":"Exome and genome sequencing were used to identify the genetic etiology of a severe neurodevelopmental disorder in two unrelated Ashkenazi Jewish families with three affected individuals. The clinical findings included a prenatal presentation of microcephaly, polyhydramnios and clenched hands while postnatal findings included microcephaly, severe developmental delay, dysmorphism, neurologic deficits, and death in infancy. A shared rare homozygous, missense variant (c.274A > G; p.Ser92Gly, NM_024516.4) was identified in PAGR1, a gene currently not associated with a Mendelian disease. PAGR1 encodes a component of the histone methyltransferase MLL2/MLL3 complex and may function in the DNA damage response pathway. Complete knockout of the murine Pagr1a is embryonic-lethal. Given the available evidence, PAGR1 is a strong candidate gene for a novel autosomal recessive severe syndromic neurodevelopmental disorder.","variants":[{"Name":"NM_024516.4(PAGR1):c.274A>G (p.Ser92Gly)","Chromosome":"16","Start":"29816799","Stop":"29816799","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1161865,"rule_based_match":true,"evidence_text":"c.274A > G; p.Ser92Gly, NM_024516.4","llm_judgment":"PRESENT","evidence":"c.274A > G; p.Ser92Gly, NM_024516.4","abstract_start":469,"abstract_end":504}]}
{"pmid":"33848270","title":"Base editing repairs an SGCA mutation in human primary muscle stem cells.","abstract":"Skeletal muscle can regenerate from muscle stem cells and their myogenic precursor cell progeny, myoblasts. However, precise gene editing in human muscle stem cells for autologous cell replacement therapies of untreatable genetic muscle diseases has not yet been reported. Loss-of-function mutations in SGCA, encoding α-sarcoglycan, cause limb-girdle muscular dystrophy 2D/R3, an early-onset, severe, and rapidly progressive form of muscular dystrophy affecting both male and female patients. Patients suffer from muscle degeneration and atrophy affecting the limbs, respiratory muscles, and heart. We isolated human muscle stem cells from 2 donors, with the common SGCA c.157G>A mutation affecting the last coding nucleotide of exon 2. We found that c.157G>A is an exonic splicing mutation that induces skipping of 2 coregulated exons. Using adenine base editing, we corrected the mutation in the cells from both donors with > 90% efficiency, thereby rescuing the splicing defect and α-sarcoglycan expression. Base-edited patient cells regenerated muscle and contributed to the Pax7+ satellite cell compartment in vivo in mouse xenografts. Here, we provide the first evidence to our knowledge that autologous gene-repaired human muscle stem cells can be harnessed for cell replacement therapies of muscular dystrophies.","variants":[{"Name":"NM_000023.4(SGCA):c.157G>A (p.Ala53Thr)","Chromosome":"17","Start":"50167487","Stop":"50167487","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":266096,"rule_based_match":true,"evidence_text":"SGCA c.157G>A","llm_judgment":"PRESENT","evidence":"SGCA c.157G>A","abstract_start":666,"abstract_end":679}]}
{"pmid":"36250278","title":"Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord.","abstract":"ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associated with Wieacker-Wolff syndrome (MIM# 314580), an X-linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish zc4h2 null mutants recapitulated the human phenotype, showed complete loss of vsx2 expression in brain, and exhibited abnormal swimming and balance problems. Here we report 7 new patients (four males and three females) with ZC4H2-related disorder from six unrelated families. Four of the 6 ZC4H2 variants are novel: three missense variants, designated as c.142T>A (p.Tyr48Asn), c.558G>A (p.Met186Ile) and c.602C>T (p.Pro201Leu), and a nonsense variant, c.618C>A (p.Cys206*). Two variants were previously reported : a nonsense variant c.199C>T (p.Arg67*) and a splice site variant (c.225+5G>A). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under-recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human ZC4H2 wild-type or variant mRNAs into zc4h2 null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue vsx2 expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with ZC4H2-related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of ZC4H2 variants.","variants":[{"Name":"NM_018684.4(ZC4H2):c.225+5G>A","Chromosome":"X","Start":"64921812","Stop":"64921812","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":380136,"rule_based_match":true,"evidence_text":"c.225+5G>A","llm_judgment":"PRESENT","evidence":"c.225+5G>A","abstract_start":1082,"abstract_end":1092}]}
{"pmid":"29410950","title":"","abstract":"Pontocerebellar hypoplasia (PCH) type 2 is a very rare autosomal recessive neurodegenerative disorder with prenatal onset that disrupts brain development. We present three patients (two siblings and one unrelated child) with PCH 2 linked to the most common mutation c.919G > T (p.Ala307Ser) in <i>TSEN54</i> gene. The disease started soon after birth with feeding difficulties, extrapyramidal symptoms, psychomotor retardation, progressive microcephaly. Two of the patients were diagnosed with dyskinetic cerebral palsy (CP) at first. Despite the neurodegenerative character of PCH 2, the absence of regression and even some developmental progress in few patients, might erroneously lead to the incorrect diagnosis of dyskinetic CP. Megacisterna magna on brain ultrasound makes the diagnosis of PCH 2 highly probable and should prompt further imaging with MRI. MRI findings of PCH are pivotal for the diagnosis. Genetic testing for the most common mutation in <i>TSEN54</i> gene should also be performed. Correct diagnosis of PCH 2 is essential not only for the prognosis of the patient, but also for prenatal diagnosis in future pregnancies. Knowledge of the clinical picture of PCH 2 will lead to correct and timely diagnosis. Advanced neuroimaging procedures and molecular genetic techniques provide valuable tools for prompt diagnosis of rare, but clinically important, neurogenetic imitators of CP.","variants":[{"Name":"NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser)","Chromosome":"17","Start":"75522000","Stop":"75522000","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":17159,"rule_based_match":true,"evidence_text":"c.919G > T (p.Ala307Ser)","llm_judgment":"PRESENT","evidence":"c.919G > T (p.Ala307Ser)","abstract_start":266,"abstract_end":290}]}
{"pmid":"18172693","title":"Nonsense-mediated messenger RNA decay of survival motor neuron 1 causes spinal muscular atrophy.","abstract":"Autosomal recessive proximal spinal muscular atrophy (SMA) is a neurodegenerative disorder resulting from functional loss of survival motor neuron 1 (SMN1). Homozygous absence of SMN1 due to deletion or gene conversion accounts for about 96% of SMA cases. In the remaining 4%, subtle SMN1 mutations are commonly identified. Here, we describe two novel intragenic SMN1 mutations in three type I SMA individuals: a point mutation in exon 3 (c.469C > T) and a substitution in intron 4 (c.628-140A > G). In-vivo splicing assays demonstrated that the intronic substitution creates a novel splice donor site, culminating in aberrant splicing and insertion of 65 bp from intron 4 between exons 4 and 5 in SMN1 transcripts (c.627_628ins65). Both mutations render SMN1 transcripts susceptible to nonsense-mediated mRNA decay (NMD), resulting in mRNA degradation, insufficient SMN protein levels and development of an SMA phenotype. Treatment of patient cell lines with the translation inhibitors puromycin and emetine markedly increased the levels of mutant SMN1 transcripts. A similar effect was observed after siRNA-mediated knockdown of UPF1, a factor essential for NMD. This study provides first evidence that NMD of SMN1 transcripts is responsible for the molecular basis of disease in a subset of SMA patients.","variants":[{"Name":"NM_000344.4(SMN1):c.469C>T (p.Gln157Ter)","Chromosome":"5","Start":"70942553","Stop":"70942553","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":793092,"rule_based_match":true,"evidence_text":"c.469C > T","llm_judgment":"PRESENT","evidence":"c.469C > T","abstract_start":439,"abstract_end":449}]}
{"pmid":"26239723","title":"Two novel compound heterozygous mutations in the BCKDHB gene that cause the intermittent form of maple syrup urine disease.","abstract":"Intermittent maple syrup urine disease (MSUD) is a potentially life-threatening metabolic disorder caused by a deficiency of branched chain α-ketoacid dehydrogenase (BCKD) complex. In contrast to classic MSUD, children with the intermittent form usually have an atypical clinical manifestation. Here, we describe the presenting symptoms and clinical course of a Chinese boy with intermittent MSUD. Mutation analysis identified two previously unreported mutations in exon 7 of the BCKDHB gene: c.767A > G (p.Y256C) and c.768C > G (p.Y256X); the parents were each heterozygous for one of these mutations. In silico analysis predicted Y256C probably affects protein structure; Y256X leads to a premature stop codon. This case demonstrates intermittent MSUD should be suspected in cases with symptoms of recurrent encephalopathy, especially ataxia or marked drowsiness, which usually present after the neonatal period and in conjunction with infection. symmetrical basal ganglia damage but normal myelination in the posterior limb will assist differential diagnosis; alloisoleucine is a useful diagnostic marker and mutation analysis may be of prognostic value. These novel mutations Y256C and Y256X result in the clinical manifestation of a variant form of MSUD, expanding the mutation spectrum of this disease.","variants":[{"Name":"NM_183050.4(BCKDHB):c.767A>G (p.Tyr256Cys)","Chromosome":"6","Start":"80200958","Stop":"80200958","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1867914,"rule_based_match":true,"evidence_text":"c.767A > G (p.Y256C)","llm_judgment":"PRESENT","evidence":"c.767A > G (p.Y256C)","abstract_start":493,"abstract_end":513}]}
{"pmid":"30418171","title":"Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy.","abstract":"Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function. However, a small number of patients carrying the CNGB3/c.1208G>A;p.R403Q mutation present with a variable retinal phenotype ranging from complete and incomplete achromatopsia to moderate cone dysfunction or progressive cone dystrophy. By exploring a large patient cohort and published cases, we identified 16 unrelated individuals who were homozygous or (compound-)heterozygous for the CNGB3/c.1208G>A;p.R403Q mutation. In-depth genetic and clinical analysis revealed a co-occurrence of a mutant CNGA3 allele in a high proportion of these patients (10 of 16), likely contributing to the disease phenotype. To verify these findings, we generated a Cngb3R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3-/-) mice to obtain triallelic Cnga3+/- Cngb3R403Q/R403Q mutants. As in human subjects, there was a striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice. These findings strongly suggest a digenic and triallelic inheritance pattern in a subset of patients with achromatopsia/severe cone dystrophy linked to the CNGB3/p.R403Q mutation, with important implications for diagnosis, prognosis, and genetic counseling.","variants":[{"Name":"NM_019098.5(CNGB3):c.1208G>A (p.Arg403Gln)","Chromosome":"8","Start":"86632864","Stop":"86632864","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":152872,"rule_based_match":true,"evidence_text":"CNGB3/c.1208G>A;p.R403Q","llm_judgment":"PRESENT","evidence":"CNGB3/c.1208G>A;p.R403Q","abstract_start":276,"abstract_end":299}]}
{"pmid":"31058963","title":"Population-based analysis of BAP1 germline variations in patients with uveal melanoma.","abstract":"Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (BAP1-TPDS) with increased risk of several cancers, the most frequent of which is uveal melanoma (UM). Pathogenicity of loss-of-function (LOF) BAP1 variants is clear, as opposed to that of missense and regulatory region variants. We sequenced the coding, promoter, untranslated region (UTR) and intronic regions of BAP1 and analyzed copy number variations (CNVs). In this nationwide study, the cohort comprised UM patients diagnosed between 2010 and 2017. These included 432 of 520 consecutive Finnish UM patients, 16 of whom were familial, and one additional patient from a Finnish-Swedish family. Twenty-one different rare variants were found: seven exonic, seven intronic, four 3' UTR and three promoter. We considered five variants likely to be pathogenic by effect on splicing, nuclear localization or deubiquitination activity. Intron 2 (c.67+1G>T) and exon 14 (c.1780_1781insT) LOF variants were presumed founder mutations, occurring in two and four families, respectively; both abolished nuclear localization in vitro. Intron 2, exons 5 (c.281A>G) and 9 (c.680G>A) missense variants markedly reduced deubiquitinating activity. A deep intronic 25 base pair deletion in intron 1 caused aberrant splicing in vitro. On the basis of functional studies and family cancer history, we classified four exon 13 missense variants as benign. No CNVs were found. The prevalence of pathogenic variants was 9/433 (2%) and 4/16 (25%) in Finnish UM families. Family cancer history and functional assays are indispensable when establishing the pathogenicity of BAP1 variants. Deep intronic variants can cause BAP1-TPDS.","variants":[{"Name":"NM_004656.4(BAP1):c.1780_1781insT (p.Gly594fs)","Chromosome":"3","Start":"52403247","Stop":"52403248","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":3417387,"rule_based_match":true,"evidence_text":"c.1780_1781insT","llm_judgment":"PRESENT","evidence":"c.1780_1781insT","abstract_start":988,"abstract_end":1003},{"Name":"NM_004656.4(BAP1):c.680G>A (p.Arg227His)","Chromosome":"3","Start":"52406356","Stop":"52406356","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2919636,"rule_based_match":true,"evidence_text":"c.680G>A","llm_judgment":"PRESENT","evidence":"c.680G>A","abstract_start":1183,"abstract_end":1191},{"Name":"NM_004656.4(BAP1):c.281A>G (p.His94Arg)","Chromosome":"3","Start":"52408052","Stop":"52408052","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":473494,"rule_based_match":true,"evidence_text":"c.281A>G","llm_judgment":"PRESENT","evidence":"c.281A>G","abstract_start":1166,"abstract_end":1174}]}
{"pmid":"23318356","title":"Familial prostate cancer: the damage done and lessons learnt.","abstract":"BACKGROUND: A 51-year-old French Canadian man presented to his family physician owing to an extensive family history of prostate cancer in five brothers, his father and two paternal uncles. His serum PSA level was 4.9 ng/ml and a six-core biopsy revealed the presence of a prostate adenocarcinoma with a Gleason score of 7 (3+4). He was treated with radical prostatectomy. Repeat PSA tests revealed a gradual rise in PSA levels despite androgen deprivation therapy with bicalutamide and goserelin over the course of 3 years. Genetic evaluation was undertaken in view of his personal and family history. The proband died at the age of 58 years of widespread metastasis.\nINVESTIGATIONS: PSA testing, six-core biopsy, genetic counselling and mutation analysis for French Canadian founder mutations in the BRCA1 and BRCA2 genes, histopathological review of tumour tissue from family members, examination of loss of heterozygosity at the BRCA2 gene locus, immunohistochemistry to determine the expression of the ERG nuclear oncoprotein in prostate tumours, genotyping with eight selected risk-associated single nucleotide polymorphisms, Doppler ultrasonography of the leg, CT of the abdomen and pelvis with intravenous and oral contrast, chest CT with intravenous contrast for the assessment of metastatic prostate cancer, genetic testing for the G84E variant in the HOXB13 gene.\nDIAGNOSIS: Early-onset and aggressive prostate cancer associated with a nonsense French Canadian BRCA2 founder mutation, c.5857G>T (p.Glu1953(*)).\nMANAGEMENT: Radical prostatectomy, hormone therapy with bicalutamide and goserelin, palliative chemotherapy initially with docetaxel plus prednisone then with mitoxantrone plus prednisone, as well as genetic counselling and testing for the proband and his family members.","variants":[{"Name":"NM_000059.4(BRCA2):c.5857G>T (p.Glu1953Ter)","Chromosome":"13","Start":"32340212","Stop":"32340212","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":66620,"rule_based_match":true,"evidence_text":"c.5857G>T (p.Glu1953(*))","llm_judgment":"PRESENT","evidence":"c.5857G>T (p.Glu1953(*))","abstract_start":1496,"abstract_end":1520}]}
{"pmid":"28295212","title":"Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager.","abstract":"Schwannomatosis is a rare neurofibromatosis clinically diagnosed by age-dependent criteria, with bilateral vestibular schwannoma and/or a constitutional NF2 mutation representing exclusion criteria. Following SMARCB1 germline mutations, constitutional mutations in LZTR1 were discovered. We report on the molecular investigation in a patient presenting at 14 years with a unilateral vestibular schwannoma, ultimately causing blindness and unilateral hearing loss, in the absence of other schwannomas or a positive family history. In DNA derived from frozen tumor tissue, a comprehensive NF2, SMARCB1 and LZTR1 analysis showed an NF2 truncating mutation c.1006_1021delins16; an LZTR1 mutation c.791+1G>A; and a partial 22q deletion including NF2, SMARCB1 and LZTR1. Sequence analysis on peripheral blood derived DNA showed the LZTR1 mutation to be constitutional, but the NF2 mutation and partial 22q deletion were not found, indicating them to be somatic events. RNA-based targeted analysis confirmed missplicing of LZTR1 intron 8, predicted to result in a premature stop codon. This LZTR1 mutation was paternally inherited. While isolated vestibular schwannoma or NF2 may be considered in a young individual with a unilateral vestibular schwannoma, this report suggests that LZTR1 -related schwannomatosis be added to this differential diagnosis.","variants":[{"Name":"NM_006767.4(LZTR1):c.791+1G>A","Chromosome":"22","Start":"20990526","Stop":"20990526","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":860703,"rule_based_match":true,"evidence_text":"LZTR1 mutation c.791+1G>A","llm_judgment":"PRESENT","evidence":"LZTR1 mutation c.791+1G>A","abstract_start":677,"abstract_end":702}]}
{"pmid":"29648665","title":"Homozygous TAF8 mutation in a patient with intellectual disability results in undetectable TAF8 protein, but preserved RNA polymerase II transcription.","abstract":"The human general transcription factor TFIID is composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). In eukaryotic cells, TFIID is thought to nucleate RNA polymerase II (Pol II) preinitiation complex formation on all protein coding gene promoters and thus, be crucial for Pol II transcription. In a child with intellectual disability, mild microcephaly, corpus callosum agenesis and poor growth, we identified a homozygous splice-site mutation in TAF8 (NM_138572.2: c.781-1G > A). Our data indicate that the patient's mutation generates a frame shift and an unstable TAF8 mutant protein with an unrelated C-terminus. The mutant TAF8 protein could not be detected in extracts from the patient's fibroblasts, indicating a loss of TAF8 function and that the mutation is most likely causative. Moreover, our immunoprecipitation and proteomic analyses show that in patient cells only partial TAF complexes exist and that the formation of the canonical TFIID is impaired. In contrast, loss of TAF8 in mouse embryonic stem cells and blastocysts leads to cell death and to a global decrease in Pol II transcription. Astonishingly however, in human TAF8 patient cells, we could not detect any cellular phenotype, significant changes in genome-wide Pol II occupancy and pre-mRNA transcription. Thus, the disorganization of the essential holo-TFIID complex did not affect global Pol II transcription in the patient's fibroblasts. Our observations further suggest that partial TAF complexes, and/or an altered TFIID containing a mutated TAF8, could support human development and thus, the absence of holo-TFIID is less deleterious for transcription than originally predicted.","variants":[{"Name":"NM_138572.3(TAF8):c.781-1G>A","Chromosome":"6","Start":"42077099","Stop":"42077099","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":626420,"rule_based_match":true,"evidence_text":"NM_138572.2: c.781-1G > A","llm_judgment":"PRESENT","evidence":"NM_138572.2: c.781-1G > A","abstract_start":481,"abstract_end":506}]}
{"pmid":"25814170","title":"Founder mutation causes classical Fukuyama congenital muscular dystrophy (FCMD) in Chinese patients.","abstract":"PURPOSE: Fukuyama congenital muscular dystrophy (FCMD) is a congenital muscular dystrophy rarely reported outside Japan. Here, we report three patients with Fukuyama congenital muscular dystrophy (FCMD) in China who shared a similar clinical phenotype and 3-kb insertion in the FKTN 3' untranslated region.\nMETHODS: Immunofluorescence staining was undertaken on muscle biopsies from three patients using alpha dystroglycan antibody (IIH6). Genomic DNA from patients and parents was extracted from peripheral blood leukocytes. Polymerase chain reaction and DNA sequencing were employed to analyze the exons and surrounding intron sequences of the fukutin (FKTN) gene to detect mutations. Haplotype analysis was also performed on each patient and their parents.\nRESULTS: All patients had delayed mental and motor development, febrile convulsions, muscle weakness, and moderate to significant raised levels of serum creatine kinase (7000-11,160 U/L, 25-60×normal). Brain MRI scans showed micropolygyria and extensive dysplasia in the white matter and brainstem. Electromyography revealed myopathic changes. Muscle immunofluorescence studies demonstrated reduced IIH6 staining. Genetic testing showed compound heterozygous mutations of FKTN. Cases 1 and 2 had a c.139C>T (p.Arg47(∗)) heterozygous mutation. Case 3 had a c.346C>T (p.Gln116(∗)) heterozygous mutation.\nCONCLUSION: All patients had a heterozygous 3-kb insertion in the FKTN 3' untranslated region. Haplotype analyses suggested that these patients had the same haplotype as Japanese patients.","variants":[{"Name":"NM_001079802.2(FKTN):c.139C>T (p.Arg47Ter)","Chromosome":"9","Start":"105596631","Stop":"105596631","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":18239,"rule_based_match":true,"evidence_text":"c.139C>T (p.Arg47(∗))","llm_judgment":"PRESENT","evidence":"c.139C>T (p.Arg47(∗))","abstract_start":1258,"abstract_end":1279}]}
{"pmid":"24084575","title":"The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype.","abstract":"Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional epimutation of MLH1, whereby promoter methylation and transcriptional silencing of one allele occurs throughout normal tissues. A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM_000249.2: c.-27C>A and c.85G>T, in a Caucasian family with Lynch syndrome from Western Australia. Subsequently, a second seemingly unrelated Caucasian Australian case with the same MLH1 haplotype and concomitant epimutation was reported. We now describe three additional, ostensibly unrelated, cancer-affected families of European heritage with this MLH1 haplotype in association with constitutional epimutation, bringing the number of index cases reported to five. Array-based genotyping in four of these families revealed shared haplotypes between individual families that extended across ≤2.6-≤6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal ≤2.6 megabase founder haplotype common to all four families was identified, which encompassed MLH1 and additional flanking genes and segregated with the MLH1 epimutation in each family. Our findings indicate that the MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype and provide conclusive evidence for its pathogenicity via a mechanism of epigenetic silencing of MLH1 within normal tissues. Additional descendants bearing this founder haplotype may exist who are also at high risk of developing Lynch syndrome-related cancers.","variants":[{"Name":"NM_000249.4(MLH1):c.85G>T (p.Ala29Ser)","Chromosome":"3","Start":"36993632","Stop":"36993632","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":95871,"rule_based_match":true,"evidence_text":"c.85G>T","llm_judgment":"PRESENT","evidence":"c.85G>T","abstract_start":587,"abstract_end":594},{"Name":"NM_000249.4(MLH1):c.-27C>A","Chromosome":"3","Start":"36993521","Stop":"36993521","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":95063,"rule_based_match":true,"evidence_text":"NM_000249.2: c.-27C>A","llm_judgment":"PRESENT","evidence":"NM_000249.2: c.-27C>A","abstract_start":561,"abstract_end":582}]}
{"pmid":"29128256","title":"MEGF10 related myopathies: A new case with adult onset disease with prominent respiratory failure and review of reported phenotypes.","abstract":"Recessive mutations in MEGF10 (multiple epidermal growth factor 10) have been reported in a severe early onset disorder named Early Myopathy, Areflexia, Respiratory Distress and Dysphagia, and a milder form with cores in the muscle biopsy; and a possible genotype-phenotype correlation determining the clinical presentation has been suggested. We undertook exome sequencing in a 66 year old male with a 20 year history of progressive proximal and distal weakness of upper and lower limbs, facial weakness and dysphagia, who developed respiratory failure requiring ventilation while still ambulant in his 50s. Muscle biopsy demonstrated myopathic changes with aggregation of myofibrillar proteins. Mutations in MEGF10 were identified: a novel essential splice site (c.1426+1G>T) and a novel missense variant (c.352T>C, p.(Cys118Arg)). We performed a detailed review of all reported MEGF10 cases (n = 20), and confirmed the presence of a genotype-phenotype correlation, namely that with ≥1 null mutation onset of respiratory dysfunction occurs in the first year of life, whereas with 2 missense mutations, respiratory dysfunction occurs at 10 years old or much later, as in the patient reported here. Our findings expand the phenotype of MEGF10 mutations to include onset in the 5th decade, and discuss the spectrum of MEGF10 related disease.","variants":[{"Name":"NM_001256545.2(MEGF10):c.352T>C (p.Cys118Arg)","Chromosome":"5","Start":"127369942","Stop":"127369942","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2417667,"rule_based_match":true,"evidence_text":"c.352T>C, p.(Cys118Arg)","llm_judgment":"PRESENT","evidence":"c.352T>C, p.(Cys118Arg)","abstract_start":808,"abstract_end":831},{"Name":"NM_001256545.2(MEGF10):c.1426+1G>T","Chromosome":"5","Start":"127419241","Stop":"127419241","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2417668,"rule_based_match":true,"evidence_text":"c.1426+1G>T","llm_judgment":"PRESENT","evidence":"c.1426+1G>T","abstract_start":765,"abstract_end":776}]}
{"pmid":"17701905","title":"CHMP4B, a novel gene for autosomal dominant cataracts linked to chromosome 20q.","abstract":"Cataracts are a clinically diverse and genetically heterogeneous disorder of the crystalline lens and a leading cause of visual impairment. Here we report linkage of autosomal dominant \"progressive childhood posterior subcapsular\" cataracts segregating in a white family to short tandem repeat (STR) markers D20S847 (LOD score [Z] 5.50 at recombination fraction [theta] 0.0) and D20S195 (Z=3.65 at theta =0.0) on 20q, and identify a refined disease interval (rs2057262-(3.8 Mb)-rs1291139) by use of single-nucleotide polymorphism (SNP) markers. Mutation profiling of positional-candidate genes detected a heterozygous transversion (c.386A-->T) in exon 3 of the gene for chromatin modifying protein-4B (CHMP4B) that was predicted to result in the nonconservative substitution of a valine residue for a phylogenetically conserved aspartic acid residue at codon 129 (p.D129V). In addition, we have detected a heterozygous transition (c.481G-->A) in exon 3 of CHMP4B cosegregating with autosomal dominant posterior polar cataracts in a Japanese family that was predicted to result in the missense substitution of lysine for a conserved glutamic acid residue at codon 161 (p.E161K). Transfection studies of cultured cells revealed that a truncated form of recombinant D129V-CHMP4B had a different subcellular distribution than wild type and an increased capacity to inhibit release of virus-like particles from the cell surface, consistent with deleterious gain-of-function effects. These data provide the first evidence that CHMP4B, which encodes a key component of the endosome sorting complex required for the transport-III (ESCRT-III) system of mammalian cells, plays a vital role in the maintenance of lens transparency.","variants":[{"Name":"NM_176812.5(CHMP4B):c.386A>T (p.Asp129Val)","Chromosome":"20","Start":"33850969","Stop":"33850969","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":16124,"rule_based_match":false,"evidence_text":"c.386A-->T","llm_judgment":"PRESENT","evidence":"c.386A-->T","abstract_start":632,"abstract_end":642},{"Name":"NM_176812.5(CHMP4B):c.481G>A (p.Glu161Lys)","Chromosome":"20","Start":"33851064","Stop":"33851064","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16125,"rule_based_match":false,"evidence_text":"c.481G-->A","llm_judgment":"PRESENT","evidence":"c.481G-->A","abstract_start":931,"abstract_end":941}]}
{"pmid":"36292983","title":"Genetic Variant in Nicotinic Receptor α4-Subunit Causes Sleep-Related Hyperkinetic Epilepsy via Increased Channel Opening.","abstract":"We describe genetic and molecular-level functional alterations in the α4β2 neuronal nicotinic acetylcholine receptor (nAChR) from a patient with sleep-related hyperkinetic epilepsy and a family history of epilepsy. Genetic sequencing revealed a heterozygous variant c.851C>G in the CHRNA4 gene encoding the α4 subunit, resulting in the missense mutation p.Ser284Trp. Patch clamp recordings from genetically engineered nAChRs incorporating the α4-Ser284Trp subunit revealed aberrant channel openings in the absence of agonist and markedly prolonged openings in its presence. Measurements of single channel current amplitude distinguished two pentameric stoichiometries of the variant nAChR containing either two or three copies of the α4-Ser284Trp subunit, each exhibiting aberrant spontaneous and prolonged agonist-elicited channel openings. The α4-Ser284 residue is highly conserved and located within the M2 transmembrane α-helix that lines the ion channel. When mapped onto the receptor’s three-dimensional structure, the larger Trp substitution sterically clashes with the M2 α-helix from the neighboring subunit, promoting expansion of the pore and stabilizing the open relative to the closed conformation of the channel. Together, the clinical, genetic, functional, and structural observations demonstrate that α4-Ser284Trp enhances channel opening, predicting increased membrane excitability and a pathogenic seizure phenotype.","variants":[{"Name":"NM_000744.7(CHRNA4):c.851C>G (p.Ser284Trp)","Chromosome":"20","Start":"63350560","Stop":"63350560","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":958864,"rule_based_match":true,"evidence_text":"c.851C>G","llm_judgment":"PRESENT","evidence":"c.851C>G","abstract_start":266,"abstract_end":274}]}
{"pmid":"31289154","title":"Normal male external genitalia do not rule out CYP11A1 deficiency.","abstract":"Defects in the initial steps of steroidogenesis usually present with female external genitalia in both 46,XX and 46,XY. Hence, they are not often considered in the differential diagnosis of primary adrenal insufficiency children with normal male external genitalia. Here, we report a boy with normal male external genitalia who presented with hyperpigmentation since the age of 2 years but diagnosis was delayed till 11 years of age. Evaluation revealed low-serum cortisol with elevated adrenocorticotropic hormone and direct renin level confirming primary adrenal insufficiency. Clinical exome sequencing analysis revealed a homozygous c.1351C>T (p.R451W) mutation in exon 8 of the <i>CYP11A1</i> gene which was confirmed on Sanger sequencing. Both parents were heterozygous for the variation. To conclude, we report the first case of CYP11A1 deficiency from India. The report reiterates the existence of non-classic CYP11A1 deficiency characterised by primary adrenal insufficiency and normal male external genitalia in 46,XY.","variants":[{"Name":"NM_000781.3(CYP11A1):c.1351C>T (p.Arg451Trp)","Chromosome":"15","Start":"74338654","Stop":"74338654","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1318532,"rule_based_match":true,"evidence_text":"c.1351C>T (p.R451W)","llm_judgment":"PRESENT","evidence":"c.1351C>T (p.R451W)","abstract_start":637,"abstract_end":656}]}
{"pmid":"27362365","title":"A novel surfactant protein C gene mutation associated with progressive respiratory failure in infancy.","abstract":"Mutations of the Surfactant Protein C (SPC) gene (SFTPC) have been associated with childhood interstitial lung disease (chILD) with variable age of onset, severity of lung disease, and outcomes. We report a novel mutation in SFTPC [c.435G->A, p.(Gln145)] that was associated with onset of symptoms in early infancy, progressive respiratory failure with need for prolonged mechanical ventilatory support, and eventual lung transplant at 1 year of age. While the mutation was not predicted to alter the amino acid sequence of the SP-C precursor protein, analysis of SP-C transcripts demonstrated skipping of exon 4. Because of limited data about the outcomes of infants with SFTPC mutations, we conducted a systematic review of all the SFTPC mutations reported in the literature in order to define their presenting features, clinical and radiologic features, and outcomes. Further advances in our understanding of chILD and creation of an international registry will help to track these patients and their outcomes. Pediatr Pulmonol. 2017;52:57-68. © 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_001317778.2(SFTPC):c.435G>A (p.Gln145=)","Chromosome":"8","Start":"22163546","Stop":"22163546","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1794445,"rule_based_match":false,"evidence_text":"c.435G->A, p.(Gln145)","llm_judgment":"PRESENT","evidence":"c.435G->A, p.(Gln145)","abstract_start":232,"abstract_end":253}]}
{"pmid":"33092414","title":"Prenatal Diagnosis and Screening of Thalassemia Mutations in Bangladesh: Presence of Rare Mutations.","abstract":"Thalassemia is the most common congenital monogenic disorder in Bangladesh. Prenatal diagnosis (PND) and pregnation termination of an affected child is one of the best options to reduce the burden of thalassemic children. This article reports the results of DNA analyses of chorionic villus sampling (CVS) and amniocentesis of fetuses of mothers who came to the thalassemia center of Dhaka Shishu (Children) Hospital, Dhaka, Bangladesh. DNA analysis was done by real-time polymerase chain reaction (qPCR) and Sanger sequencing. Maternal contamination was ruled out by variable number of tandem repeats (VNTRs). A total of 232 samples were analyzed. Hb E (<i>HBB</i>: c.79G>A)/β-thalassemia (Hb E/β-thal) was the most common type of thalassemia seen in 32 samples (13.79%) followed by β-thal major (β-TM) in 10 cases (4.31%). Molecular characterization of the most predominant mutation was IVS-I-5 (G>A) (<i>HBB</i>: c.92+5G>C). The analysis also revealed five rare mutations: IVS-II-654 (C>T) (<i>HBB</i>: c.316-197C>T), IVS-II-1 (G>A) (<i>HBB</i>: c.315+5G>A), codon 44 (-C) (<i>HBB</i>: c.135delC), -86 (C>A) (<i>HBB</i>: c.-136C>A) and codons 14/15 (+G) (<i>HBB</i>: c.45_46insG), which have not been reported previously in Bangladesh. This study provides important information for PND and will help in the development of similar diagnostic programs for other DNA centers in Bangladesh.","variants":[{"Name":"NM_000518.4(HBB):c.-136C>A","Chromosome":"11","Start":"5227157","Stop":"5227157","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2671170,"rule_based_match":true,"evidence_text":"c.-136C>A","llm_judgment":"PRESENT","evidence":"c.-136C>A","abstract_start":1124,"abstract_end":1133}]}
{"pmid":"35455965","title":"Functional Study of","abstract":"Hypomyelinating leukodystrophies (HLDs) are a rare group of heterogeneously genetic disorders characterized by persistent deficit of myelin observed on magnetic resonance imaging (MRI). To identify a new disease-associated gene of HLD, trio-based whole exome sequencing was performed for unexplained patients with HLD. Functional studies were performed to confirm the phenotypic effect of candidate protein variants. Two de novo heterozygous variants, c.227T>G p.(L76R) or c.227T>C p.(L76P) in TMEM163 were identified in two unrelated HLD patients. TMEM163 protein is a zinc efflux transporter localized within the plasma membrane, lysosomes, early endosomes, and other vesicular compartments. It has not been associated with hypomyelination. Functional zinc flux assays in HeLa cells stably-expressing TMEM163 protein variants, L76R and L76P, revealed distinct attenuation or enhancement of zinc efflux, respectively. Experiments using a zebrafish model with knockdown of tmem163a and tmem163b (morphants) showed that loss of tmem163 causes dysplasia of the larvae, locomotor disability and myelin deficit. Expression of human wild type TMEM163 mRNAs in morphants rescues the phenotype, while the TMEM163 L76P and L76R mutants aggravated the condition. Moreover, poor proliferation, elevated apoptosis of oligodendrocytes, and reduced oligodendrocytes and neurons were also observed in zebrafish morphants. Our findings suggest an unappreciated role for TMEM163 protein in myelin development and add TMEM163 to a growing list of genes associated with hypomyelination leukodystrophy.","variants":[{"Name":"NM_030923.5(TMEM163):c.227T>C (p.Leu76Pro)","Chromosome":"2","Start":"134713295","Stop":"134713295","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2417484,"rule_based_match":true,"evidence_text":"c.227T>C p.(L76P)","llm_judgment":"PRESENT","evidence":"c.227T>C p.(L76P)","abstract_start":473,"abstract_end":490},{"Name":"NM_030923.5(TMEM163):c.227T>G (p.Leu76Arg)","Chromosome":"2","Start":"134713295","Stop":"134713295","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2417485,"rule_based_match":true,"evidence_text":"c.227T>G p.(L76R)","llm_judgment":"PRESENT","evidence":"c.227T>G p.(L76R)","abstract_start":452,"abstract_end":469}]}
{"pmid":"22735794","title":"Mutation screening of TRPM1, GRM6, NYX and CACNA1F genes in patients             with congenital stationary night blindness.","abstract":"The aim of this study was to identify mutations in the TRPM1, GRM6, NYX             and CACNA1F genes in patients with congenital stationary night blindness (CSNB).             Twenty-four unrelated patients with CSNB were ascertained. Sanger sequencing was             used to analyze the coding exons and adjacent intronic regions of TRPM1, GRM6,             NYX and CACNA1F. Six mutations were identified in six unrelated patients, including             five novel and one known. Of the six, three novel hemizygous mutations, c.92G>A             (p.Cys31Tyr), c.149G>C (p.Ary50Pro), and c.[272T>A;1429G>C] (p.[Leu91Gln;Gly477Arg]),             were found in NYX in three patients, respectively. A novel c.[1984_1986delCTC;3001G>A]             (p.[Leu662del;Gly1001Arg]) mutation was detected in CACNA1F in one patient. One             novel and one known heterozygous variation, c.1267T>C (p.Cys423Arg) and c.1537G>A             (p.Val513Met), were detected in GRM6 in two patients, respectively. No variations             were found in TRPM1. The results expand the mutation spectrum of NYX, CACNA1F             and GRM6. They also suggest that NYX mutations are a common cause of CSNB.","variants":[{"Name":"NM_000843.4(GRM6):c.1537G>A (p.Val513Met)","Chromosome":"5","Start":"178986717","Stop":"178986717","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":227285,"rule_based_match":true,"evidence_text":"c.1537G>A (p.Val513Met)","llm_judgment":"PRESENT","evidence":"c.1537G>A             (p.Val513Met)","abstract_start":910,"abstract_end":945}]}
{"pmid":"32682410","title":"Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistani families.","abstract":"BACKGROUND: Hearing loss is the most common sensory defect, and it affects over 6% of the population worldwide. Approximately 50-60% of hearing loss patients are attributed to genetic causes. Currently, more than 100 genes have been reported to cause non-syndromic hearing loss. It is possible and efficient to screen all potential disease-causing genes for hereditary hearing loss by whole exome sequencing (WES).\nMETHODS: We collected 5 consanguineous pedigrees from Pakistan with hearing loss and applied WES in selected patients for each pedigree, followed by bioinformatics analysis and Sanger validation to identify the causal genes.\nRESULTS: Variants in 7 genes were identified and validated in these pedigrees. We identified single candidate variant for 3 pedigrees: GIPC3 (c.937 T > C), LOXHD1 (c.6136G > A) and TMPRSS3 (c.941 T > C). The remaining 2 pedigrees each contained two candidate variants: TECTA (c.4045G > A) and MYO15A (c.3310G > T and c.9913G > C) for one pedigree and DFNB59 (c.494G > A) and TRIOBP (c.1952C > T) for the other pedigree. The candidate variants were validated in all available samples by Sanger sequencing.\nCONCLUSION: The candidate variants in hearing-loss genes were validated to be co-segregated in the pedigrees, and they may indicate the aetiologies of hearing loss in such patients. We also suggest that WES may be a suitable strategy for hearing-loss gene screening in clinical detection.","variants":[{"Name":"NM_133261.3(GIPC3):c.937T>C (p.Ter313Gln)","Chromosome":"19","Start":"3590188","Stop":"3590188","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":609025,"rule_based_match":true,"evidence_text":"c.937 T > C","llm_judgment":"PRESENT","evidence":"c.937 T > C","abstract_start":782,"abstract_end":793}]}
{"pmid":"20083799","title":"Novel THAP1 sequence variants in primary dystonia.","abstract":"BACKGROUND: THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects.\nOBJECTIVE: To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1.\nMETHODS: With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls.\nRESULTS: Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600).\nCONCLUSIONS: A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.","variants":[{"Name":"NM_018105.3(THAP1):c.71+9C>A","Chromosome":"8","Start":"42843015","Stop":"42843015","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":309220,"rule_based_match":true,"evidence_text":"c.71+9C>A","llm_judgment":"PRESENT","evidence":"c.71+9C>A","abstract_start":1506,"abstract_end":1515}]}
{"pmid":"24555714","title":"Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics.","abstract":"BACKGROUND: Congenital cataracts are clinically and genetically heterogeneous with more than 45 known loci and 38 identified genes. They can occur as isolated defects or in association with anterior segment developmental anomalies. One of the disease genes for congenital cataract with or without anterior segment dysgenesis (ASD) is PITX3, encoding a transcription factor with a crucial role in lens and anterior segment development. Only five unique PITX3 mutations have been described, of which the 17-bp duplication c.640_656dup, p.(Gly220Profs*95), is the most common one and the only one known to cause cataract with ASD. The aim of this study was to perform a genetic study of the PITX3 gene in five probands with autosomal dominant congenital cataract (ADCC) and ASD, to compare their clinical presentations to previously reported PITX3-associated phenotypes and to functionally evaluate the PITX3 mutations found.\nMETHODS: Sanger sequencing of the coding region and targeted exons of PITX3 was performed in probands and family members respectively. Transactivation, DNA-binding and subcellular localization assays were performed for the PITX3 mutations found. Ophthalmological examinations included visual acuity measurement, slit-lamp biomicroscopy, tonometry and fundoscopy.\nRESULTS: In four Belgian families with ADCC and ASD the recurrent 17-bp duplication c.640_656dup, p.(Gly220Profs*95), was found in a heterozygous state. A novel PITX3 mutation c.573del, p.(Ser192Alafs*117), was identified in heterozygous state in a Belgo-Romanian family with a similar phenotype. Functional assays showed that this novel mutation retains its nuclear localization but results in decreased DNA-binding and transactivation activity, similar to the recurrent duplication.\nCONCLUSIONS: Our study identified a second PITX3 mutation leading to congenital cataract with ASD. The similarity in phenotypic expression was substantiated by our in vitro functional studies which demonstrated comparable molecular consequences for the novel p.(Ser192Alafs*117) and the recurrent p.(Gly220Profs*95) mutations.","variants":[{"Name":"NM_005029.4(PITX3):c.640_656dup (p.Gly220fs)","Chromosome":"10","Start":"102230766","Stop":"102230767","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCCCAGGCCCTGCAGGGC","allel_id":459553,"rule_based_match":true,"evidence_text":"c.640_656dup","llm_judgment":"PRESENT","evidence":"c.640_656dup","abstract_start":520,"abstract_end":532}]}
{"pmid":"35102031","title":"Clinical and genetic studies of thiamine metabolism dysfunction syndrome-4: case series and review of the literature.","abstract":"Thiamine metabolism dysfunction syndrome-4 (THMD-4) is an autosomal recessive inherited rare disease (OMIM #613710) characterized by febrile illness associated episodic encephalopathy, leading to transient neurological dysfunction and progressive polyneuropathy. We report three patients from two different families with normal development, episodic encephalopathy, gait disorder, progressive chronic polyneuropathy characterized by motor difficulties, distal weakness, and hoarseness (dysphonia). We identified a homozygous missense c.576G>C, p.(Gln192His) variant in the SLC25A19 gene in both families by whole-exome sequencing. Following genetic diagnosis, thiamine replacement therapy was started, and improvement was observed in all affected patients. We highlight the associated phenotypes of an SCL25A19 mutation leading to clinical features of THMD-4.","variants":[{"Name":"NM_001126121.2(SLC25A19):c.576G>C (p.Gln192His)","Chromosome":"17","Start":"75278219","Stop":"75278219","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1687765,"rule_based_match":true,"evidence_text":"c.576G>C, p.(Gln192His)","llm_judgment":"PRESENT","evidence":"c.576G>C, p.(Gln192His)","abstract_start":534,"abstract_end":557}]}
{"pmid":"34172998","title":"Loss of SPACA1 function causes autosomal recessive globozoospermia by damaging the acrosome-acroplaxome complex.","abstract":"STUDY QUESTION: Is the sperm acrosome membrane-associated protein 1 (SPACA1) gene critical to human globozoospermia?\nSUMMARY ANSWER: The biallelic loss-of-function (variant of SPACA1) causes globozoospermia as a result of acrosome-acroplaxome complex damage.\nWHAT IS KNOWN ALREADY: SPACA1 expression decreases in patients with globozoospermia. Spaca1 gene-disrupted mice have abnormally shaped sperm heads that resemble those of human globozoospermia.\nSTUDY DESIGN, SIZE, DURATION: We recruited a consanguineous family with two brothers affected by infertility as a consequence of globozoospermia. The semen analysis data and ART outcomes were collected. Exome sequencing (ES) was used to identify potential pathogenic variants. Protein-protein interaction (PPI) technologies and proteomic analysis were utilized to explore the pathogenic mechanism.\nPARTICIPANTS/MATERIALS, SETTING, METHODS: Two globozoospermic brothers and their consanguineous parents were recruited to identify the potential pathogenic variant through ES. A homozygous nonsense variant in the SPACA1 gene in both brothers inherited from the heterozygous parents was identified. Twenty normal fertile males were recruited as controls. Sperm ultrastructure was observed with transmission electron microscopy. Western blotting was performed to measure SPACA1 expression level in the sperm from the patients. Mass spectrometry (MS) analyses were used to identify differentially expressed proteins and to investigate proteins that interact with SPACA1. Co-immunoprecipitation (co-IP), yeast two-hybrid (Y2H) and immunofluorescence colocalization assays were used to confirm the PPI.\nMAIN RESULTS AND THE ROLE OF CHANCE: A nonsense variant (NM_030960.2: c.53G>A; p. Trp18*) in the SPACA1 gene was identified as the pathogenic variant in a family with globozoospermia. Patient IV:1 and Patient IV:2 had a phenotype very similar to that of Spaca1 gene-disrupted mice. The nonsense variant in SPACA1 led to premature transcriptional termination in the signal peptide, which was confirmed by western blotting. MS-based proteomics analysis showed that eight interactors of SPACA1 were differentially expressed in the patients' sperm, including actin-like Protein 7A (ACTL7A), an important component of the acrosome-acroplaxome complex. The PPI of SPACA1 and ACTL7A was confirmed via co-IP and Y2H assays. Immunofluorescence showed that SPACA1 and ACTL7A colocalized in mature sperm, revealing that these proteins were coexpressed spatially.\nLIMITATIONS, REASONS FOR CAUTION: Given the rarity of globozoospermia, only two patients from one family harbouring the SPACA1 variant were found. Future studies should evaluate SPACA1 variants in larger cohorts to corroborate this finding.\nWIDER IMPLICATIONS OF THE FINDINGS: This study revealed that the SPACA1 gene was critical for globozoospermia, which expanded the spectrum of causative genes for globozoospermia. This study also provided evidence for ICSI clinical outcomes for patients with SPACA1-deficient globozoospermia, which may guide clinical treatment strategies. Furthermore, this study explored the pathogenesis of globozoospermia caused by SPACA1 deficiency.\nSTUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Precision Medical Research of National Key Research and Development Program (2018YFC1002400), National Natural Science Foundation of China (81873724), and Natural Science Foundation of Shanghai (20ZR1472700). The authors have no conflicts of interest to disclose.\nTRIAL REGISTRATION NUMBER: N/A.","variants":[{"Name":"NM_030960.3(SPACA1):c.53G>A (p.Trp18Ter)","Chromosome":"6","Start":"88047958","Stop":"88047958","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2742366,"rule_based_match":true,"evidence_text":"NM_030960.2: c.53G>A; p. Trp18*","llm_judgment":"PRESENT","evidence":"NM_030960.2: c.53G>A; p. Trp18*","abstract_start":1705,"abstract_end":1736}]}
{"pmid":"31497481","title":"Severe neonatal multiple sulfatase deficiency presenting with hydrops fetalis in a preterm birth patient.","abstract":"Multiple sulfatase deficiency (MSD) is an ultra-rare lysosomal storage disorder (LSD). Mutations in the <i>SUMF1</i> gene encoding the formylglycine generating enzyme (FGE) result in an unstable FGE protein with reduced enzymatic activity, thereby affecting the posttranslational activation of newly synthesized sulfatases. Complete absence of FGE function results in the most severe clinical form of MSD with neonatal onset and rapid deterioration. We report on a preterm infant presenting with hydrops fetalis, lung hypoplasia, and dysmorphism as major clinical signs. The patient died after 6 days from an intraventricular hemorrhage followed by multi-organ failure. MSD was caused by a homozygous <i>SUMF1</i> stop mutation (c.191C>A, p.Ser64Ter). FGE protein and sulfatase activities were absent in patient fibroblasts. Hydrops fetalis is a rare symptom of LSDs and should be considered in the differential diagnosis in combination with dysmorphism. The diagnostic set up should include measurements of glycosaminoglycan excretion and lysosomal enzyme activities, among them at least two sulfatases, and molecular confirmation.","variants":[{"Name":"NM_182760.4(SUMF1):c.191C>A (p.Ser64Ter)","Chromosome":"3","Start":"4467055","Stop":"4467055","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":916914,"rule_based_match":true,"evidence_text":"c.191C>A, p.Ser64Ter","llm_judgment":"PRESENT","evidence":"c.191C>A, p.Ser64Ter","abstract_start":729,"abstract_end":749}]}
{"pmid":"24534542","title":"Atypical phenotype in two patients with LAMA2 mutations.","abstract":"Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene, which encodes the α2-chain of laminin. We report two patients with partial laminin-α2 deficiency and atypical phenotypes, one with almost exclusive central nervous system involvement (cognitive impairment and refractory epilepsy) and the second with marked cardiac dysfunction, rigid spine syndrome and limb-girdle weakness. Patients underwent clinical, histopathological, imaging and genetic studies. Both cases have two heterozygous LAMA2 variants sharing a potentially pathogenic missense mutation c.2461A>C (p.Thr821Pro) located in exon 18. Brain MRI was instrumental for the diagnosis, since muscular examination and motor achievements were normal in the first patient and there was a severe cardiac involvement in the second. The clinical phenotype of the patients is markedly different which could in part be explained by the different combination of mutations types (two missense versus a missense and a truncating mutation).","variants":[{"Name":"NM_000426.4(LAMA2):c.2461A>C (p.Thr821Pro)","Chromosome":"6","Start":"129280071","Stop":"129280071","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":188050,"rule_based_match":true,"evidence_text":"c.2461A>C (p.Thr821Pro)","llm_judgment":"PRESENT","evidence":"c.2461A>C (p.Thr821Pro)","abstract_start":581,"abstract_end":604}]}
{"pmid":"22264702","title":"Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation.","abstract":"Hyperekplexia is characterized by neonatal hypertonia and exaggerated startle reflex in response to loud noise or tactile stimuli. Mutations in patients with hyperekplexia were evident in several genes encoding proteins involved in glycinergic neurotransmission, i.e., glycine receptor α and β subunits, collybistin, gephyrin, and glycine transporter 2. We clinically and genetically characterized two large, unrelated consanguineous families with hyperekplexia. Affected members of the two families manifested hyperekplexia with mild mental retardation. Patients exhibited a novel homozygote c.593G>C missense mutation in GLRA1, resulting in amino acid substitution p.W170S in the corresponding mature glycine receptor α1 subunit. This mutation was absent in 400 randomly selected chromosomes in the same population. In conclusion, a novel p.W170S mutation in the extracellular ligand binding domain of glycine receptor α1 subunit was detected in patients with hyperekplexia and mild mental retardation.","variants":[{"Name":"NM_000171.4(GLRA1):c.593G>C (p.Trp198Ser)","Chromosome":"5","Start":"151855144","Stop":"151855144","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":166114,"rule_based_match":true,"evidence_text":"c.593G>C","llm_judgment":"PRESENT","evidence":"c.593G>C","abstract_start":593,"abstract_end":601}]}
{"pmid":"31813137","title":"Clinical and variant analysis of 15 patients with methylmalonic acidemia","abstract":"OBJECTIVE: To report on clinical characteristics and genetic findings in 15 Chinese patients with methylmalonic acidemia (MMA).\nMETHODS: For the 15 MMA patients detected by tandem mass spectrometry, genetic analysis was carried out in twelve pedigrees. Clinical characteristics, genetic finding, treatment and outcomes were retrospectively analyzed.\nRESULTS: The main features of the patients included poor feeding, recurrent vomiting, lethargy, seizure and development retardation. Blood propionylcarnitine (except for 3 patients), its ratio with acetylcarnitine, and urine methylmalonic acid were increased in all patients. Twelve patients were diagnosed genetically, which included 7 with MUT variants, 4 with MMACHC variants, and 1 with MMAB variant. Nine MUT variants were detected, among which c.1159A>C, 753+1delGinsTGGTTATTA and c.504del were novel. Six known pathogenic MMACHC variants and two novel MMAB variants (c.289_290delGG, c.566G>A) were also detected. Seven patients died of metabolic crises within a year, others had improved effectively following the treatment, but had mild to severe growth delay and/or developmental retardation.\nCONCLUSION: The clinical manifestation of MMA are complex. Most patients have variants of the MUT and MMACHC genes. High mortality may occur before one year of age.","variants":[{"Name":"NM_000255.4(MMUT):c.1159A>C (p.Thr387Pro)","Chromosome":"6","Start":"49451639","Stop":"49451639","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1416059,"rule_based_match":true,"evidence_text":"c.1159A>C","llm_judgment":"PRESENT","evidence":"c.1159A>C","abstract_start":800,"abstract_end":809}]}
{"pmid":"22529283","title":"Profound neonatal hypoglycemia and lactic acidosis caused by pyridoxine-dependent epilepsy.","abstract":"Pyridoxine-dependent epilepsy (PDE) was first described in 1954. The ALDH7A1 gene mutations resulting in α-aminoadipic semialdehyde dehydrogenase deficiency as a cause of PDE was identified only in 2005. Neonatal epileptic encephalopathy is the presenting feature in >50% of patients with classic PDE. We report the case of a 13-month-old girl with profound neonatal hypoglycemia (0.6 mmol/L; reference range >2.4), lactic acidosis (11 mmol/L; reference range <2), and bilateral symmetrical temporal lobe hemorrhages and thalamic changes on cranial MRI. She developed multifocal and myoclonic seizures refractory to multiple antiepileptic drugs that responded to pyridoxine. The diagnosis of α-aminoadipic semialdehyde dehydrogenase deficiency was confirmed based on the elevated urinary α-aminoadipic semialdehyde excretion, compound heterozygosity for a known splice mutation c.834G>A (p.Val278Val), and a novel putative pathogenic missense mutation c.1192G>C (p.Gly398Arg) in the ALDH7A1 gene. She has been seizure-free since 1.5 months of age on treatment with pyridoxine alone. She has motor delay and central hypotonia but normal language and social development at the age of 13 months. This case is the first description of a patient with PDE due to mutations in the ALDH7A1 gene who presented with profound neonatal hypoglycemia and lactic acidosis masquerading as a neonatal-onset gluconeogenesis defect. PDE should be included in the differential diagnosis of hypoglycemia and lactic acidosis in addition to medically refractory neonatal seizures.","variants":[{"Name":"NM_001182.5(ALDH7A1):c.1192G>C (p.Gly398Arg)","Chromosome":"5","Start":"126554295","Stop":"126554295","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1314156,"rule_based_match":true,"evidence_text":"c.1192G>C (p.Gly398Arg)","llm_judgment":"PRESENT","evidence":"c.1192G>C (p.Gly398Arg)","abstract_start":952,"abstract_end":975},{"Name":"NM_001182.5(ALDH7A1):c.834G>A (p.Val278=)","Chromosome":"5","Start":"126568296","Stop":"126568296","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":33041,"rule_based_match":true,"evidence_text":"c.834G>A (p.Val278Val)","llm_judgment":"PRESENT","evidence":"c.834G>A (p.Val278Val)","abstract_start":878,"abstract_end":900}]}
{"pmid":"19513753","title":"In vivo and in vitro splicing assay of SLC12A1 in an antenatal salt-losing tubulopathy patient with an intronic mutation.","abstract":"Type I Bartter syndrome (BS), an inherited salt-losing tubulopathy, is caused by mutations of the SLC12A1 gene. While several intronic nucleotide changes in this gene have been detected, transcriptional analysis had not been conducted because mRNA analysis is possible only when renal biopsy specimens can be obtained or occasionally when mRNA is expressed in the leukocytes. This report concerns a type I BS patient due to compound heterozygosity for the SLC12A1 gene. Genomic DNA sequencing disclosed the presence of two novel heterozygous mutations of c.724 + 4A > G in intron 5 and c.2095delG in intron 16, but it remains to be determined whether the former would be likely to influence the transcription. In this report, we conducted both in vivo assay of RT-PCR analysis using RNA extracted from the proband's urinary sediments and in vitro functional splicing study by minigene construction, and obtained evidence that this intronic mutation leads to complete exon 5 skipping. To the best of our knowledge, this is the first study to use non-invasive methods for both an in vivo assay and an in vitro functional splicing assay of inherited kidney disease. These analytical assays could be adapted for all inherited kidney diseases.","variants":[{"Name":"NM_000338.3(SLC12A1):c.724+4A>G","Chromosome":"15","Start":"48226575","Stop":"48226575","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":23794,"rule_based_match":true,"evidence_text":"c.724 + 4A > G","llm_judgment":"PRESENT","evidence":"c.724 + 4A > G","abstract_start":555,"abstract_end":569}]}
{"pmid":"23751892","title":"A ZMYM2-FGFR1 8p11 myeloproliferative neoplasm with a novel nonsense RUNX1 mutation and tumor lysis upon imatinib treatment.","abstract":"The 8p11 myeloproliferative neoplasm (8p11 MPN) is a rare disorder that is molecularly characterized by fusions of diverse partners to the tyrosine kinase receptor gene FGFR1. It can rapidly transform to acute myeloid leukemia. Here we report on a case with a t(8;13)(p11.2;q12.1) ZMYM2-FGFR1 fusion, with massive tumor lysis upon tyrosine kinase inhibition with imatinib. Upon reevaluation, we detected trisomy 21 in addition to the translocation. Sequencing revealed a nonsense c.958C →T RUNX1 mutation both at diagnosis and disease progression, resulting in a p.Arg320X carboxyl-terminal truncated RUNX1 protein. This is the first report on an 8p11 MPN with a trisomy 21 RUNX1 mutation.","variants":[{"Name":"NM_001754.5(RUNX1):c.958C>T (p.Arg320Ter)","Chromosome":"21","Start":"34799310","Stop":"34799310","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":610162,"rule_based_match":false,"evidence_text":"c.958C →T","llm_judgment":"PRESENT","evidence":"c.958C →T","abstract_start":480,"abstract_end":489}]}
{"pmid":"27025994","title":"A case of familial amyloid polyneuropathy (FAP ATTR Ile107Val) with proximal muscle weakness in the lower extremities.","abstract":"Proximal dominant muscle weakness is rare in transthyretin (TTR)-related familial amyloid polyneuropathy (FAP). A 69-year-old Japanese man developed numbness and dysesthesia of the first, second and third digits of both hands since 2008. He presented to our hospital with one year history of progressive proximal muscle weakness in the lower extremities since 2013. Neurological examinations revealed predominant proximal muscle weakness and atrophy with areflexia in the lower extremities, decreased superficial sensation in the first, second and third fingers of both hands, and decreased superficial and deep sensation in the lower extremities. Nerve conduction studies revealed an axonal degeneration type of sensorimotor polyneuropathy and bilateral carpal tunnel syndrome. Electromyogram revealed acute and chronic neurogenic changes predominantly in proximal muscles. We performed biopsy of the left quadriceps muscle and observed neurogenic changes in the muscle tissue and an amyloid deposition in the adipose tissue. This amyloid deposition was not seen in endomysium, perimysium and blood vessels. Genetic analysis of the TTR gene revealed the patient was heterozygous for a single nucleotide substitution c.379 A>G, which resulted in the replacement of valine with isoleucine at position 107 of the mature protein. We diagnosed his condition as FAP with Amyloid Transthyretin (ATTR) Ile107Val.","variants":[{"Name":"NM_000371.4(TTR):c.379A>G (p.Ile127Val)","Chromosome":"18","Start":"31598610","Stop":"31598610","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28489,"rule_based_match":true,"evidence_text":"c.379 A>G","llm_judgment":"PRESENT","evidence":"c.379 A>G","abstract_start":1217,"abstract_end":1226}]}
{"pmid":"23840564","title":"Assessment of SLX4 Mutations in Hereditary Breast Cancers.","abstract":"BACKGROUND: SLX4 encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose) polymerase (PARP) inhibitors. Recent studies have reported mutations in SLX4 in a new subtype of Fanconi anemia (FA), FA-P. Monoallelic defects in several FA genes are known to confer susceptibility to breast and ovarian cancers.\nMETHODS AND RESULTS: To determine if SLX4 is involved in breast cancer susceptibility, we sequenced the entire SLX4 coding region in 738 (270 Jewish and 468 non-Jewish) breast cancer patients with 2 or more family members affected by breast cancer and no known BRCA1 or BRCA2 mutations. We found a novel nonsense (c.2469G>A, p.W823*) mutation in one patient. In addition, we also found 51 missense variants [13 novel, 23 rare (MAF<0.1%), and 15 common (MAF>1%)], of which 22 (5 novel and 17 rare) were predicted to be damaging by Polyphen2 (score = 0.65-1). We performed functional complementation studies using p.W823* and 5 SLX4 variants (4 novel and 1 rare) cDNAs in a human SLX4-null fibroblast cell line, RA3331. While wild type SLX4 and all the other variants fully rescued the sensitivity to mitomycin C (MMC), campthothecin (CPT), and PARP inhibitor (Olaparib) the p.W823* SLX4 mutant failed to do so.\nCONCLUSION: Loss-of-function mutations in SLX4 may contribute to the development of breast cancer in very rare cases.","variants":[{"Name":"NM_032444.4(SLX4):c.2469G>A (p.Trp823Ter)","Chromosome":"16","Start":"3591169","Stop":"3591169","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1411823,"rule_based_match":true,"evidence_text":"c.2469G>A, p.W823*","llm_judgment":"PRESENT","evidence":"c.2469G>A, p.W823*","abstract_start":742,"abstract_end":760}]}
{"pmid":"17805552","title":"Alexander disease with occipital predominance and a novel c.799G>C mutation in the GFAP gene.","abstract":"","variants":[{"Name":"NM_002055.5(GFAP):c.799G>C (p.Ala267Pro)","Chromosome":"17","Start":"44911779","Stop":"44911779","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":188174,"rule_based_match":true,"evidence_text":"c.799G>C","llm_judgment":"PRESENT","evidence":"c.799G>C","abstract_start":null,"abstract_end":null}]}
{"pmid":"33359056","title":"X-linked adrenoleukodystrophy caused by a novel mutation presenting with various phenotypes in a Taiwanese family.","abstract":"X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder that primarily affects the white matter of central nervous system and the adrenal cortex. It is caused by mutations in the adenosine triphosphate-binding cassette, subfamily D, member 1 (ABCD1) gene that results in elevated plasma levels of very long chain fatty acids (VLCFAs). The disease is characterized by an unpredictable variation in phenotypic expressions, including childhood cerebral form (CCALD) and adrenomyeloneuropathy (AMN). Genetic analysis is a reliable method for the diagnosis of X-ALD. We reported a 46-year-old male admitted to Department of Neurology, Chang Gung Memorial Hospital with progressive paraparesis and Addison's disease, which was diagnosed when he was around 20-year-old. Plasma levels of VLCFA showed that his C26:0, C24:0/C22:0 and C26:0/C22:0 ratios were significantly elevated. A novel missense mutation (p.Arg163Cys) caused by the nucleotide change c.487C > T in exon 1 was identified in the ABCD1 gene of the proband and his subclinical family members. In this article, we reviewed the mutations that had been reported at the same position with different phenotypes. Given that the nerve conduction study (NCS) of the proband demonstrated a rare finding of demyelinating polyneuropathy with conduction blocks, we also reviewed the findings of NCS in patients with AMN in literature.","variants":[{"Name":"NM_000033.4(ABCD1):c.487C>T (p.Arg163Cys)","Chromosome":"X","Start":"153725753","Stop":"153725753","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":612114,"rule_based_match":true,"evidence_text":"c.487C > T (p.Arg163Cys)","llm_judgment":"PRESENT","evidence":"p.Arg163Cys","abstract_start":908,"abstract_end":919}]}
{"pmid":"28840994","title":"Identification of the PROM1 Mutation p.R373C in a Korean Patient With Autosomal Dominant Stargardt-like Macular Dystrophy.","abstract":"Stargardt-like macular dystrophy 4 (STGD4) is a rare macular dystrophy characterized by bull's eye atrophy of the macula and the underlying retinal pigment epithelium. Patients with STGD4 show decreased central vision, which often progresses to severe vision loss. The PROM1 gene encodes prominin-1, which is a 5-transmembrane glycoprotein also known as CD133 and is involved in photoreceptor disk morphogenesis. PROM1 mutations have been identified as genetic causes for STGD4 and other retinal degenerations such as retinitis pigmentosa. We report a case of STGD4 with a PROM1 p.R373C mutation in a Korean patient. Ophthalmic examinations of a 38-yr old man complaining of decreased visual acuity revealed bilateral atrophic macular lesions consistent with STGD4. Targeted exome sequencing of known inherited retinal degeneration genes revealed a heterozygous missense mutation c.1117C>T (p.R373C) of PROM1, which was confirmed by Sanger sequencing. To the best of our knowledge, this is the first case of a PROM1 mutation causing STGD4 in Koreans.","variants":[{"Name":"NM_006017.3(PROM1):c.1117C>T (p.Arg373Cys)","Chromosome":"4","Start":"16013299","Stop":"16013299","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20649,"rule_based_match":true,"evidence_text":"c.1117C>T (p.R373C)","llm_judgment":"PRESENT","evidence":"c.1117C>T (p.R373C)","abstract_start":880,"abstract_end":899}]}
{"pmid":"23813623","title":"Confirmation of GRHL2 as the gene for the DFNA28 locus.","abstract":"More than 10 years ago, a c.1609_1610insC mutation in the grainyhead-like 2 (GRHL2) gene was identified in a large family with nonsyndromic sensorineural hearing loss, so far presenting the only evidence for GRHL2 being an autosomal-dominant deafness gene (DFNA28). Here, we report on a second large family, in which post-lingual hearing loss with a highly variable age of onset and progression segregated with a heterozygous non-classical splice site mutation in GRHL2. The c.1258-1G>A mutation disrupts the acceptor recognition sequence of intron 9, creating a new AG splice site, which is shifted by only one nucleotide in the 3' direction. cDNA analysis confirmed a p.Gly420Glufs*111 frameshift mutation in exon 10.","variants":[{"Name":"NM_024915.4(GRHL2):c.1258-1G>A","Chromosome":"8","Start":"101631636","Stop":"101631636","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":97553,"rule_based_match":true,"evidence_text":"c.1258-1G>A","llm_judgment":"PRESENT","evidence":"c.1258-1G>A","abstract_start":475,"abstract_end":486}]}
{"pmid":"29355681","title":"Whole exome sequencing identifies a novel mutation (c.333 + 2T > C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease.","abstract":"Dilated Cardiomyopathy (DCM) and cardiac conduction disease (CCD) are two kinds if diseases that can induce heart failure, syncope and even sudden cardiac death (SCD). DCM patients can experience CCD at the same time. In recent research, some disease-causing genes and variants have been identified in patients with DCM and CCD, such as Alpha-Actinin-2 and TNNI3 Interacting Kinase (TNNI3K). In this study, we employed whole-exome sequencing (WES) to explore the potential causative genes in a Chinese family with DCM and CCD. A novel splice site mutation (c.333 + 2 T > C) of TNNI3K was identified and co-segregated with the affected family members. This novel mutation was also absent in 200 healthy local controls and predicted to be disease-causing by Mutationtaster. The splice site mutation (c.333 + 2 T > C) may result in a premature stop codon in exon 4 of the TNNI3K gene and can induce nonsense-mediated mRNA decay. Real-time qPCR also confirmed that the level of TNNI3K mRNA expression was decreased significantly compared with the controls, which may lead to myocardial structural disorder and arrhythmia. In this study we reported the third novel mutation of TNNI3K in DCM and CCD patients which further supported the important role of TNNI3K in heart development and expanded the spectrum of TNNI3K mutations. The results may contribute to the genetic diagnosis and counseling of families with DCM and CCD.","variants":[{"Name":"NM_015978.3(TNNI3K):c.333+2T>C","Chromosome":"1","Start":"74250771","Stop":"74250771","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":581246,"rule_based_match":true,"evidence_text":"c.333 + 2 T > C","llm_judgment":"PRESENT","evidence":"c.333 + 2 T > C","abstract_start":557,"abstract_end":572}]}
{"pmid":"23563732","title":"Screening for variants in 20 genes in 130 unrelated patients with cone-rod dystrophy.","abstract":"Cone-rod dystrophy (CORD) is a hereditary retinal disorder with primary cone impairment and subsequent rod involvement. To date, mutations responsible for CORD have been reported in 24 genes. However, the systemic evaluation of variants in these genes in a cohort of patients is rare, particularly in East Asia. In this study, 58 coding exons from 20 CORD genes, including 35 exons with previously identified mutations in 17 genes and all 23 coding exons for the other 3 genes (GUCY2D, PRPH2 and KCNV2), were analyzed by cycle sequencing on 130 unrelated probands with CORD. Four heterozygous mutations, 1 novel and 3 known, were detected in 4/130 patients, including c.259G>A (p.Asp87Asn) in UNC119, c.2512C>T (p.Arg838Cys) and c.2513G>A (p.Arg838His) in GUCY2D and c.946T>G (p.Trp316Gly) in PRPH2. The result implies a comparatively low rate of mutations in these exons in Chinese patients. These data suggest that in Chinese patients, CORD may be caused by mutations in exons that have not yet been screened or in genes that have yet to be identified. Further analysis of these patients may provide clarification.","variants":[{"Name":"NM_000322.5(PRPH2):c.946T>G (p.Trp316Gly)","Chromosome":"6","Start":"42698390","Stop":"42698390","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":1164655,"rule_based_match":true,"evidence_text":"c.946T>G (p.Trp316Gly) in PRPH2","llm_judgment":"PRESENT","evidence":"c.946T>G (p.Trp316Gly) in PRPH2","abstract_start":767,"abstract_end":798},{"Name":"NM_005148.4(UNC119):c.259G>A (p.Asp87Asn)","Chromosome":"17","Start":"28548667","Stop":"28548667","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":958015,"rule_based_match":true,"evidence_text":"c.259G>A (p.Asp87Asn)","llm_judgment":"PRESENT","evidence":"c.259G>A (p.Asp87Asn)","abstract_start":668,"abstract_end":689}]}
{"pmid":"29576868","title":"A rare cause of primary adrenal insufficiency due to a homozygous Arg188Cys mutation in the","abstract":"Steroidogenic acute regulatory protein (<i>STAR</i>) is a key protein for the intracellular transport of cholesterol to the mitochondrium in endocrine organs (e.g. adrenal gland, ovaries, testes) and essential for the synthesis of all steroid hormones. Several mutations have been described and the clinical phenotype varies strongly and may be grouped into classic lipoid congenital adrenal hyperplasia (LCAH), in which all steroidogenesis is disrupted, and non-classic LCAH, which resembles familial glucocorticoid deficiency (FGD), which affects predominantly adrenal functions. Classic LCAH is characterized by early and potentially life-threatening manifestation of primary adrenal insufficiency (PAI) with electrolyte disturbances and 46,XY disorder of sex development (DSD) in males as well as lack of pubertal development in both sexes. Non-classic LCAH manifests usually later in life with PAI. Nevertheless, life-long follow-up of gonadal function is warranted. We describe a 26-year-old female patient who was diagnosed with PAI early in life without detailed diagnostic work-up. At the age of 14 months, she presented with hyperpigmentation, elevated ACTH and low cortisol levels. As her older brother was diagnosed with PAI two years earlier, she was put on hydrocortisone and fludrocortisone replacement therapy before an Addisonian crisis occurred. Upon review of her case in adulthood, consanguinity was noted in the family. Genetic analysis for PAI revealed a homozygous mutation in the <i>STAR</i> gene (c.562C>T, p.Arg188Cys) in both siblings. This mutation has been previously described in non-classic LCAH. This case illustrates that early onset, familial PAI is likely due to autosomal recessive genetic mutations in known genes causing PAI.\nLEARNING POINTS: In childhood-onset PAI, a genetic cause is most likely, especially in families with consanguinity.Adult patients with an etiologically unsolved PAI should be reviewed repeatedly and genetic work-up should be considered.Knowing the exact genetic diagnosis in PAI is essential for genetic counselling and may allow disease-specific treatment.Young men and women with NCLAH due to homozygous <i>STAR</i> Arg188Cys mutation should be investigated for their gonadal function as hypogonadism and infertility might occur during puberty or in early adulthood.","variants":[{"Name":"NM_000349.3(STAR):c.562C>T (p.Arg188Cys)","Chromosome":"8","Start":"38146051","Stop":"38146051","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":24036,"rule_based_match":true,"evidence_text":"c.562C>T, p.Arg188Cys","llm_judgment":"PRESENT","evidence":"c.562C>T, p.Arg188Cys","abstract_start":1522,"abstract_end":1543}]}
{"pmid":"22074992","title":"Sudden death associated with danon disease in women.","abstract":"Danon disease is an X-linked systemic disorder characterized by left ventricular hypertrophy, mental retardation, and skeletal myopathy affecting young men. Electrocardiogram usually displays a Wolff-Parkinson-White preexcitation pattern. Less has been reported about the phenotype in women, although later-onset cardiac symptoms have been described. The aim of this study was to expand the knowledge of the phenotype of Danon disease in women. We clinically followed and evaluated with echocardiography, cardiac magnetic resonance imaging (cMRI), and genetic testing a family affected by Danon disease in which 2 men and 6 women showed a severe arrhythmogenic phenotype. Affected family members carried a nucleotide substitution at position 294 in exon 3 (c.294 G → A) that changed a tryptophan residue to a stop codon at position W98X in the lysosome-associated membrane protein 2 (LAMP2) gene. Four women died suddenly (1 aborted) at 37 to 54 years of age. Wolff-Parkinson-White pattern with atrioventricular block was detected in 2 of 6 women. Four had successful pregnancies without symptoms of heart failure. cMRI showed late gadolinium enhancement areas in a clinically healthy woman who was a mutation carrier. Two patients underwent heart transplantation; histology of explanted hearts demonstrated severe interstitial fibrosis, hypertrophic cardiomyocytes with cytoplasmic vacuoles, and myofibrillar disarray. In conclusion, LAMP2 mutation can cause a severe arrhythmogenic phenotype in women that includes a high risk of sudden death. cMRI may be useful in women harboring LAMP2 mutations to permit early detection of cardiac involvement and guide timely considerations of implantable cardioverter-defibrillator therapy. Heart transplantation should be considered at onset of heart failure symptoms owing to rapid progression of the disease.","variants":[{"Name":"NM_002294.3(LAMP2):c.294G>A (p.Trp98Ter)","Chromosome":"X","Start":"120455460","Stop":"120455460","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":231248,"rule_based_match":false,"evidence_text":"c.294 G → A","llm_judgment":"PRESENT","evidence":"c.294 G → A","abstract_start":757,"abstract_end":768}]}
{"pmid":"20046085","title":"Hemoglobin Yamagata: hemoglobin variant detected by HbA1c test.","abstract":"Hemoglobin (Hb) Yamagata is a rare Hb variant, which has been reported only twice-one case each in Japan and Korea. This variant arises from a Lys --> Asn substitution due to a mutation of AAA to AAC or AAT at codon 133 of the beta-globin gene. This study reports the third case of a patient detected with Hb Yamagata [HBB: c.399A>T; p.Lys133Asn] and discusses the effect of this variant on HbA1c measurement. This variant was detected in a 70-yr-old Korean man with diabetes mellitus during a routine follow-up. The HbA1c concentration determined using Variant ll Turbo (Bio-Rad, USA) was abnormally high at 47.9%. It was impossible to measure the HbA1c level accurately using Variant ll Thalassemia Mode (Bio-Rad, USA). However, the HbA1c levels analyzed by HLC-723 G7 (Tosoh, Japan), Cobas Integra (Roche, Switzerland) and NycoCard (Axis-Shield, Norway) were 5.0%, 8.0%, and 7.9%, respectively. This study shows that Hb Yamagata interferes with the accurate measurement of HbA1c levels in a diabetic patient. Taking these findings into consideration, we think that an immunoassay or affinity chromatography can be used as an alternate method for measuring the HbA1c level in a patient with this variant. In conclusion, a patient can be inferred to have an Hb variant if the HbA1c concentration is abnormally high or low or if there is a discrepancy between the results obtained using different methods, and if the clinical status of the patient suggests the presence of abnormal Hb. Subsequently, the HbA1c values can be determined by methods based on different principles.","variants":[{"Name":"NM_000518.5(HBB):c.399A>T (p.Lys133Asn)","Chromosome":"11","Start":"5225643","Stop":"5225643","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1320750,"rule_based_match":true,"evidence_text":"HBB: c.399A>T; p.Lys133Asn","llm_judgment":"PRESENT","evidence":"HBB: c.399A>T; p.Lys133Asn","abstract_start":319,"abstract_end":345}]}
{"pmid":"33977028","title":"A founder mutation in the","abstract":"Pyridoxine-dependent epilepsy (PDE) is a relatively rare subgroup of epileptic disorders. They generally present in infancy as an early onset epileptic encephalopathy or seizures, refractory to standard treatments, with rapid and variable responses to vitamin B6 treatment. Whole exome sequencing of three unrelated families identified homozygous pathogenic mutation c.370_373del, p.Asp124fs in <i>PLPBP</i> gene in five persons. Haplotype analysis showed a single shared profile for the affected persons and their parents, leading to a hypothesis about founder effect of the mutation in Saguenay-Lac-St-Jean region of French Canadians. All affected probands also shared one single mitochondrial haplotype T2b3 and two rare variations in the mitochondrial genome m.801A>G and m.5166A>G suggesting that a single individual female introduced <i>PLPBP</i> mutation c.370_373del, p.Asp124fs in Quebec. The mutation p.Asp124fs causes a severe disease phenotype with delayed myelination and cortical/subcortical brain atrophy. The most noteworthy radiological finding in this Quebec founder mutation is the presence of the temporal cysts that can be used as a marker of the disease. Also, both patients, who are alive, had a history of prenatal supplements taken by their mothers as antiemetic medication with high doses of pyridoxine. In the context of suspected PDE in patients with neonatal refractory seizures, treatment with pyridoxine and/or Pyridoxal-5-phophate has to be started immediately and continued until the results of genetic analysis received. Even with early appropriate treatment, neurological outcome of our patient is still poor.","variants":[{"Name":"NM_007198.4(PLPBP):c.370_373del (p.Asp124fs)","Chromosome":"8","Start":"37772803","Stop":"37772806","ReferenceAlleleVCF":"GCAGA","AlternateAlleleVCF":"G","allel_id":495361,"rule_based_match":true,"evidence_text":"c.370_373del, p.Asp124fs","llm_judgment":"PRESENT","evidence":"c.370_373del, p.Asp124fs","abstract_start":367,"abstract_end":391}]}
{"pmid":"33079427","title":"A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4.","abstract":"BACKGROUND: Cerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early-onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with ATP8A2 mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non-progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified.\nMETHODS: Following the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR-based Sanger sequencing.\nRESULTS: A novel homozygous missense variant (c.1339G > A, p.Gly447Arg) in the ATP8A2 gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand-binding pocket. The novel sequence variant occurred within an extremely conserved subregion of the ATP-binding domain.\nCONCLUSION: Our findings expand the spectrum of ATP8A2 mutations and confirm the reported genotype-phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.","variants":[{"Name":"NM_016529.6(ATP8A2):c.1339G>A (p.Gly447Arg)","Chromosome":"13","Start":"25559048","Stop":"25559048","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2477366,"rule_based_match":true,"evidence_text":"c.1339G > A, p.Gly447Arg","llm_judgment":"PRESENT","evidence":"c.1339G > A, p.Gly447Arg","abstract_start":1093,"abstract_end":1117}]}
{"pmid":"29976978","title":"Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency.","abstract":"Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T > C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C > T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C > T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population-specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations.","variants":[{"Name":"NM_007103.4(NDUFV1):c.1156C>T (p.Arg386Cys)","Chromosome":"11","Start":"67611972","Stop":"67611972","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":408448,"rule_based_match":true,"evidence_text":"NDUFV1 c.1156C > T (p.(Arg386Cys))","llm_judgment":"PRESENT","evidence":"NDUFV1 c.1156C > T (p.(Arg386Cys))","abstract_start":965,"abstract_end":999},{"Name":"NM_007103.4(NDUFV1):c.1118T>C (p.Phe373Ser)","Chromosome":"11","Start":"67611934","Stop":"67611934","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":424968,"rule_based_match":true,"evidence_text":"c.1118T > C (p.(Phe373Ser))","llm_judgment":"PRESENT","evidence":"c.1118T > C (p.(Phe373Ser))","abstract_start":628,"abstract_end":655}]}
{"pmid":"33938902","title":"Familial erythrocytosis 2 and von Hippel-Lindau disease in the same pediatric patient.","abstract":"BACKGROUND: Patients with familial erythrocytosis type 2 have no increased risk of von Hippel-Lindau-associated tumors, although mutations in the VHL gene cause both pathologies.\nCASE REPORT: We present a case of a compound heterozygote patient with von Hippel-Lindau disease and familial erythrocytosis type 2. One of the mutations found in our patient, c.416C>G (p.Ser139Cys) of the VHL gene, has not been previously reported. This case is the second one reported where von Hippel-Lindau disease and familial erythrocytosis type 2 coexist in the same individual.\nCONCLUSIONS: Despite the low frequency of familial erythrocytosis type 2 in patients with von Hippel-Lindau disease, the possibility of this diagnosis should be considered to avoid unnecessary invasive studies to explain the polyglobulia in these patients and guarantee an adequate follow-up and vigilance of both diseases.","variants":[{"Name":"NM_000551.4(VHL):c.416C>G (p.Ser139Cys)","Chromosome":"3","Start":"10146589","Stop":"10146589","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":139668,"rule_based_match":true,"evidence_text":"c.416C>G (p.Ser139Cys)","llm_judgment":"PRESENT","evidence":"c.416C>G (p.Ser139Cys)","abstract_start":355,"abstract_end":377}]}
{"pmid":"15776434","title":"Mutation analysis of the HOX paralogous 4-13 genes in children with acute lymphoid malignancies: identification of a novel germline mutation of HOXD4 leading to a partial loss-of-function.","abstract":"The molecular basis of susceptibility to childhood malignant hemopathy remains largely unknown. An excess of skeletal congenital anomalies has been reported among children with hematological malignancy and points towards involvement of developmental genes, like those belonging to the HOX gene family. In addition to their role in embryogenesis, HOX transcription factors are known to be regulators of proliferation and differentiation of hematopoietic cells. We aimed to explore the possibility that germline alterations of HOX genes might be involved in childhood acute lymphoid malignancies. A cohort of 86 children diagnosed with acute lymphoid malignancy was studied, 20 of them concurrently presenting a congenital anomaly of the skeleton. First, we screened for nucleotide changes throughout the HOX genes of paralogous groups 4 to 13 in the 20 patients with skeletal defects, following a skeletal phenotype-based strategy. Subsequently, we extended the HOX mutation screening to the other 66 children having a malignant lymphoproliferative disorder, but without skeletal defects. In total, 16 germline mutations were identified. While 13 changes were also observed in healthy controls, three variants were exclusively found in acute lymphoid malignancy cases. These comprised the germline c.242A>T (p.Glu81Val) missense mutation of HOXD4, detected in two children diagnosed with acute lymphoblastic leukemia (ALL). Furthermore, this mutation was found in association with other specific HOX variants of cluster D (2q31-q37), defining a unique haplotype. Functional analysis of the murine Hoxd4 homolog revealed that mutant Hoxd4 protein had lower transcriptional activity than wild-type protein in vitro. The p.Glu81Val mutation of HOXD4 thus results in a partial loss-of-function, which might be involved in childhood ALL.","variants":[{"Name":"NM_014621.3(HOXD4):c.242A>T (p.Glu81Val)","Chromosome":"2","Start":"176151875","Stop":"176151875","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":29927,"rule_based_match":true,"evidence_text":"c.242A>T (p.Glu81Val)","llm_judgment":"PRESENT","evidence":"c.242A>T (p.Glu81Val)","abstract_start":1297,"abstract_end":1318}]}
{"pmid":"23881933","title":"Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing.","abstract":"BACKGROUND: Over 100 genes have been implicated in the aetiology of amyotrophic lateral sclerosis (ALS). A detailed understanding of their independent and cumulative contributions to disease burden may help guide various clinical and research efforts.\nMETHODS: Using targeted high-throughput sequencing, we characterised the variation of 10 Mendelian and 23 low penetrance/tentative ALS genes within a population-based cohort of 444 Irish ALS cases (50 fALS, 394 sALS) and 311 age-matched and geographically matched controls.\nRESULTS: Known or potential high-penetrance ALS variants were identified within 17.1% of patients (38% of fALS, 14.5% of sALS). 12.8% carried variants of Mendelian disease genes (C9orf72 8.78%; SETX 2.48%; ALS2 1.58%; FUS 0.45%; TARDBP 0.45%; OPTN 0.23%; VCP 0.23%. ANG, SOD1, VAPB 0%), 4.7% carried variants of low penetrance/tentative ALS genes and 9.7% (30% of fALS, 7.1% of sALS) carried previously described ALS variants (C9orf72 8.78%; FUS 0.45%; TARDBP 0.45%). 1.6% of patients carried multiple known/potential disease variants, including all identified carriers of an established ALS variant (p<0.01); TARDBP:c.859G>A(p.[G287S]) (n=2/2 sALS). Comparison of our results with those from studies of other European populations revealed significant differences in the spectrum of disease variation (p=1.7×10(-4)).\nCONCLUSIONS: Up to 17% of Irish ALS cases may carry high-penetrance variants within the investigated genes. However, the precise nature of genetic susceptibility differs significantly from that reported within other European populations. Certain variants may not cause disease in isolation and concomitant analysis of disease genes may prove highly important.","variants":[{"Name":"NM_007375.4(TARDBP):c.859G>A (p.Gly287Ser)","Chromosome":"1","Start":"11022268","Stop":"11022268","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34335,"rule_based_match":true,"evidence_text":"TARDBP:c.859G>A(p.[G287S])","llm_judgment":"PRESENT","evidence":"TARDBP:c.859G>A(p.[G287S])","abstract_start":1136,"abstract_end":1162}]}
{"pmid":"19539840","title":"Carney complex: a clinicopathologic and molecular biological study of a sporadic case, including extracutaneous and cutaneous lesions and a novel mutation of the PRKAR1A gene.","abstract":"BACKGROUND: Carney complex (CNC) is an autosomal dominant disorder associated with multiple neoplasms.\nOBJECTIVE: We report a case of a 40-year-old Caucasian man with a sporadic form of CNC.\nMETHODS: This is a clinicopathologic description and molecular biological study with an emphasis on histopathologic findings.\nRESULTS: The patient presented with multiple cutaneous myxomas, cardiac myxomas, and spotty pigmentation at typical sites. Additionally, a blue nevus, a lipoma, multiple calcifications in both testes, and hypoechogenic areas suspected of being adenomas in the thyroid gland were found. Microscopically, the 2 cardiac and 6 cutaneous myxomas studied manifested a typical appearance, being composed of scattered polygonal, stellate, plump and/or spindle cells in a mucinous matrix containing small, sometimes dilated blood vessels. Of the 6 cutaneous myxomas, only in one lesion was there an abnormal epithelial component (tiny basaloid buds and a horn cyst). Molecular biologic study revealed a heterozygous shift mutation c.796dupA in exon 10 of the PRKAR1A gene. Physical examination and genetic testing of family members (both parents and two brothers) for the PRKAR1A mutation were negative, as was analysis of the peripheral blood of 110 randomly selected, unrelated healthy individuals for the above mutation. These findings suggest sporadic disease and a novel mutation in our patient.\nLIMITATIONS: None.\nCONCLUSION: Herein we report a case of sporadic CNC in which a novel mutation in PRKAR1A was identified.","variants":[{"Name":"NM_002734.5(PRKAR1A):c.796dup (p.Thr266fs)","Chromosome":"17","Start":"68528895","Stop":"68528896","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TA","allel_id":2905215,"rule_based_match":true,"evidence_text":"c.796dupA","llm_judgment":"PRESENT","evidence":"c.796dupA","abstract_start":1039,"abstract_end":1048}]}
{"pmid":"30074255","title":"Novel THRB mutation analysis in congenital hypothyroidism with thyroid dysgenesis.","abstract":"Thyroid dysgenesis (TD) accounts for most cases of congenital hypothyroidism. Although mutations in thyroid hormone receptor β (THRB) have been identified in TD, the mutational spectrum of THRB and phenotype-genotype correlations have not been fully elucidated. In this study, we aimed to find mutations of THRB, examine the functions of these mutations, and attempt to elucidate the relationship between THRB and TD. Thus, we screened the exons of THRB in 280 patients with TD and 200 normal subjects in samples collected from China. We performed cell morphology assays, MTT assays, flow cytometric analyses, and a quantitative reverse-transcription polymerase chain reaction in human thyroid follicular epithelial cells (Nthy-ori cell line) to examine the impact of THRB mutations. In two unrelated patients, two novel missense mutations, c.76G>A (p.D26N) and c.107G>A (p.C36Y), were identified in THRB. Functional studies suggested that the C36Y mutant caused changes in morphology, inhibiting cell proliferation and promoting apoptosis in a human thyroid cell line. In addition, we found that messenger RNA expressions of thyroglobulin (TG) and the Na<sup>+</sup> /I<sup>-</sup> symporter (NIS) were decreased in a time-dependent manner in mutant THRB compared with the wild type. To our knowledge, this is the first study to document the prevalence of THRB mutations and the genotype-phenotype spectrum of TD in a Chinese population. We characterized the function of a C36Y mutation, which reduced cell proliferation and increased cell death in thyroid epithelial cells. This study provides further evidence for genetic THRB defects and disease mechanisms in TD.","variants":[{"Name":"NM_001354712.2(THRB):c.107G>A (p.Cys36Tyr)","Chromosome":"3","Start":"24190250","Stop":"24190250","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3730985,"rule_based_match":true,"evidence_text":"c.107G>A (p.C36Y)","llm_judgment":"PRESENT","evidence":"c.107G>A (p.C36Y)","abstract_start":862,"abstract_end":879}]}
{"pmid":"28263186","title":"Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia.","abstract":"Shohat-type spondyloepimetaphyseal dysplasia (SEMD) is a skeletal dysplasia that affects cartilage development. Similar skeletal disorders, such as spondyloepiphyseal dysplasias, are linked to mutations in type II collagen (COL2A1), but the causative gene in SEMD is not known. Here, we have performed whole-exome sequencing to identify a recurrent homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK domain containing 1 (DDRGK1) in 4 families affected by SEMD. In zebrafish, ddrgk1 deficiency disrupted craniofacial cartilage development and led to decreased levels of the chondrogenic master transcription factor sox9 and its downstream target, col2a1. Overexpression of sox9 rescued the zebrafish chondrogenic and craniofacial phenotype generated by ddrgk1 knockdown, thus identifying DDRGK1 as a regulator of SOX9. Consistent with these results, Ddrgk1-/- mice displayed delayed limb bud chondrogenic condensation, decreased SOX9 protein expression and Col2a1 transcript levels, and increased apoptosis. Furthermore, we determined that DDRGK1 can directly bind to SOX9 to inhibit its ubiquitination and proteasomal degradation. Taken together, these data indicate that loss of DDRGK1 decreases SOX9 expression and causes a human skeletal dysplasia, identifying a mechanism that regulates chondrogenesis via modulation of SOX9 ubiquitination.","variants":[{"Name":"NM_023935.3(DDRGK1):c.408+1G>A","Chromosome":"20","Start":"3200341","Stop":"3200341","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":480578,"rule_based_match":true,"evidence_text":"c.408+1G>A","llm_judgment":"PRESENT","evidence":"c.408+1G>A","abstract_start":360,"abstract_end":370}]}
{"pmid":"25158988","title":"Molecular basis and bleeding manifestations of factor XI deficiency in 11 Turkish families.","abstract":"Factor XI (FXI) deficiency is an autosomal bleeding disorder characterized by variable bleeding tendency. In the present study, the gene encoding FXI (F11) was analyzed by direct sequencing in 33 individuals belonging to 11 unrelated Turkish families, and the bleeding tendency was quantitatively assessed by means of a bleeding questionnaire in 27 individuals with low FXI clotting activity and/or mutated F11 gene. We identified 10 distinct mutations (five missense, three nonsense and two splice site), four of which were novel. No mutation was found in one family. Of the four novel mutations, homozygosity for a c.89T>C (p.Phe30Ser) mutation and compound heterozygosity for a c.646G>A (p.Asp216Asn) mutation with the known c.403G>T (p.Glu135) type II Jewish mutation were associated with severe deficiency, whilst heterozygosity for the novel c.1655A>C (p.His552Arg) and c.1627G>A (p.Glu543Lys) mutations was associated with partial deficiency. p.Glu135 was found in 19% (5/27) of the mutated alleles. Bleeding score was positive in 57% (4/7) of individuals with severe and 39% (7/18) of those with partial deficiency. It was significantly correlated with clinical severity of bleeding (r = 0.43, P = 0.02), but not with FXI clotting activity (P > 0.05). There was no optimal cut-off level of the bleeding score that could predict FXI deficiency. We conclude that the spectrum of mutations found in this study reflects the genetic heterogeneity of FXI deficiency in the Turkish population. Quantitative assessment of the bleeding symptoms by a bleeding questionnaire seems to be useful for evaluating the severity of bleeding episodes, but it can not be recommended as a screening tool for FXI deficiency.","variants":[{"Name":"NM_000128.4(F11):c.1627G>A (p.Glu543Lys)","Chromosome":"4","Start":"186287734","Stop":"186287734","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":543499,"rule_based_match":true,"evidence_text":"c.1627G>A (p.Glu543Lys)","llm_judgment":"PRESENT","evidence":"c.1627G>A (p.Glu543Lys)","abstract_start":876,"abstract_end":899}]}
{"pmid":"18809835","title":"CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy.","abstract":"OBJECTIVE: To search for CDKL5 gene mutations in boys presenting with severe early-onset encephalopathy and intractable epilepsy, a clinical picture very similar to that already described in girls with CDKL5 mutations.\nMETHODS: Eight boys (age range 3-16 years, mean age 8.5 years, SD 4.38) with severe or profound mental retardation and early-onset intractable seizures were selected for CDKL5 gene mutation screening by denaturing high-performance liquid chromatography analysis.\nRESULTS: We found three unrelated boys carrying three different missense mutations of the CDKL5 gene: c.872G>A (p.C291Y), c.863C>T (p.T288I), and c.533G>C (p.R178P). They presented early-onset, polymorphous, and drug-resistant seizures, mostly myoclonic and tonic or spasms. EEG showed epileptiform abnormalities which were multifocal during wakefulness, and pseudoperiodic bisynchronous during sleep.\nCONCLUSIONS: This study describes three boys carrying CDKL5 missense mutations and their detailed clinical and EEG data, and indicates that CDKL5 gene mutations may represent a cause of severe or profound mental retardation and early-onset intractable seizures, also in boys. Screening for CDKL5 mutations is strongly recommended in individuals with these clinical features.","variants":[{"Name":"NM_001323289.2(CDKL5):c.863C>T (p.Thr288Ile)","Chromosome":"X","Start":"18598499","Stop":"18598499","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26543,"rule_based_match":true,"evidence_text":"c.863C>T (p.T288I)","llm_judgment":"PRESENT","evidence":"c.863C>T (p.T288I)","abstract_start":604,"abstract_end":622},{"Name":"NM_001323289.2(CDKL5):c.872G>A (p.Cys291Tyr)","Chromosome":"X","Start":"18598508","Stop":"18598508","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26544,"rule_based_match":true,"evidence_text":"c.872G>A (p.C291Y)","llm_judgment":"PRESENT","evidence":"c.872G>A (p.C291Y)","abstract_start":584,"abstract_end":602},{"Name":"NM_001323289.2(CDKL5):c.533G>C (p.Arg178Pro)","Chromosome":"X","Start":"18584332","Stop":"18584332","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":33489,"rule_based_match":true,"evidence_text":"c.533G>C (p.R178P)","llm_judgment":"PRESENT","evidence":"c.533G>C (p.R178P)","abstract_start":628,"abstract_end":646}]}
{"pmid":"25332820","title":"Potential genetic predisposition for anthracycline-associated cardiomyopathy in families with dilated cardiomyopathy.","abstract":"OBJECTIVE: Anthracyclines are successfully used in cancer treatment, but their use is limited by their cardiotoxic side effects. Several risk factors for anthracycline-associated cardiomyopathy (AACM) are known, yet the occurrence of AACM in the absence of these known risk factors suggests that other factors must play a role. The purpose of this study was to evaluate whether a genetic predisposition for dilated cardiomyopathy (DCM) could be a potential risk factor for AACM.\nMETHODS: A hospital-based registry of 162 DCM families and two hospital-based registries of patients with cancer treated with systemic cancer therapy (n>6000) were reviewed focusing on AACM. Selected patients with AACM/DCM families with possible AACM (n=21) were analysed for mutations in cardiomyopathy-associated genes and presymptomatic cardiological evaluation of first-degree relatives was performed.\nRESULTS: We identified five DCM families with AACM and one patient with AACM with a family member with a possible early sign of mild DCM. Pathogenic MYH7 mutations were identified in two of these six families. The MYH7 c.1633G>A (p.Asp545Asn) and c.2863G>A (p.Asp955Asn) mutations (one double mutant allele) were identified in a DCM family with AACM. The MYH7 c.4125T>A (p.Tyr1375X) mutation was identified in one patient with AACM.\nCONCLUSIONS: This study further extends the hypothesis that a genetic predisposition to DCM could be a potential risk factor for AACM.","variants":[{"Name":"NM_000257.4(MYH7):c.4125T>A (p.Tyr1375Ter)","Chromosome":"14","Start":"23418254","Stop":"23418254","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":572768,"rule_based_match":true,"evidence_text":"MYH7 c.4125T>A (p.Tyr1375X)","llm_judgment":"PRESENT","evidence":"MYH7 c.4125T>A (p.Tyr1375X)","abstract_start":1240,"abstract_end":1267},{"Name":"NM_000257.4(MYH7):c.2863G>A (p.Asp955Asn)","Chromosome":"14","Start":"23423966","Stop":"23423966","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":258804,"rule_based_match":true,"evidence_text":"MYH7 c.2863G>A (p.Asp955Asn)","llm_judgment":"PRESENT","evidence":"p.Asp955Asn","abstract_start":1143,"abstract_end":1154},{"Name":"NM_000257.4(MYH7):c.1633G>A (p.Asp545Asn)","Chromosome":"14","Start":"23427840","Stop":"23427840","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":258810,"rule_based_match":true,"evidence_text":"MYH7 c.1633G>A (p.Asp545Asn)","llm_judgment":"PRESENT","evidence":"MYH7 c.1633G>A (p.Asp545Asn)","abstract_start":1099,"abstract_end":1127}]}
{"pmid":"20504331","title":"Screening mutations of OTOF gene in Chinese patients with auditory neuropathy, including a familial case of temperature-sensitive auditory neuropathy.","abstract":"BACKGROUND: Mutations in OTOF gene, encoding otoferlin, cause DFNB9 deafness and non-syndromic auditory neuropathy (AN). The aim of this study is to identify OTOF mutations in Chinese patients with non-syndromic auditory neuropathy.\nMETHODS: 73 unrelated Chinese Han patients with AN, including one case of temperature sensitive non-syndromic auditory neuropathy (TS-NSRAN) and 92 ethnicity-matched controls with normal hearing were screened. Forty-five pairs of PCR primers were designed to amplify all of the exons and their flanking regions of the OTOF gene. The PCR products were sequenced and analyzed for mutation identification.\nRESULTS: Five novel possibly pathogenic variants (c.1740delC, c.2975_2978delAG, c.1194T>A, c.1780G>A, c.4819C > T) were identified in the group of 73 AN patients, in which two novel mutant alleles (c.2975_2978delAG + c.4819C > T) were identified in one Chinese TS-NSRAN case. Besides, 10 non-pathogenic variants of the OTOF gene were found in AN patients and controls.\nCONCLUSIONS: Screening revealed that mutations in the OTOF gene account for AN in 4 of 73(5.5%) sporadic AN patients, which shows a lower genetic load of that gene in contrast to the previous studies based on other populations. Notably, we found two novel mutant alleles related to temperature sensitive non-syndromic auditory neuropathy. This mutation screening study further confirms that the OTOF gene contributes to ANs and to TS-NSRAN.","variants":[{"Name":"NM_194248.3(OTOF):c.4819C>T (p.Arg1607Trp)","Chromosome":"2","Start":"26465010","Stop":"26465010","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76714,"rule_based_match":true,"evidence_text":"c.4819C > T","llm_judgment":"PRESENT","evidence":"c.4819C > T","abstract_start":738,"abstract_end":749},{"Name":"NM_194248.3(OTOF):c.1194T>A (p.Asp398Glu)","Chromosome":"2","Start":"26484485","Stop":"26484485","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":57330,"rule_based_match":true,"evidence_text":"c.1194T>A","llm_judgment":"PRESENT","evidence":"c.1194T>A","abstract_start":716,"abstract_end":725},{"Name":"NM_194248.3(OTOF):c.1740del (p.Ser581fs)","Chromosome":"2","Start":"26480849","Stop":"26480849","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":76690,"rule_based_match":true,"evidence_text":"c.1740delC","llm_judgment":"PRESENT","evidence":"c.1740delC","abstract_start":686,"abstract_end":696},{"Name":"NM_194248.3(OTOF):c.1780G>A (p.Glu594Lys)","Chromosome":"2","Start":"26480809","Stop":"26480809","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76691,"rule_based_match":true,"evidence_text":"c.1780G>A","llm_judgment":"PRESENT","evidence":"c.1780G>A","abstract_start":727,"abstract_end":736}]}
{"pmid":"38527509","title":"Clinical and genetic spectrum of 6 cases with asparagine synthetase deficiency","abstract":"<b>Objective:</b> To explore the clinical and genetic characteristics of asparagine synthase deficiency. <b>Methods:</b> Case series studies. Retrospective analysis and summary of the clinical data of 6 cases with asparagine synthase deficiency who were diagnosed by genetic testing and admitted to the Third Affiliated Hospital of Zhengzhou University from May 2017 to April 2023 were analyzed retrospectively. The main clinical features, laboratory and imaging examination characteristics of the 6 cases were summarized, and the gene variation sites of them were analyzed. <b>Results:</b> All of the 6 cases were male, with onset ages ranging from 1 month to 1 year and 4 months. All of the 6 cases had cognitive and motor developmental delay, with 3 cases starting with developmental delay, 3 cases starting with convulsions and later experiencing developmental arrest or even regression. All of 6 cases had epilepsy, in whom 2 cases with severe microcephaly developed epileptic encephalopathy in the early stages of infancy with spasms as the main form of convulsions, 4 cases with mild or no microcephaly gradually evolved into convulsions with no fever after multiple febrile convulsions with focal seizures, tonic clonic seizures and tonic seizure as the main forms of convulsions. Three cases of 4 gradually developed into stagnation or even regression of development and ataxia after multiple convulsions with no fever. There were normal cranial imaging in 2 cases, dysplasia of the brains in 1 cases, frontal lobe apex accompanied by abnormal white matter signal in the frontal lobe and thin corpus callosum in 1 case, thin corpus callosum and abnormal lateral ventricular morphology in 1 case, and normal in early stage, but gradually developing into cerebellar atrophy at the age of 5 years and 9 months in 1 case. Two cases underwent visual evoked potential tests, the results of which were both abnormal. Three cases underwent auditory evoked potential examination, with 1 being normal and 2 being abnormal. All of 6 cases had variations in the asparagine synthase gene, with 2 deletion variations and 7 missense variations. The variations of 2 cases had not been reported so far, including c.1341_1343del and c.1283A>G, c.1165_1167del and c.1075G>A. The follow-up time ranged from 3 months to 53 months. Two cases who had severe microcephaly died in infancy, while the other 4 cases with mild or no microcephaly were in survival states until the follow-up days but the control of epilepsy was poor. <b>Conclusions:</b> Asparagine synthase deficiency has a certain degree of heterogeneity in clinical phenotype. Children with obvious microcephaly often present as severe cases, while children with mild or no microcephaly have relatively mild clinical manifestations. The variation of asparagine synthetase gene is mainly missense variation.","variants":[{"Name":"NM_001673.5(ASNS):c.1075G>A (p.Val359Met)","Chromosome":"7","Start":"97855415","Stop":"97855415","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1924923,"rule_based_match":true,"evidence_text":"c.1075G>A","llm_judgment":"PRESENT","evidence":"c.1075G>A","abstract_start":2254,"abstract_end":2263}]}
{"pmid":"37340965","title":"Novel mutations in","abstract":"Oocyte maturation arrest (OMA) refers to a rare clinical phenomenon of oocyte maturation disorder caused by abnormal meiosis, which is also one of the primary causes of female infertility. The clinical manifestations of these patients are often characterized with failure to obtain mature oocytes after repeated ovulation stimulation and/or induced <i>in vitro</i> maturation. To date, mutations in <i>PATL2</i>, <i>TUBB8</i> and <i>TRIP13</i> have been demonstrated to be associated with OMA, but studies on the genetic-based factors and mechanisms of OMA are still incomplete. In this study, peripheral blood from 35 primary infertile women characterized with recurrent OMA during assisted reproductive technology (ART) were subjected to whole-exome sequencing (WES). By using Sanger sequencing and co-segregated analysis, we identified four pathogenic variants in <i>TRIP13</i>. Proband 1 had a homozygous missense mutation of c.859A>G appeared on the 9th exon, which resulted in substitution of Ile287 to valine (p.Ile287Val); proband 2 had a homozygous missense mutation of c.77A>G on the 1st exon, which resulted in substitution of His26 to arginine (p.His26Arg); and proband 3 had compound heterozygous mutations of c.409G>A and c.1150A>G on the 4th and 12th exon, which resulted in the substitutions of Asp137 to asparagine (p.Asp137Asn) and Ser384 to glycine (p.Ser384Gly) in the encoded protein respectively. Three of these mutations have not been reported previously. Further, transfection of plasmids harboring the respective mutated <i>TRIP13</i> in HeLa cells resulted in changes in TRIP13 expression and abnormal cell proliferation as demonstrated by western blotting and cell proliferation assay respectively. This study further summarizes the <i>TRIP13</i> mutations reported previously and expands the mutation spectrum of <i>TRIP13</i> pathogenic variants, thereby providing a valuable reference for further research on the pathogenic mechanism of OMA associated with <i>TRIP13</i> mutations.","variants":[{"Name":"NM_004237.4(TRIP13):c.77A>G (p.His26Arg)","Chromosome":"5","Start":"893075","Stop":"893075","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":965774,"rule_based_match":true,"evidence_text":"c.77A>G","llm_judgment":"PRESENT","evidence":"c.77A>G","abstract_start":1079,"abstract_end":1086}]}
{"pmid":"17893649","title":"HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations?","abstract":"PURPOSE: To analyze if mutations in HCCS, encoding the mitochondrial holocytochrome c-type synthase, are associated with phenotypes other than the microphthalmia with linear skin defects (MLS) syndrome, including severe eye malformations such as microphthalmia and/or anophthalmia. In addition, we investigated the impact of the p.E159K missense mutation on sorting of HCCS to mitochondria and its functional integrity.\nMETHODS: In a cohort of 27 females obtained from a population-based study on infants and fetuses with congenital eye malformations we performed mutation analysis of HCCS by PCR amplification of the coding exons and direct sequencing. The X-inactivation pattern was determined by analyzing the methylation pattern at the AR locus in one patient. For functional analysis of the identified missense mutation, we transfected CHO-K1 cells with wild-type HCCS or HCCS E159K mutant construct and analyzed subcellular localization of the expressed proteins by immunofluorescence analysis and confocal microscopy. Functional integrity of the mutated HCCS protein was investigated by complementation studies in yeast. Therefore, we ectopically expressed HCCS wild type and the E159K mutant in the S. cerevisiae strain B-8025, carrying a deletion of the HCCS ortholog CYC3, and analyzed the capacity of the yeast strain to grow on nonfermentable carbon sources.\nRESULTS: We detected the heterozygous c.475G>A mutation in exon 5 of HCCS, predicting an amino acid substitution of the highly conserved glutamate at position 159 by lysine, in a female presenting with bilateral microphthalmia and sclerocornea. This point mutation was not found on more than 460 X chromosomes. We identified a skewed X-inactivation in the patient's peripheral blood cells. Similar to HCCS wild type, ectopically expressed HCCS E159K was targeted to mitochondria in CHO-K1 cells. In contrast, expression of HCCS E159K did not complement respiratory growth of the CYC3-deficient yeast strain B-8025, while wild-type HCCS and the yeast heme lyase Cyc3p could rescue growth on nonfermentable carbon sources.\nCONCLUSIONS: Identification of the novel missense mutation p.E159K of HCCS, which leads to loss-of-function of the encoded holocytochrome c-type synthase, in a sporadic female patient with microphthalmia of both eyes and bilateral sclerocornea may suggest HCCS as candidate for severe ocular manifestations.","variants":[{"Name":"NM_005333.5(HCCS):c.475G>A (p.Glu159Lys)","Chromosome":"X","Start":"11118574","Stop":"11118574","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":34296,"rule_based_match":true,"evidence_text":"c.475G>A","llm_judgment":"PRESENT","evidence":"c.475G>A","abstract_start":1409,"abstract_end":1417}]}
{"pmid":"32400968","title":"Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy.","abstract":"BACKGROUND: To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A-related developmental epileptic encephalopathy (DEE).\nMETHODS: We enrolled five DEE patients with five de novo variants of the SCN2A. Functional analysis and pharmacological features of Nav1.2 channel protein expressed in HEK293T cells were characterized by whole-cell patch-clamp recording.\nRESULTS: The phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D) variants showed similar characteristics, including early seizure onset with severe to profound intellectual disability. Electrophysiological recordings revealed a hyperpolarizing shift in the voltage dependence of the activation curve and smaller recovery time constants of fast-inactivation than in wild type, indicating a prominent gain of function (GOF). Moreover, pharmacological electrophysiology showed that phenytoin inhibited over a 70% peak current and was more effective than oxcarbazepine and carbamazepine. In contrast, c.4972C>T (p.P1658S) and c.5317G>A (p.A1773T) led to loss of function (LOF) changes, showing reduced current density and enhanced fast inactivation. Both showed seizure onset after 3 months of age with moderate development delay. Interestingly, we discovered that choreoathetosis was a specific phenotype feature.\nCONCLUSION: These findings provided the insights into the phenotype-genotype-funotype relationships of SCN2A-related DEE. The preliminary evaluation using the distinct hints of GOF and LOF helped plan the treatment, and the next precise step should be electrophysiological study.","variants":[{"Name":"NM_001040142.2(SCN2A):c.2995G>A (p.Glu999Lys)","Chromosome":"2","Start":"165354267","Stop":"165354267","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":201348,"rule_based_match":true,"evidence_text":"c.2995G>A(p.E999K)","llm_judgment":"PRESENT","evidence":"c.2995G>A(p.E999K)","abstract_start":438,"abstract_end":456},{"Name":"NM_001040142.2(SCN2A):c.4015A>G (p.Asn1339Asp)","Chromosome":"2","Start":"165374727","Stop":"165374727","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1334254,"rule_based_match":true,"evidence_text":"c.4015A>G(p. N1339D)","llm_judgment":"PRESENT","evidence":"c.4015A>G(p. N1339D)","abstract_start":462,"abstract_end":482},{"Name":"NM_001040142.2(SCN2A):c.4712T>C (p.Ile1571Thr)","Chromosome":"2","Start":"165386906","Stop":"165386906","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1334257,"rule_based_match":true,"evidence_text":"c.4712T>C(p. I1571T)","llm_judgment":"PRESENT","evidence":"c.4712T>C(p. I1571T)","abstract_start":416,"abstract_end":436},{"Name":"NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr)","Chromosome":"2","Start":"165389123","Stop":"165389123","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":201400,"rule_based_match":true,"evidence_text":"c.5317G>A (p.A1773T)","llm_judgment":"PRESENT","evidence":"c.5317G>A (p.A1773T)","abstract_start":1040,"abstract_end":1060},{"Name":"NM_001040142.2(SCN2A):c.4972C>T (p.Pro1658Ser)","Chromosome":"2","Start":"165388778","Stop":"165388778","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":972925,"rule_based_match":true,"evidence_text":"c.4972C>T (p.P1658S)","llm_judgment":"PRESENT","evidence":"c.4972C>T (p.P1658S)","abstract_start":1015,"abstract_end":1035}]}
{"pmid":"20883402","title":"Familial cases of atypical clinical features genetically diagnosed as LEOPARD syndrome (multiple lentigines syndrome).","abstract":"Five familial cases exhibited ephelides-like multiple lentigines, and we examined three of them, a mother and two sons. All three patients presented with small dark-brown maculae on the face and neck and electrocardiographic abnormalities. These findings sufficed to fulfill the criteria for LEOPARD syndrome (multiple lentigines syndrome), although they lacked five of seven major clinical features. However, the family members presented with a webbed neck and pectus excavatum, which are more frequently seen in Turner or Noonan syndrome. Histological examination of the lentigines revealed slightly elongated rete ridges, a hyperpigmented basal layer, and melanophages in the papillary dermis. Direct sequencing of the patients' genomic DNA revealed that all three had a consistent missense mutation [c.1403C > T (p.T468M)] in the PTPN11 gene, confirming LEOPARD syndrome with an atypical phenotype. It was suggested that LEOPARD syndrome shows a diverse phenotype but its diagnosis can be verified by mutation analysis.","variants":[{"Name":"NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met)","Chromosome":"12","Start":"112488466","Stop":"112488466","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":28370,"rule_based_match":true,"evidence_text":"c.1403C > T (p.T468M)","llm_judgment":"PRESENT","evidence":"c.1403C > T (p.T468M)","abstract_start":804,"abstract_end":825}]}
{"pmid":"34702808","title":"Two novel Warburg micro syndrome 1 cases caused by pathogenic variants in RAB3GAP1.","abstract":"In this study, we detected a novel pathogenic variant and a previously reported variant in RAB3GAP1 by whole-exome sequencing (NM_001172435.2: c.1552C>T, p.Gln518*; c.1471C>T, p.Arg491*). The first patient is a 3-year-old girl who presented with bilateral congenital cataracts, developmental delay, abnormal craniofacial features, drug-resistant constipation, and corpus callosum hypoplasia. The proband of the second family is a 13-year-old boy who suffers from developmental delay, quadriplegia, intellectual disability, abnormal craniofacial features, and corpus callosum hypoplasia.","variants":[{"Name":"NM_012233.3(RAB3GAP1):c.1471C>T (p.Arg491Ter)","Chromosome":"2","Start":"135134005","Stop":"135134005","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":511319,"rule_based_match":true,"evidence_text":"c.1471C>T, p.Arg491*","llm_judgment":"PRESENT","evidence":"c.1471C>T, p.Arg491*","abstract_start":165,"abstract_end":185}]}
{"pmid":"26829733","title":"Analysis of L2HGDH gene mutation in a patient with 2-hydroxyglutaric aciduria","abstract":"OBJECTIVE: To explore pathogenic mutation in a family affected with 2-hydroxyglutaric aciduria.\nMETHODS: Exons of 3 candidate genes, including L2HGDH, D2HGDH and SLC25A1, were amplified with polymerase chain reaction and subjected to direct sequencing.\nRESULTS: DNA sequencing has found that the proband and his affected younger brother have both carried a heterozygous mutation c.845G>A (p.R282Q) in the exon 7 of the L2HGDH gene. The same mutation was not detected in the his sister who was healthy. Pedigree analysis has confirmed that the above mutation was inherited from the mother. No mutation was detected in exons and flanking sequences of the D2HGDH and SLC25A1 genes.\nCONCLUSION: Mutation of the L2HGDH gene probably underlies the 2-hydroxyglutaric aciduria in this family.","variants":[{"Name":"NM_024884.3(L2HGDH):c.845G>A (p.Arg282Gln)","Chromosome":"14","Start":"50269224","Stop":"50269224","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":841538,"rule_based_match":true,"evidence_text":"c.845G>A (p.R282Q)","llm_judgment":"PRESENT","evidence":"c.845G>A (p.R282Q)","abstract_start":379,"abstract_end":397}]}
{"pmid":"23348830","title":"Welander distal myopathy caused by an ancient founder mutation in TIA1 associated with perturbed splicing.","abstract":"Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness, which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM-associated haplotype followed by whole exome sequencing. Within the conserved haplotype, we identified a single heterozygous mutation c.1150G>A (p.E384K) in T-cell intracellular antigen-1 (TIA1) in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing, and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7, and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared with controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1,050 years, which coincides with the epoch of early seafaring across the Baltic Sea.","variants":[{"Name":"NM_022173.4(TIA1):c.1150G>A (p.Glu384Lys)","Chromosome":"2","Start":"70212730","Stop":"70212730","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49919,"rule_based_match":true,"evidence_text":"c.1150G>A (p.E384K)","llm_judgment":"PRESENT","evidence":"c.1150G>A (p.E384K)","abstract_start":414,"abstract_end":433}]}
{"pmid":"25988908","title":"A novel missense NMNAT1 mutation identified in a consanguineous family with Leber congenital amaurosis by targeted next generation sequencing.","abstract":"Leber congenital amaurosis is the earliest onset and most severe inherited retinal dystrophy. Mutations in 21 genes have been identified to be responsible for LCA. To detect the causative variants, we performed targeted next generation sequencing in two affected siblings of a consanguineous Chinese family with suspected LCA. A novel homozygous missense mutation (c.721C>T, p. Pro241Ser) of NMNAT1 has been identified. The mutation was inherited from their consanguineous parents who were heterozygous and was absent in 300 unrelated healthy individuals. NMNAT1, which encodes the nicotinamide mononucleotide adenylyltransferase 1, has been recently identified to be one of the LCA-causing genes. Our results expanded the spectrum of mutations in NMNAT1. In this study, targeted next generation sequencing provides an accurate and efficient method for identifying mutations in hereditary diseases with highly genetic and clinical heterogeneity.","variants":[{"Name":"NM_022787.4(NMNAT1):c.721C>T (p.Pro241Ser)","Chromosome":"1","Start":"9982582","Stop":"9982582","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2898157,"rule_based_match":true,"evidence_text":"c.721C>T, p. Pro241Ser","llm_judgment":"PRESENT","evidence":"c.721C>T, p. Pro241Ser","abstract_start":365,"abstract_end":387}]}
{"pmid":"23683095","title":"WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome.","abstract":"Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude ∼500 arRP mutations in ∼20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Løken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed 'sub-clinical' renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes.","variants":[{"Name":"NM_025132.4(WDR19):c.2129T>C (p.Leu710Ser)","Chromosome":"4","Start":"39231943","Stop":"39231943","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39660,"rule_based_match":true,"evidence_text":"c.2129T>C","llm_judgment":"PRESENT","evidence":"c.2129T>C","abstract_start":759,"abstract_end":768}]}
{"pmid":"27179218","title":"Identification of a novel inherited ALK variant M1199L in the WNT type of medulloblastoma.","abstract":"Rearrangements involving the ALK gene were identified in a variety of cancers, including paediatric tumour neuroblastoma where presence of ALK expression is also associated with adverse prognosis. Microarrays data indicate that ALK is expressed in another paediatric tumour - medulloblastoma. Therefore, we investigated if the ALK gene is mutated in medulloblastoma and performed simultaneously the molecular profiling of tumours. Tumours from sixty-four medulloblastoma patients were studied for detection of ALK alterations in exons 23 and 25 using Sanger method. The molecular subtypes of tumours were identified by detection of mutations in the CTNNB1 gene, monosomy 6 and by immunohistochemistry using a panel of representative antibodies. Among three ALK variants detected two resulted in intron variants (rs3738867, rs113866835) and the third one was a novel heterozygous variant c.3595A>T in exon 23 identified in the WNT type of tumour. It resulted in methionine to leucine substitution at codon position 1199 (M1199L) of the kinase domain of ALK protein. Results of analysis using three in silico algorithms confirmed the pathogenicity of this single nucleotide variation. The same gene alteration was detected in both patient and maternal peripheral blood leukocytes indicating an inherited type of the detected variant. Presence of ALK expression in tumour tissue was confirmed by immunohistochemistry. The tumour was diagnosed as classic medulloblastoma, however with visible areas of focal anaplastic features. The patient has been disease free for 6 years since diagnosis. This is the first evidence of an inherited ALK variant in the WNT type of medulloblastoma, what altogether with presence of ALK expression may point towards involvement of the ALK gene in this type of tumours.","variants":[{"Name":"NM_004304.5(ALK):c.3595A>T (p.Met1199Leu)","Chromosome":"2","Start":"29220756","Stop":"29220756","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":558360,"rule_based_match":true,"evidence_text":"c.3595A>T","llm_judgment":"PRESENT","evidence":"c.3595A>T","abstract_start":887,"abstract_end":896}]}
{"pmid":"32386048","title":"CREBBP gene mutation in an infant with Rubinstein-Taybi syndrome.","abstract":"Rubinstein-Taybi syndrome (RSTS), also known as broad thumb-great toe syndrome or broad digits syndrome, is a rare autosomal dominant genetic disease. The main features of the patients are craniofacial dysmorphisms, skeletal malformations, and delay of growth and psychomotor development. In this case, the child has a typical RSTS specific face and growth retardation, with atypical indirect inguinalhemia. A heterozygous mutation, C. 4492 C>T (p. Arg1498Ter), was found in the exon of CREBBP gene by gene sequencing. It was a nonsense mutation, which leads to the premature termination of peptide synthesis. The mutation was not observed in the child's parents, which may be a <i>de Novo</i> mutation. The disease is lack of effective therapy so far.","variants":[{"Name":"NM_004380.3(CREBBP):c.4492C>T (p.Arg1498Ter)","Chromosome":"16","Start":"3736718","Stop":"3736718","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":843865,"rule_based_match":true,"evidence_text":"C. 4492 C>T (p. Arg1498Ter)","llm_judgment":"PRESENT","evidence":"C. 4492 C>T (p. Arg1498Ter)","abstract_start":433,"abstract_end":460}]}
{"pmid":"26998597","title":"Autosomal dominant spinal muscular atrophy with lower extremity predominance: A recognizable phenotype of BICD2 mutations.","abstract":"INTRODUCTION: Heterozygous BICD2 gene mutations cause a form of autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED).\nMETHODS: We analyzed the BICD2 gene in a selected group of 25 index patients with neurogenic muscle atrophy.\nRESULTS: We identified 2 new BICD2 missense mutations, c.2515G>A, p.Gly839Arg, in a family with autosomal dominant inheritance, and c.2202G>T, p.Lys734Asn, as a de novo mutation in an isolated patient with similar phenotype. The patients had congenital foot contractures, muscle atrophy of the legs, and slowly progressive weakness of the shoulder girdle. There was no apparent sensory or brain dysfunction. One patient died of unrelated reasons at age 52 years. Autopsy revealed no upper motor neuron and only moderate lower motor neuron loss, but there was distal corticospinal tract degeneration and marked neurogenic muscular atrophy.\nCONCLUSION: These findings give further insight into the clinical and pathoanatomical consequences of BICD2 mutations. Muscle Nerve 54: 496-500, 2016.","variants":[{"Name":"NM_001003800.2(BICD2):c.2515G>A (p.Gly839Arg)","Chromosome":"9","Start":"92715207","Stop":"92715207","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":563317,"rule_based_match":true,"evidence_text":"c.2515G>A, p.Gly839Arg","llm_judgment":"PRESENT","evidence":"c.2515G>A, p.Gly839Arg","abstract_start":315,"abstract_end":337}]}
{"pmid":"22976599","title":"Novel association of a PROC variant with ischemic stroke in a Chinese Han population.","abstract":"Protein C (PC) is a well-characterized anticoagulant enzyme. However, the association between PC and ischemic stroke (IS) remains controversial. The aim of the present study was to investigate whether any genetic variant in the human protein C gene (PROC) was associated with susceptibility to IS in the Chinese Han population. All exons and the 5'- and 3'-untranslated regions of PROC were initially sequenced to identify informative variants. Potential abnormal variants were analyzed in a population of 788 IS patients and 1,200 healthy controls. The analysis was stratified by stroke etiology, and the results were replicated in 262 IS patients and 288 healthy controls. Finally, functional studies were performed to evaluate the effects of the variant. A three-nucleotide duplication/deletion variant (c.574_576del) was identified and found to be significantly associated with IS (OR 2.56, 95 % CI 1.45-4.52, P = 0.001). Stratification by stroke etiology after adjustment for IS risk factors showed that this association persisted in the lacunar and cardioembolic subtypes (P < 0.001 and P = 0.008, respectively) but not in the atherothrombotic and undetermined subtypes (P = 0.070 and P = 0.998, respectively). The functional studies showed a significant difference in the anticoagulant activity of PC in c.574_576del carriers and non-carriers (P < 0.001). Our results suggested that the novel PROC c.574_576del variant is a possible genetic determinant of an increased risk of IS and diminished anticoagulant activity of PC.","variants":[{"Name":"NM_000312.4(PROC):c.574AAG[1] (p.Lys193del)","Chromosome":"2","Start":"127426121","Stop":"127426123","ReferenceAlleleVCF":"GAGA","AlternateAlleleVCF":"G","allel_id":227218,"rule_based_match":false,"evidence_text":"c.574_576del","llm_judgment":"PRESENT","evidence":"c.574_576del","abstract_start":807,"abstract_end":819}]}
{"pmid":"26748586","title":"Truncation and microdeletion of EVC/EVC2 with missense mutation of EFCAB7 in Ellis-van Creveld syndrome.","abstract":"Ellis-van Creveld syndrome (EvC) is a ciliopathy with cardiac anomalies, disproportionate short stature, polydactyly, dystrophic nails and oral defects. To obtain further insight into the genetics of EvC, we screened EVC/EVC2 mutations in eight Vietnamese EvC patients. All the patients had a congenital heart defect with atypical oral and/or skeletal abnormalities. One had compound heterozygous EVC2 mutations: a novel mutation c.769G > T-p.E177X in exon 6 inherited from father and another previously reported c.2476C > T-p.R826X mutation in exon 14 inherited from mother. The EVC2 mRNA expression level was significantly lower in the patient and her parents compared to controls. Another case had a novel heterozygous EVC mutation (c.1717C > G-p.S572X) in exon 12, inherited from his father. Of note, the mother without any EVC mutation on Sanger sequencing showed a lower expression level of EVC mRNA compared with controls. SNP array analysis revealed that the patient and mother had a heterozygous 16.4 kb deletion in EVC. This patient also had a heterozygous novel variant in exon 9 of EFCAB7 (c.1171 T > C-p.Y391H), inherited from his father. The atypical cardiac phenotype of this patient and the father suggested that EFCAB7 may modify the phenotype by interacting with EVC. In conclusion, we detected two novel nonsense mutations and a partial deletion of EVC/EVC2 in two Vietnamese families with EvC. Moreover, we found in one family a missense mutation of EFCAB7, a possible modifier gene in EvC and its related disorders.","variants":[{"Name":"NM_147127.5(EVC2):c.2476C>T (p.Arg826Ter)","Chromosome":"4","Start":"5622562","Stop":"5622562","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":264195,"rule_based_match":true,"evidence_text":"c.2476C > T-p.R826X","llm_judgment":"PRESENT","evidence":"c.2476C > T-p.R826X","abstract_start":513,"abstract_end":532}]}
{"pmid":"35813463","title":"Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations.","abstract":"Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disease mainly affecting the skeletal and skin. Two genes involved in prostaglandin degradation are known to be responsible for PHO: HPGD and SLCO2A1. HPGD gene mutation can cause PHO autosomal recessive 1 (PHOAR1). The purpose of the present study is to analyze the clinical and biochemical characteristics and HPGD gene mutations of 12 Chinese PHOAR1 patients. Twelve PHOAR1 patients from eleven families, including eleven males and one female, were enrolled in this study. Digital clubbing and periostosis came out to be the most common features, which always occur in the early childhood. We performed HPGD gene analysis and identified six novel (c.1A>G, c.34G>T, c.317T>A, c.475G>T, c.548C>T and c.421+1G>T) and one known (c.310_311delCT) HPGD mutations. The recurrent mutation c.310_311delCT were found in all eleven patients, suggesting it is a hotspot mutation. PHOAR1 patients are considered to have an autosomal recessive inheritance pattern. Here, in addition to nine compound heterozygous patients and two homozygous patients, we found one heterozygous patient and reviewed two heterozygous patients reported in other studies. In terms of biochemical characteristics, our PHOAR1 patients have elevated urinary prostaglandin E2 (PGE2) levels (P<0.001) and decreased urinary prostaglandin E metabolite (PGE-M) levels (P=0.04) compared with healthy controls. The patients' PGE2/PGE-M (E/M) ratio came out to be lower than normal subjects (P<0.001). This study provides a comprehensive description of the clinical phenotypes of Chinese PHOAR1 patients and expands the genotypic spectrum of the disease.","variants":[{"Name":"NM_000860.6(HPGD):c.421+1G>T","Chromosome":"4","Start":"174508695","Stop":"174508695","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3849143,"rule_based_match":true,"evidence_text":"c.421+1G>T","llm_judgment":"PRESENT","evidence":"c.421+1G>T","abstract_start":763,"abstract_end":773}]}
{"pmid":"28397151","title":"Identification of novel ATP7A mutations and prenatal diagnosis in Chinese patients with Menkes disease.","abstract":"Menkes disease (MD) is a fatal X-linked multisystem disease caused by mutations in ATP7A. In this study, clinical and genetic analysis was performed in 24 male MD patients. Development delay, seizures, kinky coarse hair, and dystonia were found in 24, 22, 24, and 24 patients, respectively. Serum ceruloplasmin/copper tested in 19 patients was low. Abnormal classic features of MD presented in the MRI/MRA of 19 patients. Seventeen mutations of ATP7A were identified in 22 patients. Twelve were novel mutations including three small deletion/insertion, one missense mutation, two nonsense mutations, three splicing-site mutations, and three gross deletions. Twenty-two patients were genetically diagnosed; neither point mutation nor deletion/duplication was found in two of them. c.2179G > A found in five patients might be a hot-spot mutation. Prenatal molecular diagnosis was performed for five unrelated fetuses (1 female and 4 male), which found four fetuses to be wild type and one male carried the same mutation as the proband. This study of the largest sample of Chinese MD patients examined to date discovered the unique phenotype and genotype spectrum in Chinese patients with 12 novel mutations of ATP7A, and that c.2179G > A might be a hot-spot mutation in MD patients. Five successful prenatal diagnosis contributed important information for MD families.","variants":[{"Name":"NM_000052.7(ATP7A):c.2179G>A (p.Gly727Arg)","Chromosome":"X","Start":"78012885","Stop":"78012885","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":209243,"rule_based_match":true,"evidence_text":"c.2179G > A","llm_judgment":"PRESENT","evidence":"c.2179G > A","abstract_start":780,"abstract_end":791}]}
{"pmid":"30461122","title":"Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome.","abstract":"KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal-hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano-Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants.","variants":[{"Name":"NM_000219.6(KCNE1):c.138C>A (p.Tyr46Ter)","Chromosome":"21","Start":"34449497","Stop":"34449497","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":537651,"rule_based_match":true,"evidence_text":"c.138C>A (p.Tyr46*)","llm_judgment":"PRESENT","evidence":"c.138C>A (p.Tyr46*)","abstract_start":1179,"abstract_end":1198},{"Name":"NM_000219.6(KCNE1):c.51G>A (p.Trp17Ter)","Chromosome":"21","Start":"34449584","Stop":"34449584","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":537652,"rule_based_match":true,"evidence_text":"c.51G>A (p.Trp17*)","llm_judgment":"PRESENT","evidence":"c.51G>A (p.Trp17*)","abstract_start":1155,"abstract_end":1173},{"Name":"NM_000219.6(KCNE1):c.50G>A (p.Trp17Ter)","Chromosome":"21","Start":"34449585","Stop":"34449585","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":537653,"rule_based_match":true,"evidence_text":"c.50G>A (p.Trp17*)","llm_judgment":"PRESENT","evidence":"c.50G>A (p.Trp17*)","abstract_start":1135,"abstract_end":1153}]}
{"pmid":"35211951","title":"PURA syndrome in a child with severe developmental delay: a challenging diagnosis.","abstract":"INTRODUCTION: PURA syndrome is a rare autosomal dominant condition caused by de novo pathogenic variants in PURA gene and characterized by a multisystemic phenotype that includes global neurodevelopmental delay, early hypotonia, absence of speech, feeding difficulties, hypersomnolence, epilepsy and movement disorders.\nCASE REPORT: We report a 9-year-old girl with hypotonia and feeding difficulties with failure to thrive since the neonatal period. At the age of 3 years motor and intellectual delay were evident, she had a wide-based gait, no speech and an exaggerated acoustic startle response. She developed hand-mouthing stereotypies and epilepsy at 6 years old. The 24 hours continuous electroencephalogram monitoring revealed global slow activity and frequent epileptiform activity in left temporal and centrotemporal areas. The brain MRI revealed delayed myelination. At 6 years old the clinical exome sequencing identified a heterozygous pathogenic variant in the PURA gene, c.153delA p.(Leu54CysfsTer24).\nCONCLUSION: PURA syndrome has clinical features similar to other neurological disorders but the association with some clinical features, not as common in other neurological entities, like never being able to speak but being able to follow simple orders and exaggerated acoustic startle response, should raise the suspicion of PURA syndrome and genetic analysis must be performed to confirm the diagnosis and provide early multidisciplinary intervention.","variants":[{"Name":"NM_005859.5(PURA):c.153del (p.Leu54fs)","Chromosome":"5","Start":"140114334","Stop":"140114334","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":511560,"rule_based_match":true,"evidence_text":"c.153delA p.(Leu54CysfsTer24)","llm_judgment":"PRESENT","evidence":"c.153delA p.(Leu54CysfsTer24)","abstract_start":985,"abstract_end":1014}]}
{"pmid":"29961568","title":"De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.","abstract":"Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.","variants":[{"Name":"NM_003931.3(WASF1):c.1516C>T (p.Arg506Ter)","Chromosome":"6","Start":"110101594","Stop":"110101594","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":553120,"rule_based_match":true,"evidence_text":"c.1516C>T (p.Arg506Ter)","llm_judgment":"PRESENT","evidence":"c.1516C>T (p.Arg506Ter)","abstract_start":612,"abstract_end":635},{"Name":"NM_003931.3(WASF1):c.1482delinsGCCAGG (p.Ile494fs)","Chromosome":"6","Start":"110101628","Stop":"110101628","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"CCTGGC","allel_id":553121,"rule_based_match":true,"evidence_text":"c.1482delinsGCCAGG (p.Ile494MetfsTer23)","llm_judgment":"PRESENT","evidence":"c.1482delinsGCCAGG (p.Ile494MetfsTer23)","abstract_start":711,"abstract_end":750},{"Name":"NM_003931.3(WASF1):c.1558C>T (p.Gln520Ter)","Chromosome":"6","Start":"110100644","Stop":"110100644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":553119,"rule_based_match":true,"evidence_text":"c.1558C>T (p.Gln520Ter)","llm_judgment":"PRESENT","evidence":"c.1558C>T (p.Gln520Ter)","abstract_start":682,"abstract_end":705}]}
{"pmid":"25449079","title":"Mutation analysis of EXT2 gene in a family with hereditary multiple exostosis","abstract":"OBJECTIVE: To investigate EXT1 and EXT2 genes mutations in a family with hereditary multiple osteochondromas (HME).\nMETHODS: A four-generation family with HME from Linyi city of Shandong Province was studied. There were 6 affected individuals among the 17 family members. Physical examination and radiographical evaluations were carried out for all family members. Genomic DNA was extracted from peripheral venous blood and the samples were subjected to mutation screening by PCR of the coding regions of EXT1 and EXT2 genes.\nRESULTS: The family has featured an autosomal dominant inheritance pattern. Sequencing of the EXT1 and EXT2 genes suggested the causative gene in this family was in linkage with the second exon of EXT2. A c.244delG mutation was detected, which has resulted in a frameshift mutation p.Asp81IlefsX30. The mutation was found in all of the 6 affected individuals but not in normal family members. And the mutation has co-segregated with the phenotype.\nCONCLUSION: The mutation c.244delG in the EXT2 gene is the probably the cause of the disease in this family.","variants":[{"Name":"NM_207122.2(EXT2):c.244del (p.Asp82fs)","Chromosome":"11","Start":"44107951","Stop":"44107951","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":461611,"rule_based_match":true,"evidence_text":"c.244delG","llm_judgment":"PRESENT","evidence":"c.244delG","abstract_start":731,"abstract_end":740}]}
{"pmid":"24829075","title":"A case series of α-thalassemia intermedia due to compound heterozygosity for Hb Adana [HBA2: c179G>A (or HBA1); p.Gly60Asp] with other α-thalassemias in Malay families.","abstract":"Hb Adana [HBA2: c179G>A (or HBA1); p.Gly60Asp] is a rare hemoglobin (Hb) variant due to a mutation at codon 59 of the α2- or α1-globin gene resulting in a glycine to aspartic acid substitution. Two siblings with a unique coinheritance of Hb Adana and Hb Constant Spring (Hb CS, α142, Term→Gln, TAA>CAA; HBA2: c.427 T>C) (α(codon 59)α/α(CS)α), were compared phenotypically with another two siblings carrying the Hb Adana mutation and a 3.7 kb deletion (α(codon 59)α/-α(3.7)). Although they all had α-thalassemia intermedia (α-TI), the former were clinically more severe than the latter. The first pair of siblings presented at a much younger age than the second pair and showed lower Hb levels and significant extramedullay hemopoiesis. Another case of a hydropic fetus as a result of Hb H/Hb Adana is also described. Their clinical phenotypes and hematological parameters are all presented for comparison.","variants":[{"Name":"NM_000517.6(HBA2):c.179G>A (p.Gly60Asp)","Chromosome":"16","Start":"173208","Stop":"173208","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":432850,"rule_based_match":false,"evidence_text":"HBA2: c179G>A (or HBA1); p.Gly60Asp","llm_judgment":"PRESENT","evidence":"HBA2: c179G>A (or HBA1); p.Gly60Asp","abstract_start":10,"abstract_end":45},{"Name":"NM_000517.4(HBA2):c.427T>C (p.Ter143Gln)","Chromosome":"16","Start":"173598","Stop":"173598","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":30663,"rule_based_match":true,"evidence_text":"Hb Constant Spring (Hb CS, α142, Term→Gln, TAA>CAA; HBA2: c.427 T>C)","llm_judgment":"PRESENT","evidence":"Hb Constant Spring (Hb CS, α142, Term→Gln, TAA>CAA; HBA2: c.427 T>C)","abstract_start":251,"abstract_end":319}]}
{"pmid":"24387224","title":"Chronic renal failure of unknown origin is caused by HNF1B mutations in 9% of adult patients: a single centre cohort analysis.","abstract":"BACKGROUND: HNF1B gene mutations might be an underdiagnosed cause of nephropathy in adult patients mainly because of their pleomorphic clinical presentations. As most studies are based on paediatric populations, it is difficult to assess the likelihood of finding HNF1B mutations in adult patients and consequently define clinical settings in which genetic analysis is indicated. The aim of this study was the search for mutations in the HNF1B gene in a cohort of unrelated adult patients with nephropathy of unknown aetiology.\nMETHODS: Patients were tested for the HNF1B gene if they had chronic kidney disease of unknown origin and renal structure abnormalities (RSA) or a positive family history of nephropathy. The HNF1B coding sequence and intron-exon boundaries were analysed by direct sequencing. The search for gene deletions was performed by Multiple Ligation Probe Analysis (MLPA).\nRESULTS: Heterozygous mutations were identified in 6 out of 67 screened patients (9.0%) and included two whole gene deletions, one nonsense (p.Gln136Stop), two missense (p.Gly76Cys and p.Ala314Thr) mutations and a frameshift microdeletion (c.384_390 delCATGCAG), the latter two (c.384_390 del and p.Ala314Thr) not ever being reported to date. Mean age of the mutated patients at screening was 48.5 years with a M/F ratio of 2/4. The clinical manifestations of affected patients were extremely pleomorphic, including several urological and extra-renal manifestations.\nCONCLUSIONS: Mutations of HNF1B could explain chronic kidney disease in up to 9% of adult patients with a nephropathy of unknown aetiology and RSA: therefore an HNF1B mutation analysis should be considered in this group of patients.","variants":[{"Name":"NM_000458.4(HNF1B):c.226G>T (p.Gly76Cys)","Chromosome":"17","Start":"37744659","Stop":"37744659","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":190267,"rule_based_match":false,"evidence_text":"c.226G>T (p.Gly76Cys)","llm_judgment":"PRESENT","evidence":"p.Gly76Cys","abstract_start":1062,"abstract_end":1072}]}
{"pmid":"36537646","title":"Joubert syndrome type 5 caused by a new compound heterozygous mutation in CEP290","abstract":"Joubert syndrome (JS) is a recessive neurodegenerative disease characterized by hypotonia, ataxia, psychomotor delay, oculomotor and visual impairments. JS shows clinically variability and genetic heterogeneity. In this article, we report a case of a 14-year-old female patient with JS 5 type associated with a new compound-heterozygous mutation c.2991+1655A>G + c.6604delA (p.Ile2202fs) in CEP290. Clinical and genetic data of JS 5 type can be useful in the diagnosis of disease.","variants":[{"Name":"NM_025114.4(CEP290):c.2991+1655A>G","Chromosome":"12","Start":"88101183","Stop":"88101183","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":16376,"rule_based_match":true,"evidence_text":"c.2991+1655A>G","llm_judgment":"PRESENT","evidence":"c.2991+1655A>G","abstract_start":346,"abstract_end":360},{"Name":"NM_025114.4(CEP290):c.6604del (p.Ile2202fs)","Chromosome":"12","Start":"88059939","Stop":"88059939","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":194758,"rule_based_match":true,"evidence_text":"c.6604delA (p.Ile2202fs)","llm_judgment":"PRESENT","evidence":"c.6604delA (p.Ile2202fs)","abstract_start":363,"abstract_end":387}]}
{"pmid":"21486904","title":"Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia.","abstract":"Early onset ataxia with ocular motor apraxia and hypoalbuminaemia/ataxia-oculomotor apraxia 1 is a recessively inherited ataxia caused by mutations in the aprataxin gene. We previously reported that patients with frameshift mutations exhibit a more severe phenotype than those with missense mutations. However, reports on genotype-phenotype correlation in early onset ataxia with ocular motor apraxia and hypoalbuminaemia are controversial. To clarify this issue, we studied 58 patients from 39 Japanese families, including 40 patients homozygous for c.689_690insT and nine patients homozygous or compound heterozygous for p.Pro206Leu or p.Val263Gly mutations who were compared with regard to clinical phenotype. We performed Kaplan-Meier analysis and log-rank tests for the ages of onset of gait disturbance and the inability to walk without assistance. The cumulative rate of gait disturbance was lower among patients with p.Pro206Leu or p.Val263Gly mutations than among those homozygous for the c.689_690insT mutation (P=0.001). The cumulative rate of inability to walk without assistance was higher in patients homozygous for the c.689_690insT mutation than in those with p.Pro206Leu or p.Val263Gly mutations (P=0.004). Using a Cox proportional hazards model, we found that the homozygous c.689_690insT mutation was associated with an increased risk for onset of gait disturbance (adjusted hazard ratio: 6.60) and for the inability to walk without assistance (adjusted hazard ratio: 2.99). All patients homozygous for the c.689_690insT mutation presented ocular motor apraxia at <15 years of age. Approximately half the patients homozygous for the c.689_690insT mutation developed cognitive impairment. In contrast, in the patients with p.Pro206Leu or p.Val263Gly mutations, only ∼50% of the patients exhibited ocular motor apraxia and they never developed cognitive impairment. The stepwise multivariate regression analysis using sex, age and the number of c.689_690insT alleles as independent variables revealed that the number of c.689_690insT alleles was independently and negatively correlated with median motor nerve conduction velocities, ulnar motor nerve conduction velocities and values of serum albumin. In the patient with c.[689_690insT]+[840delT], p.[Pro206Leu]+[Pro206Leu] and p.[Pro206Leu]+[Val263Gly] mutations, aprataxin proteins were not detected by an antibody to the N-terminus of aprataxin. Furthermore Pro206Leu and Val263Gly aprataxin proteins are unstable. However, the amount of the 689_690insT aprataxin messenger RNA was also decreased, resulting in more dramatic reduction in the amount of aprataxin protein from the c.689_690insT allele. In conclusion, patients with early onset ataxia with ocular motor apraxia and hypoalbuminaemia homozygous for the c.689_690insT mutation show a more severe phenotype than those with a p.Pro206Leu or p.Val263Gly mutation.","variants":[{"Name":"NM_001195248.2(APTX):c.689dup (p.Glu232fs)","Chromosome":"9","Start":"32984711","Stop":"32984712","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CA","allel_id":19464,"rule_based_match":false,"evidence_text":"c.689_690insT","llm_judgment":"PRESENT","evidence":"c.689_690insT","abstract_start":551,"abstract_end":564}]}
{"pmid":"24891296","title":"A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype.","abstract":"The RASopathies are a relatively common group of phenotypically similar and genetically related autosomal dominant genetic syndromes caused by missense mutations affecting genes participating in the RAS/mitogen-activated protein kinase (MAPK) pathway that include Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome). NS and NSML can be difficult to differentiate during infancy, but the presence of multiple lentigines, café au lait spots, and specific cardiac defects facilitate the diagnosis. Furthermore, individual PTPN11 missense mutations are highly specific to each syndrome and engender opposite biochemical alterations on the function of SHP-2, the protein product of that gene. Here, we report on a 5-year-old male with two de novo PTPN11 mutations in cis, c.1471C>T (p.Pro491Ser), and c.1492C>T (p.Arg498Trp), which are associated with NS and NSML, respectively. This boy's phenotype is intermediate between NS and NSML with facial dysmorphism, short stature, mild global developmental delay, pulmonic stenosis, and deafness but absence of café au lait spots or lentigines. The double-mutant SHP-2 was found to be catalytically impaired. This raises the question of whether clinical differences between NS and NSML can be ascribed solely to the relative SHP-2 catalytic activity.","variants":[{"Name":"NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser)","Chromosome":"12","Start":"112489047","Stop":"112489047","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49020,"rule_based_match":true,"evidence_text":"c.1471C>T (p.Pro491Ser)","llm_judgment":"PRESENT","evidence":"c.1471C>T (p.Pro491Ser)","abstract_start":815,"abstract_end":838},{"Name":"NM_002834.5(PTPN11):c.1492C>T (p.Arg498Trp)","Chromosome":"12","Start":"112489068","Stop":"112489068","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":49023,"rule_based_match":true,"evidence_text":"c.1492C>T (p.Arg498Trp)","llm_judgment":"PRESENT","evidence":"c.1492C>T (p.Arg498Trp)","abstract_start":844,"abstract_end":867}]}
{"pmid":"34066864","title":"Characterization of","abstract":"Glutaric aciduria type II (GA-II) is a rare autosomal recessive disease caused by defects in electron transfer flavoprotein (ETF), ultimately causing insufficiencies in multiple acyl-CoA dehydrogenase (MAD). 3-phosphoglycerate dehydrogenase (3-PHGDH) deficiency, is another rare autosomal disorder that appears due to a defect in the synthesis of L-serine amino acid. Several mutations of <i>ETFDH</i> and <i>PHGDH</i> genes have been associated with different forms of GA-II and serine deficiency, respectively. In this study, we report a unique case of GA-II with serine deficiency using biochemical, genetic, and in silico approaches. The proband of Syrian descent had positive newborn screening (NBS) for GA-II. At two years of age, the patient presented with developmental regression, ataxia, and intractable seizures. Results of amino acid profiling demonstrated extremely low levels of serine. Confirmatory tests for GA-II and whole exome sequencing (WES) were performed to determine the etiology of intractable seizure. Sequencing results indicated a previously reported homozygous missense mutation, c.679 C>A (p.Pro227Thr) in the <i>ETFDH</i> gene and a novel missense homozygous mutation c.1219 T>C (p.Ser407Pro) in the <i>PHGDH</i> gene. In silico tools predicted these mutations as deleterious. Here, the clinical and biochemical investigations indicate that <i>ETFDH</i>:p.Pro227Thr and <i>PHGDH</i>:p.Ser407Pro variants likely underlie the pathogenesis of GA-II and serine deficiency, respectively. This study indicates that two rare autosomal recessive disorders should be considered in consanguineous families, more specifically in those with atypical presentation.","variants":[{"Name":"NM_004453.4(ETFDH):c.679C>A (p.Pro227Thr)","Chromosome":"4","Start":"158690420","Stop":"158690420","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":453819,"rule_based_match":true,"evidence_text":"c.679 C>A (p.Pro227Thr)","llm_judgment":"PRESENT","evidence":"c.679 C>A (p.Pro227Thr)","abstract_start":1109,"abstract_end":1132}]}
{"pmid":"23430940","title":"Mutation Profile of the MUT Gene in Chinese Methylmalonic Aciduria Patients.","abstract":"The mut-type methylmalonic aciduria (MMA, MIM 251000) is caused by a deficiency of mitochondrial methylmalonyl-CoA mutase (MCM, E.C. 5.4.99.2) activity, which results from defects in the MUT gene. To elucidate the mutation spectrum of the MUT gene in Chinese MMA patients, 13 exons of the MUT gene, including untranslated regions, were analyzed by PCR-based sequencing for 42 unrelated Chinese MMA patients. All the 42 patients were found to have at least one MUT mutation. A total of 41 mutations were identified. Of these mutations, 20 were novel ones, including one nonsense mutation (c.103C>T), 12 missense mutations (c.316A>C, c.424A>G, c.494A>G, c.554C>T, c.599T>C, c.919T>C, c.1009T>C, c.1061C>T, c.1141G>A, c.1208G>A, c.1267G>A, and c.1295A>C), one duplication (c.755dupA), three small deletions (c.398_399delGA, c.1046_1058del, and c.1835delG), two mutations that might affect mRNA splicing (c.754-1G>A and c.1084-10A>G), and one major deletion. Among the mutations identified, the c.1280G>A (15.5%), c.729_730insTT (10.7%), c.1106G>A (4.8%), c.1630_1631GG>TA (4.8%), and c.2080C>T (4.8%) accounted for 40% of the diseased alleles. The c.1280G>A and c.729_730insTT mutations were found to be the most frequent mutations in Southern and Northern Chinese, respectively. The results of microsatellite analysis suggest that the spread of c.729_730insTT among the Northern Chinese and of c.1280G>A and c.1630_1631GG>TA among the Southern Chinese may have undergone founder effects. This mutation analysis of the gene responsible for mut-type MMA will help to provide a molecular diagnostic aid for differential diagnosis of MMA and could be applied for carrier detection and prenatal diagnosis among Chinese family at risk of mut-type MMA.","variants":[{"Name":"NM_000255.4(MMUT):c.1208G>A (p.Arg403Gln)","Chromosome":"6","Start":"49451590","Stop":"49451590","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":544012,"rule_based_match":true,"evidence_text":"c.1208G>A","llm_judgment":"PRESENT","evidence":"c.1208G>A","abstract_start":715,"abstract_end":724},{"Name":"NM_000255.4(MMUT):c.1046_1058del (p.Ala349fs)","Chromosome":"6","Start":"49453610","Stop":"49453622","ReferenceAlleleVCF":"TGTCTGACAGTGTG","AlternateAlleleVCF":"T","allel_id":1867874,"rule_based_match":true,"evidence_text":"c.1046_1058del","llm_judgment":"PRESENT","evidence":"c.1046_1058del","abstract_start":821,"abstract_end":835},{"Name":"NM_000255.4(MMUT):c.1141G>A (p.Gly381Arg)","Chromosome":"6","Start":"49451657","Stop":"49451657","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2904802,"rule_based_match":true,"evidence_text":"c.1141G>A","llm_judgment":"PRESENT","evidence":"c.1141G>A","abstract_start":704,"abstract_end":713},{"Name":"NM_000255.4(MMUT):c.599T>C (p.Ile200Thr)","Chromosome":"6","Start":"49457845","Stop":"49457845","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2904806,"rule_based_match":true,"evidence_text":"c.599T>C","llm_judgment":"PRESENT","evidence":"c.599T>C","abstract_start":662,"abstract_end":670},{"Name":"NM_000255.4(MMUT):c.2080C>T (p.Arg694Trp)","Chromosome":"6","Start":"49435500","Stop":"49435500","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":216039,"rule_based_match":true,"evidence_text":"c.2080C>T","llm_judgment":"PRESENT","evidence":"c.2080C>T","abstract_start":1081,"abstract_end":1090},{"Name":"NM_000255.4(MMUT):c.494A>G (p.Asp165Gly)","Chromosome":"6","Start":"49457950","Stop":"49457950","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2904808,"rule_based_match":true,"evidence_text":"c.494A>G","llm_judgment":"PRESENT","evidence":"c.494A>G","abstract_start":642,"abstract_end":650},{"Name":"NM_000255.4(MMUT):c.103C>T (p.Gln35Ter)","Chromosome":"6","Start":"49459364","Stop":"49459364","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2904811,"rule_based_match":true,"evidence_text":"c.103C>T","llm_judgment":"PRESENT","evidence":"c.103C>T","abstract_start":588,"abstract_end":596},{"Name":"NM_000255.4(MMUT):c.1280G>A (p.Gly427Asp)","Chromosome":"6","Start":"49451518","Stop":"49451518","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":216044,"rule_based_match":true,"evidence_text":"c.1280G>A","llm_judgment":"PRESENT","evidence":"c.1280G>A","abstract_start":991,"abstract_end":1000},{"Name":"NM_000255.4(MMUT):c.1295A>C (p.Glu432Ala)","Chromosome":"6","Start":"49451503","Stop":"49451503","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1060722,"rule_based_match":true,"evidence_text":"c.1295A>C","llm_judgment":"PRESENT","evidence":"c.1295A>C","abstract_start":741,"abstract_end":750}]}
{"pmid":"19361455","title":"Splice-site mutation c.313+1, G>A in intron 3 of the LDL receptor gene results in transcripts with skipping of exon 3 and inclusion of intron 3.","abstract":"BACKGROUND: Familial hypercholesterolemia (FH) patients with the splice site mutation c.313+1, G>A in intron 3 of the low density lipoprotein receptor (LDLR) gene, present with a phenotype similar to that of FH patients in general. However, a mild phenotype would have been expected from the published data showing that the mutation only causes skipping of exon 3.\nMETHODS: Epstein Barr virus-transformed lymphocytes from eight c.313+1, G>A heterozygotes and two c.313+1, G>A homozygotes were subjected to studies of the LDLR at the mRNA and protein levels.\nRESULTS: Mutation c.313+1, G>A not only causes skipping of exon 3, but also causes inclusion of intron 3. No functional LDLR was produced from the transcript with inclusion of intron 3. The transcript with skipping of exon 3 produced a receptor which had markedly reduced ability to internalize low density lipoprotein.\nCONCLUSION: The findings that the mutation c.313+1, G>A in the LDLR gene also generates a mutant transcript with inclusion of intron 3, explains why the mutation c.313+1, G>A may result in a severe phenotype.","variants":[{"Name":"NM_000527.4(LDLR):c.313+1G>A","Chromosome":"19","Start":"11102787","Stop":"11102787","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18775,"rule_based_match":false,"evidence_text":"c.313+1, G>A","llm_judgment":"PRESENT","evidence":"c.313+1, G>A","abstract_start":86,"abstract_end":98}]}
{"pmid":"21910228","title":"Horseshoe kidney and a rare TSC2 variant in two unrelated individuals with tuberous sclerosis complex.","abstract":"Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by abnormalities involving the skin, brain, kidney (angiomyolipomas, cysts), and heart. Horseshoe kidney has not been considered to be a common renal manifestation of TSC but it has been previously reported in two patients with TSC. We report on two unrelated females with typical manifestations of TSC, horseshoe kidney, and an identical variant c.5138G>A in exon 39 (p.Arg1713His) of TSC2 gene. These cases provide evidence that horseshoe kidney is associated with TSC and add to the evidence for the pathogenicity of this variant. Furthermore, one of the patients also had a diaphragmatic hernia which has been reported twice in the medical literature in individuals with TSC. It is possible that a diaphragmatic hernia is another rare manifestation of TSC and that TSC should be included in the differential diagnosis of infants with a diaphragmatic hernia. Given that both a horseshoe kidney and a diaphragmatic hernia are findings that can be detected prenatally on an ultrasound examination, our findings may have implications for prenatal genetic counseling.","variants":[{"Name":"NM_000548.5(TSC2):c.5138G>A (p.Arg1713His)","Chromosome":"16","Start":"2088117","Stop":"2088117","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":59092,"rule_based_match":true,"evidence_text":"c.5138G>A in exon 39 (p.Arg1713His)","llm_judgment":"PRESENT","evidence":"c.5138G>A in exon 39 (p.Arg1713His)","abstract_start":440,"abstract_end":475}]}
{"pmid":"28504502","title":"Transient congenital hypothyroidism due to biallelic defects of DUOX2 gene. Two clinical cases","abstract":"Congenital hypothyroidism affects 1:2000-3000 newborns detected by neonatal screening programs. Dual oxidases, DUOX1 and 2, generate hydrogen peroxide needed for the thyroid hormone synthesis. Hipotiroidismo congénito transitorio por defectos bialélicos del gen DUOX2. Dos casos clínicos Transient congenital hypothyroidism due to biallelic defects of DUOX2 gene. Two clinical cases Mutations in the DUOX2 gene have been described in transient and permanent congenital hypothyroidism. Two brothers with congenital hypothyroidism detected by neonatal screening with eutopic gland and elevated thyroglobulin are described. They were treated with levothyroxine until it could be suspended in both during childhood, assuming the picture as transient. Organification disorder was confirmed. Both patients were compounds heterozygous for a mutation in exon 9 of the paternal allele (c.1057_1058delTT, p.F353PfsX36 or p.F353fsX388) and in exon 11 of the maternal allele (c.1271T > G, p.Y425X) of DUOX2 gene. Our finding confirms that the magnitude of the defect of DUOX2 is not related to the number of inactivated alleles, suggesting compensatory mechanisms in the peroxide supply.","variants":[{"Name":"NM_001363711.2(DUOX2):c.1057_1058del (p.Phe353fs)","Chromosome":"15","Start":"45109963","Stop":"45109964","ReferenceAlleleVCF":"GAA","AlternateAlleleVCF":"G","allel_id":2894904,"rule_based_match":true,"evidence_text":"c.1057_1058delTT, p.F353PfsX36","llm_judgment":"PRESENT","evidence":"c.1057_1058delTT, p.F353PfsX36","abstract_start":877,"abstract_end":907}]}
{"pmid":"32871652","title":"Identification of a heterozygous ACAN mutation in a 15-year-old boy with short stature who presented with advanced bone age: a case report and review of the literature.","abstract":"Longitudinal bone growth is primarily mediated by the growth plate, which is a specialized cartilaginous structure. Aggrecan, encoded by ACAN, is a primary proteoglycan component of the extracellular matrix in both the growth plate and articular cartilage. Aggrecanopathies have emerged as a phenotype of genetic skeletal disease in humans. A heterozygous ACAN mutation causes short stature, premature growth cessation, and accelerated bone age maturation. We report the case of a 15-year-old boy with familial short stature, with height of 149 cm (Korean standard deviation score [SDS] of -3.6) and weight of 50.5 kg (-1.48 SDS). He presented with mild midfacial hypoplasia, frontal bossing, a broad chest, and a short neck. The father's and mother's heights were 150 cm (-4.8 SDS) and 153 cm (-1.69 SDS), respectively. The patient's bone age was 2-3 years more advanced than his chronological age, and no endocrine abnormalities were detected. Wholeexome sequencing followed by Sanger sequencing revealed a heterozygous ACAN mutation, c.512C>T (p.Ala171Val), in both the proband and his father. Short stature is generally associated with a delayed bone age, and this case suggests that ACAN mutations may be the most likely etiology among patients with short stature and an advanced bone age and should warrant early treatment.","variants":[{"Name":"NM_001369268.1(ACAN):c.512C>T (p.Ala171Val)","Chromosome":"15","Start":"88840069","Stop":"88840069","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":536893,"rule_based_match":true,"evidence_text":"c.512C>T (p.Ala171Val)","llm_judgment":"PRESENT","evidence":"c.512C>T (p.Ala171Val)","abstract_start":1037,"abstract_end":1059}]}
{"pmid":"30266223","title":"Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil.","abstract":"Mutations in RAPSN are an important cause of congenital myasthenic syndrome (CMS), leading to endplate acetylcholine receptor deficiency. We present three RAPSN early-onset CMS patients (from a Brazilian cohort of 61 CMS patients). Patient 1 and patient 2 harbor the mutation p.N88K in homozygosity, while patient 3 harbors p.N88K in compound heterozygosity with another pathogenic variant (p.V165M; c.493G ≥ A). At onset, patient 3 presented with more severe symptoms compared to the other two, showing generalized weakness and repeated episodes of respiratory failure in the first years of life. During adolescence, she became gradually less symptomatic and does not require medication anymore, presenting better long-term outcomes than patients 1 and 2. This case series illustrates the variability of RAPSN early-onset CMS, with patient 3, despite severe onset, revealing an almost complete reversal of myasthenic symptoms, not limited to apneic episodes. Moreover, it suggests that RAPSN CMS may be underdiagnosed in non-European countries.","variants":[{"Name":"NM_005055.5(RAPSN):c.493G>A (p.Val165Met)","Chromosome":"11","Start":"47447850","Stop":"47447850","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":838552,"rule_based_match":false,"evidence_text":"c.493G ≥ A","llm_judgment":"PRESENT","evidence":"c.493G ≥ A","abstract_start":400,"abstract_end":410}]}
{"pmid":"21356526","title":"Identification of two novel missense WFS1 mutations, H696Y and R703H, in patients with non-syndromic low-frequency sensorineural hearing loss.","abstract":"Non-syndromic low-frequency sensorineural hearing loss (LFSNHL) is an unusual type of hearing loss in which frequencies ≤2000 Hz predominantly are affected. To date, different mutations in two genes, DIAPH1 and WFS1, have been found to be associated with LFSNHL. Here, we report a five-generation Chinese family with postlingual and progressive LFSNHL. We mapped the disease locus to a 2.5 Mb region on chromosome 4p16 between markers SNP_A-2167174 and D4S431, overlapping with the DFNA6/14/38 locus. Sequencing of candidate gene revealed a heterozygous c.2086C>T substitution in exon 8 of WFS1, leading to p.H696Y substitution at the C-terminus of Wolframin (WFS1). In addition, we performed mutational screening of WFS1 in 37 sporadic patients, 7-50 years of age, with LFSNHL. We detected a heterozygous c.2108G>A substitution in exon 8 of WFS1, leading to p.R703H substitution in a patient. The H696 and R703 in WFS1 are highly conserved across species, including human, orangutan, rat, mouse, and frog (Xenopus). Sequence analysis demonstrated the absence of c.2086C>T or c.2108G>A substitutions in the WFS1 genes among 200 unrelated control subjects of Chinese background, supporting the hypothesis that they represent causative mutations, and not rare polymorphisms. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype correlation for LFSNHL.","variants":[{"Name":"NM_006005.3(WFS1):c.2108G>A (p.Arg703His)","Chromosome":"4","Start":"6301903","Stop":"6301903","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1287395,"rule_based_match":true,"evidence_text":"c.2108G>A","llm_judgment":"PRESENT","evidence":"c.2108G>A","abstract_start":806,"abstract_end":815}]}
{"pmid":"22305854","title":"Fabry disease: biochemical, pathological and structural studies of the α-galactosidase A with E66Q amino acid substitution.","abstract":"Recently, male subjects harboring the c.196G>C nucleotide change which leads to the E66Q enzyme having low α-galactosidase A (GLA) activity have been identified at an unexpectedly high frequency on Japanese and Korean screening for Fabry disease involving dry blood spots and plasma/serum samples. Individuals with the E66Q enzyme have been suspected to have the later-onset Fabry disease phenotype leading to renal and cardiac disease. However, there has been no convincing evidence for this. To determine whether c.196G>C (E66Q) is disease-causing or not, we performed biochemical, pathological and structural studies. It was predicted that the E66Q amino acid substitution causes a small conformational change on the molecular surface of GLA, which leads to instability of the enzyme protein. However, biochemical studies revealed that subjects harboring the E66Q enzyme exhibited relatively high residual enzyme activity in white blood cells, and that there was no accumulation of globotriaosylceramide in cultured fibroblasts or an increased level of plasma globotriaosylsphingosine in these subjects. An electron microscopic examination did not reveal any pathological changes specific to Fabry disease in biopsied skin tissues from a male subject with the E66Q enzyme. These results strongly suggest that the c.196G>C is not a pathogenic mutation but is a functional polymorphism.","variants":[{"Name":"NM_000169.3(GLA):c.196G>C (p.Glu66Gln)","Chromosome":"X","Start":"101403984","Stop":"101403984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":25762,"rule_based_match":true,"evidence_text":"c.196G>C (E66Q)","llm_judgment":"PRESENT","evidence":"c.196G>C (E66Q)","abstract_start":515,"abstract_end":530}]}
{"pmid":"33028643","title":"Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis.","abstract":"Biallelic variants in inorganic pyrophosphatase 2 (PPA2) are known to cause infantile sudden cardiac failure (OMIM #617222), but relatively little is known about phenotypic variability of these patients prior to their death. We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited, pathogenic missense variant (c.514G > A; p.Glu172Lys) and a novel, maternally inherited missense variant of uncertain significance (c.442A > T; p.Thr148Ser). This report expands the presenting phenotype of patients with PPA2 variants. It also highlights the utility of dried blood spots for postmortem molecular diagnosis.","variants":[{"Name":"NM_176869.3(PPA2):c.514G>A (p.Glu172Lys)","Chromosome":"4","Start":"105437964","Stop":"105437964","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":359127,"rule_based_match":true,"evidence_text":"c.514G > A; p.Glu172Lys","llm_judgment":"PRESENT","evidence":"c.514G > A; p.Glu172Lys","abstract_start":547,"abstract_end":570}]}
{"pmid":"27344648","title":"Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but Little Biochemical Evidence of a Mitochondrial Disorder.","abstract":"Leigh syndrome is a subacute necrotising encephalomyopathy proven by post-mortem analysis of brain tissue showing spongiform lesions with vacuolation of the neuropil followed by demyelination, gliosis and capillary proliferation caused by mutations in one of over 75 different genes, including nuclear- and mitochondrial-encoded genes, most of which are associated with mitochondrial respiratory chain function. In this study, we report a patient with suspected Leigh syndrome presenting with seizures, ptosis, scoliosis, dystonia, symmetrical putaminal abnormalities and a lactate peak on brain MRS, but showing normal MRC enzymology in muscle and liver, thereby complicating the diagnosis. Whole exome sequencing uncovered compound heterozygous mutations in NADH dehydrogenase (ubiquinone) flavoprotein 1 gene (NDUFV1), c.1162+4A>C (NM_007103.3), resulting in skipping of exon 8, and c.640G>A, causing the amino acid substitution p.Glu214Lys, both of which have previously been reported in a patient with complex I deficiency. Patient fibroblasts showed a significant reduction in NDUFV1 protein expression, decreased complex CI and complex IV assembly and consequential reductions in the enzymatic activities of both complexes by 38% and 67%, respectively. The pathogenic effect of these variations was further confirmed by immunoblot analysis of subunits for MRC enzyme complexes in patient muscle, liver and fibroblast where we observed 90%, 60% and 95% reduction in complex CI, respectively. Together these studies highlight the importance of a comprehensive, multipronged approach to the laboratory evaluation of patients with suspected Leigh syndrome.","variants":[{"Name":"NM_007103.4(NDUFV1):c.640G>A (p.Glu214Lys)","Chromosome":"11","Start":"67610510","Stop":"67610510","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29098,"rule_based_match":true,"evidence_text":"c.640G>A","llm_judgment":"PRESENT","evidence":"c.640G>A","abstract_start":886,"abstract_end":894},{"Name":"NM_007103.4(NDUFV1):c.1162+4A>C","Chromosome":"11","Start":"67611982","Stop":"67611982","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":359994,"rule_based_match":true,"evidence_text":"c.1162+4A>C (NM_007103.3)","llm_judgment":"PRESENT","evidence":"c.1162+4A>C (NM_007103.3)","abstract_start":822,"abstract_end":847}]}
{"pmid":"21823540","title":"HNF1A mutation presenting with fetal macrosomia and hypoglycemia in childhood prior to onset of overt diabetes.","abstract":"BACKGROUND: HNF1A-MODY (MODY3) is a common subtype of autosomal dominant diabetes. Unlike HNF4-MODY where fetal macrosomia and early postnatal hyperinsulinemic hypoglycemia have been reported, a history of transient insulin overproduction has not been recognized in individuals with HNF1A-MODY yet.\nCASE REPORT: Here, we report a 40-year-old male patient with HNFJA mutation p.Arg272His (c.815G>A) with a history of fetal macrosomia (4750 g, 59 cm) and, at least, one attack of symptomatic hypoglycemia in childhood. Diabetes was subsequently diagnosed at 19 years. The proband's daughter who developed diabetes at 16 years carries the same mutation, but her birth weight and length were in the upper normal range, and she never experienced hypoglycemic symptoms.\nCONCLUSION: The observation of fetal macrosomia and hypoglycemia in childhood is suggestive of a biphasic impact of the HNF1A mutation on beta-cell function over the lifespan, leading from inappropriate insulin oversecretion to final clinical diabetes.","variants":[{"Name":"NM_000545.8(HNF1A):c.815G>A (p.Arg272His)","Chromosome":"12","Start":"120994265","Stop":"120994265","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29970,"rule_based_match":true,"evidence_text":"p.Arg272His (c.815G>A)","llm_judgment":"PRESENT","evidence":"p.Arg272His (c.815G>A)","abstract_start":375,"abstract_end":397}]}
{"pmid":"28420223","title":"Clinical and Molecular Characterization of Patients with Fructose 1,6-Bisphosphatase Deficiency.","abstract":"Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare, autosomal recessive inherited disease caused by the mutation of the <i>FBP1</i> gene, the incidence is estimated to be between 1/350,000 and 1/900,000. The symptoms of affected individuals are non-specific and are easily confused with other metabolic disorders. The present study describes the clinical features of four Chinese pediatric patients who presented with hypoglycemia, hyperlactacidemia, metabolic acidosis, and hyperuricemia. Targeted-next generation sequencing using the Agilent SureSelect XT Inherited Disease Panel was used to screen for causal variants in the genome, and the clinically-relevant variants were subsequently verified using Sanger sequencing. Here, DNA sequencing identified six variations of the <i>FBP1</i> gene (NM_000507.3) in the four patients. In Case 1, we found a compound heterozygous mutations of c.704delC (p.Pro235GlnfsX42) (novel) and c.960_961insG (p.Ser321Valfs) (known pathogenic). In Case 2, we found a compound heterozygous mutations of c.825 + 1G>A and c.960_961insG (both were known pathogenically). In Case 3, a homozygous missense mutation of c.355G>A (p.Asp119Asn) (reported in ClinVar database without functional study) was found. Case 4 had a compound heterozygous mutations c.720_729del (p.Tyr241GlyfsX33) (novel) and c.490G>A (p.Gly164Ser) (known pathogenically). Further in vitro studies in the COS-7cell line demonstrated that the mutation of ASP119ASN had no impact on protein expression, but decreased the enzyme activity, and with which the clinical significance of Asp119Asn can be determined to be likely pathogenic. This report not only expands upon the known spectrum of variation of the <i>FBP1</i> gene, but also deepens our understanding of the clinical features of FBPase deficiency.","variants":[{"Name":"NM_000507.4(FBP1):c.960_961insG (p.Ser321fs)","Chromosome":"9","Start":"94603437","Stop":"94603438","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":15906,"rule_based_match":true,"evidence_text":"c.960_961insG (p.Ser321Valfs)","llm_judgment":"PRESENT","evidence":"c.960_961insG (p.Ser321Valfs)","abstract_start":937,"abstract_end":966},{"Name":"NM_000507.4(FBP1):c.490G>A (p.Gly164Ser)","Chromosome":"9","Start":"94609998","Stop":"94609998","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15907,"rule_based_match":true,"evidence_text":"c.490G>A (p.Gly164Ser)","llm_judgment":"PRESENT","evidence":"c.490G>A (p.Gly164Ser)","abstract_start":1333,"abstract_end":1355},{"Name":"NM_000507.4(FBP1):c.704del (p.Pro235fs)","Chromosome":"9","Start":"94606816","Stop":"94606816","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":390675,"rule_based_match":true,"evidence_text":"c.704delC (p.Pro235GlnfsX42)","llm_judgment":"PRESENT","evidence":"c.704delC (p.Pro235GlnfsX42)","abstract_start":896,"abstract_end":924}]}
{"pmid":"23022099","title":"Infantile encephaloneuromyopathy and defective mitochondrial translation are due to a homozygous RMND1 mutation.","abstract":"Defects of mitochondrial protein synthesis are clinically and genetically heterogeneous. We previously described a male infant who was born to consanguineous parents and who presented with severe congenital encephalopathy, peripheral neuropathy, myopathy, and lactic acidosis associated with deficiencies of multiple mitochondrial respiratory-chain enzymes and defective mitochondrial translation. In this work, we have characterized four additional affected family members, performed homozygosity mapping, and identified a homozygous splicing mutation in the splice donor site of exon 2 (c.504+1G>A) of RMND1 (required for meiotic nuclear division-1) in the affected individuals. Fibroblasts from affected individuals expressed two aberrant transcripts and had decreased wild-type mRNA and deficiencies of mitochondrial respiratory-chain enzymes. The RMND1 mutation caused haploinsufficiency that was rescued by overexpression of the wild-type transcript in mutant fibroblasts; this overexpression increased the levels and activities of mitochondrial respiratory-chain proteins. Knockdown of RMND1 via shRNA recapitulated the biochemical defect of the mutant fibroblasts, further supporting a loss-of-function pathomechanism in this disease. RMND1 belongs to the sif2 family, an evolutionary conserved group of proteins that share the DUF155 domain, have unknown function, and have never been associated with human disease. We documented that the protein localizes to mitochondria in mammalian and yeast cells. Further studies are necessary for understanding the function of this protein in mitochondrial protein translation.","variants":[{"Name":"NM_017909.4(RMND1):c.504+1G>A","Chromosome":"6","Start":"151445307","Stop":"151445307","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48363,"rule_based_match":true,"evidence_text":"c.504+1G>A","llm_judgment":"PRESENT","evidence":"c.504+1G>A","abstract_start":589,"abstract_end":599}]}
{"pmid":"24485043","title":"Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients.","abstract":"INTRODUCTION: Mutations in the TMEM70 are the most common cause of nuclear ATP synthase deficiency resulting in a distinctive phenotype characterized by severe neonatal hypotonia, hypertrophic cardiomyopathy (HCMP), facial dysmorphism, severe lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria (3-MGA).\nMETHODS AND RESULTS: We collected 9 patients with genetically confirmed TMEM70 defect from 8 different families. Six were homozygous for the c.317-2A>G mutation, 2 were compound heterozygous for mutations c.317-2A>G and c.628A>C and 1 was homozygous for the novel c.701A>C mutation. Generalized hypotonia, lactic acidosis, hyperammonemia and 3-MGA were present in all since birth. Five patients presented acute respiratory distress at birth requiring intubation and ventilatory support. HCMP was detected in 5 newborns and appeared a few months later in 3 additional children. Five patients showed a severe and persistent neonatal pulmonary hypertension (PPHN) requiring Nitric Oxide (NO) and/or sildenafil administration combined in 2 cases with high-frequency oscillatory (HFO) ventilation. In 3 of these patients, echocardiography detected signs of HCMP at birth.\nCONCLUSIONS: PPHN is a life-threatening poorly understood condition with bad prognosis if untreated. Pulmonary hypertension has rarely been reported in mitochondrial disorders and, so far, it has been described in association with TMEM70 deficiency only in one patient. This report further expands the clinical and genetic spectrum of the syndrome indicating PPHN as a frequent and life-threatening complication regardless of the type of mutation. Moreover, in these children PPHN appears even in the absence of an overt cardiomyopathy, thus representing an early sign and a clue for diagnosis.","variants":[{"Name":"NM_017866.6(TMEM70):c.317-2A>G","Chromosome":"8","Start":"73981153","Stop":"73981153","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15579,"rule_based_match":true,"evidence_text":"c.317-2A>G","llm_judgment":"PRESENT","evidence":"c.317-2A>G","abstract_start":457,"abstract_end":467}]}
{"pmid":"17922257","title":"Contribution of the BRCA1 and BRCA2 mutations to breast cancer in Tunisia.","abstract":"Hereditary breast cancer accounts for 3-8% of all breast cancers, with mutations in the BRCA1 and BRCA2 genes responsible for up to 30% of these. To investigate the prevalence of BRCA1 and BRCA2 gene mutations in breast cancer patients with affected relatives in Tunisia, we studied 36 patients who had at least one first degree relative with breast and/or ovarian cancer Thirty-four 34 patients were suggestive of the BRCA1 mutation and two were suggestive of the BRCA2 mutation, based on the presence of male breast cancer detected in their corresponding pedigrees. Four mutations in BRCA1 were detected, including a novel frame-shift mutation (c.211dupA) in two unrelated patients and three other frameshift mutations--c.4041delAG, c.2551delG and c.5266dupC. Our study is the first to describe the c.5266dupC mutation in a non-Jewish Ashkenazi population. Two frameshift mutations (c.1309del4 and c.5682insA) were observed in BRCA2. Nineteen percent (7/36) of the familial cases had deleterious mutations of the BRCA1 or BRCA2 genes. Almost all patients with deleterious mutations of BRCA1 reported a family history of breast and/or ovarian cancer in the index case or in their relatives. Our data are the first to contribute to information on the mutation spectrum of BRCA genes in Tunisia, and we give a recommendation for improving clinical genetic testing policy.","variants":[{"Name":"NM_007294.4(BRCA1):c.211dup (p.Arg71fs)","Chromosome":"17","Start":"43106456","Stop":"43106457","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":69130,"rule_based_match":true,"evidence_text":"c.211dupA","llm_judgment":"PRESENT","evidence":"c.211dupA","abstract_start":647,"abstract_end":656},{"Name":"NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)","Chromosome":"17","Start":"43057062","Stop":"43057063","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TG","allel_id":32716,"rule_based_match":true,"evidence_text":"c.5266dupC","llm_judgment":"PRESENT","evidence":"c.5266dupC","abstract_start":750,"abstract_end":760}]}
{"pmid":"30770860","title":"A novel variant of the human mitochondrial DnaJ protein, Tid1, associates with a human disease exhibiting developmental delay and polyneuropathy.","abstract":"Here, we describe a single patient from a consanguineous family, who suffers from developmental delay, intellectual disability, hypermetropia, moderate alternating esotropia, unsteady gait, and peripheral polyneuropathy. Brain MRI revealed basal ganglia disease. Exome analysis disclosed a homozygous variant, c.452G>C (p.(Arg151Thr)), in TID1, encoding a mitochondrial J-protein chaperone that is known for its function in assisting the Hsp70 chaperone, mortalin, in mediating the refolding of denatured protein and dissolving protein aggregates. Results from in vitro import assays showed that both wild type and c.452G>C (p.(Arg151Thr)) are efficiently imported into isolated mitochondria. However, the import rate of the c.452G>C (p.(Arg151Thr)) variant was less than that of the wild-type protein. In the second part of this study, we demonstrated, in vitro, that the disaggregation function of the mortalin/Tid1 team is compromised in the TID1 c.452G>C (p.(Arg151Thr)) variant, as its chaperone activity has a level similar to that of the non-functional H→Q HPD domain variant. The results shed light on the essential function played by Tid1 during neuronal development.","variants":[{"Name":"NM_005147.6(DNAJA3):c.452G>C (p.Arg151Thr)","Chromosome":"16","Start":"4441397","Stop":"4441397","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":906218,"rule_based_match":true,"evidence_text":"c.452G>C (p.(Arg151Thr))","llm_judgment":"PRESENT","evidence":"c.452G>C (p.(Arg151Thr))","abstract_start":310,"abstract_end":334}]}
{"pmid":"19110212","title":"Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications.","abstract":"The spondylo-meta-epiphyseal dysplasia [SMED] short limb-hand type [SMED-SL] is a rare autosomal-recessive disease, first reported by Borochowitz et al. in 1993.(1) Since then, 14 affected patients have been reported.(2-5) We diagnosed 6 patients from 5 different consanguineous Arab Muslim families from the Jerusalem area with SMED-SL. Additionally, we studied two patients from Algerian and Pakistani ancestry and the parents of the first Jewish patients reported.(1) Using a homozygosity mapping strategy, we located a candidate region on chromosome 1q23 spanning 2.4 Mb. The position of the Discoidin Domain Receptor 2 (DDR2) gene within the candidate region and the similarity of the ddr2 knockout mouse to the SMED patients' phenotype prompted us to study this gene(6). We identified three missense mutations c.2254 C > T [R752C], c. 2177 T > G [I726R], c.2138C > T [T713I] and one splice site mutation [IVS17+1g > a] in the conserved sequence encoding the tyrosine kinase domain of the DDR2 gene. The results of this study will permit an accurate early prenatal diagnosis and carrier screening for families at risk.","variants":[{"Name":"NM_006182.4(DDR2):c.2254C>T (p.Arg752Cys)","Chromosome":"1","Start":"162776341","Stop":"162776341","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27352,"rule_based_match":true,"evidence_text":"c.2254 C > T [R752C]","llm_judgment":"PRESENT","evidence":"c.2254 C > T [R752C]","abstract_start":816,"abstract_end":836},{"Name":"NM_006182.4(DDR2):c.2177T>G (p.Ile726Arg)","Chromosome":"1","Start":"162776264","Stop":"162776264","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":27353,"rule_based_match":true,"evidence_text":"c. 2177 T > G [I726R]","llm_judgment":"PRESENT","evidence":"c. 2177 T > G [I726R]","abstract_start":838,"abstract_end":859},{"Name":"NM_006182.4(DDR2):c.2138C>T (p.Thr713Ile)","Chromosome":"1","Start":"162776225","Stop":"162776225","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":27354,"rule_based_match":true,"evidence_text":"c.2138C > T [T713I]","llm_judgment":"PRESENT","evidence":"c.2138C > T [T713I]","abstract_start":861,"abstract_end":880}]}
{"pmid":"34249980","title":"Saudi Familial Hypercholesterolemia Patients With Rare","abstract":"Familial hypercholesterolemia (FH), a well-known lipid disease caused by inherited genetic defects in cholesterol uptake and metabolism is underdiagnosed in many countries including Saudi Arabia. The present study aims to identify the molecular basis of severe clinical manifestations of FH patients from unrelated Saudi consanguineous families. Two Saudi families with multiple FH patients fulfilling the combined FH diagnostic criteria of Simon Broome Register, and the Dutch Lipid Clinic Network (DLCN) were recruited. LipidSeq, a targeted resequencing panel for monogenic dyslipidemias, was used to identify causative pathogenic mutation in these two families and in 92 unrelated FH cases. Twelve FH patients from two unrelated families were sharing a very rare, pathogenic and founder LDLR stop gain mutation i.e., c.2027delG (p.Gly676Alafs<sup>*</sup>33) in both the homozygous or heterozygous states, but not in unrelated patients. Based on the variant zygosity, a marked phenotypic heterogeneity in terms of LDL-C levels, clinical presentations and resistance to anti-lipid treatment regimen (ACE inhibitors, β-blockers, ezetimibe, statins) of the FH patients was observed. This loss-of-function mutation is predicted to alter the free energy dynamics of the transcribed RNA, leading to its instability. Protein structural mapping has predicted that this non-sense mutation eliminates key functional domains in LDLR, which are essential for the receptor recycling and LDL particle binding. In conclusion, by combining genetics and structural bioinformatics approaches, this study identified and characterized a very rare FH causative LDLR pathogenic variant determining both clinical presentation and resistance to anti-lipid drug treatment.","variants":[{"Name":"NM_000527.5(LDLR):c.2027del (p.Gly676fs)","Chromosome":"19","Start":"11120408","Stop":"11120408","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":228196,"rule_based_match":true,"evidence_text":"c.2027delG (p.Gly676Alafs<sup>*</sup>33)","llm_judgment":"PRESENT","evidence":"c.2027delG (p.Gly676Alafs<sup>*</sup>33)","abstract_start":820,"abstract_end":860}]}
{"pmid":"36972944","title":"Genetic analysis of a child patient with rare fibrochondrogenesis due to COL11A1 gene variant","abstract":"OBJECTIVE: To analyze the clinical data and genetic characteristics of a child with fibrocartilage hyperplasia type 1 (FBCG1).\nMETHODS: A child who was admitted to Gansu Provincial Maternity and Child Health Care Hospital on January 21, 2021 due to severe pneumonia and suspected congenital genetic metabolic disorder was selected as the study subject. Clinical data of the child was collected, and genomic DNA was extracted from peripheral blood samples from the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing.\nRESULTS: The patient, a 1-month-old girl, had presented with facial dysmorphism, abnormal skeletal development, and clubbing of upper and lower limbs. WES revealed that she has harbored compound heterozygous variants c.3358G>A/c.2295+1G>A of the COL11A1 gene, which has been associated with fibrochondrogenesis. Sanger sequencing has verified that the variants have been respectively inherited from her father and mother, both of whom were phenotypically normal. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.3358G>A variant was graded as likely pathogenic (PM1+PM2_Supporting+PM3+PP3), and so was the c.2295+1G>A variant (PVS1＋PM2_Supporting).\nCONCLUSION: The compound heterozygous variants c.3358G>A/c.2295+1G>A probably underlay the disease in this child. Above finding has facilitated definite diagnosis, genetic counseling for her family.","variants":[{"Name":"NM_001854.4(COL11A1):c.3358G>A (p.Gly1120Ser)","Chromosome":"1","Start":"102940353","Stop":"102940353","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":275696,"rule_based_match":true,"evidence_text":"c.3358G>A","llm_judgment":"PRESENT","evidence":"c.3358G>A","abstract_start":809,"abstract_end":818}]}
{"pmid":"19338054","title":"Identification and functional analysis of novel variants of the human melanocortin 1 receptor found in melanoma patients.","abstract":"The melanocortin 1 receptor, a Gs protein-coupled receptor expressed in epidermal melanocytes, is a major determinant of skin pigmentation and phototype and an important contributor to melanoma risk. MC1R activation stimulates synthesis of black, strongly photoprotective eumelanin pigments. Several MC1R alleles are associated with red hair, fair skin, increased sensitivity to ultraviolet radiation, and increased skin cancer risk. The MC1R gene is highly polymorphic, but only a few naturally occurring alleles have been functionally characterized, which complicates the establishment of accurate correlations between the signaling properties of mutant alleles and defined cutaneous phenotypes. We report the functional characterization of six MC1R alleles found in Spanish melanoma patients. Two variants (c.152T>C, p.Val51Ala and c.865T>C, p.Cys289Arg) have never been described, and the others (c.112G>A, p.Val38Met; c.122C>T, p.Ser41Phe; c.383T>C, p.Met128Thr; and c.842A>G, p.Asn281Ser) have not been analyzed for function. p.Asn281Ser corresponds to a functionally silent polymorphism. The other mutations are associated with varying degrees of loss of function (LOF), from moderate decreases in coupling to the cAMP pathway (p.Val38Met and p.Val51Ala) to nearly complete absence of functional coupling (p.Ser41Phe, p.Met128Thr, and p.Cys289Arg). The LOF p.Met128Thr and p.Cys289Arg mutants are trafficked to the cell surface, but are unable to bind agonists efficiently. Conversely, LOF of p.Val38Met, p.Ser41Phe, and p.Val51Ala is due to reduced cell surface expression as a consequence of retention in the endoplasmic reticulum (ER). Therefore, LOF of MC1R alleles is frequently associated with aberrant forward trafficking and accumulation within the ER or with inability to bind properly the activatory ligand.","variants":[{"Name":"NM_002386.4(MC1R):c.152T>C (p.Val51Ala)","Chromosome":"16","Start":"89919410","Stop":"89919410","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1360475,"rule_based_match":true,"evidence_text":"c.152T>C, p.Val51Ala","llm_judgment":"PRESENT","evidence":"c.152T>C, p.Val51Ala","abstract_start":810,"abstract_end":830},{"Name":"NM_002386.4(MC1R):c.865T>C (p.Cys289Arg)","Chromosome":"16","Start":"89920123","Stop":"89920123","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1487887,"rule_based_match":true,"evidence_text":"c.865T>C, p.Cys289Arg","llm_judgment":"PRESENT","evidence":"c.865T>C, p.Cys289Arg","abstract_start":835,"abstract_end":856},{"Name":"NM_002386.4(MC1R):c.383T>C (p.Met128Thr)","Chromosome":"16","Start":"89919641","Stop":"89919641","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":876262,"rule_based_match":true,"evidence_text":"c.383T>C (p.Met128Thr)","llm_judgment":"PRESENT","evidence":"p.Met128Thr","abstract_start":955,"abstract_end":966},{"Name":"NM_002386.4(MC1R):c.112G>A (p.Val38Met)","Chromosome":"16","Start":"89919370","Stop":"89919370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":401431,"rule_based_match":true,"evidence_text":"c.112G>A, p.Val38Met","llm_judgment":"PRESENT","evidence":"c.112G>A, p.Val38Met","abstract_start":901,"abstract_end":921}]}
{"pmid":"32706371","title":"Presence of Genetic Variants Among Young Men With Severe COVID-19.","abstract":"Importance: Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).\nObjective: To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.\nDesign, Setting, and Participants: Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.\nExposure: Severe COVID-19.\nMain Outcome and Measures: Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects.\nResults: The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod.\nConclusions and Relevance: In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.","variants":[{"Name":"NM_016562.4(TLR7):c.2129_2132del (p.Gln710fs)","Chromosome":"X","Start":"12887637","Stop":"12887640","ReferenceAlleleVCF":"CAACT","AlternateAlleleVCF":"C","allel_id":965363,"rule_based_match":true,"evidence_text":"c.2129_2132del","llm_judgment":"PRESENT","evidence":"c.2129_2132del","abstract_start":1944,"abstract_end":1958},{"Name":"NM_016562.4(TLR7):c.2383G>T (p.Val795Phe)","Chromosome":"X","Start":"12887891","Stop":"12887891","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":965364,"rule_based_match":true,"evidence_text":"c.2383G>T (p.[Val795Phe])","llm_judgment":"PRESENT","evidence":"c.2383G>T","abstract_start":2042,"abstract_end":2051}]}
{"pmid":"14635115","title":"Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2.","abstract":"Primary hyperoxaluria type 2, an inherited autosomal recessive disorder of endogenous oxalate overproduction, is caused by mutations in the GRHPR gene encoding the glyoxylate/hydroxypyruvate reductase enzyme. The GRHPR genes from nineteen unrelated patients with PH2 were analysed for mutations using a combination of PCR-SSCP and sequence analysis of genomic and cDNA. Eleven mutations were identified, seven of which are novel. The mutations included five point mutations: c.84-2A>G, c.295C>T (R99X), c.494G>A (G165D), and c.904C>T (R302C) as well as six minor deletions: c.103delG, c.375delG, c.403_405+2 delAAGT, c.540delT, c.608_609delCT and a more complex mutation in intron 1: c.84-13_c.84-12del; c.84-8_c.84-5del. Aberrant transcripts were demonstrated in hepatic mRNA as a result of the c.403_405+2 delAAGT and c.84-2A>G mutations. In addition, a splice variant lacking 28 bp of exon 1 was expressed in a number of tissues but is of unknown function. Two polymorphisms, c.579A>G in exon 6 and a (CT)(n) microsatellite in intron 8 were identified. Expression studies showed that the G165D and R302C mutants had glyoxylate reductase activity 1.5 and 5.6% respectively of the wild type protein. Both mutant proteins were unstable on purification. Although there is wide expression of the GRHPR mRNA demonstrated by northern blot analysis, our study shows that GRHPR protein distribution is predominantly hepatic and concludes that PH2, like the related type 1 disease, is primarily a disorder affecting hepatic glyoxylate metabolism.","variants":[{"Name":"NM_012203.2(GRHPR):c.103del (p.Asp35fs)","Chromosome":"9","Start":"37424862","Stop":"37424862","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":20675,"rule_based_match":true,"evidence_text":"c.103delG","llm_judgment":"PRESENT","evidence":"c.103delG","abstract_start":574,"abstract_end":583},{"Name":"NM_012203.2(GRHPR):c.295C>T (p.Arg99Ter)","Chromosome":"9","Start":"37426545","Stop":"37426545","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20676,"rule_based_match":true,"evidence_text":"c.295C>T (R99X)","llm_judgment":"PRESENT","evidence":"c.295C>T (R99X)","abstract_start":486,"abstract_end":501},{"Name":"NM_012203.2(GRHPR):c.84-13_84-12del","Chromosome":"9","Start":"37424831","Stop":"37424832","ReferenceAlleleVCF":"TCC","AlternateAlleleVCF":"T","allel_id":200618,"rule_based_match":false,"evidence_text":"c.84-13_c.84-12del","llm_judgment":"PRESENT","evidence":"c.84-13_c.84-12del","abstract_start":684,"abstract_end":702},{"Name":"NM_012203.2(GRHPR):c.84-8_84-5del","Chromosome":"9","Start":"37424837","Stop":"37424840","ReferenceAlleleVCF":"TCCCC","AlternateAlleleVCF":"T","allel_id":200619,"rule_based_match":false,"evidence_text":"c.84-8_c.84-5del","llm_judgment":"PRESENT","evidence":"c.84-8_c.84-5del","abstract_start":704,"abstract_end":720},{"Name":"NM_012203.2(GRHPR):c.84-2A>G","Chromosome":"9","Start":"37424843","Stop":"37424843","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":200620,"rule_based_match":true,"evidence_text":"c.84-2A>G","llm_judgment":"PRESENT","evidence":"c.84-2A>G","abstract_start":475,"abstract_end":484},{"Name":"NM_012203.2(GRHPR):c.375del (p.Leu126fs)","Chromosome":"9","Start":"37426624","Stop":"37426624","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":200627,"rule_based_match":true,"evidence_text":"c.375del","llm_judgment":"PRESENT","evidence":"c.375del","abstract_start":585,"abstract_end":593},{"Name":"NM_012203.2(GRHPR):c.608_609del (p.Pro203fs)","Chromosome":"9","Start":"37430520","Stop":"37430521","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":200638,"rule_based_match":true,"evidence_text":"c.608_609delCT","llm_judgment":"PRESENT","evidence":"c.608_609delCT","abstract_start":628,"abstract_end":642},{"Name":"NM_012203.2(GRHPR):c.494G>A (p.Gly165Asp)","Chromosome":"9","Start":"37429732","Stop":"37429732","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":200634,"rule_based_match":true,"evidence_text":"c.494G>A (G165D)","llm_judgment":"PRESENT","evidence":"c.494G>A (G165D)","abstract_start":503,"abstract_end":519},{"Name":"NM_012203.2(GRHPR):c.540del (p.Leu181fs)","Chromosome":"9","Start":"37429776","Stop":"37429776","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":200635,"rule_based_match":true,"evidence_text":"c.540del","llm_judgment":"PRESENT","evidence":"c.540del","abstract_start":617,"abstract_end":625},{"Name":"NM_012203.2(GRHPR):c.904C>T (p.Arg302Cys)","Chromosome":"9","Start":"37436699","Stop":"37436699","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":171743,"rule_based_match":true,"evidence_text":"c.904C>T (R302C)","llm_judgment":"PRESENT","evidence":"c.904C>T (R302C)","abstract_start":525,"abstract_end":541}]}
{"pmid":"37520055","title":"Case report: Artemis deficiency and 3M syndrome-coexistence of two distinct genetic disorders.","abstract":"The presence of two different genetic conditions in the same individual is possible, especially in populations with consanguinity. In this case report, we present the coexistence of Artemis deficiency (OMIM 602450) and Three M (3M) syndrome (OMIM 273750). A 10-months-old male patient with neuromotor developmental delay was evaluated for immunodeficiency due to recurrent respiratory infections diarrhea and oral moniliasis from the age of 1.5 months. He had facial dysmorphism with rotated ears, flat nose and hypertelorism. Neurological examination revealed generalized hypotonia and mental motor delay. Immunological screening of the patient demonstrated mild lymphopenia, hypogammaglobulinemia, reduced number of CD3<sup>+</sup> T cells (980 cells/mm<sup>3</sup>) and CD19<sup>+</sup> B cells (35 cells/mm<sup>3</sup>). He was diagnosed with leaky T<sup>-</sup>B<sup>-</sup>NK<sup>+</sup> SCID. Exome sequence analysis showed the presence of a homozygous pathogenic <i>DCLRE1C</i> variant [c.194C > T; p.T65I (NM_001033855)] and a homozygous pathogenic variant in <i>OBSL1</i>, a gene associated with 3M syndrome [c.3922C > T; p.R1308X (NM_001173431)]. Our proband died of sepsis and multiple organ failure. This case illustrates that different clinical findings in patients might not be explained with a single genetic defect, and consanguinity increases the change for coexistence of autosomal recessive diseases. Clinicians should consider exome sequencing to identify disease-causing mutations in patients with heterogeneity of clinical findings.","variants":[{"Name":"NM_015311.3(OBSL1):c.3922C>T (p.Arg1308Ter)","Chromosome":"2","Start":"219557487","Stop":"219557487","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1016005,"rule_based_match":true,"evidence_text":"c.3922C > T; p.R1308X (NM_001173431)","llm_judgment":"PRESENT","evidence":"c.3922C > T; p.R1308X (NM_001173431)","abstract_start":1119,"abstract_end":1155}]}
{"pmid":"30561107","title":"Terminal osseous dysplasia with pigmentary defects (TODPD) in a Turkish girl with new skin findings.","abstract":"Terminal osseous dysplasia with pigmentary defects (TODPD; MIM #300244) is an extremely rare, X-linked dominant, in utero male-lethal disease, characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibromatosis of childhood. Delayed/abnormal ossification of bones of the hands and feet, joint contractures, and dysmorphic facial features may accompany. A single recurrent mutation (c.5217 G>A) of the FLNA gene which causes cryptic splicing was identified as the cause of the disease. We here present the first TODPD case from Turkey with full-blown phenotype who exhibit unique additional findings, hypopigmented patch on the lower extremity following Blaschko's lines and smooth muscle hamartoma of the scalp in review of all the previously reported TODPD cases.","variants":[{"Name":"NM_001110556.2(FLNA):c.5217G>A (p.Thr1739=)","Chromosome":"X","Start":"154354825","Stop":"154354825","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26814,"rule_based_match":true,"evidence_text":"c.5217 G>A","llm_judgment":"PRESENT","evidence":"c.5217 G>A","abstract_start":431,"abstract_end":441}]}
{"pmid":"31959872","title":"Molecular mechanisms determining severity in patients with Pierson syndrome.","abstract":"Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete negativity for laminin β2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype-phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype-phenotype correlation. In addition, all four cases with milder phenotypes showed laminin β2 expression on GBM. We identified novel mechanisms leading to atypical genotype-phenotype correlation in PS.","variants":[{"Name":"NM_002292.4(LAMB2):c.3797+5G>A","Chromosome":"3","Start":"49123723","Stop":"49123723","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":452495,"rule_based_match":true,"evidence_text":"c.3797+5G>A","llm_judgment":"PRESENT","evidence":"c.3797 + 5G>A","abstract_start":964,"abstract_end":977}]}
{"pmid":"25227500","title":"Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy.","abstract":"PURPOSE: This study aimed to identify the genetic defects in 2 families with autosomal recessive macular dystrophy with central cone involvement.\nDESIGN: Case series.\nPARTICIPANTS: Two families and a cohort of 244 individuals with various inherited maculopathies and cone disorders.\nMETHODS: Genome-wide linkage analysis and exome sequencing were performed in 1 large family with 5 affected individuals. In addition, exome sequencing was performed in the proband of a second family. Subsequent analysis of the identified mutations in 244 patients was performed by Sanger sequencing or restriction enzyme digestion. The medical history of individuals carrying the MFSD8 variants was reviewed and additional ophthalmic examinations were performed, including electroretinography (ERG), multifocal ERG (mfERG), perimetry, optical coherence tomography (OCT), fundus autofluorescence, and fundus photography.\nMAIN OUTCOME MEASURES: MFSD8 variants, age at diagnosis, visual acuity, fundus appearance, color vision defects, visual field, ERG, mfERG, fundus autofluorescence, and OCT findings.\nRESULTS: Compound heterozygous variants in MFSD8, a gene encoding a lysosomal transmembrane protein, were identified in 2 families with macular dystrophy with a normal or subnormal ERG, but reduced mfERG. In both families, a heterozygous missense variant p.Glu336Gln was identified, which was predicted to have a mild effect on the protein. In the first family, a protein-truncating variant (p.Glu381*) was identified on the other allele, and in the second family, a variant (c.1102G>C) was identified that results in a splicing defect leading to skipping of exon 11 (p.Lys333Lysfs*3). The p.Glu336Gln allele was found to be significantly enriched in patients with maculopathies and cone disorders (6/488) compared with ethnically matched controls (35/18 682; P < 0.0001), suggesting that it may act as a genetic modifier.\nCONCLUSIONS: In this study, we identified variants in MFSD8 as a novel cause of nonsyndromic autosomal recessive macular dystrophy with central cone involvement. Affected individuals showed no neurologic features typical for variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a severe and devastating multisystem lysosomal storage disease previously associated with mutations in MFSD8. We propose a genotype-phenotype model in which a combination of a severe and a mild variant cause nonsyndromic macular dystrophy with central cone involvement, and 2 severe mutations cause vLINCL.","variants":[{"Name":"NM_001371596.2(MFSD8):c.1006G>C (p.Glu336Gln)","Chromosome":"4","Start":"127921956","Stop":"127921956","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":172081,"rule_based_match":false,"evidence_text":"p.Glu336Gln","llm_judgment":"PRESENT","evidence":"p.Glu336Gln","abstract_start":1340,"abstract_end":1351}]}
{"pmid":"17295913","title":"Functional analysis of splicing mutations in exon 7 of NF1 gene.","abstract":"BACKGROUND: Neurofibromatosis type 1 is one of the most common autosomal dominant disorders, affecting about 1:3,500 individuals. NF1 exon 7 displays weakly defined exon-intron boundaries, and is particularly prone to missplicing.\nMETHODS: In this study we investigated the expression of exon 7 transcripts using bioinformatic identification of splicing regulatory sequences, and functional minigene analysis of four sequence changes [c.910C>T (R304X), c.945G>A/c.946C>A (Q315Q/L316M), c.1005T>C (N335N)] identified in exon 7 of three different NF1 patients.\nRESULTS: Our results detected the presence of three exonic splicing enhancers (ESEs) and one putative exonic splicing silencer (ESS) element. The wild type minigene assay resulted in three alternative isoforms, including a transcript lacking NF1 exon 7 (NF1DeltaE7). Both the wild type and the mutated constructs shared NF1DeltaE7 in addition to the complete messenger, but displayed a different ratio between the two transcripts. In the presence of R304X and Q315Q/L316M mutations, the relative proportion between the different isoforms is shifted toward the expression of NF1DeltaE7, while in the presence of N335N variant, the NF1DeltaE7 expression is abolished.\nCONCLUSION: In conclusion, it appears mandatory to investigate the role of each nucleotide change within the NF1 coding sequence, since a significant proportion of NF1 exon 7 mutations affects pre-mRNA splicing, by disrupting exonic splicing motifs and modifying the delicate balance between aberrantly and correctly spliced transcripts.","variants":[{"Name":"NM_001042492.3(NF1):c.910C>T (p.Arg304Ter)","Chromosome":"17","Start":"31200443","Stop":"31200443","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":184531,"rule_based_match":true,"evidence_text":"c.910C>T (R304X)","llm_judgment":"PRESENT","evidence":"c.910C>T (R304X)","abstract_start":435,"abstract_end":451},{"Name":"NM_001042492.3(NF1):c.1005T>C (p.Asn335=)","Chromosome":"17","Start":"31200538","Stop":"31200538","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":184535,"rule_based_match":true,"evidence_text":"c.1005T>C (N335N)","llm_judgment":"PRESENT","evidence":"c.1005T>C (N335N)","abstract_start":486,"abstract_end":503}]}
{"pmid":"30083363","title":"A novel","abstract":"LMNA-associated congenital muscular dystrophy (L-CMD) is a severe form of muscle laminopathy. <i>LMNA</i> encodes lamin A, which an intermediate filament protein that attaches to the inner membrane of the nuclear envelope. We performed sequence analysis based on our original targeted gene panel system for muscle diseases to obtain a molecular diagnosis in a Japanese girl with L-CMD. A novel heterozygous missense mutation, c.115A>C (p.Asn39His), in <i>LMNA</i> is reported.","variants":[{"Name":"NM_170707.4(LMNA):c.115A>C (p.Asn39His)","Chromosome":"1","Start":"156115033","Stop":"156115033","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":930061,"rule_based_match":true,"evidence_text":"c.115A>C (p.Asn39His)","llm_judgment":"PRESENT","evidence":"c.115A>C (p.Asn39His)","abstract_start":426,"abstract_end":447}]}
{"pmid":"18076122","title":"Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing.","abstract":"Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of chronic renal failure in the first three decades of life. Mutations in eight genes (NPHP1-8) have been identified. We here describe a combined approach for mutation screening of NPHP1, NPHP2, NPHP3, NPHP4, and NPHP5 in a worldwide cohort of 470 unrelated patients with NPHP. First, homozygous NPHP1 deletions were detected in 97 patients (21%) by multiplex PCR. Second, 25 patients with infantile NPHP were screened for mutations in inversin (NPHP2/INVS). We detected a novel compound heterozygous frameshift mutation (p.[Q485fs]+[R687fs]), and a homozygous nonsense mutation (p.R899X). Third, 37 patients presenting with NPHP and retinitis pigmentosa (Senior-Løken syndrome [SLS]) were screened for NPHP5/IQCB1 mutations by direct sequencing. We discovered five different (three novel) homozygous premature termination codon (PTC) mutations (p.F142fsX; p.R461X; p.R489X; p.W444X; and c.488-1G>A). The remaining 366 patients were further investigated for mutations in NPHP1, NPHP3, and NPHP4. We applied a \"homozygosity only\" strategy and typed three highly polymorphic microsatellite markers at the respective loci. A total of 32, eight, and 14 patients showed homozygosity, and were screened by heteroduplex crude celery extract (CEL I) endonuclease digests. The sensitivity of CEL I was established as 92%, as it detected 73 out of 79 different known mutations simply on agarose gels. A total of 10 novel PTC mutations were found in NPHP1 (p.P186fs, p.R347X, p.V492fs, p.Y509X, and c.1884+1G>A), in NPHP3 (c.3812+2T>C and p.R1259X), and in NPHP4 (p.R59X, p.T1004fs, and p.V1091fs). The combined homozygosity mapping and CEL I endonuclease mutation analysis approach allowed us to identify rare mutations in a large cohort of patients at low cost.","variants":[{"Name":"NM_001023570.4(IQCB1):c.488-1G>A","Chromosome":"3","Start":"121807444","Stop":"121807444","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":800368,"rule_based_match":true,"evidence_text":"c.488-1G>A","llm_judgment":"PRESENT","evidence":"c.488-1G>A","abstract_start":987,"abstract_end":997}]}
{"pmid":"29497141","title":"The somatic FAH C.1061C>A change counteracts the frequent FAH c.1062+5G>A mutation and permits U1snRNA-based splicing correction.","abstract":"In tyrosinaemia type 1(HT1), a mosaic pattern of fumarylacetoacetase (FAH) immunopositive or immunonegative nodules in liver tissue has been reported in many patients. This aspect is generally explained by a spontaneous reversion of the mutation into a normal genotype. In one HT1 patient carrying the frequent FAH c.1062+5G>A mutation, a second somatic change (c.1061C>A) has been reported in the same allele, and found in immunopositive nodules. Here, we demonstrated that the c.1062+5G>A prevents usage of the exon 12 5' splice site (ss), even when forced by an engineered U1snRNA specifically designed on the FAH 5'ss to strengthen its recognition. Noticeably the new somatic c.1061C>A change, in linkage with the c.1062+5G>A mutation, partially rescues the defective 5'ss and is associated to trace level (~5%) of correct transcripts. Interestingly, this combined genetic condition strongly favored the rescue by the engineered U1snRNA, with correct transcripts reaching up to 60%. Altogether, these findings elucidate the molecular basis of HT1 caused by the frequent FAH c.1062+5G>A mutation, and demonstrate the compensatory effect of the c.1061C>A change in promoting exon definition, thus unraveling a rare mechanism leading to FAH immune-reactive mosaicism.","variants":[{"Name":"NM_000137.4(FAH):c.1062+5G>A","Chromosome":"15","Start":"80180230","Stop":"80180230","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26909,"rule_based_match":true,"evidence_text":"FAH c.1062+5G>A","llm_judgment":"PRESENT","evidence":"FAH c.1062+5G>A","abstract_start":311,"abstract_end":326}]}
{"pmid":"33811546","title":"Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome.","abstract":"Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca<sup>2+</sup> binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.","variants":[{"Name":"NM_001797.4(CDH11):c.164G>C (p.Trp55Ser)","Chromosome":"16","Start":"65004706","Stop":"65004706","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1330318,"rule_based_match":true,"evidence_text":"c.164G > C, p.(Trp55Ser)","llm_judgment":"PRESENT","evidence":"c.164G > C, p.(Trp55Ser)","abstract_start":844,"abstract_end":868}]}
{"pmid":"21397065","title":"Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease.","abstract":"Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.","variants":[{"Name":"NM_001195129.2(PRSS56):c.1066dup (p.Gln356fs)","Chromosome":"2","Start":"232523817","Stop":"232523818","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":40034,"rule_based_match":true,"evidence_text":"c.1066dupC","llm_judgment":"PRESENT","evidence":"c.1066dupC","abstract_start":662,"abstract_end":672},{"Name":"NM_001195129.2(PRSS56):c.926G>C (p.Trp309Ser)","Chromosome":"2","Start":"232523492","Stop":"232523492","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":40036,"rule_based_match":true,"evidence_text":"c.926G>C (p.Trp309Ser)","llm_judgment":"PRESENT","evidence":"c.926G>C (p.Trp309Ser)","abstract_start":534,"abstract_end":556},{"Name":"NM_001195129.2(PRSS56):c.526C>G (p.Arg176Gly)","Chromosome":"2","Start":"232522594","Stop":"232522594","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":40037,"rule_based_match":true,"evidence_text":"c.526C>G (p.Arg176Gly)","llm_judgment":"PRESENT","evidence":"c.526C>G (p.Arg176Gly)","abstract_start":599,"abstract_end":621}]}
{"pmid":"34923728","title":"EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma.","abstract":"Juvenile open-angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novel EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co-segregating with disease. Affected variant carriers (N = 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early-onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.","variants":[{"Name":"NM_001039348.3(EFEMP1):c.1480T>C (p.Ter494Gln)","Chromosome":"2","Start":"55867075","Stop":"55867075","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1284212,"rule_based_match":true,"evidence_text":"c.1480T>C, p.Ter494Glnext*29","llm_judgment":"PRESENT","evidence":"c.1480T>C, p.Ter494Glnext*29","abstract_start":247,"abstract_end":275}]}
{"pmid":"20950788","title":"De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.","abstract":"Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter.","variants":[{"Name":"NM_001349338.3(FOXP1):c.1573C>T (p.Arg525Ter)","Chromosome":"3","Start":"70972634","Stop":"70972634","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":33467,"rule_based_match":true,"evidence_text":"c.1573C>T [p.R525X]","llm_judgment":"PRESENT","evidence":"c.1573C>T [p.R525X]","abstract_start":1054,"abstract_end":1073}]}
{"pmid":"31068897","title":"A Novel Homozygous Non-sense Mutation in the Catalytic Domain of MTHFR Causes Severe 5,10-Methylenetetrahydrofolate Reductase Deficiency.","abstract":"<b>Background:</b> Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a heterogeneous metabolic disorder inherited in an autosomal recessive manner. Pathogenic mutations in <i>MTHFR</i> gene have been associated with severe MTHFR deficiency. The clinical presentation of MTHFR deficiency is highly variable and associated with several neurological anomalies. <b>Methods:</b> Direct whole-exome sequencing (WES) was performed in all the five available individuals from the family, including the affected individual (III-7) using standard procedures. <b>Results:</b> We observed a proband (III-7) with an abnormality in the cerebral white matter, apnoea, and microcephaly. WES analysis identified a novel homozygous non-sense mutation (c.154C>T; p.Arg52<sup>*</sup>) in <i>MTHFR</i> gene that segregated with the disease phenotype within the family. <b>Conclusion:</b> We identified a novel non-sense mutation in <i>MTHFR</i> gene in a single Egyptian family with severe MTHFR deficiency. The present investigation is clinically important, as it adds to the growing list of <i>MTHFR</i> mutations, which might help in genetic counseling of families of affected children and proper genotype-phenotype correlation.","variants":[{"Name":"NM_005957.5(MTHFR):c.154C>T (p.Arg52Ter)","Chromosome":"1","Start":"11802963","Stop":"11802963","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":513229,"rule_based_match":true,"evidence_text":"c.154C>T; p.Arg52<sup>*</sup>","llm_judgment":"PRESENT","evidence":"c.154C>T; p.Arg52<sup>*</sup>","abstract_start":753,"abstract_end":782}]}
{"pmid":"21044116","title":"Identification and functional analysis of novel human growth hormone-releasing hormone receptor (GHRHR) gene mutations in Japanese subjects with short stature.","abstract":"CONTEXT: Growth hormone-releasing hormone receptor (GHRHR) gene mutations have been identified in patients of different ethnic origins with isolated GH deficiency (IGHD) type IB. However, the prevalence of these mutations in the Japanese population has yet to be fully determined.\nOBJECTIVES: This study aimed to evaluate the contributions of GHRHR mutations to the molecular mechanism underlying short stature in Japanese subjects.\nDESIGN: The GHRHR gene was sequenced in 127 unrelated Japanese patients with either IGHD (n = 14) or idiopathic short stature (ISS; n = 113). Sequence variants were evaluated in family members and 188 controls, and then examined in functional studies.\nRESULTS: A novel homozygous E382E (c.1146G>A) synonymous variant, at the last base of exon 12, was identified in an IGHD family with two affected sisters. In vitro splicing studies showed this mutation to result in skipping of exon 12. In one ISS patient, a heterozygous ATG-166T>C variant was found in the distal Pit-1 P2 binding element of the GHRHR promoter. In two control subjects, a close but distinct variant, ATG-164T>C, was detected. Functional studies showed that both promoter variants diminish promoter activity by altering Pit-1 binding ability. Four missense variants were also found in both patient and control groups but had no detectable functional consequences.\nCONCLUSIONS: The homozygous GHRHR mutation was rare, being detected in only one Japanese IGHD family. Future research is needed to clarify the genetic contributions of heterozygous functional promoter variants to GHD, ISS and normal-stature variations.","variants":[{"Name":"NM_000823.4(GHRHR):c.1146G>A (p.Glu382=)","Chromosome":"7","Start":"30977322","Stop":"30977322","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3856535,"rule_based_match":true,"evidence_text":"c.1146G>A","llm_judgment":"PRESENT","evidence":"c.1146G>A","abstract_start":720,"abstract_end":729}]}
{"pmid":"33407364","title":"A Chinese family with Noonan syndrome caused by a heterozygous variant in LZTR1: a case report and literature review.","abstract":"BACKGROUND: Noonan syndrome is an inherited disease involving multiple systems. More than 15 related genes have been discovered, among which LZTR1 was discovered recently. However, the pathogenesis and inheritance pattern of LZTR1 in Noonan syndrome have not yet been elucidated.\nCASE PRESENTATION: We herein describe a family with LZTR1-related Noonan syndrome. In our study, the proband, sister, mother, maternal aunt and grandmother and female cousin showed the typical or atypical features of Noonan syndrome. Only 3 patients underwent the whole-exome sequencing analysis and results showed that the proband as well as her sister inherited the same heterozygous LZTR1 variant (c.1149 + 1G > T) from their affected mother. Moreover, the proband accompanied by growth hormone deficiency without other associated variants.\nCONCLUSION: In a Chinese family with Noonan syndrome, we find that the c.1149 + 1G > T variant in LZTR1 gene shows a different autosomal dominant inheritance from previous reports, which changes our understanding of its inheritance and improves our understanding of Noonan syndrome.","variants":[{"Name":"NM_006767.4(LZTR1):c.1149+1G>T","Chromosome":"22","Start":"20992370","Stop":"20992370","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":2135274,"rule_based_match":true,"evidence_text":"c.1149 + 1G > T","llm_judgment":"PRESENT","evidence":"c.1149 + 1G > T","abstract_start":681,"abstract_end":696}]}
{"pmid":"25470321","title":"Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B.","abstract":"Inhibitors are an impediment to the effective management of haemophilia B (HB), but there is limited understanding of the underlying genetic risk factors. In this study we aim to understand the role of F9 gene mutations on inhibitor development in patients with HB. Mutations in the F9 gene were identified and HLA typing performed for five boys with severe HB. Data from the CDC Haemophilia B Mutation Project (CHBMP) database were used to assess association between F9 gene mutation type and inhibitor development. Analysis of the CHBMP database showed that larger disruptions in the F9 gene are associated with a higher life-time prevalence of inhibitors. We detected the following mutations in the five subjects, including four novel mutations: Nonsense in three patients (c.223 C>T; p.Arg75* in two siblings, c.553 C>T; p.Glu185*); Splice site in two patients (c.723 + 1 G>A, c.278-27 A>G); Missense in one patient (c.580 A>G, p.Thr194Ala; c.723 G>T; p.Gln241His). Of the two siblings only one responded to immune tolerance induction (ITI). These siblings have identical F9 gene mutations but differ with respect to the HLA alleles. Interestingly, an analysis of peptide-MHC binding affinities shows a significantly higher (one-sided unpaired t-test, P = 0.0018) median affinity for FIX-derived peptides in the sibling that responded to ITI. We conclude that the nature of the F9 gene mutation may be an important risk factor for the development of inhibitors. In addition, the HLA alleles of the individual patients, in conjunction with the mutation type, could be a predictor for the development of inhibitors as well as the response to ITI.","variants":[{"Name":"NM_000133.4(F9):c.223C>T (p.Arg75Ter)","Chromosome":"X","Start":"139537144","Stop":"139537144","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25611,"rule_based_match":true,"evidence_text":"c.223 C>T; p.Arg75*","llm_judgment":"PRESENT","evidence":"c.223 C>T; p.Arg75*","abstract_start":777,"abstract_end":796}]}
{"pmid":"38503300","title":"Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.","abstract":"Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.","variants":[{"Name":"NM_002801.4(PSMB10):c.601G>A (p.Gly201Arg)","Chromosome":"16","Start":"67934906","Stop":"67934906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3400945,"rule_based_match":true,"evidence_text":"c.601G>A (p.Gly201Arg)","llm_judgment":"PRESENT","evidence":"p.Gly201Arg","abstract_start":1088,"abstract_end":1099},{"Name":"NM_002801.4(PSMB10):c.601G>C (p.Gly201Arg)","Chromosome":"16","Start":"67934906","Stop":"67934906","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3400946,"rule_based_match":true,"evidence_text":"c.601G>C (p.Gly201Arg)","llm_judgment":"PRESENT","evidence":"p.Gly201Arg","abstract_start":1088,"abstract_end":1099},{"Name":"NM_002801.4(PSMB10):c.166G>C (p.Asp56His)","Chromosome":"16","Start":"67936291","Stop":"67936291","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3400947,"rule_based_match":true,"evidence_text":"c.166G>C [p.Asp56His]","llm_judgment":"PRESENT","evidence":"c.166G>C [p.Asp56His]","abstract_start":1043,"abstract_end":1064}]}
{"pmid":"33960418","title":"COG1-congenital disorders of glycosylation: Milder presentation and review.","abstract":"Congenital disorders of glycosylation (CDG) are a heterogeneous group of genetic defects in glycoprotein and glycolipid glycan synthesis and attachment. A CDG subgroup are defects in the conserved oligomeric Golgi complex encoded by eight genes, COG1-COG8. Pathogenic variants in all genes except the COG3 gene have been reported. COG1-CDG has been reported in five patients. We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing. Exome sequencing identified a homozygous COG1 variant (NM_018714.3: c.2665dup: p.[Arg889Profs*12]), which has been reported previously in one patient. We review the reported patients.","variants":[{"Name":"NM_018714.3(COG1):c.2665dup (p.Arg889fs)","Chromosome":"17","Start":"73206747","Stop":"73206748","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":791825,"rule_based_match":true,"evidence_text":"NM_018714.3: c.2665dup: p.[Arg889Profs*12]","llm_judgment":"PRESENT","evidence":"NM_018714.3: c.2665dup: p.[Arg889Profs*12]","abstract_start":546,"abstract_end":588}]}
{"pmid":"30105462","title":"Substantial evidence for the clinical significance of missense variant BRCA1 c.5309G>T p.(Gly1770Val).","abstract":"PURPOSE: Classification of rare BRCA1 missense variants presents a major challenge for the counseling and treatment of patients. Variant classification can be complicated by conflicting lines of evidence. BRCA1 c.5309G>T p.(Gly1770Val) has been shown to abrogate BRCA1 protein homologous DNA repair; however, multiple sequence alignment demonstrates a lack of sequence conservation at this position, suggesting that glycine at position 1770 may not be essential for cellular maintenance in humans. We analyzed clinical information to resolve the classification of BRCA1 c.5309G>T p.(Gly1770Val).\nMETHODS: We performed multifactorial likelihood analysis combining segregation data for 14 informative families, and breast tumor histopathological data for 17 variant carriers, ascertained through the ENIGMA consortium.\nRESULTS: Bayes segregation analysis gave a likelihood ratio of 101:1 in favor of pathogenicity. The vast majority of breast tumors showed features indicative of pathogenic variant carrier status, resulting in a likelihood ratio of 15800794:1 towards pathogenicity. Despite a low prior probability of pathogenicity (0.03) based on bioinformatic prediction, multifactorial likelihood analysis including segregation and histopathology analysis gave a posterior probability of > 0.99 and final classification of Pathogenic.\nCONCLUSIONS: We provide evidence that BRCA1 c.5309G>T p.(Gly1770Val), previously described as a Moroccan founder variant, should be treated as a disease-causing variant despite a lack of evolutionary conservation at this amino acid position. Additionally, we stress that bioinformatic information should be used in combination with other data, either direct clinical evidence or some form of clinical calibration, to arrive at a final clinical classification.","variants":[{"Name":"NM_007294.4(BRCA1):c.5309G>T (p.Gly1770Val)","Chromosome":"17","Start":"43051086","Stop":"43051086","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":404710,"rule_based_match":true,"evidence_text":"BRCA1 c.5309G>T p.(Gly1770Val)","llm_judgment":"PRESENT","evidence":"BRCA1 c.5309G>T p.(Gly1770Val)","abstract_start":205,"abstract_end":235}]}
{"pmid":"35906921","title":"Pyridoxine-responsive KCNQ2 epileptic encephalopathy: Additional cases and literature review.","abstract":"BACKGROUND: Typical patients with KCNQ2 (OMIM# 602235) epileptic encephalopathy present early neonatal-onset intractable seizures with a burst suppression EEG pattern and severe developmental delay or regression, and those patients always fail first-line treatment with sodium channel blockers. Vitamin B6, either pyridoxine or pyridoxal 50-phosphate, has been demonstrated to improve seizure control in intractable epilepsy.\nMETHODS: Here, we collected and summarized the clinical data for four independent cases diagnosed with pyridoxine-responsive epileptic encephalopathy, and their exome sequencing data. Moreover, we reviewed all published cases and summarized the clinical features, genetic variants, and treatment of pyridoxine-responsive KCNQ2 epileptic encephalopathy.\nRESULTS: All four cases showed refractory seizures during the neonatal period or infancy, accompanied by global development delay. Four pathogenetic variants of KCNQ2 were uncovered and confirmed by Sanger sequencing: KCNQ2 [NM_172107.4: c.2312C &gt; T (p.Thr771Ile), c.873G &gt; C (p.Arg291Ser), c.652 T &gt; A (p.Trp218Arg) and c.913-915del (p. Phe305del)]. Sodium channel blockers and other anti-seizure medications failed to control their seizures. The frequency of seizures gradually decreased after treatment with high-dose pyridoxine. In case 1, case 2, and case 4, clinical seizures relapsed when pyridoxine was withdrawn, and seizures were controlled again when pyridoxine treatment was resumed.\nCONCLUSION: Our study suggests that pyridoxine may be a promising adjunctive treatment option for patients with KCNQ2 epileptic encephalopathy.","variants":[{"Name":"NM_172107.4(KCNQ2):c.2312C>T (p.Thr771Ile)","Chromosome":"20","Start":"63406951","Stop":"63406951","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":471463,"rule_based_match":false,"evidence_text":"KCNQ2 [NM_172107.4: c.2312C > T (p.Thr771Ile)","llm_judgment":"PRESENT","evidence":"p.Thr771Ile","abstract_start":1033,"abstract_end":1044}]}
{"pmid":"38141607","title":"A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.","abstract":"Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAX<sup>Arg60Gln</sup> (Max<sup>∗Arg60Gln</sup>) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAX<sup>Arg60Gln</sup> individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.","variants":[{"Name":"NM_002382.5(MAX):c.179G>A (p.Arg60Gln)","Chromosome":"14","Start":"65078029","Stop":"65078029","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":948631,"rule_based_match":true,"evidence_text":"c.179G>A (p.Arg60Gln)","llm_judgment":"PRESENT","evidence":"c.179G>A (p.Arg60Gln)","abstract_start":318,"abstract_end":339}]}
{"pmid":"30900640","title":"Adrenal adenoma in von Hippel-Lindau syndrome: A case report with review of literature.","abstract":"A 29-year-old hypertensive male with von Hippel-Lindau (VHL) syndrome came to the Endocrinology department for evaluation. Contrast-enhanced computed tomography of the abdomen revealed an adrenal mass, bilateral renal cell carcinoma, and multiple pancreatic cysts. The hormonal investigations for adrenal mass were normal. He underwent left-sided adrenalectomy, and the histopathological report was suggestive of an adrenocortical adenoma. Genetic analysis of VHL gene in this patient revealed a heterogeneous 5' splice site variation of intron 1 of the VHL gene that affects splice site of exon 1 (c. 340 + 1G > A). Adrenocortical adenoma is very rare in VHL syndrome. Only two cases of adrenocortical adenoma in VHL have been reported in the literature, and both were associated with pheochromocytoma. This is probably the first reported case of adrenocortical adenoma in VHL syndrome without accompanying pheochromocytoma.","variants":[{"Name":"NM_000551.4(VHL):c.340+1G>A","Chromosome":"3","Start":"10142188","Stop":"10142188","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":224922,"rule_based_match":true,"evidence_text":"c. 340 + 1G > A","llm_judgment":"PRESENT","evidence":"c. 340 + 1G > A","abstract_start":599,"abstract_end":614}]}
{"pmid":"20952280","title":"Bilateral renal tumors; conventional clear cell carcinoma and contralateral t(6;11)/t(X;17)-like tumor Histomorphologic, immunohistochemical, ultrastructural and molecular genetic studies including the report of a novel mutation in the VHL gene.","abstract":"A 34-year-old pregnant woman with bilateral kidney tumors 9.5 and 2.5 cm in maximum diameter is presented. The larger tumor was clear renal cell carcinoma. The smaller contralateral tumor was focally HMB45 positive and had unusual histomorphology, including features resembling clear renal cell carcinoma with features of both t(6;11)- and t(X;17)/ASPL-TFE3 carcinomas. This tumor displayed a complex karyotype. A novel germ line mutation in the VHL gene (c.439A>G/p.I147V) was also identified in this patient.","variants":[{"Name":"NM_000551.4(VHL):c.439A>G (p.Ile147Val)","Chromosome":"3","Start":"10146612","Stop":"10146612","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":358732,"rule_based_match":true,"evidence_text":"c.439A>G/p.I147V","llm_judgment":"PRESENT","evidence":"c.439A>G/p.I147V","abstract_start":456,"abstract_end":472}]}
{"pmid":"23053473","title":"Prediction of the functional effect of novel SLC25A13 variants using a S. cerevisiae model of AGC2 deficiency.","abstract":"AGC2, a member of the mitochondrial carrier protein family, is as an aspartate-glutamate carrier and is important for urea synthesis and the maintenance of the malate-aspartate shuttle. Mutations in SLC25A13, the gene encoding AGC2, result in two age dependent disorders: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and type II citrullinemia (CTLN2). The clinical features of CTLN2 are very similar to those of other urea cycle disorders making a clear diagnosis difficult. Analysis of the SLC25A13 gene sequence can provide a definitive diagnosis, however the predictive value of DNA sequencing requires that the disease association of variants be characterized. We utilized the yeast Saccharomyces cerevisiae lacking AGC1 as a model system to study the effect on the function of AGC2 variants and confirmed that this system is capable of distinguishing between AGC2 variants with normal (p.Pro632Leu) or impaired function (p.Gly437Glu, p.Gly531Asp, p.Thr546Met, p.Leu598Arg and p.Glu601Lys). Three novel AGC2 genetic variants, p.Met1? (c.2T>C), p.Pro502Leu (c.1505C>T), and p.Arg605Gln (c.1814G>A) were investigated and our analysis revealed that p.Pro502Leu and p.Arg605Gln substitutions in the AGC2 protein were without effect and these variants were fully functional. The p.Met1? mutant is capable of expressing a truncated p.Met1_Phe34del AGC2 variant, however this protein is not functional due to disruptions in a calcium binding EF hand as well as incorrect intracellular localization. Our study demonstrates that the characterization of AGC2 expressed in yeast cells is a powerful technique to investigate AGC2 variants, and this analysis should aid in establishing the disease association of novel variants.","variants":[{"Name":"NM_014251.3(SLC25A13):c.1637C>T (p.Thr546Met)","Chromosome":"7","Start":"96121952","Stop":"96121952","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":934048,"rule_based_match":false,"evidence_text":"p.Thr546Met","llm_judgment":"PRESENT","evidence":"p.Thr546Met","abstract_start":977,"abstract_end":988},{"Name":"NM_014251.3(SLC25A13):c.2T>C (p.Met1Thr)","Chromosome":"7","Start":"96321955","Stop":"96321955","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":190535,"rule_based_match":true,"evidence_text":"c.2T>C","llm_judgment":"PRESENT","evidence":"c.2T>C","abstract_start":1064,"abstract_end":1070},{"Name":"NM_014251.3(SLC25A13):c.1895C>T (p.Pro632Leu)","Chromosome":"7","Start":"96121324","Stop":"96121324","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2119307,"rule_based_match":false,"evidence_text":"p.Pro632Leu","llm_judgment":"PRESENT","evidence":"p.Pro632Leu","abstract_start":916,"abstract_end":927},{"Name":"NM_014251.3(SLC25A13):c.1793T>G (p.Leu598Arg)","Chromosome":"7","Start":"96121703","Stop":"96121703","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3495155,"rule_based_match":false,"evidence_text":"p.Leu598Arg","llm_judgment":"PRESENT","evidence":"p.Leu598Arg","abstract_start":990,"abstract_end":1001},{"Name":"NM_014251.3(SLC25A13):c.1592G>A (p.Gly531Asp)","Chromosome":"7","Start":"96121997","Stop":"96121997","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34361,"rule_based_match":false,"evidence_text":"p.Gly531Asp","llm_judgment":"PRESENT","evidence":"p.Gly531Asp","abstract_start":964,"abstract_end":975},{"Name":"NM_014251.3(SLC25A13):c.1505C>T (p.Pro502Leu)","Chromosome":"7","Start":"96131829","Stop":"96131829","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247322,"rule_based_match":true,"evidence_text":"c.1505C>T","llm_judgment":"PRESENT","evidence":"c.1505C>T","abstract_start":1086,"abstract_end":1095},{"Name":"NM_014251.3(SLC25A13):c.1801G>A (p.Glu601Lys)","Chromosome":"7","Start":"96121695","Stop":"96121695","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":34364,"rule_based_match":false,"evidence_text":"p.Glu601Lys","llm_judgment":"PRESENT","evidence":"p.Glu601Lys","abstract_start":1006,"abstract_end":1017},{"Name":"NM_014251.3(SLC25A13):c.1814G>A (p.Arg605Gln)","Chromosome":"7","Start":"96121682","Stop":"96121682","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":490111,"rule_based_match":true,"evidence_text":"c.1814G>A","llm_judgment":"PRESENT","evidence":"c.1814G>A","abstract_start":1115,"abstract_end":1124}]}
{"pmid":"29230159","title":"Spondyloepimetaphysial Dysplasia with Joint Laxity in Three Siblings with","abstract":"Spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) is a rare entity with a recessive inheritance. In this report, we describe 3 affected members of the same family who present with short stature, hyperlaxity with secondary spinal malalignment, ulnar subluxation, developmental dysplasia of the hips, and craniofacial alterations; one member also had learning difficulties. DNA analysis showed compound heterozygous variants in the <i>B3GALT6</i> gene (c.901_921dup, c.511C>T) in all 3 patients, inherited from the parents. This family demonstrates the clinical variability of SEMDJL1.","variants":[{"Name":"NM_080605.4(B3GALT6):c.511C>T (p.Arg171Cys)","Chromosome":"1","Start":"1232789","Stop":"1232789","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1489406,"rule_based_match":true,"evidence_text":"c.511C>T","llm_judgment":"PRESENT","evidence":"c.511C>T","abstract_start":483,"abstract_end":491}]}
{"pmid":"15957158","title":"Case reports of oculofaciocardiodental syndrome with unusual dental findings.","abstract":"We report on two new cases of oculofaciocardiodental (OFCD) syndrome characterized by cataracts, microphthalmia, facial anomalies, cleft palate, cardiac septal defects, and canine radiculomegaly. We also review previous patients. The syndrome is caused by mutations in the BCOR gene, which maps to Xp11.4. Mutational analysis in one of our patients showed a deletion of a single nucleotide, c.2613delC, predicting a novel frameshift mutation with a premature stop codon, p.F871Lfs8X.","variants":[{"Name":"NM_001123385.2(BCOR):c.2613del (p.Phe871fs)","Chromosome":"X","Start":"40072733","Stop":"40072733","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":25958,"rule_based_match":true,"evidence_text":"c.2613delC","llm_judgment":"PRESENT","evidence":"c.2613delC","abstract_start":391,"abstract_end":401}]}
{"pmid":"27108797","title":"Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome.","abstract":"Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.","variants":[{"Name":"NM_001378452.1(ITPR1):c.2182C>T (p.Arg728Ter)","Chromosome":"3","Start":"4670904","Stop":"4670904","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":237574,"rule_based_match":true,"evidence_text":"c.2182C>T [p.Arg728(∗)]","llm_judgment":"PRESENT","evidence":"c.2182C>T [p.Arg728(∗)]","abstract_start":596,"abstract_end":619}]}
{"pmid":"29434128","title":"Late-onset Cerebrotendinous Xanthomatosis with a Novel Mutation in the CYP27A1 Gene.","abstract":"Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn disruption in bile acid synthesis characterized by severe systemic xanthomas, cataracts and neurological injuries occurring before adolescence without elevation of the serum cholesterol or triglyceride levels. CTX is caused by a deficiency of the mitochondrial enzyme sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. We herein report a 50-year-old Japanese woman with late-onset CTX who had no relevant symptoms before the development of bilateral Achilles tendon xanthomas in middle age. A genetic analysis revealed a compound heterozygous mutation in the CYP27A1 gene with a previously known missense mutation (NM_000784.3:c.1421 G>A) and a novel frame shift mutation of NM_000784.3:c.1342_1343insCACC.","variants":[{"Name":"NM_000784.4(CYP27A1):c.1421G>A (p.Arg474Gln)","Chromosome":"2","Start":"218814702","Stop":"218814702","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19297,"rule_based_match":true,"evidence_text":"NM_000784.3:c.1421 G>A","llm_judgment":"PRESENT","evidence":"NM_000784.3:c.1421 G>A","abstract_start":701,"abstract_end":723}]}
{"pmid":"35006499","title":"Associations Between Fundus Types and Clinical Manifestations in Patients with RDH12 Gene Mutations.","abstract":"To study the associations between RDH12 gene mutations, fundus types, and clinical manifestations. In total, 46 patients with inherited eye diseases caused by RDH12 gene mutations were included in this study. High-throughput chip capture sequencing, Sanger sequencing, and gene panel detection were used to determine that RDH12 was the pathogenic gene. All patients underwent the following detailed ophthalmic examinations: visual acuity, visual field, intraocular pressure, fundus photography, electroretinography, and optical coherence tomography (OCT). Statistical analysis was used to evaluate the clinical phenotype. A total of 32 mutations were identified in 46 patients. The most common mutations were c.437T > A, c.184C > T, and c.524C > T; the corresponding amino acid changes were p.Val146Asp, p.Arg62Ter, and p.Ser175Leu. Of the 46 patients, retinitis pigmentosa (RP) was found in 31 (68.9%); leber congenital amaurosis (LVA) was found in 11 (24.4%); early onset of severe retinal dystrophy (EOSRD) was found in one (2.2%); cone rod dystrophy (CORD) was found in one (2.2%); and Stargardt disease was found in one (2.2%). There was a significant difference in best-corrected visual acuity among patients based on fundus type (p = 0.0124). Linear trend analysis showed that best-corrected visual acuity gradually decreased as the fundus type increased in severity. In addition, there was a significant difference in the incidence of night blindness among patients with different fundus types (p = 0.0429): types I and IV fundi were associated with the highest incidences of night blindness. RDH12 gene mutation can cause serious inherited retinal diseases, which primarily include RP and LCA. Combined with clinical symptoms and fundus types, the progression of the disease can be characterized and used to guide genetic diagnosis and gene therapy.","variants":[{"Name":"NM_152443.3(RDH12):c.184C>T (p.Arg62Ter)","Chromosome":"14","Start":"67724588","Stop":"67724588","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17089,"rule_based_match":true,"evidence_text":"c.184C > T","llm_judgment":"PRESENT","evidence":"c.184C > T","abstract_start":721,"abstract_end":731},{"Name":"NM_152443.3(RDH12):c.524C>T (p.Ser175Leu)","Chromosome":"14","Start":"67727056","Stop":"67727056","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":550250,"rule_based_match":true,"evidence_text":"c.524C>T (p.Ser175Leu)","llm_judgment":"PRESENT","evidence":"p.Ser175Leu","abstract_start":820,"abstract_end":831}]}
{"pmid":"24294134","title":"Medium-chain acyl-CoA deficiency: outlines from newborn screening, in silico predictions, and molecular studies.","abstract":"Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disorder of fatty acid oxidation characterized by hypoglycemic crisis under fasting or during stress conditions, leading to lethargy, seizures, brain damage, or even death. Biochemical acylcarnitines data obtained through newborn screening by liquid chromatography-tandem mass spectrometry (LC-MS/MS) were confirmed by molecular analysis of the medium-chain acyl-CoA dehydrogenase (ACADM) gene. Out of 324.000 newborns screened, we identified 14 MCADD patients, in whom, by molecular analysis, we found a new nonsense c.823G>T (p.Gly275∗) and two new missense mutations: c.253G>C (p.Gly85Arg) and c.356T>A (p.Val119Asp). Bioinformatics predictions based on both phylogenetic conservation and functional/structural software were used to characterize the new identified variants. Our findings confirm the rising incidence of MCADD whose existence is increasingly recognized due to the efficacy of an expanded newborn screening panel by LC-MS/MS making possible early specific therapies that can prevent possible crises in at-risk infants. We noticed that the \"common\" p.Lys329Glu mutation only accounted for 32% of the defective alleles, while, in clinically diagnosed patients, this mutation accounted for 90% of defective alleles. Unclassified variants (UVs or VUSs) are especially critical when considering screening programs. The functional and pathogenic characterization of genetic variants presented here is required to predict their medical consequences in newborns.","variants":[{"Name":"NM_000016.6(ACADM):c.356T>A (p.Val119Asp)","Chromosome":"1","Start":"75733597","Stop":"75733597","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":541360,"rule_based_match":true,"evidence_text":"c.356T>A (p.Val119Asp)","llm_judgment":"PRESENT","evidence":"c.356T>A (p.Val119Asp)","abstract_start":657,"abstract_end":679},{"Name":"NM_000016.6(ACADM):c.253G>C (p.Gly85Arg)","Chromosome":"1","Start":"75732889","Stop":"75732889","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1364306,"rule_based_match":true,"evidence_text":"c.253G>C (p.Gly85Arg)","llm_judgment":"PRESENT","evidence":"c.253G>C (p.Gly85Arg)","abstract_start":631,"abstract_end":652}]}
{"pmid":"21741611","title":"Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth.","abstract":"Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.","variants":[{"Name":"NM_001142784.3(IL11RA):c.886C>T (p.Arg296Trp)","Chromosome":"9","Start":"34659834","Stop":"34659834","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39092,"rule_based_match":true,"evidence_text":"c.886C>T (p.Arg296Trp)","llm_judgment":"PRESENT","evidence":"p.Arg296Trp","abstract_start":637,"abstract_end":648},{"Name":"NM_001142784.3(IL11RA):c.662C>G (p.Pro221Arg)","Chromosome":"9","Start":"34658535","Stop":"34658535","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":39093,"rule_based_match":true,"evidence_text":"c.662C>G [p.Pro221Arg]","llm_judgment":"PRESENT","evidence":"c.662C>G [p.Pro221Arg]","abstract_start":576,"abstract_end":598},{"Name":"NM_001142784.3(IL11RA):c.734C>G (p.Ser245Cys)","Chromosome":"9","Start":"34658607","Stop":"34658607","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":39094,"rule_based_match":true,"evidence_text":"c.734C>G (p.Ser245Cys)","llm_judgment":"PRESENT","evidence":"p.Ser245Cys","abstract_start":610,"abstract_end":621},{"Name":"NM_001142784.3(IL11RA):c.475C>T (p.Gln159Ter)","Chromosome":"9","Start":"34657331","Stop":"34657331","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39095,"rule_based_match":true,"evidence_text":"c.475C>T (p.Gln159X)","llm_judgment":"PRESENT","evidence":"c.475C>T (p.Gln159X)","abstract_start":770,"abstract_end":790}]}
{"pmid":"28178980","title":"Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome.","abstract":"BACKGROUND: Hearing loss and ovarian dysfunction are key features of Perrault syndrome (PRLTS) but the clinical and pathophysiological features of hearing impairment in PRLTS individuals have not been addressed. Mutations in one of five different genes HSD17B4, HARS2, LARS2, CLPP or TWNK (previous symbol C10orf2) cause the autosomal recessive disorder but they are found only in about half of the patients.\nMETHODS: We report on two siblings with a clinical picture resembling a severe, neurological type of PRLTS. For an exhaustive characterisation of the phenotype neuroimaging with volumetric measurements and objective measures of cochlear hair cell and auditory nerve function (otoacustic emissions and auditory brainstem responses) were used. Whole exome sequencing was applied to identify the genetic cause of the disorder. Co-segregation of the detected mutations with the phenotype was confirmed by Sanger sequencing. In silico analysis including 3D protein structure modelling was used to predict the deleterious effects of the detected variants on protein function.\nRESULTS: We found two rare biallelic mutations in TWNK, encoding Twinkle, an essential mitochondrial helicase. Mutation c.1196A>G (p.Asn399Ser) recurred for the first time in a patient with PRLTS and the second mutation c.1802G>A (p.Arg601Gln) was novel for the disorder. In both patients neuroimaging studies showed diminished cervical enlargement of the spinal cord and for the first time in PRLTS partial atrophy of the vestibulocochlear nerves and decreased grey and increased white matter volumes of the cerebellum. Morphological changes in the auditory nerves, their desynchronized activity and partial cochlear dysfunction underlay the complex mechanism of hearing impairment in the patients.\nCONCLUSIONS: Our study unveils novel features on the phenotypic landscape of PRLTS and provides further evidence that the newly identified for PRLTS TWNK gene is involved in its pathogenesis.","variants":[{"Name":"NM_021830.5(TWNK):c.1802G>A (p.Arg601Gln)","Chromosome":"10","Start":"100993257","Stop":"100993257","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1246232,"rule_based_match":true,"evidence_text":"c.1802G>A (p.Arg601Gln)","llm_judgment":"PRESENT","evidence":"c.1802G>A (p.Arg601Gln)","abstract_start":1299,"abstract_end":1322},{"Name":"NM_021830.5(TWNK):c.1196A>G (p.Asn399Ser)","Chromosome":"10","Start":"100989406","Stop":"100989406","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":211434,"rule_based_match":true,"evidence_text":"c.1196A>G (p.Asn399Ser)","llm_judgment":"PRESENT","evidence":"c.1196A>G (p.Asn399Ser)","abstract_start":1199,"abstract_end":1222}]}
{"pmid":"35513889","title":"Cystinosis and two rare mutations in CTNS gene: two case reports.","abstract":"BACKGROUND: Cystinosis is an autosomal recessive disorder characterized by an accumulation of the amino acid cystine in lysosomes throughout the body. Cystinosis is an inherited disease resulting from the failure of lysosomal cystine transport. The responsible gene, Cystinosin, Lysosomal Cystine Transporter (CTNS), encodes the lysosomal cystine carrier cystinosin.\nCASE PRESENTATION: In this case report, we reviewed the genetic basis of cystinosis and investigated two Iranian cases affected by cystinosis, one of which revealed a rare mutation in the CTNS gene. Two patients, 9-year-old (patient A) and 11-year-old (patient B) symptomatic Iranian females with renal insufficiency, were diagnosed with cystinosis on the basis of their clinical features and laboratory tests. After genetic counseling, blood samples were obtained from the patients and their parents. Genomic Deoxyribonucleic Acid (DNA) was extracted from whole blood, and mutation analysis was performed using polymerase chain reaction and sequencing methods for all exons of the CTNS gene. At least 148 different pathogenic and deleterious mutations in the CTNS gene have been reported to date. Owing to our patient's prominent clinical features of cystinosis, we carried out a targeted search for mutations in the CTNS gene.\nCONCLUSIONS: This led us to confirm the existence of a homozygous DNA variation c.257_258deletionCT (p.Ser86PhefsTer38) in exon 6 of the gene in patient A and another homozygous DNA variation, c.323delA (p.Q108RfsTer10), in the same exon in patient B. As expected, the mentioned mutation existed in both her parents in a heterozygous state. Variations c.257_258delCT and c.323delA reported in three Iranian patients in the CTNS gene are frameshifts, and truncating mutations that affect product function result in relatively mild symptoms of cystinosis. The present finding confirms previous research and proves the importance of the association of this gene rare mutations with cystinosis. Since reported mutations are rare, their previous reports in Iranian patients indicate the high frequency of these mutations in our region.","variants":[{"Name":"NM_004937.3(CTNS):c.323del (p.Gln108fs)","Chromosome":"17","Start":"3655095","Stop":"3655095","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":247620,"rule_based_match":true,"evidence_text":"c.323delA (p.Q108RfsTer10)","llm_judgment":"PRESENT","evidence":"c.323delA (p.Q108RfsTer10)","abstract_start":1489,"abstract_end":1515},{"Name":"NM_004937.3(CTNS):c.257_258del (p.Ser86fs)","Chromosome":"17","Start":"3655027","Stop":"3655028","ReferenceAlleleVCF":"CCT","AlternateAlleleVCF":"C","allel_id":247621,"rule_based_match":true,"evidence_text":"c.257_258deletionCT (p.Ser86PhefsTer38)","llm_judgment":"PRESENT","evidence":"c.257_258deletionCT (p.Ser86PhefsTer38)","abstract_start":1376,"abstract_end":1415}]}
{"pmid":"24676999","title":"A novel DCTN1 mutation with late-onset parkinsonism and frontotemporal atrophy.","abstract":"BACKGROUND: Depression, parkinsonism, and hypoventilation (Perry syndrome) or familial motor neuron disease have been linked to mutations in dynactin P150(Glued) (DCTN1).\nMETHODS: We employed genealogic, clinical, neurologic, and MRI investigations, as well as analysis of genes implicated in parkinsonism. Cellular transfection, immunocytochemistry, and immunoprecipitation analysis of wild-type (WT) and mutant DCTN1 were also performed.\nRESULTS: A novel heterozygous mutation, DCTN1 c.156T>G, encoding p.Phe52Leu, segregates with parkinsonism in a Japanese family. The substitution was not observed in affected probands with familial parkinsonism or control subjects and is evolutionarily conserved. In contrast to Perry syndrome, affected carriers have late-onset disease and slower progression, with frontotemporal atrophy revealed by MRI. In vitro studies suggest the mutant protein has impaired microtubule binding, compared to WT dynactin p150(Glued) .\nCONCLUSIONS: DCTN1 mutations may contribute to disparate neurodegenerative diagnoses, including familial motor neuron disease, parkinsonism, and frontotemporal atrophy, and further studies of dynactin-mediated cargo transport may prove insightful.","variants":[{"Name":"NM_004082.5(DCTN1):c.156T>G (p.Phe52Leu)","Chromosome":"2","Start":"74378123","Stop":"74378123","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":259260,"rule_based_match":true,"evidence_text":"DCTN1 c.156T>G, encoding p.Phe52Leu","llm_judgment":"PRESENT","evidence":"DCTN1 c.156T>G, encoding p.Phe52Leu","abstract_start":480,"abstract_end":515}]}
{"pmid":"32516135","title":"PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy.","abstract":"Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease. X-linked nuclear modifiers were proposed to modify the phenotypic manifestation of LHON-associated mitochondrial DNA (mtDNA) mutations. By whole-exome sequencing, we identified the X-linked LHON modifier (c.157C>T, p.Arg53Trp) in PRICKLE3 encoding a mitochondrial protein linked to biogenesis of ATPase in 3 Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only a single mutation exhibited normal vision. The cells carrying the p.Arg53Trp mutation exhibited defective assembly, stability, and function of ATP synthase, verified by PRICKLE3-knockdown cells. Coimmunoprecipitation indicated the direct interaction of PRICKLE3 with ATP synthase via ATP8. Strikingly, cells bearing both p.Arg53Trp and m.11778G>A mutations displayed greater mitochondrial dysfunction than those carrying only a single mutation. This finding indicated that the p.Arg53Trp mutation acted in synergy with the m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON. Furthermore, we demonstrated that Prickle3-deficient mice exhibited pronounced ATPase deficiencies. Prickle3-knockout mice recapitulated LHON phenotypes with retinal deficiencies, including degeneration of retinal ganglion cells and abnormal vasculature. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutations and X-linked nuclear modifiers.","variants":[{"Name":"NM_006150.5(PRICKLE3):c.157C>T (p.Arg53Trp)","Chromosome":"X","Start":"49183889","Stop":"49183889","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":980887,"rule_based_match":true,"evidence_text":"c.157C>T, p.Arg53Trp","llm_judgment":"PRESENT","evidence":"c.157C>T, p.Arg53Trp","abstract_start":287,"abstract_end":307}]}
{"pmid":"26063487","title":"Improved genetic counseling in Alport syndrome by new variants of COL4A5 gene.","abstract":"There are current requirements of using genetic databases for offering a better genetic assistance to patients of some syndromes, especially those with X-linked heredity patterns (like Alport Syndrome) for the high probability of having descendants affected by the disease. We describe the first reported case of COL4A5 gene missense c.1499 G>T mutation in a 16-year-old girl confirmed to be affected by Alport Syndrome after genetic counseling. Next Generation Sequencing procedures let discover this mutation and offer an accurate clinical treatment to this patient. Current scientific understanding of genetic syndromes suggests the high importance of updated databases and the inclusion of Variant of Unknown Significance related to clinical cases. All of this updating could enable patients to have a better opportunity of diagnosis and having genetic and clinical counseling. This event is even more important in women planning to start a family to have correct genetic counseling regarding the risk posed to offspring, and allowing the decision to undergo prenatal testing.","variants":[{"Name":"NM_033380.3(COL4A5):c.1499G>T (p.Gly500Val)","Chromosome":"X","Start":"108595584","Stop":"108595584","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":578126,"rule_based_match":true,"evidence_text":"c.1499 G>T","llm_judgment":"PRESENT","evidence":"c.1499 G>T","abstract_start":334,"abstract_end":344}]}
{"pmid":"22840363","title":"Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis syndrome is caused by a POC1A mutation.","abstract":"Disproportionate short stature refers to a heterogeneous group of hereditary disorders that are classified according to their mode of inheritance, clinical skeletal and nonskeletal manifestations, and radiological characteristics. In the present study, we report on an autosomal-recessive osteocutaneous disorder that we termed SOFT (short stature, onychodysplasia, facial dysmorphism, and hypotrichosis) syndrome. We employed homozygosity mapping to locate the disease-causing mutation to region 3p21.1-3p21.31. Using whole-exome-sequencing analysis complemented with Sanger direct sequencing of poorly covered regions, we identified a homozygous point mutation (c.512T>C [p.Leu171Pro]) in POC1A (centriolar protein homolog A). This mutation was found to cosegregate with the disease phenotype in two families. The p.Leu171Pro substitution affects a highly conserved amino acid residue and is predicted to interfere with protein function. Poc1, a POC1A ortholog, was previously found to have a role in centrosome stability in unicellular organisms. Accordingly, although centrosome structure was preserved, the number of centrosomes and their distribution were abnormal in affected cells. In addition, the Golgi apparatus presented a dispersed morphology, cholera-toxin trafficking from the plasma membrane to the Golgi was aberrant, and large vesicles accumulated in the cytosol. Collectively, our data underscore the importance of POC1A for proper bone, hair, and nail formation and highlight the importance of normal centrosomes in Golgi assembly and trafficking from the plasma membrane to the Golgi apparatus.","variants":[{"Name":"NM_015426.5(POC1A):c.512T>C (p.Leu171Pro)","Chromosome":"3","Start":"52147039","Stop":"52147039","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":45743,"rule_based_match":true,"evidence_text":"c.512T>C (p.Leu171Pro)","llm_judgment":"PRESENT","evidence":"p.Leu171Pro","abstract_start":674,"abstract_end":685}]}
{"pmid":"28639748","title":"Expansion of the phenotype of Kosaki overgrowth syndrome.","abstract":"Skeletal overgrowth is a characteristic of several genetic disorders that are linked to specific molecular signaling cascades. Recently, we established a novel overgrowth syndrome (Kosaki overgrowth syndrome, OMIM #616592) arising from a de novo mutation in PDGFRB, that is, c.1751C>G p.(Pro584Arg). Subsequently, other investigators provided in vitro molecular evidence that this specific mutation in the juxtamembrane domain of PDGFRB causes an overgrowth phenotype and is the first gain-of-function point mutation of PDGFRB to be reported in humans. Here, we report the identification of a mutation in PDGFRB, c.1696T>C p.(Trp566Arg), in two unrelated patients with skeletal overgrowth, further confirming the existence of PDGFRB-related overgrowth syndrome arising from mutations in the juxtamembrane domain of PDGFRB. A review of all four of these patients with an overgrowth phenotype and PDGFRB mutations revealed postnatal skeletal overgrowth, premature aging, cognitive impairment, neurodegeneration, and a prominent connective tissue component to this complex phenotype. From a functional standpoint, hypermorphic mutations in PDGFRB lead to Kosaki overgrowth syndrome, infantile myofibromatosis (OMIM #228550), and Penttinen syndrome (OMIM #601812), whereas hypomorphic mutations lead to idiopathic basal ganglia calcification (OMIM #615007). In conclusion, a specific class of mutations in PDGFRB causes a clinically recognizable syndromic form of skeletal overgrowth.","variants":[{"Name":"NM_002609.4(PDGFRB):c.1696T>C (p.Trp566Arg)","Chromosome":"5","Start":"150125556","Stop":"150125556","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":362521,"rule_based_match":true,"evidence_text":"c.1696T>C p.(Trp566Arg)","llm_judgment":"PRESENT","evidence":"c.1696T>C p.(Trp566Arg)","abstract_start":613,"abstract_end":636}]}
{"pmid":"19148133","title":"The isochromosome i(7)(q10) carrying c.258+2t>c mutation of the SBDS gene does not promote development of myeloid malignancies in patients with Shwachman syndrome.","abstract":"Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder, characterized by exocrine pancreatic insufficiency, skeletal abnormalities and bone marrow (BM) dysfunction with an increased risk to develop myelodysplastic syndrome and/or acute myeloid leukaemia (MDS/AML). SDS is caused, in nearly 90% of cases, by two common mutations (that is, c.183_184TA>CT and c.258+2T>C) in exon 2 of the SBDS gene, localized on chromosome 7. Clonal chromosome anomalies are often found in the BM of SDS patients; the most frequent is an isochromosome for long arms of chromosome 7, i(7)(q10). We studied eight patients with SDS carrying the i(7)(q10) who were compound heterozygotes for SBDS mutations. By assessing the parental origin of the i(7)(q10) using microsatellite analysis, we inferred from the results which mutation was present in double dose in the isochromosome. We demonstrate that in all cases the i(7)(q10) carries a double dose of the c.258+2T>C, and we suggest that, as the c.258+2T>C mutation still allows the production of some amount of normal protein, this may contribute to the low incidence of MDS/AML in this subset of SDS patients.","variants":[{"Name":"NM_016038.4(SBDS):c.258+2T>C","Chromosome":"7","Start":"66994210","Stop":"66994210","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18235,"rule_based_match":true,"evidence_text":"c.258+2T>C","llm_judgment":"PRESENT","evidence":"c.258+2T>C","abstract_start":370,"abstract_end":380}]}
{"pmid":"30851773","title":"A novel mutation in MERTK for rod-cone dystrophy in a North Indian family.","abstract":"OBJECTIVE: To identify the underlying genetic defect of childhood-onset severe rod-cone dystrophy (RCD) in a consanguineous family from North India with autosomal recessive retinitis pigmentosa.\nMETHODS: A detailed family history, clinical data, and blood samples were collected from 11 members of the family, including 4 affected by an autosomal recessive rod-cone dystrophy (arRCD), and DNA was extracted. Whole-exome sequencing (WES) was performed on DNA samples of proband and her unaffected maternal uncle. Ion Reporter software (ver. 4.4) was used for the annotation of variants obtained by WES. The variants detected in proband were tested for validation in all other affected and unaffected family members using Sanger sequencing technique.\nRESULTS: We have identified a novel nonsense mutation-c.1647T>G (p.Tyr549Ter)-in the exon 11 of MERTK that co-segregated completely with the disease phenotype in all the 4 affected members and was not observed in the 7 unaffected members of the family. This mutation was also not detected in 120 ethnically matched controls (240 chromosomes), hence excluding it as a polymorphism.\nCONCLUSIONS: MERTK has a role in retinal pigment epithelium as a regulator of rod outer segments' phagocytosis. Due to c.1647T > G substitution, the stop codon (p.Tyr549Ter) appears early in the transcript. It seems that either the altered transcript would degenerate through nonsense-mediated decay (NMD) or potentially form truncated protein lacking a functionally important domain (i.e., tyrosine kinase domain). These findings thus further expand the mutation spectrum in MERTK and substantiate its role in the pathogenesis of retinal dystrophy.","variants":[{"Name":"NM_006343.3(MERTK):c.1647T>G (p.Tyr549Ter)","Chromosome":"2","Start":"112001243","Stop":"112001243","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1684174,"rule_based_match":true,"evidence_text":"c.1647T>G (p.Tyr549Ter)","llm_judgment":"PRESENT","evidence":"c.1647T>G (p.Tyr549Ter)","abstract_start":803,"abstract_end":826}]}
{"pmid":"29783825","title":"Clinical and molecular analysis of two Chinese siblings with Bloom syndrome","abstract":"<b>Objective:</b> To expand the knowledge of the clinical and molecular characteristics of the children with Bloom syndrome. <b>Methods:</b> Clinical data of two siblings with classic Bloom syndrome of Shanghai Children's Medical Center from January 2009 to June 2017 were obtained and analyzed. The DNA of peripheral blood was collected from two Bloom syndrome siblings and their parents during 2015. The mutations were detected with high-throughput sequencing by Illumina sequencing platform. <b>Results:</b> The two siblings (probands) visited our department for short stature and growth retardation, they had full-term normal delivery after normal pregnancy of their mother. Both cases presented with feeding difficulties, malnutrition, microcephaly and mental retardation, repeated infection, symmetrical short stature and special faces. At first, the proband was an 8-year-3-month old girl, her height was 99.7 cm, body mass index (BMI) 12.07 kg/m(2), head circumference was 45.5 cm, and birth weight was 1.6 kg. Her younger brother was 3-year-11-month old, his height was 86.6 cm, BMI was 14 kg/m(2), birth weight was 1.95 kg, and the head circumference reached 36 cm at 16 months. No evidence of cancer and characteristic rash was detected at 8-year follow-up. Pathogenic complex heterozygous mutations c.772_773delCT, p.Leu258Glufs*7 and c.959+ 2T>A in BLM gene were detected in both siblings, which were separately inherited from their unaffected parents. Besides , c.959 + 2T>A has not been reported previously. <b>Conclusions:</b> Children with Bloom syndrome are characterized by short stature, microcephaly, special faces, feeding difficulties, and immunodeficiency. And butterfly erythematous rash may be absent. The c.959+2T>A mutation detected in our patients maybe a novel pathogenic mutation.","variants":[{"Name":"NM_000057.4(BLM):c.772_773del (p.Leu258fs)","Chromosome":"15","Start":"90750036","Stop":"90750037","ReferenceAlleleVCF":"ACT","AlternateAlleleVCF":"A","allel_id":51258,"rule_based_match":true,"evidence_text":"c.772_773delCT","llm_judgment":"PRESENT","evidence":"c.772_773delCT","abstract_start":1311,"abstract_end":1325}]}
{"pmid":"29681105","title":"Lethal persistent pulmonary hypertension of the newborn in Bohring-Opitz syndrome.","abstract":"Bohring-Opitz syndrome (BOS) is a rare disease with a number of characteristic features, including hypertelorism, prominent metopic suture, exophthalmos, cleft palate, abnormal posture, and developmental retardation. Here, we report a BOS patient presenting with lethal persistent pulmonary hypertension of the newborn (PPHN) and inspiratory respiratory failure. The female infant was treated with nitric oxide and vasodilator, which did not improve her condition. The inspiratory respiratory failure required management with deep sedation. She died on postnatal day 60 due to progressed heart failure. Whole exome sequencing revealed de novo mutation in the ASXL1 gene, c.1934dupG, p.Gly646TrpfsTer12.","variants":[{"Name":"NM_015338.6(ASXL1):c.1934dup (p.Gly646fs)","Chromosome":"20","Start":"32434638","Stop":"32434639","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AG","allel_id":415680,"rule_based_match":true,"evidence_text":"c.1934dupG","llm_judgment":"PRESENT","evidence":"c.1934dupG","abstract_start":671,"abstract_end":681}]}
{"pmid":"32747156","title":"A genetic mimic of cerebral palsy: Homozygous NFU1 mutation with marked intrafamilial phenotypic variation.","abstract":"BACKGROUND: Genetic defects in the NFU1, an iron-sulfur cluster scaffold protein coding gene, which is vital in the final stage of assembly for iron sulfur proteins, have been defined as multiple mitochondrial dysfunctions syndrome I. This disorder is a severe autosomal recessive disease with onset in early infancy. It is characterized by disruption of the energy metabolism, resulting in weakness, neurological regression, hyperglycinemia, lactic acidosis, and early death.\nPATIENT DESCRIPTION: This report documents the case of a 27-month-old girl, who showed clinical signs and symptoms of spastic paraparesis with a relapsing-remitting course. The patient had a sister with a severe phenotype who died at the age of 16 months.\nRESULTS: Magnetic resonance imaging revealed hyperintensity of the cerebral white matter that was more prominent in the frontal regions, with milder involvement in the posterior periventricular regions. There was also evidence of partial cystic degeneration and cavitation in the frontal regions. In addition, she had hyperglycinemia. Homozygous NM_001002755.4:c.565G>A (p.Gly189Arg) mutation was identified in the NFU1 gene; this had not previously been reported as homozygous.\nCONCLUSION: Hyperglycinemia and cavitating leukodystrophy are suggestive of an NFU1 mutation diagnosis. An intrafamilial phenotypic variation has not been published in NFU1-associated disorders before. Presenting with spasticity as a rare phenotype, NFU1 mutations could be considered a genetic mimic of cerebral palsy.","variants":[{"Name":"NM_001002755.4(NFU1):c.565G>A (p.Gly189Arg)","Chromosome":"2","Start":"69400519","Stop":"69400519","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1275319,"rule_based_match":true,"evidence_text":"NM_001002755.4:c.565G>A (p.Gly189Arg)","llm_judgment":"PRESENT","evidence":"NM_001002755.4:c.565G>A (p.Gly189Arg)","abstract_start":1079,"abstract_end":1116}]}
{"pmid":"29382611","title":"Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment.","abstract":"Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by low bone density and recurrent fractures with a wide genotypic and phenotypic spectrum. Common features include short stature, opalescent teeth, blue sclerae and hearing impairment. The majority (>90%) of patients with OI have autosomal dominant variants in COL1A1/COL1A2, which lead to defects in type 1 collagen. More recently, numerous recessive variants involving other genes have also been identified. Sp7/Osx gene, is a protein coding gene that encodes a zinc finger transcription factor, osterix, which is a member of the Sp subfamily of sequence-specific DNA-binding proteins. Osterix is expressed primarily by osteoblasts and has been shown to be vital for bone formation and bone homeostasis by promoting osteoblast differentiation and maturation. In animal models, Sp7/Osx has also been shown to regulate biomineralization of otoliths, calcium carbonate structures found in the inner ear of vertebrates. Until recently, only one report of a boy with an Sp7/Osx pathogenic variant presenting with bone fragility, limb deformities and normal hearing has been described in the literature. We have identified a novel Sp7/Osx variant in another sibship that presented with osteoporosis, low-trauma fractures and short stature. Progressive moderate-to-severe and severe-to-profound hearing loss secondary to otospongiosis and poor mineralization of ossicles and petrous temporal bone was also noted in two of the siblings. A homozygous pathogenic variant in exon 2 of the Sp7/Osx gene was found in all affected relatives; c.946C>T (p.Arg316Cys). Bone biopsies in the proband and his male sibling revealed significant cortical porosity and high trabecular bone turnover. This is the second report to describe children with OI associated with an Sp7/Osx variant. However, it is the first to describe the bone histomorphometry associated with this disorder and identifies a significant hearing loss as a potential feature in this OI subtype. Early audiology screening in these children is therefore warranted.","variants":[{"Name":"NM_001173467.3(SP7):c.946C>T (p.Arg316Cys)","Chromosome":"12","Start":"53328496","Stop":"53328496","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":551264,"rule_based_match":true,"evidence_text":"c.946C>T (p.Arg316Cys)","llm_judgment":"PRESENT","evidence":"c.946C>T (p.Arg316Cys)","abstract_start":1605,"abstract_end":1627}]}
{"pmid":"32028018","title":"Musculoskeletal phenotype in two unrelated individuals with a recurrent nonsense variant in SGMS2.","abstract":"Heterozygous mutations in the gene encoding the sphingomyelin synthase 2, SGMS2, have recently been linked to childhood-onset osteoporosis and skeletal dysplasia. One nonsense variant at position c.148C>T (p.Arg50*) has been associated with mild bone fragility with or without cranial sclerosis. Here we assessed the effect of the SGMS2 p.Arg50* variant in two unrelated probands with childhood-onset osteoporosis and their unaffected family members. We found that the p.Arg50* variant was associated with phenotypic variability, ranging from absence of a bone phenotype to severe vertebral compression fractures and low lumbar spine areal bone mineral density (BMD) as measured by dual energy x-ray absorptiometry. Peripheral quantitative computed tomography of the radius and tibia in the two probands revealed low cortical volumetric BMD and reduced cortical thickness. In addition, both probands were obese and suffered from muscle function deficits compared to sex- and age-matched controls. Long-term bisphosphonate treatment was associated with reshaping of previously compressed vertebral bodies.","variants":[{"Name":"NM_001375905.1(SGMS2):c.148C>T (p.Arg50Ter)","Chromosome":"4","Start":"107895701","Stop":"107895701","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":623119,"rule_based_match":true,"evidence_text":"c.148C>T (p.Arg50*)","llm_judgment":"PRESENT","evidence":"c.148C>T (p.Arg50*)","abstract_start":196,"abstract_end":215}]}
{"pmid":"28052128","title":"GBA2 Mutations Cause a Marinesco-Sjögren-Like Syndrome: Genetic and Biochemical Studies.","abstract":"BACKGROUND: With the advent new sequencing technologies, we now have the tools to understand the phenotypic diversity and the common occurrence of phenocopies. We used these techniques to investigate two Norwegian families with an autosomal recessive cerebellar ataxia with cataracts and mental retardation.\nMETHODS AND RESULTS: Single nucleotide polymorphism (SNP) chip analysis followed by Exome sequencing identified a 2 bp homozygous deletion in GBA2 in both families, c.1528_1529del [p.Met510Valfs*17]. Furthermore, we report the biochemical characterization of GBA2 in these patients. Our studies show that a reduced activity of GBA2 is sufficient to elevate the levels of glucosylceramide to similar levels as seen in Gaucher disease. Furthermore, leucocytes seem to be the proper enzyme source for in vitro analysis of GBA2 activity.\nCONCLUSIONS: We report GBA2 mutations causing a Marinesco-Sjögren-like syndrome in two Norwegian families. One of the families was originally diagnosed with Marinesco-Sjögren syndrome based on an autosomal recessive cerebellar ataxia with cataracts and mental retardation. Our findings highlight the phenotypic variability associated with GBA2 mutations, and suggest that patients with Marinesco-Sjögren-like syndromes should be tested for mutations in this gene.","variants":[{"Name":"NM_020944.3(GBA2):c.1528_1529del (p.Met510fs)","Chromosome":"9","Start":"35739681","Stop":"35739682","ReferenceAlleleVCF":"CAT","AlternateAlleleVCF":"C","allel_id":2152716,"rule_based_match":true,"evidence_text":"c.1528_1529del [p.Met510Valfs*17]","llm_judgment":"PRESENT","evidence":"c.1528_1529del [p.Met510Valfs*17]","abstract_start":473,"abstract_end":506}]}
{"pmid":"20598774","title":"A de novo missense mutation of the FUS gene in a \"true\" sporadic ALS case.","abstract":"Mutations in the Cu/Zn superoxide dismutase (SOD1), transactive response (TAR)-DNA binding protein (TARDBP) and fused in sarcoma (FUS) genes account for approximately 1 third of familial amyotrophic lateral sclerosis (ALS) cases. Mutations in these genes have been found in 1% to 2% of apparently sporadic cases. We present the first case of an ALS patient carrying a de novo missense mutation of the FUS gene (c.1561C>T, p.R521C). This report highlights the importance of screening ALS patients, both familial and sporadic, for FUS mutations and also suggests that de novo mutations is a relevant mechanism underlying sporadic neurodegenerative disease.","variants":[{"Name":"NM_004960.4(FUS):c.1561C>T (p.Arg521Cys)","Chromosome":"16","Start":"31191418","Stop":"31191418","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31263,"rule_based_match":true,"evidence_text":"c.1561C>T, p.R521C","llm_judgment":"PRESENT","evidence":"c.1561C>T, p.R521C","abstract_start":411,"abstract_end":429}]}
{"pmid":"34828281","title":"An Updated","abstract":"Establishing the genotypes of patients with hyperphenylalaninemia (HPA)/phenylketonuria (PKU, MIM#261600) has been considered a cornerstone for rational medical management. However, knowledge of the phenylalanine hydroxylase gene (<i>PAH)</i> mutational spectrum in Latin American populations is still limited. Herein, we aim to update the mutational <i>PAH</i> spectrum in the largest cohort of HPA/PKU Mexican patients (<i>N</i> = 124) reported to date. The biallelic <i>PAH</i> genotype was investigated by Sanger automated sequencing, and genotypes were correlated with documented biochemical phenotypes and theoretical tetrahydrobiopterin (BH<sub>4</sub>) responsiveness. Patients were biochemically classified as having classic PKU (50%, 62/124), mild PKU (20.2%, 25/124) and mild HPA (29.8%, 37/124). Furthermore, 78.2% of the included patients (97/124) were identified by newborn screening. A total of 60 different pathogenic variants were identified, including three novel ones (c. 23del, c. 625_626insC and c. 1315 + 5_1315 + 6insGTGTAACAG), the main categories being missense changes (58%, 35/60) and those affecting the catalytic domain (56.6%, 34/60), and c. 60 + 5G > T was the most frequent variant (14.5%, 36/248) mainly restricted (69.2%) to patients from the central and western parts of Mexico. These 60 types of variants constituted 100 different biallelic PAH genotypes, with the predominance of compound-heterozygous ones (96/124, 77%). The expected BH<sub>4</sub> responsiveness based on the <i>PAH</i> genotype was estimated in 52% of patients (65/124), mainly due to the p. (Val388Met) (rs62516101) allele. Instead, our study identified 27 null variants with an allelic phenotype value of zero, with a predominance of c. 60 + 5G > T, which predicts the absence of BH<sub>4</sub> responsiveness. An identical genotype reported in BIOPKUdb was found in 92/124 (74%) of our patients, leading to a genotype-phenotype concordance in 80/92 (86.9%) of them. The high number of variants found confirms the heterogeneous and complex mutational landscape of HPA/PKU in Mexico.","variants":[{"Name":"NM_000277.3(PAH):c.60+5G>T","Chromosome":"12","Start":"102917066","Stop":"102917066","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":108487,"rule_based_match":true,"evidence_text":"c. 60 + 5G > T","llm_judgment":"PRESENT","evidence":"c. 60 + 5G > T","abstract_start":1169,"abstract_end":1183}]}
{"pmid":"36264506","title":"Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure.","abstract":"DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis. This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.856A > T; p.Lys286Ter), or homozygous missense variants (c.74G > A; p.Arg25Gln and c.785 T > C; p.Leu262Ser) in DNAJB4. Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life. Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh. On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles. DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients supporting a loss of function. Functional studies confirmed that the p.Lys286Ter and p.Leu262Ser mutant proteins are rapidly degraded in cells. In contrast, the p.Arg25Gln mutant protein is stable but failed to complement for DNAJB function in yeast, disaggregate client proteins or protect from heat shock-induced cell death consistent with its loss of function. DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis. DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones. These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure. DNAJB4 loss of function variants may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration.","variants":[{"Name":"NM_007034.5(DNAJB4):c.785T>C (p.Leu262Ser)","Chromosome":"1","Start":"78016018","Stop":"78016018","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2477464,"rule_based_match":true,"evidence_text":"c.785 T > C; p.Leu262Ser","llm_judgment":"PRESENT","evidence":"c.785 T > C; p.Leu262Ser","abstract_start":427,"abstract_end":451},{"Name":"NM_007034.5(DNAJB4):c.74G>A (p.Arg25Gln)","Chromosome":"1","Start":"78005184","Stop":"78005184","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2477465,"rule_based_match":true,"evidence_text":"c.74G>A (p.Arg25Gln)","llm_judgment":"PRESENT","evidence":"p.Arg25Gln","abstract_start":412,"abstract_end":422},{"Name":"NM_007034.5(DNAJB4):c.856A>T (p.Lys286Ter)","Chromosome":"1","Start":"78016089","Stop":"78016089","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2477463,"rule_based_match":true,"evidence_text":"c.856A > T; p.Lys286Ter","llm_judgment":"PRESENT","evidence":"c.856A > T; p.Lys286Ter","abstract_start":342,"abstract_end":365}]}
{"pmid":"24334170","title":"Perinatal hypophosphatasia caused by uniparental isodisomy.","abstract":"Hypophosphatasia (HPP) is an inherited disorder characterized by defective bone mineralization caused by mutations in the alkaline phosphatase gene (ALPL). Clinically, the disease spans a great continuum of disease severity and six forms can be distinguished according to the age of onset. The most severe is the autosomal recessive perinatal form, a major prenatal skeletal dysplasia in Japan. The ALPL mutation c.1559delT causes perinatal HPP and occurs frequently in the Japanese. Most patients with perinatal HPP in Japan are homozygous for c.1559delT, and their parents are usually heterozygous with no evidence of consanguinity. Here we identified a fetus with perinatal HPP resulting from an unusual mechanism known as paternal uniparental isodisomy (UPD) of chromosome 1. Sequence analysis of ALPL in the patient revealed the presence of the homozygous mutation c.1559delT. We suspected UPD because the father and mother were heterozygous and wild type, respectively. Analysis of polymorphic microsatellite markers spanning chromosome 1 and whole-genome arrays revealed a uniparental inheritance from the father and excluded deletions or de novo mutations. This is the first description of perinatal HPP caused by UPD. This report also emphasizes the low recurrence risk of a non-Mendelian inheritance pattern in UPD and the value of determining parental genotypes with homozygous mutations in a patient to confirm whether the condition is caused by UPD or not, even when the mutation is detected as a hot spot, as described in the literature.","variants":[{"Name":"NM_000478.6(ALPL):c.1559del (p.Leu520fs)","Chromosome":"1","Start":"21577632","Stop":"21577632","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":28713,"rule_based_match":true,"evidence_text":"c.1559delT","llm_judgment":"PRESENT","evidence":"c.1559delT","abstract_start":413,"abstract_end":423}]}
{"pmid":"16802107","title":"Subclinical course of adult visceral Niemann-Pick type C1 disease. A rare or underdiagnosed disorder?","abstract":"We present the third case of Niemann-Pick disease type C without neurological symptoms. The patient was a 53-year-old woman without significant prior health problems who died of acute pulmonary embolism. Autopsy findings of hepatosplenomegaly, lymphadenopathy and ceroid-rich foam cells raised the suspicion of the visceral form of acid sphingomyelinase deficiency (Niemann-Pick disease type B; NPB) or a much rarer disorder, variant adult visceral form of Niemann-Pick disease type C (NPC). To verify the histopathological findings, SMPD1, NPC1 and NPC2 genes were analysed. Two novel sequence variants, c.1997G>A (S666N) and c.2882A>G (N961S) were detected in the NPC1 gene. No pathogenic sequence variants were found either in the SMPD1 gene mutated in NPB or in NPC2 gene. The pathogenicity of both NPC1 variants was supported by their location in regions important for the protein function. Both variations were not found in more than 300 control alleles. Identified sequence variations confirm the diagnosis of the extremely rare adult visceral form of Niemann-Pick disease type C, which is otherwise dominated by neurovisceral symptoms. Although only three patients have been reported, this (most probably underdiagnosed) form of NPC should be considered in differential diagnosis of isolated hepatosplenomegaly with foam cells in adulthood.","variants":[{"Name":"NM_000271.5(NPC1):c.2882A>G (p.Asn961Ser)","Chromosome":"18","Start":"23539384","Stop":"23539384","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":247146,"rule_based_match":true,"evidence_text":"c.2882A>G (N961S)","llm_judgment":"PRESENT","evidence":"c.2882A>G (N961S)","abstract_start":627,"abstract_end":644},{"Name":"NM_000271.5(NPC1):c.1997G>A (p.Ser666Asn)","Chromosome":"18","Start":"23544477","Stop":"23544477","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1868290,"rule_based_match":true,"evidence_text":"c.1997G>A (S666N)","llm_judgment":"PRESENT","evidence":"c.1997G>A (S666N)","abstract_start":605,"abstract_end":622}]}
{"pmid":"35851598","title":"Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.","abstract":"Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.","variants":[{"Name":"NM_005052.3(RAC3):c.187G>A (p.Asp63Asn)","Chromosome":"17","Start":"82032790","Stop":"82032790","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":860458,"rule_based_match":true,"evidence_text":"c.187G > A p.D63N","llm_judgment":"PRESENT","evidence":"c.187G > A p.D63N","abstract_start":873,"abstract_end":890},{"Name":"NM_005052.3(RAC3):c.191A>G (p.Tyr64Cys)","Chromosome":"17","Start":"82032794","Stop":"82032794","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":970510,"rule_based_match":true,"evidence_text":"c.191A > G p.Y64C","llm_judgment":"PRESENT","evidence":"c.191A > G p.Y64C","abstract_start":892,"abstract_end":909},{"Name":"NM_005052.3(RAC3):c.34G>C (p.Gly12Arg)","Chromosome":"17","Start":"82031795","Stop":"82031795","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":965884,"rule_based_match":true,"evidence_text":"c.34G > C p.G12R","llm_judgment":"PRESENT","evidence":"c.34G > C p.G12R","abstract_start":810,"abstract_end":826}]}
{"pmid":"36457943","title":"Neurodevelopmental Disorder, Obesity, Pancytopenia, Diabetes Mellitus, Cirrhosis, and Renal Failure in","abstract":"Objectives: Neurodevelopmental disorders (NDDs) are a group of conditions that are clinically and etiologically heterogeneous. Biallelic variants in <i>ACBD6</i> were previously reported in 7 patients with NDDs. Unfortunately, their clinical information remains very limited with descriptions of only their neurologic and craniofacial features. The purpose of this report is to expand the clinical phenotype of the <i>ACBD6</i>-associated NDDs.\nMethods: We identified 2 Thai siblings with NDDs. Clinical and radiologic features of the proband were described. The affected siblings and parents underwent whole-exome sequencing and PCR-Sanger sequencing.\nResults: Clinical manifestations that have never been previously reported include morbid obesity, pancytopenia with severe infections, diabetes mellitus, cirrhosis, and renal failure, leading to deaths in their early 30s. Molecular studies identified a novel homozygous 1 base-pair duplication (c.360dup; p.Leu121Thrfs*27) in the <i>ACBD6</i> gene.\nDiscussion: This study reported 1 novel single base-pair duplication, expanding the mutational spectrum, and described the clinical features establishing the entity of <i>ACBD6</i>-associated NDDs.","variants":[{"Name":"NM_032360.4(ACBD6):c.360dup (p.Leu121fs)","Chromosome":"1","Start":"180492292","Stop":"180492293","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":1166964,"rule_based_match":true,"evidence_text":"c.360dup","llm_judgment":"PRESENT","evidence":"c.360dup","abstract_start":948,"abstract_end":956}]}
{"pmid":"20739944","title":"Carrier frequency of GJB2 gene mutations c.35delG, c.235delC and c.167delT among the populations of Eurasia.","abstract":"Hearing impairment is one of the most common disorders of sensorineural function and the incidence of profound prelingual deafness is about 1 per 1000 at birth. GJB2 gene mutations make the largest contribution to hereditary hearing impairment. The spectrum and prevalence of some GJB2 mutations are known to be dependent on the ethnic origin of the population. This study presents data on the carrier frequencies of major GJB2 mutations, c.35delG, c.167delT and c.235delC, among 2308 healthy persons from 18 various populations of Eurasia: Russians, Bashkirs, Tatars, Chuvashes, Udmurts, Komi-Permyaks and Mordvins (Volga-Ural region of Russia); Belarusians and Ukrainians (East Europe); Abkhazians, Avars, Cherkessians and Ingushes (Caucasus); Kazakhs, Uighurs and Uzbeks (Central Asia); and Yakuts and Altaians (Siberia). The data on c.35delG and c.235delC mutation prevalence in the studied ethnic groups can be used to investigate the prospective founder effect in the origin and prevalence of these mutations in Eurasia and consequently in populations around the world.","variants":[{"Name":"NM_004004.6(GJB2):c.167del (p.Leu56fs)","Chromosome":"13","Start":"20189415","Stop":"20189415","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":32049,"rule_based_match":true,"evidence_text":"c.167delT","llm_judgment":"PRESENT","evidence":"c.167delT","abstract_start":449,"abstract_end":458},{"Name":"NM_004004.6(GJB2):c.35del (p.Gly12fs)","Chromosome":"13","Start":"20189547","Stop":"20189547","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":32043,"rule_based_match":true,"evidence_text":"c.35delG","llm_judgment":"PRESENT","evidence":"c.35delG","abstract_start":439,"abstract_end":447}]}
{"pmid":"22690115","title":"Evidence of genetic heterogeneity in Alberta Hutterites with Usher syndrome type I.","abstract":"PURPOSE: To identify the genetic defect in a Hutterite population from northern Alberta with Usher syndrome type I.\nMETHODS: Complete ophthalmic examinations were conducted on two boys and two girls from two related Hutterite families diagnosed with Usher syndrome type I. DNA from patients and their parents was first evaluated for a mutation in exon 10 of the protocadherin-related 15 (PCDH15) gene (c.1471delG), previously reported in southern Alberta Hutterite patients with Usher syndrome (USH1F). Single nucleotide polymorphic linkage analysis was then used to confirm another locus, and DNA was analyzed with the Usher Chip v4.0 platform.\nRESULTS: Severe hearing impairment, unintelligible speech, and retinitis pigmentosa with varying degrees of visual acuity and visual field loss established a clinical diagnosis of Usher syndrome type I. The patients did not carry the exon 10 mutation in the PCDH15 gene; however, with microarray analysis, a previously reported mutation (c.52C>T; p.Q18X) in the myosin VIIA (MYO7A) gene was found in the homozygous state in the affected siblings.\nCONCLUSIONS: The finding of a MYO7A mutation in two related Hutterite families from northern Alberta provides evidence of genetic heterogeneity in Hutterites affected by Usher syndrome type I.","variants":[{"Name":"NM_000260.4(MYO7A):c.52C>T (p.Gln18Ter)","Chromosome":"11","Start":"77142742","Stop":"77142742","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":497811,"rule_based_match":true,"evidence_text":"c.52C>T; p.Q18X","llm_judgment":"PRESENT","evidence":"c.52C>T; p.Q18X","abstract_start":984,"abstract_end":999}]}
{"pmid":"24940034","title":"Whole exome sequencing identifies a novel splice-site mutation in ADAMTS17 in an Indian family with Weill-Marchesani syndrome.","abstract":"PURPOSE: Weill-Marchesani syndrome (WMS) is a rare connective tissue disorder, characterized by short stature, microspherophakic lens, and stubby hands and feet (brachydactyly). WMS is caused by mutations in the FBN1, ADAMTS10, and LTBP2 genes. Mutations in the LTBP2 and ADAMTS17 genes cause a WMS-like syndrome, in which the affected individuals show major features of WMS but do not display brachydactyly and joint stiffness. The main purpose of our study was to determine the genetic cause of WMS in an Indian family.\nMETHODS: Whole exome sequencing (WES) was used to identify the genetic cause of WMS in the family. The cosegregation of the mutation was determined with Sanger sequencing. Reverse transcription (RT)-PCR analysis was used to assess the effect of a splice-site mutation on splicing of the ADAMTS17 transcript.\nRESULTS: The WES analysis identified a homozygous novel splice-site mutation c.873+1G>T in a known WMS-like syndrome gene, ADAMTS17, in the family. RT-PCR analysis in the patient showed that exon 5 was skipped, which resulted in the deletion of 28 amino acids in the ADAMTS17 protein.\nCONCLUSIONS: The mutation in the WMS-like syndrome gene ADAMTS17 also causes WMS in an Indian family. The present study will be helpful in genetic diagnosis of this family and increases the number of mutations of this gene to six.","variants":[{"Name":"NM_139057.4(ADAMTS17):c.873+1G>T","Chromosome":"15","Start":"100262351","Stop":"100262351","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":485880,"rule_based_match":true,"evidence_text":"c.873+1G>T","llm_judgment":"PRESENT","evidence":"c.873+1G>T","abstract_start":907,"abstract_end":917}]}
{"pmid":"12213871","title":"A polymorphism in the human agouti-related protein is associated with late-onset obesity.","abstract":"The mouse agouti-related protein (AGRP) is a powerful appetite effector that results in hyperphagia and the development of obesity when administered intracerebroventricularly or when overexpressed in transgenic mice. Animal studies have also shown that exogenous administration of AGRP predisposes toward hedonic intake of high fat and high sucrose diets. The human ortholog (hAGRP) maps on chromosome 16q22 and has similar physiological properties, as tested in animal models. A polymorphism was identified in the third exon of hAGRP, c.199G-->A, that resulted in a nonconservative amino acid substitution, Ala(67)Thr. Computational analysis of the protein showed significant differences in the coils of the two polymorphic isoforms of the protein. Human studies showed no genotype effects in individuals with a mean age of 25 yr. However, the G/G genotype was significantly associated with fatness and abdominal adiposity in the parental population with a mean age of 53 yr. The c.199G-->A polymorphism in hAGRP could, therefore, play a role in the development of human obesity in an age-dependent fashion.","variants":[{"Name":"NM_001138.2(AGRP):c.199G>A (p.Ala67Thr)","Chromosome":"16","Start":"67483042","Stop":"67483042","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22368,"rule_based_match":false,"evidence_text":"c.199G-->A","llm_judgment":"PRESENT","evidence":"c.199G-->A","abstract_start":536,"abstract_end":546}]}
{"pmid":"26535877","title":"Early-Onset Severe Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of Causes.","abstract":"A variety of pathologies can underlie early-onset severe encephalopathy with epilepsy. To aid the diagnostic process in such patients we present an overview of causes, including the rapidly expanding list of genes involved. When no explanation is found, whole-exome sequencing (WES) can be used in an attempt to identify gene defects in patients suspected to suffer from a genetic form. We describe three siblings, born to consanguineous parents, with a lethal severe epileptic encephalopathy with early-infantile onset, including their magnetic resonance imaging, electroencephalography and, in one case, neuropathological findings. Using WES a homozygous frameshift mutation in the BRAT1 gene, c.638dup p.(Val214Glyfs*189), was identified. We present our cases in the context of all published cases with mutations in the BRAT1 gene and conclude that BRAT1 should be added to the growing list of genes related to early-onset severe encephalopathy with epilepsy.","variants":[{"Name":"NM_152743.4(BRAT1):c.638dup (p.Val214fs)","Chromosome":"7","Start":"2543754","Stop":"2543755","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":40156,"rule_based_match":true,"evidence_text":"c.638dup p.(Val214Glyfs*189)","llm_judgment":"PRESENT","evidence":"c.638dup p.(Val214Glyfs*189)","abstract_start":696,"abstract_end":724}]}
{"pmid":"32386558","title":"Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.","abstract":"Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.","variants":[{"Name":"NM_004798.4(KIF3B):c.748G>C (p.Glu250Gln)","Chromosome":"20","Start":"32310525","Stop":"32310525","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":961556,"rule_based_match":true,"evidence_text":"c.748G>C (p.Glu250Gln)","llm_judgment":"PRESENT","evidence":"c.748G>C (p.Glu250Gln)","abstract_start":508,"abstract_end":530},{"Name":"NM_004798.4(KIF3B):c.1568T>C (p.Leu523Pro)","Chromosome":"20","Start":"32316588","Stop":"32316588","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":961557,"rule_based_match":true,"evidence_text":"c.1568T>C (p.Leu523Pro)","llm_judgment":"PRESENT","evidence":"c.1568T>C (p.Leu523Pro)","abstract_start":729,"abstract_end":752}]}
{"pmid":"38337354","title":"Natural History of Dilated Cardiomyopathy Due to","abstract":"(1) <b>Introduction</b>: Dilated cardiomyopathy (DCM) mainly affects young individuals and is the main indication of heart transplantation. The variant <i>c.77T>C (p.Val26Ala)</i> of the gene coding for emerin <i>(EMD)</i> in chromosome <i>Xq28</i> has been catalogued as a pathogenic variant for the development of DCM, exhibiting an X-linked inheritance pattern. (2) <b>Methods</b>: A retrospective study was conducted covering the period 2015-2023 in patients with DCM of genetic origin. The primary endpoint was patient age at onset of the first composite major cardiac event, in the form of a first episode of heart failure, malignant ventricular arrhythmia, or end-stage heart failure, according to the presence of truncating variant in titin gene <i>(TTNtv)</i> versus the <i>p.Val26Ala</i> mutation in the <i>EMD</i> protein. (3) <b>Results</b>: A total of 31 and 22 patients were included in the <i>EMD</i> group and <i>TTNtv</i> group, respectively. The primary endpoint was significantly higher in the <i>EMD</i> group, with a hazard ratio of 4.16 (95% confidence interval: 1.83-9.46; <i>p</i> = 0.001). At 55 years of age, all the patients in the <i>EMD</i> group had already presented heart failure, nine presented malignant ventricular arrhythmia (29%), and 13 required heart transplantation (42%). (4) <b>Conclusions</b>: DCM secondary to the <i>c.77T>C (p.Val26Ala)</i> mutation in the <i>EMD</i> gene is associated to an increased risk of major cardiac events compared to patients with DCM due to <i>TTNtv</i>, with a large proportion of transplanted patients in the fifth decade of life.","variants":[{"Name":"NM_000117.3(EMD):c.77T>C (p.Val26Ala)","Chromosome":"X","Start":"154379561","Stop":"154379561","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":178291,"rule_based_match":true,"evidence_text":"c.77T>C (p.Val26Ala)","llm_judgment":"PRESENT","evidence":"c.77T>C (p.Val26Ala)","abstract_start":155,"abstract_end":175}]}
{"pmid":"33966749","title":"Fetal akinesia: The need for clinical vigilance in first trimester with decreased fetal movements.","abstract":"OBJECTIVE: We present two cases of fetal akinesia detected by first trimester ultrasound with noticing reduced fetal movements.\nCASE REPORT: Both of the two cases presented with reduced fetal movements. Fetal microarray results were normal. Follow-up sonographic examinations showed that Case 1 had structural anomalies with reduced fetal movements, and Case 2 had findings of reduced fetal movements and olyhydramnios. Case 1 ended with termination of pregnancy, and was confirmed to suffer from distal arthrogryposis (DA) type 5D (DA5D) with two pathogenic ECEL1 variants, NM_004826: c.110_155del46 (p.F37Cfs∗151) and c.633G > C (p.W211C). Case 2 continued to term. However, the infant developed breathing problems and severe hypotonia after birth, and died at 3 months. Nemaline myopathy was diagnosed with two NEB variants, NM_001271208.1: c.3255+1G > T and c.7165delA (p.W211C) detected in the patient.\nCONCLUSION: The first trimester ultrasound can detect clues that lead to the diagnosis of fetal akinesias presenting with reduced or absent fetal movements. Our results would be useful in counselling parents of affected pregnancies and in alerting physicians to plan the appropriate follow-up investigations for such cases.","variants":[{"Name":"NM_004826.4(ECEL1):c.110_155del (p.Phe37fs)","Chromosome":"2","Start":"232486499","Stop":"232486544","ReferenceAlleleVCF":"CAGCCCGGACCGGGCCCCGGTGGCGCTGCGCGCAGCGCCCAACGGGA","AlternateAlleleVCF":"C","allel_id":427996,"rule_based_match":true,"evidence_text":"NM_004826: c.110_155del46 (p.F37Cfs∗151)","llm_judgment":"PRESENT","evidence":"NM_004826: c.110_155del46 (p.F37Cfs∗151)","abstract_start":575,"abstract_end":615}]}
{"pmid":"35505422","title":"VHL Ser65 mutations enhance HIF2α signaling and promote epithelial-mesenchymal transition of renal cancer cells.","abstract":"BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic neoplastic disorder caused by germline mutation or deletion of the VHL gene, characterized by the tendency to develop multisystem benign or malignant tumors. The mechanism of VHL mutants in pathogenicity is poorly understand.\nRESULTS: Here we identified heterozygous missense mutations c.193T > C and c.194C > G in VHL in several patients from two Chinese families. These mutations are predicted to cause Serine (c.193T > C) to Proline and Tryptophan (c.194C > G) substitution at residue 65 of VHL protein (p.Ser65Pro and Ser65Trp). Ser65 residue, located within the β-domain and nearby the interaction sites with hypoxia-inducing factor α (HIFα), is highly conserved among different species. We observed gain of functions in VHL mutations, thereby stabilizing HIF2α protein and reprograming HIF2α genome-wide target gene transcriptional programs. Further analysis of independent cohorts of patients with renal carcinoma revealed specific HIF2α gene expression signatures in the context of VHL Ser65Pro or Ser65Trp mutation, showing high correlations with hypoxia and epithelial-mesenchymal transition signaling activities and strong associations with poor prognosis.\nCONCLUSIONS: Together, our findings highlight the crucial role of pVHL-HIF dysregulation in VHL disease and strengthen the clinical relevance and significance of the missense mutations of Ser65 residue in pVHL in the familial VHL disease.","variants":[{"Name":"NM_000551.4(VHL):c.194C>G (p.Ser65Trp)","Chromosome":"3","Start":"10142041","Stop":"10142041","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":52766,"rule_based_match":true,"evidence_text":"c.194C > G","llm_judgment":"PRESENT","evidence":"c.194C > G","abstract_start":378,"abstract_end":388}]}
{"pmid":"32770121","title":"Heteromeric Kv7.2 current changes caused by loss-of-function of KCNQ2 mutations are correlated with long-term neurodevelopmental outcomes.","abstract":"Pediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE). Patients might manifest mild to profound neurodevelopmental disabilities. We analysed c.853C > A (P285T) and three mutations that cause KCNQ2 protein changes in the 247 position: c.740C > T (S247L), c.740C > A (S247X), and c.740C > G (S247W). S247L, S247W, and P285T cause neonatal-onset EE and poor neurodevelopmental outcomes; S247X cause BFNC and normal outcome. We investigated the phenotypes correlated with human embryonic kidney 293 (HEK293) cell functional current changes. More cell-current changes and a worse conductance curve were present in the homomeric transfected S247X than in S247L, S247W, and P285T. But in the heteromeric channel, S247L, S247W and P285T had more current impairments than did S247X. The protein expressions of S247X were nonfunctional. The outcomes were most severe in S247L and S247W, and severity was correlated with heteromeric current. Current changes were more significant in cells with homomeric S247X, but currents were \"rescued\" after heteromeric transfection of KCNQ2 and KCNQ3. This was not the case in cells with S247L, S247W. Our findings support that homomeric current changes are common in KCNQ2 neonatal-onset EE and KCNQ2 BFNC; however, heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes.","variants":[{"Name":"NM_172107.4(KCNQ2):c.740C>T (p.Ser247Leu)","Chromosome":"20","Start":"63442482","Stop":"63442482","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":203782,"rule_based_match":true,"evidence_text":"c.740C>T (S247L)","llm_judgment":"PRESENT","evidence":"c.740C > T (S247L)","abstract_start":330,"abstract_end":348}]}
{"pmid":"21184276","title":"A BRCA2 mutation incorrectly mapped in the original BRCA2 reference sequence, is a common West Danish founder mutation disrupting mRNA splicing.","abstract":"Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose carriers to breast and ovarian cancer. The authors have identified a mutation in BRCA2, 7845+1G>A (c.7617+1G>A), not previously regarded as deleterious because of incorrect mapping of the splice junction in the originally published genomic reference sequence. This reference sequence is generally used in many laboratories and it maps the mutation 16 base pairs inside intron 15. However, according to the recent reference sequences the mutation is located in the consensus donor splice sequence. By reverse transcriptase analysis, loss of exon 15 in the final transcript interrupting the open reading frame was demonstrated. Furthermore, the mutation segregates with a cancer phenotype in 18 Danish families. By genetic analysis of more than 3,500 Danish breast/ovarian cancer risk families, the mutation was identified as the most common BRCA2 mutation in West Denmark, while it is rare in Central and East Denmark and not identified in South Sweden. Haplotype analysis using dense SNP arrays indicated a common founder of the mutation approximately 1,500 years ago.","variants":[{"Name":"NM_000059.4(BRCA2):c.7617+1G>A","Chromosome":"13","Start":"32356610","Stop":"32356610","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67030,"rule_based_match":true,"evidence_text":"c.7617+1G>A","llm_judgment":"PRESENT","evidence":"c.7617+1G>A","abstract_start":176,"abstract_end":187}]}
{"pmid":"31472299","title":"Bruck syndrome 2 variant lacking congenital contractures and involving a novel compound heterozygous PLOD2 mutation.","abstract":"Bruck syndrome (BRKS) is the rare disorder that features congenital joint contractures often with pterygia and subsequent fractures, also known as osteogenesis imperfecta (OI) type XI (OMIM # 610968). Its two forms, BRKS1 (OMIM # 259450) and BRKS2 (OMIM # 609220), reflect autosomal recessive (AR) inheritance of FKBP10 and PLOD2 loss-of-function mutations, respectively. A 10-year-old girl was referred with blue sclera, osteopenia, poorly-healing fragility fractures, Wormian skull bones, cleft soft palate, congenital fusion of cervical vertebrae, progressive scoliosis, bell-shaped thorax, restrictive and reactive pulmonary disease, protrusio acetabuli, short stature, and additional dysmorphic features without joint contractures. Iliac crest biopsy after alendronate treatment that improved her bone density revealed low trabecular connectivity, abundant patchy osteoid, and active bone formation with widely-spaced tetracycline labels. Chromosome 22q11 deletion analysis for velocardiofacial syndrome, COL1A1 and COL1A2 sequencing for prevalent types of OI, and Sanger sequencing of LRP5, PPIB, FKBP10, and IFITM5 for rare pediatric osteoporoses were negative. Copy number microarray excluded a contiguous gene syndrome. Instead, exome sequencing revealed two missense variants in PLOD2 which encodes procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (lysyl hydroxylase 2, LH2); exon 8, c.797G>T, p.Gly266Val (paternal), and exon 12, c.1280A>G, p.Asn427Ser (maternal). In the Exome Aggregation Consortium (ExAC) database, low frequency (Gly266Val, 0.0000419) and absence (Asn427Ser) implicated both variants as mutations of PLOD2. The father, mother, and sister (who carried the exon 12 defect) were reportedly well with normal parental DXA findings. BRKS2, characterized by under-hydroxylation of type I collagen telopeptides compromising their crosslinking, has been reported in at least 16 probands/families. Most PLOD2 mutations involve exons 17-19 (of 20 total) encoding the C-terminal domain with LH activity. However, truncating defects (nonsense, frameshift, splice site mutations) are also found throughout PLOD2. In three reports, AR PLOD2 mutations are not associated with congenital contractures. Our patient's missense defects lie within the central domain of unknown function of PLOD2. In our patient, compound heterozygosity with PLOD2 mutations is associated with a clinical phenotype distinctive from classic BRKS2 indicating that when COL1A1 and COL1A2 mutation testing is negative for OI without congenital contractures or pterygia, atypical BRKS should be considered.","variants":[{"Name":"NM_182943.3(PLOD2):c.1280A>G (p.Asn427Ser)","Chromosome":"3","Start":"146081816","Stop":"146081816","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":798523,"rule_based_match":true,"evidence_text":"c.1280A>G, p.Asn427Ser","llm_judgment":"PRESENT","evidence":"c.1280A>G, p.Asn427Ser","abstract_start":1443,"abstract_end":1465},{"Name":"NM_182943.3(PLOD2):c.797G>T (p.Gly266Val)","Chromosome":"3","Start":"146091882","Stop":"146091882","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":2141695,"rule_based_match":true,"evidence_text":"c.797G>T, p.Gly266Val","llm_judgment":"PRESENT","evidence":"c.797G>T, p.Gly266Val","abstract_start":1396,"abstract_end":1417}]}
{"pmid":"36999477","title":"Börjeson","abstract":"Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked intellectual disability. The main features of the patients include intellectual disability/global developmental delay, characteristic face, anomalies of fingers and toes, hypogonadism, linear skin hyperpigmentation, and tooth abnormalities in female patients, and obesity in male patients. A case of BFLS caused by a novel mutation of <i>PHF6</i> gene who was treated in the Department of Pediatrics, Xiangya Hospital, Central South University was reported. The 11 months old girl presented the following symptons: Global developmental delay, characteristic face, sparse hair, ocular hypertelorism, flat nasal bridge, hairy anterior to the tragus, thin upper lip, dental anomalies, ankyloglossia, simian line, tapering fingers, camptodactylia, and linear skin hyperpigmentation. The gene results of the second-generation sequencing technology showed that there was a novel heterozygous mutation site c.346C>T (p.Arg116*) of the <i>PHF6</i> (NM032458.3), variation rating as pathogenic variation. During the follow-up, the patient developed astigmatism, strabismus, awake bruxism, and stereotyped behavior, and the linear skin hyperpigmentation became gradually more evident. The disease is lack of effective therapy so far.","variants":[{"Name":"NM_001015877.2(PHF6):c.346C>T (p.Arg116Ter)","Chromosome":"X","Start":"134393606","Stop":"134393606","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2923423,"rule_based_match":true,"evidence_text":"c.346C>T (p.Arg116*)","llm_judgment":"PRESENT","evidence":"c.346C>T (p.Arg116*)","abstract_start":961,"abstract_end":981}]}
{"pmid":"24907393","title":"Defective pre-mRNA splicing in PKD1 due to presumed missense and synonymous mutations causing autosomal dominant polycystic disease.","abstract":"Autosomal dominant polycystic kidney disease is the most common human monogenic disorder and is caused by mutations in the PKD1 or PKD2 genes. Most patients with the disease present mutations in PKD1, and a considerable number of these alterations are single base substitutions within the coding sequence that are usually predicted to lead to missense or synonymous mutations. There is growing evidence that some of these mutations can be detrimental by affecting the pre-mRNA splicing process. The aim of our study was to test PKD1 mutations, described as missense or synonymous in the literature or databases, for their effects on exon inclusion. Bioinformatics tools were used to select mutations with a potential effect on pre-mRNA splicing. Mutations were experimentally tested using minigene assays. Exons and adjacent intronic sequences were PCR-amplified and cloned in the splicing reporter minigene, and selected mutations were introduced by site-directed mutagenesis. Minigenes were transfected into kidney derived cell lines. RNA from cultured cells was analyzed by RT-PCR and DNA sequencing. Analysis of thirty-three PKD1 exonic mutations revealed three mutations that induce splicing defects. The substitution c.11156G>A, previously predicted as missense mutation p.R3719Q, abolished the donor splice site of intron 38 and resulted in the incorporation of exon 38 with 117bp of intron 38 and skipping of exon 39. Two synonymous variants, c.327A>T (p.G109G) and c.11257C>A (p.R3753R), generated strong donor splice sites within exons 3 and 39 respectively, resulting in incorporation of incomplete exons. These three nucleotide substitutions represent the first PKD1 exonic mutations that induce aberrant mRNAs. Our results strengthen the importance to evaluate the consequences of presumed missense and synonymous mutations at the mRNA level.","variants":[{"Name":"NM_001009944.3(PKD1):c.11156G>A (p.Arg3719Gln)","Chromosome":"16","Start":"2092954","Stop":"2092954","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":433168,"rule_based_match":true,"evidence_text":"c.11156G>A","llm_judgment":"PRESENT","evidence":"c.11156G>A","abstract_start":1223,"abstract_end":1233}]}
{"pmid":"23239472","title":"Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations.","abstract":"Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-β-related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis syndrome (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and features of Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.","variants":[{"Name":"NM_005359.6(SMAD4):c.1245_1248del (p.Asp415Glufs)","Chromosome":"18","Start":"51067121","Stop":"51067124","ReferenceAlleleVCF":"TAGAC","AlternateAlleleVCF":"T","allel_id":151967,"rule_based_match":true,"evidence_text":"c.1245_1248delCAGA","llm_judgment":"PRESENT","evidence":"c.1245_1248delCAGA","abstract_start":1129,"abstract_end":1147}]}
{"pmid":"25383945","title":"A novel mutation in the RPE65 gene causing Leber congenital amaurosis and its transcriptional expression in vitro.","abstract":"The retinal pigment epithelium-specific 65 kDa protein is an isomerase encoded by the RPE65 gene (MIM 180069) that is responsible for an essential enzymatic step required for the function of the visual cycle. Mutations in the RPE65 gene cause not only subtype II of Leber congenital amaurosis (LCA) but also early-onset severe retinal dystrophy (EOSRD). This study aims to investigate a Chinese case diagnosed as EOSRD and to characterize the polymorphisms of the RPE65 gene. A seven-year-old girl with clinical symptoms of EOSRD and her parents were recruited into this study. Ophthalmologic examinations, including best-corrected visual acuity, slit-lamp, Optical coherence tomography (OCT), and fundus examination with dilated pupils, were performed to determine the clinical characteristics of the whole family. We amplified and sequenced the entire coding region and adjacent intronic sequences of the coding regions of the RPE65 gene for the whole family to explore the possible mutation. Our results demonstrate that the patient exhibited the typical clinically features of EOSRD. Her bilateral decimal visual acuity was 0.3 and 0.4 in the left and right eyes, respectively. Spectral-domain optical coherence tomography (SD-OCT) was used to assess the retinal stratification for the whole family. All together, we identified four mutations within the RPE65 gene (c.1056G>A, c.1243+2T>A, c.1338+20A>C and c.1590C>A) in the patient. Among the four mutations, c.1056G>A and c.1338+20A>C had been reported previously and another two were found for the first time in this study. Her mother also carried the novel mutation (c.1243+2T>A). Either a single or a compound heterozygous or a homozygous one mutation is expected to cause EOSRD because mutations of RPE65 gene usually cause an autosomal recessive disease. Therefore, we speculate that the c.1590C>A mutation together with the c.1243+2T>A mutation may cause the patient's phenotype.","variants":[{"Name":"NM_000329.3(RPE65):c.1590C>A (p.Phe530Leu)","Chromosome":"1","Start":"68429788","Stop":"68429788","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1375870,"rule_based_match":true,"evidence_text":"c.1590C>A","llm_judgment":"PRESENT","evidence":"c.1590C>A","abstract_start":1411,"abstract_end":1420}]}
{"pmid":"28332073","title":"Aicardi-Goutières syndrome: unusual neuro-radiological manifestations.","abstract":"Aicardi-Goutières syndrome (AGS) is one of the expanding group of inherited congenital infection like syndromes. Here, we describe the detailed clinical and imaging findings of two sibs with AGS. Each shows scattered periventricular intracranial calcifications, severe global delay, seizures, microcephaly and spasticity. Interestingly, chilblains were observed in the two sisters as well as their parents and a paternal uncle. The brain MRI of the older sister showed marked ventricular dilatation as a result of unusual associated porencephalic cysts. Unexpectedly, unilateral cerebellar hypoplasia was also noted. In comparison, her younger sister displayed the classic atrophic changes and white matter loss of AGS. The diagnosis of AGS was confirmed by sequence analysis, which identified a previously reported homozygous RNASEH2B mutation, c.554 T > G (p.V185G). Parents were heterozygous for the same mutation. Further molecular analysis excluded mutations in potentially related manifestations of COL4A1 gene. This is the first report of chilblains associated with heterozygous RNASEH2B mutation. Further, the brain imaging findings appear particularly interesting, which until now has not been reported in any AGS patient. We discuss the possible reasons for this unusual presentation.","variants":[{"Name":"NM_024570.4(RNASEH2B):c.554T>G (p.Val185Gly)","Chromosome":"13","Start":"50945470","Stop":"50945470","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":16302,"rule_based_match":true,"evidence_text":"c.554 T > G (p.V185G)","llm_judgment":"PRESENT","evidence":"c.554 T > G (p.V185G)","abstract_start":846,"abstract_end":867}]}
{"pmid":"20104590","title":"Enigmatic in vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome.","abstract":"Sequence analysis of the X-linked iduronate-2-sulfatase (IDS) gene in two Hunter syndrome patients revealed a lack of concordance between IDS genomic DNA and cDNA. These individuals were found to be hemizygous respectively for a nonsense mutation [c.22C>T;p.R8X] and a frameshift micro-insertion [c.10insT;p.P4Sfs] in their genomic DNA. However, both wild-type and mutant IDS sequences were evident upon cDNA analysis. Similar discrepant results were also obtained in a third unrelated patient carrying the same p.R8X mutation. Since both p.R8X mutations were inherited from carrier mothers, somatic mosaicism could be excluded. Although the presence of wild-type IDSmRNA-transcripts was confirmed in all three patients by restriction enzyme digestion, clone sequencing, pyrosequencing and single nucleotide primer extension (SNuPE), no wild-type IDS genomic sequence was detectable. The relative abundance of wild-type and mutation-bearing IDS-transcripts in different tissues was quantified by SNuPE. Although IDS transcript levels, as measured by real-time PCR, were reduced (51-71% normal) in these patients, some wild-type IDS protein was detectable by western blotting. Various possible explanations for these unprecedented findings (e.g. accidental contamination, artefactual in vitro nucleotide misincorporation, malsegregation of an extra maternal X-chromosome) were explored and experimentally excluded. PCR-based discriminant assay and segregation analysis of a linked IDS polymorphism (rs1141608) also served to exclude the presence of IDS cDNA derived from the maternal wild-type chromosome. Although it remains to be formally demonstrated by direct experimentation, the intriguing possibility arises that we have observed the in vivo correction of heritable gene lesions at the RNA level operating via a correction mechanism akin to RNA-editing. (c) 2010 Wiley-Liss, Inc.","variants":[{"Name":"NM_000202.8(IDS):c.22C>T (p.Arg8Ter)","Chromosome":"X","Start":"149505116","Stop":"149505116","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":929590,"rule_based_match":true,"evidence_text":"c.22C>T;p.R8X","llm_judgment":"PRESENT","evidence":"c.22C>T;p.R8X","abstract_start":248,"abstract_end":261}]}
{"pmid":"21552498","title":"A novel mutation in the GJA3 (connexin46) gene is associated with autosomal dominant congenital nuclear cataract in a Chinese family.","abstract":"PURPOSE: Congenital cataract is both a clinically and genetically heterogeneous lens disorder. The purpose of this study is to map and identify the mutation in an autosomal dominant congenital nuclear cataract in a Chinese family.\nMETHODS: Patients were given physical examinations and their blood samples were collected for DNA extraction. Genotyping was performed by microsatellite markers and logarithm of odds (LOD) scores were calculated using the LINKAGE programs. Mutation detection was performed by direct sequencing.\nRESULTS: Linkage to the gap-junction protein α3 (GJA3) locus was verified. Sequencing of GJA3 revealed a G>A transition at nucleotide position c.139, which causes an Asn substitution for the conservative Asp at codon 47 (P.D47N).This mutation is identified in all affected individuals but is not found in 100 control chromosomes.\nCONCLUSIONS: Our results identify that the mutation (D47N) in GJA3 is responsible for this Chinese pedigree. It is further identified that GJA3 is responsible for congenital cataract. In our study, the novel mutation broadens the spectrum of GJA3 mutations.","variants":[{"Name":"NM_021954.4(GJA3):c.139G>A (p.Asp47Asn)","Chromosome":"13","Start":"20143150","Stop":"20143150","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3412471,"rule_based_match":false,"evidence_text":"c.139G>A (p.Asp47Asn)","llm_judgment":"PRESENT","evidence":"D47N","abstract_start":749,"abstract_end":753}]}
{"pmid":"31350202","title":"Next Generation Sequencing Reveals Novel Mutations in Mismatch Repair Genes and Other Cancer Predisposition Genes in Asian Patients with Suspected Lynch Syndrome.","abstract":"BACKGROUND: Although at least 5 genes are implicated in Lynch Syndrome (LS), up to 50% of suspected cases are owing to undefined genes. We utilized next generation sequencing (NGS) to characterize the mutation profile of patients with cancer (CA) suspected to have LS.\nPATIENTS AND METHODS: We enrolled 174 Asian patients with CA from our CA Genetics Clinic from 2000 to 2014 suspected to have LS, and obtained germline DNA for NGS using TruSight Cancer. Frameshift, nonsense, and known deleterious mutations were considered pathogenic. Polymorphisms ≤ 1% frequency in 1000 Genomes (Asian) were classified using established databases.\nRESULTS: Of the 174 probands, 80.5% were Chinese, the median age at CA diagnosis was 45 years (range, 18-82 years), and 84.5% and 8.6% had colon and LS-like CA, respectively. Forty-seven of 100 evaluable colon CA probands had LS-like histopathologic features. Nineteen of 174 had family history fulfilling Amsterdam I/II Criteria, whereas the rest fulfilled Bethesda Guidelines. Thirty-one of 174 harbored pathogenic mutations with 10 in LS genes only, 20 in non-LS genes only, and 1 in both. Of the 11 with LS gene mutations, MLH1 was most commonly involved (n = 7), followed by MSH2, MSH6, and PMS2. Nine of 174 had pathogenic mutations diagnostic of alternative hereditary syndromes including 2 each in CDH1, APC, and BRCA1, and 1 each in BRCA2, SMAD4, and MUTYH. Ten unique mutations were detected in low-to-moderate penetrance genes: 6 individuals had a recurring novel KIT:c.2836C>T nonsense mutation (n = 3) or ERCC4:c.2169C>A nonsense mutation (n = 3) without LS gene mutation, which is of clinical interest.\nCONCLUSIONS: In this Asian study, NGS proved to be feasible in screening for causative mutations in patients with CA suspected to have LS.","variants":[{"Name":"NM_000222.3(KIT):c.2836C>T (p.Arg946Ter)","Chromosome":"4","Start":"54738462","Stop":"54738462","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":563999,"rule_based_match":true,"evidence_text":"KIT:c.2836C>T","llm_judgment":"PRESENT","evidence":"KIT:c.2836C>T","abstract_start":1510,"abstract_end":1523}]}
{"pmid":"29169765","title":"Whole Exome Sequencing allows the identification of two novel groups of Xeroderma pigmentosum in Tunisia, XP-D and XP-E: Impact on molecular diagnosis.","abstract":"BACKGROUND: Skin cancers (SC) are complex diseases that develop from complex combinations of genetic and environmental risk factors. One of the most severe and rare genetic diseases predisposing to SC is the Xeroderma pigmentosum (XP) syndrome.\nOBJECTIVES: First, to identify the genetic etiology of XP and to better classify affected patients. Second, to provide early molecular diagnosis for pre-symptomatic patient and finally to offer genetic counseling for related individuals.\nMETHODS: Whole Exome Sequencing (WES) and Run Of Homozygosity (ROH) were performed for two patients belonging to two different multiplex consanguineous families. The identified mutations were confirmed by Sanger sequencing and researched in ten Tunisian families including a total of 25 affected individuals previously suspected as having XP group V (XP-V) form. All patients had mild dermatological manifestations, absence of neurological abnormalities and late onset of skin tumors.\nRESULTS: Screening for functional variations showed the presence of the ERCC2 p.Arg683Gln in XP14KA-2 patient and a novel mutation, DDB2 p. (Lys381Argfs*2), in XP51-MAH-1 patient. Sanger sequencing and familial segregation showed that the ERCC2 mutation is present at a homozygous state in 10 affected patients belonging to 3 families. The second mutation in DDB2, is present at a homozygous state in 5 affected cases belonging to the same family. These two mutations are absent in the remaining 10 affected patients. The ERCC2 c.2048G > A mutation is present in a medium ROH region (class B) suggesting that it mostly arises from ancient relatedness within individuals. However, the c.1138delG DDB2 mutation is present in a large ROH region (class C) suggesting that it arises from recent relatedness.\nCONCLUSION: To our knowledge, this is the first study that identifies XP-D and XP-E complementation groups in Tunisia. These two groups are very rare and under-diagnosed in the world and were not reported in North Africa.","variants":[{"Name":"NM_000400.4(ERCC2):c.2048G>A (p.Arg683Gln)","Chromosome":"19","Start":"45352351","Stop":"45352351","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":259254,"rule_based_match":true,"evidence_text":"ERCC2 c.2048G > A","llm_judgment":"PRESENT","evidence":"ERCC2 c.2048G > A","abstract_start":1490,"abstract_end":1507}]}
{"pmid":"30513141","title":"Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy.","abstract":"CACNA1C (NM_000719.6) encodes an L-type calcium voltage-gated calcium channel (Ca<sub>v</sub> 1.2), and pathogenic variants have been associated with two distinct clinical entities: Timothy syndrome and Brugada syndrome. Thus far, CACNA1C has not been reported as a gene associated with epileptic encephalopathy and is less commonly associated with epilepsy. We report three individuals from two families with variants in CACNA1C. Patient 1 presented with neonatal onset epileptic encephalopathy (NOEE) and was found to have a de novo missense variant in CACNA1C (c.4087G>A (p.V1363M)) on exome sequencing. In Family 2, Patient 2 presented with congenital cardiac anomalies and cardiomyopathy and was found to have a paternally inherited splice site variant, c.3717+1_3717+2insA, on a cardiomyopathy panel. Her father, Patient 3, presented with learning difficulties, late-onset epilepsy, and congenital cardiac anomalies. Family 2 highlights variable expressivity seen within a family. This case series expands the clinical and molecular phenotype of CACNA1C-related disorders and highlights the need to include CACNA1C on epilepsy gene panels.","variants":[{"Name":"NM_000719.7(CACNA1C):c.4087G>A (p.Val1363Met)","Chromosome":"12","Start":"2653847","Stop":"2653847","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":444973,"rule_based_match":true,"evidence_text":"c.4087G>A (p.V1363M)","llm_judgment":"PRESENT","evidence":"c.4087G>A (p.V1363M)","abstract_start":564,"abstract_end":584}]}
{"pmid":"20503332","title":"Facioaudiosymphalangism syndrome and growth acceleration associated with a heterozygous NOG mutation.","abstract":"We report on a father and son with facioaudiosymphalangism syndrome, an alternative designation for multiple synostoses syndrome, type I. This syndrome includes synostosis, brachydactyly, craniofacial dysmorphic features, stapes fixation, hyperopia, and growth retardation. In contrast to the typical presentation, the height of the 10-year-old son was above the 97th centile from the age of 3.5 years and he had markers of an activated bone metabolism. The father and son had a novel heterozygous missense mutation c.696C > G, p.Cys232Trp, in the NOG gene. While not yet described in human NOG-related disorders, there is experimental evidence that suppression of noggin might accelerate osteogenesis, which could explain the phenotype in the family reported here.","variants":[{"Name":"NM_005450.6(NOG):c.696C>G (p.Cys232Trp)","Chromosome":"17","Start":"56594919","Stop":"56594919","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":39246,"rule_based_match":true,"evidence_text":"c.696C > G, p.Cys232Trp","llm_judgment":"PRESENT","evidence":"c.696C > G, p.Cys232Trp","abstract_start":516,"abstract_end":539}]}
{"pmid":"32576226","title":"Clinical, pathological, imaging, and genetic characterization in a Taiwanese cohort with limb-girdle muscular dystrophy.","abstract":"BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous, hereditary disease characterized by limb-girdle weakness and histologically dystrophic changes. The prevalence of each subtype of LGMD varies among different ethnic populations. This study for the first time analyzed the phenotypes and genotypes in Taiwanese patients with LGMD in a referral center for neuromuscular diseases (NMDs).\nRESULTS: We enrolled 102 patients clinically suspected of having LGMD who underwent muscle biopsy with subsequent genetic analysis in the previous 10 years. On the basis of different pathological categories, we performed sequencing of target genes or panel for NMDs and then identified patients with type 1B, 1E, 2A, 2B, 2D, 2I, 2G, 2 N, and 2Q. The 1B patients with LMNA mutation presented with mild limb-girdle weakness but no conduction defect at the time. All 1E patients with DES mutation exhibited predominantly proximal weakness along with distal weakness. In our cohort, 2B and 2I were the most frequent forms of LGMD; several common or founder mutations were identified, including c.1097_1099delACA (p.Asn366del) in DES, homozygous c.101G > T (p.Arg34Leu) in SGCA, homozygous c.26_33dup (p.Glu12Argfs*20) in TCAP, c.545A > G (p.Tyr182Cys), and c.948delC (p.Cys317Alafs*111) in FKRP. Clinically, the prevalence of dilated cardiomyopathy in our patients with LGMD2I aged > 18 years was 100%, much higher than that in European cohorts. The only patient with LGMD2Q with PLEC mutation did not exhibit skin lesions or gastrointestinal abnormalities but had mild facial weakness. Muscle imaging of LGMD1E and 2G revealed a more uniform involvement than did other LGMD types.\nCONCLUSION: Our study revealed that detailed clinical manifestation together with muscle pathology and imaging remain critical in guiding further molecular analyses and are crucial for establishing genotype-phenotype correlations. We also determined the common mutations and prevalence for different subtypes of LGMD in our cohort, which could be useful when providing specific care and personalized therapy to patients with LGMD.","variants":[{"Name":"NM_024301.5(FKRP):c.545A>G (p.Tyr182Cys)","Chromosome":"19","Start":"46755995","Stop":"46755995","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":266484,"rule_based_match":true,"evidence_text":"c.545A > G (p.Tyr182Cys)","llm_judgment":"PRESENT","evidence":"c.545A > G (p.Tyr182Cys)","abstract_start":1239,"abstract_end":1263},{"Name":"NM_001927.4(DES):c.1094ACA[1] (p.Asn366del)","Chromosome":"2","Start":"219421410","Stop":"219421412","ReferenceAlleleVCF":"GACA","AlternateAlleleVCF":"G","allel_id":31871,"rule_based_match":false,"evidence_text":"c.1097_1099delACA (p.Asn366del) in DES","llm_judgment":"PRESENT","evidence":"c.1097_1099delACA (p.Asn366del) in DES","abstract_start":1106,"abstract_end":1144}]}
{"pmid":"36086804","title":"Clinical features and spectrum of NOTCH3 variants in Finnish patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).","abstract":"OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene. In Finland, the majority of CADASIL patients carry the pathogenic founder variant c.397C>T, (p.Arg133Cys), but the spectrum of other NOTCH3 variants has not been investigated previously. The aim of the study was to investigate the spectrum and prevalence of NOTCH3 variants Finnish CADASIL patients and to examine the clinical features associated with them.\nMATERIALS AND METHODS: The spectrum of NOTCH3 variants and the clinical features associated with them were retrospectively examined in 294 Finnish CADASIL patients tested during January 1996 to October 2021 in the Medical Genetics laboratory of Department of Genomics of Turku University Hospital, where practically all samples of patients with suspected CADASIL in Finland are investigated.\nRESULTS: The most common NOTCH3 variants in the study cohort were c.397C>T, (p.Arg133Cys) (68%) and c.3206A>G p.(Tyr1069Cys) (18%), but other less common NOTCH3 variants were detected in as many as 14% of the patients. Eight of the detected NOTCH3 variants were novel: c.520T>A,p.(Cys174Ser), c.836A>G,p.(Gln279Arg), c.1369T>G,p.(Cys457Gly), c.1338C>G,p.(Cys446Trp), c.1564T>G,p.(Cys522Gly), c.2848T>G,p.(Cys950Gly), c.6102dup,p.(Gly2035Argfs*60), and c.2410+6C>G. Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features.\nCONCLUSION: This study revealed the genetic and clinical spectrum of CADASIL in the Finnish population. Sequencing of the whole NOTCH3 gene performing a gene-panel or exome sequencing is recommended when suspecting CADASIL.","variants":[{"Name":"NM_000435.3(NOTCH3):c.6102dup (p.Gly2035fs)","Chromosome":"19","Start":"15161525","Stop":"15161526","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":1864365,"rule_based_match":true,"evidence_text":"c.6102dup,p.(Gly2035Argfs*60)","llm_judgment":"PRESENT","evidence":"c.6102dup,p.(Gly2035Argfs*60)","abstract_start":1365,"abstract_end":1394}]}
{"pmid":"37684520","title":"A population-based survey of FBN1 variants in Iceland reveals underdiagnosis of Marfan syndrome.","abstract":"Marfan syndrome (MFS) is an autosomal dominant condition characterized by aortic aneurysm, skeletal abnormalities, and lens dislocation, and is caused by variants in the FBN1 gene. To explore causes of MFS and the prevalence of the disease in Iceland we collected information from all living individuals with a clinical diagnosis of MFS in Iceland (n = 32) and performed whole-genome sequencing of those who did not have a confirmed genetic diagnosis (27/32). Moreover, to assess a potential underdiagnosis of MFS in Iceland we attempted a genotype-based approach to identify individuals with MFS. We interrogated deCODE genetics' database of 35,712 whole-genome sequenced individuals to search for rare sequence variants in FBN1. Overall, we identified 15 pathogenic or likely pathogenic variants in FBN1 in 44 individuals, only 22 of whom were previously diagnosed with MFS. The most common of these variants, NM_000138.4:c.8038 C > T p.(Arg2680Cys), is present in a multi-generational pedigree, and was found to stem from a single forefather born around 1840. The p.(Arg2680Cys) variant associates with a form of MFS that seems to have an enrichment of abdominal aortic aneurysm, suggesting that this may be a particularly common feature of p.(Arg2680Cys)-associated MFS. Based on these combined genetic and clinical data, we show that MFS prevalence in Iceland could be as high as 1/6,600 in Iceland, compared to 1/10,000 based on clinical diagnosis alone, which indicates underdiagnosis of this actionable genetic disorder.","variants":[{"Name":"NM_000138.5(FBN1):c.8038C>T (p.Arg2680Cys)","Chromosome":"15","Start":"48415549","Stop":"48415549","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":197585,"rule_based_match":true,"evidence_text":"NM_000138.4:c.8038 C > T p.(Arg2680Cys)","llm_judgment":"PRESENT","evidence":"NM_000138.4:c.8038 C > T p.(Arg2680Cys)","abstract_start":912,"abstract_end":951}]}
{"pmid":"31421687","title":"A mutation in the filamin c gene causes myofibrillar myopathy with lower motor neuron syndrome: a case report.","abstract":"BACKGROUND: Myofibrillar myopathies (MFMs) are a genetically heterogeneous group of muscle disorders. Mutations in the filamin C gene (FLNC) have previously been identified in patients with MFM. The phenotypes of FLNC-related MFM are heterogeneous.\nCASE PRESENTATION: The patient was a 37-year-old male who first experienced weakness in the distal muscles of his hand, which eventually spread to the lower limbs and proximal muscles. Serum creatine kinase levels were moderately elevated. Obvious neuropathic changes in the electromyographic exam and edema changes in lower distal limb magnetic resonance imaging were observed. Histopathological examination revealed the presence of abnormal protein aggregates and angular atrophy in some muscle fibers. Ultrastructural analysis showed inordinate myofibrillar structures and dissolved myofilaments. DNA sequencing analysis detected a heterozygous missense mutation (c.7123G > A, p.V2375I) in the immunoglobulin (Ig)-like domain 21 of FLNC.\nCONCLUSIONS: FLNC mutation c.7123G > A, p.V2375I in the immunoglobulin (Ig)-like domain 21 can be associated with distal myopathy with typical MFM features and lower motor neuron syndrome. Although electromyographic examination of our patient showed obvious neuropathic changes, MFM could not be excluded. Therefore, genetic testing is necessary to make an accurate diagnosis.","variants":[{"Name":"NM_001458.5(FLNC):c.7123G>A (p.Val2375Ile)","Chromosome":"7","Start":"128854900","Stop":"128854900","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":561357,"rule_based_match":true,"evidence_text":"c.7123G > A, p.V2375I","llm_judgment":"PRESENT","evidence":"c.7123G > A, p.V2375I","abstract_start":916,"abstract_end":937}]}
{"pmid":"33345658","title":"Novel BRCA2 c.8434_8435insTT (p. Gly2812Valfs*10) mutation in a family with multiple hematologic malignancies and solid tumors.","abstract":"","variants":[{"Name":"NM_000059.4(BRCA2):c.8434_8435insTT (p.Gly2812fs)","Chromosome":"13","Start":"32370504","Stop":"32370505","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GTT","allel_id":3391199,"rule_based_match":true,"evidence_text":"BRCA2 c.8434_8435insTT (p. Gly2812Valfs*10)","llm_judgment":"PRESENT","evidence":"BRCA2 c.8434_8435insTT (p. Gly2812Valfs*10)","abstract_start":null,"abstract_end":null}]}
{"pmid":"24850569","title":"Two novel mutations in the C-terminal region of centrosomal protein 290 (CEP290) result in classic Joubert syndrome.","abstract":"Joubert syndrome is a neurologic disorder with a pathognomonic \"molar tooth sign\" on brain imaging. The purpose of this study was to identify potential mutations in a Chinese patient with Joubert syndrome by targeted massively parallel sequencing. Taking advantage of high-throughput DNA sequencing technologies, 18 Joubert-causing genes of a Chinese patient with classic Joubert syndrome were sequenced at a time, and 2 novel variants in the CEP290 gene (c.7323_7327delAGAAG and c.6012-2A>G) were identified in this patient. Sanger validation showed that 2 variants were inherited from each parents, respectively. Both variants are located in the C-terminal region of the CEP290 protein and are predicted to be deleterious. The results support that the combination of targeted genes enrichment and next-generation sequencing is valuable molecular diagnostic tool and suitable for clinical application.","variants":[{"Name":"NM_025114.4(CEP290):c.6012-2A>G","Chromosome":"12","Start":"88068647","Stop":"88068647","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":920320,"rule_based_match":true,"evidence_text":"c.6012-2A>G","llm_judgment":"PRESENT","evidence":"c.6012-2A>G","abstract_start":480,"abstract_end":491}]}
{"pmid":"26008862","title":"Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome.","abstract":"BACKGROUND: Two siblings with hypertrophic cardiomyopathy and brain atrophy were diagnosed with Complex I deficiency based on low enzyme activity in muscle and high lactate/pyruvate ratio in fibroblasts.\nMETHODS: Whole exome sequencing results of fibroblast gDNA from one sibling was narrowed down to 190 SNPs or In/Dels in 185 candidate genes by selecting non-synonymous coding sequence base pair changes that were not present in the SNP database.\nRESULTS: Two compound heterozygous mutations were identified in both siblings in NDUFV2, encoding the 24 kDa subunit of Complex I. The intronic mutation (c.IVS2 + 1delGTAA) is disease causing and has been reported before. The other mutation is novel (c.669_670insG, p.Ser224Valfs*3) and predicted to cause a pathogenic frameshift in the protein. Subsequent investigation of 10 probands with complex I deficiency from different families revealed homozygosity for the intronic c.IVS2 + 1delGTAA mutation in a second, consanguineous family. In this family three of five siblings were affected. Interestingly, they presented with Leigh syndrome but no cardiac involvement. The same genotype had been reported previously in a two families but presenting with hypertrophic cardiomyopathy, trunk hypotonia and encephalopathy.\nCONCLUSION: We have identified NDUFV2 mutations in two families with Complex I deficiency, including a novel mutation. The diagnosis of Leigh syndrome expands the clinical phenotypes associated with the c.IVS2 + 1delGTAA mutation in this gene.","variants":[{"Name":"NM_021074.5(NDUFV2):c.669_670insG (p.Ser224fs)","Chromosome":"18","Start":"9134198","Stop":"9134199","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":608862,"rule_based_match":true,"evidence_text":"c.669_670insG, p.Ser224Valfs*3","llm_judgment":"PRESENT","evidence":"c.669_670insG, p.Ser224Valfs*3","abstract_start":700,"abstract_end":730}]}
{"pmid":"25675413","title":"Founder Effect of a c.828+3A&gt;T Splice Site Mutation in Peripherin 2 (PRPH2) Causing Autosomal Dominant Retinal Dystrophies.","abstract":"IMPORTANCE: Screening for splice site mutation c.828+3A>T in the peripherin 2 (PRPH2) gene should be a high priority in families with highly variable retinal dystrophies. The correction of missplicing is a potential therapeutic target.\nOBJECTIVE: To determine the prevalence, genetic origin, and molecular mechanism of a donor c.828+3A>T mutation in the PRPH2 (peripherin 2, retinal degeneration slow) gene in individuals with retinal dystrophies.\nDESIGN, SETTING, AND PARTICIPANTS: Case-control study that took place at the University of Texas Health Science Center, the University of Iowa, and the Retina Foundation of the Southwest, from January 1, 1987, to August 1, 2014, including affected individuals from 200 families with a diagnosis of autosomal dominant retinitis pigmentosa, 35 families with unspecified macular dystrophies, and 116 families with pattern dystrophy. Participants were screened for the c.828+3A>T mutation by restriction-enzyme digest, single-strand conformational polymorphism screening, or bidirectional sequencing. Haplotypes of polymorphic markers flanking the PRPH2 locus and sequence variants within the gene were determined by denaturing gel electrophoresis or automated capillary-based cycle sequencing. The effect of the splice site mutation on the PRPH2 transcript was analyzed using NetGene2, a splice prediction program and by the reverse transcription polymerase chain reaction of illegitimate transcripts from peripheral white blood cells.\nMAIN OUTCOMES AND MEASURES: Results of testing for splice site mutation, haplotypes, and alternate transcripts.\nRESULTS: The PRPH2 mutation was found in 97 individuals of 19 independently ascertained families with a clinical diagnosis of retinitis pigmentosa, macular dystrophy, and/or pattern dystrophy. All affected individuals also shared a rare haplotype of approximately 644 kilobase pairs containing the c.828+3A>T mutation, which extends from the short tandem repeat polymorphism D6S282 to c.1013G>A (rs434102, a single-nucleotide polymorphism) in exon 3 of PRPH2, suggesting this mutation is from a common ancestor and is a founder mutation. It has a prevalence of 2% in families diagnosed as having autosomal dominant retinitis pigmentosa and 10% in families with variable clinical diagnosis of pattern, macular, and retinal dystrophies. Individuals with the c.828+3A>T mutation expressed a PRPH2 transcript not found in control participants and that was consistent with abnormal splicing.\nCONCLUSIONS AND RELEVANCE: The PRPH2 c.828+3A>T splice site mutation is a frequent cause of inherited retinal dystrophies and is owing to the founder effect. The likely cause of disease is the missplicing of the PRPH2 message that results in a truncated protein product. Identifying the genetic etiology assists in more accurate management and possible future therapeutic options.","variants":[{"Name":"NM_000322.5(PRPH2):c.828+3A>T","Chromosome":"6","Start":"42704362","Stop":"42704362","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":104603,"rule_based_match":true,"evidence_text":"c.828+3A>T","llm_judgment":"PRESENT","evidence":"c.828+3A>T","abstract_start":47,"abstract_end":57}]}
{"pmid":"37881805","title":"Case report: Identification of a recurrent pathogenic","abstract":"<b>Background:</b> Heterozygous mutations in the <i>dehydrodolichol diphosphate synthase</i> (<i>DHDDS</i>) gene are one of the causes generating developmental and epileptic encephalopathies. So far, only eleven mutations in the DHDDS gene have been identified. The mutation spectrum of the <i>DHDDS</i> gene in the Chinese population remains unclear. <b>Methods:</b> In this study, we enrolled a Chinese family with myoclonus and/or epilepsy and intellectual disability. The epilepsy and myoclonic tremor were improved after deep brain stimulation (DBS) of the subthalamic nucleus (STN) treatment. Whole exome sequencing and Sanger sequencing were employed to explore the genetic variations of the family. <b>Results:</b> Subsequent to data filtering, we identified a recurrent pathogenic mutation (NM_001243564.1, c.113G>A/p.R38H) in the <i>DHDDS</i> gene in the proband. Sanger sequencing further validated that the presence of the mutation in his affected mother but absent in the health family members. Further bioinformatics analysis revealed that this mutation (p.R38H), located in an evolutionarily conserved region of DHDDS, was predicted to be deleterious. <b>Discussion:</b> In this report, we present the first case of intractable epilepsy and/or myoclonus caused by p.R38H mutation of the <i>DHDDS</i> gene in the Chinese population. Furthermore, this study represents the third report of autosomal dominant familial inheritance of <i>DHDDS</i> mutation worldwide.","variants":[{"Name":"NM_205861.3(DHDDS):c.113G>A (p.Arg38His)","Chromosome":"1","Start":"26438217","Stop":"26438217","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":798469,"rule_based_match":true,"evidence_text":"NM_001243564.1, c.113G>A/p.R38H","llm_judgment":"PRESENT","evidence":"NM_001243564.1, c.113G>A/p.R38H","abstract_start":800,"abstract_end":831}]}
{"pmid":"36531003","title":"Germline and somatic variants in ovarian carcinoma: A next-generation sequencing (NGS) analysis.","abstract":"Background: Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers, while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations. Beyond these mutations, germline or somatic aberrations in genes of the homologous recombination (HR) pathway such as <i>RAD51B/C/D, PALB2, ATM, BRIP1</i> may confer an HR deficiency in up to 50% of ovarian tumors. Next-generation sequencing (NGS) is a high-throughput massive parallel sequencing method that enables the simultaneous detection of several mutations in entire genomes.\nMethods: We performed NGS analysis in 86 patients with ovarian cancer treated in the Oncology Department of Alexandra University Hospital in order to identify the molecular landscape of germline and somatic mutations in ovarian cancer.\nResults: The genes with the highest number of pathogenic somatic mutations in high grade serous carcinoma (HGSC) patients were TP53 [68%; 34/50] and BRCA1 [22%; 11/50] followed by somatic mutations in RB1 [2%; 1/50], NF1 [2%; 1/50], BRCA2 [2%; 1/50], AKT1 [2%; 1/50], RAD50 [2%; 1/50], PIK3CA [2%; 1/50] genes. Of note, the most common TP53 genetic polymorphism was c.524G>A p.Arg175His in exon 5. Variants of unknown significance (VUS) detected in HGSC included ROS1 [26%; 13/50], RAD50 [6%; 3/50], BRCA2 [6%; 3/50], NOTCH1 [6%; 3/50], TP53 [6%; 3/50], AR [6%; 3/50]. As for germline mutations, BRCA1 [8/30; 27%] and BRCA2 [4/30; 13%] were the most common genes bearing pathogenic alterations in HGSC, while VUS germline mutations commonly affected HRR-related genes, including ATM (c.7816A>G), BRIP (c.2327 C>A), CHEK2 (c.320-5T>A).\nConclusion: Overall, genetic testing should be offered in most patients with ovarian cancer to identify mutations in HRR genes and determine the population that would be susceptible to poly ADP ribose polymerase (PARP) inhibitors.","variants":[{"Name":"NM_000051.4(ATM):c.7816A>G (p.Ile2606Val)","Chromosome":"11","Start":"108332789","Stop":"108332789","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":183407,"rule_based_match":true,"evidence_text":"ATM (c.7816A>G)","llm_judgment":"PRESENT","evidence":"ATM (c.7816A>G)","abstract_start":1561,"abstract_end":1576}]}
{"pmid":"33977023","title":"Familial variability of cerebrotendinous xanthomatosis lacking typical biochemical findings.","abstract":"Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by pathogenic variants in the <i>CYP27A1</i> gene encoding the mitochondrial enzyme sterol 27-hydroxylase. Patients with CTX can present with a wide range of symptoms, but most often have evidence of tendon xanthomas along with possible cataracts, atherosclerosis, or neurological dysfunction. Regardless of clinical phenotype, CTX patients typically exhibit levels of cholestanol and bile acid precursors in the circulation that are many fold increased over normal control concentrations. Here we report two siblings, one with the rare spinal xanthomatosis phenotype and the other with a very mild form of CTX manifesting as minor tendon xanthomatosis and gastrointestinal complaints who both carry compound heterozygous variants in <i>CYP27A1</i>: NM_000784.3: c.410G > A (p.Arg137Gln) and c.1183C > T (p.Arg395Cys). However, biochemical analysis of these patients revealed normal levels of serum cholestanol and relatively mild elevations of the bile acid precursors 7α-hydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-4-cholesten-3-one. The atypical biochemical presentation of these cases represents a diagnostic challenge for a disorder once thought to have a sensitive biomarker in cholestanol and highlight the need for thorough investigation of patients with symptomatology consistent with CTX that includes bile acid precursor biochemical testing and molecular analysis.","variants":[{"Name":"NM_000784.4(CYP27A1):c.1183C>T (p.Arg395Cys)","Chromosome":"2","Start":"218814186","Stop":"218814186","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19294,"rule_based_match":true,"evidence_text":"c.1183C > T (p.Arg395Cys)","llm_judgment":"PRESENT","evidence":"c.1183C > T (p.Arg395Cys)","abstract_start":898,"abstract_end":923}]}
{"pmid":"33168985","title":"Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1.","abstract":"Pontocerebellar hypoplasia (PCH) describes a group of rare heterogeneous neurodegenerative diseases with prenatal onset. Here we describe eight children with PCH from four unrelated families harboring the homozygous MINPP1 (NM_004897.4) variants; c.75_94del, p.(Leu27Argfs*39), c.851 C > A, p.(Ala284Asp), c.1210 C > T, p.(Arg404*), and c.992 T > G, p.(Ile331Ser). The homozygous p.(Leu27Argfs*39) change is predicted to result in a complete absence of MINPP1. The p.(Arg404*) would likely lead to a nonsense mediated decay, or alternatively, a loss of several secondary structure elements impairing protein folding. The missense p.(Ala284Asp) affects a buried, hydrophobic residue within the globular domain. The introduction of aspartic acid is energetically highly unfavorable and therefore predicted to cause a significant reduction in protein stability. The missense p.(Ile331Ser) affects the tight hydrophobic interactions of the isoleucine by the disruption of the polar side chain of serine, destabilizing the structure of MINPP1. The overlap of the above-mentioned genotypes and phenotypes is highly improbable by chance. MINPP1 is the only enzyme that hydrolyses inositol phosphates in the endoplasmic reticulum lumen and several studies support its role in stress induced apoptosis. The pathomechanism explaining the disease mechanism remains unknown, however several others genes of the inositol phosphatase metabolism (e.g., INPP5K, FIG4, INPP5E, ITPR1) are correlated with phenotypes of neurodevelopmental disorders. Taken together, we present MINPP1 as a novel autosomal recessive pontocerebellar hypoplasia gene.","variants":[{"Name":"NM_004897.5(MINPP1):c.75_94del (p.Leu27fs)","Chromosome":"10","Start":"87504979","Stop":"87504998","ReferenceAlleleVCF":"GGCGCTGCTCTCGTCGCTTGC","AlternateAlleleVCF":"G","allel_id":1275460,"rule_based_match":true,"evidence_text":"c.75_94del","llm_judgment":"PRESENT","evidence":"c.75_94del","abstract_start":247,"abstract_end":257},{"Name":"NM_004897.5(MINPP1):c.1210C>T (p.Arg404Ter)","Chromosome":"10","Start":"87552224","Stop":"87552224","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1275462,"rule_based_match":true,"evidence_text":"c.1210 C > T, p.(Arg404*)","llm_judgment":"PRESENT","evidence":"c.1210 C > T, p.(Arg404*)","abstract_start":306,"abstract_end":331},{"Name":"NM_004897.5(MINPP1):c.992T>G (p.Ile331Ser)","Chromosome":"10","Start":"87521094","Stop":"87521094","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1275463,"rule_based_match":true,"evidence_text":"c.992 T>G, p.(Ile331Ser)","llm_judgment":"PRESENT","evidence":"c.992 T > G, p.(Ile331Ser)","abstract_start":337,"abstract_end":363},{"Name":"NM_004897.5(MINPP1):c.851C>A (p.Ala284Asp)","Chromosome":"10","Start":"87513139","Stop":"87513139","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1316045,"rule_based_match":true,"evidence_text":"c.851 C > A, p.(Ala284Asp)","llm_judgment":"PRESENT","evidence":"c.851 C > A, p.(Ala284Asp)","abstract_start":278,"abstract_end":304}]}
{"pmid":"31212292","title":"Novel and Recurring NOTCH3 Mutations in Two Chinese Patients with CADASIL.","abstract":"BACKGROUND: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominant, inherited, systemic, vascular disorder primarily involving the small arteries. It is characterized by migraine, recurrent ischemic strokes, cognitive decline, and dementia. Mutations in the Notch receptor 3 gene (NOTCH3) and the HtrA serine peptidase 1 gene (HTRA1) are 2 genetic causes for CADASIL. The NOTCH3 gene, located on chromosome 19p13.12, is the most common disease-causing gene in CADASIL.\nOBJECTIVE: To investigate genetic causes in 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL.\nMETHODS: Exome sequencing was performed on both patients and potential pathogenic mutations were validated by Sanger sequencing.\nRESULTS: This study reports on 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL, identifying that NOTCH3 mutations were the genetic cause. A common mutation, c.268C>T (p.Arg90Cys), and a novel mutation, c.331G>T (p.Gly111Cys) in the NOTCH3 gene, were detected and confirmed in the patients, respectively, and were predicted to be deleterious based on bioinformation analyses.\nCONCLUSIONS: We identified 2 NOTCH3 mutations as likely genetic causes for CADASIL in these 2 patients. Our findings broaden the mutational spectrum of the NOTCH3 gene accountable for CADASIL. Clinical manifestations supplemented with molecular genetic analyses are critical for accurate diagnosis, the provision of genetic counseling, and the development of therapies for CADASIL.","variants":[{"Name":"NM_000435.3(NOTCH3):c.268C>T (p.Arg90Cys)","Chromosome":"19","Start":"15192449","Stop":"15192449","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":442180,"rule_based_match":true,"evidence_text":"c.268C>T (p.Arg90Cys)","llm_judgment":"PRESENT","evidence":"c.268C>T (p.Arg90Cys)","abstract_start":989,"abstract_end":1010}]}
{"pmid":"31549751","title":"Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish.","abstract":"Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high-genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole-exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients' fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog-signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left-right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.","variants":[{"Name":"NM_152558.5(IQCE):c.895_904del (p.Val301fs)","Chromosome":"7","Start":"2586273","Stop":"2586282","ReferenceAlleleVCF":"TTGTCCCGGAG","AlternateAlleleVCF":"T","allel_id":625969,"rule_based_match":true,"evidence_text":"c.895_904del (p.Val301Serfs*8)","llm_judgment":"PRESENT","evidence":"c.895_904del (p.Val301Serfs*8)","abstract_start":537,"abstract_end":567}]}
{"pmid":"29066118","title":"A de novo p.Arg756Cys mutation in ATP1A3 causes a distinct phenotype with prolonged weakness and encephalopathy triggered by fever.","abstract":"Patients with a mutation at Arg756 in ATP1A3 have been known to exhibit a distinct phenotype, characterized by prolonged weakness and encephalopathy, triggered by febrile illness. With only eight reports published to date, more evidence is required to correlate clinical features with a mutation at Arg756. Here we report an additional case with an Arg756Cys mutation in ATP1A3. A four-year-old boy showed mild developmental delay with recurrent paroxysmal episodes of weakness and encephalopathy from nine months of age. Motor deficits, which included bilateral hypotonia, ataxia, dysmetria, limb incoordination, dysarthria, choreoathetosis, and dystonia, were observed from one year and three months. Whole-exome sequencing detected a heterozygous de novo variant at c.2266C>T (p.Arg756Cys) in ATP1A3. The episodic course and clinical features of this case were consistent with previously reported cases with mutations at Arg756. Furthermore, his phenotype of marked ataxia was more similar to that of an Arg756Cys patient with relapsing encephalopathy and cerebellar ataxia syndrome, than to those with Arg756His and Arg756Leu mutations. This report therefore provides evidence of genotype-phenotype correlations in ATP1A3-related disorders as well as in patients with mutations at Arg756 in ATP1A3.","variants":[{"Name":"NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)","Chromosome":"19","Start":"41970540","Stop":"41970540","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":413523,"rule_based_match":true,"evidence_text":"c.2266C>T (p.Arg756Cys)","llm_judgment":"PRESENT","evidence":"c.2266C>T (p.Arg756Cys)","abstract_start":769,"abstract_end":792}]}
{"pmid":"16078051","title":"Maternal mosaicism for mutations in the ARX gene in a family with X linked mental retardation.","abstract":"We describe two brothers with mental retardation (MR) due to a c.428_451dup24 in the ARX gene. The mother did not apparently carry the mutation, as determined by dHPLC and by fragment size analysis. Using semiquantitative fluorescent PCR, we show however that 4% of her lymphocytes and 24% of her fibroblasts harbored the duplication. We thus show that the mother displays somatic mosaicism for the duplication thereby highlighting the need to reconsider the molecular screening in sporadic cases of MR.","variants":[{"Name":"NM_139058.3(ARX):c.428_451dup (p.Gly143_Ala150dup)","Chromosome":"X","Start":"25013543","Stop":"25013544","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GCGGCCGCGGCTGCCGCGGCGGCCC","allel_id":26226,"rule_based_match":true,"evidence_text":"c.428_451dup24","llm_judgment":"PRESENT","evidence":"c.428_451dup24","abstract_start":63,"abstract_end":77}]}
{"pmid":"30497413","title":"Identification of novel compound heterozygous SPG7 mutations-related hereditary spastic paraplegia in a Chinese family: a case report.","abstract":"BACKGROUND: Autosomal recessive hereditary spastic paraplegias (ARHSPs) are a group of clinically and genetically heterogeneous neurodegenerative diseases with progressive spasticity and weakness in the lower limbs. Mutations in the Spastic Paraplegia gene 7 (SPG7) account for about 5-21% of ARHSP cases. However, in Asians, few reports about the mutations exist. In this study, we firstly report a novel finding from a Chinese family with compound heterozygous SPG7 mutations, in which three siblings were affected with a complicated form of ARHSP.\nCASE PRESENTATION: A 56-year-old man presented with progressive stiffness, weakness and ataxia in the lower limbs. Two sisters of him had similar symptoms and dysarthria. Brain magnetic resonance imaging (MRI) revealed cerebellar atrophy in each of the patients. Genetic analysis, which exerted a targeted next generation sequencing (NGS) panel covering 917 comprehensive ataxia genes to the proband, followed by Sanger sequencing of candidate genes in other eight family members, was used to find the etiology of the disease. Ultimately, we identified compound heterozygous SPG7 mutations with two mutations: (c.1150_1150-1insCTAC and c.2062C > T, p.Arg688Trp) and one single nucleotide polymorphism (c.2063G > A, p.Arg688Gln).\nCONCLUSIONS: The four bases insertion mutation (4bIM) was predicted to cause frameshift mutation or affect the splicing, and the last two variants were led to a stop codon mutation (p.Arg688Ter). As located in highly conserved positions and encoded paraplegin, the mutations were speculated to result in a truncated or defective protein and would be pathogenic factors of the disease. This paper proves to be the first case report of SPG7 mutation in ARHSP reported in Chinese population. Our findings widen the spectrum of SPG7 mutations of ARHSP and indicate that the SPG7 mutation is an important cause of adult-onset undiagnosed ataxia.","variants":[{"Name":"NM_003119.4(SPG7):c.2062C>T (p.Arg688Trp)","Chromosome":"16","Start":"89553919","Stop":"89553919","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1421280,"rule_based_match":true,"evidence_text":"c.2062C > T, p.Arg688Trp","llm_judgment":"PRESENT","evidence":"c.2062C > T, p.Arg688Trp","abstract_start":1187,"abstract_end":1211}]}
{"pmid":"34596301","title":"Biallelic AOPEP Loss-of-Function Variants Cause Progressive Dystonia with Prominent Limb Involvement.","abstract":"BACKGROUND: Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene-disease relationships can be challenging.\nOBJECTIVE: We sought to expand the catalogue of monogenic etiologies for isolated dystonia.\nMETHODS: After the discovery of a candidate variant in a multicenter exome-sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles.\nRESULTS: Seven different biallelic loss-of-function variants in AOPEP were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C>T [p.Arg493*]). A second proband harbored compound heterozygous nonsense variants (c.763C>T [p.Arg255*]; c.777G>A [p.Trp259*]), whereas a third proband possessed a frameshift variant (c.696_697delAG [p.Ala234Serfs*5]) in trans with a splice-disrupting alteration (c.2041-1G>A). Two probands (siblings) from a fourth family shared compound heterozygous frameshift alleles (c.1215delT [p.Val406Cysfs*14]; c.1744delA [p.Met582Cysfs*6]). All variants were rare and expected to result in truncated proteins devoid of functionally important amino acid sequence. AOPEP, widely expressed in developing and adult human brain, encodes a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance. The probands presented with disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles. Dystonia was unaccompanied by any additional symptoms in three families, whereas the fourth family presented co-occurring late-onset parkinsonism.\nCONCLUSIONS: Our findings suggest a likely causative role of predicted inactivating biallelic AOPEP variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss-of-function variation in AOPEP. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.","variants":[{"Name":"NM_001193329.3(AOPEP):c.777G>A (p.Trp259Ter)","Chromosome":"9","Start":"94760560","Stop":"94760560","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1310208,"rule_based_match":true,"evidence_text":"c.777G>A [p.Trp259*]","llm_judgment":"PRESENT","evidence":"c.777G>A [p.Trp259*]","abstract_start":881,"abstract_end":901},{"Name":"NM_001193329.3(AOPEP):c.763C>T (p.Arg255Ter)","Chromosome":"9","Start":"94760546","Stop":"94760546","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1310209,"rule_based_match":true,"evidence_text":"c.763C>T [p.Arg255*]","llm_judgment":"PRESENT","evidence":"c.763C>T [p.Arg255*]","abstract_start":859,"abstract_end":879},{"Name":"NM_001193329.3(AOPEP):c.1215del (p.Val406fs)","Chromosome":"9","Start":"94800853","Stop":"94800853","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":1310210,"rule_based_match":true,"evidence_text":"c.1215delT (p.Val406Cysfs*14)","llm_judgment":"PRESENT","evidence":"p.Val406Cys","abstract_start":1160,"abstract_end":1171},{"Name":"NM_001193329.3(AOPEP):c.1744del (p.Met582fs)","Chromosome":"9","Start":"94955259","Stop":"94955259","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":1310211,"rule_based_match":true,"evidence_text":"c.1744delA [p.Met582Cysfs*6]","llm_judgment":"PRESENT","evidence":"c.1744delA [p.Met582Cysfs*6]","abstract_start":1179,"abstract_end":1207},{"Name":"NM_001193329.3(AOPEP):c.1477C>T (p.Arg493Ter)","Chromosome":"9","Start":"94924098","Stop":"94924098","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1310207,"rule_based_match":true,"evidence_text":"c.1477C>T [p.Arg493*]","llm_judgment":"PRESENT","evidence":"c.1477C>T [p.Arg493*]","abstract_start":768,"abstract_end":789}]}
{"pmid":"37188672","title":"A novel compound heterozygous of β-thalassemia with HbG-Coushatta: case report of Iran.","abstract":"A 30-year-old male couple from Ardabil city, Iran, were admitted for premarital screening. An abnormal band in HbS/D regions with high levels of HbF and HbA 2 led us to suspect the possibility of a compound heterozygous state of β-thalassemia in our affected proband. Therefore, beta globin chain sequencing of proband discovered a heterozygote combination of the Hb G-Coushatta [b22 (B4) Glu>Ala, HBB: c.68A>C) with HBB: IVS-II-1 (G>A) mutation as a compound heterozygote.","variants":[{"Name":"NM_000518.4(HBB):c.68A>C (p.Glu23Ala)","Chromosome":"11","Start":"5226954","Stop":"5226954","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":30210,"rule_based_match":true,"evidence_text":"HBB: c.68A>C","llm_judgment":"PRESENT","evidence":"HBB: c.68A>C","abstract_start":398,"abstract_end":410}]}
{"pmid":"22312164","title":"Adult-onset vanishing white matter disease due to a novel EIF2B3 mutation.","abstract":"OBJECTIVE: To report a novel mutation in the gene EIF2B3 responsible for a late-onset form of vanishing white matter disease.\nDESIGN: Case report.\nSETTING: University teaching hospital.\nPATIENT: A 29-year-old pregnant woman with a history of premature ovarian failure and hemiplegic migraines presented with a 10-week history of progressive confusion and headaches. Magnetic resonance imaging of the brain revealed a diffuse leukoencephalopathy.\nRESULTS: Sequencing of the exons and intron boundaries of EIF2B3 uncovered 2 missense mutations: c.260C>T(p.Ala87Val) and c.272G>A(p.Arg91His). To our knowledge,the latter missense mutation has never been previously reported.\nCONCLUSION: This is the second report of adult-onset vanishing white matter disease due to mutations in EIF2B3 and the first report of the c.272G>A (p.Arg91His) missense mutation.","variants":[{"Name":"NM_020365.5(EIF2B3):c.272G>A (p.Arg91His)","Chromosome":"1","Start":"44978337","Stop":"44978337","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":425377,"rule_based_match":true,"evidence_text":"c.272G>A (p.Arg91His)","llm_judgment":"PRESENT","evidence":"c.272G>A (p.Arg91His)","abstract_start":811,"abstract_end":832},{"Name":"NM_020365.5(EIF2B3):c.260C>T (p.Ala87Val)","Chromosome":"1","Start":"44978349","Stop":"44978349","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19478,"rule_based_match":true,"evidence_text":"c.260C>T(p.Ala87Val)","llm_judgment":"PRESENT","evidence":"c.260C>T(p.Ala87Val)","abstract_start":543,"abstract_end":563}]}
{"pmid":"30944907","title":"Therapeutic approach with Ataluren in Duchenne symptomatic carriers with nonsense mutations in dystrophin gene. Results of a 9-month follow-up in a case report.","abstract":"Duchenne muscular Dystrophy (DMD) is a X-linked degenerative disorder affecting skeletal muscles and myocardium caused by mutations in the dystrophin gene, mainly deletions and duplications. Point-mutations account for 13% and stop codon mutations are even more unfrequent. A drug treatment for patients with DMD caused by stop codon gene mutations and still ambulant, has become recently available, based on the clear demonstration of its efficacy in slowing the course of the disease. The drug is able to read through the stop codon; furthermore it has the advantage of an oral administration and a better patient's compliance. We report a case of a still ambulant 27 year-old DMD symptomatic carrier with a stop-codon mutation in exon 53 (c.7792C > T; p.Gln2598Stop), who started the treatment with Ataluren at a dosage of 2,250 mg/die, reporting a prompt subjective improvement in muscle strength. Unfortunately two months after, the patient discontinued taking the drug for a traumatic femur fracture requiring surgical repair and prolonged rehabilitation. With the resumption of the drug intake in February 2018, the patient reported almost immediately an improvement in motor skills, including the possibility of recovering walking, first with support and then unsupported. These results seem even more encouraging, as Duchenne patients hardly recover the ability to walk following a fracture at this age and extend the possibility to treat with ataluren also the symptomatic Duchenne carriers who have nonsense dystrophin gene mutations. Furthermore the case here reported supports the concept that symptomatic DMD female carriers must enjoy the same therapeutic opportunities offered to males.","variants":[{"Name":"NM_004006.3(DMD):c.7792C>T (p.Gln2598Ter)","Chromosome":"X","Start":"31679455","Stop":"31679455","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1491115,"rule_based_match":true,"evidence_text":"c.7792C > T; p.Gln2598Stop","llm_judgment":"PRESENT","evidence":"c.7792C > T; p.Gln2598Stop","abstract_start":742,"abstract_end":768}]}
{"pmid":"29058386","title":"New mutations in the SLC7A7 gene of two chinese sisters with lysinuric protein intolerance.","abstract":"Lysinuric protein intolerance (LPI) is an inherited aminoaciduria with an autosomal recessive mode of inheritance.The first two cases of sisters being diagnosed with LPI in China is contained within this report. In our cases, there were two heterozygous mutations in the SLC7A7 gene of the two sisters: deletion of c.1387: del C and IVS4+1C>T. One patient was treated with inhaled rGM-CSF for 1.5 years at 5 μg/kg two times a day. Her condition is improving with no side effects.","variants":[{"Name":"NM_003982.4(SLC7A7):c.1387del (p.Val463fs)","Chromosome":"14","Start":"22773975","Stop":"22773975","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":70997,"rule_based_match":false,"evidence_text":"deletion of c.1387: del C","llm_judgment":"PRESENT","evidence":"deletion of c.1387: del C","abstract_start":303,"abstract_end":328}]}
{"pmid":"31621442","title":"Eleven-year follow-up of a Japanese retinitis pigmentosa patient with an HK1 gene mutation.","abstract":"<b>Background</b>: Retinitis pigmentosa (RP) is a heterogeneous group of disorders that have a high genotypic diversity. Therefore, it is difficult to presume the genotype and/or prognosis from the presented phenotype. Establishment of a viable method for prognostic prediction requires accumulation and aggregation of long-term, follow-up data for respective RP genotypes. In this report, we present the long-term follow-up data for a patient with autosomal dominant RP resulting from a mutation in the <i>HK1</i> gene.<b>Materials and methods</b>: A Japanese patient suffering from RP that was followed-up at our hospital for 11 years consented to participate in this study. The patient's medical and family histories were gathered through patient interviews and clinical data were collected from medical records. The patient's genotype was investigated using whole exome sequencing (WES).<b>Results</b>: Although the fundus showed typical RP, the patient's visual deterioration over the 11-year follow-up period was limited. WES revealed a heterozygous, nonsynonymous variant in the <i>HK1</i> gene (NM_000188: c. 2539G>A, p. E847K). This variant has previously been reported as a pathogenic variant of autosomal dominant RP. Autosomal dominant inheritance pattern was consistent with his family tree.<b>Conclusions</b>: We used WES to identify the first case of RP due to an <i>HK1</i> gene mutation in Japanese patients and presented long-term, follow-up clinical data relating to the progression of the disorder. The detailed and long-term follow-up data for this genetically diagnosed RP patient are a valuable augmentation of existing knowledge and can help inform development of a prognostic prediction method for RP.","variants":[{"Name":"NM_000188.3(HK1):c.2539G>A (p.Glu847Lys)","Chromosome":"10","Start":"69398758","Stop":"69398758","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":411619,"rule_based_match":true,"evidence_text":"NM_000188: c. 2539G>A, p. E847K","llm_judgment":"PRESENT","evidence":"NM_000188: c. 2539G>A, p. E847K","abstract_start":1103,"abstract_end":1134}]}
{"pmid":"22246673","title":"Novel CLDN14 mutations in Pakistani families with autosomal recessive non-syndromic hearing loss.","abstract":"Mutations in the CLDN14 gene are known to cause autosomal recessive (AR) non-sydromic hearing loss (NSHL) at the DFNB29 locus on chromosome 21q22.13. As part of an ongoing study to localize and identify NSHL genes, the ARNSHL segregating in four Pakistani consanguineous families were mapped to the 21q22.13 region with either established or suggestive linkage. Given the known involvement of CLDN14 gene in NSHL, DNA samples from hearing-impaired members from the four families were sequenced to potentially identify causal variants within this gene. Three novel CLDN14 mutations, c.167G>A (p.Trp56*), c.242G>A (p.Arg81His), and c.694G>A (p.Gly232Arg), segregate with hearing loss (HL) in three of the families. The previously reported CLDN14 mutation c.254T>A (p.Val85Asp) was observed in the fourth family. None of the mutations were detected in 400 Pakistani control chromosomes and all were deemed damaging based on bioinformatics analyses. The non-sense mutation c.167G>A (p.Trp56*) is the first stop codon mutation in CLDN14 gene to be identified to cause NSHL. The c.242G>A (p.Arg81His) and c.694G>A (p.Gly232Arg) mutations were identified within the first extracellular loop and the carboxyl-tail of claudin-14, respectively, which highlights the importance of the extracellular domains and phosphorylation of cytoplasmic tail residues to claudin function within the inner ear. The HL due to novel CLDN14 mutations is prelingual, severe-to-profound with greater loss in the high frequencies.","variants":[{"Name":"NM_001146079.2(CLDN14):c.254T>A (p.Val85Asp)","Chromosome":"21","Start":"36461442","Stop":"36461442","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":19890,"rule_based_match":true,"evidence_text":"c.254T>A (p.Val85Asp)","llm_judgment":"PRESENT","evidence":"c.254T>A (p.Val85Asp)","abstract_start":753,"abstract_end":774},{"Name":"NM_001146079.2(CLDN14):c.242G>A (p.Arg81His)","Chromosome":"21","Start":"36461454","Stop":"36461454","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187219,"rule_based_match":true,"evidence_text":"c.242G>A (p.Arg81His)","llm_judgment":"PRESENT","evidence":"c.242G>A (p.Arg81His)","abstract_start":603,"abstract_end":624},{"Name":"NM_001146079.2(CLDN14):c.167G>A (p.Trp56Ter)","Chromosome":"21","Start":"36461529","Stop":"36461529","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187220,"rule_based_match":true,"evidence_text":"c.167G>A (p.Trp56*)","llm_judgment":"PRESENT","evidence":"c.167G>A (p.Trp56*)","abstract_start":582,"abstract_end":601},{"Name":"NM_001146079.2(CLDN14):c.694G>A (p.Gly232Arg)","Chromosome":"21","Start":"36461002","Stop":"36461002","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":187221,"rule_based_match":true,"evidence_text":"c.694G>A (p.Gly232Arg)","llm_judgment":"PRESENT","evidence":"c.694G>A (p.Gly232Arg)","abstract_start":630,"abstract_end":652}]}
{"pmid":"28397219","title":"Analysis of clinical phenotype and CGH1 gene mutations in a family affected with dopa-responsive dystonia","abstract":"OBJECTIVE: To explore genetic mutations and clinical features of a pedigree affected with dopa-responsive dystonia.\nMETHODS: PCR and Sanger sequencing were applied to detect mutations of the GCH1 gene among 7 members from the pedigree.\nRESULTS: The family was detected to have a known heterozygous mutation of the GCH1 gene (c.550C>T). For the 7 members from the pedigree, the age of onset has ranged from 13 to 60 years. The mother of the proband has carried the same mutation but was still healthy at 80. The symptoms of the other three patients were in slow progression, with diurnal fluctuation which can be improved with sleeping, dystonias of lower limbs, and tremor of both hands. Treatment with small dose of levodopa has resulted in significant improvement of clinical symptoms. By database analysis, the c.550C>T mutation was predicted as probably pathological.\nCONCLUSION: The c.550C>T mutation probably underlies the disease in this pedigree. The clinical phenotypes of family members may be variable for their ages of onset. Some may even be symptom free.","variants":[{"Name":"NM_000161.3(GCH1):c.550C>T (p.Arg184Cys)","Chromosome":"14","Start":"54845844","Stop":"54845844","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1504442,"rule_based_match":true,"evidence_text":"c.550C>T","llm_judgment":"PRESENT","evidence":"c.550C>T","abstract_start":325,"abstract_end":333}]}
{"pmid":"26229699","title":"Presentation of Complex Homozygous Allele in ABCA4 Gene in a Patient with Retinitis Pigmentosa.","abstract":"Retinitis pigmentosa is a degenerative retinal disease characterized by progressive photoreceptor damage, which causes loss of peripheral and night vision and the development of tunnel vision and may result in loss of central vision. This study describes a patient with retinitis pigmentosa caused by a mutation in the ABCA4 gene with complex allele c.1622T>C, p.L541P; c.3113C>T, p.A1038V in homozygous state.","variants":[{"Name":"NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro)","Chromosome":"1","Start":"94063250","Stop":"94063250","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":22940,"rule_based_match":true,"evidence_text":"c.1622T>C","llm_judgment":"PRESENT","evidence":"c.1622T>C","abstract_start":350,"abstract_end":359}]}
{"pmid":"26629787","title":"Whole USH2A Gene Sequencing Identifies Several New Deep Intronic Mutations.","abstract":"Deep intronic mutations leading to pseudoexon (PE) insertions are underestimated and most of these splicing alterations have been identified by transcript analysis, for instance, the first deep intronic mutation in USH2A, the gene most frequently involved in Usher syndrome type II (USH2). Unfortunately, analyzing USH2A transcripts is challenging and for 1.8%-19% of USH2 individuals carrying a single USH2A recessive mutation, a second mutation is yet to be identified. We have developed and validated a DNA next-generation sequencing approach to identify deep intronic variants in USH2A and evaluated their consequences on splicing. Three distinct novel deep intronic mutations have been identified. All were predicted to affect splicing and resulted in the insertion of PEs, as shown by minigene assays. We present a new and attractive strategy to identify deep intronic mutations, when RNA analyses are not possible. Moreover, the bioinformatics pipeline developed is independent of the gene size, implying the possible application of this approach to any disease-linked gene. Finally, an antisense morpholino oligonucleotide tested in vitro for its ability to restore splicing caused by the c.9959-4159A>G mutation provided high inhibition rates, which are indicative of its potential for molecular therapy.","variants":[{"Name":"NM_206933.4(USH2A):c.9959-4159A>G","Chromosome":"1","Start":"215794441","Stop":"215794441","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":940617,"rule_based_match":true,"evidence_text":"c.9959-4159A>G","llm_judgment":"PRESENT","evidence":"c.9959-4159A>G","abstract_start":1197,"abstract_end":1211}]}
{"pmid":"32194638","title":"A Novel Heterozygous Variant in F2 Gene in a Chinese Patient With Coronary Thrombosis and Acute Myocardial Infarction Leads to Antithrombin Resistance.","abstract":"Thrombophilia refers to a group of conditions where the blood clots more easily than normal. These blood clots can cause problems such as deep vein thrombosis or pulmonary embolism. Most kinds of mutated coagulation factors II (F2) exhibit lower procoagulant activity, but in some cases, a higher coagulation rate has been observed. The underlying mechanism is that those variations can prevent F2s from being inhibited by antithrombin, leading to a contiguous activation of procoagulation, and causing recurrent thromboembolism. In this study, a patient was admitted to our hospital due to repeated chest pain for 2 days and aggravated for 4 h. A medical history investigation showed that he had three deep venous thromboses in the lower limbs and one portal vein thrombosis events during the past 10 years. The electrocardiogram showed Q wave elevation and slight ST segment elevation in lead V2, and coronary angiogram showed a total occlusion of the left anterior descending artery. Laboratory testing found that troponin I was obviously elevated. Family history also indicated that both his father (II-3) and grandfather (I-1) died from pulmonary thromboembolism. Whole-exome sequencing was performed to detect the genetic lesion of the patient, and a novel mutation (c.1621 C>T/p.R541W) of <i>F2</i> was identified in the patient. This novel mutation resulted in a substitution of arginine by tryptophan, leading to antithrombin resistance (ATR). Our study is consistent with previously published papers. In conclusion, this study not only identifies a novel mutation of <i>F2</i> and will contribute to the genetic diagnosis and counseling of families with thrombosis but also suggests that the site p.R541 of <i>F2</i> may play a crucial role in thrombosis.","variants":[{"Name":"NM_000506.5(F2):c.1621C>T (p.Arg541Trp)","Chromosome":"11","Start":"46729528","Stop":"46729528","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":973796,"rule_based_match":true,"evidence_text":"c.1621 C>T/p.R541W","llm_judgment":"PRESENT","evidence":"c.1621 C>T/p.R541W","abstract_start":1273,"abstract_end":1291}]}
{"pmid":"32286009","title":"Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy.","abstract":"OBJECTIVE: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.\nMETHODS: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.\nRESULTS: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.\nCONCLUSION: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.","variants":[{"Name":"NM_000844.4(GRM7):c.2671G>A (p.Glu891Lys)","Chromosome":"3","Start":"7680268","Stop":"7680268","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":961060,"rule_based_match":true,"evidence_text":"c.2671G>A:p.Glu891Lys","llm_judgment":"PRESENT","evidence":"c.2671G>A:p.Glu891Lys","abstract_start":1193,"abstract_end":1214},{"Name":"NM_000844.4(GRM7):c.1975C>T (p.Arg659Ter)","Chromosome":"3","Start":"7578881","Stop":"7578881","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":961061,"rule_based_match":true,"evidence_text":"c.1975C>T:p.Arg659Ter","llm_judgment":"PRESENT","evidence":"c.1975C>T:p.Arg659Ter","abstract_start":1280,"abstract_end":1301}]}
{"pmid":"30526585","title":"Conservation analysis and pathogenicity prediction of mutant genes of ectodysplasin a.","abstract":"BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a common recessive X-linked hereditary disease that affects the development of ectoderm. Gene mutations of ectodysplasin A (EDA) play key roles in process of this disease. In our preliminary study, three unknown mutation sites (c.878 T > G, c.663-697del and c.587-615del) were detected from the pedigrees of HED.\nMETHODS: Conservation analysis of the related homologous proteins in 3 unknown EDA gene mutation sites was conducted using the University of California Santa Cruz (UCSC) Genome Browser database. SIFT and PolyPhen-2, the online gene function prediction software, were utilized to predict the pathogenicity of point mutation of c.878 T > G.\nRESULTS: All three unknown mutation sites were located in the highly-conserved region of EDA and possessed strong amino acid conservation among different species. In addition, the results of the pathogenicity prediction of point mutation of c.878 T > G by SIFT (P = 0.00) and PolyPhen-2 (S = 0.997) demonstrated that the mutation site had considerable pathogenicity theoretically.\nCONCLUSIONS: The EDA mutations of c.878 T > G, c.663-697del and c.587-615del may be responsible for the pathogenesis of HED in their pedigrees.","variants":[{"Name":"NM_001399.5(EDA):c.878T>G (p.Leu293Arg)","Chromosome":"X","Start":"70033482","Stop":"70033482","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":2669605,"rule_based_match":true,"evidence_text":"c.878 T > G","llm_judgment":"PRESENT","evidence":"c.878 T > G","abstract_start":283,"abstract_end":294}]}
{"pmid":"25790805","title":"Coagulation Factor XII Gene Mutation in Brazilian Families with Hereditary Angioedema with Normal C1 Inhibitor.","abstract":"BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare disorder. Mutations of the gene encoding coagulation factor XII have been identified in a subset of patients with this condition. Our aim was to investigate mutations in the F12 gene in patients with HAE with normal C1-INH from Brazil.\nMETHODS: We studied 5 Brazilian families with index female patients who presented with recurrent angioedema with normal C1-INH and C4 levels. Genomic DNA was isolated from whole blood and PCR was performed. Mutations were detected by the sequencing of exon 9 of the F12 gene and allelic discrimination.\nRESULTS: The c.983C>A (p.Thr328Lys) mutation was identified in 16 subjects, from 4 of the 5 families studied, including 8 patients with symptoms of HAE with normal C1-INH (87.5% women) and 8 subjects asymptomatic for HAE (25% women). Mean age at onset of symptoms among the FXII-HAE patients was 13.8 years (range 6-25 years). Recurrent abdominal pain (100%) and subcutaneous angioedema (87.5%) were the most frequent clinical presentations. Two patients presented with associated laryngeal edema. In keeping with previous observations in patients with both C1-INH-HAE and HAE with normal C1-INH, all 7 women with FXII-HAE reported triggering or worsening of symptoms upon intake of estrogen-containing oral contraceptives and/or pregnancy.\nCONCLUSIONS: We report for the first time in Brazil a mutation in the F12 gene as a likely cause of HAE with normal C1-INH in patients with recurrent attacks of angioedema and/or abdominal pain. A higher frequency of abdominal pain attacks and onset of symptoms at a younger age were observed among Brazilian patients when compared to those from other parts of the world.","variants":[{"Name":"NM_000505.4(F12):c.983C>A (p.Thr328Lys)","Chromosome":"5","Start":"177404231","Stop":"177404231","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":16208,"rule_based_match":true,"evidence_text":"c.983C>A (p.Thr328Lys)","llm_judgment":"PRESENT","evidence":"c.983C>A (p.Thr328Lys)","abstract_start":636,"abstract_end":658}]}
{"pmid":"35001891","title":"De novo Mutation Enables NOTCH3ECD Aggregation and Mitochondrial Dysfunction via Interactions with BAX and BCL-2.","abstract":"BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most common monogenic hereditary pattern of cerebral small vessel disease. The aggregation of the mutant NOTCH3 may play a cytotoxic role in CADASIL. However, the main mechanism of this process remains unclear.\nOBJECTIVE: We aimed to investigate the possible pathogenesis of the mutant NOTCH3 in CADASIL.\nMETHODS: The clinical information of two pedigrees were collected and analyzed. Furthermore, we constructed cell lines corresponding to this mutation in vitro. The degradation of the extracellular domain of NOTCH3 (NOTCH3ECD) was analyzed by Cycloheximide Pulse-Chase Experiment. Flow cytometry and cell counting kit-8 assay were performed to observe the effects of the NOTCH3 mutation on mitochondrial function and apoptosis.\nRESULTS: We confirmed a de novo heterozygous missense NOTCH3 mutation (c.1690G > A, p. A564T) in two pedigrees. In vitro, the NOTCH3ECD aggregation of A564T mutant may be related to their more difficult to degrade. The mitochondrial membrane potential was attenuated, and cell viability was significant decreased in NOTCH3ECD A564T group. Interestingly, BAX and cytochrome c were significantly increased, which are closely related to the mitochondrial-mediated pathway to apoptosis.\nCONCLUSION: In our study, the aggregation of NOTCH3ECD A564T mutation may be associated with more difficult degradation of the mutant, and the aggregation may produce toxic effects to induce apoptosis through the mitochondrial-mediated pathway. Therefore, we speculated that mitochondrial dysfunction may hopefully become a new breakthrough point to explain the pathogenesis of cysteine-sparing NOTCH3 mutations.","variants":[{"Name":"NM_000435.3(NOTCH3):c.1690G>A (p.Ala564Thr)","Chromosome":"19","Start":"15187255","Stop":"15187255","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":348268,"rule_based_match":true,"evidence_text":"c.1690G > A, p. A564T","llm_judgment":"PRESENT","evidence":"c.1690G > A, p. A564T","abstract_start":950,"abstract_end":971}]}
{"pmid":"15146459","title":"Identification of a new complementation group of the peroxisome biogenesis disorders and PEX14 as the mutated gene.","abstract":"Peroxisome biogenesis disorders (PBD) are lethal hereditary diseases caused by abnormalities in the biogenesis of peroxisomes. At present, 12 different complementation groups have been identified and to date, all genes responsible for each of these complementation groups have been identified. The peroxisomal membrane protein PEX14 is a key component of the peroxisomal import machinery and may be the initial docking site for the two import receptors PEX5 and PEX7. Although PEX14 mutants have been identified in yeasts and CHO-cells, human PEX14 deficiency has apparently not been documented. We now report the identification of a new complementation group of the peroxisome biogenesis disorders with PEX14 as the defective gene. Indeed, human PEX14 rescues the import of a PTS1-dependent as well as a PTS2-dependent protein into the peroxisomes in fibroblasts from a patient with Zellweger syndrome belonging to the new complementation group. This patient was homozygous for a nonsense mutation in a putative coiled-coil region of PEX14, c.553C>T (p.Q185X). Furthermore, we showed that the patient's fibroblasts lacked PEX14 as determined by immunocytochemical analysis. These findings indicate that there are 13 genotypes in PBD and that the role of PEX14 is also essential in humans.","variants":[{"Name":"NM_004565.3(PEX14):c.553C>T (p.Gln185Ter)","Chromosome":"1","Start":"10624405","Stop":"10624405","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22740,"rule_based_match":true,"evidence_text":"c.553C>T (p.Q185X)","llm_judgment":"PRESENT","evidence":"c.553C>T (p.Q185X)","abstract_start":1042,"abstract_end":1060}]}
{"pmid":"18478590","title":"Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C.","abstract":"Mutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibulo acral dysplasia, Hutchinson Gilford progeria syndrome, restrictive dermopathy and autosomal recessive Charcot Marie Tooth type 2. The c.1930C > T (R644C) missense mutation has previously been reported in eight unrelated patients with variable features including left ventricular hypertrophy, limb girdle muscle weakness, dilated cardiomyopathy and atypical progeria. Here we report on the details of nine additional patients in eight families with this mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance, Patient 1 having in addition focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, Patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular non-compaction, Patient 5 with severe scoliosis and contractures, Patient 6 with limb girdle weakness and Patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 are brothers with proximal weakness and contractures. Nonpenetrance was observed frequently in first degree relatives. This report provides further evidence of the extreme phenotypic diversity and low penetrance associated with the R644C mutation. Possible explanations for these observations are discussed.","variants":[{"Name":"NM_170707.4(LMNA):c.1930C>T (p.Arg644Cys)","Chromosome":"1","Start":"156138719","Stop":"156138719","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29566,"rule_based_match":true,"evidence_text":"c.1930C > T (R644C)","llm_judgment":"PRESENT","evidence":"c.1930C > T (R644C)","abstract_start":378,"abstract_end":397}]}
{"pmid":"31208513","title":"Clinical features and TTC21B genotype of a child with nephronophthisis type 12","abstract":"Nephronophthisis (NPHP) is a group of autosomal recessive tubulointerstitial cystic kidney disorders. This article reports a case of NPHP type 12 caused by TTC21B mutations. The girl had an insidious onset, with moderate proteinuria, renal dysfunction, stage 2 hypertension, situs inversus, and short phalanges when she visited the hospital for the first time at the age of 3 years and 6 months. The renal lesions progressed to end-stage renal disease (ESRD) before she was 4 years old. Urine protein electrophoresis showed glomerular proteinuria. There were significant increases in urinary β2-microglobulin and α1-microglobulin. Gene detection revealed two compound heterozygous mutations, c.1552T>C (p.C518R) and c.752T>G (p.M251R), in the TTC21B gene, which came from her father and mother respectively. The c.752T>G mutation was a novel mutation. It is concluded that besides typical tubular changes of NPHP, marked glomerular damage is also observed in patients with TTC21B gene mutations.","variants":[{"Name":"NM_024753.5(TTC21B):c.752T>G (p.Met251Arg)","Chromosome":"2","Start":"165933016","Stop":"165933016","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2842807,"rule_based_match":true,"evidence_text":"c.752T>G (p.M251R)","llm_judgment":"PRESENT","evidence":"c.752T>G (p.M251R)","abstract_start":716,"abstract_end":734}]}
{"pmid":"28602422","title":"Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome.","abstract":"Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10% of affected individuals, the genetic cause of the disease is unknown, suggesting that other loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with no variants in the known MMIHS-associated genes. By performing homozygosity mapping and whole-exome sequencing, we found homozygous variants in myosin light chain kinase (MYLK) in both families. We identified a 7 bp duplication (c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs<sup>∗</sup>51]) in one family and a putative splice-site variant (c.3985+5C>A) in the other. Expression studies and splicing assays indicated that both variants affect normal MYLK expression. Because MYLK encodes an important kinase required for myosin activation and subsequent interaction with actin filaments, it is likely that in its absence, contraction of smooth muscle cells is impaired. The existence of a conditional-Mylk-knockout mouse model with severe gut dysmotility and abnormal function of the bladder supports the involvement of this gene in MMIHS pathogenesis. In aggregate, our findings implicate MYLK as a gene involved in the recessive form of MMIHS, confirming that this disease of the visceral organs is heterogeneous with a myopathic origin.","variants":[{"Name":"NM_053025.4(MYLK):c.3838_3844dup (p.Glu1282fs)","Chromosome":"3","Start":"123664245","Stop":"123664246","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TCGCTTTC","allel_id":259621,"rule_based_match":true,"evidence_text":"c.3838_3844dupGAAAGCG","llm_judgment":"PRESENT","evidence":"c.3838_3844dupGAAAGCG","abstract_start":736,"abstract_end":757}]}
{"pmid":"35908153","title":"The recurrent TCF4 missense variant p.(Arg389Cys) causes a neurodevelopmental disorder overlapping with but not typical for Pitt-Hopkins syndrome.","abstract":"TCF4 haploinsufficiency by deletions, truncating variants or loss-of-function missense variants within the DNA-binding and protein interacting bHLH domain causes Pitt-Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N-terminus of TCF4 were associated with milder or atypical phenotypes. By personal communication and searching databases we assembled six cases with the novel, recurrent, de novo missense variant c.1165C &gt; T, p.(Arg389Cys) in TCF4. This variant was identified by diagnostic exome or panel sequencing and is located upstream of the bHLH domain. All six individuals presented with moderate to severe ID with language impairment. Microcephaly occurred in two individuals, epilepsy only in one, and no breathing anomalies or myopia were reported. Facial gestalt showed some aspects of PTHS but was rather non-specific in most individuals. Interestingly, the variant is located within the AD2 activation domain next to a highly conserved coactivator-recruitment motif and might alter interaction with coactivator proteins independently from the bHLH domain. Our findings of a recurrent missense variant outside the bHLH domain in six individuals with an ID phenotype overlapping with but not typical for PTHS delineate a novel genotype-phenotype correlation for TCF4-related NDDs.","variants":[{"Name":"NM_001083962.2(TCF4):c.1165C>T (p.Arg389Cys)","Chromosome":"18","Start":"55254682","Stop":"55254682","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1309593,"rule_based_match":false,"evidence_text":"c.1165C > T, p.(Arg389Cys)","llm_judgment":"PRESENT","evidence":"T, p.(Arg389Cys","abstract_start":580,"abstract_end":595}]}
{"pmid":"16299064","title":"A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome.","abstract":"BACKGROUND: Mutations of the filamin A locus (FLNA) on Xq28 have been established in girls with periventricular nodular heterotopia and in patients with otopalatodigital and overlapping phenotypes, the pathogenesis of these phenotypes being thought to be quite distinct. To date only six male cases of periventricular nodular heterotopia (PVNH) have been reported and these almost invariably associated with severe neurological signs.\nMETHODS AND RESULTS: We report a new phenotype of male PVNH, with relatively normal development, no epilepsy or other neurological abnormality, severe constipation, and facial dysmorphism and without a discernible skeletal phenotype. This phenotype is associated with a splice site mutation in FLNA c.1923C>T, resulting in the generation of both normal and aberrant mRNA.\nCONCLUSIONS: We postulate that the patient retains enough FLNA function to avoid the usual lethality associated with loss of function mutations in males and suggest that the severe constipation may be a clue to the molecular aetiology of other X linked conditions associated with severe constipation.","variants":[{"Name":"NM_001110556.2(FLNA):c.1923C>T (p.Gly641=)","Chromosome":"X","Start":"154364625","Stop":"154364625","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":26809,"rule_based_match":true,"evidence_text":"c.1923C>T","llm_judgment":"PRESENT","evidence":"c.1923C>T","abstract_start":734,"abstract_end":743}]}
{"pmid":"19618371","title":"A single-base substitution within an intronic repetitive element causes dominant retinitis pigmentosa with reduced penetrance.","abstract":"We report the study of a large American family displaying autosomal dominant retinitis pigmentosa with reduced penetrance, a form of hereditary retinal degeneration. Although the inheritance pattern and previous linkage mapping pointed to the involvement of the PRPF31 gene, extensive screening of all its exons and their boundaries failed in the past to reveal any mutation. In this work, we sequenced the entire PRPF31 genomic region by both the classical Sanger method and ultrahigh throughput (UHT) sequencing. Among the many variants identified, a single-base substitution (c.1374+654C>G) located deep within intron 13 and inside a repetitive DNA element was common to all patients and obligate asymptomatic carriers. This change created a new splice donor site leading to the synthesis of two mutant PRPF31 isoforms, degraded by nonsense-mediated mRNA decay. As a consequence, amounts of PRPF31 mRNA derived from the mutant allele were very reduced, with no evidence of mutant proteins being synthesized. Our results indicate that c.1374+654C>G causes retinitis pigmentosa via haploinsufficiency, similar to the vast majority of PRPF31 mutations described so far. We discuss the potential of UHT sequencing technologies in mutation screening and the continued identification of pathogenic splicing mutations buried deep within intronic regions.","variants":[{"Name":"NM_015629.4(PRPF31):c.1374+654C>G","Chromosome":"19","Start":"54130024","Stop":"54130024","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":19405,"rule_based_match":true,"evidence_text":"c.1374+654C>G","llm_judgment":"PRESENT","evidence":"c.1374+654C>G","abstract_start":579,"abstract_end":592}]}
{"pmid":"32494556","title":"Identification of novel compound heterozygous mutations of the","abstract":"A prenatal sonograph revealed a 26-week-old fetus with short limbs and a narrow chest in a 23-year-old woman with a history of fetal skeletal dysplasia. A single nucleotide polymorphism-based chromosomal microarray (CMA) indicated a normal karyotype, and no chromosomal segments with abnormal copy numbers were noted in the fetus. Whole exome sequencing identified compound heterozygous mutations in the <i>DYNC2H1</i> gene responsible for a lethal type of bone growth disorder, short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3), and revealed a missense mutation c.515C>A (p. Pro172Gln) of paternal origin and a missense mutation c.5983G>A (p. Ala1995Thr) of maternal origin. These variants were further confirmed by Sanger sequencing. To the extent known, the c.515C>A (p. Pro172Gln) mutation is novel for SRTD3, and the site is conserved across species. This study found a novel mutation of the <i>DYNC2H1</i> gene for SRTD3 and it has increased the number of reported cases and expanded the spectrum of mutations causing this rare disease.","variants":[{"Name":"NM_001377.3(DYNC2H1):c.5983G>A (p.Ala1995Thr)","Chromosome":"11","Start":"103177664","Stop":"103177664","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":408032,"rule_based_match":true,"evidence_text":"c.5983G>A (p. Ala1995Thr)","llm_judgment":"PRESENT","evidence":"c.5983G>A (p. Ala1995Thr)","abstract_start":647,"abstract_end":672}]}
{"pmid":"24172246","title":"Novel mutation in AAA domain of BCS1L causing Bjornstad syndrome.","abstract":"Bjørnstad syndrome is an extremely rare condition characterized by pilitorti and nerve deafness. Only few large families have been reported worldwide. Here we describe a large Pakistani family with five affected individuals. The hair fibers of all the patients were twisted around their axis and devoid of any pigment. In addition the patients had a moderate-to-severe degree of hearing impairment. Genotyping with high-density single-nucleotide polymorphism arrays showed homozygosity in two intervals on chromosome 2. Linkage with one of these regions (genomic position 218745685-221025443, hg19) was confirmed. This region encompasses the BCS1L gene. Mutations in this gene have previously been associated with Bjørnstad's syndrome. We sequenced the BCS1L gene for identification of the causative mutation in the family. A novel homozygous missense mutation c.901T>A was identified, which segregated with the disease in the family. This mutation results in the amino acid change p.Tyr301Asn and was predicted to be pathogenic by bioinformatics tools.","variants":[{"Name":"NM_001079866.2(BCS1L):c.901T>A (p.Tyr301Asn)","Chromosome":"2","Start":"218662894","Stop":"218662894","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":132021,"rule_based_match":true,"evidence_text":"c.901T>A","llm_judgment":"PRESENT","evidence":"c.901T>A","abstract_start":861,"abstract_end":869}]}
{"pmid":"17159356","title":"Genetic analysis of Gitelman syndrome patients from the Czech Republic and Slovakia--three novel mutations found.","abstract":"BACKGROUND: To investigate the genetic cause of inherited hypokalemic metabolic alkalosis associated with Gitelman's syndrome, we searched for mutations in the SLC12A3 gene (thiazide-sensitive NaCl cotransporter) among a set of patients from the Czech Republic and Slovakia.\nMETHODS: We collected blood samples of patients from 16 families with characteristic clinical features. DNA was analyzed for mutation detection with SSCP and subsequent sequencing. Several mutations might be missed when only the SSCP method is applied, therefore direct sequencing of all the 26 exons became an essential tool.\nRESULTS: Genetic analysis revealed mainly missense mutations. Two novel mutations, c.480dupC (p.Pro160fsX97) and c.238dupCC (p. Pro79fsX35), caused a frameshift and preliminary stop codon appearance. Missense mutation c.790 G --> C (p.Gly264Arg) has never been reported before. Mutation c.1315G --> A (p.Gly439Ser) was frequent among our collection of unrelated patients (5 out of 16). Homozygous Gly439Ser was observed in a patient with chondrocalcinosis.\nCONCLUSION: We identified 13 different causative mutations in a cohort of Gitelman syndrome patients. Three of those mutations are novel. The occurrence of two mutation detections per individual corresponding to a recessive trait of inheritance was 62.5%. Gly439Ser is the most frequent type of mutation among our patients. Statistic evaluation of genotype/phenotype correlation could not be carried out.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1315G>A (p.Gly439Ser)","Chromosome":"16","Start":"56879207","Stop":"56879207","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":577552,"rule_based_match":false,"evidence_text":"c.1315G --> A (p.Gly439Ser)","llm_judgment":"PRESENT","evidence":"c.1315G --> A (p.Gly439Ser)","abstract_start":889,"abstract_end":916}]}
{"pmid":"18381613","title":"A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy.","abstract":"Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy.","variants":[{"Name":"NM_194248.3(OTOF):c.2905_2923delinsCTCCGAGCGCA (p.Ala969fs)","Chromosome":"2","Start":"26475982","Stop":"26476000","ReferenceAlleleVCF":"CGGCAAAGAGGCTGCGGGC","AlternateAlleleVCF":"TGCGCTCGGAG","allel_id":76702,"rule_based_match":true,"evidence_text":"c.2905_2923delinsCTCCGAGCGCA","llm_judgment":"PRESENT","evidence":"c.2905_2923delinsCTCCGAGCGCA","abstract_start":1321,"abstract_end":1349}]}
{"pmid":"33132204","title":"Novel compound heterozygous variants in the STIL gene identified in a Chinese family with presentation of foetal microcephaly.","abstract":"Primary microcephaly 7 (MCPH7) is an autosomal recessive human neurodevelopmental disorder characterized by microcephaly, sloping forehead, and prominent midface. The STIL gene encodes a protein that regulates the mitotic spindle checkpoint. STIL is the pathogenic gene of MCPH7. Although more than 25 genes have been reported to cause MCPH, many patients lack a molecular diagnosis. The clinical manifestations and genetic factors of MCPH7 remain to be revealed. This research reported two consecutive microcephalic foetuses from unaffected parents. Prenatal ultrasound examination and pre- and postnatal MRI studies were performed. Whole-genome sequencing (WGS) was performed using blood derived from the umbilical cord, and variants were confirmed by Sanger sequencing on the parents. Ultrasound examination showed that the two foetuses suffered primary microcephaly. Using the WGS approach, novel compound heterozygous variants in STIL (c.2344_2347delTTGC, p. Leu782Thrfs*2 in exon 13; c.3838C > T, p. Arg1280Cys in exon 17) were identified in two foetuses with MCPH7. The MRI results of the two siblings were quite similar. Postnatal MRI confirmed the ultrasound and prenatal examinations. The two foetuses had typical microcephaly. Ultrasound and MRI showed that the two foetuses had a thick skull plate, significantly reduced bilateral frontal lobe, upward rotated cerebellum vermis, and dilated fourth ventricle. Our findings have important implications for prenatal diagnosis and genetic counselling for any patients with MCPH7. We extend both the mutational spectrum in the STIL gene and the clinical spectrum of MCPH7.","variants":[{"Name":"NM_001048166.1(STIL):c.2344_2347del (p.Leu782fs)","Chromosome":"1","Start":"47272112","Stop":"47272115","ReferenceAlleleVCF":"TGCAA","AlternateAlleleVCF":"T","allel_id":965356,"rule_based_match":true,"evidence_text":"c.2344_2347delTTGC","llm_judgment":"PRESENT","evidence":"c.2344_2347delTTGC","abstract_start":941,"abstract_end":959},{"Name":"NM_001048166.1(STIL):c.3838C>T (p.Arg1280Cys)","Chromosome":"1","Start":"47251165","Stop":"47251165","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":493551,"rule_based_match":true,"evidence_text":"c.3838C > T, p. Arg1280Cys in exon 17","llm_judgment":"PRESENT","evidence":"c.3838C > T, p. Arg1280Cys in exon 17","abstract_start":990,"abstract_end":1027}]}
{"pmid":"30816539","title":"PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population.","abstract":"The present study aimed to identify the disease‑causing gene of a four‑generation Chinese family affected with congenital posterior subcapsular cataracts (CPSC), to additionally investigate the frequency of paired like homeodomain 3 (PITX3) mutations in Chinese patients with autosomal dominant congenital cataract (ADCC) and to analyze the pathogenesis of the mutations identified in the present study. Whole exome sequencing (WES) was utilized to identify the genetic cause of CPSC in the four‑generation family. Sanger sequencing was performed to verify the WES results and to screen for mutations of the PITX3 gene in probands of an additional 194 Chinese ADCC families. Co‑segregation analysis was performed in the family members with available DNA. Subcellular localization analyses and transactivation assays were performed for the PITX3 mutations identified. From the WES data, the c.608delC (p.A203GfsX106) mutation of PITX3 was identified in the four‑generation family with CPSC. A second PITX3 mutation c.640_656del (p.A214RfsX42) was detected in two of the additional 194 ADCC families and one of these two families exhibited incomplete penetrance. Functional studies indicated that these 2 PITX3 mutant proteins retained a nuclear localization pattern, but resulted in decreased transactivation activity, similar to other previously identified PITX3 mutations. In the present study, 2 different mutations (p.A203GfsX106 and p.A214RfsX42) in PITX3 were identified as the causative defect in a four‑generation family with CPSC and two ADCC families, respectively. The prevalence of PITX3 gene‑associated cataract was 1.54% (3/195) in the Chinese congenital cataract (CC) family cohort. In vitro functional analyses of these 2 PITX3 mutations were performed, in order to enhance understanding of the pathogenesis of CC caused by PITX3 mutations.","variants":[{"Name":"NM_005029.4(PITX3):c.640_656del (p.Ala214fs)","Chromosome":"10","Start":"102230767","Stop":"102230783","ReferenceAlleleVCF":"GCCCAGGCCCTGCAGGGC","AlternateAlleleVCF":"G","allel_id":459812,"rule_based_match":true,"evidence_text":"c.640_656del (p.A214RfsX42)","llm_judgment":"PRESENT","evidence":"c.640_656del (p.A214RfsX42)","abstract_start":1014,"abstract_end":1041}]}
{"pmid":"20852937","title":"S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes.","abstract":"This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S-adenosylhomocysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel mutations, c.145C>T; p.Arg49Cys and c.257A>G; p.Asp86Gly. Clinically, the major abnormalities in addition to fetal hydrops (very likely due to impaired synthetic liver function) were severe hypotonia/myopathy, feeding problems, and respiratory failure. Metabolic abnormalities included elevated plasma S-adenosylhomocysteine, S-adenosylmethionine, and methionine, with hypoalbuminemia, coagulopathies, and serum transaminase elevation. The older sister died at age 25 days, but the definitive diagnosis was made only retrospectively. The underlying genetic abnormality was diagnosed in the second sister, but treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122 days. These cases extend the experience with AHCY deficiency in humans, based until now on only the four patients previously identified, and suggest that the deficiency in question may be a cause of fetal hydrops and developmental abnormalities of the brain.","variants":[{"Name":"NM_000687.4(AHCY):c.145C>T (p.Arg49Cys)","Chromosome":"20","Start":"34295469","Stop":"34295469","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":974190,"rule_based_match":true,"evidence_text":"c.145C>T; p.Arg49Cys","llm_judgment":"PRESENT","evidence":"c.145C>T; p.Arg49Cys","abstract_start":246,"abstract_end":266},{"Name":"NM_000687.4(AHCY):c.257A>G (p.Asp86Gly)","Chromosome":"20","Start":"34294119","Stop":"34294119","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":620656,"rule_based_match":true,"evidence_text":"c.257A>G; p.Asp86Gly","llm_judgment":"PRESENT","evidence":"c.257A>G; p.Asp86Gly","abstract_start":271,"abstract_end":291}]}
{"pmid":"12887446","title":"Evidence for S284L mutation of the CHRNA4 in a white family with autosomal dominant nocturnal frontal lobe epilepsy.","abstract":"PURPOSE: To identify mutations of the neuronal nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a group of white patients.\nMETHODS: A group of 47 patients from 21 unrelated families with ADNFLE were screened for mutations in CHRNA4. Clinical features and EEG findings in the patients were consistent with those reported in the literature for other affected families. The entire gene was amplified from genomic DNA by polymerase chain reaction (PCR) followed by multitemperature single-strand conformation polymorphism analysis (MSSCP) and sequencing.\nRESULTS: A c.851C>T transition in exon 5 of CHRNA4 was identified in three affected individuals from two generations of the same family, but not in the remaining patients or in 100 healthy volunteers. This mutation caused an S284L substitution in the transmembrane domain M2 segment of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor. The same mutation had previously been detected in a single Japanese family with ADNFLE, and in an Australian woman with a sporadic form of NFLE.\nCONCLUSIONS: This is the first report of an occurrence of c.851C>T transition in a white family with ADNFLE.","variants":[{"Name":"NM_000744.7(CHRNA4):c.851C>T (p.Ser284Leu)","Chromosome":"20","Start":"63350560","Stop":"63350560","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":32539,"rule_based_match":true,"evidence_text":"c.851C>T","llm_judgment":"PRESENT","evidence":"c.851C>T","abstract_start":654,"abstract_end":662}]}
{"pmid":"28816644","title":"CYP2B6 Haplotype Predicts Efavirenz Plasma Concentration in Black South African HIV-1-Infected Children: A Longitudinal Pediatric Pharmacogenomic Study.","abstract":"South Africa has the highest burden of the human immunodeficiency virus (HIV) infection globally. Efavirenz (EFV), a frequently used drug against HIV infection, displays a relationship between drug concentration and pharmacodynamics effects clinically. However, haplotype-based genetic variation in drug metabolism in a pediatric sample has been little considered in a longitudinal long-term context. CYP2B6 plays a key role in variation of EFV plasma concentration through altered drug metabolism. We report here on a prospective clinical pharmacogenomics/pharmacokinetic study of Bantu-speaking children, importantly, over a period of 24 months post-initiation of EFV-based treatment in South Africa. We characterized the HIV-1-infected children (n = 60) for the CYP2B6 c.516G>T, c.785A>G, c.983T>C, and c.1459C>T single nucleotide polymorphisms (SNPs). These SNPs were determined using polymerase chain reaction/restricted fragment length polymorphism and SNaPshot genotyping. Longitudinal mid-dose EFV plasma concentrations were determined by LC-MS/MS and association analyses with genotypes and haplotypes at 1, 3, and 24 months were performed. The CYP2B6 c.516T/T genotype showed significantly higher EFV plasma concentrations (p < 0.001) compared to non 516T-allele carriers at all three time points. The minor allele frequencies (MAF) for CYP2B6 c.516T, c.785G, c.983C, and c.1459T were 0.410, 0.408, 0.110, and 0.000 respectively. Haplotypes were constructed using CYP2B6 c.516G>T,-c.785A>G and c.983T>C. The haplotype T-G-T presented with significantly increased EFV plasma concentrations compared to the reference G-A-T haplotype at 1, 3, and 24 months (p = 0.009; p = 0.003; p = 0.001), suggesting that the T-G-T haplotype predisposes a risk of EFV plasma concentrations >4 μg/mL. The clinical implications of these pharmacogenomics observations for EFV toxicity and treatment resistance warrant further future research.","variants":[{"Name":"NM_000767.5(CYP2B6):c.516G>T (p.Gln172His)","Chromosome":"19","Start":"41006936","Stop":"41006936","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":38626,"rule_based_match":true,"evidence_text":"CYP2B6 c.516G>T","llm_judgment":"PRESENT","evidence":"CYP2B6 c.516G>T","abstract_start":765,"abstract_end":780}]}
{"pmid":"37554704","title":"Molecular Detection of Hemoglobin O-Arab in the Sudanese Population.","abstract":"Background and Purpose: Sickle cell disease (SCD) is an inherited hemoglobin disease affecting the red cells and causing hemolytic anemia. It is a very common, endemic disease in Sudan, particularly in the central and western areas of Sudan. Sickle cell anemia (SCA) is when the patient has beta-globin gene variant (Hb S variant). In this study, we screened the co-inheritance of hemoglobin O-Arab mutation among Sudanese sickle cell disease patients.\nStudy Population and Methods: This cross-sectional study was conducted in the Sudan-Khartoum state from November 2016 to December 2021. Blood samples were collected from a random sample of the known sickle cell disease patients of Kordofan-central Sudan origin. Study-appropriate blood samples were subjected to complete blood count (CBC), hemoglobin capillary electrophoresis (CE) and molecular laboratory investigations. Initial laboratory investigations were done in Sudan, where the DNA sequencing technique was carried out at the Egyptian National Research Center (NRC)-Cairo-Egypt.\nResults: The final study's main results revealed the presence of HB O-Arab genetic mutations among Sudanese Sickle cell disease patients, which estimated to be (5%) co-inherited mutations among our study population (Hb-O Arab; (HBB):c.364G>A (p.Glu122Lys)).\nConclusion: The frequency of Hb-O Arab gene mutations was determined among Sudanese sickle cell disease patients, and the results have shown a (5%) frequency of Hb-O Arab mutation. The study result is the first molecular confirmation of co-inherited Hb-O Arab/sickle cell disease clinical condition in Sudan. The results raise the importance of extended studies of other sickle variant conditions.","variants":[{"Name":"NM_000518.4(HBB):c.364G>A (p.Glu122Lys)","Chromosome":"11","Start":"5225678","Stop":"5225678","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30331,"rule_based_match":true,"evidence_text":"(HBB):c.364G>A (p.Glu122Lys)","llm_judgment":"PRESENT","evidence":"(HBB):c.364G>A (p.Glu122Lys)","abstract_start":1268,"abstract_end":1296}]}
{"pmid":"30430035","title":"A Familial Case of Multicentric Carpotarsal Osteolysis Syndrome and Treatment Outcome.","abstract":"Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder caused by heterozygous mutations in the <i>MAFB</i> gene (v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B). This is an autosomal dominant condition with a high frequency of sporadic cases. MCTO is characterized by osteolysis of the carpal, metacarpal, and tarsal bones beginning in early childhood with musculoskeletal rheumatologic symptoms such as pain and disability. Renal involvement can be seen in more than half of the patients; from ages 16 months to 42 years and manifests from proteinuria to end-stage renal failure requiring renal transplantation. The association of <i>MAFB</i> gene mutations with this genetic condition has aided in understanding the pathophysiology of the disease. We report here a 7-year-old Caucasian boy and his 33-year-old mother diagnosed with MCTO, with the boy having concomitant juvenile idiopathic arthritis. He was initially diagnosed with arthritis at age 5 years based on bilateral wrist synovial swelling, morning stiffness, and weakness with family history of his mother being diagnosed with erosive psoriatic arthritis leading to limb deformities. Initial therapy for the boy included methotrexate and infliximab with moderate response. Later, during the course of his disease, he underwent a genetic evaluation at age 7 years for history of learning disabilities and dysmorphic features. Maternal evaluation and radiographic examination led to a clinical diagnosis of MCTO in the mother, and subsequent testing for <i>MAFB</i> gene in the son revealed a mutation at c.206C > T (p.Ser69Leu), the most commonly reported genetic change in MCTO. Nevertheless, further imaging still confirmed ongoing arthritis, and therapy was adjusted based on its progression including abatacept, tocilizumab, and pamidronate. Our report highlights the possibility of concomitant inflammatory arthropathy in MCTO.","variants":[{"Name":"NM_005461.5(MAFB):c.206C>T (p.Ser69Leu)","Chromosome":"20","Start":"40688645","Stop":"40688645","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":426334,"rule_based_match":true,"evidence_text":"c.206C > T (p.Ser69Leu)","llm_judgment":"PRESENT","evidence":"c.206C > T (p.Ser69Leu)","abstract_start":1603,"abstract_end":1626}]}
{"pmid":"24207119","title":"Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.","abstract":"\"Nagashima-type\" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK.","variants":[{"Name":"NM_003784.4(SERPINB7):c.796C>T (p.Arg266Ter)","Chromosome":"18","Start":"63804288","Stop":"63804288","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":108188,"rule_based_match":true,"evidence_text":"c.796C>T (p.Arg266(∗))","llm_judgment":"PRESENT","evidence":"c.796C>T (p.Arg266(∗))","abstract_start":669,"abstract_end":691}]}
{"pmid":"27426733","title":"Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.","abstract":"Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex.","variants":[{"Name":"NM_001292034.3(TAB2):c.1705G>A (p.Glu569Lys)","Chromosome":"6","Start":"149397705","Stop":"149397705","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":259298,"rule_based_match":true,"evidence_text":"c.1705G>A, p.Glu569Lys","llm_judgment":"PRESENT","evidence":"c.1705G>A, p.Glu569Lys","abstract_start":1218,"abstract_end":1240},{"Name":"NM_145331.3(MAP3K7):c.208G>C (p.Glu70Gln)","Chromosome":"6","Start":"90571720","Stop":"90571720","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":259291,"rule_based_match":true,"evidence_text":"c.208G>C [p.Glu70Gln]","llm_judgment":"PRESENT","evidence":"c.208G>C [p.Glu70Gln]","abstract_start":1010,"abstract_end":1031},{"Name":"NM_145331.3(MAP3K7):c.299T>A (p.Val100Glu)","Chromosome":"6","Start":"90561666","Stop":"90561666","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":259292,"rule_based_match":true,"evidence_text":"c.299T>A (p.Val100Glu)","llm_judgment":"PRESENT","evidence":"p.Val100Glu","abstract_start":1043,"abstract_end":1054},{"Name":"NM_145331.3(MAP3K7):c.502G>C (p.Gly168Arg)","Chromosome":"6","Start":"90556605","Stop":"90556605","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":259293,"rule_based_match":true,"evidence_text":"c.502G>C (p.Gly168Arg)","llm_judgment":"PRESENT","evidence":"p.Gly168Arg","abstract_start":1071,"abstract_end":1082}]}
{"pmid":"31368252","title":"Adams-Oliver syndrome caused by mutations of the EOGT gene.","abstract":"Adams-Oliver syndrome (AOS) is a rare congenital disease characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It shows significant genetic heterogeneity and can be transmitted by autosomal dominant or recessive inheritance. Recessive inheritance is associated with mutations of DOCK6 or EOGT; however, only few cases have been published so far. We present two families with EOGT-associated AOS. Due to pseudodominance in one family, the recognition of the recessive inheritance pattern was difficult. We identified two novel AOS-causing mutations (c.404G>A/p.Cys135Tyr and c.311+1G>T). The phenotype in the presented families was dominated by large ACC, whereas TTLD were mostly subtle or even absent and no major malformations occured. Our observations along with the previously published cases indicate that the two types of recessive AOS (EOGT- vs. DOCK6-associated) differ significanty regarding the frequency of neurologic or ocular deficits.","variants":[{"Name":"NM_001278689.2(EOGT):c.404G>A (p.Cys135Tyr)","Chromosome":"3","Start":"69007729","Stop":"69007729","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":514232,"rule_based_match":true,"evidence_text":"c.404G>A/p.Cys135Tyr","llm_judgment":"PRESENT","evidence":"c.404G>A/p.Cys135Tyr","abstract_start":587,"abstract_end":607},{"Name":"NM_001278689.2(EOGT):c.311+1G>T","Chromosome":"3","Start":"69008427","Stop":"69008427","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":514233,"rule_based_match":true,"evidence_text":"c.311+1G>T","llm_judgment":"PRESENT","evidence":"c.311+1G>T","abstract_start":612,"abstract_end":622}]}
{"pmid":"18055789","title":"A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews.","abstract":"PURPOSE: To investigate the genetic basis and clinical manifestations of a characteristic form of retinal degeneration in the Yemenite Jewish population.\nMETHODS: Haplotype analysis for all known genes and loci underlying autosomal recessive nonsyndromic retinal degeneration was performed in a Yemenite Jewish family segregating autosomal recessive severe retinal degeneration. The causative mutation was detected by direct sequencing of the underlying gene, and its prevalence in additional affected and unaffected Yemenite Jews was determined. Patients who were homozygous for this mutation underwent ophthalmic evaluation, including funduscopy, electroretinography, electro-oculography, perimetry, and color vision testing.\nRESULTS: In the studied Yemenite Jewish family, we found evidence for linkage to the CERKL gene. Direct sequencing revealed a novel homozygous splice-site mutation, c.238+1G>A. An in vitro splicing assay demonstrated that this mutation leads to incorrect splicing. c.238+1G>A was found to cause retinal degeneration in six additional Yemenite Jewish families. The carrier frequency of this mutation in the Yemenite Jewish population is 4.4%. All c.238+1G>A homozygotes manifest widespread progressive impairment of rod and cone function with early macular involvement.\nCONCLUSIONS: c.238+1G>A is the second reported mutation of CERKL and is a prevalent founder mutation that underlies approximately 33% of autosomal recessive retinal degeneration cases in the Yemenite Jewish population. It is associated with a characteristic retinal degeneration phenotype with early macular involvement, concomitant progression of rod and cone impairment, and characteristic fundus findings. The identification of this mutation and phenotype will facilitate molecular diagnosis, carrier screening, and genetic counseling in the Yemenite Jewish population.","variants":[{"Name":"NM_201548.5(CERKL):c.238+1G>A","Chromosome":"2","Start":"181656768","Stop":"181656768","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":800687,"rule_based_match":true,"evidence_text":"c.238+1G>A","llm_judgment":"PRESENT","evidence":"c.238+1G>A","abstract_start":893,"abstract_end":903}]}
{"pmid":"33570243","title":"Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene.","abstract":"BACKGROUND: Stickler syndrome (STL) is a clinically variable and genetically heterogeneous collagenopathy characterized by ophthalmic, auditory, skeletal, and orofacial abnormalities. STL is mainly inherited in an autosomal dominant pattern with mutations in the COL2A1, COL11A1, and COL11A2 genes. Autosomal recessive forms are rare. However, 19 patients have been reported to date, with STL caused by homozygous or compound heterozygous mutations in genes that encode for the three chains of type IX collagen: COL9A1, COL9A2, and COL9A3.\nMETHODS: Genetic analysis was performed using the next-generation sequencing of 166 genes associated with skeletal disorders and sequenced on an Ion Torrent S5 system with a minimum coverage of 100X. The two variants in the COL9A3 gene identified in the proband and the parents were confirmed by Sanger sequencing on an ABI3130xl sequencer.\nRESULTS: We describe a novel case of autosomal recessive Stickler syndrome caused by two undescribed mutations in the COL9A3 gene: c.268C>T (p.Arg90Ter) and c.1729C>T (p.Arg577Ter). The clinical features included severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs. Radiography revealed mild spondyloepiphyseal dysplasia.\nCONCLUSION: This case further expands the mutational and phenotypic spectrum of COL9A-associated STL with a more severe presentation.","variants":[{"Name":"NM_001853.4(COL9A3):c.268C>T (p.Arg90Ter)","Chromosome":"20","Start":"62819941","Stop":"62819941","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1675353,"rule_based_match":true,"evidence_text":"c.268C>T (p.Arg90Ter)","llm_judgment":"PRESENT","evidence":"c.268C>T (p.Arg90Ter)","abstract_start":1012,"abstract_end":1033},{"Name":"NM_001853.4(COL9A3):c.1729C>T (p.Arg577Ter)","Chromosome":"20","Start":"62837208","Stop":"62837208","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1675354,"rule_based_match":true,"evidence_text":"c.1729C>T (p.Arg577Ter)","llm_judgment":"PRESENT","evidence":"c.1729C>T (p.Arg577Ter)","abstract_start":1038,"abstract_end":1061}]}
{"pmid":"27942883","title":"Mutation screening of PLA2G6 in Japanese patients with early onset dystonia-parkinsonism.","abstract":"A recessive mutation in PLA2G6, which is known to cause infantile neuroaxonal dystrophy (INAD) and neurodegeneration associated with brain iron accumulation (NBIA), has recently been shown to be responsible for PARK14-linked dystonia-parkinsonism. To study the frequency of PLA2G6 mutations, including those caused by gene rearrangement in patients with parkinsonism, we performed direct sequencing and investigated copy number variations (CNVs) of this gene in 109 Japanese patients with parkinsonism. Direct sequencing revealed a homozygous mutation (c.1495G>A; p.A499T), which is likely to be pathogenic and is already registered as rs141045127, and two compound-heterozygous mutations we have previously reported. No CNVs in PLA2G6 were detected in our subjects. Our results suggest that CNV in PLA2G6 is rare in parkinsonism, at least in the Japanese population, in contrast to the reports of its frequency in INAD. Further large studies in various populations are warranted to elucidate what causes the difference in frequencies of PLA2G6 rearrangement mutations between INAD and dystonia-parkinsonism.","variants":[{"Name":"NM_003560.4(PLA2G6):c.1495G>A (p.Ala499Thr)","Chromosome":"22","Start":"38123191","Stop":"38123191","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":792068,"rule_based_match":true,"evidence_text":"c.1495G>A","llm_judgment":"PRESENT","evidence":"c.1495G>A","abstract_start":553,"abstract_end":562}]}
{"pmid":"34923715","title":"Novel biallelic mutations in SLC26A8 cause severe asthenozoospermia in humans owing to midpiece defects: Insights into a putative dominant genetic disease.","abstract":"To investigate the genetic cause of male infertility characterized by severe asthenozoospermia, two unrelated infertile men with severe asthenozoospermia from nonconsanguineous Chinese families were enrolled, and whole exome sequencing were performed to identify the potential pathogenic mutations. Novel compound heterozygous mutations (NK062 III-1: c.290T>C, p.Leu97Pro; c.1664delT, p.Ile555Thrfs*11/NK038 III-1: c.212G>T, p.Arg71Leu; c.290T>C, p.Leu97Pro) in SLC26A8 were identified. All mutations were inherited from their heterozygous parents and are predicted to be disease-causing by sorts intolerant from tolerant, PolyPhen-2, Mutation Taster, and Combined Annotation Dependent Depletion. In silico mutant SLC26A8 models predict that mutations p.Leu97Pro and p.Arg71Leu cause changes in the α-helix, which may result in functional defects in the protein. Notably, heterozygous male carriers of each mutation in both families were able to reproduce naturally, which is inconsistent with previous reports. Ultrastructural analysis revealed severe asthenozoospermia associated with absence of the mitochondrial sheath and annulus in spermatozoa from both the probands, and both structural defects were verified by HSP60 and SEPT4 immunofluorescence analysis. SLC26A8 levels were significantly reduced in spermatozoa from patients harboring biallelic SLC26A8 mutations, and both patients achieved good prognosis following intracytoplasmic sperm injection. Our findings indicate that mutations in SLC26A8 could manifest as a recessive genetic cause of severe asthenozoospermia and male infertility.","variants":[{"Name":"NM_052961.4(SLC26A8):c.290T>C (p.Leu97Pro)","Chromosome":"6","Start":"36012271","Stop":"36012271","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1679042,"rule_based_match":true,"evidence_text":"c.290T>C, p.Leu97Pro","llm_judgment":"PRESENT","evidence":"c.290T>C, p.Leu97Pro","abstract_start":351,"abstract_end":371},{"Name":"NM_052961.4(SLC26A8):c.1664del (p.Ile555fs)","Chromosome":"6","Start":"35959781","Stop":"35959781","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1679043,"rule_based_match":true,"evidence_text":"c.1664delT","llm_judgment":"PRESENT","evidence":"c.1664delT","abstract_start":373,"abstract_end":383},{"Name":"NM_052961.4(SLC26A8):c.212G>T (p.Arg71Leu)","Chromosome":"6","Start":"36012349","Stop":"36012349","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1679044,"rule_based_match":true,"evidence_text":"c.212G>T, p.Arg71Leu","llm_judgment":"PRESENT","evidence":"c.212G>T, p.Arg71Leu","abstract_start":415,"abstract_end":435}]}
{"pmid":"26304763","title":"Clinical and molecular genetic analysis of a family with late-onset LAMA2-related muscular dystrophy.","abstract":"PURPOSE: LAMA2-related muscular dystrophy (LAMA2 MD) is an autosomal recessive inherited disease caused by LAMA2 gene mutation. The spectrum of the phenotype is expanding in recent years partially due to the definitive diagnosis of molecular genetics. We investigated the phenotype and genotype in a LAMA2 MD family manifesting as limb-girdle muscular dystrophy (LGMD).\nMETHODS: The clinical information of the proband and his family was collected. Muscle biopsy and immunohistochemical staining for the muscle specimen were performed. The genomic DNA of the family was extracted from the peripheral blood, and genetic testing was analyzed using the next generation sequencing and multiplex ligation dependent probe amplification (MLPA). The point mutation was verified by Sanger sequencing while exonic deletion was verified by array comparative genomic hybridization.\nRESULTS: The patient had mild motor retardation when he was young, and no obvious weakness was reported. Muscle biopsy showed mild atrophy in histochemical staining. Immunohistochemical staining using antibody against merosin showed nearly normal expression surrounding the muscle fiber. The proband's sister had similar symptoms. By analyzing the gene test we found that compound heterozygous LAMA2 mutation inherited from the parents respectively. One coming from the father was a gross deletion expanding from exon 36 to exon 65. The other from the mother was a missense mutation c.1358G>C (p.Cys453Ser). Sanger sequencing verified the point mutation. Array comparative genomic hybridization confirmed a long stretch of deletion about 27.6-34.7 kb. The sister had the same mutations as the proband. We diagnosed the first late onset LAMA2 MD Chinese patients on molecular level and genetic counseling is available.\nCONCLUSION: We investigated the phenotype and genotype in a family manifesting as limb-girdle muscular dystrophy (LGMD). This LAMA2 MD family manifesting as LGMD was identified in molecular genetic level and their phenotypes was described.","variants":[{"Name":"NM_000426.4(LAMA2):c.1358G>C (p.Cys453Ser)","Chromosome":"6","Start":"129177757","Stop":"129177757","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":543501,"rule_based_match":true,"evidence_text":"c.1358G>C (p.Cys453Ser)","llm_judgment":"PRESENT","evidence":"c.1358G>C (p.Cys453Ser)","abstract_start":1453,"abstract_end":1476}]}
{"pmid":"19158808","title":"Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.","abstract":"Vanishing white matter (VWM) disease, inherited in an autosomal recessive manner, is one of the most prevalent inherited leukoencephalopathies in childhood. It is a hereditary human disease resulting from the direct defects during protein synthesis, with the gene defects in EIF2B1-5 (identified in 2001-2002) encoding the five subunits of eukaryotic translation initiation factor (eIF2B alpha, beta, gamma, delta and epsilon), respectively. Most of the published studies were carried out in the white population. The analysis of clinical features and EIF2B mutation screening were performed in 11 Chinese patients for the first time. Mutations were identified exclusively in EIF2B5 and EIF2B3 in these patients, with six novel mutations, including five missense mutations (EIF2B5: c.185A>T, p.D62V; c.1004G>C, p.C335S; c.1126A>G, p.N376D; EIF2B3: c.140G>A, p.G47E; c.1037T>C, p.I346T) and one deletion leading to amino-acid deletion (EIF2B5: c.1827-1838del, p.S610-D613del). EIF2B3 mutation, accounting for 20% of the total number of mutations found in this study, is more prevalent than expected according to an earlier report (7%). A hot spot mutation in EIF2B3 was identified in this study. A unique EIF2B mutation spectrum in Chinese VWM patients was shown. A systemic study to assess mutation spectrum in different populations needs to be carried out.","variants":[{"Name":"NM_020365.5(EIF2B3):c.1037T>C (p.Ile346Thr)","Chromosome":"1","Start":"44875634","Stop":"44875634","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19479,"rule_based_match":true,"evidence_text":"c.1037T>C","llm_judgment":"PRESENT","evidence":"c.1037T>C","abstract_start":866,"abstract_end":875}]}
{"pmid":"30423442","title":"A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22).","abstract":"Joubert syndrome (JS) is an autosomal or X-linked recessive syndrome principally characterized by hypotonia, ataxia, cognitive impairment, and a specific finding on brain imaging called a \"molar tooth sign\" (MTS), which can be isolated or in conjunction with variable organ involvement. The genetic basis of JS is heterogeneous, with over 35 ciliary genes being implicated in its pathogenesis. However, some of these genes (such as PDE6D) have been associated to JS only in single families, seeking confirmation. Here we report a boy, born to first cousin parents, presenting with developmental delay, hypotonia, microcephaly, post axial polydactyly, oculomotor apraxia, and MTS. Whole exome sequencing revealed the presence of a novel homozygous truncating variant in the PDE6D gene: NM_002601.3:c.367_368insG [p.(Leu123Cysfs*13)]. The variant was confirmed by Sanger sequencing and found at the heterozygous state in both parents. A review of the literature pertaining to the role of PDE6D in JS is discussed.","variants":[{"Name":"NM_002601.4(PDE6D):c.367_368insG (p.Leu123fs)","Chromosome":"2","Start":"231737190","Stop":"231737191","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":581741,"rule_based_match":true,"evidence_text":"NM_002601.3:c.367_368insG [p.(Leu123Cysfs*13)]","llm_judgment":"PRESENT","evidence":"NM_002601.3:c.367_368insG [p.(Leu123Cysfs*13)]","abstract_start":785,"abstract_end":831}]}
{"pmid":"28417072","title":"Atypical juvenile presentation of G","abstract":"G<sub>M2</sub>-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the <i>GM2A</i> gene that encodes G<sub>M2</sub> ganglioside activator protein (GM2AP). GM2AP is necessary for solubilisation of G<sub>M2</sub> ganglioside in endolysosomes and its presentation to β-hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of G<sub>M2</sub> ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of G<sub>M2</sub>-gangliosidosis AB. At the age of 3 years he presented with global developmental delay, progressive epilepsy, intellectual disability, axial hypertonia, spasticity, seizures and ataxia, but without the macular cherry-red spots typical for G<sub>M2</sub> gangliosidosis. Brain MRI detected a rapid onset of diffuse atrophy, whereas whole exome sequencing showed that the patient is a compound heterozygote for two mutations in <i>GM2A</i>: a novel nonsense mutation, c.259G > T (p.E87X) and a missense mutation c.164C > T (p.P55L) that was recently identified in homozygosity in patients of a Saudi family with a progressive chorea-dementia syndrome. Western blot analysis showed an absence of GM2AP in cultured fibroblasts from the patient, suggesting that both mutations interfere with the synthesis and/or folding of the protein. Finally, impaired catabolism of G<sub>M2</sub> ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled G<sub>M1</sub> ganglioside and by immunohistochemistry with anti-G<sub>M2</sub> and anti-G<sub>M3</sub> antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to G<sub>M2</sub>-gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps ganglioside analysis in cultured patient's cells.","variants":[{"Name":"NM_000405.5(GM2A):c.164C>T (p.Pro55Leu)","Chromosome":"5","Start":"151259837","Stop":"151259837","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":181419,"rule_based_match":true,"evidence_text":"c.164C > T (p.P55L)","llm_judgment":"PRESENT","evidence":"c.164C > T (p.P55L)","abstract_start":1073,"abstract_end":1092}]}
{"pmid":"18411254","title":"The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity.","abstract":"Roberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth capacity, and hypersensitivity to DNA damaging agents. RBS is caused by mutations in ESCO2, which encodes a protein belonging to the highly conserved Eco1/Ctf7 family of acetyltransferases that is involved in regulating sister chromatid cohesion. We identified 10 new mutations expanding the number to 26 known ESCO2 mutations. We observed that these mutations result in complete or partial loss of the acetyltransferase domain except for the only missense mutation that occurs in this domain (c.1615T>G, W539G). To investigate the mechanism underlying RBS, we analyzed ESCO2 mutations for their effect on enzymatic activity and cellular phenotype. We found that ESCO2 W539G results in loss of autoacetyltransferase activity. The cellular phenotype produced by this mutation causes cohesion defects, proliferation capacity reduction and mitomycin C sensitivity equivalent to those produced by frameshift and nonsense mutations associated with decreased levels of mRNA and absence of protein. We found decreased proliferation capacity in RBS cell lines associated with cell death, but not with increased cell cycle duration, which could be a factor in the development of phocomelia and cleft palate in RBS. In summary, we provide the first evidence that loss of acetyltransferase activity contributes to the pathogenesis of RBS, underscoring the essential role of the enzymatic activity of the Eco1p family of proteins.","variants":[{"Name":"NM_001017420.3(ESCO2):c.1615T>G (p.Trp539Gly)","Chromosome":"8","Start":"27799658","Stop":"27799658","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":16774,"rule_based_match":true,"evidence_text":"c.1615T>G, W539G","llm_judgment":"PRESENT","evidence":"c.1615T>G, W539G","abstract_start":794,"abstract_end":810}]}
{"pmid":"23531866","title":"Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans.","abstract":"Congenital cataracts are an important cause of bilateral visual impairment in infants. Through genome-wide linkage analysis in a four-generation family of Irish descent, the disease-associated gene causing autosomal-dominant congenital nuclear cataract was mapped to chromosome 4p16.1. The maximum logarithm of odds (LOD) score was 2.62 at a recombination fraction θ=0, obtained for marker D4S432 physically close to the Wolfram gene (WFS1). By sequencing the coding regions and intron-exon boundaries of WFS1, we identified a DNA substitution (c.1385A-to-G) in exon 8, causing a missense mutation at codon 462 (E462G) of the Wolframin protein. This is the first report of a mutation in this gene causing an isolated nuclear congenital cataract. These findings suggest that the membrane trafficking protein Wolframin may be important for supporting the developing lens.","variants":[{"Name":"NM_006005.3(WFS1):c.1385A>G (p.Glu462Gly)","Chromosome":"4","Start":"6301180","Stop":"6301180","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":98163,"rule_based_match":false,"evidence_text":"c.1385A-to-G","llm_judgment":"PRESENT","evidence":"c.1385A-to-G","abstract_start":545,"abstract_end":557}]}
{"pmid":"36657711","title":"VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.","abstract":"Dilated cardiomyopathy (DCM), characteristic of left ventricular or biventricular dilation with systolic dysfunction, is the most common form of cardiomyopathy, and a leading cause of heart failure and sudden cardiac death. Aggregating evidence highlights the underlying genetic basis of DCM, and mutations in over 100 genes have been causally linked to DCM. Nevertheless, due to pronounced genetic heterogeneity, the genetic defects underpinning DCM in most cases remain obscure. Hence, this study was sought to identify novel genetic determinants of DCM. In this investigation, whole-exome sequencing and bioinformatics analyses were conducted in a family suffering from DCM, and a novel heterozygous mutation in the VEZF1 gene (coding for a zinc finger-containing transcription factor critical for cardiovascular development and structural remodeling), NM_007146.3: c.490A > T; p.(Lys164*), was identified. The nonsense mutation was validated by Sanger sequencing and segregated with autosome-dominant DCM in the family with complete penetrance. The mutation was neither detected in another cohort of 200 unrelated DCM patients nor observed in 400 unrelated healthy individuals nor retrieved in the Single Nucleotide Polymorphism database, the Human Gene Mutation Database and the Genome Aggregation Database. Biological analyses by utilizing a dual-luciferase reporter assay system revealed that the mutant VEZF1 protein failed to transactivate the promoters of MYH7 and ET1, two genes that have been associated with DCM. The findings indicate VEZF1 as a new gene responsible for DCM, which provides novel insight into the molecular pathogenesis of DCM, implying potential implications for personalized precisive medical management of the patients affected with DCM.","variants":[{"Name":"NM_007146.3(VEZF1):c.490A>T (p.Lys164Ter)","Chromosome":"17","Start":"57982937","Stop":"57982937","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":2417607,"rule_based_match":true,"evidence_text":"NM_007146.3: c.490A > T; p.(Lys164*)","llm_judgment":"PRESENT","evidence":"NM_007146.3: c.490A > T; p.(Lys164*)","abstract_start":856,"abstract_end":892}]}
{"pmid":"25187895","title":"Large deletion in KCNQ1 identified in a family with Jervell and Lange-Nielsen syndrome.","abstract":"Long QT syndrome (LQTS) is a genetically heterogeneous disorder associated with sequence variations in more than 10 genes; in some cases, it is caused by large deletions or duplications among the main, known LQTS-associated genes. Here, we describe a 14-month-old Korean boy with congenital hearing loss and prolonged QT interval whose condition was clinically diagnosed as Jervell and Lange-Nielsen syndrome (JLNS), a recessive form of LQTS. Genetic analyses using sequence analysis and multiplex ligation-dependent probe amplification (MLPA) assay revealed a large deletion spanning exons 7-10 as well as a frameshift mutation (c.1893dup; p.Arg632Glnfs*20). To our knowledge, this is the first report of a large deletion in KCNQ1 identified in JLNS patients. This case indicates that a method such as MLPA, which can identify large deletions or duplications needs to be considered in addition to sequence analysis to diagnose JLNS.","variants":[{"Name":"NM_000218.3(KCNQ1):c.1893dup (p.Arg632fs)","Chromosome":"11","Start":"2847858","Stop":"2847859","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":67695,"rule_based_match":true,"evidence_text":"c.1893dup","llm_judgment":"PRESENT","evidence":"c.1893dup","abstract_start":630,"abstract_end":639}]}
{"pmid":"23361109","title":"Impaired CFTR function in mild cystic fibrosis associated with the S977F/T5TG12complex allele in trans with F508del mutation.","abstract":"BACKGROUND: The S977F mutation (c.2930C>T) in the CFTR gene (CFTR/ABCC7) is extremely rare. We describe the case of an adult patient carrying the complex allele S977F/T5TG12 in trans with the F508del mutation. Mild respiratory manifestations arose in adulthood associated with azoospermia, acute pancreatitis, minor hemoptysis and Cl(-) levels ranging from 40 to 42 mEq/L.\nMETHOD: Diagnosis was confirmed by repeated NPD measurements, genetic DHPLC analysis and a recently described functional assay measuring cAMP-dependent cell depolarization in peripheral blood monocytes.\nRESULTS: NPD measurements, DHPLC and monocyte functional assay (CF index=-18). Results were consistent with a CF phenotype.\nCONCLUSIONS: The combined application of DHPLC and NPD analysis in the algorithm for CF diagnosis appears useful for the management of similar cases. In addition, the novel monocyte functional assay might contribute to improve our diagnostic capability, counseling and better treatment of these challenging clinical cases.","variants":[{"Name":"NM_000492.4(CFTR):c.2930C>T (p.Ser977Phe)","Chromosome":"7","Start":"117606695","Stop":"117606695","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":68269,"rule_based_match":true,"evidence_text":"c.2930C>T","llm_judgment":"PRESENT","evidence":"c.2930C>T","abstract_start":32,"abstract_end":41}]}
{"pmid":"27455001","title":"Analysis of a cerebrotendinous xanthomatosis case with mental retardation as the initial symptom","abstract":"OBJECTIVE: To analyze a case of cerebrotendinous xanthomatosis (CTX) with mental retardation as the initial neurological symptom.\nMETHODS: Medical imaging, histopathological assay and genetic testing were carried out to analyze the patient.\nRESULTS: Neurological manifestations of the 27-year-old male patient were initiated by mental retardation and subsequently memory lapses, ataxia, spastic paraplegia and fuzzy language. Other symptoms included cataract, xanthomatosis in Achilles tendon, kidney stones and high arches. The total bile acid in serum has risen to 14.7 umol/L. There were symmetrical abnormal signals in bilateral cerebellar dentate nuclei, hypointensities on T1WI and DWI and mixed signals on T2WI. Cholesterol crystallization and cholesterol granulomatous inflammation were found upon pathological examination of the Achilles tendon. The patient was found to have carried a compound heterozygous mutation of the CTX gene, which consisted of two novel mutations including c.379C>T (p.Arg127Trp) in exon 2 and c.1174G>A (p.Glu392Lys) in exon 6 of the CYP27A1 gene.\nCONCLUSION: Clinicians should be alert to cerebrotendinous xanthomatosis when the patient has mental retardation caused by genetic and metabolic factors beginning at a young age, particularly accompanied with tendinous xanthomatosis and cataracts. CTX can be readily diagnosed by histopathological assay and sequencing of the CYP27A1 gene.","variants":[{"Name":"NM_000784.4(CYP27A1):c.379C>T (p.Arg127Trp)","Chromosome":"2","Start":"218809700","Stop":"218809700","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":76773,"rule_based_match":true,"evidence_text":"c.379C>T (p.Arg127Trp)","llm_judgment":"PRESENT","evidence":"c.379C>T (p.Arg127Trp)","abstract_start":992,"abstract_end":1014}]}
{"pmid":"29178655","title":"RYR1 causing distal myopathy.","abstract":"BACKGROUND: Congenital myopathies due to ryanodine receptor (RYR1) mutations are increasingly identified and correlate with a wide range of phenotypes, most commonly that of malignant hyperthermia susceptibility and central cores on muscle biopsy with rare reports of distal muscle weakness, but in the setting of early onset global weakness.\nMETHODS: We report a case of a patient presenting with childhood onset hand stiffness and adult onset progressive hand weakness and jaw contractures discovered to have two variants in the RYR1 gene.\nRESULTS: The patient manifested with distal upper limb weakness which progressed to involve the distal lower limb, proximal upper limb, as well as the face in addition to limited jaw opening. Creatine kinase was mildly elevated with EMG findings supporting a myopathy. Muscle biopsy showed features consistent with centronuclear myopathy. Whole exome sequencing revealed a novel heterozygous pathogenic variant in RYR1 (c.12315_12328delAGAAATCCAGTTCC, p.Glu4106Alafs*8), and a heterozygous missense variant (c.10648C>T, p.Arg3550Trp) of unknown significance in compound heterozygous state.\nCONCLUSION: We expand the spectrum of RYR1-related myopathy with the description of a novel phenotype in an adult patient presenting with hand weakness and suggest considering RYR1 analysis in the diagnosis of distal myopathies.","variants":[{"Name":"NM_000540.3(RYR1):c.10648C>T (p.Arg3550Trp)","Chromosome":"19","Start":"38527014","Stop":"38527014","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":265716,"rule_based_match":true,"evidence_text":"c.10648C>T (p.Arg3550Trp)","llm_judgment":"PRESENT","evidence":"p.Arg3550Trp","abstract_start":1062,"abstract_end":1074}]}
{"pmid":"29362677","title":"Frequency of c.35delG Mutation in","abstract":"BACKGROUND: Hearing impairments (HI) are the most common birth defect worldwide. Very large numbers of genes have been identified but the most profound is <i>GJB2</i>. The clinical interest regarding this gene is very pronounced due to its high carrier frequency (0.5-5.4%) across different ethnic groups. This study aimed to determine the prevalence of common <i>GJB2</i> mutations in Syrian patients with profound sensorineural HI.\nMETHODS: We carried out PCR, restriction enzyme based screening, and sequencing of 132 Syrian patients diagnosed clinically with hereditary deafness for different <i>GJB2</i> mutations.\nRESULTS: The result revealed that, in <i>GJB2</i> gene, c.35delG is the most prevalent among affected studied subjects (13.64%), followed by c.457G>A (2.4%).\nCONCLUSION: The benefit of this study on the one hand is its first report of prelingual deafness causative gene mutations identified by sequencing technology in the Syrian families. It is obvious from the results that the deployment in biomedical research is highly effective and has a great impact on the ability to uncover the cause of genetic variation in different genetic diseases.","variants":[{"Name":"NM_004004.6(GJB2):c.35del (p.Gly12fs)","Chromosome":"13","Start":"20189547","Stop":"20189547","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":32043,"rule_based_match":true,"evidence_text":"c.35delG","llm_judgment":"PRESENT","evidence":"c.35delG","abstract_start":676,"abstract_end":684}]}
{"pmid":"15746149","title":"A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor.","abstract":"The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C>T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.","variants":[{"Name":"NM_005765.3(ATP6AP2):c.321C>T (p.Asp107=)","Chromosome":"X","Start":"40597269","Stop":"40597269","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25840,"rule_based_match":true,"evidence_text":"c.321C>T (p.D107D)","llm_judgment":"PRESENT","evidence":"c.321C>T","abstract_start":470,"abstract_end":478}]}
{"pmid":"22154821","title":"Exome sequencing reveals SPG11 mutations causing juvenile ALS.","abstract":"We report here the description of a nonconsanguineous family with 2 affected individuals with a recessively inherited juvenile motor neuron disease. Exome sequencing of these 2 affected individuals led us to identify 2 compound heterozygous deletions leading to a frameshift and a premature stop codon in the SPG11 gene. One of these deletions, c.5199delA in exon 30, has not been previously reported. Interestingly, these deletions are associated with an intrafamilial phenotypic heterogeneity as one affected has atypical juvenile amyotrophic lateral sclerosis (ALS) and the other has classical hereditary spastic paraplegia with thin corpus callosum. Our findings confirm SPG11 as a genetic cause of juvenile amyotrophic lateral sclerosis and indicate that SPG11 mutations could be associated with 2 different clinical phenotypes within the same family.","variants":[{"Name":"NM_025137.4(SPG11):c.5199del (p.Lys1733fs)","Chromosome":"15","Start":"44584481","Stop":"44584481","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":792796,"rule_based_match":true,"evidence_text":"c.5199delA in exon 30","llm_judgment":"PRESENT","evidence":"c.5199delA in exon 30","abstract_start":345,"abstract_end":366}]}
{"pmid":"34789173","title":"Prenatal diagnosis of auriculocondylar syndrome with a novel missense variant of GNAI3: a case report.","abstract":"BACKGROUND: Auriculocondylar syndrome (ACS) is a rare disorder characterized by micrognathia, mandibular condyle hypoplasia, and auricular abnormalities. Only 6 pathogenic variants of GNAI3 have been identified associated with ACS so far. Here, we report a case of prenatal genetic diagnosis of ACS carrying a novel GNAI3 variant.\nCASE PRESENTATION: A woman with 30 weeks of gestation was referred to genetic counseling for polyhydramnios and fetal craniofacial anomaly. Severe micrognathia and mandibular hypoplasia were identified on ultrasonography. The mandibular length was 2.4 cm, which was markedly smaller than the 95th percentile. The ears were low-set with no cleft or notching between the lobe and helix. The face was round with prominent cheeks. Whole-exome sequencing identified a novel de novo missense variant of c.140G > A in the GNAI3 gene. This mutation caused an amino acid substitution of p.Ser47Asn in the highly conserved G1 motif, which was predicted to impair the guanine nucleotide-binding function. All ACS cases with GNAI3 mutations were literature reviewed, revealing female-dominated severe cases and right-side-prone deformities.\nCONCLUSION: Severe micrognathia and mandibular hypoplasia accompanied by polyhydramnios are prenatal indicators of ACS. We expanded the mutation spectrum of GNAI3 and summarized clinical features to promote awareness of ACS.","variants":[{"Name":"NM_006496.4(GNAI3):c.140G>A (p.Ser47Asn)","Chromosome":"1","Start":"109573758","Stop":"109573758","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":442576,"rule_based_match":true,"evidence_text":"c.140G > A","llm_judgment":"PRESENT","evidence":"c.140G > A","abstract_start":828,"abstract_end":838}]}
{"pmid":"26182283","title":"A young boy with elevated aminotransferases in physical examination--Two novel missense mutations associated with Wilson's disease were found","abstract":"A 3-year-old boy had abnormal liver function, which was found in physical examination, for 5 months before admission. He had no symptoms such as anorexia, poor appetite, and jaundice, had normal growth and development, and showed no hepatosplenomegaly. Laboratory examination revealed significantly reduced ceruloplasmin (35 mg/L), as well as negative hepatotropic virus, cytomegalovirus, and Epstein-Barr virus. There were normal muscle enzymes, blood glucose, and blood ammonia and negative liver-specific autoantibodies. The boy had negative K-F ring and normal 24-hour urine copper (0.56 μmol/L). The ATP7B gene testing for the boy, his sister, and their parents detected two novel missense mutations in the boy and his sister, i.e., compound heterozygous mutations in exon 7 (c.2075T>C, p.L692P) and exon 13 (c.3044T>C, p.L1015P), which were inherited from their father and mother, respectively. Wilson's disease was confirmed by genetic diagnosis in the boy and his sister. The boy and his sister were given a low-copper diet. The boy was administered with penicillamine for decoppering and zinc supplement against copper uptake. His sister received zinc supplement alone because no clinical symptoms were observed. The boy showed normal liver function in the reexamination after 3 months of treatment.","variants":[{"Name":"NM_000053.4(ATP7B):c.2075T>C (p.Leu692Pro)","Chromosome":"13","Start":"51960194","Stop":"51960194","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3525948,"rule_based_match":true,"evidence_text":"c.2075T>C","llm_judgment":"PRESENT","evidence":"c.2075T>C","abstract_start":781,"abstract_end":790}]}
{"pmid":"30585608","title":"Coincidence of hereditary motor and sensory neuropathy type 1A and limb girdle muscular dystrophy type 2A","abstract":"A rare case of two neuromuscular disorders in a 29-year-old female is presented: autosomal dominant hereditary motor and sensory neuropathy type 1A (HMSN1A) due to PMP22 duplication and autosomal recessive limb girdle muscular dystrophy type 2A (LGMD2A) produced by CAPN3 common mutation c.550delA and novel c.575C>G (p.Thr192Ser).Walking difficulties appeared in 27 years, the patient had signs of both disorders, more of LGMD, but was not disabled. HMSN1A was inherited from her father whose disease was not recognized earlier.","variants":[{"Name":"NM_000070.3(CAPN3):c.575C>G (p.Thr192Ser)","Chromosome":"15","Start":"42387829","Stop":"42387829","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2742260,"rule_based_match":true,"evidence_text":"c.575C>G (p.Thr192Ser)","llm_judgment":"PRESENT","evidence":"c.575C>G (p.Thr192Ser)","abstract_start":308,"abstract_end":330}]}
{"pmid":"27374774","title":"Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype.","abstract":"Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs(∗)2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.","variants":[{"Name":"NM_018480.7(TMEM126B):c.401del (p.Asn134fs)","Chromosome":"11","Start":"85635669","Stop":"85635669","ReferenceAlleleVCF":"TA","AlternateAlleleVCF":"T","allel_id":237763,"rule_based_match":true,"evidence_text":"c.401delA [p.Asn134Ilefs(∗)2]","llm_judgment":"PRESENT","evidence":"c.401delA [p.Asn134Ilefs(∗)2]","abstract_start":1073,"abstract_end":1102},{"Name":"NM_018480.7(TMEM126B):c.635G>T (p.Gly212Val)","Chromosome":"11","Start":"85636171","Stop":"85636171","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":237764,"rule_based_match":true,"evidence_text":"c.635G>T [p.Gly212Val]","llm_judgment":"PRESENT","evidence":"c.635G>T [p.Gly212Val]","abstract_start":1043,"abstract_end":1065}]}
{"pmid":"28236585","title":"The importance of genetic counseling and genetic screening: a case report of a 16-year-old boy with resistant hypertension and severe hypokalemia.","abstract":"Liddle's syndrome, an autosomal dominant form of monogenic hypertension, is characterized by salt-sensitive hypertension with early penetrance, hypokalemia, metabolic alkalosis, suppression of plasma rennin activity and aldosterone secretion, and a clear-cut response to epithelial sodium channel blockers but not spironolactone therapy. Here, we describe the case of a 16-year-old boy patient with resistant hypertension (maintain 170-180/100-110 mm Hg after administration four kinds of antiypertensive drugs) and severe hypokalemia. After a series of checks, we exclude primary aldosteronism and renal artery stenosis and other diseases. Finally, the Liddle syndrome was diagnosed because of the DNA sequencing found that the proband's mother and himself had mutations P616L (c.1847 C>T) in the SCNN1B gene. Liddle syndrome should be considered as a cause of hypertension in children or adolescents particularly with suppressed renin activity. Early diagnosis and appropriately tailored treatment avoid complications of long-term unrecognized or inappropriately managed hypertension. Genetic testing has made it possible to make accurate diagnoses and develop tailored therapies for mutation carriers. The role of genetic testing and genetic counseling in establishing the early diagnosis of Liddle's syndrome is important.","variants":[{"Name":"NM_000336.3(SCNN1B):c.1847C>T (p.Pro616Leu)","Chromosome":"16","Start":"23380725","Stop":"23380725","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23870,"rule_based_match":true,"evidence_text":"c.1847 C>T","llm_judgment":"PRESENT","evidence":"c.1847 C>T","abstract_start":779,"abstract_end":789}]}
{"pmid":"27507644","title":"In silico analysis of novel mutations in maple syrup urine disease patients from Iran.","abstract":"Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by mutations either in the BCKDHA, BCKDHB, DBT or DLD genes encoding components of the E1α, E1β, E2 and E3 subunits of branched-chain α-keto acid dehydrogenase complex (BCKDC), respectively. BCKDC is a mitochondrial enzyme which is responsible for the normal breakdown of BCAA. The rate of consanguineous marriage in Iran is 38.6 %, so the prevalence of autosomal recessive disorders is higher in comparison to other countries. Consanguinity increases the chance of the presence of pathogenic mutations in a homoallelic state. This phenomenon has made homozygosity mapping a powerful tool for finding the probable causative gene in heterogeneous disorders like IEM (Inborn Errors of Metabolism). In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above-mentioned genes were selected to identify the probable pathogenic gene in the studied families. The families who showed a homozygous haplotype for the STR markers of the BCKDHB gene were subsequently sequenced. Four novel mutations including c.633 + 1G > A, c.988G > A, c.833_834insCAC, and a homozygous deletion of whole exon 3 c. (274 + 1_275-1) _(343 + 1_344-1), as well as one recently reported (c. 508G > T) mutation have been identified. Interestingly, three families shared a common haplotype structure along with the c. 508G > T mutation. Also, four other families revealed another similar haplotype with c.988G > A mutation. Founder effect can be a suggestive mechanism for the disease. Additionally, structural models of MSUD mutations have been performed to predict the pathogenesis of the newly identified variants.","variants":[{"Name":"NM_183050.4(BCKDHB):c.988G>A (p.Glu330Lys)","Chromosome":"6","Start":"80273171","Stop":"80273171","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":544274,"rule_based_match":true,"evidence_text":"c.988G>A","llm_judgment":"PRESENT","evidence":"c.988G > A","abstract_start":1206,"abstract_end":1216},{"Name":"NM_183050.4(BCKDHB):c.633+1G>A","Chromosome":"6","Start":"80169031","Stop":"80169031","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":102495,"rule_based_match":true,"evidence_text":"c.633 + 1G > A","llm_judgment":"PRESENT","evidence":"c.633 + 1G > A","abstract_start":1190,"abstract_end":1204}]}
{"pmid":"34786177","title":"Acute liver failure with hemolytic anemia in children with Wilson's disease: Genotype-phenotype correlations?","abstract":"BACKGROUND: Wilson's disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism. Acute liver failure (ALF) and hemolytic anemia represent the most severe presentation of WD in children. No clear genotype-phenotype correlations exist in WD. Protein-truncating nonsense, frame-shift, or splice-site variants may be associated with more severe disease. In contrast, missense variants may be associated with late-onset, less severe disease, and more neurological manifestations. Recently, a gene variant (HSD17B13:TA, rs72613567) with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.\nAIM: To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.\nMETHODS: The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed. The clinical manifestations (ALF with non-immune hemolytic anemia or other less severe forms), laboratory parameters, copper metabolism, <i>ATP7B</i> variants, and the HSD17B13:TA (rs72613567) variant were reviewed to analyze the possible genotype-phenotype correlations.\nRESULTS: We analyzed the data of 51 patients with WD, 26 females (50.98%), with the mean age at the diagnosis of 12.36 ± 3.74 years. ALF and Coombs-negative hemolytic anemia was present in 8 children (15.67%), all adolescent girls. The Kayser-Fleisher ring was present in 9 children (17.65%). The most frequent variants of the <i>ATP7B</i> gene were p.His1069Gln (c.3207A>G) in 38.24% of all alleles, p.Gly1341Asp (c.4021G>A) in 26.47%, p.Trp939Cys (c.2817G>T) in 9.80%, and p.Lys844Ter (c.2530A>T) in 4.90%. In ALF with hemolytic anemia, p.Trp939Cys (c.2817G>T) and p.Lys844Ter (c.2530A>T) variants were more frequent than in other less severe forms, in which p.His1069Gln (c.3207A>G) was more frequent. p.Gly1341Asp (c.4021G>A) has a similar frequency in all hepatic forms. For 33 of the patients, the HSD17B13 genotype was evaluated. The overall HSD17B13:TA allele frequency was 24.24%. Its frequency was higher in patients with less severe liver disease (26.92%) than those with ALF and hemolytic anemia (14.28%).\nCONCLUSION: It remains challenging to prove a genotype-phenotype correlation in WD patients. In children with ALF and hemolytic anemia, the missense variants other than p.His1069Gln (c.3207A>G) and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants. As genetic analysis is usually time-consuming and the results are late, the importance at the onset of the ALF is questionable. If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease, this could be essential to predict a possible severe evolution.","variants":[{"Name":"NM_000053.4(ATP7B):c.2817G>T (p.Trp939Cys)","Chromosome":"13","Start":"51949710","Stop":"51949710","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":358224,"rule_based_match":true,"evidence_text":"c.2817G>T","llm_judgment":"PRESENT","evidence":"c.2817G>T","abstract_start":1672,"abstract_end":1681}]}
{"pmid":"28790152","title":"","abstract":"BACKGROUND: Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the <i>LMNA</i> c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies.\nMETHODS AND RESULTS: Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other <i>LMNA</i> mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic <i>LMNA</i> mutations. A shared haplotype of 1 Mb around <i>LMNA</i> suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear <i>LMNA</i>-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy.\nCONCLUSIONS: Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other <i>LMNA</i> mutations but with a more benign course.","variants":[{"Name":"NM_170707.4(LMNA):c.992G>A (p.Arg331Gln)","Chromosome":"1","Start":"156135956","Stop":"156135956","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":57262,"rule_based_match":true,"evidence_text":"LMNA c.992G>A (p.(Arg331Gln))","llm_judgment":"PRESENT","evidence":"LMNA</i> c.992G>A (p.(Arg331Gln))","abstract_start":170,"abstract_end":203}]}
{"pmid":"37924809","title":"RAB1A haploinsufficiency phenocopies the 2p14-p15 microdeletion and is associated with impaired neuronal differentiation.","abstract":"Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C>T [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and a mosaic missense mutation (c.83T>C [p.Leu28Pro]), were identified in three individuals with similar neurodevelopmental presentations. In rescue experiments, production of the full-length, but not the truncated, RAB1a rescued Golgi structure and cell proliferation in Rab1-depleted cells. In contrast, the missense-variant RAB1a disrupted Golgi structure despite intact Rab1 expression, suggesting a dominant-negative function of the mosaic missense mutation. Knock-down of RAB1A in cultured human embryonic stem cell-derived neurons resulted in impaired neuronal arborization. Finally, RAB1A is located within the 2p14-p15 microdeletion syndrome locus. The similar clinical presentations of individuals with RAB1A loss-of-function mutations and the 2p14-p15 microdeletion syndrome implicate loss of RAB1A in the pathogenesis of neurodevelopmental manifestations of this microdeletion syndrome. Our study identifies a RAB1A-related neurocognitive disorder with speech and motor delay, demonstrates an essential role for RAB1a in neuronal differentiation, and implicates RAB1A in the etiology of the neurodevelopmental sequelae associated with the 2p14-p15 microdeletion syndrome.","variants":[{"Name":"NM_004161.5(RAB1A):c.523C>T (p.Arg175Ter)","Chromosome":"2","Start":"65088588","Stop":"65088588","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3806232,"rule_based_match":true,"evidence_text":"c.523C>T (p.Arg175Ter)","llm_judgment":"PRESENT","evidence":"p.Arg175Ter","abstract_start":422,"abstract_end":433}]}
{"pmid":"28434495","title":"Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy.","abstract":"Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options.","variants":[{"Name":"NM_001080397.3(SLC45A1):c.629C>T (p.Ala210Val)","Chromosome":"1","Start":"8325956","Stop":"8325956","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":420284,"rule_based_match":true,"evidence_text":"c.629C>T [p.Ala210Val]","llm_judgment":"PRESENT","evidence":"c.629C>T [p.Ala210Val]","abstract_start":390,"abstract_end":412},{"Name":"NM_001080397.3(SLC45A1):c.526C>T (p.Arg176Trp)","Chromosome":"1","Start":"8325853","Stop":"8325853","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":420285,"rule_based_match":true,"evidence_text":"c.526C>T [p.Arg176Trp]","llm_judgment":"PRESENT","evidence":"c.526C>T [p.Arg176Trp]","abstract_start":363,"abstract_end":385}]}
{"pmid":"23798057","title":"Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia.","abstract":"Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic oto-sino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Diagnosis has traditionally relied on ciliary ultrastructural abnormalities seen by electron microscopy. Mutations in radial spoke head proteins occur in PCD patients with central apparatus defects. Advances in genetic testing have been crucial in addressing the diagnostic challenge. Here, we describe a novel splice-site mutation (c.921+3_6delAAGT) in RSPH4A, which leads to a premature translation termination signal in nine subjects with PCD (seven families). Loss-of-function was confirmed with quantitative ciliary ultrastructural analysis, measurement of ciliary beat frequency and waveform, and transcript analysis. All nine individuals carrying c.921+3_6delAAGT splice-site mutation in RSPH4A were Hispanic with ancestry tracing to Puerto Rico. This mutation is a founder mutation and a common cause of PCD without situs abnormalities in patients of Puerto Rican descent.","variants":[{"Name":"NM_001010892.3(RSPH4A):c.921+3_921+6del","Chromosome":"6","Start":"116623002","Stop":"116623005","ReferenceAlleleVCF":"TAGTA","AlternateAlleleVCF":"T","allel_id":94432,"rule_based_match":false,"evidence_text":"c.921+3_6delAAGT","llm_judgment":"PRESENT","evidence":"c.921+3_6delAAGT","abstract_start":606,"abstract_end":622}]}
{"pmid":"19252935","title":"Molecular analysis of NPC1 and NPC2 gene in 34 Niemann-Pick C Italian patients: identification and structural modeling of novel mutations.","abstract":"Niemann-Pick C, the autosomal recessive neuro-visceral disease resulting from a failure of cholesterol trafficking within the endosomal-lysosomal pathway, is due to mutations in NPC1 or NPC2 genes. We characterized 34 unrelated patients including 32 patients with mutations in NPC1 gene and two patients in NPC2 gene. Overall, 33 distinct genotypes were encountered. Among the 21 unpublished NPC1 alleles, 15 were due to point mutations resulting in 13 codon replacements (p.C100S, p.P237L, p.R389L, p.L472H, p.Y634C, p.S636F, p.V780G, p.Q921P, p.Y1019C, p.R1077Q, p.L1102F, p.A1187V, and p.L1191F) and in two premature stop codons (p.R934X and p.Q447X); a new mutant carried two in cis mutations, p.[L648H;M1142T] and four other NPC1 alleles were small deletions/insertions leading both to frame shifts and premature protein truncations (p.C31WfsX26, p.F284LfsX26, p.E1188fsX54, and p.T1205NfsX53). Finally, the new intronic c.464-2A>C change at the 3' acceptor splice site of intron 4 affected NPC1 messenger RNA processing. We also found a new NPC2 mutant caused by a change of the first codon (p.M1L). The novel missense mutations were further investigated by two bioinformatics approaches. Panther proein classification system computationally predicted the detrimental effect of all new missense mutations occurring at evolutionary conserved positions. The other bioinformatics approach was based on prediction of structural alterations induced by missense mutations on the NPC1 atomic models. The in silico analysis predicted protein malfunctioning and/or local folding alteration for most missense mutations. Moreover, the effects of the missense mutations (p.Y634C, p.S636F, p.L648H, and p.V780G) affecting the sterol-sensing domain (SSD) were evaluated by docking simulation between the atomic coordinates of SSD model and cholesterol.","variants":[{"Name":"NM_000271.5(NPC1):c.1901A>G (p.Tyr634Cys)","Chromosome":"18","Start":"23545006","Stop":"23545006","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":548550,"rule_based_match":false,"evidence_text":"p.Y634C","llm_judgment":"PRESENT","evidence":"p.Y634C","abstract_start":509,"abstract_end":516}]}
{"pmid":"29037160","title":"\"Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports\".","abstract":"BACKGROUND: Jervell and Lange-Nielsen syndrome (JLNS) isa recessive model of long QT syndrome which might also be related to possible hearing loss. Although the syndrome has been demonstrated to be originated from homozygous or compound heterozygous mutations in either the KCNQ1 or KCNE1 genes, additional mutations in other genetic loci should be considered, particularly in malignant course patients.\nCASE PRESENTATIONS: Three patients were admitted into hospital due to recurrent seizures/syncope, intrauterine and postnatal bradycardia respectively; moreover all three patients had congenital sensorineural hearing-loss. Their electrocardiograms showed markedly prolonged QT interval. Implantable defibrillator was implanted and left cardiac sympathetic denervation was performed due to the progressive disease in case 1. She had countless ventricular fibrillation and appropriate shock while using an implantable defibrillator. The DNA sequencing analysis of the KCNQ1 gene disclosed a homozygous c.728G > A (p.Arg243His) missense mutation in case1. Further targeted next generation sequencing of cardiac panel comprising 68 gene revealed a heterozygous c.1346 T > G (p.Ile449Arg) variant in RYR2 gene and a heterozygous c.809G > A (p.Cys270Tyr) variant in NKX2-5 gene in the same patient. Additional gene alterations in RYR2 and NKX2-5 genes were thought to be responsible for progressive and malignant course of the disease. As a result of DNA sequencing analysis of KCNQ1 and KCNE1 genes, a compound heterozygosity for two mutations had been detected in KCNQ1 gene in case 2: a maternally derived c.477 + 1G > A splice site mutation and a paternally derived c.520C > T (p.Arg174Cys) missense mutation. Sanger sequencing of KCNQ1 and KCNE1 genes displayed a homozygous c.1097G > A (p.Arg366Gln) mutation in KCNQ1 gene in case 3. β-blocker therapy was initiated to all the index subjects.\nCONCLUSIONS: Three families of JLNS who presented with long QT and deafness and who carry homozygous, or compound heterozygous mutation in KCNQ1 gene were presented in this report. It was emphasized that broad targeted cardiac panels may be useful to predict the outcome especially in patients with unexplained phenotype-genotype correlation. Clinical presentations and molecular findings will be discussed further to clarify the phenotype genotype associations.","variants":[{"Name":"NM_000218.3(KCNQ1):c.1097G>A (p.Arg366Gln)","Chromosome":"11","Start":"2585276","Stop":"2585276","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67624,"rule_based_match":true,"evidence_text":"c.1097G > A (p.Arg366Gln)","llm_judgment":"PRESENT","evidence":"c.1097G > A (p.Arg366Gln)","abstract_start":1777,"abstract_end":1802},{"Name":"NM_004387.4(NKX2-5):c.809G>A (p.Cys270Tyr)","Chromosome":"5","Start":"173232735","Stop":"173232735","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":165960,"rule_based_match":true,"evidence_text":"c.809G > A (p.Cys270Tyr)","llm_judgment":"PRESENT","evidence":"c.809G > A (p.Cys270Tyr)","abstract_start":1227,"abstract_end":1251},{"Name":"NM_001035.3(RYR2):c.1346T>G (p.Ile449Arg)","Chromosome":"1","Start":"237454444","Stop":"237454444","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":1002632,"rule_based_match":true,"evidence_text":"c.1346 T > G (p.Ile449Arg)","llm_judgment":"PRESENT","evidence":"c.1346 T > G (p.Ile449Arg)","abstract_start":1160,"abstract_end":1186},{"Name":"NM_000218.3(KCNQ1):c.520C>T (p.Arg174Cys)","Chromosome":"11","Start":"2570670","Stop":"2570670","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":67726,"rule_based_match":true,"evidence_text":"c.520C > T (p.Arg174Cys)","llm_judgment":"PRESENT","evidence":"c.520C > T (p.Arg174Cys)","abstract_start":1667,"abstract_end":1691},{"Name":"NM_000218.3(KCNQ1):c.728G>A (p.Arg243His)","Chromosome":"11","Start":"2572057","Stop":"2572057","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67760,"rule_based_match":true,"evidence_text":"c.728G > A (p.Arg243His)","llm_judgment":"PRESENT","evidence":"c.728G > A (p.Arg243His)","abstract_start":1003,"abstract_end":1027},{"Name":"NM_000218.3(KCNQ1):c.477+1G>A","Chromosome":"11","Start":"2528019","Stop":"2528019","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":197427,"rule_based_match":true,"evidence_text":"c.477 + 1G > A splice site mutation","llm_judgment":"PRESENT","evidence":"c.477 + 1G > A splice site mutation","abstract_start":1606,"abstract_end":1641}]}
{"pmid":"26750749","title":"Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia.","abstract":"A discrepancy has been identified between numbers of expected and identified patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency. Patients homozygous for the frequent c.833T>C (p.I278T) are most often responsive to vitamin B6, and can present with a total-homocysteine (tHcy) <100 μM on a normal diet. In Denmark, patients with tHcy <100 μM are not routinely sequenced for CBS(2) mutations. This study investigated the prevalence of CBS mutations and the common methylenetetrahydrofolate reductase (MTHFR) c.677C>T polymorphism in patients with tHcy ≥ 50 μM and the association with clinical manifestations. We studied a cohort of patients with intermediate and severe hyperhomocysteinemia (tHcy ≥ 50 μM) determined between 1996 and 2011. Among the 413 eligible patients, 184 (45%) patients agreed to participate in the present follow-up study. A MTHFR(3)c.677TT genotype was found in 49% of the patients. Eight patients were found to have mutations in CBS(2). Of those, two were homozygous for c.833T>C (p.I278T), and four were compound heterozygous for c.833T>C. One c.833T>C (p.I278T) compound heterozygote was identified by lowering the threshold for sequencing from tHcy at 100 μM to 50 μM. The most prominent clinical presentation among patients with a CBS(2) mutation was thrombosis presenting at a median age of 25 years. In case of arterial or venous thrombosis without any explanation in individuals below 40 years, tHcy should be part of the thrombophilia screening. When tHcy is between 50 and 100 μM genotyping for the MTHFR(3) c.677TT is relevant, and when tHcy >100 μM CBS should be genotyped.","variants":[{"Name":"NM_000071.3(CBS):c.833T>C (p.Ile278Thr)","Chromosome":"21","Start":"43063074","Stop":"43063074","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15159,"rule_based_match":true,"evidence_text":"c.833T>C (p.I278T)","llm_judgment":"PRESENT","evidence":"c.833T>C (p.I278T)","abstract_start":196,"abstract_end":214}]}
{"pmid":"29662154","title":"Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma.","abstract":"Retinoblastoma is the most common eye cancer in children. Numerous families have been described displaying reduced penetrance and expressivity. An extensive molecular characterization of seven families led us to characterize the two main mechanisms impacting on phenotypic expression, as follows: (i) mosaicism of amorphic pathogenic variants; and (ii) parent-of-origin-effect of hypomorphic pathogenic variants. Somatic mosaicism for RB1 splicing variants (c.1960+5G>C and c.2106+2T>C), leading to a complete loss of function was demonstrated by high-depth NGS in two families. In both cases, the healthy carrier parent (one with retinoma) showed a variant frequency lower than that expected for a heterozygous individual, indicating a 56-60% mosaicism level. Previous evidences of a ~3-fold excess of RB1 maternal canonical transcript led us to hypothesize that this differential allelic expression could influence phenotypic outcome in families at risk for RB onset. Accordingly, in five families, we identified a higher tumor risk associated with paternally inherited hypomorphic pathogenic variants, namely a deletion resulting in the loss of 37 amino acids at the N-terminus (c.608-16_608del), an exonic substitution with a \"leaky\" splicing effect (c.1331A>G), a partially deleterious substitution (c.1981C>T) and a truncating C-terminal variant (c.2663+2T>C). The identification of these mechanisms changes the genetic/prenatal counseling and the clinical management of families, indicating a higher recurrence risk when the hypomorphic pathogenic variant is inherited from the father, and suggesting the need for second tumor surveillance in unaffected carriers at risk of developing adult-onset cancer such as osteosarcoma or leiomyosarcoma.","variants":[{"Name":"NM_000321.3(RB1):c.2106+2T>C","Chromosome":"13","Start":"48459835","Stop":"48459835","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":568600,"rule_based_match":true,"evidence_text":"c.2106+2T>C","llm_judgment":"PRESENT","evidence":"c.2106+2T>C","abstract_start":474,"abstract_end":485},{"Name":"NM_000321.3(RB1):c.1960+5G>C","Chromosome":"13","Start":"48456354","Stop":"48456354","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":420564,"rule_based_match":true,"evidence_text":"c.1960+5G>C","llm_judgment":"PRESENT","evidence":"c.1960+5G>C","abstract_start":458,"abstract_end":469}]}
{"pmid":"31119896","title":"Telomerase insufficiency induced telomere erosion accumulation in successive generations in dyskeratosis congenita family.","abstract":"BACKGROUND: Dyskeratosis congenita (DC) is a rare heritable bone marrow failure syndrome that is associated with telomere dysfunction, and has high genetic heterogeneity and varied features.\nOBJECTIVE: This study aimed to identify the underlying genetic etiology of a DC family with more severe symptoms in the younger generation and to explore the relationship between the genetic causes and the severity of DC phenotype.\nMETHODS: Whole-exome sequencing was performed on the proband to screen the candidate causative gene. The protein structure was then predicted by SWISS-MODEL software. Telomere length (TL) assay was performed on family members along with large-scale population controls. The prenatal diagnosis (PND) was performed on the fetus of parents with secondary pregnancy.\nRESULTS: Novel heterozygous mutations in TERT (NM_198253.2), c.1796G>A (p.Arg599Gln), c.2839T>C (p.Ser947Pro), and c.3346G>C (p.Glu1116Gln) were identified in the proband. His TL was below the first percentile of the peers, which also appeared on the fetus with epidermal dyskeratosis through PND. The TL data of large-scale population and members of the DC family implied the accumulation of telomere erosion in successive generations in this family.\nCONCLUSIONS: Our study identified three clinical pathologic TERT mutations and implied that telomere erosion might be accumulated through successive generations, contributing to the severity of DC in the younger generation.","variants":[{"Name":"NM_198253.3(TERT):c.3346G>C (p.Glu1116Gln)","Chromosome":"5","Start":"1253781","Stop":"1253781","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":623376,"rule_based_match":true,"evidence_text":"c.3346G>C (p.Glu1116Gln)","llm_judgment":"PRESENT","evidence":"c.3346G>C (p.Glu1116Gln)","abstract_start":901,"abstract_end":925},{"Name":"NM_198253.3(TERT):c.2839T>C (p.Ser947Pro)","Chromosome":"5","Start":"1264408","Stop":"1264408","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":623377,"rule_based_match":true,"evidence_text":"c.2839T>C (p.Ser947Pro)","llm_judgment":"PRESENT","evidence":"c.2839T>C (p.Ser947Pro)","abstract_start":872,"abstract_end":895},{"Name":"NM_198253.3(TERT):c.1796G>A (p.Arg599Gln)","Chromosome":"5","Start":"1280312","Stop":"1280312","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":623378,"rule_based_match":true,"evidence_text":"c.1796G>A (p.Arg599Gln)","llm_judgment":"PRESENT","evidence":"c.1796G>A (p.Arg599Gln)","abstract_start":847,"abstract_end":870}]}
{"pmid":"19515026","title":"An infant with combination gene mutations for Monogenic Diabetes of Youth (MODY) 2 and 4, presenting with Diabetes Mellitus Requiring Insulin (DMRI) at 8 months of age.","abstract":"Monogenic Diabetes of Youth (MODY) is an autosomal dominant form of diabetes. [Fajans SS, et al. NEJM 2001: 345: 971-980.] There are at least six different types of MODY, all of which involve a loss of function gene mutation that results in diminished insulin production. MODY2 results from a mutation in the glucokinase gene (GCK), which decreases enzyme activity. MODY4 results from a mutation in the insulin promoter factor-1 (IPF-1) gene, a transcription factor which regulates the transcription of insulin. [Sperling M, et al. NEJM 2006: 355: 507-510.] TJ presented at 8 months of age with diabetes mellitus requiring insulin (DMRI) with negative islet autoantibodies. She had a prolonged honeymoon period, as evidenced by her insulin requirement of 0.5 units/kg/day at three years of age. Genetic testing showed combination MODY2 (c.1019+18G >A) and MODY4 (c.226G>A) gene mutations. The father was homozygous for MODY2 and the mother was heterozygous for MODY4. [Athena Diagnostics Evaluations \"2007 # 839 - Monogenic Diabetes (MODY) Evaluation for the patient, the patient's father, and the patient's mother] Neither parent had diabetes mellitus. The clinical course and negative islet autoantibodies support that the combination of benign MODY2 and MODY4 gene mutations in the parents resulted in DMRI in TJ.","variants":[{"Name":"NM_000209.4(PDX1):c.226G>A (p.Asp76Asn)","Chromosome":"13","Start":"27920364","Stop":"27920364","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23898,"rule_based_match":true,"evidence_text":"c.226G>A","llm_judgment":"PRESENT","evidence":"c.226G>A","abstract_start":863,"abstract_end":871},{"Name":"NM_000162.5(GCK):c.1019+18G>A","Chromosome":"7","Start":"44146445","Stop":"44146445","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":371149,"rule_based_match":true,"evidence_text":"c.1019+18G >A","llm_judgment":"PRESENT","evidence":"c.1019+18G >A","abstract_start":837,"abstract_end":850}]}
{"pmid":"26378117","title":"Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay.","abstract":"BACKGROUND: A homozygous loss-of-function mutation p.(Arg316Gln) in the fat mass and obesity-associated (FTO) gene, which encodes for an iron and 2-oxoglutarate-dependent oxygenase, was previously identified in a large family in which nine affected individuals present with a lethal syndrome characterised by growth retardation and multiple malformations. To date, no other pathogenic mutation in FTO has been identified as a cause of multiple congenital malformations.\nMETHODS: We investigated a 21-month-old girl who presented distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. We performed targeted next-generation sequencing of 4813 clinically relevant genes in the patient and her parents.\nRESULTS: We identified a novel FTO homozygous missense mutation (c.956C>T; p.(Ser319Phe)) in the affected individual. This mutation affects a highly conserved residue located in the same functional domain as the previously characterised mutation p.(Arg316Gln). Biochemical studies reveal that p.(Ser319Phe) FTO has reduced 2-oxoglutarate turnover and N-methyl-nucleoside demethylase activity.\nCONCLUSION: Our findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems.","variants":[{"Name":"NM_001080432.3(FTO):c.956C>T (p.Ser319Phe)","Chromosome":"16","Start":"53873846","Stop":"53873846","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":204571,"rule_based_match":true,"evidence_text":"c.956C>T; p.(Ser319Phe)","llm_judgment":"PRESENT","evidence":"c.956C>T; p.(Ser319Phe)","abstract_start":866,"abstract_end":889}]}
{"pmid":"20447124","title":"Clinical and molecular features of familial and sporadic cases of von Hippel-Lindau disease from Mexico.","abstract":"BACKGROUND: von Hippel-Lindau disease (VHL) is an uncommon autosomal dominant condition predisposing to the development of tumours in a variety of body organs and caused by germline mutations in VHL, a tumour suppressor gene located on 3p. Up to 60% of VHL patients show ocular involvement with retinal hemangioblastoma being the most common observed lesion. In this study, we describe the clinical and genetic characteristics of two familial and one apparently non-familial case of VHL ascertained at our institution.\nMETHODS: Clinical evaluation included ophthalmologic examination and imaging exams for tumours identification; molecular analysis consisted of PCR amplification of the complete VHL gene coding sequence (three exons) and automated nucleotide sequencing.\nRESULTS: A total of eight affected subjects were demonstrated to carry a causative mutation in VHL. Affected subjects from family #1 had a c.245G > C change, predicting a p.R82P substitution, affected individuals from family #2 were shown to have a c.266T > C change, leading to a p.L89P missense substitution, whereas the apparently non-familial case had a c.298-299insA mutation. One subject from family #2 was a non-penetrant carrier. No ocular anomalies were found in two adult affected subjects carrying the p.L89P mutation.\nCONCLUSION: Considerable interfamilial and intrafamilial clinical variability as well as one instance of non penetrance were recorded in these VHL disease cases. Three different mutations were demonstrated, including the c.298-299insA one base insertion, which has been previously described in two unrelated families from our country. Although additional studies are needed, our data suggest that this insertion could be a 'founder' mutation.","variants":[{"Name":"NM_000551.4(VHL):c.245G>C (p.Arg82Pro)","Chromosome":"3","Start":"10142092","Stop":"10142092","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":190283,"rule_based_match":true,"evidence_text":"c.245G > C","llm_judgment":"PRESENT","evidence":"c.245G > C","abstract_start":911,"abstract_end":921},{"Name":"NM_000551.4(VHL):c.266T>C (p.Leu89Pro)","Chromosome":"3","Start":"10142113","Stop":"10142113","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":180117,"rule_based_match":true,"evidence_text":"c.266T > C","llm_judgment":"PRESENT","evidence":"c.266T > C","abstract_start":1021,"abstract_end":1031}]}
{"pmid":"32044282","title":"Genetic analysis of familial hypercholesterolemia in Asian Indians: A single-center study.","abstract":"BACKGROUND: Familial hypercholesterolemia (FH), an autosomal codominant disorder characterized by very high low-density lipoprotein cholesterol, is strongly associated with premature coronary artery disease.\nOBJECTIVES: Molecular landscape of FH in Asian Indians is not well studied, although this ethnic group comprises a large proportion of the world population. Knowledge of mutations in these groups is useful for identifying persons affected with FH, saving their lives, and cascade screening in their relatives.\nMETHODS: Potential cases of FH (n = 100) were identified by criteria adapted for the Indian population from Dutch Lipid Clinic Network criteria. Pathogenic variants were analyzed in LDLR, APOB 100 (exons 26 and 29), PCSK9, and APOE genes using Sanger sequencing and multiplex ligation-dependent probe amplification technique. Cases in whom there were no pathogenic variants were tested by next-generation sequencing using a targeted panel of genes.\nRESULTS: Thirty-eight pathogenic variants were identified in 47 of 100 unrelated probands. Of these variants, 33 were identified in LDLR, 3 in APOB, and 2 in PCSK9 genes. Ten pathogenic variants were novel. Mutations were detected in 91.4% of those subjects classified as definite, 40% as probable, and in 18.8% as possible FH cases based on modified Dutch Lipid Clinic Network criteria. A likely founder mutation in intron 10 (c.1587-1G>A) of LDLR gene was observed in 6 North Indian families. The conventional pathogenic variants in APOB and PCSK9 genes and those previously reported in LDLR gene among Asian Indians were not detected in this cohort.\nCONCLUSION: This study demonstrates genetic heterogeneity of FH in India. The variants observed were different from those described in Western populations. Next-generation sequencing technology helped identify new mutations in APOB gene, suggesting that in less-studied populations, it is better to sequence the whole gene rather than test for specific mutations.","variants":[{"Name":"NM_000527.5(LDLR):c.1587-1G>A","Chromosome":"19","Start":"11116093","Stop":"11116093","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":246227,"rule_based_match":true,"evidence_text":"c.1587-1G>A","llm_judgment":"PRESENT","evidence":"c.1587-1G>A","abstract_start":1395,"abstract_end":1406}]}
{"pmid":"21411353","title":"Late-onset nonketotic hyperglycinemia caused by a novel homozygous missense mutation in the GLDC gene.","abstract":"Nonketotic hyperglycinemia (NKH) is an inborn error of the glycine metabolism. A 9-year-old boy with learning disability and intermittent choreoathetosis during febrile illnesses had elevated plasma glycine level and CSF/plasma glycine ratio (0.044) and a novel homozygous missense mutation (c.605C>T; p.Ala202Val) in the GLDC gene, confirming the diagnosis of NKH. This is the first report of late-onset NKH with a confirmed underlying genetic defect. NKH should be in the differential diagnosis of intermittent choreoathetosis.","variants":[{"Name":"NM_000170.3(GLDC):c.605C>T (p.Ala202Val)","Chromosome":"9","Start":"6610222","Stop":"6610222","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":70740,"rule_based_match":true,"evidence_text":"c.605C>T; p.Ala202Val","llm_judgment":"PRESENT","evidence":"c.605C>T; p.Ala202Val","abstract_start":292,"abstract_end":313}]}
{"pmid":"33025377","title":"Novel Frameshift Autosomal Recessive Loss-of-Function Mutation in SMARCD2 Encoding a Chromatin Remodeling Factor Mediates Granulopoiesis.","abstract":"PURPOSE: Recently, a new form of congenital neutropenia that is caused by germline biallelic loss-of-function mutations in the SMARCD2 gene was described in four patients. Given the rarity of the condition, the clinical spectrum of the disease has remained elusive. We here report a new patient with a novel frameshift mutation and compare our patient with the previously reported SMARCD2-mutant patients, aiming to provide a more comprehensive understanding of the natural course of the disease.\nMETHODS: Clinical and laboratory findings of all reported patients were reviewed. Next-generation sequencing was performed to identify the causative genetic defect. Data on the hematopoietic stem cell transplantation including stem cell sources, conditioning regimen, engraftment, graft-versus-host disease, and infections were also collected.\nRESULTS: An 11-year-old female patient had a variety of infections including sepsis, deep tissue abscesses, otitis, pneumonia, gingivitis, and diarrhea since infancy. A novel homozygous mutation in SMARCD2 (c.93delG, p.Ala32Argfs*80) was detected. Bone marrow examination showed hypocellularity and decreased neutrophils with diminished granules and myeloid dysplasia, but no blast excess as in previously reported patients. The neutropenia was non-responsive even to higher doses of granulocyte colony-stimulating factor (G-CSF); therefore, the patient was transplanted at 10 years of age from a HLA-A allele-mismatched unrelated donor using a reduced toxicity conditioning regimen and recovered successfully. Compared with the previous four cases, our patient showed longer survival before transplantation without blastic transformation.\nCONCLUSION: Distinctive myeloid features and long-term follow-up including therapy options are presented for the newly described case of SMARCD2 deficiency. This disorder is apparent at infancy and requires early transplantation due to the unrelenting disease course despite conventional therapy.","variants":[{"Name":"NM_001098426.2(SMARCD2):c.93del (p.Ala32fs)","Chromosome":"17","Start":"63842582","Stop":"63842582","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":610471,"rule_based_match":true,"evidence_text":"c.93delG","llm_judgment":"PRESENT","evidence":"c.93delG","abstract_start":1048,"abstract_end":1056}]}
{"pmid":"30953287","title":"Interleukin-36 Receptor Antagonist Deficiency (DITRA) with a Novel IL36RN Homozygous Mutation c.200G > T (P.Cys67Phe) in a Young Colombian Woman.","abstract":"","variants":[{"Name":"NM_012275.3(IL36RN):c.200G>T (p.Cys67Phe)","Chromosome":"2","Start":"113062208","Stop":"113062208","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":516311,"rule_based_match":true,"evidence_text":"c.200G > T (P.Cys67Phe)","llm_judgment":"PRESENT","evidence":"c.200G > T (P.Cys67Phe)","abstract_start":null,"abstract_end":null}]}
{"pmid":"19196998","title":"Analysis of rare APC variants at the mRNA level: six pathogenic mutations and literature review.","abstract":"In monogenic disorders, the functional evaluation of rare, unclassified variants helps to assess their pathogenic relevance and can improve differential diagnosis and predictive testing. We characterized six rare APC variants in patients with familial adenomatous polyposis at the mRNA level. APC variants c.531 + 5G>C and c.532-8G>A in intron 4, c.1409-2_1409delAGG in intron 10, c.1548G>A in exon 11, and a large duplication of exons 10 and 11 result in a premature stop codon attributable to aberrant transcripts whereas the variant c.1742A>G leads to the in-frame deletion of exon 13 and results in the removal of a functional motif. Mutation c.1548G>A was detected in the index patient but not in his affected father, suggesting mutational mosaicism. A literature review shows that most of the rare APC variants detected by routine diagnostics and further analyzed at the transcript level were evaluated as pathogenic. The majority of rare APC variants, particularly those located close to exon-intron boundaries, could be classified as pathogenic because of aberrant splicing. Our study shows that the characterization of rare variants at the mRNA level is crucial for the evaluation of pathogenicity and underlying mutational mechanisms, and could lead to better treatment modalities.","variants":[{"Name":"NM_000038.6(APC):c.531+5G>C","Chromosome":"5","Start":"112775742","Stop":"112775742","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":264174,"rule_based_match":true,"evidence_text":"c.531 + 5G>C","llm_judgment":"PRESENT","evidence":"c.531 + 5G>C","abstract_start":306,"abstract_end":318},{"Name":"NM_000038.6(APC):c.1548G>A (p.Lys516=)","Chromosome":"5","Start":"112827247","Stop":"112827247","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":419609,"rule_based_match":true,"evidence_text":"c.1548G>A","llm_judgment":"PRESENT","evidence":"c.1548G>A","abstract_start":381,"abstract_end":390},{"Name":"NM_000038.6(APC):c.532-8G>A","Chromosome":"5","Start":"112780782","Stop":"112780782","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":394685,"rule_based_match":true,"evidence_text":"c.532-8G>A","llm_judgment":"PRESENT","evidence":"c.532-8G>A","abstract_start":323,"abstract_end":333}]}
{"pmid":"31200758","title":"Novel genotypes and phenotypes among Chinese patients with Floating-Harbor syndrome.","abstract":"BACKGROUND: Floating-Harbor syndrome (FHS) is a rare syndromic short stature disorder caused by truncating variants in SRCAP. Few Chinese FHS patients had been reported so far and limited knowledge regarding the benefit of growth hormone treatment existed.\nMETHODS: We ascertained 12 short stature patients with molecularly confirmed diagnosis of FHS by whole exome sequencing. We performed a comprehensive clinical evaluation for all patients and assessed the responsiveness of growth hormone treatment in a subset of the patients.\nRESULTS: Five distinct pathogenic/likely pathogenic variants were identified in 12 independent FHS patients including two previously reported variants (c.7303C > T/p.Arg2435Ter and c.7330C > T/p.Arg2444Ter) and three novel variants (c.7189G > T/p.Glu2397Ter, c.7245_7246delAT/p.Ser2416ArgfsTer26 and c.7466C > G/p.Ser2489Ter). The c.7303C > T/p.Arg2435Ter mutation appears more common in Chinese FHS patients. The clinical presentations of Chinese FHS patients are very similar to those of previously reported patients of different ethnicities. Yet we noticed micropenis and ear abnormalities in multiple patients, suggesting that these may be novel phenotypes of Floating-Harbor syndrome. Eight patients (one with GH deficiency, one with undetermined GH level, six without GH deficiency) underwent growth hormone treatment, 3 patients had good responses, one with modest and two with poor responses.\nCONCLUSION: We described novel genotypes and phenotypes in a Chinese FHS patient cohort. We showed that about half of FHS patients exhibited modest to good response to GH treatment regardless of their respective GH deficiency status. We didn't find any correlation between different mutations and response to GH treatment.","variants":[{"Name":"NM_006662.3(SRCAP):c.7330C>T (p.Arg2444Ter)","Chromosome":"16","Start":"30737370","Stop":"30737370","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39865,"rule_based_match":true,"evidence_text":"c.7330C > T/p.Arg2444Ter","llm_judgment":"PRESENT","evidence":"c.7330C > T/p.Arg2444Ter","abstract_start":714,"abstract_end":738},{"Name":"NM_006662.3(SRCAP):c.7303C>T (p.Arg2435Ter)","Chromosome":"16","Start":"30737343","Stop":"30737343","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":39866,"rule_based_match":true,"evidence_text":"c.7303C > T/p.Arg2435Ter","llm_judgment":"PRESENT","evidence":"c.7303C > T/p.Arg2435Ter","abstract_start":685,"abstract_end":709}]}
{"pmid":"23234825","title":"Type IV Ehlers-Danlos syndrome presenting as recurrent, bilateral carotid dissections.","abstract":"Vascular (type IV) Ehlers-Danlos is an autosomally dominant inherited condition that results from a defect in type III collagen production. It can result in vascular complications such as rupture and dissection, as well as gastrointestinal and uterine rupture. We present the case of a 17-year-old girl who presented with transient neurological signs and pulsatile tinnitus secondary to carotid dissection 1 year after suffering from a stroke caused also by a carotid dissection on the contralateral side. We managed acutely and investigated for an underlying connective tissue disorder. Genetic analysis of COL 3A1 was performed and a heterozygous missense, non-conservative mutation of c.970G>A was detected. This replication mutation has previously been associated with type IV Ehlers-Danlos syndrome.","variants":[{"Name":"NM_000090.4(COL3A1):c.970G>A (p.Gly324Ser)","Chromosome":"2","Start":"188992202","Stop":"188992202","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":107134,"rule_based_match":true,"evidence_text":"c.970G>A","llm_judgment":"PRESENT","evidence":"c.970G>A","abstract_start":688,"abstract_end":696}]}
{"pmid":"29566152","title":"Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency.","abstract":"Primary ovarian insufficiency (POI) is characterized by amenorrhea and loss or dysfunction of ovarian follicles prior to the age of 40. POI has been associated with autosomal recessive mutations in genes involving hormonal signaling and folliculogenesis, however, the genetic etiology of POI most often remains unknown. Here we report MRPS22 homozygous missense variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) identified in four females from two independent consanguineous families as a novel genetic cause of POI in adolescents. Both missense mutations identified in MRPS22 are rare, occurred in highly evolutionarily conserved residues, and are predicted to be deleterious to protein function. In contrast to prior reports of mutations in MRPS22 associated with severe mitochondrial disease, the POI phenotype is far less severe. Consistent with this genotype-phenotype correlation, mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, suggesting a non-bioenergetic or tissue-specific mitochondrial defect. Furthermore, we demonstrate in a Drosophila model that mRpS22 deficiency specifically in somatic cells of the ovary had no effect on fertility, whereas flies with mRpS22 deficiency specifically in germ cells were infertile and agametic, demonstrating a cell autonomous requirement for mRpS22 in germ cell development. These findings collectively identify that MRPS22, a component of the small mitochondrial ribosome subunit, is critical for ovarian development and may therefore provide insight into the pathophysiology and treatment of ovarian dysfunction.","variants":[{"Name":"NM_020191.4(MRPS22):c.605G>A (p.Arg202His)","Chromosome":"3","Start":"139350279","Stop":"139350279","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":434897,"rule_based_match":true,"evidence_text":"c.605G>A (p.R202H)","llm_judgment":"PRESENT","evidence":"c.605G>A (p.R202H)","abstract_start":394,"abstract_end":412},{"Name":"NM_020191.4(MRPS22):c.404G>A (p.Arg135Gln)","Chromosome":"3","Start":"139348224","Stop":"139348224","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":488076,"rule_based_match":true,"evidence_text":"c.404G>A (p.R135Q)","llm_judgment":"PRESENT","evidence":"c.404G>A (p.R135Q)","abstract_start":371,"abstract_end":389}]}
{"pmid":"32164353","title":"Recurrent Germline BRCA2 Gene Mutation in Lithuanian Family.","abstract":"Approximately 10% of all breast cancer (BC) cases are familial and caused by inheritance of mutant <i>BRCA1</i>, <i>BRCA2</i><i>,</i> or some other genes from the same DNA reparation pathway. Genetic counseling in families with cancer history is a powerful means for early cancer detection and active risk reduction through preventive interventions. This is the first report of the rare inherited <i>BRCA2</i> frameshift-deletion mutation c.3847_3848delGT in one Lithuanian pedigree with the intense familial history of BC. Three <i>BRCA2</i>-positive blood relatives with BC of different biological types were identified in this pedigree with the same type mutation. All three cases were diagnosed with advanced stage ductal carcinoma. Markedly, polymorphic cells and numerous mitoses were identified in BC from the cases. Two patients from the family were diagnosed with the triple negative tumors, while one case had early onset of the hormone positive BC. Despite the variation in clinical and biological presentation of BC, all cases showed a good response to conventional treatment. In conclusion, the strong influence of <i>BRCA2</i> mutation on the onset of BC of various biological types reveals the complexity of genetic counselling in families with BC history.","variants":[{"Name":"NM_000059.4(BRCA2):c.3847_3848del (p.Val1283fs)","Chromosome":"13","Start":"32338201","Stop":"32338202","ReferenceAlleleVCF":"CTG","AlternateAlleleVCF":"C","allel_id":46415,"rule_based_match":true,"evidence_text":"c.3847_3848delGT","llm_judgment":"PRESENT","evidence":"c.3847_3848delGT","abstract_start":439,"abstract_end":455}]}
{"pmid":"28880435","title":"Thrombocytopenia and CD34 expression is decoupled from α-granule deficiency with mutation of the first growth factor-independent 1B zinc finger.","abstract":"Essentials The phenotypes of different growth factor-independent 1B (GFI1B) variants are not established. GFI1B variants produce heterogeneous clinical phenotypes dependent on the site of mutation. Mutation of the first non-DNA-binding zinc-finger causes a mild platelet and clinical phenotype. GFI1B regulates the CD34 promoter; platelet CD34 expression is an indicator of GFI1B mutation.\nSUMMARY: Background Mutation of the growth factor-independent 1B (GFI1B) fifth DNA-binding zinc-finger domain causes macrothrombocytopenia and α-granule deficiency leading to clinical bleeding. The phenotypes associated with GFI1B variants disrupting non-DNA-binding zinc-fingers remain uncharacterized. Objectives To determine the functional and phenotypic consequences of GFI1B variants disrupting non-DNA-binding zinc-finger domains. Methods The GFI1B C168F variant and a novel GFI1B c.2520 + 1_2520 + 8delGTGGGCAC splice variant were identified in four unrelated families. Phenotypic features, DNA-binding properties and transcriptional effects were determined and compared with those in individuals with a GFI1B H294 fs mutation of the fifth DNA-binding zinc-finger. Patient-specific induced pluripotent stem cell (iPSC)-derived megakaryocytes were generated to facilitate disease modeling. Results The DNA-binding GFI1B variant C168F, which is predicted to disrupt the first non-DNA-binding zinc-finger domain, is associated with macrothrombocytopenia without α-granule deficiency or bleeding symptoms. A GFI1B splice variant, c.2520 + 1_2520 + 8delGTGGGCAC, which generates a short GFI1B isoform that lacks non-DNA-binding zinc-fingers 1 and 2, is associated with increased platelet CD34 expression only, without quantitative or morphologic platelet abnormalities. GFI1B represses the CD34 promoter, and this repression is attenuated by different GFI1B zinc-finger mutations, suggesting that deregulation of CD34 expression occurs at a direct transcriptional level. Patient-specific iPSC-derived megakaryocytes phenocopy these observations. Conclusions Disruption of GFI1B non-DNA-binding zinc-finger 1 is associated with mild to moderate thrombocytopenia without α-granule deficiency or bleeding symptomatology, indicating that the site of GFI1B mutation has important phenotypic implications. Platelet CD34 expression appears to be a common feature of perturbed GFI1B function, and may have diagnostic utility.","variants":[{"Name":"NM_001377304.1(GFI1B):c.503G>T (p.Cys168Phe)","Chromosome":"9","Start":"132988461","Stop":"132988461","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1687809,"rule_based_match":false,"evidence_text":"GFI1B C168F variant","llm_judgment":"PRESENT","evidence":"GFI1B C168F variant","abstract_start":839,"abstract_end":858}]}
{"pmid":"28825143","title":"Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer.","abstract":"BACKGROUND: PALB2 (Partner and Localizer of BRCA2) is recently recognized as a breast cancer predisposition gene. Germline loss-of-function mutations in PALB2 lead to increased breast cancer risk. Since the germline mutation frequency of PALB2 is much less than BRCA1/2, the distinct mutation spectrum of PALB2 is still obscure. To verify the utility of PALB2 genetic testing in Chinese population, we assessed the mutational frequency, spectrum, and predictors of the PALB2 gene in a sequential series of Chinese breast cancer patients from our Research DNA Bank.\nMETHODS: We examined breast cancer samples (n = 2279) collected from 2000 through 2016 from Chinese patients who agreed to participate in research DNA banking. To identify the mutations, complete coding sequence and intron-exon boundaries of PALB2 were screened with Next-Generation Sequencing. Personal and family histories were synchronously collected for mutation identification.\nRESULTS: Among the 2279 breast cancer patients, 305 patients were familial breast cancer cases and the rest 1967 patients were sporadic breast cancer cases. PALB2 loss-of-function mutation carriers accounted for 1.31% (n = 4) and 0.56% (n = 11) in familial and sporadic breast cancer cohort separately. In total, 30 missenses, four nonsenses, three frameshifts, three splicings, and one inframe deletions of PALB2 were identified in this study. Among the deleterious mutations, PALB2 c.1744C>T, c.2748+1G>A, c.2749-1G>C, c.3114-1G>A were newly identified in sporadic breast cancer, and c.3271delC newly found in familial breast cancer. Based on in silico analysis, we found two potentially damaging missense variants with high frequency: c.1213C>G, c.3054G>C, and classified six new potentially damaging missense variants.\nCONCLUSIONS: Our data presented the germline mutation status of PALB2 in Chinese breast cancer patients, suggesting that loss-of-function germline mutations of PALB2 are important in both familial and sporadic breast cancer. Clinically, these data may be helpful in genetic counseling of breast cancer patients with PALB2 germline mutation.","variants":[{"Name":"NM_024675.4(PALB2):c.2748+1G>A","Chromosome":"16","Start":"23626235","Stop":"23626235","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":477582,"rule_based_match":true,"evidence_text":"c.2748+1G>A","llm_judgment":"PRESENT","evidence":"c.2748+1G>A","abstract_start":1443,"abstract_end":1454},{"Name":"NM_024675.4(PALB2):c.2749-1G>C","Chromosome":"16","Start":"23624095","Stop":"23624095","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":401061,"rule_based_match":true,"evidence_text":"c.2749-1G>C","llm_judgment":"PRESENT","evidence":"c.2749-1G>C","abstract_start":1456,"abstract_end":1467}]}
{"pmid":"34570759","title":"A biallelic SNIP1 Amish founder variant causes a recognizable neurodevelopmental disorder.","abstract":"SNIP1 (Smad nuclear interacting protein 1) is a widely expressed transcriptional suppressor of the TGF-β signal-transduction pathway which plays a key role in human spliceosome function. Here, we describe extensive genetic studies and clinical findings of a complex inherited neurodevelopmental disorder in 35 individuals associated with a SNIP1 NM_024700.4:c.1097A>G, p.(Glu366Gly) variant, present at high frequency in the Amish community. The cardinal clinical features of the condition include hypotonia, global developmental delay, intellectual disability, seizures, and a characteristic craniofacial appearance. Our gene transcript studies in affected individuals define altered gene expression profiles of a number of molecules with well-defined neurodevelopmental and neuropathological roles, potentially explaining clinical outcomes. Together these data confirm this SNIP1 gene variant as a cause of an autosomal recessive complex neurodevelopmental disorder and provide important insight into the molecular roles of SNIP1, which likely explain the cardinal clinical outcomes in affected individuals, defining potential therapeutic avenues for future research.","variants":[{"Name":"NM_024700.4(SNIP1):c.1097A>G (p.Glu366Gly)","Chromosome":"1","Start":"37537842","Stop":"37537842","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":39674,"rule_based_match":true,"evidence_text":"NM_024700.4:c.1097A>G, p.(Glu366Gly)","llm_judgment":"PRESENT","evidence":"NM_024700.4:c.1097A>G, p.(Glu366Gly)","abstract_start":346,"abstract_end":382}]}
{"pmid":"32358377","title":"A case report and literature review: Identification of a novel AIRE gene mutation associated with Autoimmune Polyendocrine Syndrome Type 1 in East Asians.","abstract":"RATIONALE: Autoimmune polyendocrine syndrome type 1 (APS-1), also referred as the autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED), is a rare autosomal inherited disease predominantly among Caucasians from Northern Europe. This syndrome is very rare in East Asian population.\nPATIENTS CONCERNS: Here, we describe a case of a 15-year-old Chinese boy admitted due to a 1-month history of intermittent fatigue, nausea, vomiting, and diarrhea. His symptom became worse accompanied with chest tightness 4 days before admission. On physical examination, his temperature was 38.5°C, blood pressure was 75/38 mm Hg, and pulse was 98/min. He was a thin boy with mild hyperpigmentation and xanthochromia.\nDIAGNOSIS: After abdominal computed technology and laboratory tests, his diagnosis was APS-1 accompanied with adrenal crisis. Further investigation on whole-exome sequencing revealed a novel homozygous mutation c.47C>G (p.T16R) in exon 1 in the autoimmune regulator (AIRE) gene.\nINTERVENTIONS: This patient underwent replacement therapy of glucocorticoids, corticosteroid, and levothyroxine, as well as calcium and calcitriol supplementation.\nOUTCOMES: He continues to do well 4 years after his hospitalization. During his last follow-up, he had serum thyroid-stimulating hormone level of 3.07 μIU/mL, free triiodothyronine level of 1.92 pg/mL, and free thyroxine level of 13.95 pg/mL. His serum cortisol and ACTH (8 a.m.) levels were 28.53 μg/dL and 69.48 pg/mL, respectively.\nLESSONS: APS-1 is very rare in East Asians and the variable clinical presentations of the disease make the initial diagnosis especially difficult. Autoimmune thyroiditis, type 1 diabetes mellitus, and hepatitis were the three most frequent minor components of APS-1 in East Asian patients with age of onset in late teens and 20s. Sequence analysis of AIRE gene is necessary to verify its diagnostic efficacy in association with clinical findings.","variants":[{"Name":"NM_000383.4(AIRE):c.47C>G (p.Thr16Arg)","Chromosome":"21","Start":"44286053","Stop":"44286053","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3410377,"rule_based_match":true,"evidence_text":"c.47C>G (p.T16R)","llm_judgment":"PRESENT","evidence":"c.47C>G (p.T16R)","abstract_start":929,"abstract_end":945}]}
{"pmid":"18678442","title":"The ovarioleukodystrophy.","abstract":"The \"ovarioleukodystrophies\" comprise a group of rare leukodystrophies associated with primary or premature ovarian failure. Some of the patients have a variant of \"vanishing white matter disease\" with mutations in subunits of eukaryotic initiation factor 2B (EIF2B). A 32-year-old woman who developed neurological signs related to an extensive leukoencephalopathy on magnetic resonance imaging (MRI) in the context of amenorrhea since the age of 18 years was found to be homozygous for a mutation in the EIF2B5 gene: c.338G>A/p.Arg113His. She had a progressive disease with development of tetraparesia in less than 6 years. Our observation confirms that ovarian failure in the context of a leukodystrophy warrants mutational analysis of the genes encoding the subunits of EIF2B.","variants":[{"Name":"NM_003907.3(EIF2B5):c.338G>A (p.Arg113His)","Chromosome":"3","Start":"184137637","Stop":"184137637","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20984,"rule_based_match":true,"evidence_text":"c.338G>A/p.Arg113His","llm_judgment":"PRESENT","evidence":"c.338G>A/p.Arg113His","abstract_start":518,"abstract_end":538}]}
{"pmid":"16451139","title":"Genetic and biochemical approach to early prenatal diagnosis in a family with mut methylmalonic aciduria.","abstract":"Genetic and biochemical prenatal diagnosis was performed at 11 weeks of gestation in a family with a proband affected by mut methylmalonic aciduria (MMA) and homozygotes for the MUT gene c.643G>A (p.Gly215Ser) mutation. Both chorionic villus and amniotic fluid samples were used. The presence of high levels of methylmalonic acid and propionylcarnitine determined by gas chromatography/mass spectrometry and LC/MS/MS analysis, respectively, and the identification of the p.Gly215Ser at a homozygous level in foetal DNA allowed a certain, rapid and early diagnosis. To our knowledge, this is the first mut MMA prenatal diagnosis carried out by genetic and biochemical approach.","variants":[{"Name":"NM_000255.4(MMUT):c.643G>A (p.Gly215Ser)","Chromosome":"6","Start":"49457801","Stop":"49457801","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16927,"rule_based_match":true,"evidence_text":"c.643G>A (p.Gly215Ser)","llm_judgment":"PRESENT","evidence":"c.643G>A (p.Gly215Ser)","abstract_start":187,"abstract_end":209}]}
{"pmid":"25403460","title":"Reduced Penetrance of PRRT2 Mutation in a Chinese Family With Infantile Convulsion and Choreoathetosis Syndrome.","abstract":"Paroxysmal kinesigenic dyskinesia is a rare episodic movement disorder that can be isolated or associated with benign infantile seizures as part of choreoathetosis syndrome. Mutations in the PRRT2 gene have been recently identified as a cause of paroxysmal kinesigenic dyskinesia and infantile convulsion and choreoathetosis (ICCA). We reported a PRRT2 heterozygous mutation (c.604-607delTCAC, p.S202Hfs*25) in a 3-generation Chinese family with infantile convulsion and choreoathetosis and paroxysmal kinesigenic dyskinesia. The mutation was present in 5 family members, of which 4 were clinically affected and 1 was an obligate carrier with reduced penetrance of PRRT2. The affected carriers of this mutation presented with a similar type of infantile convulsion during early childhood and developed additional paroxysmal kinesigenic dyskinesia symptoms later in life. In addition, they all had a dramatic clinical response to oxcarbazepine/phenytoin therapy. Reduced penetrance of the PRRT2 mutation in this family could warrant genetic counseling.","variants":[{"Name":"NM_145239.3(PRRT2):c.604_607del (p.Ser202fs)","Chromosome":"16","Start":"29813653","Stop":"29813656","ReferenceAlleleVCF":"CCTCA","AlternateAlleleVCF":"C","allel_id":409614,"rule_based_match":false,"evidence_text":"c.604-607delTCAC, p.S202Hfs*25","llm_judgment":"PRESENT","evidence":"c.604-607delTCAC, p.S202Hfs*25","abstract_start":376,"abstract_end":406}]}
{"pmid":"23430498","title":"Urinary neopterin and phenylalanine loading test as tools for the biochemical diagnosis of segawa disease.","abstract":"Background. The diagnosis of autosomal dominant GTP-cyclohydrolase deficiency relies on the examination of the GCH1 gene and/or pterins and neurotransmitters in CSF. The aim of the study was to assess the diagnostic value, if any, of pterins in urine and blood phenylalanine (Phe) and tyrosine (Tyr) under oral Phe loading test.               Methods. We report on two new pedigrees with four symptomatic and four asymptomatic carriers whose pattern of urinary pterins and blood Phe/Tyr ratio under oral Phe loading pointed to GTP-cyclohydrolase deficiency. The study was then extended to 3 further patients and 90 controls. The diagnostic specificity and sensitivity of these metabolic markers were analysed by backwards logistic analysis.               Results. Two genetic alterations segregated alternatively in Family 1 (c.631-632 del AT and c.671A > G), while exon 1 deletion was transmitted along three generations in Family 2. Neopterin and biopterin concentrations in urine clustered differently in controls under and over the age of 15. Therefore patients and controls were sub grouped according to this age. Neopterin was significantly reduced in GCH1 mutated subjects younger than 15, and both neopterin and biopterin in those older than 15. Moreover, the Phe/Tyr ratios at the second and third hour were both significantly higher in patients than in controls. Backwards logistic regression demonstrated the high diagnostic sensitivity and specificity of combined values of neopterin concentration and Phe/Tyr ratio at the second hour.               Conclusions. Pterins in urine and Phe loading test are non-invasive and reliable tools for the biochemical diagnosis of GTP-cyclohydrolase deficiency.","variants":[{"Name":"NM_000161.3(GCH1):c.671A>G (p.Lys224Arg)","Chromosome":"14","Start":"54844099","Stop":"54844099","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":24322,"rule_based_match":true,"evidence_text":"c.671A > G","llm_judgment":"PRESENT","evidence":"c.671A > G","abstract_start":847,"abstract_end":857}]}
{"pmid":"17726231","title":"Novel mutations in the NF1 gene in Czech patients with neurofibromatosis type 1.","abstract":"Neurofibromatosis type 1 (NF1) is one of the most common inherited human disorders, with an estimated incidence of 1 per 3500 births. In most cases, the disease is caused either by mutation in the NF1 gene, or by a particular or complete deletion of the NF1 gene. The NF1 gene exhibits one of the highest mutation rates of any human disorder. In this experimental study of the NF1 gene, we screened the mutational spectrum of 22 unrelated patients from the Czech Republic using the denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) methods. We found NF1 mutations in 17 patients: 15 causal mutations were detected with the use of the DHPLC method (15/20, 75%). With the MPLA method, we also confirmed and specified two large deletions that were previously genotyped by microsatellite markers. Twelve of the above-mentioned mutations were newly found: c.1_2delATinsCC, c.1185+1G>C, c.1757_1760delCTAG, c.1642-7A>G, c.2329 T>G, c.2816delA, c.3738_3741delGTTT, c.4733 C>T, c.5220delT, c.6473_6474insGAAG, ex14_49del, ex28_49del. We present this study as a first effectual step in the routine diagnosis of the NF1 in patients from the Czech Republic.","variants":[{"Name":"NM_001042492.3(NF1):c.1642-7A>G","Chromosome":"17","Start":"31221843","Stop":"31221843","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":804938,"rule_based_match":true,"evidence_text":"c.1642-7A>G","llm_judgment":"PRESENT","evidence":"c.1642-7A>G","abstract_start":969,"abstract_end":980},{"Name":"NM_001042492.3(NF1):c.2816del (p.Asn939fs)","Chromosome":"17","Start":"31229430","Stop":"31229430","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1484874,"rule_based_match":true,"evidence_text":"c.2816delA","llm_judgment":"PRESENT","evidence":"c.2816delA","abstract_start":994,"abstract_end":1004},{"Name":"NM_001042492.3(NF1):c.2329T>G (p.Trp777Gly)","Chromosome":"17","Start":"31227526","Stop":"31227526","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":623344,"rule_based_match":true,"evidence_text":"c.2329 T>G","llm_judgment":"PRESENT","evidence":"c.2329 T>G","abstract_start":982,"abstract_end":992},{"Name":"NM_001042492.3(NF1):c.1185+1G>C","Chromosome":"17","Start":"31201160","Stop":"31201160","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":2895197,"rule_based_match":true,"evidence_text":"c.1185+1G>C","llm_judgment":"PRESENT","evidence":"c.1185+1G>C","abstract_start":936,"abstract_end":947}]}
{"pmid":"22950452","title":"Ophthalmic findings in a family with early-onset isolated ectopia lentis and the p.Arg62Cys mutation of the fibrillin-1 gene (FBN1).","abstract":"PURPOSE: The purpose of this paper is to describe ophthalmic findings in a family with isolated ectopia lentis (EL) caused by a specific FBN1 mutation.\nMETHODS: Detailed family histories and clinical data were recorded for six isolated EL patients of 11 family members. The ophthalmological and systematic examinations were performed on patients and unaffected members of the investigated family. The detailed ocular examinations included visual acuity, anterior chamber depth, pupil size, lens location, optometry, central corneal thickness, keratometry, slitlamp examination, fundus examination, axial length, ocular B-ultrasound, gonioscope checking, ultrasound biomicroscopy (UBM) and intraocular pressure (IOP; Goldmann applanation tonometer). Systematic examinations included the measurement of echocardiogram, height, arm span, skull, face, jaw, tooth, breast bone, spinal column, and skin. Genomic DNA was extracted using the phenol-chloroform extraction method for all subjects, and sequencing was carried out on an ABI Prism 3730 Genetic Analyzer.\nRESULTS: A heterozygous mutation, c.184C>T (p.Arg62Cys) in exon 2 of FBN1 was identified in all affected members but was not found in any unaffected member of the family. Our study presented detailed clinical manifestations, including some novel ophthalmic findings, such as pupillary abnormality, different types of glaucoma, and progressive hyperopia.\nCONCLUSIONS: Ophthalmic findings and the p.Arg62Cys mutation of FBN1 gene were reported in a family with early-onset isolated ectopia lentis.","variants":[{"Name":"NM_000138.5(FBN1):c.184C>T (p.Arg62Cys)","Chromosome":"15","Start":"48613073","Stop":"48613073","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":51465,"rule_based_match":true,"evidence_text":"c.184C>T (p.Arg62Cys)","llm_judgment":"PRESENT","evidence":"c.184C>T (p.Arg62Cys)","abstract_start":1092,"abstract_end":1113}]}
{"pmid":"29568967","title":"Novel MSH2 splice-site mutation in a young patient with Lynch syndrome.","abstract":"Lynch Syndrome (LS) is associated with germline mutations in one of the mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, PMS1 homolog 2, mismatch repair system component (PMS2), MLH3 and MSH3. The mutations identified in MMR genes are point mutations or large rearrangements. The point mutations are certainly pathogenetic whether they determine formation of truncated protein. The mutations that arise in splice sites are classified as 'likely pathogenic' variants. In the present study, a novel splicing mutation was identified, (named c.212‑1g>a), in the MSH2 gene. This novel mutation in the consensus splice site of MSH2 exon 2 leads to the loss of the canonical splice site, without skipping in‑frame of exon 2; also with the formation of 2 aberrant transcripts, due to the activation of novel splice sites in exon 2. This mutation was identified in a young patient who developed colon cancer at the age of 26 years and their belongs to family that met the 'Revised Amsterdam Criteria'. The present study provided insight into the molecular mechanism determining the pathogenicity of this novel MSH2 mutation and it reaffirms the importance of genetic testing in LS.","variants":[{"Name":"NM_000251.3(MSH2):c.212-1G>A","Chromosome":"2","Start":"47408400","Stop":"47408400","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":96367,"rule_based_match":false,"evidence_text":"c.212‑1g>a","llm_judgment":"PRESENT","evidence":"c.212‑1g>a","abstract_start":580,"abstract_end":590}]}
{"pmid":"19457309","title":"Birt-Hogg-Dubé syndrome in a patient with cutaneous symptoms and a c.1429 C > T;p.R477X mutation in exon 12 of the folliculin gene","abstract":"Birt-Hogg-Dubé syndrome is an autosomal dominant genodermatosis characterized by the presence of fibrofolliculomas, renal cancer, pulmonary cysts, and spontaneous pneumothorax. Recently, the folliculin gene responsible for this process has been identified, located on the short arm of chromosome 17. We present the case of a 49-year-old man with multiple whitish papules on the face, neck, and retroauricular area. Histology was compatible with fibrofolliculoma and genetic study showed a pathogenic mutation of the folliculin gene.","variants":[{"Name":"NM_144997.7(FLCN):c.1429C>T (p.Arg477Ter)","Chromosome":"17","Start":"17215188","Stop":"17215188","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":247653,"rule_based_match":true,"evidence_text":"c.1429 C > T;p.R477X","llm_judgment":"PRESENT","evidence":"c.1429 C > T;p.R477X","abstract_start":null,"abstract_end":null}]}
{"pmid":"26804652","title":"Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene.","abstract":"Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil, thymine and the antineoplastic agent 5-fluorouracil. Genetic variations in the gene encoding DPD (DPYD) have emerged as predictive risk alleles for 5FU-associated toxicity. Here we report an in-depth analysis of genetic variants in DPYD and their consequences for DPD activity and pyrimidine metabolites in 100 Dutch healthy volunteers. 34 SNPs were detected in DPYD and 15 SNPs were associated with altered plasma concentrations of pyrimidine metabolites. DPD activity was significantly associated with the plasma concentrations of uracil, the presence of a specific DPYD mutation (c.1905+1G>A) and the combined presence of three risk variants in DPYD (c.1905+1G>A, c.1129-5923C>G, c.2846A>T), but not with an altered uracil/dihydrouracil (U/UH2) ratio. Various haplotypes were associated with different DPD activities (haplotype D3, a decreased DPD activity; haplotype F2, an increased DPD activity). Functional analysis of eight recombinant mutant DPD enzymes showed a reduced DPD activity, ranging from 35% to 84% of the wild-type enzyme. Analysis of a DPD homology model indicated that the structural effect of the novel p.G401R mutation is most likely minor. The clinical relevance of the p.D949V mutation was demonstrated in a cancer patient heterozygous for the c.2846A>T mutation and a novel nonsense mutation c.1681C>T (p.R561X), experiencing severe grade IV toxicity. Our studies showed that the endogenous levels of uracil and the U/UH2 ratio are poor predictors of an impaired DPD activity. Loading studies with uracil to identify patients with a DPD deficiency warrants further investigation.","variants":[{"Name":"NM_000110.4(DPYD):c.2846A>T (p.Asp949Val)","Chromosome":"1","Start":"97082391","Stop":"97082391","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":94529,"rule_based_match":true,"evidence_text":"c.2846A>T","llm_judgment":"PRESENT","evidence":"c.2846A>T","abstract_start":811,"abstract_end":820},{"Name":"NM_000110.4(DPYD):c.1681C>T (p.Arg561Ter)","Chromosome":"1","Start":"97515785","Stop":"97515785","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":357164,"rule_based_match":true,"evidence_text":"c.1681C>T (p.R561X)","llm_judgment":"PRESENT","evidence":"c.1681C>T (p.R561X)","abstract_start":1447,"abstract_end":1466},{"Name":"NM_000110.4(DPYD):c.1905+1G>A","Chromosome":"1","Start":"97450058","Stop":"97450058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15471,"rule_based_match":true,"evidence_text":"c.1905+1G>A","llm_judgment":"PRESENT","evidence":"c.1905+1G>A","abstract_start":711,"abstract_end":722}]}
{"pmid":"24823460","title":"Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization.","abstract":"CONTEXT: Most cases of autosomal dominant hypoparathyroidism (ADH) are caused by gain-of-function mutations in CASR or dominant inhibitor mutations in GCM2 or PTH.\nOBJECTIVE: Our objectives were to identify the genetic basis for ADH in a multigenerational family and define the underlying disease mechanism.\nSUBJECTS: Here we evaluated a multigenerational family with ADH in which affected subjects had normal sequences in these genes and were shorter than unaffected family members.\nMETHODS: We collected clinical and biochemical data from 6 of 11 affected subjects and performed whole-exome sequence analysis on DNA from two affected sisters and their affected father. Functional studies were performed after expression of wild-type and mutant Gα11 proteins in human embryonic kidney-293-CaR cells that stably express calcium-sensing receptors.\nRESULTS: Whole-exome-sequencing followed by Sanger sequencing revealed a heterozygous mutation, c.179G>T; p.R60L, in GNA11, which encodes the α-subunit of G11, the principal heterotrimeric G protein that couples calcium-sensing receptors to signal activation in parathyroid cells. Functional studies of Gα11 R60L showed increased accumulation of intracellular concentration of free calcium in response to extracellular concentration of free calcium with a significantly decreased EC50 compared with wild-type Gα11. By contrast, R60L was significantly less effective than the oncogenic Q209L form of Gα11 as an activator of the MAPK pathway. Compared to subjects with CASR mutations, patients with GNA11 mutations lacked hypercalciuria and had normal serum magnesium levels.\nCONCLUSIONS: Our findings indicate that the germline gain-of-function mutation of GNA11 is a cause of ADH and implicate a novel role for GNA11 in skeletal growth.","variants":[{"Name":"NM_002067.5(GNA11):c.179G>T (p.Arg60Leu)","Chromosome":"19","Start":"3110191","Stop":"3110191","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":165722,"rule_based_match":true,"evidence_text":"c.179G>T; p.R60L","llm_judgment":"PRESENT","evidence":"c.179G>T; p.R60L","abstract_start":943,"abstract_end":959}]}
{"pmid":"28241805","title":"Rapidly progressive psychotic symptoms triggered by infection in a patient with methylenetetrahydrofolate reductase deficiency: a case report.","abstract":"BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn error of metabolism inherited in autosomal recessive pattern and is associated with a wide spectrum of neurological abnormalities.\nCASE PRESENTATION: We herein describe a 15-year-old boy with MTHFR deficiency who presented with a slowly progressive decline of school performance and a spastic gait. Rapidly deteriorating psychosis and repetitive seizures triggered by a febrile infection prompted neurological investigation. He had significantly elevated total plasma homocysteine and urinary homocystine levels, as well as a decreased plasma methionine level. Brain magnetic resonance imaging (MRI) revealed leukoencephalopathy. DNA gene sequencing showed c.446_447 del GC ins TT and c.137G > A, and c.665C > T heterozygous mutations in the MTHFR gene of the patient. Oral administration of betaine drastically improved his clinical symptoms within a few months. After 8 months of treatment, his total plasma homocysteine level moderately decreased; and the plasma methionine concentration became normalized. Furthermore, the white matter lesions on MRI had disappeared.\nCONCLUSION: This patient demonstrates the possibility that MTHFR deficiency should be considered in mentally retarded adolescents who display an abnormally elevated plasma level of homocysteine in association with progressive neurological dysfunction and leukoencephalopathy. Febrile infections may be an aggravating factor in patients with MTHFR deficiency.","variants":[{"Name":"NM_005957.5(MTHFR):c.446_447delinsTT (p.Gly149Val)","Chromosome":"1","Start":"11801189","Stop":"11801190","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"AA","allel_id":822593,"rule_based_match":false,"evidence_text":"c.446_447 del GC ins TT","llm_judgment":"PRESENT","evidence":"c.446_447 del GC ins TT","abstract_start":741,"abstract_end":764},{"Name":"NM_005957.5(MTHFR):c.137G>A (p.Arg46Gln)","Chromosome":"1","Start":"11802980","Stop":"11802980","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":185796,"rule_based_match":true,"evidence_text":"c.137G > A","llm_judgment":"PRESENT","evidence":"c.137G > A","abstract_start":769,"abstract_end":779}]}
{"pmid":"28460050","title":"IFT81 as a Candidate Gene for Nonsyndromic Retinal Degeneration.","abstract":"Purpose: IFT81, a core component of the IFT-B complex, involved in the bidirectional transport of ciliary proteins, has been recently implicated in syndromic ciliopathies. However, none of the IFT-B core complex proteins have been associated with nonsyndromic retinal dystrophies. Given the importance of ciliary transport in photoreceptor function and structural maintenance, we sought to investigate the impact of IFT (intraflagellar transport) mutations in nonsyndromic retinopathies.\nMethods: Whole exome sequencing was performed on 50 cone-rod dystrophy (CRD) patients that were previously screened for mutations in known retinal disease genes. The impact of candidate mutation was studied using in vitro cell system and in vivo zebrafish assay to determine the pathogenicity of the variant.\nResults: Compound heterozygous mutations in IFT81, including one nonsense (c.1213C>T, p.R405*) and one missense variant (c.1841T>C, p.L614P), were identified in a nonsyndromic CRD proband. Extensive functional analyses of the missense variant in cell culture and zebrafish strongly suggests its pathogenic nature. Loss of IFT81 impairs ciliogenesis and, interestingly, the missense variant displayed significantly reduced rescue of ciliogenesis in the IFT81 knockdown in vitro system. Consistently, dramatic reduction of rescue efficiency of the ift81 mutant zebrafish embryo by mRNA with the missense variant was observed, further supporting its pathogenicity.\nConclusions: Consistent with the function of the IFT-B complex in the maintenance of photoreceptor cilium, we report a case of mutations in a core IFT-B protein, IFT81. This represents the first report of mutations in IFT81 as a candidate gene for nonsyndromic retinal dystrophy, hence expanding the phenotype spectrum of IFT-B components.","variants":[{"Name":"NM_014055.4(IFT81):c.1841T>C (p.Leu614Pro)","Chromosome":"12","Start":"110209209","Stop":"110209209","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1414880,"rule_based_match":true,"evidence_text":"c.1841T>C (p.L614P)","llm_judgment":"PRESENT","evidence":"c.1841T>C","abstract_start":918,"abstract_end":927},{"Name":"NM_014055.4(IFT81):c.1213C>T (p.Arg405Ter)","Chromosome":"12","Start":"110180446","Stop":"110180446","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":839298,"rule_based_match":true,"evidence_text":"c.1213C>T, p.R405*","llm_judgment":"PRESENT","evidence":"c.1213C>T, p.R405*","abstract_start":872,"abstract_end":890}]}
{"pmid":"20981223","title":"Tufting Enteropathy with EpCAM Mutations in Two Siblings.","abstract":"Tufting enteropathy is a rare autosomal recessive disorder presenting with early-onset severe intractable diarrhea. The epithelial cell adhesion molecule gene (EpCAM) has recently been identified as the gene responsible for tufting enteropathy. Based on histology, a diagnosis of tufting enteropathy was made in two Korean siblings. They developed chronic diarrhea and failure to thrive. They had a broad nasal bridge and micrognathia. Duodenal and colonic biopsies showed villous atrophy, disorganization of surface enterocytes, and focal crowding resembling tufts. Protracted diarrhea continued and so cyclic parenteral nutrition was supplied. The sister had juvenile rheumatoid arthritis. Mutation analysis of EpCAM identified two compound heterozygous mutations in these siblings: 1) a donor splicing site mutation in intron 5 (c.491+1G>A) and 2) a novel nonsense mutation in exon 3 (c.316A>T, Lys106X). Analysis of EpCAM will be useful for genetic counseling and prenatal diagnosis of tufting enteropathy.","variants":[{"Name":"NM_002354.3(EPCAM):c.491+1G>A","Chromosome":"2","Start":"47375300","Stop":"47375300","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27810,"rule_based_match":true,"evidence_text":"c.491+1G>A","llm_judgment":"PRESENT","evidence":"c.491+1G>A","abstract_start":832,"abstract_end":842}]}
{"pmid":"15459971","title":"A point mutation in the lariat branch point of intron 6 of NPC1 as the cause of abnormal pre-mRNA splicing in Niemann-Pick type C disease.","abstract":"The lariat branch point sequence (BPS) is crucial for splicing pre-mRNA even if BPS mutations have infrequently been reported in human disease. In two siblings with Niemann-Pick type C (NPC) disease we identified two mutations of the NPC1 gene: i) one in exon 20 (c.2932C>T) (p.R978C) previously reported in NPC patients; ii) the other (c.882-28A>G) unreported, in the highly conserved adenosine of a putative lariat BPS of intron 6. Using RT-PCR we found that, besides the normally spliced mRNA, patients' fibroblasts contained minute amounts of an mRNA devoid of exon 7. The exon 6--exon 8 junction in this mRNA causes a frameshift and a premature stop codon, predicted to result in a truncated protein. To assess the effect of c.882-28A>G mutation we constructed two minigenes (wild type and mutant), spanning from intron 5 to intron 8, which were inserted into a pTarget vector and transfected in COS1 cells. The wild type minigene generated an mRNA of the expected size and sequence; the mutant minigene generated only an mRNA devoid of exon 7. This is the first example of a splicing defect due to a mutation in the lariat BPS in an intron of NPC1 found in NPC patients.","variants":[{"Name":"NM_000271.5(NPC1):c.2932C>T (p.Arg978Cys)","Chromosome":"18","Start":"23538651","Stop":"23538651","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18015,"rule_based_match":true,"evidence_text":"c.2932C>T","llm_judgment":"PRESENT","evidence":"c.2932C>T","abstract_start":264,"abstract_end":273}]}
{"pmid":"31166470","title":"A RECURRENT MUTATION IN TSHB GENE UNDERLYING CENTRAL CONGENITAL HYPOTHYROIDISM UNDETECTABLE IN NEONATAL SCREENING.","abstract":"OBJECTIVE: To describe the case of a patient with central congenital hypothyroidism (CCH) due to a recurrent mutation in the TSHB gene, as well as to conduct a genetic study of his family.\nCASE DESCRIPTION: It is presented a case report of a 5-month-old boy with a delayed diagnosis of isolated CCH in whom the molecular analysis was performed 12 years later and detected a recurrent mutation (c.373delT) in TSHB gene. The parents and sister were carriers of the mutant allele.\nCOMMENTS: The c.373delT mutation has previously been reported in patients from Brazil, Germany, Belgium, United States, Switzerland, Argentina, France, Portugal, United Kingdom and Ireland. In summary, our case and other ones reported in the literature support the theory that this mutation may be a common cause of isolated TSH deficiency. Isolated TSH deficiency is not detected by routine TSH-based neonatal screening, representing a clinical challenge. Therefore, when possible, molecular genetic study is indicated. Identification of affected and carriers allows the diagnosis, treatment and adequate genetic counseling.","variants":[{"Name":"NM_000549.5(TSHB):c.373del (p.Cys125fs)","Chromosome":"1","Start":"115034183","Stop":"115034183","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":427630,"rule_based_match":true,"evidence_text":"c.373delT","llm_judgment":"PRESENT","evidence":"c.373delT","abstract_start":394,"abstract_end":403}]}
{"pmid":"26680117","title":"Disease causing homozygous variants in the human hairless gene.","abstract":"BACKGROUND: Atrichia with papular lesions (APL) is a rare irreversible form of complete hair loss inherited in autosomal recessive manner. Hair loss is often followed by the appearance of multiple keratin-filled cysts or papules on exterior parts of the body. This phenotype results due to mutations in the human hairless gene (HR) mapped on chromosome 8p21.3. The present study was aimed to search for disease-causing sequence variants in the HR gene in five consanguineous families exhibiting features of APL.\nMETHODS: Linkage in five Pakistani lineal consanguineous families, displaying features of APL, was tested using microsatellite markers flanking the HR gene on chromosome 8p21.3. After constructing the haplotypes, variants in the gene HR were searched by dideoxy-chain termination sequencing.\nRESULTS: Haplotype analysis established linkage in all five families to the HR gene located on chromosome 8p.21.3. Subsequently, sequencing HR identified a novel homozygous nonsense variant (c.2541G>A, p.Trp847*) in one and previously reported two pathogenic variants (p.Cys690*, p.Pro1157Arg) in the other four families.\nCONCLUSION: Mutations identified extend the spectrum of mutations in the HR gene resulting in APL. Characterizing the clinical spectrum resulting from the disease-causing homozygous variants in the HR gene will direct clinical care of the family members.","variants":[{"Name":"NM_005144.5(HR):c.2541G>A (p.Trp847Ter)","Chromosome":"8","Start":"22120785","Stop":"22120785","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1679565,"rule_based_match":true,"evidence_text":"c.2541G>A, p.Trp847*","llm_judgment":"PRESENT","evidence":"c.2541G>A, p.Trp847*","abstract_start":995,"abstract_end":1015}]}
{"pmid":"24691054","title":"Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR.","abstract":"Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases, but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283 G>A; p.Gly428Asp) in a male infant with lifelong inflammation affecting the skin, bowel, and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules--similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient's skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died at the age of 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues.","variants":[{"Name":"NM_005228.5(EGFR):c.1283G>A (p.Gly428Asp)","Chromosome":"7","Start":"55157738","Stop":"55157738","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":167357,"rule_based_match":true,"evidence_text":"c.1283 G>A; p.Gly428Asp","llm_judgment":"PRESENT","evidence":"c.1283 G>A; p.Gly428Asp","abstract_start":440,"abstract_end":463}]}
{"pmid":"31509793","title":"Derivation of a human DOA iPSC line, IISHDOi006-A, with a mutation in the ACO2 gene: c.1999G>A; p.Glu667Lys.","abstract":"Human iPSC line, IISHDOi006-A, was obtained from fibroblasts of a patient with Dominant Optic Atrophy (DOA) carrying a heterozygous mutation in the gene ACO2: c.1999G>A; p.Glu667Lys. Reprogramming factors Oct3/4, Sox2, Klf4, and c-Myc were delivered using a non-integrative methodology that involves the use of Sendai virus.","variants":[{"Name":"NM_001098.3(ACO2):c.1999G>A (p.Glu667Lys)","Chromosome":"22","Start":"41527333","Stop":"41527333","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1488085,"rule_based_match":true,"evidence_text":"c.1999G>A; p.Glu667Lys","llm_judgment":"PRESENT","evidence":"c.1999G>A; p.Glu667Lys","abstract_start":159,"abstract_end":181}]}
{"pmid":"20052779","title":"Neonatal cholestasis and glucose-6-P-dehydrogenase deficiency.","abstract":"We report a Caucasian neonate with chronic non-spherocytic hemolytic anemia due to a class I G6PD deficiency. A novel mutation missense mutation in exon eight of the G6PD gene was detected (c.827C>T p.Pro276Leu). Bilirubin peaked on day 5 at 24 mg/dl with a conjugated bilirubin of 17 mg/dl. Jaundice resolved within 4 weeks. A detailed work-up failed to reveal other specific factors contributing to cholestasis. Severe hemolytic disease of the newborn may cause cholestasis even in the absence of associated primary hepato-biliary disease.","variants":[{"Name":"NM_001360016.2(G6PD):c.827C>T (p.Pro276Leu)","Chromosome":"X","Start":"154533613","Stop":"154533613","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1780175,"rule_based_match":true,"evidence_text":"c.827C>T p.Pro276Leu","llm_judgment":"PRESENT","evidence":"c.827C>T p.Pro276Leu","abstract_start":190,"abstract_end":210}]}
{"pmid":"22152680","title":"Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation.","abstract":"Lipoic acid is an essential prosthetic group of four mitochondrial enzymes involved in the oxidative decarboxylation of pyruvate, α-ketoglutarate, and branched chain amino acids and in the glycine cleavage. Lipoic acid is synthesized stepwise within mitochondria through a process that includes lipoic acid synthetase. We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity. A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins.","variants":[{"Name":"NM_006859.4(LIAS):c.746G>A (p.Arg249His)","Chromosome":"4","Start":"39470027","Stop":"39470027","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39586,"rule_based_match":true,"evidence_text":"c.746G>A (p.Arg249His)","llm_judgment":"PRESENT","evidence":"c.746G>A (p.Arg249His)","abstract_start":357,"abstract_end":379}]}
{"pmid":"15308132","title":"The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency.","abstract":"3-Hydroxy-3-methylglutaric aciduria (OMIM 246450) is an autosomal recessive inborn error of the final step of leucine catabolic and ketogenic pathways, caused by deficiency of the enzyme 3-hydroxy-3-methylglutaryl CoA lyase (HL, HMGCL, EC 4.1.3.4). Clinically, deficiency of the enzyme results in metabolic acidosis, hyperammonemia, and infantile hypoketotic hypoglycaemia usually presenting during the first year of life with vomiting, lethargy, hypotonia, and sometimes with respiratory distress and coma. HL deficiency is relatively common in Arabic populations but seems to be rare in Europe. Our recent experience suggests that HL deficiency is the most frequent organic aciduria in the Portuguese population. We herein report on the molecular study of the HMGCL gene in 11 cases originated from the Northern area of Portugal. We detected the E37X (c.109G > T) mutation, in 84.1% of the alleles, one allele carried the V168fs(-2) (504_505delCT) and other allele the novel D204N (c.610G > A) mutation. The mutation of the last allele remained unidentified. The relatively high frequency of the \"common\" HMGCL Portuguese mutation makes useful the development of a rapid and specific molecular confirmation of new cases with HL deficiency in our country.","variants":[{"Name":"NM_000191.3(HMGCL):c.109G>T (p.Glu37Ter)","Chromosome":"1","Start":"23820545","Stop":"23820545","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":192195,"rule_based_match":true,"evidence_text":"c.109G > T","llm_judgment":"PRESENT","evidence":"c.109G > T","abstract_start":854,"abstract_end":864}]}
{"pmid":"25082129","title":"Schinzel-Giedion syndrome: a new mutation in SETBP1","abstract":"Schinzel-Giedion syndrome (SGS) (#MIM 269150) is a rare genetic disorder characterized by very marked craniofacial dysmorphism, multiple congenital anomalies and severe intellectual disability. Most affected patients die in early childhood. SETBP1 was identified as the causative gene, but a limited number of patients with molecular confirmation have been reported to date. The case is reported of a 4 and a half year-old male patient, affected by SGS. SETBP1 sequencing analysis revealed the presence of a non-previously described mutation: c.2608G>T (p.Gly870Cys). The clinical features and differential diagnosis of this rare condition are reviewed. Dysmorphic features are strongly suggestive of SGS. Its clinical recognition is essential to enable an early diagnosis, a proper follow-up, and to provide the family with genetic counseling. To date, this is the seventeenth SGS patient published with SETBP1 mutation, and the first in Spain, helping to widen clinical and molecular knowledge of the disease.","variants":[{"Name":"NM_015559.3(SETBP1):c.2608G>T (p.Gly870Cys)","Chromosome":"18","Start":"44951948","Stop":"44951948","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":3536462,"rule_based_match":true,"evidence_text":"c.2608G>T (p.Gly870Cys)","llm_judgment":"PRESENT","evidence":"c.2608G>T (p.Gly870Cys)","abstract_start":543,"abstract_end":566}]}
{"pmid":"32203252","title":"De novo mutations of TUBB2A cause infantile-onset epilepsy and developmental delay.","abstract":"We analyzed our two new cases of infantile-onset epilepsy with developmental delay with de novo variant in TUBB2A and review the related literatures. Our two probands were both girls with infantile-onset epilepsy and global developmental delay. Case 1 had a novel de novo heterozygous missense variant: c.728C>T [p.Pro243Leu] (NM_001069.2). Her brain magnetic resonance imaging (MRI) showed nonspecific white matter myelination delay and slightly enlarged anterior horn of lateral ventricle. Her epilepsy had been controlled by TPM monotherapy. Case 2 had a reported de novo variant c.743C>T [p.Ala248Val] (NM_001069.2). Her brain MRI showed bilateral microgyria and corpus callosum dysplasia. A total of seven TUBB2A mutations cases had been published previously in five papers, therefore, until now, there were nine patients with TUBB2A mutations. All patients had developmental delay, among them seven cases also with infantile-onset epilepsy, one case with abnormal EEG but without clinical seizures. There are six cases that have different degree of cortical dysplasia, one case with cerebellar vermis atrophy and brainstem sacsinopathy, the rest two cases have no obvious brain structural abnormalities. There was one case with variant c.1249G>A (p.D417N) that had atypical clinical presentation, including prominent progressive spastic ataxia, sensory motor axonal neuropathy, and bilateral optic macular dystrophy, but relatively mild intellectual disability, his MRI showed cerebellar atrophy, thinning of the corpus callosum and pons sacsinopathy, but no cortical malformation. The p.A248V mutation was the most common mutation occurred in three patients (3/9). The clinical phenotypes of these three patients were similar, all of them had global developmental delay with no language and corpus callosum dysplasia, two cases with epilepsy and the other one only have EEG epileptic discharges without clinical seizure, two cases with cortical dysplasia and the other one without obvious brain malformation. In brief, global developmental delay was the most common phenotype of TUBB2A mutation-related disease, most cases also had infantile-onset epilepsy and cortical dysplasia and corpus callosum dysplasia. The region between seventh and eighth alpha-helix of TUBB2A may be a \"hot spot\" mutation domain.","variants":[{"Name":"NM_001069.3(TUBB2A):c.728C>T (p.Pro243Leu)","Chromosome":"6","Start":"3154473","Stop":"3154473","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":536712,"rule_based_match":true,"evidence_text":"c.728C>T [p.Pro243Leu] (NM_001069.2)","llm_judgment":"PRESENT","evidence":"c.728C>T [p.Pro243Leu] (NM_001069.2)","abstract_start":303,"abstract_end":339},{"Name":"NM_001069.3(TUBB2A):c.743C>T (p.Ala248Val)","Chromosome":"6","Start":"3154458","Stop":"3154458","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":132610,"rule_based_match":true,"evidence_text":"c.743C>T [p.Ala248Val] (NM_001069.2)","llm_judgment":"PRESENT","evidence":"c.743C>T [p.Ala248Val] (NM_001069.2)","abstract_start":583,"abstract_end":619}]}
{"pmid":"31009037","title":"Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus.","abstract":"Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C>T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr-/- mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.","variants":[{"Name":"NM_001621.5(AHR):c.1861C>T (p.Gln621Ter)","Chromosome":"7","Start":"17339686","Stop":"17339686","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":622996,"rule_based_match":true,"evidence_text":"c.1861C>T;p.Q621*","llm_judgment":"PRESENT","evidence":"c.1861C>T;p.Q621*","abstract_start":366,"abstract_end":383}]}
{"pmid":"28881388","title":"Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21.","abstract":"INTRODUCTION: A calpain-3 (CAPN3) gene heterozygous deletion (c.643_663del21) was recently linked to autosomal dominant (AD) limb-girdle muscular dystrophy. However, the possibility of digenic disease was raised. We describe 3 families with AD calpainopathy carrying this isolated mutation.\nMETHODS: Probands heterozygous for CAPN3 c.643_663del21 were identified by targeted next generation or whole exome sequencing. Clinical findings were collected for probands and families. Calpain-3 muscle Western blots were performed in 3 unrelated individuals.\nRESULTS: Probands reported variable weakness in their 40s or 50s, with myalgia, back pain, or hyperlordosis. Pelvic girdle muscles were affected with adductor and hamstring sparing. Creatine kinase was normal to 1,800 U/L, independent of weakness severity. Imaging demonstrated lumbar paraspinal muscle atrophy. Electromyographic findings and muscle biopsies were normal to mildly myopathic. Muscle calpain-3 expression was reduced.\nDISCUSSION: This study provides further evidence for AD calpainopathy associated with CAPN3 c.643_663del21. No pathogenic variants in other genes known to cause myopathy were detected. Muscle Nerve 57: 679-683, 2018.","variants":[{"Name":"NM_000070.2(CAPN3):c.643_663del(p.Ser215_Gly221del)","Chromosome":"15","Start":"42388935","Stop":"42388955","ReferenceAlleleVCF":"TGGTTCCTACGAAGCTCTGAAA","AlternateAlleleVCF":"T","allel_id":213824,"rule_based_match":false,"evidence_text":"c.643_663del21","llm_judgment":"PRESENT","evidence":"c.643_663del21","abstract_start":62,"abstract_end":76}]}
{"pmid":"27928777","title":"Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency.","abstract":"Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase (T2) deficiency) is an inherited disease of isoleucine catabolism and ketone body utilization caused by ACAT1 mutations. We identified ten Indian patients who manifested with ketoacidotic episodes of variable severity. The patients showed increased urinary excretion of isoleucine-catabolic intermediates: 2-methyl-3-hydroxybutyrate, 2-methylacetoacetate, and tiglylglycine. Six patients had a favorable outcome, one died, and three developed neurodevelopmental sequela. Mutational analysis revealed a common (p.Met193Arg) and four novel (p.Ile323Thr, p.Ala215Asn, c.1012_1015dup, and c.730+1G>A) ACAT1 mutations. Transient expression analyses of wild-type and mutant cDNA were performed at 30, 37, and 40°C. A p.Ile323Thr mutant T2 was detected with relative enzyme activity and protein amount of 20% and 25%, respectively, compared with wild type at 37°C; it was more prevalent at 30°C but ablated at 40°C. These findings showed that p.Ile323Thr had a significant residual T2 activity with temperature-sensitive instability. Neither residual enzymatic activity nor mutant T2 protein was identified in p.Met193Arg, p.Ala215Asn, and c.1012_1015dup mutations using supernatants; however, these mutant T2 proteins were detected in insoluble pellets by immunoblot analysis. Expression analyses confirmed pathogenicity of these mutations. T2 deficiency has a likely high incidence in India and p.Met193Arg may be a common mutation in the Indian population.","variants":[{"Name":"NM_000019.4(ACAT1):c.968T>C (p.Ile323Thr)","Chromosome":"11","Start":"108144010","Stop":"108144010","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":654065,"rule_based_match":false,"evidence_text":"p.Ile323Thr","llm_judgment":"PRESENT","evidence":"p.Ile323Thr","abstract_start":608,"abstract_end":619},{"Name":"NM_000019.4(ACAT1):c.578T>G (p.Met193Arg)","Chromosome":"11","Start":"108139040","Stop":"108139040","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":654045,"rule_based_match":false,"evidence_text":"p.Met193Arg","llm_judgment":"PRESENT","evidence":"p.Met193Arg","abstract_start":579,"abstract_end":590}]}
{"pmid":"34230638","title":"Missense NAA20 variants impairing the NatB protein N-terminal acetyltransferase cause autosomal recessive developmental delay, intellectual disability, and microcephaly.","abstract":"PURPOSE: N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. In five individuals with overlapping phenotypes, we identified recessive homozygous missense variants in NAA20.\nMETHODS: Two different NAA20 variants were identified in affected individuals in two consanguineous families by exome and genome sequencing. Biochemical studies were employed to assess the impact of the NAA20 variants on NatB complex formation and catalytic activity.\nRESULTS: Two homozygous variants, NAA20 p.Met54Val and p.Ala80Val (GenBank: NM_016100.4, c.160A>G and c.239C>T), segregated with affected individuals in two unrelated families presenting with developmental delay, intellectual disability, and microcephaly. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates. Thus, both NAA20 variants are impaired in their ability to perform cellular NatB-mediated N-terminal acetylation.\nCONCLUSION: We present here a report of pathogenic NAA20 variants causing human disease and data supporting an essential role for NatB-mediated N-terminal acetylation in human development and physiology.","variants":[{"Name":"NM_016100.5(NAA20):c.160A>G (p.Met54Val)","Chromosome":"20","Start":"20025758","Stop":"20025758","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1329782,"rule_based_match":true,"evidence_text":"NM_016100.4, c.160A>G","llm_judgment":"PRESENT","evidence":"NM_016100.4, c.160A>G","abstract_start":741,"abstract_end":762},{"Name":"NM_016100.5(NAA20):c.239C>T (p.Ala80Val)","Chromosome":"20","Start":"20026853","Stop":"20026853","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1329783,"rule_based_match":true,"evidence_text":"c.239C>T","llm_judgment":"PRESENT","evidence":"c.239C>T","abstract_start":767,"abstract_end":775}]}
{"pmid":"28644393","title":"Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions.","abstract":"A significant portion of patients diagnosed with vitelliform macular dystrophy (VMD) do not carry causative mutations in the classic VMD genes <i>BEST1</i> or <i>PRPH2</i>. We therefore performed a mutational screen in a cohort of 106 <i>BEST1/PRPH2</i>-negative VMD patients in two genes encoding secreted interphotoreceptor matrix proteoglycans-1 and -2 (<i>IMPG1</i> and <i>IMPG2</i>). We identified two novel mutations in <i>IMPG1</i> in two simplex VMD cases with disease onset in their early childhood, a heterozygous p.(Leu238Pro) missense mutation and a homozygous c.807 + 5G > A splice site mutation. The latter induced partial skipping of exon 7 of <i>IMPG1</i> in an in vitro splicing assay. Furthermore, we found heterozygous mutations including three stop [p.(Glu226*), p.(Ser522*), p.(Gln856*)] and five missense mutations [p.(Ala243Pro), p.(Gly1008Asp), p.(Phe1016Ser), p.(Tyr1042Cys), p.(Cys1077Phe)] in the <i>IMPG2</i> gene, one of them, p.(Cys1077Phe), previously associated with VMD. Asymptomatic carriers of the p.(Ala243Pro) and p.(Cys1077Phe) mutations show subtle foveal irregularities that could characterize a subclinical stage of disease. Taken together, our results provide further evidence for an involvement of dominant and recessive mutations in <i>IMPG1</i> and <i>IMPG2</i> in VMD pathology. There is a remarkable similarity in the clinical appearance of mutation carriers, presenting with bilateral, central, dome-shaped foveal accumulation of yellowish material with preserved integrity of the retinal pigment epithelium (RPE). Clinical symptoms tend to be more severe for <i>IMPG1</i> mutations.","variants":[{"Name":"NM_016247.4(IMPG2):c.3125A>G (p.Tyr1042Cys)","Chromosome":"3","Start":"101232889","Stop":"101232889","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1293986,"rule_based_match":false,"evidence_text":"p.(Tyr1042Cys)","llm_judgment":"PRESENT","evidence":"p.(Tyr1042Cys)","abstract_start":885,"abstract_end":899},{"Name":"NM_016247.4(IMPG2):c.727G>C (p.Ala243Pro)","Chromosome":"3","Start":"101273682","Stop":"101273682","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":856267,"rule_based_match":false,"evidence_text":"p.(Ala243Pro)","llm_judgment":"PRESENT","evidence":"p.(Ala243Pro)","abstract_start":838,"abstract_end":851},{"Name":"NM_001563.4(IMPG1):c.807+5G>A","Chromosome":"6","Start":"76018713","Stop":"76018713","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1229995,"rule_based_match":true,"evidence_text":"c.807 + 5G > A","llm_judgment":"PRESENT","evidence":"c.807 + 5G > A","abstract_start":573,"abstract_end":587},{"Name":"NM_016247.4(IMPG2):c.3230G>T (p.Cys1077Phe)","Chromosome":"3","Start":"101232784","Stop":"101232784","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":171853,"rule_based_match":false,"evidence_text":"p.(Cys1077Phe)","llm_judgment":"PRESENT","evidence":"p.(Cys1077Phe)","abstract_start":901,"abstract_end":915},{"Name":"NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro)","Chromosome":"6","Start":"76018812","Stop":"76018812","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":856532,"rule_based_match":false,"evidence_text":"p.(Leu238Pro)","llm_judgment":"PRESENT","evidence":"p.(Leu238Pro)","abstract_start":524,"abstract_end":537},{"Name":"NM_016247.4(IMPG2):c.3047T>C (p.Phe1016Ser)","Chromosome":"3","Start":"101232967","Stop":"101232967","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2795126,"rule_based_match":false,"evidence_text":"p.(Phe1016Ser)","llm_judgment":"PRESENT","evidence":"p.(Phe1016Ser)","abstract_start":869,"abstract_end":883},{"Name":"NM_016247.4(IMPG2):c.3023G>A (p.Gly1008Asp)","Chromosome":"3","Start":"101232991","Stop":"101232991","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3408695,"rule_based_match":false,"evidence_text":"p.(Gly1008Asp)","llm_judgment":"PRESENT","evidence":"p.(Gly1008Asp)","abstract_start":853,"abstract_end":867}]}
{"pmid":"25168385","title":"Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome.","abstract":"Keratoderma-hypotrichosis-leukonychia totalis syndrome (KHLS) is an extremely rare, autosomal-dominant disorder characterized by severe skin hyperkeratosis, congenital alopecia and leukonychia totalis. The genetic defect underlying KHLS remained undetermined. By performing whole-exome sequencing in a family with KHLS, we identified a heterozygous mutation (c.23G>T [p.Gly8Val]) in GJA1, which cosegregated with the phenotype in the family. In an additional affected individual, we also found the identical de novo mutation which was absent in his unaffected family members. GJA1 encodes a gap junction protein connexin 43 (Cx43) which is ubiquitously expressed in various organs, including the epidermis and hair follicles. In vitro studies on HEK293 cells expressing Cx43(Gly8Val) found that the protein formed gap junction plaques between adjacent transfected cells, as observed in the wild-type. Dye-transfer experiments by microinjection of Lucifer yellow displayed functional gap junction of the Cx43(Gly8Val) mutant. Using patch clamp and Ca(2+) imaging methods, we observed that the Cx43(Gly8Val) hemichannel had significantly more openings than Cx43(WT), facilitating Ca(2+) influx at resting potential. Such gain-of-function effect might result in cytoplasmic Ca(2+) overload, accelerated apoptosis of keratinocytes and subsequent skin hyperkeratosis. Taken together, our results demonstrated that, with probably enhanced hemichannel activities, a mutation in GJA1 is linked to KHLS without extracutaneous involvement.","variants":[{"Name":"NM_000165.5(GJA1):c.23G>T (p.Gly8Val)","Chromosome":"6","Start":"121446870","Stop":"121446870","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":199878,"rule_based_match":true,"evidence_text":"c.23G>T [p.Gly8Val]","llm_judgment":"PRESENT","evidence":"c.23G>T [p.Gly8Val]","abstract_start":359,"abstract_end":378}]}
{"pmid":"35759269","title":"Mutations in TAF8 cause a neurodegenerative disorder.","abstract":"TAF8 is part of the transcription factor II D complex, composed of the TATA-binding protein and 13 TATA-binding protein-associated factors (TAFs). Transcription factor II D is the first general transcription factor recruited at promoters to assemble the RNA polymerase II preinitiation complex. So far disorders related to variants in 5 of the 13 subunits of human transcription factor II D have been described. Recently, a child with a homozygous c.781-1G>A mutation in TAF8 has been reported. Here we describe seven further patients with mutations in TAF8 and thereby confirm the TAF8 related disorder. In two sibling patients, we identified two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8. In five further patients, the previously described c.781-1G > A mutation was present on both alleles. The clinical phenotype associated with the different TAF8 mutations is characterized by severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Cerebral imaging showed hypomyelination, a thin corpus callosum and brain atrophy. Moreover, repeated imaging in the sibling pair demonstrated progressive cerebral and cerebellar atrophy. Consistently, reduced N-acetylaspartate, a marker of neuronal viability, was observed on magnetic resonance spectroscopy. Further review of the literature shows that mutations causing a reduced expression of transcription factor II D subunits have an overlapping phenotype of microcephaly, developmental delay and intellectual disability. Although transcription factor II D plays an important role in RNA polymerase II transcription in all cells and tissues, the symptoms associated with such defects are almost exclusively neurological. This might indicate a specific vulnerability of neuronal tissue to widespread deregulation of gene expression as also seen in Rett syndrome or Cornelia de Lange syndrome.","variants":[{"Name":"NM_138572.3(TAF8):c.781-1G>A","Chromosome":"6","Start":"42077099","Stop":"42077099","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":626420,"rule_based_match":true,"evidence_text":"c.781-1G>A","llm_judgment":"PRESENT","evidence":"c.781-1G>A","abstract_start":448,"abstract_end":458},{"Name":"NM_138572.3(TAF8):c.45+4A>G","Chromosome":"6","Start":"42050590","Stop":"42050590","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1690830,"rule_based_match":true,"evidence_text":"c.45+4A > G","llm_judgment":"PRESENT","evidence":"c.45+4A > G","abstract_start":704,"abstract_end":715},{"Name":"NM_138572.3(TAF8):c.489G>A (p.Pro163=)","Chromosome":"6","Start":"42057513","Stop":"42057513","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1690831,"rule_based_match":true,"evidence_text":"c.489G>A","llm_judgment":"PRESENT","evidence":"c.489G>A","abstract_start":720,"abstract_end":728}]}
{"pmid":"25678693","title":"Novel FRMD7 Mutations and Genomic Rearrangement Expand the Molecular Pathogenesis of X-Linked Idiopathic Infantile Nystagmus.","abstract":"PURPOSE: Idiopathic infantile nystagmus (IIN; OMIM 31700) with X-linked inheritance is one of the most common forms of infantile nystagmus. Up to date, three X-linked loci have been identified, Xp11.4-p11.3 (calcium/calmodulin-dependent serine protein kinase [CASK]), Xp22 (GPR143), and Xq26-q27 (FRMD7), respectively. Here, we investigated the role of mutations and copy number variations (CNV) of FRMD7 and GPR143 in the molecular pathogenesis of IIN in 49 unrelated Belgian probands.\nMETHODS: We set up a comprehensive molecular genetic workflow based on Sanger sequencing, targeted next generation sequencing (NGS) and CNV analysis using multiplex ligation-dependent probe amplification (MLPA) for FRMD7 (NM_194277.2) and GPR143 (NM_000273.2).\nRESULTS: In 11/49 probands, nine unique FRMD7 changes were found, five of which are novel: frameshift mutation c.2036del, missense mutations c.801C>A and c.875T>C, splice-site mutation c.497+5G>A, and one genomic rearrangement (1.29 Mb deletion) in a syndromic case. Additionally, four known mutations were found: c.70G>A, c.886G>C, c.910C>T, and c.660del. The latter was found in three independent families. In silico predictions and segregation testing of the novel mutations support their pathogenic effect. No GPR143 mutations or CNVs were found in the remainder of the probands (38/49).\nCONCLUSIONS: Overall, genetic defects of FRMD7 were found in 11/49 (22.4%) probands, including the first reported genomic rearrangement of FRMD7 in IIN, expanding its mutational spectrum. Finally, we generate a discovery cohort of IIN patients potentially harboring either hidden a variation of FRMD7 or mutations in genes at known or novel loci sustaining the genetic heterogeneity of IIN.","variants":[{"Name":"NM_194277.3(FRMD7):c.70G>A (p.Gly24Arg)","Chromosome":"X","Start":"132100704","Stop":"132100704","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":25825,"rule_based_match":true,"evidence_text":"c.70G>A","llm_judgment":"PRESENT","evidence":"c.70G>A","abstract_start":1062,"abstract_end":1069},{"Name":"NM_194277.3(FRMD7):c.910C>T (p.Arg304Ter)","Chromosome":"X","Start":"132080262","Stop":"132080262","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2902026,"rule_based_match":true,"evidence_text":"c.910C>T","llm_judgment":"PRESENT","evidence":"c.910C>T","abstract_start":1081,"abstract_end":1089},{"Name":"NM_194277.3(FRMD7):c.886G>C (p.Gly296Arg)","Chromosome":"X","Start":"132082382","Stop":"132082382","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":860784,"rule_based_match":true,"evidence_text":"c.886G>C","llm_judgment":"PRESENT","evidence":"c.886G>C","abstract_start":1071,"abstract_end":1079},{"Name":"NM_194277.3(FRMD7):c.875T>C (p.Leu292Pro)","Chromosome":"X","Start":"132082393","Stop":"132082393","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1314704,"rule_based_match":true,"evidence_text":"c.875T>C","llm_judgment":"PRESENT","evidence":"c.875T>C","abstract_start":902,"abstract_end":910}]}
{"pmid":"32684921","title":"Four Novel Variants in","abstract":"Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 <i>(POU4F3</i>) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in <i>POU4F3</i>, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that <i>POU4F3</i> pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of <i>POU4F3</i> should be a routine examination for the diagnosis of hereditary hearing loss.","variants":[{"Name":"NM_002700.3(POU4F3):c.325C>T (p.His109Tyr)","Chromosome":"5","Start":"146339752","Stop":"146339752","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":961807,"rule_based_match":true,"evidence_text":"c.325C>T (p.His109Tyr)","llm_judgment":"PRESENT","evidence":"c.325C>T (p.His109Tyr)","abstract_start":381,"abstract_end":403}]}
{"pmid":"28096187","title":"","abstract":"BACKGROUND: A substantial amount of nuclear genes have been identified to be implicated in genetic hearing loss, while X-linked hearing loss is genetically heterogeneous and relatively infrequent.\nOBJECTIVE: To identify the causative gene mutation in a five-generation Chinese family with an X-linked recessive syndromic hearing loss (SHL).\nMETHODS: Targeted X-chromosome exome sequencing was conducted, and cosegregation analysis was performed in the members of the affected family. The in silico and expression studies were also performed.\nRESULTS: A 2-bp missense mutation (c.1717_1718GC>AA, p.A573N) in the G protein-coupled receptor associated sorting protein 2 (<i>GPRASP2</i>) gene was identified in four hemizygous male patients and two heterozygous female carriers, which was cosegregated with the clinical phenotypes in this family. In silico analysis supported that this gene mutation is functionally deleterious, and it was detected that homologous <i>Gprasp2</i> was highly expressed in multiple structures of the mouse cochlea, which suggested that <i>GPRASP2</i> might be the genetic cause for the described disease phenotypes.\nCONCLUSIONS: This study presented a novel X-linked SHL combined with unique and unrecognised clinical features, and a missense variation of <i>GPRASP2</i> was first identified to be implicated in X-linked SHL.","variants":[{"Name":"NM_001004051.4(GPRASP2):c.1717_1718delinsAA (p.Ala573Asn)","Chromosome":"X","Start":"102716586","Stop":"102716587","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"AA","allel_id":581718,"rule_based_match":false,"evidence_text":"c.1717_1718GC>AA, p.A573N","llm_judgment":"PRESENT","evidence":"c.1717_1718GC>AA, p.A573N","abstract_start":577,"abstract_end":602}]}
{"pmid":"31100584","title":"In-silico analysis of Thr767Ile pathogenic variant in the MSH6 gene in family with endometrial cancer.","abstract":"OBJECTIVE: To examine the mechanism of pathogenity of Thr767Ile variant on MSH6 protein.\nSTUDY DESIGN: We describe a family diagnosed with endometrial cancer in two generations associated with variant in the MSH6 gene (p. Thr767Ile / c. 2300C>T) (rs587781462). MSH6 c. 2300C>T was associated with autosomal-dominant pattern of inheritance. MSH6 c. 2300C>T has pathogenic status in ClinVar and LOVD3 databases but it has never been described in context of hereditary endometrial cancer. We utilized a number of in-silico bioinformatic approaches using MSH6 protein sequence and structural information to assess influence of Thr767Ile on MSH6 properties.\nRESULTS: MSH6 Thr767 is highly conservative amino acid among various kingdoms of organisms. Thr767Ile was predicted deleterious and likely decreases affinity of MSH2-MSH6 complex to DNA but not affect interaction between MSH2 and MSH6.\nCONCLUSIONS: To the best of our knowledge, this is the first description of MSH6 T767I pathogenic variant that could be associated with a hereditary endometrial cancer. Bioinformatic analyses showed that T767I substitution most likely affects the MSH6 most important role, which is a DNA binding.","variants":[{"Name":"NM_000179.3(MSH6):c.2300C>T (p.Thr767Ile)","Chromosome":"2","Start":"47800283","Stop":"47800283","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":150772,"rule_based_match":true,"evidence_text":"c. 2300C>T","llm_judgment":"PRESENT","evidence":"c. 2300C>T","abstract_start":234,"abstract_end":244}]}
{"pmid":"27882258","title":"Dysmorphic Facial Features and Other Clinical Characteristics in Two Patients with","abstract":"Peroxisomal disorders are a group of genetically heterogeneous metabolic diseases related to dysfunction of peroxisomes. Dysmorphic features, neurological abnormalities, and hepatic dysfunction can be presenting signs of peroxisomal disorders. Here we presented dysmorphic facial features and other clinical characteristics in two patients with <i>PEX1</i> gene mutation. Follow-up periods were 3.5 years and 1 year in the patients. Case I was one-year-old girl that presented with neurodevelopmental delay, hepatomegaly, bilateral hearing loss, and visual problems. Ophthalmologic examination suggested septooptic dysplasia. Cranial magnetic resonance imaging (MRI) showed nonspecific gliosis at subcortical and periventricular deep white matter. Case II was 2.5-year-old girl referred for investigation of global developmental delay and elevated liver enzymes. Ophthalmologic examination findings were consistent with bilateral nystagmus and retinitis pigmentosa. Cranial MRI was normal. Dysmorphic facial features including broad nasal root, low set ears, downward slanting eyes, downward slanting eyebrows, and epichantal folds were common findings in two patients. Molecular genetic analysis indicated homozygous novel IVS1-2A>G mutation in Case I and homozygous p.G843D (c.2528G>A) mutation in Case II in the <i>PEX1</i> gene. Clinical findings and developmental prognosis vary in <i>PEX1</i> gene mutation. Kabuki-like phenotype associated with liver pathology may indicate Zellweger spectrum disorders (ZSD).","variants":[{"Name":"NM_000466.3(PEX1):c.2528G>A (p.Gly843Asp)","Chromosome":"7","Start":"92501562","Stop":"92501562","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22555,"rule_based_match":true,"evidence_text":"p.G843D (c.2528G>A)","llm_judgment":"PRESENT","evidence":"p.G843D (c.2528G>A)","abstract_start":1268,"abstract_end":1287}]}
{"pmid":"34118692","title":"High throughput proteomic and metabolic profiling identified target correction of metabolic abnormalities as a novel therapeutic approach in head and neck paraganglioma.","abstract":"Head and neck paragangliomas (HNPGLs) are rare neoplasms that represent difficult treatment paradigms in neurotology. Germline mutations in genes encoding succinate dehydrogenase (SDH) are the cause of nearly all familial HNPGLs. However, the molecular mechanisms underlying tumorigenesis remain unclear. Mutational analysis identified 6 out of 14 HNPGLs harboring clinicopathologic SDH gene mutations. The SDHB gene was most frequently mutated in these patients, and western blot showed loss of SDHB protein in tumors with SDHB mutations. The paraganglioma cell line (PGL-626) was established from a sample that harbored a missense SDHB mutation (c.649C > T). Spectrometric analysis using tandem mass tags identified 151 proteins significantly differentially expressed in HNPGLs compared with normal nerves. Bioinformatics analyses confirmed the high level of enrichment of oxidative phosphorylation and metabolism pathways in HNPGLs. The mitochondrial complex subunits NDUFA2, NDUFA10, and NDUFA4, showed the most significantly increased expression and were localized predominantly in the cytoplasm of PGL-626 cells. The mitochondrial complex I inhibitor metformin exerted dose-dependent inhibitory effects on PGL-626 cells via cooperative down-regulation of NDUFA2, 4, and 10, with a significant decrease in the levels of reactive oxygen species and mitochondrial membrane potential. Further metabolomic analysis of PGL-626 cells showed that metabolites involved in central carbon metabolism in cancer and sphingolipid signaling pathways, pantothenate and CoA biosynthesis, and tryptophan and carbon metabolism were significantly altered after metformin treatment. Thus, this study provides insights into the molecular mechanisms underlying HNPGL tumorigenesis and identifies target correction of metabolic abnormalities as a novel therapeutic approach for this disease.","variants":[{"Name":"NM_003000.3(SDHB):c.649C>T (p.Arg217Cys)","Chromosome":"1","Start":"17022724","Stop":"17022724","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":181609,"rule_based_match":true,"evidence_text":"c.649C > T","llm_judgment":"PRESENT","evidence":"c.649C > T","abstract_start":648,"abstract_end":658}]}
{"pmid":"27317792","title":"Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism.","abstract":"Approximately 10% of von Willebrand factor (VWF) gene mutations are thought to alter messenger RNA (mRNA) splicing through disruption of consensus splice sites. This mechanism is likely underrecognized and affected by mutations outside consensus splice sites. During VWF synthesis, splicing abnormalities lead to qualitative defects or quantitative deficiencies in VWF. This study investigated the pathologic mechanism acting in 3 von Willebrand disease (VWD) families with putative splicing mutations using patient-derived blood outgrowth endothelial cells (BOECs) and a heterologous human embryonic kidney (HEK 293(T)) cell model. The exonic mutation c.3538G>A causes 3 in-frame splicing variants (23del, 26del, and 23/26del) which cannot bind platelets, blood coagulation factor VIII, or collagen, causing VWD through dominant-negative intracellular retention of coexpressed wild-type (WT) VWF, and increased trafficking to lysosomes. Individuals heterozygous for the c.5842+1G>C mutation produce exon 33 skipping, exons 33-34 skipping, and WT VWF transcripts. Pathogenic intracellular retention of VWF lacking exons 33-34 causes their VWD. The branch site mutation c.6599-20A>T causes type 1 VWD through mRNA degradation of exon 38 skipping transcripts. Splicing ratios of aberrant transcripts and coexpressed WT were altered in the BOECs with exposure to shear stress. This study provides evidence of mutations outside consensus splice sites disrupting splicing and introduces the concept that VWF splicing is affected by shear stress on endothelial cells.","variants":[{"Name":"NM_000552.5(VWF):c.3538G>A (p.Gly1180Arg)","Chromosome":"12","Start":"6022740","Stop":"6022740","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":106145,"rule_based_match":true,"evidence_text":"c.3538G>A","llm_judgment":"PRESENT","evidence":"c.3538G>A","abstract_start":653,"abstract_end":662}]}
{"pmid":"33268592","title":"Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss.","abstract":"The pathophysiology underlying spiral ganglion cell defect-induced deafness remains elusive. Using the whole exome sequencing approach, in combination with functional assays and a mouse disease model, we identified the potentially novel deafness-causative MAP1B gene encoding a highly conserved microtubule-associated protein. Three novel heterozygous MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families. Here, we show that MAP1B is highly expressed in the spiral ganglion neurons in the mouse cochlea. Using otic sensory neuron-like cells, generated by pluripotent stem cells from patients carrying the MAP1B mutation and control subject, we demonstrated that the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B, which are involved in the microtubule stability and dynamics. Strikingly, otic sensory neuron-like cells exhibited disturbed dynamics of microtubules, axonal elongation, and defects in electrophysiological properties. Dysfunctions of these derived otic sensory neuron-like cells were rescued by genetically correcting MAP1B mutation using CRISPR/Cas9 technology. Involvement of MAP1B in hearing was confirmed by audiometric evaluation of Map1b heterozygous KO mice. These mutant mice displayed late-onset progressive sensorineural hearing loss that was more pronounced in the high frequencies. The spiral ganglion neurons isolated from Map1b mutant mice exhibited the deficient phosphorylation and disturbed dynamics of microtubules. Map1b deficiency yielded defects in the morphology and electrophysiology of spiral ganglion neurons, but it did not affect the morphologies of cochlea in mice. Therefore, our data demonstrate that dysfunctions of spiral ganglion neurons induced by MAP1B deficiency caused hearing loss.","variants":[{"Name":"NM_005909.5(MAP1B):c.4198A>G (p.Ser1400Gly)","Chromosome":"5","Start":"72197553","Stop":"72197553","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1519421,"rule_based_match":true,"evidence_text":"c.4198A>G","llm_judgment":"PRESENT","evidence":"c.4198A>G","abstract_start":369,"abstract_end":378}]}
{"pmid":"25118025","title":"VPS35 and DNAJC13 disease-causing variants in essential tremor.","abstract":"Exome-sequencing analyses have identified vacuolar protein sorting 35 homolog (VPS35) and DnaJ (Hsp40) homolog, subfamily C, member 13 (DNAJC13) harboring disease-causing variants for Parkinson disease (PD). Owing to the suggested clinical, pathological and genetic overlap between PD and essential tremor (ET) we assessed the presence of two VPS35 and DNAJC13 disease-causing variants in ET patients. TaqMan probes were used to genotype VPS35 c.1858G>A (p.(D620N)) (rs188286943) and DNAJC13 c.2564A>G (p.(N855S)) (rs387907571) in 571 ET patients of European descent, and microsatellite markers were used to define the disease haplotype in variant carriers. Genotyping of DNAJC13 identified two ET patients harboring the c.2564A>G (p.(N855S)) variant previously identified in PD patients. Both patients appear to share the disease haplotype previously reported. ET patients with the VPS35 c.1858G>A (p.(D620N)) variants were not observed. Although a genetic link between PD and ET has been suggested, DNAJC13 c.2564A>G (p.(N855S)) represents the first disease-causing variant identified in both, and suggests the regulation of clathrin dynamics and endosomal trafficking in the pathophysiology of a subset of ET patients.","variants":[{"Name":"NM_015268.4(DNAJC13):c.2564A>G (p.Asn855Ser)","Chromosome":"3","Start":"132477995","Stop":"132477995","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":70810,"rule_based_match":true,"evidence_text":"DNAJC13 c.2564A>G (p.(N855S))","llm_judgment":"PRESENT","evidence":"DNAJC13 c.2564A>G (p.(N855S))","abstract_start":484,"abstract_end":513}]}
{"pmid":"32385905","title":"Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy.","abstract":"Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi-allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant-onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.","variants":[{"Name":"NM_014845.6(FIG4):c.506A>C (p.Tyr169Ser)","Chromosome":"6","Start":"109735158","Stop":"109735158","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":244482,"rule_based_match":true,"evidence_text":"c.506A>C p.(Tyr169Ser)","llm_judgment":"PRESENT","evidence":"c.506A>C p.(Tyr169Ser)","abstract_start":494,"abstract_end":516}]}
{"pmid":"23378218","title":"A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3.","abstract":"Missense mutations in TUBB3, the gene that encodes the neuronal-specific protein β-tubulin isotype 3, can cause isolated or syndromic congenital fibrosis of the extraocular muscles, a form of complex congenital strabismus characterized by cranial nerve misguidance. One of the eight TUBB3 mutations reported to cause congenital fibrosis of the extraocular muscles, c.1228G>A results in a TUBB3 E410K amino acid substitution that directly alters a kinesin motor protein binding site. We report the detailed phenotypes of eight unrelated individuals who harbour this de novo mutation, and thus define the 'TUBB3 E410K syndrome'. Individuals harbouring this mutation were previously reported to have congenital fibrosis of the extraocular muscles, facial weakness, developmental delay and possible peripheral neuropathy. We now confirm by electrophysiology that a progressive sensorimotor polyneuropathy does indeed segregate with the mutation, and expand the TUBB3 E410K phenotype to include Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), stereotyped midface hypoplasia, intellectual disabilities and, in some cases, vocal cord paralysis, tracheomalacia and cyclic vomiting. Neuroimaging reveals a thin corpus callosum and anterior commissure, and hypoplastic to absent olfactory sulci, olfactory bulbs and oculomotor and facial nerves, which support underlying abnormalities in axon guidance and maintenance. Thus, the E410K substitution defines a new genetic aetiology for Moebius syndrome, Kallmann syndrome and cyclic vomiting. Moreover, the c.1228G>A mutation was absent in DNA from ∼600 individuals who had either Kallmann syndrome or isolated or syndromic ocular and/or facial dysmotility disorders, but who did not have the combined features of the TUBB3 E410K syndrome, highlighting the specificity of this phenotype-genotype correlation. The definition of the TUBB3 E410K syndrome will allow clinicians to identify affected individuals and predict the mutation based on clinical features alone.","variants":[{"Name":"NM_006086.4(TUBB3):c.1228G>A (p.Glu410Lys)","Chromosome":"16","Start":"89935679","Stop":"89935679","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":22006,"rule_based_match":true,"evidence_text":"c.1228G>A","llm_judgment":"PRESENT","evidence":"c.1228G>A","abstract_start":365,"abstract_end":374}]}
{"pmid":"28993909","title":"Coexistence of CLCN1 and SCN4A mutations in one family suffering from myotonia.","abstract":"Non-dystrophic myotonias are characterized by clinical overlap making it challenging to establish genotype-phenotype correlations. We report clinical and electrophysiological findings in a girl and her father concomitantly harbouring single heterozygous mutations in SCN4A and CLCN1 genes. Functional characterization of N1297S hNav1.4 mutant was performed by patch clamp. The patients displayed a mild phenotype, mostly resembling a sodium channel myotonia. The CLCN1 c.501C>G (p.F167L) mutation has been already described in recessive pedigrees, whereas the SCN4A c.3890A>G (p.N1297S) variation is novel. Patch clamp experiments showed impairment of fast and slow inactivation of the mutated Nav1.4 sodium channel. The present findings suggest that analysis of both SCN4A and CLCN1 genes should be considered in myotonic patients with atypical clinical and neurophysiological features.","variants":[{"Name":"NM_000083.3(CLCN1):c.501C>G (p.Phe167Leu)","Chromosome":"7","Start":"143321432","Stop":"143321432","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":205752,"rule_based_match":true,"evidence_text":"CLCN1 c.501C>G (p.F167L)","llm_judgment":"PRESENT","evidence":"CLCN1 c.501C>G (p.F167L)","abstract_start":463,"abstract_end":487},{"Name":"NM_000334.4(SCN4A):c.3890A>G (p.Asn1297Ser)","Chromosome":"17","Start":"63944695","Stop":"63944695","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3072904,"rule_based_match":true,"evidence_text":"SCN4A c.3890A>G (p.N1297S)","llm_judgment":"PRESENT","evidence":"SCN4A c.3890A>G (p.N1297S)","abstract_start":560,"abstract_end":586}]}
{"pmid":"31636395","title":"Functional characterization of 84 PALB2 variants of uncertain significance.","abstract":"PURPOSE: Inherited pathogenic variants in PALB2 are associated with increased risk of breast and pancreatic cancer. However, the functional and clinical relevance of many missense variants of uncertain significance (VUS) identified through clinical genetic testing is unclear. The ability of patient-derived germline missense VUS to disrupt PALB2 function was assessed to identify variants with potential clinical relevance.\nMETHODS: The influence of 84 VUS on PALB2 function was evaluated using a cellular homology directed DNA repair (HDR) assay and VUS impacting activity were further characterized using secondary functional assays.\nRESULTS: Four (~5%) variants (p.L24S,c.71T>C; p.L35P,c.104T>C; pI944N,c.2831T>A; and p.L1070P,c.3209T>C) disrupted PALB2-mediated HDR activity. These variants conferred sensitivity to cisplatin and a poly(ADP-ribose) polymerase (PARP) inhibitor and reduced RAD51 foci formation in response to DNA damage. The p.L24S and p.L35P variants disrupted BRCA1-PALB2 protein complexes, p.I944N was associated with protein instability, and both p.I944N and p.L1070P mislocalized PALB2 to the cytoplasm.\nCONCLUSION: These findings show that the HDR assay is an effective method for screening the influence of inherited variants on PALB2 function, that four missense variants impact PALB2 function and may influence cancer risk and response to therapy, and suggest that few inherited PALB2 missense variants disrupt PALB2 function in DNA repair.","variants":[{"Name":"NM_024675.4(PALB2):c.3209T>C (p.Leu1070Pro)","Chromosome":"16","Start":"23608005","Stop":"23608005","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":213154,"rule_based_match":true,"evidence_text":"c.3209T>C","llm_judgment":"PRESENT","evidence":"c.3209T>C","abstract_start":731,"abstract_end":740},{"Name":"NM_024675.4(PALB2):c.71T>C (p.Leu24Ser)","Chromosome":"16","Start":"23638107","Stop":"23638107","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":235336,"rule_based_match":true,"evidence_text":"c.71T>C","llm_judgment":"PRESENT","evidence":"c.71T>C","abstract_start":674,"abstract_end":681},{"Name":"NM_024675.4(PALB2):c.2831T>A (p.Ile944Asn)","Chromosome":"16","Start":"23624012","Stop":"23624012","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":184178,"rule_based_match":true,"evidence_text":"c.2831T>A","llm_judgment":"PRESENT","evidence":"c.2831T>A","abstract_start":707,"abstract_end":716},{"Name":"NM_024675.4(PALB2):c.104T>C (p.Leu35Pro)","Chromosome":"16","Start":"23638074","Stop":"23638074","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":644494,"rule_based_match":true,"evidence_text":"c.104T>C","llm_judgment":"PRESENT","evidence":"c.104T>C","abstract_start":690,"abstract_end":698}]}
{"pmid":"35654103","title":"A novel GALC gene mutation associated with adult-onset Krabbe disease: a case report.","abstract":"To analyze the clinical, imaging, and genetic characteristics of a patient diagnosed with adult-onset Krabbe disease (KD). Clinical and imaging features of the patient were retrospectively reviewed. The patient, a 40-year-old female, presented adult-onset spastic paraplegia. Brain magnetic resonance imaging (MRI) showed white matter hyperintensities along bilateral optic radiations. Colorimetry of galactocerebrosidase enzyme activity showed low enzyme levels. A heterozygous missense mutation: c.1658G>A (p.G553E) and c.1901T>C (p.L634S) was identified in the <i>GALC</i> gene by whole exome sequencing, and was verified by Sanger sequencing. KD should be considered when patients presented adult-onset spastic paraplegia with classical MRI imaging features. Mutation c.1658G>A (p.G553E) was novel in <i>GALC</i> gene and broaden the mutation spectrum.","variants":[{"Name":"NM_000153.4(GALC):c.1901T>C (p.Leu634Ser)","Chromosome":"14","Start":"87939915","Stop":"87939915","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":227363,"rule_based_match":true,"evidence_text":"c.1901T>C (p.L634S)","llm_judgment":"PRESENT","evidence":"c.1901T>C (p.L634S)","abstract_start":522,"abstract_end":541}]}
{"pmid":"28462455","title":"A novel MERTK mutation causing retinitis pigmentosa.","abstract":"PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous inherited retinal dystrophy. To date, over 80 genes have been implicated in RP. However, the disease demonstrates significant locus and allelic heterogeneity not entirely captured by current testing platforms. The purpose of the present study was to characterize the underlying mutation in a patient with RP without a molecular diagnosis after initial genetic testing.\nMETHODS: Whole-exome sequencing of the affected proband was performed. Candidate gene mutations were selected based on adherence to expected genetic inheritance pattern and predicted pathogenicity. Sanger sequencing of MERTK was completed on the patient's unaffected mother, affected brother, and unaffected sister to determine genetic phase.\nRESULTS: Eight sequence variants were identified in the proband in known RP-associated genes. Sequence analysis revealed that the proband was a compound heterozygote with two independent mutations in MERTK, a novel nonsense mutation (c.2179C > T) and a previously reported missense variant (c.2530C > T). The proband's affected brother also had both mutations. Predicted phase was confirmed in unaffected family members.\nCONCLUSION: Our study identifies a novel nonsense mutation in MERTK in a family with RP and no prior molecular diagnosis. The present study also demonstrates the clinical value of exome sequencing in determining the genetic basis of Mendelian diseases when standard genetic testing is unsuccessful.","variants":[{"Name":"NM_006343.3(MERTK):c.2179C>T (p.Arg727Ter)","Chromosome":"2","Start":"112019512","Stop":"112019512","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":856142,"rule_based_match":true,"evidence_text":"c.2179C > T","llm_judgment":"PRESENT","evidence":"c.2179C > T","abstract_start":1012,"abstract_end":1023},{"Name":"NM_006343.3(MERTK):c.2530C>T (p.Arg844Cys)","Chromosome":"2","Start":"112028394","Stop":"112028394","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":790031,"rule_based_match":true,"evidence_text":"c.2530C > T","llm_judgment":"PRESENT","evidence":"c.2530C > T","abstract_start":1069,"abstract_end":1080}]}
{"pmid":"33397043","title":"Whole Exome Sequencing Identifies Novel Genetic Alterations in Patients with Pheochromocytoma/Paraganglioma.","abstract":"BACKGROUND: Pheochromocytoma and paragangliomas (PPGL) are known as tumors with the highest level of heritability, approximately 30% of all cases. Clinical practice guidelines of PPGL recommend genetic testing for germline variants in all patients. In this study, we used whole exome sequencing to identify novel causative variants associated with PPGL to improve the detection of rare genetic variants in our cohort.\nMETHODS: Thirty-six tested negative for pathogenic variants in previous Sanger sequencing or targeted gene panel testing for PPGL underwent whole exome sequencing. Whole exome sequencing was performed using DNA samples enriched using TruSeq Custom Enrichment Kit and sequenced with MiSeq (Illumina Inc.). Sequencing alignment and variant calling were performed using SAMtools.\nRESULTS: Among previously mutation undetected 36 patients, two likely pathogenic variants and 13 variants of uncertain significance (VUS) were detected in 32 pheochromocytoma-related genes. SDHA c.778G>A (p.Gly260Arg) was detected in a patient with head and neck paraganglioma, and KIF1B c.2787-2A>C in a patient with a bladder paraganglioma. Additionally, a likely pathogenic variant in BRCA2, VUS in TP53, and VUS in NFU1 were detected.\nCONCLUSION: Exome sequencing further identified genetic alterations by 5.6% in previously mutation undetected patients in PPGL. Implementation of targeted gene sequencing consisted of extended genes of PPGL in routine clinical screening can support the level of comprehensive patient assessment.","variants":[{"Name":"NM_004168.4(SDHA):c.778G>A (p.Gly260Arg)","Chromosome":"5","Start":"230883","Stop":"230883","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":395029,"rule_based_match":true,"evidence_text":"SDHA c.778G>A (p.Gly260Arg)","llm_judgment":"PRESENT","evidence":"SDHA c.778G>A (p.Gly260Arg)","abstract_start":985,"abstract_end":1012}]}
{"pmid":"29907875","title":"A novel homozygous missense mutation in the SH3-binding motif of STAMBP causing microcephaly-capillary malformation syndrome.","abstract":"Microcephaly-capillary malformation syndrome is a congenital and neurodevelopmental disorder caused by biallelic mutations in the STAMBP gene. Here we identify the novel homozygous mutation located in the SH3 binding motif of STAMBP (NM_006463.4) (c.707C>T: p.Ser236Phe) through whole-exome sequencing. The case patient was a 2-year-old boy showing severe global developmental delay, progressive microcephaly, refractory seizures, dysmorphic facial features, and multiple capillary malformations. Immunoblot analysis of patient-derived lymphoblastoid cell lines (LCLs) revealed a severe reduction in STAMBP expression, indicating that Ser236Phe induces protein instability. STAMBP interacts with the SH3 domain of STAM and transduces downstream signals from the Jaks-STAM complex. The substitution of Ser236Phe found in the case patient was located in the SH3-binding motif, and we propose the mutation may block STAM binding and subsequently induce STAMBP degradation. Contrary to previously reported STAMBP mutations, the Ser236Phe mutation did not lead to constitutive activation of the PI3K-AKT-mTOR pathway in patient-derived LCLs, as indicated by the expression of phosphorylated S6 ribosomal protein, suggesting that it is not the major pathomechanism underlying the disorder in this patient.","variants":[{"Name":"NM_213622.4(STAMBP):c.707C>T (p.Ser236Phe)","Chromosome":"2","Start":"73847718","Stop":"73847718","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":485890,"rule_based_match":true,"evidence_text":"NM_006463.4) (c.707C>T: p.Ser236Phe","llm_judgment":"PRESENT","evidence":"NM_006463.4) (c.707C>T: p.Ser236Phe","abstract_start":234,"abstract_end":269}]}
{"pmid":"38358893","title":"Clinical, immunohistochemical, and genetic characterization of splice-altering biallelic DES variants: Therapeutic implications.","abstract":"Pathogenic variants in the DES gene clinically manifest as progressive skeletal muscle weakness, cardiomyopathy with associated severe arrhythmias, and respiratory insufficiency, and are collectively known as desminopathies. While most DES pathogenic variants act via a dominant mechanism, recessively acting variants have also been reported. Currently, there are no effective therapeutic interventions for desminopathies of any type. Here, we report an affected individual with rapidly progressive dilated cardiomyopathy, requiring heart transplantation at age 13 years, in the setting of childhood-onset skeletal muscle weakness. We identified biallelic DES variants (c.640-13 T>A and c.1288+1 G>A) and show aberrant DES gene splicing in the affected individual's muscle. Through the generation of an inducible lentiviral system, we transdifferentiated fibroblast cultures derived from the affected individual into myoblasts and validated this system using RNA sequencing. We tested rationally designed, custom antisense oligonucleotides to screen for splice correction in these transdifferentiated cells and a functional minigene splicing assay. However, rather than correctly redirecting splicing, we found them to induce undesired exon skipping. Our results indicate that, while an individual precision-based molecular therapeutic approach to splice-altering pathogenic variants is promising, careful preclinical testing is imperative for each novel variant to test the feasibility of this type of approach for translation.","variants":[{"Name":"NM_001927.4(DES):c.1288+1G>A","Chromosome":"2","Start":"219423821","Stop":"219423821","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":650939,"rule_based_match":true,"evidence_text":"c.1288+1 G>A","llm_judgment":"PRESENT","evidence":"c.1288+1 G>A","abstract_start":687,"abstract_end":699}]}
{"pmid":"22930593","title":"A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.","abstract":"Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed.","variants":[{"Name":"NM_002109.6(HARS1):c.410G>A (p.Arg137Gln)","Chromosome":"5","Start":"140679114","Stop":"140679114","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48573,"rule_based_match":true,"evidence_text":"c.410G>A/p.Arg137Gln","llm_judgment":"PRESENT","evidence":"c.410G>A/p.Arg137Gln","abstract_start":556,"abstract_end":576}]}
{"pmid":"20597108","title":"Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotype.","abstract":"We have previously shown that mutations in the genes encoding DNA Ligase IV (LIGIV) and RAD50, involved in DNA repair by nonhomologous-end joining (NHEJ) and homologous recombination, respectively, lead to clinical and cellular features similar to those of Nijmegen Breakage Syndrome (NBS). Very recently, a new member of the NHEJ repair pathway, NHEJ1, was discovered, and mutations in patients with features resembling NBS were described. Here we report on five patients from four families of different ethnic origin with the NBS-like phenotype. Sequence analysis of the NHEJ1 gene in a patient of Spanish and in a patient of Turkish origin identified homozygous, previously reported mutations, c.168C>G (p.Arg57Gly) and c.532C>T (p.Arg178Ter), respectively. Two novel, paternally inherited truncating mutations, c.495dupA (p.Asp166ArgfsTer20) and c.526C>T (p.Arg176Ter) and two novel, maternal genomic deletions of 1.9 and 6.9 kb of the NHEJ1 gene, were found in a compound heterozygous state in two siblings of German origin and in one Malaysian patient, respectively. Our findings confirm that patients with NBS-like phenotypes may have mutations in the NHEJ1 gene including multiexon deletions, and show that considerable clinical variability could be observed even within the same family.","variants":[{"Name":"NM_024782.3(NHEJ1):c.532C>T (p.Arg178Ter)","Chromosome":"2","Start":"219146736","Stop":"219146736","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16022,"rule_based_match":true,"evidence_text":"c.532C>T (p.Arg178Ter)","llm_judgment":"PRESENT","evidence":"c.532C>T (p.Arg178Ter)","abstract_start":723,"abstract_end":745},{"Name":"NM_024782.3(NHEJ1):c.526C>T (p.Arg176Ter)","Chromosome":"2","Start":"219147660","Stop":"219147660","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":2894434,"rule_based_match":true,"evidence_text":"c.526C>T (p.Arg176Ter)","llm_judgment":"PRESENT","evidence":"c.526C>T (p.Arg176Ter)","abstract_start":850,"abstract_end":872}]}
{"pmid":"12955723","title":"Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young.","abstract":"Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of disorders characterized by early onset non-insulin-dependent diabetes mellitus, autosomal dominant inheritance, and primary defect in the function of the beta cells of the pancreas. Mutations in the glucokinase (GCK) gene account for 8%-56% of MODY, with the highest prevalences being found in the southern Europe. While screening for GCK mutations in 28 MODY families of Italian origin, we identified 17 different mutations (corresponding to 61% prevalence), including eight previously undescribed ones. The novel sequence variants included five missense mutations (p.Lys161Asn c.483G>C in exon 4, p.Phe171Leu c.511T>C in exon 5 and p.Thr228Ala c.682A>G, p.Thr228Arg c.683C>G, p.Gly258Cys c.772G>T in exon 7), one nonsense mutation (p.Ser383Ter c.1148C>A in exon 9), the splice site variant c.1253+1G>T in intron 9, and the deletion of 12 nucleotides in exon 10 (p.Ser433_Ile436del c.1298_1309del12). Our study indicates that mutations in the GCK/MODY2 gene are a very common cause of MODY in the Italian population and broadens our knowledge of the naturally occurring GCK mutation repertoire.","variants":[{"Name":"NM_000162.5(GCK):c.1298_1309del (p.Ser433_Ile436del)","Chromosome":"7","Start":"44145225","Stop":"44145236","ReferenceAlleleVCF":"GTGATCTCGCAGC","AlternateAlleleVCF":"G","allel_id":2831818,"rule_based_match":true,"evidence_text":"c.1298_1309del12","llm_judgment":"PRESENT","evidence":"c.1298_1309del12","abstract_start":966,"abstract_end":982},{"Name":"NM_000162.5(GCK):c.772G>T (p.Gly258Cys)","Chromosome":"7","Start":"44147741","Stop":"44147741","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":793230,"rule_based_match":true,"evidence_text":"c.772G>T","llm_judgment":"PRESENT","evidence":"c.772G>T","abstract_start":773,"abstract_end":781},{"Name":"NM_000162.5(GCK):c.682A>G (p.Thr228Ala)","Chromosome":"7","Start":"44147831","Stop":"44147831","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":441107,"rule_based_match":true,"evidence_text":"c.682A>G","llm_judgment":"PRESENT","evidence":"c.682A>G","abstract_start":729,"abstract_end":737},{"Name":"NM_000162.5(GCK):c.683C>G (p.Thr228Arg)","Chromosome":"7","Start":"44147830","Stop":"44147830","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3184692,"rule_based_match":true,"evidence_text":"c.683C>G","llm_judgment":"PRESENT","evidence":"c.683C>G","abstract_start":751,"abstract_end":759}]}
{"pmid":"34580245","title":"NONSYNDROMIC RETINITIS PIGMENTOSA WITH BILATERAL RETINAL NEOVASCULARIZATION DUE TO HGSNAT MUTATION.","abstract":"PURPOSE: To describe a case of nonsyndromic retinitis pigmentosa caused by presumed compound heterozygous A615T and T522M mutations in HGSNAT, characterized by bilateral cystoid macular edema and retinal neovascularization.\nMETHODS: Case report. The patient underwent clinical evaluation, multimodal imaging, and next-generation panel sequencing. In silico analysis was performed with PolyPhen-2, SIFT, and MutationTaster. Segregation analysis was not available.\nRESULTS: A 35-year-old hypertensive man presented with nyctalopia, photopsia, and difficulty reading for six months. He had no family history of visual deficits. The best-corrected visual acuity was 20/25 in the right eye and 20/20 in the left eye. Examination revealed midperipheral bone spicules and macular neovascularization in both eyes. Multimodal imaging demonstrated cystoid macular edema, ellipsoid band loss outside the central macula, and leakage from the neovascularization in both eyes. Sequencing detected four mutations in three genes, including two heterozygous mutations in HGSNAT (c.1843G>A, p.A615T and c.1565C>T, p.T522M). A615T is a pathogenic, hypomorphic mutation. T522M has not been previously phenotypically described. It is predicted damaging by in silico analysis and occurs at a conserved position near the eighth transmembrane domain, adjacent to residues in which missense mutations result in protein misfolding.\nCONCLUSION: This is, to the best of our knowledge, the first reported case of retinal neovascularization in a case of nonsyndromic retinitis pigmentosa due to HGSNAT mutation. The T522M variant likely functions as a severe mutation alongside the hypomorphic A615T mutation. These findings expand the genotypic and phenotypic spectrum of nonsyndromic retinitis pigmentosa.","variants":[{"Name":"NM_152419.3(HGSNAT):c.1843G>A (p.Ala615Thr)","Chromosome":"8","Start":"43199504","Stop":"43199504","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":205377,"rule_based_match":true,"evidence_text":"c.1843G>A, p.A615T","llm_judgment":"PRESENT","evidence":"c.1843G>A, p.A615T","abstract_start":1062,"abstract_end":1080},{"Name":"NM_152419.3(HGSNAT):c.1565C>T (p.Thr522Met)","Chromosome":"8","Start":"43197694","Stop":"43197694","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":946085,"rule_based_match":true,"evidence_text":"c.1565C>T, p.T522M","llm_judgment":"PRESENT","evidence":"c.1565C>T, p.T522M","abstract_start":1085,"abstract_end":1103}]}
{"pmid":"34785479","title":"Generation of two induced pluripotent stem cell lines, SHIPMi001-A from a patient with hypertrophic cardiomyopathy caused by MYBPC3 gene mutation and SHIPMi002-A from a healthy male individual.","abstract":"Hypertrophic cardiomyopathy is a hereditary disease with high incidence of sudden death and heart failure. Myosin-binding protein C3 (MYBPC3) is the most commonly mutation gene. Here, we report the establishment of two human induced pluripotent stem cell (iPSC) lines: one from a patient carrying a heterozygous c.1377delC mutation in MYBPC3 (c.1377delC: p.L460Wfs) and one from a healthy donor. The generated iPSC lines showed comparable pluripotent genes, demonstrated the capacity to differentiate into derivatives of all three germ layers and normal karyotypes. These lines are valuable for the mechanism research and drug development of hypertrophic cardiomyopathy.","variants":[{"Name":"NM_000256.3(MYBPC3):c.1377del (p.Leu460fs)","Chromosome":"11","Start":"47342910","Stop":"47342910","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":186386,"rule_based_match":true,"evidence_text":"c.1377delC mutation in MYBPC3 (c.1377delC: p.L460Wfs)","llm_judgment":"PRESENT","evidence":"c.1377delC mutation in MYBPC3 (c.1377delC: p.L460Wfs)","abstract_start":312,"abstract_end":365}]}
{"pmid":"31415707","title":"Late-Stage Sorsby Fundus Dystrophy Manifesting Severe Vision Loss in the Absence of Choroidal Neovascularization.","abstract":"A patient with a family history of molecularly confirmed Sorsby fundus dystrophy (SFD) presented with 9 years of progressive, bilateral central vision loss. Specific mutation analysis of the TIMP3 gene confirmed SFD, identifying a pathogenic mutation of p.Ser204Cys:c.610A>T. Optical coherence tomography imaging revealed diffuse retinal, retinal pigment epithelium, and choroidal atrophy without evidence for choroidal neovascularization (CNV). Although SFD is classically associated with CNV and subretinal fibrosis, some cases follow an atrophic course in the absence of CNV formation. This case highlights the extent to which extensive atrophic degeneration can lead to visual disability without choroidal neovascularization in late-stage SFD. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e215-e217.].","variants":[{"Name":"NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys)","Chromosome":"22","Start":"32859351","Stop":"32859351","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":27715,"rule_based_match":true,"evidence_text":"p.Ser204Cys:c.610A>T","llm_judgment":"PRESENT","evidence":"p.Ser204Cys:c.610A>T","abstract_start":254,"abstract_end":274}]}
{"pmid":"22876138","title":"A novel mutation in GJA3 associated with congenital Coppock-like cataract in a large Chinese family.","abstract":"PURPOSE: To identify the potential pathogenic mutation over five generations of a Chinese family with congenital Coppock-like cataracts (CCL).\nMETHODS: We investigated five generations of a Chinese family affected with CCL. The family resides in a relatively isolated region of northern China. Peripheral blood samples were collected from all of the family members, and genomic DNA was then extracted from the blood samples. A genome-wide linkage scan was performed using about 400 microsatellite markers. Two-point LOD (linkage odd disequilibrium) scores (Z) were calculated using the LINKAGE programs (ver. 5.1). Cyrillic software processed the resulting haplotypes. Mutation detection was performed in the candidate gene by direct sequencing.\nRESULTS: The maximum LOD score was obtained at marker D13S175 (lod score [Z(max)]=5.90; recombination fraction [θ]=0.0). Haplotype analysis traced the disease gene to a 6.99-cM interval bounded by D13S1316 and D13S1275 on chromosome 13q12.11. Direct sequencing of the candidate gene GJA3 (gap junction protein alpha-3) revealed a c.427G>A transition in exon 2 of GJA3 that co-segregated with the cataract in the family members and was not observed in 100 control patients. This single-nucleotide change resulted in the substitution of a highly conserved glycine by arginine (G143R).\nCONCLUSIONS: The present study identified a novel mutation in GJA3 that causes CCL. As the first report to relate p.G143R mutation in GJA3, it expands the mutation spectrum of GJA3. Our report is the first in identification of the mutation of GJA3 in the cytoplasmic-loop domain. This mutation is associated with multiple members of a five-generation family with congenital CCL.","variants":[{"Name":"NM_021954.4(GJA3):c.427G>A (p.Gly143Arg)","Chromosome":"13","Start":"20142862","Stop":"20142862","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":65608,"rule_based_match":true,"evidence_text":"c.427G>A","llm_judgment":"PRESENT","evidence":"c.427G>A","abstract_start":1076,"abstract_end":1084}]}
{"pmid":"18723471","title":"Genetic analysis in patients with Kallmann syndrome: coexistence of mutations in prokineticin receptor 2 and KAL1.","abstract":"Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. To date, 4 different genes have been identified as responsible for the presence of KS; however, in many cases no mutations have been found in any of these genes. Herein, we report the molecular findings regarding the analysis of fibroblast growth factor receptor 1 (FGFR1), prokineticin receptor 2 (PROKR2), and prokineticin (PROK2) in patients with KS. Twenty-four patients with KS were studied in whom mutations in KAL1 had been investigated previously. Polymerase chain reaction products from FGFR1, PROKR2, and PROK2 were sequenced and mutations were sought in the open reading frame of the 3 genes. Two patients presented a heterozygous T-to-G transversion in exon 2 (c.518T>G) of the PROKR2, which results in a leucine-to-arginine substitution at codon 173. Our results strengthen the hypothesis of possible digenic inheritance in some patients with KS. Likewise, our data extend previous reports demonstrating that PROKR2 plays a role in the etiology of this syndrome.","variants":[{"Name":"NM_144773.4(PROKR2):c.518T>G (p.Leu173Arg)","Chromosome":"20","Start":"5302677","Stop":"5302677","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":18488,"rule_based_match":true,"evidence_text":"c.518T>G","llm_judgment":"PRESENT","evidence":"c.518T>G","abstract_start":790,"abstract_end":798}]}
{"pmid":"22521418","title":"PSORS2 is due to mutations in CARD14.","abstract":"Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.","variants":[{"Name":"NM_001366385.1(CARD14):c.349G>A (p.Gly117Ser)","Chromosome":"17","Start":"80182790","Stop":"80182790","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40290,"rule_based_match":true,"evidence_text":"c.349G>A (p.Gly117Ser)","llm_judgment":"PRESENT","evidence":"c.349G>A (p.Gly117Ser)","abstract_start":654,"abstract_end":676},{"Name":"NM_001366385.1(CARD14):c.349+5G>A","Chromosome":"17","Start":"80182795","Stop":"80182795","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40291,"rule_based_match":true,"evidence_text":"c.349+5G>A","llm_judgment":"PRESENT","evidence":"c.349+5G>A","abstract_start":717,"abstract_end":727},{"Name":"NM_001366385.1(CARD14):c.413A>C (p.Glu138Ala)","Chromosome":"17","Start":"80183976","Stop":"80183976","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":40293,"rule_based_match":true,"evidence_text":"c.413A>C (p.Glu138Ala)","llm_judgment":"PRESENT","evidence":"c.413A>C (p.Glu138Ala)","abstract_start":828,"abstract_end":850}]}
{"pmid":"27401137","title":"Next-generation sequencing for molecular diagnosis of autosomal recessive polycystic kidney disease.","abstract":"Autosomal recessive polycystic kidney disease (ARPKD) a rare genetic disorder, described by formation of cysts in the kidney. A targeted customized sequencing of genes implicated in ARPKD phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified likely pathogenic disease causing variants during the validation process. Four potential pathogenic variants [c.4870C>T, p.(Arg1624Trp)], [c.5725C>T, p.(Arg1909Trp)], c.1736C>T, p.(Thr579Met)] and [(c.10628T>G), p.(Leu3543Trp)] were observed in PKHD1 gene among 12 out of 18 samples. The rest of the patient samples also showed few variants in ADPKD (Autosomal Dominant Polycystic Kidney Disease) disease causing genes PKD1 and PKD2 i.e. [c.12433G>A, p.(Val4145Ile)] and [c.1445T>G, p.(Phe482Cys)], respectively. All causative variants were validated by capillary sequencing, confirming the presence of a novel homozygous variants [c.10628T>G, p.(Leu3543Trp)] found in exon 61 of a male proband. All potentially deleterious variants identified in PKHD1, PKD1, and PKD2 gene, also exhibited pathologically or clinically significance based on the computational predictions involved in predicting the impact of non-synonymous SNPs (nsSNPs) on protein function such as Sorting Intolerant From Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen2). SIFT classified 50% of our nsSNPs as \"deleterious\", while PolyPhen2 identified 45% of our nsSNPs as \"Probably damaged\" and the results from both programs were largely complementary. Taken together, these results suggest that the NGS strategies provide a fast, accurate and cost-effective molecular diagnostic tool for identifying mutations in targeted genes sequence analysis.","variants":[{"Name":"NM_000297.4(PKD2):c.1445T>G (p.Phe482Cys)","Chromosome":"4","Start":"88046767","Stop":"88046767","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":221477,"rule_based_match":true,"evidence_text":"c.1445T>G, p.(Phe482Cys)","llm_judgment":"PRESENT","evidence":"c.1445T>G, p.(Phe482Cys)","abstract_start":792,"abstract_end":816}]}
{"pmid":"21396098","title":"Clinical and molecular characterization of a cohort of patients with novel nucleotide alterations of the Dystrophin gene detected by direct sequencing.","abstract":"BACKGROUND: Duchenne and Becker Muscular dystrophies (DMD/BMD) are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements.\nMETHODS: We selected 47 patients (41 families; 35 DMD, 6 BMD) without deletions and duplications in DMD gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis). This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis.\nRESULTS: We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n=10 patients), followed by TAG (n=7) and TAA (n=4). We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the DMD gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65.\nCONCLUSION: The analysis of our patients' sample, carrying point mutations or complex rearrangements in DMD gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects and dystrophin functional domains. These data can have a prognostic relevance and can be useful in directing new therapeutic approaches, which rely on a precise definition of the genetic defects as well as their molecular consequences.","variants":[{"Name":"NM_004006.3(DMD):c.6118-3C>A","Chromosome":"X","Start":"32287704","Stop":"32287704","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":178763,"rule_based_match":true,"evidence_text":"IVS42: c.6118-3C>A","llm_judgment":"PRESENT","evidence":"IVS42: c.6118-3C>A","abstract_start":1522,"abstract_end":1540}]}
{"pmid":"30996762","title":"MYH7 mutation identified by next-generation sequencing in three infant siblings with bi-ventricular noncompaction presenting with restrictive hemodynamics: A report of three siblings with a severe phenotype and poor prognosis.","abstract":"Noncompaction of the ventricular myocardium (NVM) is a genetically heterogeneous cardiomyopathy. Various mutations associated with NVM have been identified in several genes. NVM patients usually present with complications of dilated cardiomyopathy. We identified a missense mutation, c.5740G>A, p.Glu1914Lys of <i>MYH7</i>, by targeted next-generation sequencing in three infant siblings with isolated bi-ventricular noncompaction who presented with restrictive hemodynamics and severe clinical courses. This mutation appears to be associated with a severe phenotype and poor prognosis. Early heart transplantation should be considered in similar cases. <<b>Learning objective:</b> No clear noncompaction of the ventricular myocardium genotype-phenotype correlations have been found to predict the clinical course. This report describes a <i>MYH7</i> mutation in three infant siblings with isolated bi-ventricular noncompaction who presented with restrictive hemodynamics and severe clinical courses. Early heart transplantation should be considered in cases with a similar genotype and/or phenotype.>.","variants":[{"Name":"NM_000257.4(MYH7):c.5740G>A (p.Glu1914Lys)","Chromosome":"14","Start":"23413809","Stop":"23413809","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":52258,"rule_based_match":true,"evidence_text":"c.5740G>A, p.Glu1914Lys","llm_judgment":"PRESENT","evidence":"c.5740G>A, p.Glu1914Lys","abstract_start":284,"abstract_end":307}]}
{"pmid":"28378438","title":"Legius syndrome: A case report.","abstract":"Legius syndrome is a rare genetic disorder caused by heterozygous germ line loss-of-function SPRED1 mutation. In Japan, a family with Legius syndrome was first described in 2015 by Sakai et al. We described a first solitary case of Legius syndrome identified by next-generation sequencing in Japan. A 37-year-old woman presented with multiple café-au-lait macules and freckles but has no other features of neurofibromatosis type 1 (NF-1). Sequencing results showed the presence of a mutation in exon 2 of SPRED1 c.70C>T, resulting in the protein at position 24 (p.Arg24X). When a dermatological clinician sees an adult patient showing only pigmented lesions and no other specifically diagnostic features of NF-1, it is important to suspect the possibility of Legius syndrome.","variants":[{"Name":"NM_152594.3(SPRED1):c.70C>T (p.Arg24Ter)","Chromosome":"15","Start":"38299410","Stop":"38299410","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16849,"rule_based_match":true,"evidence_text":"c.70C>T","llm_judgment":"PRESENT","evidence":"c.70C>T","abstract_start":512,"abstract_end":519}]}
{"pmid":"28032038","title":"Recurrent missense mutation of","abstract":"Proximal symphalangism (SYM1B) (OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands, typically of the ring and little finger, with the thumb typically being spared. SYM1 is frequently associated with coalition of tarsal bones and conductive hearing loss. Molecular studies have identified two possible genetic aetiologies for this syndrome, <i>NOG</i> and <i>GDF5</i>. We herein present a British caucasian family with SYM1B caused by a mutation of the <i>GDF5</i> gene. A mother and her three children presented to the orthopaedic outpatient department predominantly for feet related problems. All patients had multiple tarsal coalitions and hand involvement in the form of either brachydactyly or symphalangism of the proximal and middle phalanx of the little fingers. Genetic testing in the eldest child and his mother identified a heterozygous missense mutation in <i>GDF5</i> c.1313G>T (<i>p.R438L</i>), thereby establishing SYM1B as the cause of the orthopaedic problems in this family. There were no mutations identified in the <i>NOG</i> gene. This report highlights the importance of thorough history taking, including a three generation family history, and detailed clinical examination of children with fixed planovalgus feet and other family members to detect rare skeletal dysplasia conditions causing pain and deformity, and provides details of the spectrum of problems associated with SYM1B.","variants":[{"Name":"NM_000557.5(GDF5):c.1313G>T (p.Arg438Leu)","Chromosome":"20","Start":"35434102","Stop":"35434102","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":23425,"rule_based_match":true,"evidence_text":"c.1313G>T (p.R438L)","llm_judgment":"PRESENT","evidence":"c.1313G>T","abstract_start":1006,"abstract_end":1015}]}
{"pmid":"22883975","title":"Genetic analysis of familial hypercholesterolaemia in Western Australia.","abstract":"OBJECTIVE: To determine the spectrum of mutations associated with familial hypercholesterolaemia (FH) and their detection rate in the FH Western Australia (FHWA) Program.\nMETHODS: Mutation testing of the LDLR gene, plus select regions in APOB and PCSK9, was performed in the first 343 patients considered to be phenotypic index cases of FH and classified on the basis of the Dutch Lipid Clinic Network Criteria (DLCNC) score as \"possible\", \"probable\", or \"definite\" FH.\nRESULTS: Overall, 86 different pathogenic (or likely pathogenic) mutations were identified in 129 patients, including four compound heterozygotes manifesting a more severe clinical phenotype. Fourteen of these mutations were novel and twelve (9.6%) were large deletions/duplications of the LDLR. The most common mutations were the familial defective apoB-100 mutation APOB p.Arg3527Gln (7.2%) and an LDLR intron 3 splice site mutation c.313 + 1G > A (4.8%). While 70% of 'definite' FH patients were found to carry a mutation, only 29% of 'probable' and 11% of 'possible' FH patients were mutation-positive.\nCONCLUSION: This information provides a useful DNA database on which to base ongoing cascade screening for FH and future research into the genetic aetiology of FH in Western Australia. These findings suggest genetic testing should be prioritised to those with high DLCNC scores and offers a cost-effective family screening method from FH index cases, leading to detection of other previously undiagnosed and younger family members, enabling early instigation of intervention and preventative measures for premature coronary heart disease.","variants":[{"Name":"NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln)","Chromosome":"2","Start":"21006288","Stop":"21006288","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32929,"rule_based_match":false,"evidence_text":"APOB p.Arg3527Gln","llm_judgment":"PRESENT","evidence":"APOB p.Arg3527Gln","abstract_start":838,"abstract_end":855},{"Name":"NM_000527.4(LDLR):c.313+1G>A","Chromosome":"19","Start":"11102787","Stop":"11102787","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":18775,"rule_based_match":true,"evidence_text":"c.313 + 1G > A","llm_judgment":"PRESENT","evidence":"c.313 + 1G > A","abstract_start":905,"abstract_end":919}]}
{"pmid":"31231422","title":"Genetic Screening of the Usher Syndrome in Cuba.","abstract":"BACKGROUND: Usher syndrome (USH) is a recessive inherited disease characterized by sensorineural hearing loss, retinitis pigmentosa, and sometimes, vestibular dysfunction. Although the molecular epidemiology of Usher syndrome has been well studied in Europe and United States, there is a lack of studies in other regions like Africa or Central and South America.\nMETHODS: We designed a NGS panel that included the 10 USH causative genes (<i>MYO7A</i>, <i>USH1C</i>, <i>CDH23</i>, <i>PCDH15</i>, <i>USH1G</i>, <i>CIB2</i>, <i>USH2A</i>, <i>ADGRV1</i>, <i>WHRN</i>, and <i>CLRN1</i>), four USH associated genes (<i>HARS</i>, <i>PDZD7</i>, <i>CEP250</i>, and <i>C2orf71</i>), and the region comprising the deep-intronic c.7595-2144A>G mutation in <i>USH2A</i>.\nRESULTS: NGS sequencing was performed in 11 USH patients from Cuba. All the cases were solved. We found the responsible mutations in the <i>USH2A</i>, <i>ADGRV1</i>, <i>CDH23</i>, <i>PCDH15</i>, and <i>CLRN1</i> genes. Four mutations have not been previously reported. Two mutations are recurrent in this study: c.619C>T (p.Arg207<sup>∗</sup>) in <i>CLRN1</i>, previously reported in two unrelated Spanish families of Basque origin, and c.4488G>C (p.Gln1496His) in <i>CDH23</i>, first described in a large Cuban family. Additionally, c.4488G>C has been reported two more times in the literature in two unrelated families of Spanish origin.\nCONCLUSION: Although the sample size is very small, it is tempting to speculate that the gene frequencies in Cuba are distinct from other populations mainly due to an \"island effect\" and genetic drift. The two recurrent mutations appear to be of Spanish origin. Further studies with a larger cohort are needed to elucidate the real genetic landscape of Usher syndrome in the Cuban population.","variants":[{"Name":"NM_022124.6(CDH23):c.4488G>C (p.Gln1496His)","Chromosome":"10","Start":"71739772","Stop":"71739772","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":19954,"rule_based_match":true,"evidence_text":"c.4488G>C (p.Gln1496His)","llm_judgment":"PRESENT","evidence":"c.4488G>C (p.Gln1496His)","abstract_start":1195,"abstract_end":1219}]}
{"pmid":"35790350","title":"Bi-allelic variants in","abstract":"BACKGROUND: Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants in <i>RARB</i> and <i>STRA6</i>, which have been previously associated with this disorder.\nMETHODS: We sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants.\nRESULTS: We identified bi-allelic variants in <i>WNT7B</i> in fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found that <i>wnt7bb</i> mutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures.\nCONCLUSION: Our findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT-β-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development.","variants":[{"Name":"NM_058238.3(WNT7B):c.292C>T (p.Arg98Ter)","Chromosome":"22","Start":"45949926","Stop":"45949926","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":431508,"rule_based_match":true,"evidence_text":"c.292C>T (p.(Arg98*))","llm_judgment":"PRESENT","evidence":"c.292C>T (p.(Arg98*))","abstract_start":622,"abstract_end":643}]}
{"pmid":"32064984","title":"A new compound heterozygous mutation in adult-onset Krabbe disease.","abstract":"<b>Purpose:</b> Krabbe disease (KD) or globoid cell leukodystrophy is an autosomal recessive lysosomal disorder caused by a lack of the lysosomal enzyme galactocerebrosidase (GALC) because of mutations in <i>GALC</i>. Patients with KD exhibit a wide spectrum of clinical symptoms; therefore, their diagnosis can be challenging. We report the clinical features and gene mutations in a 48-year-oldpatient with adult-onset KD.<b>Methods:</b> We collected and analyzed clinical data of the patientwith a diagnosis of KD. Gene mutations were identified by whole exome sequencing.<b>Results:</b> We describe a case of adult-onset KD caused by a novel compound heterozygous mutation; a missense mutation, c. 1901 T > C (p. L634S); and a novel nonsense mutation, c.1005C > G (p. Y335X), in <i>GALC</i>. The disease onset started when the patient was 40 years old, and manifested as typical paralytic paraplegia. Magnetic resonance imaging indicated demyelination of the white matter, which is consistent with the typical symptoms of adult-onset KD. Biochemical analysis revealed GALC activity to be 1.5 nmol/17 h/mg protein, confirming its deficiency and KD diagnosis.<b>Conclusions:</b> Our findings provide evidence of a novel mutation, providing additional information toward to the <i>GALC</i> mutation database.","variants":[{"Name":"NM_000153.4(GALC):c.1901T>C (p.Leu634Ser)","Chromosome":"14","Start":"87939915","Stop":"87939915","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":227363,"rule_based_match":true,"evidence_text":"c. 1901 T > C (p. L634S)","llm_judgment":"PRESENT","evidence":"c. 1901 T > C (p. L634S)","abstract_start":698,"abstract_end":722}]}
{"pmid":"30020262","title":"Audiologic Manifestations of Marshall Syndrome.","abstract":"OBJECTIVE: Marshall syndrome is a genetic disorder caused by mutations in the COL11A1 gene. This syndrome is characterized by skeletal, ophthalmologic, craniofacial, and auditory abnormalities. Hearing loss is among the main manifestations reported in this disorder being observed in approximately 80% of affected individuals.The present study aims to describe the audiologic characteristics of three members of a family with Marshall syndrome and also serves as a review of the literature.\nSTUDY DESIGN: Family study.\nSETTING: Tertiary care otology and skull base center.\nPATIENTS: We report the audiologic findings in a family with Marshall syndrome consisting of a mother and her son and daughter.\nINTERVENTION(S): The audiologic evaluation included tympanometry, acoustic reflexes testing, auditory brainstem response, transient otoacoustic emissions, pure-tone audiometry, speech audiometry in quiet, and conditioned play audiometry. These methods were applied according to the age of the patients. In addition, we provide a review of the English-language literature in an attempt to clarify the auditory phenotype of this syndrome.\nRESULTS: All 3 affected individuals had heterozygous c.3816+1G>A mutation in the splicing donor site of intron 50 of the COL11A1 gene. All three patients in our study had bilateral sensorineural hearing loss. Hearing impairment ranged from mild to moderate in the daughter, moderate in the son, and from mild to moderate in their mother.\nCONCLUSION: The majority of individuals with Marshall syndrome present early-onset bilateral sensorineural hearing loss. Hearing impairment is usually detected in early childhood, progresses gradually, and becomes stable in late adulthood, with a severity ranging from mild to severe.","variants":[{"Name":"NM_001854.4(COL11A1):c.3816+1G>A","Chromosome":"1","Start":"102915630","Stop":"102915630","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48375,"rule_based_match":true,"evidence_text":"c.3816+1G>A","llm_judgment":"PRESENT","evidence":"c.3816+1G>A","abstract_start":1191,"abstract_end":1202}]}
{"pmid":"25457163","title":"Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects.","abstract":"Anophthalmia/microphthalmia (A/M) is a genetically heterogeneous birth defect for which the etiology is unknown in more than 50% of patients. We used exome sequencing with the ACE Exome(TM) (Personalis, Inc; 18 cases) and UCSF Genomics Core (21 cases) to sequence 28 patients with A/M and four patients with varied developmental eye defects. In the 28 patients with A/M, we identified de novo mutations in three patients (OTX2, p.(Gln91His), RARB, p.Arg387Cys and GDF6, p.Ala249Glu) and inherited mutations in STRA6 in two patients. In patients with developmental eye defects, a female with cataracts and cardiomyopathy had a de novo COL4A1 mutation, p.(Gly773Arg), expanding the phenotype associated with COL4A1 to include cardiomyopathy. A male with a chorioretinal defect, microcephaly, seizures and sensorineural deafness had two PNPT1 mutations, p.(Ala507Ser) and c.401-1G>A, and we describe eye defects associated with this gene for the first time. Exome sequencing was efficient for identifying mutations in pathogenic genes for which there is no clinical testing available and for identifying cases that expand phenotypic spectra, such as the PNPT1 and COL4A1-associated disorders described here.","variants":[{"Name":"NM_001845.6(COL4A1):c.2317G>A (p.Gly773Arg)","Chromosome":"13","Start":"110179298","Stop":"110179298","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":372611,"rule_based_match":false,"evidence_text":"p.(Gly773Arg)","llm_judgment":"PRESENT","evidence":"p.(Gly773Arg)","abstract_start":651,"abstract_end":664},{"Name":"NM_000965.5(RARB):c.1159C>T (p.Arg387Cys)","Chromosome":"3","Start":"25596428","Stop":"25596428","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":94343,"rule_based_match":false,"evidence_text":"p.Arg387Cys","llm_judgment":"PRESENT","evidence":"p.Arg387Cys","abstract_start":448,"abstract_end":459},{"Name":"NM_033109.5(PNPT1):c.1519G>T (p.Ala507Ser)","Chromosome":"2","Start":"55647430","Stop":"55647430","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":210875,"rule_based_match":false,"evidence_text":"p.(Ala507Ser)","llm_judgment":"PRESENT","evidence":"p.(Ala507Ser)","abstract_start":851,"abstract_end":864}]}
{"pmid":"30544381","title":"Targeted next-generation sequencing identifies a novel mutation of LAMB3 in a Chinese neonatal patient presented with junctional epidermolysis bullosa.","abstract":"RATIONALE: Epidermolysis bullosa (EB) refers to a group of rare inherited mechanobullous disorders that present with great clinical and genetic heterogeneity. Its severity ranges from mild blistering to life-threatening. However, the clinical symptoms of different types of EB overlap significantly, especially at an early stage. Thus it is important to clarify the diagnosis for prognostic implications, patient management, and genetic counseling.\nPATIENT CONCERNS: Here, we report a 10-day-old male neonate from a nonconsanguineous Chinese family. He showed a bulla on the left lower limb lasting for 3 days, erosions around fingertips and toe tips at birth (predominantly on fingers), with the progressive spread of generalized blisters over the body as well as the development of the illness.\nDIAGNOSIS: The patient was diagnosed with suspected epidermolysis bullosa according to the blisters and erosions of the body as well as the pyogenic fingernails and toenails.\nINTERVENTIONS: The patient was performed targeted next-generation sequencing (NGS) with 9 candidate known genes, subsequently, his parents were screened for the mutations identified in the patient by Sanger sequencing. Then, prenatal diagnosis with amniotic fluid was performed in the subsequent pregnancy by Sanger sequencing.\nOUTCOMES: Targeted NGS revealed a previously unreported splice site variant c.822+1G>A (IVS 8) and a known recurrent nonsense variant c.124C>T (p.Arg42Ter, exon 3) in LAMB3 gene. The patient's father possessed a heterozygous c.822+1G>A mutation, his mother possessed a heterozygous c.124C>T mutation. For the subsequent pregnancy, the analyses of amniotic fluid sample indicated that the fetus carried neither of the mutations.\nLESSONS: Our finding will further enlarge LAMB3 genotype-phenotype correlations spectrum. Targeted capture sequencing is a valuable method to illustrate precise molecular pathology in patients with EB disorders, especially at an early stage of the clinical evaluation of complex disorders to avoid unnecessary and economically wasteful tests.","variants":[{"Name":"NM_000228.3(LAMB3):c.124C>T (p.Arg42Ter)","Chromosome":"1","Start":"209650023","Stop":"209650023","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29580,"rule_based_match":true,"evidence_text":"c.124C>T (p.Arg42Ter, exon 3)","llm_judgment":"PRESENT","evidence":"c.124C>T (p.Arg42Ter, exon 3)","abstract_start":1434,"abstract_end":1463}]}
{"pmid":"26539208","title":"A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability.","abstract":"Dominant optic neuropathies causing fiber loss in the optic nerve are among the most frequent inherited mitochondrial diseases. In most genetically resolved cases, the disease is associated to a mutation in OPA1, which encodes an inner mitochondrial dynamin involved in network fusion, cristae structure and mitochondrial genome maintenance. OPA1 cleavage is regulated by two m-AAA proteases, SPG7 and AFG3L2, which are, respectively involved in Spastic Paraplegia 7 and Spino-Cerebellar Ataxia 28. Here, we identified a novel mutation c.1402C>T in AFG3L2, modifying the arginine 468 in cysteine in an evolutionary highly conserved arginine-finger motif, in a family with optic atrophy and mild intellectual disability. Ophthalmic examinations disclosed a loss of retinal nerve fibers on the temporal and nasal sides of the optic disk and a red-green dyschromatopsia. Thus, our results suggest that neuro-ophthalmological symptom as optic atrophy might be associated with AFG3L2 mutations, and should prompt the screening of this gene in patients with isolated and syndromic inherited optic neuropathies.","variants":[{"Name":"NM_006796.3(AFG3L2):c.1402C>T (p.Arg468Cys)","Chromosome":"18","Start":"12351330","Stop":"12351330","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":556459,"rule_based_match":true,"evidence_text":"c.1402C>T","llm_judgment":"PRESENT","evidence":"c.1402C>T","abstract_start":536,"abstract_end":545}]}
{"pmid":"30352407","title":"Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients.","abstract":"Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.","variants":[{"Name":"NM_003000.3(SDHB):c.343C>T (p.Arg115Ter)","Chromosome":"1","Start":"17028680","Stop":"17028680","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":194371,"rule_based_match":true,"evidence_text":"c.343C>T","llm_judgment":"PRESENT","evidence":"c.343C>T","abstract_start":1176,"abstract_end":1184},{"Name":"NM_003000.3(SDHB):c.541-2A>G","Chromosome":"1","Start":"17024076","Stop":"17024076","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":181613,"rule_based_match":true,"evidence_text":"c.541-2A>G","llm_judgment":"PRESENT","evidence":"c.541-2A>G","abstract_start":1189,"abstract_end":1199}]}
{"pmid":"36231035","title":"Novel","abstract":"Germline defects in the transcription factor GATA1 are known to cause dyserythropoiesis with(out) anemia and variable abnormalities in platelet count and function. However, damaging variants closely located to the C-terminal zinc finger domain of GATA1 are nearly unknown. In this study, a 36-year-old male index patient and his 4-year-old daughter suffered from moderate mucocutaneous bleeding diathesis since birth. Whole exome sequencing detected a novel hemizygous <i>GATA1</i> missense variant, c.886A>C p.T296P, located between the C-terminal zinc finger and the nuclear localization sequence with non-random X-chromosome inactivation in the heterozygous daughter. Blood smears from both patients demonstrated large platelet fractions and moderate thrombocytopenia in the index. Flow cytometry and electron microscopy analysis supported a combined α-/δ (AN-subtype)-storage pool deficiency as cause for impaired agonist-induced platelet aggregation (light transmission aggregometry) and granule exocytosis (flow cytometry). The absence of BCAM in the index (Lu(a-b-)) and its low expression in the daughter (Lu(a-b+)) confirmed a less obvious effect of defective GATA1 also on erythrocytes. Borderline anemia, elevated HbF levels, and differential transcription of GATA1-regulated genes indicated mild dyserythropoiesis in both patients. Furthermore, a mild SLC4A1 defect associated with a heterozygous <i>SLC4A1</i> c.2210C>T p.A737V variant maternally transmitted in the daughter may modify the disease to mild spherocytosis and hemolysis.","variants":[{"Name":"NM_000342.4(SLC4A1):c.2210C>T (p.Ala737Val)","Chromosome":"17","Start":"44253219","Stop":"44253219","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":328672,"rule_based_match":true,"evidence_text":"NM_000342.4(SLC4A1):c.2210C>T (p.Ala737Val)","llm_judgment":"PRESENT","evidence":"c.2210C>T","abstract_start":1423,"abstract_end":1432},{"Name":"NM_002049.4(GATA1):c.886A>C (p.Thr296Pro)","Chromosome":"X","Start":"48793808","Stop":"48793808","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":2742916,"rule_based_match":true,"evidence_text":"c.886A>C p.T296P","llm_judgment":"PRESENT","evidence":"c.886A>C p.T296P","abstract_start":500,"abstract_end":516}]}
{"pmid":"31020658","title":"A Tunisian family with a novel mutation in the gene CYP4F22 for lamellar ichthyosis and co-occurrence of hearing loss in a child due to mutation in the SLC26A4 gene.","abstract":"BACKGROUND: Co-occurrence of two genetic diseases is challenging for accurate diagnosis and genetic counseling. The recent availability of whole exome sequencing (WES) has dramatically improved the molecular diagnosis of rare genetic diseases in particular in consanguineous populations.\nMETHODS: We report here on a consanguineous family from Southern Tunisia including three members affected with congenital ichthyosis. The index case had a hearing loss (HL) and ichthyosis and was primarily suspected as suffering from keratitis-ichthyosis-deafness (KID) syndrome. WES was performed for the index case, and all members of the nuclear family were sequenced (Sanger method).\nRESULTS: The WES approach allowed the identification of two strong candidate variants in two different genes; a missense mutation c.1334T>G (p.Leu445Trp) in exon 11 of SLC26A4 gene, associated with isolated HL and a novel missense mutation c.728G>T (p.Arg243Leu) in exon 8 of CYP4F22 gene likely responsible for ichthyosis. These two mutations were predicted to be pathogenic by three pathogenicity prediction softwares (Scale-Invariant Feature Transform [SIFT], Polymorphism Phenotyping [PolyPhen], Mutation Taster) to underlie the HL and ichthyosis, respectively.\nCONCLUSIONS: The present study raises awareness about the importance of familial history for accurate diagnosis of syndromic genetic diseases and differential diagnosis with co-occurrence of two distinct clinical entities. In addition, in countries with limited resources, WES sequencing for a single individual provides a cost effective tool for molecular diagnosis confirmation and genetic counseling.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1334T>G (p.Leu445Trp)","Chromosome":"7","Start":"107694473","Stop":"107694473","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":19868,"rule_based_match":true,"evidence_text":"c.1334T>G (p.Leu445Trp)","llm_judgment":"PRESENT","evidence":"c.1334T>G (p.Leu445Trp)","abstract_start":806,"abstract_end":829}]}
{"pmid":"24315737","title":"RAD51C--a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC).","abstract":"INTRODUCTION: Head and neck squamous cell carcinomas (HNSSCs) are one of the leading causes of cancer-associated death worldwide. Although certain behavioral risk factors are well recognized as tumor promoting, there is very little known about the presence of predisposing germline mutations in HNSCC patients.\nMETHODS: In this study, we analyzed 121 individuals with HNSCCs collected at our institution for germline alterations in the newly identified cancer susceptibility gene RAD51C.\nRESULTS: Sequencing of all exons and the adjacent introns revealed five distinct heterozygous sequence deviations in RAD51C in seven patients (5.8%). A female patient without any other risk factors carried a germline mutation that disrupted the canonical splice acceptor site of exon 5 (c.706-2A>G).\nCONCLUSIONS: As there are only a few publications in the literature identifying germline mutations in head and neck cancer patients, our results provide the first indication that paralogs of RAD51, recently described as mutated in breast and ovarian cancer patients, might also be candidates for genetic risk factors in sporadic squamous cell carcinomas of the head and neck.","variants":[{"Name":"NM_058216.3(RAD51C):c.706-2A>G","Chromosome":"17","Start":"58709857","Stop":"58709857","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":133666,"rule_based_match":true,"evidence_text":"c.706-2A>G","llm_judgment":"PRESENT","evidence":"c.706-2A>G","abstract_start":775,"abstract_end":785}]}
{"pmid":"18618990","title":"Craniosynostosis and congenital tracheal anomalies in an infant with Pfeiffer syndrome carrying the W290C FGFR2 mutation.","abstract":"Pfeiffer syndrome (OMIM 101600) is an autosomal dominant disorder characterized by craniosynostosis, midface hypoplasia, ocular proptosis and digital malformations. We report on a type II Pfeiffer female infant with craniosynostosis, hydrocephalus, and characteristic craniofacial and digital abnormalities. The patient had a history of airway difficulty. Bronchoscopy at age four months revealed low tracheal stenosis and fibrous cartilaginous rings. She underwent tracheostomy for the treatment of cyanotic episodes. Molecular analysis revealed a de novo missense mutation c.870 G>T (TGG>TGT) in the FGFR2 gene that predicts a substitution of cysteine for tryptophan at the codon 290, (W290C). There is phenotypic heterogeneity of tracheal anomalies due to FGFR2 mutations. A review of the literature shows that Pfeiffer patients with the similar tracheal abnormalities can be caused by different FGFR2 mutations and, likewise, the patients with the same FGFR2 mutation may manifest different kinds of tracheal anomalies. Tracheal anomalies may occur in Pfeiffer patients and cause morbidity and mortality because of airway obstruction. Recognition and detailed evaluation of tracheal anomalies should be included in the early diagnostic workup for severe Pfeiffer patients.","variants":[{"Name":"NM_000141.5(FGFR2):c.870G>T (p.Trp290Cys)","Chromosome":"10","Start":"121520048","Stop":"121520048","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":28332,"rule_based_match":true,"evidence_text":"c.870 G>T (TGG>TGT)","llm_judgment":"PRESENT","evidence":"c.870 G>T (TGG>TGT)","abstract_start":575,"abstract_end":594}]}
{"pmid":"24301756","title":"A preliminary mutation analysis of phenylketonuria in southwest Iran.","abstract":"Phenylketonuria (PKU) is a heterogeneous and autosomal recessive metabolic disorder that is mainly caused by mutations in the hepatic phenylalanine hydroxylase (PAH) gene. This study was designed to identify PAH mutations within exons 6, 7, and 10-12 in PKU patients from southwest Iran. Forty Iranian patients with clinical and biochemically confirmed PKU were enrolled. The exons were sequenced directly and 13 different mutations were identified including I224T, S231P, R176X, c.592_613del22, R243X, R252W, R261Q, Y356X, V388M, IVS10-11G>A, IVS11+1G>C, IVS11-2A>G, and Q375R, which were associated with 23 genotypes. A novel sequence variant, Q375R (c.1124A>G), was detected in exon 11. In one patient, a typical genotype with more than two mutations (R243X/S231P/S231P) was found. Seven different polymorphisms and three new variants were also detected in intron regions of PAH. A high mutation spectrum was predicted in the southwestern region of Iran due to its ethnic heterogeneity, especially the Khuzestan Province. The detection of 13 different mutations, corresponding to a mutation detection rate of 53.75%, confirmed this phenomenon.","variants":[{"Name":"NM_000277.3(PAH):c.1124A>G (p.Gln375Arg)","Chromosome":"12","Start":"102843721","Stop":"102843721","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":920564,"rule_based_match":true,"evidence_text":"Q375R (c.1124A>G)","llm_judgment":"PRESENT","evidence":"Q375R (c.1124A>G)","abstract_start":646,"abstract_end":663}]}
{"pmid":"27288985","title":"Genetic background of uric acid metabolism in a patient with severe chronic tophaceous gout.","abstract":"Hyperuricemia depends on the balance of endogenous production and renal excretion of uric acid. Transporters for urate are located in the proximal tubule where uric acid is secreted and extensively reabsorbed: secretion is principally ensured by the highly variable ABCG2 gene. Enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) plays a central role in purine metabolism and its deficiency is an X-linked inherited metabolic disorder associated with clinical manifestations of purine overproduction. Here we report the case of a middle-aged man with severe chronic tophaceous gout with a poor response to allopurinol and requiring repeated surgical intervention. We identified the causal mutations in the HPRT1 gene, variant c.481G>T (p.A161S), and in the crucial urate transporter ABCG2, a heterozygous variant c.421C>A (p.Q141K). This case shows the value of an analysis of the genetic background of serum uric acid.","variants":[{"Name":"NM_000194.2(HPRT1):c.481G>T (p.Ala161Ser)","Chromosome":"X","Start":"134493586","Stop":"134493586","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":25080,"rule_based_match":true,"evidence_text":"c.481G>T (p.A161S)","llm_judgment":"PRESENT","evidence":"c.481G>T (p.A161S)","abstract_start":735,"abstract_end":753}]}
{"pmid":"29264390","title":"Characterization of a","abstract":"OBJECTIVE: To perform functional characterization of a potentially pathogenic <i>KCNB1</i> variant identified by clinical exome sequencing of a proband with a neurodevelopmental disorder that included epilepsy and centrotemporal spikes on EEG.\nMETHODS: Whole-exome sequencing identified the <i>KCNB1</i> variant c.595A>T (p.Ile199Phe). Biochemical and electrophysiologic experiments were performed to determine whether this variant affected protein expression, trafficking, and channel functional properties.\nRESULTS: Biochemical characterization of the variant suggested normal protein expression and trafficking. Functional characterization revealed biophysical channel defects in assembled homotetrameric and heterotetrameric channels.\nCONCLUSIONS: The identification of the <i>KCNB1</i> variant c.595A>T (p.Ile199Phe) in a neurodevelopmental disorder that included epilepsy with centrotemporal spikes expands the phenotypic spectrum of epilepsies associated with <i>KCNB1</i> variants. The KCNB1-I199F variant exhibited partial loss of function relative to the wild-type channel. This defect is arguably less severe than previously reported <i>KCNB1</i> variants, suggesting the possibility that the degree of KCNB1 protein dysfunction may influence disease severity.","variants":[{"Name":"NM_004975.4(KCNB1):c.595A>T (p.Ile199Phe)","Chromosome":"20","Start":"49374965","Stop":"49374965","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":791988,"rule_based_match":true,"evidence_text":"c.595A>T (p.Ile199Phe)","llm_judgment":"PRESENT","evidence":"c.595A>T (p.Ile199Phe)","abstract_start":312,"abstract_end":334}]}
{"pmid":"29222009","title":"Redefining the phenotypic spectrum of de novo heterozygous CDK13 variants: Three patients without cardiac defects.","abstract":"Recently, 7 patients with de novo constitutional non-synonymous mutations in the CDK13 gene were ascertained through a trio exome analysis of a large cohort of 610 patients with congenital cardiac diseases. Despite another report describing 9 additional patients, the clinical spectrum of this condition has yet to be defined. Herein, we report 3 patients with heterozygous constitutional CDK13 mutations, who were ascertained through exome analysis of children with intellectual disability and minor anomalies, who lacked cardiac anomalies. Two patients had a c.2149G > A, p.Gly717Arg mutation, and one had a c.2525A > G, p. Asn842Ser mutation. A review of the previously described patients and those described herein has enabled the following points to be clarified. First, congenital heart diseases are not an essential feature (13/19). Second, nasal features may help syndromic recognition (14/16). Third, widely spaced and peg-shaped teeth may represent a previously unappreciated diagnostic clue for this newly identified syndrome. Here, we show that p.Gly717Arg represents a hotspot in addition to p.Asn842Ser. We suggest that this CDK13-related disorder may represent a clinically recognizable syndrome.","variants":[{"Name":"NM_003718.5(CDK13):c.2525A>G (p.Asn842Ser)","Chromosome":"7","Start":"40046007","Stop":"40046007","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":237522,"rule_based_match":true,"evidence_text":"c.2525A>G, p. Asn842Ser","llm_judgment":"PRESENT","evidence":"c.2525A > G, p. Asn842Ser","abstract_start":610,"abstract_end":635},{"Name":"NM_003718.5(CDK13):c.2149G>A (p.Gly717Arg)","Chromosome":"7","Start":"39999467","Stop":"39999467","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":362622,"rule_based_match":true,"evidence_text":"c.2149G > A, p.Gly717Arg","llm_judgment":"PRESENT","evidence":"c.2149G > A, p.Gly717Arg","abstract_start":561,"abstract_end":585}]}
{"pmid":"27137747","title":"A known mutation in GJB6 in a large Chinese family with hidrotic ectodermal dysplasia.","abstract":"BACKGROUND: Hidrotic ectodermal dysplasia (HED), also named as Clouston syndrome, is a rare autosomal dominant disease. Mutations in GJB6, GJB2 and GJA1 are related to HED.\nOBJECTIVE: Summarize the clinical feature and analyse the mutation of the GJB6 gene in a large Chinese family with HED.\nMETHODS: We collected a very large Chinese family with HED. Clinical information was analysed. Blood samples were obtained. The whole coding region of GJB6 was amplified by polymerase chain reaction and sequenced. The results were further confirmed at mRNA level by reverse transcription polymerase chain reaction.\nRESULTS: Sequence analysis identified a heterozygous missense mutation c.263C>T (p.A88V) in genomic DNAs of 25 patients, and this mutation was excluded from 14 normal individuals in this HED family and 218 unrelated, population-matched control individuals. The transcription of mutated allele was confirmed by RT-PCR of Cx30 mRNA from proband(,) s scalp skin. We found a novel phenotype of this variant in this Chinese HED family.\nCONCLUSION: Our data reveals that a recurrent mutation p.A88V in GJB6 played a pathogenic role in a large Chinese family and emphasizes the importance of gene test in this congenital disorder.","variants":[{"Name":"NM_001110219.3(GJB6):c.263C>T (p.Ala88Val)","Chromosome":"13","Start":"20223218","Stop":"20223218","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":20584,"rule_based_match":true,"evidence_text":"c.263C>T (p.A88V)","llm_judgment":"PRESENT","evidence":"c.263C>T (p.A88V)","abstract_start":679,"abstract_end":696}]}
{"pmid":"33538445","title":"Identification of a Novel Mutation in the Runt-Related Transcription Factor 2 Gene in a Chinese Family With Cleidocranial Dysplasia.","abstract":"ABSTRACT: Cleidocranial dysplasia (CCD) is an uncommon autosomal dominant disease, characterized by hypoplasia of clavicles, delayed fontanelle closure, dental anomalies, and short stature. It has been reported in the literature that the pathogenic variants of Runt-related transcription factor 2 (RUNX2) gene are correlated with CCD patients.Here, we report a consanguineous Chinese family with 2 patients suffering from CCD, presenting similar skeleton and dentition malformation. Upon whole-exome sequencing, 52863 variants were detected in the propositus. Based on the genotype phenotype correlation, a frameshift deletion c.1554delG p.(Trp518Cysfs∗61), located in exon 8 of RUNX2, remained after filtration. For Sanger sequencing, all exons of the RUNX2 gene in members of this Chinese family were amplified by polymerase chain reaction. Mutation mentioned above was confirmed in the propositus and his mother, which has not been reported previously and cannot be found in the publicly available databases. The present study expands the pathogenic variant spectrum of RUNX2 gene and contributes to molecular diagnosis.","variants":[{"Name":"NM_001024630.4(RUNX2):c.1554del (p.Trp518fs)","Chromosome":"6","Start":"45547292","Stop":"45547292","ReferenceAlleleVCF":"TG","AlternateAlleleVCF":"T","allel_id":2157574,"rule_based_match":true,"evidence_text":"c.1554delG p.(Trp518Cysfs∗61)","llm_judgment":"PRESENT","evidence":"c.1554delG p.(Trp518Cysfs∗61)","abstract_start":627,"abstract_end":656}]}
{"pmid":"32360402","title":"Severe congenital myasthenic syndrome associated with novel biallelic mutation of the CHRND gene.","abstract":"Congenital myasthenic syndromes (CMS) are a group of inherited disorders caused by mutations in genes encoding proteins essential for neuromuscular transmission. CMS is characterized by fatigable muscle weakness with onset at birth or in early childhood; rarely, symptoms may present later. The most frequently involved proteins are choline acetyltransferase, the endplate species of acetylcholinesterase and the acetylcholine receptor subunits. Defects in the cholinergic receptor nicotinic delta subunit (CHRND) are a rare cause for CMS but they should be considered in patients with a severe, early onset disease, with respiratory distress. We describe two sisters, clinically and genetically diagnosed with CMS, carrying two heteroallelic variants in the CHRND gene: c.730C>T; p.(Arg244Cys) and c.1304T>C; p.(Leu435Pro). The first variant has already been described yet no clinical relevance has been proved; the second one, is a novel variant documented here for the first time. These two cases expand the clinical spectrum of CMS linked to CHRND mutations.","variants":[{"Name":"NM_000751.3(CHRND):c.730C>T (p.Arg244Cys)","Chromosome":"2","Start":"232530049","Stop":"232530049","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":576670,"rule_based_match":true,"evidence_text":"c.730C>T; p.(Arg244Cys)","llm_judgment":"PRESENT","evidence":"c.730C>T; p.(Arg244Cys)","abstract_start":771,"abstract_end":794}]}
{"pmid":"30352407","title":"Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients.","abstract":"Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.","variants":[{"Name":"NM_003000.3(SDHB):c.343C>T (p.Arg115Ter)","Chromosome":"1","Start":"17028680","Stop":"17028680","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":194371,"rule_based_match":true,"evidence_text":"c.343C>T","llm_judgment":"PRESENT","evidence":"c.343C>T","abstract_start":1176,"abstract_end":1184},{"Name":"NM_003000.3(SDHB):c.541-2A>G","Chromosome":"1","Start":"17024076","Stop":"17024076","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":181613,"rule_based_match":true,"evidence_text":"c.541-2A>G","llm_judgment":"PRESENT","evidence":"c.541-2A>G","abstract_start":1189,"abstract_end":1199}]}
{"pmid":"15365993","title":"BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer.","abstract":"In order to evaluate the role of BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer, 97 patients with sporadic breast cancer were analyzed for mutations in the BRCA1 and BRCA2 coding regions, by using a combination of fluorescent-conformation sensitive gel electrophoresis (F-CSGE) and direct sequencing. Fifty-five distinct sequence variants were detected, which included three pathogenic truncating mutations, 15 missense mutations, 16 polymorphisms, and 21 intronic variants. Twenty-six of these variants have never been previously reported and may be of Korean-specific origin. Two pathogenic BRCA1 mutations (c.922_924delinsT, c.5445G>A) and one pathogenic BRCA2 mutation (c.2259delT) were observed, and two of these (BRCA1 c.5445G>A and BRCA2 c.2259delT) are novel. The total prevalence of germline pathogenic mutations in BRCA1 and/or BRCA2 in Korean sporadic breast cancer is estimated to be about 3.1%. Considering that the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of germline BRCA mutations in sporadic breast cancer patients. Further study using a larger sample size is required to determine the merits of genetic diagnosis and counseling in breast cancer patients.","variants":[{"Name":"NM_007294.4(BRCA1):c.5445G>A (p.Trp1815Ter)","Chromosome":"17","Start":"43047665","Stop":"43047665","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":70248,"rule_based_match":true,"evidence_text":"BRCA1 c.5445G>A","llm_judgment":"PRESENT","evidence":"BRCA1 c.5445G>A","abstract_start":754,"abstract_end":769}]}
{"pmid":"38099988","title":"Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome.","abstract":"The DNA polymerase δ complex (PolD), comprising catalytic subunit POLD1 and accessory subunits POLD2, POLD3, and POLD4, is essential for DNA synthesis and is central to genome integrity. We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome. The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination. The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years. We performed molecular and functional analysis of the mutant POLD3 and assessed cell cycle progression as well as replication-associated DNA damage. Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components. The cell cycle defect was rescued by transduction with WT POLD3. This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome.","variants":[{"Name":"NM_006591.3(POLD3):c.1118A>C (p.Lys373Thr)","Chromosome":"11","Start":"74634694","Stop":"74634694","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3409160,"rule_based_match":true,"evidence_text":"c.1118A > C; p.K373T","llm_judgment":"PRESENT","evidence":"c.1118A > C; p.K373T","abstract_start":261,"abstract_end":281}]}
{"pmid":"31598951","title":"Prenatal diagnosis of a fetus affected with Finnish type congenital nephrotic syndrome","abstract":"OBJECTIVE: To explore the genetic basis for a fetus suspected for congenital nephrotic syndrome of Finland (CNF).\nMETHODS: Genomic DNA was extracted from peripheral and umbilical cord blood samples derived from both parents and the fetus. Potential variants were detected by using next-generation sequencing. Suspected variants were confirmed by Sanger sequencing.\nRESULTS: The fetus was found to carry compound heterozygous variants c.1440+1G>A and c.925G>T of the NPHS1 gene, which were respectively inherited from its mother and father.\nCONCLUSION: Identification of the compound heterozygous NPHS1 variants has enabled diagnosis of CNF in the fetus and genetic counseling for the affected family.","variants":[{"Name":"NM_004646.4(NPHS1):c.925G>T (p.Glu309Ter)","Chromosome":"19","Start":"35849063","Stop":"35849063","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":3709572,"rule_based_match":true,"evidence_text":"c.925G>T","llm_judgment":"PRESENT","evidence":"c.925G>T","abstract_start":450,"abstract_end":458}]}
{"pmid":"19887791","title":"GJB2 and GJB6 genes: molecular study and identification of novel GJB2 mutations in the hearing-impaired Argentinean population.","abstract":"Mutations in the GJB2 gene are responsible for more than half of all cases of recessive non-syndromic deafness. This article presents a mutation analysis of the GJB2, GJB6, OTOF and MTRNR1 genes in 252 patients with sensorineural non-syndromic hearing loss. Thirty-one different mutations were identified in GJB2 and GJB6 in 86 of the 252 (34%) patients. We describe for the first time two new mutations in GJB2: the missense mutation c.29 T>C (p.Leu10Pro) in the N terminal domain and c.326 G>T (p.Gly109Val) in the intracytoplasmic domain of connexin 26. This work shows the high prevalence of GJB2 mutations in the Argentinean population, with frequencies that are comparable to those of the Mediterranean area. Most important, it adds two novel GJB2 mutations to be taken into consideration in the genetic diagnosis of non-syndromic sensorineural hearing loss.","variants":[{"Name":"NM_004004.6(GJB2):c.29T>C (p.Leu10Pro)","Chromosome":"13","Start":"20189553","Stop":"20189553","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":966546,"rule_based_match":true,"evidence_text":"c.29 T>C (p.Leu10Pro)","llm_judgment":"PRESENT","evidence":"c.29 T>C (p.Leu10Pro)","abstract_start":435,"abstract_end":456}]}
{"pmid":"23407919","title":"Mutation screening in a Norwegian cohort with pheochromocytoma.","abstract":"Pheochromocytomas (PHEOs) are neuroendocrine tumours, originating from chromaffin cells in the adrenal medulla. They are either sporadic or hereditary. It is important to identify the hereditary cases, so that patients and relatives with germline mutations can be offered regular surveillance. The objective of this study was the detection of pathogenic germline mutations in a cohort of Norwegian PHEO patients. Blood samples and/or formalin-fixed, paraffin-embedded tissue specimens, were collected from 60 patients who were operated upon between 1986 and 2004 at two university hospitals in Norway. DNA mutation analyses were performed successfully in the 42 blood samples and in one of the paraffin-embedded tissue specimen in VHL, RET, SDHB, SDHC, SDHD and NF1. In all, 32 different DNA variants were observed, of which 8 were classified as pathogenic (19 %), or possibly pathogenic; three in NF1, two in RET and VHL and one in SDHB. Two variants were observed in one patient, one in SDHB and one in NF1. Three of these variants are, to the best of our knowledge, new ones; two in NF1 [c.950_51insGCTGA, (p.Glu318LeufsX59) and c.1588G > A, (p.Val530Ile)] and one in VHL (c.308C > T, p.Pro103Leu). In conclusion the overall incidence of germline mutations in genes associated with familial PHEO was found to be of the same order of magnitude in the present Norwegian series as in those from other countries. Two new NF1 variants and one new VHL gene variant were detected.","variants":[{"Name":"NM_000551.4(VHL):c.308C>T (p.Pro103Leu)","Chromosome":"3","Start":"10142155","Stop":"10142155","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1505094,"rule_based_match":true,"evidence_text":"c.308C > T, p.Pro103Leu","llm_judgment":"PRESENT","evidence":"c.308C > T, p.Pro103Leu","abstract_start":1176,"abstract_end":1199},{"Name":"NM_001042492.3(NF1):c.1588G>A (p.Val530Ile)","Chromosome":"17","Start":"31219065","Stop":"31219065","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":151083,"rule_based_match":true,"evidence_text":"c.1588G > A, (p.Val530Ile)","llm_judgment":"PRESENT","evidence":"c.1588G > A, (p.Val530Ile)","abstract_start":1132,"abstract_end":1158}]}
{"pmid":"23933162","title":"Clinical presentation of mild cystic fibrosis in a Serbian patient homozygous for the CFTR mutation c.1393-1G>A.","abstract":"We present a case of a 19-year old male with uncommon initial clinical cystic fibrosis (CF) presentation and a rare CFTR genotype, homozygote for c.1393-1G>A mutation (legacy name 1525-1G>A).","variants":[{"Name":"NM_000492.4(CFTR):c.1393-1G>A","Chromosome":"7","Start":"117559463","Stop":"117559463","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67910,"rule_based_match":true,"evidence_text":"c.1393-1G>A","llm_judgment":"PRESENT","evidence":"c.1393-1G>A","abstract_start":146,"abstract_end":157}]}
{"pmid":"20574985","title":"Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency.","abstract":"Systemic primary carnitine deficiency (CDSP) is caused by recessive mutations in the SLC22A5 (OCTN2) gene encoding the plasmalemmal carnitine transporter and characterized by hypoketotic hypoglycemia, and skeletal and cardiac myopathy. The entire coding regions of the OCTN2 gene were sequenced in 143 unrelated subjects suspected of having CDSP. In 70 unrelated infants evaluated because of abnormal newborn screening (NBS) results, 48 were found to have at least 1 mutation/unclassified missense variant. Twenty-eight of 33 mothers whose infants had abnormal NBS results were found to carry at least 1 mutation/unclassified missense variant, including 11 asymptomatic mothers who had 2 mutations. Therefore, sequencing of the OCTN2 gene is recommended for infants with abnormal NBS results and for their mothers. Conversely, 52 unrelated subjects were tested due to clinical indications other than abnormal NBS and only 14 of them were found to have at least one mutation/unclassified variant. Custom designed oligonucleotide array CGH analysis revealed a heterozygous approximately 1.6 Mb deletion encompassing the entire OCTN2 gene in one subject who was apparently homozygous for the c.680G>A (p.R227H) mutation. Thus, copy number abnormalities at the OCTN2 locus should be considered if by sequencing, an apparently homozygous mutation or only one mutant allele is identified.","variants":[{"Name":"NM_003060.4(SLC22A5):c.680G>A (p.Arg227His)","Chromosome":"5","Start":"132385355","Stop":"132385355","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":367924,"rule_based_match":true,"evidence_text":"c.680G>A (p.R227H)","llm_judgment":"PRESENT","evidence":"c.680G>A (p.R227H)","abstract_start":1189,"abstract_end":1207}]}
{"pmid":"26794302","title":"Distally pronounced infantile spinal muscular atrophy with severe axonal and demyelinating neuropathy associated with the S230L mutation of SMN1.","abstract":"Two Croatian siblings with atypical clinical findings in the presence of SMN1 gene mutations are reported. The girl presented with delayed motor development and weakness in hands and feet in her first year of life. She never stood or walked and developed scoliosis and joint contractures during childhood. Her hands and feet were non-functional when last seen at age 14 years. Her 4-year-old brother was more severely affected and had a clinical picture resembling infantile spinal muscular atrophy (SMA) type 1. He also showed unusual distally pronounced weakness and facial weakness. Both patients had no sensory deficits but gave evidence of a mixed axonal and demyelinating neuropathy with pronounced slowing in the distal nerve segments. Unexpectedly, both siblings showed a compound heterozygous SMN1 mutation (heterozygous deletion and missense mutation c.689C > T; p.S230L), thus confirming infantile SMA. In addition, next generation sequencing of 52 genes for hereditary neuropathies revealed a heterozygous missense mutation c.505T > C; p.Y169H in the SH3TC2 gene that was transmitted by the healthy father. Our observations widen the phenotypic consequences of SMN1 gene mutations and support the notion to look for additional genetic factors which may modify the clinical picture in atypical cases.","variants":[{"Name":"NM_024577.4(SH3TC2):c.505T>C (p.Tyr169His)","Chromosome":"5","Start":"149042718","Stop":"149042718","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":17524,"rule_based_match":true,"evidence_text":"c.505T > C; p.Y169H","llm_judgment":"PRESENT","evidence":"c.505T > C; p.Y169H","abstract_start":1036,"abstract_end":1055}]}
{"pmid":"24162162","title":"Cost-effective PKHD1 genetic testing for autosomal recessive polycystic kidney disease.","abstract":"BACKGROUND: Genetic diagnosis of autosomal recessive polycystic kidney disease (ARPKD) is challenging due to the length and allelic heterogeneity of the PKHD1 gene. Mutations appear to be clustered at specific exons, depending on the geographic origin of the patient. We aimed to identify the PKHD1 exons most likely mutated in Spanish ARPKD patients.\nMETHODS: Mutation analysis was performed in 50 ARPKD probands and nine ARPKD-suspicious patients by sequencing PKHD1 exons arranged by their reported mutation frequency. Haplotypes containing the most frequent mutations were analyzed. Other PKD genes (HNF1B, PKD1, PKD2) were sequenced in PKHD1-negative cases.\nRESULTS: Thirty-six different mutations (concentrated in 24 PKHD1 exons) were detected, giving a mutation detection rate of 86%. The screening of five exons (58, 32, 34, 36, 37) yielded a 54% chance of detecting one mutation; the screening of nine additional exons (3, 9, 39, 61, 5, 22, 26, 41, 57) increased the chance to 76%. The c.9689delA mutation was present in 17 (34%) patients, all of whom shared the same haplotype. Two HNF1B mutations and one PKD1 variant were detected in negative cases.\nCONCLUSIONS: Establishing a PKHD1 exon mutation profile in a specific population and starting the analysis with the most likely mutated exons might significantly enhance the efficacy of genetic testing in ARPKD. Analysis of other PKD genes might be considered, especially in suspicious cases.","variants":[{"Name":"NM_138694.4(PKHD1):c.9689del (p.Asp3230fs)","Chromosome":"6","Start":"51747927","Stop":"51747927","ReferenceAlleleVCF":"AT","AlternateAlleleVCF":"A","allel_id":102338,"rule_based_match":true,"evidence_text":"c.9689delA","llm_judgment":"PRESENT","evidence":"c.9689delA","abstract_start":995,"abstract_end":1005}]}
{"pmid":"36588762","title":"Recurrent Vein of Galen Aneurysmal Malformation as a Presentation of Hereditary Hemorrhagic Telangiectasia.","abstract":"Introduction: Vein of Galen malformation (VGM) results from an aneurysmal aberration with an arteriovenous shunting of blood and is the most frequent arteriovenous malformation in infants and fetuses. The congenital malformation develops during weeks 6-11 of fetal development. Infants often die from high-output congestive heart failure. VGM is mostly considered as a sporadic condition with minimal recurrence risk in subsequent pregnancies. Mendelian forms of VGM have rarely been described as infrequent phenotypic presentations of 2 disorders: capillary malformation-arteriovenous malformation syndrome (<i>RASA1</i>, <i>EPHB4</i>) and hereditary hemorrhagic telangiectasia (<i>ENG</i>, <i>ACVRL1</i>, and <i>SMAD4</i>), both showing autosomal dominant inheritance.\nCase Presentation: Here, we report on a consanguineous couple with recurrent VGM in 2 pregnancies. Both partners were found to be affected by hereditary hemorrhagic telangiectasia due to a known pathogenic heterozygous c.790G>A (p.Asp264Asn) variant in <i>ENG</i>. Fetal DNA was unavailable, however in view of the mild phenotype in the couple, along with the severe prenatal presentation in 2 pregnancies, the fetus was presumed to be homozygous for the <i>ENG</i> variant. A subsequent pregnancy revealed a fetus heterozygous for the variant, which had an uneventful perinatal course.\nConclusion: This report highlights a severe perinatal lethal phenotype due to biallelic variants in a gene hitherto known to cause an autosomal dominant disorder.","variants":[{"Name":"NM_001114753.3(ENG):c.790G>A (p.Asp264Asn)","Chromosome":"9","Start":"127825257","Stop":"127825257","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1334285,"rule_based_match":true,"evidence_text":"c.790G>A (p.Asp264Asn)","llm_judgment":"PRESENT","evidence":"c.790G>A (p.Asp264Asn)","abstract_start":990,"abstract_end":1012}]}
{"pmid":"27495310","title":"Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort.","abstract":"Germline mutations in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. Molecular screening of these two genes in patients with a family history of breast or ovarian cancer has revealed pathogenic variants as well as genetic variants of unknown significance (VUS). These VUS may cause a challenge in the genetic counseling process regarding clinical management of the patient and the family. We investigated 32 variants previously detected in 33 samples from patients with a family history of breast or ovarian cancer. cDNA was analyzed for alternative transcripts and selected missense variants located in the BRCT domains of BRCA1 were assessed for their trans-activation ability. Although an extensive cDNA analysis was done, only three of the 32 variants appeared to affect the splice-process (BRCA1 c.213-5T>A, BRCA1 c.5434C>G and BRCA2 c.68-7T>A). In addition, two variants located in the BRCT domains of BRCA1 (c.5075A>C p.Asp1692Ala and c.5513T>G p.Val1838Gly) were shown to abolish the BRCT domain trans-activation ability, whereas BRCA1 c.5125G>A p.Gly1709Arg exhibited equal trans-activation capability as the WT domain. These functional studies may offer further insights into the pathogenicity of certain identified variants; however, this assay is only applicable for a subset of missense variants.","variants":[{"Name":"NM_007294.4(BRCA1):c.5434C>G (p.Pro1812Ala)","Chromosome":"17","Start":"43047676","Stop":"43047676","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":46226,"rule_based_match":true,"evidence_text":"BRCA1 c.5434C>G","llm_judgment":"PRESENT","evidence":"BRCA1 c.5434C>G","abstract_start":826,"abstract_end":841},{"Name":"NM_000059.4(BRCA2):c.68-7T>A","Chromosome":"13","Start":"32319070","Stop":"32319070","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":66855,"rule_based_match":true,"evidence_text":"BRCA2 c.68-7T>A","llm_judgment":"PRESENT","evidence":"BRCA2 c.68-7T>A","abstract_start":846,"abstract_end":861},{"Name":"NM_007294.4(BRCA1):c.5513T>G (p.Val1838Gly)","Chromosome":"17","Start":"43045757","Stop":"43045757","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":249180,"rule_based_match":true,"evidence_text":"BRCA1 c.5513T>G p.Val1838Gly","llm_judgment":"PRESENT","evidence":"p.Val1838Gly","abstract_start":965,"abstract_end":977},{"Name":"NM_007294.4(BRCA1):c.5125G>A (p.Gly1709Arg)","Chromosome":"17","Start":"43063901","Stop":"43063901","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":249181,"rule_based_match":true,"evidence_text":"BRCA1 c.5125G>A p.Gly1709Arg","llm_judgment":"PRESENT","evidence":"BRCA1 c.5125G>A p.Gly1709Arg","abstract_start":1051,"abstract_end":1079},{"Name":"NM_007294.4(BRCA1):c.5075A>C (p.Asp1692Ala)","Chromosome":"17","Start":"43063951","Stop":"43063951","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":249182,"rule_based_match":true,"evidence_text":"BRCA1 c.5075A>C p.Asp1692Ala","llm_judgment":"PRESENT","evidence":"p.Asp1692Ala","abstract_start":938,"abstract_end":950},{"Name":"NM_007294.4(BRCA1):c.213-5T>A","Chromosome":"17","Start":"43104961","Stop":"43104961","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":249184,"rule_based_match":true,"evidence_text":"BRCA1 c.213-5T>A","llm_judgment":"PRESENT","evidence":"BRCA1 c.213-5T>A","abstract_start":808,"abstract_end":824}]}
{"pmid":"28969374","title":"Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.","abstract":"Hypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain. A trio-based whole exome sequencing analysis in the first family detected a homozygous frameshift change [c.606delinsTA; p.(Lys202Asnfs*?)]. In the second family, homozygosity mapping coupled to whole exome sequencing identified a homozygous nucleotide substitution (c.565G>T) introducing a premature stop codon (p.Glu189*). In the third family, whole exome sequencing established compound heterozygosity for a non-conservative missense change affecting a key residue participating in DNA binding (c.599G>A; p.Arg200Gln) and a nonsense substitution (c.589C>T; p.Gln197*), in both affected siblings. The clinical presentation was homogeneous, with four subjects having severe motor delays, nystagmus and absent head control, and one individual showing gross motor delay at the age of 6 months. All exhibited neuroimaging that was consistent with hypomyelination. These findings define a novel, severe form of leukodystrophy caused by impaired NKX6-2 function.","variants":[{"Name":"NM_177400.3(NKX6-2):c.606delinsTA (p.Lys202fs)","Chromosome":"10","Start":"132785144","Stop":"132785144","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"TA","allel_id":615971,"rule_based_match":true,"evidence_text":"c.606delinsTA; p.(Lys202Asnfs*?)","llm_judgment":"PRESENT","evidence":"c.606delinsTA; p.(Lys202Asnfs*?)","abstract_start":797,"abstract_end":829},{"Name":"NM_177400.3(NKX6-2):c.599G>A (p.Arg200Gln)","Chromosome":"10","Start":"132785151","Stop":"132785151","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":615972,"rule_based_match":true,"evidence_text":"c.599G>A; p.Arg200Gln","llm_judgment":"PRESENT","evidence":"c.599G>A; p.Arg200Gln","abstract_start":1189,"abstract_end":1210},{"Name":"NM_177400.3(NKX6-2):c.589C>T (p.Gln197Ter)","Chromosome":"10","Start":"132785161","Stop":"132785161","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":615973,"rule_based_match":true,"evidence_text":"c.589C>T (p.Gln197*)","llm_judgment":"PRESENT","evidence":"p.Gln197*","abstract_start":1251,"abstract_end":1260},{"Name":"NM_177400.3(NKX6-2):c.565G>T (p.Glu189Ter)","Chromosome":"10","Start":"132785294","Stop":"132785294","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":615974,"rule_based_match":true,"evidence_text":"c.565G>T","llm_judgment":"PRESENT","evidence":"c.565G>T","abstract_start":958,"abstract_end":966}]}
{"pmid":"14517959","title":"Ten novel mutations in VMD2 associated with Best macular dystrophy (BMD).","abstract":"Mutations in the vitelliform macular dystrophy 2 (VMD2) gene encoding besrtophin are responsible for Best macular dystrophy (BMD), a juvenile-onset autosomal dominant disorder of the central retina. Here, we report ten novel VMD2 mutations identified in clinically diagnosed BMD patients. The heterozygous alterations include nine missense mutations (c.32A>T, c.76G>C, c.85T>C, c.122T>C, c.122T>C, c.310G>C, c.722C>A, c.880C>G, c.893T>C) resulting in amino acid changes (respectively: Asn11Ile, Gly26Arg, Tyr29His, Leu41Pro, Trp102Arg, Asp104His, Thr241Asn, Leu294Val and Phe298Ser) located within four previously defined hotspot regions of the gene. In addition, a silent exonic mutation (c.624G>A) was identified in a two generation BMD pedigree. To determine a possible pathogenic effect of this variant, the consequences on splicing behaviour and potential exonic splice enhancer (ESE) motifs were analyzed. Finally, a 1-bp deletion (c.779delC) resulting in a frameshift mutation (Pro260fsX288) was found in exon 7, representing the first case of a potential frameshift mutation that affects the N-terminal half of the VMD2 protein. Besides a dominant negative effect which is likely attributable to the identified missense mutations, the deletion mutation suggests haploinsufficiency as an infrequent disease-causing mechanism in BMD.","variants":[{"Name":"NM_004183.4(BEST1):c.310G>C (p.Asp104His)","Chromosome":"11","Start":"61955780","Stop":"61955780","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":105601,"rule_based_match":true,"evidence_text":"c.310G>C","llm_judgment":"PRESENT","evidence":"c.310G>C","abstract_start":398,"abstract_end":406},{"Name":"NM_004183.4(BEST1):c.722C>A (p.Thr241Asn)","Chromosome":"11","Start":"61958153","Stop":"61958153","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":105637,"rule_based_match":true,"evidence_text":"c.722C>A","llm_judgment":"PRESENT","evidence":"c.722C>A","abstract_start":408,"abstract_end":416},{"Name":"NM_004183.4(BEST1):c.779del (p.Pro260fs)","Chromosome":"11","Start":"61958208","Stop":"61958208","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":805702,"rule_based_match":true,"evidence_text":"c.779delC","llm_judgment":"PRESENT","evidence":"c.779delC","abstract_start":938,"abstract_end":947},{"Name":"NM_004183.4(BEST1):c.624G>A (p.Gln208=)","Chromosome":"11","Start":"61956986","Stop":"61956986","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":105618,"rule_based_match":true,"evidence_text":"c.624G>A","llm_judgment":"PRESENT","evidence":"c.624G>A","abstract_start":690,"abstract_end":698},{"Name":"NM_004183.4(BEST1):c.122T>C (p.Leu41Pro)","Chromosome":"11","Start":"61951928","Stop":"61951928","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":17782,"rule_based_match":true,"evidence_text":"c.122T>C","llm_judgment":"PRESENT","evidence":"c.122T>C","abstract_start":378,"abstract_end":386},{"Name":"NM_004183.4(BEST1):c.893T>C (p.Phe298Ser)","Chromosome":"11","Start":"61959523","Stop":"61959523","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":105656,"rule_based_match":true,"evidence_text":"c.893T>C","llm_judgment":"PRESENT","evidence":"c.893T>C","abstract_start":428,"abstract_end":436}]}
{"pmid":"37719058","title":"BRCA1 and BRCA2 mutations and their clinical relevance in selected women diagnosed with triple-negative breast cancer in Kenya: a descriptive cross-sectional study.","abstract":"Introduction: triple-negative breast cancer (TNBC) is a heterogeneous breast cancer type with a poor prognosis. About 25% of TNBC patients carry breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) mutations. Screening for BRCA mutations would facilitate early detection and initiation of personalized therapy, thus improving prognosis. However, this has not been explored in our population. We aimed at identifying BRCA1 and BRCA2 gene mutations and their clinical relevance among selected women with TNBC in Kenya.\nMethods: six participants enrolled in a larger descriptive cross-sectional study who met the inclusion criteria were selected. Structured questionnaires were used to obtain qualitative data. Deoxyribonucleic acid (DNA) was extracted from saliva. Whole exome sequencing of BRCA1 and BRCA2 genes using a next-generation sequencer was done.\nResults: overall, 83.3% of BRCA1 and BRCA2 gene mutations with clinical relevance were detected. Most of the variants (63%) were found in BRCA1 whereas 37% were found in BRCA2. Pathogenic mutations in BRCA1 gene included c.5513T>A, c.5291T>C, c.5297T>G, c.110C>A, c.5212G>C, c.122A>C, c.5117G>A, c.5095C>T, c.5054C>T, c.5053A>G, c.115T>A, c.5143A>G, and c.130T>G. Those in BRCA2 gene were c.7878G>A, c.9154C>T, c.8243G>A, c.7976G>A, c.8165C>G, c.8167G>C, and c.8168A>T. One variant (c.5352delG: p. Leu1785Terfs) not matching any in the BRCA Exchange and ClinVar databases was detected.\nConclusion: our study revealed BRCA mutations that could be common among our population. Further, it has shown that BRCA1 and BRCA2 genetic mutations identified are of clinical relevance and there is a need to screen for these mutations in breast cancer patients to understand their implication in patient management outcomes.","variants":[{"Name":"NM_007294.4(BRCA1):c.5212G>C (p.Gly1738Arg)","Chromosome":"17","Start":"43057117","Stop":"43057117","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":853771,"rule_based_match":true,"evidence_text":"c.5212G>C","llm_judgment":"PRESENT","evidence":"c.5212G>C","abstract_start":1127,"abstract_end":1136}]}
{"pmid":"25234566","title":"Homozygous familial hypercholesterolemia: the c.1055G>A mutation in the LDLR gene and clinical heterogeneity.","abstract":"Familial hypercholesterolemia (FH) is a world public health issue because of its high frequency, morbidity, and mortality. FH is characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C) levels and a high risk for premature cardiovascular disease. We report an 8-year-old male with homozygous familial hypercholesterolemia. The clinical and biochemical characteristics of this case were bilateral corneal arcus, xanthomas in several body parts, severe stenosis of the left carotid artery and serum total cholesterol levels of 782.0 mg/dL and 715.0 mg/dL LDL-C. The initial treatment was atorvastatin (40 mg) and ezetimibe (20 mg), with no satisfactory response. LDLR gene was analyzed and homozygosity for c.1055G>A mutation was observed, resulting in an amino acid change from cysteine to tyrosine in codon 352 (p.Cys352Tyr). This mutation is known as Mexico 2 and has only been observed in the Mexican population. Both parents and siblings were carriers of the same mutation, but the paternal grandmother and the father of the index case showed the phenomenon of incomplete penetrance. With the analysis 5 polymorphisms (rs1003723C>T, rs5930A>G, rs688C>T, rs5929T>C and rs5927A>G), a common ancestor for the mutation can be suggested and linkage to TGTCG haplotype.","variants":[{"Name":"NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr)","Chromosome":"19","Start":"11110766","Stop":"11110766","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45113,"rule_based_match":true,"evidence_text":"c.1055G>A","llm_judgment":"PRESENT","evidence":"c.1055G>A","abstract_start":725,"abstract_end":734}]}
{"pmid":"31584309","title":"Genetic Analysis of Tyrosinemia Type 1 and Fructose-1, 6 Bisphosphatase Deficiency Affected in Pakistani Cohorts.","abstract":"<b>Background:</b> Inborn errors of metabolism are inherited disorders that present in early childhood and are usually caused by monogenic recessive mutations in specific enzymes that metabolize dietary components. Distinct mutations are present in specific populations.<b>Objective:</b> To determine which genomic variants are present in Pakistani cohorts with hepatorenal tyrosinemia type 1 (HT1) and fructose 1,6-bisphosphatase deficiency (FBPD).<b>Materials and Methods:</b> We sequenced the fumaryl acetoacetate hydrolase encoding gene (<i>FAH</i>) including flanking regions in four unrelated HT1 cohorts and the fructose 1,6-bisphosphatase gene (<i>FBP1</i>) in eight FBPD cohorts.<b>Results:</b> We mapped two recessive mutations in <i>FAH</i> gene for HT1; c.1062 + 5G > A(IVS12 + 5G > A) in three families and c.974C > T(pT325M) in one. We identified three mutations in <i>FBP1</i> gene; c.841G > A(p.E281K) in five FBPD families, c.472C > T(p.R158W) in two families and c.778G > A(p.G260R) in one.<b>Conclusion:</b> Knowledge of common variants for HTI and FBDP in our study population can be used in the future to build a diagnostic algorithm.","variants":[{"Name":"NM_000507.4(FBP1):c.472C>T (p.Arg158Trp)","Chromosome":"9","Start":"94610016","Stop":"94610016","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":553128,"rule_based_match":true,"evidence_text":"c.472C > T(p.R158W)","llm_judgment":"PRESENT","evidence":"c.472C > T(p.R158W)","abstract_start":941,"abstract_end":960},{"Name":"NM_000507.4(FBP1):c.778G>A (p.Gly260Arg)","Chromosome":"9","Start":"94605504","Stop":"94605504","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":553126,"rule_based_match":true,"evidence_text":"c.778G > A(p.G260R)","llm_judgment":"PRESENT","evidence":"c.778G > A(p.G260R)","abstract_start":981,"abstract_end":1000}]}
{"pmid":"31972369","title":"Whole exome sequencing identifies SCD5 as a novel causative gene for autosomal dominant nonsyndromic deafness.","abstract":"We report a genetic assessment of autosomal dominant, nonsyndromic, progressive sensorineural hearing loss in a Chinese family, combining whole-exome sequencing and genome-wide linkage analysis. A novel missense mutation, c.626G > C, in the SCD5 gene was identified in this family. The heterozygous missense mutation could segregate hearing loss cases among family members, and was predicted to be deleterious by Polyphen-2, LRT and Mutation Taster. SCD5 is an endoplasmic reticulum enzyme, catalyzing the formation of monounsaturated fatty acids (MUFAs) from saturated fatty acids (SFAs). It plays a crucial role in regulating lipid metabolism. The SCD5 protein is expressed in inner and outer hair cells of the organ of Corti, the stria vascularis, cells of the lateral cochlear wall behind the spiral prominence, and more strongly in spiral ganglion cells of guinea pig and human fetal cochleas. SCD5 protein was also expressed in the brain, consistent with the hearing loss feature: the patients had a poor speech discrimination score at young age and mild hearing loss as evaluated by pure tone audiometry. In summary, we identified SCD5 as a novel gene responsible for autosomal dominant nonsyndromic deafness.","variants":[{"Name":"NM_001037582.3(SCD5):c.626G>C (p.Trp209Ser)","Chromosome":"4","Start":"82636767","Stop":"82636767","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":972756,"rule_based_match":true,"evidence_text":"c.626G > C","llm_judgment":"PRESENT","evidence":"c.626G > C","abstract_start":222,"abstract_end":232}]}
{"pmid":"23295294","title":"Clinical and molecular spectrum of patients with 17β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) deficiency.","abstract":"The enzyme 17β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) catalyzes the conversion of androstenedione to testosterone in the testes, and its deficiency is a rare disorder of sex development in 46,XY individuals. It can lead to a wide range of phenotypic features, with variable hormonal profiles. We report four patients with the 46,XY karyotype and 17-β-HSD3 deficiency, showing different degrees of genital ambiguity, increased androstenedione and decreased testosterone levels, and testosterone to androstenedione ratio < 0.8. In three of the patients, diagnosis was only determined due to the presence of signs of virilization at puberty. All patients had been raised as females, and female gender identity was maintained in all of them. Compound heterozygosis for c.277+2T>G novel mutation, and c.277+4A>T mutation, both located within the intron 3 splice donor site of the HSD17B3 gene, were identified in case 3. In addition, homozygosis for the missense p.Ala203Val, p.Gly289Ser, p.Arg80Gln mutations were found upon HSD17B3 gene sequencing in cases 1, 2, and 4, respectively.","variants":[{"Name":"NM_000197.2(HSD17B3):c.277+4A>T","Chromosome":"9","Start":"96254864","Stop":"96254864","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":205160,"rule_based_match":true,"evidence_text":"c.277+4A>T","llm_judgment":"PRESENT","evidence":"c.277+4A>T","abstract_start":805,"abstract_end":815},{"Name":"NM_000197.2(HSD17B3):c.608C>T (p.Ala203Val)","Chromosome":"9","Start":"96244393","Stop":"96244393","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19914,"rule_based_match":false,"evidence_text":"p.Ala203Val","llm_judgment":"PRESENT","evidence":"p.Ala203Val","abstract_start":967,"abstract_end":978}]}
{"pmid":"20931527","title":"A novel GATA4 mutation leading to congenital ventricular septal defect","abstract":"OBJECTIVE: To identify the GATA4 gene mutation of congenital ventricular septal defect (VSD) and study the molecular mechanism of a novel mutation.\nMETHODS: The clinical data and blood samples from 185 unrelated subjects with congenital VSD were collected and evaluated together with 200 healthy individuals. The coding exons and the flanking intron regions of the GATA4 gene were amplified by PCR and sequenced using the di-deoxynucleotide chain termination approach. The GATA4 gene was cloned and the corresponding mutant was acquired by site directed mutagenesis. The recombinant plasmid expressing GATA4 and the reporter vector expressing enhanced green fluorescence protein (EGFP) driven by the promoter of atrial natrium peptide (ANP) gene were transfected into HeLa cells with Lipofectamine. The effect of mutated GATA4 gene on the transcriptional activity of encoded transcriptional factor was analyzed by reverse transcription (RT)-PCR.\nRESULTS: A novel heterozygous missense GATA4 mutation, c.191G>A was identified in 1 VSD patient. The mutation leads to glycine to glutamic acid change at amino acid residue 64 (G64E) in the GATA4 protein. Functional analysis showed that GATA4 G64E mutation decreased the transcriptional activity of GATA4 transcriptional factor.\nCONCLUSION: A novel heterozygous missense GATA4 mutation, G64E, was identified in 1 VSD patient. The mutation might cause VSD by impairing the transcriptional activity of GATA4 transcriptional factor.","variants":[{"Name":"NM_001308093.3(GATA4):c.191G>A (p.Gly64Glu)","Chromosome":"8","Start":"11708503","Stop":"11708503","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3124723,"rule_based_match":true,"evidence_text":"c.191G>A","llm_judgment":"PRESENT","evidence":"c.191G>A","abstract_start":1001,"abstract_end":1009}]}
{"pmid":"30077349","title":"A novel variant of SLC26A4 and first report of the c.716T>A variant in Iranian pedigrees with non-syndromic sensorineural hearing loss.","abstract":"The autosomal recessive non-syndromic hearing loss (ARNSHL) can be associated with variants in solute carrier family 26, member 4 (SLC26A4) gene and is the second most common cause of ARNSHL worldwide. Therefore, this study aims to determine the contribution of the SLC26A4 genotype in the hearing loss (HL) of 40 ARNSHL pedigrees in Iran. A cohort of the 40 Iranian pedigrees with ARNSHL, having no mutation in the GJB2 gene, was selected. The linkage analysis with five short tandem repeat (STR) markers linked to SLC26A4 was performed for the 40 ARNSHL pedigrees. Then, two out of the 40 pedigrees with ARNSHL that linked to DFNB4 locus were further screened to determine the variants in all exons of SLC26A4 gene by direct DNA sequencing. The 21 exons of SCL26A4 were analyzed for the two pedigrees. A known variant (c.716T>A homozygote), it is the first reported incidence in Iran, a novel variant (c.493A>C homozygote) were detected in the two pedigrees and pathogenesis of c.493A>C confirmed in this study with review 100 hearing ethnically matched controls by PCR-RFLP analysis. The present study suggests that the SLC26A4 gene plays a crucial role in the HL occurring in Iranian pedigrees. Also, the results probably support the specificity and unique spectrum of SLC26A4 variants among Iranian HL patients. Molecular study of SLC26A4 gene may lead to elucidation of the profile of the population-specific variants which has importance in diagnostics of HL.","variants":[{"Name":"NM_000441.2(SLC26A4):c.716T>A (p.Val239Asp)","Chromosome":"7","Start":"107675060","Stop":"107675060","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":52735,"rule_based_match":true,"evidence_text":"c.716T>A homozygote","llm_judgment":"PRESENT","evidence":"c.716T>A homozygote","abstract_start":821,"abstract_end":840}]}
{"pmid":"28792508","title":"DCTN1 gene analysis in Chinese patients with sporadic amyotrophic lateral sclerosis.","abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Missense mutations of DCTN1 have been identified as a possible genetic risk factor for ALS. Here, we tested the DCTN1 protein-coding exons in 510 sporadic ALS patients in whom SOD1, TARDBP, FUS, and C9orf72 genes were screened before. Polymerase chain reaction and Sanger sequencing were used for mutation discovery. The results revealed two rare heterozygous missense variants, c.1867C>T (p.R623W) and c.2798C>T (p.A933V). These two patients exhibited spinal disease onset without cognitive impairment, and their onset age and diagnosis delay was within the average range of Chinese ALS patients. Our results suggested that variants in DCTN1 are not common risk factors for Chinese sporadic ALS and that the frequency of variants of unknown significance in the cohort study was 0.39%.","variants":[{"Name":"NM_004082.5(DCTN1):c.1867C>T (p.Arg623Trp)","Chromosome":"2","Start":"74368119","Stop":"74368119","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":931593,"rule_based_match":true,"evidence_text":"c.1867C>T (p.R623W)","llm_judgment":"PRESENT","evidence":"c.1867C>T (p.R623W)","abstract_start":454,"abstract_end":473}]}
{"pmid":"30834272","title":"First Record Mutations in the Genes","abstract":"Leukodystrophies (LDs) are heterogeneous genetic disorders characterized by abnormal white matter in the central nervous system. Some of the LDs are progressive and often fatal. In general, LD is primarily diagnosed based on the neuroimaging; however, definitive diagnosis of the LD type is done using genetic testing such as next-generation sequencing. The aim of this study is to identify the genetic causes of LD in two independent Jordanian cases that exhibit MRI findings confirming LD with no definitive diagnosis using whole exome sequencing (WES). The most likely causative variants were identified. In one case, the homozygous pathogenic variant NM_000049.2:c.914C>A;p.Ala305Glu, which is previously reported in ClinVar, in the gene <i>ASPA</i> was identified causing Canavan disease. In the second case, the homozygous novel variant NM_000487.5:c.256C>G;p.Arg86Gly in the gene <i>ARSA</i> was identified causing metachromatic leukodystrophy. The two variants segregate in their families. The phenotypes of the two studied cases overlap with assigned diseases. The present study raises the importance of using WES to identify the precise neurodevelopmental diseases in Jordan.","variants":[{"Name":"NM_000487.6(ARSA):c.256C>G (p.Arg86Gly)","Chromosome":"22","Start":"50627375","Stop":"50627375","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":3043398,"rule_based_match":true,"evidence_text":"NM_000487.5:c.256C>G;p.Arg86Gly","llm_judgment":"PRESENT","evidence":"NM_000487.5:c.256C>G;p.Arg86Gly","abstract_start":843,"abstract_end":874}]}
{"pmid":"19622949","title":"Lipodystrophy: an unusual diagnosis in a case of oligomenorrhea and hirsutism.","abstract":"BACKGROUND: Familial partial lipodystrophy, Dunnigan variety, is a rare autosomal dominant disorder caused by missense mutations in LMNA gene. Individuals are predisposed to insulin resistance and its complications, including features of polycystic ovary syndrome.\nCASE: A 27-year-old Hispanic woman presented with oligomenorrhea and hirsutism. Examination revealed cushingoid facies, significant hirsutism, acanthosis nigricans, and a lean body habitus. Metabolic testing identified diabetes mellitus, dyslipidemia, and steatohepatitis. A diagnosis of familial partial lipodystrophy, Dunnigan variety, was confirmed by the detection of a heterozygous p.Arg482Trp (c.1444C>T) missense mutation in the lamin A/C (LMNA) gene. Subsequently, seven female relatives were diagnosed with familial partial lipodystrophy, Dunnigan variety, four of whom had menstrual irregularities.\nCONCLUSION: Familial partial lipodystrophy, Dunnigan variety, can present with features similar to polycystic ovary syndrome. Diagnosis is critical because the metabolic complications of the disorder have significant morbidity.","variants":[{"Name":"NM_170707.4(LMNA):c.1444C>T (p.Arg482Trp)","Chromosome":"1","Start":"156136984","Stop":"156136984","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29528,"rule_based_match":true,"evidence_text":"c.1444C>T","llm_judgment":"PRESENT","evidence":"c.1444C>T","abstract_start":665,"abstract_end":674}]}
{"pmid":"33489762","title":"A deep intronic variant is a common cause of OTC deficiency in individuals with previously negative genetic testing.","abstract":"Pathogenic variants in non-coding regions of genes encoding enzymes or transporters of the urea cycle can lead to urea cycle disorders (UCDs). However, not all commercially available testing platforms interrogate these regions. Here, we used a gene panel based on massively parallel sequencing (MPS) in 10 individuals with clinical or pedigree-based evidence of a proximal UCD but without a molecular confirmation of the diagnosis. We identified causal variant(s) in 5 of 10 individuals, including in 3 of 7 individuals in whom prior molecular testing was unrevealing. We show that a deep-intronic pathogenic variant in <i>OTC</i>, c.540+265G>A, is an important cause of ornithine transcarbamylase (OTC) deficiency.","variants":[{"Name":"NM_000531.6(OTC):c.540+265G>A","Chromosome":"X","Start":"38401693","Stop":"38401693","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":446643,"rule_based_match":true,"evidence_text":"c.540+265G>A","llm_judgment":"PRESENT","evidence":"c.540+265G>A","abstract_start":632,"abstract_end":644}]}
{"pmid":"31226583","title":"Pathogenic mechanism and gene correction for LQTS-causing double mutations in KCNQ1 using a pluripotent stem cell model.","abstract":"AIMS: To establish a KCNQ1 mutant-specific induced pluripotent stem cell (iPSC) model of a Chinese inherited long QT syndrome (LQTS) patient and to explore the pathogenesis of KCNQ1 mutations.\nMETHODS AND RESULTS: (1) Two patient-specific iPSC lines from the proband were obtained. (2) The experiments produced spontaneously beating cardiomyocytes (CMs) from patient iPSCs. Splicing mutation c. 605-2A > G in iPSC-derived cardiomyocytes (iPSC-CMs) resulted in the skipping of exon 4, exons 3-4, or exons 3-6 in KCNQ1 transcription what was observed in the patient's peripheral leukocytes. (3) Action potential duration (APD) at 50% and 90% repolarization (APD50 and APD90) of the patient's iPSC-derived ventricular-like-CMs was significantly longer than that of the control. Moreover, early after depolarization (EAD) and coupled beats were observed only in L1-iPSC-CMs. (4) A c.815G > A corrected iPSC line was obtained by using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 (Cas9) system.\nCONCLUSION: (1) Cardiomyocytes with spontaneous pulsation were successfully differentiated from LQTS patient-specific iPSC lines. (2) For KCNQ1 splicing mutations, there is a chance that splicing patterns in peripheral leukocytes are similar to that in patient iPSC-CMs. (3) The truncated KCNQ1 proteins induced by such splicing mutation might cause Iks decrease, which in turn produced APD prolongation and triggered activities. (4) Our data showed that CRISPR-Cas9 system could be used to rescue the LQTS-related mutations.","variants":[{"Name":"NM_000218.3(KCNQ1):c.815G>A (p.Gly272Asp)","Chromosome":"11","Start":"2572880","Stop":"2572880","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":67777,"rule_based_match":true,"evidence_text":"c.815G > A","llm_judgment":"PRESENT","evidence":"c.815G > A","abstract_start":877,"abstract_end":887}]}
{"pmid":"33531666","title":"A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features.","abstract":"PURPOSE: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10.\nMETHODS: Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry.\nRESULTS: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein.\nCONCLUSION: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.","variants":[{"Name":"NM_206538.4(EMC10):c.287del (p.Gly96fs)","Chromosome":"19","Start":"50479053","Stop":"50479053","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":976525,"rule_based_match":true,"evidence_text":"EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9)","llm_judgment":"PRESENT","evidence":"EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9)","abstract_start":803,"abstract_end":855}]}
{"pmid":"31760938","title":"Two novel mutations in the ALPL gene of unrelated Chinese children with Hypophosphatasia: case reports and literature review.","abstract":"OBJECTIVE: Hypophosphatasia (HPP) is an inherited disorder of defective skeletal mineralization caused by mutations in the ALPL gene that encodes the Tissue Non-specific Alkaline Phosphatase (TNSALP). It is subdivided into six forms depending on the age of onset: perinatal lethal, prenatal benign, infantile, childhood, adult, and odonto HPP. Among these, infantile HPP is characterized by early onset and high frequency of lethal outcome. Few studies have reported the phenotype and genetic characteristics of HPP in Chinese children.\nCASE PRESENTATION: Three forms of HPP were identified in four unrelated patients from four different Chinese families, including one lethal infantile (patient 1), two childhood (patient 2 and 3) and one odonto HPP (patient 4). Six variants in the ALPL gene were identified, including five missense mutations and one frameshift mutation. Of which, none were reported previously in the Chinese population, and two were novel (c.359G > C: p.G120A and c.1017dupG: p.H340AfsX3). Patient 1 carrying a novel homozygous (c.359G > C) mutation showed respiratory distress and pneumonia at first day of his life. He presented nearly negligible level of serum ALP activity, overall skeletal hypominaralization and died at 3 months old. Patient 2, 3 and 4 were compound heterozygotes with decreased serum ALP activity. Patient 2 and 3 presented premature loss of deciduous teeth, muscle weakness and bone pain, whereas patient 4 had early loss of deciduous teeth only. All four pedigrees exhibited autosomal recessive pattern of inheritance.\nCONCLUSIONS: In this study, six mutations in the ALPL gene were found in four Chinese HPP patients, two of which were novel: c.359G > C in exon 5 and c.1017dupG in exon 10. Our results strongly indicated that the novel mutation c.359G > C might be disease-causing and associated with severe infantile form of HPP.","variants":[{"Name":"NM_000478.6(ALPL):c.1017dup (p.His340fs)","Chromosome":"1","Start":"21575749","Stop":"21575750","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CG","allel_id":540890,"rule_based_match":true,"evidence_text":"c.1017dupG: p.H340AfsX3","llm_judgment":"PRESENT","evidence":"c.1017dupG: p.H340AfsX3","abstract_start":985,"abstract_end":1008}]}
{"pmid":"20132422","title":"Brooke-Spiegler syndrome: report of a case with a novel mutation in the CYLD gene and different types of somatic mutations in benign and malignant tumors.","abstract":"The authors report a case of Brooke-Spiegler syndrome (BSS) with a novel germline CYLD mutation and various somatic mutations identified in the lesional tissues. The patient was a 46-year-old man with multiple lesions on the face. The available histopathological material included 24 trichoepitheliomas, 2 large nodular basal cell carcinomas (BCCs), 2 spiradenomas, 1 spiradenocylindroma and 1 trichoblastoma composed of large and small nodules with prominent clear cell differentiation. Whereas one of the two BCCs manifested a conventional morphology, the second neoplasm additionally showed foci with high grade cytological features characterized by marked pleomorphism and numerous mitotic figures. There were also numerous signet ring cells and cells containing intracytoplasmic eosinophilic inclusions. The germline mutation was a substitution mutation c.1684 + 1G> A. Somatic mutations were investigated in eight tissue blocks from which high quality genomic DNA had been successfully extracted. Somatic mutations included loss of heterozygosity (LOH) in four lesions and a single sequence mutation, namely a single base deletion c. 2322delA causing a frameshift mutation E774DfsX2. LOH occurred in both BCCs, one trichoepithelioma and one spiradenoma. In the remaining three lesions, the somatic event remained undetected.","variants":[{"Name":"NM_001378743.1(CYLD):c.1684+1G>A","Chromosome":"16","Start":"50781412","Stop":"50781412","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3860290,"rule_based_match":true,"evidence_text":"c.1684 + 1G> A","llm_judgment":"PRESENT","evidence":"c.1684 + 1G> A","abstract_start":859,"abstract_end":873}]}
{"pmid":"25381944","title":"Novel mutations in the SLC25A13 gene in a patient with NICCD and severe manifestations.","abstract":"Neonatal intrahepatic cholestatic due to citrin deficiency (NICCD) is an autosomal recessive disorder caused by mutations in the SLC25A13 gene and characterized by neonatal/infantile-onset cholestatic hepatitis syndrome associated with conjugated hyperbilirubinemia and multiple aminoacidemias. We report the case of a Chinese female patient with NICCD disease who manifested prominent clinical features. The patient was diagnosed with NICCD based on cholestasis, aminoacidemia, and hypoproteinemia. She exhibited extreme aminoacidemia, coagulation disorders and untypical myocardial damage, which are rare in other NICCD patients genetically confirmed by us. This myocardial damage observed in obstructive jaundice could be caused by both hyperbilirubinemia and redundant blood bile acids. Screening the SLC25A13 gene revealed that this patient was compound heterozygous harboring two novel mutations, the c. 640C>T (p. Gln214X) in exon 7 and the c. 1709_1710insA (p. Ile570fs573X) in exon 16. Both mutations cause a premature stop codon and thereby truncated peptide or nonsense-mediated with loss of natural function accordingly. In conclusion, extremely manifested clinical features, including significant hyperbilirubinemia, multiple aminoacidemia, hypoproteinemia, coagulation disorders, and myocardial damage related to redundant blood bilirubin and bile acids, were observed in a NICCD patients with two novel mutations.","variants":[{"Name":"NM_014251.3(SLC25A13):c.640C>T (p.Gln214Ter)","Chromosome":"7","Start":"96191223","Stop":"96191223","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1490948,"rule_based_match":true,"evidence_text":"c. 640C>T (p. Gln214X)","llm_judgment":"PRESENT","evidence":"c. 640C>T (p. Gln214X)","abstract_start":907,"abstract_end":929}]}
{"pmid":"24628582","title":"Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene.","abstract":"Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.","variants":[{"Name":"NM_014053.4(FLVCR1):c.1547G>A (p.Arg516Gln)","Chromosome":"1","Start":"212895007","Stop":"212895007","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1054789,"rule_based_match":true,"evidence_text":"c.1547G > A (p.R516Q)","llm_judgment":"PRESENT","evidence":"c.1547G > A (p.R516Q)","abstract_start":851,"abstract_end":872}]}
{"pmid":"26199944","title":"Novel FGFR1 and KISS1R Mutations in Chinese Kallmann Syndrome Males with Cleft Lip/Palate.","abstract":"Kallmann syndrome (KS) is characterized by isolated hypogonadotropic hypogonadism (IHH) with anosmia and is sometimes associated with cleft lip/palate (CLP). In order to describe the clinical features, genetic etiology, and treatment outcome of KS males with CLP, we performed genetic screening for 15 known causal IHH genes (KAL1, FGFR1, NELF, FGF8, CHD7, WDR11, SEMA3A, KISS1R, KISS1, PROKR2, PROK2, TAC3, TACR3, GNRH1, and GNRHR) in four KS with CLP patients and six IHH patients without CLP. Two novel heterozygous missense mutations in FGFR1, (NM_001174066): c.776G>A (p.G259E) and (NM_001174066): c.358C>T (p.R120C), were identified in a 23-year-old KS male with cleft lip and an 18-year-old KS patient with cleft lip and palate, dental agenesis, and high arched palate, respectively. These two mutations were not presented in their healthy parents and 200 normal controls. One novel heterozygous missense mutation in KISS1R, (NM_032551): c.587C>A (p.P196H), was identified in an 18-year-old KS male with cleft lip and dental agenesis who developed sperm after being treated with gonadotropin. This mutation was also presented in his healthy father and grandfather. These results have implications for the diagnosis, genetic counseling, and treatment of KS and CLP males with mutations in FGFR1 gene.","variants":[{"Name":"NM_032551.5(KISS1R):c.587C>A (p.Pro196His)","Chromosome":"19","Start":"919955","Stop":"919955","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1541892,"rule_based_match":true,"evidence_text":"(NM_032551): c.587C>A (p.P196H)","llm_judgment":"PRESENT","evidence":"(NM_032551): c.587C>A (p.P196H)","abstract_start":932,"abstract_end":963}]}
{"pmid":"29925901","title":"Gitelman's Syndrome: characterization of a novel c.1181G>A point mutation and functional classification of the known mutations.","abstract":"We have investigated the mechanisms by which a novel missense point mutation (c.1181G>A) found in two sisters causes Gitelman's syndrome by impairing the sodium chloride co-transporter (NCC, encoded by SLC12A3 gene) function. The cDNA and in vitro transcribed mRNA of either wild-type or mutated SLC12A3 were transfected into HEK293 cells and injected into Xenopus laevis oocytes, respectively. The expression, maturation, trafficking, and function of the mutated and wild-type NCC were assessed by Western blotting, immunohistochemistry and <sup>22</sup>Na<sup>+</sup> uptake studies. By immunoblotting of lysates from HEK293 cells and oocytes expressing wild-type NCC, two NCC-related bands of approximately 130 kDa and 115 kDa, corresponding to fully and core-glycosylated NCC, respectively, were identified. In contrast, the mutant NCC only showed a single band of approximately 115 kDa, indicating impaired maturation of the protein. Moreover, oocytes injected with wild-type NCC showed thiazide-sensitive <sup>22</sup>Na<sup>+</sup> uptake, which was absent in those injected with the mutant NCC. The novel mutation was discussed in the context of the functionally characterized NCC mutations causing Gitelman's syndrome, which fit into five classes. In conclusion, the functional characterization of this novel Gly394Asp NCC and its localization on the NCC structure, alongside that of previously known mutations causing Gitelman's syndrome, may provide novel information on the function of the different domains of the human NCC.","variants":[{"Name":"NM_001126108.2(SLC12A3):c.1181G>A (p.Gly394Asp)","Chromosome":"16","Start":"56879073","Stop":"56879073","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1000942,"rule_based_match":true,"evidence_text":"c.1181G>A","llm_judgment":"PRESENT","evidence":"c.1181G>A","abstract_start":78,"abstract_end":87}]}
{"pmid":"31006510","title":"A CCR4-NOT Transcription Complex, Subunit 1, CNOT1, Variant Associated with Holoprosencephaly.","abstract":"Holoprosencephaly is the incomplete separation of the forebrain during embryogenesis. Both genetic and environmental etiologies have been determined for holoprosencephaly; however, a genetic etiology is not found in most cases. In this report, we present two unrelated individuals with semilobar holoprosencephaly who have the identical de novo missense variant in the gene CCR4-NOT transcription complex, subunit 1 (CNOT1). The variant (c.1603C>T [p.Arg535Cys]) is predicted to be deleterious and is not present in public databases. CNOT1 has not been previously associated with holoprosencephaly or other brain malformations. In situ hybridization analyses of mouse embryos show that Cnot1 is expressed in the prosencephalic neural folds at gestational day 8.25 during the critical period for subsequent forebrain division. Combining human and mouse data, we show that CNOT1 is associated with incomplete forebrain division.","variants":[{"Name":"NM_016284.5(CNOT1):c.1603C>T (p.Arg535Cys)","Chromosome":"16","Start":"58576564","Stop":"58576564","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":611004,"rule_based_match":true,"evidence_text":"c.1603C>T (p.Arg535Cys)","llm_judgment":"PRESENT","evidence":"p.Arg535Cys","abstract_start":449,"abstract_end":460}]}
{"pmid":"23430803","title":"Prevalence and Novel Mutations of Lysosomal Storage Disorders in United Arab Emirates : LSD in UAE.","abstract":"Lysosomal storage disorders (LSD) are rare entities of recessive inheritance. The presence of a \"founder\" mutation in isolated communities with a high degree of consanguinity (e.g., tribes in the Middle East North Africa, MENA, region) is expected to lead to unusually high disease prevalence. The primary aim of this study was to estimate the prevalence of LSD and report their mutation spectrum in UAE. Between 1995 and 2010, 119 patients were diagnosed with LSD (65 Emiratis and 54 non-Emiratis). Genotyping was performed in 59 (50 %) patients (39 Emirati from 17 families and 20 non-Emiratis from 17 families). The prevalence of LSD in Emiratis was 26.9/100,000 live births. Sphingolipidoses were relatively common (9.8/100,000), with GM1-gangliosidosis being the most prevalent (4.7/100,000). Of the Mucopolysaccharidoses VI, IVA and IIIB were the predominant subtypes (5.5/100,000). Compared to Western countries, the prevalence of fucosidosis, Batten disease, and α-mannosidosis was 40-, sevenfold, and fourfold higher in UAE, respectively. The prevalence of Pompe disease (2.7/100,000) was similar to The Netherlands, but only the infantile subtype was found in UAE. Sixteen distinct LSD mutations were identified in 39 Emirati patients. Eight (50 %) mutations were reported only in Emirati, of which three were novel [c.1694G>T in the NAGLU gene, c.1336 C>T in the GLB1 gene, and homozygous deletions in the CLN3 gene]. Twenty-seven (42 %) patients were clustered in five of the 70 Emirati tribes. These findings highlight the need for tribal-based premarital testing and genetic counseling.","variants":[{"Name":"NM_000263.4(NAGLU):c.1694G>T (p.Arg565Leu)","Chromosome":"17","Start":"42543700","Stop":"42543700","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":548160,"rule_based_match":true,"evidence_text":"c.1694G>T","llm_judgment":"PRESENT","evidence":"c.1694G>T","abstract_start":1327,"abstract_end":1336}]}
{"pmid":"36675162","title":"","abstract":"Oligodontia manifests as a congenital reduction in the number of permanent teeth. Despite the major efforts that have been made, the genetic etiology of oligodontia remains largely unknown. Bone morphogenetic protein receptor type 2 (BMPR2) variants have been associated with pulmonary arterial hypertension (PAH). However, the genetic significance of BMPR2 in oligodontia has not been previously reported. In the present study, we identified a novel heterozygous variant (c.814C > T; p.Arg272Cys) of BMPR2 in a family with nonsyndromic oligodontia by performing whole-exome sequencing. In addition, we identified two additional heterozygous variants (c.1042G > A; p.Val348Ile and c.1429A > G; p.Lys477Glu) among a cohort of 130 unrelated individuals with nonsyndromic oligodontia by performing Sanger sequencing. Functional analysis demonstrated that the activities of phospho-SMAD1/5/8 were significantly inhibited in BMPR2-knockout 293T cells transfected with variant-expressing plasmids, and were significantly lower in BMPR2 heterozygosity simulation groups than in the wild-type group, indicating that haploinsufficiency may represent the genetic mechanism. RNAscope in situ hybridization revealed that BMPR2 transcripts were highly expressed in the dental papilla and adjacent inner enamel epithelium in mice tooth germs, suggesting that BMPR2 may play important roles in tooth development. Our findings broaden the genetic spectrum of oligodontia and provide clinical and genetic evidence supporting the importance of BMPR2 in nonsyndromic oligodontia.","variants":[{"Name":"NM_001204.7(BMPR2):c.1042G>A (p.Val348Ile)","Chromosome":"2","Start":"202530868","Stop":"202530868","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":284004,"rule_based_match":true,"evidence_text":"c.1042G > A; p.Val348Ile","llm_judgment":"PRESENT","evidence":"c.1042G > A; p.Val348Ile","abstract_start":652,"abstract_end":676}]}
{"pmid":"31847799","title":"Case reports of a c.475G>T, p.E159* lamin A/C mutation with a family history of conduction disorder, dilated cardiomyopathy and sudden cardiac death.","abstract":"BACKGROUND: Patients with some mutations in the lamin A/C (LMNA) gene are characterized by the presence of dilated cardiomyopathy (DCM), conduction abnormalities, ventricular tachyarrhythmias (VT), and sudden cardiac death (SCD). Various clinical features have been observed among patients who have the same LMNA mutation. Here, we show a family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, and a family history of conduction disorder, DCM, VT, and SCD.\nCASE PRESENTATION: A proband (female) with atrial fibrillation and bradycardia was implanted with a pacemaker in her fifties. Twenty years later, she experienced a loss of consciousness due to polymorphic VT. She had a serious family history; her mother and elder sister died suddenly in their fifties and sixties, respectively, and her nephew and son were diagnosed as having DCM. Genetic screening of the proband, her son, and nephew identified a nonsense mutation (c.475G > T, p.E159*) in the LMNA gene. Although the proband's left ventricular ejection fraction remained relatively preserved, her son and nephew's left ventricular ejection fraction were reduced, resulting in cardiac resynchronization therapy by implantation of a defibrillator.\nCONCLUSIONS: In this family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, DCM, SCD, and malignant VT occurred. Clinical manifestation of various atrial and ventricular arrhythmias and heart failure with reduced ejection fraction occurred in an age-dependent manner in all family members who had the nonsense mutation. It appears highly likely that the E159* LMNA mutation is related to various cardiac problems in the family of the current report.","variants":[{"Name":"NM_170707.4(LMNA):c.475G>T (p.Glu159Ter)","Chromosome":"1","Start":"156130735","Stop":"156130735","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":681874,"rule_based_match":true,"evidence_text":"c.475G > T, p.E159*","llm_judgment":"PRESENT","evidence":"c.475G > T, p.E159*","abstract_start":378,"abstract_end":397}]}
{"pmid":"35596872","title":"Genetic analysis of 18 families with tuberous sclerosis complex.","abstract":"Tuberous sclerosis complex (TSC) is mainly caused by variants in TSC1 and TSC2, which encodes hamartin protein and tuberin protein, respectively. Here, we report clinical and molecular characteristics of 18 families with TSC. High-throughput DNA sequencing was employed to detect variants in all the exons and flanking region of TSC1 and TSC2. TA clone and real-time PCR were performed to verify the pathogenicity of candidate variants. A total of 17 mutations were identified, including 13 mutations in TSC2 and 4 mutations in TSC1. Fifty-six percent (10/18) of the families carried de novo mutations, and 8 of these mutations were not reported previously. Most mutations detected were loss-of-function mutations (15/17). One splice-site mutation (TSC2 c.599 + 5G > A) caused abnormal splicing and was confirmed by in vitro analysis. Facial angiofibromas (94%) and epilepsy (89%) were the most prevalent clinical features in our patients. Treatment with anti-seizure medication (ASM) or in combination with rapamycin results in clinical remission in most patients with TSC-associated seizures (14/15). For genotype-phenotype correlation, patients in our cohort with TSC2 mutations had an earlier onset age and patients with TSC1 showed better response to ASM. Our study has expanded the spectrum of TSC1 and TSC2 causing TSC.","variants":[{"Name":"NM_000548.5(TSC2):c.599+5G>A","Chromosome":"16","Start":"2055524","Stop":"2055524","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":59039,"rule_based_match":true,"evidence_text":"TSC2 c.599 + 5G > A","llm_judgment":"PRESENT","evidence":"TSC2 c.599 + 5G > A","abstract_start":749,"abstract_end":768}]}
{"pmid":"30047296","title":"Characterization of Two Deep Intronic Variants on the β-Globin Gene with Inconsistent Interpretations of Clinical Significance.","abstract":"Sequence variants located in the introns of the β-globin gene may affect the mRNA processing and cause β-thalassemia (β-thal). Sequence variants that change one of the invariant dinucleotides at the exon-intron boundaries may have fatal consequences for normal mRNA splicing. Intronic variants located far from obvious regulatory sequences can be more difficult to evaluate. There is a potential for misinterpretation of such sequence variants. Hence, thorough evaluation of patient data together with critical use of databases and in silico prediction tools are important. Here, we describe two rare sequence variants in the second intron of the β-globin gene, HBB: c.316-70C>G and HBB: c.316-125A>G (NM_000518.4), both previously reported as variants causing β-thal, and later as benign sequence variants. Due to the limited number of published cases and inconsistent interpretations, the significance of these sequence variants has been unclear. We have identified these two sequence variants in multiple individuals, alone and in a variety of combinations with other δ- and β-globin defects, and we find no influence of the sequence variants on the phenotype.","variants":[{"Name":"NM_000518.5(HBB):c.316-70C>G","Chromosome":"11","Start":"5225796","Stop":"5225796","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":44984,"rule_based_match":true,"evidence_text":"HBB: c.316-70C>G","llm_judgment":"PRESENT","evidence":"HBB: c.316-70C>G","abstract_start":662,"abstract_end":678},{"Name":"NM_000518.5(HBB):c.316-125A>G","Chromosome":"11","Start":"5225851","Stop":"5225851","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":432677,"rule_based_match":true,"evidence_text":"HBB: c.316-125A>G","llm_judgment":"PRESENT","evidence":"HBB: c.316-125A>G","abstract_start":683,"abstract_end":700}]}
{"pmid":"34178674","title":"Prevalence and Spectrum of Germline","abstract":"About 10-20% of breast/ovarian (BC/OC) cancer patients undergoing germline <i>BRCA1/2</i> genetic testing have been shown to harbor Variants of Uncertain Significance (VUSs). Since little is known about the prevalence of germline <i>BRCA1/2</i> VUS in Southern Italy, our study aimed at describing the spectrum of these variants detected in BC/OC patients in order to improve the identification of potentially high-risk <i>BRCA</i> variants helpful in patient clinical management. Eight hundred and seventy-four BC or OC patients, enrolled from October 2016 to December 2020 at the \"Sicilian Regional Center for the Prevention, Diagnosis and Treatment of Rare and Heredo-Familial Tumors\" of University Hospital Policlinico \"P. Giaccone\" of Palermo, were genetically tested for germline <i>BRCA1/2</i> variants through Next-Generation Sequencing analysis. The mutational screening showed that 639 (73.1%) out of 874 patients were <i>BRCA</i>-<i>w.t.</i>, whereas 67 (7.7%) were carriers of germline <i>BRCA1/2</i> VUSs, and 168 (19.2%) harbored germline <i>BRCA1/2</i> pathogenic/likely pathogenic variants. Our analysis revealed the presence of 59 different VUSs detected in 67 patients, 46 of which were affected by BC and 21 by OC. Twenty-one (35.6%) out of 59 variants were located on <i>BRCA1</i> gene, whereas 38 (64.4%) on <i>BRCA2</i>. We detected six alterations in <i>BRCA1</i> and two in <i>BRCA2</i> with unclear interpretation of clinical significance. Familial anamnesis of a patient harboring the <i>BRCA1</i>-c.3367G>T suggests for this variant a potential of pathogenicity, therefore it should be carefully investigated. Understanding clinical significance of germline <i>BRCA1/2</i> VUS could improve, in future, the identification of potentially high-risk variants useful for clinical management of BC or OC patients and family members.","variants":[{"Name":"NM_007294.4(BRCA1):c.3367G>T (p.Asp1123Tyr)","Chromosome":"17","Start":"43092164","Stop":"43092164","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":69527,"rule_based_match":true,"evidence_text":"BRCA1-c.3367G>T","llm_judgment":"PRESENT","evidence":"c.3367G>T","abstract_start":1524,"abstract_end":1533}]}
{"pmid":"30109272","title":"Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23).","abstract":"Objective: To address the relationship between mutations in the DNA strand break repair protein tyrosyl DNA phosphodiesterase 2 (TDP2) and spinocerebellar ataxia autosomal recessive 23 (SCAR23) and to characterize the cellular phenotype of primary fibroblasts from this disease.\nMethods: We have used exome sequencing, Sanger sequencing, gene editing and cell biology, biochemistry, and subcellular mitochondrial analyses for this study.\nResults: We have identified a patient in the United States with SCAR23 harboring the same homozygous <i>TDP2</i> mutation as previously reported in 3 Irish siblings (c.425+1G>A). The current and Irish patients share the same disease haplotype, but the current patient lacks a homozygous variant present in the Irish siblings in the closely linked gene <i>ZNF193,</i> eliminating this as a contributor to the disease. The current patient also displays symptoms consistent with mitochondrial dysfunction, although levels of mitochondrial function in patient primary skin fibroblasts are normal. However, we demonstrate an inability in patient primary fibroblasts to rapidly repair topoisomerase-induced DNA double-strand breaks (DSBs) in the nucleus and profound hypersensitivity to this type of DNA damage.\nConclusions: These data confirm the <i>TDP2</i> mutation as causative for SCAR23 and highlight the link between defects in nuclear DNA DSB repair, developmental delay, epilepsy, and ataxia.","variants":[{"Name":"NM_016614.3(TDP2):c.425+1G>A","Chromosome":"6","Start":"24658560","Stop":"24658560","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":228225,"rule_based_match":true,"evidence_text":"c.425+1G>A","llm_judgment":"PRESENT","evidence":"c.425+1G>A","abstract_start":604,"abstract_end":614}]}
{"pmid":"30728880","title":"Radiography of Chitayat syndrome in an infant male.","abstract":"Chitayat syndrome is a rare genetic syndrome characterised by bilateral hyperphalangism, bronchomalacia, hallux valgus, and other facial dysmorphism including large anterior fontanelle, hypertelorism, and anteverted nostrils. Since the initial discovery, only few cases of Chitayat syndrome have been reported in the literature. Previous literatures showed the genetic link between 5 case reports, showing that a unique link of recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene may be the contributory genetic cause of Chitayat syndrome. However, it still remains as an unfamiliar genetic syndrome. In this case report, we aim to discuss a rare case of Chitayat syndrome and demonstrate the radiological findings associated.","variants":[{"Name":"NM_006494.4(ERF):c.266A>G (p.Tyr89Cys)","Chromosome":"19","Start":"42249934","Stop":"42249934","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":262701,"rule_based_match":true,"evidence_text":"c.266A>G p.(Tyr89Cys)","llm_judgment":"PRESENT","evidence":"c.266A>G p.(Tyr89Cys)","abstract_start":438,"abstract_end":459}]}
{"pmid":"30032985","title":"Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities.","abstract":"The natriuretic peptide signaling pathway has been implicated in many cellular processes, including endochondral ossification and bone growth. More precisely, different mutations in the NPR-B receptor and the CNP ligand have been identified in individuals with either short or tall stature. In this study we show that the NPR-C receptor (encoded by NPR3) is also important for the regulation of linear bone growth. We report four individuals, originating from three different families, with a phenotype characterized by tall stature, long digits, and extra epiphyses in the hands and feet. In addition, aortic dilatation was observed in two of these families. In each affected individual, we identified a bi-allelic loss-of-function mutation in NPR3. The missense mutations (c.442T>C [p.Ser148Pro] and c.1088A>T [p.Asp363Val]) resulted in intracellular retention of the NPR-C receptor and absent localization on the plasma membrane, whereas the nonsense mutation (c.1524delC [p.Tyr508<sup>∗</sup>]) resulted in nonsense-mediated mRNA decay. Biochemical analysis of plasma from two affected and unrelated individuals revealed a reduced NTproNP/NP ratio for all ligands and also high cGMP levels. These data strongly suggest a reduced clearance of natriuretic peptides by the defective NPR-C receptor and consequently increased activity of the NPR-A/B receptors. In conclusion, this study demonstrates that loss-of-function mutations in NPR3 result in increased NPR-A/B signaling activity and cause a phenotype marked by enhanced bone growth and cardiovascular abnormalities.","variants":[{"Name":"NM_001204375.2(NPR3):c.442T>C (p.Ser148Pro)","Chromosome":"5","Start":"32712218","Stop":"32712218","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1275467,"rule_based_match":true,"evidence_text":"c.442T>C [p.Ser148Pro]","llm_judgment":"PRESENT","evidence":"c.442T>C [p.Ser148Pro]","abstract_start":775,"abstract_end":797},{"Name":"NM_001204375.2(NPR3):c.1088A>T (p.Asp363Val)","Chromosome":"5","Start":"32774736","Stop":"32774736","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":1275469,"rule_based_match":true,"evidence_text":"c.1088A>T (p.Asp363Val)","llm_judgment":"PRESENT","evidence":"p.Asp363Val","abstract_start":813,"abstract_end":824}]}
{"pmid":"32721895","title":"Generation of patient-specific induced pluripotent stem cells (ZZUSAHi001-A) derived from a familial atrial fibrillation patient carrying KCNA5 c.775G>A mutation.","abstract":"Peripheral blood mononuclear cells (PBMCs) were isolated from a 57-year-old female who was clinically diagnosed as familial atrial fibrillation and were reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, SOX2, KLF4 and cMYC. The generated human induced pluripotent stem cell (hiPSC) line, ZZUSAHi001-A, exhibited a normal karyotype, showed robust expression of pluripotency markers and differentiated towards three germ layers in vivo.","variants":[{"Name":"NM_002234.4(KCNA5):c.775G>A (p.Val259Ile)","Chromosome":"12","Start":"5044922","Stop":"5044922","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3077153,"rule_based_match":true,"evidence_text":"c.775G>A","llm_judgment":"PRESENT","evidence":"c.775G>A","abstract_start":null,"abstract_end":null}]}
{"pmid":"26947586","title":"Mutation in the caveolin-3 gene causes asymmetrical distal myopathy.","abstract":"Mutations in the gene encoding caveolin-3 (CAV3) can cause a broad spectrum of clinical phenotypes, including limb girdle muscular dystrophy, rippling muscle disease, distal myopathy (MD), idiopathic persistent elevation of serum creatine kinase and cardiomyopathy. MD is a relatively rare subtype of caveolinopathy. Here, we report a sporadic case of a middle-aged female Chinese patient with MD in which a CAV3 mutation was identical to that previously reported in cases of rippling muscle disease. T1-weighted enhanced skeletal muscle MRI of the lower limbs showed an abnormal signal in the distal and proximal muscles. A muscle biopsy revealed moderate dystrophic changes, and immunohistochemical staining showed reduced CAV-3 expression in the plasmalemma. Genetic analysis revealed a heterozygous c.136G > A (p.Ala46Thr) CAV3 mutation that appeared to be de novo because it was absent from the patient's parents. This study suggested that the CAV3 c.136G > A (p.Ala46Thr) mutation can cause MD as well as different phenotypes in different individuals, suggesting that additional unknown loci must affect the disease phenotypes.","variants":[{"Name":"NM_033337.3(CAV3):c.136G>A (p.Ala46Thr)","Chromosome":"3","Start":"8745547","Stop":"8745547","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":23320,"rule_based_match":true,"evidence_text":"c.136G > A (p.Ala46Thr)","llm_judgment":"PRESENT","evidence":"c.136G > A (p.Ala46Thr)","abstract_start":803,"abstract_end":826}]}
{"pmid":"26968735","title":"Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140.","abstract":"PURPOSE: Mutations in the ciliary transporter gene IFT140, usually associated with a severe syndromic ciliopathy, may also cause isolated retinal dystrophy. A series of patients with nonsyndromic retinitis pigmentosa (RP) due to IFT140 was investigated in this study.\nMETHODS: Five probands and available affected family members underwent detailed phenotyping including retinal imaging and electrophysiology. Whole exome sequencing was performed on two probands, a targeted sequencing panel of 176 retinal genes on a further two, and whole genome sequencing on the fifth. Missense mutations of IFT140 were further investigated in vitro using transient plasmid transfection of hTERT-RPE1 cells.\nRESULTS: Eight affected patients from five families had preserved visual acuity until at least the second decade; all had normal development without skeletal manifestations or renal failure at age 13 to 67 years (mean, 42 years; median, 44.5 years). Bi-allelic mutations in IFT140 were identified in all families including two novel mutations: c.2815T > C (p.Ser939Pro) and c.1422_23insAA (p.Arg475Asnfs*14). Expression studies demonstrated a significantly reduced number of cells showing localization of mutant IFT140 with the basal body for two nonsyndromic mutations and two syndromic mutations compared with the wild type and a polymorphism.\nCONCLUSIONS: This study highlights the phenotype of nonsyndromic RP due to mutations in IFT140 with milder retinal dystrophy than that associated with the syndromic disease.","variants":[{"Name":"NM_014714.4(IFT140):c.2815T>C (p.Ser939Pro)","Chromosome":"16","Start":"1525280","Stop":"1525280","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":439756,"rule_based_match":true,"evidence_text":"c.2815T > C (p.Ser939Pro)","llm_judgment":"PRESENT","evidence":"c.2815T > C (p.Ser939Pro)","abstract_start":1038,"abstract_end":1063}]}
{"pmid":"23688511","title":"An asparagine at position 417 of tissue-nonspecific alkaline phosphatase is essential for its structure and function as revealed by analysis of the N417S mutation associated with severe hypophosphatasia.","abstract":"Various loss-of function mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene cause a rare genetic disorder called hypophosphatasia (HPP), which is characterized by defective mineralization in the bones and teeth and a deficiency in serum alkaline phosphatase. A point mutation (c.1250A>G), which leads to replacement of an asparagine at position 417 of TNSALP with serine [TNSALP (N417S)], has been reported in a patient diagnosed with perinatal HPP (Sergi C. et al. Am, J. Med. Genet. 103, 235-240, 2001). In order to characterize the molecular properties of TNSALP (N417S), we expressed and analyzed TNSALP (N417S) both in COS-1 cells (transient expression) and CHO K1 Tet-On cells (inducible cell system). In contrast to wild-type TNSALP [TNSALP (W)], cells expressing TNSALP (N417S) lacked its alkaline phosphatase activity. However, this mutant underwent N-linked oligosaccharide processing and appeared on the cell surface similar to TNSALP (W). Importantly, this mutant failed to assemble into a dimer structure, which is needed for the catalytic function of TNSALP, as evidenced by newly developed SDS-PAGE as well as sucrose-density-gradient centrifugation. Substitution of the asparagine at position 417 with structurally related amino acids such as an aspartate and a glutamine also abolished the dimerization of TNSALP without perturbing its cell surface localization. Taken together, the asparagine at position 417 is crucial for the assembly and function of TNSALP, which may explain the severity of the N417S mutation.","variants":[{"Name":"NM_000478.6(ALPL):c.1250A>G (p.Asn417Ser)","Chromosome":"1","Start":"21576582","Stop":"21576582","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":28718,"rule_based_match":true,"evidence_text":"c.1250A>G","llm_judgment":"PRESENT","evidence":"c.1250A>G","abstract_start":297,"abstract_end":306}]}
{"pmid":"25636094","title":"Analysis of PCCA and PCCB gene mutations in patients with propionic acidemia","abstract":"OBJECTIVE: To analyze PCCA and PCCB gene mutations in 10 Chinese patients with propionic acidemia(PA).\nMETHODS: Genomic DNA was extracted from peripheral blood leukocytes. The 39 exons and flanking sequences of the PCCA and PCCB genes were amplified with polymerase chain reaction and subjected to direct DNA sequencing.\nRESULTS: DNA sequencing has revealed that 7 patients have carried a PCCA gene mutation, 2 patients carried PCCB gene mutation and 1 patient carried mutations in both PCCA and PCCB genes. Ten PA mutations were confirmed, including 8 affecting the PCCA gene and 2 affecting the PCCB gene. Three PCCA mutations c.245G>A, IVS15+5del5, c.1288C>T and 2 PCCB mutations c.838insC, c.1087T>C were found for the first time.\nCONCLUSION: Among Chinese patients with propionic acidemia patients, their genetic mutations are mainly found on the PCCA gene.","variants":[{"Name":"NM_000532.5(PCCB):c.1087T>C (p.Ser363Pro)","Chromosome":"3","Start":"136317061","Stop":"136317061","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":931779,"rule_based_match":true,"evidence_text":"c.1087T>C","llm_judgment":"PRESENT","evidence":"c.1087T>C","abstract_start":694,"abstract_end":703}]}
{"pmid":"22246721","title":"Mucopolysaccharidosis type II in females and response to enzyme replacement therapy.","abstract":"Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked lysosomal storage disease caused by a deficiency of iduronate-2-sulfatase (IDS). Two affected girls with moderate and severe forms of MPS II with normal karyotypes and increased urinary dermatan sulphate and heparin sulphate excretion and marked deficiencies of IDS activity are reported. Molecular studies showed that case 1 has a heterozygous mutation c.1568A > G (p.Y523C) associated with almost totally skewed inactivation of the normal maternal X chromosome, and case 2 has a heterozygous deletion that includes exons 1-4 of IDS (minimal deletion range c.1-103_184del). The multi-exon deletion correlated with early onset of the disease and severe phenotype with intellectual disability, whereas the missense mutation was associated with moderate developmental delay. Although genotype-phenotype correlation in MPS II is difficult, gene deletions seem to correlate with more severe clinical manifestation of the disease. Enzyme replacement therapy (ERT) in these two females resulted in disease stabilization in both.","variants":[{"Name":"NM_000202.8(IDS):c.1568A>G (p.Tyr523Cys)","Chromosome":"X","Start":"149482831","Stop":"149482831","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":984648,"rule_based_match":true,"evidence_text":"c.1568A > G (p.Y523C)","llm_judgment":"PRESENT","evidence":"c.1568A > G (p.Y523C)","abstract_start":425,"abstract_end":446}]}
{"pmid":"34439168","title":"Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma.","abstract":"The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype-phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (<i>MAX</i>, <i>SDHB</i>, <i>SDHC</i>, <i>SDHD</i>, <i>TMEM127</i>, <i>VHL</i>, and <i>RET</i>) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. <i>SDHB</i> was the most frequently mutated gene (57, 15.4%), followed by <i>SDHD</i> (27, 7.3%), and <i>VHL</i> (18, 4.9%). The incidence of metastatic PPGL was high in <i>SDHB</i> carriers (21/57, 36.8%). A few unique recurrent variants (<i>SDHB</i> c.137G>A and <i>SDHB</i> c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.","variants":[{"Name":"NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)","Chromosome":"1","Start":"17044824","Stop":"17044824","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":181624,"rule_based_match":true,"evidence_text":"SDHB c.137G>A","llm_judgment":"PRESENT","evidence":"SDHB</i> c.137G>A","abstract_start":1034,"abstract_end":1051}]}
{"pmid":"38488435","title":"Identification of novel pathogenic variants of CUBN in patients with isolated proteinuria.","abstract":"BACKGROUND: Although proteinuria is long recognized as an independent risk factor for progressive chronic kidney diseases, not all forms of proteinuria are detrimental to kidney function, one of which is isolated proteinuria caused by cubilin (CUBN)-specific mutations. CUBN encodes an endocytic receptor, initially found to be responsible for the Imerslund-Gräsbeck syndrome (IGS; OMIM #261100) characterized by a combined phenotype of megaloblastic anemia and proteinuria.\nMETHODS: After analyzing their clinical and pathological characterizations, next-generation sequencing for renal disease genes or whole-exome sequencing (WES) was performed on four patients with non-progressive isolated proteinuria. CUBN biallelic pathogenic variants were identified and further analyzed by cDNA-PCR sequencing, immunohistochemistry, minigene assay, and multiple in silico prediction tools, including 3D protein modeling.\nRESULTS: Here, we present four patients with isolated proteinuria caused by CUBN C-terminal biallelic pathogenic variants, all of which showed no typical IGS symptoms, such as anemia and vitamin B12 deficiency. Their urine protein levels fluctuated between +~++ and estimated glomerular filtration rate (eGFR) were normal or slightly higher. Mild mesangial hypercellularity was found in three children's renal biopsies. A homozygous splice-site variant of CUBN (c.6821+3 (IVS44) A>G) was proven to result in the exon 44 skipping and premature translation termination by cDNA sequencing and immunohistochemistry. Compound heterozygous mutations were identified among the other three children, including another novel splice-site variant (c.10764+1 (IVS66) G>A) causing the retention of first 4 nucleotides in intron 66 by minigene assay, two unreported missense mutations (c.4907G>A (p.R1636Q); c. 9095 A>G (p.Y3032C)), and two reported missense mutations in China (c.8938G>A (p.D2980N); c. 9287T>C (p.L3096P)), locating behind the vitamin B12-binding domain, affecting CUB11, CUB16, CUB22, CUB23, and CUB27 domains, respectively.\nCONCLUSION: These results demonstrate that above CUBN mutations may cause non-progressive and isolated proteinuria, expanding the variant spectrum of CUBN and benefiting our understanding of proteinuria and renal function.","variants":[{"Name":"NM_001081.4(CUBN):c.10764+1G>A","Chromosome":"10","Start":"16828804","Stop":"16828804","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":620820,"rule_based_match":false,"evidence_text":"c.10764+1 (IVS66) G>A","llm_judgment":"PRESENT","evidence":"c.10764+1 (IVS66) G>A","abstract_start":1651,"abstract_end":1672}]}
{"pmid":"21566516","title":"Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression.","abstract":"Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive brain tumors of early childhood poorly responding to therapy. The majority of cases show inactivation of SMARCB1 (INI1, hSNF5, BAF47), a core member of the adenosine triphosphate (ATP)-dependent SWI/SNF chromatin-remodeling complex. We here report the case of a supratentorial AT/RT in a 9-month-old boy, which showed retained SMARCB1 staining on immunohistochemistry and lacked genetic alterations of SMARCB1. Instead, the tumor showed loss of protein expression of another SWI/SNF chromatin-remodeling complex member, the ATPase subunit SMARCA4 (BRG1) due to a homozygous SMARCA4 mutation [c.2032C>T (p.Q678X)]. Our findings highlight the role of SMARCA4 in the pathogenesis of SMARCB1-positive AT/RT and the usefulness of antibodies directed against SMARCA4 in this diagnostic setting.","variants":[{"Name":"NM_003072.5(SMARCA4):c.2032C>T (p.Gln678Ter)","Chromosome":"19","Start":"11007932","Stop":"11007932","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":479639,"rule_based_match":true,"evidence_text":"c.2032C>T (p.Q678X)","llm_judgment":"PRESENT","evidence":"c.2032C>T (p.Q678X)","abstract_start":657,"abstract_end":676}]}
{"pmid":"22414746","title":"Molecular characterization of amelogenesis imperfecta in Chinese patients.","abstract":"BACKGROUND: Mutations in 6 genes have been identified as being part of the etiology of amelogenesis imperfecta (AI) with various phenotypes in an isolated condition. Among them the FAM83H gene is the major contributor to the etiology of AI with unknown function.\nOBJECTIVE: This study aims to determine the phenotypic and molecular characterization of Chinese AI patients and to analyze the structure and function of the FAM83H protein.\nMETHODS: We enrolled 6 hypocalcified AI and 3 hypoplastic AI families from the Chinese population. Mutation analysis was performed by amplifying and sequencing all exons including intron-exon borders for FAM83H and ENAM genes. Structural modeling and function analysis on the FAM83H protein were carried out by bioinformatic processing.\nRESULTS: No obvious anterior open bite was observed in all the investigated individuals. Five mutations (c.906T>G, c.924dupT, c.973C>T, c.1354C>T and c.2029C>T) in the C-terminal of the FAM83H gene were revealed, respectively, in 5 out of 6 hypocalcified AI families, and a splicing mutation c.534 + 1G>A in the ENAM gene was identified in 1 out of 3 hypoplastic AI families. Structural models of the N- and C-terminal regions of FAM83H were generated by homology modeling. The predicted structure of the FAM83H N-terminal shows resemblance to that of glycosyltransferases with GT-A folds, and the predicted structure of the FAM83H C-terminal possesses similarity to type I collagen protein.\nCONCLUSIONS: To our knowledge, this is the first report of AI with specific molecular variations in families of Chinese descent. Our study provides new insights into the structure and function of the FAM83H protein.","variants":[{"Name":"NM_198488.5(FAM83H):c.973C>T (p.Arg325Ter)","Chromosome":"8","Start":"143728488","Stop":"143728488","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15809,"rule_based_match":true,"evidence_text":"c.973C>T","llm_judgment":"PRESENT","evidence":"c.973C>T","abstract_start":900,"abstract_end":908},{"Name":"NM_031889.3(ENAM):c.534+1G>A","Chromosome":"4","Start":"70635895","Stop":"70635895","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19275,"rule_based_match":true,"evidence_text":"c.534 + 1G>A","llm_judgment":"PRESENT","evidence":"c.534 + 1G>A","abstract_start":1066,"abstract_end":1078},{"Name":"NM_198488.5(FAM83H):c.2029C>T (p.Gln677Ter)","Chromosome":"8","Start":"143727432","Stop":"143727432","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":15814,"rule_based_match":true,"evidence_text":"c.2029C>T","llm_judgment":"PRESENT","evidence":"c.2029C>T","abstract_start":924,"abstract_end":933}]}
{"pmid":"26693516","title":"Data in support of a functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II.","abstract":"This data article contains insights into the methodology used for the analysis of three exonic mutations altering the splicing of the IDS gene: c.241C>T, c.257C>T and c.1122C>T. We have performed splicing assays for the wild-type and mutant minigenes corresponding to these substitutions. In addition, bioinformatic predictions of splicing regulatory sequence elements as well as RNA interference and overexpression experiments were conducted. The interpretation of these data and further extensive experiments into the analysis of these three mutations and also into the methodology applied to correct one of them can be found in \"Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II\" Matos et al. (2015) [1].","variants":[{"Name":"NM_000202.8(IDS):c.1122C>T (p.Gly374=)","Chromosome":"X","Start":"149486983","Stop":"149486983","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25530,"rule_based_match":true,"evidence_text":"c.1122C>T","llm_judgment":"PRESENT","evidence":"c.1122C>T","abstract_start":167,"abstract_end":176}]}
{"pmid":"25290043","title":"The role and spectrum of SLC26A4 mutations in Iranian patients with autosomal recessive hereditary deafness.","abstract":"OBJECTIVE: To determine the prevalence and types of SLC26A4 mutations and the relevant phenotypes in a series of Iranian deaf patients.\nDESIGN: A descriptive laboratory study.\nSTUDY SAMPLE: One hundred and twenty-one families including 60 unrelated patients and 61 unrelated multiplex families with autosomal recessive deafness were included. In the 61 multiplex families, linkage was conducted for short tandem repeats (STRs) of the DFNB4. Selected individuals from the linked families and all of the 60 deaf individuals were subjected to sequencing of SLC26A4.\nRESULTS: Seven out of the 61 (11.5%) families were linked to the locus which upon further inquiry led to identification of eight different mutations. Also, five out of the 60 (8.3%) patients were positive for the mutations. The SLC26A4 mutations clarified in 9.1% (12 families) of total investigated alleles included: c.2106delG, c.65-66insT, c.881-882delAC, c.863-864insT, c.1226G> A, c.1238A> G, c.1334T> G, c.1790T> C, c.1489G> A, c.919-2A> G (IVS7-2A> G), c.1412delT, and c.1197delT. Six out of 12 (50%) families with mutations were confirmed to be Pendred syndrome (PS).\nCONCLUSIONS: The results probably suggest a high prevalence and specificity of SLC26A4 mutations among Iranian deaf patients. Molecular study of SLC26A4 may lead to elucidation of the population-specific mutation profile which is of importance in diagnostics of deafness.","variants":[{"Name":"NM_000441.2(SLC26A4):c.1238A>G (p.Gln413Arg)","Chromosome":"7","Start":"107690212","Stop":"107690212","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":357541,"rule_based_match":true,"evidence_text":"c.1238A> G","llm_judgment":"PRESENT","evidence":"c.1238A> G","abstract_start":949,"abstract_end":959},{"Name":"NM_000441.2(SLC26A4):c.1489G>A (p.Gly497Ser)","Chromosome":"7","Start":"107695984","Stop":"107695984","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19855,"rule_based_match":true,"evidence_text":"c.1489G> A","llm_judgment":"PRESENT","evidence":"c.1489G> A","abstract_start":985,"abstract_end":995}]}
{"pmid":"35228300","title":"Homozygous variants in","abstract":"BACKGROUND: As a common type of asthenoteratozoospermia, multiple morphological abnormalities of the sperm flagella (MMAF) can cause male infertility. Previous studies have revealed genetic factors as a major cause of MMAF. The known MMAF-associated genes are involved in the mitochondrial sheath, outer dense fibre or axoneme of the sperm flagella. These findings indicate the genetic heterogeneity of MMAF.\nMETHODS AND RESULTS: Here, we conducted genetic analyses using whole-exome sequencing in a cohort of 150 Han Chinese men with asthenoteratozoospermia. Homozygous deleterious variants of <i>AKAP3</i> (A-kinase anchoring protein 3) were identified in two MMAF-affected men from unrelated families. One <i>AKAP3</i> variant was a frameshift (c.2286_2287del, p.His762Glnfs*22) and the other variant was a missense mutation (c.44G>A, p.Cys15Tyr), which was predicted to be damaging by multiple bioinformatics tools. Further western blotting and immunofluorescence assays revealed the absence of AKAP3 in the spermatozoa from the man harbouring the homozygous frameshift variant, whereas the expression of AKAP3 was markedly reduced in the spermatozoa of the man with the <i>AKAP3</i> missense variant p.Cys15Tyr. Notably, the clinical outcomes after intracytoplasmic sperm injection (ICSI) were divergent between these two cases, suggesting a possibility of AKAP3 dosage-dependent prognosis of ICSI treatment.\nCONCLUSIONS: Our study revealed <i>AKAP3</i> as a novel gene involved in human asthenoteratozoospermia.","variants":[{"Name":"NM_001278309.2(AKAP3):c.2286_2287del (p.His762fs)","Chromosome":"12","Start":"4626615","Stop":"4626616","ReferenceAlleleVCF":"TTG","AlternateAlleleVCF":"T","allel_id":2518072,"rule_based_match":true,"evidence_text":"c.2286_2287del","llm_judgment":"PRESENT","evidence":"c.2286_2287del","abstract_start":748,"abstract_end":762},{"Name":"NM_001278309.2(AKAP3):c.44G>A (p.Cys15Tyr)","Chromosome":"12","Start":"4638153","Stop":"4638153","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2518073,"rule_based_match":true,"evidence_text":"c.44G>A (p.Cys15Tyr)","llm_judgment":"PRESENT","evidence":"p.Cys15Tyr","abstract_start":838,"abstract_end":848}]}
{"pmid":"37006978","title":"Genetic Spectrum in F13A1 Detected by Next-Generation Sequencing Among North Indian Patients with FXIII Deficiency.","abstract":"Purpose: The study aimed to explore the molecular defects underlying FXIII deficiency.\nMaterials and Methods: Sixteen unrelated cases were enrolled based on the indication of the urea clot solubility test and Factor XIII-A antigen levels. Cases were further subjected to targeted next-generation sequencing (custom gene panel: <i>F7</i>, <i>F8</i>, <i>VWF</i>, <i>F9</i>, <i>F13A1, F13B).</i> The pathogenic/likely pathogenic variants were validated by Sanger sequencing in the patients and family members.\nResults: Mean age of referral to our center was 27.2 years (8 week-67 years). Consanguinity was found in only one of the 16 cases and 9 cases presented in infancy. The most common symptoms were skin bleeds (69%) and umbilical cord bleed (50%). The clot solubility test was positive in 12, inconclusive in 1, and normal in 3. Mean FXIII-A levels were 15.7 IU/dL (range 0.6 to 49.5 IU/dL). Pathogenic/likely pathogenic variants in <i>F13A1</i> were found in 11 (69%). Nine cases (82%) were homozygous, and two were compound heterozygous. Total eleven variants were found of which four were missense (c.1226G>A; c.998C>T; c.631G>C; c.2134A>C); three deletion (c.521delG; c.742delA; c.1405_1408delCAAA); two nonsense (c.1112G>A; c.1127G>A) and two splice site (c.1909-1G>C; c.2045G>A). No probably pathogenic variant was found in the <i>F13B</i>.\nConclusion: Inherited FXIII deficiency with bleeding is associated with genetic defects in predominantly the <i>F13A1</i> gene. A variety of variants were seen in this cohort. A nonsense variant c.1127G>A found in three of our cases seems to be recurrent. This data will contribute to designing functional studies and antenatal testing in affected families.\nSupplementary Information: The online version contains supplementary material available at 10.1007/s12288-022-01579-1.","variants":[{"Name":"NM_000129.4(F13A1):c.1226G>A (p.Arg409Gln)","Chromosome":"6","Start":"6195876","Stop":"6195876","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3540170,"rule_based_match":true,"evidence_text":"c.1226G>A","llm_judgment":"PRESENT","evidence":"c.1226G>A","abstract_start":1105,"abstract_end":1114},{"Name":"NM_000129.4(F13A1):c.2045G>A (p.Arg682His)","Chromosome":"6","Start":"6151813","Stop":"6151813","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31563,"rule_based_match":true,"evidence_text":"c.2045G>A","llm_judgment":"PRESENT","evidence":"c.2045G>A","abstract_start":1277,"abstract_end":1286}]}
{"pmid":"25512093","title":"Novel mutations in the DYNC1H1 tail domain refine the genetic and clinical spectrum of dyneinopathies.","abstract":"The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole-exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases.","variants":[{"Name":"NM_001376.5(DYNC1H1):c.1792C>T (p.Arg598Cys)","Chromosome":"14","Start":"101986017","Stop":"101986017","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":143271,"rule_based_match":true,"evidence_text":"c.1792C>T, p.Arg598Cys","llm_judgment":"PRESENT","evidence":"c.1792C>T, p.Arg598Cys","abstract_start":448,"abstract_end":470},{"Name":"NM_001376.5(DYNC1H1):c.791G>T (p.Arg264Leu)","Chromosome":"14","Start":"101980380","Stop":"101980380","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":171752,"rule_based_match":true,"evidence_text":"c.791G>T (p.Arg264Leu)","llm_judgment":"PRESENT","evidence":"p.Arg264Leu","abstract_start":587,"abstract_end":598}]}
{"pmid":"24496061","title":"Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation.","abstract":"Split-hand/foot malformation (SHFM) is a congenital limb deformity due to the absence or dysplasia of central rays of the autopod. Six SHFM loci have already been identified. Here we describe a Chinese family with autosomal-dominant SHFM1 that has previously been mapped to 7q21.2-21.3. The two affected family members, mother and son, showed deep median clefts between toes, ectrodactyly and syndactyly; the mother also showed triphalangeal thumbs. Exome sequencing and variant screening of candidate genes in the six loci known to be responsible for SHFM revealed a novel heterozygous mutation, c.558G>T (p.(Gln186His)), in distal-less homeobox 5 (DLX5). As DLX5 encodes a transcription factor capable of transactivating MYC, we also tested whether the mutation could affect DLX5 transcription acitivity. Results from luciferase reporter assay revealed that a mutation in DLX5 compromised its transcriptional activity. This is the first report of a mutation in DLX5 leading to autosomal-dominant SHFM1.","variants":[{"Name":"NM_005221.6(DLX5):c.558G>T (p.Gln186His)","Chromosome":"7","Start":"97021048","Stop":"97021048","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":97338,"rule_based_match":true,"evidence_text":"c.558G>T (p.(Gln186His))","llm_judgment":"PRESENT","evidence":"c.558G>T (p.(Gln186His))","abstract_start":597,"abstract_end":621}]}
{"pmid":"35456397","title":"Identification of a Cancer-Predisposing Germline","abstract":"Germline disruptive variants in <i>Protection of Telomeres 1</i> (<i>POT1</i>) predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marginal zone lymphoma (SMZL) arising in a patient with a germline <i>POT1</i> variant: a 65-year-old male with an extensive history of cancer, including melanoma and papillary thyroid carcinoma, who presented with circulating atypical lymphocytosis. Bone marrow biopsy revealed 20% involvement by a CD5<sup>-</sup>CD10<sup>-</sup> B-cell lymphoma that was difficult to classify. During the clinical workup of his low-grade lymphoma, targeted next-generation sequencing (NGS) identified <i>POT1</i> p.I49Mfs*7 (NM_015450:c. 147delT) at a variant allele frequency (VAF) of 51%. NGS of skin fibroblasts confirmed the <i>POT1</i> variant was germline. This likely pathogenic <i>POT1</i> loss-of-function variant has only been reported once before as a germline variant in a patient with glioma and likely represents one of the most deleterious germline <i>POT1</i> variants ever linked to familial cancer. The spectrum of cancers associated with germline pathogenic <i>POT1</i> variants (i.e., autosomal dominant <i>POT1</i> tumor predisposition syndrome) should potentially be expanded to include SMZL, a disease often associated with the loss of chromosome 7q: the location of the <i>POT1</i> genetic locus (7q31.33).","variants":[{"Name":"NM_015450.3(POT1):c.147del (p.Ile49fs)","Chromosome":"7","Start":"124871019","Stop":"124871019","ReferenceAlleleVCF":"CA","AlternateAlleleVCF":"C","allel_id":406962,"rule_based_match":true,"evidence_text":"POT1 p.I49Mfs*7 (NM_015450:c. 147delT)","llm_judgment":"PRESENT","evidence":"POT1</i> p.I49Mfs*7 (NM_015450:c. 147delT)","abstract_start":762,"abstract_end":804}]}
{"pmid":"27530795","title":"Clinical feature and ATP8B1 mutation analysis of a patient with progressive familial intrahepatic cholestasis type I","abstract":"Progressive familial intrahepatic cholestasis type I (PFIC1) is an autosomal recessive disorder caused by biallelic mutations of ATP8B1 gene, with progressive cholestasis as the main clinical manifestation. This paper reports the clinical and genetic features of a PFIC1 patient definitely diagnosed by ATP8B1 genetic analysis. The patient, a boy aged 14 months, was referred to the hospital with the complaint of jaundiced skin and sclera over 10 months. The patient had been managed in different hospitals, but the therapeutic effects were unsatisfactory due to undetermined etiology. On physical examination, hepatosplenomegaly was discovered in addition to jaundice of the skin and sclera. The liver was palpable 4 cm below the right subcostal margin and 2 cm below the xiphoid while the spleen 2 cm below the left subcostal margin. The liver function test revealed elevated levels of serum total bile acids, bilirubin, and transaminases; however, the γ-glutamyl transferase level was normal. The diagnosis was genetic cholestasis of undetermined origin. At the age of 1 year and 8 months, a Roux-en-Y cholecystocolonic bypass operation was performed, and thereafter the jaundice disappeared. At 5 years and 1 month, via whole genome sequencing analysis and Sanger sequencing confirmation, the boy was found to be a homozygote of mutation c.2081T>A(p.I694N) of ATP8B1 gene, and thus PFIC1 was definitely diagnosed. The boy was followed up until he was 6 years, and jaundice did not recur, but the long-term outcome remains to be observed.","variants":[{"Name":"NM_001374385.1(ATP8B1):c.2081T>A (p.Ile694Asn)","Chromosome":"18","Start":"57669334","Stop":"57669334","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":2833578,"rule_based_match":true,"evidence_text":"c.2081T>A(p.I694N)","llm_judgment":"PRESENT","evidence":"c.2081T>A(p.I694N)","abstract_start":1343,"abstract_end":1361}]}
{"pmid":"33767456","title":"Autosomal recessive cataract (CTRCT18) in the Yakut population isolate of Eastern Siberia: a novel founder variant in the FYCO1 gene.","abstract":"Congenital autosomal recessive cataract with unknown genetic etiology is one of the most common Mendelian diseases among the Turkic-speaking Yakut population (Eastern Siberia, Russia). To identify the genetic cause of congenital cataract spread in this population, we performed whole-exome sequencing (Illumina NextSeq 500) in one Yakut family with three affected siblings whose parents had preserved vision. We have revealed the novel homozygous c.1621C>T transition leading to premature stop codon p.(Gln541*) in exon 8 of the FYCO1 gene (NM_024513.4). Subsequent screening of c.1621C>T p.(Gln541*) revealed this variant in a homozygous state in 25 out of 29 Yakut families with congenital cataract (86%). Among 424 healthy individuals from seven populations of Eastern Siberia (Russians, Yakuts, Evenks, Evens, Dolgans, Chukchi, and Yukaghirs), the highest carrier frequency of c.1621C>T p.(Gln541*) was found in the Yakut population (7.9%). DNA samples of 25 homozygous for c.1621C>T p.(Gln541*) patients with congenital cataract and 114 unaffected unrelated individuals without this variant were used for a haplotype analysis based on the genotyping of six STR markers (D3S3512, D3S3685, D3S3582, D3S3561, D3S1289, and D3S3698). The structure of the identified haplotypes indicates a common origin for all of the studied mutant chromosomes bearing c.1621C>T p.(Gln541*). The age of the с.1621C>T p.(Gln541*) founder haplotype was estimated to be approximately 260 ± 65 years (10 generations). These findings characterize Eastern Siberia as the region of the world with the most extensive accumulation of the unique variant c.1621C>T p.(Gln541*) in the FYCO1 gene as a result of the founder effect.","variants":[{"Name":"NM_024513.4(FYCO1):c.1621C>T (p.Gln541Ter)","Chromosome":"3","Start":"45967713","Stop":"45967713","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":681803,"rule_based_match":true,"evidence_text":"c.1621C>T p.(Gln541*)","llm_judgment":"PRESENT","evidence":"c.1621C>T p.(Gln541*)","abstract_start":579,"abstract_end":600}]}
{"pmid":"34430442","title":"Progressive pseudorheumatoid dysplasia: a case series report.","abstract":"rogressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal-recessive, noninflammatory arthropathy. Several cases have been reported worldwide; however, diagnosis remains challenging. Three unrelated children with PPRD were retrospectively studied. All three patients in this study were initially misdiagnosed. The misdiagnoses included juvenile rheumatoid arthritis, myodystrophy and idiopathic short stature. The time from the onset of symptoms to a definitive diagnosis was 3 to 8 years. Clinical signs and radiological phenotypes were analyzed carefully, and they were all consistent with the characteristics of PPRD and noninflammatory polyarticular enlargement. The small joints of both the hands and lower limbs are the most affected. The imaging findings of the patients were flat vertebrae with beak- or bullet-like changes in front of the cone and peripheral metaphysis widening. DNA samples obtained from the family were sequenced to identify the causal gene using whole-exome sequencing (WES). Four Wnt1-inducible signaling pathway protein 3 (<i>WISP3</i>) mutations were verified. c.271delC was not reported previously. The other three mutations, namely, c.136C>T (p. Gln46*), c.667T>G (p. Cys223Gly) and c.589+2T>C, were previously identified. All three patients had a long journey to diagnosis. Early genetic diagnosis can help prevent unnecessary treatments and procedures in patients. Growth hormone is not a good choice for treatment.","variants":[{"Name":"NM_198239.2(CCN6):c.589+2T>C","Chromosome":"6","Start":"112064999","Stop":"112064999","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3856515,"rule_based_match":true,"evidence_text":"c.589+2T>C","llm_judgment":"PRESENT","evidence":"c.589+2T>C","abstract_start":1223,"abstract_end":1233}]}
{"pmid":"29182666","title":"GnRH receptor gene mutations in adolescents and young adults presenting with signs of partial gonadotropin deficiency.","abstract":"Biallelic, partial loss-of-function mutations in GNRHR cause a wide spectrum of reproductive phenotypes from constitutional delay of growth and puberty to complete congenital hypogonadotropic hypogonadism. We studied the frequency of GNRHR, FGFR1, TAC3, and TACR3 mutations in nine adolescent and young adult females with clinical cues consistent with partial gonadotropin deficiency (stalled puberty, unexplained secondary amenorrhea), and describe phenotypic features and molecular genetic findings of monozygotic twin brothers with stalled puberty. Two girls out of nine (22%, 95%CI 6-55%) carried biallelic mutations in GNRHR. The girl with compound heterozygous c.317A>G p.(Gln106Arg) and c.924_926delCTT p.(Phe309del) GNRHR mutations displayed incomplete puberty and clinical signs of hypoestrogenism. The patient carrying a homozygous c.785G>A p.(Arg262Gln) mutation presented with signs of hypoestrogenism and unexplained secondary amenorrhea. None of the patients exhibited mutations in FGFR1, TAC3, or TACR3. The twin brothers, compound heterozygous for GNRHR mutations c.317A>G p.(Gln106Arg) and c.785G>A p.(Arg262Gln), presented with stalled puberty and were discordant for weight, and the heavier of them had lower testosterone levels. These results suggest that genetic testing of the GNRHR gene should be offered to adolescent females with low-normal gonadotropins and unexplained stalled puberty or menstrual dysfunction. In male patients with partial gonadotropin deficiency, excess adipose tissue may suppress hypothalamic-pituitary-gonadal axis.","variants":[{"Name":"NM_000406.3(GNRHR):c.317A>G (p.Gln106Arg)","Chromosome":"4","Start":"67754019","Stop":"67754019","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":31062,"rule_based_match":true,"evidence_text":"c.317A>G p.(Gln106Arg)","llm_judgment":"PRESENT","evidence":"c.317A>G p.(Gln106Arg)","abstract_start":667,"abstract_end":689},{"Name":"NM_000406.3(GNRHR):c.785G>A (p.Arg262Gln)","Chromosome":"4","Start":"67740682","Stop":"67740682","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":31063,"rule_based_match":true,"evidence_text":"c.785G>A p.(Arg262Gln)","llm_judgment":"PRESENT","evidence":"c.785G>A p.(Arg262Gln)","abstract_start":842,"abstract_end":864}]}
{"pmid":"20209645","title":"Osteopathia striata with cranial sclerosis owing to WTX gene defect.","abstract":"Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition marked by linear striations mainly affecting the metaphyseal region of the long bones and pelvis in combination with cranial sclerosis. Recently, the disease-causing gene was identified as the WTX gene (FAM123B), an inhibitor of WNT signaling. A correlation was suggested between the position of the mutation and male lethality. We performed genotype and phenotype studies using 18 patients from eight families with possible WTX gene defects and expanded the clinical spectrum of the affected females. All investigated families diagnosed with OSCS had WTX gene defects. One family had a WTX gene deletion; three of four point mutations were novel. The earlier reported WTX c.1072C>T was detected in four sporadic patients and appears to be a hotspot for mutations. Based on the nature of the mutation present in a surviving male patient, our data do not support the hypothesis raised by Jenkins et al. (2009) regarding a genotype-phenotype correlation for male lethality. The finding of a gene involved in WNT signaling as the cause of this sclerosing bone phenotype is not unexpected, but further functional studies are needed to explain the specific features. The WTX gene is mutated in different types of cancer, and it remains to be explained why osteopathia striata patients appear not to have an increased risk of cancer.","variants":[{"Name":"NM_152424.4(AMER1):c.1072C>T (p.Arg358Ter)","Chromosome":"X","Start":"64192215","Stop":"64192215","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":25747,"rule_based_match":true,"evidence_text":"WTX c.1072C>T","llm_judgment":"PRESENT","evidence":"WTX c.1072C>T","abstract_start":753,"abstract_end":766}]}
{"pmid":"18583168","title":"High prevalence of SURF1 c.845_846delCT mutation in Polish Leigh patients.","abstract":"Leigh syndrome is a neuropathological disorder with typical morphological changes in brain, appearing regardless of diverse molecular background. One of the most common enzymatic defects in Leigh patients is cytochrome c oxidase deficiency associated with recessive mutations in the SURF1 gene. To assess the SURF1 mutation profile among Polish patients we studied 41 affected children from 34 unrelated families by PCR-SSCP and sequencing. Four novel mutations, c.39delG, c.752-1G>C, c.800_801insT, c.821A>G, and five described pathogenic changes, c.311_312insAT312_321del10, c.688C>T, c.704T>C, c.756_757delCA, c.845_846delCT, were identified in 85.3% of analysed probands. One mutation, c.845_846delCT, was identified in 77.6% of SURF1 alleles. Up to now, it has been reported only in 9% of alleles in other parts of the world. The deletion was used as LS(SURF1-) marker in population studies. Eight heterozygous carriers of the mutation were found in a cohort of 2890 samples. The estimated c.845_846delCT allele frequency is 1:357 (0.28+/-0.2%), and the lowest predicted LS(SURF1-) frequency in Poland 1:126,736.births. Relatively high frequency of LS(SURF1-) in Poland with remarkable c.845_846delCT mutation dominance allows one to start the differential diagnosis of LS in each patient of Polish (and probably Slavonic) origin from the direct search for c.845_846delCT SURF1 mutation.","variants":[{"Name":"NM_003172.4(SURF1):c.845_846del (p.Ser282fs)","Chromosome":"9","Start":"133351970","Stop":"133351971","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":27809,"rule_based_match":true,"evidence_text":"c.845_846delCT","llm_judgment":"PRESENT","evidence":"c.845_846delCT","abstract_start":613,"abstract_end":627}]}
{"pmid":"26223887","title":"Medium-chain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening.","abstract":"BACKGROUND: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial fatty acid β-oxidation and a target disease of newborn screening in many countries.\nCASE PRESENTATION: We report on two siblings with mild MCAD deficiency associated with a novel splice site mutation in the ACADM gene. The younger sibling was detected by newborn screening, while the older sister was missed, but diagnosed later on by genetic family testing. Both children were found to be compound heterozygous for the common c.985A > G (p.K329E) mutation and a novel splice site mutation, c.600-18G > A, in the ACADM gene. To determine the biological consequence of the c.600-18G > A mutation putative missplicing was investigated at RNA level in granulocytes and monocytes of one of the patients. The splice site mutation was shown to lead to partial missplicing of the ACADM pre-mRNA. Of three detected transcripts two result in truncated, non-functional MCAD proteins as reflected by the reduced octanoyl-CoA oxidation rate in both patients. In one patient a decrease of the octanoyl-CoA oxidation rate was found during a febrile infection indicating that missplicing may be temperature-sensitive.\nCONCLUSIONS: Our data indicate that the c.600-18G > A variant activates a cryptic splice site, which competes with the natural splice site. Due to only partial missplicing sufficient functional MCAD protein remains to result in mild MCADD that may be missed by newborn screening.","variants":[{"Name":"NM_000016.6(ACADM):c.985A>G (p.Lys329Glu)","Chromosome":"1","Start":"75761161","Stop":"75761161","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":18625,"rule_based_match":true,"evidence_text":"c.985A > G (p.K329E)","llm_judgment":"PRESENT","evidence":"c.985A > G (p.K329E)","abstract_start":538,"abstract_end":558},{"Name":"NM_000016.6(ACADM):c.600-18G>A","Chromosome":"1","Start":"75745788","Stop":"75745788","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":227889,"rule_based_match":true,"evidence_text":"c.600-18G>A","llm_judgment":"PRESENT","evidence":"c.600-18G > A","abstract_start":602,"abstract_end":615}]}
{"pmid":"22025892","title":"Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma - a distinct phenotype caused by recessive LTBP2 mutations.","abstract":"PURPOSE: To clinically and genetically characterize a distinct phenotype of congenital megalocornea (horizontal corneal diameter ≥13 mm) with secondary glaucoma from spherophakia and/or ectopia lentis during childhood in affected Saudi families.\nMETHODS: Clinical exam, homozygosity scan, and candidate gene analysis.\nRESULTS: From 2005 to 2010, eight affected individuals from three consanguineous families were identified. In addition to congenital megalocornea, affected children presented with secondary glaucoma from spherophakia and/or ectopia lentis. One member from each family developed spontaneous complete crystalline lens dislocation into the anterior chamber with associated acute glaucoma during early childhood. Older individuals had phenotypes that would have suggested prior uncontrolled primary congenital/infantile glaucoma had past ophthalmic and/or family histories not been available. Homozygosity mapping performed for the first two families suggested the candidate gene latent transforming growth factor-beta-binding protein 2 (LTBP2), which when sequenced revealed a novel homozgyous mutation that segregated with the phenotype in each family (p.S338PfsX4 [c.1012delT], p.Q1619X[(c.4855C>T]). LTBP2 sequencing in the third family revealed a third novel homozygous mutation (p.C1438Y [c.4313G>A]).\nCONCLUSIONS: Congenital megalocornea with childhood secondary glaucoma from spherophakia and/or ectopia lentis is a distinct condition caused by recessive LTBP2 mutations that needs to be distinguished from buphthalmos secondary to primary congenital/infantile glaucoma because typical initial surgical treatment is lens removal in the former and angle surgery in the latter. Complete dislocation of the crystalline lens into the anterior chamber during early childhood can occur in young children with this unique phenotype.","variants":[{"Name":"NM_000428.3(LTBP2):c.1012del (p.Ser338fs)","Chromosome":"14","Start":"74555512","Stop":"74555512","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":40307,"rule_based_match":true,"evidence_text":"c.1012delT","llm_judgment":"PRESENT","evidence":"c.1012delT","abstract_start":1182,"abstract_end":1192},{"Name":"NM_000428.3(LTBP2):c.4855C>T (p.Gln1619Ter)","Chromosome":"14","Start":"74503252","Stop":"74503252","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":40308,"rule_based_match":true,"evidence_text":"c.4855C>T","llm_judgment":"PRESENT","evidence":"c.4855C>T","abstract_start":1205,"abstract_end":1214},{"Name":"NM_000428.3(LTBP2):c.4313G>A (p.Cys1438Tyr)","Chromosome":"14","Start":"74505039","Stop":"74505039","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":40309,"rule_based_match":true,"evidence_text":"c.4313G>A","llm_judgment":"PRESENT","evidence":"c.4313G>A","abstract_start":1309,"abstract_end":1318}]}
{"pmid":"23238279","title":"A nonsense mutation in the gene ROR2 underlying autosomal dominant brachydactyly type B.","abstract":"Brachydactyly type B1 (BDB1), an autosomal dominant condition characterized by terminal deficiency of the fingers and toes, results from mutations in the gene ROR2 encoding a receptor tyrosine kinase. In addition to BDB1, mutations in the gene ROR2 also cause a more severe form of skeletal dysplasia, autosomal recessive Robinow syndrome. The present study reports on a large Punjabi-speaking Pakistani family segregating autosomal dominant BDB1. In total, 34 individuals in this family showed features of BDB1. Sequence analysis of the gene ROR2 identified a previously reported nonsense mutation (c.2278C>T, p.Q760X) in all affected individuals of the family.","variants":[{"Name":"NM_004560.4(ROR2):c.2278C>T (p.Gln760Ter)","Chromosome":"9","Start":"91724216","Stop":"91724216","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1877792,"rule_based_match":true,"evidence_text":"c.2278C>T, p.Q760X","llm_judgment":"PRESENT","evidence":"c.2278C>T, p.Q760X","abstract_start":600,"abstract_end":618}]}
{"pmid":"18583467","title":"Dominant-negative GCMB mutations cause an autosomal dominant form of hypoparathyroidism.","abstract":"CONTEXT: Hypoparathyroidism (HP) is characterized by low PTH levels, hypocalcemia, and hyperphosphatemia. Heterozygous mutations in pre-pro-PTH or the calcium-sensing receptor (CaSR) cause some forms of autosomal dominant HP (AD-HP). Furthermore, homozygous mutations in glial cells missing B (GCMB) have been implicated in autosomal recessive HP (AR-HP). In most other HP patients, however, the molecular defect remains undefined.\nOBJECTIVE: Our objectives were to determine the genetic defect in the affected members of two unrelated families with AD-HP and define the underlying disease mechanism.\nSUBJECTS: Several family members affected by AD-HP were investigated. The proband in family A had low calcium detected on routine blood testing, whereas the proband in family B had symptomatic hypocalcemia.\nMETHODS: Mutational analysis of the genes encoding pre-pro-PTH, CaSR, and GCMB was performed using PCR-amplified genomic DNA of the probands and other available members of each family. The identified GCMB mutants were characterized by Western blot analysis and luciferase reporter assay using DF-1 fibroblasts.\nRESULTS: Two novel heterozygous mutations located in the last GCMB exon (c.1389delT and c.1399delC in families A and B, respectively) were identified that both lead to frame-shifts and replacement of the putative second transactivation domain within carboxyl-terminal region by unrelated amino acid sequence. The mutant GCMB proteins were well expressed, and both showed dose-dependent inhibition of the transactivation capacity of wild-type protein in luciferase reporter assays.\nCONCLUSIONS: The dominant-negative effect observed in vitro for both GCMB mutations provides a plausible explanation for the impaired PTH secretion observed in the two unrelated families with AD-HP.","variants":[{"Name":"NM_004752.4(GCM2):c.1389del (p.His465fs)","Chromosome":"6","Start":"10874127","Stop":"10874127","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1053712,"rule_based_match":true,"evidence_text":"c.1389delT","llm_judgment":"PRESENT","evidence":"c.1389delT","abstract_start":1192,"abstract_end":1202}]}
{"pmid":"34904718","title":"Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis.","abstract":"Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3<sup>C57Y</sup> expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3<sup>C57Y</sup> in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3<sup>C57Y</sup> expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3<sup>C57Y</sup> has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.","variants":[{"Name":"NM_005313.5(PDIA3):c.170G>A (p.Cys57Tyr)","Chromosome":"15","Start":"43753826","Stop":"43753826","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":485864,"rule_based_match":true,"evidence_text":"c.170G>A (p.Cys57Tyr or C57Y)","llm_judgment":"PRESENT","evidence":"c.170G>A (p.Cys57Tyr or C57Y)","abstract_start":161,"abstract_end":190}]}
{"pmid":"37895316","title":"Determination of Carrier Frequency of Actionable Pathogenic Variants in Autosomal Recessive Genetic Diseases in the Turkish Cypriot Population.","abstract":"Whole-exome DNA sequencing is a rich source of clinically useful information for specialists, patients, and their families, as well as elucidating the genetic basis of monogenic and complex diseases in clinical diagnosis. However, interpreting and reporting variants encompassing exome and genome sequence analysis outcome data are one of the greatest challenges of the genomic era. In this study, we aimed to investigate the frequency and allele frequency spectrum of single nucleotide variants accepted as recessive disease carrier status in Turkish Cypriot exomes. The same sequencing platform and data processing line were used for the analysis of data from 100 Turkish Cypriot whole-exome sequence analysis. Identified variants were classified according to ACMG guidelines, and pathogenic variants were confirmed in other databases such as ClinVar, HGMD, Varsome, etc. Pathogenic variants were detected in 68 genes out of 100 whole-exome sequence data. The carriage rate was the highest in the <i>CYP21A2</i> gene, causing 21-hydroxylase deficiency (14.70%), 11.76% in the <i>HBB</i> gene causing β-thalassemia, 10.29% in the <i>BTD</i> gene causing biotinidase deficiency, 8.82% in the <i>CFTR</i> gene causing cystic fibrosis, 8.82% in the <i>RBM8A</i> gene causing thrombocytopenia-absent radius syndrome, which is an ultra-rare disease, and 5.88% in the <i>GAA</i> gene causing glycogen storage disease II. The carriage of pathogenic variants in other genes causing the disease (<i>GJB2</i>, <i>PAH</i>, <i>GALC</i>, <i>CYP11B2</i>, <i>COL4A3</i>, <i>HBA1</i>, etc.) was determined as less than 5.00%. Also, the identified variations in the mentioned gene within the examined population were reported. The most prevalent mutation in North Cyprus was a missense variant (c.1360 C>T, p.Pro454Ser) detected in the <i>CYP21A2</i> gene (rs6445), and the most frequently seen variant in the <i>HBB</i> gene was c.93-21G>A (rs35004220). We investigated reported pathogenic variants by estimating the lower and upper limits of carrier and population frequencies for autosomal recessive diseases, for which exome sequencing may reveal additional medically relevant information. Determining the lower and upper limits of these frequencies will shed light on preventive medicine practices and governmental actions.","variants":[{"Name":"NM_000518.5(HBB):c.93-21G>A","Chromosome":"11","Start":"5226820","Stop":"5226820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30493,"rule_based_match":true,"evidence_text":"c.93-21G>A (rs35004220)","llm_judgment":"PRESENT","evidence":"c.93-21G>A (rs35004220)","abstract_start":1914,"abstract_end":1937}]}
{"pmid":"24260153","title":"SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15).","abstract":"Autosomal dominant non-syndromic hearing loss (AD-NSHL) is one of the most common genetic diseases in human and is well-known for the considerable genetic heterogeneity. In this study, we utilized whole exome sequencing (WES) and linkage analysis for direct genetic diagnosis in AD-NSHL. The Korean family had typical AD-NSHL running over 6 generations. Linkage analysis was performed by using genome-wide single nucleotide polymorphism (SNP) chip and pinpointed a genomic region on 5q31 with a significant linkage signal. Sequential filtering of variants obtained from WES, application of the linkage region, bioinformatic analyses, and Sanger sequencing validation identified a novel missense mutation Arg326Lys (c.977G>A) in the POU homeodomain of the POU4F3 gene as the candidate disease-causing mutation in the family. POU4F3 is a known disease gene causing AD-HSLH (DFNA15) described in 5 unrelated families until now each with a unique mutation. Arg326Lys was the first missense mutation affecting the 3(rd) alpha helix of the POU homeodomain harboring a bipartite nuclear localization signal sequence. The phenotype findings in our family further supported previously noted intrafamilial and interfamilial variability of DFNA15. This study demonstrated that WES in combination with linkage analysis utilizing bi-allelic SNP markers successfully identified the disease locus and causative mutation in AD-NSHL.","variants":[{"Name":"NM_002700.3(POU4F3):c.977G>A (p.Arg326Lys)","Chromosome":"5","Start":"146340404","Stop":"146340404","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":102599,"rule_based_match":true,"evidence_text":"c.977G>A (p.Arg326Lys)","llm_judgment":"PRESENT","evidence":"c.977G>A","abstract_start":715,"abstract_end":723}]}
{"pmid":"27942778","title":"Novel mutations in the SEC24D gene in Chinese families with autosomal recessive osteogenesis imperfecta.","abstract":"We sought to characterize the phenotypes and identify the SEC24D gene mutations associated with Chinese families of osteogenesis imperfecta (OI). Using whole-exome sequencing, we discovered two novel compound SEC24D mutations of OI patients. Our study extended both the phenotypic and the genotype of the OI patients with SEC24D mutations.\nINTRODUCTION: To date, only three compound heterozygous mutations in the SEC24D gene have been found to cause recessively inherited forms of OI. We sought to characterize the phenotypes and to identify the SEC24D gene mutations associated with Chinese families with OI.\nMETHODS: Using whole-exome sequencing in two probands, we identified two novel compound heterozygous mutations in SEC24D. In family 1, the proband was a 23-year-old male; he had recurrent fractures and dentinogenesis imperfecta. His anterior fontanel was not closed, and he showed facial dysmorphism. A computed tomography three-dimensional imaging of the cranium showed skull deformities associated with a broad ossification defect in the frontoapical area, a widened sagittal suture, and Wormian bones. In family 2, the proband was a 7-year-old boy, who also had recurrent fractures and dentinogenesis imperfecta. His anterior fontanel was not closed, and he did not have obvious facial dysmorphism.\nRESULTS: We identified one novel compound heterozygous missense substitution in the proband in family 1, including c.2723G>A (p. Cys908Tyr) and c.2842T>C (p. Ser948Pro). In the proband in family 2, we identified another novel compound heterozygous missense substitution, including c.938G>A (p. Arg313His) and c.875C>T (p. Pro292Leu).\nCONCLUSIONS: We discovered two novel compound SEC24D mutations of autosomal recessive OI patients. Our study extended both the phenotypic and the genotypic spectrum of the autosomal recessive OI patients with SEC24D mutations.","variants":[{"Name":"NM_014822.4(SEC24D):c.2723G>A (p.Cys908Tyr)","Chromosome":"4","Start":"118731461","Stop":"118731461","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":626002,"rule_based_match":true,"evidence_text":"c.2723G>A (p. Cys908Tyr)","llm_judgment":"PRESENT","evidence":"c.2723G>A (p. Cys908Tyr)","abstract_start":1427,"abstract_end":1451},{"Name":"NM_014822.4(SEC24D):c.2842T>C (p.Ser948Pro)","Chromosome":"4","Start":"118731342","Stop":"118731342","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":626003,"rule_based_match":true,"evidence_text":"c.2842T>C (p. Ser948Pro)","llm_judgment":"PRESENT","evidence":"c.2842T>C (p. Ser948Pro)","abstract_start":1456,"abstract_end":1480},{"Name":"NM_014822.4(SEC24D):c.938G>A (p.Arg313His)","Chromosome":"4","Start":"118797786","Stop":"118797786","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":626004,"rule_based_match":true,"evidence_text":"c.938G>A (p. Arg313His)","llm_judgment":"PRESENT","evidence":"c.938G>A (p. Arg313His)","abstract_start":1593,"abstract_end":1616},{"Name":"NM_014822.4(SEC24D):c.875C>T (p.Pro292Leu)","Chromosome":"4","Start":"118805881","Stop":"118805881","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":626005,"rule_based_match":true,"evidence_text":"c.875C>T (p. Pro292Leu)","llm_judgment":"PRESENT","evidence":"c.875C>T (p. Pro292Leu)","abstract_start":1621,"abstract_end":1644}]}
{"pmid":"22185990","title":"Novel mutations in the gene encoding acid α-1,4-glucosidase in a patient with late-onset glycogen storage disease type II (Pompe disease) with impaired intelligence.","abstract":"A 17-year-old Japanese man was referred to our hospital because of highly elevated serum levels of creatine kinase (CK) and transaminases. On admission, the proximal muscles of the lower extremities were found to be predominantly affected, and a score of 3/5 was obtained on Medical Research Council (MRC) scale. Muscular atrophy was evident and Gowers' sign was positive. His functional vital capacity (FVC) was markedly reduced. The results of the third edition of the Wechsler Adult Intelligence Scale (WAIS-III) indicated impairment of the patient's intelligence. Muscle biopsy showed scattered intracytoplasmic vacuoles with basophilic amorphous materials inside which were strongly stained by both periodic acid Schiff (PAS) and acid phosphatase. Biochemical analysis of the muscle tissue confirmed the diagnosis of GSDII because the glucosidase activity was 1.0 nmol/4 MU/mg/30 min (control range, 7.3 ± 2.2). Genetic analysis revealed a novel compound heterozygous missense mutation in GAA--c.1814 G >A (p.Gly605Asp) and c.1846 G >A (p.Asp616Asn) both in exon 13.","variants":[{"Name":"NM_000152.5(GAA):c.1846G>A (p.Asp616Asn)","Chromosome":"17","Start":"80112669","Stop":"80112669","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1447960,"rule_based_match":true,"evidence_text":"c.1846 G >A (p.Asp616Asn)","llm_judgment":"PRESENT","evidence":"c.1846 G >A (p.Asp616Asn)","abstract_start":1029,"abstract_end":1054}]}
{"pmid":"32446246","title":"FRMD7 Mutations Disrupt the Interaction with GABRA2 and May Result in Infantile Nystagmus Syndrome.","abstract":"Purpose: To identify the pathogenic gene of infantile nystagmus syndrome (INS) in three Chinese families and explore the potential pathogenic mechanism of FERM domain-containing 7 (FRMD7) mutations.\nMethods: Genetic testing was performed via Sanger sequencing. Western blotting was used to analyze protein expression of FRMD7. Glutathione S-transferase pull-down and immunoprecipitation were conducted to investigate the proteins interacting with FRMD7. Rescue assays were performed in Caenorhabditis elegans to explore the potential role of FRMD7 in vivo.\nResults: We recruited three Chinese families with X-linked INS and identified a duplication and two missense mutations in FRMD7: c.998dupA/p.His333Glnfs*2, c.580G>A/p.Ala194Thr, and c.973A>G/p.Arg325Gly (one in each family). Expression levels of three mutants were similar to that of wild-type FRMD7 in vitro. Interestingly, the mutant p.His333Glnfs*2 exhibited a predominantly nuclear location, whereas wild-type FRMD7 localized to the cytoplasm. In addition, we found FRMD7 to directly interact with the loop between transmembrane domains 3 and 4 of GABRA2, a type A gamma-aminobutyric acid (GABA) receptor (GABAARs) subunit critical for receptor transport and localization, whereas the mutants p.Ala194Thr and p.Arg325Gly exhibited decreased binding to GABRA2. In frm-3 (a nematode homologue of FRMD7) null C. elegans, we found that FRMD7 mutants exhibited a poor rescue effect on the defects of locomotion and fluorescence recovery after photobleaching of GABAARs.\nConclusions: Our findings identified three FRMD7 mutants in three Chinese families with X-linked INS and confirmed GABRA2 as a novel binding partner of FRMD7. These findings suggest that FRMD7 plays an important role by targeting GABAARs.","variants":[{"Name":"NM_194277.3(FRMD7):c.580G>A (p.Ala194Thr)","Chromosome":"X","Start":"132085646","Stop":"132085646","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1014743,"rule_based_match":true,"evidence_text":"c.580G>A/p.Ala194Thr","llm_judgment":"PRESENT","evidence":"c.580G>A/p.Ala194Thr","abstract_start":713,"abstract_end":733}]}
{"pmid":"26494257","title":"BRAT1-related disease--identification of a patient without early lethality.","abstract":"We present a patient with neonatal onset of hypertonia and seizures identified through whole exome sequencing to have compound heterozygous variants, c.294dupA (p.Leu99fs) and c.1925C>A (p.Ala642Glu), in the BRCA1-associated protein required for ATM activation-1 (BRAT1) gene. Variants in BRAT1 have been identified to cause lethal neonatal rigidity and multifocal seizure syndrome (OMIM# 614498), which consistently manifests a severe neurological phenotype that includes neonatal presentation of rigidity and hypertonia, microcephaly and arrested head growth, intractable seizures, absence of developmental progress, apneic episodes, and death usually by 6 months of age. Our patient initially had a similarly severe neurological picture but remains alive at 6 years of age, expanding the phenotype to include longer term survival and providing further insights into genotype-phenotype correlations and the natural history of this disease.","variants":[{"Name":"NM_152743.4(BRAT1):c.1925C>A (p.Ala642Glu)","Chromosome":"7","Start":"2538610","Stop":"2538610","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":444115,"rule_based_match":true,"evidence_text":"c.1925C>A (p.Ala642Glu)","llm_judgment":"PRESENT","evidence":"c.1925C>A (p.Ala642Glu)","abstract_start":176,"abstract_end":199},{"Name":"NM_152743.4(BRAT1):c.294dup (p.Leu99fs)","Chromosome":"7","Start":"2545044","Stop":"2545045","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GT","allel_id":264325,"rule_based_match":true,"evidence_text":"c.294dupA (p.Leu99fs)","llm_judgment":"PRESENT","evidence":"c.294dupA (p.Leu99fs)","abstract_start":150,"abstract_end":171}]}
{"pmid":"32333447","title":"Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome.","abstract":"Mutations in histidyl-tRNA synthetase (HARS1), an enzyme that charges transfer RNA with the amino acid histidine in the cytoplasm, have only been associated to date with autosomal recessive Usher syndrome type III and autosomal dominant Charcot-Marie-Tooth disease type 2W. Using massive parallel sequencing, we identified bi-allelic HARS1 variants in a child (c.616G>T, p.Asp206Tyr and c.730delG, p.Val244Cysfs*6) and in two sisters (c.1393A>C, p.Ile465Leu and c.910_912dupTTG, p.Leu305dup), all characterized by a multisystem ataxic syndrome. All mutations are rare, segregate with the disease, and are predicted to have a significant effect on protein function. Functional studies helped to substantiate their disease-related roles. Indeed, yeast complementation assays showing that one out of two mutations in each patient is loss-of-function, and the reduction of messenger RNA and protein levels and enzymatic activity in patient's skin-derived fibroblasts, together support the pathogenicity of the identified HARS1 variants in the patient phenotypes. Thus, our efforts expand the allelic and clinical spectrum of HARS1-related disease.","variants":[{"Name":"NM_002109.6(HARS1):c.1393A>C (p.Ile465Leu)","Chromosome":"5","Start":"140674744","Stop":"140674744","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":792641,"rule_based_match":true,"evidence_text":"c.1393A>C (p.Ile465Leu)","llm_judgment":"PRESENT","evidence":"p.Ile465Leu","abstract_start":446,"abstract_end":457}]}
{"pmid":"33617693","title":"A Novel SNCA A30G Mutation Causes Familial Parkinson's Disease.","abstract":"BACKGROUND: The SNCA gene encoding α-synuclein (αSyn) is the first gene identified to cause autosomal-dominant Parkinson's disease (PD).\nOBJECTIVE: We report the identification of a novel heterozygous A30G mutation of the SNCA gene in familial PD and describe clinical features of affected patients, genetic findings, and functional consequences.\nMETHODS: Whole exome sequencing was performed in the discovery family proband. Restriction digestion with Bbvl was used to screen SNCA A30G in two validation cohorts. The Greek cohort included 177 familial PD probands, 109 sporadic PD cases, and 377 neurologically healthy controls. The German cohort included 136 familial PD probands, 380 sporadic PD cases, and 116 neurologically healthy controls. We also conducted haplotype analysis using 13 common single nucleotide variants around A30G to determine the possibility of a founder effect for A30G. We then used biophysical methods to characterize A30G αSyn.\nRESULTS: We identified a novel SNCA A30G (GRCh37, Chr4:90756730, c.89 C>G) mutation that co-segregated with the disease in five affected individuals of three Greek families and was absent from controls. A founder effect was strongly suggested by haplotype analysis. The A30G mutation had a local effect on the intrinsically disordered structure of αSyn, slightly perturbed membrane binding, and promoted fibril formation.\nCONCLUSION: Based on the identification of A30G co-segregating with the disease in three families, the absence of the mutation in controls and population databases, and the observed functional effects, we propose SNCA A30G as a novel causative mutation for familial PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.","variants":[{"Name":"NM_000345.4(SNCA):c.89C>G (p.Ala30Gly)","Chromosome":"4","Start":"89835579","Stop":"89835579","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":1670371,"rule_based_match":true,"evidence_text":"c.89 C>G","llm_judgment":"PRESENT","evidence":"c.89 C>G","abstract_start":1023,"abstract_end":1031}]}
{"pmid":"28382084","title":"Diverse Phenotypic Expression of Cardiomyopathies in a Family with TNNI3 p.Arg145Trp Mutation.","abstract":"Genetic diagnosis of cardiomyopathies is challenging, due to the marked genetic and allelic heterogeneity and the lack of knowledge of the mutations that lead to clinical phenotypes. Here, we present the case of a large family, in which a single TNNI3 mutation caused variable phenotypic expression, ranging from restrictive cardiomyopathy (RCMP) to hypertrophic cardiomyopathy (HCMP) to near-normal phenotype. The proband was a 57-year-old female with HCMP. Examining the family history revealed that her elder sister had expired due to severe RCMP. Using a next-generation sequencing-based gene panel to analyze the proband, we identified a known TNNI3 gene mutation, c.433C>T, which is predicted to cause an amino acid substitution (p.Arg145Trp) in the highly conserved inhibitory region of the cardiac troponin I protein. Sanger sequencing confirmed that six relatives with RCMP or near-normal phenotypes also carried this mutation. To our knowledge, this is the first genetically confirmed family with diverse phenotypic expression of cardiomyopathies in Korea. Our findings demonstrate familial implications, where a single mutation in a sarcomere protein can cause diverse phenotypic expression of cardiomyopathies.","variants":[{"Name":"NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp)","Chromosome":"19","Start":"55154146","Stop":"55154146","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27465,"rule_based_match":true,"evidence_text":"c.433C>T","llm_judgment":"PRESENT","evidence":"c.433C>T","abstract_start":670,"abstract_end":678}]}
{"pmid":"36873107","title":"Novel","abstract":"Objectives: Galloway-Mowat syndrome-4 (GAMOS4) is a very rare renal-neurological disease caused by <i>TP53RK</i> gene mutations. GAMOS4 is characterized by early-onset nephrotic syndrome, microcephaly, and brain anomalies. To date, only nine GAMOS4 cases with detailed clinical data (caused by eight deleterious variants in <i>TP53RK</i>) have been reported. This study aimed to examine the clinical and genetic characteristics of three unrelated GAMOS4 patients with <i>TP53RK</i> gene compound heterozygous mutations.\nMethods: Whole-exome sequencing (WES) was used to identify four novel <i>TP53RK</i> variants in three unrelated Chinese children. Clinical characteristics such as biochemical parameters and image findings of patients were also evaluated. Furthermore, four studies of GAMOS4 patients with <i>TP53RK</i> variants were reviewed. In addition, clinical and genetic features were described after a retrospective analysis of clinical symptoms, laboratory data, and genetic test results.\nResults: The three patients showed facial abnormalities, developmental delays, microcephaly, and aberrant cerebral imaging. Furthermore, patient 1 had slight proteinuria, while patient 2 had epilepsy. However, none of the individuals had nephrotic syndrome, and all were alive for more than 3 years of age. This is the first study to assess four variants in the <i>TP53RK</i> gene (NM_033550.4: c.15_16dup/p.A6Efs*29, c.745A > G/p.R249G, c.185G > A/p.R62H, and c.335A > G/p.Y112C).\nConclusion: The clinical characteristics of the three children with <i>TP53RK</i> mutations are significantly different from the known GAMOS4 traits, including early nephrotic syndrome and mortality mainly occurring in the first year of life. This study provides insights into the pathogenic <i>TP53RK</i> gene mutation spectrum and clinical phenotypes of GAMOS4.","variants":[{"Name":"NM_033550.4(TP53RK):c.185G>A (p.Arg62His)","Chromosome":"20","Start":"46689230","Stop":"46689230","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1861909,"rule_based_match":true,"evidence_text":"c.185G > A/p.R62H","llm_judgment":"PRESENT","evidence":"c.185G > A/p.R62H","abstract_start":1438,"abstract_end":1455}]}
{"pmid":"32558238","title":"Two homozygous missense mutations in ITGB3 gene as a cause of Glanzmann Thrombasthenia in four consanguineous Pakistani pedigrees.","abstract":"INTRODUCTION: Glanzmann thrombasthenia (GT) is most common of inherited platelet disorders, resulting from quantitative/qualitative defects in platelet surface integrin αIIbβ3, encoded by ITGA2B and ITGB3 genes. Little is known about clinical and molecular characteristics of GT patients from highly consanguineous Pakistani population.\nMETHODS: This study analyzed the clinical and molecular spectrum of six GT patients from four unrelated but consanguineous families. Platelet surface expression of αIIbβ3 integrin was determined using flow cytometry analysis. ITGA2B and ITGB3 genes were screened for causative mutations by DNA sequencing. Detected mutations were characterized for their pathogenicity using a variety of in silico tools.\nRESULTS: Glanzmann thrombasthenia patients in this study generally presented early in life, had a severe course of clinical disease with transfusion dependency for management of bleeding episodes. Molecular analysis revealed 2 homozygous missense mutations in ITGB3 gene, c.422 A˃G (p.Y141C) in three GT patients from a single pedigree with familial segregation and c.1641 C>G (p.C547W) in three unrelated GT patients from three families manifesting type I GT with severe reduction in platelet αIIbβ3 levels. In silico pathogenicity predictions, multiple sequence alignment and 3D protein modeling unanimously suggested deleterious nature of the detected mutations, possibly due to aberrant disulfide bonding. Of note, clinical diversity was observed even among GT patients with same mutation in GT1 family.\nCONCLUSION: This study provides an initial yet important account of clinical and genetic characterization of GT in local patients which may spark further studies to help molecular diagnosis, optimal disease management, and genetic counseling based prevention efforts.","variants":[{"Name":"NM_000212.3(ITGB3):c.422A>G (p.Tyr141Cys)","Chromosome":"17","Start":"47284503","Stop":"47284503","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1683961,"rule_based_match":false,"evidence_text":"c.422 A˃G (p.Y141C)","llm_judgment":"PRESENT","evidence":"c.422 A˃G (p.Y141C)","abstract_start":1013,"abstract_end":1032}]}
{"pmid":"17914448","title":"RSPO4 is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the Wnt signaling ligand R-spondin 4.","abstract":"Congenital anonychia is a rare autosomal-recessive disorder characterized by the absence of finger- and toenails. Recently, we and others identified the secreted Wnt signaling ligand R-spondin 4 (RSPO4) as the first gene known to be responsible for inherited anonychia. R-spondins are secreted proteins that activate the Wnt/beta-catenin signaling pathway. This puts anonychia on the growing list of congenital malformation syndromes caused by Wnt signaling pathway defects. Here, we expand the RSPO4 mutational spectrum by identification of the previously unknown mutations c.190C>T (p.Arg64Cys) in exon 2 and c.301C>T (p.Gln101X) in exon 3, thereby corroborating R-spondin 4 as the major protein in autosomal-recessive anonychia. Almost all RSPO4 mutations detected so far affect the highly conserved exons 2 and 3. Thus, we postulate that RSPO4 mutations preferentially cluster in the furin-like cysteine-rich domains of R-spondin 4, which is in line with experimental data proposing that for beta-catenin stabilization, a shortened protein comprising just these two regions is sufficient.","variants":[{"Name":"NM_001029871.4(RSPO4):c.301C>T (p.Gln101Ter)","Chromosome":"20","Start":"967282","Stop":"967282","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39802,"rule_based_match":true,"evidence_text":"c.301C>T (p.Gln101X)","llm_judgment":"PRESENT","evidence":"c.301C>T (p.Gln101X)","abstract_start":611,"abstract_end":631},{"Name":"NM_001029871.4(RSPO4):c.190C>T (p.Arg64Cys)","Chromosome":"20","Start":"968028","Stop":"968028","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39803,"rule_based_match":true,"evidence_text":"c.190C>T (p.Arg64Cys)","llm_judgment":"PRESENT","evidence":"c.190C>T (p.Arg64Cys)","abstract_start":575,"abstract_end":596}]}
{"pmid":"27467858","title":"Effects of Different Variants in the ENPP1 Gene on the Functional Properties of Ectonucleotide Pyrophosphatase/Phosphodiesterase Family Member 1.","abstract":"Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (E-NPP1), encoded by ENPP1, is a plasma membrane protein that generates inorganic pyrophosphate (PP<sub>i</sub> ), a physiologic inhibitor of hydroxyapatite formation. In humans, variants in ENPP1 are associated with generalized arterial calcification of infancy, an autosomal-recessive condition causing premature onset of arterial calcification and intimal proliferation resulting in stenoses. ENPP1 variants also cause pseudoxanthoma elasticum characterized by ectopic calcification of soft connective tissues. To determine the functional impact of ENPP1 missense variants, we analyzed 13 putative pathogenic variants in vitro regarding their functional properties, that is, activity, localization, and PP<sub>i</sub> generation. Transfection of eight of the 13 variants led to complete loss of NPP activity, whereas four mutants (c.1412A > G, p.Tyr471Cys; c.1510A > C, p.Ser504Arg; c.1976A > G, p.Tyr659Cys; c.2330A > G, p.His777Arg) showed residual activity compared with wild-type E-NPP1. One putative pathologic variant (c.2462 G > A, p.Arg821His) showed normal activity. The five mutants with normal or residual E-NPP1 enzyme activity were still able to generate PP<sub>i</sub> and localized in the plasma membrane. In this study, we identified a functional ENPP1 polymorphism, which was expected to be pathogenic till now. Furthermore, we identified four mutants (p.Tyr471Cys, p.Ser504Arg, p.Tyr659Cys, p.His777Arg) with residual E-NPP1 function, which would be potential therapeutical targets for conformational-stabilizing agents.","variants":[{"Name":"NM_006208.3(ENPP1):c.1412A>G (p.Tyr471Cys)","Chromosome":"6","Start":"131872076","Stop":"131872076","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1867941,"rule_based_match":true,"evidence_text":"c.1412A > G, p.Tyr471Cys","llm_judgment":"PRESENT","evidence":"c.1412A > G, p.Tyr471Cys","abstract_start":899,"abstract_end":923},{"Name":"NM_006208.3(ENPP1):c.1510A>C (p.Ser504Arg)","Chromosome":"6","Start":"131872995","Stop":"131872995","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":3245227,"rule_based_match":true,"evidence_text":"c.1510A > C, p.Ser504Arg","llm_judgment":"PRESENT","evidence":"c.1510A > C, p.Ser504Arg","abstract_start":925,"abstract_end":949},{"Name":"NM_006208.3(ENPP1):c.2330A>G (p.His777Arg)","Chromosome":"6","Start":"131884949","Stop":"131884949","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":552093,"rule_based_match":true,"evidence_text":"c.2330A > G, p.His777Arg","llm_judgment":"PRESENT","evidence":"c.2330A > G, p.His777Arg","abstract_start":977,"abstract_end":1001}]}
{"pmid":"23034980","title":"Novel mutation in Sjogren-Larsson syndrome is associated with divergent neurologic phenotypes.","abstract":"Sjögren-Larsson syndrome is an inherited disorder of lipid metabolism caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase, which results in accumulation of fatty aldehydes and alcohols and is characterized by ichthyosis, intellectual disability, and spastic diplegia/quadriplegia. The authors describe 2 unrelated Honduran patients who carried the same novel homozygous nonsense mutation (c.1309A>T, p.K437X) and ALDH3A2 DNA haplotype, but widely differed in disease severity. One patient exhibited spastic quadriplegia with unusual neuroregression, whereas the other patient had the usual static form of spastic diplegia with neurodevelopmental disabilities. Biochemical analyses showed a similar profound deficiency of fatty aldehyde dehydrogenase activity and impaired fatty alcohol metabolism in both patients' cultured fibroblasts. These results indicate that variation in the neurologic phenotype of Sjögren-Larsson syndrome is not strictly determined by the ALDH3A2 mutation or the biochemical defect as expressed in cultured fibroblasts, but by unidentified epigenetic/environmental factors, gene modifiers, or other mechanisms.","variants":[{"Name":"NM_000382.3(ALDH3A2):c.1309A>T (p.Lys437Ter)","Chromosome":"17","Start":"19671822","Stop":"19671822","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":610422,"rule_based_match":true,"evidence_text":"c.1309A>T (p.K437X)","llm_judgment":"PRESENT","evidence":"c.1309A>T","abstract_start":421,"abstract_end":430}]}
{"pmid":"20195870","title":"Female carriers of X-chromosomal adrenoleukodystrophy: a major differential diagnosis in progressive myelopathy.","abstract":"Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are allelic X-chromosomal disorders of peroxisomal lipid metabolism due to mutations of the ABCD1-gene, leading, respectively, to leukoencephalopathy or myeloneuropathy in male patients. We report a family with two symptomatic carriers in subsequent generations who both suffer from symptoms of an AMN. In both patients, molecular genetic testing revealed a heterozygous c.1552C>T-transition (p.Arg518Trp) in exon 6 of ABCD1. Our observations underline the importance of identifying such symptomatic ALD carriers.","variants":[{"Name":"NM_000033.4(ABCD1):c.1552C>T (p.Arg518Trp)","Chromosome":"X","Start":"153740155","Stop":"153740155","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":26346,"rule_based_match":true,"evidence_text":"c.1552C>T-transition (p.Arg518Trp)","llm_judgment":"PRESENT","evidence":"c.1552C>T-transition (p.Arg518Trp)","abstract_start":430,"abstract_end":464}]}
{"pmid":"26114819","title":"Keratopathy in Autoimmune Polyendocrinopathy Syndrome Type 1.","abstract":"PURPOSE: To report the spectrum of phenotypes in patients with autoimmune polyendocrinopathy syndrome type 1 (APS1)-related keratopathy.\nMETHODS: In this retrospective observational case series, 6 patients followed for APS1 were included. Data collected included family history, age at presentation, and systemic and ophthalmic manifestations. The 14 coding exons of the autoimmune regulator (AIRE) gene were sequenced.\nRESULTS: The age at the onset of keratopathy ranged from 4 to 20 years. The ocular symptoms varied from mild photophobia to severe pain, and visual acuity was from light perception to 20/20 Snellen equivalent. Heterogeneous corneal involvement was observed, ranging from minimal superficial punctate staining to severe stromal scarring with deep corneal neovascularization. The severity of ophthalmic findings was uncorrelated to that of systemic manifestations. The genetic analyses identified 2 novel mutations (c.173C>A in exon 2 and c.892G>T in exon 8) and 4 known mutations (c.62C>T in exon 1, c.415C>T in exon 3, c.1096-1G>A in intron 9, and c.1193delC in exon 10) in the AIRE gene. In patients with identical AIRE mutations, including within a sib-pair, heterogeneous phenotypes were observed.\nCONCLUSIONS: Keratopathy can be an early and severe manifestation of APS1, which contributes to the global prognosis of the disease. Its mechanisms remain to be elucidated.","variants":[{"Name":"NM_000383.4(AIRE):c.173C>A (p.Ala58Asp)","Chromosome":"21","Start":"44286597","Stop":"44286597","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":549058,"rule_based_match":true,"evidence_text":"c.173C>A","llm_judgment":"PRESENT","evidence":"c.173C>A","abstract_start":934,"abstract_end":942},{"Name":"NM_000383.4(AIRE):c.1193del (p.Pro398fs)","Chromosome":"21","Start":"44293089","Stop":"44293089","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":549147,"rule_based_match":true,"evidence_text":"c.1193delC in exon 10","llm_judgment":"PRESENT","evidence":"c.1193delC in exon 10","abstract_start":1068,"abstract_end":1089},{"Name":"NM_000383.4(AIRE):c.1096-1G>A","Chromosome":"21","Start":"44292992","Stop":"44292992","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":549068,"rule_based_match":true,"evidence_text":"c.1096-1G>A","llm_judgment":"PRESENT","evidence":"c.1096-1G>A","abstract_start":1039,"abstract_end":1050}]}
{"pmid":"35903363","title":"Case Report:","abstract":"<b>Background</b> <b>:</b> Primary ciliary dyskinesia (PCD) is a rare genetic disorder, predominantly autosomal recessive. The dynein axonemal assembly factor 4 (<i>DNAAF4</i>) is mainly involved in the preassembly of multisubunit dynein protein, which is fundamental to the proper functioning of cilia and flagella. There are few reports of PCD-related pathogenic variants of <i>DNAAF4</i>, and almost no <i>DNAAF4</i>-related articles focused on sperm phenotype. Moreover, the association between <i>DNAAF4</i> and scoliosis has never been reported, to the best of our knowledge. <b>Materials and Methods:</b> We recruited two patients with a clinical diagnosis of PCD. One came from a consanguineous and another from a non-consanguineous family. Clinical data, laboratory test results, and imaging data were analyzed. Through whole exome sequencing, immunofluorescence, electron microscopy, high-speed video microscopy analysis, and hematoxylin-eosin (HE) staining, we identified the disease-associated variants and validated the pathogenicity. <b>Results:</b> Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a non-consanguineous family-I, and proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-II. Both had sinusitis, bronchiectasis, situs inversus, and scoliosis. P1 also had asthenoteratozoospermia, and P2 had an immature uterus. Two homozygous pathogenic variants in <i>DNAAF4</i> (NM_130810.4), c.988C > T, p.(Arg330Trp), and <i>DNAAF4</i> (NM_130810.4), c.733 C > T, p.(Arg245*), were identified through whole exome sequencing. High-speed microscopy analysis showed that most of the cilia were static in P1, with complete static of the respiratory cilia in P2. Immunofluorescence showed that the outer dynein arms (ODA) and inner dynein arms (IDA) were absent in the respiratory cilia of both probands, as well as in the sperm flagellum of P1. Transmission electron microscopy revealed the absence of ODA and IDA of respiratory cilia of P2, and HE staining showed irregular, short, absent, coiled, and bent flagella. <b>Conclusion:</b> Our study identified a novel variant c.733C > T, which expanded the spectrum of <i>DNAAF4</i> variants. Furthermore, we linked <i>DNAAF4</i> to asthenoteratozoospermia and likely scoliosis in patients with PCD. This study will contribute to a better understanding of PCD.","variants":[{"Name":"NM_130810.4(DNAAF4):c.733C>T (p.Arg245Ter)","Chromosome":"15","Start":"55450272","Stop":"55450272","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":976403,"rule_based_match":true,"evidence_text":"c.733C > T, p.(Arg245*)","llm_judgment":"PRESENT","evidence":"c.733C > T","abstract_start":2122,"abstract_end":2132},{"Name":"NM_130810.4(DNAAF4):c.988C>T (p.Arg330Trp)","Chromosome":"15","Start":"55434964","Stop":"55434964","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":948951,"rule_based_match":true,"evidence_text":"c.988C > T, p.(Arg330Trp)","llm_judgment":"PRESENT","evidence":"c.988C > T, p.(Arg330Trp)","abstract_start":1443,"abstract_end":1468}]}
{"pmid":"22729223","title":"De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.","abstract":"De novo somatic mutations in focal areas are well documented in diseases such as neoplasia but are rarely reported in malformation of the developing brain. Hemimegalencephaly (HME) is characterized by overgrowth of either one of the two cerebral hemispheres. The molecular etiology of HME remains a mystery. The intractable epilepsy that is associated with HME can be relieved by the surgical treatment hemispherectomy, allowing sampling of diseased tissue. Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with HME (n = 20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes. A recurrent PIK3CA c.1633G>A mutation was found in four separate cases. Identified mutations were present in 8-40% of sequenced alleles in various brain regions and were associated with increased neuronal S6 protein phosphorylation in the brains of affected individuals, indicating aberrant activation of mammalian target of rapamycin (mTOR) signaling. Thus HME is probably a genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling.","variants":[{"Name":"NM_006218.4(PIK3CA):c.1633G>A (p.Glu545Lys)","Chromosome":"3","Start":"179218303","Stop":"179218303","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28694,"rule_based_match":true,"evidence_text":"PIK3CA c.1633G>A","llm_judgment":"PRESENT","evidence":"PIK3CA c.1633G>A","abstract_start":693,"abstract_end":709}]}
{"pmid":"32685188","title":"Homozygous","abstract":"BACKGROUND: Classical heterozygous pathogenic variants of the lamin A/C (<i>LMNA</i>) gene cause autosomal dominant familial partial lipodystrophy type 2 (FPLD2). However, recent reports indicate phenotypic heterogeneity among carriers of <i>LMNA</i> pathogenic variants, and a few patients have been associated with generalized fat loss.\nCASE PRESENTATION: Here, we report a patient with a lamin A specific pathogenic variant in exon 11, denoted <i>LMNA</i> (c.1745G > A; p.R582H), present in the homozygous state. Fat distribution was compared radiographically to an unrelated heterozygote <i>LMNA</i> p.R582H patient from another pedigree, a healthy female control, a series of adult female subjects with congenital generalized lipodystrophy type 1 (CGL1, <i>n</i> = 9), and typical FPLD2 (<i>n</i> = 8). The whole-body MRI of the index case confirmed near-total loss of subcutaneous adipose tissue with well-preserved fat in the retroorbital area, palms and soles, mons pubis, and external genital region. This pattern resembled the fat loss pattern observed in CGL1 with only one difference: strikingly more fat was observed around mons pubis and the genital region. Also, the p.R582H <i>LMNA</i> variant in homozygous fashion was associated with lower leptin level and earlier onset of metabolic abnormalities compared to heterozygous p.R582H variant and typical FPLD2 cases. On the other hand, the heterozygous <i>LMNA</i> p.R582H variant was associated with partial fat loss which was similar to typical FPLD2 but less severe than the patients with the hot-spot variants at position 482.\nCONCLUSIONS: Our observations and radiological comparisons demonstrate an additive effect of <i>LMNA</i> pathogenic variants on the severity of fat loss and add to the body of evidence that there may be complex genotype-phenotype relationships in this interesting disease known as FPLD2. Although the pathological basis for fat loss is not well understood in patients harboring pathogenic variants in the <i>LMNA</i> gene, our observation suggests that genetic factors modulate the extent of fat loss in <i>LMNA</i> associated lipodystrophy.","variants":[{"Name":"NM_170707.4(LMNA):c.1745G>A (p.Arg582His)","Chromosome":"1","Start":"156138534","Stop":"156138534","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":29533,"rule_based_match":true,"evidence_text":"LMNA (c.1745G > A; p.R582H)","llm_judgment":"PRESENT","evidence":"LMNA</i> (c.1745G > A; p.R582H)","abstract_start":450,"abstract_end":481}]}
{"pmid":"25365615","title":"The same haplotype for two unrelated Wilson disease patients with new ATP7B mutation.","abstract":"BACKGROUND: Wilson disease is a rare autosomal recessive disorder of copper metabolism caused by mutation in the ATP7B gene. The combination of markers (such as SNPs) on a single chromosome can be used to understand the structure of haplotype in the human genome, in which provide notable information on the origin of the mutation in human genetic disorders. The purpose of this study was to determine a haplotype analysis of two unrelated Wilson disease patients with the same missense mutation, c.2335T>G (g.58164 T>G) in exon 8.\nMETHODS: DNA was prepared from two patients with the c.2335T>G mutation, their first-degree relatives, and 50 selected homozygous individuals from consanguineous marriage for eight SNPs around this particular ATP7B mutation. PCR was performed for SNPs of exons 4 (g.47964 C>T), 5 (g.51482G>A), 6 (g.54622A>G), 7 (g.56255G>A), 9 (g.59042G>T), 11 (g.66363G>A), 13 (g.70004 G>C), and 14 (g.72244 A>G), which are located in upstream and downstream of this mutation. Then, restriction fragment length polymorphism (RFLP) for these eight SNPs was designed and performed using eight different restriction enzymes.\nRESULTS: Eight different haplotypes were found in the present study and the patients with the same missense mutation had the same haplotype. The most prevalent haplotype in 100 normal studied ATP7B alleles was the same as reference haplotype (C G A G T G G G A) for ATP7B gene (NG_008806.1).\nCONCLUSION: As these two geographically separated families with the same mutation had the same haplotype, we concluded that this mutation possibly had the same origin in this population.","variants":[{"Name":"NM_000053.4(ATP7B):c.2335T>G (p.Trp779Gly)","Chromosome":"13","Start":"51958331","Stop":"51958331","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":547056,"rule_based_match":true,"evidence_text":"c.2335T>G (g.58164 T>G)","llm_judgment":"PRESENT","evidence":"c.2335T>G (g.58164 T>G)","abstract_start":497,"abstract_end":520}]}
{"pmid":"23566849","title":"Mucolipidosis II and III alpha/beta in Brazil: analysis of the GNPTAB gene.","abstract":"UNLABELLED: Mucolipidosis II and III (MLII and MLIII) alpha/beta are rare autosomal recessive lysosomal storage diseases (LSDs) caused by pathogenic variations in the GNPTAB gene. GNPTAB gene codes for the α and β subunits of phosphotransferase, the enzyme responsible for synthesis of the mannose-6-phosphate (M6P) marker that directs lysosomal enzymes to the lysosome.\nOBJECTIVES: The objective of this study is to identify sequence variations of the GNPTAB gene in Brazilian patients with MLII and MLIII alpha/beta.\nMETHOD: Sequencing of the GNPTAB gene was performed in samples of gDNA extracted from the peripheral blood of patients with MLII/III diagnosed at a national reference center for LSDs.\nRESULTS: Twelve unrelated patients, from several regions of Brazil, were included in this study. Only one was born of consanguineous parents. All patients were found to carry at least one nonpathogenic variation. Nine causal sequence variations were found: c.242G>T (p.W81L); c.1123C>T (p.R375X); c.1196C>T (p.S399F); c.1208T>C (p.I403T); c.1514G>A (p.C505Y); c.1759C>T (p.R587X); c.2808A>G (p.Y937_M972del, novel mutation); c. 2269_2273delGAAAC (p.E757KfsX2, novel mutation); and c.3503_3504delTC (p.L1168QfsX5). Both pathogenic variations were identified in 8 of 12 patients; in four patients, only one pathogenic variation was identified. Mutation c.3503_3504delTC, located in exon 19, was the most frequent pathogenic variation found (n=11/24 alleles). The deleterious effect of the c.2808A>C mutation on splicing was confirmed by cDNA analysis.\nDISCUSSION/CONCLUSIONS: Our findings confirm that the GNPTAB gene presents broad allelic heterogeneity and suggests that, in Brazilian ML II and III patients, screening for mutations should begin at exon 19 of the GNPTAB gene. Further analyses will be conducted on patients in whom both pathogenic mutations have not been found in this study.","variants":[{"Name":"NM_024312.5(GNPTAB):c.242G>T (p.Trp81Leu)","Chromosome":"12","Start":"101790019","Stop":"101790019","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":47656,"rule_based_match":true,"evidence_text":"c.242G>T (p.W81L)","llm_judgment":"PRESENT","evidence":"c.242G>T (p.W81L)","abstract_start":960,"abstract_end":977},{"Name":"NM_024312.5(GNPTAB):c.1123C>T (p.Arg375Ter)","Chromosome":"12","Start":"101770182","Stop":"101770182","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":47625,"rule_based_match":true,"evidence_text":"c.1123C>T (p.R375X)","llm_judgment":"PRESENT","evidence":"c.1123C>T (p.R375X)","abstract_start":979,"abstract_end":998},{"Name":"NM_024312.5(GNPTAB):c.1208T>C (p.Ile403Thr)","Chromosome":"12","Start":"101770097","Stop":"101770097","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":47629,"rule_based_match":true,"evidence_text":"c.1208T>C (p.I403T)","llm_judgment":"PRESENT","evidence":"c.1208T>C (p.I403T)","abstract_start":1021,"abstract_end":1040},{"Name":"NM_024312.5(GNPTAB):c.2269_2273del (p.Glu757fs)","Chromosome":"12","Start":"101764644","Stop":"101764648","ReferenceAlleleVCF":"TGTTTC","AlternateAlleleVCF":"T","allel_id":3086383,"rule_based_match":true,"evidence_text":"c. 2269_2273delGAAAC (p.E757KfsX2, novel mutation)","llm_judgment":"PRESENT","evidence":"c. 2269_2273delGAAAC (p.E757KfsX2, novel mutation)","abstract_start":1128,"abstract_end":1178},{"Name":"NM_024312.5(GNPTAB):c.3503_3504del (p.Leu1168fs)","Chromosome":"12","Start":"101753470","Stop":"101753471","ReferenceAlleleVCF":"TGA","AlternateAlleleVCF":"T","allel_id":17810,"rule_based_match":true,"evidence_text":"c.3503_3504delTC (p.L1168QfsX5)","llm_judgment":"PRESENT","evidence":"c.3503_3504delTC (p.L1168QfsX5)","abstract_start":1184,"abstract_end":1215},{"Name":"NM_024312.5(GNPTAB):c.1514G>A (p.Cys505Tyr)","Chromosome":"12","Start":"101766189","Stop":"101766189","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":47638,"rule_based_match":true,"evidence_text":"c.1514G>A (p.C505Y)","llm_judgment":"PRESENT","evidence":"c.1514G>A (p.C505Y)","abstract_start":1042,"abstract_end":1061},{"Name":"NM_024312.5(GNPTAB):c.1759C>T (p.Arg587Ter)","Chromosome":"12","Start":"101765158","Stop":"101765158","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":47643,"rule_based_match":true,"evidence_text":"c.1759C>T (p.R587X)","llm_judgment":"PRESENT","evidence":"c.1759C>T (p.R587X)","abstract_start":1063,"abstract_end":1082},{"Name":"NM_024312.5(GNPTAB):c.1196C>T (p.Ser399Phe)","Chromosome":"12","Start":"101770109","Stop":"101770109","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":46972,"rule_based_match":true,"evidence_text":"c.1196C>T (p.S399F)","llm_judgment":"PRESENT","evidence":"c.1196C>T (p.S399F)","abstract_start":1000,"abstract_end":1019}]}
{"pmid":"24793888","title":"Distribution and phenotype of GJB2 mutations in 102 Sicilian patients with congenital non syndromic sensorineural hearing loss.","abstract":"OBJECTIVE: To evaluate the frequency of GJB2 mutations and their correlation with phenotype in Sicilian non-syndromic sensorineural hearing loss (NSHL) patients.\nDESIGN: Sequencing of the coding region, basal promoter, exon 1, and donor splice site of the GJB2 gene; screening for the presence of the two common GJB6 deletions.\nSTUDY SAMPLE: A cohort of 102 Sicilian NSHL patients.\nRESULTS: Fifteen different mutations in GJB2 and seventeen different genotypes were detected. No GJB6 mutations were found. The hearing impairment was profound in the 64.72% of probands (mean PTA0.25-4 kHz of 88.82 ± 26.52 dB HL). A total of 81.37% of patients harboured at least one c.35delG allele; c.167delT and c.-23 + 1G> A were identified in 10.78% and the 9.8% of patients respectively; c.35delG homozygotes presented more severe hearing impairment (75.59% of profound hearing loss) and a higher mean PTA0.25-4 kHz (96.79 ± 21.11 dB HL) with respect to c.35delG/non-c.35delG and c.35delG/Wt patients (P < 0.05).\nCONCLUSIONS: This work underlines the role of c.35delG, c.167delT and c.-23 + 1G> A as the most frequent causes of NSHL in Sicily. The c.35delG frequency found is similar to those reported in other populations of the Mediterranean area. The analysis of genetic and audiologic data confirmed a variability in the phenotype associated to a single genotype.","variants":[{"Name":"NM_004004.6(GJB2):c.-23+1G>A","Chromosome":"13","Start":"20192782","Stop":"20192782","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":32068,"rule_based_match":true,"evidence_text":"c.-23 + 1G> A","llm_judgment":"PRESENT","evidence":"c.-23 + 1G> A","abstract_start":697,"abstract_end":710}]}
{"pmid":"24150548","title":"A novel mutation of DNAH5 in chronic rhinosinusitis and primary ciliary dyskinesia in a Chinese family.","abstract":"The genetic factors underlying the pathogenesis of chronic rhinosinusitis (CRS) remains unclear. We herein identified four related subjects with CRS and primary ciliary dyskinesia (PCD) from geographically disperse Chinese Han communities and performed exome capture and sequencing of one affected individual and unaffected parents. We found a novel mutation in DNAH5 (c. 8030G>A) in CRS and PCD which was different from those attributed to cystic fibrosis and a defect of cilia motility in a Chinese family through exome capture and sequencing. Our findings showed that c. 8030G>A of DNAH5 may be implicated as the disease-causing gene of CRS and PCD in this Chinese family, which may expand the understanding of clinicians on the pathogenesis of CRS. Moreover, the identification of this novel mutation in DNAH5 indirectly indicates that exome capture and sequencing are beneficial in the genetic research of midget consanguinity families.","variants":[{"Name":"NM_001369.3(DNAH5):c.8030G>A (p.Arg2677Gln)","Chromosome":"5","Start":"13793709","Stop":"13793709","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":270913,"rule_based_match":true,"evidence_text":"c. 8030G>A","llm_judgment":"PRESENT","evidence":"c. 8030G>A","abstract_start":369,"abstract_end":379}]}
{"pmid":"32014045","title":"Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns.","abstract":"BACKGROUND: The necessity of early treatment for lysosomal storage diseases (LSDs) has triggered the development of newborn screening for LSDs in recent years. Here we report the first 70,000 newborns screened for Mucopolysaccharidosis (MPS) type 4A (Morquio syndrome) and other LSDs by an 8-plex assay including the original 4-plex LSD screening tandem mass spectrometry (MS/MS) assay for Pompe disease, Fabry disease, Gaucher disease, and MPS I disease.\nMETHODS: The additional reaction for MPS II, MPS 3B, MPS 4A, and MPS 6 enzymes was performed separately from the 4-plex reaction. The two reactions were quenched and extracted, then combined before carrying out a single 2-min UPLC-MS/MS analysis.\nRESULTS: From Mar. 2018 to Apr. 2019, 73,743 newborns were screened with the 8-plex LSD screening assay. The 8-plex assay revealed a better analytical precision than the previous 4-plex assay possibly because the 8-plex was carried out using UPLC-MS/MS. Six newborns were found to have low MPS-4A enzyme (N-acetylgalactosamine-6-sulfatase) activity and biallelic GALNS pathogenic mutations in trans; these patients are presumably affected with MPS4A, making an incidence of one in 12,291 (95% confident interval (CI): 5633-26,817). One mutation, c.857C > T (p.T286 M) of the GALNS gene, accounted 5 of the 12 mutated alleles. These newborns had immature vertebral bodies at 1 month of age, and one case was treated with elosulfase alfa 2 mg/kg/week starting from 4 months of age. Among other MPSs screened, one case of MPS I, 3 cases of MPS II, and 3 cases of MPS 3B were detected. One case of mucolipidosis type III was also diagnosed. In conjunction with another 9 patients of Pompe disease, Gaucher disease, and classical Fabry disease, making an incidence of LSDs as one in 3206 newborns (95% CI: 2137 - 4811). The one with infantile-onset Pompe disease and the one with Gaucher disease were treated since the age of 8 days and 41 days respectively.\nCONCLUSIONS: Routine newborn screening of MPS 4A and other LSDs were made possible by the 8-plex LSD screening assay. However, detailed phenotype prediction and the time to start treatment will need further elucidation.","variants":[{"Name":"NM_000512.5(GALNS):c.857C>T (p.Thr286Met)","Chromosome":"16","Start":"88835254","Stop":"88835254","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":621552,"rule_based_match":true,"evidence_text":"c.857C > T (p.T286 M)","llm_judgment":"PRESENT","evidence":"c.857C > T (p.T286 M)","abstract_start":1249,"abstract_end":1270}]}
{"pmid":"31086307","title":"Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease.","abstract":"PURPOSE: To characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date.\nMETHODS: Patients aged ≥1 year with confirmed Pompe disease previously receiving 160 L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments.\nRESULTS: Of 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n = 23), c.-32-13T>G (n = 13), and c.525delT (n = 12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean ± SD, median, range): overall 46.3 ± 33.0% (47.9%, 0.0-100.0%), IOPD 41.6 ± 31.64% (38.9%, 0.0-99.7%), LOPD: 61.8 ± 33.2 (70.9%, 0.0-100.0%).\nCONCLUSION: ADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.","variants":[{"Name":"NM_000152.5(GAA):c.525del (p.Glu176fs)","Chromosome":"17","Start":"80105111","Stop":"80105111","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":19072,"rule_based_match":true,"evidence_text":"c.525delT","llm_judgment":"PRESENT","evidence":"c.525delT","abstract_start":943,"abstract_end":952},{"Name":"NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)","Chromosome":"17","Start":"80118271","Stop":"80118271","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19073,"rule_based_match":true,"evidence_text":"c.2560C>T (n = 23)","llm_judgment":"PRESENT","evidence":"c.2560C>T (n = 23)","abstract_start":897,"abstract_end":915},{"Name":"NM_000152.5(GAA):c.-32-13T>G","Chromosome":"17","Start":"80104542","Stop":"80104542","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":19066,"rule_based_match":true,"evidence_text":"c.-32-13T>G","llm_judgment":"PRESENT","evidence":"c.-32-13T>G","abstract_start":917,"abstract_end":928}]}
{"pmid":"26603945","title":"Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data.","abstract":"BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity.\nMETHODS: We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction).\nFINDINGS: 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively).\nINTERPRETATION: DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines.\nFUNDING: None.","variants":[{"Name":"NM_000110.4(DPYD):c.1679T>G (p.Ile560Ser)","Chromosome":"1","Start":"97515787","Stop":"97515787","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":94530,"rule_based_match":true,"evidence_text":"c.1679T>G","llm_judgment":"PRESENT","evidence":"c.1679T>G","abstract_start":262,"abstract_end":271},{"Name":"NM_000110.4(DPYD):c.1601G>A (p.Ser534Asn)","Chromosome":"1","Start":"97515865","Stop":"97515865","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105971,"rule_based_match":true,"evidence_text":"c.1601G>A","llm_judgment":"PRESENT","evidence":"c.1601G>A","abstract_start":294,"abstract_end":303},{"Name":"NM_000110.4(DPYD):c.1236G>A (p.Glu412=)","Chromosome":"1","Start":"97573863","Stop":"97573863","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105977,"rule_based_match":true,"evidence_text":"c.1236G>A/HapB3","llm_judgment":"PRESENT","evidence":"c.1236G>A/HapB3","abstract_start":273,"abstract_end":288}]}
{"pmid":"17439980","title":"A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology.","abstract":"Mutations in the progranulin (GRN) gene have recently been reported as a cause of the frontotemporal dementia (FTD) syndrome. We performed a clinical, neuropathological and molecular genetic study of two families with FTD and the same novel mutation in GRN. Age of onset ranged from 35 to 75 years and all individuals progressed to a severe dementia syndrome with a mean disease duration of approximately 6-10 years. Variable clinical presentations included language impairment, behaviour change or parkinsonism. Seven total autopsies in the families (five in Family 1, two in Family 2) showed gross and microscopic evidence of neuronal loss in the neocortex, striatum, hippocampus and substantia nigra. All cases with material available for immunohistochemistry had cytoplasmic and intranuclear ubiquitin positive, tau negative inclusions that stained best with an antibody to the TDP43 protein. In addition, all but one had evidence of distinctive tau pathology. Two cases in Family 1 also had alpha-synuclein (SNCA) pathology, one with diffuse neocortical inclusions and neurites and unusual striatal cytoplasmic inclusions. Affected persons in both families had the same mutation in GRN (c.709-2A>G). A minigene construct showed that this mutation alters splicing of exon 7 and results in reduced mRNA message in brain. A single GRN mutation in these two families was associated with variable clinical presentations consistent with the FTD syndrome. All cases had ubiquitin/TDP43 immuno-positive inclusions and most had additional tau pathology. Two cases had SNCA pathology. These findings suggest a link between mutations in GRN and aggregation of tau, TDP43 and SNCA.","variants":[{"Name":"NM_002087.4(GRN):c.709-2A>G","Chromosome":"17","Start":"44351035","Stop":"44351035","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":104042,"rule_based_match":true,"evidence_text":"c.709-2A>G","llm_judgment":"PRESENT","evidence":"c.709-2A>G","abstract_start":1192,"abstract_end":1202}]}
{"pmid":"34411974","title":"Generation of three induced pluripotent stem cell lines (SCVIi014-A, SCVIi015-A, and SCVIi016-A) from patients with LQT1 caused by heterozygous mutations in the KCNQ1 gene.","abstract":"Congenital long QT syndrome type 1 (LQT1) results from KCNQ1 mutations that cause loss of Kv7.1 channel function, leading to arrhythmias, syncope, and sudden cardiac death. Here, we generated three human-induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of LQT1 patients carrying pathogenic variants (c.569 G>A, c.585delG, and c.573_577delGCGCT) in KCNQ1. All lines show typical iPSC morphology, high expression of pluripotent markers, normal karyotype, and are able to differentiate into three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of LQT1 caused by KCNQ1 mutations.","variants":[{"Name":"NM_000218.3(KCNQ1):c.585del (p.Lys196fs)","Chromosome":"11","Start":"2570734","Stop":"2570734","ReferenceAlleleVCF":"CG","AlternateAlleleVCF":"C","allel_id":67744,"rule_based_match":true,"evidence_text":"c.585delG","llm_judgment":"PRESENT","evidence":"c.585delG","abstract_start":353,"abstract_end":362}]}
{"pmid":"24530046","title":"Novel mitofusin 2 splice-site mutation causes Charcot-Marie-Tooth disease type 2 with prominent sensory dysfunction.","abstract":"MFN2 mutations are a major cause of the axonal form of Charcot-Marie-Tooth disease (CMT2). MFN2 encodes mitofusin 2, a mitochondrial fusion protein that is critical for mitochondrial DNA integrity and function. Here we describe CMT2 in a Finnish man and his son, with disease onset in young adulthood, slow progression, and prominent sensory as well as autonomic dysfunction. Molecular analysis revealed in both subjects a previously unreported heterozygous MFN2 mutation c.708G>A that is predicted to abolish a donor splice site for exon 7 of the MFN2 gene. An incorrectly spliced transcript without exon 7 was detected in RT-PCR analysis. The lack of exon 7 creates frameshift and, consequently, premature termination within exon 8. We demonstrated the presence of the aberrant mRNA suggesting either dominant-negative or toxic gain-of-function effect of the heterozygous c.708G>A mutation. This novel mutation adds to the few previously reported pathogenic MFN2 splice site mutations causing CMT2.","variants":[{"Name":"NM_014874.4(MFN2):c.708G>A (p.Thr236=)","Chromosome":"1","Start":"11998878","Stop":"11998878","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":619948,"rule_based_match":true,"evidence_text":"c.708G>A","llm_judgment":"PRESENT","evidence":"c.708G>A","abstract_start":472,"abstract_end":480}]}
{"pmid":"32346159","title":"Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.","abstract":"Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.","variants":[{"Name":"NM_014712.3(SETD1A):c.4495T>G (p.Tyr1499Asp)","Chromosome":"16","Start":"30980571","Stop":"30980571","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":970040,"rule_based_match":false,"evidence_text":"c.4495T>G (p.Tyr1499Asp)","llm_judgment":"PRESENT","evidence":"p.Tyr1499Asp","abstract_start":799,"abstract_end":811}]}
{"pmid":"22035158","title":"Novel plakophilin2 mutation: three-generation family with arrhythmogenic right ventricular cardiomyopathy.","abstract":"OBJECTIVES: The autosomal dominant form of arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to mutations in desmosomal proteins. A mutation in plakophilin 2 (PKP 2) is a frequent cause for ARVC. We describe a new mutation in the PKP2 gene, the genotype-phenotype variation in this mutation and its clinical consequences.\nDESIGN: Individuals in a three-generation family were investigated after the sudden cardiac death of a young male. Clinical evaluation, electrocardiography, echocardiography, magnetic resonance imaging, endomyocardial biopsy and genetic testing were performed.\nRESULTS: A novel heterozygote mutation, a c.368G > A transition, located in exon 3 of the PKP2 gene was found (p.Trp123X). The phenotype was characterized by arrhythmia at an early age in some individuals, with mild abnormalities on imaging.\nCONCLUSIONS: This new plakophilin mutation demonstrates variable penetrance and phenotypic expression in ARVC, and highlights the need of genetic testing and thorough phenotype examination in ARVC pedigrees.","variants":[{"Name":"NM_001005242.3(PKP2):c.368G>A (p.Trp123Ter)","Chromosome":"12","Start":"32878512","Stop":"32878512","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":193556,"rule_based_match":true,"evidence_text":"c.368G > A","llm_judgment":"PRESENT","evidence":"c.368G > A","abstract_start":646,"abstract_end":656}]}
{"pmid":"24448548","title":"Fragile X syndrome due to a missense mutation.","abstract":"Fragile X syndrome is a common inherited form of intellectual disability and autism spectrum disorder. Most patients exhibit a massive CGG-repeat expansion mutation in the FMR1 gene that silences the locus. In over two decades since the discovery of FMR1, only a single missense mutation (p.(Ile304Asn)) has been reported as causing fragile X syndrome. Here we describe a 16-year-old male presenting with fragile X syndrome but without the repeat expansion mutation. Rather, we find a missense mutation, c.797G>A, that replaces glycine 266 with glutamic acid (p.(Gly266Glu)). The Gly266Glu FMR protein abolished many functional properties of the protein. This patient highlights the diagnostic utility of FMR1 sequencing.","variants":[{"Name":"NM_002024.6(FMR1):c.797G>A (p.Gly266Glu)","Chromosome":"X","Start":"147932591","Stop":"147932591","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":580945,"rule_based_match":true,"evidence_text":"c.797G>A","llm_judgment":"PRESENT","evidence":"c.797G>A","abstract_start":504,"abstract_end":512}]}
{"pmid":"24253414","title":"PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy.","abstract":"Defects of the human glycosylphosphatidylinositol (GPI) anchor biosynthetic pathway show a broad range of clinical phenotypes. A homozygous mutation in PIGN, a member of genes involved in the GPI anchor-synthesis pathway, was previously reported to cause dysmorphic features, multiple congenital anomalies, severe neurological impairment, and seizure in a consanguineous family. Here, we report two affected siblings with compound heterozygous PIGN mutations [c.808T >C (p.Ser270Pro) and c.963G >A] showing congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy. The c.808C >T mutation altered an evolutionarily conserved amino acid residue (Ser270), while reverse transcription-PCR and sequencing demonstrated that c.963G >A led to aberrant splicing, in which two mutant transcripts with premature stop codons (p.Ala322Valfs*24 and p.Glu308Glyfs*2) were generated. Expression of GPI-anchored proteins such as CD16 and CD24 on granulocytes from affected siblings was significantly decreased, and expression of the GPI-anchored protein CD59 in PIGN-knockout human embryonic kidney 293 cells was partially or hardly restored by transient expression of p.Ser270Pro and p.Glu308Glyfs*2 mutants, respectively, suggesting severe and complete loss of PIGN activity. Our findings confirm that developmental delay, hypotonia, and epilepsy combined with congenital anomalies are common phenotypes of PIGN mutations and add progressive cerebellar atrophy to this clinical spectrum.","variants":[{"Name":"NM_176787.5(PIGN):c.808T>C (p.Ser270Pro)","Chromosome":"18","Start":"62146023","Stop":"62146023","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":106812,"rule_based_match":true,"evidence_text":"c.808T >C (p.Ser270Pro)","llm_judgment":"PRESENT","evidence":"c.808T >C (p.Ser270Pro)","abstract_start":460,"abstract_end":483}]}
{"pmid":"35640127","title":"Mosaic variants in TNFRSF1A: an emerging cause of tumour necrosis factor receptor-associated periodic syndrome.","abstract":"OBJECTIVE: To identify the molecular basis of a systemic autoinflammatory disorder (SAID) evocative of TNF receptor-associated periodic syndrome (TRAPS).\nMETHODS: (i) Deep next generation sequencing (NGS) through a SAID gene panel; (ii) variant allele distribution in peripheral blood subpopulations; (iii) in silico analyses of mosaic variants using TNF receptor superfamily 1A (TNFRSF1A) crystal structure; (iv) review of the very rare TNFRSF1A mosaic variants reported previously.\nRESULTS: In a 36-year-old man suffering from recurrent fever for 12 years, high-depth NGS revealed a TNFRSF1A mosaic variant, c.176G>A p.(Cys59Tyr), which Sanger sequencing failed to detect. This mosaic variant displayed a variant allele fraction of 14% in whole blood; it affects both myeloid and lymphoid lineages. p.(Cys59Tyr), a recurrent germline pathogenic variant, affects a crucial cysteine located in the first cysteine-rich domain (CRD1) and involved in a disulphide bridge. Introduction of a tyrosine at this position is expected to disrupt the CRD1 structure. Review of the three previously reported TNFRSF1A mosaic variants revealed that they are all located in a small region of CRD2 and that germinal cells can be affected.\nCONCLUSION: This study expands the localization of TNFRSF1A mosaic variants to the CRD1 domain. Noticeably, residues involved in germline TNFRSF1A mutational hot spots can also be involved in post-zygotic mutational events. Including our study, only four patients have been thus far reported with TNFRSF1A mosaicism, highlighting the need for a high-depth NGS-based approach to avoid the misdiagnosis of TRAPS. Genetic counselling has to consider the potential occurrence of TNFRSF1A mosaic variants in germinal cells.","variants":[{"Name":"NM_001065.4(TNFRSF1A):c.176G>A (p.Cys59Tyr)","Chromosome":"12","Start":"6334108","Stop":"6334108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":103544,"rule_based_match":true,"evidence_text":"c.176G>A p.(Cys59Tyr)","llm_judgment":"PRESENT","evidence":"c.176G>A p.(Cys59Tyr)","abstract_start":610,"abstract_end":631}]}
{"pmid":"22537151","title":"Early muscle and brain ultrastructural changes in polymerase gamma 1-related encephalomyopathy.","abstract":"Mutations affecting the mitochondrial DNA-polymerase gamma 1 (POLG1) gene have been shown to cause Alpers-Huttenlocher disease. Ultrastructural data on brain and muscle tissue are rare. We report on ultrastructural changes in brain and muscle tissue of two sisters who were compound heterozygous for the c.2243G>C and c.1879C>T POLG1 mutations. Patient 1 (16 years) presented with epilepsia partialis continua that did not respond to antiepileptic treatment. Neuroimaging showed right occipital and bithalamic changes. Light microscopy from a brain biopsy performed after 3 weeks suggested chronic encephalitis showing astro- and microgliosis as well as perivascular CD8-positive T-cells. However, immunosuppressive therapy failed to improve her condition. When her 17-year-old sister (patient 2) also developed epilepsy, an intensified search for metabolic diseases led to the diagnosis. On electron microscopy mitochondrial abnormalities mainly affecting neurons were detected in the brain biopsy of patient 1, including an increase in number and size, structural changes and globoid inclusions. In patient 2, light and electron microscopy on a muscle biopsy confirmed a mitochondrial myopathy, also revealing an increase in mitochondrial size and number, as well as globoid inclusions. Neurons may be the primary target of mitochondrial dysfunction in brains of patients with Alpers disease related to POLG1 mutations. During early disease stages, brain histopathology may be misleading, showing reactive inflammatory changes.","variants":[{"Name":"NM_002693.3(POLG):c.1879C>T (p.Arg627Trp)","Chromosome":"15","Start":"89325520","Stop":"89325520","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":28538,"rule_based_match":true,"evidence_text":"c.1879C>T","llm_judgment":"PRESENT","evidence":"c.1879C>T","abstract_start":318,"abstract_end":327}]}
{"pmid":"32451163","title":"Whole-genome DNA sequencing: The key to detecting a sarcomeric mutation in a 'false genotype-negative' family with hypertrophic cardiomyopathy.","abstract":"The authors report the clinical and genetic investigation of a family with hypertrophic cardiomyopathy (HCM). The individuals described are three affected first-degree relatives (father, daughter and son), one affected niece and unaffected nephew and niece. Those affected all share a very similar phenotype consisting of asymmetric HCM, with hypertrophy particularly affecting the septum and the anterior wall, and similar electrocardiographic features, including a short PR interval. Case 1 (proband) presented with obstructive HCM and had undergone myectomy and mitral valve replacement. Case 2 (oldest offspring of Case 1) had non-obstructive HCM with exertional angina and NYHA II heart failure (HF) symptoms; she developed non-sustained ventricular tachycardia during follow-up and received a single-chamber ICD for primary prevention of sudden cardiac death. Case 3 (son of case 1) presented with asymptomatic non-obstructive HCM and developed NYHA II HF symptoms during follow-up. Case 4 had non-obstructive HCM, mainly with NYHA II HF symptoms. Testing of the proband for sarcomeric mutations and phenocopies was initially negative. After eight years of clinical follow-up, the suspicion of an undiscovered pathogenic gene mutation shared among the members of this family led us to enroll the proband in a whole-genome sequencing research project, which revealed a heterozygous pathogenic intronic MYBPC3 variant (c.1227-13G>A [rs397515893]), cosegregating with the phenotype.","variants":[{"Name":"NM_000256.3(MYBPC3):c.1227-13G>A","Chromosome":"11","Start":"47343158","Stop":"47343158","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":51683,"rule_based_match":true,"evidence_text":"c.1227-13G>A [rs397515893]","llm_judgment":"PRESENT","evidence":"c.1227-13G>A [rs397515893]","abstract_start":1423,"abstract_end":1449}]}
{"pmid":"31804667","title":"Reanalysis of Association of Pro50Leu Substitution in Guanylate Cyclase Activating Protein-1 With Dominant Retinal Dystrophy.","abstract":"Importance: As genetic and genomic screening is becoming more widely accessed, correctly distinguishing pathogenic from nonpathogenic variants is of increasing relevance.\nObjective: To reevaluate a previously reported family in whom the p.(Pro50Leu) variant in the gene GUCA1A was associated with a dominant retinal dystrophy, in light of new examination findings in the proband's daughter.\nDesign, Setting, and Participants: A genetic study relating to a family with an inherited retinal dystrophy was performed at the retinal genetics service of Moorfields Eye Hospital from October 27, 2009, to May 23, 2019, after the proband's daughter underwent fundus examination.\nMain Outcomes and Measures: Results of sequencing of X chromosome-linked retinitis pigmentosa genes in the proband and specific analysis of the repetitive ORF15 region of the RPGR gene.\nResults: A frame-shifting single-nucleotide deletion was found in the ORF15 exon of RPGR (GRCh37 [hg19] x:38145160delT; NM_001034853.1: c.3092delA p.[Glu1031Glyfs*58]), which may be associated with the loss of 121 amino acid residues at the carboxyl terminus of the protein. The p.(Pro50Leu) variant in GUCA1A was also found to be too common in a publicly available genome database to be a fully penetrant cause of a dominant retinal dystrophy.\nConclusions and Relevance: The phenotype in the family is now associated with the variant in RPGR. The findings suggest that the p.(Pro50Leu) variant in GUCA1A should not be regarded as pathogenic. This report also highlights the relevance of examining relatives, of reevaluating diagnoses in light of new data, and of considering X chromosome-linked inheritance in apparently autosomal dominant pedigrees unless there is clear male-to-male transmission.","variants":[{"Name":"NM_001034853.2(RPGR):c.3092del (p.Glu1031fs)","Chromosome":"X","Start":"38285907","Stop":"38285907","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":856985,"rule_based_match":true,"evidence_text":"NM_001034853.1: c.3092delA p.[Glu1031Glyfs*58]","llm_judgment":"PRESENT","evidence":"NM_001034853.1: c.3092delA p.[Glu1031Glyfs*58]","abstract_start":977,"abstract_end":1023}]}
{"pmid":"24072694","title":"Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia.","abstract":"OBJECTIVE: Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family.\nAPPROACH AND RESULTS: We used exome sequencing to assess all protein-coding regions of the genome in 3 family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Because homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease, we performed directed follow-up phenotyping by noninvasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of cholesterol ester storage disease. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27 000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance.\nCONCLUSIONS: By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent cholesterol ester storage disease in the affected individuals from this kindred and addressed an outstanding question about risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.","variants":[{"Name":"NM_000235.4(LIPA):c.894G>A (p.Gln298=)","Chromosome":"10","Start":"89222511","Stop":"89222511","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":199794,"rule_based_match":true,"evidence_text":"c.894G>A","llm_judgment":"PRESENT","evidence":"c.894G>A","abstract_start":698,"abstract_end":706}]}
{"pmid":"28777845","title":"Rapid detection of hot spot mutations of FGFR3 gene with PCR-high resolution melting assay","abstract":"OBJECTIVE: To identify the causative mutations in five individuals affected with dyschondroplasia and develop an efficient procedure for detecting hot spot mutations of the FGFR3 gene.\nMETHODS: Genomic DNA was extracted from peripheral blood samples with a standard phenol/chloroform method. PCR-Sanger sequencing was used to analyze the causative mutations in the five probands. PCR-high resolution melting (HRM) was developed to detect the identified mutations.\nRESULTS: A c.1138G>A mutation in exon 8 was found in 4 probands, while a c.1620C>G mutation was found in exon 11 of proband 5 whom had a mild phenotype. All patients were successfully distinguished from healthy controls with the PCR-HRM method. The results of HRM analysis were highly consistent with that of Sanger sequencing.\nCONCLUSION: The Gly380Arg and Asn540Lys are hot spot mutations of the FGFR3 gene among patients with ACH/HCH. PCR-HRM analysis is more efficient for detecting hot spot mutations of the FGFR3 gene.","variants":[{"Name":"NM_000142.5(FGFR3):c.1138G>A (p.Gly380Arg)","Chromosome":"4","Start":"1804392","Stop":"1804392","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":31366,"rule_based_match":true,"evidence_text":"c.1138G>A","llm_judgment":"PRESENT","evidence":"c.1138G>A","abstract_start":475,"abstract_end":484}]}
{"pmid":"28255014","title":"Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features.","abstract":"Congenital macrothrombocytopenia is a family of rare diseases, of which a significant fraction remains to be genetically characterized. To analyze cases of unexplained thrombocytopenia, 27 individuals from a patient cohort of the Bleeding and Thrombosis Exploration Center of the University Hospital of Marseille were recruited for a high-throughput gene sequencing study. This strategy led to the identification of two novel <i>FLI1</i> variants (c.1010G>A and c.1033A>G) responsible for macrothrombocytopenia. The <i>FLI1</i> variant carriers' platelets exhibited a defect in aggregation induced by low-dose adenosine diphosphate (ADP), collagen and thrombin receptor-activating peptide (TRAP), a defect in adenosine triphosphate (ATP) secretion, a reduced mepacrine uptake and release and a reduced CD63 expression upon TRAP stimulation. Precise ultrastructural analysis of platelet content was performed using transmission electron microscopy and focused ion beam scanning electron microscopy. Remarkably, dense granules were nearly absent in the carriers' platelets, presumably due to a biogenesis defect. Additionally, 25-29% of the platelets displayed giant α-granules, while a smaller proportion displayed vacuoles (7-9%) and autophagosome-like structures (0-3%). <i>In vitro</i> study of megakaryocytes derived from circulating CD34<sup>+</sup> cells of the carriers revealed a maturation defect and reduced proplatelet formation potential. The study of the <i>FLI1</i> variants revealed a significant reduction in protein nuclear accumulation and transcriptional activity properties. Intraplatelet flow cytometry efficiently detected the biomarker MYH10 in <i>FLI1</i> variant carriers. Overall, this study provides new insights into the phenotype, pathophysiology and diagnosis of <i>FLI1</i> variant-associated thrombocytopenia.","variants":[{"Name":"NM_002017.5(FLI1):c.1010G>A (p.Arg337Gln)","Chromosome":"11","Start":"128810639","Stop":"128810639","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":411536,"rule_based_match":true,"evidence_text":"c.1010G>A","llm_judgment":"PRESENT","evidence":"c.1010G>A","abstract_start":448,"abstract_end":457},{"Name":"NM_002017.5(FLI1):c.1033A>G (p.Lys345Glu)","Chromosome":"11","Start":"128810662","Stop":"128810662","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":411537,"rule_based_match":true,"evidence_text":"c.1033A>G","llm_judgment":"PRESENT","evidence":"c.1033A>G","abstract_start":462,"abstract_end":471}]}
{"pmid":"22964162","title":"Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort.","abstract":"Spastic paraplegia type 7 is an autosomal recessive neurodegenerative disorder mainly characterized by progressive bilateral lower limb spasticity and referred to as a form of hereditary spastic paraplegia. Additional disease features may also be observed as part of a more complex phenotype. Many different mutations have already been identified, but no genotype-phenotype correlations have been found so far. From a total of almost 800 patients referred for testing, we identified 60 patients with mutations in the SPG7 gene. We identified 14 previously unreported mutations and detected a high recurrence rate of several earlier reported mutations. We were able to collect detailed clinical data for 49 patients, who were ranked based on a pure versus complex phenotype, ataxia versus no ataxia and missense versus null mutations. A generally complex phenotype occurred in 69% of all patients and was associated with a younger age at onset (trend with P = 0.07). Ataxia was observed in 57% of all patients. We found that null mutations were associated with the co-occurrence of cerebellar ataxia (trend with P = 0.06). The c.1409 G > A (p.Arg470Gln) mutation, which was found homozygously in two sibs, was associated with a specific complex phenotype that included predominant visual loss due to optical nerve atrophy. Neuropathology in one of these cases showed severe degeneration of the optic system, with less severe degeneration of the ascending tracts of the spinal cord and cerebellum. Other disease features encountered in this cohort included cervical dystonia, vertical gaze palsy, ptosis and severe intellectual disability. In this large Dutch cohort, we seem to have identified the first genotype-phenotype correlation in spastic paraplegia type 7 by observing an association between the cerebellar phenotype of spastic paraplegia type 7 and SPG7 null alleles. An overlapping phenotypic presentation with its biological counterpart AFG3L2, which when mutated causes spinocerebellar ataxia type 28, is apparent and possibly suggests that abnormal levels of the SPG7 protein impact the function of the mitochondrial ATPases associated with diverse cellular activities-protease complex (formed by SPG7 and AFG3L2) in the cerebellum. In addition, a missense mutation in exon 10 resulted in predominant optical nerve atrophy, which might suggest deleterious interactions of this SPG7 variant with its substrate OPA1, the mutated gene product in optic atrophy type 1. Functional studies are required to further investigate these interactions.","variants":[{"Name":"NM_003119.4(SPG7):c.1409G>A (p.Arg470Gln)","Chromosome":"16","Start":"89544732","Stop":"89544732","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":645146,"rule_based_match":true,"evidence_text":"c.1409 G > A (p.Arg470Gln)","llm_judgment":"PRESENT","evidence":"c.1409 G > A (p.Arg470Gln)","abstract_start":1126,"abstract_end":1152}]}
{"pmid":"24566826","title":"Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia.","abstract":"IMPORTANCE: The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described.\nOBJECTIVE: To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing.\nDESIGN, SETTING, AND PARTICIPANTS: A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations.\nMAIN OUTCOMES AND MEASURES: Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life.\nRESULTS: We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers.\nCONCLUSIONS AND RELEVANCE: We report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome β-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.","variants":[{"Name":"NM_022726.4(ELOVL4):c.504G>C (p.Leu168Phe)","Chromosome":"6","Start":"79921662","Stop":"79921662","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":152775,"rule_based_match":true,"evidence_text":"c.504G>C","llm_judgment":"PRESENT","evidence":"c.504G>C","abstract_start":1356,"abstract_end":1364}]}
{"pmid":"23462291","title":"Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy.","abstract":"Two siblings from consanguineous parents died perinatally with a condition characterized by generalized hypotonia, respiratory insufficiency, arthrogryposis, microcephaly, congenital brain malformations and hyperglycinemia. Catalytic activities of the mitochondrial respiratory complexes I and II were deficient in skeletal muscle, a finding suggestive of an inborn error in mitochondrial biogenesis. Homozygosity mapping identified IBA57 located in the largest homozygous region on chromosome 1 as a culprit candidate gene. IBA57 is known to be involved in the biosynthesis of mitochondrial [4Fe-4S] proteins. Sequence analysis of IBA57 revealed the homozygous mutation c.941A > C, p.Gln314Pro. Severely decreased amounts of IBA57 protein were observed in skeletal muscle and cultured skin fibroblasts from the affected subjects. HeLa cells depleted of IBA57 showed biochemical defects resembling the ones found in patient-derived cells, including a decrease in various mitochondrial [4Fe-4S] proteins and in proteins covalently linked to lipoic acid (LA), a cofactor produced by the [4Fe-4S] protein LA synthase. The defects could be complemented by wild-type IBA57 and partially by mutant IBA57. As a result of the mutation, IBA57 protein was excessively degraded, an effect ameliorated by protease inhibitors. Hence, we propose that the mutation leads to partial functional impairment of IBA57, yet the major pathogenic impact is due to its proteolytic degradation below physiologically critical levels. In conclusion, the ensuing lethal complex biochemical phenotype of a novel metabolic syndrome results from multiple Fe/S protein defects caused by a deficiency in the Fe/S cluster assembly protein IBA57.","variants":[{"Name":"NM_001010867.4(IBA57):c.941A>C (p.Gln314Pro)","Chromosome":"1","Start":"228175383","Stop":"228175383","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":71452,"rule_based_match":true,"evidence_text":"c.941A > C, p.Gln314Pro","llm_judgment":"PRESENT","evidence":"c.941A > C, p.Gln314Pro","abstract_start":671,"abstract_end":694}]}
{"pmid":"30982608","title":"Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia.","abstract":"Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia. The second individual had a homozygous missense mutation (c.1929C>A [p.His643Gln]) and presented with developmental delay and epilepsy in childhood. We analyzed a zebrafish model (csf1r<sup>DM</sup>) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor. CUX1<sup>+</sup> neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1<sup>+</sup> neurons. Since a large fraction of CUX1<sup>+</sup> neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1<sup>+</sup> neurons. Our results suggest that CSF1R is required for human brain development and establish the csf1r<sup>DM</sup> fish as a model for microgliopathies. In addition, our results exemplify an under-recognized form of phenotypic expansion, in which genes associated with well-recognized, dominant conditions produce different phenotypes when biallelically mutated.","variants":[{"Name":"NM_001288705.3(CSF1R):c.1754-1G>C","Chromosome":"5","Start":"150061596","Stop":"150061596","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":622959,"rule_based_match":true,"evidence_text":"c.1754-1G>C","llm_judgment":"PRESENT","evidence":"c.1754-1G>C","abstract_start":562,"abstract_end":573},{"Name":"NM_001288705.3(CSF1R):c.1929C>A (p.His643Gln)","Chromosome":"5","Start":"150060902","Stop":"150060902","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":622960,"rule_based_match":true,"evidence_text":"c.1929C>A [p.His643Gln]","llm_judgment":"PRESENT","evidence":"c.1929C>A [p.His643Gln]","abstract_start":863,"abstract_end":886}]}
{"pmid":"26416840","title":"Two different nucleotide substitutions of APC gene in a family with familial adenomatous polyposis.","abstract":"Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome leading to colorectal cancer. This disease appears as a result of germline mutation in adenomatous polyposis coli (APC) gene. The aim of the present study is to report the association between two different nucleotide substitutions detected in a family with FAP. In the proband, p.His1172Gln (c.3516delT) was detected in exon 15 of the APC gene. Furthermore, p.His1172Gln (c.3516delT) and, in addition to this mutation, p.Met1413Val (c.4237 A > G) were detected in exon 15 in both daughters of the proband. However, we believe that single nucleotide change in codon 1413 may be a polymorphic variant and deletion T in codon 1172 of APC gene is associated with FAP, attenuated FAP and extracolonic FAP involvement. Along with common use of genetic tests in the clinical practice, genotype-phenotype correlation may be recognized better and useful for early diagnosis and prevention of familial cancer syndromes.","variants":[{"Name":"NM_000038.6(APC):c.4237A>G (p.Met1413Val)","Chromosome":"5","Start":"112839831","Stop":"112839831","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":137249,"rule_based_match":true,"evidence_text":"c.4237 A > G","llm_judgment":"PRESENT","evidence":"c.4237 A > G","abstract_start":504,"abstract_end":516}]}
{"pmid":"23090741","title":"SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation.","abstract":"Systemic primary carnitine deficiency (CDSP) is a rare autosomal recessive disorder that presents episodic periods of hypoketotic hypoglycemia. The main symptoms of CDSP are skeletal and cardiac myopathy. CDSP is caused by a defect in plasma membrane uptake of carnitine, ultimately caused by the SLC22A5 gene. We report the case of a Korean patient with CDSP. He had an abnormal free carnitine level of 5.56 μmol/L (reference range, RR 10.4~87.1 μmol/L) and a palmitoylcarnitine level of 0.27 μmol/L (RR 0.5~9.7 μmol/L) in a newborn screening test. The patient showed an ammonia level of 129.4 ug/dL (RR, 25~65 ug/dL), a lactate level of 4.5 mmol/L (RR, 0.5-2.2 mmol/L), and a free carnitine level of 10.3 μmol/L (RR, 36-74 μmol/L) in blood. After PCR-sequencing analysis of the SLC22A5 gene, the patient was found to be a compound heterozygote for c.506G>A (p.R169Q) and c.1400C>G (p.S467C) mutations. These missense mutations are reported previously. The patient was started on L-carnitine supplement after CDSP diagnosis. The patient was treated with L-carnitine to reach a normal free carnitine level and has remained asymptomatic up to the current age of 21 months. The plasma free carnitine level normalized to 66.6 μmol/L at 4 weeks after treatment. To the best of our knowledge, this is the first report of a CDSP patient confirmed by molecular genetic investigation.","variants":[{"Name":"NM_003060.4(SLC22A5):c.506G>A (p.Arg169Gln)","Chromosome":"5","Start":"132384155","Stop":"132384155","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":21460,"rule_based_match":true,"evidence_text":"c.506G>A (p.R169Q)","llm_judgment":"PRESENT","evidence":"c.506G>A (p.R169Q)","abstract_start":850,"abstract_end":868},{"Name":"NM_003060.4(SLC22A5):c.1400C>G (p.Ser467Cys)","Chromosome":"5","Start":"132392565","Stop":"132392565","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":36757,"rule_based_match":true,"evidence_text":"c.1400C>G (p.S467C)","llm_judgment":"PRESENT","evidence":"c.1400C>G (p.S467C)","abstract_start":873,"abstract_end":892}]}
{"pmid":"19553121","title":"Nemaline (actin) myopathy with myofibrillar dysgenesis and abnormal ossification.","abstract":"We report a 2-year-old boy who presented with marked hypotonia and was dependent on artificial ventilation since birth. He was diagnosed with nemaline (actin) myopathy, based on the cytoplasmic accumulation of thin filament aggregates and marked myofibrillar dysgenesis. Intranuclear rods and dispersed tiny nemaline bodies were also observed. The patient was shown to be heterozygous for a de novo mutation, c.430C>T (p.Leu144Phe), in the alpha-actin (ACTA1) gene. He also showed orbital osteosclerosis, longitudinal striations of the iliac bones, hepatomegaly, undescended testis, a unilateral vesico-ureteric stenosis, severe failure to thrive, and dilatation of the lateral cerebral ventricles. Besides the severe muscle involvement, these clinical findings further broaden the clinical spectrum of actinopathy phenotypes.","variants":[{"Name":"NM_001100.4(ACTA1):c.430C>T (p.Leu144Phe)","Chromosome":"1","Start":"229432580","Stop":"229432580","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":259655,"rule_based_match":true,"evidence_text":"c.430C>T (p.Leu144Phe)","llm_judgment":"PRESENT","evidence":"c.430C>T (p.Leu144Phe)","abstract_start":409,"abstract_end":431}]}
{"pmid":"30885219","title":"Identification of a novel and heterozygous LMF1 nonsense mutation in an acute pancreatitis patient with severe hypertriglyceridemia, severe obesity and heavy smoking.","abstract":"BACKGROUND: Hypertriglyceridemia (HTG) is one of the most common etiologies of acute pancreatitis (AP). Variants in five genes involved in the regulation of plasma lipid metabolism, namely LPL, APOA5, APOC2, GPIHBP1 and LMF1, have been frequently reported to cause or predispose to HTG.\nMETHODS: A Han Chinese patient with HTG-induced AP was assessed for genetic variants by Sanger sequencing of the entire coding and flanking sequences of the above five genes.\nRESULTS: The patient was a 32-year-old man with severe obesity (Body Mass Index = 35) and heavy smoking (ten cigarettes per day for more than ten years). At the onset of AP, his serum triglyceride concentration was elevated to 1450.52 mg/dL. We sequenced the entire coding and flanking sequences of the LPL, APOC2, APOA5, GBIHBP1 and LMF1 genes in the patient. We found no putative deleterious variants, with the exception of a novel and heterozygous nonsense variant, c.1024C > T (p.Arg342*; rs776584760), in exon 7 of the LMF1 gene.\nCONCLUSIONS: This is the first time that a heterozygous LMF1 nonsense variant was found in a HTG-AP patient with severe obesity and heavy smoking, highlighting an important interplay between genetic and lifestyle factors in the etiology of HTG.","variants":[{"Name":"NM_022773.4(LMF1):c.1024C>T (p.Arg342Ter)","Chromosome":"16","Start":"871215","Stop":"871215","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1826086,"rule_based_match":true,"evidence_text":"c.1024C > T (p.Arg342*; rs776584760)","llm_judgment":"PRESENT","evidence":"c.1024C > T (p.Arg342*; rs776584760)","abstract_start":931,"abstract_end":967}]}
{"pmid":"27920058","title":"A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome.","abstract":"BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the <i>LMNA</i> gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels.\nMETHODS AND RESULTS: We report a novel form of somatic mosaicism, where a child possessed two cell populations with different HGPS disease-producing mutations of the same nucleotide-one producing severe HGPS and one mild HGPS. The proband possessed an intermediate phenotype. The mosaicism was initially discovered when Sanger sequencing showed a c.1968+2T>A mutation in blood DNA and a c.1968+2T>C in DNA from cultured fibroblasts. Deep sequencing of DNA from the proband's blood revealed 4.7% c.1968+2T>C mutation, and 41.3% c.1968+2T>A mutation.\nCONCLUSIONS: We hypothesise that the germline mutation was c.1968+2T>A, but a rescue event occurred during early development, where the somatic mutation from A to C at 1968+2 provided a selective advantage. This type of mosaicism where a partial phenotypic rescue event results from a second but milder disease-causing mutation in the same nucleotide has not been previously characterised for any disease.","variants":[{"Name":"NM_170707.4(LMNA):c.1968+2T>A","Chromosome":"1","Start":"156138759","Stop":"156138759","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":172115,"rule_based_match":true,"evidence_text":"c.1968+2T>A","llm_judgment":"PRESENT","evidence":"c.1968+2T>A","abstract_start":704,"abstract_end":715}]}
{"pmid":"33733458","title":"Expansion of the clinical and molecular spectrum of an XPD-related disorder linked to biallelic mutations in ERCC2 gene.","abstract":"Bi-allelic inactivation of XPD protein, a nucleotide excision repair (NER) signaling pathway component encoded by ERCC2 gene, has been associated with several defective DNA repair phenotypes, including xeroderma pigmentosum, photosensitive trichothiodystrophy, and cerebro-oculo-facio-skeletal syndrome. We report a pediatric patient harboring two compound heterozygous variants in ERCC2 gene, c.361-1G>A and c.2125A>C (p.Thr709Pro), affected by severe postnatal growth deficiency, microcephaly, facial dysmorphisms and pilocytic astrocytoma of the brainstem. Some of these features point to a DNA repair syndrome, and altogether delineate a phenotype differentiating from disorders known to be associated with ERCC2 mutations. The DNA repair efficiency following UV irradiation in the proband's skin fibroblasts was defective indicating that the new set of ERCC2 alleles impacts on NER efficiency. Sequencing analysis on tumor DNA did not reveal any somatic deleterious point variant in cancer-related genes, while SNP-array analysis disclosed a 2 Mb microduplication involving the 7q34 region, spanning from KIAA1549 to BRAF, and resulting in the KIAA1549:BRAF fusion protein, a marker of pilocytic astrocytoma. In conclusion, this report expands the clinical and mutational spectrum of ERCC2-related disorders.","variants":[{"Name":"NM_000400.4(ERCC2):c.2125A>C (p.Thr709Pro)","Chromosome":"19","Start":"45352274","Stop":"45352274","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":3046019,"rule_based_match":true,"evidence_text":"c.2125A>C (p.Thr709Pro)","llm_judgment":"PRESENT","evidence":"c.2125A>C (p.Thr709Pro)","abstract_start":409,"abstract_end":432}]}
{"pmid":"25319874","title":"A newly identified missense mutation in RET codon 666 is associated with the development of medullary thyroid carcinoma.","abstract":"A 38-year-old woman with a thyroid nodule measuring approximately 2 cm was suspected to have medullary thyroid carcinoma (MTC) because of markedly elevated serum calcitonin and carcinoembryonic antigen levels. There were no signs of pheochromocytoma, whereas primary hyperparathyroidism was suspected based on the findings of inappropriate hypersecretion of parathyroid hormone although no parathyroid tumor was detected with imaging studies. RET mutation analysis revealed a novel germline missense mutation in codon 666, c.1997A>G (p.K666R). She underwent total thyroidectomy with lymphadenectomy and simultaneous total parathyroidectomy with autotransplantation of parathyroid tissue. She was given calcium lactate and alfacalcidol to prevent postoperative hypocalcemia. Pathological findings of the thyroid tumor were compatible with MTC, but the resected parathyroid glands were intact. To our knowledge, c.1997A>G (p.K666R) is a new RET mutation. This is a minor variant, but it is significant because of the possible pathogenicity in tumor formation. It is often difficult to determine whether MTC is generated as part of MEN2-related disease or familial MTC when it is a unique manifestation. In addition, it is still unclear whether all missense mutations in this codon reported previously will lead to the same clinical course and prognosis. Further careful observations of clinical presentation are required to determine the clinical features associated with this variant.","variants":[{"Name":"NM_020975.6(RET):c.1997A>G (p.Lys666Arg)","Chromosome":"10","Start":"43114597","Stop":"43114597","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":540547,"rule_based_match":true,"evidence_text":"c.1997A>G (p.K666R)","llm_judgment":"PRESENT","evidence":"c.1997A>G (p.K666R)","abstract_start":523,"abstract_end":542}]}
{"pmid":"15217520","title":"HNPCC: six new pathogenic mutations.","abstract":"BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease with a high risk for colorectal and endometrial cancer caused by germline mutations in DNA mismatch-repair genes (MMR). HNPCC accounts for approximately 2 to 5% of all colorectal cancers. Here we present 6 novel mutations in the DNA mismatch-repair genes MLH1, MSH2 and MSH6.\nMETHODS: Patients with clinical diagnosis of HNPCC were counselled. Tumor specimen were analysed for microsatellite instability and immunohistochemistry for MLH1, MSH2 and MSH6 protein was performed. If one of these proteins was not detectable in the tumor mutation analysis of the corresponding gene was carried out.\nRESULTS: We identified 6 frameshift mutations (2 in MLH1, 3 in MSH2, 1 in MSH6) resulting in a premature stop: two mutations in MLH1 (c.2198_2199insAACA [p.N733fsX745], c.2076_2077delTG [p.G693fsX702]), three mutations in MSH2 (c.810_811delGT [p.C271fsX282], c.763_766delAGTGinsTT [p.F255fsX282], c.873_876delGACT [p.L292fsX298]) and one mutation in MSH6 (c.1421_1422dupTG [p.C475fsX480]). All six tumors tested for microsatellite instability showed high levels of microsatellite instability (MSI-H).\nCONCLUSIONS: HNPCC in families with MSH6 germline mutations may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations.","variants":[{"Name":"NM_000179.3(MSH6):c.1421_1422dup (p.Gln475fs)","Chromosome":"2","Start":"47799402","Stop":"47799403","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGT","allel_id":94667,"rule_based_match":true,"evidence_text":"c.1421_1422dupTG [p.C475fsX480]","llm_judgment":"PRESENT","evidence":"c.1421_1422dupTG [p.C475fsX480]","abstract_start":1046,"abstract_end":1077}]}
{"pmid":"20095043","title":"Deafness and retinal degeneration in a novel USH1C knock-in mouse model.","abstract":"Usher syndrome is the leading cause of combined deaf-blindness, but the molecular mechanisms underlying the auditory and visual impairment are poorly understood. Usher I is characterized by profound congenital hearing loss, vestibular dysfunction, and progressive retinitis pigmentosa beginning in early adolescence. Using the c.216G>A cryptic splice site mutation in Exon 3 of the USH1C gene found in Acadian Usher I patients in Louisiana, we constructed the first mouse model that develops both deafness and retinal degeneration. The same truncated mRNA transcript found in Usher 1C patients is found in the cochleae and retinas of these knock-in mice. Absent auditory-evoked brainstem responses indicated that the mutant mice are deaf at 1 month of age. Cochlear histology showed disorganized hair cell rows, abnormal bundles, and loss of both inner and outer hair cells in the middle turns and at the base. Retinal dysfunction as evident by an abnormal electroretinogram was seen as early as 1 month of age, with progressive loss of rod photoreceptors between 6 and 12 months of age. This knock-in mouse reproduces the dual sensory loss of human Usher I, providing a novel resource to study the disease mechanism and the development of therapies.","variants":[{"Name":"NM_153676.4(USH1C):c.216G>A (p.Val72=)","Chromosome":"11","Start":"17531431","Stop":"17531431","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":20182,"rule_based_match":true,"evidence_text":"c.216G>A","llm_judgment":"PRESENT","evidence":"c.216G>A","abstract_start":327,"abstract_end":335}]}
{"pmid":"28624464","title":"Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains.","abstract":"Dominant mutations in STIM1 are a cause of three allelic conditions: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcaemia and bleeding diathesis), and a platelet dysfunction disorder, York platelet syndrome. Previous reports have suggested a genotype-phenotype correlation with mutations in the N-terminal EF-hand domain associated with tubular aggregate myopathy, and a common mutation at p.R304W in a coiled coil domain associated with Stormorken syndrome. In this study individuals with STIM1 variants were identified by exome sequencing or STIM1 direct sequencing, and assessed for neuromuscular, haematological and biochemical evidence of the allelic disorders of STIM1. STIM1 mutations were investigated by fibroblast calcium imaging and 3D modelling. Six individuals with STIM1 mutations, including two novel mutations (c.262A>G (p.S88G) and c.911G>A (p.R304Q)), were identified. Extra-neuromuscular symptoms including thrombocytopenia, platelet dysfunction, hypocalcaemia or hyposplenism were present in 5/6 patients with mutations in both the EF-hand and CC domains. 3/6 patients had psychiatric disorders, not previously reported in STIM1 disease. Review of published STIM1 patients (n = 49) confirmed that neuromuscular symptoms are present in most patients. We conclude that the phenotype associated with activating STIM1 mutations frequently includes extra-neuromuscular features such as hypocalcaemia, hypo-/asplenia and platelet dysfunction regardless of mutation domain.","variants":[{"Name":"NM_001382567.1(STIM1):c.262A>G (p.Ser88Gly)","Chromosome":"11","Start":"3967674","Stop":"3967674","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1425232,"rule_based_match":true,"evidence_text":"c.262A>G (p.S88G)","llm_judgment":"PRESENT","evidence":"c.262A>G (p.S88G)","abstract_start":891,"abstract_end":908}]}
{"pmid":"36776904","title":"The molecular mechanism of Gaucher disease caused by compound heterozygous mutations in","abstract":"Gaucher disease (GD, ORPHA355) is a rare autosomal recessive genetic disease caused by mutations in <i>GBA1</i>, which encodes the lysosomal enzyme glucocerebrosidase (GCase). Here, we report a patient with GD who carried the heterozygous c.1240G > C (p.Val414Leu) mutation and the heterozygous pathogenic c.1342G > C (p.Asp448His) mutation in <i>GBA1</i>. Bioinformatics analysis suggested that the two mutations are pathogenic. Functional studies showed that <i>GBA1</i> mRNA and GCase protein levels of mutant types were significantly less than the wild-type. In the cell lysates, the two mutations of <i>GBA1</i> c.1240G > C and c.1342G > C caused a decreased GCase concentration, while the two mutations did not change the distribution in the cell. The pathogenicity of the compound heterozygous mutations was verified. Early diagnosis and treatment can improve the quality of life and prevent unnecessary procedures in patients with GD.","variants":[{"Name":"NM_000157.4(GBA1):c.1240G>C (p.Val414Leu)","Chromosome":"1","Start":"155235829","Stop":"155235829","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1165456,"rule_based_match":true,"evidence_text":"c.1240G > C (p.Val414Leu)","llm_judgment":"PRESENT","evidence":"c.1240G > C (p.Val414Leu)","abstract_start":239,"abstract_end":264}]}
{"pmid":"24096472","title":"Clinical spectrum in three families with familial hemiplegic migraine type 2 including a novel mutation in the ATP1A2 gene.","abstract":"INTRODUCTION: Familial hemiplegic migraine (FHM) is a rare subtype of migraine with transient hemiplegic aura.\nPATIENTS AND METHODS: We describe three unrelated families with familial hemiplegic migraine type II (FHM2). Retrospectively, information on 47 family members could be obtained, 15 by personal examination and 32 by indirect anamnesis from relatives. Genetic analyses were performed in 13 patients.\nRESULTS: One family had a novel missense mutation in the ATP1A2 gene (c.659C>T, p.Ser220Leu) that segregated with the phenotype in three generations. Two further unrelated families with different ethnic backgrounds (one from Germany and one from Russia) had a missense mutation that has not been described as yet in FHM, but occurred in only a single patient with sporadic hemiplegic migraine (c.2723G>A, p.Arg908Gln). Clinically the patients had severe attacks lasting up to several weeks as well as epileptic seizures. Three patients with a proven mutation in the ATP1A2 gene clinically presented without hemiparesis. Furthermore, there was a possible relation of FHM2 to mental retardation in another two patients.\nCONCLUSION: Clinical symptoms may last for several weeks in some patients. Patients with FHM2 may also present without hemiplegia. Therefore, the full family history has to be taken into account to establish the diagnosis of FHM.","variants":[{"Name":"NM_000702.4(ATP1A2):c.659C>T (p.Ser220Leu)","Chromosome":"1","Start":"160125164","Stop":"160125164","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2401547,"rule_based_match":true,"evidence_text":"c.659C>T, p.Ser220Leu","llm_judgment":"PRESENT","evidence":"c.659C>T, p.Ser220Leu","abstract_start":479,"abstract_end":500}]}
{"pmid":"25728775","title":"De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay.","abstract":"Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129∗]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024∗]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.","variants":[{"Name":"NM_006766.5(KAT6A):c.3385C>T (p.Arg1129Ter)","Chromosome":"8","Start":"41934835","Stop":"41934835","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":178417,"rule_based_match":true,"evidence_text":"c.3385C>T (p.Arg1129∗)","llm_judgment":"PRESENT","evidence":"c.3385C>T","abstract_start":655,"abstract_end":664},{"Name":"NM_006766.5(KAT6A):c.3070C>T (p.Arg1024Ter)","Chromosome":"8","Start":"41937538","Stop":"41937538","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":178418,"rule_based_match":true,"evidence_text":"c.3070C>T (p.Arg1024∗)","llm_judgment":"PRESENT","evidence":"c.3070C>T","abstract_start":780,"abstract_end":789}]}
{"pmid":"30684275","title":"Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights.","abstract":"Lysosomal acid lipase deficiency (LAL-D) is a multi-organ autosomal recessive disease caused by mutations in LIPA. We reviewed data from 681 samples (white blood cells [WBC] n = 625, fibroblasts = 30, liver = 4, amniocytes = 13, chorionic villus = 9) received for analysis of lysosomal acid lipase (LAL) activity over a 15-year period. LIPA sequencing was performed in 49 patients with reduced (n = 26) or deficient (n = 23) LAL activity. The Exome Aggregation Consortium and Genome Aggregation Database dataset were used for LAL-D prevalence calculations. LAL WBC activity was reduced in 67 patients (10.72%) and deficient in 37 (5.92%). The average of LAL activity ± margin of error (CI 95%) was 19.32 ± 0.86 pmol/min/mg for reduced activity patients and 5.90 ± 1.42 pmol/min/mg for deficient patients. The average age at diagnosis for LAL-D was 23.6 years with several patients older than age 30. The correlation between the age at diagnosis and LAL activity showed a significant moderate direct correlation (Pearson's r = 0.46, P < 0.005). Homozygous or compound heterozygous mutations were identified in 9 out of 23 patients with deficient results (detection rate 39.1%). The average LAL activity in molecularly confirmed patients was 4.02 ± 2.02 pmol/min/mg protein, while in molecularly negative patients was 13.886 ± 1.49 pmol/min/mg (P < 0.0001). Twenty-two different mutations were identified including two novel variants (c.309C>A and c.856G>C). A carrier frequency of approximately 1 in 350 was inferred. LAL activity in WBC is a validated tool for LAL-D diagnosis. Higher residual enzymatic activity might result in a milder phenotype leading to diagnosis delay. A cut-off below 12 pmol/min/mg protein might be useful to discriminate patients with LIPA mutations.","variants":[{"Name":"NM_000235.4(LIPA):c.309C>A (p.Ser103Arg)","Chromosome":"10","Start":"89228319","Stop":"89228319","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":545647,"rule_based_match":true,"evidence_text":"c.309C>A","llm_judgment":"PRESENT","evidence":"c.309C>A","abstract_start":1433,"abstract_end":1441}]}
{"pmid":"17225135","title":"Autosomal recessive juvenile onset cataract associated with mutation in BFSP1.","abstract":"A genome wide scan in a consanguineous family of Indian origin with autosomal recessive developmental cataracts was performed by two-point linkage analysis with 382 microsatellite markers. It showed linkage to markers on chromosome 20q, between D20S852 and D20S912, with a maximum lod score of 5.4 obtained with D20S860. This region encompasses the beaded filament structural protein 1 (BFSP1) gene. Direct sequencing revealed a 3343 bp deletion including exon 6 (c.736-1384_c.957-66 del) predicted to result in a shift of the open reading frame. This mutation was absent in 50 control individuals from south India. This is the first report of a mutation in the BFSP1 gene associated with human inherited cataracts. This further increases the genetic heterogeneity of inherited cataracts and provides clues as to the importance of BFSP1 in the cell biology of intermediate filaments and their role in the eye lens.","variants":[{"Name":"NM_001195.5(BFSP1):c.736-1384_957-66del","Chromosome":"20","Start":"17497089","Stop":"17500424","ReferenceAlleleVCF":"TGTTGAGCAAAAATGAAAAAAAAGCTTTCTCTAGACCAAATTGCTCACGAATTAGATATCATTTTAAACAGACAGCCATACACACATTTACATACTGGATGAGGACATAAAGGAAGTGATCATTTCTTTGAGCTCAAGAGTCATAAACTGTGAAACATACCTATAAAAAATTGTAAAGTGGGGATTGCTTATAACCTAAAAATGCCACTTCTCCATGAGACAGTGCCTTTTTTATTTTTTTGCCTTTTGTTTTTTTGCCTTTTTGATTTTTTTAGTTAGAGTAGTCAACCCAGGCTGAAGTATTTAGGGCAAACAGAGTATGATATCTCCAACTTAAGATATATGTATATATACGTGTATGTATATATATATACACACACACACGTATATATACGTGTGTATATATATATACACGTATATATACGTATATATATACACACACGTATGTATATATGTGTGTATATATGTATATGTGTGTGTATATGTATATATACGTATATATATACGTGTATATATATACGTATATATACATATACACACACATATATACATATATACATATATCTACTCATATATACGTATATACATATATACATATACATGTACACACACACATCATATATAAATAGAGAAAAAATGATAAAGCAATTGAGATAAAATATAAACAACTGGTGAATCTGGAGTATTCAGGAGTTCCTTGTTCTATTCTTGCAACATTTCTATCAATTTAAAATTAGACCAAAATCAGAACTTATAGATAAATAAAAGAGGTATCCAGTCACCTTTCTGTGAAGCCCTGTCCCAAAACAAAAATGTTTACAAAGTCACCGAAATGCCAGCTCCAGACTTATTCTTGCAGATGTGTGCATAGTGTTCACTGTGACATAAATATAATGTGGAATCATGCCAGATACACCGACCAGCACTGGAGAAAGAAAAATAAAATCCTGCTTCTCCTGCCAAGCATTCGAGTGCTCACAGCCAAGAGAGAGCACCCAGCGCGAAGGGAAGAGCTGCTCCTGGTGGGGACCTCAGTTGTGGGGGGCTTCTCTTTTCATTCAGTCGAAACCCAGGAATTTAGCAAGACTGAAGTGAAGAATCACAAATTAATTCCCAACCCGTTCTCTGGAAATCACCGTAGCTATGAATACCAGCATAGCTGGAGAGAAAGAGAGAATTTCCCAGCTTTCTTAAAGTGAGTAGGGATCGACTCACAGCTCCATTATGGAGAAGACCAGACAGCCACATAGTCACAGCCACAGACTGACTCAGCAAGGTGCTAAGAATTGTGAGGATGGCAGCAGGAGCATCACCAACACCTCTGAGTGCCCTCAAGTGCCAGGCTCCGTGCCACGTAGCTCACCTGCAGCACCTCATTAAATACTCCTGGGCATCCCACCTGCTGGGACACTTATGTCCCCAGAGGCCTATGAGCAAAACACAGGCTTCTCAGTGAGGCCTTTTCTGACCACCCTACTTAAAACTGCAAGCATTCCCCCATCACCCCTATTGCCACCACCCTCCTCCCTGCGGGAACTTCCTCCTCAGCACTGGTCGTACCTTCATCCTCTGTCTCCCCTACTAGTTATCCAACACCCATGGGGTCAGGAATTGTTCTGTTTCCTTCCCTGACACATGCCCACTGCCTATAACTGTGCCTGGCACACAATAGGCACTCAATAAAGAGTTGTGGAAGGAATAAGTGGCCTGGATGGGGAGGGCACACGCTCACCTGTTGCCTTCAATCTCGATGATACGATGATACCGGTCCAGCTCATTCTTCAGGGTTTGCTGGGCGACCGCCAGCTGCCGGCAGTCGTAAGAAGACTTCTCCAGGACCCGCTCTGTCTCCTCAATCTCCTTGCGCAGTGTCTCAATCTGCTCGTTATAAAGCTGAATCTCATCGTCATAACACTCATGGGCACTTTTAATAGCTTGTTCCAGAGTTGTTGTCTGTGGGCAAGGACACGCTGTAAGAAAATCCATCCCCCTTCTTCTCTAAGAGACAGACCTCACCAGGAAAAGGAACCTGGACTCGGTGAATGTTTTATGTTGTTTGTGTGTTTCTCTGTCCATTCGAGATTAGCAATGAATCACTTTGGAATCCTTAAGCTAAAAAGCAATGTGAAAACTGAGCTCCTGTGTCCTTACACAATTTTTTTTTTTTTTTTTTTTGATAGAGGATCTCACTTTGTCACCAGGCTGGAATGCAGGAGTGCAATCTCGGCTCACTGCATCCTCGACCTCCCAGGCTAAAGGCTTCCACCTCAGCCTCCTGAGTAGCTGTGACTACAGGCAAGCACCAACATGCTGGGCTTTTTTTTTTTTTTTTTTTTTTTGGTAGTGATAGGGTCCCACTTCGTTGCCCAGGCTGGTTTCAAACTCCTGGCTTCAAGTGATCCTCCCACCTCAGCCTCCCAAAGTGCTGGAATTACAGGTGCGAGTCACCGCACCCAGCCCTTCTTGCACTAATATCAGCACCCTCTGCAATTAGTCCATAAGGAGGCCCACCCCAAAGGCAGTCTGAAGACAAACCTAGAAAATAAAACGAAACCTAGGCCAGGTGGCTCACACTTGTAATCCCAGAACTTTGGGAGGCCGAGGCTAGCAGATCACTTGAGGTCAGGAGTTTGAGACCAGCCTGGCCAACATAGTGAAACCCCATCTCTACTAAAAATACAAAAATTAGCTGGGAGTGGTGGCACACGCCATAATCCCAGATACTTGGGAGGCTGAGGCAGGAGAATCACTTGAACCTGGGAGGCAGAGGCTGCAGTGAGCCAAGACCACACCATTGCACTCCAGCCTGGGCAACAGAGCAAGACTCTGTCTAAAAGAAAAAGAAAAAAAACTTGCTATCGGTGGAATAATATGTATAATTCAAATAAAGTACATTCTTCAGACTTTAATGAACAAGCATAAATCTGATAGCAAAAAAATAAGTAAAAAGAAGCACATACTAAATAGATAAGATGCTACCTTTATTGAAATACTGAGTGGGAGAAAAGTTTCCTTGTTCTCATTCAGCTTTGATTTTCTCCCGAGTTTGGATCGGCAGAGTTACATTTATGTTTTGGTAGCTAAGGTGTATGTGTGTGCCCTTGTGTACACATAAAATAATGTCAGAGAAATACAGTACATTAATCAGAGCAAGTAAAAATTAAGGGAGGAAAACAGAAAGAGATAGTTTTATATTCAGTGTAAGAGGTTGTGATGATACACAAAGACCCACAAATGCTCAGTCATGGGCCACATAACAGTACTGCAGTCAACAATGGACTGCATATAGGATGGTGGTCCCATAAGAGTACAATGGAGCTGGACAATTCCTGTCGCC","AlternateAlleleVCF":"T","allel_id":21536,"rule_based_match":false,"evidence_text":"c.736-1384_c.957-66 del","llm_judgment":"PRESENT","evidence":"c.736-1384_c.957-66 del","abstract_start":464,"abstract_end":487}]}
{"pmid":"36479285","title":"Case report: Acrodermatitis enteropathica result from a novel","abstract":"The clinical data and gene sequencing results in a child with acrodermatitis enteropathica were retrospectively reported, and the related literature was reviewed. A girl aged 9 years and 4 months presented with a repeated skin rash, mainly distributed in the perioral, anogenital, and acral areas, accompanied with alopecia, and a low blood zinc level was found many times. A significant improvement was seen after continuous zinc supplementation. The genetic sequencing test demonstrated that the patient had compound heterozygous for two <i>SLC39A4</i> mutations: c.1466dupT (p.S490Efs*155) and c.295G > A (p.A99T), and her parents were heterozygous carriers of these two mutations. An improvement was achieved after continuous zinc supplementation. This case report might guide further research on this aspect.","variants":[{"Name":"NM_130849.4(SLC39A4):c.295G>A (p.Ala99Thr)","Chromosome":"8","Start":"144415989","Stop":"144415989","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":796143,"rule_based_match":true,"evidence_text":"c.295G > A (p.A99T)","llm_judgment":"PRESENT","evidence":"c.295G > A (p.A99T)","abstract_start":597,"abstract_end":616}]}
{"pmid":"28973667","title":"A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility.","abstract":"Intellectual Disability is a common and heterogeneous disorder characterized by limitations in intellectual functioning and adaptive behaviour, whose molecular mechanisms remain largely unknown. Among the numerous genes found to be involved in the pathogenesis of intellectual disability, 10% are located on the X-chromosome. We identified a missense mutation (c.236 C > G; p.S79W) in the SYN1 gene coding for synapsin I in the MRX50 family, affected by non-syndromic X-linked intellectual disability. Synapsin I is a neuronal phosphoprotein involved in the regulation of neurotransmitter release and neuronal development. Several mutations in SYN1 have been identified in patients affected by epilepsy and/or autism. The S79W mutation segregates with the disease in the MRX50 family and all affected members display intellectual disability as sole clinical manifestation. At the protein level, the S79W Synapsin I mutation is located in the region of the B-domain involved in recognition of highly curved membranes. Expression of human S79W Synapsin I in Syn1 knockout hippocampal neurons causes aberrant accumulation of small clear vesicles in the soma, increased clustering of synaptic vesicles at presynaptic terminals and increased frequency of excitatory spontaneous release events. In addition, the presence of S79W Synapsin I strongly reduces the mobility of synaptic vesicles, with possible implications for the regulation of neurotransmitter release and synaptic plasticity. These results implicate SYN1 in the pathogenesis of non-syndromic intellectual disability, showing that alterations of synaptic vesicle trafficking are one possible cause of this disease, and suggest that distinct mutations in SYN1 may lead to distinct brain pathologies.","variants":[{"Name":"NM_006950.3(SYN1):c.236C>G (p.Ser79Trp)","Chromosome":"X","Start":"47619493","Stop":"47619493","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":984730,"rule_based_match":true,"evidence_text":"c.236 C > G; p.S79W","llm_judgment":"PRESENT","evidence":"c.236 C > G; p.S79W","abstract_start":361,"abstract_end":380}]}
{"pmid":"32205117","title":"Biallelic mutations in DCDC2 cause neonatal sclerosing cholangitis in a Chinese family.","abstract":"BACKGROUND: Neonatal sclerosing cholangitis (NSC) is a severe cholestatic liver disease, which often develops into end-stage liver disease in childhood and requires liver transplantation. Mutations in CLDN1 and DCDC2 are confirmed to be the main pathogenic mechanism of NSC.\nMETHODS: Whole exon sequencing (WES) was performed to find the possible disease-causing mutations of this family. The mutation was confirmed by Sanger sequencing, and large fragment copy number variation was confirmed by qPCR.\nRESULTS: We found novel biallelic mutations c.[705-2A>G];[923_1023del] in the DCDC2 gene of the proband. The proband's father had the heterozygous mutation c.705-2A>G, and his mother had a heterozygous c.923_1023del. The proband's younger brother, who had similar clinical manifestations, was found the same biallelic mutations with the proband.\nCONCLUSION: Novel biallelic mutations were identified in DCDC2 of this Chinese family, according to the American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants, both mutations were classified as pathogenic, which might be the cause of NSC in this family.","variants":[{"Name":"NM_016356.5(DCDC2):c.705-2A>G","Chromosome":"6","Start":"24288908","Stop":"24288908","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":2797557,"rule_based_match":true,"evidence_text":"c.705-2A>G","llm_judgment":"PRESENT","evidence":"c.705-2A>G","abstract_start":658,"abstract_end":668}]}
{"pmid":"22339077","title":"Rapid detection of G1138A and G1138C mutations of the FGFR3 gene in patients with achondroplasia using high-resolution melting analysis.","abstract":"Achondroplasia (ACH) is a genetic disorder with autosomal dominant inheritance and is the cause of one of the most common forms of short limb dwarfism in humans. Mutations of special sites in the fibroblast growth factor receptor-3 gene (FGFR3) are reported as a cause of ACH, and almost 98% of cases are caused by mutations in nucleotide 1138 (Gly380Arg), with 97% involving a c.1138G>A mutation and 1% involving a c.1138G>C mutation. Therefore, the development of a simple, reliable, and rapid approach for molecular detection of nucleotide 1138 mutations is of great significance for prevention and early diagnosis of ACH. High-resolution melting (HRM) is a new, rapid, and inexpensive molecular detection method that has been generally applied to mutation scanning. In this study, 12 cases of ACH, including 10 sporadic cases and 2 cases in a pedigree, were detected simultaneously using HRM analysis and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Eleven cases were identified as carrying the c.1138 G>A heterozygous mutation, and one case was identified as carrying the c.1138 G>C heterozygous mutation. Compared with RFLP-PCR, HRM analysis provided a more rapid, simpler, and less expensive approach for detecting the most common FGFR3 mutations carried by patients with ACH.","variants":[{"Name":"NM_000142.5(FGFR3):c.1138G>C (p.Gly380Arg)","Chromosome":"4","Start":"1804392","Stop":"1804392","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":31367,"rule_based_match":true,"evidence_text":"c.1138 G>C","llm_judgment":"PRESENT","evidence":"c.1138 G>C","abstract_start":1111,"abstract_end":1121}]}
{"pmid":"32381729","title":"Autosomal dominant polycystic kidney disease in absence of renal cyst formation illustrates genetic interaction between","abstract":"PURPOSE: Autosomal dominant polycystic kidney disease (ADPKD), caused by pathogenic variants of either <i>PKD1</i> or <i>PKD2</i>, is characterised by wide interfamilial and intrafamilial phenotypic variability. This study aimed to determine the molecular basis of marked clinical variability in ADPKD family members and sought to analyse whether alterations of <i>WT1</i> (Wilms tumour 1), encoding a regulator of gene expression, may have an impact on renal cyst formation.\nMETHODS: ADPKD family members underwent clinical and molecular evaluation. Functionally, <i>Pkd1</i> mRNA and protein expression upon <i>Wt1</i> knockdown was evaluated in mouse embryonic kidneys and mesonephric M15 cells.\nRESULTS: By renal gene panel analysis, we identified two pathogenic variants in an individual with maternal history of ADPKD, however, without cystic kidneys but polycystic liver disease: a known <i>PKD1</i> missense variant (c.8311G>A, p.Glu2771Lys) and a known de novo <i>WT1</i> splice site variant (c.1432+4C>T). The latter was previously associated with imbalanced +/-KTS isoform ratio of <i>WT1</i>. In ex vivo organ cultures from mouse embryonic kidneys, <i>Wt1</i> knockdown resulted in decreased <i>Pkd1</i> expression on mRNA and protein level.\nCONCLUSION: While the role of WT1 in glomerulopathies has been well established, this report by illustrating genetic interaction with <i>PKD1</i> proposes <i>WT1</i> as potential modifier in ADPKD.","variants":[{"Name":"NM_001009944.3(PKD1):c.8311G>A (p.Glu2771Lys)","Chromosome":"16","Start":"2103746","Stop":"2103746","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":360989,"rule_based_match":true,"evidence_text":"c.8311G>A, p.Glu2771Lys","llm_judgment":"PRESENT","evidence":"c.8311G>A, p.Glu2771Lys","abstract_start":925,"abstract_end":948}]}
{"pmid":"33138793","title":"Mutation screening of germline TP53 mutations in high-risk Chinese breast cancer patients.","abstract":"BACKGROUND: Germline TP53 mutations are associated with Li-Fraumeni syndrome, a severe and rare hereditary cancer syndrome. Despite the rarity of germline TP53 mutations, the clinical implication for mutation carriers and their families is significant. The risk management of TP53 germline mutation carriers is more stringent than BRCA carriers, and radiotherapy should be avoided when possible.\nMETHODS: TP53 gene mutation screening was performed in 2538 Chinese breast cancer patients who tested negative for BRCA mutations.\nRESULTS: Twenty TP53 mutations were identified with high next-generation sequencing concerning for germline mutations in Chinese breast cancer families. The majorities of the TP53 carriers had early-onset, hormone receptor-positive breast cancer, and had strong family history of cancer. Among all, 11 patients carried a germline mutation and 6 of which were likely de novo germline mutations. In addition, 1 case was suspected to be induced by chemotherapy or radiation, as this patient had no significant family history of cancer and aberrant clonal expansion can commonly include TP53 mutations. Furthermore, we have identified one mosaic LFS case. Two novel mutations (c.524_547dup and c.529_546del) were identified in patients with early-onset.\nCONCLUSIONS: In view of the high lifetime risk of malignancy, identification of patients with germline TP53 mutations are important for clinicians to aid in accurate risk assessment and offer surveillance for patients and their families.","variants":[{"Name":"NM_000546.6(TP53):c.529_546del (p.Pro177_Cys182del)","Chromosome":"17","Start":"7675066","Stop":"7675083","ReferenceAlleleVCF":"AGCAGCGCTCATGGTGGGG","AlternateAlleleVCF":"A","allel_id":846278,"rule_based_match":true,"evidence_text":"c.529_546del","llm_judgment":"PRESENT","evidence":"c.529_546del","abstract_start":1217,"abstract_end":1229}]}
{"pmid":"34234782","title":"Case Report:","abstract":"<i>Talaromyces marneffei</i> (TM) infection is rarely seen in clinical practice, and its pathogenesis may be related to deficiency in antifungal immune function. Human caspase recruitment domain-containing protein 9 (CARD9) is a key molecule in fungal immune surveillance. There have been no previous case reports of TM infection in individuals with <i>CARD9</i> gene mutations. Herein, we report the case of a 7-month-old Chinese boy who was admitted to our hospital with recurring cough and fever with a papular rash. A blood culture produced TM growth, which was confirmed by metagenomic next-generation sequencing. One of the patient's sisters had died of TM septicaemia at 9 months of age. Whole exome sequencing revealed that the patient had a complex heterozygous <i>CARD9</i> gene mutation with a c.1118G>C p.R373P variation in exon 8 and a c.610C>T p.R204C variation in exon 4. Based on the culture results, voriconazole antifungal therapy was administered. On the third day of antifungal administration, his temperature dropped to within normal range, the rash gradually subsided, and the enlargement of his lymph nodes, liver, and spleen improved. Two months after discharge, he returned to the hospital for a follow-up examination. His general condition was good, and no specific abnormalities were detected. Oral voriconazole treatment was continued. Unexplained TM infection in HIV-negative individuals warrants investigation for immune deficiencies.","variants":[{"Name":"NM_052813.5(CARD9):c.1118G>C (p.Arg373Pro)","Chromosome":"9","Start":"136367788","Stop":"136367788","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":94420,"rule_based_match":true,"evidence_text":"c.1118G>C p.R373P","llm_judgment":"PRESENT","evidence":"c.1118G>C p.R373P","abstract_start":805,"abstract_end":822},{"Name":"NM_052813.5(CARD9):c.610C>T (p.Arg204Cys)","Chromosome":"9","Start":"136370858","Stop":"136370858","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1344597,"rule_based_match":true,"evidence_text":"c.610C>T p.R204C variation","llm_judgment":"PRESENT","evidence":"c.610C>T p.R204C variation","abstract_start":849,"abstract_end":875}]}
{"pmid":"30348537","title":"DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.","abstract":"BACKGROUND: Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care.\nMETHODS: In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete.\nFINDINGS: Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63-2·73) for genotype-guided dosing compared with 2·87 (2·14-3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10-8·80) in c.1679T>G carriers, 2·00 (1·19-3·34) compared with 3·11 (2·25-4·28) for c.2846A>T carriers, and 1·69 (1·18-2·42) compared with 1·72 (1·22-2·42) for c.1236G>A carriers.\nINTERPRETATION: Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care.\nFUNDING: Dutch Cancer Society.","variants":[{"Name":"NM_000110.4(DPYD):c.1679T>G (p.Ile560Ser)","Chromosome":"1","Start":"97515787","Stop":"97515787","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":94530,"rule_based_match":true,"evidence_text":"c.1679T>G","llm_judgment":"PRESENT","evidence":"c.1679T>G","abstract_start":439,"abstract_end":448},{"Name":"NM_000110.4(DPYD):c.1905+1G>A","Chromosome":"1","Start":"97450058","Stop":"97450058","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":15471,"rule_based_match":true,"evidence_text":"c.1905+1G>A","llm_judgment":"PRESENT","evidence":"c.1905+1G>A","abstract_start":382,"abstract_end":393}]}
{"pmid":"27900367","title":"Whole-genome sequencing of two probands with hereditary spastic paraplegia reveals novel splice-donor region variant and known pathogenic variant in","abstract":"Hereditary spastic paraplegias (HSPs) are a group of heterogeneous neurodegenerative disorders, which are often presented with overlapping phenotypes such as progressive paraparesis and spasticity. To assist the diagnosis of HSP subtypes, next-generation sequencing is often used to provide supporting evidence. In this study, we report the case of two probands from the same family with HSP symptoms, including bilateral lower limb weakness, unsteady gait, cognitive decline, dysarthria, and slurring of speech since the age of 14. Subsequent whole-genome sequencing revealed that the patients are compound heterozygous for variants in the <i>SPG11</i> gene, including the paternally inherited c.6856C>T (p.Arg2286*) variant and the novel maternally inherited c.2316+5G>A splice-donor region variant. Variants in <i>SPG11</i> are the common cause of autosomal recessive spastic paraplegia type 11. According to the ClinVar database, there are already 101 reported pathogenic variants in <i>SPG11</i> that are associated with HSPs. To our knowledge, this is the first report of <i>SPG11</i> variants in our local population. The novel splice variant identified in this study enriches the catalog of <i>SPG11</i> variants, potentially leading to better genetic diagnosis of HSPs.","variants":[{"Name":"NM_025137.4(SPG11):c.6856C>T (p.Arg2286Ter)","Chromosome":"15","Start":"44565997","Stop":"44565997","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":49777,"rule_based_match":true,"evidence_text":"c.6856C>T (p.Arg2286*)","llm_judgment":"PRESENT","evidence":"c.6856C>T (p.Arg2286*)","abstract_start":695,"abstract_end":717},{"Name":"NM_025137.4(SPG11):c.2316+5G>A","Chromosome":"15","Start":"44622723","Stop":"44622723","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":247360,"rule_based_match":true,"evidence_text":"c.2316+5G>A splice-donor region variant","llm_judgment":"PRESENT","evidence":"c.2316+5G>A splice-donor region variant","abstract_start":761,"abstract_end":800}]}
{"pmid":"27431810","title":"Case report of a 45-year old female Fabry disease patient carrying two alpha-galactosidase A gene mutation alleles.","abstract":"BACKGROUND: X-chromosomal inheritance patterns and generally rare occurrence of Fabry disease (FD) account for mono-mutational hemizygous male and heterozygous female patients. Female mutation carriers are usually clinically much less severely affected, which has been explained by a suggested mosaicism in cell phenotype due to random allele shutdown. However, clinical evidence is scarce and potential additional effects in female gene carriers, which might account for specific clinical characteristics such as less severe chronic kidney disease, are yet unknown.\nCASE PRESENTATION: This article reports on a 45 year old female patient carrying the two alpha-galactosidase A gene mutations c.416A > G, p.N139S in exon 3 and c.708G > C, p.W236C in exon 5, but still showing only mild organ manifestations.\nCONCLUSION: This current case highlights the importance of careful clinical characterization in patients with Fabry disease, who may show additional rare constellations and, therefore, are in need of personalized medicine. The impact of potential additional protective effects exceeding the presence of a non-pathogenic GLA allele in female gene carriers requires further investigation.","variants":[{"Name":"NM_000169.3(GLA):c.416A>G (p.Asn139Ser)","Chromosome":"X","Start":"101401763","Stop":"101401763","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":224055,"rule_based_match":true,"evidence_text":"c.416A > G, p.N139S","llm_judgment":"PRESENT","evidence":"c.416A > G, p.N139S","abstract_start":693,"abstract_end":712}]}
{"pmid":"29130651","title":"Further delineation of the GDF6 related multiple synostoses syndrome.","abstract":"A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome.","variants":[{"Name":"NM_001001557.4(GDF6):c.1287C>A (p.Ser429Arg)","Chromosome":"8","Start":"96144644","Stop":"96144644","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":486669,"rule_based_match":true,"evidence_text":"c.1287C>A/p.Ser429Arg","llm_judgment":"PRESENT","evidence":"c.1287C>A/p.Ser429Arg","abstract_start":202,"abstract_end":223}]}
{"pmid":"32537548","title":"Familial Hypocalciuric Hypercalcemia in Pregnancy: Diagnostic Pitfalls.","abstract":"Familial hypocalciuric hypercalcemia (FHH) is a group of autosomal dominant disorders caused by dysfunction of the calcium sensing receptor (CaSR) and its downstream signaling proteins, leading to generally asymptomatic hypercalcemia. During pregnancy, distinguishing FHH from primary hyperparathyroidism (PHPT) is important, as the latter is associated with adverse outcomes and can be treated surgically during pregnancy, whereas the former is benign. This case report highlights the difficulties in diagnosing FHH during pregnancy. A 32-year-old woman was found to have asymptomatic hypercalcemia at 14-weeks' gestation. Investigations showed a corrected calcium (cCa) of 2.61 mmol/L (2.10 to 2.60), ionized Ca (iCa) of 1.40 mmol/L (1.15 to 1.28), 25OHD of 33 nmol/L (75 to 250), and PTH of 9.5 pmol/L (1.5 to 7.0). The patient was treated with 2000 IU cholecalciferol daily with normalization of 25OHD. The urine calcium / creatinine clearance ratio (CCCR) was 0.0071, and neck US did not visualize a parathyroid adenoma. Upon a retrospective review of the patient's biochemistry from 2 years prior, hypercalcemia was found that was not investigated. The patient was monitored with serial iCa levels and obstetric US. She delivered a healthy boy at 38-weeks' gestation. Postnatal iCa was 1.48 mmol/L and remained elevated. Her son had elevated iCa at birth of 1.46 mmol/L (1.15 to 1.33), which rose to 1.81 mmol/L by 2 weeks. He was otherwise well. Given the familial hypercalcemia, a likely diagnosis of FHH was made. Genetic testing of the son revealed a missense mutation, NM_000388.3(CASR):c.2446A > G, in exon 7 of the CaSR, consistent with FHH type 1. To our knowledge, there are only three existing reports of FHH in pregnancy. When differentiating between FHH and PHPT in pregnancy, interpretation of biochemistry requires an understanding of changes in Ca physiology, and urine CCCR may be unreliable. If the decision is made to observe, clinical symptoms, calcium levels, and fetal US should be monitored, with biochemistry and urine CCCR performed postpartum, once lactation is completed © 2020 The Authors. <i>JBMR Plus</i> published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.","variants":[{"Name":"NM_000388.4(CASR):c.2446A>G (p.Ile816Val)","Chromosome":"3","Start":"122284400","Stop":"122284400","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1416812,"rule_based_match":true,"evidence_text":"NM_000388.3(CASR):c.2446A > G","llm_judgment":"PRESENT","evidence":"NM_000388.3(CASR):c.2446A > G","abstract_start":1580,"abstract_end":1609}]}
{"pmid":"24246249","title":"A compound heterozygous mutation in SLC34A3 causes hereditary hypophosphatemic rickets with hypercalciuria in a Chinese patient.","abstract":"Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder inherited in an autosomal recessive fashion and characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. HHRH was recently mapped to chromosome 9q34, which contains the gene SLC34A3 which encodes the renal proximal tubular sodium-phosphate cotransporter NaPi-IIc. Here we describe a 29-year-old man with a history of childhood rickets who presented with increased renal phosphate clearance leading to hypophosphatemia, hypercalciuria, low serum parathyroid hormone (PTH), elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and recurrent nephrolithiasis. We performed a mutation analysis of SLC34A3 (exons and adjacent introns) of the proband and his parents to determine if there was a genetic contribution. The proband proved to be compound heterozygous for two missense mutations in SLC34A3: one novel mutation in exon 7 c.571G>C (p.G191R) and one previously identified mutation in exon 13 c.1402C>T (p.R468W). His parents were both asymptomatic heterozygous carriers of one of these two mutations. We also performed an oral phosphate loading test and compared serum phosphate, intact PTH, and intact fibroblast growth factor 23 (iFGF23) in this patient versus patients with other forms of hypophosphatemic rickets, the results of which further revealed that the mechanism of hypophosphatemia in HHRH is independent of FGF23. This is the first report of HHRH in the Chinese population. Our findings of the novel mutation in exon 7 add to the list of more than 20 reported mutations of SLC34A3.","variants":[{"Name":"NM_001177316.2(SLC34A3):c.1402C>T (p.Arg468Trp)","Chromosome":"9","Start":"137236018","Stop":"137236018","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":16471,"rule_based_match":true,"evidence_text":"c.1402C>T (p.R468W)","llm_judgment":"PRESENT","evidence":"c.1402C>T (p.R468W)","abstract_start":1048,"abstract_end":1067}]}
{"pmid":"33784018","title":"Deciphering DSC2 arrhythmogenic cardiomyopathy electrical instability: From ion channels to ECG and tailored drug therapy.","abstract":"BACKGROUND: Severe ventricular rhythm disturbances are the hallmark of arrhythmogenic cardiomyopathy (ACM), and are often explained by structural conduction abnormalities. However, comprehensive investigations of ACM cell electrical instability are lacking. This study aimed to elucidate early electrical myogenic signature of ACM.\nMETHODS: We investigated a 41-year-old ACM patient with a missense mutation (c.394C>T) in the DSC2 gene, which encodes desmocollin 2. Pathogenicity of this variant was confirmed using a zebrafish DSC2 model system. Control and DSC2 patient-derived pluripotent stem cells were reprogrammed and differentiated into cardiomyocytes (hiPSC-CM) to examine the specific electromechanical phenotype and its modulation by antiarrhythmic drugs (AADs). Samples of the patient's heart and hiPSC-CM were examined to identify molecular and cellular alterations.\nRESULTS: A shortened action potential duration was associated with reduced Ca<sup>2+</sup> current density and increased K<sup>+</sup> current density. This finding led to the elucidation of previously unknown abnormal repolarization dynamics in ACM patients. Moreover, the Ca<sup>2+</sup> mobilised during transients was decreased, and the Ca<sup>2+</sup> sparks frequency was increased. AAD testing revealed the following: (1) flecainide normalised Ca<sup>2+</sup> transients and significantly decreased Ca<sup>2+</sup> spark occurrence and (2) sotalol significantly lengthened the action potential and normalised the cells' contractile properties.\nCONCLUSIONS: Thorough analysis of hiPSC-CM derived from the DSC2 patient revealed abnormal repolarization dynamics, prompting the discovery of a short QT interval in some ACM patients. Overall, these results confirm a myogenic origin of ACM electrical instability and provide a rationale for prescribing class 1 and 3 AADs in ACM patients with increased ventricular repolarization reserve.","variants":[{"Name":"NM_024422.6(DSC2):c.394C>T (p.Arg132Cys)","Chromosome":"18","Start":"31091108","Stop":"31091108","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":176520,"rule_based_match":true,"evidence_text":"c.394C>T","llm_judgment":"PRESENT","evidence":"c.394C>T","abstract_start":409,"abstract_end":417}]}
{"pmid":"33122583","title":"Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS.","abstract":"OBJECTIVE: Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematologic malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric (PC) localization of a variant of IKZF discovered in a patient.\nMATERIALS AND METHODS: DNA-binding ability of a pathogenic IKZF variant was tested using electrophoretic mobility shift assay and PC localization of the variant was assessed by immunofluorescent microscopy in NIH3T3 cells.\nRESULTS: Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described. DNA studies revealed a heterozygous missense variant (IKZF1 NM_006060 c.427C>T; p.R143W). Cotransfection studies revealed that mutant R143W has a partial dominant-negative effect over PC targeting and DNA binding.\nCONCLUSIONS: IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed.","variants":[{"Name":"NM_006060.6(IKZF1):c.427C>T (p.Arg143Trp)","Chromosome":"7","Start":"50382545","Stop":"50382545","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3062522,"rule_based_match":true,"evidence_text":"IKZF1 NM_006060 c.427C>T; p.R143W","llm_judgment":"PRESENT","evidence":"IKZF1 NM_006060 c.427C>T; p.R143W","abstract_start":1010,"abstract_end":1043}]}
{"pmid":"18273900","title":"Usher syndrome type 1 due to missense mutations on both CDH23 alleles: investigation of mRNA splicing.","abstract":"Usher syndrome (USH) is an autosomal recessive condition characterized by sensorineural hearing loss, vestibular dysfunction, and visual impairment due to retinitis pigmentosa. Truncating mutations in the cadherin-23 gene (CDH23) result in Usher syndrome type 1D (USH1D), whereas missense mutations affecting strongly conserved motifs of the CDH23 protein cause non-syndromic deafness (DFNB12). Four missense mutations constitute an exception from this genotype-phenotype correlation: they have been described in USH1 patients in homozygous state. Using a minigene assay, we have investigated these changes (c.1450G>C, p.A484P; c.3625A>G, p.T1209A; c.4520G>A, p.R1507Q; and c.5237G>A, p.R1746Q) for a possible impact on mRNA splicing which could explain the syndromic phenotype. While in silico analysis suggested impairment of splicing in all four cases, we found aberrant splicing for only one mutation, p.R1746Q. However, splicing was normal in case of p.A484P, p.T1209A and p.R1507Q. These three latter CDH23 missense mutations could interfere with functions of both, the auditory and the visual system. Alternatively, they could represent rare non-pathogenic polymorphisms.","variants":[{"Name":"NM_022124.6(CDH23):c.4520G>A (p.Arg1507Gln)","Chromosome":"10","Start":"71740853","Stop":"71740853","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":866134,"rule_based_match":true,"evidence_text":"c.4520G>A, p.R1507Q","llm_judgment":"PRESENT","evidence":"c.4520G>A, p.R1507Q","abstract_start":649,"abstract_end":668},{"Name":"NM_022124.6(CDH23):c.5237G>A (p.Arg1746Gln)","Chromosome":"10","Start":"71779316","Stop":"71779316","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":19955,"rule_based_match":true,"evidence_text":"c.5237G>A, p.R1746Q","llm_judgment":"PRESENT","evidence":"c.5237G>A, p.R1746Q","abstract_start":674,"abstract_end":693},{"Name":"NM_022124.6(CDH23):c.3625A>G (p.Thr1209Ala)","Chromosome":"10","Start":"71730514","Stop":"71730514","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19966,"rule_based_match":true,"evidence_text":"c.3625A>G, p.T1209A","llm_judgment":"PRESENT","evidence":"c.3625A>G, p.T1209A","abstract_start":628,"abstract_end":647}]}
{"pmid":"35165004","title":"TNNT1 myopathy with novel compound heterozygous mutations.","abstract":"Nemaline myopathies are clinically and genetically heterogeneous disorders caused by several different genes. One of them is TNNT1, which was initially described in Amish families and has not been reported in Asian populations. Although most TNNT1 myopathies are caused by loss-of-function mutations, several recent studies have shown that missense mutations can also be pathogenic. A 16-year-old Korean boy with progressive muscle weakness visited the Seoul National University Hospital. He showed generalized myopathy, which was predominant in the paraspinal and neck muscles. Moreover, nemaline rods were observed in a muscle biopsy. Whole-exome sequencing of DNA samples of the patient and his younger brother, who had a similar phenotype, revealed novel compound heterozygous mutations in TNNT1 (c.724G>C (p.Ala242Pro) and c.611+1G>A). Sanger sequencing of cDNA extracted from muscle samples of the patient confirmed partial or total skipping of exon 11 in the splicing variant. The impact of the missense variant on muscle integrity and locomotor activity was verified using a zebrafish loss-of-function model. Here, we reported novel familial cases of TNNT1 myopathy with intermediate clinical presentations caused by compound heterozygous mutations and demonstrated their functional defects using an animal model.","variants":[{"Name":"NM_003283.6(TNNT1):c.611+1G>A","Chromosome":"19","Start":"55137102","Stop":"55137102","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2668683,"rule_based_match":true,"evidence_text":"c.611+1G>A","llm_judgment":"PRESENT","evidence":"c.611+1G>A","abstract_start":828,"abstract_end":838},{"Name":"NM_003283.6(TNNT1):c.724G>C (p.Ala242Pro)","Chromosome":"19","Start":"55134092","Stop":"55134092","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2668685,"rule_based_match":true,"evidence_text":"c.724G>C (p.Ala242Pro)","llm_judgment":"PRESENT","evidence":"c.724G>C (p.Ala242Pro)","abstract_start":801,"abstract_end":823}]}
{"pmid":"23090344","title":"Carnitine palmitoyltransferase I and sudden unexpected infant death in British Columbia First Nations.","abstract":"OBJECTIVE: Infant mortality in British Columbia (BC) First Nations remains elevated relative to other residents. The p.P479L (c.1436C>T) variant of carnitine palmitoyltransferase 1 (CPT1A) is frequent in some aboriginal populations and may be associated with increased infant deaths. This work was initiated to determine the performance of acylcarnitine profiling for detecting this variant, to determine its frequency in BC, and to determine if it is associated with sudden infant deaths in this population.\nMETHODS: Newborn screening cards from all BC First Nations infants in 2004 and all sudden unexpected deaths in BC First Nations infants (1999-2009) were genotyped for the CPT1A p.P479L variant and linked to archival acylcarnitine data.\nRESULTS: The CPT1A p.P479L variant is frequent in BC First Nations but is not evenly distributed, with higher rates in coastal regions (up to 25% homozygosity) with historically increased infant mortality. There is also an overrepresentation of p.P479L homozygotes in unexpected infant deaths from these regions, with an odds ratio of 3.92 (95% confidence interval: 1.69-9.00). Acylcarnitine profiling will identify p.P479L homozygotes with a 94% sensitivity and specificity.\nCONCLUSIONS: The CPT1A p.P479L variant is common to some coastal BC First Nations, and homozygosity for this variant is associated with unexpected death in infancy. The high frequency of this variant in a wide range of coastal aboriginal communities, however, suggests a selective advantage, raising the possibility that this variant may have differing impacts on health depending on the environmental or developmental context.","variants":[{"Name":"NM_001876.4(CPT1A):c.1436C>T (p.Pro479Leu)","Chromosome":"11","Start":"68780662","Stop":"68780662","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":76552,"rule_based_match":true,"evidence_text":"c.1436C>T","llm_judgment":"PRESENT","evidence":"c.1436C>T","abstract_start":126,"abstract_end":135}]}
{"pmid":"37382551","title":"Spondyloenchondrodysplasia with immune dysregulation related to ACP5. A report of 4 cases.","abstract":"Spondyloenchondrodysplasia with immune dysregulation related to ACP5 (SPENCDI, OMIM number 607944) is an uncommon immune-skeletal dysplasia with heterogeneous manifestations and variable severity. It is characterized by spondylar and metaphyseal lesions, immune dysfunction, and neurological involvement. Here we report the clinical, radiological and genetic aspects of 4 girls with SPENCDI treated at a children's hospital. They all had skeletal manifestations and 3 developed severe immune disease. In 3 patients, the likely pathogenic variant c.791T>A; p.Met264Lys (homozygous mutation) was observed, while 1 patient had variants c.791T>A; p.Met264Lys and c.632T>C; p.lle211Thr (variant of uncertain significance with pathogenic prediction based on bioinformatics algorithms) caused by a compound heterozygous mutation in ACP5. The repeated presence of variant c.791T>A suggests the possibility of a common ancestor in our population. The recognition and diagnosis of this disorder is important to achieve a timely approach, which should be multidisciplinary and aimed at preventing possible complications.","variants":[{"Name":"NM_001611.5(ACP5):c.791T>A (p.Met264Lys)","Chromosome":"19","Start":"11575197","Stop":"11575197","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":38786,"rule_based_match":true,"evidence_text":"c.791T>A; p.Met264Lys","llm_judgment":"PRESENT","evidence":"c.791T>A; p.Met264Lys","abstract_start":546,"abstract_end":567}]}
{"pmid":"17185898","title":"Several mutations in the melanocortin 4 receptor gene are associated with obesity in Chinese children and adolescents.","abstract":"AIM: To screen mutations in the melanocortin 4 receptor (MC4R) in obese and normal-weight Chinese children and adolescents.\nMETHODS: Three hundred Chinese children and adolescents, including 200 obese and 100 healthy non-obese individuals, were evaluated. The coding region of the MC4R gene was amplified by polymerase chain reaction (PCR) and sequenced.\nRESULTS: In obese individuals, we detected two novel heterozygous non-synonymous mutations (c.496G>A, resulting in Val166Ile; c.929G>A, resulting in Arg310Lys) and a novel heterozygous non-sense mutation (c.831T>A, resulting in a premature stop codon Cys277Stop). In both obese individuals and controls, a novel heterozygous non-synonymous mutation (c.68T>G, resulting in Leu23Arg, 0.5 and 1%, respectively) and the Val103Ile polymorphism (c.307G>A, 3 and 2%, respectively) were found. There was no difference in alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), cholesterol (CHOL) and whole body insulin sensitivity index (WBISI) between obese individuals with and without mutation. The prevalence for heterozygous MC4R mutations was 1.5% in the obese.\nCONCLUSIONS: Two novel heterozygous non-synonymous mutations (Val166Ile; Arg310Lys) and a novel heterozygous non-sense mutation (Cys277Stop) were detected in Chinese obese individuals. Leu23Arg variant might be a polymorphism in the Chinese population. There were no differences between clinical and biochemical profiles in the heterozygous mutations and the wild type.","variants":[{"Name":"NM_005912.3(MC4R):c.929G>A (p.Arg310Lys)","Chromosome":"18","Start":"60371421","Stop":"60371421","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":879674,"rule_based_match":true,"evidence_text":"c.929G>A","llm_judgment":"PRESENT","evidence":"c.929G>A","abstract_start":481,"abstract_end":489},{"Name":"NM_005912.3(MC4R):c.307G>A (p.Val103Ile)","Chromosome":"18","Start":"60372043","Stop":"60372043","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":215037,"rule_based_match":true,"evidence_text":"c.307G>A","llm_judgment":"PRESENT","evidence":"c.307G>A","abstract_start":795,"abstract_end":803}]}
{"pmid":"24674142","title":"Clinical features and mutation of NPHP5 in two Chinese siblings with Senior-Løken syndrome.","abstract":"Senior-Løken syndrome is a rare syndromic form of nephronophthisis that is associated with retinal dystrophy. Presently, seven genes (NPHP1-6 and NPHP10) have been associated with Senior-Løken syndrome. NPHP5 mutations are known to cause classical Senior-Løken syndrome. Here, we report two sisters (II-4, II-5) from a Chinese Han ethnic family who presented with classical Senior-Løken syndrome. Both affected sisters exhibited Leber's congenital amaurosis and juvenile nephronophthisis that progressed to end-stage renal disease by the age of 16 years and 9 months in patient II-4 and 12 years and 9 months in patient II-5. Sequence analysis showed a homozygous truncated mutation in NPHP5, c.1090C>T (p.R364X), in the patient II-4. This mutation is predicted to introduce a new open reading frame that results in the truncation of the C-terminal 235 amino acids of nephrocystin-5 and its consequent loss of function. Both parents carried a single heterozygous mutation in the same position, and no homozygous deletion of NPHP1 was found in this pedigree.","variants":[{"Name":"NM_001023570.4(IQCB1):c.1090C>T (p.Arg364Ter)","Chromosome":"3","Start":"121790112","Stop":"121790112","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":177349,"rule_based_match":true,"evidence_text":"c.1090C>T (p.R364X)","llm_judgment":"PRESENT","evidence":"c.1090C>T (p.R364X)","abstract_start":693,"abstract_end":712}]}
{"pmid":"34229741","title":"Novel folliculin gene mutations in Polish patients with Birt-Hogg-Dubé syndrome.","abstract":"BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare, autosomal dominant, inherited disease caused by mutations in the folliculin gene (FLCN). The disease is characterised by skin lesions (fibrofolliculomas, trichodiscomas, acrochordons), pulmonary cysts with pneumothoraces and renal tumours. We present the features of Polish patients with BHDS.\nMATERIALS AND METHODS: The first case of BHDS in Poland was diagnosed in 2016. Since then, 15 cases from 10 families have been identified. Thirteen patients were confirmed via direct FLCN sequencing, and two according to their characteristic clinical and radiological presentations.\nRESULTS: BHDS was diagnosed in 15 cases (13 women and 2 men) from 10 families. The mean ages at the time of first pneumothorax and diagnosis were 38.4 ± 13.9 and 47.7 ± 13 years, respectively. Five patients (33%) were ex-smokers (2.1 ± 1.37 packyears), and 10 (67%) had never smoked cigarettes. Twelve patients (83%) had a history of recurrent symptomatic pneumothorax. Three patients had small, asymptomatic pneumothoraces, which were only detected upon computed tomography examination. All patients had multiple bilateral pulmonary cysts, distributed predominantly in the lower and middle, peripheral, and subpleural regions of the lungs. Generally, patients exhibited preserved lung function. Skin lesions were seen in four patients (27%), one patient had renal angiomyolipoma, and one had bilateral renal cancer. Different mutations of the FLCN gene were identified (mainly in exon 6), with two novel heterozygous variants: c.490delA p.(Arg164GlyTer13) and c.40delC p.(His14ThrsfTer41).\nCONCLUSIONS: All analysed patients with BHDS presented with lung lesions and with less frequent skin and renal lesions than previously reported in other populations. In addition, more frequent mutations located in exon 6 were detected, and two novel FLCN gene mutations were identified.","variants":[{"Name":"NM_144997.7(FLCN):c.490del (p.Arg164fs)","Chromosome":"17","Start":"17224050","Stop":"17224050","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":813051,"rule_based_match":true,"evidence_text":"c.490delA p.(Arg164GlyTer13)","llm_judgment":"PRESENT","evidence":"c.490delA p.(Arg164GlyTer13)","abstract_start":1559,"abstract_end":1587}]}
{"pmid":"23213274","title":"BEST1 sequence variants in Italian patients with vitelliform macular dystrophy.","abstract":"PURPOSE: To analyze the spectrum of sequence variants in the BEST1 gene in a group of Italian patients affected by Best vitelliform macular dystrophy (VMD).\nMETHODS: Thirty Italian patients with a diagnosis of VMD and 20 clinically healthy relatives were recruited. They belonged to 19 Italian families predominantly originating from central Italy. They received a standard ophthalmologic examination, OCT scan, and electrophysiological tests (ERG and EOG). Fluorescein and ICG angiographies and fundus autofluorescence imaging were performed in selected cases. DNA samples were analyzed for sequence variants of the BEST1 gene by direct sequencing techniques.\nRESULTS: Nine missense variants and one deletion were found in the affected patients; each patient carried one mutation. Five variants [c.73C>T (p.Arg25Trp), c.652C>T (p.Arg218Cys), c.652C>G (p.Arg218Gly), c.728C>T (p.Ala243Val), c.893T>C (p.Phe298Ser)] have already been described in literature while another five variants [c.217A>C (p.Ile73Leu), c.239T>G (p.Phe80Cys), c.883_885del (p.Ile295del), c.907G>A (p.Asp303Asn), c.911A>G (p.Asp304Gly)] had not previously been reported. Affected patients, sometimes even from the same family, occasionally showed variable phenotypes. One heterozygous variant was also found in five clinically healthy relatives with normal fundus, visual acuity and ERG but with abnormal EOG.\nCONCLUSIONS: Ten variants in the BEST1 gene were detected in a group of individuals with clinically apparent VMD, and in some clinically normal individuals with an abnormal EOG. The high prevalence of novel variants and the frequent report of a specific variant (p.Arg25Trp) that has rarely been described in other ethnic groups suggests a distribution of BEST1 variants peculiar to Italian VMD patients.","variants":[{"Name":"NM_004183.4(BEST1):c.73C>T (p.Arg25Trp)","Chromosome":"11","Start":"61951879","Stop":"61951879","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":105640,"rule_based_match":true,"evidence_text":"c.73C>T (p.Arg25Trp)","llm_judgment":"PRESENT","evidence":"c.73C>T (p.Arg25Trp)","abstract_start":797,"abstract_end":817},{"Name":"NM_004183.4(BEST1):c.217A>C (p.Ile73Leu)","Chromosome":"11","Start":"61955171","Stop":"61955171","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"C","allel_id":105581,"rule_based_match":true,"evidence_text":"c.217A>C (p.Ile73Leu)","llm_judgment":"PRESENT","evidence":"c.217A>C (p.Ile73Leu)","abstract_start":986,"abstract_end":1007},{"Name":"NM_004183.4(BEST1):c.728C>T (p.Ala243Val)","Chromosome":"11","Start":"61958159","Stop":"61958159","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":17776,"rule_based_match":true,"evidence_text":"c.728C>T (p.Ala243Val)","llm_judgment":"PRESENT","evidence":"c.728C>T (p.Ala243Val)","abstract_start":867,"abstract_end":889},{"Name":"NM_004183.4(BEST1):c.652C>G (p.Arg218Gly)","Chromosome":"11","Start":"61957402","Stop":"61957402","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":1062391,"rule_based_match":true,"evidence_text":"c.652C>G (p.Arg218Gly)","llm_judgment":"PRESENT","evidence":"c.652C>G (p.Arg218Gly)","abstract_start":843,"abstract_end":865},{"Name":"NM_004183.4(BEST1):c.893T>C (p.Phe298Ser)","Chromosome":"11","Start":"61959523","Stop":"61959523","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":105656,"rule_based_match":true,"evidence_text":"c.893T>C (p.Phe298Ser)","llm_judgment":"PRESENT","evidence":"c.893T>C (p.Phe298Ser)","abstract_start":891,"abstract_end":913}]}
{"pmid":"25925845","title":"Germline TP53 mutational spectrum in French Canadians with breast cancer.","abstract":"BACKGROUND: Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer.\nMETHODS: TP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer.\nRESULTS: Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age.\nCONCLUSIONS: In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.","variants":[{"Name":"NM_000546.6(TP53):c.685T>C (p.Cys229Arg)","Chromosome":"17","Start":"7674278","Stop":"7674278","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":410266,"rule_based_match":true,"evidence_text":"c.685T>C [p.Cys229Arg]","llm_judgment":"PRESENT","evidence":"c.685T>C [p.Cys229Arg]","abstract_start":1925,"abstract_end":1947}]}
{"pmid":"27207683","title":"Report on Ten Years' Experience of Premarital Hemoglobinopathy Screening at a Center in Antalya, Southern Turkey.","abstract":"Thalassemia and hemoglobinopathies are a major public health problem in Turkey. Hemoglobinopathy prevention programs (HPPs) were started in 33 provinces situated in Thrace, Marmara, Aegean, Mediterranean and South Eastern regions of Turkey in 2003. A premarital hemoglobinopathy test is mandatory and free of charge in this program. According to the Ministry of Health reports, 46 first level hemoglobinopathy diagnostic centers were established for premarital tests. Within the last 10 years, approximately 79.0% of married individuals per year were screened by the centers. While the percentage of premarital screening tests was 30.0% of all couples in 2003, it reached 86.0% in 2013. The number of newborn with thalassemia and hemoglobinopathies were 272 in 2002 and dropped to 25 in 2013. There has been a 90.0% reduction in affected births. Our hemoglobinopathy diagnostic center was established in 2003 and licensed by the Ministry of Health in 2004. We studied a total of 89,981 blood samples from premarital tests for 10 years and the incidence of β- and α-thalassemia (β- and α-thal) trait was found to be 6.57 and 3.56%, respectively. The distribution of the most common abnormal hemoglobins (Hbs) was: Hb S (HBB: c.20A > T) (0.31%), Hb D-Los Angeles (HBB: c.364G > C) (0.15%), Hb G-Coushatta (HBB: c.68A > C) (0.06%) and Hb E (HBB: c.79G > A) (0.02%). A total of 60 couples, both carrying β-thal trait, were directed to the prenatal diagnosis (PND) center in 10 years. The premarital hemoglobinopathy screening program is running successfully at our center and other centers in Turkey.","variants":[{"Name":"NM_000518.4(HBB):c.68A>C (p.Glu23Ala)","Chromosome":"11","Start":"5226954","Stop":"5226954","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":30210,"rule_based_match":true,"evidence_text":"Hb G-Coushatta (HBB: c.68A > C)","llm_judgment":"PRESENT","evidence":"Hb G-Coushatta (HBB: c.68A > C)","abstract_start":1288,"abstract_end":1319}]}
{"pmid":"25761052","title":"Fifteen novel EIF2B1-5 mutations identified in Chinese children with leukoencephalopathy with vanishing white matter and a long term follow-up.","abstract":"Leukoencephalopathy with vanishing white matter (VWM) is one of the most prevalent inherited childhood white matter disorders, which caused by mutations in each of the five subunits of eukaryotic translation initiation factor 2B (EIF2B1-5). In our study, 34 out of the 36 clinically diagnosed children (94%) were identified to have EIF2B1-5 mutations by sequencing. 15 novel mutations were identified. CNVs were not detected in patients with only one mutant allele and mutation-negative determined by gene sequencing. There is a significantly higher incidence of patients with EIF2B3 mutations compared with Caucasian patients (32% vs. 4%). c.1037T>C (p.Ile346Thr) in EIF2B3 was confirmed to be a founder mutation in Chinese, which probably one of the causes of the genotypic differences between ethnicities. Our average 4.4 years-follow-up on infantile, early childhood and juvenile VWM children suggested a rapid deterioration in motor function. Episodic aggravation was presented in 90% of infantile cases and 71.4% of childhood cases. 10 patients died during the follow-up. The Kaplan-Meier curve showed that the median survival time is 8.83 ± 1.51 years. This is the largest sample of children in a VWM follow-up study, which is helpful for a more depth understanding about the natural course.","variants":[{"Name":"NM_020365.5(EIF2B3):c.1037T>C (p.Ile346Thr)","Chromosome":"1","Start":"44875634","Stop":"44875634","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":19479,"rule_based_match":true,"evidence_text":"c.1037T>C (p.Ile346Thr)","llm_judgment":"PRESENT","evidence":"c.1037T>C (p.Ile346Thr)","abstract_start":641,"abstract_end":664}]}
{"pmid":"22759690","title":"Moyamoya vascular pattern in Alagille syndrome.","abstract":"We describe a girl with Alagille syndrome and a moyamoya angiographic pattern on magnetic resonance angiography. She was referred for genetic consultation because of posterior embryotoxon and peripheral pulmonary stenosis. Her facial appearance was typical, but she had no cholestasis or vertebral involvement. A heterozygous duplication of one nucleotide (a c.715dupA mutation) not previously described was identified in exon 5 of the JAG1 gene. We review similar cases in the literature and possible pathophysiologic mechanisms (e.g., the Jagged 1 and Notch signaling pathway) of this association.","variants":[{"Name":"NM_000214.3(JAG1):c.715dup (p.Ser239fs)","Chromosome":"20","Start":"10656437","Stop":"10656438","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":1868490,"rule_based_match":true,"evidence_text":"c.715dupA","llm_judgment":"PRESENT","evidence":"c.715dupA","abstract_start":359,"abstract_end":368}]}
{"pmid":"27216975","title":"Identification and functional analysis of two novel connexin 50 mutations associated with autosome dominant congenital cataracts.","abstract":"Autosomal dominant congenital cataracts (ADCC) are clinically and genetically heterogeneous diseases. The present study recruited two Chinese families with bilateral nuclear cataract or zonular pulverulent phenotype. Direct sequencing of candidate genes identified two novel missense mutations of Cx50, Cx50P59A (c.175C > G) and Cx50R76H (c.227G > A), both co-segregated well with all affected individuals. Bioinformatics analysis predicted deleterious for both mutations. Functional and cellular behaviors of wild type and mutant Cx50 examined by stably transfecting recombinant systems revealed similar protein expression levels. Protein distribution pattern by fluorescence microscopy showed that Cx50R76H localized at appositional membranes forming gap junctions with enormous cytoplasmic protein accumulation, whereas the Cx50P59A mutation was found inefficient at forming detectable plaques. Cell growth test by MTT assay showed that induction of Cx50P59A decreased cell viability. Our study constitutes the first report that the Cx50P59A and Cx50R76H mutations are associated with ADCC and expands the mutation spectrum of Cx50 in association with congenital cataracts. The genetic, cellular, and functional data suggest that the altered intercellular communication governed by mutated Cx50 proteins may act as the molecular mechanism underlying ADCC, which further confirms the role of Cx50 in the maintenance of human lens transparency.","variants":[{"Name":"NM_005267.5(GJA8):c.175C>G (p.Pro59Ala)","Chromosome":"1","Start":"147908130","Stop":"147908130","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":3412507,"rule_based_match":true,"evidence_text":"c.175C > G","llm_judgment":"PRESENT","evidence":"c.175C > G","abstract_start":313,"abstract_end":323},{"Name":"NM_005267.5(GJA8):c.227G>A (p.Arg76His)","Chromosome":"1","Start":"147908182","Stop":"147908182","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1318969,"rule_based_match":true,"evidence_text":"c.227G > A","llm_judgment":"PRESENT","evidence":"c.227G > A","abstract_start":339,"abstract_end":349}]}
{"pmid":"25361775","title":"A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy.","abstract":"OBJECTIVE: We report a consanguineous family with 2 affected individuals whose clinical symptoms closely resembled MERRF (myoclonus epilepsy with ragged red fibers) syndrome including severe myoclonic epilepsy, progressive spastic tetraparesis, progressive impairment of vision and hearing, as well as progressive cognitive decline.\nMETHODS: After excluding the presence of pathogenic mitochondrial DNA mutations, whole-exome sequencing of blood DNA from the index patient was performed. Detected homozygous mutations and their cosegregation were confirmed by Sanger sequencing. CARS2 (cysteinyl-tRNA synthetase 2, mitochondrial) messenger RNA analysis was performed by reverse transcription PCR and sequencing.\nRESULTS: We identified a homozygous c.655G>A mutation in the CARS2 gene cosegregating in the family. The mutation is localized at the last nucleotide of exon 6 and thus is predicted to cause aberrant splicing. Analysis of the CARS2 messenger RNA showed that the presence of the mutation resulted in removal of exon 6. This leads to an in-frame deletion of 28 amino acids in a conserved sequence motif of the protein involved in stabilization of the acceptor end hairpin of tRNA(Cys).\nCONCLUSION: CARS2 is a novel disease gene associated with a severe progressive myoclonic epilepsy most resembling MERRF syndrome.","variants":[{"Name":"NM_024537.4(CARS2):c.655G>A (p.Ala219Thr)","Chromosome":"13","Start":"110683051","Stop":"110683051","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":178316,"rule_based_match":true,"evidence_text":"c.655G>A","llm_judgment":"PRESENT","evidence":"c.655G>A","abstract_start":748,"abstract_end":756}]}
{"pmid":"29556725","title":"Congenital glaucoma and CYP1B1: an old story revisited.","abstract":"Primary congenital glaucoma is a trabecular meshwork dysgenesis with resultant increased intraocular pressure and ocular damage. CYP1B1 mutations remain the most common identifiable genetic cause. However, important questions about the penetrance of CYP1B1-related congenital glaucoma remain unanswered. Furthermore, mutations in other genes have been described although their exact contribution and potential genetic interaction, if any, with CYP1B1 mutations are not fully explored. In this study, we employed modern genomic approaches to re-examine CYP1B1-related congenital glaucoma. A cohort of 193 patients (136 families) diagnosed with congenital glaucoma. We identified biallelic CYP1B1 mutations in 80.8% (87.5 and 66.1% in familial and sporadic cases, respectively, p < 0.0086). The large family size of the study population allowed us to systematically examine penetrance of all identified alleles. With the exception of c.1103G>A (p.R368H), previously reported pathogenic mutations were highly penetrant (91.2%). We conclude from the very low penetrance and genetic epidemiological analyses that c.1103G>A (p.R368H) is unlikely to be a disease-causing recessive mutation in congenital glaucoma as previously reported. All cases that lacked biallelic CYP1B1 mutations underwent whole exome sequencing. No mutations in LTBP2, MYOC or TEK were encountered. On the other hand, mutations were identified in genes linked to other ophthalmic phenotypes, some inclusive of glaucoma, highlighting conditions that might phenotypically overlap with primary congenital glaucoma (SLC4A4, SLC4A11, CPAMD8, and KERA). We also encountered candidate causal variants in genes not previously linked to human diseases: BCO2, TULP2, and DGKQ. Our results both expand and refine the genetic spectrum of congenital glaucoma with important clinical implications.","variants":[{"Name":"NM_000104.4(CYP1B1):c.1103G>A (p.Arg368His)","Chromosome":"2","Start":"38071251","Stop":"38071251","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22778,"rule_based_match":true,"evidence_text":"c.1103G>A (p.R368H)","llm_judgment":"PRESENT","evidence":"c.1103G>A (p.R368H)","abstract_start":932,"abstract_end":951}]}
{"pmid":"37119015","title":"Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families.","abstract":"BACKGROUND: Autosomal recessive cutis laxa type 2A (ARCL2A; OMIM: 219200) is characterized by neurovegetative, developmental and progeroid elastic skin anomalies. It is caused by biallelic variation in ATPase, H<sup>+</sup> transporting V0 subunit A2 (ATP6V0A2; OMIM: 611716) located on chromosome 12q24.31. Autosomal recessive cutis laxa type 3A (ARCL3A; OMIM: 219150) is another subclinical type characterized by short stature, ophthalmological abnormalities and a progeria-like appearance. The ARCL3A is caused by loss of function alterations in the aldehyde dehydrogenase 18 family member A1 (ALDH18A1; OMIM: 138250) gene located at chromosome 10q24.1.\nMETHODS: Whole-exome sequencing (WES), and Sanger sequencing were performed for molecular diagnosis. 3D protein modeling was performed to investigate the deleterious effect of the variant on protein structure.\nRESULTS: In this study, clinical and molecular diagnosis were performed for two families, ED-01 and DWF-41, which displayed hallmark features of ARCL2A and ARCL3A, respectively. Three affected individuals in the ED-01 family (IV-4, IV-5 and V-3) displayed sagging loose skin, down-slanting palpebral fissures, excessive wrinkles on the abdomen, hands and feet, and prominent veins on the trunk. Meanwhile the affected individuals in the DWF-41 family (V-2 and V-3) had progeroid skin, short stature, dysmorphology, low muscle tone, epilepsy, lordosis, scoliosis, delayed puberty and internal genitalia. WES in the index patient (ED-01: IV-4) identified a novel homozygous deletion (NM_012463.3: c.1977_1980del; p.[Val660LeufsTer23]) in exon 16 of the ATP6V0A2 while in DWF-41 a novel homozygous missense variant (NM_001323413.1:c.1867G>A; p.[Asp623Asn]) in exon 15 of the ALDH18A1 was identified. Sanger validation in all available family members confirmed the autosomal recessive modes of inheritances in each family. Three dimensional in-silico protein modeling suggested deleterious impact of the identified variants. Furthermore, these variants were assigned class 1 or \"pathogenic\" as per guidelines of American College of Medical Genetics 2015. Screening of ethnically matched healthy controls (n = 200 chromosomes), excluded the presence of these variations in general population.\nCONCLUSIONS: To the best of our knowledge, this is the first report of ATP6V0A2 and ALDH18A1 variations in the Pakhtun ethnicity of Pakistani population. The study confirms that WES can be used as a first-line diagnostic test in patients with cutis laxa, and provides basis for population screening and premarital testing to reduce the diseases burden in future generations.","variants":[{"Name":"NM_002860.4(ALDH18A1):c.1867G>A (p.Asp623Asn)","Chromosome":"10","Start":"95613798","Stop":"95613798","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":413295,"rule_based_match":true,"evidence_text":"NM_001323413.1:c.1867G>A; p.[Asp623Asn]","llm_judgment":"PRESENT","evidence":"NM_001323413.1:c.1867G>A; p.[Asp623Asn]","abstract_start":1680,"abstract_end":1719}]}
{"pmid":"31465153","title":"Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B.","abstract":"Developmental and epileptic encephalopathies are genetic disorders in which both the developmental disability and the frequent epileptic activity are the effect of a specific gene variant. While heterozygous variants in SCN1B have been described in families with generalized epilepsy with febrile seizures plus, Type 1, only three cases of homozygous, missense variants in SCN1B have been reported in association with autosomal recessive inheritance of a severe developmental and epileptic encephalopathy. We present two siblings who are homozygous for a novel, missense variant in SCN1B, c.265C>T, predicting p.Arg89Cys. The proband is an 11-year-old female with infantile-onset, fever-induced, intractable generalized tonic-clonic seizures, myoclonic seizures, and developmental slowing and autism spectrum disorder occurring later in the course of the disease. Her 4-year-old brother had a similar epilepsy phenotype, but still displays normal development. This variant has not been previously reported in the homozygous state in control databases. The variant was predicted to be damaging and occurred in the vicinity of other epileptic encephalopathy-associated missense variants that are biallelic and located in the extracellular immunoglobulin loop domain of the protein, which mediates interaction of the beta-1 subunit with cellular adhesion molecules. Our report is the first set of siblings with homozygosity for the p.Arg89Cys variant in SCN1B and further implicates biallelic mutations in this gene as a cause of epileptic encephalopathy mimicking Dravet syndrome. Interestingly, the phenotype we observed was milder compared to that previously described in patients with recessive SCN1B mutations.","variants":[{"Name":"NM_001037.5(SCN1B):c.265C>T (p.Arg89Cys)","Chromosome":"19","Start":"35033556","Stop":"35033556","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":805109,"rule_based_match":true,"evidence_text":"c.265C>T","llm_judgment":"PRESENT","evidence":"c.265C>T","abstract_start":589,"abstract_end":597}]}
{"pmid":"34999892","title":"Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder.","abstract":"In the framework of the UK 100 000 Genomes Project, we investigated the genetic origin of a previously undescribed recessive dermatological condition, which we named LIPHAK (LTV1-associated Inflammatory Poikiloderma with Hair abnormalities and Acral Keratoses), in four affected individuals from two UK families of Pakistani and Indian origins, respectively. Our analysis showed that only one gene, LTV1, carried rare biallelic variants that were shared in all affected individuals, and specifically they bore the NM_032860.5:c.503A > G, p.(Asn168Ser) change, found homozygously in all of them. In addition, high-resolution homozygosity mapping revealed the presence of a small 652-kb stretch on chromosome 6, encompassing LTV1, that was haploidentical and common to all affected individuals. The c.503A > G variant was predicted by in silico tools to affect the correct splicing of LTV1's exon 5. Minigene-driven splicing assays in HEK293T cells and in a skin sample from one of the patients confirmed that this variant was indeed responsible for the creation of a new donor splice site, resulting in aberrant splicing and in a premature termination codon in exon 6 of this gene. LTV1 encodes one of the ribosome biogenesis factors that promote the assembly of the small (40S) ribosomal subunit. In yeast, defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm; however, the role of this gene in human pathology is unknown to date. Our data suggest that LIPHAK could be a previously unrecognized ribosomopathy.","variants":[{"Name":"NM_032860.5(LTV1):c.503A>G (p.Asn168Ser)","Chromosome":"6","Start":"143857408","Stop":"143857408","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2417493,"rule_based_match":true,"evidence_text":"NM_032860.5:c.503A > G, p.(Asn168Ser)","llm_judgment":"PRESENT","evidence":"NM_032860.5:c.503A > G, p.(Asn168Ser)","abstract_start":514,"abstract_end":551}]}
{"pmid":"33431708","title":"Hypopituitarism in Wilson's disease resolved after copper-chelating therapy.","abstract":"SUMMARY: Wilson's disease (WD) is a rare disorder of copper metabolism usually presenting with variable liver damage and neuropsychiatric symptoms. Here we report a 39-year-old Taiwanese female with late manifestation of WD presenting with gonadotroph, thyreotroph and corticotroph hypopituitarism. Molecular genetic testing revealed compound heterozygosity for two mutations in exons 12 and 14 (c.2828G>A and c.3140A>T). Copper-chelating therapy with D-penicillamine and zinc was initiated along with supplementation of hydrocortisone and L-thyroxine. Hypopituitarism resolved when urinary copper excretion returned to normal levels under copper chelation. This case should raise awareness of pituitary function in WD patients.\nLEARNING POINTS: Hypopituitarism can complicate Wilson's disease (WD) and endocrinologists should be aware of it when caring for hypopituitary patients. Hepatologists should consider endocrinologic testing for hypopituitarism when WD patients present with symptoms of adrenal insufficiency, thyroid or gonadal dysfunction. Copper-chelating treatment is mandatory and may lead to the recovery of pituitary function in such patients.","variants":[{"Name":"NM_000053.4(ATP7B):c.3140A>T (p.Asp1047Val)","Chromosome":"13","Start":"51944212","Stop":"51944212","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":1063018,"rule_based_match":true,"evidence_text":"c.3140A>T","llm_judgment":"PRESENT","evidence":"c.3140A>T","abstract_start":410,"abstract_end":419}]}
{"pmid":"31412107","title":"Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2.","abstract":"Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.","variants":[{"Name":"NM_133267.3(GSX2):c.26C>A (p.Ser9Ter)","Chromosome":"4","Start":"54100370","Stop":"54100370","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":681868,"rule_based_match":true,"evidence_text":"c.26C>A; p.(S9*)","llm_judgment":"PRESENT","evidence":"c.26C>A; p.(S9*)","abstract_start":965,"abstract_end":981}]}
{"pmid":"22012410","title":"Mild clinical and biochemical phenotype in two patients with PMM2-CDG (congenital disorder of glycosylation Ia).","abstract":"Phosphomannomutase 2 deficiency (PMM2-CDG) patients may present as mild phenotypes, with the cerebellum frequently involved. In those cases, false-negative results in screening may occur when applying conventional biochemical procedures. Our aim was to report two patients with a diagnosis of PMM2-CDG presenting with mild clinical phenotype. Patient 1-at 9 months of age, she presented with just psychomotor delay, tremor, hypotonia, and slight lipodystrophy. Patient 2-she presented at 8 months of age with psychomotor delay, hand stereotypes, hypotonia, convergent bilateral strabismus, and tremor but no lipodystrophy. Routine biochemical parameters including blood count, clotting factors, proteins, and thyroid hormone were normal in both cases. Cranial MRI evidenced mild cerebellar atrophy with moderate vermis hypoplasia. In case 1, sialotransferrin pattern showed very slightly increased disialotransferrin with no asialotransferrin, and in case 2, the transferrin pattern was impaired in the first study but nearly normal in the second. Nevertheless, in all the samples, quantification of the patterns obtained by capillary zone electrophoresis analysis gave results out of the control range. High residual PMM2 activity was observed in both cases and the genetic analysis showed that patient 1 was heterozygous for c.722G>C (p.C241S) and c.368G>A (p.R123Q) mutations, and patient 2 showed the c.722G>C and the c.470T>C (p.F157S) mutations in the PMM2 gene. We would like to stress the importance of the use of sensitive semiquantitative methods of screening for CDG in order to achieve early identification of patients with mild phenotypes. Intentional tremor was an atypical but remarkable clinical feature in both cases, and the global cerebellar atrophy with vermis hypoplasia reinforced the early clinical suspicion of a PMM2-CDG disease.","variants":[{"Name":"NM_000303.3(PMM2):c.722G>C (p.Cys241Ser)","Chromosome":"16","Start":"8847806","Stop":"8847806","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":22756,"rule_based_match":true,"evidence_text":"c.722G>C (p.C241S)","llm_judgment":"PRESENT","evidence":"c.722G>C (p.C241S)","abstract_start":1327,"abstract_end":1345},{"Name":"NM_000303.3(PMM2):c.470T>C (p.Phe157Ser)","Chromosome":"16","Start":"8811660","Stop":"8811660","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":186953,"rule_based_match":true,"evidence_text":"c.470T>C (p.F157S)","llm_judgment":"PRESENT","evidence":"c.470T>C (p.F157S)","abstract_start":1422,"abstract_end":1440}]}
{"pmid":"26096710","title":"Identification of Two Novel β-Thalassemia Mutations (HBB: c.335-346del and HBB: c.108 C > G) in Han Chinese.","abstract":"β-Thalassemia (β-thal) is an inherited blood disorder characterized by reduced or absent synthesis of the β chains of hemoglobin (Hb). Although a number of causative mutations have been reported, here we report two novel mutations detected in Chinese patients. Red blood cell (RBC) indices were indicative of β-thal, but no mutations were detected by routine methods. Sequencing of the β-globin gene uncovered one mutant with a 12 bp deletion (TCTGTGTGCTGG) from codon 111 to codon 115 (HBB: c.335-346del12bp) in exon 3. The other was found to be a nonsense mutation at codon 35 (HBB: c.108 C > G). The identification of these novel mutations will facilitate future diagnoses of β-thal caused by either of these mutations and will also be useful for genetic counseling and prenatal diagnosis.","variants":[{"Name":"NM_000518.5(HBB):c.108C>G (p.Tyr36Ter)","Chromosome":"11","Start":"5226784","Stop":"5226784","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":857491,"rule_based_match":true,"evidence_text":"HBB: c.108 C > G","llm_judgment":"PRESENT","evidence":"HBB: c.108 C > G","abstract_start":580,"abstract_end":596}]}
{"pmid":"34588271","title":"Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males.","abstract":"OBJECTIVE: One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that <i>MYBPC3</i> c.2149-1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: <i>MYBPC3</i> p.Arg502Trp/Gln.\nMETHODS: We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of <i>MYBPC3</i> c.2149-1G>A. Carriers with this mutation were compared with those from <i>MYBPC3</i> p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes.\nRESULTS: <i>MYBPC3</i> c.2149-1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). <i>MYBPC3</i> c.2149-1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with <i>MYBPC3</i> p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups.\nCONCLUSIONS: <i>MYBPC3</i> c.2149-1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than <i>MYBPC3</i> p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes.","variants":[{"Name":"NM_000256.3(MYBPC3):c.2149-1G>A","Chromosome":"11","Start":"47338680","Stop":"47338680","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":174763,"rule_based_match":true,"evidence_text":"MYBPC3 c.2149-1G>A","llm_judgment":"PRESENT","evidence":"MYBPC3</i> c.2149-1G>A","abstract_start":219,"abstract_end":241}]}
{"pmid":"24282183","title":"Clinical features and molecular characterization of a patient with muscle-eye-brain disease: a novel mutation in the POMGNT1 gene.","abstract":"Muscle-eye-brain disease is a congenital muscular dystrophy characterized by structural brain and eye defects. Here, we describe a 12-year-old boy with partial agenesis of corpus callosum, ventriculomegaly, flattened brain stem, diffuse pachygyria, blindness, profound cognitive deficiencies, and generalized muscle weakness, yet without a clear dystrophic pattern on muscle biopsy. There was no glycosylation of α-dystroglycan and the genetic screening revealed a novel truncating mutation, c.1545delC (p.Tyr516Thrfs*21), and a previously identified missense mutation, c.1469G>A (p.Cys490Tyr), in the protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) gene. These findings broaden the clinical spectrum of muscle-eye-brain disease to include pronounced hypotonia with severe brain and eye malformations, yet with mild histopathologic changes in the muscle specimen, despite the absence of glycosylated α-dystroglycan.","variants":[{"Name":"NM_017739.4(POMGNT1):c.1545del (p.Tyr516fs)","Chromosome":"1","Start":"46190779","Stop":"46190779","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":1058775,"rule_based_match":true,"evidence_text":"c.1545delC (p.Tyr516Thrfs*21)","llm_judgment":"PRESENT","evidence":"c.1545delC (p.Tyr516Thrfs*21)","abstract_start":492,"abstract_end":521},{"Name":"NM_017739.4(POMGNT1):c.1469G>A (p.Cys490Tyr)","Chromosome":"1","Start":"46192168","Stop":"46192168","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":19039,"rule_based_match":true,"evidence_text":"c.1469G>A (p.Cys490Tyr)","llm_judgment":"PRESENT","evidence":"c.1469G>A (p.Cys490Tyr)","abstract_start":570,"abstract_end":593}]}
{"pmid":"34016807","title":"KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant.","abstract":"KIAA0753-related skeletal ciliopathy is a recently described recessive disorder causing skeletal dysplasia and overlapping features of certain ciliopathies; Joubert, Jeune and Oro-facial-digital syndromes. We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia. Testing for FGFR3 achondroplasia-related hotspots and mucopolysaccharidosis were negative. Whole-exome sequencing, aged eight, via skeletal dysplasia panel analysis and subsequent whole-genome sequencing (via the 100,000 genomes project) found no cause. WGS data reanalysis using exomiser uncovered compound heterozygous pathogenic KIAA0753 variants (frameshift and splice site). Further clinical and radiological surveys were consistent with the expected phenotype. We discuss the emerging phenotype of this uncommon disorder. This report details the sixth published case of skeletal dysplasia in all cases of KIAA0753-related disease and the first case to describe a novel c.1830-2A>G splice variant. Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.","variants":[{"Name":"NM_014804.3(KIAA0753):c.1830-2A>G","Chromosome":"17","Start":"6607272","Stop":"6607272","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1186010,"rule_based_match":true,"evidence_text":"c.1830-2A>G","llm_judgment":"PRESENT","evidence":"c.1830-2A>G","abstract_start":1229,"abstract_end":1240}]}
{"pmid":"30479897","title":"Family-based whole-exome sequencing identifies novel loss-of-function mutations of","abstract":"BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes.\nMETHODS: We sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing.\nRESULTS: Two novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of <i>FBN1</i> were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of <i>FBN1</i> were located in the cbEGF region and a conserved domain across species and were not reported previously.\nCONCLUSIONS: Our study extended and strengthened the vital role of <i>FBN1</i> LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS.","variants":[{"Name":"NM_000138.5(FBN1):c.5856del (p.Ser1953fs)","Chromosome":"15","Start":"48445437","Stop":"48445437","ReferenceAlleleVCF":"AC","AlternateAlleleVCF":"A","allel_id":3093718,"rule_based_match":true,"evidence_text":"c.5856delG, p.S1953Lfs*27","llm_judgment":"PRESENT","evidence":"c.5856delG, p.S1953Lfs*27","abstract_start":856,"abstract_end":881}]}
{"pmid":"36894310","title":"Comprehensive laboratory diagnosis of Fanconi anaemia: comparison of cellular and molecular analysis.","abstract":"BACKGROUND: Fanconi anaemia (FA) is a rare inherited bone marrow failure disease caused by germline pathogenic variants in any of the 22 genes involved in the FA-DNA interstrand crosslink (ICL) repair pathway. Accurate laboratory investigations are required for FA diagnosis for the clinical management of the patients. We performed chromosome breakage analysis (CBA), FANCD2 ubiquitination (FANCD2-Ub) analysis and exome sequencing of 142 Indian patients with FA and evaluated the efficiencies of these methods in FA diagnosis.\nMETHODS: We performed CBA and FANCD2-Ub analysis in the blood cells and fibroblasts of patients with FA. Exome sequencing with improved bioinformatics to detect the single number variants and CNV was carried out for all the patients. Functional validation of the variants with unknown significance was done by lentiviral complementation assay.\nRESULTS: Our study showed that FANCD2-Ub analysis and CBA on peripheral blood cells could diagnose 97% and 91.5% of FA cases, respectively. Exome sequencing identified the FA genotypes consisting of 45 novel variants in 95.7% of the patients with FA. <i>FANCA</i> (60.2%), <i>FANCL</i> (19.8%) and <i>FANCG</i> (11.7%) were the most frequently mutated genes in the Indian population. A <i>FANCL</i> founder mutation c.1092G>A; p.K364=was identified at a very high frequency (~19%) in our patients.\nCONCLUSION: We performed a comprehensive analysis of the cellular and molecular tests for the accurate diagnosis of FA. A new algorithm for rapid and cost-effective molecular diagnosis for~90% of FA cases has been established.","variants":[{"Name":"NM_018062.4(FANCL):c.1092G>A (p.Lys364=)","Chromosome":"2","Start":"58160108","Stop":"58160108","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":918140,"rule_based_match":true,"evidence_text":"c.1092G>A; p.K364=","llm_judgment":"PRESENT","evidence":"c.1092G>A; p.K364=","abstract_start":1289,"abstract_end":1307}]}
{"pmid":"30177960","title":"A Novel Homozygous","abstract":"We report a novel homozygous <i>JAK3</i> mutation in two female Brazilian SCID infants from two unrelated kindreds. Patient 1 was referred at 2 months of age due to a family history of immunodeficiency and the appearance of a facial rash. The infant was screened for TRECs (T-cell receptor excision circles) and KRECs (kappa-deleting recombination excision circles) for the assessment of newly formed naïve T and B cells respectively, which showed undetectable TRECs and normal numbers of KRECs. Lymphocyte immunophenotyping by flow cytometry confirmed the screening results, revealing a T-B+NK- SCID. The patient underwent successful HSCT. Patient 2 was admitted to an intensive care unit at 8 months of age with severe pneumonia, BCGosis, and oral moniliasis; she also had a positive family history for SCID but newborn screening was not performed at birth. At 10 months of age she was diagnosed as a T-B+NK- SCID and underwent successful HSCT. <i>JAK3</i> sequencing revealed the same homozygous missense mutation (c.2350G>A) in both patients. This mutation affects the last nucleotide of exon 17 and it is predicted to disrupt the donor splice site. cDNA sequencing revealed skipping of exon 17 missing in both patients, confirming the predicted effect on mRNA splicing. Skipping of exon 17 leads to an out of frame deletion of 151 nucleotides, frameshift and creation of a new stop codon 60 amino acids downstream of the mutation resulting in a truncated protein which is likely nonfunctional.","variants":[{"Name":"NM_000215.4(JAK3):c.2350G>A (p.Asp784Asn)","Chromosome":"19","Start":"17834571","Stop":"17834571","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1892383,"rule_based_match":true,"evidence_text":"c.2350G>A","llm_judgment":"PRESENT","evidence":"c.2350G>A","abstract_start":1018,"abstract_end":1027}]}
{"pmid":"21549337","title":"Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome.","abstract":"Accelerated aging syndromes represent a valuable source of information about the molecular mechanisms involved in normal aging. Here, we describe a progeroid syndrome that partially phenocopies Hutchinson-Gilford progeria syndrome (HGPS) but also exhibits distinctive features, including the absence of cardiovascular deficiencies characteristic of HGPS, the lack of mutations in LMNA and ZMPSTE24, and a relatively long lifespan of affected individuals. Exome sequencing and molecular analysis in two unrelated families allowed us to identify a homozygous mutation in BANF1 (c.34G>A [p.Ala12Thr]), encoding barrier-to-autointegration factor 1 (BAF), as the molecular abnormality responsible for this Mendelian disorder. Functional analysis showed that fibroblasts from both patients have a dramatic reduction in BAF protein levels, indicating that the p.Ala12Thr mutation impairs protein stability. Furthermore, progeroid fibroblasts display profound abnormalities in the nuclear lamina, including blebs and abnormal distribution of emerin, an interaction partner of BAF. These nuclear abnormalities are rescued by ectopic expression of wild-type BANF1, providing evidence for the causal role of this mutation. These data demonstrate the utility of exome sequencing for identifying the cause of rare Mendelian disorders and underscore the importance of nuclear envelope alterations in human aging.","variants":[{"Name":"NM_003860.4(BANF1):c.34G>A (p.Ala12Thr)","Chromosome":"11","Start":"66003284","Stop":"66003284","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39347,"rule_based_match":true,"evidence_text":"c.34G>A [p.Ala12Thr]","llm_judgment":"PRESENT","evidence":"c.34G>A [p.Ala12Thr]","abstract_start":576,"abstract_end":596}]}
{"pmid":"20698049","title":"Germline mutation analysis of hPMS2 gene in Chinese families with hereditary nonpolyposis colorectal cancer.","abstract":"AIM: To study the germline mutation of hPMS2 gene in 26 unrelated Chinese hereditary nonpolyposis colorectal cancer (HNPCC) probands and to fulfill the screening strategy for HNPCC in Chinese.\nMETHODS: Genomic DNA was extracted from the peripheral blood. To avoid the interference of pseudogene in detection of the remaining 11 exons (exon 1-5, 9, 11-15), long-range polymerase chain reaction (PCR) was conducted to amplify the complete coding region of hPMS2 gene firstly. Then 1/8 of the PCR products were used as template to amplify the individual exon respectively and DNA sequencing was done. Direct DNA sequencing of the conventional PCR products of exon 6, 7, 8 and 10 of hPMS2 gene was performed. The same analysis was made in 130 healthy persons without family histories of HNPCC to further investigate the pathological effects of the detected missense mutation.\nRESULTS: One HNPCC proband fulfilled Bethesda guidelines and was found to carry the germline mutation of hPMS2 gene, which has not been reported in Chinese HNPCC families. It was a missense mutation at c.1532C>T of exon 11. It was detected in three controls as well with an occurrence rate of 2.3% (3/130). Since it could not be found in the PMS2-single nucleotide polymorphism (SNP) database, this missense mutation is a new SNP unreported up to date. Meanwhile, 260 reported SNPs of hPMS2 gene were detected in the 26 HNPCC probands. The 2nd and 5th exons were probably the hot SNP regions of hPMS2 gene in Chinese HNPCC families involving 53.1% of all reported SNP.\nCONCLUSION: The germline mutation of hPMS2 gene may be rare in Chinese HNPCC families. The 2nd and 5th exons are hot SNP regions of hPMS2 gene.","variants":[{"Name":"NM_000535.7(PMS2):c.1532C>T (p.Thr511Met)","Chromosome":"7","Start":"5987233","Stop":"5987233","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":50143,"rule_based_match":true,"evidence_text":"c.1532C>T","llm_judgment":"PRESENT","evidence":"c.1532C>T","abstract_start":1074,"abstract_end":1083}]}
{"pmid":"24797986","title":"BRCA1 gene-related hereditary susceptibility to breast and ovarian cancer in Latvia.","abstract":"PURPOSE: In this report, we summarise data on BRCA1 gene analysis in Latvia to characterise criteria of genetic testing for breast and ovarian cancer susceptibility.\nMATERIAL/METHODS: Analysis by SSCP/HD, MALDI-TOF mass spectrometry or DNA sequencing was used for mutation detection. Mutations identified were confirmed by direct DNA sequencing.\nRESULTS: Out of 1068 breast and 231 ovarian cancer patients from different families: 58 carried the c.5266dupC and 43 carried the c.4035delA mutations. Every 4th patient in our study did not report cancer in the family. The breast cancer was diagnosed earlier in carriers of the c.5266dupC than in carriers of the c.4035delA (p=0.003). The incidence of breast or ovarian cancer does not differ among the 2 mutation carriers in our patient group. The nature of the c.5266dupC mutation might be more deleterious.\nCONCLUSIONS: We recommend the screening of 4 founder BRCA1 mutations in all breast and ovarian cancer patients in Latvia at diagnosis of disease regardless of family history or age. The BRCA1 screening can be carried out efficiently using the MALDI-TOF mass spectrometry mutation detection method developed in the Biomedical Research and Study Centre (Riga, Latvia).","variants":[{"Name":"NM_007294.4(BRCA1):c.4035del (p.Glu1346fs)","Chromosome":"17","Start":"43091496","Stop":"43091496","ReferenceAlleleVCF":"CT","AlternateAlleleVCF":"C","allel_id":46116,"rule_based_match":true,"evidence_text":"c.4035delA","llm_judgment":"PRESENT","evidence":"c.4035delA","abstract_start":476,"abstract_end":486}]}
{"pmid":"27265524","title":"A novel CDKL5 mutation in a Japanese patient with atypical Rett syndrome.","abstract":"Rett syndrome (RTT) is a severe X-linked dominant inheritance disorder with a wide spectrum of clinical manifestations. Mutations in Methyl CpG binding protein 2 (MECP2), Cyclin dependent kinase-like 5 (CDKL5) and Forkhead box G1 (FOXG1) have been associated with classic and/or variant RTT. This study was conducted to identify the responsible gene(s) in atypical RTT patient, and to examine the effect of the mutation on protein function. DNA sequence analysis showed a novel heterozygous mutation in CDKL5 identified as c.530A>G which resulted in an amino acid substitution at position 177, from tyrosine to cysteine. Genotyping analysis indicated that the mutation was not merely a single nucleotide polymorphism (SNP). We also revealed that patient's blood lymphocytes had random X-chromosome inactivation (XCI) pattern. Further examination by bioinformatics analysis demonstrated the mutation caused damage or deleterious in its protein. In addition, we demonstrated in vitro kinase assay of mutant protein showed impairment of its activity. Taken together, the results suggested the mutant CDKL5 was responsible for the disease.","variants":[{"Name":"NM_001323289.2(CDKL5):c.530A>G (p.Tyr177Cys)","Chromosome":"X","Start":"18584329","Stop":"18584329","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1382318,"rule_based_match":true,"evidence_text":"c.530A>G","llm_judgment":"PRESENT","evidence":"c.530A>G","abstract_start":523,"abstract_end":531}]}
{"pmid":"12955721","title":"Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica.","abstract":"Acrodermatitis enteropathica is rare autosomal recessive disorder characterized by a severe nutritional zinc deficiency. We and others have recently identified the human gene encoding an intestinal zinc transporter of the ZIP family, SLC39A4, as the mutated gene in acrodermatitis enteropathica (AE). A first mutation screening in 8 AE families (15 patients out of 36 individuals) revealed the presence of six different mutations described elsewhere. Based on these results, we have evaluated the involvement of SLC39A4 in 14 patients of 12 additional AE pedigees coming either from France, Tunisia, Austria or Lithuania. A total of 7 SLC39A4 mutations were identified (1 deletion, 2 nonsense, 2 missense, and 2 modifications of splice site), of which 4 are novel: a homozygous nonsense mutation in 3 consanguineous Tunisian families [c.143T>G (p.Leu48X)], a heterozygous nonsense mutation (c.1203G>A (p.Trp401X)) in a compound heterozygote from Austria also exhibiting an already known missense mutation, and distinct homozygous mutations in families from France or Tunisia [c.475-2A>G and c.184T>C (p.Cys62Arg)]. Furthermore, two other potential mutations [c.850G>A (p.Glu284Lys) and c.193-113T>C] were also observed at homozygous state in a French family formerly described. This study brings to 21 the number of reported SLC39A4 mutations in AE families.","variants":[{"Name":"NM_130849.4(SLC39A4):c.850G>A (p.Glu284Lys)","Chromosome":"8","Start":"144414851","Stop":"144414851","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":313491,"rule_based_match":true,"evidence_text":"c.850G>A (p.Glu284Lys)","llm_judgment":"PRESENT","evidence":"c.850G>A (p.Glu284Lys)","abstract_start":1159,"abstract_end":1181},{"Name":"NM_130849.4(SLC39A4):c.475-2A>G","Chromosome":"8","Start":"144415421","Stop":"144415421","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":1367209,"rule_based_match":true,"evidence_text":"c.475-2A>G","llm_judgment":"PRESENT","evidence":"c.475-2A>G","abstract_start":1076,"abstract_end":1086},{"Name":"NM_130849.4(SLC39A4):c.1203G>A (p.Trp401Ter)","Chromosome":"8","Start":"144414042","Stop":"144414042","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1061246,"rule_based_match":true,"evidence_text":"c.1203G>A (p.Trp401X)","llm_judgment":"PRESENT","evidence":"c.1203G>A (p.Trp401X)","abstract_start":891,"abstract_end":912},{"Name":"NM_130849.4(SLC39A4):c.184T>C (p.Cys62Arg)","Chromosome":"8","Start":"144416606","Stop":"144416606","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":3543935,"rule_based_match":true,"evidence_text":"c.184T>C (p.Cys62Arg)","llm_judgment":"PRESENT","evidence":"c.184T>C (p.Cys62Arg)","abstract_start":1091,"abstract_end":1112}]}
{"pmid":"38358893","title":"Clinical, immunohistochemical, and genetic characterization of splice-altering biallelic DES variants: Therapeutic implications.","abstract":"Pathogenic variants in the DES gene clinically manifest as progressive skeletal muscle weakness, cardiomyopathy with associated severe arrhythmias, and respiratory insufficiency, and are collectively known as desminopathies. While most DES pathogenic variants act via a dominant mechanism, recessively acting variants have also been reported. Currently, there are no effective therapeutic interventions for desminopathies of any type. Here, we report an affected individual with rapidly progressive dilated cardiomyopathy, requiring heart transplantation at age 13 years, in the setting of childhood-onset skeletal muscle weakness. We identified biallelic DES variants (c.640-13 T>A and c.1288+1 G>A) and show aberrant DES gene splicing in the affected individual's muscle. Through the generation of an inducible lentiviral system, we transdifferentiated fibroblast cultures derived from the affected individual into myoblasts and validated this system using RNA sequencing. We tested rationally designed, custom antisense oligonucleotides to screen for splice correction in these transdifferentiated cells and a functional minigene splicing assay. However, rather than correctly redirecting splicing, we found them to induce undesired exon skipping. Our results indicate that, while an individual precision-based molecular therapeutic approach to splice-altering pathogenic variants is promising, careful preclinical testing is imperative for each novel variant to test the feasibility of this type of approach for translation.","variants":[{"Name":"NM_001927.4(DES):c.1288+1G>A","Chromosome":"2","Start":"219423821","Stop":"219423821","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":650939,"rule_based_match":true,"evidence_text":"c.1288+1 G>A","llm_judgment":"PRESENT","evidence":"c.1288+1 G>A","abstract_start":687,"abstract_end":699}]}
{"pmid":"28386063","title":"Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.","abstract":"Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.","variants":[{"Name":"NM_001018115.3(FANCD2):c.2715+1G>A","Chromosome":"3","Start":"10073363","Stop":"10073363","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":654309,"rule_based_match":true,"evidence_text":"c.2715 + 1G > A","llm_judgment":"PRESENT","evidence":"c.2715 + 1G > A","abstract_start":843,"abstract_end":858}]}
{"pmid":"36442996","title":"Characterization of a novel deep-intronic variant in","abstract":"Biallelic pathogenic variants in <i>DYNC2H1</i> are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the <i>DYNC2H1</i> gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in <i>DYNC2H1</i> was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited <i>DYNC2H1</i> deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of <i>DYNCH2H1</i> mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.","variants":[{"Name":"NM_001377.3(DYNC2H1):c.10606-14A>G","Chromosome":"11","Start":"103259874","Stop":"103259874","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1671409,"rule_based_match":true,"evidence_text":"c.10606-14A > G","llm_judgment":"PRESENT","evidence":"c.10606-14A > G","abstract_start":1333,"abstract_end":1348}]}
{"pmid":"29185800","title":"Eight Novel Mutations of the ADAR1 Gene in Chinese Patients with Dyschromatosis Symmetrica Hereditaria.","abstract":"AIMS: To identify potential novel gene mutations in Chinese patients with dyschromatosis symmetrica hereditaria (DSH).\nMETHODS: We enrolled 8 Chinese patients with familial DSH, 5 Chinese patients with sporadic DSH, and 100 randomly selected healthy individuals in this study. The genome of each participant was extracted from peripheral blood samples. Sanger sequencing of the ADAR1 gene was performed after polymerase chain reaction amplifications. Comparisons between the DNA sequences of the affected individuals and the NCBI database were performed.\nRESULTS: We detected eight novel heterozygous mutations and five previously reported mutations in the ADAR1 gene in our patients. The novel mutations include c.1934 + 3A>G, c.2749A>G, c.2311insA, c.3233G>A, c.3019 + 1G>T, c.2894C>A, c.1202_1205del, and c.2280C>A. These detected novel mutations are predicted to induce two frame-shift mutations, one nonsense mutation, three missense mutations, and two splice-site mutations.\nCONCLUSIONS: The findings of this study expand our knowledge of the range of ADAR1 gene mutations in DSH and will contribute to identifying correlations between the various DSH phenotypes and genotypes. Furthermore, they may provide insight into the underlying pathogenic mechanism.","variants":[{"Name":"NM_001111.5(ADAR):c.3233G>A (p.Arg1078His)","Chromosome":"1","Start":"154585835","Stop":"154585835","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3086744,"rule_based_match":true,"evidence_text":"c.3233G>A","llm_judgment":"PRESENT","evidence":"c.3233G>A","abstract_start":751,"abstract_end":760}]}
{"pmid":"24170412","title":"Recurrent central nervous system white matter changes in charcot-Marie-tooth type X disease.","abstract":"INTRODUCTION: X-linked Charcot-Marie-Tooth (CMT1X) disease is caused by mutations in the GJB1 gene. We describe a young man who presented with recurrent central nervous symptoms and transient white matter changes in the setting of a novel mutation in the GJB1 gene.\nMETHODS: Evaluation included clinical examination, neuroimaging, electrophysiological, and molecular genetic studies.\nRESULTS: Clinical examination on 2 admissions 5 years apart demonstrated hemiparesis with findings of underlying peripheral neuropathy. Electrophysiologic studies revealed a sensorimotor polyneuropathy. MRI studies from both admissions revealed white matter changes, with improvement on an intervening study. Mutation analysis showed a novel mutation (c.98T>A; p.Ile33Asn) in the GJB1 gene.\nCONCLUSIONS: Mutations in GJB1 can result in recurrent central nervous system symptoms with transient white matter signal changes on MRI. In patients presenting with hemiparesis, the presence of signs of a peripheral neuropathy may facilitate identification of CMT1X, and is likely to affect clinical management.","variants":[{"Name":"NM_000166.6(GJB1):c.98T>A (p.Ile33Asn)","Chromosome":"X","Start":"71223805","Stop":"71223805","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":625486,"rule_based_match":true,"evidence_text":"c.98T>A; p.Ile33Asn","llm_judgment":"PRESENT","evidence":"c.98T>A; p.Ile33Asn","abstract_start":736,"abstract_end":755}]}
{"pmid":"25914329","title":"An Interdomain KCNH2 Mutation Produces an Intermediate Long QT Syndrome.","abstract":"Hereditary long QT syndrome is caused by deleterious mutation in one of several genetic loci, including locus LQT2 that contains the KCNH2 gene (or hERG, human ether-a-go-go related gene), causing faulty cardiac repolarization. Here, we describe and characterize a novel mutation, p.Asp219Val in the hERG channel, identified in an 11-year-old male with syncope and prolonged QT interval. Genetic sequencing showed a nonsynonymous variation in KCNH2 (c.656A>T: amino acid p.Asp219Val). p.Asp219Val resides in a region of the channel predicted to be unstructured and flexible, located between the PAS (Per-Arnt-Sim) domain and its interaction sites in the transmembrane domain. The p.Asp219Val hERG channel produced K(+) current that activated with modest changes in voltage dependence. Mutant channels were also slower to inactivate, recovered from inactivation more readily and demonstrated a significantly accelerated deactivation rate compared with the slow deactivation of wild-type channels. The intermediate nature of the biophysical perturbation is consistent with the degree of severity in the clinical phenotype. The findings of this study demonstrate a previously unknown role of the proximal N-terminus in deactivation and support the hypothesis that the proximal N-terminal domain is essential in maintaining slow hERG deactivation.","variants":[{"Name":"NM_000238.4(KCNH2):c.656A>T (p.Asp219Val)","Chromosome":"7","Start":"150958319","Stop":"150958319","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":167508,"rule_based_match":true,"evidence_text":"c.656A>T (p.Asp219Val)","llm_judgment":"PRESENT","evidence":"p.Asp219Val","abstract_start":281,"abstract_end":292}]}
{"pmid":"26804200","title":"A distinct X-linked syndrome involving joint contractures, keloids, large optic cup-to-disc ratio, and renal stones results from a filamin A (FLNA) mutation.","abstract":"We further evaluated a previously reported family with an apparently undescribed X-linked syndrome involving joint contractures, keloids, an increased optic cup-to-disc ratio, and renal stones to elucidate the genetic cause. To do this, we obtained medical histories and performed physical examination on 14 individuals in the family, five of whom are affected males and three are obligate carrier females. Linkage analysis was performed on all but one individual and chromosome X-exome sequencing was done on two affected males. The analysis localized the putative gene to Xq27-qter and chromosome X-exome sequencing revealed a mutation in exon 28 (c.4726G>A) of the filamin A (FLNA) gene, predicting that a conserved glycine had been replaced by arginine at amino acid 1576 (p.G1576R). Segregation analysis demonstrated that all known carrier females tested were heterozygous (G/A), all affected males were hemizygous for the mutation (A allele) and all normal males were hemizygous for the normal G allele. The data and the bioinformatic analysis indicate that the G1576R mutation in the FLNA gene is very likely pathogenic in this family. The syndrome affecting the family shares phenotypic overlap with other syndromes caused by FLNA mutations, but appears to be a distinct phenotype, likely representing a unique genetic syndrome.","variants":[{"Name":"NM_001110556.2(FLNA):c.4726G>A (p.Gly1576Arg)","Chromosome":"X","Start":"154358228","Stop":"154358228","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":205799,"rule_based_match":true,"evidence_text":"c.4726G>A","llm_judgment":"PRESENT","evidence":"c.4726G>A","abstract_start":650,"abstract_end":659}]}
{"pmid":"35698239","title":"Clinical characteristics and genetic testing outcome of suspected hereditary peripheral nerve sheath tumours in a tertiary cancer institution in Singapore.","abstract":"BACKGROUND: Peripheral Nerve Sheath Tumors (PNST) are a diverse group of mostly benign tumours uncommon in the general population. About 5-10% of PNSTs are hereditary, predominantly arising from germline variants in NF1, NF2, SMARCB1, or LZTR1 gene.\nMETHODS: We reviewed the clinical characteristics and genetic testing results of patients referred to the NCIS Adult Cancer Genetics Clinic for suspected hereditary PNST.\nRESULTS: 3,001 patients suspected to have various hereditary cancer syndromes were evaluated between year 2000 to March 2021. 13 (0.4%) were clinically diagnosed to have hereditary PNSTs. The majority were male (54%), with a median age at presentation to the genetics clinic of 29 years (range 19-48). 11/13 (85%) patients had multiple PNSTs, 12/13 (92%) had young onset PNSTs, 5/13 (38.5%) had personal and family history of PNST. 11/13 patients (85%) had clinical features of neurofibromatosis type 1 (NF1) including one patient who also fulfilled clinical criteria of neurofibromatosis type 2 (NF2); 2/13 (14%) had multiple schwannomas. Four patients underwent multi-gene panel testing, including one patient with clinical NF1, one patient who met both clinical NF1 and NF2 criteria, and two patients with multiple schwannomas. The patient with clinical features of NF1 was heterozygous for a pathogenic c. 2033dup variant in the NF1 gene. The patient with both NF1/NF2 features was heterozygous for a novel c.732 T > A nonsense variant in the NF2 gene. The two patients with multiple schwannomas were heterozygous for a pathogenic/likely pathogenic variant in the LZTR1 gene and are the first LZTR1-positive schwannomatosis patients reported in Asia.\nCONCLUSION: Hereditary PNSTs are rare referrals to an adult cancer genetics clinic. NF1 is the most common PNST seen. LZTR1 variants may be the underlying cause in Asian patients with multiple schwannomatosis.","variants":[{"Name":"NM_001042492.3(NF1):c.2033dup (p.Ile679fs)","Chromosome":"17","Start":"31226459","Stop":"31226460","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"AC","allel_id":151227,"rule_based_match":true,"evidence_text":"c. 2033dup","llm_judgment":"PRESENT","evidence":"c. 2033dup","abstract_start":1328,"abstract_end":1338}]}
{"pmid":"35242572","title":"Familial lecithin-cholesterol acyltransferase deficiency: If so rare, why so frequent in the state of Piauí, northeastern Brazil?","abstract":"Lecithin-cholesterol acyltransferase (LCAT), an enzyme that participates in lipoprotein metabolism, plays an important role in cholesterol homeostasis. Mutations in the <i>LCAT</i> gene can cause two rare genetic disorders: familial LCAT deficiency (FLD), which is characterized by corneal opacities, normocytic anemia, dyslipidemia, and proteinuria progressing to chronic renal failure, and fish-eye disease (FED), which causes dyslipidemia and progressive corneal opacities. Herein, we report six suspected cases of FLD in the backlands of Piauí, located in northeast Brazil. A genetic diagnosis was performed in index cases. Among these, a further investigation was performed to identify new cases in the families. In addition, molecular analyses were performed to verify the levels of consanguinity within families and the existence of a genetic relationship between them. All six index cases were confirmed as FLD with an identical mutation (c.803G > A, p.R268H). The genetic investigation confirmed another 7 new cases of FLD, 52 heterozygous and 6 individuals without mutations. The rate of consanguinity revealed that marriages within the family did not contribute to the high number of FLD cases within the restricted region. The elders of each family (patriarchs and matriarchs) were subjected to a kinship analysis and were more genetically related to each other than the control group. Bayesian analysis was implemented to confirm the hypothesis of connectivity among patriarchs and matriarchs and indicated that they were genetically more related to each other than would be randomly expected, thus suggesting the occurrence of a possible founder effect in these families.","variants":[{"Name":"NM_000229.2(LCAT):c.803G>A (p.Arg268His)","Chromosome":"16","Start":"67940424","Stop":"67940424","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2895060,"rule_based_match":true,"evidence_text":"c.803G > A, p.R268H","llm_judgment":"PRESENT","evidence":"c.803G > A, p.R268H","abstract_start":947,"abstract_end":966}]}
{"pmid":"24052722","title":"Muscle hemangiomatosis presenting as a severe feature in a patient with the pten mutation: expanding the phenotype of vascular malformations in bannayan-riley-ruvalcaba syndrome.","abstract":"Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare autosomal, dominantly-inherited, hamartoma syndrome with distinct phenotypic features. Mutations in the PTEN gene have been identified in PTEN hamartoma tumor syndromes. Our aim was to determine the correlation of phenotype-genotype relationships in a BRRS case. We have evaluated a PTEN mutation in a patient with vascular anomalies and the phenotypic findings of BRRS. We described an 8-year-old girl with the clinical features of BRRS, specifically with vascular anomalies. The mutation in the PTEN gene was identified by DNA sequencing. In our patient, we defined a de novo nonsense R335X (c.1003 C>T) mutation in exon 8, which results in a premature termination codon. Due to vascular anomalies and hemangioma, the patient's left leg was amputated 1 year after the hemangioma diagnosis. Bannayan - Riley - Ruvalcaba syndrome patients with macrocephaly and vascular anomalies should be considered for PTEN mutation analysis and special medical care.","variants":[{"Name":"NM_000314.8(PTEN):c.1003C>T (p.Arg335Ter)","Chromosome":"10","Start":"87961095","Stop":"87961095","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":22872,"rule_based_match":true,"evidence_text":"c.1003 C>T","llm_judgment":"PRESENT","evidence":"c.1003 C>T","abstract_start":645,"abstract_end":655}]}
{"pmid":"25794774","title":"Prevalence of PALB2 mutations in the Creighton University Breast Cancer Family Registry.","abstract":"The purpose of this study is to determine the prevalence of PALB2 mutations among breast cancer families from the United States. The PALB2 gene was screened for mutations in 90 familial breast cancer patients from the Creighton University Breast Cancer Family Registry. These patients had previously tested negative for mutations in BRCA1 and BRCA2. Two of 90 breast cancer patients (2.2 %) were found to carry a truncating mutation in PALB2 (c.2411_2412delCT and c.2053delC). Both probands were diagnosed with breast cancer before age 35 and each had three relatives with breast cancer. Mutations in PALB2 are less common than BRCA1 and BRCA2 in familial breast cancer patients. However, testing for PALB2 mutations is a useful adjunct for patients undergoing testing for BRCA1 and BRCA2.","variants":[{"Name":"NM_024675.4(PALB2):c.2411_2412del (p.Ser804fs)","Chromosome":"16","Start":"23629742","Stop":"23629743","ReferenceAlleleVCF":"CAG","AlternateAlleleVCF":"C","allel_id":235227,"rule_based_match":true,"evidence_text":"c.2411_2412delCT","llm_judgment":"PRESENT","evidence":"c.2411_2412delCT","abstract_start":443,"abstract_end":459}]}
{"pmid":"26266034","title":"A Novel Noonan Syndrome RAF1 Mutation: Lethal Course in a Preterm Infant.","abstract":"Noonan syndrome is a relatively common and heterogeneous genetic disorder, associated with congenital heart defect in about 50% of the cases. If the defect is not severe, life expectancy is normal. We report a case of Noonan syndrome in a preterm infant with hypertrophic cardiomyopathy and lethal outcome associated to acute respiratory distress syndrome caused by Adenovirus pneumonia. A novel mutation in the RAF1 gene was identified: c.782C>G (p.Pro261Arg) in heterozygosity, not described previously in the literature. Consequently, the common clinical course in this mutation and its respective contribution to the early fatal outcome is unknown. No conclusion can be established regarding genotype/phenotype correlation.","variants":[{"Name":"NM_002880.4(RAF1):c.782C>G (p.Pro261Arg)","Chromosome":"3","Start":"12604188","Stop":"12604188","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":49076,"rule_based_match":true,"evidence_text":"c.782C>G (p.Pro261Arg)","llm_judgment":"PRESENT","evidence":"c.782C>G (p.Pro261Arg)","abstract_start":438,"abstract_end":460}]}
{"pmid":"23864971","title":"Clinical manifest x-linked recessive adrenoleukodystrophy in a female.","abstract":"Adrenoleukodystrophy (ALD) is a rare X-linked inherited leukodystrophy with a reduced capacity for degradation of very long chain fatty acids (VLCFAs). The intracellular accumulation of VLCFA leads to demyelination in the central nervous system (CNS) and cell destruction in the adrenal glands. ALD primarily affects males; however, females may develop milder symptoms that may be difficult to recognize. The present report describes a 35-year-old female who experienced a feeling of heaviness in the upper and lower limbs, pain in both knees, and difficulty climbing stairs, running, and jumping. Clinical examination revealed decreased sensitivity in the feet, particularly to touch. Deep tendon reflexes in the lower limbs were brisk, and Babinski's sign was present bilaterally. Multiple sclerosis (MS) was excluded, and all clinical and biochemical tests were normal. After two years of progressing symptoms, the patient was reevaluated and plasma levels of VLCFA were found to be elevated. Seven years prior to this finding, the patient had been found to be heterozygous for the missense mutation c.1679C> T, p.Pro560Leu on the ABCD1 gene (ATP-Binding Cassette subfamily D1). In conclusion, the patient's symptoms could be attributed to ALD. The present case underlines the importance of reevaluating family history in women presenting with vague neurological symptoms.","variants":[{"Name":"NM_000033.4(ABCD1):c.1679C>T (p.Pro560Leu)","Chromosome":"X","Start":"153740618","Stop":"153740618","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":98231,"rule_based_match":true,"evidence_text":"c.1679C> T, p.Pro560Leu","llm_judgment":"PRESENT","evidence":"c.1679C> T, p.Pro560Leu","abstract_start":1103,"abstract_end":1126}]}
{"pmid":"21326312","title":"Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome.","abstract":"Hypospadias is a common congenital malformation in boys in which the urethral meatus opens on the underside of the penis. It is considered a complex disorder with several genes involved and the molecular etiology is just beginning to be revealed. As more than 85% of Opitz G/BBB syndrome (OS) patients with MID1 mutations are manifested with hypospadias, we have investigated the association between the MID1 gene and hypospadias. DNA from 114 hypospadias cases was analyzed with direct sequencing of the MID1 gene. Genotyping analysis was performed for the single-nucleotide polymorphism (SNP) c.1230G>A in 370 individuals with varying degrees of hypospadias and compared with 759 healthy controls. We identified one nonsense mutation c.712G>T (p.E238X), one missense mutation c.1679A>G (p.K560R) and two synonymous variants c.1230G>A (p.S410S) and c.1284T>G (p.V428V). We also detected a significant difference in the rare allele frequency of SNP c.1230G>A in hypospadias patients as compared with controls (P=0.016). Our finding suggests that hypospadias associated with hypertelorism is the mildest phenotype in OS caused by MID1 mutations.","variants":[{"Name":"NM_000381.4(MID1):c.712G>T (p.Glu238Ter)","Chromosome":"X","Start":"10523136","Stop":"10523136","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":38930,"rule_based_match":true,"evidence_text":"c.712G>T (p.E238X)","llm_judgment":"PRESENT","evidence":"c.712G>T (p.E238X)","abstract_start":736,"abstract_end":754}]}
{"pmid":"21480867","title":"Mucopolysaccharidosis I mutations in Chinese patients: identification of 27 novel mutations and 6 cases involving prenatal diagnosis.","abstract":"Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease that results from the deficiency of α-l-iduronidase and is transmitted in an autosomally recessive manner. This report describes the first systematic screening for mutations in Chinese MPS I patients from mainland China, wherein we have summarized the phenotype/genotype correlation of the individuals in Chinese MPS I patients. Mutational analyses were performed in 57 unrelated Chinese MPS I patients. Overall, 105 mutant alleles were identified from a set of 41 different mutations. Notably, of these 41 mutations, 27 were novel mutations that consisted of 8 splicing mutations (c.1-2C>G, c.296+4G>A, c.300-1G>C, c.792+1G>C, c.973-4G>A, c.1189+5G>T, c.1402+1G>T and c.1402+2T>G), 1 nonsense mutation (p.W41X), 1 insertion (c.668-670ins GCG), 5 duplications (c.531dupT, c.657dupG, c.883dupC, c.1147dupG and c.1225dupG), 3 deletions (c.349delT, c.1593delG and c.1244-1271del27),1 nucleotide substitution c.2T>C and 8 missense mutations (p.H33P,p.F52L, p.G168V,p.T179R,p. E182D, p.L237R, p.L238R and p.L421P). The missense mutations p.A79V and p.L346R, which accounted for 16.7% (19/114) and 12.3% (14/114) respectively, were the common mutations in Chinese patients but were rare in the mutational profiles reported for other populations. These results indicate that Chinese MPS I patients may have a different mutational spectrum compared to those of other populations. Moreover, for the first time in China, molecular genetic methods were used for prenatal diagnosis of six cases in five families.","variants":[{"Name":"NM_000203.5(IDUA):c.1402+1G>T","Chromosome":"4","Start":"1002945","Stop":"1002945","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":1313385,"rule_based_match":true,"evidence_text":"c.1402+1G>T","llm_judgment":"PRESENT","evidence":"c.1402+1G>T","abstract_start":716,"abstract_end":727},{"Name":"NM_000203.5(IDUA):c.2T>C (p.Met1Thr)","Chromosome":"4","Start":"987086","Stop":"987086","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":632532,"rule_based_match":true,"evidence_text":"c.2T>C","llm_judgment":"PRESENT","evidence":"c.2T>C","abstract_start":968,"abstract_end":974},{"Name":"NM_000203.5(IDUA):c.973-4G>A","Chromosome":"4","Start":"1002265","Stop":"1002265","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":543179,"rule_based_match":true,"evidence_text":"c.973-4G>A","llm_judgment":"PRESENT","evidence":"c.973-4G>A","abstract_start":691,"abstract_end":701},{"Name":"NM_000203.5(IDUA):c.1402+2T>G","Chromosome":"4","Start":"1002946","Stop":"1002946","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":543203,"rule_based_match":true,"evidence_text":"c.1402+2T>G","llm_judgment":"PRESENT","evidence":"c.1402+2T>G","abstract_start":732,"abstract_end":743}]}
{"pmid":"36647078","title":"A novel case of two siblings harbouring homozygous variant in the NEUROG1 gene with autism as an additional phenotype: a case report.","abstract":"INTRODUCTION: NEUROG1 gene is yet to be associated with a set of human phenotypes in the OMIM database. Three cases have previously been diagnosed with cranial dysinnervation due to biallelic variants in the NEUROG1 gene. This is the fourth and a novel report of a sibling pair harboring a homozygous variant in the NEUROG1 gene with autism as an additional phenotype. A brief review of the literature in conjunction with a genotype-phenotype correlation has been described. A potential hypothesis for the presence of the autistic phenotype in the present case has also been elucidated.\nCASE PRESENTATION: A female aged 6 years and 9 months born to endogamous and phenotypically healthy parents was diagnosed with global developmental delay, autism spectrum disorder, hearing loss, corneal opacity and no eye blinking. Her MRI of the brain revealed mild peritrigonal white matter hyperintensity, and MRI and CT scan of the temporal bones showed abnormal cranial nerves. The proband's younger sister, aged 4-years, was similarly affected. Whole exome sequencing was performed in the proband, which revealed a novel homozygous, likely pathogenic, truncating frameshift variant, c.228_231dup (p.Thr78ProfsTer122) in exon 1 of the NEUROG1 gene (ENST00000314744.4). Segregation analysis by Sanger sequencing showed the proband and her younger sister to be homozygotes and their parents to be heterozygous carriers.\nCONCLUSION: This is the fourth report across the globe with a variant identified in the NEUROG1 gene to be associated with cranial dysinnervation phenotype. An additional phenotype of autism in two female siblings was a novel observation. We provide a hypothetical framework which could explain the pleiotropic effect of a dysfunctional NEUROG1 protein leading to autism and posit it as a candidate for diagnosis of autism spectrum disorder with congenital cranial dysinnervation disorder.","variants":[{"Name":"NM_006161.3(NEUROG1):c.228_231dup (p.Thr78fs)","Chromosome":"5","Start":"135535459","Stop":"135535460","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TCCGG","allel_id":1290439,"rule_based_match":true,"evidence_text":"c.228_231dup (p.Thr78ProfsTer122)","llm_judgment":"PRESENT","evidence":"c.228_231dup (p.Thr78ProfsTer122)","abstract_start":1176,"abstract_end":1209}]}
{"pmid":"28391758","title":"The Frequency of HBB Mutations Among β-Thalassemia Patients in Hamadan Province, Iran.","abstract":"β-Thalassemia (β-thal) caused by mutations on the HBB gene is the most common single-gene disorder in the world. In this study, the HBB gene mutation was investigated in Hamadan province, Iran. Forty-one patients referred to a referral hospital were admitted to the study. DNA samples were extracted from peripheral blood. The HBB gene was sequenced in all recruited patients. Eleven mutations and eight polymorphisms were found in the studied patients. IVS-II-1 (G>A) (HBB: c.315+1 G>A) was the most common mutation, accounting for 25.61% of mutant alleles. Other mutations included codon 8 (-AA) (HBB: c.25-26delAA); IVS-I-110 (G>A) (HBB: c.93-21 G>A); codons 8/9 (+G) (HBB: c.27-28insG); IVS-I-1 (G>A) (HBB: c.92 G>A); codon 44 (-C) (HBB: c.135delC); codons 25/26 (+T) (HBB: c.78-79insT); IVS-I-130 (G>C) (HBB: c.93-1 G>C); -28 (A>C) (HBB: c.-78 A>C); codons 36/37 (-T) (HBB: c.112delT) and IVS-I-6 (T>C) (HBB: c.92+6 T>C). According to our findings, the IVS-II-1 mutation has the highest prevalence in Hamadan Province. It was found that the total frequency of the IVS-II-1, codons 25/26 (+T), codons 8/9 (+G), IVS-I-110 and IVS-I-1 mutations was 82.92%. Therefore, given these findings, it is recommended that these five mutations are screened for as a first step in laboratories without sequencing instruments, and that the rest of the gene is subsequently examined.","variants":[{"Name":"NM_000518.5(HBB):c.315+1G>A","Chromosome":"11","Start":"5226576","Stop":"5226576","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30477,"rule_based_match":true,"evidence_text":"IVS-II-1 (G>A) (HBB: c.315+1 G>A)","llm_judgment":"PRESENT","evidence":"IVS-II-1 (G>A) (HBB: c.315+1 G>A)","abstract_start":454,"abstract_end":487},{"Name":"NM_000518.5(HBB):c.92+6T>C","Chromosome":"11","Start":"5226924","Stop":"5226924","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":30489,"rule_based_match":true,"evidence_text":"IVS-I-6 (T>C) (HBB: c.92+6 T>C)","llm_judgment":"PRESENT","evidence":"IVS-I-6 (T>C) (HBB: c.92+6 T>C)","abstract_start":894,"abstract_end":925},{"Name":"NM_000518.5(HBB):c.93-21G>A","Chromosome":"11","Start":"5226820","Stop":"5226820","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":30493,"rule_based_match":true,"evidence_text":"IVS-I-110 (G>A) (HBB: c.93-21 G>A)","llm_judgment":"PRESENT","evidence":"IVS-I-110 (G>A) (HBB: c.93-21 G>A)","abstract_start":619,"abstract_end":653}]}
{"pmid":"30250054","title":"Stereocilin gene variants associated with episodic vertigo: expansion of the DFNB16 phenotype.","abstract":"Vestibular disorders comprise a heterogeneous group of diseases with transient or permanent loss of vestibular function. Vestibulopathy is in most cases associated with migraine, Ménière disease, hereditary ataxias, or sensorineural hearing loss. We identified two brothers and their first cousin affected by hearing loss and episodic vertigo. The brothers were homozygous STRC nonsense variant [c.4027 C > T, p.(Q1343*)], whereas their first cousin was compound heterozygous for the STRC nonsense variant and a 97 kb deletion spanning the entire STRC gene. Clinical investigations confirmed pathological vestibular responses in addition to a characteristic DFNB16 hearing loss. The STRC gene encodes Stereocilin in the cochlea and in the vestibular organ where it ensheathes the kinocilium of the otolithic membranes. Stereocilin is associated with the gel overlaying the vestibular kinocilia, suggesting a role for the protein in sensing balance and spatial orientation. Our findings support such a function for Stereocilin in the vestibular organ and expand the phenotype associated with DFNB16.","variants":[{"Name":"NM_153700.2(STRC):c.4027C>T (p.Gln1343Ter)","Chromosome":"15","Start":"43604750","Stop":"43604750","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":442483,"rule_based_match":true,"evidence_text":"c.4027 C > T, p.(Q1343*)","llm_judgment":"PRESENT","evidence":"c.4027 C > T, p.(Q1343*)","abstract_start":396,"abstract_end":420}]}
{"pmid":"35550617","title":"A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: a case report and literature review.","abstract":"BACKGROUND: The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by variant. We reported a Chinese male newborn with a de novo variant in CASK gene.\nCASE PRESENTATION: We present an 18-day-old baby with growth retardation and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense variant c.764G > A of CASK gene. The variant changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.\nCONCLUSIONS: In this paper, a de novo variant of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported. CASK variants cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.","variants":[{"Name":"NM_001367721.1(CASK):c.764G>A (p.Arg255His)","Chromosome":"X","Start":"41660506","Stop":"41660506","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":167935,"rule_based_match":true,"evidence_text":"c.764G > A","llm_judgment":"PRESENT","evidence":"c.764G > A","abstract_start":592,"abstract_end":602}]}
{"pmid":"33158637","title":"PNPT1 mutations may cause Aicardi-Goutières-Syndrome.","abstract":"BACKGROUND: Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogenous autoinflammatory disorder caused by constitutive activation of the type I interferon axis. It has been associated with the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1. The clinical diagnosis of AGS is usually made in the context of early-onset encephalopathy in combination with basal ganglia calcification or white matter abnormalities on cranial MRI and laboratory prove of interferon I activation.\nCASE PRESENTATION: We report a patient with early-onset encephalopathy, severe neurodevelopmental regression, progressive secondary microcephaly, epilepsy, movement disorder, and white matter hyperintensities on T2 weighted MRI images. Via whole-exome sequencing, we identified a novel homozygous missense variant (c.1399C > T, p.Pro467Ser) in PNPT1 (NM_033109). Longitudinal assessment of the interferon signature showed a massively elevated interferon score and chronic type I interferon-mediated autoinflammation.\nCONCLUSION: Bi-allelic mutations in PNPT1 have been reported in early-onset encephalopathy. Insufficient nuclear RNA import into mitochondria with consecutive disruption of the respiratory chain was proposed as the main underlying pathomechanism. Recent studies have shown that PNPT1 deficiency causes an accumulation of double-stranded mtRNAs in the cytoplasm, leading to aberrant type I interferon activation, however, longitudinal assessment has been lacking. Here, we present a case of AGS with continuously elevated type I interferon signature with a novel likely-pathogenic homozygous PNTP1 variant. We highlight the clinical value of assessing the interferon signature in children with encephalopathy of unknown origin and suggest all patients presenting with a phenotype of AGS should be screened for mutations in PNPT1.","variants":[{"Name":"NM_033109.5(PNPT1):c.1399C>T (p.Pro467Ser)","Chromosome":"2","Start":"55656173","Stop":"55656173","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":859180,"rule_based_match":true,"evidence_text":"c.1399C > T, p.Pro467Ser","llm_judgment":"PRESENT","evidence":"c.1399C > T, p.Pro467Ser","abstract_start":826,"abstract_end":850}]}
{"pmid":"21909610","title":"The mutations of germline succinate dehydrogrnase subunit B (SDHB) in sporadic paragangliomas","abstract":"PURPOSE: The purpose of this study was to investigate the somatic mutations of human mitochondria succinate dehydrogenase subunit B (SDHB) in sporadic paragangliomas.\nMETHODS: Eight exons of SDHB gene in 8 sporadic paragangliomas cases were amplified by PCR and sequenced, respectively. The sequences were analyzed to find mutations compared with human homology sequence in Genebank and SNP database.\nRESULTS: Nine sequence variations were found in 8 cases, in which one mutation was found in one case (1/8, 12.5%). The mutation was identified as the sixty four base pair in exon 2 of SDHB(c.136C>T), resulting in a change from a arginine to a stop codon (p.Arg90X). The left 8 variations were polymorphisms.\nCONCLUSIONS: The mutation of SDHB exists in sporadic paragangliomas patients and it might play a significant role in paragangliomas tumorigenesis.","variants":[{"Name":"NM_003000.3(SDHB):c.136C>T (p.Arg46Ter)","Chromosome":"1","Start":"17044825","Stop":"17044825","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":152477,"rule_based_match":true,"evidence_text":"c.136C>T","llm_judgment":"PRESENT","evidence":"c.136C>T","abstract_start":590,"abstract_end":598}]}
{"pmid":"31651342","title":"Pathogenic Cav3.2 channel mutation in a child with primary generalized epilepsy.","abstract":"Two paternally-inherited missense variants in CACNA1H were identified and characterized in a 6-year-old child with generalized epilepsy. Febrile and unprovoked seizures were present in this child. Both variants were expressed in cis or isolation using human recombinant Cav3.2 calcium channels in tsA-201 cells. Whole-cell patch-clamp recordings indicated that one variant (c.3844C > T; p.R1282W) caused a significant increase in current density consistent with a pathogenic gain-of-function phenotype; while the other cis-related variant (c.5294C > T; p.A1765V) had a benign profile.","variants":[{"Name":"NM_021098.3(CACNA1H):c.3844C>T (p.Arg1282Trp)","Chromosome":"16","Start":"1210134","Stop":"1210134","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1513919,"rule_based_match":true,"evidence_text":"c.3844C > T; p.R1282W","llm_judgment":"PRESENT","evidence":"c.3844C > T; p.R1282W","abstract_start":374,"abstract_end":395}]}
{"pmid":"27073431","title":"Delayed diagnosis of Townes-Brocks syndrome with multicystic kidneys and renal failure caused by a novel","abstract":"Townes-Brocks syndrome (TBS) is a rare autosomal dominant congenital anomaly syndrome characterized by the triad of anorectal, hand and external ear malformations. Kidney involvement is less common and may progress to end-stage renal failure (ESRF) early in life. The present study reports the case of a male patient presenting with multiple bilateral cortical kidney cysts at the age of 4 years, at which time the kidneys were of normal size and function. A clinical diagnosis of autosomal recessive polycystic kidney disease was made initially as the patient's parents are clinically healthy. However, the consideration of extra-renal involvements (imperforate anus at birth, preaxial polydactyly and dysplastic right ear) following the progression of the patient to ESRF at the age of 16 years, led to the diagnosis of TBS. This prompted sequencing of the SALL1 gene, which identified a novel heterozygous nonsense mutation in the mutational 'hotspot' of exon 2 (c.874C>T, p.Q292X), and this mutation was not detected in healthy controls. The current case highlights that TBS may present with normal sized, cystic kidneys in childhood, while recognition of extra-renal features of cystic kidney diseases, such as TBS, and genetic testing may facilitate the correct diagnosis and transmission mode. Reaching a correct diagnosis of as TBS is important since this condition has a 50% rate of transmission to offspring and can progress to ESRF early in life.","variants":[{"Name":"NM_002968.3(SALL1):c.874C>T (p.Gln292Ter)","Chromosome":"16","Start":"51141348","Stop":"51141348","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1871416,"rule_based_match":true,"evidence_text":"c.874C>T, p.Q292X","llm_judgment":"PRESENT","evidence":"c.874C>T, p.Q292X","abstract_start":966,"abstract_end":983}]}
{"pmid":"37743782","title":"De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities.","abstract":"The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.","variants":[{"Name":"NM_145166.4(ZBTB47):c.2039A>G (p.Glu680Gly)","Chromosome":"3","Start":"42664393","Stop":"42664393","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":2403696,"rule_based_match":true,"evidence_text":"c.2039A>G","llm_judgment":"PRESENT","evidence":"c.2039A>G","abstract_start":719,"abstract_end":728}]}
{"pmid":"22781091","title":"Atrioventricular canal defect in patients with RASopathies.","abstract":"Congenital heart defects affect 60-85% of patients with RASopathies. We analysed the clinical and molecular characteristics of atrioventricular canal defect in patients with mutations affecting genes coding for proteins with role in the RAS/MAPK pathway. Between 2002 and 2011, 101 patients with cardiac defect and a molecularly confirmed RASopathy were collected. Congenital heart defects within the spectrum of complete or partial (including cleft mitral valve) atrioventricular canal defect were diagnosed in 8/101 (8%) patients, including seven with a PTPN11 gene mutation, and one single subject with a RAF1 gene mutation. The only recurrent mutation was the missense PTPN11 c.124 A>G change (T42A) in PTPN11. Partial atrioventricular canal defect was found in six cases, complete in one, cleft mitral valve in one. In four subjects the defect was associated with other cardiac defects, including subvalvular aortic stenosis, mitral valve anomaly, pulmonary valve stenosis and hypertrophic cardiomyopathy. Maternal segregation of PTPN11 and RAF1 gene mutations occurred in two and one patients, respectively. Congenital heart defects in the affected relatives were discordant in the families with PTPN11 mutations, and concordant in that with RAF1 mutation. In conclusion, our data confirm previous reports indicating that atrioventricular canal defect represents a relatively common feature in Noonan syndrome. Among RASopathies, atrioventricular canal defect was observed to occur with higher prevalence among subjects with PTPN11 mutations, even though this association was not significant possibly because of low statistical power. Familial segregation of atrioventricular canal defect should be considered in the genetic counselling of families with RASopathies.","variants":[{"Name":"NM_002834.5(PTPN11):c.124A>G (p.Thr42Ala)","Chromosome":"12","Start":"112446385","Stop":"112446385","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":48952,"rule_based_match":true,"evidence_text":"PTPN11 c.124 A>G change (T42A)","llm_judgment":"PRESENT","evidence":"PTPN11 c.124 A>G change (T42A)","abstract_start":673,"abstract_end":703}]}
{"pmid":"27519903","title":"Two novel MYH7 proline substitutions cause Laing Distal Myopathy-like phenotypes with variable expressivity and neck extensor contracture.","abstract":"BACKGROUND: Human skeletal muscles express three major myosin heavy chain (MyHC) isoforms: MyHCIIx (MYH1) in fast type 2B muscle fibers, MyHCIIa (MYH2) in fast type 2A fibers and MyHCI/β-cardiac MyHC (MYH7) in slow type I skeletal fibers and cardiac ventricles. In line with its expression pattern, MYH7 mutations have been reported in association with hypertrophic or dilated cardiomyopathy, skeletal myopathies or a combination of both. We analyzed the clinical and molecular phenotype of two unrelated families of Jewish Moroccan ancestry that presented with apparently autosomal dominant inheritance of progressive Laing-like distal myopathy with non-specific myopathic changes, but uncommon marked contractures and wasting of the neck extensors.\nMETHODS: Clinical phenotyping, whole exome sequencing and restriction analysis, generation of mutants followed by cell culture transfection and imaging.\nRESULTS: Using whole exome sequencing we identified in both families two novel heterozygous proline substitutions located in exon 31 of MYH7 within its rod domain: c.4309G>C (p.Ala1437Pro) and c.4301G>C (p.Arg1434Pro). Here we show that the phenotype caused by these mutations includes marked cervical muscle contracture, and report that the severity of the phenotype varies significantly, to the extent of non-penetrance in one of the families. Finally, we provide evidence that both proline substitutions impair myosin self-assembly in non-muscle cells transfected with β-myosin constructs carrying the mutations, but do not prevent incorporation of the mutant molecules into the sarcomere.\nCONCLUSIONS: This study expands our clinical and molecular knowledge of MYH7 rod mutations causing skeletal myopathies, and underscores the importance of discussing disease penetrance during genetic counseling.","variants":[{"Name":"NM_000257.4(MYH7):c.4309G>C (p.Ala1437Pro)","Chromosome":"14","Start":"23417547","Stop":"23417547","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":2839444,"rule_based_match":true,"evidence_text":"c.4309G>C (p.Ala1437Pro)","llm_judgment":"PRESENT","evidence":"c.4309G>C (p.Ala1437Pro)","abstract_start":1068,"abstract_end":1092},{"Name":"NM_000257.4(MYH7):c.4301G>C (p.Arg1434Pro)","Chromosome":"14","Start":"23417555","Stop":"23417555","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":841269,"rule_based_match":true,"evidence_text":"c.4301G>C (p.Arg1434Pro)","llm_judgment":"PRESENT","evidence":"c.4301G>C (p.Arg1434Pro)","abstract_start":1097,"abstract_end":1121}]}
{"pmid":"26493561","title":"Identification of novel mutations by targeted exome sequencing and the genotype-phenotype assessment of patients with achromatopsia.","abstract":"BACKGROUND: Achromatopsia (ACHM) is a severe congenital autosomal recessive retinal disorder caused by loss of cone photoreceptors. Here, we aimed to determine the underlying genetic lesions and phenotypic correlations in two Chinese families with ACHM.\nMETHODS: Medical history and clinical evaluation were obtained from both families. Targeted exome sequencing (TES) was performed on 201 disease-causing genes of inherited retinal dystrophies to screen for ACHM causative mutations in the two probands.\nRESULTS: The compound heterozygous mutations in CNGA3 (c.1074G > A, p.W358X; c.1706G > A, p.R569H) were identified in the first proband, and a novel homozygous mutation (c.968C > A, p.A323D) was detected in the other pedigree. The proposed topological model of the CNGA3 polypeptide suggested that the missense mutations primarily affected the transmembrane helix 5 and the cGMP-binding domain, respectively. Crystal structure modeling of the cyclic nucleotide-gated cation channel α-3 (CNGA3) protein encoded by the CNGA3 gene revealed an abnormal combined structure generated by R569H.\nCONCLUSIONS: We firstly used the TES approach to identify genetic alterations in patients with ACHM. We uncovered three mutations in CNGA3, including one novel mutation. Our results not only expand the genotypic spectrum for CNGA3 mutations, but also demonstrate that the TES approach is a valuable tool for molecular diagnosis.","variants":[{"Name":"NM_001298.3(CNGA3):c.1074G>A (p.Trp358Ter)","Chromosome":"2","Start":"98396244","Stop":"98396244","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1384696,"rule_based_match":true,"evidence_text":"c.1074G > A, p.W358X","llm_judgment":"PRESENT","evidence":"c.1074G > A, p.W358X","abstract_start":560,"abstract_end":580},{"Name":"NM_001298.3(CNGA3):c.1706G>A (p.Arg569His)","Chromosome":"2","Start":"98396876","Stop":"98396876","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":827196,"rule_based_match":true,"evidence_text":"c.1706G > A, p.R569H","llm_judgment":"PRESENT","evidence":"c.1706G > A, p.R569H","abstract_start":582,"abstract_end":602}]}
{"pmid":"22744660","title":"PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population.","abstract":"OBJECTIVE: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterized by recurrent attacks of hyperkinetic movements. PKD can be isolated or associated with benign infantile seizures as part of the infantile convulsions with choreoathetosis (ICCA) syndrome. Mutations in the PRRT2 gene were recently identified in patients with PKD and ICCA. We studied the prevalence of PRRT2 mutations and characteristics of the patients in a European population of patients with PKD and ICCA.\nMETHODS: Patients were recruited through the 1996-2011 database of our DNA bank, to which physicians refer DNA with a putative diagnosis and clinical information. Two movement disorders experts reviewed the information on patients with a putative diagnosis of PKD. Patients who fulfilled the criteria for PKD and ICCA were included. The PRRT2 coding sequence was analyzed by direct sequencing.\nRESULTS: Among 42 index cases of unrelated families referred with a putative diagnosis of PKD, a total of 34 patients, including 32 with isolated PKD and 2 with ICCA, were selected for genetic analysis. Mutations introducing premature termination codons were identified in 22 of 34 patients including 13 of 14 families and 9 of 20 patients with sporadic cases. The previously described c.649dupC/pArg217ProfsX8 and c.629dupC/pAla211SerfsX14 were present, respectively, in 17 patients and 1 patient; we also report 3 novel mutations: c.649delC/pArg217GlufsX12 in 2 patients, and c.562C>T/pGln188X and c.649C>T/pArg217X, each in 1 patient. The group with mutations was characterized by a younger age at onset (9 years) compared with the patients without mutations (15 years; p < 0.01).\nCONCLUSION: Mutations in PRRT2 are a major cause of PKD in familial and sporadic cases in the European population.","variants":[{"Name":"NM_145239.3(PRRT2):c.649C>T (p.Arg217Ter)","Chromosome":"16","Start":"29813703","Stop":"29813703","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":466366,"rule_based_match":true,"evidence_text":"c.649C>T/pArg217X","llm_judgment":"PRESENT","evidence":"c.649C>T/pArg217X","abstract_start":1487,"abstract_end":1504},{"Name":"NM_145239.3(PRRT2):c.629dup (p.Ala211fs)","Chromosome":"16","Start":"29813676","Stop":"29813677","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"TC","allel_id":40128,"rule_based_match":true,"evidence_text":"c.629dupC/pAla211SerfsX14","llm_judgment":"PRESENT","evidence":"c.629dupC/pAla211SerfsX14","abstract_start":1302,"abstract_end":1327},{"Name":"NM_145239.3(PRRT2):c.562C>T (p.Gln188Ter)","Chromosome":"16","Start":"29813616","Stop":"29813616","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":48352,"rule_based_match":true,"evidence_text":"c.562C>T/pGln188X","llm_judgment":"PRESENT","evidence":"c.562C>T/pGln188X","abstract_start":1465,"abstract_end":1482},{"Name":"NM_145239.3(PRRT2):c.649del (p.Arg217fs)","Chromosome":"16","Start":"29813695","Stop":"29813695","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":48351,"rule_based_match":true,"evidence_text":"c.649delC/pArg217GlufsX12","llm_judgment":"PRESENT","evidence":"c.649delC/pArg217GlufsX12","abstract_start":1420,"abstract_end":1445},{"Name":"NM_145239.3(PRRT2):c.649dup (p.Arg217fs)","Chromosome":"16","Start":"29813694","Stop":"29813695","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GC","allel_id":76666,"rule_based_match":true,"evidence_text":"c.649dupC/pArg217ProfsX8","llm_judgment":"PRESENT","evidence":"c.649dupC/pArg217ProfsX8","abstract_start":1273,"abstract_end":1297}]}
{"pmid":"33471711","title":"Germline GCM2 Mutation Screening in Chinese Primary Hyperparathyroidism Patients.","abstract":"OBJECTIVE: Glial cell missing 2 (GCM2), the critical regulator in the development of parathyroid glands, has been associated with the pathogenesis of primary hyperparathyroidism (PHPT). Relevant data in Chinese and other Asian populations are still lacking. This study aimed to screen the germline mutations of GCM2 in Chinese PHPT patients.\nMETHODS: A total of 232 patients diagnosed with PHPT at the Peking Union Medical College Hospital from July, 2016, to February, 2019, were screened using targeted next-generation sequencing to identify rare variants of 8 candidate genes associated with PHPT, including GCM2. Luciferase assays were performed to determine the functional impact of the GCM2 variants.\nRESULTS: Four male patients were found to carry 3 rare missense variants of the GCM2 gene, including c.1162A>G (p.K388E), c.1144G>A (p.V382M), and c.1247A>G (p.Y416C). Two variants (p.K388E and p.V382M) located within a highly conserved region were associated with GCM2 transactivation function. The 2 cases carrying the p.K388E mutation had a pathology of carcinoma, and the case with the p.V382M mutation had atypical adenoma.\nCONCLUSION: This study determined an overall GCM2 gain-of-function mutation frequency of 1.3% in a relatively large-sample-sized Chinese PHPT cohort and supported a higher malignant tendency in cases carrying activating GCM2 mutations. Hence, preoperative screening for these GCM2 mutations might be beneficial to treatment decisions, and longer follow-up for such patients is recommended.","variants":[{"Name":"NM_004752.4(GCM2):c.1144G>A (p.Val382Met)","Chromosome":"6","Start":"10874372","Stop":"10874372","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":895185,"rule_based_match":true,"evidence_text":"c.1144G>A (p.V382M)","llm_judgment":"PRESENT","evidence":"c.1144G>A (p.V382M)","abstract_start":829,"abstract_end":848}]}
{"pmid":"29737433","title":"Report of a bi-allelic truncating germline mutation in TP53.","abstract":"The TP53 gene is fundamental to genomic integrity, cell cycle regulation, and apoptosis; it is the most commonly mutated gene in human cancer. Heterozygous germline mutations cause the autosomal dominant cancer predisposition syndrome, Li-Fraumeni Syndrome. Homozygous germline TP53 mutations in humans are rare. We report an infant from a consanguineous family who presented with synchronous malignancies. Remarkably, he carries a homozygous germline TP53 mutation (NM_000546.4:c.52delA), predicted to cause protein truncation. The family history is consistent with Li-Fraumeni syndrome.","variants":[{"Name":"NM_000546.6(TP53):c.52del (p.Thr18fs)","Chromosome":"17","Start":"7676543","Stop":"7676543","ReferenceAlleleVCF":"GT","AlternateAlleleVCF":"G","allel_id":236518,"rule_based_match":true,"evidence_text":"NM_000546.4:c.52delA","llm_judgment":"PRESENT","evidence":"NM_000546.4:c.52delA","abstract_start":467,"abstract_end":487}]}
{"pmid":"21264817","title":"Novel exon nucleotide deletion causes adrenoleukodystrophy in a Brazilian family.","abstract":"Adrenoleukodystrophy is a neurodegenerative X-linked recessive disorder. It is characterized by abnormal function of peroxisomes, which leads to an accumulation of very long-chain fatty acids in plasma and tissues, especially in the cortex of adrenal glands and white matter of the central nervous system, causing demyelinating disease and adrenocortical insufficiency (Addison's disease). It is caused by a mutation in the ABCD1 gene (ATP-binding cassette, subfamily D, member 1), which encodes the protein adrenoleukodystrophy that is involved in the transport of fatty acids into the peroxisome for degradation. Variable expression has been recognized in families of patients who have this disease. A Brazilian family from Minas Gerais State, Brazil, was studied. The proband is an adult living in Minas Gerais State, Brazil; he had adrenomyeloneuropathy, adrenocortical insufficiency and a stable cerebral form. DNA was extracted from a blood sample and was sequenced to identify the mutation. The patient's exons were cloned for confirmation. A new mutation was found in exon 5 of the ABCD1 gene (c.1430delA), as well as a single-nucleotide polymorphism in exon 6. The mutation causes a frame shift, resulting in a truncated protein with almost total absence of the ATP binding domain.","variants":[{"Name":"NM_000033.4(ABCD1):c.1430del (p.Glu477fs)","Chromosome":"X","Start":"153737193","Stop":"153737193","ReferenceAlleleVCF":"GA","AlternateAlleleVCF":"G","allel_id":1677511,"rule_based_match":true,"evidence_text":"c.1430delA","llm_judgment":"PRESENT","evidence":"c.1430delA","abstract_start":1102,"abstract_end":1112}]}
{"pmid":"27576954","title":"Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations.","abstract":"Osteogenesis Imperfecta (OI) is an inherited bone fragility disorder most commonly associated with autosomal dominant mutations in the type I collagen genes. Autosomal recessive mutations in a number of genes have also been described, including the BMP1 gene that encodes the mammalian Tolloid (mTLD) and its shorter isoform bone morphogenic protein-1 (BMP1). To date, less than 20 individuals with OI have been identified with BMP1 mutations, with skeletal phenotypes ranging from mild to severe and progressively deforming. In the majority of patients, bone fragility was associated with increased bone mineral density (BMD); however, the full range of phenotypes associated with BMP1 remains unclear. Here, we describe three children with mutations in BMP1 associated with a highly variable phenotype: a sibship homozygous for the c.2188delC mutation that affects only the shorter BMP1 isoform and a further patient who is compound heterozygous for a c.1293C>G nonsense mutation and a c.1148G>A missense mutation in the CUB1 domain. These individuals had recurrent fractures from early childhood, are hypermobile and have no evidence of dentinogenesis imperfecta. The homozygous siblings with OI had normal areal BMD by dual energy X-ray absorptiometry whereas the third patient presented with a high bone mass phenotype. Intravenous bisphosphonate therapy was started in all patients, but discontinued in two patients and reduced in another due to concerns about increasing bone stiffness leading to chalk-stick fractures. Given the association of BMP1-related OI with very high bone material density, concerns remain whether anti-resorptive therapy is indicated in this ultra-rare form of OI.© 2016 Wiley Periodicals, Inc.","variants":[{"Name":"NM_006129.5(BMP1):c.1148G>A (p.Arg383Gln)","Chromosome":"8","Start":"22192119","Stop":"22192119","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":3534591,"rule_based_match":true,"evidence_text":"c.1148G>A","llm_judgment":"PRESENT","evidence":"c.1148G>A","abstract_start":988,"abstract_end":997}]}
{"pmid":"32236636","title":"Mutational spectrum and classification of novel mutations in patients with metastatic gastrointestinal stromal tumours.","abstract":"In total, ~85% of malignant gastrointestinal stromal tumours (GISTs) harbour activating mutations in one of the genes KIT or PDGFRA, while 10‑15% of all GISTs have no detectable KIT or PDGFRA mutations, but could have alterations in genes of the succinate dehydrogenase complex or in BRAF, PIK3CA or rarely RAS family genes. The clinical benefit of tyrosine kinase inhibitors, such as imatinib, depends on the GIST genotype, therefore molecular characterization of GIST has a crucial role in overall management of GIST. The aim of the present study was to molecularly characterize a cohort of 70 patients with metastatic GISTs from the Slovenian Cancer Registry (National Cancer Registry) treated between January 2002 and December 2011. Exons 9, 11, 13 and 17 of the KIT gene and exons 12, 14 and 18 of the PDGFRA gene were analysed by direct Sanger sequencing. All KIT/PDGFRA wild‑type GISTs were tested for the presence of mutations in hot spot regions of KRAS, NRAS, BRAF, PIK3CA and AKT1 genes. Novel variants were characterized and classified using Cancer Genome Interpreter and according to The American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. In total, 60 (85.7%) patients had mutations in KIT and 2 (2.9%) in PDGFRA. Whereas, 8 (11.4%) patients with GIST had no mutation in either of the analysed genes. The majority of GIST cases (n=52) had a mutation in KIT exon 11, where 40 different mutations were detected. Eight of the variants were novel: c.1652_1672del, c.1653_1660delinsAA, c.1665_1672delinsCC, c.1668_1686del, c.1676_1720del, c.1715_1756dup, c.1721_1765dup, and c.1722_1766dup. Mutation frequencies of KIT and PDGFRA genes observed in Slovenian patients are comparable with those in other European populations. In the present group of patients analysed, the most frequently mutated region was exon 11 in the KIT gene, responsible for coding juxtamembrane domain of KIT protein. In this region, eight novel mutations were identified and classified as likely pathogenic driver variants. In addition, the present study identified 6 patients with secondary KIT mutation and 1 patient with double mutant GIST, who had two different mutations in PDGFRA exon 14.","variants":[{"Name":"NM_000222.3(KIT):c.1652_1672del (p.Pro551_Lys558delinsGln)","Chromosome":"4","Start":"54727420","Stop":"54727440","ReferenceAlleleVCF":"CCCATGTATGAAGTACAGTGGA","AlternateAlleleVCF":"C","allel_id":615992,"rule_based_match":true,"evidence_text":"c.1652_1672del","llm_judgment":"PRESENT","evidence":"c.1652_1672del","abstract_start":1504,"abstract_end":1518},{"Name":"NM_000222.3(KIT):c.1722_1766dup (p.Gln575_Leu589dup)","Chromosome":"4","Start":"54727489","Stop":"54727490","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CACAACTTCCTTATGATCACAAATGGGAGTTTCCCAGAAACAGGCT","allel_id":615999,"rule_based_match":true,"evidence_text":"c.1722_1766dup","llm_judgment":"PRESENT","evidence":"c.1722_1766dup","abstract_start":1630,"abstract_end":1644}]}
{"pmid":"26586665","title":"BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.","abstract":"BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.\nMETHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.\nRESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.\nCONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.","variants":[{"Name":"NM_000059.4(BRCA2):c.9976A>T (p.Lys3326Ter)","Chromosome":"13","Start":"32398489","Stop":"32398489","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"T","allel_id":46822,"rule_based_match":true,"evidence_text":"BRCA2*c.9976A>T; p.Lys3326*","llm_judgment":"PRESENT","evidence":"BRCA2*c.9976A>T; p.Lys3326*","abstract_start":41,"abstract_end":68}]}
{"pmid":"28762473","title":"Late diagnosis and atypical brain imaging of Aicardi-Goutières syndrome: are we failing to diagnose Aicardi-Goutières syndrome-2?","abstract":"Aicardi-Goutières syndrome (AGS) is a rare disorder with in utero or postnatal onset of encephalopathy and progressive neurological deterioration. The seven genetic subtypes of AGS are associated with abnormal type I interferon-mediated innate immune response. Most patients with AGS present with progressive microcephaly, spasticity, and cognitive impairment. Some, especially those with type 2 (AGS2), manifest milder phenotypes, reduced childhood mortality, and relative preservation of physical and cognitive abilities. In this report, we describe two siblings (sister and brother) diagnosed with AGS2 in their second decade, who exhibited static encephalopathy since 1 year of age with spastic quadriplegia and anarthria but preserved intellect. Both were homozygous for the common pathogenic RNASEH2B allele (c.529G>A, p.Ala177Thr). Rather than manifesting calcifications and leukoencephalopathy, both had increased iron signal in the basal ganglia. Our report broadens the clinical and imaging spectrum of AGS2 and emphasizes the importance of including AGS2 in the differential diagnosis of idiopathic spastic cerebral palsy.\nWHAT THIS PAPER ADDS: We identified two siblings (sister and brother) with atypical Aicardi-Goutières syndrome type 2 due to RNASEH2B mutation. Manifestations included spastic quadriplegia and anarthria but preserved intellect and increased iron signal in the basal ganglia. RNASEH2B-related Aicardi-Goutières syndrome type 2 can have present with a variable phenotype, including idiopathic spastic cerebral palsy.","variants":[{"Name":"NM_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr)","Chromosome":"13","Start":"50945445","Stop":"50945445","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":16301,"rule_based_match":true,"evidence_text":"c.529G>A, p.Ala177Thr","llm_judgment":"PRESENT","evidence":"c.529G>A, p.Ala177Thr","abstract_start":815,"abstract_end":836}]}
{"pmid":"28585349","title":"CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy.","abstract":"De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy. One of them presented pharmacoresistant myoclonic epilepsy. We identified two de novo splice variants (c.175+2T>G; c.367+2T>C) in the CSNK2B gene encoding the β subunit of the Caseine kinase 2 (CK2). CK2 is a ubiquitously expressed kinase that is present in high levels in brain and it appears to be constitutively active. The mRNA transcripts were abnormal and significantly reduced in affected fibroblasts and most likely produced truncated proteins. Taking into account that mutations in CSNK2A1, encoding the α subunit of CK2, were previously identified in patients with neurodevelopmental disorders and dysmorphic features, our study confirmed that the protein kinase CK2 plays a major role in brain, and showed that CSNK2, encoding the β subunit, is a novel ID gene. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy, and highlights CSNK2B as a new gene for neurodevelopmental disorders.","variants":[{"Name":"NM_001320.7(CSNK2B):c.367+2T>C","Chromosome":"6","Start":"31669174","Stop":"31669174","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":800763,"rule_based_match":true,"evidence_text":"c.367+2T>C","llm_judgment":"PRESENT","evidence":"c.367+2T>C","abstract_start":643,"abstract_end":653},{"Name":"NM_001320.7(CSNK2B):c.175+2T>G","Chromosome":"6","Start":"31667972","Stop":"31667972","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":794103,"rule_based_match":true,"evidence_text":"c.175+2T>G","llm_judgment":"PRESENT","evidence":"c.175+2T>G","abstract_start":631,"abstract_end":641}]}
{"pmid":"25606469","title":"A novel GLI3c.750delC truncation mutation in a multiplex Greig cephalopolysyndactyly syndrome family with an unusual phenotypic combination in a patient.","abstract":"Greig cephalopolysyndactyly (GCPS) syndrome is an autosomal dominant disorder with high penetrance in majority of cases, characterized by a triad of polysyndactyly, macrocephaly and hypertelorism. GCPS is known to be caused by mutations in the transcription factor GLI3 gene (7p13) which results in functional haploinsufficiency of this gene. The present study reports a large multiplex family having 12 members affected with GCPS in 3 generations and several unaffected members showing autosomal dominant pattern of inheritance with complete penetrance. Interestingly an affected member of the family had unusual features including thumb which is although biphalangeal (confirmed with X-ray) but morphologically looks like finger and a unilateral tiny bony outgrown (externally indistinguishable) on the distal phalanx of the first toe of the left foot. This member also presented with mild ichthyosis. Although it is also possible that one or more of these features are coincidentally present in this member and might not be part of GCPS. Resequencing of the GLI3 gene detected a novel frame-shift mutation c.750delC in heterozygous state transmitting in the family and co-segregating with the disorder suggesting it to be the causal for the GCPS phenotype in the family. In silico analysis suggests that this mutation creates a truncated GLI3 protein resulting in its haploinsufficiency leading to GCPS syndrome. Furthermore, genotype-phenotype correlation is supported by the mutation as it lies in the amino terminal domain of the protein.","variants":[{"Name":"NM_000168.6(GLI3):c.750del (p.Tyr251fs)","Chromosome":"7","Start":"42045460","Stop":"42045460","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":514283,"rule_based_match":true,"evidence_text":"c.750del","llm_judgment":"PRESENT","evidence":"c.750del","abstract_start":1109,"abstract_end":1117}]}
{"pmid":"23227064","title":"A case of mucolipidosis II presenting with prenatal skeletal dysplasia and severe secondary hyperparathyroidism at birth.","abstract":"Mucolipidosis II (ML II) or inclusion cell disease (I-cell disease) is a rarely occurring autosomal recessive lysosomal enzyme-targeting disease. This disease is usually found to occur in individuals aged between 6 and 12 months, with a clinical phenotype resembling that of Hurler syndrome and radiological findings resembling those of dysostosis multiplex. However, we encountered a rare case of an infant with ML II who presented with prenatal skeletal dysplasia and typical clinical features of severe secondary hyperparathyroidism at birth. A female infant was born at 37(+1) weeks of gestation with a birth weight of 1,690 g (<3rd percentile). Prenatal ultrasonographic findings revealed intrauterine growth retardation and skeletal dysplasia. At birth, the patient had characteristic features of ML II, and skeletal radiographs revealed dysostosis multiplex, similar to rickets. In addition, the patient had high levels of alkaline phosphatase and parathyroid hormone, consistent with severe secondary neonatal hyperparathyroidism. The activities of β-D-hexosaminidase and α-N-acetylglucosaminidase were moderately decreased in the leukocytes but were 5- to 10-fold higher in the plasma. Examination of a placental biopsy specimen showed foamy vacuolar changes in trophoblasts and syncytiotrophoblasts. The diagnosis of ML II was confirmed via GNPTAB genetic testing, which revealed compound heterozygosity of c.3091C>T (p.Arg1031X) and c.3456_3459dupCAAC (p.Ile1154GlnfsX3), the latter being a novel mutation. The infant was treated with vitamin D supplements but expired because of asphyxia at the age of 2 months.","variants":[{"Name":"NM_024312.5(GNPTAB):c.3091C>T (p.Arg1031Ter)","Chromosome":"12","Start":"101761171","Stop":"101761171","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":47668,"rule_based_match":true,"evidence_text":"c.3091C>T (p.Arg1031X)","llm_judgment":"PRESENT","evidence":"c.3091C>T (p.Arg1031X)","abstract_start":1417,"abstract_end":1439}]}
{"pmid":"30825425","title":"Exome sequencing identifies compound heterozygous KCTD7 mutations in a girl with progressivemyoclonus epilepsy.","abstract":"Progressive myoclonic epilepsies (PME) are a clinically and genetically heterogeneous group of rare diseases characterized by myoclonic seizures, tonic-clonic seizures, and neurological deterioration. Here, we genetically analyzed a Chinese patient affected by infantile-onset progressive myoclonic epilepsy. We applied next-generation whole exome capture sequencing with Sanger direct sequencing to the proband and her unaffected parents. Two compound heterozygous mutations were identified in the KCTD7 gene. The first mutation [c. 434A > G(p.Q145R)] was inherited from her father, while the second [c.631C > T(p.R211X)] was inherited from her mother. The two were co-segregated with disease phenotype in the family. To our knowledge, this is the first report of KCTD7 mutations causing PME in the Chinese population, with c. 434A > G in particular being a novel mutation. Our findings supported the important role of KCTD7 in PME and broadened the gene's mutation spectrum. Thus, this study contributes to genetic diagnoses and counselling of families with PME.","variants":[{"Name":"NM_153033.5(KCTD7):c.631C>T (p.Arg211Ter)","Chromosome":"7","Start":"66638993","Stop":"66638993","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":369575,"rule_based_match":true,"evidence_text":"c.631C > T(p.R211X)","llm_judgment":"PRESENT","evidence":"c.631C > T(p.R211X)","abstract_start":602,"abstract_end":621}]}
{"pmid":"23712425","title":"Kuskokwim syndrome, a recessive congenital contracture disorder, extends the phenotype of FKBP10 mutations.","abstract":"Recessive mutations in FKBP10 at 17q21.2, encoding FKBP65, cause both osteogenesis imperfecta (OI) and Bruck syndrome (OI plus congenital contractures). Contractures are a variable manifestation of null/missense FKBP10 mutations. Kuskokwim syndrome (KS) is an autosomal recessive congenital contracture disorder found among Yup'ik Eskimos. Linkage mapping of KS to chromosome 17q21, together with contractures as a feature of FKBP10 mutations, made FKBP10 a candidate gene. We identified a homozygous three-nucleotide deletion in FKBP10 (c.877_879delTAC) in multiple Kuskokwim pedigrees; 3% of regional controls are carriers. The mutation deletes the highly conserved p.Tyr293 residue in FKBP65's third peptidyl-prolyl cis-trans isomerase domain. FKBP10 transcripts are normal, but mutant FKBP65 is destabilized to a residual 5%. Collagen synthesized by KS fibroblasts has substantially decreased hydroxylation of the telopeptide lysine crucial for collagen cross-linking, with 2%-10% hydroxylation in probands versus 60% in controls. Matrix deposited by KS fibroblasts has marked reduction in maturely cross-linked collagen. KS collagen is disorganized in matrix, and fibrils formed in vitro had subtle loosening of monomer packing. Our results imply that FKBP10 mutations affect collagen indirectly, by ablating FKBP65 support for collagen telopeptide hydroxylation by lysyl hydroxylase 2, thus decreasing collagen cross-links in tendon and bone matrix. FKBP10 mutations may also underlie other arthrogryposis syndromes.","variants":[{"Name":"NM_021939.4(FKBP10):c.877_879del (p.Tyr293del)","Chromosome":"17","Start":"41819357","Stop":"41819359","ReferenceAlleleVCF":"CACT","AlternateAlleleVCF":"C","allel_id":204645,"rule_based_match":true,"evidence_text":"c.877_879delTAC","llm_judgment":"PRESENT","evidence":"c.877_879delTAC","abstract_start":538,"abstract_end":553}]}
{"pmid":"23146215","title":"Use of miglustat in a child with late-infantile-onset Niemann-Pick disease type C and frequent seizures: a case report.","abstract":"UNLABELLED: \nINTRODUCTION: Niemann-Pick disease type C is a rare genetic lysosomal storage disease associated with impaired intracellular lipid trafficking and a range of progressive neurological manifestations. The influence of seizure activity on disease course and response to miglustat therapy is not currently clear.\nCASE PRESENTATION: Niemann-Pick disease type C homozygous for NPC1 mutation p.S940L [c. 2819 C>T] was diagnosed in a four-and-a-half-year-old Norwegian Caucasian girl. The patient, who died at eight years and seven months of age, had a history of prolonged neonatal jaundice and subsequently displayed progressive neurological manifestations that started with delayed speech, ataxia, and gelastic cataplexy. A regimen of 100mg of miglustat three times a day was initiated when she was four years and 11 months old. She showed decreased neurological deterioration during about three and a half years of treatment. However, she displayed periods of distinct worsening that coincided with frequent epileptic seizures. Anti-epileptic therapy reduced seizure frequency and severity and allowed re-stabilization of her neurological function. Prior to her death, which was possibly due to acute cardiac arrest, seizure activity was well controlled.\nCONCLUSIONS: Miglustat delayed the expected deterioration of neurological function in this patient with p.S940L-homozygous late-infantile-onset Niemann-Pick disease type C and provided important quality-of-life benefits. This case demonstrates the importance of effective seizure control therapy in achieving and maintaining neurological stabilization in Niemann-Pick disease type C.","variants":[{"Name":"NM_000271.5(NPC1):c.2819C>T (p.Ser940Leu)","Chromosome":"18","Start":"23539447","Stop":"23539447","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":187026,"rule_based_match":true,"evidence_text":"c. 2819 C>T","llm_judgment":"PRESENT","evidence":"c. 2819 C>T","abstract_start":407,"abstract_end":418}]}
{"pmid":"36048137","title":"Fetal Presentation of Walker-Warburg Syndrome with Compound Heterozygous","abstract":"<b>Background:</b> Walker-Warburg syndrome (WWS) (OMIM #236670) is an autosomal recessive disorder characterized by congenital muscular dystrophy, hydrocephalus, cobblestone lissencephaly, and retinal dysplasia. The main genes involved are: <i>POMT1, POMT2, POMGNT1, FKTN, LARGE1</i>, and <i>FKRP</i>. <b>Case report:</b> We present a fetus with WWS showing at ultrasound severe triventricular hydrocephalus. Pregnancy was legally terminated at 21 weeks +2 days of gestation. In vivo and postmortem magnetic resonance revealed corpus callosum agenesis and cerebellar hypoplasia. Cobblestone lissencephaly was observed at post-mortem. Next generation sequencing (NGS) of 193 genes, performed on fetal DNA extracted from amniocytes, detected two heterozygous mutations in the <i>POMT2</i> gene. The c.1238G > C p.(Arg413Pro) mutation was paternally inherited and is known to be pathogenic. The c.553G > A p.(Gly185Arg) mutation was maternally inherited and has not been previously described. <b>Conclusion:</b> Compound heterozygous mutations in the <i>POMT2</i> gene caused a severe cerebral fetal phenotype diagnosed prenatally at midgestation allowing therapeutic pregnancy termination.","variants":[{"Name":"NM_013382.7(POMT2):c.1238G>C (p.Arg413Pro)","Chromosome":"14","Start":"77288777","Stop":"77288777","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":18264,"rule_based_match":true,"evidence_text":"c.1238G > C p.(Arg413Pro)","llm_judgment":"PRESENT","evidence":"c.1238G > C p.(Arg413Pro)","abstract_start":797,"abstract_end":822}]}
{"pmid":"23503723","title":"Symmetric snapback primers for scanning and genotyping of the cystic fibrosis transmembrane conductance regulator gene.","abstract":"BACKGROUND: High-resolution melting of PCR products is an efficient and analytically sensitive method to scan for sequence variation, but detected variants must still be identified. Snapback primer genotyping uses a 5' primer tail complementary to its own extension product to genotype the resulting hairpin via melting. If the 2 methods were combined to analyze the same PCR product, the residual sequencing burden could be reduced or even eliminated.\nMETHODS: The 27 exons and neighboring splice sites of the CFTR [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)] gene were amplified by the PCR in 39 fragments. Primers included snapback tails for genotyping 7 common variants and the 23 CFTR mutations recommended for screening by the American College of Medical Genetics. After symmetric PCR, the amplicons were analyzed by high-resolution melting to scan for variants. Then, a 5-fold excess of H2O was added to each reaction to produce intramolecular hairpins for snapback genotyping by melting. Each melting step required <10 min. Of the 133 DNA samples analyzed, 51 were from CFTR patient samples or cell lines.\nRESULTS: As expected, the analytical sensitivity of heterozygote detection in blinded studies was 100%. Snapback genotyping reduced the need for sequencing from 7.9% to 0.5% of PCR products; only 1 amplicon every 5 patients required sequencing to identify nonanticipated rare variants. We identified 2 previously unreported variants: c.3945A>G and c.4243-5C>T.\nCONCLUSIONS: CFTR analysis by sequential scanning and genotyping with snapback primers is a good match for targeted clinical genetics, for which high analytical accuracy and rapid turnaround times are important.","variants":[{"Name":"NM_000492.4(CFTR):c.3945A>G (p.Ile1315Met)","Chromosome":"7","Start":"117652913","Stop":"117652913","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":433041,"rule_based_match":true,"evidence_text":"c.3945A>G","llm_judgment":"PRESENT","evidence":"c.3945A>G","abstract_start":1503,"abstract_end":1512},{"Name":"NM_000492.4(CFTR):c.4243-5C>T","Chromosome":"7","Start":"117666903","Stop":"117666903","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":252573,"rule_based_match":true,"evidence_text":"c.4243-5C>T","llm_judgment":"PRESENT","evidence":"c.4243-5C>T","abstract_start":1517,"abstract_end":1528}]}
{"pmid":"31576025","title":"Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families.","abstract":"X-linked Alport syndrome (XLAS) is an inherited renal disease caused by mutations in COL4A5 gene. The c.2858G>T(p.(G953V)) in COL4A5 gene (rs78972735) has been considered pathogenic previously. However, there are conflicting interpretations of its pathogenicity recently. Here we presented 19 Chinese families, out of which 36 individuals (18 probands and 18 family members) carried the c.2858G>T(p.(G953V)) in COL4A5 gene. The clinical manifestations and genetic findings of them were analyzed. We found there were no clinical features of Alport syndrome not only in six probands with c.2858G>T(p.(G953V)) in COL4A5 plus pathogenic variants in other genes (e.g., WT1, ADCK4, NPHP1, TRPC6, COL4A4, and PAX2) but also in another six probands with only the c.2858G>T(p.(G953V)) variant. The other six probands with a combination of c.2858G>T(p.(G953V)) and another pathogenic variant in COL4A5 had XLAS. Eleven family members (11/18, nine females and two males) who had only the c.2858G>T(p.(G953V)) variant were asymptomatic. These two males (at age of 42 and 35 years) had normal result of urine analysis and no more clinical traits of Alport syndrome. We conclude c.2858G>T(p.(G953V)) in COL4A5 gene is not a pathogenic variant for XLAS. Individuals should not be diagnosed as XLAS only based on the detection of c.2858G>T(p.(G953V)) in COL4A5 gene.","variants":[{"Name":"NM_033380.3(COL4A5):c.2858G>T (p.Gly953Val)","Chromosome":"X","Start":"108622766","Stop":"108622766","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":35914,"rule_based_match":true,"evidence_text":"c.2858G>T(p.(G953V))","llm_judgment":"PRESENT","evidence":"c.2858G>T(p.(G953V))","abstract_start":102,"abstract_end":122}]}
{"pmid":"29656491","title":"Recurrent F8 and F9 gene variants result from a founder effect in two large French haemophilia cohorts.","abstract":"INTRODUCTION: Haemophilia A (HA) and haemophilia B (HB) are X-linked recessive diseases, caused by a large number of pathogenic variants in the F8 and F9 genes. With the exception of introns 22 and 1 inversions which are frequent in severe HA cases, about 2000 unique variants in F8 and 1000 in F9 have been described in databases and their recurrence remains limited.\nAIM AND METHODS: During routine analysis, we identified two recurrent missense variants, the F8 gene c.1244C>T, p.Ala415Val variant in 27 HA patients and the F9 gene c.835G>A, p.Ala279Thr variant in 34 HB patients, in two groups of haemophiliac patients from two different regions of France. We aimed to identify whether these variants result from a founder effect. We performed haplotype reconstruction after analysis of extragenic and intragenic polymorphic markers. The ESTIAGE programme was used to estimate the age of the variant.\nRESULTS: We identified a common ancestral haplotype HA1, in all the HA patients sharing the p.Ala415Val variant, and HB1 for 22 of 34 HB patients sharing the p.Ala279Thr variant. The estimated time of occurrence of the founder variant was between the 13th and 17th century (95% CI: 16 to 29 generations) for the F8 variant and between the 3rd and the 11th century for the F9 variant (95% CI: 44 to 72 generations).\nCONCLUSION: This study supports a founder effect for these two variants in the two largest reported cohorts of haemophilia patients with an identical variant. These pathogenic variants are among the three most early reported variants in haemophilia.","variants":[{"Name":"NM_000133.4(F9):c.835G>A (p.Ala279Thr)","Chromosome":"X","Start":"139560852","Stop":"139560852","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":213664,"rule_based_match":true,"evidence_text":"F9 gene c.835G>A, p.Ala279Thr","llm_judgment":"PRESENT","evidence":"F9 gene c.835G>A, p.Ala279Thr","abstract_start":527,"abstract_end":556}]}
{"pmid":"22781769","title":"Clinical features and screening of ACVRL1 gene in II hereditary hemorrhagic telangiectasia","abstract":"OBJECTIVE: To analyze the clinical features and pathogenic gene of the patients with hereditary hemorrhagic telangiectasia (HHT).\nMETHODS: The clinical features of 3 HHT families were collected. And the patients were diagnosed according to clinical diagnostic analyzed criteria of HHT, the ACVRL1 gene screened and the conservation of mutation protein.\nRESULTS: Three probands and 1 patient were diagnostic for HHT and 2 patients were suspected. In family I, there was a missense mutation of ACVRL1 gene in c.287A > G on 2 patients, leading to the transferal of amino acids from Asn to Ser at 96(th) place. In family II, there was a missense mutation of c.1271C > T on ACVRL1 in 2 patients, leading to the transfer of amino acids from Pro to Leu at 424(th) place. In family III, there was a deletion mutation of c.147delC on ACVRL1 so as to produce only the former 53 amino acids of ALK1 protein. Through an analysis of multi-species conservation, the mutations were conserved between multiple species. By querying the National Center for Biotechnology Information (NCBI) database, we confirmed that the mutation was not of a single nucleotide polymorphism (SNP).\nCONCLUSION: The genetic screening of HHT patients may identify their virulence gene. And genetic screening of their offspring is helpful for the early diagnosis and prevention before disease onset.","variants":[{"Name":"NM_000020.3(ACVRL1):c.287A>G (p.Asn96Ser)","Chromosome":"12","Start":"51913324","Stop":"51913324","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":1855722,"rule_based_match":true,"evidence_text":"c.287A > G","llm_judgment":"PRESENT","evidence":"c.287A > G","abstract_start":507,"abstract_end":517}]}
{"pmid":"23564749","title":"A new seipin-associated neurodegenerative syndrome.","abstract":"BACKGROUND: Seipin/BSCL2 mutations can cause type 2 congenital generalised lipodystrophy (BSCL) or dominant motor neurone diseases. Type 2 BSCL is frequently associated with some degree of intellectual impairment, but not to fatal neurodegeneration. In order to unveil the aetiology and pathogenetic mechanisms of a new neurodegenerative syndrome associated with a novel BSCL2 mutation, six children, four of them showing the BSCL features, were studied.\nMETHODS: Mutational and splicing analyses of BSCL2 were performed. The brain of two of these children was examined postmortem. Relative expression of BSCL2 transcripts was analysed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in different tissues of the index case and controls. Overexpressed mutated seipin in HeLa cells was analysed by immunofluorescence and western blotting.\nRESULTS: Two patients carried a novel homozygous c.985C>T mutation, which appeared in the other four patients in compound heterozygosity. Splicing analysis showed that the c.985C>T mutation causes an aberrant splicing site leading to skipping of exon 7. Expression of exon 7-skipping transcripts was very high with respect to that of the non-skipped transcripts in all the analysed tissues of the index case. Neuropathological studies showed severe neurone loss, astrogliosis and intranuclear ubiquitin(+) aggregates in neurones from multiple cortical regions and in the caudate nucleus.\nCONCLUSIONS: Our results suggest that exon 7 skipping in the BSCL2 gene due to the c.985C>T mutation is responsible for a novel early onset, fatal neurodegenerative syndrome involving cerebral cortex and basal ganglia.","variants":[{"Name":"NM_001122955.4(BSCL2):c.985C>T (p.Arg329Ter)","Chromosome":"11","Start":"62691300","Stop":"62691300","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":153583,"rule_based_match":true,"evidence_text":"c.985C>T","llm_judgment":"PRESENT","evidence":"c.985C>T","abstract_start":908,"abstract_end":916}]}
{"pmid":"23423671","title":"Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome.","abstract":"Leigh syndrome is an early onset, often fatal progressive neurodegenerative disorder caused by mutations in the mitochondrial or nuclear DNA. Until now, mutations in more than 35 genes have been reported to cause Leigh syndrome, indicating an extreme genetic heterogeneity for this disorder, but still only explaining part of the cases. The possibility of whole exome sequencing enables not only mutation detection in known candidate genes, but also the identification of new genes associated with Leigh syndrome in small families and isolated cases. Exome sequencing was combined with homozygosity mapping to identify the genetic defect in a Moroccan family with fatal Leigh syndrome in early childhood and specific magnetic resonance imaging abnormalities in the brain. We detected a homozygous nonsense mutation (c.20C>A; p.Ser7Ter) in the thiamine transporter SLC19A3. In vivo overexpression of wild-type SLC19A3 showed an increased thiamine uptake, whereas overexpression of mutant SLC19A3 did not, confirming that the mutation results in an absent or non-functional protein. Seventeen additional patients with Leigh syndrome were screened for mutations in SLC19A3 using conventional Sanger sequencing. Two unrelated patients, both from Moroccan origin and one from consanguineous parents, were homozygous for the same p.Ser7Ter mutation. One of these patients showed the same MRI abnormalities as the patients from the first family. Strikingly, patients receiving thiamine had an improved life-expectancy. One patient in the third family deteriorated upon interruption of the thiamine treatment and recovered after reinitiating. Although unrelated, all patients came from the province Al Hoceima in Northern Morocco. Based on the recombination events the mutation was estimated to have occurred 1250-1750 years ago. Our data shows that SLC19A3 is a new candidate for mutation screening in patients with Leigh syndrome, who might benefit from high doses of thiamine and/or biotin. Especially, Moroccan patients with Leigh syndrome should be tested for the c.20C>A founder mutation in SLC19A3.","variants":[{"Name":"NM_025243.4(SLC19A3):c.20C>A (p.Ser7Ter)","Chromosome":"2","Start":"227702299","Stop":"227702299","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":171852,"rule_based_match":true,"evidence_text":"c.20C>A (p.Ser7Ter)","llm_judgment":"PRESENT","evidence":"p.Ser7Ter","abstract_start":825,"abstract_end":834}]}
{"pmid":"24122200","title":"Predictive genetic testing in children: constitutional mismatch repair deficiency cancer predisposing syndrome.","abstract":"Biallelic germline mutations in mismatch repair genes predispose to constitutional mismatch repair deficiency syndrome (CMMR-D). The condition is characterized by a broad spectrum of early-onset tumors, including hematological, brain and bowel and is frequently associated with features of Neurofibromatosis type 1. Few definitive screening recommendations have been suggested and no published reports have described predictive testing. We report on the first case of predictive testing for CMMR-D following the identification of two non-consanguineous parents, with the same heterozygous mutation in MLH1: c.1528C > T. The genetic counseling offered to the family, for their two at-risk daughters, is discussed with a focus on the ethical considerations of testing children for known cancer-causing variants. The challenges that are encountered when reporting on heterozygosity in a child younger than 18 years (disclosure of carrier status and risk for Lynch syndrome), when discovered during testing for homozygosity, are addressed. In addition, the identification of CMMR-D in a three year old, and the recommended clinical surveillance that was proposed for this individual is discussed. Despite predictive testing and presymptomatic screening, the sudden death of the child with CMMR-D syndrome occurred 6 months after her last surveillance MRI. This report further highlights the difficulty of developing guidelines, as a result of the rarity of cases and diversity of presentation.","variants":[{"Name":"NM_000249.4(MLH1):c.1528C>T (p.Gln510Ter)","Chromosome":"3","Start":"37028902","Stop":"37028902","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":95235,"rule_based_match":true,"evidence_text":"c.1528C > T","llm_judgment":"PRESENT","evidence":"c.1528C > T","abstract_start":607,"abstract_end":618}]}
{"pmid":"31743498","title":"A novel mutation Gly222Arg in PROS1 causing protein S deficiency in a patient with pulmonary embolism.","abstract":"BACKGROUND: Thrombophilia is becoming a more frequently reported disorder these years. Hereditary protein S deficiency is one of the anticoagulant deficiencies that eventually results in thrombophilia.\nCASE PRESENTATION: A 24-year-old male patient was suffering from unexplained thrombosis for the second time with a family history of deep venous thrombosis. Screening tests for anticoagulant proteins found the activity of protein S markedly lowered (5.0%). The patient was discharged after anticoagulation treatment. Four years later, the review still showed the activity of protein S in his plasma decreased (16.0%). Molecular genetic analysis revealed him homozygous for a missense mutation, c.664G>A, in the exon7 of PROS1. The mutation discovered here is the first mutation affecting the codon 222 of PROS1. This mutation results in the replacement of the glycine at the codon 222 of protein S with arginine, leading to a reduction of protein S function.\nCONCLUSIONS: The finding of this mutation may help with the understanding of the mechanism of protein S deficiency, especially in the Chinese population.","variants":[{"Name":"NM_000313.4(PROS1):c.664G>A (p.Gly222Arg)","Chromosome":"3","Start":"93900867","Stop":"93900867","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":3540148,"rule_based_match":true,"evidence_text":"c.664G>A","llm_judgment":"PRESENT","evidence":"c.664G>A","abstract_start":696,"abstract_end":704}]}
{"pmid":"27621663","title":"Identification of a novel pathogenic OTOF variant causative of nonsyndromic hearing loss with high frequency in the Ashkenazi Jewish population.","abstract":"Mutations in the OTOF gene have previously been shown to cause nonsyndromic prelingual deafness (DFNB9, OMIM 601071) as well as auditory neuropathy/dys-synchrony. In this study, the OTOF NM_194248.2 c.5332G>T, p.Val1778Phe variant was identified in a large Ashkenazi Jewish family as the causative variant in four siblings with hearing loss. Our analysis reveals a carrier frequency of the OTOF c.5332G>T, p.Val1778Phe variant of 1.27% in the Ashkenazi Jewish population, suggesting that this variant may be a significant contributor to nonsyndromic sensorineural hearing loss and should be considered for inclusion in targeted hearing loss panels for this population. Of note, the degree of hearing loss associated with this phenotype ranged from mild to moderately severe, with two of the four siblings not known to have hearing loss until they were genotyped and underwent pure tone audiometry and auditory brainstem response testing. The phenotypic variability along with the auditory neuropathy/dys-synchrony, which allows for the production of otoacoustic emissions, supports that nonsyndromic hearing loss caused by OTOF mutations may be much more common in the Ashkenazi Jewish population than currently appreciated due to a lack of diagnosis.","variants":[{"Name":"NM_194248.3(OTOF):c.5332G>T (p.Val1778Phe)","Chromosome":"2","Start":"26461897","Stop":"26461897","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":57422,"rule_based_match":true,"evidence_text":"OTOF NM_194248.2 c.5332G>T, p.Val1778Phe","llm_judgment":"PRESENT","evidence":"OTOF NM_194248.2 c.5332G>T, p.Val1778Phe","abstract_start":182,"abstract_end":222}]}
{"pmid":"32441320","title":"Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity.","abstract":"Primary immune deficiencies are usually attributed to genetic defects and, therefore, frequently referred to as inborn errors of immunity (IEI). We subjected the genomic DNA of 333 patients with clinical signs of IEI to next generation sequencing (NGS) analysis of 344 immunity-related genes and, in some instances, additional genetic techniques. Genetic causes of the disease were identified in 69/333 (21%) of subjects, including 11/18 (61%) of children with syndrome-associated IEIs, 45/202 (22%) of nonsyndromic patients with Jeffrey Modell Foundation (JMF) warning signs, 9/56 (16%) of subjects with periodic fever, 3/30 (10%) of cases of autoimmune cytopenia, 1/21 (5%) of patients with unusually severe infections and 0/6 (0%) of individuals with isolated elevation of IgE level. There were unusual clinical observations: twins with severe immunodeficiency carried a de novo CHARGE syndrome-associated SEMA3E c.2108C>T (p.S703L) allele; however, they lacked clinical features of CHARGE syndrome. Additionally, there were genetically proven instances of Netherton syndrome, Х-linked agammaglobulinemia, severe combined immune deficiency (SCID), IPEX and APECED syndromes, among others. Some patients carried recurrent pathogenic alleles, such as AIRE c.769C>T (p.R257*), NBN c.657del5, DCLRE1C c.103C>G (p.H35D), NLRP12 c.1054C>T (p.R352C) and c.910C>T (p.H304Y). NGS is a powerful tool for high-throughput examination of patients with malfunction of immunity.","variants":[{"Name":"NM_012431.3(SEMA3E):c.2108C>T (p.Ser703Leu)","Chromosome":"7","Start":"83367806","Stop":"83367806","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":17544,"rule_based_match":true,"evidence_text":"SEMA3E c.2108C>T (p.S703L)","llm_judgment":"PRESENT","evidence":"SEMA3E c.2108C>T (p.S703L)","abstract_start":909,"abstract_end":935}]}
{"pmid":"25851806","title":"Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies.","abstract":"OBJECTIVE: 5-Oxoprolinuria is a rare inherited metabolic disorder caused by a defective gamma-glutamyl cycle resulting from mutations in the genes encoding 5-oxoprolinase (OPLAH) and glutathione synthetase (GSS). No inherited 5-oxoprolinuria case has been reported in mainland China until now. In this study, clinical, biochemical, and genetic aspects of five Chinese 5-oxoprolinuria patients with OPLAH or GSS gene mutations were investigated.\nMETHODS: Three boys and two girls from five unrelated Chinese families with symptomatic 5-oxoprolinuria were identified within the past 3years in Peking University First Hospital. OPLAH and GSS genes were analyzed.\nRESULTS: Patients were hospitalized between the age of 13days to 1year and 3months for hypersomnia, developmental retardation, feeding deficiency, vomiting, icterus and recurrent pneumonia. All patients had significantly elevated urine 5-oxoproline. Three novel mutations (c.1904G>A and c.2813_2815delGGG in Patient 1, c.2978G>T in Patient 2) on OPLAH, on GSS, one novel mutation (c.1252C>T in Patient 3) and a reported mutation (c.491G>A in Patients 3-5) were detected. Patient 4 has homozygous mutation c.491G>A, the others are heterozygous. After treatment by l-carnitine, vitamin E, B1, B2 and coenzyme Q10, three patients with GSS deficiency improved, but the two 5-oxoprolinase-deficient patients did not respond to treatment.\nCONCLUSIONS: 5-Oxoprolinase deficiency and GSS deficiency share some clinical and biochemical features. Genetic analysis is important for the deferential diagnosis. In this study, five Chinese patients had severe central nervous system damage. Antioxidant treatments were proved effective for the three patients with GSS deficiency but not for the two patients with 5-oxoprolinase deficiency.","variants":[{"Name":"NM_000178.4(GSS):c.1252C>T (p.Arg418Ter)","Chromosome":"20","Start":"34929450","Stop":"34929450","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":1021986,"rule_based_match":true,"evidence_text":"c.1252C>T in Patient 3","llm_judgment":"PRESENT","evidence":"c.1252C>T in Patient 3","abstract_start":1041,"abstract_end":1063},{"Name":"NM_000178.4(GSS):c.491G>A (p.Arg164Gln)","Chromosome":"20","Start":"34942488","Stop":"34942488","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":23564,"rule_based_match":true,"evidence_text":"c.491G>A","llm_judgment":"PRESENT","evidence":"c.491G>A","abstract_start":1090,"abstract_end":1098}]}
{"pmid":"33302760","title":"Novel","abstract":"<b>Purpose</b>: To report novel mutations in the <i>FZD4</i> and <i>LRP5 genes</i>, associated with familial exudative vitreoretinopathy (FEVR), and to correlate with clinical features of 7 FEVR patients.<b>Methods</b>: In this retrospective case series, 7 patients who had undergone genetic panel testing and carried a diagnosis of FEVR were identified. Comprehensive ophthalmic examination and direct DNA sequencing of FEVR-associated genes were performed in all patients. Identified sequence variants were analyzed <i>in silico</i>.<b>Results</b>: Eight mutations were identified amongst the 7 patients, that included 4 <i>FZD4</i> mutations and 4 <i>LRP5</i> mutations. Four novel mutations were identified, two in <i>FZD4</i> (c.615delC, p.Y206MfsX34) and (c.964A>T, p.I322F), and two in <i>LRP5</i> (c.2585A>T, p.D862V) and (c.1412 + 1 G > A, splice donor). A broad phenotypic spectrum was noted and no clear genotypic-phenotypic correlation was observed.<b>Conclusion</b>: These findings expand the mutation spectrum of <i>FZD4</i> and <i>LRP5</i>.","variants":[{"Name":"NM_002335.4(LRP5):c.1412+1G>A","Chromosome":"11","Start":"68386713","Stop":"68386713","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":917621,"rule_based_match":true,"evidence_text":"c.1412 + 1 G > A","llm_judgment":"PRESENT","evidence":"c.1412 + 1 G > A","abstract_start":831,"abstract_end":847}]}
{"pmid":"16789645","title":"Triple-A syndrome--the first Chinese patient with novel mutations in the AAAS gene.","abstract":"We report on the first Chinese patient with triple-A syndrome, who presented at 22 months with status epilepticus secondary to hyponatraemia and hypoglycaemia. Subsequent endocrine investigations confirmed primary adrenal insufficiency and aldosterone deficiency. In the presence of achalasia and alacrima, this patient satisfies the diagnostic criteria of triple-A syndrome. Further molecular testing detected compound heterozygous mutations in the AAAS gene: a c.580C --> T transition in exon 7 and a c.771delG single nucleotide deletion in exon 8. Testing of parents and brother confirmed their heterozygous carrier status.","variants":[{"Name":"NM_015665.6(AAAS):c.771del (p.Arg258fs)","Chromosome":"12","Start":"53309640","Stop":"53309640","ReferenceAlleleVCF":"GC","AlternateAlleleVCF":"G","allel_id":1313832,"rule_based_match":true,"evidence_text":"c.771delG","llm_judgment":"PRESENT","evidence":"c.771delG","abstract_start":503,"abstract_end":512}]}
{"pmid":"37907725","title":"Distal hereditary motor neuronopathy as a new phenotype associated with variants in BAG3.","abstract":"OBJECTIVE: To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy.\nMETHODS: This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3.\nRESULTS: Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novel heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members.\nCONCLUSIONS: We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adult-onset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies.","variants":[{"Name":"NM_004281.4(BAG3):c.1513_1514insGGAC (p.Val505fs)","Chromosome":"10","Start":"119677067","Stop":"119677068","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GGGAC","allel_id":3735976,"rule_based_match":true,"evidence_text":"c.1513_1514insGGAC (p.Val505GlyfsTer6)","llm_judgment":"PRESENT","evidence":"c.1513_1514insGGAC (p.Val505GlyfsTer6)","abstract_start":1138,"abstract_end":1176}]}
{"pmid":"23360689","title":"Cardioembolic stroke related to limb-girdle muscular dystrophy 1B.","abstract":"BACKGROUND: Cardioembolic stroke is an under-recognized complication in patients with limb-girdle muscular dystrophy 1B. Here we present a young stroke patient who had a novel lamin A/C gene (LMNA) mutation.\nCASE PRESENTATION: This is a 39-year-old man who had slowly progressive proximal muscle weakness and cardiac arrhythmia since adolescent and a family history of similar manifestation. He sustained acute ischemic stroke in the left middle cerebral artery territory. Intravenous recombinant tissue plasminogen activator therapy was given with significant neurological improvement. Additionally, genetic sequencing of the LMNA gene of the patient identified a mutation in c.513+1 G>A that resulted in a splicing aberration.\nCONCLUSION: We suggested that LMNA gene related myopathies should be considered in young stroke patients with long-standing myopathic features.","variants":[{"Name":"NM_170707.4(LMNA):c.513+1G>A","Chromosome":"1","Start":"156130774","Stop":"156130774","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":244219,"rule_based_match":true,"evidence_text":"c.513+1 G>A","llm_judgment":"PRESENT","evidence":"c.513+1 G>A","abstract_start":677,"abstract_end":688}]}
{"pmid":"28111184","title":"LRP5-linked osteoporosis-pseudoglioma syndrome mimicking isolated microphthalmia.","abstract":"Microphthalmia is defined as the measurement of the total axial length of the eyeball to be below average of the two standard deviation according to the age. While several genes have been identified so far related to microphthalmia, the genetic etiology of the disease has not been fully understood because of genetic heterogeneity observed in this disease. After exclusion of the genes that had been known to be the cause of microphthalmia, we performed homozygosity mapping and exome sequencing to clarify the genetic etiology of the bilateral microphthalmia in this family. When the results of the exome and microarray data were considered together as a splice-site mutation in LRP5 gene [c.2827 + 1G > A], which is known to be important for eye development and Wnt receptor signaling pathway, was found to be the cause of microphthalmia in our family. It was understood that after finding this mutation, when bone mineral density was measured with DXA in the family whose ages range between 19 and 28 and who have no bone problem before, osteoporosis was diagnosed. It was also understood that microphthalmia found in this family is a clinical finding of OPPG syndrome.","variants":[{"Name":"NM_002335.4(LRP5):c.2827+1G>A","Chromosome":"11","Start":"68414013","Stop":"68414013","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":584374,"rule_based_match":true,"evidence_text":"c.2827+1G>A","llm_judgment":"PRESENT","evidence":"c.2827 + 1G > A","abstract_start":692,"abstract_end":707}]}
{"pmid":"21763485","title":"Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis.","abstract":"Inherited retinal degenerations, including retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), comprise a group of disorders showing high genetic and allelic heterogeneity. The determination of a full catalog of genes that can, when mutated, cause human retinal disease is a powerful means to understand the molecular physiology and pathology of the human retina. As more genes are found, remaining ones are likely to be rarer and/or unexpected candidates. Here, we identify a family in which all known RP/LCA-related genes are unlikely to be associated with their disorder. A combination of homozygosity mapping and exome sequencing identifies a homozygous nonsense mutation, c.496C>T (p.Arg166X), in a gene, KCNJ13, encoding a potassium channel subunit Kir7.1. A screen of a further 333 unrelated individuals with recessive retinal degeneration identified an additional proband, homozygous for a missense mutation, c.722T>C (p.Leu241Pro), in the same gene. The three affected members of the two families have been diagnosed with LCA. All have a distinct and unusual retinal appearance and a similar early onset of visual loss, suggesting both impaired retinal development and progressive retinal degeneration, involving both rod and cone pathways. Examination of heterozygotes revealed no ocular disease. This finding implicates Kir7.1 as having an important role in human retinal development and maintenance. This disorder adds to a small diverse group of diseases consequent upon loss or reduced function of inwardly rectifying potassium channels affecting various organs. The distinct retinal phenotype that results from biallelic mutations in KCNJ13 should facilitate the molecular diagnosis in further families.","variants":[{"Name":"NM_002242.4(KCNJ13):c.722T>C (p.Leu241Pro)","Chromosome":"2","Start":"232768552","Stop":"232768552","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":39288,"rule_based_match":true,"evidence_text":"c.722T>C (p.Leu241Pro)","llm_judgment":"PRESENT","evidence":"c.722T>C (p.Leu241Pro)","abstract_start":929,"abstract_end":951},{"Name":"NM_002242.4(KCNJ13):c.496C>T (p.Arg166Ter)","Chromosome":"2","Start":"232768778","Stop":"232768778","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":39287,"rule_based_match":true,"evidence_text":"c.496C>T (p.Arg166X)","llm_judgment":"PRESENT","evidence":"c.496C>T (p.Arg166X)","abstract_start":689,"abstract_end":709}]}
{"pmid":"21856579","title":"Founder mutation for α-sarcoglycan-LGMD2D in a Magdalen Islands Acadian cluster.","abstract":"BACKGROUND: We have recruited a group of four living and reviewed the records of six deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive limb-girdle muscular dystrophy (LGMD). All cases originate from the small archipelago of the Magdalen Islands (population: 13,000) isolated in the Gulf of St-Lawrence.\nMETHODS: Based on the likely sharing of the same founder mutation we completed a 319K SNPs genome-wide scan to identify the disease locus and then screen candidate genes in this region.\nRESULTS: All patients had normal initial motor milestones. They presented with limb girdle weakness at the average age of seven years (5-11). Progressive weakness led to loss of ambulation at a wide range of ages (10-39). Patients also developed macroglossia, large calves and mild to moderate contractures, hyperlordosis and decreased pulmonary function. Creatine kinase levels were elevated (1,800-10,000 U/L) in the first decades, but decreased with progression of disease. Homozygosity mapping uncovered a shared chromosomal region of 6.33Mb. The alpha sarcoglycan (SGCA) gene, mutated in LGMD2D, lay in this candidate interval. Sequencing of all SGCA exons uncovered a shared homozygous missense mutation (c. 229C>T, p.R77C), the most common SGCA mutation internationally reported. Using demographic data, we estimated a high carrier rate of 1/22.\nCONCLUSION: The p.R77C mutation has also been observed in many populations, including in France and Spain (Basques). This corresponds to the first reported recessive founder disease for the Magdalen Islands, an archipelago settled in the XIXth century, largely by Acadian immigrants.","variants":[{"Name":"NM_000023.4(SGCA):c.229C>T (p.Arg77Cys)","Chromosome":"17","Start":"50167653","Stop":"50167653","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":24476,"rule_based_match":true,"evidence_text":"c. 229C>T, p.R77C","llm_judgment":"PRESENT","evidence":"c. 229C>T, p.R77C","abstract_start":1261,"abstract_end":1278}]}
{"pmid":"21232165","title":"The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population.","abstract":"BACKGROUND: the BRCA1 and BRCA2 mutation spectrum and mutation detection rates according to different family histories were investigated in 521 subjects from 322 unrelated Slovenian cancer families with breast and/or ovarian cancer.\nMETHODS: the BRCA1 and BRCA2 genes were screened using DGGE, PTT, HRM, MLPA and direct sequencing.\nRESULTS: eighteen different mutations were found in BRCA1 and 13 in BRCA2 gene. Mutations in one or other gene were found in 96 unrelated families. The mutation detection rates were the highest in the families with at least one breast and at least one ovarian cancer - 42% for BRCA1 and 8% for BRCA2. The mutation detection rate observed in the families with at least two breast cancers with disease onset before the age of 50 years and no ovarian cancer was 23% for BRCA1 and 13% for BRCA2. The mutation detection rate in the families with at least two breast cancers and only one with the disease onset before the age of 50 years was 11% for BRCA1 and 8% for BRCA2. In the families with at least two breast cancers, all of them with disease onset over the age of 50 years, the detection rate was 5% for BRCA2 and 0% for BRCA1.\nCONCLUSION: among the mutations detected in Slovenian population, 5 mutations in BRCA1 and 4 mutations in BRCA2 have not been described in other populations until now. The most frequent mutations in our population were c.181T > G, c.1687C > T, c.5266dupC and c.844_850dupTCATTAC in BRCA1 gene and c.7806-2A > G, c.5291C > G and c.3978insTGCT in BRCA2 gene (detected in 69% of BRCA1 and BRCA2 positive families).","variants":[{"Name":"NM_000059.4(BRCA2):c.7806-2A>G","Chromosome":"13","Start":"32362521","Stop":"32362521","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":67086,"rule_based_match":true,"evidence_text":"c.7806-2A > G","llm_judgment":"PRESENT","evidence":"c.7806-2A > G","abstract_start":1458,"abstract_end":1471},{"Name":"NM_007294.4(BRCA1):c.1687C>T (p.Gln563Ter)","Chromosome":"17","Start":"43093844","Stop":"43093844","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45982,"rule_based_match":true,"evidence_text":"c.1687C > T","llm_judgment":"PRESENT","evidence":"c.1687C > T","abstract_start":1392,"abstract_end":1403}]}
{"pmid":"30222867","title":"Investigation of the variable In(Lu) phenotype caused by KLF1 variants.","abstract":"INTRODUCTION: KLF1 is an essential transcriptional activator that drives erythropoiesis. KLF1 variants can result in the Inhibitor of Lutheran, or In(Lu), phenotype where red blood cells (RBCs) have reduced BCAM (LU) and CD44 (IN). Other RBC surface molecules also have changed expression; however, there is controversy in the literature regarding which are truly impacted. We aimed to investigate KLF1 variants in the Australian population.\nSTUDY DESIGN AND METHODS: In(Lu) samples were sourced through screening and through the RBC reference laboratory. Blood donor samples (8036) were screened to identify weakened/absent Lu<sup>b</sup> antigen. Samples were genotyped by massively parallel sequencing, while surface carbohydrates and blood group molecules were assessed by flow cytometry. Hemoglobin (Hb) types were analyzed by high-performance liquid chromatography.\nRESULTS: Four of 8036 donors were identified to be In(Lu), and two previously identified In(Lu) samples were provided from the RBC reference laboratory. Five different KLF1 variants were identified; two were novel: c.954G>C/p.Trp318Cys and c.421C>T/p.Arg141*. BCAM and CD44 were reduced in all samples, consistent with previous reports. As a group, In(Lu) RBCs had reduced CD35 (KN), ICAM4 (LW), and CD147 (OK), and demonstrated increased binding of lectins ECA and SNAI. One In(Lu) sample had elevated HbF and another elevated HbA2.\nCONCLUSION: Different KLF1 variants may potentially produce variable phenotypes. A framework for investigating KLF1 variants and their phenotypic impact has been provided. In the future, given available international databases, further testing algorithms (as advocated here) will allow for correlation of phenotype with genotype and therefore accurately document this variability between KLF1 variants.","variants":[{"Name":"NM_006563.5(KLF1):c.954G>C (p.Trp318Cys)","Chromosome":"19","Start":"12885020","Stop":"12885020","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"G","allel_id":247752,"rule_based_match":true,"evidence_text":"c.954G>C/p.Trp318Cys","llm_judgment":"PRESENT","evidence":"c.954G>C/p.Trp318Cys","abstract_start":1087,"abstract_end":1107}]}
{"pmid":"32677356","title":"Adult-onset Krabbe disease due to a homozygous GALC mutation without abnormal signals on an MRI in a consanguineous family: A case report.","abstract":"BACKGROUND: The most frequent and common form of Krabbe disease (KD) is early-onset KD in infants, and late-onset KD has been reported to be a rare disease. In the present study, we reported an adult-onset KD patient in a consanguineous Chinese family.\nMETHODS: Clinical and radiological data were collected for a family pedigree. The patient was diagnosed with late-onset KD through next-generation sequencing. The result was confirmed by Sanger sequencing. GALC enzyme activity was also examined by the colorimetry method. Both the grey matter volume (GMV) and white matter volume values were examined and compared with the average values from ten age-matched normal controls. Moreover, we reviewed all the available KD studies on PubMed to understand the correlation between the phenotype and genotype of the identified mutation.\nRESULTS: The main manifestations of the proband were sudden onset seizures and cognitive decline. Mutation analysis of the GALC revealed a homozygous c.1901T>C mutation in exon 16, which resulted in an amino acid change in p.L634S. Sanger sequencing results showed that the homozygous mutation was inherited from the patient's parents, both of whom were revealed to be heterozygous carriers. Moreover, a decrease in GALC enzyme activity was also detected. However, no abnormal signals were found in the brain MRI. Further structural MRI analysis revealed a significantly decreased GMV in the proband compared to the normal controls. Moreover, it is of interest that all patients with the c.1901T>C mutation had late-onset KD and were selected from Asian countries, especially Japan and China.\nCONCLUSIONS: This patient with a homozygous GALC mutation expands the clinical presentation and characteristics of adult-onset KD, as indicated by grey matter atrophy without abnormal white matter signals.","variants":[{"Name":"NM_000153.4(GALC):c.1901T>C (p.Leu634Ser)","Chromosome":"14","Start":"87939915","Stop":"87939915","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":227363,"rule_based_match":true,"evidence_text":"c.1901T>C","llm_judgment":"PRESENT","evidence":"c.1901T>C","abstract_start":983,"abstract_end":992}]}
{"pmid":"28392828","title":"Screening of Wilson's disease in a psychiatric population: difficulties and pitfalls. A preliminary study.","abstract":"BACKGROUND: Wilson's disease (WD) is a rare autosomal-recessive, inherited disorder caused by a mutation in the copper-transporting gene <i>ATP7B</i> affecting the liver and nervous system. About 30% of patients with WD may initially present with psychiatric symptoms, and diagnosis can be difficult to establish. The objectives of the present preliminary study were [1] to evaluate the relevance of serum copper (Cu) and ceruloplasmin (Cp) measures in hospitalized patients with psychiatric disorders; and [2] to identify possible mutations in the <i>ATP7B</i> gene in patients with abnormal biological copper profile.\nMETHODS: All psychiatric patients who participated in this study were hospitalized in Saint-Jean de Dieu Hospital (Lyon, France). Cp was measured by immunoturbidimetry and serum Cu by inductively coupled plasma-optical emission spectrometry. When Cp and serum Cu levels were inferior to, respectively, 0.18 g/L and 0.88 mg/L in combination with atypical psychiatric presentations, complete clinical examinations were performed by multidisciplinary physicians specialized in WD. In addition, mutation detection in the <i>ATP7B</i> gene was performed.\nRESULTS: A total of 269 patients completed the study. (1) 51 cases (19%) showed both decreased Cp and Cu concentrations. (2) Molecular genetic tests were performed in 29 patients, and one <i>ATP7B</i> mutation (heterozygous state) was found in four patients. We identified three different missense mutations: p.His1069Gln, c.3207C>A (exon 14), p.Pro1379Ser, c.4135C>T (exon 21) and p.Thr1434Met, c.4301C>T (exon 21). No pathogenic mutation on either <i>ATP7B</i> allele was detected.\nCONCLUSION: Results of Cp and/or serum Cu concentrations below the normal limits are common in patients with psychiatric disorders and nonrelevant and/or informative for the WD diagnosis. WD diagnosis is based on a combination of clinical and biological arguments. Psychiatric patients with suspicion of WD should be evaluated in a reference center. <i>Trial registration</i> CPP Lyon Sud-Est IVNo 10/044, CNIL No DR-2011-470, Afssaps No B100832-40 and CCTIRS No 10.612 bis, registered 8 June 2010.","variants":[{"Name":"NM_000053.4(ATP7B):c.4301C>T (p.Thr1434Met)","Chromosome":"13","Start":"51934853","Stop":"51934853","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":44394,"rule_based_match":true,"evidence_text":"c.4301C>T (exon 21)","llm_judgment":"PRESENT","evidence":"c.4301C>T (exon 21)","abstract_start":1566,"abstract_end":1585}]}
{"pmid":"32761602","title":"Clinical and genetic analysis of a child with spondyloepimetaphyseal dysplasia type 1 and joint laxity","abstract":"OBJECTIVE: To explore the genetic basis for a child with spondyloepimetaphyseal dysplasia type 1 and joint laxity.\nMETHODS: High-throughput sequencing and Sanger sequencing were used to analyze potential variant of the B3GALT6 gene.\nRESULTS: DNA sequencing has identified 2 variants of the B3GALT6 gene in the patient, namely c.694C>T and c.539_540insCCT, which were respectively derived from his father and mother.\nCONCLUSION: The c.694C>T and c.539_540insCCT variants of the B3GALT6 gene probably underlie the disease in the patient. The result has enabled molecular diagnosis, genetic counseling and prenatal diagnosis for his family.","variants":[{"Name":"NM_080605.4(B3GALT6):c.694C>T (p.Arg232Cys)","Chromosome":"1","Start":"1232972","Stop":"1232972","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":75080,"rule_based_match":true,"evidence_text":"c.694C>T","llm_judgment":"PRESENT","evidence":"c.694C>T","abstract_start":326,"abstract_end":334}]}
{"pmid":"33679716","title":"Life-Threatening Influenza, Hemophagocytic Lymphohistiocytosis and Probable Vaccine-Strain Varicella in a Novel Case of Homozygous","abstract":"STAT2 is a transcription factor that plays an essential role in antiviral immunity by mediating the activity of type I and III interferons (IFN-I and IFN-III). It also has a recently established function in the negative regulation of IFN-I signaling. Homozygous STAT2 deficiency is an ultra-rare inborn error of immunity which provides unique insight into the pathologic consequence of STAT2 dysfunction. We report here a novel genetic cause of homozygous STAT2 deficiency with several notable clinical features. The proband presented aged 12 months with hemophagocytic lymphohistiocytosis (HLH) closely followed by clinical varicella, both occurring within three weeks of measles, mumps, and rubella (MMR) and varicella vaccinations. There was a history of life-threatening influenza A virus (IAV) disease 2 months previously. Genetic investigation uncovered homozygosity for a novel nonsense variant in <i>STAT2</i> (c. 1999C>T, p. Arg667Ter) that abrogated STAT2 protein expression. Compatible with STAT2 deficiency, dermal fibroblasts from the child demonstrated a defect of interferon-stimulated gene expression and a failure to mount an antiviral state in response to treatment with IFN-I, a phenotype that was rescued by lentiviral complementation by wild type <i>STAT2</i>. This case significantly expands the phenotypic spectrum of STAT2 deficiency. The occurrence of life-threatening influenza, which has not previously been reported in this condition, adds <i>STAT2</i> to the list of monogenetic causes of this phenotype and underscores the critical importance of IFN-I and IFN-III to influenza immunity. The development of probable vaccine-strain varicella is also a novel occurrence in STAT2 deficiency, implying a role for IFN-I/III immunity in control of attenuated varicella zoster virus <i>in vivo</i> and reinforcing the susceptibility to pathologic effects of live-attenuated viral vaccines in disorders of IFN-I immunity. Finally, the occurrence of HLH in this case reinforces emerging links to hyperinflammation in patients with STAT2 deficiency and other related defects of IFN-I signaling-highlighting an important avenue for further scientific enquiry.","variants":[{"Name":"NM_005419.4(STAT2):c.1999C>T (p.Arg667Ter)","Chromosome":"12","Start":"56346487","Stop":"56346487","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":566961,"rule_based_match":true,"evidence_text":"c. 1999C>T, p. Arg667Ter","llm_judgment":"PRESENT","evidence":"c. 1999C>T, p. Arg667Ter","abstract_start":919,"abstract_end":943}]}
{"pmid":"17847007","title":"Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia.","abstract":"Odonto-onycho-dermal dysplasia is a rare autosomal recessive syndrome in which the presenting phenotype is dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin. We studied three consanguineous Lebanese Muslim Shiite families that included six individuals affected with odonto-onycho-dermal dysplasia. Using a homozygosity-mapping strategy, we assigned the disease locus to an ~9-cM region at chromosome 2q35-q36.2, located between markers rs16853834 and D2S353, with a maximum multipoint LOD score of 5.7. Screening of candidate genes in this region led us to identify the same c.697G-->T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients. At the protein level, the mutation is predicted to result in a premature truncated protein of 232 aa instead of 417 aa. This is the first report to our knowledge of a human phenotype resulting from a mutation in WNT10A, and it is the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, expanding the list of WNT-related diseases.","variants":[{"Name":"NM_025216.3(WNT10A):c.697G>T (p.Glu233Ter)","Chromosome":"2","Start":"218890304","Stop":"218890304","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":19499,"rule_based_match":false,"evidence_text":"c.697G-->T (p.Glu233X)","llm_judgment":"PRESENT","evidence":"c.697G-->T (p.Glu233X)","abstract_start":724,"abstract_end":746}]}
{"pmid":"30139987","title":"DNAJC12-associated developmental delay, movement disorder, and mild hyperphenylalaninemia identified by whole-exome sequencing re-analysis.","abstract":"Hyperphenylalaninemia, movement disorder, and intellectual disability due to variants in DNAJC12 is a recently reported inherited neurotransmitter disorder. We report two new patients with this new genetic disorder. Patient 1 is a 6-year-11-month-old boy with mild hyperphenylalaninemia and global developmental delay (GDD). Seventeen-year-old male sibling of patient 1 had GDD from the first year of life. He had mild hyperphenylalaninemia at 11.5 years of age following his younger brother's diagnosis. He had low levels of homovanillic acid and 5-hydroxyindolacetic acid in the cerebrospinal fluid. Whole-exome sequencing (WES) was normal in 2016. After the first description of DNAJC12-associated hyperphenylalaninemia, dystonia, and intellectual disability in 2017, WES re-analysis identified a homozygous c.58_59delGG (p.(Gly20Metfs*2)) variant in DNAJC12. His younger brother was homozygous for the same variant, confirming the diagnosis of DNAJC12-associated hyperphenylalaninemia, movement disorder, and intellectual disability. Mild hyperphenylalaninemia and GDD should warrant targeted DNAJC12 genetic testing for the early diagnosis of DNAJC12-associated hyperphenylalaninemia, movement disorder, and intellectual disability.","variants":[{"Name":"NM_021800.3(DNAJC12):c.58_59del (p.Gly20fs)","Chromosome":"10","Start":"67837953","Stop":"67837954","ReferenceAlleleVCF":"TCC","AlternateAlleleVCF":"T","allel_id":624072,"rule_based_match":true,"evidence_text":"c.58_59delGG (p.(Gly20Metfs*2))","llm_judgment":"PRESENT","evidence":"c.58_59delGG (p.(Gly20Metfs*2))","abstract_start":811,"abstract_end":842}]}
{"pmid":"20356854","title":"PINK1-linked parkinsonism is associated with Lewy body pathology.","abstract":"Phosphatase and tensin homolog-induced putative kinase 1 gene mutations have been associated with autosomal recessive early-onset Parkinson's disease. To date, no neuropathological reports have been published from patients with Parkinson's disease with both phosphatase and tensin homolog-induced putative kinase 1 gene copies mutated. We analysed the coding region of phosphatase and tensin homolog-induced putative kinase 1 gene in a large Spanish family with six members with parkinsonism. The phenotype was characterized by an early-onset (mean: 31.6, standard deviation: 9.6 years, range: 14-45 years), slowly progressive levodopa-responsive parkinsonism, initial gait impairment and psychiatric symptoms. We identified two segregating pathogenic phosphatase and tensin homolog-induced putative kinase 1 mutations that were either in homozygous or heterozygous compound state in all affected family members. We found an exon 7 deletion (g.16089_16383del293; c.1252_1488del) and a novel+1U1-dependent 5' splice-site mutation in exon 7 (g.16378G>A; c.1488+1G>A). Leukocyte-derived messenger RNA analysis showed that both mutations caused exon 7 skipping and c.1488+1G>A also lead to an in-frame transcript with a 33 base-pair deletion (p.L485_R497del) resulting from activation of a 5' cryptic exon 7 splice site. Single photon emission computed tomography quantification of striatal dopamine transporter binding (123I-Ioflupane) revealed a posterior-anterior gradient similar to that of idiopathic Parkinson's disease, but there was no correlation between striatal reduced uptake and disease duration. Post-mortem neuropathological examination of an early-onset Parkinson's disease carrier of two heterozygous compound phosphatase and tensin homolog-induced putative kinase 1 mutations showed neuronal loss in the substantia nigra pars compacta, Lewy bodies and aberrant neurites in the reticular nuclei of the brainstem, substantia nigra pars compacta and Meynert nucleus, but the locus ceruleus and the amygdala were spared. This is the first neuropathological report of the brain from an early-onset phosphatase and tensin homolog-induced putative kinase 1-linked parkinsonism showing that mutated phosphatase and tensin homolog-induced putative kinase 1 protein induces Lewy body pathology. Unbalanced preservation of the locus ceruleus may well play a role in the slow evolution of motor symptoms and, probably, in the psychiatric symptoms often encountered in Parkinson's disease associated with phosphatase and tensin homolog-induced putative kinase 1 mutation.","variants":[{"Name":"NM_032409.3(PINK1):c.1488+1G>A","Chromosome":"1","Start":"20649232","Stop":"20649232","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":959540,"rule_based_match":true,"evidence_text":"c.1488+1G>A","llm_judgment":"PRESENT","evidence":"c.1488+1G>A","abstract_start":1052,"abstract_end":1063}]}
{"pmid":"19467224","title":"An apparent inconsistency in parent to offspring transmission of point mutations of LDLR gene in familial hypercholesterolemia.","abstract":"BACKGROUND: Familial Hypercholesterolemia (FH), the most common form of autosomal co-dominant hypercholesterolemia, is due to mutations in the LDLR gene, mostly minute or point mutations in the coding sequence.\nMETHODS: Analysis of LDLR gene was performed by direct resequencing and multiplex ligation-dependent probe amplification (MLPA).\nRESULTS: LDLR gene resequencing showed that proband I.G., with the clinical diagnosis of homozygous FH, was homozygous for a mutation in exon 12 (c.1775 G>A, G571E) known to be pathogenic, and heterozygous for a mutation in intron 14 (c.2140 +5G>A). Proband's daughter with heterozygous FH carried only the intron 14 mutation. To explain this inconsistency we assumed that the proband was a carrier of a gene deletion. MLPA showed that the proband and her daughter were heterozygous for a deletion of exons 11 and 12. This explains the apparent homozygosity of the c.1175 G>A mutation in the proband. Ex 11-12 deletion was linked to the c.2140 +5G>A mutation. Other FH patients, heterozygotes for c.2140 +5G>A, were found to carry the Ex 11-12 deletion found in the proband or other pathogenic mutations.\nCONCLUSIONS: Inconsistencies in the parent to offspring transmission of point mutations in LDLR gene may be due to a large deletion not detected by resequencing.","variants":[{"Name":"NM_000527.5(LDLR):c.2140+5G>A","Chromosome":"19","Start":"11120527","Stop":"11120527","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":45123,"rule_based_match":true,"evidence_text":"c.2140 +5G>A","llm_judgment":"PRESENT","evidence":"c.2140 +5G>A","abstract_start":575,"abstract_end":587}]}
{"pmid":"15146473","title":"Identification and functional analysis of two novel mutations in the CBS gene in Polish patients with homocystinuria.","abstract":"Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is an inherited disorder of homocysteine transsulfuration, which manifests by neurological, vascular and connective tissue involvement. So far, 130 pathogenic mutations have been recognized in the CBS gene. We examined 10 independent alleles in Polish patients suffering from CBS deficiency, and we detected four already described mutations (c.1224-2A>C, c.684C>A, c.833T>C, and c.442G>A) and two novel mutations (c.429C>G and c.1039+1G>T). The pathogenicity of the novel mutations was demonstrated by expression in E.coli. This is the first published communication on mutations leading to CBS deficiency in Poland.","variants":[{"Name":"NM_000071.3(CBS):c.429C>G (p.Ile143Met)","Chromosome":"21","Start":"43066265","Stop":"43066265","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"C","allel_id":929329,"rule_based_match":true,"evidence_text":"c.429C>G","llm_judgment":"PRESENT","evidence":"c.429C>G","abstract_start":481,"abstract_end":489},{"Name":"NM_000071.3(CBS):c.442G>A (p.Gly148Arg)","Chromosome":"21","Start":"43066252","Stop":"43066252","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":358643,"rule_based_match":true,"evidence_text":"c.442G>A","llm_judgment":"PRESENT","evidence":"c.442G>A","abstract_start":446,"abstract_end":454},{"Name":"NM_000071.3(CBS):c.833T>C (p.Ile278Thr)","Chromosome":"21","Start":"43063074","Stop":"43063074","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":15159,"rule_based_match":true,"evidence_text":"c.833T>C","llm_judgment":"PRESENT","evidence":"c.833T>C","abstract_start":432,"abstract_end":440},{"Name":"NM_000071.3(CBS):c.1039+1G>T","Chromosome":"21","Start":"43062310","Stop":"43062310","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"A","allel_id":1330874,"rule_based_match":true,"evidence_text":"c.1039+1G>T","llm_judgment":"PRESENT","evidence":"c.1039+1G>T","abstract_start":494,"abstract_end":505},{"Name":"NM_000071.3(CBS):c.684C>A (p.Asn228Lys)","Chromosome":"21","Start":"43065255","Stop":"43065255","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"T","allel_id":906109,"rule_based_match":true,"evidence_text":"c.684C>A","llm_judgment":"PRESENT","evidence":"c.684C>A","abstract_start":422,"abstract_end":430},{"Name":"NM_000071.3(CBS):c.1224-2A>C","Chromosome":"21","Start":"43058970","Stop":"43058970","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"G","allel_id":15167,"rule_based_match":true,"evidence_text":"c.1224-2A>C","llm_judgment":"PRESENT","evidence":"c.1224-2A>C","abstract_start":409,"abstract_end":420}]}
{"pmid":"21850185","title":"Mutation spectrum of CYP1B1 and MYOC genes in Korean patients with primary congenital glaucoma.","abstract":"PURPOSE: To elucidate the incidence of cytochrome P450 1B1 (CYP1B1) and myocillin (MYOC) mutations in Korean patients with primary congenital glaucoma (PCG).\nMETHODS: Genomic DNA was collected from peripheral blood of 85 unrelated Korean patients who were diagnosed as having PCG by standard ophthalmological examinations and screened for mutations in the CYP1B1 and MYOC genes by using bi-directional sequencing.\nRESULTS: Among 85 patients with PCG, 22 patients (22/85; 25.9%) had either one (n=11) or two (n=11) mutant alleles of the CYP1B1 gene. Among 11 different CYP1B1 mutations identified, a frameshift mutation (c.970_971dupAT; p.T325SfsX104) was the most frequent mutant allele (6/33; 18.2%) while p.G329S and p.V419Gfs11X were novel. In the MYOC gene, two variants of unknown significance (p.L228S and p.E240G) were identified in two PCG patients (2/85; 2.4%), respectively. No patient had mutations in both genes.\nCONCLUSIONS: Although CYP1B1 mutations are major causes of PCG in Korea, ~70% of PCG patients have neither CYP1B1 nor MYOC mutations suggesting a high degree of genetic heterogeneity. Furthermore, the fact that 11 out of 22 patients had only one mutant allele in the CYP1B1 gene necessitates further investigation for other genetic backgrounds underlying PCG.","variants":[{"Name":"NM_000104.4(CYP1B1):c.970_971dup (p.Thr325fs)","Chromosome":"2","Start":"38074417","Stop":"38074418","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"GAT","allel_id":1330880,"rule_based_match":true,"evidence_text":"c.970_971dupAT","llm_judgment":"PRESENT","evidence":"c.970_971dupAT","abstract_start":620,"abstract_end":634}]}
{"pmid":"28868593","title":"Mutation in the AGK gene in two siblings with unusual Sengers syndrome.","abstract":"Sengers syndrome is a rare autosomal recessive metabolic disorder caused by lack of acylglycerol kinase due to mutations in the AGK gene. It is characterized by congenital cataract, hypertrophic cardiomyopathy, myopathy and lactic acidosis. Two clinical forms have been described: a severe neonatal form, and a more benign form displaying exercise intolerance. We describe two siblings with congenital cataract, cardiomyopathy, hypotonia, intellectual disability and lactic acidosis. Whole exome sequencing revealed a homozygous c.1035dup mutation in the two siblings, supporting a diagnosis of Sengers syndrome. Our patients presented an intermediate form with intellectual deficiency, an unusual feature in Sengers syndrome. This permitted a prenatal diagnosis for a following pregnancy.","variants":[{"Name":"NM_018238.4(AGK):c.1035dup (p.Ile346fs)","Chromosome":"7","Start":"141649319","Stop":"141649320","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"CT","allel_id":1061022,"rule_based_match":true,"evidence_text":"c.1035dup","llm_judgment":"PRESENT","evidence":"c.1035dup","abstract_start":529,"abstract_end":538}]}
{"pmid":"27265460","title":"Phenotypes and Genotypes in Five Children with Congenital Insensitivity to Pain with Anhidrosis.","abstract":"BACKGROUND: Congenital insensitivity to pain with anhidrosis is an extremely rare hereditary disorder linked to variants in NTRK1. Our goal was to characterize the clinical features and the genetic basis of the disorder in Chinese patients.\nMETHODS: Patients were enrolled via social networking. Clinical features were investigated by interview, chart review, and physical examination. DNA was extracted from peripheral blood to genotype NTRK1 in patients and their parents. Variants identified were checked against a control cohort by high-throughput sequencing, and the effects of these variants were assessed in silico.\nRESULTS: Clinical features in five patients were cataloged, and six loss-of-function NTRK1 variants were identified, including a frameshift variant c.963delG, a nonsense variant c.1804C>T, an intron variant c.851-33T>A, and three missense variants c.1802T>G, c.2074C>T, and c.2311C>T.\nCONCLUSIONS: The results expand the spectrum of clinical and genetic features of congenital insensitivity to pain with anhidrosis and will help facilitate analysis of genotype-phenotype association in the future.","variants":[{"Name":"NM_002529.4(NTRK1):c.1804C>T (p.Arg602Ter)","Chromosome":"1","Start":"156876571","Stop":"156876571","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":611494,"rule_based_match":true,"evidence_text":"c.1804C>T","llm_judgment":"PRESENT","evidence":"c.1804C>T","abstract_start":801,"abstract_end":810},{"Name":"NM_002529.4(NTRK1):c.2074C>T (p.Arg692Cys)","Chromosome":"1","Start":"156880026","Stop":"156880026","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1349543,"rule_based_match":true,"evidence_text":"c.2074C>T","llm_judgment":"PRESENT","evidence":"c.2074C>T","abstract_start":882,"abstract_end":891},{"Name":"NM_002529.4(NTRK1):c.851-33T>A","Chromosome":"1","Start":"156873600","Stop":"156873600","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"A","allel_id":34160,"rule_based_match":true,"evidence_text":"c.851-33T>A","llm_judgment":"PRESENT","evidence":"c.851-33T>A","abstract_start":830,"abstract_end":841},{"Name":"NM_002529.4(NTRK1):c.2311C>T (p.Arg771Cys)","Chromosome":"1","Start":"156881562","Stop":"156881562","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1353170,"rule_based_match":true,"evidence_text":"c.2311C>T","llm_judgment":"PRESENT","evidence":"c.2311C>T","abstract_start":897,"abstract_end":906}]}
{"pmid":"32943904","title":"Hutchinson-Gilford Progeria Syndrome: Clinical and Molecular Characterization.","abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is a rare congenital disease caused by mutations in the <i>LMNA</i> gene. Children with HGPS are phenotypically characterized by lipodystrophy, short height, low body weight, scleroderma, reduced joint mobility, osteolysis, senile facial features, and cardiovascular compromise that usually lead to death. We aimed to describe the case of a patient who reached above-average age expectancy for children with HGPS in Latin America and describe the clinical and molecular characteristics of the patient. A 14-year-old female patient was presented with progeria-compatible phenotypic characteristics. HGPS was confirmed via <i>LMNA</i> gene sequencing that detected a heterozygous c.1824C>T (p.Gly608Gly) mutation. The primary aim is to describe the HGPS case, the molecular gene mutation finding, and make a short review of the limited available treatment options for children with HGPS. Such as the farnesyl transferase inhibitors in conjunction with other pharmacological therapies that have insinuated improvement in health, and survival rate.","variants":[{"Name":"NM_170707.4(LMNA):c.1824C>T (p.Gly608=)","Chromosome":"1","Start":"156138613","Stop":"156138613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29539,"rule_based_match":true,"evidence_text":"c.1824C>T (p.Gly608Gly)","llm_judgment":"PRESENT","evidence":"c.1824C>T (p.Gly608Gly)","abstract_start":722,"abstract_end":745}]}
{"pmid":"21398422","title":"A new Italian FHM2 family: clinical aspects and functional analysis of the disease-associated mutation.","abstract":"OBJECTIVE: To describe a new FHM kindred, and to analyse the functional consequences of the disease-associated ATP1A2 p.G301R mutation in human cellular models grown at 37°C.\nPATIENTS AND METHODS: Seven patients were clinically evaluated and gave informed consent for molecular analysis. Extra-pyramidal rigidity of the limbs was present in four subjects and in three of them tongue apraxia was also observed. ATP1A2 and CACNA1A were analysed by direct sequencing. Functional consequences of the mutation were investigated by cell viability assays, Western blots, and immunocytochemistry. Three-dimensional models of the human Na(+)/K(+)-ATPase α2 subunit were generated by homology modelling using SWISS-MODEL.\nFINDINGS: Analysis of ATP1A2 showed a heterozygous mutation, c.901G>A predicting the replacement of arginine for glycine at residue 301 (p.G301R). Functional analysis suggested that the mutation completely abolished Na(+)/K(+)-ATPase function.\nCONCLUSIONS: The phenotypic spectrum of our FHM2 family includes some peculiar features. Functional data confirm that Na(+)/K(+)-ATPase haploinsufficiency caused by the ATP1A2 p.G301R mutation is responsible for FHM in the described family.","variants":[{"Name":"NM_000702.4(ATP1A2):c.901G>A (p.Gly301Arg)","Chromosome":"1","Start":"160127704","Stop":"160127704","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":27961,"rule_based_match":true,"evidence_text":"c.901G>A","llm_judgment":"PRESENT","evidence":"c.901G>A","abstract_start":773,"abstract_end":781}]}
{"pmid":"23653224","title":"Carnitine levels in 26,462 individuals from the nationwide screening program for primary carnitine deficiency in the Faroe Islands.","abstract":"BACKGROUND: Primary carnitine deficiency (PCD) is an autosomal recessive disorder of fatty acid oxidation and has been associated to episodes of sudden death in the Faroe Islands. Data are presented from the nationwide population based Faroese screening program to find people with low carnitine levels indicating PCD.\nMETHODS: Whole blood samples from dried blood spots were analysed by tandem mass spectrometry with and without butylation. Genetic analyses were performed in all people with non-butylated free carnitine (fC0) below 7 μmol/L.\nRESULTS: 55 % (n = 26,462) of the entire population was screened and 89 PCD patients were identified, yielding an overall prevalence of 1:297 of PCD in the Faroe Islands. Carnitine levels were positively correlated to age in both males and females (p < 0.003) although levels decreased in females when reaching fertile age. The gender difference in mean carnitine levels was significant during female fertile age (4.71 μmol/L fC0 in the age group 25-30 years, p < 0.01). A lower cut-off of 5 μmol/L in fC0 identified all homozygous for the severe genotype c.95A > G (p.N32S) (n = 20).\nCONCLUSION: Carnitine levels differ by gender and age. A lower cut-off of 5 μmol/L in fC0 was appropriate to identify c.95A > G homozygotes. The prevalence of PCD in the Faroe Islands is the highest reported in the world (1:297).","variants":[{"Name":"NM_003060.4(SLC22A5):c.95A>G (p.Asn32Ser)","Chromosome":"5","Start":"132370067","Stop":"132370067","ReferenceAlleleVCF":"A","AlternateAlleleVCF":"G","allel_id":36689,"rule_based_match":true,"evidence_text":"c.95A > G (p.N32S)","llm_judgment":"PRESENT","evidence":"c.95A > G (p.N32S)","abstract_start":1100,"abstract_end":1118}]}
{"pmid":"30684668","title":"Whole-exome sequencing identifies rare compound heterozygous mutations in the MSTO1 gene associated with cerebellar ataxia and myopathy.","abstract":"Human MSTO1 is involved in the regulation of mitochondrial distribution and morphology and its unregulated expression leads to mitochondrial disorder. Despite its significance for mitochondrial functions, human MSTO1 gene is rarely studied before 2017. As of late, MSTO1 mutations have been reported to cause clinical manifestations such as myopathy, cerebellar atrophy and ataxia, motor developmental delay, and pigmentary retinopathy. Here we have performed a whole-exome sequencing in a family which includes two brothers showing cerebellar atrophy and ataxia, intellectual disability, and myopathy. As a result, two mutations were identified. One of these mutations has been identified as a missense mutation, c.836G > A; p. (Arg279His) and a novel frameshift variant, c.1259delG; p. (Gly420ValfsTer2). So, the two brothers both had compound heterozygous mutations with a combination of protein-truncation mutation and missense mutation. These findings suggested an association of MSTO1 mutations with the early onset of symptoms and revealed the genotype-phenotype correlation between different mutation cases. In this case, the two brothers both have pes planus which is not reported in other cases. This might suggest that the novel mutation is responsible for dysmorphia. Thus, the recessive and novel MSTO1 mutations enriches genetic information on the pathogenicity of MSTO1 in humans.","variants":[{"Name":"NM_018116.4(MSTO1):c.1259del (p.Gly420fs)","Chromosome":"1","Start":"155613206","Stop":"155613206","ReferenceAlleleVCF":"AG","AlternateAlleleVCF":"A","allel_id":495073,"rule_based_match":true,"evidence_text":"c.1259delG; p. (Gly420ValfsTer2)","llm_judgment":"PRESENT","evidence":"c.1259delG; p. (Gly420ValfsTer2)","abstract_start":773,"abstract_end":805},{"Name":"NM_018116.4(MSTO1):c.836G>A (p.Arg279His)","Chromosome":"1","Start":"155612440","Stop":"155612440","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":581219,"rule_based_match":true,"evidence_text":"c.836G > A; p. (Arg279His)","llm_judgment":"PRESENT","evidence":"c.836G > A; p. (Arg279His)","abstract_start":714,"abstract_end":740}]}
{"pmid":"29046207","title":"Clinical characteristics and GAA gene mutation in children with glycogen storage disease type II: an analysis of 3 cases","abstract":"Glycogen storage disease type II (GSD II) is an autosomal recessive disorder caused by a deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA) and can affect multiple systems including the heart and skeletal muscle. The aim of this study was to investigate three children with GSD II confirmed by GAA gene analysis and to report their clinical characteristics and gene mutations. One case was classified as infantile-onset GSD II, and two cases as late-onset GSD II. The infantile-onset patient (aged 4 months) showed no weight increase and had dyspnea, muscle hypotonia, and increased alanine aminotransferase and creatine kinase; echocardiography showed hypertrophic cardiomyopathy. The late-onset patients (aged 8 years and 13 years respectively) showed persistently elevated liver enzymes; one of them had recurrent respiratory tract infection and restrictive ventilation disorder, and the other case showed significantly increased creatase but normal electromyographic findings. Peripheral blood genetic testing for GAA gene showed six pathogenic mutations in the three cases, and the mutations c.2738C>T and c.568C>T had not been reported. Therefore, peripheral blood genetic testing for GAA gene is an effective diagnostic method.","variants":[{"Name":"NM_000152.5(GAA):c.568C>T (p.Arg190Cys)","Chromosome":"17","Start":"80105770","Stop":"80105770","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":646871,"rule_based_match":true,"evidence_text":"c.568C>T","llm_judgment":"PRESENT","evidence":"c.568C>T","abstract_start":1141,"abstract_end":1149}]}
{"pmid":"32767731","title":"Perrault syndrome: Clinical report and retrospective analysis.","abstract":"BACKGROUND: Perrault syndrome (PRLTS4; OMIM# 615300) is a rare autosomal recessive disorder and only a few cases have been reported worldwide. We report a Chinese female characterized by sensorineural hearing loss and premature ovarian insufficiency.\nMETHODS: We evaluated audiological, endocrine, and ultrasound examinations and examined the genetic causes using whole-exome sequencing. We reviewed the literature to discuss the pathogenesis, genotype-phenotype correlation, treatment, and prevention of PRLTS4.\nRESULTS: Bioinformatic analysis revealed compound heterozygous mutations in the LARS2 gene, c.880G>A (p.Glu294Lys), and c.2108T>C (p.Ile703Thr) which is a novel missense mutation, co-segregated in this family. Taken together, the patient was clinically diagnosed as PRLTS4. The literature review showed that the phenotype for PRLTS4 varies widely, but the sensorineural hearing loss, increased gonadotropin levels, and amenorrhea occurred frequently. All reported mutations are highly conserved in mammals based on conservation analysis, and there is a mutation hotspot for PRLTS4.\nCONCLUSION: This study expanded the mutation spectrum of LARS2 and is the first report of PRLTS4 in a Chinese family. Genetic testing plays an important role in early diagnosis of syndromic deafness and clinical genetic evaluation is essential to guide prevention.","variants":[{"Name":"NM_015340.4(LARS2):c.880G>A (p.Glu294Lys)","Chromosome":"3","Start":"45476489","Stop":"45476489","ReferenceAlleleVCF":"G","AlternateAlleleVCF":"A","allel_id":980889,"rule_based_match":true,"evidence_text":"c.880G>A (p.Glu294Lys)","llm_judgment":"PRESENT","evidence":"c.880G>A (p.Glu294Lys)","abstract_start":605,"abstract_end":627}]}
{"pmid":"16965274","title":"Oculocutaneous albinism type 4: six novel mutations in the membrane-associated transporter protein gene and their phenotypes.","abstract":"Oculocutaneous albinism type 4 (OCA4) is an autosomal recessive hypopigmentary disorder caused by mutations in the Membrane-Associated Transporter Protein gene (SLC45A2). The SLC45A2 protein is a 530-amino-acid polypeptide that contains 12 putative transmembrane domains, and appears to be a transporter that mediates melanin synthesis. Eighteen pathological mutations have been reported so far. In this study, six novel mutations, p.Y49C (c.146A > G), p.G89R (c.265G > A), p.C229Y (c.686G > A), p.T437A (c.1309A > G), p.T440A (c.1318A > G) and p.G473D (c.1418G > A) were found in eight Japanese patients with various clinical phenotypes. The phenotypes of OCA4 were as various as the other types of OCA and probably depended on the mutation sites in the SLC45A2 gene.","variants":[{"Name":"NM_016180.5(SLC45A2):c.146A>G (p.Tyr49Cys)","Chromosome":"5","Start":"33984438","Stop":"33984438","ReferenceAlleleVCF":"T","AlternateAlleleVCF":"C","allel_id":3494825,"rule_based_match":true,"evidence_text":"c.146A > G","llm_judgment":"PRESENT","evidence":"c.146A > G","abstract_start":440,"abstract_end":450},{"Name":"NM_016180.5(SLC45A2):c.686G>A (p.Cys229Tyr)","Chromosome":"5","Start":"33963893","Stop":"33963893","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":2894732,"rule_based_match":true,"evidence_text":"c.686G > A","llm_judgment":"PRESENT","evidence":"c.686G > A","abstract_start":483,"abstract_end":493},{"Name":"NM_016180.5(SLC45A2):c.265G>A (p.Gly89Arg)","Chromosome":"5","Start":"33984319","Stop":"33984319","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1405550,"rule_based_match":true,"evidence_text":"c.265G > A","llm_judgment":"PRESENT","evidence":"c.265G > A","abstract_start":461,"abstract_end":471},{"Name":"NM_016180.5(SLC45A2):c.1418G>A (p.Gly473Asp)","Chromosome":"5","Start":"33944823","Stop":"33944823","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":1934907,"rule_based_match":true,"evidence_text":"c.1418G > A","llm_judgment":"PRESENT","evidence":"c.1418G > A","abstract_start":554,"abstract_end":565}]}
{"pmid":"30911407","title":"Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome.","abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease is characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo <i>LMNA</i> c.1824C > T mutation, which provokes the expression of a dominant-negative mutant protein called progerin. Therapies proven effective in HGPS-like mouse models have yielded only modest benefit in HGPS clinical trials. To overcome the gap between HGPS mouse models and patients, we have generated by CRISPR-Cas9 gene editing the first large animal model for HGPS, a knockin heterozygous <i>LMNA</i> c.1824C > T Yucatan minipig. Like HGPS patients, HGPS minipigs endogenously co-express progerin and normal lamin A/C, and exhibit severe growth retardation, lipodystrophy, skin and bone alterations, cardiovascular disease, and die around puberty. Remarkably, the HGPS minipigs recapitulate critical cardiovascular alterations seen in patients, such as left ventricular diastolic dysfunction, altered cardiac electrical activity, and loss of vascular smooth muscle cells. Our analysis also revealed reduced myocardial perfusion due to microvascular damage and myocardial interstitial fibrosis, previously undescribed readouts potentially useful for monitoring disease progression in patients. The HGPS minipigs provide an appropriate preclinical model in which to test human-size interventional devices and optimize candidate therapies before advancing to clinical trials, thus accelerating the development of effective applications for HGPS patients.","variants":[{"Name":"NM_170707.4(LMNA):c.1824C>T (p.Gly608=)","Chromosome":"1","Start":"156138613","Stop":"156138613","ReferenceAlleleVCF":"C","AlternateAlleleVCF":"T","allel_id":29539,"rule_based_match":true,"evidence_text":"c.1824C > T","llm_judgment":"PRESENT","evidence":"c.1824C > T","abstract_start":289,"abstract_end":300}]}